83	32477151	By using the spectral features in the short wavelength range (375-425 nm) and the lifetime features at 385, 395, 405, and 415 nm, the esophagitis can be differentiated from normal esophagus tissue with 100% sensitivity and 93% specificity.	('esophagitis', 'Disease', 'MESH:D004938', (134, 145))	('esophagitis', 'Phenotype', 'HP:0100633', (134, 145))	('esophagitis', 'Disease', (134, 145))	('375-425 nm', 'Var', (62, 72))
124	31632701	As an example, mutations in the (ALK) gene in non-small cell lung cancer have been shown to exhibit a propensity for CNS involvement.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('ALK', 'Gene', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (15, 24))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (50, 72))	('ALK', 'Gene', '238', (33, 36))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (46, 72))
222	30716092	Compared with the methylation status in normal samples, 3 CpG sites were hypomethylated (cg27388036, cg27443373, and cg24651824) in EA, among which two sites (cg27443373 and cg24651824) showed moderately negative correlation with CENPE expression.	('cg24651824', 'Var', (174, 184))	('cg27443373', 'Chemical', '-', (159, 169))	('cg24651824', 'Var', (117, 127))	('cg27388036', 'Var', (89, 99))	('cg27443373', 'Chemical', '-', (101, 111))	('cg27443373', 'Var', (159, 169))	('cg27388036', 'Chemical', '-', (89, 99))	('cg24651824', 'Chemical', '-', (174, 184))	('CENPE', 'Gene', '1062', (230, 235))	('cg24651824', 'Chemical', '-', (117, 127))	('negative', 'NegReg', (204, 212))	('CENPE', 'Gene', (230, 235))	('cg27443373', 'Var', (101, 111))
225	30716092	The methylation status of cg27443373 and cg24651824 might play a critical role in modulating CENPE expression.	('cg24651824', 'Var', (41, 51))	('modulating', 'Reg', (82, 92))	('CENPE', 'Gene', (93, 98))	('cg27443373', 'Chemical', '-', (26, 36))	('cg24651824', 'Chemical', '-', (41, 51))	('CENPE', 'Gene', '1062', (93, 98))	('cg27443373', 'Var', (26, 36))
274	30716092	Compared with the methylation status in the 6 normal samples, 4 sites (cg18094824, cg26727807, cg03675082 and cg21163042) were hypermethylated (red arrows, Fig 3B), while 3 sites were hypomethylated (cg27388036, cg27443373, and cg24651824) in EA (green arrows, Fig 3B).	('cg27388036', 'Chemical', '-', (200, 210))	('cg21163042', 'Var', (110, 120))	('cg24651824', 'Chemical', '-', (228, 238))	('cg27443373', 'Var', (212, 222))	('cg26727807', 'Var', (83, 93))	('cg21163042', 'Chemical', '-', (110, 120))	('cg18094824', 'Chemical', '-', (71, 81))	('cg26727807', 'Chemical', '-', (83, 93))	('cg03675082', 'Chemical', '-', (95, 105))	('cg03675082', 'Var', (95, 105))	('cg24651824', 'Var', (228, 238))	('cg27388036', 'Var', (200, 210))	('cg27443373', 'Chemical', '-', (212, 222))	('cg18094824', 'Var', (71, 81))
276	30716092	Only the methylation level of 4 CpG sites (cg19590290, cg27443373, cg24651824 and cg21346648) were associated with CENPE expression (absolute Pearson's r>=0.2) (Fig 4A, green arrows).	('cg24651824', 'Chemical', '-', (67, 77))	('cg21346648', 'Chemical', '-', (82, 92))	('cg27443373', 'Chemical', '-', (55, 65))	('cg21346648', 'Var', (82, 92))	('cg19590290', 'Var', (43, 53))	('cg24651824', 'Var', (67, 77))	('CENPE', 'Gene', (115, 120))	('cg27443373', 'Var', (55, 65))	('cg19590290', 'Chemical', '-', (43, 53))	('associated', 'Reg', (99, 109))	('CENPE', 'Gene', '1062', (115, 120))
277	30716092	Actually, the methylation level of 4 CpG sites were all negatively correlated with CENPE expression, among which cg27443373 and cg24651824 were the significantly hypomethylated sites compared with normal tissues (Fig 4A, dark green arrows).	('CENPE', 'Gene', '1062', (83, 88))	('CENPE', 'Gene', (83, 88))	('cg27443373', 'Var', (113, 123))	('negatively', 'NegReg', (56, 66))	('methylation level', 'MPA', (14, 31))	('cg24651824', 'Var', (128, 138))	('cg27443373', 'Chemical', '-', (113, 123))	('cg24651824', 'Chemical', '-', (128, 138))
279	30716092	By divided the patients into methylation-high and methylation-low groups, according to the best cutoff of the methylation of cg27443373 and cg24651824, we found that the methylation-low group had significantly higher CENPE expression (Fig 4B, p = 0.002), as well as significantly worse OS (Fig 4C, p = 0.005).	('cg27443373', 'Chemical', '-', (125, 135))	('methylation-low', 'Var', (170, 185))	('patients', 'Species', '9606', (15, 23))	('CENPE', 'Gene', (217, 222))	('OS', 'Chemical', '-', (286, 288))	('worse', 'NegReg', (280, 285))	('cg24651824', 'Chemical', '-', (140, 150))	('cg27443373', 'Var', (125, 135))	('CENPE', 'Gene', '1062', (217, 222))	('higher', 'PosReg', (210, 216))	('cg24651824', 'Var', (140, 150))
281	30716092	However, the copy number loss was not necessarily associated with decreased CENPE expression compared with the copy neutral (0) cases (Fig 5B).	('decreased', 'NegReg', (66, 75))	('copy number loss', 'Var', (13, 29))	('CENPE', 'Gene', (76, 81))	('CENPE', 'Gene', '1062', (76, 81))
282	30716092	By checking the average methylation of cg27443373 and cg24651824 between +1/0 and -1 groups, we found that the methylation of the -1 group was significantly lower than that of the +1/0 group (p = 0.04) (Fig 5C).	('cg24651824', 'Chemical', '-', (54, 64))	('cg27443373', 'Chemical', '-', (39, 49))	('methylation', 'MPA', (111, 122))	('cg24651824', 'Var', (54, 64))	('cg27443373', 'Var', (39, 49))	('lower', 'NegReg', (157, 162))
283	30716092	These results suggest that hypomethylation might be an adaptive mechanism to compensate the influence of DNA loss on CENPE expression in EA.	('CENPE', 'Gene', (117, 122))	('hypomethylation', 'Var', (27, 42))	('loss', 'NegReg', (109, 113))	('DNA', 'Gene', (105, 108))	('CENPE', 'Gene', '1062', (117, 122))
297	30716092	Inhibition of CENPE expression or selectively inhibiting CENPE motor function results in mitotic arrest due to polar chromosomes and following cell apoptosis.	('inhibiting', 'NegReg', (46, 56))	('mitotic arrest', 'Disease', (89, 103))	('CENPE', 'Gene', (14, 19))	('mitotic arrest', 'Disease', 'MESH:D006323', (89, 103))	('CENPE', 'Gene', '1062', (57, 62))	('function', 'MPA', (69, 77))	('CENPE', 'Gene', (57, 62))	('Inhibition', 'Var', (0, 10))	('CENPE', 'Gene', '1062', (14, 19))
301	30716092	CCNA2 is a cell cycle regulatory gene and its dysregulation is associated with esophageal tumorigenesis.	('CCNA2', 'Gene', '890', (0, 5))	('associated', 'Reg', (63, 73))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('dysregulation', 'Var', (46, 59))	('CCNA2', 'Gene', (0, 5))
305	30716092	These results suggest that epigenetic regulation might be a mechanism of CENPE dysregulation in cancer cells.	('epigenetic regulation', 'Var', (27, 48))	('CENPE', 'Gene', '1062', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CENPE', 'Gene', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
307	30716092	In this study, by checking the methylation status of 18 CpG sites in CENPE DNA in EA, we found that three CpG sites with hypomethylated in EA, among which two sites (cg27443373 and cg24651824) showed moderately negative correlation with CENPE expression.	('CENPE', 'Gene', (69, 74))	('cg27443373', 'Chemical', '-', (166, 176))	('CENPE', 'Gene', (237, 242))	('cg24651824', 'Chemical', '-', (181, 191))	('CENPE', 'Gene', '1062', (237, 242))	('cg27443373', 'Var', (166, 176))	('negative', 'NegReg', (211, 219))	('CENPE', 'Gene', '1062', (69, 74))	('cg24651824', 'Var', (181, 191))
308	30716092	Besides, the high methylation group was associated with better OS.	('high methylation', 'Var', (13, 29))	('better OS', 'Disease', (56, 65))	('OS', 'Chemical', '-', (63, 65))
310	30716092	The significantly lower level of the average methylation of cg27443373 and cg24651824 in this group provides a plausible explanation of this phenomenon.	('methylation', 'MPA', (45, 56))	('cg24651824', 'Chemical', '-', (75, 85))	('lower', 'NegReg', (18, 23))	('cg27443373', 'Chemical', '-', (60, 70))	('cg24651824', 'Var', (75, 85))	('cg27443373', 'Var', (60, 70))
311	30716092	Based on these findings, we infer that hypomethylation of certain CpG sites in CENPE DNA might be an important epigenetic mechanism of upregulated CENPE in EA.	('CENPE', 'Gene', (79, 84))	('CENPE', 'Gene', (147, 152))	('CENPE', 'Gene', '1062', (79, 84))	('CENPE', 'Gene', '1062', (147, 152))	('hypomethylation', 'Var', (39, 54))	('upregulated', 'PosReg', (135, 146))
314	30716092	Secondly, we only confirmed the association between methylation and CENPE expression in EA.	('CENPE', 'Gene', (68, 73))	('CENPE', 'Gene', '1062', (68, 73))	('association', 'Interaction', (32, 43))	('methylation', 'Var', (52, 63))
324	30156356	On subgroup analysis, according to NAC history, patients with high MFG-E8 expression had significantly shorter relapse-free survival (P = .027) and OS (P = .0039) only when they had been treated with NAC.	('expression', 'MPA', (74, 84))	('relapse-free survival', 'CPA', (111, 132))	('NAC', 'Chemical', '-', (35, 38))	('OS', 'Chemical', '-', (148, 150))	('shorter', 'NegReg', (103, 110))	('patients', 'Species', '9606', (48, 56))	('NAC', 'Chemical', '-', (200, 203))	('high', 'Var', (62, 66))	('MFG-E8', 'Gene', (67, 73))
325	30156356	Furthermore, tumors with high MFG-E8 expression had a significantly lower ratio of CD8+ T cells/regulatory T cells in tumor-infiltrating lymphocytes (P = .042) only in the patients treated with NAC, and those with a lower ratio had a shorter OS (P = .026).	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('CD8', 'Gene', (83, 86))	('MFG-E8', 'Gene', (30, 36))	('lower', 'NegReg', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('NAC', 'Chemical', '-', (194, 197))	('patients', 'Species', '9606', (172, 180))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('lower ratio of CD8+ T cells', 'Phenotype', 'HP:0005415', (68, 95))	('tumors', 'Disease', (13, 19))	('CD8', 'Gene', '925', (83, 86))	('expression', 'MPA', (37, 47))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('OS', 'Chemical', '-', (242, 244))	('high', 'Var', (25, 29))	('tumor', 'Disease', (118, 123))
330	30156356	Such expression has been found to be associated with tumor proliferation, epithelial-mesenchymal transition, cell migration, M2 macrophage polarization, and the induction of Tregs.15, 16, 17, 18, 19 However, there are limited reports that clarified its prognostic impact on cancer patients.16, 20 Furthermore, although MFG-E8 is predicted to affect the balance of the expression of tumor-infiltrating lymphocytes such as CD8+ T cells and Tregs,14 this relationship and its influence on survival are yet to be revealed.	('CD8', 'Gene', '925', (421, 424))	('Treg', 'Chemical', '-', (438, 442))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('MFG-E8', 'Var', (319, 325))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumor', 'Disease', (382, 387))	('patients', 'Species', '9606', (281, 289))	('balance', 'MPA', (353, 360))	('cancer', 'Disease', (274, 280))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('affect', 'Reg', (342, 348))	('expression', 'MPA', (368, 378))	('Treg', 'Chemical', '-', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('CD8', 'Gene', (421, 424))
342	30156356	Patients with progressive disease (PD; with >25% enlargement of the tumor or with appearance of new lesions) or with stable disease (with residual tumor and neither categorized as partial response nor PD) were defined as non-responders.25 The pathological response was categorized into 5 groups according to the criteria of the Japanese Society for Esophageal Diseases.26 The grades were as follows: grade 0, no therapeutic effect; grade1a, viable cancer cells accounting for 2/3 or more tumor tissue; grade 1b, viable cancer cells accounting for 1/3 to 2/3 of tumor tissue; grade 2, viable cancer cells accounting for less than 1/3 of tumor tissue; and grade 3, no viable cancer cells.	('cancer', 'Disease', (519, 525))	('tumor', 'Disease', (488, 493))	('cancer', 'Phenotype', 'HP:0002664', (519, 525))	('tumor', 'Disease', 'MESH:D009369', (488, 493))	('cancer', 'Phenotype', 'HP:0002664', (448, 454))	('cancer', 'Disease', 'MESH:D009369', (591, 597))	('grade1a', 'Var', (432, 439))	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (561, 566))	('cancer', 'Disease', 'MESH:D009369', (448, 454))	('Esophageal Diseases', 'Disease', 'MESH:D004935', (349, 368))	('Esophageal Diseases', 'Disease', (349, 368))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (636, 641))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', (673, 679))	('cancer', 'Disease', 'MESH:D009369', (519, 525))	('tumor', 'Phenotype', 'HP:0002664', (488, 493))	('cancer', 'Phenotype', 'HP:0002664', (673, 679))	('tumor', 'Disease', 'MESH:D009369', (636, 641))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Disease', (591, 597))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('therapeutic effect', 'CPA', (412, 430))	('cancer', 'Disease', (448, 454))	('tumor', 'Phenotype', 'HP:0002664', (636, 641))	('tumor', 'Disease', (561, 566))	('cancer', 'Phenotype', 'HP:0002664', (591, 597))	('cancer', 'Disease', 'MESH:D009369', (673, 679))	('tumor', 'Disease', 'MESH:D009369', (561, 566))
367	30156356	In the group with high MFG-E8 expression, the frequency of patients with tumors located in the upper thoracic esophagus (P = .028), tumors with pathologically diagnosed advanced lymph nodes metastasis (pN2-3) (P = 0.015), or non-regional lymph node metastasis (pM1) (P = .0005) and a history of NAC (P < .0001) were significantly higher compared with the patients with low MFG-E8 expression.	('lymph nodes metastasis', 'Disease', 'MESH:D009362', (178, 200))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('expression', 'Var', (30, 40))	('tumors', 'Disease', (73, 79))	('MFG-E8', 'Gene', (23, 29))	('patients', 'Species', '9606', (355, 363))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('patients', 'Species', '9606', (59, 67))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('higher', 'PosReg', (330, 336))	('non-regional lymph node metastasis', 'CPA', (225, 259))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Disease', (132, 138))	('NAC', 'Chemical', '-', (295, 298))	('pM1', 'Gene', '8834', (261, 264))	('pM1', 'Gene', (261, 264))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('high', 'Var', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('lymph nodes metastasis', 'Disease', (178, 200))	('NAC', 'Disease', (295, 298))
369	30156356	Among all 134 patients, the RFS and OS of the high MFG-E8 expression group were significantly worse than those of the low-expression group (P = .012 in RFS and P = .0047 in OS; Figure 2A).	('high', 'Var', (46, 50))	('MFG-E8', 'Gene', (51, 57))	('OS', 'Chemical', '-', (173, 175))	('worse', 'NegReg', (94, 99))	('OS', 'Chemical', '-', (36, 38))	('patients', 'Species', '9606', (14, 22))	('RFS', 'CPA', (28, 31))
371	30156356	Within the patients without NAC, there was no significant difference in the RFS or OS between those with high MFG-E8 expression and those with low expression (RFS, P = .65; OS, P = .68; Figure 2B].	('high', 'Var', (105, 109))	('OS', 'Chemical', '-', (83, 85))	('expression', 'MPA', (117, 127))	('NAC', 'Chemical', '-', (28, 31))	('OS', 'Chemical', '-', (173, 175))	('MFG-E8', 'Gene', (110, 116))	('patients', 'Species', '9606', (11, 19))
372	30156356	However, among patients treated with NAC, those with high MFG-E8 expression showed significantly shorter RFS and OS compared with those with low expression (RFS, P = .027; OS, P = .0039; Figure 2C).	('patients', 'Species', '9606', (15, 23))	('OS', 'Chemical', '-', (172, 174))	('high', 'Var', (53, 57))	('MFG-E8', 'Gene', (58, 64))	('RFS', 'CPA', (105, 108))	('expression', 'MPA', (65, 75))	('shorter', 'NegReg', (97, 104))	('OS', 'Chemical', '-', (113, 115))	('NAC', 'Chemical', '-', (37, 40))
373	30156356	As shown in Table 3, the high MFG-E8 expression group among patients who received NAC had a significantly larger percentage of N2-3 lymph node metastasis and non-regional lymph node metastasis.	('MFG-E8', 'Gene', (30, 36))	('N2-3 lymph node metastasis', 'CPA', (127, 153))	('patients', 'Species', '9606', (60, 68))	('high', 'Var', (25, 29))	('non-regional lymph node metastasis', 'CPA', (158, 192))	('expression', 'MPA', (37, 47))	('NAC', 'Chemical', '-', (82, 85))
375	30156356	To analyze the causes that led to the worse survival rate of patients with high MFG-E8 expression after receiving NAC, the relationships between MFG-E8 expression and both the clinical and pathological response to therapy were examined.	('high', 'Var', (75, 79))	('NAC', 'Chemical', '-', (114, 117))	('patients', 'Species', '9606', (61, 69))	('expression', 'MPA', (87, 97))	('MFG-E8', 'Gene', (80, 86))
378	30156356	Within the 61 patients without NAC, there were no significant differences in the CD8/Foxp3 ratio between those with high MFG-E8 expression and those with low expression (median value, 1.0 vs 1.71; P = .34) (Figure 3A).	('Foxp3', 'Gene', (85, 90))	('CD8', 'Gene', (81, 84))	('NAC', 'Chemical', '-', (31, 34))	('CD8', 'Gene', '925', (81, 84))	('high', 'Var', (116, 120))	('MFG-E8', 'Gene', (121, 127))	('expression', 'MPA', (128, 138))	('Foxp3', 'Gene', '50943', (85, 90))	('patients', 'Species', '9606', (14, 22))
379	30156356	Within the 66 patients who underwent NAC, the CD8/Foxp3 ratios were significantly lower in patients with high MFG-E8 expression compared with those with low expression (median value, 1.53 vs 3.28; P = .042) (Figure 3B).	('high', 'Var', (105, 109))	('CD8', 'Gene', '925', (46, 49))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (14, 22))	('expression', 'MPA', (117, 127))	('MFG-E8', 'Gene', (110, 116))	('Foxp3', 'Gene', '50943', (50, 55))	('CD8', 'Gene', (46, 49))	('NAC', 'Chemical', '-', (37, 40))	('Foxp3', 'Gene', (50, 55))	('lower', 'NegReg', (82, 87))
384	30156356	When the OS was compared between the two groups, the low CD8/Foxp3 group showed a significantly worse prognosis (P = .026; Figure 3C).	('CD8', 'Gene', (57, 60))	('CD8', 'Gene', '925', (57, 60))	('low', 'Var', (53, 56))	('OS', 'Chemical', '-', (9, 11))	('Foxp3', 'Gene', '50943', (61, 66))	('Foxp3', 'Gene', (61, 66))
386	30156356	In the univariate analysis among patients with NAC history, poor tumor differentiation, pathologically diagnosed N2-3 lymph node metastasis, non-regional lymph node metastasis, tumor stage III-IV, and high MFG-E8 expression were the factors correlated with worse OS (Table 4).	('worse OS', 'Disease', (257, 265))	('patients', 'Species', '9606', (33, 41))	('tumor', 'Disease', (65, 70))	('expression', 'MPA', (213, 223))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('OS', 'Chemical', '-', (263, 265))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('MFG-E8', 'Gene', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('NAC', 'Chemical', '-', (47, 50))	('high', 'Var', (201, 205))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
387	30156356	In the multivariate analysis, poor tumor differentiation, tumor stage III-IV, and high MFG-E8 expression were found to be independent prognostic factors (Table 4).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('high', 'Var', (82, 86))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('MFG-E8', 'Gene', (87, 93))	('expression', 'MPA', (94, 104))
389	30156356	Analysis of all patients examined showed that tumors with high MFG-E8 expression had a significantly higher possibility of having advanced lymph node and non-regional lymph node metastasis (M1), as previously suggested in malignant melanoma patients.16 Our study also showed that the RFS and OS of the high MFG-E8 expression group were significantly worse than those of the low-expression group.	('worse', 'NegReg', (350, 355))	('malignant melanoma', 'Disease', (222, 240))	('OS', 'Chemical', '-', (292, 294))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patients', 'Species', '9606', (16, 24))	('malignant melanoma', 'Phenotype', 'HP:0002861', (222, 240))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('MFG-E8', 'Gene', (307, 313))	('tumors', 'Disease', (46, 52))	('high', 'Var', (302, 306))	('malignant melanoma', 'Disease', 'MESH:D008545', (222, 240))	('patients', 'Species', '9606', (241, 249))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
391	30156356	In the patient group with NAC history, high MFG-E8 expression in the tumors correlated with worse RFS and OS.	('MFG-E8', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('high', 'Var', (39, 43))	('RFS', 'Disease', (98, 101))	('patient', 'Species', '9606', (7, 14))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'MPA', (51, 61))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('NAC', 'Chemical', '-', (26, 29))	('OS', 'Chemical', '-', (106, 108))
396	30156356	Multiple reports elsewhere have shown that lower CD8/Foxp3, not the absolute number of Foxp3+ or CD8+ T cells, better indicates the extent of suppression of antitumor immunity and has a relationship with worse patient survival in multiple cancer types, including esophageal squamous cell carcinoma.32, 33, 34, 35, 36, 37 In the current study, among patients treated with NAC, tumors with high MFG-E8 expression had a significantly lower CD8/Foxp3 ratio compared with those with low MFG-E8 expression.	('NAC', 'Chemical', '-', (371, 374))	('tumor', 'Disease', (376, 381))	('Foxp3', 'Gene', '50943', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('Foxp3', 'Gene', (441, 446))	('tumors', 'Disease', 'MESH:D009369', (376, 382))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('tumor', 'Disease', (161, 166))	('esophageal squamous cell carcinoma', 'Disease', (263, 297))	('patient', 'Species', '9606', (349, 356))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('Foxp3', 'Gene', '50943', (441, 446))	('cancer', 'Disease', (239, 245))	('CD8', 'Gene', (49, 52))	('CD8', 'Gene', (97, 100))	('CD8', 'Gene', (437, 440))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('lower', 'NegReg', (431, 436))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('Foxp3', 'Gene', (87, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (263, 297))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (376, 382))	('high MFG-E8 expression', 'Var', (388, 410))	('Foxp3', 'Gene', '50943', (87, 92))	('patients', 'Species', '9606', (349, 357))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('CD8', 'Gene', '925', (437, 440))	('patient', 'Species', '9606', (210, 217))	('tumors', 'Disease', (376, 382))	('CD8', 'Gene', '925', (49, 52))	('Foxp3', 'Gene', (53, 58))	('CD8', 'Gene', '925', (97, 100))
397	30156356	Furthermore, the patients with lower CD8/Foxp3 ratio had worse survival compared with those with high ratio, consistent with previous reports.32, 37 These findings in patients treated with NAC suggest that high MFG-E8 expression in the tumors treated with chemotherapy might induce Treg propagation to suppress antitumor immunity exerted by CD8+ T cells.	('CD8', 'Gene', (37, 40))	('NAC', 'Chemical', '-', (189, 192))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('high', 'Var', (206, 210))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('CD8', 'Gene', '925', (341, 344))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('Treg propagation', 'CPA', (282, 298))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumors', 'Disease', (236, 242))	('MFG-E8', 'Gene', (211, 217))	('suppress', 'NegReg', (302, 310))	('CD8', 'Gene', '925', (37, 40))	('Foxp3', 'Gene', (41, 46))	('tumor', 'Disease', (236, 241))	('patients', 'Species', '9606', (17, 25))	('CD8', 'Gene', (341, 344))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('Foxp3', 'Gene', '50943', (41, 46))	('induce', 'Reg', (275, 281))	('patients', 'Species', '9606', (167, 175))	('Treg', 'Chemical', '-', (282, 286))	('tumor', 'Disease', (315, 320))
403	30156356	In the current study, there was a significantly higher rate of high MFG-E8 expression in the tumors of patients treated with NAC compared with those not treated with NAC.	('MFG-E8', 'Gene', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('NAC', 'Var', (125, 128))	('NAC', 'Chemical', '-', (166, 169))	('NAC', 'Chemical', '-', (125, 128))	('higher', 'PosReg', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('patients', 'Species', '9606', (103, 111))	('expression', 'MPA', (75, 85))
494	29621982	LNM increases the risk of locoregional recurrence and may influence cancer-specific survival in some patients with PTC.	('locoregional recurrence', 'CPA', (26, 49))	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('LNM', 'Var', (0, 3))	('PTC', 'Phenotype', 'HP:0002895', (115, 118))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('influence', 'Reg', (58, 67))	('cancer', 'Disease', (68, 74))	('PTC', 'Gene', '8030', (115, 118))	('PTC', 'Gene', (115, 118))
528	29621982	As shown in Table 2, PTC patients with high serum fibrinogen levels had a higher rate of postoperative recurrence.	('high', 'Var', (39, 43))	('postoperative recurrence', 'CPA', (89, 113))	('PTC', 'Gene', '8030', (21, 24))	('fibrinogen', 'Gene', '2244', (50, 60))	('fibrinogen', 'Gene', (50, 60))	('high serum fibrinogen levels', 'Phenotype', 'HP:0011899', (39, 67))	('PTC', 'Gene', (21, 24))	('patients', 'Species', '9606', (25, 33))	('PTC', 'Phenotype', 'HP:0002895', (21, 24))
573	27714646	Development of fistula between esophagogastric anastomotic site and cartilage portion of trachea after subtotal esophagectomy for cervical esophageal cancer: a case report A 65-year-old man with cT3N2M0 stage III cervical esophageal cancer underwent subtotal esophagectomy and gastric tube reconstruction through the retrosternal route after neoadjuvant chemoradiotherapy.	('cervical esophageal cancer', 'Disease', (213, 239))	('esophageal cancer', 'Disease', 'MESH:D004938', (222, 239))	('cervical esophageal cancer', 'Disease', 'MESH:D004938', (213, 239))	('cartilage portion of trachea', 'Disease', 'MESH:C557675', (68, 96))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cartilage portion of trachea', 'Disease', (68, 96))	('cervical esophageal cancer', 'Disease', 'MESH:D004938', (130, 156))	('cT3N2M0', 'Var', (195, 202))	('cervical esophageal cancer', 'Disease', (130, 156))	('man', 'Species', '9606', (186, 189))	('fistula', 'Disease', 'MESH:D005402', (15, 22))	('cartilage portion of trachea', 'Phenotype', 'HP:0005347', (68, 96))	('fistula', 'Disease', (15, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
588	27714646	The preoperative diagnosis was clinical T3N2M0 stage III cervical esophageal cancer according to the tumor, node, and metastasis classification.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('T3N2M0 stage', 'Var', (40, 52))	('cervical esophageal cancer', 'Disease', (57, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cervical esophageal cancer', 'Disease', 'MESH:D004938', (57, 83))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
592	27714646	The following lymph nodes in the neck and upper and middle mediastinum were dissected: the cervical paraesophageal (#101), supraclavicular (#104), upper thoracic paraesophageal (#105), recurrent nerve (#106recL and #106recR), tracheobronchial (#106tbL), subcarinal (#107), middle thoracic paraesophageal (#108), and main bronchus (#109 L and #109R) lymph nodes.	('#109 L', 'Var', (331, 337))	('middle thoracic paraesophageal', 'Disease', 'MESH:D020244', (273, 303))	('lymph nodes in the neck', 'Phenotype', 'HP:0025289', (14, 37))	('#106tbL', 'Var', (244, 251))	('upper thoracic paraesophageal', 'Disease', 'MESH:D006551', (147, 176))	('#106recL', 'Var', (202, 210))	('#106recR', 'Var', (215, 223))	('upper thoracic paraesophageal', 'Disease', (147, 176))	('middle thoracic paraesophageal', 'Disease', (273, 303))
689	25640628	The proportion of treatment completion by PS was as follows: PS0 74% (26/35) and 89% (31/35), PS1 91% (29/32) and 86% (30/35), and PS2 100% (1/1) and 0% (0/1) in arm A and arm B, respectively.	('PS1', 'Gene', (94, 97))	('PS', 'Chemical', '-', (61, 63))	('PS2', 'Gene', (131, 134))	('PS', 'Chemical', '-', (42, 44))	('PS1', 'Gene', '338399', (94, 97))	('PS', 'Chemical', '-', (94, 96))	('PS', 'Chemical', '-', (131, 133))	('PS0', 'Var', (61, 64))	('PS2', 'Gene', '338412', (131, 134))
703	25640628	In May 2009, the OS among patients receiving LDPF-RT was slightly inferior to patients treated with SDPF-RT (hazard ratio, 1.05; 80% confidence interval [CI], 0.78-1.41; unstratified one-sided log-rank P for non-inferiority =0.42).	('LDPF-RT', 'Var', (45, 52))	('patients', 'Species', '9606', (78, 86))	('LDPF', 'Chemical', '-', (45, 49))	('patients', 'Species', '9606', (26, 34))	('inferior', 'NegReg', (66, 74))	('OS', 'Chemical', '-', (17, 19))	('SDPF-RT', 'Chemical', '-', (100, 107))
707	25640628	We carried out a randomized phase II study that compared LDPF-RT (arm B) with SDPF-RT (arm A) for patients with cT4 or M1Lym esophageal squamous cell carcinoma.	('LDPF', 'Chemical', '-', (57, 61))	('cT4', 'Var', (112, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (125, 159))	('M1Lym', 'Var', (119, 124))	('patients', 'Species', '9606', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('SDPF-RT', 'Chemical', '-', (78, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('esophageal squamous cell carcinoma', 'Disease', (125, 159))
711	25640628	In Japan, LDPF-RT is believed to be less toxic and more effective, despite insufficient supporting evidence, because LDPF has a theoretical radiosensitizing effect and low toxicity.	('insufficient', 'Disease', (75, 87))	('low toxicity', 'Disease', 'MESH:D009800', (168, 180))	('LDPF', 'Chemical', '-', (10, 14))	('LDPF', 'Var', (117, 121))	('LDPF', 'Chemical', '-', (117, 121))	('low toxicity', 'Disease', (168, 180))	('radiosensitizing', 'CPA', (140, 156))	('insufficient', 'Disease', 'MESH:D000309', (75, 87))
719	25640628	We noted that the treatment completion rate was slightly higher in arm B (86%) than in arm A (82%); we speculated that this difference in completion rate might have been due to the difference in the total dose of cisplatin, which was slightly lower in arm B (120 mg/m2) than in arm A (140 mg/m2).	('120 mg/m2', 'Var', (259, 268))	('cisplatin', 'Chemical', 'MESH:D002945', (213, 222))	('treatment completion', 'CPA', (18, 38))
721	25640628	JCOG9516 was a phase II trial of SDPF-RT (the same protocol as arm A in this study) in patients with cT4 or M1Lym advanced esophageal cancer and demonstrated relatively low %CR (15%) with an acceptable 2-year survival (31.5%), fairly similar to the rates reported in the present study.	('esophageal cancer', 'Disease', (123, 140))	('%CR', 'MPA', (173, 176))	('patients', 'Species', '9606', (87, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('SDPF-RT', 'Chemical', '-', (33, 40))	('CR', 'Chemical', '-', (174, 176))	('M1Lym', 'Var', (108, 113))	('low', 'NegReg', (169, 172))	('cT4', 'Var', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
791	25608626	Measurement using light microscopy on histopathological specimens demonstrated that the mean vessel caliber in IPCL-IV (5.9 mum) was significantly larger than IPCL-III (4.8 mum) (P=0.013).	('IPCL-IV', 'Var', (111, 118))	('IPCL', 'Chemical', '-', (111, 115))	('vessel caliber', 'CPA', (93, 107))	('IPCL', 'Chemical', '-', (159, 163))	('IPCL-III', 'Chemical', '-', (159, 167))	('larger', 'PosReg', (147, 153))
809	25608626	IPCL-V1 corresponds to carcinoma in situ (M1) with the four characteristic morphological changes: dilatation, meandering, irregular caliber, and non-uniformity between each IPCL.	('carcinoma in situ', 'Disease', 'MESH:D002278', (23, 40))	('meandering', 'CPA', (110, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('irregular caliber', 'CPA', (122, 139))	('carcinoma in situ', 'Disease', (23, 40))	('dilatation', 'MPA', (98, 108))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (23, 40))	('IPCL', 'Chemical', '-', (173, 177))	('IPCL-V1', 'Var', (0, 7))	('dilatation', 'Phenotype', 'HP:0002617', (98, 108))	('IPCL', 'Chemical', '-', (0, 4))
817	25608626	In our data, IPCL V3b has relatively higher risk of SM invasion: IPCL-V3a related to M2 60%, M3SM1 40%.	('SM invasion', 'Disease', (52, 63))	('IPCL', 'Chemical', '-', (65, 69))	('IPCL', 'Var', (13, 17))	('IPCL V', 'Chemical', '-', (13, 19))	('IPCL', 'Chemical', '-', (13, 17))	('M3SM1', 'Var', (93, 98))
884	33505626	This study was to analyze the composition and possible mechanisms of ANE 30-100K-induced autophagy (AIA).	('ANE 30-100K-induced', 'Var', (69, 88))	('autophagy', 'CPA', (89, 98))	('ANE', 'Chemical', '-', (69, 72))
887	33505626	After ANE 30-100K stimulation, CE81T/VGH cells showed intracellular vacuoles, acidic vesicles, double-membrane vacuoles, and elevated LC3-II level.	('elevated', 'PosReg', (125, 133))	('LC3-II', 'Chemical', '-', (134, 140))	('CE81T/VGH', 'Var', (31, 40))	('LC3-II level', 'MPA', (134, 146))	('ANE', 'Chemical', '-', (6, 9))	('elevated LC3', 'Phenotype', 'HP:0003141', (125, 137))
888	33505626	ANE 30-100K-induced cytotoxicity and LC3-II accumulation were significantly inhibited by Atg5 knockdown.	('knockdown', 'Var', (94, 103))	('Atg5', 'Gene', (89, 93))	('cytotoxicity', 'Disease', (20, 32))	('LC3-II', 'Chemical', '-', (37, 43))	('LC3-II', 'Protein', (37, 43))	('ANE', 'Chemical', '-', (0, 3))	('cytotoxicity', 'Disease', 'MESH:D064420', (20, 32))	('inhibited', 'NegReg', (76, 85))
891	33505626	CE81T/VGH also exhibited autophagic responses to ANE 30-100K.	('CE81T/VGH', 'Var', (0, 9))	('exhibited', 'Reg', (15, 24))	('ANE', 'Chemical', '-', (49, 52))	('autophagic responses', 'CPA', (25, 45))
899	33505626	ANE 30-100K induced the accumulation of microtubule-associated protein 1 light chain 3A/B-II (LC3-II), acidic vesicles, and autophagic vacuoles in OECM-1, indicating the induction of macroautophagy (hereafter referred to as autophagy).	('3A/B', 'Var', (85, 89))	('accumulation', 'PosReg', (24, 36))	('autophagic vacuole', 'Phenotype', 'HP:0003736', (124, 142))	('macroautophagy', 'CPA', (183, 197))	('LC3-II', 'Chemical', '-', (94, 100))	('autophagic vacuoles', 'Phenotype', 'HP:0003736', (124, 143))	('ANE', 'Chemical', '-', (0, 3))	('LC3-II', 'Gene', (94, 100))	('3A/B', 'SUBSTITUTION', 'None', (85, 89))
906	33505626	In this study, we provided evidences of autophagic responses of CE81T/VGH cells to ANE 30-100K including double-membraned autophagosome (or autophagolysosome) by TEM.	('CE81T/VGH', 'Var', (64, 73))	('ANE', 'Chemical', '-', (83, 86))	('autophagic responses', 'CPA', (40, 60))
909	33505626	Methyl-beta-cyclodextrin (128446-36-6), lactacystin (133343-34-7), and epoxomicin (134381-21-8) were purchased from Sigma-Aldrich (Saint Louis, MO, USA).	('133343-34-7', 'Var', (53, 64))	('128446-36-6', 'Var', (26, 37))	('epoxomicin', 'Chemical', 'MESH:C078846', (71, 81))	('Methyl-beta-cyclodextrin', 'Chemical', 'MESH:C108732', (0, 24))	('lactacystin', 'Chemical', 'MESH:C067713', (40, 51))
940	33505626	Finally, ANE 30-100K-induced double-membrane autophagic vacuole structure was demonstrated here for the first time in CE81T/VGH cells by transmission electron microscope (Fig.	('autophagic vacuole', 'Phenotype', 'HP:0003736', (45, 63))	('double-membrane autophagic vacuole structure', 'CPA', (29, 73))	('ANE', 'Chemical', '-', (9, 12))	('CE81T/VGH', 'Var', (118, 127))
941	33505626	Some of these morphological changes are similar to those of OECM-1 cells as observed in our previous study, indicating that ANE 30-100K can stimulate a massive degradation of cytoplasmic materials in both OECM-1 and CE81T/VGH cells through autophagy.	('autophagy', 'CPA', (240, 249))	('ANE', 'Chemical', '-', (124, 127))	('degradation of cytoplasmic materials', 'MPA', (160, 196))	('stimulate', 'PosReg', (140, 149))	('ANE 30-100K', 'Var', (124, 135))
942	33505626	In addition to these observations, we also demonstrated that treatment of CE81T/VGH cells with ANE 30-100K for 24 h induced the elevation of LC3-II levels in both dose- and time- dependent manners (Fig.	('LC3-II levels', 'MPA', (141, 154))	('LC3-II', 'Chemical', '-', (141, 147))	('ANE', 'Chemical', '-', (95, 98))	('elevation', 'PosReg', (128, 137))	('CE81T/VGH', 'Var', (74, 83))
943	33505626	Meanwhile, LC3-II level was further increased in the presence of lysosomal inhibitors including pepstatin A (10 mug/ml), E64d (10 mug/ml), and leupeptin (10 mug/ml) (Fig.	('LC3-II', 'Chemical', '-', (11, 17))	('leupeptin', 'Chemical', 'MESH:C032854', (143, 152))	('pepstatin A', 'Chemical', 'MESH:C031375', (96, 107))	('increased', 'PosReg', (36, 45))	('10 mug/ml', 'Var', (109, 118))	('E64d', 'Chemical', 'MESH:C108192', (121, 125))	('LC3-II level', 'MPA', (11, 23))
944	33505626	This feature is regarded as the induction of autophagic flux, and similar effect of ANE 30-100K on oral fibroblasts has also been demonstrated in our previous studies.	('ANE', 'Var', (84, 87))	('autophagic flux', 'CPA', (45, 60))	('ANE', 'Chemical', '-', (84, 87))
945	33505626	3A showed that Atg5 protein level was significantly decreased in CE81T/VGH cells infected with atg5 shRNA-containing virus compared to non-infected cells (control) and cells infected with empty plasmid-containing virus (virus-plasmid control, VPC).	('infected', 'Disease', 'MESH:D007239', (174, 182))	('infected', 'Disease', (139, 147))	('infected', 'Disease', (174, 182))	('decreased', 'NegReg', (52, 61))	('infected', 'Disease', (81, 89))	('atg5 shRNA-containing', 'Var', (95, 116))	('CE81T/VGH', 'Var', (65, 74))	('infected', 'Disease', 'MESH:D007239', (139, 147))	('Atg5 protein level', 'MPA', (15, 33))	('infected', 'Disease', 'MESH:D007239', (81, 89))
949	33505626	Collectively, these data suggested that ANE 30-100K is capable of inducing autophagic cell death of CE81T/VGH in an Atg5-dependent manner.	('death', 'Disease', 'MESH:D003643', (91, 96))	('death', 'Disease', (91, 96))	('inducing', 'PosReg', (66, 74))	('ANE', 'Chemical', '-', (40, 43))	('CE81T/VGH', 'Var', (100, 109))
951	33505626	We firstly tested the cytotoxic effects of this compound on CE81T/VGH and OECM-1 cells, and found that up to 0.5 muM of MbetaCD, no significant cytotoxicity was observed in both cells (Fig.	('MbetaCD', 'Chemical', 'MESH:C108732', (120, 127))	('cytotoxicity', 'Disease', (144, 156))	('tested', 'Reg', (11, 17))	('MbetaCD', 'Var', (120, 127))	('cytotoxicity', 'Disease', 'MESH:D064420', (144, 156))
954	33505626	XTT analysis revealed that 7999- and 8002-infected CE81T/VGH and OECM-1 cells were more resistant to cytotoxic ANE 30-100K insult compared to uninfected cells (control) and VPC cells (Fig.	('infected', 'Disease', 'MESH:D007239', (144, 152))	('ANE', 'Chemical', '-', (111, 114))	('infected', 'Disease', 'MESH:D007239', (42, 50))	('CE81T/VGH', 'Var', (51, 60))	('infected', 'Disease', (144, 152))	('infected', 'Disease', (42, 50))	('resistant to cytotoxic ANE', 'MPA', (88, 114))
965	33505626	1D) have further confirmed that ANE 30-100K not only induces autophagic cell death in OECM-1 but also in CE81T/VGH cells (ref 19 and Figure 1, Figure 2, Figure 3).	('death', 'Disease', 'MESH:D003643', (77, 82))	('death', 'Disease', (77, 82))	('ANE', 'Chemical', '-', (32, 35))	('ANE 30-100K', 'Var', (32, 43))	('induces', 'Reg', (53, 60))
966	33505626	It is thus thought that ANE 30-100K is capable of inducing autophagy in a wide range of different cell types.	('autophagy', 'CPA', (59, 68))	('inducing', 'PosReg', (50, 58))	('ANE', 'Chemical', '-', (24, 27))	('ANE', 'Var', (24, 27))
982	33505626	6, effective attenuation of ANE 30-100K-induced autophagic cell death by epoxomicin and lactacystin implied the involvement of the proteasome in AIA.	('epoxomicin', 'Chemical', 'MESH:C078846', (73, 83))	('death', 'Disease', 'MESH:D003643', (64, 69))	('death', 'Disease', (64, 69))	('attenuation', 'NegReg', (13, 24))	('ANE', 'Var', (28, 31))	('involvement', 'Reg', (112, 123))	('lactacystin', 'Chemical', 'MESH:C067713', (88, 99))	('ANE', 'Chemical', '-', (28, 31))
983	33505626	Epoxomicin (50 and 25 nM for CE81T/VGH and OECM-1, respectively) was more effective than lactacystin (5 muM for both cells) in blocking AIA.	('lactacystin', 'Chemical', 'MESH:C067713', (89, 100))	('Epoxomicin', 'Chemical', 'MESH:C078846', (0, 10))	('AIA', 'MPA', (136, 139))	('CE81T/VGH', 'Var', (29, 38))
985	33505626	Furthermore, inhibition of proteasome also blocked glutamate agonist AMPA-induced internalization of glutamate receptors.	('AMPA', 'Chemical', 'MESH:D018350', (69, 73))	('inhibition', 'Var', (13, 23))	('blocked', 'NegReg', (43, 50))	('glutamate', 'Chemical', 'MESH:D018698', (51, 60))	('glutamate', 'Chemical', 'MESH:D018698', (101, 110))	('proteasome', 'Protein', (27, 37))
1007	30901943	The benefit of FLOT was shown in all the subgroups analyzed, such as proximal versus distal tumors, well versus poorly differentiated as well as in the early stages (cT1,2), in which FLOT showed greater survival benefit than ECF/X.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('FLOT', 'Var', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
1020	30901943	Noteworthy, adjuvant treatment was shown to be an independent prognostic factor related to survival at multivariate analysis, observing the largest benefit in pts with node-positive disease or sub-optimal histological tumor regression grade (TRG).	('TRG', 'Chemical', '-', (242, 245))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('pts', 'Species', '9606', (159, 162))	('sub-optimal', 'Var', (193, 204))
1056	30901943	Another German analysis confirmed that signet ring cell histology was significantly associated with lower probability of R0 resection and worse histopathological response (16.3 versus 28.9 %, p < 0.001) in pts affected by resectable gastric and GEJ cancer and treated with preoperative chemotherapy (CF-based, with taxans or epirubicin).	('gastric', 'Disease', (233, 240))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('signet ring cell histology', 'Var', (39, 65))	('lower', 'NegReg', (100, 105))	('cancer', 'Disease', (249, 255))	('pts', 'Species', '9606', (206, 209))	('epirubicin', 'Chemical', 'MESH:D015251', (325, 335))	('taxans', 'Chemical', '-', (315, 321))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
1057	30901943	It is noteworthy that the prognosis of these pts was significantly worse in comparison with other adenocarcinomas, making the presence of signet ring cell an independent prognostic factor.	('adenocarcinomas', 'Disease', 'MESH:D000230', (98, 113))	('adenocarcinomas', 'Disease', (98, 113))	('pts', 'Species', '9606', (45, 48))	('presence', 'Var', (126, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
1078	30901943	The prognostic and predictive role of microsatellites and mismatch repair proteins (MMR) is well defined in colon cancer.	('colon cancer', 'Disease', (108, 120))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))	('microsatellites', 'Var', (38, 53))
1081	30901943	Moreover, pts with MSI status showed a better OS than pts with microsatellite stability (MSS) (HR: 0.69, 95% CI: 0.56-0.86; p < 0.001).	('pts', 'Species', '9606', (54, 57))	('MSS', 'Disease', 'MESH:D013132', (89, 92))	('MSS', 'Disease', (89, 92))	('MSI', 'Var', (19, 22))	('pts', 'Species', '9606', (10, 13))	('OS', 'Gene', '17451', (46, 48))	('better', 'PosReg', (39, 45))
1089	30901943	However, we should consider that in this post hoc study, only GC showed an MSI or MMRD status compared to the GEJ tumors (0%), which is in accordance with low prevalence of the deficiency in proximal gastric or esophageal cancers.	('MMRD', 'CPA', (82, 86))	('GC', 'Phenotype', 'HP:0012126', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MSI', 'Var', (75, 78))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('deficiency in proximal gastric or esophageal cancers', 'Disease', 'MESH:D013274', (177, 229))
1092	30901943	On the other hand, pts with MSI-L, MSS and/or MMRP may have a better outcome when treated with chemotherapy first.	('pts', 'Species', '9606', (19, 22))	('MMRP', 'Disease', (46, 50))	('MSS', 'Disease', 'MESH:D013132', (35, 38))	('MSS', 'Disease', (35, 38))	('MSI-L', 'Var', (28, 33))
1114	30901943	Among other studies that investigated the predictive value of molecular markers expression for treatment response and survival, great interest has been garnered by Phase II randomized trial FLOT4-AIO with a significantly higher proportion of pts achieving pCR (according to Becker's classification, 16% versus 6% in the group treated with docetaxel-based versus epirubicin-based triplet, respectively).	('docetaxel', 'Chemical', 'MESH:D000077143', (339, 348))	('higher', 'PosReg', (221, 227))	('epirubicin', 'Chemical', 'MESH:D015251', (362, 372))	('FLOT4-AIO', 'Var', (190, 199))	('pCR', 'Disease', (256, 259))	('pts', 'Species', '9606', (242, 245))
1151	30123343	Conclusions: Rates of OS and CR were improved after treatment with DCF-RT compared with CF-RT.	('DCF-RT', 'Chemical', '-', (67, 73))	('DCF-RT', 'Var', (67, 73))	('CF-RT', 'Chemical', '-', (88, 93))	('CR', 'Chemical', '-', (29, 31))	('improved', 'PosReg', (37, 45))	('OS', 'Chemical', '-', (22, 24))	('CF-RT', 'Chemical', '-', (68, 73))	('men', 'Species', '9606', (57, 60))
1158	30123343	However, treatment outcomes of CF are slightly inferior to those of surgery, hovering around 26%-27% for clinical T1-3, N0-1 cases and 31% for clinical T1-4, N0-1 cases.	('N0-1', 'Var', (120, 124))	('T1-3', 'Gene', (114, 118))	('men', 'Species', '9606', (14, 17))	('T1-4', 'Gene', (152, 156))	('T1-4', 'Gene', '939;921;292', (152, 156))	('T1-3', 'Gene', '29123;921;292', (114, 118))
1199	30123343	The mean CR rate was higher in the DCF-RT group (52.6%) compared with the CF-RT group (37.8%), although this difference was not statistically significant (p = 0.13; Table 2).	('DCF-RT', 'Var', (35, 41))	('CF-RT', 'Chemical', '-', (74, 79))	('CR rate', 'CPA', (9, 16))	('CR', 'Chemical', '-', (9, 11))	('higher', 'PosReg', (21, 27))	('CF-RT', 'Chemical', '-', (36, 41))	('DCF-RT', 'Chemical', '-', (35, 41))
1222	30123343	In our study, OS rates were significantly improved and PFS and LC rates were favorable in the DCF-RT group.	('DCF-RT', 'Chemical', '-', (94, 100))	('OS rates', 'CPA', (14, 22))	('OS', 'Chemical', '-', (14, 16))	('improved', 'PosReg', (42, 50))	('DCF-RT', 'Var', (94, 100))	('PFS', 'CPA', (55, 58))	('LC rates', 'CPA', (63, 71))
1223	30123343	Taken together, our findings suggest that the anticancer effect of CRT is more potent with DCF-RT than with CF-RT.	('CF-RT', 'Chemical', '-', (108, 113))	('RT', 'Chemical', 'MESH:D006854', (111, 113))	('DCF-RT', 'Chemical', '-', (91, 97))	('CF-RT', 'Chemical', '-', (92, 97))	('CR', 'Chemical', '-', (67, 69))	('RT', 'Chemical', 'MESH:D006854', (95, 97))	('DCF-RT', 'Var', (91, 97))	('RT', 'Chemical', 'MESH:D006854', (68, 70))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('anticancer effect', 'CPA', (46, 63))	('potent', 'PosReg', (79, 85))
1250	30123343	Also, the proportion of elderly patients was slightly higher in the CF-RT group than in the DCF-RT group because the expected toxicity of DCF-RT was slightly greater than that of CF-RT.	('greater', 'PosReg', (158, 165))	('patients', 'Species', '9606', (32, 40))	('toxicity', 'Disease', 'MESH:D064420', (126, 134))	('DCF-RT', 'Var', (138, 144))	('CF-RT', 'Chemical', '-', (139, 144))	('DCF-RT', 'Chemical', '-', (92, 98))	('toxicity', 'Disease', (126, 134))	('CF-RT', 'Chemical', '-', (179, 184))	('CF-RT', 'Chemical', '-', (68, 73))	('CF-RT', 'Chemical', '-', (93, 98))	('DCF-RT', 'Chemical', '-', (138, 144))
1253	30123343	In conclusion, DCF-RT has an extremely potent anticancer effect and extends overall patient survival compared with CF-RT albeit with some limitations.	('CF-RT', 'Chemical', '-', (115, 120))	('DCF-RT', 'Chemical', '-', (15, 21))	('CF-RT', 'Chemical', '-', (16, 21))	('DCF-RT', 'Var', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('extends', 'PosReg', (68, 75))	('anticancer effect', 'CPA', (46, 63))	('patient survival', 'CPA', (84, 100))	('patient', 'Species', '9606', (84, 91))
1273	26651958	The objective of the present study was to determine the outcomes of patients with LAEC clinically staged as T2N0M0 or higher who had survived at least 5 years after esophagectomy and were without disease at that time point.	('patients', 'Species', '9606', (68, 76))	('EC', 'Chemical', '-', (84, 86))	('LAEC', 'Disease', (82, 86))	('T2N0M0', 'Var', (108, 114))
1306	26651958	Patients treated with an en bloc resection were generally younger (P = .165), less likely to have pulmonary comorbidity (P = .051), and more likely to have a higher tumor burden (pN1-3: 53% vs 33%; P = .141) compared with patients treated with non-en bloc resection (data not shown).	('patients', 'Species', '9606', (222, 230))	('less', 'NegReg', (78, 82))	('higher', 'PosReg', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Patients', 'Species', '9606', (0, 8))	('en bloc resection', 'Var', (25, 42))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('pulmonary', 'CPA', (98, 107))	('tumor', 'Disease', (165, 170))
1433	21523227	Polymorphism in these genes may partly explain why subjects differ in their liability for the development of cancer; it may be a question of higher or lower metabolic activities involved in alcohol metabolism.	('alcohol', 'Chemical', 'MESH:D000438', (190, 197))	('metabolic activities involved in', 'MPA', (157, 189))	('Polymorphism', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('men', 'Species', '9606', (101, 104))	('lower', 'NegReg', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
1435	21523227	Similarly, smoking associates with cancer and smoking also causes an increase in salivary acetaldehyde concentrations thus adding to the risk related to alcohol.	('acetaldehyde', 'Chemical', 'MESH:D000079', (90, 102))	('increase', 'PosReg', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('salivary acetaldehyde concentrations', 'MPA', (81, 117))	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (81, 102))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('smoking', 'Var', (11, 18))	('associates', 'Reg', (19, 29))	('alcohol', 'Chemical', 'MESH:D000438', (153, 160))	('cancer', 'Disease', (35, 41))
1444	21523227	In oral cancer patients mutated salivary DNA at the 53p gene was observed in 62.5% of 10 patients when compared with 18.5% among 27 healthy controls in a study from Taiwan.	('mutated', 'Var', (24, 31))	('patients', 'Species', '9606', (15, 23))	('oral cancer', 'Disease', 'MESH:D009062', (3, 14))	('oral cancer', 'Disease', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('patients', 'Species', '9606', (89, 97))
1495	21523227	A 1-year randomized trial from our clinic on 79 Hodgkin and non-Hodgkin lymphoma patients showed that using mouthwash containing 0.025% amine fluoride-stannous-fluoride caused a significant decrease in visible plaque, gingival bleeding, and salivary S. mutans counts while an increase was found in the group using 0.05% sodium fluoride rinses.	('decrease', 'NegReg', (190, 198))	('0.025%', 'Var', (129, 135))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (64, 80))	('non-Hodgkin lymphoma', 'Disease', (60, 80))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (60, 80))	('Hodgkin', 'Disease', (64, 71))	('gingival bleeding', 'Disease', (218, 235))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))	('Hodgkin', 'Disease', 'MESH:D006689', (64, 71))	('salivary S. mutans counts', 'CPA', (241, 266))	('Hodgkin', 'Disease', (48, 55))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (60, 80))	('Hodgkin', 'Disease', 'MESH:D006689', (48, 55))	('stannous-fluoride', 'Chemical', 'MESH:D014002', (151, 168))	('S. mutans', 'Species', '1309', (250, 259))	('gingival bleeding', 'Disease', 'MESH:D005884', (218, 235))	('patients', 'Species', '9606', (81, 89))	('visible plaque', 'CPA', (202, 216))	('gingival bleeding', 'Phenotype', 'HP:0000225', (218, 235))	('sodium fluoride', 'Chemical', 'MESH:D012969', (320, 335))	('amine fluoride', 'Chemical', 'MESH:C036238', (136, 150))
1510	21523227	Cysteine has also been shown to exert inhibitory effect on the gelatinolytic activity of matrix metalloproteinases and to reduce metastases in animal models.	('gelatinolytic activity', 'MPA', (63, 85))	('reduce', 'NegReg', (122, 128))	('Cysteine', 'Var', (0, 8))	('matrix metalloproteinases', 'Enzyme', (89, 114))	('metastases', 'Disease', (129, 139))	('Cysteine', 'Chemical', 'MESH:D003545', (0, 8))	('metastases', 'Disease', 'MESH:D009362', (129, 139))	('inhibitory effect', 'MPA', (38, 55))
1566	33383776	In a randomized crossover study enrolling twenty young subjects (10 females and 10 males; Body Mass Index (BMI) = 21.7 +- 2.2 kg/m2), Kristensen and co-workers reported that, with respect to refined counterparts, WG wheat bread ingestion led to increased satiety and reduced hunger, without modifying energy intake at the subsequent meals.	('WG wheat', 'Var', (213, 221))	('satiety', 'MPA', (255, 262))	('red', 'Gene', (267, 270))	('increased', 'PosReg', (245, 254))	('reduced hunger', 'Phenotype', 'HP:0004396', (267, 281))	('hunger', 'MPA', (275, 281))	('red', 'Gene', '15357', (267, 270))	('increased satiety', 'Phenotype', 'HP:0002591', (245, 262))
1580	33383776	As it will be discussed, high dietary fiber intake improves intestinal health, increases satiety, and reduces risk of some chronic diseases, including cancer.	('red', 'Gene', '15357', (102, 105))	('red', 'Gene', (102, 105))	('increases', 'PosReg', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('increases satiety', 'Phenotype', 'HP:0002591', (79, 96))	('intestinal health', 'MPA', (60, 77))	('chronic diseases', 'Disease', (123, 139))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('fiber', 'Chemical', 'MESH:D004043', (38, 43))	('improves', 'PosReg', (51, 59))	('chronic diseases', 'Disease', 'MESH:D002908', (123, 139))	('satiety', 'MPA', (89, 96))	('high dietary fiber', 'Var', (25, 43))
1617	33383776	In this context, WGs represent protective factors, as high intakes have been associated with significant decrease of cancer risk (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('decrease of cancer', 'Disease', 'MESH:D009369', (105, 123))	('decrease of cancer', 'Disease', (105, 123))	('high intakes', 'Var', (54, 66))
1634	33383776	High fiber and WG intake after diagnosis also leads to lower death rate, and this positive association again depends on fiber sources, with cereal fiber (especially from WG) showing the strongest link.	('fiber', 'Chemical', 'MESH:D004043', (5, 10))	('High fiber', 'Var', (0, 10))	('death', 'Disease', 'MESH:D003643', (61, 66))	('death', 'Disease', (61, 66))	('fiber', 'Chemical', 'MESH:D004043', (120, 125))	('lower', 'NegReg', (55, 60))	('fiber', 'Chemical', 'MESH:D004043', (147, 152))
1640	33383776	Likewise, in human colon cancer cells, secoisolariciresinol diglycoside and its metabolites (enterolactone and enterodiol) induce S-phase cell cycle arrest, by modulating key regulatory proteins (cyclin A and cyclin-dependent kinase 4).	('diglycoside', 'Chemical', '-', (60, 71))	('human', 'Species', '9606', (13, 18))	('cyclin-dependent kinase 4', 'Gene', (209, 234))	('enterolactone', 'Chemical', 'MESH:C029497', (93, 106))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('colon cancer', 'Disease', 'MESH:D015179', (19, 31))	('cyclin A', 'Gene', (196, 204))	('colon cancer', 'Phenotype', 'HP:0003003', (19, 31))	('secoisolariciresinol', 'Var', (39, 59))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('arrest', 'Disease', (149, 155))	('colon cancer', 'Disease', (19, 31))	('cyclin A', 'Gene', '890', (196, 204))	('enterodiol', 'Chemical', 'MESH:C029498', (111, 121))	('secoisolariciresinol', 'Chemical', 'MESH:C060283', (39, 59))	('cyclin-dependent kinase 4', 'Gene', '1019', (209, 234))	('modulating', 'Reg', (160, 170))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (138, 155))
1642	33383776	Finally, some miRNAs involved in colorectal cancer are sensitive to phenolic compounds: for example, miRNA384 is up-regulated by luteolin, thus resulting in decreased expression levels of pleiotrophin, a cytokine upregulated in colorectal tumors.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('rectal cancer', 'Phenotype', 'HP:0100743', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('pleiotrophin', 'Gene', '5764', (188, 200))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('colorectal tumors', 'Disease', 'MESH:D015179', (228, 245))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('luteolin', 'Chemical', 'MESH:D047311', (129, 137))	('up-regulated', 'PosReg', (113, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('colorectal tumors', 'Disease', (228, 245))	('miRNA384', 'Var', (101, 109))	('pleiotrophin', 'Gene', (188, 200))	('decreased', 'NegReg', (157, 166))	('expression levels', 'MPA', (167, 184))	('colorectal cancer', 'Disease', (33, 50))
1670	33383776	Potential mechanisms of protective action include modification of gastroesophageal reflux and/or weight control, neutralization of carcinogens contained in food, amelioration of cancer-associated esophageal dysbiosis, and direct action on cancer cells.	('gastroesophageal reflux', 'MPA', (66, 89))	('modification', 'Var', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('amelioration', 'PosReg', (162, 174))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('esophageal reflux', 'Phenotype', 'HP:0002020', (72, 89))	('esophageal dysbiosis', 'Disease', (196, 216))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('esophageal dysbiosis', 'Disease', 'MESH:D064806', (196, 216))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (66, 89))	('neutralization', 'MPA', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
1674	33383776	Additionally, polyphenols could be beneficial in esophageal cancer, thanks to their antioxidant activity, ability to improve esophageal reflux-related inflammation, and modulation of cell proliferation and survival.	('esophageal reflux', 'Phenotype', 'HP:0002020', (125, 142))	('modulation', 'Reg', (169, 179))	('esophageal cancer', 'Disease', (49, 66))	('survival', 'CPA', (206, 214))	('antioxidant activity', 'MPA', (84, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('polyphenols', 'Chemical', 'MESH:D059808', (14, 25))	('inflammation', 'Disease', 'MESH:D007249', (151, 163))	('improve', 'PosReg', (117, 124))	('cell proliferation', 'CPA', (183, 201))	('polyphenols', 'Var', (14, 25))	('inflammation', 'Disease', (151, 163))	('esophageal reflux-related', 'Disease', (125, 150))
1680	33383776	It has been estimated, in fact, that low WG intake resulted in almost 270,000 avoidable deaths and almost 4 million disability-adjusted life years in the European Union in 2015.	('deaths', 'Disease', (88, 94))	('low', 'Var', (37, 40))	('deaths', 'Disease', 'MESH:D003643', (88, 94))
1698	33391772	This is a rare case showing that nivolumab monotherapy might induce bronchoesophageal fistulae.	('induce', 'PosReg', (61, 67))	('bronchoesophageal fistulae', 'Phenotype', 'HP:0002575', (68, 94))	('bronchoesophageal fistula', 'Disease', 'MESH:D005402', (68, 93))	('bronchoesophageal fistula', 'Phenotype', 'HP:0002575', (68, 93))	('bronchoesophageal fistula', 'Disease', (68, 93))	('nivolumab', 'Chemical', 'MESH:D000077594', (33, 42))	('monotherapy', 'Var', (43, 54))
1725	33391772	Recently, it was reported that durvalumab after chemoradiotherapy might cause bronchomediastinal fistulae in stage III non-small cell lung cancer.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('fistula', 'Disease', 'MESH:D005402', (97, 104))	('cause', 'Reg', (72, 77))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('fistula', 'Disease', (97, 104))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('durvalumab', 'Chemical', 'MESH:C000613593', (31, 41))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))	('durvalumab', 'Var', (31, 41))
1744	32759723	Moreover, we focus on other rare variants and on the relationship with head and neck squamous cell carcinomas.	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (80, 109))	('neck squamous cell carcinomas', 'Disease', (80, 109))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (85, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (71, 109))	('variants', 'Var', (33, 41))
1757	32759723	In addition, polycyclic aromatic hydrocarbons (PAHs) are strongly associated with an increased risk of ESCC: Iranian, Brazilian and Chinese populations are highly exposed to PAHs coming from food or beverages.	('PAHs', 'Chemical', 'MESH:D011084', (174, 178))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (13, 45))	('age', 'Gene', '5973', (204, 207))	('associated', 'Reg', (66, 76))	('ESCC', 'Disease', (103, 107))	('polycyclic', 'Var', (13, 23))	('age', 'Gene', (204, 207))	('PAHs', 'Chemical', 'MESH:D011084', (47, 51))
1761	32759723	Moreover, individuals carrying specific variants of ALDH2, the aldehyde dehydrogenase 2 family genes, have a higher risk of ESCC if alcohol assumption is added (43-fold in moderate drinkers and 73-fold in heavy drinkers); these genetic alterations are typically found in people from East Asia.	('people', 'Species', '9606', (271, 277))	('ALDH2', 'Gene', '217', (52, 57))	('alcohol assumption', 'Phenotype', 'HP:0030955', (132, 150))	('aldehyde dehydrogenase 2', 'Gene', '217', (63, 87))	('ALDH2', 'Gene', (52, 57))	('variants', 'Var', (40, 48))	('aldehyde dehydrogenase 2', 'Gene', (63, 87))	('ESCC', 'Disease', (124, 128))	('alcohol', 'Chemical', 'MESH:D000438', (132, 139))
1762	32759723	Several key single nucleotide polymorphisms (SNPs) of PLCE1 have been associated with an higher risk of ESCC: of note, PLCE1 encodes for the 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1, a protein which appears to have a role in modulating carcinogenetic effects.	('associated', 'Reg', (70, 80))	('PLCE1', 'Gene', (54, 59))	('PLCE1', 'Gene', (119, 124))	('ESCC', 'Disease', (104, 108))	('single nucleotide polymorphisms', 'Var', (12, 43))	('1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1', 'Gene', '51196', (141, 208))	('PLCE1', 'Gene', '51196', (54, 59))	('PLCE1', 'Gene', '51196', (119, 124))
1772	32759723	Liu and colleagues found several ESCC-associated mutations in basal cell hyperplasia, such as in the TP53, NOTCH1, CDKN2A, EP300 and MLL2 genes.	('CDKN2A', 'Gene', (115, 121))	('hyperplasia', 'Disease', (73, 84))	('mutations', 'Var', (49, 58))	('CDKN2A', 'Gene', '1029', (115, 121))	('EP300', 'Gene', (123, 128))	('EP300', 'Gene', '2033', (123, 128))	('TP53', 'Gene', '7157', (101, 105))	('ESCC-associated', 'Disease', (33, 48))	('MLL2', 'Gene', (133, 137))	('hyperplasia', 'Disease', 'MESH:D006965', (73, 84))	('TP53', 'Gene', (101, 105))	('NOTCH1', 'Gene', '4851', (107, 113))	('NOTCH1', 'Gene', (107, 113))	('MLL2', 'Gene', '8085', (133, 137))
1776	32759723	Furthermore, mutations of TP53 (71% of esophageal dysplastic samples), NOTCH1, CDKN2A, PIK3CA, EP300 and MLL2 have been reported.	('TP53', 'Gene', (26, 30))	('CDKN2A', 'Gene', '1029', (79, 85))	('EP300', 'Gene', '2033', (95, 100))	('PIK3CA', 'Gene', '5290', (87, 93))	('TP53', 'Gene', '7157', (26, 30))	('NOTCH1', 'Gene', (71, 77))	('EP300', 'Gene', (95, 100))	('mutations', 'Var', (13, 22))	('MLL2', 'Gene', (105, 109))	('esophageal dysplastic', 'Disease', (39, 60))	('esophageal dysplastic', 'Disease', 'MESH:D004938', (39, 60))	('PIK3CA', 'Gene', (87, 93))	('MLL2', 'Gene', '8085', (105, 109))	('CDKN2A', 'Gene', (79, 85))	('reported', 'Reg', (120, 128))	('NOTCH1', 'Gene', '4851', (71, 77))
1779	32759723	According to their results, clonal expansion in normal esophageal epithelium is a consequence of normal aging but can be accelerated by alcohol and tobacco consumption.	('alcohol', 'Chemical', 'MESH:D000438', (136, 143))	('clonal expansion', 'Var', (28, 44))	('age', 'Gene', '5973', (60, 63))	('tobacco', 'Species', '4097', (148, 155))	('age', 'Gene', (60, 63))
1781	32759723	The mutational analysis revealed significant differences in the frequency of mutation of many genes between normal and dysplastic epithelium.	('mutation', 'Var', (77, 85))	('dysplastic', 'Disease', 'MESH:D004416', (119, 129))	('dysplastic', 'Disease', (119, 129))
1784	32759723	Finally, uniparental disomy and LOH of 9q, gain of 3q and LOH of 17p have been described in normal esophageal mucosa.	('age', 'Gene', '5973', (104, 107))	('LOH', 'Var', (58, 61))	('LOH of 9q', 'Var', (32, 41))	('age', 'Gene', (104, 107))	('uniparental disomy', 'Disease', (9, 27))	('gain', 'PosReg', (43, 47))	('uniparental disomy', 'Disease', 'MESH:D024182', (9, 27))
1785	32759723	ESCC genome holds a wide variety of genetic alteration types ranging from single point mutations to chromosomal structure variations, some of which have a pivotal role in carcinogenesis.	('single point mutations', 'Var', (74, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (171, 185))	('variations', 'Var', (122, 132))	('carcinogenesis', 'Disease', (171, 185))
1786	32759723	Moreover, a growing body of evidence is defining epigenetic dysregulation as a main actor in ESCC development.	('ESCC', 'Disease', (93, 97))	('epigenetic dysregulation', 'Var', (49, 73))	('men', 'Species', '9606', (105, 108))
1787	32759723	Gene mutations, leading to loss or alteration of gene function, play an important role in ESCC carcinogenesis.	('alteration', 'Reg', (35, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (95, 109))	('mutations', 'Var', (5, 14))	('carcinogenesis', 'Disease', (95, 109))	('gene function', 'MPA', (49, 62))	('loss', 'NegReg', (27, 31))
1791	32759723	Signature 1 is defined by an enrichment of C>T mutations in XpCpG trinucleotides, a well-recognized mutational process related to spontaneous deamination of 5-methyl-cytosine.	('5-methyl-cytosine', 'Chemical', 'MESH:D044503', (157, 174))	('men', 'Species', '9606', (35, 38))	('C>T mutations', 'Var', (43, 56))	('trinucleotides', 'Chemical', '-', (66, 80))	('XpCpG', 'Gene', (60, 65))
1792	32759723	Signature 2 and Signature 13 are characterized by C>G and C>T/C>A mutations in TpCpX trinucleotides, respectively and are associated with mutations of the APOBEC (Apolipoprotein B mRNA Editing Catalytic Polypeptide-like) family of cytidine deaminases, which have important roles in immunologic processes due to their deaminase activity.	('associated', 'Reg', (122, 132))	('mutations', 'Var', (66, 75))	('trinucleotides', 'Chemical', '-', (85, 99))	('Apolipoprotein B', 'Gene', (163, 179))	('EC', 'Disease', 'MESH:D005955', (159, 161))	('Apolipoprotein B', 'Gene', '338', (163, 179))	('C>T/C>A mutations', 'Var', (58, 75))	('TpCpX', 'Gene', (79, 84))	('C>G', 'Var', (50, 53))
1793	32759723	Signature 4 is probably due to tobacco carcinogens and is characterized by an augmented rate of C>A mutations.	('carcinogens', 'Disease', 'MESH:D063646', (39, 50))	('men', 'Species', '9606', (81, 84))	('tobacco', 'Species', '4097', (31, 38))	('carcinogens', 'Disease', (39, 50))	('C>A mutations', 'Var', (96, 109))
1794	32759723	Signature 16 is defined by T>C mutations in ApTpX trinucleotide and has been associated with alcohol consumption.	('T>C mutations', 'Var', (27, 40))	('ApTpX', 'Gene', (44, 49))	('alcohol consumption', 'Disease', (93, 112))	('trinucleotide', 'Chemical', '-', (50, 63))	('alcohol', 'Chemical', 'MESH:D000438', (93, 100))	('associated', 'Reg', (77, 87))
1797	32759723	CDKN2A is another well-known tumor suppressor gene inhibiting cell cycle progression through its interaction with both the p53 and the Rb pathways, and it is mutated in 4.9 to 20% of ESCCs.	('cell cycle progression', 'CPA', (62, 84))	('Rb pathways', 'Pathway', (135, 146))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('inhibiting', 'NegReg', (51, 61))	('tumor', 'Disease', (29, 34))	('p53', 'Gene', (123, 126))	('interaction', 'Interaction', (97, 108))	('mutated', 'Var', (158, 165))	('CDKN2A', 'Gene', (0, 6))	('p53', 'Gene', '7157', (123, 126))	('ESCCs', 'Disease', (183, 188))	('CDKN2A', 'Gene', '1029', (0, 6))
1798	32759723	The cell cycle regulator gene RB1 is mutated in 4.2 to 9% of ESCC.	('mutated', 'Var', (37, 44))	('RB1', 'Gene', (30, 33))	('ESCC', 'Disease', (61, 65))	('RB1', 'Gene', '5925', (30, 33))
1801	32759723	Genes involved in this pathway, specifically the SMGs PIK3CA (10.8-17%) and PTEN (3%), are reported to be mutated in 29% of ESCCs.	('PTEN', 'Gene', (76, 80))	('PIK3CA', 'Gene', '5290', (54, 60))	('PTEN', 'Gene', '5728', (76, 80))	('mutated', 'Var', (106, 113))	('ESCCs', 'Disease', (124, 129))	('PIK3CA', 'Gene', (54, 60))
1802	32759723	PIK3CA encodes for PI3K, an intercellular mediator of cell survival signals and functions as an oncogene leading to AKT activation and, consequently, mTOR phosphorylation.	('activation', 'PosReg', (120, 130))	('PIK3CA', 'Gene', (0, 6))	('AKT', 'Gene', '207', (116, 119))	('PIK3CA', 'Gene', '5290', (0, 6))	('PI3K', 'Var', (19, 23))	('mTOR', 'Gene', '2475', (150, 154))	('mTOR', 'Gene', (150, 154))	('AKT', 'Gene', (116, 119))
1804	32759723	Hotspot mutations in the p110a domain (p.N345K, p.C420R, p.E545K, p.E542K) and in C-terminal portion (p.H1047R, p.H1047L) encoding portions of the PIK3CA gene have been detected, which are reported to induce a gain of function in oncogenicity.	('p.H1047L', 'Mutation', 'rs121913279', (112, 120))	('p.E542K', 'Var', (66, 73))	('p.E545K', 'Mutation', 'rs104886003', (57, 64))	('p.H1047R', 'Mutation', 'rs121913279', (102, 110))	('p.N345K', 'Var', (39, 46))	('p.C420R', 'Var', (48, 55))	('oncogenicity', 'CPA', (230, 242))	('p.N345K', 'Mutation', 'rs121913284', (39, 46))	('PIK3CA', 'Gene', (147, 153))	('p.H1047L', 'Var', (112, 120))	('gain of function', 'PosReg', (210, 226))	('p.E542K', 'Mutation', 'rs121913273', (66, 73))	('PIK3CA', 'Gene', '5290', (147, 153))	('p.C420R', 'Mutation', 'rs121913272', (48, 55))	('p.E545K', 'Var', (57, 64))	('p.H1047R', 'Var', (102, 110))
1805	32759723	Another study found that hotspot mutations c.1624G>A[p.E542K] and c.1633G>A [p.E545K] on PIK3CA were significantly enriched in ESCCs with Signatures 2 and 13, suggesting that APOBEC activity is a driver of PIK3CA mutagenesis in ESCC.	('p.E545K', 'Mutation', 'rs104886003', (77, 84))	('c.1624G>A', 'Var', (43, 52))	('EC', 'Disease', 'MESH:D005955', (179, 181))	('PIK3CA', 'Gene', (89, 95))	('c.1633G>A [', 'Var', (66, 77))	('c.1624G>A', 'Mutation', 'rs121913273', (43, 52))	('age', 'Gene', (216, 219))	('PIK3CA', 'Gene', '5290', (89, 95))	('PIK3CA', 'Gene', (206, 212))	('ESCCs', 'Disease', (127, 132))	('c.1633G>A', 'Mutation', 'rs104886003', (66, 75))	('PIK3CA', 'Gene', '5290', (206, 212))	('age', 'Gene', '5973', (216, 219))	('p.E542K', 'Mutation', 'rs121913273', (53, 60))
1807	32759723	Alterations in NOTCH signaling pathways have been reported in up to 33.4% of ESCCs; in particular, the SMGs NOTCH1, NOTCH3 and FBXW7 are mutated in 16%, 6% and 5% of ESCC, respectively.	('NOTCH3', 'Gene', (116, 122))	('NOTCH', 'Gene', (108, 113))	('FBXW7', 'Gene', '55294', (127, 132))	('NOTCH3', 'Gene', '4854', (116, 122))	('ESCCs', 'Disease', (77, 82))	('NOTCH', 'Gene', (15, 20))	('NOTCH', 'Gene', '4851;4853;4854', (116, 121))	('NOTCH', 'Gene', (116, 121))	('FBXW7', 'Gene', (127, 132))	('NOTCH1', 'Gene', (108, 114))	('mutated', 'Var', (137, 144))	('NOTCH', 'Gene', '4851;4853;4854', (108, 113))	('NOTCH1', 'Gene', '4851', (108, 114))	('ESCC', 'Disease', (166, 170))	('Alterations', 'Reg', (0, 11))	('NOTCH', 'Gene', '4851;4853;4854', (15, 20))
1808	32759723	Interestingly, NOTCH1 mutations in ESCC are clustered within epidermal growth factor-like repeats 11-12, involved in ligand binding.	('ESCC', 'Gene', (35, 39))	('NOTCH1', 'Gene', '4851', (15, 21))	('mutations', 'Var', (22, 31))	('NOTCH1', 'Gene', (15, 21))
1813	32759723	Two stop-gain mutations (c.985G>T [p.E329*] and c.1057C>T [p.Q353*]) and two frameshift indels (c.790_791insT [p.V264fs*] and c.152delG [p.G51fs*]) in AJUBA gene have been identified.	('c.790_791insT [p.V264fs*]', 'Var', (96, 121))	('c.1057C>T', 'Mutation', 'rs898956652', (48, 57))	('AJUBA', 'Gene', (151, 156))	('p.Q353*', 'Mutation', 'rs898956652', (59, 66))	('c.1057C>T [p.Q353*]', 'Var', (48, 67))	('p.V264fs', 'Mutation', 'p.V264fsX', (111, 119))	('p.E329*', 'Mutation', 'p.E329*', (35, 42))	('c.152delG', 'Var', (126, 135))	('c.985G>T [p.E329*]', 'Var', (25, 43))	('c.985G>T', 'Mutation', 'c.985G>T', (25, 33))	('AJUBA', 'Gene', '84962', (151, 156))	('p.G51fs', 'Mutation', 'p.G51fsX', (137, 144))	('c.790_791insT', 'Mutation', 'c.790_791insT', (96, 109))	('c.152delG', 'Mutation', 'c.152delG', (126, 135))
1814	32759723	These mutations result in protein products that lack the LIM domain, indicating that they are loss-of-function mutations: since mutated AJUBA seems to promote ESCC carcinogenesis, these data suggest that AJUBA has a tumor suppressive role in ESCC.	('tumor', 'Disease', (216, 221))	('ESCC', 'Disease', (242, 246))	('AJUBA', 'Gene', '84962', (136, 141))	('mutated', 'Var', (128, 135))	('AJUBA', 'Gene', (204, 209))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('LIM', 'Gene', (57, 60))	('carcinogenesis', 'Disease', (164, 178))	('promote', 'PosReg', (151, 158))	('AJUBA', 'Gene', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('AJUBA', 'Gene', '84962', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('LIM', 'Gene', '10611', (57, 60))	('mutations', 'Var', (6, 15))	('ESCC', 'Disease', (159, 163))
1816	32759723	Histone-modifying enzymes control chromatin structure and regulate gene expression: mutations of these enzymes play an important role in carcinogenesis.	('mutations', 'Var', (84, 93))	('role', 'Reg', (129, 133))	('carcinogenesis', 'Disease', (137, 151))	('carcinogenesis', 'Disease', 'MESH:D063646', (137, 151))
1819	32759723	Mutations of these genes have been observed in many squamous cell carcinomas, ESCC included.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('ESCC included', 'Disease', (78, 91))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (52, 76))	('Mutations', 'Var', (0, 9))	('squamous cell carcinomas', 'Disease', (52, 76))	('observed', 'Reg', (35, 43))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (52, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))
1821	32759723	Furthermore, CUL3 mutations or deletion have been associated with upregulation of beta-catenin with concordant changes in Wnt-beta catenin downstream factors such as c-MYC, cyclin D1 and p27.	('upregulation', 'PosReg', (66, 78))	('cyclin D1', 'Gene', '595', (173, 182))	('CUL3', 'Gene', '8452', (13, 17))	('c-MYC', 'Gene', (166, 171))	('beta catenin', 'Gene', '1499', (126, 138))	('cyclin D1', 'Gene', (173, 182))	('CUL3', 'Gene', (13, 17))	('beta catenin', 'Gene', (126, 138))	('deletion', 'Var', (31, 39))	('p27', 'Gene', '3429', (187, 190))	('p27', 'Gene', (187, 190))	('c-MYC', 'Gene', '4609', (166, 171))	('beta-catenin', 'Gene', (82, 94))	('changes', 'Reg', (111, 118))	('beta-catenin', 'Gene', '1499', (82, 94))	('mutations', 'Var', (18, 27))
1822	32759723	Mutations in NRF2 signaling pathway have been described in 24% of ESCC, in particular the SMGs NFE2L2 and CUL3 are mutated in 9.6 to 16.7% and 2.9% of cases, respectively.	('NFE2L2', 'Gene', '4780', (95, 101))	('CUL3', 'Gene', '8452', (106, 110))	('CUL3', 'Gene', (106, 110))	('NFE2L2', 'Gene', (95, 101))	('described', 'Reg', (46, 55))	('NRF2', 'Gene', '4780', (13, 17))	('Mutations', 'Var', (0, 9))	('ESCC', 'Disease', (66, 70))	('NRF2', 'Gene', (13, 17))
1826	32759723	Of note, TENM3 mutation has been associated with poorer outcome.	('mutation', 'Var', (15, 23))	('TENM3', 'Gene', (9, 14))	('TENM3', 'Gene', '55714', (9, 14))
1829	32759723	Gene amplification is one of the leading causes of proto-oncogene activations, playing a crucial role in carcinogenesis.	('Gene amplification', 'Var', (0, 18))	('carcinogenesis', 'Disease', (105, 119))	('carcinogenesis', 'Disease', 'MESH:D063646', (105, 119))
1830	32759723	CCND1 (11q13.3) amplification is common in many tumors and has been associated with lymph node metastasis in ESCC and poorer clinical outcome.	('associated with', 'Reg', (68, 83))	('ESCC', 'Disease', (109, 113))	('lymph node metastasis', 'CPA', (84, 105))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('amplification', 'Var', (16, 29))	('CCND1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('CCND1', 'Gene', '595', (0, 5))
1832	32759723	SOX2 (3q26.33) amplification has been found in 15% of ESCC and it has been postulated that its downregulation may inhibit ESCC carcinogenesis and improve the efficacy of chemotherapy.	('SOX2', 'Gene', '6657', (0, 4))	('inhibit', 'NegReg', (114, 121))	('efficacy of chemotherapy', 'CPA', (158, 182))	('amplification', 'Var', (15, 28))	('ESCC', 'Disease', (54, 58))	('ESCC', 'Disease', (122, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('downregulation', 'NegReg', (95, 109))	('carcinogenesis', 'Disease', (127, 141))	('improve', 'PosReg', (146, 153))	('SOX2', 'Gene', (0, 4))
1833	32759723	TP63 gene encodes a squamous transcription factor; amplifications of SOX2 or TP63 were reported in 48% of ESCCs.	('SOX2', 'Gene', (69, 73))	('SOX2', 'Gene', '6657', (69, 73))	('TP63', 'Gene', '8626', (77, 81))	('reported', 'Reg', (87, 95))	('ESCCs', 'Disease', (106, 111))	('TP63', 'Gene', (77, 81))	('amplifications', 'Var', (51, 65))	('TP63', 'Gene', '8626', (0, 4))	('TP63', 'Gene', (0, 4))
1837	32759723	Deletion of FBXW7 (4q31.3) has been described in 6% to 45% of ESCC and seems to be associated with a worse prognosis.	('FBXW7', 'Gene', (12, 17))	('associated', 'Reg', (83, 93))	('described', 'Reg', (36, 45))	('FBXW7', 'Gene', '55294', (12, 17))	('ESCC', 'Disease', (62, 66))	('Deletion', 'Var', (0, 8))
1838	32759723	Deletions of TP53 (17p13.1) have been detected in 55% of ESCCs, correlating with the grade of differentiation and lymph node metastasis.	('TP53', 'Gene', (13, 17))	('detected', 'Reg', (38, 46))	('ESCCs', 'Disease', (57, 62))	('TP53', 'Gene', '7157', (13, 17))	('Deletions', 'Var', (0, 9))
1841	32759723	Increasing evidence suggest that epigenetic alterations plays an important role in the development of many malignancies, including ESCC.	('epigenetic alterations', 'Var', (33, 55))	('men', 'Species', '9606', (94, 97))	('malignancies', 'Disease', 'MESH:D009369', (107, 119))	('role', 'Reg', (75, 79))	('malignancies', 'Disease', (107, 119))	('ESCC', 'Disease', (131, 135))
1845	32759723	The DNA methylation profile of ESCC genome is characterized, similarly to other human malignancies, by a widespread hypomethylation and site-specific CpG island promoter hypermethylation.	('hypomethylation', 'Var', (116, 131))	('malignancies', 'Disease', 'MESH:D009369', (86, 98))	('human', 'Species', '9606', (80, 85))	('malignancies', 'Disease', (86, 98))	('ESCC', 'Gene', (31, 35))
1848	32759723	APC hypermethylation status has controversial clinical relations: it has been described to be associated with a reduced survival time, and with a lower number of nodal metastases and better prognosis.	('metastases', 'Disease', 'MESH:D009362', (168, 178))	('survival time', 'CPA', (120, 133))	('metastases', 'Disease', (168, 178))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('lower', 'NegReg', (146, 151))	('APC', 'Disease', (0, 3))	('reduced', 'NegReg', (112, 119))	('hypermethylation', 'Var', (4, 20))
1849	32759723	Hypermethylation of CDH1, the gene encoding for E-cadherin, is reported in 14% to 61% of ESCCs and has been associated with poor/lower recurrence-free survival in early stage ESCCs.	('Hypermethylation', 'Var', (0, 16))	('poor/lower', 'NegReg', (124, 134))	('age', 'Gene', (171, 174))	('ESCCs', 'Disease', (89, 94))	('CDH1', 'Gene', '999', (20, 24))	('age', 'Gene', '5973', (171, 174))	('E-cadherin', 'Gene', (48, 58))	('E-cadherin', 'Gene', '999', (48, 58))	('CDH1', 'Gene', (20, 24))
1850	32759723	Methylation-induced inactivation of CDKN2A is reported in 19% to 88% of ESCCs and has been associated with metastatic disease.	('CDKN2A', 'Gene', (36, 42))	('inactivation', 'NegReg', (20, 32))	('CDKN2A', 'Gene', '1029', (36, 42))	('Methylation-induced', 'Var', (0, 19))	('ESCCs', 'Disease', (72, 77))	('metastatic disease', 'Disease', (107, 125))	('associated with', 'Reg', (91, 106))
1852	32759723	Hypermethylation of FHIT promoter is reported in 14% to 85% of ESCC and has been associated with aggressive forms and poor prognosis in early ESCC and with exposure to tobacco smoke.	('associated with', 'Reg', (81, 96))	('Hypermethylation', 'Var', (0, 16))	('tobacco', 'Species', '4097', (168, 175))	('FHIT', 'Gene', (20, 24))	('FHIT', 'Gene', '2272', (20, 24))	('ESCC', 'Disease', (63, 67))
1854	32759723	Lu and colleagues suggest that hypermethylation of CCD8 and FBXO17 is significantly associated with a poorer prognosis, while hypermethylation of ABCD1 correlates with a better one.	('hypermethylation', 'Var', (31, 47))	('FBXO17', 'Gene', (60, 66))	('ABCD1', 'Gene', (146, 151))	('associated', 'Reg', (84, 94))	('ABCD1', 'Gene', '215', (146, 151))	('FBXO17', 'Gene', '115290', (60, 66))	('CCD8', 'Gene', (51, 55))	('hypermethylation', 'Var', (126, 142))
1855	32759723	Wang and colleagues, analyzing samples from Chinese Han patients, demonstrated that ADHFE1, EOMES, SALL and TFPI2 are hypermethylated in ESCCs, and hypomethylated in the corresponding non-neoplastic tissues.	('patients', 'Species', '9606', (56, 64))	('EOMES', 'Gene', (92, 97))	('ADHFE1', 'Gene', '137872', (84, 90))	('ESCCs', 'Disease', (137, 142))	('TFPI2', 'Gene', (108, 113))	('TFPI2', 'Gene', '7980', (108, 113))	('ADHFE1', 'Gene', (84, 90))	('hypermethylated', 'Var', (118, 133))	('EOMES', 'Gene', '8320', (92, 97))
1856	32759723	Hypermethylation of TFF1, a mucosal protective factor, seems to be an early event in ESCC development and, intriguingly, could be used as a biomarker for early ESCC detection.	('TFF1', 'Gene', '7031', (20, 24))	('men', 'Species', '9606', (97, 100))	('Hypermethylation', 'Var', (0, 16))	('ESCC', 'Disease', (85, 89))	('TFF1', 'Gene', (20, 24))
1857	32759723	Methylation of IGFBPL1 have also been proposed as an early detection marker and a predictive marker for PI3K-targeted therapy.	('Methylation', 'Var', (0, 11))	('IGFBPL1', 'Gene', '347252', (15, 22))	('IGFBPL1', 'Gene', (15, 22))
1859	32759723	Global hypomethylation status contributes to carcinogenesis in many different malignancies by activating some proto-oncogenes, leading to deletions and translocations, promoting mitotic recombination, chromosomal rearrangements and, in general, resulting in genomic instability.	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	('promoting', 'PosReg', (168, 177))	('chromosomal rearrangements', 'CPA', (201, 227))	('malignancies', 'Disease', (78, 90))	('genomic instability', 'MPA', (258, 277))	('deletions', 'Var', (138, 147))	('activating', 'PosReg', (94, 104))	('men', 'Species', '9606', (222, 225))	('leading to', 'Reg', (127, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('resulting in', 'Reg', (245, 257))	('carcinogenesis', 'Disease', (45, 59))	('mitotic recombination', 'CPA', (178, 199))	('translocations', 'CPA', (152, 166))
1861	32759723	LINE-1 hypomethylation in ESCC has been associated with lymph node metastasis, lymphovascular invasion, increased frequency of TP53 mutations, higher CDK6 protein expression levels and a shorter overall survival.	('overall', 'MPA', (195, 202))	('lymph node metastasis', 'CPA', (56, 77))	('hypomethylation', 'Var', (7, 22))	('increased', 'PosReg', (104, 113))	('mutations', 'Var', (132, 141))	('CDK6', 'Gene', (150, 154))	('CDK6', 'Gene', '1021', (150, 154))	('ESCC', 'Gene', (26, 30))	('higher', 'PosReg', (143, 149))	('shorter', 'NegReg', (187, 194))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('associated', 'Reg', (40, 50))	('lymphovascular invasion', 'CPA', (79, 102))
1863	32759723	Alterations in miRNA expression are involved in different malignancies, affecting cellular processes of proliferation, motility, invasion and apoptosis.	('cellular processes', 'CPA', (82, 100))	('Alterations', 'Var', (0, 11))	('invasion', 'CPA', (129, 137))	('malignancies', 'Disease', 'MESH:D009369', (58, 70))	('miRNA', 'Gene', (15, 20))	('motility', 'CPA', (119, 127))	('affecting', 'Reg', (72, 81))	('apoptosis', 'CPA', (142, 151))	('malignancies', 'Disease', (58, 70))	('involved', 'Reg', (36, 44))
1865	32759723	Overexpression of miR-200c, miR-96, miR-141 and miR-27 has been associated with resistance to platinum-based chemotherapy while combined downregulation of miR-133a and miR-133b increase the sensitivity to paclitaxel-based chemotherapy.	('associated', 'Reg', (64, 74))	('miR-200c', 'Gene', '406985', (18, 26))	('resistance to platinum-based chemotherapy', 'MPA', (80, 121))	('miR-96', 'Gene', (28, 34))	('miR-133b', 'Gene', '442890', (168, 176))	('miR-133b', 'Gene', (168, 176))	('miR-141', 'Gene', (36, 43))	('platinum', 'Chemical', 'MESH:D010984', (94, 102))	('downregulation', 'NegReg', (137, 151))	('increase', 'PosReg', (177, 185))	('paclitaxel', 'Chemical', 'MESH:D017239', (205, 215))	('miR-141', 'Gene', '406933', (36, 43))	('miR-27', 'Gene', '407018', (48, 54))	('miR-27', 'Gene', (48, 54))	('miR-96', 'Gene', '407053', (28, 34))	('miR-133a', 'Var', (155, 163))	('sensitivity to paclitaxel-based chemotherapy', 'MPA', (190, 234))	('miR-200c', 'Gene', (18, 26))
1873	32759723	Despite TP53 and CDKN2A are frequently mutated as in ESCC, ARID1A, SMAD4 and ERBB2 mutations occur preeminently in EAC.	('mutations', 'Var', (83, 92))	('ESCC', 'Disease', (53, 57))	('ERBB2', 'Gene', '2064', (77, 82))	('SMAD4', 'Gene', (67, 72))	('ERBB2', 'Gene', (77, 82))	('ARID1A', 'Gene', '8289', (59, 65))	('CDKN2A', 'Gene', (17, 23))	('ARID1A', 'Gene', (59, 65))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('SMAD4', 'Gene', '4089', (67, 72))	('CDKN2A', 'Gene', '1029', (17, 23))
1874	32759723	Moreover, inactivating mutations of NOTCH1 have been described in ESCC, but not in EAC.	('inactivating mutations', 'Var', (10, 32))	('NOTCH1', 'Gene', '4851', (36, 42))	('NOTCH1', 'Gene', (36, 42))	('ESCC', 'Disease', (66, 70))	('described', 'Reg', (53, 62))
1876	32759723	Amplifications of VEGFA (6p21.1), ERBB2 (17p12), GATA6 (18q11.2) and CCNE1 (19q12) are significantly more frequent in EAC than in ESCC.	('VEGFA', 'Gene', (18, 23))	('EAC', 'Disease', (118, 121))	('19q12', 'Var', (76, 81))	('ERBB2', 'Gene', (34, 39))	('ERBB2', 'Gene', '2064', (34, 39))	('frequent', 'Reg', (106, 114))	('VEGFA', 'Gene', '7422', (18, 23))	('CCNE1', 'Gene', (69, 74))	('Amplifications', 'Var', (0, 14))	('CCNE1', 'Gene', '898', (69, 74))	('18q11.2', 'Var', (56, 63))	('GATA6', 'Gene', '2627', (49, 54))	('17p12', 'Var', (41, 46))	('GATA6', 'Gene', (49, 54))
1877	32759723	On the other hand, amplifications of FGF3, FGF4, FGF19, and CCND1 (colocalized on 11q13) and FGFR1 (8p11.23) have been more frequently described in EAC.	('FGF4', 'Gene', (43, 47))	('EAC', 'Disease', (148, 151))	('FGF3', 'Gene', (37, 41))	('described', 'Reg', (135, 144))	('FGF19', 'Gene', '9965', (49, 54))	('FGF4', 'Gene', '2249', (43, 47))	('CCND1', 'Gene', (60, 65))	('FGF19', 'Gene', (49, 54))	('FGFR1', 'Gene', (93, 98))	('FGF3', 'Gene', '2248', (37, 41))	('CCND1', 'Gene', '595', (60, 65))	('amplifications', 'Var', (19, 33))	('FGFR1', 'Gene', '2260', (93, 98))
1878	32759723	Finally, deletion of SMAD4 (18q21.2) is recurrent in EAC, but not in ESCC.	('SMAD4', 'Gene', (21, 26))	('EAC', 'Disease', (53, 56))	('SMAD4', 'Gene', '4089', (21, 26))	('deletion', 'Var', (9, 17))
1893	32759723	The TP53-mutated VEC harbored a heterozygous point mutation in position c.738G >A of exon 7 of TP53, resulting in the mutant variant p.M246I of p53.	('p.M246I', 'Mutation', 'rs1019340046', (133, 140))	('p53', 'Gene', '7157', (144, 147))	('TP53', 'Gene', (4, 8))	('p.M246I', 'Var', (133, 140))	('EC', 'Disease', 'MESH:D005955', (18, 20))	('TP53', 'Gene', (95, 99))	('c.738G >A', 'Mutation', 'rs1019340046', (72, 81))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', '7157', (95, 99))	('p53', 'Gene', (144, 147))
1894	32759723	These data suggest that TP53 missense point mutations, EGFR overexpression and E-cadherin downregulation may have a role in VEC progression and metastasis.	('EGFR', 'Gene', '1956', (55, 59))	('missense point mutations', 'Var', (29, 53))	('TP53', 'Gene', (24, 28))	('EGFR', 'Gene', (55, 59))	('overexpression', 'PosReg', (60, 74))	('EC', 'Disease', 'MESH:D005955', (125, 127))	('E-cadherin', 'Gene', (79, 89))	('metastasis', 'CPA', (144, 154))	('E-cadherin', 'Gene', '999', (79, 89))	('downregulation', 'NegReg', (90, 104))	('TP53', 'Gene', '7157', (24, 28))
1900	32759723	Mutually exclusive EGFR mutations or amplifications have been reported.	('mutations', 'Var', (24, 33))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))
1901	32759723	Furthermore, activation of Wnt signaling pathway is common and unrelated to mutations in CTNNB1; mutations in APC, AXIN1 or AXIN2 genes and by hypermethylation of the SRFP2 gene promoter seem to be involved in this process.	('mutations', 'Var', (97, 106))	('SRFP2', 'Gene', (167, 172))	('CTNNB1', 'Gene', (89, 95))	('AXIN1', 'Gene', '8312', (115, 120))	('AXIN1', 'Gene', (115, 120))	('Wnt signaling pathway', 'Pathway', (27, 48))	('activation', 'PosReg', (13, 23))	('AXIN2', 'Gene', (124, 129))	('APC', 'Disease', 'MESH:D011125', (110, 113))	('AXIN2', 'Gene', '8313', (124, 129))	('hypermethylation', 'Var', (143, 159))	('CTNNB1', 'Gene', '1499', (89, 95))	('APC', 'Disease', (110, 113))
1902	32759723	Finally, mutations in PTCH1 have been reported in nearly 53% of basaloid ESCC.	('PTCH1', 'Gene', (22, 27))	('reported', 'Reg', (38, 46))	('mutations', 'Var', (9, 18))	('PTCH1', 'Gene', '5727', (22, 27))	('basaloid ESCC', 'Disease', (64, 77))
1903	32759723	Alterations of PTCH1 lead to constitutive activation of the hedgehog signaling pathway and germinal mutation of PTCH1 are linked to Gorlin syndrome (i.e., nevoid basal cell carcinoma syndrome).	('Gorlin syndrome', 'Disease', (132, 147))	('PTCH1', 'Gene', (112, 117))	('basal cell carcinoma syndrome', 'Disease', 'MESH:D002280', (162, 191))	('Alterations', 'Var', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('PTCH1', 'Gene', '5727', (15, 20))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (162, 182))	('PTCH1', 'Gene', '5727', (112, 117))	('activation', 'PosReg', (42, 52))	('linked', 'Reg', (122, 128))	('basal cell carcinoma syndrome', 'Disease', (162, 191))	('PTCH1', 'Gene', (15, 20))	('hedgehog signaling pathway', 'Pathway', (60, 86))
1913	32759723	Specifically, HPV-negative HNSCC are characterized by deletions of CDKN2A, FAT1, NOTCH1, SMAD4 and amplification of EGFR, ERBB2, CCND1 and FGFR1.	('HNSCC', 'Disease', (27, 32))	('CDKN2A', 'Gene', (67, 73))	('HPV', 'Species', '10566', (14, 17))	('ERBB2', 'Gene', '2064', (122, 127))	('CCND1', 'Gene', (129, 134))	('NOTCH1', 'Gene', '4851', (81, 87))	('FGFR1', 'Gene', '2260', (139, 144))	('SMAD4', 'Gene', '4089', (89, 94))	('CDKN2A', 'Gene', '1029', (67, 73))	('amplification', 'Var', (99, 112))	('FAT1', 'Gene', (75, 79))	('EGFR', 'Gene', '1956', (116, 120))	('deletions', 'Var', (54, 63))	('FGFR1', 'Gene', (139, 144))	('ERBB2', 'Gene', (122, 127))	('NOTCH1', 'Gene', (81, 87))	('SMAD4', 'Gene', (89, 94))	('FAT1', 'Gene', '2195', (75, 79))	('CCND1', 'Gene', '595', (129, 134))	('EGFR', 'Gene', (116, 120))
1915	32759723	Amplification of 3q 26-28 have been described in both HPV positive and negative HNSCCs.	('Amplification', 'Var', (0, 13))	('HNSCCs', 'Disease', (80, 86))	('3q 26-28', 'Gene', (17, 25))	('HPV', 'Species', '10566', (54, 57))	('HNSCCs', 'Disease', 'MESH:D000077195', (80, 86))
1917	32759723	HPV-positive HNSCCs have been associated with amplifications of TRAF3 and E2F1, but those genes do not seem to have a role in ESCC carcinogenesis.	('amplifications', 'Var', (46, 60))	('carcinogenesis', 'Disease', (131, 145))	('associated', 'Reg', (30, 40))	('TRAF3', 'Gene', '7187', (64, 69))	('HPV', 'Species', '10566', (0, 3))	('HNSCCs', 'Disease', 'MESH:D000077195', (13, 19))	('E2F1', 'Gene', '1869', (74, 78))	('E2F1', 'Gene', (74, 78))	('TRAF3', 'Gene', (64, 69))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('ESCC', 'Disease', (126, 130))	('HNSCCs', 'Disease', (13, 19))
1918	32759723	Structural alterations of TP53 and RB1 have also been described in HNSCC.	('TP53', 'Gene', (26, 30))	('RB1', 'Gene', (35, 38))	('RB1', 'Gene', '5925', (35, 38))	('described', 'Reg', (54, 63))	('HNSCC', 'Disease', (67, 72))	('TP53', 'Gene', '7157', (26, 30))	('Structural alterations', 'Var', (0, 22))
1920	32759723	Mutations of TP53 have been described in more than 80% of HPV-negative HNSCCs and they seem to be early events in HNSCC carcinogenesis.	('TP53', 'Gene', (13, 17))	('HNSCCs', 'Disease', 'MESH:D000077195', (71, 77))	('HNSCCs', 'Disease', (71, 77))	('Mutations', 'Var', (0, 9))	('HNSCC carcinogenesis', 'Disease', (114, 134))	('HNSCC carcinogenesis', 'Disease', 'MESH:D000077195', (114, 134))	('TP53', 'Gene', '7157', (13, 17))	('HPV', 'Species', '10566', (58, 61))	('described', 'Reg', (28, 37))
1923	32759723	Mutations of RB1 have been described in 3% of HNSCC and seem to be early events in HNSCC development and similar data have been found in ESCC (vide supra).	('men', 'Species', '9606', (96, 99))	('HNSCC', 'Disease', (83, 88))	('RB1', 'Gene', '5925', (13, 16))	('HNSCC', 'Disease', (46, 51))	('described', 'Reg', (27, 36))	('ESCC', 'Disease', (137, 141))	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', (13, 16))
1924	32759723	Mutations of CDKN2A (22% of HNSCCs), FAT1 (23%) and AJUBA (6%) have been described predominantly in HPV-negative HNSCC.	('AJUBA', 'Gene', (52, 57))	('HPV', 'Species', '10566', (100, 103))	('FAT1', 'Gene', '2195', (37, 41))	('CDKN2A', 'Gene', (13, 19))	('HNSCCs', 'Disease', 'MESH:D000077195', (28, 34))	('Mutations', 'Var', (0, 9))	('FAT1', 'Gene', (37, 41))	('AJUBA', 'Gene', '84962', (52, 57))	('CDKN2A', 'Gene', '1029', (13, 19))	('HNSCC', 'Disease', (113, 118))	('HNSCCs', 'Disease', (28, 34))
1925	32759723	Inactivating mutations of NOTCH1-3 have been described in 17% of HPV-positive and 26% of HPV-negative HNSCC.	('described', 'Reg', (45, 54))	('NOTCH1-3', 'Gene', '4851;4853;4854', (26, 34))	('HPV', 'Species', '10566', (65, 68))	('Inactivating mutations', 'Var', (0, 22))	('HPV-positive', 'Disease', (65, 77))	('HNSCC', 'Disease', (102, 107))	('HPV', 'Species', '10566', (89, 92))	('NOTCH1-3', 'Gene', (26, 34))
1927	32759723	Mutations of PIK3CA have been reported in nearly 16% of HNSCCs.	('reported', 'Reg', (30, 38))	('HNSCCs', 'Disease', (56, 62))	('PIK3CA', 'Gene', (13, 19))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('HNSCCs', 'Disease', 'MESH:D000077195', (56, 62))
1928	32759723	Finally, MLL2, ZNF750, TGFBR2 and FBXW7 mutations have also been described in HNSCC, but their clinical impact is unclear.	('FBXW7', 'Gene', '55294', (34, 39))	('described', 'Reg', (65, 74))	('MLL2', 'Gene', (9, 13))	('TGFBR2', 'Gene', '7048', (23, 29))	('ZNF750', 'Gene', '79755', (15, 21))	('FBXW7', 'Gene', (34, 39))	('mutations', 'Var', (40, 49))	('HNSCC', 'Disease', (78, 83))	('MLL2', 'Gene', '8085', (9, 13))	('ZNF750', 'Gene', (15, 21))	('TGFBR2', 'Gene', (23, 29))
1929	32759723	CDKN2A hypermethylation has been identified in HNSCC.	('hypermethylation', 'Var', (7, 23))	('HNSCC', 'Disease', (47, 52))	('identified', 'Reg', (33, 43))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))
1936	32759723	Future studies are warranted to study the introduction of immune checkpoints inhibitors in high molecular mutational load ESCCs and the introduction of new molecular targeted therapies, as EGFR inhibitors and mTOR pathway modulators.	('EGFR', 'Gene', '1956', (189, 193))	('EGFR', 'Gene', (189, 193))	('mTOR', 'Gene', (209, 213))	('mTOR', 'Gene', '2475', (209, 213))	('mutational', 'Var', (106, 116))
1944	30854039	By inducing point mutations of the assumed degradation motif of OLC1, it was revealed that an intact destruction (D)-box was necessary.	('OLC1', 'Gene', (64, 68))	('inducing', 'Reg', (3, 11))	('OLC1', 'Gene', '9798', (64, 68))	('point mutations', 'Var', (12, 27))
1945	30854039	As expected, the D-box-mutated OLC1 exhibited a higher capacity for promoting cell growth and clone formation.	('OLC1', 'Gene', (31, 35))	('clone formation', 'CPA', (94, 109))	('D-box-mutated', 'Var', (17, 30))	('cell growth', 'CPA', (78, 89))	('higher', 'PosReg', (48, 54))	('promoting', 'PosReg', (68, 77))	('OLC1', 'Gene', '9798', (31, 35))
1962	30854039	Mutations of the D-box motif enhanced OLC1 protein stability and induced an increase in cell growth and colony formation.	('OLC1', 'Gene', (38, 42))	('increase', 'PosReg', (76, 84))	('cell growth', 'CPA', (88, 99))	('Mutations', 'Var', (0, 9))	('colony formation', 'CPA', (104, 120))	('enhanced', 'PosReg', (29, 37))	('OLC1', 'Gene', '9798', (38, 42))
2013	30854039	The addition of different concentrations of MG132 resulted in an increase in OLC1 expression compared with cells treated only with CHX.	('MG132', 'Var', (44, 49))	('increase', 'PosReg', (65, 73))	('expression', 'Species', '29278', (82, 92))	('CHX', 'Chemical', 'MESH:D003513', (131, 134))	('expression', 'MPA', (82, 92))	('OLC1', 'Gene', '9798', (77, 81))	('OLC1', 'Gene', (77, 81))	('MG132', 'Chemical', 'MESH:C072553', (44, 49))
2014	30854039	Similarly, with increasing MG132 treatment times, OLC1 protein expression levels were increased accordingly (Fig.	('increased', 'PosReg', (86, 95))	('MG132', 'Chemical', 'MESH:C072553', (27, 32))	('expression', 'Species', '29278', (63, 73))	('OLC1', 'Gene', '9798', (50, 54))	('MG132', 'Var', (27, 32))	('OLC1', 'Gene', (50, 54))
2017	30854039	Ubiquitin was detected in the OLC1 immuno complex, and as expected, the amount present was increased following the addition of MG132 (Fig.	('MG132', 'Var', (127, 132))	('MG132', 'Chemical', 'MESH:C072553', (127, 132))	('amount', 'MPA', (72, 78))	('Ubiquitin', 'MPA', (0, 9))	('increased', 'PosReg', (91, 100))	('OLC1', 'Gene', '9798', (30, 34))	('OLC1', 'Gene', (30, 34))
2035	30854039	H1299 cells were co-transfected with D-box-mutated GFP-OLC1 (GFP-mut-OLC1) and different concentrations of Cdh1 or Cdc20 expression vectors.	('GFP-OLC1', 'Gene', (51, 59))	('OLC1', 'Gene', (55, 59))	('OLC1', 'Gene', (69, 73))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))	('GFP-OLC1', 'Gene', '9798', (51, 59))	('Cdh1', 'Gene', (107, 111))	('Cdh1', 'Gene', '999', (107, 111))	('OLC1', 'Gene', '9798', (55, 59))	('expression vectors', 'Species', '29278', (121, 139))	('OLC1', 'Gene', '9798', (69, 73))	('D-box-mutated', 'Var', (37, 50))
2039	30854039	Thus, additional experiments were performed to confirm if the cells with mutated OLC1 may exhibit more malignant characteristics.	('OLC1', 'Gene', '9798', (81, 85))	('mutated', 'Var', (73, 80))	('malignant characteristics', 'CPA', (103, 128))	('OLC1', 'Gene', (81, 85))
2040	30854039	First, a cell growth assay was performed; the growth curve revealed that H1299 cells expressing OLC1 with a mutated D-box grew significantly faster compared with those expressing wild-type OLC1 (Fig.	('OLC1', 'Gene', (96, 100))	('mutated', 'Var', (108, 115))	('OLC1', 'Gene', (189, 193))	('faster', 'PosReg', (141, 147))	('H1299', 'CellLine', 'CVCL:0060', (73, 78))	('grew', 'CPA', (122, 126))	('OLC1', 'Gene', '9798', (96, 100))	('OLC1', 'Gene', '9798', (189, 193))
2041	30854039	This indicated that the D-box mutated OLC1 exhibited a greater capacity to facilitate cell growth.	('cell growth', 'CPA', (86, 97))	('OLC1', 'Gene', (38, 42))	('D-box mutated', 'Var', (24, 37))	('mutated', 'Var', (30, 37))	('facilitate', 'PosReg', (75, 85))	('OLC1', 'Gene', '9798', (38, 42))
2042	30854039	Colony formation assays were also conducted; the cells expressing mutant OLC1 developed a significantly higher number of colonies compared with the control cells (Fig.	('OLC1', 'Gene', '9798', (73, 77))	('higher', 'PosReg', (104, 110))	('OLC1', 'Gene', (73, 77))	('mutant', 'Var', (66, 72))
2043	30854039	These results indicated that the mutated D-box motif was not recognized by APC/c E3 ligase, affecting the subsequent degradation of the OLC1 protein.	('APC/c', 'Gene', (75, 80))	('mutated', 'Var', (33, 40))	('OLC1', 'Gene', (136, 140))	('OLC1', 'Gene', '9798', (136, 140))	('APC/c', 'Gene', '324', (75, 80))	('affecting', 'Reg', (92, 101))
2046	30854039	When it was first identified in non-lethal yeast mutants in 1999, it was named the IST1 gene.	('IST1', 'Gene', '9798', (83, 87))	('IST1', 'Gene', (83, 87))	('yeast', 'Species', '4932', (43, 48))	('mutants', 'Var', (49, 56))
2049	30854039	In humans, a previous study identified that OLC1 was essential for cytokinesis, another membrane scission event that is topologically similar to MVB formation, and that the depletion of OLC1 resulted in the accumulation of multinucleated cells.	('depletion', 'Var', (173, 182))	('multinucleated cells', 'CPA', (223, 243))	('OLC1', 'Gene', (186, 190))	('OLC1', 'Gene', '9798', (186, 190))	('cytokinesis', 'CPA', (67, 78))	('OLC1', 'Gene', (44, 48))	('OLC1', 'Gene', '9798', (44, 48))	('humans', 'Species', '9606', (3, 9))	('accumulation', 'PosReg', (207, 219))
2050	30854039	Therefore, abnormal cytokinesis will result in the uneven distribution of the chromosomes in the cell, inducing cell genome instability and potentially leading to the development of a tumor.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('leading to', 'Reg', (152, 162))	('abnormal', 'Var', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('result in', 'Reg', (37, 46))	('inducing', 'Reg', (103, 111))	('tumor', 'Disease', (184, 189))	('cell genome instability', 'CPA', (112, 135))
2052	30854039	It was identified that the over expression of OLC1 was associated with smoking history in patients with lung cancer, and that this overexpression induced tumor formation in athymic mice, whereas the knockdown of OLC1 increased apoptosis and decreased colony formation.	('mice', 'Species', '10090', (181, 185))	('decreased', 'NegReg', (241, 250))	('OLC1', 'Gene', (46, 50))	('OLC1', 'Gene', (212, 216))	('colony formation', 'CPA', (251, 267))	('tumor', 'Disease', (154, 159))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('associated', 'Reg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('apoptosis', 'CPA', (227, 236))	('increased', 'PosReg', (217, 226))	('over expression', 'PosReg', (27, 42))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('knockdown', 'Var', (199, 208))	('patients', 'Species', '9606', (90, 98))	('OLC1', 'Gene', '9798', (46, 50))	('expression', 'Species', '29278', (135, 145))	('lung cancer', 'Disease', (104, 115))	('expression', 'Species', '29278', (32, 42))	('OLC1', 'Gene', '9798', (212, 216))	('smoking', 'Disease', (71, 78))	('induced', 'Reg', (146, 153))
2055	30854039	Furthermore, high expression levels of OLC1 are associated with a poor prognosis in a number of these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('expression levels', 'MPA', (18, 35))	('high', 'Var', (13, 17))	('associated', 'Reg', (48, 58))	('expression', 'Species', '29278', (18, 28))	('OLC1', 'Gene', (39, 43))	('cancer', 'Disease', (102, 108))	('OLC1', 'Gene', '9798', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
2067	30854039	A previous study revealed that a cancer-associated Akt mutation within the Akt PH domain (E17K) was identified in a range of human cancer types, including colon and breast cancer.	('cancer', 'Disease', (33, 39))	('E17K', 'Mutation', 'rs121434592', (90, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('Akt', 'Gene', (75, 78))	('Akt', 'Gene', (51, 54))	('Akt', 'Gene', '207', (75, 78))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('human', 'Species', '9606', (125, 130))	('Akt', 'Gene', '207', (51, 54))	('mutation', 'Var', (55, 63))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('identified', 'Reg', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('colon and breast cancer', 'Disease', 'MESH:D001943', (155, 178))
2068	30854039	Akt E17K mutants displayed enhanced Akt ubiquitination, contributing to Akt hyperactivation and constitutive Akt membrane recruitment, suggesting a potential role for Akt ubiquitination in cancer.	('Akt', 'Gene', '207', (109, 112))	('Akt', 'Gene', (72, 75))	('enhanced', 'PosReg', (27, 35))	('Akt', 'Gene', '207', (36, 39))	('E17K', 'Var', (4, 8))	('Akt', 'Gene', '207', (167, 170))	('Akt', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('E17K', 'Mutation', 'rs121434592', (4, 8))	('Akt', 'Gene', '207', (0, 3))	('Akt', 'Gene', (109, 112))	('Akt', 'Gene', (0, 3))	('hyperactivation', 'Disease', (76, 91))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('hyperactivation', 'Disease', 'MESH:D011504', (76, 91))	('Akt', 'Gene', (167, 170))	('Akt', 'Gene', '207', (72, 75))	('cancer', 'Disease', (189, 195))
2071	30854039	In the present study, it was demonstrated that the expression of OLC1 was elevated following treatment with MG132, a proteasome inhibitor.	('OLC1', 'Gene', '9798', (65, 69))	('elevated', 'PosReg', (74, 82))	('expression', 'Species', '29278', (51, 61))	('MG132', 'Chemical', 'MESH:C072553', (108, 113))	('MG132', 'Var', (108, 113))	('expression', 'MPA', (51, 61))	('OLC1', 'Gene', (65, 69))
2084	30854039	Furthermore, mutations to the OLC1 D-box significantly reduced OLC1 degradation.	('OLC1', 'Gene', (63, 67))	('reduced', 'NegReg', (55, 62))	('OLC1', 'Gene', '9798', (63, 67))	('OLC1', 'Gene', '9798', (30, 34))	('mutations', 'Var', (13, 22))	('OLC1', 'Gene', (30, 34))
2088	30854039	These findings reveal that the destruction of the degradation domain results in the abnormal accumulation of the OLC1 mutant, which could not be degraded through the APC/c-mediated ubiquitin-proteasome pathway.	('APC/c', 'Gene', '324', (166, 171))	('OLC1', 'Gene', (113, 117))	('accumulation', 'PosReg', (93, 105))	('OLC1', 'Gene', '9798', (113, 117))	('mutant', 'Var', (118, 124))	('APC/c', 'Gene', (166, 171))
2105	30561117	Patients diagnosed with primary ESCC (SEER cancer site code: 27.0; SEER histology codes: 8052, 8070 to 8078, 8053, 8083, and 8084) in American Joint Committee on Cancer (AJCC) stages II to III were included in our study.	('8070 to 8078', 'Var', (95, 107))	('primary ESCC', 'Disease', (24, 36))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('8053', 'Var', (109, 113))	('Cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (43, 49))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Cancer', 'Disease', (162, 168))
2213	30697615	In the current study, poor PS was an independent factor associated with anastomotic stenosis.	('poor PS', 'Var', (22, 29))	('anastomotic stenosis', 'Disease', (72, 92))	('anastomotic stenosis', 'Disease', 'MESH:D057868', (72, 92))
2214	30697615	Results showed that poor PS tended to be associated with the presence of cardiovascular disease (P = 0.097).	('associated', 'Reg', (41, 51))	('cardiovascular disease', 'Disease', (73, 95))	('poor PS', 'Var', (20, 27))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (73, 95))	('cardiovascular disease', 'Disease', 'MESH:D002318', (73, 95))
2244	26426993	Multivariate Cox analysis adjusted for significant factors indicated that LODDS was independent risk factor on overall survival (OS), and a higher LODDS was associated with worse OS (hazard ratio = 3.297, 95% confidence interval: 2.684-4.050, p < 0.001).	('Cox', 'Gene', (13, 16))	('overall survival', 'MPA', (111, 127))	('LODDS', 'Chemical', '-', (74, 79))	('LODDS', 'Chemical', '-', (147, 152))	('LODDS', 'Var', (74, 79))	('Cox', 'Gene', '1351', (13, 16))
2337	26114883	Among the tumor types, PD-L1 was associated with worse 3 year-OS of esophageal cancer, gastric cancer, hepatocellular carcinoma, and urothelial cancer, and 5 year-OS of esophageal cancer, gastric cancer and colorectal cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (188, 202))	('colorectal cancer', 'Disease', 'MESH:D015179', (207, 224))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('OS of esophageal cancer', 'Disease', (62, 85))	('OS of esophageal cancer', 'Disease', 'MESH:C567932', (62, 85))	('colorectal cancer', 'Disease', (207, 224))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PD-L1', 'Var', (23, 28))	('tumor', 'Disease', (10, 15))	('hepatocellular carcinoma', 'Disease', (103, 127))	('gastric cancer', 'Disease', (188, 202))	('OS of esophageal cancer', 'Disease', (163, 186))	('OS of esophageal cancer', 'Disease', 'MESH:C567932', (163, 186))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('gastric cancer', 'Disease', 'MESH:D013274', (188, 202))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('urothelial cancer', 'Disease', 'MESH:D014523', (133, 150))	('gastric cancer', 'Disease', (87, 101))	('urothelial cancer', 'Disease', (133, 150))
2338	26114883	These results suggest that expression of PD-L1 is associated with worse survival in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('worse', 'NegReg', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('expression', 'Var', (27, 37))	('associated', 'Reg', (50, 60))	('PD-L1', 'Gene', (41, 46))	('solid tumors', 'Disease', (84, 96))
2343	26114883	The abnormal expression of these ligands has been linked with prognosis and treatment response of multiple malignancies.	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('multiple malignancies', 'Disease', 'MESH:D009369', (98, 119))	('linked', 'Reg', (50, 56))	('multiple malignancies', 'Disease', (98, 119))
2348	26114883	Another two studies showed that across multiple cancer types, responses were observed in patients with tumors expressing high levels of PD-L1, especially when PD-L1 expressed on tumor-infiltrating immune cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (178, 183))	('multiple cancer', 'Disease', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumors', 'Disease', (103, 109))	('PD-L1', 'Var', (136, 141))	('multiple cancer', 'Disease', 'MESH:D009369', (39, 54))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
2375	26114883	A decade ago some studies reported that blockade of PD-L1 could improve antitumor immunity.	('blockade', 'Var', (40, 48))	('improve', 'PosReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PD-L1', 'Gene', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
2381	26114883	Among the tumor types evaluated, esophageal cancer was the tumor type most linked with worse 3-year and 5-year outcome for patients with high levels of PD-L1.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Disease', (10, 15))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('esophageal cancer', 'Disease', (33, 50))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('PD-L1', 'Gene', (152, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('high levels', 'Var', (137, 148))
2385	26114883	A recent study reported that epithelial-originated cancer patients with positive expression of PD-L1 on tumor tissues were associated with significantly poorer OS when compared to those with negative expression of PD-L1.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PD-L1', 'Gene', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('poorer', 'NegReg', (153, 159))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (51, 57))	('positive expression', 'Var', (72, 91))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
2477	25038797	Levels of ANXA1 expression was increased in AGS and N87 cells induced ANXA1/pcDNA3.1 transfection (Figure 5A, B).	('ANXA1', 'Gene', (10, 15))	('ANXA1/pcDNA3.1', 'Gene', (70, 84))	('AGS', 'Gene', '182', (44, 47))	('transfection', 'Var', (85, 97))	('N87', 'CellLine', 'CVCL:1603', (52, 55))	('expression', 'Species', '29278', (16, 26))	('AGS', 'Gene', (44, 47))	('expression', 'MPA', (16, 26))
2480	25038797	However, silencing of ANXA1 by ANXA1-shRNA promoted cell viability in N87 cells (Figure 6A).	('promoted', 'PosReg', (43, 51))	('silencing', 'Var', (9, 18))	('cell viability', 'CPA', (52, 66))	('N87', 'CellLine', 'CVCL:1603', (70, 73))	('ANXA1', 'Gene', (22, 27))
2482	25038797	Western blotting analysis revealed that silencing of ANXA1 leaded to up-regulation of COX-2 (Figure 6B), while forced expression of ANXA1 decreased COX-2 production (Figure 6C).	('up-regulation', 'PosReg', (69, 82))	('decreased', 'NegReg', (138, 147))	('COX-2', 'Enzyme', (86, 91))	('COX-2 production', 'MPA', (148, 164))	('ANXA1', 'Gene', (53, 58))	('expression', 'Species', '29278', (118, 128))	('silencing', 'Var', (40, 49))
2514	25038797	In line with our previous study, loss of ANXA1 is a frequent event in gastric carcinogenesis.	('ANXA1', 'Gene', (41, 46))	('gastric carcinogenesis', 'Disease', (70, 92))	('loss', 'Var', (33, 37))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (70, 92))
2523	25038797	Notably, knockdown ANXA1 expression with ANXA1-specific shRNA leads to an increase of COX-2 expression, suggesting ANXA1 mediating many diverse cellular functions, such as inflammation and proliferation.	('inflammation', 'Disease', 'MESH:D007249', (172, 184))	('expression', 'Species', '29278', (25, 35))	('knockdown', 'Var', (9, 18))	('inflammation', 'Disease', (172, 184))	('proliferation', 'CPA', (189, 202))	('expression', 'MPA', (92, 102))	('increase', 'PosReg', (74, 82))	('ANXA1', 'Gene', (19, 24))	('expression', 'Species', '29278', (92, 102))	('COX-2', 'Protein', (86, 91))
2525	25038797	This notion is supported by a previous study showing that IL-1beta increased the expression of COX-2 and concomittantly decreased the expression of lipocortin 1 (ANXA1) on the surface of A549 cells.	('decreased', 'NegReg', (120, 129))	('expression', 'MPA', (134, 144))	('IL-1beta', 'Var', (58, 66))	('A549', 'CellLine', 'CVCL:0023', (187, 191))	('lipocortin 1', 'Gene', (148, 160))	('COX-2', 'Gene', (95, 100))	('increased', 'PosReg', (67, 76))	('expression', 'Species', '29278', (81, 91))	('expression', 'MPA', (81, 91))	('expression', 'Species', '29278', (134, 144))
2601	21845152	Human DNA adducts, as biomarkers of exposure, internal dose and biologically effective dose, are capable of initiating mutagenesis in critical genes, ultimately leading to a loss of growth control followed by tumor development.	('Human', 'Species', '9606', (0, 5))	('tumor', 'Disease', (209, 214))	('initiating', 'Reg', (108, 118))	('men', 'Species', '9606', (222, 225))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('mutagenesis', 'Var', (119, 130))	('growth control', 'CPA', (182, 196))	('loss', 'NegReg', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
2627	21845152	Using samples from the Navy Colon Adenoma study we found a 3-fold increased risk of colorectal adenoma in the quartile of individuals with the highest leukocyte PAH-DNA adducts, compared to the quartile with the lowest PAH-DNA adducts.	('PAH', 'Chemical', 'MESH:D011084', (161, 164))	('PAH', 'Chemical', 'MESH:D011084', (219, 222))	('Colon Adenoma', 'Disease', (28, 41))	('colorectal adenoma', 'Disease', (84, 102))	('Colon Adenoma', 'Disease', 'MESH:D000236', (28, 41))	('adducts', 'Var', (169, 176))	('colorectal adenoma', 'Disease', 'MESH:D015179', (84, 102))
2628	21845152	These were, coincidentally, the same individuals who consistently ingested the largest quantities of heavily-cooked beef, suggesting a causal association between ingestion of well-cooked beef, PAH-DNA adduct formation and adenoma risk.	('PAH', 'Chemical', 'MESH:D011084', (193, 196))	('adenoma', 'Disease', (222, 229))	('adenoma', 'Disease', 'MESH:D000236', (222, 229))	('adduct', 'Var', (201, 207))
2668	21845152	The particular susceptibility of the PZ to form tumors may result from the influence of PAH-DNA damage as well as other types of DNA damage and additional factors such as increased cell proliferation, inflammatory stimulation and epigenetic alterations.	('cell proliferation', 'CPA', (181, 199))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('epigenetic alterations', 'Var', (230, 252))	('PAH', 'Chemical', 'MESH:D011084', (88, 91))	('increased', 'PosReg', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
2693	21845152	In a long-term series of studies, children born in Teplice were found to have multiple health problems including intrauterine growth retardation, low birth weight and respiratory ailments.	('intrauterine growth retardation', 'Disease', 'MESH:D005317', (113, 144))	('low birth weight', 'Disease', 'MESH:C537577', (146, 162))	('low birth weight', 'Phenotype', 'HP:0001518', (146, 162))	('intrauterine growth retardation', 'Phenotype', 'HP:0001511', (113, 144))	('growth retardation', 'Phenotype', 'HP:0001510', (126, 144))	('intrauterine growth retardation', 'Disease', (113, 144))	('low birth weight', 'Disease', (146, 162))	('respiratory ailments', 'Disease', (167, 187))	('Teplice', 'Var', (51, 58))	('men', 'Species', '9606', (182, 185))	('children', 'Species', '9606', (34, 42))
2710	21845152	It is important to note, however, that IHC/ACIS values reflect investigator-selected areas, which are typically regions having the highest PAH-DNA adduct color intensity, whereas extraction of DNA from all the cells in a tissue results in effective dilution, as PAH-DNA adducts are not uniformly distributed to all tissues.	('dilution', 'MPA', (249, 257))	('extraction', 'Var', (179, 189))	('PAH', 'Chemical', 'MESH:D011084', (139, 142))	('PAH', 'Chemical', 'MESH:D011084', (262, 265))
2730	21845152	Availability of new specialized techniques, such as laser capture microdissection, may provide additional opportunities to collect and evaluate very specific portions of whole tissue, or individual cells, in which PAH-DNA damage can potentially be related to other molecular markers such as gene expression, micro-RNAs or epigenetics.	('PAH', 'Chemical', 'MESH:D011084', (214, 217))	('micro-RNAs', 'Var', (308, 318))	('related', 'Reg', (248, 255))
2736	19136509	Adjusted hazard ratios and 95% confidence intervals for the association between serum PGI/II ratio and caner risk Compared to subjects with PGI/II ratio of > 4, those with <=4 had HRs (95%CIs) of 2.72 (1.77-4.20) and 2.12 (1.42-3.16) for noncardia and cardia gastric cancers, respectively.	('I', 'Chemical', 'MESH:D007455', (90, 91))	('caner', 'Disease', (103, 108))	('PGI', 'Gene', '633', (86, 89))	('I', 'Chemical', 'MESH:D007455', (142, 143))	('gastric cancers', 'Phenotype', 'HP:0012126', (259, 274))	('I', 'Chemical', 'MESH:D007455', (88, 89))	('PGI', 'Gene', (140, 143))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('serum', 'Var', (80, 85))	('PGI', 'Gene', (86, 89))	('I', 'Chemical', 'MESH:D007455', (91, 92))	('I', 'Chemical', 'MESH:D007455', (144, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (259, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('noncardia and cardia gastric cancers', 'Disease', 'MESH:D013274', (238, 274))	('I', 'Chemical', 'MESH:D007455', (189, 190))	('PGI', 'Gene', '633', (140, 143))	('I', 'Chemical', 'MESH:D007455', (145, 146))
2738	19136509	Risk of ESCC was marginally increased in those with PGI/II ratio <=4, with HR (95% CI) of 1.56 (0.99-2.47), but quartile models and continuous models showed no increased risk.	('I', 'Chemical', 'MESH:D007455', (56, 57))	('ESCC', 'Disease', (8, 12))	('I', 'Chemical', 'MESH:D007455', (84, 85))	('PGI', 'Gene', '633', (52, 55))	('I', 'Chemical', 'MESH:D007455', (57, 58))	('I', 'Chemical', 'MESH:D007455', (54, 55))	('<=4', 'Var', (65, 68))	('PGI', 'Gene', (52, 55))
2740	19136509	In this prospective study, we found similar and significantly increased risks of noncardia and cardia gastric adenocarcinomas in subjects with low PGI/II ratio, but little evidence for an association with ESCC risk.	('increased', 'PosReg', (62, 71))	('I', 'Chemical', 'MESH:D007455', (149, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('PGI', 'Gene', (147, 150))	('I', 'Chemical', 'MESH:D007455', (152, 153))	('noncardia and cardia gastric adenocarcinomas', 'Disease', 'MESH:D004938', (81, 125))	('low', 'Var', (143, 146))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('I', 'Chemical', 'MESH:D007455', (151, 152))	('PGI', 'Gene', '633', (147, 150))
2792	19136509	Seropositivity cut points were defined as <= 50 mug/L for PGI and <= 3, 4, 5, or 6 for PGI/II ratio.	('PGI', 'Gene', '633', (87, 90))	('PGI', 'Gene', (58, 61))	('PGI', 'Gene', (87, 90))	('<= 50 mug/L', 'Var', (42, 53))	('PGI', 'Gene', '633', (58, 61))
2827	19136509	There were statistically significant differences in HRs for the association between low serum PGI and gastric noncardia cancer diagnosed in the three time periods.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('gastric noncardia cancer', 'Disease', 'MESH:D013274', (102, 126))	('low', 'Var', (84, 87))	('PGI', 'Gene', '633', (94, 97))	('low serum PGI', 'Phenotype', 'HP:0031817', (84, 97))	('PGI', 'Gene', (94, 97))	('gastric noncardia cancer', 'Disease', (102, 126))
2830	19136509	For gastric noncardia adenocarcinoma, atrophy increased risk more in those who were H. pylori seropositive rather than in those who were H. pylori seronegative but the interaction term was not statistically significant (P for interaction = 0.13).	('atrophy', 'Disease', (38, 45))	('H. pylori', 'Species', '210', (137, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('seropositive', 'Var', (94, 106))	('H. pylori', 'Var', (84, 93))	('gastric noncardia adenocarcinoma', 'Disease', (4, 36))	('atrophy', 'Disease', 'MESH:D001284', (38, 45))	('gastric noncardia adenocarcinoma', 'Disease', 'MESH:D013274', (4, 36))	('H. pylori', 'Species', '210', (84, 93))
2836	19136509	Most previous studies of the association between serum pepsinogens and gastric or esophageal cancer risk have used dichotomous comparisons based on single cut points, generally PG1 <=70-30, PGI/II <3, or a combination of these cut points.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PGI', 'Gene', '633', (190, 193))	('PG1 <=70-30', 'Var', (177, 188))	('gastric', 'Disease', 'MESH:D013274', (71, 78))	('esophageal cancer', 'Disease', (82, 99))	('gastric', 'Disease', (71, 78))	('PG1', 'Chemical', '-', (177, 180))	('PGI', 'Gene', (190, 193))
2887	33314798	11  Other recent studies revealed that the programmed cell death-1 (PD-1) antibody could benefit patients with advanced esophageal or gastroesophageal junction cancer compared with chemotherapy, especially for those with high PD-L1 expression.	('death-1 (PD-1) antibody', 'Disease', 'MESH:D010300', (59, 82))	('esophageal', 'Disease', (120, 130))	('gastroesophageal junction cancer', 'Disease', (134, 166))	('gastroesophageal junction cancer', 'Disease', 'MESH:D009369', (134, 166))	('PD-L1', 'Gene', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('high', 'Var', (221, 225))	('benefit', 'PosReg', (89, 96))	('PD-L1', 'Gene', '29126', (226, 231))	('patients', 'Species', '9606', (97, 105))
2895	33314798	Eligible patients were 18 years of age or older with the diagnosis of either squamous cell carcinoma (ICD-O-3 codes 8050-8082) or adenocarcinoma (ICD-O-3 codes 8140-8573) of the esophagus (ICD-O-3 for topography codes: C150-C155, C158-C159) or the gastroesophageal junction (ICD-O-3 for topography codes: C160) between January 2000 and December 2016.	('patients', 'Species', '9606', (9, 17))	('adenocarcinoma', 'Disease', (130, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (130, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))	('C158-C159', 'Var', (230, 239))
2986	32660034	Results: The incidence rates of overall proximal cancers in FIT-, FIT+/CRC-, and FIT+/CRC+ patients within 1, 2, and 3 years after FIT were 0.38%, 0.68%, and 2.26%; 0.57%, 0.93%, and 2.74%; and 0.79%, 1.21%, and 3.15%, respectively.	('FIT', 'Chemical', '-', (131, 134))	('FIT+/CRC-', 'Var', (66, 75))	('patients', 'Species', '9606', (91, 99))	('FIT', 'Chemical', '-', (60, 63))	('FIT', 'Chemical', '-', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('FIT', 'Chemical', '-', (66, 69))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('FIT+/CRC+', 'Var', (81, 90))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
2987	32660034	After adjusting confounding variables, the risks of esophageal, stomach, and small intestine cancers as well as overall proximal cancers within 1, 2, and 3 years after FIT were higher in FIT+/CRC- patients than those in FIT- patients.	('patients', 'Species', '9606', (197, 205))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('FIT', 'Chemical', '-', (168, 171))	('esophageal', 'Disease', (52, 62))	('CRC', 'Phenotype', 'HP:0003003', (192, 195))	('patients', 'Species', '9606', (225, 233))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('small intestine cancer', 'Phenotype', 'HP:0100833', (77, 99))	('stomach', 'Disease', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('higher', 'PosReg', (177, 183))	('cancers', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('FIT+/CRC-', 'Var', (187, 196))	('FIT', 'Chemical', '-', (220, 223))	('FIT', 'Chemical', '-', (187, 190))
2989	32660034	The risks for oral or throat cancer and small intestine cancer were higher in FIT+/CRC+ patients than those in FIT+/CRC- patients.	('FIT', 'Chemical', '-', (111, 114))	('cancer', 'Disease', (29, 35))	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('FIT', 'Chemical', '-', (78, 81))	('small intestine cancer', 'Phenotype', 'HP:0100833', (40, 62))	('throat cancer', 'Disease', 'MESH:D009369', (22, 35))	('patients', 'Species', '9606', (88, 96))	('higher', 'PosReg', (68, 74))	('FIT+/CRC+', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('oral or throat cancer', 'Phenotype', 'HP:0012288', (14, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('throat cancer', 'Disease', (22, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('patients', 'Species', '9606', (121, 129))
2990	32660034	Conclusions: In this population-based study, FIT+/CRC- patients were at higher risk for esophageal, stomach, and small intestine cancers than were FIT- patients, suggesting that positive FIT results were associated with these cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('stomach', 'Disease', (100, 107))	('FIT+/CRC-', 'Var', (45, 54))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('patients', 'Species', '9606', (55, 63))	('small intestine cancer', 'Phenotype', 'HP:0100833', (113, 135))	('cancers', 'Disease', (226, 233))	('FIT', 'Chemical', '-', (147, 150))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('FIT', 'Chemical', '-', (45, 48))	('CRC', 'Phenotype', 'HP:0003003', (50, 53))	('esophageal', 'Disease', (88, 98))	('FIT', 'Chemical', '-', (187, 190))	('patients', 'Species', '9606', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
3001	32660034	We compared the risks of proximal cancers between three groups classified on the basis of FIT results and CRC status (FIT-, FIT+/CRC-, and FIT+/CRC+).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('CRC', 'Phenotype', 'HP:0003003', (106, 109))	('FIT+/CRC+', 'Var', (139, 148))	('FIT', 'Chemical', '-', (139, 142))	('CRC', 'Phenotype', 'HP:0003003', (144, 147))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('FIT', 'Chemical', '-', (90, 93))	('FIT', 'Chemical', '-', (124, 127))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('FIT', 'Chemical', '-', (118, 121))	('CRC', 'Phenotype', 'HP:0003003', (129, 132))
3012	32660034	Diabetes mellitus (DM) was defined as having the diagnostic code (E11-E14) prior to FIT.	('Diabetes mellitus', 'Disease', (0, 17))	('FIT', 'Chemical', '-', (84, 87))	('E11-E14', 'Var', (66, 73))	('Diabetes mellitus', 'Phenotype', 'HP:0000819', (0, 17))	('Diabetes mellitus', 'Disease', 'MESH:D003920', (0, 17))	('DM', 'Phenotype', 'HP:0000819', (19, 21))	('DM', 'Disease', 'MESH:D009223', (19, 21))
3027	32660034	The study population was divided into three groups as follows: Group 1 (FIT-), n = 5,551,755; Group 2 (FIT+/CRC-), n = 368,553; and Group 3 (FIT+/CRC+), n = 12,236 (Figure 1).	('FIT', 'Chemical', '-', (72, 75))	('FIT+/CRC-', 'Var', (103, 112))	('FIT+/CRC+', 'Var', (141, 150))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('CRC', 'Phenotype', 'HP:0003003', (146, 149))	('FIT', 'Chemical', '-', (141, 144))	('FIT', 'Chemical', '-', (103, 106))
3048	32660034	The results of this Korean population-based study showed that FIT+/CRC- patients were at a higher risk of UGI cancers than FIT- patients.	('FIT', 'Chemical', '-', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('UGI cancers', 'Disease', 'MESH:D009369', (106, 117))	('FIT', 'Chemical', '-', (62, 65))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('UGI cancers', 'Disease', (106, 117))	('patients', 'Species', '9606', (128, 136))	('FIT+/CRC-', 'Var', (62, 71))	('patients', 'Species', '9606', (72, 80))
3059	32660034	A Danish study including 20,671 screenees reported a significantly higher incidence of gastric and esophageal cancers within 2 years after gFOBT in gFOBT+ persons than that in gFOBT- individuals.	('gFOBT', 'Chemical', '-', (148, 153))	('gFOBT', 'Var', (139, 144))	('higher', 'PosReg', (67, 73))	('gFOBT', 'Chemical', '-', (176, 181))	('gastric and esophageal cancers', 'Disease', 'MESH:D013274', (87, 117))	('gFOBT', 'Chemical', '-', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gFOBT+', 'Var', (148, 154))	('persons', 'Species', '9606', (155, 162))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))
3062	32660034	Although this study showed an increased short-term risk of gastric cancer in FOBT+/colonoscopy- subjects, the authors also concluded that recommending routine EGD for these subjects was questionable because of the low PPV of FOBT (0.4% [n = 14/3555]).	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('FOBT+/colonoscopy-', 'Var', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gastric cancer', 'Disease', (59, 73))	('men', 'Species', '9606', (143, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))
3065	32660034	This is the first study to show increased short- and long-term risks for esophageal, stomach, and small intestine cancers in FIT+/CRC- patients than those in FIT- patients through an analysis of a nationwide population-based database.	('FIT', 'Chemical', '-', (125, 128))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('FIT+/CRC-', 'Var', (125, 134))	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (163, 171))	('cancers', 'Disease', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('small intestine cancer', 'Phenotype', 'HP:0100833', (98, 120))	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('FIT', 'Chemical', '-', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('esophageal', 'Disease', (73, 83))	('stomach', 'Disease', (85, 92))
3073	32660034	Based on previous studies showing an association between higher f-Hb concentrations and increased CRC risk, high f-Hb concentration may also increase the yield of UGI evaluations among FIT+/CRC- patients.	('higher', 'PosReg', (57, 63))	('increase', 'PosReg', (141, 149))	('CRC', 'Phenotype', 'HP:0003003', (190, 193))	('CRC', 'Disease', (98, 101))	('patients', 'Species', '9606', (195, 203))	('high', 'Var', (108, 112))	('FIT', 'Chemical', '-', (185, 188))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))
3075	32660034	In the present study, the risk of hepatopancreatobiliary cancers was also higher in FIT+/CRC- patients than that in FIT- patients.	('FIT+/CRC- patients', 'Var', (84, 102))	('patients', 'Species', '9606', (94, 102))	('higher', 'PosReg', (74, 80))	('FIT', 'Chemical', '-', (84, 87))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('hepatopancreatobiliary cancers', 'Disease', (34, 64))	('FIT', 'Chemical', '-', (116, 119))	('hepatopancreatobiliary cancers', 'Disease', 'MESH:D009369', (34, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('patients', 'Species', '9606', (121, 129))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))
3079	32660034	Additionally, these results suggest that FIT positivity may be associated with diseases other than CRC.	('FIT positivity', 'Var', (41, 55))	('associated', 'Reg', (63, 73))	('CRC', 'Disease', (99, 102))	('FIT', 'Chemical', '-', (41, 44))	('CRC', 'Phenotype', 'HP:0003003', (99, 102))
3080	32660034	A recent study from Scotland reported that positive FOBT results were significantly associated with increased risks of non-CRC mortality (increased risk of death from respiratory, circulatory, and digestive diseases), suggesting that FOBT positivity could be used to alert CRC-screened participants to the risk of diseases other than CRC, regardless of the presence or absence of CRC.	('FOBT', 'Gene', (52, 56))	('death', 'Disease', 'MESH:D003643', (156, 161))	('death', 'Disease', (156, 161))	('positive', 'Var', (43, 51))	('mortality', 'Disease', 'MESH:D003643', (127, 136))	('CRC', 'Phenotype', 'HP:0003003', (334, 337))	('mortality', 'Disease', (127, 136))	('participants', 'Species', '9606', (286, 298))	('CRC', 'Phenotype', 'HP:0003003', (380, 383))	('digestive diseases', 'Phenotype', 'HP:0011024', (197, 215))	('CRC', 'Phenotype', 'HP:0003003', (273, 276))	('CRC', 'Phenotype', 'HP:0003003', (123, 126))
3085	32660034	Another noteworthy finding of our study was that FIT+/CRC+ patients had higher risks of small intestine cancer and hepatopancreatobiliary cancer than FIT+/CRC- patients.	('cancer', 'Disease', (138, 144))	('patients', 'Species', '9606', (160, 168))	('FIT+/CRC+', 'Var', (49, 58))	('small intestine cancer', 'Phenotype', 'HP:0100833', (88, 110))	('FIT', 'Chemical', '-', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('hepatopancreatobiliary cancer', 'Disease', 'MESH:D009369', (115, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('patients', 'Species', '9606', (59, 67))	('CRC', 'Phenotype', 'HP:0003003', (54, 57))	('FIT', 'Chemical', '-', (49, 52))	('cancer', 'Disease', (104, 110))	('hepatopancreatobiliary cancer', 'Disease', (115, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
3095	32660034	In conclusion, FIT+/CRC- patients had significantly higher risks of esophageal, stomach, and small intestine cancers than FIT- patients.	('esophageal', 'Disease', (68, 78))	('FIT', 'Chemical', '-', (15, 18))	('CRC', 'Phenotype', 'HP:0003003', (20, 23))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('FIT+/CRC-', 'Var', (15, 24))	('stomach', 'Disease', (80, 87))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (25, 33))	('FIT', 'Chemical', '-', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('small intestine cancer', 'Phenotype', 'HP:0100833', (93, 115))
3096	32660034	Our results indicate that positive FIT findings are associated with an increased risk of UGI cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('positive', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('FIT', 'Chemical', '-', (35, 38))
3126	29416690	Subgroup analysis by cancer type showed that high HMGA2 expression was associated with worse OS in GC (pooled HR = 1.77; 95% CI =1.31-2.41; P < 0.001), BC (pooled HR = 2.26; 95% CI =1.56-3.28; P < 0.001), HCC (pooled HR = 1.90; 95% CI =1.37-2.64; P < 0.001), CRC (pooled HR = 1.78; 95% CI =1.29-2.44; P < 0.001), NPC (pooled HR = 1.96; 95% CI =1.26-3.05; P = 0.003), and EC (pooled HR = 1.82; 95% CI =1.19-2.77; P = 0.006).	('CRC', 'Disease', (259, 262))	('EC', 'Phenotype', 'HP:0011459', (371, 373))	('CRC', 'Phenotype', 'HP:0003003', (259, 262))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('HMGA2', 'Gene', '8091', (50, 55))	('HCC', 'Gene', '619501', (205, 208))	('NPC', 'Phenotype', 'HP:0100630', (313, 316))	('HCC', 'Phenotype', 'HP:0001402', (205, 208))	('expression', 'MPA', (56, 66))	('high', 'Var', (45, 49))	('HCC', 'Gene', (205, 208))	('BC', 'Phenotype', 'HP:0003002', (152, 154))	('NPC', 'Gene', (313, 316))	('cancer', 'Disease', (21, 27))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('HMGA2', 'Gene', (50, 55))	('OS', 'Chemical', '-', (93, 95))	('NPC', 'Gene', '4864', (313, 316))
3128	29416690	In subgroup analysis by study region, patients from both Asian (HR = 1.95; 95% CI = 1.69-2.25; P < 0.001) and non-Asian regions (HR = 1.60; 95% CI = 1.14-2.25; P = 0.007) showed a significant correlation between high HMGA2 expression and poor OS.	('expression', 'MPA', (223, 233))	('high', 'Var', (212, 216))	('HMGA2', 'Gene', '8091', (217, 222))	('OS', 'Chemical', '-', (243, 245))	('poor OS', 'Disease', (238, 245))	('patients', 'Species', '9606', (38, 46))	('HMGA2', 'Gene', (217, 222))
3130	29416690	High HMGA2 expression was related to advanced tumor node metastasis (TNM) stage (stage III/IV) (odds ratio [OR] = 2.44; 95% CI =1.87-3.2; P < 0.001), positive lymphovascular space invasion (OR = 2.46, 95% CI = 1.67-3.64; P < 0.001), distant metastasis (OR = 2.66; 95% CI = 1.51-4.69; P < 0.001), and lymph node metastasis (OR = 1.83; 95% CI = 1.27-2.64; P = 0.001).	('tumor node metastasis', 'Disease', (46, 67))	('positive lymphovascular space invasion', 'CPA', (150, 188))	('lymph node metastasis', 'CPA', (300, 321))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('expression', 'MPA', (11, 21))	('HMGA2', 'Gene', (5, 10))	('tumor node metastasis', 'Disease', 'MESH:D009362', (46, 67))	('distant metastasis', 'CPA', (233, 251))	('HMGA2', 'Gene', '8091', (5, 10))
3132	29416690	The results indicated that there was no obvious publication bias for OS (P = 0.199 for Begg's test and 0.271 for Egger's test) or DFS/PFS/RFS (P = 0.764 for Begg's test and P = 0.076 for Egger's test) among the included studies (Figure 5A and 5B).	('OS', 'Chemical', '-', (69, 71))	('0.271', 'Var', (103, 108))	('DFS/PFS/RFS', 'Var', (130, 141))
3137	29416690	Moreover, aberrant expression of HMGA2 promotes cancer invasion, metastasis, and epithelial-to-mesenchymal transition (EMT) by activating the transforming growth factor beta (TGFbeta) and Wnt/beta-catenin signaling pathways.	('transforming growth factor beta', 'Gene', (142, 173))	('metastasis', 'CPA', (65, 75))	('promotes', 'PosReg', (39, 47))	('HMGA2', 'Gene', (33, 38))	('beta-catenin', 'Gene', '1499', (192, 204))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('activating', 'PosReg', (127, 137))	('transforming growth factor beta', 'Gene', '7040', (142, 173))	('epithelial-to-mesenchymal transition', 'CPA', (81, 117))	('aberrant expression', 'Var', (10, 29))	('TGFbeta', 'Gene', (175, 182))	('cancer', 'Disease', (48, 54))	('beta-catenin', 'Gene', (192, 204))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('HMGA2', 'Gene', '8091', (33, 38))	('TGFbeta', 'Gene', '7040', (175, 182))
3139	29416690	Furthermore, miRNAs like miR-490-3p and miR-145 can inhibit cancer development and progression by direct regulation of HMGA2 expression.	('inhibit', 'NegReg', (52, 59))	('miR-145', 'Gene', (40, 47))	('HMGA2', 'Gene', '8091', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('HMGA2', 'Gene', (119, 124))	('cancer', 'Disease', (60, 66))	('expression', 'MPA', (125, 135))	('miR-145', 'Gene', '406937', (40, 47))	('miR-490-3p', 'Var', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('regulation', 'Reg', (105, 115))
3140	29416690	showed that long non-coding ribonucleic acid (lncRNA) HIT000218960 promotes papillary thyroid cancer by upregulating HMGA2 expression.	('thyroid cancer', 'Phenotype', 'HP:0002890', (86, 100))	('promotes', 'PosReg', (67, 75))	('expression', 'MPA', (123, 133))	('upregulating', 'PosReg', (104, 116))	('HMGA2', 'Gene', '8091', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('HIT000218960', 'Var', (54, 66))	('HMGA2', 'Gene', (117, 122))	('papillary thyroid cancer', 'Disease', (76, 100))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (76, 100))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (76, 100))
3149	29416690	In this meta-analysis, we included 4114 patients from 29 studies, and the outcomes demonstrated a statistically significant correlation between high HMGA2 expression and poor OS.	('HMGA2', 'Gene', (149, 154))	('OS', 'Chemical', '-', (175, 177))	('patients', 'Species', '9606', (40, 48))	('expression', 'MPA', (155, 165))	('high', 'Var', (144, 148))	('poor OS', 'Disease', (170, 177))	('HMGA2', 'Gene', '8091', (149, 154))
3150	29416690	Meanwhile, high HMGA2 expression was significantly correlated with short DFS/PFS/RFS.	('HMGA2', 'Gene', '8091', (16, 21))	('HMGA2', 'Gene', (16, 21))	('high', 'Var', (11, 15))	('expression', 'MPA', (22, 32))	('short DFS/PFS/RFS', 'Disease', (67, 84))	('correlated', 'Reg', (51, 61))
3151	29416690	In subgroup analysis, we found that high expression of HMGA2 conferred a worse OS in patients regardless of the study region, sample size, detection method, or analysis method, which further confirmed the prognostic potential of HMGA2.	('high expression', 'Var', (36, 51))	('OS', 'Chemical', '-', (79, 81))	('worse OS', 'Disease', (73, 81))	('HMGA2', 'Gene', (229, 234))	('patients', 'Species', '9606', (85, 93))	('HMGA2', 'Gene', '8091', (55, 60))	('HMGA2', 'Gene', (55, 60))	('HMGA2', 'Gene', '8091', (229, 234))
3155	29416690	Meanwhile, according to Califano et al., overexpression of HMGA2 has no significant prognostic value for DFS and OS in multivariate analysis; even high HMGA2 expression combined with high body mass index (BMI; >=25 kg/m2) indicated a poor prognosis in patients with ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (266, 280))	('expression', 'MPA', (158, 168))	('patients', 'Species', '9606', (252, 260))	('ovarian cancer', 'Disease', (266, 280))	('HMGA2', 'Gene', '8091', (59, 64))	('ovarian cancer', 'Phenotype', 'HP:0100615', (266, 280))	('high', 'Var', (147, 151))	('HMGA2', 'Gene', (59, 64))	('HMGA2', 'Gene', '8091', (152, 157))	('high body mass index', 'Phenotype', 'HP:0031418', (183, 203))	('OS', 'Chemical', '-', (113, 115))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('HMGA2', 'Gene', (152, 157))
3164	29416690	In conclusion, this meta-analysis confirmed that high HMGA2 expression in cancer is linked to poor prognosis, and HMGA2 is a potential predictive biomarker for OS.	('expression', 'MPA', (60, 70))	('HMGA2', 'Gene', (114, 119))	('HMGA2', 'Gene', '8091', (54, 59))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('HMGA2', 'Gene', (54, 59))	('cancer', 'Disease', (74, 80))	('OS', 'Chemical', '-', (160, 162))	('high', 'Var', (49, 53))	('HMGA2', 'Gene', '8091', (114, 119))
3167	29416690	The author name(s), publication year, country, sample size, cancer type, clinic stage, HMGA2 detection method, follow-up time, and survival data including OS, DFS/PFS/RFS, were extracted.	('DFS/PFS/RFS', 'Var', (159, 170))	('OS', 'Chemical', '-', (155, 157))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('HMGA2', 'Gene', '8091', (87, 92))	('HMGA2', 'Gene', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
3253	28594897	Studies have shown dysregulation of lncRNAs contribute to cancer progression through abnormal regulation of cancer-related cellular processes, such as proliferation, invasion, metastasis, apoptosis and multi-drug resistance, and lncRNAs have been implicated as promising markers for predicting the prognosis of cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (311, 317))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('dysregulation', 'Var', (19, 32))	('proliferation', 'CPA', (151, 164))	('lncRNAs', 'Gene', (36, 43))	('contribute', 'Reg', (44, 54))	('apoptosis', 'CPA', (188, 197))	('drug resistance', 'Phenotype', 'HP:0020174', (208, 223))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('abnormal', 'Reg', (85, 93))	('cancer', 'Disease', (108, 114))	('metastasis', 'CPA', (176, 186))	('invasion', 'CPA', (166, 174))	('regulation', 'MPA', (94, 104))	('multi-drug resistance', 'CPA', (202, 223))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (58, 64))
3255	28594897	Many studies have shown that high levels of CCAT1 expression may be associated with prognosis of human cancers.	('high', 'Var', (29, 33))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('associated', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('human', 'Species', '9606', (97, 102))	('CCAT1', 'Gene', '100507056', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('CCAT1', 'Gene', (44, 49))	('expression', 'MPA', (50, 60))	('cancers', 'Disease', (103, 110))
3276	28594897	An HR>1 indicates that the patients with high CCAT1 expression have a poor prognosis and the patients with low CCAT1 expression have a good prognosis.	('CCAT1', 'Gene', '100507056', (46, 51))	('CCAT1', 'Gene', '100507056', (111, 116))	('CCAT1', 'Gene', (111, 116))	('CCAT1', 'Gene', (46, 51))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (93, 101))
3315	28594897	In recent years, mounting evidence has demonstrated that lncRNAs are important regulatory molecules in diverse biological and pathological processes, such as lncRNA UCA1 increases the cisplatin resistance of bladder cancer cells, lncRNA MALAT1 enhances the metastasis of osteosarcoma cells, LncRNA-ROR induces epithelial-to-mesenchymal transition of breast cancer cells and lncRNA CCAT1 promotes the proliferation and migration of hepatocellular carcinoma cells.	('breast cancer', 'Disease', 'MESH:D001943', (350, 363))	('osteosarcoma', 'Phenotype', 'HP:0002669', (271, 283))	('bladder cancer', 'Disease', 'MESH:D001749', (208, 222))	('breast cancer', 'Disease', (350, 363))	('promotes', 'PosReg', (387, 395))	('increases', 'PosReg', (170, 179))	('bladder cancer', 'Disease', (208, 222))	('bladder cancer', 'Phenotype', 'HP:0009725', (208, 222))	('UCA1', 'Gene', '652995', (165, 169))	('cisplatin resistance', 'MPA', (184, 204))	('UCA1', 'Gene', (165, 169))	('MALAT1', 'Gene', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (431, 455))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('migration', 'CPA', (418, 427))	('MALAT1', 'Gene', '378938', (237, 243))	('CCAT1', 'Gene', '100507056', (381, 386))	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('epithelial-to-mesenchymal transition', 'CPA', (310, 346))	('CCAT1', 'Gene', (381, 386))	('proliferation', 'CPA', (400, 413))	('osteosarcoma', 'Disease', (271, 283))	('osteosarcoma', 'Disease', 'MESH:D012516', (271, 283))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (431, 455))	('lncRNA', 'Var', (158, 164))	('enhances', 'PosReg', (244, 252))	('metastasis', 'CPA', (257, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (350, 363))	('induces', 'Reg', (302, 309))	('hepatocellular carcinoma', 'Disease', (431, 455))	('carcinoma', 'Phenotype', 'HP:0030731', (446, 455))
3324	28594897	In colon cancer and pancreatic cancer, abnormally expressed CCAT1 promotes cell proliferation and migration.	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('abnormally expressed', 'Var', (39, 59))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cell proliferation', 'CPA', (75, 93))	('CCAT1', 'Gene', '100507056', (60, 65))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('migration', 'CPA', (98, 107))	('promotes', 'PosReg', (66, 74))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('CCAT1', 'Gene', (60, 65))	('pancreatic cancer', 'Disease', (20, 37))	('colon cancer', 'Disease', (3, 15))
3327	28594897	In non-small cell lung cancer cell line, inhibition of CARLo-5 by siRNA suppressed the proliferation, migration, and invasion of cells and reversed the epithelial-mesenchymal transition.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('reversed', 'PosReg', (139, 147))	('inhibition', 'Var', (41, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('suppressed', 'NegReg', (72, 82))	('epithelial-mesenchymal transition', 'CPA', (152, 185))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('CARLo-5', 'Gene', (55, 62))	('non-small cell lung cancer', 'Disease', (3, 29))	('CARLo-5', 'Gene', '100507056', (55, 62))	('invasion of cells', 'CPA', (117, 134))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
3328	28594897	Based on these studies and owing to its functions, targeting CCAT1 may be beneficial to the outcome of cancer patients and CCAT1 may serve as a prognostic biomarker.	('CCAT1', 'Gene', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('CCAT1', 'Gene', '100507056', (61, 66))	('beneficial', 'PosReg', (74, 84))	('CCAT1', 'Gene', (61, 66))	('targeting', 'Var', (51, 60))	('cancer', 'Disease', (103, 109))	('CCAT1', 'Gene', '100507056', (123, 128))	('patients', 'Species', '9606', (110, 118))
3331	28594897	By combining the HRs, we found that high CCAT1 expression was a poor prognostic marker for OS in tumor patients (pooled HR 2.335, 95%CI: 1.551-3.517).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CCAT1', 'Gene', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'MPA', (47, 57))	('tumor', 'Disease', (97, 102))	('OS', 'Chemical', '-', (91, 93))	('CCAT1', 'Gene', '100507056', (41, 46))	('patients', 'Species', '9606', (103, 111))	('high', 'Var', (36, 40))
3341	28594897	Meta-analysis showed that patients with high CCAT1 expression were more possible to have significantly poorer RFS (pooled HR 2.659, 95%CI: 1.755-4.029) with no significant heterogeneity.	('high', 'Var', (40, 44))	('CCAT1', 'Gene', '100507056', (45, 50))	('RFS', 'CPA', (110, 113))	('CCAT1', 'Gene', (45, 50))	('poorer', 'NegReg', (103, 109))	('patients', 'Species', '9606', (26, 34))	('expression', 'Var', (51, 61))
3374	28594897	This meta-analysis is the first to demonstrate that high expression of the lncRNA CCAT1 is related to poor prognosis for cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CCAT1', 'Gene', '100507056', (82, 87))	('high', 'Var', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CCAT1', 'Gene', (82, 87))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Disease', (121, 127))
3441	19137073	In addition, hypermethylation of some genes has been shown to occur early in esophageal squamous dysplasia and is common in ESCC (observed in up to 80% of cases in some series).	('common', 'Reg', (114, 120))	('esophageal squamous dysplasia', 'Disease', 'MESH:D000077277', (77, 106))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (88, 106))	('hypermethylation', 'Var', (13, 29))	('esophageal squamous dysplasia', 'Disease', (77, 106))	('ESCC', 'Disease', (124, 128))
3443	19137073	The purpose of this study was to evaluate whether the presence of methylation in these genes in EBC samples could identify individuals with high-grade (moderate or severe) esophageal squamous dysplasia, who should be referred for endoscopic examination.	('EBC', 'Chemical', '-', (96, 99))	('esophageal squamous dysplasia', 'Disease', (172, 201))	('presence', 'Var', (54, 62))	('high-grade', 'Disease', (140, 150))	('methylation', 'Var', (66, 77))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (183, 201))	('esophageal squamous dysplasia', 'Disease', 'MESH:D000077277', (172, 201))
3458	19137073	The sensitivity and specificity for methylation in discriminating patients with high-grade dysplasia (including moderate and severe dysplasia) from all other patients was calculated.	('moderate', 'Disease', (112, 120))	('severe dysplasia', 'Disease', (125, 141))	('severe dysplasia', 'Disease', 'MESH:D001523', (125, 141))	('dysplasia', 'Disease', (132, 141))	('patients', 'Species', '9606', (66, 74))	('dysplasia', 'Disease', 'MESH:D004476', (132, 141))	('dysplasia', 'Disease', (91, 100))	('patients', 'Species', '9606', (158, 166))	('dysplasia', 'Disease', 'MESH:D004476', (91, 100))	('methylation', 'Var', (36, 47))
3464	19137073	The prevalence of methylation in individual genes ranged from 0-12% in patients with normal mucosa, 0-32% in patients with mild dysplasia, 4-35% in patients with moderate dysplasia, and 10-34% in patients with severe dysplasia.	('patients', 'Species', '9606', (148, 156))	('dysplasia', 'Disease', 'MESH:D004476', (217, 226))	('severe dysplasia', 'Disease', 'MESH:D001523', (210, 226))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (71, 79))	('dysplasia', 'Disease', (128, 137))	('patients', 'Species', '9606', (196, 204))	('dysplasia', 'Disease', 'MESH:D004476', (128, 137))	('dysplasia', 'Disease', (171, 180))	('methylation', 'Var', (18, 29))	('severe dysplasia', 'Disease', (210, 226))	('dysplasia', 'Disease', (217, 226))	('dysplasia', 'Disease', 'MESH:D004476', (171, 180))
3465	19137073	The proportion of patients with one or more methylated genes also increased with the degree of dyplasia (Fig 1).	('methylated', 'Var', (44, 54))	('increased', 'PosReg', (66, 75))	('dyplasia', 'Disease', 'MESH:D063169', (95, 103))	('dyplasia', 'Disease', (95, 103))	('patients', 'Species', '9606', (18, 26))
3468	19137073	The sensitivities and specificities of finding methylation in the eight single genes or in several combinations of genes for identifying patients with high-grade (moderate or severe) dysplasia are shown in Table 3.	('dysplasia', 'Disease', (183, 192))	('methylation', 'Var', (47, 58))	('dysplasia', 'Disease', 'MESH:D004476', (183, 192))	('patients', 'Species', '9606', (137, 145))
3469	19137073	For example, finding methylation in AHRR, p16INK4a, or MT1G had a sensitivity and specificity of 30% and 86%, respectively.	('p16INK4a', 'Gene', '1029', (42, 50))	('MT1G', 'Gene', '4495', (55, 59))	('AHRR', 'Gene', (36, 40))	('MT1G', 'Gene', (55, 59))	('methylation', 'Var', (21, 32))	('p16INK4a', 'Gene', (42, 50))	('AHRR', 'Gene', '57491', (36, 40))
3478	19137073	For most genes, methylation was more common in the EBC samples of patients with worse disease, consistent with previous findings in esophageal tissue specimens.	('men', 'Species', '9606', (155, 158))	('EBC', 'Disease', (51, 54))	('EBC', 'Chemical', '-', (51, 54))	('common', 'Reg', (37, 43))	('methylation', 'Var', (16, 27))	('patients', 'Species', '9606', (66, 74))
3479	19137073	Methylation of individual genes had sensitivities and specificities ranging from 9-34% and 77-99%, respectively, for identifying patients with high-grade squamous dysplasia.	('patients', 'Species', '9606', (129, 137))	('Methylation', 'Var', (0, 11))	('squamous dysplasia', 'Disease', (154, 172))	('squamous dysplasia', 'Disease', 'MESH:D002294', (154, 172))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (154, 172))
3484	19137073	This suggests that promoter methylation may be an early event in carcinogenesis.	('carcinogenesis', 'Disease', (65, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (65, 79))	('promoter methylation', 'Var', (19, 39))
3485	19137073	Thus, given the cross-sectional nature of our study, it is unclear if the methylation-positive samples in subjects with normal endoscopic and histologic findings identified field effects associated with occult early neoplasia or if they were non-specific findings unrelated to carcinogenesis.	('neoplasia', 'Disease', 'MESH:D009369', (216, 225))	('carcinogenesis', 'Disease', 'MESH:D063646', (277, 291))	('carcinogenesis', 'Disease', (277, 291))	('neoplasia', 'Disease', (216, 225))	('neoplasia', 'Phenotype', 'HP:0002664', (216, 225))	('methylation-positive', 'Var', (74, 94))
3491	19137073	Prospective studies evaluating multiple genes that have a high prevalence of methylation in ESCC should also shed light on the clinical usefulness of methylation markers in the early detection of ESCC.	('methylation', 'Var', (77, 88))	('clinical', 'Species', '191496', (127, 135))	('ESCC', 'Disease', (196, 200))	('ESCC', 'Gene', (92, 96))
3521	33652817	Thoracic descending aorta dorsal LNs (112aoP in the 11th Edition of Japanese Classification of Esophageal Cancer) were defined as regional LNs based on the eighth edition of the TNM classification of Malignant Tumors by the UICC, and patients with these LN metastases were included in this study.	('Malignant Tumors', 'Disease', 'MESH:D009369', (200, 216))	('metastases', 'Disease', 'MESH:D009362', (257, 267))	('descending aorta', 'Phenotype', 'HP:0025495', (9, 25))	('Cancer', 'Disease', (106, 112))	('Malignant Tumors', 'Disease', (200, 216))	('Tumors', 'Phenotype', 'HP:0002664', (210, 216))	('TNM', 'Gene', (178, 181))	('112aoP', 'Var', (38, 44))	('Cancer', 'Disease', 'MESH:D009369', (106, 112))	('patients', 'Species', '9606', (234, 242))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Thoracic descending aorta', 'Phenotype', 'HP:0004959', (0, 25))	('TNM', 'Gene', '10178', (178, 181))	('metastases', 'Disease', (257, 267))
3614	33692946	Moreover, TIM-3 expression was found to be related to worse OS in 9491 TCGA patients (HR = 1.2, P < 0.001), but was not associated with DFS.	('TIM-3', 'Gene', (10, 15))	('patients', 'Species', '9606', (76, 84))	('expression', 'Var', (16, 26))	('TCGA', 'Disease', (71, 75))	('TIM-3', 'Gene', '84868', (10, 15))	('worse OS', 'Disease', (54, 62))
3636	33692946	reported a significant association between TIM-3 expression and worse OS in esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (76, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('worse OS', 'Disease', (64, 72))	('esophageal squamous cell carcinoma', 'Disease', (76, 110))	('TIM-3', 'Gene', '84868', (43, 48))	('TIM-3', 'Gene', (43, 48))	('expression', 'Var', (49, 59))
3657	33692946	Of these eligible studies, only three articles reported that TIM-3 expression was correlated with worse OS in cervical cancer (n= 43 cases), gastric cancer (n=305 cases), and colorectal cancer (n=201 cases).	('correlated with', 'Reg', (82, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('gastric cancer', 'Disease', (141, 155))	('TIM-3', 'Gene', '84868', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('expression', 'Var', (67, 77))	('colorectal cancer', 'Disease', (175, 192))	('cancer', 'Disease', (119, 125))	('TIM-3', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (186, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
3658	33692946	The result from 22 studies indicated that the expression of TIM-3 led to poorer OS (HR= 1.54, 95% CI = 1.19-1.98, P = 0.001) (Figure 2), including 3317 malignant tumor patients.	('TIM-3', 'Gene', '84868', (60, 65))	('expression', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('malignant tumor', 'Disease', (152, 167))	('poorer', 'NegReg', (73, 79))	('malignant tumor', 'Disease', 'MESH:D009369', (152, 167))	('patients', 'Species', '9606', (168, 176))	('TIM-3', 'Gene', (60, 65))
3661	33692946	The results by age group showed that TIM-3 expression was correlated with worse OS in the elder age group (> 60 years: n = 8 studies with 1600 cases: HR = 2.10, 95% CI = 1.34-3.31, P = 0.001) and the younger group (<= 60 years: n = 10 studies with 1348 cases: HR = 1.45, 95% CI = 1.01-2.08, P = 0.046).	('TIM-3', 'Gene', '84868', (37, 42))	('expression', 'Var', (43, 53))	('TIM-3', 'Gene', (37, 42))
3662	33692946	The results grouped by ethnicity showed that TIM-3 expression was associated with poor OS in Asian populations (n = 16 studies with 2452 cases: HR = 1.64, 95% CI = 1.14-2.35, P = 0.007), but not in European populations (n = 6 studies with 865 cases: P = 0.203).	('poor OS', 'Disease', (82, 89))	('TIM-3', 'Gene', '84868', (45, 50))	('TIM-3', 'Gene', (45, 50))	('expression', 'Var', (51, 61))
3666	33692946	The re-calculated result from the remaining studies showed that TIM-3 expression was still significantly correlated with shorter OS (HR= 1.71, 95% CI = 1.44-2.04, P < 0.001), with no heterogeneity (P = 0.102).	('shorter OS', 'Disease', (121, 131))	('expression', 'Var', (70, 80))	('TIM-3', 'Gene', '84868', (64, 69))	('TIM-3', 'Gene', (64, 69))
3680	33692946	TIM-3 expression is related to worse prognosis in some cancers, such as gastric cancer and ovarian cancer, but is not correlated with prognosis in some cancers, such as renal cell carcinoma and sarcoma.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (91, 105))	('expression', 'Var', (6, 16))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('cancers', 'Disease', (152, 159))	('gastric cancer', 'Disease', (72, 86))	('renal cell carcinoma', 'Disease', (169, 189))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Disease', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('cancers', 'Disease', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('sarcoma', 'Disease', (194, 201))	('TIM-3', 'Gene', '84868', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (169, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TIM-3', 'Gene', (0, 5))
3683	33692946	reported that TIM-3 single nucleotide polymorphisms (SNPs) were correlated with an increased cancer risk (case-control studies with 4852 participants).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TIM-3', 'Gene', (14, 19))	('participants', 'Species', '9606', (137, 149))	('TIM-3', 'Gene', '84868', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('single nucleotide polymorphisms', 'Var', (20, 51))
3684	33692946	reported that TIM-3 expression was associated with shorter OS in solid tumors (n=869 patients).	('TIM-3', 'Gene', (14, 19))	('TIM-3', 'Gene', '84868', (14, 19))	('expression', 'Var', (20, 30))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
3698	33692946	These analyses suggest that TIM-3 could become an independent prognostic marker for predicting worse OS, and targeting TIM-3 is a potentially effective approach for cancer immunotherapy.	('TIM-3', 'Gene', '84868', (119, 124))	('TIM-3', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('targeting', 'Var', (109, 118))	('TIM-3', 'Gene', '84868', (28, 33))	('worse OS', 'Disease', (95, 103))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('TIM-3', 'Gene', (119, 124))
3700	33692946	reported that TIM-3 expression was correlated with worse CSS in clear cell renal cell carcinoma (n=137 cases), but Burugu 2018 et al.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('TIM-3', 'Gene', (14, 19))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (75, 95))	('TIM-3', 'Gene', '84868', (14, 19))	('expression', 'Var', (20, 30))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (64, 95))	('clear cell renal cell carcinoma', 'Disease', (64, 95))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (64, 95))
3701	33692946	reported that TIM-3 expression was related to favorable CSS in a large cohort of breast cancer (> 3000 cases).	('breast cancer', 'Disease', (81, 94))	('TIM-3', 'Gene', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('TIM-3', 'Gene', '84868', (14, 19))	('expression', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
3707	33692946	Subgroup analysis by ethnicity demonstrated that TIM-3 expression was related to worse OS in Asian populations, but not in European populations.	('TIM-3', 'Gene', (49, 54))	('worse OS', 'Disease', (81, 89))	('TIM-3', 'Gene', '84868', (49, 54))	('expression', 'Var', (55, 65))
3720	33692946	The present study provided more evidence that TIM-3 expression was significantly associated with worse OS, and it might be a useful prognosticator in malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('malignant tumors', 'Disease', (150, 166))	('malignant tumors', 'Disease', 'MESH:D009369', (150, 166))	('worse OS', 'Disease', (97, 105))	('TIM-3', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('TIM-3', 'Gene', '84868', (46, 51))	('expression', 'Var', (52, 62))	('associated', 'Reg', (81, 91))
3800	26715559	Epithelial injury and disruption of intercellular tight junctions leading to DIS formation as well as loss of barrier function has been well characterized in rabbit as well as human esophagus using ex vivo culture systems.	('disruption', 'Var', (22, 32))	('intercellular tight junctions', 'Protein', (36, 65))	('human', 'Species', '9606', (176, 181))	('Epithelial injury', 'Disease', 'MESH:D002277', (0, 17))	('DIS', 'Chemical', '-', (77, 80))	('DIS formation', 'Disease', (77, 90))	('Epithelial injury', 'Disease', (0, 17))
3838	26715559	Bile acid, possible by activating EGFR pathway and downstream Akt phosphorylation, might cause beta-catenin phosphorylation at Ser552 residue triggering its release and subsequent disruption of the adherens junction complex.	('EGFR', 'Gene', (34, 38))	('cause', 'Reg', (89, 94))	('Akt', 'Gene', '207', (62, 65))	('release', 'MPA', (157, 164))	('EGFR', 'Gene', '1956', (34, 38))	('beta-catenin', 'Gene', (95, 107))	('Bile acid', 'Chemical', 'MESH:D001647', (0, 9))	('Ser552', 'Chemical', '-', (127, 133))	('beta-catenin', 'Gene', '1499', (95, 107))	('Akt', 'Gene', (62, 65))	('Ser552', 'Var', (127, 133))	('activating', 'PosReg', (23, 33))
3849	31308377	Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC).	('esophageal adenocarcinoma', 'Disease', (287, 312))	('cancer', 'Disease', (17, 23))	('esophageal adenocarcinoma', 'Disease', (120, 145))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('cancer', 'Disease', (270, 276))	('cancers', 'Disease', (270, 277))	('alterations', 'Var', (193, 204))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('EAC', 'Phenotype', 'HP:0011459', (314, 317))	('cancers', 'Disease', 'MESH:D009369', (270, 277))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (287, 312))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (120, 145))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (287, 312))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (120, 145))	('Patient', 'Species', '9606', (0, 7))
3854	31308377	Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.	('EAC', 'Phenotype', 'HP:0011459', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('alterations', 'Var', (29, 40))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('alterations', 'MPA', (173, 184))
3857	31308377	Genome instability enables the onset of several hallmarks of cancer with some acquired alterations conferring selective advantages to the mutated cells and driving their outgrowth and eventual dominance.	('outgrowth', 'CPA', (170, 179))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('alterations', 'Var', (87, 98))	('cancer', 'Disease', (61, 67))	('advantages', 'PosReg', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
3863	31308377	In over 400 EACs sequenced so far, mutations in TP53, CDKN2A, SMARCA4, ARID1A, SMAD4, ERBB2, MYD88, PIK3CA, KAT6A, ARID2, as well as amplifications of VEGFA, ERBB2, EGFR, GATA4/6, CCNE1 are the most recurrent driver events.	('ARID2', 'Gene', (115, 120))	('PIK3CA', 'Gene', (100, 106))	('CDKN2A', 'Gene', '1029', (54, 60))	('CCNE1', 'Gene', (180, 185))	('KAT6A', 'Gene', '7994', (108, 113))	('EGFR', 'Gene', '1956', (165, 169))	('TP53', 'Gene', '7157', (48, 52))	('SMARCA4', 'Gene', (62, 69))	('SMAD4', 'Gene', '4089', (79, 84))	('MYD88', 'Gene', '4615', (93, 98))	('GATA4/6', 'Gene', '2626;2627', (171, 178))	('ERBB2', 'Gene', (158, 163))	('CCNE1', 'Gene', '898', (180, 185))	('ERBB2', 'Gene', (86, 91))	('ARID1A', 'Gene', (71, 77))	('EAC', 'Phenotype', 'HP:0011459', (12, 15))	('VEGFA', 'Gene', (151, 156))	('MYD88', 'Gene', (93, 98))	('KAT6A', 'Gene', (108, 113))	('amplifications', 'Var', (133, 147))	('ERBB2', 'Gene', '2064', (158, 163))	('ERBB2', 'Gene', '2064', (86, 91))	('ARID1A', 'Gene', '8289', (71, 77))	('PIK3CA', 'Gene', '5290', (100, 106))	('ARID2', 'Gene', '196528', (115, 120))	('EGFR', 'Gene', (165, 169))	('GATA4/6', 'Gene', (171, 178))	('TP53', 'Gene', (48, 52))	('CDKN2A', 'Gene', (54, 60))	('SMARCA4', 'Gene', '6597', (62, 69))	('VEGFA', 'Gene', '7422', (151, 156))	('SMAD4', 'Gene', (79, 84))	('mutations', 'Var', (35, 44))
3865	31308377	Here we hypothesise that, alongside the critical role of recurrent and well-known drivers, complementary somatic alterations of other genes help cancer progression in individual patients.	('cancer', 'Disease', (145, 151))	('patients', 'Species', '9606', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('help', 'PosReg', (140, 144))	('alterations', 'Var', (113, 124))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
3893	31308377	The properties of top scoring genes therefore resemble those of known cancer genes.	('cancer', 'Disease', (70, 76))	('genes', 'Var', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
3915	31308377	EACs in cluster 1H are also significantly associated with several known drivers including RECQL4, RARA, MYC, SMARCE1 and ERBB2 (Fig.	('RARA', 'Gene', (98, 102))	('SMARCE1', 'Gene', (109, 116))	('SMARCE1', 'Gene', '6605', (109, 116))	('associated', 'Reg', (42, 52))	('RECQL4', 'Gene', (90, 96))	('MYC', 'Gene', (104, 107))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('RECQL4', 'Gene', '9401', (90, 96))	('ERBB2', 'Gene', '2064', (121, 126))	('MYC', 'Gene', '4609', (104, 107))	('EACs', 'Var', (0, 4))	('RARA', 'Gene', '5914', (98, 102))	('ERBB2', 'Gene', (121, 126))	('1H', 'Chemical', '-', (16, 18))
3916	31308377	They have a prevalence of mutational signature S3 and are enriched in early (stage 2) tumours (Fig.	('mutational signature S3', 'Var', (26, 49))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))
3921	31308377	Dysregulation of E2F transcription factors or the MCM complex can induce genomic instability through either aberrant cell-cycle control or replicative stress.	('MCM', 'Gene', '4176;31449;4172;39014;4176', (50, 53))	('genomic instability', 'CPA', (73, 92))	('Dysregulation', 'Var', (0, 13))	('induce', 'Reg', (66, 72))	('replicative stress', 'CPA', (139, 157))	('MCM', 'Gene', (50, 53))	('E2F transcription factors', 'Protein', (17, 42))
3934	31308377	To test whether the germline genetic makeup of EAC patients was associated with the somatic perturbation of specific processes, we identified patients with potentially damaging germline variants in 152 known cancer predisposition genes.	('cancer', 'Disease', (208, 214))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('patients', 'Species', '9606', (51, 59))	('variants', 'Var', (186, 194))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
3957	31308377	Consistently with the suggested tumour suppressor role of NCOR2 in lymphoma and prostate cancer, the most frequent NCOR2 alterations in EAC lead to a loss of function.	('lymphoma and prostate cancer', 'Disease', 'MESH:D011471', (67, 95))	('alterations', 'Var', (121, 132))	('NCOR2', 'Gene', '9612', (115, 120))	('lymphoma', 'Phenotype', 'HP:0002665', (67, 75))	('tumour', 'Disease', (32, 38))	('EAC', 'Phenotype', 'HP:0011459', (136, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('NCOR2', 'Gene', (58, 63))	('NCOR2', 'Gene', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('NCOR2', 'Gene', '9612', (58, 63))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('loss of function', 'NegReg', (150, 166))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
3964	31308377	PSMD3 is amplified and overexpressed in three EACs of cluster 1H, which overall contains 14 samples with alterations in six proteasome subunits (Fig.	('1H', 'Chemical', '-', (62, 64))	('alterations', 'Var', (105, 116))	('PSMD3', 'Gene', (0, 5))	('EAC', 'Phenotype', 'HP:0011459', (46, 49))	('PSMD3', 'Gene', '5709', (0, 5))
3969	31308377	The fold changes in proliferation rate observed upon perturbation of helpers are in the same range as those observed following alteration of known strong drivers including TP53 or PIK3CA.	('proliferation', 'CPA', (20, 33))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('perturbation', 'Var', (53, 65))	('PIK3CA', 'Gene', (180, 186))	('PIK3CA', 'Gene', '5290', (180, 186))
3977	31308377	Most state-of-the-art approaches to discovering cancer driver events rely on the detection of positively selected alterations of genes that promote cancer development.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('alterations', 'Var', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('promote', 'PosReg', (140, 147))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
3987	31308377	By experimentally mimicking the amplification of E2F1 (representative of cluster 2H) and MCM7 (representative of cluster 4H), we increased proliferation in EAC cells (Fig.	('2H', 'Chemical', 'MESH:D003903', (81, 83))	('EAC', 'Disease', (156, 159))	('MCM7', 'Gene', (89, 93))	('amplification', 'Var', (32, 45))	('increased', 'PosReg', (129, 138))	('proliferation', 'CPA', (139, 152))	('4H', 'Chemical', '-', (121, 123))	('EAC', 'Phenotype', 'HP:0011459', (156, 159))	('E2F1', 'Gene', (49, 53))
3990	31308377	For example, MCM7 interacts with the tumour suppressor protein Rb, a well-characterised inhibitor of E2F1.	('tumour', 'Disease', (37, 43))	('MCM7', 'Var', (13, 17))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('interacts', 'Interaction', (18, 27))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
3994	31308377	We therefore speculate that it is the contribution of several genes perturbing the same pathways that promotes cancer progression rather than the alteration of one gene alone.	('perturbing', 'Var', (68, 78))	('promotes', 'PosReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
3997	31308377	Consistent with this, the perturbation of helpers leads to increased proliferation in BE cells and the effect is comparable to that of perturbing TP53 (Fig.	('BE', 'Phenotype', 'HP:0100580', (86, 88))	('TP53', 'Gene', '7157', (146, 150))	('proliferation', 'CPA', (69, 82))	('TP53', 'Gene', (146, 150))	('perturbation', 'Var', (26, 38))	('increased', 'PosReg', (59, 68))
4007	31308377	Nonframeshift and nonsynonymous mutations were considered as non-truncating damaging alterations if predicted by at least five of seven function-based methods (SIFT, PolyPhen-2 HDIV, PolyPhen-2 HVAR, MutationTaster, MutationAssessor, LRTand FATHMM) or by two out of three conservation-based methods (PhyloP, GERP + + RS, SiPhy), using the scores from dbNSFP v.3.0.	('Nonframeshift', 'Var', (0, 13))	('HD', 'Disease', 'MESH:D006816', (177, 179))	('SIFT', 'Disease', (160, 164))	('nonsynonymous mutations', 'Var', (18, 41))	('GERP', 'Gene', (308, 312))	('mutations', 'Var', (32, 41))	('GERP', 'Gene', '81603', (308, 312))	('SIFT', 'Disease', 'None', (160, 164))
4015	31308377	In step 2, 476 known cancer genes with damaging alterations (Supplementary Data 2) were used as a set of true positives for model selection.	('alterations', 'Var', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
4019	31308377	A manual revision of 476 known cancer genes altered in the ICGC cohort was performed and genes were considered as known drivers if (a) their somatic alteration had been previously associated with EAC, (b) they had a loss-of-function alteration and their tumour suppressor role had been reported in other cancer types, (c) they had a gain-of-function alteration and their oncogenic role had been reported in other cancer types.	('cancer', 'Disease', (413, 419))	('cancer', 'Disease', 'MESH:D009369', (413, 419))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('loss-of-function', 'NegReg', (216, 232))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('alteration', 'MPA', (350, 360))	('gain-of-function', 'PosReg', (333, 349))	('cancer', 'Disease', (304, 310))	('tumour', 'Disease', (254, 260))	('EAC', 'Phenotype', 'HP:0011459', (196, 199))	('alteration', 'Var', (233, 243))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (413, 419))	('EAC', 'Disease', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('cancer', 'Disease', (31, 37))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))
4023	31308377	EAC patients that carried a rare damaging germline variant in one of these genes were considered to carry a cancer predisposition variant.	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('patients', 'Species', '9606', (4, 12))	('germline variant', 'Var', (42, 58))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
4027	31308377	CP-A cells were grown at 37  C and five per cent CO2 in Keratinocyte serum-free medium with 50 microg ml-1 bovine pituitary extract and 5 ng ml-1 recombinant human EGF (17005042, Thermo Fisher).	('human', 'Species', '9606', (158, 163))	('CP-A', 'Gene', '1357', (0, 4))	('CP-A', 'Gene', (0, 4))	('bovine', 'Species', '9913', (107, 113))	('17005042', 'Var', (169, 177))	('CO2', 'Chemical', '-', (49, 52))
4038	31308377	To induce ABI2 and NCOR2 gene knock-out (KO) in FLO-1 cells, the vector-free CRISPR-mediated editing approach was used as previously described.	('ABI2', 'Gene', (10, 14))	('NCOR2', 'Gene', '9612', (19, 24))	('knock-out', 'Var', (30, 39))	('ABI2', 'Gene', '10152', (10, 14))	('FLO-1', 'Chemical', '-', (48, 53))	('NCOR2', 'Gene', (19, 24))
4040	31308377	In CP-A cells, vector-free CRISPR-mediated editing of ABI2, NCOR2 or TP53 was performed by introducing two gene-specific crRNAs (Synthego, Supplementary Table 3) and GeneArt Platinum Cas9 nuclease (Life technologies) into the cells by nucleofection following the Neon  kit protocol (Thermo Fisher), with 2 pulses of 1200 V for 20 ms.	('NCOR2', 'Gene', (60, 65))	('ABI2', 'Gene', '10152', (54, 58))	('GeneArt', 'Var', (166, 173))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('CP-A', 'Gene', '1357', (3, 7))	('CP-A', 'Gene', (3, 7))	('NCOR2', 'Gene', '9612', (60, 65))	('ABI2', 'Gene', (54, 58))
4222	29594226	We hypothesized here that IMPT would be associated with lower rates of treatment-related lymphocytopenia in a cohort of 2:1 case-matched patients given IMRT or IMPT with curative intent.	('lymphocytopenia', 'Phenotype', 'HP:0001888', (89, 104))	('patients', 'Species', '9606', (137, 145))	('lower', 'NegReg', (56, 61))	('lymphocytopenia', 'Disease', 'MESH:D008231', (89, 104))	('lymphocytopenia', 'Disease', (89, 104))	('IMPT', 'Var', (26, 30))
4226	29594226	The two groups were matched based on treatment laterality (unilateral vs. bilateral), disease site (tonsil vs. base of tongue), p16/HPV status (positive vs. negative, with missing data considered as "any category"), T status (T1-T2 vs. T3-T4), N status (N0-N1 vs. N2-N3), receipt of concurrent chemotherapy, and smoking status.	('HPV', 'Species', '10566', (132, 135))	('T1-T2', 'Var', (226, 231))	('N0-N1', 'Var', (254, 259))
4271	29594226	High neutrophil counts before treatment were associated with high comorbidity scores and possibly with larger tumors, whereas lymphopenia during treatment was not associated with any clinical or tumor-related characteristics.	('lymphopenia', 'Phenotype', 'HP:0001888', (126, 137))	('tumor', 'Disease', (195, 200))	('high comorbidity scores', 'MPA', (61, 84))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('lymphopenia', 'Disease', 'MESH:D008231', (126, 137))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumors', 'Disease', (110, 116))	('lymphopenia', 'Disease', (126, 137))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('High neutrophil counts', 'Var', (0, 22))
4309	26633513	However, dysregulation or mutations in HH signaling leads to genomic instability (GI) and various cancers, for example, germline mutation in PTCH1 lead to Gorlin syndrome, a condition where patients develop numerous basal cell carcinomas and rarely rhabdomyosarcoma (RMS).	('rhabdomyosarcoma', 'Disease', (249, 265))	('HH', 'Gene', '42737', (39, 41))	('patients', 'Species', '9606', (190, 198))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('numerous basal cell carcinomas', 'Disease', 'MESH:D002280', (207, 237))	('mutations', 'Var', (26, 35))	('germline mutation', 'Var', (120, 137))	('cancers', 'Disease', (98, 105))	('RMS', 'Phenotype', 'HP:0002859', (267, 270))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (155, 170))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (249, 265))	('lead to', 'Reg', (147, 154))	('PTCH1', 'Gene', (141, 146))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (249, 265))	('dysregulation', 'Var', (9, 22))	('Gorlin syndrome', 'Disease', (155, 170))	('genomic', 'MPA', (61, 68))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (216, 237))	('numerous basal cell carcinomas', 'Disease', (207, 237))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (216, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (258, 265))	('leads to', 'Reg', (52, 60))
4310	26633513	Activating mutations in SMO have also been recognized in sporadic cases of medulloblastoma and SMO is overexpressed in many other cancers.	('SMO', 'Gene', '6608', (24, 27))	('medulloblastoma', 'Phenotype', 'HP:0002885', (75, 90))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('Activating mutations', 'Var', (0, 20))	('medulloblastoma', 'Disease', (75, 90))	('SMO', 'Gene', (24, 27))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('SMO', 'Gene', '6608', (95, 98))	('SMO', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('medulloblastoma', 'Disease', 'MESH:D008527', (75, 90))
4312	26633513	In fact, this aberrantly regulated GLI1 has been linked to several non-canonical oncogenic growth signals such as Kirsten rat sarcoma viral oncogene homolog (KRAS), avian myelocytomatosis virus oncogene cellular homolog (C-MYC), transforming growth factor beta (TGFbeta), wingless-type MMTV integration site family (WNT) and beta-catenin.	('aberrantly', 'Var', (14, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('C-MYC', 'Gene', '4609', (221, 226))	('avian myelocytomatosis virus', 'Species', '11867', (165, 193))	('MMTV', 'Species', '11757', (286, 290))	('TGFbeta', 'Gene', '7040', (262, 269))	('linked', 'Reg', (49, 55))	('GLI1', 'Gene', (35, 39))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('beta-catenin', 'Gene', (325, 337))	('C-MYC', 'Gene', (221, 226))	('rat', 'Species', '10116', (122, 125))	('rat', 'Species', '10116', (296, 299))	('beta-catenin', 'Gene', '1499', (325, 337))	('TGFbeta', 'Gene', (262, 269))	('sarcoma', 'Disease', (126, 133))
4313	26633513	Recent studies from our lab and other independent studies demonstrate that aberrantly expressed GLI1 influences the integrity of several DNA damage response and repair signals, and if altered, these networks can contribute to GI and impact tumor response to chemo- and radiation therapies.	('GLI1', 'Gene', (96, 100))	('impact tumor', 'Disease', 'MESH:D004834', (233, 245))	('aberrantly expressed', 'Var', (75, 95))	('contribute', 'Reg', (212, 222))	('impact tumor', 'Disease', (233, 245))	('influences', 'Reg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('rat', 'Species', '10116', (65, 68))
4315	26633513	In this review, we focus on summarizing current understanding of the molecular, biochemical and cellular basis for aberrant GLI1 expression and discuss GLI1-mediated HH signaling on DNA damage responses, carcinogenesis and chemoresistance.	('carcinogenesis', 'Disease', (204, 218))	('GLI1', 'Gene', (124, 128))	('HH', 'Gene', '42737', (166, 168))	('carcinogenesis', 'Disease', 'MESH:D063646', (204, 218))	('aberrant', 'Var', (115, 123))	('DNA damage', 'MPA', (182, 192))
4319	26633513	Dysregulation of HH signaling leads to numerous differentiation defects like segment polarity, holoprosencephaly, microencephaly or cyclopia, absent nose or cleft palate.	('leads to', 'Reg', (30, 38))	('cleft palate', 'Phenotype', 'HP:0000175', (157, 169))	('Dysregulation', 'Var', (0, 13))	('absent nose', 'Disease', (142, 153))	('holoprosencephaly', 'Disease', 'MESH:D016142', (95, 112))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (95, 112))	('cyclopia', 'Phenotype', 'HP:0009914', (132, 140))	('cleft palate', 'Disease', 'MESH:D002972', (157, 169))	('HH', 'Gene', '42737', (17, 19))	('microencephaly or cyclopia', 'Disease', 'MESH:D016142', (114, 140))	('microencephaly or cyclopia', 'Disease', (114, 140))	('holoprosencephaly', 'Disease', (95, 112))	('segment polarity', 'Disease', (77, 93))	('cleft palate', 'Disease', (157, 169))	('absent nose', 'Phenotype', 'HP:0009927', (142, 153))
4323	26633513	While the balanced physiologic activation of GLI1 regulates differentiation and development of various organs, mutations in HH signaling genes or oncogenic signals upregulate the expression of GLI1 in a non-homeostatic manner (aberrant GLI1) leading to the development of neoplasm.	('mutations', 'Var', (111, 120))	('neoplasm', 'Disease', (272, 280))	('expression', 'MPA', (179, 189))	('development of various organs', 'CPA', (80, 109))	('leading to', 'Reg', (242, 252))	('HH', 'Gene', '42737', (124, 126))	('neoplasm', 'Disease', 'MESH:D009369', (272, 280))	('neoplasm', 'Phenotype', 'HP:0002664', (272, 280))	('GLI1', 'Gene', (193, 197))	('upregulate', 'PosReg', (164, 174))	('differentiation', 'CPA', (60, 75))	('regulates', 'Reg', (50, 59))
4324	26633513	Somatic or germline mutations of GLI1 have been reported in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('reported', 'Reg', (48, 56))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('GLI1', 'Gene', (33, 37))	('germline mutations', 'Var', (11, 29))
4329	26633513	Together these observations suggest an important role for aberrant GLI1 signaling in various stages of tumor development, from inducing mutagenic lesions, carcinogenesis, metastasis and resistance to cancer therapeutics.	('inducing', 'Reg', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('carcinogenesis', 'Disease', (155, 169))	('tumor', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('aberrant', 'Var', (58, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (155, 169))	('metastasis', 'CPA', (171, 181))	('resistance', 'CPA', (186, 196))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Disease', (200, 206))	('mutagenic lesions', 'MPA', (136, 153))
4331	26633513	In this review we have discussed the role of aberrant GLI1 in DNA damage response (DDR), carcinogenesis and chemoresistance.	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('aberrant', 'Var', (45, 53))	('DNA damage', 'Disease', (62, 72))	('carcinogenesis', 'Disease', (89, 103))	('GLI1', 'Gene', (54, 58))
4334	26633513	Phosphorylated SMO then facilitates the dissociation of GLI proteins from kinesin-family protein, kinesin superfamily 7 (Kif7), and suppressor of fused (SUFU).	('Phosphorylated', 'Var', (0, 14))	('Kif7', 'Gene', (121, 125))	('kinesin superfamily 7', 'Gene', '374654', (98, 119))	('facilitates', 'PosReg', (24, 35))	('dissociation', 'MPA', (40, 52))	('Kif7', 'Gene', '374654', (121, 125))	('SMO', 'Gene', '6608', (15, 18))	('kinesin superfamily 7', 'Gene', (98, 119))	('GLI', 'Gene', '2735', (56, 59))	('SMO', 'Gene', (15, 18))	('SUFU', 'Gene', (153, 157))	('SUFU', 'Gene', '51684', (153, 157))	('GLI', 'Gene', (56, 59))
4337	26633513	In addition to this, certain mutations in the HH signaling pathway members upstream of GLI1 induce its overexpression and alter the regulation of target genes that are involved in differentiation, DNA repair, and cell cycle checkpoint regulation.	('alter', 'Reg', (122, 127))	('GLI1', 'Gene', (87, 91))	('mutations', 'Var', (29, 38))	('HH', 'Gene', '42737', (46, 48))	('regulation of', 'MPA', (132, 145))	('overexpression', 'MPA', (103, 117))
4343	26633513	Activating mutations in KRAS have been linked to several cancers, including pancreatic, ovarian, lung and colon.	('Activating mutations', 'Var', (0, 20))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('linked', 'Reg', (39, 45))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('pancreatic, ovarian, lung and colon', 'Disease', 'MESH:D008175', (76, 111))	('KRAS', 'Gene', (24, 28))
4349	26633513	Similarly, aberrant expression of the transcription factor and oncogene EWS-FLI1, which is responsible for the Ewing sarcoma family of tumors, transcriptionally increases GLI1 expression.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('EWS', 'Gene', '2130', (72, 75))	('EWS', 'Gene', (72, 75))	('FLI1', 'Gene', '2313', (76, 80))	('aberrant expression', 'Var', (11, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('FLI1', 'Gene', (76, 80))	('Ewing sarcoma', 'Disease', (111, 124))	('tumors', 'Disease', (135, 141))	('expression', 'MPA', (176, 186))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('increases', 'PosReg', (161, 170))	('GLI1', 'Gene', (171, 175))
4357	26633513	Genetic analysis of pancreatic cancers showed mutations in GLI1 with clear functional relevance to neoplasia.	('neoplasia', 'Disease', 'MESH:D009369', (99, 108))	('GLI1', 'Gene', (59, 63))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('neoplasia', 'Disease', (99, 108))	('pancreatic cancers', 'Disease', 'MESH:D010190', (20, 38))	('pancreatic cancers', 'Disease', (20, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('neoplasia', 'Phenotype', 'HP:0002664', (99, 108))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (20, 38))
4358	26633513	Missense and nonsense mutations of GLI1 were also documented in melanoma and squamous cell carcinoma.	('nonsense mutations', 'Var', (13, 31))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('melanoma', 'Disease', (64, 72))	('documented', 'Reg', (50, 60))	('GLI1', 'Gene', (35, 39))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))	('Missense', 'Var', (0, 8))
4359	26633513	Additionally, the fusion of ACTB (beta-actin) with GLI1 t(7;12), has been associated in pericytoma.	('ACTB', 'Gene', '60', (28, 32))	('associated', 'Reg', (74, 84))	('beta-actin', 'Gene', '728378', (34, 44))	('beta-actin', 'Gene', (34, 44))	('fusion', 'Var', (18, 24))	('ACTB', 'Gene', (28, 32))	('pericytoma', 'Disease', (88, 98))
4361	26633513	Apart from cancers, mutations in GLI1 were found in Hirschsprung disease, which is characterized as abnormal neural crest cells differentiation.	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('found', 'Reg', (43, 48))	('Hirschsprung disease', 'Disease', (52, 72))	('GLI1', 'Gene', (33, 37))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('Hirschsprung disease', 'Disease', 'MESH:D006627', (52, 72))	('mutations', 'Var', (20, 29))
4363	26633513	The (GLI1DeltaN) variant acts on genes similarly to GLI1 in both normal and cancer cells.	('GLI1DeltaN) variant', 'Var', (5, 24))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('variant', 'Var', (17, 24))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
4364	26633513	Interestingly, the tGLI1 variant is expressed only in the tumor tissues and has been characterized as a stronger promoter of epithelial-mesenchymal transition (EMT) phenotype, an important feature in carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('epithelial-mesenchymal transition', 'CPA', (125, 158))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('variant', 'Var', (25, 32))	('stronger promoter', 'PosReg', (104, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (200, 214))	('tGLI1', 'Gene', (19, 24))	('carcinogenesis', 'Disease', (200, 214))
4365	26633513	Overall, aberrant expression of GLI1 and its isoforms in the setting of either canonical or non-canonical signaling regulates genes that are involved in the repair of DNA damage, cell cycle, carcinogenesis, and multidrug resistance (MDR).	('carcinogenesis', 'Disease', (191, 205))	('regulates', 'Reg', (116, 125))	('drug resistance', 'Phenotype', 'HP:0020174', (216, 231))	('genes', 'Gene', (126, 131))	('multidrug resistance', 'Disease', (211, 231))	('GLI1', 'Gene', (32, 36))	('aberrant', 'Var', (9, 17))	('carcinogenesis', 'Disease', 'MESH:D063646', (191, 205))
4368	26633513	Even though, many questions remain concerning how aberrant activation of GLI1 influences cell cycle checkpoints and DNA repair, there are few reports that clearly indicate potential mechanisms that GLI1 could control in order to protect tumor cells from oncogenic stress and chemotherapy.	('tumor', 'Disease', (237, 242))	('influences', 'Reg', (78, 88))	('GLI1', 'Gene', (73, 77))	('activation', 'PosReg', (59, 69))	('cell cycle checkpoints', 'CPA', (89, 111))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('aberrant', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
4374	26633513	In this study, loss of either non-homologous end joining (NHEJ) gene DNA Ligase IV (Lig4), or genes involved in homologous recombination (HR) like X-ray cross complementation 2 (XRCC2), and breast cancer growth suppressor protein 2 (BRCA2), or (Lig4/XRCC2) in combination with p53 deficiency resulted in PTCH1 downregulation, GLI1 activation and rapid development of medulloblastoma.	('activation', 'PosReg', (331, 341))	('DNA Ligase IV', 'Gene', '3981', (69, 82))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('GLI1', 'Gene', (326, 330))	('XRCC2', 'Gene', '7516', (250, 255))	('BRCA2', 'Gene', '675', (233, 238))	('XRCC2', 'Gene', '7516', (178, 183))	('X-ray cross complementation 2', 'Gene', '7516', (147, 176))	('Lig4', 'Gene', (245, 249))	('deficiency', 'Var', (281, 291))	('X-ray cross complementation 2', 'Gene', (147, 176))	('DNA Ligase IV', 'Gene', (69, 82))	('Lig4', 'Gene', '3981', (245, 249))	('p53', 'Gene', (277, 280))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Lig4', 'Gene', (84, 88))	('PTCH1', 'Gene', (304, 309))	('medulloblastoma', 'Disease', 'MESH:D008527', (367, 382))	('XRCC2', 'Gene', (250, 255))	('medulloblastoma', 'Phenotype', 'HP:0002885', (367, 382))	('loss', 'NegReg', (15, 19))	('XRCC2', 'Gene', (178, 183))	('Lig4', 'Gene', '3981', (84, 88))	('medulloblastoma', 'Disease', (367, 382))	('BRCA2', 'Gene', (233, 238))	('downregulation', 'NegReg', (310, 324))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
4375	26633513	This study not only confirms a function link between DDR, repair and HH signaling, but reveals that DNA damage induced expression of GLI1 was kept in check by p53 and loss of p53 results in GLI1 overexpression, a novel regulation of GLI1 by tumor suppressor protein p53.	('tumor', 'Disease', (241, 246))	('HH', 'Gene', '42737', (69, 71))	('overexpression', 'PosReg', (195, 209))	('GLI1', 'Gene', (190, 194))	('p53', 'Gene', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('loss', 'Var', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
4376	26633513	The above observations were further supported by mechanistic studies that demonstrated p53 mediated regulation of GLI1 by post-translational modification in response to genotoxic stress.	('regulation', 'MPA', (100, 110))	('rat', 'Species', '10116', (81, 84))	('post-translational modification', 'MPA', (122, 153))	('GLI1', 'Gene', (114, 118))	('p53', 'Var', (87, 90))
4381	26633513	It is interesting to note that GLI1 is one of the primary targets of p53 in response to genotoxic stress, and degradation of GLI1 prevents the proliferation of cells.	('degradation', 'Var', (110, 121))	('GLI1', 'Gene', (125, 129))	('rat', 'Species', '10116', (150, 153))	('prevents', 'NegReg', (130, 138))	('proliferation of cells', 'CPA', (143, 165))
4384	26633513	In human colon carcinoma cells, inhibition of GLI1 induced extensive cell death while the inhibition of HH signaling at the level of SMO did not.	('inhibition', 'Var', (32, 42))	('HH', 'Gene', '42737', (104, 106))	('human', 'Species', '9606', (3, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('GLI1', 'Gene', (46, 50))	('SMO', 'Gene', '6608', (133, 136))	('colon carcinoma', 'Disease', 'MESH:D015179', (9, 24))	('SMO', 'Gene', (133, 136))	('colon carcinoma', 'Disease', (9, 24))	('cell death', 'CPA', (69, 79))
4387	26633513	Thus, inhibition of GLI1 blocks the replication-associated checkpoints and therefore, cancer cells with high proliferation rate and without proper cell cycle arrest/regulation will undergo cell death.	('replication-associated checkpoints', 'CPA', (36, 70))	('GLI1', 'Gene', (20, 24))	('undergo', 'Reg', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cell death', 'CPA', (189, 199))	('blocks', 'NegReg', (25, 31))	('rat', 'Species', '10116', (123, 126))	('rat', 'Species', '10116', (116, 119))	('inhibition', 'Var', (6, 16))	('arrest', 'Disease', 'MESH:D006323', (158, 164))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (147, 164))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('arrest', 'Disease', (158, 164))	('cancer', 'Disease', (86, 92))
4390	26633513	Under these conditions, the levels of pATM, pMDC1 and pNBS1Ser343 were increased and the level of gammaH2AX was found to be decreased, suggesting inhibition of GLI1 by GANT61 attenuates DDR and repair.	('pNBS1Ser343', 'Var', (54, 65))	('H2AX', 'Gene', (103, 107))	('ATM', 'Gene', (39, 42))	('decreased', 'NegReg', (124, 133))	('MDC1', 'Gene', '9656', (45, 49))	('increased', 'PosReg', (71, 80))	('ATM', 'Gene', '472', (39, 42))	('MDC1', 'Gene', (45, 49))	('inhibition', 'Var', (146, 156))	('attenuates', 'NegReg', (175, 185))	('H2AX', 'Gene', '3014', (103, 107))
4391	26633513	The authors concluded that decreased pNBS1Ser343 mediated DNA repair in 48 h GANT61 exposed cells lead to the cell death, whereas in cells exposed to only 24 h GANT61 treatment recovered from GLI1 inhibition mediated DNA damage due to the pNBS1 ser343 reexpression and its mediated DNA repair.	('NBS1', 'Gene', '4683', (38, 42))	('reexpression', 'PosReg', (252, 264))	('NBS1', 'Gene', '4683', (240, 244))	('decreased', 'NegReg', (27, 36))	('ser343', 'Chemical', '-', (245, 251))	('ser343', 'Var', (245, 251))	('NBS1', 'Gene', (240, 244))	('NBS1', 'Gene', (38, 42))
4392	26633513	These studies demonstrate an important role for aberrant GLI1 in regulation of the DDR and repair signaling in cancer cells, which could contribute to tumor cell survival from oncogenic stress and develop chemoresistance.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('chemoresistance', 'CPA', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (151, 156))	('cancer', 'Disease', (111, 117))	('aberrant', 'Var', (48, 56))	('rat', 'Species', '10116', (21, 24))	('develop', 'PosReg', (197, 204))	('contribute', 'Reg', (137, 147))	('GLI1', 'Gene', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
4406	26633513	Impaired SHH signaling has been shown to induce spontaneous and ionizing radiation (IR)-induced genome instability and tumors development in mice.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('induce', 'Reg', (41, 47))	('genome instability', 'CPA', (96, 114))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('SHH', 'Protein', (9, 12))	('Impaired', 'Var', (0, 8))
4408	26633513	Although mutations in PTCH1 in humans and Ptc heterozygous mice (ptc+/-) known to develop increased spontaneous medulloblastoma; however, the mechanisms that lead to tumor development were not known.	('PTCH1', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('mice', 'Species', '10090', (59, 63))	('medulloblastoma', 'Phenotype', 'HP:0002885', (112, 127))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('medulloblastoma', 'Disease', 'MESH:D008527', (112, 127))	('increased', 'PosReg', (90, 99))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', (166, 171))	('medulloblastoma', 'Disease', (112, 127))	('humans', 'Species', '9606', (31, 37))
4411	26633513	GLI1 expression abrogated IR-induced ATR-CHK1 signaling in these cells by disrupting DNA damage-induced binding of claspin to CHK1 and subsequent phosphorylation of CHK1 by ATR at Ser317 and Ser345 (Figure 2B).	('claspin', 'Gene', '63967', (115, 122))	('GLI1', 'Gene', (0, 4))	('claspin', 'Gene', (115, 122))	('CHK1', 'Gene', (126, 130))	('disrupting', 'NegReg', (74, 84))	('CHK1', 'Gene', (165, 169))	('DNA damage-induced', 'MPA', (85, 103))	('Ser317', 'Chemical', '-', (180, 186))	('expression', 'Var', (5, 15))	('binding', 'Interaction', (104, 111))	('Ser345', 'Chemical', '-', (191, 197))	('Ser345', 'Var', (191, 197))	('abrogated', 'NegReg', (16, 25))	('Ser317', 'Var', (180, 186))	('phosphorylation', 'MPA', (146, 161))
4413	26633513	In contrast to above mechanism, our recent studies have revealed a tumor-specific role for aberrant GLI1 in regulation of S phase checkpoint.	('GLI1', 'Gene', (100, 104))	('S phase checkpoint', 'MPA', (122, 140))	('regulation', 'MPA', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('aberrant', 'Var', (91, 99))
4414	26633513	Inhibition of GLI1 in several tumor cell lines originated from different tissues induced replication associated DNA damage as indicated by gammaH2AX and attenuated tumor cell growth.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('GLI1', 'Gene', (14, 18))	('tumor', 'Disease', (164, 169))	('induced', 'Reg', (81, 88))	('replication associated DNA damage', 'MPA', (89, 122))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('attenuated tumor', 'Disease', (153, 169))	('attenuated tumor', 'Disease', 'MESH:C538265', (153, 169))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('H2AX', 'Gene', '3014', (144, 148))	('H2AX', 'Gene', (144, 148))	('tumor', 'Disease', (30, 35))
4415	26633513	Further analysis of replication stress-induced by DNA topoisomerase 1 (TOP 1) poison CPT revealed aberrant GLI1 important for the activation of S-phase checkpoint mediated by CHK1 in tumor cells.	('aberrant', 'Var', (98, 106))	('CPT', 'Gene', '56994', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('activation', 'PosReg', (130, 140))	('GLI1', 'Gene', (107, 111))	('CPT', 'Gene', (85, 88))	('DNA topoisomerase 1', 'Gene', '7150', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('S-phase checkpoint mediated', 'MPA', (144, 171))	('tumor', 'Disease', (183, 188))	('DNA topoisomerase 1', 'Gene', (50, 69))
4417	26633513	Furthermore, inhibition of GLI1 by either siRNAs or by pharmacological inhibitor GANT61 transcriptionally repressed the expression of BID, affected the association of RPA with the (ATRIP)-ATR complex, and compromised ATR-mediated phosphorylation/activation of CHK1.	('RPA', 'Gene', (167, 170))	('inhibition', 'Var', (13, 23))	('ATRIP', 'Gene', '84126', (181, 186))	('RPA', 'Gene', '6117', (167, 170))	('BID', 'Gene', '637', (134, 137))	('ATRIP', 'Gene', (181, 186))	('ATR-mediated phosphorylation/activation', 'MPA', (217, 256))	('association', 'Interaction', (152, 163))	('BID', 'Gene', (134, 137))	('compromised', 'NegReg', (205, 216))	('CHK1', 'Enzyme', (260, 264))	('affected', 'Reg', (139, 147))
4419	26633513	Similar to CHK1 inhibitors, pharmacological inhibition of aberrantly expressed GLI1 in tumor cells abrogated CPT-induced checkpoint responses, enhanced CPT-induced replication-mediated DNA damage and increased its cytotoxicity.	('CPT', 'Gene', '56994', (109, 112))	('GLI1', 'Gene', (79, 83))	('cytotoxicity', 'Disease', (214, 226))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('enhanced', 'PosReg', (143, 151))	('CPT', 'Gene', (109, 112))	('increased', 'PosReg', (200, 209))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cytotoxicity', 'Disease', 'MESH:D064420', (214, 226))	('replication-mediated DNA damage', 'MPA', (164, 195))	('CPT', 'Gene', '56994', (152, 155))	('abrogated', 'NegReg', (99, 108))	('aberrantly expressed', 'Var', (58, 78))	('CPT', 'Gene', (152, 155))
4422	26633513	), our studies suggests role for aberrant GLI1 during carcinogenesis, as well as their response to chemotherapy.	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('carcinogenesis', 'Disease', (54, 68))	('aberrant', 'Var', (33, 41))
4425	26633513	Secondly, depletion of GLI1 causes a loss of BID which also leads to disruption of CHK1 activation.	('disruption', 'NegReg', (69, 79))	('BID', 'Gene', (45, 48))	('GLI1', 'Gene', (23, 27))	('depletion', 'Var', (10, 19))	('CHK1', 'Protein', (83, 87))	('loss', 'NegReg', (37, 41))	('activation', 'MPA', (88, 98))	('BID', 'Gene', '637', (45, 48))
4426	26633513	As disrupted DNA repair can directly lead to persistence of mutations that may promote carcinogenesis, studying GLI1 could lead to improved targeted therapies in repair-deficient tumors.	('lead', 'Reg', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('deficient tumors', 'Disease', (169, 185))	('deficient tumors', 'Disease', 'MESH:D009369', (169, 185))	('promote', 'PosReg', (79, 86))	('carcinogenesis', 'Disease', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mutations', 'Var', (60, 69))
4427	26633513	As previously described, GLI1-mediated dysregulation of DNA repair can directly or indirectly lead to GI and such GI can promote carcinogenesis.	('dysregulation', 'Var', (39, 52))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('DNA repair', 'Gene', (56, 66))	('carcinogenesis', 'Disease', (129, 143))	('lead to', 'Reg', (94, 101))	('promote', 'PosReg', (121, 128))
4440	26633513	It is also necessary to analyze the roles of the different GLI1 mutations that are found in cancer on the development and progression of the cancer.	('GLI1', 'Gene', (59, 63))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (141, 147))
4442	26633513	Almost 90% of pancreatic ductal adenocarcinoma (PDA) has shown mutation in KRAS oncogene.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (14, 46))	('KRAS oncogene', 'Gene', (75, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('mutation', 'Var', (63, 71))	('PDA', 'Phenotype', 'HP:0006725', (48, 51))	('pancreatic ductal adenocarcinoma', 'Disease', (14, 46))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (14, 46))
4452	26633513	Increased tumor growth was noticed in the GKO/KPC mice compared to KPC group alone.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('mice', 'Species', '10090', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('GKO/KPC', 'Var', (42, 49))
4462	26633513	It is important to highlight here again that in addition to GLI1 role in regulation of various mechanisms in tumor development, GLI1-induced disruption of ATR-CHK1 checkpoint signaling in the developing brain may generate the precursor lesions that lead to medulloblastoma formation.	('lead to', 'Reg', (249, 256))	('medulloblastoma', 'Disease', 'MESH:D008527', (257, 272))	('medulloblastoma', 'Phenotype', 'HP:0002885', (257, 272))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('GLI1-induced', 'Gene', (128, 140))	('disruption', 'Var', (141, 151))	('medulloblastoma', 'Disease', (257, 272))	('rat', 'Species', '10116', (217, 220))	('tumor', 'Disease', (109, 114))
4467	26633513	Patients with nuclear GLI1 or FOXC2 typically exhibited diminished length of survival.	('FOXC2', 'Gene', '2303', (30, 35))	('length', 'MPA', (67, 73))	('Patients', 'Species', '9606', (0, 8))	('diminished', 'NegReg', (56, 66))	('nuclear', 'Var', (14, 21))	('FOXC2', 'Gene', (30, 35))
4471	26633513	Interestingly, silencing GLI1 expression in GLI1-induced tumors did not result in tumor regression, as the cells unexpectedly continued proliferation independent of GLI1.	('GLI1', 'Gene', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('silencing', 'Var', (15, 24))	('rat', 'Species', '10116', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('continued', 'PosReg', (126, 135))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (82, 87))	('proliferation', 'CPA', (136, 149))
4472	26633513	The promoter region of the HH gene was found to be hypo-methylated in breast cancers and this correlated with increased HH and nuclear factor (NF)-kB expression, and nuclear accumulation of GLI1.	('HH', 'Gene', '42737', (27, 29))	('expression', 'MPA', (150, 160))	('increased HH', 'Phenotype', 'HP:0001900', (110, 122))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('nuclear accumulation', 'CPA', (166, 186))	('increased', 'PosReg', (110, 119))	('breast cancers', 'Phenotype', 'HP:0003002', (70, 84))	('HH', 'Gene', '42737', (120, 122))	('breast cancers', 'Disease', 'MESH:D001943', (70, 84))	('breast cancers', 'Disease', (70, 84))	('nuclear', 'Protein', (127, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('hypo-methylated', 'Var', (51, 66))
4480	26633513	Loss of E-cadherin causes beta-catenin to migrate into the nucleus, where it acts as a transcription factor and induces cell transformation.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('beta-catenin', 'Gene', '1499', (26, 38))	('migrate', 'CPA', (42, 49))	('induces', 'Reg', (112, 119))	('beta-catenin', 'Gene', (26, 38))	('Loss', 'Var', (0, 4))	('rat', 'Species', '10116', (45, 48))	('cell transformation', 'CPA', (120, 139))
4483	26633513	Ectopic expression of GLI1 induced beta-catenin expression in the nuclei of endometrial cancer cell lines, and aberrant activation of this pathway may have a role in the development of endometrial cancer.	('beta-catenin', 'Gene', (35, 47))	('endometrial cancer', 'Phenotype', 'HP:0012114', (185, 203))	('endometrial cancer', 'Disease', 'MESH:D016889', (185, 203))	('endometrial cancer', 'Disease', (76, 94))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('expression', 'MPA', (48, 58))	('Ectopic expression', 'Var', (0, 18))	('activation', 'PosReg', (120, 130))	('beta-catenin', 'Gene', '1499', (35, 47))	('endometrial cancer', 'Phenotype', 'HP:0012114', (76, 94))	('induced', 'Reg', (27, 34))	('aberrant', 'Var', (111, 119))	('endometrial cancer', 'Disease', 'MESH:D016889', (76, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('GLI1', 'Gene', (22, 26))	('role', 'Reg', (158, 162))	('endometrial cancer', 'Disease', (185, 203))
4491	26633513	Loss of hTERT induces cellular senescence, while increased hTERT has been observed in many cancer cells.	('cellular senescence', 'CPA', (22, 41))	('hTERT', 'Gene', (59, 64))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('hTERT', 'Gene', '7015', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('hTERT', 'Gene', (8, 13))	('hTERT', 'Gene', '7015', (59, 64))	('Loss', 'Var', (0, 4))
4495	26633513	Aberrant expression of these DNMTs and dysregulation of DNA methylation has been reported in many cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('dysregulation', 'Var', (39, 52))	('DNMT', 'Gene', '1786', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('DNMT', 'Gene', (29, 33))	('DNA', 'Gene', (56, 59))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('expression', 'MPA', (9, 19))	('cancers', 'Disease', (98, 105))	('reported', 'Reg', (81, 89))
4504	26633513	It has also been reported that GLI1 is over-expressed in more than 50% of hepatocellular carcinomas, and inhibition of HH signaling attenuated tumor growth and induced apoptosis.	('inhibition', 'Var', (105, 115))	('attenuated tumor', 'Disease', (132, 148))	('induced', 'Reg', (160, 167))	('GLI1', 'Gene', (31, 35))	('attenuated tumor', 'Disease', 'MESH:C538265', (132, 148))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (74, 99))	('apoptosis', 'CPA', (168, 177))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (74, 99))	('over-expressed', 'PosReg', (39, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('HH', 'Gene', '42737', (119, 121))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('hepatocellular carcinomas', 'Disease', (74, 99))
4511	26633513	It will be interesting to note whether GLI1 alone is enough to induce tumor recurrence or if it works in combination with other oncogenic signals.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('induce', 'Reg', (63, 69))	('tumor', 'Disease', (70, 75))	('GLI1', 'Var', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
4518	26633513	GLI1 has diverse functions including regulation of epigenetic methylation, cancer stem cells, hypoxia and human telomerase.	('epigenetic', 'Var', (51, 61))	('GLI1', 'Gene', (0, 4))	('human', 'Species', '9606', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('hypoxia', 'Disease', 'MESH:D000860', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('hypoxia', 'Disease', (94, 101))
4523	26633513	On the other hand, inhibition of GLI1 signaling enhances the sensitivity of CD133 cells to temozolomide.	('inhibition', 'Var', (19, 29))	('CD133', 'Gene', (76, 81))	('CD133', 'Gene', '8842', (76, 81))	('temozolomide', 'Chemical', 'MESH:D000077204', (91, 103))	('enhances', 'PosReg', (48, 56))	('sensitivity', 'MPA', (61, 72))	('GLI1', 'Protein', (33, 37))
4534	26633513	Inhibition of GLI1 in ovarian cancer cells that are resistant to cisplatin caused an accumulation of cisplatin in the nucleus.	('ovarian cancer', 'Disease', 'MESH:D010051', (22, 36))	('cisplatin', 'MPA', (101, 110))	('GLI1', 'Gene', (14, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('accumulation', 'PosReg', (85, 97))	('ovarian cancer', 'Disease', (22, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
4536	26633513	Inhibition of GLI1 not only suppresses tumor growth, but also sensitizes the cancer cells to chemotherapeutic agents.	('GLI1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('suppresses', 'NegReg', (28, 38))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', (39, 44))	('sensitizes', 'Reg', (62, 72))
4542	26633513	Recently, it has been shown that in acute myeloid leukemia (AML) patients, GLI1 expression induces resistance to ribavirin by modifying the activity of the drug.	('AML', 'Disease', 'MESH:D015470', (60, 63))	('acute myeloid leukemia', 'Disease', (36, 58))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (36, 58))	('resistance to ribavirin', 'MPA', (99, 122))	('ribavirin', 'Chemical', 'MESH:D012254', (113, 122))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (36, 58))	('modifying', 'Reg', (126, 135))	('AML', 'Phenotype', 'HP:0004808', (60, 63))	('AML', 'Disease', (60, 63))	('patients', 'Species', '9606', (65, 73))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (42, 58))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('activity of the drug', 'MPA', (140, 160))	('GLI1', 'Gene', (75, 79))	('induces', 'Reg', (91, 98))	('expression', 'Var', (80, 90))
4545	26633513	Knocking down GLI1 affects the protein stability of UGT1A and sensitizes the cells to ribavirin.	('UGT1A', 'Gene', (52, 57))	('GLI1', 'Gene', (14, 18))	('Knocking down', 'Var', (0, 13))	('affects', 'Reg', (19, 26))	('ribavirin', 'Chemical', 'MESH:D012254', (86, 95))	('protein stability', 'MPA', (31, 48))	('UGT1A', 'Gene', '7361', (52, 57))	('sensitizes', 'Reg', (62, 72))
4552	26633513	Inhibition of SMO prevents UV-induced basal cell carcinomas through the regulation of Fas expression and apoptosis.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (38, 58))	('SMO', 'Gene', '6608', (14, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('SMO', 'Gene', (14, 17))	('apoptosis', 'CPA', (105, 114))	('basal cell carcinomas', 'Disease', (38, 59))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (38, 59))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (38, 59))	('Inhibition', 'Var', (0, 10))	('Fas', 'Protein', (86, 89))
4565	26633513	Overall, our review summarizes and updates the role of aberrant GLI1 activation in the DNA damage response, carcinogenesis and chemoresistance.	('DNA damage', 'MPA', (87, 97))	('aberrant', 'Var', (55, 63))	('GLI1', 'Gene', (64, 68))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))	('activation', 'PosReg', (69, 79))
4567	26633513	The results may provide new directions for targeting aberrant GLI1 expression in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('GLI1', 'Gene', (62, 66))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('aberrant', 'Var', (53, 61))
4571	26633513	In 2011, the authors appended two new hallmarks of cancer, dysregulated cellular metabolism and avoiding immune destruction.	('dysregulated', 'Var', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cellular metabolism', 'CPA', (72, 91))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
4574	26633513	Apart from these hallmarks, other important functions like epigenetic modification, angiogenesis, hypoxia, cancer stem cells, hTERT activity, DNA damage, repair and GI are induced or regulated by GLI1.	('hTERT', 'Gene', (126, 131))	('angiogenesis', 'CPA', (84, 96))	('repair', 'CPA', (154, 160))	('hypoxia', 'Disease', (98, 105))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('hTERT', 'Gene', '7015', (126, 131))	('cancer', 'Disease', (107, 113))	('epigenetic', 'Var', (59, 69))
4580	26633513	Inhibiting GLI1 alone or in combination with oncogenic signals will help to solve the complex roles of GLI1 in carcinogenesis.	('carcinogenesis', 'Disease', (111, 125))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('Inhibiting', 'Var', (0, 10))	('GLI1', 'Gene', (11, 15))
4632	22279419	Recent studies have linked dysregulation of specific miRNAs to histological grade, neoplastic progression and metastatic potential.	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('metastatic potential', 'CPA', (110, 130))	('dysregulation', 'Var', (27, 40))	('neoplastic progression', 'CPA', (83, 105))
4635	22279419	We report for the first time C-PAC-induced modulation of five miRNAs in three EAC cell lines resulting in 26 validated gene targets and identification of key signaling pathways including p53, angiogenesis, T-cell activation and apoptosis.	('apoptosis', 'CPA', (228, 237))	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('p53', 'Gene', (187, 190))	('miR', 'Gene', '220972', (62, 65))	('C-PAC', 'Chemical', '-', (29, 34))	('miR', 'Gene', (62, 65))	('PAC', 'Phenotype', 'HP:0006699', (31, 34))	('p53', 'Gene', '7157', (187, 190))	('angiogenesis', 'CPA', (192, 204))	('modulation', 'Var', (43, 53))	('T-cell activation', 'CPA', (206, 223))
4650	22279419	In brief, in this report, we sought first to summarize the current findings on microRNA (miRNA or miR) expression patterns in BE through EAC pathologies and second, to identify C-PAC-induced alterations of miRNAs following treatment of a panel of three validated EAC human cell lines.	('EAC', 'Phenotype', 'HP:0011459', (263, 266))	('PAC', 'Phenotype', 'HP:0006699', (179, 182))	('EAC', 'Phenotype', 'HP:0011459', (137, 140))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (89, 92))	('miR', 'Gene', (98, 101))	('alterations', 'Reg', (191, 202))	('C-PAC', 'Chemical', '-', (177, 182))	('miR', 'Gene', '220972', (206, 209))	('miR', 'Gene', (206, 209))	('BE', 'Phenotype', 'HP:0100580', (126, 128))	('C-PAC-induced', 'Var', (177, 190))	('rat', 'Species', '10116', (195, 198))	('human', 'Species', '9606', (267, 272))
4652	22279419	Recent studies have linked dysregulation of specific miRNAs to histological grade, neoplastic progression, metastatic potential, treatment responiveness and patient prognosis.	('miR', 'Gene', '220972', (53, 56))	('metastatic potential', 'CPA', (107, 127))	('miR', 'Gene', (53, 56))	('patient', 'Species', '9606', (157, 164))	('dysregulation', 'Var', (27, 40))	('neoplastic progression', 'CPA', (83, 105))
4690	22279419	Similar concentrations of C-PAC have previously been found to inhibit the viability and proliferation of lung (NCI-H460) and colon cancer (SW460) cell lines, increase the percentage of cells accumulating at the G1 checkpoint, induce apoptosis, modulate global gene expression profiles and alter select proteins linked to cell cycle regulation and apoptosis.	('colon cancer', 'Disease', 'MESH:D015179', (125, 137))	('PAC', 'Phenotype', 'HP:0006699', (28, 31))	('induce', 'PosReg', (226, 232))	('rat', 'Species', '10116', (95, 98))	('C-PAC', 'Chemical', '-', (26, 31))	('inhibit', 'NegReg', (62, 69))	('alter', 'Reg', (289, 294))	('increase', 'PosReg', (158, 166))	('colon cancer', 'Disease', (125, 137))	('rat', 'Species', '10116', (15, 18))	('global gene expression profiles', 'MPA', (253, 284))	('C-PAC', 'Var', (26, 31))	('select', 'MPA', (295, 301))	('apoptosis', 'CPA', (233, 242))	('colon cancer', 'Phenotype', 'HP:0003003', (125, 137))	('NCI-H460', 'CellLine', 'CVCL:0459', (111, 119))	('viability', 'CPA', (74, 83))	('SW460', 'CellLine', 'CVCL:0459', (139, 144))	('proteins', 'Protein', (302, 310))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('proliferation', 'CPA', (88, 101))	('modulate', 'Reg', (244, 252))
4691	22279419	In addition, C-PACs' inhibitory effects are greater in cancer cells compared to normal HET1A esophageal cells (data not shown) and C-PAC shows superior inhibition of EAC cell viability (85-90% inhibition) compared to black raspberry extract (<40%).	('PAC', 'Phenotype', 'HP:0006699', (133, 136))	('C-PAC', 'Chemical', '-', (131, 136))	('-PACs', 'Phenotype', 'HP:0006699', (14, 19))	('inhibition', 'NegReg', (152, 162))	('EAC cell viability', 'CPA', (166, 184))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('EAC', 'Phenotype', 'HP:0011459', (166, 169))	('C-PAC', 'Chemical', '-', (13, 18))	('black raspberry', 'Species', '75079', (217, 232))	('PACs', 'Phenotype', 'HP:0006699', (15, 19))	('PAC', 'Phenotype', 'HP:0006699', (15, 18))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('inhibitory effects', 'MPA', (21, 39))	('C-PAC', 'Var', (131, 136))	('cancer', 'Disease', (55, 61))
4692	22279419	C-PAC has unique A-type chemical linkages found only in a limited number of fruits to date including cranberry, chokeberry, plums and avocado, which may account for some of the improved inhibitory capacity and other unique mechanisms by which C-PAC inhibits cancer-related processes in EAC cells.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('EAC', 'Phenotype', 'HP:0011459', (286, 289))	('improved', 'PosReg', (177, 185))	('plums', 'Species', '3758', (124, 129))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('C-PAC', 'Var', (243, 248))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('PAC', 'Phenotype', 'HP:0006699', (245, 248))	('C-PAC', 'Chemical', '-', (243, 248))	('cancer', 'Disease', (258, 264))	('avocado', 'Species', '3435', (134, 141))	('inhibits', 'NegReg', (249, 257))
4695	22279419	Table 1 summarizes aberrant miRNA expression in BE and EAC tissues as identified in 13 original research studies.	('EAC', 'Phenotype', 'HP:0011459', (55, 58))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('aberrant', 'Var', (19, 27))	('BE', 'Phenotype', 'HP:0100580', (48, 50))
4703	22279419	In addition, six of C-PAC-modulated miRs identified have been reported to be differentially expressed between EAC compared to NSE and also in premalignant pathologies, supporting that C-PAC may hold cancer inhibitory potential at late stages of neoplastic transformation, as well as early during the development of esophageal premalignancy.	('C-PAC', 'Chemical', '-', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('PAC', 'Phenotype', 'HP:0006699', (186, 189))	('esophageal premalignancy', 'Disease', (315, 339))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('PAC', 'Phenotype', 'HP:0006699', (22, 25))	('C-PAC', 'Chemical', '-', (20, 25))	('cancer', 'Disease', (199, 205))	('EAC', 'Phenotype', 'HP:0011459', (110, 113))	('miR', 'Gene', '220972', (36, 39))	('esophageal premalignancy', 'Disease', 'MESH:D004941', (315, 339))	('miR', 'Gene', (36, 39))	('C-PAC', 'Var', (184, 189))
4707	22279419	C-PAC also inversely impacted let-7b, miR-136, and miR-34a based upon BE and EAC cell line findings summarized in Supplemental Table 1.	('impacted', 'Reg', (21, 29))	('miR-136', 'Gene', (38, 45))	('BE', 'Phenotype', 'HP:0100580', (70, 72))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('miR-34a', 'Gene', (51, 58))	('miR-136', 'Gene', '406927', (38, 45))	('let-7b', 'Gene', '406884', (30, 36))	('let-7b', 'Gene', (30, 36))	('C-PAC', 'Var', (0, 5))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('miR-34a', 'Gene', '407040', (51, 58))
4729	22279419	These data support that C-PAC modulated some common cancer-linked pathways across all three EAC cell lines; however, unique pathways were also detected between the EAC cell lines in terms of C-PAC-induced changes likely reflecting differences in the molecular profiles of the individual cell lines.	('changes', 'Reg', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('C-PAC', 'Chemical', '-', (24, 29))	('C-PAC', 'Chemical', '-', (191, 196))	('EAC', 'Phenotype', 'HP:0011459', (164, 167))	('PAC', 'Phenotype', 'HP:0006699', (26, 29))	('PAC', 'Phenotype', 'HP:0006699', (193, 196))	('C-PAC-induced', 'Var', (191, 204))	('modulated', 'Reg', (30, 39))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('detected', 'Reg', (143, 151))
4737	22279419	C-PAC altered miRs (>=2 EAC cell lines) also resulted in the identification of 26 modulated pathways with 21 of the 26 overlapping with those identified as altered in EAC or BE tissues, supporting that C-PAC may normalize altered miRNA profiles in BE and EAC.	('BE', 'Phenotype', 'HP:0100580', (248, 250))	('normalize', 'NegReg', (212, 221))	('miR', 'Gene', '220972', (230, 233))	('EAC', 'Phenotype', 'HP:0011459', (167, 170))	('miR', 'Gene', (230, 233))	('EAC', 'Phenotype', 'HP:0011459', (24, 27))	('EAC', 'Phenotype', 'HP:0011459', (255, 258))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('miR', 'Gene', '220972', (14, 17))	('PAC', 'Phenotype', 'HP:0006699', (204, 207))	('miR', 'Gene', (14, 17))	('BE', 'Phenotype', 'HP:0100580', (174, 176))	('C-PAC', 'Var', (202, 207))	('C-PAC', 'Chemical', '-', (202, 207))
4740	22279419	Similarly, C-PAC altered a small number of PANTHER pathways not reported in EAC tissues, including oxidative stress response, hypoxia response via hypoxia-inducible factor activation, DNA replication and Notch signaling pathways.	('altered', 'Reg', (17, 24))	('hypoxia', 'Disease', (147, 154))	('DNA replication', 'Pathway', (184, 199))	('hypoxia', 'Disease', 'MESH:D000860', (147, 154))	('hypoxia', 'Disease', (126, 133))	('oxidative stress response', 'MPA', (99, 124))	('hypoxia', 'Disease', 'MESH:D000860', (126, 133))	('C-PAC', 'Chemical', '-', (11, 16))	('PANTHER pathways', 'Pathway', (43, 59))	('C-PAC', 'Var', (11, 16))	('oxidative stress', 'Phenotype', 'HP:0025464', (99, 115))	('Notch signaling pathways', 'Pathway', (204, 228))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))	('PAC', 'Phenotype', 'HP:0006699', (13, 16))
4742	22279419	As an example, mutations in P53, P16, PTEN, PIK3CA, RAS, and more recently, NOTCH have all been linked to cancers of the head and neck and based on the results presented are targets potentially modulated by C-PAC treatment.	('P16', 'Gene', '1029', (33, 36))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('P16', 'Gene', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('PIK3CA', 'Gene', (44, 50))	('PTEN', 'Gene', '5728', (38, 42))	('C-PAC', 'Chemical', '-', (207, 212))	('mutations', 'Var', (15, 24))	('NOTCH', 'Gene', (76, 81))	('cancers of the head and neck', 'Phenotype', 'HP:0012288', (106, 134))	('RAS', 'Gene', (52, 55))	('P53', 'Gene', (28, 31))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('linked to', 'Reg', (96, 105))	('PIK3CA', 'Gene', '5290', (44, 50))	('PAC', 'Phenotype', 'HP:0006699', (209, 212))	('P53', 'Gene', '7157', (28, 31))	('PTEN', 'Gene', (38, 42))
4745	22279419	Overall, the data support that C-PAC, a proanthocyanidin-rich cranberry extract, has potent inhibitory effects on the viability of EAC cells, which is in part attributable to modulation of select miRNAs, some of which are known to be altered in EAC and precursor lesions.	('C-PAC', 'Chemical', '-', (31, 36))	('EAC', 'Disease', (245, 248))	('EAC', 'Disease', (131, 134))	('modulation', 'Reg', (175, 185))	('miR', 'Gene', '220972', (196, 199))	('miR', 'Gene', (196, 199))	('proanthocyanidin', 'Chemical', 'MESH:C013221', (40, 56))	('PAC', 'Phenotype', 'HP:0006699', (33, 36))	('C-PAC', 'Var', (31, 36))	('EAC', 'Phenotype', 'HP:0011459', (131, 134))	('viability', 'CPA', (118, 127))	('inhibitory effects', 'NegReg', (92, 110))	('EAC', 'Phenotype', 'HP:0011459', (245, 248))
4850	20515502	Another finding in our study was that the high-dose preoperative CRT group had a much higher frequency of serious toxicities compared to other studies applying lower doses of concomitant cisplatin, 5-fluorouracil and RT.	('5-fluorouracil', 'Chemical', 'MESH:D005472', (198, 212))	('toxicities', 'Disease', (114, 124))	('high-dose', 'Var', (42, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('toxicities', 'Disease', 'MESH:D064420', (114, 124))
4871	32657048	The levels of beta-catenin, c-myc, and survivin were also downregulated by ART.	('c-myc', 'Gene', '4609', (28, 33))	('beta-catenin', 'Gene', (14, 26))	('ART', 'Var', (75, 78))	('beta-catenin', 'Gene', '1499', (14, 26))	('c-myc', 'Gene', (28, 33))	('levels of', 'MPA', (4, 13))	('downregulated', 'NegReg', (58, 71))	('survivin', 'Protein', (39, 47))	('ART', 'Chemical', 'MESH:C031327', (75, 78))
4882	32657048	Furthermore, ART also enhanced the antitumor effect of oxaliplatin (OXA) in esophageal cancer cells.	('ART', 'Chemical', 'MESH:C031327', (13, 16))	('esophageal cancer', 'Disease', (76, 93))	('ART', 'Var', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('OXA', 'Chemical', 'MESH:D000077150', (68, 71))	('tumor', 'Disease', (39, 44))	('enhanced', 'PosReg', (22, 30))
4892	32657048	14  Specifically, the misregulation of the Wnt/beta-catenin signaling pathway mediated by the tumor suppressor or activating agents has been associated with EC.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('beta-catenin', 'Gene', '1499', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('associated', 'Reg', (141, 151))	('beta-catenin', 'Gene', (47, 59))	('misregulation', 'Var', (22, 35))
4931	32657048	Here too, ART significantly inhibited the cell migration in a dose-dependent manner, and 20 muM of ART was most effective in migration suppression compared with the control group (Fig 1b).	('ART', 'Chemical', 'MESH:C031327', (99, 102))	('cell migration', 'CPA', (42, 56))	('ART', 'Var', (99, 102))	('ART', 'Chemical', 'MESH:C031327', (10, 13))	('ART', 'Var', (10, 13))	('inhibited', 'NegReg', (28, 37))	('migration suppression', 'CPA', (125, 146))
4944	32657048	To verify whether the aforementioned antitumor effects of ART were indeed associated with the Wnt/beta-catenin signaling pathway, ART (20 muM) treated cells were subjected to 20 mM LiCl, an activator of the Wnt/beta-catenin signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('LiCl', 'Chemical', '-', (181, 185))	('tumor', 'Disease', (41, 46))	('ART', 'Chemical', 'MESH:C031327', (130, 133))	('ART', 'Chemical', 'MESH:C031327', (58, 61))	('beta-catenin', 'Gene', (211, 223))	('ART', 'Var', (130, 133))	('beta-catenin', 'Gene', '1499', (211, 223))	('beta-catenin', 'Gene', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('beta-catenin', 'Gene', '1499', (98, 110))	('associated', 'Reg', (74, 84))
4954	32657048	We found that after treating cells with ART, OXA, or ART+OXA (0-100 muM) for 48 hours, cell viabilities were significantly suppressed.	('ART', 'Chemical', 'MESH:C031327', (40, 43))	('cell viabilities', 'CPA', (87, 103))	('ART+OXA', 'Var', (53, 60))	('suppressed', 'NegReg', (123, 133))	('OXA', 'Chemical', 'MESH:D000077150', (57, 60))	('OXA', 'Chemical', 'MESH:D000077150', (45, 48))	('ART', 'Chemical', 'MESH:C031327', (53, 56))
4968	32657048	More strikingly, cell cycle arrest of EC109 cells was also observed upon treatment with ART.	('EC109', 'Chemical', '-', (38, 43))	('ART', 'Var', (88, 91))	('arrest', 'Disease', (28, 34))	('ART', 'Chemical', 'MESH:C031327', (88, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (17, 34))	('arrest', 'Disease', 'MESH:D006323', (28, 34))
4991	32681017	We identified a novel natural ECRG2 promoter variant harboring a small deletion that exists in the genomes of ~38.5% of world population and showed this variant to be defective in responding to p53 and DNA-damage.	('variant', 'Var', (153, 160))	('ECRG2', 'Gene', '84651', (30, 35))	('defective', 'NegReg', (167, 176))	('ECRG2', 'Gene', (30, 35))	('p53', 'Gene', (194, 197))	('p53', 'Gene', '7157', (194, 197))	('variant', 'Var', (45, 52))
4992	32681017	ECRG2 overexpression induced cancer cell death; ECRG2 gene disruption enhanced cell survival following anticancer drug treatments even when p53 was induced.	('cancer', 'Disease', (29, 35))	('cell survival', 'CPA', (79, 92))	('ECRG2', 'Gene', '84651', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ECRG2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('expression', 'Species', '29278', (10, 20))	('ECRG2', 'Gene', '84651', (48, 53))	('gene disruption', 'Var', (54, 69))	('enhanced', 'PosReg', (70, 78))	('ECRG2', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('p53', 'Gene', (140, 143))	('cancer', 'Disease', (107, 113))	('p53', 'Gene', '7157', (140, 143))
4998	32681017	Upon DNA damage, p53 protein is stabilized via post-translational modifications and binds to the response elements present within the promoters or introns of its target genes in a sequence-specific manner.	('binds', 'Interaction', (84, 89))	('DNA', 'Var', (5, 8))	('p53', 'Gene', (17, 20))	('protein', 'Protein', (21, 28))	('p53', 'Gene', '7157', (17, 20))
5013	32681017	Genetic alterations (missense mutations, deletion/frameshift mutations) in the ECRG2 gene were also reported in various human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('reported', 'Reg', (100, 108))	('human', 'Species', '9606', (120, 125))	('malignancies', 'Disease', (126, 138))	('ECRG2', 'Gene', (79, 84))	('deletion/frameshift mutations', 'Var', (41, 70))	('ECRG2', 'Gene', '84651', (79, 84))
5015	32681017	reported that ECRG2 knockdown caused chromosomal instability and aneuploidy.	('aneuploidy', 'Disease', (65, 75))	('chromosomal instability', 'CPA', (37, 60))	('ECRG2', 'Gene', '84651', (14, 19))	('aneuploidy', 'Disease', 'MESH:D000782', (65, 75))	('ECRG2', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('caused', 'Reg', (30, 36))	('chromosomal instability', 'Phenotype', 'HP:0040012', (37, 60))
5026	32681017	S2, which indicates that ECRG2 knockdown by shRNA reduced the band-intensity of ECRG2 protein.	('ECRG2', 'Gene', '84651', (80, 85))	('ECRG2', 'Gene', (80, 85))	('ECRG2', 'Gene', '84651', (25, 30))	('reduced', 'NegReg', (50, 57))	('ECRG2', 'Gene', (25, 30))	('knockdown', 'Var', (31, 40))
5042	32681017	Given that ECRG2 promoter (either full-length or the deletion variant) has never been functionally characterized, next, we investigated how these two promoter variants are regulated.	('ECRG2', 'Gene', (11, 16))	('deletion', 'Var', (53, 61))	('ECRG2', 'Gene', '84651', (11, 16))
5063	32681017	This could be due to the lower basal activity of ECRG2-del-luc, which shows that 8-nt deletion within ECRG2 promoter affects its basal activity under the unstressed condition.	('ECRG2', 'Gene', '84651', (102, 107))	('ECRG2', 'Gene', (102, 107))	('basal activity', 'MPA', (129, 143))	('ECRG2', 'Gene', (49, 54))	('ECRG2', 'Gene', '84651', (49, 54))	('affects', 'Reg', (117, 124))	('deletion', 'Var', (86, 94))
5076	32681017	Figure 6a and b show that expression of exogenous ECRG2 induced strong growth suppression in both A549 and HeLa cancer cells.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('ECRG2', 'Gene', (50, 55))	('ECRG2', 'Gene', '84651', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('HeLa cancer', 'Disease', (107, 118))	('exogenous', 'Var', (40, 49))	('expression', 'Species', '29278', (26, 36))	('growth suppression', 'CPA', (71, 89))	('HeLa cancer', 'Disease', 'MESH:D009369', (107, 118))
5081	32681017	Figure 7 shows that disruption of endogenous ECRG2 markedly enhanced the survival of RKO and HeLa cells under etoposide-induced DNA damage (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (93, 97))	('etoposide', 'Chemical', 'MESH:D005047', (110, 119))	('disruption', 'Var', (20, 30))	('survival', 'CPA', (73, 81))	('ECRG2', 'Gene', (45, 50))	('ECRG2', 'Gene', '84651', (45, 50))	('enhanced', 'PosReg', (60, 68))
5083	32681017	Under unstressed conditions, ECRG2 gene disruption did not change the growth rate of ECRG2-targeted HeLa cells compared to the scrambled control cells (data not shown), but significantly accelerated the growth of ECRG2-targeted RKO cells (Fig.	('ECRG2', 'Gene', (29, 34))	('ECRG2', 'Gene', (85, 90))	('disruption', 'Var', (40, 50))	('ECRG2', 'Gene', '84651', (213, 218))	('ECRG2', 'Gene', '84651', (85, 90))	('ECRG2', 'Gene', (213, 218))	('growth', 'MPA', (203, 209))	('HeLa', 'CellLine', 'CVCL:0030', (100, 104))	('ECRG2', 'Gene', '84651', (29, 34))	('accelerated', 'PosReg', (187, 198))
5098	32681017	If the extent of DNA damage is beyond the repair capacity, cell death becomes imminent or the genetic errors are passed on to the daughter cells, accumulation of which can lead to cancer formation.	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lead to', 'Reg', (172, 179))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('errors', 'Var', (102, 108))	('cancer', 'Disease', (180, 186))
5102	32681017	We have shown that disruption of ECRG2 significantly enhanced cell survival and prevented or reduced the cleavage (activation) of caspase 3 and PARP following etoposide treatment; such ECRG2-deficiency-associated changes occurred in wild type p53 cells (RKO), even when p53 was induced (Fig.	('ECRG2', 'Gene', '84651', (33, 38))	('etoposide', 'Chemical', 'MESH:D005047', (159, 168))	('ECRG2', 'Gene', (185, 190))	('p53', 'Gene', '7157', (270, 273))	('ECRG2', 'Gene', (33, 38))	('cleavage', 'MPA', (105, 113))	('p53', 'Gene', (270, 273))	('deficiency', 'Disease', 'MESH:D007153', (191, 201))	('PARP', 'Gene', '1302', (144, 148))	('deficiency', 'Disease', (191, 201))	('p53', 'Gene', '7157', (243, 246))	('enhanced', 'PosReg', (53, 61))	('disruption', 'Var', (19, 29))	('cell survival', 'CPA', (62, 75))	('ECRG2', 'Gene', '84651', (185, 190))	('reduced', 'NegReg', (93, 100))	('PARP', 'Gene', (144, 148))	('caspase 3', 'Gene', (130, 139))	('p53', 'Gene', (243, 246))	('caspase 3', 'Gene', '836', (130, 139))
5106	32681017	have also shown that silencing DR5 promoted resistance to 5-fluorouracil (5-FU) in tumor cells with wild type p53 (HCT 116).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('p53', 'Gene', (110, 113))	('DR5', 'Gene', '8795', (31, 34))	('5-FU', 'Chemical', 'MESH:D005472', (74, 78))	('tumor', 'Disease', (83, 88))	('p53', 'Gene', '7157', (110, 113))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (58, 72))	('promoted', 'PosReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('silencing', 'Var', (21, 30))	('DR5', 'Gene', (31, 34))
5113	32681017	Studies have shown that HuR protein expression levels positively correlate with the expression of XIAP, Bcl-2, and Mcl-1; HuR knockdown reduces Mcl-1 and Bcl-2 expression and promotes cell death.	('Bcl-2', 'Gene', '596', (104, 109))	('Mcl-1', 'Gene', (144, 149))	('expression', 'Species', '29278', (84, 94))	('cell death', 'CPA', (184, 194))	('reduces', 'NegReg', (136, 143))	('HuR', 'Gene', (122, 125))	('Mcl-1', 'Gene', '4170', (115, 120))	('XIAP', 'Gene', (98, 102))	('expression', 'Species', '29278', (36, 46))	('Bcl-2', 'Gene', (154, 159))	('HuR', 'Gene', '1994', (122, 125))	('expression', 'MPA', (160, 170))	('HuR', 'Gene', (24, 27))	('Mcl-1', 'Gene', (115, 120))	('Bcl-2', 'Gene', '596', (154, 159))	('Mcl-1', 'Gene', '4170', (144, 149))	('HuR', 'Gene', '1994', (24, 27))	('Bcl-2', 'Gene', (104, 109))	('promotes', 'PosReg', (175, 183))	('knockdown', 'Var', (126, 135))	('expression', 'Species', '29278', (160, 170))	('XIAP', 'Gene', '331', (98, 102))
5120	32681017	Another novel finding from our current study indicates that ECRG2 promoter allele with rs3214447 variant (TAGAATTC deletion) negatively impacts ECRG2 promoter activity under unstressed condition as well as under DNA-damage (Fig.	('rs3214447', 'Mutation', 'rs3214447', (87, 96))	('rs3214447', 'Var', (87, 96))	('ECRG2', 'Gene', '84651', (60, 65))	('ECRG2', 'Gene', (60, 65))	('ECRG2', 'Gene', '84651', (144, 149))	('ECRG2', 'Gene', (144, 149))	('negatively impacts', 'NegReg', (125, 143))
5121	32681017	Our discovery of rs3214447 variant in relation to its negative impact on ECRG2 promoter activity is highly significant.	('ECRG2', 'Gene', (73, 78))	('rs3214447', 'Mutation', 'rs3214447', (17, 26))	('ECRG2', 'Gene', '84651', (73, 78))	('rs3214447', 'Var', (17, 26))
5122	32681017	This finding is potentially important as information revealed by the 1000 Genomes Project Phase-3 indicates that about 38.5% of world population harbors one or both alleles with TAGAATTC deletion within ECRG2 promoter (Fig.	('TAGAATTC deletion', 'Var', (178, 195))	('ECRG2', 'Gene', (203, 208))	('ECRG2', 'Gene', '84651', (203, 208))
5125	32681017	In this context, it will be interesting to investigate in the future whether cancer patients with the TAGAATTC deletion in the ECRG2 promoter would exhibit strong apoptotic response following DNA damage-inducing anticancer drugs.	('TAGAATTC deletion', 'Var', (102, 119))	('patients', 'Species', '9606', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('ECRG2', 'Gene', '84651', (127, 132))	('ECRG2', 'Gene', (127, 132))	('apoptotic response', 'CPA', (163, 181))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
5133	32681017	The antibodies against DR5 (D4E9), cleaved caspase 3 (D175) and cleaved PARP (Asp214) (D64E10) were from Cell Signaling Technology (Danvers, MA, USA).	('PARP', 'Gene', '1302', (72, 76))	('DR5', 'Gene', (23, 26))	('D175', 'Var', (54, 58))	('PARP', 'Gene', (72, 76))	('caspase 3', 'Gene', (43, 52))	('caspase 3', 'Gene', '836', (43, 52))	('DR5', 'Gene', '8795', (23, 26))	('Asp214', 'Chemical', '-', (78, 84))
5163	32681017	ECRG2 gene disruption was achieved using lentivirus-mediated CRISPR/Cas9 approach.	('ECRG2', 'Gene', (0, 5))	('gene disruption', 'Var', (6, 21))	('ECRG2', 'Gene', '84651', (0, 5))
5217	31950049	Moreover, the BBR and galangin combination not only suppressed Wnt3a and beta-catenin expression but also induced apoptosis in esophageal cancer cells.	('Wnt3a', 'Gene', '89780', (63, 68))	('beta-catenin', 'Gene', (73, 85))	('esophageal cancer', 'Disease', (127, 144))	('combination', 'Var', (31, 42))	('Wnt3a', 'Gene', (63, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('induced', 'Reg', (106, 113))	('beta-catenin', 'Gene', '1499', (73, 85))	('suppressed', 'NegReg', (52, 62))	('galangin', 'Chemical', 'MESH:C037032', (22, 30))	('BBR', 'Chemical', 'MESH:D001599', (14, 17))	('apoptosis', 'CPA', (114, 123))
5219	31950049	found that the radiosensitivity of xenografts in nude mice and ESCC cells was significantly enhanced by BBR via the suppression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1alpha) expression.	('nude mice', 'Species', '10090', (49, 58))	('hypoxia inducible factor-1 alpha', 'Gene', (177, 209))	('ESCC', 'Disease', 'MESH:C562729', (63, 67))	('expression', 'MPA', (223, 233))	('nt', 'Chemical', 'MESH:D009711', (87, 89))	('BBR', 'Var', (104, 107))	('HIF-1alpha', 'Gene', (211, 221))	('vascular endothelial growth factor', 'Gene', '22339', (131, 165))	('radiosensitivity', 'CPA', (15, 31))	('ESCC', 'Disease', (63, 67))	('vascular endothelial growth factor', 'Gene', (131, 165))	('hypoxia inducible factor-1 alpha', 'Gene', '15251', (177, 209))	('BBR', 'Chemical', 'MESH:D001599', (104, 107))	('suppression', 'NegReg', (116, 127))	('enhanced', 'PosReg', (92, 100))
5245	31950049	Liu found that BBR represses the proliferation and migration of CRC cells in vitro and in vivo by inhibiting JAK2 and STAT3 phosphorylation, which prevents the increase in COX-2/PGE2 levels and consequently decreases MMP-2/-9 expression.	('CRC', 'Disease', 'MESH:D015179', (64, 67))	('inhibiting', 'NegReg', (98, 108))	('JAK2', 'Gene', '3717', (109, 113))	('PGE2', 'Chemical', 'MESH:D015232', (178, 182))	('nt', 'Chemical', 'MESH:D009711', (202, 204))	('STAT3', 'Gene', (118, 123))	('prevents', 'NegReg', (147, 155))	('represses', 'NegReg', (19, 28))	('COX-2', 'Gene', (172, 177))	('JAK2', 'Gene', (109, 113))	('STAT3', 'Gene', '6774', (118, 123))	('MMP-2/-9', 'Gene', (217, 225))	('CRC', 'Disease', (64, 67))	('nt', 'Chemical', 'MESH:D009711', (152, 154))	('MMP-2/-9', 'Gene', '4313;4318', (217, 225))	('BBR', 'Chemical', 'MESH:D001599', (15, 18))	('COX-2', 'Gene', '5743', (172, 177))	('increase', 'PosReg', (160, 168))	('proliferation', 'CPA', (33, 46))	('decreases', 'NegReg', (207, 216))	('BBR', 'Var', (15, 18))
5249	31950049	Their in vitro experiment showed that BBR exerts antiproliferative and proapoptotic effects on CRC cells via AMPK-dependent inhibition of the mTOR signaling pathway and prevents NF-kappaB activation, decreases cyclin D1 and survivin levels, induces p53 phosphorylation, and enhances caspase-3 cleavage in an AMPK-independent manner.	('nt', 'Chemical', 'MESH:D009711', (23, 25))	('AMP', 'Chemical', 'MESH:D000249', (109, 112))	('BBR', 'Var', (38, 41))	('AMP', 'Chemical', 'MESH:D000249', (308, 311))	('p53', 'Gene', (249, 252))	('activation', 'MPA', (188, 198))	('nt', 'Chemical', 'MESH:D009711', (322, 324))	('caspase-3 cleavage', 'MPA', (283, 301))	('nt', 'Chemical', 'MESH:D009711', (121, 123))	('nt', 'Chemical', 'MESH:D009711', (50, 52))	('NF-kappaB', 'Protein', (178, 187))	('phosphorylation', 'MPA', (253, 268))	('inhibition', 'NegReg', (124, 134))	('survivin levels', 'MPA', (224, 239))	('CRC', 'Disease', (95, 98))	('decreases', 'NegReg', (200, 209))	('cyclin D1', 'MPA', (210, 219))	('prevents', 'NegReg', (169, 177))	('induces', 'PosReg', (241, 248))	('nt', 'Chemical', 'MESH:D009711', (174, 176))	('mTOR signaling pathway', 'Pathway', (142, 164))	('enhances', 'PosReg', (274, 282))	('BBR', 'Chemical', 'MESH:D001599', (38, 41))	('p53', 'Gene', '7157', (249, 252))	('CRC', 'Disease', 'MESH:D015179', (95, 98))
5258	31950049	In a study by Zhang, BBR was found to reduce the number and size of intestinal polyps in ApcMin/+ mice, in addition to reducing the Wnt activity and downregulating the expression of its target genes, cyclin D1 and c-Myc.	('intestinal polyps', 'Disease', (68, 85))	('expression', 'MPA', (168, 178))	('nt', 'Chemical', 'MESH:D009711', (133, 135))	('intestinal polyps', 'Phenotype', 'HP:0005266', (68, 85))	('cyclin D1', 'Gene', (200, 209))	('downregulating', 'NegReg', (149, 163))	('BBR', 'Var', (21, 24))	('Wnt activity', 'CPA', (132, 144))	('BBR', 'Chemical', 'MESH:D001599', (21, 24))	('intestinal polyp', 'Phenotype', 'HP:0005266', (68, 84))	('Apc', 'Gene', (89, 92))	('reduce', 'NegReg', (38, 44))	('Apc', 'Gene', '11789', (89, 92))	('nt', 'Chemical', 'MESH:D009711', (69, 71))	('intestinal polyps', 'Disease', 'MESH:D007417', (68, 85))	('c-Myc', 'Gene', (214, 219))	('mice', 'Species', '10090', (98, 102))	('reducing', 'NegReg', (119, 127))
5262	31950049	They found that BBR directly bound to the nuclear receptor retinoid X receptor alpha (RXRalpha) at the region containing Gln275, Arg316, and Arg371 residues and promoted its interaction with nuclear beta-catenin, leading to c-Cbl-mediated degradation of beta-catenin and consequent prevention of colon cancer cell proliferation.	('c-Cbl', 'Gene', (224, 229))	('colon cancer', 'Phenotype', 'HP:0003003', (296, 308))	('beta-catenin', 'Gene', (199, 211))	('beta-catenin', 'Gene', (254, 266))	('beta-catenin', 'Gene', '1499', (199, 211))	('Arg316', 'Var', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('beta-catenin', 'Gene', '1499', (254, 266))	('bound', 'Interaction', (29, 34))	('nt', 'Chemical', 'MESH:D009711', (287, 289))	('nt', 'Chemical', 'MESH:D009711', (112, 114))	('colon cancer', 'Disease', 'MESH:D015179', (296, 308))	('BBR', 'Chemical', 'MESH:D001599', (16, 19))	('BBR', 'Gene', (16, 19))	('nt', 'Chemical', 'MESH:D009711', (279, 281))	('Gln275', 'Var', (121, 127))	('prevention', 'NegReg', (282, 292))	('colon cancer', 'Disease', (296, 308))	('Arg371', 'Chemical', 'MESH:C116795', (141, 147))	('nt', 'Chemical', 'MESH:D009711', (175, 177))	('promoted', 'PosReg', (161, 169))	('degradation', 'MPA', (239, 250))	('c-Cbl', 'Gene', '867', (224, 229))	('Arg371 residues', 'Var', (141, 156))	('Arg316', 'Chemical', 'MESH:C002934', (129, 135))	('interaction', 'Interaction', (174, 185))
5283	31950049	MiRNAs are short 20-22-nt-long ncRNAs that repress the translation of their target mRNAs by binding to their 3'-untranslated region (UTR) by imperfect complementary matches.	('binding', 'Interaction', (92, 99))	('nt', 'Chemical', 'MESH:D009711', (23, 25))	('nt', 'Chemical', 'MESH:D009711', (159, 161))	('nt', 'Chemical', 'MESH:D009711', (113, 115))	('repress', 'NegReg', (43, 50))	('translation', 'MPA', (55, 66))	('imperfect', 'Var', (141, 150))
5300	31950049	In their study, overexpressed miRNA-429 inhibited cell apoptosis by directly targeting SOX2 in CRC cells, suggesting that miRNA-429 plays an oncogenic role in CRC and can thus be used as a new prognostic biomarker for CRC.	('CRC', 'Disease', 'MESH:D015179', (218, 221))	('targeting', 'Reg', (77, 86))	('SOX2', 'Gene', '6657', (87, 91))	('cell apoptosis', 'CPA', (50, 64))	('SOX2', 'Gene', (87, 91))	('inhibited', 'NegReg', (40, 49))	('CRC', 'Disease', 'MESH:D015179', (159, 162))	('CRC', 'Disease', (95, 98))	('CRC', 'Disease', (218, 221))	('CRC', 'Disease', 'MESH:D015179', (95, 98))	('miRNA-429', 'Var', (122, 131))	('miRNA-429', 'Var', (30, 39))	('CRC', 'Disease', (159, 162))
5301	31950049	investigated the effect of BBR and evodiamine on CRC and miRNA-429 expression using an in vitro culture of colorectal tissue and found that BBR and evodiamine exert therapeutic effects on CRC by downregulating miRNA-429 expression.	('colorectal tissue', 'Disease', (107, 124))	('CRC', 'Disease', 'MESH:D015179', (188, 191))	('evodiamine', 'Chemical', 'MESH:C049639', (148, 158))	('colorectal tissue', 'Disease', 'MESH:D015179', (107, 124))	('BBR', 'Var', (140, 143))	('expression', 'MPA', (220, 230))	('miRNA-429', 'Gene', (210, 219))	('evodiamine', 'Chemical', 'MESH:C049639', (35, 45))	('BBR', 'Chemical', 'MESH:D001599', (27, 30))	('CRC', 'Disease', 'MESH:D015179', (49, 52))	('BBR', 'Chemical', 'MESH:D001599', (140, 143))	('CRC', 'Disease', (188, 191))	('downregulating', 'NegReg', (195, 209))	('CRC', 'Disease', (49, 52))
5305	31950049	revealed that the combination of NVP-AUY922 (a Hsp90 inhibitor) and BBR retards human colon adenocarcinoma cell proliferation by inhibiting cyclin dependent kinase 4 (CDK4) expression and inducing miRNA-296-mediated suppression of the Pin1-beta-catenin-cyclin D1 signaling pathway.	('cyclin dependent kinase 4', 'Gene', '1019', (140, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('beta-catenin', 'Gene', (240, 252))	('beta-catenin', 'Gene', '1499', (240, 252))	('BBR', 'Chemical', 'MESH:D001599', (68, 71))	('miRNA-296', 'Gene', '407022', (197, 206))	('cyclin dependent kinase 4', 'Gene', (140, 165))	('Hsp90', 'Gene', '3320', (47, 52))	('retards human colon adenocarcinoma', 'Disease', (72, 106))	('Hsp90', 'Gene', (47, 52))	('NVP-AUY922', 'Var', (33, 43))	('Pin1', 'Gene', (235, 239))	('inducing', 'Reg', (188, 196))	('inhibiting', 'NegReg', (129, 139))	('retards human colon adenocarcinoma', 'Disease', 'MESH:D015179', (72, 106))	('CDK4', 'Gene', (167, 171))	('miRNA-296', 'Gene', (197, 206))	('expression', 'MPA', (173, 183))	('Pin1', 'Gene', '5300', (235, 239))	('CDK4', 'Gene', '1019', (167, 171))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (33, 43))	('suppression', 'NegReg', (216, 227))
5306	31950049	These findings suggest that the therapeutic effects of the combination of NVP-AUY922 and BBR occur via the inhibition of multiple oncogenic signaling pathways.	('NVP-AUY922', 'Var', (74, 84))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (74, 84))	('BBR', 'Chemical', 'MESH:D001599', (89, 92))	('oncogenic signaling pathways', 'Pathway', (130, 158))	('BBR', 'Gene', (89, 92))	('inhibition', 'NegReg', (107, 117))
5312	31950049	Accumulating evidence has indicated that the aberrant expression of lncRNAs may induce the onset and progression of various cancers.	('cancer', 'Disease', (124, 130))	('aberrant expression', 'Var', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('nt', 'Chemical', 'MESH:D009711', (51, 53))	('lncRNAs', 'Gene', (68, 75))	('induce', 'PosReg', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('progression', 'CPA', (101, 112))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
5316	31950049	In their functional experiment, BBR exerted its effects by inducing the overexpression of lncRNA cancer susceptibility candidate 2 (CASC2), the downstream target of which was found to be the antiapoptotic gene BCL2.	('inducing', 'PosReg', (59, 67))	('BBR', 'Chemical', 'MESH:D001599', (32, 35))	('BCL2', 'Gene', '596', (210, 214))	('cancer', 'Disease', (97, 103))	('CASC2', 'Gene', (132, 137))	('nt', 'Chemical', 'MESH:D009711', (192, 194))	('CASC2', 'Gene', '255082', (132, 137))	('nt', 'Chemical', 'MESH:D009711', (28, 30))	('BCL2', 'Gene', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('BBR', 'Var', (32, 35))	('overexpression', 'MPA', (72, 86))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
5328	31950049	At the genus level, BBR decreased the abundance of Akkermansia, blocked mucin degradation, and increased that of some short chain fatty acid-producing bacteria.	('decreased', 'NegReg', (24, 33))	('Akkermansia', 'MPA', (51, 62))	('mucin degradation', 'MPA', (72, 89))	('blocked', 'NegReg', (64, 71))	('BBR', 'Var', (20, 23))	('BBR', 'Chemical', 'MESH:D001599', (20, 23))	('fatty acid', 'Chemical', 'MESH:D005227', (130, 140))	('increased', 'PosReg', (95, 104))	('short chain fatty acid-producing bacteria', 'MPA', (118, 159))	('abundance', 'MPA', (38, 47))
5331	31950049	In particular, Yu showed that the accumulation of F. nucleatum in the gut accelerated the onset of colonic tumors in mice.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('accelerated', 'PosReg', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mice', 'Species', '10090', (117, 121))	('colonic tumors', 'Disease', (99, 113))	('F. nucleatum', 'Var', (50, 62))	('colonic tumors', 'Disease', 'MESH:D015179', (99, 113))	('F. nucleatum', 'Species', '851', (50, 62))
5332	31950049	BBR treatment alleviated the F. nucleatum-mediated increase in opportunistic pathogens and decreased the secretion of IL-21/22/31 and CD40L and the expression of p-STAT3, p-STAT5, and p-ERK1/2 in vivo.	('p-STAT5', 'Var', (171, 178))	('increase', 'PosReg', (51, 59))	('F. nucleatum', 'Species', '851', (29, 41))	('alleviated', 'NegReg', (14, 24))	('CD40L', 'MPA', (134, 139))	('secretion of IL-21/22/31', 'MPA', (105, 129))	('opportunistic pathogens', 'MPA', (63, 86))	('p-ERK1/2', 'Gene', (184, 192))	('nt', 'Chemical', 'MESH:D009711', (11, 13))	('BBR', 'Chemical', 'MESH:D001599', (0, 3))	('STAT3', 'Gene', '6774', (164, 169))	('expression', 'MPA', (148, 158))	('decreased', 'NegReg', (91, 100))	('STAT3', 'Gene', (164, 169))
5353	30918105	Both oncogene activation and/or tumor suppressor gene (TSG) inactivation have been found to contribute to the occurrence and progress of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('activation', 'PosReg', (14, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('oncogene', 'Protein', (5, 13))	('breast cancer', 'Disease', (137, 150))	('contribute', 'Reg', (92, 102))	('tumor suppressor', 'Gene', (32, 48))	('TSG', 'Gene', '57045', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumor suppressor', 'Gene', '7248', (32, 48))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TSG', 'Gene', (55, 58))	('inactivation', 'Var', (60, 72))
5354	30918105	Gene point mutations and deletions are the main causes of TSG inactivation in breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('TSG', 'Gene', '57045', (58, 61))	('inactivation', 'NegReg', (62, 74))	('causes', 'Reg', (48, 54))	('deletions', 'Var', (25, 34))	('TSG', 'Gene', (58, 61))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
5355	30918105	However, recent studies have revealed that epigenetic alterations, including aberrant promoter methylation and histone modification, may provide a novel mechanism for TSG silencing without the need for changes in nucleotide sequence.	('promoter methylation', 'MPA', (86, 106))	('TSG', 'Gene', '57045', (167, 170))	('histone', 'MPA', (111, 118))	('silencing', 'NegReg', (171, 180))	('TSG', 'Gene', (167, 170))	('aberrant', 'Var', (77, 85))
5358	30918105	Therefore, aberrant TSG methylation is linked with breast cancer pathogenesis, and is an important tumor marker in the context of this disease.	('tumor', 'Disease', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TSG', 'Gene', '57045', (20, 23))	('aberrant', 'Var', (11, 19))	('methylation', 'Var', (24, 35))	('linked', 'Reg', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('TSG', 'Gene', (20, 23))	('breast cancer', 'Disease', (51, 64))
5361	30918105	Overexpression of ECRG4 was able to inhibit the proliferation, migration, and invasion of several tumor cells.	('ECRG4', 'Gene', (18, 23))	('inhibit', 'NegReg', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ECRG4', 'Gene', '84417', (18, 23))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (98, 103))	('migration', 'CPA', (63, 72))
5364	30918105	We observed that human breast cancer samples showed reduced ECRG4 expression, and this was associated with hypermethylation of the ECRG4 promoter.	('breast cancer', 'Disease', (23, 36))	('ECRG4', 'Gene', (60, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('reduced', 'NegReg', (52, 59))	('human', 'Species', '9606', (17, 22))	('hypermethylation', 'Var', (107, 123))	('ECRG4', 'Gene', '84417', (60, 65))	('expression', 'MPA', (66, 76))	('ECRG4', 'Gene', (131, 136))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('ECRG4', 'Gene', '84417', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
5400	30918105	We found that ECRG4 mRNA and protein expression in MCF-7 and BT483 cells was increased by 5-Aza-CdR treatment, and was further enhanced by TSA co-treatment (Figure 3B,C).	('BT483', 'CellLine', 'CVCL:2319', (61, 66))	('enhanced', 'PosReg', (127, 135))	('5-Aza-CdR', 'Chemical', '-', (90, 99))	('ECRG4', 'Gene', '84417', (14, 19))	('ECRG4', 'Gene', (14, 19))	('MCF-7', 'CellLine', 'CVCL:0031', (51, 56))	('increased', 'PosReg', (77, 86))	('TSA', 'Chemical', 'MESH:C012589', (139, 142))	('5-Aza-CdR', 'Var', (90, 99))
5403	30918105	We found that ECRG4 promoter methylation was decreased following 5-Aza-CdR and/or TSA treatment.	('TSA', 'Chemical', 'MESH:C012589', (82, 85))	('decreased', 'NegReg', (45, 54))	('ECRG4', 'Gene', (14, 19))	('5-Aza-CdR', 'Var', (65, 74))	('ECRG4', 'Gene', '84417', (14, 19))	('5-Aza-CdR', 'Chemical', '-', (65, 74))
5406	30918105	We found that the proximal region of the ECRG4 promoter (-400 to -100 bp) exhibited much high promoter activity upon 5-Aza-CdR and/or TSA treatment (Figure 3E).	('promoter activity', 'MPA', (94, 111))	('5-Aza-CdR', 'Chemical', '-', (117, 126))	('TSA', 'Chemical', 'MESH:C012589', (134, 137))	('ECRG4', 'Gene', (41, 46))	('5-Aza-CdR', 'Var', (117, 126))	('ECRG4', 'Gene', '84417', (41, 46))
5407	30918105	This suggests that hypermethylation of the promoter region of ECRG4 may be an important mechanism mediating the down-regulation of ECRG4.	('ECRG4', 'Gene', (62, 67))	('ECRG4', 'Gene', (131, 136))	('down-regulation', 'NegReg', (112, 127))	('hypermethylation', 'Var', (19, 35))	('ECRG4', 'Gene', '84417', (62, 67))	('ECRG4', 'Gene', '84417', (131, 136))
5441	30918105	Recent studies have revealed that silencing of ECRG4 expression in colorectal carcinoma, kidney cancer, and esophageal cancer is associated with the hypermethylation of the ECRG4 promoter region.	('colorectal carcinoma', 'Disease', (67, 87))	('ECRG4', 'Gene', '84417', (173, 178))	('kidney cancer', 'Phenotype', 'HP:0009726', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ECRG4', 'Gene', '84417', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('esophageal cancer', 'Disease', (108, 125))	('kidney cancer', 'Disease', (89, 102))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (67, 87))	('hypermethylation', 'Var', (149, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('silencing', 'NegReg', (34, 43))	('ECRG4', 'Gene', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('kidney cancer', 'Disease', 'MESH:D007680', (89, 102))	('ECRG4', 'Gene', (47, 52))
5444	30918105	Therefore, the hypermethylation of ECRG4 promoter may contribute to the down-regulation of ECRG4 mRNA levels in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('ECRG4', 'Gene', '84417', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('ECRG4', 'Gene', (35, 40))	('hypermethylation', 'Var', (15, 31))	('ECRG4', 'Gene', '84417', (35, 40))	('ECRG4', 'Gene', (91, 96))	('down-regulation', 'NegReg', (72, 87))
5448	30918105	MCF-7 and BT483 cells were estrogen receptor (ER)-positive breast cancer cells, and ER positive tumors cells displayed more hypermethylated loci than ER-negative cells.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('MCF-7', 'CellLine', 'CVCL:0031', (0, 5))	('estrogen receptor', 'Gene', (27, 44))	('tumors', 'Disease', (96, 102))	('breast cancer', 'Disease', (59, 72))	('BT483', 'CellLine', 'CVCL:2319', (10, 15))	('estrogen receptor', 'Gene', '2099', (27, 44))	('ER', 'Gene', '2099', (84, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ER', 'Gene', '2099', (46, 48))	('ER', 'Gene', '2099', (150, 152))	('hypermethylated', 'Var', (124, 139))
5451	30918105	These results strongly suggest that reduced ECRG4 expression in breast cancer may be mediated by methylation of the ECRG4 promoter.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('ECRG4', 'Gene', (116, 121))	('ECRG4', 'Gene', '84417', (44, 49))	('methylation', 'Var', (97, 108))	('ECRG4', 'Gene', (44, 49))	('ECRG4', 'Gene', '84417', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('reduced', 'NegReg', (36, 43))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('expression', 'MPA', (50, 60))	('breast cancer', 'Disease', (64, 77))
5468	30918105	Fas can recruit pro-caspase-8 to induce self-shearing resulting in the formation of cleaved caspase-8, which can both activate caspase-3 and Bid; thereby inducing mitochondrial apoptotic pathway activation.	('inducing', 'Reg', (154, 162))	('caspase-8', 'Gene', (20, 29))	('mitochondrial apoptotic pathway', 'Pathway', (163, 194))	('caspase-3', 'Gene', '836', (127, 136))	('caspase-8', 'Gene', '841', (20, 29))	('Bid', 'Gene', '637', (141, 144))	('cleaved', 'Var', (84, 91))	('activation', 'PosReg', (195, 205))	('Bid', 'Gene', (141, 144))	('activate', 'PosReg', (118, 126))	('caspase-8', 'Gene', (92, 101))	('caspase-3', 'Gene', (127, 136))	('caspase-8', 'Gene', '841', (92, 101))
5479	30918105	Collectively, we found that ECRG4 expression is reduced in human breast cancer samples, possibly as a result of the hypermethylation of the ECRG4 promoter region.	('ECRG4', 'Gene', (140, 145))	('human', 'Species', '9606', (59, 64))	('expression', 'MPA', (34, 44))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('reduced', 'NegReg', (48, 55))	('ECRG4', 'Gene', '84417', (140, 145))	('breast cancer', 'Disease', (65, 78))	('ECRG4', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ECRG4', 'Gene', '84417', (28, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('hypermethylation', 'Var', (116, 132))
5484	30918105	Our study validated that ECRG4 promoter hypermethylation is a potentially important mechanism governing ECRG4 down-regulation in breast cancer.	('breast cancer', 'Disease', (129, 142))	('down-regulation', 'NegReg', (110, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('ECRG4', 'Gene', (25, 30))	('hypermethylation', 'Var', (40, 56))	('ECRG4', 'Gene', (104, 109))	('ECRG4', 'Gene', '84417', (25, 30))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('ECRG4', 'Gene', '84417', (104, 109))
5576	30246718	XB130 Knockdown Inhibits the Proliferation, Invasiveness, and Metastasis of Hepatocellular Carcinoma Cells and Sensitizes them to TRAIL-Induced Apoptosis XB130 is a recently discovered adaptor protein that is highly expressed in many malignant tumors, but few studies have investigated its role in hepatocellular carcinoma (HCC).	('Knockdown', 'Var', (6, 15))	('malignant tumors', 'Disease', 'MESH:D018198', (234, 250))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (298, 322))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('TRAIL', 'Gene', (130, 135))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('Proliferation', 'CPA', (29, 42))	('XB130', 'Gene', '84632', (154, 159))	('malignant tumors', 'Disease', (234, 250))	('Metastasis of Hepatocellular Carcinoma Cells', 'Disease', 'MESH:D009362', (62, 106))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (298, 322))	('XB130', 'Gene', (154, 159))	('Carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Metastasis of Hepatocellular Carcinoma Cells', 'Disease', (62, 106))	('Inhibits', 'NegReg', (16, 24))	('XB130', 'Gene', '84632', (0, 5))	('Invasiveness', 'CPA', (44, 56))	('hepatocellular carcinoma', 'Disease', (298, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('XB130', 'Gene', (0, 5))	('TRAIL', 'Gene', '8743', (130, 135))
5579	30246718	XB130 silencing was performed using small hairpin RNA.	('XB130', 'Gene', (0, 5))	('XB130', 'Gene', '84632', (0, 5))	('silencing', 'Var', (6, 15))
5580	30246718	The effect of silencing XB130 was examined using Cell Counting Kit-8, colony assay, wound healing assay, and cell cycle analysis.	('silencing', 'Var', (14, 23))	('XB130', 'Gene', (24, 29))	('XB130', 'Gene', '84632', (24, 29))
5582	30246718	The Cell Counting Kit-8 assay, colony formation assay, and xenograft model in nude mice showed that silencing XB130 inhibited cell proliferative ability both in vivo and in vitro, with flow cytometry demonstrating that the cells were arrested in the G0/G1 phase in HepG2 (HepG2 XB130-silenced group [shA] vs. HepG2 scramble group [NA]: 74.32 +- 5.86% vs. 60.21 +- 3.07%, P < 0.05) and that the number of G2/M phase cells was decreased (HepG2 shA vs. HepG2 NA: 8.06 +- 2.41% vs. 18.36 +- 4.42%, P < 0.05).	('XB130', 'Gene', '84632', (110, 115))	('decreased', 'NegReg', (425, 434))	('silencing', 'Var', (100, 109))	('G2/M phase cells', 'CPA', (404, 420))	('inhibited', 'NegReg', (116, 125))	('nude mice', 'Species', '10090', (78, 87))	('XB130', 'Gene', (278, 283))	('XB130', 'Gene', (110, 115))	('cell proliferative ability', 'CPA', (126, 152))	('HepG2', 'CellLine', 'CVCL:0027', (309, 314))	('XB130', 'Gene', '84632', (278, 283))	('HepG2', 'CellLine', 'CVCL:0027', (450, 455))	('HepG2', 'CellLine', 'CVCL:0027', (436, 441))	('HepG2', 'CellLine', 'CVCL:0027', (272, 277))	('HepG2', 'CellLine', 'CVCL:0027', (265, 270))
5583	30246718	Furthermore, the cell invasion and migration abilities were impaired, and the levels of the epithelial-mesenchymal transition-related indicators vimentin and N-cadherin were decreased, although the level of E-cadherin was increased after silencing XB130.	('decreased', 'NegReg', (174, 183))	('N-cadherin', 'Gene', (158, 168))	('vimentin', 'Gene', '7431', (145, 153))	('XB130', 'Gene', (248, 253))	('E-cadherin', 'Gene', (207, 217))	('E-cadherin', 'Gene', '999', (207, 217))	('vimentin', 'Gene', (145, 153))	('impaired', 'NegReg', (60, 68))	('silencing', 'Var', (238, 247))	('N-cadherin', 'Gene', '1000', (158, 168))	('increased', 'PosReg', (222, 231))	('XB130', 'Gene', '84632', (248, 253))
5626	30246718	The membrane was then blocked in Tris-buffered saline and Tween 20 (TBST: 25 mmol/L Tris-HCl [pH 7.5], 125 mmol/L NaCl, and 0.1% Tween 20) containing 5% bovine serum albumin (BSA) and incubated with antibodies targeting XB130, E-cadherin, N-cadherin, vimentin, Akt, Ser473, Thr308, PTEN, p-PTEN, phos-PI3K (p-PI3K), PI3K, or GAPHD in TBST containing 1% BSA at 4 C overnight.	('Akt', 'Gene', (261, 264))	('Ser473', 'Chemical', '-', (266, 272))	('PTEN', 'Gene', (290, 294))	('phos-PI3K', 'Var', (296, 305))	('GAPHD', 'Gene', '2597', (325, 330))	('bovine', 'Species', '9913', (153, 159))	('Akt', 'Gene', '207', (261, 264))	('XB130', 'Gene', '84632', (220, 225))	('E-cadherin', 'Gene', (227, 237))	('E-cadherin', 'Gene', '999', (227, 237))	('Thr308', 'Chemical', '-', (274, 280))	('PTEN', 'Gene', (282, 286))	('XB130', 'Gene', (220, 225))	('PTEN', 'Gene', '5728', (290, 294))	('GAPHD', 'Gene', (325, 330))	('PTEN', 'Gene', '5728', (282, 286))	('vimentin', 'Gene', '7431', (251, 259))	('vimentin', 'Gene', (251, 259))	('N-cadherin', 'Gene', (239, 249))	('N-cadherin', 'Gene', '1000', (239, 249))	('PI3K', 'Var', (316, 320))
5651	30246718	Furthermore, the number of clones formed was significantly reduced after silencing XB130 (HepG2 shA vs. HepG2 NC: 1.26 +- 0.14 vs. 2.09 +- 0.14, P < 0.05; MHCC97H shA vs. MHCC97H NC: 1.35 +- 0.12 vs. 1.99 +- 0.10, P < 0.05).	('silencing', 'Var', (73, 82))	('reduced', 'NegReg', (59, 66))	('HepG2', 'CellLine', 'CVCL:0027', (90, 95))	('HepG2', 'CellLine', 'CVCL:0027', (104, 109))	('HepG2 NC', 'CellLine', 'CVCL:0027', (104, 112))	('XB130', 'Gene', (83, 88))	('XB130', 'Gene', '84632', (83, 88))
5652	30246718	Flow cytometry showed that the number of G0/G1 phase cells increased in HepG2 shA compared with those in HepG2 NC (HepG2 shA vs. HepG2 NA: 74.32 +- 5.86% vs. 60.21 +- 3.07%, P < 0.05) and that the number of G2/M phase cells decreased following a reduction in XB130 both in HepG2 shA and MHCC97H shA groups (HepG2 shA vs. HepG2 NA: 8.06 +- 2.41% vs. 18.36 +- 4.42%, P < 0.05; Figures 2f and 2g].	('G2/M phase cells', 'CPA', (207, 223))	('HepG2', 'CellLine', 'CVCL:0027', (307, 312))	('XB130', 'Gene', '84632', (259, 264))	('decreased', 'NegReg', (224, 233))	('HepG2', 'CellLine', 'CVCL:0027', (321, 326))	('HepG2', 'CellLine', 'CVCL:0027', (129, 134))	('HepG2 NC', 'CellLine', 'CVCL:0027', (105, 113))	('HepG2', 'CellLine', 'CVCL:0027', (105, 110))	('reduction', 'NegReg', (246, 255))	('HepG2', 'CellLine', 'CVCL:0027', (273, 278))	('HepG2', 'CellLine', 'CVCL:0027', (72, 77))	('G0/G1 phase cells', 'CPA', (41, 58))	('HepG2', 'CellLine', 'CVCL:0027', (115, 120))	('increased', 'PosReg', (59, 68))	('XB130', 'Gene', (259, 264))	('HepG2', 'Var', (72, 77))
5653	30246718	Thus, the proliferation of MHCC97H and HepG2 cells decreased after silencing XB130.	('proliferation', 'CPA', (10, 23))	('HepG2', 'CellLine', 'CVCL:0027', (39, 44))	('XB130', 'Gene', '84632', (77, 82))	('decreased', 'NegReg', (51, 60))	('silencing', 'Var', (67, 76))	('XB130', 'Gene', (77, 82))
5654	30246718	Next, we evaluated the effect of silencing XB130 on the invasiveness and metastasis of HCC cell lines using a Transwell assay and wound healing assay [Figure 3a-3d], which showed that HepG2 shA and MHCC97H shA groups had significantly lower invasion and metastasis abilities than the NC groups (Transwell assay: HepG2 shA vs. HepG2 NC: 33.3 +- 5.2 vs. 207.0 +- 22.7, P < 0.05; Transwell assay: MHCC97H shA vs. MHCC97H NC: 112.3 +- 11.5 vs. 285.3 +- 11.3, P < 0.05; wound assay: HepG2 shA vs. HepG2 NC: 22.83 +- 4.93 vs. 46.31 +- 2.21 mum, P < 0.05; wound assay: MHCC97H shA vs. MHCC97H NC: 25.27 +- 0.78 vs. 50.08 +- 3.85 mum, P < 0.05).	('HepG2', 'CellLine', 'CVCL:0027', (184, 189))	('XB130', 'Gene', '84632', (43, 48))	('HepG2', 'CellLine', 'CVCL:0027', (326, 331))	('HepG2', 'CellLine', 'CVCL:0027', (312, 317))	('silencing', 'Var', (33, 42))	('HepG2 NC', 'CellLine', 'CVCL:0027', (492, 500))	('HepG2', 'CellLine', 'CVCL:0027', (492, 497))	('lower', 'NegReg', (235, 240))	('HepG2', 'CellLine', 'CVCL:0027', (478, 483))	('HepG2 NC', 'CellLine', 'CVCL:0027', (326, 334))	('XB130', 'Gene', (43, 48))
5655	30246718	We then analyzed the epithelial-mesenchymal transition (EMT)-associated proteins by Western blotting, which showed that the expressions of vimentin and N-cadherin were decreased in the shA groups than those in the NC groups, although the expressions of E-cadherin were increased [all P < 0.05; Figure 3e and 3f].	('N-cadherin', 'Gene', '1000', (152, 162))	('decreased', 'NegReg', (168, 177))	('increased', 'PosReg', (269, 278))	('E-cadherin', 'Gene', (253, 263))	('E-cadherin', 'Gene', '999', (253, 263))	('shA', 'Var', (185, 188))	('vimentin', 'Gene', '7431', (139, 147))	('expressions', 'MPA', (238, 249))	('expressions', 'MPA', (124, 135))	('vimentin', 'Gene', (139, 147))	('N-cadherin', 'Gene', (152, 162))
5656	30246718	To evaluate the effect of silencing XB130 on tumorigenesis in vitro, we established a nude mouse model of tumor formation and injected the shA and NC groups subcutaneously.	('XB130', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('XB130', 'Gene', '84632', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('silencing', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mouse', 'Species', '10090', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', (106, 111))
5658	30246718	These findings suggest that XB130 knockdown inhibits the growth of HCC.	('XB130', 'Gene', (28, 33))	('HCC', 'CPA', (67, 70))	('growth', 'CPA', (57, 63))	('XB130', 'Gene', '84632', (28, 33))	('knockdown', 'Var', (34, 43))	('inhibits', 'NegReg', (44, 52))
5660	30246718	We found that Ser473 (HepG2 shA vs. HepG2 NC: 0.31 +- 0.01 vs. 0.9 +- 0.02, P < 0.05 and MHCC97H shA vs. MHCC97H NC: 0.17 +- 0.02 vs. 0.69 +- 0.02, P < 0.05), threonine 308 (Thr308; HepG2 shA vs. HepG2 NC: 0.12 +- 0.01 vs. 0.43 +- 0.04, P < 0.05 and MHCC97H shA vs. MHCC97H NC: 0.21 +- 0.05 vs. 0.52 +- 0.03, P < 0.05), and p-PI3K were significantly lower in HepG2 shA and MHCC97H shA groups (HepG2 shA vs. HepG2 NC: 0.26 +- 0.04 vs. 0.85 +- 0.03, P < 0.05 and MHCC97H shA vs. MHCC97H NC: 0.19 +- 0.02 vs. 0.86 +- 0.03, P < 0.05), and the level of p-PTEN, which is an inhibitor of p-Akt, was upregulated (HepG2 shA vs. HepG2 NC: 0.42 +- 0.04 vs. 0.25 +- 0.05, P < 0.05 and MHCC97H shA vs. MHCC97H NC: 0.26 +- 0.02 vs. 0.14 +- 0.01, P < 0.05), whereas there was no change in the levels of Akt, PTEN, and PI3K.	('HepG2', 'CellLine', 'CVCL:0027', (359, 364))	('Ser473', 'Chemical', '-', (14, 20))	('HepG2', 'CellLine', 'CVCL:0027', (605, 610))	('HepG2', 'CellLine', 'CVCL:0027', (407, 412))	('HepG2 NC', 'CellLine', 'CVCL:0027', (619, 627))	('upregulated', 'PosReg', (592, 603))	('PTEN', 'Gene', '5728', (793, 797))	('HepG2', 'CellLine', 'CVCL:0027', (619, 624))	('HepG2 NC', 'CellLine', 'CVCL:0027', (196, 204))	('HepG2 NC', 'CellLine', 'CVCL:0027', (36, 44))	('Akt', 'Gene', (583, 586))	('HepG2', 'CellLine', 'CVCL:0027', (182, 187))	('Akt', 'Gene', (788, 791))	('PTEN', 'Gene', (550, 554))	('MHCC97H shA vs.', 'Var', (673, 688))	('HepG2', 'CellLine', 'CVCL:0027', (22, 27))	('Akt', 'Gene', '207', (583, 586))	('Akt', 'Gene', '207', (788, 791))	('HepG2', 'CellLine', 'CVCL:0027', (196, 201))	('Thr308', 'Chemical', '-', (174, 180))	('HepG2', 'CellLine', 'CVCL:0027', (393, 398))	('PTEN', 'Gene', '5728', (550, 554))	('HepG2', 'CellLine', 'CVCL:0027', (36, 41))	('PTEN', 'Gene', (793, 797))	('HepG2 NC', 'CellLine', 'CVCL:0027', (407, 415))
5662	30246718	Then, we explored the effect of silencing XB130 on the apoptosis of HCC cell lines using flow cytometry assay and caspase assay.	('XB130', 'Gene', (42, 47))	('silencing', 'Var', (32, 41))	('caspase', 'Gene', '841;842', (114, 121))	('XB130', 'Gene', '84632', (42, 47))	('caspase', 'Gene', (114, 121))
5681	30246718	found that silencing XB130 arrested thyroid cancer WRO cells in the G0/G1 phase, although the number of S phase cells and levels of the proliferation-associated proteins Ki-67 and proliferating cell nuclear antigen decreased, as did the tumorigenicity of tumor cells in vitro.	('silencing', 'Var', (11, 20))	('tumor', 'Disease', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('XB130', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('thyroid cancer', 'Phenotype', 'HP:0002890', (36, 50))	('thyroid cancer', 'Disease', (36, 50))	('levels', 'MPA', (122, 128))	('XB130', 'Gene', '84632', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('decreased', 'NegReg', (215, 224))	('thyroid cancer', 'Disease', 'MESH:D013964', (36, 50))	('proliferating', 'MPA', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
5683	30246718	also found similar results in gastric cancer, wherein the knockdown of XB130 in SGC7901 and MNK45 cells led to a decrease in cell proliferation, an increase in G0/G1 phase, and a decrease in S phase cells.	('decrease', 'NegReg', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('increase', 'PosReg', (148, 156))	('XB130', 'Gene', '84632', (71, 76))	('S phase cells', 'CPA', (191, 204))	('G0/G1 phase', 'CPA', (160, 171))	('gastric cancer', 'Disease', 'MESH:D013274', (30, 44))	('decrease', 'NegReg', (179, 187))	('gastric cancer', 'Disease', (30, 44))	('cell proliferation', 'CPA', (125, 143))	('SGC7901', 'CellLine', 'CVCL:0520', (80, 87))	('knockdown', 'Var', (58, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (30, 44))	('XB130', 'Gene', (71, 76))
5691	30246718	It has been shown that SH2 on XB130 has a YxxM modification site and that its specific binding to the p85alpha subunit of PI3K activates the Akt pathway, whereas a reduction in XB130 can affect multiple molecules downstream of Akt.	('XB130', 'Gene', (30, 35))	('Akt', 'Gene', (227, 230))	('YxxM modification site', 'MPA', (42, 64))	('XB130', 'Gene', '84632', (177, 182))	('p85alpha', 'Gene', (102, 110))	('XB130', 'Gene', '84632', (30, 35))	('affect', 'Reg', (187, 193))	('binding', 'Interaction', (87, 94))	('p85alpha', 'Gene', '5295', (102, 110))	('SH2', 'Var', (23, 26))	('Akt', 'Gene', (141, 144))	('Akt', 'Gene', '207', (141, 144))	('activates', 'PosReg', (127, 136))	('Akt', 'Gene', '207', (227, 230))	('XB130', 'Gene', (177, 182))
5692	30246718	Akt is a serine/threonine kinase, also known as protein kinase B, which is highly homologous to protein kinase A and protein kinase C, is one of the major downstream effector molecules of PI3K, and can directly phosphorylate many transcriptional factors; its activation requires the activation of Thr308 and Ser473.	('protein kinase B', 'Gene', (48, 64))	('activation', 'PosReg', (259, 269))	('Thr308', 'Var', (297, 303))	('protein kinase B', 'Gene', '2185', (48, 64))	('Ser473', 'Var', (308, 314))	('Akt', 'Gene', '207', (0, 3))	('Ser473', 'Chemical', '-', (308, 314))	('Thr308', 'Chemical', '-', (297, 303))	('Akt', 'Gene', (0, 3))
5693	30246718	Consistent with this, in the present study, we found that a reduction in XB130 can regulate the expression of the Akt-related phosphorylation markers Ser473 and Thr308 and inhibit the phosphorylation of PI3K but had no effect on the total levels of Akt and PI3K.	('XB130', 'Gene', '84632', (73, 78))	('Thr308', 'Chemical', '-', (161, 167))	('Akt', 'Gene', '207', (249, 252))	('Akt', 'Gene', (114, 117))	('expression', 'MPA', (96, 106))	('reduction', 'NegReg', (60, 69))	('Ser473', 'MPA', (150, 156))	('Akt', 'Gene', (249, 252))	('Ser473', 'Chemical', '-', (150, 156))	('regulate', 'Reg', (83, 91))	('inhibit', 'NegReg', (172, 179))	('Thr308', 'Var', (161, 167))	('XB130', 'Gene', (73, 78))	('PI3K', 'Pathway', (203, 207))	('Akt', 'Gene', '207', (114, 117))	('phosphorylation', 'MPA', (184, 199))
5696	30246718	In contrast, the mutations or deletions of PTEN will lose normal inhibition of PIP2 conversion to PIP3, increasing intracellular PIP3 accumulation and Akt activation, thereby inhibiting apoptosis, promoting cell growth, and stimulating tumor angiogenesis.	('PIP3', 'Chemical', '-', (129, 133))	('PIP2', 'Chemical', 'MESH:D019269', (79, 83))	('PIP3', 'Chemical', '-', (98, 102))	('deletions', 'Var', (30, 39))	('Akt', 'Gene', '207', (151, 154))	('inhibition', 'MPA', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('promoting', 'PosReg', (197, 206))	('mutations', 'Var', (17, 26))	('cell growth', 'CPA', (207, 218))	('PTEN', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('apoptosis', 'CPA', (186, 195))	('inhibiting', 'NegReg', (175, 185))	('PTEN', 'Gene', '5728', (43, 47))	('stimulating', 'Reg', (224, 235))	('intracellular PIP3 accumulation', 'MPA', (115, 146))	('lose', 'NegReg', (53, 57))	('increasing', 'PosReg', (104, 114))	('tumor', 'Disease', (236, 241))	('Akt', 'Gene', (151, 154))	('activation', 'PosReg', (155, 165))
5701	30246718	We used Western blotting to detect EMT-related markers, which showed that downregulation of XB130 upregulated E-cadherin expression, although downregulation of N-cadherin and vimentin could inhibit the progression of EMT and affect the invasion and metastasis of HCC.	('downregulation', 'Var', (74, 88))	('inhibit', 'NegReg', (190, 197))	('XB130', 'Gene', '84632', (92, 97))	('E-cadherin', 'Gene', '999', (110, 120))	('N-cadherin', 'Gene', '1000', (160, 170))	('HCC', 'Disease', (263, 266))	('upregulated', 'PosReg', (98, 109))	('XB130', 'Gene', (92, 97))	('E-cadherin', 'Gene', (110, 120))	('expression', 'MPA', (121, 131))	('affect', 'Reg', (225, 231))	('progression of EMT', 'CPA', (202, 220))	('metastasis', 'CPA', (249, 259))	('vimentin', 'Gene', '7431', (175, 183))	('N-cadherin', 'Gene', (160, 170))	('downregulation', 'NegReg', (142, 156))	('vimentin', 'Gene', (175, 183))
5726	29928545	For the treatment of gastric cancer, there are three accepted approaches, all of which include chemotherapy and resection: Surgery followed by postoperative (adjuvant) chemotherapy with fluorouracil (5-FU) and radiotherapy, primarily for patients in whom resection was less than level D1 (i.e., a suboptimal number of nodes were resected); Preoperative and postoperative chemotherapy with epirubicin, cisplatin, and 5-FU (ECF), for patients with D1-2 resection; Postoperative chemotherapy with capecit-abine and oxaliplatin (XELOX) for patients with D2 resection.	('D1-2', 'Var', (446, 450))	('fluorouracil', 'Chemical', 'MESH:D005472', (186, 198))	('epirubicin', 'Chemical', 'MESH:D015251', (389, 399))	('gastric cancer', 'Phenotype', 'HP:0012126', (21, 35))	('capecit-abine', 'Chemical', 'MESH:D000069287', (494, 507))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (512, 523))	('5-FU', 'Chemical', 'MESH:D005472', (416, 420))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (536, 544))	('gastric cancer', 'Disease', (21, 35))	('XELOX', 'Chemical', 'MESH:C519688', (525, 530))	('patients', 'Species', '9606', (432, 440))	('5-FU', 'Chemical', 'MESH:D005472', (200, 204))	('gastric cancer', 'Disease', 'MESH:D013274', (21, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (401, 410))	('patients', 'Species', '9606', (238, 246))
5793	29928545	Among 149 esophageal adenocarcinomas, 26 significant genes with mutations or genomic loss have been identified.	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (10, 36))	('esophageal adenocarcinomas', 'Disease', (10, 36))	('mutations', 'Var', (64, 73))
5796	29928545	However, inhibition of EGFR and of MET has universally failed to improve outcomes, and results are mixed for the targeting of ERBB2.	('ERBB2', 'Gene', '2064', (126, 131))	('ERBB2', 'Gene', (126, 131))	('MET', 'Gene', (35, 38))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('inhibition', 'Var', (9, 19))
5806	26498753	The hybrids also increased expression of stemness factors Oct4, Nanog, Sox2 and Lin28.	('increased', 'PosReg', (17, 26))	('stemness', 'CPA', (41, 49))	('Oct4', 'Gene', (58, 62))	('Oct4', 'Gene', '5460', (58, 62))	('Lin28', 'Gene', (80, 85))	('Lin28', 'Gene', '79727', (80, 85))	('Sox2', 'Gene', '6657', (71, 75))	('expression', 'MPA', (27, 37))	('Nanog', 'Gene', '79923', (64, 69))	('Sox2', 'Gene', (71, 75))	('Nanog', 'Gene', (64, 69))	('hybrids', 'Var', (4, 11))
5809	26498753	Taken together, our results suggest that cell fusion between hucMSCs and gastric cancer cells could contribute to tumorigenic hybrids with EMT and stem cell-like properties, which may provide a flexible tool for investigating the roles of MSCs in gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('gastric cancer', 'Phenotype', 'HP:0012126', (247, 261))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (247, 261))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('tumor', 'Disease', (114, 119))	('gastric cancer', 'Disease', (247, 261))	('contribute', 'Reg', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cell fusion', 'Var', (41, 52))	('gastric cancer', 'Disease', (73, 87))
5817	26498753	For instance, tumor associated macrophage may fuse with epithelial cancer cells at the sites of primary tumor, giving rise to hybrids that have enhanced migratory and invasive capabilities.	('migratory', 'CPA', (153, 162))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('epithelial cancer', 'Disease', (56, 73))	('epithelial cancer', 'Disease', 'MESH:D000077216', (56, 73))	('enhanced', 'PosReg', (144, 152))	('invasive capabilities', 'CPA', (167, 188))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('hybrids', 'Var', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('epithelial cancer', 'Phenotype', 'HP:0031492', (56, 73))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
5823	26498753	Several studies have shown that the hybrids between pre-malignant cell and stem cells are more malignant than the parental cells and gain self-renewal and migratory abilities, which highlight the pro-tumor role of stem cells by fusing with other cells.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('migratory abilities', 'CPA', (155, 174))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('hybrids', 'Var', (36, 43))	('tumor', 'Disease', (200, 205))	('self-renewal', 'CPA', (138, 150))	('more', 'PosReg', (90, 94))	('gain', 'PosReg', (133, 137))
5861	26498753	Cell fusion was induced by PEG1500 in co-cultured DIO-HGC27 and DID-hucMSCs.	('induced', 'Reg', (16, 23))	('PEG1500', 'Var', (27, 34))	('Cell fusion', 'CPA', (0, 11))	('DIO', 'Chemical', '-', (50, 53))	('PEG', 'Chemical', 'MESH:D011092', (27, 30))
5882	26498753	CD133 expression increased in hybrids compared with the parental cells (increase from 0.1 to 1.5 % in HGC-27 fusion and 0.2 to 2.5 % in SGC-7901 fusion) (Fig.	('increased', 'PosReg', (17, 26))	('SGC', 'Gene', '6443', (136, 139))	('expression', 'MPA', (6, 16))	('hybrids', 'Var', (30, 37))	('CD133', 'Gene', (0, 5))	('CD133', 'Gene', '8842', (0, 5))	('SGC', 'Gene', (136, 139))
5889	26498753	The neoplasm tissues of hybrids presented highly heterogeneity, abnormally elevated nuclear/cytoplasmic ratios, and derangement distribution in some regions (Additional file 4).	('neoplasm', 'Disease', 'MESH:D009369', (4, 12))	('neoplasm', 'Phenotype', 'HP:0002664', (4, 12))	('nuclear/cytoplasmic ratios', 'CPA', (84, 110))	('elevated', 'PosReg', (75, 83))	('derangement', 'Reg', (116, 127))	('neoplasm', 'Disease', (4, 12))	('hybrids', 'Var', (24, 31))
5898	26498753	This hypothesis proposes that fusion between BMDCs and "altered" tissue cells/pre-malignant cells would result in malignant tumors, which may be more migratory and more invasive.	('malignant tumors', 'Disease', 'MESH:D018198', (114, 130))	('fusion', 'Var', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('invasive', 'CPA', (169, 177))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('malignant tumors', 'Disease', (114, 130))	('result in', 'Reg', (104, 113))	('more', 'PosReg', (145, 149))
5903	26498753	Fusion of MSC with gastric epithelial cells increases invasion and metastasis of gastric cancer.	('metastasis of gastric cancer', 'Disease', (67, 95))	('Fusion', 'Var', (0, 6))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('invasion', 'CPA', (54, 62))	('metastasis of gastric cancer', 'Disease', 'MESH:D009362', (67, 95))	('increases', 'PosReg', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
5906	26498753	In contrary, there are some studies showing that fusion of MSCs with esophageal carcinoma cells inhibits the tumorigenicity of esophageal carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('inhibits', 'NegReg', (96, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('esophageal carcinoma', 'Disease', (127, 147))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (127, 147))	('esophageal carcinoma', 'Disease', (69, 89))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (127, 147))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (69, 89))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (69, 89))	('fusion', 'Var', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
5910	26498753	PEG could induce cell agglutination and cell-to-cell contact, leading to subsequent cell fusion.	('PEG', 'Var', (0, 3))	('induce', 'Reg', (10, 16))	('cell-to-cell contact', 'CPA', (40, 60))	('cell fusion', 'CPA', (84, 95))	('cell agglutination', 'CPA', (17, 35))	('PEG', 'Chemical', 'MESH:D011092', (0, 3))
5913	26498753	The aritifical fusion process such as PEG-induced cell fusion also has its limitation, PEG can cause the uncontrollable fusion of multiple cells, leading to the appearance of giant polykaryons.	('PEG', 'Chemical', 'MESH:D011092', (38, 41))	('uncontrollable', 'MPA', (105, 119))	('PEG', 'Chemical', 'MESH:D011092', (87, 90))	('cause', 'Reg', (95, 100))	('PEG', 'Var', (87, 90))
5929	25544767	TGF-beta1 induces epigenetic silence of TIP30 to promote tumor metastasis in esophageal carcinoma TGF-beta1, a potent EMT (epithelial-mesenchymal transition) inducer present in the tumor microenvironment, is involved in the metastasis and progression of various carcinomas, including esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('promote', 'PosReg', (49, 56))	('TGF-beta1', 'Gene', '7040', (98, 107))	('involved', 'Reg', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('TGF-beta1', 'Gene', (0, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (262, 272))	('carcinomas', 'Disease', 'MESH:D002277', (262, 272))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (77, 97))	('tumor', 'Disease', (57, 62))	('TGF-beta1', 'Gene', '7040', (0, 9))	('esophageal squamous cell carcinoma', 'Disease', (284, 318))	('esophageal carcinoma', 'Disease', (77, 97))	('tumor metastasis', 'Disease', 'MESH:D009362', (57, 73))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('TIP30', 'Gene', '10553', (40, 45))	('carcinomas', 'Disease', (262, 272))	('tumor', 'Disease', (181, 186))	('tumor metastasis', 'Disease', (57, 73))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (77, 97))	('epigenetic silence', 'Var', (18, 36))	('TIP30', 'Gene', (40, 45))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (284, 318))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (295, 318))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('TGF-beta1', 'Gene', (98, 107))
5932	25544767	In our in vitro and in vivo studies, we showed that silence of TIP30 led to EMT, enhanced migrative and invasive abilities of ESCC cells, promoted tumor metastasis in xenografted mice; alternatively, overexpression of TIP30inhibited TGF-beta1-induced EMT, and metastatic abilities of ESCC cells.	('overexpression', 'PosReg', (200, 214))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor metastasis', 'Disease', 'MESH:D009362', (147, 163))	('enhanced', 'PosReg', (81, 89))	('mice', 'Species', '10090', (179, 183))	('EMT', 'CPA', (76, 79))	('metastatic abilities of', 'CPA', (260, 283))	('silence', 'Var', (52, 59))	('tumor metastasis', 'Disease', (147, 163))	('TIP30', 'Gene', (63, 68))	('promoted', 'PosReg', (138, 146))	('TIP30inhibited', 'Gene', (218, 232))
5933	25544767	Mechanically, TIP30 silencing induced the nuclear translocation and transcriptional activation of beta-catenin in an AKT-dependent manner, which further resulted in the initiation of EMT.	('AKT', 'Gene', '207', (117, 120))	('nuclear translocation', 'MPA', (42, 63))	('EMT', 'CPA', (183, 186))	('AKT', 'Gene', (117, 120))	('transcriptional activation', 'MPA', (68, 94))	('initiation', 'PosReg', (169, 179))	('TIP30', 'Gene', (14, 19))	('beta-catenin', 'Gene', (98, 110))	('resulted in', 'Reg', (153, 164))	('silencing', 'Var', (20, 29))	('beta-catenin', 'Gene', '1499', (98, 110))
5934	25544767	Consistently, TIP30 was frequently methylated and downregulated in ESCC patients.	('ESCC', 'Disease', (67, 71))	('methylated', 'Var', (35, 45))	('TIP30', 'Gene', (14, 19))	('downregulated', 'NegReg', (50, 63))	('patients', 'Species', '9606', (72, 80))
5945	25544767	TIP30, also called CC3 or HTATIP2, is a putative tumor suppressor initially identified by a differential display analysis of mRNA in highly metastatic human variant small cell lung carcinoma (v-SCLC), versus less metastatic classic small cell lung carcinoma (c-SCLC) cell lines.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (232, 257))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (232, 257))	('HTATIP2', 'Gene', '10553', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('human variant', 'Species', '9606', (151, 164))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (165, 190))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (165, 190))	('CC3', 'Gene', '10553', (19, 22))	('tumor', 'Disease', (49, 54))	('variant', 'Var', (157, 164))	('small cell lung carcinoma', 'Disease', (232, 257))	('HTATIP2', 'Gene', (26, 33))	('small cell lung carcinoma', 'Disease', (165, 190))	('CC3', 'Gene', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
5948	25544767	TIP30 is able to interact with Ets-1 and inhibit Ets-1-mediated transactivation of osteopontin, an important molecule for tumor metastasis in HCC.	('Ets-1', 'Gene', '2113', (31, 36))	('Ets-1', 'Gene', (31, 36))	('Ets-1', 'Gene', '2113', (49, 54))	('Ets-1', 'Gene', (49, 54))	('tumor metastasis', 'Disease', 'MESH:D009362', (122, 138))	('osteopontin', 'Gene', (83, 94))	('TIP30', 'Var', (0, 5))	('tumor metastasis', 'Disease', (122, 138))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('inhibit', 'NegReg', (41, 48))	('interact', 'Interaction', (17, 25))	('osteopontin', 'Gene', '6696', (83, 94))
5949	25544767	Recently, inhibition of the EGFR/AKT signaling pathway by TIP30 was elucidated in breast cancer and hepatocellular carcinoma.	('breast cancer', 'Disease', (82, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('EGFR', 'Gene', '1956', (28, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('hepatocellular carcinoma', 'Disease', (100, 124))	('EGFR', 'Gene', (28, 32))	('AKT', 'Gene', '207', (33, 36))	('TIP30', 'Var', (58, 63))	('AKT', 'Gene', (33, 36))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
5961	25544767	The decreased expression of TIP30 by TGF-beta1 was independent of canonical TGF-beta1 signaling, since siRNA-mediated knockdown of Smad3 did not restore TIP30 expression upon TGF-beta1 treatment (Fig.	('Smad3', 'Gene', (131, 136))	('TIP30', 'Gene', (153, 158))	('decreased', 'NegReg', (4, 13))	('knockdown', 'Var', (118, 127))	('expression', 'MPA', (14, 24))	('expression', 'MPA', (159, 169))	('Smad3', 'Gene', '4088', (131, 136))	('TIP30', 'Gene', (28, 33))
5964	25544767	In contrast, the anti-TGF-beta antibody decreased DNMT1 and DNMT3A expression in KYSE450 and KYSE150 (Fig.	('KYSE150', 'Var', (93, 100))	('DNMT3A', 'Gene', (60, 66))	('TGF-beta', 'Gene', '7040', (22, 30))	('DNMT1', 'Gene', (50, 55))	('KYSE150', 'CellLine', 'CVCL:1348', (93, 100))	('DNMT3A', 'Gene', '1788', (60, 66))	('DNMT1', 'Gene', '1786', (50, 55))	('expression', 'MPA', (67, 77))	('TGF-beta', 'Gene', (22, 30))	('decreased', 'NegReg', (40, 49))
5966	25544767	The results showed that the silencing of DNMT1 or DNMT3A restored TIP30 expression in TGF-beta1 treated cells (Fig.	('DNMT1', 'Gene', (41, 46))	('DNMT3A', 'Gene', (50, 56))	('DNMT1', 'Gene', '1786', (41, 46))	('DNMT3A', 'Gene', '1788', (50, 56))	('silencing', 'Var', (28, 37))	('expression', 'MPA', (72, 82))	('TIP30', 'Gene', (66, 71))	('restored', 'PosReg', (57, 65))
5971	25544767	Compared to non-specific RNA interference, knockdown of TIP30 significantly enhanced the growth and invasion of tumor cells (Supplemental Fig.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('knockdown', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('enhanced', 'PosReg', (76, 84))	('tumor', 'Disease', (112, 117))	('growth', 'CPA', (89, 95))	('TIP30', 'Gene', (56, 61))
5974	25544767	However, irregular tumor invasion with a decreased E-cadherin expression and an increased Vimentin expression were observed in tumors induced by KYSE30-shTIP30 cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('KYSE30-shTIP30', 'Var', (145, 159))	('expression', 'MPA', (99, 109))	('tumors', 'Disease', (127, 133))	('Vimentin', 'Gene', (90, 98))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('decreased', 'NegReg', (41, 50))	('increased', 'PosReg', (80, 89))	('expression', 'MPA', (62, 72))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Vimentin', 'Gene', '7431', (90, 98))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('E-cadherin', 'Gene', (51, 61))	('E-cadherin', 'Gene', '999', (51, 61))
5978	25544767	The number of metastatic nodules on the surface of the lungs and livers was significantly higher in mice injected with KYSE30-shTIP30 cells than in mice injected with KYSE30-shNon cells (Fig.	('mice', 'Species', '10090', (100, 104))	('KYSE30-shTIP30 cells', 'Var', (119, 139))	('mice', 'Species', '10090', (148, 152))	('metastatic nodules on the surface', 'CPA', (14, 47))	('higher', 'PosReg', (90, 96))
5987	25544767	Consistent with the in vitro experimental results, cytosol and nucleus staining of beta-catenin were found in KYSE30-shTIP30 cells generated tumors, while the control tumors showed a membranous staining of beta-catenin (Fig.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('beta-catenin', 'Gene', (83, 95))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('beta-catenin', 'Gene', '1499', (206, 218))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('beta-catenin', 'Gene', '1499', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('beta-catenin', 'Gene', (206, 218))	('KYSE30-shTIP30', 'Var', (110, 124))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
5989	25544767	As expected, TIP30 silence sharply increased beta-catenin-dependent transcriptional activity.	('increased', 'PosReg', (35, 44))	('beta-catenin', 'Gene', '1499', (45, 57))	('TIP30', 'Gene', (13, 18))	('silence', 'Var', (19, 26))	('beta-catenin', 'Gene', (45, 57))
5992	25544767	In our study, TIP30 regulates Vimentin expression but not ZEB1 in ESCC (Supplemental Fig.	('Vimentin', 'Gene', '7431', (30, 38))	('TIP30', 'Var', (14, 19))	('regulates', 'Reg', (20, 29))	('Vimentin', 'Gene', (30, 38))	('ZEB1', 'Gene', (58, 62))	('ZEB1', 'Gene', '6935', (58, 62))
5993	25544767	To confirm the importance of beta-catenin in increased expression of Vimentin induced by TIP30 silence, siRNA against beta-catenin was used.	('Vimentin', 'Gene', (69, 77))	('increased', 'PosReg', (45, 54))	('Vimentin', 'Gene', '7431', (69, 77))	('beta-catenin', 'Gene', (118, 130))	('TIP30', 'Gene', (89, 94))	('expression', 'MPA', (55, 65))	('beta-catenin', 'Gene', '1499', (118, 130))	('beta-catenin', 'Gene', (29, 41))	('beta-catenin', 'Gene', '1499', (29, 41))	('silence', 'Var', (95, 102))
5995	25544767	To underlie the regulatory mechanism of beta-catenin activity by TIP30, the phosphorylation status of beta-catenin was examined via western blots with indicated antibodies (Fig.	('beta-catenin', 'Gene', '1499', (102, 114))	('TIP30', 'Var', (65, 70))	('beta-catenin', 'Gene', (40, 52))	('beta-catenin', 'Gene', '1499', (40, 52))	('beta-catenin', 'Gene', (102, 114))
5997	25544767	However, AKT mediated phosphorylation of S552 was significantly increased after TIP30 depletion and TGF-beta1 treatment.	('TIP30', 'Gene', (80, 85))	('AKT', 'Gene', '207', (9, 12))	('S552', 'Gene', (41, 45))	('AKT', 'Gene', (9, 12))	('increased', 'PosReg', (64, 73))	('depletion', 'Var', (86, 95))
5999	25544767	The results indicate that TIP30 inhibits phosphorylate of beta-catenin at S552 and suppresses activation of beta-catenin.	('beta-catenin', 'Gene', (108, 120))	('beta-catenin', 'Gene', (58, 70))	('TIP30', 'Var', (26, 31))	('phosphorylate', 'MPA', (41, 54))	('beta-catenin', 'Gene', '1499', (108, 120))	('beta-catenin', 'Gene', '1499', (58, 70))	('activation', 'MPA', (94, 104))	('inhibits', 'NegReg', (32, 40))	('S552', 'Var', (74, 78))	('suppresses', 'NegReg', (83, 93))
6002	25544767	TIP30 silence significantly increased AKT activation, and overexpression of TIP30 inhibits TGF-beta1 mediated AKT activation.	('increased', 'PosReg', (28, 37))	('silence', 'Var', (6, 13))	('AKT', 'Gene', (38, 41))	('TGF-beta1', 'Protein', (91, 100))	('AKT', 'Gene', (110, 113))	('AKT', 'Gene', '207', (110, 113))	('TIP30', 'Gene', (0, 5))	('activation', 'PosReg', (42, 52))	('AKT', 'Gene', '207', (38, 41))	('inhibits', 'NegReg', (82, 90))	('TIP30', 'Gene', (76, 81))
6003	25544767	Furthermore, blockage of AKT by MK-2206 attenuated TIP30 decrease-induced activation of beta-catenin and upregulation of Vimentin (Fig.	('AKT', 'Gene', (25, 28))	('upregulation', 'PosReg', (105, 117))	('Vimentin', 'Gene', (121, 129))	('Vimentin', 'Gene', '7431', (121, 129))	('blockage', 'NegReg', (13, 21))	('MK-2206', 'Var', (32, 39))	('activation', 'PosReg', (74, 84))	('MK-2206', 'Chemical', 'MESH:C548887', (32, 39))	('beta-catenin', 'Gene', (88, 100))	('AKT', 'Gene', '207', (25, 28))	('attenuated', 'NegReg', (40, 50))	('beta-catenin', 'Gene', '1499', (88, 100))	('TIP30', 'Gene', (51, 56))	('decrease-induced', 'NegReg', (57, 73))
6013	25544767	We found loss of TIP30 correlated with nuclear beta-catenin, and aberrant E-cadherin expression (P<0.001, Mann-Whitney U test, Fig.	('expression', 'MPA', (85, 95))	('beta-catenin', 'Gene', '1499', (47, 59))	('aberrant', 'Var', (65, 73))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', '999', (74, 84))	('loss', 'NegReg', (9, 13))	('beta-catenin', 'Gene', (47, 59))	('TIP30', 'Gene', (17, 22))
6015	25544767	Log-rank test showed that ESCC patients with low TIP30 expression experienced poor overall survival (OS) than patients with high TIP30 expression (median survival time, 29 months vs. 49 months; P < 0.001; Fig.	('overall survival', 'MPA', (83, 99))	('ESCC', 'Disease', (26, 30))	('poor', 'NegReg', (78, 82))	('OS', 'Chemical', '-', (101, 103))	('patients', 'Species', '9606', (31, 39))	('low TIP30 expression', 'Var', (45, 65))	('patients', 'Species', '9606', (110, 118))
6022	25544767	Previous studies have suggested that the expression of TIP30 could be activated by JAK/STAT3 pathway or suppressed by DNA methylation and mir-10b.	('STAT3', 'Gene', (87, 92))	('DNA methylation', 'Var', (118, 133))	('activated', 'PosReg', (70, 79))	('expression', 'MPA', (41, 51))	('mir-10b', 'Gene', (138, 145))	('suppressed', 'NegReg', (104, 114))	('STAT3', 'Gene', '6774', (87, 92))	('TIP30', 'Gene', (55, 60))	('mir-10b', 'Gene', '406903', (138, 145))
6026	25544767	We examined methylation status of TIP30 in ESCC cell lines and ESCC patients to find that TIP30 is also frequently hypermethylated in both ESCC cell lines and ESCC patients.	('hypermethylated', 'Var', (115, 130))	('patients', 'Species', '9606', (68, 76))	('ESCC', 'Disease', (139, 143))	('patients', 'Species', '9606', (164, 172))	('TIP30', 'Gene', (90, 95))
6029	25544767	DNMT1 has been implicated primarily in the maintenance of methylation patterns that occurs during cellular replication and preferentially methylates hemimethylated DNA.	('hemimethylated', 'Var', (149, 163))	('DNMT1', 'Gene', (0, 5))	('DNMT1', 'Gene', '1786', (0, 5))	('methylation patterns', 'MPA', (58, 78))	('methylates', 'Var', (138, 148))	('preferentially', 'PosReg', (123, 137))
6030	25544767	We demonstrate that TIP30 can be methylated by TGF-beta1 via up-regulation of DNMT1 and DNMT3A.	('DNMT3A', 'Gene', '1788', (88, 94))	('DNMT1', 'Gene', (78, 83))	('TIP30', 'Gene', (20, 25))	('DNMT1', 'Gene', '1786', (78, 83))	('up-regulation', 'PosReg', (61, 74))	('TGF-beta1', 'Gene', (47, 56))	('methylated', 'Var', (33, 43))	('DNMT3A', 'Gene', (88, 94))
6034	25544767	We also demonstrate that TIP30 may inhibit phosphorylation and activation of beta-catenin.	('phosphorylation', 'MPA', (43, 58))	('TIP30', 'Var', (25, 30))	('activation', 'MPA', (63, 73))	('beta-catenin', 'Gene', (77, 89))	('inhibit', 'NegReg', (35, 42))	('beta-catenin', 'Gene', '1499', (77, 89))
6035	25544767	Our data shows that silence of TIP30 facilitates TGF-beta1-mediated activation of AKT/beta-catenin signaling, which subsequently induces EMT and pro-metastatic responses.	('beta-catenin', 'Gene', (86, 98))	('silence', 'Var', (20, 27))	('AKT', 'Gene', (82, 85))	('beta-catenin', 'Gene', '1499', (86, 98))	('activation', 'PosReg', (68, 78))	('AKT', 'Gene', '207', (82, 85))	('TGF-beta1-mediated', 'Gene', (49, 67))	('pro-metastatic responses', 'CPA', (145, 169))	('EMT', 'CPA', (137, 140))	('induces', 'PosReg', (129, 136))	('TIP30', 'Gene', (31, 36))	('facilitates', 'PosReg', (37, 48))
6037	25544767	ESCC cell lines (YES2, KYSE30, KYSE450, KYSE150, KYSE180 and KYSE410) were cultured at 37 C in an atmosphere containing 5% CO2 in RPMI 1640 medium supplemented with 10% fetal bovine serum.	('YES2', 'Gene', '7526', (17, 21))	('bovine', 'Species', '9913', (175, 181))	('KYSE150', 'CellLine', 'CVCL:1348', (40, 47))	('RPMI 1640 medium', 'Chemical', '-', (130, 146))	('YES2', 'Gene', (17, 21))	('KYSE410', 'Var', (61, 68))	('CO2', 'Chemical', '-', (123, 126))	('KYSE180', 'Var', (49, 56))
6062	25544767	For the tumorigenicity assay, KYSE30 cells were infected with LV-shTIP30 and LV-shNon at MOI 20 and 5x106 cells were injected subcutaneously into each mouse (n = 6 mice / group).	('LV-shTIP30', 'Var', (62, 72))	('mouse', 'Species', '10090', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('mice', 'Species', '10090', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))
6079	24899581	In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-delta, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p.	('miR-223', 'Var', (144, 151))	('EBP2', 'Gene', (84, 88))	('miR-27a', 'Gene', (153, 160))	('Pin1', 'Gene', '5300', (90, 94))	('EBP2', 'Gene', '10969', (84, 88))	('Hes-5', 'Gene', (96, 101))	('C/EBP-delta', 'Gene', (71, 82))	('FBW7', 'Gene', (9, 13))	('Numb', 'Gene', (106, 110))	('Hes-5', 'Gene', '388585', (96, 101))	('Numb', 'Gene', '8650', (106, 110))	('miR-129-5p', 'Gene', (174, 184))	('C/EBP-delta', 'Gene', '1052', (71, 82))	('miR-27a', 'Gene', '407018', (153, 160))	('Pin1', 'Gene', (90, 94))	('miR-129-5p', 'Gene', '100302178', (174, 184))	('p53', 'Var', (66, 69))	('miR-25', 'Var', (162, 168))
6084	24899581	Consistent with the notion that FBW7 exerts its anti-tumor activity in various human malignancies, FBW7 mutation and/or deletion are frequently identified in a variety of human neoplasms; for example, FBW7 mutation rate in T-cell acute lymphoblastic leukemia is approximately 30%.	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (230, 258))	('FBW7', 'Gene', (201, 205))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('deletion', 'Var', (120, 128))	('tumor', 'Disease', (53, 58))	('neoplasms', 'Disease', (177, 186))	('FBW7', 'Gene', (99, 103))	('human', 'Species', '9606', (79, 84))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (236, 258))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutation', 'Var', (104, 112))	('neoplasms', 'Phenotype', 'HP:0002664', (177, 186))	('mutation', 'Var', (206, 214))	('human', 'Species', '9606', (171, 176))	('leukemia', 'Phenotype', 'HP:0001909', (250, 258))	('malignancies', 'Disease', 'MESH:D009369', (85, 97))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (236, 258))	('malignancies', 'Disease', (85, 97))	('neoplasms', 'Disease', 'MESH:D009369', (177, 186))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (223, 258))	('lymphoblastic leukemia', 'Disease', (236, 258))
6106	24899581	More importantly, MED13 and MED13L are phosphorylated at T326, which was shown to be required for FBW7-mediated degradation function.	('MED13', 'Gene', '9969', (18, 23))	('MED13', 'Gene', '9969', (28, 33))	('MED13L', 'Gene', (28, 34))	('MED13', 'Gene', (28, 33))	('MED13L', 'Gene', '23389', (28, 34))	('MED13', 'Gene', (18, 23))	('T326', 'Var', (57, 61))
6114	24899581	Consistently, prostate or breast cancer patients with low expression of KLF2 and high levels of EZH2 have a shorter overall survival.	('breast cancer', 'Disease', (26, 39))	('high levels', 'Var', (81, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('low', 'NegReg', (54, 57))	('EZH2', 'Gene', '2146', (96, 100))	('KLF2', 'Gene', '10365', (72, 76))	('expression', 'MPA', (58, 68))	('patients', 'Species', '9606', (40, 48))	('EZH2', 'Gene', (96, 100))	('shorter', 'NegReg', (108, 115))	('KLF2', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('prostate', 'Disease', (14, 22))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('overall', 'MPA', (116, 123))
6121	24899581	Consistently, inhibition of GSK3beta increased the basal levels of KLF2 and extended KLF2 protein half-life.	('extended', 'PosReg', (76, 84))	('KLF2', 'Gene', (85, 89))	('GSK3beta', 'Gene', '2932', (28, 36))	('KLF2', 'Gene', '10365', (67, 71))	('increased', 'PosReg', (37, 46))	('KLF2', 'Gene', (67, 71))	('GSK3beta', 'Gene', (28, 36))	('inhibition', 'Var', (14, 24))	('KLF2', 'Gene', '10365', (85, 89))
6133	24899581	Consistently, FBW7 inactivation up-regulated p100 levels, which subsequently suppressed the canonical NF-kappaB1 signaling as p100 precursor could suppress NF-kappaB1 transcriptional activities in an IkappaB-like manner.	('suppressed', 'NegReg', (77, 87))	('NF-kappaB', 'Gene', '4790', (102, 111))	('NF-kappaB', 'Gene', (102, 111))	('up-regulated', 'PosReg', (32, 44))	('p100 levels', 'MPA', (45, 56))	('NF-kappaB', 'Gene', '4790', (156, 165))	('suppress', 'NegReg', (147, 155))	('inactivation', 'Var', (19, 31))	('FBW7', 'Gene', (14, 18))	('NF-kappaB', 'Gene', (156, 165))
6141	24899581	observed that truncated G-CSFR cooperated with the PML-RARalpha (promyelocytic leukemia-retinoic acid receptor alpha) oncogene to induce acute myeloid leukemia (AML) in mice.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (137, 159))	('induce', 'PosReg', (130, 136))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (137, 159))	('truncated', 'Var', (14, 23))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('leukemia', 'Phenotype', 'HP:0001909', (151, 159))	('PML', 'Gene', '5371', (51, 54))	('AML', 'Disease', 'MESH:D015470', (161, 164))	('leukemia-retinoic', 'Disease', 'MESH:D007938', (79, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (143, 159))	('mice', 'Species', '10090', (169, 173))	('G-CSFR', 'Gene', (24, 30))	('leukemia-retinoic', 'Disease', (79, 96))	('acute myeloid leukemia', 'Disease', (137, 159))	('AML', 'Phenotype', 'HP:0004808', (161, 164))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (65, 87))	('AML', 'Disease', (161, 164))	('PML', 'Gene', (51, 54))
6142	24899581	G-CSFR mutations could disrupt its ubiquitination and subsequently cause aberrant receptor signaling, leading to leukemic transformation.	('cause', 'Reg', (67, 72))	('leukemic transformation', 'Disease', 'MESH:D007938', (113, 136))	('aberrant receptor signaling', 'MPA', (73, 100))	('leading to', 'Reg', (102, 112))	('ubiquitination', 'MPA', (35, 49))	('disrupt', 'NegReg', (23, 30))	('G-CSFR', 'Gene', (0, 6))	('leukemic transformation', 'Disease', (113, 136))	('mutations', 'Var', (7, 16))
6144	24899581	More importantly, FBW7-mediated destruction of G-CSFR suppressed STAT3 (signal transducer and activator of transcription 3) phosphorylation and activation.	('signal transducer and activator of transcription 3', 'Gene', '6774', (72, 122))	('suppressed', 'NegReg', (54, 64))	('activation', 'MPA', (144, 154))	('G-CSFR', 'Gene', (47, 53))	('STAT3', 'Gene', '6774', (65, 70))	('destruction', 'Var', (32, 43))	('STAT3', 'Gene', (65, 70))
6145	24899581	In line with this finding, inhibition of FBW7 restored G-CSFR signaling and subsequently increased STAT3 transcriptional activity.	('restored', 'PosReg', (46, 54))	('STAT3', 'Gene', '6774', (99, 104))	('inhibition', 'Var', (27, 37))	('G-CSFR signaling', 'MPA', (55, 71))	('STAT3', 'Gene', (99, 104))	('increased', 'PosReg', (89, 98))	('FBW7', 'Gene', (41, 45))
6147	24899581	Overall, these reports suggest that G-CSFR could be a substrate of FBW7 and aberrant upregulation of G-CSFR due to impairments in FBW7-mediated destruction could contribute to the development of AML.	('AML', 'Phenotype', 'HP:0004808', (195, 198))	('FBW7-mediated', 'Gene', (130, 143))	('AML', 'Disease', 'MESH:D015470', (195, 198))	('impairments', 'Var', (115, 126))	('contribute', 'Reg', (162, 172))	('upregulation', 'PosReg', (85, 97))	('AML', 'Disease', (195, 198))
6152	24899581	Since p53 mutation/deletion has been identified in, at least, 50% of all human cancers, cancers with a p53 mutation/deletion generally have bad prognosis due to poor response to therapeutics.	('cancers', 'Disease', (79, 86))	('p53', 'Gene', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('human', 'Species', '9606', (73, 78))	('cancers', 'Disease', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('mutation/deletion', 'Var', (107, 124))
6164	24899581	Furthermore, reduced C/EBP-delta gene expression due to promoter methylation has been found in breast cancer cell lines and primary breast tumors.	('breast tumors', 'Disease', 'MESH:D001943', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('expression', 'MPA', (38, 48))	('breast tumors', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('promoter methylation', 'Var', (56, 76))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('breast tumors', 'Phenotype', 'HP:0100013', (132, 145))	('reduced', 'NegReg', (13, 20))	('C/EBP-delta', 'Gene', '1052', (21, 32))	('breast tumor', 'Phenotype', 'HP:0100013', (132, 144))	('C/EBP-delta', 'Gene', (21, 32))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
6178	24899581	Fourth, inactivation of FBW7 did not cause any noticeable changes to neither endogenous EBP2 abundance nor EBP2 stability.	('EBP2', 'Gene', (88, 92))	('EBP2', 'Gene', (107, 111))	('abundance', 'MPA', (93, 102))	('EBP2', 'Gene', '10969', (88, 92))	('inactivation', 'Var', (8, 20))	('FBW7', 'Gene', (24, 28))	('EBP2', 'Gene', '10969', (107, 111))
6181	24899581	These Pin1-induced conformational changes could regulate protein stability, catalytic activity, phosphorylation status, protein-protein interactions, and subcellular localization to further impact a wide range of cellular processes.	('impact', 'Reg', (190, 196))	('catalytic activity', 'MPA', (76, 94))	('Pin1', 'Gene', (6, 10))	('protein-protein interactions', 'MPA', (120, 148))	('phosphorylation status', 'MPA', (96, 118))	('Pin1', 'Gene', '5300', (6, 10))	('regulate', 'Reg', (48, 56))	('subcellular', 'MPA', (154, 165))	('protein stability', 'MPA', (57, 74))	('conformational changes', 'Var', (19, 41))
6182	24899581	Because regulating these protein functions by Pin1 is involved in diverse physiological and pathological processes, Pin1 deregulation is implicated in a number of diseases, including aging and age-related diseases, such as Alzheimer disease and cancer.	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('Pin1', 'Gene', '5300', (46, 50))	('cancer', 'Disease', (245, 251))	('Alzheimer disease', 'Disease', 'MESH:D000544', (223, 240))	('Alzheimer disease', 'Disease', (223, 240))	('deregulation', 'Var', (121, 133))	('Alzheimer disease', 'Phenotype', 'HP:0002511', (223, 240))	('implicated', 'Reg', (137, 147))	('Pin1', 'Gene', '5300', (116, 120))	('Pin1', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('Pin1', 'Gene', (116, 120))	('involved', 'Reg', (54, 62))
6185	24899581	Accumulated evidence has demonstrated that Pin1 exerts its oncogenic functions in large through activation of numerous oncogenes including Neu, Ras, c-Jun, Mcl-1, Notch-1, c-Myb, and inactivation of a large number of tumor suppressors such as p53, PML, and Foxos.	('Ras', 'Protein', (144, 147))	('Pin1', 'Gene', '5300', (43, 47))	('Foxos', 'Gene', (257, 262))	('Notch-1', 'Gene', '4851', (163, 170))	('oncogenic functions', 'CPA', (59, 78))	('PML', 'Gene', (248, 251))	('c-Myb', 'Gene', '4602', (172, 177))	('c-Myb', 'Gene', (172, 177))	('tumor', 'Disease', (217, 222))	('Neu', 'Gene', (139, 142))	('Neu', 'Gene', '2064', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('Notch-1', 'Gene', (163, 170))	('c-Jun', 'Gene', '3725', (149, 154))	('activation', 'PosReg', (96, 106))	('c-Jun', 'Gene', (149, 154))	('PML', 'Gene', '5371', (248, 251))	('inactivation', 'Var', (183, 195))	('oncogenes', 'Gene', (119, 128))	('Pin1', 'Gene', (43, 47))	('Mcl-1', 'Gene', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('p53', 'Gene', (243, 246))
6192	24899581	Consistently, depletion of Pin1 caused higher expression of FBW7, subsequently decreased Mcl-1 abundance, leading to enhanced Taxol sensitivity in cancer cells.	('decreased Mcl', 'Phenotype', 'HP:0025066', (79, 92))	('Pin1', 'Gene', (27, 31))	('higher', 'PosReg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('decreased', 'NegReg', (79, 88))	('FBW7', 'Gene', (60, 64))	('Taxol', 'Chemical', 'MESH:D017239', (126, 131))	('depletion', 'Var', (14, 23))	('enhanced', 'PosReg', (117, 125))	('Taxol sensitivity', 'MPA', (126, 143))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('expression', 'MPA', (46, 56))	('Pin1', 'Gene', '5300', (27, 31))	('Mcl-1 abundance', 'MPA', (89, 104))
6197	24899581	Notch intracellular domain (NICD) is produced by the cleavage of membrane-bound Notch by multiple enzymes and released into the cytoplasm, subsequently translocates to the nucleus and activates its target genes including Hes-1, Hes-5, Hey-1, etc.	('Hey-1', 'Gene', (235, 240))	('NICD', 'Disease', (28, 32))	('Hes-1', 'Gene', (221, 226))	('activates', 'PosReg', (184, 193))	('Hes-5', 'Gene', '388585', (228, 233))	('Hes-5', 'Gene', (228, 233))	('Hes-1', 'Gene', '3280', (221, 226))	('Notch', 'Gene', (80, 85))	('NICD', 'Disease', 'None', (28, 32))	('cleavage', 'Var', (53, 61))	('Hey-1', 'Gene', '23462', (235, 240))
6201	24899581	Notably, Hes-1 high expression could be a potential poor prognostic factor for ovarian cancer patients.	('high', 'Var', (15, 19))	('Hes-1', 'Gene', (9, 14))	('patients', 'Species', '9606', (94, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('ovarian cancer', 'Disease', (79, 93))	('Hes-1', 'Gene', '3280', (9, 14))
6211	24899581	Consistently, Numb deletions and low Numb expression have also been observed in pro-neural glioblastomas.	('low', 'NegReg', (33, 36))	('glioblastomas', 'Phenotype', 'HP:0012174', (91, 104))	('Numb', 'Gene', (37, 41))	('Numb', 'Gene', '8650', (37, 41))	('expression', 'MPA', (42, 52))	('observed', 'Reg', (68, 76))	('glioblastomas', 'Disease', 'MESH:D005909', (91, 104))	('Numb', 'Gene', '8650', (14, 18))	('glioblastomas', 'Disease', (91, 104))	('Numb', 'Gene', (14, 18))	('deletions', 'Var', (19, 28))
6240	24899581	Notably, miR-27a knockdown increased FBW7 levels and subsequently decreased the expression of FBW7 substrates such as c-Myc, c-Jun and Notch-1 in colon cancer.	('FBW7 levels', 'MPA', (37, 48))	('Notch-1', 'Gene', '4851', (135, 142))	('increased', 'PosReg', (27, 36))	('c-Jun', 'Gene', (125, 130))	('miR-27a', 'Gene', (9, 16))	('FBW7', 'Gene', (94, 98))	('colon cancer', 'Disease', (146, 158))	('decreased', 'NegReg', (66, 75))	('c-Myc', 'Gene', '4609', (118, 123))	('miR-27a', 'Gene', '407018', (9, 16))	('c-Myc', 'Gene', (118, 123))	('expression', 'MPA', (80, 90))	('knockdown', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('c-Jun', 'Gene', '3725', (125, 130))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))	('colon cancer', 'Disease', 'MESH:D015179', (146, 158))	('Notch-1', 'Gene', (135, 142))
6246	24899581	High expression of miR-223 was also found to be associated with poor survival in gastric carcinomas, ovarian cancer, and esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('High', 'Var', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (121, 155))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('ovarian cancer', 'Disease', (101, 115))	('gastric carcinomas', 'Disease', 'MESH:D013274', (81, 99))	('gastric carcinomas', 'Disease', (81, 99))	('poor', 'NegReg', (64, 68))	('ovarian cancer', 'Disease', 'MESH:D010051', (101, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('esophageal squamous cell carcinoma', 'Disease', (121, 155))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (81, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('miR-223', 'Gene', (19, 26))
6288	19383811	p53 Arg72Pro and MDM2 T309G Polymorphisms, Histology, and Esophageal Cancer Prognosis This study aimed to evaluate the prognostic significance of two functional single nucleotide polymorphisms (SNP) in the p53 pathway (p53 Arg72Pro and MDM2 T309G) in patients with esophageal cancer, and to determine the importance of histologic subtype in the SNP-outcome relationships.	('T309G', 'Mutation', 'rs2279744', (22, 27))	('Arg72Pro', 'SUBSTITUTION', 'None', (223, 231))	('MDM2', 'Gene', (236, 240))	('patients', 'Species', '9606', (251, 259))	('Arg72Pro', 'Var', (4, 12))	('p53', 'Gene', '7157', (206, 209))	('p53', 'Gene', '7157', (0, 3))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (58, 75))	('MDM2', 'Gene', '4193', (236, 240))	('MDM2', 'Gene', (17, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (265, 282))	('T309G', 'Mutation', 'rs2279744', (241, 246))	('Arg72Pro', 'SUBSTITUTION', 'None', (4, 12))	('p53', 'Gene', (206, 209))	('p53', 'Gene', (0, 3))	('esophageal cancer', 'Disease', (265, 282))	('MDM2', 'Gene', '4193', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('Arg72Pro', 'Var', (223, 231))	('p53', 'Gene', '7157', (219, 222))	('Esophageal Cancer', 'Disease', (58, 75))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('p53', 'Gene', (219, 222))
6289	19383811	A cohort of 371 patients with esophageal carcinoma enrolled in Boston, USA from 1999 to 2004 were genotyped for the p53 and MDM2 SNPs.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (30, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (30, 50))	('patients', 'Species', '9606', (16, 24))	('p53', 'Var', (116, 119))	('esophageal carcinoma', 'Disease', (30, 50))
6291	19383811	p53 Pro/Pro was strongly associated with shorter survival in the entire cohort (MS of 11.8 versus 29.1 months, P < 0.0001; adjusted hazard ratio for death, 2.05; 95% confidence interval, 1.30-3.24; P = 0.002 for Pro/Pro versus Arg/Arg).	('p53 Pro/Pro', 'Var', (0, 11))	('Arg', 'Chemical', 'MESH:D001120', (227, 230))	('shorter', 'NegReg', (41, 48))	('Arg', 'Chemical', 'MESH:D001120', (231, 234))	('Pro', 'Chemical', 'MESH:D011392', (212, 215))	('Pro', 'Chemical', 'MESH:D011392', (4, 7))	('Pro', 'Chemical', 'MESH:D011392', (216, 219))	('Pro', 'Chemical', 'MESH:D011392', (8, 11))	('death', 'Disease', 'MESH:D003643', (149, 154))	('survival', 'MPA', (49, 57))	('death', 'Disease', (149, 154))
6292	19383811	MDM2 G/G was associated with markedly reduced survival in squamous cell carcinoma (MS of 10.3 versus 49.4 months; adjusted hazard ratio for death, 7.9; 95% confidence interval, 2.4-26.0; P = 0.0007 for G/G versus T/T) but not in adenocarcinoma (SNP-histology interaction P = 0.004).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (58, 81))	('adenocarcinoma', 'Disease', (229, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinoma', 'Disease', (58, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('reduced', 'NegReg', (38, 45))	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('survival', 'MPA', (46, 54))	('G/G', 'Var', (202, 205))	('adenocarcinoma', 'Disease', 'MESH:D000230', (229, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('MDM2 G/G', 'Var', (0, 8))
6293	19383811	In a large prospective cohort, p53 Arg72Pro Pro/Pro was associated with a 2-fold increased risk of death in all esophageal cancers, whereas MDM2 T309G G/G was associated with a 7-fold increased risk of death in squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Arg72Pro', 'Var', (35, 43))	('esophageal cancers', 'Disease', (112, 130))	('death in squamous cell carcinoma', 'Disease', 'MESH:D002294', (202, 234))	('MDM2', 'Var', (140, 144))	('Pro', 'Chemical', 'MESH:D011392', (44, 47))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', 'MESH:D003643', (202, 207))	('T309G', 'Mutation', 'rs2279744', (145, 150))	('esophageal cancers', 'Disease', 'MESH:D004938', (112, 130))	('Arg72Pro', 'SUBSTITUTION', 'None', (35, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('Pro', 'Chemical', 'MESH:D011392', (40, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('death', 'Disease', (99, 104))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('death', 'Disease', (202, 207))	('death in squamous cell carcinoma', 'Disease', (202, 234))	('Pro', 'Chemical', 'MESH:D011392', (48, 51))
6297	19383811	Both genes contain functional single nucleotide polymorphisms (SNP) known to impact tumor biology, which have been implicated in the development and prognosis of several cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('implicated', 'Reg', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('impact', 'Reg', (77, 83))	('tumor', 'Disease', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('single nucleotide polymorphisms', 'Var', (30, 61))
6298	19383811	A common G-to-C SNP in the p53 gene (p53 Arg72Pro) results in an amino acid change from arginine (Arg72) to proline (Pro72; ref.).	('arginine', 'Chemical', 'MESH:D001120', (88, 96))	('Arg72Pro', 'SUBSTITUTION', 'None', (41, 49))	('arginine', 'MPA', (88, 96))	('Pro72', 'Chemical', '-', (117, 122))	('amino acid change', 'MPA', (65, 82))	('Arg72Pro', 'Var', (41, 49))	('p53', 'Gene', (27, 30))	('Arg72) to proline', 'Mutation', 'rs1042522', (98, 115))
6300	19383811	MDM2 T309G is located within the MDM2 promoter: the G variant enhances transcription factor binding leading to increased MDM2 expression and reduced apoptosis in response to DNA damage.	('apoptosis', 'CPA', (149, 158))	('transcription factor binding', 'Interaction', (71, 99))	('increased', 'PosReg', (111, 120))	('expression', 'MPA', (126, 136))	('reduced', 'NegReg', (141, 148))	('T309G', 'Mutation', 'rs2279744', (5, 10))	('response to DNA damage', 'MPA', (162, 184))	('enhances', 'PosReg', (62, 70))	('T309G', 'Var', (5, 10))	('MDM2', 'Gene', (121, 125))
6301	19383811	The G/G genotype has been associated with poor prognosis in other sporadic aerodigestive cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('G/G', 'Var', (4, 7))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
6303	19383811	Given the critical importance of the p53 pathway on malignant tumor behavior, and the previously observed biological and clinical effects of p53 Arg72Pro and MDM2 T309G, we evaluated the association of these SNPs with survival and recurrence in a large cohort of patients with esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (277, 294))	('Arg72Pro', 'Var', (145, 153))	('p53', 'Gene', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('patients', 'Species', '9606', (263, 271))	('tumor', 'Disease', (62, 67))	('Arg72Pro', 'SUBSTITUTION', 'None', (145, 153))	('T309G', 'Var', (163, 168))	('esophageal cancer', 'Disease', (277, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('T309G', 'Mutation', 'rs2279744', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
6305	19383811	Moreover, tumor histologic subtype has been recognized as a determinant of the effect of MDM2 T309G on outcomes in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('T309G', 'Var', (94, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('MDM2', 'Gene', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('lung cancer', 'Disease', (115, 126))	('T309G', 'Mutation', 'rs2279744', (94, 99))
6317	19383811	The p53 Arg72Pro (rs1042522) and MDM2 T309G (rs2279744) SNPs were genotyped using the TaqMan assay and a 384-well ABI 7900HT Sequence Detection System (Applied Biosystems).	('Arg72Pro', 'Var', (8, 16))	('MDM2', 'Gene', (33, 37))	('Arg72Pro', 'SUBSTITUTION', 'None', (8, 16))	('rs1042522', 'Var', (18, 27))	('rs2279744', 'Var', (45, 54))	('T309G', 'Mutation', 'rs2279744', (38, 43))	('rs1042522', 'Mutation', 'rs1042522', (18, 27))	('rs2279744', 'Mutation', 'rs2279744', (45, 54))
6326	19383811	Genotype frequencies for the wild-type, heterozygous, and homozygous variants were 51%, 39%, and 9%, respectively, for p53 Arg72Pro; and 40%, 48%, and 12%, respectively, for MDM2 T309G.	('Arg72Pro', 'Var', (123, 131))	('Arg72Pro', 'SUBSTITUTION', 'None', (123, 131))	('T309G', 'Mutation', 'rs2279744', (179, 184))	('MDM2 T309G', 'Var', (174, 184))
6330	19383811	p53 Pro/Pro was significantly associated with shorter OS and PFS in the whole cohort (Table 3 and Fig.	('p53 Pro/Pro', 'Var', (0, 11))	('shorter OS', 'Disease', (46, 56))	('Pro', 'Chemical', 'MESH:D011392', (4, 7))	('PFS', 'Disease', (61, 64))	('Pro', 'Chemical', 'MESH:D011392', (8, 11))
6334	19383811	In contrast, MDM2 G/G showed a significant association with worse outcome in the squamous cell carcinoma population, but not in adenocarcinoma or the overall cohort.	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('MDM2 G/G', 'Var', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('adenocarcinoma', 'Disease', (128, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('squamous cell carcinoma', 'Disease', (81, 104))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 104))
6335	19383811	In patients with squamous cell carcinoma, median OS and PFS were markedly shorter in individuals with the G/G genotype (Table 4 and Fig.	('shorter', 'NegReg', (74, 81))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 40))	('G/G', 'Var', (106, 109))	('patients', 'Species', '9606', (3, 11))	('PFS', 'CPA', (56, 59))	('median', 'MPA', (42, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('squamous cell carcinoma', 'Disease', (17, 40))
6336	19383811	In adenocarcinoma, the heterozygous T/G genotype was weakly associated with longer OS (but not PFS) in the adjusted model (AHR for death, 0.70; 95% CI, 0.50-0.99; P = 0.04), although this association does not remain significant after Bonferroni correction, and may represent a chance finding.	('longer OS', 'Disease', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('adenocarcinoma', 'Disease', (3, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (3, 17))	('T/G', 'Var', (36, 39))	('death', 'Disease', 'MESH:D003643', (131, 136))	('death', 'Disease', (131, 136))
6337	19383811	This relationship between the MDM2 T309G polymorphism and survival was consistent across all stages (data not shown).	('T309G', 'Var', (35, 40))	('MDM2', 'Gene', (30, 34))	('T309G', 'Mutation', 'rs2279744', (35, 40))
6342	19383811	As observed in the entire study cohort, the MDM2 T309G genotype was not associated with outcomes in this treatment subgroup.	('T309G', 'Var', (49, 54))	('T309G', 'Mutation', 'rs2279744', (49, 54))	('MDM2', 'Gene', (44, 48))
6343	19383811	In the subset of patients with squamous cell carcinoma intended for cisplatin-based trimodality therapy, the number of patients was small (n = 37), and no outcome association with MDM2 T309G was detected.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('squamous cell carcinoma', 'Disease', (31, 54))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (31, 54))	('patients', 'Species', '9606', (119, 127))	('MDM2 T309G', 'Var', (180, 190))	('T309G', 'Mutation', 'rs2279744', (185, 190))	('patients', 'Species', '9606', (17, 25))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
6345	19383811	When adjusted for these, the association between p53 Arg72Pro and outcomes in all cases, as well as MDM2 T309G SNP-histology interaction remained statistically significant.	('T309G', 'Mutation', 'rs2279744', (105, 110))	('significant', 'Reg', (160, 171))	('MDM2', 'Var', (100, 104))	('Arg72Pro', 'Var', (53, 61))	('Arg72Pro', 'SUBSTITUTION', 'None', (53, 61))
6346	19383811	In this large, predominantly Caucasian, cohort of patients with esophageal cancer and mature outcome data, we have shown that variant genotypes in two key p53 pathway SNPs, p53 Arg72Pro and MDM2 T309G, are associated with shortened survival.	('MDM2', 'Gene', (190, 194))	('patients', 'Species', '9606', (50, 58))	('p53', 'Pathway', (155, 158))	('Arg72Pro', 'Var', (177, 185))	('T309G', 'Mutation', 'rs2279744', (195, 200))	('Arg72Pro', 'SUBSTITUTION', 'None', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('shortened', 'NegReg', (222, 231))
6347	19383811	The p53 Pro/Pro genotype was associated with a 2-fold increased risk of death and relapse/progression in the entire population, regardless of histology, and after Bonferroni correction for multiple comparisons.	('Pro', 'Chemical', 'MESH:D011392', (12, 15))	('death', 'Disease', 'MESH:D003643', (72, 77))	('death', 'Disease', (72, 77))	('p53', 'Var', (4, 7))	('relapse/progression', 'CPA', (82, 101))	('Pro', 'Chemical', 'MESH:D011392', (8, 11))
6348	19383811	The MDM2 G/G genotype was associated with a >7-fold increased risk of death in the subgroup of patients with squamous cell carcinoma, but not among those with adenocarcinoma.	('patients', 'Species', '9606', (95, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('death', 'Disease', 'MESH:D003643', (70, 75))	('MDM2 G/G', 'Var', (4, 12))	('death', 'Disease', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('squamous cell carcinoma', 'Disease', (109, 132))	('adenocarcinoma', 'Disease', (159, 173))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 132))	('adenocarcinoma', 'Disease', 'MESH:D000230', (159, 173))
6349	19383811	The association between p53 Pro/Pro genotype and worse prognosis in our cohort is in keeping with the functional consequences of this polymorphism: the p53 Pro variant protein has been shown to have a reduced ability to induce apoptosis attributed, at least in part, to impaired mitochondrial trafficking, and inhibition of p73-dependent apoptosis.	('inhibition', 'NegReg', (310, 320))	('Pro', 'Chemical', 'MESH:D011392', (156, 159))	('protein', 'Protein', (168, 175))	('variant', 'Var', (160, 167))	('Pro', 'Chemical', 'MESH:D011392', (32, 35))	('p73', 'Gene', '7161', (324, 327))	('p53', 'Gene', (152, 155))	('p73', 'Gene', (324, 327))	('impaired', 'NegReg', (270, 278))	('mitochondrial trafficking', 'MPA', (279, 304))	('reduced', 'NegReg', (201, 208))	('induce', 'PosReg', (220, 226))	('apoptosis', 'CPA', (227, 236))	('Pro', 'Chemical', 'MESH:D011392', (28, 31))
6351	19383811	The only published study to assess the impact of the p53 Arg72Pro polymorphism in patients with esophageal cancer, which included a smaller number of patients (n = 210) and shorter follow-up time, did not show a statistically significant association with survival or recurrence, although the hazard ratio point estimates were similar to our results.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (82, 90))	('Arg72Pro', 'Var', (57, 65))	('esophageal cancer', 'Disease', (96, 113))	('patients', 'Species', '9606', (150, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('Arg72Pro', 'SUBSTITUTION', 'None', (57, 65))
6352	19383811	We also found that MDM2 T309G G/G is associated with markedly worse OS and PFS, although in this case the detrimental effect was limited to patients with squamous cell carcinoma, as shown by both subgroup and interaction analyses.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('worse', 'NegReg', (62, 67))	('PFS', 'Disease', (75, 78))	('MDM2 T309G G/G', 'Var', (19, 33))	('T309G', 'Mutation', 'rs2279744', (24, 29))	('patients', 'Species', '9606', (140, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('squamous cell carcinoma', 'Disease', (154, 177))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 177))
6353	19383811	A similar histology-specific relationship between MDM2 G/G and adverse outcomes was recently shown in a cohort of patients with non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))	('non-small cell lung cancer', 'Disease', (128, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('MDM2 G/G', 'Var', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('patients', 'Species', '9606', (114, 122))
6357	19383811	Although MDM2 T309G has been shown to modulate the association between alterations of p53 and outcomes in breast cancer, Heist et al.	('p53', 'Gene', (86, 89))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('association', 'Interaction', (51, 62))	('alterations', 'Var', (71, 82))	('T309G', 'Mutation', 'rs2279744', (14, 19))	('MDM2', 'Var', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('modulate', 'Reg', (38, 46))
6358	19383811	did not find a correlation between MDM2 T309G and p53 status or expression in non-small cell lung cancer,9 suggesting that a more complex or tumor-specific relationship might exist.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (78, 104))	('T309G', 'Mutation', 'rs2279744', (40, 45))	('MDM2 T309G', 'Var', (35, 45))	('tumor', 'Disease', (141, 146))	('non-small cell lung cancer', 'Disease', (78, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (78, 104))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (82, 104))
6359	19383811	As routine untreated tissue availability is limited in esophageal cancer and tumor samples were not available to investigate the relationship among tumor p53 alterations, SNP genotypes, and outcomes in our cohort, prospective studies including tissue collection are warranted to evaluate this potential association.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', (148, 153))	('esophageal cancer', 'Disease', (55, 72))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('alterations', 'Var', (158, 169))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
6361	19383811	In summary, we show, in a large cohort of patients with esophageal cancer, that p53 Arg72Pro Pro/Pro is strongly associated with shortened survival in esophageal cancer.	('esophageal cancer', 'Disease', (151, 168))	('Arg72Pro', 'Var', (84, 92))	('esophageal cancer', 'Disease', (56, 73))	('Pro', 'Chemical', 'MESH:D011392', (89, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('Pro', 'Chemical', 'MESH:D011392', (97, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Arg72Pro', 'SUBSTITUTION', 'None', (84, 92))	('patients', 'Species', '9606', (42, 50))	('shortened', 'NegReg', (129, 138))	('Pro', 'Chemical', 'MESH:D011392', (93, 96))
6362	19383811	Further, MDM2 T309G G/G is associated with shortened survival in esophageal squamous cell carcinoma.	('shortened', 'NegReg', (43, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('MDM2 T309G G/G', 'Var', (9, 23))	('esophageal squamous cell carcinoma', 'Disease', (65, 99))	('survival', 'MPA', (53, 61))	('T309G', 'Mutation', 'rs2279744', (14, 19))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (65, 99))
6363	19383811	Our results show the prognostic value of SNPs in the p53 pathway and underscore the distinct differences between squamous cell and adenocarcinomas of the esophagus.	('adenocarcinomas of the esophagus', 'Disease', 'MESH:C562730', (131, 163))	('squamous cell', 'Disease', (113, 126))	('p53 pathway', 'Pathway', (53, 64))	('SNPs', 'Var', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('adenocarcinomas of the esophagus', 'Disease', (131, 163))
6392	20624335	Animal studies have demonstrated that vitamin E or alpha-tocopherol inhibits the development of esophageal adenocarcinoma through its antioxidant properties, and inadequate selenium in the diet may promote carcinogenesis by enhancing oxidative stress.	('promote', 'PosReg', (198, 205))	('inadequate', 'Var', (162, 172))	('selenium', 'Chemical', 'MESH:D012643', (173, 181))	('enhancing', 'PosReg', (224, 233))	('vitamin E', 'Chemical', 'MESH:D014810', (38, 47))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (51, 67))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (96, 121))	('oxidative stress', 'Phenotype', 'HP:0025464', (234, 250))	('inhibits', 'NegReg', (68, 76))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (96, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('men', 'Species', '9606', (88, 91))	('carcinogenesis', 'CPA', (206, 220))	('esophageal adenocarcinoma', 'Disease', (96, 121))	('selenium', 'Protein', (173, 181))	('oxidative stress', 'MPA', (234, 250))	('antioxidant properties', 'MPA', (134, 156))
6400	20624335	A population-based case-control study using a Kaiser Permanente Northern California population demonstrated that dietary intakes of vitamin C and beta-carotene were inversely associated with the risk of Barrett's esophagus [OR=0.48; 95% CI=0.26-0.90; OR=0.56; 95% CI=0.32-0.99, Q4 vs. Q1, respectively].	('beta-carotene', 'Var', (146, 159))	('inversely', 'NegReg', (165, 174))	('vitamin C', 'Chemical', 'MESH:D001205', (132, 141))	("Barrett's esophagus", 'Disease', (203, 222))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (203, 222))	('beta-carotene', 'Chemical', 'MESH:D019207', (146, 159))
6419	20624335	In addition, significant inverse associations were observed between supplemental vitamin C and E use and the risk of esophageal adenocarcinoma in this study [HR=0.25; 95% CI=0.11-0.58, >=250 mg vs. none; HR=0.25; 95% CI=0.10-0.60, >=180 mg vs. none, respectively].	('>=250 mg', 'Var', (185, 193))	('vitamin C', 'Chemical', 'MESH:D001205', (81, 90))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (117, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('inverse', 'NegReg', (25, 32))	('men', 'Species', '9606', (74, 77))	('esophageal adenocarcinoma', 'Disease', (117, 142))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (117, 142))
6422	20624335	DNA content abnormalities such as increased 4N fractions, aneuploidy, and tetraploidy have been validated as being highly predictive of subsequent cancer development and mechanistically related to the progression of Barrett's esophagus to esophageal adenocarcinoma.	('4N fractions', 'MPA', (44, 56))	('related', 'Reg', (186, 193))	("Barrett's esophagus to esophageal adenocarcinoma", 'Disease', 'MESH:D001471', (216, 264))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('aneuploidy', 'Disease', 'MESH:D000782', (58, 68))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (239, 264))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (216, 235))	("Barrett's esophagus to esophageal adenocarcinoma", 'Disease', (216, 264))	('tetraploidy', 'Var', (74, 85))	('cancer', 'Disease', (147, 153))	('increased', 'PosReg', (34, 43))	('men', 'Species', '9606', (161, 164))	('aneuploidy', 'Disease', (58, 68))
6485	20624335	Previous studies have linked folate intake and genetic polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism, with colorectal cancer.	('linked', 'Interaction', (22, 28))	('colorectal cancer', 'Disease', 'MESH:D015179', (166, 183))	('genetic polymorphisms', 'Var', (47, 68))	('folate', 'Chemical', 'MESH:D005492', (96, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (166, 183))	('folate', 'Chemical', 'MESH:D005492', (142, 148))	('MTHFR', 'Gene', '4524', (114, 119))	('folate', 'Chemical', 'MESH:D005492', (29, 35))	('colorectal cancer', 'Disease', (166, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('MTHFR', 'Gene', (114, 119))	('5,10-methylenetetrahydrofolate reductase', 'Gene', '4524', (72, 112))
6486	20624335	Certain folate-metabolizing enzyme genotypes are associated with an increased risk of gastric cardia adenocarcinoma and esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('gastric cardia adenocarcinoma', 'Disease', (86, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('genotypes', 'Var', (35, 44))	('associated', 'Reg', (49, 59))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('folate', 'Chemical', 'MESH:D005492', (8, 14))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (86, 115))
6487	20624335	Also, folate deficiency has been hypothesized to increase the risk of cancer via mediation by p53 tumor suppressor gene, or by decreasing intracellular S-adenosylmethionine (SAM) which inhibits cytosine methylation in DNA, activating proto-oncogenes, inducing malignant transformations, causing DNA precursor imbalances, misincorporating uracil into DNA, and promoting chromosome breakage.	('folate', 'Chemical', 'MESH:D005492', (6, 12))	('activating', 'PosReg', (223, 233))	('proto-oncogenes', 'Gene', (234, 249))	('DNA precursor imbalances', 'MPA', (295, 319))	('tumor', 'Disease', (98, 103))	('misincorporating', 'Var', (321, 337))	('chromosome breakage', 'CPA', (369, 388))	('p53', 'Gene', '7157', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cytosine methylation', 'MPA', (194, 214))	('cancer', 'Disease', (70, 76))	('uracil', 'MPA', (338, 344))	('SAM', 'Chemical', 'MESH:D012436', (174, 177))	('malignant transformations', 'CPA', (260, 285))	('inducing', 'Reg', (251, 259))	('p53', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('intracellular', 'MPA', (138, 151))	('promoting', 'PosReg', (359, 368))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('folate deficiency', 'Phenotype', 'HP:0100507', (6, 23))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (152, 172))	('inhibits', 'NegReg', (185, 193))	('imbalances', 'Phenotype', 'HP:0002172', (309, 319))	('uracil', 'Chemical', 'MESH:D014498', (338, 344))	('decreasing', 'NegReg', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('causing', 'Reg', (287, 294))	('chromosome breakage', 'Phenotype', 'HP:0040012', (369, 388))
6488	20624335	A recent small study evaluating the effect of dietary folate and vitamin B6 on p53 mutations in esophageal adenocarcinoma reported that dietary intake was not associated with p53 mutations, p53 mutations at CpG sites, and p53 protein overexpression.	('mutations', 'Var', (83, 92))	('p53', 'Gene', (175, 178))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', '7157', (175, 178))	('p53', 'Gene', (190, 193))	('p53', 'Gene', '7157', (190, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (96, 121))	('p53', 'Gene', '7157', (222, 225))	('esophageal adenocarcinoma', 'Disease', (96, 121))	('p53', 'Gene', (222, 225))	('vitamin B6', 'Chemical', 'MESH:D025101', (65, 75))	('overexpression', 'PosReg', (234, 248))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (96, 121))	('folate', 'Chemical', 'MESH:D005492', (54, 60))
6491	20624335	No studies have evaluated the association between folate and Barrett's esophagus, progression from Barrett's esophagus into cancer, or the role of functional polymorphisms in genes encoding folate-metabolizing enzymes on the risk of esophageal adenocarcinoma or Barrett's esophagus.	('cancer', 'Disease', (124, 130))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (61, 80))	('polymorphisms', 'Var', (158, 171))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (233, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (262, 281))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (99, 118))	('folate', 'Chemical', 'MESH:D005492', (190, 196))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (233, 258))	('esophageal adenocarcinoma', 'Disease', (233, 258))	('folate', 'Chemical', 'MESH:D005492', (50, 56))	("Barrett's esophagus", 'Disease', (262, 281))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
6493	20624335	In the studies of gastric cardia adenocarcinoma, strong effect modification has been observed between the MTHFR C677T polymorphism and alcohol drinking.	('alcohol drinking', 'Disease', (135, 151))	('C677T', 'Mutation', 'rs1801133', (112, 117))	('alcohol', 'Chemical', 'MESH:D000438', (135, 142))	('C677T', 'Var', (112, 117))	('MTHFR', 'Gene', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('alcohol drinking', 'Phenotype', 'HP:0030955', (135, 151))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (18, 47))	('gastric cardia adenocarcinoma', 'Disease', (18, 47))	('MTHFR', 'Gene', '4524', (106, 111))
6499	20624335	In the EPIC prospective cohort study that involved a mean follow-up of 6.5 years and 65 newly-diagnosed cases of esophageal adenocarcinoma, a positive association was observed for processed meat [HR=3.54; 95% CI=1.57-7.99, T3 vs. T1] while the result for total meat intake was not significant [HR=1.79; 95% CI=0.86-3.75, T3 vs. T1].	('esophageal adenocarcinoma', 'Disease', (113, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (113, 138))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (113, 138))	('processed meat', 'Var', (180, 194))
6512	20624335	In addition, this study found a significant interaction between vitamin C and nitrite intakes: those with low vitamin C and high nitrite intake were at significantly higher risk of developing esophageal adenocarcinoma compared to those with high vitamin C and low nitrite intake [OR=2.72; 95% CI=1.73-4.27].	('vitamin C', 'Chemical', 'MESH:D001205', (64, 73))	('high vitamin C', 'Phenotype', 'HP:0100510', (241, 255))	('high nitrite intake', 'Var', (124, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('nitrite', 'Chemical', 'MESH:D009573', (264, 271))	('esophageal adenocarcinoma', 'Disease', (192, 217))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (192, 217))	('low', 'NegReg', (106, 109))	('vitamin C', 'Chemical', 'MESH:D001205', (110, 119))	('vitamin C', 'Chemical', 'MESH:D001205', (246, 255))	('nitrite', 'Chemical', 'MESH:D009573', (78, 85))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (192, 217))	('nitrite', 'Chemical', 'MESH:D009573', (129, 136))	('low vitamin C', 'Phenotype', 'HP:0100510', (106, 119))
6520	20624335	Among the seven case-control studies that evaluated the association between fat intake and the risk of esophageal adenocarcinoma, four reported an increased risk among individuals with high total fat intake compared to those in the lowest category of fat intake, but three reported no association.	('fat', 'Gene', '2195', (76, 79))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (103, 128))	('fat', 'Gene', (196, 199))	('fat', 'Gene', (251, 254))	('fat', 'Gene', '2195', (196, 199))	('high', 'Var', (185, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('fat', 'Gene', '2195', (251, 254))	('fat', 'Gene', (76, 79))	('esophageal adenocarcinoma', 'Disease', (103, 128))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (103, 128))
6526	20624335	On the other hand, polyunsaturated fatty acids and omega-3 fatty acids, mainly found in plants and fish, may decrease the risk of esophageal adenocarcinoma.	('decrease', 'NegReg', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('esophageal adenocarcinoma', 'Disease', (130, 155))	('polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (19, 46))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (130, 155))	('omega-3 fatty acids', 'Var', (51, 70))	('polyunsaturated fatty acids', 'Var', (19, 46))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (130, 155))	('omega-3 fatty acids', 'Chemical', 'MESH:D015525', (51, 70))
6560	33883026	Epigenetic deregulations are also important risk factors during tumor progression which are reversible transcriptional alterations without any genomic changes.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('Epigenetic deregulations', 'Var', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
6563	33883026	Promoter hyper methylation is frequently observed as an inhibitory molecular mechanism in various genes associated with DNA repair, cell cycle regulation, and apoptosis during tumor progression.	('Promoter hyper methylation', 'Var', (0, 26))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))
6564	33883026	Since aberrant promoter methylations have critical roles in early stages of neoplastic transformations, in present review we have summarized all of the aberrant methylations which have been reported during tumor progression among Iranian cancer patients.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('patients', 'Species', '9606', (245, 253))	('tumor', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('aberrant', 'Var', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
6565	33883026	Aberrant promoter methylations are targetable and prepare novel therapeutic options for the personalized medicine in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (124, 132))
6579	33883026	DNA hypo methylation leads to aberrant activation of oncogenes while the hyper methylation is associated with inhibition of tumor suppressor genes.	('inhibition', 'NegReg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('activation', 'PosReg', (39, 49))	('tumor', 'Disease', (124, 129))	('oncogenes', 'Protein', (53, 62))	('hypo methylation', 'Var', (4, 20))
6580	33883026	Various tumor suppressor genes such as p16, MutL homolog 1 (MLH1), and breast cancer type 1 susceptibility protein (BRCA1) which are involved in DNA repair, cell cycle, cell adhesion, and apoptosis have been shown to undergo tumor-specific silencing by hyper methylation.	('BRCA1', 'Gene', (116, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('breast cancer type 1 susceptibility protein', 'Gene', '672', (71, 114))	('MutL homolog 1', 'Gene', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('MLH1', 'Gene', (60, 64))	('silencing', 'NegReg', (240, 249))	('MLH1', 'Gene', '4292', (60, 64))	('breast cancer type 1 susceptibility protein', 'Gene', (71, 114))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('MutL homolog 1', 'Gene', '4292', (44, 58))	('hyper methylation', 'Var', (253, 270))	('tumor', 'Disease', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('p16', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('p16', 'Gene', '1029', (39, 42))	('BRCA1', 'Gene', '672', (116, 121))
6581	33883026	Histone modifications through histone acetyl-transferase (HATs), histone methyltransferase (HMTs), kinases, ubiquitin ligases, and sumoligases are important regulatory processes in chromatin remodeling, gene expression, and carcinogenesis.	('histone methyltransferase', 'Gene', (65, 90))	('HMTs', 'Gene', '56979', (92, 96))	('HATs', 'Disease', (58, 62))	('HATs', 'Disease', 'None', (58, 62))	('HMTs', 'Gene', (92, 96))	('histone methyltransferase', 'Gene', '56979', (65, 90))	('modifications', 'Var', (8, 21))	('Histone modifications', 'Var', (0, 21))	('carcinogenesis', 'Disease', 'MESH:D063646', (224, 238))	('carcinogenesis', 'Disease', (224, 238))
6583	33883026	Epigenetic markers are considered as emerging diagnostic and prognostic biomarkers in cancer.	('Epigenetic markers', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))
6584	33883026	Since, aberrant DNA methylation can be tracked in body fluids; they can be suggested as efficient diagnostic and prognostic markers in primary stages of tumor progression.	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('aberrant', 'Var', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
6587	33883026	In present review we have summarized all of the significant epigenetic deregulations associated with tumor progression which have been reported until now among Iranian cancer patients (Fig.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('epigenetic deregulations', 'Var', (60, 84))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Disease', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
6600	33883026	There was a significant correlation between BRCA1 hyper methylation and poor survival.	('poor survival', 'CPA', (72, 85))	('BRCA1', 'Gene', '672', (44, 49))	('BRCA1', 'Gene', (44, 49))	('hyper methylation', 'Var', (50, 67))
6608	33883026	P53 is stabilized by posttranslational modification in the primary stages of glioblastoma progression.	('glioblastoma', 'Disease', (77, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('P53', 'Gene', (0, 3))	('posttranslational modification', 'Var', (21, 51))	('P53', 'Gene', '7157', (0, 3))
6609	33883026	The MGMT suppression induces p53 mutation which can further deregulate the methylation pattern of MGMT.	('MGMT', 'Gene', '4255', (4, 8))	('deregulate', 'Reg', (60, 70))	('mutation', 'Var', (33, 41))	('induces', 'Reg', (21, 28))	('methylation pattern', 'MPA', (75, 94))	('p53', 'Gene', (29, 32))	('MGMT', 'Gene', (98, 102))	('p53', 'Gene', '7157', (29, 32))	('MGMT', 'Gene', '4255', (98, 102))	('MGMT', 'Gene', (4, 8))
6617	33883026	The expression profile of the genes located within cancer/placenta hypomethylated blocks were assessed for CRC that showed the epigenetic regulation of NF-kB signaling during tumorigenesis and placentogenesis.	('CRC', 'Disease', (107, 110))	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('CRC', 'Disease', 'MESH:D015179', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('cancer', 'Disease', (51, 57))	('epigenetic', 'Var', (127, 137))
6627	33883026	It was observed that the RASSF6 methylation was more frequent in B-Cell Acute Lymphoblastic Leukemia (B-ALL) cases compared with T-cell acute lymphoblastic leukaemia (T-ALL) cases, whereas the RASSF10 hyper methylation was more frequent in T-ALL compared with pre-B-ALL and B-ALL patients.	('T-ALL', 'Phenotype', 'HP:0006727', (167, 172))	('methylation', 'Var', (32, 43))	('T-cell acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006727', (129, 165))	('RASSF6', 'Gene', (25, 31))	('T-cell acute lymphoblastic leukaemia', 'Disease', 'MESH:D054218', (129, 165))	('RASSF10', 'Gene', '644943', (193, 200))	('RASSF10', 'Gene', (193, 200))	('ALL', 'Phenotype', 'HP:0006721', (104, 107))	('B-ALL', 'Phenotype', 'HP:0004812', (102, 107))	('T-cell acute lymphoblastic leukaemia', 'Disease', (129, 165))	('-Cell Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0006727', (66, 100))	('ALL', 'Phenotype', 'HP:0006721', (276, 279))	('patients', 'Species', '9606', (280, 288))	('B-Cell Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0004812', (65, 100))	('B-Cell Acute Lymphoblastic Leukemia', 'Disease', (65, 100))	('ALL', 'Phenotype', 'HP:0006721', (242, 245))	('ALL', 'Phenotype', 'HP:0006721', (266, 269))	('acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006721', (136, 165))	('B-ALL', 'Phenotype', 'HP:0004812', (274, 279))	('B-Cell Acute Lymphoblastic Leukemia', 'Disease', 'MESH:D015456', (65, 100))	('Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0006721', (72, 100))	('frequent', 'Reg', (53, 61))	('T-ALL', 'Phenotype', 'HP:0006727', (240, 245))	('B-ALL', 'Phenotype', 'HP:0004812', (264, 269))	('Leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('Lymphoblastic Leukemia', 'Phenotype', 'HP:0005526', (78, 100))	('ALL', 'Phenotype', 'HP:0006721', (169, 172))	('RASSF6', 'Gene', '166824', (25, 31))
6628	33883026	Moreover, there was a significant correlation between RASSF6 hyper methylation and poor prognosis in pre-B-ALL patients which can be related to the NF-kB activation in the absence of RASSF6.	('RASSF6', 'Gene', (54, 60))	('ALL', 'Phenotype', 'HP:0006721', (107, 110))	('RASSF6', 'Gene', '166824', (183, 189))	('activation', 'PosReg', (154, 164))	('patients', 'Species', '9606', (111, 119))	('hyper methylation', 'Var', (61, 78))	('RASSF6', 'Gene', '166824', (54, 60))	('RASSF6', 'Gene', (183, 189))	('B-ALL', 'Phenotype', 'HP:0004812', (105, 110))	('poor prognosis', 'CPA', (83, 97))
6630	33883026	It has been reported that there were significant correlations between tumor sizes more than 2 cm, lymph node involvement, and HIC1 methylation among a sub population of Iranian breast cancer patients.	('breast cancer', 'Disease', (177, 190))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('HIC1', 'Gene', (126, 130))	('patients', 'Species', '9606', (191, 199))	('HIC1', 'Gene', '3090', (126, 130))	('tumor', 'Disease', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('correlations', 'Interaction', (49, 61))	('men', 'Species', '9606', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('methylation', 'Var', (131, 142))
6632	33883026	It was concluded that the HIC1 and RASSF1A hyper methylations can be used as prognostic markers of breast cancer in this population.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('HIC1', 'Gene', '3090', (26, 30))	('RASSF1A', 'Gene', (35, 42))	('hyper methylations', 'Var', (43, 61))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('RASSF1A', 'Gene', '11186', (35, 42))	('HIC1', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
6633	33883026	Similarly, the RASSF1A methylation has been shown as an efficient prognostic marker in a sample of Saudi breast cancer patients.	('methylation', 'Var', (23, 34))	('Saudi breast cancer', 'Disease', (99, 118))	('RASSF1A', 'Gene', '11186', (15, 22))	('patients', 'Species', '9606', (119, 127))	('Saudi breast cancer', 'Disease', 'MESH:D001943', (99, 118))	('RASSF1A', 'Gene', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
6636	33883026	It has been reported that there were higher rates of p16, TSHR, and RASSF1A hyper methylations in a sample of Iranian malignant papillary thyroid tumors compared with benign tumors.	('TSHR', 'Gene', '7253', (58, 62))	('p16', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('higher', 'PosReg', (37, 43))	('malignant papillary thyroid tumors', 'Disease', (118, 152))	('RASSF1A', 'Gene', '11186', (68, 75))	('benign tumors', 'Disease', 'MESH:D009369', (167, 180))	('malignant papillary thyroid tumors', 'Disease', 'MESH:D000077273', (118, 152))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('p16', 'Gene', '1029', (53, 56))	('TSHR', 'Gene', (58, 62))	('benign tumors', 'Disease', (167, 180))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('hyper methylations', 'Var', (76, 94))	('papillary thyroid tumors', 'Phenotype', 'HP:0002895', (128, 152))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('RASSF1A', 'Gene', (68, 75))
6639	33883026	The alpha4 integrin hyper methylation was observed in the majority of an Iranian prostate cancer patients group.	('alpha4', 'Gene', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Iranian prostate cancer', 'Disease', (73, 96))	('Iranian prostate cancer', 'Disease', 'MESH:D011471', (73, 96))	('hyper', 'Var', (20, 25))	('alpha4', 'Gene', '28898', (4, 10))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('patients', 'Species', '9606', (97, 105))
6642	33883026	It has been shown that the tumor tissues had higher rates of CDH1 hyper methylation compared with normal samples in Iranian breast cancer patients.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CDH1', 'Gene', '999', (61, 65))	('hyper', 'Var', (66, 71))	('tumor', 'Disease', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('CDH1', 'Gene', (61, 65))	('higher', 'PosReg', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patients', 'Species', '9606', (138, 146))
6650	33883026	It has been reported that there was higher ratio of p14ARF methylation in a sample of Iranian oral squamous cell carcinoma (OSCC) patients compared with controls which was also directly correlated with tumor stage.	('p14ARF', 'Gene', '1029', (52, 58))	('higher', 'PosReg', (36, 42))	('tumor', 'Disease', (202, 207))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('p14ARF', 'Gene', (52, 58))	('patients', 'Species', '9606', (130, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('methylation', 'Var', (59, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('oral squamous cell carcinoma', 'Disease', (94, 122))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
6651	33883026	Similarly, It was reported that there were significant associations between p14ARF hyper methylation, advanced stages, and lymph node involvement among Japanese OSCC patients.	('men', 'Species', '9606', (141, 144))	('advanced stages', 'CPA', (102, 117))	('hyper methylation', 'Var', (83, 100))	('p14ARF', 'Gene', '1029', (76, 82))	('p14ARF', 'Gene', (76, 82))	('lymph node involvement', 'CPA', (123, 145))	('patients', 'Species', '9606', (166, 174))
6653	33883026	MDM2 is an oncogene that inactivates p53 during tumorigenesis.	('tumor', 'Disease', (48, 53))	('inactivates', 'Var', (25, 36))	('MDM2', 'Gene', '4193', (0, 4))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('MDM2', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
6658	33883026	It has been observed that there was a significant inverse correlation between p16 hyper methylation and P53 expression in a sample of Iranian esophageal squamous cell carcinoma (ESCC) patients.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (142, 176))	('p16', 'Gene', (78, 81))	('inverse', 'NegReg', (50, 57))	('patients', 'Species', '9606', (184, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('esophageal squamous cell carcinoma', 'Disease', (142, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('p16', 'Gene', '1029', (78, 81))	('P53', 'Gene', (104, 107))	('expression', 'MPA', (108, 118))	('hyper methylation', 'Var', (82, 99))	('P53', 'Gene', '7157', (104, 107))
6661	33883026	It was shown that the sporadic cases had higher ratio of p16 methylation compared with familial ESCC cases, while there was not any p16 methylation among controls.	('familial ESCC', 'Disease', (87, 100))	('methylation', 'Var', (61, 72))	('p16', 'Gene', (57, 60))	('p16', 'Gene', '1029', (132, 135))	('higher', 'PosReg', (41, 47))	('p16', 'Gene', '1029', (57, 60))	('p16', 'Gene', (132, 135))
6663	33883026	Another group has been reported that there were direct correlations between p16 hyper methylation, tumor grade, HP infection, and smoking in a subpopulation of Iranian OSCC cases.	('tumor', 'Disease', (99, 104))	('HP infection', 'Disease', 'MESH:C537262', (112, 124))	('p16', 'Gene', '1029', (76, 79))	('hyper methylation', 'Var', (80, 97))	('HP infection', 'Disease', (112, 124))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('p16', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('correlations', 'Interaction', (55, 67))	('Iranian OSCC', 'Disease', (160, 172))
6664	33883026	Another group has been reported that there was higher ratio of p16 and p15 methylations in tumors compared with normal margins in a sample of Iranian OSCC patients.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('p15', 'Gene', '1030', (71, 74))	('methylations', 'Var', (75, 87))	('p16', 'Gene', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (155, 163))	('p15', 'Gene', (71, 74))	('p16', 'Gene', '1029', (63, 66))
6665	33883026	The aberrant methylation of the p15 and p16 have been also reported during OSCC progression among Japanese patients.	('methylation', 'MPA', (13, 24))	('p16', 'Gene', (40, 43))	('reported', 'Reg', (59, 67))	('aberrant', 'Var', (4, 12))	('OSCC progression', 'Disease', (75, 91))	('p15', 'Gene', '1030', (32, 35))	('p16', 'Gene', '1029', (40, 43))	('p15', 'Gene', (32, 35))	('patients', 'Species', '9606', (107, 115))
6669	33883026	It has been reported that there was significantly higher frequency of DBC2 methylation in tumor and blood samples of a group of Iranian breast cancer patients compared with normal margins.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('higher', 'PosReg', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('methylation', 'Var', (75, 86))	('breast cancer', 'Disease', (136, 149))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('patients', 'Species', '9606', (150, 158))	('DBC2', 'Gene', (70, 74))	('DBC2', 'Gene', '23221', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
6679	33883026	It has been observed that there were higher levels of methylated UBE2Q1 in colorectal tumor samples compared with normal margins among a sub population of Iranian subjects.	('UBE2Q1', 'Gene', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('UBE2Q1', 'Gene', '55585', (65, 71))	('higher', 'PosReg', (37, 43))	('colorectal tumor', 'Disease', (75, 91))	('colorectal tumor', 'Disease', 'MESH:D015179', (75, 91))	('methylated', 'Var', (54, 64))
6680	33883026	Aberrant methylation of cell cycle regulators during tumor progressions among Iranian patients are illustrated in Fig.	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('methylation', 'MPA', (9, 20))	('patients', 'Species', '9606', (86, 94))
6688	33883026	Moreover, there were significant correlations between DOK7 and VIM methylations and negative ER status.	('methylations', 'Var', (67, 79))	('DOK7', 'Gene', '285489', (54, 58))	('negative ER status', 'Disease', (84, 102))	('correlations', 'Interaction', (33, 45))	('VIM', 'Gene', '7431', (63, 66))	('DOK7', 'Gene', (54, 58))	('VIM', 'Gene', (63, 66))
6689	33883026	Another reports also showed DOK7 and VIM hyper methylations in Spanish and Australian breast cancer patients, respectively.	('VIM', 'Gene', '7431', (37, 40))	('DOK7', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('VIM', 'Gene', (37, 40))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('patients', 'Species', '9606', (100, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('hyper methylations', 'Var', (41, 59))	('breast cancer', 'Disease', (86, 99))	('DOK7', 'Gene', '285489', (28, 32))
6691	33883026	Ghrelin is associated with regulation of glucose and lipid metabolism and activates Ca2+ and P13K/AKT signaling pathways that are contributed with secretion of growth hormone in pituitary cells.	('growth hormone', 'Gene', (160, 174))	('glucose and lipid metabolism', 'Disease', 'MESH:D044882', (41, 69))	('growth hormone', 'Gene', '2688', (160, 174))	('Ghrelin', 'Chemical', 'MESH:D054439', (0, 7))	('activates', 'PosReg', (74, 83))	('P13K', 'Var', (93, 97))	('AKT', 'Gene', '207', (98, 101))	('Ca2+', 'Chemical', 'MESH:D000069285', (84, 88))	('Ghrelin', 'Gene', (0, 7))	('AKT', 'Gene', (98, 101))	('P13K', 'SUBSTITUTION', 'None', (93, 97))
6697	33883026	It has been reported that there was higher frequency of EDNRB hyper methylation in a sample of Iranian colorectal cancer tissues compared with normal margins.	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('hyper methylation', 'Var', (62, 79))	('EDNRB', 'Gene', '1910', (56, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('colorectal cancer', 'Disease', (103, 120))	('EDNRB', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))
6698	33883026	Similarly, the Chinese colorectal cancer tumors had significantly higher frequency of EDNRB promoter hyper methylation compared with normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('EDNRB', 'Gene', '1910', (86, 91))	('colorectal cancer tumors', 'Disease', 'MESH:D015179', (23, 47))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('hyper methylation', 'Var', (101, 118))	('EDNRB', 'Gene', (86, 91))	('higher', 'PosReg', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (23, 40))	('colorectal cancer tumors', 'Disease', (23, 47))
6700	33883026	DNA methylation of APC, AXIN2, SFRP, and DKK as important WNT inhibitors have been reported in colorectal cancer patients.	('APC', 'Gene', (19, 22))	('SFRP', 'Gene', (31, 35))	('APC', 'Gene', '324', (19, 22))	('colorectal cancer', 'Disease', (95, 112))	('reported', 'Reg', (83, 91))	('patients', 'Species', '9606', (113, 121))	('AXIN2', 'Gene', (24, 29))	('AXIN2', 'Gene', '8313', (24, 29))	('methylation', 'Var', (4, 15))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('DKK', 'Gene', (41, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
6701	33883026	It has been observed that there were significant correlations between APC and DDK3 aberrant promoter methylations and age and sex, respectively among a sub population of Iranian colorectal patients.	('DDK3', 'Gene', (78, 82))	('aberrant', 'Var', (83, 91))	('colorectal', 'Disease', 'MESH:D015179', (178, 188))	('APC', 'Gene', (70, 73))	('colorectal', 'Disease', (178, 188))	('APC', 'Gene', '324', (70, 73))	('patients', 'Species', '9606', (189, 197))
6702	33883026	The SFRP4 and WIF1 promoter methylations were significantly associated with stage and grade.	('WIF1', 'Gene', (14, 18))	('WIF1', 'Gene', '11197', (14, 18))	('grade', 'CPA', (86, 91))	('stage', 'CPA', (76, 81))	('methylations', 'Var', (28, 40))	('SFRP4', 'Gene', (4, 9))	('SFRP4', 'Gene', '6424', (4, 9))	('associated', 'Reg', (60, 70))
6703	33883026	Moreover, there were significant correlations between SFRP2 and SFRP5 methylations and tumor type.	('SFRP2', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('correlations', 'Reg', (33, 45))	('tumor', 'Disease', (87, 92))	('SFRP5', 'Gene', '6425', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('methylations', 'Var', (70, 82))	('SFRP5', 'Gene', (64, 69))	('SFRP2', 'Gene', '6423', (54, 59))
6712	33883026	Similarly, there were also high levels of SFRP1 and SFRP2 hyper methylations among a group of Hungarian CRC patients.	('CRC', 'Disease', (104, 107))	('SFRP1', 'Gene', '6422', (42, 47))	('SFRP1', 'Gene', (42, 47))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('CRC', 'Disease', 'MESH:D015179', (104, 107))	('SFRP2', 'Gene', '6423', (52, 57))	('SFRP2', 'Gene', (52, 57))	('patients', 'Species', '9606', (108, 116))	('hyper', 'Var', (58, 63))
6713	33883026	Phosphatase and tensin homolog (PTEN) is a suppressor of PI3K/AKT pathways which inhibits signal transduction from HER1, HER2, and IGFR growth factor receptors through the P13K/AKT signaling.	('inhibits', 'NegReg', (81, 89))	('AKT', 'Gene', (62, 65))	('HER2', 'Gene', '2064', (121, 125))	('HER1', 'Gene', (115, 119))	('AKT', 'Gene', '207', (177, 180))	('P13K', 'Var', (172, 176))	('signal transduction', 'MPA', (90, 109))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('AKT', 'Gene', (177, 180))	('IGFR growth factor receptors', 'Protein', (131, 159))	('HER1', 'Gene', '1956', (115, 119))	('P13K', 'SUBSTITUTION', 'None', (172, 176))	('AKT', 'Gene', '207', (62, 65))	('HER2', 'Gene', (121, 125))	('Phosphatase and tensin homolog', 'Gene', '5728', (0, 30))
6721	33883026	Another study on Iranian sporadic breast cancer patients showed that there were correlations between PTEN hyper methylation, advanced stages, and lymph node involvement.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('correlations', 'Interaction', (80, 92))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (25, 47))	('PTEN', 'Gene', (101, 105))	('PTEN', 'Gene', '5728', (101, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('patients', 'Species', '9606', (48, 56))	('hyper methylation', 'Var', (106, 123))	('sporadic breast cancer', 'Disease', (25, 47))	('men', 'Species', '9606', (164, 167))
6723	33883026	Iranian Kurdish breast cancer patients also had a higher frequency of PTEN methylation compared with healthy controls.	('methylation', 'Var', (75, 86))	('PTEN', 'Gene', (70, 74))	('PTEN', 'Gene', '5728', (70, 74))	('Kurdish breast cancer', 'Disease', 'MESH:D001943', (8, 29))	('patients', 'Species', '9606', (30, 38))	('Kurdish breast cancer', 'Disease', (8, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
6724	33883026	The female relatives of patients had also a significantly higher frequency of PTEN methylation compared with controls.	('methylation', 'Var', (83, 94))	('PTEN', 'Gene', (78, 82))	('PTEN', 'Gene', '5728', (78, 82))	('higher', 'PosReg', (58, 64))	('patients', 'Species', '9606', (24, 32))
6728	33883026	Similarly, ALX4 methylation was observed among German patients with colorectal, esophageal, and gastric cancers.	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('patients', 'Species', '9606', (54, 62))	('ALX4', 'Gene', (11, 15))	('colorectal', 'Disease', 'MESH:D015179', (68, 78))	('gastric cancers', 'Disease', (96, 111))	('gastric cancers', 'Disease', 'MESH:D013274', (96, 111))	('ALX4', 'Gene', '60529', (11, 15))	('colorectal', 'Disease', (68, 78))	('esophageal', 'Disease', (80, 90))	('gastric cancers', 'Phenotype', 'HP:0012126', (96, 111))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('methylation', 'Var', (16, 27))
6730	33883026	Deregulation of PAX5 has been observed in various types of human tumors.	('human', 'Species', '9606', (59, 64))	('PAX5', 'Gene', '5079', (16, 20))	('PAX5', 'Gene', (16, 20))	('Deregulation', 'Var', (0, 12))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
6736	33883026	It has been shown that there was a significant correlation between PAX5 methylation and survival in a sample of Chinese gastric cancer patients.	('PAX5', 'Gene', (67, 71))	('PAX5', 'Gene', '5079', (67, 71))	('patients', 'Species', '9606', (135, 143))	('survival', 'Disease', (88, 96))	('gastric cancer', 'Disease', (120, 134))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('methylation', 'Var', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))
6738	33883026	MiR-192-2 induces the apoptosis through targeting SOX4 in gastric tumor cells.	('MiR-192-2', 'Chemical', '-', (0, 9))	('gastric tumor', 'Disease', 'MESH:D013274', (58, 71))	('gastric tumor', 'Phenotype', 'HP:0006753', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('SOX4', 'Gene', (50, 54))	('SOX4', 'Gene', '6659', (50, 54))	('MiR-192-2', 'Var', (0, 9))	('apoptosis', 'CPA', (22, 31))	('gastric tumor', 'Disease', (58, 71))
6742	33883026	It has been observed that there was significantly higher ER4 methylation in tumors with P53 expression among a sub population of Iranian breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('P53', 'Gene', (88, 91))	('higher', 'PosReg', (50, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('expression', 'Var', (92, 102))	('P53', 'Gene', '7157', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('patients', 'Species', '9606', (151, 159))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('methylation', 'MPA', (61, 72))	('ER4', 'Protein', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
6743	33883026	The ER5 methylation was observed in tumors with lymph node metastasis and higher grades.	('lymph node metastasis', 'CPA', (48, 69))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('ER5 methylation', 'Var', (4, 19))	('observed', 'Reg', (24, 32))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('methylation', 'Var', (8, 19))
6745	33883026	There was also significant higher frequency of ER5 methylation in Her-2+ tumors.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('Her-2', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('methylation', 'Var', (51, 62))	('higher', 'PosReg', (27, 33))	('tumors', 'Disease', (73, 79))	('ER5', 'Protein', (47, 50))	('Her-2', 'Gene', '2064', (66, 71))
6746	33883026	ER-alpha hyper methylation was frequently observed in invasive ductal cell carcinoma patients.	('hyper methylation', 'Var', (9, 26))	('ER-alpha', 'Gene', (0, 8))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('invasive ductal cell carcinoma', 'Disease', 'MESH:D044584', (54, 84))	('observed', 'Reg', (42, 50))	('ER-alpha', 'Gene', '2099', (0, 8))	('invasive ductal cell carcinoma', 'Disease', (54, 84))
6749	33883026	There was a correlation between ER-alpha methylation and poor prognosis in basal and Her2+ tumors.	('tumors', 'Disease', (91, 97))	('ER-alpha', 'Gene', (32, 40))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Her2', 'Gene', (85, 89))	('ER-alpha', 'Gene', '2099', (32, 40))	('methylation', 'Var', (41, 52))	('basal', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Her2', 'Gene', '2064', (85, 89))
6751	33883026	ER3 and ER5 methylations have been also reported in majority of a sample of Iranian ER negative breast tumors.	('ER5', 'Gene', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('breast tumors', 'Disease', (96, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('breast tumor', 'Phenotype', 'HP:0100013', (96, 108))	('breast tumors', 'Phenotype', 'HP:0100013', (96, 109))	('ER3', 'Gene', (0, 3))	('reported', 'Reg', (40, 48))	('methylations', 'Var', (12, 24))	('breast tumors', 'Disease', 'MESH:D001943', (96, 109))
6753	33883026	It has been reported that there was higher frequency of RARB hyper methylation in poor prognosis cases compared with good prognosis in a sample of Iranian prostate cancer patients.	('RARB', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('RARB', 'Gene', '5915', (56, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (155, 170))	('Iranian prostate cancer', 'Disease', 'MESH:D011471', (147, 170))	('patients', 'Species', '9606', (171, 179))	('Iranian prostate cancer', 'Disease', (147, 170))	('hyper methylation', 'Var', (61, 78))
6755	33883026	Similarly, RARB methylation was associated with a higher prostate cancer risk among American patients.	('prostate cancer', 'Disease', (57, 72))	('RARB', 'Gene', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('RARB', 'Gene', '5915', (11, 15))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('patients', 'Species', '9606', (93, 101))	('methylation', 'Var', (16, 27))
6759	33883026	It has been shown that there was a significant association between the levels of APAF1 methylation, tumor stage, and grade in blood samples of a subpopulation of Iranian gastric cancer patients.	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', (100, 105))	('gastric cancer', 'Disease', (170, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('APAF1', 'Gene', (81, 86))	('patients', 'Species', '9606', (185, 193))	('methylation', 'Var', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('APAF1', 'Gene', '317', (81, 86))
6765	33883026	Moreover, it cleaves BID to generate truncated BID which enters to the mitochondria and triggers the mitochondrial apoptotic pathway.	('BID', 'Gene', (21, 24))	('triggers', 'Reg', (88, 96))	('mitochondrial apoptotic pathway', 'Pathway', (101, 132))	('BID', 'Gene', '637', (47, 50))	('enters', 'Reg', (57, 63))	('BID', 'Gene', '637', (21, 24))	('truncated', 'Var', (37, 46))	('BID', 'Gene', (47, 50))
6766	33883026	It has been observed that there was aberrant FAS promoter methylation in majority of a sample of Iranian oral squamous cell carcinoma patients, whereas the aberrant FADD methylation was observed in a minority of cases.	('methylation', 'MPA', (58, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('oral squamous cell carcinoma', 'Disease', (105, 133))	('patients', 'Species', '9606', (134, 142))	('aberrant', 'Var', (36, 44))	('FAS promoter', 'Protein', (45, 57))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))
6767	33883026	Ataxia telangiectasia mutated (ATM) is a serine threonine kinase which is activated by DNA double-strand break (DSB).	('DNA double-strand break', 'Var', (87, 110))	('Ataxia telangiectasia mutated', 'Gene', '472', (0, 29))	('ATM', 'Gene', '472', (31, 34))	('Ataxia telangiectasia mutated', 'Gene', (0, 29))	('serine', 'Chemical', 'MESH:D012694', (41, 47))	('telangiectasia', 'Phenotype', 'HP:0001009', (7, 21))	('Ataxia', 'Phenotype', 'HP:0001251', (0, 6))	('ATM', 'Gene', (31, 34))
6768	33883026	Deregulated expression of E2F1 transcription factor up regulates ATM that leads to the apoptosis induction, cell cycle regulation, and DNA repair via phosphorylation of CHK1, CHK2, P53, and CDC25.	('CDC25', 'Gene', '995', (190, 195))	('ATM', 'Gene', '472', (65, 68))	('phosphorylation', 'MPA', (150, 165))	('CDC25', 'Gene', (190, 195))	('Deregulated', 'Var', (0, 11))	('CHK1', 'Gene', '1111', (169, 173))	('CHK2', 'Gene', (175, 179))	('up regulates', 'PosReg', (52, 64))	('P53', 'Gene', (181, 184))	('E2F1', 'Gene', '1869', (26, 30))	('DNA repair', 'CPA', (135, 145))	('E2F1', 'Gene', (26, 30))	('apoptosis induction', 'CPA', (87, 106))	('cell cycle regulation', 'CPA', (108, 129))	('CHK1', 'Gene', (169, 173))	('CHK2', 'Gene', '11200', (175, 179))	('ATM', 'Gene', (65, 68))	('P53', 'Gene', '7157', (181, 184))
6772	33883026	Moreover, there was a significant association between D1853N polymorphism and ATM promoter methylation.	('D1853N', 'Var', (54, 60))	('ATM', 'Gene', (78, 81))	('D1853N', 'Mutation', 'rs1801516', (54, 60))	('ATM', 'Gene', '472', (78, 81))
6777	33883026	It has been observed that there was significantly higher frequency of CTLA4 promoter methylation in a sample of Iranian gastric cancer patients compared with normal margins.	('methylation', 'Var', (85, 96))	('higher', 'PosReg', (50, 56))	('patients', 'Species', '9606', (135, 143))	('CTLA4', 'Gene', '1493', (70, 75))	('gastric cancer', 'Disease', (120, 134))	('promoter', 'MPA', (76, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('CTLA4', 'Gene', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))
6779	33883026	Role of aberrant methylations in regulation of apoptosis during tumor progressions among Iranian patients are illustrated in Fig.	('aberrant methylations', 'Var', (8, 29))	('tumor', 'Disease', (64, 69))	('methylations', 'Var', (17, 29))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('patients', 'Species', '9606', (97, 105))
6782	33883026	It was frequently observed that the p16 and CDH1 aberrant promoter methylations can be involved in tumor progression of ESCC, thyroid, oral, breast, gastric, and prostate cancers.	('oral', 'Disease', (135, 139))	('breast', 'Disease', (141, 147))	('aberrant', 'Var', (49, 57))	('p16', 'Gene', '1029', (36, 39))	('prostate cancer', 'Phenotype', 'HP:0012125', (162, 177))	('prostate cancers', 'Phenotype', 'HP:0012125', (162, 178))	('CDH1', 'Gene', '999', (44, 48))	('prostate cancers', 'Disease', (162, 178))	('tumor', 'Disease', (99, 104))	('involved', 'Reg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CDH1', 'Gene', (44, 48))	('thyroid', 'Disease', (126, 133))	('ESCC', 'Disease', (120, 124))	('gastric', 'Disease', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('prostate cancers', 'Disease', 'MESH:D011471', (162, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('p16', 'Gene', (36, 39))
6783	33883026	The MGMT promoter hyper methylation was also frequently reported in CRC, GB, BC, and OSCC.	('MGMT', 'Gene', '4255', (4, 8))	('CRC', 'Disease', 'MESH:D015179', (68, 71))	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('hyper methylation', 'Var', (18, 35))	('reported', 'Reg', (56, 64))	('CRC', 'Disease', (68, 71))	('OSCC', 'Disease', (85, 89))	('MGMT', 'Gene', (4, 8))
6785	33883026	Moreover, there were various reports of PTEN and ER-alpha promoter hyper methylations in Iranian BC patients which introduces them as methylation based markers of BC in this population.	('ER-alpha', 'Gene', '2099', (49, 57))	('hyper methylations', 'Var', (67, 85))	('PTEN', 'Gene', (40, 44))	('PTEN', 'Gene', '5728', (40, 44))	('Iranian BC', 'Disease', (89, 99))	('patients', 'Species', '9606', (100, 108))	('ER-alpha', 'Gene', (49, 57))
6803	33729467	Furthermore, deaths caused by tumor progression or recurrence were significantly less in the nCRT group than in the nCT group (9 of 132 [6.8%] vs 19 of 132 [14.4%]; P = .046); however, deaths from nontumor causes were similar (8 of 132 [6.1%] vs 4 of 132 [3.0%]; P = .24).	('deaths', 'Disease', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('nCRT', 'Var', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (200, 205))	('less', 'NegReg', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('deaths', 'Disease', (13, 19))	('deaths', 'Disease', 'MESH:D003643', (13, 19))	('tumor', 'Disease', (30, 35))	('deaths', 'Disease', 'MESH:D003643', (185, 191))
6814	33729467	On the other hand, a meta-analysis reported that nCRT was significantly associated with increased risk of perioperative morbidity or mortality for patients with ESCC, which may impose restrictions on the application of nCRT.	('mortality', 'Disease', 'MESH:D003643', (133, 142))	('nCRT', 'Var', (49, 53))	('mortality', 'Disease', (133, 142))	('ESCC', 'Disease', (161, 165))	('patients', 'Species', '9606', (147, 155))	('perioperative morbidity', 'CPA', (106, 129))
6827	33729467	Only patients with tumors of clinical stages from T3 to T4aN0 to N1 and no clinical evidence of metastatic spread (M0), according to the International Union Against Cancer Tumor, Node, Metastasis (TNM) Classification (8th edition), were enrolled.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('patients', 'Species', '9606', (5, 13))	('T4aN0', 'Var', (56, 61))	('Cancer Tumor', 'Disease', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Cancer Tumor', 'Disease', 'MESH:D009369', (165, 177))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
6867	33729467	Furthermore, deaths caused by tumor progression or recurrence were significantly less in the nCRT group than in the nCT group (9 of 132 [6.8%] vs 19 of 132 [14.4%]; P = .046); however, deaths from nontumor causes were similar (8 of 132 [6.1%] vs 4 of 132 [3.0%]; P = .24) (Table 4).	('deaths', 'Disease', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('nCRT', 'Var', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (200, 205))	('less', 'NegReg', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('deaths', 'Disease', (13, 19))	('deaths', 'Disease', 'MESH:D003643', (13, 19))	('tumor', 'Disease', (30, 35))	('deaths', 'Disease', 'MESH:D003643', (185, 191))
6871	33729467	In the CROSS trial, patients with esophageal cancer staging of cT1N1M0 or cT2 to T3N0 to 1M0 were enrolled, of whom 75% had adenocarcinoma, 23% had ESCC, and 2% had other subtypes.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cT2', 'Gene', (74, 77))	('cT2', 'Gene', '386757', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cT1N1M0', 'Var', (63, 70))	('adenocarcinoma', 'Disease', (124, 138))	('patients', 'Species', '9606', (20, 28))	('ESCC', 'Disease', (148, 152))	('cancer', 'Disease', (45, 51))	('adenocarcinoma', 'Disease', 'MESH:D000230', (124, 138))
6874	33729467	In the Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC 5010) clinical trial enrolling patients with ESCC staging as T1 to 4N1M0 or T4N0M0, the nCRT group had a higher R0 resection rate (98.4% vs 91.2%; P = .002), a better median overall survival (100.1 vs 66.5 months; P = .03), and a prolonged disease-free survival (100.1 vs 41.7 months; P = .001) compared with patients undergoing surgery alone.	('patients', 'Species', '9606', (459, 467))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('R0 resection', 'CPA', (262, 274))	('Carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Carcinoma of the Esophagus', 'Phenotype', 'HP:0011459', (113, 139))	('T4N0M0', 'Var', (226, 232))	('ESCC', 'Disease', (195, 199))	('Squamous Cell Carcinoma', 'Disease', (99, 122))	('higher', 'PosReg', (255, 261))	('patients', 'Species', '9606', (181, 189))	('disease-free survival', 'CPA', (390, 411))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('T1 to 4N1M0', 'Var', (211, 222))
6875	33729467	In the JCOG 9907 trial, in which patients with clinical stage II or III (excluding T4) ESCC were enrolled, 5-year overall survival was higher among those who received nCT plus surgery than among those who received adjuvant chemotherapy (55% vs 43%; P = .04), and there were no remarkable differences in postoperative complications or mortality between the 2 groups.	('mortality', 'Disease', (334, 343))	('patients', 'Species', '9606', (33, 41))	('overall survival', 'CPA', (114, 130))	('nCT', 'Var', (167, 170))	('ESCC', 'Disease', (87, 91))	('mortality', 'Disease', 'MESH:D003643', (334, 343))	('higher', 'PosReg', (135, 141))
6877	33729467	The Preoperative Therapy in Esophagogastric Adenocarcinoma Trial (POET), which was conducted from 2000 to 2005, enrolled 119 patients with clinical staging of T3 to 4NXM0, all of whom had esophagogastric junction adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (44, 58))	('Adenocarcinoma', 'Disease', (44, 58))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (188, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('Esophagogastric Adenocarcinoma', 'Phenotype', 'HP:0011459', (28, 58))	('junction adenocarcinoma', 'Disease', 'MESH:D000230', (204, 227))	('T3 to', 'Var', (159, 164))	('junction adenocarcinoma', 'Disease', (204, 227))	('patients', 'Species', '9606', (125, 133))
6879	33729467	The Neoadjuvant Chemotherapy Versus Radiochemotherapy for Cancer of the Esophagus or Cardia (NeoRes) trial, which was conducted from 2006 to 2013, enrolled 181 patients with clinical staging of T1 to 3NX (except T1N0), of which 73% were adenocarcinoma and 27% were ESCC.	('ESCC', 'Disease', (265, 269))	('patients', 'Species', '9606', (160, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('adenocarcinoma', 'Disease', (237, 251))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Cancer', 'Disease', (58, 64))	('Cancer of the Esophagus', 'Phenotype', 'HP:0100751', (58, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (237, 251))	('Cardia', 'Disease', 'MESH:D004938', (85, 91))	('Cancer', 'Disease', 'MESH:D009369', (58, 64))	('T1 to 3NX', 'Var', (194, 203))	('Cardia', 'Disease', (85, 91))
6882	33729467	The clinical trial reported by Burmeister et al, which began in November 2000 and ceased in December 2006, enrolled 75 patients with clinical staging of T2 to 3N0 to 1M0, all of which were adenocarcinoma.	('T2 to 3N0 to 1M0', 'Var', (153, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('patients', 'Species', '9606', (119, 127))	('adenocarcinoma', 'Disease', (189, 203))	('adenocarcinoma', 'Disease', 'MESH:D000230', (189, 203))
6893	33729467	However, MIE could significantly decrease such trauma and decrease morbidity and mortality compared with open esophagectomy, which has been confirmed in the studies published.	('decrease', 'NegReg', (33, 41))	('mortality', 'Disease', 'MESH:D003643', (81, 90))	('trauma', 'Disease', 'MESH:D014947', (47, 53))	('MIE', 'Var', (9, 12))	('decrease', 'NegReg', (58, 66))	('mortality', 'Disease', (81, 90))	('morbidity', 'CPA', (67, 76))	('trauma', 'Disease', (47, 53))
6900	32426049	Predicting STAT1 as a prognostic marker in patients with solid cancer Aberrant activities of signal transducer and activator of transcription 1 (STAT1) have been implicated in cancer development.	('implicated', 'Reg', (162, 172))	('STAT1', 'Gene', (11, 16))	('patients', 'Species', '9606', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('STAT1', 'Gene', (145, 150))	('STAT1', 'Gene', '6772', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('signal transducer and activator of transcription 1', 'Gene', '6772', (93, 143))	('STAT1', 'Gene', '6772', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('Aberrant activities', 'Var', (70, 89))	('cancer', 'Disease', (63, 69))
6905	32426049	Pooled data showed that overexpressed STAT1 favored long overall survival (OS) (HR = 0.604, 95% CI = 0.431-0.846, p = 0.003) and disease-specific survival (DSS) (HR = 0.650, 95% CI = 0.512-0.825, p = 0.000).	('disease-specific survival', 'CPA', (129, 154))	('STAT1', 'Gene', (38, 43))	('DSS', 'Chemical', '-', (156, 159))	('favored', 'PosReg', (44, 51))	('overexpressed', 'Var', (24, 37))
6926	32426049	Patients with STAT1 or phospho-STAT1 at a high expression level have a worse outcome compared with patients with STAT1 at a low expression level.	('phospho-STAT1 at', 'Var', (23, 39))	('STAT1', 'Var', (14, 19))	('patients', 'Species', '9606', (99, 107))	('Patients', 'Species', '9606', (0, 8))
6948	32426049	Our analysis revealed that highly expressed STAT1 was a positive predictor for OS among cancer patients (HR = 0.604, 95% CI = 0.431-0.846, p = 0.003) (Figure 3).	('highly expressed', 'Var', (27, 43))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('STAT1', 'Gene', (44, 49))
6952	32426049	The pooled results indicated a positive correlation between highly expressed STAT1 and longer DSS (HR = 0.650, 95% CI = 0.512-0.825, p = 0.000) (Figure 4B).	('highly expressed', 'Var', (60, 76))	('DSS', 'Chemical', '-', (94, 97))	('longer DSS', 'Disease', (87, 97))	('STAT1', 'Gene', (77, 82))
6953	32426049	The first subgroup analyses by region revealed that the pooled HRs were 0.630 (95% CI = 0.337-1.178, p = 0.148) for Asian patients (five studies) and 0.666 (95% CI = 0.431-0.846, p = 0.000) for Non-Asian patients (six studies).	('Asian patients', 'Disease', (116, 130))	('patients', 'Species', '9606', (204, 212))	('0.666', 'Var', (150, 155))	('0.630', 'Var', (72, 77))	('patients', 'Species', '9606', (122, 130))
6954	32426049	The fourth subgroup analyses by cancer types displayed that highly expressed STAT1 was associated with favorable OS of patients with high-grade serous ovarian cancer (HR = 0.683, 95% CI = 0.497-0.938, p = 0.019) (2 studies), oral squamous cell carcinoma (HR = 0.486, 95% CI = 0.241-0.980, p = 0.044) (two studies), and another five cancers (pooled HR = 0.542, 95% CI = 0.361-0.813, p = 0.003), but not in lung cancer (HR = 1.223, 95% CI = 0.996-1.501, p = 0.055) (two studies).	('oral squamous cell carcinoma', 'Disease', (225, 253))	('lung cancer', 'Disease', (405, 416))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('cancers', 'Disease', 'MESH:D009369', (332, 339))	('serous ovarian cancer', 'Disease', (144, 165))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (405, 416))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (405, 416))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('cancers', 'Disease', (332, 339))	('cancer', 'Disease', (332, 338))	('STAT1', 'Gene', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (144, 165))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Disease', (410, 416))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (225, 253))	('highly expressed', 'Var', (60, 76))
6971	32426049	The outcomes after analyses indicate that expression of STAT1 is associated with survival of patients based on their cancer type.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('STAT1', 'Gene', (56, 61))	('associated with', 'Reg', (65, 80))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('expression', 'Var', (42, 52))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (93, 101))
6977	32426049	The tumor-suppressive role of STAT1 is driven by findings that the reconstitution of STAT1 in STAT1-deficient murine fibrosarcoma cells significantly suppressed tumorigenicity and metastasis in nude mice.	('STAT1-deficient', 'Gene', (94, 109))	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (161, 166))	('fibrosarcoma', 'Disease', 'MESH:D005354', (117, 129))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (117, 129))	('nude mice', 'Species', '10090', (194, 203))	('suppressed', 'NegReg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('reconstitution', 'Var', (67, 81))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('fibrosarcoma', 'Disease', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('STAT1', 'Gene', (85, 90))	('murine', 'Species', '10090', (110, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
6978	32426049	The high expression of STAT1 is reported to have a good prognosis compared with the low or negative expression of STAT1 in some cancer patients.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('patients', 'Species', '9606', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('high', 'Var', (4, 8))	('STAT1', 'Gene', (23, 28))	('cancer', 'Disease', (128, 134))
6979	32426049	However, on the other hand, two studies have identified high STAT1 mRNA levels associated with poor prognosis, tumor progression, and worse survival in breast cancer.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('associated', 'Reg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('tumor', 'Disease', (111, 116))	('STAT1 mRNA levels', 'MPA', (61, 78))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('high', 'Var', (56, 60))
6982	32426049	The survival analysis of TCGA data revealed that highly expressed STAT1 was associated with longer OS in ovarian cancer, rectum adenocarcinoma, sarcoma, and skin cutaneous melanoma.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('highly expressed', 'Var', (49, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('skin cutaneous melanoma', 'Disease', (157, 180))	('STAT1', 'Gene', (66, 71))	('longer OS in ovarian cancer', 'Disease', (92, 119))	('rectum adenocarcinoma', 'Disease', (121, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('associated', 'Reg', (76, 86))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (121, 142))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('longer OS in ovarian cancer', 'Disease', 'MESH:C567932', (92, 119))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (157, 180))
6984	32426049	Again, on the other hand, highly expressed STAT1 may predict poor OS in patients with renal carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, and lower grade glioma.	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (124, 149))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('highly expressed', 'Var', (26, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (124, 149))	('poor OS', 'Disease', (61, 68))	('glioma', 'Disease', (167, 173))	('glioma', 'Disease', 'MESH:D005910', (167, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('pancreatic adenocarcinoma', 'Disease', (124, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('lung adenocarcinoma', 'Disease', (103, 122))	('renal carcinoma', 'Disease', 'MESH:C538614', (86, 101))	('STAT1', 'Gene', (43, 48))	('renal carcinoma', 'Disease', (86, 101))	('renal carcinoma', 'Phenotype', 'HP:0005584', (86, 101))	('patients', 'Species', '9606', (72, 80))
6992	32426049	For instance, STAT1 can arrest the cell cycle in response to IFNgamma through direct interaction with cyclin D1 and CDK4 proteins.	('arrest', 'Disease', (24, 30))	('cell cycle', 'CPA', (35, 45))	('IFNgamma', 'Gene', '3458', (61, 69))	('IFNgamma', 'Gene', (61, 69))	('CDK4', 'Gene', (116, 120))	('CDK4', 'Gene', '1019', (116, 120))	('arrest', 'Disease', 'MESH:D006323', (24, 30))	('cyclin D1', 'Gene', (102, 111))	('cyclin D1', 'Gene', '595', (102, 111))	('interaction', 'Interaction', (85, 96))	('STAT1', 'Var', (14, 19))
6998	32426049	Full-length STAT1alpha isoform has traditionally been considered as the physiologically active form of STAT1 after phosphorylation at Tyr701 and Ser727 residues, and the truncated STAT1beta isoform is considered as a physiological inhibitor of STAT1.	('Tyr701', 'Chemical', '-', (134, 140))	('Ser727', 'Var', (145, 151))	('Ser727', 'Chemical', '-', (145, 151))	('Tyr701', 'Var', (134, 140))
6999	32426049	The expression and activation ratio of STAT1alpha and STAT1beta in different cancer types may impact cancer progression and promote a 'switch' from tumor cell proliferation to a death phenotype.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('STAT1beta', 'Var', (54, 63))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (77, 83))	('tumor', 'Disease', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('death', 'Disease', 'MESH:D003643', (178, 183))	('death', 'Disease', (178, 183))	("'switch'", 'PosReg', (134, 142))	('STAT1alpha', 'Gene', (39, 49))	('promote', 'PosReg', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('impact', 'Reg', (94, 100))
7001	32426049	Interestingly, another study shows that STAT1beta protects STAT1alpha from degradation and enhances STAT1 function in esophageal squamous cell carcinoma.	('STAT1alpha', 'Protein', (59, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('STAT1 function', 'MPA', (100, 114))	('enhances', 'PosReg', (91, 99))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (118, 152))	('STAT1beta', 'Var', (40, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('degradation', 'MPA', (75, 86))	('esophageal squamous cell carcinoma', 'Disease', (118, 152))
7022	31602161	Multivariate Logistic regression analysis revealed that patients with high T stage and M stage and high expression of miR-21 (> 5.80) and miR-93 (> 4.71) suffered an increased risk of ineffective radiotherapy and chemotherapy, and multivariate Cox regression analysis revealed that patients with high T stage, N stage, and M stage, and high expression of miR-21 (> 5.60), and miR-93 (> 3.87) suffered an increased risk of death in 3 years.	('patients', 'Species', '9606', (56, 64))	('miR-21', 'Gene', '406991', (118, 124))	('M stage', 'CPA', (323, 330))	('death', 'Disease', 'MESH:D003643', (422, 427))	('death', 'Disease', (422, 427))	('high expression', 'Var', (336, 351))	('miR-93', 'Gene', '407051', (138, 144))	('N stage', 'CPA', (310, 317))	('miR-21', 'Gene', (355, 361))	('miR-93', 'Gene', (138, 144))	('miR-93', 'Gene', '407051', (376, 382))	('Cox', 'Gene', '1351', (244, 247))	('Cox', 'Gene', (244, 247))	('miR-21', 'Gene', (118, 124))	('miR-93', 'Gene', (376, 382))	('patients', 'Species', '9606', (282, 290))	('miR-21', 'Gene', '406991', (355, 361))
7068	31602161	Multivariate Logistic regression analysis was adopted for factors with significant differences, which revealed that T stage (P < 0.05), M stage (P < 0.05), miR-21 (P < 0.01), and miR-93 (P < 0.05) were independent risk factors for radiotherapy and chemotherapy efficacy, and patients with high T stage, M stage, and high expression of miR-21 (> 5.80) and miR-93 (> 4.71) suffered an increased risk of ineffective radiotherapy and chemotherapy.	('miR-21', 'Gene', (335, 341))	('miR-93', 'Gene', '407051', (179, 185))	('miR-21', 'Gene', '406991', (156, 162))	('T stage', 'CPA', (294, 301))	('miR-93', 'Gene', '407051', (355, 361))	('miR-93', 'Gene', (179, 185))	('miR-93', 'Gene', (355, 361))	('high expression', 'Var', (316, 331))	('high', 'Var', (289, 293))	('miR-21', 'Gene', '406991', (335, 341))	('patients', 'Species', '9606', (275, 283))	('miR-21', 'Gene', (156, 162))
7071	31602161	The AUCs of miR-21 and miR-93 for assessing 3-year OS were 0.861 and 0.807, respectively, and their optimal critical values were 5.60 and 3.87, respectively.	('miR-93', 'Gene', (23, 29))	('0.807', 'Var', (69, 74))	('miR-21', 'Gene', '406991', (12, 18))	('miR-21', 'Gene', (12, 18))	('miR-93', 'Gene', '407051', (23, 29))
7073	31602161	Multivariate Cox regression analysis revealed that T stage (P < 0.01), N stage (P < 0.05), M stage (P < 0.01), miR-21(P < 0.01), and miR-93 (P < 0.01) were all independent prognostic factors for ESCC patients, and patients with high T stage, N stage, and M stage, and high expression of miR-21 (> 5.60) and miR-93 (> 3.87) suffered an increased risk of death in 3 years.	('patients', 'Species', '9606', (214, 222))	('ESCC', 'Disease', (195, 199))	('Cox', 'Gene', (13, 16))	('miR-21', 'Gene', '406991', (287, 293))	('T stage', 'CPA', (233, 240))	('death', 'Disease', 'MESH:D003643', (353, 358))	('miR-21', 'Gene', '406991', (111, 117))	('high', 'Var', (228, 232))	('miR-93', 'Gene', (133, 139))	('miR-93', 'Gene', (307, 313))	('miR-21', 'Gene', (287, 293))	('ESCC', 'Disease', 'MESH:C562729', (195, 199))	('miR-93', 'Gene', '407051', (133, 139))	('patients', 'Species', '9606', (200, 208))	('miR-21', 'Gene', (111, 117))	('death', 'Disease', (353, 358))	('miR-93', 'Gene', '407051', (307, 313))	('high expression', 'Var', (268, 283))	('Cox', 'Gene', '1351', (13, 16))
7087	31602161	This study revealed that patients with high expression of miR-21 (> 5.80) and miR-93 (> 4.71) suffered an increased risk of ineffective radiotherapy and chemotherapy.	('miR-93', 'Gene', (78, 84))	('miR-21', 'Gene', (58, 64))	('high expression', 'Var', (39, 54))	('patients', 'Species', '9606', (25, 33))	('miR-21', 'Gene', '406991', (58, 64))	('miR-93', 'Gene', '407051', (78, 84))
7094	31602161	In addition, a study by Li et al confirmed that miR-93 was closely related to clinical stage, lymph node metastasis, and T stage of patients with head and neck squamous cell carcinoma; the patients with high miR-93 expression showed a significantly lower survival rate than those with low expression, and lymph node metastasis was related to a poor prognosis of patients with high miR-93 expression.	('patients', 'Species', '9606', (362, 370))	('lower', 'NegReg', (249, 254))	('miR-93', 'Gene', '407051', (381, 387))	('lymph node metastasis', 'Disease', (305, 326))	('miR-93', 'Gene', '407051', (48, 54))	('miR-93', 'Gene', (48, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('survival rate', 'CPA', (255, 268))	('miR-93', 'Gene', (381, 387))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (146, 183))	('miR-93', 'Gene', '407051', (208, 214))	('high', 'Var', (203, 207))	('miR-93', 'Gene', (208, 214))	('patients', 'Species', '9606', (189, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('patients', 'Species', '9606', (132, 140))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (146, 183))
7097	31602161	The AUCs of miR-21 and miR-93 for assessing the 3-year OS of ESCC patients were 0.861 and 0.807, respectively, and Cox regression analysis revealed that patients with high T stage, N stage, M stage, and high expression of miR-21 (> 5.60) and miR-93 (> 3.87) suffered an increased risk of death in 3 years, which indicated that detection of miR-21 and miR-93 can be adopted for judging the prognosis of ESCC patients.	('miR-93', 'Gene', '407051', (351, 357))	('miR-21', 'Gene', '406991', (12, 18))	('death', 'Disease', (288, 293))	('ESCC', 'Disease', (61, 65))	('high expression', 'Var', (203, 218))	('ESCC', 'Disease', (402, 406))	('miR-21', 'Gene', (340, 346))	('Cox', 'Gene', '1351', (115, 118))	('miR-21', 'Gene', (12, 18))	('miR-93', 'Gene', (23, 29))	('death', 'Disease', 'MESH:D003643', (288, 293))	('miR-21', 'Gene', '406991', (222, 228))	('Cox', 'Gene', (115, 118))	('miR-93', 'Gene', (242, 248))	('patients', 'Species', '9606', (66, 74))	('miR-93', 'Gene', '407051', (23, 29))	('ESCC', 'Disease', 'MESH:C562729', (61, 65))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (407, 415))	('ESCC', 'Disease', 'MESH:C562729', (402, 406))	('M stage', 'CPA', (190, 197))	('miR-93', 'Gene', (351, 357))	('miR-93', 'Gene', '407051', (242, 248))	('miR-21', 'Gene', (222, 228))	('miR-21', 'Gene', '406991', (340, 346))	('N stage', 'CPA', (181, 188))
7133	31403035	Based on our comparisons, pre-operative FLOT had a manageable toxicity profile compared to other pre-operative doublet or triplet regimens.	('FLOT', 'Chemical', '-', (40, 44))	('FLOT', 'Var', (40, 44))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('toxicity', 'Disease', (62, 70))
7174	31403035	However, post-operative CF+RT showed less grade 1-2 toxicity (neutropenia, mucositis, hand foot syndrome) compared to post-operative ECF.	('neutropenia', 'Disease', 'MESH:D009503', (62, 73))	('hand foot syndrome', 'Disease', (86, 104))	('hand foot syndrome', 'Disease', 'MESH:D060831', (86, 104))	('neutropenia', 'Phenotype', 'HP:0001875', (62, 73))	('CF', 'Chemical', '-', (24, 26))	('ECF', 'Chemical', '-', (133, 136))	('mucositis', 'Disease', (75, 84))	('mucositis', 'Disease', 'MESH:D052016', (75, 84))	('toxicity', 'Disease', 'MESH:D064420', (52, 60))	('toxicity', 'Disease', (52, 60))	('CF+RT', 'Var', (24, 29))	('neutropenia', 'Disease', (62, 73))	('CF', 'Chemical', '-', (134, 136))
7184	31403035	In terms of grade 3-4 adverse events, 5-FU+RT was significantly more toxic than CAPOX and S-1 monotherapy (hematological toxicity, anorexia fatigue, mucositis).	('anorexia fatigue', 'Disease', 'MESH:D000855', (131, 147))	('hematological toxicity', 'Disease', (107, 129))	('5-FU+RT', 'Var', (38, 45))	('fatigue', 'Phenotype', 'HP:0012378', (140, 147))	('5-FU', 'Chemical', 'MESH:D005472', (38, 42))	('S-1', 'Gene', '5707', (90, 93))	('mucositis', 'Disease', (149, 158))	('hematological toxicity', 'Disease', 'MESH:D006402', (107, 129))	('anorexia', 'Phenotype', 'HP:0002039', (131, 139))	('mucositis', 'Disease', 'MESH:D052016', (149, 158))	('CAPOX', 'Chemical', '-', (80, 85))	('S-1', 'Gene', (90, 93))	('anorexia fatigue', 'Disease', (131, 147))
7185	31403035	Treatment with S-1 monotherapy was associated with more grade 1-2 adverse events compared to CAPOX and 5-FU+RT (Supplementary Table 5).	('S-1', 'Gene', (15, 18))	('CAPOX', 'Chemical', '-', (93, 98))	('5-FU', 'Chemical', 'MESH:D005472', (103, 107))	('S-1', 'Gene', '5707', (15, 18))	('monotherapy', 'Var', (19, 30))
7209	31403035	In the FLOT-4 trial perioperative FLOT substantially improved overall survival compared to perioperative ECF for gastric cancer.	('FLOT', 'Var', (34, 38))	('ECF', 'Chemical', '-', (105, 108))	('FLOT', 'Chemical', '-', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('improved', 'PosReg', (53, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('FLOT', 'Chemical', '-', (7, 11))	('overall survival', 'MPA', (62, 78))
7228	31403035	In the adjuvant setting, S-1 monotherapy had a more favorable toxicity profile compared to CAPOX and 5-FU with RT and could thus be an more attractive option for patients with co-morbidity limiting more intensive treatment.	('patients', 'Species', '9606', (162, 170))	('CAPOX', 'Chemical', '-', (91, 96))	('S-1', 'Gene', '5707', (25, 28))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('S-1', 'Gene', (25, 28))	('toxicity', 'Disease', (62, 70))	('5-FU', 'Chemical', 'MESH:D005472', (101, 105))	('monotherapy', 'Var', (29, 40))
7255	31100935	that GPC3 is a potential suppressor of metastasis as loss of GPC3 was associated with increased lymph node metastasis and poor overall survival (OS).	('GPC3', 'Gene', (5, 9))	('increased', 'PosReg', (86, 95))	('GPC3', 'Gene', (61, 65))	('GPC3', 'Gene', '2719', (61, 65))	('GPC3', 'Gene', '2719', (5, 9))	('poor', 'NegReg', (122, 126))	('lymph node metastasis', 'CPA', (96, 117))	('loss', 'Var', (53, 57))	('overall', 'MPA', (127, 134))
7335	31100935	We observed a significant correlation between tumor grade and high expression of tGPC3 (p = 0.050) whereas none of the other clinical or histopathological parameters showed a significant association.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('GPC3', 'Gene', (82, 86))	('tumor', 'Disease', (46, 51))	('high expression', 'Var', (62, 77))	('GPC3', 'Gene', '2719', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
7343	31100935	Interestingly, univariate analysis showed that high expression of GPC3 on exosome-bound latex beads was associated with improved OS (low expression of eGPC3: median OS: 60.926 months, high expression of eGPC3: median OS: 87.403 months, p = 0.041) (Figure 3B, Table 2) Further univariate analysis revealed that there was no significant correlation between aberrant expression of CEA, CA 72-4 or CA 19-9 and overall survival (p > 0.05, respectively, Supplementary Figure S4A-C).	('CEA', 'Gene', (378, 381))	('improved', 'PosReg', (120, 128))	('GPC3', 'Gene', (204, 208))	('GPC3', 'Gene', '2719', (66, 70))	('GPC3', 'Gene', '2719', (152, 156))	('GPC3', 'Gene', '2719', (204, 208))	('high expression', 'Var', (47, 62))	('latex', 'Chemical', 'MESH:D007840', (88, 93))	('GPC3', 'Gene', (66, 70))	('CEA', 'Gene', '1048', (378, 381))	('GPC3', 'Gene', (152, 156))
7344	31100935	In multivariate analysis, high expression of tGPC3 remained formal statistical significance as a prognostic marker for poor OS in patients with GEA (p = 0.026; Table 3).	('high expression', 'Var', (26, 41))	('GPC3', 'Gene', '2719', (46, 50))	('patients', 'Species', '9606', (130, 138))	('poor OS', 'Disease', (119, 126))	('GPC3', 'Gene', (46, 50))
7348	31100935	The second validation cohort of 876 patients with GEA also revealed that patients with high GPC3 mRNA levels had significantly lower OS (low expression of tGPC3: median overall survival: 45.1 months, high expression of tGPC3: median overall survival: 26 months, p = 0.00011; Figure 3D).	('GPC3', 'Gene', (92, 96))	('GPC3', 'Gene', '2719', (156, 160))	('patients', 'Species', '9606', (36, 44))	('lower', 'NegReg', (127, 132))	('GPC3', 'Gene', (220, 224))	('patients', 'Species', '9606', (73, 81))	('GPC3', 'Gene', '2719', (92, 96))	('high', 'Var', (87, 91))	('GPC3', 'Gene', '2719', (220, 224))	('GPC3', 'Gene', (156, 160))
7359	31100935	In concordance with our current data, the authors show that positive staining for these panel markers including GPC3 was associated with poor prognosis and was an independent risk factor for disease-free survival.	('disease-free survival', 'CPA', (191, 212))	('positive staining', 'Var', (60, 77))	('GPC3', 'Gene', (112, 116))	('poor', 'CPA', (137, 141))	('GPC3', 'Gene', '2719', (112, 116))
7383	31100935	Additionally, we can show that a combined panel of serum biomarkers including exosomal GPC3 can increase the diagnostic power for the non-invasive discrimination of patient with GEA vs. healthy donors of patients with a non-malignant disease.	('patients', 'Species', '9606', (204, 212))	('patient', 'Species', '9606', (204, 211))	('donor', 'Species', '9606', (194, 199))	('patient', 'Species', '9606', (165, 172))	('non-invasive', 'MPA', (134, 146))	('GPC3', 'Gene', (87, 91))	('exosomal', 'Var', (78, 86))	('increase', 'PosReg', (96, 104))	('GPC3', 'Gene', '2719', (87, 91))
7461	27120794	Interestingly, miR-675 is considered to be a disease remission-induced miRNA in patients with eosinophilic esophagitis.	('miR-675', 'Var', (15, 22))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('eosinophilic esophagitis', 'Phenotype', 'HP:0410151', (94, 118))	('patients', 'Species', '9606', (80, 88))	('eosinophilic esophagitis', 'Disease', (94, 118))	('esophagitis', 'Phenotype', 'HP:0100633', (107, 118))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('eosinophilic esophagitis', 'Disease', 'MESH:D004802', (94, 118))	('si', 'Chemical', 'MESH:D012825', (96, 98))
7488	27120794	As shown in Figure 2A, both in EC109 and EC9706 cells, miR-675-5p was significantly inhibited in miR-675-inhibition group compared with negative control and blank control group (cells without any treatment); however, no significant difference was found between negative control and blank control group.	('miR-675-5p', 'Gene', (55, 65))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('miR-675-inhibition', 'Var', (97, 115))	('miR-675-5p', 'Gene', '102465452', (55, 65))	('EC109', 'CellLine', 'CVCL:6898', (31, 36))	('EC9706', 'CellLine', 'CVCL:E307', (41, 47))	('men', 'Species', '9606', (201, 204))	('si', 'Chemical', 'MESH:D012825', (220, 222))	('inhibited', 'NegReg', (84, 93))
7492	27120794	Similarly, colony formation assays showed that cell proliferation in both EC9706 and EC109 cells was significantly repressed by down-regulation of miR-675-5p (Figure 2E, 2F).	('miR-675-5p', 'Gene', '102465452', (147, 157))	('repressed', 'NegReg', (115, 124))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('down-regulation', 'NegReg', (128, 143))	('EC9706', 'Var', (74, 80))	('miR-675-5p', 'Gene', (147, 157))	('EC109', 'CellLine', 'CVCL:6898', (85, 90))	('EC9706', 'CellLine', 'CVCL:E307', (74, 80))	('cell proliferation', 'CPA', (47, 65))
7494	27120794	The data showed that down-regulation of miR-675-5p inhibited cell cycle by inducing G1 arrest and decreased the percentages of EC9706 and EC109 cells in S phase compared to the negative control (Figure 2C and 2D).	('inhibited', 'NegReg', (51, 60))	('G1 arrest', 'CPA', (84, 93))	('EC109', 'CellLine', 'CVCL:6898', (138, 143))	('EC9706', 'CellLine', 'CVCL:E307', (127, 133))	('miR-675-5p', 'Gene', (40, 50))	('S phase', 'CPA', (153, 160))	('down-regulation', 'NegReg', (21, 36))	('miR-675-5p', 'Gene', '102465452', (40, 50))	('cell cycle', 'CPA', (61, 71))	('decreased', 'NegReg', (98, 107))	('inducing', 'Reg', (75, 83))	('EC9706', 'Var', (127, 133))
7498	27120794	To further explore the role of miR-675-5p on tumorigenicity and tumor metastasis in vivo, miR-675-5p-inhibition EC9706 cells and negative control cells were inoculated into the left upper flank region of nude mice or into the tail veins of nude mice.	('tumor metastasis', 'Disease', 'MESH:D009362', (64, 80))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (64, 69))	('miR-675-5p', 'Gene', (31, 41))	('miR-675-5p', 'Gene', (90, 100))	('nude mice', 'Species', '10090', (204, 213))	('tumor metastasis', 'Disease', (64, 80))	('miR-675-5p', 'Gene', '102465452', (31, 41))	('miR-675-5p', 'Gene', '102465452', (90, 100))	('tumor', 'Disease', (45, 50))	('EC9706', 'Var', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('nude mice', 'Species', '10090', (240, 249))	('EC9706', 'CellLine', 'CVCL:E307', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
7515	27120794	As shown in Figure 4B, the intensity of fluorescence was reduced significantly after miR-675-5p mimic cotransfection compared with the negative control.	('miR-675-5p', 'Gene', '102465452', (85, 95))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('intensity', 'MPA', (27, 36))	('miR-675-5p', 'Gene', (85, 95))	('cotransfection', 'Var', (102, 116))	('reduced', 'NegReg', (57, 64))	('si', 'Chemical', 'MESH:D012825', (65, 67))
7518	27120794	Furthermore, western blotting analysis showed that REPS2 protein expression was greatly up-regulated in EC9706 and EC109 cells after LV-miR-675-5p-inhibition transfection compared with the negative control (Figure 4C).	('EC9706', 'Var', (104, 110))	('EC109', 'CellLine', 'CVCL:6898', (115, 120))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('REPS2', 'Gene', '9185', (51, 56))	('transfection', 'Var', (158, 170))	('REPS2', 'Gene', (51, 56))	('EC9706', 'CellLine', 'CVCL:E307', (104, 110))	('up-regulated', 'PosReg', (88, 100))	('expression', 'MPA', (65, 75))	('miR-675-5p', 'Gene', (136, 146))	('miR-675-5p', 'Gene', '102465452', (136, 146))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('protein', 'Protein', (57, 64))
7519	27120794	In addition, qRT-PCR analysis showed that REPS2 mRNA apparently increased after LV-miR-675-5p-inhibition transfection in EC9706 and EC109 cell lines (Figure 4D).	('mRNA', 'MPA', (48, 52))	('transfection', 'Var', (105, 117))	('REPS2', 'Gene', (42, 47))	('miR-675-5p', 'Gene', (83, 93))	('EC9706', 'CellLine', 'CVCL:E307', (121, 127))	('REPS2', 'Gene', '9185', (42, 47))	('miR-675-5p', 'Gene', '102465452', (83, 93))	('EC109', 'CellLine', 'CVCL:6898', (132, 137))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('increased', 'PosReg', (64, 73))
7527	27120794	Interestingly, the miR-675-5p-inhibition+si-REPS2 EC9706 cells exhibited higher cell proliferation, colony formation, migration and invasion potential and lower cell G1 arrest when compared with the miR-675-5p-inhibition+si-NC EC9706 cells, which resembled the miR-675-5p-precursor EC9706 cells (Figure 5C, 5D, 5E, 5F).	('miR-675-5p', 'Gene', '102465452', (261, 271))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('lower', 'NegReg', (155, 160))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('colony formation', 'CPA', (100, 116))	('REPS2', 'Gene', (44, 49))	('miR-675-5p', 'Gene', (261, 271))	('EC9706', 'Var', (50, 56))	('migration', 'CPA', (118, 127))	('cell proliferation', 'CPA', (80, 98))	('invasion potential', 'CPA', (132, 150))	('REPS2', 'Gene', '9185', (44, 49))	('si', 'Chemical', 'MESH:D012825', (221, 223))	('EC9706', 'CellLine', 'CVCL:E307', (282, 288))	('EC9706', 'CellLine', 'CVCL:E307', (227, 233))	('miR-675-5p', 'Gene', '102465452', (19, 29))	('miR-675-5p', 'Gene', '102465452', (199, 209))	('cell G1 arrest', 'CPA', (161, 175))	('miR-675-5p', 'Gene', (19, 29))	('miR-675-5p', 'Gene', (199, 209))	('EC9706', 'CellLine', 'CVCL:E307', (50, 56))	('higher', 'PosReg', (73, 79))
7532	27120794	Expression of RalBP1, RAC1, CDC42 MMP9, MMP2 and CyclinD1 were decreased in miR-675-5p-inhibition EC9706 and EC109 cells (Figure 6A, left and middle, lane 1).	('RalBP1', 'Gene', (14, 20))	('CDC42', 'Gene', '998', (28, 33))	('RAC1', 'Gene', '5879', (22, 26))	('EC9706', 'CellLine', 'CVCL:E307', (98, 104))	('CyclinD1', 'Gene', '595', (49, 57))	('miR-675-5p', 'Gene', '102465452', (76, 86))	('decreased', 'NegReg', (63, 72))	('EC9706', 'Var', (98, 104))	('MMP2', 'Gene', (40, 44))	('CyclinD1', 'Gene', (49, 57))	('miR-675-5p', 'Gene', (76, 86))	('Expression', 'MPA', (0, 10))	('EC109', 'CellLine', 'CVCL:6898', (109, 114))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('MMP9', 'Gene', '4318', (34, 38))	('MMP2', 'Gene', '4313', (40, 44))	('MMP9', 'Gene', (34, 38))	('RalBP1', 'Gene', '10928', (14, 20))	('CDC42', 'Gene', (28, 33))	('RAC1', 'Gene', (22, 26))
7559	27120794	More importantly, knockdown of REPS2 gene could mimic the oncogenic effect of overexpressed miR-675-5p.	('knockdown', 'Var', (18, 27))	('REPS2', 'Gene', (31, 36))	('miR-675-5p', 'Gene', (92, 102))	('REPS2', 'Gene', '9185', (31, 36))	('miR-675-5p', 'Gene', '102465452', (92, 102))
7565	27120794	These researches suggest that signals from REPS2 might suppress tumor growth and metastasis through RalBP1/RAC1/CDC42 signaling pathway.	('CDC42', 'Gene', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('RAC1', 'Gene', (107, 111))	('tumor', 'Disease', (64, 69))	('RalBP1', 'Gene', '10928', (100, 106))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('signals', 'Var', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('REPS2', 'Gene', '9185', (43, 48))	('CDC42', 'Gene', '998', (112, 117))	('RalBP1', 'Gene', (100, 106))	('REPS2', 'Gene', (43, 48))	('suppress', 'NegReg', (55, 63))	('RAC1', 'Gene', '5879', (107, 111))
7569	27120794	Consist with the previous researches, our data demonstrated that inhibition of REPS2 would activate RalBP1/RAC1/CDC42, increase MMP2/9, thus promote tumor invasion and metastasis.	('RAC1', 'Gene', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('activate', 'PosReg', (91, 99))	('RAC1', 'Gene', '5879', (107, 111))	('CDC42', 'Gene', (112, 117))	('si', 'Chemical', 'MESH:D012825', (159, 161))	('REPS2', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('promote', 'PosReg', (141, 148))	('inhibition', 'Var', (65, 75))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('CDC42', 'Gene', '998', (112, 117))	('MMP2/9', 'Gene', (128, 134))	('REPS2', 'Gene', '9185', (79, 84))	('RalBP1', 'Gene', '10928', (100, 106))	('MMP2/9', 'Gene', '4313;4318', (128, 134))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('tumor', 'Disease', (149, 154))	('increase', 'PosReg', (119, 127))	('RalBP1', 'Gene', (100, 106))
7576	27120794	Recently, miR-675 is demonstrated to activate EGF signaling pathway in breast cancer.	('activate', 'PosReg', (37, 45))	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('EGF signaling pathway', 'Pathway', (46, 67))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('miR-675', 'Var', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
7604	27120794	The pMIR-REPS2-Mut vector was built with REPS2 that had undergone site-directed mutagenesis of the miR-675-5p target site using the Stratagene Quik-Change site-directed mutagenesis kit (Stratagene, Germany).	('mutagenesis', 'Var', (80, 91))	('miR-675-5p', 'Gene', '102465452', (99, 109))	('si', 'Chemical', 'MESH:D012825', (177, 179))	('REPS2', 'Gene', (41, 46))	('REPS2', 'Gene', (9, 14))	('REPS2', 'Gene', '9185', (41, 46))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('REPS2', 'Gene', '9185', (9, 14))	('miR-675-5p', 'Gene', (99, 109))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('si', 'Chemical', 'MESH:D012825', (155, 157))
7826	26751694	Interobserver and intraobserver variability  The Az values calculated from ROC analysis were 0.723 (95%CI 0.543-0.903) for Rad1, 0.667 (95%CI 0.479-0.854) and 0.759 (95%CI 0.587-0.931) for the two evaluations of Rad2.	('Rad2', 'Gene', '2237', (212, 216))	('Rad2', 'Gene', (212, 216))	('Rad1', 'Gene', '5810', (123, 127))	('0.667', 'Var', (129, 134))	('Rad1', 'Gene', (123, 127))	('0.759', 'Var', (159, 164))
7880	23639644	Those with T1-2 and N0 lesions on EUS were considered low risk for M1 disease (n = 26), and those with T3-4 or N+ were considered high risk (n = 68).	('T1-2', 'Gene', '923;9173;292', (11, 15))	('N0 lesions', 'Var', (20, 30))	('M1 disease', 'Disease', (67, 77))	('T1-2', 'Gene', (11, 15))
7894	23639644	On multivariate analysis, poorer overall survival was associated with positive cytology (relative risk 2.7, P<.001), distal tumor location, and preoperative T stage and N stage.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('T stage', 'CPA', (157, 164))	('N stage', 'CPA', (169, 176))	('tumor', 'Disease', (124, 129))	('positive cytology', 'Var', (70, 87))	('overall', 'MPA', (33, 40))	('poorer', 'NegReg', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
7982	23639644	On multivariate analysis, positive margins, increased patient age, and nodal disease were independently associated with poorer survival.	('patient', 'Species', '9606', (54, 61))	('positive', 'Var', (26, 34))	('nodal disease', 'Disease', 'MESH:D013611', (71, 84))	('nodal disease', 'Disease', (71, 84))	('poorer', 'NegReg', (120, 126))
8041	23639644	Between 1995 and 2001, patients with potentially curable T2b, T3, or T4 gastric adenocarcinoma were included, because para-aortic nodal involvement may only occur once the subserosa is invaded.	('patients', 'Species', '9606', (23, 31))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (72, 94))	('gastric adenocarcinoma', 'Disease', (72, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('T2b', 'Var', (57, 60))	('para-aortic nodal involvement', 'Disease', (118, 147))	('para-aortic nodal involvement', 'Disease', 'MESH:D001018', (118, 147))
8150	18775019	However, celecoxib increased the risk of myocardial infarction (MI) while aspirin reduced the risk.	('myocardial infarction', 'Disease', (41, 62))	('myocardial infarction', 'Disease', 'MESH:D009203', (41, 62))	('aspirin', 'Chemical', 'MESH:D001241', (74, 81))	('MI', 'Phenotype', 'HP:0001658', (64, 66))	('myocardial infarction', 'Phenotype', 'HP:0001658', (41, 62))	('celecoxib', 'Chemical', 'MESH:D000068579', (9, 18))	('celecoxib', 'Var', (9, 18))
8158	18775019	There is evidence suggesting that both aspirin and selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) can prevent esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE).	('aspirin', 'Chemical', 'MESH:D001241', (39, 46))	('COX-2', 'Gene', '5743', (79, 84))	('esophageal adenocarcinoma', 'Disease', (118, 143))	('patients', 'Species', '9606', (153, 161))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (118, 143))	("Barrett's esophagus", 'Disease', (167, 186))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (118, 143))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (167, 186))	('cyclooxygenase-2', 'Gene', (61, 77))	('prevent', 'NegReg', (110, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('cyclooxygenase-2', 'Gene', '5743', (61, 77))	('EAC', 'Phenotype', 'HP:0011459', (145, 148))	('BE', 'Phenotype', 'HP:0100580', (188, 190))	('inhibitors', 'Var', (86, 96))	('COX-2', 'Gene', (79, 84))
8183	18775019	Both celecoxib and aspirin were presented as increasing the risk of gastrointestinal events (GIE; ulcer or gastrointestinal bleeding) by the same amount.	('GIE', 'Phenotype', 'HP:0011024', (93, 96))	('celecoxib', 'Var', (5, 14))	('gastrointestinal events', 'Disease', (68, 91))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (107, 132))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (107, 132))	('increasing', 'PosReg', (45, 55))	('ulcer', 'Disease', 'MESH:D014456', (98, 103))	('ulcer', 'Disease', (98, 103))	('gastrointestinal events', 'Phenotype', 'HP:0011024', (68, 91))	('gastrointestinal bleeding', 'Disease', (107, 132))	('celecoxib', 'Chemical', 'MESH:D000068579', (5, 14))	('aspirin', 'Chemical', 'MESH:D001241', (19, 26))
8260	18775019	Over a lifetime, 50% of men will have a heart attack, so Medicine A increases your chance of having a heart attack to 75%.	('men', 'Species', '9606', (24, 27))	('heart attack', 'Disease', (40, 52))	('heart attack', 'Phenotype', 'HP:0001658', (40, 52))	('Medicine', 'Var', (57, 65))	('heart attack', 'Phenotype', 'HP:0001658', (102, 114))
8262	18775019	Since 20% of men will have a stroke in their lifetime, Medicine A increases your lifetime chance of having a stroke to 30%.	('stroke', 'Disease', (109, 115))	('stroke', 'Disease', 'MESH:D020521', (29, 35))	('stroke', 'Phenotype', 'HP:0001297', (109, 115))	('stroke', 'Disease', 'MESH:D020521', (109, 115))	('stroke', 'Phenotype', 'HP:0001297', (29, 35))	('Medicine', 'Var', (55, 63))	('stroke', 'Disease', (29, 35))	('men', 'Species', '9606', (13, 16))
8330	19838919	Turkmen men had a higher intake of fruit, non-Alcoholic beverages, and poly-unsaturated fatty acids (PUFA), and lower intake of beta-carotene, compared to non-Turkmen men.	('men', 'Species', '9606', (4, 7))	('PUFA', 'Chemical', 'MESH:D005231', (101, 105))	('beta-carotene', 'Chemical', 'MESH:D019207', (128, 141))	('poly-unsaturated', 'Var', (71, 87))	('men', 'Species', '9606', (163, 166))	('intake', 'MPA', (25, 31))	('men', 'Species', '9606', (8, 11))	('intake', 'MPA', (118, 124))	('poly-unsaturated fatty acids', 'Chemical', 'MESH:D005231', (71, 99))	('higher', 'PosReg', (18, 24))	('lower', 'NegReg', (112, 117))	('men', 'Species', '9606', (167, 170))
8365	32432570	Moreover, QGS decreased Gas6/Axl levels, increased E-cadherin expression, decreased Snail and N-cadherin expression, and inhibited epithelial-mesenchymal transition (EMT) in EC cells.	('Snail', 'Gene', '6615', (84, 89))	('increased', 'PosReg', (41, 50))	('N-cadherin', 'Gene', '1000', (94, 104))	('decreased', 'NegReg', (14, 23))	('Axl', 'Gene', (29, 32))	('EC', 'Phenotype', 'HP:0011459', (174, 176))	('expression', 'MPA', (62, 72))	('N-cadherin', 'Gene', (94, 104))	('epithelial-mesenchymal transition', 'CPA', (131, 164))	('Gas6', 'Gene', '2621', (24, 28))	('decreased', 'NegReg', (74, 83))	('QGS', 'Var', (10, 13))	('inhibited', 'NegReg', (121, 130))	('Snail', 'Gene', (84, 89))	('Gas6', 'Gene', (24, 28))	('Axl', 'Gene', '558', (29, 32))	('E-cadherin', 'Gene', (51, 61))	('E-cadherin', 'Gene', '999', (51, 61))
8366	32432570	QGS thus suppresses EMT in EC by inhibiting Gas6/Axl binding.	('EMT', 'CPA', (20, 23))	('Gas6', 'Gene', '2621', (44, 48))	('Axl', 'Gene', '558', (49, 52))	('Gas6', 'Gene', (44, 48))	('QGS', 'Var', (0, 3))	('EC', 'Phenotype', 'HP:0011459', (27, 29))	('Axl', 'Gene', (49, 52))	('inhibiting', 'NegReg', (33, 43))	('suppresses', 'NegReg', (9, 19))
8382	32432570	Studies have shown that QGS inhibits metastasis in EC patients more effectively than other standard prescription medications.	('QGS', 'Var', (24, 27))	('inhibits', 'NegReg', (28, 36))	('patients', 'Species', '9606', (54, 62))	('metastasis', 'CPA', (37, 47))	('EC', 'Phenotype', 'HP:0011459', (51, 53))
8383	32432570	Clinical observations following the treatment of many EC patients in Henan and Hebei provinces, areas of China where EC incidence is particularly high, indicate that QGS can reduce recurrence and metastasis rates in patients with radical EC after disease eradication, prolong disease-free survival (DFS), and improve quality of life.	('quality of life', 'CPA', (317, 332))	('EC', 'Phenotype', 'HP:0011459', (54, 56))	('prolong', 'PosReg', (268, 275))	('reduce', 'NegReg', (174, 180))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (216, 224))	('recurrence', 'CPA', (181, 191))	('improve', 'PosReg', (309, 316))	('EC', 'Phenotype', 'HP:0011459', (117, 119))	('disease-free survival', 'CPA', (276, 297))	('QGS', 'Var', (166, 169))	('EC', 'Phenotype', 'HP:0011459', (238, 240))
8385	32432570	We therefore hypothesized that QGS inhibits EC cell invasion and subsequent EMT and migration by inhibiting Gas6 protein functions and the Gas6/Axl pathway.	('EC cell invasion', 'CPA', (44, 60))	('Gas6', 'Gene', '2621', (139, 143))	('Gas6', 'Gene', (108, 112))	('EC', 'Phenotype', 'HP:0011459', (44, 46))	('Gas6', 'Gene', (139, 143))	('inhibits', 'NegReg', (35, 43))	('Axl', 'Gene', '558', (144, 147))	('QGS', 'Var', (31, 34))	('Axl', 'Gene', (144, 147))	('Gas6', 'Gene', '2621', (108, 112))	('inhibiting', 'NegReg', (97, 107))
8411	32432570	Clinical observations indicate that QGS can alleviate airway obstruction, dysphagia, pain, nausea, vomiting, and other symptoms, reduce the toxicity and side effects of radiotherapy and chemotherapy, and inhibit recurrence and metastasis after surgery in EC patients.	('dysphagia', 'Disease', 'MESH:D003680', (74, 83))	('dysphagia', 'Disease', (74, 83))	('pain', 'Disease', 'MESH:D010146', (85, 89))	('nausea', 'Disease', 'MESH:D009325', (91, 97))	('obstruction', 'Disease', 'MESH:D000402', (61, 72))	('alleviate', 'PosReg', (44, 53))	('patients', 'Species', '9606', (258, 266))	('dysphagia', 'Phenotype', 'HP:0002015', (74, 83))	('metastasis', 'CPA', (227, 237))	('toxicity', 'Disease', 'MESH:D064420', (140, 148))	('inhibit', 'NegReg', (204, 211))	('vomiting', 'Disease', 'MESH:D014839', (99, 107))	('EC', 'Phenotype', 'HP:0011459', (255, 257))	('obstruction', 'Disease', (61, 72))	('pain', 'Disease', (85, 89))	('nausea', 'Phenotype', 'HP:0002018', (91, 97))	('QGS', 'Var', (36, 39))	('toxicity', 'Disease', (140, 148))	('reduce', 'NegReg', (129, 135))	('vomiting', 'Phenotype', 'HP:0002013', (99, 107))	('vomiting', 'Disease', (99, 107))	('pain', 'Phenotype', 'HP:0012531', (85, 89))	('airway obstruction', 'Phenotype', 'HP:0002781', (54, 72))	('nausea', 'Disease', (91, 97))
8413	32432570	In addition, previous research has shown that QGS increases the distribution and expression of Cx26 and Cx43 on the cell membrane, which enhances gap junction (GJ) function and inhibits EC cell invasion and migration.	('QGS', 'Var', (46, 49))	('Cx26', 'Gene', (95, 99))	('function', 'MPA', (164, 172))	('enhances', 'PosReg', (137, 145))	('increases', 'PosReg', (50, 59))	('inhibits', 'NegReg', (177, 185))	('Cx43', 'Gene', (104, 108))	('Cx43', 'Gene', '2697', (104, 108))	('Cx26', 'Gene', '2706', (95, 99))	('EC', 'Phenotype', 'HP:0011459', (186, 188))	('distribution', 'MPA', (64, 76))	('expression', 'MPA', (81, 91))
8421	32432570	Here, we found that QGS significantly inhibits Gas6 and Axl protein expression and prevents them from binding, thereby reducing Gas6/Axl complex formation.	('Axl', 'Gene', (56, 59))	('binding', 'Interaction', (102, 109))	('Gas6', 'Gene', (128, 132))	('Gas6', 'Gene', '2621', (47, 51))	('inhibits', 'NegReg', (38, 46))	('Axl', 'Gene', (133, 136))	('QGS', 'Var', (20, 23))	('Axl', 'Gene', '558', (56, 59))	('prevents', 'NegReg', (83, 91))	('Gas6', 'Gene', (47, 51))	('Gas6', 'Gene', '2621', (128, 132))	('Axl', 'Gene', '558', (133, 136))	('reducing', 'NegReg', (119, 127))
8425	32432570	These changes occurred after QGS inhibited Gas6/Axl complex expression, and wound healing and transwell experiments showed that QGS also suppressed ESCC cell invasion and migration.	('suppressed', 'NegReg', (137, 147))	('Gas6', 'Gene', '2621', (43, 47))	('Axl', 'Gene', '558', (48, 51))	('Gas6', 'Gene', (43, 47))	('migration', 'CPA', (171, 180))	('QGS', 'Var', (128, 131))	('Axl', 'Gene', (48, 51))	('inhibited', 'NegReg', (33, 42))	('ESCC cell invasion', 'CPA', (148, 166))
8426	32432570	In summary, we found that QGS inhibits formation of the Gas6/Axl complex and suppresses EMT, which in turn inhibits EC cell mobility.	('Gas6', 'Gene', (56, 60))	('EC', 'Phenotype', 'HP:0011459', (116, 118))	('suppresses', 'NegReg', (77, 87))	('QGS', 'Var', (26, 29))	('Axl', 'Gene', (61, 64))	('inhibits', 'NegReg', (107, 115))	('EMT', 'CPA', (88, 91))	('Axl', 'Gene', '558', (61, 64))	('EC cell mobility', 'CPA', (116, 132))	('Gas6', 'Gene', '2621', (56, 60))	('inhibits', 'NegReg', (30, 38))	('formation', 'MPA', (39, 48))
8433	32432570	Tissues were then incubated with anti-GAS6 primary antibody (67202, Cell Signaling Technology (CST)) and secondary antibody (G23301, Servicebio), nuclei were counterstained with DAPI, and tissues were mounted on slides and dehydrated.	('DAPI', 'Chemical', 'MESH:C007293', (178, 182))	('G23301', 'Var', (125, 131))	('GAS6', 'Gene', '2621', (38, 42))	('GAS6', 'Gene', (38, 42))	('67202', 'Var', (61, 66))
8439	32432570	After blocking with 10% BSA serum, cells were incubated with the following primary antibodies at 4 C overnight: anti-GAS6 (67020, CST), anti-mouseAXL (ab89224, Abcam), anti-E-cadherin (ET1607-75, Hangzhou HuaAn Biotechnology Co., Ltd), anti-N-Cadherin (ET1607-37, Hangzhou HuaAn Biotechnology Co., Ltd), and anti-Snail1 (ER1706-22, Hangzhou HuaAn Biotechnology Co., Ltd).	('ER1706-22', 'Var', (321, 330))	('E-cadherin', 'Gene', (173, 183))	('E-cadherin', 'Gene', '999', (173, 183))	('AXL', 'Gene', (146, 149))	('N-Cadherin', 'Gene', (241, 251))	('ER1706-22', 'CellLine', 'CVCL:0H89', (321, 330))	('N-Cadherin', 'Gene', '1000', (241, 251))	('ET1607-37', 'Var', (253, 262))	('AXL', 'Gene', '558', (146, 149))	('GAS6', 'Gene', '2621', (117, 121))	('GAS6', 'Gene', (117, 121))	('Snail1', 'Gene', '6615', (313, 319))	('Snail1', 'Gene', (313, 319))
8445	32432570	The membranes were then incubated the with the following primary antibodies at 4 C overnight: anti-GAS6 (67202, CST), anti-rabbit AXL (8661, CST), anti-E-cadherin (ET1607-75, Hangzhou HuaAn Biotechnology Co., Ltd), anti-N-cadherin (ET1607-37, Hangzhou HuaAn Biotechnology Co., Ltd), anti-Snail1 (ER1706-22, Hangzhou HuaAn Biotechnology Co., Ltd), and anti-beta-ACT (AC026, Abclonal Technology).	('E-cadherin', 'Gene', (152, 162))	('E-cadherin', 'Gene', '999', (152, 162))	('ER1706-22', 'CellLine', 'CVCL:0H89', (296, 305))	('Snail1', 'Gene', (288, 294))	('N-cadherin', 'Gene', (220, 230))	('GAS6', 'Gene', (99, 103))	('AXL', 'Gene', '558', (130, 133))	('ER1706-22', 'Var', (296, 305))	('Snail1', 'Gene', '6615', (288, 294))	('GAS6', 'Gene', '2621', (99, 103))	('ET1607-37', 'Var', (232, 241))	('N-cadherin', 'Gene', '1000', (220, 230))	('AXL', 'Gene', (130, 133))	('anti-beta-ACT', 'Var', (351, 364))
8459	32311927	High RDW was associated with larger tumor size (P < .01), worse differentiation (P = .02), deeper invasion (P < .01), earlier lymph node metastasis (P < .01), more advanced clinical stage (P < .01) and higher carcinoembryonic antigen level (P < .01) when compared to low RDW.	('earlier lymph node metastasis', 'CPA', (118, 147))	('High RDW', 'Var', (0, 8))	('carcinoembryonic', 'Disease', (209, 225))	('larger', 'PosReg', (29, 35))	('carcinoembryonic', 'Disease', 'None', (209, 225))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('higher', 'PosReg', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('worse differentiation', 'CPA', (58, 79))	('higher carcinoembryonic antigen level', 'Phenotype', 'HP:0031029', (202, 239))	('deeper invasion', 'CPA', (91, 106))	('tumor', 'Disease', (36, 41))	('more', 'PosReg', (159, 163))
8460	32311927	High RDW was significantly associated with worse prognosis of GI cancers, which could be regarded as a prognostic biomarker for GI cancers.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('GI cancer', 'Phenotype', 'HP:0007378', (62, 71))	('High RDW', 'Var', (0, 8))	('GI cancer', 'Phenotype', 'HP:0007378', (128, 137))	('GI cancers', 'Disease', 'MESH:D009369', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('GI cancers', 'Disease', (62, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('GI cancers', 'Disease', (128, 138))	('GI cancers', 'Disease', 'MESH:D009369', (62, 72))
8481	32311927	As shown in Figure 2, a fixed-effect model was used (I2 = 43%), and high RDW was associated with shorter OS compared to low RDW in GI cancers (HR = 1.75, 95%CI = 1.57-1.94, P < .01).	('GI cancers', 'Disease', 'MESH:D009369', (131, 141))	('GI cancer', 'Phenotype', 'HP:0007378', (131, 140))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('high RDW', 'Var', (68, 76))	('shorter', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('GI cancers', 'Disease', (131, 141))
8483	32311927	As listed in Table 2, high RDW was significantly related to worse OS compared to low RDW in GI cancers (P < .05).	('GI cancers', 'Disease', (92, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('high RDW', 'Var', (22, 30))	('GI cancer', 'Phenotype', 'HP:0007378', (92, 101))	('GI cancers', 'Disease', 'MESH:D009369', (92, 102))	('worse OS', 'Disease', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
8485	32311927	However, compared to low RDW, high RDW was significantly associated with larger tumor size (P < .01), worse differentiation (P = .02), deeper invasion (P < .01), earlier lymph node metastasis (P < .01), more advanced clinical stage (P < .01) and higher carcinoembryonic antigen level (P < .01).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('carcinoembryonic', 'Disease', 'None', (253, 269))	('larger', 'PosReg', (73, 79))	('higher', 'PosReg', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('higher carcinoembryonic antigen level', 'Phenotype', 'HP:0031029', (246, 283))	('tumor', 'Disease', (80, 85))	('high RDW', 'Var', (30, 38))	('worse differentiation', 'CPA', (102, 123))	('earlier lymph node metastasis', 'CPA', (162, 191))	('deeper invasion', 'CPA', (135, 150))	('carcinoembryonic', 'Disease', (253, 269))
8487	32311927	In this study, our findings showed high RDW might predict worse OS and DFS in GI cancers.	('worse OS', 'Disease', (58, 66))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('RDW', 'Var', (40, 43))	('GI cancer', 'Phenotype', 'HP:0007378', (78, 87))	('high RDW', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('DFS in GI cancers', 'Disease', 'MESH:D009369', (71, 88))	('DFS in GI cancers', 'Disease', (71, 88))
8488	32311927	Besides, high RDW was related to larger tumor size, worse differentiation, deeper invasion, earlier lymph node metastasis, more advanced clinical stage and higher carcinoembryonic antigen level in GI cancers.	('earlier lymph node metastasis', 'CPA', (92, 121))	('higher', 'PosReg', (156, 162))	('high RDW', 'Var', (9, 17))	('GI cancers', 'Disease', (197, 207))	('higher carcinoembryonic antigen level', 'Phenotype', 'HP:0031029', (156, 193))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('GI cancer', 'Phenotype', 'HP:0007378', (197, 206))	('carcinoembryonic', 'Disease', (163, 179))	('GI cancers', 'Disease', 'MESH:D009369', (197, 207))	('carcinoembryonic', 'Disease', 'None', (163, 179))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('deeper invasion', 'CPA', (75, 90))
8489	32311927	All these findings showed RDW could serve as a promising biomarker to predict the prognosis of GI cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('GI cancers', 'Disease', (95, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('RDW', 'Var', (26, 29))	('GI cancers', 'Disease', 'MESH:D009369', (95, 105))	('GI cancer', 'Phenotype', 'HP:0007378', (95, 104))
8490	32311927	Our results, based on the subgroup analysis, showed RDW could predict the prognosis of patients with esophageal cancer.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (87, 95))	('predict', 'Reg', (62, 69))	('RDW', 'Var', (52, 55))
8492	32311927	Besides, we firstly observed the association between RDW and prognosis in gastric cancer, colorectal cancer, hepatocellular carcinoma and hilar cholangiocarcinoma in the current study.	('cholangiocarcinoma', 'Disease', (144, 162))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (144, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (144, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('gastric cancer', 'Disease', (74, 88))	('RDW', 'Var', (53, 56))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (109, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('hepatocellular carcinoma', 'Disease', (109, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (109, 133))	('colorectal cancer', 'Disease', (90, 107))	('association', 'Interaction', (33, 44))
8498	32311927	What's more, RDW is believed to regulate the cancer progression by affecting the glycolytic process of tumor cells, and low RDW is found to be associated with increased incidence of diabetes mellitus.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('associated', 'Reg', (143, 153))	('affecting', 'Reg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (103, 108))	('diabetes mellitus', 'Disease', 'MESH:D003920', (182, 199))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (182, 199))	('cancer', 'Disease', (45, 51))	('diabetes mellitus', 'Disease', (182, 199))	('low RDW', 'Var', (120, 127))
8499	32311927	Therefore, high RDW may be a surrogate indicator of improved glucose metabolism, which is of great importance for the survival of patients with GI cancers.	('glucose metabolism', 'Disease', 'MESH:D044882', (61, 79))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('glucose metabolism', 'Disease', (61, 79))	('improved', 'PosReg', (52, 60))	('patients', 'Species', '9606', (130, 138))	('GI cancers', 'Disease', (144, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('high RDW', 'Var', (11, 19))	('GI cancer', 'Phenotype', 'HP:0007378', (144, 153))	('GI cancers', 'Disease', 'MESH:D009369', (144, 154))
8505	32311927	High RDW was significantly associated with worse prognosis when compared to low RDW in GI cancers, which could be regarded as a prognostic biomarker for GI cancers.	('GI cancers', 'Disease', (153, 163))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('High RDW', 'Var', (0, 8))	('GI cancers', 'Disease', 'MESH:D009369', (87, 97))	('GI cancer', 'Phenotype', 'HP:0007378', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('GI cancers', 'Disease', 'MESH:D009369', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('GI cancer', 'Phenotype', 'HP:0007378', (87, 96))	('GI cancers', 'Disease', (87, 97))
8605	30233251	Tumor occurrence in the antrum of the stomach was slightly higher in familial patients (19%), compared to sporadic patients (15%) with gastric cancer.	('gastric cancer', 'Disease', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('patients', 'Species', '9606', (115, 123))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('patients', 'Species', '9606', (78, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('familial', 'Var', (69, 77))	('higher', 'PosReg', (59, 65))	('Tumor', 'CPA', (0, 5))
8655	30087707	Knockdown of C1GalT1 inhibits radioresistance of human esophageal cancer cells through modifying beta1-integrin glycosylation Radiotherapy has played a limited role for the treatment of human esophageal cancer owing to the risk of tumor radioresistance.	('C1GalT1', 'Gene', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (55, 72))	('beta1-integrin', 'Gene', '3688', (97, 111))	('C1GalT1', 'Gene', '56913', (13, 20))	('inhibits', 'NegReg', (21, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (192, 209))	('human', 'Species', '9606', (49, 54))	('tumor', 'Disease', (231, 236))	('esophageal cancer', 'Disease', (192, 209))	('modifying', 'Reg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('radioresistance', 'CPA', (30, 45))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('beta1-integrin', 'Gene', (97, 111))	('si', 'Chemical', 'MESH:D012825', (244, 246))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('Knockdown', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('human', 'Species', '9606', (186, 191))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))
8659	30087707	Upon irradiation, we found that esophageal cancer cells with high levels of C1GalT1 could tolerate cell death and had increased resistance to radiotherapy.	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('C1GalT1', 'Gene', '56913', (76, 83))	('increased', 'PosReg', (118, 127))	('tolerate', 'CPA', (90, 98))	('resistance to radiotherapy', 'CPA', (128, 154))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('high levels', 'Var', (61, 72))	('esophageal cancer', 'Disease', (32, 49))	('C1GalT1', 'Gene', (76, 83))
8661	30087707	C1GalT1 knockdown increased the radiosensitivity of esophageal cancer cells, and attenuated irradiation-enhanced migration and invasion.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('increased', 'PosReg', (18, 27))	('C1GalT1', 'Gene', (0, 7))	('knockdown', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('increased the radiosensitivity of esophageal cancer', 'Phenotype', 'HP:0010997', (18, 69))	('radiosensitivity', 'MPA', (32, 48))	('attenuated', 'NegReg', (81, 91))	('C1GalT1', 'Gene', '56913', (0, 7))
8672	30087707	Aberrant glycosylation is often observed as a hallmark of cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Aberrant', 'Var', (0, 8))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('hallmark of cancer', 'Disease', (46, 64))	('hallmark of cancer', 'Disease', 'MESH:D009369', (46, 64))	('glycosylation', 'MPA', (9, 22))
8675	30087707	Especially, more and more studies have shown that aberrant glycosylation may be linked to treatment failure in many patients after radiotherapy.	('linked', 'Reg', (80, 86))	('patients', 'Species', '9606', (116, 124))	('treatment failure', 'Disease', (90, 107))	('glycosylation', 'MPA', (59, 72))	('treatment failure', 'Disease', 'MESH:D016609', (90, 107))	('aberrant', 'Var', (50, 58))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (50, 72))
8677	30087707	Therefore, identification of differentially expressed glycosyltransferases contributing to aberrant glycosylation is critical in overcoming radioresistance.	('glycosylation', 'MPA', (100, 113))	('glycosyltransferases', 'Enzyme', (54, 74))	('si', 'Chemical', 'MESH:D012825', (147, 149))	('aberrant', 'Var', (91, 99))	('contributing', 'Reg', (75, 87))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (91, 113))
8680	30087707	The results showed that inhibition of C1GalT1 may sensitize esophageal cancer cells to radiation.	('C1GalT1', 'Gene', '56913', (38, 45))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('sensitize', 'Reg', (50, 59))	('esophageal cancer', 'Disease', (60, 77))	('inhibition', 'Var', (24, 34))	('C1GalT1', 'Gene', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
8694	30087707	The siRNA sequences used were: si-1, 5'-CCAGCCUAAUGUUCUUCAUTT-3'; si-2, 5'-GGGAGAAGAUUUAAGCCUUTT-3'; si-3, 5'-GCAGAUUCUAGCCAACAUATT-3'; and negative control, 5'-UUCUCCGAACGU GUCACGUTT-3'.	('si', 'Chemical', 'MESH:D012825', (101, 103))	('si-3', 'Var', (101, 105))	('si-1', 'Var', (31, 35))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('si', 'Chemical', 'MESH:D012825', (4, 6))
8731	30087707	Kaplan-Meier curves of overall survival revealed that esophageal cancer patients with high expression of C1GalT1 had a poorer prognosis than those with low C1GalT1 expression (Fig.	('C1GalT1', 'Gene', (105, 112))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('si', 'Chemical', 'MESH:D012825', (170, 172))	('C1GalT1', 'Gene', '56913', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('C1GalT1', 'Gene', '56913', (105, 112))	('esophageal cancer', 'Disease', (54, 71))	('high expression', 'Var', (86, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('C1GalT1', 'Gene', (156, 163))	('patients', 'Species', '9606', (72, 80))
8740	30087707	Taken together, these results suggest that esophageal cancer cells with high levels of C1GalT1 could tolerate cell death and has enhanced resistance to radiotherapy.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('enhanced', 'PosReg', (129, 137))	('C1GalT1', 'Gene', '56913', (87, 94))	('high levels', 'Var', (72, 83))	('resistance to radiotherapy', 'CPA', (138, 164))	('tolerate', 'CPA', (101, 109))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('C1GalT1', 'Gene', (87, 94))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
8753	30087707	The qPCR and Western blot analyses revealed that the knockdown of endogenous C1GalT1 by si-1, 2, and 3 resulted in the reduction of C1GalT1 expression at both the mRNA and protein levels (Fig.	('C1GalT1', 'Gene', (77, 84))	('si', 'Chemical', 'MESH:D012825', (146, 148))	('expression', 'MPA', (140, 150))	('C1GalT1', 'Gene', '56913', (132, 139))	('C1GalT1', 'Gene', '56913', (77, 84))	('N', 'Chemical', 'MESH:D009584', (165, 166))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('si-1', 'Var', (88, 92))	('C1GalT1', 'Gene', (132, 139))	('reduction', 'NegReg', (119, 128))
8756	30087707	The percentages of apoptotic cells exposed to 4 Gy irradiation for each group were as follows: Eca109-NC: 4.58 +- 1.03%, Eca109-si: 6.19 +- 0.42%, Eca109-NC + IR: 9.17+- 0.55%, and Eca109-si + IR: 20.24+- 1.53%.	('Eca109-NC + IR', 'Var', (147, 161))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('Eca109-si + IR', 'Var', (181, 195))	('Eca109-si', 'Var', (121, 130))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('si', 'Chemical', 'MESH:D012825', (188, 190))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('Eca109-NC', 'Var', (95, 104))	('apoptotic cells', 'CPA', (19, 34))
8763	30087707	In addition, the clones formed by Eca109-si cells had fewer cells than clones formed by Eca109-NC cells, implying slower cell division.	('N', 'Chemical', 'MESH:D009584', (95, 96))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('fewer', 'NegReg', (54, 59))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('slower', 'NegReg', (114, 120))	('Eca109-si', 'Var', (34, 43))	('cells', 'CPA', (60, 65))	('cell division', 'CPA', (121, 134))
8769	30087707	Matrigel invasion assay showed that Eca109-si cells also displayed a significantly lower transmembrane invasion activity as compared to Eca109-NC cells (Fig.	('si', 'Chemical', 'MESH:D012825', (43, 45))	('lower', 'NegReg', (83, 88))	('Eca109-si', 'Var', (36, 45))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('transmembrane invasion activity', 'CPA', (89, 120))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('si', 'Chemical', 'MESH:D012825', (69, 71))
8770	30087707	These results suggest that knockdown of C1GalT1 could block irradiation-enhanced invasion in esophageal cancer cells.	('knockdown', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('C1GalT1', 'Gene', '56913', (40, 47))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('invasion in', 'CPA', (81, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('block', 'NegReg', (54, 59))	('C1GalT1', 'Gene', (40, 47))
8772	30087707	6A, knockdown of C1GalT1 suppressed Jacalin binding to cell surfaces of Eca109 cells.	('C1GalT1', 'Gene', (17, 24))	('suppressed', 'NegReg', (25, 35))	('Jacalin', 'Protein', (36, 43))	('C1GalT1', 'Gene', '56913', (17, 24))	('knockdown', 'Var', (4, 13))
8776	30087707	6C, knockdown of C1GalT1 reduced Jacalin binding to beta1-integrin in Eca109 cells.	('reduced', 'NegReg', (25, 32))	('beta1-integrin', 'Gene', '3688', (52, 66))	('C1GalT1', 'Gene', (17, 24))	('binding', 'Interaction', (41, 48))	('beta1-integrin', 'Gene', (52, 66))	('Jacalin', 'Protein', (33, 40))	('C1GalT1', 'Gene', '56913', (17, 24))	('knockdown', 'Var', (4, 13))
8781	30087707	7A, knockdown of C1GalT1 in Eca109 cells resulted in significantly decreased focal adhesion kinase (FAK) phosphorylation (Tyr397).	('si', 'Chemical', 'MESH:D012825', (87, 89))	('focal adhesion kinase', 'Gene', (77, 98))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('C1GalT1', 'Gene', (17, 24))	('Tyr397', 'Chemical', '-', (122, 128))	('C1GalT1', 'Gene', '56913', (17, 24))	('focal adhesion kinase', 'Gene', '5747', (77, 98))	('FAK', 'Gene', (100, 103))	('FAK', 'Gene', '5747', (100, 103))	('decreased', 'NegReg', (67, 76))	('knockdown', 'Var', (4, 13))
8783	30087707	FAK phosphorylation was inhibited by pre-treatment with the P4C10 in Eca109 cells (Fig.	('FAK', 'Gene', (0, 3))	('P4C10', 'Var', (60, 65))	('FAK', 'Gene', '5747', (0, 3))	('inhibited', 'NegReg', (24, 33))
8784	30087707	Signaling inhibition by FAK inhibitor was also confirmed, as shown by the decreased expression of p-FAK (Tyr397) and p-Akt (Ser473) (Fig.	('si', 'Chemical', 'MESH:D012825', (90, 92))	('FAK', 'Gene', '5747', (100, 103))	('Ser473', 'Var', (124, 130))	('Ser473', 'Chemical', '-', (124, 130))	('p-Akt', 'Protein', (117, 122))	('FAK', 'Gene', (24, 27))	('decreased', 'NegReg', (74, 83))	('FAK', 'Gene', (100, 103))	('expression', 'MPA', (84, 94))	('Tyr397', 'Chemical', '-', (105, 111))	('FAK', 'Gene', '5747', (24, 27))
8785	30087707	In addition, the apoptosis induced by X-ray irradiation was considerably enhanced by the pretreatment of P4C10 or FAK inhibitor in Eca109 cells (Fig.7D).	('FAK', 'Gene', (114, 117))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('apoptosis', 'CPA', (17, 26))	('enhanced', 'PosReg', (73, 81))	('FAK', 'Gene', '5747', (114, 117))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('P4C10', 'Var', (105, 110))
8789	30087707	Radiation also induced the upregulation of C1GalT1 and knockdown of C1GalT1 significantly enhanced the radiosensitivity of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('knockdown', 'Var', (55, 64))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('C1GalT1', 'Gene', (68, 75))	('C1GalT1', 'Gene', (43, 50))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('enhanced', 'PosReg', (90, 98))	('upregulation', 'PosReg', (27, 39))	('cancer', 'Disease', (123, 129))	('C1GalT1', 'Gene', '56913', (43, 50))	('C1GalT1', 'Gene', '56913', (68, 75))
8802	30087707	Hence, inhibition of core 1 O-glycans' formation, siRNA-mediated knockdown of C1GalT1 increased the radiosensitivity of esophageal cancer cells.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('increased the radiosensitivity of esophageal cancer', 'Phenotype', 'HP:0010997', (86, 137))	('C1GalT1', 'Gene', (78, 85))	('radiosensitivity', 'CPA', (100, 116))	('increased', 'PosReg', (86, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('C1GalT1', 'Gene', '56913', (78, 85))	('1 O-glycans', 'Chemical', '-', (26, 37))	('knockdown', 'Var', (65, 74))	('esophageal cancer', 'Disease', (120, 137))	('inhibition', 'NegReg', (7, 17))	('si', 'Chemical', 'MESH:D012825', (108, 110))
8811	30087707	Previous study indicated that inhibition of N-acetylglucosaminyltransferase V enhanced sensitivity of radiotherapy in prostate cancer by reduction of cell cycle G2-M arrest.	('prostate cancer', 'Disease', (118, 133))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('N-acetylglucosaminyltransferase V', 'Gene', '4249', (44, 77))	('inhibition', 'Var', (30, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (118, 133))	('reduction', 'NegReg', (137, 146))	('sensitivity', 'MPA', (87, 98))	('arrest', 'Disease', 'MESH:D006323', (166, 172))	('N-acetylglucosaminyltransferase V', 'Gene', (44, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('arrest', 'Disease', (166, 172))	('enhanced', 'PosReg', (78, 86))
8813	30087707	Therefore, changes in cell cycle might be a factor underlying radioresistance after C1GalT1 knockdown.	('knockdown', 'Var', (92, 101))	('radioresistance', 'CPA', (62, 77))	('C1GalT1', 'Gene', '56913', (84, 91))	('changes', 'Reg', (11, 18))	('cell cycle', 'CPA', (22, 32))	('C1GalT1', 'Gene', (84, 91))	('si', 'Chemical', 'MESH:D012825', (69, 71))
8821	30087707	Furthermore, the phosphorylation level of FAK was inhibited in C1GalT1 knockdown cells.	('C1GalT1', 'Gene', '56913', (63, 70))	('FAK', 'Gene', '5747', (42, 45))	('knockdown', 'Var', (71, 80))	('phosphorylation level', 'MPA', (17, 38))	('C1GalT1', 'Gene', (63, 70))	('FAK', 'Gene', (42, 45))	('inhibited', 'NegReg', (50, 59))
8825	30087707	reported that RNF2 gene knockdown could reverse radioresistance in esophageal cancer ECa109 cells.	('ECa109', 'CellLine', 'CVCL:6898', (85, 91))	('esophageal cancer', 'Disease', (67, 84))	('RNF2', 'Gene', (14, 18))	('radioresistance', 'CPA', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('knockdown', 'Var', (24, 33))	('RNF2', 'Gene', '6045', (14, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('si', 'Chemical', 'MESH:D012825', (55, 57))
8831	30087707	It is well known that the mutation or loss of expression of Cosmc mediated aberrant O-glycosylation and promoted oncogenic properties in several cancers.	('cancers', 'Disease', (145, 152))	('loss of', 'NegReg', (38, 45))	('promoted', 'PosReg', (104, 112))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('mutation', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('O-glycosylation', 'MPA', (84, 99))	('Cosmc', 'Gene', '29071', (60, 65))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('oncogenic properties', 'CPA', (113, 133))	('expression', 'MPA', (46, 56))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('Cosmc', 'Gene', (60, 65))
8924	29805549	Patients that underwent CECT-CNFV exhibited reduced plasma concentrations of FGFR and VRGFR, both of which reached a minimum at 16 h post-treatment compared with the plasma concentrations prior to diagnosis (Fig.	('FGF', 'Gene', (77, 80))	('FGF', 'Gene', '2247', (77, 80))	('plasma concentrations', 'MPA', (52, 73))	('Patients', 'Species', '9606', (0, 8))	('CECT-CNFV', 'Var', (24, 33))	('reduced', 'NegReg', (44, 51))	('CECT-CNFV', 'Chemical', '-', (24, 33))	('VRGFR', 'Gene', (86, 91))	('reduced plasma concentrations', 'Phenotype', 'HP:0020171', (44, 73))
8964	29719615	The major risk factors associated with ESCC include tobacco, alcohol, red meat, hot drinks, poor oral hygiene, ingestion of mycotoxins, salted food, smoked foods, and deficiency of essential micronutrients such as vitamin A and zinc, genetics and conditions like Plummer-Vinson/Patterson-Kelly syndrome.	('ESCC', 'Disease', (39, 43))	('poor oral', 'Phenotype', 'HP:0000160', (92, 101))	('Kelly syndrome', 'Disease', (288, 302))	('alcohol', 'Chemical', 'MESH:D000438', (61, 68))	('salted food', 'Phenotype', 'HP:0030083', (136, 147))	('Kelly syndrome', 'Disease', 'MESH:C567101', (288, 302))	('hot drinks', 'Phenotype', 'HP:0031217', (80, 90))	('tobacco', 'Species', '4097', (52, 59))	('vitamin A', 'Chemical', 'MESH:D014801', (214, 223))	('deficiency', 'Var', (167, 177))
8976	29719615	We used TE8 (SYK negative) and TE11 (SYK positive) lines for functional studies using siRNA based silencing of SYK.	('TE11', 'Chemical', '-', (31, 35))	('SYK', 'Gene', (111, 114))	('silencing', 'Var', (98, 107))
8979	29719615	SYK has the ability to activate PI3K by using adaptor proteins like CBL, GRB2 or CD19.	('CBL', 'Gene', '867', (68, 71))	('GRB2', 'Gene', '2885', (73, 77))	('CD19', 'Gene', (81, 85))	('PI3K', 'Var', (32, 36))	('CD19', 'Gene', '930', (81, 85))	('GRB2', 'Gene', (73, 77))	('CBL', 'Gene', (68, 71))
8980	29719615	Overall, SYK regulates anti-apoptotic mammalian target of rapamycin (mTOR), NFkappaB, and STAT3 pathways.	('NFkappaB', 'Gene', '4790', (76, 84))	('STAT3', 'Gene', '6774', (90, 95))	('mTOR', 'Gene', (69, 73))	('STAT3', 'Gene', (90, 95))	('mammalian target of rapamycin', 'Gene', '2475', (38, 67))	('mammalian target of rapamycin', 'Gene', (38, 67))	('regulates', 'Reg', (13, 22))	('SYK', 'Var', (9, 12))	('NFkappaB', 'Gene', (76, 84))	('mTOR', 'Gene', '2475', (69, 73))
8983	29719615	Inhibition of SYK has shown promising results in Hodgkin lymphoma and leukemia.	('SYK', 'Protein', (14, 17))	('lymphoma', 'Phenotype', 'HP:0002665', (57, 65))	('Hodgkin lymphoma', 'Disease', (49, 65))	('leukemia', 'Disease', (70, 78))	('Inhibition', 'Var', (0, 10))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (49, 65))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (49, 65))
8992	29719615	SYK inhibitors including fostamatinib and BAY61-3606 have been reported to reduce growth of B-ALL in vitro.	('fostamatinib', 'Chemical', 'MESH:C523665', (25, 37))	('reduce', 'NegReg', (75, 81))	('BAY61-3606', 'Chemical', 'MESH:C477642', (42, 52))	('BAY61-3606', 'Var', (42, 52))	('growth of B-ALL', 'CPA', (82, 97))	('reduce growth', 'Phenotype', 'HP:0001510', (75, 88))
8996	29719615	The ratio of phosphorylated SYK vs SYK was found to be positively associated with paclitaxel- resistance in ovarian cancer cells in vitro.	('ovarian cancer', 'Disease', (108, 122))	('associated', 'Reg', (66, 76))	('phosphorylated', 'Var', (13, 27))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))	('paclitaxel', 'Chemical', 'MESH:D017239', (82, 92))	('paclitaxel- resistance', 'MPA', (82, 104))
9002	29719615	siRNA based knockdown of SYK significantly decreased (p<0.002) invasion/migration capability of TE11 cells (Figure 4A, 4B).	('knockdown', 'Var', (12, 21))	('TE11', 'Chemical', '-', (96, 100))	('SYK', 'Gene', (25, 28))	('decreased', 'NegReg', (43, 52))	('invasion/migration capability of TE11 cells', 'CPA', (63, 106))
9005	29719615	Inhibition of SYK significantly reduced proliferation of TE11 cells.	('SYK', 'Protein', (14, 17))	('TE11', 'Chemical', '-', (57, 61))	('reduced', 'NegReg', (32, 39))	('Inhibition', 'Var', (0, 10))	('proliferation', 'CPA', (40, 53))
9017	29719615	Genes with activating mutations that are recurrent among ESCC tumors could be potentially targeted for therapeutic intervention.	('ESCC tumors', 'Disease', 'MESH:D004938', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('activating', 'PosReg', (11, 21))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (22, 31))	('ESCC tumors', 'Disease', (57, 68))
9019	29719615	Functional studies in esophageal cancer cell line showed siRNA mediated knock down of SYK inhibited proliferation, invasion/migration capability of cells.	('knock down', 'Var', (72, 82))	('esophageal cancer', 'Disease', (22, 39))	('proliferation', 'CPA', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('invasion/migration capability of cells', 'CPA', (115, 153))	('SYK', 'Gene', (86, 89))	('inhibited', 'NegReg', (90, 99))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))
9037	29719615	We performed siRNA-based knockdown of SYK in TE11 and TE8 cell lines.	('SYK', 'Gene', (38, 41))	('TE11', 'Chemical', '-', (45, 49))	('knockdown', 'Var', (25, 34))
9054	29719615	The characteristics of these mice combine the features of the NOD/ShiLtJ background, the severe combined immune deficiency mutation (SCID) and IL2 receptor gamma chain deficiency that results in lack of mature T, B or functional NK cells, and are deficient in cytokine signaling in NSG mice leading to better engraftment of cells of interest.	('lack', 'NegReg', (195, 199))	('immune deficiency', 'Phenotype', 'HP:0002721', (105, 122))	('mutation', 'Var', (123, 131))	('SCID', 'Disease', (133, 137))	('mice', 'Species', '10090', (29, 33))	('IL2', 'Gene', '16183', (143, 146))	('immune deficiency', 'Disease', (105, 122))	('combined immune deficiency', 'Phenotype', 'HP:0005387', (96, 122))	('severe combined immune deficiency', 'Phenotype', 'HP:0004430', (89, 122))	('NOD', 'Gene', '1822', (62, 65))	('deficient in cytokine signaling', 'Phenotype', 'HP:0031407', (247, 278))	('cytokine signaling', 'MPA', (260, 278))	('NOD', 'Gene', (62, 65))	('deficient', 'NegReg', (247, 256))	('better', 'PosReg', (302, 308))	('gamma chain deficiency', 'Disease', (156, 178))	('gamma chain deficiency', 'Disease', 'MESH:D006362', (156, 178))	('SCID', 'Disease', 'MESH:D053632', (133, 137))	('immune deficiency', 'Disease', 'MESH:D007153', (105, 122))	('B or', 'CPA', (213, 217))	('mice', 'Species', '10090', (286, 290))	('IL2', 'Gene', (143, 146))
9232	25415190	Role of Proton Pump Inhibitor on Esophageal Carcinogenesis and Pancreatic Acinar Cell Metaplasia Development: An Experimental In Vivo Study Chronic gastro-duodenal reflux in the esophagus is a major risk for intestinal metaplasia and Barrett's adenocarcinoma.	('Pancreatic Acinar Cell Metaplasia', 'Disease', (63, 96))	('Esophageal Carcinogenesis', 'Disease', 'MESH:D063646', (33, 58))	('Pancreatic Acinar Cell Metaplasia', 'Disease', 'MESH:D010190', (63, 96))	('Esophageal Carcinogenesis', 'Disease', (33, 58))	('Chronic gastro-duodenal', 'Var', (140, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	("Barrett's adenocarcinoma", 'Disease', 'MESH:D001471', (234, 258))	('duodenal reflux', 'Phenotype', 'HP:0002020', (155, 170))	('Proton Pump', 'Gene', '24216', (8, 19))	('intestinal metaplasia', 'Disease', (208, 229))	("Barrett's adenocarcinoma", 'Disease', (234, 258))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (208, 229))	('Proton Pump', 'Gene', (8, 19))
9237	25415190	Gastric pancreatic acinar cell metaplasia (PACM) was more frequently observed in PPI-treated rats (p = 0.003).	('pancreatic acinar cell metaplasia', 'Disease', 'MESH:D010190', (8, 41))	('pancreatic acinar cell metaplasia', 'Disease', (8, 41))	('PPI-treated', 'Var', (81, 92))	('rats', 'Species', '10116', (93, 97))
9239	25415190	Locally invasive esophageal epithelial neoplasia were observed in 23/39 PPI-treated versus 14/42 placebo-animals (p = 0.03).	('invasive esophageal epithelial neoplasia', 'Disease', (8, 48))	('invasive esophageal epithelial neoplasia', 'Disease', 'MESH:D009369', (8, 48))	('PPI-treated', 'Var', (72, 83))	('epithelial neoplasia', 'Phenotype', 'HP:0031492', (28, 48))	('neoplasia', 'Phenotype', 'HP:0002664', (39, 48))
9241	25415190	Locally invasive neoplastic lesions and PACM prevailed among PPI-treated animals.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (17, 35))	('invasive neoplastic lesions', 'Disease', (8, 35))	('invasive neoplastic lesions', 'Disease', 'MESH:D009361', (8, 35))	('PACM', 'Disease', (40, 44))	('PPI-treated', 'Var', (61, 72))
9248	25415190	However, concerns that PPI-induced hypergastrinaemia may increase the risk of adenocarcinoma development have also been expressed.	('hypergastrinaemia', 'Disease', (35, 52))	('adenocarcinoma', 'Disease', (78, 92))	('adenocarcinoma', 'Disease', 'MESH:D000230', (78, 92))	('hypergastrinaemia', 'Disease', 'None', (35, 52))	('hypergastrinaemia may increase', 'Phenotype', 'HP:0500167', (35, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('PPI-induced', 'Var', (23, 34))
9251	25415190	On the contrary, a preventive role of PPI in Barrett's adenocarcinogenesis has also been proposed, based on laboratory data of both in vitro and ex vivo experiments.	('PPI', 'Var', (38, 41))	("Barrett's adenocarcinogenesis", 'Disease', (45, 74))	("Barrett's adenocarcinogenesis", 'Disease', 'MESH:D001471', (45, 74))	('rat', 'Species', '10116', (112, 115))
9310	25415190	On the contrary, pancreatic acinar cell metaplasia and neoplastic lesions were more frequently found in the PPI group (p = 0.003 and 0.03, respectively).	('neoplastic lesions', 'Phenotype', 'HP:0002664', (55, 73))	('found', 'Reg', (95, 100))	('pancreatic acinar cell metaplasia', 'Disease', (17, 50))	('neoplastic lesions', 'CPA', (55, 73))	('pancreatic acinar cell metaplasia', 'Disease', 'MESH:D010190', (17, 50))	('PPI', 'Var', (108, 111))
9311	25415190	The neoplastic lesions mainly consisted of well differentiated mucinous tumours (18 in the PPI group and 9 in the placebo group); in one case in the PPI-group, the neoplasia only consisted of misplaced (well differentiated) glandular structures.	('mucinous tumours', 'Disease', (63, 79))	('neoplasia', 'Disease', 'MESH:D009369', (164, 173))	('PPI', 'Var', (91, 94))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('neoplasia', 'Disease', (164, 173))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (4, 22))	('neoplasia', 'Phenotype', 'HP:0002664', (164, 173))	('mucinous tumours', 'Disease', 'MESH:D002288', (63, 79))
9314	25415190	When mortality or esophageal metaplasia rates were considered, no significant differences resulted when comparing PPI- group versus placebo-group.	('esophageal metaplasia', 'Disease', 'MESH:D008679', (18, 39))	('rat', 'Species', '10116', (40, 43))	('esophageal metaplasia', 'Disease', (18, 39))	('PPI- group', 'Var', (114, 124))
9334	25415190	In an in vivo study in humans, PPI treatment has been associated with increased cell differentiation and decreased proliferation, both considered major goals in cancer chemoprevention.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('increased', 'PosReg', (70, 79))	('cell differentiation', 'CPA', (80, 100))	('proliferation', 'CPA', (115, 128))	('humans', 'Species', '9606', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('PPI', 'Var', (31, 34))	('rat', 'Species', '10116', (122, 125))	('cancer', 'Disease', (161, 167))	('decreased', 'NegReg', (105, 114))
9340	25415190	We observed an increase in pancreatic acinar cell metaplasia of the oxyntic mucosa in the animals treated with PPI, as already described in humans.	('PPI', 'Var', (111, 114))	('increase', 'PosReg', (15, 23))	('humans', 'Species', '9606', (140, 146))	('pancreatic acinar cell metaplasia', 'Disease', (27, 60))	('pancreatic acinar cell metaplasia', 'Disease', 'MESH:D010190', (27, 60))
9345	25004084	Epigenetic silencing of the non-coding RNA nc886 provokes oncogenes during human esophageal tumorigenesis nc886 (= vtRNA2-1 or pre-miR-886) is a recently discovered noncoding RNA that is a cellular PKR (Protein Kinase RNA-activated) ligand and repressor.	('nc886', 'Gene', (43, 48))	('miR-886', 'Gene', (131, 138))	('nc886', 'Gene', (106, 111))	('nc886', 'Gene', '100126299', (43, 48))	('PKR', 'Gene', (198, 201))	('Protein Kinase RNA-activated', 'Gene', (203, 231))	('vtRNA2-1', 'Gene', (115, 123))	('Protein Kinase RNA-activated', 'Gene', '5610', (203, 231))	('miR-886', 'Gene', '100126299', (131, 138))	('nc886', 'Gene', '100126299', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('human esophageal tumorigenesis', 'Disease', (75, 105))	('Epigenetic silencing', 'Var', (0, 20))	('vtRNA2-1', 'Gene', '100126299', (115, 123))	('oncogenes', 'Gene', (58, 67))	('human', 'Species', '9606', (75, 80))	('PKR', 'Gene', '5610', (198, 201))
9350	25004084	Suppression of nc886 is mediated by CpG hypermethylation of its promoter, as evidenced by its significant negative correlation to nc886 expression in ESCC tumors and by induced expression of nc886 upon demethylation of its promoter.	('nc886', 'Gene', (15, 20))	('nc886', 'Gene', (191, 196))	('expression', 'MPA', (136, 146))	('ESCC tumors', 'Disease', (150, 161))	('nc886', 'Gene', '100126299', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ESCC tumors', 'Disease', 'MESH:D004938', (150, 161))	('nc886', 'Gene', (130, 135))	('negative', 'NegReg', (106, 114))	('nc886', 'Gene', '100126299', (191, 196))	('nc886', 'Gene', '100126299', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('demethylation', 'Var', (202, 215))	('Suppression', 'NegReg', (0, 11))	('expression', 'MPA', (177, 187))	('correlation', 'Interaction', (115, 126))
9363	25004084	Tumorigenesis is a multi-step process driven by genetic/epigenetic alterations causing activation of oncogenes as well as inactivation of tumor suppressor genes.	('inactivation', 'NegReg', (122, 134))	('activation', 'PosReg', (87, 97))	('tumor', 'Disease', (138, 143))	('Tumorigenesis', 'CPA', (0, 13))	('oncogenes', 'Protein', (101, 110))	('genetic/epigenetic alterations', 'Var', (48, 78))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
9379	25004084	Our inspection of the nc886 genomic region (by using http://cpgislands.usc.edu/,) detected a strong CpG island (Fig 2A).	('CpG island', 'Var', (100, 110))	('nc886', 'Gene', '100126299', (22, 27))	('nc886', 'Gene', (22, 27))
9381	25004084	This CpG hypermethylation was a cause of nc886's suppressed expression in ESCC, as evidenced by the following data.	('expression', 'MPA', (60, 70))	('ESCC', 'Gene', (74, 78))	('hypermethylation', 'Var', (9, 25))	('nc886', 'Gene', '100126299', (41, 46))	('suppressed', 'NegReg', (49, 59))	('nc886', 'Gene', (41, 46))
9382	25004084	First, negative correlation was seen between CpG DNA methylation and RNA expression in the ESCC tumors and cell lines (Fig 2C-D).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ESCC tumors', 'Disease', 'MESH:D004938', (91, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('expression', 'MPA', (73, 83))	('negative', 'NegReg', (7, 15))	('CpG', 'Var', (45, 48))	('RNA', 'Gene', (69, 72))	('ESCC tumors', 'Disease', (91, 102))	('methylation', 'Var', (53, 64))
9394	25004084	Interestingly, these genes are also induced by dsRNA, which is a viral replication intermediate and the best ligand for PKR activation.	('PKR', 'Gene', (120, 123))	('PKR', 'Gene', '5610', (120, 123))	('dsRNA', 'Var', (47, 52))	('induced', 'Reg', (36, 43))
9398	25004084	In our data here, nc886 knockdown activated PKR in the three cell lines, as shown by the appearance of phospho-PKR, an active form of PKR (Fig 3A).	('PKR', 'Gene', (44, 47))	('PKR', 'Gene', '5610', (134, 137))	('nc886', 'Gene', (18, 23))	('PKR', 'Gene', (134, 137))	('PKR', 'Gene', '5610', (111, 114))	('activated', 'PosReg', (34, 43))	('nc886', 'Gene', '100126299', (18, 23))	('PKR', 'Gene', '5610', (44, 47))	('PKR', 'Gene', (111, 114))	('knockdown', 'Var', (24, 33))
9399	25004084	The induction of FOS, MYC and ID2 upon nc886 knockdown was significantly mitigated by siRNA-mediated knockdown of PKR (Fig 3E).	('ID2', 'Gene', '3398', (30, 33))	('MYC', 'Gene', '4609', (22, 25))	('FOS', 'Gene', (17, 20))	('nc886', 'Gene', '100126299', (39, 44))	('mitigated', 'NegReg', (73, 82))	('ID2', 'Gene', (30, 33))	('FOS', 'Gene', '2353', (17, 20))	('PKR', 'Gene', '5610', (114, 117))	('MYC', 'Gene', (22, 25))	('PKR', 'Gene', (114, 117))	('knockdown', 'Var', (45, 54))	('nc886', 'Gene', (39, 44))
9401	25004084	nc886 knockdown also induced inflammation/infection genes and pro-apoptotic genes (Fig 3B).	('induced', 'PosReg', (21, 28))	('nc886', 'Gene', (0, 5))	('nc886', 'Gene', '100126299', (0, 5))	('knockdown', 'Var', (6, 15))	('inflammation/infection', 'Disease', 'MESH:D007249', (29, 51))	('inflammation/infection', 'Disease', (29, 51))
9403	25004084	As PKR activation typically occurs during viral assault, cells would have responded to nc886 knockdown as if virus infected and were committed to death before exhibiting any malignant phenotype (data not shown).	('knockdown', 'Var', (93, 102))	('PKR', 'Gene', '5610', (3, 6))	('PKR', 'Gene', (3, 6))	('nc886', 'Gene', (87, 92))	('activation', 'PosReg', (7, 17))	('nc886', 'Gene', '100126299', (87, 92))
9404	25004084	As in a cellular response to pathogen or stress, nc886 knockdown provoked many signaling pathways and consequently induced transcription factors (Fig S5).	('knockdown', 'Var', (55, 64))	('signaling pathways', 'Pathway', (79, 97))	('provoked', 'PosReg', (65, 73))	('transcription factors', 'MPA', (123, 144))	('nc886', 'Gene', (49, 54))	('nc886', 'Gene', '100126299', (49, 54))	('induced', 'Reg', (115, 122))
9415	25004084	First, nc886 expression was significantly decreased in ESCC tumors by CpG hypermethylation at its promoter, a common mechanism to silence tumor suppressor genes.	('decreased', 'NegReg', (42, 51))	('tumor', 'Disease', (138, 143))	('expression', 'MPA', (13, 23))	('CpG hypermethylation', 'Var', (70, 90))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('nc886', 'Gene', (7, 12))	('ESCC tumors', 'Disease', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('nc886', 'Gene', '100126299', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (60, 65))	('ESCC tumors', 'Disease', 'MESH:D004938', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
9417	25004084	Third, nc886 knockdown activated oncogenes.	('activated', 'PosReg', (23, 32))	('oncogenes', 'Protein', (33, 42))	('nc886', 'Gene', (7, 12))	('nc886', 'Gene', '100126299', (7, 12))	('knockdown', 'Var', (13, 22))
9421	25004084	Also, our anti-oligo for nc886 knockdown was off-target from miR-886.	('miR-886', 'Gene', (61, 68))	('nc886', 'Gene', (25, 30))	('miR-886', 'Gene', '100126299', (61, 68))	('nc886', 'Gene', '100126299', (25, 30))	('knockdown', 'Var', (31, 40))
9423	25004084	We infer that nc886's central portion is more important than either ends harboring mature miR-886-5p or -3p, because the central portion is the binding domain for PKR and PKR activation was a reason for the induction of several oncogenes upon nc886 knockdown (Fig 3).	('oncogenes', 'Gene', (228, 237))	('knockdown', 'Var', (249, 258))	('miR-886', 'Gene', '100126299', (90, 97))	('PKR', 'Gene', '5610', (163, 166))	('PKR', 'Gene', (171, 174))	('nc886', 'Gene', (243, 248))	('nc886', 'Gene', '100126299', (243, 248))	('nc886', 'Gene', (14, 19))	('nc886', 'Gene', '100126299', (14, 19))	('induction', 'Reg', (207, 216))	('miR-886', 'Gene', (90, 97))	('PKR', 'Gene', (163, 166))	('PKR', 'Gene', '5610', (171, 174))
9424	25004084	A striking result in this study was that nc886 knockdown induced many genes including the renowned oncogenes MYC and FOS (Fig 3).	('FOS', 'Gene', (117, 120))	('MYC', 'Gene', '4609', (109, 112))	('knockdown', 'Var', (47, 56))	('nc886', 'Gene', '100126299', (41, 46))	('nc886', 'Gene', (41, 46))	('FOS', 'Gene', '2353', (117, 120))	('MYC', 'Gene', (109, 112))	('induced', 'PosReg', (57, 64))
9427	25004084	Based on our data regarding PKR (Fig 3A and E), it would be most reasonable to interpret that nc886 knockdown was a mimicry of viral infection and accordingly induced MYC and FOS as well as genes related to inflammation and infection such as oncogenic NF-kappaB.	('MYC', 'Gene', (167, 170))	('FOS', 'Gene', (175, 178))	('knockdown', 'Var', (100, 109))	('NF-kappaB', 'Gene', '4790', (252, 261))	('PKR', 'Gene', '5610', (28, 31))	('NF-kappaB', 'Gene', (252, 261))	('FOS', 'Gene', '2353', (175, 178))	('viral infection', 'Disease', (127, 142))	('MYC', 'Gene', '4609', (167, 170))	('inflammation and infection', 'Disease', 'MESH:D007249', (207, 233))	('PKR', 'Gene', (28, 31))	('nc886', 'Gene', (94, 99))	('induced', 'Reg', (159, 166))	('nc886', 'Gene', '100126299', (94, 99))	('viral infection', 'Disease', 'MESH:D001102', (127, 142))
9432	25004084	Detection of nc886 depletion by methylation in ESCC might classify the high risk patients with recurrence and identify candidates for therapy with peri-operative adjuvant treatment.	('methylation', 'Var', (32, 43))	('nc886', 'Gene', (13, 18))	('depletion', 'MPA', (19, 28))	('patients', 'Species', '9606', (81, 89))	('ESCC', 'Gene', (47, 51))	('nc886', 'Gene', '100126299', (13, 18))
9437	25004084	We speculate that epigenetic silencing of nc886 is a cell autonomous cue to provoke inflammation and promotes ESCC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('epigenetic silencing', 'Var', (18, 38))	('tumor', 'Disease', (115, 120))	('inflammation', 'Disease', (84, 96))	('provoke', 'PosReg', (76, 83))	('nc886', 'Gene', (42, 47))	('nc886', 'Gene', '100126299', (42, 47))	('ESCC', 'Disease', (110, 114))	('promotes', 'PosReg', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
9459	23186308	Three-dimensional conformal radiation for esophageal squamous cell carcinoma with involved-field irradiation may deliver considerable doses of incidental nodal irradiation To quantify the incidental irradiation dose to esophageal lymph node stations when irradiating T1-4N0M0 thoracic esophageal squamous cell carcinoma (ESCC) patients with a dose of 60 Gy/30f.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (42, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (285, 319))	('T1-4N0M0', 'Var', (267, 275))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('esophageal squamous cell carcinoma', 'Disease', (42, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('esophageal squamous cell carcinoma', 'Disease', (285, 319))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (296, 319))	('patients', 'Species', '9606', (327, 335))
9489	23186308	Each treatment plan consisted of a median of three static fields (range: 3-4) with the following normal tissue constraints: (1) the mean lung dose (MLD) was <=13 Gy, V5 (i.e., percentage of lung volume receiving >=5 Gy) was <=50%, V20 <=25%, and V30 <=20%, (2) the volume of heart receiving >=40 Gy was <=30%, and (3) the maximum spinal cord dose was <=45 Gy.	('MLD', 'Disease', (148, 151))	('V30 <=20', 'Var', (246, 254))	('V20 <=25%', 'Var', (231, 240))	('<=13', 'Var', (157, 161))	('MLD', 'Disease', 'MESH:D007966', (148, 151))
9633	33227662	The C-index for PFS (0.716, 95% CI: 67.856-75.385) was also superior to that of the 8th AJCC TNM staging (0.610, 95% CI: 57.199-64.892).	('TNM', 'Gene', (93, 96))	('TNM', 'Gene', '10178', (93, 96))	('PFS', 'Var', (16, 19))
9657	33227662	Consistent with our results, a study has reported that LNR is an independent predictor of survival in esophageal cancer.	('cancer', 'Disease', (113, 119))	('LNR', 'Var', (55, 58))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
9684	32232599	We made the diagnosis of esophageal cancer (Ut, type 0-IIc, T1b/MtLt, type 0-IIc, T1b, N2, M0, cStage II) and planned to treat the patient by radical surgery after neoadjuvant therapy.	('T1b', 'Var', (82, 85))	('esophageal cancer', 'Disease', (25, 42))	('MtLt', 'Gene', (64, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (25, 42))	('type 0-IIc', 'Var', (70, 80))	('patient', 'Species', '9606', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('MtLt', 'Gene', '9633', (64, 68))
9728	31565147	The weight of evidence indicates that the mechanism of carcinogenesis is epigenetic and related to compensatory cell proliferation accompanying apoptosis.	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('epigenetic', 'Var', (73, 83))	('carcinogenesis', 'Disease', (55, 69))
9751	31565147	Thus, FB1 is possibly carcinogenic to humans (Group 2B).	('carcinogenic', 'Disease', 'MESH:D063646', (22, 34))	('carcinogenic', 'Disease', (22, 34))	('FB1', 'Chemical', 'MESH:C056933', (6, 9))	('FB1', 'Var', (6, 9))	('humans', 'Species', '9606', (38, 44))
9760	30868765	Combined with LiCl or MG-132 treatment, SPINK5 can inhibit GSK3beta phosphorylation and promote beta-catenin protein degradation, thus inhibit Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', '1499', (147, 159))	('SPINK5', 'Var', (40, 46))	('beta-catenin', 'Gene', '1499', (96, 108))	('GSK3beta', 'Gene', '2932', (59, 67))	('inhibit', 'NegReg', (135, 142))	('promote', 'PosReg', (88, 95))	('beta-catenin', 'Gene', (147, 159))	('MG-132', 'Chemical', 'MESH:C072553', (22, 28))	('LiCl', 'Chemical', 'MESH:D018021', (14, 18))	('inhibit', 'NegReg', (51, 58))	('GSK3beta', 'Gene', (59, 67))	('beta-catenin', 'Gene', (96, 108))
9769	30868765	The SPINK5 gene encodes a lymphoid epithelial-associated inhibitor LEKTI, a serine protease inhibitor.9 This study has found that dysfunction of SPINK5 is mainly related to Netherton Syndrome (NS).	('SPINK5', 'Gene', (145, 151))	('Netherton Syndrome', 'Disease', 'MESH:D056770', (173, 191))	('NS', 'Disease', 'MESH:D009404', (193, 195))	('LEKTI', 'Gene', (67, 72))	('serine', 'Chemical', 'MESH:D012694', (76, 82))	('Netherton Syndrome', 'Disease', (173, 191))	('LEKTI', 'Gene', '11005', (67, 72))	('dysfunction', 'Var', (130, 141))	('related', 'Reg', (162, 169))
9780	30868765	The TOP/FOP flash reporter plasmids containing wild-type (TOP flash) or mutated (FOP flash) TCF/LEF DNA binding sites were conserved in our laboratory.	('rat', 'Species', '10116', (144, 147))	('mutated', 'Var', (72, 79))	('TCF/LEF', 'Gene', (92, 99))
9818	30868765	The results showed that overexpression of SPINK5 significantly inhibited the proliferation of esophageal cancer cells KYSE510 and ECA109 (Figure 2B,D), while knockdown of SPINK5 significantly promoted proliferation of esophageal cancer cells KYSE510 and ECA109 (Figure 2C,E).	('rat', 'Species', '10116', (208, 211))	('promoted', 'PosReg', (192, 200))	('rat', 'Species', '10116', (84, 87))	('esophageal cancer', 'Disease', (94, 111))	('proliferation', 'CPA', (201, 214))	('SPINK5', 'Gene', (171, 177))	('overexpression', 'PosReg', (24, 38))	('knockdown', 'Var', (158, 167))	('inhibited', 'NegReg', (63, 72))	('esophageal cancer', 'Disease', (218, 235))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('SPINK5', 'Gene', (42, 48))	('proliferation', 'CPA', (77, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))
9821	30868765	Transwell migration assay showed that overexpression of SPINK5 significantly inhibited the migration of esophageal cancer cells KYSE510 and ECA109 (Figure 3A), while knockdown of SPINK5 significantly promoted the migration of esophageal cancer cells KYSE510 and ECA109 (Figure 3B).	('knockdown', 'Var', (166, 175))	('rat', 'Species', '10116', (94, 97))	('promoted', 'PosReg', (200, 208))	('esophageal cancer', 'Disease', 'MESH:D004938', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('inhibited', 'NegReg', (77, 86))	('esophageal cancer', 'Disease', (226, 243))	('migration', 'CPA', (213, 222))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('overexpression', 'PosReg', (38, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('rat', 'Species', '10116', (13, 16))	('migration', 'CPA', (91, 100))	('rat', 'Species', '10116', (216, 219))	('SPINK5', 'Gene', (56, 62))	('SPINK5', 'Gene', (179, 185))
9829	30868765	In esophageal cancer cells KYSE510 and ECA109, overexpression of SPINK5 significantly inhibited TOP flash reporter activity (Figure 4C), while knockdown of SPINK5 significantly increased TOP flash reporter activity (Figure 4D), suggesting that overexpression of SPINK5 inhibits Wnt/beta-catenin signaling pathway activity, while SPINK5 knockdown is able to activate Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', (282, 294))	('SPINK5', 'Gene', (156, 162))	('esophageal cancer', 'Disease', (3, 20))	('beta-catenin', 'Gene', '1499', (370, 382))	('TOP flash reporter activity', 'MPA', (96, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('increased', 'PosReg', (177, 186))	('inhibits', 'NegReg', (269, 277))	('beta-catenin', 'Gene', '1499', (282, 294))	('TOP flash reporter activity', 'MPA', (187, 214))	('inhibited', 'NegReg', (86, 95))	('knockdown', 'Var', (143, 152))	('beta-catenin', 'Gene', (370, 382))	('SPINK5', 'Gene', (65, 71))
9832	30868765	These results indicate that SPINK5 is able to inhibit the Wnt/beta-catenin signaling pathway in esophageal cancer.	('beta-catenin', 'Gene', (62, 74))	('inhibit', 'NegReg', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('SPINK5', 'Var', (28, 34))	('beta-catenin', 'Gene', '1499', (62, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))
9833	30868765	The cytoplasmic CK1, AXIN, APC, GSK3beta, and other proteins form a degradation complex, which promotes the phosphorylation of the ser33 and ser37 of beta-catenin by binding to beta-catenin protein, which leads to the ubiquitination degradation of beta-catenin.15 In previous studies, we found that overexpression of SPINK5 in esophageal cancer cells inhibited the expression of p-GSK3beta (S9), whereas knockdown of SPINK5 upregulated the expression of p-GSK3beta (S9), suggesting that SPINK5 can affect the activity of GSK3beta.	('beta-catenin', 'Gene', (248, 260))	('activity', 'MPA', (509, 517))	('SPINK5', 'Gene', (417, 423))	('beta-catenin', 'Gene', '1499', (248, 260))	('expression', 'MPA', (440, 450))	('beta-catenin', 'Gene', (177, 189))	('CK1', 'Species', '2498238', (16, 19))	('beta-catenin', 'Gene', '1499', (177, 189))	('affect', 'Reg', (498, 504))	('GSK3beta', 'Gene', (32, 40))	('expression', 'MPA', (365, 375))	('esophageal cancer', 'Disease', 'MESH:D004938', (327, 344))	('GSK3beta', 'Gene', '2932', (521, 529))	('inhibited', 'NegReg', (351, 360))	('GSK3beta', 'Gene', (381, 389))	('beta-catenin', 'Gene', (150, 162))	('beta-catenin', 'Gene', '1499', (150, 162))	('GSK3beta', 'Gene', '2932', (456, 464))	('upregulated', 'PosReg', (424, 435))	('APC', 'Disease', 'MESH:D011125', (27, 30))	('esophageal cancer', 'Disease', (327, 344))	('APC', 'Disease', (27, 30))	('knockdown', 'Var', (404, 413))	('GSK3beta', 'Gene', '2932', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('GSK3beta', 'Gene', (521, 529))	('GSK3beta', 'Gene', (456, 464))	('GSK3beta', 'Gene', '2932', (381, 389))
9834	30868765	LiCl is often used as an inhibitor of GSK3beta which promotes GSK3beta phosphorylation and inactivation.16 We found that knockdown of SPINK5 in esophageal cancer cells has a similar effect to LiCl and upregulates the expression level of p-GSK3beta (S9) (Figure 5A).	('knockdown', 'Var', (121, 130))	('LiCl', 'Chemical', 'MESH:D018021', (192, 196))	('expression level', 'MPA', (217, 233))	('upregulates', 'PosReg', (201, 212))	('GSK3beta', 'Gene', '2932', (62, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('GSK3beta', 'Gene', '2932', (38, 46))	('LiCl', 'Chemical', 'MESH:D018021', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('GSK3beta', 'Gene', (239, 247))	('SPINK5', 'Gene', (134, 140))	('GSK3beta', 'Gene', '2932', (239, 247))	('GSK3beta', 'Gene', (62, 70))	('GSK3beta', 'Gene', (38, 46))	('esophageal cancer', 'Disease', (144, 161))
9837	30868765	In esophageal cancer cells, we overexpressed beta-catenin (GFP-beta-catenin) in combination with protease inhibitor MG132, the results showed that MG132 significantly upregulated the expression of GFP-beta-catenin and reversed the overexpression of SPINK5 to inhibit GFP-beta-catenin (Figure 5D).	('beta-catenin', 'Gene', (63, 75))	('MG132', 'Chemical', 'MESH:C072553', (116, 121))	('MG132', 'Var', (147, 152))	('esophageal cancer', 'Disease', (3, 20))	('upregulated', 'PosReg', (167, 178))	('inhibit', 'NegReg', (259, 266))	('beta-catenin', 'Gene', (201, 213))	('MG132', 'Chemical', 'MESH:C072553', (147, 152))	('beta-catenin', 'Gene', '1499', (45, 57))	('beta-catenin', 'Gene', '1499', (271, 283))	('beta-catenin', 'Gene', '1499', (63, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('expression', 'MPA', (183, 193))	('beta-catenin', 'Gene', '1499', (201, 213))	('beta-catenin', 'Gene', (45, 57))	('beta-catenin', 'Gene', (271, 283))
9843	30868765	These results indicate that SPINK5 can inhibit the proliferation and migration of esophageal cancer cells through the Wnt/beta-catenin signaling pathway.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('rat', 'Species', '10116', (72, 75))	('beta-catenin', 'Gene', '1499', (122, 134))	('inhibit', 'NegReg', (39, 46))	('SPINK5', 'Var', (28, 34))	('proliferation', 'CPA', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rat', 'Species', '10116', (58, 61))	('esophageal cancer', 'Disease', (82, 99))	('beta-catenin', 'Gene', (122, 134))
9856	30868765	The results of the In vitro study further demonstrated that SPINK5 significantly inhibits the activity of the Wnt/beta-catenin signaling pathway in esophageal cancer cells.	('inhibits', 'NegReg', (81, 89))	('beta-catenin', 'Gene', (114, 126))	('SPINK5', 'Var', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('beta-catenin', 'Gene', '1499', (114, 126))	('esophageal cancer', 'Disease', (148, 165))	('activity', 'MPA', (94, 102))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('rat', 'Species', '10116', (49, 52))
9859	30868765	In this study, we found that SPINK5 overexpression significantly inhibited the expression of beta-catenin, while knockdown of SPINK5 promoted the expression of beta-catenin.	('SPINK5', 'Gene', (29, 35))	('beta-catenin', 'Gene', (93, 105))	('expression', 'MPA', (79, 89))	('promoted', 'PosReg', (133, 141))	('beta-catenin', 'Gene', (160, 172))	('SPINK5', 'Gene', (126, 132))	('beta-catenin', 'Gene', '1499', (93, 105))	('knockdown', 'Var', (113, 122))	('inhibited', 'NegReg', (65, 74))	('beta-catenin', 'Gene', '1499', (160, 172))	('expression', 'MPA', (146, 156))
9861	30868765	The kinase activity of GSK3beta is closely related to the phosphorylation of ser9.28 GSK3beta is inactivated by phosphorylating at Ser9, so the expression level of p-GSK3beta (S9) in cells is one of the indicators to measure the activity of degradation complex.29 In this study, we found that SPINK5 inhibits the expression level of p-GSK3beta (S9), but has no significant effect on the expression level of GSK3beta.	('GSK3beta', 'Gene', '2932', (335, 343))	('GSK3beta', 'Gene', '2932', (85, 93))	('GSK3beta', 'Gene', (166, 174))	('ser9', 'Chemical', '-', (77, 81))	('Ser9', 'Chemical', '-', (131, 135))	('GSK3beta', 'Gene', (407, 415))	('GSK3beta', 'Gene', (23, 31))	('GSK3beta', 'Gene', '2932', (166, 174))	('inhibits', 'NegReg', (300, 308))	('GSK3beta', 'Gene', '2932', (407, 415))	('GSK3beta', 'Gene', (335, 343))	('GSK3beta', 'Gene', (85, 93))	('GSK3beta', 'Gene', '2932', (23, 31))	('SPINK5', 'Var', (293, 299))	('expression level', 'MPA', (313, 329))
9862	30868765	Furthermore, using the GSK3beta inhibitor LiCl in combination with SPINK5 overexpression or knockdown, we further determined that SPINK5 can activate GSK3beta and inhibit the activity of Wnt/beta-catenin signaling pathway by affecting the GSK3beta/beta-catenin degradation complex.	('inhibit', 'NegReg', (163, 170))	('beta-catenin', 'Gene', (248, 260))	('GSK3beta', 'Gene', (239, 247))	('beta-catenin', 'Gene', (191, 203))	('GSK3beta', 'Gene', (23, 31))	('LiCl', 'Chemical', 'MESH:D018021', (42, 46))	('beta-catenin', 'Gene', '1499', (248, 260))	('GSK3beta', 'Gene', (150, 158))	('activity', 'MPA', (175, 183))	('beta-catenin', 'Gene', '1499', (191, 203))	('activate', 'PosReg', (141, 149))	('GSK3beta', 'Gene', '2932', (239, 247))	('GSK3beta', 'Gene', '2932', (23, 31))	('affecting', 'Reg', (225, 234))	('GSK3beta', 'Gene', '2932', (150, 158))	('SPINK5', 'Var', (130, 136))
9863	30868765	In the process of tumor development, activation of Wnt/beta-catenin signaling pathway can upregulate cell proliferation and migration-related target genes, such as c-myc and cyclin D1, which promote cell proliferation and migration.30 Therefore, we further demonstrated that SPINK5 overexpression could reverse the effect of LiCl treatment, which confirmed that SPINK5 could indeed inhibit the proliferation and migration of esophageal cancer cells by inhibiting the activity of Wnt/beta-catenin signaling pathway.	('c-myc', 'Gene', '4609', (164, 169))	('inhibit', 'NegReg', (382, 389))	('esophageal cancer', 'Disease', 'MESH:D004938', (425, 442))	('rat', 'Species', '10116', (127, 130))	('SPINK5', 'Var', (362, 368))	('esophageal cancer', 'Disease', (425, 442))	('migration', 'CPA', (412, 421))	('beta-catenin', 'Gene', (55, 67))	('tumor', 'Disease', (18, 23))	('LiCl', 'Chemical', 'MESH:D018021', (325, 329))	('beta-catenin', 'Gene', '1499', (55, 67))	('beta-catenin', 'Gene', (483, 495))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cyclin D1', 'Gene', (174, 183))	('beta-catenin', 'Gene', '1499', (483, 495))	('proliferation', 'CPA', (394, 407))	('activity', 'MPA', (467, 475))	('rat', 'Species', '10116', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('c-myc', 'Gene', (164, 169))	('cyclin D1', 'Gene', '595', (174, 183))	('rat', 'Species', '10116', (401, 404))	('inhibiting', 'NegReg', (452, 462))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('rat', 'Species', '10116', (225, 228))	('rat', 'Species', '10116', (113, 116))	('rat', 'Species', '10116', (415, 418))	('rat', 'Species', '10116', (264, 267))
9865	30868765	In conclusion, in this study, we first explored the role of SPINK5 as a tumor suppressor gene in the development of esophageal carcinoma, and further found that SPINK5 can inhibit the Wnt/beta-catenin signaling pathway to play a role in the proliferation, migration, and invasion of esophageal cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('esophageal cancer', 'Disease', (283, 300))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (116, 136))	('invasion', 'CPA', (271, 279))	('inhibit', 'NegReg', (172, 179))	('beta-catenin', 'Gene', (188, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('beta-catenin', 'Gene', '1499', (188, 200))	('esophageal carcinoma', 'Disease', (116, 136))	('tumor', 'Disease', (72, 77))	('rat', 'Species', '10116', (259, 262))	('SPINK5', 'Var', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (116, 136))	('proliferation', 'CPA', (241, 254))	('migration', 'CPA', (256, 265))	('esophageal cancer', 'Disease', 'MESH:D004938', (283, 300))	('rat', 'Species', '10116', (248, 251))
9875	30147366	The results of the current study suggest that for esophageal cancer patients with a cCR after standard-dose radiotherapy with concurrent chemotherapy, those with dose-escalated radiotherapy showed significantly better local control, recurrence-free survival, and overall survival than patients receiving 50.4 Gy radiotherapy.	('cCR', 'Var', (84, 87))	('recurrence-free survival', 'CPA', (233, 257))	('local control', 'CPA', (218, 231))	('patients', 'Species', '9606', (68, 76))	('overall survival', 'CPA', (263, 279))	('esophageal cancer', 'Disease', (50, 67))	('patients', 'Species', '9606', (285, 293))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('CR', 'Chemical', '-', (85, 87))	('better', 'PosReg', (211, 217))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
9948	30147366	The results of the current study suggest that the subgroup of patients who underwent dose escalation had significantly better LC and OS than patients receiving 50.4 Gy when treated with concurrent chemotherapy.	('dose escalation', 'Var', (85, 100))	('better', 'PosReg', (119, 125))	('OS', 'Chemical', '-', (133, 135))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (141, 149))
9965	28828004	The reported risk factors for post-ESD esophageal stricture include a mucosal defect that covers more than three-quarters of the circumference (68-90%) and a tumor diameter of >=5 cm (28%).	('tumor', 'Disease', (158, 163))	('post-ESD', 'Var', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('esophageal stricture', 'Disease', (39, 59))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('esophageal stricture', 'Phenotype', 'HP:0002043', (39, 59))
9973	28828004	A single-channel endoscope with forward water supply function (GIF-Q260J; Olympus Medical Systems Corp., Tokyo, Japan) was used with carbon dioxide insufflation.	('Q260J', 'Var', (67, 72))	('insufflation', 'Disease', (148, 160))	('water', 'Chemical', 'MESH:D014867', (40, 45))	('carbon dioxide', 'Chemical', 'MESH:D002245', (133, 147))	('insufflation', 'Disease', 'None', (148, 160))	('Q260J', 'SUBSTITUTION', 'None', (67, 72))
9982	28828004	Esophageal stricture was defined as the failure of the passage of a 9.9 mm endoscope (GIF-Q260J).	('Esophageal stricture', 'Phenotype', 'HP:0002043', (0, 20))	('Esophageal stricture', 'Disease', (0, 20))	('Q260J', 'SUBSTITUTION', 'None', (90, 95))	('Q260J', 'Var', (90, 95))
10010	27441783	For example, PPIs have been showed to promote cancer promotion in animal models owing to hypergastrinemia or CYP1A1 induction.	('hypergastrinemia', 'Phenotype', 'HP:0500167', (89, 105))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('hypergastrinemia', 'Disease', 'None', (89, 105))	('PPIs', 'Var', (13, 17))	('CYP1A1', 'Gene', (109, 115))	('hypergastrinemia', 'Disease', (89, 105))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('promote', 'PosReg', (38, 45))	('CYP1A1', 'Gene', '1543', (109, 115))
10102	27441783	It has also been reported that IL-4-producing CD4+ T cells cause goblet cell transformation in the small intestine, and that T-cells within BE tissue are mainly IL-4+CD8- cells.	('CD4+ T cells', 'Var', (46, 58))	('IL-4', 'Gene', (161, 165))	('goblet cell transformation in the', 'CPA', (65, 98))	('cause', 'Reg', (59, 64))	('IL-4', 'Gene', '3565', (161, 165))	('IL-4', 'Gene', (31, 35))	('BE', 'Phenotype', 'HP:0100580', (140, 142))	('IL-4', 'Gene', '3565', (31, 35))
10171	27478411	Both Sequenom MassARRAY and TaqMan genotyping assays demonstrated that SNP rs10788656 in the PADI2 gene was significantly associated with breast cancer.	('associated', 'Reg', (122, 132))	('SNP rs10788656', 'Var', (71, 85))	('PADI2', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('rs10788656', 'Mutation', 'rs10788656', (75, 85))
10172	27478411	PCR arrays indicated that inhibiting PADI2 expression significantly increased expression of CA9 and decreased expression of ACSL4 and BIRC3 in MCF-7 cells, which was verified using real-time PCR.	('CA9', 'Gene', '768', (92, 95))	('expression', 'MPA', (78, 88))	('ACSL4', 'Gene', '2182', (124, 129))	('MCF-7', 'CellLine', 'CVCL:0031', (143, 148))	('ACSL4', 'Gene', (124, 129))	('decreased', 'NegReg', (100, 109))	('PADI2', 'Gene', (37, 42))	('expression', 'MPA', (110, 120))	('BIRC3', 'Gene', (134, 139))	('CA9', 'Gene', (92, 95))	('BIRC3', 'Gene', '330', (134, 139))	('expression', 'MPA', (43, 53))	('inhibiting', 'Var', (26, 36))	('increased', 'PosReg', (68, 77))
10173	27478411	Inhibiting PADI2 expression also significantly decreased the migration ability of MCF-7 cells but did not affect cell proliferation or apoptosis.	('migration ability', 'CPA', (61, 78))	('PADI2', 'Gene', (11, 16))	('Inhibiting', 'Var', (0, 10))	('MCF-7', 'CellLine', 'CVCL:0031', (82, 87))	('decreased', 'NegReg', (47, 56))
10189	27478411	The present study investigated the possible association between candidate SNPs (single nucleotide polymorphisms) in the PADI2 locus and various tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('SNPs', 'Var', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PADI2', 'Gene', (120, 125))
10190	27478411	We aimed to determine whether these common polymorphisms in the PADI2 region are associated with various tumor risks using the Sequenom MassARRAY genotyping method.	('polymorphisms', 'Var', (43, 56))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('associated', 'Reg', (81, 91))
10194	27478411	The case-control analysis showed a significant difference in allele frequency and genotype frequency for rs2746533 in PADI2 between gastric carcinoma patients and controls.	('difference', 'Reg', (47, 57))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (132, 149))	('rs2746533', 'Mutation', 'rs2746533', (105, 114))	('gastric carcinoma', 'Disease', 'MESH:D013274', (132, 149))	('patients', 'Species', '9606', (150, 158))	('PADI2', 'Gene', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('rs2746533', 'Var', (105, 114))	('gastric carcinoma', 'Disease', (132, 149))
10195	27478411	The analysis also showed a significant difference in allele frequency and genotype frequency for rs2076616 between gastric carcinoma patients and controls.	('patients', 'Species', '9606', (133, 141))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (115, 132))	('gastric carcinoma', 'Disease', 'MESH:D013274', (115, 132))	('rs2076616', 'Var', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('difference', 'Reg', (39, 49))	('rs2076616', 'Mutation', 'rs2076616', (97, 106))	('gastric carcinoma', 'Disease', (115, 132))
10196	27478411	In addition, the analysis showed a significant difference for rs10788656 between the following groups: breast cancer patients and controls in genotype frequency; cervical carcinoma patients and controls in allele frequency; esophageal carcinoma patients and controls in allele frequency and genotype frequency; lung cancer patients and controls in allele frequency; and rectal carcinoma patients and controls in genotype frequency.	('carcinoma', 'Phenotype', 'HP:0030731', (377, 386))	('rectal carcinoma', 'Disease', 'MESH:D012004', (370, 386))	('patients', 'Species', '9606', (245, 253))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('patients', 'Species', '9606', (387, 395))	('cervical carcinoma', 'Disease', (162, 180))	('breast cancer', 'Disease', (103, 116))	('lung cancer', 'Disease', 'MESH:D008175', (311, 322))	('patients', 'Species', '9606', (181, 189))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (224, 244))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (323, 331))	('lung cancer', 'Phenotype', 'HP:0100526', (311, 322))	('cervical carcinoma', 'Disease', 'MESH:D002575', (162, 180))	('difference', 'Reg', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('rs10788656', 'Mutation', 'rs10788656', (62, 72))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (224, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (370, 386))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('lung cancer', 'Disease', (311, 322))	('esophageal carcinoma', 'Disease', (224, 244))	('rectal carcinoma', 'Disease', (370, 386))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('rs10788656', 'Var', (62, 72))
10198	27478411	To verify the above results, genotyping for tag SNP rs10788656 was performed in samples from cohorts of patients with breast cancer, colon cancer, esophageal cancer, cervical cancer, gastric cancer, liver cancer, lung cancer and rectal cancer and from healthy controls using the TaqMan method.	('gastric cancer', 'Disease', (183, 197))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('lung cancer', 'Disease', (213, 224))	('colon cancer', 'Disease', (133, 145))	('rs10788656', 'Var', (52, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('rectal cancer', 'Disease', (229, 242))	('rectal cancer', 'Phenotype', 'HP:0100743', (229, 242))	('esophageal cancer', 'Disease', (147, 164))	('cervical cancer', 'Disease', (166, 181))	('cervical cancer', 'Disease', 'MESH:D002583', (166, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('gastric cancer', 'Disease', 'MESH:D013274', (183, 197))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('lung cancer', 'Disease', 'MESH:D008175', (213, 224))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('liver cancer', 'Disease', 'MESH:D006528', (199, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (183, 197))	('rectal cancer', 'Disease', 'MESH:D012004', (229, 242))	('patients', 'Species', '9606', (104, 112))	('liver cancer', 'Phenotype', 'HP:0002896', (199, 211))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('rs10788656', 'Mutation', 'rs10788656', (52, 62))	('liver cancer', 'Disease', (199, 211))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))
10201	27478411	Genotyping did not detect a significant difference in allele or genotype frequencies for rs10788656 between patients with colon cancer, cervical cancer, esophageal cancer, gastric cancer, liver cancer, lung cancer or rectal cancer (p > 0.05).	('gastric cancer', 'Phenotype', 'HP:0012126', (172, 186))	('liver cancer', 'Disease', (188, 200))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('patients', 'Species', '9606', (108, 116))	('rs10788656', 'Mutation', 'rs10788656', (89, 99))	('rectal cancer', 'Disease', 'MESH:D012004', (217, 230))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Disease', (172, 186))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Disease', (202, 213))	('rs10788656', 'Var', (89, 99))	('esophageal cancer', 'Disease', (153, 170))	('colon cancer', 'Disease', (122, 134))	('gastric cancer', 'Disease', 'MESH:D013274', (172, 186))	('liver cancer', 'Disease', 'MESH:D006528', (188, 200))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cervical cancer', 'Disease', (136, 151))	('cervical cancer', 'Disease', 'MESH:D002583', (136, 151))	('rectal cancer', 'Disease', (217, 230))	('rectal cancer', 'Phenotype', 'HP:0100743', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))	('liver cancer', 'Phenotype', 'HP:0002896', (188, 200))
10208	27478411	A significantly decreased migration of MCF-7 cells was observed when PADI2 expression was suppressed by anti-PADI2 siRNA compared with the cells treated with Allstar siRNA (p < 0.001) or HiPerFect transfection reagent (p < 0.001).	('PADI2', 'Gene', (69, 74))	('migration', 'CPA', (26, 35))	('suppressed', 'NegReg', (90, 100))	('MCF-7', 'CellLine', 'CVCL:0031', (39, 44))	('anti-PADI2', 'Var', (104, 114))	('expression', 'MPA', (75, 85))	('decreased', 'NegReg', (16, 25))
10217	27478411	In the present study, we used the Sequenom MassARRAY system to genotype the tag SNPs rs2746533, rs79395834, rs2076616 and rs10788656 in the PADI2 locus to determine their association with susceptibility to various tumors.	('rs2076616', 'Mutation', 'rs2076616', (108, 117))	('rs79395834', 'Mutation', 'rs79395834', (96, 106))	('rs10788656', 'Var', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('rs2746533', 'Mutation', 'rs2746533', (85, 94))	('tumors', 'Disease', (214, 220))	('rs2076616', 'Var', (108, 117))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('rs79395834', 'Var', (96, 106))	('rs10788656', 'Mutation', 'rs10788656', (122, 132))	('rs2746533', 'Var', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (214, 220))
10218	27478411	Analysis indicated that the SNPs rs2746533, rs2076616 and rs10788656 had a significant difference in allele frequency, genotype frequency or both between breast cancer, cervical carcinoma, gastric carcinoma, lung cancer and rectal carcinoma cases and the controls.	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('rs2076616', 'Mutation', 'rs2076616', (44, 53))	('rectal carcinoma', 'Disease', (224, 240))	('rs2746533', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('rectal carcinoma', 'Disease', 'MESH:D012004', (224, 240))	('gastric carcinoma', 'Disease', 'MESH:D013274', (189, 206))	('rs10788656', 'Var', (58, 68))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('gastric carcinoma', 'Disease', (189, 206))	('cervical carcinoma', 'Disease', (169, 187))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (189, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('rs2076616', 'Var', (44, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('difference', 'Reg', (87, 97))	('cervical carcinoma', 'Disease', 'MESH:D002575', (169, 187))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('breast cancer', 'Disease', (154, 167))	('rs2746533', 'Mutation', 'rs2746533', (33, 42))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (224, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('lung cancer', 'Disease', (208, 219))	('rs10788656', 'Mutation', 'rs10788656', (58, 68))
10220	27478411	The analysis showed a significant difference in allele frequency and genotype frequency for rs10788656 between breast cancer samples and the controls, which was completely consistent with the Sequenom MassARRAY result.	('difference', 'Reg', (34, 44))	('rs10788656', 'Var', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('rs10788656', 'Mutation', 'rs10788656', (92, 102))	('breast cancer', 'Disease', (111, 124))
10224	27478411	We will screen more SNPs in this region, especially in the exon region and its surrounding region, to find functional SNPs and determine how these SNPs affect PADI2 expression and the enzyme activity in which PADI2 has been implicated in some diseases and, more recently, in cancers.	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('PADI2', 'Gene', (159, 164))	('expression', 'MPA', (165, 175))	('enzyme activity', 'MPA', (184, 199))	('SNPs', 'Var', (147, 151))	('affect', 'Reg', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('implicated', 'Reg', (224, 234))	('cancers', 'Disease', (275, 282))
10232	27478411	They then found that the human squamous cell carcinoma cell line A431 with overexpressed PADI2 was more tumorigenic and contained elevated levels of markers for inflammation and epithelial-mesenchymal transition.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('squamous cell carcinoma', 'Disease', (31, 54))	('more', 'PosReg', (99, 103))	('inflammation', 'Disease', (161, 173))	('A431', 'CellLine', 'CVCL:0037', (65, 69))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (31, 54))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('human', 'Species', '9606', (25, 30))	('epithelia', 'Disease', 'None', (178, 187))	('inflammation', 'Disease', 'MESH:D007249', (161, 173))	('elevated', 'PosReg', (130, 138))	('epithelia', 'Disease', (178, 187))	('overexpressed', 'Var', (75, 88))	('levels of', 'MPA', (139, 148))	('PADI2', 'Gene', (89, 94))
10245	27478411	The present study detected decreased expression of ACSL4 and decreased cell migration ability in MCF-7 cells treated with anti-PADI2 siRNA.	('anti-PADI2', 'Var', (122, 132))	('ACSL4', 'Gene', '2182', (51, 56))	('ACSL4', 'Gene', (51, 56))	('decreased', 'NegReg', (27, 36))	('cell migration ability', 'CPA', (71, 93))	('MCF-7', 'CellLine', 'CVCL:0031', (97, 102))	('decreased', 'NegReg', (61, 70))	('expression', 'MPA', (37, 47))
10257	27478411	Patients with high levels of CA9 expression show significantly worse overall survival.	('overall', 'MPA', (69, 76))	('worse', 'NegReg', (63, 68))	('high levels', 'Var', (14, 25))	('Patients', 'Species', '9606', (0, 8))	('CA9', 'Gene', (29, 32))	('CA9', 'Gene', '768', (29, 32))
10258	27478411	High CA9 protein expression occurs in patients with the BRCA1 mutant signature and low levels of the BRCA1 protein.	('CA9', 'Gene', '768', (5, 8))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA1', 'Gene', '672', (101, 106))	('mutant signature', 'Var', (62, 78))	('expression', 'MPA', (17, 27))	('High', 'PosReg', (0, 4))	('protein', 'Protein', (9, 16))	('BRCA1', 'Gene', (56, 61))	('BRCA1', 'Gene', (101, 106))	('patients', 'Species', '9606', (38, 46))	('CA9', 'Gene', (5, 8))
10260	27478411	The current study detected increased expression of CA9 in the anti-PADI2 siRNA-treated breast cancer cell lines, supporting the importance of the PADI2-CA9 pathway in breast cancer progression.	('breast cancer', 'Disease', (167, 180))	('increased', 'PosReg', (27, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('CA9', 'Gene', (51, 54))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('CA9', 'Gene', '768', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('CA9', 'Gene', (152, 155))	('breast cancer', 'Disease', (87, 100))	('anti-PADI2', 'Var', (62, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('CA9', 'Gene', '768', (152, 155))	('expression', 'MPA', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
10261	27478411	In addition, some studies have reported that a subgroup of gastric cancers retains CA9 expression in cancer cells at the invasion front and that expression of CA9 is associated with increased invasion.	('increased', 'PosReg', (182, 191))	('CA9', 'Gene', (159, 162))	('gastric cancers', 'Disease', 'MESH:D013274', (59, 74))	('CA9', 'Gene', '768', (83, 86))	('gastric cancers', 'Disease', (59, 74))	('gastric cancers', 'Phenotype', 'HP:0012126', (59, 74))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('CA9', 'Gene', '768', (159, 162))	('invasion', 'CPA', (192, 200))	('expression', 'Var', (145, 155))	('expression', 'MPA', (87, 97))	('associated with', 'Reg', (166, 181))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (101, 107))	('CA9', 'Gene', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
10266	27478411	They further found that citrullination of H3R26 is catalyzed by PADI2, whereas H4R3 is catalyzed by PADI4.	('PADI4', 'Gene', '23569', (100, 105))	('PADI2', 'Var', (64, 69))	('PADI4', 'Gene', (100, 105))	('catalyzed', 'Reg', (51, 60))	('citrullination', 'MPA', (24, 38))	('H3R26', 'Chemical', '-', (42, 47))	('H3R26', 'Protein', (42, 47))
10281	27478411	Four tag SNPs, including rs2746533, rs79395834, rs2076616 and rs10788656, in the PADI2-encoding gene were selected and genotyped using an allele-specific MALDI-TOF mass spectrometry assay (Sequenom MassARRAY).	('rs79395834', 'Var', (36, 46))	('rs10788656', 'Mutation', 'rs10788656', (62, 72))	('rs2746533', 'Var', (25, 34))	('rs2746533', 'Mutation', 'rs2746533', (25, 34))	('rs2076616', 'Var', (48, 57))	('rs2076616', 'Mutation', 'rs2076616', (48, 57))	('rs10788656', 'Var', (62, 72))	('rs79395834', 'Mutation', 'rs79395834', (36, 46))
10282	27478411	To verify the above genotyping result, tag SNP rs10788656 was selected for genotyping in new cohorts of patients with breast cancer (n = 285, 285 women, mean age = 47.65), colon cancer (n = 144, 55 women, mean age = 54.13), esophageal cancer (n = 285, 40 women, mean age = 61.20), cervical cancer (n = 190, 190 women, mean age = 52.75), liver cancer (n = 190, 42 women, mean age = 54.05), lung cancer (n = 190, 56 women, mean age = 58.17), gastric cancer (n = 190, 44 women, mean age = 56.97), and rectal cancer (n = 136, 50 women, mean age = 54.61), as well as in healthy controls (n = 285, 71 women, mean age = 40.1).	('women', 'Species', '9606', (414, 419))	('gastric cancer', 'Disease', 'MESH:D013274', (440, 454))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('women', 'Species', '9606', (311, 316))	('liver cancer', 'Disease', 'MESH:D006528', (337, 349))	('women', 'Species', '9606', (525, 530))	('women', 'Species', '9606', (468, 473))	('women', 'Species', '9606', (255, 260))	('colon cancer', 'Disease', 'MESH:D015179', (172, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('lung cancer', 'Disease', 'MESH:D008175', (389, 400))	('women', 'Species', '9606', (595, 600))	('women', 'Species', '9606', (198, 203))	('women', 'Species', '9606', (363, 368))	('gastric cancer', 'Phenotype', 'HP:0012126', (440, 454))	('esophageal cancer', 'Disease', 'MESH:D004938', (224, 241))	('liver cancer', 'Phenotype', 'HP:0002896', (337, 349))	('lung cancer', 'Phenotype', 'HP:0100526', (389, 400))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('rectal cancer', 'Disease', (498, 511))	('rectal cancer', 'Phenotype', 'HP:0100743', (498, 511))	('breast cancer', 'Disease', (118, 131))	('liver cancer', 'Disease', (337, 349))	('rs10788656', 'Mutation', 'rs10788656', (47, 57))	('esophageal cancer', 'Disease', (224, 241))	('colon cancer', 'Disease', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('patients', 'Species', '9606', (104, 112))	('gastric cancer', 'Disease', (440, 454))	('women', 'Species', '9606', (146, 151))	('rs10788656', 'Var', (47, 57))	('rectal cancer', 'Disease', 'MESH:D012004', (498, 511))	('cervical cancer', 'Disease', (281, 296))	('lung cancer', 'Disease', (389, 400))	('cervical cancer', 'Disease', 'MESH:D002583', (281, 296))	('colon cancer', 'Phenotype', 'HP:0003003', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
10314	23686769	Aberrant cyclin expression profiles have a negative prognosis in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cyclin', 'Gene', (9, 15))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cyclin', 'Gene', '18538', (9, 15))
10323	23686769	HDAC knock-down causes check point arrest that inhibits cancer cell growth.	('HDAC', 'Gene', (0, 4))	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('knock-down', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('arrest', 'Disease', (35, 41))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('inhibits', 'NegReg', (47, 55))
10377	23686769	Fluorescence-based multiplex assays were with a staining station (Leica Microsystems, Buffalo Grove, IL) using antibodies to detect T cells with CD8 (Leica), macrophages with CD68 (Leica), B cells with CD20 (Leica), or myeloid cells with myeloperoxidase (MPO, Thermo Fisher Scientific, Waltham, MA).	('Leica Microsystems', 'Disease', 'None', (66, 84))	('Leica Microsystems', 'Disease', (66, 84))	('MPO', 'Gene', '17523', (255, 258))	('CD8', 'Var', (145, 148))	('CD20', 'Gene', (202, 206))	('myeloperoxidase', 'Gene', (238, 253))	('CD20', 'Gene', '12482', (202, 206))	('CD68', 'Gene', '12514', (175, 179))	('myeloperoxidase', 'Gene', '17523', (238, 253))	('CD68', 'Gene', (175, 179))	('MPO', 'Gene', (255, 258))
10378	23686769	Genomic DNA was isolated from paraffin-embedded sections from study cases and independently analyzed for EGFR and KRAS mutations using optimized methods.	('KRAS', 'Gene', (114, 118))	('EGFR', 'Gene', (105, 109))	('EGFR', 'Gene', '13649', (105, 109))	('mutations', 'Var', (119, 128))	('paraffin', 'Chemical', 'MESH:D010232', (30, 38))
10410	23686769	All cases had wild-type epidermal growth factor receptor (EGFR, data not shown) sequences; 4 had KRAS codon 12 mutations in their lung cancers (Table 1).	('lung cancers', 'Disease', (130, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('epidermal growth factor receptor', 'Gene', (24, 56))	('EGFR', 'Gene', (58, 62))	('epidermal growth factor receptor', 'Gene', '13649', (24, 56))	('EGFR', 'Gene', '13649', (58, 62))	('lung cancers', 'Disease', 'MESH:D008175', (130, 142))	('KRAS codon', 'Var', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancers', 'Phenotype', 'HP:0100526', (130, 142))
10419	23686769	These responses were correlated with presence of KRAS mutations in these tumors (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('KRAS', 'Gene', (49, 53))
10421	23686769	All 4 NSCLC cases with KRAS mutations had necrosis, and acute or chronic inflammation in post-treatment tumors.	('acute', 'CPA', (56, 61))	('inflammation', 'Disease', 'MESH:D007249', (73, 85))	('inflammation', 'Disease', (73, 85))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('necrosis', 'Disease', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('KRAS', 'Gene', (23, 27))	('tumors', 'Disease', (104, 110))	('necrosis', 'Disease', 'MESH:D009336', (42, 50))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('men', 'Species', '9606', (99, 102))	('mutations', 'Var', (28, 37))	('NSCLC', 'Disease', (6, 11))
10440	23686769	5 and Table 1 included changes in expressed cell cycle regulators and reduced proliferation of human tumors despite the presence of KRAS mutations.	('human', 'Species', '9606', (95, 100))	('reduced', 'NegReg', (70, 77))	('KRAS', 'Gene', (132, 136))	('changes', 'Reg', (23, 30))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutations', 'Var', (137, 146))	('expressed cell cycle regulators', 'MPA', (34, 65))	('proliferation', 'CPA', (78, 91))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
10467	23686769	After p21 knockdown, cancer cells become sensitive to vorinostat treatment.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('p21', 'Gene', (6, 9))	('men', 'Species', '9606', (70, 73))	('sensitive to vorinostat treatment', 'MPA', (41, 74))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('vorinostat', 'Chemical', 'MESH:D000077337', (54, 64))	('knockdown', 'Var', (10, 19))
10476	23686769	Findings were translated into a vorinostat window of opportunity clinical trial where induced p21 and p27 and reduced G1 cyclin expression occurred in lung cancers independent of the presence of KRAS mutations.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('p21', 'Var', (94, 97))	('lung cancers', 'Disease', (151, 163))	('p27', 'Var', (102, 105))	('reduced', 'NegReg', (110, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancers', 'Disease', 'MESH:D008175', (151, 163))	('lung cancers', 'Phenotype', 'HP:0100526', (151, 163))	('vorinostat', 'Chemical', 'MESH:D000077337', (32, 42))	('cyclin', 'Gene', '18538', (121, 127))	('cyclin', 'Gene', (121, 127))
10502	33627631	There are three common processes of circRNA reverse splicing: exon skipping, intron pairing, and RNA-binding-protein-driven circularization.	('RNA-binding-protein', 'Gene', (97, 116))	('exon skipping', 'Var', (62, 75))	('intron pairing', 'Var', (77, 91))	('RNA-binding-protein', 'Gene', '84549', (97, 116))
10504	33627631	For example, circ_0055625, which is highly expressed in colon cancer, acts as a "sponge" for miR-106b to further promote the development of the disease.	('miR-106b', 'Gene', '406900', (93, 101))	('colon cancer', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('promote', 'PosReg', (113, 120))	('circ_0055625', 'Var', (13, 25))	('miR-106b', 'Gene', (93, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (56, 68))	('colon cancer', 'Disease', 'MESH:D015179', (56, 68))	('development', 'CPA', (125, 136))
10522	33627631	The expression level of Circ_100876 in ESCC was found to be significantly increased; furthermore, its expression level was strongly correlated with the depth of invasion, lymph node metastasis, and vascular invasion of esophageal cancer cells, and the survival time of patients with high expression of Circ_100876 was significantly shortened.	('expression level', 'MPA', (4, 20))	('shortened', 'NegReg', (332, 341))	('Circ_100876', 'Var', (302, 313))	('Circ_100876', 'Var', (24, 35))	('esophageal cancer', 'Disease', (219, 236))	('correlated', 'Reg', (132, 142))	('ESCC', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('esophageal cancer', 'Disease', 'MESH:D004938', (219, 236))	('lymph node metastasis', 'CPA', (171, 192))	('increased', 'PosReg', (74, 83))	('depth of invasion', 'CPA', (152, 169))	('vascular invasion', 'CPA', (198, 215))	('expression level', 'MPA', (102, 118))	('patients', 'Species', '9606', (269, 277))	('survival time', 'CPA', (252, 265))
10523	33627631	In addition, after the knockout of Circ_100876, the proliferation level of tumor cells decreased significantly (resulting in G2/M-phase cell cycle arrest and the occurrence of apoptosis in vitro), and the occurrence of cell metastasis, invasion, and epithelial mesenchymal transformation (EMT) was inhibited, which clearly indicated that Circ_100876 was closely related to the proliferation, metastasis, and invasion of esophageal cancer, such that it can be used as a marker to detect esophageal cancer.	('invasion', 'CPA', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('proliferation level', 'CPA', (52, 71))	('tumor', 'Disease', (75, 80))	('decreased', 'NegReg', (87, 96))	('inhibited', 'NegReg', (298, 307))	('epithelial mesenchymal transformation', 'CPA', (250, 287))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (486, 503))	('arrest', 'Disease', (147, 153))	('Circ_100876', 'Var', (35, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (420, 437))	('cancer', 'Phenotype', 'HP:0002664', (497, 503))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('apoptosis', 'CPA', (176, 185))	('esophageal cancer', 'Disease', (486, 503))	('knockout', 'Var', (23, 31))	('esophageal cancer', 'Disease', (420, 437))	('cell metastasis', 'CPA', (219, 234))	('arrest', 'Disease', 'MESH:D006323', (147, 153))
10530	33627631	In ESCC, miR-3680-3p is expressed at a low level and plays a role in inhibiting tumor growth, while circ-PRKCI can bind to miR-3680-3p and reverse its regulatory effect.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('miR-3680-3p', 'Var', (9, 20))	('regulatory effect', 'MPA', (151, 168))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PRKCI', 'Gene', '5584', (105, 110))	('bind', 'Interaction', (115, 119))	('PRKCI', 'Gene', (105, 110))	('tumor', 'Disease', (80, 85))	('miR-3680-3p', 'Var', (123, 134))	('reverse', 'NegReg', (139, 146))	('inhibiting', 'NegReg', (69, 79))
10531	33627631	In addition, some overexpressed circRNAs regulate biological processes in tumors through their own pathways; for example, circ_0003340 is overexpressed in ESCC and promotes tumor development through the miR-564/TPX2 pathway.	('circ_0003340', 'Var', (122, 134))	('TPX2', 'Gene', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('miR-564', 'Gene', '693149', (203, 210))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('regulate', 'Reg', (41, 49))	('promotes', 'PosReg', (164, 172))	('TPX2', 'Gene', '22974', (211, 215))	('miR-564', 'Gene', (203, 210))	('tumor', 'Disease', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('ESCC', 'Disease', (155, 159))	('tumors', 'Disease', (74, 80))
10533	33627631	The expression of hsa_circ_0012563 in ESCC was significantly upregulated, while hsa_circ_0012563 knockout inhibited the XRCC1-mediated EMT pathway, which, in turn, inhibited cell migration and invasion.	('upregulated', 'PosReg', (61, 72))	('XRCC1', 'Gene', (120, 125))	('inhibited', 'NegReg', (106, 115))	('expression', 'MPA', (4, 14))	('hsa_circ_0012563', 'Var', (18, 34))	('hsa_circ_0012563', 'Var', (80, 96))	('inhibited', 'NegReg', (164, 173))	('XRCC1', 'Gene', '7515', (120, 125))
10534	33627631	Hsa_circ_0004771 is significantly upregulated in ESCC, and, by acting as a molecular sponge of miR-339-5p, it positively regulates CDC25A to promote the proliferation of ESCC.	('ESCC', 'CPA', (170, 174))	('upregulated', 'PosReg', (34, 45))	('Hsa_circ_0004771', 'Var', (0, 16))	('proliferation', 'CPA', (153, 166))	('ESCC', 'Disease', (49, 53))	('regulates', 'Reg', (121, 130))	('promote', 'PosReg', (141, 148))	('CDC25A', 'Gene', (131, 137))	('CDC25A', 'Gene', '993', (131, 137))
10535	33627631	Hsa_circ_0006948, which is overexpressed in ESCC tissue, can induce EMT and promote tumor progression by acting as a sponge for miR490-3p.	('promote', 'PosReg', (76, 83))	('induce', 'PosReg', (61, 67))	('Hsa_circ_0006948', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('EMT', 'CPA', (68, 71))
10558	33627631	), circRNA_100269, circYAP1, CircLARP4, circ-ZFR, circFAT1 (e2), and circ_0027599 (ref. )	('CircLARP4', 'Gene', '113251', (29, 38))	('YAP1', 'Gene', (23, 27))	('CircLARP4', 'Gene', (29, 38))	('circ_0027599', 'Var', (69, 81))	('YAP1', 'Gene', '10413', (23, 27))
10565	33627631	Its abnormal expression affects the proliferation of tumor cells and the development of PDAC.	('abnormal', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('affects', 'Reg', (24, 31))	('tumor', 'Disease', (53, 58))	('development', 'CPA', (73, 84))
10566	33627631	Studies have shown that the expression of circRNA_100782 in PDAC tissue is significantly upregulated and plays a positive role in regulating the proliferation of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('regulating', 'Reg', (130, 140))	('positive', 'PosReg', (113, 121))	('upregulated', 'PosReg', (89, 100))	('tumor', 'Disease', (162, 167))	('expression', 'MPA', (28, 38))	('circRNA_100782', 'Var', (42, 56))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
10567	33627631	found that circRNA_100782 inhibits the biological activity of miR-124 and further activates its downstream targets, interleukin-6 receptor (IL6R) and signal transducer and activator of transcription 3 (STAT3), by acting as a sponge for miR-124, thus enabling cell proliferation to be promoted.	('cell proliferation', 'CPA', (259, 277))	('inhibits', 'NegReg', (26, 34))	('STAT3', 'Gene', (202, 207))	('promoted', 'PosReg', (284, 292))	('STAT3', 'Gene', '6774', (202, 207))	('miR-124', 'Gene', (62, 69))	('IL6R', 'Gene', (140, 144))	('interleukin-6 receptor', 'Gene', (116, 138))	('activates', 'PosReg', (82, 91))	('signal transducer and activator of transcription 3', 'Gene', '6774', (150, 200))	('enabling', 'PosReg', (250, 258))	('biological activity', 'MPA', (39, 58))	('IL6R', 'Gene', '3570', (140, 144))	('interleukin-6 receptor', 'Gene', '3570', (116, 138))	('circRNA_100782', 'Var', (11, 25))
10570	33627631	In addition, circRNA_0007534 and ciRS-7 are also highly expressed in PDAC tissues; circRNA_0007534 regulates miR-625 and miR-892b, increasing the carcinogenicity of PDAC, while ciRS-7 targets miR-7 and regulates the EGFR/STAT3 signal pathway, thus playing a carcinogenic role.	('STAT3', 'Gene', (221, 226))	('carcinogenic', 'Disease', (258, 270))	('carcinogenic', 'Disease', (146, 158))	('STAT3', 'Gene', '6774', (221, 226))	('EGFR', 'Gene', (216, 220))	('miR-7', 'Gene', '10859', (192, 197))	('regulates', 'Reg', (99, 108))	('ciRS-7', 'Gene', '103611090', (177, 183))	('ciRS-7', 'Gene', '103611090', (33, 39))	('regulates', 'Reg', (202, 211))	('carcinogenic', 'Disease', 'MESH:D063646', (258, 270))	('carcinogenic', 'Disease', 'MESH:D063646', (146, 158))	('increasing', 'PosReg', (131, 141))	('miR-625', 'Gene', (109, 116))	('ciRS-7', 'Gene', (177, 183))	('ciRS-7', 'Gene', (33, 39))	('miR-892b', 'Gene', '100126307', (121, 129))	('circRNA_0007534', 'Var', (83, 98))	('EGFR', 'Gene', '1956', (216, 220))	('miR-625', 'Gene', '693210', (109, 116))	('miR-892b', 'Gene', (121, 129))	('miR-7', 'Gene', (192, 197))
10576	33627631	The expression level of hsa_circ_100338 in HC is closely related to tumor metastasis and the rate of patient survival.	('expression level', 'MPA', (4, 20))	('hsa_circ_100338', 'Var', (24, 39))	('tumor metastasis', 'Disease', 'MESH:D009362', (68, 84))	('tumor metastasis', 'Disease', (68, 84))	('related', 'Reg', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('patient', 'Species', '9606', (101, 108))
10577	33627631	In addition, the study found that an increase in hsa_circ_100338 can also activate the mTOR signaling pathway in HC through the circRNA_100338/miR141-3p/RHEB axis and is related to poor prognosis in patients with hepatitis B-related HC.	('mTOR', 'Gene', '2475', (87, 91))	('hsa_circ_100338', 'Var', (49, 64))	('hepatitis', 'Phenotype', 'HP:0012115', (213, 222))	('hepatitis B-related HC', 'Disease', 'MESH:D006509', (213, 235))	('hepatitis B-related HC', 'Disease', (213, 235))	('increase', 'PosReg', (37, 45))	('patients', 'Species', '9606', (199, 207))	('RHEB', 'Gene', (153, 157))	('activate', 'PosReg', (74, 82))	('RHEB', 'Gene', '6009', (153, 157))	('mTOR', 'Gene', (87, 91))
10578	33627631	found that circ_104075 is abundant in liver cancer tumor tissues, cells, and patient serum and can act as a sponge for miR-582-3p to upregulate the expression of the downstream target YAP.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('liver cancer tumor', 'Disease', 'MESH:D006528', (38, 56))	('liver cancer', 'Phenotype', 'HP:0002896', (38, 50))	('YAP', 'Gene', '10413', (184, 187))	('miR-582-3p', 'Var', (119, 129))	('upregulate', 'PosReg', (133, 143))	('YAP', 'Gene', (184, 187))	('circ_104075', 'Var', (11, 22))	('expression', 'MPA', (148, 158))	('patient', 'Species', '9606', (77, 84))	('liver cancer tumor', 'Disease', (38, 56))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
10581	33627631	Circ_0067934 is also upregulated in HC tissues and cell lines, while knockout of the circ_0067934 gene can inhibit proliferation, migration, invasion, and apoptosis in Hep3B and Huh7 cells.	('inhibit', 'NegReg', (107, 114))	('invasion', 'CPA', (141, 149))	('Hep3B', 'CellLine', 'CVCL:0326', (168, 173))	('Huh7', 'CellLine', 'CVCL:0336', (178, 182))	('proliferation', 'CPA', (115, 128))	('migration', 'CPA', (130, 139))	('knockout', 'Var', (69, 77))	('apoptosis', 'CPA', (155, 164))	('circ_0067934', 'Gene', (85, 97))
10584	33627631	In HCC patients with high body fat percentages, the expression of circ-DB is upregulated, and circ-DB downregulates the expression of miR-34a by acting as a miRNA sponge, thus activating USP7, which can promote tumor growth and metastasis by reducing the ubiquitination of Cyclin A2 and many other proteins.	('upregulated', 'PosReg', (77, 88))	('USP7', 'Gene', '7874', (187, 191))	('tumor', 'Disease', (211, 216))	('patients', 'Species', '9606', (7, 15))	('expression', 'MPA', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('metastasis', 'CPA', (228, 238))	('circ-DB', 'Gene', (66, 73))	('Cyclin A2', 'Gene', '890', (273, 282))	('reducing', 'NegReg', (242, 250))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('miR-34a', 'Gene', (134, 141))	('Cyclin A2', 'Gene', (273, 282))	('USP7', 'Gene', (187, 191))	('downregulates', 'NegReg', (102, 115))	('miR-34a', 'Gene', '407040', (134, 141))	('expression', 'MPA', (52, 62))	('activating', 'PosReg', (176, 186))	('promote', 'PosReg', (203, 210))	('circ-DB', 'Var', (94, 101))
10589	33627631	It can mediate sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1, and N-methylated CircRNA-SORE can also maintain sorafenib resistance through beta-catenin signaling.	('stabilizing', 'NegReg', (67, 78))	('YBX1', 'Gene', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('mediate', 'Reg', (7, 14))	('beta-catenin', 'Gene', (162, 174))	('maintain', 'Reg', (124, 132))	('sorafenib resistance', 'MPA', (133, 153))	('sorafenib', 'Chemical', 'MESH:D000077157', (15, 24))	('YBX1', 'Gene', '4904', (79, 83))	('beta-catenin', 'Gene', '1499', (162, 174))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('sorafenib', 'Chemical', 'MESH:D000077157', (133, 142))	('hepatocellular carcinoma', 'Disease', (39, 63))	('N-methylated', 'Var', (89, 101))
10598	33627631	The overall survival rate of CCA patients with high expression of CDR1as is significantly lower than that of CCA patients with low expression of CDR1as.	('CDR1as', 'Gene', (145, 151))	('patients', 'Species', '9606', (33, 41))	('CDR1as', 'Gene', '103611090', (66, 72))	('CDR1as', 'Gene', '103611090', (145, 151))	('patients', 'Species', '9606', (113, 121))	('CCA', 'Disease', (29, 32))	('high expression', 'Var', (47, 62))	('lower', 'NegReg', (90, 95))	('CDR1as', 'Gene', (66, 72))
10601	33627631	found that circ_0005230 is highly expressed in CCA, playing a carcinogenic role by acting as a sponge for miR-1238 and miR-1299, and is positively correlated with clinical severity.	('miR-1238', 'Gene', (106, 114))	('miR-1299', 'Gene', (119, 127))	('miR-1238', 'Gene', '100302226', (106, 114))	('miR-1299', 'Gene', '100302167', (119, 127))	('circ_0005230', 'Var', (11, 23))	('CCA', 'Disease', (47, 50))	('carcinogenic', 'Disease', 'MESH:D063646', (62, 74))	('carcinogenic', 'Disease', (62, 74))	('correlated', 'Reg', (147, 157))
10602	33627631	The other circRNA, hsa_circ_0001649, is scarce in CCA tissues and cells, while high levels of hsa_circ_0001649 can inhibit the proliferation, migration, and invasion of CCA cells and induce cell apoptosis to exert a tumor suppressor effect.	('cell apoptosis', 'CPA', (190, 204))	('tumor', 'Disease', (216, 221))	('CCA', 'Disease', (169, 172))	('proliferation', 'CPA', (127, 140))	('migration', 'CPA', (142, 151))	('inhibit', 'NegReg', (115, 122))	('hsa_circ_0001649', 'Var', (94, 110))	('invasion', 'CPA', (157, 165))	('induce', 'Reg', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
10620	33627631	In addition, hsa_circ_0004585, hsa_circRNA_102958, circRNA_101951, circ_0060745, circ_0001946, circRNA_0000392, and circRNA_100876 are highly expressed in CRC and regulate tumor growth through their own pathways.	('regulate', 'Reg', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('circ_0060745', 'Var', (67, 79))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('circRNA_101951', 'Var', (51, 65))	('circRNA_0000392', 'Var', (95, 110))	('circ_0001946', 'Var', (81, 93))	('circRNA_100876', 'Var', (116, 130))	('CRC', 'Disease', (155, 158))
10621	33627631	Other circRNAs play inhibitory roles in CRC: hsa_circRNA_103809 is expressed at low levels in CRC, and as a tumor suppressor gene, it regulates tumor cell proliferation and migration through the miR-532-3p/FOXO4 axis; circRNA_0026344 also acts as a tumor suppressor gene to affect the occurrence and development of tumors.	('circRNA_0026344', 'Var', (218, 233))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Disease', (249, 254))	('occurrence', 'CPA', (285, 295))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('FOXO4', 'Gene', '4303', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('migration', 'CPA', (173, 182))	('affect', 'Reg', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', (144, 149))	('tumors', 'Disease', (315, 321))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CRC', 'Phenotype', 'HP:0003003', (40, 43))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('regulates', 'Reg', (134, 143))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('FOXO4', 'Gene', (206, 211))	('tumor', 'Disease', (315, 320))
10622	33627631	The expression of circRNA_0026344 in CRC is significantly downregulated, and it functions as a sponge for miR-21/miR-31.	('miR-21', 'Gene', (106, 112))	('miR-31', 'Gene', '407035', (113, 119))	('expression', 'MPA', (4, 14))	('circRNA_0026344', 'Var', (18, 33))	('downregulated', 'NegReg', (58, 71))	('miR-21', 'Gene', '406991', (106, 112))	('CRC', 'Phenotype', 'HP:0003003', (37, 40))	('miR-31', 'Gene', (113, 119))
10623	33627631	The downregulation of circRNA_0026344 levels will lead to an increase in CRC progression and lymph node metastasis; therefore, low expression of circRNA_0026344 may predict a poor prognosis in CRC patients.	('CRC', 'Disease', (73, 76))	('patients', 'Species', '9606', (197, 205))	('CRC', 'Disease', (193, 196))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))	('circRNA_0026344', 'Var', (145, 160))	('expression', 'MPA', (131, 141))	('CRC', 'Phenotype', 'HP:0003003', (193, 196))	('downregulation', 'NegReg', (4, 18))	('increase', 'PosReg', (61, 69))	('lymph node metastasis', 'CPA', (93, 114))
10640	32917154	Chemotherapy-induced release of circulating-tumor cells into the bloodstream in collective migration units with cancer-associated fibroblasts in metastatic cancer patients Recent studies have shown that chemotherapy destabilizes the blood vasculature and increases circulating tumor cell (CTC) influx into the circulation of metastatic cancer patients (Met-pa).	('cancer', 'Disease', (112, 118))	('blood vasculature', 'MPA', (233, 250))	('Met-pa', 'Chemical', '-', (353, 359))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('cancer', 'Disease', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('chemotherapy', 'Var', (203, 215))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (343, 351))	('increases', 'PosReg', (255, 264))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('destabilizes', 'NegReg', (216, 228))	('tumor', 'Disease', (277, 282))	('cancer', 'Disease', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
10703	32917154	Then, cells were incubated with 100 muL of 10 mug/mL Streptavidin-Alexa Fluor 594 (Biolegend), 10 mug/mL of anti-cytokeratin conjugated with FITC (CK, Clone CAM5.2, BD) and 10 mug/mL of anti-vimentin conjugated with Alexa Fluor 647 (Clone W16220A, Biolegend) in 0.02% Tween-20 (Research Products) for 45 min.	('FITC', 'Chemical', 'MESH:D016650', (141, 145))	('Tween-20', 'Chemical', 'MESH:D011136', (268, 276))	('vimentin', 'Gene', '7431', (191, 199))	('Alexa Fluor 647', 'Chemical', 'MESH:C569686', (216, 231))	('vimentin', 'Gene', (191, 199))	('W16220A', 'Var', (239, 246))	('Alexa Fluor 594', 'Chemical', '-', (66, 81))	('W16220A', 'SUBSTITUTION', 'None', (239, 246))
10711	32917154	To generate 100 nm unilamellar liposomes, the multilamellar liposomes were subjected to 10 extrusion cycles using polycarbonate membranes of two different sizes (200 nm and 100 nm) at 55  C. Freshly made liposomes were incubated with E-selectin (17.5 mug/mL) and TRAIL (15 mug/mL) at 37  C for 15 min.	('17.5', 'Var', (246, 250))	('E-selectin', 'Gene', '6401', (234, 244))	('E-selectin', 'Gene', (234, 244))
10723	32917154	This is expected due to the theory that tumor cells migrate in aggregate form with stromal cells such as CAFs, consistent with the aggregates we have observed in several Met-pa (Fig.	('Met-pa', 'Chemical', '-', (170, 176))	('CAF', 'Gene', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CAF', 'Gene', '8850', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Met-pa', 'Var', (170, 176))
10789	30922343	The 5-year OS rate of patients with cN0, cN1 SLNM (-), cN2 SLNM (-), cN3 SLNM (-) and SLNM (+) were 62.8 (P < 0.001), 34.0 (P = 0.16), 20.0 (P = 0.785), 0 (P < 0.001) and 26.9%, respectively.	('OS', 'Chemical', '-', (11, 13))	('cN1', 'Gene', '84618', (41, 44))	('cN2', 'Gene', '55748', (55, 58))	('cN1', 'Gene', (41, 44))	('patients', 'Species', '9606', (22, 30))	('cN2', 'Gene', (55, 58))	('cN0', 'Var', (36, 39))	('cN3 SLNM', 'Var', (69, 77))
10835	30922343	Survival analysis was conducted considering the SLNM as distant metastatic disease, and the 5-year OS rates of the patients with cN0 with SLNM (-), cN1 with SLNM (-), cN2 with SLNM (-), cN3 with SLNM (-), and SLNM (+) with cN1 or cN2 or cN3 were 62.8, 34.0, 20.0, 0 and 26.9%, respectively.	('cN0', 'Var', (129, 132))	('cN1', 'Gene', '84618', (223, 226))	('patients', 'Species', '9606', (115, 123))	('cN1', 'Gene', '84618', (148, 151))	('cN2', 'Gene', (167, 170))	('SLNM (-', 'Var', (157, 164))	('cN2', 'Gene', (230, 233))	('cN1', 'Gene', (223, 226))	('cN1', 'Gene', (148, 151))	('OS', 'Chemical', '-', (99, 101))	('cN2', 'Gene', '55748', (167, 170))	('SLNM', 'Var', (138, 142))	('cN2', 'Gene', '55748', (230, 233))
10958	29845017	This cancer incidence in developed countries is higher than developing countries, because of higher prevalence of the cancer risk factors in developed countries, such as low parity, older age at first pregnancy, sedentary occupation, high-calorie intake, and use of hormonal replacement therapy.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('high-calorie', 'Var', (234, 246))	('cancer', 'Disease', (5, 11))	('men', 'Species', '9606', (282, 285))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('sedentary', 'Disease', (212, 221))
10993	29396516	Moreover, inhibition of RAP80 greatly sensitized EC cells to ATM inhibitor KU-55933, triggering a potential combination of RAP80 inhibitors and ATM inhibitors to enhance the therapeutic efficiency of ESCC patients for the clinicians.	('ATM', 'Gene', '472', (144, 147))	('patients', 'Species', '9606', (205, 213))	('sensitized', 'Reg', (38, 48))	('inhibitors', 'Var', (129, 139))	('KU-55933', 'Chemical', 'MESH:C495818', (75, 83))	('enhance', 'PosReg', (162, 169))	('ATM', 'Gene', (61, 64))	('RAP80', 'Gene', '51720', (123, 128))	('ATM', 'Gene', (144, 147))	('ATM', 'Gene', '472', (61, 64))	('inhibition', 'Var', (10, 20))	('RAP80', 'Gene', (24, 29))	('combination', 'Interaction', (108, 119))	('RAP80', 'Gene', (123, 128))	('RAP80', 'Gene', '51720', (24, 29))
11007	29396516	In summary, our findings support a possible combination of RAP80 inhibitors with ATM inhibitors or USP13 inhibitors to enhance the therapeutic efficiency for ESCC patients.	('enhance', 'PosReg', (119, 126))	('USP13', 'Gene', '8975', (99, 104))	('patients', 'Species', '9606', (163, 171))	('ATM', 'Gene', (81, 84))	('USP13', 'Gene', (99, 104))	('combination', 'Interaction', (44, 55))	('ESCC', 'Disease', (158, 162))	('therapeutic', 'MPA', (131, 142))	('ATM', 'Gene', '472', (81, 84))	('inhibitors', 'Var', (65, 75))	('RAP80', 'Gene', (59, 64))	('RAP80', 'Gene', '51720', (59, 64))
11025	29396516	In response to DNA damage, RAP80 is phosphorylated by ATM/ATR at numerous serine sites (S101, S205, S140, S402, S419) and then forms a pivotal complex with CCDC98-BRCC45-MERIT40-BRCC36-NBA1-BRCA1 (BRCA-A) to regulate the G2/M checkpoint and the cellular sensitivity to irradiation (IR).	('RAP80', 'Gene', (27, 32))	('S101', 'Var', (88, 92))	('cellular', 'CPA', (245, 253))	('MERIT40', 'Gene', '29086', (170, 177))	('NBA1', 'Gene', '29086', (185, 189))	('ATR', 'Gene', '545', (58, 61))	('BRCC36', 'Gene', (178, 184))	('ATM', 'Gene', '472', (54, 57))	('S140', 'Var', (100, 104))	('G2/M checkpoint', 'CPA', (221, 236))	('CCDC98', 'Gene', (156, 162))	('BRCC45', 'Gene', (163, 169))	('RAP80', 'Gene', '51720', (27, 32))	('S205', 'Var', (94, 98))	('S419', 'Var', (112, 116))	('serine', 'Chemical', 'MESH:D012694', (74, 80))	('ATM', 'Gene', (54, 57))	('ATR', 'Gene', (58, 61))	('BRCA1', 'Gene', '672', (190, 195))	('BRCA1', 'Gene', (190, 195))	('NBA1', 'Gene', (185, 189))	('CCDC98', 'Gene', '84142', (156, 162))	('BRCC36', 'Gene', '79184', (178, 184))	('BRCC45', 'Gene', '9577', (163, 169))	('regulate', 'Reg', (208, 216))	('MERIT40', 'Gene', (170, 177))	('S402', 'Var', (106, 110))
11027	29396516	Intriguingly, the expression of pATM/ATM was obviously reduced in shRAP80 #1 infected EC cells, especially when treated with KU-55933 (Fig.	('RAP80', 'Gene', (68, 73))	('KU-55933', 'Var', (125, 133))	('reduced', 'NegReg', (55, 62))	('pATM/ATM', 'Gene', '472', (32, 40))	('expression', 'MPA', (18, 28))	('RAP80', 'Gene', '51720', (68, 73))	('pATM/ATM', 'Gene', (32, 40))	('KU-55933', 'Chemical', 'MESH:C495818', (125, 133))
11033	29396516	Results from flow cytometry showed that EC1/shRAP80 #1 cells were significantly arrested in G2/M phase, especially when treated with KU-55933 (Fig.	('RAP80', 'Gene', '51720', (46, 51))	('RAP80', 'Gene', (46, 51))	('KU-55933', 'Chemical', 'MESH:C495818', (133, 141))	('KU-55933', 'Var', (133, 141))	('G2/M phase', 'CPA', (92, 102))	('EC1', 'Gene', (40, 43))	('EC1', 'Gene', '4819', (40, 43))	('arrested', 'NegReg', (80, 88))
11034	29396516	Besides, the following western blotting assays of G2/M checkpoint-specific proteins, such as CHK1/2, Cyclin A, further confirmed the G2/M cell cycle arrest in EC1/shRAP80 #1 cells, particularly in response to KU-55933 treatment (Fig.	('G2/M cell cycle arrest', 'CPA', (133, 155))	('EC1', 'Gene', '4819', (159, 162))	('KU-55933', 'Chemical', 'MESH:C495818', (209, 217))	('EC1', 'Gene', (159, 162))	('RAP80', 'Gene', '51720', (165, 170))	('RAP80', 'Gene', (165, 170))	('KU-55933', 'Var', (209, 217))
11037	29396516	In the study, data from colonial survival assays showed that ATM inhibitor KU-55933 strongly enhanced the cell growth inhibition of EC1/shRAP80 #1 cells(Fig.	('KU-55933', 'Chemical', 'MESH:C495818', (75, 83))	('cell growth inhibition', 'CPA', (106, 128))	('KU-55933', 'Var', (75, 83))	('ATM', 'Gene', (61, 64))	('EC1', 'Gene', (132, 135))	('enhanced', 'PosReg', (93, 101))	('EC1', 'Gene', '4819', (132, 135))	('ATM', 'Gene', '472', (61, 64))	('RAP80', 'Gene', '51720', (138, 143))	('RAP80', 'Gene', (138, 143))
11038	29396516	4e), uncovering a possible combination therapy of RAP80 inhibitors and ATM inhibitors for ESCC patients.	('patients', 'Species', '9606', (95, 103))	('ATM', 'Gene', (71, 74))	('RAP80', 'Gene', '51720', (50, 55))	('ATM', 'Gene', '472', (71, 74))	('RAP80', 'Gene', (50, 55))	('inhibitors', 'Var', (56, 66))	('ESCC', 'Disease', (90, 94))
11045	29396516	Interestingly, similar to pATM, the expression of USP13 was also reduced in EC cells infected with shRAP80 #1, which could be further enhanced by KU-55933 (Fig.	('USP13', 'Gene', (50, 55))	('RAP80', 'Gene', '51720', (101, 106))	('RAP80', 'Gene', (101, 106))	('reduced', 'NegReg', (65, 72))	('enhanced', 'PosReg', (134, 142))	('ATM', 'Gene', (27, 30))	('KU-55933', 'Chemical', 'MESH:C495818', (146, 154))	('USP13', 'Gene', '8975', (50, 55))	('ATM', 'Gene', '472', (27, 30))	('expression', 'MPA', (36, 46))	('KU-55933', 'Var', (146, 154))
11055	29396516	It is reported that the foci formation of gammaH2AX is positively correlated with the severity of DNA damage both in vivo and in vitro.	('DNA damage', 'Disease', (98, 108))	('correlated', 'Reg', (66, 76))	('gammaH2AX', 'Chemical', '-', (42, 51))	('gammaH2AX', 'Var', (42, 51))
11056	29396516	Results from our confocal IF assays showed that gammaH2AX foci-positive cells in 200 cells were significantly increased in shRAP80 #1 transfected cells, especially when treated with cisplatin (Fig.	('RAP80', 'Gene', '51720', (125, 130))	('RAP80', 'Gene', (125, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (182, 191))	('increased', 'PosReg', (110, 119))	('gammaH2AX', 'Protein', (48, 57))	('gammaH2AX', 'Chemical', '-', (48, 57))	('transfected', 'Var', (134, 145))
11084	29396516	Paradoxically, in pancreatic cancer cells, it is reported that inhibition of RAP80 using siRNAs, the cell apoptosis is significantly induced, indicated by the expression of apoptotic biomarkers, including BAX, BCL-2, SURVIVIN, and Caspas-8 at both mRNA and protein levels, revealing an oncogenic role of RAP80 in pancreatic tumorigenesis.	('cell apoptosis', 'CPA', (101, 115))	('RAP80', 'Gene', '51720', (77, 82))	('siRNAs', 'Gene', (89, 95))	('BCL-2', 'Gene', '596', (210, 215))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))	('BCL-2', 'Gene', (210, 215))	('pancreatic', 'Disease', 'MESH:D010195', (313, 323))	('RAP80', 'Gene', '51720', (304, 309))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('BAX', 'Gene', (205, 208))	('pancreatic', 'Disease', 'MESH:D010195', (18, 28))	('BAX', 'Gene', '581', (205, 208))	('induced', 'PosReg', (133, 140))	('pancreatic', 'Disease', (313, 323))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('RAP80', 'Gene', (77, 82))	('inhibition', 'Var', (63, 73))	('pancreatic', 'Disease', (18, 28))	('pancreatic cancer', 'Disease', (18, 35))	('tumor', 'Disease', (324, 329))	('RAP80', 'Gene', (304, 309))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
11087	29396516	It is reported that knockdown of RAP80 using siRNAs in Hela cells treated with IR showed a defective G2/M checkpoint control.	('Hela', 'CellLine', 'CVCL:0030', (55, 59))	('RAP80', 'Gene', '51720', (33, 38))	('defective', 'NegReg', (91, 100))	('RAP80', 'Gene', (33, 38))	('G2/M checkpoint control', 'CPA', (101, 124))	('knockdown', 'Var', (20, 29))
11089	29396516	Upon DNA damage, RAP80 is reported to be phosphorylated at several serine sites, such as S101, S140, S205, S402, S419, S677, which requires the involvement of ATM kinase, substrates of which have also been suggested to control the G2/M checkpoint, including BRCA1, CHK2, RAD17.	('RAP80', 'Gene', '51720', (17, 22))	('BRCA1', 'Gene', '672', (258, 263))	('CHK2', 'Gene', '11200', (265, 269))	('ATM', 'Gene', '472', (159, 162))	('BRCA1', 'Gene', (258, 263))	('control', 'Reg', (219, 226))	('S419', 'Var', (113, 117))	('ATM', 'Gene', (159, 162))	('S101', 'Var', (89, 93))	('RAD17', 'Gene', '5884', (271, 276))	('S205', 'Var', (101, 105))	('S677', 'Var', (119, 123))	('S140', 'Var', (95, 99))	('serine', 'Chemical', 'MESH:D012694', (67, 73))	('S402', 'Var', (107, 111))	('RAP80', 'Gene', (17, 22))	('RAD17', 'Gene', (271, 276))	('CHK2', 'Gene', (265, 269))
11090	29396516	In the study, our data showed that inhibition of RAP80 caused a significant G2/M cell cycle arrest, which could be obviously enhanced by ATM inhibitor KU-55933, suggesting that the activated ATM is necessarily required for RAP80 to facilitate the G2/M checkpoint transition in EC cells.	('ATM', 'Gene', (191, 194))	('G2/M cell cycle arrest', 'CPA', (76, 98))	('KU-55933', 'Chemical', 'MESH:C495818', (151, 159))	('enhanced', 'PosReg', (125, 133))	('ATM', 'Gene', (137, 140))	('ATM', 'Gene', '472', (191, 194))	('G2/M', 'CPA', (247, 251))	('inhibition', 'Var', (35, 45))	('ATM', 'Gene', '472', (137, 140))	('RAP80', 'Gene', '51720', (223, 228))	('RAP80', 'Gene', (223, 228))	('RAP80', 'Gene', '51720', (49, 54))	('RAP80', 'Gene', (49, 54))
11110	29396516	However, the recruitment of RAD51 was unimpaired in RAP80 knockdown cells treated with or without cisplatin.	('RAP80', 'Gene', (52, 57))	('RAD51', 'Gene', (28, 33))	('RAD51', 'Gene', '5888', (28, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('knockdown', 'Var', (58, 67))	('RAP80', 'Gene', '51720', (52, 57))
11112	29396516	Overall, our data support the following conclusions: first, RAP80 is a novel and independent biomarker for predicting the development of ESCC; second, targeting RAP80 is a promising way for ESCC patients' therapy; third, combination application of RAP80 inhibitors and ATM inhibitors or USP13 inhibitors will remarkably increase the therapeutic opportunities for ESCC patients in the future.	('USP13', 'Gene', (287, 292))	('increase', 'PosReg', (320, 328))	('ATM', 'Gene', '472', (269, 272))	('ESCC', 'Disease', (363, 367))	('inhibitors', 'Var', (254, 264))	('RAP80', 'Gene', '51720', (60, 65))	('RAP80', 'Gene', (60, 65))	('RAP80', 'Gene', '51720', (161, 166))	('RAP80', 'Gene', (161, 166))	('ATM', 'Gene', (269, 272))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (368, 376))	('RAP80', 'Gene', '51720', (248, 253))	('RAP80', 'Gene', (248, 253))	('USP13', 'Gene', '8975', (287, 292))	('combination', 'Interaction', (221, 232))
11113	29396516	EC cell lines, including EC109, EC1, EC9706, TE1, KYSE150, and the immortalized esophageal epithelial cell line HEEC were all cultured in Dulbecco's modified Eagle's medium (DMEM) with addition of 12% fetal bovine serum, 100 U/ml penicillin, and 100 U/ml streptomycin, and maintained at 37  C incubator with 5% CO2.	('DMEM', 'Chemical', '-', (174, 178))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (138, 172))	('HEEC', 'CellLine', 'None', (112, 116))	('EC1', 'Gene', '4819', (25, 28))	('EC1', 'Gene', (25, 28))	('EC9706', 'Var', (37, 43))	('CO2', 'Chemical', '-', (311, 314))	('EC1', 'Gene', '4819', (32, 35))	('penicillin', 'Chemical', 'MESH:D010406', (230, 240))	('EC1', 'Gene', (32, 35))	('streptomycin', 'Chemical', 'MESH:D013307', (255, 267))	('EC9706', 'CellLine', 'CVCL:E307', (37, 43))	('bovine', 'Species', '9913', (207, 213))
11119	29396516	The establishment of stable RAP80 knockdown EC cells and the transfection of plasmids were performed according to our previous protocols.	('knockdown', 'Var', (34, 43))	('RAP80', 'Gene', '51720', (28, 33))	('RAP80', 'Gene', (28, 33))
11129	29396516	For the detection of foci formation of gammaH2AX, RAD51, and BRCA1 in EC cells treated with or without cisplatin, the immunofluorescence assays (IF) were carried out and finally, the slides were analyzed under the confocal microscope (Zeiss).	('BRCA1', 'Gene', (61, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('gammaH2AX', 'Chemical', '-', (39, 48))	('gammaH2AX', 'Var', (39, 48))	('RAD51', 'Gene', (50, 55))	('BRCA1', 'Gene', '672', (61, 66))	('RAD51', 'Gene', '5888', (50, 55))
11257	28207537	The dissection rates of lymph nodes in the middle (P = 0.012) and lower esophagus (P = 0.027) in the LTT group was higher than that in the LTA group (P = 0.069).	('LTT', 'Var', (101, 104))	('dissection rates', 'CPA', (4, 20))	('LTA', 'Chemical', '-', (139, 142))	('higher', 'PosReg', (115, 121))	('LTT', 'Chemical', '-', (101, 104))
11259	28207537	The dissection rates of lymph nodes in the superior pyloric (P = 0.022) and inferior pylorus (P = 0.001) in the LTA group were significantly higher than those in the IL and LTT groups.	('LTA', 'Var', (112, 115))	('dissection rates', 'CPA', (4, 20))	('LTT', 'Chemical', '-', (173, 176))	('higher', 'PosReg', (141, 147))	('LTA', 'Chemical', '-', (112, 115))
11283	28207537	Yamashita et al believe that dissection of the abdominal proximal perigastric lymph nodes, including the para-cardiac, lesser curvature of the stomach, left gastric artery, and splenic artery lymph nodes, has great survival benefits.	('cardia', 'Disease', 'MESH:D004938', (110, 116))	('cardia', 'Disease', (110, 116))	('splenic artery lymph nodes', 'Disease', (177, 203))	('splenic artery lymph nodes', 'Disease', 'MESH:D000072717', (177, 203))	('dissection', 'Var', (29, 39))	('survival benefits', 'CPA', (215, 232))
11291	28207537	Three studies discussed the optimal extent of the thoracic lymph node dissection for Siewert type II AEG and reported that dissection of the middle and lower esophageal lymph nodes under the inferior mediastinum had significant survival benefits.	('dissection', 'Var', (123, 133))	('AEG', 'Chemical', '-', (101, 104))	('esophageal lymph nodes', 'Disease', (158, 180))	('survival benefits', 'CPA', (228, 245))	('esophageal lymph nodes', 'Disease', 'MESH:D000072717', (158, 180))
11314	28111535	Regarding the stage of cancer, T1aN1 is now classified as Stage II, as is the case with T1bN1.	('N1', 'Chemical', 'MESH:C058271', (91, 93))	('T1aN1', 'Var', (31, 36))	('N1', 'Chemical', 'MESH:C058271', (34, 36))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
11339	28111535	: Mt, 5 cm, Type 2, moderately differentiated squamous cell carcinoma, pT3, INFa, ly1, v1, IM0, pPM0, pDM0, pRM0, multiple primary carcinomas (present, two lesions), CRT-grade 2, pN1 (2/30), sM0, fStage III.	('pDM0', 'Var', (102, 106))	('RM0', 'Chemical', '-', (109, 112))	('pN1', 'Gene', (179, 182))	('DM0', 'Chemical', '-', (103, 106))	('ly', 'Chemical', '-', (28, 30))	('moderately', 'Disease', (20, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('pN1', 'Gene', '5270', (179, 182))	('pRM0', 'Var', (108, 112))	('carcinomas', 'Disease', (131, 141))	('ly', 'Chemical', '-', (82, 84))	('pT3', 'Gene', (71, 74))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (46, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('carcinomas', 'Disease', 'MESH:D002277', (131, 141))	('INFa', 'Gene', '3451', (76, 80))	('CR', 'Chemical', 'MESH:D002857', (166, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('squamous cell carcinoma', 'Disease', (46, 69))	('pT3', 'Gene', '7694', (71, 74))	('pPM0', 'Var', (96, 100))	('INFa', 'Gene', (76, 80))
11379	28111535	T4b Aorta (great artery), trachea, bronchus, pulmonary vein, pulmonary artery, vertebral body.	('ac', 'Chemical', 'MESH:D000186', (28, 30))	('T4b', 'Var', (0, 3))	('pulmonary vein', 'Disease', 'MESH:D000071078', (45, 59))	('pulmonary vein', 'Disease', (45, 59))	('pulmonary artery', 'Disease', (61, 77))	('pulmonary artery', 'Disease', 'MESH:D000071079', (61, 77))
11383	28111535	Note 2: Superficial esophageal cancer: T1a and T1b are designated as superficial cancer regardless of lymph node or distant organ metastasis.	('esophageal cancer', 'Disease', (20, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('T1b', 'Var', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('T1a', 'Gene', '10630', (39, 42))	('cancer', 'Disease', (81, 87))	('T1a', 'Gene', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('ly', 'Chemical', '-', (102, 104))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (31, 37))
11521	28111535	Proximal and distal margin (pPM, pDM)Note  Note: The distance from surgical margin to tumor edge in pPM0 or pDM0 is measured in histological specimens (mm).	('DM', 'Disease', 'MESH:D009223', (109, 111))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('DM0', 'Chemical', '-', (109, 112))	('tumor', 'Disease', (86, 91))	('DM', 'Disease', 'MESH:D009223', (34, 36))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('pPM0', 'Var', (100, 104))
11738	27832115	The aberrations in miRNA expression have been reported to be involved in tumorigenesis and cancer development.	('aberrations', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('involved', 'Reg', (61, 69))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('miRNA', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
11768	27832115	Accumulating evidence has demonstrated that miRNAs are stable in body fluids such as saliva and have a great potential to become noninvasive screening tools for cancer detection.	('cancer', 'Disease', (161, 167))	('miRNAs', 'Var', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))
11790	23986848	reported the shunt-preserving disconnection of the portal and systemic circulation (SPDPS) for immediate and permanent clearing of encephalopathy without elicitation of these complications during prolonged follow-up.	('man', 'Species', '9606', (112, 115))	('encephalopathy', 'Phenotype', 'HP:0001298', (131, 145))	('encephalopathy', 'Disease', (131, 145))	('SPDPS', 'Chemical', 'MESH:C018151', (84, 89))	('disconnection', 'Var', (30, 43))	('encephalopathy', 'Disease', 'MESH:D001927', (131, 145))
11826	23986848	reported three patients in whom embolization of the proximal part of the splenic vein resulted in a disconnection of the mesenteric-portal blood flow from the systemic circulation while preserving the shunt.	('shunt', 'MPA', (201, 206))	('patients', 'Species', '9606', (15, 23))	('mesenteric-portal blood flow', 'MPA', (121, 149))	('disconnection', 'NegReg', (100, 113))	('embolization', 'Var', (32, 44))
11955	21556122	In this study, the survival rate was higher in NY-ESO-1 positive cases, but did not reach statistical significance.	('higher', 'PosReg', (37, 43))	('positive', 'Var', (56, 64))	('NY-ESO-1', 'Gene', '246100', (47, 55))	('survival rate', 'CPA', (19, 32))	('NY-ESO-1', 'Gene', (47, 55))
11997	33430937	Wound healing disorders with special wound treatment, abscess, and lymphatic fistula caused by damage to the lymphatic system with leakage of chyle fluid into the cavities (defined as a milky-colored fluid from a drain, drain site, or wound on or after POD 3, with a triglyceride content >= 110 mg/dL respectively >= 1.2 mmol/L) also accounts for postoperative morbidity.	('lymphatic fistula', 'Disease', 'MESH:D008206', (67, 84))	('lymphatic fistula', 'Disease', (67, 84))	('abscess', 'Disease', (54, 61))	('abscess', 'Phenotype', 'HP:0025615', (54, 61))	('triglyceride', 'Chemical', 'MESH:D014280', (267, 279))	('leakage', 'MPA', (131, 138))	('healing disorders', 'Disease', (6, 23))	('damage', 'Var', (95, 101))	('healing disorders', 'Disease', 'MESH:C563468', (6, 23))
12022	33430937	This is clearly relevant in order to reduce surgeon-related influences as it could be shown by Nimptsch in 2018 that the mortality rate after esophageal surgery was lower in centers with high case numbers compared to those with very low case numbers with an OR[CI] of 0.50 ([0.42; 0.60]).	('mortality', 'Disease', 'MESH:D003643', (121, 130))	('high case numbers', 'Var', (187, 204))	('mortality', 'Disease', (121, 130))	('lower', 'NegReg', (165, 170))
12080	33193757	Inhibition of miR-21 reduced migration and invasion in two ESCC cell lines, and overexpression of miR-21 promoted migration and invasion in vitro.	('overexpression', 'PosReg', (80, 94))	('miR-21', 'Gene', (98, 104))	('promoted', 'PosReg', (105, 113))	('reduced', 'NegReg', (21, 28))	('miR-21', 'Gene', '406991', (14, 20))	('migration', 'CPA', (114, 123))	('miR-21', 'Gene', (14, 20))	('migration', 'CPA', (29, 38))	('Inhibition', 'Var', (0, 10))	('miR-21', 'Gene', '406991', (98, 104))	('invasion', 'CPA', (128, 136))
12083	33193757	Moreover, the forced overexpression of miR-21 repressed the TPM1 expression, while silencing of miR-21 restored the TPM1 expression in ESCC cell lines.	('TPM1', 'Gene', (60, 64))	('miR-21', 'Gene', '406991', (39, 45))	('miR-21', 'Gene', (96, 102))	('expression', 'MPA', (121, 131))	('overexpression', 'PosReg', (21, 35))	('miR-21', 'Gene', (39, 45))	('miR-21', 'Gene', '406991', (96, 102))	('silencing', 'Var', (83, 92))
12085	33193757	In conclusion, the aberrant overexpression of miR-21 is common in cancer and promotes the migration and invasion of ESCC through inhibiting the TPM1 expression.	('inhibiting', 'NegReg', (129, 139))	('promotes', 'PosReg', (77, 85))	('migration', 'CPA', (90, 99))	('ESCC', 'Disease', (116, 120))	('miR-21', 'Gene', '406991', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('TPM1', 'Gene', (144, 148))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('expression', 'MPA', (149, 159))	('miR-21', 'Gene', (46, 52))	('overexpression', 'PosReg', (28, 42))	('invasion', 'CPA', (104, 112))	('aberrant', 'Var', (19, 27))	('cancer', 'Disease', (66, 72))
12124	33193757	Subsequently, transwell assays were performed to test the effects of changes in the miR-21 expression on ESCC migration and invasion.	('ESCC', 'Disease', (105, 109))	('miR-21', 'Gene', '406991', (84, 90))	('miR-21', 'Gene', (84, 90))	('invasion', 'CPA', (124, 132))	('changes', 'Var', (69, 76))
12125	33193757	In EC109 cells, antagonism of miRNA-21 significantly impeded migration and invasion (Figure 2(c)).	('impeded', 'NegReg', (53, 60))	('antagonism', 'Var', (16, 26))	('miRNA-21', 'Gene', '406991', (30, 38))	('miRNA-21', 'Gene', (30, 38))	('EC109', 'CellLine', 'CVCL:6898', (3, 8))
12131	33193757	In EC109 transfected with the TPM1-3'UTR vector (wild type), transfection with miR-21 oligonucleotide mimics significantly reduced the luciferase activity of the 3'UTR-TPM1, compared with the blank group or the negative control double-stranded oligonucleotide group (P < 0.05).	('luciferase', 'Enzyme', (135, 145))	('activity', 'MPA', (146, 154))	('oligonucleotide', 'Chemical', 'MESH:D009841', (86, 101))	('TPM1-3', 'Gene', (30, 36))	('TPM1-3', 'Gene', '7168;7169;7170', (30, 36))	('oligonucleotide', 'Chemical', 'MESH:D009841', (244, 259))	('miR-21', 'Gene', (79, 85))	("3'UTR-TPM1", 'Var', (162, 172))	('miR-21', 'Gene', '406991', (79, 85))	('reduced', 'NegReg', (123, 130))	('EC109', 'CellLine', 'CVCL:6898', (3, 8))
12132	33193757	In contrast, transfection with the miR-21 antisense oligonucleotide increased the luciferase activity from the 3'UTR-TMPI reporter by more than 19% compared with the negative control single-stranded oligonucleotide (P < 0.05) (Figure 3(b)).	('antisense oligonucleotide', 'Var', (42, 67))	('activity', 'MPA', (93, 101))	('oligonucleotide', 'Chemical', 'MESH:D009841', (199, 214))	('luciferase', 'Enzyme', (82, 92))	('miR-21', 'Gene', (35, 41))	('oligonucleotide', 'Chemical', 'MESH:D009841', (52, 67))	('increased', 'PosReg', (68, 77))	('miR-21', 'Gene', '406991', (35, 41))
12142	33193757	In accordance with the luciferase assay results, the miR-21 expression was reduced by miR-21 inhibitors in EC109 cells, relative to the negative control inhibitor, and miR-21 was upregulated by miR-21 mimics in EC1 cells compared to the negative control mimics (Figure 3(h)).	('miR-21', 'Gene', '406991', (86, 92))	('expression', 'MPA', (60, 70))	('miR-21', 'Gene', '406991', (194, 200))	('miR-21', 'Gene', '406991', (53, 59))	('miR-21', 'Gene', (168, 174))	('EC109', 'CellLine', 'CVCL:6898', (107, 112))	('miR-21', 'Gene', (86, 92))	('reduced', 'NegReg', (75, 82))	('upregulated', 'PosReg', (179, 190))	('EC1', 'CellLine', 'CVCL:5V05', (107, 110))	('miR-21', 'Gene', '406991', (168, 174))	('miR-21', 'Gene', (194, 200))	('miR-21', 'Gene', (53, 59))	('EC1', 'CellLine', 'CVCL:5V05', (211, 214))	('inhibitors', 'Var', (93, 103))
12145	33193757	Considering that TPM1 is known as a potent inhibitor of tumor migration and invasion, we determined whether posttranslation silencing of TPM1 is required for miR-21 to promote ESCC migration and invasion.	('ESCC', 'Disease', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TPM1', 'Gene', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('silencing', 'Var', (124, 133))	('tumor', 'Disease', (56, 61))	('promote', 'PosReg', (168, 175))	('invasion', 'CPA', (195, 203))	('miR-21', 'Gene', '406991', (158, 164))	('miR-21', 'Gene', (158, 164))
12173	33193757	Silencing of the miR-21 target gene PTEN promotes invasion and migration in ovarian epithelial carcinomas, and the repression of the miR-21 target genes TPM1, PDCD4, and maspin can enhance invasion and metastasis in breast cancer.	('PTEN', 'Gene', (36, 40))	('Silencing', 'Var', (0, 9))	('maspin', 'Gene', (170, 176))	('repression', 'NegReg', (115, 125))	('TPM1', 'Gene', (153, 157))	('invasion', 'CPA', (50, 58))	('miR-21', 'Gene', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('ovarian epithelial carcinomas', 'Disease', 'MESH:D010051', (76, 105))	('enhance', 'PosReg', (181, 188))	('PTEN', 'Gene', '5728', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('miR-21', 'Gene', '406991', (17, 23))	('PDCD4', 'Gene', (159, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('promotes', 'PosReg', (41, 49))	('PDCD4', 'Gene', '27250', (159, 164))	('ovarian epithelial carcinomas', 'Disease', (76, 105))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('miR-21', 'Gene', (17, 23))	('breast cancer', 'Disease', (216, 229))	('miR-21', 'Gene', '406991', (133, 139))	('ovarian epithelial carcinomas', 'Phenotype', 'HP:0025318', (76, 105))	('maspin', 'Gene', '5268', (170, 176))
12180	33193757	With advancements in RNA interference and its clinical application, RNAi-mediated rescue of the silenced TPM1 expression, as well as other potential antioncogenes in ESCC cells with synthetic miR-21 inhibitors, may be a therapeutic method to control ESCC invasion and migration.	('migration', 'CPA', (268, 277))	('TPM1', 'Gene', (105, 109))	('miR-21', 'Gene', (192, 198))	('silenced', 'Var', (96, 104))	('ESCC', 'Disease', (250, 254))	('miR-21', 'Gene', '406991', (192, 198))
12183	33193757	These findings raise the possibility that miR-21 is a potential biomarker to predict ESCC progression, and that miR-21 interference could be an adjuvant therapeutic method for ESCC by inhibiting cancer cell migration and invasion through relieving the TPM1 repression.	('ESCC', 'Disease', (176, 180))	('repression', 'MPA', (257, 267))	('miR-21', 'Gene', (42, 48))	('miR-21', 'Gene', '406991', (112, 118))	('TPM1', 'Gene', (252, 256))	('interference', 'Var', (119, 131))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('ESCC', 'Disease', (85, 89))	('miR-21', 'Gene', '406991', (42, 48))	('relieving', 'NegReg', (238, 247))	('inhibiting', 'NegReg', (184, 194))	('miR-21', 'Gene', (112, 118))	('invasion', 'CPA', (221, 229))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
12268	32533533	In the 2L setting, taxanes significantly improved survival compared with non-taxane therapies, but only to a modest degree.	('taxanes', 'Var', (19, 26))	('improved', 'PosReg', (41, 49))	('survival', 'MPA', (50, 58))	('taxane', 'Chemical', 'MESH:C080625', (19, 25))	('taxanes', 'Chemical', 'MESH:D043823', (19, 26))	('taxane', 'Chemical', 'MESH:C080625', (77, 83))
12375	32214837	Association of XRCC1, XRCC2 and XRCC3 Gene Polymorphism with Esophageal Cancer Risk The X-ray repair cross-complementing (XRCC) gene polymorphisms influence esophageal carcinogenesis by altering the DNA repair capacity.	('DNA repair capacity', 'MPA', (199, 218))	('XRCC3', 'Gene', (32, 37))	('esophageal carcinogenesis', 'Disease', (157, 182))	('Esophageal Cancer', 'Disease', (61, 78))	('polymorphisms', 'Var', (133, 146))	('XRCC2', 'Gene', (22, 27))	('XRCC3', 'Gene', '7517', (32, 37))	('XRCC1', 'Gene', '7515', (15, 20))	('altering', 'Reg', (186, 194))	('influence', 'Reg', (147, 156))	('men', 'Species', '9606', (113, 116))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (61, 78))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('XRCC2', 'Gene', '7516', (22, 27))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (157, 182))	('XRCC1', 'Gene', (15, 20))
12376	32214837	The present study was designed to screen five single nucleotide polymorphisms (SNPs) of XRCC genes for their susceptibility to esophageal cancer (EC) risk.	('susceptibility', 'Reg', (109, 123))	('esophageal cancer', 'Disease', (127, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('XRCC genes', 'Gene', (88, 98))	('single nucleotide polymorphisms', 'Var', (46, 77))
12379	32214837	For XRCC1 p.Arg399Gln, a decreased risk for EC was associated with the AA genotype [OR (95% CI): 0.53 (0.3-0.95), p=0.03] even after adjusting for various covariates [OR (95% CI): 0.49 (0.26-0.9), p=0.024] and with the recessive model [OR (95% CI): 0.49 (0.27-0.8), p=0.016].	('p.Arg399Gln', 'Var', (10, 21))	('XRCC1', 'Gene', (4, 9))	('p.Arg399Gln', 'Mutation', 'rs25487', (10, 21))	('decreased', 'NegReg', (25, 34))
12381	32214837	The two XRCC1 polymorphisms, p.Arg399Gln and p.Arg194Trp were in slight LD among EC patients (D=0.845, r2=0.042).	('XRCC1 p', 'Gene', '7515', (8, 15))	('p.Arg399Gln', 'Var', (29, 40))	('p.Arg399Gln', 'Mutation', 'rs25487', (29, 40))	('patients', 'Species', '9606', (84, 92))	('p.Arg194Trp', 'Mutation', 'rs1799782', (45, 56))	('p.Arg194Trp', 'Var', (45, 56))	('XRCC1 p', 'Gene', (8, 15))
12382	32214837	XRCC2 and XRCC3 polymorphisms were not associated with EC risk.	('polymorphisms', 'Var', (16, 29))	('XRCC2', 'Gene', '7516', (0, 5))	('XRCC2', 'Gene', (0, 5))	('XRCC3', 'Gene', (10, 15))	('XRCC3', 'Gene', '7517', (10, 15))
12383	32214837	XRCC1 p.Arg399Gln plays a protective role in the development of the EC.	('p.Arg399Gln', 'Mutation', 'rs25487', (6, 17))	('XRCC1', 'Gene', (0, 5))	('men', 'Species', '9606', (56, 59))	('p.Arg399Gln', 'Var', (6, 17))
12384	32214837	The study is the first report from India, providing baseline data about genetic polymorphisms in DNA repair genes XRCC1, XRCC2 and XRCC3 modulating overall EC risk.	('XRCC3', 'Gene', '7517', (131, 136))	('modulating', 'Reg', (137, 147))	('XRCC1', 'Gene', '7515', (114, 119))	('XRCC2', 'Gene', '7516', (121, 126))	('polymorphisms', 'Var', (80, 93))	('XRCC2', 'Gene', (121, 126))	('XRCC3', 'Gene', (131, 136))	('XRCC1', 'Gene', (114, 119))
12389	32214837	XRCC1 protein as a part of Base excision repair (BER) pathway plays an efficient role in repairing DNA single-strand breaks.	('XRCC1 p', 'Gene', (0, 7))	('DNA', 'Var', (99, 102))	('repairing', 'MPA', (89, 98))	('XRCC1 p', 'Gene', '7515', (0, 7))
12391	32214837	Two XRCC1 polymorphisms, p.Arg194Trp (exon 6) and p. Arg280His (exon 9) affect the function of the protein.	('Arg280His', 'Var', (53, 62))	('affect', 'Reg', (72, 78))	('p.Arg194Trp', 'Mutation', 'rs1799782', (25, 36))	('p.Arg194Trp', 'Var', (25, 36))	('XRCC1 p', 'Gene', (4, 11))	('XRCC1 p', 'Gene', '7515', (4, 11))	('Arg280His', 'SUBSTITUTION', 'None', (53, 62))	('function of the protein', 'MPA', (83, 106))
12392	32214837	XRCC1 p.Arg399Gln polymorphism in exon 10 has been associated with breast, lung and head and neck cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('neck cancers', 'Disease', (93, 105))	('XRCC1', 'Gene', (0, 5))	('head and neck cancer', 'Disease', 'MESH:D006258', (84, 104))	('p.Arg399Gln', 'Var', (6, 17))	('associated', 'Reg', (51, 61))	('p.Arg399Gln', 'Mutation', 'rs25487', (6, 17))	('neck cancers', 'Disease', 'MESH:D006258', (93, 105))	('breast', 'Disease', (67, 73))	('head and neck cancer', 'Phenotype', 'HP:0012288', (84, 104))	('lung', 'Disease', (75, 79))	('head and neck cancers', 'Phenotype', 'HP:0012288', (84, 105))
12394	32214837	XRCC2 p.Arg188His polymorphism located in exon3 has been associated with cancers like pancreatic, ovarian, oral and upper aerodigestive tract cancers.	('upper aerodigestive tract cancers', 'Disease', (116, 149))	('cancers', 'Disease', (73, 80))	('pancreatic', 'Disease', (86, 96))	('upper aerodigestive tract cancers', 'Disease', 'MESH:D006258', (116, 149))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('XRCC2', 'Gene', '7516', (0, 5))	('p.Arg188His', 'Mutation', 'rs3218536', (6, 17))	('p.Arg188His', 'Var', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('XRCC2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('pancreatic', 'Disease', 'MESH:D010195', (86, 96))	('ovarian', 'Disease', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('associated', 'Reg', (57, 67))
12396	32214837	Variation in expression of XRCC3 has been reported in various cancers, like gastric, breast, lung, skin and colorectal.	('colorectal', 'Disease', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('expression', 'MPA', (13, 23))	('breast', 'Disease', (85, 91))	('reported', 'Reg', (42, 50))	('lung', 'Disease', (93, 97))	('XRCC3', 'Gene', (27, 32))	('skin', 'Disease', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('gastric', 'Disease', (76, 83))	('XRCC3', 'Gene', '7517', (27, 32))	('Variation', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
12397	32214837	The most common polymorphism in XRCC3 p.Thr241Met in exon 7 can influence the ability to repair DNA.	('XRCC3', 'Gene', (32, 37))	('p.Thr241Met', 'Var', (38, 49))	('ability', 'MPA', (78, 85))	('XRCC3', 'Gene', '7517', (32, 37))	('influence', 'Reg', (64, 73))	('p.Thr241Met', 'Mutation', 'rs861539', (38, 49))
12398	32214837	Allelic variants of XRCC1, XRCC2, and XRCC3 are associated with risk of different types of cancer among different populations all over the world.	('associated', 'Reg', (48, 58))	('Allelic variants', 'Var', (0, 16))	('cancer', 'Disease', (91, 97))	('XRCC1', 'Gene', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('XRCC2', 'Gene', '7516', (27, 32))	('XRCC3', 'Gene', (38, 43))	('XRCC2', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('XRCC3', 'Gene', '7517', (38, 43))	('XRCC1', 'Gene', '7515', (20, 25))
12401	32214837	Therefore, the present study was carried out to explore the role of five polymorphisms of XRCC genes; XRCC1 (p.Arg399Gln, p.Arg194Trp, p.Arg280His), XRCC2 (p.Arg188His) and XRCC3 (p.Thr241Met) in the risk of EC in the population of Punjab, India.	('p.Arg280His', 'Var', (135, 146))	('XRCC3', 'Gene', (173, 178))	('p.Arg399Gln', 'Var', (109, 120))	('XRCC3', 'Gene', '7517', (173, 178))	('p.Arg399Gln', 'Mutation', 'rs25487', (109, 120))	('p.Arg280His', 'Mutation', 'rs25489', (135, 146))	('p.Arg194Trp', 'Mutation', 'rs1799782', (122, 133))	('XRCC1', 'Gene', (102, 107))	('p.Arg194Trp', 'Var', (122, 133))	('p.Thr241Met', 'Mutation', 'rs861539', (180, 191))	('XRCC genes', 'Gene', (90, 100))	('p.Arg188His', 'Mutation', 'rs3218536', (156, 167))	('p.Arg188His', 'Var', (156, 167))	('XRCC1', 'Gene', '7515', (102, 107))	('p.Thr241Met', 'Var', (180, 191))	('XRCC2', 'Gene', '7516', (149, 154))	('XRCC2', 'Gene', (149, 154))
12406	32214837	Previously published primer sequences for XRCC1 p.Arg399Gln, XRCC1 p.Arg194Trp, XRCC1 p.Arg280His, XRCC2 p.Arg188His and XRCC3 p.Thr241Met polymorphisms were used to amplify the target region.	('XRCC1', 'Gene', (61, 66))	('p.Thr241Met', 'Mutation', 'rs861539', (127, 138))	('p.Arg194Trp', 'Mutation', 'rs1799782', (67, 78))	('p.Thr241Met', 'Var', (127, 138))	('XRCC2', 'Gene', '7516', (99, 104))	('XRCC2', 'Gene', (99, 104))	('XRCC1', 'Gene', (42, 47))	('XRCC3', 'Gene', '7517', (121, 126))	('p.Arg399Gln', 'Var', (48, 59))	('p.Arg280His', 'Var', (86, 97))	('p.Arg399Gln', 'Mutation', 'rs25487', (48, 59))	('p.Arg194Trp', 'Var', (67, 78))	('p.Arg280His', 'Mutation', 'rs25489', (86, 97))	('p.Arg188His', 'Var', (105, 116))	('XRCC1', 'Gene', (80, 85))	('XRCC3', 'Gene', (121, 126))	('p.Arg188His', 'Mutation', 'rs3218536', (105, 116))
12413	32214837	In the present study 5 polymorphisms; XRCC1 (p.Arg399Gln, p.Arg280His, p.Arg194Trp), XRCC2 (p.Arg188His) and XRCC3 (p.Thr241Met) were studied for the association with risk of esophageal cancer (EC).	('p.Thr241Met', 'Var', (116, 127))	('XRCC2', 'Gene', '7516', (85, 90))	('XRCC1', 'Gene', (38, 43))	('p.Arg399Gln', 'Var', (45, 56))	('XRCC3', 'Gene', '7517', (109, 114))	('p.Arg280His', 'Mutation', 'rs25489', (58, 69))	('p.Arg194Trp', 'Mutation', 'rs1799782', (71, 82))	('p.Arg188His', 'Mutation', 'rs3218536', (92, 103))	('p.Arg188His', 'Var', (92, 103))	('p.Arg194Trp', 'Var', (71, 82))	('XRCC1', 'Gene', '7515', (38, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('XRCC2', 'Gene', (85, 90))	('XRCC3', 'Gene', (109, 114))	('p.Thr241Met', 'Mutation', 'rs861539', (116, 127))	('esophageal cancer', 'Disease', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('p.Arg280His', 'Var', (58, 69))	('p.Arg399Gln', 'Mutation', 'rs25487', (45, 56))
12414	32214837	For XRCC1 p.Arg280His polymorphism, A allele was associated with an increased risk of EC (OR=1.60, 95% CI= 1.02-2.52, p=0.04).	('XRCC1', 'Gene', (4, 9))	('p.Arg280His', 'Var', (10, 21))	('p.Arg280His', 'Mutation', 'rs25489', (10, 21))
12420	32214837	No significant difference in allele (p=0.54) and genotype (p=0.52) frequencies of XRCC1 p.Arg194Trp polymorphism was observed.	('p.Arg194Trp', 'Var', (88, 99))	('XRCC1', 'Gene', (82, 87))	('p.Arg194Trp', 'Mutation', 'rs1799782', (88, 99))
12421	32214837	No association with EC risk was observed for XRCC2 p.Arg188His and XRCC3 p.Thr241Met polymorphism (p=0.53) in the subjects.	('p.Thr241Met', 'Mutation', 'rs861539', (73, 84))	('XRCC3', 'Gene', '7517', (67, 72))	('XRCC3', 'Gene', (67, 72))	('p.Arg188His', 'Mutation', 'rs3218536', (51, 62))	('p.Thr241Met', 'Var', (73, 84))	('p.Arg188His', 'Var', (51, 62))	('XRCC2', 'Gene', '7516', (45, 50))	('XRCC2', 'Gene', (45, 50))
12422	32214837	Genetic model analysis of XRCC1 p.Arg399Gln and XRCC3p.Thr241Met (Table 6) revealed a decreased risk of EC under the recessive model AA vs GG+GA (OR=0.55, 95% CI=0.32-0.95, p=0.027) for XRCC1p.Arg399Gln polymorphism which became more significant after adjustment with binomial logistic regression (OR=0.49, 95% CI=0.27-0.88, p=0.016).	('p.Arg399Gln', 'Mutation', 'rs25487', (191, 202))	('men', 'Species', '9606', (258, 261))	('XRCC1', 'Gene', (26, 31))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (32, 43))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (191, 202))	('p.Thr241Met', 'Var', (53, 64))	('decreased', 'NegReg', (86, 95))	('p.Thr241Met', 'SUBSTITUTION', 'None', (53, 64))	('p.Arg399Gln', 'Var', (32, 43))	('p.Arg399Gln', 'Var', (191, 202))	('p.Arg399Gln', 'Mutation', 'rs25487', (32, 43))
12423	32214837	For p.Thr241Met polymorphism no genotype combination was associated with EC.	('p.Thr241Met', 'Mutation', 'rs861539', (4, 15))	('p.Thr241Met', 'Var', (4, 15))	('associated', 'Reg', (57, 67))
12425	32214837	Based on the measures of linkage disequilibrium (LD), the two polymorphisms of XRCC1gene, p.Arg399Gln and p.Arg194Trp, were in slight LD among EC patients (D=0.845, r2=0.042) (Figure 1A).	('XRCC1', 'Gene', '7515', (79, 84))	('p.Arg194Trp', 'Var', (106, 117))	('p.Arg194Trp', 'Mutation', 'rs1799782', (106, 117))	('XRCC1', 'Gene', (79, 84))	('p.Arg399Gln', 'Var', (90, 101))	('p.Arg399Gln', 'Mutation', 'rs25487', (90, 101))	('patients', 'Species', '9606', (146, 154))
12426	32214837	The haplotype GGT (p.Arg399Gln, p.Arg280His, and p.Arg194Trp) was predominant in EC cases as compared to controls, but the difference was statistically non-significant (p=0.1).	('p.Arg280His', 'Var', (32, 43))	('p.Arg399Gln', 'Mutation', 'rs25487', (19, 30))	('p.Arg280His', 'Mutation', 'rs25489', (32, 43))	('p.Arg194Trp', 'Mutation', 'rs1799782', (49, 60))	('p.Arg194Trp', 'Var', (49, 60))	('p.Arg399Gln', 'Var', (19, 30))
12428	32214837	The combinations comprising the AA genotype (p.Arg399Gln) occurred significantly more often in controls than patients, with AA-CC-CC combination associated with significantly decreased risk of EC (OR=0.5, 95% CI=0.29-0.91, p=0.020).	('p.Arg399Gln', 'Mutation', 'rs25487', (45, 56))	('decreased', 'NegReg', (175, 184))	('p.Arg399Gln', 'Var', (45, 56))	('patients', 'Species', '9606', (109, 117))
12429	32214837	According to MDR analysis, the best MDR model included all the five studied polymorphisms XRCC1 (p.Arg399Gln, p.Arg194Trp, p.Arg280His), XRCC2 (p.Arg188His) and XRCC3 (p.Thr241Met).	('p.Arg188His', 'Var', (144, 155))	('XRCC1', 'Gene', '7515', (90, 95))	('p.Arg280His', 'Var', (123, 134))	('XRCC3', 'Gene', (161, 166))	('p.Thr241Met', 'Var', (168, 179))	('p.Arg194Trp', 'Var', (110, 121))	('p.Arg280His', 'Mutation', 'rs25489', (123, 134))	('XRCC2', 'Gene', (137, 142))	('XRCC2', 'Gene', '7516', (137, 142))	('XRCC3', 'Gene', '7517', (161, 166))	('p.Arg194Trp', 'Mutation', 'rs1799782', (110, 121))	('p.Thr241Met', 'Mutation', 'rs861539', (168, 179))	('XRCC1', 'Gene', (90, 95))	('p.Arg399Gln', 'Var', (97, 108))	('p.Arg399Gln', 'Mutation', 'rs25487', (97, 108))	('p.Arg188His', 'Mutation', 'rs3218536', (144, 155))
12432	32214837	In India, the inter-individual differences in susceptibility to cancer due to the genetic polymorphisms in XRCC1 previously found.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('XRCC1 p', 'Gene', (107, 114))	('susceptibility', 'MPA', (46, 60))	('polymorphisms', 'Var', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('XRCC1 p', 'Gene', '7515', (107, 114))
12433	32214837	As DNA-repair gene polymorphisms play a very important role in carcinogenesis, we carried out this case-control study to evaluate whether XRCC1 (p.Arg399Gln, p.Arg194Trp and p.Arg280His), XRCC2 (p.Arg188His), and XRCC3 (p.Thr241Met) gene polymorphisms modulate the risk of esophageal cancer.	('XRCC2', 'Gene', '7516', (188, 193))	('modulate', 'Reg', (252, 260))	('p.Arg399Gln', 'Mutation', 'rs25487', (145, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (63, 77))	('p.Arg194Trp', 'Mutation', 'rs1799782', (158, 169))	('esophageal cancer', 'Disease', 'MESH:D004938', (273, 290))	('p.Arg188His', 'Mutation', 'rs3218536', (195, 206))	('p.Arg188His', 'Var', (195, 206))	('p.Arg280His', 'Var', (174, 185))	('XRCC3', 'Gene', (213, 218))	('XRCC1', 'Gene', (138, 143))	('p.Arg399Gln', 'Var', (145, 156))	('esophageal cancer', 'Disease', (273, 290))	('p.Thr241Met', 'Mutation', 'rs861539', (220, 231))	('p.Arg194Trp', 'Var', (158, 169))	('p.Arg280His', 'Mutation', 'rs25489', (174, 185))	('XRCC2', 'Gene', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('XRCC1', 'Gene', '7515', (138, 143))	('p.Thr241Met', 'Var', (220, 231))	('XRCC3', 'Gene', '7517', (213, 218))	('carcinogenesis', 'Disease', (63, 77))
12434	32214837	The XRCC1p.Arg399Gln polymorphism is involved in various protein-protein interactions and higher sister chromatid exchanges and DNA adducts.	('p.Arg399Gln', 'Var', (9, 20))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (9, 20))	('protein-protein interactions', 'Protein', (57, 85))	('higher', 'PosReg', (90, 96))	('involved', 'Reg', (37, 45))
12435	32214837	In the present study, we found that A allele and the AA genotype of XRCC1p.Arg399Gln polymorphism was associated with a decreased risk of esophageal cancer.	('decreased', 'NegReg', (120, 129))	('esophageal cancer', 'Disease', (138, 155))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (73, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('p.Arg399Gln', 'Var', (73, 84))
12436	32214837	Very few studies relating the XRCC1 Arg399Gln polymorphism with esophageal cancer risk are available from which only one is from India.	('XRCC1', 'Gene', (30, 35))	('esophageal cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('XRCC1', 'Gene', '7515', (30, 35))	('Arg399Gln', 'Var', (36, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('Arg399Gln', 'SUBSTITUTION', 'None', (36, 45))
12437	32214837	Among previous reports from North India on EC; a study of Chandigarh region found association with a decreased risk of XRCC1 p.Arg399Gln, another study from Uttar Pradesh also reported Arg/Gln (p=0.03, OR= 0.62) and Gln/Gln (p=0.003, OR=0.37) genotype to be associated with a decreased risk of gall bladder cancer; a study from Kashmir on colorectal cancer also reported a protective role of AA genotype.	('colorectal cancer', 'Phenotype', 'HP:0003003', (339, 356))	('Gln', 'Chemical', 'MESH:D005973', (189, 192))	('Arg', 'Chemical', 'MESH:D001120', (185, 188))	('colorectal cancer', 'Disease', 'MESH:D015179', (339, 356))	('colorectal cancer', 'Disease', (339, 356))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('decreased', 'NegReg', (101, 110))	('XRCC1', 'Gene', (119, 124))	('Arg', 'Chemical', 'MESH:D001120', (127, 130))	('gall bladder cancer', 'Disease', (294, 313))	('Gln', 'Chemical', 'MESH:D005973', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('bladder cancer', 'Phenotype', 'HP:0009725', (299, 313))	('gall bladder cancer', 'Disease', 'MESH:D005706', (294, 313))	('p.Arg399Gln', 'Var', (125, 136))	('Gln', 'Chemical', 'MESH:D005973', (216, 219))	('p.Arg399Gln', 'Mutation', 'rs25487', (125, 136))	('Gln', 'Chemical', 'MESH:D005973', (220, 223))
12439	32214837	Contrary to the results of the present study, some previous studies from North India have reported an increased risk with AA genotype of XRCC1p.Arg399Gln polymorphism in lung cancer, head and neck cancer, colorectal cancer and prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (227, 242))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (142, 153))	('head and neck cancer', 'Disease', 'MESH:D006258', (183, 203))	('colorectal cancer', 'Disease', 'MESH:D015179', (205, 222))	('prostate cancer', 'Phenotype', 'HP:0012125', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (205, 222))	('head and neck cancer', 'Phenotype', 'HP:0012288', (183, 203))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('prostate cancer', 'Disease', (227, 242))	('colorectal cancer', 'Disease', (205, 222))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', (170, 181))	('p.Arg399Gln', 'Var', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
12441	32214837	However, few studies from South India reported no association of XRCC1p.Arg399Gln polymorphism with any of cancer (Table 1).	('p.Arg399Gln', 'SUBSTITUTION', 'None', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p.Arg399Gln', 'Var', (70, 81))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
12442	32214837	Results of the present study on XRCC1 p.Arg399Gln polymorphism is in agreement with the studies from different parts of the globe like esophageal cancer in Han Chinese, colorectal adenocarcinoma in Norwegian population, gallbladder cancer, and non-melanoma skin cancers.	('gallbladder cancer', 'Disease', (220, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('men', 'Species', '9606', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (244, 269))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (169, 194))	('skin cancer', 'Phenotype', 'HP:0008069', (257, 268))	('bladder cancer', 'Phenotype', 'HP:0009725', (224, 238))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('non-melanoma skin cancers', 'Disease', (244, 269))	('gallbladder cancer', 'Disease', 'MESH:D005706', (220, 238))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('p.Arg399Gln', 'Mutation', 'rs25487', (38, 49))	('skin cancers', 'Phenotype', 'HP:0008069', (257, 269))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('p.Arg399Gln', 'Var', (38, 49))	('esophageal cancer', 'Disease', (135, 152))	('colorectal adenocarcinoma', 'Disease', (169, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('XRCC1', 'Gene', (32, 37))
12443	32214837	In contrast, some previous studies have reported the association of Arg399Gln polymorphism with an increased risk of esophageal, stomach and oral cancers, colorectal cancers in Korean, Egyptian and Japanese populations, lung cancer and breast cancer.	('oral cancers', 'Disease', (141, 153))	('oral cancers', 'Disease', 'MESH:D009062', (141, 153))	('esophageal', 'Disease', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('association', 'Reg', (53, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('lung cancer', 'Disease', (220, 231))	('stomach', 'Disease', (129, 136))	('colorectal cancers', 'Disease', (155, 173))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('breast cancer', 'Disease', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('Arg399Gln', 'SUBSTITUTION', 'None', (68, 77))	('colorectal cancers', 'Disease', 'MESH:D015179', (155, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('Arg399Gln', 'Var', (68, 77))
12444	32214837	However, three studies did not find any association between p.Arg399Gln polymorphism and cancer of the esophagus, gall bladder and breast.	('gall bladder', 'Disease', 'MESH:D005705', (114, 126))	('p.Arg399Gln', 'Var', (60, 71))	('p.Arg399Gln', 'Mutation', 'rs25487', (60, 71))	('gall bladder', 'Disease', (114, 126))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('breast', 'Disease', (131, 137))	('cancer', 'Disease', (89, 95))	('cancer of the esophagus', 'Phenotype', 'HP:0100751', (89, 112))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
12446	32214837	Among international studies, no association of XRCC1 p.Arg194Trp has been reported with EC risk in the population of North Carolina, gastric cancer in Korean population and breast cancer in Caucasian women.	('women', 'Species', '9606', (200, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('XRCC1', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('gastric cancer', 'Disease', 'MESH:D013274', (133, 147))	('gastric cancer', 'Disease', (133, 147))	('p.Arg194Trp', 'Var', (53, 64))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('p.Arg194Trp', 'Mutation', 'rs1799782', (53, 64))	('breast cancer', 'Disease', (173, 186))
12447	32214837	On the contrary, Trp allele has been reported to be associated with an increased risk of gastric cancer in the Chinese population.	('associated', 'Reg', (52, 62))	('Trp', 'Gene', (17, 20))	('Trp', 'Chemical', 'MESH:D014364', (17, 20))	('gastric cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (71, 103))	('allele', 'Var', (21, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))
12449	32214837	In the present study, we observed a lower risk of esophageal cancer associated with p.Arg399Gln polymorphism of XRCC1.	('p.Arg399Gln', 'Var', (84, 95))	('p.Arg399Gln', 'Mutation', 'rs25487', (84, 95))	('XRCC1', 'Gene', (112, 117))	('esophageal cancer', 'Disease', (50, 67))	('XRCC1', 'Gene', '7515', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
12450	32214837	A relationship between polymorphism in XRCC1Arg399Gln and increased rate of apoptosis has been reported in patients of ulcerative colitis and in schizophrenia patients.	('schizophrenia', 'Disease', 'MESH:D012559', (145, 158))	('colitis', 'Phenotype', 'HP:0002583', (130, 137))	('increased', 'PosReg', (58, 67))	('patients', 'Species', '9606', (159, 167))	('schizophrenia', 'Phenotype', 'HP:0100753', (145, 158))	('polymorphism', 'Var', (23, 35))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (119, 137))	('ulcerative colitis', 'Disease', (119, 137))	('apoptosis', 'CPA', (76, 85))	('XRCC1Arg399Gln', 'Gene', (39, 53))	('patients', 'Species', '9606', (107, 115))	('schizophrenia', 'Disease', (145, 158))	('ulcerative colitis', 'Disease', 'MESH:D003093', (119, 137))	('rate', 'MPA', (68, 72))
12451	32214837	The increased rates of the apoptosis results into the elimination of potential premalignant cells and hence, the XRCC1 Gln399 may play a protective role in esophageal cancer risk.	('rates', 'MPA', (14, 19))	('XRCC1', 'Gene', (113, 118))	('Gln399', 'Var', (119, 125))	('esophageal cancer', 'Disease', (156, 173))	('apoptosis', 'CPA', (27, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Gln399', 'Chemical', '-', (119, 125))	('XRCC1', 'Gene', '7515', (113, 118))
12452	32214837	The A allele of XRCC1p.Arg280His was associated with an increased risk of esophageal cancer in the present study.	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('p.Arg280His', 'Var', (21, 32))	('p.Arg280His', 'SUBSTITUTION', 'None', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
12454	32214837	From the North Indian population, p.Arg280His has been associated with an increased risk of hepatocellular carcinoma but no association has been reported with SCC head and neck.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('SCC', 'Gene', (159, 162))	('p.Arg280His', 'Var', (34, 45))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('p.Arg280His', 'Mutation', 'rs25489', (34, 45))	('SCC', 'Gene', '6317', (159, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('hepatocellular carcinoma', 'Disease', (92, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('increased risk of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 116))
12456	32214837	A meta-analysis within the Asian population has reported an association of p.Arg280His polymorphism with bladder cancer risk.	('p.Arg280His', 'Var', (75, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('p.Arg280His', 'Mutation', 'rs25489', (75, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('bladder cancer', 'Disease', (105, 119))	('association', 'Interaction', (60, 71))
12459	32214837	A study on the Chinese population reported no association between p.Arg280His polymorphism and ESCC.	('SCC', 'Gene', (96, 99))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('SCC', 'Gene', '6317', (96, 99))	('p.Arg280His', 'Mutation', 'rs25489', (66, 77))	('p.Arg280His', 'Var', (66, 77))
12461	32214837	No association of XRCC2 p.Arg188His with EC has been observed in the present study, which is the first report from India for esophageal cancer risk.	('p.Arg188His', 'Mutation', 'rs3218536', (24, 35))	('p.Arg188His', 'Var', (24, 35))	('esophageal cancer', 'Disease', (125, 142))	('XRCC2', 'Gene', '7516', (18, 23))	('XRCC2', 'Gene', (18, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
12462	32214837	In previous reports from India, no association of XRCC2 p.Arg188His polymorphism was reported with nasopharyngeal carcinoma whereas another study found an association of GA genotype with increased risk of SCC head and neck.	('XRCC2', 'Gene', '7516', (50, 55))	('XRCC2', 'Gene', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (99, 123))	('SCC', 'Gene', (205, 208))	('p.Arg188His', 'Mutation', 'rs3218536', (56, 67))	('p.Arg188His', 'Var', (56, 67))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (99, 123))	('SCC', 'Phenotype', 'HP:0002860', (205, 208))	('nasopharyngeal carcinoma', 'Disease', (99, 123))	('SCC', 'Gene', '6317', (205, 208))
12463	32214837	The contradictory reports from different parts of the world have shown that XRCC2 p.Arg188His polymorphism was associated with a significantly increased risk of pharyngeal cancer and breast cancer but not with bladder cancer, colorectal adenoma, skin cancer, thyroid cancer and breast cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (210, 224))	('bladder cancer', 'Disease', (210, 224))	('skin cancer', 'Disease', 'MESH:D012878', (246, 257))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('breast cancer', 'Disease', 'MESH:D001943', (278, 291))	('associated', 'Reg', (111, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (210, 224))	('breast cancer', 'Disease', (278, 291))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('thyroid cancer', 'Disease', 'MESH:D013964', (259, 273))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('XRCC2', 'Gene', '7516', (76, 81))	('breast cancer', 'Disease', (183, 196))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('colorectal adenoma', 'Disease', 'MESH:D015179', (226, 244))	('thyroid cancer', 'Phenotype', 'HP:0002890', (259, 273))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', (285, 291))	('skin cancer', 'Disease', (246, 257))	('p.Arg188His', 'Mutation', 'rs3218536', (82, 93))	('cancer', 'Disease', (267, 273))	('p.Arg188His', 'Var', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (161, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (251, 257))	('skin cancer', 'Phenotype', 'HP:0008069', (246, 257))	('XRCC2', 'Gene', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (218, 224))	('thyroid cancer', 'Disease', (259, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('colorectal adenoma', 'Disease', (226, 244))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
12465	32214837	XRCC3 gene mainly repairs using the HR pathway and in vitro studies revealed high sensitivity to DNA damaging agents in cells with XRCC3 gene knockouts.	('knockouts', 'Var', (142, 151))	('XRCC3', 'Gene', '7517', (131, 136))	('XRCC3', 'Gene', '7517', (0, 5))	('XRCC3', 'Gene', (0, 5))	('XRCC3', 'Gene', (131, 136))	('sensitivity to DNA damaging agents', 'MPA', (82, 116))
12466	32214837	No association of XRCC3 p.Thr241Met polymorphism with esophageal cancer has been observed in the present study.	('XRCC3', 'Gene', (18, 23))	('p.Thr241Met', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('XRCC3', 'Gene', '7517', (18, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('p.Thr241Met', 'Mutation', 'rs861539', (24, 35))
12469	32214837	For XRCC3 p.Thr241Met polymorphism, no association was reported with gastric cancer in Italian population and with colorectal cancer in the West Algerian population but an association with an increased risk was reported for lung cancer in an Italian population, oral SCC in Thai population, and gastric cancer in the Chinese population.	('SCC', 'Gene', '6317', (267, 270))	('XRCC3', 'Gene', '7517', (4, 9))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (295, 309))	('SCC', 'Gene', (267, 270))	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('p.Thr241Met', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (295, 309))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gastric cancer', 'Disease', (69, 83))	('XRCC3', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('SCC', 'Phenotype', 'HP:0002860', (267, 270))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('lung cancer', 'Disease', (224, 235))	('gastric cancer', 'Disease', (295, 309))	('colorectal cancer', 'Disease', (115, 132))	('p.Thr241Met', 'Mutation', 'rs861539', (10, 21))
12471	32214837	The haplotype analysis in the present study shows an association of haplotype GGT of XRCC1 gene (Arg399-Arg280-194Trp of p.Arg399Gln, p.Arg280His, and p.Arg194Trp polymorphisms) with a risk of EC, however, the association was not statistically significant (Table 7).	('p.Arg280His', 'Mutation', 'rs25489', (134, 145))	('p.Arg194Trp', 'Mutation', 'rs1799782', (151, 162))	('p.Arg280His', 'Var', (134, 145))	('XRCC1', 'Gene', (85, 90))	('p.Arg194Trp', 'Var', (151, 162))	('Arg399-Arg280-194Trp', 'Var', (97, 117))	('p.Arg399Gln', 'Var', (121, 132))	('p.Arg399Gln', 'Mutation', 'rs25487', (121, 132))	('Arg399-Arg280-194Trp', 'Mutation', 'p.R,R399,280-194W', (97, 117))	('association', 'Interaction', (53, 64))	('XRCC1', 'Gene', '7515', (85, 90))
12473	32214837	However, a study from West Bengal (East India) reported CAG haplotype (Arg194-His280-Arg399) to have reduced risk against gastric cancer.	('His280', 'Chemical', '-', (78, 84))	('Arg194', 'Chemical', '-', (71, 77))	('Arg194-His280-Arg399', 'Var', (71, 91))	('gastric cancer', 'Disease', (122, 136))	('reduced', 'NegReg', (101, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('Arg399', 'Chemical', '-', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
12474	32214837	A study from Uttar Pradesh (North India) reported CGA and CAG haplotype of XRCC1 (Arg194-His280-Arg399) to be associated with prostate cancer and haplotype CGA to be associated with bladder cancer.	('CGA', 'Gene', '1113', (156, 159))	('CGA', 'Gene', (50, 53))	('CGA', 'Gene', '1113', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('associated', 'Reg', (110, 120))	('Arg194', 'Chemical', '-', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('associated', 'Reg', (166, 176))	('bladder cancer', 'Disease', 'MESH:D001749', (182, 196))	('bladder cancer', 'Disease', (182, 196))	('XRCC1', 'Gene', (75, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (182, 196))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))	('Arg399', 'Chemical', '-', (96, 102))	('His280', 'Chemical', '-', (89, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('CGA', 'Gene', (156, 159))	('Arg194-His280-Arg399', 'Var', (82, 102))	('prostate cancer', 'Disease', (126, 141))	('XRCC1', 'Gene', '7515', (75, 80))
12476	32214837	The XRCC1 codon 399 Arg/Arg genotype has been associated with increased risk of acute radiation dermatitis in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy.	('Arg', 'Chemical', 'MESH:D001120', (20, 23))	('patients', 'Species', '9606', (135, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('Arg', 'Chemical', 'MESH:D001120', (24, 27))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (110, 134))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (110, 134))	('XRCC1', 'Gene', (4, 9))	('nasopharyngeal carcinoma', 'Disease', (110, 134))	('dermatitis', 'Phenotype', 'HP:0011123', (96, 106))	('radiation dermatitis', 'Disease', 'MESH:D004194', (86, 106))	('radiation dermatitis', 'Disease', (86, 106))	('codon 399 Arg/Arg', 'Var', (10, 27))	('XRCC1', 'Gene', '7515', (4, 9))
12478	32214837	The present study indicates a protective role of the XRCC1 p.Arg399Gln towards the development of EC.	('p.Arg399Gln', 'Mutation', 'rs25487', (59, 70))	('XRCC1', 'Gene', (53, 58))	('p.Arg399Gln', 'Var', (59, 70))	('men', 'Species', '9606', (90, 93))
12480	32214837	The present study being the first report from India, providing baseline data about five genetic polymorphisms in three DNA repair genes XRCC1, XRCC2 and XRCC3 modulating overall esophageal cancer susceptibility in ethnic Punjabi Indian subjects.	('esophageal cancer', 'Disease', (178, 195))	('XRCC3', 'Gene', (153, 158))	('XRCC3', 'Gene', '7517', (153, 158))	('XRCC1', 'Gene', (136, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('modulating', 'Reg', (159, 169))	('XRCC2', 'Gene', '7516', (143, 148))	('XRCC2', 'Gene', (143, 148))	('polymorphisms', 'Var', (96, 109))	('XRCC1', 'Gene', '7515', (136, 141))
12484	32214837	The results suggest a role of XRCC gene polymorphisms in esophageal cancer risk and a need to confirm our findings with higher sample size in different ethnic groups inhabiting different geographical areas of India.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('polymorphisms', 'Var', (40, 53))	('XRCC gene', 'Gene', (30, 39))	('esophageal cancer', 'Disease', (57, 74))	('role', 'Reg', (22, 26))
12487	31126874	IL-5 signal transduction involves JAK-STAT-p38MAPK-NFkB activation and executes extracellular matrix remodeling, EMT transition and immune responses in allergic diseases.	('allergic diseases', 'Disease', (152, 169))	('IL-5', 'Gene', (0, 4))	('EMT transition', 'CPA', (113, 127))	('immune responses', 'CPA', (132, 148))	('allergic diseases', 'Disease', 'MESH:D004342', (152, 169))	('EM', 'Chemical', '-', (113, 115))	('activation', 'PosReg', (56, 66))	('JAK-STAT-p38MAPK-NFkB', 'Var', (34, 55))
12489	31126874	In, addition, several other cytokines like IL-2, IL-4, IL-13, IL-21, and IL-33 also contribute in advancing eosinophils associated immune responses in innate and adaptive immunity.	('IL-2', 'Gene', '3558', (62, 66))	('eosinophils associated immune', 'MPA', (108, 137))	('IL-21', 'Gene', (62, 67))	('IL-2', 'Gene', (62, 66))	('IL-21', 'Gene', '59067', (62, 67))	('IL-33', 'Var', (73, 78))	('advancing', 'PosReg', (98, 107))	('IL-2', 'Gene', (43, 47))	('IL-2', 'Gene', '3558', (43, 47))
12548	31126874	Neutralization of galectin-10 partially abrogated the suppressive function of the eosinophils, and recombinant galectin-10 was able to suppress T cell proliferation.	('galectin-10', 'Gene', '1178', (18, 29))	('suppress', 'NegReg', (135, 143))	('galectin-10', 'Gene', '1178', (111, 122))	('T cell proliferation', 'CPA', (144, 164))	('abrogated', 'NegReg', (40, 49))	('Neutralization', 'Var', (0, 14))	('galectin-10', 'Gene', (18, 29))	('galectin-10', 'Gene', (111, 122))	('suppressive function', 'MPA', (54, 74))
12552	31126874	Phosphorylation of these proteins activates down-stream molecules such as Pim-1, c-fos, c-jun, NFkappab, and thus induce cell survival and proliferation, immune responses and eosinophil number.	('c-jun', 'Gene', '3725', (88, 93))	('c-jun', 'Gene', (88, 93))	('NFkappab', 'Gene', (95, 103))	('c-fos', 'Gene', (81, 86))	('eosinophil number', 'CPA', (175, 192))	('immune responses', 'CPA', (154, 170))	('Phosphorylation', 'Var', (0, 15))	('cell survival', 'CPA', (121, 134))	('Pim-1', 'Gene', '5292', (74, 79))	('induce', 'PosReg', (114, 120))	('c-fos', 'Gene', '2353', (81, 86))	('Pim-1', 'Gene', (74, 79))	('activates', 'PosReg', (34, 43))	('NFkappab', 'Gene', '4790', (95, 103))	('down-stream molecules', 'MPA', (44, 65))
12558	31126874	The inhibitor for p38 MAP kinase SB239063 abolish lung eosinophilia in mice, another inhibitor SB203580 enhances apoptosis of eosinophils.	('mice', 'Species', '10090', (71, 75))	('SB239063', 'Var', (33, 41))	('SB203580', 'Chemical', 'MESH:C093642', (95, 103))	('abolish', 'NegReg', (42, 49))	('apoptosis of eosinophils', 'CPA', (113, 137))	('lung eosinophilia', 'Disease', 'MESH:D004802', (50, 67))	('lung eosinophilia', 'Disease', (50, 67))	('lung eosinophilia', 'Phenotype', 'HP:0032071', (50, 67))	('eosinophilia', 'Phenotype', 'HP:0001880', (55, 67))	('SB239063', 'Chemical', 'MESH:C406525', (33, 41))	('enhances', 'PosReg', (104, 112))	('SB203580', 'Var', (95, 103))
12576	31126874	Further reports showed the role of IL-18 in eosinophil-mediated tumoricidal activity against a Colo-205 carcinoma cell line by upregulating LFA-1 and ICAM-1, however neutralization of IL-18 reduced eosinophil-mediated Colo-205 apoptosis and inhibited cell-cell adhesion.	('LFA-1', 'Gene', '3683', (140, 145))	('ICAM-1', 'Gene', (150, 156))	('upregulating', 'PosReg', (127, 139))	('neutralization', 'Var', (166, 180))	('tumoricidal activity', 'CPA', (64, 84))	('Colo', 'Species', '307630', (95, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cell-cell adhesion', 'CPA', (251, 269))	('IL-18', 'Gene', (184, 189))	('reduced eosinophil', 'Phenotype', 'HP:0031891', (190, 208))	('carcinoma', 'Disease', (104, 113))	('reduced', 'NegReg', (190, 197))	('ICAM-1', 'Gene', '3383', (150, 156))	('LFA-1', 'Gene', (140, 145))	('inhibited', 'NegReg', (241, 250))	('eosinophil-mediated Colo-205 apoptosis', 'CPA', (198, 236))	('Colo', 'Species', '307630', (218, 222))	('carcinoma', 'Disease', 'MESH:D009369', (104, 113))
12584	31126874	Administration of mice with anti-human IL-18 antibodies protected against eosinophil-mediated airway inflammation and demonstrated the role of IL-18 in the development of asthmatic inflammation.	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('asthma', 'Phenotype', 'HP:0002099', (171, 177))	('inflammation', 'Disease', (101, 113))	('anti-human', 'Var', (28, 38))	('protected', 'NegReg', (56, 65))	('asthmatic inflammation', 'Disease', 'MESH:D007249', (171, 193))	('mice', 'Species', '10090', (18, 22))	('asthmatic inflammation', 'Phenotype', 'HP:0002099', (171, 193))	('airway inflammation', 'Phenotype', 'HP:0002099', (94, 113))	('IL-18', 'Gene', (39, 44))	('human', 'Species', '9606', (33, 38))	('inflammation', 'Disease', 'MESH:D007249', (181, 193))	('inflammation', 'Disease', (181, 193))	('asthmatic inflammation', 'Disease', (171, 193))
12594	31126874	Mast cells interact with eosinophils on IgE activation or dexamethasone challenge, and this interaction helps in eosinophils survival and communication and mediated by CD48, and 2B4 mediate mast cell-eosinophil interactions and increase eosinophil survival.	('IgE', 'Gene', (40, 43))	('communication', 'CPA', (138, 151))	('IgE', 'Gene', '3497', (40, 43))	('2B4', 'Var', (178, 181))	('mediate', 'Reg', (182, 189))	('CD48', 'Gene', '962', (168, 172))	('CD48', 'Gene', (168, 172))	('dexamethasone', 'Chemical', 'MESH:D003907', (58, 71))	('increase', 'PosReg', (228, 236))	('eosinophil survival', 'CPA', (237, 256))	('helps', 'PosReg', (104, 109))	('eosinophils', 'MPA', (113, 124))	('interactions', 'Interaction', (211, 223))	('increase eosinophil', 'Phenotype', 'HP:0001880', (228, 247))
12603	31126874	Activation of TLR4 leads to DC migration and recruitment and induce Th2 responses.	('TLR4', 'Gene', '7099', (14, 18))	('induce', 'PosReg', (61, 67))	('TLR4', 'Gene', (14, 18))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('recruitment', 'CPA', (45, 56))	('Activation', 'Var', (0, 10))	('Th2', 'Gene', (68, 71))	('DC migration', 'CPA', (28, 40))	('Th2', 'Gene', '15111', (68, 71))
12607	31126874	IL-5 Tg hypereosinophilic mice with profound B cell expansion showed a decrease in B cell lymphocytosis upon genetic deletion of eosinophils.	('lymphocytosis', 'Phenotype', 'HP:0100827', (90, 103))	('decrease', 'NegReg', (71, 79))	('B cell lymphocytosis', 'MPA', (83, 103))	('hypereosinophilic', 'Disease', (8, 25))	('hypereosinophilic', 'Disease', 'MESH:D017681', (8, 25))	('genetic deletion', 'Var', (109, 125))	('mice', 'Species', '10090', (26, 30))
12622	31126874	IL-9 governs allergen-induced mast cell activation, and anti-IL-9 treatment protects from airway remodeling in asthma in mice.	('asthma', 'Disease', 'MESH:D001249', (111, 117))	('asthma', 'Disease', (111, 117))	('airway remodeling', 'CPA', (90, 107))	('anti-IL-9', 'Var', (56, 65))	('mice', 'Species', '10090', (121, 125))	('asthma', 'Phenotype', 'HP:0002099', (111, 117))
12627	31126874	Similarly, a report also indicates that esophageal eosinophilia is observedeven in IL-4/IL-13 double gene-deficient and STAT6 gene-deficient mice.	('eosinophilia', 'Disease', 'MESH:D004802', (51, 63))	('eosinophilia', 'Disease', (51, 63))	('eosinophilia', 'Phenotype', 'HP:0001880', (51, 63))	('mice', 'Species', '10090', (141, 145))	('IL-4/IL-13', 'Gene', (83, 93))	('STAT6', 'Gene', (120, 125))	('double gene-deficient', 'Var', (94, 115))
12639	31126874	Allergen-sensitized IL-22-deficient mice suffer from significantly higher airway hyperreactivity upon airway challenge with an increase in eosinophil infiltration, lymphocyte invasion and production of CCL17 (TARC), IL-5 and IL-13 in the lung.	('higher', 'PosReg', (67, 73))	('eosinophil infiltration', 'Phenotype', 'HP:0001880', (139, 162))	('production', 'MPA', (188, 198))	('IL-22-deficient', 'Var', (20, 35))	('eosinophil infiltration', 'CPA', (139, 162))	('lymphocyte invasion', 'CPA', (164, 183))	('increase', 'PosReg', (127, 135))	('airway hyperreactivity', 'CPA', (74, 96))	('mice', 'Species', '10090', (36, 40))	('AR', 'Phenotype', 'HP:0003193', (210, 212))	('TARC', 'Gene', (209, 213))	('IL-22-deficient', 'Gene', (20, 35))	('CCL17', 'MPA', (202, 207))	('TARC', 'Gene', '20295', (209, 213))
12642	31126874	IL-25 neutralization in allergen-exposed mice exhibited a reduction in pulmonary eosinophilia and levels of Th2 associated cytokines, IL-5 and IL-13 and decreased fibrosis, airway smooth muscle hyperplasia and airway hyperreactivity.	('IL-25', 'Gene', (0, 5))	('reduction', 'NegReg', (58, 67))	('fibrosis', 'Disease', (163, 171))	('Th2', 'Gene', (108, 111))	('pulmonary eosinophilia', 'Disease', (71, 93))	('airway hyperreactivity', 'CPA', (210, 232))	('mice', 'Species', '10090', (41, 45))	('muscle hyperplasia', 'Disease', 'MESH:D006965', (187, 205))	('eosinophilia', 'Phenotype', 'HP:0001880', (81, 93))	('pulmonary eosinophilia', 'Phenotype', 'HP:0032071', (71, 93))	('muscle hyperplasia', 'Disease', (187, 205))	('Th2', 'Gene', '15111', (108, 111))	('decreased', 'NegReg', (153, 162))	('muscle hyperplasia', 'Phenotype', 'HP:0003712', (187, 205))	('fibrosis', 'Disease', 'MESH:D005355', (163, 171))	('neutralization', 'Var', (6, 20))	('pulmonary eosinophilia', 'Disease', 'MESH:D011657', (71, 93))
12655	31126874	Several animal and human studies are correlated with eosinophils mediated asthma development with an increase in IL-5 and IL-18 levels.	('asthma', 'Phenotype', 'HP:0002099', (74, 80))	('increase', 'PosReg', (101, 109))	('asthma', 'Disease', 'MESH:D001249', (74, 80))	('human', 'Species', '9606', (19, 24))	('eosinophils', 'Var', (53, 64))	('asthma', 'Disease', (74, 80))
12726	31126874	It is characterized by the presence of anti-myeloperoxidase (MPO), anti-neutrophil antibodies in the cytoplasm of 30-38% of patients and most frequently involves peripheral nerves and skin.	('MPO', 'Gene', '4353', (61, 64))	('myeloperoxidase', 'Gene', (44, 59))	('anti-neutrophil', 'Var', (67, 82))	('MPO', 'Gene', (61, 64))	('myeloperoxidase', 'Gene', '4353', (44, 59))	('patients', 'Species', '9606', (124, 132))	('neutrophil antibodies', 'Phenotype', 'HP:0003453', (72, 93))
12739	31126874	HES patients showed clonal T-cell receptor rearrangements and IL-5 producing T cells characterized by CD3- CD4+ T cells.	('HES', 'Phenotype', 'HP:0032061', (0, 3))	('HES', 'Disease', (0, 3))	('IL-5', 'Gene', (62, 66))	('CD', 'Chemical', 'MESH:D002104', (102, 104))	('HES', 'Disease', 'MESH:D017681', (0, 3))	('patients', 'Species', '9606', (4, 12))	('T-cell receptor', 'Protein', (27, 42))	('rearrangements', 'Var', (43, 57))	('CD', 'Chemical', 'MESH:D002104', (107, 109))
12763	31126874	The JAK-3 inhibitor CP-690550 acts as an anti-inflammatory agent for pulmonary eosinophilia in a mouse model.	('eosinophilia', 'Phenotype', 'HP:0001880', (79, 91))	('CP-690550', 'Var', (20, 29))	('pulmonary eosinophilia', 'Disease', 'MESH:D011657', (69, 91))	('mouse', 'Species', '10090', (97, 102))	('pulmonary eosinophilia', 'Disease', (69, 91))	('pulmonary eosinophilia', 'Phenotype', 'HP:0032071', (69, 91))	('JAK-3', 'Gene', '16453', (4, 9))	('JAK-3', 'Gene', (4, 9))	('CP-690550', 'Chemical', 'MESH:C479163', (20, 29))
12784	31126874	Small molecule antagonists of CCR3, CRTH2 or eosinophil inhibitory receptors might also be an effective strategy to treat eosinophils in allergic diseases.	('CCR3', 'Gene', (30, 34))	('CRTH2', 'Gene', '11251', (36, 41))	('CRTH2', 'Gene', (36, 41))	('antagonists', 'Var', (15, 26))	('CCR3', 'Gene', '1232', (30, 34))	('Small molecule antagonists', 'Var', (0, 26))	('allergic diseases', 'Disease', (137, 154))	('allergic diseases', 'Disease', 'MESH:D004342', (137, 154))
12797	29774104	Seven metabolic tumor sub-volumes were obtained on the baseline scans using a fixed percentage of SUVmax (I30, I40, I50, I60, I70, I80, and I90) and were subsequently compared with two post-treatment sub-volumes (R40, R90) in 38 cases of local recurrence or residual metabolic disease.	('I80', 'Var', (131, 134))	('metabolic tumor', 'Disease', 'MESH:D008659', (6, 21))	('I70', 'Var', (126, 129))	('I40', 'Var', (111, 114))	('I50', 'Var', (116, 119))	('metabolic disease', 'Disease', 'MESH:D008659', (267, 284))	('I90', 'Var', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('I30', 'Var', (106, 109))	('metabolic tumor', 'Disease', (6, 21))	('metabolic disease', 'Disease', (267, 284))	('I60', 'Var', (121, 124))
12806	29774104	These studies have indeed shown that the sub-volumes with high 18F-FDG uptake tend to correlate with a higher risk of local recurrence after a treatment by radiochemotherapy in non-small cell lung cancer, in rectal cancer and esophageal cancer.	('rectal cancer', 'Phenotype', 'HP:0100743', (208, 221))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (177, 203))	('esophageal cancer', 'Disease', 'MESH:D004938', (226, 243))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('esophageal cancer', 'Disease', (226, 243))	('cancer', 'Disease', (215, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('non-small cell lung cancer', 'Disease', (177, 203))	('local', 'Disease', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', (197, 203))	('FDG', 'Chemical', 'MESH:D019788', (67, 70))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (181, 203))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (177, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('high', 'Var', (58, 62))
12854	29774104	reported initial I40 MTVs of 53 cm3 in lung cancer while in our HNSCC study mean I4O was only 24.6 cm3.	('MTV', 'Chemical', '-', (21, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lung cancer', 'Disease', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (64, 69))	('I40 MTVs', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
12889	29774104	The measurement of VcI considering R40 determines the smaller initial sub-volume (Ix) that contains the recurrence volume, while the measurement considering R90 corresponds to the smaller initial sub-volume (Ix) that contains the highest activity regions in the tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('R40', 'Var', (35, 38))
12898	27863424	Moreover, CDH1, which encodes the adhesion molecule E-cadherin, was the most significantly downregulated gene in FLO-1LM compared to FLO-1.	('CDH1', 'Gene', (10, 14))	('downregulated', 'NegReg', (91, 104))	('CDH1', 'Gene', '999', (10, 14))	('FLO-1', 'Chemical', '-', (133, 138))	('FLO-1LM', 'Var', (113, 120))	('FLO-1LM', 'Chemical', '-', (113, 120))	('FLO-1', 'Chemical', '-', (113, 118))	('E-cadherin', 'Gene', (52, 62))	('E-cadherin', 'Gene', '999', (52, 62))
12907	27863424	These alterations affect signaling pathways that ultimately enable cancer cells to invade locally, traverse the systemic circulation and colonize distant sites.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('alterations', 'Var', (6, 17))	('cancer', 'Disease', (67, 73))	('affect', 'Reg', (18, 24))	('traverse', 'CPA', (99, 107))	('signaling pathways', 'Pathway', (25, 43))	('enable', 'Reg', (60, 66))	('invade', 'CPA', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
12935	27863424	Importantly, given that EMT may result in tumor de-differentiation, invasion and metastasis, we next compared the mRNA and protein levels of well validated EMT genes across our cell line panel.	('tumor', 'Disease', (42, 47))	('result in', 'Reg', (32, 41))	('invasion', 'CPA', (68, 76))	('metastasis', 'CPA', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('de-differentiation', 'NegReg', (48, 66))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('EMT', 'Var', (24, 27))
12942	27863424	In comparison to parental cells, we found that FLO-1LM were smaller in size, and exhibited greater migratory, invasive, proliferative and clonogenic capacity in vitro (Figure 3A-3E).	('FLO-1LM', 'Var', (47, 54))	('migratory', 'CPA', (99, 108))	('FLO-1LM', 'Chemical', '-', (47, 54))	('clonogenic capacity', 'CPA', (138, 157))	('greater', 'PosReg', (91, 98))	('invasive', 'CPA', (110, 118))
12946	27863424	Interestingly, we found that FLO-1LM cells were also tumorigenic and metastatic in nude mice (Figure 4F-4H), whereas FLO-1 parental cells completely failed to grow in these mice with relatively higher immunocompetency.	('FLO-1', 'Chemical', '-', (117, 122))	('metastatic', 'CPA', (69, 79))	('FLO-1LM', 'Var', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('FLO-1', 'Chemical', '-', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('FLO-1LM', 'Chemical', '-', (29, 36))	('tumor', 'Disease', (53, 58))	('mice', 'Species', '10090', (88, 92))	('nude mice', 'Species', '10090', (83, 92))	('mice', 'Species', '10090', (173, 177))
12954	27863424	We stratified this cohort based on CDH1 expression, with low CDH1 defined a priori as the bottom 25% (and high CDH1 the top 75%).	('CDH1', 'Gene', '999', (61, 65))	('CDH1', 'Gene', (111, 115))	('CDH1', 'Gene', (35, 39))	('low', 'Var', (57, 60))	('CDH1', 'Gene', '999', (35, 39))	('CDH1', 'Gene', '999', (111, 115))	('CDH1', 'Gene', (61, 65))
12956	27863424	Top enriched GO processes found in FLO-1LM (vs. FLO-1 parental) and CDH1 low tumors (vs. CDH1 high tumours) were subsequently compared.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('CDH1 high tumours', 'Disease', 'MESH:D009369', (89, 106))	('FLO-1', 'Chemical', '-', (35, 40))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('CDH1 high tumours', 'Disease', (89, 106))	('CDH1 low tumors', 'Disease', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CDH1 low tumors', 'Disease', 'MESH:D009800', (68, 83))	('FLO-1', 'Chemical', '-', (48, 53))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('FLO-1LM', 'Var', (35, 42))	('FLO-1LM', 'Chemical', '-', (35, 42))
12963	27863424	Strikingly, we found that metastatic burden from cells with low E-cadherin expression was on average 160,000-fold greater in the liver and 12-fold greater in the lungs than high E-cadherin expressing cells (Figure 6C).	('greater', 'PosReg', (147, 154))	('low', 'Var', (60, 63))	('E-cadherin', 'Gene', (64, 74))	('greater', 'PosReg', (114, 121))	('metastatic burden', 'CPA', (26, 43))	('E-cadherin', 'Gene', (178, 188))	('E-cadherin', 'Gene', '999', (178, 188))	('E-cadherin', 'Gene', '999', (64, 74))
12964	27863424	Extending these findings, we found that E-cadherin knockdown in FLO1-parental cells (Figure 6D) resulted in smaller cells, enhanced migration, and increased the expression of SNAI2, ZEB2 and TWIST1 in vitro (Figure 6E-6G, Supplementary Figure S5A), effectively phenocopying FLO-1LM cells.	('enhanced', 'PosReg', (123, 131))	('TWIST1', 'Gene', '7291', (191, 197))	('increased', 'PosReg', (147, 156))	('SNAI2', 'Gene', '6591', (175, 180))	('SNAI2', 'Gene', (175, 180))	('expression', 'MPA', (161, 171))	('E-cadherin', 'Gene', (40, 50))	('E-cadherin', 'Gene', '999', (40, 50))	('migration', 'CPA', (132, 141))	('ZEB2', 'Gene', '9839', (182, 186))	('smaller', 'NegReg', (108, 115))	('FLO-1LM', 'Chemical', '-', (274, 281))	('FLO1-parental', 'Gene', (64, 77))	('TWIST1', 'Gene', (191, 197))	('ZEB2', 'Gene', (182, 186))	('cells', 'CPA', (116, 121))	('knockdown', 'Var', (51, 60))
12965	27863424	To investigate the clinical importance of CDH1/E-cadherin dysregulation in esophageal cancer, we firstly analyzed TCGA datasets (publicly available at cBioportal for Cancer Genomics: www.cbioportal.org) and reviewed the literature to determine the extent of CDH1/E-cadherin aberration in esophageal EAC.	('Cancer', 'Disease', 'MESH:D009369', (166, 172))	('Cancer', 'Phenotype', 'HP:0002664', (166, 172))	('CDH1', 'Gene', (258, 262))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('E-cadherin', 'Gene', (263, 273))	('CDH1', 'Gene', (42, 46))	('E-cadherin', 'Gene', '999', (263, 273))	('E-cadherin', 'Gene', (47, 57))	('CDH1', 'Gene', '999', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CDH1', 'Gene', '999', (258, 262))	('E-cadherin', 'Gene', '999', (47, 57))	('esophageal EAC', 'Disease', (288, 302))	('EAC', 'Phenotype', 'HP:0011459', (299, 302))	('Cancer', 'Disease', (166, 172))	('esophageal cancer', 'Disease', (75, 92))	('aberration', 'Var', (274, 284))
12967	27863424	This is in part explained by the frequent hyper-methylation of the CDH1 promoter resulting in impaired gene transcription (Figure 6I).	('CDH1', 'Gene', (67, 71))	('impaired', 'NegReg', (94, 102))	('gene transcription', 'MPA', (103, 121))	('hyper-methylation', 'Var', (42, 59))	('CDH1', 'Gene', '999', (67, 71))
12968	27863424	Additionally, genomic abnormalities such as mutations and deletions, albeit uncommon, have also been reported (Figure 6I).	('mutations', 'Var', (44, 53))	('genomic abnormalities', 'Disease', 'MESH:D042822', (14, 35))	('genomic abnormalities', 'Disease', (14, 35))	('deletions', 'Var', (58, 67))
12979	27863424	Furthermore, since parental FLO-1 cells were originally established from a treatment-naive patient (Table 1), these pathway alterations are likely to reflect innate tumor biology absent of therapy-related selection pressures.	('alterations', 'Var', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('FLO-1', 'Chemical', '-', (28, 33))	('patient', 'Species', '9606', (91, 98))	('tumor', 'Disease', (165, 170))
12986	27863424	Interestingly, parental FLO-1 cells were metastatic in NSG mice but not in NOD-SCID mice.	('mice', 'Species', '10090', (59, 63))	('NSG', 'Var', (55, 58))	('mice', 'Species', '10090', (84, 88))	('SCID', 'Disease', 'MESH:D053632', (79, 83))	('SCID', 'Disease', (79, 83))	('FLO-1', 'Chemical', '-', (24, 29))	('metastatic', 'CPA', (41, 51))
12987	27863424	The main difference between these two transgenic strains is the knockout of IL-2 receptor gamma-chain in NSG mice, which results in loss of cytokine signalling and impaired T, B, and natural killer cell function.	('cytokine signalling', 'MPA', (140, 159))	('loss', 'NegReg', (132, 136))	('knockout', 'Var', (64, 72))	('IL-2', 'Gene', (76, 80))	('loss of cytokine signalling', 'Phenotype', 'HP:0031407', (132, 159))	('mice', 'Species', '10090', (109, 113))	('impaired', 'NegReg', (164, 172))
12990	27863424	A key strength of our study is the establishment of FLO-1LM, which in contrast to parental FLO-1, is significantly more invasive in vitro and more metastatic in vivo.	('metastatic', 'CPA', (147, 157))	('more', 'PosReg', (115, 119))	('FLO-1LM', 'Var', (52, 59))	('FLO-1LM', 'Chemical', '-', (52, 59))	('FLO-1', 'Chemical', '-', (91, 96))	('invasive', 'CPA', (120, 128))	('FLO-1', 'Chemical', '-', (52, 57))
12992	27863424	Consistently, the most differentially altered pathways between FLO-1LM and parental FLO-1 were processes involved in regulating cell adhesion, migration, differentiation, proliferation, cytoskeletal organization, angiogenesis and apoptosis.	('altered', 'Reg', (38, 45))	('FLO-1', 'Chemical', '-', (84, 89))	('cell adhesion', 'CPA', (128, 141))	('FLO-1', 'Chemical', '-', (63, 68))	('migration', 'CPA', (143, 152))	('proliferation', 'CPA', (171, 184))	('FLO-1LM', 'Var', (63, 70))	('FLO-1LM', 'Chemical', '-', (63, 70))
12998	27863424	Here, we showed that FLO-1 parental cells with low levels of E-cadherin expression have increased metastatic capacity compared with E-cadherin high expressers.	('E-cadherin', 'Gene', (132, 142))	('E-cadherin', 'Gene', '999', (132, 142))	('metastatic capacity', 'CPA', (98, 117))	('E-cadherin', 'Gene', (61, 71))	('E-cadherin', 'Gene', '999', (61, 71))	('increased', 'PosReg', (88, 97))	('low levels', 'Var', (47, 57))	('FLO-1', 'Chemical', '-', (21, 26))
12999	27863424	Additionally, E-cadherin knockdown in FLO-1 parental cells induced a mesenchymal-like cell morphology, increased cell migration and upregulated EMT genes.	('E-cadherin', 'Gene', '999', (14, 24))	('increased', 'PosReg', (103, 112))	('induced', 'PosReg', (59, 66))	('EMT genes', 'Gene', (144, 153))	('mesenchymal-like cell morphology', 'CPA', (69, 101))	('upregulated', 'PosReg', (132, 143))	('cell migration', 'CPA', (113, 127))	('E-cadherin', 'Gene', (14, 24))	('knockdown', 'Var', (25, 34))	('FLO-1', 'Chemical', '-', (38, 43))
13002	27863424	It is unlikely however, that genomic aberrations alone will explain this phenomenon, as the incidence of CDH1 mutation is relatively low in EAC.	('low', 'NegReg', (133, 136))	('EAC', 'Phenotype', 'HP:0011459', (140, 143))	('CDH1', 'Gene', (105, 109))	('mutation', 'Var', (110, 118))	('CDH1', 'Gene', '999', (105, 109))
13005	27863424	Their expression is further elevated in FLO-1LM, which concordantly has lower CDH1 levels.	('FLO-1LM', 'Var', (40, 47))	('expression', 'MPA', (6, 16))	('lower', 'NegReg', (72, 77))	('FLO-1LM', 'Chemical', '-', (40, 47))	('CDH1', 'Gene', (78, 82))	('elevated', 'PosReg', (28, 36))	('CDH1', 'Gene', '999', (78, 82))
13035	27863424	Antibodies against the following proteins were used: human mitochondrial antigen (MAB1273, Merck Millipore), AE1/AE3 (Leica Biosystems), CD45 (2B11, Dako) and E-cadherin (EP700Y, Abcam).	('EP700Y', 'Var', (171, 177))	('E-cadherin', 'Gene', '999', (159, 169))	('AE3', 'Gene', '6508', (113, 116))	('E-cadherin', 'Gene', (159, 169))	('human', 'Species', '9606', (53, 58))	('AE1', 'Gene', '6521', (109, 112))	('AE3', 'Gene', (113, 116))	('AE1', 'Gene', (109, 112))
13074	27058412	The knockdown of Cat S significantly suppressed the migration and invasion of GC cells.	('C', 'Chemical', 'MESH:D002244', (17, 18))	('Cat S', 'Gene', '1520', (17, 22))	('Cat S', 'Gene', (17, 22))	('knockdown', 'Var', (4, 13))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('suppressed', 'NegReg', (37, 47))
13078	27058412	Serum biomarkers, for example, CEA, CA72-4, CA19-9, lack sufficient sensitivity and specificity.	('CA72-4', 'Chemical', '-', (36, 42))	('CEA', 'Gene', '1084', (31, 34))	('CA19-9', 'Var', (44, 50))	('CA19-9', 'Chemical', 'MESH:C086528', (44, 50))	('CA72-4', 'Var', (36, 42))	('CEA', 'Gene', (31, 34))
13093	27058412	High Cat L expression has been found in gastrointestinal stromal tumors.	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (40, 71))	('Cat L', 'Gene', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('gastrointestinal stromal tumors', 'Disease', (40, 71))	('Cat L', 'Gene', '1514', (5, 10))	('found', 'Reg', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (40, 71))
13110	27058412	In contrast, the AUCs of the traditional biomarkers of CEA, CA724 and CA199 were 0.626, 0.575, and 0.564, respectively.	('CEA', 'Gene', (55, 58))	('CEA', 'Gene', '1084', (55, 58))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('CA724', 'Chemical', '-', (60, 65))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('CA199', 'Var', (70, 75))	('CA199', 'Chemical', '-', (70, 75))
13112	27058412	The combination of Cat S, CEA, CA724 and CA199 resulted in a better AUC of 0.851 with a specificity of 91.2% and a sensitivity of 72.6% (Figure 2A).	('C', 'Chemical', 'MESH:D002244', (31, 32))	('CA199', 'Chemical', '-', (41, 46))	('C', 'Chemical', 'MESH:D002244', (41, 42))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('CA724', 'Var', (31, 36))	('Cat S', 'Gene', '1520', (19, 24))	('AUC', 'MPA', (68, 71))	('CEA', 'Gene', (26, 29))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('CEA', 'Gene', '1084', (26, 29))	('CA724', 'Chemical', '-', (31, 36))	('CA199', 'Var', (41, 46))	('Cat S', 'Gene', (19, 24))
13144	27058412	The knockdown of Cat S clearly reduced both the migration ability and the invasive nature of the GC cells and even elicited significant reductions compared to the wild-type Cat S cells (Figure 5C and 5D).	('C', 'Chemical', 'MESH:D002244', (17, 18))	('reduced', 'NegReg', (31, 38))	('C', 'Chemical', 'MESH:D002244', (194, 195))	('Cat S', 'Gene', (173, 178))	('Cat S', 'Gene', (17, 22))	('C', 'Chemical', 'MESH:D002244', (173, 174))	('invasive nature of the GC cells', 'CPA', (74, 105))	('reductions', 'NegReg', (136, 146))	('Cat S', 'Gene', '1520', (173, 178))	('migration ability', 'CPA', (48, 65))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('knockdown', 'Var', (4, 13))	('Cat S', 'Gene', '1520', (17, 22))
13189	27058412	In summary, we observed high levels of expression of Cat S in GC, and the knockdown Cat S suppressed GC cell migration and invasion.	('Cat S', 'Gene', (53, 58))	('GC', 'Phenotype', 'HP:0012126', (62, 64))	('Cat S', 'Gene', '1520', (84, 89))	('C', 'Chemical', 'MESH:D002244', (84, 85))	('knockdown', 'Var', (74, 83))	('Cat S', 'Gene', '1520', (53, 58))	('GC', 'Phenotype', 'HP:0012126', (101, 103))	('C', 'Chemical', 'MESH:D002244', (53, 54))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('suppressed', 'NegReg', (90, 100))	('Cat S', 'Gene', (84, 89))	('C', 'Chemical', 'MESH:D002244', (63, 64))
13212	27058412	After being blocked with 5% non-fat dry milk in PBS containing 0.05% Tween-20, the blotted membranes were incubated with anti-human Cat S antibody (sc74429, Santa Cruz; 1:100) and then secondary antibody (1:5000, Boster, China).	('human', 'Species', '9606', (126, 131))	('PBS', 'Disease', (48, 51))	('sc74429', 'Var', (148, 155))	('C', 'Chemical', 'MESH:D002244', (221, 222))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('Tween-20', 'Chemical', 'MESH:D011136', (69, 77))	('Cat S', 'Gene', '1520', (132, 137))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('Cat S', 'Gene', (132, 137))	('PBS', 'Disease', 'MESH:D011535', (48, 51))
13354	24704912	ICC values <0.20, 0.21-0.40, 0.41-0.60, 0.61-0.80, and 0.81-1.00 were considered to indicate poor, fair, moderate, good, and very good agreement, respectively.	('men', 'Species', '9606', (140, 143))	('0.21-0.40', 'Var', (18, 27))	('0.81-1.00', 'Var', (55, 64))	('0.41-0.60', 'Var', (29, 38))	('0.61-0.80', 'Var', (40, 49))	('<0.20', 'Var', (11, 16))
13365	24704912	Initial clinical tumor stage, based on 18F FDG PET/CT and endoscopic ultrasonography findings, varied from cT1N1 to cT4aN3.	('tumor', 'Disease', (17, 22))	('cT1N1', 'Var', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cT4aN3', 'Var', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
13393	24704912	The deep location of the esophagus, movement related to respiration, peristalsis and cardiac motion, and the presence of local field inhomogeneities caused by susceptibility changes at tissue interface make DW-MRI of esophageal cancer challenging.	('esophageal cancer', 'Disease', (217, 234))	('changes', 'Var', (174, 181))	('esophageal cancer', 'Disease', 'MESH:D004938', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('men', 'Species', '9606', (40, 43))
13395	24704912	The final scanning protocol we used was based on our experience in the use of DW-MRI in other tumors (such as rectal cancer), published literature, and test scanning in cooperation with the medical physics department.	('rectal cancer', 'Phenotype', 'HP:0100743', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('DW-MRI', 'Var', (78, 84))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('rectal cancer', 'Disease', 'MESH:D012004', (110, 123))	('rectal cancer', 'Disease', (110, 123))	('men', 'Species', '9606', (212, 215))
13443	33563329	The E7-induced degradation of the tumour suppressor RB protein renders infected cells irresponsive to growth control mechanisms by promoting them to the S phase.	('infected', 'Disease', 'MESH:D007239', (71, 79))	('RB', 'Disease', 'MESH:D012175', (52, 54))	('infected', 'Disease', (71, 79))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('promoting', 'PosReg', (131, 140))	('degradation', 'MPA', (15, 26))	('E7-induced', 'Var', (4, 14))	('tumour', 'Disease', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
13507	33019440	Moderately differentiated esophageal squamous cell cancer (pT1bN0M0G2, IB) was confirmed.	('esophageal squamous cell cancer', 'Disease', (26, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (37, 57))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (26, 57))	('pT1bN0M0G2', 'Var', (59, 69))
13708	28954418	The updated meta-analysis confirms an important inverse association between adherence to a MedD and cancer mortality and risk of several cancer types, especially colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('cancer', 'Disease', (173, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('adherence', 'Var', (76, 85))	('colorectal cancer', 'Disease', (162, 179))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('inverse', 'NegReg', (48, 55))
13722	28954418	Some specific bioactive compounds from foods with tumor-preventive potential have been characterized in the past, e.g., polyphenols, n-3 fatty acids, or monounsaturated fatty acids.	('n-3 fatty acids', 'Chemical', 'MESH:D015525', (133, 148))	('monounsaturated', 'Var', (153, 168))	('polyphenols', 'Chemical', 'MESH:D059808', (120, 131))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('monounsaturated fatty acids', 'Chemical', 'MESH:D005229', (153, 180))	('tumor', 'Disease', (50, 55))
13750	28954418	Pooled estimates for the single components of the Mediterranean dietary pattern shown in Figure 1 revealed an inverse association for fruit consumption (RR: 0.93, 95% CI 0.89 to 0.97, I2 = 60%, n = 13 studies), vegetable intake (RR: 0.96, 95% CI 0.93 to 0.98, I2 = 0%, n = 14 studies), whole grain intake (RR: 0.91, 95% CI 0.87 to 0.95, I2 = 31%, n = 9 studies), and moderate alcohol consumption (within the range) (RR: 0.89, 95% CI 0.85 to 0.93), compared to higher intakes and cancer risk.	('cancer', 'Disease', (479, 485))	('cancer', 'Disease', 'MESH:D009369', (479, 485))	('moderate alcohol consumption', 'Var', (367, 395))	('inverse', 'NegReg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (479, 485))	('alcohol', 'Chemical', 'MESH:D000438', (376, 383))
13754	28954418	Following the synthesis of data from RCTs as well as cohort and case-control studies in the present systematic review, strongest adherence to a MedD was inversely associated with cancer mortality and risk of colorectal, breast, gastric, liver, head and neck, gallbladder, and biliary tract cancer.	('inversely', 'NegReg', (153, 162))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('colorectal', 'Disease', (208, 218))	('breast', 'Disease', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('adherence', 'Var', (129, 138))	('cancer', 'Disease', (290, 296))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (276, 296))	('gastric', 'Disease', (228, 235))	('liver', 'Disease', (237, 242))	('gallbladder', 'Disease', (259, 270))	('associated with', 'Reg', (163, 178))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('cancer', 'Disease', (179, 185))	('MedD', 'Gene', (144, 148))	('biliary tract cancer', 'Disease', 'MESH:D001661', (276, 296))	('biliary tract cancer', 'Disease', (276, 296))
13756	28954418	Consequently, the Greek cohort of the EPIC study revealed that the inverse association between adherence to a MedD and cancer risk is not due to any single component of this diet but rather an effect of the complete pattern.	('inverse', 'NegReg', (67, 74))	('adherence', 'Var', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
13789	28954418	In some studies, the inverse association between adherence to a MedD and risk of tobacco-related cancers was significantly more pronounced in the subgroup of active smokers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('tobacco', 'Species', '4097', (81, 88))	('inverse', 'NegReg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('adherence', 'Var', (49, 58))
13798	28954418	In conclusion, the present update of our systematic review and meta-analyses provided additional important evidence for a beneficial effect of high adherence to MedD with respect to primary prevention overall cancer risk and specific types of cancer, especially colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (262, 279))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('colorectal cancer', 'Phenotype', 'HP:0003003', (262, 279))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (243, 249))	('high adherence', 'Var', (143, 157))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('cancer', 'Disease', (209, 215))	('colorectal cancer', 'Disease', (262, 279))	('beneficial', 'PosReg', (122, 132))	('MedD', 'Gene', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
13803	28744359	Molecular hydrogen has antioxidant and antiapoptotic effects and a preventive effect on oxidative stress-induced cell death.	('oxidative', 'CPA', (88, 97))	('antiapoptotic effects', 'CPA', (39, 60))	('hydrogen', 'Chemical', 'MESH:D006859', (10, 18))	('Molecular', 'Var', (0, 9))	('antioxidant', 'MPA', (23, 34))	('oxidative stress', 'Phenotype', 'HP:0025464', (88, 104))
13809	28744359	Apoptosis-inducing effect on KYSE-70 cells was observed in 10, 300, 600, and 1,200 ppm H2-silica, and only 1,200 ppm H2-silica caused a 2.4-fold increase in apoptosis in HEEpiCs compared with the control group as the index of Bax/Bcl-2.	('H2-silica', 'Var', (87, 96))	('apoptosis', 'CPA', (157, 166))	('Apoptosis-inducing', 'CPA', (0, 18))	('Bax', 'Gene', '581', (226, 229))	('increase', 'PosReg', (145, 153))	('H2-silica', 'Chemical', '-', (117, 126))	('H2-silica', 'Chemical', '-', (87, 96))	('Bax', 'Gene', (226, 229))	('Bcl-2', 'Gene', (230, 235))	('Bcl-2', 'Gene', '596', (230, 235))
13881	28744359	In addition, from the results of the ratios of activated caspase-3 and Bax/Bcl-2 experiment, it was confirmed that H2-silica had the effect of inducing and enhancing cancer cell apoptosis.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('H2-silica', 'Var', (115, 124))	('Bax', 'Gene', (71, 74))	('H2-silica', 'Chemical', '-', (115, 124))	('Bcl-2', 'Gene', (75, 80))	('Bcl-2', 'Gene', '596', (75, 80))	('Bax', 'Gene', '581', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('enhancing', 'PosReg', (156, 165))	('inducing', 'PosReg', (143, 151))
13903	28744359	As shown in Figure 2, H2-silica has a certain antiproliferative effect on KYSE-70 cells, particularly during the initial 48 hours after treatment (P < 0.05).	('H2-silica', 'Var', (22, 31))	('H2-silica', 'Chemical', '-', (22, 31))	('antiproliferative effect', 'CPA', (46, 70))
13916	28744359	According to our results showing that H2-silica can inhibit proliferation, promote apoptosis, and prevent cell migration in KYSE-70 cells, H2-silica may be a potential therapeutic agent in cancer prevention and inhibition of metastasis through its anti-ROS effects.	('inhibit', 'NegReg', (52, 59))	('prevent', 'NegReg', (98, 105))	('promote', 'PosReg', (75, 82))	('ROS', 'Chemical', 'MESH:D017382', (253, 256))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('H2-silica', 'Var', (139, 148))	('H2-silica', 'Chemical', '-', (38, 47))	('metastasis', 'CPA', (225, 235))	('apoptosis', 'CPA', (83, 92))	('proliferation', 'CPA', (60, 73))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('H2-silica', 'Chemical', '-', (139, 148))	('cell migration', 'CPA', (106, 120))	('cancer', 'Disease', (189, 195))
13937	28744359	It suggests that H2-silica may sometimes trigger cell death via the non-caspase pathway or the initiator-caspase-skipping route rather than the typical effector caspase-3 mediated pathway, or it is possible that activated caspase-3 would be degraded by other proteases.	('H2-silica', 'Var', (17, 26))	('H2-silica', 'Chemical', '-', (17, 26))	('non-caspase pathway', 'Pathway', (68, 87))	('trigger', 'Reg', (41, 48))	('cell death', 'CPA', (49, 59))
14052	24736706	Meat Consumption and Risk of Oral Cavity and Oropharynx Cancer: A Meta-Analysis of Observational Studies High meat consumption, especially red and processed meat consumption is associated with an increased risk of several cancers, however, evidence for oral cavity and oropharynx cancer is limited.	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (280, 286))	('cancer', 'Disease', (222, 228))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Oropharynx Cancer', 'Disease', (45, 62))	('cancers', 'Disease', (222, 229))	('High meat', 'Var', (105, 114))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('Oropharynx Cancer', 'Disease', 'MESH:D009959', (45, 62))
14073	24736706	In subgroup analyses, when stratified the various studies by study location, no significant association was noted among studies conducted in Europe (RR = 0.93, 95%CI [0.55, 1.59]), and Asia (RR = 0.98, 95%CI [0.42, 2.29]), however, high consumption of total meat was significantly associated with a 118% increased risk of oral cavity and oropharynx cancer in South America (RR = 2.18, 95%CI [1.49, 3.20]).	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('cancer', 'Disease', (349, 355))	('high', 'Var', (232, 236))	('cancer', 'Disease', 'MESH:D009369', (349, 355))
14086	24736706	NOCs intake may contribute to carcinogenesis at a variety of anatomic sites in animals.	('contribute', 'Reg', (16, 26))	('NOCs', 'Var', (0, 4))	('carcinogenesis', 'Disease', (30, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (30, 44))
14123	24259307	Furthermore, many post-translational modifications affect the chemokine receptor signaling, receptor specificity as well as chemotactic property of chemokines and thus affect their biological functions.	('al', 'Chemical', 'MESH:D000535', (34, 36))	('biological functions', 'MPA', (181, 201))	('affect', 'Reg', (51, 57))	('chemotactic property', 'MPA', (124, 144))	('al', 'Chemical', 'MESH:D000535', (189, 191))	('chemokine receptor', 'Gene', '7852', (62, 80))	('post-translational modifications', 'Var', (18, 50))	('chemokine receptor', 'Gene', (62, 80))	('affect', 'Reg', (168, 174))	('al', 'Chemical', 'MESH:D000535', (85, 87))	('receptor specificity', 'MPA', (92, 112))
14128	24259307	This alteration occurs due to inactivation of the tumor suppressor genes or constitutive activation of the oncogenes that play a role in the regulation of the chemokines.	('rat', 'Species', '10116', (9, 12))	('inactivation', 'Var', (30, 42))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('activation', 'PosReg', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('al', 'Chemical', 'MESH:D000535', (5, 7))	('oncogenes', 'Gene', (107, 116))	('tumor', 'Disease', (50, 55))
14129	24259307	Furthermore, deregulated expression of the transcription factors also affects the levels of chemokine and receptors regulated by them and promotes tumorigenesis.	('levels of chemokine', 'MPA', (82, 101))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('al', 'Chemical', 'MESH:D000535', (65, 67))	('deregulated', 'Var', (13, 24))	('expression', 'MPA', (25, 35))	('affects', 'Reg', (70, 77))	('promotes', 'PosReg', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
14138	24259307	However, the loss of chemokine receptor CXCR2 reduces oncogene induced senescence along with the DNA damage response.	('oncogene', 'Gene', (54, 62))	('CXCR2', 'Gene', (40, 45))	('chemokine receptor', 'Gene', '7852', (21, 39))	('CXCR2', 'Gene', '3579', (40, 45))	('chemokine receptor', 'Gene', (21, 39))	('reduces', 'NegReg', (46, 53))	('loss', 'Var', (13, 17))	('al', 'Chemical', 'MESH:D000535', (82, 84))
14140	24259307	Also, the reintroduction of the chemokine receptor CXCR2 leads to premature senescence by a p53 dependent mechanism.	('chemokine receptor', 'Gene', (32, 50))	('reintroduction', 'Var', (10, 24))	('premature senescence', 'MPA', (66, 86))	('CXCR2', 'Gene', '3579', (51, 56))	('p53', 'Gene', (92, 95))	('CXCR2', 'Gene', (51, 56))	('p53', 'Gene', '7157', (92, 95))	('chemokine receptor', 'Gene', '7852', (32, 50))
14143	24259307	However, mutations in CXCR2 or downregulation of CXCR2 expression may affect the ability of this chemokine receptor to induce senescence.	('affect', 'Reg', (70, 76))	('chemokine receptor', 'Gene', '7852', (97, 115))	('CXCR2', 'Gene', '3579', (49, 54))	('ability', 'MPA', (81, 88))	('mutations', 'Var', (9, 18))	('senescence', 'CPA', (126, 136))	('CXCR2', 'Gene', (49, 54))	('CXCR2', 'Gene', '3579', (22, 27))	('downregulation', 'NegReg', (31, 45))	('CXCR2', 'Gene', (22, 27))	('chemokine receptor', 'Gene', (97, 115))
14145	24259307	The inability to induce senescence by mutated CXCR2 may in fact promote tumorigenesis instead of blocking it.	('mutated', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('promote', 'PosReg', (64, 71))	('senescence', 'MPA', (24, 34))	('tumor', 'Disease', (72, 77))	('CXCR2', 'Gene', '3579', (46, 51))	('CXCR2', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
14155	24259307	Furthermore, the knockdown of CXCR4 in these cells or treatment with CXCR4 antagonist leads to a decrease in cell migration.	('decrease', 'NegReg', (97, 105))	('rat', 'Species', '10116', (117, 120))	('cell migration', 'CPA', (109, 123))	('knockdown', 'Var', (17, 26))
14160	24259307	The authors suggest that inhibiting CXCL8 signaling may help inhibit EMT by targeting the cells with the mesenchymal and invasive phenotype.	('EMT', 'CPA', (69, 72))	('inhibiting', 'Var', (25, 35))	('inhibit', 'NegReg', (61, 68))	('al', 'Chemical', 'MESH:D000535', (114, 116))	('al', 'Chemical', 'MESH:D000535', (46, 48))	('CXCL8', 'Gene', '3576', (36, 41))	('CXCL8', 'Gene', (36, 41))
14231	24259307	Additional studies demonstrate that de novo expression of CXCR4 is sufficient to increase tumor invasion and metastasis in an organ-specific manner.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CXCR4', 'Var', (58, 63))	('tumor', 'Disease', (90, 95))	('rat', 'Species', '10116', (26, 29))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('metastasis', 'CPA', (109, 119))	('increase', 'PosReg', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
14236	24259307	CXCR4 expression in prostate cancer enhances the invasive, metastatic ability of tumor cells in the presence of CXCL12 ligand, while inhibition of CXCR4 decreases metastatic ability.	('enhances', 'PosReg', (36, 44))	('prostate cancer', 'Disease', 'MESH:D011471', (20, 35))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('CXCL12', 'Gene', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('prostate cancer', 'Disease', (20, 35))	('CXCL12', 'Gene', '6387', (112, 118))	('CXCR4 expression', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('invasive', 'CPA', (49, 57))	('tumor', 'Disease', (81, 86))
14238	24259307	Additionally, CXCR4 mediates prostate tumor cell adhesion through the alpha5 and beta3 integrins.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('prostate tumor', 'Phenotype', 'HP:0100787', (29, 43))	('prostate tumor', 'Disease', (29, 43))	('CXCR4', 'Var', (14, 19))	('al', 'Chemical', 'MESH:D000535', (70, 72))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('prostate tumor', 'Disease', 'MESH:D011471', (29, 43))	('beta3 integrins', 'Protein', (81, 96))
14246	24259307	In breast cancer, CXCR4 promotes metastasis to the lungs, liver, and lymph nodes.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('CXCR4', 'Var', (18, 23))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('metastasis to the lungs', 'CPA', (33, 56))	('promotes', 'PosReg', (24, 32))
14247	24259307	In gastric cancer, studies show that CXCR4 promotes metastasis to the lymph nodes.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('promotes', 'PosReg', (43, 51))	('metastasis to the lymph nodes', 'CPA', (52, 81))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('CXCR4', 'Var', (37, 42))
14248	24259307	Also, a study demonstrates that CXCR4 expression in esophageal cancer enhances metastasis to the lymph nodes and bone marrow.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (52, 69))	('CXCR4 expression', 'Var', (32, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('rat', 'Species', '10116', (21, 24))	('enhances', 'PosReg', (70, 78))
14260	24259307	Interestingly, expression of CCR7 in B16 melanoma cells induces metastasis to the lymph nodes, while, as previously discussed, expression of CXCR4 in murine B16 cells increases metastasis to the lungs.	('CCR7', 'Gene', (29, 33))	('expression', 'Var', (15, 25))	('murine', 'Species', '10090', (150, 156))	('metastasis to the lymph nodes', 'CPA', (64, 93))	('metastasis', 'CPA', (177, 187))	('melanoma', 'Disease', (41, 49))	('induces', 'Reg', (56, 63))	('B16', 'CellLine', 'CVCL:N540', (37, 40))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('increases', 'PosReg', (167, 176))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('B16', 'CellLine', 'CVCL:N540', (157, 160))
14262	24259307	High CCR7 expression in human non-Hodgkin's lymphoma induces metastatic spread through the PI3K/Akt signal pathway.	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	('human', 'Species', '9606', (24, 29))	('High', 'Var', (0, 4))	('al', 'Chemical', 'MESH:D000535', (104, 106))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (30, 52))	("non-Hodgkin's lymphoma", 'Disease', (30, 52))	('metastatic spread', 'CPA', (61, 78))	('Akt', 'Gene', '207', (96, 99))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (34, 52))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (30, 52))	('CCR7', 'Gene', (5, 9))	('Akt', 'Gene', (96, 99))	('induces', 'Reg', (53, 60))
14263	24259307	CCR7 expression also induces lymphatic spread in human pancreatic ductal adenocarcinoma.	('lymphatic spread', 'CPA', (29, 45))	('CCR7', 'Gene', (0, 4))	('induces', 'Reg', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('human', 'Species', '9606', (49, 54))	('expression', 'Var', (5, 15))	('al', 'Chemical', 'MESH:D000535', (70, 72))	('al', 'Chemical', 'MESH:D000535', (16, 18))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (55, 87))	('pancreatic ductal adenocarcinoma', 'Disease', (55, 87))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (55, 87))
14267	24259307	Similar to CXCR4, CCR7-CCL21 interactions induces directional invasion of breast tumor cells, pseudopodia formation, and actin polymerization which increases the invasiveness of tumor cells.	('tumor', 'Disease', (178, 183))	('breast tumor', 'Phenotype', 'HP:0100013', (74, 86))	('al', 'Chemical', 'MESH:D000535', (59, 61))	('pseudopodia formation', 'CPA', (94, 115))	('increases', 'PosReg', (148, 157))	('breast tumor', 'Disease', 'MESH:D001943', (74, 86))	('CCL21', 'Gene', '6366', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CCL21', 'Gene', (23, 28))	('induces', 'Reg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('directional invasion', 'CPA', (50, 70))	('breast tumor', 'Disease', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('interactions', 'Var', (29, 41))	('tumor', 'Disease', (81, 86))	('actin polymerization', 'CPA', (121, 141))
14275	24259307	Expressing oncogenic Notch 1 causes mice to develop characteristic pathological features of T-ALL and infiltration of the leptomeningeal spaces of the brain, demonstrating that oncogenic Notch1 is capable of inducing T-ALL and targeting transformed cells to the CNS.	('rat', 'Species', '10116', (108, 111))	('oncogenic Notch1', 'Var', (177, 193))	('Notch1', 'Var', (187, 193))	('Notch 1', 'Gene', '18128', (21, 28))	('al', 'Chemical', 'MESH:D000535', (134, 136))	('inducing', 'PosReg', (208, 216))	('ALL', 'Phenotype', 'HP:0006721', (219, 222))	('ALL', 'Phenotype', 'HP:0006721', (94, 97))	('mice', 'Species', '10090', (36, 40))	('al', 'Chemical', 'MESH:D000535', (77, 79))	('rat', 'Species', '10116', (165, 168))	('Notch 1', 'Gene', (21, 28))	('T-ALL', 'CPA', (217, 222))
14276	24259307	Analysis of primary T-ALL samples as well as T-ALL cell-lines containing Notch1-activating mutations have CCR7 upregulation caused by Notch1 signaling.	('CCR7', 'Gene', (106, 110))	('upregulation', 'PosReg', (111, 123))	('ALL', 'Phenotype', 'HP:0006721', (22, 25))	('ALL', 'Phenotype', 'HP:0006721', (47, 50))	('al', 'Chemical', 'MESH:D000535', (145, 147))	('Notch1', 'Var', (134, 140))	('Notch1-activating', 'Gene', (73, 90))	('al', 'Chemical', 'MESH:D000535', (2, 4))	('mutations', 'Var', (91, 100))
14283	24259307	Inhibition of CCR7, PI3K, Akt and mTOR successfully stops phosphorylation and DNA-binding.	('Akt', 'Gene', '207', (26, 29))	('CCR7', 'Gene', (14, 18))	('phosphorylation', 'MPA', (58, 73))	('DNA-binding', 'Interaction', (78, 89))	('Akt', 'Gene', (26, 29))	('Inhibition', 'Var', (0, 10))	('stops', 'NegReg', (52, 57))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', (34, 38))
14298	24259307	Given the role of CCR10-CCL27 in leukocyte migration to the skin, it is likely that CCR10 expression in melanoma induces metastasis to the skin.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('induces', 'Reg', (113, 120))	('melanoma', 'Disease', (104, 112))	('rat', 'Species', '10116', (46, 49))	('metastasis to the skin', 'CPA', (121, 143))	('CCR10', 'Gene', (18, 23))	('CCR10', 'Gene', '2826', (18, 23))	('CCR10', 'Gene', '2826', (84, 89))	('CCL27', 'Gene', (24, 29))	('leukocyte migration to the skin', 'CPA', (33, 64))	('CCR10', 'Gene', (84, 89))	('CCL27', 'Gene', '10850', (24, 29))	('expression', 'Var', (90, 100))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
14299	24259307	However, another study suggests that CCR10 expression in melanoma promotes metastasis to the lymph nodes in addition to enhancing invasion, growth, and immune escape of tumor cells.	('CCR10', 'Gene', '2826', (37, 42))	('enhancing', 'PosReg', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('expression', 'Var', (43, 53))	('invasion', 'CPA', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('promotes', 'PosReg', (66, 74))	('metastasis to the lymph nodes', 'CPA', (75, 104))	('CCR10', 'Gene', (37, 42))	('tumor', 'Disease', (169, 174))	('growth', 'CPA', (140, 146))
14305	24259307	al demonstrate that expressing CXCR3 in a colon cancer cell line increases in vivo metastasis to the lymph nodes, but not to the liver or lungs.	('metastasis to the lymph nodes', 'CPA', (83, 112))	('al', 'Chemical', 'MESH:D000535', (0, 2))	('increases', 'PosReg', (65, 74))	('CXCR3', 'Var', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('rat', 'Species', '10116', (10, 13))	('expressing CXCR3', 'Var', (20, 36))	('colon cancer', 'Disease', (42, 54))
14309	24259307	In osteosarcoma, studies suggest that CXCR3 and its ligands induce metastasis to the lungs and later stimulate growth and expansion of the metastases.	('growth', 'CPA', (111, 117))	('osteosarcoma', 'Disease', (3, 15))	('metastases', 'Disease', (139, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('expansion', 'CPA', (122, 131))	('metastases', 'Disease', 'MESH:D009362', (139, 149))	('metastasis to the lungs', 'CPA', (67, 90))	('stimulate', 'PosReg', (101, 110))	('CXCR3', 'Var', (38, 43))
14328	24259307	Meanwhile, expression of CCR7 in DND41 cells is sufficient to induce brain and spinal cord infiltration, while silencing CCR7 successfully inhibits T-ALL CNS metastasis.	('T-ALL CNS metastasis', 'Disease', 'MESH:D009362', (148, 168))	('rat', 'Species', '10116', (97, 100))	('silencing', 'Var', (111, 120))	('ALL', 'Phenotype', 'HP:0006721', (150, 153))	('induce', 'PosReg', (62, 68))	('al', 'Chemical', 'MESH:D000535', (83, 85))	('DND41', 'CellLine', 'CVCL:2022', (33, 38))	('CCR7', 'Gene', (121, 125))	('T-ALL CNS metastasis', 'Disease', (148, 168))	('inhibits', 'NegReg', (139, 147))
14420	19457415	H. pylori typically does not cause any adverse effects, but is associated with an increased risk of non-cardia gastric adenocarcinoma, gastric lymphoma and peptic ulcer.	('gastric lymphoma', 'Phenotype', 'HP:0045038', (135, 151))	('non-cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (100, 133))	('H. pylori', 'Species', '210', (0, 9))	('gastric lymphoma', 'Disease', 'MESH:C535648', (135, 151))	('associated', 'Reg', (63, 73))	('ulcer', 'Disease', 'MESH:D014456', (163, 168))	('peptic ulcer', 'Phenotype', 'HP:0004398', (156, 168))	('lymphoma', 'Phenotype', 'HP:0002665', (143, 151))	('non-cardia gastric adenocarcinoma', 'Disease', (100, 133))	('ulcer', 'Disease', (163, 168))	('gastric lymphoma', 'Disease', (135, 151))	('H. pylori', 'Var', (0, 9))
14422	19457415	In this review, we discuss biologic factors that allow H. pylori to colonize the human stomach, mechanisms by which H. pylori increases the risk for peptic ulcer disease and non-cardia gastric adenocarcinoma, and potential benefits that H. pylori might confer to humans.	('non-cardia gastric adenocarcinoma', 'Disease', (174, 207))	('increases', 'PosReg', (126, 135))	('H. pylori', 'Species', '210', (116, 125))	('humans', 'Species', '9606', (263, 269))	('colon', 'Disease', (68, 73))	('peptic ulcer disease', 'Disease', 'MESH:D010437', (149, 169))	('H. pylori', 'Species', '210', (237, 246))	('peptic ulcer', 'Phenotype', 'HP:0004398', (149, 161))	('peptic ulcer disease', 'Disease', (149, 169))	('H. pylori', 'Var', (116, 125))	('colon', 'Disease', 'MESH:D015179', (68, 73))	('human', 'Species', '9606', (263, 268))	('H. pylori', 'Species', '210', (55, 64))	('human', 'Species', '9606', (81, 86))	('non-cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (174, 207))
14457	19457415	Approaches such as signature-tagged mutagenesis and microarray tracking of transposon mutants have led to the identification of more than 100 bacterial genes required for gastric colonization .	('mutants', 'Var', (86, 93))	('colon', 'Disease', (179, 184))	('bacterial genes', 'Gene', (142, 157))	('colon', 'Disease', 'MESH:D015179', (179, 184))	('transposon', 'Gene', (75, 85))
14464	19457415	In the future, with an increasingly narrow bottleneck for H. pylori transmission, there could be selection for variants that colonize a broader range of epithelial surfaces; such variants might be more readily transmitted to new hosts.	('variants', 'Var', (179, 187))	('colon', 'Disease', 'MESH:D015179', (125, 130))	('H. pylori', 'Species', '210', (58, 67))	('variants', 'Var', (111, 119))	('colon', 'Disease', (125, 130))
14473	19457415	H. pylori lipopolysaccharide (LPS) is characterized by modifications of the lipid A component that make it less proinflammatory than LPSs from other gram-negative bacterial species .	('less proinflammatory', 'MPA', (107, 127))	('H. pylori', 'Species', '210', (0, 9))	('LPSs', 'Chemical', '-', (133, 137))	('H. pylori', 'Disease', (0, 9))	('modifications', 'Var', (55, 68))	('LPS', 'Disease', (30, 33))	('LPS', 'Disease', (133, 136))	('lipid', 'Chemical', 'MESH:D008055', (76, 81))	('LPS', 'Disease', 'MESH:C536528', (133, 136))	('LPS', 'Disease', 'MESH:C536528', (30, 33))
14474	19457415	H. pylori flagella are poorly recognized by TLR5 (a component of the innate immune recognition system), due to modifications in the TLR5 recognition site .	('modifications', 'Var', (111, 124))	('H. pylori', 'Species', '210', (0, 9))	('flagella', 'Disease', (10, 18))	('flagella', 'Disease', 'None', (10, 18))	('TLR5', 'Gene', (132, 136))
14504	19457415	Concordant with these predictions, CagA+, s1-VacA+, BabA+ strains are associated with increased gastric mucosal inflammatory cell infiltration and increased gastric epithelial injury, compared to strains that do not express these factors .	('increased', 'PosReg', (147, 156))	('gastric mucosal inflammatory cell infiltration', 'CPA', (96, 142))	('increased', 'PosReg', (86, 95))	('increased gastric', 'Phenotype', 'HP:0005207', (86, 103))	('gastric epithelial injury', 'Disease', 'MESH:D013274', (157, 182))	('gastric epithelial injury', 'Disease', (157, 182))	('CagA+', 'Var', (35, 40))	('increased gastric', 'Phenotype', 'HP:0005207', (147, 164))
14511	19457415	Although H. pylori typically colonizes the human stomach for many decades without adverse consequences, the presence of H. pylori is associated with an increased risk for several diseases, including peptic ulcers, non-cardia gastric adenocarinoma, and gastric MALT lymphoma (reviewed in ).	('H. pylori', 'Species', '210', (120, 129))	('presence', 'Var', (108, 116))	('ulcers', 'Disease', (206, 212))	('associated with', 'Reg', (133, 148))	('gastric MALT lymphoma', 'Disease', 'MESH:D018442', (252, 273))	('ulcers', 'Disease', 'MESH:D014456', (206, 212))	('gastric MALT lymphoma', 'Disease', (252, 273))	('colon', 'Disease', 'MESH:D015179', (29, 34))	('lymphoma', 'Phenotype', 'HP:0002665', (265, 273))	('peptic ulcers', 'Phenotype', 'HP:0004398', (199, 212))	('gastric MALT lymphoma', 'Phenotype', 'HP:0045038', (252, 273))	('non-cardia gastric adenocarinoma', 'Disease', 'MESH:D004938', (214, 246))	('non-cardia gastric adenocarinoma', 'Disease', (214, 246))	('peptic ulcer', 'Phenotype', 'HP:0004398', (199, 211))	('H. pylori', 'Species', '210', (9, 18))	('human', 'Species', '9606', (43, 48))	('colon', 'Disease', (29, 34))
14514	19457415	Most of the H. pylori polymorphisms associated with varying disease risk are found in genes that encode bacterial products that interact with host tissue.	('H. pylori', 'Species', '210', (12, 21))	('polymorphisms', 'Var', (22, 35))	('H. pylori', 'Disease', (12, 21))
14515	19457415	Numerous studies, particularly in Western countries, have shown that cag PAI-positive H. pylori strains are associated with an increased risk of peptic ulcer disease, premalignant gastric lesions and gastric cancer, compared to strains that lack the cag PAI .	('gastric cancer', 'Disease', (200, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('premalignant gastric lesions', 'Disease', (167, 195))	('peptic ulcer disease', 'Disease', 'MESH:D010437', (145, 165))	('peptic ulcer', 'Phenotype', 'HP:0004398', (145, 157))	('peptic ulcer disease', 'Disease', (145, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('strains', 'Var', (96, 103))	('associated', 'Reg', (108, 118))	('H. pylori', 'Species', '210', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('premalignant gastric lesions', 'Disease', 'MESH:D013272', (167, 195))
14516	19457415	Moreover, the number of tyrosine phosphorylation (EPIYA) motifs in CagA proteins correlates with gastric cancer risk .	('gastric cancer', 'Disease', (97, 111))	('tyrosine', 'Chemical', 'MESH:D014443', (24, 32))	('CagA', 'Gene', (67, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('tyrosine phosphorylation', 'MPA', (24, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('motifs', 'Var', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
14524	19457415	For example, male gender, specific IL-1beta haplotypes, and various other proinflammatory gene polymorphisms are associated with an increased risk of non-cardia adenocarcinoma .	('non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (150, 175))	('haplotypes', 'Var', (44, 54))	('IL-1beta', 'Gene', (35, 43))	('associated', 'Reg', (113, 123))	('non-cardia adenocarcinoma', 'Disease', (150, 175))
14529	19457415	H. pylori colonization is associated with many biological costs to the host; conversely, a growing body of literature suggests that the absence of H. pylori might also be associated with an increased risk of various diseases.	('H. pylori', 'Species', '210', (0, 9))	('H. pylori', 'Gene', (147, 156))	('absence', 'Var', (136, 143))	('H. pylori', 'Species', '210', (147, 156))	('colon', 'Disease', (10, 15))	('associated', 'Reg', (171, 181))	('colon', 'Disease', 'MESH:D015179', (10, 15))
14534	19457415	There are inverse associations between the presence of H. pylori (especially cagA+ strains) and disorders such as gastroesophageal reflux disease, Barrett's esophagus and esophageal adenocarcinoma , suggesting a protective role of H. pylori.	('gastroesophageal reflux disease', 'Disease', (114, 145))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (114, 137))	('cagA', 'Gene', (77, 81))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (114, 145))	('H. pylori', 'Gene', (55, 64))	("Barrett's esophagus", 'Disease', (147, 166))	('esophageal adenocarcinoma', 'Disease', (171, 196))	('cagA', 'Gene', '6279', (77, 81))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (147, 166))	('presence', 'Var', (43, 51))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (171, 196))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (171, 196))	('inverse', 'NegReg', (10, 17))	('H. pylori', 'Species', '210', (55, 64))	('H. pylori', 'Species', '210', (231, 240))
14536	19457415	One potential mechanism for this effect could be that H. pylori colonization diminishes gastric acidity; therefore, during reflux episodes, the acidic refluxate might be more damaging to the esophageal epithelium of H. pylori-negative than of H. pylori-positive persons.	('acidic refluxate', 'MPA', (144, 160))	('H. pylori', 'Species', '210', (243, 252))	('gastric acidity', 'Disease', (88, 103))	('H. pylori', 'Var', (54, 63))	('H. pylori', 'Species', '210', (54, 63))	('H. pylori', 'Species', '210', (216, 225))	('colon', 'Disease', (64, 69))	('gastric acidity', 'Disease', 'MESH:D005764', (88, 103))	('reflux episodes', 'Phenotype', 'HP:0002020', (123, 138))	('diminishes gastric acidity', 'Phenotype', 'HP:0002578', (77, 103))	('persons', 'Species', '9606', (262, 269))	('colon', 'Disease', 'MESH:D015179', (64, 69))	('acidic refluxate', 'Phenotype', 'HP:0002020', (144, 160))	('diminishes', 'NegReg', (77, 87))	('damaging', 'MPA', (175, 183))
14538	19457415	The presence or absence of H. pylori might also affect other microbiota of the stomach  and/or the distal esophagus , which may have an effect on esophageal mucosal integrity.	('absence', 'Var', (16, 23))	('affect', 'Reg', (48, 54))	('esophageal', 'MPA', (146, 156))	('H. pylori', 'Gene', (27, 36))	('H. pylori', 'Species', '210', (27, 36))	('effect', 'Reg', (136, 142))
14542	19457415	The absence of H. pylori is associated with an increased risk for allergies ; this inverse association is specific for childhood-onset, but not later-onset, asthma, and is most pronounced for cagA+ H. pylori strains.	('asthma', 'Disease', (157, 163))	('asthma', 'Disease', 'MESH:D001249', (157, 163))	('cagA', 'Gene', (192, 196))	('asthma', 'Phenotype', 'HP:0002099', (157, 163))	('cagA', 'Gene', '6279', (192, 196))	('allergies', 'Disease', 'MESH:D004342', (66, 75))	('absence', 'Var', (4, 11))	('allergies', 'Phenotype', 'HP:0012393', (66, 75))	('allergies', 'Disease', (66, 75))	('H. pylori', 'Species', '210', (198, 207))	('H. pylori', 'Species', '210', (15, 24))
14558	19457415	Multiple studies have shown that H. pylori-positive persons produce lower amounts of ghrelin than do H. pylori-negative persons  and H. pylori eradication is associated with a subsequent increase in ghrelin production .	('ghrelin', 'Chemical', 'MESH:D054439', (199, 206))	('lower', 'NegReg', (68, 73))	('ghrelin production', 'MPA', (199, 217))	('eradication', 'Var', (143, 154))	('increase', 'PosReg', (187, 195))	('persons', 'Species', '9606', (120, 127))	('persons', 'Species', '9606', (52, 59))	('H. pylori', 'Species', '210', (101, 110))	('ghrelin', 'Chemical', 'MESH:D054439', (85, 92))	('ghrelin', 'MPA', (85, 92))	('H. pylori', 'Species', '210', (33, 42))	('H. pylori', 'Species', '210', (133, 142))
14570	19457415	The finding that H. pylori also increased the risk of gastric adenocarcinoma bolstered the view that H. pylori is a human pathogen.	('gastric adenocarcinoma', 'Disease', (54, 76))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (54, 76))	('H. pylori', 'Species', '210', (17, 26))	('increased', 'PosReg', (32, 41))	('H. pylori', 'Var', (17, 26))	('H. pylori', 'Species', '210', (101, 110))	('human', 'Species', '9606', (116, 121))
14646	33757534	In addition, good clinical condition (WHO performance status 0 to 1) with normal liver (bilirubin < 1.5 mg/dl, cholinesterase > 3000 U/l, total protein > 60 g/l), renal (creatinine clearance > 60 ml/min, creatinin < 1,3 mg/dl) and bone marrow function (leukocytes > 4000/mul, thrombocytes > 150,000/mul, Hb > 10 g/dl) were prerequisites for study enrolment.	('> 3000', 'Var', (126, 132))	('creatinin', 'Chemical', '-', (170, 179))	('creatinin', 'Chemical', '-', (204, 213))	('bilirubin', 'Chemical', 'MESH:D001663', (88, 97))	('creatinine', 'Chemical', 'MESH:D003404', (170, 180))	('cholinesterase', 'Enzyme', (111, 125))
14741	33757534	Radiobiological modeling suggested a potential gain of tumor control by dose escalation in the GTV and shall be validated in ongoing clinical trials.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('GTV', 'Chemical', '-', (95, 98))	('dose escalation', 'Var', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('gain', 'PosReg', (47, 51))
14851	33096708	The logarithmic regression curve, with 95% CIs, was constructed to evaluate the heterogeneity of each diagnostic value, and three molecules (lncSNHG1, miR-216a, and a combination of miRNAs (miR16-5p, miR197-5p, and miR92a-3p)) were considered as favorable candidates for the early detection of ECs.	('miR-216a', 'Gene', '406998', (151, 159))	('miR16', 'Gene', (190, 195))	('miR92a-3p', 'Var', (215, 224))	('miR197', 'Gene', '406974', (200, 206))	('ECs', 'Disease', (294, 297))	('miR197', 'Gene', (200, 206))	('SNHG1', 'Gene', '23642', (144, 149))	('miR-216a', 'Gene', (151, 159))	('miR16', 'Gene', '51573', (190, 195))	('SNHG1', 'Gene', (144, 149))
14870	33096708	Another cancer meta-analysis, as described above, applied a combination of multiple molecules and the copy-number of ctDNA as a comprehensive marker (AUC = 0.99, 95% CI = 0.98-1.00), as well as a combination of miR-30a-5p, miR-205-5p, and miR-574-3p (AUC = 0.95, 95% CI = 0.90-1.00), demonstrating a favorable diagnostic value.	('ctDNA', 'Gene', (117, 122))	('cancer', 'Disease', (8, 14))	('miR-30a', 'Gene', '407029', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('miR-205', 'Gene', (223, 230))	('miR-574-3p', 'Gene', (239, 249))	('miR-574-3p', 'Gene', '693159', (239, 249))	('miR-30a', 'Gene', (211, 218))	('miR-205', 'Gene', '406988', (223, 230))	('copy-number', 'Var', (102, 113))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
14880	33096708	The analysis of gene mutations, not only in CTCs but also CTM, will be a new candidate for molecular targeted therapy.	('CTCs', 'Disease', (44, 48))	('CTM', 'Chemical', '-', (58, 61))	('mutations', 'Var', (21, 30))
14883	33096708	Our meta-analysis confirmed the diagnostic value of liquid biopsies using a molecular combination in esophageal cancer and demonstrated that the presence of CTCs is associated with poor prognosis for both OS and PFS.	('presence', 'Var', (145, 153))	('esophageal cancer', 'Disease', (101, 118))	('CTCs', 'Gene', (157, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PFS', 'Disease', (212, 215))
14904	31802262	Aberrant right subclavian artery is a developmental anomaly that is present in approximately 0.5-2% of the population and is the most common congenital anomaly of the aortic arch.	('Aberrant', 'Var', (0, 8))	('developmental anomaly', 'Disease', (38, 59))	('congenital anomaly of the aortic arch', 'Disease', 'MESH:D001015', (141, 178))	('Aberrant right subclavian artery', 'Phenotype', 'HP:0031014', (0, 32))	('developmental anomaly', 'Disease', 'MESH:D000014', (38, 59))	('congenital anomaly of the aortic arch', 'Disease', (141, 178))
14950	31802262	On MR imaging, flowing anterior longitudinal ligament ossification is hypointense on T1W1 and T2WI, unless there is substantial fatty marrow content, in which case they may be hyperintense.	('T1W1', 'Var', (85, 89))	('T2WI', 'Var', (94, 98))	('anterior longitudinal ligament ossification', 'Disease', 'MESH:D017887', (23, 66))	('fat', 'Gene', (128, 131))	('fat', 'Gene', '2195', (128, 131))	('anterior longitudinal ligament ossification', 'Disease', (23, 66))
14957	31802262	Some frequently encountered congenital anomalies of the thoracic inlet are tracheobronchomegaly, dilated thoracic duct, branchial cleft cysts, narrowed thoracic inlet, and fibromatosis colli, as well as the previously discussed tracheoesophageal fistula and vascular anomalies including the aberrant right subclavian artery and partial anomalous pulmonary venous return.	('tracheobronchomegaly', 'Disease', 'MESH:D014137', (75, 95))	('anomalous pulmonary venous return', 'Phenotype', 'HP:0010772', (336, 369))	('fibromatosis', 'Disease', (172, 184))	('dilated', 'Disease', (97, 104))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (228, 253))	('vascular anomalies', 'Disease', 'MESH:D000783', (258, 276))	('partial', 'Disease', (328, 335))	('partial anomalous pulmonary venous return', 'Phenotype', 'HP:0010773', (328, 369))	('fibromatosis', 'Disease', 'MESH:D005350', (172, 184))	('branchial cleft cysts', 'Phenotype', 'HP:0009796', (120, 141))	('tracheobronchomegaly', 'Disease', (75, 95))	('aberrant right subclavian artery', 'Phenotype', 'HP:0031014', (291, 323))	('aberrant', 'Var', (291, 299))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (228, 253))	('anomalous pulmonary venous return', 'Disease', 'MESH:D012587', (336, 369))	('tracheoesophageal fistula', 'Disease', (228, 253))	('anomalous pulmonary venous return', 'Disease', (336, 369))	('vascular anomalies', 'Disease', (258, 276))	('branchial cleft cysts', 'Disease', 'MESH:D001935', (120, 141))	('branchial cleft cysts', 'Disease', (120, 141))	('vascular anomalies', 'Phenotype', 'HP:0002597', (258, 276))
15128	30593712	Part of the mortality of patients treated for head and neck squamous cell carcinoma (HNSCC) is caused by the occurrence of second primary tumors (SPTs).1 Risk factors for their development include alcohol and tobacco use, age, and the sub-location of the index tumor (eg, hypopharynx).2 Most SPTs in patients with HNSCC occur in the head and neck region, esophagus, and lungs.1, 3, 4, 5, 6 The risk of esophageal cancer after HNSCC treatment is an 8-fold to 22-fold greater than in the general population.7, 8, 9 These SPTs are often diagnosed in advanced stages, which lead to a very low 5-year survival rate for affected patients.6, 10, 11, 12 The prevalence of esophageal-SPTs in patients with HNSCC is estimated to range from 0% to 22%.13  The occurrence of esophageal-SPTs in patients with HNSCC is often explained by field cancerization of the entire upper aerodigestive tract.14, 15 The theory of field cancerization states that the mucosal field around the index tumor possesses subtle histologic and genetic changes that increase the risk of synchronous and metachronous malignancies.	('HNSCC', 'Phenotype', 'HP:0012288', (426, 431))	('tumor', 'Disease', (138, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (402, 419))	('HNSCC', 'Phenotype', 'HP:0012288', (314, 319))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (910, 916))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('malignancies', 'Disease', 'MESH:D009369', (1080, 1092))	('tumor', 'Disease', (971, 976))	('malignancies', 'Disease', (1080, 1092))	('patients', 'Species', '9606', (300, 308))	('cancer', 'Disease', 'MESH:D009369', (829, 835))	('cancer', 'Disease', (413, 419))	('alcohol', 'Chemical', 'MESH:D000438', (197, 204))	('tobacco', 'Species', '4097', (209, 216))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('esophageal cancer', 'Disease', (402, 419))	('HNSCC', 'Phenotype', 'HP:0012288', (795, 800))	('tumor', 'Disease', 'MESH:D009369', (971, 976))	('SPT', 'Gene', '189', (773, 776))	('neck squamous cell carcinoma', 'Disease', (55, 83))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (55, 83))	('SPT', 'Gene', '189', (519, 522))	('SPT', 'Gene', '189', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (413, 419))	('SPT', 'Gene', (519, 522))	('SPT', 'Gene', (773, 776))	('SPT', 'Gene', (146, 149))	('patients', 'Species', '9606', (781, 789))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('patients', 'Species', '9606', (623, 631))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Disease', (910, 916))	('SPT', 'Gene', '189', (675, 678))	('tumor', 'Phenotype', 'HP:0002664', (971, 976))	('changes', 'Var', (1017, 1024))	('SPT', 'Gene', (675, 678))	('cancer', 'Disease', 'MESH:D009369', (413, 419))	('HNSCC', 'Phenotype', 'HP:0012288', (697, 702))	('cancer', 'Disease', (829, 835))	('cancer', 'Phenotype', 'HP:0002664', (910, 916))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (46, 83))	('tumor', 'Disease', (261, 266))	('SPT', 'Gene', '189', (292, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('SPT', 'Gene', (292, 295))	('cancer', 'Phenotype', 'HP:0002664', (829, 835))	('tumors', 'Disease', (138, 144))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('patients', 'Species', '9606', (683, 691))
15381	27631227	The MST and 5-year OS of patients with pathological T1/2 were 86.0 months and 51.8%, respectively, and with pathological T3/4 were 13.0 months and 29.6%, respectively (Fig.	('pathological T1/2', 'Var', (39, 56))	('patients', 'Species', '9606', (25, 33))	('T1/2', 'Var', (52, 56))
15389	27631227	Only in patients with pathological T1/2, the 5-year OS of the SpCC group showed the tendency to be longer than that of the typical SCC group (51.8% vs 45.6%, P = 0.054).	('longer', 'PosReg', (99, 105))	('SCC', 'Phenotype', 'HP:0002860', (131, 134))	('pathological', 'Var', (22, 34))	('SCC', 'Gene', (131, 134))	('SpCC', 'Disease', (62, 66))	('SCC', 'Gene', '6317', (131, 134))	('patients', 'Species', '9606', (8, 16))
15426	28384229	The ESCC detection rate per 100 person-years was 9.8 in the high-HRA-score group (n = 104) and 4.5 in the low-HRA-score group (n = 174), and the risk of development of metachronous ESCC was higher in the high-HRA-score group than in the low-HRA-score group (adjusted hazard ratio: 2.00 [95% CI: 1.12-3.30]).	('SCC', 'Gene', (182, 185))	('SCC', 'Gene', '6317', (5, 8))	('SCC', 'Phenotype', 'HP:0002860', (182, 185))	('SCC', 'Gene', '6317', (182, 185))	('person', 'Species', '9606', (32, 38))	('men', 'Species', '9606', (160, 163))	('SCC', 'Gene', (5, 8))	('high-HRA-score', 'Var', (204, 218))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))
15437	28384229	We devised a simple alcohol flushing questionnaire for predicting the presence of inactive ALDH2, and a health risk appraisal (HRA) model for esophageal SCC that consists of alcohol flushing and drinking, smoking, and dietary habits was developed based on the results of a Japanese male case-control study (; Fig 1).	('SCC', 'Gene', '6317', (153, 156))	('presence', 'Var', (70, 78))	('ALDH2', 'Gene', (91, 96))	('alcohol flushing', 'Disease', (174, 190))	('alcohol flushing', 'Disease', 'MESH:D005483', (174, 190))	('flushing', 'Phenotype', 'HP:0031284', (28, 36))	('flushing', 'Phenotype', 'HP:0031284', (182, 190))	('SCC', 'Gene', (153, 156))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('alcohol flushing', 'Disease', (20, 36))	('alcohol flushing', 'Disease', 'MESH:D005483', (20, 36))	('ALDH2', 'Gene', '217', (91, 96))
15439	28384229	Cross-sectional and follow-up mass-screening studies have shown very high esophageal SCC detection rates in groups with high-HRA-scores, i.e., scores >=11.	('SCC', 'Gene', '6317', (85, 88))	('SCC', 'Gene', (85, 88))	('scores', 'Var', (143, 149))	('high-HRA-scores', 'Var', (120, 135))	('high', 'PosReg', (69, 73))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))
15440	28384229	Higher risks of developing metachronous and multiple SCC in the UAT of Japanese subjects with esophageal SCC have been found to be associated with the presence of ALDH2*2, drinking, smoking, and lower fruit intake.	('SCC', 'Gene', '6317', (53, 56))	('ALDH2', 'Gene', (163, 168))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))	('metachronous', 'Disease', (27, 39))	('SCC', 'Gene', (105, 108))	('ALDH2', 'Gene', '217', (163, 168))	('SCC', 'Gene', (53, 56))	('presence', 'Var', (151, 159))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('SCC', 'Gene', '6317', (105, 108))
15468	28384229	High HRA scores were associated with increases in the total number (95% CI) of metachronous esophageal SCC per 100 person-years (high-HRA-score group vs. low-HRA-score group; 9.8 [6.8-13.7] vs. 4.5 [3.0-6.5], p = 0.002; Table 2).	('High', 'Var', (0, 4))	('SCC', 'Gene', (103, 106))	('person', 'Species', '9606', (115, 121))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('increases', 'PosReg', (37, 46))	('SCC', 'Gene', '6317', (103, 106))
15469	28384229	The cumulative incidences of metachronous esophageal SCC were significantly higher in the high-HRA-score group (p = 0.001; Fig 3).	('SCC', 'Gene', '6317', (53, 56))	('SCC', 'Gene', (53, 56))	('higher', 'PosReg', (76, 82))	('high-HRA-score', 'Var', (90, 104))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))
15478	28384229	The esophageal SCC detection rate was much higher (9.8 per 100 person-years) in the high-HRA-score group.	('person', 'Species', '9606', (63, 69))	('higher', 'PosReg', (43, 49))	('SCC', 'Gene', (15, 18))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('high-HRA-score', 'Var', (84, 98))	('SCC', 'Gene', '6317', (15, 18))
15481	28384229	However, the strong effect of high HRA scores on metachronous esophageal SCC was independent of the effect of LVL grades on metachronous esophageal SCC.	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('high', 'Var', (30, 34))	('SCC', 'Gene', (148, 151))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('SCC', 'Gene', '6317', (73, 76))	('HRA', 'Gene', (35, 38))	('SCC', 'Gene', '6317', (148, 151))
15484	28384229	Follow-up chromoendoscopy was performed on 404 cancer-free controls in the original study, and the esophageal SCC detection rate per 100 person-years was 2.32 in the group with HRA scores >=11 and 0.13 in the group with HRA scores <11.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('>=11', 'Var', (188, 192))	('cancer', 'Disease', (47, 53))	('SCC', 'Gene', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('SCC', 'Gene', '6317', (110, 113))	('person', 'Species', '9606', (137, 143))
15488	28384229	Previous Japanese studies have consistently demonstrated that the LVL grade C and alcohol drinking with inactive heterozygous ALDH2, which were associated with each other, were two strong risk factors for field cancerization in the UAT.	('ALDH2', 'Gene', '217', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('alcohol', 'Chemical', 'MESH:D000438', (82, 89))	('alcohol drinking', 'Phenotype', 'HP:0030955', (82, 98))	('cancer', 'Disease', (211, 217))	('ALDH2', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('LVL grade C', 'Var', (66, 77))
15489	28384229	Current or former flushing tendency after drinking a glass of beer, a surrogate marker of inactive ALDH2, identified inactive ALDH2 with 90% accuracy, and a very high risk of SCC in the UAT has been demonstrated in moderate or heavy drinkers who are current or former flushers.	('ALDH2', 'Gene', '217', (126, 131))	('SCC', 'Gene', (175, 178))	('flushing tendency', 'Disease', 'MESH:D005483', (18, 35))	('ALDH2', 'Gene', '217', (99, 104))	('SCC', 'Phenotype', 'HP:0002860', (175, 178))	('SCC', 'Gene', '6317', (175, 178))	('ALDH2', 'Gene', (126, 131))	('ALDH2', 'Gene', (99, 104))	('flushing tendency', 'Disease', (18, 35))	('flushing', 'Phenotype', 'HP:0031284', (18, 26))	('inactive', 'Var', (117, 125))
15492	28384229	All of the above risk factors were more common in the high-HRA-score group in this study, and that explains the good performance of the HRA score in predicting the risk of metachronous esophageal SCC.	('SCC', 'Gene', (196, 199))	('SCC', 'Gene', '6317', (196, 199))	('high-HRA-score', 'Var', (54, 68))	('SCC', 'Phenotype', 'HP:0002860', (196, 199))
15607	26240618	It is more commonly seen in cervical anastomoses than in anastomoses constructed in the thorax; however, dehiscence of a thoracic anastomosis has up to 60% mortality rates with development of mediastinitis and organ failure along with septic shock.	('thoracic anastomosis', 'Disease', (121, 141))	('shock', 'Phenotype', 'HP:0031273', (242, 247))	('septic shock', 'Disease', (235, 247))	('septic shock', 'Phenotype', 'HP:0100806', (235, 247))	('thoracic anastomosis', 'Disease', 'MESH:D013896', (121, 141))	('dehiscence', 'Var', (105, 115))	('mediastinitis and organ failure', 'Disease', 'MESH:D009102', (192, 223))	('septic shock', 'Disease', 'MESH:D012772', (235, 247))	('cervical anastomoses', 'Phenotype', 'HP:0002949', (28, 48))
15617	25598945	Aberrant Right Subclavian Artery: A Life-threatening Anomaly that should be considered during Esophagectomy Aberrant right subclavian artery (ARSA) is a rare anomaly, in which the right subclavian artery arises directly from the aortic arch instead of originating from the brachiocephalic artery.	('brachiocephalic artery', 'Phenotype', 'HP:0011589', (273, 295))	('brachiocephalic artery', 'Disease', (273, 295))	('anomaly', 'Disease', 'MESH:D000014', (158, 165))	('Anomaly', 'Disease', 'MESH:D000014', (53, 60))	('brachiocephalic artery', 'Disease', 'MESH:D020762', (273, 295))	('Aberrant', 'Var', (108, 116))	('ARSA', 'Phenotype', 'HP:0031014', (142, 146))	('anomaly', 'Disease', (158, 165))	('Aberrant Right Subclavian Artery', 'Phenotype', 'HP:0031014', (0, 32))	('Anomaly', 'Disease', (53, 60))	('Aberrant right subclavian artery', 'Phenotype', 'HP:0031014', (108, 140))
15619	25598945	A 56-year-old woman presented with dysphagia, with concurrent aberrant subclavian artery and esophageal cancer.	('dysphagia', 'Disease', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('dysphagia', 'Phenotype', 'HP:0002015', (35, 44))	('aberrant', 'Var', (62, 70))	('woman', 'Species', '9606', (14, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('dysphagia', 'Disease', 'MESH:D003680', (35, 44))	('aberrant subclavian artery', 'Phenotype', 'HP:0031014', (62, 88))
15632	25598945	Since the surgeon was aware of the presence of aberrant subclavian artery as a result of thoracic CT imaging, we did not dissect the posterior side of the esophagus bluntly, and the dissection was performed precisely, backward through the artery and forward through the trachea.	('aberrant subclavian artery', 'Phenotype', 'HP:0031014', (47, 73))	('aberrant', 'Var', (47, 55))	('esophagus bluntly', 'Disease', (155, 172))	('esophagus bluntly', 'Disease', 'MESH:D004938', (155, 172))
15638	25598945	Since the aberrant artery may pass the space between esophagus and vertebral column or the gap between esophagus and trachea in the midline, this anomaly may cause compression to the esophagus, which results in dysphagia.	('results in', 'Reg', (200, 210))	('dysphagia', 'Disease', 'MESH:D003680', (211, 220))	('vertebral column', 'Disease', (67, 83))	('anomaly', 'Disease', (146, 153))	('cause', 'Reg', (158, 163))	('aberrant artery', 'Var', (10, 25))	('vertebral column', 'Disease', 'MESH:C536342', (67, 83))	('compression', 'MPA', (164, 175))	('dysphagia', 'Disease', (211, 220))	('dysphagia', 'Phenotype', 'HP:0002015', (211, 220))	('anomaly', 'Disease', 'MESH:D000014', (146, 153))
15646	25598945	The injury to the aberrant artery will cause mediastinal hemorrhage or even arterioesophageal fistula in long-term.	('cause', 'Reg', (39, 44))	('arterioesophageal fistula', 'Phenotype', 'HP:0002575', (76, 101))	('arterioesophageal fistula', 'Disease', 'MESH:D005402', (76, 101))	('hemorrhage', 'Disease', (57, 67))	('arterioesophageal fistula', 'Disease', (76, 101))	('injury', 'Var', (4, 10))	('hemorrhage', 'Disease', 'MESH:D006470', (57, 67))
15650	25598945	The presence of an ARSA concurrent with esophageal cancer will pose a risk of injury during the procedure of esophagectomy, which should be considered by the surgeons and evaluated preoperatively through proper imaging studies.	('ARSA', 'Gene', (19, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('presence', 'Var', (4, 12))	('esophageal cancer', 'Disease', (40, 57))	('ARSA', 'Phenotype', 'HP:0031014', (19, 23))
15653	24804995	DNA extracted from peripheral blood in all patients was analyzed to determine polymorphisms of cytokines such as tumor necrosis factor-alpha -1031 T/C, IL-1beta -511C/T, IL-6 -634C/G, and IL-10 -819 T/C.	('-1031 T/C', 'Mutation', 'rs1799964', (141, 150))	('IL-1beta', 'Gene', '3553', (152, 160))	('-511C/T', 'Mutation', 'rs1143634', (161, 168))	('IL-6 -634C/G', 'Var', (170, 182))	('-819 T/C', 'Mutation', 'rs1800871', (194, 202))	('patients', 'Species', '9606', (43, 51))	('-634C/G', 'Mutation', 'rs1800796', (175, 182))	('tumor necrosis factor-alpha', 'Gene', (113, 140))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('IL-10 -819 T/C', 'Var', (188, 202))	('tumor necrosis factor-alpha', 'Gene', '7124', (113, 140))	('IL-1beta', 'Gene', (152, 160))
15655	24804995	Perioperative serum IL-10 levels were significantly higher for IL-10 -819 C/T + C/C genotypes than for T/T genotypes (POD0 16.7 +- 2.84 vs. 8.54 +- 0.87 pg/ml, p = 0.0002; POD1 14.0 +- 2.64 vs. 8.8 +- 0.87 pg/ml, p = 0.0143; POD3 8.9 +- 2.67 vs. 4.4 +- 0.52 pg/ml, p = 0.0076).	('serum IL-10 levels', 'MPA', (14, 32))	('-819 C/T', 'Mutation', 'rs1800871', (69, 77))	('IL-10', 'Gene', (63, 68))	('rat', 'Species', '10116', (7, 10))	('higher', 'PosReg', (52, 58))	('C/T + C/C', 'Var', (74, 83))
15656	24804995	The frequency of the IL-10 -819 T/T genotype was significantly higher in patients with postoperative pneumonia than in patients without pneumonia (p = 0.0323).	('pneumonia', 'Disease', (101, 110))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (87, 110))	('pneumonia', 'Disease', 'MESH:D011014', (101, 110))	('IL-10 -819', 'Gene', (21, 31))	('patients', 'Species', '9606', (119, 127))	('pneumonia', 'Phenotype', 'HP:0002090', (136, 145))	('patients', 'Species', '9606', (73, 81))	('T/T', 'Var', (32, 35))	('pneumonia', 'Disease', (136, 145))	('pneumonia', 'Disease', 'MESH:D011014', (136, 145))	('postoperative pneumonia', 'Disease', (87, 110))	('higher', 'PosReg', (63, 69))	('pneumonia', 'Phenotype', 'HP:0002090', (101, 110))
15657	24804995	Multivariate analysis of factors such as sex, smoking, length of operation, field of lymph node dissection, and IL-10 polymorphism identified IL-10 polymorphism as independent predictor of postoperative pneumonia.	('postoperative pneumonia', 'Disease', 'MESH:D010149', (189, 212))	('IL-10', 'Gene', (112, 117))	('polymorphism', 'Var', (118, 130))	('polymorphism', 'Var', (148, 160))	('rat', 'Species', '10116', (68, 71))	('pneumonia', 'Phenotype', 'HP:0002090', (203, 212))	('postoperative pneumonia', 'Disease', (189, 212))	('rat', 'Species', '10116', (196, 199))	('IL-10', 'Gene', (142, 147))
15658	24804995	Patients with IL-10 -819 T/T genotype may be at high risk for postoperative pneumonia after esophagectomy.	('postoperative pneumonia', 'Disease', 'MESH:D010149', (62, 85))	('T/T', 'Var', (25, 28))	('postoperative pneumonia', 'Disease', (62, 85))	('Patients', 'Species', '9606', (0, 8))	('IL-10', 'Gene', (14, 19))	('pneumonia', 'Phenotype', 'HP:0002090', (76, 85))
15666	24804995	recently reported that the TNF-alpha -308 polymorphism contributes to infectious complications after esophagectomy.	('polymorphism', 'Var', (42, 54))	('TNF-alpha', 'Gene', '7124', (27, 36))	('infectious complications', 'CPA', (70, 94))	('TNF-alpha', 'Gene', (27, 36))	('contributes to', 'Reg', (55, 69))
15669	24804995	We have a considerable interest in whether factors such as these polymorphisms might affect the postoperative infection, particularly in terms of the effects on postoperative pneumonia.	('pneumonia', 'Phenotype', 'HP:0002090', (175, 184))	('polymorphisms', 'Var', (65, 78))	('postoperative pneumonia', 'Disease', (161, 184))	('postoperative infection', 'Disease', 'MESH:D010149', (96, 119))	('affect', 'Reg', (85, 91))	('postoperative infection', 'Disease', (96, 119))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (161, 184))
15670	24804995	We selected TNF-alpha, IL-1beta, IL-6, and IL-10 as representative pro-inflammatory, inflammatory, and anti-inflammatory cytokines and investigated the gene promoter polymorphisms of TNF-alpha -1031 T > C (rs1799964), IL-1beta -511 T > C (rs3087258), IL-6 -634G > C (rs1800796), and IL-10 -819 T > C (rs1800871); all of which have been reported to influence cytokine production.	('IL-1beta', 'Gene', (23, 31))	('rs1800871', 'Mutation', 'rs1800871', (301, 310))	('IL-6', 'Var', (251, 255))	('rs1799964', 'Mutation', 'rs1799964', (206, 215))	('-1031 T > C', 'Mutation', 'rs1799964', (193, 204))	('IL-1beta', 'Gene', '3553', (218, 226))	('TNF-alpha', 'Gene', '7124', (12, 21))	('cytokine production', 'MPA', (358, 377))	('TNF-alpha', 'Gene', (12, 21))	('rs1800871', 'Var', (301, 310))	('influence', 'Reg', (348, 357))	('IL-1beta', 'Gene', (218, 226))	('rs1800796', 'Mutation', 'rs1800796', (267, 276))	('IL-10', 'Var', (283, 288))	('-511 T > C', 'Mutation', 'rs3087258', (227, 237))	('rs3087258', 'Mutation', 'rs3087258', (239, 248))	('IL-1beta', 'Gene', '3553', (23, 31))	('TNF-alpha', 'Gene', '7124', (183, 192))	('TNF-alpha', 'Gene', (183, 192))	('-634G > C', 'Mutation', 'rs1800796', (256, 265))	('-819 T > C', 'Mutation', 'rs1800871', (289, 299))
15671	24804995	The purpose of this study was to assess whether cytokine promoter gene polymorphisms are associated with the following: (1) perioperative cytokine production and (2) postoperative pneumonia following esophagectomy.	('postoperative pneumonia', 'Disease', (166, 189))	('polymorphisms', 'Var', (71, 84))	('associated', 'Reg', (89, 99))	('rat', 'Species', '10116', (131, 134))	('rat', 'Species', '10116', (173, 176))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (166, 189))	('cytokine promoter gene', 'Gene', (48, 70))	('pneumonia', 'Phenotype', 'HP:0002090', (180, 189))
15703	24804995	Perioperative serum IL-10 levels were significantly higher for IL-10 -819 C/T+C/C genotypes than for T/T genotypes (POD0 16.7 +- 2.84 vs. 8.54 +- 0.87 pg/ml, p = 0.0002; POD1 14.0 +- 2.64 vs. 8.8 +- 0.87 pg/ml, p = 0.0143; POD3 8.9 +- 2.69 vs. 4.4 +- 0.52 pg/ml, p = 0.0076) (Fig.	('serum IL-10 levels', 'MPA', (14, 32))	('-819 C/T', 'Mutation', 'rs1800871', (69, 77))	('rat', 'Species', '10116', (7, 10))	('higher', 'PosReg', (52, 58))	('C/T+C/C', 'Var', (74, 81))
15705	24804995	The frequency of the IL-10 -819 T/T genotype was significantly higher in patients with pneumonia than in those without pneumonia (p = 0.0323) (Table 2).	('IL-10 -819', 'Gene', (21, 31))	('patients', 'Species', '9606', (73, 81))	('T/T', 'Var', (32, 35))	('pneumonia', 'Phenotype', 'HP:0002090', (119, 128))	('pneumonia', 'Phenotype', 'HP:0002090', (87, 96))	('higher', 'PosReg', (63, 69))	('pneumonia', 'Disease', 'MESH:D011014', (119, 128))	('pneumonia', 'Disease', 'MESH:D011014', (87, 96))	('pneumonia', 'Disease', (87, 96))	('pneumonia', 'Disease', (119, 128))
15706	24804995	Although no relationship was seen between postoperative serum IL-10 levels and Il-10 polymorphisms in patients with pneumonia, these levels were significantly higher for IL-10 -819 T/C + C/C genotypes than for T/T genotypes in patients without pneumonia (Table 3).	('pneumonia', 'Disease', (244, 253))	('pneumonia', 'Disease', 'MESH:D011014', (244, 253))	('-819 T/C', 'Mutation', 'rs1800871', (176, 184))	('patients', 'Species', '9606', (102, 110))	('Il-10', 'Gene', (79, 84))	('pneumonia', 'Phenotype', 'HP:0002090', (116, 125))	('IL-10 -819 T/C + C/C', 'Var', (170, 190))	('pneumonia', 'Phenotype', 'HP:0002090', (244, 253))	('Il-10', 'Gene', '3586', (79, 84))	('pneumonia', 'Disease', (116, 125))	('pneumonia', 'Disease', 'MESH:D011014', (116, 125))	('rat', 'Species', '10116', (49, 52))	('patients', 'Species', '9606', (227, 235))	('higher', 'PosReg', (159, 165))
15708	24804995	Only IL-10 -819 polymorphism was significantly associated with pneumonia (p = 0.0334, OR = 2.68, 95 % CI = 1.08-6.67).	('pneumonia', 'Disease', (63, 72))	('pneumonia', 'Disease', 'MESH:D011014', (63, 72))	('polymorphism', 'Var', (16, 28))	('pneumonia', 'Phenotype', 'HP:0002090', (63, 72))	('associated', 'Reg', (47, 57))	('IL-10 -819', 'Gene', (5, 15))
15709	24804995	This study revealed that IL-10 -819 polymorphism is associated with postoperative pneumonia in Japanese patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('IL-10 -819', 'Gene', (25, 35))	('pneumonia', 'Phenotype', 'HP:0002090', (82, 91))	('postoperative pneumonia', 'Disease', (68, 91))	('polymorphism', 'Var', (36, 48))	('esophageal cancer', 'Disease', (118, 135))	('associated with', 'Reg', (52, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (68, 91))	('patients', 'Species', '9606', (104, 112))
15720	24804995	reported that the IL-10 -592 CC polymorphism was associated with higher IL-10 release under lipopolysaccharide stimulation and lower mortality in critically ill patients.	('IL-10 release under lipopolysaccharide stimulation', 'MPA', (72, 122))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (92, 110))	('lower', 'NegReg', (127, 132))	('mortality', 'MPA', (133, 142))	('polymorphism', 'Var', (32, 44))	('patients', 'Species', '9606', (161, 169))	('higher', 'PosReg', (65, 71))	('critically ill', 'Disease', 'MESH:D016638', (146, 160))	('IL-10 -592', 'Gene', (18, 28))	('critically ill', 'Disease', (146, 160))
15724	24804995	In patients with sepsis, a genotype associated with high IL-10 production may lead to greater immunosuppression, resulting in more severe disease burden and outcomes.	('greater', 'PosReg', (86, 93))	('severe', 'MPA', (131, 137))	('lead to', 'Reg', (78, 85))	('sepsis', 'Disease', (17, 23))	('more', 'PosReg', (126, 130))	('IL-10', 'Gene', (57, 62))	('sepsis', 'Phenotype', 'HP:0100806', (17, 23))	('sepsis', 'Disease', 'MESH:D018805', (17, 23))	('patients', 'Species', '9606', (3, 11))	('high', 'Var', (52, 56))	('immunosuppression', 'MPA', (94, 111))
15726	24804995	reported that not IL-10 -819 T/C but TNF-alpha-308G/A polymorphism contributes to infectious complications after esophagectomy.	('polymorphism', 'Var', (54, 66))	('TNF-alpha-308G/A', 'Gene', (37, 53))	('infectious complications', 'CPA', (82, 106))	('contributes', 'Reg', (67, 78))	('-819 T/C', 'Mutation', 'rs1800871', (24, 32))
15728	24804995	Identifying IL-10 polymorphisms in patients prior to esophagectomy may influence management decisions where controversy currently exists, such as the use of other therapeutic strategies.	('IL-10', 'Gene', (12, 17))	('influence', 'Reg', (71, 80))	('rat', 'Species', '10116', (177, 180))	('men', 'Species', '9606', (87, 90))	('polymorphisms', 'Var', (18, 31))	('patients', 'Species', '9606', (35, 43))
15731	24804995	Genotyping this IL-10 polymorphism in patients following esophagectomy may allow better risk stratification and tailoring of specific therapies to different risk groups.	('IL-10', 'Gene', (16, 21))	('rat', 'Species', '10116', (95, 98))	('Genotyping', 'Var', (0, 10))	('patients', 'Species', '9606', (38, 46))	('polymorphism', 'Var', (22, 34))
15733	22572016	Epigenetic silencing of key tumor suppressor genes (TSGs) is critical to ESCC initiation and progression.	('TSG', 'Gene', (52, 55))	('tumor', 'Disease', (28, 33))	('TSG', 'Gene', '57045', (52, 55))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('ESCC', 'Disease', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
15735	22572016	This review summarizes recent discoveries on aberrant promoter methylation of TSGs in ESCC, providing better understanding of the role of disrupted epigenetic regulation in tumorigenesis and insight into diagnostic and prognostic biomarkers for this malignancy.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('aberrant', 'Var', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('TSG', 'Gene', (78, 81))	('TSG', 'Gene', '57045', (78, 81))	('malignancy', 'Disease', 'MESH:D009369', (250, 260))	('malignancy', 'Disease', (250, 260))	('ESCC', 'Disease', (86, 90))
15742	22572016	Genetic abnormalities involved in ESCC tumorigenesis include chromosomal loss and gain, loss of heterozygosity (LOH), and gene amplification and mutation.	('loss of heterozygosity', 'Var', (88, 110))	('chromosomal loss', 'Disease', (61, 77))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('Genetic abnormalities', 'Disease', 'MESH:D030342', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('chromosomal loss', 'Disease', 'MESH:D015431', (61, 77))	('ESCC', 'Disease', (34, 38))	('Genetic abnormalities', 'Disease', (0, 21))	('tumor', 'Disease', (39, 44))	('gain', 'PosReg', (82, 86))	('gene amplification', 'Var', (122, 140))	('mutation', 'Var', (145, 153))
15743	22572016	Recently, epigenetic disruptions, including promoter CpG island methylation of tumor suppressor genes (TSGs) and microRNA methylation, have been recognized as key events in ESCC development.	('TSG', 'Gene', (103, 106))	('tumor', 'Disease', (79, 84))	('ESCC', 'Disease', (173, 177))	('TSG', 'Gene', '57045', (103, 106))	('microRNA methylation', 'Var', (113, 133))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
15744	22572016	Here, we provide an overview of aberrant promoter methylation of critical TSGs in ESCC and the potential of these alterations as both tumor markers and therapeutic targets for ESCC.	('ESCC', 'Disease', (82, 86))	('TSG', 'Gene', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('aberrant', 'Var', (32, 40))	('TSG', 'Gene', '57045', (74, 77))	('tumor', 'Disease', (134, 139))
15745	22572016	We briefly summarized the epigenetically silenced TSGs in ESCC according to their biological functions, such as apoptosis, cell cycle control, cell adhesion, and DNA repair (Table 1).	('ESCC', 'Gene', (58, 62))	('TSG', 'Gene', (50, 53))	('epigenetically silenced', 'Var', (26, 49))	('TSG', 'Gene', '57045', (50, 53))
15747	22572016	In ESCC, p16INK4a was methylated in 40%-61% of primary tumors and was less frequently inactivated due to homozygous deletion or mutation, whereas p14ARF was methylated at a low frequency (13%-15%) and was mainly inactivated due to homozygous deletion.	('p16INK4a', 'Gene', (9, 17))	('primary tumors', 'Disease', 'MESH:D009369', (47, 61))	('mutation', 'Var', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('p16INK4a', 'Gene', '1029', (9, 17))	('p14ARF', 'Gene', '1029', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('deletion', 'Var', (116, 124))	('primary tumors', 'Disease', (47, 61))	('p14ARF', 'Gene', (146, 152))
15750	22572016	In ESCC, RASSF1A was methylated in 51% of primary tumors, but rarely in matched non-cancerous tissues.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('primary tumors', 'Disease', (42, 56))	('cancer', 'Disease', (84, 90))	('methylated', 'Var', (21, 31))	('primary tumors', 'Disease', 'MESH:D009369', (42, 56))	('ESCC', 'Disease', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('RASSF1A', 'Gene', (9, 16))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('RASSF1A', 'Gene', '11186', (9, 16))
15751	22572016	In addition, RASSF1A methylation was correlated with the clinical stage of ESCC.	('RASSF1A', 'Gene', (13, 20))	('ESCC', 'Disease', (75, 79))	('correlated', 'Reg', (37, 47))	('RASSF1A', 'Gene', '11186', (13, 20))	('methylation', 'Var', (21, 32))
15752	22572016	Remarkably, the frequency of RASSF1A methylation in Chinese ESCC patients was relatively lower than that in Japanese ESCC patients, indicating that a possibly different mechanism is involved in RASSF1A methylation among these populations.	('lower', 'NegReg', (89, 94))	('RASSF1A', 'Gene', '11186', (29, 36))	('methylation', 'Var', (37, 48))	('RASSF1A', 'Gene', '11186', (194, 201))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (65, 73))	('RASSF1A', 'Gene', (29, 36))	('RASSF1A', 'Gene', (194, 201))
15755	22572016	Promoter methylation of DAPK was frequently detected in intraepithelial lesions and primary ESCC, but rarely in normal and non-neoplastic epithelia, suggesting a role of methylation-mediated DAPK silencing in ESCC progression.	('intraepithelial lesions', 'Disease', 'MESH:D002278', (56, 79))	('DAPK', 'Gene', (24, 28))	('DAPK', 'Gene', '1612', (24, 28))	('non-neoplastic epithelia', 'Disease', (123, 147))	('detected', 'Reg', (44, 52))	('ESCC', 'Disease', (209, 213))	('Promoter methylation', 'Var', (0, 20))	('non-neoplastic epithelia', 'Disease', 'MESH:C580335', (123, 147))	('neoplastic epithelia', 'Phenotype', 'HP:0031492', (127, 147))	('silencing', 'NegReg', (196, 205))	('DAPK', 'Gene', (191, 195))	('DAPK', 'Gene', '1612', (191, 195))	('intraepithelial lesions', 'Disease', (56, 79))
15757	22572016	In ESCC, RUNX3 silencing by promoter methylation induced tumor progression and worsened patient prognosis.	('patient', 'Species', '9606', (88, 95))	('patient prognosis', 'CPA', (88, 105))	('promoter methylation', 'Var', (28, 48))	('silencing', 'NegReg', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('RUNX3', 'Gene', '864', (9, 14))	('RUNX3', 'Gene', (9, 14))	('ESCC', 'Disease', (3, 7))	('induced', 'Reg', (49, 56))	('worsened', 'NegReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
15758	22572016	As different frequencies of RUNX3 methylation were reported in ESCC, the precise CpG region at which the RUNX3 promoter is methylated for silencing needs to be further confirmed.	('RUNX3', 'Gene', (28, 33))	('RUNX3', 'Gene', '864', (28, 33))	('methylation', 'Var', (34, 45))	('ESCC', 'Disease', (63, 67))	('RUNX3', 'Gene', (105, 110))	('RUNX3', 'Gene', '864', (105, 110))
15760	22572016	Studies showed that UCHL1 was methylated in 40% of primary ESCCs but not in the paired adjacent non-tumor tissues.	('methylated', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('UCHL1', 'Gene', '7345', (20, 25))	('UCHL1', 'Gene', (20, 25))	('primary ESCCs', 'Disease', (51, 64))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
15761	22572016	Furthermore, UCHL1 methylation was correlated with regional lymph node metastasis.	('correlated', 'Reg', (35, 45))	('methylation', 'Var', (19, 30))	('UCHL1', 'Gene', '7345', (13, 18))	('UCHL1', 'Gene', (13, 18))	('regional lymph node metastasis', 'CPA', (51, 81))
15768	22572016	MGMT was reported to be epigenetically silenced in about 30% of human cancers due to promoter methylation.	('MGMT', 'Gene', (0, 4))	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancers', 'Disease', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('promoter methylation', 'Var', (85, 105))	('MGMT', 'Gene', '4255', (0, 4))
15770	22572016	Notably, MGMT methylation was associated with TP53 mutations or the C677T polymorphism of 5, 10-methylenetetrahydrofolate (MTHFR) in ESCC patients, suggesting a synergistic effect of both epigenetic and genetic mechanisms in ESCC pathogenesis.	('associated', 'Reg', (30, 40))	('5, 10-methylenetetrahydrofolate', 'Chemical', 'MESH:C013123', (90, 121))	('ESCC', 'Disease', (225, 229))	('mutations', 'Var', (51, 60))	('C677T polymorphism', 'Var', (68, 86))	('MTHFR', 'Gene', '4524', (123, 128))	('ESCC', 'Disease', (133, 137))	('C677T', 'Mutation', 'rs1801133', (68, 73))	('TP53', 'Gene', '7157', (46, 50))	('MGMT', 'Gene', '4255', (9, 13))	('MGMT', 'Gene', (9, 13))	('MTHFR', 'Gene', (123, 128))	('TP53', 'Gene', (46, 50))	('patients', 'Species', '9606', (138, 146))
15771	22572016	Mismatch repair gene mutL homolog 1 (MLH1) was reported to be inactivated by genetic or epigenetic alterations in multiple human cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('MLH1', 'Gene', '4292', (37, 41))	('inactivated', 'NegReg', (62, 73))	('epigenetic alterations', 'Var', (88, 110))	('MLH1', 'Gene', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('human', 'Species', '9606', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('mutL homolog 1', 'Gene', '4292', (21, 35))	('mutL homolog 1', 'Gene', (21, 35))	('genetic', 'Var', (77, 84))
15773	22572016	Interestingly, epigenetically silenced MLH1 was always associated with microsatellite instability in ESCC, indicating that MLH1 plays a critical role in ESCC progression.	('MLH1', 'Gene', '4292', (39, 43))	('MLH1', 'Gene', '4292', (123, 127))	('MLH1', 'Gene', (39, 43))	('MLH1', 'Gene', (123, 127))	('associated', 'Reg', (55, 65))	('epigenetically silenced', 'Var', (15, 38))	('microsatellite instability', 'MPA', (71, 97))	('ESCC', 'Disease', (101, 105))	('ESCC', 'Disease', (153, 157))
15774	22572016	MSH2, another important DNA mismatch repair gene, was also silenced by promoter methylation in 32% of ESCCs but none of the matched normal tissues.	('MSH2', 'Gene', (0, 4))	('ESCCs', 'Disease', (102, 107))	('promoter methylation', 'Var', (71, 91))	('MSH2', 'Gene', '4436', (0, 4))	('silenced', 'NegReg', (59, 67))
15778	22572016	In addition, aberrant methylation of FHIT can also be induced by nicotine, indicating its role in smoking-related ESCC tumorigenesis.	('tumor', 'Disease', (119, 124))	('ESCC', 'Disease', (114, 118))	('induced', 'Reg', (54, 61))	('FHIT', 'Gene', (37, 41))	('FHIT', 'Gene', '2272', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('methylation', 'MPA', (22, 33))	('nicotine', 'Chemical', 'MESH:D009538', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('aberrant', 'Var', (13, 21))
15793	22572016	Promoter methylation of CDH1 and ITGA4 have been linked to tumor recurrence, and methylation of other genes including adenomatous poly-posis coli (APC), N-methyl D-aspartate 2B (NMDAR2B), tachykinin 1 (TAC1) TIMP metallopeptidase inhibitor 3 (TIMP3), UCHL1, and uroplakin 1A (UPK1A) have been linked to shorter survival.	('CDH1', 'Gene', (24, 28))	('tumor', 'Disease', (59, 64))	('adenomatous poly-posis coli', 'Disease', (118, 145))	('ITGA4', 'Gene', (33, 38))	('adenomatous poly-posis', 'Phenotype', 'HP:0005227', (118, 140))	('NMDAR2B', 'Gene', (178, 185))	('tachykinin 1', 'Gene', '6863', (188, 200))	('TIMP3', 'Gene', (243, 248))	('N-methyl D-aspartate 2B', 'Gene', (153, 176))	('TIMP3', 'Gene', '7078', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('UCHL1', 'Gene', (251, 256))	('TAC1', 'Gene', '6863', (202, 206))	('TIMP metallopeptidase inhibitor 3', 'Gene', '7078', (208, 241))	('linked', 'Reg', (49, 55))	('adenomatous poly-posis coli', 'Disease', 'MESH:D011125', (118, 145))	('N-methyl D-aspartate 2B', 'Gene', '2904', (153, 176))	('UCHL1', 'Gene', '7345', (251, 256))	('TIMP metallopeptidase inhibitor 3', 'Gene', (208, 241))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tachykinin 1', 'Gene', (188, 200))	('UPK1A', 'Gene', (276, 281))	('APC', 'Disease', 'MESH:D011125', (147, 150))	('shorter', 'NegReg', (303, 310))	('APC', 'Disease', (147, 150))	('NMDAR2B', 'Gene', '2904', (178, 185))	('UPK1A', 'Gene', '11045', (276, 281))	('methylation', 'Var', (81, 92))	('CDH1', 'Gene', '999', (24, 28))	('uroplakin 1A', 'Gene', '11045', (262, 274))	('TAC1', 'Gene', (202, 206))	('ITGA4', 'Gene', '3676', (33, 38))	('uroplakin 1A', 'Gene', (262, 274))
15794	22572016	Epigenetic reagents intended to reactivate epigenetically silenced TSGs or tumor antigens are being tested for their anticancer effects.	('TSG', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('TSG', 'Gene', '57045', (67, 70))	('epigenetically silenced', 'Var', (43, 66))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('tumor', 'Disease', (75, 80))
15799	22572016	Silencing TSGs by promoter methylation plays essential roles in ESCC initiation and development.	('TSG', 'Gene', '57045', (10, 13))	('Silencing', 'Var', (0, 9))	('TSG', 'Gene', (10, 13))	('ESCC', 'Disease', (64, 68))
15800	22572016	Numerous methylated genes have been identified in ESCC in recent years and thus provide new insights into the molecular mechanism of ESCC pathogenesis and expand the knowledge of tumor markers for clinical application.	('ESCC', 'Disease', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('methylated', 'Var', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('ESCC', 'Disease', (50, 54))	('tumor', 'Disease', (179, 184))
15828	21672200	as follows: grade 0 = normal examination; grade 1 = edema and hyperemia of the mucosa; grade 2a = superficial ulceration, erosions, friability, blisters, exudates, hemorrhages, or whitish membranes; grade 2b = grade 2a plus deep, discrete or circumferential ulcerations; grade 3a = small scattered areas of multiple ulcerations and areas of necrosis with brown-black or grayish discoloration; grade 3b = extensive necrosis.	('edema', 'Disease', 'MESH:D004487', (52, 57))	('hyperemia of the mucosa', 'Disease', (62, 85))	('edema', 'Phenotype', 'HP:0000969', (52, 57))	('hemorrhages', 'Disease', 'MESH:D006470', (164, 175))	('edema', 'Disease', (52, 57))	('hemorrhages', 'Disease', (164, 175))	('necrosis', 'Disease', (341, 349))	('necrosis', 'Disease', (414, 422))	('grade 2a', 'Var', (210, 218))	('hyperemia of the mucosa', 'Disease', 'MESH:D006940', (62, 85))	('blisters', 'Phenotype', 'HP:0008066;HP:0200037', (144, 152))	('necrosis', 'Disease', 'MESH:D009336', (341, 349))	('necrosis', 'Disease', 'MESH:D009336', (414, 422))
15887	34012400	The association between dysregulated store-operated calcium entry (SOCE), a key intracellular Ca2+ signaling pathway and gastroesophageal cancers are emerging.	('dysregulated', 'Var', (24, 36))	('calcium', 'Chemical', 'MESH:D002118', (52, 59))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (121, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('gastroesophageal cancers', 'Disease', (121, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))
15911	34012400	Different from mutant forms in lung cancer and breast cancer, EGFR often presents high copy number and its expression is correlate with advanced stage, poorly differentiated histology, vascular invasion, and poor survival rate in GC and EC.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('breast cancer', 'Disease', (47, 60))	('EGFR', 'Gene', '1956', (62, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('EGFR', 'Gene', (62, 66))	('lung cancer', 'Disease', (31, 42))	('expression', 'MPA', (107, 117))	('high copy number', 'Var', (82, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('advanced stage', 'CPA', (136, 150))	('poorly differentiated histology', 'CPA', (152, 183))	('vascular invasion', 'CPA', (185, 202))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
15954	34012400	While genetic mutations in Orai1 or STIM1 were found in immune disorders, skeletal muscle myopathy and heart hypertrophy, changes in expression and/or channel complex components are more commonly reported in various types of malignant, including GE cancers.	('muscle myopathy', 'Disease', (83, 98))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('Orai1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('heart hypertrophy', 'Disease', 'MESH:D006332', (103, 120))	('GE cancers', 'Disease', 'MESH:D009369', (246, 256))	('mutations', 'Var', (14, 23))	('Orai1', 'Gene', '84876', (27, 32))	('STIM1', 'Gene', (36, 41))	('found', 'Reg', (47, 52))	('immune disorders', 'Disease', 'MESH:D007154', (56, 72))	('heart hypertrophy', 'Disease', (103, 120))	('GE cancers', 'Disease', (246, 256))	('muscle myopathy', 'Disease', 'MESH:D009135', (83, 98))	('STIM1', 'Gene', '6786', (36, 41))	('reported', 'Reg', (196, 204))	('expression', 'MPA', (133, 143))	('heart hypertrophy', 'Phenotype', 'HP:0001639', (103, 120))	('immune disorders', 'Disease', (56, 72))	('changes', 'Reg', (122, 129))	('genetic mutations', 'Var', (6, 23))	('myopathy', 'Phenotype', 'HP:0003198', (90, 98))
15956	34012400	The high expression of Orai1 is associated with poor disease-free and overall survival rates.	('Orai1', 'Gene', (23, 28))	('Orai1', 'Gene', '84876', (23, 28))	('overall survival rates', 'CPA', (70, 92))	('high', 'Var', (4, 8))	('disease-free', 'CPA', (53, 65))	('poor', 'NegReg', (48, 52))
15957	34012400	Both gene manipulation and pharmacologic studies demonstrated that elevated Orai1 results in hyperactivity of intracellular Ca2+ oscillations and, thus, controls rampant cell proliferation in ESCC cells.	('hyperactivity', 'Phenotype', 'HP:0000752', (93, 106))	('Orai1', 'Gene', '84876', (76, 81))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (110, 141))	('elevated', 'Var', (67, 75))	('hyperactivity', 'Disease', 'MESH:D006948', (93, 106))	('hyperactivity', 'Disease', (93, 106))	('intracellular Ca2+ oscillations', 'MPA', (110, 141))	('controls', 'Reg', (153, 161))	('Orai1', 'Gene', (76, 81))
15960	34012400	STIM1 can promote gastric cancer progression and silencing STIM1 inhibits cell proliferation via arrest of the cell cycle at the G0/G1 phase and increases cell apoptosis in vitro.	('gastric cancer', 'Disease', (18, 32))	('cell proliferation', 'CPA', (74, 92))	('silencing', 'Var', (49, 58))	('STIM1', 'Gene', '6786', (0, 5))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('STIM1', 'Gene', '6786', (59, 64))	('inhibits', 'NegReg', (65, 73))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('STIM1', 'Gene', (0, 5))	('STIM1', 'Gene', (59, 64))	('arrest', 'Disease', (97, 103))	('increases', 'PosReg', (145, 154))	('promote', 'PosReg', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cell apoptosis', 'CPA', (155, 169))
15970	34012400	Due to the important role of TRPC6-mediated Ca2+ signaling, it is not surprising to see that the inhibition of TRPC6 leads to cell cycle arrest via Cdk1 in ESCC cells and decreased tumor formation in a mouse xenograft ESCC model.	('inhibition', 'Var', (97, 107))	('arrest', 'Disease', (137, 143))	('decreased', 'NegReg', (171, 180))	('tumor', 'Disease', (181, 186))	('Cdk1', 'Gene', '12534', (148, 152))	('Cdk1', 'Gene', (148, 152))	('TRPC6', 'Gene', (111, 116))	('mouse', 'Species', '10090', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (126, 143))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
15971	34012400	In GC epithelial cells, the TRPC6 has been shown to be upregulated on protein and mRNA level and was responsible for regulation of the cell cycle, as the inhibition of TRPC6 resulted in cell cycle arrest in the G2/M phase and inhibited cell growth.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (186, 203))	('inhibition', 'Var', (154, 164))	('inhibited', 'NegReg', (226, 235))	('cell growth', 'CPA', (236, 247))	('arrest', 'Disease', 'MESH:D006323', (197, 203))	('upregulated', 'PosReg', (55, 66))	('arrest', 'Disease', (197, 203))	('TRPC6', 'Gene', (28, 33))	('TRPC6', 'Gene', (168, 173))
15974	34012400	The authors showed that TRPC1/3/6 complex mediates Ca2+ influx and actives downstream the Ras/Raf1/ERK signaling pathway and the inhibition of TRPC1/3/6 impedes TGF-beta1-induced EMT.	('Ca2+ influx', 'MPA', (51, 62))	('Raf1', 'Gene', (94, 98))	('inhibition', 'Var', (129, 139))	('TRPC1', 'Gene', '7220', (143, 148))	('TRPC1', 'Gene', '7220', (24, 29))	('ERK', 'Gene', '5594', (99, 102))	('ERK', 'Gene', (99, 102))	('TRPC1', 'Gene', (143, 148))	('actives', 'PosReg', (67, 74))	('TRPC1', 'Gene', (24, 29))	('Raf1', 'Gene', '5894', (94, 98))	('TGF-beta1', 'Gene', '7040', (161, 170))	('impedes', 'NegReg', (153, 160))	('TGF-beta1', 'Gene', (161, 170))
15975	34012400	Using a newly developed potent TRPC6 antagonist, a separate study also showed that inhibition of this Ca2+ channel suppresses proliferation of several GC cell lines as well as GC tumor growth in a xenograft model.	('suppresses', 'NegReg', (115, 125))	('proliferation', 'CPA', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('inhibition', 'Var', (83, 93))	('tumor', 'Disease', (179, 184))
15978	34012400	The earliest SOCE blocker to be used is SKF-96365, which was shown to inhibit cancer cell migration and tumor metastasis in breast and cervical cancers.	('SKF-96365', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('tumor metastasis in breast and cervical cancers', 'Disease', 'MESH:D001943', (104, 151))	('SKF-96365', 'Chemical', 'MESH:C063159', (40, 49))	('inhibit', 'NegReg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
15984	34012400	RO2959, a novel, potent and selective SOCE inhibitor, inhibits gene expression, cytokine production, and proliferation in T cells.	('RO2959', 'Var', (0, 6))	('cytokine production', 'MPA', (80, 99))	('proliferation', 'CPA', (105, 118))	('gene expression', 'MPA', (63, 78))	('inhibits', 'NegReg', (54, 62))	('RO2959', 'Chemical', '-', (0, 6))
15985	34012400	SB01990, SPB06836, KM06293 and RH01882 are a cluster of SOCE inhibitors targeting and altering the Ca2+ selectivity filter of Orai1.	('RH01882', 'Gene', (31, 38))	('Orai1', 'Gene', (126, 131))	('SPB06836', 'Var', (9, 17))	('altering', 'Reg', (86, 94))	('RH01882', 'Chemical', '-', (31, 38))	('Ca2+ selectivity filter', 'MPA', (99, 122))	('SB01990', 'Var', (0, 7))	('Orai1', 'Gene', '84876', (126, 131))	('SB01990', 'Chemical', '-', (0, 7))	('KM06293', 'Var', (19, 26))
15986	34012400	GSK-5503A and GSK-7975A are Orai1-and Orai3-mediated SOCE inhibitors that slowly affect SOCE currents with no effect on STIM1-Orai1 coupling.	('Orai3', 'Gene', '93129', (38, 43))	('GSK-5503A', 'Var', (0, 9))	('Orai1', 'Gene', (126, 131))	('GSK-7975A', 'Var', (14, 23))	('STIM1', 'Gene', (120, 125))	('affect', 'Reg', (81, 87))	('Orai3', 'Gene', (38, 43))	('Orai1', 'Gene', (28, 33))	('STIM1', 'Gene', '6786', (120, 125))	('Orai1', 'Gene', '84876', (126, 131))	('Orai1', 'Gene', '84876', (28, 33))	('SOCE currents', 'MPA', (88, 101))
15988	34012400	BTP2 or YM-58483 is a potent inhibitor for both CRAC and TRPC-mediated SOCE.	('TRPC-mediated', 'Protein', (57, 70))	('YM-58483', 'Chemical', 'MESH:C476308', (8, 16))	('CRAC', 'CPA', (48, 52))	('YM-58483', 'Var', (8, 16))	('BTP', 'Chemical', '-', (0, 3))
15989	34012400	A report showed that BTP-2 can depolarize the cell membrane via TRPM4 activation and, thus contribute to the inhibition of SOCE and cytokine release.	('BTP-2', 'Var', (21, 26))	('depolarize', 'NegReg', (31, 41))	('TRPM4', 'Gene', (64, 69))	('inhibition', 'NegReg', (109, 119))	('BTP', 'Chemical', '-', (21, 24))	('activation', 'PosReg', (70, 80))	('TRPM4', 'Gene', '54795', (64, 69))
15991	34012400	CM2489, CM3457 and CM4620 are three more selective SOCE inhibitors, which have been shown to prevent Ca2+ entry, and, thus, are used either to treat moderate-to-severe plaque psoriasis, or to reduce acute pancreatitis severity, or to inhibit lymphocytes and T cell-derived cytokine production (Table 1).	('plaque psoriasis', 'Disease', 'MESH:D011565', (168, 184))	('SOCE', 'Gene', (51, 55))	('CM2489', 'Var', (0, 6))	('pancreatitis', 'Phenotype', 'HP:0001733', (205, 217))	('pancreatitis', 'Disease', 'MESH:D010195', (205, 217))	('CM3457', 'Var', (8, 14))	('reduce', 'NegReg', (192, 198))	('CM4620', 'Var', (19, 25))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (199, 217))	('pancreatitis', 'Disease', (205, 217))	('Ca2+ entry', 'MPA', (101, 111))	('plaque psoriasis', 'Disease', (168, 184))	('inhibit', 'NegReg', (234, 241))	('CM2489', 'Chemical', '-', (0, 6))	('prevent', 'NegReg', (93, 100))	('psoriasis', 'Phenotype', 'HP:0003765', (175, 184))
15992	34012400	The Pyrazole analogs, including Pyr2, 3, 6 and 10, show different selectivity on TRPC3 and Orai1-mediated SOCE.	('Pyr2', 'Var', (32, 36))	('Orai1', 'Gene', (91, 96))	('TRPC3', 'Gene', '7222', (81, 86))	('Pyrazole', 'Chemical', 'MESH:C031280', (4, 12))	('Orai1', 'Gene', '84876', (91, 96))	('Pyr2', 'Chemical', '-', (32, 36))	('TRPC3', 'Gene', (81, 86))
15993	34012400	Pyr10 is potent and selective for TRPC3-mediated SOCE.	('TRPC3', 'Gene', '7222', (34, 39))	('Pyr10', 'Var', (0, 5))	('TRPC3', 'Gene', (34, 39))	('Pyr10', 'Chemical', '-', (0, 5))
15994	34012400	Pyr6 is potent to Orai1-mediated SOCE, while Pyr3 equally inhibits both channels.	('Orai1', 'Gene', (18, 23))	('Orai1', 'Gene', '84876', (18, 23))	('Pyr6', 'Var', (0, 4))
15996	34012400	CM2489 and CM 4620 from CalciMedica are used to block the production and release of pro-inflammatory cytokines from immune cells, and they are used in clinical trials for the treatment of plaque psoriasis and pancreatitis.	('block', 'NegReg', (48, 53))	('CM2489', 'Var', (0, 6))	('pancreatitis', 'Disease', (209, 221))	('plaque psoriasis', 'Disease', (188, 204))	('production', 'MPA', (58, 68))	('plaque psoriasis', 'Disease', 'MESH:D011565', (188, 204))	('release of pro-inflammatory cytokines from immune', 'MPA', (73, 122))	('pancreatitis', 'Phenotype', 'HP:0001733', (209, 221))	('psoriasis', 'Phenotype', 'HP:0003765', (195, 204))	('pancreatitis', 'Disease', 'MESH:D010195', (209, 221))	('CM2489', 'Chemical', '-', (0, 6))
15998	34012400	With improved selectivity and reduced toxicity, modified forms of these SOCE channel inhibitors may still hold promise for further cancer therapeutic drug development.	('cancer', 'Disease', (131, 137))	('SOCE channel', 'Gene', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('toxicity', 'Disease', 'MESH:D064420', (38, 46))	('toxicity', 'Disease', (38, 46))	('modified', 'Var', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
15999	34012400	RP4010 from Rhizen Pharmaceuticals is another selective SOCE channel inhibitor.	('RP4010', 'Chemical', '-', (0, 6))	('SOCE', 'Pathway', (56, 60))	('RP4010', 'Var', (0, 6))
16003	34012400	Compared with other reported SOCE channel inhibitors, RP4010 is more potent in blocking SOCE in ESCC cells.	('blocking', 'NegReg', (79, 87))	('RP4010', 'Var', (54, 60))	('RP4010', 'Chemical', '-', (54, 60))	('SOCE', 'Gene', (88, 92))
16005	34012400	Our studies showed that treatment of RP4010 resulted in reduction of intracellular Ca2+ oscillations, and caused cell cycle arrest at G0/G1 phase in several cultured human ESCC cell lines.	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (69, 100))	('RP4010', 'Chemical', '-', (37, 43))	('arrest', 'Disease', 'MESH:D006323', (124, 130))	('human', 'Species', '9606', (166, 171))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (113, 130))	('arrest', 'Disease', (124, 130))	('RP4010', 'Var', (37, 43))	('reduction', 'NegReg', (56, 65))	('intracellular Ca2+ oscillations', 'MPA', (69, 100))
16009	34012400	Drug resistance is responsible for relapses of cancers and remains to be a big challenge in most cancer treatment.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('responsible', 'Reg', (19, 30))	('cancer', 'Disease', (47, 53))	('Drug resistance', 'Var', (0, 15))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
16019	34012400	While some cell surface markers, such as CD44, CD24, and CD133, have been identified as common CSC markers for almost all cancer types, CSC in GC and EC cancers present their specific markers as well.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (122, 128))	('CD24', 'Gene', (47, 51))	('CD44', 'Var', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('EC cancers', 'Disease', 'MESH:D009369', (150, 160))	('EC cancers', 'Disease', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('CD133', 'Gene', (57, 62))	('CD133', 'Gene', '8842', (57, 62))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('CSC', 'Disease', (136, 139))
16030	34012400	With RyR1 knockdown, the CSCs diminish in the severe combined immunodeficiency (SCID) mice model.	('immunodeficiency', 'Phenotype', 'HP:0002721', (62, 78))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (53, 78))	('immunodeficiency', 'Disease', (62, 78))	('immunodeficiency', 'Disease', 'MESH:D007153', (62, 78))	('mice', 'Species', '10090', (86, 90))	('diminish', 'NegReg', (30, 38))	('RyR1', 'Gene', (5, 9))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (46, 78))	('CSCs', 'MPA', (25, 29))	('knockdown', 'Var', (10, 19))	('SCID', 'Disease', (80, 84))	('SCID', 'Disease', 'MESH:D053632', (80, 84))
16037	34012400	Furthermore, the treatment of SKF-96365 can reduce CSC cell proliferation and decrease stemness in glioblastoma.	('reduce', 'NegReg', (44, 50))	('decrease stemness in glioblastoma', 'Disease', 'MESH:D005909', (78, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('SKF-96365', 'Var', (30, 39))	('decrease stemness in glioblastoma', 'Disease', (78, 111))	('CSC cell proliferation', 'CPA', (51, 73))	('SKF-96365', 'Chemical', 'MESH:C063159', (30, 39))
16043	34012400	Metformin, a widely used diabetes drug, has been administrated in combination with chemotherapy in several clinical trials to treat multiple cancers, including colon cancer (NCT01440127), ovarian, fallopian tube, and primary peritoneal cancer (NCT01579812).	('diabetes', 'Disease', (25, 33))	('NCT01440127', 'Var', (174, 185))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('fallopian tube', 'Disease', (197, 211))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('primary peritoneal cancer', 'Phenotype', 'HP:0030406', (217, 242))	('colon cancer', 'Phenotype', 'HP:0003003', (160, 172))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('ovarian', 'Disease', 'MESH:D010049', (188, 195))	('cancers', 'Disease', (141, 148))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', (166, 172))	('colon cancer', 'Disease', 'MESH:D015179', (160, 172))	('diabetes', 'Disease', 'MESH:D003920', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('colon cancer', 'Disease', (160, 172))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('ovarian', 'Disease', (188, 195))
16051	34012400	We speculate that combined inhibitors for both SOCE and EGFR pathways could achieve better anti-cancer effects than single agent alone for GE cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EGFR', 'Gene', '1956', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('inhibitors', 'Var', (27, 37))	('EGFR', 'Gene', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('SOCE', 'Pathway', (47, 51))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (142, 148))
16131	32850797	Aberrant expression of LINE-1 retrotransposon can provide strong stimuli for an innate immune response, activate the immune system, and induce autoimmunity and inflammation.	('autoimmunity', 'CPA', (143, 155))	('Aberrant expression', 'Var', (0, 19))	('inflammation', 'Disease', 'MESH:D007249', (160, 172))	('inflammation', 'Disease', (160, 172))	('autoimmunity', 'Phenotype', 'HP:0002960', (143, 155))	('activate', 'PosReg', (104, 112))	('innate immune response', 'MPA', (80, 102))	('immune system', 'CPA', (117, 130))	('LINE-1 retrotransposon', 'Gene', (23, 45))	('induce', 'Reg', (136, 142))
16146	32850797	LINE-1 promoter hypomethylation is a biomarker for genome-wide DNA hypomethylation, which is itself a major hallmark of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('DNA hypomethylation', 'Var', (63, 82))	('hallmark of cancer', 'Disease', (108, 126))	('hallmark of cancer', 'Disease', 'MESH:D009369', (108, 126))	('LINE-1', 'Gene', (0, 6))
16149	32850797	LINE-1 hypomethylation was reported to be associated with poor survival in more than 200 cases of gastric cancer, suggesting its potential as a prognostic biomarker.	('hypomethylation', 'Var', (7, 22))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gastric cancer', 'Disease', (98, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('poor', 'NegReg', (58, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('LINE-1', 'Gene', (0, 6))
16152	32850797	It has been reported that global DNA hypomethylation promotes aggressive tumor behavior by amplifying oncogenes or through abnormal expression of microRNAs.	('amplifying', 'PosReg', (91, 101))	('promotes', 'PosReg', (53, 61))	('global DNA hypomethylation', 'Var', (26, 52))	('aggressive tumor', 'Disease', 'MESH:D001523', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('oncogenes', 'Gene', (102, 111))	('aggressive tumor', 'Disease', (62, 78))	('expression', 'MPA', (132, 142))
16153	32850797	In esophageal cancer with high mortality and poor endoscopic screening sensitivity, LINE-1 hypomethylation can serve as a good diagnostic biomarker, thereby improving 5-year survival.	('cancer', 'Disease', (14, 20))	('mortality', 'Disease', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('improving', 'PosReg', (157, 166))	('mortality', 'Disease', 'MESH:D003643', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('hypomethylation', 'Var', (91, 106))	('5-year survival', 'MPA', (167, 182))
16154	32850797	LINE-1 hypomethylation can also be seen in some precancerous lesions.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('precancerous lesions', 'Disease', 'MESH:D011230', (48, 68))	('precancerous lesions', 'Disease', (48, 68))	('hypomethylation', 'Var', (7, 22))
16155	32850797	For example, in colorectal cancer, LINE-1 hypomethylation had no significant difference between adenomas and cancerous tissues, but it was significantly lower in adenomas than in normal tissues.	('adenomas', 'Disease', 'MESH:D000236', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('hypomethylation', 'Var', (42, 57))	('adenomas', 'Disease', (162, 170))	('adenomas', 'Disease', (96, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('cancerous', 'Disease', (109, 118))	('lower', 'NegReg', (153, 158))	('adenomas', 'Disease', 'MESH:D000236', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('cancerous', 'Disease', 'MESH:D009369', (109, 118))	('colorectal cancer', 'Disease', (16, 33))
16156	32850797	Therefore, LINE-1 hypomethylation also can be used as an early biomarker for cancer.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hypomethylation', 'Var', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('LINE-1', 'Gene', (11, 17))
16159	32850797	Pan-cancer Analysis of Whole Genomes analysis of 2,954 cancer genomes from 38 histological subtypes revealed that aberrant LINE-1 integrations could lead to gene rearrangement.	('gene rearrangement', 'MPA', (157, 175))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('aberrant', 'Var', (114, 122))	('integrations', 'Var', (130, 142))	('LINE-1', 'Gene', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('lead to', 'Reg', (149, 156))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', (55, 61))
16160	32850797	In breast cancer, Morse and colleagues first proposed that hypomethylation activates LINE-1 which can utilize the target primed reverse transcription pathway to insert into the oncogene MYC, causing tumor-specific rearrangement and amplification.	('tumor', 'Disease', (199, 204))	('MYC', 'Gene', '4609', (186, 189))	('amplification', 'MPA', (232, 245))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('hypomethylation', 'Var', (59, 74))	('rearrangement', 'MPA', (214, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('insert', 'Reg', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('MYC', 'Gene', (186, 189))	('causing', 'Reg', (191, 198))	('activates', 'PosReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
16162	32850797	LINE-1 can mediate the deletion of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('deletion', 'Var', (23, 31))
16164	32850797	reported that LINE-1 insertion disrupts the tumor suppressor gene APC, which can lead to gene inactivation.	('disrupts', 'NegReg', (31, 39))	('APC', 'Gene', (66, 69))	('insertion', 'Var', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('APC', 'Gene', '324', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
16165	32850797	In lung squamous cell carcinoma, we found that LINE-1 insertion into tumor suppressor gene FGGY promotes cell proliferation and invasion in vitro, and facilitates tumorigenesis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('facilitates', 'PosReg', (151, 162))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('tumor', 'Disease', (69, 74))	('FGGY', 'Gene', (91, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('promotes', 'PosReg', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('tumor', 'Disease', (163, 168))	('insertion', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('invasion', 'CPA', (128, 136))	('cell proliferation', 'CPA', (105, 123))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))
16168	32850797	In breast cancer, high expression of nuclear ORF1 is associated with distant metastasis and poor prognosis.	('ORF1', 'Gene', (45, 49))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('nuclear', 'Protein', (37, 44))	('associated', 'Reg', (53, 63))	('high', 'Var', (18, 22))	('ORF1', 'Gene', '55354', (45, 49))	('distant metastasis', 'CPA', (69, 87))
16182	32850797	LINE-1 methylation is associated with type 2 diabetes mellitus (T2DM).	('type 2 diabetes mellitus', 'Disease', (38, 62))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (38, 62))	('methylation', 'Var', (7, 18))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (45, 62))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (38, 53))	('associated', 'Reg', (22, 32))	('LINE-1', 'Gene', (0, 6))
16183	32850797	This discovery highlights the potential role for LINE-1 DNA methylation as a predictor of the risk of T2DM or other related metabolic disorders.	('methylation', 'Var', (60, 71))	('metabolic disorders', 'Disease', 'MESH:D008659', (124, 143))	('metabolic disorders', 'Disease', (124, 143))	('T2DM', 'Disease', (102, 106))
16184	32850797	LINE-1 DNA methylation is associated with increased LDL cholesterol and decreased HDL cholesterol levels, and these metabolic changes increase the risk of cardiovascular disease.	('increased', 'PosReg', (42, 51))	('increase', 'Reg', (134, 142))	('cardiovascular disease', 'Disease', (155, 177))	('decreased', 'NegReg', (72, 81))	('LDL cholesterol', 'Disease', (52, 67))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (155, 177))	('methylation', 'Var', (11, 22))	('increased LDL', 'Phenotype', 'HP:0003141', (42, 55))	('cholesterol', 'Chemical', 'MESH:D002784', (86, 97))	('decreased HDL cholesterol', 'Phenotype', 'HP:0003233', (72, 97))	('cardiovascular disease', 'Disease', 'MESH:D002318', (155, 177))	('cholesterol', 'Chemical', 'MESH:D002784', (56, 67))	('HDL cholesterol levels', 'MPA', (82, 104))	('LINE-1', 'Gene', (0, 6))
16187	32850797	Therefore, the methylation status of LINE-1 can be a predictor of some metabolic diseases.	('methylation status', 'Var', (15, 33))	('predictor', 'Reg', (53, 62))	('metabolic diseases', 'Disease', (71, 89))	('metabolic diseases', 'Disease', 'MESH:D008659', (71, 89))
16188	32850797	It was reported that LINE-1 insertions in the FGGY gene can upregulate cytochrome P450, arachidonic acid metabolism, and glycerolipid metabolism.	('glycerolipid metabolism', 'Disease', 'MESH:D008659', (121, 144))	('insertions', 'Var', (28, 38))	('upregulate', 'PosReg', (60, 70))	('arachidonic acid metabolism', 'MPA', (88, 115))	('arachidonic acid', 'Chemical', 'MESH:D016718', (88, 104))	('FGGY', 'Gene', (46, 50))	('glycerolipid metabolism', 'Disease', (121, 144))	('cytochrome P450', 'Enzyme', (71, 86))
16191	32850797	In 2011, researchers found that in nasopharyngeal carcinomas with ATM deficiency, LINE-1 retrotransposition increased, and ORF2 copy number increased in AT neurons, thus verifying the correlation between LINE-1 retrotransposition and ATM deficiency.	('ATM', 'Gene', '472', (66, 69))	('nasopharyngeal carcinomas', 'Phenotype', 'HP:0100630', (35, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('increased', 'PosReg', (108, 117))	('ORF2', 'Gene', (123, 127))	('copy', 'MPA', (128, 132))	('ATM', 'Gene', (234, 237))	('ORF2', 'Gene', '100128274', (123, 127))	('carcinomas', 'Disease', 'MESH:D009369', (50, 60))	('retrotransposition', 'MPA', (89, 107))	('deficiency', 'Var', (70, 80))	('ATM', 'Gene', (66, 69))	('LINE-1', 'Gene', (82, 88))	('increased', 'PosReg', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('carcinomas', 'Disease', (50, 60))	('ATM', 'Gene', '472', (234, 237))
16192	32850797	High expression of LINE-1 was found in Rett syndrome caused by mutation of methyl CpG binding protein 2 (MeCP2) in the X-linked gene, which was caused by the inclusion of LINE-1 5'-UTR sequence in the MeCP2 target, leading to methylation-dependent repression.	('MeCP2', 'Gene', '4204', (105, 110))	('methyl CpG binding protein 2', 'Gene', (75, 103))	('Rett syndrome', 'Disease', 'MESH:D015518', (39, 52))	('MeCP2', 'Gene', (201, 206))	('MeCP2', 'Gene', (105, 110))	('caused by', 'Reg', (53, 62))	('methylation-dependent repression', 'MPA', (226, 258))	('mutation', 'Var', (63, 71))	('Rett syndrome', 'Disease', (39, 52))	('MeCP2', 'Gene', '4204', (201, 206))	('methyl CpG binding protein 2', 'Gene', '4204', (75, 103))
16194	32850797	LINE-1 hypomethylation has been observed in most psychiatric studies.	('psychiatric', 'Disease', 'MESH:D001523', (49, 60))	('psychiatric', 'Disease', (49, 60))	('hypomethylation', 'Var', (7, 22))
16195	32850797	Increased copy numbers of LINE-1 as a result of LINE-1 hypomethylation were also found in patients with schizophrenia, bipolar disorder, and major depressive disorder.	('depressive disorder', 'Disease', (147, 166))	('depressive disorder', 'Disease', 'MESH:D000275', (147, 166))	('copy', 'MPA', (10, 14))	('schizophrenia, bipolar disorder', 'Disease', 'MESH:D001714', (104, 135))	('schizophrenia', 'Phenotype', 'HP:0100753', (104, 117))	('LINE-1', 'Gene', (26, 32))	('found', 'Reg', (81, 86))	('hypomethylation', 'Var', (55, 70))	('depressive disorder', 'Phenotype', 'HP:0000716', (147, 166))	('Increased', 'PosReg', (0, 9))	('bipolar disorder', 'Phenotype', 'HP:0007302', (119, 135))	('LINE-1', 'Gene', (48, 54))	('patients', 'Species', '9606', (90, 98))
16199	32850797	Then, a LINE-1 insertion was found in the CHM gene of a patient diagnosed with choroideremia.	('insertion', 'Var', (15, 24))	('choroideremia', 'Gene', '1121', (79, 92))	('CHM', 'Gene', '1121', (42, 45))	('CHM', 'Gene', (42, 45))	('choroideremia', 'Phenotype', 'HP:0001139', (79, 92))	('patient', 'Species', '9606', (56, 63))	('choroideremia', 'Gene', (79, 92))
16201	32850797	Retrotransposon insertions were found to account for up to 0.4% of all NF1 mutations.	('NF1', 'Gene', '4763', (71, 74))	('mutations', 'Var', (75, 84))	('NF1', 'Gene', (71, 74))
16202	32850797	Neurofibromatosis type I is an autosomal dominant disorder caused by NF1 gene mutations.	('NF1', 'Gene', '4763', (69, 72))	('autosomal dominant disorder', 'Disease', (31, 58))	('Neurofibromatosis type I', 'Disease', (0, 24))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('mutations', 'Var', (78, 87))	('Neurofibromatosis type I', 'Disease', 'MESH:C537392', (0, 24))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (31, 58))	('caused by', 'Reg', (59, 68))	('NF1', 'Gene', (69, 72))
16203	32850797	Alu insertion is located 44 bp upstream of NF1 exon 41, causing the exon 41 to skip and change the open reading frame.	('NF1', 'Gene', (43, 46))	('NF1', 'Gene', '4763', (43, 46))	('open reading frame', 'MPA', (99, 117))	('change', 'Reg', (88, 94))	('exon', 'Var', (68, 72))
16204	32850797	Only two cases were thought to be a result of independent SVA insertion in SUZ12P accompanied by 867-kb and 1-Mb deletions that encompassed the NF1 gene.	('deletions', 'Var', (113, 122))	('SUZ12P', 'Gene', '440423', (75, 81))	('insertion', 'Var', (62, 71))	('NF1', 'Gene', '4763', (144, 147))	('NF1', 'Gene', (144, 147))	('SUZ12P', 'Gene', (75, 81))
16205	32850797	In autosomal recessive genetic disease, such as Fanconi anemia caused by SLX4FANCP deficiency and Aicardi-Goutieres syndrome (AGS) of three-prime repair exonuclease 1 mutations, LINE-1 expression was upregulated and pro-inflammatory cytokines were produced through the cGAS-STING pathway.	('SLX4FANCP', 'Gene', (73, 82))	('expression', 'MPA', (185, 195))	('Fanconi anemia', 'Disease', 'MESH:D005199', (48, 62))	('anemia', 'Phenotype', 'HP:0001903', (56, 62))	('autosomal recessive genetic disease', 'Disease', (3, 38))	('mutations', 'Var', (167, 176))	('cGAS-STING', 'Pathway', (269, 279))	('AGS', 'Disease', (126, 129))	('Aicardi-Goutieres syndrome', 'Disease', (98, 124))	('LINE-1', 'Gene', (178, 184))	('upregulated', 'PosReg', (200, 211))	('AGS', 'Disease', 'MESH:C535607', (126, 129))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (48, 62))	('deficiency', 'Var', (83, 93))	('Fanconi anemia', 'Disease', (48, 62))	('autosomal recessive genetic disease', 'Disease', 'MESH:D030342', (3, 38))	('Aicardi-Goutieres syndrome', 'Disease', 'MESH:C535607', (98, 124))
16206	32850797	Hypomethylated and highly expressed LINE-1 has been found in autoimmune diseases such as systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), and psoriasis.	('found', 'Reg', (52, 57))	('autoimmune diseases', 'Disease', (61, 80))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (61, 80))	('Hypomethylated', 'Var', (0, 14))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (89, 117))	("Sjogren's syndrome", 'Disease', 'MESH:D012859', (125, 143))	('psoriasis', 'Phenotype', 'HP:0003765', (154, 163))	('LINE-1', 'Gene', (36, 42))	('psoriasis', 'Disease', 'MESH:D011565', (154, 163))	("Sjogren's syndrome", 'Disease', (125, 143))	('autoimmune diseases', 'Disease', 'MESH:D001327', (61, 80))	('systemic lupus erythematosus', 'Disease', (89, 117))	('SLE', 'Disease', (119, 122))	('psoriasis', 'Disease', (154, 163))	('SLE', 'Disease', 'MESH:D008180', (119, 122))	('SLE', 'Phenotype', 'HP:0002725', (119, 122))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (89, 117))
16224	32850797	Lung squamous cell carcinoma patients with L1-FGGY+ tissue have a poor prognosis, have low levels of CD3+ T cells, and have high levels of CD68+ macrophages and CD33+ myeloid-derived cells.	('patients', 'Species', '9606', (29, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 28))	('L1-FGGY+', 'Var', (43, 51))	('CD68', 'Gene', (139, 143))	('CD68', 'Gene', '968', (139, 143))	('low levels of CD3+ T cells', 'Phenotype', 'HP:0045080', (87, 113))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('low', 'NegReg', (87, 90))	('CD3+ T cells', 'MPA', (101, 113))	('Lung squamous cell carcinoma', 'Disease', (0, 28))
16227	32850797	Some cell-based studies and clinical data have shown that LINE-1 dysregulation is associated with tumor drug resistance.	('associated', 'Reg', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('dysregulation', 'Var', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('LINE-1', 'Gene', (58, 64))	('tumor', 'Disease', (98, 103))
16253	32850797	A clinical trial has shown that combination therapy with carboplatin and anti-programmed death-1 has a good therapeutic effect in lung cancer because carboplatin can induce LINE-1 expression.	('carboplatin', 'Chemical', 'MESH:D016190', (150, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('carboplatin', 'Var', (150, 161))	('LINE-1', 'Gene', (173, 179))	('death', 'Disease', 'MESH:D003643', (89, 94))	('expression', 'MPA', (180, 190))	('death', 'Disease', (89, 94))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('induce', 'Reg', (166, 172))	('carboplatin', 'Chemical', 'MESH:D016190', (57, 68))	('lung cancer', 'Disease', (130, 141))
16271	32850797	The dysregulation of LINE-1 can lead to the disorder of glucose and lipid metabolism, and the inhibition of glucose and lipid metabolism may reverse the disease progression caused by LINE-1.	('lead to', 'Reg', (32, 39))	('disorder', 'MPA', (44, 52))	('disease', 'Disease', (153, 160))	('glucose and lipid metabolism', 'Disease', 'MESH:D044882', (108, 136))	('glucose and lipid metabolism', 'Disease', 'MESH:D044882', (56, 84))	('dysregulation', 'Var', (4, 17))	('inhibition', 'Var', (94, 104))	('LINE-1', 'Gene', (21, 27))
16288	32280307	Accumulating evidences have showed that aberrant expression of lncRNA could drive tumor phenotypes, including initiation, invasion, and metastasis, via interacting with other cellular macromolecules.	('aberrant expression', 'Var', (40, 59))	('interacting', 'Interaction', (152, 163))	('lncRNA', 'Gene', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('invasion', 'CPA', (122, 130))	('metastasis', 'CPA', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('initiation', 'CPA', (110, 120))	('drive', 'PosReg', (76, 81))	('tumor', 'Disease', (82, 87))
16330	32280307	Increasing evidences have established a strong relationship between dysfunction of lncRNAs and cell fate determination as well as disease pathogenesis, such as aging, arthritis, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cell fate determination', 'CPA', (95, 118))	('arthritis', 'Disease', (167, 176))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('arthritis', 'Disease', 'MESH:D001168', (167, 176))	('arthritis', 'Phenotype', 'HP:0001369', (167, 176))	('dysfunction', 'Var', (68, 79))
16336	32280307	Notably, MIR31HG expression was even higher in gefitinib-resistant NSCLC cells, and knockdown of MIR31HG could promote cell apoptosis and cell cycle arrest, and subsequently induce gefitinib sensitivity.	('gefitinib', 'Chemical', 'MESH:D000077156', (181, 190))	('induce', 'Reg', (174, 180))	('MIR31HG', 'Gene', (97, 104))	('higher', 'PosReg', (37, 43))	('MIR31HG', 'Gene', (9, 16))	('MIR31HG', 'Gene', '554202', (97, 104))	('cell apoptosis', 'CPA', (119, 133))	('MIR31HG', 'Gene', '554202', (9, 16))	('knockdown', 'Var', (84, 93))	('expression', 'MPA', (17, 27))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('arrest', 'Disease', (149, 155))	('gefitinib', 'Chemical', 'MESH:D000077156', (47, 56))	('NSCLC', 'Disease', (67, 72))	('gefitinib sensitivity', 'MPA', (181, 202))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('promote', 'PosReg', (111, 118))
16342	32280307	The pooled results of subgroup analysis as per the tumor types demonstrated that high MIR31HG expression predicted unfavorable OS in patients with lung cancer and other cancers, and poor RFS in all selected studies, respectively.	('cancers', 'Disease', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('high', 'Var', (81, 85))	('tumor', 'Disease', (51, 56))	('lung cancer', 'Disease', (147, 158))	('patients', 'Species', '9606', (133, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('MIR31HG', 'Gene', (86, 93))	('predicted', 'Reg', (105, 114))	('unfavorable', 'Disease', (115, 126))	('MIR31HG', 'Gene', '554202', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
16354	32280307	In OSCC, MIR31HG knockdown impaired the HIF-1alpha transactivation, sphere-forming ability, metabolic shift and metastatic cascade both in vitro and in vivo.	('metastatic cascade', 'CPA', (112, 130))	('metabolic shift', 'CPA', (92, 107))	('HIF-1alpha', 'Gene', '3091', (40, 50))	('MIR31HG', 'Gene', (9, 16))	('MIR31HG', 'Gene', '554202', (9, 16))	('HIF-1alpha', 'Gene', (40, 50))	('impaired', 'NegReg', (27, 35))	('knockdown', 'Var', (17, 26))	('sphere-forming ability', 'CPA', (68, 90))
16372	32280307	81902745), Natural Science Foundation of Hunan Province, China (2018JJ3716, 2018JJ3762), China Scholarship Council (201806375067, 201806375068), and the Fundamental Research Funds for the Central Universities of Central South University (2017zzts231).	('2018JJ3762', 'Var', (76, 86))	('2018JJ3716', 'Var', (64, 74))	('JJ3716', 'CellLine', 'CVCL:8Z96', (68, 74))	('201806375067', 'Var', (116, 128))	('2018JJ3762', 'CellLine', 'CVCL:6553', (76, 86))	('201806375068', 'Var', (130, 142))
16475	31435459	The review that included 1 RCT and 47 observational studies indicated that minimally invasive procedures (n = 4509) have lower pulmonary complications compared with open surgery (n = 6347).	('pulmonary complications', 'Phenotype', 'HP:0006532', (127, 150))	('minimally', 'Var', (75, 84))	('lower', 'NegReg', (121, 126))	('pulmonary complications', 'Disease', (127, 150))	('pulmonary complications', 'Disease', 'MESH:D008171', (127, 150))
16515	29991802	By using an APE1 redox-specific mutant (C65A) and APE1 redox inhibitor (E3330), we demonstrate that APE1 activates STAT3 in a redox-dependent manner.	('STAT3', 'Gene', '6774', (115, 120))	('rat', 'Species', '10116', (90, 93))	('APE1', 'Gene', '328', (100, 104))	('STAT3', 'Gene', (115, 120))	('redox-dependent', 'MPA', (126, 141))	('APE1', 'Gene', (50, 54))	('APE1', 'Gene', (12, 16))	('C65A', 'SUBSTITUTION', 'None', (40, 44))	('activates', 'PosReg', (105, 114))	('APE1', 'Gene', '328', (50, 54))	('APE1', 'Gene', '328', (12, 16))	('E3330', 'Chemical', 'MESH:C075569', (72, 77))	('C65A', 'Var', (40, 44))	('APE1', 'Gene', (100, 104))
16517	29991802	EGFR phosphorylation (Y1068) was directly associated with APE1 levels and redox function.	('phosphorylation', 'MPA', (5, 20))	('Y1068', 'Chemical', '-', (22, 27))	('APE1', 'Gene', '328', (58, 62))	('EGFR', 'Gene', (0, 4))	('Y1068', 'Var', (22, 27))	('associated', 'Reg', (42, 52))	('redox function', 'MPA', (74, 88))	('EGFR', 'Gene', '1956', (0, 4))	('APE1', 'Gene', (58, 62))
16521	29991802	Inhibition of APE1/REF-1 redox activity using E3330 abrogated STAT3 DNA binding and transcriptional activity.	('abrogated', 'NegReg', (52, 61))	('STAT3', 'Gene', (62, 67))	('REF-1', 'Gene', '328', (19, 24))	('REF-1', 'Gene', (19, 24))	('transcriptional activity', 'CPA', (84, 108))	('STAT3', 'Gene', '6774', (62, 67))	('E3330', 'Var', (46, 51))	('APE1', 'Gene', (14, 18))	('E3330', 'Chemical', 'MESH:C075569', (46, 51))	('APE1', 'Gene', '328', (14, 18))
16532	29991802	The redox- selective inhibitor of APE1, E3330, has been shown to reduce STAT3 transcriptional activity.	('APE1', 'Gene', '328', (34, 38))	('E3330', 'Var', (40, 45))	('STAT3', 'Gene', (72, 77))	('E3330', 'Chemical', 'MESH:C075569', (40, 45))	('reduce', 'NegReg', (65, 71))	('APE1', 'Gene', (34, 38))	('STAT3', 'Gene', '6774', (72, 77))
16533	29991802	Dysregulation of APE1 expression level is associated with cancer development, angiogenesis, progression, and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('progression', 'CPA', (92, 103))	('Dysregulation', 'Var', (0, 13))	('angiogenesis', 'CPA', (78, 90))	('associated', 'Reg', (42, 52))	('expression level', 'MPA', (22, 38))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('metastasis', 'CPA', (109, 119))	('APE1', 'Gene', (17, 21))	('expression', 'Species', '29278', (22, 32))	('cancer', 'Disease', (58, 64))	('APE1', 'Gene', '328', (17, 21))
16534	29991802	Of note, high levels of APE1 have been linked to resistance to chemotherapy and poor clinical outcome.	('APE1', 'Gene', '328', (24, 28))	('linked', 'Reg', (39, 45))	('high levels', 'Var', (9, 20))	('APE1', 'Gene', (24, 28))	('resistance to chemotherapy', 'CPA', (49, 75))
16536	29991802	EGFR activation results in its dimerization to facilitate the phosphorylation of its tyrosine residue, Y1068, the binding site for STAT3.	('EGFR', 'Gene', (0, 4))	('STAT3', 'Gene', (131, 136))	('phosphorylation', 'MPA', (62, 77))	('activation', 'PosReg', (5, 15))	('facilitate', 'PosReg', (47, 57))	('Y1068', 'Chemical', '-', (103, 108))	('tyrosine', 'Chemical', 'MESH:D014443', (85, 93))	('dimerization', 'MPA', (31, 43))	('Y1068', 'Var', (103, 108))	('EGFR', 'Gene', '1956', (0, 4))	('STAT3', 'Gene', '6774', (131, 136))
16547	29991802	Of note, high levels of phospho-STAT3 (Y705) have been observed in dysplastic BE and EAC.	('EAC', 'Phenotype', 'HP:0011459', (85, 88))	('STAT3', 'Gene', '6774', (32, 37))	('STAT3', 'Gene', (32, 37))	('EAC', 'Disease', (85, 88))	('dysplastic', 'Disease', (67, 77))	('Y705', 'Var', (39, 43))	('BE', 'Phenotype', 'HP:0100580', (78, 80))	('dysplastic', 'Disease', 'MESH:D004416', (67, 77))
16553	29991802	To examine the involvement of APE1 in bile salts-induced STAT3 activation, we developed stable knockdown of APE1 in CPB and OE33 cells (sh-APE1), and control cells (sh-Ctrl).	('APE1', 'Gene', '328', (108, 112))	('APE1', 'Gene', (139, 143))	('STAT3', 'Gene', '6774', (57, 62))	('knockdown', 'Var', (95, 104))	('APE1', 'Gene', '328', (139, 143))	('APE1', 'Gene', '328', (30, 34))	('CPB', 'Chemical', '-', (116, 119))	('STAT3', 'Gene', (57, 62))	('APE1', 'Gene', (30, 34))	('bile salts', 'Chemical', 'MESH:D001647', (38, 48))	('APE1', 'Gene', (108, 112))
16555	29991802	We observed that APE1 knockdown in CPB and OE33 cells decreased basal levels of STAT3 phosphorylation (p-STAT3Y705) and completely abrogated the acidic bile salts-induced increase in phosphorylated STAT3, as compared to the control cells (sh-Ctrl) (Figures 1C and D).	('CPB', 'Chemical', '-', (35, 38))	('acidic bile salts-induced', 'MPA', (145, 170))	('STAT3', 'Gene', '6774', (80, 85))	('STAT3', 'Gene', '6774', (198, 203))	('STAT3', 'Gene', '6774', (105, 110))	('abrogated', 'NegReg', (131, 140))	('STAT3', 'Gene', (80, 85))	('p-STAT3Y705', 'Gene', (103, 114))	('knockdown', 'Var', (22, 31))	('bile salts', 'Chemical', 'MESH:D001647', (152, 162))	('APE1', 'Gene', (17, 21))	('STAT3', 'Gene', (198, 203))	('decreased', 'NegReg', (54, 63))	('STAT3', 'Gene', (105, 110))	('APE1', 'Gene', '328', (17, 21))	('increase', 'PosReg', (171, 179))	('p-STAT3Y705', 'Gene', '6774', (103, 114))
16556	29991802	These results were confirmed in CPA cells where the levels of p-STAT3Y705 were significantly diminished by using transient siRNA-mediated knockdown of APE1 (Supplementary Figure S2A).	('knockdown', 'Var', (138, 147))	('APE1', 'Gene', '328', (151, 155))	('p-STAT3Y705', 'Gene', (62, 73))	('p-STAT3Y705', 'Gene', '6774', (62, 73))	('APE1', 'Gene', (151, 155))	('levels', 'MPA', (52, 58))	('diminished', 'NegReg', (93, 103))
16568	29991802	To investigate whether APE1 is required for the acidic bile salt-induced nuclear accumulation of p-STAT3Y705, we used stable APE1 knockdown cells (sh-APE1) and control cells (sh-Ctrl) for immunofluorescent staining.	('p-STAT3Y705', 'Gene', '6774', (97, 108))	('APE1', 'Gene', (125, 129))	('bile salt', 'Chemical', 'MESH:D001647', (55, 64))	('APE1', 'Gene', '328', (125, 129))	('APE1', 'Gene', (23, 27))	('knockdown', 'Var', (130, 139))	('p-STAT3Y705', 'Gene', (97, 108))	('APE1', 'Gene', '328', (23, 27))	('APE1', 'Gene', (150, 154))	('APE1', 'Gene', '328', (150, 154))
16574	29991802	Using a FLAG-tagged adenoviral expression system (Ad) containing the wild-type (WT) or redox-defective (C65A) mutant of APE1, we found that Ad-APE1 (WT) increased the p-STAT3Y705 levels in CPB and OE33 cells, whereas the redox-defective mutant Ad-APE1 (C65A) failed to induce p-STAT3Y705 (Figures 3A-B).	('C65A', 'SUBSTITUTION', 'None', (104, 108))	('p-STAT3Y705', 'Gene', (167, 178))	('p-STAT3Y705', 'Gene', '6774', (276, 287))	('increased', 'PosReg', (153, 162))	('expression', 'Species', '29278', (31, 41))	('C65A', 'Var', (104, 108))	('C65A', 'SUBSTITUTION', 'None', (253, 257))	('p-STAT3Y705', 'Gene', '6774', (167, 178))	('APE1', 'Gene', (120, 124))	('APE1', 'Gene', (143, 147))	('p-STAT3Y705', 'Gene', (276, 287))	('APE1', 'Gene', (247, 251))	('APE1', 'Gene', '328', (247, 251))	('APE1', 'Gene', '328', (120, 124))	('APE1', 'Gene', '328', (143, 147))	('CPB', 'Chemical', '-', (189, 192))	('C65A', 'Var', (253, 257))
16576	29991802	In contrast, a similar response was not obtained upon overexpressing the redox-defective mutant Ad-APE1 (C65A) (Figures 3C, D).	('APE1', 'Gene', (99, 103))	('APE1', 'Gene', '328', (99, 103))	('C65A', 'Var', (105, 109))	('C65A', 'SUBSTITUTION', 'None', (105, 109))
16577	29991802	To further validate the role of the redox function of APE1 on STAT3 transcriptional activity, we used a small molecule inhibitor E3330, which selectively inhibits APE1 redox activity without affecting its endonuclease function.	('inhibits', 'NegReg', (154, 162))	('STAT3', 'Gene', (62, 67))	('E3330', 'Var', (129, 134))	('APE1', 'Gene', (163, 167))	('E3330', 'Chemical', 'MESH:C075569', (129, 134))	('APE1', 'Gene', (54, 58))	('APE1', 'Gene', '328', (163, 167))	('redox activity', 'MPA', (168, 182))	('APE1', 'Gene', '328', (54, 58))	('STAT3', 'Gene', '6774', (62, 67))
16579	29991802	On the other hand, pretreatment of cells with E3330 significantly (p< 0.001) inhibited bile salts-induced STAT3 activity (Supplementary Figures S3A and B).	('inhibited', 'NegReg', (77, 86))	('bile salts', 'Chemical', 'MESH:D001647', (87, 97))	('S3A and B', 'Gene', '6189', (144, 153))	('STAT3', 'Gene', '6774', (106, 111))	('E3330', 'Var', (46, 51))	('STAT3', 'Gene', (106, 111))	('E3330', 'Chemical', 'MESH:C075569', (46, 51))
16583	29991802	This elevation in mRNA levels was significantly decreased following APE1 knockdown (Figure 3E, F and Supplementary Figure S4A-D).	('mRNA levels', 'MPA', (18, 29))	('elevation', 'PosReg', (5, 14))	('decreased', 'NegReg', (48, 57))	('APE1', 'Gene', (68, 72))	('APE1', 'Gene', '328', (68, 72))	('knockdown', 'Var', (73, 82))
16590	29991802	Furthermore, we detected a positive correlation between the levels of APE1, p-STAT3Y705, and p-EGFRY1068 (Figure 4A).	('APE1', 'Gene', (70, 74))	('p-STAT3Y705', 'Gene', (76, 87))	('APE1', 'Gene', '328', (70, 74))	('p-EGFRY1068', 'Var', (93, 104))	('p-STAT3Y705', 'Gene', '6774', (76, 87))
16591	29991802	Using Tet-on-APE1 CPA cells, the base line expression levels of APE1, p-EGFRY1068 and p-STAT3Y705 was low (Figure 4B).	('Tet', 'Chemical', 'MESH:C010349', (6, 9))	('p-STAT3Y705', 'Gene', (86, 97))	('APE1', 'Gene', (64, 68))	('low', 'NegReg', (102, 105))	('APE1', 'Gene', '328', (64, 68))	('p-EGFRY1068', 'Var', (70, 81))	('expression', 'Species', '29278', (43, 53))	('APE1', 'Gene', '328', (13, 17))	('APE1', 'Gene', (13, 17))	('expression levels', 'MPA', (43, 60))	('p-STAT3Y705', 'Gene', '6774', (86, 97))
16592	29991802	Following induction with doxycycline, there was a notable increase in expression of APE1 along with an increase in p-EGFRY1068 and p-STAT3.Y705 The strongest activation was observed at 48 and 72h of doxycycline treatment.	('increase', 'PosReg', (58, 66))	('2h', 'Chemical', 'MESH:D003903', (193, 195))	('STAT3', 'Gene', '6774', (133, 138))	('expression', 'Species', '29278', (70, 80))	('APE1', 'Gene', (84, 88))	('STAT3', 'Gene', (133, 138))	('expression', 'MPA', (70, 80))	('activation', 'PosReg', (158, 168))	('APE1', 'Gene', '328', (84, 88))	('doxycycline', 'Chemical', 'MESH:D004318', (25, 36))	('p-EGFRY1068', 'Var', (115, 126))	('doxycycline', 'Chemical', 'MESH:D004318', (199, 210))
16594	29991802	Because of the observed induction of APE1 upon exposure to bile acids (Figure 1A), we aimed to further confirm its role by knocking down APE1 prior to exposure to acidic bile salts.	('knocking', 'Var', (123, 131))	('bile acids', 'Chemical', 'MESH:D001647', (59, 69))	('APE1', 'Gene', (37, 41))	('bile salts', 'Chemical', 'MESH:D001647', (170, 180))	('APE1', 'Gene', (137, 141))	('APE1', 'Gene', '328', (37, 41))	('APE1', 'Gene', '328', (137, 141))
16606	29991802	To further validate the involvement of EGFR in APE1-mediated bile salts-induced STAT3 activation, we depleted EGFR by using small interfering RNA (siRNA) in OE33 cells.	('STAT3', 'Gene', '6774', (80, 85))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('STAT3', 'Gene', (80, 85))	('APE1', 'Gene', '328', (47, 51))	('small', 'Var', (124, 129))	('APE1', 'Gene', (47, 51))	('bile salts', 'Chemical', 'MESH:D001647', (61, 71))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('depleted', 'NegReg', (101, 109))
16608	29991802	Our results have shown nuclear accumulation of APE1, p-EGFRY1068 and p-STAT3Y705 in response to bile salts exposure (Figures 2C-E and 4D-E).	('bile salts', 'Chemical', 'MESH:D001647', (96, 106))	('APE1', 'Gene', '328', (47, 51))	('p-STAT3Y705', 'Gene', (69, 80))	('APE1', 'Gene', (47, 51))	('nuclear accumulation', 'MPA', (23, 43))	('p-EGFRY1068', 'Var', (53, 64))	('bile salts', 'MPA', (96, 106))	('p-STAT3Y705', 'Gene', '6774', (69, 80))
16616	29991802	By using the CellTiter-Glo luminescence-based viability assay, we found that the APE1 knockdown significantly decreased cell viability, a finding that is further exacerbated in response to acidic bile salts (Figure 7A-C; p<0.01, p<0.001).	('bile salts', 'Chemical', 'MESH:D001647', (196, 206))	('knockdown', 'Var', (86, 95))	('decreased', 'NegReg', (110, 119))	('APE1', 'Gene', (81, 85))	('APE1', 'Gene', '328', (81, 85))	('cell viability', 'CPA', (120, 134))
16617	29991802	Using the TUNEL assay for cell apoptosis, we confirmed that APE1 knockdown increased the number of apoptotic cells in response to bile salts (Figure 7D).	('knockdown', 'Var', (65, 74))	('APE1', 'Gene', (60, 64))	('APE1', 'Gene', '328', (60, 64))	('bile salts', 'Chemical', 'MESH:D001647', (130, 140))	('increased', 'PosReg', (75, 84))	('response to bile salts', 'MPA', (118, 140))
16618	29991802	Using the Click-IT plus EdU for analyzing DNA replication in proliferating cells, we detected a significant reduction in the proliferative capacity, following knockdown of APE1 (Figure 7E).	('knockdown', 'Var', (159, 168))	('APE1', 'Gene', '328', (172, 176))	('rat', 'Species', '10116', (132, 135))	('rat', 'Species', '10116', (68, 71))	('proliferative capacity', 'CPA', (125, 147))	('APE1', 'Gene', (172, 176))	('reduction', 'NegReg', (108, 117))
16635	29991802	STAT3 DNA binding and transcriptional activity is decreased by oxidation of critical cysteine residues in STAT3 protein through peroxide treatment.	('cysteine', 'Chemical', 'MESH:D003545', (85, 93))	('oxidation', 'Var', (63, 72))	('decreased', 'NegReg', (50, 59))	('STAT3', 'Gene', '6774', (106, 111))	('STAT3', 'Gene', '6774', (0, 5))	('transcriptional activity', 'MPA', (22, 46))	('STAT3', 'Gene', (0, 5))	('STAT3', 'Gene', (106, 111))	('peroxide', 'Chemical', 'MESH:D010545', (128, 136))
16638	29991802	Overexpression of a redox-deficient APE1 (C65A) failed to promote STAT3 transactivation.	('STAT3', 'Gene', (66, 71))	('expression', 'Species', '29278', (4, 14))	('APE1', 'Gene', (36, 40))	('C65A', 'Var', (42, 46))	('APE1', 'Gene', '328', (36, 40))	('STAT3', 'Gene', '6774', (66, 71))	('C65A', 'SUBSTITUTION', 'None', (42, 46))
16639	29991802	Similarly, blockade of the redox function of APE1 by using E3330 inhibitor, dramatically inhibited the bile salts-induced phosphorylation and transcriptional activity of STAT3.	('APE1', 'Gene', '328', (45, 49))	('E3330 inhibitor', 'Var', (59, 74))	('STAT3', 'Gene', '6774', (170, 175))	('bile salts', 'Chemical', 'MESH:D001647', (103, 113))	('blockade', 'NegReg', (11, 19))	('inhibited', 'NegReg', (89, 98))	('STAT3', 'Gene', (170, 175))	('transcriptional activity', 'MPA', (142, 166))	('E3330', 'Chemical', 'MESH:C075569', (59, 64))	('redox', 'MPA', (27, 32))	('bile salts-induced phosphorylation', 'MPA', (103, 137))	('APE1', 'Gene', (45, 49))
16646	29991802	Indeed, genetic knockdown and pharmacologic inhibition of EGFR abolished APE1-induced activation of STAT3 in response to acidic bile salts, indicating that EGFR mediates APE1-induced phosphorylation and activation of STAT3.	('APE1', 'Gene', (73, 77))	('EGFR', 'Gene', '1956', (58, 62))	('STAT3', 'Gene', (100, 105))	('inhibition', 'Var', (44, 54))	('APE1', 'Gene', (170, 174))	('APE1', 'Gene', '328', (73, 77))	('abolished', 'NegReg', (63, 72))	('EGFR', 'Gene', (58, 62))	('response to acidic bile salts', 'MPA', (109, 138))	('activation', 'MPA', (86, 96))	('bile salts', 'Chemical', 'MESH:D001647', (128, 138))	('APE1', 'Gene', '328', (170, 174))	('knockdown', 'Var', (16, 25))	('EGFR', 'Gene', '1956', (156, 160))	('EGFR', 'Gene', (156, 160))	('STAT3', 'Gene', '6774', (217, 222))	('STAT3', 'Gene', '6774', (100, 105))	('STAT3', 'Gene', (217, 222))
16659	29991802	Antibodies against p-STAT3 (Y705), STAT3, p-EGFR (Y1068), EGFR, BCL-xL, Survivin, alpha - Tubulin were purchased from Cell Signaling Technology (Danvers, Massachusetts, USA).	('BCL-xL', 'Gene', '598', (64, 70))	('Y705', 'Var', (28, 32))	('STAT3', 'Gene', (21, 26))	('STAT3', 'Gene', (35, 40))	('STAT3', 'Gene', '6774', (35, 40))	('Y1068', 'Chemical', '-', (50, 55))	('Y1068', 'Var', (50, 55))	('alpha - Tubulin', 'Gene', (82, 97))	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (58, 62))	('alpha - Tubulin', 'Gene', '10376', (82, 97))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('STAT3', 'Gene', '6774', (21, 26))	('BCL-xL', 'Gene', (64, 70))
16671	29991802	Control siRNA (sc-29470) and APE1 siRNA (sc-29470) were obtained from Santa Cruz Biotechnology.	('APE1', 'Gene', (29, 33))	('APE1', 'Gene', '328', (29, 33))	('sc-29470', 'Var', (41, 49))
16709	29872320	Inhibition of survivin enhances radiosensitivity of esophageal cancer cells by switching radiation-induced senescence to apoptosis Strategies to increase radiosensitivity are urgently needed.	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (145, 170))	('survivin', 'Protein', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('enhances', 'PosReg', (23, 31))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('Inhibition', 'Var', (0, 10))	('radiosensitivity', 'CPA', (32, 48))
16712	29872320	In this study, we try to investigate the function of YM155 on radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('YM155', 'Chemical', 'MESH:C523798', (53, 58))	('YM155', 'Var', (53, 58))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))
16717	29872320	YM155 could inhibit the upregulation of survivin induced by radiation in all ESCC cell lines, but the efficacy of radiosensitization varied in different cell lines.	('inhibit', 'NegReg', (12, 19))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('YM155', 'Var', (0, 5))	('survivin', 'Protein', (40, 48))	('upregulation', 'PosReg', (24, 36))
16718	29872320	Radiation-induced senescence in KYSE150 and KYSE410 cells, and the combination with YM155 inhibited senescence and promoted apoptosis of ESCC cells, thereby enhancing radiosensitivity.	('promoted', 'PosReg', (115, 123))	('radiosensitivity', 'MPA', (167, 183))	('enhancing', 'PosReg', (157, 166))	('YM155', 'Chemical', 'MESH:C523798', (84, 89))	('YM155', 'Var', (84, 89))	('senescence', 'MPA', (100, 110))	('combination', 'Var', (67, 78))	('inhibited', 'NegReg', (90, 99))	('apoptosis', 'CPA', (124, 133))
16719	29872320	Combination with YM155 and radiation delayed the growth of KYSE150 xenografts in nude mice by switching radiation-induced senescence to apoptosis.	('delayed', 'NegReg', (37, 44))	('switching', 'Reg', (94, 103))	('nude mice', 'Species', '10090', (81, 90))	('radiation-induced senescence', 'MPA', (104, 132))	('growth', 'MPA', (49, 55))	('YM155', 'Chemical', 'MESH:C523798', (17, 22))	('YM155', 'Var', (17, 22))
16720	29872320	When p21 was inhibited in KYSE150 cells, radiation did not induce senescence, and the radiosensitization of YM155 was also attenuated.	('YM155', 'Chemical', 'MESH:C523798', (108, 113))	('p21', 'Gene', '644914', (5, 8))	('YM155', 'Var', (108, 113))	('inhibited', 'NegReg', (13, 22))	('p21', 'Gene', (5, 8))	('radiosensitization', 'CPA', (86, 104))	('attenuated', 'NegReg', (123, 133))
16722	29872320	Our results suggest a new mechanism that YM155 might sensitize ESCC cells to radiation by switching radiation-induced senescence to apoptosis.	('YM155', 'Chemical', 'MESH:C523798', (41, 46))	('YM155', 'Var', (41, 46))	('radiation-induced senescence', 'MPA', (100, 128))
16723	29872320	The major determinant of radiosensitization by YM155 might be the induction of senescence by radiation.	('YM155', 'Var', (47, 52))	('senescence', 'CPA', (79, 89))	('YM155', 'Chemical', 'MESH:C523798', (47, 52))
16728	29872320	MiR-338-5p enhanced the radiosensitivity of esophageal squamous cell carcinoma (ESCC) by inducing apoptosis through targeting survivin.	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('radiosensitivity', 'MPA', (24, 40))	('apoptosis', 'CPA', (98, 107))	('MiR-338-5p', 'Var', (0, 10))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('targeting', 'Reg', (116, 125))	('esophageal squamous cell carcinoma', 'Disease', (44, 78))	('enhanced', 'PosReg', (11, 19))	('MiR-338-5p', 'Chemical', '-', (0, 10))	('survivin', 'Protein', (126, 134))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (44, 78))	('inducing', 'PosReg', (89, 97))
16729	29872320	Downregulation of ROGDI can mediate radiosensitivity by blocking cells at G2/M, the most radiosensitive phase of the cell cycle.	('ROGDI', 'Gene', (18, 23))	('blocking', 'NegReg', (56, 64))	('Downregulation', 'Var', (0, 14))	('ROGDI', 'Gene', '79641', (18, 23))	('cells at G2/M', 'CPA', (65, 78))
16736	29872320	Recently, some preclinical studies showed that YM155 could sensitize cancer cells to radiation by inhibiting the survivin protein.	('inhibiting', 'NegReg', (98, 108))	('YM155', 'Chemical', 'MESH:C523798', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('YM155', 'Var', (47, 52))	('sensitize', 'Reg', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('survivin protein', 'Protein', (113, 129))	('cancer', 'Disease', (69, 75))
16739	29872320	Our results provided an evidence for the potential use of YM155 in certain cancers to enhance radiosensitivity.	('enhance', 'PosReg', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (86, 110))	('cancers', 'Disease', (75, 82))	('radiosensitivity', 'CPA', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('YM155', 'Chemical', 'MESH:C523798', (58, 63))	('YM155', 'Var', (58, 63))
16740	29872320	The human ESCC cell lines KYSE150, KYSE410, KYSE180, and KYSE510, generously provided by Dr Yutaka Shimada, were cultured in RPMI1640 medium containing 10% fetal bovine serum and supplemented with 100 U/mL penicillin and 100 mug/mL streptomycin at 37 C with 5% CO2.	('KYSE510', 'Var', (57, 64))	('human', 'Species', '9606', (4, 9))	('penicillin', 'Chemical', 'MESH:D010406', (206, 216))	('streptomycin', 'Chemical', 'MESH:D013307', (232, 244))	('bovine', 'Species', '9913', (162, 168))	('CO2', 'Chemical', '-', (261, 264))	('KYSE410', 'Var', (35, 42))	('RPMI1640 medium', 'Chemical', '-', (125, 140))
16770	29872320	Twenty nude mice with established tumors (all 150-200 mm3) were divided into four groups and treated with 1) vehicle (saline) alone; 2) a single dose of 10 Gy irradiation (IR); 3) YM155 alone (5 mg/kg as 7-day continuous intraperitoneal injections); or 4) YM155 plus IR (a single fraction of 10 Gy IR delivered on day 3 of drug treatment).	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('YM155', 'Chemical', 'MESH:C523798', (256, 261))	('YM155', 'Var', (256, 261))	('saline', 'Chemical', 'MESH:D012965', (118, 124))	('YM155', 'Chemical', 'MESH:C523798', (180, 185))	('nude mice', 'Species', '10090', (7, 16))	('YM155', 'Var', (180, 185))
16776	29872320	The CCK-8 assay showed that after 48 h of YM155 treatment, YM155 inhibited cell survival in a dose-dependent manner (Figure S1A).	('cell survival', 'CPA', (75, 88))	('YM155', 'Chemical', 'MESH:C523798', (59, 64))	('YM155', 'Var', (59, 64))	('YM155', 'Chemical', 'MESH:C523798', (42, 47))	('inhibited', 'NegReg', (65, 74))	('YM155', 'Var', (42, 47))
16778	29872320	Thus, the subtoxic concentrations of YM155 were chosen for treatment of the cells (2, 15, 20, and 30 nM for KYSE150, KYSE410, KYSE180, and KYSE510, respectively) in the following experiments.	('KYSE510', 'Var', (139, 146))	('KYSE150', 'Var', (108, 115))	('YM155', 'Chemical', 'MESH:C523798', (37, 42))	('KYSE180', 'Var', (126, 133))	('KYSE410', 'Var', (117, 124))
16780	29872320	Moreover, YM155 inhibited survivin upregulation induced by radiation (Figure 1B).	('inhibited', 'NegReg', (16, 25))	('YM155', 'Chemical', 'MESH:C523798', (10, 15))	('YM155', 'Var', (10, 15))	('upregulation', 'PosReg', (35, 47))	('survivin', 'Protein', (26, 34))
16784	29872320	Compared with the control cells, the survival fraction was significantly decreased after radiation combined with YM155 in the KYSE150 and KYSE410 cells (Figure 2A and B) but not in the KYSE180 and KYSE510 cells (Figure 2C and D).	('decreased', 'NegReg', (73, 82))	('YM155', 'Chemical', 'MESH:C523798', (113, 118))	('YM155', 'Var', (113, 118))	('KYSE410', 'Var', (138, 145))	('survival fraction', 'CPA', (37, 54))
16785	29872320	Therefore, YM155 could sensitize KYSE150 and KYSE410 cells to radiation, but combination with YM155 could not enhance the effect of radiation in KYSE180 and KYSE510 cells.	('YM155', 'Chemical', 'MESH:C523798', (94, 99))	('YM155', 'Var', (94, 99))	('sensitize', 'Reg', (23, 32))	('YM155', 'Chemical', 'MESH:C523798', (11, 16))	('YM155', 'Var', (11, 16))
16789	29872320	With the YM155 treatment, the SA-beta-Gal positive cells decreased to 9% and 16% in the KYSE150 and KYSE410 cells, respectively (Figure 3A).	('YM155', 'Var', (9, 14))	('SA-beta-Gal', 'Chemical', '-', (30, 41))	('SA-beta-Gal', 'Protein', (30, 41))	('to 9', 'Species', '1214577', (67, 71))	('KYSE150', 'Var', (88, 95))	('decreased', 'NegReg', (57, 66))	('YM155', 'Chemical', 'MESH:C523798', (9, 14))	('KYSE410', 'Var', (100, 107))
16790	29872320	Western blot analysis showed that p53 and p21 were upregulated after 8 Gy irradiation and that YM155 inhibited the upregulation (Figure 3B).	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('p21', 'Gene', (42, 45))	('p21', 'Gene', '644914', (42, 45))	('YM155', 'Chemical', 'MESH:C523798', (95, 100))	('YM155', 'Var', (95, 100))	('upregulated', 'PosReg', (51, 62))	('inhibited', 'NegReg', (101, 110))
16791	29872320	The TUNEL assay showed that radiation and YM155 could both induce apoptosis, but the combination of YM155 with radiation significantly increased the percentage of apoptotic cells from 24% to 69% for the KYSE150 cells and 18% to 65% for the KYSE410 cells (Figure 3C).	('combination', 'Interaction', (85, 96))	('apoptotic cells', 'CPA', (163, 178))	('increased', 'PosReg', (135, 144))	('YM155', 'Chemical', 'MESH:C523798', (42, 47))	('YM155', 'Chemical', 'MESH:C523798', (100, 105))	('YM155', 'Var', (100, 105))
16792	29872320	PARP cleavage was significantly induced after YM155 treatment combined with radiation in the KYSE150 and the KYSE410 cells (Figure 3D).	('YM155 treatment', 'Var', (46, 61))	('PARP', 'Gene', (0, 4))	('induced', 'PosReg', (32, 39))	('PARP', 'Gene', '142', (0, 4))	('YM155', 'Chemical', 'MESH:C523798', (46, 51))
16793	29872320	In agreement with the TUNEL assay result, Annexin V/PI staining showed that the combination of YM155 with radiation significantly increased the percentage of double-staining cells in the KYSE150 and KYSE410 cells (Figure 3E).	('KYSE150', 'Var', (187, 194))	('Annexin V', 'Gene', '308', (42, 51))	('Annexin V', 'Gene', (42, 51))	('YM155', 'Chemical', 'MESH:C523798', (95, 100))	('KYSE410', 'Var', (199, 206))	('YM155', 'Var', (95, 100))	('increased', 'PosReg', (130, 139))	('double-staining', 'MPA', (158, 173))	('combination', 'Interaction', (80, 91))
16794	29872320	These data indicated that YM155 could inhibit cell senescence and promote apoptosis of ESCC cells when radiation induced cell senescence.	('apoptosis', 'CPA', (74, 83))	('cell senescence', 'CPA', (46, 61))	('YM155', 'Chemical', 'MESH:C523798', (26, 31))	('YM155', 'Var', (26, 31))	('promote', 'PosReg', (66, 73))	('inhibit', 'NegReg', (38, 45))
16795	29872320	Cell senescence was evaluated in the KYSE180 and KYSE510 cells, and few SA-beta-Gal positive cells were observed after radiation (Figure 4A).	('KYSE510', 'Var', (49, 56))	('Cell senescence', 'CPA', (0, 15))	('SA-beta-Gal', 'Chemical', '-', (72, 83))
16797	29872320	The TUNEL assay showed that radiation and YM155 could both induce apoptosis, but the combination of YM155 with radiation did not increase the percentage of apoptosis cells in the KYSE180 and KYSE510 cells (Figure 4C).	('YM155', 'Chemical', 'MESH:C523798', (42, 47))	('apoptosis', 'CPA', (66, 75))	('YM155', 'Var', (42, 47))	('YM155', 'Chemical', 'MESH:C523798', (100, 105))	('YM155', 'Var', (100, 105))
16801	29872320	As shown in Figure 5A and B, tumor volumes and tumor weights were significantly inhibited in the group treated with YM155 in combination with radiation.	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('YM155', 'Chemical', 'MESH:C523798', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('YM155', 'Var', (116, 121))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('inhibited', 'NegReg', (80, 89))
16803	29872320	In agreement with the in vitro results, SA-beta-Gal staining was observed after radiation, and the SA-beta-Gal positive cells decreased in tumors treated with YM155 and radiation (Figure 5D).	('YM155', 'Var', (159, 164))	('decreased', 'NegReg', (126, 135))	('SA-beta-Gal', 'Chemical', '-', (99, 110))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('YM155', 'Chemical', 'MESH:C523798', (159, 164))	('SA-beta-Gal', 'Chemical', '-', (40, 51))
16804	29872320	In contrast, the TUNEL assay showed that the combination of YM155 with radiation significantly increased the percentage of apoptosis (Figure 5E).	('YM155', 'Chemical', 'MESH:C523798', (60, 65))	('YM155', 'Var', (60, 65))	('apoptosis', 'CPA', (123, 132))	('combination', 'Interaction', (45, 56))	('increased', 'PosReg', (95, 104))
16806	29872320	These data show that radiation could induce cell senescence in the KYSE150 xenograft, and YM155 could enhance tumor inhibition by reducing senescence and promoting apoptosis.	('promoting', 'PosReg', (154, 163))	('YM155', 'Var', (90, 95))	('reducing', 'NegReg', (130, 138))	('enhance', 'PosReg', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('cell senescence', 'CPA', (44, 59))	('apoptosis', 'CPA', (164, 173))	('senescence', 'MPA', (139, 149))	('YM155', 'Chemical', 'MESH:C523798', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
16814	29872320	YM155, a small-molecule inhibitor of survivin, could sensitize cancer cells to radiation both in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('sensitize', 'Reg', (53, 62))	('YM155', 'Var', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
16815	29872320	In our study, survivin was upregulated by radiation in all ESCC cell lines; therefore, we used YM155 as a survivin inhibitor and confirmed that YM155 could inhibit the upregulation of survivin induced by radiation.	('inhibit', 'NegReg', (156, 163))	('survivin', 'Protein', (184, 192))	('YM155', 'Chemical', 'MESH:C523798', (95, 100))	('YM155', 'Chemical', 'MESH:C523798', (144, 149))	('upregulated', 'PosReg', (27, 38))	('YM155', 'Var', (144, 149))	('upregulation', 'PosReg', (168, 180))
16816	29872320	But the radiosensitization effect of YM155 varied in different ESCC cell lines.	('YM155', 'Var', (37, 42))	('YM155', 'Chemical', 'MESH:C523798', (37, 42))	('radiosensitization', 'MPA', (8, 26))
16817	29872320	This study is the first that demonstrates the difference in efficacy of YM155 in promoting the radiosensitivity of ESCC cells.	('promoting', 'PosReg', (81, 90))	('YM155', 'Chemical', 'MESH:C523798', (72, 77))	('radiosensitivity', 'CPA', (95, 111))	('YM155', 'Var', (72, 77))
16818	29872320	Recently published data reported that YM155 could promote radiation-induced clonogenic cell death of Eca109 and TE3 cells, but the sensitization enhancement ratio of the two cell lines exhibited no large difference.	('YM155', 'Chemical', 'MESH:C523798', (38, 43))	('radiation-induced clonogenic cell death', 'CPA', (58, 97))	('promote', 'PosReg', (50, 57))	('YM155', 'Var', (38, 43))
16819	29872320	For example, herceptin was used in breast cancer patients with ErbB2 overexpression; EGFR with specific mutations conferred sensitivity to gefitinib and erlotinib, and EGFR monoclonal antibody could be combined with radiotherapy when EGFR is overexpressed.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', (234, 238))	('EGFR', 'Gene', '1956', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ErbB2', 'Gene', '2064', (63, 68))	('herceptin', 'Chemical', 'MESH:D000068878', (13, 22))	('erlotinib', 'MPA', (153, 162))	('mutations', 'Var', (104, 113))	('erlotinib', 'Chemical', 'MESH:D000069347', (153, 162))	('EGFR', 'Gene', '1956', (85, 89))	('EGFR', 'Gene', '1956', (234, 238))	('EGFR', 'Gene', (168, 172))	('ErbB2', 'Gene', (63, 68))	('conferred', 'Reg', (114, 123))	('gefitinib', 'MPA', (139, 148))	('gefitinib', 'Chemical', 'MESH:D000077156', (139, 148))	('patients', 'Species', '9606', (49, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('sensitivity', 'MPA', (124, 135))	('breast cancer', 'Disease', (35, 48))
16820	29872320	A previous study showed that YM155 could suppress survivin expression and therefore inhibit the growth of cancer cells.	('YM155', 'Chemical', 'MESH:C523798', (29, 34))	('YM155', 'Var', (29, 34))	('inhibit', 'NegReg', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('expression', 'MPA', (59, 69))	('cancer', 'Disease', (106, 112))	('survivin', 'Protein', (50, 58))	('suppress', 'NegReg', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
16821	29872320	YM155 could reverse cisplatin resistance in head and neck cancer cells and enhance the sensitivity of docetaxel in human malignant melanoma models.	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cisplatin resistance', 'MPA', (20, 40))	('sensitivity of docetaxel', 'MPA', (87, 111))	('malignant melanoma', 'Phenotype', 'HP:0002861', (121, 139))	('neck cancer', 'Disease', 'MESH:D006258', (53, 64))	('neck cancer', 'Disease', (53, 64))	('reverse', 'NegReg', (12, 19))	('human', 'Species', '9606', (115, 120))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('malignant melanoma', 'Disease', (121, 139))	('YM155', 'Var', (0, 5))	('malignant melanoma', 'Disease', 'MESH:D008545', (121, 139))	('docetaxel', 'Chemical', 'MESH:D000077143', (102, 111))	('enhance', 'PosReg', (75, 82))	('head and neck cancer', 'Phenotype', 'HP:0012288', (44, 64))
16822	29872320	Additionally, YM155 could enhance radiosensitization in ESCC and NSCLC cells.	('ESCC', 'Disease', (56, 60))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('NSCLC', 'Disease', (65, 70))	('radiosensitization', 'CPA', (34, 52))	('YM155', 'Chemical', 'MESH:C523798', (14, 19))	('YM155', 'Var', (14, 19))	('enhance', 'PosReg', (26, 33))
16825	29872320	We observed that YM155 could promote radiosensitivity only when radiation induced senescence of ESCC cells.	('promote', 'PosReg', (29, 36))	('YM155', 'Var', (17, 22))	('radiosensitivity', 'MPA', (37, 53))	('YM155', 'Chemical', 'MESH:C523798', (17, 22))
16827	29872320	These results suggested that survivin was important in radiation-induced senescence and that inhibition of survivin by YM155 could inhibit senescence and promote apoptosis of ESCC cells.	('inhibit', 'NegReg', (131, 138))	('senescence', 'CPA', (139, 149))	('promote', 'PosReg', (154, 161))	('survivin', 'Protein', (107, 115))	('YM155', 'Chemical', 'MESH:C523798', (119, 124))	('apoptosis', 'CPA', (162, 171))	('inhibition', 'Var', (93, 103))	('YM155', 'Gene', (119, 124))
16830	29872320	Therefore, the major determinant of radiosensitization by YM155 could be the ability of radiation to induce senescence.	('YM155', 'Var', (58, 63))	('YM155', 'Chemical', 'MESH:C523798', (58, 63))	('senescence', 'MPA', (108, 118))
16838	29872320	Disruptive TP53 mutations increased radioresistance via the inhibition of senescence in headneck squamous cell carcinoma tumors.	('radioresistance', 'CPA', (36, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (16, 25))	('inhibition', 'NegReg', (60, 70))	('senescence', 'CPA', (74, 84))	('headneck squamous cell carcinoma tumors', 'Disease', 'MESH:D002294', (88, 127))	('increased', 'PosReg', (26, 35))	('headneck squamous cell carcinoma tumors', 'Disease', (88, 127))
16839	29872320	Cells with mutant p53 underwent mitotic catastrophe and apoptosis after chemotherapy.	('mutant', 'Var', (11, 17))	('p53', 'Gene', (18, 21))	('mitotic catastrophe', 'CPA', (32, 51))	('p53', 'Gene', '7157', (18, 21))	('underwent', 'Reg', (22, 31))	('apoptosis', 'CPA', (56, 65))
16840	29872320	After sequenced p53 exons of ESCC cells used in our study, we observed deletion mutations in exon7 of p53 in KYSE510 and KYSE180 cells, leading to amino acid deletion in the DNA binding site of the p53 protein (data not shown).	('protein', 'Protein', (202, 209))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (16, 19))	('DNA', 'MPA', (174, 177))	('deletion mutations', 'Var', (71, 89))	('amino acid deletion', 'Var', (147, 166))	('p53', 'Gene', '7157', (16, 19))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('p53', 'Gene', (102, 105))
16841	29872320	Therefore, we could suppose that the cells of patients with wide-type p53 were more likely to be induced to senescence and might show better response to YM155 treatment combined with radiation.	('YM155', 'Chemical', 'MESH:C523798', (153, 158))	('induced', 'Reg', (97, 104))	('patients', 'Species', '9606', (46, 54))	('better', 'PosReg', (134, 140))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('wide-type', 'Var', (60, 69))
16842	29872320	Although additional studies are required to test the correlation of p53 status and the radiosensitive efficiency of YM155, our study has discussed a potential strategy of combining YM155 treatment with radiotherapy in ESCC patients.	('ESCC', 'Disease', (218, 222))	('YM155', 'Chemical', 'MESH:C523798', (116, 121))	('YM155', 'Chemical', 'MESH:C523798', (181, 186))	('YM155', 'Var', (181, 186))	('p53', 'Gene', '7157', (68, 71))	('p53', 'Gene', (68, 71))	('patients', 'Species', '9606', (223, 231))
16844	29872320	Our results suggest a new pathway through which YM155 could partially sensitize ESCC cells to radiation by inhibiting radiation-induced senescence and enhancing apoptosis.	('enhancing', 'PosReg', (151, 160))	('apoptosis', 'CPA', (161, 170))	('inhibiting', 'NegReg', (107, 117))	('YM155', 'Chemical', 'MESH:C523798', (48, 53))	('YM155', 'Var', (48, 53))	('radiation-induced', 'CPA', (118, 135))	('ESCC', 'Disease', (80, 84))
16845	29258181	PRIMA-1 and PRIMA-1Met (APR-246): From Mutant/Wild Type p53 Reactivation to Unexpected Mechanisms Underlying Their Potent Anti-Tumor Effect in Combinatorial Therapies p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis.	('APR', 'Gene', (24, 27))	('apoptosis', 'CPA', (244, 253))	('PRIMA-1', 'Gene', '145270', (12, 19))	('PRIMA-1', 'Gene', (0, 7))	('PRIMA', 'Gene', '145270', (0, 5))	('p53', 'Gene', '7157', (167, 170))	('PRIMA', 'Gene', (12, 17))	('Tumor', 'Phenotype', 'HP:0002664', (127, 132))	('p53', 'Gene', '7157', (56, 59))	('p53', 'Gene', (167, 170))	('triggering', 'Reg', (211, 221))	('PRIMA-1', 'Gene', (12, 19))	('arrest', 'Disease', (233, 239))	('PRIMA', 'Gene', (0, 5))	('p53', 'Gene', (56, 59))	('Mutant/Wild', 'Var', (39, 50))	('PRIMA-1', 'Gene', '145270', (0, 7))	('PRIMA', 'Gene', '145270', (12, 17))	('APR', 'Gene', '5366', (24, 27))	('arrest', 'Disease', 'MESH:D006323', (233, 239))
16846	29258181	Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('degradation', 'MPA', (142, 153))	('protein', 'Protein', (161, 168))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('p53 pathway', 'Pathway', (16, 27))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('missense mutations', 'Var', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Inactivation', 'NegReg', (0, 12))	('human', 'Species', '9606', (61, 66))
16847	29258181	The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1Met (APR-246), that are at an advanced stage of development, with several clinical trials in progress.	('APR', 'Gene', (138, 141))	('APR', 'Gene', '5366', (138, 141))	('PRIMA-1Met', 'Var', (126, 136))
16849	29258181	p53, so called "the guardian of the genome", appears as a key factor in the carcinogenesis.	('p53', 'Var', (0, 3))	('carcinogenesis', 'Disease', (76, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))
16851	29258181	The outcome of mutations in the tumor suppressor gene p53 results in the loss of the wild-type p53 (wt-p53) activity and the gain of oncogenic functions such as resistance to apoptosis and escalation in genome instability.	('loss', 'NegReg', (73, 77))	('escalation', 'Reg', (189, 199))	('activity', 'MPA', (108, 116))	('gain', 'PosReg', (125, 129))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('p53', 'Gene', (54, 57))	('oncogenic functions', 'CPA', (133, 152))	('genome instability', 'CPA', (203, 221))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('resistance to apoptosis', 'CPA', (161, 184))
16852	29258181	In addition, such mutations push cancer cells to acquire new properties, promoting invasion, migration, angiogenesis, proliferation, genomic instability, or drug resistance.	('drug resistance', 'CPA', (157, 172))	('drug resistance', 'Phenotype', 'HP:0020174', (157, 172))	('rat', 'Species', '10116', (125, 128))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('promoting', 'PosReg', (73, 82))	('migration', 'CPA', (93, 102))	('proliferation', 'CPA', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('invasion', 'CPA', (83, 91))	('genomic instability', 'CPA', (133, 152))	('angiogenesis', 'CPA', (104, 116))	('rat', 'Species', '10116', (96, 99))	('mutations', 'Var', (18, 27))
16853	29258181	Mutant-p53 are, consequently, associated with aggressive tumor phenotypes and poor patient survival.	('associated', 'Reg', (30, 40))	('Mutant-p53', 'Var', (0, 10))	('aggressive tumor', 'Disease', 'MESH:D001523', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('patient', 'Species', '9606', (83, 90))	('aggressive tumor', 'Disease', (46, 62))
16862	29258181	Boecker et al., 2008 focused their studies on a specific hot mutation in p53 (Y220C) and they designed Y220C-targeting compounds based on in silico analysis of the crystal structure of the p53 core domain including PK083 and PK7088.	('PK7088', 'Var', (225, 231))	('Y220C', 'Mutation', 'rs121912666', (103, 108))	('PK083', 'Var', (215, 220))	('Y220C', 'Mutation', 'rs121912666', (78, 83))
16863	29258181	These molecules have shown to induce Y220C-dependent apoptosis in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Y220C', 'Mutation', 'rs121912666', (37, 42))	('induce', 'PosReg', (30, 36))	('tumor', 'Disease', (66, 71))	('Y220C-dependent', 'Var', (37, 52))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
16867	29258181	(2002) screened compounds that could suppress the proliferation of human tumor cells harboring mutation in p53.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('p53', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('proliferation', 'CPA', (50, 63))	('suppress', 'NegReg', (37, 45))	('tumor', 'Disease', (73, 78))	('rat', 'Species', '10116', (57, 60))	('human', 'Species', '9606', (67, 72))	('mutation', 'Var', (95, 103))
16887	29258181	Indeed, although the tested doses were cytotoxic for non-small cell lung cancer, prostate cancer or soft tissue sarcoma cell lines, neither modification of the cell cycle, nor apoptotic bodies under microscope evaluation, nor PARP cleavage were observed, regardless of the p53 status (wild type, mutated, or absent).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (53, 79))	('soft tissue sarcoma', 'Disease', (100, 119))	('prostate cancer', 'Disease', (81, 96))	('non-small cell lung cancer', 'Disease', (53, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (57, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (53, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (100, 119))	('cell cycle', 'CPA', (160, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('mutated', 'Var', (296, 303))
16888	29258181	To demonstrate the reactivation of mutant-p53 under PRIMA-1/APR-246 treatment, several points have been evaluated.	('mutant-p53', 'Var', (35, 45))	('PRIMA-1/APR-246', 'Gene', '145270', (52, 67))	('reactivation', 'MPA', (19, 31))	('PRIMA-1/APR-246', 'Gene', (52, 67))	('rat', 'Species', '10116', (10, 13))
16890	29258181	(2009) reported that both PRIMA-1 and APR-246 were converted in compounds, as MQ (methylene quinuclidinone), that reacted covalently with thiol groups of mutant, as well as wild-type p53.	('APR', 'Gene', '5366', (38, 41))	('methylene quinuclidinone', 'Chemical', '-', (82, 106))	('APR', 'Gene', (38, 41))	('thiol', 'Chemical', 'MESH:D013438', (138, 143))	('MQ', 'Chemical', '-', (78, 80))	('mutant', 'Var', (154, 160))
16892	29258181	Secondly, the effects on the p53 protein in mutant-p53 cells treated with PRIMA-1/APR-246, were assessed.	('mutant-p53', 'Var', (44, 54))	('PRIMA-1/APR-246', 'Gene', '145270', (74, 89))	('PRIMA-1/APR-246', 'Gene', (74, 89))
16894	29258181	Thirdly, the activity of p53 in cells with mutant-p53 treated with PRIMA-1/APR-246 has been explored.	('mutant-p53', 'Var', (43, 53))	('PRIMA-1/APR-246', 'Gene', '145270', (67, 82))	('PRIMA-1/APR-246', 'Gene', (67, 82))
16895	29258181	The restoration of transcriptional activity of mutant p53 has also been assessed.	('rat', 'Species', '10116', (9, 12))	('transcriptional activity', 'MPA', (19, 43))	('mutant', 'Var', (47, 53))	('p53', 'Gene', (54, 57))
16900	29258181	This dependency has been tested directly, introducing mutant-p53 protein previously treated with PRIMA-1 into cells without p53, using the Chariot protein transfer reagent: this introduction induced cell death, G2 cell cycle arrest, phosphorylation at Ser15, expression of Bax, PUMA, and Noxa, improvement of specific DNA binding, and/or caspases activation.	('induced', 'Reg', (191, 198))	('Noxa', 'Gene', '5366', (288, 292))	('Noxa', 'Gene', (288, 292))	('G2', 'CellLine', 'CVCL:Z793', (211, 213))	('cell death', 'CPA', (199, 209))	('Bax', 'Gene', '581', (273, 276))	('Bax', 'Gene', (273, 276))	('phosphorylation', 'MPA', (233, 248))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (214, 231))	('arrest', 'Disease', 'MESH:D006323', (225, 231))	('improvement', 'PosReg', (294, 305))	('mutant-p53', 'Var', (54, 64))	('activation', 'PosReg', (347, 357))	('arrest', 'Disease', (225, 231))	('caspases', 'Gene', (338, 346))	('specific DNA binding', 'Interaction', (309, 329))	('Ser15', 'Chemical', '-', (252, 257))	('caspases', 'Gene', '842', (338, 346))
16903	29258181	Although mutant-p53-dependency appeared to be verified in five studies for breast cancer and four studies for thyroid cancer, the conclusions must be nuanced because of several results were obtained using the same cell lines and by the same team (, and, respectively).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('thyroid cancer', 'Phenotype', 'HP:0002890', (110, 124))	('thyroid cancer', 'Disease', (110, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('thyroid cancer', 'Disease', 'MESH:D013964', (110, 124))	('mutant-p53-dependency', 'Var', (9, 30))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
16904	29258181	On the contrary, the mutant-p53-independency of PRIMA-1/APR-246 effects in myeloma cells were verified by three different teams, using varied cell lines.	('myeloma', 'Disease', (75, 82))	('PRIMA-1/APR-246', 'Gene', '145270', (48, 63))	('PRIMA-1/APR-246', 'Gene', (48, 63))	('mutant-p53-independency', 'Var', (21, 44))	('myeloma', 'Disease', 'MESH:D009101', (75, 82))
16905	29258181	Finally, it clearly appeared that PRIMA-1/APR-246 are tumor suppressor molecules, inducing apoptosis by the caspases activation in varied mutant-p53 cells.	('PRIMA-1/APR-246', 'Gene', (34, 49))	('apoptosis', 'CPA', (91, 100))	('mutant-p53', 'Var', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('caspases', 'Gene', (108, 116))	('inducing', 'PosReg', (82, 90))	('PRIMA-1/APR-246', 'Gene', '145270', (34, 49))	('tumor', 'Disease', (54, 59))	('activation', 'PosReg', (117, 127))	('caspases', 'Gene', '842', (108, 116))
16906	29258181	If the proof of its mutant-p53 reactivation property has also been made in several cancer models, the variability of the results incites to look forward other elements likely to influence the effects of PRIMA-1/APR-246, as a cell content dependency, or unexpected cytotoxic mechanisms.	('PRIMA-1/APR-246', 'Gene', '145270', (203, 218))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('PRIMA-1/APR-246', 'Gene', (203, 218))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('mutant-p53', 'Var', (20, 30))	('cancer', 'Disease', (83, 89))
16907	29258181	The possibility of effects of PRIMA-1/APR-246 that were different from apoptosis and mutant-p53 reactivation has been underlined by the use of cell lines without p53 (p53-null), or with a knock-down of p53 (p53-KD).	('knock-down', 'Var', (188, 198))	('PRIMA-1/APR-246', 'Gene', '145270', (30, 45))	('mutant-p53', 'Var', (85, 95))	('PRIMA-1/APR-246', 'Gene', (30, 45))
16920	29258181	On the contrary, the conversion of TrxR1 enzyme into a dedicated NADPH oxidase produced an increase oxidant activity.	('increase oxidant activity', 'Phenotype', 'HP:0025464', (91, 116))	('conversion', 'Var', (21, 31))	('TrxR1', 'Gene', (35, 40))	('increase', 'PosReg', (91, 99))	('TrxR1', 'Gene', '7296', (35, 40))	('oxidant activity', 'MPA', (100, 116))
16923	29258181	(2009) observed that APR-246 causes increased oxidation in a mutant p53-dependent manner.	('APR', 'Gene', (21, 24))	('APR', 'Gene', '5366', (21, 24))	('oxidation', 'MPA', (46, 55))	('p53-dependent', 'Gene', (68, 81))	('mutant', 'Var', (61, 67))
16924	29258181	The implication of mutant p53 proteins in the redox effects of APR-246 has been recently reported by Liu et al.	('APR', 'Gene', '5366', (63, 66))	('APR', 'Gene', (63, 66))	('p53', 'Gene', (26, 29))	('redox effects', 'MPA', (46, 59))	('mutant', 'Var', (19, 25))	('proteins', 'Protein', (30, 38))
16925	29258181	(2017), considering that mutant p53 sensitized tumor cells to APR-246 induced oxidative stress, inhibiting the glutathione synthesis through the inhibition of system xc.	('mutant', 'Var', (25, 31))	('oxidative stress', 'Phenotype', 'HP:0025464', (78, 94))	('APR', 'Gene', '5366', (62, 65))	('APR', 'Gene', (62, 65))	('system xc', 'Enzyme', (159, 168))	('glutathione synthesis', 'MPA', (111, 132))	('p53', 'Gene', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('glutathione', 'Chemical', 'MESH:D005978', (111, 122))	('oxidative stress', 'MPA', (78, 94))	('inhibiting', 'NegReg', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('sensitized', 'Reg', (36, 46))	('tumor', 'Disease', (47, 52))	('inhibition', 'NegReg', (145, 155))
16932	29258181	(2016), knocking-down CHOP, a specific factor mediating the ER stress-induced apoptosis, that led to a significant cytotoxicity decrease in p53-null cells.	('CHOP', 'Gene', '1649', (22, 26))	('knocking-down', 'Var', (8, 21))	('cytotoxicity', 'Disease', 'MESH:D064420', (115, 127))	('CHOP', 'Gene', (22, 26))	('decrease', 'NegReg', (128, 136))	('cytotoxicity', 'Disease', (115, 127))
16945	29258181	(2012), which demonstrated no effect of PRIMA-1 on thyroid cancer cells without p53, but with wild-type p73.	('p53', 'Var', (80, 83))	('thyroid cancer', 'Phenotype', 'HP:0002890', (51, 65))	('p73', 'Gene', '7161', (104, 107))	('thyroid cancer', 'Disease', 'MESH:D013964', (51, 65))	('p73', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('rat', 'Species', '10116', (21, 24))	('thyroid cancer', 'Disease', (51, 65))
16950	29258181	Basically, the chemotherapy drugs which lead to DNA damages and interfere with DNA synthesis were supposed to trigger p53 activation, and thus, to synergize with PRIMA-1/APR-246 in mutant-p53 cells.	('mutant-p53', 'Var', (181, 191))	('p53', 'Gene', (118, 121))	('PRIMA-1/APR-246', 'Gene', '145270', (162, 177))	('interfere', 'NegReg', (64, 73))	('activation', 'PosReg', (122, 132))	('DNA synthesis', 'MPA', (79, 92))	('PRIMA-1/APR-246', 'Gene', (162, 177))
16956	29258181	Similarly, with topo-isomerase inhibitors, the results of their association with PRIMA-1/APR-246 varied as a synergic effect was obtained in lung, colon and osteosarcoma cell lines with camptothecin, but not in pancreatic cancer with irinotecan.	('PRIMA-1/APR-246', 'Gene', (81, 96))	('osteosarcoma', 'Phenotype', 'HP:0002669', (157, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('pancreatic cancer', 'Disease', (211, 228))	('irinotecan', 'Chemical', 'MESH:D000077146', (234, 244))	('colon and osteosarcoma', 'Disease', 'MESH:D012516', (147, 169))	('camptothecin', 'Chemical', 'MESH:D002166', (186, 198))	('pancreatic cancer', 'Disease', 'MESH:D010190', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('PRIMA-1/APR-246', 'Gene', '145270', (81, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (211, 228))	('camptothecin', 'Var', (186, 198))	('association', 'Interaction', (64, 75))
16965	29258181	In pre-clinical studies, 3-BrPA, a halogenated pyruvate derivative and an alkylating agent, depleting the cellular ATP pool and inhibiting glycolysis, has been associated to PRIMA-1.	('glycolysis', 'MPA', (139, 149))	('3-BrPA', 'Var', (25, 31))	('cellular ATP pool', 'MPA', (106, 123))	('pyruvate', 'Chemical', 'MESH:D019289', (47, 55))	('3-BrPA', 'Chemical', '-', (25, 31))	('depleting', 'NegReg', (92, 101))	('PRIMA-1', 'Disease', (174, 181))	('inhibiting', 'NegReg', (128, 138))	('ATP', 'Chemical', 'MESH:D000255', (115, 118))
16966	29258181	The association led to an enhanced anti-proliferative effect in mutant KRAS (Kirsten rat sarcoma viral oncogene homolog) lung cancer and melanoma cells, and in mutant-p53 bladder cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('enhanced', 'PosReg', (26, 34))	('rat', 'Species', '10116', (85, 88))	('rat', 'Species', '10116', (47, 50))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('mutant', 'Var', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (171, 185))	('bladder cancer', 'Disease', (171, 185))	('lung cancer', 'Disease', (121, 132))	('sarcoma', 'Disease', 'MESH:D012509', (89, 96))	('sarcoma', 'Disease', (89, 96))	('mutant-p53', 'Var', (160, 170))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('KRAS', 'Gene', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('anti-proliferative effect', 'CPA', (35, 60))
16969	29258181	APR-246 sensitized to irradiation the mutant-p53, and p53-null cells, but had no impact on wt-p53 cells.	('APR', 'Gene', (0, 3))	('APR', 'Gene', '5366', (0, 3))	('sensitized', 'Reg', (8, 18))	('mutant-p53', 'Var', (38, 48))
16971	29258181	Combined with the PARP-inhibitor, olaparib, APR-246 sensitized lung cancer cell lines to the targeted therapy, independently of p53 status; besides, the combination restored the sensitivity to olaparib in mutant-p53 cells that were previously olaparib-resistant.	('APR', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('sensitivity', 'MPA', (178, 189))	('olaparib', 'Chemical', 'MESH:C531550', (34, 42))	('restored', 'PosReg', (165, 173))	('APR', 'Gene', '5366', (44, 47))	('lung cancer', 'Disease', (63, 74))	('mutant-p53', 'Var', (205, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('olaparib', 'Chemical', 'MESH:C531550', (193, 201))	('olaparib', 'Chemical', 'MESH:C531550', (243, 251))
16972	29258181	In breast cancer cell lines, the combination had a cytotoxic synergic effect in mutant p53 cells.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('mutant', 'Var', (80, 86))	('p53', 'Gene', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cytotoxic synergic effect', 'MPA', (51, 76))
16973	29258181	With the mTOR inhibitor, rapamycin, APR-246 had a cytotoxic synergic effect in a mutant-p53 AML cell line and in primary cultures.	('AML', 'Disease', 'MESH:D015470', (92, 95))	('mTOR', 'Gene', (9, 13))	('mTOR', 'Gene', '2475', (9, 13))	('mutant-p53', 'Var', (81, 91))	('cytotoxic', 'CPA', (50, 59))	('APR', 'Gene', '5366', (36, 39))	('AML', 'Phenotype', 'HP:0004808', (92, 95))	('AML', 'Disease', (92, 95))	('APR', 'Gene', (36, 39))
16975	29258181	Strikingly and similarly, p53 reactivation by APR-246 also broke intrinsic and acquired resistance and synergized with the MEK inhibitor pimasertib to induce massive apoptosis in NRAS-mutant melanoma cells with wild-type or mutant-p53, identifying MITF/Bcl-2 as a key mechanism underlying resistance of mutant-NRAS melanoma cells to apoptosis by MEK inhibitors and propose clinically relevant drug combinations able to prevent or reverse it.	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('melanoma', 'Disease', (191, 199))	('NRAS', 'Gene', '4893', (310, 314))	('p53', 'Gene', (26, 29))	('broke', 'NegReg', (59, 64))	('Bcl-2', 'Gene', '596', (253, 258))	('MITF', 'Gene', (248, 252))	('pimasertib', 'Chemical', 'MESH:C550600', (137, 147))	('melanoma', 'Disease', 'MESH:D008545', (315, 323))	('APR', 'Gene', (46, 49))	('MEK', 'Gene', '5609', (123, 126))	('MEK', 'Gene', '5609', (346, 349))	('NRAS', 'Gene', '4893', (179, 183))	('MEK', 'Gene', (346, 349))	('NRAS', 'Gene', (310, 314))	('MEK', 'Gene', (123, 126))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('induce', 'Reg', (151, 157))	('mutant-p53', 'Var', (224, 234))	('melanoma', 'Phenotype', 'HP:0002861', (315, 323))	('melanoma', 'Disease', (315, 323))	('Bcl-2', 'Gene', (253, 258))	('MITF', 'Gene', '4286', (248, 252))	('APR', 'Gene', '5366', (46, 49))	('NRAS', 'Gene', (179, 183))	('intrinsic', 'MPA', (65, 74))
16976	29258181	Combined with a tyrosine kinase inhibitor, erlotinib, PRIMA-1 synergized in mutant-p53 head and neck cancer and pancreas cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutant-p53', 'Var', (76, 86))	('head and neck cancer', 'Phenotype', 'HP:0012288', (87, 107))	('pancreas cancer', 'Disease', (112, 127))	('erlotinib', 'Chemical', 'MESH:D000069347', (43, 52))	('pancreas cancer', 'Disease', 'MESH:D010190', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('pancreas cancer', 'Phenotype', 'HP:0002894', (112, 127))	('head and neck cancer', 'Disease', 'MESH:D006258', (87, 107))
16977	29258181	The anti-tumoral effect of PRIMA-1/APR-246 was enhanced when combined to the proteasome inhibitor, bortezomib, in mutant-p53 pancreas cancer cells, in wt-p53 Waldenstrom cells and in myeloma cells, independently of p53 status, with a restoration to sensitivity in bortezomib-resistant cells.	('PRIMA-1/APR-246', 'Gene', '145270', (27, 42))	('pancreas cancer', 'Disease', 'MESH:D010190', (125, 140))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('enhanced', 'PosReg', (47, 55))	('bortezomib', 'Chemical', 'MESH:D000069286', (99, 109))	('pancreas cancer', 'Phenotype', 'HP:0002894', (125, 140))	('PRIMA-1/APR-246', 'Gene', (27, 42))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutant-p53', 'Var', (114, 124))	('bortezomib', 'Chemical', 'MESH:D000069286', (264, 274))	('rat', 'Species', '10116', (239, 242))	('myeloma', 'Disease', 'MESH:D009101', (183, 190))	('tumor', 'Disease', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('combined', 'Interaction', (61, 69))	('myeloma', 'Disease', (183, 190))	('pancreas cancer', 'Disease', (125, 140))
16978	29258181	According to the essential role of ROS production and glutathione content in PRIMA-1/APR-246 efficacy, associations between inhibitors of glutathione synthesis or cysteine transporter and PRIMA-1/APR-246 appear particularly relevant: thus, an inhibitor of the system xc, (cystine/glutamate antiporter), sulfasalazine, had a synergic anti-tumor effect with APR-246 in mutant p53 oesophageal adenocarcinoma cells and xenografts.	('APR', 'Gene', '5366', (85, 88))	('APR', 'Gene', '5366', (356, 359))	('APR', 'Gene', '5366', (196, 199))	('tumor', 'Disease', (338, 343))	('glutathione', 'Chemical', 'MESH:D005978', (138, 149))	('PRIMA-1/APR-246', 'Gene', '145270', (77, 92))	('mutant', 'Var', (367, 373))	('PRIMA-1/APR-246', 'Gene', '145270', (188, 203))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('APR', 'Gene', (85, 88))	('APR', 'Gene', (356, 359))	('APR', 'Gene', (196, 199))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (379, 404))	('oesophageal adenocarcinoma', 'Disease', (378, 404))	('carcinoma', 'Phenotype', 'HP:0030731', (395, 404))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (378, 404))	('PRIMA-1/APR-246', 'Gene', (77, 92))	('p53', 'Gene', (374, 377))	('PRIMA-1/APR-246', 'Gene', (188, 203))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('sulfasalazine', 'Chemical', 'MESH:D012460', (303, 316))	('glutathione', 'Chemical', 'MESH:D005978', (54, 65))	('cystine', 'Chemical', 'MESH:D003553', (272, 279))	('ROS', 'Chemical', 'MESH:D017382', (35, 38))
16981	29258181	In vivo, an increase of the anti-tumor impacts has been observed when PRIMA-1 was associated to Deazaneplanocin A (a negative regulator of polycomb group actions that inhibits histone methyltransferase activity) in mutant-p53 thyroid cancer xenografts, and with 2aG4 (a monoclonal anti-body that binds specifically to the surface of tumor blood vessels and disrupts tumor vasculature) in breast cancer xenografts.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (388, 401))	('histone methyltransferase activity', 'MPA', (176, 210))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('thyroid cancer', 'Disease', 'MESH:D013964', (226, 240))	('breast cancer', 'Disease', 'MESH:D001943', (388, 401))	('increase', 'PosReg', (12, 20))	('breast cancer', 'Disease', (388, 401))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', (33, 38))	('thyroid cancer', 'Phenotype', 'HP:0002890', (226, 240))	('tumor', 'Disease', (366, 371))	('disrupts tumor', 'Disease', (357, 371))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('mutant-p53', 'Var', (215, 225))	('tumor', 'Disease', (333, 338))	('cancer', 'Phenotype', 'HP:0002664', (395, 401))	('disrupts tumor', 'Disease', 'MESH:D019958', (357, 371))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('thyroid cancer', 'Disease', (226, 240))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('Deazaneplanocin A', 'Chemical', '-', (96, 113))	('inhibits', 'NegReg', (167, 175))
16982	29258181	Altogether, these multiple efficient associations between PRIMA-1 or APR-246 and anti-cancer treatments make conceivable to treat many malignant diseases, and in particular, tumor sub-types, currently associated with poor prognosis because of genetic profile (mutant p53, KRAS, or BRAF) or acquired resistance to treatment (doxorubicin, cisplatin, olaparib, bortezomib, or vemurafenib).	('APR', 'Gene', '5366', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('bortezomib', 'Chemical', 'MESH:D000069286', (358, 368))	('cisplatin', 'Disease', (337, 346))	('APR', 'Gene', (69, 72))	('olaparib', 'Chemical', 'MESH:C531550', (348, 356))	('doxorubicin', 'Chemical', 'MESH:D004317', (324, 335))	('vemurafenib', 'Chemical', 'MESH:D000077484', (373, 384))	('cancer', 'Disease', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutant', 'Var', (260, 266))	('tumor', 'Disease', (174, 179))	('malignant diseases', 'Disease', (135, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (337, 346))	('KRAS', 'CPA', (272, 276))	('BRAF', 'Gene', '673', (281, 285))	('BRAF', 'Gene', (281, 285))	('p53', 'Gene', (267, 270))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('malignant diseases', 'Disease', 'MESH:D009369', (135, 153))
16984	29258181	PRIMA-1 as well as APR-246 triggers an upregulation of genes involved in cell cycle control and apoptosis in mutant-p53 and wild-type p53 cancer cells.	('APR', 'Gene', (19, 22))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('upregulation', 'PosReg', (39, 51))	('cell cycle', 'CPA', (73, 83))	('mutant-p53', 'Var', (109, 119))	('APR', 'Gene', '5366', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
16986	29258181	Combined with chemotherapies, ionizing radiations or targeted therapies, PRIMA-1 and APR-246 could offer new perspectives to treat the more aggressive tumor sub-types such as mutant-cKIT metastatic melanoma, HPV (Human papillomavirus)-positive head and neck squamous cell carcinoma, and anaplastic thyroid cancer.	('Human papillomavirus', 'Species', '10566', (213, 233))	('APR', 'Gene', '5366', (85, 88))	('aggressive tumor', 'Disease', 'MESH:D001523', (140, 156))	('ionizing radiations', 'Disease', 'MESH:D004194', (30, 49))	('ionizing radiations', 'Disease', (30, 49))	('APR', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (287, 312))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('aggressive tumor', 'Disease', (140, 156))	('mutant-cKIT', 'Var', (175, 186))	('neck squamous cell carcinoma', 'Disease', (253, 281))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (287, 312))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (253, 281))	('HPV', 'Species', '10566', (208, 211))	('thyroid cancer', 'Phenotype', 'HP:0002890', (298, 312))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('anaplastic thyroid cancer', 'Disease', (287, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))
16988	29258181	Three clinical trials are currently recruiting, with the objectives to test the safety and efficacy of APR-246 treatment in advanced oesophageal carcinoma (NCT02999893), high grade serous ovarian cancer (NCT02098343), and mutant p53 hematologic myeloid malignant disease (NCT03072043).	('serous ovarian cancer', 'Disease', 'MESH:D010051', (181, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ovarian cancer', 'Phenotype', 'HP:0100615', (188, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('hematologic myeloid malignant disease', 'Disease', 'MESH:D019337', (233, 270))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (133, 154))	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (133, 154))	('p53', 'Gene', (229, 232))	('oesophageal carcinoma', 'Disease', (133, 154))	('APR', 'Gene', '5366', (103, 106))	('mutant', 'Var', (222, 228))	('APR', 'Gene', (103, 106))	('serous ovarian cancer', 'Disease', (181, 202))	('hematologic myeloid malignant disease', 'Disease', (233, 270))
16990	28152502	Methylation decreases the Bin1 tumor suppressor in ESCC and restoration by decitabine inhibits the epithelial mesenchymal transition Bridging integrator-1 (Bin1), as a tumor suppressor, is frequently attenuated or even abolished in multiple primary cancers.	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('cancers', 'Disease', (249, 256))	('ESCC', 'Disease', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('Bin1', 'Gene', '274', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Bridging integrator-1', 'Gene', (133, 154))	('Bin1', 'Gene', (156, 160))	('Methylation', 'Var', (0, 11))	('inhibits', 'NegReg', (86, 94))	('decreases', 'NegReg', (12, 21))	('tumor', 'Disease', (168, 173))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('decitabine', 'Chemical', 'MESH:D000077209', (75, 85))	('Bin1', 'Gene', '274', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (31, 36))	('Bin1', 'Gene', (26, 30))	('Bridging integrator-1', 'Gene', '274', (133, 154))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
16991	28152502	A reduced expression of Bin1 caused by DNA methylation, has been reported in breast and prostate cancers.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('prostate cancers', 'Phenotype', 'HP:0012125', (88, 104))	('breast and prostate cancers', 'Disease', 'MESH:D011471', (77, 104))	('expression', 'MPA', (10, 20))	('reduced', 'NegReg', (2, 9))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('DNA methylation', 'Var', (39, 54))	('Bin1', 'Gene', (24, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))
16993	28152502	In addition, the Bin1 hypermethylation was associated with the poorer clinical parameters and shorter survival times of ESCC patients.	('ESCC', 'Disease', (120, 124))	('shorter', 'NegReg', (94, 101))	('survival times', 'CPA', (102, 116))	('Bin1 hypermethylation', 'Var', (17, 38))	('patients', 'Species', '9606', (125, 133))
16995	28152502	In conclusion, these results demonstrated that Bin1 methylation could augment the malignant biological behaviors of ESCC and predict the poor prognosis for ESCC patients, thus indicating the potential clinical application value of DAC-based de-methylation therapy in ESCC.	('augment', 'PosReg', (70, 77))	('ESCC', 'Disease', (116, 120))	('DAC', 'Chemical', '-', (231, 234))	('Bin1', 'Gene', (47, 51))	('patients', 'Species', '9606', (161, 169))	('methylation', 'Var', (52, 63))	('malignant biological behaviors of', 'CPA', (82, 115))
17000	28152502	Therefore obtaining more knowledge of the associated mechanisms of aberrant tumor suppressor gene expression in ESCC tumorigenesis is urgently needed to initiate new therapeutic strategies.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('ESCC', 'Disease', (112, 116))	('aberrant', 'Var', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
17001	28152502	Growing evidence indicates that aberrant epigenetic alterations play an important role in carcinogenesis and cancer progression.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('aberrant epigenetic alterations', 'Var', (32, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('carcinogenesis', 'Disease', (90, 104))
17007	28152502	revealed that Bin1 deficiency might be a consequence of epigenetic alterations, such as methylation, which had been reported in prostate and breast cancers.	('Bin1 deficiency', 'Disease', 'MESH:D007153', (14, 29))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('methylation', 'Disease', (88, 99))	('breast cancers', 'Disease', (141, 155))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('prostate', 'Disease', (128, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('epigenetic alterations', 'Var', (56, 78))	('Bin1 deficiency', 'Disease', (14, 29))
17009	28152502	Then, we identified the prognostic roles of Bin1 methylation for ESCC patients.	('patients', 'Species', '9606', (70, 78))	('Bin1', 'Gene', (44, 48))	('ESCC', 'Disease', (65, 69))	('methylation', 'Var', (49, 60))
17015	28152502	The expression of methylated Bin1 was significantly related with the TNM stage, tumor differentiation grade, invasion range, and lymph node metastasis status but not with gender and age (Table 1).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('invasion range', 'CPA', (109, 123))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Bin1', 'Gene', (29, 33))	('TNM', 'Gene', '10178', (69, 72))	('lymph node metastasis status', 'CPA', (129, 157))	('expression', 'MPA', (4, 14))	('tumor', 'Disease', (80, 85))	('methylated', 'Var', (18, 28))	('TNM', 'Gene', (69, 72))	('related', 'Reg', (52, 59))
17016	28152502	ESCC patients with poor differentiation grade, high TNM stage (stage III+IV), deep tumor invasion (T3), and positive lymph node metastasis had significantly higher rate of methylated Bin1 than did those with well or moderate differentiation grade, low TNM stage (stage I and II), superficial tumor invasion (T1 and T2), and negative lymph node metastasis (Table 1).	('TNM', 'Gene', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('patients', 'Species', '9606', (5, 13))	('deep tumor', 'Disease', 'MESH:D057887', (78, 88))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (292, 297))	('methylated', 'Var', (172, 182))	('TNM', 'Gene', '10178', (52, 55))	('higher', 'PosReg', (157, 163))	('TNM', 'Gene', '10178', (252, 255))	('deep tumor', 'Disease', (78, 88))	('TNM', 'Gene', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('Bin1', 'Gene', (183, 187))	('poor differentiation', 'Var', (19, 39))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
17018	28152502	Univariate analysis indicated that the factors significantly associated with PFS were Bin1 methylation status, TNM stage, invasion depth, tumor differentiation grade and lymph node metastasis (all P < 0.01), whereas age and gender were not related to the PFS time of ESCC patients (P = 0.762; P = 0.499).	('lymph node metastasis', 'CPA', (170, 191))	('tumor', 'Disease', (138, 143))	('Bin1 methylation status', 'Var', (86, 109))	('PFS', 'Disease', (77, 80))	('TNM', 'Gene', '10178', (111, 114))	('patients', 'Species', '9606', (272, 280))	('invasion depth', 'CPA', (122, 136))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('associated', 'Reg', (61, 71))	('TNM', 'Gene', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
17019	28152502	Kaplan-Meier analysis showed that the PFS time of patients with Bin1 methylation was significantly shorter than that without methylation (P = 0.001; Figure 1C).	('shorter', 'NegReg', (99, 106))	('Bin1 methylation', 'Var', (64, 80))	('patients', 'Species', '9606', (50, 58))	('PFS time', 'CPA', (38, 46))
17021	28152502	Kaplan-Meier analysis indicated that the OS time of patients with methylation of Bin1 was significantly shorter than did those without methylation (P < 0.001; Figure 1D).	('methylation', 'Var', (66, 77))	('shorter', 'NegReg', (104, 111))	('Bin1', 'Gene', (81, 85))	('patients', 'Species', '9606', (52, 60))
17038	28152502	To understand whether Bin1 de-methylation directly inhibited the EMT-induced invasion and migration of ESCC cells, we detected the surface markers and phenotypic changes of DAC-treated ESCC cells.	('DAC', 'Chemical', '-', (173, 176))	('de-methylation', 'Var', (27, 41))	('EMT-induced invasion', 'CPA', (65, 85))	('Bin1', 'Gene', (22, 26))	('inhibited', 'NegReg', (51, 60))
17039	28152502	We treated YES-2 and TE13 cells with 90muM of DAC, and the qRT-PCR results showed DAC-restored expression of Bin1 remarkably inhibited the expression of mesenchymal markers (N-cadherin and Snail) and significantly up-regulated the expression of epithelial markers (E-cadherin) in YES-2 and TE13 cells (Figure 4A).	('Bin1', 'Gene', (109, 113))	('up-regulated', 'PosReg', (214, 226))	('Snail', 'Gene', '6615', (189, 194))	('DAC', 'Chemical', '-', (82, 85))	('YES-2', 'Gene', (11, 16))	('TE13', 'CellLine', 'CVCL:4463', (21, 25))	('expression', 'MPA', (231, 241))	('YES-2', 'Gene', (280, 285))	('TE13', 'CellLine', 'CVCL:4463', (290, 294))	('expression', 'MPA', (139, 149))	('muM', 'Gene', '56925', (39, 42))	('YES-2', 'Gene', '7526', (11, 16))	('muM', 'Gene', (39, 42))	('mesenchymal', 'CPA', (153, 164))	('DAC', 'Chemical', '-', (46, 49))	('N-cadherin', 'Gene', (174, 184))	('Snail', 'Gene', (189, 194))	('expression', 'Var', (95, 105))	('N-cadherin', 'Gene', '1000', (174, 184))	('YES-2', 'Gene', '7526', (280, 285))	('inhibited', 'NegReg', (125, 134))
17040	28152502	In addition, the western blot results also revealed that DAC-induced expression of Bin1 in YES-2 and TE13 cells inhibited typical EMT-like phenotypes, including the down-regulation of mesenchymal markers N-cadherin and Snail, and up-regulation of the epithelial markers E-cadherin.	('inhibited', 'NegReg', (112, 121))	('YES-2', 'Gene', (91, 96))	('N-cadherin', 'Gene', '1000', (204, 214))	('TE13', 'CellLine', 'CVCL:4463', (101, 105))	('DAC', 'Chemical', '-', (57, 60))	('YES-2', 'Gene', '7526', (91, 96))	('E-cadherin', 'Protein', (270, 280))	('Snail', 'Gene', (219, 224))	('Snail', 'Gene', '6615', (219, 224))	('N-cadherin', 'Gene', (204, 214))	('mesenchymal markers', 'CPA', (184, 203))	('Bin1', 'Gene', (83, 87))	('up-regulation', 'PosReg', (230, 243))	('down-regulation', 'NegReg', (165, 180))	('EMT-like phenotypes', 'CPA', (130, 149))	('expression', 'Var', (69, 79))
17049	28152502	In conclusion, the de-methylation of Bin1 inhibited the malignant activities of ESCC cells via inactivating invasion-related molecules MMP-2 and MMP-9, apoptosis-related molecule BCL-2 and activating apoptosis-associated molecule Bax.	('Bax', 'Gene', '581', (230, 233))	('malignant activities of ESCC cells', 'CPA', (56, 90))	('inactivating', 'NegReg', (95, 107))	('MMP-9', 'Gene', (145, 150))	('de-methylation', 'Var', (19, 33))	('Bin1', 'Gene', (37, 41))	('MMP-9', 'Gene', '4318', (145, 150))	('activating', 'PosReg', (189, 199))	('inhibited', 'NegReg', (42, 51))	('apoptosis-related', 'MPA', (152, 169))	('MMP-2', 'Gene', (135, 140))	('Bax', 'Gene', (230, 233))
17053	28152502	To further clarify these results, we examined whether the siRNA-mediated knockdown of Bin1 in DAC-treated YES-2 and TE13 cells could reactive PTEN/AKT signaling pathways.	('YES-2', 'Gene', (106, 111))	('TE13', 'CellLine', 'CVCL:4463', (116, 120))	('reactive', 'Reg', (133, 141))	('YES-2', 'Gene', '7526', (106, 111))	('PTEN/AKT signaling pathways', 'Pathway', (142, 169))	('DAC', 'Chemical', '-', (94, 97))	('Bin1', 'Gene', (86, 90))	('knockdown', 'Var', (73, 82))
17054	28152502	Silencing Bin1 with Bin1-siRNA in DAC-treated YES-2 and TE13 cells increased the expression of p-AKT and p-GSK-3beta and decreased the expression of PTEN compared with control cells (P < 0.01) (Figure 5B and 5C).	('PTEN', 'Protein', (149, 153))	('YES-2', 'Gene', '7526', (46, 51))	('GSK-3beta', 'Gene', '2932', (107, 116))	('GSK-3beta', 'Gene', (107, 116))	('TE13', 'CellLine', 'CVCL:4463', (56, 60))	('p-AKT', 'Protein', (95, 100))	('decreased', 'NegReg', (121, 130))	('increased', 'PosReg', (67, 76))	('expression', 'MPA', (135, 145))	('Bin1', 'Gene', (10, 14))	('DAC', 'Chemical', '-', (34, 37))	('YES-2', 'Gene', (46, 51))	('Silencing', 'Var', (0, 9))	('expression', 'MPA', (81, 91))
17057	28152502	Moreover, transwell migration and wound healing assays also indicated that Bin1 knockdown using siRNA significantly promoted the migration and invasion of DAC-treated YES-2 and TE13 cells (Figure 5D, 5E and 5F).	('knockdown', 'Var', (80, 89))	('promoted', 'PosReg', (116, 124))	('YES-2', 'Gene', (167, 172))	('invasion', 'CPA', (143, 151))	('migration', 'CPA', (129, 138))	('YES-2', 'Gene', '7526', (167, 172))	('Bin1', 'Gene', (75, 79))	('TE13', 'CellLine', 'CVCL:4463', (177, 181))	('DAC', 'Chemical', '-', (155, 158))
17067	28152502	Previous studies have demonstrated that the silencing of tumor-protective signature genes is one of the major causes of ESCC carcinogenesis and progression.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ESCC carcinogenesis', 'Disease', (120, 139))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('causes', 'Reg', (110, 116))	('silencing', 'Var', (44, 53))	('tumor', 'Disease', (57, 62))	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (120, 139))
17069	28152502	The silencing of tumor suppressor genes by DNA methylation is one of the mechanisms for most aggressive neoplasms and the poor overall prognosis in cancer patients.	('cancer', 'Disease', (148, 154))	('aggressive neoplasms', 'Disease', (93, 113))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('neoplasms', 'Phenotype', 'HP:0002664', (104, 113))	('tumor', 'Disease', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('aggressive neoplasms', 'Disease', 'MESH:D001523', (93, 113))	('DNA methylation', 'Var', (43, 58))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('patients', 'Species', '9606', (155, 163))	('silencing', 'NegReg', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
17070	28152502	Significantly, the methylation status of Bin1 was remarkably associated with poor differentiation grade, high TNM stage, deep tumor invasion, positive lymph node metastasis, and poor PFS and OS, indicating that the hypermethylation of Bin1 could be regarded as an independent predictor of the poor prognosis of ESCC patients.	('poor differentiation grade', 'CPA', (77, 103))	('positive lymph node metastasis', 'CPA', (142, 172))	('Bin1', 'Gene', (235, 239))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('methylation status', 'Var', (19, 37))	('TNM', 'Gene', '10178', (110, 113))	('ESCC', 'Disease', (311, 315))	('hypermethylation', 'Var', (215, 231))	('deep tumor', 'Disease', 'MESH:D057887', (121, 131))	('associated', 'Reg', (61, 71))	('Bin1', 'Gene', (41, 45))	('TNM', 'Gene', (110, 113))	('patients', 'Species', '9606', (316, 324))	('deep tumor', 'Disease', (121, 131))
17081	28152502	The present study indicated that DAC-restored Bin1 expression could inhibit the cell migration, invasion and EMT of ESCC cellss.	('Bin1', 'Gene', (46, 50))	('DAC', 'Chemical', '-', (33, 36))	('inhibit', 'NegReg', (68, 75))	('cell migration', 'CPA', (80, 94))	('invasion', 'CPA', (96, 104))	('EMT of ESCC cellss', 'CPA', (109, 127))	('expression', 'Var', (51, 61))
17083	28152502	Moreover, transfected Bin1-siRNA in DAC-treated YES-2 and TE13 cells could reactivate the PTEN/AKT pathway.	('TE13', 'CellLine', 'CVCL:4463', (58, 62))	('DAC', 'Chemical', '-', (36, 39))	('reactivate', 'Reg', (75, 85))	('transfected', 'Var', (10, 21))	('PTEN/AKT pathway', 'Pathway', (90, 106))	('YES-2', 'Gene', (48, 53))	('YES-2', 'Gene', '7526', (48, 53))
17087	28152502	These results demonstrated that the Bin1 methylation, primarily accounting for Bin1 attenuated expression, was closely related to the poorer clinicopathological characteristics and the worse survival of ESCC patients.	('patients', 'Species', '9606', (208, 216))	('Bin1', 'Gene', (36, 40))	('related', 'Reg', (119, 126))	('methylation', 'Var', (41, 52))	('ESCC', 'Disease', (203, 207))	('attenuated', 'NegReg', (84, 94))	('Bin1', 'Gene', (79, 83))	('expression', 'MPA', (95, 105))
17088	28152502	Therefore, de-methylation treatment with Decitabine could neutralize these malignant activities including EMT by restoring Bin1 expression.	('de-methylation', 'Var', (11, 25))	('Decitabine', 'Chemical', 'MESH:D000077209', (41, 51))	('Bin1', 'Gene', (123, 127))	('expression', 'MPA', (128, 138))	('restoring', 'PosReg', (113, 122))	('EMT', 'CPA', (106, 109))
17089	28152502	Moreover, we also observed that Bin1 could inhibit EMT and invasion via inactivating PTEN/AKT signaling pathway and suppressing MMP-2 and MMP-9.	('MMP-9', 'Gene', '4318', (138, 143))	('Bin1', 'Var', (32, 36))	('PTEN/AKT signaling pathway', 'Pathway', (85, 111))	('MMP-9', 'Gene', (138, 143))	('inhibit', 'NegReg', (43, 50))	('suppressing', 'NegReg', (116, 127))	('MMP-2', 'CPA', (128, 133))	('inactivating', 'NegReg', (72, 84))
17090	28152502	The present study revealed the potential role of Bin1 methylation in ESCC carcinogenesis, suggesting that the DAC-based restoration of Bin1 could be a potential therapeutic strategy for improving the prognosis of ESCC patients.	('DAC', 'Chemical', '-', (110, 113))	('Bin1', 'Gene', (135, 139))	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (69, 88))	('patients', 'Species', '9606', (218, 226))	('ESCC', 'Disease', (213, 217))	('ESCC carcinogenesis', 'Disease', (69, 88))	('restoration', 'Var', (120, 131))
17189	27923268	In most studies, it has been reported that salt and salty foods can increase the incidence of this cancer, while the consumption of fruits, fresh vegetables, and fish can have a protective effect.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('salt', 'Var', (43, 47))	('increase', 'PosReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('salty foods', 'Phenotype', 'HP:0030083', (52, 63))
17216	27923268	Physical activity and maintaining an ideal weight can lead to a significant decrease in the incidence of colorectal cancer, as physically active people are 20 to 30% less affected by this cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('people', 'Species', '9606', (145, 151))	('Physical', 'Var', (0, 8))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('decrease', 'NegReg', (76, 84))	('colorectal cancer', 'Disease', (105, 122))
17258	27794582	Interestingly, exogenous PUFA may be associated with prevention of some cancers.	('PUFA', 'Protein', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('prevention', 'NegReg', (53, 63))	('exogenous', 'Var', (15, 24))	('PUFA', 'Chemical', 'MESH:D005231', (25, 29))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
17300	27794582	It was suggested that the FAS expression is of functional importance in human esophageal tumorigenesis, and that inhibiting FAS might be applied to treat esophageal cancer.	('FAS', 'Gene', '2194', (124, 127))	('FAS', 'Gene', (124, 127))	('esophageal cancer', 'Disease', (154, 171))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('human', 'Species', '9606', (72, 77))	('FAS', 'Gene', '2194', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('FAS', 'Gene', (26, 29))	('inhibiting', 'Var', (113, 123))	('tumor', 'Disease', (89, 94))
17335	27794582	It was recently found that cisplatin in adult C57Bl/6J male mice caused a decrease in the lipogenic enzymes FAS and SCD1 in liver, white adipose tissue (WAT), and muscle; concurrently, cisplatin increased lipolysis in WAT and beta-oxidation in liver and WAT.	('FAS', 'Gene', (108, 111))	('WAT', 'Disease', (254, 257))	('decrease', 'NegReg', (74, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('WAT', 'Disease', 'None', (153, 156))	('FAS', 'Gene', '2194', (108, 111))	('WAT', 'Disease', 'None', (218, 221))	('lipolysis', 'MPA', (205, 214))	('cisplatin', 'Var', (185, 194))	('SCD1', 'Enzyme', (116, 120))	('beta-oxidation', 'MPA', (226, 240))	('WAT', 'Disease', (153, 156))	('WAT', 'Disease', 'None', (254, 257))	('WAT', 'Disease', (218, 221))	('cisplatin', 'Var', (27, 36))	('increased', 'PosReg', (195, 204))	('mice', 'Species', '10090', (60, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))
17350	27628042	Recent evidence had suggested that deregulation of miR-424-5p took an important role in cancers.	('miR-424', 'Gene', (51, 58))	('deregulation', 'Var', (35, 47))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('miR-424', 'Gene', '494336', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
17364	27628042	Furthermore, the abnormal expression of microRNAs has also been shown to be associated with tumor development.	('expression', 'MPA', (26, 36))	('microRNAs', 'Protein', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('associated', 'Reg', (76, 86))	('tumor', 'Disease', (92, 97))	('abnormal', 'Var', (17, 25))
17365	27628042	In addition, abnormal microRNAs expression has also been implicated in affecting metastatic and progression stage of cancers by the acquisition of metastatic potential.	('affecting', 'Reg', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('implicated', 'Reg', (57, 67))	('microRNAs', 'Protein', (22, 31))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('progression stage', 'CPA', (96, 113))	('metastatic', 'CPA', (81, 91))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('abnormal', 'Var', (13, 21))	('metastatic potential', 'CPA', (147, 167))	('expression', 'MPA', (32, 42))	('cancers', 'Disease', (117, 124))
17456	27628042	Furthermore, the three kinds of ESCC cell lines (EC9706, Eca109 and EC-1) we chose were also showed lower expression levels of miR-424-5p compared to that in SHEE cells, stating clearly that the loss of miR-424-5p might be a common event in tumorigenesis.	('miR-424', 'Gene', '494336', (127, 134))	('miR-424', 'Gene', (203, 210))	('tumor', 'Disease', (241, 246))	('miR-424', 'Gene', (127, 134))	('lower', 'NegReg', (100, 105))	('miR-424', 'Gene', '494336', (203, 210))	('EC-1', 'CellLine', 'CVCL:5V05', (68, 72))	('EC9706', 'CellLine', 'CVCL:E307', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('loss', 'Var', (195, 199))	('expression levels', 'MPA', (106, 123))	('HE', 'Chemical', '-', (159, 161))
17472	27628042	In the current study, we demonstrated that with the restoration of miR-424-5p, the expression of epithelial marker E-cadherin which was also a hall marker of the occurrence of EMT was increased while the expression of mesenchymal marker vimentin decreased.	('vimentin', 'Gene', '7431', (237, 245))	('vimentin', 'Gene', (237, 245))	('restoration', 'Var', (52, 63))	('increased', 'PosReg', (184, 193))	('miR-424', 'Gene', (67, 74))	('expression', 'MPA', (83, 93))	('expression', 'MPA', (204, 214))	('miR-424', 'Gene', '494336', (67, 74))	('E-cadherin', 'Gene', (115, 125))	('E-cadherin', 'Gene', '999', (115, 125))
17489	25317352	Our study suggests that BM can occur in patients with EC lesions smaller than those previously reported; moreover, SmCC may be a risk factor for BM from EC.	('risk factor', 'Reg', (129, 140))	('patients', 'Species', '9606', (40, 48))	('SmCC', 'Var', (115, 119))
17621	30186159	Moreover, we found that the addition of S3I-201, a STAT3 inhibitor, led to a decreased expression level of Bcl-2 in Eca109 cells.	('STAT3', 'Gene', '6774', (51, 56))	('Bcl-2', 'Gene', (107, 112))	('Bcl-2', 'Gene', '596', (107, 112))	('STAT3', 'Gene', (51, 56))	('decreased', 'NegReg', (77, 86))	('S3I-201', 'Var', (40, 47))	('S3I-201', 'Chemical', 'MESH:C520337', (40, 47))
17623	30186159	Furthermore, the mutation of four STAT3 binding sites (-1733/-1723, -1627/-1617, -807/-797, and -134/-124) on the promote of Bcl-2 gene alone attenuated the transcriptional activation of STAT3.	('STAT3', 'Gene', (34, 39))	('Bcl-2', 'Gene', (125, 130))	('STAT3', 'Gene', '6774', (187, 192))	('Bcl-2', 'Gene', '596', (125, 130))	('STAT3', 'Gene', (187, 192))	('-1733/-1723', 'Var', (55, 66))	('attenuated', 'NegReg', (142, 152))	('STAT3', 'Gene', '6774', (34, 39))	('transcriptional activation', 'MPA', (157, 183))
17644	30186159	Many modifications of curcumin have been explored with an aim to improve its potency and biochemical properties.	('potency', 'MPA', (77, 84))	('curcumin', 'Chemical', 'MESH:D003474', (22, 30))	('biochemical', 'MPA', (89, 100))	('improve', 'PosReg', (65, 72))	('modifications', 'Var', (5, 18))
17654	30186159	Antibodies against caspase-3 (#9662), poly(ADP-ribose) polymerase (PARP) (#9542s), Bcl-2 (#2870s), Bcl-xL (#2764), Bax (#2772s), Bid (#8762), p38 (#8690), p-p38 (#9211s), ERK (#4695), p-ERK (#T202), STAT3 (#9139), p-STAT3 (Tyr705) (#9145), JAK2 (#3230p), p-JAK2 (Tyr1007/1008) (#3776s), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (#5174) were purchased from Cell Signaling Technology (Beverly, MA, United States).	('Bax', 'Gene', (115, 118))	('ERK', 'Gene', '5594', (186, 189))	('Bcl-xL', 'Gene', (99, 105))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (291, 331))	('JAK2', 'Gene', (240, 244))	('ERK', 'Gene', (171, 174))	('p38', 'Gene', '1432', (142, 145))	('Bax', 'Gene', '581', (115, 118))	('STAT3', 'Gene', '6774', (199, 204))	('Bcl-xL', 'Gene', '598', (99, 105))	('#9145', 'Var', (232, 237))	('Bid', 'Gene', (129, 132))	('Bcl-2', 'Gene', (83, 88))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (291, 331))	('p38', 'Gene', '1432', (157, 160))	('ERK', 'Gene', (186, 189))	('PARP', 'Gene', '142', (67, 71))	('GAPDH', 'Gene', '2597', (333, 338))	('Bcl-2', 'Gene', '596', (83, 88))	('PARP', 'Gene', (67, 71))	('#9139', 'Var', (206, 211))	('JAK2', 'Gene', '3717', (257, 261))	('caspase-3', 'Gene', '836', (19, 28))	('STAT3', 'Gene', (216, 221))	('GAPDH', 'Gene', (333, 338))	('p38', 'Gene', (142, 145))	('Bid', 'Gene', '637', (129, 132))	('caspase-3', 'Gene', (19, 28))	('poly(ADP-ribose) polymerase', 'Gene', '142', (38, 65))	('poly(ADP-ribose) polymerase', 'Gene', (38, 65))	('JAK2', 'Gene', '3717', (240, 244))	('STAT3', 'Gene', '6774', (216, 221))	('ERK', 'Gene', '5594', (171, 174))	('JAK2', 'Gene', (257, 261))	('STAT3', 'Gene', (199, 204))	('p38', 'Gene', (157, 160))
17680	30186159	In further experiments, Eca109 cells (40,000/ml) with STAT3 overexpression were incubated with S3I-201 (100 muM), a STAT3 inhibitor, for 48 h to evaluate the inhibitory effect of S3I-201.	('S3I-201', 'Chemical', 'MESH:C520337', (95, 102))	('S3I-201', 'Chemical', 'MESH:C520337', (179, 186))	('overexpression', 'PosReg', (60, 74))	('muM', 'Gene', '56925', (108, 111))	('STAT3', 'Gene', '6774', (54, 59))	('STAT3', 'Gene', '6774', (116, 121))	('STAT3', 'Gene', (54, 59))	('muM', 'Gene', (108, 111))	('STAT3', 'Gene', (116, 121))	('S3I-201', 'Var', (95, 102))
17695	30186159	Furthermore, at concentrations of 1.6 and 3.2 muM 2-pyridyl cyclohexanone caused cell death as indicated by Annexin V-FITC and Annexin V-FITC/PI staining.	('2-pyridyl', 'Var', (50, 59))	('cell death', 'CPA', (81, 91))	('Annexin V', 'Gene', '308', (127, 136))	('Annexin V', 'Gene', (127, 136))	('2-pyridyl cyclohexanone', 'Chemical', '-', (50, 73))	('Annexin V', 'Gene', '308', (108, 117))	('muM', 'Gene', '56925', (46, 49))	('Annexin V', 'Gene', (108, 117))	('muM', 'Gene', (46, 49))
17696	30186159	In the Eca109 cells, 2-pyridyl cyclohexanone caused an increase in apoptotic cells at concentrations of 1.6 and 3.2 muM; however, it caused a relatively large increase in apoptotic cells (65.8%) at 3.2 muM.	('muM', 'Gene', '56925', (202, 205))	('muM', 'Gene', (116, 119))	('2-pyridyl cyclohexanone', 'Chemical', '-', (21, 44))	('muM', 'Gene', (202, 205))	('2-pyridyl cyclohexanone', 'Var', (21, 44))	('apoptotic cells', 'CPA', (67, 82))	('muM', 'Gene', '56925', (116, 119))	('increase', 'PosReg', (159, 167))	('apoptotic cells', 'CPA', (171, 186))
17699	30186159	Further confirmation that the cells were undergoing apoptosis was obtained by western blot analyses for caspases 3 and its substrate PARP proteins in the cell lines treated with 0.8, 1.6, or 3.2 muM 2-pyridyl cyclohexanone for 48 h. As seen in Figure 2C, 2-pyridyl cyclohexanone could induce the activation of caspase 3.	('PARP', 'Gene', (133, 137))	('2-pyridyl cyclohexanone', 'Chemical', '-', (199, 222))	('muM', 'Gene', '56925', (195, 198))	('muM', 'Gene', (195, 198))	('caspase 3', 'Gene', (310, 319))	('2-pyridyl cyclohexanone', 'Chemical', '-', (255, 278))	('caspase 3', 'Gene', '836', (310, 319))	('PARP', 'Gene', '142', (133, 137))	('2-pyridyl cyclohexanone', 'Var', (255, 278))
17726	30186159	Figure 8A showed point mutations created in Bcl-2.	('Bcl-2', 'Gene', (44, 49))	('Bcl-2', 'Gene', '596', (44, 49))	('point mutations', 'Var', (17, 32))
17727	30186159	As shown in Figure 8B, we observed the relative luciferase activity was 1.82, 1.76, 1.71, and 2.18 in promoter activity in the elements carrying each mutant region (Bcl-2), as compared with the wild-type promoter (3.40) in the Eca109 cells.	('activity', 'MPA', (59, 67))	('Bcl-2', 'Gene', (165, 170))	('promoter activity', 'MPA', (102, 119))	('luciferase', 'Enzyme', (48, 58))	('mutant', 'Var', (150, 156))	('Bcl-2', 'Gene', '596', (165, 170))
17730	30186159	S3I-201 blocks STAT3 function in cancer cells by binding to the STAT3 SH2 domain to disrupt STAT3 protein complexation events.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('STAT3', 'Gene', '6774', (15, 20))	('S3I-201', 'Chemical', 'MESH:C520337', (0, 7))	('binding', 'Interaction', (49, 56))	('STAT3', 'Gene', '6774', (92, 97))	('STAT3', 'Gene', (15, 20))	('STAT3', 'Gene', '6774', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('STAT3', 'Gene', (92, 97))	('disrupt', 'NegReg', (84, 91))	('blocks', 'NegReg', (8, 14))	('STAT3', 'Gene', (64, 69))	('S3I-201', 'Var', (0, 7))
17738	30186159	Accumulating evidences have shown that inhibition of constitutively active STAT3 leads to impaired cell survival and proliferation.	('impaired', 'NegReg', (90, 98))	('inhibition', 'Var', (39, 49))	('STAT3', 'Gene', '6774', (75, 80))	('STAT3', 'Gene', (75, 80))	('cell survival', 'CPA', (99, 112))
17758	30186159	These findings indicate that loss of Deltapsim plays an important role in 2-pyridyl-cyclohexanone-induced apoptosis of esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('apoptosis', 'CPA', (106, 115))	('2-pyridyl-cyclohexanone', 'Chemical', '-', (74, 97))	('esophageal cancer', 'Disease', (119, 136))	('loss', 'Var', (29, 33))	('2-pyridyl-cyclohexanone-induced', 'MPA', (74, 105))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Deltapsim', 'Protein', (37, 46))
17765	30186159	The ChIP experiments and luciferase assays indicate that promotor regions of Bcl-2 (-1733/-1723), Bcl-2 (-1627/-1617), Bcl-2 (-807/-797), and Bcl-2 (-134/-124) were binding sites for STAT3.	('STAT3', 'Gene', '6774', (183, 188))	('Bcl-2', 'Gene', (119, 124))	('Bcl-2', 'Gene', (142, 147))	('binding', 'Interaction', (165, 172))	('Bcl-2', 'Gene', '596', (142, 147))	('STAT3', 'Gene', (183, 188))	('-1627/-1617', 'Var', (105, 116))	('Bcl-2', 'Gene', '596', (119, 124))	('Bcl-2', 'Gene', (98, 103))	('-807/-797', 'Var', (126, 135))	('Bcl-2', 'Gene', '596', (98, 103))	('Bcl-2', 'Gene', (77, 82))	('Bcl-2', 'Gene', '596', (77, 82))	('-134/-124', 'Var', (149, 158))	('-1733/-1723', 'Var', (84, 95))
17769	30186159	As described in Figure 7, the expression levels of Bcl-2 reduced when we reduced the STAT3 expression levels with S3I-201 (STAT3 inhibitor).	('STAT3', 'Gene', (123, 128))	('Bcl-2', 'Gene', (51, 56))	('Bcl-2', 'Gene', '596', (51, 56))	('reduced', 'NegReg', (73, 80))	('S3I-201', 'Var', (114, 121))	('STAT3', 'Gene', '6774', (85, 90))	('S3I-201', 'Chemical', 'MESH:C520337', (114, 121))	('STAT3', 'Gene', '6774', (123, 128))	('STAT3', 'Gene', (85, 90))	('reduced', 'NegReg', (57, 64))	('expression levels', 'MPA', (30, 47))
17805	30112023	On the other hand, some reports suggest that the exposure to E. tirucalli crude can be a risk factor for Burkitt's lymphoma, since it act as a genotoxic agent, especially when it contains phorbol ester.	('lymphoma', 'Phenotype', 'HP:0002665', (115, 123))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (105, 123))	('E. tirucalli', 'Var', (61, 73))	("Burkitt's lymphoma", 'Disease', (105, 123))	('E. tirucalli', 'Species', '142860', (61, 73))	('phorbol ester', 'Chemical', 'MESH:D010703', (188, 201))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (105, 123))
17822	30112023	The MS spectra were recorded on a Perkin Elmer instrument, model API 150 and run in ES-MS positive mode: MH+ 427 m/e, MH+ _H2O 409 m/e.	('MH+ _H2O 409 m/e', 'Var', (118, 134))	('H2O', 'Chemical', 'MESH:D014867', (123, 126))	('MH+ 427 m/e', 'Var', (105, 116))
17862	30112023	Thus, comparing the effects on cell viability in concentrations of the same magnitude, euphol seemed to inhibit growth through a more cytotoxic than cytostatic fashion.	('inhibit', 'NegReg', (104, 111))	('euphol', 'Chemical', 'MESH:C062557', (87, 93))	('growth', 'CPA', (112, 118))	('euphol', 'Var', (87, 93))
17871	30112023	Panc-1 cells formed colonies on agar after 20 days of incubation, and the presence of euphol at IC50 value resulted in a significant suppression of number and size of colonies (P<0.05; Fig.	('euphol', 'Chemical', 'MESH:C062557', (86, 92))	('Panc-1', 'CellLine', 'CVCL:0480', (0, 6))	('IC50 value', 'Var', (96, 106))	('agar', 'Chemical', 'MESH:D000362', (32, 36))	('suppression', 'NegReg', (133, 144))
17894	30112023	The ERK pathway inhibitors PD98059 and U0126 inhibit the migration of diverse cell types in response to cell matrix proteins, such as fibronectin, vitronectin and collagen.	('U0126', 'Var', (39, 44))	('fibronectin', 'Gene', '2335', (134, 145))	('PD98059', 'Var', (27, 34))	('vitronectin', 'Gene', '7448', (147, 158))	('vitronectin', 'Gene', (147, 158))	('PD98059', 'Chemical', 'MESH:C093973', (27, 34))	('U0126', 'Chemical', 'MESH:C113580', (39, 44))	('migration of diverse cell types', 'CPA', (57, 88))	('inhibit', 'NegReg', (45, 52))	('fibronectin', 'Gene', (134, 145))	('ERK pathway', 'Pathway', (4, 15))
17895	30112023	Supporting a possible role of ERK inhibition on migration modulation by euphol, Passos et al, showed that, at the intracellular level, euphol reduced TPA-induced extracellular signal-regulated ERK activation in skin inflammation in mice.	('reduced', 'NegReg', (142, 149))	('skin inflammation', 'Disease', (211, 228))	('TPA', 'Chemical', 'MESH:D013755', (150, 153))	('activation', 'PosReg', (197, 207))	('skin inflammation', 'Phenotype', 'HP:0011123', (211, 228))	('euphol', 'Chemical', 'MESH:C062557', (72, 78))	('skin inflammation', 'Disease', 'MESH:D007249', (211, 228))	('euphol', 'Chemical', 'MESH:C062557', (135, 141))	('euphol', 'Var', (135, 141))	('TPA-induced extracellular signal-regulated ERK', 'MPA', (150, 196))	('mice', 'Species', '10090', (232, 236))
17898	30112023	In addition, we investigated the combination of euphol to chemotherapy in pancreas and esophageal cancer lines and we found that euphol when combined with a gemcitabine and paclitaxel treatment seems to have a synergistic effect (chemo-sensitization) leading to lower doses of therapeutic agents.	('euphol', 'Chemical', 'MESH:C062557', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gemcitabine', 'Chemical', 'MESH:C056507', (157, 168))	('euphol', 'Chemical', 'MESH:C062557', (48, 54))	('euphol', 'Var', (129, 135))	('paclitaxel', 'Chemical', 'MESH:D017239', (173, 183))	('lower', 'NegReg', (262, 267))	('pancreas and esophageal cancer', 'Disease', 'MESH:D004938', (74, 104))
17954	30011784	Moreover, hyperemia evoked by the reflux of gastric juice in rat esophagus was inhibited by ablation of capsaicin-sensitive sensory nerves by neurotoxic dose of capsaicin, this latter effect being reversed in part by the treatment of capsaicin-sensory inactivated rats with exogenous CGRP.	('rat', 'Species', '10116', (264, 267))	('reflux of gastric juice', 'MPA', (34, 57))	('neurotoxic', 'Disease', (142, 152))	('ablation', 'Var', (92, 100))	('capsaicin', 'Chemical', 'MESH:D002211', (104, 113))	('rat', 'Species', '10116', (61, 64))	('hyperemia', 'Disease', (10, 19))	('rats', 'Species', '10116', (264, 268))	('inhibited', 'NegReg', (79, 88))	('neurotoxic', 'Disease', 'MESH:D020258', (142, 152))	('reflux of gastric', 'Phenotype', 'HP:0002020', (34, 51))	('hyperemia', 'Disease', 'MESH:D006940', (10, 19))	('capsaicin', 'Chemical', 'MESH:D002211', (161, 170))	('capsaicin', 'Chemical', 'MESH:D002211', (234, 243))
17957	30011784	The major rationale behind this method is from one side, the reduction of the gastric capacity by ligation of the reservoir part of the stomach, but from the other side, the pylorus ligation to prevent the passage of the gastric contents into duodenum.	('prevent', 'NegReg', (194, 201))	('reduction', 'NegReg', (61, 70))	('rat', 'Species', '10116', (10, 13))	('ligation', 'Var', (98, 106))	('gastric capacity', 'MPA', (78, 94))	('passage of the gastric contents into duodenum', 'MPA', (206, 251))
17992	30011784	demonstrated that oral application of L-tryptophan causes a rapid elevation of circulating melatonin in rats.	('circulating melatonin', 'MPA', (79, 100))	('L-tryptophan', 'Chemical', 'MESH:D014364', (38, 50))	('L-tryptophan', 'Var', (38, 50))	('melatonin', 'Chemical', 'MESH:D008550', (91, 100))	('rats', 'Species', '10116', (104, 108))	('rat', 'Species', '10116', (7, 10))	('elevation', 'PosReg', (66, 75))	('rat', 'Species', '10116', (104, 107))
18007	30011784	Interestingly, L-tryptophan administered orally raised melatonin not only in the pineal gland, but also in the GI-tract and the liver by about 6 and 10-fold, respectively.	('melatonin', 'MPA', (55, 64))	('L-tryptophan', 'Var', (15, 27))	('L-tryptophan', 'Chemical', 'MESH:D014364', (15, 27))	('raised', 'PosReg', (48, 54))	('melatonin', 'Chemical', 'MESH:D008550', (55, 64))
18008	30011784	L-tryptophan also increased the circulating levels of melatonin, mainly in the portal circulation.	('L-tryptophan', 'Chemical', 'MESH:D014364', (0, 12))	('melatonin', 'Chemical', 'MESH:D008550', (54, 63))	('increased', 'PosReg', (18, 27))	('circulating levels of melatonin', 'MPA', (32, 63))	('L-tryptophan', 'Var', (0, 12))
18009	30011784	The local alterations in melatonin levels in the GI-tract following tryptophan application were unaffected by pinealectomy but significantly reduced by the partial occlusion of the portal vein.	('reduced', 'NegReg', (141, 148))	('partial occlusion', 'Var', (156, 173))	('melatonin', 'Chemical', 'MESH:D008550', (25, 34))	('tryptophan', 'Chemical', 'MESH:D014364', (68, 78))	('rat', 'Species', '10116', (14, 17))	('melatonin levels', 'MPA', (25, 41))
18023	30011784	Moreover, indomethacin, used at a dose suppressing the esophageal mucosal generation of PGE2 by about 75%, or L-NNA which blunted the plasma nitrate/nitrite (NOx) level by about 60%, were more effective in suppressing the generation of mucosal PGE2 and plasma levels of NOx, respectively, in animals treated with melatonin than in vehicle-treated control rats.	('L-NNA', 'Chemical', 'MESH:D019335', (110, 115))	('suppressing', 'NegReg', (39, 50))	('rat', 'Species', '10116', (144, 147))	('rat', 'Species', '10116', (78, 81))	('NOx', 'Chemical', 'MESH:C024270', (270, 273))	('PGE2', 'Chemical', 'MESH:D015232', (88, 92))	('NOx', 'Chemical', 'MESH:C024270', (158, 161))	('rat', 'Species', '10116', (355, 358))	('L-NNA', 'Var', (110, 115))	('nitrate', 'Chemical', 'MESH:D009566', (141, 148))	('melatonin', 'Chemical', 'MESH:D008550', (313, 322))	('rat', 'Species', '10116', (226, 229))	('plasma levels of NOx', 'MPA', (253, 273))	('PGE2', 'Chemical', 'MESH:D015232', (244, 248))	('indomethacin', 'Chemical', 'MESH:D007213', (10, 22))	('generation of mucosal PGE2', 'MPA', (222, 248))	('suppressing', 'NegReg', (206, 217))	('rats', 'Species', '10116', (355, 359))	('nitrite', 'Chemical', 'MESH:D009573', (149, 156))	('esophageal mucosal generation of PGE2', 'MPA', (55, 92))
18024	30011784	The functional ablation of sensory nerves by capsaicin has been found to abolish melatonin-induced esophagoprotection.	('ablation', 'Var', (15, 23))	('abolish', 'NegReg', (73, 80))	('capsaicin', 'Chemical', 'MESH:D002211', (45, 54))	('melatonin', 'Chemical', 'MESH:D008550', (81, 90))	('melatonin-induced esophagoprotection', 'MPA', (81, 117))
18025	30011784	Moreover, capsaicin deactivation of sensory nerves significantly attenuated the melatonin-induced increase in plasma NOx levels.	('capsaicin', 'Chemical', 'MESH:D002211', (10, 19))	('plasma NOx levels', 'MPA', (110, 127))	('NOx', 'Chemical', 'MESH:C024270', (117, 120))	('attenuated', 'NegReg', (65, 75))	('increase', 'PosReg', (98, 106))	('deactivation', 'Var', (20, 32))	('melatonin-induced', 'MPA', (80, 97))	('melatonin', 'Chemical', 'MESH:D008550', (80, 89))
18035	30011784	This is in keeping with the observation that reduced plasma levels of NOx in capsaicin denervated rats were reversed in part by co-treatment with melatonin or L-tryptophan.	('rats', 'Species', '10116', (98, 102))	('L-tryptophan', 'Var', (159, 171))	('L-tryptophan', 'Chemical', 'MESH:D014364', (159, 171))	('NOx', 'Chemical', 'MESH:C024270', (70, 73))	('plasma levels', 'MPA', (53, 66))	('capsaicin', 'Chemical', 'MESH:D002211', (77, 86))	('melatonin', 'Chemical', 'MESH:D008550', (146, 155))
18036	30011784	In another experimental model of GERD, the effect of exogenous administration of melatonin and melatonin-derived endogenously from L-tryptophan with that of pantoprazole or ranitidine was studied in rats with RE evoked by two ligations, namely, (1) pylorus ligation and (2) the ligation of the limiting ridge between the forestomach and the corpus.	('ranitidine', 'Chemical', 'MESH:D011899', (173, 183))	('rat', 'Species', '10116', (71, 74))	('rats', 'Species', '10116', (199, 203))	('melatonin', 'Chemical', 'MESH:D008550', (95, 104))	('melatonin', 'Chemical', 'MESH:D008550', (81, 90))	('L-tryptophan', 'Chemical', 'MESH:D014364', (131, 143))	('pantoprazole', 'Chemical', 'MESH:D000077402', (157, 169))	('pylorus', 'Disease', (249, 256))	('GERD', 'Disease', (33, 37))	('rat', 'Species', '10116', (199, 202))	('GERD', 'Disease', 'MESH:D005764', (33, 37))	('ligation', 'Var', (278, 286))
18062	30011784	This suggests that deficiency of this indoleamine may weaken esophageal and/or duodenal barrier mechanisms, thus exerting deleterious effects on the upper GI-tract mucosa.	('deficiency', 'Var', (19, 29))	('weaken', 'NegReg', (54, 60))	('effects', 'Reg', (134, 141))	('esophageal and/or', 'CPA', (61, 78))	('indoleamine', 'Chemical', 'MESH:C067042', (38, 49))
18075	30011784	However, the common side effect of long term PPI administration is hypergastrinemia followed by the upregulation of COX-2 expression and an increase in PG activity observed in BE.	('hypergastrinemia', 'Disease', (67, 83))	('expression', 'MPA', (122, 132))	('hypergastrinemia', 'Disease', 'None', (67, 83))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (67, 83))	('rat', 'Species', '10116', (57, 60))	('PPI', 'Var', (45, 48))	('COX-2', 'Gene', (116, 121))	('PG', 'Chemical', 'MESH:D011453', (152, 154))	('increase', 'PosReg', (140, 148))	('upregulation', 'PosReg', (100, 112))
18088	28930282	EAC is a heterogeneous cancer dominated by copy number alterations, a high mutational burden, co-amplification of receptor tyrosine kinase, frequent TP53 mutations.	('copy number alterations', 'Var', (43, 66))	('TP53', 'Gene', '7157', (149, 153))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('TP53', 'Gene', (149, 153))	('rat', 'Species', '10116', (59, 62))	('mutations', 'Var', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('EAC', 'Disease', (0, 3))
18109	28930282	Only an integrated genomic and cellular characterization at the level of single esophageal cancer, considering the major driver mutations, the tumor heterogeneity and the major biochemical pathways sustaining tumor survival and proliferation, may led to the identification of clinically suitable biomarkers and to drive the development of new multitargeting therapeutic approaches.	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', (143, 148))	('mutations', 'Var', (128, 137))	('clinical', 'Species', '191496', (276, 284))	('esophageal cancer', 'Disease', (80, 97))	('rat', 'Species', '10116', (235, 238))	('rat', 'Species', '10116', (13, 16))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('led to', 'Reg', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
18111	28930282	TP53 point mutations represent the most frequent gene mutations occurring in about 50% of cases, these mutations being detectable both in EAC and ESCC; TP53 mutations are detectable also in early metaplastic precancerous lesions.	('point mutations', 'Var', (5, 20))	('precancerous lesions', 'Disease', 'MESH:D011230', (208, 228))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('ESCC', 'Phenotype', 'HP:0011459', (146, 150))	('TP53', 'Gene', '7157', (152, 156))	('precancerous lesions', 'Disease', (208, 228))	('TP53', 'Gene', (152, 156))	('EAC', 'Phenotype', 'HP:0011459', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('detectable', 'Reg', (171, 181))	('ESCC', 'Disease', (146, 150))	('EAC', 'Disease', (138, 141))
18116	28930282	The two most significant tumor suppressors mutated in EAC are TP53 (72% of cases) and p16/CDKN2A (12% of cases).	('CDKN2A', 'Gene', '1029', (90, 96))	('EAC', 'Phenotype', 'HP:0011459', (54, 57))	('TP53', 'Gene', '7157', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('EAC', 'Disease', (54, 57))	('TP53', 'Gene', (62, 66))	('p16', 'Gene', (86, 89))	('CDKN2A', 'Gene', (90, 96))	('mutated', 'Var', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('p16', 'Gene', '1029', (86, 89))
18117	28930282	Among them, two significantly mutated genes are ELMO1 and DOCK2, encoding dimerization partners and intracellular mediators of the Rho family; ELMO1 or DOCK2 are mutated in 17% of cases, and their mutation determines an enhancement of cellular motility and favors tumor invasion.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('ELMO1', 'Gene', (48, 53))	('cellular motility', 'CPA', (235, 252))	('ELMO1', 'Gene', (143, 148))	('DOCK2', 'Gene', (152, 157))	('tumor', 'Disease', (264, 269))	('DOCK2', 'Gene', '1794', (58, 63))	('DOCK2', 'Gene', '1794', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('ELMO1', 'Gene', '9844', (48, 53))	('ELMO1', 'Gene', '9844', (143, 148))	('DOCK2', 'Gene', (58, 63))	('favors', 'PosReg', (257, 263))	('mutation', 'Var', (197, 205))	('enhancement', 'PosReg', (220, 231))
18120	28930282	Finally, TLR4 mutations are observed in 6% of EACs.	('EAC', 'Phenotype', 'HP:0011459', (46, 49))	('TLR4', 'Gene', '7099', (9, 13))	('TLR4', 'Gene', (9, 13))	('observed', 'Reg', (28, 36))	('mutations', 'Var', (14, 23))	('EACs', 'Disease', (46, 50))
18121	28930282	It is of interest to note that if one considers both gene mutations and gene amplifications, 48% of esophageal cancers have a genomic alteration in a pathway that can be pharmacologically targeted: this is the case for PI3KCCA, EGFR, ERBB2 and MET, just to mention the most frequently altered.	('rat', 'Species', '10116', (138, 141))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('PI3KCCA', 'Var', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('esophageal cancers', 'Disease', (100, 118))	('ERBB2', 'Gene', '2064', (234, 239))	('MET', 'Gene', (244, 247))	('ERBB2', 'Gene', (234, 239))	('esophageal cancers', 'Disease', 'MESH:D004938', (100, 118))	('EGFR', 'Gene', (228, 232))
18123	28930282	The extreme genomic instability observed in EAC could be derived by somatic BRCA2 mutations.	('BRCA2', 'Gene', (76, 81))	('EAC', 'Phenotype', 'HP:0011459', (44, 47))	('EAC', 'Disease', (44, 47))	('BRCA2', 'Gene', '675', (76, 81))	('mutations', 'Var', (82, 91))
18124	28930282	A very recent study provided a detailed whole genome sequencing analysis of EACs with the molecular characterization of 129 cases, showing that EAC is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('copy number alterations', 'Var', (187, 210))	('EAC', 'Disease', (144, 147))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))	('rat', 'Species', '10116', (203, 206))
18126	28930282	Somatic mobile element insertions were also frequent at the level of relevant genes: ERBB4 (about 5%); CTNNA3 (5%), CTNNA2 (3%); CDH 18 (3%) and SOX5 (2%).	('insertions', 'Var', (23, 33))	('ERBB4', 'Gene', (85, 90))	('ERBB4', 'Gene', '2066', (85, 90))	('SOX5', 'Gene', '6660', (145, 149))	('CDH 18', 'Gene', (129, 135))	('CTNNA2', 'Gene', '1496', (116, 122))	('CTNNA3', 'Gene', (103, 109))	('CTNNA3', 'Gene', '29119', (103, 109))	('CDH 18', 'Gene', '1016', (129, 135))	('SOX5', 'Gene', (145, 149))	('CTNNA2', 'Gene', (116, 122))
18128	28930282	The most frequent mutational events occurred at the level of TP53 (81%), ARID1A (17%), SMAD4 (16%), CDKN2A (15%), KCNQ3 (12%), CCDC 102B (9%) and CYP7B1 (7%).	('CDKN2A', 'Gene', '1029', (100, 106))	('mutational', 'Var', (18, 28))	('CYP7B1', 'Gene', '9420', (146, 152))	('TP53', 'Gene', '7157', (61, 65))	('CCDC 102B', 'Gene', (127, 136))	('SMAD4', 'Gene', '4089', (87, 92))	('CCDC 102B', 'Gene', '79839', (127, 136))	('CDKN2A', 'Gene', (100, 106))	('ARID1A', 'Gene', '8289', (73, 79))	('KCNQ3', 'Gene', (114, 119))	('ARID1A', 'Gene', (73, 79))	('CYP7B1', 'Gene', (146, 152))	('SMAD4', 'Gene', (87, 92))	('TP53', 'Gene', (61, 65))	('KCNQ3', 'Gene', '3786', (114, 119))
18130	28930282	In addition, genetic alterations are also frequent at the level of the downstream signaling pathways MAPK and PI3K.	('MAPK', 'Pathway', (101, 105))	('PI3K', 'Disease', (110, 114))	('rat', 'Species', '10116', (25, 28))	('frequent', 'Reg', (42, 50))	('genetic alterations', 'Var', (13, 32))
18131	28930282	Importantly, through the analysis of molecular signatures three distinct molecular subtypes with potential therapeutic relevance have been identified: (a) enrichment for BRCA signature with prevalent defects in the homologous recombinant pathway; (b) dominant T > G mutational pattern associated with a high mutational load and neoantigen burden; (c) C > A/T mutational pattern with evidence of an aging imprint.	('homologous recombinant pathway', 'Pathway', (215, 245))	('BRCA', 'Gene', '672', (170, 174))	('dominant T > G', 'Var', (251, 265))	('associated', 'Reg', (285, 295))	('BRCA', 'Gene', (170, 174))	('C > A/T', 'Var', (351, 358))
18134	28930282	Findlay and coworkers observed that the response of EAC genome to neo-adjuvant chemotherapy greatly varies: a group of poor responders EAC display only minor genomic changes following treatment; another group of patients displays multiple genetic driver mutations that variably increase or decrease in frequency following treatment, sometimes showing complete loss or gain; finally, a third group of patients was marked by clonal shifts, reminiscent of genetic bottlenecking.	('decrease', 'NegReg', (290, 298))	('increase', 'PosReg', (278, 286))	('patients', 'Species', '9606', (400, 408))	('patients', 'Species', '9606', (212, 220))	('loss or gain', 'Disease', 'MESH:D015430', (360, 372))	('loss or gain', 'Disease', (360, 372))	('EAC', 'Phenotype', 'HP:0011459', (52, 55))	('EAC', 'Phenotype', 'HP:0011459', (135, 138))	('mutations', 'Var', (254, 263))
18135	28930282	In this context, the behavior of p53-mutant cells may be considered paradigmatic: some cancers retain their p53 mutation after treatment; other cancers harbor multiple single nucleotide variation or copy number alterations that can be lost, gained or change in their frequency after treatment; finally, in other cancers, p53 mutations can be lost in the absence of CNAs, since the mutant p53 resides in tumor cell clones that are lost as they pass through a genetic bottleneck.	('tumor', 'Disease', 'MESH:D009369', (403, 408))	('rat', 'Species', '10116', (215, 218))	('cancers', 'Phenotype', 'HP:0002664', (312, 319))	('cancers', 'Disease', (312, 319))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('tumor', 'Phenotype', 'HP:0002664', (403, 408))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('p53', 'Gene', (388, 391))	('cancers', 'Disease', (144, 151))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('mutant', 'Var', (381, 387))	('cancers', 'Disease', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (312, 319))	('p53', 'Gene', (321, 324))	('tumor', 'Disease', (403, 408))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
18140	28930282	Initial studies have highlighted the low frequency (<5%) of K-Ras mutations in both esophageal adenocarcinomas and squamous carcinomas, while a high frequency (around 40%) was observed in colon cancer.	('mutations', 'Var', (66, 75))	('K-Ras', 'Gene', '3845', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('esophageal adenocarcinomas and squamous carcinomas', 'Disease', 'MESH:D000077277', (84, 134))	('colon cancer', 'Disease', 'MESH:D015179', (188, 200))	('colon cancer', 'Phenotype', 'HP:0003003', (188, 200))	('K-Ras', 'Gene', (60, 65))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (84, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('colon cancer', 'Disease', (188, 200))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (115, 133))
18142	28930282	As stated above, observational studies have indicated that a number of factors, including chronic gastro-esophageal reflux, cigarette smoking, obesity and Helicobacter pylori Cag A seronegativity account for the large majority (about 75%-80%) of esophageal adenocarcinomas.	('obesity', 'Phenotype', 'HP:0001513', (143, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (262, 272))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (246, 272))	('Helicobacter pylori', 'Species', '210', (155, 174))	('gastro-esophageal reflux', 'Disease', (98, 122))	('obesity', 'Disease', 'MESH:D009765', (143, 150))	('Helicobacter pylori', 'Disease', (155, 174))	('gastro-esophageal reflux', 'Disease', 'MESH:D005764', (98, 122))	('obesity', 'Disease', (143, 150))	('seronegativity', 'Var', (181, 195))	('esophageal adenocarcinomas', 'Disease', (246, 272))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (246, 271))	('esophageal reflux', 'Phenotype', 'HP:0002020', (105, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))
18155	28930282	Studies on the transition of Barrett's esophagus to EAC have initially focused on the alterations of p16 and TP53 genes.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (29, 48))	('p16', 'Gene', '1029', (101, 104))	('alterations', 'Var', (86, 97))	('TP53', 'Gene', '7157', (109, 113))	('EAC', 'Phenotype', 'HP:0011459', (52, 55))	('TP53', 'Gene', (109, 113))	('p16', 'Gene', (101, 104))	('rat', 'Species', '10116', (90, 93))
18156	28930282	One model proposed by Maley and coworkers suggests that an initial mutation (most commonly inactivation of p16) confers a selective advantage to a cell population and this mutation is present in most of cells of Barrett's esophagus; the acquisition of additional mutations (i.e., inactivating TP53 mutations) give rise to cell clones able to expand across the Barrett's lesion.	('cell clones', 'CPA', (322, 333))	("Barrett's lesion", 'Disease', 'MESH:D001471', (360, 376))	("Barrett's lesion", 'Disease', (360, 376))	('p16', 'Gene', '1029', (107, 110))	('TP53', 'Gene', '7157', (293, 297))	('inactivating', 'Var', (280, 292))	('TP53', 'Gene', (293, 297))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (212, 231))	('p16', 'Gene', (107, 110))	('mutations', 'Var', (298, 307))
18157	28930282	In this context, Agrawal and coworkers have performed exome sequencing on 11 EAC samples and 2 samples of Barrett's esophagus adjacent to the cancer; surprisingly, most of mutations were found to be present even in the Barrett's esophagus samples.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('mutations', 'Var', (172, 181))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('EAC', 'Disease', (77, 80))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (106, 125))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (219, 238))	('cancer', 'Disease', (142, 148))
18159	28930282	Thus, using whole-genome sequencing and amplicon sequencing, these authors have identified recurrent genetic alterations occurring in 112 EACs and in transition tumor lesions: Barrett's esophagus (66 cases) and high-grade dysplasia (43 cases).	('EACs', 'Disease', (138, 142))	('rat', 'Species', '10116', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('dysplasia', 'Disease', (222, 231))	('alterations', 'Var', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('EAC', 'Phenotype', 'HP:0011459', (138, 141))	("Barrett's esophagus", 'Disease', (176, 195))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (176, 195))	('dysplasia', 'Disease', 'MESH:D004476', (222, 231))	('tumor', 'Disease', (161, 166))
18160	28930282	Only TP53 and SMAD4 mutations occurred in a stage-specific manner, the first one being confined to high-grade dysplasia and the second-one to non-dysplastic Barrett's esophagus (Figure 2).	('SMAD4', 'Gene', '4089', (14, 19))	("non-dysplastic Barrett's esophagus", 'Disease', (142, 176))	('dysplasia', 'Disease', (110, 119))	('dysplasia', 'Disease', 'MESH:D004476', (110, 119))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (157, 176))	('SMAD4', 'Gene', (14, 19))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (142, 176))	('mutations', 'Var', (20, 29))
18161	28930282	These findings clearly indicate that the few cancer driver mutations characterizing EC occur early during esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (106, 131))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('mutations', 'Var', (59, 68))	('cancer', 'Disease', (45, 51))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (106, 131))
18165	28930282	These studies showed also that Barrett's esophagus is highly mutated even in the absence of dysplasia (6.76 mutations/Mb, a mutation rate higher than for many other tumors at an advanced stage of development).	('mutations/Mb', 'Var', (108, 120))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('absence of dysplasia', 'Disease', 'MESH:D004832', (81, 101))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('absence of dysplasia', 'Disease', (81, 101))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('rat', 'Species', '10116', (133, 136))	("Barrett's esophagus", 'Disease', (31, 50))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (31, 50))
18167	28930282	TP53 mutations were less common in Barrett's esophagus (39%) than in EAC (83%); similarly, other putative EAC driver genes, such as EYS, ARID1A and ABCB1, were mutated less commonly and are shared in only 28% of cases between paired Barrett's and EAC samples.	('TP53', 'Gene', '7157', (0, 4))	('ARID1A', 'Gene', '8289', (137, 143))	('TP53', 'Gene', (0, 4))	('ARID1A', 'Gene', (137, 143))	('EAC', 'Phenotype', 'HP:0011459', (247, 250))	('EAC', 'Phenotype', 'HP:0011459', (106, 109))	('mutations', 'Var', (5, 14))	('EYS', 'Gene', '346007', (132, 135))	('EYS', 'Gene', (132, 135))	('EAC', 'Phenotype', 'HP:0011459', (69, 72))	('ABCB1', 'Gene', (148, 153))	('ABCB1', 'Gene', '5243', (148, 153))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (35, 54))
18169	28930282	Another study published in parallel carried out on 25 pairs of Barrett's esophagus/EAC confirmed that the number of focal deletions and amplifications clearly increased during progression from Barrett's esophagus without dysplasia, to Barrett's esophagus with dysplasia and then to EAC.	('amplifications', 'Var', (136, 150))	('EAC', 'Disease', (282, 285))	("Barrett's esophagus", 'Disease', (235, 254))	('dysplasia', 'Disease', (221, 230))	("Barrett's esophagus", 'Disease', (193, 212))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (193, 212))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (235, 254))	('dysplasia', 'Disease', 'MESH:D004476', (221, 230))	('increased', 'PosReg', (159, 168))	('dysplasia', 'Disease', (260, 269))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (63, 82))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))	('EAC', 'Phenotype', 'HP:0011459', (282, 285))	('dysplasia', 'Disease', 'MESH:D004476', (260, 269))
18171	28930282	Particularly, mutations of genes encoding chromatin modifiers, cell cycle regulators and TGF-beta pathway are more common in non-genome doubled EAC, compared to those with genome doubled; in contrast, genome doubled EACs contain more frequent amplifications in cell cycle regulators and transcription factors (Figure 3).	('common', 'Reg', (115, 121))	('cell', 'Gene', (261, 265))	('EAC', 'Phenotype', 'HP:0011459', (216, 219))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('TGF-beta', 'Gene', '7040', (89, 97))	('mutations', 'Var', (14, 23))	('amplifications', 'MPA', (243, 257))	('TGF-beta', 'Gene', (89, 97))
18180	28930282	In some cases, TP53 mutation can lead to cancer development more rapidly through chromosomal catastrophe or genome doubling and genetic instability.	('lead to', 'Reg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('genetic instability', 'CPA', (128, 147))	('mutation', 'Var', (20, 28))	('chromosomal catastrophe', 'CPA', (81, 104))	('TP53', 'Gene', '7157', (15, 19))	('genome doubling', 'CPA', (108, 123))	('TP53', 'Gene', (15, 19))	('chromosomal catastrophe', 'Phenotype', 'HP:0040012', (81, 104))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
18181	28930282	Various genetic mutations have been identified in esophageal squamous cell cancers and many of them are associated with specific cellular pathways, such as cell cycle, apoptosis, DNA repair mechanisms, growth factor receptors.	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('mutations', 'Var', (16, 25))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (61, 82))	('associated', 'Reg', (104, 114))	('esophageal squamous cell cancers', 'Disease', (50, 82))	('apoptosis', 'CPA', (168, 177))	('esophageal squamous cell cancers', 'Disease', 'MESH:D002294', (50, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cell cycle', 'CPA', (156, 166))
18183	28930282	These authors have reported the comparative exome sequencing of 11 EACs and 12 ESCCs and observed that, while the mutational frequency at the level of the tumor suppressor TP53 was similar (73% in EAC and 92% in ESCC), NOTCH1 and NOTCH3 mutations were much more frequent among ESCC (33 and 25%, respectively) than EAC (0 and 9%, respectively).	('tumor', 'Disease', (155, 160))	('NOTCH3', 'Gene', (230, 236))	('EAC', 'Phenotype', 'HP:0011459', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('TP53', 'Gene', (172, 176))	('NOTCH1', 'Gene', (219, 225))	('frequent', 'Reg', (262, 270))	('EAC', 'Phenotype', 'HP:0011459', (67, 70))	('mutations', 'Var', (237, 246))	('ESCC', 'Phenotype', 'HP:0011459', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('rat', 'Species', '10116', (37, 40))	('NOTCH1', 'Gene', '4851', (219, 225))	('ESCC', 'Phenotype', 'HP:0011459', (277, 281))	('ESCC', 'Phenotype', 'HP:0011459', (212, 216))	('EAC', 'Phenotype', 'HP:0011459', (314, 317))	('TP53', 'Gene', '7157', (172, 176))	('ESCC', 'Disease', (277, 281))	('NOTCH3', 'Gene', '4854', (230, 236))
18184	28930282	According to these findings these authors have explored NOTCH1 mutations in two larger groups ESCC patients, originating from two different geographical areas and observed a frequency of NOTCH1 mutations markedly higher in Northern American ESCCs (11 of 53 cases) than in Chinese ESCCs (1 of 48 cases).	('ESCC', 'Phenotype', 'HP:0011459', (241, 245))	('ESCC', 'Phenotype', 'HP:0011459', (94, 98))	('NOTCH1', 'Gene', (187, 193))	('ESCC', 'Phenotype', 'HP:0011459', (280, 284))	('mutations', 'Var', (194, 203))	('higher', 'PosReg', (213, 219))	('patients', 'Species', '9606', (99, 107))	('NOTCH1', 'Gene', '4851', (56, 62))	('NOTCH1', 'Gene', (56, 62))	('NOTCH1', 'Gene', '4851', (187, 193))
18185	28930282	Now, the significance and the origin of this consistent geographic variation in the frequency of NOTCH1 mutations are largely unknown.	('NOTCH1', 'Gene', '4851', (97, 103))	('NOTCH1', 'Gene', (97, 103))	('mutations', 'Var', (104, 113))
18186	28930282	More recently, Chen and coworkers explored the occurrence and the possible functional implications of NOTCH 1 mutations and NOTCH pathway mutations in ESCC cancer development and progression.	('ESCC cancer', 'Disease', 'MESH:D004938', (151, 162))	('ESCC cancer', 'Disease', (151, 162))	('mutations', 'Var', (110, 119))	('NOTCH pathway', 'Gene', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('NOTCH 1', 'Gene', (102, 109))	('ESCC', 'Phenotype', 'HP:0011459', (151, 155))	('NOTCH 1', 'Gene', '4851', (102, 109))	('mutations', 'Var', (138, 147))
18187	28930282	These authors reported a frequency of NOTCH1 mutations in Chinese stage III ESCCs corresponding to 8%.	('mutations', 'Var', (45, 54))	('NOTCH1', 'Gene', '4851', (38, 44))	('NOTCH1', 'Gene', (38, 44))	('ESCC', 'Phenotype', 'HP:0011459', (76, 80))
18188	28930282	Interestingly, the frequency of NOTCH1 mutations was markedly higher for stage I ESCC patients, corresponding to 35%.	('NOTCH1', 'Gene', '4851', (32, 38))	('NOTCH1', 'Gene', (32, 38))	('stage I ESCC', 'Disease', (73, 85))	('mutations', 'Var', (39, 48))	('ESCC', 'Phenotype', 'HP:0011459', (81, 85))	('higher', 'Reg', (62, 68))	('patients', 'Species', '9606', (86, 94))
18189	28930282	Mutations of the whole NOTCH pathway were observed in 55% of stage I tumors, versus 32% of stage III tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('I tumors', 'Disease', 'MESH:D009369', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('I tumors', 'Disease', 'MESH:D009369', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('observed', 'Reg', (42, 50))	('Mutations', 'Var', (0, 9))	('III tumors', 'Disease', 'MESH:D009369', (97, 107))	('NOTCH pathway', 'Pathway', (23, 36))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('I tumors', 'Disease', (67, 75))	('III tumors', 'Disease', (97, 107))
18190	28930282	According to these findings, it was concluded that NOTCH alterations are an early event in ESCC pathogenesis, playing an important role in early stages of tumor development.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ESCC', 'Disease', (91, 95))	('tumor', 'Disease', (155, 160))	('rat', 'Species', '10116', (61, 64))	('NOTCH alterations', 'Var', (51, 68))	('ESCC', 'Phenotype', 'HP:0011459', (91, 95))
18193	28930282	In spite the not frequent NOTCH mutations in EAC, the NOTCH pathway is frequently activated in EAC due to impairment of the TGF-beta signaling.	('EAC', 'Phenotype', 'HP:0011459', (95, 98))	('activated', 'PosReg', (82, 91))	('TGF-beta', 'Gene', (124, 132))	('NOTCH pathway', 'Pathway', (54, 67))	('EAC', 'Disease', (95, 98))	('mutations', 'Var', (32, 41))	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('TGF-beta', 'Gene', '7040', (124, 132))
18194	28930282	In fact, an impairment of the TGF-beta signaling pathway was frequently observed in Barrett's metaplasia-dysplasia and esophageal carcinoma due to the frequent downmodulation of Smad4 related to various mechanisms, including promoter methylation, gene deletion and protein modification.	('Smad4', 'Gene', (178, 183))	("Barrett's metaplasia-dysplasia", 'Disease', 'MESH:D001471', (84, 114))	('observed', 'Reg', (72, 80))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (119, 139))	('Smad4', 'Gene', '4089', (178, 183))	('gene deletion', 'Var', (247, 260))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (119, 139))	('downmodulation', 'NegReg', (160, 174))	('promoter methylation', 'Var', (225, 245))	('TGF-beta', 'Gene', '7040', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	("Barrett's metaplasia-dysplasia", 'Disease', (84, 114))	('protein modification', 'Var', (265, 285))	('TGF-beta', 'Gene', (30, 38))	('esophageal carcinoma', 'Disease', (119, 139))
18197	28930282	EGFR is overexpressed at protein level in about 50% of ESCCs and in about 30% of cases this gene is amplified; interestingly, EGFR overexpression and TP53 mutations are very frequent in precancerous lesions and TP53 mutations are correlated with EGFR overexpression.	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('EGFR', 'Gene', (126, 130))	('precancerous lesions', 'Disease', (186, 206))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('TP53', 'Gene', '7157', (211, 215))	('TP53', 'Gene', (211, 215))	('mutations', 'Var', (216, 225))	('TP53', 'Gene', '7157', (150, 154))	('overexpression', 'PosReg', (131, 145))	('precancerous lesions', 'Disease', 'MESH:D011230', (186, 206))	('ESCC', 'Phenotype', 'HP:0011459', (55, 59))
18198	28930282	In line with these findings, EGFR overexpression and p53 mutations are necessary and sufficient to transform epithelial esophageal cells, leading to increased cell motility, anchorage independent growth, and tumor formation in nude mice.	('nude mice', 'Species', '10090', (227, 236))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('increased', 'PosReg', (149, 158))	('anchorage independent growth', 'CPA', (174, 202))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('mutations', 'Var', (57, 66))	('p53', 'Gene', (53, 56))	('EGFR', 'Gene', (29, 33))	('tumor', 'Disease', (208, 213))	('cell motility', 'CPA', (159, 172))
18200	28930282	P16INK4a expression is frequently reduced in ESCC and this is due to various mechanisms, including aberrant p16INK4a gene methylation observed in 62% of cases, loss of heterozygosity of the p16INK4a gene observed in 13% of cases, mutations of the p16INK4a gene observed in 6% of cases.	('p16INK4a', 'Gene', (190, 198))	('methylation', 'MPA', (122, 133))	('p16INK4a', 'Gene', '1029', (108, 116))	('reduced', 'NegReg', (34, 41))	('P16INK4a', 'Gene', (0, 8))	('ESCC', 'Phenotype', 'HP:0011459', (45, 49))	('p16INK4a', 'Gene', (247, 255))	('p16INK4a', 'Gene', '1029', (190, 198))	('expression', 'MPA', (9, 19))	('ESCC', 'Disease', (45, 49))	('p16INK4a', 'Gene', (108, 116))	('P16INK4a', 'Gene', '1029', (0, 8))	('p16INK4a', 'Gene', '1029', (247, 255))	('loss of heterozygosity', 'Var', (160, 182))
18202	28930282	In initial studies mutations of the PI3KCA gene, which encodes the p110alpha catalytic subunit of PI3K have been reported in 2%-12% of ESCC patients.	('ESCC', 'Disease', (135, 139))	('ESCC', 'Phenotype', 'HP:0011459', (135, 139))	('mutations', 'Var', (19, 28))	('patients', 'Species', '9606', (140, 148))	('reported', 'Reg', (113, 121))	('PI3KCA', 'Gene', (36, 42))
18203	28930282	Recently, the occurrence and the prognostic impact of PI3KCA mutations was analyzed in many ESCC patients, showing that PI3KCA mutations were detected in 21% of patients and, compared with wild-type PI3KCA patients, these patients displayed a better prognosis, as analyzed in disease-free survival and overall survival.	('ESCC', 'Disease', (92, 96))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (206, 214))	('ESCC', 'Phenotype', 'HP:0011459', (92, 96))	('mutations', 'Var', (127, 136))	('PI3KCA', 'Gene', (120, 126))	('patients', 'Species', '9606', (97, 105))
18211	28930282	A copy gain number of SOX2 gene was observed in 15% of ESCC patients and SOX2 protein was overexpressed in 70% of ESCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('SOX2', 'Gene', '6657', (73, 77))	('SOX2', 'Gene', (73, 77))	('copy', 'Var', (2, 6))	('patients', 'Species', '9606', (60, 68))	('ESCC', 'Phenotype', 'HP:0011459', (114, 118))	('overexpressed', 'PosReg', (90, 103))	('ESCC tumors', 'Disease', (114, 125))	('SOX2', 'Gene', '6657', (22, 26))	('SOX2', 'Gene', (22, 26))	('ESCC', 'Disease', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ESCC tumors', 'Disease', 'MESH:D004938', (114, 125))	('ESCC', 'Phenotype', 'HP:0011459', (55, 59))
18217	28930282	A first study by Lin and coworkers provided evidence about the recurrent mutation of TP53, PIK3CA, NOTCH1, FAT1, FAT2, ZNF750 and KTM2D genes in Chinese ESCC primary tumor samples.	('PIK3CA', 'Gene', (91, 97))	('TP53', 'Gene', (85, 89))	('FAT2', 'Gene', (113, 117))	('ZNF750', 'Gene', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('FAT1', 'Gene', '2195', (107, 111))	('FAT1', 'Gene', (107, 111))	('NOTCH1', 'Gene', '4851', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('PIK3CA', 'Gene', '5290', (91, 97))	('ESCC', 'Phenotype', 'HP:0011459', (153, 157))	('NOTCH1', 'Gene', (99, 105))	('tumor', 'Disease', (166, 171))	('ZNF750', 'Gene', '79755', (119, 125))	('TP53', 'Gene', '7157', (85, 89))	('mutation', 'Var', (73, 81))	('FAT2', 'Gene', '2196', (113, 117))
18219	28930282	This analysis provided evidence about recurrent mutations at the level of: six well known tumor-associated genes, such as TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2; two not previously reported genes, such as ADAM29 and FAM135B; six histone regulator genes, such as MLL2 (KMTD2), MLL3 (KMT2C), ASH1L, SETD1B, CREBBP and EP300.	('ASH1L', 'Gene', '55870', (293, 298))	('MLL2', 'Gene', (265, 269))	('NFE2L2', 'Gene', '4780', (157, 163))	('ADAM29', 'Gene', (208, 214))	('FAM135B', 'Gene', '51059', (219, 226))	('RB1', 'Gene', '5925', (128, 131))	('CREBBP', 'Gene', '1387', (308, 314))	('CDKN2A', 'Gene', '1029', (133, 139))	('mutations', 'Var', (48, 57))	('NOTCH1', 'Gene', (149, 155))	('SETD1B', 'Gene', '23067', (300, 306))	('ADAM29', 'Gene', '11086', (208, 214))	('tumor', 'Disease', (90, 95))	('NFE2L2', 'Gene', (157, 163))	('PIK3CA', 'Gene', '5290', (141, 147))	('NOTCH1', 'Gene', '4851', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('TP53', 'Gene', (122, 126))	('FAM135B', 'Gene', (219, 226))	('EP300', 'Gene', '2033', (319, 324))	('MLL3', 'Gene', '58508', (279, 283))	('KMT2C', 'Gene', '58508', (285, 290))	('KMT2C', 'Gene', (285, 290))	('EP300', 'Gene', (319, 324))	('ASH1L', 'Gene', (293, 298))	('RB1', 'Gene', (128, 131))	('CREBBP', 'Gene', (308, 314))	('SETD1B', 'Gene', (300, 306))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CDKN2A', 'Gene', (133, 139))	('MLL3', 'Gene', (279, 283))	('PIK3CA', 'Gene', (141, 147))	('MLL2', 'Gene', '8085', (265, 269))	('TP53', 'Gene', '7157', (122, 126))
18222	28930282	This fundamental analysis showed that: (a) genes involved in the regulation of apoptosis and cell cycle are mutated in virtually all cases (99%): TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%); (b) histone regulatory genes are frequently mutated: KMTD2 (9%), KMT2C (6%), KDM6A (7%), EP300 (10%) and CREBBP (6%); (c) the Hippo pathway is frequently deregulated due to mutations in FAT1, FAT2, FAT3 or FAT4 (27%); (d) the NOTCH pathway is frequently deregulated by mutations inn NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%) (Figure 1).	('EP300', 'Gene', (301, 306))	('NOTCH2', 'Gene', '4853', (503, 509))	('FAT3', 'Gene', '120114', (410, 414))	('CREBBP', 'Gene', '1387', (317, 323))	('FAT4', 'Gene', (418, 422))	('FAT2', 'Gene', (404, 408))	('KDM6A', 'Gene', (289, 294))	('CDKN2A', 'Gene', '1029', (171, 177))	('FAT1', 'Gene', '2195', (398, 402))	('NOTCH3', 'Gene', '4854', (513, 519))	('Hippo pathway', 'Pathway', (338, 351))	('TP53', 'Gene', (146, 150))	('deregulated', 'Reg', (366, 377))	('NOTCH3', 'Gene', (513, 519))	('FBXW7', 'Gene', (529, 534))	('NOTCH2', 'Gene', (503, 509))	('RB1', 'Gene', (202, 205))	('CCND1', 'Gene', '595', (158, 163))	('KMT2C', 'Gene', '58508', (277, 282))	('KMT2C', 'Gene', (277, 282))	('NFE2L2', 'Gene', '4780', (185, 191))	('FAT4', 'Gene', '79633', (418, 422))	('CCND1', 'Gene', (158, 163))	('FAT2', 'Gene', '2196', (404, 408))	('FAT1', 'Gene', (398, 402))	('CREBBP', 'Gene', (317, 323))	('NOTCH1', 'Gene', (495, 501))	('FAT3', 'Gene', (410, 414))	('mutations', 'Var', (481, 490))	('KDM6A', 'Gene', '7403', (289, 294))	('EP300', 'Gene', '2033', (301, 306))	('TP53', 'Gene', '7157', (146, 150))	('FBXW7', 'Gene', '55294', (529, 534))	('RB1', 'Gene', '5925', (202, 205))	('CDKN2A', 'Gene', (171, 177))	('NOTCH pathway', 'Pathway', (438, 451))	('deregulated', 'Reg', (466, 477))	('NFE2L2', 'Gene', (185, 191))	('NOTCH1', 'Gene', '4851', (495, 501))	('mutations', 'Var', (385, 394))
18223	28930282	The structural variations frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('structural variations', 'Var', (4, 25))	('disruption', 'NegReg', (44, 54))	('led to', 'Reg', (37, 43))	('CDKN2A', 'Gene', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('NOTCH1', 'Gene', '4851', (100, 106))	('CDKN2A', 'Gene', '1029', (89, 95))	('cancer', 'Disease', (58, 64))	('NOTCH1', 'Gene', (100, 106))
18225	28930282	Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC.	('ESCC', 'Disease', (190, 194))	('CDCA7', 'Gene', (142, 147))	('whole-genome duplication', 'Var', (74, 98))	('ESCC', 'Phenotype', 'HP:0011459', (190, 194))	('rat', 'Species', '10116', (41, 44))	('CDCA7', 'Gene', '83879', (142, 147))
18228	28930282	A high proportion of mutations in these patients were C to G/T substitutions with a flanking 5' thymine ("APOBEC signature").	('patients', 'Species', '9606', (40, 48))	('C to G/T', 'Var', (54, 62))	('BE', 'Phenotype', 'HP:0100580', (109, 111))	('mutations', 'Var', (21, 30))
18231	28930282	In addition, frequent CNAs were observed at the level of TERT (amplification, 23%), PCDH (amplification 13%), LRP1B (deletion 21%), FOXA1 (amplification, 8%), FAM190A (deletion, 8%), HOXA cluster (amplification, 4%).	('HOXA', 'Gene', '3197', (183, 187))	('FOXA1', 'Gene', '3169', (132, 137))	('TERT', 'Gene', (57, 61))	('FAM190A', 'Gene', '401145', (159, 166))	('TERT', 'Gene', '7015', (57, 61))	('LRP1B', 'Gene', '53353', (110, 115))	('FAM190A', 'Gene', (159, 166))	('FOXA1', 'Gene', (132, 137))	('PCDH', 'Gene', (84, 88))	('LRP1B', 'Gene', (110, 115))	('HOXA', 'Gene', (183, 187))	('deletion', 'Var', (117, 125))
18232	28930282	The biochemical pathways most frequently deregulated in ESCC for the occurrence of genetic alterations are the cell cycle pathway (98%), epigenetic regulation pathway (59%), the NOTCH (33%) and RTK/PI3K pathway (32%).	('ESCC', 'Disease', (56, 60))	('deregulated', 'Reg', (41, 52))	('genetic alterations', 'Var', (83, 102))	('ESCC', 'Phenotype', 'HP:0011459', (56, 60))	('rat', 'Species', '10116', (95, 98))	('RTK/PI3K pathway', 'Pathway', (194, 210))	('NOTCH', 'Pathway', (178, 183))	('epigenetic regulation pathway', 'Pathway', (137, 166))	('cell cycle pathway', 'Pathway', (111, 129))	('biochemical pathways', 'Pathway', (4, 24))
18235	28930282	A recent study characterized at molecular level a population of sub-Saharan ESCC and showed in these patients, similar genetic aberrations as those reported in Asian and North American cohorts, including frequent mutations of TP53, CDKN2A, NFE2L2, CHEK2, NOTCH1, FAT1 and FBXW7.	('CHEK2', 'Gene', '11200', (248, 253))	('patients', 'Species', '9606', (101, 109))	('rat', 'Species', '10116', (131, 134))	('CDKN2A', 'Gene', (232, 238))	('CHEK2', 'Gene', (248, 253))	('FAT1', 'Gene', '2195', (263, 267))	('FBXW7', 'Gene', '55294', (272, 277))	('ESCC', 'Phenotype', 'HP:0011459', (76, 80))	('NFE2L2', 'Gene', '4780', (240, 246))	('CDKN2A', 'Gene', '1029', (232, 238))	('FBXW7', 'Gene', (272, 277))	('FAT1', 'Gene', (263, 267))	('NOTCH1', 'Gene', (255, 261))	('NOTCH1', 'Gene', '4851', (255, 261))	('NFE2L2', 'Gene', (240, 246))	('mutations', 'Var', (213, 222))	('TP53', 'Gene', '7157', (226, 230))	('TP53', 'Gene', (226, 230))
18238	28930282	Through this extensive analysis, they identified a mutational signature unique in ESCC, linker to alcohol intake and genetic variants in alcohol-metabolizing enzymes; the alcohol-driven ESCCs were characterized by a high frequency of mutations at the level of TP53, EP300, PTCH1, NOTCH3, TGFBR2 and ZNF750.	('ESCC', 'Phenotype', 'HP:0011459', (186, 190))	('TGFBR2', 'Gene', '7048', (288, 294))	('ESCC', 'Phenotype', 'HP:0011459', (82, 86))	('EP300', 'Gene', '2033', (266, 271))	('ZNF750', 'Gene', '79755', (299, 305))	('TP53', 'Gene', (260, 264))	('ZNF750', 'Gene', (299, 305))	('PTCH1', 'Gene', '5727', (273, 278))	('TGFBR2', 'Gene', (288, 294))	('EP300', 'Gene', (266, 271))	('NOTCH3', 'Gene', '4854', (280, 286))	('alcohol', 'Chemical', 'MESH:D000438', (171, 178))	('NOTCH3', 'Gene', (280, 286))	('mutations', 'Var', (234, 243))	('TP53', 'Gene', '7157', (260, 264))	('PTCH1', 'Gene', (273, 278))	('alcohol', 'Chemical', 'MESH:D000438', (98, 105))	('alcohol', 'Chemical', 'MESH:D000438', (137, 144))	('ESCCs', 'Disease', (186, 191))
18240	28930282	Another recent study identified some mutations preferentially associated with ESCCs with lymph node metastases.	('metastases', 'Disease', (100, 110))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('ESCCs', 'Disease', (78, 83))	('associated with', 'Reg', (62, 77))	('mutations', 'Var', (37, 46))	('ESCC', 'Phenotype', 'HP:0011459', (78, 82))
18241	28930282	Metastatic ESCCs harbor frequent TP53, KMT2D, ZNF750 and IRF5 mutations; among these mutations, ZNF50 mutations were clearly more frequent in ESCC with lymph node metastasis than in those without metastasis.	('ESCC', 'Phenotype', 'HP:0011459', (142, 146))	('KMT2D', 'Gene', (39, 44))	('KMT2D', 'Gene', '8085', (39, 44))	('ESCC', 'Phenotype', 'HP:0011459', (11, 15))	('IRF5', 'Gene', (57, 61))	('frequent', 'Reg', (130, 138))	('TP53', 'Gene', '7157', (33, 37))	('ZNF750', 'Gene', '79755', (46, 52))	('mutations', 'Var', (102, 111))	('IRF5', 'Gene', '3663', (57, 61))	('TP53', 'Gene', (33, 37))	('ZNF50', 'Gene', '342945', (96, 101))	('ESCC', 'Disease', (142, 146))	('ZNF50', 'Gene', (96, 101))	('ZNF750', 'Gene', (46, 52))	('mutations', 'Var', (62, 71))
18243	28930282	Cao and coworkers profiled the mutations and copy number alterations that were identified in multiple regions within an ESCC from two patients.	('mutations', 'Var', (31, 40))	('copy number alterations', 'Var', (45, 68))	('patients', 'Species', '9606', (134, 142))	('ESCC', 'Disease', (120, 124))	('rat', 'Species', '10116', (61, 64))	('ESCC', 'Phenotype', 'HP:0011459', (120, 124))
18244	28930282	The average mutational heterogeneity was 90% in all regions of each tumor in each patient.	('tumor', 'Disease', (68, 73))	('patient', 'Species', '9606', (82, 89))	('mutational', 'Var', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
18249	28930282	Phylogenetic tree construction, based on the results of multiregion whole-exome sequencing, allowed to establish that most of truncal and clonal driver mutations occurred in tumor-suppressor genes, such as TP53, KMT2D and ZNI750; in contrast, half of the driver mutations located on the branches of tumor phylogenetic trees involve oncogenes, such as PIK3CA, NFE2L2, KIT and mTOR (Figure 4).	('mutations', 'Var', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutations', 'Var', (262, 271))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('TP53', 'Gene', '7157', (206, 210))	('mTOR', 'Gene', (375, 379))	('PIK3CA', 'Gene', (351, 357))	('NFE2L2', 'Gene', '4780', (359, 365))	('KMT2D', 'Gene', (212, 217))	('KIT', 'Gene', (367, 370))	('mTOR', 'Gene', '2475', (375, 379))	('NFE2L2', 'Gene', (359, 365))	('tumor', 'Disease', (174, 179))	('TP53', 'Gene', (206, 210))	('tumor', 'Disease', (299, 304))	('KMT2D', 'Gene', '8085', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('PIK3CA', 'Gene', '5290', (351, 357))
18255	28930282	Thus, Dulak and coworkers observed a higher number of focal amplifications in the upper gastrointestinal adenocarcinomas (esophagus and stomach), compared to colon/rectal cancers.	('upper gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (82, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('colon/rectal cancers', 'Disease', 'MESH:D012004', (158, 178))	('colon/rectal cancers', 'Disease', (158, 178))	('upper gastrointestinal adenocarcinomas', 'Disease', (82, 120))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('focal amplifications', 'Var', (54, 74))
18265	28930282	SNCAs recurrent in EACs, but absent in ESCC, were amplifications of VEGFA, ERBB2, GATA6 and CCNE1 and deletion of SMAD4; in contrast, recurrent focal SNCAs in ESCCs included amplifications of SOX2, TERT, FGFR1, MDM2, NKX2-1 and deletion of RB1, VGLL4 and ATG7.	('MDM2', 'Gene', (211, 215))	('VEGFA', 'Gene', (68, 73))	('FGFR1', 'Gene', '2260', (204, 209))	('TERT', 'Gene', '7015', (198, 202))	('ERBB2', 'Gene', '2064', (75, 80))	('GATA6', 'Gene', (82, 87))	('NKX2-1', 'Gene', '7080', (217, 223))	('VGLL4', 'Gene', (245, 250))	('SMAD4', 'Gene', '4089', (114, 119))	('RB1', 'Gene', '5925', (240, 243))	('SOX2', 'Gene', '6657', (192, 196))	('ATG7', 'Gene', (255, 259))	('MDM2', 'Gene', '4193', (211, 215))	('SOX2', 'Gene', (192, 196))	('NKX2-1', 'Gene', (217, 223))	('amplifications', 'Var', (174, 188))	('CCNE1', 'Gene', (92, 97))	('VEGFA', 'Gene', '7422', (68, 73))	('VGLL4', 'Gene', '9686', (245, 250))	('FGFR1', 'Gene', (204, 209))	('CCNE1', 'Gene', '898', (92, 97))	('ESCC', 'Phenotype', 'HP:0011459', (159, 163))	('deletion', 'Var', (228, 236))	('GATA6', 'Gene', '2627', (82, 87))	('ESCC', 'Phenotype', 'HP:0011459', (39, 43))	('SMAD4', 'Gene', (114, 119))	('RB1', 'Gene', (240, 243))	('ERBB2', 'Gene', (75, 80))	('EAC', 'Phenotype', 'HP:0011459', (19, 22))	('ATG7', 'Gene', '10533', (255, 259))	('TERT', 'Gene', (198, 202))
18266	28930282	The analysis of the mutational profile confirmed frequent mutations of TP53, NFE2L2, MLL2, ZNF750, NOTCH1 and TGFBR2 in ESCC, while in EAC frequent are the mutations of TP53, CDKN2A, ARID1A, SMAD4 and ERBB2.	('ERBB2', 'Gene', (201, 206))	('mutations', 'Var', (58, 67))	('SMAD4', 'Gene', (191, 196))	('TP53', 'Gene', '7157', (169, 173))	('EAC', 'Phenotype', 'HP:0011459', (135, 138))	('ERBB2', 'Gene', '2064', (201, 206))	('NFE2L2', 'Gene', (77, 83))	('CDKN2A', 'Gene', (175, 181))	('ZNF750', 'Gene', '79755', (91, 97))	('ESCC', 'Phenotype', 'HP:0011459', (120, 124))	('TP53', 'Gene', '7157', (71, 75))	('SMAD4', 'Gene', '4089', (191, 196))	('ZNF750', 'Gene', (91, 97))	('ARID1A', 'Gene', (183, 189))	('TGFBR2', 'Gene', '7048', (110, 116))	('MLL2', 'Gene', '8085', (85, 89))	('ESCC', 'Disease', (120, 124))	('NOTCH1', 'Gene', (99, 105))	('CDKN2A', 'Gene', '1029', (175, 181))	('ARID1A', 'Gene', '8289', (183, 189))	('TP53', 'Gene', (169, 173))	('MLL2', 'Gene', (85, 89))	('NOTCH1', 'Gene', '4851', (99, 105))	('TGFBR2', 'Gene', (110, 116))	('TP53', 'Gene', (71, 75))	('NFE2L2', 'Gene', '4780', (77, 83))
18267	28930282	An overview of the various genetic abnormalities occurring in esophageal cancers showed that: abnormalities of cell cycle-related genes are highly frequent (90% in ESCC and 86% in EAC), followed by RTK abnormalities (59% in ESCC and 76% in EAC), cell differentiation (57% in ESCC and 42% in EAC), embryonic development (38% in ESCC and 53% in EAC) and chromatin remodeling (36% in ESCC and 22% in EAC).	('abnormalities', 'Var', (94, 107))	('ESCC', 'Disease', (164, 168))	('cell differentiation', 'CPA', (246, 266))	('abnormalities of cell cycle', 'Phenotype', 'HP:0011018', (94, 121))	('RTK abnormalities', 'Disease', (198, 215))	('ESCC', 'Phenotype', 'HP:0011459', (224, 228))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('ESCC', 'Phenotype', 'HP:0011459', (327, 331))	('RTK abnormalities', 'Disease', 'MESH:D000014', (198, 215))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ESCC', 'Phenotype', 'HP:0011459', (381, 385))	('ESCC', 'Disease', (327, 331))	('EAC', 'Phenotype', 'HP:0011459', (180, 183))	('EAC', 'Phenotype', 'HP:0011459', (291, 294))	('esophageal cancers', 'Disease', (62, 80))	('ESCC', 'Disease', (381, 385))	('ESCC', 'Phenotype', 'HP:0011459', (275, 279))	('EAC', 'Phenotype', 'HP:0011459', (343, 346))	('cell cycle-related genes', 'Gene', (111, 135))	('embryonic development', 'CPA', (297, 318))	('genetic abnormalities', 'Disease', 'MESH:D030342', (27, 48))	('ESCC', 'Disease', (275, 279))	('esophageal cancers', 'Disease', 'MESH:D004938', (62, 80))	('EAC', 'Phenotype', 'HP:0011459', (240, 243))	('EAC', 'Phenotype', 'HP:0011459', (397, 400))	('ESCC', 'Phenotype', 'HP:0011459', (164, 168))	('genetic abnormalities', 'Disease', (27, 48))
18268	28930282	Importantly, the integrated analysis of genetic abnormalities occurring in ESCC allowed a new classification in three subtypes: ESCC1 was characterized by frequent alterations of the NRF2 pathway, involved in the adaptation to oxidative stress [with frequent alterations of the NRF2 (NFE2L2), KEAP1, CUL3 and ATG7 genes] and of SOX2 and TP63 (gene amplification); ESCC2 was characterized by frequent mutations of NOTCH1 or ZNF750, inactivating alterations of KDM6A or KDM2D, amplifications of CDK6 and inactivation of PTEN or PIK3R1; ESCC3 tumors do not display deregulation of cell cycle genes, more rarely (25%) had TP53 mutations and many genetic alterations are related to the activation of the PI3K pathway.	('TP63', 'Gene', '8626', (337, 341))	('KDM6A', 'Gene', '7403', (459, 464))	('TP53', 'Gene', (618, 622))	('CDK6', 'Gene', '1021', (493, 497))	('tumor', 'Phenotype', 'HP:0002664', (540, 545))	('rat', 'Species', '10116', (263, 266))	('ESCC', 'Phenotype', 'HP:0011459', (534, 538))	('ATG7', 'Gene', '10533', (309, 313))	('ESCC', 'Phenotype', 'HP:0011459', (75, 79))	('SOX2', 'Gene', (328, 332))	('tumors', 'Disease', (540, 546))	('ESCC3', 'Disease', (534, 539))	('SOX2', 'Gene', '6657', (328, 332))	('NRF2', 'Gene', '4780', (183, 187))	('NOTCH1', 'Gene', '4851', (413, 419))	('CDK6', 'Gene', (493, 497))	('genetic abnormalities', 'Disease', 'MESH:D030342', (40, 61))	('ESCC', 'Phenotype', 'HP:0011459', (128, 132))	('NFE2L2', 'Gene', (284, 290))	('rat', 'Species', '10116', (22, 25))	('genetic abnormalities', 'Disease', (40, 61))	('PIK3R1', 'Gene', (526, 532))	('PTEN', 'Gene', (518, 522))	('KDM6A', 'Gene', (459, 464))	('tumors', 'Disease', 'MESH:D009369', (540, 546))	('CUL3', 'Gene', '8452', (300, 304))	('TP53', 'Gene', '7157', (618, 622))	('NRF2', 'Gene', '4780', (278, 282))	('ATG7', 'Gene', (309, 313))	('NFE2L2', 'Gene', '4780', (284, 290))	('NRF2', 'Gene', (183, 187))	('PTEN', 'Gene', '5728', (518, 522))	('KEAP1', 'Gene', '9817', (293, 298))	('oxidative stress', 'Phenotype', 'HP:0025464', (227, 243))	('KEAP1', 'Gene', (293, 298))	('ESCC', 'Phenotype', 'HP:0011459', (364, 368))	('TP63', 'Gene', (337, 341))	('ZNF750', 'Gene', '79755', (423, 429))	('NRF2', 'Gene', (278, 282))	('rat', 'Species', '10116', (654, 657))	('PIK3R1', 'Gene', '5295', (526, 532))	('mutations', 'Var', (623, 632))	('PI3K pathway', 'Pathway', (699, 711))	('rat', 'Species', '10116', (448, 451))	('ZNF750', 'Gene', (423, 429))	('rat', 'Species', '10116', (168, 171))	('tumors', 'Phenotype', 'HP:0002664', (540, 546))	('CUL3', 'Gene', (300, 304))	('NOTCH1', 'Gene', (413, 419))
18272	28930282	In spite the important limitations, the available evidences indicate that gene signatures observed in esophageal cancer patients are of prognostic value for clinical outcomes and may represent a precious tool for selecting optimized therapy for the single patient.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('patient', 'Species', '9606', (120, 127))	('patients', 'Species', '9606', (120, 128))	('esophageal cancer', 'Disease', (102, 119))	('clinical', 'Species', '191496', (157, 165))	('gene', 'Var', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('patient', 'Species', '9606', (256, 263))
18276	28930282	Genome-wide association studies have identified two SNPs, rs671 in ALDH2 on 4q23 and rs1229984 in ALDH1B on 12q24 that are clearly associated with the risk of developing ESCC in a manner related with alcohol drinking and tobacco smoking status.	('tobacco', 'Species', '4097', (221, 228))	('alcohol drinking', 'Phenotype', 'HP:0030955', (200, 216))	('rs1229984', 'Var', (85, 94))	('ESCC', 'Phenotype', 'HP:0011459', (170, 174))	('rs671', 'Var', (58, 63))	('ALDH2', 'Gene', (67, 72))	('associated', 'Reg', (131, 141))	('rs671', 'Mutation', 'rs671', (58, 63))	('ALDH1', 'Gene', (98, 103))	('ALDH1', 'Gene', '216', (98, 103))	('ALDH2', 'Gene', '217', (67, 72))	('rs1229984', 'Mutation', 'rs1229984', (85, 94))	('alcohol', 'Chemical', 'MESH:D000438', (200, 207))	('ESCC', 'Disease', (170, 174))
18277	28930282	Chang et al., showed that the frequency of a peculiar mutation profile, called signature E4, was significantly higher in ESCC from drinkers with the risk ALDH2 genotype than in ESCC from drinkers with the non-risk genotype.	('ALDH2', 'Gene', '217', (154, 159))	('ESCC', 'Phenotype', 'HP:0011459', (121, 125))	('genotype', 'Var', (160, 168))	('drinkers', 'Var', (131, 139))	('ALDH2', 'Gene', (154, 159))	('ESCC', 'Phenotype', 'HP:0011459', (177, 181))	('higher', 'PosReg', (111, 117))	('ESCC', 'Disease', (121, 125))
18307	28930282	In fact, the introduction of a NOTCH mutant causing inhibition of the NOTCH signaling at the level of the esophageal basal cells promotes a suppression of differentiative mitosis of these cells, thus inducing their expansion as undifferentiated cells and the formation of clones expanding and progressively replacing the entire epithelium.	('clones', 'CPA', (272, 278))	('expansion', 'PosReg', (215, 224))	('mutant', 'Var', (37, 43))	('mitosis', 'Disease', 'None', (171, 178))	('mitosis', 'Disease', (171, 178))	('suppression', 'NegReg', (140, 151))	('inducing', 'Reg', (200, 208))	('NOTCH signaling', 'MPA', (70, 85))	('inhibition', 'NegReg', (52, 62))
18308	28930282	Analysis of gene expression in mutant cells reveals alterations in the expression of genes implicated in keratinocyte differentiation: thus, the stress-induced keratin Krt6 is strongly induced in mutant cells.	('expression', 'MPA', (71, 81))	('mutant', 'Var', (31, 37))	('induced', 'PosReg', (185, 192))	('rat', 'Species', '10116', (162, 165))	('rat', 'Species', '10116', (56, 59))	('Krt6', 'Gene', (168, 172))	('Krt6', 'Gene', '140807', (168, 172))	('mutant', 'Var', (196, 202))	('rat', 'Species', '10116', (107, 110))
18309	28930282	In contrast, Sox9 is downmodulated in mutant cells.	('mutant', 'Var', (38, 44))	('Sox9', 'Gene', '6662', (13, 17))	('downmodulated', 'NegReg', (21, 34))	('Sox9', 'Gene', (13, 17))
18329	28930282	This hypothesis was directly evaluated by studying the effect of NSAIDs administration on the number of somatic genetic abnormalities in patients with Barrett's esophagus: the evaluation in the time of these patients showed that those receiving NSAIDs developed significantly less somatic genetic abnormalities than those not treated with these drugs.	('genetic abnormalities', 'Disease', (289, 310))	('patients', 'Species', '9606', (208, 216))	('less', 'NegReg', (276, 280))	('rat', 'Species', '10116', (80, 83))	('genetic abnormalities', 'Disease', (112, 133))	('patients', 'Species', '9606', (137, 145))	('NSAIDs', 'Var', (245, 251))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (151, 170))	('genetic abnormalities', 'Disease', 'MESH:D030342', (289, 310))	('genetic abnormalities', 'Disease', 'MESH:D030342', (112, 133))
18333	28930282	The p63 null embryo rapidly develops intestine-like metaplasia, with gene expression profiles like those observed in Barrett's metaplasia.	('p63 null', 'Var', (4, 12))	('develops', 'PosReg', (28, 36))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (117, 137))	("Barrett's metaplasia", 'Disease', (117, 137))	('intestine-like metaplasia', 'CPA', (37, 62))
18336	28930282	At later times of metaplasia development, the role of inflammation is more clear contributing to the development of proliferation-related mutations and of epigenetic basis the becomes the essential molecular mechanism for the development of a clonal selection condition which determines disease progression.	('epigenetic', 'Var', (155, 165))	('inflammation', 'Disease', 'MESH:D007249', (54, 66))	('inflammation', 'Disease', (54, 66))	('rat', 'Species', '10116', (123, 126))	('mutations', 'Var', (138, 147))
18343	28930282	Leedham and coworkers have provided evidence, through the analysis of tumor suppressor loss of heterozygosity at the level of individual crypts, that the ducts could represent the source of the Barrett's metaplasia, as supported by the finding that normal squamous ducts contained the same somatic mutation as the contiguous metaplastic epithelium.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('loss', 'Var', (87, 91))	('tumor', 'Disease', (70, 75))	("Barrett's metaplasia", 'Disease', (194, 214))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (194, 214))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
18361	28930282	The genomic analysis of Barrett's stem cells shows a broad and variable mutational spectrum: 25% of cases do not show typical cancer-related genomic changes; most of cases display patterns of deletions like those observed in EAC, but gene-amplifications were absent; importantly, the cases showing signs of low-grade dysplasia, exhibit p53 mutations or amplifications of proto-oncogenes and RTK.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('amplifications', 'Var', (353, 367))	('dysplasia', 'Disease', 'MESH:D004476', (317, 326))	('proto-oncogenes', 'Gene', (371, 386))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('deletions', 'Var', (192, 201))	('mutations', 'Var', (340, 349))	('dysplasia', 'Disease', (317, 326))	('EAC', 'Phenotype', 'HP:0011459', (225, 228))	('p53', 'Gene', (336, 339))
18377	28930282	CD90+ cells were isolated from these tumor specimens and were shown to exhibit an enhanced capacity to initiate tumor formation into immunodeficient mice, self-renew, differentiate and are resistant to standard cytotoxic drugs; furthermore, CD90+ cells were shown to possess a high metastatic potential in vivo.	('enhanced', 'PosReg', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('immunodeficient', 'Disease', 'MESH:D007153', (133, 148))	('immunodeficient', 'Disease', (133, 148))	('CD90+', 'Var', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('self-renew', 'CPA', (155, 165))	('differentiate', 'CPA', (167, 180))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mice', 'Species', '10090', (149, 153))	('tumor', 'Disease', (112, 117))
18391	28930282	Taking advantage on this observation, these authors have explored ALH1A expression at the level of tumor specimens obtained from 165 patients, showing that the level of ALDH1 positivity was associated with various tumor parameters related to the invasiveness and metastatic properties of ESCC and with poor prognosis.	('tumor', 'Disease', (99, 104))	('positivity', 'Var', (175, 185))	('ESCC', 'Disease', (288, 292))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('invasiveness', 'CPA', (246, 258))	('patients', 'Species', '9606', (133, 141))	('ALDH1', 'Gene', (169, 174))	('ESCC', 'Phenotype', 'HP:0011459', (288, 292))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('metastatic properties', 'CPA', (263, 284))	('ALDH1', 'Gene', '216', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('associated', 'Reg', (190, 200))	('tumor', 'Disease', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
18410	28930282	SOX2 overexpression induces the expansion of basal progenitors with development of a premalignant lesion that progresses to carcinoma in the presence of an inflammatory stimulus that induces Stat3 activation.	('SOX2', 'Gene', '6657', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('Stat3', 'Gene', (191, 196))	('basal progenitors', 'CPA', (45, 62))	('Stat3', 'Gene', '6774', (191, 196))	('carcinoma', 'Disease', (124, 133))	('expansion', 'PosReg', (32, 41))	('overexpression', 'Var', (5, 19))	('SOX2', 'Gene', (0, 4))	('carcinoma', 'Disease', 'MESH:D002277', (124, 133))
18416	28930282	Importantly, YAP1 inhibitors sensitize esophageal cancer cells to cytotoxic agents and may offer a strategy to bypass chemoresistance in these cells.	('YAP1', 'Gene', (13, 17))	('sensitize', 'Reg', (29, 38))	('rat', 'Species', '10116', (101, 104))	('YAP1', 'Gene', '10413', (13, 17))	('esophageal cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))	('inhibitors', 'Var', (18, 28))
18419	28930282	Epithelial-mesenchymal transition is of critical importance for the generation of cancer stem cells and EGFR inhibitors block EMT at the invasive front of ESCCs.	('rat', 'Species', '10116', (72, 75))	('ESCC', 'Phenotype', 'HP:0011459', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('inhibitors', 'Var', (109, 119))	('EGFR', 'Gene', (104, 108))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('EMT at the invasive front of', 'CPA', (126, 154))	('block', 'NegReg', (120, 125))
18421	28930282	The aberrant beta-catenin expression and consequent Wnt pathway activation are determinants of ESCC cancer progression, invasion and metastasis.	('expression', 'MPA', (26, 36))	('beta-catenin', 'Gene', '1499', (13, 25))	('aberrant', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('ESCC', 'Phenotype', 'HP:0011459', (95, 99))	('activation', 'PosReg', (64, 74))	('Wnt', 'Gene', '7475;7477;80326', (52, 55))	('ESCC cancer', 'Disease', (95, 106))	('ESCC cancer', 'Disease', 'MESH:D004938', (95, 106))	('beta-catenin', 'Gene', (13, 25))	('Wnt', 'Gene', (52, 55))
18437	28930282	A second recent study was carried out on 96 primary ESCC samples derived from Chinese patients providing evidence about a rate of engraftment corresponding to 38.5% with similar rates of engraftment in patients whose tumors display or not PI3KCA mutations.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('ESCC', 'Phenotype', 'HP:0011459', (52, 56))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('patients', 'Species', '9606', (202, 210))	('rat', 'Species', '10116', (122, 125))	('rat', 'Species', '10116', (178, 181))	('PI3KCA mutations', 'Var', (239, 255))	('patients', 'Species', '9606', (86, 94))
18438	28930282	The presence of HER2 overexpression, due to gene amplification or not, was associated with absent engraftment in xenotransplantation assay.	('HER2', 'Gene', (16, 20))	('overexpression', 'PosReg', (21, 35))	('HER2', 'Gene', '2064', (16, 20))	('absent', 'NegReg', (91, 97))	('gene amplification', 'Var', (44, 62))
18455	27812016	After controlling for risk factors, a doubling of 25(OH)D3 was associated with 30% lower odds of HNC (OR 0.70, 95% confidence interval [95% CI] 0.56-0.88, Ptrend = 0.001).	('25(OH)D3', 'Chemical', 'MESH:D002112', (50, 58))	('HNC', 'Disease', (97, 100))	('25(OH)D3', 'Var', (50, 58))	('lower', 'NegReg', (83, 88))
18457	27812016	Low 25(OH)D3 concentrations were also associated with higher risk of death from any cause among HNC cases.	('HNC', 'Disease', (96, 99))	('25(OH)D3', 'Chemical', 'MESH:D002112', (4, 12))	('death', 'Disease', 'MESH:D003643', (69, 74))	('death', 'Disease', (69, 74))	('Low', 'Var', (0, 3))
18459	27812016	Study participants with elevated circulating concentrations of 25(OH)D3 had decreased risk of HNC, as well as improved survival following diagnosis.	('25(OH)D3', 'Var', (63, 71))	('improved', 'PosReg', (110, 118))	('HNC', 'Disease', (94, 97))	('decreased', 'NegReg', (76, 85))	('participants', 'Species', '9606', (6, 18))	('survival', 'MPA', (119, 127))	('25(OH)D3', 'Chemical', 'MESH:D002112', (63, 71))
18472	27812016	In addition, we aimed to evaluate if pre-diagnostic circulating 25(OH)D is associated with survival following cancer diagnosis.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('circulating 25(OH)D', 'Var', (52, 71))	('associated', 'Reg', (75, 85))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
18486	27812016	Compared to participants having 25(OH)D3 blood concentrations of 50 nmol/L, odds of HNC were 42% higher for those with 25(OH)D3 blood concentrations of 25 nmol/L, and 30% lower for those with 25(OH)D3 blood concentrations of 100 nmol/L.	('higher', 'PosReg', (97, 103))	('25(OH)D3', 'Chemical', 'MESH:D002112', (32, 40))	('25(OH)D3', 'Chemical', 'MESH:D002112', (119, 127))	('25(OH)D3', 'Chemical', 'MESH:D002112', (192, 200))	('HNC', 'Disease', (84, 87))	('25(OH)D3', 'Var', (119, 127))	('participants', 'Species', '9606', (12, 24))
18487	27812016	Risk analyses stratified by HNC sub-sites are displayed in Table 3, and indicated that the association of 25(OH)D3 was particularly prominent for cancers of the larynx and hypopharynx (OR 0.55, 95% CI 0.39-0.78) and for cancers of the oral cavity (OR 0.60, 95% CI 0.42-0.87).	('25(OH)D3', 'Var', (106, 114))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cancers of the larynx', 'Phenotype', 'HP:0012118', (146, 167))	('25(OH)D3', 'Chemical', 'MESH:D002112', (106, 114))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Disease', (220, 227))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('association', 'Interaction', (91, 102))
18494	27812016	Some indications of differences in strength of association between circulating 25(OH)D3 and HNC risk were also seen when stratifying for groups of alcohol intake at recruitment, where no association was seen among subject with 0 grams of alcohol intake per day, although OR estimates in the other drinking categories were compatible with that overall.	('25(OH)D3', 'Var', (79, 87))	('alcohol', 'Chemical', 'MESH:D000438', (147, 154))	('25(OH)D3', 'Chemical', 'MESH:D002112', (79, 87))	('alcohol', 'Chemical', 'MESH:D000438', (238, 245))	('men', 'Species', '9606', (172, 175))	('association', 'Interaction', (47, 58))	('HNC', 'Disease', (92, 95))
18497	27812016	Results of Cox proportional hazards regression for 25(OH)D3 of all-cause mortality are shown in Fig.	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('25(OH)D3', 'Var', (51, 59))	('25(OH)D3', 'Chemical', 'MESH:D002112', (51, 59))
18533	27812016	Furthermore, subsequent cause-specific survival indicated that the association of 25(OH)D3 was primarily driven by deaths caused by HNC, but not other causes of death.	('death', 'Disease', 'MESH:D003643', (161, 166))	('deaths', 'Disease', 'MESH:D003643', (115, 121))	('deaths', 'Disease', (115, 121))	('death', 'Disease', (161, 166))	('25(OH)D3', 'Chemical', 'MESH:D002112', (82, 90))	('HNC', 'Disease', (132, 135))	('death', 'Disease', 'MESH:D003643', (115, 120))	('death', 'Disease', (115, 120))	('25(OH)D3', 'Var', (82, 90))
18554	27812016	These cancer cases were defined on the basis of the International Classification of Diseases for Oncology, Second Edition (ICD-O-2), and included: oral cavity (ICD C02.0-C02.9, C04.0-C04.9, C03.0-C03.9, C05.0-C06.9, C14.0-C14.9), oropharynx (C01.9, C02.4, C09.0-C10.9), hypopharynx (C13.0-C13.9), larynx (C32.0-C32.9), and oesophagus (C15.0-C15.9).	('C15.0-C15.9', 'Var', (335, 346))	('C03', 'CellLine', 'CVCL:J167', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('C09.0-C10.9', 'Var', (256, 267))	('C01.9', 'CellLine', 'CVCL:E303', (242, 247))	('C03', 'CellLine', 'CVCL:J167', (190, 193))	('C02.4', 'Var', (249, 254))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('C13.0-C13.9', 'Var', (283, 294))	('C32.0-C32.9', 'Var', (305, 316))	('cancer', 'Disease', (6, 12))	('Oncology', 'Phenotype', 'HP:0002664', (97, 105))	('C01.9', 'Var', (242, 247))
18566	27812016	We performed sensitivity analyses by using the sum of 25(OH)D3 and 25(OH)D2 (setting undetectable levels of 25(OH)D2 to 0) and we observed similar results.	('25(OH)D2', 'Chemical', '-', (108, 116))	('25(OH)D3', 'Chemical', 'MESH:D002112', (54, 62))	('25(OH)D2', 'Var', (67, 75))	('25(OH)D2', 'Chemical', '-', (67, 75))	('25(OH)D3', 'Var', (54, 62))
18687	26510452	A meta-analysis of eight Asian studies comparing ESD and EMR in the treatment of superficial esophageal cancer (primarily squamous cell carcinoma), demonstrated that ESD had a significantly higher en bloc resection rate (97.1% vs. 49.3%; OR = 52.76; 95% CI 25.57-108.84) and a lower recurrence rate (0.3% vs. 11.5%; OR = 0.08; 95% CI 0.03-0.23).	('ESD', 'Var', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('en bloc resection', 'CPA', (197, 214))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('squamous cell carcinoma', 'Disease', (122, 145))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 145))	('higher', 'PosReg', (190, 196))
18695	26510452	When comparing the procedure durations of two different EMR techniques, a randomized trial for resection of Barrett's-associated neoplasia demonstrated that ligation-assisted EMR was significantly faster than cap-assisted EMR, with median procedure times of 34 min vs. 50 min, respectively (P = 0.02) with no differences in complication rates or quality of the resection specimens.	('neoplasia', 'Disease', (129, 138))	('ligation-assisted', 'Var', (157, 174))	('neoplasia', 'Disease', 'MESH:D009369', (129, 138))	('neoplasia', 'Phenotype', 'HP:0002664', (129, 138))
18706	26510452	In another study of 17 patients treated with APC monotherapy for T1a & T1b SCC, there were 2 recurrences (9.5%), with a median follow-up of 36 months, requiring an average of 2 treatments and 15 minutes per treatment session.	('SCC', 'Gene', '6317', (75, 78))	('patients', 'Species', '9606', (23, 31))	('T1a &', 'Var', (65, 70))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (45, 48))	('SCC', 'Gene', (75, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))
18762	26488471	Knockout Cyclin Y in glioma cell lines makes the cell cycle blocked in S period.	('Cyclin Y', 'Gene', '219771', (9, 17))	('blocked', 'NegReg', (60, 67))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('cell cycle', 'CPA', (49, 59))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('Cyclin Y', 'Gene', (9, 17))	('Knockout', 'Var', (0, 8))	('glioma', 'Disease', (21, 27))
18795	26488471	MGC803 cells were cultivated in six-well culture plates (Corning inc, Corning NY) at a density of 200 cells/well after transfecting PFTK1#siRNA and Flag-PFTK1 according to the manufacturer's instructions.	('transfecting', 'Var', (119, 131))	('PFTK1', 'Gene', (132, 137))	('MGC803', 'CellLine', 'CVCL:5334', (0, 6))
18797	26488471	MGC803 cells which included normal, transfection of PFTK1#siRNA and Flag-PFTK1 were seeded onto 96-well cell culture cluster plates (Corning inc, Corning NY) at a density of 2x104 cells/well in 100 mul culture and grown overnight.	('PFTK1', 'Gene', (52, 57))	('transfection', 'Var', (36, 48))	('MGC803', 'CellLine', 'CVCL:5334', (0, 6))
18822	26488471	Further, matrigel invasion assays also demonstrated that upregulation of PFTK1 by transfect Flag-PFTK1 could advance the invasive ability, and knockdown of PFTK1 could attenuate the invasive ability of gastric cancer cells (Fig 5C).	('gastric cancer', 'Disease', 'MESH:D013274', (202, 216))	('invasive ability', 'CPA', (121, 137))	('advance', 'PosReg', (109, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (202, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('attenuate', 'NegReg', (168, 177))	('transfect Flag-PFTK1', 'Var', (82, 102))	('PFTK1', 'Gene', (73, 78))	('upregulation', 'PosReg', (57, 69))	('knockdown', 'Var', (143, 152))	('gastric cancer', 'Disease', (202, 216))	('Flag-PFTK1', 'Gene', (92, 102))	('PFTK1', 'Gene', (156, 161))
18826	26488471	Finally, we explored the proliferation mechanism of PFTK1 by flow cytometric analysis,and data suggested that more gastric cancer cells were found in the S phase in the presence of ectopic PFTK1, less gastric cancer cells were found in the S phase in transfecting with PFTK1-siRNA#4 (Fig 6C).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('PFTK1', 'Gene', (189, 194))	('gastric cancer', 'Disease', (201, 215))	('gastric cancer', 'Disease', 'MESH:D013274', (201, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (201, 215))	('ectopic', 'Var', (181, 188))	('gastric cancer', 'Disease', (115, 129))
18831	26488471	What's more, we found that knockdown of endogenous PFTK1 expression could decrease Dvl2, Naked1, MMP2, Cyclin E expression, but not changed Dvl1, beta-catenin (Fig 7).	('knockdown', 'Var', (27, 36))	('decrease', 'NegReg', (74, 82))	('Dvl2', 'Gene', '1856', (83, 87))	('Naked1', 'Gene', (89, 95))	('Dvl1', 'Gene', (140, 144))	('beta-catenin', 'Gene', (146, 158))	('PFTK1', 'Gene', (51, 56))	('MMP2', 'Gene', (97, 101))	('MMP2', 'Gene', '4313', (97, 101))	('Dvl1', 'Gene', '1855', (140, 144))	('beta-catenin', 'Gene', '1499', (146, 158))	('Naked1', 'Gene', '85407', (89, 95))	('Cyclin E expression', 'MPA', (103, 122))	('Dvl2', 'Gene', (83, 87))
18845	26488471	At the same time, PFTK1 increased the G1:S phase transformation according to flow cytometric, coinciding with the finding of PFTK1 in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (134, 158))	('hepatocellular carcinoma', 'Disease', (134, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('G1:S phase transformation', 'CPA', (38, 63))	('PFTK1', 'Var', (18, 23))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (134, 158))	('increased', 'PosReg', (24, 33))
18847	26488471	Interestingly, PFTK1 level was increased after transfecting with Flag-PFTK1 consistented with PCNA, MMP2 and Cyclin E (Fig 7).	('Flag-PFTK1', 'Var', (65, 75))	('increased', 'PosReg', (31, 40))	('MMP2', 'Gene', (100, 104))	('PCNA', 'Gene', '5111', (94, 98))	('PFTK1 level', 'MPA', (15, 26))	('MMP2', 'Gene', '4313', (100, 104))	('PCNA', 'Gene', (94, 98))
18898	25765098	In the multivariate analysis, only age and histologic grade, when combined, increased the risk of death by 3% per year of age (HR=1.03; p=0.01) and patients with poorly differentiated L-EAC were >3 times as likely to die compared those with well to moderate differentiation (HR=3.14; p<0.001).	('death', 'Disease', 'MESH:D003643', (98, 103))	('patients', 'Species', '9606', (148, 156))	('death', 'Disease', (98, 103))	('L-EAC', 'Chemical', '-', (184, 189))	('poorly differentiated', 'Var', (162, 183))
18903	25765098	As we suspected, L-EAC patients with nodes ABD fared poorly compared to those with nodes AD or BD.	('patients', 'Species', '9606', (23, 31))	('L-EAC', 'Disease', (17, 22))	('L-EAC', 'Chemical', '-', (17, 22))	('nodes ABD', 'Var', (37, 46))	('AD', 'Disease', 'MESH:D000544', (89, 91))	('AD', 'Disease', (89, 91))
18946	19524578	Patients who had mucosal carcinoma diagnosed on mucosal biopsy specimens alone without visible lesions were also more likely to receive PDT.	('mucosal carcinoma', 'Disease', (17, 34))	('PDT', 'Var', (136, 139))	('mucosal carcinoma', 'Disease', 'MESH:D052016', (17, 34))	('Patients', 'Species', '9606', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
18947	19524578	During the latter phase of the study this was performed selectively given the lack of consensus on whether ablation following initial remission definitively reduces risk of metachronous neoplasia.	('ablation', 'Var', (107, 115))	('metachronous neoplasia', 'Disease', 'MESH:D016609', (173, 195))	('metachronous neoplasia', 'Disease', (173, 195))	('neoplasia', 'Phenotype', 'HP:0002664', (186, 195))	('reduces', 'NegReg', (157, 164))
19090	18790767	Although H2AX is known to co-operate with JNK to induce apoptosis following UV-irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis.	('JNK', 'Gene', (42, 45))	('JNK', 'Gene', '5599', (42, 45))	('H2AX', 'Gene', '3014', (9, 13))	('knockdown', 'Var', (92, 101))	('H2AX', 'Gene', (9, 13))	('H2AX', 'Gene', '3014', (105, 109))	('bortezomib', 'Chemical', 'MESH:D000069286', (127, 137))	('H2AX', 'Gene', (105, 109))
19091	18790767	Instead, blockade of p38 MAP kinase signaling, using either siRNA or a pharmacological inhibitor, reversed bortezomib-induced apoptosis and the upregulation of Noxa.	('p38 MAP kinase', 'Gene', '1432', (21, 35))	('p38 MAP kinase', 'Gene', (21, 35))	('apoptosis', 'CPA', (126, 135))	('bortezomib', 'Chemical', 'MESH:D000069286', (107, 117))	('Noxa', 'Gene', '5366', (160, 164))	('upregulation', 'PosReg', (144, 156))	('Noxa', 'Gene', (160, 164))	('blockade', 'Var', (9, 17))
19134	18790767	As targeted therapeutic approaches have not been attempted in ESCC in an extensive fashion, we initiated our studies by screening a panel of ESCC lines against inhibitors of MEK (U0126), PI3K (LY294002), glycogen synthase kinase (GSK) 3-beta (DW1/2), the proteasome (MG-132, PI1 and bortezomib), Hedgehog (cyclopamine) and cyclooxygenase-2 (NS-398) (Supplemental Table 1).	('MEK', 'Gene', (174, 177))	('cyclooxygenase-2', 'Gene', (323, 339))	('cyclooxygenase-2', 'Gene', '5743', (323, 339))	('MG-132', 'Chemical', 'MESH:C072553', (267, 273))	('LY294002', 'Var', (193, 201))	('PI1', 'Gene', '5265', (275, 278))	('PI1', 'Gene', (275, 278))	('cyclopamine', 'Chemical', 'MESH:C000541', (306, 317))	('bortezomib', 'Chemical', 'MESH:D000069286', (283, 293))	('glycogen synthase kinase (GSK) 3-beta', 'Gene', '2932', (204, 241))	('U0126', 'Chemical', 'MESH:C113580', (179, 184))
19144	18790767	As the TE12 cell line has mutated p53, we did not observe any increase in the expression of p53 or its downstream target p21 following bortezomib administration.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('p21', 'Gene', '1026', (121, 124))	('p21', 'Gene', (121, 124))	('mutated', 'Var', (26, 33))	('p53', 'Gene', (92, 95))	('TE12', 'CellLine', 'CVCL:1762', (7, 11))	('bortezomib', 'Chemical', 'MESH:D000069286', (135, 145))	('p53', 'Gene', '7157', (92, 95))
19151	18790767	Here, we found that treatment with bortezomib (500 nM or 1 muM) led to a concentration-dependent increase in the level of apoptosis as seen by the enhanced TUNEL staining (Figure 2A,B).	('increase', 'PosReg', (97, 105))	('muM', 'Gene', '56925', (59, 62))	('500 nM', 'Var', (47, 53))	('muM', 'Gene', (59, 62))	('bortezomib', 'Chemical', 'MESH:D000069286', (35, 45))	('bortezomib', 'Gene', (35, 45))
19165	18790767	Any possible role of H2AX in bortezomib-induced apoptosis induction was discounted by the fact that protein knockdown did not reduce either caspase-3 cleavage or DNA laddering (Figure 4C and data not shown).	('knockdown', 'Var', (108, 117))	('caspase-3', 'Gene', '836', (140, 149))	('protein', 'Protein', (100, 107))	('reduce', 'NegReg', (126, 132))	('H2AX', 'Gene', '3014', (21, 25))	('bortezomib', 'Chemical', 'MESH:D000069286', (29, 39))	('caspase-3', 'Gene', (140, 149))	('H2AX', 'Gene', (21, 25))	('DNA', 'MPA', (162, 165))
19174	18790767	We further demonstrated that knockdown of p38 MAPKalpha protein expression using an siRNA was similarly able to block bortezomib-induced caspase cleavage (Figure 5C).	('p38', 'Gene', (42, 45))	('knockdown', 'Var', (29, 38))	('bortezomib-induced caspase cleavage', 'MPA', (118, 153))	('p38', 'Gene', '1432', (42, 45))	('block', 'NegReg', (112, 117))	('bortezomib', 'Chemical', 'MESH:D000069286', (118, 128))
19205	18790767	Another possible explanation for the observed DNA damage response involved the direct role of caspase activation in the cleavage of genomic DNA leading to subsequent H2AX/ATM activation.	('H2AX', 'Gene', '3014', (166, 170))	('cleavage', 'MPA', (120, 128))	('activation', 'PosReg', (175, 185))	('ATM', 'Gene', (171, 174))	('H2AX', 'Gene', (166, 170))	('ATM', 'Gene', '472', (171, 174))	('genomic', 'Var', (132, 139))
19227	32308479	Risk of Recurrence and Metastasis for Patients with T1N0M0 Esophageal Carcinoma Who Achieve Completed Resection via Endoscopic Submucosal Resection: Evidence for the Appropriateness of the Watch and Wait Follow-Up Strategy Endoscopic submucosal dissection (ESD) is a widely performed procedure for esophageal carcinoma when the depth of invasion reaches the epithelium and lamina propria.	('esophageal carcinoma', 'Disease', (298, 318))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (298, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('Carcinoma', 'Disease', (70, 79))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (298, 318))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (59, 79))	('Carcinoma', 'Disease', 'MESH:D009369', (70, 79))	('Carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('Patients', 'Species', '9606', (38, 46))	('T1N0M0', 'Var', (52, 58))
19229	32308479	This study aimed to evaluate the long-term outcomes of ESD for T1N0M0 (tumor invading the mucosa and submucosa [T1], no regional lymph node metastasis [N0], no distant metastasis [M0]) esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('T1N0M0', 'Var', (63, 69))	('distant metastasis', 'CPA', (160, 178))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Disease', (196, 202))	('tumor', 'Disease', (71, 76))
19279	32308479	Meanwhile, there were no significant differences in recurrence rate (P =0.432) and metastasis rate (P=0.354) between the M1+M2, M3 and SM groups (Figure 2).	('M1+M2', 'Var', (121, 126))	('SM', 'Chemical', 'MESH:D012493', (135, 137))	('metastasis', 'CPA', (83, 93))	('recurrence', 'CPA', (52, 62))
19293	32308479	In this study, we observed patients who underwent ESD for T1N0M0 (tumor invading the mucosa and submucosa[T1], no regional lymph node metastasis [N0], no distant metastasis [M0]) esophageal carcinoma and achieved negative margins and received no additional treatment.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('tumor', 'Disease', (66, 71))	('esophageal carcinoma', 'Disease', (179, 199))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (179, 199))	('patients', 'Species', '9606', (27, 35))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (179, 199))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('T1N0M0', 'Var', (58, 64))
19304	32308479	Furthermore, ESD was associated with a higher recurrence-free survival in infiltrative tumors.	('recurrence-free survival', 'CPA', (46, 70))	('higher', 'PosReg', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ESD', 'Var', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
19402	31949393	Among them, 9 patients responded to chemotherapy before treatment with ICIs, whereas the number of patients achieving a PR or CR increased to 12 during re-exposure chemotherapy, suggesting that the anti-PD-1 antibodies might have restored chemosensitivity.	('ICI', 'Chemical', 'MESH:C481040', (71, 74))	('restored', 'PosReg', (230, 238))	('PD-1', 'Gene', (203, 207))	('PD-1', 'Gene', '5133', (203, 207))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (14, 22))	('chemosensitivity', 'CPA', (239, 255))	('antibodies', 'Var', (208, 218))
19404	31949393	In our current analysis, the response rate to irinotecan-based chemotherapy after PD-1 blockade was only slightly higher than the rate of response to the last chemotherapy before PD-1 inhibition (17.9% vs. 14.3%).	('PD-1', 'Gene', (82, 86))	('PD-1', 'Gene', '5133', (82, 86))	('irinotecan', 'Chemical', 'MESH:C051890', (46, 56))	('PD-1', 'Gene', (179, 183))	('response', 'MPA', (29, 37))	('PD-1', 'Gene', '5133', (179, 183))	('blockade', 'Var', (87, 95))	('higher', 'PosReg', (114, 120))
19415	31949393	Nonetheless, this is the only report on advanced esophageal cancer patients treated with chemotherapy after PD-1 inhibition and might shed light on the management of ESCC patients in this specific setting, and the understanding of the interactions between ICIs and cytotoxic agents.	('esophageal cancer', 'Disease', (49, 66))	('ICI', 'Chemical', 'MESH:C481040', (256, 259))	('patients', 'Species', '9606', (67, 75))	('inhibition', 'Var', (113, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('patients', 'Species', '9606', (171, 179))	('ESCC', 'Disease', 'MESH:D018307', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('PD-1', 'Gene', (108, 112))	('PD-1', 'Gene', '5133', (108, 112))	('interactions', 'Interaction', (235, 247))	('ESCC', 'Disease', (166, 170))
19503	30215197	In a multicenter nested case-control study, Morton et al demonstrated that the odds of developing esophageal squamous cell carcinoma were 780% greater in breast cancer survivors who received >= 3500cGY in radiation compared to those who had not received any radiation.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (98, 132))	('esophageal squamous cell carcinoma', 'Disease', (98, 132))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('>= 3500cGY', 'Var', (191, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('greater', 'PosReg', (143, 150))
19526	30215197	Although our findings are limited by small sample size, they suggest that undertreatment of ESCC-R may result in worse overall survival and earlier recurrence compared to ESCC.	('ESCC-R', 'Disease', 'MESH:C562729', (92, 98))	('ESCC', 'Disease', 'MESH:C562729', (171, 175))	('ESCC', 'Disease', (92, 96))	('earlier recurrence', 'CPA', (140, 158))	('ESCC-R', 'Disease', (92, 98))	('undertreatment', 'Var', (74, 88))	('ESCC', 'Disease', (171, 175))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))	('overall', 'MPA', (119, 126))	('worse', 'NegReg', (113, 118))
19539	30215197	Although our study contained a small number of cases, the observed trends support the conclusion that undertreatment of ESCC-R may yield worse prognosis.	('ESCC-R', 'Disease', 'MESH:C562729', (120, 126))	('undertreatment', 'Var', (102, 116))	('ESCC-R', 'Disease', (120, 126))
19620	30356981	Univariate Cox regression analysis, Table 3, showed that HGD was not a significant predictor non-BE cancer (HR = 3.40, 95%CI: 0.78-14.84, P = 0.104), but in multivariable Cox regression adjusting for age, cancer history and number of endoscopies, HGD was significantly associated with increased risk for non-BE cancer (Adj.HR = 8.32, 95%CI: 1.35-51.33, P = 0.022).	('Cox', 'Gene', '1351', (171, 174))	('Cox', 'Gene', (171, 174))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('BE', 'Phenotype', 'HP:0100580', (97, 99))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (311, 317))	('associated', 'Reg', (269, 279))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BE', 'Phenotype', 'HP:0100580', (308, 310))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('HGD', 'Var', (247, 250))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
19631	30356981	Our main finding is that BE patients with HGD had a significantly higher risk of having non-BE cancer compared to patients with lower grades of dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (144, 153))	('HGD', 'Var', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('BE', 'Phenotype', 'HP:0100580', (92, 94))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (28, 36))	('BE', 'Phenotype', 'HP:0100580', (25, 27))	('dysplasia', 'Disease', (144, 153))
19651	30356981	Our findings imply that HGD in BE may be a marker of increased risk for cancer morbidity and therefore may require extraesophageal surveillance and lifestyle modification to prevent and decrease cancer risk.	('HGD', 'Var', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('BE', 'Phenotype', 'HP:0100580', (31, 33))	('decrease', 'NegReg', (186, 194))	('cancer', 'Disease', (72, 78))
19692	29707772	Association of low-activity ALDH2 and alcohol consumption with risk of esophageal cancer in Chinese adults: A population-based cohort study Existing evidence remains inconclusive as to how the association between inactive ALDH2 and esophageal cancer (EC) depends on alcohol consumption.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('alcohol', 'Chemical', 'MESH:D000438', (266, 273))	('ALDH2', 'Gene', (222, 227))	('low-activity', 'Var', (15, 27))	('ALDH2', 'Gene', '217', (28, 33))	('alcohol', 'Chemical', 'MESH:D000438', (38, 45))	('ALDH2', 'Gene', (28, 33))	('ALDH2', 'Gene', '217', (222, 227))	('esophageal cancer', 'Disease', (232, 249))	('esophageal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('esophageal cancer', 'Disease', 'MESH:D004938', (232, 249))
19693	29707772	ALDH2 activity was assessed by both self-reported flushing response and Glu504Lys (rs671 G > A) polymorphism.	('activity', 'MPA', (6, 14))	('flushing', 'Phenotype', 'HP:0031284', (50, 58))	('flushing', 'Disease', (50, 58))	('flush', 'Phenotype', 'HP:0031284', (50, 55))	('ALDH2', 'Gene', (0, 5))	('flushing', 'Disease', 'MESH:D005483', (50, 58))	('rs671', 'Mutation', 'rs671', (83, 88))	('Glu504Lys', 'Var', (72, 81))	('Glu504Lys', 'SUBSTITUTION', 'None', (72, 81))	('ALDH2', 'Gene', '217', (0, 5))
19694	29707772	Among both male and female participants who consumed alcohol less than weekly (n = 69,519; 211 EC cases), low active or inactive ALDH2 was not associated with increased EC risk [HRs (95% CIs): GA vs. GG 0.75 (0.54, 1.04); AA vs. GG 1.01 (0.46, 2.20)].	('alcohol', 'Chemical', 'MESH:D000438', (53, 60))	('ALDH2', 'Gene', (129, 134))	('participants', 'Species', '9606', (27, 39))	('low active', 'Var', (106, 116))	('ALDH2', 'Gene', '217', (129, 134))
19695	29707772	Among male weekly alcohol consumers, both flushing response [n = 59,380; 501 EC cases; HRs (95% CIs): "soon after drinking" vs. "no" flushing response 1.45 (1.05, 2.01)] and rs671 [n = 10,692; 94 EC cases; GA vs. GG 3.31 (1.94, 5.67)] were associated with EC risk.	('flushing', 'Disease', 'MESH:D005483', (42, 50))	('rs671 [', 'Var', (174, 181))	('flushing', 'Phenotype', 'HP:0031284', (133, 141))	('flush', 'Phenotype', 'HP:0031284', (133, 138))	('rs671', 'Mutation', 'rs671', (174, 179))	('associated', 'Reg', (240, 250))	('flushing', 'Disease', (133, 141))	('flushing', 'Disease', 'MESH:D005483', (133, 141))	('flushing', 'Phenotype', 'HP:0031284', (42, 50))	('flush', 'Phenotype', 'HP:0031284', (42, 47))	('flushing', 'Disease', (42, 50))	('alcohol', 'Chemical', 'MESH:D000438', (18, 25))
19698	29707772	Self-reported flushing response had low sensitivity (56.8%) and high specificity (88.4%) in identifying rs671 A allele among male weekly alcohol consumers.	('flushing', 'Disease', 'MESH:D005483', (14, 22))	('flushing', 'Phenotype', 'HP:0031284', (14, 22))	('rs671 A', 'Var', (104, 111))	('alcohol', 'Chemical', 'MESH:D000438', (137, 144))	('rs671', 'Mutation', 'rs671', (104, 109))	('flush', 'Phenotype', 'HP:0031284', (14, 19))	('flushing', 'Disease', (14, 22))
19699	29707772	In conclusion, low-activity ALDH2 was associated with increased EC risk among male heavy alcohol consumers.	('alcohol', 'Chemical', 'MESH:D000438', (89, 96))	('ALDH2', 'Gene', '217', (28, 33))	('low-activity', 'Var', (15, 27))	('ALDH2', 'Gene', (28, 33))	('heavy alcohol consumers', 'Phenotype', 'HP:0030955', (83, 106))
19702	29707772	The key enzyme for acetaldehyde elimination is acetaldehyde dehydrogenase 2 (ALDH2), and an association between ALDH2 genotype and EC risk that is dependent on alcohol consumption has been suggested.	('acetaldehyde', 'Chemical', 'MESH:D000079', (19, 31))	('alcohol', 'Chemical', 'MESH:D000438', (160, 167))	('ALDH2', 'Gene', (112, 117))	('acetaldehyde', 'Chemical', 'MESH:D000079', (47, 59))	('ALDH2', 'Gene', (77, 82))	('acetaldehyde dehydrogenase 2', 'Gene', (47, 75))	('ALDH2', 'Gene', '217', (77, 82))	('ALDH2', 'Gene', '217', (112, 117))	('acetaldehyde dehydrogenase 2', 'Gene', '217', (47, 75))	('genotype', 'Var', (118, 126))
19703	29707772	In this large prospective cohort of Chinese adults, the ALDH2 rs671 A allele was not associated with increased EC risk in the absence of alcohol consumption.	('rs671 A', 'Var', (62, 69))	('ALDH2', 'Gene', '217', (56, 61))	('alcohol', 'Chemical', 'MESH:D000438', (137, 144))	('rs671', 'Mutation', 'rs671', (62, 67))	('ALDH2', 'Gene', (56, 61))
19704	29707772	The increased EC risk associated with low-activity ALDH2, characterized as self-reported flushing response or rs671 GA, was apparent in men consuming alcohol >=30g/day, but not among light-to-moderate consumers.	('flushing', 'Disease', 'MESH:D005483', (89, 97))	('alcohol', 'Chemical', 'MESH:D000438', (150, 157))	('ALDH2', 'Gene', '217', (51, 56))	('flushing', 'Phenotype', 'HP:0031284', (89, 97))	('flush', 'Phenotype', 'HP:0031284', (89, 94))	('low-activity', 'Var', (38, 50))	('rs671 GA', 'Var', (110, 118))	('flushing', 'Disease', (89, 97))	('rs671', 'Mutation', 'rs671', (110, 115))	('ALDH2', 'Gene', (51, 56))	('men', 'Species', '9606', (136, 139))
19705	29707772	ALDH2 acetaldehyde dehydrogenase 2 CI confidence interval CKB China Kadoorie Biobank EC esophageal cancer ESCC esophageal squamous cell cancer HRs hazard ratios IARC International Agency for Research on Cancer ICD International Classification of Diseases Esophageal cancer (EC) remains a global concern because of its increasing incidence and persistently poor survival.1, 2 China is among the highest EC incidence countries.2 Alcohol consumption is a well-established risk factor for esophageal squamous cell cancer (ESCC),3 the most common histological subtype globally.2 Acetaldehyde, a toxic metabolite of alcohol that damages DNA, has been classified as a Group 1 human carcinogen by the International Agency for Research on Cancer (IARC) and is considered a major cause underlying alcohol-induced carcinogenesis.4  The key enzyme for acetaldehyde elimination is acetaldehyde dehydrogenase 2 (ALDH2), encoded by the ALDH2 gene.5 A Glu504Lys polymorphism in ALDH2 which reduces its activity is almost exclusively present and highly prevalent among East Asians.6 In carriers of ALDH2 Lys/Lys and Glu/Lys, the enzyme activity is nearly 0% and 17-38% of the normal activity, respectively.7 This dramatic reduction in enzyme activity leads to accumulation of acetaldehyde in the circulation even after moderate alcohol consumption.8 The ALDH2 Lys variant also causes the well-known Asian flush, an unpleasant physiological response to alcohol consumption that includes facial flushing, nausea and tachycardia and inhibits alcohol consumption.9  It has been suggested that there is an association between ALDH2 genotype and EC risk which is dependent on alcohol consumption.	('Glu504Lys', 'Var', (936, 945))	('flush', 'Disease', 'MESH:D005483', (1476, 1481))	('nausea', 'Phenotype', 'HP:0002018', (1486, 1492))	('human', 'Species', '9606', (669, 674))	('Glu504Lys', 'SUBSTITUTION', 'None', (936, 945))	('ALDH2', 'Gene', (1337, 1342))	('ALDH2', 'Gene', (1081, 1086))	('acetaldehyde', 'Chemical', 'MESH:D000079', (840, 852))	('acetaldehyde', 'Chemical', 'MESH:D000079', (6, 18))	('flush', 'Disease', 'MESH:D005483', (1388, 1393))	('acetaldehyde dehydrogenase 2', 'Gene', (868, 896))	('IARC', 'Disease', (738, 742))	('accumulation of acetaldehyde', 'Phenotype', 'HP:0003533', (1243, 1271))	('nausea and tachycardia', 'Phenotype', 'HP:0002017', (1486, 1508))	('flush', 'Phenotype', 'HP:0031284', (1476, 1481))	('cancer', 'Phenotype', 'HP:0002664', (510, 516))	('ALDH2', 'Gene', (962, 967))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Esophageal cancer', 'Disease', (255, 272))	('alcohol', 'Chemical', 'MESH:D000438', (610, 617))	('ALDH2', 'Gene', (898, 903))	('acetaldehyde', 'Chemical', 'MESH:D000079', (1259, 1271))	('flush', 'Phenotype', 'HP:0031284', (1388, 1393))	('acetaldehyde', 'Chemical', 'MESH:D000079', (868, 880))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (111, 142))	('tachycardia', 'Phenotype', 'HP:0001649', (1497, 1508))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (485, 516))	('tachycardia', 'Disease', 'MESH:D013610', (1497, 1508))	('nausea', 'Disease', (1486, 1492))	('tachycardia', 'Disease', (1497, 1508))	('ALDH2', 'Gene', (0, 5))	('ICD', 'Gene', '79158', (210, 213))	('Acetaldehyde', 'Chemical', 'MESH:D000079', (574, 586))	('alcohol', 'Chemical', 'MESH:D000438', (1435, 1442))	('alcohol', 'Chemical', 'MESH:D000438', (1522, 1529))	('ALDH2', 'Gene', (921, 926))	('ALDH2', 'Gene', (1604, 1609))	('IARC', 'Disease', 'None', (161, 165))	('facial flushing', 'Disease', 'MESH:D005483', (1469, 1484))	('ALDH2', 'Gene', '217', (1337, 1342))	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('ALDH2', 'Gene', '217', (1081, 1086))	('acetaldehyde dehydrogenase 2', 'Gene', '217', (6, 34))	('CKB', 'Chemical', '-', (58, 61))	('Cancer', 'Phenotype', 'HP:0002664', (730, 736))	('flushing', 'Phenotype', 'HP:0031284', (1476, 1484))	('nausea', 'Disease', 'MESH:D009325', (1486, 1492))	('facial flushing', 'Disease', (1469, 1484))	('Esophageal cancer', 'Disease', 'MESH:D004938', (255, 272))	('IARC', 'Disease', 'None', (738, 742))	('ALDH2', 'Gene', '217', (962, 967))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (496, 516))	('esophageal squamous cell cancer', 'Disease', (485, 516))	('ALDH2', 'Gene', '217', (898, 903))	('carcinogenesis', 'Disease', (803, 817))	('esophageal cancer', 'Disease', (88, 105))	('esophageal squamous cell cancer', 'Disease', (111, 142))	('alcohol', 'Chemical', 'MESH:D000438', (1653, 1660))	('ALDH2', 'Gene', '217', (0, 5))	('Alcohol', 'Chemical', 'MESH:D000438', (427, 434))	('flush', 'Disease', (1476, 1481))	('acetaldehyde dehydrogenase 2', 'Gene', '217', (868, 896))	('carcinogenesis', 'Disease', 'MESH:D063646', (803, 817))	('flush', 'Disease', (1388, 1393))	('ALDH2', 'Gene', '217', (1604, 1609))	('ICD', 'Gene', (210, 213))	('ALDH2', 'Gene', '217', (921, 926))	('Cancer', 'Phenotype', 'HP:0002664', (203, 209))	('alcohol', 'Chemical', 'MESH:D000438', (1311, 1318))	('acetaldehyde dehydrogenase 2', 'Gene', (6, 34))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('alcohol', 'Chemical', 'MESH:D000438', (787, 794))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (122, 142))	('IARC', 'Disease', (161, 165))
19707	29707772	Two prospective studies conducted in Japanese men, with 33 and 215 incident EC cases separately, yielded inconsistent results.12, 13 Thus, the existing evidence remains inconclusive as to the association between inactive ALDH2 and EC risk.	('ALDH2', 'Gene', '217', (221, 226))	('ALDH2', 'Gene', (221, 226))	('inactive', 'Var', (212, 220))	('men', 'Species', '9606', (46, 49))
19709	29707772	In the China Kadoorie Biobank (CKB) prospective study, we first examined whether ALDH2 genotype was associated with EC risk in the absence of alcohol consumption in both men and women.	('ALDH2', 'Gene', '217', (81, 86))	('CKB', 'Chemical', '-', (31, 34))	('ALDH2', 'Gene', (81, 86))	('associated with', 'Reg', (100, 115))	('men', 'Species', '9606', (180, 183))	('men', 'Species', '9606', (170, 173))	('women', 'Species', '9606', (178, 183))	('alcohol', 'Chemical', 'MESH:D000438', (142, 149))	('genotype', 'Var', (87, 95))
19723	29707772	Genotyping using a 384-SNP Illumina  GoldenGate array, including ALDH2 rs671 G > A (Glu504Lys), was done in 95,680 randomly selected CKB participants at the BGI laboratory in Shenzhen, China.	('Glu504Lys', 'Var', (84, 93))	('Glu504Lys', 'SUBSTITUTION', 'None', (84, 93))	('ALDH2', 'Gene', '217', (65, 70))	('participants', 'Species', '9606', (137, 149))	('ALDH2', 'Gene', (65, 70))	('CKB', 'Chemical', '-', (133, 136))	('rs671', 'Mutation', 'rs671', (71, 76))
19735	29707772	The analysis of ALDH2 genotype and alcohol consumption on EC risk was confined to 27,791 men with rs671 GA/GG because only 14 (1.0%) men with AA consumed alcohol weekly.	('ALDH2', 'Gene', (16, 21))	('rs671', 'Mutation', 'rs671', (98, 103))	('alcohol', 'Chemical', 'MESH:D000438', (154, 161))	('rs671 GA/GG', 'Var', (98, 109))	('men', 'Species', '9606', (133, 136))	('ALDH2', 'Gene', '217', (16, 21))	('men', 'Species', '9606', (89, 92))	('alcohol', 'Chemical', 'MESH:D000438', (35, 42))
19743	29707772	We also estimated the population attributable fraction (PAF) as Px[(HRadj-1)/HRadj], where P is the proportion of EC cases having exposure of interests, and HRadj is the multivariable-adjusted relative risk for this exposure category relative to the unexposed group.17  We also assessed the questions for detecting inactive ALDH2 in terms of sensitivity (the proportion of participants possessing rs671 A allele who were correctly identified as a flusher by the questionnaire) and specificity (the proportion of participants possessing active rs671 GG genotype who were correctly identified as a non-flusher by the questionnaire) among male weekly alcohol consumers.	('alcohol', 'Chemical', 'MESH:D000438', (648, 655))	('flush', 'Disease', 'MESH:D005483', (447, 452))	('-flusher', 'Phenotype', 'HP:0031284', (599, 607))	('PAF', 'Chemical', '-', (56, 59))	('participants', 'Species', '9606', (373, 385))	('rs671 A', 'Var', (397, 404))	('rs671', 'Mutation', 'rs671', (397, 402))	('rs671', 'Mutation', 'rs671', (543, 548))	('ALDH2', 'Gene', '217', (324, 329))	('flush', 'Phenotype', 'HP:0031284', (600, 605))	('flush', 'Disease', (600, 605))	('flush', 'Phenotype', 'HP:0031284', (447, 452))	('participants', 'Species', '9606', (512, 524))	('ALDH2', 'Gene', (324, 329))	('flush', 'Disease', 'MESH:D005483', (600, 605))	('flush', 'Disease', (447, 452))
19748	29707772	Compared to men with rs671 GG, those with A alleles were less likely to be daily alcohol consumers and consumed less alcohol on a typical drinking day.	('rs671', 'Var', (21, 26))	('alcohol', 'Chemical', 'MESH:D000438', (81, 88))	('rs671', 'Mutation', 'rs671', (21, 26))	('less', 'NegReg', (112, 116))	('men', 'Species', '9606', (12, 15))	('less', 'NegReg', (57, 61))	('alcohol', 'Chemical', 'MESH:D000438', (117, 124))
19753	29707772	After adjustment for the amount of alcohol consumed and other potential confounders, the adjusted HRs (95% CIs) for EC were 0.96 (0.79, 1.18) for those reporting "large," 1.19 (0.88, 1.61) for "small" and 1.45 (1.05, 2.01) for "soon," compared to men reporting "no" flush response.	('flush', 'Phenotype', 'HP:0031284', (266, 271))	('men', 'Species', '9606', (12, 15))	('flush', 'Disease', (266, 271))	('small', 'Var', (194, 199))	('flush', 'Disease', 'MESH:D005483', (266, 271))	('alcohol', 'Chemical', 'MESH:D000438', (35, 42))	('men', 'Species', '9606', (247, 250))
19757	29707772	Among male weekly alcohol consumers, when stratified by the amount of alcohol consumed, the statistically significant increase in EC risk associated with "soon" flushing response was present in daily consumers of >=60 g/d of alcohol, and increased EC risk associated with rs671 GA present in those of >=30 g/d of alcohol.	('increase', 'PosReg', (118, 126))	('flushing', 'Phenotype', 'HP:0031284', (161, 169))	('rs671', 'Mutation', 'rs671', (272, 277))	('rs671 GA', 'Var', (272, 280))	('flush', 'Phenotype', 'HP:0031284', (161, 166))	('alcohol', 'Chemical', 'MESH:D000438', (70, 77))	('alcohol', 'Chemical', 'MESH:D000438', (313, 320))	('flushing', 'Disease', (161, 169))	('flushing', 'Disease', 'MESH:D005483', (161, 169))	('alcohol', 'Chemical', 'MESH:D000438', (18, 25))	('alcohol', 'Chemical', 'MESH:D000438', (225, 232))
19758	29707772	However, there was no statistically significant difference in the association of EC risk with self-reported flushing response (p interaction = 0.618) or ALDH2 genotype (p interaction = 0.376) across the amount of alcohol consumed per day (Table 2).	('flushing', 'Disease', 'MESH:D005483', (108, 116))	('alcohol', 'Chemical', 'MESH:D000438', (213, 220))	('ALDH2', 'Gene', '217', (153, 158))	('genotype', 'Var', (159, 167))	('flushing', 'Phenotype', 'HP:0031284', (108, 116))	('flushing', 'Disease', (108, 116))	('flush', 'Phenotype', 'HP:0031284', (108, 113))	('ALDH2', 'Gene', (153, 158))
19760	29707772	However, heavier alcohol consumption was associated with greater increase in EC risk for those with "soon" flushing response or rs671 GA.	('flushing', 'Disease', (107, 115))	('flushing', 'Disease', 'MESH:D005483', (107, 115))	('alcohol', 'Chemical', 'MESH:D000438', (17, 24))	('rs671 GA', 'Var', (128, 136))	('flushing', 'Phenotype', 'HP:0031284', (107, 115))	('flush', 'Phenotype', 'HP:0031284', (107, 112))	('rs671', 'Mutation', 'rs671', (128, 133))
19764	29707772	Among men who consumed alcohol >=90 g/d, the highest EC risk was for those with "soon" flushing response (HR = 11.73; 95% CI: 6.17, 22.31) and for those with rs671 GA (HR = 22.54; 95% CI: 8.30, 61.21).	('flushing', 'Disease', 'MESH:D005483', (87, 95))	('alcohol', 'Chemical', 'MESH:D000438', (23, 30))	('rs671', 'Mutation', 'rs671', (158, 163))	('rs671 GA', 'Var', (158, 166))	('flushing', 'Disease', (87, 95))	('flushing', 'Phenotype', 'HP:0031284', (87, 95))	('flush', 'Phenotype', 'HP:0031284', (87, 92))	('men', 'Species', '9606', (6, 9))
19765	29707772	If the exposure of interest is causal, the fraction of EC risk in the male population that would be eliminated if participants who have low-activity ALDH2 (rs671 GA) and consume alcohol >=30 g/d changed to be light-to-moderate consumers or abstain from alcohol (i.e., the population attributable fraction, PAF) was 7%.	('low-activity', 'NegReg', (136, 148))	('ALDH2', 'Gene', (149, 154))	('rs671', 'Mutation', 'rs671', (156, 161))	('alcohol', 'Chemical', 'MESH:D000438', (253, 260))	('PAF', 'Chemical', '-', (306, 309))	('alcohol', 'Chemical', 'MESH:D000438', (178, 185))	('participants', 'Species', '9606', (114, 126))	('ALDH2', 'Gene', '217', (149, 154))	('rs671', 'Var', (156, 161))
19767	29707772	Low-activity ALDH2, characterized as self-reported flushing response or rs671 GA heterozygotes, was associated with an increased EC risk among male heavy alcohol consumers of >=30 g/d.	('Low-activity', 'Var', (0, 12))	('ALDH2', 'Gene', '217', (13, 18))	('flushing', 'Disease', 'MESH:D005483', (51, 59))	('alcohol', 'Chemical', 'MESH:D000438', (154, 161))	('rs671', 'Var', (72, 77))	('ALDH2', 'Gene', (13, 18))	('heavy alcohol consumers', 'Phenotype', 'HP:0030955', (148, 171))	('flushing', 'Phenotype', 'HP:0031284', (51, 59))	('rs671', 'Mutation', 'rs671', (72, 77))	('flushing', 'Disease', (51, 59))	('flush', 'Phenotype', 'HP:0031284', (51, 56))
19768	29707772	The increased EC risk associated with 15 g of alcohol per day was 30-40% among daily alcohol consumers with low-activity ALDH2, greater than those with active ALDH2.	('alcohol', 'Chemical', 'MESH:D000438', (46, 53))	('alcohol', 'Chemical', 'MESH:D000438', (85, 92))	('ALDH2', 'Gene', '217', (121, 126))	('ALDH2', 'Gene', '217', (159, 164))	('low-activity', 'Var', (108, 120))	('ALDH2', 'Gene', (159, 164))	('ALDH2', 'Gene', (121, 126))
19770	29707772	The rs671 GA heterozygotes were linked to an increased EC risk (OR = 2.34; 95% CI: 1.75, 3.13) in a recent meta-analysis of 31 case-control studies, almost exclusively conducted in China and Japan.10 The OR (95% CI) of GA heterozygotes for EC was 1.21 (0.95, 1.73) among non-alcohol consumers, 3.79 (3.04, 4.72) among light consumers (1-350 g/week of alcohol) and 6.50 (5.34, 7.92) among heavy consumers (>=350 g/week of alcohol).	('alcohol', 'Chemical', 'MESH:D000438', (351, 358))	('alcohol', 'Chemical', 'MESH:D000438', (421, 428))	('1-350 g/week', 'Var', (335, 347))	('rs671', 'Mutation', 'rs671', (4, 9))	('alcohol', 'Chemical', 'MESH:D000438', (275, 282))	('>=350 g/week', 'Var', (405, 417))
19775	29707772	The EC risk associated with the synergistic interaction between inactive ALDH2 and alcohol consumption underscores the importance of screening for the ALDH2 deficiency.	('ALDH2', 'Gene', (73, 78))	('ALDH2 deficiency', 'Disease', (151, 167))	('inactive', 'Var', (64, 72))	('ALDH2', 'Gene', '217', (151, 156))	('ALDH2', 'Gene', '217', (73, 78))	('ALDH2 deficiency', 'Disease', 'MESH:D007153', (151, 167))	('alcohol', 'Chemical', 'MESH:D000438', (83, 90))	('ALDH2', 'Gene', (151, 156))
19781	29707772	Individuals with rs671 AA genotype tend to avoid alcohol consumption due to the very unpleasant responses they experience and are naturally protected from alcohol-induced carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (171, 185))	('alcohol consumption', 'MPA', (49, 68))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))	('carcinogenesis', 'Disease', (171, 185))	('avoid', 'NegReg', (43, 48))	('rs671', 'Mutation', 'rs671', (17, 22))	('alcohol', 'Chemical', 'MESH:D000438', (155, 162))	('rs671 AA', 'Var', (17, 25))
19791	29707772	Less than one-fifth of the CKB participants was genotyped, resulting in wide confidence intervals for the effect estimates of interaction between ALDH2 genotype and alcohol consumption.	('interaction', 'Interaction', (126, 137))	('participants', 'Species', '9606', (31, 43))	('ALDH2', 'Gene', '217', (146, 151))	('alcohol', 'Chemical', 'MESH:D000438', (165, 172))	('ALDH2', 'Gene', (146, 151))	('genotype', 'Var', (152, 160))	('CKB', 'Chemical', '-', (27, 30))
19794	29707772	However, a noticeably extra increased EC risk related to low-activity ALDH2 was observed among heavy alcohol consumers, but not among light-to-moderate consumers.	('alcohol', 'Chemical', 'MESH:D000438', (101, 108))	('low-activity', 'Var', (57, 69))	('heavy alcohol consumers', 'Phenotype', 'HP:0030955', (95, 118))	('ALDH2', 'Gene', '217', (70, 75))	('ALDH2', 'Gene', (70, 75))
19867	29228742	reported their data from a large-scale retrospective study of 502 esophageal squamous cell carcinoma (ESCC) patients and showed that ECOG PS (unfavorable: ECOG 2; HR 2.809, 95%CI 1.962-4.020; P<0.001) was also an independent prognostic factor in multivariate analysis of OS.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (66, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('ECOG PS', 'Var', (133, 140))	('esophageal squamous cell carcinoma', 'Disease', (66, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('patients', 'Species', '9606', (108, 116))
19881	29228742	A patient's BMI was calculated and classified according to the Asian-specific BMI cutoff values as follows: underweight (<18.5 kg/m2); normal weight (18.5-22.9 kg/m2); overweight and obese (>=23.0 kg/m2).	('obese', 'Disease', (183, 188))	('<18.5', 'Var', (121, 126))	('overweight', 'Phenotype', 'HP:0025502', (168, 178))	('18.5-22.9', 'Var', (150, 159))	('obese', 'Disease', 'MESH:D009765', (183, 188))	('patient', 'Species', '9606', (2, 9))
19934	28968416	In network D, SEMS and SEMS+BT increased the risk of bleeding when compared to brachytherapy (Fig 5).	('SEMS+BT', 'Var', (23, 30))	('bleeding', 'Disease', 'MESH:D006470', (53, 61))	('bleeding', 'Disease', (53, 61))	('increased', 'PosReg', (31, 40))
19955	28968416	However, it should be noted the plastic stents compared with other stents, increased the risk of TRD, bleeding, stent migration and aspiration.	('plastic stents', 'Var', (32, 46))	('aspiration', 'Phenotype', 'HP:0002835', (132, 142))	('aspiration', 'Disease', (132, 142))	('stent migration', 'CPA', (112, 127))	('bleeding', 'Disease', 'MESH:D006470', (102, 110))	('bleeding', 'Disease', (102, 110))	('TRD', 'Disease', (97, 100))
19958	28968416	In the aforementioned meta-analysis, the odds ratio of stent migration in patients who had received ultraflex stents versus other types of stents was 1.17 (95% CI: 0.71, 1.93).	('stent migration', 'CPA', (55, 70))	('patients', 'Species', '9606', (74, 82))	('ultraflex', 'Var', (100, 109))
19959	28968416	In our study, the risk of stent migration was higher for ultraflex stent versus covered Evolution  stent, Flamingo stent, and Ultraflex stent plus radiotherapy.	('ultraflex', 'Var', (57, 66))	('stent migration', 'CPA', (26, 41))	('Flamingo', 'Species', '435638', (106, 114))
19961	28968416	According to this meta-analysis, the odds ratio of severe pain for the ultraflex stent versus the other stents was 0.52; 95% CI (0.19, 1.45).	('ultraflex', 'Var', (71, 80))	('pain', 'Disease', 'MESH:D010146', (58, 62))	('pain', 'Disease', (58, 62))	('pain', 'Phenotype', 'HP:0012531', (58, 62))
19967	28968416	When compared with brachytherapy, SEMS 18 increased the risk of TRD and bleeding 5.61 and 2.62 times, respectively.	('increased', 'PosReg', (42, 51))	('bleeding', 'Disease', (72, 80))	('TRD', 'Disease', (64, 67))	('SEMS 18', 'Var', (34, 41))	('bleeding', 'Disease', 'MESH:D006470', (72, 80))
20037	26056434	Modulation of apoptotic pathways and selective induction of apoptosis by chemical agents have been shown to be a promising approach in the treatment of cancer.	('Modulation', 'Var', (0, 10))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('apoptotic pathways', 'Pathway', (14, 32))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
20042	26056434	Herbs with "heat and toxin-clearing" activity as well as "supplementing the center and boost the energy", can be used for cancer treatment.	('boost', 'PosReg', (87, 92))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('supplementing', 'Var', (58, 71))	('center', 'MPA', (76, 82))	('energy', 'MPA', (97, 103))
20077	26056434	(50-400 mug/mL), a TCM used to treat various cancers in Asian countries, can induce apoptosis in HepG2 cells by stimulating the apoptotic factors Bcl-2, Bcl-XL, MCL-1, XIAP, BID, BIK, caspase-3, caspase-9, and PARP.	('Bcl-XL', 'Gene', '598', (153, 159))	('HepG2', 'CellLine', 'CVCL:0027', (97, 102))	('caspase-3', 'Gene', (184, 193))	('Bcl-XL', 'Gene', (153, 159))	('stimulating', 'PosReg', (112, 123))	('caspase-9', 'Gene', '842', (195, 204))	('50-400 mug/mL', 'Var', (1, 14))	('BIK', 'Gene', '638', (179, 182))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('BID', 'Gene', (174, 177))	('PARP', 'Gene', '142', (210, 214))	('BIK', 'Gene', (179, 182))	('XIAP', 'Gene', '331', (168, 172))	('apoptotic', 'MPA', (128, 137))	('apoptosis', 'CPA', (84, 93))	('PARP', 'Gene', (210, 214))	('BID', 'Gene', '637', (174, 177))	('caspase-9', 'Gene', (195, 204))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('MCL-1', 'Gene', '4170', (161, 166))	('cancers', 'Disease', (45, 52))	('induce', 'PosReg', (77, 83))	('XIAP', 'Gene', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('caspase-3', 'Gene', '836', (184, 193))	('MCL-1', 'Gene', (161, 166))
20101	26056434	Further study shows that the anticancer effect of P. abalonus Y. H. Han, K. M. Chen et S. Cheng is attributed to the ROS-mediated mitochondrial apoptotic pathway.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('ROS-mediated mitochondrial apoptotic pathway', 'Pathway', (117, 161))	('ROS', 'Chemical', 'MESH:D017382', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('P. abalonus', 'Species', '47962', (50, 61))	('P. abalonus', 'Var', (50, 61))
20116	26056434	It has been reported that longikaurin A can induce apoptosis via the ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells.	('JNK', 'Gene', (73, 76))	('induce', 'PosReg', (44, 50))	('c-Jun', 'Gene', '3725', (77, 82))	('longikaurin A', 'Var', (26, 39))	('longikaurin A', 'Chemical', 'MESH:C581034', (26, 39))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (94, 118))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (94, 118))	('JNK', 'Gene', '5599', (73, 76))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('hepatocellular carcinoma', 'Disease', (94, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('c-Jun', 'Gene', (77, 82))	('apoptosis', 'CPA', (51, 60))
20122	26056434	Recent studies showed the BDL301 can suppress the STAT3 pathway, resulting in apoptosis in colorectal cancer cells in vitro and in vivo.	('colorectal cancer', 'Disease', (91, 108))	('apoptosis', 'CPA', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('STAT3', 'Gene', '6774', (50, 55))	('suppress', 'NegReg', (37, 45))	('STAT3', 'Gene', (50, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('BDL301', 'Var', (26, 32))
20133	26056434	Analysis of the structure-activity relationship suggested that the NF-kappaB inhibitory activity of trans-N-caffeoyltyramine was related with its Michael acceptor-type structure (an alpha,beta-unsaturated carbonyl group).	('NF-kappaB', 'Gene', '4790', (67, 76))	('inhibitory', 'NegReg', (77, 87))	('trans-N-caffeoyltyramine', 'Var', (100, 124))	('NF-kappaB', 'Gene', (67, 76))	('trans-N-caffeoyltyramine', 'Chemical', '-', (100, 124))
20147	26056434	Several preclinical and clinical studies have demonstrated the anticancer potential of P. ginseng C. A. Mey.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('P. ginseng C. A. Mey', 'Species', '4054', (87, 107))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('C. A. Mey', 'Var', (98, 107))
20149	26056434	In a Korean study, P. ginseng C. A. Mey caused apoptosis by downregulating antiapoptotic Bcl-2, Bcl-XL, and IAP family members and activating caspase-3.	('antiapoptotic Bcl-2', 'MPA', (75, 94))	('apoptosis', 'CPA', (47, 56))	('caspase-3', 'Gene', '836', (142, 151))	('activating', 'PosReg', (131, 141))	('P. ginseng C. A. Mey', 'Var', (19, 39))	('P. ginseng C. A. Mey', 'Species', '4054', (19, 39))	('downregulating', 'NegReg', (60, 74))	('Bcl-XL', 'Gene', '598', (96, 102))	('Bcl-XL', 'Gene', (96, 102))	('caspase-3', 'Gene', (142, 151))	('IAP family members', 'Protein', (108, 126))
20163	26056434	It has been demonstrated that KLT induces apoptosis of certain types of cancer cells by upregulating expression of p53, Fas, caspase-3, PCNA, and p21 WAF1/CIP1, and downregulating expression of cyclins A, E1, and F. Bufalin, the major bioactive component of V. bufonis, is a TCM obtained from the skin and parotid venom glands of the toad.	('p53', 'Gene', (115, 118))	('bufonis', 'Chemical', '-', (261, 268))	('p21 WAF1/CIP1', 'Gene', (146, 159))	('cancer', 'Disease', (72, 78))	('downregulating', 'NegReg', (165, 179))	('PCNA', 'Gene', (136, 140))	('KLT', 'Var', (30, 33))	('p21 WAF1/CIP1', 'Gene', '1026', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('caspase-3', 'Gene', '836', (125, 134))	('upregulating', 'PosReg', (88, 100))	('caspase-3', 'Gene', (125, 134))	('expression', 'MPA', (180, 190))	('apoptosis', 'CPA', (42, 51))	('PCNA', 'Gene', '5111', (136, 140))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Bufalin', 'Chemical', 'MESH:C022777', (216, 223))	('induces', 'Reg', (34, 41))	('p53', 'Gene', '7157', (115, 118))	('expression', 'MPA', (101, 111))	('Fas', 'Gene', (120, 123))
20164	26056434	Studies have shown that bufalin induces apoptosis in various types of cancer cells, including hepatocellular carcinoma (0.001-0.1 muM), colon cancer (25-100 nM), leukemia (10-12.5 nM), gastric cancer (80 nmol/L), prostate cancer (0.1-10 muM), and malignant melanoma (150-550 nmol/L).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('induces', 'Reg', (32, 39))	('apoptosis', 'CPA', (40, 49))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (94, 118))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('muM', 'Gene', '56925', (130, 133))	('malignant melanoma', 'Phenotype', 'HP:0002861', (247, 265))	('25-100', 'Var', (150, 156))	('bufalin', 'Chemical', 'MESH:C022777', (24, 31))	('gastric cancer', 'Phenotype', 'HP:0012126', (185, 199))	('muM', 'Gene', (130, 133))	('malignant melanoma', 'Disease', 'MESH:D008545', (247, 265))	('cancer', 'Disease', (222, 228))	('colon cancer', 'Phenotype', 'HP:0003003', (136, 148))	('hepatocellular carcinoma', 'Disease', (94, 118))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (70, 76))	('prostate cancer', 'Disease', 'MESH:D011471', (213, 228))	('prostate cancer', 'Phenotype', 'HP:0012125', (213, 228))	('cancer', 'Disease', (142, 148))	('muM', 'Gene', '56925', (237, 240))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (185, 199))	('muM', 'Gene', (237, 240))	('colon cancer', 'Disease', 'MESH:D015179', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('prostate cancer', 'Disease', (213, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('gastric cancer', 'Disease', (185, 199))	('leukemia', 'Phenotype', 'HP:0001909', (162, 170))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (94, 118))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('malignant melanoma', 'Disease', (247, 265))	('leukemia', 'Disease', (162, 170))	('leukemia', 'Disease', 'MESH:D007938', (162, 170))	('colon cancer', 'Disease', (136, 148))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
20174	26056434	As already mentioned, apoptosis is one of the main mechanisms by which TCM induces death of cancer cell, but the direct targets involved have not been documented.	('apoptosis', 'CPA', (22, 31))	('death of cancer', 'Disease', (83, 98))	('TCM', 'Var', (71, 74))	('death of cancer', 'Disease', 'MESH:D003643', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
20194	24618814	Although many molecular biomarker candidates of ESCC, such as squamous cell carcinoma antigen (SCC-Ag), carcinoembryonic antigen (CEA), CA19-9, and mutated p53, have been identified; biomarkers with the necessary sensitivity and specificity are still lacking.	('carcinoembryonic antigen', 'Gene', (104, 128))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('squamous cell carcinoma', 'Disease', (62, 85))	('CEA', 'Gene', (130, 133))	('mutated', 'Var', (148, 155))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('CEA', 'Gene', '1048', (130, 133))	('carcinoembryonic antigen', 'Gene', '1048', (104, 128))	('ESCC', 'Disease', (48, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
20245	24618814	Two hours after injecting the probe, we observed a strong specific fluorescence signal localized at the tumor sites (9.78x109+-1.1x109) which gradually increased up to about 32 hrs (2.90x1010+-1.84x109) in tumor bearing mice compared to normal nude mice (Fig.	('9.78x109+-1.1x109', 'Var', (117, 134))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (206, 211))	('mice', 'Species', '10090', (220, 224))	('tumor', 'Disease', (104, 109))	('mice', 'Species', '10090', (249, 253))	('nude mice', 'Species', '10090', (244, 253))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
20290	19568551	Also patients who received cervical anastomosis and ER with colon had significantly fewer reflux symptoms.	('cervical anastomosis', 'Phenotype', 'HP:0002949', (27, 47))	('patients', 'Species', '9606', (5, 13))	('reflux', 'Disease', (90, 96))	('reflux symptoms', 'Phenotype', 'HP:0002020', (90, 105))	('fewer', 'NegReg', (84, 89))	('cervical anastomosis', 'Var', (27, 47))
20340	19568551	Patients with cervical anastomosis had significantly fewer symptoms of reflux when compared with those who received intrathoracic anastomosis.	('thoracic anastomosis', 'Disease', (121, 141))	('cervical anastomosis', 'Phenotype', 'HP:0002949', (14, 34))	('fewer', 'NegReg', (53, 58))	('thoracic anastomosis', 'Disease', 'MESH:D013896', (121, 141))	('reflux', 'MPA', (71, 77))	('symptoms', 'MPA', (59, 67))	('Patients', 'Species', '9606', (0, 8))	('cervical anastomosis', 'Var', (14, 34))
20346	19568551	Patients who received transhiatal esophagectomy have better quality of life than those with transthoracic esophagectomy.	('Patients', 'Species', '9606', (0, 8))	('transhiatal', 'Var', (22, 33))	('quality of life', 'CPA', (60, 75))
20380	33112558	This study aimed to assess whether polymorphisms of PARP1 gene could be used as predictive biomarkers for the survival of esophageal squamous cell carcinoma (ESCC) patients from Cixian high-incidence region in northern China.	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('PARP1', 'Gene', (52, 57))	('esophageal squamous cell carcinoma', 'Disease', (122, 156))	('polymorphisms', 'Var', (35, 48))	('patients', 'Species', '9606', (164, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (122, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))
20381	33112558	In 203 ESCC patients with survival information, PARP1 rs1136410 T/C and rs8679 T/C single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) method.	('rs8679 T/C', 'Var', (72, 82))	('rs1136410', 'Mutation', 'rs1136410', (54, 63))	('patients', 'Species', '9606', (12, 20))	('PARP1', 'Gene', (48, 53))	('rs1136410 T/C', 'Var', (54, 67))	('rs8679', 'Mutation', 'rs8679', (72, 78))	('ESCC', 'Disease', (7, 11))
20386	33112558	For rs8679, the mean survival time of T/T genotype carriers was 43.7 months, which was not significantly different from that of the patients with T/C genotype (42.1 months).	('rs8679', 'Mutation', 'rs8679', (4, 10))	('patients', 'Species', '9606', (132, 140))	('T/T', 'Var', (38, 41))	('rs8679', 'Var', (4, 10))
20387	33112558	In Cixian high-incidence region from northern China, rs1136410 and rs8679 SNPs might not be used to predict survival of ESCC patients.	('rs1136410', 'Mutation', 'rs1136410', (53, 62))	('ESCC', 'Disease', (120, 124))	('rs1136410', 'Var', (53, 62))	('rs8679 SNPs', 'Var', (67, 78))	('rs8679', 'Mutation', 'rs8679', (67, 73))	('patients', 'Species', '9606', (125, 133))
20388	33112558	There is a need to explore whether other SNPs of PARP1 gene have an effect on prognosis of ESCC patients.	('PARP1', 'Gene', (49, 54))	('ESCC', 'Disease', (91, 95))	('SNPs', 'Var', (41, 45))	('patients', 'Species', '9606', (96, 104))	('effect', 'Reg', (68, 74))
20393	33112558	Aberrant expression of PARP1 has been recorded in different human cancers.	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('PARP1', 'Gene', (23, 28))	('expression', 'MPA', (9, 19))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('recorded', 'Reg', (38, 46))	('human', 'Species', '9606', (60, 65))
20396	33112558	In addition, promoter hypermethylation of PARP1, which might be associated with lower expression level of PARP1, predisposed females to breast cancer (Sabit et al., 2019).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('expression level', 'MPA', (86, 102))	('PARP1', 'Gene', (42, 47))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('promoter hypermethylation', 'Var', (13, 38))	('PARP1', 'Gene', (106, 111))	('predisposed', 'Reg', (113, 124))
20407	33112558	Accumulated evidences demonstrated that genetic polymorphisms in DNA repair genes may affect individual DNA repair capacity and change cancer risk (Hou et al., 2002; Wang et al., 2013).	('change cancer', 'Disease', 'MESH:D009369', (128, 141))	('affect', 'Reg', (86, 92))	('genetic polymorphisms', 'Var', (40, 61))	('DNA repair capacity', 'MPA', (104, 123))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('change cancer', 'Disease', (128, 141))	('DNA repair genes', 'Gene', (65, 81))
20408	33112558	PARP1 gene rs1136410 single nucleotide polymorphism (SNP) is a T to C transition at codon 762 located in the catalytic domain that leads to a change from valine to alanine, which is related to reduction of PARP1 enzymatic activity (Lockett et al., 2004; Wang et al., 2007).	('rs1136410 single nucleotide polymorphism', 'Var', (11, 51))	('T to C transition at codon 762', 'Mutation', 'c.762T>C', (63, 93))	('valine to alanine', 'MPA', (154, 171))	('valine', 'Chemical', 'MESH:D014633', (154, 160))	('change', 'Reg', (142, 148))	('rs1136410', 'Mutation', 'rs1136410', (11, 20))	('PARP1', 'Gene', (0, 5))	('alanine', 'Chemical', 'MESH:D000409', (164, 171))
20409	33112558	The rs8679 SNP is situated in the 3'-untranslated region (3'-UTR) of PARP1 gene, the T to C substitution may affect PARP1 expression level (Teo et al., 2012; Schneiderova et al., 2017).	('PARP1', 'Gene', (69, 74))	('T to C substitution', 'Var', (85, 104))	('rs8679', 'Mutation', 'rs8679', (4, 10))	('affect', 'Reg', (109, 115))	('expression level', 'MPA', (122, 138))	('rs8679', 'Var', (4, 10))	('PARP1', 'Gene', (116, 121))
20410	33112558	These two polymorphisms were reported to be associated with risk of various tumors such as prostate cancer, esophageal cancer, cervical cancer, colorectal cancer, bladder cancer, and breast cancer (Hao et al., 2004; Lockett et al., 2004; Teo et al., 2012; Roszak et al., 2013; Schneiderova et al., 2017 ).	('prostate cancer', 'Disease', (91, 106))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('polymorphisms', 'Var', (10, 23))	('cancer', 'Disease', (136, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('breast cancer', 'Disease', (183, 196))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', (190, 196))	('colorectal cancer', 'Disease', (144, 161))	('esophageal cancer', 'Disease', (108, 125))	('cancer', 'Disease', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (171, 177))	('tumors', 'Disease', (76, 82))	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (155, 161))	('associated', 'Reg', (44, 54))	('bladder cancer', 'Disease', 'MESH:D001749', (163, 177))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('bladder cancer', 'Disease', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (91, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (163, 177))	('prostate cancer', 'Phenotype', 'HP:0012125', (91, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
20412	33112558	To date, no study has been conducted to assess whether PARP1 rs1136410 and rs8679 SNPs, two potentially functional sites, are useful biomarkers to predict the survival of esophageal squamous cell carcinoma (ESCC) patients in Cixian high-incidence region.	('rs8679', 'Mutation', 'rs8679', (75, 81))	('esophageal squamous cell carcinoma', 'Disease', (171, 205))	('PARP1', 'Gene', (55, 60))	('rs1136410', 'Mutation', 'rs1136410', (61, 70))	('rs1136410', 'Var', (61, 70))	('patients', 'Species', '9606', (213, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (171, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('rs8679 SNPs', 'Var', (75, 86))
20420	33112558	The two specific probes used to discriminate the specific bases were 5'-ctgttcttttgctcctccaggccaaggt-3' and 5'-ttcttttgctcctccaggccaaggc-3' for rs1136410, and 5'-ctgactgaaaagagctttccttctccaggaat-3' and 5'-ctgaaaaagagctttccttctccaggaac-3' for rs8679.	('rs1136410', 'Mutation', 'rs1136410', (144, 153))	('rs8679', 'Mutation', 'rs8679', (242, 248))	('rs1136410', 'Var', (144, 153))	('rs8679', 'Var', (242, 248))
20422	33112558	For rs1136410 and rs8679, the common probes were 5'-P-ggaaatgcttgacaacctgctggac-FAM-3' and 5'-P-actgaacatgggagctcttgaaatctga-FAM-3' respectively.	('rs8679', 'Mutation', 'rs8679', (18, 24))	('rs1136410', 'Var', (4, 13))	('rs8679', 'Var', (18, 24))	('rs1136410', 'Mutation', 'rs1136410', (4, 13))
20427	33112558	The T/T, T/C and C/C genotype frequencies of rs1136410 in the ESCC patients were 38.9%, 42.4% and 18.7%, respectively.	('rs1136410', 'Mutation', 'rs1136410', (45, 54))	('ESCC', 'Disease', (62, 66))	('patients', 'Species', '9606', (67, 75))	('rs1136410', 'Var', (45, 54))
20430	33112558	For rs8679, the T/T and T/C genotype frequencies of the ESCC patients were 88.7% and 11.3%.	('ESCC', 'Disease', (56, 60))	('T/C', 'Var', (24, 27))	('patients', 'Species', '9606', (61, 69))	('rs8679', 'Mutation', 'rs8679', (4, 10))	('T/T', 'Var', (16, 19))	('rs8679', 'Var', (4, 10))
20433	33112558	When stratified by sex, age, smoking status and UGIC family history, rs1136410 and rs8679 SNPs were not associated with the survival time of ESCC patients (Table 2 and Table 3).	('rs1136410', 'Var', (69, 78))	('rs8679 SNPs', 'Var', (83, 94))	('rs8679', 'Mutation', 'rs8679', (83, 89))	('rs1136410', 'Mutation', 'rs1136410', (69, 78))	('patients', 'Species', '9606', (146, 154))	('ESCC', 'Disease', (141, 145))
20434	33112558	In this study, we for the first time evaluated the association between PARP1 rs1136410 and rs8679 SNPs and the survival of ESCC patients from Cixian high-incidence region.	('rs1136410', 'Mutation', 'rs1136410', (77, 86))	('ESCC', 'Disease', (123, 127))	('PARP1', 'Gene', (71, 76))	('rs1136410', 'Var', (77, 86))	('patients', 'Species', '9606', (128, 136))	('rs8679 SNPs', 'Var', (91, 102))	('rs8679', 'Mutation', 'rs8679', (91, 97))
20436	33112558	PARP1 gene rs1136410 is a missense variant located in the catalytic domain.	('rs1136410', 'Mutation', 'rs1136410', (11, 20))	('PARP1', 'Gene', (0, 5))	('rs1136410', 'Var', (11, 20))
20437	33112558	The loss of a methyl group from valine to alaline increases the distance between residue 762 in the regulatory domain and glycine 888, the closet neighbor of residue in the active site, looses the binding with NAD+ and reduces the catalytic activity (Cottet et al., 2000).	('reduces', 'NegReg', (219, 226))	('glycine', 'Chemical', 'MESH:D005998', (122, 129))	('catalytic activity', 'MPA', (231, 249))	('binding', 'Interaction', (197, 204))	('valine', 'Chemical', 'MESH:D014633', (32, 38))	('NAD+', 'Chemical', 'MESH:D009243', (210, 214))	('looses', 'NegReg', (186, 192))	('increases', 'PosReg', (50, 59))	('alaline', 'Chemical', '-', (42, 49))	('NAD+', 'Protein', (210, 214))	('distance', 'MPA', (64, 72))	('glycine 888', 'Var', (122, 133))	('loss', 'Var', (4, 8))
20438	33112558	The rs1136410 was documented to have an influence on risk of some tumors or prognosis of cancer patients (Hao et al., 2004; Lockett et al., 2004; Kim et al., 2010; Roszak et al., 2013; Zhou et al., 2015).	('prognosis', 'CPA', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('influence', 'Reg', (40, 49))	('tumors', 'Disease', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (89, 95))	('patients', 'Species', '9606', (96, 104))	('rs1136410', 'Mutation', 'rs1136410', (4, 13))	('rs1136410', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
20440	33112558	Likewise, there was no significant relation between rs1136410 and PARP1 activity of 19 human cancer cell lines (Zaremba et al., 2009).	('cancer', 'Disease', (93, 99))	('rs1136410', 'Var', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('human', 'Species', '9606', (87, 92))	('activity', 'MPA', (72, 80))	('PARP1', 'Enzyme', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rs1136410', 'Mutation', 'rs1136410', (52, 61))
20442	33112558	Similar to some studies, we failed to find the association between rs1136410 and prognosis of ESCC patients (Gao et al., 2010; Li et al., 2013).	('patients', 'Species', '9606', (99, 107))	('rs1136410', 'Var', (67, 76))	('ESCC', 'Disease', (94, 98))	('rs1136410', 'Mutation', 'rs1136410', (67, 76))
20444	33112558	PARP1 gene rs8679 SNP is located at microRNA-binding site, which might change the expression level of PARP1 by affecting the binding of microRNA with PARP1 mRNA (Teo et al., 2012; Schneiderova et al., 2017).	('PARP1 mRNA', 'Protein', (150, 160))	('PARP1', 'Gene', (102, 107))	('microRNA', 'Protein', (136, 144))	('rs8679', 'Mutation', 'rs8679', (11, 17))	('rs8679 SNP', 'Var', (11, 21))	('binding', 'Interaction', (125, 132))	('affecting', 'Reg', (111, 120))	('expression level', 'MPA', (82, 98))	('PARP1', 'Gene', (0, 5))	('change', 'Reg', (71, 77))
20445	33112558	The rs8679 T/C genotype and C/C genotype were associated with increased risk of bladder cancer and breast cancer, respectively (Teo et al., 2012).	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('bladder cancer', 'Disease', (80, 94))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('rs8679', 'Mutation', 'rs8679', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('C/C', 'Var', (28, 31))	('rs8679 T/C', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
20446	33112558	In other studies, T/C or C/C genotype was related to decreased risk of colorectal cancer (Alhadheq et al., 2016; Schneiderova et al., 2017).	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('T/C', 'Var', (18, 21))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('C/C', 'Var', (25, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('decreased', 'NegReg', (53, 62))
20447	33112558	Interestingly, rs8679 had no effect on susceptibility to neuroblastoma (Cheng et al., 2019).	('neuroblastoma', 'Disease', 'MESH:D009447', (57, 70))	('rs8679', 'Var', (15, 21))	('neuroblastoma', 'Disease', (57, 70))	('neuroblastoma', 'Phenotype', 'HP:0003006', (57, 70))	('rs8679', 'Mutation', 'rs8679', (15, 21))
20448	33112558	As for effect of rs8679 on prognosis of cancer patients, Cheng et al investigated the association of rs8679 with clinical outcome of colorectal cancer patients and found that C/C genotype carriers that received 5-FU-based chemotherapy had a shorter event-free survival (Schneiderova et al., 2017).	('C/C genotype', 'Var', (175, 187))	('colorectal cancer', 'Disease', (133, 150))	('shorter', 'NegReg', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('rs8679', 'Mutation', 'rs8679', (17, 23))	('rs8679', 'Var', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (133, 150))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (151, 159))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', (144, 150))	('event-free', 'MPA', (249, 259))	('5-FU', 'Chemical', 'MESH:D005472', (211, 215))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('rs8679', 'Mutation', 'rs8679', (101, 107))
20449	33112558	In the previous study about bladder and present study on ESCC, no relation was observed between rs8679 and survival of cancer patients (Teo et al., 2012).	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('rs8679', 'Mutation', 'rs8679', (96, 102))	('patients', 'Species', '9606', (126, 134))	('rs8679', 'Var', (96, 102))	('bladder', 'Disease', 'MESH:D001745', (28, 35))	('bladder', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
20450	33112558	To this day, limited studies have been conducted to test the possibility of rs8679 to be used as genetic biomarker for cancer susceptibility or prognosis of cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('rs8679', 'Mutation', 'rs8679', (76, 82))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (157, 163))	('patients', 'Species', '9606', (164, 172))	('rs8679', 'Var', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
20451	33112558	Therefore, it is necessary to determine the role of rs8679 in further studies on different tumors with larger sample size.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Disease', (91, 97))	('rs8679', 'Mutation', 'rs8679', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('rs8679', 'Var', (52, 58))
20452	33112558	Examining the association of PARP1 expression with different genotype of rs8679 in esophageal cancer tissues may be helpful in providing mechanistic evidence for the results.	('rs8679', 'Var', (73, 79))	('esophageal cancer', 'Disease', (83, 100))	('association', 'Interaction', (14, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PARP1', 'Gene', (29, 34))	('rs8679', 'Mutation', 'rs8679', (73, 79))
20455	33112558	Fourthly, we did not measure the expression level of PARP1 in esophageal cancer tissues with different genotype of rs1136410 and rs8679 SNPs.	('rs8679 SNPs', 'Var', (129, 140))	('rs8679', 'Mutation', 'rs8679', (129, 135))	('rs1136410', 'Var', (115, 124))	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('rs1136410', 'Mutation', 'rs1136410', (115, 124))
20456	33112558	In summary, the present study assessed the relation of PARP1 rs1136410 and rs8679 SNPs with prognosis of ESCC patients from Cixian high-incidence region.	('rs8679', 'Mutation', 'rs8679', (75, 81))	('ESCC', 'Disease', (105, 109))	('PARP1', 'Gene', (55, 60))	('rs1136410', 'Mutation', 'rs1136410', (61, 70))	('rs1136410', 'Var', (61, 70))	('patients', 'Species', '9606', (110, 118))	('rs8679 SNPs', 'Var', (75, 86))
20471	33339271	CIN includes changes in the chromosome number and structure, such as deletions, gains, translocations, and other chromosomal rearrangements.	('CIN', 'Disease', (0, 3))	('gains', 'CPA', (80, 85))	('changes', 'Reg', (13, 20))	('translocations', 'CPA', (87, 101))	('deletions', 'Var', (69, 78))	('CIN', 'Disease', 'MESH:D007674', (0, 3))	('men', 'Species', '9606', (134, 137))
20472	33339271	For example, Lynch syndrome or hereditary nonpolyposis colorectal cancer syndrome is caused by inherited mutations in one of the mismatch repair (MMR) genes (predominantly MLH1 and MSH2).	('MSH2', 'Gene', (181, 185))	('MMR', 'Gene', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('MSH2', 'Gene', '4436', (181, 185))	('Lynch syndrome', 'Disease', 'MESH:D003123', (13, 27))	('hereditary nonpolyposis colorectal cancer syndrome', 'Disease', 'MESH:D003123', (31, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('MLH1', 'Gene', '4292', (172, 176))	('mutations', 'Var', (105, 114))	('caused by', 'Reg', (85, 94))	('MLH1', 'Gene', (172, 176))	('hereditary nonpolyposis colorectal cancer syndrome', 'Disease', (31, 81))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (31, 72))	('Lynch syndrome', 'Disease', (13, 27))
20474	33339271	The first pathway involves genomic instability due to CIN, MSI, and aberrant DNA methylation.	('aberrant DNA methylation', 'Var', (68, 92))	('MSI', 'Var', (59, 62))	('CIN', 'Disease', 'MESH:D007674', (54, 57))	('CIN', 'Disease', (54, 57))
20475	33339271	The second pathway involves mutational inactivation of tumor-suppressor genes, such as APC, TP53, and TGF-beta.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('TGF-beta', 'Gene', '7039', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('APC', 'Phenotype', 'HP:0005227', (87, 90))	('tumor', 'Disease', (55, 60))	('APC', 'Disease', 'MESH:D011125', (87, 90))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('APC', 'Disease', (87, 90))	('mutational inactivation', 'Var', (28, 51))	('TGF-beta', 'Gene', (102, 110))
20478	33339271	Methylation leads to transcriptional silencing and plays a crucial role in the loss of expression of tumor suppressor or DNA repair genes.	('loss of', 'NegReg', (79, 86))	('Methylation', 'Var', (0, 11))	('silencing', 'NegReg', (37, 46))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('expression', 'MPA', (87, 97))	('DNA repair genes', 'Gene', (121, 137))	('transcriptional', 'MPA', (21, 36))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
20480	33339271	However, in up to 20% of CRC tumors, APC mutation is not present and gene inactivation via transcriptional silencing due to promoter hypermethylation led to the loss of APC function.	('promoter hypermethylation', 'Var', (124, 149))	('CRC', 'Phenotype', 'HP:0003003', (25, 28))	('APC', 'Disease', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('APC', 'Disease', 'MESH:D011125', (37, 40))	('transcriptional', 'MPA', (91, 106))	('CRC tumors', 'Disease', 'MESH:D015179', (25, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('APC', 'Phenotype', 'HP:0005227', (169, 172))	('APC', 'Disease', 'MESH:D011125', (169, 172))	('loss of APC function', 'Disease', 'MESH:D011125', (161, 181))	('loss of APC function', 'Disease', (161, 181))	('inactivation', 'NegReg', (74, 86))	('APC', 'Phenotype', 'HP:0005227', (37, 40))	('APC', 'Disease', (169, 172))	('CRC tumors', 'Disease', (25, 35))
20482	33339271	Currently used tests in clinics related to prognosis and treatment in CRCs include MSI testing, mutations in RAS, and EGFR immunohistochemical test for anti-EGFR therapy.	('men', 'Species', '9606', (62, 65))	('EGFR', 'Gene', (157, 161))	('EGFR', 'Gene', '1956', (157, 161))	('CRC', 'Phenotype', 'HP:0003003', (70, 73))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('RAS', 'Gene', (109, 112))	('mutations', 'Var', (96, 105))
20489	33339271	The human single stranded DNA binding protein 2 (SSBP2) gene was first identified in primary leukemic blasts and was found to be translocated and deleted in myelodysplasia and acute myelogenous leukemia (AML).	('AML', 'Disease', 'MESH:D015470', (204, 207))	('SSBP2', 'Gene', (49, 54))	('single stranded DNA binding protein 2', 'Gene', (10, 47))	('human', 'Species', '9606', (4, 9))	('AML', 'Disease', (204, 207))	('SSBP2', 'Gene', '23635', (49, 54))	('AML', 'Phenotype', 'HP:0004808', (204, 207))	('deleted', 'Var', (146, 153))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (176, 202))	('leukemia', 'Phenotype', 'HP:0001909', (194, 202))	('leukemic blasts', 'Disease', 'MESH:D001753', (93, 108))	('single stranded DNA binding protein 2', 'Gene', '23635', (10, 47))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (182, 202))	('leukemic blasts', 'Disease', (93, 108))	('myelodysplasia and acute myelogenous leukemia', 'Disease', 'MESH:D015470', (157, 202))	('myelodysplasia', 'Phenotype', 'HP:0002863', (157, 171))
20491	33339271	The loss of SSBP2 expression is associated with various types of malignancies, such as esophageal squamous cell carcinoma, prostate cancer, gallbladder cancer, and acute myeloid leukemia.	('prostate cancer', 'Phenotype', 'HP:0012125', (123, 138))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('prostate cancer', 'Disease', (123, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('malignancies', 'Disease', (65, 77))	('associated', 'Reg', (32, 42))	('SSBP2', 'Gene', (12, 17))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('acute myeloid leukemia', 'Disease', (164, 186))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('gallbladder cancer', 'Disease', 'MESH:D005706', (140, 158))	('leukemia', 'Phenotype', 'HP:0001909', (178, 186))	('loss', 'Var', (4, 8))	('SSBP2', 'Gene', '23635', (12, 17))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (170, 186))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (164, 186))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (164, 186))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (123, 138))	('gallbladder cancer', 'Disease', (140, 158))
20494	33339271	described that the candidate myeloid leukemia suppressor gene encoding sequence-SSBP2 from chromosome 5q13.3 was frequently deleted in AML.	('myeloid leukemia', 'Disease', 'MESH:D007951', (29, 45))	('AML', 'Disease', 'MESH:D015470', (135, 138))	('SSBP2', 'Gene', (80, 85))	('AML', 'Phenotype', 'HP:0004808', (135, 138))	('AML', 'Disease', (135, 138))	('deleted', 'Var', (124, 131))	('myeloid leukemia', 'Disease', (29, 45))	('SSBP2', 'Gene', '23635', (80, 85))	('leukemia', 'Phenotype', 'HP:0001909', (37, 45))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (29, 45))
20500	33339271	Meanwhile, several studies on promoter methylation of SSBP2 in tumors have shown that SSBP2 is one of the genes that are downregulated by methylation.	('SSBP2', 'Gene', '23635', (54, 59))	('SSBP2', 'Gene', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('SSBP2', 'Gene', '23635', (86, 91))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('downregulated', 'NegReg', (121, 134))	('methylation', 'Var', (138, 149))	('SSBP2', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
20548	33339271	compared SSBP2 methylation in normal and tumor tissues in 20 pairs of esophageal squamous cell carcinoma and matched normal esophageal tissues using TaqMan-MSP analysis, and a higher degree of SSBP2 methylation in paired tumors than in paired normal tissues was observed in 15 of 20 esophageal squamous cell carcinoma patients.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (294, 317))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (283, 317))	('methylation', 'Var', (199, 210))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('methylation', 'Var', (15, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('tumors', 'Disease', (221, 227))	('SSBP2', 'Gene', (9, 14))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (221, 226))	('SSBP2', 'Gene', (193, 198))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('esophageal squamous cell carcinoma', 'Disease', (70, 104))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('esophageal squamous cell carcinoma', 'Disease', (283, 317))	('patients', 'Species', '9606', (318, 326))	('SSBP2', 'Gene', '23635', (9, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('SSBP2', 'Gene', '23635', (193, 198))
20549	33339271	reported that the SSBP2 promoter region was hypermethylated in 61.4% (54 of 88) of prostate cancer cases, whereas none of the 23 benign prostatic hyperplasia cases showed hypermethylation.	('hypermethylated', 'Var', (44, 59))	('SSBP2', 'Gene', '23635', (18, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('benign prostatic hyperplasia', 'Phenotype', 'HP:0008711', (129, 157))	('prostatic hyperplasia', 'Disease', (136, 157))	('prostate cancer', 'Disease', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('SSBP2', 'Gene', (18, 23))	('prostatic hyperplasia', 'Disease', 'MESH:D011470', (136, 157))
20551	33339271	In addition, another study was conducted to identify a panel of epigenetic biomarkers that can distinguish cholecystitis from gallbladder cancer patients.	('patients', 'Species', '9606', (145, 153))	('cholecystitis', 'Disease', 'MESH:D002764', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('epigenetic', 'Var', (64, 74))	('gallbladder cancer', 'Disease', (126, 144))	('cholecystitis', 'Disease', (107, 120))	('cholecystitis', 'Phenotype', 'HP:0001082', (107, 120))	('gallbladder cancer', 'Disease', 'MESH:D005706', (126, 144))
20553	33339271	Furthermore, in ovarian cancer, SSBP2 methylation was found in 9% of tumor cases, whereas no cases showed methylation of the SSBP2 promoter in normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('SSBP2', 'Gene', (125, 130))	('ovarian cancer', 'Disease', (16, 30))	('methylation', 'Var', (38, 49))	('tumor', 'Disease', (69, 74))	('SSBP2', 'Gene', (32, 37))	('found', 'Reg', (54, 59))	('SSBP2', 'Gene', '23635', (125, 130))	('ovarian cancer', 'Phenotype', 'HP:0100615', (16, 30))	('SSBP2', 'Gene', '23635', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (16, 30))
20585	31527170	Blood-based biomarkers for EC have been investigated in small studies; these include circulating tumor cells, autoantibodies, microRNA, and aberrantly methylated DNA.	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('aberrantly methylated', 'Var', (140, 161))
20586	31527170	Hypermethylation of CpG islands in promoter regions can silence tumor suppressor genes, while hypomethylation of repetitive gene elements may lead to genomic instability and activation of oncogenes.	('oncogenes', 'CPA', (188, 197))	('silence tumor', 'Disease', (56, 69))	('Hypermethylation', 'Var', (0, 16))	('hypomethylation', 'Var', (94, 109))	('silence tumor', 'Disease', 'MESH:D009369', (56, 69))	('activation', 'PosReg', (174, 184))	('genomic instability', 'CPA', (150, 169))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('lead to', 'Reg', (142, 149))
20588	31527170	Furthermore, technological advances in assay chemistry have dramatically improved the analytical sensitivity for MDMs in plasma to allow detection of low copy numbers associated with early stage cancer, notably of the liver and stomach.	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('improved', 'PosReg', (73, 81))	('MDM', 'Gene', (113, 116))	('MDM', 'Gene', '57152', (113, 116))	('associated', 'Reg', (167, 177))	('low copy numbers', 'Var', (150, 166))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
20627	31527170	Following variance-inflated logistic regression, candidate DMRs were ranked according to p-value, area under the receiver operating characteristics curve (AUC), methylation fold-change ratio (FC), and absolute methylation difference between cases and controls (DeltaM).	('methylation', 'Var', (161, 172))	('DMR', 'Gene', (59, 62))	('DMR', 'Gene', '91833', (59, 62))
20645	31527170	Pre-specified filtering criteria for candidate DMRs included AUC >= 0.90, ,FC >= 50, DeltaM >= 0.15, p-value <= 0.01, CpG density of 0.05 - 0.3, and a minimum range of 40 base pairs.	('DMR', 'Gene', (47, 50))	('DeltaM >= 0.15', 'Var', (85, 99))	('DMR', 'Gene', '91833', (47, 50))	('AUC >= 0.90', 'Var', (61, 72))
20684	31527170	It was anticipated from prior experiments that markers selected for EC detection in the present study would be methylated in other GI cancers.	('GI cancers', 'Disease', 'MESH:D009369', (131, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('methylated', 'Var', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('GI cancers', 'Disease', (131, 141))
20686	31527170	In TCGA data examined in the present study, the MDMs we interrogated in plasma are methylated in other GI cancers, most commonly colorectal cancer.	('MDM', 'Gene', '57152', (48, 51))	('colorectal cancer', 'Disease', (129, 146))	('MDM', 'Gene', (48, 51))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('methylated', 'Var', (83, 93))	('GI cancers', 'Disease', (103, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('GI cancers', 'Disease', 'MESH:D009369', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
20698	31527170	These epigenetic similarities allowed us to select representative candidates for both cancer types in combination.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))	('epigenetic', 'Var', (6, 16))
20745	31192298	Current research indicates that biopsies should be tested for the presence of a TP53 mutation that has been shown to be mutated in the vast majority of esophageal adenocarcinomas and a potential biomarker for the progression of Barrett esophagus to adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (228, 245))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (152, 177))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('esophageal adenocarcinomas', 'Disease', (152, 178))	('Barrett esophagus to adenocarcinoma', 'Disease', (228, 263))	('mutation', 'Var', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('Barrett esophagus to adenocarcinoma', 'Disease', 'MESH:D001471', (228, 263))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (152, 178))
20750	31192298	An alternate pathway involves a TP53 mutation followed by a whole-genome doubling that leads to genomic instability and oncogene activation, It has been suggested that the genome-doubling pathway allows the development of adenocarcinoma from Barrett esophagus to occur much more rapidly than the traditional pathway and helps explain why surveillance biopsy is not always able to detect the progression of metaplasia to dysplasia.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('metaplasia to dysplasia', 'Disease', 'MESH:D008679', (406, 429))	('mutation', 'Var', (37, 45))	('leads', 'Reg', (87, 92))	('TP53', 'Gene', (32, 36))	('metaplasia to dysplasia', 'Disease', (406, 429))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (242, 259))	('adenocarcinoma', 'Disease', (222, 236))
20754	31192298	The genome-doubling pathway begins with a p53 mutation and subsequent genome duplication.	('p53', 'Gene', (42, 45))	('mutation', 'Var', (46, 54))	('genome-doubling pathway', 'Pathway', (4, 27))	('p53', 'Gene', '7157', (42, 45))
20762	31001901	Cats receiving glucocorticoids or oncolytic agents (OR = 3.91; 95% CI, 1.14-13.44) and with discharge at the stoma site (OR = 159.8; CI, 18.9-1351) were at an increased odds of developing a stoma site infection, whereas those with a lower weight (OR = 1.33; 95% CI, 1.02-1.75) or (pancreatic [OR = 4.33; 95% CI, 1.02-18.47], neoplastic [OR = 15.44; 95% CI, 3.67-65.07], respiratory [OR = 19.66; 95% CI, 2.81-137.48], urogenital [OR = 5.78; 95% CI, 1.15-28.99], and infectious diseases [OR = 11.57; 95% CI, 2.27-58.94]) had an increased odds of death.	('stoma', 'Disease', 'None', (109, 114))	('respiratory', 'Disease', (370, 381))	('lower weight', 'Phenotype', 'HP:0004325', (233, 245))	('pancreatic', 'Disease', 'MESH:D010195', (281, 291))	('stoma', 'Disease', (109, 114))	('urogenital', 'Disease', (417, 427))	('Cats', 'Species', '9685', (0, 4))	('infectious diseases', 'Disease', (465, 484))	('glucocorticoids', 'Var', (15, 30))	('pancreatic', 'Disease', (281, 291))	('neoplastic', 'Disease', (325, 335))	('stoma site infection', 'Disease', (190, 210))	('stoma site infection', 'Disease', 'MESH:D009371', (190, 210))	('stoma', 'Disease', 'None', (190, 195))	('death', 'Disease', 'MESH:D003643', (544, 549))	('infectious diseases', 'Disease', 'MESH:D003141', (465, 484))	('stoma', 'Disease', (190, 195))	('death', 'Disease', (544, 549))
20781	31001901	One of the variables of interest was death, with potential associated factors including age, weight, BCS, the presence of systemic inflammation (based on the final diagnosis and whether this would be expected to cause systemic inflammation, e.g., pancreatitis), presence of systemic infection (based on the final diagnosis and whether this would be expected to cause systemic infection, e.g., sepsis), classification of underlying disease, glucocorticoids or oncolytic agents administered, and institution where the tube was placed.	('pancreatitis', 'Disease', (247, 259))	('systemic inflammation', 'Disease', (218, 239))	('systemic inflammation', 'Disease', (122, 143))	('systemic infection', 'Disease', 'MESH:D034721', (274, 292))	('presence', 'Var', (110, 118))	('systemic infection', 'Disease', (274, 292))	('cause', 'Reg', (212, 217))	('systemic inflammation', 'Disease', 'MESH:D007249', (218, 239))	('systemic infection', 'Disease', 'MESH:D034721', (367, 385))	('systemic inflammation', 'Disease', 'MESH:D007249', (122, 143))	('death', 'Disease', (37, 42))	('systemic infection', 'Disease', (367, 385))	('pancreatitis', 'Phenotype', 'HP:0001733', (247, 259))	('sepsis', 'Phenotype', 'HP:0100806', (393, 399))	('cause', 'Reg', (361, 366))	('BCS', 'Disease', (101, 104))	('sepsis', 'Disease', 'MESH:D018805', (393, 399))	('sepsis', 'Disease', (393, 399))	('pancreatitis', 'Disease', 'MESH:D010195', (247, 259))	('death', 'Disease', 'MESH:D003643', (37, 42))
20877	30546449	TUBB3 positivity was not associated with the International Union Against Cancer classification, World Health Organization grading, lymph node involvement or distant metastasis in any entity.	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('positivity', 'Var', (6, 16))	('Cancer', 'Disease', (73, 79))	('TUBB3', 'Gene', (0, 5))	('TUBB3', 'Gene', '10381', (0, 5))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))
20879	30546449	In conclusion, the substantial rate of positivity for TUBB3 already in early stages of gastric cancer in combination with the lack of a further increase in frequency with tumor stage, may suggest, that TUBB3 upregulation is rather relevant for cancer development than for cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('TUBB3', 'Gene', (54, 59))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('TUBB3', 'Gene', '10381', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('TUBB3', 'Gene', (202, 207))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('TUBB3', 'Gene', '10381', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('positivity', 'Var', (39, 49))	('cancer', 'Disease', (272, 278))	('gastric cancer', 'Disease', (87, 101))	('tumor', 'Disease', (171, 176))
20957	29951370	Breast cancer:the most frequent cancer of European women:has been linked with red meat, alcoholic beverages, and high-glycemic load.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('cancer', 'Disease', (32, 38))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('alcohol', 'Chemical', 'MESH:D000438', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('Breast cancer', 'Disease', (0, 13))	('high-glycemic load', 'Var', (113, 131))	('women', 'Species', '9606', (51, 56))
21004	29951370	Most of these cancers also correlate significantly with high dietary protein quality (the "protein index"), especially prostate cancer (r = 0.69) and melanoma (r = 0.59 in men, r = 0.65 in women; p < 0.001).	('cancers', 'Disease', (14, 21))	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('especially prostate cancer', 'Disease', (108, 134))	('especially prostate cancer', 'Disease', 'MESH:D011471', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('men', 'Species', '9606', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('women', 'Species', '9606', (189, 194))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('men', 'Species', '9606', (172, 175))	('high', 'Var', (56, 60))
21051	29951370	Factor 1 includes the largest proportion of variance by far (36.5%) and in the left half of the graph, it groups together the incidence of most types of cancer (particularly prostate, breast, and NHL), raised cholesterol and high animal fat and animal protein consumption.	('cholesterol', 'MPA', (209, 220))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('breast', 'Disease', (184, 190))	('prostate', 'Disease', (174, 182))	('cholesterol', 'Chemical', 'MESH:D002784', (209, 220))	('fat', 'Gene', (237, 240))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('NHL', 'Phenotype', 'HP:0012539', (196, 199))	('fat', 'Gene', '2195', (237, 240))	('high animal', 'Var', (225, 236))	('raised cholesterol', 'Phenotype', 'HP:0003124', (202, 220))	('raised', 'PosReg', (202, 208))
21069	29951370	Also noteworthy is the identification of high BMI as the main denominator of kidney cancer and men's gallbladder cancer.	("men's gallbladder cancer", 'Disease', (95, 119))	('kidney cancer', 'Disease', (77, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('high', 'Var', (41, 45))	("men's gallbladder cancer", 'Disease', 'MESH:D005706', (95, 119))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('kidney cancer', 'Phenotype', 'HP:0009726', (77, 90))	('kidney cancer', 'Disease', 'MESH:D007680', (77, 90))
21085	29951370	Although some recent studies and reviews link high fat consumption and high total cholesterol with increased cancer risk, and hypercholesterolemia in mammals indeed promotes cancer growth, this debate has not been definitely settled yet.	('cholesterol', 'Chemical', 'MESH:D002784', (131, 142))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (126, 146))	('high', 'Var', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('promotes', 'PosReg', (165, 173))	('cholesterol', 'Chemical', 'MESH:D002784', (82, 93))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('fat', 'Gene', (51, 54))	('high total cholesterol', 'Phenotype', 'HP:0003124', (71, 93))	('fat', 'Gene', '2195', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('hypercholesterolemia', 'Disease', (126, 146))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (126, 146))
21086	29951370	Actually, some authors regard high HDL-cholesterol as a protective factor against both cancer and CVDs, but this opinion completely contradicts the ecological picture because the incidence of cancer and CVDs in Europe has an inverse geographical pattern.	('high HDL', 'Phenotype', 'HP:0012184', (30, 38))	('cancer', 'Disease', (87, 93))	('high HDL-cholesterol', 'Phenotype', 'HP:0012184', (30, 50))	('cholesterol', 'Chemical', 'MESH:D002784', (39, 50))	('CVDs', 'Phenotype', 'HP:0001626', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('high', 'Var', (30, 34))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('CVDs', 'Phenotype', 'HP:0001626', (203, 207))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('CVDs', 'Disease', (98, 102))
21209	29951370	On the other hand, this relationship may not apply to all types of cancer and considering that high cholesterol usually mirrors high HDL-cholesterol (a major indicator of low CVD risk), the picture is not black-and-white.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('high HDL-cholesterol', 'Var', (128, 148))	('cancer', 'Disease', (67, 73))	('cholesterol', 'Chemical', 'MESH:D002784', (137, 148))	('high HDL', 'Phenotype', 'HP:0012184', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cholesterol', 'Chemical', 'MESH:D002784', (100, 111))	('high HDL-cholesterol', 'Phenotype', 'HP:0012184', (128, 148))	('high cholesterol', 'Phenotype', 'HP:0003124', (95, 111))
21229	29951370	Because a recent metaanalysis also found a dramatic reduction in cancer mortality in individuals participating in strength exercises, but not in those participating in aerobic exercises, the use of generalized, self-reported data on physical activity is unlikely to produce any meaningful results, leaving aside their notorious unreliability.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('strength exercises', 'Var', (114, 132))	('reduction', 'NegReg', (52, 61))
21285	27992856	Inhibiting TGF-beta signaling using siRNA knockdown of Smad3, a pan-TGF-beta antibody or a specific inhibitor of TGF-beta receptor 1 (TGF-betaR1) kinase activity suppressed SMA upregulation by irradiation and H2O2 (Fig.	('SMA', 'Chemical', '-', (173, 176))	('SMA', 'MPA', (173, 176))	('Inhibiting', 'NegReg', (0, 10))	('upregulation', 'PosReg', (177, 189))	('Smad3', 'Gene', '4088', (55, 60))	('suppressed', 'NegReg', (162, 172))	('H2O2', 'Chemical', 'MESH:D006861', (209, 213))	('H2O2', 'Var', (209, 213))	('Smad3', 'Gene', (55, 60))
21332	27992856	TGF-beta1 treatment - IGF1, PDGF-A, VEGF-A, MMP-2, POSTN (periostin); senescence induction - SPP1 (Osteopontin), CXCL14, FGF1, EGF, MMP-12; all p<0.001); we recently found that suppression of the SASP in senescent fibroblasts through mTOR inhibition abrogates this invasion-promoting effect.	('PDGF-A', 'Gene', (28, 34))	('EGF', 'Gene', '1950', (37, 40))	('EGF', 'Gene', (127, 130))	('SPP1', 'Gene', (93, 97))	('MMP-12', 'Gene', (132, 138))	('invasion-promoting effect', 'CPA', (265, 290))	('mTOR', 'Gene', '2475', (234, 238))	('POSTN', 'Gene', (51, 56))	('Osteopontin', 'Gene', '6696', (99, 110))	('VEGF-A', 'Gene', (36, 42))	('abrogates', 'NegReg', (250, 259))	('MMP-2', 'Gene', '4313', (44, 49))	('periostin', 'Gene', (58, 67))	('Osteopontin', 'Gene', (99, 110))	('SPP1', 'Gene', '6696', (93, 97))	('VEGF-A', 'Gene', '7422', (36, 42))	('IGF1', 'Gene', '3479', (22, 26))	('POSTN', 'Gene', '10631', (51, 56))	('SASP', 'Gene', (196, 200))	('PDGF-A', 'Gene', '5154', (28, 34))	('inhibition', 'Var', (239, 249))	('EGF', 'Gene', (37, 40))	('FGF1', 'Gene', (121, 125))	('MMP-12', 'Gene', '4321', (132, 138))	('periostin', 'Gene', '10631', (58, 67))	('EGF', 'Gene', '1950', (127, 130))	('FGF1', 'Gene', '2246', (121, 125))	('IGF1', 'Gene', (22, 26))	('MMP-2', 'Gene', (44, 49))	('CXCL14', 'Gene', (113, 119))	('suppression', 'NegReg', (177, 188))	('CXCL14', 'Gene', '9547', (113, 119))	('SASP', 'Gene', '7295', (196, 200))	('mTOR', 'Gene', (234, 238))
21349	27992856	Scoring for SMA and p16 staining was carried out independently (GJT, KM, TU; blinded to clinical outcome) using a semi-quantitative scoring system, according to the extent of stromal positivity (low/negative [<5% stroma positive], moderate [patchy/focal expression, 5-50% stroma positive], high [diffuse expression throughout tumor, >50% stroma positive]).	('SMA', 'Chemical', '-', (12, 15))	('low/negative', 'Var', (195, 207))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('p16', 'Gene', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('tumor', 'Disease', (326, 331))	('p16', 'Gene', '1029', (20, 23))
21420	27070449	We next assessed the percentage of tumors that highly expressed MAGE-A (staining of >50% of tumor cells) and found that the majority of malignancies that expressed MAGE-A were indeed high expressers (Table 2).	('MAGE-A', 'Chemical', '-', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('MAGE-A', 'Var', (164, 170))	('MAGE-A', 'Chemical', '-', (164, 170))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('malignancies', 'Disease', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', (92, 97))
21430	27070449	In summary, the expression patterns of MAGE-A and NY-ESO-1 in metastatic lesions are similar to the staining patterns seen in primary lesions with MAGE-A expression being significantly higher than NY-ESO-1 in multiple primary and metastatic malignancies (Table 1, 2, and 3).	('MAGE-A', 'Var', (147, 153))	('MAGE-A', 'Chemical', '-', (147, 153))	('NY-ESO-1', 'Gene', (197, 205))	('NY-ESO-1', 'Gene', '246100', (197, 205))	('NY-ESO-1', 'Gene', '246100', (50, 58))	('malignancies', 'Disease', 'MESH:D009369', (241, 253))	('MAGE-A', 'Chemical', '-', (39, 45))	('NY-ESO-1', 'Gene', (50, 58))	('higher', 'PosReg', (185, 191))	('malignancies', 'Disease', (241, 253))	('expression', 'MPA', (154, 164))
21460	25886559	Overall, significant association was found between CYP1A1 MspI polymorphism and EC risk when all studies in the Chinese population pooled into this meta-analysis (C vs. T: OR = 1.25, 95% CI = 1.04 to 1.51; CC + CT vs. TT: OR = 1.35, 95% CI = 1.06 to 1.72; CC vs. TT + CT: OR = 1.35, 95% CI = 1.03 to 1.76).	('MspI', 'Gene', (58, 62))	('CYP1A1', 'Gene', (51, 57))	('polymorphism', 'Var', (63, 75))	('CYP1A1', 'Gene', '1543', (51, 57))
21461	25886559	This meta-analysis provides the evidence that CYP1A1 MspI polymorphism may contribute to the EC development in the Chinese population.	('contribute', 'Reg', (75, 85))	('polymorphism', 'Var', (58, 70))	('CYP1A1', 'Gene', (46, 52))	('EC development', 'CPA', (93, 107))	('CYP1A1', 'Gene', '1543', (46, 52))
21472	25886559	CYP1A1 A2455G and T3801C are two most commonly studied polymorphism loci.	('T3801C', 'Var', (18, 24))	('A2455G', 'Var', (7, 13))	('CYP1A1', 'Gene', '1543', (0, 6))	('A2455G', 'Mutation', 'rs1048943', (7, 13))	('T3801C', 'Mutation', 'rs4646903', (18, 24))	('CYP1A1', 'Gene', (0, 6))
21473	25886559	CYP1A1 T3801C polymorphism (MspI, rs4646903), also known as the m1 allele, is a substitution of T with C in the non-coding 3'-flanking region which resulting in a highly inducible activity of the enzyme.	('CYP1A1', 'Gene', '1543', (0, 6))	('inducible activity', 'MPA', (170, 188))	('rs4646903', 'Mutation', 'rs4646903', (34, 43))	('T3801C', 'Mutation', 'rs4646903', (7, 13))	('T3801C polymorphism', 'Var', (7, 26))	('CYP1A1', 'Gene', (0, 6))
21474	25886559	The first research of the association between CYP1A1 MspI polymorphism and EC was reported by Hori and co-workers in 1997 among the Japan population.	('MspI', 'Gene', (53, 57))	('CYP1A1', 'Gene', (46, 52))	('CYP1A1', 'Gene', '1543', (46, 52))	('polymorphism', 'Var', (58, 70))
21476	25886559	In order to lessen the impact of different genetic background, we performed this meta-analysis to assess the relationship of CYP1A1 MspI polymorphism with risk of EC in Chinese population.	('CYP1A1', 'Gene', (125, 131))	('CYP1A1', 'Gene', '1543', (125, 131))	('polymorphism', 'Var', (137, 149))
21477	25886559	A comprehensive literature search was performed using the PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) for relevant articles published with the following Mesh terms: ('Esophageal Neoplasms' [MeSH] or 'esophageal cancer' or 'esophageal tumor' or 'esophageal carcinoma' or 'esophageal squamous cell' or 'esophageal adenocarcinoma') and ('P4501A1' or 'CYP1A1') and (China or Chinese or Taiwan).	("'esophageal tumor", 'Disease', 'MESH:D004938', (341, 358))	("'Esophageal Neoplasms", 'Phenotype', 'HP:0100751', (285, 306))	("'Esophageal Neoplasms", 'Disease', 'MESH:D004938', (285, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (436, 445))	('CYP1A1', 'Gene', '1543', (467, 473))	("'esophageal tumor", 'Disease', (341, 358))	("'esophageal cancer", 'Disease', (318, 336))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (375, 384))	("'esophageal carcinoma' or 'esophageal squamous cell' or 'esophageal adenocarcinoma'", 'Disease', 'MESH:D004938', (363, 446))	("'esophageal tumor'", 'Phenotype', 'HP:0100751', (341, 359))	("'esophageal carcinoma", 'Phenotype', 'HP:0011459', (363, 384))	("'esophageal cancer", 'Disease', 'MESH:D004938', (318, 336))	("'Esophageal Neoplasms", 'Disease', (285, 306))	('Neoplasms', 'Phenotype', 'HP:0002664', (297, 306))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('CYP1A1', 'Gene', (467, 473))	("'P4501A1'", 'Var', (453, 462))
21480	25886559	Crude odds ratios (ORs) together with their corresponding 95% CIs were used to assess the strength of association between the CYP1A1 MspI polymorphism and the risk of EC.	('CYP1A1', 'Gene', (126, 132))	('CYP1A1', 'Gene', '1543', (126, 132))	('polymorphism', 'Var', (138, 150))
21481	25886559	A total of 51 articles regarding CYP1A1 MspI polymorphism with respect to EC were identified.	('CYP1A1', 'Gene', (33, 39))	('CYP1A1', 'Gene', '1543', (33, 39))	('polymorphism', 'Var', (45, 57))
21488	25886559	Although many studies analyzing the research results about the association between CYP1A1 MspI polymorphism and EC, definite conclusions cannot be drawn.	('CYP1A1', 'Gene', (83, 89))	('MspI', 'Gene', (90, 94))	('CYP1A1', 'Gene', '1543', (83, 89))	('association', 'Interaction', (63, 74))	('polymorphism', 'Var', (95, 107))
21489	25886559	Therefore, we did this meta-analysis to estimate the relationship between CYP1A1 MspI polymorphism and susceptibility to EC among the Chinese population, in order to lessen the impact of different genetic background.	('CYP1A1', 'Gene', (74, 80))	('CYP1A1', 'Gene', '1543', (74, 80))	('polymorphism', 'Var', (86, 98))
21490	25886559	The results indicated a significant association between CYP1A1 MspI gene polymorphism and EC risk in the Chinese population.	('polymorphism', 'Var', (73, 85))	('CYP1A1', 'Gene', (56, 62))	('CYP1A1', 'Gene', '1543', (56, 62))
21491	25886559	Therefore, the findings from our meta-analysis provide a strong evidence for the association between CYP1A1 MspI polymorphism and risk of EC in the Chinese population.	('association', 'Interaction', (81, 92))	('polymorphism', 'Var', (113, 125))	('CYP1A1', 'Gene', (101, 107))	('CYP1A1', 'Gene', '1543', (101, 107))
21497	25886559	In conclusion, our meta-analysis supports that CYP1A1 MspI polymorphism might contribute to individual susceptibility to EC in the Chinese population.	('polymorphism', 'Var', (59, 71))	('susceptibility', 'Reg', (103, 117))	('contribute', 'Reg', (78, 88))	('CYP1A1', 'Gene', (47, 53))	('CYP1A1', 'Gene', '1543', (47, 53))
21499	25886559	Such studies may eventually lead to have a better, comprehensive understanding of the association between the CYP1A1 MspI polymorphism and EC risk.	('CYP1A1', 'Gene', '1543', (110, 116))	('polymorphism', 'Var', (122, 134))	('association', 'Interaction', (86, 97))	('CYP1A1', 'Gene', (110, 116))
21519	20171520	Sanguineti found that neck stage, nodal diameter , mean laryngeal dose and laryngeal V30Gy  V70Gy were all significantly associated with edema grade >=2 on univariate analysis.	('associated', 'Reg', (121, 131))	('edema', 'Disease', (137, 142))	('V70Gy', 'Var', (92, 97))	('edema', 'Disease', 'MESH:D004487', (137, 142))	('edema', 'Phenotype', 'HP:0000969', (137, 142))	('V30Gy  V70Gy', 'Var', (85, 97))
21556	20171520	For aspiration to occur, the GSL dose-volume threshold was V50Gy>50% (>50% of volume receiving 50Gy).	('aspiration', 'Disease', (4, 14))	('GSL', 'Disease', (29, 32))	('GSL', 'Disease', 'MESH:C536411', (29, 32))	('V50Gy>', 'Var', (59, 65))	('aspiration', 'Phenotype', 'HP:0002835', (4, 14))
21557	20171520	In a retrospective study, Jensen found that doses <60 Gy to the supraglottic area, larynx, and upper esophageal sphincter resulted in a low risk of aspiration.	('aspiration', 'Phenotype', 'HP:0002835', (148, 158))	('aspiration', 'Disease', (148, 158))	('upper esophageal sphincter', 'Disease', 'MESH:D009122', (95, 121))	('upper esophageal sphincter', 'Disease', (95, 121))	('doses', 'Var', (44, 49))
21596	19863824	Conflicting data have been reported on the association between low serum cholesterol levels and the risk for cancer mortality.	('low serum cholesterol levels', 'Phenotype', 'HP:0003146', (63, 91))	('c', 'Chemical', 'MESH:D002244', (6, 7))	('low serum cholesterol', 'Phenotype', 'HP:0003146', (63, 84))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('serum cholesterol levels', 'MPA', (67, 91))	('cancer', 'Disease', (109, 115))	('cholesterol', 'Chemical', 'MESH:D002784', (73, 84))	('c', 'Chemical', 'MESH:D002244', (73, 74))	('low', 'Var', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('c', 'Chemical', 'MESH:D002244', (47, 48))	('c', 'Chemical', 'MESH:D002244', (109, 110))	('c', 'Chemical', 'MESH:D002244', (112, 113))
21597	19863824	Some observational studies show that low serum cholesterol is associated with an increased risk of cancer mortality, but some failed to establish a connection.	('serum cholesterol', 'MPA', (41, 58))	('c', 'Chemical', 'MESH:D002244', (83, 84))	('cholesterol', 'Chemical', 'MESH:D002784', (47, 58))	('low', 'Var', (37, 40))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('low serum cholesterol', 'Phenotype', 'HP:0003146', (37, 58))	('c', 'Chemical', 'MESH:D002244', (66, 67))	('cancer', 'Disease', (99, 105))	('c', 'Chemical', 'MESH:D002244', (153, 154))	('c', 'Chemical', 'MESH:D002244', (148, 149))	('c', 'Chemical', 'MESH:D002244', (47, 48))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('c', 'Chemical', 'MESH:D002244', (99, 100))	('c', 'Chemical', 'MESH:D002244', (102, 103))
21599	19863824	There may be a causal link between low cholesterol and cancer.	('low cholesterol', 'Phenotype', 'HP:0003146', (35, 50))	('c', 'Chemical', 'MESH:D002244', (58, 59))	('cholesterol', 'Chemical', 'MESH:D002784', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('c', 'Chemical', 'MESH:D002244', (55, 56))	('c', 'Chemical', 'MESH:D002244', (15, 16))	('low cholesterol', 'Var', (35, 50))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('c', 'Chemical', 'MESH:D002244', (39, 40))	('cancer', 'Disease', (55, 61))
21606	19863824	Oxidized LDL, as an autoantigen, plays a crucial role in atherogenic lesion formation.	('c', 'Chemical', 'MESH:D002244', (44, 45))	('Oxidized', 'Var', (0, 8))	('c', 'Chemical', 'MESH:D002244', (41, 42))	('c', 'Chemical', 'MESH:D002244', (67, 68))	('atherogenic', 'Disease', (57, 68))	('LDL', 'Protein', (9, 12))
21608	19863824	Although still controversial, overall evidence supports the notion that IgG autoantibodies to OxLDL are associated with pro-atherogenic properties and IgM autoantibodies to OxLDL with anti-atherogenic properties.	('c', 'Chemical', 'MESH:D002244', (44, 45))	('c', 'Chemical', 'MESH:D002244', (134, 135))	('c', 'Chemical', 'MESH:D002244', (199, 200))	('autoantibodies', 'Var', (76, 90))	('associated', 'Reg', (104, 114))	('c', 'Chemical', 'MESH:D002244', (15, 16))	('c', 'Chemical', 'MESH:D002244', (108, 109))	('pro-atherogenic properties', 'MPA', (120, 146))
21631	19863824	Hypertension was defined as having systolic pressure (SBP) >= 140 mmHg and/or diastolic pressure (DBP) >= 90 mmHg, or those who were already undergoing medications for hypertension.	('diastolic pressure', 'MPA', (78, 96))	('>= 140', 'Var', (59, 65))	('DBP', 'Gene', (98, 101))	('hypertension', 'Disease', 'MESH:D006973', (168, 180))	('c', 'Chemical', 'MESH:D002244', (42, 43))	('DBP', 'Gene', '1628', (98, 101))	('c', 'Chemical', 'MESH:D002244', (86, 87))	('SBP', 'Gene', '8991', (54, 57))	('Hypertension', 'Phenotype', 'HP:0000822', (0, 12))	('Hypertension', 'Disease', 'MESH:D006973', (0, 12))	('SBP', 'Gene', (54, 57))	('systolic', 'MPA', (35, 43))	('hypertension', 'Disease', (168, 180))	('hypertension', 'Phenotype', 'HP:0000822', (168, 180))	('c', 'Chemical', 'MESH:D002244', (156, 157))	('Hypertension', 'Disease', (0, 12))
21661	19863824	As shown in Table 3, the Odds ratio (OR) of ADP, oxLDL, oxLDL-ab, oxLDL-lgG and oxLDL-lgM were associated with the different stages in the development of esophageal carcinoma (basal cell hyperplasia, dysplasia and early invasive cancer) after adjusted for age, albumin, TC, HDL and LDL.	('c', 'Chemical', 'MESH:D002244', (168, 169))	('oxLDL-lgG', 'Chemical', '-', (66, 75))	('men', 'Species', '9606', (146, 149))	('oxLDL-lgM', 'Var', (80, 89))	('c', 'Chemical', 'MESH:D002244', (229, 230))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (154, 174))	('c', 'Chemical', 'MESH:D002244', (182, 183))	('c', 'Chemical', 'MESH:D002244', (165, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('associated with', 'Reg', (95, 110))	('esophageal carcinoma', 'Disease', (154, 174))	('TC', 'Chemical', '-', (270, 272))	('basal cell hyperplasia, dysplasia', 'Disease', 'MESH:D002280', (176, 209))	('oxLDL-lgG', 'Var', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('c', 'Chemical', 'MESH:D002244', (99, 100))	('oxLDL-lgM', 'Chemical', '-', (80, 89))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (154, 174))	('oxLDL-ab', 'Chemical', '-', (56, 64))	('invasive cancer', 'Disease', (220, 235))	('ADP', 'Chemical', 'MESH:D000244', (44, 47))	('c', 'Chemical', 'MESH:D002244', (232, 233))	('invasive cancer', 'Disease', 'MESH:D009362', (220, 235))
21785	32042337	Conclusion: Our results suggest that ZNF750 may act as a tumor suppressor by directly repressing SNAI1 and inhibiting EMT process in ESCC and other types of SCC.	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('repressing', 'NegReg', (86, 96))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('ESCC', 'Disease', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ZNF750', 'Var', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('inhibiting', 'NegReg', (107, 117))	('EMT process', 'CPA', (118, 129))	('tumor', 'Disease', (57, 62))	('SNAI1', 'Gene', (97, 102))
21788	32042337	As reported, the frameshift mutation and the variation of the promoter region in ZNF750 gene may lead to lower protein expression and result in the occurrence of seborrheic dermatitis-like psoriasis.	('lower', 'NegReg', (105, 110))	('seborrheic dermatitis-like psoriasis', 'Disease', 'MESH:D012628', (162, 198))	('protein expression', 'MPA', (111, 129))	('result in', 'Reg', (134, 143))	('seborrheic dermatitis-like psoriasis', 'Disease', (162, 198))	('variation', 'Var', (45, 54))	('seborrheic dermatitis', 'Phenotype', 'HP:0001051', (162, 183))	('dermatitis', 'Phenotype', 'HP:0011123', (173, 183))	('frameshift mutation', 'Var', (17, 36))	('psoriasis', 'Phenotype', 'HP:0003765', (189, 198))	('occurrence', 'Reg', (148, 158))	('ZNF750', 'Gene', (81, 87))
21790	32042337	Here, we verified the tumor-suppressor role of ZNF750 in ESCC and elaborated on its possible mechanisms that ZNF750 directly bound to the promoter region of Snail Family Transcriptional Repressor 1 (SNAI1) and down-regulated the expression of SNAI1 to inhibit the epithelial-mesenchymal transition (EMT) of ESCC cells, in order to provide useful clues for clinical treatment of ESCC.	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('inhibit', 'NegReg', (252, 259))	('ESCC', 'Disease', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('ZNF750', 'Var', (109, 115))	('bound', 'Interaction', (125, 130))	('down-regulated', 'NegReg', (210, 224))	('SNAI1', 'Gene', (243, 248))	('tumor', 'Disease', (22, 27))	('SCC', 'Phenotype', 'HP:0002860', (379, 382))	('SCC', 'Phenotype', 'HP:0002860', (308, 311))	('expression', 'MPA', (229, 239))
21794	32042337	In addition, through cBioPortal based on the Cancer Genome Atlas (TCGA) or other cancer genome database, we found that the inactivating mutation rates of ZNF750 in different squamous cell carcinomas (SCC) were much higher than those in the corresponding adenocarcinomas (Figure 1C).	('ZNF750', 'Gene', (154, 160))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (174, 198))	('squamous cell carcinomas', 'Disease', (174, 198))	('higher', 'PosReg', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('adenocarcinomas', 'Disease', 'MESH:D000230', (254, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('carcinomas', 'Phenotype', 'HP:0030731', (259, 269))	('cancer', 'Disease', (81, 87))	('inactivating mutation', 'Var', (123, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (174, 198))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('adenocarcinomas', 'Disease', (254, 269))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))
21795	32042337	Similarly, the ratio of truncating and missense mutation was 3.93% (7/178) in lung squamous cell carcinoma (LUSC), however, there was no truncating or missense mutation of ZNF750 gene in lung adenocarcinoma (LUAC).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 106))	('missense mutation', 'Var', (151, 168))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (187, 206))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (187, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('LUSC', 'Phenotype', 'HP:0030359', (108, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('lung squamous cell carcinoma', 'Disease', (78, 106))	('ZNF750', 'Gene', (172, 178))	('lung adenocarcinoma', 'Disease', (187, 206))	('LUAC', 'Phenotype', 'HP:0030078', (208, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (78, 106))	('missense mutation', 'Var', (39, 56))
21798	32042337	To detect the protein level of ZNF750 in ESCC, we detected its expression in several paired of fresh tumors with or without ZNF750 mutation.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('expression', 'MPA', (63, 73))	('detected', 'Reg', (50, 58))	('ZNF750', 'Gene', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('mutation', 'Var', (131, 139))
21803	32042337	The patients with ZNF750low had a deeper invasion and a worse prognosis compared with the ZNF750high patients.	('deeper invasion', 'Disease', (34, 49))	('deeper invasion', 'Disease', 'MESH:D009361', (34, 49))	('ZNF750low', 'Var', (18, 27))
21813	32042337	The results showed that tumor growth rate of ZNF750wt group was significantly slower than that of the NC group (t-test, P < 0.01, Figure 4F).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('slower', 'NegReg', (78, 84))	('tumor', 'Disease', (24, 29))	('ZNF750wt', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
21814	32042337	The xenograft mice model results showed that the mean tumor volume of the control group, SCR group and the ZNF750wt group were (1212.41 +- 157.84) mm3, (394.74 +- 33.83) mm3, respectively.	('394.74', 'Var', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('1212.41 +-', 'Var', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
21816	32042337	Taken together, the results suggested that ZNF750 gene may act as a tumor suppressor in ESCC and its inactivating-mutation or decreased expression may promote the malignant phenotype of ESCC cells, such as invasion, migration and so on.	('tumor', 'Disease', (68, 73))	('decreased', 'NegReg', (126, 135))	('ESCC', 'Disease', (88, 92))	('expression', 'MPA', (136, 146))	('invasion', 'CPA', (206, 214))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SCC', 'Phenotype', 'HP:0002860', (187, 190))	('promote', 'PosReg', (151, 158))	('migration', 'CPA', (216, 225))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('malignant phenotype', 'CPA', (163, 182))	('ZNF750', 'Gene', (43, 49))	('ESCC', 'Disease', (186, 190))	('inactivating-mutation', 'Var', (101, 122))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
21819	32042337	The results showed SNAI1 knockdown decreased the proliferation (Figure 6F), colony formation (Figure 6G), migration (Figure 6H) and invasion (Figure 6I) induced by ZNF750 knockdown in KYSE140 cells.	('KYSE140', 'CellLine', 'CVCL:1347', (184, 191))	('ZNF750', 'Gene', (164, 170))	('colony formation', 'CPA', (76, 92))	('proliferation', 'CPA', (49, 62))	('SNAI1', 'Gene', (19, 24))	('decreased', 'NegReg', (35, 44))	('knockdown', 'Var', (171, 180))	('migration', 'CPA', (106, 115))	('knockdown', 'Var', (25, 34))	('invasion', 'CPA', (132, 140))
21826	32042337	also implicated that ZNF750 harbored many early frameshift and nonsense mutations in head and neck and lung squamous cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('nonsense mutations', 'Var', (63, 81))	('ZNF750', 'Gene', (21, 27))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('lung squamous cancers', 'Disease', 'MESH:D008175', (103, 124))	('lung squamous cancers', 'Disease', (103, 124))	('frameshift', 'Var', (48, 58))
21830	32042337	Its truncation mutation, or copy number loss, or other factors, may cause its inactivation or down-regulation, which may lead to the dedifferentiation and reprogram of squamous epithelium cells and result in tumorigenesis of ESCC.	('truncation mutation', 'Var', (4, 23))	('ESCC', 'Disease', (225, 229))	('SCC', 'Phenotype', 'HP:0002860', (226, 229))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('result in', 'Reg', (198, 207))	('dedifferentiation', 'CPA', (133, 150))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('reprogram', 'CPA', (155, 164))	('inactivation', 'MPA', (78, 90))	('tumor', 'Disease', (208, 213))	('lead to', 'Reg', (121, 128))	('down-regulation', 'NegReg', (94, 109))	('copy number loss', 'Var', (28, 44))
21833	32042337	Therefore, the decrease or inactivation of ZNF750 may lead SNAI1 to be free from the expression inhibition and trigger the EMT process associated with increased cancer invasion and metastasis.	('increased', 'PosReg', (151, 160))	('decrease', 'NegReg', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('inactivation', 'Var', (27, 39))	('EMT process', 'CPA', (123, 134))	('trigger', 'PosReg', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('SNAI1', 'Gene', (59, 64))	('cancer', 'Disease', (161, 167))	('metastasis', 'CPA', (181, 191))	('ZNF750', 'Gene', (43, 49))
21834	32042337	In conclusion, our work shows that ZNF750, a novel significantly mutated gene in ESCC, may act as a tumor suppressor via directly regulating SNAI1 expression and inhibit the EMT process of ESCC cells.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ZNF750', 'Var', (35, 41))	('SNAI1', 'Gene', (141, 146))	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('regulating', 'Reg', (130, 140))	('inhibit', 'NegReg', (162, 169))	('tumor', 'Disease', (100, 105))	('expression', 'MPA', (147, 157))	('ESCC', 'Gene', (81, 85))	('EMT process of ESCC cells', 'CPA', (174, 199))	('SCC', 'Phenotype', 'HP:0002860', (190, 193))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
21835	32042337	Its decrease or inactivation may result in tumorigenesis and progression of ESCC, even in other types of SCC.	('progression', 'CPA', (61, 72))	('result in', 'Reg', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('decrease', 'NegReg', (4, 12))	('inactivation', 'Var', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('ESCC', 'Disease', (76, 80))	('tumor', 'Disease', (43, 48))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))
21878	31578133	Methylation testing of secreted frizzled-related protein 2 using epigenetic marker may be a significative screening method for patients with esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (141, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('patients', 'Species', '9606', (127, 135))	('Methylation testing', 'Var', (0, 19))	('secreted frizzled-related protein 2', 'Gene', '6423', (23, 58))	('secreted frizzled-related protein 2', 'Gene', (23, 58))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))
21888	31578133	To our knowledge, epigenetic gene silencing constitutes an alternative or complementary mechanism to mutational events in tumorigenesis.	('tumor', 'Disease', (122, 127))	('epigenetic gene silencing', 'Var', (18, 43))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
21890	31578133	Thus, it is critical to identify the underlying epigenetically silenced cancer-related genes as new prognostic and therapeutic targets in ESCC diagnosis and treatment.	('epigenetically silenced', 'Var', (48, 71))	('ESCC', 'Disease', 'MESH:C562729', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('ESCC', 'Disease', (138, 142))	('cancer', 'Disease', (72, 78))
21892	31578133	Esophageal squamous cell carcinoma can develop through aberrant Wnt signaling which influences gene expression levels and methylation status, finally leading to carcinoma initiation and progression.	('Wnt signaling', 'Pathway', (64, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('carcinoma initiation', 'Disease', 'MESH:D007319', (161, 181))	('Esophageal squamous cell carcinoma', 'Disease', (0, 34))	('carcinoma initiation', 'Disease', (161, 181))	('gene expression levels', 'MPA', (95, 117))	('leading to', 'Reg', (150, 160))	('aberrant', 'Var', (55, 63))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (0, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('influences', 'Reg', (84, 94))	('methylation status', 'MPA', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
21942	31578133	The frequency of SFRP2 promoter methylation in ESCC tissues was significantly higher than that in the adjacent tissues (chi2 = 4.39; P = .046).	('methylation', 'Var', (32, 43))	('higher', 'PosReg', (78, 84))	('ESCC', 'Disease', (47, 51))	('SFRP2', 'Gene', '6423', (17, 22))	('SFRP2', 'Gene', (17, 22))	('ESCC', 'Disease', 'MESH:C562729', (47, 51))	('promoter', 'MPA', (23, 31))
21944	31578133	Statistical analysis indicated that methylation of the SFRP2 gene was significantly related to tumor size, AJCC stage, lymph node metastasis, and infiltration degree.	('related', 'Reg', (84, 91))	('methylation', 'Var', (36, 47))	('SFRP2', 'Gene', '6423', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('lymph', 'Disease', (119, 124))	('SFRP2', 'Gene', (55, 60))	('AJCC stage', 'Disease', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
21948	31578133	In our study, all the 73 (81.11%) cases with SFRP2 promoter methylation-positive ESCC tissues showed almost all IHC results were negative.	('ESCC', 'Disease', 'MESH:C562729', (81, 85))	('SFRP2', 'Gene', '6423', (45, 50))	('ESCC', 'Disease', (81, 85))	('SFRP2', 'Gene', (45, 50))	('methylation-positive', 'Var', (60, 80))
21951	31578133	DNA methylation may lead to downregulation or deletion of protein expression, which can be confirmed by IHC, MSP, and BSP.	('downregulation', 'NegReg', (28, 42))	('deletion', 'Var', (46, 54))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('protein', 'Protein', (58, 65))
21956	31578133	The results showed that the patients with methylation of SFRP2 had a poorer prognosis than those with unmethylation of SFRP2, but has no statistical significance (P > .05; Figure 5B).	('SFRP2', 'Gene', '6423', (119, 124))	('SFRP2', 'Gene', (57, 62))	('SFRP2', 'Gene', (119, 124))	('SFRP2', 'Gene', '6423', (57, 62))	('poorer', 'NegReg', (69, 75))	('methylation', 'Var', (42, 53))	('patients', 'Species', '9606', (28, 36))
21963	31578133	A delicate control of Wnt signaling is crucial for the proper maintenance of the organism, while aberrant Wnt signaling may lead to developmental defects and disease initiation and progression.	('developmental defects and disease initiation', 'Disease', 'MESH:D007319', (132, 176))	('Wnt signaling', 'Gene', (106, 119))	('progression', 'CPA', (181, 192))	('aberrant', 'Var', (97, 105))	('lead to', 'Reg', (124, 131))
21971	31578133	The SFRP2 methylation rates were detected in fecal samples in patients with adenoma (46%) and colorectal cancer (84%), respectively.	('adenoma', 'Disease', (76, 83))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('SFRP2', 'Gene', (4, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('detected', 'Reg', (33, 41))	('methylation', 'Var', (10, 21))	('colorectal cancer', 'Disease', (94, 111))	('adenoma', 'Disease', 'MESH:D000236', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (62, 70))	('SFRP2', 'Gene', '6423', (4, 9))
21972	31578133	The SFRP2 methylation rates were detected in serum samples in patients with adenoma (6%) and colorectal cancer (67%), respectively.	('adenoma', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('SFRP2', 'Gene', (4, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('detected', 'Reg', (33, 41))	('colorectal cancer', 'Disease', (93, 110))	('methylation', 'Var', (10, 21))	('adenoma', 'Disease', 'MESH:D000236', (76, 83))	('patients', 'Species', '9606', (62, 70))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('SFRP2', 'Gene', '6423', (4, 9))
21984	31578133	Our results confirmed that the study of SFRP2 promoter showed that the incidence of CpG methylation in ESCC tissues was significantly higher than that in adjacent nontumor tissues, which indicated that abnormal methylation in SFRP2 promoter region was not a cell line-specific event but a common phenomenon in the development of ESCC.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('ESCC', 'Disease', 'MESH:C562729', (329, 333))	('methylation', 'Var', (88, 99))	('SFRP2', 'Gene', (40, 45))	('methylation', 'Var', (211, 222))	('ESCC', 'Disease', 'MESH:C562729', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('SFRP2', 'Gene', (226, 231))	('higher', 'PosReg', (134, 140))	('ESCC', 'Disease', (329, 333))	('tumor', 'Disease', (166, 171))	('ESCC', 'Disease', (103, 107))	('abnormal methylation', 'Var', (202, 222))	('SFRP2', 'Gene', '6423', (226, 231))	('SFRP2', 'Gene', '6423', (40, 45))
21995	31578133	The test of SFRP2 methylation status may be a promising screening method for ESCC.	('ESCC', 'Disease', (77, 81))	('methylation', 'Var', (18, 29))	('SFRP2', 'Gene', '6423', (12, 17))	('SFRP2', 'Gene', (12, 17))	('ESCC', 'Disease', 'MESH:C562729', (77, 81))
22000	31121824	H3K18Ac as a Marker of Cancer Progression and Potential Target of Anti-Cancer Therapy Acetylation and deacetylation are posttranslational modifications (PTMs) which affect the regulation of chromatin structure and its remodeling.	('affect', 'Reg', (165, 171))	('regulation', 'MPA', (176, 186))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('H3K18Ac', 'Var', (0, 7))	('chromatin structure', 'MPA', (190, 209))	('acetyl', 'Chemical', 'MESH:D003545', (104, 110))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
22004	31121824	Finally, we describe future perspectives of cancer therapeutic strategies based on H3K18 modifications.	('modifications', 'Var', (89, 102))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('H3', 'Gene', '126961', (83, 85))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('rat', 'Species', '10116', (65, 68))
22010	31121824	N-tails of histones within the nucleosome octamer are considered a well-known target for specific chromatin epigenetic posttranslational modifications (PTMs).	('histone', 'Gene', (11, 18))	('epigenetic', 'Var', (108, 118))	('histone', 'Gene', '24829', (11, 18))
22012	31121824	Epigenetic alterations in chromatin structure could occur as a direct result of modifier's operations through chromatin-remodeling complexes such as SWItch/Sucrose Non-Fermentable SWI/SNF and non-coding RNAs, as well as indirectly through modification of chromatin binding molecules.	('rat', 'Species', '10116', (94, 97))	('modification', 'Reg', (239, 251))	('rat', 'Species', '10116', (15, 18))	('Epigenetic', 'Var', (0, 10))	('Sucrose', 'Chemical', 'MESH:D013395', (156, 163))
22014	31121824	The most common epigenetic histone modifications are acetylation, which is described in this chapter, and methylation.	('acetylation', 'MPA', (53, 64))	('acetyl', 'Chemical', 'MESH:D003545', (53, 59))	('methylation', 'Var', (106, 117))	('histone', 'Gene', (27, 34))	('histone', 'Gene', '24829', (27, 34))
22026	31121824	Removal of acetyl-groups from lysine residues by HDACs has an impact on chromatin compaction through interaction between positively charged N-tail histone residues and negatively charged DNA.	('positively charged', 'Var', (121, 139))	('HDAC', 'Gene', (49, 53))	('HDAC', 'Gene', '9734', (49, 53))	('histone', 'Gene', (147, 154))	('interaction', 'Interaction', (101, 112))	('lysine', 'Chemical', 'MESH:D008239', (30, 36))	('chromatin compaction', 'CPA', (72, 92))	('impact', 'Reg', (62, 68))	('histone', 'Gene', '24829', (147, 154))	('acetyl', 'Chemical', 'MESH:D003545', (11, 17))
22032	31121824	It has been demonstrated that mutation of the C-terminal site of p53, where acetylation occurs, prompts comprehensively the loss of p53-dependent cyclin-dependent kinase inhibitor p21 transcription.	('p53', 'Gene', (65, 68))	('loss', 'NegReg', (124, 128))	('p53', 'Gene', '7157', (65, 68))	('p53', 'Gene', (132, 135))	('mutation', 'Var', (30, 38))	('p21', 'Gene', '1026', (180, 183))	('p53', 'Gene', '7157', (132, 135))	('p21', 'Gene', (180, 183))	('rat', 'Species', '10116', (19, 22))	('transcription', 'MPA', (184, 197))	('acetyl', 'Chemical', 'MESH:D003545', (76, 82))
22039	31121824	In contrast, hypoacetylation often includes non-acetylated or single-acetylated N-terminal lysines.	('acetyl', 'Chemical', 'MESH:D003545', (69, 75))	('single-acetylated', 'Var', (62, 79))	('non-acetylated', 'MPA', (44, 58))	('hypoacetylation', 'Disease', (13, 28))	('lysines', 'Chemical', 'MESH:D008239', (91, 98))	('acetyl', 'Chemical', 'MESH:D003545', (17, 23))	('acetyl', 'Chemical', 'MESH:D003545', (48, 54))
22042	31121824	It has been demonstrated that the most important positions for acetylation are lysines placed at positions 9, 14, 18, and 27 on the N-tail of H3 (Lys9, Lys14, Lys18, and Lys27 respectively), and lysines placed at positions 5, 8, 12, and 16 on the N-tail of H4 (Lys5, Lys8, Lys12, and Lys16, respectively).	('Lys27', 'Var', (170, 175))	('lysines', 'Chemical', 'MESH:D008239', (79, 86))	('acetylation', 'MPA', (63, 74))	('acetyl', 'Chemical', 'MESH:D003545', (63, 69))	('Lys12', 'Chemical', '-', (273, 278))	('Lys18', 'Var', (159, 164))	('Lys16', 'Chemical', '-', (284, 289))	('Lys16', 'Var', (284, 289))	('H3', 'Gene', '126961', (142, 144))	('lysines', 'Chemical', 'MESH:D008239', (195, 202))	('Lys5', 'Gene', (261, 265))	('Lys18', 'Chemical', 'MESH:C066704', (159, 164))	('Lys5', 'Gene', '60496', (261, 265))	('Lys14', 'Chemical', '-', (152, 157))	('Lys27', 'Chemical', '-', (170, 175))	('Lys14', 'Var', (152, 157))	('Lys12', 'Var', (273, 278))	('Lys8', 'Var', (267, 271))	('Lys8', 'Chemical', '-', (267, 271))	('rat', 'Species', '10116', (19, 22))	('Lys9', 'Chemical', '-', (146, 150))
22064	31121824	Aberrant expression of HDACs have been noticed in many human diseases, including cancer, making them important therapeutic targets.	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (55, 60))	('cancer', 'Disease', (81, 87))	('HDAC', 'Gene', (23, 27))	('HDAC', 'Gene', '9734', (23, 27))
22091	31121824	The influence of under-expression of TIP60 in breast cancer has been tested using athymic Balb-c mice, in which the TIP60 knockdown was induced in MDA-MB-231 (ER+) and MCF-7 (ER-) cell lines.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (147, 157))	('MCF-7', 'CellLine', 'CVCL:0031', (168, 173))	('TIP60', 'Gene', (116, 121))	('mice', 'Species', '10090', (97, 101))	('knockdown', 'Var', (122, 131))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))
22092	31121824	The experiment showed that TIP60 is able to affect reduction of acetylation on H3K4 and that tumor development is increased in sh-TIP60 MDA-MB-231 xenografts, in contrast to sh-TIP60 MCF-7 xenografts, in which tumor development is inhibited.	('reduction', 'NegReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('increased', 'PosReg', (114, 123))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (210, 215))	('acetylation', 'MPA', (64, 75))	('acetyl', 'Chemical', 'MESH:D003545', (64, 70))	('H3', 'Gene', '126961', (79, 81))	('MCF-7', 'CellLine', 'CVCL:0031', (183, 188))	('sh-TIP60', 'Var', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (136, 146))
22095	31121824	Inhibition of TIP60 may modify expression of genes dependent on steroid hormone regulation, which in turn is associated with promotion or inhibition of tumor development.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('inhibition', 'NegReg', (138, 148))	('steroid hormone', 'Chemical', 'MESH:D013256', (64, 79))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('expression of genes', 'MPA', (31, 50))	('promotion', 'PosReg', (125, 134))	('tumor', 'Disease', (152, 157))	('modify', 'Reg', (24, 30))	('Inhibition', 'Var', (0, 10))	('TIP60', 'Gene', (14, 19))
22104	31121824	Additionally, knockout of CCAT1 has been found to inhibit cell proliferation and migration both in vitro and in vivo.	('rat', 'Species', '10116', (70, 73))	('rat', 'Species', '10116', (84, 87))	('inhibit', 'NegReg', (50, 57))	('cell proliferation', 'CPA', (58, 76))	('CCAT1', 'Gene', '100507056', (26, 31))	('CCAT1', 'Gene', (26, 31))	('knockout', 'Var', (14, 22))
22111	31121824	Additionally, mTOR depletion leads to enhanced recruitment of SIRT6 to promoters of glycolytic genes, which in turn allows metabolic reprogramming in glioma cells.	('mTOR', 'Gene', '2475', (14, 18))	('depletion', 'Var', (19, 28))	('enhanced', 'PosReg', (38, 46))	('allows', 'Reg', (116, 122))	('SIRT6', 'Gene', (62, 67))	('metabolic reprogramming', 'CPA', (123, 146))	('SIRT6', 'Gene', '51548', (62, 67))	('glioma', 'Disease', (150, 156))	('recruitment', 'MPA', (47, 58))	('glycolytic genes', 'Gene', (84, 100))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('mTOR', 'Gene', (14, 18))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
22113	31121824	It has been discovered that activation of microglia by glioma cells is connected with global H4K16 acetylation and that a high level of H4K16Ac expression promotes a tumor-supporting phenotype in microglia.	('glioma', 'Disease', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('H4K16', 'Protein', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('H4K16Ac', 'Var', (136, 143))	('acetylation', 'MPA', (99, 110))	('acetyl', 'Chemical', 'MESH:D003545', (99, 105))	('tumor', 'Disease', (166, 171))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('activation', 'PosReg', (28, 38))	('promotes', 'PosReg', (155, 163))
22124	31121824	The relationship between acetylation and cancer progression is demonstrated at the epigenetic, cellular, and tissue level.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('rat', 'Species', '10116', (70, 73))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('acetyl', 'Chemical', 'MESH:D003545', (25, 31))	('acetylation', 'Var', (25, 36))
22130	31121824	The levels of H3K18Ac were found to be higher in primary cancers and metastases compared to benign tissues and increased H3K18Ac identified patients at increased risk of PCa recurrence.	('metastases', 'Disease', (69, 79))	('higher', 'PosReg', (39, 45))	('increased', 'PosReg', (111, 120))	('PCa', 'Phenotype', 'HP:0012125', (170, 173))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('metastases', 'Disease', 'MESH:D009362', (69, 79))	('cancers', 'Disease', (57, 64))	('H3K18Ac', 'Chemical', '-', (14, 21))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('H3K18Ac', 'Chemical', '-', (121, 128))	('PCa recurrence', 'Disease', (170, 184))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('H3K18Ac', 'Var', (121, 128))
22136	31121824	The knock down of SIRT7 inhibits the migration of two androgen-independent prostate cancer cells (DU145 and PC3), although the overexpression of the native protein, but not the mutated form, promotes cell migration and invasion of the poorly aggressive, androgen-dependent LNCaP cell line.	('knock down', 'Var', (4, 14))	('prostate cancer', 'Disease', (75, 90))	('SIRT7', 'Gene', (18, 23))	('rat', 'Species', '10116', (208, 211))	('PC3', 'Gene', '3853', (108, 111))	('inhibits', 'NegReg', (24, 32))	('LNCaP', 'CellLine', 'CVCL:0395', (273, 278))	('rat', 'Species', '10116', (40, 43))	('DU145', 'CellLine', 'CVCL:0105', (98, 103))	('migration', 'CPA', (37, 46))	('cell migration', 'CPA', (200, 214))	('invasion', 'CPA', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (75, 90))	('SIRT7', 'Gene', '51547', (18, 23))	('promotes', 'PosReg', (191, 199))	('prostate cancer', 'Phenotype', 'HP:0012125', (75, 90))	('PC3', 'Gene', (108, 111))
22141	31121824	Expression of H4K12Ac and HDAC2, but not H3K18Ac, has been found to rise from normal tissue through adenoma to moderately and well-differentiated colorectal carcinoma (CRC), suggesting that HDAC2 and H4K12Ac together may play a role in the progression of colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (255, 267))	('CR', 'Chemical', '-', (168, 170))	('H4K12Ac', 'Var', (14, 21))	('play', 'Reg', (221, 225))	('colon cancer', 'Disease', 'MESH:D015179', (255, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('CRC', 'Phenotype', 'HP:0003003', (168, 171))	('colorectal carcinoma', 'Disease', (146, 166))	('H3K18Ac', 'Chemical', '-', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (146, 166))	('CRC', 'Phenotype', 'HP:0030731', (168, 171))	('adenoma', 'Disease', (100, 107))	('colon cancer', 'Disease', (255, 267))	('HDAC2', 'Gene', '3066', (26, 31))	('rat', 'Species', '10116', (115, 118))	('HDAC2', 'Gene', (26, 31))	('adenoma', 'Disease', 'MESH:D000236', (100, 107))	('rise', 'PosReg', (68, 72))	('HDAC2', 'Gene', (190, 195))	('HDAC2', 'Gene', '3066', (190, 195))
22146	31121824	The results to date are encouraging because they demonstrate that aberrant expression of HDAC2 frequently occurs in patients with CRC, providing potential biomarkers for use in future clinical trials.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('rat', 'Species', '10116', (56, 59))	('HDAC2', 'Gene', '3066', (89, 94))	('patients', 'Species', '9606', (116, 124))	('HDAC2', 'Gene', (89, 94))	('occurs', 'Reg', (106, 112))	('aberrant expression', 'Var', (66, 85))	('CR', 'Chemical', '-', (130, 132))	('CRC', 'Disease', (130, 133))	('CRC', 'Phenotype', 'HP:0030731', (130, 133))
22150	31121824	This study has shown that the IFNgamma-producing cells of the host immune system counteract the silencing of GPR109A mediated by DNA methylation to suppress cancer development.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('silencing', 'Var', (96, 105))	('GPR109A', 'Gene', '338442', (109, 116))	('suppress', 'NegReg', (148, 156))	('GPR109A', 'Gene', (109, 116))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('IFNgamma', 'Gene', (30, 38))	('DNA methylation', 'Var', (129, 144))	('cancer', 'Disease', (157, 163))	('IFNgamma', 'Gene', '3458', (30, 38))
22152	31121824	It has been discovered that most breast tumors score low for H4K16Ac, whereas H3K18ac and H4K20Me3 are expressed at relatively high levels.	('low', 'NegReg', (53, 56))	('breast tumors', 'Disease', 'MESH:D001943', (33, 46))	('H3', 'Gene', '126961', (78, 80))	('breast tumors', 'Disease', (33, 46))	('H4K16Ac', 'Var', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('H4K20Me3', 'Var', (90, 98))	('breast tumors', 'Phenotype', 'HP:0100013', (33, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
22153	31121824	Low levels of H3K18Ac are associated with high tumor grade, and high expression of histone modifications is correlated with cancers positive for steroid receptors (androgen receptor, estrogen receptor, and progesterone receptor), increased expression of E-cadherin and BRCA1, and low p53 and HER-2 expressions.	('low', 'NegReg', (280, 283))	('H3K18Ac', 'Chemical', '-', (14, 21))	('steroid receptors (androgen receptor, estrogen receptor, and progesterone receptor', 'Gene', '367;2099;5241', (145, 227))	('histone', 'Gene', (83, 90))	('HER-2', 'Gene', '2064', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('HER-2', 'Gene', (292, 297))	('expression', 'MPA', (240, 250))	('p53', 'Gene', '7157', (284, 287))	('high tumor', 'Disease', (42, 52))	('histone', 'Gene', '24829', (83, 90))	('expressions', 'MPA', (298, 309))	('high tumor', 'Disease', 'MESH:D009369', (42, 52))	('p53', 'Gene', (284, 287))	('H3K18Ac', 'Var', (14, 21))	('E-cadherin', 'Gene', (254, 264))	('E-cadherin', 'Gene', '999', (254, 264))	('increased', 'PosReg', (230, 239))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('BRCA1', 'Gene', '672', (269, 274))	('expression', 'MPA', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BRCA1', 'Gene', (269, 274))
22158	31121824	Nonetheless, this research supports the evidence that global hypoacetylation of H3K18 is demonstrative of cell transformation and may be a crucial prognostic marker in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('breast cancer', 'Disease', (168, 181))	('global hypoacetylation', 'Var', (54, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('H3', 'Gene', '126961', (80, 82))	('rat', 'Species', '10116', (96, 99))	('acetyl', 'Chemical', 'MESH:D003545', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cell transformation', 'CPA', (106, 125))
22160	31121824	It has been observed that HBx oncoprotein of hepatitis B virus (HBV) stabilizes SIRT7 and stimulates H3K18 deacetylation, and depletion of SIRT7 decreases cell viability and transformation.	('SIRT7', 'Gene', '51547', (80, 85))	('SIRT7', 'Gene', '51547', (139, 144))	('hepatitis', 'Phenotype', 'HP:0012115', (45, 54))	('HBx', 'Gene', (26, 29))	('SIRT7 decreases cell viability', 'Disease', 'MESH:D012021', (139, 169))	('HBV', 'Species', '10407', (64, 67))	('deacetylation', 'MPA', (107, 120))	('depletion', 'Var', (126, 135))	('HBx', 'Gene', '944566', (26, 29))	('acetyl', 'Chemical', 'MESH:D003545', (109, 115))	('SIRT7', 'Gene', (80, 85))	('SIRT7', 'Gene', (139, 144))	('stimulates', 'PosReg', (90, 100))	('hepatitis B virus', 'Species', '10407', (45, 62))	('H3', 'Gene', '126961', (101, 103))	('SIRT7 decreases cell viability', 'Disease', (139, 169))	('transformation', 'CPA', (174, 188))
22162	31121824	In other research, high expressions of SIRT7 and H3K18Ac in hepatocellular carcinoma (HCC) were associated with worse patient overall survival (OS), and H3K18Ac levels turned out to be an independent prognostic factor in multivariate analysis.	('high', 'Var', (19, 23))	('SIRT7', 'Gene', '51547', (39, 44))	('H3K18Ac', 'Chemical', '-', (49, 56))	('H3K18Ac', 'Chemical', '-', (153, 160))	('H3K18Ac', 'Var', (49, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('SIRT7', 'Gene', (39, 44))	('hepatocellular carcinoma', 'Disease', (60, 84))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (60, 84))	('patient', 'Species', '9606', (118, 125))	('worse', 'NegReg', (112, 117))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
22166	31121824	Interestingly, HDAC9, a histone deacetylase responsible for H3K18 deacetylation, was established as the target of miR-376a, and its inhibition was found to increase the expression of miR-376a by up-regulating the global histone H3K18Ac.	('histone', 'Gene', '24829', (24, 31))	('miR-376a', 'Var', (114, 122))	('histone deacetylase', 'Gene', '9734', (24, 43))	('expression', 'MPA', (169, 179))	('histone', 'Gene', '24829', (220, 227))	('miR-376a', 'Gene', (183, 191))	('increase', 'PosReg', (156, 164))	('histone deacetylase', 'Gene', (24, 43))	('H3', 'Gene', '126961', (228, 230))	('inhibition', 'NegReg', (132, 142))	('histone', 'Gene', (24, 31))	('acetyl', 'Chemical', 'MESH:D003545', (34, 40))	('acetyl', 'Chemical', 'MESH:D003545', (68, 74))	('H3', 'Gene', '126961', (60, 62))	('HDAC9', 'Gene', '9734', (15, 20))	('HDAC9', 'Gene', (15, 20))	('histone', 'Gene', (220, 227))	('H3K18Ac', 'Chemical', '-', (228, 235))	('up-regulating', 'PosReg', (195, 208))
22167	31121824	Finally, both miR-376a and HDAC9 were inversely correlated in HCC.	('miR-376a', 'Var', (14, 22))	('HCC', 'Disease', (62, 65))	('HCC', 'Phenotype', 'HP:0001402', (62, 65))	('HDAC9', 'Gene', '9734', (27, 32))	('HDAC9', 'Gene', (27, 32))	('correlated', 'Reg', (48, 58))
22169	31121824	C646, a specific p300 HAT inhibitor, has been found to reduce ING5-induced acetylation of p53K382 and H3K18 and subsequent expression of Bax and p21 proteins.	('Bax', 'Gene', '581', (137, 140))	('p21', 'Gene', '1026', (145, 148))	('p53', 'Gene', (90, 93))	('p300', 'Gene', (17, 21))	('expression', 'MPA', (123, 133))	('ING5', 'Gene', (62, 66))	('C646', 'Var', (0, 4))	('acetylation', 'MPA', (75, 86))	('p53', 'Gene', '7157', (90, 93))	('p21', 'Gene', (145, 148))	('H3', 'Gene', '126961', (102, 104))	('acetyl', 'Chemical', 'MESH:D003545', (75, 81))	('p300', 'Gene', '2033', (17, 21))	('Bax', 'Gene', (137, 140))	('ING5', 'Gene', '84289', (62, 66))	('reduce', 'NegReg', (55, 61))
22176	31121824	E1A has a strong influence on the global reduction of H3K18Ac (about 70%) compared to uninfected cells.	('H3K18Ac', 'Chemical', '-', (54, 61))	('E1A', 'Var', (0, 3))	('H3K18Ac', 'Protein', (54, 61))	('reduction', 'NegReg', (41, 50))
22180	31121824	CR1 and CR2 domains of both small and large E1A interact with histone HAT p300/CBP and the retinoblastoma (RB) family of proteins (RB1, p107, and p130) which reprogram gene expression in host cells and allow quiescent cells to enter the S-phase.	('RB', 'Phenotype', 'HP:0009919', (131, 133))	('retinoblastoma', 'Phenotype', 'HP:0009919', (91, 105))	('CBP', 'Gene', (79, 82))	('CR2', 'Species', '2498238', (8, 11))	('p300', 'Gene', '2033', (74, 78))	('CBP', 'Gene', '1387', (79, 82))	('histone', 'Gene', (62, 69))	('CR', 'Chemical', '-', (8, 10))	('retinoblastoma', 'Disease', 'MESH:D012175', (91, 105))	('retinoblastoma', 'Disease', (91, 105))	('CR', 'Chemical', '-', (0, 2))	('RB', 'Phenotype', 'HP:0009919', (107, 109))	('p300', 'Gene', (74, 78))	('histone', 'Gene', '24829', (62, 69))	('p107', 'Var', (136, 140))
22188	31121824	It has been demonstrated that the major repression function of E1A 243R oncoprotein resides within its N-terminal 1-80 amino acids domain.	('repression', 'MPA', (40, 50))	('rat', 'Species', '10116', (19, 22))	('oncoprotein', 'Protein', (72, 83))	('E1A 243R', 'Var', (63, 71))
22189	31121824	This domain is sufficient for inhibition of H3K18 acetylation and p300 mediated H3K18 acetylation in reconstituted chromatin in vivo, and it is known that hypoacetylation of histone H3 at this position is correlated with aggressive tumor phenotypes and poor prognosis in different cancers.	('acetyl', 'Chemical', 'MESH:D003545', (159, 165))	('p300', 'Gene', (66, 70))	('H3', 'Gene', '126961', (80, 82))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('hypoacetylation', 'Var', (155, 170))	('cancers', 'Disease', (281, 288))	('acetylation', 'MPA', (86, 97))	('p300', 'Gene', '2033', (66, 70))	('acetyl', 'Chemical', 'MESH:D003545', (86, 92))	('H3', 'Gene', '126961', (182, 184))	('inhibition', 'NegReg', (30, 40))	('histone', 'Gene', (174, 181))	('aggressive tumor', 'Disease', 'MESH:D001523', (221, 237))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('H3', 'Gene', '126961', (44, 46))	('acetylation', 'MPA', (50, 61))	('acetyl', 'Chemical', 'MESH:D003545', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('histone', 'Gene', '24829', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('aggressive tumor', 'Disease', (221, 237))
22192	31121824	The repression of MYC expression via epigenetic modifications may become a novel anticancer therapy in the future.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('MYC', 'Gene', (18, 21))	('cancer', 'Disease', (85, 91))	('repression', 'NegReg', (4, 14))	('MYC', 'Gene', '4609', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('epigenetic modifications', 'Var', (37, 61))
22193	31121824	Hypoacetylation of H3K18 is associated with aggressive tumor phenotypes and poor prognosis in patients with several cancer types.	('aggressive tumor', 'Disease', (44, 60))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('associated', 'Reg', (28, 38))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('Hypoacetylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('acetyl', 'Chemical', 'MESH:D003545', (4, 10))	('aggressive tumor', 'Disease', 'MESH:D001523', (44, 60))	('H3', 'Gene', '126961', (19, 21))
22194	31121824	It has been discovered that that SIRT6 actively removes acetyl groups from histones H3K9, H3K18, and H3K27, but that it has relatively low activity toward histones H3K4 and K3K23, and poor activity toward histones H3K14, H3K36, H3K56, and H3K79.	('SIRT6', 'Gene', (33, 38))	('histone', 'Gene', '24829', (205, 212))	('K3K23', 'Var', (173, 178))	('H3', 'Gene', '126961', (214, 216))	('SIRT6', 'Gene', '51548', (33, 38))	('H3', 'Gene', '126961', (239, 241))	('histone', 'Gene', '24829', (155, 162))	('histone', 'Gene', '24829', (75, 82))	('H3', 'Gene', '126961', (228, 230))	('H3', 'Gene', '126961', (84, 86))	('H3', 'Gene', '126961', (221, 223))	('activity', 'MPA', (189, 197))	('H3', 'Gene', '126961', (164, 166))	('histone', 'Gene', (205, 212))	('H3', 'Gene', '126961', (101, 103))	('acetyl groups', 'MPA', (56, 69))	('histone', 'Gene', (155, 162))	('activity', 'MPA', (139, 147))	('removes', 'NegReg', (48, 55))	('H3', 'Gene', '126961', (90, 92))	('acetyl', 'Chemical', 'MESH:D003545', (56, 62))	('histone', 'Gene', (75, 82))
22200	31121824	Inactivation of SIRT7 reverses the malignant phenotype of cancer cells and decreases their tumorigenicity.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('reverses', 'NegReg', (22, 30))	('SIRT7', 'Gene', '51547', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancer', 'Disease', (58, 64))	('SIRT7', 'Gene', (16, 21))	('tumor', 'Disease', (91, 96))	('decreases', 'NegReg', (75, 84))	('Inactivation', 'Var', (0, 12))
22202	31121824	Deacetylation of H3K18Ac by SIRT7 is crucial for maintaining essential features of cancer cells, including escape from contact inhibition and anchorage-independent growth.	('H3K18Ac', 'Chemical', '-', (17, 24))	('H3K18Ac', 'Protein', (17, 24))	('acetyl', 'Chemical', 'MESH:D003545', (2, 8))	('SIRT7', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Deacetylation', 'Var', (0, 13))	('SIRT7', 'Gene', '51547', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
22203	31121824	Additionally, SIRT7 is required for a global H3K18 hypoacetylation that leads to cellular transformation by the E1A viral oncoprotein.	('acetyl', 'Chemical', 'MESH:D003545', (55, 61))	('SIRT7', 'Gene', (14, 19))	('E1A', 'Gene', (112, 115))	('cellular transformation', 'CPA', (81, 104))	('H3', 'Gene', '126961', (45, 47))	('leads to', 'Reg', (72, 80))	('hypoacetylation', 'Var', (51, 66))	('SIRT7', 'Gene', '51547', (14, 19))
22204	31121824	Importantly, depletion of SIRT7 markedly decreases the tumorigenicity of human cancer cell xenografts in vivo.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('decreases', 'NegReg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SIRT7', 'Gene', '51547', (26, 31))	('depletion', 'Var', (13, 22))	('tumor', 'Disease', (55, 60))	('human', 'Species', '9606', (73, 78))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('SIRT7', 'Gene', (26, 31))
22206	31121824	SIRT7 depletion induces acetylation of H3K18 at promoters of these genes, and as a consequence increases transcription of target genes.	('SIRT7', 'Gene', (0, 5))	('SIRT7', 'Gene', '51547', (0, 5))	('depletion', 'Var', (6, 15))	('acetyl', 'Chemical', 'MESH:D003545', (24, 30))	('transcription', 'MPA', (105, 118))	('induces', 'Reg', (16, 23))	('acetylation', 'MPA', (24, 35))	('H3', 'Gene', '126961', (39, 41))	('increases', 'PosReg', (95, 104))
22215	31121824	Epigenetic changes, including H3K9Ac, H3K18Ac, and H4K16Ac, respectively, as well as H3K4Me2, H4K20Me3, and H4R3Meare, are considered as being potential biomarkers in patients with glioma.	('H3K9Ac', 'Gene', (30, 36))	('H3', 'Gene', '126961', (85, 87))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('H4R3Meare', 'Var', (108, 117))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('H3K9Ac', 'Gene', '126961', (30, 36))	('H3', 'Gene', '126961', (38, 40))	('H3K18Ac', 'Chemical', '-', (38, 45))	('patients', 'Species', '9606', (167, 175))	('glioma', 'Disease', (181, 187))	('H4K16Ac', 'Var', (51, 58))	('H4K20Me3', 'Var', (94, 102))	('H3', 'Gene', '126961', (30, 32))
22216	31121824	Relatively high median expression of H3K9Ac, H3K18Ac, and H4K16Ac (74%, 78%, and 68%, respectively), and H3K4Me2, H4K20Me3, and H4R3Me (63%, 75%, and 60%, respectively) has been detected in gliomas.	('H4R3Me', 'Var', (128, 134))	('gliomas', 'Disease', 'MESH:D005910', (190, 197))	('H3K18Ac', 'Chemical', '-', (45, 52))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('gliomas', 'Disease', (190, 197))	('H3', 'Gene', '126961', (45, 47))	('H3K9Ac', 'Gene', '126961', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('H3K9Ac', 'Gene', (37, 43))	('H4K16Ac', 'Var', (58, 65))	('H4K20Me3', 'Var', (114, 122))	('H3', 'Gene', '126961', (37, 39))	('H3', 'Gene', '126961', (105, 107))
22218	31121824	Expression of seven biomarkers, including H3K9Ac, H3K18Ac, H4K12Ac, H4K16Ac, H4K20Me3, H3K4Me2, and H4R3Me2 have been detected in 880 breast carcinomas.	('H3', 'Gene', '126961', (50, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('breast carcinomas', 'Disease', 'MESH:D001943', (134, 151))	('breast carcinomas', 'Disease', (134, 151))	('H3K9Ac', 'Gene', '126961', (42, 48))	('H4R3Me2', 'Var', (100, 107))	('detected', 'Reg', (118, 126))	('H3K9Ac', 'Gene', (42, 48))	('H4K20Me3', 'Var', (77, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('H3', 'Gene', '126961', (42, 44))	('H4K16Ac', 'Var', (68, 75))	('breast carcinomas', 'Phenotype', 'HP:0003002', (134, 151))	('H3', 'Gene', '126961', (87, 89))	('H4K12Ac', 'Var', (59, 66))	('H3K18Ac', 'Chemical', '-', (50, 57))
22219	31121824	Lower levels of histone modifications have been connected with unfavorable outcomes of patients, and higher levels of histone mark expression, excluding H4K20Me3, have been connected with better breast cancer-specific survival.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('better', 'PosReg', (188, 194))	('histone', 'Gene', '24829', (118, 125))	('histone', 'Gene', '24829', (16, 23))	('breast cancer', 'Disease', (195, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('histone', 'Gene', (118, 125))	('patients', 'Species', '9606', (87, 95))	('histone', 'Gene', (16, 23))	('H4K20Me3', 'Var', (153, 161))
22220	31121824	Higher expressions of H3K9Ac, H3K18Ac, and H4R3Me2 have been correlated with longer disease-free survival and metastatic-specific survival (except for H4K20Me3 expression).	('longer', 'PosReg', (77, 83))	('metastatic-specific survival', 'CPA', (110, 138))	('H3K18Ac', 'Var', (30, 37))	('H3K18Ac', 'Chemical', '-', (30, 37))	('expressions', 'MPA', (7, 18))	('Higher', 'PosReg', (0, 6))	('H4R3Me2', 'Var', (43, 50))	('disease-free survival', 'CPA', (84, 105))	('H3K9Ac', 'Gene', (22, 28))	('H3K9Ac', 'Gene', '126961', (22, 28))
22221	31121824	In multivariate analysis only, H3K18Ac was an independent prognostic factor with respect to BCSS and DFS.	('H3K18Ac', 'Chemical', '-', (31, 38))	('BCSS', 'Disease', (92, 96))	('H3K18Ac', 'Var', (31, 38))	('SS', 'Phenotype', 'HP:0100242', (94, 96))	('DFS', 'Disease', (101, 104))
22222	31121824	Moreover, higher cellular levels of H3K9Ac, H3K18Ac, and H4K16Ac were present in tissues from patients who were not subjected to postoperative adjuvant treatment and who were connected with longer BCSS, DFS, and metastatic-specific survival.	('DFS', 'CPA', (203, 206))	('H3K18Ac', 'Chemical', '-', (44, 51))	('patients', 'Species', '9606', (94, 102))	('SS', 'Phenotype', 'HP:0100242', (199, 201))	('cellular levels', 'MPA', (17, 32))	('H4K16Ac', 'Var', (57, 64))	('higher', 'PosReg', (10, 16))	('rat', 'Species', '10116', (136, 139))	('H3K9Ac', 'Gene', '126961', (36, 42))	('H3K9Ac', 'Gene', (36, 42))	('metastatic-specific survival', 'CPA', (212, 240))	('H3K18Ac', 'Var', (44, 51))
22224	31121824	Another study has discovered lower levels of H3K18Ac and H4K20Me3 in malignant breast tumors (MBT) compared to benign breast tumors (BBT).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('H4K20Me3', 'Var', (57, 65))	('benign breast tumors', 'Disease', (111, 131))	('H3K18Ac', 'Protein', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('malignant breast tumors', 'Disease', 'MESH:D001943', (69, 92))	('H3K18Ac', 'Chemical', '-', (45, 52))	('breast tumors', 'Phenotype', 'HP:0100013', (79, 92))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('malignant breast tumors', 'Disease', (69, 92))	('benign breast tumors', 'Disease', 'MESH:D001943', (111, 131))	('lower', 'NegReg', (29, 34))	('breast tumors', 'Phenotype', 'HP:0100013', (118, 131))
22226	31121824	These findings support the view that deacetylation of histones drives tumorigenic process.	('histone', 'Gene', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('acetyl', 'Chemical', 'MESH:D003545', (39, 45))	('tumor', 'Disease', (70, 75))	('histone', 'Gene', '24829', (54, 61))	('drives', 'PosReg', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('deacetylation', 'Var', (37, 50))
22227	31121824	In gastric carcinoma, trimethylation of H3K9 has been positively correlated with tumor stage, cancer recurrence, lymphovascular invasion, and independently predicted poor survival.	('H3', 'Gene', '126961', (40, 42))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('lymphovascular invasion', 'CPA', (113, 136))	('predicted', 'Reg', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('trimethylation', 'Var', (22, 36))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric carcinoma', 'Disease', (3, 20))	('poor survival', 'CPA', (166, 179))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('cancer', 'Disease', (94, 100))	('correlated', 'Reg', (65, 75))
22228	31121824	Higher cellular levels of H3K9Ac have been correlated with poorly differentiated adenocarcinomas and loss of H3K9Ac expression has been associated with intestinal-type tumors.	('associated', 'Reg', (136, 146))	('adenocarcinomas', 'Disease', (81, 96))	('expression', 'MPA', (116, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('intestinal-type tumors', 'Disease', 'MESH:D007414', (152, 174))	('cellular levels', 'MPA', (7, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('loss', 'Var', (101, 105))	('correlated', 'Reg', (43, 53))	('intestinal-type tumors', 'Disease', (152, 174))	('adenocarcinomas', 'Disease', 'MESH:D000230', (81, 96))	('Higher', 'PosReg', (0, 6))	('H3K9Ac', 'Gene', '126961', (26, 32))	('H3K9Ac', 'Gene', '126961', (109, 115))	('H3K9Ac', 'Gene', (109, 115))	('H3K9Ac', 'Gene', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
22229	31121824	Another study showed that the levels of H3K9Ac and H4K16Ac are increased at the promoter region of the bone morphogenetic 8B (BMP8B) gene in gastric cancer.	('increased', 'PosReg', (63, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('H3K9Ac', 'Gene', '126961', (40, 46))	('BMP8B', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('BMP8B', 'Gene', '656', (126, 131))	('bone morphogenetic 8B', 'Gene', (103, 124))	('bone morphogenetic 8B', 'Gene', '656', (103, 124))	('gastric cancer', 'Disease', (141, 155))	('H4K16Ac', 'Var', (51, 58))	('H3K9Ac', 'Gene', (40, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))
22230	31121824	Interestingly, these modifications were found not only in gastric cancer but in non-tumor tissues as well.	('modifications', 'Var', (21, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (58, 72))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('non-tumor', 'Disease', (80, 89))	('non-tumor', 'Disease', 'MESH:D009369', (80, 89))	('gastric cancer', 'Disease', (58, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (58, 72))
22231	31121824	The reduction of H3K9Ac and H4K16Ac expressions at the BMP8B promoter region has been connected with poorly-differentiated gastric cancer in comparison with moderately differentiated tumors.	('H4K16Ac', 'Var', (28, 35))	('BMP8B', 'Gene', (55, 60))	('BMP8B', 'Gene', '656', (55, 60))	('H3K9Ac', 'Gene', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('gastric cancer', 'Disease', (123, 137))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('rat', 'Species', '10116', (161, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('reduction', 'NegReg', (4, 13))	('tumors', 'Disease', (183, 189))	('expressions', 'MPA', (36, 47))	('H3K9Ac', 'Gene', '126961', (17, 23))
22236	31121824	Another study has confirmed that high levels of H3K18Ac and H4K12Ac are independently associated with poor survival of patients with pancreatic cancer.	('H4K12Ac', 'Var', (60, 67))	('patients', 'Species', '9606', (119, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('H3K18Ac', 'Chemical', '-', (48, 55))	('poor', 'NegReg', (102, 106))	('H3K18Ac', 'Var', (48, 55))	('pancreatic cancer', 'Disease', (133, 150))	('pancreatic cancer', 'Disease', 'MESH:D010190', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
22237	31121824	The expression of H3K9Ac, H3K18Ac, and H4K12Ac was found to be low in normal areas adjacent to the tumor, and metastatic lesions had higher expression of histone acetylation compared to normal and primary pancreatic cancers.	('H3K18Ac', 'Var', (26, 33))	('histone', 'Gene', (154, 161))	('H4K12Ac', 'Var', (39, 46))	('expression', 'MPA', (4, 14))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (205, 223))	('tumor', 'Disease', (99, 104))	('pancreatic cancers', 'Disease', (205, 223))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('higher', 'PosReg', (133, 139))	('histone', 'Gene', '24829', (154, 161))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (205, 222))	('H3K18Ac', 'Chemical', '-', (26, 33))	('pancreatic cancers', 'Disease', 'MESH:D010190', (205, 223))	('H3K9Ac', 'Gene', '126961', (18, 24))	('H3K9Ac', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('expression', 'MPA', (140, 150))	('acetyl', 'Chemical', 'MESH:D003545', (162, 168))
22243	31121824	Analysis of global histone modifications (H2AK5Ac, H3K9Ac, H4K8Ac, H2BK12Ac, and H3K4Me2) in non-small-cell lung cancer (NSCLC) tissues has revealed that patients with pathologic tumor stage II and low expression of H2AK5Ac have worse survival.	('H3', 'Gene', '126961', (81, 83))	('expression', 'MPA', (202, 212))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('histone', 'Gene', (19, 26))	('H3K9Ac', 'Gene', '126961', (51, 57))	('H3K9Ac', 'Gene', (51, 57))	('lung cancer', 'Disease', (108, 119))	('H4K8Ac', 'Var', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('low', 'NegReg', (198, 201))	('patients', 'Species', '9606', (154, 162))	('histone', 'Gene', '24829', (19, 26))	('H2BK12Ac', 'CellLine', 'CVCL:T475', (67, 75))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('NSCLC', 'Disease', (121, 126))	('H3', 'Gene', '126961', (51, 53))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (97, 119))	('H2AK5Ac', 'Gene', (216, 223))	('H2AK5Ac', 'Chemical', '-', (216, 223))	('H2BK12Ac', 'Var', (67, 75))	('H2AK5Ac', 'Chemical', '-', (42, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('H2AK5Ac', 'Var', (42, 49))	('tumor', 'Disease', (179, 184))
22244	31121824	Furthermore, high H3K4Me2 expression is connected with a better survival of patients with stage I large-cell carcinomas (LCC) or squamous cell carcinomas (SCC).	('survival', 'CPA', (64, 72))	('squamous cell carcinomas', 'Disease', (129, 153))	('carcinomas', 'Disease', (143, 153))	('H3', 'Gene', '126961', (18, 20))	('carcinomas', 'Disease', (109, 119))	('expression', 'MPA', (26, 36))	('high', 'Var', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('better', 'PosReg', (57, 63))	('patients', 'Species', '9606', (76, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('carcinomas', 'Disease', 'MESH:D002277', (143, 153))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (129, 153))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (129, 153))	('carcinomas', 'Disease', 'MESH:D002277', (109, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))
22246	31121824	Another study has shown that low expression of H4K5Ac and H4K8Ac, and high expression of H4K12Ac and H4K16Ac, are present in parenchyma of normal lungs compared to cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('H4K5Ac', 'Var', (47, 53))	('H4K16Ac', 'Var', (101, 108))	('H4K8Ac', 'Var', (58, 64))	('H4K12Ac', 'Var', (89, 96))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('expression', 'MPA', (33, 43))	('expression', 'MPA', (75, 85))
22248	31121824	A loss of trimethylation of H4K20 has been observed in lung tumors compared with normal lungs, and the H4K20Me3 expression was found to decrease with disease progression from cell hyperplasia to metaplasia, dysplasia, and then to carcinoma in situ.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (230, 247))	('lung tumors', 'Disease', 'MESH:D008175', (55, 66))	('H4K20Me3', 'Var', (103, 111))	('decrease', 'NegReg', (136, 144))	('H4K20', 'Protein', (28, 33))	('loss', 'NegReg', (2, 6))	('carcinoma in situ', 'Disease', 'MESH:D002278', (230, 247))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('hyperplasia to metaplasia, dysplasia', 'Disease', 'MESH:D008679', (180, 216))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('carcinoma in situ', 'Disease', (230, 247))	('trimethylation', 'MPA', (10, 24))	('lung tumors', 'Disease', (55, 66))	('lung tumors', 'Phenotype', 'HP:0100526', (55, 66))	('expression', 'MPA', (112, 122))
22249	31121824	Patients with stage 1 adenocarcinomas expressing higher levels of H4K20Me3 had longer cancer-related survival.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (79, 85))	('adenocarcinomas', 'Disease', 'MESH:D000230', (22, 37))	('H4K20Me3', 'Var', (66, 74))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))	('adenocarcinomas', 'Disease', (22, 37))
22251	31121824	The SUV420H2 is considered a promoter of EMT in pancreatic cancer cells, and this histone methyltransferase inhibits expression of transcription factors, including OVOL1, OVOL2, and FOXA1, which are indispensable for MET promotion through their repressive mark trimethylated H4K20.	('pancreatic cancer', 'Disease', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('FOXA1', 'Gene', '3169', (182, 187))	('transcription factors', 'Gene', (131, 152))	('histone', 'Gene', (82, 89))	('FOXA1', 'Gene', (182, 187))	('inhibits', 'NegReg', (108, 116))	('OVOL2', 'Gene', '58495', (171, 176))	('H4K20', 'Protein', (275, 280))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (48, 65))	('expression', 'MPA', (117, 127))	('trimethylated', 'Var', (261, 274))	('SUV420H2', 'Gene', '84787', (4, 12))	('histone', 'Gene', '24829', (82, 89))	('OVOL2', 'Gene', (171, 176))	('OVOL1', 'Gene', '5017', (164, 169))	('SUV420H2', 'Gene', (4, 12))	('pancreatic cancer', 'Disease', 'MESH:D010190', (48, 65))	('OL', 'Phenotype', 'HP:0002745', (173, 175))	('OVOL1', 'Gene', (164, 169))	('OL', 'Phenotype', 'HP:0002745', (166, 168))
22256	31121824	Furthermore, hypoacetylation of H3 has been associated with lymphatic permeation and hypoacetylation of H4 has been correlated with a history of alcohol consumption.	('associated', 'Reg', (44, 54))	('hypoacetylation', 'Var', (13, 28))	('hypoacetylation', 'Var', (85, 100))	('lymphatic permeation', 'MPA', (60, 80))	('alcohol', 'Chemical', 'MESH:D000438', (145, 152))	('correlated', 'Reg', (116, 126))	('acetyl', 'Chemical', 'MESH:D003545', (17, 23))	('acetyl', 'Chemical', 'MESH:D003545', (89, 95))	('H3', 'Gene', '126961', (32, 34))
22259	31121824	Moreover, H3K9Me2 has been found to be positively correlated with histone lysine methyltransferase G9a in tumor tissues, which indicates that interference of G9a may become a novel epigenetic treatment of HCC.	('interference', 'Var', (142, 154))	('HCC', 'Disease', (205, 208))	('HCC', 'Phenotype', 'HP:0001402', (205, 208))	('histone', 'Gene', (66, 73))	('correlated', 'Reg', (50, 60))	('H3', 'Gene', '126961', (10, 12))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('G9a', 'Gene', (99, 102))	('G9a', 'Gene', (158, 161))	('G9a', 'Gene', '10919', (99, 102))	('G9a', 'Gene', '10919', (158, 161))	('lysine', 'Chemical', 'MESH:D008239', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('histone', 'Gene', '24829', (66, 73))	('tumor', 'Disease', (106, 111))
22262	31121824	Importantly, inhibition of histone deacetylase in HCT15 and HT29 human colon cancer cell lines increases cell uptake of nucleoside anti-cancer agent cladribine and decreases its IC50.	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (136, 142))	('colon cancer', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('HT29 human', 'CellLine', 'CVCL:3285', (60, 70))	('decreases', 'NegReg', (164, 173))	('nucleoside', 'Chemical', 'MESH:D009705', (120, 130))	('IC50', 'MPA', (178, 182))	('cell', 'CPA', (105, 109))	('histone deacetylase', 'Gene', '9734', (27, 46))	('cancer', 'Disease', (77, 83))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('HCT15', 'CellLine', 'CVCL:0292', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('increases', 'PosReg', (95, 104))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('inhibition', 'Var', (13, 23))	('histone deacetylase', 'Gene', (27, 46))	('cladribine', 'Chemical', 'MESH:D017338', (149, 159))
22267	31121824	In oral cancer, H3K9 hypoacetylation is contemplated as a marker of poor prognosis.	('oral cancer', 'Disease', 'MESH:D009062', (3, 14))	('oral cancer', 'Disease', (3, 14))	('hypoacetylation', 'Var', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('acetyl', 'Chemical', 'MESH:D003545', (25, 31))	('H3', 'Gene', '126961', (16, 18))
22277	31121824	Taken together, these results indicate that aberrations of global histone modifications, including acetylation and methylation, influence growth and progression of a wide range of tumors.	('influence', 'Reg', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('growth', 'CPA', (138, 144))	('acetylation', 'MPA', (99, 110))	('acetyl', 'Chemical', 'MESH:D003545', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('histone', 'Gene', (66, 73))	('methylation', 'MPA', (115, 126))	('aberrations', 'Var', (44, 55))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('progression', 'CPA', (149, 160))	('histone', 'Gene', '24829', (66, 73))	('rat', 'Species', '10116', (48, 51))
22284	31121824	Furthermore, the combination of bendamustine or 4-OHCY with HDAC1 and HDAC2 inhibitors results in synergistic effects on histone acetylation and cytotoxicity.	('4-OHCY', 'Var', (48, 54))	('cytotoxicity', 'Disease', 'MESH:D064420', (145, 157))	('HDAC1', 'Gene', (60, 65))	('histone', 'Gene', '24829', (121, 128))	('bendamustine', 'Chemical', 'MESH:D000069461', (32, 44))	('4-OHCY', 'Chemical', '-', (48, 54))	('acetyl', 'Chemical', 'MESH:D003545', (129, 135))	('combination', 'Interaction', (17, 28))	('HDAC2', 'Gene', (70, 75))	('HDAC2', 'Gene', '3066', (70, 75))	('HDAC1', 'Gene', '3065', (60, 65))	('cytotoxicity', 'Disease', (145, 157))	('histone', 'Gene', (121, 128))
22287	31121824	The benefits of epigenetic therapies may be limited by their side effects compared to standard anticancer treatment.	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('epigenetic therapies', 'Var', (16, 36))
22297	31121824	In particular, the investigation of cellular levels of H3K18 modifications may reveal innovative methods in anti-cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('H3', 'Gene', '126961', (55, 57))	('modifications', 'Var', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
22298	31121824	As H3K18Ac is a selectively deacetylated by SIRT7, SIRT7 may be considered a promising drug target.	('H3K18Ac', 'Chemical', '-', (3, 10))	('SIRT7', 'Gene', (51, 56))	('H3K18Ac', 'Var', (3, 10))	('acetyl', 'Chemical', 'MESH:D003545', (30, 36))	('SIRT7', 'Gene', '51547', (44, 49))	('SIRT7', 'Gene', (44, 49))	('SIRT7', 'Gene', '51547', (51, 56))
22302	31121824	Histone acetylation is one of the most common histone epigenetic modifications that regulates DNA transcriptional machinery and in turn impacts gene expression.	('regulates', 'Reg', (84, 93))	('Histone', 'Gene', (0, 7))	('DNA transcriptional machinery', 'MPA', (94, 123))	('gene expression', 'MPA', (144, 159))	('acetylation', 'Var', (8, 19))	('impacts', 'Reg', (136, 143))	('acetyl', 'Chemical', 'MESH:D003545', (8, 14))	('histone', 'Gene', '24829', (46, 53))	('histone', 'Gene', (46, 53))	('Histone', 'Gene', '24829', (0, 7))
22306	31121824	Cancer is a consequence of aberrations in the regulation of these processes as inappropriate activation of oncogenes and inactivation of tumor suppressors results in neoplastic transformation.	('results in', 'Reg', (155, 165))	('activation', 'PosReg', (93, 103))	('tumor', 'Disease', (137, 142))	('neoplastic transformation', 'CPA', (166, 191))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('inactivation', 'Var', (121, 133))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('oncogenes', 'Gene', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('rat', 'Species', '10116', (31, 34))
22311	31121824	In vitro studies have demonstrated that acetylation affects many pathways involved in carcinogenesis in a wide range of different cancer cells.	('carcinogenesis', 'Disease', (86, 100))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('rat', 'Species', '10116', (29, 32))	('acetyl', 'Chemical', 'MESH:D003545', (40, 46))	('acetylation', 'Var', (40, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('affects', 'Reg', (52, 59))
22313	31121824	The aberrant level of global histone acetylation is usually associated with outcomes, including OS and DFS, in patients with different types of cancer.	('histone', 'Gene', (29, 36))	('acetyl', 'Chemical', 'MESH:D003545', (37, 43))	('aberrant', 'Var', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('histone', 'Gene', '24829', (29, 36))	('cancer', 'Disease', (144, 150))	('DFS', 'Disease', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('associated', 'Reg', (60, 70))	('patients', 'Species', '9606', (111, 119))
22315	31121824	Aberrant H3K18Ac levels have been found in blood, brain, breast, colon, esophageal, gastric, liver, lung, pancreas, prostate, and oral cancers.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('Aberrant', 'Var', (0, 8))	('colon', 'Disease', (65, 70))	('pancreas', 'Disease', (106, 114))	('esophageal', 'Disease', (72, 82))	('prostate', 'Disease', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast', 'Disease', (57, 63))	('H3K18Ac', 'Protein', (9, 16))	('oral cancers', 'Disease', 'MESH:D009062', (130, 142))	('found', 'Reg', (34, 39))	('pancreas', 'Disease', 'MESH:D010190', (106, 114))	('H3K18Ac', 'Chemical', '-', (9, 16))	('oral cancers', 'Disease', (130, 142))
22318	31121824	H3K18Ac is an important prognostic factor in patients with different types of cancer, although its detailed participation in carcinogenesis requires further investigation.	('H3K18Ac', 'Chemical', '-', (0, 7))	('cancer', 'Disease', (78, 84))	('H3K18Ac', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('carcinogenesis', 'Disease', (125, 139))
22333	31040705	Interestingly, Cheng et al demonstrated that tryptophan metabolism confers tumorigenesis and metastasis to ESCC, which help biologists to investigate the mechanism of the disease.	('tryptophan', 'Var', (45, 55))	('tryptophan', 'Chemical', 'MESH:D014364', (45, 55))	('metastasis', 'CPA', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ESCC', 'Disease', (107, 111))	('tumor', 'Disease', (75, 80))
22344	31040705	For example, the proportions of both CD90+ and CD271+ cells in ESCC were dramatically increased in chemoresistant ESCC cells and confers self-renewal and tumor initiation capability.	('increased', 'PosReg', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('self-renewal', 'CPA', (137, 149))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CD90', 'Gene', '7070', (37, 41))	('ESCC', 'Disease', (63, 67))	('CD90', 'Gene', (37, 41))	('CD271+', 'Var', (47, 53))	('tumor', 'Disease', (154, 159))
22351	31040705	ESCC cell lines KYSE30, KYSE140, KYSE180, KYSE410, KYSE510, and KYSE520 were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen, the German Resource Centre for Biological Material.	('KYSE520', 'Var', (64, 71))	('KYSE140', 'Var', (24, 31))	('KYSE510', 'Var', (51, 58))	('KYSE180', 'Var', (33, 40))	('von', 'Disease', 'MESH:D014842', (109, 112))	('KYSE410', 'Var', (42, 49))	('von', 'Disease', (109, 112))
22373	31040705	Stable cell lines expressing PRR11 or PRR11 shRNA(s) were selected for 10 days with 0.5 mug/mL puromycin 48 h after infection.	('infection', 'Disease', (116, 125))	('infection', 'Disease', 'MESH:D007239', (116, 125))	('PRR11', 'Var', (38, 43))	('puromycin', 'Chemical', 'MESH:D011691', (95, 104))	('PRR11', 'Var', (29, 34))
22398	31040705	Furthermore, we found that PRR11 overexpression dramatically increased the proportion of SP+ cells, a subpopulation of cells that process stem cell-like traits in KYSE30 and ECA109 cells (Figure 2D).	('increased', 'PosReg', (61, 70))	('overexpression', 'Var', (33, 47))	('SP+', 'Chemical', 'MESH:C000604007', (89, 92))	('PRR11', 'Gene', (27, 32))
22400	31040705	As expected, silencing PRR11 decreased the number and size of tumor spheres (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('silencing', 'Var', (13, 22))	('decreased', 'NegReg', (29, 38))	('PRR11', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
22402	31040705	Furthermore, to test whether ESCC inhibits the tumorigenesis of human ESCC in vivo, ECA109 cell was used to stably overexpress PRR11 or PRR11-shRNA.	('human', 'Species', '9606', (64, 69))	('PRR11', 'Gene', (127, 132))	('PRR11-shRNA', 'Var', (136, 147))	('inhibits', 'NegReg', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('overexpress', 'PosReg', (115, 126))	('tumor', 'Disease', (47, 52))
22405	31040705	Conversely, tumors in the PRR11-shRNA group were smaller than the tumors in the vector group.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('PRR11-shRNA', 'Var', (26, 37))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('smaller', 'NegReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
22409	31040705	Furthermore, cellular fractionation showed that PRR11 overexpression enhances nuclear accumulation of beta-catenin (Figure 5C), indicating that PRR11 activates the Wnt/beta-catenin pathway by promoted beta-catenin nuclear accumulation.	('beta-catenin', 'Gene', '1499', (102, 114))	('PRR11', 'Var', (144, 149))	('beta-catenin', 'Gene', (201, 213))	('promoted', 'PosReg', (192, 200))	('PRR11', 'Gene', (48, 53))	('beta-catenin', 'Gene', '1499', (168, 180))	('nuclear accumulation', 'CPA', (214, 234))	('activates', 'PosReg', (150, 159))	('enhances', 'PosReg', (69, 77))	('beta-catenin', 'Gene', '1499', (201, 213))	('beta-catenin', 'Gene', (102, 114))	('beta-catenin', 'Gene', (168, 180))
22410	31040705	Moreover, the expression levels of numerous well-characterized Wnt/beta-catenin downstream genes were shown to be increased in PRR11 overexpressing cells but were lower in PRR11-silenced cells (Figure 5D).	('expression levels', 'MPA', (14, 31))	('PRR11', 'Gene', (127, 132))	('increased', 'PosReg', (114, 123))	('overexpressing', 'Var', (133, 147))	('beta-catenin', 'Gene', (67, 79))	('lower', 'NegReg', (163, 168))	('beta-catenin', 'Gene', '1499', (67, 79))
22412	31040705	As shown in Figure 5E and F, the stimulatory effect of PRR11 on beta-catenin activation was significantly inhibited by transfection of knockdown beta-catenin or treatment with beta-catenin inhibitor (ICG001).	('knockdown', 'Var', (135, 144))	('beta-catenin', 'Gene', (145, 157))	('beta-catenin', 'Gene', (176, 188))	('activation', 'PosReg', (77, 87))	('inhibited', 'NegReg', (106, 115))	('beta-catenin', 'Gene', '1499', (176, 188))	('stimulatory effect', 'MPA', (33, 51))	('PRR11', 'Gene', (55, 60))	('beta-catenin', 'Gene', (64, 76))	('beta-catenin', 'Gene', '1499', (145, 157))	('beta-catenin', 'Gene', '1499', (64, 76))
22416	31040705	Importantly, statistical analysis showed that patients with ESCC cancer with high beta-catenin expression had worse overall and disease-free survival than those with low beta-catenin expression (Figure 6B, P<0.01; P<0.01).	('patients', 'Species', '9606', (46, 54))	('high', 'Var', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('overall', 'CPA', (116, 123))	('beta-catenin', 'Gene', (170, 182))	('disease-free survival', 'CPA', (128, 149))	('worse', 'NegReg', (110, 115))	('ESCC cancer', 'Disease', (60, 71))	('beta-catenin', 'Gene', '1499', (170, 182))	('ESCC cancer', 'Disease', 'MESH:D004938', (60, 71))	('beta-catenin', 'Gene', (82, 94))	('beta-catenin', 'Gene', '1499', (82, 94))
22417	31040705	Collectively, these results further supported the notion that PRR11 overexpression enhanced tumorigenic capability and promoted recurrence of ESCC via upregulation of the Wnt/beta-catenin signaling pathway, consequently resulting in poor survival of ESCC patients.	('beta-catenin', 'Gene', '1499', (175, 187))	('promoted', 'PosReg', (119, 127))	('enhanced', 'PosReg', (83, 91))	('PRR11', 'Gene', (62, 67))	('overexpression', 'Var', (68, 82))	('ESCC', 'Disease', (250, 254))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('patients', 'Species', '9606', (255, 263))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('poor', 'NegReg', (233, 237))	('ESCC', 'Disease', (142, 146))	('upregulation', 'PosReg', (151, 163))	('beta-catenin', 'Gene', (175, 187))	('recurrence', 'CPA', (128, 138))
22421	31040705	Our study showed that patients with high PRR11 expression revealed a 17.3% cumulative 5-year survival rate, which was significantly lower than that in patients with low PRR11 expression (64.3%), suggesting the possibility of using PRR11 as a predictor for ESCC patient prognosis and survival.	('patient', 'Species', '9606', (22, 29))	('ESCC', 'Disease', (256, 260))	('patients', 'Species', '9606', (22, 30))	('expression', 'Var', (47, 57))	('PRR11', 'Gene', (41, 46))	('patient', 'Species', '9606', (151, 158))	('patient', 'Species', '9606', (261, 268))	('patients', 'Species', '9606', (151, 159))	('lower', 'NegReg', (132, 137))	('high', 'Var', (36, 40))
22422	31040705	Moreover, the high PRR11 expression group revealed a lower 5-year disease-free survival rate than low PRR11 expression group, which indicates that PRR11 may involve in drug resistance and tumor recurrence.	('tumor', 'Disease', (188, 193))	('drug resistance', 'Phenotype', 'HP:0020174', (168, 183))	('disease-free survival rate', 'CPA', (66, 92))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('high', 'Var', (14, 18))	('involve', 'Reg', (157, 164))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('lower', 'NegReg', (53, 58))	('PRR11', 'Gene', (19, 24))
22425	31040705	CSC-dependent pathways, such as Wnt/beta-catenin signaling, are emerging as attractive targets owing to the fact that their inactivation may allow the elimination of CSCs.	('inactivation', 'Var', (124, 136))	('beta-catenin', 'Gene', '1499', (36, 48))	('CSCs', 'Disease', (166, 170))	('beta-catenin', 'Gene', (36, 48))
22427	31040705	Expression of WISP1, a downstream target gene of the Wnt/beta-catenin pathway, predicted prognosis of ESCC patients treated with radiotherapy, and inhibition of WISP1 may be a potential target to overcome radioresistance in ESCC.	('WISP1', 'Gene', '8840', (161, 166))	('predicted', 'Reg', (79, 88))	('ESCC', 'Disease', (102, 106))	('WISP1', 'Gene', '8840', (14, 19))	('WISP1', 'Gene', (161, 166))	('inhibition', 'Var', (147, 157))	('ESCC', 'Disease', (224, 228))	('WISP1', 'Gene', (14, 19))	('beta-catenin', 'Gene', (57, 69))	('patients', 'Species', '9606', (107, 115))	('beta-catenin', 'Gene', '1499', (57, 69))
22434	31040705	In fact, we found that PRR11 overexpression enhances but PRR11 downregulation decreases nuclear accumulation of beta-catenin by using cellular fractionation assay (Figure 5C), which indicates that PRR11 activates the Wnt/beta-catenin pathway probably via breaking negative regulation of the Wnt/beta-catenin pathway.	('PRR11', 'Gene', (57, 62))	('beta-catenin', 'Gene', '1499', (295, 307))	('enhances', 'PosReg', (44, 52))	('beta-catenin', 'Gene', '1499', (112, 124))	('beta-catenin', 'Gene', (221, 233))	('downregulation decreases', 'NegReg', (63, 87))	('beta-catenin', 'Gene', '1499', (221, 233))	('beta-catenin', 'Gene', (112, 124))	('PRR11', 'Gene', (23, 28))	('activates', 'PosReg', (203, 212))	('beta-catenin', 'Gene', (295, 307))	('PRR11', 'Var', (197, 202))
22438	30386177	DNA methylation has been found to participate in the development of cancer drug resistance.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('methylation', 'Var', (4, 15))	('participate', 'Reg', (34, 45))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('drug resistance', 'Phenotype', 'HP:0020174', (75, 90))
22459	30386177	The primary anti-PON3 (17422-1-AP) antibodies and anti-GAPDH (60004-1-lg) antibodies were purchased from Proteintech (San Ying Biotechnology, China) and were recognized with anti-rabbit IgG peroxidase-conjugated antibody (30000-0-AP) (San Ying Biotechnology, China), followed by an enhanced chemiluminescence reaction (Thermo Fisher Scientific, Waltham, MA, USA).	('chemiluminescence reaction', 'MPA', (291, 317))	('GAPDH', 'Gene', '14433', (55, 60))	('anti-PON3', 'Gene', (12, 21))	('GAPDH', 'Gene', (55, 60))	('17422-1-AP', 'Var', (23, 33))	('enhanced', 'PosReg', (282, 290))	('rabbit', 'Species', '9986', (179, 185))
22463	30386177	In the assay, cells were suspended in 100 microl of RPMI1640 without FBS when they were seeded into the upper chamber.	('RPMI1640', 'Var', (52, 60))	('FBS', 'Disease', 'MESH:D005198', (69, 72))	('RPMI1640', 'Chemical', '-', (52, 60))	('FBS', 'Disease', (69, 72))
22464	30386177	In the lower chamber, 500 microl of RPMI1640 supplemented with 10% FBS was added.	('FBS', 'Disease', (67, 70))	('RPMI1640', 'Var', (36, 44))	('RPMI1640', 'Chemical', '-', (36, 44))	('FBS', 'Disease', 'MESH:D005198', (67, 70))
22478	30386177	1, the drug resistance index revealed that K510 is the most multi-drug sensitive cell lines, with the lowest IC50 values against all the four drugs.	('IC50 values', 'MPA', (109, 120))	('K510', 'Chemical', '-', (43, 47))	('drug resistance', 'Phenotype', 'HP:0020174', (7, 22))	('lowest', 'NegReg', (102, 108))	('K510', 'Var', (43, 47))
22484	30386177	Following the changes of the PON3 level in K510 cells, the cell death triggered by all four drugs was- reduced, except that against VP16 (Fig.	('reduced', 'NegReg', (103, 110))	('cell death', 'CPA', (59, 69))	('changes', 'Var', (14, 21))	('K510', 'Chemical', '-', (43, 47))
22487	30386177	Similar results are also found for the invasion assays, as revealed by the transfection of either si-PON3 into K510 cells, or GFP-PON3 into K150 cells (Fig.	('si-PON3', 'Gene', (98, 105))	('transfection', 'Reg', (75, 87))	('GFP-PON3', 'Var', (126, 134))	('K510', 'Chemical', '-', (111, 115))
22492	30386177	As shown in Figure 6B and 6C, upon the repression of PON3 level by si-PON3 in K510 cells, the activities of p53/DNA damage, NF-kB, and PI3K/AKT were elevated, which correlate well with the negative regulation of these pathways by PON3 in K510 cells (Fig.	('K510', 'Chemical', '-', (78, 82))	('AKT', 'Gene', (140, 143))	('elevated', 'PosReg', (149, 157))	('p53', 'Gene', (108, 111))	('si-PON3', 'Var', (67, 74))	('activities', 'MPA', (94, 104))	('p53', 'Gene', '22060', (108, 111))	('NF-kB', 'Enzyme', (124, 129))	('AKT', 'Gene', '11651', (140, 143))	('K510', 'Chemical', '-', (238, 242))
22497	30386177	Upon transfection of si-PON3, K510-derived tumors were approximately 2.4-folds heavier than the control cells, suggesting that PON3 inhibits tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('K510', 'Chemical', '-', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('PON3', 'Var', (127, 131))	('tumor', 'Disease', (141, 146))	('inhibits', 'NegReg', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumor', 'Disease', (43, 48))	('si-PON3', 'Var', (21, 28))	('K510-derived', 'Var', (30, 42))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
22498	30386177	In addition, after an intraperitoneal injection of DDP, the K510 tumors were much smaller than the control cells with the injection of PBS (Fig.	('smaller', 'NegReg', (82, 89))	('DDP', 'Var', (51, 54))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('DDP', 'Chemical', 'MESH:D002945', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('K510', 'Var', (60, 64))	('PBS', 'Chemical', 'MESH:D007854', (135, 138))	('K510', 'Chemical', '-', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
22499	30386177	Furthermore, the tumor weight for the si-PON3/DDP K510 mice was heavier than that in the DDP K510 mice (Fig.	('tumor', 'Disease', (17, 22))	('DDP', 'Chemical', 'MESH:D002945', (89, 92))	('si-PON3/DDP K510', 'Var', (38, 54))	('mice', 'Species', '10090', (55, 59))	('K510', 'Chemical', '-', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('K510', 'Chemical', '-', (50, 54))	('DDP', 'Chemical', 'MESH:D002945', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('heavier', 'PosReg', (64, 71))	('mice', 'Species', '10090', (98, 102))
22502	30386177	The intratumoral injection of si-PON3 into K510 indeed led to the decrease of the PON3 level in the tumor sections (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('K510', 'Chemical', '-', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('si-PON3', 'Var', (30, 37))	('tumor', 'Disease', (9, 14))	('K510', 'Var', (43, 47))	('PON3 level', 'MPA', (82, 92))	('decrease', 'NegReg', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
22503	30386177	7c), which further confirmed that PON3 has a positive effect on both the growth and drug resistance of EC cell-derived tumor xenografts in nude mice Accumulating evidences have been shown that DNA methylation play important roles in drug resistance of cancers, which prevents the effective treatment of cancers.	('cancers', 'Disease', 'MESH:D009369', (303, 310))	('drug resistance', 'CPA', (233, 248))	('tumor', 'Disease', (119, 124))	('nude mice', 'Species', '10090', (139, 148))	('drug resistance', 'Phenotype', 'HP:0020174', (233, 248))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancers', 'Disease', (252, 259))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('cancers', 'Phenotype', 'HP:0002664', (303, 310))	('growth', 'CPA', (73, 79))	('PON3', 'Var', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('drug resistance', 'CPA', (84, 99))	('drug resistance', 'Phenotype', 'HP:0020174', (84, 99))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancers', 'Disease', (303, 310))
22510	30386177	Previous studies also showed that PON3 is hypermethylated in colorectal cancer and chordomas.	('colorectal cancer', 'Disease', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('chordomas', 'Disease', (83, 92))	('PON3', 'Gene', (34, 38))	('chordomas', 'Disease', 'MESH:D002817', (83, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('hypermethylated', 'Var', (42, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))
22511	30386177	Notably, the genome-wide DNA methylation analysis identified that several genes, including PON3, are aberrantly methylated in the high-grade non-muscle invasive bladder cancer.	('invasive bladder cancer', 'Disease', (152, 175))	('aberrantly methylated', 'Var', (101, 122))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (152, 175))	('bladder cancer', 'Phenotype', 'HP:0009725', (161, 175))	('PON3', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('invasive bladder', 'Phenotype', 'HP:0100645', (152, 168))
22512	30386177	These findings suggest that epigenetic modifications are usually associated with the development and/or progression of different type of tumors.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('associated', 'Reg', (65, 75))	('epigenetic modifications', 'Var', (28, 52))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
22513	30386177	In accordance with previous studies, we identified that the promoter region of PON3 is hypermethylated in EC cancer.	('EC cancer', 'Disease', 'MESH:D009369', (106, 115))	('EC cancer', 'Disease', (106, 115))	('PON3', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('hypermethylated', 'Var', (87, 102))
22514	30386177	The hypermethylation of PON3 may serve as a marker of poor prognosis in human EC.	('PON3', 'Gene', (24, 28))	('human EC', 'Disease', (72, 80))	('human', 'Species', '9606', (72, 77))	('hypermethylation', 'Var', (4, 20))
22525	23835390	(4)  CCT can significantly increase tumors' response to radiation and patients' median survival duration, but may also increase the severity of early effects in normal tissue.	('patients', 'Species', '9606', (70, 78))	('CCT', 'Var', (5, 8))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	("increase tumors' response to radiation", 'Phenotype', 'HP:0011133', (27, 65))	('response to radiation', 'MPA', (44, 65))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('increase', 'PosReg', (119, 127))	('tumors', 'Disease', (36, 42))	('increase', 'PosReg', (27, 35))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
22529	23835390	(3)  found significance between V10-V45 and high-grade radiation esophagitis (RE), and V20 and CCT as significant in multivariate analysis.	('V20', 'Var', (87, 90))	('V10-V45', 'Var', (32, 39))	('esophagitis', 'Phenotype', 'HP:0100633', (65, 76))	('radiation esophagitis', 'Disease', (55, 76))	('radiation esophagitis', 'Disease', 'MESH:D004194', (55, 76))
22530	23835390	Other studies have shown V50 and V60 have a better correlation to patient outcome then other studies using DVH metrics.	('patient', 'Species', '9606', (66, 73))	('V60', 'Var', (33, 36))	('correlation', 'Interaction', (51, 62))	('V50', 'Var', (25, 28))
22581	28434215	Cryoablation has been shown to be effective particularly for early T-stage, superficial esophageal cancers.	('early T-stage', 'Disease', (61, 74))	('esophageal cancers', 'Disease', 'MESH:D004938', (88, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('esophageal cancers', 'Disease', (88, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Cryoablation', 'Var', (0, 12))
22751	27186374	Overexpression of IFITM1 was associated with M0-disease (no distant metastases).	('IFITM1', 'Gene', (18, 24))	('M0-disease', 'Disease', 'MESH:D004194', (45, 55))	('IFITM1', 'Gene', '8519', (18, 24))	('M0-disease', 'Disease', (45, 55))	('Overexpression', 'Var', (0, 14))	('associated', 'Reg', (29, 39))	('metastases', 'Disease', (68, 78))	('metastases', 'Disease', 'MESH:D009362', (68, 78))
22752	27186374	In gastric cancer IFITM1 expression was significantly associated with improved TTR (time to recurrence) in Kaplan-Meier analysis and Cox regression, both in the unadjusted analysis (HR 0.33, 95 % CI 0.12-0.88) and in the adjusted analysis (HR 0.32, 95 % CI 0.12-0.87) but there was no significant impact on OS (overall survival).	('Cox', 'Gene', '1351', (133, 136))	('Cox', 'Gene', (133, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('IFITM1', 'Gene', (18, 24))	('IFITM1', 'Gene', '8519', (18, 24))	('TTR', 'MPA', (79, 82))	('OS', 'Chemical', '-', (307, 309))	('improved', 'PosReg', (70, 78))	('gastric cancer', 'Disease', (3, 17))	('expression', 'Var', (25, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
22768	27186374	Overexpression of IFITM1 has been reported to correlate with improved survival in glioma and chronic myeloid leukemia but in a South Korean study on gastric cancer, there was a trend towards worse survival in patients with high expression of IFITM1.	('gastric cancer', 'Disease', (149, 163))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (93, 117))	('IFITM1', 'Gene', (18, 24))	('IFITM1', 'Gene', '8519', (18, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('high expression', 'Var', (223, 238))	('IFITM1', 'Gene', (242, 248))	('IFITM1', 'Gene', '8519', (242, 248))	('patients', 'Species', '9606', (209, 217))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (93, 117))	('chronic myeloid leukemia', 'Disease', (93, 117))	('glioma', 'Disease', (82, 88))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (101, 117))
22799	27186374	In the subset of gastric tumors there were significant associations of high IFITM1 expression with age and Lauren's intestinal type, respectively.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('IFITM1', 'Gene', (76, 82))	('high', 'Var', (71, 75))	('gastric tumors', 'Disease', 'MESH:D013274', (17, 31))	('IFITM1', 'Gene', '8519', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('gastric tumors', 'Disease', (17, 31))	('expression', 'MPA', (83, 93))	('gastric tumors', 'Phenotype', 'HP:0006753', (17, 31))	("Lauren's intestinal type", 'Disease', (107, 131))
22802	27186374	In esophageal adenocarcinoma, expression of IFITM1 had no impact on TTR and OS in the Kaplan-Meier-analyses (Fig.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (3, 28))	('OS', 'Chemical', '-', (76, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('expression', 'Var', (30, 40))	('esophageal adenocarcinoma', 'Disease', (3, 28))	('IFITM1', 'Gene', (44, 50))	('IFITM1', 'Gene', '8519', (44, 50))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (3, 28))	('TTR', 'MPA', (68, 71))
22803	27186374	3a, d), but in the adjusted Cox regression analyses (Table 3 and Additional file 1: Table S1)) high IFITM1 expression had a negative impact on both TTR (HR 3.05, 95 % CI 1.09-8.53, p = 0.034) and OS (HR 2.71, 95 % CI 1.11-6.67, p = 0.029).	('IFITM1', 'Gene', (100, 106))	('IFITM1', 'Gene', '8519', (100, 106))	('high', 'Var', (95, 99))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('negative', 'NegReg', (124, 132))	('TTR', 'CPA', (148, 151))	('OS', 'Chemical', '-', (196, 198))
22806	27186374	In gastric cancer, high IFITM1 expression was significantly associated with improved TTR in the Kaplan-Meier analyses (Fig.	('high', 'Var', (19, 23))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('improved', 'PosReg', (76, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('expression', 'MPA', (31, 41))	('gastric cancer', 'Disease', (3, 17))	('IFITM1', 'Gene', (24, 30))	('IFITM1', 'Gene', '8519', (24, 30))	('TTR', 'CPA', (85, 88))
22814	27186374	The association of high IFITM1 expression and M0-disease, particularly seen in gastric cancer, has to our knowledge not been described previously.	('high', 'Var', (19, 23))	('M0-disease', 'Disease', (46, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('expression', 'MPA', (31, 41))	('M0-disease', 'Disease', 'MESH:D004194', (46, 56))	('gastric cancer', 'Disease', (79, 93))	('IFITM1', 'Gene', (24, 30))	('IFITM1', 'Gene', '8519', (24, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
22815	27186374	In gastric cancer with high expression of IFITM1, we have demonstrated consistent findings of a beneficial effect on TTR.	('high expression', 'Var', (23, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('beneficial effect', 'PosReg', (96, 113))	('gastric cancer', 'Disease', (3, 17))	('TTR', 'Disease', (117, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('IFITM1', 'Gene', (42, 48))	('IFITM1', 'Gene', '8519', (42, 48))
22819	27186374	A possible explanation might be that gastric tumorigenesis associated with elevated IFITM1 confers a less malignant phenotype.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('IFITM1', 'Gene', '8519', (84, 90))	('IFITM1', 'Gene', (84, 90))	('elevated', 'Var', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
22820	27186374	Support for this is the observed association of high IFITM1 expression and the prognostically favorable Lauren's intestinal type demonstrated both in this study and by others.	('expression', 'MPA', (60, 70))	('IFITM1', 'Gene', '8519', (53, 59))	('IFITM1', 'Gene', (53, 59))	('high', 'Var', (48, 52))	("Lauren's intestinal type", 'Disease', (104, 128))
22821	27186374	A similar contradiction has been described in glioma cells where knockdown of IFITM1 was demonstrated to inhibit proliferation, migration and invasion, whereas reduced expression of IFITM1 correlated with shorter survival in a cohort of 30 glioma patients.	('migration', 'CPA', (128, 137))	('IFITM1', 'Gene', '8519', (78, 84))	('IFITM1', 'Gene', (182, 188))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('expression', 'MPA', (168, 178))	('reduced', 'NegReg', (160, 167))	('IFITM1', 'Gene', (78, 84))	('knockdown', 'Var', (65, 74))	('glioma', 'Disease', (240, 246))	('glioma', 'Disease', 'MESH:D005910', (240, 246))	('patients', 'Species', '9606', (247, 255))	('invasion', 'CPA', (142, 150))	('inhibit', 'NegReg', (105, 112))	('glioma', 'Disease', (46, 52))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('shorter', 'NegReg', (205, 212))	('IFITM1', 'Gene', '8519', (182, 188))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('proliferation', 'CPA', (113, 126))
22828	27186374	It has been shown that IFITM1 expression is regulated by DNA methylation of its promoter region.	('expression', 'MPA', (30, 40))	('DNA methylation', 'Var', (57, 72))	('regulated', 'Reg', (44, 53))	('IFITM1', 'Gene', (23, 29))	('IFITM1', 'Gene', '8519', (23, 29))
22831	27186374	An association between high IFITM1 expression and sensitivity to cisplatin has been described in esophageal squamous cell carcinoma whereas in gastric cancer, overexpression of IFITM1 may confer resistance to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('expression', 'MPA', (35, 45))	('gastric cancer', 'Disease', (143, 157))	('esophageal squamous cell carcinoma', 'Disease', (97, 131))	('IFITM1', 'Gene', '8519', (28, 34))	('high', 'Var', (23, 27))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('IFITM1', 'Gene', (28, 34))	('association', 'Interaction', (3, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (97, 131))	('IFITM1', 'Gene', '8519', (177, 183))	('resistance to cisplatin', 'MPA', (195, 218))	('sensitivity to cisplatin', 'MPA', (50, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('overexpression', 'PosReg', (159, 173))	('IFITM1', 'Gene', (177, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (209, 218))
22849	25884729	Finally, we tested whether the FGFR inhibitor PD-173074 could eliminate the rescue effect against lapatinib that was induced by fibroblast supernatants.	('tested', 'Reg', (12, 18))	('lapatinib', 'Chemical', 'MESH:D000077341', (98, 107))	('PD-173074', 'Chemical', 'MESH:C115711', (46, 55))	('PD-173074', 'Var', (46, 55))	('eliminate', 'NegReg', (62, 71))
22874	25884729	Stock solutions of PHA-665752, PD-173074 and lapatinib were prepared in dimethyl sulfoxide and stored at -80 C until use.	('lapatinib', 'Chemical', 'MESH:D000077341', (45, 54))	('PHA-665752', 'Var', (19, 29))	('PD-173074', 'Chemical', 'MESH:C115711', (31, 40))	('PD-173074', 'Var', (31, 40))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (72, 90))
22876	25884729	We used 22 esophageal squamous cell lines: TE-1, TE-4, TE-5, TE-6, TE-8 TE-9, TE-10, TE-11, TE-14, TE-15, and EC-GI-10 were obtained from RIKEN Cell Bank (Tsukuba, Japan), while KYSE30, KYSE50, KYSE70, KYSE140, KYSE150, KYSE170, KYSE180, KYSE220, KYSE270, T.T, and TTN were obtained from Health Science Research Resources Bank (Osaka, Japan).	('TE', 'Chemical', 'MESH:D013691', (72, 74))	('KYSE180', 'Var', (229, 236))	('TE', 'Chemical', 'MESH:D013691', (49, 51))	('TE', 'Chemical', 'MESH:D013691', (55, 57))	('TE', 'Chemical', 'MESH:D013691', (61, 63))	('TE', 'Chemical', 'MESH:D013691', (85, 87))	('KYSE220', 'Var', (238, 245))	('KYSE70', 'Var', (194, 200))	('TE', 'Chemical', 'MESH:D013691', (78, 80))	('KYSE140', 'Var', (202, 209))	('TE-11', 'Chemical', '-', (85, 90))	('TE', 'Chemical', 'MESH:D013691', (43, 45))	('TTN', 'Gene', '7273', (265, 268))	('TE', 'Chemical', 'MESH:D013691', (67, 69))	('KYSE50', 'Var', (186, 192))	('TE', 'Chemical', 'MESH:D013691', (99, 101))	('TE', 'Chemical', 'MESH:D013691', (92, 94))	('KYSE270', 'Var', (247, 254))	('TTN', 'Gene', (265, 268))	('KYSE150', 'Var', (211, 218))	('KYSE170', 'Var', (220, 227))
22896	25884729	The fibroblast supernatant was prepared by incubating HEF75 or HEF75-hTERT in DMEM containing 0.1%FBS for 12 hrs.	('HEF75', 'CellLine', 'CVCL:5248', (54, 59))	('HEF75', 'Var', (54, 59))	('HEF75', 'CellLine', 'CVCL:5248', (63, 68))	('HEF75-hTERT', 'CellLine', 'CVCL:4388', (63, 74))	('DMEM', 'Chemical', '-', (78, 82))	('HEF75-hTERT', 'Var', (63, 74))
22899	25884729	After the addition of fibroblast supernatant or growth factors, cells were incubated for four days at 37 C. For inhibition experiments, cells were incubated in the presence of 1 muM of lapatinib (a dual inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2), PHA-665752 (MET inhibitor), PD-173074 (FGFR inhibitor), or 0.1% of dimethyl sulfoxide (DMSO, negative control).	('DMSO', 'Chemical', 'MESH:D004121', (383, 387))	('PHA-665752', 'Var', (296, 306))	('epidermal growth factor receptor', 'Gene', '1956', (259, 291))	('epidermal growth factor receptor', 'Gene', (216, 248))	('muM', 'Gene', (178, 181))	('epidermal growth factor receptor', 'Gene', '1956', (216, 248))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (363, 381))	('epidermal growth factor receptor 2', 'Gene', '2064', (259, 293))	('PD-173074', 'Chemical', 'MESH:C115711', (324, 333))	('epidermal growth factor receptor 2', 'Gene', (259, 293))	('human', 'Species', '9606', (253, 258))	('lapatinib', 'Chemical', 'MESH:D000077341', (185, 194))	('muM', 'Gene', '56925', (178, 181))
22901	25884729	To describe the blocking effect of PHA-665752 and PD-173074 on the growth promoting effect of fibroblast supernatant, a blunting index was calculated by the formula: blunting index (%) = 100-(fold change in the presence of PHA-665752 (or PD-173074) and fibroblast supernatant/fold change in the presence fibroblast supernatant alone) x 100.	('PD-173074', 'Chemical', 'MESH:C115711', (50, 59))	('growth', 'MPA', (67, 73))	('PD-173074', 'Chemical', 'MESH:C115711', (238, 247))	('PD-173074', 'Var', (50, 59))
22904	25884729	Using the cell count assay, fibroblast supernatant from HEF75 and HEF75-hTERT increased cell proliferation by 1.25 fold or more in 12 and 21 of 22 cell lines, respectively (Figure 1).	('HEF75', 'CellLine', 'CVCL:5248', (66, 71))	('HEF75', 'CellLine', 'CVCL:5248', (56, 61))	('HEF75', 'Var', (56, 61))	('increased', 'PosReg', (78, 87))	('cell proliferation', 'CPA', (88, 106))	('HEF75-hTERT', 'Var', (66, 77))	('HEF75-hTERT', 'CellLine', 'CVCL:4388', (66, 77))
22915	25884729	Cell proliferation assays were performed after adding 0.1% of DMSO (control), PD-173074 (MET inhibitor), or PD-173074 (FGFR inhibitor).	('PD-173074', 'Chemical', 'MESH:C115711', (78, 87))	('PD-173074', 'Var', (78, 87))	('Cell proliferation assays', 'CPA', (0, 25))	('PD-173074', 'Var', (108, 117))	('DMSO', 'Chemical', 'MESH:D004121', (62, 66))	('PD-173074', 'Chemical', 'MESH:C115711', (108, 117))
22927	25884729	When the MET (HGF receptor) inhibitor PHA-665752 was added to fibroblast culture supernatants at a final concentration of 1 muM, stimulation by fibroblast supernatant is modestly blunted in KYSE220, but not significantly affected in TE-14.	('KYSE220', 'Var', (190, 197))	('TE', 'Chemical', 'MESH:D013691', (233, 235))	('muM', 'Gene', '56925', (124, 127))	('HGF receptor', 'Gene', (14, 26))	('HGF receptor', 'Gene', '4233', (14, 26))	('blunted', 'NegReg', (179, 186))	('muM', 'Gene', (124, 127))	('stimulation', 'MPA', (129, 140))	('PHA-665752', 'Var', (38, 48))
22928	25884729	In contrast, when the FGFR inhibitor (PD-173074) is added to fibroblast culture supernatants at a final concentration of 1 muM, the opposite pattern is observed.	('PD-173074', 'Var', (38, 47))	('muM', 'Gene', '56925', (123, 126))	('PD-173074', 'Chemical', 'MESH:C115711', (38, 47))	('muM', 'Gene', (123, 126))
22929	25884729	Stimulation by fibroblast supernatant is markedly blunted by FGFR inhibitor in TE-14, but the blunting effect of FGFR inhibitor is less obvious in KYSE220.	('FGFR', 'Gene', (61, 65))	('blunted', 'NegReg', (50, 57))	('inhibitor', 'Var', (66, 75))	('TE', 'Chemical', 'MESH:D013691', (79, 81))
22930	25884729	A high blunting index for PHA-665752 indicates that the stimulating effect of fibroblast supernatant is dependent on HGF/MET.	('HGF', 'Gene', (117, 120))	('HGF', 'Gene', '3082', (117, 120))	('PHA-665752', 'Var', (26, 36))
22950	25884729	These results show that PD-173074 blocks the rescue effect of fibroblast supernatants against lapatinib.	('blocks', 'NegReg', (34, 40))	('rescue effect', 'MPA', (45, 58))	('lapatinib', 'Chemical', 'MESH:D000077341', (94, 103))	('PD-173074', 'Chemical', 'MESH:C115711', (24, 33))	('PD-173074', 'Var', (24, 33))
22951	25884729	The concentrations of HGF in culture supernatants of the fibroblasts HEF75, HEF75-hTERT, and HFL-III were 4049 pg/mL, 9390 pg/mL, and 9381 pg/mL, respectively, and the concentrations of FGF7 were 249 pg/mL, 1087 pg/mL, and 17 pg/mL, respectively.	('FGF7', 'Gene', '2252', (186, 190))	('HGF', 'Gene', '3082', (22, 25))	('HEF75', 'CellLine', 'CVCL:5248', (76, 81))	('FGF7', 'Gene', (186, 190))	('4049 pg/mL', 'Var', (106, 116))	('HFL', 'CellLine', 'CVCL:0298', (93, 96))	('HEF75', 'CellLine', 'CVCL:5248', (69, 74))	('HGF', 'Gene', (22, 25))	('HEF75-hTERT', 'CellLine', 'CVCL:4388', (76, 87))
22953	25884729	The culture supernatants of measured cancer cells (KYSE30, KYSE50, KYSE150, KYSE220, T.TN, TE-8, TE-11, TE-14, and TE-15) contained virtually no HGF or FGF7, suggesting that the autocrine activity of these cells was minimal.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('TE-11', 'Chemical', '-', (97, 102))	('FGF7', 'Gene', (152, 156))	('cancer', 'Disease', (37, 43))	('TE', 'Chemical', 'MESH:D013691', (104, 106))	('HGF', 'Gene', (145, 148))	('KYSE150', 'Var', (67, 74))	('TE', 'Chemical', 'MESH:D013691', (97, 99))	('TE', 'Chemical', 'MESH:D013691', (115, 117))	('KYSE30', 'Var', (51, 57))	('KYSE50', 'Var', (59, 65))	('HGF', 'Gene', '3082', (145, 148))	('TE', 'Chemical', 'MESH:D013691', (91, 93))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('KYSE220', 'Var', (76, 83))	('FGF7', 'Gene', '2252', (152, 156))
22959	25884729	HEF75-hTERT, immortalized fibroblasts, increased cell proliferation by 1.25 fold or more in 21 of 22 cell lines, while normal fibroblasts increased proliferation in 12 of 22 cell lines (Figure 1).	('cell proliferation', 'CPA', (49, 67))	('HEF75-hTERT', 'Var', (0, 11))	('increased', 'PosReg', (39, 48))	('HEF75-hTERT', 'CellLine', 'CVCL:4388', (0, 11))
22974	25884729	In two representative cell lines (TE-11 and TE-14), fibroblast supernatant restored the growth of cancer cells inhibited by lapatinib, but the subsequent addition of PD-173074 abrogated the rescue effect of fibroblast supernatant against lapatinib (Figure 8).	('TE', 'Chemical', 'MESH:D013691', (34, 36))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('growth', 'MPA', (88, 94))	('abrogated', 'NegReg', (176, 185))	('lapatinib', 'Chemical', 'MESH:D000077341', (124, 133))	('lapatinib', 'Chemical', 'MESH:D000077341', (238, 247))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('inhibited', 'NegReg', (111, 120))	('TE-11', 'Chemical', '-', (34, 39))	('PD-173074', 'Chemical', 'MESH:C115711', (166, 175))	('PD-173074', 'Var', (166, 175))	('TE', 'Chemical', 'MESH:D013691', (44, 46))
22980	25884729	However, the rescue effect of fibroblast supernatant is abrogated by combining an FGFR inhibitor with lapatinib.	('abrogated', 'NegReg', (56, 65))	('FGFR', 'Gene', (82, 86))	('inhibitor', 'Var', (87, 96))	('lapatinib', 'Chemical', 'MESH:D000077341', (102, 111))	('combining', 'Interaction', (69, 78))
23000	24604236	In cancer, a greater number of genes use the proximal polyA site, which leads to high expression of isoforms with shortened 3' UTRs In addition, it has recently been identified that the shortening of 3' UTRs has a greater association with proliferation than with transformation induced by oncogene activation.	('shortening', 'Var', (186, 196))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('expression', 'MPA', (86, 96))	('cancer', 'Disease', (3, 9))	('proliferation', 'CPA', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
23041	24604236	A previous study suggested the association of shortened 3' UTRs with gene regulation and cancer development.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('association', 'Interaction', (31, 42))	('gene regulation', 'MPA', (69, 84))	('cancer', 'Disease', (89, 95))	('shortened', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
23044	24604236	These findings suggest that the fundamental mechanism underlying polyA site switching in the development of esophageal carcinoma may be more similar to the process of inflammation than to that in a tumor.	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('polyA site', 'Var', (65, 75))	('esophageal carcinoma', 'Disease', (108, 128))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (108, 128))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('inflammation', 'Disease', 'MESH:D007249', (167, 179))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (108, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumor', 'Disease', (198, 203))	('inflammation', 'Disease', (167, 179))
23056	24604236	These findings suggest that the shortening of the six candidate genes may be, at least in part, associated with the molecular pathology of esophageal cancer development.	('associated', 'Reg', (96, 106))	('shortening', 'Var', (32, 42))	('esophageal cancer', 'Disease', (139, 156))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
23070	24604236	Polyadenylation profiles were generated for one patient with SCC and several candidate biomarkers were validated in a further eight patients with esophageal cancer using qPCR analysis.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Polyadenylation', 'Var', (0, 15))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('SCC', 'Gene', '6317', (61, 64))	('esophageal cancer', 'Disease', (146, 163))	('patient', 'Species', '9606', (48, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))	('SCC', 'Gene', (61, 64))
23294	31852498	With advances in genetic engineering technologies, people have found that cloning the tumor antigen-specific TCRs and transducing the TCRs into normal T cells by lentivirus or retrovirus can quickly imbue normal T cells with antigen-specific recognition abilities.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('people', 'Species', '9606', (51, 57))	('cloning', 'Var', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
23307	31852498	They found that the genetically modified T cells could be activated by the specific virus antigen in vivo, was home to effector sites, and contributed to tumor clearance.	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('genetically modified', 'Var', (20, 40))	('contributed', 'Reg', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('activated', 'PosReg', (58, 67))	('tumor', 'Disease', (154, 159))
23325	31852498	Another method is to introduce mutations into the transferred TCR alpha and beta chains, by generating an extra cysteine bridge into the constant region, mutating key amino acids found at the interfaces between constant regions, or convert the transferred TCR alpha and beta chains into a single-chain TCR (scTCR) structure.	('mutations', 'Var', (31, 40))	('cysteine bridge', 'MPA', (112, 127))	('convert', 'Reg', (232, 239))	('TCR', 'Gene', (256, 259))	('cysteine', 'Chemical', 'MESH:D003545', (112, 120))	('mutating', 'Var', (154, 162))
23327	31852498	The silencing of endogenous TCRs alpha and beta chains can be achieved through the use of small-interfering RNAs (siRNA), zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs ), or by clustered regularly interspaced short palindromic repeats (CRISPR) technology (Fig.	('ZFNs', 'Disease', 'None', (145, 149))	('CR', 'Chemical', 'MESH:D002857', (29, 31))	('CR', 'Chemical', 'MESH:D002857', (276, 278))	('ZFNs', 'Disease', (145, 149))	('silencing', 'NegReg', (4, 13))	('small-interfering', 'Var', (90, 107))
23328	31852498	Although the TCR mispairing phenotype has not been observed in a clinic, the silencing of endogenous TCRs was shown to reduce the occurrence of the lethal graft versus host disease (GvHD) in a mouse model.	('graft versus host disease', 'Disease', 'MESH:D006086', (155, 180))	('GvHD', 'Disease', 'MESH:D006086', (182, 186))	('reduce', 'NegReg', (119, 125))	('silencing', 'Var', (77, 86))	('graft versus host disease', 'Disease', (155, 180))	('mouse', 'Species', '10090', (193, 198))	('TCRs', 'Gene', (101, 105))	('GvHD', 'Disease', (182, 186))
23330	31852498	The second group is neoantigens, which are derived from chromosomal and genetic mutations in tumor cells, which include beta-catenin S37F in melanoma, alpha-actinin-4 K122 N in lung cancer, and heat shock protein 70 kilodalton-2 (hsp70-2) F293I in renal cancer.	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('hsp70-2', 'Gene', (230, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('shock', 'Phenotype', 'HP:0031273', (199, 204))	('beta-catenin', 'Gene', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('beta-catenin', 'Gene', '1499', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('alpha-actinin-4', 'Gene', '81', (151, 166))	('S37F', 'Var', (133, 137))	('F293I', 'SUBSTITUTION', 'None', (239, 244))	('alpha-actinin-4', 'Gene', (151, 166))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('melanoma', 'Disease', (141, 149))	('renal cancer', 'Disease', (248, 260))	('F293I', 'Var', (239, 244))	('S37F', 'Mutation', 'p.S37F', (133, 137))	('renal cancer', 'Phenotype', 'HP:0009726', (248, 260))	('lung cancer', 'Disease', (177, 188))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('heat shock protein 70 kilodalton-2', 'Gene', (194, 228))	('tumor', 'Disease', (93, 98))	('K122 N', 'Mutation', 'rs1046044885', (167, 173))	('renal cancer', 'Disease', 'MESH:D007680', (248, 260))	('hsp70-2', 'Gene', '3304', (230, 237))	('heat shock protein 70 kilodalton-2', 'Gene', '3304', (194, 228))
23336	31852498	Moreover, the procedure for identifying genetic mutations and preparing TCR-based therapies for each patient is tedious and expensive, which has hampered the wide application of TCR-based cellular immunotherapies that target oncovirus antigens and neoantigens in a clinic.	('patient', 'Species', '9606', (101, 108))	('mutations', 'Var', (48, 57))	('hampered', 'NegReg', (145, 153))
23339	31852498	Using the RNA electroporation method, they transduced four RNAs, encoding TCRs that recognized MART-1:27-35, gp100:209-217, NY-ESO-1:157-165, and p53:264-272 peptide/human leukocyte antigen (HLA) A2, into the PBMCs of patients (Fig.	('NY-ESO-1', 'Gene', '246100', (124, 132))	('NY-ESO-1', 'Gene', (124, 132))	('patients', 'Species', '9606', (218, 226))	('human', 'Species', '9606', (166, 171))	('MART-1', 'Gene', '2315', (95, 101))	('MART-1', 'Gene', (95, 101))	('p53:264-272', 'Var', (146, 157))
23357	31852498	Thus, they used a highly avid TCR that was generated in HLA A2 transgenic mice, and they found that 3 out of 16 (17%) patients experienced objective clinical responses after receiving the gp100-specific TCR-T cells, with metastatic tumors regressing in multiple organs, including the brain, lung, liver, lymph nodes, and subcutaneous sites.	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('gp100-specific', 'Var', (188, 202))	('transgenic mice', 'Species', '10090', (63, 78))	('patients', 'Species', '9606', (118, 126))	('tumors', 'Disease', (232, 238))
23396	31852498	In addition, 14 of 20 DMF5 patients and 13 of 16 gp100 patients demonstrated the destruction of epidermal melanocytes, starting as early as day 5 after treatment.	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (27, 35))	('destruction of epidermal melanocytes', 'CPA', (81, 117))	('DMF5', 'Var', (22, 26))
23433	31852498	reported the generation of a novel molecule (ALT-801, 264scTCR/IL-2), comprised of an anti-p53 (aa264-272) scTCR fused to an IL-2 molecule.	('IL-2', 'Gene', (63, 67))	('IL-2', 'Gene', '3558', (63, 67))	('IL-2', 'Gene', '3558', (125, 129))	('IL-2', 'Gene', (125, 129))	('anti-p53', 'Var', (86, 94))
23434	31852498	The scTCR can specifically bind to tumor cell surfaces that express p53 peptide and the HLA A2 complex, and IL-2 can activate a broad range of immune cell types, including T cells, B cells, monocytes, macrophages, lymphokine-activated killer (LAK) cells, and natural killer (NK) cells, located in the proximity of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('IL-2', 'Gene', '3558', (108, 112))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (314, 319))	('p53', 'Var', (68, 71))	('activate', 'PosReg', (117, 125))	('IL-2', 'Gene', (108, 112))
23451	31852498	In vitro-synthesized TCRs tend to be low affinity because of a lack of association with CD3, CD4, and CD8 molecules; however, some genetic engineering can increase the affinity of in vitro-synthesized TCRs, as in ImmTACs.	('genetic engineering', 'Var', (131, 150))	('increase', 'PosReg', (155, 163))	('CD8', 'Gene', (102, 105))	('CD8', 'Gene', '925', (102, 105))	('ImmTAC', 'Chemical', '-', (213, 219))	('CD4', 'Gene', (93, 96))	('CD4', 'Gene', '920', (93, 96))	('affinity', 'MPA', (168, 176))
23480	31852498	In a premelanosome protein (Pmel-1) mouse model, ACT using gp100-specific T cells caused ocular damage, which paralleled the findings in human melanoma patients who received gp100-specific TCR-T therapy.	('mouse', 'Species', '10090', (36, 41))	('human', 'Species', '9606', (137, 142))	('ocular damage', 'CPA', (89, 102))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('gp100-specific', 'Var', (59, 73))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('patients', 'Species', '9606', (152, 160))	('caused', 'Reg', (82, 88))
23490	31852498	This finding indicates that the modulation of the numbers and phenotypes of the transferred tumor antigen-specific TCR-T cells may affect the toxicity associated with TCR-T therapies.	('affect', 'Reg', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('toxicity', 'Disease', 'MESH:D064420', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('toxicity', 'Disease', (142, 150))	('modulation', 'Var', (32, 42))	('tumor', 'Disease', (92, 97))
23731	28574599	Moreover, STAT3 inhibition mimicked the effects of GSK3beta inhibition on ESCC cell migration and viability, while overexpression of a plasmid encoding mutant STAT3 (Y705F) abrogated these effects, and these results were further substantiated by clinicopathological data.	('GSK3beta', 'Protein', (51, 59))	('STAT3', 'Gene', (159, 164))	('inhibition', 'NegReg', (16, 26))	('ESCC cell migration', 'CPA', (74, 93))	('inhibition', 'NegReg', (60, 70))	('Y705F', 'Var', (166, 171))	('Y705F', 'Mutation', 'p.Y705F', (166, 171))	('viability', 'CPA', (98, 107))
23743	28574599	PI3K activation results in Akt phosphorylation and the subsequent phosphorylation/inactivation of GSK3beta, which has been demonstrated to suppress the production of pro-inflammatory cytokines including IL-12, TNFalpha, IL-1beta, IL-6, IFNgamma, and IL-17, while it concurrently promotes the production of IL-10, IL-1Ra, and IFNbeta by immune cells .	('IL-1Ra', 'Gene', (313, 319))	('suppress', 'NegReg', (139, 147))	('GSK3beta', 'Gene', (98, 106))	('IL-1beta', 'Gene', (220, 228))	('phosphorylation/inactivation', 'NegReg', (66, 94))	('production', 'MPA', (152, 162))	('Akt', 'Pathway', (27, 30))	('phosphorylation/inactivation', 'MPA', (66, 94))	('IL-1Ra', 'Gene', '3554', (313, 319))	('IFNgamma', 'Gene', (236, 244))	('TNFalpha', 'Gene', '7124', (210, 218))	('IFNgamma', 'Gene', '3458', (236, 244))	('production', 'MPA', (292, 302))	('PI3K', 'Var', (0, 4))	('promotes', 'PosReg', (279, 287))	('IL-10', 'Gene', '3586', (306, 311))	('IL-17', 'Gene', (250, 255))	('IL-17', 'Gene', '3605', (250, 255))	('IL-6', 'Gene', '3569', (230, 234))	('IL-10', 'Gene', (306, 311))	('TNFalpha', 'Gene', (210, 218))	('IL-1beta', 'Gene', '3553', (220, 228))	('IL-6', 'Gene', (230, 234))	('pro-inflammatory cytokines', 'MPA', (166, 192))
23748	28574599	Aberrant expression of GSK3beta has been shown to promote cell growth in some cancers and to suppress it in others.	('suppress', 'NegReg', (93, 101))	('Aberrant expression', 'Var', (0, 19))	('promote', 'PosReg', (50, 57))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('GSK3beta', 'Gene', (23, 31))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cell growth', 'CPA', (58, 69))
23752	28574599	Phosphorylation at Serine 727 and Tyrosine 705 leads to its dimerization and translocation into the nucleus, where it activates the transcription of target genes .	('translocation', 'MPA', (77, 90))	('Phosphorylation', 'Var', (0, 15))	('activates', 'PosReg', (118, 127))	('Tyrosine 705', 'Var', (34, 46))	('Serine', 'Chemical', 'MESH:D012694', (19, 25))	('dimerization', 'MPA', (60, 72))	('transcription', 'MPA', (132, 145))	('Tyrosine', 'Chemical', 'MESH:D014443', (34, 42))
23756	28574599	In squamous cell carcinomas, increased STAT3 activation has been found to enhance cell proliferation and migration, while siRNA-mediated stat3 gene silencing efficiently inhibited STAT3 activation, increased tumor cell apoptosis, and dramatically decreased tumor growth in vitro and in vivo .	('stat3', 'Gene', '6774', (137, 142))	('STAT3', 'Gene', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('inhibited', 'NegReg', (170, 179))	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('stat3', 'Gene', (137, 142))	('decreased', 'NegReg', (247, 256))	('tumor', 'Disease', (257, 262))	('cell proliferation', 'CPA', (82, 100))	('activation', 'MPA', (186, 196))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (3, 27))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (3, 27))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('enhance', 'PosReg', (74, 81))	('squamous cell carcinomas', 'Disease', (3, 27))	('increased', 'PosReg', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('gene silencing', 'Var', (143, 157))	('migration', 'CPA', (105, 114))	('activation', 'PosReg', (45, 55))
23787	28574599	For migration assays, KYSE-30 and KYSE-70 cells were pre-treated with LiCl (25mM) or WP-1066 (20muM) or transiently transfected with GSK3beta siRNA or a constitutively active mutant of GSK3beta or STAT3 mutant, STAT3 (Y705F).	('muM', 'Gene', '56925', (96, 99))	('Y705F', 'Var', (218, 223))	('Y705F', 'Mutation', 'p.Y705F', (218, 223))	('muM', 'Gene', (96, 99))	('WP-1066', 'Chemical', 'MESH:C519885', (85, 92))	('LiCl', 'Chemical', 'MESH:D018021', (70, 74))
23792	28574599	LiCl (100 mg/kg), WP-1066 (20 mg/kg), LiCl and WP-1066 together, or the respective solvent control(s) were injected peritoneally beginning on day 10, when the inoculated KYSE-70 cells had developed into a tumor of appreciable size (approximately 60-80 mm3).	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('WP-1066', 'Chemical', 'MESH:C519885', (18, 25))	('LiCl', 'Chemical', 'MESH:D018021', (0, 4))	('LiCl', 'Chemical', 'MESH:D018021', (38, 42))	('WP-1066', 'Var', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('WP-1066', 'Chemical', 'MESH:C519885', (47, 54))	('WP-1066', 'Var', (18, 25))
23806	28574599	These results show for the first time the expression profile of total and phospho-GSK3beta and indicate that GSK3beta activity is increased in the cancerous tissue of ESCC patients.	('phospho-GSK3beta', 'Var', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('activity', 'MPA', (118, 126))	('expression', 'MPA', (42, 52))	('ESCC', 'Disease', (167, 171))	('cancerous', 'Disease', 'MESH:D009369', (147, 156))	('increased', 'PosReg', (130, 139))	('patients', 'Species', '9606', (172, 180))	('cancerous', 'Disease', (147, 156))
23809	28574599	Moreover, the overall survival time of the patients with positive GSK3beta staining was only 26.446 months, which was significantly lower (P=0.027) than that of patients with negative GSK3 expression, who exhibited a survival time of 36.845 months (Fig.	('positive', 'Var', (57, 65))	('GSK3', 'Gene', (184, 188))	('patients', 'Species', '9606', (43, 51))	('GSK3', 'Gene', '56637', (66, 70))	('patients', 'Species', '9606', (161, 169))	('GSK3', 'Gene', '56637', (184, 188))	('lower', 'NegReg', (132, 137))	('GSK3', 'Gene', (66, 70))
23818	28574599	As shown in Figure 4B and C, a significant decrease was observed in STAT3 phosphorylation at both Tyrosine 705 and Serine 727 in KYSE-70 cells when GSK3beta was inhibited by LiCl or SB216763 (Fig.	('decrease', 'NegReg', (43, 51))	('LiCl', 'Chemical', 'MESH:D018021', (174, 178))	('inhibited', 'NegReg', (161, 170))	('Tyrosine', 'Chemical', 'MESH:D014443', (98, 106))	('GSK3beta', 'Enzyme', (148, 156))	('Serine 727', 'MPA', (115, 125))	('SB216763', 'Var', (182, 190))	('SB216763', 'Chemical', 'MESH:C417521', (182, 190))	('Serine', 'Chemical', 'MESH:D012694', (115, 121))	('STAT3 phosphorylation at', 'MPA', (68, 92))
23823	28574599	Importantly, the overall survival period of the patients with positive STAT3 expression (26.705 months) was significantly lower (P<0.05) than that of patients with negative STAT3 expression (36.460 months) (Fig.	('lower', 'NegReg', (122, 127))	('positive STAT3 expression', 'Var', (62, 87))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (150, 158))
23826	28574599	As shown in Figure 6, transfection with STAT3 (Y705F), a mutant plasmid that has been demonstrated to enhance the activity of STAT3 , significantly increased the total expression level of STAT3 (Fig.	('activity', 'MPA', (114, 122))	('enhance', 'PosReg', (102, 109))	('STAT3', 'MPA', (188, 193))	('increased', 'PosReg', (148, 157))	('Y705F', 'Var', (47, 52))	('Y705F', 'Mutation', 'p.Y705F', (47, 52))	('expression level', 'MPA', (168, 184))
23831	28574599	Collectively, these results demonstrated that the ability of GSK3 inhibition to suppress the viability of ESCC cells is dependent at least in part on the activity of STAT3.	('GSK3', 'Gene', '56637', (61, 65))	('viability of ESCC cells', 'CPA', (93, 116))	('suppress', 'NegReg', (80, 88))	('inhibition', 'Var', (66, 76))	('GSK3', 'Gene', (61, 65))
23836	28574599	The average tumor volume was considerably reduced in mice pre-treated with LiCl, WP-1066, or both compared with mice treated with a solvent control (Fig.	('LiCl', 'Chemical', 'MESH:D018021', (75, 79))	('reduced', 'NegReg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('WP-1066', 'Var', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('WP-1066', 'Chemical', 'MESH:C519885', (81, 88))	('tumor', 'Disease', (12, 17))	('mice', 'Species', '10090', (53, 57))	('mice', 'Species', '10090', (112, 116))
23837	28574599	Moreover, the mean tumor weights of LiCl-, WP-1066-, or LiCl- and WP-1066-treated mice were significantly decreased compared with those of solvent control-treated mice (Fig.	('decreased', 'NegReg', (106, 115))	('mice', 'Species', '10090', (82, 86))	('WP-1066-treated', 'Var', (66, 81))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('LiCl', 'Chemical', 'MESH:D018021', (56, 60))	('mice', 'Species', '10090', (163, 167))	('WP-1066', 'Chemical', 'MESH:C519885', (43, 50))	('tumor', 'Disease', (19, 24))	('WP-1066-', 'Var', (43, 51))	('LiCl', 'Chemical', 'MESH:D018021', (36, 40))	('WP-1066', 'Chemical', 'MESH:C519885', (66, 73))
23838	28574599	The differences in tumor volume between the control and inhibitor(s)-treated mice were statistically significant after 22 days for WP-1066 and LiCl, 22 days for WP-1066, and 26 days for LiCl (Fig.	('mice', 'Species', '10090', (77, 81))	('LiCl', 'Chemical', 'MESH:D018021', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('WP-1066', 'Chemical', 'MESH:C519885', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('LiCl', 'Chemical', 'MESH:D018021', (186, 190))	('tumor', 'Disease', (19, 24))	('WP-1066', 'Var', (161, 168))	('WP-1066', 'Chemical', 'MESH:C519885', (161, 168))	('WP-1066', 'Var', (131, 138))
23839	28574599	7C), demonstrating that inhibition of the GSK3-STAT3 signaling axis blocked tumor growth in the esophageal squamous cancer xenograft model.	('esophageal squamous cancer', 'Disease', (96, 122))	('GSK3', 'Gene', (42, 46))	('squamous cancer', 'Phenotype', 'HP:0002860', (107, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('blocked', 'NegReg', (68, 75))	('GSK3', 'Gene', '56637', (42, 46))	('inhibition', 'Var', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (96, 122))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
23840	28574599	Moreover, immunohistochemical staining showed that the expression of phospho-STAT3 was decreased in the cancer tissues of LiCl-treated mice compared with the control mice (Fig.	('LiCl', 'Chemical', 'MESH:D018021', (122, 126))	('decreased', 'NegReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('expression', 'MPA', (55, 65))	('mice', 'Species', '10090', (135, 139))	('mice', 'Species', '10090', (166, 170))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('phospho-STAT3', 'Var', (69, 82))
23853	28574599	Moreover, GSK3beta inhibition has been shown to enhance lysosomal acidification and thus increase the degradation of the epidermal growth factor receptor , indicating an alternative pro-tumorigenesis mechanism of GSK3beta.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('inhibition', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('GSK3beta', 'Gene', (10, 18))	('epidermal growth factor receptor', 'Gene', (121, 153))	('tumor', 'Disease', (186, 191))	('enhance', 'PosReg', (48, 55))	('lysosomal acidification', 'MPA', (56, 79))	('degradation', 'MPA', (102, 113))	('epidermal growth factor receptor', 'Gene', '1956', (121, 153))	('increase', 'PosReg', (89, 97))
23854	28574599	Here, we provided direct evidence of higher expression of the active GSK3beta form in the cancerous tissues of ESCC patients than in normal tissues and elucidate a novel molecular mechanism by which GSK3beta promotes the viability and migration of ESCC cells in vitro and in vivo that involves regulating STAT3 phosphorylation (Figure 8).	('promotes', 'PosReg', (208, 216))	('STAT3 phosphorylation', 'MPA', (305, 326))	('expression', 'MPA', (44, 54))	('cancerous', 'Disease', (90, 99))	('higher', 'PosReg', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('patients', 'Species', '9606', (116, 124))	('migration', 'CPA', (235, 244))	('GSK3beta', 'Var', (199, 207))	('cancerous', 'Disease', 'MESH:D009369', (90, 99))	('viability', 'CPA', (221, 230))	('ESCC', 'Disease', (248, 252))
23858	28574599	Dysregulation of STAT3 has been reported in several epithelial cancers, such as lung, head and neck, stomach, and esophageal cancer .	('STAT3', 'Gene', (17, 22))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('lung', 'Disease', (80, 84))	('stomach', 'Disease', (101, 108))	('reported', 'Reg', (32, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
23863	28574599	The aberrant signaling in cancer cells is likely a result of "multiples to multiples" effects and not straightforward "individual to individual" effects, emphasizing the necessity of high-throughput signaling research in cancer development.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('aberrant', 'Var', (4, 12))	('signaling', 'MPA', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))
23864	28574599	Since our data show that GSK3beta inhibition suppressed STAT3 phosphorylation and in turn reduced the viability and migration of ESCC cells, GSK3beta might directly control STAT3 activation and may thus be a critical factor in ESCC tumorigenesis.	('ESCC', 'Disease', (227, 231))	('reduced', 'NegReg', (90, 97))	('STAT3 activation', 'MPA', (173, 189))	('inhibition', 'Var', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('STAT3 phosphorylation', 'MPA', (56, 77))	('suppressed', 'NegReg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (232, 237))	('GSK3beta', 'Protein', (25, 33))
23868	28574599	Since esophageal cancer is well characterized as a group of heterogeneous diseases caused by many genomic and epigenetic alterations as well as various environmental stresses, further studies on the function of genomic mutation-mediated aberrant activity and expression of GSK3beta and STAT3 and the detailed signaling network that acts upstream of GSK3beta and downstream of STAT3 would be beneficial to the development of efficient interventional therapeutics for the control of ESCC.	('esophageal cancer', 'Disease', (6, 23))	('caused', 'Reg', (83, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (6, 23))	('mutation-mediated', 'Var', (219, 236))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
23945	26511079	ESCC patients with low HSF1 in both tumor cells and stromal cells had the longest survivals (P < 0.001).	('HSF1', 'Gene', (23, 27))	('patients', 'Species', '9606', (5, 13))	('low', 'Var', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
23958	26511079	In addition, a study has demonstrated that high expression of HSF1 in peritumoral tissue but not in hepatocellular carcinoma tissue was associated with poorer survival and shorter time to recurrence.	('survival', 'MPA', (159, 167))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('high expression', 'Var', (43, 58))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('hepatocellular carcinoma', 'Disease', (100, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('HSF1', 'Gene', (62, 66))	('tumor', 'Disease', (74, 79))	('poorer', 'NegReg', (152, 158))
23961	26511079	The ESCC cell lines Eca109, Kyse530, Kyse510 and mouse embryo fibroblast cell line NIH 3T3 (Chinese Academy of Sciences, Shanghai, China) were grown in RPMI 1640 (Invitrogen, USA) supplemented with 10 % fetal bovine serum.	('NIH 3T3', 'CellLine', 'CVCL:0594', (83, 90))	('bovine', 'Species', '9913', (209, 215))	('Kyse510', 'Var', (37, 44))	('mouse', 'Species', '10090', (49, 54))	('Kyse530', 'Var', (28, 35))
24014	26511079	The multivariate analysis demonstrated that except for certain conventional clinicopathological parameters, such as gender and nodal status, the HSF1 in stromal cells but not in tumor cells was an independent unfavorable factor for DFS (P = 0.019) and OS (P = 0.017) (Table 3).	('tumor', 'Disease', (178, 183))	('HSF1', 'Var', (145, 149))	('OS', 'Chemical', '-', (252, 254))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('DFS', 'Disease', (232, 235))
24043	26511079	Additionally, we observed that high expression of HSF1, whether in tumor cells or in stromal cells, was an independent predictor of DFS and OS in patients with metastatic ESCC, but not locoregional ESCC.	('predictor', 'Reg', (119, 128))	('OS', 'Chemical', '-', (140, 142))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('HSF1', 'Gene', (50, 54))	('metastatic ESCC', 'Disease', (160, 175))	('tumor', 'Disease', (67, 72))	('high', 'Var', (31, 35))	('patients', 'Species', '9606', (146, 154))	('DFS', 'Disease', (132, 135))
24056	26511079	Furthermore, the high level of HSF1 expression in both tumor cells and stromal cells was significantly associated with worse DFS and OS of ESCC patients.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('high', 'Var', (17, 21))	('tumor', 'Disease', (55, 60))	('patients', 'Species', '9606', (144, 152))	('HSF1', 'Gene', (31, 35))	('associated with', 'Reg', (103, 118))	('DFS', 'Disease', (125, 128))	('OS', 'Chemical', '-', (133, 135))	('ESCC', 'Disease', (139, 143))
24057	26511079	High HSF1 expression in stromal cells was a better predictor for ESCC patients' prognosis than its expression in tumor cells, especially in patients with metastatic ESCC.	('tumor', 'Disease', (113, 118))	('patients', 'Species', '9606', (70, 78))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('ESCC', 'Disease', (65, 69))	('patients', 'Species', '9606', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('metastatic ESCC', 'Disease', (154, 169))	('HSF1', 'Gene', (5, 9))
24068	25548913	This meta-analysis showed that EGA might be associated with improvement in prognosis of patients with operable prostate cancer and the cancer patients with follow-up less than or equal to two years.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prognosis', 'MPA', (75, 84))	('cancer', 'Disease', (135, 141))	('prostate cancer', 'Disease', (111, 126))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('improvement', 'PosReg', (60, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('EGA', 'Var', (31, 34))
24098	25548913	The overall results suggested that EGA could obviously decrease the prostate cancer recurrence or metastasis compared with GA alone (OR = 0.66, 95% CI = 0.46-0.95, Z = 2.21, P = 0.027, Fig.	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('metastasis', 'CPA', (98, 108))	('prostate cancer', 'Disease', (68, 83))	('decrease', 'NegReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('EGA', 'Var', (35, 38))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))
24101	25548913	The pooled results demonstrated that EGA could significantly decrease the cancer recurrence or metastasis with follow-up less than or equal to two years in comparison with GA alone (OR = 0.70, 95% CI = 0.51-0.98, Z = 2.11, P = 0.035, Fig.	('decrease', 'NegReg', (61, 69))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('EGA', 'Var', (37, 40))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
24122	25548913	In our meta-analysis, there was no association between EGA and decreased overall cancer recurrence and metastasis, even in subgroup analysis for colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (145, 157))	('colon cancer', 'Disease', (145, 157))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('decreased', 'NegReg', (63, 72))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('colon cancer', 'Phenotype', 'HP:0003003', (145, 157))	('EGA', 'Var', (55, 58))	('metastasis', 'CPA', (103, 113))
24144	18929146	The high potential for cure of core-binding factor type AML (characterized by the cytogenetic translocation t8;21), the intermediate prognosis of a normal karyotype, and the profoundly unfavorable implications of other cytogenetic abnormalities were defined in CALGB studies.	('t8', 'Var', (108, 110))	('AML', 'Disease', 'MESH:D015470', (56, 59))	('AML', 'Disease', (56, 59))
24230	18929146	For example, Committee investigators showed that groups of patients whose colon cancers had a high frequency of microsatellite instability had greater probability of disease-free survival at five years than those individuals whose tumors did not express this characteristic of altered mismatch repair.	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('colon cancer', 'Phenotype', 'HP:0003003', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colon cancers', 'Disease', (74, 87))	('microsatellite instability', 'Var', (112, 138))	('colon cancers', 'Phenotype', 'HP:0003003', (74, 87))	('patients', 'Species', '9606', (59, 67))	('disease-free survival', 'CPA', (166, 187))	('colon cancers', 'Disease', 'MESH:D015179', (74, 87))	('tumors', 'Disease', (231, 237))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
24231	18929146	They subsequently showed that approximately 70% of tumors with high levels of microsatellite instability had methylation of the hMLH1 promoter, indicating that an epigenetic event in sporadic colon cancer can lead to the MSI phenotype.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (192, 204))	('hMLH1', 'Gene', '4292', (128, 133))	('lead to', 'Reg', (209, 216))	('colon cancer', 'Disease', 'MESH:D015179', (192, 204))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('MSI', 'Disease', (221, 224))	('hMLH1', 'Gene', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('methylation', 'MPA', (109, 120))	('MSI', 'Disease', 'None', (221, 224))	('colon cancer', 'Disease', (192, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('epigenetic event', 'Var', (163, 179))
24233	18929146	In molecular studies of GIST tumors coordinated by CALGB GI committee investigators, the very high frequency of KIT oncogene mutations was confirmed and the presence of an exon 11 mutation in KIT correlated with both a high likelihood of response to imatinib and a favorable time to progression.	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('imatinib', 'Chemical', 'MESH:D000068877', (250, 258))	('KIT', 'Gene', (192, 195))	('KIT', 'Gene', (112, 115))	('GIST tumors', 'Disease', 'MESH:D046152', (24, 35))	('presence', 'Var', (157, 165))	('response to imatinib', 'MPA', (238, 258))	('GIST tumors', 'Disease', (24, 35))
24247	18929146	Correlative science studies performed on metastatic prostate cancer recovered from bone marrow biopsies failed to demonstrate a high frequency of androgen receptor mutations as an explanation for the hormone refractory state.	('androgen receptor', 'Gene', (146, 163))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('androgen receptor', 'Gene', '367', (146, 163))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (164, 173))	('prostate cancer', 'Disease', (52, 67))
24290	18929146	For example, in the pivotal test of 5-azacytidine chemotherapy (led by the CALGB Leukemia Committee, vide supra) for patients with myelodysplastic syndrome, the improved survival produced by the chemotherapy was accompanied by significant improvements in fatigue, physical functioning, and psychological distress.	('chemotherapy', 'Var', (195, 207))	('Leukemia', 'Disease', 'MESH:D007938', (81, 89))	('fatigue', 'Disease', (255, 262))	('Leukemia', 'Disease', (81, 89))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (131, 155))	('fatigue', 'Phenotype', 'HP:0012378', (255, 262))	('myelodysplastic syndrome', 'Disease', (131, 155))	('Leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('improvements', 'PosReg', (239, 251))	('survival', 'CPA', (170, 178))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (131, 155))	('patients', 'Species', '9606', (117, 125))	('psychological distress', 'CPA', (290, 312))	('5-azacytidine', 'Chemical', 'MESH:D001374', (36, 49))	('physical functioning', 'CPA', (264, 284))	('fatigue', 'Disease', 'MESH:D005221', (255, 262))	('improved', 'PosReg', (161, 169))
24302	18929146	The last of these areas, pharmacogenetics, is the unifying theme of the Committee's current research, developed around the hypothesis that "germ line polymorphisms are a significant determinant of the toxicity and efficacy of anti-cancer therapy".	('determinant', 'Reg', (182, 193))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('polymorphisms', 'Var', (150, 163))	('cancer', 'Disease', (231, 237))	('toxicity', 'Disease', 'MESH:D064420', (201, 209))	('toxicity', 'Disease', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
24306	18929146	Detailed evaluations of this last agent served as a transitional link to pharmacogenetic studies by the Committee, through studies of UGT1A1 polymorphisms and appropriate dosing of irinotecan therapy.	('UGT1A1', 'Gene', (134, 140))	('irinotecan', 'Chemical', 'MESH:D000077146', (181, 191))	('polymorphisms', 'Var', (141, 154))	('UGT1A1', 'Gene', '54658', (134, 140))
24318	18929146	Select examples of the output of Pathology Committee activities include the demonstration that Her-2 positive breast cancers are less responsive to paclitaxel than are Her-2 negative tumors; serum hepatocyte growth factor levels are prognostic for patients with androgen independent prostate cancer; immunohistochemistry detects lymph node metastases twice as often as evaluation by routine light microscopy in patients with clinical stage I NSCLC; epigenetic alterations in DNA repair genes are common in colon cancer specimens with microsatellite instability; morphology predicts the presence of cytogenetic abnormalities [inv (16) and t(8;21)] in AML.	('paclitaxel', 'Chemical', 'MESH:D017239', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Her-2', 'Gene', '2064', (95, 100))	('breast cancers', 'Phenotype', 'HP:0003002', (110, 124))	('t(8;21)]', 'Var', (638, 646))	('patients', 'Species', '9606', (411, 419))	('NSCLC', 'Disease', 'MESH:D002289', (442, 447))	('tumors', 'Disease', (183, 189))	('Her-2', 'Gene', (168, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('colon cancer', 'Disease', (506, 518))	('NSCLC', 'Disease', (442, 447))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('Her-2', 'Gene', (95, 100))	('AML', 'Disease', 'MESH:D015470', (650, 653))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('AML', 'Disease', (650, 653))	('prostate cancer', 'Disease', 'MESH:D011471', (283, 298))	('prostate cancer', 'Phenotype', 'HP:0012125', (283, 298))	('patients', 'Species', '9606', (248, 256))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (506, 518))	('metastases', 'Disease', 'MESH:D009362', (340, 350))	('prostate cancer', 'Disease', (283, 298))	('hepatocyte growth factor', 'Gene', '3082', (197, 221))	('cancer', 'Phenotype', 'HP:0002664', (512, 518))	('breast cancers', 'Disease', 'MESH:D001943', (110, 124))	('DNA repair genes', 'Gene', (475, 491))	('breast cancers', 'Disease', (110, 124))	('hepatocyte growth factor', 'Gene', (197, 221))	('Her-2', 'Gene', '2064', (168, 173))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('metastases', 'Disease', (340, 350))	('colon cancer', 'Disease', 'MESH:D015179', (506, 518))
24341	33811752	The median follow-up period was 35.97 +- 30.99 months, perineural invasion was confirmed in 25 patients, and three-year overall and disease-free survival were significantly lower in the perineural invasion group than in the no-perineural invasion group (75.9% vs. 40.0%, p < 0.001; 70.3% vs. 21.6%, p < 0.001).	('patients', 'Species', '9606', (95, 103))	('perineural invasion', 'CPA', (55, 74))	('disease-free survival', 'CPA', (132, 153))	('lower', 'NegReg', (173, 178))	('perineural invasion', 'Var', (186, 205))
24416	33811752	In conclusion, PNI was an independent prognostic factor for shorter DFS in patients with surgically treated ESCC as assessed by multivariable analyses.	('PNI', 'Var', (15, 18))	('DFS', 'MPA', (68, 71))	('patients', 'Species', '9606', (75, 83))	('ESCC', 'Disease', (108, 112))	('shorter', 'NegReg', (60, 67))
24433	31814330	Initial analysis of esophageal brushing samples identified aberrant cytosine methylation at the CCNA1 locus as a potential biomarker for BE, dysplasia and EAC.	('EAC', 'Disease', (155, 158))	('dysplasia', 'Disease', (141, 150))	('CCNA1', 'Gene', (96, 101))	('aberrant cytosine methylation', 'Var', (59, 88))	('CCNA1', 'Gene', '8900', (96, 101))	('EAC', 'Phenotype', 'HP:0011459', (155, 158))	('BE', 'Phenotype', 'HP:0100580', (137, 139))
24434	31814330	When combined with aberrant vimentin methylation  these biomarkers together showed a sensitivity and specificity of 95% and 91% respectively for BE which was replicated in an independent cohort of brushing samples .	('BE', 'Phenotype', 'HP:0100580', (145, 147))	('vimentin', 'Gene', '7431', (28, 36))	('aberrant', 'Var', (19, 27))	('vimentin', 'Gene', (28, 36))
24445	31814330	Fourteen candidates were identified of which two, trefoil factor 3 (TFF3) and dopa decarboxylase (DDC), were confirmed to have increased expression at the mRNA level by RT-PCR in BE relative to esophageal and gastric mucosa.	('trefoil factor 3', 'Gene', (50, 66))	('expression', 'MPA', (137, 147))	('DDC', 'Gene', (98, 101))	('gastric mucosa', 'Disease', 'MESH:D013274', (209, 223))	('dopa decarboxylase', 'Gene', '1644', (78, 96))	('gastric mucosa', 'Disease', (209, 223))	('dopa decarboxylase', 'Gene', (78, 96))	('trefoil factor 3', 'Gene', '7033', (50, 66))	('BE', 'Phenotype', 'HP:0100580', (179, 181))	('RT-PCR', 'Var', (169, 175))	('increased', 'PosReg', (127, 136))	('DDC', 'Gene', '1644', (98, 101))
24522	31448233	There were two patients with EGFR mutations received tyrosine kinase inhibitors.	('patients', 'Species', '9606', (15, 23))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('tyrosine kinase inhibitors', 'MPA', (53, 79))	('mutations', 'Var', (34, 43))
24523	31448233	Two patients without EGFR mutations received chemotherapy.	('EGFR', 'Gene', '1956', (21, 25))	('mutations', 'Var', (26, 35))	('EGFR', 'Gene', (21, 25))	('patients', 'Species', '9606', (4, 12))
24537	31448233	The patients with grade 1-2 had significantly higher V20 and V30 Gy (RBE), and mean dose of esophagus than those with grade 0.	('V20', 'MPA', (53, 56))	('patients', 'Species', '9606', (4, 12))	('V30 Gy', 'Var', (61, 67))	('higher', 'PosReg', (46, 52))
24542	31448233	These results indicated that local control rate associated with carbon-ion RT was as high as those of photon therapy.	('local control', 'CPA', (29, 42))	('carbon', 'Chemical', 'MESH:D002244', (64, 70))	('carbon-ion RT', 'Var', (64, 77))
24547	31448233	reported that grade 2 or higher radiation pneumonitis was 43% in the post-RT group which was relatively higher than 31% of the post-surgery group.	('pneumonitis', 'Disease', (42, 53))	('pneumonitis', 'Disease', 'MESH:D011014', (42, 53))	('post-RT', 'Var', (69, 76))
24550	31448233	On the other hand, our study using carbon-ion RT showed that severe pneumonitis rates were 0% in the post-carbon-ion RT and post-surgery groups.	('carbon', 'Chemical', 'MESH:D002244', (106, 112))	('carbon', 'Chemical', 'MESH:D002244', (35, 41))	('pneumonitis', 'Disease', 'MESH:D011014', (68, 79))	('pneumonitis', 'Disease', (68, 79))	('post-carbon-ion RT', 'Var', (101, 119))
24564	31448233	This adverse event rate associated with carbon-ion RT was considered less than other photon therapy of 33% with esophagitis grade 2.	('esophagitis', 'Phenotype', 'HP:0100633', (112, 123))	('esophagitis', 'Disease', 'MESH:D004941', (112, 123))	('esophagitis', 'Disease', (112, 123))	('carbon', 'Chemical', 'MESH:D002244', (40, 46))	('carbon-ion', 'Var', (40, 50))
24567	31448233	And, our study showed that symptomatic esophagitis (grade 1-2) was significantly associated with high esophageal dose.	('symptomatic', 'Disease', (27, 38))	('esophagitis', 'Phenotype', 'HP:0100633', (39, 50))	('esophagitis', 'Disease', (39, 50))	('high', 'Var', (97, 101))	('esophagitis', 'Disease', 'MESH:D004941', (39, 50))
24575	31448233	Recently, molecular-based personalized therapy has highly developed in lung cancer field, and tyrosine kinase inhibitor is more effective than chemotherapy for patient with EGFR mutations.	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('EGFR', 'Gene', '1956', (173, 177))	('EGFR', 'Gene', (173, 177))	('patient', 'Species', '9606', (160, 167))	('mutations', 'Var', (178, 187))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
24660	29430233	Overexpression and/or amplification of the HER2 receptor has been associated with an aggressive growth pattern of esophageal and gastric cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gastric cancers', 'Disease', 'MESH:D013274', (129, 144))	('gastric cancers', 'Disease', (129, 144))	('HER2', 'Gene', (43, 47))	('associated with', 'Reg', (66, 81))	('gastric cancers', 'Phenotype', 'HP:0012126', (129, 144))	('HER2', 'Gene', '2064', (43, 47))	('amplification', 'Var', (22, 35))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('esophageal', 'Disease', (114, 124))
24693	29430233	Between 10 and 30% of gastroesophageal adenocarcinomas have amplification and/or overexpression of HER2.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (28, 53))	('amplification', 'Var', (60, 73))	('overexpression', 'PosReg', (81, 95))	('HER2', 'Gene', (99, 103))	('HER2', 'Gene', '2064', (99, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('gastroesophageal adenocarcinomas', 'Disease', (22, 54))	('gastroesophageal adenocarcinomas', 'Disease', 'MESH:D005764', (22, 54))
24699	29430233	The objective response rate was higher in those subjects who received trastuzumab, and the median overall survival was significantly increased in this group.	('objective response', 'CPA', (4, 22))	('trastuzumab', 'Var', (70, 81))	('higher', 'PosReg', (32, 38))	('trastuzumab', 'Chemical', 'MESH:D000068878', (70, 81))	('increased', 'PosReg', (133, 142))	('overall survival', 'MPA', (98, 114))
24709	29430233	In a study completed by Van Cutsem et al., a correlation was noted in HER2 positivity and location of the tumor.	('HER2', 'Gene', (70, 74))	('HER2', 'Gene', '2064', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('positivity', 'Var', (75, 85))	('tumor', 'Disease', (106, 111))
24718	29430233	Further studies are required to evaluate the duration of therapy, the prognosis status of HER2 positivity, and the overall survivability of metastatic gastroesophageal adenocarcinoma with HER2 expression.	('HER2', 'Gene', (90, 94))	('HER2', 'Gene', '2064', (90, 94))	('gastroesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (151, 182))	('HER2', 'Gene', (188, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('HER2', 'Gene', '2064', (188, 192))	('gastroesophageal adenocarcinoma', 'Disease', (151, 182))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (157, 182))	('positivity', 'Var', (95, 105))
24872	28636989	The analysis revealed that regional lymph node metastasis was associated with SATB1 overexpression.	('regional lymph node metastasis', 'CPA', (27, 57))	('SATB1', 'Gene', (78, 83))	('SATB1', 'Gene', '6304', (78, 83))	('overexpression', 'Var', (84, 98))
25009	26065493	Cooking also causes an increase in protein concentration, which reaches up to 60% in weight for skinless turkey drumstick and skinless chicken drumstick.	('protein concentration', 'MPA', (35, 56))	('skinless turkey drumstick', 'Disease', (96, 121))	('skinless turkey drumstick', 'Disease', 'MESH:D004753', (96, 121))	('increase', 'PosReg', (23, 31))	('chicken drumstick', 'Phenotype', 'HP:0006129', (135, 152))	('skinless chicken', 'Var', (126, 142))	('chicken', 'Species', '9031', (135, 142))
25039	26065493	Several prospective studies support the association between poultry consumption, within a balanced diet, and a reduction in the risk of developing cardiovascular (CV) diseases and their risk factors, such as overweight and insulin resistance, and tumors.	('reduction', 'NegReg', (111, 120))	('overweight', 'Phenotype', 'HP:0025502', (208, 218))	('tumors', 'Disease', (247, 253))	('overweight', 'Disease', (208, 218))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('insulin', 'Gene', '396145', (223, 230))	('poultry', 'Var', (60, 67))	('cardiovascular', 'Disease', (147, 161))	('insulin resistance', 'Phenotype', 'HP:0000855', (223, 241))	('insulin', 'Gene', (223, 230))
25042	26065493	up to 6 months), weight loss increased in hypocaloric, high-protein diets if compared with hypocaloric diets with low protein content.	('weight loss', 'Phenotype', 'HP:0001824', (17, 28))	('weight loss', 'Disease', 'MESH:D015431', (17, 28))	('hypocaloric', 'Var', (42, 53))	('weight loss', 'Disease', (17, 28))
25066	26065493	As concerns processed products, the temperature used in the preparation can also influence the impact on health: high temperatures, commonly used in the industrial meat manufacture, can induce the formation of heterocyclic amines and polycyclic aromatic hydrocarbons that could increase the risk of coronary artery disease, diabetes mellitus, and cancer (see below).	('diabetes mellitus', 'Phenotype', 'HP:0000819', (324, 341))	('increase', 'PosReg', (278, 286))	('diabetes mellitus', 'Disease', (324, 341))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('induce', 'Reg', (186, 192))	('heterocyclic amines', 'Chemical', '-', (210, 229))	('diabetes mellitus', 'Disease', 'MESH:D003920', (324, 341))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (234, 266))	('coronary artery disease', 'Disease', 'MESH:D003324', (299, 322))	('heterocyclic amines', 'MPA', (210, 229))	('cancer', 'Disease', (347, 353))	('cancer', 'Disease', 'MESH:D009369', (347, 353))	('polycyclic aromatic', 'Var', (234, 253))	('formation', 'MPA', (197, 206))	('coronary artery disease', 'Disease', (299, 322))
25088	26065493	In a prospective study conducted in a subpopulation of American nurses in premenopause at the time of recruitment, the incidence of invasive mammary carcinoma across 20 years of observation was inversely associated with poultry consumption.	('inversely', 'NegReg', (194, 203))	('carcinoma', 'Disease', 'MESH:D002277', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('poultry consumption', 'Var', (220, 239))	('men', 'Species', '9606', (77, 80))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (141, 158))	('carcinoma', 'Disease', (149, 158))	('men', 'Species', '9606', (109, 112))
25089	26065493	The assessment of the effects of different protein sources on the progression of the disease enabled one to estimate that the substitution of one daily portion of red meat with one of poultry could reduce the risk of breast cancer by approximately 17% in general and by 24% in postmenopausal women.	('reduce', 'NegReg', (198, 204))	('men', 'Species', '9606', (10, 13))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', (217, 230))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('substitution', 'Var', (126, 138))	('men', 'Species', '9606', (294, 297))	('women', 'Species', '9606', (292, 297))	('men', 'Species', '9606', (281, 284))
25097	26065493	The incidence of several common metabolic diseases associated with deficiencies in critical dietary minerals, vitamins, and amino acids can be reduced by the contribution of poultry products, which are rich in all essential nutrients except vitamin C. Moreover, poultry meat consumption also contributes to the overall quality of the diet in specific ages and conditions.	('metabolic diseases', 'Disease', 'MESH:D008659', (32, 50))	('vitamin C', 'Chemical', 'MESH:D001205', (241, 250))	('metabolic diseases', 'Disease', (32, 50))	('deficiencies', 'Var', (67, 79))
25164	23323025	The test-retest variability of the median metabolic volume according to the image characteristics ranged from 8.3% to 23% and from 7.4% to 29% for 18F-FDG and 18F-FLT, respectively.	('FLT', 'Gene', '2321', (163, 166))	('FLT', 'Gene', (163, 166))	('18F-FDG', 'Chemical', '-', (147, 154))	('metabolic volume', 'MPA', (42, 58))	('18F-FDG', 'Var', (147, 154))
25277	19470182	Radio-resistance increased sensitivity to chemotherapeutic drugs of 5-fluorouracil, doxorubicin, paclitaxel and etoposide significantly.	('increased', 'PosReg', (17, 26))	('doxorubicin', 'Chemical', 'MESH:D004317', (84, 95))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (68, 82))	('paclitaxel', 'Chemical', 'MESH:D017239', (97, 107))	('sensitivity to chemotherapeutic drugs', 'MPA', (27, 64))	('Radio-resistance', 'Var', (0, 16))	('doxorubicin', 'MPA', (84, 95))	('etoposide', 'Chemical', 'MESH:D005047', (112, 121))
25292	19470182	EC109/R, which survived 80 Gy irradiation, became more sensitive to different concentrations of 5-fluorouracil, doxorubicin, paclitaxel and etoposide, but maintained tolerance to cisplatin, as assessed by MTT assay (Figure 4).	('EC109/R', 'Var', (0, 7))	('tolerance', 'MPA', (166, 175))	('paclitaxel', 'Chemical', 'MESH:D017239', (125, 135))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (96, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('etoposide', 'Chemical', 'MESH:D005047', (140, 149))	('MTT', 'Chemical', 'MESH:C070243', (205, 208))	('sensitive', 'MPA', (55, 64))
25302	19470182	Data have shown that suppression of ERCC1 expression enhances or restores cisplatin sensitivity, and combination of p53 inactivation and MMR deficiency results in cisplatin resistance.	('ERCC1', 'Gene', '2067', (36, 41))	('inactivation', 'Var', (120, 132))	('p53', 'Gene', (116, 119))	('results in', 'Reg', (152, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('enhances', 'PosReg', (53, 61))	('MMR deficiency', 'Disease', (137, 151))	('cisplatin resistance', 'MPA', (163, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('p53', 'Gene', '7157', (116, 119))	('restores', 'PosReg', (65, 73))	('MMR deficiency', 'Disease', 'MESH:C536143', (137, 151))	('ERCC1', 'Gene', (36, 41))	('suppression', 'NegReg', (21, 32))	('cisplatin sensitivity', 'MPA', (74, 95))
25310	32699215	Multi-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma Epigenetic landscapes can shape physiologic and disease phenotypes.	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('promotes', 'PosReg', (58, 66))	('shape', 'Reg', (128, 133))	('epigenetic dysregulation', 'Var', (14, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (67, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('esophageal squamous cell carcinoma', 'Disease', (67, 101))
25312	32699215	Hypo-methylated regions are enriched in areas with heterochromatin binding markers (H3K9me3, H3K27me3), while hyper-methylated regions are enriched in polycomb repressive complex (EZH2/SUZ12) recognizing regions.	('H3', 'Chemical', 'MESH:C012616', (93, 95))	('SUZ12', 'Gene', (185, 190))	('heterochromatin binding', 'Protein', (51, 74))	('H3', 'Chemical', 'MESH:C012616', (84, 86))	('EZH2', 'Gene', (180, 184))	('EZH2', 'Gene', '2146', (180, 184))	('H3K27me3', 'Var', (93, 101))	('SUZ12', 'Gene', '23512', (185, 190))
25313	32699215	Altered methylation in promoters, enhancers, and gene bodies, as well as in polycomb repressive complex occupancy and CTCF binding sites are associated with cancer-specific gene dysregulation.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gene dysregulation', 'Disease', (173, 191))	('methylation', 'MPA', (8, 19))	('Altered', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('associated', 'Reg', (141, 151))	('CTCF', 'Gene', (118, 122))	('cancer', 'Disease', (157, 163))	('CTCF', 'Gene', '10664', (118, 122))
25314	32699215	Epigenetic-mediated activation of non-canonical WNT/beta-catenin/MMP signaling and a YY1/lncRNA ESCCAL-1/ribosomal protein network are uncovered and validated as potential novel ESCC driver alterations.	('ESCCAL-1', 'Gene', (96, 104))	('beta-catenin', 'Gene', (52, 64))	('ESCCAL-1', 'Gene', '101805492', (96, 104))	('MMP', 'Gene', '4314;4318', (65, 68))	('Epigenetic-mediated', 'Var', (0, 19))	('YY1', 'Gene', (85, 88))	('WNT', 'Gene', (48, 51))	('MMP', 'Gene', (65, 68))	('beta-catenin', 'Gene', '1499', (52, 64))	('activation', 'PosReg', (20, 30))	('ESCC', 'Disease', (178, 182))	('WNT', 'Gene', '114487', (48, 51))	('YY1', 'Gene', '7528', (85, 88))
25323	32699215	Notable and frequently mutated epigenetic modulator genes in ESCC include KMT2D, KMT2C, KDM6A, EP300, and CREBBP, and epigenetic perturbations might interact with other somatic genomic alterations to promote the progression of ESCC.	('epigenetic perturbations', 'Var', (118, 142))	('EP300', 'Gene', '2033', (95, 100))	('KMT2D', 'Gene', (74, 79))	('KMT2D', 'Gene', '8085', (74, 79))	('KDM6A', 'Gene', '7403', (88, 93))	('EP300', 'Gene', (95, 100))	('KMT2C', 'Gene', (81, 86))	('ESCC', 'Disease', (61, 65))	('KMT2C', 'Gene', '58508', (81, 86))	('CREBBP', 'Gene', (106, 112))	('KDM6A', 'Gene', (88, 93))	('epigenetic modulator genes', 'Gene', (31, 57))	('ESCC', 'Disease', (227, 231))	('interact', 'Reg', (149, 157))	('promote', 'PosReg', (200, 207))	('CREBBP', 'Gene', '1387', (106, 112))
25324	32699215	The interplay between epigenetic perturbations and other somatic genetic alterations may play a critical role during ESCC tumorigenesis.	('epigenetic perturbations', 'Var', (22, 46))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('ESCC', 'Disease', (117, 121))	('tumor', 'Disease', (122, 127))
25337	32699215	Methylation loss in cytosines in ESCC accounted for 97.3% of the DMCs and was mostly confined to intergenic regions of the genome.	('Methylation', 'Var', (0, 11))	('cytosines', 'Chemical', 'MESH:D003596', (20, 29))	('DMCs', 'Chemical', '-', (65, 69))	('ESCC', 'Gene', (33, 37))
25345	32699215	DNA methylation heterogeneity has been observed in other cancer types and stochastically increasing variation in DNA methylation appears to be a property of the cancer epigenome.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', (57, 63))	('variation', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (161, 167))
25351	32699215	We examined additional squamous types of cancer including TCGA-head and neck squamous carcinoma cohort (n = 516) and found that again the high variance of DNA methylation changes associates with poor survival outcome (p value <2e-16) (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (77, 95))	('methylation changes', 'Var', (159, 178))	('changes', 'Var', (171, 178))	('poor', 'NegReg', (195, 199))	('neck squamous carcinoma', 'Disease', (72, 95))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (72, 95))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
25353	32699215	Only 1.8% of these DMRs are hypermethylated, while 98.2% of DMRs are hypomethylated (proportional test, p value <2.2e-16) in tumors relative to normal tissues.	('hypomethylated', 'Var', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('DMRs', 'Chemical', '-', (60, 64))	('DMRs', 'Chemical', '-', (19, 23))
25359	32699215	For example, around the gene of SOX17 (Chr8: 55,360,000-55,400,000), CpG island regions were hypermethylated but CpG shore regions were hypomethylated (Fig.	('SOX17', 'Gene', '64321', (32, 37))	('SOX17', 'Gene', (32, 37))	('hypermethylated', 'Var', (93, 108))
25360	32699215	Two CpG islands with a significant hypermethylation upstream of the SOX17 gene were observed but that was not associated with low gene expression (p value = 0.668, Fig.	('hypermethylation', 'Var', (35, 51))	('SOX17', 'Gene', (68, 73))	('SOX17', 'Gene', '64321', (68, 73))
25363	32699215	The region around the lncRNA ESCCAL-1 (Chr8:76,130,000-76,240,000), which was previously identified by us, contained significantly hypomethylated DMRs in its promoters and we further investigated the uncharacterized biological function of this lncRNA later in this study.	('hypomethylated', 'Var', (131, 145))	('DMRs', 'Var', (146, 150))	('DMRs', 'Chemical', '-', (146, 150))	('ESCCAL-1', 'Gene', (29, 37))	('ESCCAL-1', 'Gene', '101805492', (29, 37))
25365	32699215	Notably, the Polycomb Repressor Complex 2 (PRC2) subunits SUZ12 and EZH2 binding sites were substantially affected by hypermethylation in the CpGs (Supplementary Fig.	('EZH2', 'Gene', (68, 72))	('SUZ12', 'Gene', '23512', (58, 63))	('SUZ12', 'Gene', (58, 63))	('binding sites', 'Interaction', (73, 86))	('hypermethylation', 'Var', (118, 134))	('affected', 'Reg', (106, 114))	('EZH2', 'Gene', '2146', (68, 72))	('PRC2', 'Gene', (43, 47))
25370	32699215	ESCC-derived hypo-DMRs were enriched in genomic regions with heterochromatin markers such as H3K9me3 and H3K27me3, whereas hyper-DMRs were enriched in genomic regions with EZH2 or SUZ12 protein-binding sites (Fig.	('hyper-DMRs', 'Disease', (123, 133))	('H3', 'Chemical', 'MESH:C012616', (93, 95))	('H3K27me3', 'Var', (105, 113))	('EZH2', 'Gene', '2146', (172, 176))	('H3', 'Chemical', 'MESH:C012616', (105, 107))	('SUZ12', 'Gene', '23512', (180, 185))	('SUZ12', 'Gene', (180, 185))	('EZH2', 'Gene', (172, 176))	('heterochromatin', 'MPA', (61, 76))	('H3K9me3', 'Var', (93, 100))	('hyper-DMRs', 'Disease', 'MESH:D053306', (123, 133))
25371	32699215	The DMRs enriched in regulatory elements in cancer indicates cancer-specific dysregulation of gene expression contributing to cancer progression, which we explore further later in this study.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('DMRs', 'Var', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('dysregulation', 'MPA', (77, 90))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('DMRs', 'Chemical', '-', (4, 8))
25372	32699215	Functional annotation of these target genes harboring promoter hypomethylation indicated an over-representation of WNT/beta-catenin signaling, whereas gene promoters harboring hypermethylation were enriched for KIT signaling genes (Supplementary Fig.	('beta-catenin', 'Gene', '1499', (119, 131))	('KIT', 'Gene', '3815', (211, 214))	('KIT', 'Gene', (211, 214))	('WNT', 'Gene', (115, 118))	('over-representation', 'PosReg', (92, 111))	('beta-catenin', 'Gene', (119, 131))	('promoter hypomethylation', 'Var', (54, 78))	('WNT', 'Gene', '114487', (115, 118))
25373	32699215	We merged DMRs and DEGs and identified 694 genes that showed significant differential methylation alteration in promoters and concomitant dysregulation of gene expression (Fig.	('DMRs', 'Chemical', '-', (10, 14))	('methylation', 'Var', (86, 97))	('alteration', 'Reg', (98, 108))
25376	32699215	Third, hypermethylation at cohesion and CCCTC-binding factor-binding sites could compromise binding of this methylation-sensitive insulator protein and result in gene activation.	('CCCTC-binding factor', 'Gene', (40, 60))	('gene', 'MPA', (162, 166))	('hypermethylation', 'Var', (7, 23))	('binding', 'Interaction', (92, 99))	('CCCTC-binding factor', 'Gene', '10664', (40, 60))	('compromise', 'NegReg', (81, 91))	('activation', 'PosReg', (167, 177))
25380	32699215	We searched for ENCODE-defined EZH2 and SUZ12-binding sites across gene promoters in C1-C4 and observed that EZH2 occupancy was enriched in C3 (1.5970 +- 1.2316) and C4 (0.6000 +- 0.7684) compared with C1 (0.9167 +- 0.8464) and C2 (0.2336 +- 0.5870), respectively (p value < 0.001) (Fig.	('SUZ12', 'Gene', (40, 45))	('0.6000 +- 0.7684', 'Var', (170, 186))	('EZH2', 'Gene', (109, 113))	('EZH2', 'Gene', '2146', (31, 35))	('EZH2', 'Gene', (31, 35))	('SUZ12', 'Gene', '23512', (40, 45))	('EZH2', 'Gene', '2146', (109, 113))	('1.5970 +- 1.2316', 'Var', (144, 160))
25381	32699215	SUZ12 occupancy was higher only in C3 gene promoter regions (1.5522 +- 1.7946) (Fig.	('SUZ12', 'Gene', (0, 5))	('1.5522 +- 1.7946', 'Var', (61, 77))	('higher', 'PosReg', (20, 26))	('occupancy', 'MPA', (6, 15))	('SUZ12', 'Gene', '23512', (0, 5))
25386	32699215	Epigenetic dysregulation of the components of MAPK, AKT, and WNT pathway can promote aberrant activation of these pro-growth pathways in ESCC.	('Epigenetic dysregulation', 'Var', (0, 24))	('AKT', 'Gene', (52, 55))	('ESCC', 'Disease', (137, 141))	('WNT', 'Gene', '114487', (61, 64))	('AKT', 'Gene', '207', (52, 55))	('WNT', 'Gene', (61, 64))	('activation', 'PosReg', (94, 104))
25389	32699215	Although high expression of WNT2 is not a prognostic marker, it was associated with tumor progression (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('associated', 'Reg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('WNT2', 'Gene', (28, 32))	('high', 'Var', (9, 13))
25398	32699215	Furthermore, we confirmed the promoter region of WNT2 was hypermethylated in three esophageal cancer cell lines (EC9706, EC109, and EC1) while no methylation was detected in normal esophagus epithelial cells (Het-1A) (Fig.	('WNT2', 'Gene', (49, 53))	('EC9706', 'CellLine', 'CVCL:E307', (113, 119))	('EC109', 'CellLine', 'CVCL:6898', (121, 126))	('EC1', 'Gene', '4819', (121, 124))	('EC1', 'Gene', (121, 124))	('EC1', 'Gene', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('hypermethylated', 'Var', (58, 73))	('EC1', 'Gene', '4819', (132, 135))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
25408	32699215	WNT2 knockdown decreased expression of MMP3 and MMP9, known targets of WNT/beta-catenin signaling (Fig.	('beta-catenin', 'Gene', '1499', (75, 87))	('WNT', 'Gene', (0, 3))	('MMP3', 'Gene', (39, 43))	('WNT', 'Gene', '114487', (71, 74))	('MMP9', 'Gene', '4318', (48, 52))	('knockdown', 'Var', (5, 14))	('expression', 'MPA', (25, 35))	('MMP9', 'Gene', (48, 52))	('MMP3', 'Gene', '4314', (39, 43))	('WNT', 'Gene', (71, 74))	('beta-catenin', 'Gene', (75, 87))	('decreased', 'NegReg', (15, 24))	('WNT', 'Gene', '114487', (0, 3))
25409	32699215	Since MMPs can promote tumor invasion and metastasis, we tested whether WNT2 knockdown abrogates the migratory and invasive potential of ESCC tumor cells.	('MMPs', 'Gene', '4314;4318', (6, 10))	('promote', 'PosReg', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tested', 'Reg', (57, 63))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('knockdown', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('MMPs', 'Gene', (6, 10))	('tumor', 'Disease', (23, 28))	('abrogates', 'NegReg', (87, 96))	('migratory', 'CPA', (101, 110))
25414	32699215	Moreover, WNT2 knockdown in EC9706 tumors significantly suppressed tumor growth and tumor burden (Student's t-test, p value < 0.05, Fig.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('knockdown', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('EC9706', 'CellLine', 'CVCL:E307', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('suppressed', 'NegReg', (56, 66))	('tumor', 'Disease', (84, 89))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', (67, 72))	('EC9706', 'Var', (28, 34))
25422	32699215	There was no mutation or copy number variation of ESCCAL-1 reported or observed in TCGA-ESCA genomic dataset or in our WGS data of ESCC patients (Fig.	('TCGA-ESCA', 'Disease', (83, 92))	('ESCCAL-1', 'Gene', (50, 58))	('patients', 'Species', '9606', (136, 144))	('copy number variation', 'Var', (25, 46))	('ESCCAL-1', 'Gene', '101805492', (50, 58))	('ESCC', 'Disease', (131, 135))
25423	32699215	Independent verification of the methylation status of the ESCCAL-1 promoter region showed 62.5% (20/32) hypomethylation in ESCC tumors versus 71.8% (23/32) hypermethylation in adjacent normal tissues (chi square test p value < 0.01) (Fig.	('ESCCAL-1', 'Gene', (58, 66))	('ESCC tumors', 'Disease', (123, 134))	('ESCCAL-1', 'Gene', '101805492', (58, 66))	('ESCC tumors', 'Disease', 'MESH:D004938', (123, 134))	('hypomethylation', 'Var', (104, 119))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
25433	32699215	RNA-seq profiling in cells with YY1 knockdown also revealed ESCCAL-1 as a YY1-regulated target-gene (Supplementary Fig.	('YY1', 'Gene', (32, 35))	('YY1', 'Gene', (74, 77))	('knockdown', 'Var', (36, 45))	('ESCCAL-1', 'Gene', (60, 68))	('YY1', 'Gene', '7528', (32, 35))	('ESCCAL-1', 'Gene', '101805492', (60, 68))	('YY1', 'Gene', '7528', (74, 77))
25438	32699215	In order to explore the causative roles of ESCCAL-1 in ESCC progression, we conducted RNA-seq profiling in EC9706 cells with ESCCAL-1 knockdown by shRNA (or with shControl).	('ESCCAL-1', 'Gene', (125, 133))	('knockdown', 'Var', (134, 143))	('EC9706', 'CellLine', 'CVCL:E307', (107, 113))	('ESCCAL-1', 'Gene', '101805492', (125, 133))	('ESCCAL-1', 'Gene', (43, 51))	('ESCCAL-1', 'Gene', '101805492', (43, 51))
25439	32699215	We hypothesized that depletion of ESCCAL-1 could reverse the phenotype of cells to the relative normal cell state.	('ESCCAL-1', 'Gene', (34, 42))	('depletion', 'Var', (21, 30))	('ESCCAL-1', 'Gene', '101805492', (34, 42))
25441	32699215	Using an iterative clustering approach, we identified 210 significant genes whose expression was differential between shControl EC9706 and shESCCAL-1 EC9706 cohort and was similar between shESCCAL-1 EC9706 and Het-1A (normal) cohort (gene list in Supplementary Data File 5).	('EC9706', 'CellLine', 'CVCL:E307', (150, 156))	('shControl', 'Gene', (118, 127))	('EC9706', 'CellLine', 'CVCL:E307', (199, 205))	('expression', 'MPA', (82, 92))	('EC9706', 'Var', (128, 134))	('ESCCAL-1', 'Gene', (141, 149))	('ESCCAL-1', 'Gene', '101805492', (141, 149))	('EC9706', 'Var', (150, 156))	('ESCCAL-1', 'Gene', (190, 198))	('differential', 'Reg', (97, 109))	('ESCCAL-1', 'Gene', '101805492', (190, 198))	('EC9706', 'CellLine', 'CVCL:E307', (128, 134))
25443	32699215	Myc knockdown depleted ribosomal translational processes in ESCC, phenocopying the effect of ESCCAL-1 knockdown (Fig.	('Myc', 'Gene', '4609', (0, 3))	('ESCCAL-1', 'Gene', (93, 101))	('Myc', 'Gene', (0, 3))	('ESCCAL-1', 'Gene', '101805492', (93, 101))	('depleted', 'NegReg', (14, 22))	('knockdown', 'Var', (4, 13))	('ribosomal translational processes', 'MPA', (23, 56))
25451	32699215	The characteristics of CpG methylation alterations can discriminate cellular states between tumor and normal conditions, and histological subtypes of esophageal cancer.	('discriminate', 'Reg', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CpG', 'Gene', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('alterations', 'Var', (39, 50))	('tumor', 'Disease', (92, 97))	('cancer', 'Disease', (161, 167))	('methylation alterations', 'Var', (27, 50))
25452	32699215	Cancer-specific DMRs have been identified in colon cancer and such stochastic methylation variations distinguish cancer from normal and may serve as diagnostic or therapeutic biomarkers.	('colon cancer', 'Disease', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (113, 119))	('variations', 'Var', (90, 100))	('Cancer', 'Disease', (0, 6))	('colon cancer', 'Disease', 'MESH:D015179', (45, 57))	('DMRs', 'Chemical', '-', (16, 20))	('DMRs', 'Var', (16, 20))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
25453	32699215	Higher variance of DNA methylation alteration in squamous carcinomas (ESCC, HNSC) is strongly associated with poor clinical outcome.	('squamous carcinomas', 'Disease', (49, 68))	('squamous carcinomas', 'Disease', 'MESH:D002294', (49, 68))	('associated', 'Reg', (94, 104))	('methylation alteration', 'Var', (23, 45))	('alteration', 'Var', (35, 45))	('DNA', 'Gene', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (49, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
25454	32699215	Our findings provide insight into the potential clinical relevance of epigenetic dysregulation and heterogeneity as a molecular biomarker of clinical outcome in cancer.	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('epigenetic dysregulation', 'Var', (70, 94))
25458	32699215	Our findings indicate that hypermethylation-mediated de-repression of WNT2 activates the WNT pathway in ESCC.	('de-repression', 'NegReg', (53, 66))	('hypermethylation-mediated', 'Var', (27, 52))	('WNT', 'Gene', '114487', (89, 92))	('WNT', 'Gene', (70, 73))	('activates', 'PosReg', (75, 84))	('ESCC', 'Disease', (104, 108))	('WNT', 'Gene', (89, 92))	('WNT', 'Gene', '114487', (70, 73))
25461	32699215	Our data provide new insight into the mechanism of epigenetic dysregulation that results in non-canonical gene-expression regulation in cancer and the underlying molecular events promoting WNT pathway activation in ESCC.	('ESCC', 'Disease', (215, 219))	('activation', 'PosReg', (201, 211))	('WNT', 'Gene', (189, 192))	('results in', 'Reg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('epigenetic dysregulation', 'Var', (51, 75))	('cancer', 'Disease', (136, 142))	('WNT', 'Gene', '114487', (189, 192))	('non-canonical gene-expression regulation', 'MPA', (92, 132))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
25464	32699215	We discovered that loss of methylation in its promoter and an increase of YY1 TF binding is a principle molecular mechanism of ESCCAL-1 dysregulation in ESCC, resulting in cell cycle and ribosomal pathway dysfunction.	('ESCCAL-1', 'Gene', '101805492', (127, 135))	('dysregulation', 'Var', (136, 149))	('methylation', 'MPA', (27, 38))	('ribosomal', 'Pathway', (187, 196))	('loss', 'NegReg', (19, 23))	('cell cycle', 'CPA', (172, 182))	('YY1', 'Gene', (74, 77))	('binding', 'Interaction', (81, 88))	('YY1', 'Gene', '7528', (74, 77))	('ESCCAL-1', 'Gene', (127, 135))	('increase', 'PosReg', (62, 70))
25465	32699215	We found that ESCCAL-1 plays an epigenetic-mediated causal role in tumor growth and is a biomarker of worse clinical outcome in ESCC.	('ESCCAL-1', 'Gene', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('epigenetic-mediated', 'Var', (32, 51))	('ESCCAL-1', 'Gene', '101805492', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('ESCC', 'Disease', (128, 132))
25467	32699215	Whether ESCCAL-1 is similarly dysregulated by epigenetic mechanisms in other cancer types beyond ESCC remains to be investigated.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('ESCCAL-1', 'Gene', (8, 16))	('epigenetic', 'Var', (46, 56))	('ESCCAL-1', 'Gene', '101805492', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ESCC', 'Disease', (97, 101))
25469	32699215	Overall, our study provides a rationale and a roadmap for delineating the landscape and functional roles of epigenetic dysregulation in cancer at a genome-wide, high resolution.	('cancer', 'Disease', (136, 142))	('epigenetic', 'Var', (108, 118))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
25470	32699215	Further analysis will provide a better understanding of the impact of epigenetic dysregulation and heterogeneity on various cancer-associated phenotypes and treatment responses.	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('epigenetic', 'Var', (70, 80))
25480	32699215	Somatic mutations include single-nucleotide variants (SNVs), small insertions and/or deletions (indels), and structural variants (SVs).	('deletions', 'Var', (85, 94))	('single-nucleotide variants', 'Var', (26, 52))	('structural variants', 'Var', (109, 128))	('single-nucleotide', 'Chemical', '-', (26, 43))
25482	32699215	), to detect somatic SNVs and indels, and packages including LUMPY, Manta, CNVkit, and MetaSV to detect SVs.	('kit', 'Gene', (78, 81))	('kit', 'Gene', '3815', (78, 81))	('indels', 'Var', (30, 36))
25489	32699215	Sequencing libraries were generated using NEBNext  Ultra  RNA Library Prep Kit for Illumina  (#E7530L, NEB, USA) following the manufacturer's recommendations.	('Kit', 'Gene', '3815', (75, 78))	('#E7530L', 'Var', (94, 101))	('Kit', 'Gene', (75, 78))	('Illumina', 'Chemical', '-', (83, 91))
25526	32699215	Among 5,092,845 of DMCs 97.29% are hypomethylated in ESCC samples while only 2.71% are hypermethylated in ESCC samples.	('ESCC', 'Disease', (53, 57))	('hypomethylated', 'Var', (35, 49))	('DMCs', 'Chemical', '-', (19, 23))
25530	32699215	Among hypermethylated in DMCs in ESCC, 83.67% has overlapped with regulatory elements while only 56.77% of hypomethylated DMCs has overlaps.	('hypermethylated', 'Var', (6, 21))	('DMCs', 'Chemical', '-', (122, 126))	('DMCs', 'Chemical', '-', (25, 29))	('ESCC', 'Gene', (33, 37))
25534	32699215	The majority of the hypermethylated DMCs are mapped to antisense RNAs (58.01%) followed by lncRNA (39.28%) while that of the hypomethylated DMCs are mapped to lncRNAs (63.08%) followed by antisense RNA (29.89%).	('antisense', 'Var', (55, 64))	('DMCs', 'Chemical', '-', (140, 144))	('hypermethylated', 'Var', (20, 35))	('DMCs', 'Chemical', '-', (36, 40))
25541	32699215	Hypomethylated DMCs dominated in the most TFs except for three TFs: SUZ12, EZH2, and CTBP2, which is related to endometrial cancer pathway and WNT pathway (Supplementary Fig.	('CTBP2', 'Gene', (85, 90))	('endometrial cancer', 'Disease', 'MESH:D016889', (112, 130))	('EZH2', 'Gene', (75, 79))	('Hypomethylated', 'Var', (0, 14))	('SUZ12', 'Gene', (68, 73))	('CTBP2', 'Gene', '1488', (85, 90))	('DMCs', 'Chemical', '-', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('WNT', 'Gene', '114487', (143, 146))	('endometrial cancer', 'Disease', (112, 130))	('endometrial cancer', 'Phenotype', 'HP:0012114', (112, 130))	('EZH2', 'Gene', '2146', (75, 79))	('SUZ12', 'Gene', '23512', (68, 73))	('WNT', 'Gene', (143, 146))
25547	32699215	As a result, we learned that 4391 genes have significant DMRs in their promoter regions.	('promoter regions', 'MPA', (71, 87))	('DMRs', 'Var', (57, 61))	('DMRs', 'Chemical', '-', (57, 61))
25553	32699215	CNVkit-RNA was used to infer copy number alterations from RNAseq reads.	('copy number alterations', 'Var', (29, 52))	('kit', 'Gene', '3815', (3, 6))	('kit', 'Gene', (3, 6))
25562	32699215	Human ESCC cell lines (EC109, EC9706, EC1) and immortalized esophageal epithelial cell line Het-1A were purchased from the Shanghai Institutes for Biological Science (Shanghai, China).	('EC9706', 'CellLine', 'CVCL:E307', (30, 36))	('Human', 'Species', '9606', (0, 5))	('EC1', 'Gene', '4819', (38, 41))	('EC1', 'Gene', (38, 41))	('EC9706', 'Var', (30, 36))	('EC109', 'CellLine', 'CVCL:6898', (23, 28))	('EC1', 'Gene', '4819', (23, 26))	('EC1', 'Gene', (23, 26))
25591	31351238	Specifically, NPs induce intracellular inflammation, promote the formation of reactive oxygen species (ROS) and compromise viability in a variety cell types.	('compromise', 'NegReg', (112, 122))	('viability in a variety cell types', 'CPA', (123, 156))	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('inflammation', 'Disease', 'MESH:D007249', (39, 51))	('induce', 'Reg', (18, 24))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (78, 101))	('formation of reactive oxygen species', 'MPA', (65, 101))	('inflammation', 'Disease', (39, 51))	('NPs', 'Var', (14, 17))	('promote', 'PosReg', (53, 60))
25592	31351238	Further, NPs stimulate fibroblast-induced fibrosis and/or dysregulate immune cell behavior.	('dysregulate immune cell', 'Phenotype', 'HP:0002958', (58, 81))	('dysregulate', 'Reg', (58, 69))	('fibrosis', 'Disease', 'MESH:D005355', (42, 50))	('fibrosis', 'Disease', (42, 50))	('stimulate', 'PosReg', (13, 22))	('immune cell behavior', 'CPA', (70, 90))	('NPs', 'Var', (9, 12))
25630	31351238	The differences observed in spheroid size could be attributed to differences in proliferation rates induced by AgNPs in 3D culture; however, previous studies have repeatedly shown AgNPs decrease epithelial cell proliferation in 2D cultures.	('AgNPs', 'Chemical', '-', (180, 185))	('AgNPs', 'Chemical', '-', (111, 116))	('epithelial cell proliferation', 'CPA', (195, 224))	('AgNPs', 'Var', (180, 185))	('decrease', 'NegReg', (186, 194))
25634	31351238	A significant increase in spheroid number (Fig.2D&F) was also observed with AgNP treatment of HET1A, CCD841 and MCF10A cells but not with BEAS2B bronchial cells, in which the spheroid number decreased significantly upon AgNP exposure, suggesting the possibility of cell type specificity related to this feature.	('spheroid number', 'CPA', (26, 41))	('number', 'NegReg', (184, 190))	('BEAS2B', 'CellLine', 'CVCL:0168', (138, 144))	('increase', 'PosReg', (14, 22))	('AgNP', 'Chemical', '-', (220, 224))	('MCF10A', 'CellLine', 'CVCL:0598', (112, 118))	('AgNP', 'Chemical', '-', (76, 80))	('the spheroid', 'CPA', (171, 183))	('with', 'Var', (71, 75))
25642	31351238	CD44 abundance (staining intensity) and localization (staining distribution) were significantly increased in the AgNP-treated lung tissues compared to controls (Fig.3B&C).	('increased', 'PosReg', (96, 105))	('AgNP', 'Chemical', '-', (113, 117))	('AgNP-treated', 'Var', (113, 125))	('abundance', 'MPA', (5, 14))	('CD44', 'Protein', (0, 4))	('localization', 'MPA', (40, 52))
25667	31351238	While overall FAK expression in vivo was reduced in AgNP-treated lung compared to controls, FAK phosphorylation (activity) was significantly higher in AgNP treated epithelia.	('reduced', 'NegReg', (41, 48))	('FAK', 'Gene', '5747', (14, 17))	('FAK', 'Gene', (92, 95))	('FAK', 'Gene', '5747', (92, 95))	('AgNP', 'Chemical', '-', (151, 155))	('AgNP', 'Var', (151, 155))	('higher', 'PosReg', (141, 147))	('AgNP', 'Chemical', '-', (52, 56))	('FAK', 'Gene', (14, 17))	('AgNP-treated', 'Var', (52, 64))
25690	31351238	Although cytokines such as TGFbeta1 are crucial in initiating and regulating the post-injury response, TGFbeta1 deregulation has been implicated in impaired wound healing such as hypertrophic and keloid scars, uncontrolled inflammation, immune suppression, as well as induction of epithelial cell epithelial-mesenchymal transition (EMT), transformation and tumorigenesis.	('inflammation', 'Disease', (223, 235))	('hypertrophic', 'Disease', (179, 191))	('TGFbeta1', 'Gene', '7040', (27, 35))	('hypertrophic', 'Disease', 'MESH:D006984', (179, 191))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('epithelial cell epithelial-mesenchymal transition', 'CPA', (281, 330))	('TGFbeta1', 'Gene', (27, 35))	('keloid scars', 'Disease', (196, 208))	('induction', 'Reg', (268, 277))	('transformation', 'CPA', (338, 352))	('implicated', 'Reg', (134, 144))	('TGFbeta1', 'Gene', '7040', (103, 111))	('keloid', 'Phenotype', 'HP:0010562', (196, 202))	('inflammation', 'Disease', 'MESH:D007249', (223, 235))	('tumor', 'Disease', (357, 362))	('immune', 'Disease', (237, 243))	('tumor', 'Disease', 'MESH:D009369', (357, 362))	('deregulation', 'Var', (112, 124))	('TGFbeta1', 'Gene', (103, 111))	('scars', 'Phenotype', 'HP:0100699', (203, 208))
25699	31351238	Indeed, research on the tensile properties of healed skin has found that AgNP treatment increased collagen production and deposition, improved fibril alignment, and generally improved the ECM tensile properties in repaired skin.	('improved', 'PosReg', (134, 142))	('ECM tensile properties', 'CPA', (188, 210))	('AgNP', 'Gene', (73, 77))	('treatment', 'Var', (78, 87))	('collagen', 'CPA', (98, 106))	('increased', 'PosReg', (88, 97))	('fibril alignment', 'CPA', (143, 159))	('deposition', 'CPA', (122, 132))	('AgNP', 'Chemical', '-', (73, 77))	('improved', 'PosReg', (175, 183))
25703	31351238	Previous studies in lung, breast and colon cultures have repeatedly shown AgNPs decrease cell proliferation in 2D cultures by generating various types of intracellular stress via reactive oxygen species and inducing DNA damage.	('stress', 'Disease', (168, 174))	('stress', 'Disease', 'MESH:D000079225', (168, 174))	('cell proliferation', 'CPA', (89, 107))	('reactive oxygen species', 'MPA', (179, 202))	('AgNPs', 'Var', (74, 79))	('AgNPs', 'Chemical', '-', (74, 79))	('inducing', 'Reg', (207, 215))	('generating', 'Reg', (126, 136))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (179, 202))	('DNA damage', 'MPA', (216, 226))	('decrease', 'NegReg', (80, 88))
25706	31351238	Our collective data suggest that AgNP exposure interfered with integrin-BM interactions and subsequent intracellular signaling, thereby pre-selecting for cells most capable of surviving integrin-BM detachment conditions.	('AgNP', 'Chemical', '-', (33, 37))	('intracellular signaling', 'MPA', (103, 126))	('integrin-BM', 'Protein', (63, 74))	('exposure', 'Var', (38, 46))	('interfered', 'NegReg', (47, 57))	('interactions', 'Interaction', (75, 87))
25716	31351238	Deregulated MAPK/ERK signaling is one hallmark of cancer progression and other diseases.	('Deregulated', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Disease', (50, 56))	('ERK', 'Gene', '5594', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ERK', 'Gene', (17, 20))
25717	31351238	It is of note that ERK1/2 activity is also a primary mediator of the physiochemical properties between CD44, hyaluronan, the BM, and the cell.	('ERK1/2', 'Gene', (19, 25))	('ERK1/2', 'Gene', '5595;5594', (19, 25))	('CD44', 'Var', (103, 107))
25726	31351238	Our data suggest AgNPs have the potential to influence epithelial cell-BM interactions, provide a candidate list of molecules altered by AgNP-exposure, and demonstrate phenotypic changes in epithelial cells including deregulated 3D growth, enhanced survival in anchorage independent conditions, and changes in TGFbeta1 production.	('TGFbeta1', 'Gene', '7040', (310, 318))	('AgNPs', 'Chemical', '-', (17, 22))	('TGFbeta1', 'Gene', (310, 318))	('enhanced', 'PosReg', (240, 248))	('AgNP', 'Chemical', '-', (17, 21))	('AgNP', 'Chemical', '-', (137, 141))	('production', 'MPA', (319, 329))	('epithelial cell-BM interactions', 'CPA', (55, 86))	('3D growth', 'CPA', (229, 238))	('AgNPs', 'Var', (17, 22))	('deregulated', 'NegReg', (217, 228))	('influence', 'Reg', (45, 54))	('changes', 'Reg', (299, 306))	('survival', 'CPA', (249, 257))
25728	31351238	Whether these changes have the potential to induce epithelial disorganization that persists over time and predisposes affected tissue to diseases such as fibrosis or cancer remain to be determined.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('fibrosis', 'Disease', 'MESH:D005355', (154, 162))	('fibrosis', 'Disease', (154, 162))	('changes', 'Var', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('induce', 'Reg', (44, 50))
25738	30813149	A administration of GLN was associated with a decrease in the incidence of grade 2 or 3 ARIE (6.7% vs 53.4% for Gln+ vs Gln-; P = .004).	('grade 2 or 3 ARIE', 'Disease', (75, 92))	('GLN', 'Chemical', 'MESH:D005973', (20, 23))	('GLN', 'Var', (20, 23))	('Gln', 'Chemical', 'MESH:D005973', (112, 115))	('decrease', 'NegReg', (46, 54))	('Gln', 'Chemical', 'MESH:D005973', (120, 123))	('Gln+', 'Var', (112, 116))
25772	30813149	Compared to sequential radiochemotherapy, CCRT have an advantage in overall survival but also increase the risk of severe acute esophageal toxicity from 4% to 18% .	('increase', 'PosReg', (94, 102))	('esophageal toxicity', 'Disease', (128, 147))	('CCRT', 'Var', (42, 46))	('advantage', 'PosReg', (55, 64))	('esophageal toxicity', 'Disease', 'MESH:D004935', (128, 147))
25847	29720850	In one of the largest reports, which included over 500 early SCCs treated endoscopically and followed over 5 years, the cumulative risk of lymph-node metastases ranged from 0.4% for T1a m1-2 SCC, 8.7% for T1am3, 7.7% for T1bsm1, to 36.2% for T1bsm2 lesions.	('sm1', 'Gene', '7911', (224, 227))	('sm2', 'Gene', (245, 248))	('T1am3', 'Var', (205, 210))	('sm2', 'Gene', '53366', (245, 248))	('lymph-node metastases', 'Disease', (139, 160))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('SCC', 'Gene', '6317', (61, 64))	('sm1', 'Gene', (224, 227))	('SCC', 'Gene', (191, 194))	('lymph-node metastases', 'Disease', 'MESH:D009362', (139, 160))	('SCC', 'Phenotype', 'HP:0002860', (191, 194))	('T1a', 'Var', (182, 185))	('SCC', 'Gene', (61, 64))	('SCC', 'Gene', '6317', (191, 194))
25848	29720850	These numbers are in line with those reported by other teams, including surgical series, with a 0-2% risk of lymph-node metastases for T1am1-2 lesions, 8-18% for lesions invading the muscularis mucosae (m3), and 7.7 to 19% for lesions invading the submucosa to less than 200 microm (sm1), and 30-54% for sm2 or sm3 lesions.	('am1', 'Species', '408139', (137, 140))	('sm2', 'Gene', (304, 307))	('sm2', 'Gene', '53366', (304, 307))	('T1am1-2', 'Gene', (135, 142))	('lesions', 'Var', (143, 150))	('sm1', 'Gene', '7911', (283, 286))	('lymph-node metastases', 'Disease', (109, 130))	('lymph-node metastases', 'Disease', 'MESH:D009362', (109, 130))	('sm1', 'Gene', (283, 286))
25863	29720850	However, circumferential resection of the Barrett's mucosa results in an esophageal stricture in up to 88% of patients, with a 4% recurrence rate of neoplasia at 24 months.	('neoplasia', 'Disease', (149, 158))	('esophageal stricture', 'Disease', (73, 93))	('patients', 'Species', '9606', (110, 118))	('neoplasia', 'Phenotype', 'HP:0002664', (149, 158))	('esophageal stricture', 'Phenotype', 'HP:0002043', (73, 93))	('neoplasia', 'Disease', 'MESH:D009369', (149, 158))	('results in', 'Reg', (59, 69))	('circumferential', 'Var', (9, 24))
25877	29720850	Most data pertain to EAC, and in the only large cohort including SCC patients both treatment groups were hardly comparable, with over three times more T1b lesions in the surgery group.	('SCC', 'Gene', (65, 68))	('EAC', 'Phenotype', 'HP:0011459', (21, 24))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('lesions', 'Var', (155, 162))	('more', 'PosReg', (146, 150))	('T1b', 'Gene', (151, 154))	('patients', 'Species', '9606', (69, 77))	('EAC', 'Disease', (21, 24))
25886	29720850	Nemoto et al, in a large multicenter study that included 141 patients with T1 esophageal cancers treated by CRT or radiotherapy alone, found a 3-year overall survival of 90% and 70% for patients with T1a and T1b lesions, respectively, and better outcomes with CRT compared with radiotherapy alone.	('esophageal cancers', 'Disease', (78, 96))	('T1a', 'Var', (200, 203))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('esophageal cancers', 'Disease', 'MESH:D004938', (78, 96))	('patients', 'Species', '9606', (61, 69))	('T1b lesions', 'Var', (208, 219))	('T1 esophageal cancer', 'Phenotype', 'HP:0011459', (75, 95))	('patients', 'Species', '9606', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
25891	29720850	For example, p53 aberrant expression (either absent or overexpression) detected by immunohistochemistry has been extensively studied, and could be as discriminative as the presence of LGD in the prediction of neoplastic progression.	('overexpression', 'PosReg', (55, 69))	('aberrant', 'Var', (17, 25))	('absent', 'NegReg', (45, 51))	('neoplastic progression', 'CPA', (209, 231))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (13, 16))
25893	29720850	Specific genetic alterations of the MYC, p16, Her-2/neu, or ZNF217 genes, detected by fluorescence in situ hybridization on cytological brush samples, are associated with a lower rate of response to endoscopic therapy.	('response', 'MPA', (187, 195))	('Her-2/neu', 'Gene', '2064', (46, 55))	('Her-2/neu', 'Gene', (46, 55))	('genetic alterations', 'Var', (9, 28))	('p16', 'Gene', (41, 44))	('MYC', 'Gene', (36, 39))	('ZNF217', 'Gene', (60, 66))	('lower', 'NegReg', (173, 178))	('p16', 'Gene', '1029', (41, 44))	('ZNF217', 'Gene', '7764', (60, 66))
25930	29686470	A single-channel endoscope equipped with a water jet (GIF-H260Z; Olympus Corp, Tokyo, Japan) and attached transparent tip hood was routinely used, along with carbon dioxide insufflation.	('water', 'Chemical', 'MESH:D014867', (43, 48))	('insufflation', 'Disease', (173, 185))	('carbon dioxide', 'Chemical', 'MESH:D002245', (158, 172))	('H260Z', 'Var', (58, 63))	('H260Z', 'SUBSTITUTION', 'None', (58, 63))	('water jet', 'Phenotype', 'HP:0000969', (43, 52))	('insufflation', 'Disease', 'None', (173, 185))
26005	26893442	Results: The incidence of postoperative dysphagia and anastomotic stricture was significantly lower in the disc-shaped resection group (dysphagia 45% vs 75%, P = 0.02; stricture 12.5% vs 32.5%, P = 0.03), whilst the length of stay in an intensive care unit (ICU), anastomotic leakage and other complications were not significantly different between the two groups (all P > 0.05).	('dysphagia', 'Phenotype', 'HP:0002015', (136, 145))	('dysphagia', 'Disease', 'MESH:D003680', (40, 49))	('disc-shaped resection', 'Var', (107, 128))	('dysphagia', 'Disease', 'MESH:D003680', (136, 145))	('anastomotic stricture', 'Disease', (54, 75))	('anastomotic leak', 'Disease', 'MESH:D057868', (264, 280))	('dysphagia', 'Disease', (40, 49))	('lower', 'NegReg', (94, 99))	('dysphagia', 'Disease', (136, 145))	('dysphagia', 'Phenotype', 'HP:0002015', (40, 49))	('anastomotic leak', 'Disease', (264, 280))	('postoperative dysphagia', 'Disease', 'MESH:D003680', (26, 49))	('postoperative dysphagia', 'Disease', (26, 49))
26064	26893442	In conclusion, we showed that disc-shaped (circular) gastric resection during esophagogastric anastomosis may lead to a lower rate of postoperative dysphagia and anastomotic stricture compared with the former linear incision method.	('postoperative dysphagia', 'Disease', 'MESH:D003680', (134, 157))	('lower', 'NegReg', (120, 125))	('anastomotic stricture', 'Disease', (162, 183))	('postoperative dysphagia', 'Disease', (134, 157))	('dysphagia', 'Phenotype', 'HP:0002015', (148, 157))	('esophagogastric anastomosis', 'Phenotype', 'HP:0100628', (78, 105))	('disc-shaped', 'Var', (30, 41))
26123	26229530	NBI-ME and LCE-PS were performed by using a high-definition zoom endoscope (GIF-H260Z; Olympus Co., Tokyo, Japan) and a 19-in high-resolution liquid-crystal monitor (OEV191H; Olympus Co.) that enabled endoscopic observation at a 90-fold maximum magnification.	('NBI-ME', 'Chemical', '-', (0, 6))	('H260Z', 'Var', (80, 85))	('LCE-PS', 'Gene', '79071', (11, 17))	('H260Z', 'SUBSTITUTION', 'None', (80, 85))	('LCE-PS', 'Gene', (11, 17))
26186	26229530	Thus, although the present study showed no significant difference in all diagnostic accuracy measures for SESCC between NBI-ME and LCE-PS, we suggest that NBI-ME has a substantial clinical advantage over LCE-PS.	('LCE-PS', 'Gene', (131, 137))	('LCE-PS', 'Gene', (204, 210))	('NBI-ME', 'Chemical', '-', (155, 161))	('advantage', 'PosReg', (189, 198))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('NBI-ME', 'Chemical', '-', (120, 126))	('SESCC', 'Chemical', '-', (106, 111))	('LCE-PS', 'Gene', '79071', (131, 137))	('LCE-PS', 'Gene', '79071', (204, 210))	('NBI-ME', 'Var', (155, 161))
26192	26229530	Several studies suggested that an increased number of LVLs carry a greater risk of metachronous development of SCC in the head and neck as well as in the esophagus.	('metachronous development', 'CPA', (83, 107))	('LVLs', 'Var', (54, 58))	('SCC', 'Gene', (111, 114))	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('SCC', 'Gene', '6317', (111, 114))
26214	25914550	Patients with COCC <=8.0 had a significantly better CSS than patients with COCC >8.0 (53.1% vs 15.3%, P<0.001).	('CSS', 'Chemical', '-', (52, 55))	('better', 'PosReg', (45, 51))	('patients', 'Species', '9606', (61, 69))	('CSS', 'CPA', (52, 55))	('COCC <=8.0', 'Var', (14, 24))	('Patients', 'Species', '9606', (0, 8))	('COCC', 'Chemical', '-', (75, 79))	('COCC', 'Chemical', '-', (14, 18))
26261	25914550	Patients with COCC <=8.0 had a significantly better CSS than patients with COCC >8.0 (53.1% vs 15.3%, P<0.001) (Figure 5A).	('CSS', 'Chemical', '-', (52, 55))	('better', 'PosReg', (45, 51))	('patients', 'Species', '9606', (61, 69))	('CSS', 'CPA', (52, 55))	('COCC <=8.0', 'Var', (14, 24))	('Patients', 'Species', '9606', (0, 8))	('COCC', 'Chemical', '-', (75, 79))	('COCC', 'Chemical', '-', (14, 18))
26264	25914550	The predictive value of COCC was significant in patients with T1-T2 (P=0.010), T3-T4a (P<0.001), N0 (P<0.001), and N1-N3 (P<0.001) (Figure 6).	('N1-N3', 'Var', (115, 120))	('COCC', 'Gene', (24, 28))	('T1-T2', 'Var', (62, 67))	('COCC', 'Chemical', '-', (24, 28))	('patients', 'Species', '9606', (48, 56))	('T3-T4a', 'Var', (79, 85))
26294	25914550	In our study, the predictive value of COCC was also significant in patients with T1-T2 (P=0.010), T3-T4a (P<0.001), N0 (P<0.001), and N1-N3 (P<0.001) (Figure 5).	('T1-T2', 'Var', (81, 86))	('patients', 'Species', '9606', (67, 75))	('COCC', 'Gene', (38, 42))	('N1-N3', 'Var', (134, 139))	('T3-T4a', 'Var', (98, 104))	('COCC', 'Chemical', '-', (38, 42))
26440	24220097	Following tumor enrichment by macro-dissection of an area containing approximately 85% melanoma nuclei, molecular testing demonstrated the presence of a 1799T>A (V600E) mutation in BRAF (Figure 3).	('1799T>A', 'Mutation', 'rs113488022', (153, 160))	('1799T>A (V600E', 'Var', (153, 167))	('melanoma', 'Disease', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('BRAF', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (181, 185))	('presence', 'Reg', (139, 147))	('V600E', 'Mutation', 'rs113488022', (162, 167))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
26457	24220097	The discovery of constitutively activating mutations in the BRAF and KIT genes in subsets of melanoma has expanded treatment options to include specific molecularly targeted kinase inhibitors such as vemurafinib and imatinib.	('KIT', 'Gene', (69, 72))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('vemurafinib', 'Chemical', '-', (200, 211))	('mutations', 'Var', (43, 52))	('activating', 'PosReg', (32, 42))	('imatinib', 'Chemical', 'MESH:D000068877', (216, 224))
26458	24220097	The V600E mutation in BRAF has now been associated with approximately 80% of melanomas and seen predominantly in melanomas arising on skin without chronic sun damage.	('V600E', 'Var', (4, 9))	('melanomas', 'Disease', (113, 122))	('melanomas', 'Disease', (77, 86))	('sun damage', 'Phenotype', 'HP:0000992', (155, 165))	('BRAF', 'Gene', '673', (22, 26))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('V600E', 'Mutation', 'rs113488022', (4, 9))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('BRAF', 'Gene', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('melanomas', 'Disease', 'MESH:D008545', (113, 122))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('associated', 'Reg', (40, 50))
26459	24220097	Inhibition of mutated BRAF with targeted inhibitor therapy such as vemurafinib has proven successful in achieving complete or partial regression of tumors in many patients, although resistance frequently develops.	('patients', 'Species', '9606', (163, 171))	('mutated', 'Var', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('BRAF', 'Gene', '673', (22, 26))	('BRAF', 'Gene', (22, 26))	('vemurafinib', 'Chemical', '-', (67, 78))	('Inhibition', 'Var', (0, 10))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
26460	24220097	Our patient demonstrated a 1799T>A (V600E) mutation in his tumor, providing secondary evidence that his tumor most likely arose from a cutaneous lesion.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (104, 109))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('1799T>A', 'Mutation', 'rs113488022', (27, 34))	('1799T>A (V600E', 'Var', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
26461	24220097	No activating mutations were detected in the kinase, juxtamembrane or extracellular domains the KIT gene, consistent with the observation that BRAF and KIT mutation are associated with different subsets of melanoma and are generally mutually exclusive.	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('associated with', 'Reg', (169, 184))	('melanoma', 'Disease', (206, 214))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))	('mutation', 'Var', (156, 164))
26462	24220097	In summary, we describe the first report of metastatic melanoma of the esophagus arising in a background of BE with molecular analysis for the presence of BRAF and KIT mutations.	('BE', 'Phenotype', 'HP:0100580', (108, 110))	('BRAF', 'Gene', (155, 159))	('melanoma of the esophagus', 'Disease', 'MESH:D008545', (55, 80))	('melanoma of the esophagus', 'Disease', (55, 80))	('BRAF', 'Gene', '673', (155, 159))	('KIT', 'Gene', (164, 167))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('mutations', 'Var', (168, 177))
26465	24220097	SO performed the sequence analysis and interpretation of the BRAF and KIT mutations and helped in drafting the paper.	('mutations', 'Var', (74, 83))	('KIT', 'Gene', (70, 73))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (61, 65))
26481	22844531	Besides, activation an oncogene or inactivation of certain tumor suppressor gene, DNA damage, oxidative stress, some chemotherapeutic drugs, radiation and cell reprogramming could also induce cell senescence in vitro .	('tumor', 'Disease', (59, 64))	('induce', 'Reg', (185, 191))	('inactivation', 'Var', (35, 47))	('oncogene', 'Gene', (23, 31))	('cell senescence', 'CPA', (192, 207))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('oxidative stress', 'Phenotype', 'HP:0025464', (94, 110))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
26497	22844531	Western blot analysis showed that p21WAF1/CIP1, one of the most important proteins that mediates cellular senescence, was also increased by ectopic expression of DEC1 (Fig.	('p21WAF1/CIP1', 'Gene', '1026', (34, 46))	('ectopic expression', 'Var', (140, 158))	('p21WAF1/CIP1', 'Gene', (34, 46))	('DEC1', 'Gene', (162, 166))	('DEC1', 'Gene', '50514', (162, 166))	('increased', 'PosReg', (127, 136))
26499	22844531	Then we found DEC1 overexpression significantly suppressed the growth of EC9706 and HEK293, as measured by growth rate and colony formation assay (Fig.	('overexpression', 'PosReg', (19, 33))	('EC9706', 'Var', (73, 79))	('colon', 'Disease', (123, 128))	('suppressed', 'NegReg', (48, 58))	('DEC1', 'Gene', '50514', (14, 18))	('growth', 'MPA', (63, 69))	('EC9706', 'CellLine', 'CVCL:E307', (73, 79))	('DEC1', 'Gene', (14, 18))	('HEK293', 'CellLine', 'CVCL:0045', (84, 90))	('colon', 'Disease', 'MESH:D015179', (123, 128))	('growth rate', 'CPA', (107, 118))
26558	22844531	EC9706 cells were co-transfected with pCMV6-XL5-DEC1 and pcDNA3.1 (-)/myc-His B, and cells that transfected with pcDNA3.1 (-)/myc-His B alone were used as control.	('DEC1', 'Gene', (48, 52))	('pcDNA3.1 (-)/myc-His B', 'Var', (57, 79))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('DEC1', 'Gene', '50514', (48, 52))
26565	21689432	Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (349, 372))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('Association', 'Interaction', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (330, 337))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('Phospholipase C epsilon 1', 'Gene', (172, 197))	('variants', 'Var', (32, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (363, 372))	('roles', 'Reg', (279, 284))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (349, 372))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('esophageal cancer', 'Disease', (65, 82))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (363, 393))	('Phospholipase C epsilon 1', 'Gene', '51196', (172, 197))	('carcinogenesis', 'Disease', (288, 302))	('cancers', 'Phenotype', 'HP:0002664', (330, 337))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (141, 171))	('squamous cell carcinoma', 'Disease', (127, 150))	('cancers', 'Disease', (330, 337))	('squamous cell carcinoma', 'Disease', (349, 372))	('carcinogenesis', 'Disease', 'MESH:D063646', (288, 302))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PLCE1', 'Gene', (26, 31))	('PLCE1', 'Gene', '51196', (26, 31))	('PLCE1', 'Gene', (199, 204))	('PLCE1', 'Gene', '51196', (199, 204))
26566	21689432	A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN.	('single nucleotide polymorphism', 'Var', (2, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('PLCE1', 'Gene', (53, 58))	('rs2274223', 'Mutation', 'rs2274223', (39, 48))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (156, 190))	('PLCE1', 'Gene', '51196', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (202, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (167, 190))	('susceptibility', 'Reg', (90, 104))	('gastric cardia adenocarcinoma', 'Disease', (202, 231))	('esophageal squamous cell carcinoma', 'Disease', (156, 190))
26567	21689432	Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN.	('SNPs', 'Var', (74, 78))	('investigated', 'Reg', (14, 26))	('PLCE1', 'Gene', (82, 87))	('PLCE1', 'Gene', '51196', (82, 87))	('SCCHN', 'Disease', (110, 115))
26568	21689432	We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population.	('rs11599672', 'Mutation', 'rs11599672', (79, 89))	('PLCE1', 'Gene', (97, 102))	('PLCE1', 'Gene', '51196', (97, 102))	('patients', 'Species', '9606', (118, 126))	('rs11599672T/G', 'Var', (79, 92))	('rs2274223A/G', 'Var', (48, 60))	('rs3203713', 'Mutation', 'rs3203713', (62, 71))	('functional', 'Reg', (31, 41))	('SCCHN', 'Disease', (112, 117))	('rs3203713A/G', 'Var', (62, 74))	('rs2274223', 'Mutation', 'rs2274223', (48, 57))
26569	21689432	Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (Ptrend = 0.046), particularly for non-oropharyngeal tumors (Ptrend = 0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR = 1.29, 95% CI = 1.01-1.64; AG/GG vs. AA: adjusted OR = 1.30, 95% CI = 1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR = 0.54, 95% CI = 0.34-0.86; TG/GG vs. TT: adjusted OR = 0.76, 95% CI = 0.61-0.95).	('non-oropharyngeal tumors', 'Disease', 'MESH:D009959', (283, 307))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('rs2274223', 'Mutation', 'rs2274223', (131, 140))	('non-oropharyngeal tumors', 'Disease', (283, 307))	('rs3203713', 'Mutation', 'rs3203713', (143, 152))	('rs11599672G', 'Var', (158, 169))	('rs11599672', 'Var', (514, 524))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('rs11599672', 'Mutation', 'rs11599672', (514, 524))	('rs2274223', 'Mutation', 'rs2274223', (340, 349))	('rs2274223', 'Var', (340, 349))	('rs11599672', 'Mutation', 'rs11599672', (158, 168))	('oropharyngeal tumors', 'Phenotype', 'HP:0100638', (287, 307))	('rs3203713G', 'Var', (143, 153))
26570	21689432	Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non-oropharyngeal sites.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('alcohol', 'Chemical', 'MESH:D000438', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('effect', 'Reg', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('PLCE1', 'Gene', (26, 31))	('variants', 'Var', (32, 40))	('PLCE1', 'Gene', '51196', (26, 31))	('SCCHN', 'Disease', (71, 76))	('tumors', 'Disease', (146, 152))	('tobacco', 'Species', '4097', (93, 100))	('associated', 'Reg', (77, 87))
26576	21689432	However, only one recent GWAS focused on SCCHN risk and identified five variants at 4q21, 12q24 and ADH gene cluster, significantly associated with risk of upper aerodigestive tract cancers (UATC) including SCCHN.	('upper aerodigestive tract cancers', 'Disease', 'MESH:D006258', (156, 189))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('associated', 'Reg', (132, 142))	('variants', 'Var', (72, 80))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('SCCHN', 'Disease', (207, 212))	('ADH', 'Disease', 'MESH:D007177', (100, 103))	('upper aerodigestive tract cancers', 'Disease', (156, 189))	('ADH', 'Disease', (100, 103))
26577	21689432	In 2010, two large-scale genome-wide association studies simultaneously reported that a new and notable low-penetrance susceptibility locus (rs2274223) located in the phospholipase C epsilon 1 gene (PLCE1) was strongly associated with risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in Chinese population.	('rs2274223', 'Mutation', 'rs2274223', (141, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (254, 277))	('rs2274223', 'Var', (141, 150))	('gastric cardia adenocarcinoma', 'Disease', (289, 318))	('associated with', 'Reg', (219, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('phospholipase C epsilon 1', 'Gene', '51196', (167, 192))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (243, 277))	('phospholipase C epsilon 1', 'Gene', (167, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('PLCE1', 'Gene', (199, 204))	('PLCE1', 'Gene', '51196', (199, 204))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (289, 318))	('esophageal squamous cell carcinoma', 'Disease', (243, 277))
26578	21689432	Rs2274223 is a non-synonymous SNP located in exon 26 of the PLCE1 gene, causing the amino acid change from histidine to arginine.	('Rs2274223', 'Mutation', 'Rs2274223', (0, 9))	('causing', 'Reg', (72, 79))	('amino acid change from histidine to arginine', 'MPA', (84, 128))	('arginine', 'Chemical', 'MESH:D001120', (120, 128))	('PLCE1', 'Gene', (60, 65))	('PLCE1', 'Gene', '51196', (60, 65))	('Rs2274223', 'Var', (0, 9))	('histidine', 'Chemical', 'MESH:D006639', (107, 116))
26583	21689432	All these findings further support the biological plausibility that genetic variations, such as single nucleotide polymorphisms (SNPs) in PLCE1 that affect the gene expression or protein functions, may affect the risk of some cancers.	('gene expression', 'MPA', (160, 175))	('protein', 'Protein', (179, 186))	('single nucleotide polymorphisms', 'Var', (96, 127))	('affect', 'Reg', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('PLCE1', 'Gene', (138, 143))	('PLCE1', 'Gene', '51196', (138, 143))	('affect', 'Reg', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
26585	21689432	Thus, the exciting results in the GWAS of ESCC and GCA, and the strong biological evidence encouraged us to investigate the association between functional SNPs in PLCE1 and susceptibility to SCCHN.	('PLCE1', 'Gene', '51196', (163, 168))	('SNPs', 'Var', (155, 159))	('PLCE1', 'Gene', (163, 168))	('SCCHN', 'Disease', (191, 196))
26586	21689432	In the present study, we performed genotyping analyses of three potentially functional SNPs in PLCE1 (rs2274223A/G, rs3203713A/G and rs11599672T/G) in non-Hispanic whites and assessed their associations with risk of SCCHN in our ongoing hospital-based case-control study of 1,098 SCCHN cases and 1,090 cancer-free controls matched to cases on age (+- 5 years) and sex.	('SCCHN', 'Disease', (280, 285))	('rs11599672T/G', 'Var', (133, 146))	('rs2274223A/G', 'Var', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('rs3203713A/G', 'Var', (116, 128))	('rs3203713', 'Mutation', 'rs3203713', (116, 125))	('rs2274223', 'Mutation', 'rs2274223', (102, 111))	('PLCE1', 'Gene', (95, 100))	('associations', 'Interaction', (190, 202))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('rs11599672', 'Mutation', 'rs11599672', (133, 143))	('PLCE1', 'Gene', '51196', (95, 100))	('cancer', 'Disease', (302, 308))	('SCCHN', 'Disease', (216, 221))
26598	21689432	We selected additional two potentially functional SNPs in PLCE1: rs3203713, located in the miRNA binding site (3'UTR) and rs11599672, located in the transcription factor binding site (TFBS in 5' near gene).	('rs3203713', 'Var', (65, 74))	('rs11599672', 'Var', (122, 132))	('rs11599672', 'Mutation', 'rs11599672', (122, 132))	('rs3203713', 'Mutation', 'rs3203713', (65, 74))	('PLCE1', 'Gene', (58, 63))	('PLCE1', 'Gene', '51196', (58, 63))
26599	21689432	Taken together, we included three SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) in PLCE1 for the final genotyping.	('rs11599672T/G', 'Var', (71, 84))	('rs3203713A/G', 'Var', (54, 66))	('rs2274223', 'Mutation', 'rs2274223', (40, 49))	('rs11599672', 'Mutation', 'rs11599672', (71, 81))	('PLCE1', 'Gene', (89, 94))	('rs2274223A/G', 'Var', (40, 52))	('PLCE1', 'Gene', '51196', (89, 94))	('rs3203713', 'Mutation', 'rs3203713', (54, 63))
26600	21689432	We extracted genomic DNA from the buffy-coat fraction of the blood samples using the Qiagen Blood DNA Mini Kit (Qiagen Inc., Valencia, Calif) according to the manufacturer's instruction and genotyped SNPs rs2274223 and rs3203713 using the TaqMan allelic discrimination assay on an ABI 7900 system (Applied Biosystems).	('rs2274223', 'Mutation', 'rs2274223', (205, 214))	('rs3203713', 'Var', (219, 228))	('rs2274223', 'Var', (205, 214))	('rs3203713', 'Mutation', 'rs3203713', (219, 228))	('Calif', 'Gene', (135, 140))	('Calif', 'Gene', '9337', (135, 140))
26606	21689432	We estimated associations between PLCE1 variants and SCCHN risk by computing odds ratios (ORs) and 95% confidence intervals (CIs) from both univariate and multivariate logistic regression analyses with adjustment for the known risk factors for SCCHN, such as age, sex, smoking status and alcohol use.	('SCCHN', 'Disease', (244, 249))	('alcohol', 'Chemical', 'MESH:D000438', (288, 295))	('associations', 'Interaction', (13, 25))	('SCCHN', 'Disease', (53, 58))	('PLCE1', 'Gene', (34, 39))	('variants', 'Var', (40, 48))	('alcohol use', 'Phenotype', 'HP:0030955', (288, 299))	('PLCE1', 'Gene', '51196', (34, 39))
26608	21689432	The genotype and allele distributions of three SNPs (rs2274223, rs3203713 and rs11599672) in cases and controls are shown in Table 2.	('rs2274223', 'Mutation', 'rs2274223', (53, 62))	('rs2274223', 'Var', (53, 62))	('rs3203713', 'Mutation', 'rs3203713', (64, 73))	('rs11599672', 'Var', (78, 88))	('rs3203713', 'Var', (64, 73))	('rs11599672', 'Mutation', 'rs11599672', (78, 88))
26609	21689432	The single locus analyses revealed that genotype distributions of these three polymorphisms were not significantly different between overall cases and controls (P = 0.554 for rs2274223, P = 0.860 for rs3203713 and P = 0.265 for rs11599672, respectively).	('rs3203713', 'Var', (200, 209))	('rs11599672', 'Var', (228, 238))	('rs11599672', 'Mutation', 'rs11599672', (228, 238))	('rs2274223', 'Mutation', 'rs2274223', (175, 184))	('rs2274223', 'Var', (175, 184))	('rs3203713', 'Mutation', 'rs3203713', (200, 209))
26610	21689432	However, we found that the frequencies of variant rs2274223G and rs3203713G alleles (0.335 and 0.170, respectively) among the cases were slightly higher than those in the controls (0.320 and 0.162, respectively), while the frequency of the variant rs11599672G allele among the cases was slightly lower than that among the controls (0.277 vs. 0.297), suggesting rs2274223G, rs3203713G and rs11599672T alleles may be risk alleles to be considered in further analyses.	('higher', 'PosReg', (146, 152))	('rs3203713G', 'Var', (373, 383))	('rs2274223', 'Mutation', 'rs2274223', (361, 370))	('rs2274223', 'Mutation', 'rs2274223', (50, 59))	('rs3203713G', 'Var', (65, 75))	('rs11599672', 'Mutation', 'rs11599672', (248, 258))	('rs3203713', 'Mutation', 'rs3203713', (373, 382))	('rs2274223G', 'Var', (361, 371))	('rs3203713', 'Mutation', 'rs3203713', (65, 74))	('rs11599672', 'Mutation', 'rs11599672', (388, 398))	('rs11599672T', 'Var', (388, 399))
26611	21689432	The LD analysis showed that two PLCE1 polymorphisms rs2274223 and rs3203713 were in incomplete LD in our study population (D' = 0.99, r2 = 0.40), but these two SNPs were not in LD with rs11599672.	('rs2274223', 'Var', (52, 61))	('rs3203713', 'Var', (66, 75))	('PLCE1', 'Gene', (32, 37))	('PLCE1', 'Gene', '51196', (32, 37))	('rs3203713', 'Mutation', 'rs3203713', (66, 75))	('rs11599672', 'Mutation', 'rs11599672', (185, 195))	('rs2274223', 'Mutation', 'rs2274223', (52, 61))
26612	21689432	To estimate possible joint effects and potential locus-locus interactions of PLCE1 polymorphisms on risk of SCCHN, we then examined the combined effects of these three variants by the number of putative risk alleles (i.e.	('polymorphisms', 'Var', (83, 96))	('SCCHN', 'Disease', (108, 113))	('PLCE1', 'Gene', (77, 82))	('PLCE1', 'Gene', '51196', (77, 82))
26613	21689432	rs2274223G, rs3203713G and rs11599672T).	('rs3203713', 'Mutation', 'rs3203713', (12, 21))	('rs11599672', 'Mutation', 'rs11599672', (27, 37))	('rs11599672T', 'Var', (27, 38))	('rs2274223', 'Mutation', 'rs2274223', (0, 9))	('rs2274223G', 'Var', (0, 10))	('rs3203713G', 'Var', (12, 22))
26615	21689432	To investigate the modifying effects of PLCE1 variants on risk of SCCHN with different tumor sites, we conducted the stratification analysis by oropharyngeal and non-oropharyngeal cancers.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('SCCHN', 'Disease', (66, 71))	('tumor', 'Disease', (87, 92))	('non-oropharyngeal cancers', 'Disease', (162, 187))	('PLCE1', 'Gene', (40, 45))	('non-oropharyngeal cancers', 'Disease', 'MESH:D009959', (162, 187))	('variants', 'Var', (46, 54))	('PLCE1', 'Gene', '51196', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
26616	21689432	As shown in Table 2, rs2274223 variant genotypes were associated with a significantly increased risk of SCCHN only for non-oropharyngeal sites (AG vs. AA: adjusted OR = 1.29, 95% CI = 1.01-1.64, adjusted P = 0.042; AG/GG vs. AA: adjusted OR = 1.30, 95% CI = 1.03-1.64; adjusted P = 0.025), while rs11599672 variant genotypes were associated with a significantly decreased risk of SCCHN for this group of patients (GG vs. TT: adjusted OR = 0.54, 95% CI = 0.34-0.86, adjusted P = 0.009; TG/GG vs. TT: adjusted OR = 0.76, 95% CI = 0.61-0.95, adjusted P = 0.018).	('rs11599672', 'Var', (296, 306))	('rs11599672', 'Mutation', 'rs11599672', (296, 306))	('patients', 'Species', '9606', (404, 412))	('SCCHN', 'Disease', (104, 109))	('decreased', 'NegReg', (362, 371))	('rs2274223 variant', 'Var', (21, 38))	('rs2274223', 'Mutation', 'rs2274223', (21, 30))	('SCCHN', 'Disease', (380, 385))	('variant', 'Var', (31, 38))
26617	21689432	No association was observed for rs3203713 variant genotypes and risk of SCCHN in both subgroups.	('rs3203713', 'Mutation', 'rs3203713', (32, 41))	('SCCHN', 'Disease', (72, 77))	('rs3203713', 'Var', (32, 41))
26619	21689432	A total of six haplotypes were derived from the observed genotypes, of which Trs11599672Ars2274223Ars3203713 was the most common haplotype in cases and controls with the frequencies of 53.6% and 53.0%, respectively.	('rs3203713', 'Mutation', 'rs3203713', (99, 108))	('rs2274223', 'Mutation', 'rs2274223', (89, 98))	('common', 'Reg', (122, 128))	('Trs11599672Ars2274223Ars3203713', 'Var', (77, 108))	('rs11599672', 'Mutation', 'rs11599672', (78, 88))
26620	21689432	Compared with the common haplotype, the G rs11599672A rs2274223A rs3203713 haplotype was associated with a 28% decreased risk of SCCHN arising at non- oropharyngeal sites (adjusted OR = 0.72, 95% CI = 0.56-0.92); in contract, the T rs11599672G rs2274223A rs3203713 haplotype was associated with a 31% increased risk of SCCHN arising at non-oropharyngeal sites (adjusted OR = 1.31, 95% CI = 1.00-1.72).	('rs2274223', 'Mutation', 'rs2274223', (54, 63))	('T rs11599672G rs2274223A rs3203713', 'Var', (230, 264))	('rs11599672', 'Mutation', 'rs11599672', (232, 242))	('rs3203713', 'Mutation', 'rs3203713', (65, 74))	('rs3203713', 'Mutation', 'rs3203713', (255, 264))	('rs2274223', 'Mutation', 'rs2274223', (244, 253))	('SCCHN', 'Disease', (319, 324))	('rs11599672', 'Mutation', 'rs11599672', (42, 52))
26622	21689432	The results showed that the risk effect of rs2274223 was more evident in the younger (adjusted OR = 1.44, 95% CI = 1.02-2.02), male (adjusted OR = 1.51, 95% CI = 1.14-2.00), smokers (adjusted OR = 1.33, 95% CI = 1.02-1.72), drinkers (adjusted OR = 1.69, 95% CI = 1.25-2.28) and subjects with early stage (adjusted OR = 1.40, 95% CI = 1.03-1.91), whereas the protective effect of rs11599672 was more prominent in the younger (adjusted OR = 0.71, 95% CI = 0.50-1.00), smokers (adjusted OR = 0.73, 95% CI = 0.56-0.94) and non-drinkers (adjusted OR = 0.67, 95% CI = 0.46-0.99).	('rs11599672', 'Var', (379, 389))	('rs11599672', 'Mutation', 'rs11599672', (379, 389))	('rs2274223', 'Mutation', 'rs2274223', (43, 52))	('rs2274223', 'Var', (43, 52))
26624	21689432	However, no significant associations were found for rs3203713 variant genotypes and risk of SCCHN arising at non-oropharyngeal sites in every stratum (data not shown).	('rs3203713', 'Mutation', 'rs3203713', (52, 61))	('SCCHN arising', 'Disease', (92, 105))	('rs3203713', 'Var', (52, 61))
26627	21689432	In this case-control study, we investigated the associations between three novel, potentially functional SNPs of PLCE1 (rs2274223, rs3203713 and rs11599672) and risk of SCCHN in a non-Hispanic white population.	('rs3203713', 'Var', (131, 140))	('rs11599672', 'Var', (145, 155))	('associations', 'Interaction', (48, 60))	('rs11599672', 'Mutation', 'rs11599672', (145, 155))	('SCCHN', 'Disease', (169, 174))	('PLCE1', 'Gene', (113, 118))	('rs2274223', 'Var', (120, 129))	('rs2274223', 'Mutation', 'rs2274223', (120, 129))	('PLCE1', 'Gene', '51196', (113, 118))	('rs3203713', 'Mutation', 'rs3203713', (131, 140))
26628	21689432	Although we did not find evidence of a main effect of each PLCE1 SNP on overall SCCHN risk, the joint effect of these variants appeared to contribute to risk of SCCHN in a dose-response manner, especially for cancers arising at non-oropharyngeal sites.	('contribute', 'Reg', (139, 149))	('variants', 'Var', (118, 126))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('SCCHN', 'Disease', (80, 85))	('cancers', 'Disease', (209, 216))	('PLCE1', 'Gene', (59, 64))	('PLCE1', 'Gene', '51196', (59, 64))	('SCCHN', 'Disease', (161, 166))
26629	21689432	Further, the subgroup analysis of SCCHN arising at non-oropharyngeal sites showed that variant genotypes of both rs2274223 and rs11599672 were independently associated with the risk.	('rs11599672', 'Mutation', 'rs11599672', (127, 137))	('associated', 'Reg', (157, 167))	('rs2274223', 'Mutation', 'rs2274223', (113, 122))	('rs2274223', 'Var', (113, 122))	('rs11599672', 'Var', (127, 137))
26630	21689432	These findings suggested, for the first time, that potentially functional polymorphisms of PLCE1 may play a role in the development of SCCHN, particularly of those tumors at non-oropharyngeal sites.	('polymorphisms', 'Var', (74, 87))	('play', 'Reg', (101, 105))	('role', 'Reg', (108, 112))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('PLCE1', 'Gene', (91, 96))	('PLCE1', 'Gene', '51196', (91, 96))	('SCCHN', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
26632	21689432	Since mutations in the RAS gene family are associated with about 30% of all human cancers, several studies have investigated the possible role of PLCE1 in cancer development and progression.	('PLCE1', 'Gene', '51196', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancer', 'Disease', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('human', 'Species', '9606', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('associated', 'Reg', (43, 53))	('cancer', 'Disease', (155, 161))	('mutations', 'Var', (6, 15))	('PLCE1', 'Gene', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
26634	21689432	Recent evidence has demonstrated that PLCE1 mutations might cause the nephritic syndrome and diffuse mesangial sclerosis (DMS); however, few studies have investigated the association between genetic variants of PLCE1 and risk of human cancers.	('cause', 'Reg', (60, 65))	('DMS', 'Phenotype', 'HP:0001967', (122, 125))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('PLCE1', 'Gene', (211, 216))	('cancers', 'Disease', (235, 242))	('PLCE1', 'Gene', '51196', (211, 216))	('diffuse mesangial sclerosis', 'Phenotype', 'HP:0001967', (93, 120))	('mutations', 'Var', (44, 53))	('human', 'Species', '9606', (229, 234))	('nephritic syndrome', 'Disease', (70, 88))	('PLCE1', 'Gene', (38, 43))	('diffuse mesangial sclerosis', 'Disease', 'MESH:C537346', (93, 120))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('PLCE1', 'Gene', '51196', (38, 43))	('diffuse mesangial sclerosis', 'Disease', (93, 120))	('nephritic syndrome', 'Disease', 'MESH:D013577', (70, 88))
26635	21689432	found that rs2274223, a nonsynonymous SNP of the PLCE1 gene, was associated with an increased risk of ESCC and GCA in a Chinese population by a two-stage GWAS in 9,053 ESCC cases, 2,766 GCA cases and 11,013 controls.	('PLCE1', 'Gene', '51196', (49, 54))	('ESCC', 'Disease', (102, 106))	('GCA', 'Disease', (111, 114))	('rs2274223', 'Var', (11, 20))	('ESCC', 'Disease', (168, 172))	('rs2274223', 'Mutation', 'rs2274223', (11, 20))	('PLCE1', 'Gene', (49, 54))
26637	21689432	also reported that rs2274223 was a notable signal for susceptibility to ESCC and GCA.	('rs2274223', 'Mutation', 'rs2274223', (19, 28))	('rs2274223', 'Var', (19, 28))	('ESCC', 'Disease', (72, 76))	('GCA', 'Disease', (81, 84))
26638	21689432	Despite the present study with 1,098 SCCHN cases and 1,090 controls may have a limited power to detect weak associations between polymorphisms of PLCE1 including rs2274223 and overall risk of SCCHN compared with the published GWA studies, our results did show that subjects carrying more risk alleles in PLCE1 (rs2274223G, rs3203713G and rs11599672T) had a higher risk of SCCHN than those with zero to one risk allele, especially for SCCHN arising at non-oropharyngeal sites, suggesting a joint effect of these SNPs on susceptibility to SCCHN.	('PLCE1', 'Gene', '51196', (146, 151))	('rs2274223G', 'Var', (311, 321))	('rs11599672', 'Mutation', 'rs11599672', (338, 348))	('rs11599672T', 'Var', (338, 349))	('SCCHN', 'Disease', (372, 377))	('PLCE1', 'Gene', (304, 309))	('rs3203713G', 'Var', (323, 333))	('PLCE1', 'Gene', '51196', (304, 309))	('SCCHN', 'Disease', (537, 542))	('rs2274223', 'Mutation', 'rs2274223', (162, 171))	('rs2274223', 'Mutation', 'rs2274223', (311, 320))	('rs3203713', 'Mutation', 'rs3203713', (323, 332))	('PLCE1', 'Gene', (146, 151))
26640	21689432	Furthermore, different carcinogenic mechanisms between esophageal and gastric cardia cancers and SCCHN or genetic difference in different populations may result in the discrepancy for the main effect of rs2274223 between our study on SCCHN and two GWASs of esophageal and gastric cancers.	('gastric cancer', 'Phenotype', 'HP:0012126', (272, 286))	('carcinogenic', 'Disease', 'MESH:D063646', (23, 35))	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('gastric cardia cancers', 'Disease', 'MESH:D013274', (70, 92))	('carcinogenic', 'Disease', (23, 35))	('gastric cardia cancers', 'Disease', (70, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('gastric cancers', 'Phenotype', 'HP:0012126', (272, 287))	('result in', 'Reg', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('rs2274223', 'Mutation', 'rs2274223', (203, 212))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (257, 287))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('rs2274223', 'Var', (203, 212))
26643	21689432	In our study, we found that rs2274223 and rs11599672 had an independent effect on risk of smoking and drinking related SCCHN arising at non-oropharyngeal sites but not HPV-related oropharyngeal cancer.	('HPV', 'Species', '10566', (168, 171))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (180, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('smoking', 'Disease', (90, 97))	('SCCHN arising', 'Disease', (119, 132))	('rs2274223', 'Mutation', 'rs2274223', (28, 37))	('rs2274223', 'Var', (28, 37))	('oropharyngeal cancer', 'Disease', (180, 200))	('rs11599672', 'Var', (42, 52))	('rs11599672', 'Mutation', 'rs11599672', (42, 52))
26644	21689432	Even after Bonferroni corrections, the association of rs11599672 with non-oropharyngeal SCCHN and association of rs2274223 with drinking at non-orpharyngeal sites remained significant, suggesting different roles of these polymorphisms in the etiology of two different tumor subsites.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (268, 273))	('rs11599672', 'Var', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('rs11599672', 'Mutation', 'rs11599672', (54, 64))	('rs2274223', 'Mutation', 'rs2274223', (113, 122))	('rs2274223', 'Var', (113, 122))	('non-oropharyngeal SCCHN', 'Disease', (70, 93))	('association', 'Interaction', (39, 50))
26645	21689432	Additionally, subgroup analyses restricted to oropharygeal cancer did find a similar pattern of risk (though non-significant) associated with variant genotypes of rs2274223, rs11599672 and combined risk alleles among smokers but not among never smokers (data not shown).	('rs2274223', 'Mutation', 'rs2274223', (163, 172))	('rs2274223', 'Var', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('rs11599672', 'Var', (174, 184))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('rs11599672', 'Mutation', 'rs11599672', (174, 184))
26646	21689432	The findings from GWASs and our study implied that polymorphisms of PLCE1 are likely to be associated with the development of human cancers related to tobacco and alcohol exposure, which will need the validation from large studies on different cancers.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('human', 'Species', '9606', (126, 131))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tobacco', 'Species', '4097', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PLCE1', 'Gene', (68, 73))	('polymorphisms', 'Var', (51, 64))	('PLCE1', 'Gene', '51196', (68, 73))	('cancers', 'Disease', (244, 251))	('associated with', 'Reg', (91, 106))	('alcohol', 'Chemical', 'MESH:D000438', (163, 170))
26647	21689432	Further, compared to the most common T rs11599672A rs2274223A rs3203713 haplotype, both Trs11599672G rs2274223A rs3203713 and G rs11599672A rs2274223A rs3203713 haplotypes had a significant association with risk of SCCHN arising at non-oropharyngeal sites, which further reflected the main effect of rs2274223 G and rs11599672 G alleles on risk of SCCHN arising at non-oropharyngeal sites.	('rs2274223 G', 'Var', (300, 311))	('rs2274223', 'Mutation', 'rs2274223', (300, 309))	('association', 'Reg', (190, 201))	('rs11599672', 'Mutation', 'rs11599672', (316, 326))	('rs3203713', 'Mutation', 'rs3203713', (112, 121))	('rs2274223', 'Mutation', 'rs2274223', (101, 110))	('rs11599672', 'Mutation', 'rs11599672', (128, 138))	('rs11599672', 'Mutation', 'rs11599672', (39, 49))	('rs2274223', 'Mutation', 'rs2274223', (140, 149))	('rs3203713', 'Var', (112, 121))	('rs3203713', 'Mutation', 'rs3203713', (62, 71))	('rs11599672', 'Mutation', 'rs11599672', (89, 99))	('rs3203713', 'Mutation', 'rs3203713', (151, 160))	('rs11599672 G', 'Var', (316, 328))	('SCCHN', 'Disease', (215, 220))	('rs2274223A rs3203713', 'Var', (140, 160))	('Trs11599672G rs2274223A rs3203713', 'Var', (88, 121))	('rs2274223', 'Mutation', 'rs2274223', (51, 60))
26648	21689432	We also found that the effects of rs2274223 and rs11599672 on risk of SCCHN arising at non-oropharyngeal sites were segregated between the subgroups by smoking or drinking status, indicating the possibility of gene-environment interactions.	('SCCHN arising', 'Disease', (70, 83))	('rs2274223', 'Mutation', 'rs2274223', (34, 43))	('rs2274223', 'Var', (34, 43))	('rs11599672', 'Var', (48, 58))	('rs11599672', 'Mutation', 'rs11599672', (48, 58))
26649	21689432	Indeed, we detected a significant interaction between variant genotypes of rs2274223 and alcohol status with a relatively small sample size, supporting the role of a gene-environment interaction in the development of SCCHN.	('rs2274223', 'Mutation', 'rs2274223', (75, 84))	('alcohol', 'Chemical', 'MESH:D000438', (89, 96))	('rs2274223', 'Var', (75, 84))	('SCCHN', 'Disease', (217, 222))
26650	21689432	It has been identified that rs2274223 is a non-synonymous SNP of PLCE1, and bioinformatics tools show that rs3203713 in PLCE1 is located in the 3'UTR (http://snpinfo.niehs.nih.gov/snpfunc.htm), which may affect the binding of miRNA and target gene PLCE1.	('affect', 'Reg', (204, 210))	('PLCE1', 'Gene', (120, 125))	('PLCE1', 'Gene', '51196', (120, 125))	('rs2274223', 'Mutation', 'rs2274223', (28, 37))	('miRNA', 'Protein', (226, 231))	('rs3203713', 'Mutation', 'rs3203713', (107, 116))	('PLCE1', 'Gene', (65, 70))	('rs2274223', 'Var', (28, 37))	('PLCE1', 'Gene', '51196', (65, 70))	('binding', 'Interaction', (215, 222))	('PLCE1', 'Gene', (248, 253))	('PLCE1', 'Gene', '51196', (248, 253))
26651	21689432	Further, rs11599672 is located in the transcription factor binding site (TFBS) of PLCE1 (http://snpinfo.niehs.nih.gov/snpfunc.htm) and may result in the variation of transcription activity and expression of PLCE1.	('result in', 'Reg', (139, 148))	('rs11599672', 'Var', (9, 19))	('PLCE1', 'Gene', (207, 212))	('PLCE1', 'Gene', (82, 87))	('rs11599672', 'Mutation', 'rs11599672', (9, 19))	('PLCE1', 'Gene', '51196', (207, 212))	('PLCE1', 'Gene', '51196', (82, 87))	('variation', 'Reg', (153, 162))	('expression', 'MPA', (193, 203))	('transcription activity', 'MPA', (166, 188))
26652	21689432	Considering the potentially functional significance of these SNPs, it is biologically plausible that PLCE1 polymorphisms may contribute to the development of SCCHN.	('PLCE1', 'Gene', (101, 106))	('SCCHN', 'Disease', (158, 163))	('PLCE1', 'Gene', '51196', (101, 106))	('polymorphisms', 'Var', (107, 120))	('contribute', 'Reg', (125, 135))
26654	21689432	However, the agreement of observed genotype distributions with Hardy-Weinberg equilibrium and similar allele frequencies of our controls with those reported in CEU populations from the dbSNP database (0.320 vs. 0.314 for rs2274223 G allele, 0.162 vs. 0.120 for rs3203713 G allele, and 0.297 vs. 0.347 for rs11599672, respectively) suggested that selection bias in terms of genotype distribution would not be substantial, if any.	('rs3203713 G', 'Var', (261, 272))	('rs2274223 G', 'Var', (221, 232))	('rs11599672', 'Var', (305, 315))	('rs11599672', 'Mutation', 'rs11599672', (305, 315))	('rs3203713', 'Mutation', 'rs3203713', (261, 270))	('rs2274223', 'Mutation', 'rs2274223', (221, 230))
26656	21689432	Actually, only P values for the effect of rs11599672 variant genotypes on tumors arising at non-oropharyngeal sites and the association of rs2274223 variant genotypes with drinking for non-oropharyngeal SCCHN risk remained significant after Bonferroni corrections.	('rs2274223', 'Mutation', 'rs2274223', (139, 148))	('rs2274223', 'Var', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('rs11599672', 'Var', (42, 52))	('rs11599672', 'Mutation', 'rs11599672', (42, 52))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
26658	21689432	Furthermore, those results from subgroup analysis suggest that variant genotypes of rs2274223 and rs11599672 may independently affect the risk of SCCHN arising at non-oropharyngeal sites.	('SCCHN arising', 'Disease', (146, 159))	('rs2274223', 'Mutation', 'rs2274223', (84, 93))	('rs2274223', 'Var', (84, 93))	('rs11599672', 'Var', (98, 108))	('rs11599672', 'Mutation', 'rs11599672', (98, 108))	('affect', 'Reg', (127, 133))
26661	21689432	This work was supported by National Institute of Health grants R01 CA131274 and R01 ES011740 (Q. Wei), P50 CA097007 (Scott Lippman), and P30 CA016672 (The University of Texas M. D. Anderson Cancer Center).	('P30 CA016672', 'Var', (137, 149))	('Cancer', 'Phenotype', 'HP:0002664', (190, 196))	('R01 ES011740', 'Var', (80, 92))	('P50 CA097007', 'Var', (103, 115))	('Cancer', 'Disease', (190, 196))	('Cancer', 'Disease', 'MESH:D009369', (190, 196))
26676	32886924	Male sex, alcohol consumption, smoking, multiple Lugol-voiding lesions (LVLs), and single nucleotide polymorphisms in aldehyde dehydrogenase-2 and alcohol dehydrogenase 1B were associated with metachronous recurrence.	('aldehyde dehydrogenase-2', 'Gene', (118, 142))	('alcohol dehydrogenase', 'Gene', (147, 168))	('single nucleotide polymorphisms', 'Var', (83, 114))	('alcohol', 'Chemical', 'MESH:D000438', (147, 154))	('Lugol', 'Chemical', 'MESH:C010389', (49, 54))	('alcohol', 'Chemical', 'MESH:D000438', (10, 17))	('associated', 'Reg', (177, 187))	('metachronous recurrence', 'CPA', (193, 216))
26706	32886924	There are several independent risk factors associated with recurrence, including male sex, low BMI, alcohol consumption, smoking, multiple LVLs, single nucleotide polymorphisms in aldehyde dehydrogenase-2 and alcohol dehydrogenase 1B, and treatment history of (sub)circumferential ESD.	('SD', 'Disease', 'MESH:D029461', (282, 284))	('low BMI', 'Phenotype', 'HP:0045082', (91, 98))	('alcohol', 'Chemical', 'MESH:D000438', (209, 216))	('single nucleotide polymorphisms', 'Var', (145, 176))	('aldehyde', 'Gene', (180, 188))	('alcohol', 'Chemical', 'MESH:D000438', (100, 107))
26725	32266022	The results of the present study revealed that MIAT knockdown decreased cell viability, migration, invasion and cell cycle arrest in the G1 phase.	('arrest', 'Disease', (123, 129))	('decreased', 'NegReg', (62, 71))	('cell viability', 'CPA', (72, 86))	('MIAT', 'Gene', (47, 51))	('migration', 'CPA', (88, 97))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (112, 129))	('invasion', 'CPA', (99, 107))	('arrest', 'Disease', 'MESH:D006323', (123, 129))	('knockdown', 'Var', (52, 61))
26727	32266022	MIAT knockdown suppressed cell invasion and migration by regulation MMP-2/9 protein expressions.	('knockdown', 'Var', (5, 14))	('MMP-2/9', 'Gene', '4313;4318', (68, 75))	('MIAT', 'Gene', (0, 4))	('suppressed', 'NegReg', (15, 25))	('cell invasion', 'CPA', (26, 39))	('regulation', 'Reg', (57, 67))	('MMP-2/9', 'Gene', (68, 75))
26738	32266022	A previous study reported that when the lncRNA myocardial infarction-associated transcript (MIAT) is knocked-out in mice, they do not exhibit any significant abnormality with cancer development, but are increasingly hyperactive.	('mice', 'Species', '10090', (116, 120))	('abnormality', 'Disease', 'MESH:D018376', (158, 169))	('hyperactive', 'PosReg', (216, 227))	('MIAT', 'Gene', (92, 96))	('myocardial infarction', 'Phenotype', 'HP:0001658', (47, 68))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('knocked-out', 'Var', (101, 112))	('abnormality', 'Disease', (158, 169))	('myocardial infarction', 'Disease', (47, 68))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('myocardial infarction', 'Disease', 'MESH:D009203', (47, 68))
26777	32266022	To determine whether MIAT causes cell cycle arrest, the cell cycle was analyzed via flow cytometry.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (33, 50))	('arrest', 'Disease', 'MESH:D006323', (44, 50))	('cell cycle', 'CPA', (33, 43))	('MIAT', 'Var', (21, 25))	('arrest', 'Disease', (44, 50))
26778	32266022	The results revealed that 25 and 50 nM siMIAT transfection significantly and dose-dependently increased Kyse 150 and Eca 109 cell G1 phase compared with NC cells (Fig.	('nM siMIAT', 'Disease', (36, 45))	('Kyse 150', 'CPA', (104, 112))	('increased', 'PosReg', (94, 103))	('Kyse', 'Chemical', '-', (104, 108))	('Eca 109 cell G1 phase', 'CPA', (117, 138))	('transfection', 'Var', (46, 58))	('nM siMIAT', 'Disease', 'None', (36, 45))
26787	32266022	For example, HOX Transcript Antisense RNA is highly expressed in breast, gastric and liver cancer, and increases the proliferation and invasion of tumor cells.	('Antisense RNA', 'Var', (28, 41))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('increases', 'PosReg', (103, 112))	('proliferation', 'CPA', (117, 130))	('liver cancer', 'Disease', 'MESH:D006528', (85, 97))	('breast', 'Disease', (65, 71))	('liver cancer', 'Disease', (85, 97))	('gastric', 'Disease', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('liver cancer', 'Phenotype', 'HP:0002896', (85, 97))
26790	32266022	The results of the current study revealed that the viability, migration and invasion of two ESCC cell lines (Kyse 150 and Eca 109 cells) were significantly and dose-dependently suppressed following treatment with a si-MIAT.	('suppressed', 'NegReg', (177, 187))	('migration', 'CPA', (62, 71))	('viability', 'CPA', (51, 60))	('si-MIAT', 'Var', (215, 222))	('invasion', 'CPA', (76, 84))	('Kyse', 'Chemical', '-', (109, 113))
26798	32266022	The underlying mechanism of MIAT attenuating esophageal cancer invasion and migration might be correlated with a reduction in MMP-2 and MMP-9 protein expression.	('esophageal cancer', 'Disease', (45, 62))	('MMP-2', 'Gene', (126, 131))	('migration', 'CPA', (76, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('attenuating', 'NegReg', (33, 44))	('protein', 'Protein', (142, 149))	('MMP-2', 'Gene', '4313', (126, 131))	('reduction', 'NegReg', (113, 122))	('MMP-9', 'Gene', '4318', (136, 141))	('MIAT', 'Var', (28, 32))	('MMP-9', 'Gene', (136, 141))
26802	32266022	MIAT knockdown might suppress esophageal cancer cell proliferation by keeping the cell cycle in G1 phase.	('cell cycle', 'CPA', (82, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('knockdown', 'Var', (5, 14))	('G1 phase', 'CPA', (96, 104))	('MIAT', 'Gene', (0, 4))	('suppress', 'NegReg', (21, 29))	('esophageal cancer', 'Disease', (30, 47))
26803	32266022	In conclusion, MIAT knockdown suppresses esophageal cancer cell viability by enhancing the invasion, migration and G1 phase of the cell cycle in vitro and in future esophageal cancer treatment, MIAT might be used as a potential target gene.	('esophageal cancer', 'Disease', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('invasion', 'CPA', (91, 99))	('migration', 'CPA', (101, 110))	('suppresses', 'NegReg', (30, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('MIAT', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('G1 phase of the cell cycle', 'CPA', (115, 141))	('knockdown', 'Var', (20, 29))	('enhancing', 'PosReg', (77, 86))	('esophageal cancer', 'Disease', (41, 58))
26813	32216815	Overexpression of LTBP1 was positively associated with lymphatic metastasis in ESCC (p = 0.002).	('lymphatic metastasis', 'CPA', (55, 75))	('ESCC', 'Disease', (79, 83))	('associated', 'Reg', (39, 49))	('Overexpression', 'Var', (0, 14))	('LTBP1', 'Gene', (18, 23))	('LTBP1', 'Gene', '4052', (18, 23))
26817	32216815	Inhibition of LTBP1 expression could also attenuate induction of CAFs transformation and restrain fibroblast express fibronectin (FN1) in ESCC cells.	('CAFs transformation', 'CPA', (65, 84))	('FN1', 'Gene', '2335', (130, 133))	('fibronectin', 'Gene', (117, 128))	('attenuate', 'NegReg', (42, 51))	('FN1', 'Gene', (130, 133))	('fibronectin', 'Gene', '2335', (117, 128))	('LTBP1', 'Gene', (14, 19))	('LTBP1', 'Gene', '4052', (14, 19))	('Inhibition', 'Var', (0, 10))	('restrain', 'NegReg', (89, 97))
26818	32216815	Overexpression of LTBP1 was associated with lymph node metastasis in ESCC.	('associated', 'Reg', (28, 38))	('lymph node metastasis', 'CPA', (44, 65))	('Overexpression', 'Var', (0, 14))	('LTBP1', 'Gene', (18, 23))	('ESCC', 'Disease', (69, 73))	('LTBP1', 'Gene', '4052', (18, 23))
26832	32216815	LTBP1 elimination seems to attenuate fibrogenesis in hepatic stellate cells.	('fibrogenesis in', 'CPA', (37, 52))	('elimination', 'Var', (6, 17))	('LTBP1', 'Gene', '4052', (0, 5))	('attenuate', 'NegReg', (27, 36))	('LTBP1', 'Gene', (0, 5))
26839	32216815	Silence of LTBP1 reduces TGF-beta activity and Smad2 phosphorylation without affecting TGF-beta protein levels in malignant glioma cells.	('malignant glioma', 'Disease', (114, 130))	('reduces', 'NegReg', (17, 24))	('malignant glioma', 'Disease', 'MESH:D005910', (114, 130))	('TGF-beta', 'Gene', (87, 95))	('Smad2', 'Gene', '4087', (47, 52))	('TGF-beta', 'Gene', '7039', (25, 33))	('Smad2', 'Gene', (47, 52))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('LTBP1', 'Gene', '4052', (11, 16))	('TGF-beta', 'Gene', '7039', (87, 95))	('LTBP1', 'Gene', (11, 16))	('phosphorylation', 'MPA', (53, 68))	('Silence', 'Var', (0, 7))	('TGF-beta', 'Gene', (25, 33))
26840	32216815	Elevation of LTBP1 appears to play a role in enhancing metastatic behavior in breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('metastatic behavior', 'CPA', (55, 74))	('Elevation', 'Var', (0, 9))	('LTBP1', 'Gene', (13, 18))	('LTBP1', 'Gene', '4052', (13, 18))	('enhancing', 'PosReg', (45, 54))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
26847	32216815	The cell lines HET-1A, ECA109, KYSE510, HF and HUVEC were donated by the Central Laboratory of Southern Medical University Affiliated Nanfang Hospital and grown in high glucose Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum (FBS) (both from Gibco), augmented with 1% penicillin and streptomycin.	('DMEM', 'Chemical', '-', (213, 217))	('FBS', 'Disease', (248, 251))	('penicillin', 'Chemical', 'MESH:D010406', (290, 300))	('high glucose', 'Phenotype', 'HP:0003074', (164, 176))	('glucose', 'Chemical', 'MESH:D005947', (169, 176))	('bovine', 'Species', '9913', (234, 240))	('KYSE510', 'Var', (31, 38))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (177, 211))	('HE', 'Chemical', 'MESH:D006371', (15, 17))	('HF', 'CellLine', 'CVCL:M656;0.009775922406973392', (40, 42))	('FBS', 'Disease', 'MESH:D005198', (248, 251))	('streptomycin', 'Chemical', 'MESH:D013307', (305, 317))
26853	32216815	Cells were incubated in primary antibodies alpha-SMA (1:100, #14395; Proteintech) and FN1 (1:100, #66042; Proteintech).	('alpha-SMA', 'Gene', '58', (43, 52))	('alpha-SMA', 'Gene', (43, 52))	('FN1', 'Gene', '2335', (86, 89))	('1:100', 'Var', (91, 96))	('FN1', 'Gene', (86, 89))
26891	32216815	3d, e), suggesting that LTBP1 knockdown attenuated the migration and invasion of ESCC cells.	('LTBP1', 'Gene', '4052', (24, 29))	('attenuated', 'NegReg', (40, 50))	('knockdown', 'Var', (30, 39))	('LTBP1', 'Gene', (24, 29))
26893	32216815	The number of lung pulmonary metastatic foci was 15 +- 2.65 and 5.67 +- 1.53 in the control and shLTBP1 groups respectively (*p < 0.05, one-way ANOVA), indicating that LTBP1 knockdown reduced the metastasis capacity of ESCC cells in vivo (Fig.	('lung pulmonary metastatic foci', 'Disease', (14, 44))	('LTBP1', 'Gene', (98, 103))	('LTBP1', 'Gene', '4052', (98, 103))	('lung pulmonary metastatic foci', 'Disease', 'MESH:C538445', (14, 44))	('LTBP1', 'Gene', '4052', (168, 173))	('reduced', 'NegReg', (184, 191))	('knockdown', 'Var', (174, 183))	('LTBP1', 'Gene', (168, 173))	('metastasis capacity', 'CPA', (196, 215))
26900	32216815	Thus, inhibition of LTBP1 may be a potential pathway to suppress EMT of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('suppress', 'NegReg', (56, 64))	('tumor', 'Disease', (72, 77))	('LTBP1', 'Gene', (20, 25))	('LTBP1', 'Gene', '4052', (20, 25))	('inhibition', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
26902	32216815	Compared with the control group, knockdown of LTBP1 increased inhibition rate induced by 5-Fu (Fig.	('increased', 'PosReg', (52, 61))	('LTBP1', 'Gene', '4052', (46, 51))	('5-Fu', 'Chemical', 'MESH:D005472', (89, 93))	('knockdown', 'Var', (33, 42))	('LTBP1', 'Gene', (46, 51))	('inhibition rate', 'MPA', (62, 77))
26913	32216815	SiLTBP1 could reduce alpha-SMA and FN1 expression in fibroblasts, suggesting that down-regulation of LTBP1 may suppress CAFs transformation.	('LTBP1', 'Gene', (2, 7))	('suppress', 'NegReg', (111, 119))	('LTBP1', 'Gene', '4052', (2, 7))	('FN1', 'Gene', '2335', (35, 38))	('FN1', 'Gene', (35, 38))	('CAFs', 'Disease', (120, 124))	('alpha-SMA', 'Gene', '58', (21, 30))	('expression', 'MPA', (39, 49))	('alpha-SMA', 'Gene', (21, 30))	('reduce', 'NegReg', (14, 20))	('LTBP1', 'Gene', (101, 106))	('LTBP1', 'Gene', '4052', (101, 106))	('down-regulation', 'Var', (82, 97))
26927	32216815	Moreover, we found that high LTBP1 expression was statistically associated with lymph node metastasis in ESCC.	('associated with', 'Reg', (64, 79))	('LTBP1', 'Gene', (29, 34))	('ESCC', 'Disease', (105, 109))	('LTBP1', 'Gene', '4052', (29, 34))	('lymph node metastasis', 'CPA', (80, 101))	('expression', 'MPA', (35, 45))	('high', 'Var', (24, 28))
26928	32216815	The above findings are consistent with the researches of LTBP1 in breast cancer, which also illustrated a positive relationship between high LTBP1 expression and metastasis.	('metastasis', 'CPA', (162, 172))	('LTBP1', 'Gene', (57, 62))	('high', 'Var', (136, 140))	('positive', 'PosReg', (106, 114))	('expression', 'MPA', (147, 157))	('LTBP1', 'Gene', '4052', (141, 146))	('LTBP1', 'Gene', '4052', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('LTBP1', 'Gene', (141, 146))
26929	32216815	In another study, silencing of LTBP1 expression increases cell proliferation in malignant glioma.	('LTBP1', 'Gene', '4052', (31, 36))	('silencing', 'Var', (18, 27))	('malignant glioma', 'Disease', (80, 96))	('increases', 'PosReg', (48, 57))	('malignant glioma', 'Disease', 'MESH:D005910', (80, 96))	('cell proliferation', 'CPA', (58, 76))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('LTBP1', 'Gene', (31, 36))
26944	32216815	In this study, we also found that knockdown of LTBP1 also promoted 5-FU-induced apoptosis of ECSS cells, along with the alterations of apoptotic markers, such as the decreased level of BCL-2 and increased level of BAX protein.	('BAX', 'Gene', (214, 217))	('BCL-2', 'Gene', '596', (185, 190))	('BAX', 'Gene', '581', (214, 217))	('LTBP1', 'Gene', '4052', (47, 52))	('BCL-2', 'Gene', (185, 190))	('LTBP1', 'Gene', (47, 52))	('decreased', 'NegReg', (166, 175))	('5-FU-induced', 'MPA', (67, 79))	('promoted', 'PosReg', (58, 66))	('knockdown', 'Var', (34, 43))	('increased', 'PosReg', (195, 204))	('apoptosis', 'CPA', (80, 89))	('5-FU', 'Chemical', 'MESH:D005472', (67, 71))
26955	32216815	In our study, we found that silencing LTBP1 in ESCC cells could inhibit CAFs transformation and activity.And silencing LTBP1 in ESCC cells which were co-cultured with fibroblasts can decrease FN1 in fibroblasts.	('FN1', 'Gene', '2335', (192, 195))	('FN1', 'Gene', (192, 195))	('LTBP1', 'Gene', '4052', (119, 124))	('LTBP1', 'Gene', (38, 43))	('LTBP1', 'Gene', (119, 124))	('LTBP1', 'Gene', '4052', (38, 43))	('silencing', 'Var', (109, 118))	('decrease', 'NegReg', (183, 191))
26963	32216815	Overexpression of LTBP1 was positively associated with lymphatic metastasis in ESCC.	('lymphatic metastasis', 'CPA', (55, 75))	('ESCC', 'Disease', (79, 83))	('associated', 'Reg', (39, 49))	('Overexpression', 'Var', (0, 14))	('LTBP1', 'Gene', (18, 23))	('LTBP1', 'Gene', '4052', (18, 23))
26964	32216815	Inhibition of LTBP1 decreased ESCC cells invasion and migration capacities and induced EMT changes.	('ESCC cells invasion', 'CPA', (30, 49))	('EMT changes', 'CPA', (87, 98))	('decreased', 'NegReg', (20, 29))	('LTBP1', 'Gene', (14, 19))	('LTBP1', 'Gene', '4052', (14, 19))	('Inhibition', 'Var', (0, 10))	('induced', 'Reg', (79, 86))	('decreased ESCC', 'Phenotype', 'HP:0025022', (20, 34))
26967	32216815	In general, our study suggested that LTBP1 may be a molecular biomarker of ESCC progression and inhibition of LTBP1 may supply a potential therapy for ESCC.	('LTBP1', 'Gene', (37, 42))	('LTBP1', 'Gene', '4052', (37, 42))	('LTBP1', 'Gene', '4052', (110, 115))	('ESCC', 'Disease', (75, 79))	('ESCC', 'Disease', (151, 155))	('inhibition', 'Var', (96, 106))	('LTBP1', 'Gene', (110, 115))
27015	30808336	In the meta-analysis based on ethnicity, GDF-15 testing in Caucasian and Asian patients yielded an AUC of 0.83, whereas the Asian-based test conferred a higher specificity of 0.81 (95% CI: 0.79-0.83).	('GDF-15', 'Gene', (41, 47))	('testing', 'Var', (48, 55))	('GDF-15', 'Gene', '9518', (41, 47))	('AUC', 'MPA', (99, 102))	('patients', 'Species', '9606', (79, 87))
27097	29046776	In addition, the presence of a PPC resulted in a prolonged postprocedural hospital stay (4.9 +- 3.5 and 3.2 +- 0.7 days for patients with and without PPCs, respectively; P = 0.026) (Table 4).	('PPC', 'Gene', (31, 34))	('patients', 'Species', '9606', (124, 132))	('presence', 'Var', (17, 25))
27107	29046776	CO2 insufflation during endoscopic esophageal procedures is known to reduce the risk of severe perforation-related PPCs.	('CO2', 'Chemical', 'MESH:D002245', (0, 3))	('reduce', 'NegReg', (69, 75))	('insufflation', 'Disease', (4, 16))	('CO2', 'Var', (0, 3))	('insufflation', 'Disease', 'None', (4, 16))
27133	26636574	The median PFS and 3-year PFS rate in the ENI group were 13 months and 20.6%, compared to 11 months and 21.0% in the IFI groups (p = 0.61).	('PFS', 'CPA', (26, 29))	('PFS', 'CPA', (11, 14))	('ENI', 'Chemical', '-', (42, 45))	('ENI', 'Var', (42, 45))
27135	26636574	The rate of grade >= 3 acute irradiation esophagitis in the ENI group was significantly higher than that in the IFI group (18.5% vs. 6.0%; p = 0.027).	('higher', 'PosReg', (88, 94))	('esophagitis', 'Phenotype', 'HP:0100633', (41, 52))	('irradiation esophagitis', 'Disease', 'MESH:D004941', (29, 52))	('irradiation esophagitis', 'Disease', (29, 52))	('ENI', 'Chemical', '-', (60, 63))	('ENI', 'Var', (60, 63))
27199	26636574	The rate of grade >= 3 acute RE in the ENI group (10/54, 18.5%) was significantly higher than that in the IFI group (5/83, 6.0%), with a p value of 0.027.	('ENI', 'Var', (39, 42))	('acute RE', 'CPA', (23, 31))	('higher', 'PosReg', (82, 88))	('ENI', 'Chemical', '-', (39, 42))
27200	26636574	The incidence of grade >= 3 acute irradiation pneumonitis (RP) was 7.4% in the ENI group (4/54) and 12.0% in the IFI group (10/83), but the difference was not significant (p = 0.40).	('pneumonitis', 'Disease', (46, 57))	('ENI', 'Var', (79, 82))	('ENI', 'Chemical', '-', (79, 82))	('pneumonitis', 'Disease', 'MESH:D011014', (46, 57))
27203	26636574	There have been reports in the literature that IFI can provide similar OS and LRC with a smaller volume and lower toxicities when compared with ENI.	('IFI', 'Var', (47, 50))	('ENI', 'Chemical', '-', (144, 147))	('toxicities', 'Disease', (114, 124))	('OS', 'Chemical', '-', (71, 73))	('toxicities', 'Disease', 'MESH:D064420', (114, 124))	('LRC', 'MPA', (78, 81))
27221	26636574	Another study has reported that the 3-year OS rate with IFI was even higher than that obtained with ENI (49%, IFI vs. 47%, ENI; p = 0.741).	('ENI', 'Chemical', '-', (100, 103))	('IFI', 'Var', (56, 59))	('OS', 'Chemical', '-', (43, 45))	('higher', 'PosReg', (69, 75))	('ENI', 'Chemical', '-', (123, 126))
27236	26636574	One is a Japanese study including 22 elderly patients who were treated with concurrent chemotherapy consisting of local-field irradiation or prophylactic nodal irradiation; the results indicated that grade >= 2 hematological toxicities were less frequent in local-field patients than in the remaining patients (30% vs. 92%, p = 0.006).	('patients', 'Species', '9606', (270, 278))	('patients', 'Species', '9606', (301, 309))	('hematological toxicities', 'Disease', (211, 235))	('patients', 'Species', '9606', (45, 53))	('hematological toxicities', 'Disease', 'MESH:D006402', (211, 235))	('local-field', 'Var', (258, 269))	('less', 'NegReg', (241, 245))
27239	26636574	In our study, only 6% of patients in the IFI group experienced grade >= 3 acute esophagitis compared to 18.5% in the ENI group (p = 0.027).	('IFI', 'Var', (41, 44))	('ENI', 'Chemical', '-', (117, 120))	('esophagitis', 'Phenotype', 'HP:0100633', (80, 91))	('esophagitis', 'Disease', (80, 91))	('esophagitis', 'Disease', 'MESH:D004941', (80, 91))	('patients', 'Species', '9606', (25, 33))
27247	26636574	According to analysis of the DVH, we found that the proportion of patients with a V20 > 28% in the ENI group was similar to that in the IFI group (5.6% vs. 4.8%).	('V20', 'Var', (82, 85))	('ENI', 'Chemical', '-', (99, 102))	('patients', 'Species', '9606', (66, 74))	('ENI', 'Var', (99, 102))
27295	25110711	Expression levels were measured for the following gene: KCC3 (Hs00994548_m1) (Applied Biosystems).	('KCC3', 'Gene', (56, 60))	('Expression levels', 'MPA', (0, 17))	('KCC3', 'Gene', '9990', (56, 60))	('Hs00994548_m1', 'Var', (62, 75))
27307	25110711	Figures 1(c) and 1(d) show the representative histopathological findings of low or high KCC3 expression samples.	('KCC3', 'Gene', (88, 92))	('low', 'Var', (76, 79))	('KCC3', 'Gene', '9990', (88, 92))
27325	25110711	Regarding comparisons of KCC3 score, the 5-year survival rate of the patients with CN > MT (55.5%) was lower than that of patients with CN <= MT (76.7%) (P = 0.133) (Figure 3(c)).	('lower', 'NegReg', (103, 108))	('KCC3', 'Gene', (25, 29))	('CN > MT', 'Var', (83, 90))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (69, 77))	('KCC3', 'Gene', '9990', (25, 29))
27326	25110711	The 5-year survival rate of the patients with KCC3 expression in the invasive front (57.1%) was lower than that of the patients without it (81.8%), although there was no statistical difference (P = 0.089) (Figure 3(d)).	('KCC3', 'Gene', (46, 50))	('patients', 'Species', '9606', (32, 40))	('lower', 'NegReg', (96, 101))	('patients', 'Species', '9606', (119, 127))	('KCC3', 'Gene', '9990', (46, 50))	('expression', 'Var', (51, 61))
27327	25110711	Interestingly, when patients were divided into 2 groups, CN > MT and invasive front positive, n = 31, and others, n = 39, the 5-year survival rate of patients with CN > MT and invasive front positive (46.1%) was significantly lower than that of other patients (79.0%) (P = 0.022) (Figure 3(e)).	('survival', 'CPA', (133, 141))	('lower', 'NegReg', (226, 231))	('CN > MT', 'Var', (164, 171))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (251, 259))	('patients', 'Species', '9606', (20, 28))
27349	25110711	Furthermore, both the progression-free and overall survival rates of patients with the high grade expression of KCC4 were significantly poorer than those of patients with the low grade expression of KCC4 in cervical cancer, which suggested a relationship between the expression pattern of KCC and clinical outcome.	('cervical cancer', 'Disease', 'MESH:D002583', (207, 222))	('poorer', 'NegReg', (136, 142))	('progression-free', 'CPA', (22, 38))	('KCC4', 'Gene', (199, 203))	('cervical cancer', 'Disease', (207, 222))	('expression', 'Var', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('high grade expression', 'Var', (87, 108))	('patients', 'Species', '9606', (157, 165))	('KCC4', 'Gene', (112, 116))	('KCC4', 'Gene', '10723', (112, 116))	('patients', 'Species', '9606', (69, 77))	('overall survival rates', 'CPA', (43, 65))	('KCC4', 'Gene', '10723', (199, 203))
27351	25110711	Although the expression of KCC3 in CN itself had no prognostic impact, the 5-year survival rate of patients with a CN > MT score was slightly lower than that of patients with a CN <= MT score.	('CN >', 'Var', (115, 119))	('KCC3', 'Gene', '9990', (27, 31))	('lower', 'NegReg', (142, 147))	('KCC3', 'Gene', (27, 31))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (161, 169))
27362	25110711	showed that an alteration in the [Cl-]i concentration affected the activity of the retinoblastoma protein and cdc2 kinase, two key cell-cycle regulators that control progression from the G1 into the S phase and from the G2 into the M phase, respectively.	('retinoblastoma', 'Disease', (83, 97))	('affected', 'Reg', (54, 62))	('cdc2 kinase', 'Enzyme', (110, 121))	('retinoblastoma', 'Phenotype', 'HP:0009919', (83, 97))	('activity', 'MPA', (67, 75))	('alteration', 'Var', (15, 25))	('retinoblastoma', 'Disease', 'MESH:D012175', (83, 97))
27363	25110711	We considered KCC to be one of the important transporters that regulates [Cl-]i in the steady state and previously showed that the blockage of KCC decreased [Cl-]i in breast cancer cells.	('breast cancer', 'Disease', (167, 180))	('blockage', 'Var', (131, 139))	('[Cl-]i', 'MPA', (73, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('decreased', 'NegReg', (147, 156))	('KCC', 'Gene', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('[Cl-]i', 'MPA', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
27373	33362844	TranswellTM assays were employed to examine the migration ability of cells after knockdown of LINC01614 expression, followed by investigation of epithelial-mesenchymal transition (EMT) by western blotting (WB).	('si', 'Chemical', 'MESH:D012825', (110, 112))	('knockdown', 'Var', (81, 90))	('migration ability', 'CPA', (48, 65))	('LINC01614', 'Gene', '105373869', (94, 103))	('si', 'Chemical', 'MESH:D012825', (172, 174))	('LINC01614', 'Gene', (94, 103))
27376	33362844	In vitro experiments show that knockdown of LINC01614 expression could significantly inhibit the migration of ESCC cells by regulating EMT, which was confirmed by WB.	('LINC01614', 'Gene', '105373869', (44, 53))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('LINC01614', 'Gene', (44, 53))	('inhibit', 'NegReg', (85, 92))	('migration of ESCC cells', 'CPA', (97, 120))	('EMT', 'CPA', (135, 138))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('regulating', 'Reg', (124, 134))	('knockdown', 'Var', (31, 40))
27388	33362844	A microarray data set for ESCC (GSE53625) and TCGA data set for head and neck squamous cell carcinoma (HNSCC) (TCGA_HNSCC) were used to explore the prognostic value of these "hub" genes in discovery data sets.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('hub', 'Gene', '1993', (175, 178))	('neck squamous cell carcinoma', 'Disease', (73, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (64, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (116, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (73, 101))	('hub', 'Gene', (175, 178))	('GSE53625', 'Var', (32, 40))
27440	33362844	The best cutoff value for BGN and SPP1 in GSE53625 was 14.8 and 15.9 RPKM, respectively.	('BGN', 'Gene', '633', (26, 29))	('SPP1', 'Gene', '6696', (34, 38))	('BGN', 'Gene', (26, 29))	('SPP1', 'Gene', (34, 38))	('GSE53625', 'Var', (42, 50))
27447	33362844	First, we screened LINC01614 expression in five ESCC cell lines (KYSE150, KYSE410, KYSE30, Eca109, and TE-1) using RT-qPCR (Figure 7A).	('si', 'Chemical', 'MESH:D012825', (110, 112))	('LINC01614', 'Gene', (19, 28))	('KYSE410', 'Var', (74, 81))	('KYSE30', 'Var', (83, 89))	('LINC01614', 'Gene', '105373869', (19, 28))	('si', 'Chemical', 'MESH:D012825', (35, 37))
27452	33362844	The results of the Transwell assay showed that the migration rate of LINC01614 knockdown cells was less than that of control cells (P < 0.001, Figures 7D,E).	('LINC01614', 'Gene', '105373869', (69, 78))	('less', 'NegReg', (99, 103))	('knockdown', 'Var', (79, 88))	('LINC01614', 'Gene', (69, 78))	('migration rate', 'CPA', (51, 65))
27454	33362844	We also explored the role of LINC01415 in ESCC: knockdown of LINC01415 expression reduced the migration of ESCC cells without affecting EMT-related markers (Supplementary Figure 3).	('LINC01415', 'Gene', (61, 70))	('LINC01415', 'Gene', '100132501', (61, 70))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('migration', 'CPA', (94, 103))	('LINC01415', 'Gene', '100132501', (29, 38))	('reduced', 'NegReg', (82, 89))	('LINC01415', 'Gene', (29, 38))	('ESCC', 'Disease', (107, 111))	('knockdown', 'Var', (48, 57))
27468	33362844	According to previous studies, ESCC and HNSCC can be considered almost a single disease entity with similar molecular characteristics according to multiplatform data, including data on somatic copy number alterations, DNA methylation, and transcription.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('HNSCC', 'Disease', (40, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('ESCC', 'Disease', (31, 35))	('copy number alterations', 'Var', (193, 216))	('si', 'Chemical', 'MESH:D012825', (100, 102))
27495	32195175	Helicobacter pylori Is Associated With Precancerous and Cancerous Lesions of the Gastric Cardia Mucosa: Results of a Large Population-Based Study in China Background: Helicobacter pylori (H. pylori) is widely accepted to be the most important cause of gastric non-cardia adenocarcinoma (GNCA), while its role in the development of gastric cardia adenocarcinoma (GCA) is not well-defined.	('GNCA', 'Disease', 'MESH:D004938', (287, 291))	('Precancerous and Cancerous Lesions of the Gastric Cardia Mucosa', 'Disease', 'MESH:D013274', (39, 102))	('Helicobacter pylori', 'Species', '210', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (351, 360))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('gastric non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (252, 285))	('GNCA', 'Disease', (287, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('Cancerous Lesions of the Gastric', 'Phenotype', 'HP:0006753', (56, 88))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('gastric cardia adenocarcinoma', 'Disease', (331, 360))	('GCA', 'Disease', (362, 365))	('H. pylori', 'Species', '210', (188, 197))	('Helicobacter pylori', 'Var', (167, 186))	('cause', 'Reg', (243, 248))	('gastric non-cardia adenocarcinoma', 'Disease', (252, 285))	('men', 'Species', '9606', (323, 326))	('GCA', 'Disease', 'MESH:D004938', (362, 365))	('Helicobacter pylori', 'Species', '210', (167, 186))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (331, 360))
27513	32195175	Previously, H. pylori was believed to induce tissue responses in colonized hosts, a persistent process could further increase the risk of developing inflammation, intestinal metaplasia, dysplasia, and finally adenocarcinoma of the stomach non-cardia.	('increase', 'PosReg', (117, 125))	('adenocarcinoma of the stomach non-cardia', 'Disease', 'MESH:D004938', (209, 249))	('inflammation', 'Disease', 'MESH:D007249', (149, 161))	('adenocarcinoma of the stomach', 'Phenotype', 'HP:0006753', (209, 238))	('H. pylori', 'Var', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('inflammation', 'Disease', (149, 161))	('adenocarcinoma of the stomach non-cardia', 'Disease', (209, 249))	('H. pylori', 'Species', '210', (12, 21))	('intestinal metaplasia, dysplasia', 'Disease', 'MESH:D008679', (163, 195))
27536	32195175	During careful examinations of the stomach cardia and non-cardia (including the fundus, corpus, antrum, pylorus, and angle), suspicious lesions showing congestion, bleeding, roughness, erosion, plaque, or nodularity were targeted, and biopsies were taken.	('nodularity', 'Var', (205, 215))	('non-cardia', 'Disease', (54, 64))	('roughness', 'Disease', (174, 183))	('congestion', 'Disease', (152, 162))	('erosion', 'Disease', (185, 192))	('stomach cardia', 'Disease', (35, 49))	('non-cardia', 'Disease', 'MESH:D004938', (54, 64))	('bleeding', 'Disease', 'MESH:D006470', (164, 172))	('bleeding', 'Disease', (164, 172))	('stomach cardia', 'Disease', 'MESH:D004938', (35, 49))
27568	32195175	A number of previous epidemiological studies conducted in Asian populations, such as China, Korea, Japan, and Iran found that seropositivity to H. pylori was associated with a significantly increased risk of GCA.	('GCA', 'Disease', (208, 211))	('GCA', 'Disease', 'MESH:D004938', (208, 211))	('H. pylori', 'Species', '210', (144, 153))	('seropositivity', 'Var', (126, 140))
27580	32195175	Current H. pylori positivity rate was positively associated with the severity of both precancerous and cancerous lesions in the gastric cardia after adjusting for possible confounding factors.	('cancerous lesions in the gastric cardia', 'Phenotype', 'HP:0006753', (103, 142))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('precancerous and cancerous lesions', 'Disease', 'MESH:D011230', (86, 120))	('associated', 'Reg', (49, 59))	('cancerous lesions in the gastric cardia', 'Disease', (103, 142))	('pylori positivity', 'Phenotype', 'HP:0005202', (11, 28))	('positivity', 'Var', (18, 28))	('H. pylori', 'Gene', (8, 17))	('cancerous lesions in the gastric cardia', 'Disease', 'MESH:D013274', (103, 142))	('H. pylori', 'Species', '210', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
27585	32195175	However, one speculative explanation is that H. pylori induces persistent tissue responses in colonized cardia mucosa, and the persistent process may increase the risk of developing inflammation, atrophy, intestinal metaplasia, intraepithelial neoplasia, and adenocarcinoma of the gastric cardia.	('intraepithelial neoplasia', 'Disease', (228, 253))	('increase', 'PosReg', (150, 158))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (205, 226))	('cardia mucosa', 'Disease', 'MESH:D004938', (104, 117))	('atrophy', 'Disease', 'MESH:D001284', (196, 203))	('tissue responses', 'CPA', (74, 90))	('atrophy', 'Disease', (196, 203))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (228, 253))	('cardia mucosa', 'Disease', (104, 117))	('H. pylori', 'Species', '210', (45, 54))	('intestinal metaplasia', 'Disease', (205, 226))	('inflammation', 'Disease', 'MESH:D007249', (182, 194))	('adenocarcinoma of the gastric cardia', 'Disease', 'MESH:D004938', (259, 295))	('H. pylori', 'Var', (45, 54))	('adenocarcinoma of the gastric cardia', 'Disease', (259, 295))	('neoplasia', 'Phenotype', 'HP:0002664', (244, 253))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (228, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('inflammation', 'Disease', (182, 194))
27607	27539087	Overall and cancer-free survival rates were significantly higher in REG-I positive group (p = 0.000434 and 1.0847E-8, respectively).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('REG', 'Gene', (68, 71))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Overall', 'CPA', (0, 7))	('higher', 'PosReg', (58, 64))	('REG', 'Gene', '5967', (68, 71))	('positive', 'Var', (74, 82))
27645	27539087	Also, the cancer-free survival rate was significantly higher among patients with a positive REG-I index than among those with a negative index (5-year survival rates were 59 and 8 %, respectively, p = 1.0847E-8).	('REG', 'Gene', (92, 95))	('patients', 'Species', '9606', (67, 75))	('higher', 'PosReg', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('positive', 'Var', (83, 91))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('REG', 'Gene', '5967', (92, 95))
27652	27539087	We compared those patients with the REG-I negative group (24 patients) and found that the REG-I positive group had a lower incidence of lymphatic permeation (absent in 22 patients (61 %) in the positive group but only six patients (25 %) in the negative group) and vascular invasion (absent in 27 patients (75 %) in the positive group and 11 patients (46 %) in the negative group); and that pathological lymph nodes were absent in 26 patients (72 %) in the positive group, but only nine patients (38 %) in the negative group.	('lymphatic permeation', 'MPA', (136, 156))	('patients', 'Species', '9606', (434, 442))	('REG', 'Gene', '5967', (90, 93))	('vascular invasion', 'CPA', (265, 282))	('patients', 'Species', '9606', (297, 305))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (487, 495))	('patients', 'Species', '9606', (342, 350))	('patients', 'Species', '9606', (61, 69))	('lower', 'NegReg', (117, 122))	('positive', 'Var', (96, 104))	('patients', 'Species', '9606', (171, 179))	('REG', 'Gene', (90, 93))	('REG', 'Gene', '5967', (36, 39))	('patients', 'Species', '9606', (18, 26))	('absent', 'NegReg', (284, 290))	('REG', 'Gene', (36, 39))	('absent', 'NegReg', (158, 164))
27664	27539087	We found that REG-I expression is associated with longer survival in advanced head and neck cancer treated by chemoradiotherapy; our results are consistent with previous results regarding esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (188, 205))	('neck cancer', 'Disease', 'MESH:D006258', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('REG', 'Gene', '5967', (14, 17))	('neck cancer', 'Disease', (87, 98))	('expression', 'Var', (20, 30))	('REG', 'Gene', (14, 17))	('head and neck cancer', 'Phenotype', 'HP:0012288', (78, 98))	('esophageal cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('longer', 'PosReg', (50, 56))
27666	27539087	It has also been demonstrated that, REG-I positivity is associated with a worse overall survival rate in patients with surgically treated gastric carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('patients', 'Species', '9606', (105, 113))	('overall survival', 'MPA', (80, 96))	('positivity', 'Var', (42, 52))	('gastric carcinoma', 'Disease', 'MESH:D013274', (138, 155))	('REG', 'Gene', '5967', (36, 39))	('gastric carcinoma', 'Disease', (138, 155))	('worse', 'NegReg', (74, 79))	('REG', 'Gene', (36, 39))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (138, 155))
27673	27539087	The results of our study indicate that REG-I is expressed by advanced head and neck squamous cell carcinoma and that REG-I positivity, in cases treated with chemo-radiotherapy, is associated with a lower incidence of lymphatic permeation, vascular invasion and pathological lymph nodes.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (70, 107))	('REG', 'Gene', '5967', (117, 120))	('positivity', 'Var', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('neck squamous cell carcinoma', 'Disease', (79, 107))	('REG', 'Gene', (117, 120))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (79, 107))	('lymphatic permeation', 'CPA', (217, 237))	('vascular invasion', 'CPA', (239, 256))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('REG', 'Gene', '5967', (39, 42))	('REG', 'Gene', (39, 42))	('lower', 'NegReg', (198, 203))
27704	24083572	The definition of anemia used in this study was kept consistent with the definitions used by our laboratory: a hemoglobin level under 12 g/dL for men and under 11 g/dL for women.	('anemia', 'Disease', 'MESH:D000740', (18, 24))	('under', 'NegReg', (128, 133))	('anemia', 'Phenotype', 'HP:0001903', (18, 24))	('men', 'Species', '9606', (146, 149))	('hemoglobin level', 'MPA', (111, 127))	('under 11', 'Var', (154, 162))	('men', 'Species', '9606', (174, 177))	('women', 'Species', '9606', (172, 177))	('anemia', 'Disease', (18, 24))
27731	24083572	Zenda and colleagues concluded that the pre-chemoradiotherapy hemoglobin level may be an important determinant of outcome in patients with T4/M1 LYM squamous cell carcinoma of the esophagus.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('squamous cell carcinoma of the esophagus', 'Disease', (149, 189))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (149, 189))	('T4/M1 LYM', 'Var', (139, 148))	('hemoglobin level', 'MPA', (62, 78))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (163, 189))	('patients', 'Species', '9606', (125, 133))
27780	21542926	For the ESD procedure, a single-channel upper gastrointestinal endoscope with a water-jet system (GIF-Q260J, Olympus Medical Systems, Tokyo, Japan) was used with a transparent cap attached to the endoscope tip.	('Q260J', 'Var', (102, 107))	('upper gastrointestinal endoscope', 'Disease', (40, 72))	('Q260J', 'SUBSTITUTION', 'None', (102, 107))	('water', 'Chemical', 'MESH:D014867', (80, 85))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (40, 72))
27856	19326432	Exclusions were made for response by proxy (n=15,760), self-report of prostate (n=10,640), breast (n=10,875), colon (n=4,584), or other cancers (n=23,219), cancer diagnoses or death before baseline (n=1,899), extreme calorie intake (n=4,999), or extreme alpha-tocopherol intake (n=1,867; ref), resulting in a final analytic cohort of 492,559 study participants (293,775 men and 198,784 women).	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('extreme', 'Var', (209, 216))	('death', 'Disease', 'MESH:D003643', (176, 181))	('men', 'Species', '9606', (388, 391))	('breast', 'Disease', (91, 97))	('prostate', 'Disease', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('participants', 'Species', '9606', (348, 360))	('cancer', 'Disease', (156, 162))	('women', 'Species', '9606', (386, 391))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (254, 270))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('death', 'Disease', (176, 181))	('colon', 'Disease', (110, 115))	('men', 'Species', '9606', (370, 373))
27979	32476017	This approach consists of the occlusion (days to a week before the planned resection and anastomosis) of most or all of the gastric arteries, except for the right gastroepiploic artery, in order to provide time for the stomach to adapt to the reduced oxygenation occurring during its mobilization for the creation of the conduit.	('right gastroepiploic artery', 'Disease', (157, 184))	('oxygen', 'Chemical', 'MESH:D010100', (251, 257))	('occlusion', 'Var', (30, 39))	('right gastroepiploic artery', 'Disease', 'MESH:D020244', (157, 184))
28019	32476017	Also, the positioning close to the esophageal sphincter may cause airway compromise, globus sensation (that can be avoided by leaving at least 2 cm between the upper edge of the stent and the upper esophageal sphincter), pain, and aspiration pneumonia.	('globus sensation', 'Disease', (85, 101))	('cause', 'Reg', (60, 65))	('pneumonia', 'Phenotype', 'HP:0002090', (242, 251))	('pain', 'Phenotype', 'HP:0012531', (221, 225))	('pain', 'Disease', 'MESH:D010146', (221, 225))	('pain', 'Disease', (221, 225))	('aspiration pneumonia', 'Disease', (231, 251))	('aspiration', 'Phenotype', 'HP:0002835', (231, 241))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (231, 251))	('airway compromise', 'CPA', (66, 83))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (231, 251))	('positioning', 'Var', (10, 21))
28035	32476017	Complications are rare and include detached clip necessitating a late surgical intervention; contralateral esophageal ulceration or esophageal perforation during system introduction; misplaced clip occluding the lumen, necessitating a surgical intervention; and tongue laceration.	('occluding', 'NegReg', (198, 207))	('tongue laceration', 'Disease', (262, 279))	('misplaced', 'Var', (183, 192))	('ulceration', 'Disease', 'MESH:D014456', (118, 128))	('esophageal ulceration', 'Phenotype', 'HP:0004791', (107, 128))	('ulceration', 'Disease', (118, 128))
28061	31833539	Interestingly, dietary protein intake could significantly increase the risk of esophageal squamous cell carcinoma (pooled OR = 1.29, 95% CI = 1.02-1.62), instead of other disease type.	('increase', 'PosReg', (58, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('dietary', 'Var', (15, 22))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (79, 113))
28062	31833539	To sum up, dietary protein intake had no significant association with esophageal cancer risk in the overall analysis; but, protein intake may be associated with the risk of esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (173, 207))	('esophageal cancer', 'Disease', (70, 87))	('protein', 'Var', (123, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('associated', 'Reg', (145, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('esophageal squamous cell carcinoma', 'Disease', (173, 207))
28079	31833539	Interestingly, dietary protein intake could significantly increase the risk of esophageal squamous cell carcinoma (pooled OR = 1.29, 95% CI = 1.02-1.62), instead of other disease types, when we performed the analysis between dietary protein intake and disease type (Figure 2).	('increase', 'PosReg', (58, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('dietary', 'Var', (15, 22))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (79, 113))
28090	31833539	However, we found an increased risk on esophageal squamous cell carcinoma with high protein intake when we conducted a subgroup analysis by cancer subtypes.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (39, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('high protein', 'Var', (79, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal squamous cell carcinoma', 'Disease', (39, 73))
28095	31833539	In conclusion, dietary protein intake had no significant association on esophageal cancer risk in the overall analysis; but, protein intake may be associated with the risk of esophageal squamous cell carcinoma.	('associated', 'Reg', (147, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('esophageal squamous cell carcinoma', 'Disease', (175, 209))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (175, 209))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('protein', 'Var', (125, 132))
28097	30756308	We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor.	('FAK', 'Gene', '5747', (91, 94))	('FAK', 'Gene', (91, 94))	('BI 853520', 'Chemical', '-', (46, 55))	('human', 'Species', '9606', (23, 28))	('BI 853520', 'Var', (46, 55))
28108	30756308	BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('malignancies', 'Disease', 'MESH:D009369', (175, 187))	('BI 853520', 'Var', (0, 9))	('tumor', 'Disease', (87, 92))	('malignancies', 'Disease', (175, 187))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patients', 'Species', '9606', (128, 136))	('BI 853520', 'Chemical', '-', (0, 9))
28117	30756308	Preclinical studies have demonstrated antitumor activity with FAK blockade, and several orally bioavailable, adenosine triphosphate (ATP)-competitive, small-molecule inhibitors of FAK are undergoing evaluation in early-phase clinical trials in patients with cancer, including VS-6063, GSK2256098, and PF-00562271.	('FAK', 'Gene', (180, 183))	('ATP', 'Chemical', 'MESH:D000255', (133, 136))	('tumor', 'Disease', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (109, 131))	('GSK2256098', 'Chemical', 'MESH:C000600809', (285, 295))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('PF-00562271', 'Var', (301, 312))	('FAK', 'Gene', '5747', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('FAK', 'Gene', (62, 65))	('VS-6063', 'Var', (276, 283))	('cancer', 'Disease', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('FAK', 'Gene', '5747', (180, 183))	('patients', 'Species', '9606', (244, 252))
28118	30756308	BI 853520 is a novel, potent, highly selective, ATP-competitive inhibitor of FAK that has demonstrated activity in a variety of preclinical human tumor xenograft models.	('FAK', 'Gene', '5747', (77, 80))	('human', 'Species', '9606', (140, 145))	('activity', 'MPA', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('FAK', 'Gene', (77, 80))	('BI 853520', 'Var', (0, 9))	('tumor', 'Disease', (146, 151))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('BI 853520', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
28119	30756308	In vitro, BI 853520 inhibited recombinant FAK with a half maximal (50%) inhibitory concentration (IC50) of 1 nM, which is largely comparable to the IC50 values reported for VS-6063 (0.6 nM), PF-00562271 (1.5 nM), and GSK2256098 (2-15 nM).	('BI 853520', 'Chemical', '-', (10, 19))	('FAK', 'Gene', '5747', (42, 45))	('BI 853520', 'Var', (10, 19))	('inhibited', 'NegReg', (20, 29))	('FAK', 'Gene', (42, 45))	('GSK2256098', 'Chemical', 'MESH:C000600809', (217, 227))
28121	30756308	The antitumor activity of BI 853520 was found to vary widely across a diverse panel of 16 murine subcutaneous adenocarcinoma xenograft models, from complete tumor inhibition to an absolute lack of sensitivity.	('tumor', 'Disease', (157, 162))	('BI 853520', 'Var', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('adenocarcinoma', 'Disease', (110, 124))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('BI 853520', 'Chemical', '-', (26, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (110, 124))	('murine', 'Species', '10090', (90, 96))
28122	30756308	Biomarker analysis suggests that the in vivo efficacy of BI 853520 in these models is linked to a mesenchymal tumor phenotype characterized by low E-cadherin messenger RNA (mRNA) and protein levels, and by low expression of the microRNA hsa-miR-200c-3p, an epithelial-specific microRNA that promotes E-cadherin expression.	('BI 853520', 'Var', (57, 66))	('low', 'NegReg', (143, 146))	('expression', 'MPA', (210, 220))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mesenchymal tumor', 'Disease', (98, 115))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (98, 115))	('BI 853520', 'Chemical', '-', (57, 66))
28123	30756308	All xenograft models that were highly sensitive to BI 853520, including kidney, lung, ovary, pancreas and prostate adenocarcinomas, were found to lack E-cadherin expression or to express low levels of E-cadherin.	('lack', 'NegReg', (146, 150))	('BI 853520', 'Chemical', '-', (51, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('BI 853520', 'Var', (51, 60))	('expression', 'MPA', (162, 172))	('pancreas and prostate adenocarcinomas', 'Disease', 'MESH:D010190', (93, 130))	('E-cadherin', 'Protein', (151, 161))
28125	30756308	In murine breast cancer models, BI 853520 most effectively prevented the establishment of metastases in tumors in which E-cadherin was either deficient or downregulated.	('BI 853520', 'Var', (32, 41))	('deficient', 'Disease', 'MESH:D007153', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('prevented', 'NegReg', (59, 68))	('metastases in tumors', 'Disease', 'MESH:D009362', (90, 110))	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('deficient', 'Disease', (142, 151))	('breast cancer', 'Disease', (10, 23))	('murine', 'Species', '10090', (3, 9))	('downregulated', 'NegReg', (155, 168))	('E-cadherin', 'Protein', (120, 130))	('metastases in tumors', 'Disease', (90, 110))	('BI 853520', 'Chemical', '-', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
28126	30756308	We report here the first-in-human phase I study of BI 853520, which comprised a dose-escalation phase followed by an expansion phase in patients with advanced nonhematologic cancers.	('human', 'Species', '9606', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('BI 853520', 'Chemical', '-', (51, 60))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('BI 853520', 'Var', (51, 60))	('patients', 'Species', '9606', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
28181	30756308	Table 5 summarizes the PK parameters for BI 853520, and unbound BI 853520, after single- and multiple-dose administration (200 mg QD; see Electronic Supplementary Tables 2-5 for all dose groups).	('BI 853520', 'Chemical', '-', (41, 50))	('BI 853520', 'Var', (64, 73))	('BI 853520', 'Var', (41, 50))	('BI 853520', 'Chemical', '-', (64, 73))
28193	30756308	This phase I trial demonstrated that continuous monotherapy with BI 853520 is feasible in heavily pretreated patients with advanced or metastatic nonhematologic malignancies; the MTD is determined at 200 mg QD.	('patients', 'Species', '9606', (109, 117))	('BI 853520', 'Chemical', '-', (65, 74))	('malignancies', 'Disease', (161, 173))	('BI 853520', 'Var', (65, 74))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
28194	30756308	The tolerability profile for BI 853520 is acceptable and is similar to that observed with other FAK inhibitors [e.g.	('BI 853520', 'Var', (29, 38))	('BI 853520', 'Chemical', '-', (29, 38))	('FAK', 'Gene', '5747', (96, 99))	('FAK', 'Gene', (96, 99))
28201	30756308	To date, no predisposing or risk factors for the development of BI 853520-associated proteinuria have been identified, and no clear correlation was identified with prior nephrotoxic therapy.	('nephrotoxic', 'Disease', 'MESH:D007674', (170, 181))	('BI 853520', 'Chemical', '-', (64, 73))	('nephrotoxic', 'Disease', (170, 181))	('proteinuria', 'Disease', (85, 96))	('BI 853520-associated', 'Var', (64, 84))	('proteinuria', 'Phenotype', 'HP:0000093', (85, 96))	('proteinuria', 'Disease', 'MESH:D011507', (85, 96))
28205	30756308	Proteinuria has also been reported as an AE following treatment with GSK2256098 and PF-00562271.	('GSK2256098', 'Var', (69, 79))	('GSK2256098', 'Chemical', 'MESH:C000600809', (69, 79))	('Proteinuria', 'Disease', 'MESH:D011507', (0, 11))	('PF-00562271', 'Var', (84, 95))	('Proteinuria', 'Phenotype', 'HP:0000093', (0, 11))	('Proteinuria', 'Disease', (0, 11))
28206	30756308	PK analysis demonstrated that BI 853520 was rapidly absorbed and exhibited at least biphasic disposition kinetics.	('BI 853520', 'Var', (30, 39))	('biphasic', 'MPA', (84, 92))	('BI 853520', 'Chemical', '-', (30, 39))
28209	30756308	The PK data demonstrate oral bioavailability of BI 853520 and support a QD dosing schedule.	('oral bioavailability', 'MPA', (24, 44))	('BI 853520', 'Var', (48, 57))	('BI 853520', 'Chemical', '-', (48, 57))
28210	30756308	In five of eight cases, including three patients with soft tissue sarcoma, the ratio of active pFAK/total FAK was substantially reduced at the end of the first cycle, thus providing clinical evidence supporting target engagement with BI 853520 in patients treated with the 200 mg QD dose.	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('BI 853520', 'Chemical', '-', (234, 243))	('reduced', 'NegReg', (128, 135))	('BI 853520', 'Var', (234, 243))	('ratio', 'MPA', (79, 84))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (54, 73))	('patients', 'Species', '9606', (40, 48))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (54, 73))	('patients', 'Species', '9606', (247, 255))	('FAK', 'Gene', (106, 109))	('FAK', 'Gene', '5747', (106, 109))	('FAK', 'Gene', (96, 99))	('soft tissue sarcoma', 'Disease', (54, 73))	('FAK', 'Gene', '5747', (96, 99))
28216	30756308	Given the cytostatic activity of BI 853520, the combination with other compounds such as immunotherapy should be considered for further development.	('BI 853520', 'Chemical', '-', (33, 42))	('BI 853520', 'Var', (33, 42))	('cytostatic activity', 'MPA', (10, 29))
28221	30756308	These data demonstrate that BI 853520 has a manageable and acceptable safety profile, favorable PK, and preliminary antitumor activity, including, for some patients, SD lasting >= 150 days, and PD modulation at the MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies.	('patients', 'Species', '9606', (156, 164))	('PD', 'Disease', 'MESH:D010300', (194, 196))	('BI 853520', 'Chemical', '-', (28, 37))	('patients', 'Species', '9606', (235, 243))	('BI 853520', 'Var', (28, 37))	('malignancies', 'Disease', 'MESH:D009369', (282, 294))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('modulation', 'Var', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('malignancies', 'Disease', (282, 294))	('tumor', 'Disease', (120, 125))
28239	24580917	Collectively, these findings highlight the emerging roles of microRNAs in esophageal carcinomas, and the significance of miR-17~92 as a potential biomarker and therapeutic target in these malignancies.	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (74, 95))	('malignancies', 'Disease', 'MESH:D009369', (188, 200))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (74, 95))	('malignancies', 'Disease', (188, 200))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('microRNAs', 'Var', (61, 70))	('esophageal carcinomas', 'Disease', (74, 95))	('miR-17~92', 'Gene', (121, 130))	('miR-17~92', 'Gene', '407975', (121, 130))
28240	29908962	Targeting Orai1-mediated store-operated calcium entry by RP4010 for anti-tumor activity in esophagus squamous cell carcinoma Esophageal cancer (EC) is the 6th leading cause of cancer mortality worldwide with poor prognosis, hence more effective chemotherapeutic drugs for this deadly disease are urgently needed.	('esophagus squamous cell carcinoma', 'Disease', (91, 124))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (136, 142))	('Orai1', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('Orai1', 'Gene', '84876', (10, 15))	('Esophageal cancer', 'Disease', (125, 142))	('calcium', 'Chemical', 'MESH:D002118', (40, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('carcinoma Esophageal cancer', 'Phenotype', 'HP:0011459', (115, 142))	('tumor', 'Disease', (73, 78))	('EC', 'Disease', 'MESH:D004938', (144, 146))	('esophagus squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 124))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('Esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('RP4010', 'Var', (57, 63))	('cancer', 'Disease', (176, 182))
28243	29908962	Here, we evaluated the anti-cancer effect of a novel SOCE inhibitor, RP4010, in cultured EC cells and xenograft models.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('RP4010', 'Var', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('EC', 'Disease', 'MESH:D004938', (89, 91))	('cancer', 'Disease', (28, 34))
28244	29908962	Compared to other previously reported SOCE channel inhibitors, RP4010 is more potent in blocking SOCE and inhibiting cell proliferation in EC and other cancer cells.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('SOCE', 'Protein', (97, 101))	('inhibiting', 'NegReg', (106, 116))	('RP4010', 'Var', (63, 69))	('cell proliferation in', 'CPA', (117, 138))	('EC', 'Disease', 'MESH:D004938', (139, 141))	('blocking', 'NegReg', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
28245	29908962	Treatment with RP4010 resulted in reduction of intracellular Ca2+ oscillations, caused cell cycle arrest at G0/G1 phase in vitro, decreased nuclear translocation of nuclear factor kappa B (NF-kappaB) in vivo and in vitro, and inhibited tumor growth in vivo.	('nuclear translocation', 'MPA', (140, 161))	('intracellular Ca2+ oscillations', 'MPA', (47, 78))	('RP4010', 'Var', (15, 21))	('Ca2+', 'Chemical', 'MESH:D002118', (61, 65))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (47, 78))	('inhibited', 'NegReg', (226, 235))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', (236, 241))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('reduction', 'NegReg', (34, 43))	('cell cycle arrest at G0/G1 phase', 'CPA', (87, 119))	('nuclear factor kappa B', 'Gene', '4790', (165, 187))	('nuclear factor kappa B', 'Gene', (165, 187))	('decreased', 'NegReg', (130, 139))
28246	29908962	Taken together, data demonstrated the therapeutic potential of RP4010 in EC patients via inhibition of SOCE-mediated intracellular Ca2+ signaling.	('patients', 'Species', '9606', (76, 84))	('EC', 'Disease', 'MESH:D004938', (73, 75))	('RP4010', 'Var', (63, 69))	('inhibition', 'NegReg', (89, 99))	('SOCE-mediated intracellular Ca2+ signaling', 'MPA', (103, 145))	('Ca2+', 'Chemical', 'MESH:D002118', (131, 135))
28263	29908962	Anti-tumor activity of skf-96765, a tool compound with non-specific activity against SOCE, in animal models of breast further established the role of SOCE in cancer.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('breast', 'Disease', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('cancer', 'Disease', (158, 164))	('tumor', 'Disease', (5, 10))	('skf-96765', 'Chemical', 'MESH:C502178', (23, 32))	('skf-96765', 'Var', (23, 32))
28264	29908962	Previous work from our lab demonstrated that skf-96765 inhibited Orai1-mediated intracellular Ca2+ oscillations, proliferation of ESCC cells, and tumor growth in vivo.	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (80, 111))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('skf-96765', 'Chemical', 'MESH:C502178', (45, 54))	('tumor', 'Disease', (146, 151))	('skf-96765', 'Var', (45, 54))	('Orai1', 'Gene', (65, 70))	('proliferation', 'CPA', (113, 126))	('Ca2+', 'Chemical', 'MESH:D002118', (94, 98))	('Orai1', 'Gene', '84876', (65, 70))	('inhibited', 'NegReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
28265	29908962	RP4010 is a novel, oral inhibitor of Orai1 channel developed by Rhizen Pharmaceuticals and currently in Phase I/IB clinical development.	('Orai1', 'Gene', '84876', (37, 42))	('Orai1', 'Gene', (37, 42))	('RP4010', 'Var', (0, 6))
28266	29908962	Herein, we examined the anti-proliferative effects of RP4010 and the possible underlying mechanism in cultured human ESCC cells as well as an ESCC xenograft mouse model.	('mouse', 'Species', '10090', (157, 162))	('anti-proliferative', 'MPA', (24, 42))	('RP4010', 'Var', (54, 60))	('human', 'Species', '9606', (111, 116))
28268	29908962	Human ESCC (KYSE-30, KYSE-150, KYSE-790 and KYSE-190), normal epithelial (HET-1A), lung cancer (A549) and ovarian cancer (A2780 and A2780-DX) cell lines were used in this study.	('Human', 'Species', '9606', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('ovarian cancer', 'Disease', (106, 120))	('KYSE-150', 'CellLine', 'CVCL:1348', (21, 29))	('lung cancer', 'Disease', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('KYSE-190', 'Var', (44, 52))	('A2780-DX', 'Chemical', 'MESH:D004317', (132, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))
28271	29908962	A549, A2780 and A2780-DX cells were cultured in RPMI-1640 medium supplemented with 10% FBS.	('A2780', 'Var', (6, 11))	('A2780-DX', 'Var', (16, 24))	('A2780-DX', 'Chemical', 'MESH:D004317', (16, 24))	('A549', 'CellLine', 'CVCL:0023', (0, 4))
28274	29908962	Primary antibodies used in this study included anti-STIM1 (1:500, BD Transduction), anti-Orai1 (1:1000, Millipore), anti-Cyclin B1 (1:1000, Cell Signaling Technology, US), anti-Cyclin D1 (1:1000, Cell Signaling Technology, US), anti-P27 (1:1000, Cell Signaling Technology, US), anti-STIM1 (1:1000, BD Transduction Laboratories, Clone 44), anti-Orai1 (1:1500, Millipore, against residues 22-40 of human protein, US), and anti-GAPDH (1:1000, GeneTex, US).	('Orai1', 'Gene', '84876', (344, 349))	('Cyclin B1', 'Gene', '891', (121, 130))	('P27', 'Gene', (233, 236))	('STIM1', 'Gene', (283, 288))	('Cyclin D1', 'Gene', '595', (177, 186))	('P27', 'Gene', '3429', (233, 236))	('Cyclin B1', 'Gene', (121, 130))	('1:1500', 'Var', (351, 357))	('Orai1', 'Gene', (89, 94))	('Cyclin D1', 'Gene', (177, 186))	('human', 'Species', '9606', (396, 401))	('STIM1', 'Gene', '6786', (52, 57))	('Orai1', 'Gene', '84876', (89, 94))	('anti-GAPDH', 'Var', (420, 430))	('STIM1', 'Gene', '6786', (283, 288))	('1:1000', 'Var', (290, 296))	('STIM1', 'Gene', (52, 57))	('Orai1', 'Gene', (344, 349))
28285	29908962	SOCE activity is presented as the difference between basal and maximal values of F350/F385 (DeltaF350/F385) after addition of 2 mM CaCl2 in BSS solution.	('DeltaF350', 'Var', (92, 101))	('CaCl2', 'Chemical', 'MESH:D002122', (131, 136))	('DeltaF350', 'DELETION', 'None', (92, 101))	('F350/F385', 'Var', (81, 90))
28291	29908962	After 36 h, the cells were treated with RP4010 or vehicle for 4 h followed by 10 microM TG to deplete ER Ca2+ stores and activate SOCE.	('deplete ER Ca2+ stores', 'MPA', (94, 116))	('SOCE', 'CPA', (130, 134))	('activate', 'PosReg', (121, 129))	('Ca2+', 'Chemical', 'MESH:D002118', (105, 109))	('TG', 'Chemical', 'MESH:D019284', (88, 90))	('RP4010', 'Var', (40, 46))
28315	29908962	Two tail t-test was employed to evaluate the significance of tumor weight in the RP4010 and control groups.	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('RP4010', 'Var', (81, 87))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
28316	29908962	MTT assays were performed to evaluate the anti-cancer efficacy of RP4010 in cultured human ESCC cell lines.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('RP4010', 'Var', (66, 72))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('MTT', 'Chemical', 'MESH:C022616', (0, 3))	('human', 'Species', '9606', (85, 90))
28317	29908962	The IC50 of RP4010 for KYSE-30, KYSE-70, KYSE-150, and KYSE-790 were 1.244, 1.412, 1.402, and 5.545 microM, respectively.	('KYSE-150', 'CellLine', 'CVCL:1348', (41, 49))	('KYSE-150', 'Var', (41, 49))	('RP4010', 'Var', (12, 18))
28321	29908962	2A, the RP4010 treated cells displayed almost no positive PI signal while MK2206, a known AKT inhibitor with highly cytotoxic manifested by increased PI stained (red) nuclei in majority of the cells.	('MK2206', 'Var', (74, 80))	('AKT', 'Gene', (90, 93))	('RP4010', 'Var', (8, 14))	('increased', 'PosReg', (140, 149))	('MK2206', 'Chemical', 'MESH:C548887', (74, 80))	('AKT', 'Gene', '207', (90, 93))
28322	29908962	Hoechst 33342 images failed to reveal any apoptotic hallmarks, such as nuclear condensation or fragmentation in KYSE-150 cells treated with RP4010.	('RP4010', 'Var', (140, 146))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (0, 13))	('nuclear condensation', 'CPA', (71, 91))	('KYSE-150', 'CellLine', 'CVCL:1348', (112, 120))
28325	29908962	Western blot analysis further indicated that the protein level of P27Kip1, an inhibitor for cyclin-Cdk, was increased in cells treated with RP4010 especially at higher concentrations (Fig.	('RP4010', 'Var', (140, 146))	('cyclin', 'Gene', '5111', (92, 98))	('increased', 'PosReg', (108, 117))	('cyclin', 'Gene', (92, 98))	('protein level', 'MPA', (49, 62))	('P27Kip1', 'Gene', '1027', (66, 73))	('P27Kip1', 'Gene', (66, 73))
28326	29908962	Two other important cell cycle regulatory proteins, cyclin B1 and cyclin D1, were dramatically decreased in KYSE-150 cells treated with RP4010 at 2 and 10 microM (Fig.	('RP4010', 'Var', (136, 142))	('decreased', 'NegReg', (95, 104))	('cyclin D1', 'Gene', (66, 75))	('cyclin B1', 'Gene', '891', (52, 61))	('cyclin B1', 'Gene', (52, 61))	('KYSE-150', 'CellLine', 'CVCL:1348', (108, 116))	('cyclin D1', 'Gene', '595', (66, 75))
28328	29908962	Therefore, we tested whether the anti-proliferation function of RP4010 could be via blockade of SOCE and SOCE-mediated intracellular Ca2+ oscillations.	('RP4010', 'Var', (64, 70))	('Ca2+', 'Chemical', 'MESH:D002118', (133, 137))	('anti-proliferation', 'CPA', (33, 51))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (119, 150))	('tested', 'Reg', (14, 20))
28331	29908962	Once extracellular solution was changed to BSS-2Ca2+, SOCE was induced (second peak of F350/F385).	('BSS-2Ca2+', 'Chemical', 'MESH:C097031', (43, 52))	('SOCE', 'Disease', (54, 58))	('F350/F385', 'Var', (87, 96))
28333	29908962	While BSS-2Ca2+ solution containing RP4010 (10 microM) failed to inhibit SOCE, pre-incubation of RP4010 for 2 h and 4 h significantly inhibited SOCE in KYSE-150 cells compared to the control (Fig.	('SOCE', 'MPA', (144, 148))	('inhibited', 'NegReg', (134, 143))	('RP4010', 'Var', (97, 103))	('BSS-2Ca2+', 'Chemical', 'MESH:C097031', (6, 15))	('KYSE-150', 'CellLine', 'CVCL:1348', (152, 160))
28334	29908962	Similarly, pre-incubation of RP4010 for 4 h significantly inhibited SOCE in other cancer cell lines, such as KYSE-150, KYSE-720, A549, A2780 as well as the doxorubicin resistant A2780-DX cells (Supplementary Materials, Fig.	('SOCE', 'MPA', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('doxorubicin', 'Chemical', 'MESH:D004317', (156, 167))	('KYSE-150', 'CellLine', 'CVCL:1348', (109, 117))	('A2780-DX', 'Chemical', 'MESH:D004317', (178, 186))	('cancer', 'Disease', (82, 88))	('RP4010', 'Var', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('inhibited', 'NegReg', (58, 67))	('A549', 'CellLine', 'CVCL:0023', (129, 133))
28338	29908962	While 80% of cells demonstrated intracellular Ca2+ oscillations in control group, only 15% of cells did so in RP4010 treatment group (Fig.	('intracellular Ca2+ oscillations', 'MPA', (32, 63))	('RP4010', 'Var', (110, 116))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (32, 63))	('Ca2+', 'Chemical', 'MESH:D002118', (46, 50))
28339	29908962	Clearly, these data demonstrated that RP4010 significantly blocked SOCE and SOCE-mediated intracellular Ca2+ oscillations in ESCC cells.	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (90, 121))	('SOCE', 'MPA', (67, 71))	('RP4010', 'Var', (38, 44))	('SOCE-mediated intracellular Ca2+ oscillations', 'MPA', (76, 121))	('Ca2+', 'Chemical', 'MESH:D002118', (104, 108))	('blocked', 'NegReg', (59, 66))
28340	29908962	Since the "kick-in" time for RP4010 was more than 2 hours, we first studied whether the expression of STIM1 or Orai1 proteins was down-regulated.	('down-regulated', 'NegReg', (130, 144))	('STIM1', 'Gene', '6786', (102, 107))	('Orai1', 'Gene', '84876', (111, 116))	('proteins', 'Protein', (117, 125))	('expression', 'MPA', (88, 98))	('STIM1', 'Gene', (102, 107))	('RP4010', 'Var', (29, 35))	('Orai1', 'Gene', (111, 116))
28341	29908962	Next, we investigated whether RP4010 could interrupt the translocation of Orai1.	('RP4010', 'Var', (30, 36))	('Orai1', 'Gene', '84876', (74, 79))	('Orai1', 'Gene', (74, 79))	('interrupt', 'NegReg', (43, 52))	('translocation', 'MPA', (57, 70))
28342	29908962	After ER Ca2+ stores were depleted by 10 microM TG, colocalized "puncta" of both STIM1 and Orai1 were observed in both untreated and RP4010 treated cells (Fig.	('Orai1', 'Gene', (91, 96))	('TG', 'Chemical', 'MESH:D019284', (48, 50))	('STIM1', 'Gene', (81, 86))	('Orai1', 'Gene', '84876', (91, 96))	('colocalized "puncta', 'MPA', (52, 71))	('Ca2+', 'Chemical', 'MESH:D002118', (9, 13))	('ER Ca2+ stores', 'MPA', (6, 20))	('STIM1', 'Gene', '6786', (81, 86))	('RP4010', 'Var', (133, 139))
28344	29908962	Data suggest that the mechanism underlying the inhibitory function of RP4010 may not through interrupting STIM1-Orai1 interaction or translocation of Orai1.	('translocation', 'MPA', (133, 146))	('Orai1', 'Gene', (112, 117))	('Orai1', 'Gene', '84876', (112, 117))	('Orai1', 'Gene', (150, 155))	('RP4010', 'Var', (70, 76))	('interaction', 'Interaction', (118, 129))	('Orai1', 'Gene', '84876', (150, 155))	('STIM1', 'Gene', (106, 111))	('interrupting', 'NegReg', (93, 105))	('STIM1', 'Gene', '6786', (106, 111))
28346	29908962	Since RP4010 inhibited SOCE and intracellular Ca2+ oscillations, we investigated whether RP4010 could block nuclear factor kappa B (NF-kappaB/p65) nuclear translocation upon serum stimulation in ESCC cells.	('RP4010', 'Var', (89, 95))	('nuclear factor kappa B', 'Gene', '4790', (108, 130))	('p65', 'Gene', '5970', (142, 145))	('RP4010', 'Var', (6, 12))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (32, 63))	('inhibited', 'NegReg', (13, 22))	('block', 'NegReg', (102, 107))	('p65', 'Gene', (142, 145))	('Ca2+', 'Chemical', 'MESH:D002118', (46, 50))	('nuclear translocation', 'MPA', (147, 168))	('nuclear factor kappa B', 'Gene', (108, 130))
28349	29908962	Treatment with either 20 microM BTP-2 or 10 microM RP4010 reduced the number of cells with NF-kappaB/p65 nuclear localization to 8.53% and 10.52%, respectively.	('BTP-2', 'Chemical', 'MESH:C476308', (32, 37))	('p65', 'Gene', '5970', (101, 104))	('RP4010', 'Var', (51, 57))	('reduced', 'NegReg', (58, 65))	('p65', 'Gene', (101, 104))
28350	29908962	Besides NF-kappaB pathway, we also examined Akt and ERK pathways and found that RP4010 did not alter these pathways in KYSE-150 cells (Supplementary Materials, Fig.	('ERK', 'Gene', '5594', (52, 55))	('Akt', 'Gene', '207', (44, 47))	('ERK', 'Gene', (52, 55))	('RP4010', 'Var', (80, 86))	('KYSE-150', 'CellLine', 'CVCL:1348', (119, 127))	('examined', 'Reg', (35, 43))	('Akt', 'Gene', (44, 47))
28352	29908962	In consistent with in vitro studies, immunofluorescence staining of tumor tissues also demonstrated that nuclear NF-kappaB/p65 positive cells number was only 9% in RP4010 group compared with 41% in control animals (Fig.	('tumor', 'Disease', (68, 73))	('RP4010', 'Var', (164, 170))	('p65', 'Gene', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('p65', 'Gene', '5970', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
28353	29908962	5C); the expression of cyclin D1 which was a target of NF-kappaB/p65 was also dramatically reduced in tumors removed from RP4010 treated animals compared with that removed from control group (Fig.	('p65', 'Gene', '5970', (65, 68))	('RP4010 treated', 'Var', (122, 136))	('tumors', 'Disease', (102, 108))	('cyclin D1', 'Gene', '595', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cyclin D1', 'Gene', (23, 32))	('expression', 'MPA', (9, 19))	('reduced', 'NegReg', (91, 98))	('p65', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
28354	29908962	Data therefore indicate a role for RP4010 in the NF-kappaB/p65 signaling pathway both in vivo and in vitro.	('p65', 'Gene', '5970', (59, 62))	('RP4010', 'Var', (35, 41))	('p65', 'Gene', (59, 62))
28355	29908962	Lastly, we evaluated the anti-cancer effect of RP4010 in ESCC xenograft nude mice.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('RP4010', 'Var', (47, 53))	('nude mice', 'Species', '10090', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
28356	29908962	One week after inoculation of 1x106 KYSE-150 cells and development of visible tumors, mice were randomly assigned into vehicle control and RP4010 treatment (20 mg/kg, i.p.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('KYSE-150', 'CellLine', 'CVCL:1348', (36, 44))	('mice', 'Species', '10090', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('RP4010', 'Var', (139, 145))
28357	29908962	Compared with control group, RP4010 treatment group demonstrated significantly slower tumor growth (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('slower', 'NegReg', (79, 85))	('RP4010 treatment', 'Var', (29, 45))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
28359	29908962	Results showed that the volume and weights of tumors from RP4010 treated animals were significantly less than those of the control group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Disease', (46, 52))	('RP4010 treated', 'Var', (58, 72))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('less', 'NegReg', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
28360	29908962	H&E staining of the heart, spleen, liver and kidney collected from the RP4010 treatment group showed no obvious toxicity, with similar histology features as control group (Fig.	('the', 'Var', (67, 70))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))	('toxicity', 'Disease', (112, 120))
28362	29908962	While typical squamous cells carcinoma feature was clearly presented in tumors removed from control group, interestingly, the feature was missing in tumors harvested from RP4010 treated mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('carcinoma', 'Disease', 'MESH:D002277', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('squamous cells carcinoma', 'Phenotype', 'HP:0002860', (14, 38))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('carcinoma', 'Disease', (29, 38))	('mice', 'Species', '10090', (186, 190))	('RP4010', 'Var', (171, 177))
28363	29908962	Collectively, the in vivo data suggest that RP4010 could inhibit the tumor growth in xenograft ESCC nude mice without any obvious toxicity to vital organs.	('RP4010', 'Var', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('nude mice', 'Species', '10090', (100, 109))	('toxicity', 'Disease', 'MESH:D064420', (130, 138))	('toxicity', 'Disease', (130, 138))	('tumor', 'Disease', (69, 74))	('inhibit', 'NegReg', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
28365	29908962	Treatment of RP4010 (10 microM) inhibited intracellular Ca2+ oscillations, halted Ca2+-dependent nuclear translocation of NF-kappaB, and resulted in cell cycles arrested at G0/G1 phase.	('Ca2+', 'Chemical', 'MESH:D002118', (82, 86))	('halted', 'NegReg', (75, 81))	('RP4010', 'Var', (13, 19))	('inhibited', 'NegReg', (32, 41))	('Ca2+-dependent nuclear translocation', 'MPA', (82, 118))	('resulted in', 'Reg', (137, 148))	('intracellular Ca2+ oscillations', 'MPA', (42, 73))	('NF-kappaB', 'Protein', (122, 131))	('Ca2+', 'Chemical', 'MESH:D002118', (56, 60))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (42, 73))	('cell cycles arrested', 'CPA', (149, 169))
28368	29908962	At this dose, RP4010 significantly reduced ESCC tumor growth compared to vehicle treated control group.	('tumor', 'Disease', (48, 53))	('reduced', 'NegReg', (35, 42))	('ESCC', 'Disease', (43, 47))	('RP4010', 'Var', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
28371	29908962	DPB-162AE and DPB-163AE were constructed with 100-fold potency compared to 2-APB without affecting IP3R function.	('IP3R', 'Gene', '3710', (99, 103))	('IP3R', 'Gene', (99, 103))	('DPB', 'Chemical', 'MESH:C029034', (0, 3))	('2-APB', 'Chemical', 'MESH:C109986', (75, 80))	('DPB-163AE', 'Var', (14, 23))	('DPB-162AE', 'Var', (0, 9))	('DPB', 'Chemical', 'MESH:C029034', (14, 17))
28372	29908962	Targeting the pore geometry, especially the Ca2+ selectivity filter of Orai1 channel, another class of inhibitors of Orai1 were synthesized including SB01990, SPB06836, KM06293 and RH01882.	('RH01882', 'Chemical', 'MESH:C019126', (181, 188))	('SB01990', 'Var', (150, 157))	('Orai1', 'Gene', (71, 76))	('RH01882', 'Var', (181, 188))	('Ca2+', 'Chemical', 'MESH:D002118', (44, 48))	('KM06293', 'Chemical', 'MESH:C010470', (169, 176))	('Orai1', 'Gene', '84876', (71, 76))	('SPB06836', 'Chemical', 'MESH:C511752', (159, 167))	('Orai1', 'Gene', (117, 122))	('KM06293', 'Var', (169, 176))	('SPB06836', 'Var', (159, 167))	('SB01990', 'Chemical', 'MESH:C475340', (150, 157))	('Orai1', 'Gene', '84876', (117, 122))
28374	29908962	Being a slow process, RP4010 could act against STIM1 oligomerisation, and/or STIM1-Orai1 coupling, and/or Orai1 activation.	('activation', 'PosReg', (112, 122))	('Orai1', 'Gene', (106, 111))	('STIM1', 'Gene', (47, 52))	('STIM1', 'Gene', (77, 82))	('Orai1', 'Gene', '84876', (106, 111))	('Orai1', 'Gene', (83, 88))	('RP4010', 'Var', (22, 28))	('STIM1', 'Gene', '6786', (77, 82))	('STIM1', 'Gene', '6786', (47, 52))	('Orai1', 'Gene', '84876', (83, 88))
28375	29908962	Although RP4010 has no effect on the expression of STIM1 or Orai1 nor on the STIM1-Orai1 translocation and interaction, the possibility that the SOCE inhibition is due to secondary effects of RP4010 cannot be ruled out.	('STIM1', 'Gene', (51, 56))	('RP4010', 'Var', (192, 198))	('translocation', 'MPA', (89, 102))	('Orai1', 'Gene', (60, 65))	('STIM1', 'Gene', '6786', (51, 56))	('RP4010', 'Var', (9, 15))	('STIM1', 'Gene', (77, 82))	('interaction', 'Interaction', (107, 118))	('Orai1', 'Gene', '84876', (60, 65))	('Orai1', 'Gene', (83, 88))	('expression', 'MPA', (37, 47))	('STIM1', 'Gene', '6786', (77, 82))	('Orai1', 'Gene', '84876', (83, 88))
28376	29908962	The exact mechanism underlying the inhibitory function of RP4010 on Orai1 require further investigation.	('Orai1', 'Gene', (68, 73))	('Orai1', 'Gene', '84876', (68, 73))	('RP4010', 'Var', (58, 64))
28377	29908962	Compared to the commonly used BTP-2, RP4010 was more potent with respect to inhibition of ESCC cell proliferation.	('inhibition', 'NegReg', (76, 86))	('ESCC', 'Disease', (90, 94))	('BTP-2', 'Chemical', 'MESH:C476308', (30, 35))	('RP4010', 'Var', (37, 43))
28379	29908962	Interestingly, RP4010 inhibited cell proliferation not only in ESCC cell lines, but also in other cancer cell lines, including lung cancer (A549), ovarian cancer (A2780) and even the doxorubicin resistant A2780-DX cells (Supplementary Materials, Fig.	('lung cancer', 'Disease', (127, 138))	('inhibited', 'NegReg', (22, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (147, 161))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('doxorubicin', 'Chemical', 'MESH:D004317', (183, 194))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('ovarian cancer', 'Disease', (147, 161))	('cell proliferation', 'CPA', (32, 50))	('A2780-DX', 'Chemical', 'MESH:D004317', (205, 213))	('RP4010', 'Var', (15, 21))	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (155, 161))	('A549', 'CellLine', 'CVCL:0023', (140, 144))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
28380	29908962	Data suggest that RP4010 could inhibit a common SOCE pathway in various cancers and may have useful application in cancer cells that have developed drug-resistance.	('cancers', 'Disease', (72, 79))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('drug-resistance', 'Phenotype', 'HP:0020174', (148, 163))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('RP4010', 'Var', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('inhibit', 'NegReg', (31, 38))	('SOCE pathway', 'Pathway', (48, 60))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (72, 78))
28381	29908962	It is noteworthy that RP4010 treatment results in cell cycle arrest but does not cause cell death even at concentrations as high as 30 microM, which is unlike other SOCE inhibitors (skf-96765, 2-APB, BTP-2, our unpublished observations).	('skf-96765', 'Chemical', 'MESH:C502178', (182, 191))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('2-APB', 'Chemical', 'MESH:C109986', (193, 198))	('cell cycle arrest', 'CPA', (50, 67))	('RP4010', 'Var', (22, 28))	('BTP-2', 'Chemical', 'MESH:C476308', (200, 205))
28382	29908962	Since ESCC cells require higher Orai1-mediated SOCE to support their fast proliferation compared to normal epithelial cells, inhibiting to data suggest that RP4010 may be tumor specific while sparing healthy cells.	('RP4010', 'Var', (157, 163))	('Orai1', 'Gene', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('Orai1', 'Gene', '84876', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
28392	29908962	Consistent with that report, RP4010 likely blocked nuclear translocation of NF-kappaB by inhibiting SOCE-mediated intracellular Ca2+ oscillations.	('NF-kappaB', 'Protein', (76, 85))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (114, 145))	('nuclear translocation', 'MPA', (51, 72))	('inhibiting', 'NegReg', (89, 99))	('blocked', 'NegReg', (43, 50))	('RP4010', 'Var', (29, 35))	('Ca2+', 'Chemical', 'MESH:D002118', (128, 132))	('SOCE-mediated intracellular Ca2+ oscillations', 'MPA', (100, 145))
28396	29908962	Taking together, our data suggest that RP4010 can inhibit SOCE-mediated intracellular Ca2+ oscillations, which in turn resulted in cycle arrest and cell proliferation inhibition in ESCC cells.	('inhibit', 'NegReg', (50, 57))	('inhibition', 'NegReg', (167, 177))	('cell proliferation', 'CPA', (148, 166))	('cycle arrest', 'CPA', (131, 143))	('Ca2+', 'Chemical', 'MESH:D002118', (86, 90))	('RP4010', 'Var', (39, 45))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (72, 103))	('SOCE-mediated intracellular Ca2+ oscillations', 'MPA', (58, 103))
28400	29908962	Treatment with RP4010 significantly reduced the expression of Vimentin besides increase E-cadherin level, consistent with the data from cell migration assay (Supplementary Materials, Fig.	('increase', 'PosReg', (79, 87))	('Vimentin', 'Gene', (62, 70))	('E-cadherin', 'Gene', (88, 98))	('E-cadherin', 'Gene', '999', (88, 98))	('Vimentin', 'Gene', '7431', (62, 70))	('expression', 'MPA', (48, 58))	('reduced', 'NegReg', (36, 43))	('RP4010', 'Var', (15, 21))
28404	29908962	Reduction of intracellular Ca2+ oscillations by RP4010 can inhibit cell proliferation and arrest cell cycle at G0/G1 phase in human esophageal squamous cancer cells.	('arrest', 'NegReg', (90, 96))	('human', 'Species', '9606', (126, 131))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (132, 158))	('RP4010', 'Var', (48, 54))	('Ca2+', 'Chemical', 'MESH:D002118', (27, 31))	('esophageal squamous cancer', 'Disease', (132, 158))	('intracellular Ca2+ oscillations', 'MPA', (13, 44))	('cell cycle at G0/G1 phase', 'CPA', (97, 122))	('Reduction', 'NegReg', (0, 9))	('squamous cancer', 'Phenotype', 'HP:0002860', (143, 158))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (13, 44))	('inhibit', 'NegReg', (59, 66))	('cell proliferation', 'CPA', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
28405	29908962	RP4010 inhibits tumor growth in esophageal cancer xenograft mice with no obvious adverse effect.	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('RP4010', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('inhibits', 'NegReg', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('esophageal cancer', 'Disease', (32, 49))	('mice', 'Species', '10090', (60, 64))
28450	29351773	It is well known that circumferential resection of more than three quarters of the lumen leads to esophageal stenosis.	('leads to', 'Reg', (89, 97))	('esophageal stenosis', 'Disease', (98, 117))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (98, 117))	('esophageal stenosis', 'Disease', 'MESH:D004940', (98, 117))	('circumferential resection', 'Var', (22, 47))
28467	28700364	Helicobacter pylori infection among patients with liver cirrhosis Inflammatory changes in the stomach caused by Helicobacter pylori indirectly and directly affect liver function.	('Helicobacter pylori', 'Species', '210', (0, 19))	('infection', 'Disease', (20, 29))	('liver cirrhosis', 'Disease', (50, 65))	('patients', 'Species', '9606', (36, 44))	('Helicobacter pylori', 'Var', (112, 131))	('infection', 'Disease', 'MESH:D007239', (20, 29))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (50, 65))	('affect', 'Reg', (156, 162))	('liver function', 'MPA', (163, 177))	('affect liver function', 'Phenotype', 'HP:0001410', (156, 177))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (0, 29))	('cirrhosis', 'Phenotype', 'HP:0001394', (56, 65))	('liver cirrhosis', 'Disease', 'MESH:D008103', (50, 65))	('Inflammatory changes in the stomach', 'Phenotype', 'HP:0005263', (66, 101))	('Helicobacter pylori', 'Species', '210', (112, 131))
28468	28700364	Moreover, the bacteria may worsen the course of the liver cirrhosis.	('liver cirrhosis', 'Phenotype', 'HP:0001394', (52, 67))	('bacteria', 'Var', (14, 22))	('worsen', 'PosReg', (27, 33))	('liver cirrhosis', 'Disease', 'MESH:D008103', (52, 67))	('cirrhosis', 'Phenotype', 'HP:0001394', (58, 67))	('liver cirrhosis', 'Disease', (52, 67))
28475	28700364	Ammonia concentration was significantly higher in patients infected with H. pylori, compared with noninfected individuals (129 vs. 112 mumol/l; P=0.002).	('higher', 'PosReg', (40, 46))	('patients', 'Species', '9606', (50, 58))	('Ammonia concentration', 'MPA', (0, 21))	('H. pylori', 'Species', '210', (73, 82))	('Ammonia', 'Chemical', 'MESH:D000641', (0, 7))	('H. pylori', 'Var', (73, 82))
28544	28700364	In the past, eradication of this bacteria led to increased platelet number, which allowed administration of antiviral treatment (with interferon).	('increased platelet number', 'Phenotype', 'HP:0001894', (49, 74))	('eradication', 'Var', (13, 24))	('increased', 'PosReg', (49, 58))	('men', 'Species', '9606', (123, 126))	('platelet number', 'MPA', (59, 74))
28550	28700364	performed in 225 patients chronically infected with HBV and compensated liver cirrhosis with thrombocytopenia, eradication of H. pylori irrespectively of the antiviral therapy positively impacted the progression of the disease and increased platelet count.	('cirrhosis', 'Phenotype', 'HP:0001394', (78, 87))	('HBV', 'Species', '10407', (52, 55))	('thrombocytopenia', 'Disease', 'MESH:D013921', (93, 109))	('H. pylori', 'Species', '210', (126, 135))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (93, 109))	('liver cirrhosis', 'Disease', 'MESH:D008103', (72, 87))	('increased', 'PosReg', (231, 240))	('impacted', 'Reg', (187, 195))	('patients', 'Species', '9606', (17, 25))	('eradication', 'Var', (111, 122))	('thrombocytopenia', 'Disease', (93, 109))	('platelet count', 'MPA', (241, 255))	('liver cirrhosis', 'Disease', (72, 87))	('increased platelet count', 'Phenotype', 'HP:0001894', (231, 255))	('progression', 'MPA', (200, 211))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (72, 87))	('H. pylori', 'Gene', (126, 135))
28735	26327132	While care must be taken when comparing the current results to those from meta-analyses and previous cohort data due to the potential for heterogeniety of the compared patients and the possibility of a "healthy patient effect" in those treated with RFA, given the present data and past studies, RFA appears effective for reducing the incidence of EAC after BE, regardless of histologic grade.	('EAC after', 'Disease', (347, 356))	('patient', 'Species', '9606', (168, 175))	('patients', 'Species', '9606', (168, 176))	('RFA', 'Var', (295, 298))	('reducing', 'NegReg', (321, 329))	('patient', 'Species', '9606', (211, 218))
28747	26327132	Patients treated with RFA for their BE were far more likely to die from cardiac disease or cancer at sites outside the esophagus than from esophageal cancer, which is consistent with previous research.	('cardiac disease', 'Disease', (72, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('RFA', 'Var', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cardiac disease', 'Disease', 'MESH:D006331', (72, 87))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (150, 156))	('esophageal cancer', 'Disease', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
28811	24633624	2c and d, an improvement in the NPRQ level was seen in the BAA-EN group compared to the control and snack groups (-1.5 vs. +6.4 %, p = 0.002; -1.9 vs. +6.4 %, p < 0.001, respectively).	('BAA-EN', 'Var', (59, 65))	('EN', 'Chemical', '-', (63, 65))	('BAA', 'Chemical', '-', (59, 62))	('NPRQ', 'Chemical', '-', (32, 36))	('NPRQ level', 'MPA', (32, 42))	('improvement', 'PosReg', (13, 24))
28812	24633624	2e and f, the BTR levels were increased in the BCAA-EN group relative to those of the control and general liquid groups (+5.6 vs. +34.5 %, p < 0.001; -2.0 vs. +34.5 %, p < 0.001, respectively).	('BCAA-EN', 'Chemical', '-', (47, 54))	('BCAA-EN', 'Var', (47, 54))	('BTR', 'Gene', (14, 17))	('BTR', 'Gene', '344561', (14, 17))	('increased', 'PosReg', (30, 39))
28836	24633624	For the BCAA-EN group, a significant increase in NPRQ levels was seen on day 7 (Supplementary Figure S1), as compared with the control and snack groups (Fig.	('NPRQ levels', 'MPA', (49, 60))	('increase', 'PosReg', (37, 45))	('BCAA-EN', 'Chemical', '-', (8, 15))	('BCAA-EN', 'Var', (8, 15))	('NPRQ', 'Chemical', '-', (49, 53))
28863	24633624	Even in study 2, a maintained improvement in energy metabolism was seen in the BCAA-EN group when compared with the BCAA group (Fig.	('BCAA', 'Chemical', 'MESH:D000597', (79, 83))	('BCAA-EN', 'Var', (79, 86))	('energy metabolism', 'MPA', (45, 62))	('BCAA-EN', 'Chemical', '-', (79, 86))	('improvement', 'PosReg', (30, 41))	('BCAA', 'Chemical', 'MESH:D000597', (116, 120))
28883	23757351	MicroRNA 223 is Up-regulated in the Multistep Progression of Barrett's Esophagus and Modulates Sensitivity to Chemotherapy by Targeting PARP1 Recent microarray and RNA-sequencing studies have uncovered aberrantly expressed microRNAs (miRs)in Barrett's esophagus (BE)-associated esophageal adenocarcinoma (EAC).	('Up-regulated', 'PosReg', (16, 28))	("Barrett's esophagus", 'Disease', (242, 261))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (242, 261))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (242, 261))	('MicroRNA 223', 'Gene', '407008', (0, 12))	('MicroRNA 223', 'Gene', (0, 12))	('miR', 'Gene', '220972', (234, 237))	('miR', 'Gene', (234, 237))	("Barrett's Esophagus", 'Disease', 'MESH:D001471', (61, 80))	('microRNAs', 'Protein', (223, 232))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (61, 80))	("Barrett's Esophagus", 'Disease', (61, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('esophageal adenocarcinoma', 'Disease', (278, 303))	('aberrantly expressed', 'Var', (202, 222))	('PARP1', 'Gene', (136, 141))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (278, 303))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (278, 303))
28942	23757351	The gene expression was down-regulated by at least 1.5 fold in miR-223 transfectedOE33 cells compared to the scramble transfected OE33 cells.	('down-regulated', 'NegReg', (24, 38))	('transfectedOE33', 'Var', (71, 86))	('miR-223', 'Gene', (63, 70))	('expression', 'MPA', (9, 19))	('miR-223', 'Gene', '407008', (63, 70))
28982	23757351	In short-term viability assays, miR-223 transfected EAC cells had lower cell numbers than scramble transfected EAC cells (P<0.001, data not shown).	('miR-223', 'Gene', '407008', (32, 39))	('cell numbers', 'CPA', (72, 84))	('lower', 'NegReg', (66, 71))	('miR-223', 'Gene', (32, 39))	('transfected', 'Var', (40, 51))
28999	23757351	PARP1 is involved in the repair of single stranded DNA breaks, and studies have shown that PARP1 inhibitors improve the sensitivity of carcinomas to chemotherapeutics.	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('sensitivity', 'CPA', (120, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('carcinomas', 'Disease', 'MESH:D002277', (135, 145))	('carcinomas', 'Disease', (135, 145))	('PARP1', 'Gene', (91, 96))	('improve', 'PosReg', (108, 115))	('inhibitors', 'Var', (97, 107))
29000	23757351	We investigated whether ectopic miR-223 expression, and thus PARP1 down-regulation, can increase the sensitivity of OE33 and JHesoAD1 cells to the DNA-damaging agents Cisplatin, Mitomycin C and Doxorubicin.	('miR-223', 'Gene', '407008', (32, 39))	('down-regulation', 'NegReg', (67, 82))	('Doxorubicin', 'Chemical', 'MESH:D004317', (194, 205))	('JHesoAD1', 'CellLine', 'CVCL:8098', (125, 133))	('Mitomycin C', 'Chemical', '-', (178, 189))	('increase', 'PosReg', (88, 96))	('Cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('miR-223', 'Gene', (32, 39))	('PARP1', 'Gene', (61, 66))	('sensitivity', 'MPA', (101, 112))	('ectopic', 'Var', (24, 31))
29002	23757351	MiR-223 transfected JHesoAD1 were also significantly less viable after Mitomycin C treatment at all tested concentrations (P<0.001, data not shown), while miR-223 transfected OE33 cells were only more sensitive to 7.5-10microM Mitomycin C (P=0.009, data not shown) than scramble transfected cells.	('Mitomycin C', 'Chemical', '-', (71, 82))	('less', 'NegReg', (53, 57))	('miR-223', 'Gene', (155, 162))	('transfected', 'Var', (8, 19))	('Mitomycin C', 'Chemical', '-', (227, 238))	('JHesoAD1', 'CellLine', 'CVCL:8098', (20, 28))	('MiR-223', 'Gene', '407008', (0, 7))	('MiR-223', 'Gene', (0, 7))	('to 7', 'Species', '1214577', (211, 215))	('miR-223', 'Gene', '407008', (155, 162))
29018	23757351	These studies have furthermore reported that high miR-223 levels are correlated with advanced disease and poor outcome in these cancers.To further explore how miR-223 regulates cancer-promoting cellular processes, we profiled EAC cells in the setting of ectopic miR-223 expression.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('miR-223', 'Gene', '407008', (159, 166))	('miR-223', 'Gene', '407008', (262, 269))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Disease', (128, 135))	('advanced disease', 'Disease', (85, 101))	('miR-223', 'Gene', '407008', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('advanced disease', 'Disease', 'MESH:D020178', (85, 101))	('miR-223', 'Gene', (262, 269))	('miR-223', 'Gene', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ectopic', 'Var', (254, 261))	('miR-223', 'Gene', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (128, 134))
29022	23757351	SMARCD1 possesses a binding site for p53, and inhibition of SMARCD1 reduces the SWI/SNF complex-mediated transcriptional activity of p53.	('SMARCD1', 'Gene', '6602', (60, 67))	('inhibition', 'Var', (46, 56))	('SWI/SNF complex-mediated transcriptional activity', 'MPA', (80, 129))	('SMARCD1', 'Gene', '6602', (0, 7))	('SMARCD1', 'Gene', (60, 67))	('p53', 'Gene', '7157', (133, 136))	('SMARCD1', 'Gene', (0, 7))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('p53', 'Gene', (133, 136))	('reduces', 'NegReg', (68, 75))
29031	23757351	Reduced PARP1 activity promotes homologous recombination, and it has been extensively reported that homologous deficient cells, for instance BRCA1/2 deficient cells, are sensitive to PARP1 inhibitors since these cells are incapable of repairing recombinogenic lesions induced by PARP1 inhibition.	('promotes', 'PosReg', (23, 31))	('activity', 'MPA', (14, 22))	('BRCA1', 'Gene', '672', (141, 146))	('homologous recombination', 'CPA', (32, 56))	('BRCA1', 'Gene', (141, 146))	('PARP1', 'Gene', (8, 13))	('Reduced', 'Var', (0, 7))
29046	21593195	Early G1 cyclin-dependent kinases as prognostic markers and potential therapeutic targets in esophageal adenocarcinoma Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC).	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (93, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (93, 118))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (167, 192))	('esophageal adenocarcinoma', 'Disease', (167, 192))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (167, 192))	('Chromosomal gain at 7q21', 'Var', (119, 143))	('esophageal adenocarcinoma', 'Disease', (93, 118))
29049	21593195	PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage-independence of EAC cells through activation of the pRB pathway.	('PD-0332991', 'Var', (0, 10))	('pRB', 'Gene', '5925', (152, 155))	('suppresses', 'NegReg', (61, 71))	('proliferation', 'CPA', (72, 85))	('anchorage-independence of EAC cells', 'CPA', (90, 125))	('activation', 'PosReg', (134, 144))	('both', 'Protein', (42, 46))	('kinase activity', 'MPA', (23, 38))	('pRB', 'Gene', (152, 155))	('PD-0332991', 'Chemical', 'MESH:C500026', (0, 10))
29054	21593195	Progression from BE to dysplasia and adenocarcinoma is associated with the accumulation of genetic and epigenetic alterations such as copy number gain and loss, mutations and promoter methylation that presumably lead to oncogenic changes in mRNA and protein expression.	('loss', 'NegReg', (155, 159))	('copy number', 'Var', (134, 145))	('changes', 'Reg', (230, 237))	('gain', 'PosReg', (146, 150))	('dysplasia and adenocarcinoma', 'Disease', 'MESH:D000230', (23, 51))	('mutations', 'Var', (161, 170))	('promoter methylation', 'Var', (175, 195))
29059	21593195	One approach for the discovery of new therapeutic targets is through identification of genes whose expression is deregulated by genetic alterations in the tumor.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('expression', 'MPA', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('genetic alterations', 'Var', (128, 147))	('tumor', 'Disease', (155, 160))	('deregulated', 'PosReg', (113, 124))
29065	21593195	Finally, functional analysis of both CDK4 and CDK6 in EAC cell lines shows that siRNA knockdown or inhibition of both CDK4 and CDK6 activity with the small molecule inhibitor PD-0332991 suppresses proliferation and anchorage independent growth.	('knockdown', 'Var', (86, 95))	('CDK4', 'Gene', (118, 122))	('suppresses', 'NegReg', (186, 196))	('activity', 'MPA', (132, 140))	('PD-0332991', 'Chemical', 'MESH:C500026', (175, 185))	('CDK6', 'Gene', (127, 131))	('inhibition', 'NegReg', (99, 109))	('proliferation', 'CPA', (197, 210))
29066	21593195	Thus, our data provide direct evidence that CDK6 is the functional target of 7q21 amplification in EAC and both CDK6 and CDK4 expression is a strong predictor of patient survival.	('CDK6', 'Gene', (112, 116))	('7q21 amplification', 'Var', (77, 95))	('EAC', 'Disease', (99, 102))	('patient', 'Species', '9606', (162, 169))	('CDK4', 'Gene', (121, 125))
29086	21593195	Amplification of 7q21 was observed in 35% (40/116) of tumors (Figure 1A).	('7q21', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
29088	21593195	In order to assess the prognostic value of amplification at 7q21 we determined whether this amplification correlated with overall and recurrence-free survival of patients.	('patients', 'Species', '9606', (162, 170))	('amplification', 'Var', (43, 56))	('correlated', 'Reg', (106, 116))
29089	21593195	Kaplan-Meier survival estimates indicate a modest association of 7q21 amplification with increased risk of death (p=0.049) but no statistically significant association with disease recurrence (p=0.23: Figure 1B).	('death', 'Disease', (107, 112))	('7q21 amplification', 'Var', (65, 83))	('death', 'Disease', 'MESH:D003643', (107, 112))
29093	21593195	Since the amplification event is associated with patient survival we also explored whether expression of genes in the amplicon is associated with survival.	('associated', 'Reg', (33, 43))	('amplification', 'Var', (10, 23))	('patient', 'Species', '9606', (49, 56))
29101	21593195	As shown in Figure 3C, knocking down CDK6 in EAC cells reduced phosphorylation of pRB at serines 780 and 795 (both are known targets of CDK6/Cyclin D1 complex) although with much lesser effect in OE33.	('pRB', 'Gene', (82, 85))	('CDK6', 'Gene', (37, 41))	('Cyclin D1', 'Gene', (141, 150))	('reduced', 'NegReg', (55, 62))	('serines', 'Chemical', 'MESH:D012694', (89, 96))	('knocking down', 'Var', (23, 36))	('phosphorylation', 'MPA', (63, 78))	('pRB', 'Gene', '5925', (82, 85))	('Cyclin D1', 'Gene', '595', (141, 150))
29102	21593195	Given the observation that EAC cell lines seemed to respond most strongly to combined CDK4 and CDK6 knockdown, we explored CDK4 amplification and expression in our primary tumors.	('CDK4', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('knockdown', 'Var', (100, 109))	('tumors', 'Disease', (172, 178))	('CDK6', 'Gene', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('respond', 'Reg', (52, 59))
29103	21593195	Amplification of the 12q13 region containing CDK4 was observed in 12/116 tumors (10%) and was associated with worse overall survival (p=0.019: supplementary Figure 1).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('Amplification', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('worse', 'NegReg', (110, 115))	('overall survival', 'MPA', (116, 132))	('CDK4', 'Gene', (45, 49))	('tumors', 'Disease', (73, 79))
29107	21593195	PD-0332991 inhibited cell proliferation in a dose-dependent manner in all three cell lines tested (Figure 4A) and, as with the siRNA knockdown of CDK6, this was associated with hypophosphorylation of pRB at serines 780 and 795 (Figure 4D).	('hypophosphorylation', 'MPA', (177, 196))	('PD-0332991', 'Var', (0, 10))	('serines', 'Chemical', 'MESH:D012694', (207, 214))	('cell proliferation', 'CPA', (21, 39))	('pRB', 'Gene', '5925', (200, 203))	('PD-0332991', 'Chemical', 'MESH:C500026', (0, 10))	('inhibited', 'NegReg', (11, 20))	('pRB', 'Gene', (200, 203))
29108	21593195	To confirm that the effects of PD-0332991 are through activation of the pRB tumor suppressor pathway we determined the effect of the drug on the known pRB target, Cyclin A (in the RB axis where CDK4/6 inhibition activates RB and stabilizes the RB/E2F1 complex leading to inhibition of the transcriptional activation of Cyclin A by E2F1).	('pRB', 'Gene', '5925', (72, 75))	('Cyclin A', 'Gene', (163, 171))	('pRB', 'Gene', (151, 154))	('tumor', 'Disease', (76, 81))	('E2F1', 'Gene', '1869', (247, 251))	('activates', 'PosReg', (212, 221))	('pRB', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('Cyclin A', 'Gene', '890', (163, 171))	('PD-0332991', 'Chemical', 'MESH:C500026', (31, 41))	('Cyclin A', 'Gene', (319, 327))	('transcriptional activation', 'MPA', (289, 315))	('E2F1', 'Gene', (331, 335))	('stabilizes', 'PosReg', (229, 239))	('PD-0332991', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('E2F1', 'Gene', '1869', (331, 335))	('Cyclin A', 'Gene', '890', (319, 327))	('E2F1', 'Gene', (247, 251))	('pRB', 'Gene', '5925', (151, 154))	('inhibition', 'NegReg', (271, 281))
29109	21593195	As shown in Figure 4D (bottom panel), PD-0332991 reduces expression of Cyclin A in all three cell lines.	('PD-0332991', 'Var', (38, 48))	('expression', 'MPA', (57, 67))	('Cyclin A', 'Gene', '890', (71, 79))	('reduces', 'NegReg', (49, 56))	('PD-0332991', 'Chemical', 'MESH:C500026', (38, 48))	('Cyclin A', 'Gene', (71, 79))
29110	21593195	PD-0332991 has no effect on the expression level of either total pRB or RB2 (p130) in EAC cells (Figure 4D, bottom panel).	('pRB', 'Gene', '5925', (65, 68))	('PD-0332991', 'Var', (0, 10))	('expression', 'MPA', (32, 42))	('RB2', 'Gene', '5934', (72, 75))	('p130', 'Gene', '5934', (77, 81))	('pRB', 'Gene', (65, 68))	('RB2', 'Gene', (72, 75))	('PD-0332991', 'Chemical', 'MESH:C500026', (0, 10))	('p130', 'Gene', (77, 81))
29111	21593195	PD-0332991 delays cell cycle progression at the G1/S boundary and is not cytotoxic to a variety of cancer cell lines.	('PD-0332991', 'Var', (0, 10))	('cell cycle progression at the G1/S boundary', 'CPA', (18, 61))	('delays', 'NegReg', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('PD-0332991', 'Chemical', 'MESH:C500026', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
29113	21593195	As shown in Figure 4B and C, in all three cell lines tested there is a decrease in S/G2 population compared to G0/G1 five days after incubation with PD-0332991 and this is without any remarkable hypodiploidy.	('S/G2', 'SUBSTITUTION', 'None', (83, 87))	('PD-0332991', 'Chemical', 'MESH:C500026', (149, 159))	('decrease', 'NegReg', (71, 79))	('PD-0332991', 'Var', (149, 159))	('hypodiploidy', 'Disease', 'None', (195, 207))	('hypodiploidy', 'Disease', (195, 207))	('S/G2', 'Var', (83, 87))
29114	21593195	Given the effect of PD-0332991 on cell proliferation, we tested whether the drug will reduce the transformation potential of EAC cells.	('tested', 'Reg', (57, 63))	('transformation potential', 'CPA', (97, 121))	('PD-0332991', 'Chemical', 'MESH:C500026', (20, 30))	('reduce', 'NegReg', (86, 92))	('PD-0332991', 'Var', (20, 30))
29116	21593195	As shown in Figure 4E, PD-0332991 caused a significant reduction in colony formation in soft agar in all three cell lines tested indicative of a reduction of anchorage-independence.	('reduction', 'NegReg', (55, 64))	('reduction', 'NegReg', (145, 154))	('PD-0332991', 'Chemical', 'MESH:C500026', (23, 33))	('anchorage-independence', 'CPA', (158, 180))	('colony formation in soft agar', 'CPA', (68, 97))	('agar', 'Chemical', 'MESH:D000362', (93, 97))	('PD-0332991', 'Var', (23, 33))
29117	21593195	Chromosomal abnormalities resulting in gene amplification or deletion are a common mechanism to confer mitogenic advantage in tumors.	('mitogenic advantage', 'CPA', (103, 122))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('deletion', 'Var', (61, 69))	('gene', 'MPA', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
29119	21593195	The classic example of this is the identification of locus-specific amplification and overexpression of ERBB2 in breast cancer which led to the successful development of targeted therapy, Trastuzumab.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (188, 199))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('overexpression', 'PosReg', (86, 100))	('ERBB2', 'Gene', '2064', (104, 109))	('amplification', 'Var', (68, 81))	('ERBB2', 'Gene', (104, 109))
29122	21593195	Amplification at 7q21 has been observed in T-cell lymphoma, gliomas and in medulloblastoma, where CDK6 expression was associated with poor prognosis.	('Amplification', 'Var', (0, 13))	('medulloblastoma', 'Phenotype', 'HP:0002885', (75, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (43, 58))	('cell lymphoma', 'Phenotype', 'HP:0012191', (45, 58))	('medulloblastoma', 'Disease', (75, 90))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (43, 58))	('T-cell lymphoma', 'Disease', (43, 58))	('gliomas', 'Disease', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('observed', 'Reg', (31, 39))	('medulloblastoma', 'Disease', 'MESH:D008527', (75, 90))
29124	21593195	Here we used high density Affymetrix SNP 6.0 microarrays and tissues from a cohort of 116 patients in order to fine map the genomic alterations at 7q21 in EAC and explored 7q21 gene expression in a subset of 107 tumors.	('EAC', 'Disease', (155, 158))	('7q21', 'Gene', (147, 151))	('alterations', 'Var', (132, 143))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('patients', 'Species', '9606', (90, 98))
29130	21593195	Aberrant expression of these cell cycle regulators has been observed in many tumors including EAC as a result of chromosomal amplification, e.g.	('tumors', 'Disease', (77, 83))	('EAC', 'Disease', (94, 97))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('observed', 'Reg', (60, 68))	('expression', 'MPA', (9, 19))	('result', 'Reg', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('chromosomal amplification', 'Var', (113, 138))
29131	21593195	cyclin D1, CDK4, CDK6, cyclin E1 or deletion e.g.	('cyclin E1', 'Gene', '898', (23, 32))	('deletion', 'Var', (36, 44))	('CDK6', 'Gene', (17, 21))	('cyclin E1', 'Gene', (23, 32))	('cyclin D1', 'Gene', '595', (0, 9))	('cyclin D1', 'Gene', (0, 9))	('CDK4', 'Gene', (11, 15))
29134	21593195	Downregulation of CDK6 in vitro by miR-129 induces cell cycle arrest in lung adenocarcinoma cells whereas epigenetic silencing of Hsa-miR-124a in acute lymphoblastic leukemia results in CDK6 upregulation, hyperproliferation of cells and poor prognosis.	('upregulation', 'PosReg', (191, 203))	('Downregulation', 'NegReg', (0, 14))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (152, 174))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('CDK6', 'Gene', (18, 22))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (51, 68))	('acute lymphoblastic leukemia', 'Disease', (146, 174))	('miR-129', 'Chemical', '-', (35, 42))	('Hsa', 'Gene', '213', (130, 133))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (146, 174))	('lung adenocarcinoma', 'Disease', (72, 91))	('hyperproliferation of cells', 'CPA', (205, 232))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (146, 174))	('miR-129', 'Gene', (35, 42))	('Hsa', 'Gene', (130, 133))	('induces', 'Reg', (43, 50))	('epigenetic silencing', 'Var', (106, 126))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('cell cycle arrest', 'CPA', (51, 68))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('CDK6', 'Gene', (186, 190))
29135	21593195	In contrast, ectopic expression of CDK6 in vitro suppresses proliferation of breast cancer cells presumably through activation of RB2 (p103) tumor suppressor protein.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('breast cancer', 'Disease', (77, 90))	('RB2', 'Gene', (130, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('activation', 'PosReg', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('RB2', 'Gene', '5934', (130, 133))	('proliferation', 'CPA', (60, 73))	('ectopic expression', 'Var', (13, 31))	('suppresses', 'NegReg', (49, 59))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('CDK6', 'Gene', (35, 39))
29137	21593195	In our study, expression of CDK6 was higher in tumors with 7q21amplification but CDK6 expression correlated more strongly with poor prognosis than amplification alone (Figures 1B and 2C).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('higher', 'PosReg', (37, 43))	('CDK6', 'Gene', (81, 85))	('7q21amplification', 'Var', (59, 76))	('expression', 'MPA', (86, 96))	('expression', 'MPA', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
29140	21593195	This hypothesis is based on the following observations: First, and as shown in Figure 3B, the combined knockdown of both CDK6 and CDK4 strongly suppresses proliferation in OE33, second, the reduction of phosphorylation of pRB at Ser780 and 795 when CDK6 is knocked down is less in OE33 compared to OE19 and Flo1A (Figure 3C), and third, PD-0332991 (which specifically inhibits both CDK4 and 6 kinase activity) significantly inhibits proliferation of OE33 cells (Figure 4A).	('pRB', 'Gene', (222, 225))	('proliferation', 'CPA', (433, 446))	('PD-0332991', 'Var', (337, 347))	('proliferation', 'CPA', (155, 168))	('suppresses', 'NegReg', (144, 154))	('phosphorylation', 'MPA', (203, 218))	('pRB', 'Gene', '5925', (222, 225))	('inhibits', 'NegReg', (424, 432))	('PD-0332991', 'Chemical', 'MESH:C500026', (337, 347))
29141	21593195	Such compensatory mechanisms among CDKs and also D-type cyclins have previously been suggested to account for several phenotypes resulting from the knockout of these molecules in vitro and in vivo.	('knockout', 'Var', (148, 156))	('CDKs', 'Gene', '1019;12567;1021;12571', (35, 39))	('CDKs', 'Gene', (35, 39))
29144	21593195	The small molecule PD-0332991 is a specific and reversible inhibitor of CDK4/6 kinase activity.	('PD-0332991', 'Chemical', 'MESH:C500026', (19, 29))	('PD-0332991', 'Var', (19, 29))	('CDK4/6', 'Enzyme', (72, 78))
29145	21593195	When used as a single agent, PD-0332991 is cytostatic causing inhibition of proliferation without remarkable apoptosis in responsive cell lines and its function can be monitored through reduced pRB phosphorylation at serine 780 and 795.	('PD-0332991', 'Chemical', 'MESH:C500026', (29, 39))	('serine', 'Chemical', 'MESH:D012694', (217, 223))	('reduced', 'NegReg', (186, 193))	('proliferation', 'CPA', (76, 89))	('pRB', 'Gene', '5925', (194, 197))	('PD-0332991', 'Var', (29, 39))	('inhibition', 'NegReg', (62, 72))	('pRB', 'Gene', (194, 197))
29147	21593195	In EAC cells, however, PD-0332991 treatment reduces phosphorylation of pRB but does not alter expression of total pRB or RB2 (Fig 4D).	('RB2', 'Gene', '5934', (121, 124))	('pRB', 'Gene', '5925', (114, 117))	('phosphorylation', 'MPA', (52, 67))	('PD-0332991', 'Chemical', 'MESH:C500026', (23, 33))	('RB2', 'Gene', (121, 124))	('reduces', 'NegReg', (44, 51))	('pRB', 'Gene', '5925', (71, 74))	('pRB', 'Gene', (114, 117))	('pRB', 'Gene', (71, 74))	('PD-0332991', 'Var', (23, 33))
29148	21593195	The suppression of proliferation (Figure 4A and B) and anchorage independence caused by PD-0332991 (Figure 4D and E) and the parallel cell cycle blockage (Figure 4B) and hypophosphorylation of pRB (Figure 4C) suggest that PD-0332991 may be an attractive therapeutic candidate for EAC.	('cell cycle', 'CPA', (134, 144))	('PD-0332991', 'Chemical', 'MESH:C500026', (88, 98))	('PD-0332991', 'Chemical', 'MESH:C500026', (222, 232))	('suppression', 'NegReg', (4, 15))	('blockage', 'NegReg', (145, 153))	('pRB', 'Gene', '5925', (193, 196))	('EAC', 'Disease', (280, 283))	('proliferation', 'CPA', (19, 32))	('PD-0332991', 'Var', (222, 232))	('anchorage independence', 'CPA', (55, 77))	('PD-0332991', 'Gene', (88, 98))	('pRB', 'Gene', (193, 196))	('hypophosphorylation', 'Var', (170, 189))
29158	21593195	We introduce the CDK inhibitor PD-0332991 as a potential therapeutic agent in EAC.	('PD-0332991', 'Chemical', 'MESH:C500026', (31, 41))	('PD-0332991', 'Var', (31, 41))	('EAC', 'Disease', (78, 81))
29194	33935718	Moreover, abnormal expression of MMP12 was significantly correlated with pathological degree, TNM stage, lymph nodes metastasis, and overall survival of ESCC patients (p < 0.05).	('expression', 'MPA', (19, 29))	('abnormal', 'Var', (10, 18))	('TNM', 'Gene', '10178', (94, 97))	('lymph nodes metastasis', 'CPA', (105, 127))	('correlated', 'Reg', (57, 67))	('MMP12', 'Gene', (33, 38))	('patients', 'Species', '9606', (158, 166))	('TNM', 'Gene', (94, 97))	('ESCC', 'Disease', (153, 157))	('MMP12', 'Gene', '4321', (33, 38))
29217	33935718	The results revealed that patients with high level of MMP-12 exhibited poorer prognosis than patients in low expression groups (hazardous ratio for survival probability, 1.737; p < 0.05).	('patients', 'Species', '9606', (26, 34))	('high level', 'Var', (40, 50))	('poorer', 'NegReg', (71, 77))	('MMP-12', 'Gene', '4321', (54, 60))	('patients', 'Species', '9606', (93, 101))	('MMP-12', 'Gene', (54, 60))
29223	33935718	Finally, univariate regression analysis in ESCC patients revealed that high expression of MMP12 was significantly correlated to poor prognosis.	('MMP12', 'Gene', (90, 95))	('patients', 'Species', '9606', (48, 56))	('MMP12', 'Gene', '4321', (90, 95))	('high', 'Var', (71, 75))
29236	33935718	Aberrant expression of special miRNAs have been detected in ESCC patients such as upregulated of miR-10b, miR-21, miR-26a and downregulated miR-125b, miR-203, and miR-205.	('miR-205', 'Gene', '406988', (163, 170))	('miR-21', 'Gene', (106, 112))	('downregulated', 'NegReg', (126, 139))	('ESCC', 'Disease', (60, 64))	('upregulated', 'PosReg', (82, 93))	('miR-125b', 'Var', (140, 148))	('miR-203', 'Gene', (150, 157))	('miR-26a', 'Gene', '407015', (114, 121))	('miR-10b', 'Gene', '406903', (97, 104))	('expression', 'MPA', (9, 19))	('miR-203', 'Gene', '406986', (150, 157))	('miR-21', 'Gene', '406991', (106, 112))	('patients', 'Species', '9606', (65, 73))	('miR-26a', 'Gene', (114, 121))	('miR-205', 'Gene', (163, 170))	('miR-10b', 'Gene', (97, 104))
29237	33935718	A recent study showed that downregulation of miR-486-5p was reported in esophageal carcinoma samples and it might function as a tumor suppressor gene in disease metastasis via regulating cellular migration.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('function', 'Reg', (114, 122))	('miR-486-5p', 'Chemical', '-', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cellular migration', 'CPA', (187, 205))	('esophageal carcinoma', 'Disease', (72, 92))	('regulating', 'Reg', (176, 186))	('downregulation', 'NegReg', (27, 41))	('tumor', 'Disease', (128, 133))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (72, 92))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('miR-486-5p', 'Var', (45, 55))
29238	33935718	also found that decreased miR-486-5p was identified in 66.2% of cases and abnormal expression of miR-486-5p were related to prognosis of esophageal carcinoma.	('miR-486-5p', 'MPA', (26, 36))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (137, 157))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (137, 157))	('related', 'Reg', (113, 120))	('miR-486-5p', 'Var', (97, 107))	('miR-486-5p', 'Chemical', '-', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('miR-486-5p', 'Chemical', '-', (97, 107))	('esophageal carcinoma', 'Disease', (137, 157))	('decreased', 'NegReg', (16, 25))
29241	33935718	Dysregulation of ICAM1 has been confirmed in liver cancer and ESCC stem cells.	('ESCC stem cells', 'CPA', (62, 77))	('liver cancer', 'Phenotype', 'HP:0002896', (45, 57))	('ICAM1', 'Gene', '3383', (17, 22))	('Dysregulation', 'Var', (0, 13))	('liver cancer', 'Disease', 'MESH:D006528', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('liver cancer', 'Disease', (45, 57))	('ICAM1', 'Gene', (17, 22))
29245	33935718	A previous study reported that down-regulation of miR-486-5p could suppress tumor metastasis by regulating metastatic mediator of ICAM-1 in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('metastatic mediator of', 'MPA', (107, 129))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('miR-486-5p', 'Var', (50, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('ICAM-1', 'Gene', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('suppress', 'NegReg', (67, 75))	('regulating', 'Reg', (96, 106))	('ICAM-1', 'Gene', '3383', (130, 136))	('down-regulation', 'NegReg', (31, 46))	('miR-486-5p', 'Chemical', '-', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
29246	33935718	It is speculated that ICAM-1 might be regulated by miR-486-5p and played a crucial role in development and metastasis of ESCC.	('role', 'Reg', (83, 87))	('miR-486-5p', 'Chemical', '-', (51, 61))	('ICAM-1', 'Gene', '3383', (22, 28))	('played', 'Reg', (66, 72))	('regulated', 'Reg', (38, 47))	('ESCC', 'Disease', (121, 125))	('ICAM-1', 'Gene', (22, 28))	('miR-486-5p', 'Var', (51, 61))
29247	33935718	Therefore, inhibition of ICAM-1 might be a potential strategy for ESCC treatment.	('ICAM-1', 'Gene', '3383', (25, 31))	('ICAM-1', 'Gene', (25, 31))	('inhibition', 'Var', (11, 21))	('ESCC', 'Disease', (66, 70))
29256	33935718	Moreover, miRNA-34b played an oncogenic role in ESCC development, the polymorphisms of rs4938723/pri-miR-34b/c were associated with ESCC susceptibility based an analysis on a large number of Chinese population.	('miR-34b', 'Gene', (101, 108))	('miR-34b', 'Gene', '407041', (101, 108))	('associated with', 'Reg', (116, 131))	('rs4938723', 'Mutation', 'rs4938723', (87, 96))	('miRNA-34b', 'Gene', (10, 19))	('miRNA-34b', 'Gene', '407041', (10, 19))	('polymorphisms', 'Var', (70, 83))	('ESCC', 'Disease', (48, 52))	('ESCC', 'Disease', (132, 136))
29261	33935718	Aberrant expression of MMP12 was reported in several types of cancers, including hepatocellular carcinoma, lung cancer, colon cancer and nasopharyngeal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('MMP12', 'Gene', '4321', (23, 28))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('MMP12', 'Gene', (23, 28))	('carcinoma', 'Disease', (152, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Aberrant', 'Var', (0, 8))	('carcinoma', 'Disease', (96, 105))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('reported', 'Reg', (33, 41))	('carcinoma', 'Disease', 'MESH:D009369', (152, 161))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (137, 161))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('carcinoma', 'Disease', 'MESH:D009369', (96, 105))	('lung cancer', 'Disease', (107, 118))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))	('hepatocellular carcinoma', 'Disease', (81, 105))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('colon cancer', 'Disease', (120, 132))
29267	33935718	A recent study showed that overexpression of MMP12 was identified in cohorts of resectable tumor tissues compared with normal squamous epithelium, and overexpression of MMP12 was correlated with poor overall survival in ESCCs.	('MMP12', 'Gene', (45, 50))	('overexpression', 'Var', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('MMP12', 'Gene', (169, 174))	('ESCCs', 'Disease', (220, 225))	('poor', 'NegReg', (195, 199))	('overall', 'MPA', (200, 207))	('MMP12', 'Gene', '4321', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('overexpression', 'PosReg', (27, 41))	('tumor', 'Disease', (91, 96))	('MMP12', 'Gene', '4321', (169, 174))
29275	33935718	We found that abnormal expression of MMP12 was significantly correlated with pathological degree, TNM stage, lymph nodes metastasis, survival time of ESCC patients.	('survival time', 'CPA', (133, 146))	('MMP12', 'Gene', '4321', (37, 42))	('abnormal', 'Var', (14, 22))	('TNM', 'Gene', (98, 101))	('MMP12', 'Gene', (37, 42))	('lymph nodes metastasis', 'CPA', (109, 131))	('correlated', 'Reg', (61, 71))	('patients', 'Species', '9606', (155, 163))	('TNM', 'Gene', '10178', (98, 101))	('expression', 'MPA', (23, 33))
29331	32650400	ANA and MDA5 antibodies are reported to be associated with a reduced risk of dysphagia.	('dysphagia', 'Disease', 'MESH:D003680', (77, 86))	('antibodies', 'Var', (13, 23))	('dysphagia', 'Disease', (77, 86))	('MDA5', 'Gene', '64135', (8, 12))	('dysphagia', 'Phenotype', 'HP:0002015', (77, 86))	('reduced', 'NegReg', (61, 68))	('MDA5', 'Gene', (8, 12))
29383	32650400	In addition, the antibody is associated with calcinosis and in adult patients possibly also with malignancy.	('calcinosis', 'Phenotype', 'HP:0003761', (45, 55))	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('calcinosis', 'Disease', 'MESH:D002114', (45, 55))	('associated', 'Reg', (29, 39))	('patients', 'Species', '9606', (69, 77))	('antibody', 'Var', (17, 25))	('malignancy', 'Disease', (97, 107))	('calcinosis', 'Disease', (45, 55))
29434	32517780	Pathogenic microorganisms such as Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia lead to chronic inflammation and destruction of periodontal soft and hard tissues.	('inflammation', 'Disease', 'MESH:D007249', (121, 133))	('Treponema denticola', 'Species', '158', (60, 79))	('lead to', 'Reg', (105, 112))	('inflammation', 'Disease', (121, 133))	('Porphyromonas gingivalis', 'Species', '837', (34, 58))	('Treponema denticola', 'Disease', (60, 79))	('Tannerella forsythia', 'Species', '28112', (84, 104))	('Porphyromonas gingivalis', 'Var', (34, 58))
29610	30121626	The direct mechanical effect of central obesity on oesophageal adenocarcinoma risk is widely accepted; central adiposity amplifies intra-gastric pressure and disturbs normal sphincter function, culminating in a higher propensity for GERD and subsequent increased risk of malignant transformation.	('oesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (51, 77))	('malignant transformation', 'CPA', (271, 295))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (52, 77))	('GERD', 'Disease', (233, 237))	('central adiposity', 'Var', (103, 120))	('central obesity', 'Disease', (32, 47))	('amplifies', 'PosReg', (121, 130))	('intra-gastric pressure', 'MPA', (131, 153))	('disturbs', 'NegReg', (158, 166))	('GERD', 'Disease', 'MESH:D005764', (233, 237))	('obesity', 'Phenotype', 'HP:0001513', (40, 47))	('central obesity', 'Disease', 'MESH:D056128', (32, 47))	('oesophageal adenocarcinoma', 'Disease', (51, 77))	('normal sphincter function', 'MPA', (167, 192))	('central obesity', 'Phenotype', 'HP:0012743', (32, 47))
29669	30121626	The posthoc cross-classification results:in which the strongest associations with oesophageal adenocarcinoma were observed for subjects with high TNFR2 and high/medium TNFA:may point to the importance of uncontrolled chronic inflammation in this disease process.	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('oesophageal adenocarcinoma', 'Disease', (82, 108))	('TNFA', 'Gene', (168, 172))	('high/medium', 'Var', (156, 167))	('TNFR2', 'Gene', (146, 151))	('inflammation', 'Disease', (225, 237))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (82, 108))	('TNFA', 'Gene', '7124', (168, 172))	('associations', 'Interaction', (64, 76))	('high', 'Var', (141, 145))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (83, 108))	('TNFR2', 'Gene', '7133', (146, 151))
29672	30121626	In addition, bile acids have been suggested to elicit a proinflammatory response (including upregulation of TNFA) which could induce oxidative damage and further increase risk of malignancy.	('bile acids', 'Chemical', 'MESH:D001647', (13, 23))	('induce', 'Reg', (126, 132))	('malignancy', 'Disease', (179, 189))	('increase', 'PosReg', (162, 170))	('TNFA', 'Gene', '7124', (108, 112))	('TNFA', 'Gene', (108, 112))	('proinflammatory response', 'MPA', (56, 80))	('upregulation', 'PosReg', (92, 104))	('bile acids', 'Var', (13, 23))	('oxidative damage', 'MPA', (133, 149))	('malignancy', 'Disease', 'MESH:D009369', (179, 189))
29739	29344149	Interestingly, HDGF mRNA expression was augmented as the WHO grades increased (*P<0.05) and was higher in subjects whose Ki-67 index >=20% (*P<0.05) and KPS <80 (*P<0.05).	('HDGF', 'Gene', (15, 19))	('higher', 'PosReg', (96, 102))	('KPS <80', 'Var', (153, 160))	('HDGF', 'Gene', '3068', (15, 19))	('augmented', 'PosReg', (40, 49))	('increased', 'PosReg', (68, 77))
29748	29344149	The quantity of HDGF expression was significantly higher in glioma tissues with Ki-67 index >=20%, KPS <80 and grades II ~IV than in those with Ki-67 index <20%, KPS >=80 and grades I (Table II; *P<0.05).	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('higher', 'PosReg', (50, 56))	('grades II', 'Var', (111, 120))	('HDGF', 'Gene', (16, 20))	('expression', 'MPA', (21, 31))	('glioma', 'Disease', (60, 66))	('Ki-67 index >=20%', 'Var', (80, 97))	('KPS <80', 'Var', (99, 106))	('HDGF', 'Gene', '3068', (16, 20))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
29750	29344149	102 glioma patients (78.5%) died during follow-up (80 from the HDGF high expression group (level 2) and 22 from the HDGF low expression group (level 0 and 1)).	('HDGF', 'Gene', '3068', (116, 120))	('HDGF', 'Gene', '3068', (63, 67))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('high expression', 'Var', (68, 83))	('HDGF', 'Gene', (116, 120))	('glioma', 'Disease', 'MESH:D005910', (4, 10))	('patients', 'Species', '9606', (11, 19))	('HDGF', 'Gene', (63, 67))	('glioma', 'Disease', (4, 10))
29751	29344149	Among the 102 dead patients, 6 died because of accidents or other diseases not directly related to gliomas (4 from HDGF high expression group (level 2) and 2 from the HDGF low expression group (level 0 and 1)).	('accidents', 'Disease', (47, 56))	('HDGF', 'Gene', (115, 119))	('patients', 'Species', '9606', (19, 27))	('accidents', 'Disease', 'MESH:D000081084', (47, 56))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('HDGF', 'Gene', (167, 171))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('HDGF', 'Gene', '3068', (115, 119))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('high expression group', 'Var', (120, 141))	('HDGF', 'Gene', '3068', (167, 171))
29772	29344149	Zhang et al revealed that the knockdown of HDGF significantly inhibited tumorigenesis as well as colony formation, migration and invasion of U87 glioma cells.	('HDGF', 'Gene', '3068', (43, 47))	('glioma', 'Disease', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('colony formation', 'CPA', (97, 113))	('migration', 'CPA', (115, 124))	('tumor', 'Disease', (72, 77))	('invasion', 'CPA', (129, 137))	('HDGF', 'Gene', (43, 47))	('U87', 'CellLine', 'CVCL:0022', (141, 144))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('inhibited', 'NegReg', (62, 71))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('knockdown', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
29773	29344149	Song et al's observed in their early studies that knocking out of HDGF obviously inhibited the formation, development and spread of glioma cell as well as restored the expression of E-cadherin and inhabited the biomarkers of mesenchymal cell such as beta-catenin and N-cadherin and vimentin.	('vimentin', 'Gene', '7431', (282, 290))	('glioma', 'Disease', (132, 138))	('formation', 'CPA', (95, 104))	('vimentin', 'Gene', (282, 290))	('development', 'CPA', (106, 117))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('HDGF', 'Gene', (66, 70))	('expression', 'MPA', (168, 178))	('HDGF', 'Gene', '3068', (66, 70))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('inhibited', 'NegReg', (81, 90))	('restored', 'PosReg', (155, 163))	('beta-catenin', 'Gene', (250, 262))	('beta-catenin', 'Gene', '1499', (250, 262))	('knocking out', 'Var', (50, 62))	('E-cadherin', 'Gene', (182, 192))	('N-cadherin', 'Gene', (267, 277))	('E-cadherin', 'Gene', '999', (182, 192))	('N-cadherin', 'Gene', '1000', (267, 277))
29806	27956966	Adhesions tend to bring the parietal surface of the viscera in contact with the abdominal wall, and portal hypertension results in the formation of varices below intestinal mucosa.	('Adhesions', 'Var', (0, 9))	('hypertension', 'Phenotype', 'HP:0000822', (107, 119))	('varices', 'Disease', (148, 155))	('portal', 'Var', (100, 106))	('hypertension', 'Disease', 'MESH:D006973', (107, 119))	('results in', 'Reg', (120, 130))	('Adhesions tend', 'Phenotype', 'HP:0100550', (0, 14))	('portal hypertension', 'Phenotype', 'HP:0001409', (100, 119))	('hypertension', 'Disease', (107, 119))
29848	27756419	Patients are only included if the tumour is considered resectable (cT1b-4a, N0-3, M0) and the bulk of the tumour is located in the distal or mid esophagus (distal to the level of the carina) or at the level of the cardia-esophageal junction (up to Siewert II).	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('cardia-esophageal junction', 'Disease', 'MESH:D004938', (214, 240))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Disease', (106, 112))	('cardia-esophageal junction', 'Disease', (214, 240))	('cT1b-4a', 'Var', (67, 74))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
29891	27756419	A better healing of the IEA might be explained by resecting the relatively ischemic tip of the gastric tube, providing better vascularized tissue for anastomosis.	('IEA', 'Chemical', '-', (24, 27))	('ischemic tip of the gastric tube', 'Disease', (75, 107))	('ischemic tip of the gastric tube', 'Disease', 'MESH:D060725', (75, 107))	('better', 'PosReg', (2, 8))	('resecting', 'Var', (50, 59))	('healing', 'CPA', (9, 16))
30203	32638533	Abnormalities related to oral fungi and parasites might also be associated with carcinogenesis, though the evidence regarding their role is lacking (Figure 1; Tables 1 and 2).	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('associated', 'Reg', (64, 74))	('Abnormalities', 'Var', (0, 13))	('carcinogenesis', 'Disease', (80, 94))
30216	32638533	Studies have also revealed a close relationship between F. nucleatum-positive CRC and diet, 51 ,  75  demonstrating the complexity of the bacteria-cancer interacting network.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('bacteria-cancer', 'Disease', (138, 153))	('bacteria-cancer', 'Disease', 'MESH:D009369', (138, 153))	('F. nucleatum', 'Species', '851', (56, 68))	('F. nucleatum-positive', 'Var', (56, 77))	('CRC', 'Phenotype', 'HP:0003003', (78, 81))
30219	32638533	40  Recently, high F. nucleatum burden exhibited a poor chemotherapeutic response in two cohorts, 52  suggesting that F. nucleatum might impair the effect of chemotherapy and upregulate the drug tolerance in ESCC.	('ESCC', 'Disease', (208, 212))	('impair', 'NegReg', (137, 143))	('upregulate', 'PosReg', (175, 185))	('effect of chemotherapy', 'CPA', (148, 170))	('F. nucleatum', 'Var', (118, 130))	('F. nucleatum', 'Species', '851', (118, 130))	('drug tolerance', 'CPA', (190, 204))	('F. nucleatum', 'Species', '851', (19, 31))
30221	32638533	However, during the progression of pancreatic cancer, phylum Fusobacteria was associated with lower pancreatic cancer risk.	('pancreatic cancer', 'Disease', (100, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (100, 117))	('pancreatic cancer', 'Disease', (35, 52))	('lower', 'NegReg', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (100, 117))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (35, 52))	('phylum Fusobacteria', 'Var', (54, 73))
30225	32638533	57  Due to its property of perturbing epithelial tissues and host defense mechanisms, P. gingivalis has recently been considered to have potential influence on the development of tumors.	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('P. gingivalis', 'Var', (86, 99))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('P. gingivalis', 'Species', '837', (86, 99))	('perturbing', 'Reg', (27, 37))	('influence', 'Reg', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))
30227	32638533	41  As orodigestive tract is a continuous smooth passage, P. gingivalis, which has substantial abilities of mobility and invasion when compared with other oral bacteria, could possibly spread through the whole area and accelerate the process of in-situ tumorigenesis.	('accelerate', 'PosReg', (219, 229))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('P. gingivalis', 'Species', '837', (58, 71))	('P. gingivalis', 'Var', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))
30231	32638533	59  Connection between oral bacteria and esophageal cancer has recently been confirmed through a clinical research suggesting that higher levels of P. gingivalis were associated with a higher incidence of ESCC.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('P. gingivalis', 'Species', '837', (148, 161))	('P. gingivalis', 'Var', (148, 161))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('associated', 'Reg', (167, 177))
30237	32638533	62  Association of P. gingivalis with higher risk of pancreatic cancer was demonstrated by 16S rRNA sequencing of oral wash samples.	('P. gingivalis', 'Species', '837', (19, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('pancreatic cancer', 'Disease', (53, 70))	('P. gingivalis', 'Var', (19, 32))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
30238	32638533	27  Based on previous studies, serum antibody level of P. gingivalis could serve as a clinical biomarker for pancreatic cancer, as P. gingivalis serum antibody level was positively correlated with orodigestive cancer mortality.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mortality', 'Disease', 'MESH:D003643', (217, 226))	('correlated with', 'Reg', (181, 196))	('cancer', 'Disease', (120, 126))	('pancreatic cancer', 'Disease', (109, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('P. gingivalis', 'Species', '837', (55, 68))	('P. gingivalis', 'Species', '837', (131, 144))	('P. gingivalis', 'Var', (131, 144))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('mortality', 'Disease', (217, 226))	('cancer', 'Disease', (210, 216))
30244	32638533	79 ,  80  Thus, it might be speculated that P. gingivalis originating in the oral cavity may spread to the cancer sites or may disturb the immune system to accelerate the development of pancreatic cancer.	('P. gingivalis', 'Var', (44, 57))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('P. gingivalis', 'Species', '837', (44, 57))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('pancreatic cancer', 'Disease', (186, 203))	('disturb', 'Reg', (127, 134))	('pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('disturb the immune system', 'Phenotype', 'HP:0002715', (127, 152))	('accelerate', 'PosReg', (156, 166))	('cancer', 'Disease', (107, 113))	('immune system', 'CPA', (139, 152))
30252	32638533	As a predominant salivary genus, variation in its levels is proposed to be linked to abnormalities including cancers.	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('abnormalities', 'Disease', (85, 98))	('cancers', 'Disease', (109, 116))	('levels', 'MPA', (50, 56))	('linked', 'Reg', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('variation', 'Var', (33, 42))
30289	32638533	38  It could be speculated that variations in the levels of oral parasites and fungi might be associated with oral carcinogenesis, but lack of adequate evidence prevents us from arriving at a definite conclusion.	('variations', 'Var', (32, 42))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (110, 129))	('associated', 'Reg', (94, 104))	('oral carcinogenesis', 'Disease', (110, 129))
30326	32638533	Thus, there is ample evidence to speculate that after translocation, oral microbiota could contribute to cancer development in regions other than the oral cavity.	('contribute', 'Reg', (91, 101))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('translocation', 'Var', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
30364	32638533	134  With accumulation of genetic alterations, transformation from normal cell to invasive cancer cell finally takes place.	('cancer', 'Disease', (91, 97))	('genetic alterations', 'Var', (26, 45))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
30367	32638533	82  Based on the finding that F. nucleatum could interact with intestinal epithelium as well as with oral epithelium, studies have identified that F. nucleatum could initiate the host molecules of normal oral epithelium and promote the predisposition to malignant transformation through epithelial-mesenchymal transition.	('initiate', 'PosReg', (166, 174))	('malignant transformation', 'CPA', (254, 278))	('F. nucleatum', 'Var', (147, 159))	('F. nucleatum', 'Species', '851', (30, 42))	('F. nucleatum', 'Species', '851', (147, 159))	('promote', 'PosReg', (224, 231))	('epithelial-mesenchymal transition', 'CPA', (287, 320))
30372	32638533	P. gingivalis-induced promotion of antiapoptotic activity is the best example to explain the role of oral microbiota in this phenomenon.	('promotion', 'PosReg', (22, 31))	('P. gingivalis-induced', 'Var', (0, 21))	('antiapoptotic activity', 'MPA', (35, 57))	('P. gingivalis', 'Species', '837', (0, 13))
30373	32638533	Reportedly, P. gingivalis induces changes in the intrinsic mitochondrial apoptotic activity via JAK1/AKT/STAT3 pathway.	('intrinsic mitochondrial apoptotic activity', 'MPA', (49, 91))	('JAK1/AKT/STAT3 pathway', 'Pathway', (96, 118))	('changes', 'Reg', (34, 41))	('P. gingivalis', 'Species', '837', (12, 25))	('P. gingivalis', 'Var', (12, 25))
30388	32638533	146 ,  147  Gingipains produced by P. gingivalis are major pathogenic substances whose pathologic features have been reported in periodontitis and Alzheimer's disease.	('periodontitis', 'Disease', 'MESH:D010518', (129, 142))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (147, 166))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (147, 166))	("Alzheimer's disease", 'Disease', (147, 166))	('periodontitis', 'Phenotype', 'HP:0000704', (129, 142))	('periodontitis', 'Disease', (129, 142))	('P. gingivalis', 'Species', '837', (35, 48))	('P. gingivalis', 'Var', (35, 48))
30531	32194792	Tumors were staged into various pathologic stage groups (pTNM) as follows according to the 8th edition of the AJCC staging system for ESCC: pStage 0 (pTis), pStage IA (pT1aN0M0G1) and pStage IB (pT1aN0M0G2-3, pT1bN0M0 and pT2N0M0G1), pStage IIA (pT2N0M0G2-3 cancers, pT3N0M0 cancers of the lower thoracic esophagus and pT3N0M0G1 cancers of the upper middle thoracic esophagus), pStage IIB (pT3N0M0G2-3 cancers of the upper middle thoracic esophagus and pT1N1M0 cancers), pStage IIIA (pT2N1M0 and pT1N2M0), pStage IIIB (pT2N2M0, pT3N1-2M0 and pT4aN0-1M0) and pStage IVA (pT4aN2M0, pT4bN0-2M0 and pTanyN3M0) (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('pT3', 'Gene', (267, 270))	('pT3', 'Gene', (528, 531))	('cancers of the upper middle thoracic esophagus', 'Disease', 'MESH:D004938', (402, 448))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('pT4aN2M0', 'Var', (570, 578))	('cancers', 'Disease', 'MESH:D009369', (402, 409))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('TNM', 'Gene', '10178', (58, 61))	('pT3', 'Gene', (319, 322))	('cancers of the upper middle thoracic esophagus', 'Disease', 'MESH:D004938', (329, 375))	('pT4aN0-1M0', 'Var', (542, 552))	('pT4bN0-2M0', 'Var', (580, 590))	('pTanyN3M0', 'Var', (595, 604))	('cancer', 'Phenotype', 'HP:0002664', (461, 467))	('TNM', 'Gene', (58, 61))	('cancers', 'Disease', 'MESH:D009369', (329, 336))	('Tumors', 'Disease', (0, 6))	('pT2N2M0', 'Var', (519, 526))	('IVA', 'Disease', (565, 568))	('cancers', 'Disease', 'MESH:D009369', (258, 265))	('pT3', 'Gene', (390, 393))	('pT3', 'Gene', '7694', (267, 270))	('cancers', 'Phenotype', 'HP:0002664', (461, 468))	('cancers', 'Disease', (461, 468))	('pT3', 'Gene', '7694', (528, 531))	('cancers', 'Phenotype', 'HP:0002664', (402, 409))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('cancers', 'Disease', (402, 409))	('cancers of the upper middle thoracic esophagus', 'Disease', (402, 448))	('pT3', 'Gene', '7694', (319, 322))	('cancers', 'Disease', (275, 282))	('cancer', 'Phenotype', 'HP:0002664', (402, 408))	('IVA', 'Disease', 'MESH:C538167', (565, 568))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('ESCC', 'Disease', 'MESH:D002294', (134, 138))	('cancers', 'Phenotype', 'HP:0002664', (329, 336))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('ESCC', 'Disease', (134, 138))	('cancers', 'Disease', (329, 336))	('cancers of the upper middle thoracic esophagus', 'Disease', (329, 375))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('pT3', 'Gene', '7694', (390, 393))	('cancers', 'Disease', (258, 265))	('cancers', 'Disease', 'MESH:D009369', (461, 468))
30532	32194792	Post-neoadjuvant pathologic stage groups (ypTNM) included ypStage I (ypT0-2N0M0 cancers), ypStage II (ypT3N0M0), ypStage IIIA (ypT0-2N1M1), ypStage IIIB (ypT1-3N2M0, ypT3N1M0 and ypT4aN0M0 cancers) and ypStage IVA (ypT4aN1-2M0, ypT4bN0-2M0 and ypTanyN3M0) (Table 1).	('IVA', 'Disease', (210, 213))	('pT3', 'Gene', '7694', (167, 170))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('pT3', 'Gene', '7694', (103, 106))	('TNM', 'Gene', '10178', (44, 47))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('TNM', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ypT4bN0-2M0', 'Var', (228, 239))	('IVA', 'Disease', 'MESH:C538167', (210, 213))	('ypT1', 'Gene', '5861', (154, 158))	('ypT4aN1-2M0', 'Var', (215, 226))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('pT3', 'Gene', (167, 170))	('cancers', 'Disease', (80, 87))	('ypT1', 'Gene', (154, 158))	('pT3', 'Gene', (103, 106))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('cancers', 'Disease', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))
30669	31119136	Numerous studies have indicated that aberrant expression levels of exosomal miRNAs are closely related to the onset of multiple diseases, including cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('exosomal miRNAs', 'Protein', (67, 82))	('related', 'Reg', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('expression levels', 'MPA', (46, 63))	('multiple diseases', 'Disease', (119, 136))	('multiple diseases', 'Disease', 'MESH:D000015', (119, 136))	('aberrant', 'Var', (37, 45))
30671	31119136	MiR-93-5p: MicroRNA-93-5p can be transferred between EC9706 cells by exosomes and promote the proliferation of recipient EC9706 cells.	('MiR-93-5p', 'Gene', '100126325', (0, 9))	('promote', 'PosReg', (82, 89))	('MicroRNA-93-5p', 'Var', (11, 25))	('EC9706', 'CellLine', 'CVCL:E307', (121, 127))	('MiR-93-5p', 'Gene', (0, 9))	('proliferation', 'CPA', (94, 107))	('EC9706', 'CellLine', 'CVCL:E307', (53, 59))
30687	31119136	MiR-223-3p: Exo-miRNAs are also important biomarkers for EA diagnosis and progression.	('MiR-223', 'Gene', (0, 7))	('MiR-223', 'Gene', '407008', (0, 7))	('EA', 'Phenotype', 'HP:0011459', (57, 59))	('Exo-miRNAs', 'Var', (12, 22))
30689	31119136	Results showed that a total of eight miRNAs (miR-126-5p, miR-146a-5p, miR-192-5p, miR-196b-5p, miR-223-3p, miR-223-5p, miR-409-3p and miR-483-5p) were significantly overexpressed.	('miR-483-5p', 'Var', (134, 144))	('miR-1', 'Gene', '83856', (70, 75))	('miR-192', 'Gene', '406967', (70, 77))	('miR-223', 'Gene', (95, 102))	('miR-1', 'Gene', (70, 75))	('miR-223', 'Gene', '407008', (107, 114))	('miR-1', 'Gene', '83856', (45, 50))	('miR-126-5p', 'Gene', '100302116', (45, 55))	('miR-126-5p', 'Gene', (45, 55))	('miR-1', 'Gene', '83856', (82, 87))	('miR-1', 'Gene', (45, 50))	('miR-192', 'Gene', (70, 77))	('miR-223', 'Gene', '407008', (95, 102))	('miR-1', 'Gene', (82, 87))	('miR-1', 'Gene', '83856', (57, 62))	('overexpressed', 'PosReg', (165, 178))	('miR-1', 'Gene', (57, 62))	('miR-223', 'Gene', (107, 114))	('miR-409-3p', 'Var', (119, 129))
30690	31119136	Conversely, ten miRNAs (miR-22-3p, miR-23b-5p, miR-27b-3p, miR-149-5p, miR-203-5p, miR-224-5p, miR-452-5p, miR-671-3p, miR-944-5p and miR-1201-5p) were significantly downregulated.	('miR-27b', 'Gene', (47, 54))	('miR-1', 'Gene', (134, 139))	('miR-22-3p', 'Gene', '407008', (24, 33))	('miR-1', 'Gene', '83856', (59, 64))	('miR-203-5p', 'Var', (71, 81))	('miR-27b', 'Gene', '407019', (47, 54))	('miR-224-5p', 'Var', (83, 93))	('downregulated', 'NegReg', (166, 179))	('miR-944', 'Gene', (119, 126))	('miR-22-3p', 'Gene', (24, 33))	('miR-1', 'Gene', (59, 64))	('miR-1201', 'Gene', '100113391', (134, 142))	('miR-671-3p', 'Var', (107, 117))	('miR-23b', 'Gene', '407011', (35, 42))	('miR-944', 'Gene', '100126340', (119, 126))	('miR-452-5p', 'Var', (95, 105))	('miR-1201', 'Gene', (134, 142))	('miR-23b', 'Gene', (35, 42))	('miR-1', 'Gene', '83856', (134, 139))
30692	31119136	There was no statistical difference in the overexpression of miR-223-5p and miR-483-5p in EA and ESCC.	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('miR-223', 'Gene', (61, 68))	('SCC', 'Gene', '6317', (98, 101))	('EA', 'Phenotype', 'HP:0011459', (90, 92))	('miR-483-5p', 'Var', (76, 86))	('miR-223', 'Gene', '407008', (61, 68))	('SCC', 'Gene', (98, 101))
30693	31119136	MiR-584: A four-stage study including screening, training, testing and validating identified that miR-106a, miR-18a, miR-20b, miR-486-5p and miR-584 were upregulated, but miR-223-3p was downregulated in the plasma of patients with ESCC.	('miR-18a', 'Gene', (108, 115))	('MiR-584', 'Gene', '693169', (0, 7))	('miR-223', 'Gene', '407008', (171, 178))	('SCC', 'Gene', '6317', (232, 235))	('upregulated', 'PosReg', (154, 165))	('miR-20b', 'Gene', (117, 124))	('miR-106a', 'Gene', (98, 106))	('SCC', 'Gene', (232, 235))	('miR-18a', 'Gene', '406953', (108, 115))	('miR-584', 'Gene', '693169', (141, 148))	('MiR-584', 'Gene', (0, 7))	('miR-20b', 'Gene', '574032', (117, 124))	('patients', 'Species', '9606', (217, 225))	('miR-584', 'Gene', (141, 148))	('miR-223', 'Gene', (171, 178))	('miR-106a', 'Gene', '406899', (98, 106))	('miR-486-5p', 'Var', (126, 136))	('SCC', 'Phenotype', 'HP:0002860', (232, 235))	('downregulated', 'NegReg', (186, 199))
30703	31119136	Kang et al demonstrated that long non-coding RNA PART1, as a competitive endogenous RNA, regulated and transported by exosomes, took part in the formation of drug resistance in ESCC patients via the STAT1-long non-coding RNA PART-Bcl-2 pathway in a gefitinib drug-resistant cell line.	('STAT1', 'Gene', (199, 204))	('STAT1', 'Gene', '6772', (199, 204))	('drug resistance', 'Phenotype', 'HP:0020174', (158, 173))	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('SCC', 'Gene', '6317', (178, 181))	('drug resistance', 'MPA', (158, 173))	('gefitinib', 'Chemical', 'MESH:D000077156', (249, 258))	('long non-coding', 'Var', (29, 44))	('Bcl-2', 'Gene', (230, 235))	('patients', 'Species', '9606', (182, 190))	('Bcl-2', 'Gene', '596', (230, 235))	('formation', 'MPA', (145, 154))	('took part', 'Reg', (128, 137))	('SCC', 'Gene', (178, 181))
30758	29451181	Signs of portal hypertension, such as history of ascites and esophageal varices, were more frequent in the PVT group than in the non-PVT group (P = 0.05 and <0.000, respectively).	('hypertension', 'Phenotype', 'HP:0000822', (16, 28))	('portal hypertension', 'Phenotype', 'HP:0001409', (9, 28))	('PVT', 'Var', (107, 110))	('esophageal varices', 'Phenotype', 'HP:0002040', (61, 79))	('PVT', 'Phenotype', 'HP:0030242', (133, 136))	('ascites', 'Disease', (49, 56))	('ascites', 'Phenotype', 'HP:0001541', (49, 56))	('hypertension', 'Disease', 'MESH:D006973', (16, 28))	('ascites', 'Disease', 'MESH:D001201', (49, 56))	('esophageal varices', 'Disease', (61, 79))	('PVT', 'Phenotype', 'HP:0030242', (107, 110))	('hypertension', 'Disease', (16, 28))
30796	28904855	Over-expression of miR-483-3p results in a poor prognosis for patients through promoting ESCC progression as a result of targeting EI24 6.	('promoting', 'PosReg', (79, 88))	('miR-483-3p', 'Var', (19, 29))	('Over-expression', 'PosReg', (0, 15))	('ESCC', 'Disease', (89, 93))	('patients', 'Species', '9606', (62, 70))	('EI24 6', 'Gene', (131, 137))
30798	28904855	The expression of protease, serine 8 (PRSS8) with hypermethylation is significantly decreased in ESCC, which predicts a shorter overall survival of patients with ESCC.	('patients', 'Species', '9606', (148, 156))	('overall survival', 'MPA', (128, 144))	('shorter', 'NegReg', (120, 127))	('PRSS8', 'Gene', '5652', (38, 43))	('decreased', 'NegReg', (84, 93))	('expression', 'MPA', (4, 14))	('hypermethylation', 'Var', (50, 66))	('PRSS8', 'Gene', (38, 43))	('ESCC', 'Disease', (97, 101))
30799	28904855	Demethylation of PRSS8 contributes to the inhibition of tumor progression, including cell proliferation, migration and cell cycle arrest 8.	('cell proliferation', 'CPA', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PRSS8', 'Gene', '5652', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('Demethylation', 'Var', (0, 13))	('cell cycle arrest 8', 'CPA', (119, 138))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (119, 136))	('migration', 'CPA', (105, 114))	('inhibition', 'NegReg', (42, 52))	('PRSS8', 'Gene', (17, 22))
30824	28904855	In total, 1322 genes associated with the tumor grade of ESCC were significantly enriched in 14 signaling pathways, including pathways in cancer (hsa05200), the phospholipase D signaling pathway (hsa04072), small cell lung cancer (hsa05222) and gastric acid secretion (hsa04971) (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('phospholipase D signaling pathway', 'Pathway', (160, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('cancer', 'Disease', (137, 143))	('small cell lung cancer', 'Disease', 'MESH:D055752', (206, 228))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('signaling pathways', 'Pathway', (95, 113))	('enriched', 'Reg', (80, 88))	('small cell lung cancer', 'Disease', (206, 228))	('cancer', 'Disease', (222, 228))	('gastric acid secretion', 'Disease', (244, 266))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Disease', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (206, 228))	('ESCC', 'Disease', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('hsa04072', 'Var', (195, 203))
30849	28904855	Self-aggregation of TIAF1in the human hippocampus leads to the generation of amyloid beta plaques, which results in neurodegeneration in Alzheimer's disease 18.	('TIAF1', 'Gene', '9220', (20, 25))	('amyloid beta plaques', 'MPA', (77, 97))	('Self-aggregation', 'Var', (0, 16))	("Alzheimer's disease", 'Disease', (137, 156))	('TIAF1', 'Gene', (20, 25))	('results in', 'Reg', (105, 115))	('neurodegeneration', 'Phenotype', 'HP:0002180', (116, 133))	('human', 'Species', '9606', (32, 37))	('neurodegeneration', 'Disease', (116, 133))	('neurodegeneration', 'Disease', 'MESH:D019636', (116, 133))	('leads to', 'Reg', (50, 58))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (137, 156))
30869	28904855	However, the expression status of LAMB3 in GSE23400 was in agreement with the previous studies.	('GSE23400', 'Var', (43, 51))	('LAMB3', 'Gene', (34, 39))	('LAMB3', 'Gene', '3914', (34, 39))
30879	28904855	Inhibition of ARNT2 expression promotes NSCLC cell growth in a xenograft model 31.	('ARNT2', 'Gene', '9915', (14, 19))	('promotes', 'PosReg', (31, 39))	('ARNT2', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
30883	28904855	However, the expression status of PPARG in GSE23400 was in agreement with previous studies.	('GSE23400', 'Var', (43, 51))	('PPARG', 'Gene', '5468', (34, 39))	('PPARG', 'Gene', (34, 39))
30884	28904855	PPARG is reported to function as an oncogene in ESCC and the activation of PPARG suppresses cell proliferation and induces cell apoptosis of esophageal cancer cells by inhibiting the TLR-4 dependent mitogen-activated protein kinase pathway 33.	('esophageal cancer', 'Disease', (141, 158))	('inhibiting', 'NegReg', (168, 178))	('suppresses', 'NegReg', (81, 91))	('PPARG', 'Gene', '5468', (75, 80))	('TLR-4', 'Gene', '7099', (183, 188))	('cell apoptosis', 'CPA', (123, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('PPARG', 'Gene', (0, 5))	('PPARG', 'Gene', (75, 80))	('induces', 'Reg', (115, 122))	('PPARG', 'Gene', '5468', (0, 5))	('cell proliferation', 'CPA', (92, 110))	('activation', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('TLR-4', 'Gene', (183, 188))
30959	28405006	The results showed that survival was prolonged by APW, Cisplatin + 5-FU and APW + Cisplatin + 5-FU as compared to control treatment in nude mice with EC-109 xenografts (Fig.	('Cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('nude mice', 'Species', '10090', (135, 144))	('EC-109', 'CellLine', 'CVCL:6898', (150, 156))	('Cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('survival', 'CPA', (24, 32))	('5-FU', 'Chemical', 'MESH:D005472', (94, 98))	('APW', 'Var', (50, 53))	('prolonged', 'PosReg', (37, 46))	('Cisplatin + 5-FU', 'Var', (55, 71))	('5-FU', 'Chemical', 'MESH:D005472', (67, 71))
30966	28405006	In addition, tumor weights were significantly decreased in the group treated with APW + Cisplatin + 5-FU by 51.2%, when compared with control group (mean tumor weight decreased from 2.313 to 1.128 g).	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('5-FU', 'Chemical', 'MESH:D005472', (100, 104))	('Cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('decreased', 'NegReg', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('APW + Cisplatin', 'Var', (82, 97))	('weight decreased', 'Phenotype', 'HP:0004325', (160, 176))	('decreased', 'NegReg', (167, 176))	('tumor', 'Disease', (154, 159))
30981	28405006	The activity of muscle-related enzyme CK was significantly higher in Cisplatin + 5-FU treated mice comparing with control group (p < 0.05).	('5-FU', 'Chemical', 'MESH:D005472', (81, 85))	('muscle-related enzyme CK', 'Enzyme', (16, 40))	('mice', 'Species', '10090', (94, 98))	('higher', 'PosReg', (59, 65))	('Cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('activity', 'MPA', (4, 12))	('Cisplatin + 5-FU', 'Var', (69, 85))
30982	28405006	Meanwhile, no significant difference in the level of CK was found among the control, APW and APW + Cisplatin + 5-FU groups, suggesting that APW treatment not only has no obvious toxicity to the heart, but also attenuated the toxicities of the heart induced by chemotherapeutics (Fig.	('toxicity', 'Disease', 'MESH:D064420', (178, 186))	('toxicity', 'Disease', (178, 186))	('APW', 'Var', (140, 143))	('attenuated', 'NegReg', (210, 220))	('toxicities', 'Disease', (225, 235))	('5-FU', 'Chemical', 'MESH:D005472', (111, 115))	('Cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('toxicities', 'Disease', 'MESH:D064420', (225, 235))
31000	28405006	In addition, the inhibitory effect of AAPC was stronger in the cells exposed to SDF1alpha than that in the cells without SDF1alpha exposure (Fig.	('stronger', 'PosReg', (47, 55))	('AAPC', 'Disease', 'MESH:D011125', (38, 42))	('AAPC', 'Disease', (38, 42))	('inhibitory effect', 'MPA', (17, 34))	('SDF1alpha', 'Var', (80, 89))
31043	28405006	Primary antibodies against p-NFkappaB p65 (pS536), NFkappaB, HER2 and MMP2 were obtained from Cell Signaling Technology, USA.	('NFkappaB', 'Gene', '4790', (29, 37))	('pS536', 'Var', (43, 48))	('MMP2', 'Gene', (70, 74))	('p65', 'Gene', (38, 41))	('NFkappaB', 'Gene', '4790', (51, 59))	('HER2', 'Gene', (61, 65))	('NFkappaB', 'Gene', (51, 59))	('HER2', 'Gene', '2064', (61, 65))	('MMP2', 'Gene', '4313', (70, 74))	('NFkappaB', 'Gene', (29, 37))	('p65', 'Gene', '5970', (38, 41))
31066	28405006	NFkappaB activity was determined by NFkappaB p65 (pS536) + total NFkappaB p65 SimpleStep ELISA kit (Abcam, Cambridge, UK) according to the manufacturer's instruction.	('pS536', 'Var', (50, 55))	('p65', 'Gene', '5970', (45, 48))	('NFkappaB', 'Gene', '4790', (36, 44))	('p65', 'Gene', (74, 77))	('NFkappaB', 'Gene', (0, 8))	('p65', 'Gene', '5970', (74, 77))	('NFkappaB', 'Gene', '4790', (0, 8))	('NFkappaB', 'Gene', '4790', (65, 73))	('NFkappaB', 'Gene', (65, 73))	('p65', 'Gene', (45, 48))	('NFkappaB', 'Gene', (36, 44))
31076	28405006	To quantify the amount of mRNA of TM4SF3, MMP9, HER2 and CXCR4, real time-PCR was carried out as previously described.	('CXCR4', 'Gene', '7852', (57, 62))	('HER2', 'Gene', '2064', (48, 52))	('MMP9', 'Gene', '4318', (42, 46))	('MMP9', 'Gene', (42, 46))	('CXCR4', 'Gene', (57, 62))	('TM4SF3', 'Var', (34, 40))	('HER2', 'Gene', (48, 52))
31107	28266965	Predictors of receiving esophagectomy for patients with T1-3N1M0 mid or distal esophageal cancer in the National Cancer Data Base from 2006 to 2011 were identified using multivariable logistic regression.	('esophageal cancer', 'Disease', (79, 96))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('T1-3N1M0', 'Var', (56, 64))	('patients', 'Species', '9606', (42, 50))
31125	28266965	This retrospective study of patients with locally advanced T1-3N1M0 esophageal cancer in the National Cancer Data Base (NCDB) was approved by the Duke University Institutional Review Board.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('T1-3N1M0', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('esophageal cancer', 'Disease', (68, 85))	('patients', 'Species', '9606', (28, 36))
31137	28266965	A total of 4979 patients with locally advanced T1-3N1M0 esophageal cancer were identified in the NCDB from 2006 to 2011 and met inclusion criteria (Fig.	('esophageal cancer', 'Disease', (56, 73))	('patients', 'Species', '9606', (16, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('T1-3N1M0', 'Var', (47, 55))
31182	20235007	The precursor lesion of ESCC is squamous intraepithelial neoplasia (squamous dysplasia), defined histologically as nuclear atypia (enlargement, pleomorphism and hyperchromasia), loss of normal cellular polarity, and abnormal tissue maturation.	('hyperchromasia', 'Disease', 'None', (161, 175))	('squamous intraepithelial neoplasia', 'Disease', (32, 66))	('squamous dysplasia', 'Disease', (68, 86))	('hyperchromasia', 'Disease', (161, 175))	('pleomorphism', 'Var', (144, 156))	('squamous dysplasia', 'Disease', 'MESH:D002294', (68, 86))	('squamous intraepithelial neoplasia', 'Disease', 'MESH:D019048', (32, 66))	('neoplasia', 'Phenotype', 'HP:0002664', (57, 66))	('ESCC', 'Disease', (24, 28))	('enlargement', 'PosReg', (131, 142))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (41, 66))	('abnormal tissue', 'Phenotype', 'HP:0002664', (216, 231))	('nuclear atypia', 'Disease', (115, 129))	('tissue maturation', 'CPA', (225, 242))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (68, 86))	('loss', 'NegReg', (178, 182))
31200	20235007	Second, circumferential RFA with the HALO360+ has been associated with a low rate of post-RFA stenosis in BE, and if this is true in ESCN as well this would enable treatment of widespread or mosaic-like early ESCN for which ER or ESD would surely result in severe esophageal stricturing.	('HALO360+', 'Chemical', '-', (37, 45))	('esophageal stricturing', 'Disease', (264, 286))	('early ESCN', 'Disease', (203, 213))	('esophageal stricturing', 'Phenotype', 'HP:0002043', (264, 286))	('BE', 'Phenotype', 'HP:0100580', (106, 108))	('result in', 'Reg', (247, 256))	('HALO360+', 'Var', (37, 45))
31201	20235007	Third, RFA in BE is associated with a complete "reset" of genetic abnormalities, and if this is also true in ESCN it may reduce the rate of late recurrences compared to resection techniques where the resection margin is generally less than 2 mm.	('BE', 'Phenotype', 'HP:0100580', (14, 16))	('late recurrences', 'CPA', (140, 156))	('genetic abnormalities', 'Disease', 'MESH:D030342', (58, 79))	('genetic abnormalities', 'Disease', (58, 79))	('reduce', 'NegReg', (121, 127))	('RFA in BE', 'Var', (7, 16))
31212	20235007	Focal ablation using the smaller HALO90 ablation catheter may be considered in these cases, but circumferential treatment with the HALO90 catheter may carry a higher theoretical risk of stenosis due to overlap of adjacent ablation zones The HALO360+ catheter is introduced over the guide-wire and the endoscope is introduced alongside the ablation catheter.	('stenosis', 'MPA', (186, 194))	('HALO90', 'Chemical', '-', (131, 137))	('HALO360+', 'Var', (241, 249))	('HALO90', 'Chemical', '-', (33, 39))	('HALO360+', 'Chemical', '-', (241, 249))
31225	20235007	Future studies should aim at finding the optimal energy setting and technique for circumferential RFA, the relative roles of HALO360+ and HALO90 as primary treatment tools, the optimal of combined ER and RFA treatments, the genetic and other properties of the squamous mucosa that regenerates at the site of the original lesion, and the long-term durability of the treatment outcome.	('HALO90', 'Chemical', '-', (138, 144))	('HALO360+', 'Chemical', '-', (125, 133))	('HALO90', 'Var', (138, 144))	('HALO360+', 'Var', (125, 133))
31244	33316936	Moreover, alterations in drug transporters contribute to inhibition of drug influx and/or increased drug efflux, in turn leading to diminished drug content within the tumor cells.	('alterations', 'Var', (10, 21))	('drug', 'Enzyme', (25, 29))	('drug efflux', 'MPA', (100, 111))	('increased', 'PosReg', (90, 99))	('inhibition', 'NegReg', (57, 67))	('rat', 'Species', '10116', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('drug influx', 'MPA', (71, 82))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('drug content', 'MPA', (143, 155))	('diminished', 'NegReg', (132, 142))
31245	33316936	Adduct formation with glutathione (GSH), methionine, metallothioneins, and other cytoplasmic nucleophiles inactivate cisplatin, maintaining a lower drug concentration within the nucleus.	('rat', 'Species', '10116', (160, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('GSH', 'Chemical', 'MESH:D005978', (35, 38))	('drug concentration', 'MPA', (148, 166))	('lower', 'NegReg', (142, 147))	('methionine', 'Chemical', 'MESH:D008715', (41, 51))	('lower drug concentration', 'Phenotype', 'HP:0020171', (142, 166))	('inactivate', 'NegReg', (106, 116))	('cisplatin', 'MPA', (117, 126))	('glutathione', 'Chemical', 'MESH:D005978', (22, 33))	('Adduct', 'Var', (0, 6))
31249	33316936	Erdafitinib, a fibroblast growth factor receptor inhibitor (FGFR), has also been approved by the U.S. Food and Drug Administration for patients with metastatic bladder cancer exhibiting actionable FGFR alteration.	('rat', 'Species', '10116', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('patients', 'Species', '9606', (135, 143))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('bladder cancer', 'Disease', (160, 174))	('alteration', 'Var', (202, 212))	('rat', 'Species', '10116', (206, 209))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))
31264	33316936	RT4 (grade 1), RT112 (grade 2/3), T24 (grade 3), and TCCSup (grade 4) represent transitional cell carcinomas.	('RT4', 'Var', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinomas', 'Disease', 'MESH:D009369', (98, 108))	('RT112', 'Var', (15, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('carcinomas', 'Disease', (98, 108))	('transitional cell carcinomas', 'Phenotype', 'HP:0006740', (80, 108))
31311	33316936	RT112res cells displayed a higher sensitivity to ART, compared to RT112par (parental: IC50 = 8.72 microM, resistant: IC50 = 2.65 microM, Figure 1B,F).	('ART', 'Chemical', 'MESH:D000077332', (49, 52))	('sensitivity', 'MPA', (34, 45))	('RT112par', 'Chemical', '-', (66, 74))	('RT112res', 'Var', (0, 8))
31312	33316936	In contrast, growth inhibition by ART in TCCSup was stronger in TCCSuppar, compared to the resistant cells (parental: IC50 = 1.97 microM, resistant: IC50 = 2.94 microM, Figure 1D,H).	('TCCSuppar', 'Chemical', '-', (64, 73))	('growth inhibition', 'MPA', (13, 30))	('ART', 'Chemical', 'MESH:D000077332', (34, 37))	('TCCSuppar', 'Var', (64, 73))	('stronger', 'PosReg', (52, 60))
31314	33316936	IC50s at 0.50 microM in T24par and 0.34 microM in T24res cells (Figure 1C,G) also indicate a higher sensitivity to ART in T24res cells.	('higher', 'PosReg', (93, 99))	('0.34 microM', 'Var', (35, 46))	('ART', 'Chemical', 'MESH:D000077332', (115, 118))	('T24par', 'Chemical', '-', (24, 30))	('T24res', 'Chemical', '-', (122, 128))	('T24res', 'Chemical', '-', (50, 56))	('sensitivity to ART', 'MPA', (100, 118))
31318	33316936	As with cell growth, RT112res and T24res exhibited higher sensitivity to ART treatment in regard to proliferation than their corresponding parental counterparts, RT112par and T24par.	('RT112res', 'Var', (21, 29))	('T24res', 'Chemical', '-', (34, 40))	('sensitivity', 'MPA', (58, 69))	('T24par', 'Chemical', '-', (175, 181))	('proliferation', 'CPA', (100, 113))	('RT112par', 'Chemical', '-', (162, 170))	('higher', 'PosReg', (51, 57))	('ART', 'Chemical', 'MESH:D000077332', (73, 76))	('rat', 'Species', '10116', (107, 110))
31319	33316936	In RT112res, exposure to 10 microM ART induced a 31.0% proliferation repression vs. 24.4% for RT112par (Figure 2B).	('ART', 'Chemical', 'MESH:D000077332', (35, 38))	('RT112res', 'Var', (3, 11))	('RT112par', 'Chemical', '-', (94, 102))	('proliferation repression', 'CPA', (55, 79))	('rat', 'Species', '10116', (62, 65))
31329	33316936	Furthermore, treatment with 2.5 microM ART in T24res significantly, but to a lesser extent, induced apoptosis (Figure 3C).	('induced', 'Reg', (92, 99))	('ART', 'Chemical', 'MESH:D000077332', (39, 42))	('T24res', 'Var', (46, 52))	('T24res', 'Chemical', '-', (46, 52))	('apoptosis', 'CPA', (100, 109))
31335	33316936	In good accordance was Cyclin E1, which associates with CDK2 to regulate progression from the G1 into S phase, significantly diminished in T24par after exposure to ART (Figure 4A,I and Figure S1.8).	('CDK2', 'Gene', '1017', (56, 60))	('Cyclin E1', 'Gene', '898', (23, 32))	('Cyclin E1', 'Gene', (23, 32))	('T24par', 'Var', (139, 145))	('CDK2', 'Gene', (56, 60))	('diminished', 'NegReg', (125, 135))	('ART', 'Chemical', 'MESH:D000077332', (164, 167))	('T24par', 'Chemical', '-', (139, 145))
31343	33316936	Moreover, spare respiratory capacity, reflecting cell ability to enhance respiration in response to physiological or pharmacological stress (maximal minus basal respiration), was completely abrogated by ART in T24par and T24res cells (Figure 5A,B).	('T24par', 'Var', (210, 216))	('spare respiratory capacity', 'MPA', (10, 36))	('respiration', 'MPA', (73, 84))	('rat', 'Species', '10116', (166, 169))	('enhance', 'PosReg', (65, 72))	('abrogated', 'NegReg', (190, 199))	('T24res', 'Var', (221, 227))	('rat', 'Species', '10116', (78, 81))	('rat', 'Species', '10116', (21, 24))	('T24par', 'Chemical', '-', (210, 216))	('T24res', 'Chemical', '-', (221, 227))	('ART', 'Chemical', 'MESH:D000077332', (203, 206))
31346	33316936	Since cisplatin causes DNA damage, the expression and activity of poly(ADP-ribose) polymerase 1 (PARP-1), a nuclear enzyme involved in DNA damage repair and DNA stability, was analyzed in the T24 cell lines after ART application.	('cisplatin', 'Chemical', 'MESH:D002945', (6, 15))	('poly(ADP-ribose) polymerase 1', 'Gene', (66, 95))	('poly(ADP-ribose) polymerase 1', 'Gene', '142', (66, 95))	('PARP-1', 'Gene', (97, 103))	('PARP-1', 'Gene', '142', (97, 103))	('ART', 'Chemical', 'MESH:D000077332', (213, 216))	('DNA damage', 'MPA', (23, 33))	('cisplatin', 'Var', (6, 15))
31352	33316936	Inasmuch as the higher concentration of ART resulted in an elevation of apoptotic events and ART primarily accumulates in mitochondria, expression of the key proteins Bcl-2 and Bax, involved in mitochondria-associated apoptosis, was evaluated.	('apoptotic events', 'CPA', (72, 88))	('ART', 'Var', (40, 43))	('Bax', 'Gene', (177, 180))	('ART', 'Chemical', 'MESH:D000077332', (40, 43))	('Bax', 'Gene', '581', (177, 180))	('rat', 'Species', '10116', (30, 33))	('Bcl-2', 'Gene', (167, 172))	('elevation', 'PosReg', (59, 68))	('Bcl-2', 'Gene', '596', (167, 172))	('ART', 'Chemical', 'MESH:D000077332', (93, 96))
31353	33316936	Bcl-2, an apoptosis inhibitor, was significantly down-regulated by ART in both T24par and T24res cells, whereas the expression of Bax, an apoptosis activator, was elevated in the T24res cells, compared to their respective untreated controls (Figure 6A,F,G and Figure S2.4,S2.5).	('ART', 'Chemical', 'MESH:D000077332', (67, 70))	('expression', 'MPA', (116, 126))	('Bax', 'Gene', '581', (130, 133))	('elevated', 'PosReg', (163, 171))	('T24res', 'Var', (179, 185))	('T24res', 'Chemical', '-', (179, 185))	('T24res', 'Chemical', '-', (90, 96))	('down-regulated', 'NegReg', (49, 63))	('Bax', 'Gene', (130, 133))	('T24par', 'Chemical', '-', (79, 85))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))
31371	33316936	Moreover, ART has effectively reduced tumor cell growth of BCa in an orthotopic rat model.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('rat', 'Species', '10116', (80, 83))	('ART', 'Var', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('reduced', 'NegReg', (30, 37))	('ART', 'Chemical', 'MESH:D000077332', (10, 13))	('BCa', 'Phenotype', 'HP:0009725', (59, 62))
31382	33316936	Moreover, up-regulation and gain-of-function manipulation of p21 has been proposed as a promising strategy to inhibit bladder tumor cell growth.	('bladder tumor', 'Disease', 'MESH:D001749', (118, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('bladder tumor', 'Phenotype', 'HP:0009725', (118, 131))	('manipulation', 'Var', (45, 57))	('p21', 'Gene', '1026', (61, 64))	('gain-of-function', 'PosReg', (28, 44))	('bladder tumor', 'Disease', (118, 131))	('inhibit', 'NegReg', (110, 117))	('rat', 'Species', '10116', (100, 103))	('p21', 'Gene', (61, 64))	('up-regulation', 'PosReg', (10, 23))
31397	33316936	Bcl-2 family proteins regulate DNA damage-induced apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP) and the release of mitochondrial cytochrome C. Importantly, MOMP often leads to cell death, irrespective of caspase activity.	('caspase', 'Gene', (236, 243))	('MOMP', 'Var', (188, 192))	('leads to', 'Reg', (199, 207))	('cytochrome C', 'Gene', (161, 173))	('caspase', 'Gene', '841', (236, 243))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))	('cytochrome C', 'Gene', '54205', (161, 173))	('cell death', 'CPA', (208, 218))
31406	33316936	A recent study demonstrated that ART selectively induced ferroptosis in pancreatic cancer cells carrying a mutation in the KRAS gene.	('rat', 'Species', '10116', (22, 25))	('KRAS', 'Gene', '3845', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ART', 'Chemical', 'MESH:D000077332', (33, 36))	('ferroptosis in pancreatic cancer', 'Disease', (57, 89))	('induced', 'Reg', (49, 56))	('KRAS', 'Gene', (123, 127))	('ferroptosis in pancreatic cancer', 'Disease', 'MESH:D010190', (57, 89))	('mutation', 'Var', (107, 115))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
31409	33316936	However, in the present investigation, neither ferroptosis activation nor GPX4 expression alteration, relevant for antioxidant activity, was detected as a result of ART application in either T24par or T24res BCa cells.	('GPX4', 'Gene', '2879', (74, 78))	('rat', 'Species', '10116', (94, 97))	('GPX4', 'Gene', (74, 78))	('T24res', 'Var', (201, 207))	('T24par', 'Var', (191, 197))	('BCa', 'Phenotype', 'HP:0009725', (208, 211))	('ART', 'Chemical', 'MESH:D000077332', (165, 168))	('T24res', 'Chemical', '-', (201, 207))	('T24par', 'Chemical', '-', (191, 197))
31414	33316936	The authors found that simultaneous activation of the energy-sensing kinase AMPK and inactivation of the nutrient-sensing kinase mTOR control autophagy induction via ULK1 after treatment with ART.	('inactivation', 'Var', (85, 97))	('ULK1', 'Gene', (166, 170))	('autophagy induction', 'CPA', (142, 161))	('ULK1', 'Gene', '8408', (166, 170))	('activation', 'PosReg', (36, 46))	('mTOR', 'Gene', '2475', (129, 133))	('mTOR', 'Gene', (129, 133))	('ART', 'Chemical', 'MESH:D000077332', (192, 195))	('AMPK', 'Gene', '5562', (76, 80))	('AMPK', 'Gene', (76, 80))
31421	33316936	Furthermore, temserolimus induced autophagy and thereby enhanced the sensitivity of BCa cell lines to gemcitabine and cisplatin.	('gemcitabine', 'Chemical', 'MESH:C056507', (102, 113))	('autophagy', 'CPA', (34, 43))	('temserolimus', 'Var', (13, 25))	('sensitivity', 'MPA', (69, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('BCa', 'Phenotype', 'HP:0009725', (84, 87))	('enhanced', 'PosReg', (56, 64))
31439	31897162	The NLR, PMI, neutrophil count and platelet count declined significantly following NAC, whereas no alterations in PLR, CAR, lymphocyte counts, CRP levels and albumin concentration were observed.	('CAR', 'Gene', (119, 122))	('albumin', 'Gene', (158, 165))	('albumin', 'Gene', '213', (158, 165))	('platelet count', 'CPA', (35, 49))	('neutrophil count', 'CPA', (14, 30))	('NAC', 'Var', (83, 86))	('declined', 'NegReg', (50, 58))	('PMI', 'CPA', (9, 12))	('NLR', 'MPA', (4, 7))	('CRP', 'Gene', (143, 146))	('CRP', 'Gene', '1401', (143, 146))	('CAR', 'Gene', '1525', (119, 122))
31476	31897162	The NLR and PMI decreased significantly after NAC; such decreases were not observed in the PLR and CAR (Fig.	('CAR', 'Gene', (99, 102))	('PMI', 'CPA', (12, 15))	('NAC', 'Var', (46, 49))	('NLR', 'MPA', (4, 7))	('CAR', 'Gene', '1525', (99, 102))	('decreased', 'NegReg', (16, 25))
31581	31040254	Of the clinicopathological features analyzed, BMI <=18.5 kg/m2 (27.3% vs. 9.1%, p = .002) and weight loss >=3 kg in the previous 3 months (38.6% vs. 16.1%, p = .001) were more frequently observed in patients with pretreatment lymphopenia compared with those with lymphocyte count >=1,000 cells per mm3.	('lymphopenia', 'Disease', 'MESH:D008231', (226, 237))	('>=3', 'Var', (106, 109))	('lymphopenia', 'Phenotype', 'HP:0001888', (226, 237))	('weight loss', 'Disease', 'MESH:D015431', (94, 105))	('weight loss', 'Disease', (94, 105))	('lymphopenia', 'Disease', (226, 237))	('BMI <=18.5 kg/m2', 'Var', (46, 62))	('weight loss', 'Phenotype', 'HP:0001824', (94, 105))	('patients', 'Species', '9606', (199, 207))
31636	31040254	For example, shrinking radiation fields using limited-field RT for glioblastoma has been correlated with less radiation-related lymphopenia than standard-field RT, and reduction of RT field does not seem to affect patient prognosis [37].	('glioblastoma', 'Disease', (67, 79))	('patient', 'Species', '9606', (214, 221))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('less', 'NegReg', (105, 109))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('lymphopenia', 'Disease', 'MESH:D008231', (128, 139))	('lymphopenia', 'Phenotype', 'HP:0001888', (128, 139))	('limited-field', 'Var', (46, 59))	('lymphopenia', 'Disease', (128, 139))
31664	29321719	Polyphenon E exhibited a significant reduction in both tumor multiplicity (by 46%) and tumor load (by 94%), while Epigallocatechin-3-gallate (EGCG) and Poly E-EGCG did not significantly inhibit lung tumor multiplicity.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('reduction', 'NegReg', (37, 46))	('Poly E-EGCG', 'Chemical', '-', (152, 163))	('EGCG', 'Chemical', 'MESH:C045651', (142, 146))	('EGCG', 'Chemical', 'MESH:C045651', (159, 163))	('lung tumor', 'Disease', 'MESH:D008175', (194, 204))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Polyphenon E', 'Var', (0, 12))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', (87, 92))	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (114, 140))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('lung tumor', 'Disease', (194, 204))	('tumor', 'Disease', (55, 60))	('lung tumor', 'Phenotype', 'HP:0100526', (194, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('Polyphenon E', 'Chemical', 'MESH:C472086', (0, 12))
31665	29321719	As an extract of Prunella vulgaris L (PV) with 60% ethanol, P-60 could be used to treat B[a]P-induced lung cancer and decrease the tumor multiplicity by 90.3%.	('PV', 'Species', '39358', (38, 40))	('ethanol', 'Chemical', 'MESH:D000431', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('P-60', 'Var', (60, 64))	('lung cancer', 'Disease', (102, 113))	('tumor', 'Disease', (131, 136))	('decrease', 'NegReg', (118, 126))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('Prunella vulgaris', 'Disease', (17, 34))	('Prunella vulgaris', 'Disease', 'MESH:D016112', (17, 34))
31673	29321719	In a lung adenoma model induced by 48 weeks of DMBA, it decreased the average diameter of the largest lung adenomas by 23% and the incidence of diffuse pulmonary infiltration by 63%.	('lung adenomas', 'Disease', (102, 115))	('DMBA', 'Chemical', 'MESH:D015127', (47, 51))	('lung adenoma', 'Disease', 'MESH:D000236', (102, 114))	('DMBA', 'Var', (47, 51))	('pulmonary infiltration', 'Phenotype', 'HP:0002113', (152, 174))	('decreased', 'NegReg', (56, 65))	('lung adenomas', 'Disease', 'MESH:D000236', (102, 115))	('diffuse pulmonary infiltration', 'CPA', (144, 174))	('lung adenoma', 'Disease', 'MESH:D000236', (5, 17))	('lung adenoma', 'Disease', (5, 17))
31677	29321719	KWG also significantly reduced the squamous cell lung tumor area to an average of 1.5%, compared with 9.4% in the control group.	('squamous cell lung tumor', 'Phenotype', 'HP:0030359', (35, 59))	('KWG', 'Var', (0, 3))	('lung tumor', 'Phenotype', 'HP:0100526', (49, 59))	('squamous cell lung tumor', 'Disease', 'MESH:D002294', (35, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('reduced', 'NegReg', (23, 30))	('squamous cell lung tumor', 'Disease', (35, 59))
31679	29321719	Oral administration of EFLA400 at pre-, peri-, and post-initiational phases showed reductions in tumor incidence (71.41 +- 6.73%, 72.19 +- 4.54%, and 70.46 +- 0.38% at 1, 3, and 10 mg/kg body weight, respectively), compared with 100% tumor incidence in the control group.	('EFLA400', 'Var', (23, 30))	('reductions', 'NegReg', (83, 93))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
31707	29321719	For example, the aberrant activation of intracellular signaling pathways confers malignant properties on cancer cells via the JAK/STAT and MAPK pathways.	('aberrant', 'Var', (17, 25))	('JAK/STAT', 'Pathway', (126, 134))	('intracellular signaling pathways', 'Pathway', (40, 72))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('activation', 'PosReg', (26, 36))	('malignant properties', 'CPA', (81, 101))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('MAPK pathways', 'Pathway', (139, 152))
31711	29321719	In vitro studies, have demonstrated that green tea and EGCG could blocked carcinogenesis by affecting a wide range of signal transduction pathways: JAK/STAT, MAPK, PI3K/AKT, Wnt, NF-kB, Notch, and STAT3.	('carcinogenesis', 'Disease', 'MESH:D063646', (74, 88))	('Notch', 'Gene', '4853', (186, 191))	('STAT3', 'Gene', '6774', (197, 202))	('PI3K/AKT', 'Gene', '5293;207', (164, 172))	('JAK/STAT', 'Var', (148, 156))	('STAT3', 'Gene', (197, 202))	('carcinogenesis', 'Disease', (74, 88))	('PI3K/AKT', 'Gene', (164, 172))	('MAPK', 'Disease', (158, 162))	('blocked', 'NegReg', (66, 73))	('Notch', 'Gene', (186, 191))	('EGCG', 'Chemical', 'MESH:C045651', (55, 59))	('affecting', 'Reg', (92, 101))
31716	29321719	The EGCG-induced apoptosis of HCCLM6 cells has been associated with a significant decrease in Bcl-2 and NF-kappaB expression.	('decrease', 'NegReg', (82, 90))	('HCCLM6', 'CellLine', 'CVCL:7680', (30, 36))	('Bcl-2', 'Gene', (94, 99))	('EGCG-induced', 'Var', (4, 16))	('Bcl-2', 'Gene', '596', (94, 99))	('apoptosis', 'CPA', (17, 26))	('HCC', 'Phenotype', 'HP:0001402', (30, 33))	('EGCG', 'Chemical', 'MESH:C045651', (4, 8))	('NF-kappaB', 'Gene', '4790', (104, 113))	('expression', 'MPA', (114, 124))	('NF-kappaB', 'Gene', (104, 113))
31733	29321719	Rg3 induced apoptosis in MDA-MB-231 cells by blocking the NF-kB signaling pathway via the inactivation of ERK and Akt as well as the destabilization of mutant P53.	('NF-kB signaling pathway', 'Pathway', (58, 81))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (25, 35))	('Akt', 'Gene', (114, 117))	('ERK', 'Gene', '5594', (106, 109))	('P53', 'Gene', (159, 162))	('mutant', 'Var', (152, 158))	('inactivation', 'NegReg', (90, 102))	('Akt', 'Gene', '207', (114, 117))	('ERK', 'Gene', (106, 109))	('destabilization', 'NegReg', (133, 148))	('P53', 'Gene', '7157', (159, 162))	('blocking', 'NegReg', (45, 53))
31736	29321719	This inhibition was Akt kinase-specific, as it had no effect on PI3K, the upstream kinase of Akt, whereas the levels of phosphorylated Bad and FHKR, the two downstream targets of Akt, changed as the levels of Akt changed.	('Akt', 'Gene', (93, 96))	('levels', 'MPA', (110, 116))	('Akt', 'Gene', '207', (209, 212))	('changed', 'Reg', (184, 191))	('Akt', 'Gene', '207', (20, 23))	('Akt', 'Gene', (179, 182))	('Akt', 'Gene', '207', (179, 182))	('Akt', 'Gene', (209, 212))	('Akt', 'Gene', '207', (93, 96))	('Akt', 'Gene', (20, 23))	('PI3K', 'Var', (64, 68))
31742	29321719	A recent study showed that honokiol inhibited lung SCC cells' proliferation, arrested cells at the G1-S cell-cycle checkpoint, and induced apoptosis.	('induced', 'Reg', (131, 138))	('inhibited', 'NegReg', (36, 45))	('SCC', 'Gene', (51, 54))	('arrested', 'NegReg', (77, 85))	('SCC', 'Gene', '6317', (51, 54))	('honokiol', 'Var', (27, 35))	('honokiol', 'Chemical', 'MESH:C005499', (27, 35))	('cells at the G1-S cell-cycle checkpoint', 'CPA', (86, 125))	('apoptosis', 'CPA', (139, 148))
31748	29321719	The expression of EGFR and phosphorylated EGFR (Tyr1173) was also down-regulated by ATB.	('EGFR', 'Gene', '1956', (42, 46))	('Tyr1173', 'Var', (48, 55))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (42, 46))	('expression', 'MPA', (4, 14))	('down-regulated', 'NegReg', (66, 80))	('EGFR', 'Gene', (18, 22))	('Tyr1173', 'Chemical', '-', (48, 55))
31804	28509417	Overexpression of USP14 was observed in approximately 60% of tested ESCC samples compared to their paired non-tumor esophageal tissues at both RNA and protein levels, and was significantly associated with distant metastasis (P = 0.001).	('non-tumor', 'Disease', 'MESH:D009369', (106, 115))	('ESCC', 'Disease', (68, 72))	('distant metastasis', 'CPA', (205, 223))	('associated with', 'Reg', (189, 204))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('non-tumor', 'Disease', (106, 115))	('Overexpression', 'Var', (0, 14))	('USP14', 'Gene', (18, 23))
31821	28509417	DeltaDeltaCt(sample) = DeltaCt(sample) - DeltaCt(calibrator), DeltaCt(sample) = Ct(sample) of USP14 - Ct(sample) of GAPDH; DeltaCt(calibrator) = Ct(calibrator) of USP14 - Ct(calibrator) of GAPDH.	('DeltaCt', 'MPA', (62, 69))	('GAPDH', 'Gene', (189, 194))	('DeltaDeltaCt', 'Var', (0, 12))	('GAPDH', 'Gene', '2597', (116, 121))	('GAPDH', 'Gene', '2597', (189, 194))	('GAPDH', 'Gene', (116, 121))
31842	28509417	We found that ESCC patients with high USP14 expression have poorer survival compared to those with low USP14 expression.	('poorer', 'NegReg', (60, 66))	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (19, 27))	('survival', 'MPA', (67, 75))	('ESCC', 'Disease', (14, 18))	('USP14', 'Gene', (38, 43))
31844	28509417	Previous studies have shown that elevated USP14 expression is related to liver and lymph node metastases in colorectal cancer, advanced stage of hepatocellular carcinoma, and intrahepatic cholangiocarcinoma cell differentiation.6, 7, 19 Consistent with these findings, we found that high USP14 expression was remarkably related to distant metastasis in ESCC.	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('ESCC', 'Disease', (353, 357))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('USP14', 'Gene', (288, 293))	('related', 'Reg', (320, 327))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (175, 206))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('intrahepatic cholangiocarcinoma', 'Disease', (175, 206))	('expression', 'MPA', (294, 304))	('high', 'Var', (283, 287))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('metastases', 'Disease', (94, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('hepatocellular carcinoma', 'Disease', (145, 169))	('distant metastasis', 'CPA', (331, 349))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (188, 206))	('colorectal cancer', 'Disease', (108, 125))
31848	28509417	Therefore, inhibitors targeting USP14, such as b-AP15, may be specifically effective for ESCC patients with high USP14 expression.	('expression', 'MPA', (119, 129))	('patients', 'Species', '9606', (94, 102))	('USP14', 'Gene', (32, 37))	('ESCC', 'Disease', (89, 93))	('USP14', 'Gene', (113, 118))	('high', 'Var', (108, 112))
31849	28509417	In non-small cell lung cancer, miR-4782-3p was reported to bind the 3' untranslated region region of USP14 mRNA and inhibited its expression.26 The expression status of miR-4782-3p in ESCC and its influence on USP14 expression remain unknown.	('expression.26', 'MPA', (130, 143))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('inhibited', 'NegReg', (116, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('miR-4782-3p', 'Var', (169, 180))	('non-small cell lung cancer', 'Disease', (3, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
31878	24568553	Mainly patients with tumors of clinical stage T1-2 N1 or T3N0-1 were enrolled.	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('T3N0-1', 'Var', (57, 63))	('patients', 'Species', '9606', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
32000	24109590	A large number of other regression grading systems use the principle of the estimation of residual tumor for classification of TRGs: the Japanese Society for Esophageal Disease designate tumor regression as a continuous variable and categorized into four groups as a measure of the extent of chemoradiation response: ypV0, no viable cell; ypV1, 1-33% viable tumor; ypV2, 34-66% viable tumor; and ypV3, 67-100% viable tumor.	('Esophageal Disease', 'Disease', 'MESH:D004935', (158, 176))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', (417, 422))	('TRG', 'Chemical', '-', (127, 130))	('ypV2', 'Var', (365, 369))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (417, 422))	('ypV3', 'Var', (396, 400))	('tumor', 'Disease', (385, 390))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Esophageal Disease', 'Disease', (158, 176))	('ypV0', 'Var', (317, 321))	('tumor', 'Disease', 'MESH:D009369', (385, 390))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (417, 422))	('tumor', 'Disease', (358, 363))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (385, 390))	('ypV1', 'Var', (339, 343))	('tumor', 'Disease', 'MESH:D009369', (358, 363))
32066	21210262	Hedgehog (HH) signaling pathway regulates many processes in development, homeostasis in tissues, and ectopic expression of HH signaling pathway components are responsible for tumorigenesis.	('tumor', 'Disease', (175, 180))	('regulates', 'Reg', (32, 41))	('ectopic expression', 'Var', (101, 119))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
32071	21210262	Activated Smoothened mutations have been found in sporadic basal-cell carcinomas, over expression of smoothened was found in several tumors.	('found', 'Reg', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('over expression', 'PosReg', (82, 97))	('basal-cell carcinomas', 'Disease', (59, 80))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('basal-cell carcinomas', 'Phenotype', 'HP:0002671', (59, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('basal-cell carcinomas', 'Disease', 'MESH:D002280', (59, 80))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Smoothened', 'Gene', '6608', (10, 20))	('Smoothened', 'Gene', (10, 20))	('smoothened', 'Gene', (101, 111))	('smoothened', 'Gene', '6608', (101, 111))	('mutations', 'Var', (21, 30))
32073	21210262	Silence of HIP was found in several cancer cell lines as well as tumors through genetic and/or epigenetic alternations.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('epigenetic alternations', 'Var', (95, 118))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('genetic', 'Var', (80, 87))	('HIP', 'Disease', 'OMIM:142700', (11, 14))	('HIP', 'Disease', (11, 14))
32075	21210262	Mice with both heterozygous PTCH1 and Su(fu) had higher to develop tumor.	('PTCH1', 'Var', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Su(fu', 'Gene', (38, 43))	('Su(fu)', 'Gene', '24069', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (67, 72))	('higher', 'PosReg', (49, 55))
32076	21210262	Mutations in Su(Fu) or loss of Su(Fu) expression was reported in cancer cell lines and tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('expression', 'MPA', (38, 48))	('Su(Fu', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('Su(Fu)', 'Gene', '51684', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('Mutations', 'Var', (0, 9))	('Su(Fu)', 'Gene', '51684', (31, 37))	('loss', 'NegReg', (23, 27))	('tumors', 'Disease', (87, 93))	('cancer', 'Disease', (65, 71))	('Su(Fu', 'Gene', (31, 36))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
32108	21210262	Two cases with expression of SMO, HIP and PDGFRalpha transcripts lost expression of Su(Fu), indicating that silence of Su(Fu) may responsible for HH pathway activating in these two tumors.	('Su(Fu)', 'Gene', '51684', (84, 90))	('silence', 'Var', (108, 115))	('activating', 'PosReg', (157, 167))	('Su(Fu', 'Gene', (119, 124))	('PDGFRalpha', 'Gene', (42, 52))	('tumors', 'Disease', (181, 187))	('HH pathway', 'Pathway', (146, 156))	('Su(Fu)', 'Gene', '51684', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('lost', 'NegReg', (65, 69))	('expression', 'MPA', (70, 80))	('SMO', 'Gene', '6608', (29, 32))	('SMO', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('Su(Fu', 'Gene', (84, 89))	('HIP', 'Disease', 'OMIM:142700', (34, 37))	('HIP', 'Disease', (34, 37))
32123	21210262	Mutations in Su(Fu) have been found in cancer cell lines and tumors.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('Su(Fu', 'Gene', (13, 18))	('found', 'Reg', (30, 35))	('Su(Fu)', 'Gene', '51684', (13, 19))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
32132	33204907	Retrograde percutaneous transgastric esophageal endoscopic submucosal dissection: a peculiar endoscopic submucosal dissection technique for therapy of esophageal cancer with esophageal stenosis after chemoradiation therapy The patient was a 69-year-old man who had received chemoradiotherapy for T3N2M0, stage III cervical esophageal cancer 10 years earlier and exhibited complete response.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('esophageal stenosis', 'Disease', (174, 193))	('T3N2M0', 'Var', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('esophageal stenosis', 'Disease', 'MESH:D004940', (174, 193))	('patient', 'Species', '9606', (227, 234))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (174, 193))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('cancer', 'Disease', (334, 340))
32245	33061564	However, this study suggests that a low NLR is an independent predictor for grade >=3 hematologic toxicity, which is inconsistent with previous findings, possibly due to the discrepancies in treatment regimens and histologic types.	('hematologic toxicity', 'Disease', 'MESH:D006402', (86, 106))	('hematologic toxicity', 'Disease', (86, 106))	('NLR', 'Gene', (40, 43))	('low', 'Var', (36, 39))
32260	31452748	The patients with positive PD-L1 expression had shorter disease-free survival time than those without PD-L1 expression (P=0.005).	('expression', 'Var', (33, 43))	('disease-free survival time', 'CPA', (56, 82))	('shorter', 'NegReg', (48, 55))	('patients', 'Species', '9606', (4, 12))	('PD-L1', 'Gene', (27, 32))
32272	31452748	PD-L1 is expressed by various solid tumors, such as renal cell carcinoma, breast cancer, pancreatic cancer, colorectal cancer, and esophageal cancer and is associated with a diminished antitumor T cell response In addition, PD-L1 expression is associated with a poor prognosis in patients with various solid malignancies, such as esophageal cancer, pancreatic cancer, and gastric carcinoma.	('pancreatic cancer', 'Disease', 'MESH:D010190', (349, 366))	('gastric carcinoma', 'Disease', 'MESH:D013274', (372, 389))	('PD-L1', 'Gene', (0, 5))	('esophageal cancer', 'Disease', 'MESH:D004938', (330, 347))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('gastric carcinoma', 'Disease', (372, 389))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (36, 41))	('renal cell carcinoma', 'Disease', (52, 72))	('pancreatic cancer', 'Disease', (349, 366))	('PD-L1', 'Gene', (224, 229))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (52, 72))	('solid tumors', 'Disease', (30, 42))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (372, 389))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('esophageal cancer', 'Disease', (330, 347))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('esophageal cancer', 'Disease', (131, 148))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (380, 389))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('malignancies', 'Disease', 'MESH:D009369', (308, 320))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('colorectal cancer', 'Disease', (108, 125))	('patients', 'Species', '9606', (280, 288))	('malignancies', 'Disease', (308, 320))	('diminished', 'NegReg', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (349, 366))	('associated', 'Reg', (244, 254))	('solid tumors', 'Disease', 'MESH:D009369', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('breast cancer', 'Disease', (74, 87))	('tumor', 'Disease', (189, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (52, 72))	('diminished antitumor T cell response', 'Phenotype', 'HP:0031402', (174, 210))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('expression', 'Var', (230, 240))	('pancreatic cancer', 'Disease', (89, 106))
32342	31452748	Overexpression of PD-L1 by tumor cells has been reported in various types of cancer, such as pancreatic cancer, esophageal cancer, breast cancer, and gastric cancer and impairs T cell-mediated antitumor immunity.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('pancreatic cancer', 'Disease', 'MESH:D010190', (93, 110))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('gastric cancer', 'Disease', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (104, 110))	('pancreatic cancer', 'Disease', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (158, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('impairs', 'NegReg', (169, 176))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', (77, 83))	('reported', 'Reg', (48, 56))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('esophageal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast cancer', 'Disease', (131, 144))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (123, 129))	('PD-L1', 'Gene', (18, 23))	('tumor', 'Disease', (197, 202))
32346	31452748	Sun et al reported that high PD-L1 expression in tumors was associated with decreased survival rate and poor prognosis in gastric cancer.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('survival rate', 'CPA', (86, 99))	('PD-L1', 'Protein', (29, 34))	('decreased', 'NegReg', (76, 85))	('gastric cancer', 'Disease', (122, 136))	('expression', 'MPA', (35, 45))	('tumors', 'Disease', (49, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('high', 'Var', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
32351	31452748	Kim et al reported that PD-L1 expression was associated with improved OS and DFS.	('improved', 'PosReg', (61, 69))	('OS', 'Chemical', '-', (70, 72))	('expression', 'Var', (30, 40))	('PD-L1', 'Gene', (24, 29))	('DFS', 'Disease', (77, 80))
32354	31452748	In the present study, PD-L1 expression was significantly associated with a poorer DFS, while PD-1 expression was not significantly associated with prognosis.	('PD-L1', 'Gene', (22, 27))	('DFS', 'Disease', (82, 85))	('expression', 'Var', (28, 38))	('PD-1', 'Gene', (93, 97))	('PD-1', 'Gene', '5133', (93, 97))	('associated', 'Reg', (57, 67))
32367	31452748	They also reported that the frequency of PD-1+ CD4+ T-cells from gastric cancer tissue with PD-L1 expression was significantly higher than that from gastric cancer tissue without PD-L1 expression (49.7+-10.4% vs. 30.6+-9.7%, respectively).	('gastric cancer', 'Disease', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('expression', 'Var', (98, 108))	('PD-L1', 'Gene', (92, 97))	('PD-1', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('PD-1', 'Gene', '5133', (41, 45))	('higher', 'PosReg', (127, 133))	('gastric cancer', 'Disease', (65, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))
32373	31452748	EBV+ and MSI gastric cancer exhibits lymphocytic infiltration in tumor stroma; therefore, the lymphoid stroma in these tumors has a large number of CD8 T cells, which are capable of mounting a robust antitumor inflammatory response.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (13, 27))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('EBV+', 'Var', (0, 4))	('MSI gastric cancer', 'Disease', 'MESH:D013274', (9, 27))	('tumor', 'Disease', (65, 70))	('tumors', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('MSI gastric cancer', 'Disease', (9, 27))	('tumor stroma', 'Disease', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('lymphoid stroma', 'Disease', 'MESH:D008223', (94, 109))	('CD8', 'Gene', '925', (148, 151))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor stroma', 'Disease', 'MESH:D009369', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('lymphoid stroma', 'Disease', (94, 109))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('CD8', 'Gene', (148, 151))
32374	31452748	In addition, PD-L1 expression is associated with a concomitant and significant increase in the number of CD8 T cells at the tumor invasive front.	('CD8', 'Gene', (105, 108))	('increase', 'PosReg', (79, 87))	('CD8', 'Gene', '925', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('expression', 'Var', (19, 29))	('tumor', 'Disease', (124, 129))	('PD-L1', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
32392	31028132	MicroRNA-550a is associated with muscle system conferring poorer survival for esophageal cancer Background Esophageal cancer (ESCA) is one of the most common cancers in the digestive tract.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MicroRNA-550a', 'Var', (0, 13))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('Esophageal cancer', 'Disease', (107, 124))
32399	31028132	Data mining and signal pathway enrichment analysis of TCGA database showed that abnormal miR-550a expressions affected the recurrence of tumors by the muscle system regulation.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('men', 'Species', '9606', (37, 40))	('abnormal', 'Var', (80, 88))	('affected', 'Reg', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
32408	31028132	By systematic analysis of all oncogenic and tumor suppressor genes of small variation, the mechanism of the cancer occurrence and development may have a better understanding, which finally can draw the outline of the new 'cancer prevention strategies' (https://gdc.nci.nih.gov/).	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (222, 228))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('variation', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('men', 'Species', '9606', (137, 140))	('tumor', 'Disease', (44, 49))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
32462	31028132	While in breast cancer, the expression of TRIM9 was inhibited due to the methylation of TRIM9 promoter and TRIM9 methylation of DNA could be used as a tumor marker of breast cancer.	('TRIM9', 'Gene', '114088', (88, 93))	('breast cancer', 'Disease', (167, 180))	('TRIM9', 'Gene', (88, 93))	('inhibited', 'NegReg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('TRIM9', 'Gene', '114088', (107, 112))	('TRIM9', 'Gene', (107, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('expression', 'MPA', (28, 38))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('TRIM9', 'Gene', (42, 47))	('methylation', 'Var', (73, 84))	('TRIM9', 'Gene', '114088', (42, 47))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('breast cancer', 'Disease', (9, 22))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
32536	28566729	It is reported that replacement of two OH groups in curcumin with less polar groups like methoxy increases its anti-proliferative activity.	('curcumin', 'Chemical', 'MESH:D003474', (52, 60))	('replacement', 'Var', (20, 31))	('increases', 'PosReg', (97, 106))	('anti-proliferative activity', 'CPA', (111, 138))
32547	28566729	These activities have been attributed to methoxy, hydroxyl, alpha, beta-unsaturated carbonyl moiety, or diketone groups in curcumin.	('diketone', 'Chemical', '-', (104, 112))	('activities', 'MPA', (6, 16))	('curcumin', 'Chemical', 'MESH:D003474', (123, 131))	('hydroxyl', 'Var', (50, 58))	('methoxy', 'Var', (41, 48))	('carbon', 'Chemical', 'MESH:D002244', (84, 90))	(', hydroxyl', 'Chemical', 'MESH:D017665', (48, 58))
32552	28566729	Thus, modifications of specific functional groups of curcumin that increase its bioavailability will increase its activity.	('modifications', 'Var', (6, 19))	('activity', 'MPA', (114, 122))	('curcumin', 'Chemical', 'MESH:D003474', (53, 61))	('increase', 'PosReg', (101, 109))	('curcumin', 'Protein', (53, 61))	('increase', 'PosReg', (67, 75))	('bioavailability', 'MPA', (80, 95))
32554	28566729	For instance, the natural analogues of curcumin such as dimethoxy-curcumin and bidemethoxy-curcumin were reported to have similar biological activity to curcumin.	('dimethoxy-curcumin', 'Var', (56, 74))	('curcumin', 'Chemical', 'MESH:D003474', (91, 99))	('bidemethoxy-curcumin', 'Var', (79, 99))	('curcumin', 'Chemical', 'MESH:D003474', (39, 47))	('curcumin', 'Chemical', 'MESH:D003474', (153, 161))	('bidemethoxy-curcumin', 'Chemical', '-', (79, 99))	('biological', 'MPA', (130, 140))	('dimethoxy-curcumin', 'Chemical', 'MESH:C521105', (56, 74))	('curcumin', 'Chemical', 'MESH:D003474', (66, 74))
32556	28566729	In this study, our purpose was to explore efficacy of benzylidine cyclohexanone derivatives with methoxy, ethoxy, alkoxy, and propoxy groups, to see if they possess increased anti-cancer activity and to explore the mechanism of action of these analogues.	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('benzylidine cyclohexanone', 'Chemical', '-', (54, 79))	('increased', 'PosReg', (165, 174))	('cancer', 'Disease', (180, 186))	('methoxy', 'Var', (97, 104))
32574	28566729	Then plates were centrifuged for 5 min (129 g, 1,000 rpm) at 4  C. The ethidium bromide/acridine orange (EB/AO) dye mix (100 mug/mL ethidium bromide and 100 mug/mL acridine orange) was dissolved in PBS and 20 mul of the dye mix was added to wells.	('100', 'Var', (121, 124))	('PBS', 'Chemical', 'MESH:D007854', (198, 201))	('acridine orange', 'Chemical', 'MESH:D000165', (164, 179))	('EB', 'Chemical', 'MESH:C004912', (105, 107))	('ethidium bromide', 'Chemical', 'MESH:D004996', (71, 87))	('mix', 'Gene', '83881', (116, 119))	('mix', 'Gene', '83881', (224, 227))	('mix', 'Gene', (116, 119))	('mix', 'Gene', (224, 227))	('ethidium bromide', 'Chemical', 'MESH:D004996', (132, 148))	('acridine orange', 'Chemical', 'MESH:D000165', (88, 103))
32594	28566729	We observed the same pattern after 48 h, with BM2 17 times more toxic than curcumin (Table 3, and Fig.	('toxic', 'MPA', (64, 69))	('BM2', 'Chemical', '-', (46, 49))	('curcumin', 'Chemical', 'MESH:D003474', (75, 83))	('BM2', 'Var', (46, 49))
32600	28566729	6B, treatment of AGS cells with synthesized BM2 triggered apoptotic cell death, which is characterized by fragmentation of nuclei.	('AGS', 'Gene', (17, 20))	('BM2', 'Chemical', '-', (44, 47))	('BM2', 'Var', (44, 47))	('AGS', 'Gene', '182', (17, 20))	('apoptotic cell death', 'CPA', (58, 78))
32609	28566729	Recently, it has been reported that replacement of two OH groups in curcumin with less polar groups like methoxy (OCH3) increases the anti-proliferative activity of arene-ruthenium(II) curcuminoid complexes in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('curcumin', 'Chemical', 'MESH:D003474', (68, 76))	('tumor', 'Disease', (210, 215))	('arene-ruthenium(II) curcuminoid', 'Chemical', '-', (165, 196))	('curcumin', 'Chemical', 'MESH:D003474', (185, 193))	('replacement', 'Var', (36, 47))	('increases', 'PosReg', (120, 129))	('anti-proliferative activity', 'MPA', (134, 161))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
32612	28566729	Our various experimental results on esophageal and gastric cancer cells revealed that all synthesized analogues of curcumin are more toxic than curcumin: after 48 h treatment in gastric cancer cells, BM2 was 17 times more toxic than curcumin (Fig.	('BM2', 'Chemical', '-', (200, 203))	('BM2', 'Var', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('gastric cancer', 'Phenotype', 'HP:0012126', (51, 65))	('gastric cancer', 'Disease', (178, 192))	('curcumin', 'Chemical', 'MESH:D003474', (233, 241))	('gastric cancer', 'Disease', 'MESH:D013274', (178, 192))	('curcumin', 'Chemical', 'MESH:D003474', (144, 152))	('gastric cancer', 'Phenotype', 'HP:0012126', (178, 192))	('toxic', 'MPA', (222, 227))	('gastric cancer', 'Disease', 'MESH:D013274', (51, 65))	('curcumin', 'Chemical', 'MESH:D003474', (115, 123))	('gastric cancer', 'Disease', (51, 65))
32616	28566729	It has been reported that curcumin induced apoptosis in leukemia cells by PARP-1 cleavage, increased level of caspase-3, apoptosis inducing factor (AIF) and down-regulation of Bcl2.	('caspase-3', 'Gene', (110, 119))	('AIF', 'Gene', '9131', (148, 151))	('AIF', 'Gene', (148, 151))	('apoptosis inducing factor', 'Gene', (121, 146))	('Bcl2', 'Gene', (176, 180))	('caspase-3', 'Gene', '836', (110, 119))	('curcumin', 'Chemical', 'MESH:D003474', (26, 34))	('leukemia', 'Disease', (56, 64))	('PARP-1', 'Gene', (74, 80))	('down-regulation', 'NegReg', (157, 172))	('increased', 'PosReg', (91, 100))	('PARP-1', 'Gene', '142', (74, 80))	('leukemia', 'Disease', 'MESH:D007938', (56, 64))	('apoptosis inducing factor', 'Gene', '9131', (121, 146))	('Bcl2', 'Gene', '596', (176, 180))	('leukemia', 'Phenotype', 'HP:0001909', (56, 64))	('cleavage', 'Var', (81, 89))
32629	27053248	Such an approach, in a multimodal therapy setting, could identify those patients (1) who should undergo a defined treatment (personalized therapy) (2) in whom modifications of the multimodal therapy due to observed responses might lead to an improvement of the response and/or prognosis (individualized therapy), (3) who might not benefit from a particular toxic treatment regimen, and (4) who could be identified early on and thereby be spared the morbidity associated with such treatments.	('men', 'Species', '9606', (368, 371))	('improvement', 'PosReg', (242, 253))	('patients', 'Species', '9606', (72, 80))	('modifications', 'Var', (159, 172))	('prognosis', 'CPA', (277, 286))	('men', 'Species', '9606', (249, 252))	('men', 'Species', '9606', (119, 122))	('response', 'MPA', (261, 269))	('men', 'Species', '9606', (377, 380))	('men', 'Species', '9606', (485, 488))
32663	27053248	Additionally, the number of mutated genes and mutations per gene or per cancer in the coding region varies greatly: Some 95-97 % of mutations are single-base substitutions and 3-5 % constitutes insertions and deletions.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (132, 141))	('single-base substitutions', 'Var', (146, 171))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
32666	27053248	Tissues with high rates of cell division, such as the colon or skin, have larger numbers of mutations per cell compared to cancers with slowly dividing tissues i.e., brain.	('rat', 'Species', '10116', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colon', 'Disease', (54, 59))	('colon', 'Disease', 'MESH:D015179', (54, 59))	('mutations', 'Var', (92, 101))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))
32667	27053248	The enormous variability of the mutations combined with the fact that more than 50 % of mutations occur in the cell before the cancer phenotype is established introduces a high noise to signal into genome and/or exon sequencing that confounds the interpretation of data.	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', (127, 133))
32668	27053248	Recently it was demonstrated, using tumor exome sequencing, that acute lymphoblastic B-cell leukemia (B-cell ALL) is not caused by mutations but rather by infection and that mutations of Janus-activated kinase 3 (JAK-3) occur after carcinogenesis is already underway.	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('acute lymphoblastic B-', 'Phenotype', 'HP:0004812', (65, 87))	('carcinogenesis', 'Disease', (232, 246))	('rat', 'Species', '10116', (23, 26))	('lymphoblastic B-cell leukemia', 'Disease', 'MESH:D015448', (71, 100))	('infection', 'Disease', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('rat', 'Species', '10116', (145, 148))	('infection', 'Disease', 'MESH:D007239', (155, 164))	('lymphoblastic B-cell leukemia', 'Disease', (71, 100))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutations', 'Var', (174, 183))	('carcinogenesis', 'Disease', 'MESH:D063646', (232, 246))	('Janus-activated kinase 3 (JAK-3', 'Gene', '3718', (187, 218))	('tumor', 'Disease', (36, 41))	('acute lymphoblastic B-cell leukemia', 'Phenotype', 'HP:0006721', (65, 100))
32670	27053248	The observation of a mutation within a tissue or tumor (i.e., a somatic mutation) is not synonymous with proof that mutations are causally related to the cancer.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (154, 160))	('mutation', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
32688	27053248	A recent report sheds new light on how enzymes may continuously promote mutations in cancer after the carcinogenesis process has been initiated.	('mutations', 'Var', (72, 81))	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('promote', 'PosReg', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('carcinogenesis', 'Disease', (102, 116))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
32692	27053248	Furthermore, it has been shown that a liver cancer sample of 2.5 cm (1 inch) contains more than 100 million mutations.	('liver cancer', 'Phenotype', 'HP:0002896', (38, 50))	('liver cancer', 'Disease', 'MESH:D006528', (38, 50))	('mutations', 'Var', (108, 117))	('liver cancer', 'Disease', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
32695	27053248	This raises the issue of how we can assume that any mutations being measured in tissue is necessarily pro-carcinogenic.	('mutations', 'Var', (52, 61))	('carcinogenic', 'Disease', 'MESH:D063646', (106, 118))	('carcinogenic', 'Disease', (106, 118))
32698	27053248	Another report analyzed 4742 tumor-normal pairs across 21 cancer types; the data set consisted out of "3,078,483 somatic single nucleotide variations (SSNVs), 77,270 small insertions and deletions (SINDELs) and 29,837 somatic di-, tri- or oligonucleotide variations (DNVs, TNVs and ONVs, respectively), with an average of 672 per tumour-normal pair.	('SINDELs', 'Disease', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('small insertions', 'Var', (166, 182))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('oligonucleotide variations', 'Var', (239, 265))	('tumour', 'Phenotype', 'HP:0002664', (330, 336))	('tumour', 'Disease', 'MESH:D009369', (330, 336))	('tri-', 'Var', (231, 235))	('tumor', 'Disease', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('single nucleotide variations', 'Var', (121, 149))	('DNVs', 'Chemical', '-', (267, 271))	('SINDELs', 'Disease', 'None', (198, 205))	('tumour', 'Disease', (330, 336))
32699	27053248	These authors found 145,000 genetic variations per cancer type.	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('genetic variations', 'Var', (28, 46))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
32700	27053248	Thus, it would appear that somatic mutations are likely an epiphenomena and/or constitute events that occur after carcinogenesis has begun, as there are also cancers which are not associated with mutations.	('carcinogenesis', 'Disease', (114, 128))	('men', 'Species', '9606', (67, 70))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('mutations', 'Var', (35, 44))
32702	27053248	For example, point mutations occur at a similar rate in cancer and non-cancerous cells and larger genetic material rearrangements such as translocations and changes in chromosome numbers, occur more frequently in cancer cells than in noncancerous cells which support the importance of the timing of sampling.	('point mutations', 'Var', (13, 28))	('translocations', 'CPA', (138, 152))	('cancer', 'Disease', (56, 62))	('rat', 'Species', '10116', (48, 51))	('cancer', 'Disease', (71, 77))	('changes', 'Reg', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', (213, 219))	('cancerous', 'Disease', 'MESH:D009369', (71, 80))	('cancer', 'Disease', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancerous', 'Disease', 'MESH:D009369', (237, 246))	('non-cancerous', 'Disease', 'MESH:D009369', (67, 80))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('non-cancerous', 'Disease', (67, 80))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('men', 'Species', '9606', (124, 127))	('cancerous', 'Disease', (71, 80))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancerous', 'Disease', (237, 246))
32703	27053248	Despite these important challenges of intratumoral, intermetastatic, intrametastatic and inter-patient variability, some important findings have been obtained by sequencing methods, primarily that more than 138 driver mutations identified to date can be divided into pathways involved in cell survival, cell fate, and genome maintenance.	('patient', 'Species', '9606', (95, 102))	('mutations', 'Var', (218, 227))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('rat', 'Species', '10116', (41, 44))	('tumor', 'Disease', (43, 48))
32704	27053248	Transcriptome sequencing analysis, also known as RNA-seq, has been used in cancer research for the detection of transcribed mutations and confirmation of known and unknown mutations.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
32709	27053248	Combining these data using bioinformatics might provide a better understanding of mutations and their role in cancer progression and might also provide insight into how miRNA functions as post-transcriptional regulators of gene expression in cancer progression.	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
32739	27053248	Biologists investigate certain point mutations in the genotype such as single-nucleotide polymorphisms (SNPs) or variations in homologous DNA by restriction fragment length polymorphisms (RFLPs).	('single-nucleotide polymorphisms', 'Var', (71, 102))	('men', 'Species', '9606', (161, 164))	('LPs', 'Chemical', '-', (190, 193))	('variations', 'Var', (113, 123))
32740	27053248	We do not understand how polymorphisms reflect a disease and/or respond to a treatment, or if they react in conjunction with polymorphisms of other genes.	('polymorphisms', 'Var', (25, 38))	('disease', 'Disease', (49, 56))	('men', 'Species', '9606', (82, 85))	('reflect', 'Reg', (39, 46))
32747	27053248	The mitochondrial genome is separated from the nuclear DNA by the nuclear double membrane; however, intranuclear genomic rearrangement takes place frequently by transmission of mitochondrial DNA into the nuclear genome and especially when a normal cell has undergone transformation into a cancer cell.	('rat', 'Species', '10116', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('transmission', 'Reg', (161, 173))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('men', 'Species', '9606', (130, 133))	('mitochondrial DNA', 'Var', (177, 194))	('cancer', 'Disease', (289, 295))
32751	27053248	The main obstacle to sequencing is epigenetic changes which appear to be relevant for understanding cancer occurrence and progression.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('epigenetic changes', 'Var', (35, 53))
32752	27053248	Epigenetic alterations are, by definition, mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence.	('Epigenetic alterations', 'Var', (0, 22))	('gene expression', 'MPA', (92, 107))	('rat', 'Species', '10116', (15, 18))
32753	27053248	The epigenetic modifications described in the literature generally comprise histone variants, post-translational modifications of amino acids of histone proteins, and changes in the methylation status of cytosine bases (C) in the context of CpG dinucleotides within the DNA itself.	('methylation status', 'MPA', (182, 200))	('cytosine', 'Chemical', 'MESH:D003596', (204, 212))	('changes', 'Reg', (167, 174))	('rat', 'Species', '10116', (50, 53))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (241, 258))	('histone', 'Disease', (76, 83))	('variants', 'Var', (84, 92))	('modifications', 'Var', (113, 126))
32755	27053248	A role for epigenetic factors has been shown for several cancers including esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('epigenetic factors', 'Var', (11, 29))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('esophageal cancer', 'Disease', (75, 92))
32757	27053248	Hyper- and hypo-methylation have distinct roles in the cell making the fingerprinting of cancer cells complex.	('hypo-methylation', 'Var', (11, 27))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('Hyper-', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
32758	27053248	Hypomethylation usually introduces genome instability and genetic rearrangements while hypermethylation silences various tumor suppressor genes.	('hyper', 'Disease', 'MESH:D053307', (87, 92))	('hyper', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('genetic rearrangements', 'MPA', (58, 80))	('Hypomethylation', 'Var', (0, 15))	('genome instability', 'MPA', (35, 53))	('silences', 'NegReg', (104, 112))	('tumor', 'Disease', (121, 126))	('men', 'Species', '9606', (75, 78))	('introduces', 'Reg', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
32759	27053248	The aberrant hypomethylation occurs at many different loci suggestive of an overall deregulation of methylation control in tumorigenesis in esophageal adenocarcinoma.	('hypomethylation', 'Var', (13, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('tumor', 'Disease', (123, 128))	('methylation', 'MPA', (100, 111))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (140, 165))	('aberrant hypomethylation', 'Var', (4, 28))	('esophageal adenocarcinoma', 'Disease', (140, 165))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (140, 165))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
32767	27053248	For example, these studies typically utilized PCRs specifically designed to detect hyper- or hypo- methylation of the DNA with all the downfalls of this method.	('hyper', 'Disease', (83, 88))	('hyper', 'Disease', 'MESH:D053307', (83, 88))	('hypo- methylation', 'Var', (93, 110))
32826	27053248	For this, a large number of antibodies will need to be generated, especially to each and every single possible combination of mutations and even conversion of these mutations on 2D or 3D structure and, consequently, the epitope structure.	('mutations', 'Var', (165, 174))	('rat', 'Species', '10116', (59, 62))	('mutations', 'Var', (126, 135))
32938	28653599	Utilizing informatics screening, Twist-related protein 1 (TWIST1) was hypothesized to be a possible target gene of miR-539.	('miR-539', 'Var', (115, 122))	('Twist-related protein 1', 'Gene', '22160', (33, 56))	('TWIST1', 'Gene', (58, 64))	('Twist-related protein 1', 'Gene', (33, 56))
32940	28653599	miR-539 mimics or scrambled miRs were transfected into human ESCC TE3 cells to interfere with the expression of miR-539.	('human', 'Species', '9606', (55, 60))	('miR-539', 'Var', (112, 119))	('interfere', 'NegReg', (79, 88))	('expression', 'MPA', (98, 108))
32950	28653599	In our study, we aimed to identify the specific role of miR-539 in human ESCC cells.	('ESCC', 'Disease', (73, 77))	('human', 'Species', '9606', (67, 72))	('miR-539', 'Var', (56, 63))
32972	28653599	The results showed that miR-539 overexpression remarkably decreased the expression of MAGEA4 compared with the miR-NC group (p < 0.001), while the downregulation was reversed by TWIST1 overexpression compared with the miR-539 mimic + pB-NC group (p < 0.001), indicating that miR-539 could regulate MAGEA4 expression through TWIST1.	('expression', 'MPA', (305, 315))	('MAGEA4', 'Gene', (298, 304))	('MAGEA4', 'Gene', (86, 92))	('decreased', 'NegReg', (58, 67))	('miR-539', 'Var', (24, 31))	('expression', 'MPA', (72, 82))	('pB', 'Chemical', '-', (234, 236))	('regulate', 'Reg', (289, 297))
32973	28653599	Next, cells were stably transfected with pB-MAGEA4 or pB-NC, along with transient transfection with miR-539 mimic or miR-NC.	('pB-NC', 'Gene', (54, 59))	('pB-MAGEA4', 'Var', (41, 50))	('pB', 'Chemical', '-', (41, 43))	('pB', 'Chemical', '-', (54, 56))
32977	28653599	In our study, we focused on the effect of miR-539 on ESCC cells and interestingly identified that miR-539 functioned as a tumor suppressor and inhibited EMT by regulating TWIST1-MAGEA4.	('miR-539', 'Var', (98, 105))	('inhibited', 'NegReg', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('EMT', 'CPA', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('TWIST1-MAGEA4', 'Protein', (171, 184))
32978	28653599	confirmed that ESCC patients with higher miR-483-5p levels had a significantly shorter overall survival time, suggesting that miR-483-5p might be a tumor promoter of ESCC.	('ESCC', 'Disease', (15, 19))	('miR-483-5p', 'Var', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('shorter', 'NegReg', (79, 86))	('miR-483-5p', 'Var', (41, 51))	('patients', 'Species', '9606', (20, 28))	('overall survival time', 'CPA', (87, 108))	('ESCC', 'Disease', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
33003	33391336	The DE mRNAs were enriched in 110 GO (BP, CC, and MF) terms or KEGG pathways, such as GO:0007155~cell adhesion, GO:0005576~extracellular region, GO:0055114~oxidation-reduction process, GO:0042542~response to hydrogen peroxide, and hsa05200:pathways in cancer.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (252, 258))	('GO:0042542~response', 'Var', (185, 204))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (208, 225))	('GO:0055114~oxidation-reduction', 'Var', (145, 175))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('GO:0005576~extracellular', 'Var', (112, 136))	('GO:0007155~cell', 'Var', (86, 101))	('GO:0007155~cell adhesion', 'CPA', (86, 110))
33026	33391336	In this study, MAOB, SDR16C5 and FOSL1 were found to be involved in oxidation-reduction associated functions, such as GO:0055114~oxidation-reduction process (MAOB, and SDR16C5), GO:0016491~oxidoreductase activity (MAOB), and GO:0042542~response to hydrogen peroxide (FOSL1).	('GO:0055114~oxidation-reduction process', 'MPA', (118, 156))	('MAOB', 'Gene', (15, 19))	('MAOB', 'Gene', (214, 218))	('GO:0042542~response', 'Var', (225, 244))	('FOSL1', 'Gene', '8061', (33, 38))	('MAOB', 'Gene', (158, 162))	('SDR16C5', 'Gene', '195814', (168, 175))	('SDR16C5', 'Gene', (21, 28))	('oxidoreductase', 'Gene', '8630', (189, 203))	('FOSL1', 'Gene', (267, 272))	('GO:0055114~oxidation-reduction', 'Var', (118, 148))	('involved', 'Reg', (56, 64))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (248, 265))	('MAOB', 'Gene', '4129', (15, 19))	('MAOB', 'Gene', '4129', (214, 218))	('FOSL1', 'Gene', '8061', (267, 272))	('SDR16C5', 'Gene', '195814', (21, 28))	('MAOB', 'Gene', '4129', (158, 162))	('oxidoreductase', 'Gene', (189, 203))	('GO:0042542~response to hydrogen peroxide', 'MPA', (225, 265))	('SDR16C5', 'Gene', (168, 175))	('oxidation-reduction', 'MPA', (68, 87))	('FOSL1', 'Gene', (33, 38))
33046	33391336	Additionally, this protein was involved in the GO:0032496~response to lipopolysaccharide (LPS).	('GO:0032496~response to lipopolysaccharide', 'MPA', (47, 88))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (70, 88))	('involved', 'Reg', (31, 39))	('GO:0032496~response', 'Var', (47, 66))
33075	33391336	The searched parameters included two maximal missed cleavages, fixed modifications [Carbamidomethyl (C), TMT 6plex(K), TMT 6plex (N-Terminus)], variable modifications [Oxidation(M), Acetyl (Protein N-Terminus)], Mass tolerance for precursor ions (20 ppm), Mass tolerance for fragment ions (0.02 Da).	('Oxidation', 'MPA', (168, 177))	('Acetyl', 'MPA', (182, 188))	('TMT 6plex', 'Var', (119, 128))	('TMT', 'Chemical', '-', (105, 108))	('TMT', 'Chemical', '-', (119, 122))	('TMT 6plex', 'Var', (105, 114))
33117	31064137	FAK causes focal contact disassembly once phosphorylated by AKT1.	('FAK', 'Var', (0, 3))	('focal contact disassembly', 'Disease', (11, 36))	('causes', 'Reg', (4, 10))	('AKT1', 'Gene', '207', (60, 64))	('AKT1', 'Gene', (60, 64))
33150	31064137	Loss of E-cadherin may affect the beta-catenin/WNT signaling pathway, resulting in upregulation of genes involved in growth and metastasis.	('E-cadherin', 'Gene', (8, 18))	('genes', 'MPA', (99, 104))	('E-cadherin', 'Gene', '999', (8, 18))	('upregulation', 'PosReg', (83, 95))	('beta-catenin', 'Gene', '1499', (34, 46))	('affect', 'Reg', (23, 29))	('Loss', 'Var', (0, 4))	('beta-catenin', 'Gene', (34, 46))
33154	31064137	Indeed, the silencing of integrin alphav/beta3 in B16 melanoma cells reduces their migratory capacity in vitro and metastatic potential in vivo.	('metastatic potential in vivo', 'CPA', (115, 143))	('migratory capacity in vitro', 'CPA', (83, 110))	('integrin alphav/beta3', 'Protein', (25, 46))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('reduces', 'NegReg', (69, 76))	('silencing', 'Var', (12, 21))	('melanoma', 'Disease', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('B16', 'CellLine', 'CVCL:N540', (50, 53))
33162	31064137	Besides, NEDD9 overexpression leads to increased phosphorylation of beta3-integrin on Tyr785 in the cytoplasmic domain promoting the assembly of a signaling complex containing beta3-integrin, SRC, FAK and NEDD9.	('NEDD9', 'Gene', '4739', (9, 14))	('NEDD9', 'Gene', (9, 14))	('beta3-integrin', 'Protein', (68, 82))	('NEDD9', 'Gene', (205, 210))	('NEDD9', 'Gene', '4739', (205, 210))	('Tyr785', 'Var', (86, 92))	('overexpression', 'Var', (15, 29))	('beta3-integrin', 'Protein', (176, 190))	('increased', 'PosReg', (39, 48))	('phosphorylation', 'MPA', (49, 64))	('Tyr785', 'Chemical', '-', (86, 92))	('promoting', 'PosReg', (119, 128))	('assembly', 'MPA', (133, 141))
33197	31064137	Under ER stress, GRP78 dissociation and disulfide bond modification mediated by the protein disulfide isomerase PDIA5 stabilize ATF6 and promotes its export to the Golgi apparatus.	('GRP78', 'Gene', (17, 22))	('stabilize', 'NegReg', (118, 127))	('promotes', 'PosReg', (137, 145))	('export to the Golgi apparatus', 'MPA', (150, 179))	('GRP78', 'Gene', '3309', (17, 22))	('ATF6', 'Gene', (128, 132))	('disulfide bond modification', 'MPA', (40, 67))	('PDIA5', 'Gene', (112, 117))	('disulfide', 'Chemical', 'MESH:D004220', (92, 101))	('disulfide', 'Chemical', 'MESH:D004220', (40, 49))	('PDIA5', 'Gene', '10954', (112, 117))	('dissociation', 'Var', (23, 35))	('ATF6', 'Gene', '22926', (128, 132))
33208	31064137	Phosphorylation of eIF2alpha leads to the attenuation of the global translation, reducing the folding demand on the ER.	('folding demand', 'MPA', (94, 108))	('reducing', 'NegReg', (81, 89))	('global translation', 'MPA', (61, 79))	('Phosphorylation', 'Var', (0, 15))	('eIF2alpha', 'Gene', (19, 28))	('attenuation', 'NegReg', (42, 53))	('eIF2alpha', 'Gene', '83939', (19, 28))
33213	31064137	GADD34 is activated downstream of CHOP and its expression results in a negative feedback loop for PERK signaling pathway.	('GADD34', 'Gene', (0, 6))	('PERK', 'Gene', '9451', (98, 102))	('CHOP', 'Gene', '1649', (34, 38))	('expression', 'Var', (47, 57))	('negative feedback loop', 'MPA', (71, 93))	('results in', 'Reg', (58, 68))	('CHOP', 'Gene', (34, 38))	('PERK', 'Gene', (98, 102))	('GADD34', 'Gene', '23645', (0, 6))
33220	31064137	High GRP78 expression is associated with metastasis and poor prognosis in breast, colon, esophageal, lung and skin cancers.	('skin cancers', 'Disease', 'MESH:D012878', (110, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('High', 'Var', (0, 4))	('associated', 'Reg', (25, 35))	('esophageal', 'Disease', (89, 99))	('expression', 'MPA', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('skin cancer', 'Phenotype', 'HP:0008069', (110, 121))	('GRP78', 'Gene', '3309', (5, 10))	('lung', 'Disease', (101, 105))	('GRP78', 'Gene', (5, 10))	('skin cancers', 'Disease', (110, 122))	('skin cancers', 'Phenotype', 'HP:0008069', (110, 122))	('breast', 'Disease', (74, 80))	('metastasis', 'CPA', (41, 51))	('colon', 'Disease', (82, 87))
33221	31064137	Moreover, ablation of the UPR sensors leads to a significant reduction in tumor growth in different types of cancers like colon, pancreatic, breast cancer and GBM.	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('GBM', 'Disease', (159, 162))	('colon', 'Disease', (122, 127))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Disease', (109, 116))	('reduction', 'NegReg', (61, 70))	('pancreatic', 'Disease', 'MESH:D010195', (129, 139))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('GBM', 'Phenotype', 'HP:0012174', (159, 162))	('ablation', 'Var', (10, 18))	('breast cancer', 'Disease', (141, 154))	('tumor', 'Disease', (74, 79))	('pancreatic', 'Disease', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
33228	31064137	The three sensors of the UPR have been recently linked to tumor cell migration/invasion processes such as ECM and actin cytoskeleton remodeling and cytoskeleton reorganization, modification of cellular adhesion, activation of signaling pathways associated with cell mobility, and EMT.	('signaling pathways', 'Pathway', (226, 244))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('modification', 'Var', (177, 189))	('cytoskeleton reorganization', 'CPA', (148, 175))	('ECM', 'CPA', (106, 109))	('EMT', 'CPA', (280, 283))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cellular', 'Protein', (193, 201))	('activation', 'PosReg', (212, 222))	('linked', 'Reg', (48, 54))
33262	31064137	For instance, in GBM, the inhibition of IRE1 decreases the expression of proangiogenic factors such as VEGFA, IL1beta, IL6, and CXCL8 (also named IL8) and leads to a reduction of angiogenesis.	('IL8', 'Gene', (146, 149))	('VEGFA', 'Gene', (103, 108))	('reduction', 'NegReg', (166, 175))	('IL6', 'Gene', (119, 122))	('IL8', 'Gene', '3576', (146, 149))	('decreases', 'NegReg', (45, 54))	('IL1beta', 'Gene', (110, 117))	('inhibition', 'Var', (26, 36))	('GBM', 'Phenotype', 'HP:0012174', (17, 20))	('CXCL8', 'Gene', '3576', (128, 133))	('angiogenesis', 'CPA', (179, 191))	('expression', 'MPA', (59, 69))	('VEGFA', 'Gene', '7422', (103, 108))	('IL1beta', 'Gene', '3553', (110, 117))	('IRE1', 'Gene', (40, 44))	('CXCL8', 'Gene', (128, 133))	('IL6', 'Gene', '3569', (119, 122))
33264	31064137	Selective impairment of IRE1 RNase increase invasion, vessel co-option capacity and mesenchymal features in U87 glioma cells.	('increase', 'PosReg', (35, 43))	('IRE1 RNase', 'Protein', (24, 34))	('invasion', 'CPA', (44, 52))	('impairment', 'Var', (10, 20))	('U87', 'CellLine', 'CVCL:0022', (108, 111))	('glioma', 'Disease', (112, 118))	('mesenchymal features', 'CPA', (84, 104))	('vessel co-option capacity', 'CPA', (54, 79))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
33265	31064137	Interestingly, in colorectal cancers high XBP1s expression is associated with metastatic tumors in patients and with cancer cell invasion in vitro by controlling VEGFR2 expression.	('tumors', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('XBP1s', 'Gene', (42, 47))	('expression', 'MPA', (169, 179))	('VEGFR2', 'Gene', (162, 168))	('associated', 'Reg', (62, 72))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('controlling', 'Reg', (150, 161))	('VEGFR2', 'Gene', '3791', (162, 168))	('colorectal cancers', 'Disease', 'MESH:D015179', (18, 36))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('high', 'Var', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('colorectal cancers', 'Disease', (18, 36))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
33277	31064137	However, other studies indicate that XBP1s increases the metastatic potential of tumor cells by the induction of the expression of several EMT transcription factors, including SNAI1, SNAI2, ZEB2 and TCF3.	('SNAI1', 'Gene', (176, 181))	('TCF3', 'Gene', '6929', (199, 203))	('ZEB2', 'Gene', (190, 194))	('XBP1s', 'Var', (37, 42))	('expression', 'MPA', (117, 127))	('TCF3', 'Gene', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('increases', 'PosReg', (43, 52))	('ZEB2', 'Gene', '9839', (190, 194))	('SNAI1', 'Gene', '6615', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SNAI2', 'Gene', '6591', (183, 188))	('SNAI2', 'Gene', (183, 188))	('tumor', 'Disease', (81, 86))
33283	31064137	Remarkably, the regulation of cytoskeleton dynamics by IRE1 is independent of its canonical RNase activity, but instead IRE1 serves as a scaffold that recruits FLNA, scaffolding to PKCalpha, to increase FLNA phosphorylation.	('FLNA', 'Protein', (203, 207))	('increase', 'PosReg', (194, 202))	('FLNA', 'Protein', (160, 164))	('IRE1', 'Var', (120, 124))	('PKCalpha', 'Gene', (181, 189))	('PKCalpha', 'Gene', '5578', (181, 189))
33285	31064137	In addition, using a panel of tumor cell lines, IRE1 silencing decreased tumor cell migration.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('decreased', 'NegReg', (63, 72))	('IRE1', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (73, 78))	('silencing', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
33290	31064137	Furthermore, silencing of XBP1 decreased the formation of lung metastases in an orthotopic TNBC xenograft mouse model (Figure 2, (2)).	('XBP1', 'Gene', (26, 30))	('decreased', 'NegReg', (31, 40))	('lung metastases', 'Disease', (58, 73))	('lung metastases', 'Disease', 'MESH:D009362', (58, 73))	('silencing', 'Var', (13, 22))	('mouse', 'Species', '10090', (106, 111))
33294	31064137	Using a bioinformatic approach that integrates gene mutations and DNA methylation changes, CREB3L1 was identified as an important regulatory driver in prostate cancer.	('mutations', 'Var', (52, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('CREB3L1', 'Gene', (91, 98))	('CREB3L1', 'Gene', '90993', (91, 98))	('prostate cancer', 'Disease', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))
33296	31064137	Surprisingly, CREB3L1 is lost in metastatic cells from breast and bladder tumors due to the methylation of its gene (in the promoter region and the first intronic region) leading to an epigenetic silencing.	('CREB3L1', 'Gene', '90993', (14, 21))	('bladder tumors', 'Disease', (66, 80))	('methylation', 'Var', (92, 103))	('bladder tumors', 'Phenotype', 'HP:0009725', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('breast', 'Disease', (55, 61))	('bladder tumors', 'Disease', 'MESH:D001749', (66, 80))	('epigenetic silencing', 'MPA', (185, 205))	('CREB3L1', 'Gene', (14, 21))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
33301	31064137	CREB3L1 inhibition also reduces FAK activation, an important kinase that regulates cell/ECM interaction via its impact on ECM (Figure 1, (2)).	('reduces', 'NegReg', (24, 31))	('CREB3L1', 'Gene', (0, 7))	('inhibition', 'Var', (8, 18))	('FAK activation', 'MPA', (32, 46))	('CREB3L1', 'Gene', '90993', (0, 7))
33303	31064137	PERK-mediated eIF2alpha phosphorylation also induces LAMP3-dependent cervix cancer cell migration under hypoxia.	('PERK', 'Gene', (0, 4))	('cervix cancer', 'Disease', (69, 82))	('eIF2alpha', 'Gene', (14, 23))	('PERK', 'Gene', '9451', (0, 4))	('cervix cancer', 'Disease', 'MESH:D002583', (69, 82))	('induces', 'Reg', (45, 52))	('eIF2alpha', 'Gene', '83939', (14, 23))	('LAMP3', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('hypoxia', 'Disease', (104, 111))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('cervix cancer', 'Phenotype', 'HP:0030079', (69, 82))	('phosphorylation', 'Var', (24, 39))	('LAMP3', 'Gene', '27074', (53, 58))
33304	31064137	Importantly, LAMP3 expression is also associated with metastasis and poor prognostic in breast, cervix and colorectal cancers and head and neck squamous carcinomas.	('cervix', 'Disease', (96, 102))	('associated', 'Reg', (38, 48))	('LAMP3', 'Gene', '27074', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('expression', 'Var', (19, 29))	('neck squamous carcinomas', 'Disease', 'MESH:D000077195', (139, 163))	('colorectal cancers', 'Disease', 'MESH:D015179', (107, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('head and neck squamous carcinomas', 'Phenotype', 'HP:0012288', (130, 163))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (144, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('breast', 'Disease', (88, 94))	('neck squamous carcinomas', 'Disease', (139, 163))	('metastasis', 'CPA', (54, 64))	('colorectal cancers', 'Disease', (107, 125))	('LAMP3', 'Gene', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
33310	31064137	Interestingly, several inhibitors of the ER stress sensors have been reported to affect tumor migration.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inhibitors', 'Var', (23, 33))	('affect', 'Reg', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
33314	31064137	IRE1 inhibitors such as quercetin and sunitinib also inhibit tumor migration by modulating the same molecular actors of the ECM remodeling and intracellular signaling pathways, i.e., metalloproteinases and kinases, but again, these effects were not yet proven to occur through the inhibition of IRE1.	('IRE1', 'Gene', (0, 4))	('sunitinib', 'Chemical', 'MESH:D000077210', (38, 47))	('inhibit', 'NegReg', (53, 60))	('inhibitors', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('modulating', 'Reg', (80, 90))	('metalloproteinases', 'Pathway', (183, 201))	('quercetin', 'Chemical', 'MESH:D011794', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('kinases', 'Pathway', (206, 213))	('tumor', 'Disease', (61, 66))
33316	31064137	The PERK inhibitor GSK2606414 blocks brain tumor cell migration, but this inhibitor is also known to target RIPK1 and c-KIT.	('GSK2606414', 'Chemical', 'MESH:C576403', (19, 29))	('blocks', 'NegReg', (30, 36))	('brain tumor', 'Disease', 'MESH:D001932', (37, 48))	('brain tumor', 'Disease', (37, 48))	('GSK2606414', 'Var', (19, 29))	('RIPK1', 'Gene', '8737', (108, 113))	('PERK', 'Gene', '9451', (4, 8))	('brain tumor', 'Phenotype', 'HP:0030692', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('c-KIT', 'Gene', (118, 123))	('RIPK1', 'Gene', (108, 113))	('c-KIT', 'Gene', '3815', (118, 123))	('PERK', 'Gene', (4, 8))
33320	31064137	; and FONDECYT 1140549, FONDAP program 15150012, Millennium Institute P09-015-F, Michael J Fox Foundation for Parkinson's Research, Target Validation grant 9277, FONDEF ID16I10223, FONDEF D11E1007, US Office of Naval Research-Global N62909-16-1-2003, US Air Force Office of Scientific Research FA9550-16-1-0384, ALSRP Therapeutic Idea Award AL150111, Muscular Dystrophy Association 382453, Seed grant Leading House for the Latin American Region, Switzerland, and CONICYT-Brazil 441921/2016-7 to C.H.	('Muscular Dystrophy', 'Disease', (351, 369))	('Muscular Dystrophy', 'Phenotype', 'HP:0003560', (351, 369))	('Muscular Dystrophy', 'Disease', 'MESH:D009136', (351, 369))	("Parkinson'", 'Disease', 'MESH:D010302', (110, 120))	("Parkinson'", 'Disease', (110, 120))	('AL150111', 'Var', (341, 349))
33396	29037026	In RTOG 85-01 study, 10% of patients treated with CCRT experienced acute life-threatening toxicities or treatment-related mortality (TRM), while 2% of patients treated with radiotherapy alone experienced acute life-threatening toxicities without TRM.	('toxicities', 'Disease', (227, 237))	('toxicities', 'Disease', (90, 100))	('patients', 'Species', '9606', (151, 159))	('toxicities', 'Disease', 'MESH:D064420', (227, 237))	('toxicities', 'Disease', 'MESH:D064420', (90, 100))	('patients', 'Species', '9606', (28, 36))	('CCRT', 'Var', (50, 54))
33405	29037026	In addition, grade 2 esophageal stenosis to require endoscopic treatments is occurred in two patients received ESD, while there was no grade 2 or higher esophageal stenosis in patients received radiation without ESD.	('patients', 'Species', '9606', (176, 184))	('ESD', 'Var', (111, 114))	('esophageal stenosis', 'Disease', 'MESH:D004940', (153, 172))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (153, 172))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (21, 40))	('esophageal stenosis', 'Disease', (21, 40))	('esophageal stenosis', 'Disease', 'MESH:D004940', (21, 40))	('patients', 'Species', '9606', (93, 101))	('esophageal stenosis', 'Disease', (153, 172))
33494	25547086	A recent meta-analysis showed that dietary salt intake was directly associated with risk of gastric cancer in prospective population studies, with progressively increasing risk across consumption levels.	('dietary', 'Var', (35, 42))	('associated', 'Reg', (68, 78))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('salt', 'Chemical', 'MESH:D012492', (43, 47))
33506	25547086	However, the effect of alcohol drinking on risk of gastric cancer might vary with the cancer's location (cardiac cancer vs noncardiac cancer) and a study suggested that aldehyde dehydrogenase 2 (ALDH2) polymorphisms were found to modify the susceptibility to the development of gastric cancer associated with alcohol intake.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('polymorphisms', 'Var', (202, 215))	('cancer', 'Disease', (113, 119))	('cardiac cancer', 'Disease', 'MESH:D006338', (126, 140))	('modify', 'Reg', (230, 236))	('alcohol', 'Chemical', 'MESH:D000438', (309, 316))	('gastric cancer', 'Disease', 'MESH:D013274', (278, 292))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', (286, 292))	('alcohol drinking', 'Phenotype', 'HP:0030955', (23, 39))	('cardiac cancer', 'Phenotype', 'HP:0100544', (105, 119))	('alcohol', 'Chemical', 'MESH:D000438', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('cancer', 'Disease', (134, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (51, 65))	('gastric cancer', 'Disease', (278, 292))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cardiac cancer', 'Disease', (105, 119))	('cancer', 'Disease', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (278, 292))	('cardiac cancer', 'Phenotype', 'HP:0100544', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('gastric cancer', 'Disease', (51, 65))	('ALDH2', 'Gene', (195, 200))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('noncardiac cancer', 'Disease', 'MESH:D009369', (123, 140))	('cardiac cancer', 'Disease', 'MESH:D006338', (105, 119))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (59, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (51, 65))	('noncardiac cancer', 'Disease', (123, 140))
33507	25547086	ALDH2 genetic polymorphism appears to modify the susceptibility to upper aero-digestive tract cancers induced by alcohol intake.	('alcohol', 'Chemical', 'MESH:D000438', (113, 120))	('ALDH2', 'Gene', (0, 5))	('tract cancers', 'Disease', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tract cancers', 'Disease', 'MESH:D014571', (88, 101))	('modify', 'Reg', (38, 44))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('genetic polymorphism', 'Var', (6, 26))
33510	25547086	Peak blood acetaldehyde concentrations after an alcohol challenge were reportedly 18 and 5 times higher, among homozygous ALDH2 *2 variants and heterozygous variants, respectively, compared to homozygous wild type individuals.	('higher', 'PosReg', (97, 103))	('alcohol challenge', 'Phenotype', 'HP:0030955', (48, 65))	('blood acetaldehyde concentrations', 'Phenotype', 'HP:0003533', (5, 38))	('ALDH2 *2', 'Gene', (122, 130))	('variants', 'Var', (131, 139))	('acetaldehyde', 'Chemical', 'MESH:D000079', (11, 23))	('alcohol', 'Chemical', 'MESH:D000438', (48, 55))	('variants', 'Var', (157, 165))
33511	25547086	As acetaldehyde is a plausible candidate for the carcinogenic effect of alcoholic drinks, ALDH2 genetic polymorphism may play a pivotal role on alcohol-induced carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('carcinogenesis', 'Disease', (160, 174))	('carcinogenic', 'Disease', 'MESH:D063646', (49, 61))	('carcinogenic', 'Disease', (49, 61))	('alcohol', 'Chemical', 'MESH:D000438', (144, 151))	('alcohol', 'Chemical', 'MESH:D000438', (72, 79))	('acetaldehyde', 'Chemical', 'MESH:D000079', (3, 15))	('role', 'Reg', (136, 140))	('genetic polymorphism', 'Var', (96, 116))	('ALDH2', 'Gene', (90, 95))	('play', 'Reg', (121, 125))
33515	25547086	For instance in esophageal carcinogenesis, ALDH2 *2/*2 genotype reduces esophageal cancer risk due to a lower alcohol intake; ALDH2 *1/*2 is associated with a 3-fold overall increase in risk for esophageal cancer.	('esophageal cancer', 'Disease', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('lower', 'NegReg', (104, 109))	('alcohol intake', 'MPA', (110, 124))	('ALDH2 *1/*2', 'Var', (126, 137))	('alcohol', 'Chemical', 'MESH:D000438', (110, 117))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (16, 41))	('reduces', 'NegReg', (64, 71))	('esophageal carcinogenesis', 'Disease', (16, 41))
33520	25547086	Among the ALDH2 *1/*2 carriers (n=243), current/ex-drinkers had a significantly increased risk for gastric cancer compared to never/rare drinkers (OR, 2.80; 95% CI, 1.51 to 5.19).	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('increased risk for gastric cancer', 'Phenotype', 'HP:0006753', (80, 113))	('gastric cancer', 'Disease', (99, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('carriers', 'Var', (22, 30))	('ALDH2 *1/', 'Gene', (10, 19))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))
33551	25547086	Moreover, it reported that more than half of the follow-up studies found a statistically significant association between incomplete IM and subsequent gastric cancer risk (RR of gastric cancer, 4- to 11-fold higher for the presence of incomplete type in comparison to complete type or absence of incomplete type).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gastric cancer', 'Disease', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('gastric cancer', 'Disease', 'MESH:D013274', (177, 191))	('gastric cancer', 'Disease', (150, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('presence', 'Var', (222, 230))	('gastric cancer', 'Phenotype', 'HP:0012126', (177, 191))	('incomplete IM', 'Var', (121, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('higher', 'PosReg', (207, 213))
33552	25547086	The authors concluded that most of the scientific evidence supports the utility of subtyping IM as a predictor of gastric cancer risk.	('gastric cancer', 'Disease', (114, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('subtyping', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
33558	25547086	However, a recent Korean study suggested that aberrant expression of CDX1 and CDX2 on transcriptional level correlated with IM grade in the gastric body.	('CDX2', 'Gene', (78, 82))	('CDX1', 'Gene', (69, 73))	('CDX2', 'Gene', '1045', (78, 82))	('CDX1', 'Gene', '1044', (69, 73))	('correlated with', 'Reg', (108, 123))	('aberrant', 'Var', (46, 54))
33559	25547086	A subsequent study demonstrated this association between aberrant CDX2 expression and IM grade of the gastric body at the translational level.	('expression', 'MPA', (71, 81))	('CDX2', 'Gene', '1045', (66, 70))	('CDX2', 'Gene', (66, 70))	('IM grade of the gastric body', 'CPA', (86, 114))	('aberrant', 'Var', (57, 65))
33600	25547086	However, another Korean study concluded that the risk of gastric cancer was higher in patients with a low PG ratio and H. pylori-positive than in those with a low PG ratio and H. pylori-negative (OR, 5.52, 95% CI, 2.83 to 10.77 vs OR, 2.04, 95% CI, 0.58 to 7.19).	('gastric cancer', 'Disease', (57, 71))	('to 7', 'Species', '1214577', (254, 258))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('H. pylori', 'Species', '210', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('low', 'Var', (102, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('H. pylori', 'Species', '210', (176, 185))	('patients', 'Species', '9606', (86, 94))
33622	25547086	The authors concluded that H. pylori eradication decreases the RR of gastric cancer to 0.65 (95% CI, 0.43 to 0.98).	('gastric cancer', 'Disease', (69, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('decreases', 'NegReg', (49, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('H. pylori', 'Species', '210', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('eradication', 'Var', (37, 48))
33629	25547086	The results of a meta-analysis including eight studies evaluated the long-term effects of H. pylori eradication on gastric histology; H. pylori eradication could improve AG but could not reverse IM.	('H. pylori', 'Species', '210', (134, 143))	('eradication', 'Var', (144, 155))	('AG', 'Phenotype', 'HP:0002582', (170, 172))	('H. pylori', 'Var', (134, 143))	('improve', 'PosReg', (162, 169))	('H. pylori', 'Species', '210', (90, 99))
33636	25547086	A retrospective study from Japan reported that H. pylori eradication in patients undergoing endoscopic resection for EGC reduces the incidence of metachronous gastric cancer.	('H. pylori', 'Species', '210', (47, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (159, 173))	('gastric cancer', 'Phenotype', 'HP:0012126', (159, 173))	('EGC', 'Chemical', '-', (117, 120))	('reduces', 'NegReg', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('eradication', 'Var', (57, 68))	('gastric cancer', 'Disease', (159, 173))	('H. pylori', 'Protein', (47, 56))	('patients', 'Species', '9606', (72, 80))
33786	21816251	This particular study showed that the ocular attack rate was actually significantly higher in the daclizumab arm than the placebo arm (1.27 vs. 0.17 attacks/year), and the placebo arm was better able to taper off their immunosuppressive regimen as compared to the daclizumab arm.	('daclizumab', 'Var', (98, 108))	('daclizumab', 'Chemical', 'MESH:D000077561', (264, 274))	('ocular attack', 'Disease', (38, 51))	('daclizumab', 'Chemical', 'MESH:D000077561', (98, 108))	('higher', 'PosReg', (84, 90))
33838	21266059	Gene transfection was used to restore or knock down RRIG1 expression in breast cancer cell lines for analysis of cell viability, colony formation, and migration/invasion potential.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('RRIG1', 'Gene', (52, 57))	('RRIG1', 'Gene', '56904', (52, 57))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('knock down', 'Var', (41, 51))
33842	21266059	Furthermore, restoration of RRIG1 expression inhibited proliferation, colony formation, migration, and invasion of breast cancer cells.	('expression', 'MPA', (34, 44))	('RRIG1', 'Gene', (28, 33))	('RRIG1', 'Gene', '56904', (28, 33))	('proliferation', 'CPA', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('migration', 'CPA', (88, 97))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('inhibited', 'NegReg', (45, 54))	('restoration', 'Var', (13, 24))	('invasion', 'CPA', (103, 111))	('breast cancer', 'Disease', (115, 128))	('colony formation', 'CPA', (70, 86))
33844	21266059	In contrast, knockdown of RRIG1 expression promoted breast cancer cell proliferation, colony formation, migration, and invasion potential.	('invasion potential', 'CPA', (119, 137))	('RRIG1', 'Gene', '56904', (26, 31))	('promoted', 'PosReg', (43, 51))	('migration', 'CPA', (104, 113))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('RRIG1', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('knockdown', 'Var', (13, 22))	('colony formation', 'CPA', (86, 102))
33845	21266059	The data from the current study indicated that RRIG1 expression was reduced or lost in breast cancer and that restoration of RRIG1 expression suppressed breast cancer cell growth and invasion capacity.	('lost', 'NegReg', (79, 83))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('breast cancer', 'Disease', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('suppressed', 'NegReg', (142, 152))	('RRIG1', 'Gene', (47, 52))	('RRIG1', 'Gene', '56904', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('RRIG1', 'Gene', (125, 130))	('RRIG1', 'Gene', '56904', (125, 130))	('invasion capacity', 'CPA', (183, 200))	('expression', 'MPA', (53, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('restoration', 'Var', (110, 121))	('expression', 'MPA', (131, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('reduced', 'NegReg', (68, 75))	('breast cancer', 'Disease', (153, 166))
33856	21266059	Esophageal cancer cells transfected with RRIG1 also showed reduced tumorigenicity in nude mice.	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('reduced', 'NegReg', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('transfected', 'Var', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('RRIG1', 'Gene', (41, 46))	('RRIG1', 'Gene', '56904', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('nude mice', 'Species', '10090', (85, 94))	('Esophageal cancer', 'Disease', (0, 17))	('tumor', 'Disease', (67, 72))
33858	21266059	At the level of signal transduction, expression of RRIG1 inhibited Src phosphorylation and RhoA activation, which is believed to be causally linked to reduced colony formation, invasion, and proliferation in esophageal and prostatic cancer cells.	('Src', 'Gene', '6714', (67, 70))	('expression', 'Var', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('reduced', 'NegReg', (151, 158))	('invasion', 'CPA', (177, 185))	('inhibited', 'NegReg', (57, 66))	('prostatic cancer', 'Disease', (223, 239))	('RRIG1', 'Gene', (51, 56))	('RRIG1', 'Gene', '56904', (51, 56))	('prostatic cancer', 'Disease', 'MESH:D011471', (223, 239))	('RhoA', 'Gene', (91, 95))	('prostatic cancer', 'Phenotype', 'HP:0012125', (223, 239))	('proliferation', 'CPA', (191, 204))	('RhoA', 'Gene', '387', (91, 95))	('Src', 'Gene', (67, 70))	('activation', 'PosReg', (96, 106))	('colony formation', 'CPA', (159, 175))
33859	21266059	In contrast, transfection of antisense RRIG1 increased RhoA activity and f-actin formation and led to increased colony formation, invasion, and proliferation in these cells.	('RhoA', 'Gene', (55, 59))	('f-actin formation', 'CPA', (73, 90))	('antisense', 'Var', (29, 38))	('increased', 'PosReg', (45, 54))	('RhoA', 'Gene', '387', (55, 59))	('invasion', 'CPA', (130, 138))	('colony formation', 'CPA', (112, 128))	('increased', 'PosReg', (102, 111))	('RRIG1', 'Gene', (39, 44))	('RRIG1', 'Gene', '56904', (39, 44))	('proliferation', 'CPA', (144, 157))
33861	21266059	We also explored the changes in expression and phosphorylation or activation of several relevant proteins following experimental elevation or knockdown of RRIG1 expression in breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('phosphorylation', 'MPA', (47, 62))	('breast cancer', 'Disease', (175, 188))	('activation', 'MPA', (66, 76))	('proteins', 'Protein', (97, 105))	('RRIG1', 'Gene', (155, 160))	('RRIG1', 'Gene', '56904', (155, 160))	('expression', 'MPA', (32, 42))	('knockdown', 'Var', (142, 151))
33872	21266059	The percentage of staining was scored as follows: 0, no staining; +, less than 10% of tumor cells stained; ++, 10-50%; and +++, more than 50% tumor cells stained positive.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('+++', 'Var', (123, 126))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
33886	21266059	The cells were grown and transiently transfected with RRIG1 sense or antisense cDNA and then grown in G418-containing medium for 1 or 5 days.	('antisense', 'Var', (69, 78))	('RRIG1', 'Gene', '56904', (54, 59))	('G418', 'Chemical', 'MESH:C010680', (102, 106))	('RRIG1', 'Gene', (54, 59))
33897	21266059	Student t-test was used to determine statistical differences between the control and RRIG1 sense- or antisense-transfected breast cancer cells.	('RRIG1', 'Gene', (85, 90))	('RRIG1', 'Gene', '56904', (85, 90))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('antisense-transfected', 'Var', (101, 122))	('sense-', 'Var', (91, 97))	('breast cancer', 'Disease', (123, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
33901	21266059	The antibodies used were anti-p-Erk1/2, t-Erk1/2, p-Akt, t-Akt, p-Stat3, t-Stat3, p-Rb, and Rb (Cell Signaling Technology, Beverly, MA); anti-c-Jun and E2F-1 (Santa Cruz Biotechnology, Santa Cruz, CA); and anti-beta-actin (Sigma).	('Stat3', 'Gene', (66, 71))	('anti-p-Erk1/2', 'Var', (25, 38))	('Akt', 'Gene', (59, 62))	('E2F-1', 'Gene', '1869', (152, 157))	('c-Jun', 'Gene', (142, 147))	('Akt', 'Gene', (52, 55))	('beta-actin', 'Gene', '728378', (211, 221))	('beta-actin', 'Gene', (211, 221))	('Akt', 'Gene', '207', (52, 55))	('Stat3', 'Gene', (75, 80))	('Stat3', 'Gene', '6774', (75, 80))	('Akt', 'Gene', '207', (59, 62))	('p-Rb', 'Gene', (82, 86))	('c-Jun', 'Gene', '3725', (142, 147))	('Stat3', 'Gene', '6774', (66, 71))	('p-Rb', 'Gene', '5925', (82, 86))	('E2F-1', 'Gene', (152, 157))
33904	21266059	After that, the percentage of control was calculated using the formula: value of the RRIG1 sense or antisense transfected cells/value of the vector-only transfected cells.	('RRIG1', 'Gene', (85, 90))	('RRIG1', 'Gene', '56904', (85, 90))	('antisense transfected', 'Var', (100, 121))
33920	21266059	We transiently transfected RRIG1 sense and antisense cDNAs into the MDA-MB-231 and MDA-MB-435 cell lines, respectively.	('MDA-MB-435', 'CellLine', 'CVCL:0417', (83, 93))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (68, 78))	('RRIG1', 'Gene', (27, 32))	('RRIG1', 'Gene', '56904', (27, 32))	('antisense', 'Var', (43, 52))
33922	21266059	Next, we used the MTT assay to detect the changed cell viability by RRIG1 and found that restoration of RRIG1 expression reduced cell viability in MDA-MB-231 cells, but knockdown of RRIG1 expression induced cell viability in MDA-MB-435 cells after 5 d of cultures (Figure 2C).	('cell viability', 'CPA', (129, 143))	('RRIG1', 'Gene', (68, 73))	('RRIG1', 'Gene', '56904', (68, 73))	('induced', 'PosReg', (199, 206))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (147, 157))	('MTT', 'Chemical', '-', (18, 21))	('RRIG1', 'Gene', (182, 187))	('knockdown', 'Var', (169, 178))	('RRIG1', 'Gene', '56904', (182, 187))	('reduced', 'NegReg', (121, 128))	('RRIG1', 'Gene', (104, 109))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (225, 235))	('RRIG1', 'Gene', '56904', (104, 109))	('cell viability', 'CPA', (207, 221))
33923	21266059	Furthermore, RRIG1 expression decreased the number of colonies in MDA-MB-231 cells, and knockdown of RRIG1 expression in MDA-MB-435 cells increased the numbers of colonies in soft agar (Figure 2D).	('increased', 'PosReg', (138, 147))	('RRIG1', 'Gene', (13, 18))	('RRIG1', 'Gene', '56904', (13, 18))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (66, 76))	('RRIG1', 'Gene', (101, 106))	('knockdown', 'Var', (88, 97))	('RRIG1', 'Gene', '56904', (101, 106))	('agar', 'Chemical', 'MESH:D000362', (180, 184))	('decreased', 'NegReg', (30, 39))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (121, 131))
33926	21266059	We found that RRIG1 expression downregulated p-Erk1/2, p-AKT, total AKT, c-Jun, and MMP9 expression in MDA-MB-231 cells, whereas knockdown of RRIG1 expression upregulated p-AKT, total AKT, p-Stat3, p-RB, and E2F-1 expression in MDA-MBN-435 cells (Figure 4).	('total', 'MPA', (178, 183))	('E2F-1', 'Gene', '1869', (208, 213))	('AKT', 'Gene', (173, 176))	('c-Jun', 'Gene', '3725', (73, 78))	('expression', 'MPA', (89, 99))	('c-Jun', 'Gene', (73, 78))	('AKT', 'Gene', '207', (184, 187))	('RRIG1', 'Gene', (142, 147))	('knockdown', 'Var', (129, 138))	('Stat3', 'Gene', (191, 196))	('RRIG1', 'Gene', '56904', (142, 147))	('AKT', 'Gene', '207', (57, 60))	('MMP9', 'Gene', '4318', (84, 88))	('MMP9', 'Gene', (84, 88))	('AKT', 'Gene', (68, 71))	('AKT', 'Gene', '207', (173, 176))	('RRIG1', 'Gene', (14, 19))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (103, 113))	('RRIG1', 'Gene', '56904', (14, 19))	('p-Erk1/2', 'MPA', (45, 53))	('Stat3', 'Gene', '6774', (191, 196))	('downregulated', 'NegReg', (31, 44))	('upregulated', 'PosReg', (159, 170))	('MDA-MBN-435', 'CellLine', 'CVCL:0417', (228, 239))	('E2F-1', 'Gene', (208, 213))	('p-RB', 'Gene', (198, 202))	('p-RB', 'Gene', '5925', (198, 202))	('AKT', 'Gene', '207', (68, 71))	('AKT', 'Gene', (184, 187))	('AKT', 'Gene', (57, 60))
33928	21266059	Furthermore, we confirmed that RRIG1 was able to suppress RhoA activity, whereas antisense RRIG1 promoted RhoA activity in these breast cancer cells (Figure 4C).	('breast cancer', 'Disease', (129, 142))	('RhoA', 'Gene', (58, 62))	('suppress', 'NegReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('promoted', 'PosReg', (97, 105))	('RhoA', 'Gene', '387', (58, 62))	('RRIG1', 'Gene', (31, 36))	('RRIG1', 'Gene', '56904', (31, 36))	('antisense', 'Var', (81, 90))	('RhoA', 'Gene', (106, 110))	('RhoA', 'Gene', '387', (106, 110))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('RRIG1', 'Gene', (91, 96))	('RRIG1', 'Gene', '56904', (91, 96))
33930	21266059	Antisense RRIG1 cDNA reduced RRIG1 mRNA levels but did not affect expression of SH3 domain GRB2-like endophilin B2 (SH3GLB2) (Figure 5).	('reduced', 'NegReg', (21, 28))	('SH3GLB2', 'Gene', (116, 123))	('RRIG1', 'Gene', (10, 15))	('RRIG1', 'Gene', '56904', (10, 15))	('SH3 domain GRB2-like endophilin B2', 'Gene', '56904', (80, 114))	('SH3GLB2', 'Gene', '56904', (116, 123))	('RRIG1', 'Gene', (29, 34))	('RRIG1', 'Gene', '56904', (29, 34))	('Antisense', 'Var', (0, 9))	('SH3 domain GRB2-like endophilin B2', 'Gene', (80, 114))
33944	21266059	However, our current study showed that the vector carrying antisense open reading frame of RRIG1 did not affect expression of SH3GLB2 mRNA (Figure 5).	('SH3GLB2', 'Gene', (126, 133))	('SH3GLB2', 'Gene', '56904', (126, 133))	('antisense open reading frame', 'Var', (59, 87))	('RRIG1', 'Gene', (91, 96))	('RRIG1', 'Gene', '56904', (91, 96))
33949	21266059	Our current study demonstrated that the restoration of RRIG1 expression inhibited breast cancer cell proliferation, colony formation, migration, and invasion and regulated gene expression.	('regulated', 'Reg', (162, 171))	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('colony formation', 'CPA', (116, 132))	('RRIG1', 'Gene', (55, 60))	('restoration', 'Var', (40, 51))	('migration', 'CPA', (134, 143))	('RRIG1', 'Gene', '56904', (55, 60))	('inhibited', 'NegReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('expression', 'MPA', (61, 71))	('invasion', 'CPA', (149, 157))
33953	21266059	Nevertheless, knockdown of RRIG1 expression has had opposite effects in the regulation of breast cancer cell growth, colony formation, migration, and invasion.	('migration', 'CPA', (135, 144))	('RRIG1', 'Gene', (27, 32))	('RRIG1', 'Gene', '56904', (27, 32))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('invasion', 'CPA', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('knockdown', 'Var', (14, 23))	('colony formation', 'CPA', (117, 133))
33961	21266059	The aberrant activation of RhoA proteins was found to cause cell growth, transformation, invasion, and metastasis in experimental models of carcinogenesis, and inhibition of RhoA suppressed cell proliferation, invasion, and angiogenesis in vitro and in vivo.	('RhoA', 'Gene', '387', (27, 31))	('cause', 'Reg', (54, 59))	('inhibition', 'Var', (160, 170))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('transformation', 'CPA', (73, 87))	('aberrant', 'Var', (4, 12))	('suppressed', 'NegReg', (179, 189))	('RhoA', 'Gene', '387', (174, 178))	('invasion', 'CPA', (89, 97))	('carcinogenesis', 'Disease', (140, 154))	('activation', 'PosReg', (13, 23))	('invasion', 'CPA', (210, 218))	('cell growth', 'CPA', (60, 71))	('cell proliferation', 'CPA', (190, 208))	('RhoA', 'Gene', (174, 178))	('angiogenesis', 'CPA', (224, 236))	('RhoA', 'Gene', (27, 31))	('metastasis', 'CPA', (103, 113))
33969	21266059	This study was supported in part by National Cancer Institute grants R01 CA 117895 and R01 CA078480 and an Institutional Research Grant from MD Anderson Cancer Center as well as grants from The Science Foundations of Education Department of Anhui Province, China (KJ2007B195) and The Youth Foundations of Education Department of Anhui Province, China (2007jq1075).	('Cancer', 'Disease', 'MESH:D009369', (153, 159))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (141, 159))	('R01 CA 117895', 'Var', (69, 82))	('MD Anderson Cancer', 'Disease', (141, 159))	('Cancer', 'Disease', (45, 51))	('Cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('R01 CA078480', 'Var', (87, 99))	('Cancer', 'Disease', (153, 159))
33977	31270941	Lung cancer patients with EGFR mutations had significantly lower TMB values than those with wild-type EGFR, and increased TMB was significantly associated with dMMR in colorectal cancer (CRC).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('lower', 'NegReg', (59, 64))	('CRC', 'Phenotype', 'HP:0003003', (187, 190))	('TMB', 'MPA', (122, 125))	('EGFR', 'Gene', '1956', (102, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('patients', 'Species', '9606', (12, 20))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('dMMR', 'Disease', (160, 164))	('TMB', 'Chemical', '-', (122, 125))	('TMB', 'Chemical', '-', (65, 68))	('increased', 'PosReg', (112, 121))	('EGFR', 'Gene', (102, 106))	('dMMR', 'Chemical', '-', (160, 164))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (5, 11))	('TMB values', 'MPA', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('EGFR', 'Gene', '1956', (26, 30))	('cancer', 'Disease', (179, 185))
33979	31270941	PD-L1 AMP occurred most frequently in lung squamous cell carcinoma and HER2-positive breast cancer.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (38, 66))	('HER2-positive breast cancer', 'Disease', (71, 98))	('AMP', 'Var', (6, 9))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('PD-L1', 'Gene', (0, 5))	('lung squamous cell carcinoma', 'Disease', (38, 66))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (71, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PD-L1', 'Gene', '29126', (0, 5))	('AMP', 'Chemical', 'MESH:D000249', (6, 9))
33980	31270941	While MSI and dMMR are associated with higher mutational loads, correlations between TMB-H and other biomarkers, between MSI-H and dMMR, and between PD-L1 AMP and other biomarkers were low, indicating different underlying causes of the four biomarkers.	('PD-L1', 'Gene', (149, 154))	('AMP', 'Chemical', 'MESH:D000249', (155, 158))	('MSI-H', 'Disease', 'MESH:D000848', (121, 126))	('higher', 'PosReg', (39, 45))	('TMB-H', 'Gene', (85, 90))	('dMMR', 'Var', (14, 18))	('mutational loads', 'MPA', (46, 62))	('PD-L1', 'Gene', '29126', (149, 154))	('dMMR', 'Chemical', '-', (14, 18))	('TMB-H', 'Chemical', '-', (85, 90))	('MSI', 'Var', (6, 9))	('dMMR', 'Chemical', '-', (131, 135))	('MSI-H', 'Disease', (121, 126))
33985	31270941	Several studies have analyzed, in detail, the correlation between tumor mutation burden (TMB) and the efficacy of immunotherapy, showing a high association between TMB and treatment efficacy.8, 9, 10 A study involving 151 cancer patients further confirmed a linear relationship between TMB and the clinical outcome of immunotherapy.9 Analysis of almost 1700 cancer patients receiving at least one dose of PD-1/ PD-L1 blockade showed that 20 percent of the patients with the highest TMB in each cancer type had a better overall survival.11 Furthermore, the US Food and Drug Administration (FDA) approved this treatment for unresectable or metastatic solid tumors in patients with high MSI (MSI-H) or dMMR based on five clinical trials.	('patients', 'Species', '9606', (365, 373))	('patients', 'Species', '9606', (229, 237))	('TMB', 'Chemical', '-', (164, 167))	('cancer', 'Disease', (494, 500))	('tumor', 'Disease', 'MESH:D009369', (655, 660))	('cancer', 'Phenotype', 'HP:0002664', (494, 500))	('cancer', 'Disease', (358, 364))	('tumors', 'Phenotype', 'HP:0002664', (655, 661))	('tumor', 'Disease', (66, 71))	('MSI-H', 'Disease', 'MESH:D000848', (689, 694))	('cancer', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('patients', 'Species', '9606', (665, 673))	('PD-L1', 'Gene', (411, 416))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('patients', 'Species', '9606', (456, 464))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('TMB', 'Chemical', '-', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (655, 660))	('PD-L1', 'Gene', '29126', (411, 416))	('tumors', 'Disease', (655, 661))	('PD-1', 'Gene', '5133', (405, 409))	('cancer', 'Disease', 'MESH:D009369', (494, 500))	('PD-1', 'Gene', (405, 409))	('high MSI', 'Var', (679, 687))	('cancer', 'Disease', 'MESH:D009369', (358, 364))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('dMMR', 'Chemical', '-', (699, 703))	('tumors', 'Disease', 'MESH:D009369', (655, 661))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('unresectable', 'Disease', (622, 634))	('TMB', 'Chemical', '-', (286, 289))	('TMB', 'Chemical', '-', (482, 485))	('MSI-H', 'Disease', (689, 694))	('tumor', 'Disease', (655, 660))
33986	31270941	These trials across 15 cancer types involving 149 patients with high microsatellite instability (MSI-H) or DNA mismatch repair deficiency (dMMR) reported complete or partial response to pembrolizumab in 39.6% of patients.	('high', 'Var', (64, 68))	('MSI-H', 'Disease', 'MESH:D000848', (97, 102))	('patients', 'Species', '9606', (50, 58))	('pembrolizumab', 'Chemical', 'MESH:C582435', (186, 199))	('patients', 'Species', '9606', (212, 220))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('MSI-H', 'Disease', (97, 102))	('dMMR', 'Chemical', '-', (139, 143))
34013	31270941	Although PD-1/PD-L1 blockade has been approved in Non-small cell lung cancer (NSCLC), some clinical trials have reported that NSCLC patients with EGFR mutations do not benefit from this therapy and that it may even lead to a more rapid disease progression.1, 7, 25 Therefore, we compared the median TMB of LUAD patients with mutant (n = 77) and wild-type (n = 99) EGFR genes.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('TMB', 'Chemical', '-', (299, 302))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (50, 76))	('EGFR', 'Gene', (146, 150))	('NSCLC', 'Disease', (78, 83))	('patients', 'Species', '9606', (132, 140))	('NSCLC', 'Disease', (126, 131))	('EGFR', 'Gene', '1956', (364, 368))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('Non-small cell lung cancer', 'Disease', (50, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('PD-L1', 'Gene', (14, 19))	('mutant', 'Var', (325, 331))	('PD-1', 'Gene', (9, 13))	('PD-1', 'Gene', '5133', (9, 13))	('PD-L1', 'Gene', '29126', (14, 19))	('EGFR', 'Gene', '1956', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (50, 76))	('EGFR', 'Gene', (364, 368))	('LUAD', 'Phenotype', 'HP:0030078', (306, 310))	('patients', 'Species', '9606', (311, 319))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (54, 76))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
34014	31270941	Patients with EGFR mutations had significantly lower median TMB compared with those with wild-type EGFR (74 vs 113 NSM, respectively; P = 0.0039) (Figure 2B).	('EGFR', 'Gene', (99, 103))	('lower', 'NegReg', (47, 52))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('TMB', 'MPA', (60, 63))	('Patients', 'Species', '9606', (0, 8))	('TMB', 'Chemical', '-', (60, 63))	('EGFR', 'Gene', '1956', (99, 103))
34018	31270941	Gastrointestinal stromal tumors exhibited a high frequency of dMMR, while those of hepatocellular carcinoma, sarcoma of soft tissue, and renal cell carcinoma were among the lowest.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (83, 107))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (83, 107))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('dMMR', 'Var', (62, 66))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('hepatocellular carcinoma', 'Disease', (83, 107))	('renal cell carcinoma', 'Disease', (137, 157))	('Gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (0, 31))	('dMMR', 'Chemical', '-', (62, 66))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('Gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (0, 31))	('sarcoma', 'Disease', (109, 116))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (137, 157))	('Gastrointestinal stromal tumors', 'Disease', (0, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
34030	31270941	We also calculated the TMB values of patients with amplified and normal PD-L1.	('amplified', 'Var', (51, 60))	('PD-L1', 'Gene', '29126', (72, 77))	('patients', 'Species', '9606', (37, 45))	('TMB', 'MPA', (23, 26))	('PD-L1', 'Gene', (72, 77))	('TMB', 'Chemical', '-', (23, 26))
34051	31270941	In addition, we found that patients with EGFR mutations had significantly lower median TMB compared with those with wild-type EGFR, consistent with another study in which the TMB value of EGFR-mutant nonsquamous NSCLC was half that of wild-type.37  Moreover, the cut-off value of TMB to predict treatment response has been determined in several studies.	('TMB', 'Chemical', '-', (175, 178))	('EGFR', 'Gene', (41, 45))	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('mutations', 'Var', (46, 55))	('TMB', 'MPA', (87, 90))	('EGFR', 'Gene', (126, 130))	('TMB', 'Chemical', '-', (87, 90))	('patients', 'Species', '9606', (27, 35))	('EGFR', 'Gene', '1956', (188, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('TMB', 'Chemical', '-', (280, 283))	('lower', 'NegReg', (74, 79))	('EGFR', 'Gene', '1956', (41, 45))	('EGFR', 'Gene', (188, 192))	('NSCLC', 'Disease', (212, 217))	('EGFR', 'Gene', '1956', (126, 130))
34066	31270941	This study found that patients with TMB of >100 Mut/Mb may be classified as MSS, but many contain replicative polymerase mutations resulting in replication repair deficiency.	('deficiency', 'NegReg', (163, 173))	('replicative polymerase', 'Enzyme', (98, 120))	('replication repair', 'MPA', (144, 162))	('mutations', 'Var', (121, 130))	('patients', 'Species', '9606', (22, 30))	('TMB', 'Chemical', '-', (36, 39))
34067	31270941	Moreover, TMB values of 10-100 Mut/Mb were mostly associated with MSI-H and had high levels of dMMR.40 This study, therefore, explains to a certain extent why TMB-H, MSI-H, and dMMR do not completely overlap and indicates that there may be several additional underlying causes of TMB-H, for example, replicative polymerase mutations.	('dMMR', 'Chemical', '-', (177, 181))	('mutations', 'Var', (323, 332))	('MSI-H', 'Disease', 'MESH:D000848', (166, 171))	('MSI-H', 'Disease', 'MESH:D000848', (66, 71))	('TMB', 'Chemical', '-', (10, 13))	('TMB-H', 'Chemical', '-', (159, 164))	('TMB', 'Chemical', '-', (159, 162))	('dMMR', 'Chemical', '-', (95, 99))	('TMB-H', 'Chemical', '-', (280, 285))	('replicative polymerase', 'Enzyme', (300, 322))	('MSI-H', 'Disease', (66, 71))	('TMB', 'Chemical', '-', (280, 283))	('MSI-H', 'Disease', (166, 171))
34068	31270941	High TMB and MSI are caused by defects in the DNA damage repair system,41 which is composed of many proteins in addition to MMR components, including the homologous recombination repair element RecA/Rad5142 and the non-homologous end joining repair element Ku70/Ku80.43 Research has shown that in the absence of MSI, mutations in DNA polymerase (POLE) can lead to TMB-H.44 PD-L1 AMP can be caused by the breakage-fusion-bridge cycle, extra replication, and recombination, among other mechanisms, many of which are distinct from the underlying causes attributed to the other biomarkers.	('mutations', 'Var', (317, 326))	('PD-L1', 'Gene', '29126', (373, 378))	('AMP', 'Chemical', 'MESH:D000249', (379, 382))	('TMB', 'Chemical', '-', (364, 367))	('TMB-H.44', 'Disease', (364, 372))	('lead', 'Reg', (356, 360))	('TMB-H', 'Chemical', '-', (364, 369))	('breakage-fusion-bridge cycle', 'Disease', (404, 432))	('extra replication', 'CPA', (434, 451))	('caused', 'Reg', (390, 396))	('PD-L1', 'Gene', (373, 378))	('TMB', 'Chemical', '-', (5, 8))
34083	30098109	Patients with high TRIM44 expression showed poor differentiation (P = 1.39 x 10-5), advanced TNM stage (P = 3.87 x 10-4) and, most importantly, significantly poorer prognosis (P = 2.80 x 10-5).	('poorer', 'NegReg', (158, 164))	('differentiation', 'CPA', (49, 64))	('poor', 'NegReg', (44, 48))	('TNM', 'Gene', '10178', (93, 96))	('Patients', 'Species', '9606', (0, 8))	('TNM', 'Gene', (93, 96))	('high TRIM44', 'Var', (14, 25))
34135	30098109	Based on the TRIM44 immunostaining intensity and percentage scores mentioned above, the cohort of 100 HEC patients was divided into TRIM44high and TRIM44low groups.	('TRIM44low', 'Var', (147, 156))	('HEC', 'Gene', (102, 105))	('patients', 'Species', '9606', (106, 114))	('HEC', 'Gene', '10403', (102, 105))	('TRIM44high', 'Var', (132, 142))
34137	30098109	As shown in Table 1, high TRIM44 expression correlated significantly with aggressive tumor characteristics, including poor tumor differentiation (P = 1.39 x 10-5) and advanced tumor stage (P = 3.87 x 10-4).	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (123, 128))	('aggressive tumor', 'Disease', (74, 90))	('tumor', 'Disease', (176, 181))	('high', 'Var', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('expression', 'MPA', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('aggressive tumor', 'Disease', 'MESH:D001523', (74, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
34138	30098109	High TRIM44 levels were more common in HEC with poor differentiation (88%, 22/25) than in HEC with good (25%, 8/32) or moderate (53%, 23/20) differentiation (Figure 2C).	('HEC', 'Gene', '10403', (90, 93))	('common', 'Reg', (29, 35))	('HEC', 'Gene', (39, 42))	('High TRIM44 levels', 'MPA', (0, 18))	('poor', 'Var', (48, 52))	('HEC', 'Gene', '10403', (39, 42))	('HEC', 'Gene', (90, 93))
34141	30098109	We found that gastric cancer patients with high TRIM44 expression exhibit unfavorable OS (Figure 2G).	('gastric cancer', 'Disease', 'MESH:D013274', (14, 28))	('patients', 'Species', '9606', (29, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (14, 28))	('high TRIM44 expression', 'Var', (43, 65))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('gastric cancer', 'Disease', (14, 28))
34142	30098109	Consistent with the kmplot analysis data in gastric cancer, patients in the high TRIM44 expression group had obviously worse OS than those in the low TRIM44 expression group (26.4% vs 68%, P = 2.80 x 10-5, Figure 2H).	('high TRIM44 expression', 'Var', (76, 98))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('patients', 'Species', '9606', (60, 68))	('gastric cancer', 'Disease', (44, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))
34152	30098109	Increased E-cadherin and down-regulated N-cadherin and Vimentin expression were observed in TRIM44-overexpressing HEC cells (Figure 4B,D).	('E-cadherin', 'Gene', '999', (10, 20))	('N-cadherin', 'Gene', (40, 50))	('expression', 'MPA', (64, 74))	('Vimentin', 'Gene', (55, 63))	('HEC', 'Gene', '10403', (114, 117))	('N-cadherin', 'Gene', '1000', (40, 50))	('Vimentin', 'Gene', '7431', (55, 63))	('TRIM44-overexpressing', 'Var', (92, 113))	('down-regulated', 'NegReg', (25, 39))	('Increased', 'PosReg', (0, 9))	('HEC', 'Gene', (114, 117))	('E-cadherin', 'Gene', (10, 20))
34153	30098109	We also investigated the function of TRIM44 in other cells (EC9706 and KYSE150) by overexpressing TRIM44 or knocking down TRIM44 (Figure S1).	('overexpressing', 'PosReg', (83, 97))	('knocking', 'Var', (108, 116))	('TRIM44', 'Gene', (122, 128))	('TRIM44', 'Gene', (98, 104))	('EC9706', 'CellLine', 'CVCL:E307', (60, 66))
34155	30098109	High TRIM44 expression was associated with impaired E-cadherin expression and high levels of Vimentin.	('High', 'Var', (0, 4))	('Vimentin', 'Gene', (93, 101))	('impaired', 'NegReg', (43, 51))	('E-cadherin', 'Gene', (52, 62))	('Vimentin', 'Gene', '7431', (93, 101))	('expression', 'MPA', (12, 22))	('E-cadherin', 'Gene', '999', (52, 62))	('high levels of', 'MPA', (78, 92))
34157	30098109	A significant negative association was observed between TRIM44 and E-cadherin expression in this cohort of patients (R 2 = 0.5072 and P < .001; Figure 4F), and the TRIM44 expression was positively correlated with Vimentin (R 2 = 0.4904 and P < .001; Figure 4F).	('expression', 'MPA', (171, 181))	('TRIM44', 'Var', (164, 170))	('expression', 'MPA', (78, 88))	('Vimentin', 'Gene', '7431', (213, 221))	('E-cadherin', 'Gene', (67, 77))	('E-cadherin', 'Gene', '999', (67, 77))	('correlated', 'Reg', (197, 207))	('negative', 'NegReg', (14, 22))	('TRIM44', 'Protein', (56, 62))	('Vimentin', 'Gene', (213, 221))	('patients', 'Species', '9606', (107, 115))
34163	30098109	In addition, TRIM44-positive expression was more frequently detected in HEC tissues than in non-tumorous tissues (Figure 5C).	('non-tumorous', 'Disease', (92, 104))	('HEC', 'Gene', '10403', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('detected', 'Reg', (60, 68))	('expression', 'MPA', (29, 39))	('HEC', 'Gene', (72, 75))	('TRIM44-positive', 'Var', (13, 28))	('non-tumorous', 'Disease', 'MESH:D009369', (92, 104))
34164	30098109	Immunofluorescence assays showed that TRIM44-overexpressing KYSE140 cells exhibited significant up-regulation of Ki67, whereas TRIM44-silenced KYSE150 cells showed a loss of Ki67 (Figure 5D).	('up-regulation', 'PosReg', (96, 109))	('Ki67', 'Gene', (113, 117))	('Ki67', 'Chemical', '-', (174, 178))	('TRIM44-overexpressing', 'Var', (38, 59))	('Ki67', 'Chemical', '-', (113, 117))
34165	30098109	w?>Previous studies have revealed that TRIM44 is highly associated with the PI3K pathway in esophagogastric cancer (EGC)25 and NSCLC.13 Here, we also showed that shRNA knockdown of TRIM44 in KYSE510 cells caused a decrease in p-AKT (Ser473) levels, as well as weak p-mTOR activity.	('TRIM44', 'Gene', (181, 187))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('associated', 'Reg', (56, 66))	('mTOR', 'Gene', '2475', (267, 271))	('AKT', 'Gene', (228, 231))	('Ser473', 'Chemical', '-', (233, 239))	('NSCLC', 'Disease', (127, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('gastric cancer', 'Disease', (100, 114))	('AKT', 'Gene', '207', (228, 231))	('EGC', 'Chemical', 'MESH:C057580', (116, 119))	('PI3K pathway', 'Pathway', (76, 88))	('TRIM44', 'Gene', (39, 45))	('knockdown', 'Var', (168, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('mTOR', 'Gene', (267, 271))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('decrease', 'NegReg', (214, 222))
34167	30098109	Interestingly, the phosphorylation levels of STAT3, which represents a point of convergence for numerous oncogenic pathways,25, 26, 27 were markedly enhanced in KYSE140-oe cells and down-regulated in KYSE510-sh cells compared with the levels in their respective controls (Figure 6B).	('phosphorylation levels', 'MPA', (19, 41))	('STAT3', 'Gene', (45, 50))	('KYSE140-oe', 'Var', (161, 171))	('down-regulated', 'NegReg', (182, 196))	('enhanced', 'PosReg', (149, 157))	('STAT3', 'Gene', '6774', (45, 50))
34169	30098109	As shown in Figure 6C-E, KYSE140-oe cell migration, invasion and proliferation were significantly reduced under A-674563 treatment compared with the PBS treatment.	('proliferation', 'CPA', (65, 78))	('A-674563', 'Chemical', 'MESH:C000619514', (112, 120))	('A-674563', 'Var', (112, 120))	('reduced', 'NegReg', (98, 105))	('PBS', 'Chemical', '-', (149, 152))	('KYSE140-oe cell migration', 'CPA', (25, 50))
34171	30098109	Furthermore, hydrochloride was found to down-regulate N-cadherin and Vimentin expression but up-regulate E-cadherin expression in KYSE140-oe cells (Figure 6F).	('N-cadherin', 'Gene', (54, 64))	('expression', 'MPA', (116, 126))	('down-regulate', 'NegReg', (40, 53))	('expression', 'MPA', (78, 88))	('Vimentin', 'Gene', (69, 77))	('hydrochloride', 'Chemical', '-', (13, 26))	('N-cadherin', 'Gene', '1000', (54, 64))	('Vimentin', 'Gene', '7431', (69, 77))	('E-cadherin', 'Gene', (105, 115))	('E-cadherin', 'Gene', '999', (105, 115))	('up-regulate', 'PosReg', (93, 104))	('hydrochloride', 'Var', (13, 26))
34172	30098109	These findings further indicated that high levels of TRIM44 induced HEC cell EMT by PI3K signaling.	('TRIM44', 'Var', (53, 59))	('induced', 'Reg', (60, 67))	('HEC', 'Gene', '10403', (68, 71))	('HEC', 'Gene', (68, 71))
34177	30098109	Additionally, overexpressing or knocking down TRIM44 successfully reduced or enhanced Ki67 expression, respectively, in immunofluorescence assays.	('expression', 'MPA', (91, 101))	('enhanced', 'PosReg', (77, 85))	('TRIM44', 'Gene', (46, 52))	('Ki67', 'Chemical', '-', (86, 90))	('knocking down', 'Var', (32, 45))	('Ki67', 'Gene', (86, 90))
34184	30098109	Accumulating evidence indicates that the activation of the AKT/mTOR pathway plays a key role in controlling fundamental cellular processes, including cell growth, proliferation, apoptosis and metabolism in different cancer types.29, 30 A previous study showed a statistically significant correlation between TRIM44 and the mTOR signaling pathway in EGC.31 The TRIM44-overexpression gene signature of EGC was reversed by AKT/mTOR pathway inhibitors.31 Similarly, TRIM44 overexpression resulted in high mTOR activity in NSCLC.13 In light of these previous reports, we examined the relationship between TRIM44 and the AKT/mTOR signaling pathway in HEC.	('EGC', 'Chemical', 'MESH:C057580', (349, 352))	('mTOR', 'Gene', '2475', (323, 327))	('mTOR', 'Gene', (424, 428))	('NSCLC', 'Phenotype', 'HP:0030358', (518, 523))	('AKT', 'Gene', (420, 423))	('cancer', 'Disease', (216, 222))	('HEC', 'Gene', '10403', (645, 648))	('mTOR', 'Gene', (501, 505))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('mTOR', 'Gene', '2475', (424, 428))	('TRIM44', 'Var', (462, 468))	('mTOR', 'Gene', '2475', (501, 505))	('mTOR', 'Gene', (63, 67))	('AKT', 'Gene', (615, 618))	('AKT', 'Gene', '207', (420, 423))	('AKT', 'Gene', (59, 62))	('mTOR', 'Gene', (619, 623))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('EGC', 'Chemical', 'MESH:C057580', (400, 403))	('mTOR', 'Gene', '2475', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (518, 523))	('mTOR', 'Gene', (323, 327))	('overexpression', 'PosReg', (469, 483))	('mTOR', 'Gene', '2475', (619, 623))	('HEC', 'Gene', (645, 648))	('AKT', 'Gene', '207', (59, 62))	('AKT', 'Gene', '207', (615, 618))	('NSCLC', 'Disease', (518, 523))
34185	30098109	We observed significant alterations in the phosphorylation levels of AKT/mTOR signaling pathway molecules after TRIM44 up-regulation or knockdown.	('mTOR', 'Gene', '2475', (73, 77))	('phosphorylation levels', 'MPA', (43, 65))	('mTOR', 'Gene', (73, 77))	('AKT', 'Gene', (69, 72))	('knockdown', 'Var', (136, 145))	('TRIM44', 'Gene', (112, 118))	('AKT', 'Gene', '207', (69, 72))	('up-regulation', 'PosReg', (119, 132))	('alterations', 'Reg', (24, 35))
34214	29950901	In most registries, the diagnosis code C15 in the International Classification of Diseases, version 10 (ICD-10) defined the esophageal tumor site, and the histology codes 8050-8078 and 8083-8084 in the International Classification of Disease for Oncology, version 3 (ICD-O-3) represented squamous cell carcinoma.	('Oncology', 'Phenotype', 'HP:0002664', (246, 254))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('esophageal tumor', 'Disease', 'MESH:D004938', (124, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (288, 311))	('esophageal tumor', 'Phenotype', 'HP:0100751', (124, 140))	('esophageal tumor', 'Disease', (124, 140))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (288, 311))	('squamous cell carcinoma', 'Disease', (288, 311))	('8083-8084', 'Var', (185, 194))
34281	29620258	3-Methyladenine or LY294002 significantly antagonized EBSS-induced autophagy and increased apoptosis of irradiated cells, suggesting that autophagy inhibition conferred radiosensitivity in vitro.	('LY294002', 'Chemical', 'MESH:C085911', (19, 27))	('apoptosis', 'CPA', (91, 100))	('antagonized', 'NegReg', (42, 53))	('EBSS', 'Chemical', '-', (54, 58))	('EBSS-induced', 'Disease', (54, 66))	('autophagy', 'CPA', (67, 76))	('LY294002', 'Var', (19, 27))	('increased', 'PosReg', (81, 90))	('3-Methyladenine', 'Chemical', 'MESH:C025946', (0, 15))
34317	29620258	Following treatment with 3-MA or LY294002, 10 mul CCK-8 solution was added to each well and the optical density 450 absorbance was measured by a multifunctional microplate reader (Thermo Fisher Scientific) after a 2-h incubation at 37 C. For the cell apoptosis assay, the cells were stained with Annexin V/propidium iodide (PI), and cell apoptosis was analyzed using flow cytometry.	('3-MA', 'Chemical', 'MESH:C025946', (25, 29))	('propidium iodide', 'Chemical', 'MESH:D011419', (306, 322))	('LY294002', 'Chemical', 'MESH:C085911', (33, 41))	('Annexin V', 'Gene', '308', (296, 305))	('Annexin V', 'Gene', (296, 305))	('LY294002', 'Var', (33, 41))
34348	29620258	The viability and apoptosis of cells exposed to EBSS with different concentrations of LY294002 (Fig.	('rat', 'Species', '10116', (75, 78))	('LY294002', 'Var', (86, 94))	('apoptosis', 'CPA', (18, 27))	('LY294002', 'Chemical', 'MESH:C085911', (86, 94))	('EBSS', 'Chemical', '-', (48, 52))
34350	29620258	The results indicated that autophagy inhibitors LY294002 and 3-MA did not significantly inhibit cell viability or induce cell apoptosis until the concentrations were increased to 20 muM for LY294002 and 2 mM for 3-MA.	('LY294002', 'Chemical', 'MESH:C085911', (190, 198))	('muM', 'Gene', (182, 185))	('cell viability', 'CPA', (96, 110))	('rat', 'Species', '10116', (153, 156))	('LY294002 and 3', 'Gene', '926', (48, 62))	('inhibit', 'NegReg', (88, 95))	('LY294002', 'Var', (190, 198))	('LY294002', 'Chemical', 'MESH:C085911', (48, 56))	('muM', 'Gene', '56925', (182, 185))	('3-MA', 'Chemical', 'MESH:C025946', (61, 65))	('3-MA', 'Chemical', 'MESH:C025946', (212, 216))
34351	29620258	The autophagy of cells that were pretreated with LY294002 (10 muM) and 3-MA (1 mM) under EBSS starvation conditions was also evaluated by analyzing LC3 and p53.	('muM', 'Gene', '56925', (62, 65))	('LY294002', 'Var', (49, 57))	('muM', 'Gene', (62, 65))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('LC3', 'Gene', '84557', (148, 151))	('LC3', 'Gene', (148, 151))	('LY294002', 'Chemical', 'MESH:C085911', (49, 57))	('EBSS', 'Chemical', '-', (89, 93))	('3-MA', 'Chemical', 'MESH:C025946', (71, 75))	('autophagy', 'CPA', (4, 13))
34352	29620258	4A-E, LY294002 at 10 muM not only decreased the gene expression of LC3 II and p53, but also significantly reduced the protein expression ratio of LC3 II and LC3.	('protein expression ratio', 'MPA', (118, 142))	('LY294002', 'Var', (6, 14))	('muM', 'Gene', '56925', (21, 24))	('LC3', 'Gene', (157, 160))	('decreased', 'NegReg', (34, 43))	('LC3', 'Gene', '84557', (67, 70))	('muM', 'Gene', (21, 24))	('LY294002', 'Chemical', 'MESH:C085911', (6, 14))	('LC3', 'Gene', '84557', (146, 149))	('rat', 'Species', '10116', (137, 140))	('LC3', 'Gene', (146, 149))	('p53', 'Gene', (78, 81))	('LC3', 'Gene', (67, 70))	('gene expression', 'MPA', (48, 63))	('p53', 'Gene', '7157', (78, 81))	('LC3', 'Gene', '84557', (157, 160))	('reduced', 'NegReg', (106, 113))
34353	29620258	Furthermore, despite being increased in EBSS-treated cells, p53 was also decreased by LY294002 at 10 muM.	('EBSS', 'Chemical', '-', (40, 44))	('decreased', 'NegReg', (73, 82))	('LY294002', 'Var', (86, 94))	('muM', 'Gene', '56925', (101, 104))	('p53', 'Gene', (60, 63))	('p53', 'Gene', '7157', (60, 63))	('muM', 'Gene', (101, 104))	('LY294002', 'Chemical', 'MESH:C085911', (86, 94))
34369	29620258	Furthermore, tumor growth was significantly delayed when the animals were treated with IR and 3-MA, whereas treatment with 3-MA alone did not exert a noticeable effect on tumor growth compared with the model group.	('delayed', 'NegReg', (44, 51))	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('3-MA', 'Chemical', 'MESH:C025946', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('3-MA', 'Var', (94, 98))	('3-MA', 'Chemical', 'MESH:C025946', (123, 127))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
34381	29620258	Cancer cells escape death using a variety of means, with prevention of apoptosis through loss of p53 in some cell types being a classic example.	('loss', 'Var', (89, 93))	('p53', 'Gene', (97, 100))	('p53', 'Gene', '7157', (97, 100))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
34406	29620258	EBSS Earle's balanced salt solution IR ionizing radiation MMP mitochondrial membrane potential SCC squamous cell carcinoma The present study was supported by a grant from the Jiangsu Cancer Hospital (no.	('Cancer', 'Disease', 'MESH:D009369', (183, 189))	('SCC', 'Gene', '6317', (95, 98))	('MMP', 'Var', (58, 61))	("Earle's balanced salt solution", 'Chemical', '-', (5, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('EBSS', 'Chemical', '-', (0, 4))	('SCC', 'Gene', (95, 98))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('Cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Cancer', 'Disease', (183, 189))	('squamous cell carcinoma', 'Disease', (99, 122))	('mitochondrial membrane potential', 'MPA', (62, 94))
34443	28664523	According to a national cancer registry in Japan, reconstructions using the jejunum accounted for 5.4% of all esophageal cancer resections.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('reconstructions', 'Var', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (24, 30))	('esophageal cancer', 'Disease', (110, 127))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('cancer', 'Disease', (121, 127))
34459	26056445	External beam radiotherapy synergizes 188Re-liposome against human esophageal cancer xenograft and modulates 188Re-liposome pharmacokinetics External beam radiotherapy (EBRT) treats gross tumors and local microscopic diseases.	('modulates', 'Var', (99, 108))	('EBRT', 'Chemical', '-', (169, 173))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('human', 'Species', '9606', (61, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))
34488	26056445	Although 188Re-liposome has a comparative therapeutic efficacy with chemotherapeutic drug 5-FU in colon carcinoma ascites, we found that 188Re-liposome possesses a better therapeutic efficacy in both lung-metastatic and solid-tumor animal models.	('solid-tumor', 'Disease', 'MESH:D009369', (220, 231))	('lung-metastatic', 'CPA', (200, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('better', 'PosReg', (164, 170))	('therapeutic efficacy', 'CPA', (171, 191))	('188Re', 'Chemical', 'MESH:C000615081', (9, 14))	('colon carcinoma ascites', 'Disease', 'MESH:D001201', (98, 121))	('5-FU', 'Chemical', 'MESH:D005472', (90, 94))	('colon carcinoma ascites', 'Disease', (98, 121))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('ascites', 'Phenotype', 'HP:0001541', (114, 121))	('solid-tumor', 'Disease', (220, 231))	('188Re', 'Chemical', 'MESH:C000615081', (137, 142))	('188Re-liposome', 'Var', (137, 151))
34555	26056445	Pegylated liposomes can evade the reticuloendothelial system and remain in the circulatory system for prolonged periods, resulting in sufficient tumor targeting and efficacy in vivo.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('efficacy', 'MPA', (165, 173))	('Pegylated', 'Var', (0, 9))
34560	26056445	Since the combination of EBRT and 188Re-liposome increased therapeutic efficacy compared to EBRT and 188Re-liposome treatment alone, the uptake of 188Re-liposome on esophageal adenocarcinoma BE-3 cells is likely to play a role in enhancing radiation-induced toxicity.	('188Re', 'Chemical', 'MESH:C000615081', (147, 152))	('188Re-liposome', 'Var', (147, 161))	('enhancing', 'PosReg', (230, 239))	('EBRT', 'Chemical', '-', (92, 96))	('increased', 'PosReg', (49, 58))	('188Re', 'Chemical', 'MESH:C000615081', (101, 106))	('toxicity', 'Disease', 'MESH:D064420', (258, 266))	('toxicity', 'Disease', (258, 266))	('esophageal adenocarcinoma', 'Disease', (165, 190))	('EBRT', 'Chemical', '-', (25, 29))	('uptake', 'MPA', (137, 143))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (165, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('therapeutic efficacy', 'MPA', (59, 79))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))	('188Re', 'Chemical', 'MESH:C000615081', (34, 39))
34584	25373907	hematopoietic, mesenchymal, or suprabasal), we utilized a genetic mouse model that had EGFP knocked-in to one of the endogenous Sox2 alleles (Figure 2B).	('Sox2', 'Gene', (128, 132))	('mouse', 'Species', '10090', (66, 71))	('knocked-in', 'Var', (92, 102))	('EGFP', 'Gene', (87, 91))	('Sox2', 'Gene', '20674', (128, 132))
34597	25373907	Previous studies showed that ablation of Sox2 expressing cells disrupted the esophageal basal epithelium.	('ablation', 'Var', (29, 37))	('esophageal basal epithelium', 'CPA', (77, 104))	('Sox2', 'Gene', '20674', (41, 45))	('disrupted', 'NegReg', (63, 72))	('Sox2', 'Gene', (41, 45))
34598	25373907	Here we found that genetically reducing Sox2 expression resulted in a ~20% decrease in the total number of organoids formed in vitro (Figure 3E).	('genetically', 'Var', (19, 30))	('decrease', 'NegReg', (75, 83))	('Sox2', 'Gene', '20674', (40, 44))	('reducing', 'NegReg', (31, 39))	('Sox2', 'Gene', (40, 44))	('expression', 'MPA', (45, 55))
34599	25373907	We also found a significant decrease in the size of the organoids after Sox2 deletion (Figure S3C).	('Sox2', 'Gene', '20674', (72, 76))	('size of the organoids', 'CPA', (44, 65))	('Sox2', 'Gene', (72, 76))	('deletion', 'Var', (77, 85))	('decrease', 'NegReg', (28, 36))
34646	25373907	In agreement with others, we observed a significant increase in the percent of Ki67+ esophageal basal cells as well as upregulation of cellular retinoic acid-binding protein 2 (CRABP2) upon exposure to atRA (Figures 7B and 7C).	('cellular retinoic acid-binding protein 2', 'Gene', (135, 175))	('increase', 'PosReg', (52, 60))	('atRA', 'Chemical', 'MESH:D014212', (202, 206))	('upregulation', 'PosReg', (119, 131))	('cellular retinoic acid-binding protein 2', 'Gene', '12904', (135, 175))	('Ki67+', 'Var', (79, 84))	('CRABP2', 'Gene', '12904', (177, 183))	('CRABP2', 'Gene', (177, 183))
34675	25373907	Antibodies specific to the following antigens were purchased for immunofluorescence from Abcam: Cytokeratin 14 (Cat# ab7800), p63 (Cat# ab53039), Cytokeratin 13 (Cat# ab92551), Sox2 (Cat# ab97959), and Ki67 (Cat# ab15580).	('p63', 'Gene', (126, 129))	('Cat# ab92551', 'Var', (162, 174))	('Cat# ab97959', 'Var', (183, 195))	('Cytokeratin 14', 'Gene', '16664', (96, 110))	('Cytokeratin 13', 'Gene', (146, 160))	('Sox2', 'Gene', '20674', (177, 181))	('Cat# ab15580', 'Var', (208, 220))	('Cytokeratin 13', 'Gene', '16663', (146, 160))	('Cat# ab7800', 'Var', (112, 123))	('Sox2', 'Gene', (177, 181))	('Cytokeratin 14', 'Gene', (96, 110))	('p63', 'Gene', '22061', (126, 129))	('Cat# ab53039', 'Var', (131, 143))
34676	25373907	From BD Biosciences: CD104 (Itgb4, Cat# 553745), CRABP2 (Cat# 560234), and CD73 (Cat# 550738).	('Cat# 550738', 'Var', (81, 92))	('CD104', 'Gene', '192897', (21, 26))	('CD73', 'Gene', '23959', (75, 79))	('CD73', 'Gene', (75, 79))	('Itgb4', 'Gene', '192897', (28, 33))	('CD104', 'Gene', (21, 26))	('CRABP2', 'Gene', '12904', (49, 55))	('CRABP2', 'Gene', (49, 55))	('Itgb4', 'Gene', (28, 33))	('Cat# 560234', 'Var', (57, 68))
34678	25373907	Antibodies specific to the following antigens were purchased for flow cytometric analysis from BD Biosciences: PerCP-Cy5.5 CD45 (Cat# 550994, 1:50), PE-Cy7 CD45 (Cat# 552848, 1:50), APC CD45 (Cat# 559864, 1:50), PE-Cy7 Streptavidin (Cat# 557598, 1:50), PE CD73 (Cat# 550741, 1:25), FITC CD34 (Cat# 553733, 1:25), PE CD90 (1:50), and PE CD44 (Cat# 553134, 1:25).	('APC', 'Disease', 'MESH:D011125', (182, 185))	('CD73', 'Gene', '23959', (256, 260))	('CD73', 'Gene', (256, 260))	('CD45', 'Gene', (186, 190))	('CD90', 'Gene', (316, 320))	('Cat# 553733', 'Var', (293, 304))	('APC', 'Disease', (182, 185))	('CD44', 'Gene', (336, 340))	('CD34', 'Gene', (287, 291))	('Cat# 550994', 'Var', (129, 140))	('CD44', 'Gene', '12505', (336, 340))	('Cat# 550741', 'Var', (262, 273))	('CD45', 'Gene', '19264', (156, 160))	('CD34', 'Gene', '12490', (287, 291))	('Cat# 559864', 'Var', (192, 203))	('CD45', 'Gene', '19264', (123, 127))	('Cat# 557598', 'Var', (233, 244))	('CD45', 'Gene', '19264', (186, 190))	('CD45', 'Gene', (156, 160))	('Cat# 552848', 'Var', (162, 173))	('CD45', 'Gene', (123, 127))	('CD90', 'Gene', '21838', (316, 320))
34740	25091112	It should be noted that significant differences (e.g., PC(34:1) at m/z 798.5426, PC(38:4) at m/z 832.5818, and C18:1 at m/z 281.2484) were observed between the cancerous area and the adjacent normal area in the positive and negative ion modes, respectively.	('C18:1 at m/z 281.2484', 'Var', (111, 132))	('cancerous', 'Disease', (160, 169))	('m/z 832.5818', 'Var', (93, 105))	('cancerous', 'Disease', 'MESH:D009369', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
34746	25091112	MUFAs (i.e., C16:1 at m/z 253.2174 and C18:1 at m/z 281.2484) in the cancerous area presented high intensities compared with those in the adjacent normal area, whereas PUFAs, PE and PI with polyunsaturated acyl chains (i.e., C22:4 at m/z 331.2645, [PE(38:4)-H]- at m/z 750.5441, and [PI(38:4)-H]- at m/z 885.5499) in the cancerous area had a lower level than those in the adjacent normal area.	('cancerous', 'Disease', (69, 78))	('cancerous', 'Disease', 'MESH:D009369', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('C18:1', 'Var', (39, 44))	('cancerous', 'Disease', (321, 330))	('FAs', 'Chemical', 'MESH:D005227', (2, 5))	('FAs', 'Chemical', 'MESH:D005227', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('C22:4', 'Var', (225, 230))	('cancerous', 'Disease', 'MESH:D009369', (321, 330))
34747	25091112	However, some exceptions were also observed for the alteration in the levels of these lipids, for example, the levels of C20:4 and PI(38:4) were increased in thyroid cancer, whereas no difference in their levels was detected between the cancerous area and the adjacent normal area for esophageal and gastric cancer.	('C20:4', 'Var', (121, 126))	('thyroid cancer', 'Disease', 'MESH:D013964', (158, 172))	('levels', 'MPA', (111, 117))	('lipids', 'Chemical', 'MESH:D008055', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancerous', 'Disease', 'MESH:D009369', (237, 246))	('gastric cancer', 'Phenotype', 'HP:0012126', (300, 314))	('thyroid cancer', 'Phenotype', 'HP:0002890', (158, 172))	('increased', 'PosReg', (145, 154))	('thyroid cancer', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('gastric cancer', 'Disease', (300, 314))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('cancerous', 'Disease', (237, 246))	('gastric cancer', 'Disease', 'MESH:D013274', (300, 314))
34751	25091112	PLS-DA score plot revealed the obvious differences between the cancerous area and the adjacent normal area from the patients with breast, colorectal, esophageal, lung, gastric, and thyroid cancer, with the predicted residual sum of square (PRESS) of 0.4603, 0.5379, 0.3757, 0.5069, 0.4125 and 0.4018, respectively (Fig.	('colorectal', 'Disease', (138, 148))	('0.3757', 'Var', (266, 272))	('0.4018', 'Var', (293, 299))	('esophageal', 'Disease', (150, 160))	('0.5069', 'Var', (274, 280))	('gastric', 'Disease', (168, 175))	('cancerous', 'Disease', 'MESH:D009369', (63, 72))	('thyroid cancer', 'Disease', 'MESH:D013964', (181, 195))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung', 'Disease', (162, 166))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('0.4125', 'Var', (282, 288))	('thyroid cancer', 'Phenotype', 'HP:0002890', (181, 195))	('thyroid cancer', 'Disease', (181, 195))	('breast', 'Disease', (130, 136))	('cancerous', 'Disease', (63, 72))	('0.5379', 'Var', (258, 264))
34756	25091112	Finally, 18 common variables labeled in blue were extracted, which were strongly associated with six types of cancer, and they are C16:1, C18:1, C20:1, PC(32:1), PC(34:1), PC(36:1), C20:4, C22:4, C22:5, PC(38:4), PC(38:6), PA(36:2), PA(38:3), PA(40:5), PE(38:4), PI(38:4), SM(22:0), and SM(24:1).	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('C22:5', 'Var', (196, 201))	('cancer', 'Disease', (110, 116))	('PC(34:1', 'Var', (162, 169))	('C22:4', 'Var', (189, 194))	('C16:1', 'Var', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('C18:1', 'Var', (138, 143))	('PC(32:1', 'Var', (152, 159))	('PC(36:1', 'Var', (172, 179))	('C20:4', 'Var', (182, 187))	('associated', 'Reg', (81, 91))	('C20:1', 'Var', (145, 150))	('PC(38:4', 'Var', (203, 210))
34758	25091112	It is worth noting that the levels of MUPCs (i.e., PC(32:1), PC(34:1), and PC(36:1)) and MUFAs (i.e., C16:1, C18:1, and C20:1) in the cancerous area were significantly increased compared with those in the adjacent normal area (Wilcoxon-Mann-Whitney test, p <0.05), whereas polyunsaturated lipids (i.e., PC(38:4), PC(38:6), PA(38:3), PA(40:5), PE(38:4), and PI(38:4)) and PUFAs (i.e., C20:4, C22:4, and C22:5) in the cancerous area were remarkably decreased compared with those in the adjacent normal area (Wilcoxon-Mann-Whitney test, p <0.05) except thyroid cancer.	('C22:5', 'Var', (402, 407))	('cancer', 'Phenotype', 'HP:0002664', (416, 422))	('decreased', 'NegReg', (447, 456))	('cancerous', 'Disease', 'MESH:D009369', (416, 425))	('C22:4', 'Var', (391, 396))	('PCs', 'Chemical', 'MESH:D010713', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (558, 564))	('thyroid cancer', 'Disease', (550, 564))	('FAs', 'Chemical', 'MESH:D005227', (373, 376))	('cancerous', 'Disease', (416, 425))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancerous', 'Disease', 'MESH:D009369', (134, 143))	('polyunsaturated lipids', 'Chemical', '-', (273, 295))	('C20:1', 'Var', (120, 125))	('C18:1', 'Var', (109, 114))	('thyroid cancer', 'Disease', 'MESH:D013964', (550, 564))	('FAs', 'Chemical', 'MESH:D005227', (91, 94))	('C16:1', 'Var', (102, 107))	('increased', 'PosReg', (168, 177))	('thyroid cancer', 'Phenotype', 'HP:0002890', (550, 564))	('cancerous', 'Disease', (134, 143))	('polyunsaturated lipids', 'MPA', (273, 295))
34762	25091112	S2, for breast, colorectal, and esophageal cancer, MUFAs (i.e., C16:1, C18:1, and C20:1) were strongly and positively correlated with MUPCs (i.e., PC(32:1), PC(34:1), and PC(36:1)), whereas both were negatively correlated with polyunsaturated lipids.	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('C20:1', 'Var', (82, 87))	('C18:1', 'Var', (71, 76))	('colorectal', 'Disease', (16, 26))	('PCs', 'Chemical', 'MESH:D010713', (136, 139))	('correlated', 'Reg', (118, 128))	('breast', 'Disease', (8, 14))	('FAs', 'Chemical', 'MESH:D005227', (53, 56))	('MUPCs', 'Disease', (134, 139))	('polyunsaturated lipids', 'Chemical', '-', (227, 249))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('esophageal cancer', 'Disease', (32, 49))	('C16:1', 'Var', (64, 69))
34763	25091112	PUFAs (i.e., C20:4, C22:4, and C22:5) were strongly and positively correlated with polyunsaturated lipids (i.e., PC(38:4), PC(38:6), PA(38:3), PA(40:5), PE(38:4), and PI(38:4)); for lung and gastric cancer, the above-mentioned correlations became slightly lower; and for thyroid cancer, there were no obvious correlations among the above-mentioned lipids in the cancerous area.	('gastric cancer', 'Disease', (191, 205))	('correlated', 'Reg', (67, 77))	('lipids', 'Chemical', 'MESH:D008055', (348, 354))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancerous', 'Disease', (362, 371))	('gastric cancer', 'Disease', 'MESH:D013274', (191, 205))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('polyunsaturated lipids', 'Chemical', '-', (83, 105))	('lipids', 'Chemical', 'MESH:D008055', (99, 105))	('thyroid cancer', 'Disease', (271, 285))	('lower', 'NegReg', (256, 261))	('lung', 'Disease', (182, 186))	('gastric cancer', 'Phenotype', 'HP:0012126', (191, 205))	('C22:5', 'Var', (31, 36))	('polyunsaturated lipids', 'MPA', (83, 105))	('C22:4', 'Var', (20, 25))	('thyroid cancer', 'Disease', 'MESH:D013964', (271, 285))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('cancerous', 'Disease', 'MESH:D009369', (362, 371))	('FAs', 'Chemical', 'MESH:D005227', (2, 5))	('thyroid cancer', 'Phenotype', 'HP:0002890', (271, 285))
34766	25091112	S3, most ratios of MUFAs/SFAs in the cancerous area were significantly higher than those in the adjacent normal area except the ratio of C16:1/C16:0 in thyroid cancer.	('higher', 'PosReg', (71, 77))	('thyroid cancer', 'Disease', (152, 166))	('FAs', 'Chemical', 'MESH:D005227', (21, 24))	('cancerous', 'Disease', (37, 46))	('thyroid cancer', 'Phenotype', 'HP:0002890', (152, 166))	('thyroid cancer', 'Disease', 'MESH:D013964', (152, 166))	('C16:1/C16:0', 'Var', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancerous', 'Disease', 'MESH:D009369', (37, 46))	('FAs', 'Chemical', 'MESH:D005227', (26, 29))
34768	25091112	The ratio of PC(34:1)/PC(34:0) in lung or thyroid cancerous area was significantly increased or decreased compared with that in their individual corresponding adjacent normal area, whereas no difference in this ratio was detected between the cancerous area and the adjacent normal area for breast, colorectal, esophageal, and gastric cancer.	('lung', 'Disease', (34, 38))	('gastric cancer', 'Disease', 'MESH:D013274', (326, 340))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('increased', 'PosReg', (83, 92))	('decreased', 'NegReg', (96, 105))	('cancerous', 'Disease', (242, 251))	('thyroid cancerous', 'Disease', (42, 59))	('cancerous', 'Disease', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('colorectal', 'Disease', (298, 308))	('gastric cancer', 'Phenotype', 'HP:0012126', (326, 340))	('breast', 'Disease', (290, 296))	('thyroid cancer', 'Phenotype', 'HP:0002890', (42, 56))	('PC(34:1)/PC(', 'Var', (13, 25))	('gastric cancer', 'Disease', (326, 340))	('cancerous', 'Disease', 'MESH:D009369', (242, 251))	('cancerous', 'Disease', 'MESH:D009369', (50, 59))	('thyroid cancerous', 'Disease', 'MESH:D013964', (42, 59))	('esophageal', 'Disease', (310, 320))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
34780	25091112	For breast cancer, the levels of PC(38:3), PC(38:4), C22:4, C20:2, C20:3, PC(36:0), PC(38:5), and PC(36:1) were increased.	('C20:3', 'Var', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('C20:2', 'Var', (60, 65))	('C22:4', 'Var', (53, 58))
34781	25091112	The lipids of PC(38:2) and PC(34:1) in lung cancer and lipids of C22:3, PA(40:5), SM(36:2), PA(36:3), and PA(38:5) in thyroid cancer were also up-regulated.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lipids', 'Chemical', 'MESH:D008055', (4, 10))	('thyroid cancer', 'Disease', (118, 132))	('lung cancer', 'Disease', (39, 50))	('lipids', 'Chemical', 'MESH:D008055', (55, 61))	('thyroid cancer', 'Phenotype', 'HP:0002890', (118, 132))	('lipids', 'MPA', (4, 10))	('PA(40:5', 'Var', (72, 79))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('thyroid cancer', 'Disease', 'MESH:D013964', (118, 132))	('SM(36:2', 'Var', (82, 89))	('up-regulated', 'PosReg', (143, 155))	('C22:3', 'Var', (65, 70))	('PC(34:1', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
34790	25091112	1, MUPCs (i.e., PC(32:1), PC(34:1), and PC(36:1)) and MUFAs (i.e., C16:1 and C18:1) were significantly up-regulated and species with polyunsaturated fatty acyl chains (i.e., PC(38:4), PA(40:5), PE(38:4), PI(38:4)) and PUFAs (i.e., C20:4 and C22:4) were down-regulated in the cancerous area of six different types of cancer compared with those in the adjacent normal area.	('cancerous', 'Disease', (275, 284))	('C20:4', 'Var', (231, 236))	('FAs', 'Chemical', 'MESH:D005227', (220, 223))	('up-regulated', 'PosReg', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('PCs', 'Chemical', 'MESH:D010713', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('C22:4', 'Var', (241, 246))	('down-regulated', 'NegReg', (253, 267))	('cancerous', 'Disease', 'MESH:D009369', (275, 284))	('FAs', 'Chemical', 'MESH:D005227', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (316, 322))	('cancer', 'Disease', (275, 281))
34798	25091112	S2, increase in the sum of FAs (C16:1, C16:0, C18:1, and C18:0) was positively correlated with the up-regulation of FASN in six types of cancer, indicating that FAs synthesis may play an important role in cancer pathogenesis.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('FASN', 'Gene', (116, 120))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('FASN', 'Gene', '2194', (116, 120))	('FAs', 'Chemical', 'MESH:D005227', (161, 164))	('cancer', 'Disease', (205, 211))	('up-regulation', 'PosReg', (99, 112))	('FAs', 'Chemical', 'MESH:D005227', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('C16:0', 'Var', (39, 44))	('C18:0', 'Var', (57, 62))	('cancer', 'Disease', (137, 143))	('C16:1', 'Var', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('C18:1', 'Var', (46, 51))	('increase', 'PosReg', (4, 12))
34808	25091112	This alteration of membrane fluidity may promote the carcinogenesis in six types of cancer.	('carcinogenesis', 'Disease', 'MESH:D063646', (53, 67))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('alteration', 'Var', (5, 15))	('cancer', 'Disease', (84, 90))	('carcinogenesis', 'Disease', (53, 67))	('promote', 'PosReg', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
34809	25091112	On the other hand, polyunsaturated acyl chains are more susceptible to peroxidation, and oxidized lipid species may be ultimately degraded into smaller reactive products such as 4-hydroxyalkenal and malondialdehyde, which can cause cell damage, which are consistent with our observation that modulation of de novo lipogenesis has increased the ratio of monounsaturated lipids to polyunsaturated lipids in the cancerous tissue compared with that in the adjacent normal tissue, cancer cells are protected from oxidative stress-induced cell death.	('cancer', 'Phenotype', 'HP:0002664', (409, 415))	('malondialdehyde', 'Chemical', 'MESH:D008315', (199, 214))	('oxidative stress', 'Phenotype', 'HP:0025464', (508, 524))	('cancerous', 'Disease', (409, 418))	('lipid', 'Chemical', 'MESH:D008055', (369, 374))	('lipid', 'Chemical', 'MESH:D008055', (98, 103))	('polyunsaturated lipids', 'Chemical', '-', (379, 401))	('lipids', 'Chemical', 'MESH:D008055', (395, 401))	('cancer', 'Disease', (476, 482))	('increased', 'PosReg', (330, 339))	('lipids', 'Chemical', 'MESH:D008055', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (476, 482))	('cancer', 'Disease', 'MESH:D009369', (409, 415))	('cancerous', 'Disease', 'MESH:D009369', (409, 418))	('modulation', 'Var', (292, 302))	('lipid', 'Chemical', 'MESH:D008055', (395, 400))	('cancer', 'Disease', 'MESH:D009369', (476, 482))	('ratio', 'MPA', (344, 349))	('cancer', 'Disease', (409, 415))	('degraded', 'NegReg', (130, 138))
34818	25091112	The alteration in the degree of lipid unsaturation generated by de novo lipogenic enzymes in the cancer microenvironment may related to carcinogenesis.	('related', 'Reg', (125, 132))	('cancer', 'Disease', (97, 103))	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('carcinogenesis', 'Disease', (136, 150))	('alteration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lipid', 'Chemical', 'MESH:D008055', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
34829	25091112	External calibration was performed using a lipid mixture (m/z 622.44423, m/z 734.56943, m/z 790.63203, and m/z 898.72593, which were from Avanti Polar Lipids, Inc., and identified by mass spectrometry) in positive ion mode and a tuning mixture (Part No.	('m/z 790.63203', 'Var', (88, 101))	('m/z 734.56943', 'Var', (73, 86))	('m/z 622.44423', 'Var', (58, 71))	('Lipids', 'Chemical', 'MESH:D008055', (151, 157))	('m/z 898.72593', 'Var', (107, 120))	('lipid', 'Chemical', 'MESH:D008055', (43, 48))
34837	25091112	These resulting sections were first incubated at room temperature with antibodies against FASN (1:250, Abcam, Cambridge, MA), SCD1 (1:200, Abcam), and CKalpha (1:200, Abcam), respectively, and then stored at 4 C overnight followed by rewarming at 37 C for 45 min.	('1:250', 'Var', (96, 101))	('SCD1', 'Gene', '6319', (126, 130))	('FASN', 'Gene', (90, 94))	('FASN', 'Gene', '2194', (90, 94))	('SCD1', 'Gene', (126, 130))
34848	24819879	When CASP8 expression is disrupted, RIP3-mediated embryonic lethality is observed in 10.5- to 11.5-day-old embryonic mice, coincident with vascular, cardiac, and hematopoietic defects.	('hematopoietic defects', 'Disease', (162, 183))	('embryonic lethality', 'Disease', 'MESH:D020964', (50, 69))	('cardiac', 'CPA', (149, 156))	('expression', 'MPA', (11, 21))	('hematopoietic defects', 'Disease', 'MESH:D019337', (162, 183))	('mice', 'Species', '10090', (117, 121))	('disrupted', 'Var', (25, 34))	('CASP8', 'Gene', (5, 10))	('embryonic lethality', 'Disease', (50, 69))
34893	24819879	To identify the core promoter region within the 1547-bp MAX fragment, we first constructed reporter vectors containing three different imbricating truncations of MAX that were transfected into KYSE510 cells for the luciferase activity assay (Fig.	('truncations', 'Var', (147, 158))	('MAX', 'Gene', (162, 165))	('KYSE510', 'CellLine', 'CVCL:1354', (193, 200))
34918	24819879	To evaluate the function of PURalpha and its contribution to the transcriptional machinery, we knocked down PURalpha in KYSE510 cells using siRNA-mediated RNAi and then transfected the pGL3-M5N3 construction to these cells and measured promoter activity.	('PURalpha', 'Gene', (28, 36))	('knocked', 'Var', (95, 102))	('PURalpha', 'Gene', (108, 116))	('pGL3', 'Gene', '6391', (185, 189))	('PURalpha', 'Gene', '5813', (108, 116))	('PURalpha', 'Gene', '5813', (28, 36))	('KYSE510', 'CellLine', 'CVCL:1354', (120, 127))	('pGL3', 'Gene', (185, 189))
34932	24819879	The fact that PURalpha knockdown decreased the activity of the secondary promoter fragment suggests that this protein is directly involved in CASP8 transcription.	('activity', 'MPA', (47, 55))	('PURalpha', 'Gene', (14, 22))	('knockdown', 'Var', (23, 32))	('PURalpha', 'Gene', '5813', (14, 22))	('secondary promoter fragment', 'MPA', (63, 90))	('decreased', 'NegReg', (33, 42))
34945	31412252	show that p63 and SOX2 cooperate to induce enhanced GLUT1 expression, driving a critical reliance on glucose, in squamous cell carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('enhanced', 'PosReg', (43, 51))	('p63', 'Var', (10, 13))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (113, 137))	('expression', 'MPA', (58, 68))	('glucose', 'Chemical', 'MESH:D005947', (101, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('GLUT1', 'Protein', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (113, 137))	('squamous cell carcinomas', 'Disease', (113, 137))
34946	31412252	Systemic glucose restriction by ketogenic diet or SGLT2 inhibition attenuates squamous tumor progression by disrupting redox homeostasis and insulin/AKT pathways in vivo.	('squamous tumor', 'Disease', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('glucose', 'Chemical', 'MESH:D005947', (9, 16))	('redox homeostasis', 'MPA', (119, 136))	('attenuates', 'NegReg', (67, 77))	('squamous tumor', 'Phenotype', 'HP:0002860', (78, 92))	('inhibition', 'Var', (56, 66))	('disrupting', 'NegReg', (108, 118))	('insulin', 'Gene', (141, 148))	('squamous tumor', 'Disease', 'MESH:D002294', (78, 92))	('insulin', 'Gene', '3630', (141, 148))	('SGLT2', 'Gene', (50, 55))
34951	31412252	Despite the unique microenvironmental cues of the tissues where SCCs arise, the majority of SCCs share common oncogenic abnormalities, such as the amplification of chromosome 3q, which contains important transcriptional regulators p63 and SOX2.	('SCC', 'Gene', '6317', (64, 67))	('SCC', 'Gene', '6317', (92, 95))	('oncogenic abnormalities', 'Disease', 'MESH:C537751', (110, 133))	('SCC', 'Gene', (92, 95))	('amplification', 'Var', (147, 160))	('oncogenic abnormalities', 'Disease', (110, 133))	('SCC', 'Gene', (64, 67))
34952	31412252	p63, part of the p53 protein family, is a master transcription factor of stem cell pluripotency and remains crucial in basal epithelial development, differentiation, and prevention of senescence.	('p63', 'Var', (0, 3))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
34953	31412252	Recent studies have established the oncogenicity of amplified DeltaNp63, an isoform that lacks the N-terminal transactivation (TA) domains as a result of an alternative transcriptional start site, in squamous cancer development and progression.	('amplified', 'Var', (52, 61))	('DeltaNp63', 'Gene', (62, 71))	('squamous cancer', 'Disease', (200, 215))	('squamous cancer', 'Disease', 'MESH:D018307', (200, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('squamous cancer', 'Phenotype', 'HP:0002860', (200, 215))
34956	31412252	Ectopic SOX2 expression in autochthonous mouse models of lung cancer resulted in squamous lineage restriction.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SOX2', 'Protein', (8, 12))	('mouse', 'Species', '10090', (41, 46))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('Ectopic', 'Var', (0, 7))	('squamous lineage restriction', 'CPA', (81, 109))	('resulted in', 'Reg', (69, 80))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
34959	31412252	Here, we seek to further uncover the precise mechanism through which p63 and SOX2 cooperatively exert a SCC-specific oncogenic phenotype.	('SCC', 'Gene', (104, 107))	('exert', 'Reg', (96, 101))	('SOX2', 'Gene', (77, 81))	('SCC', 'Gene', '6317', (104, 107))	('p63', 'Var', (69, 72))
34968	31412252	Moreover, glucose restriction by ketogenic diet, inhibition of renal glucose reabsorption with US Food and Drug Administration (FDA)-approved SGLT2 inhibitor canagliflozin, and genetic ablation of the SLC2A1 gene effectively and specifically suppressed the tumor growth of SCC xenografts as well as autochthonous transgenic mouse models.	('SCC', 'Gene', '6317', (273, 276))	('glucose', 'Chemical', 'MESH:D005947', (10, 17))	('glucose', 'Chemical', 'MESH:D005947', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('renal glucose reabsorption', 'Disease', 'MESH:D007674', (63, 89))	('canagliflozin', 'Chemical', 'MESH:D000068896', (158, 171))	('mouse', 'Species', '10090', (324, 329))	('SLC2A1', 'Gene', (201, 207))	('SCC', 'Gene', (273, 276))	('suppressed', 'NegReg', (242, 252))	('inhibition', 'NegReg', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('renal glucose reabsorption', 'Disease', (63, 89))	('genetic ablation', 'Var', (177, 193))
34986	31412252	Previous studies and our TCGA copy number variation (CNV) analysis have shown that transcription factor p63 is highly expressed in major SCCs mainly through genomic amplification of chromosome 3q26 and functions as a squamous lineage-specific oncogene (Figure S3A).	('transcription factor p63', 'Gene', (83, 107))	('SCC', 'Gene', '6317', (137, 140))	('genomic', 'Var', (157, 164))	('SCC', 'Gene', (137, 140))
34992	31412252	As DeltaNp63 is generally the predominant isoform expressed in squamous cancer cells, we validated that DeltaNp63 is indeed predominantly expressed in a panel of SCC cell lines (Figure S4A), whereas TAp63 was undetectable by immunoblot assays.	('squamous cancer', 'Disease', (63, 78))	('squamous cancer', 'Disease', 'MESH:D018307', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('SCC', 'Gene', (162, 165))	('squamous cancer', 'Phenotype', 'HP:0002860', (63, 78))	('SCC', 'Gene', '6317', (162, 165))	('DeltaNp63', 'Var', (104, 113))
34993	31412252	DeltaNp63-specific knockdown consistently suppressed GLUT1 mRNA and protein expression in SCC cell lines (Figure 2D), whereas TAp63 knockdown showed no effect on GLUT1 expression or glucose uptake (Figures S4B and S4C).	('GLUT1', 'Protein', (53, 58))	('knockdown', 'Var', (19, 28))	('SCC', 'Gene', (90, 93))	('suppressed', 'NegReg', (42, 52))	('S4C', 'Mutation', 'p.S4C', (214, 217))	('SCC', 'Gene', '6317', (90, 93))	('glucose', 'Chemical', 'MESH:D005947', (182, 189))	('DeltaNp63-specific', 'Gene', (0, 18))
34994	31412252	Conversely, we ectopically introduced DeltaNp63 or TAp63 and observed that only ectopically expressed DeltaNp63 further increased GLUT1 mRNA, protein levels, and glucose uptake in SCC cell lines (Figures 2E, 2F, S4D, and S4E).	('glucose', 'Chemical', 'MESH:D005947', (162, 169))	('protein levels', 'MPA', (142, 156))	('glucose uptake', 'CPA', (162, 176))	('SCC', 'Gene', (180, 183))	('DeltaNp63', 'Var', (102, 111))	('GLUT1 mRNA', 'MPA', (130, 140))	('SCC', 'Gene', '6317', (180, 183))	('increased', 'PosReg', (120, 129))	('S4E', 'Mutation', 'p.S4E', (221, 224))	('S4D', 'Mutation', 'p.S4D', (212, 215))
34995	31412252	These results indicate that DeltaNp63 but not TAp63 isoforms transcriptionally activate GLUT1 expression in SCCs.	('GLUT1', 'Gene', (88, 93))	('SCC', 'Gene', (108, 111))	('activate', 'PosReg', (79, 87))	('SCC', 'Gene', '6317', (108, 111))	('expression', 'MPA', (94, 104))	('DeltaNp63', 'Var', (28, 37))
35001	31412252	These data suggest that p63/GLUT1-mediated increased glucose influx fuels anabolic pathways to generate NADPH and GSH in SCC.	('glucose influx', 'MPA', (53, 67))	('GSH', 'Chemical', '-', (114, 117))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('SCC', 'Gene', (121, 124))	('increased glucose', 'Phenotype', 'HP:0003074', (43, 60))	('GSH', 'MPA', (114, 117))	('NADPH', 'Chemical', 'MESH:D009249', (104, 109))	('increased', 'PosReg', (43, 52))	('SCC', 'Gene', '6317', (121, 124))	('anabolic', 'MPA', (74, 82))	('NADPH', 'MPA', (104, 109))	('p63/GLUT1-mediated', 'Var', (24, 42))
35005	31412252	p63 knockdown markedly suppressed glucose influx into R5-P, serine, and lactate in SCC cells (Figures 3C, S5C, S6B, and S6C).	('lactate', 'MPA', (72, 79))	('suppressed', 'NegReg', (23, 33))	('S5C', 'Mutation', 'rs780680200', (106, 109))	('R5-P', 'Chemical', 'MESH:C031626', (54, 58))	('p63', 'Gene', (0, 3))	('serine', 'Chemical', 'MESH:D012694', (60, 66))	('SCC', 'Gene', (83, 86))	('glucose influx into R5-P', 'MPA', (34, 58))	('SCC', 'Gene', '6317', (83, 86))	('lactate', 'Chemical', 'MESH:D019344', (72, 79))	('S6C', 'Mutation', 'p.S6C', (120, 123))	('knockdown', 'Var', (4, 13))	('glucose', 'Chemical', 'MESH:D005947', (34, 41))
35006	31412252	Accordingly, reduced glucose influx into anabolic pathways by p63 or GLUT1 knockdown resulted in increases in cellular ROS measured by a universal oxidative indicator, 2'-7'-dichlorodihydrofluorescein (H2DCFDA) (Figure 3F), a small molecule probe for superoxide radicals, dihydroethidium (DHE) (Figure 3G), and a lipid peroxidation sensor, C11-BODIPY (Figure S6D).	('C11-BODIPY', 'Gene', (340, 350))	('p63', 'Gene', (62, 65))	('C11-BODIPY', 'Gene', '1109', (340, 350))	('superoxide', 'Chemical', 'MESH:D013481', (251, 261))	('increases', 'PosReg', (97, 106))	('dihydroethidium', 'Chemical', 'MESH:C067883', (272, 287))	('GLUT1', 'Gene', (69, 74))	('knockdown', 'Var', (75, 84))	('reduced', 'NegReg', (13, 20))	("2'-7'-dichlorodihydrofluorescein", 'Chemical', 'MESH:C065013', (168, 200))	('lipid', 'Chemical', 'MESH:D008055', (313, 318))	('DHE', 'Chemical', 'MESH:C067883', (289, 292))	('H2DCFDA', 'Chemical', 'MESH:C110400', (202, 209))	('glucose influx into anabolic', 'MPA', (21, 49))	('glucose', 'Chemical', 'MESH:D005947', (21, 28))	('ROS', 'Chemical', 'MESH:D017382', (119, 122))	('cellular ROS', 'MPA', (110, 122))
35007	31412252	Importantly, increased ROS upon p63 or GLUT1 knockdown is associated with significant reduction in intracellular NADPH/NADP+ and GSH/GSSG ratios (Figures 3H, 3I, and S6E), in vitro cell proliferation (Figures 3J and S6F), and transformation capacity (Figure 3K).	('reduction', 'NegReg', (86, 95))	('GLUT1', 'Gene', (39, 44))	('NADPH', 'Chemical', 'MESH:D009249', (113, 118))	('NADP+', 'Chemical', 'MESH:D009249', (119, 124))	('p63', 'Var', (32, 35))	('ROS', 'MPA', (23, 26))	('GSH/GSSG ratios', 'MPA', (129, 144))	('transformation capacity', 'CPA', (226, 249))	('S6E', 'Mutation', 'p.S6E', (166, 169))	('GSH', 'Chemical', '-', (129, 132))	('ROS', 'Chemical', 'MESH:D017382', (23, 26))	('increased', 'PosReg', (13, 22))	('knockdown', 'Var', (45, 54))	('GSSG', 'Chemical', 'MESH:D019803', (133, 137))
35009	31412252	It should be noted that p63 shRNA-induced cell death and GLUT1 attenuation were rescued by ectopic introduction of shRNA-resistant DeltaNp63 but not TAp63, validating the predominant role the DeltaNp63 isoform plays in modulating SCC GLUT1 expression and maintaining viability (Figure S6I).	('GLUT1', 'Gene', (57, 62))	('SCC', 'Gene', (230, 233))	('modulating', 'Reg', (219, 229))	('DeltaNp63', 'Var', (131, 140))	('death', 'Disease', 'MESH:D003643', (47, 52))	('death', 'Disease', (47, 52))	('SCC', 'Gene', '6317', (230, 233))	('attenuation', 'NegReg', (63, 74))
35011	31412252	In vivo tumor growth of lung SCC HCC2814 was also significantly impaired by doxycycline-inducible DeltaNp63 knockdown (Figures 3N, S6K, and S6L).	('knockdown', 'Var', (108, 117))	('doxycycline', 'Chemical', 'MESH:D004318', (76, 87))	('SCC', 'Gene', '6317', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('impaired', 'NegReg', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('S6L', 'Mutation', 'p.S6L', (140, 143))	('tumor', 'Disease', (8, 13))	('HCC2814', 'CellLine', 'CVCL:V586', (33, 40))	('DeltaNp63', 'Gene', (98, 107))	('S6K', 'Mutation', 'p.S6K', (131, 134))	('SCC', 'Gene', (29, 32))
35013	31412252	GLUT1 is expressed only in a small population of cells that retain p63 expression in Tet-shDeltaNp63 tumors, further supporting the dependency of GLUT1 expression on DeltaNp63 (Figure S6M).	('p63', 'Var', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('Tet', 'Chemical', 'MESH:C010349', (85, 88))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
35015	31412252	Collectively, these results suggest that p63 essentially contributes to cellular proliferation and survival of SCC by transcriptionally activating GLUT1, thus promoting subsequent glucose influx into NADPH and GSH-generating anabolic pathways to sustain anti-oxidative capacity in SCC.	('GSH', 'Chemical', '-', (210, 213))	('cellular proliferation', 'CPA', (72, 94))	('anti-oxidative capacity', 'MPA', (254, 277))	('activating', 'PosReg', (136, 146))	('glucose', 'Chemical', 'MESH:D005947', (180, 187))	('glucose influx into NADPH', 'MPA', (180, 205))	('SCC', 'Gene', '6317', (281, 284))	('promoting', 'PosReg', (159, 168))	('GLUT1', 'Gene', (147, 152))	('GSH-generating', 'MPA', (210, 224))	('SCC', 'Gene', (111, 114))	('NADPH', 'Chemical', 'MESH:D009249', (200, 205))	('p63', 'Var', (41, 44))	('SCC', 'Gene', '6317', (111, 114))	('SCC', 'Gene', (281, 284))
35017	31412252	Ectopic overexpression of GLUT1 in p63-deficient SCC cells markedly restored cellular proliferation and viability upon p63 knockdown in lung (HCC2814) and skin (A431) SCC cell lines (Figures 4A, 4B, S7A, and S7B).	('A431', 'CellLine', 'CVCL:0037', (161, 165))	('GLUT1', 'Gene', (26, 31))	('S7A', 'Mutation', 'p.S7A', (199, 202))	('SCC', 'Gene', (49, 52))	('SCC', 'Gene', '6317', (167, 170))	('HCC2814', 'CellLine', 'CVCL:V586', (142, 149))	('cellular proliferation', 'CPA', (77, 99))	('SCC', 'Gene', '6317', (49, 52))	('viability', 'CPA', (104, 113))	('knockdown', 'Var', (123, 132))	('SCC', 'Gene', (167, 170))	('restored', 'PosReg', (68, 76))
35018	31412252	GLUT1 reconstitution increased glucose uptake, implicating GLUT1 as primarily responsible for glucose influx (Figure 4C), and reduced oxidative stress (Figure 4D) by restoring NADPH and GSH production (Figures 4E and 4F) in p63-deficient SCC cells.	('glucose', 'Chemical', 'MESH:D005947', (94, 101))	('increased', 'PosReg', (21, 30))	('restoring', 'PosReg', (166, 175))	('GSH production', 'MPA', (186, 200))	('oxidative stress', 'Phenotype', 'HP:0025464', (134, 150))	('NADPH', 'Chemical', 'MESH:D009249', (176, 181))	('SCC', 'Gene', (238, 241))	('oxidative stress', 'MPA', (134, 150))	('GSH', 'Chemical', '-', (186, 189))	('glucose uptake', 'MPA', (31, 45))	('SCC', 'Gene', '6317', (238, 241))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))	('glucose influx', 'MPA', (94, 108))	('NADPH', 'MPA', (176, 181))	('increased glucose', 'Phenotype', 'HP:0003074', (21, 38))	('reduced', 'NegReg', (126, 133))	('reconstitution', 'Var', (6, 20))
35022	31412252	Indeed, SOX2 knockdown attenuates GLUT1 mRNA and protein expression (Figures 5A, 5B, S8B, and S8C) as well as cellular glucose uptake and lactate production in SCC cell lines (Figures 5C and S8D).	('lactate production', 'MPA', (138, 156))	('GLUT1 mRNA', 'Protein', (34, 44))	('SOX2', 'Gene', (8, 12))	('SCC', 'Gene', (160, 163))	('glucose', 'Chemical', 'MESH:D005947', (119, 126))	('lactate', 'Chemical', 'MESH:D019344', (138, 145))	('attenuates', 'NegReg', (23, 33))	('knockdown', 'Var', (13, 22))	('SCC', 'Gene', '6317', (160, 163))	('cellular glucose uptake', 'MPA', (110, 133))
35023	31412252	Analogous to p63 inhibition, SOX2 knockdown significantly attenuated NADPH/NADP+ and GSH/GSSG ratios (Figures 5H, 5I, S8G, and S8H), which is associated with an increase in ROS (Figures 5J, S8I, and S8J) and marked decreases in in vitro proliferation (Figures 5K and S8K) and cellular transformation capacity (Figure 5L).	('S8K', 'Mutation', 'p.S8K', (267, 270))	('attenuated', 'NegReg', (58, 68))	('S8H', 'Mutation', 'p.S8H', (127, 130))	('ROS', 'MPA', (173, 176))	('GSSG', 'Chemical', 'MESH:D019803', (89, 93))	('NADPH', 'Chemical', 'MESH:D009249', (69, 74))	('S8I', 'Mutation', 'p.S8I', (190, 193))	('SOX2', 'Gene', (29, 33))	('cellular transformation capacity', 'CPA', (276, 308))	('GSH', 'Chemical', '-', (85, 88))	('increase', 'PosReg', (161, 169))	('NADPH/NADP+', 'MPA', (69, 80))	('knockdown', 'Var', (34, 43))	('ROS', 'Chemical', 'MESH:D017382', (173, 176))	('S8G', 'Mutation', 'p.S8G', (118, 121))	('NADP+', 'Chemical', 'MESH:D009249', (75, 80))	('decreases', 'NegReg', (215, 224))
35031	31412252	Corroborating the in vitro results, glucose restriction by ketogenic diet induced oxidative stress in lung SCC xenograft tumors as indicated by a significant increase in p-H2AX and 4-HNE staining (Figures 6C).	('p-H2AX', 'MPA', (170, 176))	('oxidative stress', 'Phenotype', 'HP:0025464', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('glucose restriction', 'Var', (36, 55))	('lung SCC xenograft tumors', 'Disease', 'MESH:D008175', (102, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('4-HNE staining', 'MPA', (181, 195))	('lung SCC xenograft tumors', 'Disease', (102, 127))	('glucose', 'Chemical', 'MESH:D005947', (36, 43))	('4-HNE', 'Chemical', 'MESH:C027576', (181, 186))	('oxidative stress', 'MPA', (82, 98))	('increase', 'PosReg', (158, 166))
35032	31412252	We also observed increased oxidative stress in SCC tumors treated with glycolytic inhibitor, 2-deoxyglucose (2-DG), or GLUT1 inhibitor, WZB117, as well as shRNA-mediated GLUT1 knockdown, which is associated with significant tumor growth inhibition as we previously reported (Figure S10A-S10C).	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('SCC tumors', 'Disease', 'MESH:D009369', (47, 57))	('SCC tumors', 'Disease', (47, 57))	('oxidative stress', 'MPA', (27, 43))	('WZB117', 'Chemical', 'MESH:C576807', (136, 142))	('tumor', 'Disease', (51, 56))	('knockdown', 'Var', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('S10C', 'Mutation', 'p.S10C', (287, 291))	('tumor', 'Disease', (224, 229))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (17, 43))	('oxidative stress', 'Phenotype', 'HP:0025464', (27, 43))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('S10A', 'SUBSTITUTION', 'None', (282, 286))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('increased', 'PosReg', (17, 26))	('2-DG', 'Chemical', 'MESH:D003847', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('S10A', 'Var', (282, 286))	('2-deoxyglucose', 'Chemical', 'MESH:D003847', (93, 107))
35035	31412252	Our recent study and other groups have demonstrated that SCCs exhibit highly activated PI3K/AKT signaling due to the frequent amplification of chromosome 3q26 that contains PIK3CA, a catalytic subunit of the PI3K complex.	('PIK3CA', 'Gene', '5290', (173, 179))	('SCC', 'Gene', '6317', (57, 60))	('activated', 'PosReg', (77, 86))	('PI3K/AKT signaling', 'Pathway', (87, 105))	('amplification', 'Var', (126, 139))	('SCC', 'Gene', (57, 60))	('PIK3CA', 'Gene', (173, 179))
35041	31412252	Combination of ketogenic diet with cisplatin (5 mg/kg/week) was evidently more effective than a single treatment of either ketogenic diet or cisplatin alone without any noticeable adverse effects (Figures 6E, S11A, and S11D).	('S11A', 'Var', (209, 213))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('S11A', 'SUBSTITUTION', 'None', (209, 213))	('S11D', 'Var', (219, 223))	('S11D', 'SUBSTITUTION', 'None', (219, 223))
35042	31412252	Accordingly, we detected a marked reduction of proliferation with an increase in apoptosis and intratumoral oxidative stress (Figure S11B).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('S11B', 'SUBSTITUTION', 'None', (133, 137))	('tumor', 'Disease', (100, 105))	('apoptosis', 'CPA', (81, 90))	('oxidative stress', 'Phenotype', 'HP:0025464', (108, 124))	('reduction', 'NegReg', (34, 43))	('proliferation', 'CPA', (47, 60))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('S11B', 'Var', (133, 137))
35043	31412252	Notably, cisplatin treatment neither affected blood glucose levels nor attenuated PI3K/AKT pathway signaling, thus arguing for the ketogenic-diet-dependent insulin and PI3K/AKT attenuation in SCC tumors (Figures S11B and S11C).	('insulin', 'Gene', (156, 163))	('attenuation', 'NegReg', (177, 188))	('S11B', 'Var', (212, 216))	('insulin', 'Gene', '3630', (156, 163))	('S11B', 'SUBSTITUTION', 'None', (212, 216))	('PI3K/AKT pathway signaling', 'Pathway', (82, 108))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('blood glucose', 'Chemical', 'MESH:D001786', (46, 59))	('S11C', 'Var', (221, 225))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('attenuated', 'NegReg', (71, 81))	('S11C', 'SUBSTITUTION', 'None', (221, 225))	('SCC tumors', 'Disease', 'MESH:D009369', (192, 202))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('SCC tumors', 'Disease', (192, 202))
35046	31412252	Indeed, KLLuc mice fed with a ketogenic diet exhibited dramatically less SCC tumor development (Figures 7A and 7B), whereas total tumor burden or overall survival was not affected (Figures 7C, 7D, and S12A), indicating that a ketogenic diet pointedly inhibited the development of KLLuc SCC tumors but not ADC tumors.	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (309, 315))	('inhibited', 'NegReg', (251, 260))	('KLLuc SCC tumors', 'Disease', 'MESH:D009369', (280, 296))	('S12A', 'SUBSTITUTION', 'None', (201, 205))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (290, 295))	('S12A', 'Var', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('SCC tumor', 'Disease', 'MESH:D009369', (286, 295))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumors', 'Disease', (309, 315))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('KLLuc SCC tumors', 'Disease', (280, 296))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('tumor', 'Disease', (309, 314))	('tumors', 'Disease', 'MESH:D009369', (309, 315))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumors', 'Disease', (290, 296))	('less', 'NegReg', (68, 72))	('SCC tumor', 'Disease', (73, 82))	('development', 'CPA', (265, 276))	('tumor', 'Disease', (77, 82))	('SCC tumor', 'Disease', 'MESH:D009369', (73, 82))
35047	31412252	Substantiating the xenograft tumor results, ketogenic diet effectively reduced blood glucose and insulin levels in KLLuc mice (Figures 7E and 7F), which consequently increased oxidative stress and suppressed PI3K/AKT signaling in SCC tumors (Figure 7G), whereas in ADC tumors, oxidative stress or PI3K/AKT signaling was not affected by a ketogenic diet (Figure S12B).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('SCC tumors', 'Disease', (230, 240))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('S12B', 'SUBSTITUTION', 'None', (361, 365))	('SCC tumors', 'Disease', 'MESH:D009369', (230, 240))	('insulin', 'Gene', '3630', (97, 104))	('oxidative stress', 'Phenotype', 'HP:0025464', (277, 293))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('reduced', 'NegReg', (71, 78))	('tumors', 'Disease', (269, 275))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('oxidative stress', 'MPA', (176, 192))	('suppressed', 'NegReg', (197, 207))	('S12B', 'Var', (361, 365))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (166, 192))	('mice', 'Species', '10090', (121, 125))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('blood glucose', 'Chemical', 'MESH:D001786', (79, 92))	('reduced blood glucose', 'Phenotype', 'HP:0001943', (71, 92))	('insulin', 'Gene', (97, 104))	('increased', 'PosReg', (166, 175))	('tumor', 'Disease', (269, 274))	('tumors', 'Disease', (234, 240))	('PI3K/AKT signaling', 'MPA', (208, 226))	('tumor', 'Disease', (29, 34))	('oxidative stress', 'Phenotype', 'HP:0025464', (176, 192))
35050	31412252	Yet, total tumor burden or overall survival was not affected (Figures 7C, 7D, and S12A).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('S12A', 'SUBSTITUTION', 'None', (82, 86))	('tumor', 'Disease', (11, 16))	('S12A', 'Var', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
35052	31412252	However, direct SGLT2 inhibition of tumors may not be the cause of cell death in SCC as SGLT2 is not expressed in SCC cell lines (Figures S13A), human SCC tumors (Figure S13B), and KLLuc tumors (Figures S13C-S13E).	('S13C', 'Mutation', 'p.S13C', (203, 207))	('SCC tumors', 'Disease', (151, 161))	('KLLuc tumors', 'Disease', 'MESH:D009369', (181, 193))	('human', 'Species', '9606', (145, 150))	('death', 'Disease', (72, 77))	('SCC', 'Gene', '6317', (114, 117))	('S13B', 'SUBSTITUTION', 'None', (170, 174))	('SCC tumors', 'Disease', 'MESH:D009369', (151, 161))	('SCC', 'Gene', '6317', (81, 84))	('SCC', 'Gene', (114, 117))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('SCC', 'Gene', (81, 84))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('KLLuc tumors', 'Disease', (181, 193))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('SCC', 'Gene', '6317', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('death', 'Disease', 'MESH:D003643', (72, 77))	('tumors', 'Disease', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (187, 193))	('S13A', 'Var', (138, 142))	('tumors', 'Disease', (36, 42))	('SCC', 'Gene', (151, 154))	('S13E', 'Mutation', 'p.S13E', (208, 212))	('S13A', 'SUBSTITUTION', 'None', (138, 142))	('S13B', 'Var', (170, 174))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (36, 42))
35057	31412252	To further validate the necessity of glucose in SCC survival and tumor growth, we genetically ablated Slc2a1 in KLLuc mice (LSL-KrasG12DLkb1flox/floxGlut1flox/flox, KL GLUT1-knockout [KO]).	('tumor', 'Disease', (65, 70))	('Slc2a1', 'Gene', (102, 108))	('Glut1', 'Gene', (149, 154))	('SCC', 'Gene', (48, 51))	('Lkb1', 'Gene', (136, 140))	('Slc2a1', 'Gene', '20525', (102, 108))	('ablated', 'Var', (94, 101))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('SCC', 'Gene', '6317', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mice', 'Species', '10090', (118, 122))	('Lkb1', 'Gene', '20869', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Glut1', 'Gene', '20525', (149, 154))
35058	31412252	Slc2a1 deletion dramatically decreased SCC tumors (Figures 7H and 7I), yet total tumor burden was not affected (Figure 7J), again indicating that GLUT1 plays pivotal roles in SCC tumorigenesis but remains dispensable for ADC tumors.	('SCC tumor', 'Disease', (175, 184))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('SCC tumor', 'Disease', 'MESH:D009369', (175, 184))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('Slc2a1', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('SCC tumor', 'Disease', 'MESH:D009369', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('deletion', 'Var', (7, 15))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('decreased SCC tumors', 'Disease', 'None', (29, 49))	('decreased SCC tumors', 'Disease', (29, 49))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('Slc2a1', 'Gene', '20525', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Disease', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
35073	31412252	Accordingly, inhibition of DeltaNp63 or SOX2 expression deprived cellular NADPH and GSH pools and impaired cellular proliferation and viability of SCC (Figure 3).	('SCC', 'Gene', (147, 150))	('deprived', 'NegReg', (56, 64))	('DeltaNp63', 'Gene', (27, 36))	('inhibition', 'Var', (13, 23))	('SOX2', 'Gene', (40, 44))	('viability', 'CPA', (134, 143))	('GSH pools', 'MPA', (84, 93))	('SCC', 'Gene', '6317', (147, 150))	('GSH', 'Chemical', '-', (84, 87))	('impaired', 'NegReg', (98, 106))	('cellular NADPH', 'MPA', (65, 79))	('NADPH', 'Chemical', 'MESH:D009249', (74, 79))	('cellular proliferation', 'CPA', (107, 129))
35082	31412252	Our results, however, cannot completely exclude the possibility that a ketogenic diet or SGLT2 inhibitors may affect SCC metabolism and tumor growth independent of glucose- and/or insulin-mediated effects.	('insulin', 'Gene', (180, 187))	('SGLT2', 'Gene', (89, 94))	('inhibitors', 'Var', (95, 105))	('affect', 'Reg', (110, 116))	('SCC', 'Gene', (117, 120))	('insulin', 'Gene', '3630', (180, 187))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('SCC', 'Gene', '6317', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('glucose', 'Chemical', 'MESH:D005947', (164, 171))	('tumor', 'Disease', (136, 141))
35088	31412252	Importantly, SCC is among cancer types exhibiting highly activated PI3K/AKT signaling due to amplified PIK3CA by genomic amplification of chromosome 3q26 that also contains p63 and SOX2.	('SCC', 'Gene', '6317', (13, 16))	('amplified', 'Var', (93, 102))	('cancer', 'Disease', (26, 32))	('activated', 'PosReg', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('PIK3CA', 'Gene', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('PIK3CA', 'Gene', '5290', (103, 109))	('SCC', 'Gene', (13, 16))	('PI3K/AKT signaling', 'Pathway', (67, 85))
35089	31412252	Indeed, our data demonstrate a significant reduction of AKT signaling in ketogenic-diet-fed or CAG-treated SCC tumors but not in A549 ADC or KL ADC tumors, which have considerably less PI3K/AKT activity (Figures 6C, 7G, and S12B).	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('SCC tumors', 'Disease', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('reduction', 'NegReg', (43, 52))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('AKT signaling', 'MPA', (56, 69))	('S12B', 'SUBSTITUTION', 'None', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('PI3K/AKT', 'Pathway', (185, 193))	('SCC tumors', 'Disease', 'MESH:D009369', (107, 117))	('tumors', 'Disease', (148, 154))	('S12B', 'Var', (224, 228))	('less', 'NegReg', (180, 184))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('activity', 'MPA', (194, 202))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('A549', 'CellLine', 'CVCL:0023', (129, 133))	('CAG', 'Chemical', 'MESH:D000068896', (95, 98))
35090	31412252	Intriguingly, recent evidence has shown that ketogenic diet and SGLT2 inhibition enhanced the efficacy of PI3K inhibitors by blocking glucose-insulin feedback that is caused by compensatory insulin elevation in response to systemic PI3K inhibition.	('insulin', 'Gene', (190, 197))	('efficacy', 'MPA', (94, 102))	('SGLT2', 'Gene', (64, 69))	('enhanced', 'PosReg', (81, 89))	('insulin', 'Gene', '3630', (190, 197))	('blocking', 'NegReg', (125, 133))	('PI3K', 'Gene', (106, 110))	('glucose', 'Chemical', 'MESH:D005947', (134, 141))	('inhibition', 'Var', (70, 80))	('insulin', 'Gene', (142, 149))	('insulin elevation', 'Phenotype', 'HP:0000842', (190, 207))	('insulin', 'Gene', '3630', (142, 149))
35092	31412252	Our earlier study and others have demonstrated that PI3K/AKT signaling enhances glucose uptake and retention by promoting GLUT1 expression and translocation to the plasma membrane as well as increasing HK2 activity.	('PI3K/AKT', 'Var', (52, 60))	('increasing', 'PosReg', (191, 201))	('glucose', 'Chemical', 'MESH:D005947', (80, 87))	('retention', 'CPA', (99, 108))	('HK2', 'Enzyme', (202, 205))	('GLUT1', 'Protein', (122, 127))	('translocation to the plasma membrane', 'MPA', (143, 179))	('glucose uptake', 'CPA', (80, 94))	('enhances', 'PosReg', (71, 79))	('expression', 'MPA', (128, 138))	('promoting', 'PosReg', (112, 121))	('activity', 'MPA', (206, 214))
35093	31412252	Therefore, inhibition of insulin/PI3K/AKT signaling in ketogenic-diet-fed or CAG-treated mice may reduce GLUT1 transmembrane localization and HK2 activity in SCC tumors that further restricts glucose uptake and utilization.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('glucose', 'MPA', (192, 199))	('activity', 'MPA', (146, 154))	('mice', 'Species', '10090', (89, 93))	('restricts', 'NegReg', (182, 191))	('reduce', 'NegReg', (98, 104))	('HK2', 'Enzyme', (142, 145))	('insulin', 'Gene', (25, 32))	('inhibition', 'Var', (11, 21))	('glucose', 'Chemical', 'MESH:D005947', (192, 199))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('insulin', 'Gene', '3630', (25, 32))	('CAG', 'Chemical', 'MESH:D000068896', (77, 80))	('SCC tumors', 'Disease', 'MESH:D009369', (158, 168))	('GLUT1 transmembrane localization', 'MPA', (105, 137))	('SCC tumors', 'Disease', (158, 168))
35103	31412252	Lung (LC806, LC2085a, LC2081), head and neck (OR802), esophageal (ES2081), cervical (CR2089), and skin (SK2081) tumor tissue microarrays were purchased from US Biomax (Derwood, MD, USA), and patient clinical information is available on the website (https://biomax.us).	('LC806', 'Var', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('SK2081', 'CellLine', 'CVCL:K843', (104, 110))	('tumor', 'Disease', (112, 117))	('patient', 'Species', '9606', (191, 198))
35108	31412252	We adopted RBG >= 120 mg/dL to be an indication of disorders in glucose metabolism because RBG >= 120 mg/dL have been shown to have 92% specificity for detection of any glucose intolerance.	('glucose metabolism', 'Disease', 'MESH:D044882', (64, 82))	('glucose', 'Chemical', 'MESH:D005947', (169, 176))	('glucose metabolism', 'Disease', (64, 82))	('RBG', 'Chemical', '-', (91, 94))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('glucose intolerance', 'Phenotype', 'HP:0001952', (169, 188))	('RBG >= 120 mg/dL', 'Var', (91, 107))	('glucose', 'MPA', (169, 176))	('RBG', 'Chemical', '-', (11, 14))
35119	31412252	Esophageal SCC lines KYSE70, KYSE30, KYSE510 and esophageal ADC lines OE33, FLO-1 were provided by Drs.	('KYSE510', 'Var', (37, 44))	('Drs', 'Gene', (99, 102))	('SCC', 'Gene', (11, 14))	('SCC', 'Gene', '6317', (11, 14))	('KYSE70', 'Var', (21, 27))	('Drs', 'Gene', '8406', (99, 102))	('KYSE30', 'Var', (29, 35))
35134	31412252	Ketogenic diet was started when xenograft tumors were approximately 100 mm3 or 5 weeks after intratracheal inhalation of adenovirus-Cre in KLLuc mice and continued until the mice were euthanized for tissue collection.	('xenograft tumors', 'Disease', (32, 48))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('xenograft tumors', 'Disease', 'MESH:D009369', (32, 48))	('mice', 'Species', '10090', (145, 149))	('adenovirus-Cre', 'Var', (121, 135))
35182	31412252	For lentivirus production, HEK293T cells were transfected with viral packaging plasmids psPAX2 (Addgene #12260) and pMD2.G (Addgene #12259), and pLKO.1 shRNA using Lipofectamine 3000 (Invitrogen).	('Addgene #12259', 'Var', (124, 138))	('Addgene #12260', 'Var', (96, 110))	('lentivirus', 'MPA', (4, 14))	('HEK293T', 'CellLine', 'CVCL:0063', (27, 34))	('Lipofectamine', 'Chemical', 'MESH:C086724', (164, 177))
35196	31412252	The following primary antibodies were used: p63 (1:200; Biocare Medical; CM163A), p63 (1:100; R&D Systems AF-1916), GLUT1 (1:250; Alpha Diagnostic GT11-A), SGLT2 (1:1000; Abcam ab85626), TTF1 (1:1,000; Dako M3575), Ki67 (1:500; Cell Signaling Technology #12202), Cleaved Caspase-3 (1:200; Cell Signaling Technology #9664), Ser473-p-AKT (1:500; Cell signaling Technology #4058), Ser235/236-p-S6 (1:200; Cell Signaling Technology #4858) and Thr37/46-p-4EBP1 (1:200; Cell Signaling Technology #2855), Ser139-p-Histone H2A.X (1:1,000; Cell Signaling Technology #9718), 4-Hydroxynonenal (1:500; Abcam ab46545), CK5 (1:200; Abcam ab52635).	('Ki67', 'Gene', (215, 219))	('CK5', 'Gene', (606, 609))	('CK5', 'Gene', '3852', (606, 609))	('TTF1', 'Gene', '7270', (187, 191))	('p-S6', 'Gene', (389, 393))	('Ser473-p-AKT', 'Mutation', 'p.S473AKT', (323, 335))	('Ki67', 'Gene', '17345', (215, 219))	('TTF1', 'Gene', (187, 191))	('4-Hydroxynonenal', 'Var', (565, 581))	('p-S6', 'Gene', '338413', (389, 393))
35243	31795079	Conversely, the disruption of COX2 PGE (2) feedback by COX2 inhibitors suppressed the production of MDSC-associated suppressive factors and the cytotoxic T lymphocytes (CTL)-inhibitory function of fully developed MDSCs from cancer patients.	('disruption', 'Var', (16, 26))	('patients', 'Species', '9606', (231, 239))	('PGE (2)', 'Chemical', 'MESH:D015232', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('production of MDSC-associated suppressive factors', 'MPA', (86, 135))	('COX2', 'Gene', '5743', (30, 34))	('COX2', 'Gene', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('COX2', 'Gene', (55, 59))	('cancer', 'Disease', (224, 230))	('COX2', 'Gene', '5743', (55, 59))	('suppressed', 'NegReg', (71, 81))
35255	31795079	In particular, in experimental studies, ATRA improved the differentiation of myeloid cells and the immune response in cancer patients, and 13-cis-retinoic acid and beta-carotene increased both the number of IL-2 receptors and the percentage of peripheral blood lymphoid cells that express surface markers for T-helper cells.	('patients', 'Species', '9606', (125, 133))	('cancer', 'Disease', (118, 124))	('ATRA', 'Chemical', 'MESH:D014212', (40, 44))	('improved', 'PosReg', (45, 53))	('immune response', 'CPA', (99, 114))	('IL-2', 'Gene', '3558', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('13-cis-retinoic', 'Var', (139, 154))	('13-cis-retinoic acid', 'Chemical', 'MESH:D015474', (139, 159))	('differentiation of myeloid cells', 'CPA', (58, 90))	('IL-2', 'Gene', (207, 211))	('beta-carotene', 'Chemical', 'MESH:D019207', (164, 177))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('increased', 'PosReg', (178, 187))
35261	31795079	Moreover, the anti-tumoral action of Dl alpha tocopheryl is synergistic with that of some common antiblastics.	('Dl alpha', 'Var', (37, 45))	('tumoral', 'Disease', 'MESH:D009369', (19, 26))	('tumoral', 'Disease', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Dl alpha tocopheryl', 'Chemical', '-', (37, 56))
35334	31795079	pT2 No Mo was the post-operative TNM classification, G3, ER+ (30%) Pr+ (10%), Ki67 90%, and HER2 negative.	('TNM', 'Gene', (33, 36))	('HER2', 'Gene', '2064', (92, 96))	('rat', 'Species', '10116', (26, 29))	('HER2', 'Gene', (92, 96))	('TNM', 'Gene', '10178', (33, 36))	('pT2 No Mo', 'Var', (0, 9))
35353	31795079	pT2 N0 M0 was the post-operative TNM classification, and cells were HER2 negative.	('TNM', 'Gene', (33, 36))	('HER2', 'Gene', (68, 72))	('rat', 'Species', '10116', (26, 29))	('HER2', 'Gene', '2064', (68, 72))	('pT2 N0 M0', 'Var', (0, 9))	('TNM', 'Gene', '10178', (33, 36))
35389	31795079	pT3 N2a (6 regional lymph-nodes involved of 22 examined) M1 was the post-operative TNM classification.	('rat', 'Species', '10116', (76, 79))	('TNM', 'Gene', (83, 86))	('pT3 N2a', 'Var', (0, 7))	('TNM', 'Gene', '10178', (83, 86))
35468	31795079	From 10 August 2019 to 10 October 2019, he was again given cycles of IT and the mean daily PSA increase was 0.00065 ng/mL, 2 and 2.77 times lower than 0.013 ng/mL and 0.018 ng/mL, respectively.	('0.00065 ng/mL', 'Var', (108, 121))	('PSA', 'Gene', '354', (91, 94))	('PSA', 'Gene', (91, 94))
35532	30616477	Similarly, the inhibition of cyclin B1 increased ESCC cell sensitivity towards cisplatin and paclitaxel through the PTEN/AKT pathway.	('AKT', 'Gene', '207', (121, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('AKT', 'Gene', (121, 124))	('cyclin B1', 'Gene', '891', (29, 38))	('cyclin B1', 'Gene', (29, 38))	('paclitaxel', 'Chemical', 'MESH:D017239', (93, 103))	('increased ESCC', 'Phenotype', 'HP:0003565', (39, 53))	('increased', 'PosReg', (39, 48))	('PTEN', 'Gene', (116, 120))	('PTEN', 'Gene', '5728', (116, 120))	('inhibition', 'Var', (15, 25))
35556	30616477	High MTA1 expression was also linked to a high density of microvessels and poorly differentiated squamous carcinoma.	('squamous carcinoma', 'Phenotype', 'HP:0002860', (97, 115))	('High', 'Var', (0, 4))	('MTA1', 'Gene', (5, 9))	('expression', 'MPA', (10, 20))	('MTA1', 'Gene', '9112', (5, 9))	('poorly', 'Disease', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous carcinoma', 'Disease', 'MESH:D002294', (97, 115))	('linked to', 'Reg', (30, 39))	('squamous carcinoma', 'Disease', (97, 115))
35559	30616477	In pN0 ESCC patients with high TNFAIP8 protein expression, LNM developed at a rate of 43.8% within 3 years of surgery, compared with a rate of 20.4% in those with low TNFAIP8 expression.	('LNM', 'Disease', (59, 62))	('patients', 'Species', '9606', (12, 20))	('high', 'Var', (26, 30))	('TNFAIP8', 'Gene', '25816', (31, 38))	('TNFAIP8', 'Gene', (167, 174))	('TNFAIP8', 'Gene', '25816', (167, 174))	('TNFAIP8', 'Gene', (31, 38))	('protein', 'Protein', (39, 46))	('pN0', 'Gene', (3, 6))
35560	30616477	Following the use of small interfering (si)RNA for TNFAIP8, apoptosis was increased, cancer cell invasion and migration ability were decreased, and MMP1 and MMP9 expression was significantly decreased.	('MMP9', 'Gene', (157, 161))	('MMP9', 'Gene', '4318', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('small interfering', 'Var', (21, 38))	('apoptosis', 'CPA', (60, 69))	('increased', 'PosReg', (74, 83))	('cancer', 'Disease', (85, 91))	('expression', 'MPA', (162, 172))	('MMP1', 'Gene', '4312', (148, 152))	('decreased', 'NegReg', (191, 200))	('TNFAIP8', 'Gene', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('TNFAIP8', 'Gene', '25816', (51, 58))	('decreased', 'NegReg', (133, 142))	('MMP1', 'Gene', (148, 152))
35564	30616477	Promoter methylation in the 5' CpG island of RKIP gene significantly induces gene silencing and ESCC development.	('RKIP', 'Gene', (45, 49))	('ESCC development', 'CPA', (96, 112))	('induces', 'Reg', (69, 76))	('Promoter methylation', 'Var', (0, 20))	('gene silencing', 'MPA', (77, 91))	('RKIP', 'Gene', '5037', (45, 49))
35572	30616477	STMN1 overexpression was also reported to activate the PI3K pathway, with the PI3K inhibitor LY294002 found to reduce STMN1 protein expression, consistent with the down-regulation of p-Akt (S473).	('STMN1', 'Gene', (0, 5))	('PI3K pathway', 'Pathway', (55, 67))	('LY294002', 'Chemical', 'MESH:C085911', (93, 101))	('STMN1', 'Gene', '3925', (0, 5))	('LY294002', 'Var', (93, 101))	('protein', 'Protein', (124, 131))	('Akt', 'Gene', '207', (185, 188))	('STMN1', 'Gene', '3925', (118, 123))	('STMN1', 'Gene', (118, 123))	('reduce', 'NegReg', (111, 117))	('Akt', 'Gene', (185, 188))
35579	30616477	Moreover, knockdown of STMN1 enhanced ESCC cell line sensitivity to docetaxel and radiation.	('docetaxel', 'Chemical', 'MESH:D000077143', (68, 77))	('enhanced', 'PosReg', (29, 37))	('STMN1', 'Gene', (23, 28))	('ESCC cell line', 'CPA', (38, 52))	('STMN1', 'Gene', '3925', (23, 28))	('knockdown', 'Var', (10, 19))
35593	30616477	found that IFITM3 was overexpressed in 56.7% of pN0 ESCC patient tumor tissues, and the 3-year survival rate of patients with high IFITM3 expression was 50.8%, compared with 26.7% in those with low expression.	('patient', 'Species', '9606', (112, 119))	('pN0', 'Gene', (48, 51))	('tumor', 'Disease', (65, 70))	('patient', 'Species', '9606', (57, 64))	('IFITM3', 'Gene', (11, 17))	('IFITM3', 'Gene', '10410', (11, 17))	('patients', 'Species', '9606', (112, 120))	('IFITM3', 'Gene', (131, 137))	('high', 'Var', (126, 130))	('IFITM3', 'Gene', '10410', (131, 137))	('overexpressed', 'PosReg', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
35594	30616477	More recently, 5-year survival rates for stage IIA ESCC patients with high IFITM3 expression were reported to be 78.7%, versus 64.9% in those with low IFITM3 expression.	('patients', 'Species', '9606', (56, 64))	('IFITM3', 'Gene', (151, 157))	('IFITM3', 'Gene', '10410', (151, 157))	('stage IIA ESCC', 'Disease', (41, 55))	('ESCC', 'Disease', (51, 55))	('high', 'Var', (70, 74))	('IFITM3', 'Gene', '10410', (75, 81))	('IFITM3', 'Gene', (75, 81))
35597	30616477	Moreover, silencing of IFITM3 reversed the EMT process and reduced MMP-2 and MMP-9 expression.	('IFITM3', 'Gene', '10410', (23, 29))	('EMT process', 'CPA', (43, 54))	('reduced', 'NegReg', (59, 66))	('MMP-2', 'Gene', '4313', (67, 72))	('MMP-9', 'Gene', '4318', (77, 82))	('silencing', 'Var', (10, 19))	('MMP-9', 'Gene', (77, 82))	('MMP-2', 'Gene', (67, 72))	('IFITM3', 'Gene', (23, 29))
35771	33493132	The numbers of early and late apoptotic cells were analyzed and the results demonstrated that RNF168 knockdown significantly increased apoptosis when compared with the control group (Figure 4A).	('apoptosis', 'CPA', (135, 144))	('increased', 'PosReg', (125, 134))	('RNF168', 'Gene', (94, 100))	('RNF168', 'Gene', '165918', (94, 100))	('knockdown', 'Var', (101, 110))
35772	33493132	Scratch and transwell assays demonstrated that RNF168 knockdown impeded migration of ECA-109 and EC9706 cells (Figures 4B, 4C).	('RNF168', 'Gene', '165918', (47, 53))	('RNF168', 'Gene', (47, 53))	('migration', 'CPA', (72, 81))	('knockdown', 'Var', (54, 63))	('impeded', 'NegReg', (64, 71))	('EC9706', 'CellLine', 'CVCL:E307', (97, 103))
35773	33493132	We also evaluated the correlation between RNF168 expression and epithelial-mesenchymal transition (EMT) in esophageal cancer cells, and found that RNF168 knockdown significantly increased the expression of epithelial n-cadherins, but reduced expression of fibronectin and alpha-catenins, the mesenchymal markers (Figure 4D).	('cancer', 'Disease', (118, 124))	('reduced', 'NegReg', (234, 241))	('fibronectin', 'Gene', '2335', (256, 267))	('reduced expression of fibronectin', 'Phenotype', 'HP:0032463', (234, 267))	('expression', 'MPA', (192, 202))	('RNF168', 'Gene', (42, 48))	('RNF168', 'Gene', '165918', (147, 153))	('RNF168', 'Gene', (147, 153))	('RNF168', 'Gene', '165918', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('knockdown', 'Var', (154, 163))	('fibronectin', 'Gene', (256, 267))	('alpha-catenins', 'Protein', (272, 286))	('epithelial n-cadherins', 'Protein', (206, 228))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('expression', 'MPA', (242, 252))	('increased', 'PosReg', (178, 187))
35778	33493132	To verify these results, we performed Western blot assays to measure the levels of several key proteins in the classic Wnt/beta-catenin signaling pathway, and found that upon RNF168 knockdown, WNT3A and beta-catenin were inhibited, whereas glycogen synthase kinase 3beta (GSK-3beta) was activated.	('beta-catenin', 'Gene', (203, 215))	('RNF168', 'Gene', (175, 181))	('beta-catenin', 'Gene', '1499', (123, 135))	('GSK-3beta', 'Gene', (272, 281))	('RNF168', 'Gene', '165918', (175, 181))	('Wnt', 'Gene', (119, 122))	('glycogen synthase kinase 3beta', 'Gene', '2932', (240, 270))	('WNT3A', 'Gene', (193, 198))	('glycogen synthase kinase 3beta', 'Gene', (240, 270))	('GSK-3beta', 'Gene', '2931', (272, 281))	('beta-catenin', 'Gene', '1499', (203, 215))	('Wnt', 'Gene', '89780', (119, 122))	('beta-catenin', 'Gene', (123, 135))	('knockdown', 'Var', (182, 191))	('inhibited', 'NegReg', (221, 230))	('WNT3A', 'Gene', '89780', (193, 198))
35781	33493132	A Western blot was performed to verify that silencing RNF168 activated the expression of ATM in esophageal squamous cell carcinoma cells (Figure 5G).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('RNF168', 'Gene', '165918', (54, 60))	('RNF168', 'Gene', (54, 60))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (96, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('ATM', 'Gene', (89, 92))	('activated', 'PosReg', (61, 70))	('esophageal squamous cell carcinoma', 'Disease', (96, 130))	('ATM', 'Gene', '472', (89, 92))	('silencing', 'Var', (44, 53))	('expression', 'MPA', (75, 85))
35794	33493132	In this study, we found that high RNF168 expression correlated with poor survival of the patients, representing a potential risk factor for patients with ESCC.	('high', 'Var', (29, 33))	('expression', 'MPA', (41, 51))	('poor', 'NegReg', (68, 72))	('RNF168', 'Gene', '165918', (34, 40))	('RNF168', 'Gene', (34, 40))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (140, 148))
35798	33493132	Functional enrichment analysis revealed that RNF168 overexpression may cause changes in Wnt signaling and DSB repair, and the related cellular components were chromosomes and sites of DNA damage, suggesting that RNF168 is mainly localized in the nucleus and plays a major role in DSB repair.	('changes', 'Reg', (77, 84))	('overexpression', 'Var', (52, 66))	('DSB repair', 'CPA', (106, 116))	('Wnt', 'Gene', (88, 91))	('RNF168', 'Gene', (212, 218))	('Wnt', 'Gene', '89780', (88, 91))	('RNF168', 'Gene', '165918', (45, 51))	('RNF168', 'Gene', (45, 51))	('RNF168', 'Gene', '165918', (212, 218))
35799	33493132	In this study, we also knocked down RNF168 expression to see how this influenced the malignant behavior of esophageal cancer cells, and found that proliferation was significantly inhibited.	('cancer', 'Disease', (118, 124))	('RNF168', 'Gene', '165918', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('knocked', 'Var', (23, 30))	('inhibited', 'NegReg', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('malignant behavior', 'CPA', (85, 103))	('expression', 'MPA', (43, 53))	('RNF168', 'Gene', (36, 42))	('influenced', 'Reg', (70, 80))	('proliferation', 'CPA', (147, 160))
35809	33493132	In our study, RNF168 knockdown inhibited fibronectin and alpha-catenins expression and activated n-cadherins expression, suggesting induction of EMT.	('fibronectin', 'Gene', (41, 52))	('expression', 'MPA', (109, 119))	('alpha-catenins', 'Protein', (57, 71))	('n-cadherins', 'Protein', (97, 108))	('EMT', 'CPA', (145, 148))	('expression', 'MPA', (72, 82))	('fibronectin', 'Gene', '2335', (41, 52))	('RNF168', 'Gene', '165918', (14, 20))	('RNF168', 'Gene', (14, 20))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (21, 30))	('activated', 'PosReg', (87, 96))
35816	33493132	Our results also show that RNF168 knockdown interferes with the proliferation and migration of esophageal cancer cells, and suppresses Wnt/beta-catenin signaling.	('Wnt', 'Gene', (135, 138))	('suppresses', 'NegReg', (124, 134))	('Wnt', 'Gene', '89780', (135, 138))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('RNF168', 'Gene', (27, 33))	('migration', 'CPA', (82, 91))	('beta-catenin', 'Gene', (139, 151))	('proliferation', 'CPA', (64, 77))	('cancer', 'Disease', (106, 112))	('RNF168', 'Gene', '165918', (27, 33))	('beta-catenin', 'Gene', '1499', (139, 151))	('knockdown', 'Var', (34, 43))	('interferes', 'NegReg', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
35922	33374639	Although the PPV of cSM2 diagnosis based on the JES classification is excellent, the sensitivity is very low, being particularly low for Type B2 vessels with AVA-large (6-12%).	('cSM2', 'Gene', '1674', (20, 24))	('cSM2', 'Gene', (20, 24))	('Type B2', 'Var', (137, 144))	('low', 'NegReg', (129, 132))
35928	33374639	According to our institution's data, the PPVs for comprehensive diagnosis (diagnosis based on non-ME and ME without EUS) for cEP/LPM in lesions <25 mm, >=25 to <50 mm, and >=50 mm are 94, 87, and 72%, respectively (p < 0.001) (Table 1).	('>=25 to <50 mm', 'Var', (152, 166))	('cEP/LPM', 'Disease', (125, 132))	('ME', 'Chemical', '-', (105, 107))	('ME', 'Chemical', '-', (98, 100))	('>=50 mm', 'Var', (172, 179))
35930	33374639	According to our institution's data, the PPV for the comprehensive diagnosis of cMM/SM1 in lesions <25 mm, >=25 to <50 mm, and >=50 mm in length is 44, 42, and 56%, respectively (Table 1).	('SM1', 'Gene', '7911', (84, 87))	('cMM', 'Gene', '1243', (80, 83))	('cMM', 'Gene', (80, 83))	('SM1', 'Gene', (84, 87))	('>=50 mm', 'Var', (127, 134))	('>=25 to <50 mm', 'Var', (107, 121))
35972	32375686	Biomarkers of these molecular alterations, in turn, may be useful in diagnosing cancers, particularly early, curable cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('alterations', 'Var', (30, 41))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
36081	32375686	This gene is located in the tylosis esophageal cancer locus on chromosome 17q25, and its deletion is associated with both familial and sporadic forms of ESCC.	('tylosis esophageal cancer', 'Disease', 'MESH:C536164', (28, 53))	('tylosis esophageal cancer', 'Disease', (28, 53))	('deletion', 'Var', (89, 97))	('associated', 'Reg', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('ESCC', 'Disease', (153, 157))
36117	32375686	The GEO accession numbers of the array data analyzed for this manuscript are GSE44021 for the mRNA data (available at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE44021) and GSE67268 for the miRNA data (available at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE67268).	('miR', 'Gene', '220972', (199, 202))	('miR', 'Gene', (199, 202))	('GSE44021', 'Var', (77, 85))
36189	30918584	However, the evidence for their use is sparse, and the literature suggests that they are no more effective than placebo; moreover, there is concern that benzodiazepines may impair a patients alertness and thus airway protection.	('alertness', 'Disease', (191, 200))	('airway protection', 'CPA', (210, 227))	('benzodiazepines', 'Var', (153, 168))	('benzodiazepines', 'Chemical', 'MESH:D001569', (153, 168))	('patients', 'Species', '9606', (182, 190))	('rat', 'Species', '10116', (59, 62))	('impair', 'NegReg', (173, 179))	('alertness', 'Disease', 'MESH:D000071064', (191, 200))
36261	30813301	Various stress factors, such as hypoxia, starvation, oxidative insults, changes in pH, Ca2+ depletion, hypoglycemia, ATP depletion, and viral infections, can disturb ER homeostasis.	('Ca2+', 'Chemical', 'MESH:D000069285', (87, 91))	('hypoglycemia', 'Disease', 'MESH:D007003', (103, 115))	('viral infections', 'Disease', (136, 152))	('viral infections', 'Disease', 'MESH:D001102', (136, 152))	('ER homeostasis', 'MPA', (166, 180))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('ATP', 'Chemical', 'MESH:D000255', (117, 120))	('disturb', 'Reg', (158, 165))	('changes', 'Var', (72, 79))	('hypoglycemia', 'Phenotype', 'HP:0001943', (103, 115))	('ATP', 'MPA', (117, 120))	('hypoxia', 'Disease', (32, 39))	('Ca2+ depletion', 'MPA', (87, 101))	('hypoglycemia', 'Disease', (103, 115))
36284	30813301	Hence, IRE1alpha via oligomerization induces XBP1 mRNA splicing, whereas dimerization induces RIDD.	('induces', 'Reg', (37, 44))	('oligomerization', 'Var', (21, 36))	('RIDD', 'Disease', (94, 98))	('RIDD', 'Disease', 'None', (94, 98))	('XBP1', 'Gene', (45, 49))	('IRE1alpha', 'Gene', (7, 16))	('IRE1alpha', 'Gene', '2081', (7, 16))	('XBP1', 'Gene', '7494', (45, 49))	('mRNA splicing', 'MPA', (50, 63))
36287	30813301	The phosphorylation of eIF2alpha blocks the recycling of eIF2alpha in its active GTP-bound state, needed for starting polypeptide chain synthesis, leading to the attenuation of general protein translation.	('attenuation', 'NegReg', (162, 173))	('GTP', 'Chemical', 'MESH:D006160', (81, 84))	('recycling', 'MPA', (44, 53))	('eIF2alpha', 'Gene', (57, 66))	('general protein translation', 'MPA', (177, 204))	('phosphorylation', 'Var', (4, 19))	('blocks', 'NegReg', (33, 39))
36295	30813301	Following UPR activation, ATF6alpha moves to the Golgi apparatus where it is processed by site-1 and site-2 proteases (S1P and S2P) and is transformed in a cytosolic fragment: cleaved ATF6alpha.	('tea', 'Gene', '11988', (111, 114))	('tea', 'Gene', (111, 114))	('ATF6alpha', 'Var', (26, 35))
36299	30813301	Levels of ERAD components, including ER degradation-enhancing alpha-mannosidase-like protein (EDEM), hydroxymethyl glutaryl-coenzyme A reductase degradation protein 1 (HRD1), and Herp, were found to be lower in ER stress-induced ATF6alpha-/- mouse embryonic fibroblasts (MEFs) compared to ATF6alpha+/+ MEFs.	('EDEM', 'Gene', '192193', (94, 98))	('HRD1', 'Gene', (168, 172))	('EDEM', 'Gene', (94, 98))	('Herp', 'Gene', '64209', (179, 183))	('lower', 'NegReg', (202, 207))	('Herp', 'Gene', (179, 183))	('MEFs', 'CellLine', 'CVCL:9115', (271, 275))	('HRD1', 'Gene', '74126', (168, 172))	('mouse', 'Species', '10090', (242, 247))	('MEFs', 'CellLine', 'CVCL:9115', (302, 306))	('ATF6alpha-/-', 'Var', (229, 241))	('ER degradation-enhancing alpha-mannosidase-like protein', 'Gene', '192193', (37, 92))
36328	30813301	ER-associated caspase-8 cleaves BAP31, an integral ER membrane protein forming the p20 fragment, thus abolishing its pro-survival function.	('BAP31', 'Gene', (32, 37))	('caspase-8', 'Gene', (14, 23))	('p20', 'Gene', (83, 86))	('abolishing', 'NegReg', (102, 112))	('caspase-8', 'Gene', '841', (14, 23))	('cleaves', 'Var', (24, 31))	('pro-survival function', 'CPA', (117, 138))	('p20', 'Gene', '51673', (83, 86))	('BAP31', 'Gene', '10134', (32, 37))
36339	30813301	It has been reported that knockdown of BiP, ATF6, ATF4, and XBP1s can resensitize cancer cells to chemotherapy.	('ATF4', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('BiP', 'Gene', (39, 42))	('ATF6', 'Gene', '22926', (44, 48))	('BiP', 'Gene', '3309', (39, 42))	('XBP1', 'Gene', '7494', (60, 64))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ATF4', 'Gene', '468', (50, 54))	('knockdown', 'Var', (26, 35))	('ATF6', 'Gene', (44, 48))	('XBP1', 'Gene', (60, 64))
36366	30813301	In the NCI H460 human lung cancer cell line, BDMC significantly induced apoptotic death as indicated by activation of caspase-3, -8, and -9, and increased ROS levels and Ca2+ production, together with increased ER stress associated proteins such as BiP, CHOP, IRE1(-alpha and -beta), ATF6 (-alpha and -beta), and caspase-4.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CHOP', 'Gene', '1649', (254, 258))	('BiP', 'Gene', '3309', (249, 252))	('Ca2+', 'Chemical', 'MESH:D000069285', (170, 174))	('lung cancer', 'Disease', (22, 33))	('increased', 'PosReg', (201, 210))	('ROS', 'Chemical', '-', (155, 158))	('induced', 'Reg', (64, 71))	('apoptotic death', 'CPA', (72, 87))	('BDMC', 'Var', (45, 49))	('ER stress associated', 'MPA', (211, 231))	('CHOP', 'Gene', (254, 258))	('ATF6', 'Gene', (284, 288))	('human', 'Species', '9606', (16, 21))	('IRE1', 'Gene', '2081', (260, 264))	('activation', 'PosReg', (104, 114))	('ROS levels', 'MPA', (155, 165))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('BDMC', 'Chemical', 'MESH:C034786', (45, 49))	('increased', 'PosReg', (145, 154))	('caspase-3, -8, and -9', 'Gene', '836;841;842', (118, 139))	('BiP', 'Gene', (249, 252))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('IRE1', 'Gene', (260, 264))	('caspase-4', 'Gene', (313, 322))	('Ca2+ production', 'MPA', (170, 185))	('ATF6', 'Gene', '22926', (284, 288))	('increased ROS levels', 'Phenotype', 'HP:0025464', (145, 165))	('caspase-4', 'Gene', '837', (313, 322))
36367	30813301	In the same human lung cancer cell line, DMC was also able to promote apoptosis by activating caspase-3, -8, and -9, and to promote apoptosis-inducing factor (AIF), Endo G and poly (ADP-ribose) polymerase (PARP) expression.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('DMC', 'Var', (41, 44))	('Endo G and poly (ADP-ribose) polymerase', 'Gene', '2021;142', (165, 204))	('DMC', 'Chemical', 'MESH:C050229', (41, 44))	('expression', 'MPA', (212, 222))	('PARP', 'Gene', (206, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('promote', 'PosReg', (62, 69))	('apoptosis-inducing', 'MPA', (132, 150))	('activating', 'PosReg', (83, 93))	('lung cancer', 'Disease', (18, 29))	('apoptosis', 'CPA', (70, 79))	('promote', 'PosReg', (124, 131))	('caspase-3, -8, and -9', 'Gene', '836;841;842', (94, 115))	('human', 'Species', '9606', (12, 17))	('PARP', 'Gene', '142', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
36369	30813301	In SW620 colon cancer cells, B63, a mono-carbonyl analogue of curcumin synthetized to increase its biological activity and bioavailability, showed significant anti-proliferative and pro-apoptotic effects by up-regulating the levels of Bad and Bim proteins and enhancing cytochrome c release from mitochondria.	('SW620', 'CellLine', 'CVCL:0547', (3, 8))	('biological activity', 'MPA', (99, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('cytochrome c', 'Gene', '54205', (270, 282))	('levels of', 'MPA', (225, 234))	('Bad', 'Protein', (235, 238))	('increase', 'PosReg', (86, 94))	('up-regulating', 'PosReg', (207, 220))	('Bim', 'Gene', '10018', (243, 246))	('Bim', 'Gene', (243, 246))	('colon cancer', 'Disease', 'MESH:D015179', (9, 21))	('enhancing', 'PosReg', (260, 269))	('bioavailability', 'MPA', (123, 138))	('cytochrome c', 'Gene', (270, 282))	('pro-apoptotic effects', 'CPA', (182, 203))	('anti-proliferative', 'CPA', (159, 177))	('B63', 'Var', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('colon cancer', 'Disease', (9, 21))	('curcumin', 'Chemical', 'MESH:D003474', (62, 70))
36383	30813301	The A375SM treatment with resveratrol induces the increase of p38, p53, and Bax expression levels and the decrease of Bcl-2 level.	('Bax', 'Gene', (76, 79))	('p38', 'Gene', '5594', (62, 65))	('decrease', 'NegReg', (106, 114))	('p53', 'Gene', (67, 70))	('Bcl-2', 'Gene', (118, 123))	('SM', 'Species', '226208', (8, 10))	('increase', 'PosReg', (50, 58))	('Bax', 'Gene', '581', (76, 79))	('Bcl-2', 'Gene', '596', (118, 123))	('p53', 'Gene', '7157', (67, 70))	('resveratrol', 'Chemical', 'MESH:D000077185', (26, 37))	('A375SM', 'Var', (4, 10))	('p38', 'Gene', (62, 65))
36385	30813301	In the HepG2 human hepatoblastoma cell line, resveratrol induces ER stress, increasing XBP1 splicing and CHOP expression; moreover, resveratrol intensifies palmitate-induced cell death of HepG2 cells and increases palmitate-induced ER stress.	('CHOP', 'Gene', (105, 109))	('XBP1', 'Gene', (87, 91))	('hepatoblastoma', 'Disease', (19, 33))	('intensifies', 'NegReg', (144, 155))	('hepatoblastoma', 'Disease', 'MESH:D018197', (19, 33))	('ER stress', 'MPA', (232, 241))	('increasing', 'PosReg', (76, 86))	('HepG2', 'CellLine', 'CVCL:0027', (7, 12))	('palmitate-induced', 'MPA', (214, 231))	('resveratrol', 'Var', (132, 143))	('HepG2', 'CellLine', 'CVCL:0027', (188, 193))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (19, 33))	('CHOP', 'Gene', '1649', (105, 109))	('palmitate-induced', 'MPA', (156, 173))	('palmitate', 'Chemical', 'MESH:D010168', (214, 223))	('XBP1', 'Gene', '7494', (87, 91))	('human', 'Species', '9606', (13, 18))	('resveratrol', 'Chemical', 'MESH:D000077185', (45, 56))	('increases', 'PosReg', (204, 213))	('resveratrol', 'Chemical', 'MESH:D000077185', (132, 143))	('palmitate', 'Chemical', 'MESH:D010168', (156, 165))
36392	30813301	Pretreatment of the cells with specific caspase-12 inhibitors but not caspase-4 inhibitors, or silencing caspase-4 or -12 by siRNA for 24 h prior to incubation of resveratrol for 24 h, significantly reduced the activation of caspase-3 and -9 originally induced by resveratrol.	('caspase', 'Gene', (225, 232))	('caspase', 'Gene', '835;837;841;842', (225, 232))	('caspase', 'Gene', (40, 47))	('caspase-4', 'Gene', '837', (105, 114))	('caspase', 'Gene', (105, 112))	('caspase', 'Gene', '835;837;841;842', (40, 47))	('caspase', 'Gene', '835;837;841;842', (105, 112))	('resveratrol', 'Chemical', 'MESH:D000077185', (163, 174))	('activation', 'PosReg', (211, 221))	('caspase-4', 'Gene', (70, 79))	('resveratrol', 'Chemical', 'MESH:D000077185', (264, 275))	('caspase', 'Gene', (70, 77))	('caspase-3 and -9', 'Gene', '836;842', (225, 241))	('silencing', 'Var', (95, 104))	('caspase-4', 'Gene', '837', (70, 79))	('caspase', 'Gene', '835;837;841;842', (70, 77))	('caspase-4', 'Gene', (105, 114))	('reduced', 'NegReg', (199, 206))
36401	30813301	Indeed, pterostilbene upregulates BiP, ATF6, p-PERK, p-eIF2alpha, and CHOP expression, and increases intracellular calcium levels in EC109 esophageal cancer cells.	('BiP', 'Gene', '3309', (34, 37))	('increases', 'PosReg', (91, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('calcium', 'Chemical', 'MESH:D002118', (115, 122))	('EC109', 'CellLine', 'CVCL:6898', (133, 138))	('esophageal cancer', 'Disease', (139, 156))	('CHOP', 'Gene', '1649', (70, 74))	('ATF6', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('p-PERK', 'Gene', (45, 51))	('upregulates', 'PosReg', (22, 33))	('p-eIF2alpha', 'Gene', (53, 64))	('pterostilbene', 'Var', (8, 21))	('CHOP', 'Gene', (70, 74))	('ATF6', 'Gene', '22926', (39, 43))	('pterostilbene', 'Chemical', 'MESH:C107773', (8, 21))	('BiP', 'Gene', (34, 37))	('increases intracellular calcium levels', 'Phenotype', 'HP:0003575', (91, 129))	('intracellular calcium levels', 'MPA', (101, 129))
36402	30813301	Silencing CHOP by siRNA significantly decreases the pterostilbene-induced apoptosis.	('decreases', 'NegReg', (38, 47))	('pterostilbene', 'Chemical', 'MESH:C107773', (52, 65))	('CHOP', 'Gene', '1649', (10, 14))	('pterostilbene-induced', 'MPA', (52, 73))	('CHOP', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))
36411	30813301	A GTE extract, Polyphenon E , caused severe and prolonged ER stress in human prostate cancer cells PC3 by activating the PERK signaling arm, as demonstrated by prolonged activation of p-eIF2alpha and ATF4.	('p-eIF2alpha', 'Protein', (184, 195))	('ATF4', 'Gene', (200, 204))	('activation', 'PosReg', (170, 180))	('prostate cancer', 'Disease', (77, 92))	('PERK signaling arm', 'Pathway', (121, 139))	('activating', 'PosReg', (106, 116))	('PC3', 'Gene', (99, 102))	('Polyphenon', 'Var', (15, 25))	('GTE', 'Chemical', '-', (2, 5))	('ATF4', 'Gene', '468', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Polyphenon E', 'Chemical', 'MESH:C472086', (15, 27))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('PC3', 'Gene', '3853', (99, 102))	('ER stress', 'MPA', (58, 67))	('human', 'Species', '9606', (71, 76))
36418	30813301	In this cell line, JP8 reduced cell viability and increased apoptosis more effectively than in normal mouse AML-12 hepatocyte cells.	('JP8', 'Var', (19, 22))	('AML', 'Disease', (108, 111))	('increased', 'PosReg', (50, 59))	('cell viability', 'CPA', (31, 45))	('apoptosis', 'CPA', (60, 69))	('JP8', 'Chemical', '-', (19, 22))	('reduced', 'NegReg', (23, 30))	('AML', 'Disease', 'MESH:D015470', (108, 111))	('mouse', 'Species', '10090', (102, 107))
36419	30813301	Treatment with ATG5 siRNA diminished JP8-induced cell death and in these conditions also stress response proteins such as IRE1alpha, CHOP, p-eIF2alpha were downregulated.	('JP8-induced', 'Var', (37, 48))	('CHOP', 'Gene', '1649', (133, 137))	('IRE1alpha', 'Gene', (122, 131))	('diminished', 'NegReg', (26, 36))	('IRE1alpha', 'Gene', '2081', (122, 131))	('ATG5', 'Gene', '9474', (15, 19))	('JP8', 'Chemical', '-', (37, 40))	('CHOP', 'Gene', (133, 137))	('p-eIF2alpha', 'Var', (139, 150))	('stress response proteins', 'MPA', (89, 113))	('ATG5', 'Gene', (15, 19))	('downregulated', 'NegReg', (156, 169))
36428	30813301	Especially, TTs were shown to exert anti-proliferative/pro-apoptotic effects, to affect cancer stem cell subpopulation, and to decrease the metastatic or angiogenic abilities of different cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('TTs', 'Chemical', 'MESH:D024508', (12, 15))	('decrease', 'NegReg', (127, 135))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('affect', 'Reg', (81, 87))	('TTs', 'Var', (12, 15))	('metastatic', 'CPA', (140, 150))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('anti-proliferative/pro-apoptotic effects', 'CPA', (36, 76))
36430	30813301	Another study, focusing on the molecular mechanisms of anticancer activity of gamma-TT in breast cancer cell lines, showed that in MDA-MB-231 and MCF-7 cells, gamma-TT induced apoptosis, at least in part, mediated by ER stress.	('cancer', 'Disease', (97, 103))	('gamma-TT', 'Chemical', 'MESH:C013649', (159, 167))	('gamma-TT', 'Chemical', 'MESH:C013649', (78, 86))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (131, 141))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('MCF-7', 'CellLine', 'CVCL:0031', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('apoptosis', 'CPA', (176, 185))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('gamma-TT', 'Var', (159, 167))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
36432	30813301	demonstrated that, in the MDA-MB-231 and MCF-7 breast cancer cell lines, gamma-TT induced ER stress-mediated apoptosis as demonstrated by gene expression microarray analysis.	('gamma-TT', 'Var', (73, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (41, 60))	('ER stress-mediated', 'MPA', (90, 108))	('MCF-7 breast cancer', 'Disease', (41, 60))	('gamma-TT', 'Chemical', 'MESH:C013649', (73, 81))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (26, 36))
36436	30813301	demonstrated that, in the HeLa human cervical cancer cell line, and in the MCF-7 human breast cancer cell line, gamma- and delta-TT induced apoptosis by triggering signals originating from ER stress.	('cervical cancer', 'Disease', 'MESH:D002583', (37, 52))	('cervical cancer', 'Disease', (37, 52))	('apoptosis', 'CPA', (140, 149))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('human', 'Species', '9606', (31, 36))	('gamma- and delta-TT', 'Chemical', '-', (112, 131))	('HeLa', 'CellLine', 'CVCL:0030', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('gamma-', 'Var', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('triggering', 'Reg', (153, 163))	('delta-TT', 'Var', (123, 131))	('human', 'Species', '9606', (81, 86))	('MCF-7', 'CellLine', 'CVCL:0031', (75, 80))
36438	30813301	gamma- and delta-TT induced the expression of caspase-12 in HeLa cells treated with delta-TT, and this activation was associated with caspase-9 cleavage.	('caspase', 'Gene', (46, 53))	('gamma- and delta-TT', 'Chemical', '-', (0, 19))	('caspase-9', 'Gene', '842', (134, 143))	('caspase', 'Gene', (134, 141))	('caspase', 'Gene', '835;837;841;842', (46, 53))	('HeLa', 'CellLine', 'CVCL:0030', (60, 64))	('delta-TT', 'Var', (11, 19))	('caspase', 'Gene', '835;837;841;842', (134, 141))	('caspase-9', 'Gene', (134, 143))	('delta-TT', 'Chemical', 'MESH:C082097', (11, 19))	('expression', 'MPA', (32, 42))	('delta-TT', 'Chemical', 'MESH:C082097', (84, 92))
36441	30813301	The authors found that delta-TT exerts a significant anti-proliferative/pro-apoptotic effect on both cell lines but not on normal melanocytes, demonstrating that, in both cell lines, delta-TT induced the expression of different ER stress markers such as BiP PERK, IRE1alpha, p-EIF2alpha, ATF4, and CHOP.	('induced', 'PosReg', (192, 199))	('CHOP', 'Gene', '1649', (298, 302))	('ATF4', 'Gene', (288, 292))	('delta-TT', 'Chemical', 'MESH:C082097', (23, 31))	('delta-TT', 'Var', (183, 191))	('CHOP', 'Gene', (298, 302))	('EIF2alpha', 'Gene', '83939', (277, 286))	('IRE1alpha', 'Gene', (264, 273))	('IRE1alpha', 'Gene', '2081', (264, 273))	('BiP', 'Gene', (254, 257))	('ATF4', 'Gene', '468', (288, 292))	('delta-TT', 'Chemical', 'MESH:C082097', (183, 191))	('BiP', 'Gene', '3309', (254, 257))	('expression', 'MPA', (204, 214))	('EIF2alpha', 'Gene', (277, 286))
36442	30813301	The cleavage of caspase-4 was also triggered by delta-TT in both melanoma cell lines.	('caspase-4', 'Gene', '837', (16, 25))	('delta-TT', 'Var', (48, 56))	('triggered', 'Reg', (35, 44))	('cleavage', 'MPA', (4, 12))	('delta-TT', 'Chemical', 'MESH:C082097', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('caspase-4', 'Gene', (16, 25))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
36458	30813301	CHOP knockdown, indeed, partly reversed the gartanin-induced reduction in AR protein expression, suggesting a possible interplay between UPR activation and AR signaling.	('AR', 'Gene', '367', (156, 158))	('knockdown', 'Var', (5, 14))	('CHOP', 'Gene', '1649', (0, 4))	('reduction', 'NegReg', (61, 70))	('AR', 'Gene', '367', (74, 76))	('CHOP', 'Gene', (0, 4))
36467	30813301	In human breast cancer cell lines, MCF-7 and MDA-MB 231, pimpinelol, a linear sequiterpene lactone from Pimpinella haussknechtii, has been shown to induce apoptosis by increasing protein aggregation and ER stress, as demonstrated by fluorescence microscopy analysis and by mRNA expression of ATF4, CHOP, GADD34, and tribbles-related protein 3 (TRIB3).	('ATF4', 'Gene', '468', (292, 296))	('human', 'Species', '9606', (3, 8))	('GADD34', 'Gene', '23645', (304, 310))	('TRIB3', 'Gene', '57761', (344, 349))	('tribbles-related protein 3', 'Gene', (316, 342))	('lactone', 'Chemical', 'MESH:D007783', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('apoptosis', 'CPA', (155, 164))	('CHOP', 'Gene', '1649', (298, 302))	('TRIB3', 'Gene', (344, 349))	('pimpinelol', 'Var', (57, 67))	('tribbles-related protein 3', 'Gene', '57761', (316, 342))	('pimpinelol', 'Chemical', '-', (57, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('increasing', 'PosReg', (168, 178))	('CHOP', 'Gene', (298, 302))	('MCF-7', 'CellLine', 'CVCL:0031', (35, 40))	('sequiterpene', 'Chemical', '-', (78, 90))	('protein', 'MPA', (179, 186))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('GADD34', 'Gene', (304, 310))	('induce', 'PosReg', (148, 154))	('breast cancer', 'Disease', (9, 22))	('ATF4', 'Gene', (292, 296))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (45, 55))
36478	30813301	In addition, SM reduces c-Jun protein expression, which is a target of miR-216b, correlated to the induction of the cleavage of caspase-3 and PARP.	('PARP', 'Gene', '142', (142, 146))	('cleavage', 'MPA', (116, 124))	('miR-216b', 'Chemical', '-', (71, 79))	('caspase-3', 'Gene', (128, 137))	('c-Jun protein expression', 'MPA', (24, 48))	('reduces', 'NegReg', (16, 23))	('PARP', 'Gene', (142, 146))	('miR-216b', 'Var', (71, 79))	('caspase-3', 'Gene', '836', (128, 137))	('SM', 'Species', '226208', (13, 15))
36481	30813301	In their study, the authors demonstrated that the silencing of BiP and CHOP by siRNA reversed the augmented ER stress-related protein expression by PD and reduced ER stress-induced apoptosis in cervical cancer cells.	('ER stress-related protein expression', 'MPA', (108, 144))	('PD', 'Disease', 'MESH:D010300', (148, 150))	('reduced', 'NegReg', (155, 162))	('cervical cancer', 'Disease', (194, 209))	('cervical cancer', 'Disease', 'MESH:D002583', (194, 209))	('CHOP', 'Gene', (71, 75))	('silencing', 'Var', (50, 59))	('BiP', 'Gene', (63, 66))	('ER stress-induced', 'MPA', (163, 180))	('BiP', 'Gene', '3309', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('CHOP', 'Gene', '1649', (71, 75))
36497	30813301	Western blot analysis showed increased expression of p-PERK, p-eIF2alpha, ATF4, CHOP, and p-ATF2 proteins in 7-AB-treated cells.	('ATF2', 'Gene', '1386', (92, 96))	('ATF4', 'Gene', (74, 78))	('CHOP', 'Gene', (80, 84))	('proteins', 'Protein', (97, 105))	('7-AB', 'Chemical', 'MESH:C000626381', (109, 113))	('increased', 'PosReg', (29, 38))	('p-eIF2alpha', 'Var', (61, 72))	('ATF2', 'Gene', (92, 96))	('p-PERK', 'Var', (53, 59))	('ATF4', 'Gene', '468', (74, 78))	('expression', 'MPA', (39, 49))	('CHOP', 'Gene', '1649', (80, 84))
36506	30813301	In cancer cells, different conditions, such as hypoxia and lack of glucose, can lead to ER perturbation with an impact on protein folding in the ER, resulting in the accumulation of unfolded proteins, known as ER stress.	('lead to', 'Reg', (80, 87))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('impact', 'Reg', (112, 118))	('perturbation', 'Var', (91, 103))	('glucose', 'Chemical', 'MESH:D005947', (67, 74))	('hypoxia', 'Disease', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('protein folding', 'MPA', (122, 137))	('cancer', 'Disease', (3, 9))	('accumulation', 'PosReg', (166, 178))	('unfolded proteins', 'MPA', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
36512	30813301	Although knockdown of BiP by siRNA increases cell death in vitro, this may be difficult to reach in vivo and alternative approaches aimed at inhibiting GRP78 may be more effective as therapeutic strategies.	('BiP', 'Gene', '3309', (22, 25))	('knockdown', 'Var', (9, 18))	('GRP78', 'Gene', '3309', (152, 157))	('GRP78', 'Gene', (152, 157))	('cell death', 'CPA', (45, 55))	('BiP', 'Gene', (22, 25))
36527	30191522	Phase I Study Combining the Aurora Kinase A Inhibitor Alisertib with mFOLFOX in Gastrointestinal Cancer Overexpression and cellular miss-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling.	('miss-localization', 'Var', (132, 149))	('gastrointestinal cancers', 'Disease', (180, 204))	('chromosomal instability', 'Phenotype', 'HP:0040012', (216, 239))	('Aurora Kinase A', 'Gene', '6790', (28, 43))	('AURKA', 'Gene', (170, 175))	('pro-apoptotic signaling', 'Pathway', (302, 325))	('activation', 'PosReg', (241, 251))	('chromosomal instability', 'CPA', (216, 239))	('Gastrointestinal Cancer', 'Disease', (80, 103))	('mFOLFOX', 'Chemical', '-', (69, 76))	('oncogenic pathways', 'Pathway', (264, 282))	('Aurora Kinase A', 'Gene', (28, 43))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (180, 203))	('Gastrointestinal Cancer', 'Disease', 'MESH:D004067', (80, 103))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('Gastrointestinal Cancer', 'Phenotype', 'HP:0007378', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Alisertib', 'Chemical', 'MESH:C550258', (54, 63))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (180, 204))	('inhibition', 'NegReg', (288, 298))	('aurora kinase A', 'Gene', (153, 168))	('aurora kinase A', 'Gene', '6790', (153, 168))
36528	30191522	Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death.	('mitotic delays', 'CPA', (27, 41))	('p73', 'Gene', '7161', (96, 99))	('severe chromosome congression', 'CPA', (43, 72))	('p73', 'Gene', (96, 99))	('AURKA', 'Gene', (14, 19))	('p53', 'Gene', (92, 95))	('activation', 'PosReg', (78, 88))	('Inhibition', 'Var', (0, 10))	('cell death', 'CPA', (111, 121))	('p53', 'Gene', '7157', (92, 95))
36540	30191522	Because AURKA is required for cytokinesis, inhibition of AURKA causes spindle pole and chromosome congression defects leading to aneuploidy, which is then followed by cell death.	('leading to', 'Reg', (118, 128))	('inhibition', 'Var', (43, 53))	('aneuploidy', 'Disease', 'MESH:D000782', (129, 139))	('chromosome congression defects', 'Disease', 'MESH:D002869', (87, 117))	('chromosome congression defects', 'Disease', (87, 117))	('aneuploidy', 'Disease', (129, 139))	('AURKA', 'Gene', (57, 62))
36541	30191522	Knockdown of AURKA was shown to suppress centrosome maturation; in mice, genetic ablation or null mutation of AURKA caused mitotic arrest and embryonic death.	('embryonic death', 'Disease', (142, 157))	('null mutation', 'Var', (93, 106))	('mitotic arrest', 'Disease', (123, 137))	('mitotic arrest', 'Disease', 'MESH:D006323', (123, 137))	('centrosome maturation', 'CPA', (41, 62))	('AURKA', 'Gene', (110, 115))	('genetic ablation', 'Var', (73, 89))	('embryonic death', 'Disease', 'MESH:D003643', (142, 157))	('mice', 'Species', '10090', (67, 71))
36544	30191522	Overexpression or amplification of AURKA has been identified in several solid malignancies, including colorectal, gastric, esophageal, liver, and pancreas cancers.	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	('pancreas cancers', 'Disease', 'MESH:D010190', (146, 162))	('malignancies', 'Disease', (78, 90))	('esophageal', 'Disease', (123, 133))	('AURKA', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal', 'Disease', (102, 112))	('gastric', 'Disease', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('identified', 'Reg', (50, 60))	('amplification', 'Var', (18, 31))	('pancreas cancers', 'Disease', (146, 162))	('liver', 'Disease', (135, 140))
36610	30191522	Our preclinical data showed that inhibiting AURKA in combination with platinum-based chemotherapies significantly decreased cell viability and survival, as well as significantly inhibited xenograft tumor growth in multiple gastrointestinal cancer models compared to either single agent alone, thus, suggesting a potential synergistic treatment combination.	('platinum', 'Chemical', 'MESH:D010984', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumor growth in multiple gastrointestinal cancer', 'Phenotype', 'HP:0200008', (198, 246))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('inhibited', 'NegReg', (178, 187))	('inhibiting', 'Var', (33, 43))	('decreased', 'NegReg', (114, 123))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (223, 246))	('men', 'Species', '9606', (339, 342))	('tumor', 'Disease', (198, 203))	('cancer', 'Disease', (240, 246))	('AURKA', 'Gene', (44, 49))
36643	28789354	In addition, E2F1, E2F2 and MYC were associated with the cell cycle, which was the most significantly enriched function and pathway in EC.	('E2F1', 'Var', (13, 17))	('cell cycle', 'CPA', (57, 67))	('associated', 'Reg', (37, 47))	('E2F2 and MYC', 'Gene', '1870;4609', (19, 31))
36648	28789354	miRNAs, a class of endogenous short non-protein-coding RNA molecules, bind to their target sites within the mRNA molecules via base-pairing with complementary sequences at a post-transcriptional level, and thus certain miRNAs are considered to be oncogenes or tumor suppressor genes.	('tumor', 'Disease', (260, 265))	('base-pairing', 'Var', (127, 139))	('bind', 'Interaction', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('miR', 'Gene', (0, 3))	('miR', 'Gene', (219, 222))	('miR', 'Gene', '22877', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('miR', 'Gene', '22877', (219, 222))
36668	28789354	miRNAs with the cutoff criteria of log2fold change (FC) >1 and P<0.05 were considered to be significantly differentially expressed.	('miR', 'Gene', (0, 3))	('log2fold', 'Var', (35, 43))	('miR', 'Gene', '22877', (0, 3))
36681	28789354	In the network, 5 genes including Notch homolog 1 (NOTCH1), fibrinogen gamma chain (FGG), fibrinogen alpha chain (FGA), and fibrinogen beta chain (FGB) were modulated by miR-144; while 6 genes including AKT serine/threonine kinase 1 (AKT1), matrix metalloproteinase (MMP)9, and MMP2 were modulated by miR-451.	('fibrinogen alpha chain', 'Gene', (90, 112))	('FGG', 'Gene', '2266', (84, 87))	('AKT1', 'Gene', '207', (234, 238))	('AKT serine/threonine kinase 1', 'Gene', (203, 232))	('FGB', 'Gene', '2244', (147, 150))	('fibrinogen alpha chain', 'Gene', '2243', (90, 112))	('miR-144', 'Var', (170, 177))	('FGG', 'Gene', (84, 87))	('fibrinogen beta chain', 'Gene', '2244', (124, 145))	('Notch homolog 1', 'Gene', (34, 49))	('AKT1', 'Gene', (234, 238))	('modulated', 'Reg', (157, 166))	('fibrinogen gamma chain', 'Gene', (60, 82))	('FGA', 'Gene', '2243', (114, 117))	('fibrinogen beta chain', 'Gene', (124, 145))	('FGB', 'Gene', (147, 150))	('FGA', 'Gene', (114, 117))	('NOTCH1', 'Gene', (51, 57))	('matrix metalloproteinase (MMP)9', 'Gene', '4318', (241, 272))	('AKT serine/threonine kinase 1', 'Gene', '207', (203, 232))	('Notch homolog 1', 'Gene', '4851', (34, 49))	('NOTCH1', 'Gene', '4851', (51, 57))	('fibrinogen gamma chain', 'Gene', '2266', (60, 82))
36682	28789354	A total of 11 genes, including v-myc avian myelocytomatosis viral oncogene homolog (c-MYC; MYC), E2F transcription factor (E2F)1, and E2F2 were modulated by miR-98.	('c-MYC', 'Gene', '4609', (84, 89))	('E2F)1', 'Gene', '1869', (123, 128))	('c-MYC', 'Gene', (84, 89))	('miR-98', 'Var', (157, 163))	('E2F2', 'Gene', (134, 138))	('modulated', 'Reg', (144, 153))	('v-myc avian myelocytomatosis viral oncogene homolog', 'Gene', '4609', (31, 82))
36683	28789354	A total of 3 genes, including peroxisome proliferator-activated receptor alpha (PPARA) and Kruppel-like factor 4 (KLF4) were modulated by miR-10b.	('modulated', 'Reg', (125, 134))	('Kruppel-like factor 4', 'Gene', '9314', (91, 112))	('PPARA', 'Gene', (80, 85))	('miR-10b', 'Var', (138, 145))	('Kruppel-like factor 4', 'Gene', (91, 112))	('PPARA', 'Gene', '5465', (80, 85))	('KLF4', 'Gene', (114, 118))	('KLF4', 'Gene', '9314', (114, 118))
36685	28789354	The results demonstrated that the top 3 enriched GO terms were cell cycle (E2F1, E2F2 and MYC), blood vessel development (AKT1, NOTCH1 and MMP2) and vasculature (AKT1, NOTCH1 and MMP2; Table III); and the top 3 enriched KEGG pathways were cell cycle (E2F1, E2F2 and MYC), complement and coagulation cascades (FGG, FGA and FGB) and epidermal growth factor receptor signaling pathway (AKT1, CDKN1A and MYC; Table IV).	('E2F2 and MYC', 'Gene', '1870;4609', (81, 93))	('NOTCH1', 'Gene', '4851', (168, 174))	('FGG', 'Gene', (309, 312))	('blood vessel development', 'CPA', (96, 120))	('NOTCH1', 'Gene', '4851', (128, 134))	('FGB', 'Gene', '2244', (322, 325))	('AKT1', 'Gene', '207', (162, 166))	('epidermal growth factor receptor', 'Gene', (331, 363))	('AKT1', 'Gene', '207', (122, 126))	('CDKN1A', 'Gene', '1026', (389, 395))	('CDKN1A', 'Gene', (389, 395))	('cell cycle', 'CPA', (239, 249))	('epidermal growth factor receptor', 'Gene', '1956', (331, 363))	('E2F2 and MYC', 'Gene', '1870;4609', (257, 269))	('cell cycle', 'CPA', (63, 73))	('E2F1', 'Var', (251, 255))	('AKT1', 'Gene', '207', (383, 387))	('AKT1', 'Gene', (162, 166))	('FGB', 'Gene', (322, 325))	('FGG', 'Gene', '2266', (309, 312))	('FGA', 'Gene', '2243', (314, 317))	('FGA', 'Gene', (314, 317))	('AKT1', 'Gene', (122, 126))	('NOTCH1', 'Gene', (168, 174))	('AKT1', 'Gene', (383, 387))	('NOTCH1', 'Gene', (128, 134))
36712	28789354	miR-98 belongs to the lethal-7 (let-7) family of miRNAs (let-7f, let-7d, miR-98 and let-7g).	('let-7d', 'Gene', '406886', (65, 71))	('miR', 'Gene', '22877', (73, 76))	('let-7g', 'Gene', '406890', (84, 90))	('miR', 'Gene', '22877', (49, 52))	('miR', 'Gene', (0, 3))	('miR', 'Gene', '22877', (0, 3))	('miR', 'Gene', (49, 52))	('let-7f', 'Var', (57, 63))	('miR', 'Gene', (73, 76))	('let-7g', 'Gene', (84, 90))	('let-7d', 'Gene', (65, 71))
36715	28789354	Therefore, by targeting MYC, E2F1 and E2F2, miR-98 may be involved in the cell cycle of EC cells, and act as novel biomarker for EC.	('E2F2', 'Var', (38, 42))	('involved', 'Reg', (58, 66))	('MYC', 'Protein', (24, 27))	('E2F1', 'Gene', (29, 33))	('EC cells', 'CellLine', 'CVCL:E577', (88, 96))	('targeting', 'Reg', (14, 23))	('miR-98', 'Gene', (44, 50))
36717	28789354	Hsu et al indicated that miR-363 served a key function in the increment of gastric carcinogenesis via targeting c-Myc promotor binding protein 1, a negative regulator of MYC.	('targeting', 'Reg', (102, 111))	('Myc', 'Gene', '4609', (114, 117))	('miR-363', 'Var', (25, 32))	('gastric carcinogenesis', 'Disease', (75, 97))	('Myc', 'Gene', (114, 117))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (75, 97))
36726	28789354	In conclusion, the present study demonstrated that the biomarkers (miR-144, and miR-451 and miR-10b) screened by Xie et al may serve an important function in the regulation of EC by targeting NOTCH, fibrinogen, AKT1, MMPs, PPARA and KLF4.	('miR-10b', 'Var', (92, 99))	('MMPs', 'Gene', '4313;17390;4318', (217, 221))	('PPARA', 'Gene', (223, 228))	('miR-451', 'Var', (80, 87))	('KLF4', 'Gene', '9314', (233, 237))	('MMPs', 'Gene', (217, 221))	('KLF4', 'Gene', (233, 237))	('targeting', 'Reg', (182, 191))	('AKT1', 'Gene', '207', (211, 215))	('PPARA', 'Gene', '5465', (223, 228))	('fibrinogen', 'Gene', '2244', (199, 209))	('AKT1', 'Gene', (211, 215))	('fibrinogen', 'Gene', (199, 209))	('NOTCH', 'Protein', (192, 197))
36740	28345328	Although the major risk factors associated with esophageal cancer in the Asian cancer belt have been poorly understood (Igissinov et al, 2013), poor nutritional statutes, low intake of fruits and vegetables, low socioeconomic status smoking and excessive alcohol consumption are known as putative risk factors (Asombang et al, 2016; Pennathur et al, 2013).	('esophageal cancer', 'Disease', (48, 65))	('excessive alcohol', 'Phenotype', 'HP:0030955', (245, 262))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('low', 'NegReg', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('alcohol', 'Chemical', 'MESH:D000438', (255, 262))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('low socioeconomic', 'Var', (208, 225))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
36785	28463955	Furthermore, in the ESCC xenograft model, CPS-C significantly enhanced the anti-cancer effects and apoptosis of oxaliplatin.	('CPS-C', 'Chemical', 'MESH:C511098', (42, 47))	('SCC', 'Gene', (21, 24))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('SCC', 'Gene', '6317', (21, 24))	('enhanced', 'PosReg', (62, 70))	('apoptosis', 'CPA', (99, 108))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('CPS-C', 'Var', (42, 47))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (112, 123))	('cancer', 'Disease', (80, 86))
36803	28463955	The results of our study suggested that CPS-C serves as a novel anti-tumor agent to sensitize ESCC cells to oxaliplatin and that the combination therapy of CPS-C and oxaliplatin may be beneficial for patients with ESCC.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('SCC', 'Gene', '6317', (95, 98))	('patients', 'Species', '9606', (200, 208))	('tumor', 'Disease', (69, 74))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (108, 119))	('CPS-C', 'Var', (156, 161))	('combination', 'Interaction', (133, 144))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (166, 177))	('SCC', 'Gene', (215, 218))	('CPS-C', 'Chemical', 'MESH:C511098', (156, 161))	('CPS-C', 'Chemical', 'MESH:C511098', (40, 45))	('SCC', 'Gene', (95, 98))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('SCC', 'Phenotype', 'HP:0002860', (215, 218))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('SCC', 'Gene', '6317', (215, 218))
36808	28463955	PI3 kinase p110alpha (C73F8) rabbit mAb (#4249), phospho-Akt (Ser473) (D9E) rabbit mAb (#4060), phospho-mTOR (Ser2448) (D9C2) rabbit mAb (#5536), phospho-mTOR (Ser2448) (49F9) rabbit mAb (IHC Specific) (#2976), Bcl-2 (124) mouse mAb (#15071), Bcl-xL (54H6) rabbit mAb (#2764), Bax (D2E11) rabbit mAb (#5023), and caspase-3 antibody (#9662) were purchased from Cell Signaling Technology (Danvers, Massachusetts, USA).	('rabbit', 'Species', '9986', (176, 182))	('rabbit', 'Species', '9986', (76, 82))	('mouse', 'Species', '10090', (223, 228))	('rabbit', 'Species', '9986', (289, 295))	('Akt', 'Gene', '207', (57, 60))	('rabbit', 'Species', '9986', (29, 35))	('#15071', 'Var', (234, 240))	('#2764', 'Var', (269, 274))	('rabbit', 'Species', '9986', (126, 132))	('Akt', 'Gene', (57, 60))	('rabbit', 'Species', '9986', (257, 263))
36845	28463955	The results showed that oxaliplatin combined with CPS-C decreased the expressions of PI3K, phospho-Akt, phospho-mTOR, Bcl-2, and Bcl-XL, but increased the expression of Bax and caspase-3 significantly compared to oxaliplatin-only treatment, while no differences were observed in either the CPS-C group or the control group in TE-1 (Figure 5A) and TE-2 (Figure 5B) cells, respectively.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (24, 35))	('increased', 'PosReg', (141, 150))	('Bcl-XL', 'Gene', '598', (129, 135))	('expressions', 'MPA', (70, 81))	('Bcl-XL', 'Gene', (129, 135))	('decreased', 'NegReg', (56, 65))	('Akt', 'Gene', (99, 102))	('CPS-C', 'Chemical', 'MESH:C511098', (290, 295))	('PI3K', 'Protein', (85, 89))	('Akt', 'Gene', '207', (99, 102))	('CPS-C', 'Var', (50, 55))	('caspase-3', 'Protein', (177, 186))	('CPS-C', 'Chemical', 'MESH:C511098', (50, 55))	('Bax', 'Protein', (169, 172))	('TE-2', 'Gene', '8260', (347, 351))	('Bcl-2', 'Protein', (118, 123))	('expression', 'MPA', (155, 165))	('TE-2', 'Gene', (347, 351))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (213, 224))
36847	28463955	The results showed that tumor volumes and weight in the CPS-C + oxaliplatin group were reduced significantly compared to the oxaliplatin-only group, while no differences were observed in either the CPS-C group or the control group (Figure 6A, 6B).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('CPS-C +', 'Var', (56, 63))	('CPS-C', 'Chemical', 'MESH:C511098', (56, 61))	('tumor', 'Disease', (24, 29))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (125, 136))	('reduced', 'NegReg', (87, 94))	('CPS-C', 'Chemical', 'MESH:C511098', (198, 203))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
36852	28463955	The expressions of PI3K, phospho-Akt, and phospho-mTOR were decreased significantly in the CPS-C + oxaliplatin group compared to the oxaliplatin-only group (Figure 7B).	('decreased', 'NegReg', (60, 69))	('Akt', 'Gene', '207', (33, 36))	('PI3K', 'Pathway', (19, 23))	('expressions', 'MPA', (4, 15))	('CPS-C +', 'Var', (91, 98))	('phospho-mTOR', 'CPA', (42, 54))	('Akt', 'Gene', (33, 36))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (99, 110))	('CPS-C', 'Chemical', 'MESH:C511098', (91, 96))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (133, 144))
36856	28463955	Oxaliplatin [(trans-R,R)1,2-diaminocyclohexaneoxalatoplatinum (II), C8H14N2O4Pt] is equally or more effective but less toxic than cisplatin, and is a promising agent for combination chemotherapy in treating ESCC.	('H14N2', 'Species', '1346489', (70, 75))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (0, 11))	('SCC', 'Gene', '6317', (208, 211))	('SCC', 'Gene', (208, 211))	('C8H14N2O4Pt]', 'Var', (68, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('SCC', 'Phenotype', 'HP:0002860', (208, 211))	('2-diaminocyclohexaneoxalatoplatinum', 'Disease', (26, 61))	('2-diaminocyclohexaneoxalatoplatinum', 'Disease', 'MESH:D014923', (26, 61))
36863	28463955	The results indicated the pharmacologic advantage of CPS-C in enhancing oxaliplatin-induced cytotoxicity, but found little effect of CPS-C on ESCC and normal human esophageal epithelial cells.	('SCC', 'Gene', (143, 146))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (72, 83))	('cytotoxicity', 'Disease', (92, 104))	('human', 'Species', '9606', (158, 163))	('SCC', 'Gene', '6317', (143, 146))	('CPS-C', 'Var', (53, 58))	('enhancing', 'PosReg', (62, 71))	('CPS-C', 'Chemical', 'MESH:C511098', (133, 138))	('cytotoxicity', 'Disease', 'MESH:D064420', (92, 104))	('CPS-C', 'Chemical', 'MESH:C511098', (53, 58))
36864	28463955	We investigated the mechanisms by which CPS-C increases oxaliplatin sensitivity in ESCC and found that CPS-C promoted the effect of oxaliplatin by inducing apoptosis significantly and modulating the PI3K/Akt/mTOR pathway.	('inducing', 'Reg', (147, 155))	('SCC', 'Gene', '6317', (84, 87))	('promoted', 'PosReg', (109, 117))	('oxaliplatin sensitivity', 'MPA', (56, 79))	('CPS-C', 'Chemical', 'MESH:C511098', (103, 108))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (56, 67))	('increases', 'PosReg', (46, 55))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (132, 143))	('Akt', 'Gene', (204, 207))	('modulating', 'Reg', (184, 194))	('CPS-C', 'Chemical', 'MESH:C511098', (40, 45))	('effect of oxaliplatin', 'MPA', (122, 143))	('SCC', 'Gene', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('Akt', 'Gene', '207', (204, 207))	('apoptosis', 'CPA', (156, 165))	('CPS-C', 'Var', (103, 108))
36868	28463955	Overexpression of PI3K and the PI3K signaling pathway may cause cancer.	('PI3K signaling pathway', 'Pathway', (31, 53))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cause', 'Reg', (58, 63))	('PI3K', 'Var', (18, 22))	('cancer', 'Disease', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
36894	23179413	In electrochemotherapy (ECT), short and intense electric pulses are delivered to tumor nodules in vivo using appropriate electrodes to transiently electroporate the membranes of cancer cells and thus enable direct access to the cytosol (Fig.	('enable', 'Reg', (200, 206))	('rat', 'Species', '10116', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('electroporate', 'Var', (147, 160))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
37021	23179413	Finally, gene therapy to the brain may also be envisaged, in particular for Parkinson's disease.	('gene', 'Var', (9, 13))	("Parkinson's disease", 'Disease', (76, 95))	("Parkinson's disease", 'Disease', 'MESH:D010300', (76, 95))
37110	33115454	Mutations in normal tissues:some diagnostic and clinical implications It has long been known that mutations are at the core of many diseases, most notably cancer.	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
37112	33115454	The prevailing cancer development hypothesis posits that cancer originates from mutations in cancer-driving genes that accumulate in tissues over time.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
37113	33115454	These mutations then confer special characteristics to cancer cells, known as the hallmarks of cancer.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', (55, 61))
37114	33115454	Mutations in specific driver genes can lead to the formation of cancerous subclones and mutation risk increases with age.	('cancerous', 'Disease', 'MESH:D009369', (64, 73))	('lead to', 'Reg', (39, 46))	('age', 'Gene', '5973', (117, 120))	('Mutations', 'Var', (0, 9))	('age', 'Gene', (117, 120))	('cancerous', 'Disease', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
37115	33115454	New research has revealed an unexpectedly large number of mutations in normal tissues; these findings could have significant implications to the understanding of the pathobiology of cancer and for disease diagnosis and therapy.	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('implications', 'Reg', (125, 137))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))
37116	33115454	Here, we discuss how the prevalence of mutations in normal tissues provides novel and relevant insights about clonal development in cancer and other diseases.	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (39, 48))
37117	33115454	Specifically, this review will focus on discussing mutations in normal tissues in the context of developing specific, circulating tumor DNA (ctDNA) tests for cancer, and evaluating clonal hematopoiesis as a predictor of blood cancers and cardiovascular pathology, as well as their implications to the phenomena of neural mosaicism in the context of Alzheimer's disease.	("Alzheimer's disease", 'Disease', (349, 368))	('mutations', 'Var', (51, 60))	('blood cancers', 'Disease', (220, 233))	('cardiovascular pathology', 'Phenotype', 'HP:0001626', (238, 262))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (349, 368))	('clonal hematopoiesis', 'Disease', 'MESH:C536227', (181, 201))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cardiovascular pathology', 'Disease', 'MESH:D002318', (238, 262))	('cardiovascular pathology', 'Disease', (238, 262))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('blood cancers', 'Disease', 'MESH:D007022', (220, 233))	('blood cancers', 'Phenotype', 'HP:0001909', (220, 233))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('clonal hematopoiesis', 'Disease', (181, 201))	('cancer', 'Disease', (226, 232))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (349, 368))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
37118	33115454	In view of these new findings, the fundamental differences between the accumulation of genetic alterations in healthy, aging tissues compared to cancer and cardiovascular or neural diseases will need to be better delineated in the future.	('cancer', 'Disease', (145, 151))	('genetic alterations', 'Var', (87, 106))	('cardiovascular or neural diseases', 'Disease', 'MESH:D002318', (156, 189))	('cardiovascular or neural diseases', 'Disease', (156, 189))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
37119	33115454	In 1990, Fearon and Vogelstein presented a hypothesis, whereby cancer development is the result of accumulating mutations in some critical genes, occurring over years.	('mutations', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
37124	33115454	Even water and oxygen, fundamentally necessary for life, can significantly mutate DNA.	('DNA', 'Disease', (82, 85))	('mutate', 'Var', (75, 81))	('oxygen', 'Chemical', 'MESH:D010100', (15, 21))	('water', 'Chemical', 'MESH:D014867', (5, 10))
37128	33115454	Previously, genome sequencing technologies have been focused on determining cancer-related mutations from patients diagnosed clinically or through screening.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (91, 100))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
37129	33115454	However, now, there is great interest in turning these technologies and knowledge towards early detection which necessitates knowing exactly which mutations signify cancer and which mutations constitute benign passenger changes.	('mutations', 'Var', (147, 156))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
37135	33115454	The US Food and Drug Administration (FDA) has already approved a ctDNA test involving monitoring EGFR (epidermal growth factor receptor) mutations in the serum of non-small cell lung cancer patients to determine eligibility for the chemotherapy drug erlotinib, and another test to determine ctDNA residue after surgery has been granted breakthrough device status.	('lung cancer', 'Disease', (178, 189))	('patients', 'Species', '9606', (190, 198))	('EGFR', 'Gene', '1956', (97, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (167, 189))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (163, 189))	('mutations', 'Var', (137, 146))	('EGFR', 'Gene', (97, 101))	('epidermal growth factor receptor', 'Gene', (103, 135))	('erlotinib', 'Chemical', 'MESH:D000069347', (250, 259))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('epidermal growth factor receptor', 'Gene', '1956', (103, 135))
37140	33115454	A ctDNA test's success for early diagnosis is predicated on determining which mutations indicate cancer and which are associated with benign diseases, a task that is becoming more complicated as new research suggests that significant mutagenicity in normal tissues is the norm, not the exception.	('cancer', 'Disease', (97, 103))	('age', 'Gene', (237, 240))	('indicate', 'Reg', (88, 96))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('age', 'Gene', '5973', (237, 240))	('benign diseases', 'Disease', (134, 149))	('benign diseases', 'Disease', 'MESH:D009369', (134, 149))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
37141	33115454	Employing analyses of RNA sequence databases to identify somatic mutations, the team found many mutations generally associated with cancer as well as macroscopic clones (population of mutated cells descended from a common ancestor, visible without a microscope) in tissues without any cancer pathology.	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('mutations', 'Var', (96, 105))	('associated', 'Reg', (116, 126))
37144	33115454	Unsurprisingly, the number of these mutations increased with age and with cell proliferation rates; high cell turnover tissues such as the skin and esophagus had increased levels of mutations compared to the less proliferative brain and muscle cells.	('age', 'Gene', (61, 64))	('age', 'Gene', '5973', (61, 64))	('mutations', 'Var', (182, 191))	('increased', 'PosReg', (162, 171))
37148	33115454	Another study employed mathematical modeling of tumor development and determined that more than half of the mutations found in some cancers were present in the normal cell where the cancer began:the founder clone.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (132, 139))	('cancer', 'Disease', (132, 138))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
37150	33115454	The authors found that approximately 1% of normal colorectal crypts in middle age individuals contain a driver mutation, yet incidence of colorectal cancer is much lower, suggesting that these tumors are rare incidences of normal mutational processes in aging colorectal epithelium.	('age', 'Gene', (78, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('contain', 'Reg', (94, 101))	('tumors', 'Disease', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('colorectal cancer', 'Disease', (138, 155))	('age', 'Gene', '5973', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('mutation', 'Var', (111, 119))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))
37153	33115454	Other research with esophageal squamous cell carcinoma has further elucidated the underlying process influencing whether a mutation will lead to the formation of cancerous clones.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('mutation', 'Var', (123, 131))	('esophageal squamous cell carcinoma', 'Disease', (20, 54))	('lead to', 'Reg', (137, 144))	('cancerous', 'Disease', 'MESH:D009369', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (20, 54))	('cancerous', 'Disease', (162, 171))
37155	33115454	Most importantly, the team discovered that cancer-associated genes were mutated far more frequently in healthy esophagus samples than in healthy skin.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('mutated', 'Var', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
37156	33115454	Unsurprisingly, there was an increased number of mutations in both overall and in driver genes as well as a larger clone size on average in the tissue samples from older participants compared to younger participants.	('participants', 'Species', '9606', (170, 182))	('mutations', 'Var', (49, 58))	('age', 'Gene', (133, 136))	('age', 'Gene', '5973', (133, 136))	('participants', 'Species', '9606', (203, 215))
37159	33115454	Even though the esophagus does not receive the same mutagenic exposure to ultraviolet radiation compared to skin and has a tenth of the mutations compared to skin, it is still exposed to a significant number of mutagens through a human's varied diet.	('age', 'Gene', (214, 217))	('age', 'Gene', '5973', (214, 217))	('mutations', 'Var', (136, 145))	('age', 'Gene', (55, 58))	('age', 'Gene', '5973', (55, 58))	('human', 'Species', '9606', (230, 235))
37161	33115454	Previous investigations reported mutations in TP53 in more than 90% of esophageal squamous cell carcinoma (OSCC) cases.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('reported', 'Reg', (24, 32))	('TP53', 'Gene', '7157', (46, 50))	('mutations', 'Var', (33, 42))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('TP53', 'Gene', (46, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))
37163	33115454	Even though Marincorena's team detected a significant number of mutations in cancer-associated genes, their participants' tissues still appeared healthy.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('participants', 'Species', '9606', (108, 120))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
37166	33115454	Age-related mutational signatures were most prevalent in the healthy samples whereas mutational signatures associated with the cytidine deaminase APOBEC (an mRNA modifying enzyme) or alcohol were most commonly found in cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('Age', 'Gene', '5973', (0, 3))	('mutational', 'Var', (12, 22))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('alcohol', 'Chemical', 'MESH:D000438', (183, 190))	('cancer', 'Disease', (219, 225))	('Age', 'Gene', (0, 3))
37167	33115454	The studies with esophageal tissue provide compelling new information about the age-related accumulation of mutations and their transition to cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('mutations', 'Var', (108, 117))	('age', 'Gene', '5973', (80, 83))	('age', 'Gene', '5973', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('age', 'Gene', (80, 83))	('age', 'Gene', (22, 25))	('cancer', 'Disease', (142, 148))
37168	33115454	They also show the value of determining which specific gene mutations or mutational signatures most often lead to particular malignancies, crucial information for developing accurate ctDNA liquid biopsies for diagnosis as well as other related genetic tests.	('mutations', 'Var', (60, 69))	('lead to', 'Reg', (106, 113))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('malignancies', 'Disease', (125, 137))
37169	33115454	A study with paired peritoneal fluid and blood samples from women without cancer detected mutations in TP53 at low frequencies (< 0.01%) in 16 out the 17 participants.	('peritoneal fluid', 'Phenotype', 'HP:0030995', (20, 36))	('TP53', 'Gene', '7157', (103, 107))	('mutations', 'Var', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('TP53', 'Gene', (103, 107))	('women', 'Species', '9606', (60, 65))	('participants', 'Species', '9606', (154, 166))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
37171	33115454	Yet, researchers found mutations in some important proto-oncogene driver genes with a high mutant allele fraction including KRAS, PIK3CA, PTEN, ARID1A, andTP53 in 19 out 24 patients' endometriotic lesions.	('PIK3CA', 'Gene', (130, 136))	('ARID1A', 'Gene', '8289', (144, 150))	('endometriotic', 'Disease', (183, 196))	('ARID1A', 'Gene', (144, 150))	('PTEN', 'Gene', (138, 142))	('KRAS', 'Gene', (124, 128))	('PIK3CA', 'Gene', '5290', (130, 136))	('TP53', 'Gene', '7157', (155, 159))	('patients', 'Species', '9606', (173, 181))	('KRAS', 'Gene', '3845', (124, 128))	('PTEN', 'Gene', '5728', (138, 142))	('TP53', 'Gene', (155, 159))	('mutations', 'Var', (23, 32))
37173	33115454	A similar study with uterine lavage fluid samples from healthy women echoed these results with more than half of 95 healthy women having cancerous driver mutations, positively correlating mutations in cancer-causing genes with age and postmenopausal status.	('age', 'Gene', '5973', (227, 230))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('age', 'Gene', '5973', (32, 35))	('cancer', 'Disease', (201, 207))	('age', 'Gene', (32, 35))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('age', 'Gene', (227, 230))	('cancerous', 'Disease', (137, 146))	('cancer', 'Disease', (137, 143))	('women', 'Species', '9606', (63, 68))	('postmenopausal status', 'Phenotype', 'HP:0008209', (235, 256))	('mutations', 'Var', (154, 163))	('mutations', 'Var', (188, 197))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancerous', 'Disease', 'MESH:D009369', (137, 146))	('women', 'Species', '9606', (124, 129))
37175	33115454	TP53 mutations have been reported in histologically normal oral, bronchial, bladder, and esophageal epithelial tissues.	('TP53', 'Gene', '7157', (0, 4))	('age', 'Gene', '5973', (94, 97))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('age', 'Gene', (94, 97))
37176	33115454	KRAS mutations have also been detected in normal tissues adjacent to colorectal and lung cancers.	('colorectal and lung cancers', 'Disease', 'MESH:D015179', (69, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lung cancers', 'Phenotype', 'HP:0100526', (84, 96))	('mutations', 'Var', (5, 14))	('detected', 'Reg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
37181	33115454	A fascinating study showed a similar number of mutations in adult stem cells from small intestine, colon, and liver tissues even though there are very different incidences of these cancer in the general population.	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutations', 'Var', (47, 56))
37183	33115454	The extensive range of studies of mutations in normal tissues highlights the specificity challenges relevant to ctDNA test development and mutation classification, spanning a range of cancers and tissue types.	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancers', 'Disease', (184, 191))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (34, 43))
37184	33115454	Moreover, many of the mutations are present in multiple types of cancer, which would make it even more difficult to determine the tumor's tissue of origin after a positive ctDNA test.	('cancer', 'Disease', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutations', 'Var', (22, 31))	('present', 'Reg', (36, 43))	('tumor', 'Disease', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
37185	33115454	A complex net of biochemical, epigenetic, and environmental factors likely influences whether mutations remain harmless or a person develops cancer.	('influences', 'Reg', (75, 85))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
37187	33115454	In the meantime, the presence of mutations in normal tissues remains a major caveat to the development and specificity of a ctDNA test for the diagnosis of cancer.	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mutations', 'Var', (33, 42))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))
37190	33115454	For example, a recent study of peripheral blood cells obtained from 95 patients a mean of 6.3 years before AML diagnosis found that they had higher variant allele frequencies and greater clonal expansion compared to controls.	('variant', 'Var', (148, 155))	('AML', 'Phenotype', 'HP:0004808', (107, 110))	('AML', 'Disease', (107, 110))	('patients', 'Species', '9606', (71, 79))	('higher', 'PosReg', (141, 147))	('clonal expansion', 'CPA', (187, 203))	('AML', 'Disease', 'MESH:D015470', (107, 110))
37193	33115454	Thirty-nine percent of patients above age 50 in the pre-AML cohort had a driver mutation with a variant allele frequency greater than 10%, in contrast to only 4% of controls.	('patients', 'Species', '9606', (23, 31))	('AML', 'Phenotype', 'HP:0004808', (56, 59))	('AML', 'Disease', (56, 59))	('age', 'Gene', (38, 41))	('variant', 'Var', (96, 103))	('age', 'Gene', '5973', (38, 41))	('AML', 'Disease', 'MESH:D015470', (56, 59))	('mutation', 'Var', (80, 88))
37195	33115454	The researchers found clonal hematopoiesis increases with age, observing related somatic mutations in 10% of participants older than age 65.	('participants', 'Species', '9606', (109, 121))	('clonal hematopoiesis', 'Disease', (22, 42))	('hematopoiesis increases', 'Disease', (29, 52))	('age', 'Gene', (58, 61))	('age', 'Gene', (133, 136))	('clonal hematopoiesis', 'Disease', 'MESH:C536227', (22, 42))	('age', 'Gene', '5973', (133, 136))	('hematopoiesis increases', 'Disease', 'MESH:C536227', (29, 52))	('mutations', 'Var', (89, 98))	('age', 'Gene', '5973', (58, 61))
37202	33115454	However, longitudinal studies with children carrying such mutations would be useful to determine if these mutations actually predict leukemia incidence and what exogenous factors predict disease onset.	('leukemia', 'Disease', 'MESH:D007938', (133, 141))	('mutations', 'Var', (58, 67))	('predict', 'Reg', (125, 132))	('leukemia', 'Disease', (133, 141))	('leukemia', 'Phenotype', 'HP:0001909', (133, 141))	('children', 'Species', '9606', (35, 43))
37204	33115454	TET2 is one of the most commonly mutated genes related to clonal hematopoiesis, and mice that received bone marrow grafts from homozygous or heterozygous TET2 knockout mice developed larger atherosclerotic lesions compared to the control mice.	('clonal hematopoiesis', 'Disease', 'MESH:C536227', (58, 78))	('larger', 'PosReg', (183, 189))	('mice', 'Species', '10090', (168, 172))	('atherosclerotic lesions', 'Disease', (190, 213))	('atherosclerotic lesions', 'Phenotype', 'HP:0031678', (190, 213))	('atherosclerotic lesions', 'Disease', 'MESH:D050197', (190, 213))	('mice', 'Species', '10090', (238, 242))	('TET2', 'Gene', (154, 158))	('knockout', 'Var', (159, 167))	('clonal hematopoiesis', 'Disease', (58, 78))	('mice', 'Species', '10090', (84, 88))
37211	33115454	In fact, recent research using blood samples from approximately 50,000 cancer-free individuals found that positive selection for advantageous clonal mutations, not neutral genetic drift, constituted the major influencer on clonal hematopoiesis and clone fitness, providing further insight into the complex role of clonal hematopoiesis and disease development.	('clonal hematopoiesis', 'Disease', (314, 334))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('mutations', 'Var', (149, 158))	('age', 'Gene', '5973', (135, 138))	('clonal hematopoiesis', 'Disease', 'MESH:C536227', (223, 243))	('cancer', 'Disease', (71, 77))	('fitness', 'Disease', 'MESH:D012640', (254, 261))	('clonal hematopoiesis', 'Disease', 'MESH:C536227', (314, 334))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('age', 'Gene', (135, 138))	('fitness', 'Disease', (254, 261))	('clonal hematopoiesis', 'Disease', (223, 243))
37212	33115454	While the aforementioned studies represent a good start, more work and sequencing methods with greater sensitivity are needed to precisely determine which of the associated mutations or groups of mutations in blood cells are carcinogenic and pathological, or simply hallmarks of aging normal tissues.	('mutations', 'Var', (173, 182))	('carcinogenic', 'Disease', 'MESH:D063646', (225, 237))	('carcinogenic', 'Disease', (225, 237))
37213	33115454	Increased mosaicism:genetic changes/mutations in a subset of an organism's cells:has also been found in neurons, both from healthy people and those with Alzheimer's disease.	('genetic changes/mutations', 'Var', (20, 45))	('people', 'Species', '9606', (131, 137))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (153, 172))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (153, 172))	("Alzheimer's disease", 'Disease', (153, 172))	('changes/mutations', 'Var', (28, 45))
37214	33115454	The exact mechanism is unknown; however, recent research suggests that amyloid-beta precursor protein (APP) mRNA variants became permanently incorporated into the genome of neurons due to breaks in neuronal DNA and the action of reverse transcriptase.	('APP', 'Gene', (103, 106))	('breaks', 'Var', (188, 194))	('amyloid-beta precursor protein', 'Gene', '351', (71, 101))	('amyloid-beta precursor protein', 'Gene', (71, 101))
37217	33115454	Moreover, this mutational mechanism introduces another risk factor for individuals who suffered traumatic brain injury:the ensuing breaks in DNA could provide opportunities for Alzheimer-related gencDNA formation.	('breaks', 'Var', (131, 137))	('Alzheimer-related gencDNA formation', 'Disease', (177, 212))	('traumatic brain injury', 'Disease', (96, 118))	('mutational', 'Var', (15, 25))	('DNA', 'Gene', (141, 144))	('traumatic brain injury', 'Disease', 'MESH:D000070642', (96, 118))	('gencDNA', 'Chemical', '-', (195, 202))	('opportunities', 'Reg', (159, 172))
37219	33115454	Some of these APP mRNA variants are thought to translate into cytotoxic proteins, further underscoring the role of mosaicism in Alzheimer-related neuron death.	('variants', 'Var', (23, 31))	('death', 'Disease', 'MESH:D003643', (153, 158))	('translate', 'Reg', (47, 56))	('death', 'Disease', (153, 158))
37222	33115454	gencDNAs may also be important for normal brain function, playing a role in plasticity, learning and memory, or giving neurons the ability to remember and employ genetic variants beyond the wild-type genes.	('giving', 'Reg', (112, 118))	('playing', 'Reg', (58, 65))	('plasticity', 'CPA', (76, 86))	('variants', 'Var', (170, 178))	('gencDNAs', 'Chemical', '-', (0, 8))
37228	33115454	A higher rate of mutation was also observed in the hippocampus, and the authors posit that this may be relevant for Alzheimer's disease.	("Alzheimer's disease", 'Disease', (116, 135))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (116, 135))	('mutation', 'Var', (17, 25))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (116, 135))
37229	33115454	The first signature, characterized by C>T and T>C mutations, increased with age, in a clock-like fashion.	('age', 'Gene', '5973', (76, 79))	('T>C mutations', 'Var', (46, 59))	('C>T', 'Var', (38, 41))	('increased', 'PosReg', (61, 70))	('age', 'Gene', (76, 79))
37230	33115454	Perhaps related to early development, the second signature featured primarily C>T mutations and did not change with age.	('C>T mutations', 'Var', (78, 91))	('age', 'Gene', '5973', (116, 119))	('age', 'Gene', (116, 119))
37231	33115454	Finally, the third signature had C>A variants and was connected with oxidative DNA damage.	('connected', 'Reg', (54, 63))	('C>A variants', 'Var', (33, 45))	('age', 'Gene', '5973', (86, 89))	('age', 'Gene', (86, 89))
37246	33115454	Another major investigation combined the detection of oncogenic ctDNA mutations, protein markers, and PET-CT (positron emission tomography:computerized tomography) in order to increase the accuracy of cancer detection while specifying the tissue of origin.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('mutations', 'Var', (70, 79))	('increase', 'PosReg', (176, 184))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('ctDNA', 'Gene', (64, 69))
37249	33115454	Apart from some common cancer mutations that were highly enriched (like missense mutations in IDH2 or excess synonymous mutations in MP2K1), the team found strong negative selection acting on the majority missense and nonsense mutations.	('IDH2', 'Gene', '3418', (94, 98))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('MP2K1', 'Gene', (133, 138))	('missense mutations', 'Var', (72, 90))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('IDH2', 'Gene', (94, 98))
37253	31074772	Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2 (Glu504Lys) knock-in mice Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage.	('alcohol', 'Chemical', 'MESH:D000438', (53, 60))	('ALDH2', 'Gene', '217', (106, 111))	('Glu504Lys', 'SUBSTITUTION', 'None', (115, 124))	('acetaldehyde', 'Chemical', 'MESH:D000079', (253, 265))	('alcohol', 'Chemical', 'MESH:D000438', (283, 290))	('ALDH2', 'Gene', (33, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (206, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('Alcohol', 'Chemical', 'MESH:D000438', (140, 147))	('human', 'Species', '9606', (100, 105))	('ALDH2', 'Gene', (106, 111))	('alcohol', 'Chemical', 'MESH:D000438', (298, 305))	('esophageal squamous cell carcinoma', 'Disease', (206, 240))	('ALDH2', 'Gene', '217', (33, 38))	('Glu504Lys', 'Var', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (217, 240))
37254	31074772	Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism.	('activity', 'MPA', (83, 91))	('acetaldehyde', 'Chemical', 'MESH:D000079', (61, 73))	('polymorphism', 'Var', (117, 129))	('detoxifies acetaldehyde', 'MPA', (50, 73))	('ALDH2', 'Gene', (106, 111))	('reduced', 'NegReg', (95, 102))	('ALDH2', 'Gene', (25, 30))
37256	31074772	Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet.	('ESCC', 'Disease', (105, 109))	('elevates', 'Reg', (84, 92))	('Heavy alcohol consumption', 'Phenotype', 'HP:0030955', (0, 25))	('alcohol', 'Chemical', 'MESH:D000438', (6, 13))	('polymorphism', 'Var', (57, 69))	('ALDH2', 'Gene', (46, 51))
37263	31074772	These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.	('carcinogenesis', 'Disease', 'MESH:D063646', (215, 229))	('ALDH2', 'Gene', (128, 133))	('esophageal DNA damage levels', 'MPA', (79, 107))	('protective', 'MPA', (27, 37))	('acetaldehyde', 'Chemical', 'MESH:D000079', (182, 194))	('carcinogenesis', 'Disease', (215, 229))	('Alda', 'Chemical', 'MESH:C017231', (69, 73))	('polymorphism', 'Var', (139, 151))	('ALDH2', 'Gene', (49, 54))	('activation', 'PosReg', (55, 65))
37264	31074772	We generated human ALDH2*2 (Glu504Lys) knock-in mice and showed the protective effects of Alda-1 (ALDH2 activator) on esophageal DNA damage in those mice with alcohol drinking.	('human', 'Species', '9606', (13, 18))	('mice', 'Species', '10090', (48, 52))	('Glu504Lys', 'Var', (28, 37))	('Glu504Lys', 'SUBSTITUTION', 'None', (28, 37))	('mice', 'Species', '10090', (149, 153))	('alcohol drinking', 'Phenotype', 'HP:0030955', (159, 175))	('esophageal', 'Disease', (118, 128))	('alcohol', 'Chemical', 'MESH:D000438', (159, 166))	('Alda', 'Chemical', 'MESH:C017231', (90, 94))	('ALDH2*2', 'Gene', (19, 26))
37268	31074772	Acetaldehyde causes various DNA damages, such as DNA adducts including N2-ethylidene-2'-deoxyguanosine (N2-ethylidene-dG) and N2-ethyl-2'-deoxyguanosine (N2-Et-dG), single- and/or double-strand breaks, point mutations, sister chromatid exchanges and DNA-DNA cross-links.	('sister chromatid exchanges', 'CPA', (219, 245))	("N2-ethyl-2'-deoxyguanosine", 'Chemical', 'MESH:C492934', (126, 152))	('N2-ethylidene-dG', 'Chemical', 'MESH:C525837', (104, 120))	("N2-ethylidene-2'-deoxyguanosine", 'Chemical', 'MESH:C525837', (71, 102))	("N2-ethyl-2'-deoxyguanosine", 'Var', (126, 152))	('point', 'Disease', (202, 207))	('N2-Et-dG', 'Chemical', 'MESH:C492934', (154, 162))	('single-', 'Var', (165, 172))	("N2-ethylidene-2'-deoxyguanosine", 'Var', (71, 102))	('Acetaldehyde', 'Chemical', 'MESH:D000079', (0, 12))
37271	31074772	ALDH2*2 (rs671) allele, also known as Glu504Lys, encodes the ALDH2 protein, which is defective at metabolizing acetaldehyde.	('ALDH2*2', 'Gene', (0, 7))	('ALDH2', 'Gene', (61, 66))	('Glu504Lys', 'Var', (38, 47))	('defective', 'NegReg', (85, 94))	('rs671', 'Var', (9, 14))	('protein', 'Protein', (67, 74))	('Glu504Lys', 'SUBSTITUTION', 'None', (38, 47))	('rs671', 'Mutation', 'rs671', (9, 14))	('acetaldehyde', 'Chemical', 'MESH:D000079', (111, 123))	('metabolizing acetaldehyde', 'MPA', (98, 123))
37277	31074772	Alcohol intake increases acetaldehyde concentrations in the blood, saliva and the breath, and ALDH2 gene polymorphisms affect those levels.	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('acetaldehyde', 'Chemical', 'MESH:D000079', (25, 37))	('acetaldehyde concentrations', 'MPA', (25, 52))	('increases', 'PosReg', (15, 24))	('affect', 'Reg', (119, 125))	('Alcohol intake increases acetaldehyde concentrations', 'Phenotype', 'HP:0003533', (0, 52))	('polymorphisms', 'Var', (105, 118))	('ALDH2', 'Gene', (94, 99))
37280	31074772	Indeed, esophageal DNA damage levels in ALDH2 knockout mice were much higher than those in control ALDH2 wild-type mice after drinking 10% ethanol for 2 months.	('knockout', 'Var', (46, 54))	('ALDH2', 'Gene', (40, 45))	('esophageal DNA damage levels', 'MPA', (8, 36))	('mice', 'Species', '10090', (55, 59))	('ethanol', 'Chemical', 'MESH:D000431', (139, 146))	('higher', 'PosReg', (70, 76))	('mice', 'Species', '10090', (115, 119))
37281	31074772	Thus, impaired ALDH2 activity due to ALDH2 gene polymorphism is considered to be deeply involved in esophageal carcinogenesis.	('carcinogenesis', 'Disease', (111, 125))	('ALDH2', 'Gene', (37, 42))	('polymorphism', 'Var', (48, 60))	('ALDH2', 'Enzyme', (15, 20))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('impaired', 'NegReg', (6, 14))	('activity', 'MPA', (21, 29))	('involved', 'Reg', (88, 96))
37285	31074772	The aim of this study was to clarify whether Alda-1 has protective effects against alcohol-derived DNA damage in the esophagus of ALDH2*2 allele carriers.	('ALDH2*2', 'Gene', (130, 137))	('Alda', 'Chemical', 'MESH:C017231', (45, 49))	('alcohol', 'Chemical', 'MESH:D000438', (83, 90))	('allele carriers', 'Var', (138, 153))	('alcohol-derived DNA damage', 'MPA', (83, 109))
37296	31074772	After selection using neomycin, the resistant clones were isolated, and their DNAs were screened for homologous recombination by PCR using following primer set: sc_5AF2: 5 -ACC ATC CAT TCA AGG TAA AGT TCC -3  and neo_108r: 5 -CCT CAG AAG AAC TCG TCA AGA AG-3 .	('neo_108r', 'Var', (213, 221))	('CAT TCA AGG TAA AGT', 'Disease', (181, 200))	('neomycin', 'Chemical', 'MESH:D009355', (22, 30))	('CAT TCA AGG TAA AGT', 'Disease', 'MESH:C536414', (181, 200))
37310	31074772	We used the specific restriction enzyme, AcuI (R0641S, New England Biolabs Tokyo, Japan), to distinguish between human ALDH2*1 and ALDH2*2.	('R0641S', 'Var', (47, 53))	('ALDH2', 'Gene', (119, 124))	('R0641S', 'Mutation', 'p.R0641S', (47, 53))	('human', 'Species', '9606', (113, 118))
37331	31074772	To confirm the generation of human ALDH2 (ALDH2*1 or ALDH2*2) gene knock-in mice, we first checked the deletion of mice Aldh2 gene and insertion of human ALDH2 gene by PCR using the primers specifically recognizing mice Aldh2 or human ALDH2.	('Aldh2', 'Gene', (120, 125))	('ALDH2', 'Gene', (154, 159))	('human', 'Species', '9606', (148, 153))	('mice', 'Species', '10090', (76, 80))	('human', 'Species', '9606', (229, 234))	('human', 'Species', '9606', (29, 34))	('mice', 'Species', '10090', (215, 219))	('mice', 'Species', '10090', (115, 119))	('deletion', 'Var', (103, 111))
37344	31074772	When mice were given 10% ethanol as substitute for water for 7 days, the average amount of ethanol consumption in ALDH2*1/*2 or ALDH2*2/*2 mice was significantly less than that in ALDH2*1/*1 mice (Figure 4A).	('less', 'NegReg', (162, 166))	('ethanol', 'Chemical', 'MESH:D000431', (91, 98))	('ALDH2*1/*2', 'Var', (114, 124))	('ethanol consumption', 'MPA', (91, 110))	('mice', 'Species', '10090', (191, 195))	('mice', 'Species', '10090', (139, 143))	('water', 'Chemical', 'MESH:D014867', (51, 56))	('mice', 'Species', '10090', (5, 9))	('ethanol', 'Chemical', 'MESH:D000431', (25, 32))
37346	31074772	Of note, ALDH2*1/*2 and ALDH2*2/*2 mice showed significantly higher DNA damage than ALDH2*1/*1 mice (Figure 4B).	('DNA damage', 'CPA', (68, 78))	('mice', 'Species', '10090', (95, 99))	('ALDH2*', 'Var', (24, 30))	('higher', 'PosReg', (61, 67))	('ALDH2*1/*2', 'Var', (9, 19))	('mice', 'Species', '10090', (35, 39))
37361	31074772	Here, we showed that ALDH2 activity in ALDH2*1/*2 and ALDH2*2/*2 mice was significantly lower than that in ALDH2*1/*1 mice, although the messenger RNA as well as protein expression levels of ALDH2 did not differ among them.	('mice', 'Species', '10090', (65, 69))	('ALDH2*1/*2', 'Var', (39, 49))	('ALDH2*2/*2', 'Var', (54, 64))	('lower', 'NegReg', (88, 93))	('mice', 'Species', '10090', (118, 122))	('ALDH2', 'Enzyme', (21, 26))	('activity', 'MPA', (27, 35))
37362	31074772	Therefore, it is conceivable that reduced ALDH2 activity in ALDH2*1/*2 and/or ALDH2*2/*2 mice is caused by genetic polymorphism, but not by different expression levels of ALDH2.	('reduced', 'NegReg', (34, 41))	('activity', 'MPA', (48, 56))	('mice', 'Species', '10090', (89, 93))	('ALDH2', 'Protein', (42, 47))	('polymorphism', 'Var', (115, 127))
37364	31074772	This result suggests that esophagus of ALDH2*1/*2 and/or ALDH2*2/*2 mice is more susceptible to ethanol, probably due to decreased activity of ALDH2.	('mice', 'Species', '10090', (68, 72))	('ethanol', 'Chemical', 'MESH:D000431', (96, 103))	('susceptible to ethanol', 'MPA', (81, 103))	('ALDH2', 'Gene', (57, 62))	('activity', 'MPA', (131, 139))	('decreased', 'NegReg', (121, 130))	('ALDH2*1/*2', 'Var', (39, 49))	('more', 'PosReg', (76, 80))	('ALDH2', 'Enzyme', (143, 148))
37370	31074772	It also increased the amount of alcohol drinking in those mice, nevertheless, esophageal DNA damage levels were significantly reduced by Alda-1 treatment, presumably due to the increased ALDH2 activity by Alda-1 treatment.	('alcohol drinking', 'Phenotype', 'HP:0030955', (32, 48))	('Alda-1', 'Gene', (137, 143))	('Alda', 'Chemical', 'MESH:C017231', (137, 141))	('activity', 'MPA', (193, 201))	('treatment', 'Var', (144, 153))	('increased', 'PosReg', (177, 186))	('mice', 'Species', '10090', (58, 62))	('increased', 'PosReg', (8, 17))	('esophageal DNA damage levels', 'MPA', (78, 106))	('ALDH2', 'Protein', (187, 192))	('alcohol', 'Chemical', 'MESH:D000438', (32, 39))	('Alda', 'Chemical', 'MESH:C017231', (205, 209))	('reduced', 'NegReg', (126, 133))
37373	31074772	These results indicate that modulation of ALDH2 activity using ALDH2 activator (Alda-1) or ALDH2 inhibitor (cyanamide) deeply affects the levels of esophageal DNA damage associated with alcohol drinking.	('modulation', 'Var', (28, 38))	('activity', 'MPA', (48, 56))	('cyanamide', 'Chemical', 'MESH:D003484', (108, 117))	('levels', 'MPA', (138, 144))	('affects', 'Reg', (126, 133))	('ALDH2', 'Gene', (42, 47))	('esophageal DNA damage', 'MPA', (148, 169))	('alcohol', 'Chemical', 'MESH:D000438', (186, 193))	('Alda', 'Chemical', 'MESH:C017231', (80, 84))	('alcohol drinking', 'Phenotype', 'HP:0030955', (186, 202))
37376	31074772	Furthermore, Alda-1 activates both ALDH2*1 and ALDH2*2 by binding at the entrance of the catalytic tunnel in close proximity to Cys302 and Glu286, which are critical to its substrate catalysis.	('binding', 'Interaction', (58, 65))	('Alda', 'Chemical', 'MESH:C017231', (13, 17))	('Cys302', 'Chemical', '-', (128, 134))	('Glu286', 'Chemical', '-', (139, 145))	('ALDH2*', 'Gene', (47, 53))	('Glu286', 'Var', (139, 145))	('Cys302', 'Var', (128, 134))	('activates', 'PosReg', (20, 29))	('ALDH2', 'Gene', (35, 40))
37377	31074772	In line with their report, we showed that Alda-1 treatment increased ALDH2 activity not only in ALDH2*1/*2 and ALDH2*2/*2 but also in ALDH2*1/*1 mice.	('ALDH2*1/*2', 'Var', (96, 106))	('Alda', 'Chemical', 'MESH:C017231', (42, 46))	('mice', 'Species', '10090', (145, 149))	('activity', 'MPA', (75, 83))	('increased', 'PosReg', (59, 68))	('ALDH2', 'Enzyme', (69, 74))
37386	31074772	In conclusion, we established a novel mice model representing human ALDH2 gene polymorphism which causes reduced ALDH2 activity and is associated with various diseases including ESCC.	('polymorphism', 'Var', (79, 91))	('mice', 'Species', '10090', (38, 42))	('human', 'Species', '9606', (62, 67))	('ALDH2', 'Protein', (113, 118))	('ALDH2', 'Gene', (68, 73))	('reduced', 'NegReg', (105, 112))	('associated with', 'Reg', (135, 150))	('activity', 'MPA', (119, 127))	('ESCC', 'Disease', (178, 182))
37387	31074772	We further showed that ALDH2 activation by Alda-1 in mice with ALDH2 dysfunction alleviates esophageal DNA damages associated with alcohol drinking.	('alcohol', 'Chemical', 'MESH:D000438', (131, 138))	('ALDH2', 'Gene', (23, 28))	('Alda', 'Chemical', 'MESH:C017231', (43, 47))	('activation', 'PosReg', (29, 39))	('alleviates', 'NegReg', (81, 91))	('dysfunction', 'Var', (69, 80))	('ALDH2', 'Gene', (63, 68))	('alcohol drinking', 'Phenotype', 'HP:0030955', (131, 147))	('esophageal', 'Disease', (92, 102))	('mice', 'Species', '10090', (53, 57))
37399	31936858	Interruption of CCRT was the only independently poor prognostic factor of OS in the univariate and multivariate (hazard ratio 0.18, p < 0.001) analyses.	('Interruption', 'Var', (0, 12))	('OS', 'Chemical', '-', (74, 76))	('CCRT', 'Gene', (16, 20))
37438	31936858	According to a multivariate comparison, interruption of CCRT (p < 0.001, HR: 0.18, 95% CI: 0.09-0.34) represented the independently poor prognostic factor of OS.	('interruption', 'Var', (40, 52))	('OS', 'Chemical', '-', (158, 160))	('CCRT', 'Gene', (56, 60))
37441	31936858	Fatigue needing admission, febrile neutropenia, anemia needing blood transfusion, and thrombocytopenia needing blood transfusion were found to be higher in the cisplatin/5-FU group than in the weekly cisplatin group, but no significant statistical differences were obtained.	('higher', 'PosReg', (146, 152))	('5-FU', 'Chemical', '-', (170, 174))	('Fatigue', 'Phenotype', 'HP:0012378', (0, 7))	('anemia', 'Disease', 'MESH:D000740', (48, 54))	('anemia', 'Phenotype', 'HP:0001903', (48, 54))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (86, 102))	('febrile neutropenia', 'Disease', (27, 46))	('cisplatin/5-FU', 'Var', (160, 174))	('thrombocytopenia', 'Disease', (86, 102))	('febrile neutropenia', 'Disease', 'MESH:D009503', (27, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (200, 209))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('needing blood transfusion', 'Phenotype', 'HP:0011888', (55, 80))	('needing blood transfusion', 'Phenotype', 'HP:0011888', (103, 128))	('anemia', 'Disease', (48, 54))	('neutropenia', 'Phenotype', 'HP:0001875', (35, 46))	('Fatigue', 'Disease', (0, 7))	('thrombocytopenia', 'Disease', 'MESH:D013921', (86, 102))
37449	31936858	In addition, we also found that T4b status is a poor prognostic factor, and salvage surgery is indicated to prolong overall survival in selected patients.	('patients', 'Species', '9606', (145, 153))	('T4b', 'Var', (32, 35))	('prolong', 'PosReg', (108, 115))	('overall', 'MPA', (116, 123))
37457	31936858	showed that interruptions of more than four days during radiotherapy were associated with worse progression-free survival and OS in patients with nasopharyngeal cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('interruptions', 'Var', (12, 25))	('progression-free survival', 'CPA', (96, 121))	('worse', 'NegReg', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('OS', 'Chemical', '-', (126, 128))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (146, 167))	('cancer', 'Disease', (161, 167))	('patients', 'Species', '9606', (132, 140))
37462	31936858	In our study, there was a higher incidence of adverse events in the cisplatin/5-FU group compared to the weekly cisplatin group, including fatigue needing admission, febrile neutropenia, and anemia/thrombocytopenia needing blood transfusion, although the difference was not statistically significant.	('thrombocytopenia', 'Disease', (198, 214))	('anemia', 'Disease', (191, 197))	('5-FU', 'Chemical', '-', (78, 82))	('neutropenia', 'Phenotype', 'HP:0001875', (174, 185))	('anemia', 'Disease', 'MESH:D000740', (191, 197))	('febrile neutropenia', 'Disease', 'MESH:D009503', (166, 185))	('thrombocytopenia', 'Disease', 'MESH:D013921', (198, 214))	('fatigue', 'Disease', 'MESH:D005221', (139, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('anemia', 'Phenotype', 'HP:0001903', (191, 197))	('fatigue', 'Disease', (139, 146))	('febrile neutropenia', 'Disease', (166, 185))	('cisplatin/5-FU', 'Var', (68, 82))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (198, 214))	('needing blood transfusion', 'Phenotype', 'HP:0011888', (215, 240))	('fatigue', 'Phenotype', 'HP:0012378', (139, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
37467	31936858	This research was funded by grants from the National Science Council of Taiwan, grant numbers MOST 106-2314-B-182A-159-MY3 and MOST 107-2314-B-182A-156-MY3 and the Chang Gung Memorial Hospital, grant numbers CMRPG8J0401, CMRPG8G0892, CMRPG8I0201, and CMRPG8J1061.	('CMRPG8G0892', 'Var', (221, 232))	('OS', 'Chemical', '-', (128, 130))	('CMRPG8J1061', 'Var', (251, 262))	('OS', 'Chemical', '-', (95, 97))	('CMRPG8I0201', 'Var', (234, 245))	('CMRPG8J0401', 'Var', (208, 219))
37484	31795956	These accumulated genetic alterations could eventually develop to multiple progressive cancers in the same or independent fields.	('genetic alterations', 'Var', (18, 37))	('cancers', 'Disease', (87, 94))	('develop to', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
37548	30208340	While several genome-wide association studies (GWAS) of germline variants and whole-genome or whole-exome sequencing studies of somatic mutations in ESCC have been published, there is no comprehensive database publically available for this cancer.	('ESCC', 'Gene', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('mutations', 'Var', (136, 145))	('cancer', 'Disease', (240, 246))
37549	30208340	Here, we developed the Chinese Cancer Genomic Database-Esophageal Squamous Cell Carcinoma (CCGD-ESCC) database, which contains the associations of 69,593 single nucleotide polymorphisms (SNPs) with ESCC risk in 2022 cases and 2039 controls, survival time of 1006 ESCC patients (survival GWAS) and gene expression (expression quantitative trait loci, eQTL) in 94 ESCC patients.	('single nucleotide polymorphisms', 'Var', (154, 185))	('ESCC', 'Disease', (198, 202))	('ESCC', 'Disease', (263, 267))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('associations', 'Interaction', (131, 143))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('patients', 'Species', '9606', (367, 375))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (55, 89))	('Carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('patients', 'Species', '9606', (268, 276))	('Esophageal Squamous Cell Carcinoma', 'Disease', (55, 89))
37550	30208340	Moreover, this database also provides the associations between 8833 somatic mutations and survival time in 675 ESCC patients.	('associations', 'Interaction', (42, 54))	('8833', 'Var', (63, 67))	('patients', 'Species', '9606', (116, 124))	('ESCC', 'Disease', (111, 115))
37551	30208340	Our user-friendly database is a resource useful for biologists and oncologists not only in identifying the associations of genetic variants or somatic mutations with the development and progression of ESCC but also in studying the underlying mechanisms for tumorigenesis of the cancer.	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Disease', (257, 262))	('associations', 'Interaction', (107, 119))	('variants', 'Var', (131, 139))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('cancer', 'Disease', (278, 284))	('ESCC', 'Disease', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
37552	30208340	The studies of cancer genetics and genomics powered by rapidly developing high-throughput biochip and sequencing technologies have promoted our understanding of the roles of genetic variants in carcinogenesis and cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('carcinogenesis', 'Disease', (194, 208))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('carcinogenesis', 'Disease', 'MESH:D063646', (194, 208))	('variants', 'Var', (182, 190))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('promoted', 'PosReg', (131, 139))
37561	30208340	Our endeavor is not only to provide comprehensive information on the associations of genetic variants or somatic mutations with ESCC risk and prognosis but also to dissect their potential regulatory functions based on eQTL analysis in ESCC tumor and normal esophageal tissues.	('tumor', 'Disease', (240, 245))	('associations', 'Interaction', (69, 81))	('genetic variants', 'Var', (85, 101))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('ESCC', 'Disease', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
37562	30208340	These include (1) GWAS of 16,544 SNPs in 2022 ESCC cases and 2039 controls; (2) survival GWAS of 1652 SNPs in 1006 ESCC patients; (3) eQTLs from 94 ESCC patients with both WGS and RNA-seq data in tumor and paired normal tissues; and (4) 8833 single nucleotide variations (SNVs)/indels in the protein-coding regions from 675 ESCC patients with WGS or WES data and their associations with survival time in ESCC patients (Table 1).	('ESCC', 'Disease', (46, 50))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Disease', (196, 201))	('patients', 'Species', '9606', (409, 417))	('patients', 'Species', '9606', (329, 337))	('patients', 'Species', '9606', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('single nucleotide variations', 'Var', (242, 270))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
37565	30208340	We included 1006 ESCC patients with the information on survival outcome available to identify variants associated with length of survival time.	('ESCC', 'Disease', (17, 21))	('variants', 'Var', (94, 102))	('patients', 'Species', '9606', (22, 30))	('associated', 'Reg', (103, 113))
37569	30208340	Consequently, a total of 7,676,942 gene-cis-SNP pairs were tested, and we found 16,984 cis-eQTLs in tumor tissues and 54,445 cis-eQTLs in paired normal tissues, which were significantly associated with gene expression with a false discovery rate (FDR) of <0.05.	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cis-eQTLs', 'Var', (87, 96))
37573	30208340	The eQTL section provides the genes affected by SNPs with effect size and P value obtained in ESCC tumor tissues or normal esophageal tissues (Figure 1D).	('SNPs', 'Var', (48, 52))	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))
37574	30208340	We established the CCGD-ESCC to share data on the associations of genetic variants and somatic mutations with risk or survival of ESCC for cancer researchers worldwide.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('ESCC', 'Disease', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('associations', 'Interaction', (50, 62))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', (139, 145))
37576	30208340	The currently available databases, such as the GTEx Project and the NHGRI GWAS Catalog, provide only one-sided association data of genetic variants for gene expression or for cancer risk.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('variants', 'Var', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
37578	30208340	Conversely, our CCGD-ESCC database provides integrative data, from which users can explore the functional variants in both ESCC tumor tissues and normal esophageal tissues.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('variants', 'Var', (106, 114))	('ESCC', 'Disease', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
37579	30208340	More information given in our database, such as systematic analysis of the cis-regulatory variants in matched tumor and normal samples, might help users to identify the variants specific for the development of ESCC and perhaps other squamous cell carcinomas as well.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (233, 257))	('squamous cell carcinomas', 'Disease', (233, 257))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (233, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('ESCC', 'Disease', (210, 214))	('variants', 'Var', (169, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (247, 257))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
37673	29707105	Incomplete adherence to endoscopic surveillance was associated with more rehospitalizations for variceal rebleeding compared to those fully adherent to annual endoscopic surveillance (51% vs 17%, P = 0.0328).	('Incomplete adherence', 'Var', (0, 20))	('bleeding', 'Disease', 'MESH:D006470', (107, 115))	('bleeding', 'Disease', (107, 115))
37758	29263826	Our data showed that the establishment of somatic mutation landscape inferred by chromatin features occur early in the process of cancer progression, and gastric acid reflux environmental exposure-mediated epigenetic changes, represented as gastric metaplasia, at early stage can dramatically impact the somatic mutation landscape.	('impact', 'Reg', (293, 299))	('somatic mutation landscape', 'MPA', (304, 330))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('gastric metaplasia', 'Disease', 'MESH:D008679', (241, 259))	('gastric acid reflux', 'Phenotype', 'HP:0002020', (154, 173))	('cancer', 'Disease', (130, 136))	('gastric metaplasia', 'Disease', (241, 259))	('epigenetic changes', 'Var', (206, 224))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastric acid', 'MPA', (154, 166))
37760	29263826	Environmental insults that change how DNA is packaged could lead to mutations responsible for the earliest stages of cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lead to', 'Reg', (60, 67))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (68, 77))	('cancer', 'Disease', (117, 123))
37762	29263826	The authors suggest that gastric acid reflux, which is known to cause a precancerous condition known as Barrett's esophagus, could be shifting the esophageal cells to become more stomach-like, and the resulting change in chromatin features might be triggering major mutation accumulations that affect subsequent cancer progression.	('change', 'Reg', (211, 217))	('triggering', 'Reg', (249, 259))	('cancerous', 'Disease', 'MESH:D009369', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('gastric acid reflux', 'MPA', (25, 44))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancerous', 'Disease', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (312, 318))	('gastric acid reflux', 'Phenotype', 'HP:0002020', (25, 44))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (104, 123))	("Barrett's esophagus", 'Disease', (104, 123))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (104, 123))	('mutation', 'Var', (266, 274))	('chromatin features', 'MPA', (221, 239))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
37764	29263826	Identification of new driver gene mutations, deciphering clonal evolution structure, and profiling tumor heterogeneity within and among different patients through examination of mutations, mainly at the gene level, have successfully addressed the genes contributing to cancer progression and identified novel therapeutic targets.	('tumor', 'Disease', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Disease', (269, 275))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('patients', 'Species', '9606', (146, 154))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
37773	29263826	Consistent with the differences in average mutation frequency, both MBL samples and CLL samples were indistinguishably located and formed separate clusters based on immunoglobulin heavy chain variable region (IGHV) mutation status, a key marker for distinguishing either naive-B cells or memory B cell origin for both MBL and CLL.	('mutation', 'Var', (215, 223))	('IGHV', 'Gene', (209, 213))	('MBL', 'Disease', (318, 321))	('MBL', 'Disease', (68, 71))	('immunoglobulin heavy chain variable region', 'Gene', (165, 207))	('immunoglobulin heavy chain variable region', 'Gene', '390714', (165, 207))	('CLL', 'Phenotype', 'HP:0005550', (326, 329))	('CLL', 'Phenotype', 'HP:0005550', (84, 87))	('IGHV', 'Gene', '390714', (209, 213))	('MBL', 'Disease', 'MESH:C563602', (318, 321))	('MBL', 'Disease', 'MESH:C563602', (68, 71))
37779	29263826	Indeed, significant chromatin features explaining regional mutation variations were different between IGHV mutant and unmutant groups (Supplementary Fig.	('IGHV', 'Gene', (102, 106))	('IGHV', 'Gene', '390714', (102, 106))	('mutant', 'Var', (107, 113))
37781	29263826	To further examine whether the differences in chromatin features were cell-type dependent, we performed chromatin feature selection after removing the 1 Mbp regions containing IGHV mutation status-associated differential DNA methylation single-nucleotide polymorphisms (SNPs), which also highly overlaps with differential DNA methylation SNPs between naive and memory B cells.	('IGHV', 'Gene', '390714', (176, 180))	('Mbp', 'Gene', (153, 156))	('IGHV', 'Gene', (176, 180))	('Mbp', 'Gene', '4155', (153, 156))	('mutation', 'Var', (181, 189))	('status-associated', 'Reg', (190, 207))	('single-nucleotide polymorphisms', 'Var', (237, 268))	('differential', 'Var', (208, 220))
37784	29263826	Next, we compared chromatin features that might explain regional mutation variations across the genomes of IGHV-mutation-status-matched MBL and CLL tissues.	('CLL', 'Phenotype', 'HP:0005550', (144, 147))	('IGHV', 'Gene', '390714', (107, 111))	('MBL', 'Disease', (136, 139))	('IGHV', 'Gene', (107, 111))	('mutation', 'Var', (65, 73))	('MBL', 'Disease', 'MESH:C563602', (136, 139))
37800	29263826	Ninety-two 1-megabase regions displaying differential H3K4me1 levels were selected (methods) based on the speculation that these regions would likely to represent accelerated mutation accumulations through epigenetic changes during gastric metaplasia.	('gastric metaplasia', 'Disease', 'MESH:D008679', (232, 250))	('epigenetic changes', 'Var', (206, 224))	('gastric metaplasia', 'Disease', (232, 250))
37801	29263826	From all of these results, we infer an early time point for establishment of the mutation landscape for EAC, even prior to the occurrence of dysplasia for BE, but most likely after epigenetic changes due to gastric metaplasia.	('dysplasia', 'Disease', (141, 150))	('epigenetic changes', 'Var', (181, 199))	('dysplasia', 'Disease', 'MESH:D004476', (141, 150))	('gastric metaplasia', 'Disease', 'MESH:D008679', (207, 225))	('gastric metaplasia', 'Disease', (207, 225))	('EAC', 'Phenotype', 'HP:0011459', (104, 107))	('EAC', 'Disease', (104, 107))	('BE', 'Phenotype', 'HP:0100580', (155, 157))
37831	26313788	High TRG values were significantly associated with advanced pretreatment clinical stage, longer tumor length, and higher posttreatment tumor depth of invasion (yT), the presence of lymph node metastases (LNM), and lymphovascular invasion.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('lymphovascular invasion', 'CPA', (214, 237))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (135, 140))	('TRG', 'Chemical', '-', (5, 8))	('TRG', 'MPA', (5, 8))	('lymph node metastases', 'Disease', 'MESH:D009362', (181, 202))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('lymph node metastases', 'Disease', (181, 202))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
37834	26313788	Notably, the prognostic impact of TRG on OS was greater in patients without LNM (P < 0.001) and ypT3 disease (P = 0.021).	('OS', 'Chemical', '-', (41, 43))	('ypT3 disease', 'Var', (96, 108))	('greater', 'PosReg', (48, 55))	('patients', 'Species', '9606', (59, 67))	('TRG', 'Gene', (34, 37))	('TRG', 'Chemical', '-', (34, 37))
37871	26313788	The presence of advanced ypT3 tumors was more common and the rates of lymphovascular invasion were higher in patients with a TRG of 3 than in those with a TRG of 2 (P < 0.001).	('tumors', 'Disease', (30, 36))	('TRG', 'Chemical', '-', (155, 158))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('higher', 'PosReg', (99, 105))	('TRG of 3', 'Var', (125, 133))	('patients', 'Species', '9606', (109, 117))	('TRG', 'Chemical', '-', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('ypT3', 'Gene', (25, 29))	('lymphovascular invasion', 'CPA', (70, 93))
37888	26313788	Although a favorable response to nCRT at the primary site was paralleled by a better clearance of metastatic nodes (Table 2), we nonetheless demonstrated that 8.5% and 24.5% of patients with a TRG of 1 and 2, respectively, had LNM.	('patients', 'Species', '9606', (177, 185))	('TRG', 'Var', (193, 196))	('LNM', 'Disease', (227, 230))	('TRG', 'Chemical', '-', (193, 196))
37897	26313788	Notably, the survival of patients with ypT3 (TRG 2) was significantly better than those with ypT3 (TRG 3) and similar to that observed in ypT2 cases (Figure 3).	('survival', 'CPA', (13, 21))	('ypT3', 'Var', (39, 43))	('TRG 3', 'Gene', (99, 104))	('TRG 3', 'Gene', '7197', (99, 104))	('better', 'PosReg', (70, 76))	('patients', 'Species', '9606', (25, 33))	('TRG 2', 'Gene', '7196', (45, 50))	('TRG 2', 'Gene', (45, 50))
37911	26166100	Specifically, NACR resulted in significant total postoperative mortality (hazard ratio [HR] = 1.95, 95% confidence intervals [CI] = 1.06-3.60, P = 0.032), treatment-related mortality (HR = 1.97, 95% CI = 1.07-3.64, P = 0.030), and postoperative mortality (11.1% versus 3.4%, P = 0.049).	('treatment-related mortality', 'CPA', (155, 182))	('postoperative mortality', 'CPA', (231, 254))	('NACR', 'Var', (14, 18))	('NACR', 'Chemical', '-', (14, 18))	('postoperative mortality', 'CPA', (49, 72))
37935	26166100	It has been demonstrated that NACR could confer survival benefits over surgery alone by several clinical trials and meta-analyses, and it serves as a standard treatment in western countries.	('NACR', 'Chemical', '-', (30, 34))	('NACR', 'Var', (30, 34))	('survival benefits', 'CPA', (48, 65))
37950	26166100	The JCOG9907 detected a significant survival benefit by NAC compared with postoperative chemotherapy for ESCC.	('NAC', 'Var', (56, 59))	('NAC', 'Chemical', '-', (56, 59))	('survival benefit', 'CPA', (36, 52))
37959	26166100	The JCOG9907 trial detected a significant survival benefit using NAC.	('survival benefit', 'CPA', (42, 58))	('NAC', 'Var', (65, 68))	('NAC', 'Chemical', '-', (65, 68))
37975	24598538	Association of the Polymorphisms in the Fas/FasL Promoter Regions with Cancer Susceptibility: A Systematic Review and Meta-Analysis of 52 Studies Fas and its ligand (FasL) play an important role in apoptosis and carcinogenesis.	('Cancer', 'Disease', (71, 77))	('Fas', 'Chemical', 'MESH:C038178', (146, 149))	('Fas', 'Chemical', 'MESH:C038178', (166, 169))	('apoptosis', 'CPA', (198, 207))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('Fas', 'Chemical', 'MESH:C038178', (40, 43))	('Fas', 'Chemical', 'MESH:C038178', (44, 47))	('FasL', 'Gene', (44, 48))	('carcinogenesis', 'Disease', 'MESH:D063646', (212, 226))	('FasL', 'Gene', '356', (166, 170))	('carcinogenesis', 'Disease', (212, 226))	('FasL', 'Gene', (166, 170))	('Association', 'Interaction', (0, 11))	('FasL', 'Gene', '356', (44, 48))	('Polymorphisms', 'Var', (19, 32))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
37976	24598538	Therefore, the potential association of polymorphisms in the Fas (-670A>G, rs1800682; -1377G>A, rs2234767) and FasL (-844C>T, rs763110) with cancer risk has been widely investigated.	('rs1800682; -1377G>A', 'Var', (75, 94))	('Fas', 'Chemical', 'MESH:C038178', (111, 114))	('rs1800682', 'Mutation', 'rs1800682', (75, 84))	('-1377G>A', 'Mutation', 'rs2234767', (86, 94))	('-844C>T', 'Var', (117, 124))	('-670A>G', 'Mutation', 'rs1800682', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('FasL', 'Gene', (111, 115))	('Fas', 'Chemical', 'MESH:C038178', (61, 64))	('rs2234767', 'Mutation', 'rs2234767', (96, 105))	('rs763110', 'Var', (126, 134))	('rs2234767', 'Var', (96, 105))	('FasL', 'Gene', '356', (111, 115))	('-670A>G', 'Var', (66, 73))	('-844C>T', 'Mutation', 'rs763110', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('rs763110', 'Mutation', 'rs763110', (126, 134))
37977	24598538	In this work, we performed a meta-analysis to further determine whether carriers of the polymorphisms in Fas and FasL of interest could confer an altered susceptibility to cancer.	('polymorphisms', 'Var', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('susceptibility', 'Reg', (154, 168))	('carriers', 'Var', (72, 80))	('Fas', 'Chemical', 'MESH:C038178', (113, 116))	('Fas', 'Chemical', 'MESH:C038178', (105, 108))	('Fas', 'Gene', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('FasL', 'Gene', '356', (113, 117))	('FasL', 'Gene', (113, 117))
37979	24598538	For the Fas -1377G>A and FasL -844C>T polymorphisms, results revealed that the homozygotes of -1377A and -844C were associated with elevated risk of cancer as a whole.	('cancer', 'Disease', (149, 155))	('FasL', 'Gene', (25, 29))	('Fas -1377G>A', 'Var', (8, 20))	('-844C>T', 'Mutation', 'rs763110', (30, 37))	('FasL', 'Gene', '356', (25, 29))	('-1377G>A', 'Mutation', 'rs2234767', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Fas', 'Chemical', 'MESH:C038178', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('Fas', 'Chemical', 'MESH:C038178', (8, 11))
37981	24598538	We conclude that carriers of the Fas-1377A and the FasL -844C are more susceptible to the majority of cancers than non-carriers.	('susceptible', 'Reg', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('FasL', 'Gene', (51, 55))	('Fas', 'Chemical', 'MESH:C038178', (33, 36))	('FasL', 'Gene', '356', (51, 55))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('Fas', 'Chemical', 'MESH:C038178', (51, 54))	('Fas-1377A', 'Var', (33, 42))
37988	24598538	Furthermore, in these two genes, there are several functionally significant polymorphisms, such as the -670A>G and -1377G>A in the Fas promoter region, and the -844C>T in the FasL promoter region, because they might be associated with cancer risk, including cervical cancer, gastric cancer, breast cancer, lung cancer and so on.	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('-1377G>A', 'Var', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('gastric cancer', 'Phenotype', 'HP:0012126', (275, 289))	('cancer', 'Disease', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('breast cancer', 'Phenotype', 'HP:0003002', (291, 304))	('Fas', 'Chemical', 'MESH:C038178', (131, 134))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('-1377G>A', 'Mutation', 'rs2234767', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('lung cancer', 'Disease', (306, 317))	('gastric cancer', 'Disease', (275, 289))	('the -844C>T', 'Var', (156, 167))	('breast cancer', 'Disease', 'MESH:D001943', (291, 304))	('FasL', 'Gene', (175, 179))	('cancer', 'Disease', (267, 273))	('associated', 'Reg', (219, 229))	('breast cancer', 'Disease', (291, 304))	('FasL', 'Gene', '356', (175, 179))	('cancer', 'Disease', (283, 289))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('Fas', 'Chemical', 'MESH:C038178', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('lung cancer', 'Disease', 'MESH:D008175', (306, 317))	('gastric cancer', 'Disease', 'MESH:D013274', (275, 289))	('-844C>T', 'Mutation', 'rs763110', (160, 167))	('cancer', 'Disease', (235, 241))	('-670A>G', 'Mutation', 'rs1800682', (103, 110))	('cancer', 'Disease', (298, 304))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
37989	24598538	However, all available results are not always consistent with one another, partially because of the small sample size of some published studies, different ethnic backgrounds, publication bias, and little effect of the polymorphisms on cancer risk.	('polymorphisms', 'Var', (218, 231))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Disease', (235, 241))
37990	24598538	Therefore, it's necessary to retrieve and pool all eligible data to further determine whether these genetic polymorphisms could be at increased risk for developing cancer and to what extent heterogeneity existed across all the studies.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('polymorphisms', 'Var', (108, 121))
37992	24598538	The inclusion criteria were prespecified as below: (1) be a case-control study, (2) evaluate association between the Fas and/or FasL polymorphisms and cancer risk, (3) present sufficient data to calculate an odds ratio (OR) with 95% confidence interval (CI), and (4) list genotype frequency.	('polymorphisms', 'Var', (133, 146))	('Fas', 'Gene', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Fas', 'Chemical', 'MESH:C038178', (128, 131))	('FasL', 'Gene', '356', (128, 132))	('FasL', 'Gene', (128, 132))	('cancer', 'Disease', (151, 157))	('association', 'Interaction', (93, 104))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('Fas', 'Chemical', 'MESH:C038178', (117, 120))
37995	24598538	Crude ORs with 95% CIs were used to assess the strength of association between the polymorphisms in Fas-670A>G, Fas -1377G>A, and FasL -844T/C and cancer risk.	('FasL', 'Gene', '356', (130, 134))	('FasL', 'Gene', (130, 134))	('-844T/C', 'Mutation', 'rs763110', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Fas', 'Chemical', 'MESH:C038178', (112, 115))	('Fas-670A>G', 'Var', (100, 110))	('Fas -1377G>A', 'Var', (112, 124))	('Fas', 'Chemical', 'MESH:C038178', (130, 133))	('-1377G>A', 'Mutation', 'rs2234767', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Fas', 'Chemical', 'MESH:C038178', (100, 103))	('cancer', 'Disease', (147, 153))
37999	24598538	In the subgroup analysis, statistically significantly decreased risk was observed in prostate cancer and melanoma for GG+AG vs AA comparison model, whereas there was significantly increased risk among those of African ancestry for GG+AG vs AA models (all data shown in Table 2).	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('prostate cancer', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('decreased', 'NegReg', (54, 63))	('GG+AG', 'Var', (118, 123))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))
38000	24598538	For Fas -1377G>A polymorphism, significantly increased cancer risks were observed in AA vs GG (Figure 2) and AA vs GA+GG comparison models in the overall analysis.	('increased cancer', 'Disease', (45, 61))	('-1377G>A', 'Mutation', 'rs2234767', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Fas', 'Chemical', 'MESH:C038178', (4, 7))	('GA', 'Chemical', 'MESH:D005708', (115, 117))	('Fas -1377G>A', 'Var', (4, 16))	('increased cancer', 'Disease', 'MESH:D009369', (45, 61))
38006	24598538	However, no significant associations were found in Fas -670A>G polymorphism and cancer risks (shown in Table 2).	('polymorphism', 'Var', (63, 75))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Fas -670A', 'Gene', (51, 60))	('-670A>G', 'Mutation', 'rs1800682', (55, 62))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Fas', 'Chemical', 'MESH:C038178', (51, 54))	('cancer', 'Disease', (80, 86))
38011	24598538	In the genotype subgroup analysis, significant associations between mRNA expression levels and Fas -670A>G were observed in all populations (GA: P = 0.043), especially in Asian population (GG: P = 0.0003; dominant: P = 0.003; recessive: P = 0.001).	('Fas -670A>G', 'Var', (95, 106))	('Fas', 'Chemical', 'MESH:C038178', (95, 98))	('GA', 'Chemical', 'MESH:D005708', (141, 143))	('mRNA expression levels', 'MPA', (68, 90))	('-670A>G', 'Mutation', 'rs1800682', (99, 106))
38016	24598538	For the Fas -1377G>A polymorphism, the test revealed cancer type (chi2 = 22.60, degree of freedom = 8, Ph = 0.004), but not ethnicity (chi2 = 4.81, degree of freedom = 3, Ph = 0.187), source of controls (chi2 = 0.42, degree of freedom = 1, Ph = 0.518), or genotyping method (chi2 = 0.51, degree of freedom = 3, Ph = 0.917) contributed to substantial heterogeneity.	('revealed', 'Reg', (44, 52))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Fas -1377G>A', 'Var', (8, 20))	('-1377G>A', 'Mutation', 'rs2234767', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Fas', 'Chemical', 'MESH:C038178', (8, 11))
38018	24598538	For Fas -670A>G and FasL -844C>T polymorphisms, statistically similar results were observed after sequential removal of individual study in dominant and homozygote model, respectively, and the summary ORs in the other genetic models were not materially altered, suggesting that the results were stable.	('FasL', 'Gene', (20, 24))	('Fas -670A>G', 'Var', (4, 15))	('FasL', 'Gene', '356', (20, 24))	('Fas', 'Chemical', 'MESH:C038178', (20, 23))	('Fas', 'Chemical', 'MESH:C038178', (4, 7))	('-844C>T', 'Mutation', 'rs763110', (25, 32))	('-670A>G', 'Mutation', 'rs1800682', (8, 15))
38026	24598538	Given the important roles of Fas and FasL in carcinogenesis process, it is biologically plausible that Fas and FasL polymorphisms that possess the potential to influence the expression of Fas and/or FasL may be associated with cancer risk.	('influence', 'Reg', (160, 169))	('Fas', 'Gene', (103, 106))	('Fas', 'Chemical', 'MESH:C038178', (29, 32))	('Fas', 'Chemical', 'MESH:C038178', (37, 40))	('Fas', 'Gene', (188, 191))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('carcinogenesis', 'Disease', (45, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('FasL', 'Gene', (199, 203))	('expression', 'MPA', (174, 184))	('FasL', 'Gene', '356', (199, 203))	('FasL', 'Gene', (111, 115))	('Fas', 'Chemical', 'MESH:C038178', (199, 202))	('FasL', 'Gene', '356', (111, 115))	('cancer', 'Disease', (227, 233))	('associated', 'Reg', (211, 221))	('Fas', 'Chemical', 'MESH:C038178', (103, 106))	('polymorphisms', 'Var', (116, 129))	('Fas', 'Chemical', 'MESH:C038178', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('Fas', 'Chemical', 'MESH:C038178', (188, 191))	('FasL', 'Gene', (37, 41))	('FasL', 'Gene', '356', (37, 41))
38027	24598538	Therefore, associations between the Fas -670A>G, Fas -1377G>A and FasL -844C>T polymorphisms and cancer risk were determined in this meta-analysis.	('Fas', 'Chemical', 'MESH:C038178', (36, 39))	('cancer', 'Disease', (97, 103))	('-844C>T', 'Mutation', 'rs763110', (71, 78))	('associations', 'Interaction', (11, 23))	('FasL', 'Gene', '356', (66, 70))	('-1377G>A', 'Mutation', 'rs2234767', (53, 61))	('FasL', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Fas', 'Chemical', 'MESH:C038178', (49, 52))	('Fas', 'Chemical', 'MESH:C038178', (66, 69))	('Fas -1377G>A', 'Var', (49, 61))	('Fas -670A>G', 'Var', (36, 47))	('-670A>G', 'Mutation', 'rs1800682', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
38028	24598538	In this meta-analysis, 52 published studies were enrolled to determine the association between the three potentially functional polymorphisms within the Fas and FasL and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('FasL', 'Gene', (161, 165))	('Fas', 'Chemical', 'MESH:C038178', (153, 156))	('cancer', 'Disease', (170, 176))	('FasL', 'Gene', '356', (161, 165))	('Fas', 'Chemical', 'MESH:C038178', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('polymorphisms', 'Var', (128, 141))	('association', 'Interaction', (75, 86))
38029	24598538	This study revealed that the Fas -1377G>A and FasL -844C>T, but not the Fas -670A>G polymorphisms were associated with significantly increased overall cancer risk.	('Fas', 'Chemical', 'MESH:C038178', (46, 49))	('Fas', 'Chemical', 'MESH:C038178', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Fas -1377G>A', 'Var', (29, 41))	('-1377G>A', 'Mutation', 'rs2234767', (33, 41))	('-670A>G', 'Mutation', 'rs1800682', (76, 83))	('cancer', 'Disease', (151, 157))	('FasL', 'Gene', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('-844C>T', 'Mutation', 'rs763110', (51, 58))	('increased', 'PosReg', (133, 142))	('FasL', 'Gene', '356', (46, 50))	('Fas', 'Chemical', 'MESH:C038178', (72, 75))
38031	24598538	As the Fas -1377A allele reduced the ability to bind transcription factor stimulatory protein 1 that is a crucial transcriptional activator, the expression of Fas was decreased in carriers of the Fas -1377AA genotype as expected, but the Fas -670G allele didn't influence the expression of Fas.	('Fas', 'Gene', (159, 162))	('Fas', 'Chemical', 'MESH:C038178', (238, 241))	('reduced', 'NegReg', (25, 32))	('bind', 'Interaction', (48, 52))	('ability', 'MPA', (37, 44))	('Fas', 'Chemical', 'MESH:C038178', (290, 293))	('Fas -1377AA', 'Var', (196, 207))	('expression', 'MPA', (145, 155))	('Fas', 'Chemical', 'MESH:C038178', (196, 199))	('Fas', 'Chemical', 'MESH:C038178', (7, 10))	('Fas', 'Chemical', 'MESH:C038178', (159, 162))	('Fas', 'Var', (7, 10))	('decreased', 'NegReg', (167, 176))
38032	24598538	Therefore, it is reasonable that the Fas -1377A allele increased the overall cancer risk, and that the Fas -670G allele had no marked effect on overall cancer risk, which was consistent with our results.	('Fas -1377A', 'Var', (37, 47))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (77, 83))	('increased', 'PosReg', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Fas', 'Chemical', 'MESH:C038178', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Fas', 'Chemical', 'MESH:C038178', (103, 106))
38033	24598538	For the FasL -844T>C polymorphism, which is located in a binding motif for transcription factor CAAT/enhancer binding protein beta, could influence the promoter activity of the FasL gene.	('FasL', 'Gene', '356', (177, 181))	('FasL', 'Gene', '356', (8, 12))	('-844T>C', 'Mutation', 'rs763110', (13, 20))	('FasL', 'Gene', (8, 12))	('polymorphism', 'Var', (21, 33))	('influence', 'Reg', (138, 147))	('FasL', 'Gene', (177, 181))	('promoter activity', 'MPA', (152, 169))
38035	24598538	The Fas -670GG genotype was associated with decreased risk of prostate cancer and melanoma according to the cancer type subgroup analysis.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('cancer', 'Disease', (71, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('decreased', 'NegReg', (44, 53))	('prostate cancer', 'Disease', (62, 77))	('Fas', 'Chemical', 'MESH:C038178', (4, 7))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Fas -670GG', 'Var', (4, 14))	('decreased risk of prostate', 'Phenotype', 'HP:0008687', (44, 70))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
38036	24598538	It was suggested that Fas -670A>G polymorphism might have the same effect on these two cancers.	('cancers', 'Disease', (87, 94))	('polymorphism', 'Var', (34, 46))	('Fas', 'Chemical', 'MESH:C038178', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('Fas -670A>G polymorphism', 'Var', (22, 46))	('-670A>G', 'Mutation', 'rs1800682', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
38041	24598538	In the subgroup analysis by ethnicity, an increased cancer risk in carriers of the Fas -670GG genotype was found in African, while the result of mRNA expression showed that GG genotype expressed higher levels of Fas in Asian populations.	('increased cancer', 'Disease', 'MESH:D009369', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('increased cancer', 'Disease', (42, 58))	('higher', 'PosReg', (195, 201))	('Fas', 'Chemical', 'MESH:C038178', (212, 215))	('Fas -670GG', 'Var', (83, 93))	('Fas', 'Chemical', 'MESH:C038178', (83, 86))
38042	24598538	Meanwhile, the previous studies showed increased cancer risk in carriers of the Fas -1377AA and FasL -844CC genotype were found in Asian subjects, which was evidenced in mRNA expression by genotypes in Asian populations.	('Fas', 'Chemical', 'MESH:C038178', (80, 83))	('FasL', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('FasL', 'Gene', '356', (96, 100))	('increased cancer', 'Disease', 'MESH:D009369', (39, 55))	('Fas', 'Chemical', 'MESH:C038178', (96, 99))	('increased cancer', 'Disease', (39, 55))	('Fas -1377AA', 'Var', (80, 91))
38045	24598538	While Fas -1377AA genotype carriers increased cancer risk in the studies using PCR-RFLP but not TaqMan, and similar result was found in the FasL -844CC genotype carrier.	('FasL', 'Gene', '356', (140, 144))	('FasL', 'Gene', (140, 144))	('increased cancer', 'Disease', 'MESH:D009369', (36, 52))	('Fas', 'Chemical', 'MESH:C038178', (6, 9))	('Fas', 'Chemical', 'MESH:C038178', (140, 143))	('Fas -1377AA', 'Var', (6, 17))	('increased cancer', 'Disease', (36, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
38046	24598538	However, the study by Crew et al showed that the consistency rate was 100% for Fas -1377G>A, 94% for Fas -670G>A and 96% for FasL -844C>T.	('Fas', 'Chemical', 'MESH:C038178', (101, 104))	('-1377G>A', 'Mutation', 'rs2234767', (83, 91))	('Fas', 'Chemical', 'MESH:C038178', (125, 128))	('-844C>T', 'Mutation', 'rs763110', (130, 137))	('FasL', 'Gene', (125, 129))	('-670G>A', 'Mutation', 'rs1800682', (105, 112))	('FasL', 'Gene', '356', (125, 129))	('Fas -670G>A', 'Var', (101, 112))	('Fas', 'Chemical', 'MESH:C038178', (79, 82))	('Fas -1377G>A', 'Var', (79, 91))
38052	24598538	In summary, this meta-analysis indicates that the Fas-1377G>A and FasL -844T/C polymorphisms are associated with increased cancer risk, but that no significant association is observed for the Fas -670A>G polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('-844T/C', 'Mutation', 'rs763110', (71, 78))	('Fas', 'Chemical', 'MESH:C038178', (50, 53))	('-670A>G', 'Mutation', 'rs1800682', (196, 203))	('cancer', 'Disease', (221, 227))	('increased cancer', 'Disease', 'MESH:D009369', (113, 129))	('Fas-1377G>A', 'Var', (50, 61))	('FasL', 'Gene', '356', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('FasL', 'Gene', (66, 70))	('Fas', 'Chemical', 'MESH:C038178', (192, 195))	('increased cancer', 'Disease', (113, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('Fas', 'Chemical', 'MESH:C038178', (66, 69))
38064	24039728	Inhibition of proliferation is due to the occurrence of apoptosis, with 2ME2 pursuing actively proliferating cells and quiescent cells are therefore less affected.	('2ME2 pursuing', 'Var', (72, 85))	('actively proliferating cells', 'CPA', (86, 114))	('2ME2', 'Chemical', 'MESH:D000077584', (72, 76))	('Inhibition', 'NegReg', (0, 10))	('proliferation', 'CPA', (14, 27))
38065	24039728	2ME2 may be classed as a spindle poison since it disrupts tubulin dynamics by binding to the colchicine site, resulting in either stabilization of the microtubules at low concentration or inhibition of polymerization at higher concentrations.	('microtubules', 'MPA', (151, 163))	('binding', 'Interaction', (78, 85))	('stabilization', 'MPA', (130, 143))	('colchicine', 'Chemical', 'MESH:D003078', (93, 103))	('disrupts', 'NegReg', (49, 57))	('tubulin', 'Protein', (58, 65))	('polymerization', 'MPA', (202, 216))	('inhibition', 'NegReg', (188, 198))	('2ME2', 'Chemical', 'MESH:D000077584', (0, 4))	('2ME2', 'Var', (0, 4))
38133	24039728	Dose-dependent studies were conducted with the purpose of evaluating the antiproliferative effects of ESE-15-one, EMBS and ESE-16 in HeLa cells after 24 h of exposure.	('EMBS', 'Chemical', 'MESH:D004977', (114, 118))	('ESE-15-one', 'Gene', (102, 112))	('antiproliferative effects', 'MPA', (73, 98))	('HeLa', 'CellLine', 'CVCL:0030', (133, 137))	('ESE-16', 'Chemical', 'MESH:C588027', (123, 129))	('ESE-15-one', 'Chemical', '-', (102, 112))	('ESE-16', 'Var', (123, 129))
38136	24039728	A statistically significant decrease in cell growth was observed at a concentration of 0.5 microM with ESE-16 (45.30% growth), ESE-15-one (40.87% growth) and EMBS (40.01% growth) when compared to vehicle-treated cells.	('ESE-15-one', 'Var', (127, 137))	('ESE-16', 'Gene', (103, 109))	('cell growth', 'CPA', (40, 51))	('EMBS', 'CPA', (158, 162))	('decrease', 'NegReg', (28, 36))	('EMBS', 'Chemical', 'MESH:D004977', (158, 162))	('ESE-15-one', 'Chemical', '-', (127, 137))	('ESE-16', 'Chemical', 'MESH:C588027', (103, 109))
38139	24039728	Cells exposed to ESE-16 demonstrated the most prominent decrease in cell growth when compared to cells exposed to ESE-15-one and EMBS.	('ESE-16', 'Var', (17, 23))	('ESE-15-one', 'Chemical', '-', (114, 124))	('EMBS', 'Chemical', 'MESH:D004977', (129, 133))	('cell growth', 'CPA', (68, 79))	('ESE-16', 'Chemical', 'MESH:C588027', (17, 23))	('decrease', 'NegReg', (56, 64))
38143	24039728	Transmission electron microscopy revealed vacuoles in cells treated with ESE-15-one, EMBS, ESE-16 and 2-methoxyestradiol-bis-sulphamate.	('sulphamate', 'Chemical', '-', (125, 135))	('ESE-15-one', 'Chemical', '-', (73, 83))	('revealed', 'Reg', (33, 41))	('2-methoxyestradiol', 'Chemical', 'MESH:D000077584', (102, 120))	('ESE-15-one', 'Var', (73, 83))	('ESE-16', 'Chemical', 'MESH:C588027', (91, 97))	('EMBS', 'Chemical', 'MESH:D004977', (85, 89))	('ESE-16', 'Var', (91, 97))
38146	24039728	In addition, cells appeared shrunken in ESE-16-treated cells, ESE-15-one-treated cells and EMBS-treated cells when compared to vehicle-treated cells.	('cells', 'CPA', (13, 18))	('ESE-16-treated', 'Var', (40, 54))	('ESE-16', 'Chemical', 'MESH:C588027', (40, 46))	('EMBS', 'Chemical', 'MESH:D004977', (91, 95))	('ESE-15-one', 'Chemical', '-', (62, 72))
38151	24039728	Exposure of MDA-MB-231 cells to sulphamoylated compounds resulted in a significantly increased number of cells presenting a reduced mitochondrial membrane potential (22-26%), although the effect was less prominent than for HeLa cells.	('reduced', 'NegReg', (124, 131))	('mitochondrial membrane potential', 'MPA', (132, 164))	('sulphamoylated', 'Var', (32, 46))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (12, 22))	('increased', 'PosReg', (85, 94))	('HeLa', 'CellLine', 'CVCL:0030', (223, 227))
38158	24039728	Data indicated that there was an increased caspase-8 activity in ESE-15-one, EMBS and ESE-16-treated cells when compared to vehicle-treated cells (Fig.	('ESE-15-one', 'Chemical', '-', (65, 75))	('ESE-15-one', 'Var', (65, 75))	('EMBS', 'Chemical', 'MESH:D004977', (77, 81))	('activity', 'MPA', (53, 61))	('increased', 'PosReg', (33, 42))	('caspase-8', 'Gene', (43, 52))	('ESE-16', 'Chemical', 'MESH:C588027', (86, 92))	('caspase-8', 'Gene', '841', (43, 52))
38162	24039728	Caspase-6 activity of cells treated with ESE-16 increased to 3.2 and EMBS to 3.1.	('increased', 'PosReg', (48, 57))	('activity', 'MPA', (10, 18))	('ESE-16', 'Var', (41, 47))	('Caspase-6', 'Gene', '839', (0, 9))	('EMBS', 'CPA', (69, 73))	('Caspase-6', 'Gene', (0, 9))	('EMBS', 'Chemical', 'MESH:D004977', (69, 73))	('ESE-16', 'Chemical', 'MESH:C588027', (41, 47))
38164	24039728	Caspase 3 activity in ESE-15-one- and EMBS-treated samples more than doubled when compared to vehicle-treated cells.	('activity', 'MPA', (10, 18))	('ESE-15-one', 'Chemical', '-', (22, 32))	('Caspase 3', 'Gene', (0, 9))	('doubled', 'PosReg', (69, 76))	('Caspase 3', 'Gene', '836', (0, 9))	('EMBS', 'Chemical', 'MESH:D004977', (38, 42))	('ESE-15-one-', 'Var', (22, 33))
38165	24039728	In another study conducted in our laboratory caspase 3 activity was increased (8-fold) in HeLa cells after exposure to ESE-16 (data not shown).	('HeLa', 'CellLine', 'CVCL:0030', (90, 94))	('ESE-16', 'Var', (119, 125))	('caspase 3', 'Gene', (45, 54))	('activity', 'MPA', (55, 63))	('caspase 3', 'Gene', '836', (45, 54))	('ESE-16', 'Chemical', 'MESH:C588027', (119, 125))	('increased', 'PosReg', (68, 77))
38167	24039728	The antiproliferative effect of 2ME2 has been shown to stem from its ability to inhibit tubulin assembly by interacting at the colchicine site of tubulin.	('interacting', 'Interaction', (108, 119))	('2ME2', 'Chemical', 'MESH:D000077584', (32, 36))	('tubulin', 'Protein', (88, 95))	('inhibit', 'NegReg', (80, 87))	('2ME2', 'Var', (32, 36))	('antiproliferative effect', 'CPA', (4, 28))	('colchicine', 'Chemical', 'MESH:D003078', (127, 137))
38168	24039728	ESE-16 was shown to exert a more pronounced effect on tubulin polymerization when compared to the other analogues and to colchicine-treated cells.	('ESE-16', 'Var', (0, 6))	('colchicine', 'Chemical', 'MESH:D003078', (121, 131))	('tubulin polymerization', 'MPA', (54, 76))	('ESE-16', 'Chemical', 'MESH:C588027', (0, 6))
38183	24039728	Research conducted in our laboratory indicated that other analogues of 2ME2 had an inhibitory effect on cell growth in this range (0.2 muM-1 muM) in several cell lines including the MCF-7 cell line and esophageal carcinoma SNO cells.	('esophageal carcinoma', 'Disease', (202, 222))	('MCF-7', 'CellLine', 'CVCL:0031', (182, 187))	('muM', 'Gene', '56925', (141, 144))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (202, 222))	('2ME2', 'Chemical', 'MESH:D000077584', (71, 75))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (202, 222))	('muM', 'Gene', '56925', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('inhibitory effect', 'NegReg', (83, 100))	('muM', 'Gene', (141, 144))	('muM', 'Gene', (135, 138))	('cell growth', 'CPA', (104, 115))	('2ME2', 'Gene', (71, 75))	('analogues', 'Var', (58, 67))
38206	24039728	In conclusion, this work has produced evidence that these novel sulphamoylated 2ME2 analogues, ESE-15-one, EMBS and ESE-16 exert antiproliferative effects in vitro and induce apoptosis in a human cervical adenocarcinoma cell line with insignificant influences on LDH release.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('adenocarcinoma', 'Disease', 'MESH:D000230', (205, 219))	('apoptosis', 'CPA', (175, 184))	('antiproliferative effects', 'CPA', (129, 154))	('induce', 'PosReg', (168, 174))	('ESE-15-one', 'Chemical', '-', (95, 105))	('ESE-16', 'Chemical', 'MESH:C588027', (116, 122))	('human', 'Species', '9606', (190, 195))	('2ME2', 'Chemical', 'MESH:D000077584', (79, 83))	('ESE-16', 'Var', (116, 122))	('adenocarcinoma', 'Disease', (205, 219))	('EMBS', 'Chemical', 'MESH:D004977', (107, 111))
38291	22426086	A meta-analysis of nine epidemiologic studies pooling 1813 cancer cases demonstrated a 43% decreased rate of esophageal cancer in patients on NSAIDs, 50% for those on aspirin, and suggested a dose response.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('NSAIDs', 'Var', (142, 148))	('aspirin', 'Chemical', 'MESH:D001241', (167, 174))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('patients', 'Species', '9606', (130, 138))	('esophageal cancer', 'Disease', (109, 126))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('decreased', 'NegReg', (91, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
38341	22426086	The protective effect of aspirin use appears robust as our analysis suggests a dose response relationship in which the high-dose aspirin (> 325 mg/day) is significantly associated with decreased BE risk.	('decreased', 'NegReg', (185, 194))	('aspirin', 'Chemical', 'MESH:D001241', (129, 136))	('aspirin', 'Chemical', 'MESH:D001241', (25, 32))	('> 325 mg/day', 'Var', (138, 150))
38353	22426086	Stratifying aspirin use by dosage revealed that only the high-dose aspirin (> 325 mg/day) is significantly associated with a decreased risk of BE.	('aspirin', 'Chemical', 'MESH:D001241', (12, 19))	('aspirin', 'Chemical', 'MESH:D001241', (67, 74))	('decreased', 'NegReg', (125, 134))	('> 325 mg/day', 'Var', (76, 88))
38427	33435255	reported that among patients with stage I lung adenocarcinoma, those with high IL-6 and IL-17A levels had a lower 5-year survival rate (46%) than those with low levels of both markers (93%), with a similar trend having been observed for the prognostic signatures of IL-6 and IL-17A in an independent data set.	('5-year survival rate', 'CPA', (114, 134))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (42, 61))	('IL-6', 'Gene', (266, 270))	('IL-17A', 'Gene', (275, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('high', 'Var', (74, 78))	('IL-6', 'Gene', '3569', (266, 270))	('IL-17A', 'Gene', (88, 94))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (42, 61))	('lower', 'NegReg', (108, 113))	('IL-17A', 'Gene', '3605', (275, 281))	('patients', 'Species', '9606', (20, 28))	('IL-17A', 'Gene', '3605', (88, 94))	('IL-6', 'Gene', (79, 83))	('lung adenocarcinoma', 'Disease', (42, 61))	('IL-6', 'Gene', '3569', (79, 83))
38428	33435255	Multivariate analyses in another study revealed that although the NLR was not predictive of overall survival (OS), a high NLR was an independent risk factor for recurrence, in addition to age, stage, tumor differentiation, and lymphatic invasion.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('recurrence', 'Disease', (161, 171))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('high', 'Var', (117, 121))
38435	33435255	Subgroup analyses further revealed that a low ALI had a significant negative prognostic value in NSCLC, with a low ALI being clearly associated with lower PFS and recurrence-free survival (RFS) in patients with NSCLC.	('low', 'Var', (111, 114))	('patients', 'Species', '9606', (197, 205))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('NSCLC', 'Disease', (97, 102))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))	('PFS', 'MPA', (155, 158))	('RFS', 'Disease', (189, 192))	('NSCLC', 'Disease', (211, 216))	('RFS', 'Disease', 'MESH:D005198', (189, 192))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('lower', 'NegReg', (149, 154))	('recurrence-free survival', 'CPA', (163, 187))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
38444	33435255	Moreover, the inhibition of p21 synthesis increases the rate of cell division and accelerates cell cycle progression from G0 arrest to the G1 phase, the G1 phase to the S phase, and the G2 phase to the M phase.	('arrest', 'Disease', 'MESH:D006323', (125, 131))	('increases', 'PosReg', (42, 51))	('cell division', 'CPA', (64, 77))	('accelerates', 'PosReg', (82, 93))	('p21', 'Gene', (28, 31))	('arrest', 'Disease', (125, 131))	('cell cycle progression', 'CPA', (94, 116))	('inhibition', 'Var', (14, 24))
38464	33435255	Polymorphisms of the cytokine gene are reported to have some effect on breast cancer progression, which also suggests that even a partial reduction in inflammatory signaling may be protective when maintained over time.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('Polymorphisms', 'Var', (0, 13))	('effect', 'Reg', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('cytokine gene', 'Gene', (21, 34))
38492	33435255	Accordingly, patients with advanced gastric cancer have been found to benefit from fluoropyrimidine-based chemotherapy, whereas those with locally advanced gastric cancer were able to achieve an improved OS with the administration of capecitabine and platinum-based regimens.	('fluoropyrimidine', 'Chemical', '-', (83, 99))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('benefit', 'PosReg', (70, 77))	('gastric cancer', 'Disease', (36, 50))	('gastric cancer', 'Disease', (156, 170))	('capecitabine', 'Chemical', 'MESH:D000069287', (234, 246))	('patients', 'Species', '9606', (13, 21))	('fluoropyrimidine-based', 'Var', (83, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (156, 170))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('men', 'Species', '9606', (270, 273))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (156, 170))	('platinum', 'Chemical', 'MESH:D010984', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
38512	33435255	Among the cancer characteristics, low LMR was in close association with tumor presence and microvascular infiltration at the time of transplantation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('microvascular infiltration', 'CPA', (91, 117))	('tumor', 'Disease', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('low LMR', 'Var', (34, 41))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', (10, 16))
38541	33435255	After evaluating the role of GPS in patients with cervical cancer after radical resection, Seebacher's group found that a high GPS assessed before the initial treatment was independently associated with a shorter survival time.	('GPS', 'Disease', (29, 32))	('patients', 'Species', '9606', (36, 44))	('high', 'Var', (122, 126))	('GPS', 'Disease', (127, 130))	('survival time', 'CPA', (213, 226))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('shorter', 'NegReg', (205, 212))	('GPS', 'Disease', 'MESH:D055652', (29, 32))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('GPS', 'Disease', 'MESH:D055652', (127, 130))	('men', 'Species', '9606', (164, 167))
38573	33435255	According to earlier studies, most of which were retrospective in nature, allogeneic blood transfusions were associated with the increased risk of postoperative cancer recurrence and death.	('death', 'Disease', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('allogeneic', 'Var', (74, 84))	('postoperative cancer', 'Disease', (147, 167))	('postoperative cancer', 'Disease', 'MESH:D009369', (147, 167))	('death', 'Disease', 'MESH:D003643', (183, 188))
38622	31608927	In brief, the first survey consisted of the clinical work-up and treatment recommendations of all patients presenting with a new diagnosis of esophageal or gastric cancer (C15.0-C15.9 and C16.0-C16.9 according to ICD-10, C16.0A-C16.0C being coded as esophageal cancer according to TNM-7).	('C16.0A-C16.0C', 'Var', (221, 234))	('C16', 'CellLine', 'CVCL:2322', (228, 231))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('C16', 'CellLine', 'CVCL:2322', (221, 224))	('gastric cancer', 'Phenotype', 'HP:0012126', (156, 170))	('esophageal', 'Disease', (142, 152))	('C16', 'CellLine', 'CVCL:2322', (188, 191))	('C16.0-C16.9', 'Var', (188, 199))	('cancer', 'Disease', (261, 267))	('gastric cancer', 'Disease', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('patients', 'Species', '9606', (98, 106))	('men', 'Species', '9606', (80, 83))	('cancer', 'Disease', (164, 170))	('C16', 'CellLine', 'CVCL:2322', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('men', 'Species', '9606', (70, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (156, 170))	('cancer', 'Disease', 'MESH:D009369', (261, 267))
38686	32678196	GSK3beta-specific inhibitors and small interfering (si)RNA-mediated knockdown of GSK3beta attenuated tumor cell survival and proliferation, while inducing apoptosis in ESCC cells and their xenograft tumors in mice.	('mice', 'Species', '10090', (209, 213))	('tumors', 'Disease', (199, 205))	('attenuated tumor', 'Disease', (90, 106))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('attenuated tumor', 'Disease', 'MESH:C538265', (90, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('S', 'Chemical', 'MESH:D012694', (1, 2))	('S', 'Chemical', 'MESH:D012694', (169, 170))	('inducing', 'Reg', (146, 154))	('GSK3beta', 'Gene', (81, 89))	('S', 'Chemical', 'MESH:D012694', (82, 83))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('apoptosis', 'CPA', (155, 164))	('inhibitors', 'Var', (18, 28))
38687	32678196	GSK3beta inhibition spared TYNEK-3 cells and the vital organs of mice.	('spared', 'NegReg', (20, 26))	('Y', 'Chemical', 'MESH:D015019', (28, 29))	('inhibition', 'Var', (9, 19))	('mice', 'Species', '10090', (65, 69))	('GSK3beta', 'Protein', (0, 8))	('TYNEK-3 cells', 'CPA', (27, 40))
38710	32678196	Upon turning from the inactive to active form following phosphorylation of its tyrosine (Y) 216 residue, GSK3beta has been shown to participate in various diseases including glucose intolerance, neurodegenerative disorders, and chronic inflammatory and immunological diseases.	('neurodegenerative disorders', 'Disease', (195, 222))	('tyrosine', 'Chemical', 'MESH:D014443', (79, 87))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (195, 222))	('participate', 'Reg', (132, 143))	('glucose intolerance', 'Phenotype', 'HP:0001952', (174, 193))	('phosphorylation', 'Var', (56, 71))	('immunological diseases', 'Disease', 'MESH:D007154', (253, 275))	('glucose intolerance', 'Disease', (174, 193))	('GSK3beta', 'Gene', (105, 113))	('glucose', 'Chemical', 'MESH:D005947', (174, 181))	('Y', 'Chemical', 'MESH:D015019', (89, 90))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (195, 222))	('immunological diseases', 'Disease', (253, 275))
38711	32678196	Despite its functions against some pro-oncogenic pathways in untransformed cells, we have shown that aberrant expression and activity of GSK3beta in tumors sustains tumor cell survival and proliferation as well as invasion and therapy resistance in gastrointestinal and pancreatic cancer, glioblastoma and bone and soft tissue sarcomas.	('pancreatic cancer', 'Disease', 'MESH:D010190', (270, 287))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (315, 335))	('GSK3beta', 'Gene', (137, 145))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (289, 301))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('pancreatic cancer', 'Disease', (270, 287))	('proliferation', 'CPA', (189, 202))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('glioblastoma', 'Disease', (289, 301))	('glioblastoma', 'Phenotype', 'HP:0012174', (289, 301))	('tumors sustains tumor', 'Disease', 'MESH:D009369', (149, 170))	('therapy resistance', 'CPA', (227, 245))	('activity', 'MPA', (125, 133))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (270, 287))	('tumors sustains tumor', 'Disease', (149, 170))	('aberrant', 'Var', (101, 109))	('invasion', 'CPA', (214, 222))	('sarcomas', 'Disease', 'MESH:D012509', (327, 335))	('sarcomas', 'Phenotype', 'HP:0100242', (327, 335))	('sarcomas', 'Disease', (327, 335))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
38737	32678196	Cells seeded in 96-well plates were treated with DMSO or with one of the GSK3beta inhibitors: AR-A014418, SB-216763 or LY2090314 (Sigma-Aldrich) dissolved in DMSO at the indicated final concentration in the medium.	('LY2090314', 'Chemical', 'MESH:C584053', (119, 128))	('GSK3beta', 'Gene', (73, 81))	('SB-216763', 'Chemical', 'MESH:C417521', (106, 115))	('S', 'Chemical', 'MESH:D012694', (51, 52))	('AR-A014418', 'Chemical', 'MESH:C479831', (94, 104))	('DMSO', 'Chemical', 'MESH:D004121', (158, 162))	('S', 'Chemical', 'MESH:D012694', (74, 75))	('S', 'Chemical', 'MESH:D012694', (160, 161))	('S', 'Chemical', 'MESH:D012694', (130, 131))	('AR-A014418', 'Var', (94, 104))	('DMSO', 'Chemical', 'MESH:D004121', (49, 53))	('S', 'Chemical', 'MESH:D012694', (106, 107))	('LY2090314', 'Var', (119, 128))
38751	32678196	injections of DMSO or of the GSK3beta inhibitors AR-A014418 at different doses (2 mg/kg and 5 mg/kg body weight) or LY2090314 (1 mg/kg and 2.5 mg/kg body weight) for 5 weeks.	('AR-A014418', 'Chemical', 'MESH:C479831', (49, 59))	('AR-A014418', 'Gene', (49, 59))	('LY2090314', 'Var', (116, 125))	('DMSO', 'Chemical', 'MESH:D004121', (14, 18))	('LY2090314', 'Chemical', 'MESH:C584053', (116, 125))
38752	32678196	Assuming that total body fluid in mice accounts for about 60% of their body weight, AR-A014418 doses of 2 mg/kg and 5 mg/kg body weight correspond to concentrations of approximately 10 mumol/L and 25 mumol/L in culture media respectively, and LY2090314 doses of 1 mg/kg and 2.5 mg/kg body weight correspond to concentrations of approximately 2 mumol/L and 5 mumol/L, respectively.	('mice', 'Species', '10090', (34, 38))	('AR-A014418', 'Chemical', 'MESH:C479831', (84, 94))	('LY2090314', 'Var', (243, 252))	('AR-A014418', 'Gene', (84, 94))	('LY2090314', 'Chemical', 'MESH:C584053', (243, 252))	('doses', 'Var', (95, 100))
38765	32678196	Apoptosis in tumors was further evaluated by immunofluorescence staining of paraformaldehyde-fixed tumor sections with antibodies against PARP (1:500, Cell Signaling Technology) and c-PARP (1:500, Cell Signaling Technology) followed by nuclear staining with 4',6-diamidino-2-phenylindole (DAPI; H-1200, Vector Laboratories).	('tumor', 'Disease', (13, 18))	('DAPI', 'Chemical', 'MESH:C007293', (289, 293))	('S', 'Chemical', 'MESH:D012694', (156, 157))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('PARP', 'Gene', '142', (138, 142))	('tumor', 'Disease', (99, 104))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (76, 92))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('S', 'Chemical', 'MESH:D012694', (202, 203))	('PARP', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Disease', (13, 19))	('PARP', 'Gene', '142', (184, 188))	('1:500', 'Var', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PARP', 'Gene', (184, 188))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	("4',6-diamidino-2-phenylindole", 'Chemical', 'MESH:C007293', (258, 287))
38770	32678196	Increased expression and activity of GSK3beta in ESCC cells was also supported by the finding that S641 phosphorylation of GS (pGSS641, inactive form), the primary substrate of GSK3beta, was higher in ESCC than in TYNEK-3 cells (Supplementary Information, Fig.	('higher', 'PosReg', (191, 197))	('GS', 'Disease', 'MESH:D011125', (177, 179))	('S', 'Chemical', 'MESH:D012694', (124, 125))	('phosphorylation', 'MPA', (104, 119))	('S', 'Chemical', 'MESH:D012694', (130, 131))	('ESCC', 'Disease', (201, 205))	('S', 'Chemical', 'MESH:D012694', (99, 100))	('S', 'Chemical', 'MESH:D012694', (178, 179))	('GS', 'Disease', 'MESH:D011125', (128, 130))	('S', 'Chemical', 'MESH:D012694', (202, 203))	('expression', 'MPA', (10, 20))	('S', 'Chemical', 'MESH:D012694', (50, 51))	('S', 'Chemical', 'MESH:D012694', (129, 130))	('GS', 'Disease', 'MESH:D011125', (37, 39))	('S', 'Chemical', 'MESH:D012694', (229, 230))	('Y', 'Chemical', 'MESH:D015019', (215, 216))	('activity', 'MPA', (25, 33))	('S', 'Chemical', 'MESH:D012694', (38, 39))	('S641', 'Var', (99, 103))	('GS', 'Disease', 'MESH:D011125', (123, 125))	('pGSS641', 'Chemical', '-', (127, 134))
38775	32678196	GSK3beta expression and levels of pGSK3betaY216 and pGSS641 in the primary tumors were increased in most cases compared with normal squamous mucosa.	('increased', 'PosReg', (87, 96))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('pGSK3betaY216', 'Chemical', '-', (34, 47))	('pGSS641', 'Chemical', '-', (52, 59))	('pGSK3betaY216', 'Var', (34, 47))	('expression', 'MPA', (9, 19))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('levels', 'MPA', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('GSK3beta', 'Protein', (0, 8))	('pGSS641', 'Var', (52, 59))
38779	32678196	Significant association was also found between the level of pGSK3betaY216 and the presence of lymph node metastasis (Table 1).	('S', 'Chemical', 'MESH:D012694', (62, 63))	('lymph node metastasis', 'CPA', (94, 115))	('pGSK3betaY216', 'Var', (60, 73))	('pGSK3betaY216', 'Chemical', '-', (60, 73))	('S', 'Chemical', 'MESH:D012694', (0, 1))
38780	32678196	Levels of GSK3beta and pGSK3betaY216 in the tumors tended to be associated with advanced tumor stages (III and IV), although this did not reach statistical significance (P = 0.22; Table 1).	('GSK3beta', 'Protein', (10, 18))	('associated', 'Reg', (64, 74))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('pGSK3betaY216', 'Var', (23, 36))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('pGSK3betaY216', 'Chemical', '-', (23, 36))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (89, 94))
38784	32678196	Together, the results obtained with the ESCC cells and primary tumors suggest that deregulated expression and activity of GSK3beta is a characteristic of ESCC and facilitates its progression.	('S', 'Chemical', 'MESH:D012694', (41, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('S', 'Chemical', 'MESH:D012694', (123, 124))	('S', 'Chemical', 'MESH:D012694', (155, 156))	('activity', 'MPA', (110, 118))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('ESCC', 'Disease', (154, 158))	('facilitates', 'PosReg', (163, 174))	('progression', 'CPA', (179, 190))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('deregulated', 'Var', (83, 94))	('GSK3beta', 'Gene', (122, 130))	('expression', 'MPA', (95, 105))
38786	32678196	Treatment with the GSK3beta inhibitors (AR-A014418, SB-216763) reduced viability of all ESCC cells in a dose- and time-dependent manner, while sparing normal TYNEK-3 cells (Fig.	('AR-A014418', 'Var', (40, 50))	('reduced', 'NegReg', (63, 70))	('Y', 'Chemical', 'MESH:D015019', (159, 160))	('S', 'Chemical', 'MESH:D012694', (52, 53))	('viability', 'MPA', (71, 80))	('SB-216763', 'Chemical', 'MESH:C417521', (52, 61))	('AR-A014418', 'Chemical', 'MESH:C479831', (40, 50))	('SB-216763', 'Gene', (52, 61))	('S', 'Chemical', 'MESH:D012694', (89, 90))	('S', 'Chemical', 'MESH:D012694', (20, 21))
38789	32678196	The IC50 values of both inhibitors at 48 h after treatment were within the reported pharmacological dose range (1-100 mumol/L) for AR-A014418 and SB-216763.	('SB-216763', 'Chemical', 'MESH:C417521', (146, 155))	('SB-216763', 'Var', (146, 155))	('AR-A014418', 'Chemical', 'MESH:C479831', (131, 141))	('AR-A014418', 'Var', (131, 141))
38793	32678196	Treatment with LY2090314 within the reported pharmacological dose range showed therapeutic effects against ESCC cells that were comparable to AR-A014418 and SB-216763.	('SB-216763', 'Chemical', 'MESH:C417521', (157, 166))	('ESCC cells', 'Disease', (107, 117))	('S', 'Chemical', 'MESH:D012694', (108, 109))	('AR-A014418', 'Chemical', 'MESH:C479831', (142, 152))	('LY2090314', 'Var', (15, 24))	('LY2090314', 'Chemical', 'MESH:C584053', (15, 24))	('S', 'Chemical', 'MESH:D012694', (157, 158))
38802	32678196	These results indicate that ESCC depends on aberrant GSK3beta activity for tumor cell survival and proliferation and for evasion of apoptosis, thus implicating this kinase as a potential therapeutic target in ESCC.	('S', 'Chemical', 'MESH:D012694', (210, 211))	('activity', 'MPA', (62, 70))	('S', 'Chemical', 'MESH:D012694', (29, 30))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('S', 'Chemical', 'MESH:D012694', (54, 55))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('GSK3beta', 'Protein', (53, 61))	('evasion of apoptosis', 'MPA', (121, 141))	('ESCC', 'Disease', (28, 32))	('aberrant', 'Var', (44, 52))	('tumor', 'Disease', (75, 80))
38808	32678196	In line with these effects, inhibition of GSK3beta decreased the expression of cyclin D1 and CDK4, which as a complex enable cells to enter G1-phase.	('cyclin D1', 'Gene', (79, 88))	('GSK3beta', 'Protein', (42, 50))	('CDK4', 'Gene', '1019', (93, 97))	('enable', 'PosReg', (118, 124))	('decreased', 'NegReg', (51, 60))	('inhibition', 'Var', (28, 38))	('expression', 'MPA', (65, 75))	('cyclin D1', 'Gene', '595', (79, 88))	('CDK4', 'Gene', (93, 97))
38809	32678196	Inhibition of GSK3beta also increased the expression of cyclin B1 (Fig.	('increased', 'PosReg', (28, 37))	('GSK3beta', 'Protein', (14, 22))	('cyclin B1', 'Gene', '891', (56, 65))	('cyclin B1', 'Gene', (56, 65))	('expression', 'MPA', (42, 52))	('Inhibition', 'Var', (0, 10))
38811	32678196	These alterations in cell cycle profiles and in the expression of cell cycle regulatory molecules are consistent with our previous study showing that inhibition of GSK3beta induced mitotic catastrophe following G2/M-phase cell cycle arrest in colorectal cancer cells, ultimately resulting in apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('colorectal cancer', 'Disease', (243, 260))	('arrest', 'Disease', (233, 239))	('inhibition', 'Var', (150, 160))	('resulting in', 'Reg', (279, 291))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (222, 239))	('colorectal cancer', 'Disease', 'MESH:D015179', (243, 260))	('mitotic catastrophe', 'CPA', (181, 200))	('apoptosis', 'CPA', (292, 301))	('colorectal cancer', 'Phenotype', 'HP:0003003', (243, 260))	('GSK3beta', 'Gene', (164, 172))	('arrest', 'Disease', 'MESH:D006323', (233, 239))	('induced', 'Reg', (173, 180))
38812	32678196	This also suggests the large majority of ESCC cells with GSK3beta inhibition in the G2/M phase undergo apoptosis and only cells that survive enter the next round of cell cycle, which is reflected by decreased EdU labeling by GSK3beta inhibition (Fig.	('S', 'Chemical', 'MESH:D012694', (58, 59))	('S', 'Chemical', 'MESH:D012694', (226, 227))	('undergo', 'Reg', (95, 102))	('S', 'Chemical', 'MESH:D012694', (42, 43))	('decreased', 'NegReg', (199, 208))	('enter', 'Reg', (141, 146))	('EdU', 'Chemical', 'MESH:C031086', (209, 212))	('GSK3beta', 'Gene', (57, 65))	('EdU labeling', 'MPA', (209, 221))	('inhibition', 'Var', (66, 76))	('ESCC', 'Disease', (41, 45))	('apoptosis', 'CPA', (103, 112))
38817	32678196	The inhibitors included AR-A014418 and LY2090314, with the latter having previously been tested in clinical trials.	('LY2090314', 'Chemical', 'MESH:C584053', (39, 48))	('LY2090314', 'Var', (39, 48))	('AR-A014418', 'Chemical', 'MESH:C479831', (24, 34))	('AR-A014418', 'Var', (24, 34))
38820	32678196	Compared to DMSO, treatment of mice with AR-A014418 and LY2090314 significantly reduced the xenograft tumor volume in a dose- and time-dependent manner (Fig.	('DMSO', 'Chemical', 'MESH:D004121', (12, 16))	('AR-A014418', 'Chemical', 'MESH:C479831', (41, 51))	('LY2090314', 'Var', (56, 65))	('LY2090314', 'Chemical', 'MESH:C584053', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('AR-A014418', 'Var', (41, 51))	('reduced', 'NegReg', (80, 87))	('mice', 'Species', '10090', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
38825	32678196	We compared the level of pGSK3betaY216 (active form) in the tumors of mice treated with DMSO or with the GSK3beta inhibitors.	('DMSO', 'Chemical', 'MESH:D004121', (88, 92))	('pGSK3betaY216', 'Chemical', '-', (25, 38))	('mice', 'Species', '10090', (70, 74))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('pGSK3betaY216', 'Var', (25, 38))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
38826	32678196	Immunohistochemistry showed significantly lower levels of pGSK3betaY216 in the tumors of inhibitor-treated mice (Fig.	('levels', 'MPA', (48, 54))	('pGSK3betaY216', 'Chemical', '-', (58, 71))	('lower', 'NegReg', (42, 47))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('mice', 'Species', '10090', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('pGSK3betaY216', 'Var', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
38832	32678196	S5, S6), the GSK3beta inhibitors significantly reduced tumor cell proliferation (Ki-67-positive cells), pGSS641 level and cyclin D1 expression, while inducing apoptosis (TUNEL- and c-PARP-positive cells) (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('S', 'Chemical', 'MESH:D012694', (107, 108))	('cyclin D1', 'Gene', '595', (122, 131))	('S', 'Chemical', 'MESH:D012694', (106, 107))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('pGSS641', 'Var', (104, 111))	('level', 'MPA', (112, 117))	('PARP', 'Gene', '142', (183, 187))	('inducing', 'Reg', (150, 158))	('PARP', 'Gene', (183, 187))	('reduced', 'NegReg', (47, 54))	('S', 'Chemical', 'MESH:D012694', (14, 15))	('pGSS641', 'Chemical', '-', (104, 111))	('tumor', 'Disease', (55, 60))	('cyclin D1', 'Gene', (122, 131))	('S', 'Chemical', 'MESH:D012694', (4, 5))	('expression', 'MPA', (132, 142))	('apoptosis', 'CPA', (159, 168))
38843	32678196	Several previous studies on the tumor-suppressive roles of GSK3beta in various oncogenic pathways showed that it was inactivated mostly through S9 phosphorylation.	('GSK3beta', 'Protein', (59, 67))	('S', 'Chemical', 'MESH:D012694', (60, 61))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('S9 phosphorylation', 'Var', (144, 162))	('oncogenic pathways', 'Pathway', (79, 97))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('S', 'Chemical', 'MESH:D012694', (144, 145))	('S', 'Chemical', 'MESH:D012694', (0, 1))
38844	32678196	However, there was no evidence that active GSK3beta suppresses the development and progression of tumors by disrupting the major proto-oncogenic (e.g., Wnt/beta-catenin) pathways (reviewed in Ref.).	('active', 'Var', (36, 42))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('beta-catenin', 'Gene', (156, 168))	('GSK3beta', 'Gene', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('beta-catenin', 'Gene', '1499', (156, 168))	('disrupting', 'NegReg', (108, 118))	('suppresses', 'NegReg', (52, 62))	('development', 'CPA', (67, 78))
38849	32678196	), inhibition of GSK3beta attenuated tumor cell survival and proliferation and induced apoptosis in ESCC cells and in xenograft tumors.	('S', 'Chemical', 'MESH:D012694', (18, 19))	('S', 'Chemical', 'MESH:D012694', (101, 102))	('inhibition', 'Var', (3, 13))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('apoptosis', 'CPA', (87, 96))	('attenuated tumor', 'Disease', (26, 42))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('attenuated tumor', 'Disease', 'MESH:C538265', (26, 42))	('induced', 'Reg', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('GSK3beta', 'Protein', (17, 25))
38856	32678196	We and others have previously shown that inhibition of GSK3beta in human colon and breast cancer cells induced mitotic catastrophe by disturbing centrosome dynamics and the assembly of spindle apparatus, with the cells ultimately undergoing apoptosis.	('GSK3beta', 'Protein', (55, 63))	('undergoing', 'Reg', (230, 240))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('centrosome dynamics', 'MPA', (145, 164))	('inhibition', 'Var', (41, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('disturbing', 'NegReg', (134, 144))	('assembly', 'MPA', (173, 181))	('human', 'Species', '9606', (67, 72))	('induced', 'Reg', (103, 110))	('colon and breast cancer', 'Disease', 'MESH:D001943', (73, 96))	('mitotic catastrophe', 'CPA', (111, 130))
38857	32678196	Overall, our results suggest that ESCC cells depend on deregulated GSK3beta for their survival and proliferation via cyclin D1 and CDK4-mediated G0/G1-phase cell cycle progression and G2/M-phase cell cycle transition.	('S', 'Chemical', 'MESH:D012694', (68, 69))	('CDK4', 'Gene', (131, 135))	('cyclin D1', 'Gene', (117, 126))	('S', 'Chemical', 'MESH:D012694', (35, 36))	('CDK4', 'Gene', '1019', (131, 135))	('GSK3beta', 'Gene', (67, 75))	('G2/M-phase cell cycle transition', 'CPA', (184, 216))	('G0/G1-phase cell cycle progression', 'CPA', (145, 179))	('deregulated', 'Var', (55, 66))	('proliferation', 'CPA', (99, 112))	('cyclin D1', 'Gene', '595', (117, 126))
38866	32678196	Among the biological hallmark characteristics of cancer, aberrant glycolysis as represented by the Warburg effect is the strongest and most critical selective pressure for cellular transformation and malignant evolution in the majority of cancer types, including ESCC.	('S', 'Chemical', 'MESH:D012694', (264, 265))	('ESCC', 'Disease', (263, 267))	('aberrant glycolysis', 'Phenotype', 'HP:0004366', (57, 76))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('glycolysis', 'MPA', (66, 76))	('cancer', 'Disease', (49, 55))	('aberrant', 'Var', (57, 65))
38869	32678196	Accordingly, our observations suggest that deregulated GSK3beta may shift ESCC cell metabolism from glycogenesis to the glycolytic pathway.	('GSK3beta', 'Protein', (55, 63))	('S', 'Chemical', 'MESH:D012694', (56, 57))	('glycogen', 'Chemical', 'MESH:D006003', (100, 108))	('deregulated', 'Var', (43, 54))	('ESCC', 'Disease', (74, 78))	('glycogenesis', 'MPA', (100, 112))	('shift', 'Reg', (68, 73))	('S', 'Chemical', 'MESH:D012694', (75, 76))
38935	31350957	However, in recent years 18FDG PET/CT has shown a better diagnostic accuracy for nodal and distant metastasis compared to contrast enhanced CT (Lu et al., 2016).	('18FDG', 'Chemical', 'MESH:C586095', (25, 30))	('18FDG', 'Var', (25, 30))	('nodal', 'Gene', '4838', (81, 86))	('nodal', 'Gene', (81, 86))
38940	31350957	This could be explained by a significantly higher sensitivity (up to 90%) of 18FDG PET/CT for distant nodal metastasis than locoregional nodes (Napier et al., 2014).	('higher', 'PosReg', (43, 49))	('18FDG PET/CT', 'Var', (77, 89))	('18FDG', 'Chemical', 'MESH:C586095', (77, 82))	('nodal', 'Gene', (102, 107))	('nodal', 'Gene', '4838', (102, 107))
38941	31350957	A meta-analysis of 12 previous studies revealed that sensitivity of 18FDG PET/CT for regional nodal metastasis was significantly lower than that of CT (51% vs 63%-87%), but the specificity was higher than CT (84% vs. 14%-43%) (Cho et al., 2014).	('nodal', 'Gene', '4838', (94, 99))	('nodal', 'Gene', (94, 99))	('18FDG', 'Var', (68, 73))	('18FDG', 'Chemical', 'MESH:C586095', (68, 73))	('lower', 'NegReg', (129, 134))
38948	31350957	This could be explained by established higher diagnostic accuracy of 18FDG PET/CT than CT for distant metastasis (Napier et al., 2014) and stringent CT reporting criteria adopted by our radiologists.	('18FDG', 'Var', (69, 74))	('higher', 'PosReg', (39, 45))	('distant metastasis', 'CPA', (94, 112))	('18FDG', 'Chemical', 'MESH:C586095', (69, 74))
39130	27145272	Notably, MIA promotes cell detachment, migration, and invasion and suppresses cancer cell apoptosis and lymphokine activated killer cell (LAK) infiltration.	('suppresses', 'NegReg', (67, 77))	('invasion', 'CPA', (54, 62))	('promotes', 'PosReg', (13, 21))	('cell detachment', 'CPA', (22, 37))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('migration', 'CPA', (39, 48))	('men', 'Species', '9606', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('MIA', 'Var', (9, 12))
39137	27145272	Similar to MIA, MIA2 might also interact with fibronectin, which induces T lymphocyte chemotaxis when combined with stromal cell-derived factor 1alpha; therefore, MIA or MIA2 might suppress T lymphocyte chemotaxis by masking fibronectin.	('fibronectin', 'Protein', (225, 236))	('suppress', 'NegReg', (181, 189))	('MIA2', 'Gene', (170, 174))	('suppress T lymphocyte', 'Phenotype', 'HP:0005419', (181, 202))	('MIA2', 'Gene', '4253', (170, 174))	('MIA2', 'Gene', (16, 20))	('MIA', 'Var', (163, 166))	('T lymphocyte chemotaxis', 'CPA', (190, 213))	('MIA2', 'Gene', '4253', (16, 20))	('masking', 'NegReg', (217, 224))
39169	27145272	TaqMan Gene Expression Assays of MIA(Hs00197954_m1), MIA2 (Hs00365015_m1), MIA3 (TANGO) (Hs00412706_m1), and GAPDH (ID: Hs03929097_g1) were purchased from Applied Biosystems.	('GAPDH', 'Gene', (109, 114))	('MIA3', 'Gene', (75, 79))	('Hs00412706_m1', 'Var', (89, 102))	('MIA3', 'Gene', '375056', (75, 79))	('TANGO', 'Gene', (81, 86))	('MIA2', 'Gene', (53, 57))	('Hs00365015_m1', 'Var', (59, 72))	('MIA2', 'Gene', '4253', (53, 57))	('Hs00197954_m1', 'Var', (37, 50))	('GAPDH', 'Gene', '2597', (109, 114))	('TANGO', 'Gene', '375056', (81, 86))
39180	24724049	SUVmax (p = 0.029), rMTV50% (p = 0.016), rMTV75% (p = 0.023) on intra-treatment PET were found to correlate with complete clinical response.	('complete clinical response', 'CPA', (113, 139))	('MTV', 'Chemical', '-', (21, 24))	('MTV', 'Chemical', '-', (42, 45))	('rMTV75%', 'Var', (41, 48))	('rMTV50%', 'Var', (20, 27))
39256	24724049	However, SUVmax (p = 0.029), rMTV50% (p = 0.016), rMTV75% (p = 0.023) by intra-CRT PET ware found to correlated with cCR.	('rMTV75%', 'Var', (50, 57))	('MTV', 'Chemical', '-', (51, 54))	('SUVmax', 'MPA', (9, 15))	('correlated', 'Reg', (101, 111))	('cCR', 'Disease', (117, 120))	('MTV', 'Chemical', '-', (30, 33))	('rMTV50', 'MPA', (29, 35))
39257	24724049	Regarding changes in PET signals between pre-CRT to intra-CRT, rMTV50% (p = 0.016) showed the strongest correlation with cCR (Table 5).	('MTV', 'Chemical', '-', (64, 67))	('rMTV50%', 'Var', (63, 70))	('PET signals', 'MPA', (21, 32))
39286	24724049	found a rMTV2.5 of <36% had a median overall survival of 34.1 months versus 21.8 months for a rMTV2.5 of >=37%, and that MTV and TGA were good predictors of pathologic response and survival.	('TGA', 'Gene', '6899', (129, 132))	('MTV', 'Chemical', '-', (121, 124))	('rMTV2.5', 'Var', (8, 15))	('TGA', 'Gene', (129, 132))	('overall survival', 'MPA', (37, 53))	('MTV', 'Chemical', '-', (95, 98))	('MTV', 'Chemical', '-', (9, 12))
39290	24724049	We found SUVmax (p = 0.029), rMTV50% (p = 0.016), rMTV75% (p = 0.023) values as determined by intra-CRT PET correlated with cCR (Table 4).	('rMTV75%', 'Var', (50, 57))	('MTV', 'Chemical', '-', (51, 54))	('cCR', 'Disease', (124, 127))	('MTV', 'Chemical', '-', (30, 33))	('rMTV50', 'MPA', (29, 35))
39292	24724049	Regarding, changes between pre-CRT and intra-CRT PET, rMTV50% (p = 0.016) was found to be most correlated with clinical complete response (Table 5).	('correlated', 'Reg', (95, 105))	('clinical', 'Disease', (111, 119))	('MTV', 'Chemical', '-', (55, 58))	('rMTV50%', 'Var', (54, 61))
39295	24724049	In fact, the sensitivity and specificity of a rMTV50% of 0.57 were 100%, and 57% for cCR.	('rMTV50%', 'Var', (46, 53))	('MTV', 'Chemical', '-', (47, 50))	('cCR', 'Disease', (85, 88))
39297	24724049	The present study shows that rMTV50% (p = 0.016) during CRT was useful predictor of cCR, although the reason for this finding is not clear.	('rMTV50%', 'Var', (29, 36))	('cCR', 'Disease', (84, 87))	('MTV', 'Chemical', '-', (30, 33))
39299	24724049	Our results show the use of one of these in isolation is inadequate for predicting clinical response during CRT, and suggested that rMTV50% provides a more accurate means of predicting total tumor activity and clinical response.	('rMTV50%', 'Var', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('MTV', 'Chemical', '-', (133, 136))
39332	32166547	Devascularisation also included dissection of the short gastric arteries along the gastric fundus.	('gastric fundus', 'Disease', 'MESH:D013274', (83, 97))	('dissection', 'Var', (32, 42))	('Devascularisation', 'Disease', (0, 17))	('gastric fundus', 'Disease', (83, 97))
39343	32166547	The most frequent indication was a stenosis of the coeliac trunk (TC) (10 of 21 patients, 47.6%).	('coeliac trunk', 'Phenotype', 'HP:0012327', (51, 64))	('stenosis', 'Var', (35, 43))	('patients', 'Species', '9606', (80, 88))	('coeliac trunk', 'Disease', (51, 64))
39366	32166547	The incidence of anastomotic leak in patients with stenosis was 19.4% compared to 2.3% in patients without stenosis and multivariable analysis identified stenosis as independent risk factor of leakage.	('stenosis', 'Var', (51, 59))	('patients', 'Species', '9606', (37, 45))	('anastomotic leak', 'Disease', (17, 33))	('stenosis', 'Disease', (154, 162))	('patients', 'Species', '9606', (90, 98))
39487	33202734	A higher than median expression of the immunosuppressive cytokine IL-10 in treatment-naive serum was associated with a shortened survival time, in agreement with other studies in gastrointestinal cancers and a meta-analysis of 21 studies on 1788 patients with various cancer types, which showed that high serum IL-10 was associated with worse clinical outcomes.	('patients', 'Species', '9606', (246, 254))	('shortened', 'NegReg', (119, 128))	('IL-10', 'Gene', (311, 316))	('high serum IL-10', 'Phenotype', 'HP:0030783', (300, 316))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('gastrointestinal cancers', 'Disease', (179, 203))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('survival time', 'CPA', (129, 142))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', (268, 274))	('higher', 'PosReg', (2, 8))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('IL-10', 'Gene', '3586', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('expression', 'MPA', (21, 31))	('high serum', 'Var', (300, 310))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (179, 203))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (179, 202))	('IL-10', 'Gene', (66, 71))	('IL-10', 'Gene', '3586', (311, 316))
39498	33202734	Esophageal cancer studies have demonstrated that FGF2 overexpression is associated with a risk of recurrence of disease as well as reduced OS post-surgical resection.	('FGF2', 'Gene', '2247', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('FGF2', 'Gene', (49, 53))	('reduced', 'NegReg', (131, 138))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('overexpression', 'Var', (54, 68))	('cancer', 'Disease', (11, 17))
39527	32047812	The deletion of p53 gene is common in esophageal cancer, but its pathogenesis is still unclear.	('common', 'Reg', (28, 34))	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('p53', 'Gene', (16, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('deletion', 'Var', (4, 12))
39541	32047812	As known, p53 mutations occur in half of human cancers.	('occur', 'Reg', (24, 29))	('human', 'Species', '9606', (41, 46))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (14, 23))	('p53', 'Gene', (10, 13))
39542	32047812	As a tumor suppressor, p53 can repair cells damage and clear cells that cannot be repaired.	('p53', 'Var', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (5, 10))
39543	32047812	Therefore, once p53 mutation or deletion occurs, which will lead to the loss of the control of cell proliferation and cell carcinogenesis.	('control of cell proliferation', 'CPA', (84, 113))	('deletion', 'Var', (32, 40))	('loss', 'NegReg', (72, 76))	('carcinogenesis', 'Disease', 'MESH:D063646', (123, 137))	('p53', 'Gene', (16, 19))	('mutation', 'Var', (20, 28))	('carcinogenesis', 'Disease', (123, 137))
39544	32047812	As one of the most common protein variants expressed in cancer cells, p53 mutations occur in more than half of colorectal cancers and the loss of p53 is examined on gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (165, 187))	('p53', 'Gene', (70, 73))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (165, 187))	('cancer', 'Disease', (122, 128))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('colorectal cancers', 'Disease', 'MESH:D015179', (111, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('colorectal cancers', 'Disease', (111, 129))	('occur', 'Reg', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
39545	32047812	There is also some evidence that p53 mutations or deletions are closely related to esophageal cancer.	('esophageal cancer', 'Disease', (83, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('mutations', 'Var', (37, 46))	('p53', 'Gene', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('related', 'Reg', (72, 79))	('deletions', 'Var', (50, 59))
39546	32047812	For example, aberrant p53 gene alleles are common genetic events in the pathogenesis of ESCC; Kruppel-like factor 5 loss harboring mutant p53 leads to the formation of invasive tumors.	('invasive tumors', 'Disease', 'MESH:D009361', (168, 183))	('ESCC', 'Disease', (88, 92))	('p53', 'Gene', (138, 141))	('mutant', 'Var', (131, 137))	('invasive tumors', 'Disease', (168, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('loss', 'NegReg', (116, 120))	('Kruppel-like factor 5', 'Gene', '12224', (94, 115))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('Kruppel-like factor 5', 'Gene', (94, 115))
39558	32047812	Briefly, B6.p53flox/flox mice were crossbred with ED-L2-Cre+/- mice to generate two genotypes mice: B6.p53flox/wild.ED-L2-Cre+/- and B6.p53flox/wild.ED-L2-Cre-/-.	('mice', 'Species', '10090', (25, 29))	('B6.p53flox/wild.ED-L2-Cre+/-', 'Var', (100, 128))	('mice', 'Species', '10090', (63, 67))	('mice', 'Species', '10090', (94, 98))	('B6.p53flox/wild.ED-L2-Cre-/-', 'Var', (133, 161))
39559	32047812	The mice of genotype B6.p53flox/wild.ED-L2-Cre+/- were mated with each other and screened out two genotypes of mice: B6.p53flox/flox.ED-L2-Cre+/- (KO mice) and B6.p53flox/flox.ED-L2-Cre-/-(Loxp mice).	('B6.p53flox/flox.ED-L2-Cre+/-', 'Var', (117, 145))	('mice', 'Species', '10090', (150, 154))	('mice', 'Species', '10090', (4, 8))	('mice', 'Species', '10090', (111, 115))	('mice', 'Species', '10090', (194, 198))	('B6.p53flox/flox.ED-L2-Cre-/-', 'Var', (160, 188))
39601	32047812	We also found that p53 KO mice were more susceptible to lesions than Loxp mice.	('mice', 'Species', '10090', (74, 78))	('p53 KO', 'Var', (19, 25))	('susceptible', 'Reg', (41, 52))	('mice', 'Species', '10090', (26, 30))
39611	32047812	When the mice were fed for 48 weeks after the first injection, the degree of lesions in the p53 KO mice group treated with NMBA showed severe dysplasia, while the degree of lesions in the control group treated with NMBA was only mild dysplasia (Figure 3(b)) and the number of lesions at all levels in the KO mice group was significantly larger than that in the control group (Figure 3(c)).	('mice', 'Species', '10090', (99, 103))	('dysplasia', 'Disease', (142, 151))	('NMBA', 'Var', (123, 127))	('mice', 'Species', '10090', (308, 312))	('p53', 'Var', (92, 95))	('dysplasia', 'Disease', 'MESH:D015792', (234, 243))	('dysplasia', 'Disease', (234, 243))	('mice', 'Species', '10090', (9, 13))	('dysplasia', 'Disease', 'MESH:D015792', (142, 151))
39615	32047812	Compared with control group treated with NMBA, the expression of Ki67 protein and Bcl-2 protein was significantly increased (Figures 4(a) and 4(c)) and the expression of P21 protein and Bax protein was significantly reduced in the p53 KO mice group (Figures 4(b) and 4(d)).	('reduced', 'NegReg', (216, 223))	('Bax', 'Gene', (186, 189))	('Ki67', 'Gene', '17345', (65, 69))	('P21', 'Gene', (170, 173))	('increased', 'PosReg', (114, 123))	('p53 KO', 'Var', (231, 237))	('P21', 'Gene', '12575', (170, 173))	('mice', 'Species', '10090', (238, 242))	('expression', 'MPA', (51, 61))	('Bcl-2', 'Gene', '12043', (82, 87))	('Bcl-2', 'Gene', (82, 87))	('expression', 'MPA', (156, 166))	('Bax', 'Gene', '12028', (186, 189))	('Ki67', 'Gene', (65, 69))
39622	32047812	In this study, we established a mice model of esophageal precancerous lesions by specific knockout of p53 in the esophageal epithelium and induction of NMBA.	('esophageal precancerous lesions', 'Disease', (46, 77))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (46, 77))	('NMBA', 'CPA', (152, 156))	('mice', 'Species', '10090', (32, 36))	('induction', 'Reg', (139, 148))	('p53', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('knockout', 'Var', (90, 98))
39626	32047812	The present study has demonstrated that p53-KO mice in esophageal epithelium are more susceptible to esophageal precancerous lesions induced by NMBA than mice of genotype p53flox/floxCre-/-.	('esophageal precancerous lesions', 'Disease', (101, 132))	('mice', 'Species', '10090', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (101, 132))	('p53-KO', 'Var', (40, 46))	('susceptible', 'Reg', (86, 97))	('mice', 'Species', '10090', (47, 51))
39629	32047812	The expression of Ki67, as a proliferation marker, in the esophageal mucosa of the NMBA-treated P53 knockout group increased significantly.	('increased', 'PosReg', (115, 124))	('Ki67', 'Gene', '17345', (18, 22))	('expression', 'MPA', (4, 14))	('P53', 'Gene', (96, 99))	('knockout', 'Var', (100, 108))	('P53', 'Gene', '22059', (96, 99))	('Ki67', 'Gene', (18, 22))
39637	32047812	To further verify the relationship between p53 deletion and NMBA induction and esophageal cancer, we knocked down p53 gene in normal esophageal cells.	('esophageal cancer', 'Disease', (79, 96))	('p53', 'Gene', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('deletion', 'Var', (47, 55))	('p53', 'Gene', (43, 46))
39643	32014008	Epigenetic induction of tumor stemness via the lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma Esophageal squamous cell cancer (ESCC) is one kind of frequent digestive tumor.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (203, 208))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (95, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('ESCC', 'Disease', 'MESH:D018307', (163, 167))	('ESCC', 'Disease', (163, 167))	('digestive tumor', 'Phenotype', 'HP:0007378', (193, 208))	('tumor stemness', 'Disease', 'MESH:D020295', (24, 38))	('HOXB2', 'Gene', '3212', (71, 76))	('TET3', 'Gene', '200424', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('esophageal squamous cell carcinoma', 'Disease', (95, 129))	('tumor', 'Disease', (24, 29))	('tumor stemness', 'Disease', (24, 38))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (141, 161))	('Epigenetic', 'Var', (0, 10))	('TET3', 'Gene', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('HOXB2', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Esophageal squamous cell cancer', 'Disease', (130, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('Esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (130, 161))
39652	32014008	Nano-hmC-Seal-seq showed that TET3 overexpression led to a significant increase in 5hmC levels of HOXB2 gene region, which was thus identified as the downstream target of TET3.	('HOXB2', 'Gene', (98, 103))	('HOXB2', 'Gene', '3212', (98, 103))	('TET3', 'Gene', (30, 34))	('overexpression', 'Var', (35, 49))	('5hmC levels', 'MPA', (83, 94))	('increase', 'PosReg', (71, 79))	('5hmC', 'Chemical', 'MESH:C011865', (83, 87))
39669	32014008	Epigenetic modification has been proved to regulate the multi-step process of tumor development.	('regulate', 'Reg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('Epigenetic modification', 'Var', (0, 23))
39677	32014008	Then, HOXB2 was activated through the demethylation function of TET3 and promoted the transcription activity of stemness-related genes, cMYC and NANOG.	('promoted', 'PosReg', (73, 81))	('TET3', 'Gene', (64, 68))	('HOXB2', 'Gene', (6, 11))	('cMYC', 'Gene', '4609', (136, 140))	('HOXB2', 'Gene', '3212', (6, 11))	('NANOG', 'Gene', '79923', (145, 150))	('demethylation', 'Var', (38, 51))	('transcription activity', 'MPA', (86, 108))	('cMYC', 'Gene', (136, 140))	('NANOG', 'Gene', (145, 150))
39685	32014008	The human ESCC cell line (ECa109, KYSE510, KYSE150, TE-1) and human normal esophageal mucosa epithelium cell line (HEEC) were purchased from the Chinese Academy of Sciences.	('ESCC', 'Disease', 'MESH:D018307', (10, 14))	('human', 'Species', '9606', (4, 9))	('human', 'Species', '9606', (62, 67))	('HEEC', 'CellLine', 'CVCL:3285', (115, 119))	('ECa109', 'CellLine', 'CVCL:6898', (26, 32))	('ESCC', 'Disease', (10, 14))	('KYSE150', 'Var', (43, 50))
39688	32014008	We introduced dCas9-VP64 and pMS2-p65-HSF1 into cells by infection and established stable transductants.	('dCas9-VP64', 'Var', (14, 24))	('VP64', 'Chemical', 'MESH:D005047', (20, 24))	('HSF1', 'Gene', (38, 42))	('p65', 'Gene', (34, 37))	('HSF1', 'Gene', '3297', (38, 42))	('pMS2', 'Gene', (29, 33))	('pMS2', 'Gene', '5395', (29, 33))	('infection', 'Disease', (57, 66))	('p65', 'Gene', '5970', (34, 37))	('infection', 'Disease', 'MESH:D007239', (57, 66))
39741	32014008	In the analysis of survival, we applied IHC in tissue microarray and uncovered that patients with high level of TET3 suffered shorter 5-year OS than the patients with low level of TET3 did (Fig.	('TET3', 'Var', (112, 116))	('shorter', 'NegReg', (126, 133))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (84, 92))	('high level', 'Var', (98, 108))	('5-year OS', 'MPA', (134, 143))
39742	32014008	The analysis of correlationship between TET3 and clinicopathological features showed that male patients and poor tumor differentiation were significantly associated with TET3 high expression level (Table 1).	('TET3', 'Gene', (170, 174))	('tumor', 'Disease', (113, 118))	('patients', 'Species', '9606', (95, 103))	('high', 'Var', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('associated', 'Reg', (154, 164))
39744	32014008	The survival analysis showed that, when patients were distributed into high/low differentiation groups or high/low stage groups, high level of TET3 led to a shorter 5-year OS than low level of TET3 did in each distribution (Additional file 1: Figures S2A-S2D).	('5-year OS', 'MPA', (165, 174))	('patients', 'Species', '9606', (40, 48))	('TET3', 'Var', (143, 147))	('shorter', 'NegReg', (157, 164))
39749	32014008	FACS data showed that in ESCC tissues, CD133, an acknowledged and classical stem cell marker, expression was significantly higher in TET3-high cells than in TET3-low cells (Fig.	('TET3-high cells', 'Var', (133, 148))	('ESCC', 'Disease', 'MESH:D018307', (25, 29))	('higher', 'PosReg', (123, 129))	('CD133', 'Gene', (39, 44))	('ESCC', 'Disease', (25, 29))	('CD133', 'Gene', '8842', (39, 44))	('expression', 'MPA', (94, 104))
39754	32014008	Meanwhile, cells with overexpression of TET3 could form significantly larger tumors in nude mice than the normal control group did in vivo (Additional file 1: Figure S4).	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('larger', 'PosReg', (70, 76))	('overexpression', 'PosReg', (22, 36))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TET3', 'Var', (40, 44))	('nude mice', 'Species', '10090', (87, 96))
39764	32014008	Meanwhile, knockdown of TET3 could reverse the up-regulation of HOXB2 induced with LPS (Additional file 1: Figure S6A).	('LPS', 'Gene', '21898', (83, 86))	('HOXB2', 'Gene', (64, 69))	('LPS', 'Gene', (83, 86))	('HOXB2', 'Gene', '3212', (64, 69))	('TET3', 'Gene', (24, 28))	('up-regulation', 'PosReg', (47, 60))	('knockdown', 'Var', (11, 20))
39765	32014008	Furthermore, knockdown of HOXB2 had no influence in TET3 expression (Additional file 1: Fig.	('HOXB2', 'Gene', '3212', (26, 31))	('knockdown', 'Var', (13, 22))	('HOXB2', 'Gene', (26, 31))	('TET3 expression', 'MPA', (52, 67))
39766	32014008	In addition, RT-qPCR showed that knockdown of HOXB2 deceased stemness-related genes expression in ov-control groups and ov-TET3 groups (Fig.	('deceased', 'NegReg', (52, 60))	('knockdown', 'Var', (33, 42))	('stemness-related genes', 'Gene', (61, 83))	('HOXB2', 'Gene', (46, 51))	('HOXB2', 'Gene', '3212', (46, 51))
39771	32014008	Then RT-qPCR was applied to detect TET3 expression and showed that SB202190 and U0126 decreased TET3 expression significantly, while BAY11-7082 failed to inhibit the LPS stimulation on TET3 expression (Fig.	('U0126', 'Var', (80, 85))	('SB202190', 'Var', (67, 75))	('TET3 expression', 'MPA', (96, 111))	('LPS', 'Gene', '21898', (166, 169))	('BAY11-7082', 'Chemical', 'MESH:C434003', (133, 143))	('U0126', 'Chemical', 'MESH:C113580', (80, 85))	('decreased', 'NegReg', (86, 95))	('LPS', 'Gene', (166, 169))	('SB202190', 'Chemical', 'MESH:C090942', (67, 75))
39773	32014008	We further proved that SB202190 and U0126 successfully blocked the LPS simulation of stemness-related genes expression (Fig.	('U0126', 'Var', (36, 41))	('LPS', 'Gene', '21898', (67, 70))	('LPS', 'Gene', (67, 70))	('SB202190', 'Chemical', 'MESH:C090942', (23, 31))	('U0126', 'Chemical', 'MESH:C113580', (36, 41))	('blocked', 'NegReg', (55, 62))	('SB202190', 'Var', (23, 31))
39793	32014008	TET1 was proved to be fused to the mixed lineage of leukemia gene in a case of pediatric AML containing the t(10;11) (q22;q23).	('t(10;11) (q22;q23', 'Var', (108, 125))	('TET1', 'Gene', '80312', (0, 4))	('leukemia', 'Disease', (52, 60))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('leukemia', 'Disease', 'MESH:D007938', (52, 60))	('TET1', 'Gene', (0, 4))
39795	32014008	However, TET2 was reported to play a regulatory role in myeloproliferative neoplasms and myelodysplastic syndromes in the form of functional deletion mutations, whereas TET1 and TET3 were rarely characterized of functional deletion mutations to function in hematological tumors.	('deletion mutations', 'Var', (141, 159))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('TET2', 'Gene', '54790', (9, 13))	('TET1', 'Gene', (169, 173))	('neoplasms', 'Phenotype', 'HP:0002664', (75, 84))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (56, 84))	('hematological tumors', 'Disease', 'MESH:D019337', (257, 277))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('TET2', 'Gene', (9, 13))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (89, 114))	('myeloproliferative neoplasms and myelodysplastic syndromes', 'Disease', 'MESH:D054437', (56, 114))	('TET1', 'Gene', '80312', (169, 173))	('hematological tumors', 'Disease', (257, 277))
39828	22507242	Targeting epigenetic mediators of gene expression in thoracic malignancies Lung and esophageal cancers and malignant pleural mesotheliomas are highly lethal neoplasms that are leading causes of cancer-related deaths worldwide.	('pleural mesotheliomas', 'Disease', 'MESH:D008654', (117, 138))	('pleura', 'Disease', 'MESH:D054363', (117, 123))	('neoplasms', 'Disease', 'MESH:D009369', (157, 166))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('thoracic malignancies', 'Disease', (53, 74))	('death', 'Disease', 'MESH:D003643', (209, 214))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('neoplasms', 'Disease', (157, 166))	('epigenetic', 'Var', (10, 20))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (107, 138))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('pleura', 'Disease', (117, 123))	('esophageal cancers', 'Disease', (84, 102))	('malignancies', 'Disease', (62, 74))	('malignant pleural mesotheliomas', 'Disease', (107, 138))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (117, 138))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('death', 'Disease', (209, 214))	('mesothelioma', 'Disease', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('thoracic malignancies', 'Disease', 'MESH:D009369', (53, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('mesothelioma', 'Disease', 'MESH:D008654', (125, 137))	('esophageal cancers', 'Disease', 'MESH:D004938', (84, 102))
39835	22507242	Although recent studies suggest that global DNA demethylation may be linked to aberrant DNA repair, decreased DNMT1 expression, replication independent DNA demethylases, or formation of 5-hydroxymethylcytosine, the mechanisms mediating genomic demethylation in thoracic malignancies remain elusive.	('expression', 'MPA', (116, 126))	('DNMT1', 'Gene', (110, 115))	('DNMT1', 'Gene', '1786', (110, 115))	('aberrant', 'Var', (79, 87))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (186, 209))	('decreased', 'NegReg', (100, 109))	('DNA repair', 'Gene', (88, 98))	('DNMT', 'Gene', '1786', (110, 114))	('DNMT', 'Gene', (110, 114))
39839	22507242	Global DNA demethylation also results in de-repression of a variety of genes that are silent in normal somatic cells, yet exhibit stage-specific expression during germ cell development in testes or ovary (Table 1).	('testes or ovary', 'Disease', 'MESH:D013736', (188, 203))	('de-repression', 'NegReg', (41, 54))	('demethylation', 'Var', (11, 24))	('testes or ovary', 'Disease', (188, 203))
39841	22507242	Although several studies have suggested that de-repression of CT genes enhances the malignant phenotype of cancer cells by up-regulation of additional CT genes, activation of telomerase, induction of cell cycle progression and inhibition of p53 function, or increasing resistance to death receptor ligands, radiation or chemotherapeutic agents, limited evidence indicates that CT gene activation directly impacts prognosis of patients with thoracic malignancies.	('CT genes', 'Gene', (62, 70))	('patients', 'Species', '9606', (426, 434))	('telomerase', 'Protein', (175, 185))	('increasing', 'PosReg', (258, 268))	('activation', 'PosReg', (161, 171))	('inhibition', 'NegReg', (227, 237))	('patient', 'Species', '9606', (426, 433))	('enhances', 'PosReg', (71, 79))	('resistance', 'CPA', (269, 279))	('cell cycle progression', 'CPA', (200, 222))	('de-repression', 'Var', (45, 58))	('thoracic malignancies', 'Disease', (440, 461))	('impacts', 'Reg', (405, 412))	('p53', 'Gene', '7157', (241, 244))	('CT genes', 'Gene', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('malignant phenotype of cancer cells', 'CPA', (84, 119))	('p53', 'Gene', (241, 244))	('up-regulation', 'PosReg', (123, 136))
39850	22507242	observed that methylation of cdk2a, p16, CDH13, RASSF1A, and APC in resected early stage (node negative) lung cancers was associated with tumor recurrence, independent of histology or stage, gender, or smoking history.	('APC', 'Gene', (61, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('lung cancers', 'Phenotype', 'HP:0100526', (105, 117))	('CDH13', 'Gene', '1012', (41, 46))	('cdk2a', 'Gene', (29, 34))	('CDH1', 'Gene', '999', (41, 45))	('associated with', 'Reg', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('RASSF1A', 'Gene', (48, 55))	('methylation', 'Var', (14, 25))	('tumor recurrence', 'CPA', (138, 154))	('lung cancers', 'Disease', (105, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('RASSF1A', 'Gene', '11186', (48, 55))	('CDH13', 'Gene', (41, 46))	('CDH1', 'Gene', (41, 45))	('p16', 'Gene', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
39852	22507242	Combinatorial effects of DNMT1 and 3b, DMNT1 and MBD2, and DNMT3b and MBD2 were evident in male patients, and those with squamous cell carcinomas.	('MBD2', 'Gene', (49, 53))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (121, 145))	('MBD2', 'Gene', (70, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('DNMT3b', 'Var', (59, 65))	('DNMT1 and 3b', 'Gene', '1786;1789', (25, 37))	('squamous cell carcinomas', 'Disease', (121, 145))	('DMNT1', 'Gene', (39, 44))
39853	22507242	Collectively, aforementioned clinical data as well as laboratory experiments indicating that knock-down of DNMT1 and/or 3b induces genotoxic stress and apoptosis, whereas knock-down of MBD2 inhibits growth and tumorigenicity of cultured lung cancer cells, attest to the relevance of aberrant expression of these modulators of DNA methylation during pulmonary carcinogenesis.	('pulmonary carcinogenesis', 'Disease', 'MESH:D063646', (349, 373))	('tumorigenicity', 'CPA', (210, 224))	('induces', 'Reg', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (237, 248))	('inhibits', 'NegReg', (190, 198))	('genotoxic stress', 'MPA', (131, 147))	('knock-down', 'Var', (93, 103))	('pulmonary carcinogenesis', 'Disease', (349, 373))	('apoptosis', 'CPA', (152, 161))	('DNMT1', 'Gene', (107, 112))
39859	22507242	CIMP positivity correlated with more advanced TNM stage and metastases.	('TNM', 'Gene', (46, 49))	('positivity', 'Var', (5, 15))	('metastases', 'Disease', (60, 70))	('TNM', 'Gene', '10178', (46, 49))	('CIMP', 'Gene', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (60, 70))
39860	22507242	who observed that patients with esophageal adenocarcinomas exhibiting methylation of >50% of seven TSGs had significantly poorer survival and earlier tumor recurrence than patients without such methylation.	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('adenocarcinomas', 'Disease', (43, 58))	('adenocarcinoma', 'Disease', (43, 57))	('tumor recurrence', 'CPA', (150, 166))	('survival', 'CPA', (129, 137))	('TSGs', 'Gene', (99, 103))	('adenocarcinoma', 'Disease', 'MESH:D000230', (43, 57))	('esophageal adenocarcinomas', 'Disease', (32, 58))	('methylation', 'Var', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('poorer', 'NegReg', (122, 128))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (32, 58))	('adenocarcinomas', 'Disease', 'MESH:D000230', (43, 58))
39861	22507242	Furthermore, patients with tumors exhibiting methylation of any two or all three of these TSGs did significantly worse than those with no methylation of these genes, suggesting that the extent of DNA methylation coincided with aggressive tumor phenotype.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('aggressive tumor', 'Disease', 'MESH:D001523', (227, 243))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('methylation', 'Var', (45, 56))	('methylation', 'Var', (200, 211))	('aggressive tumor', 'Disease', (227, 243))
39863	22507242	Patients undergoing extra-pleural pneumonectomy for MPM with DNA methylation had shorter median overall survivals compared to patients with tumors lacking methylation of these genes (16 vs. 35 months; p=0.06).	('DNA', 'Gene', (61, 64))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('overall survivals', 'MPA', (96, 113))	('Patients', 'Species', '9606', (0, 8))	('methylation', 'Var', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('shorter', 'NegReg', (81, 88))
39864	22507242	Lysine rich tails of core histone proteins (H2A, H2B, H3, and H4), protrude from the nucleosome, providing sites for highly diverse, reversible, covalent modifications such as acetylation, methylation, phosphorylation, sumoylation, and ubiquitination that alter chromatin structure and modulate gene expression.	('acetylation', 'MPA', (176, 187))	('gene expression', 'MPA', (295, 310))	('alter', 'Reg', (256, 261))	('phosphorylation', 'MPA', (202, 217))	('methylation', 'Var', (189, 200))	('chromatin structure', 'MPA', (262, 281))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('modulate', 'Reg', (286, 294))	('sumoylation', 'Var', (219, 230))	('ubiquitination', 'MPA', (236, 250))
39869	22507242	In a recent study, lung cancer patients with high intratumor levels of HDAC3 had significantly shorter disease-free survivals than patients whose tumors exhibited low HDAC3 expression.	('shorter', 'NegReg', (95, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('disease-free survivals', 'CPA', (103, 125))	('high', 'Var', (45, 49))	('HDAC3', 'Gene', '8841', (71, 76))	('HDAC3', 'Gene', '8841', (167, 172))	('HDAC3', 'Gene', (71, 76))	('HDAC3', 'Gene', (167, 172))	('lung cancer', 'Disease', (19, 30))
39875	22507242	observed up-regulation of LSD1, which catalyzes demethylation of H3K4Me2/Me1 and possibly H3K9Me2/Me1, in small cell lung cancers relative to normal lung tissues; knock-down of LSD1 induced G1 arrest without apotosis in cultured lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('Me1', 'Gene', '4199', (98, 101))	('up-regulation', 'PosReg', (9, 22))	('arrest', 'Disease', 'MESH:D006323', (193, 199))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('Me1', 'Gene', '4199', (73, 76))	('apotosis', 'Disease', (208, 216))	('knock-down', 'Var', (163, 173))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (106, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('arrest', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('apotosis', 'Disease', 'None', (208, 216))	('Me1', 'Gene', (98, 101))	('LSD1', 'Gene', (177, 181))	('LSD1', 'Gene', (26, 30))	('lung cancers', 'Phenotype', 'HP:0100526', (117, 129))	('Me1', 'Gene', (73, 76))
39876	22507242	observed that knock-down of EZH2, which mediates trimethylation of H3K27,or knockdown of SETDB1, G9a, and SUV39H1, which methylate H3K9, inhibited proliferation and soft agar colony formation of immortalized or fully transformed respiratory epithelial cells, implicating these modifiers of histone methylation in the pathogenesis of lung cancer.	('SETDB1', 'Gene', (89, 95))	('lung cancer', 'Disease', (333, 344))	('knockdown', 'Var', (76, 85))	('inhibited', 'NegReg', (137, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (333, 344))	('respiratory epithelia', 'Phenotype', 'HP:0012253', (229, 250))	('respiratory epithelia', 'Disease', (229, 250))	('EZH2', 'Gene', '2146', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('EZH2', 'Gene', (28, 32))	('knock-down', 'Var', (14, 24))	('SETDB1', 'Gene', '9869', (89, 95))	('SUV39H1', 'Gene', (106, 113))	('methylate', 'Var', (121, 130))	('SUV39H1', 'Gene', '6839', (106, 113))	('respiratory epithelia', 'Disease', 'MESH:D012131', (229, 250))	('proliferation', 'CPA', (147, 160))
39880	22507242	Interestingly, the four groups comprising Stage I patients displayed dramatic differences, with a median survival of ten months for adenocarcinoma patients with high-level intratumoral H3K9Ac, compared to 147 months for non-adenocarcinoma patients with high-level intratumoral H3K4Me2 expression.	('H3K9Ac', 'Var', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('non-adenocarcinoma', 'Disease', 'MESH:D000230', (220, 238))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('non-adenocarcinoma', 'Disease', (220, 238))	('high-level intratumoral H3K9Ac', 'Var', (161, 191))	('adenocarcinoma', 'Disease', (132, 146))
39883	22507242	Low levels of H3K18Ac and H3K27Me3 were associated with improved prognosis in early stage tumors.	('H3K27Me3', 'Var', (26, 34))	('stage tumors', 'Disease', 'MESH:D062706', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('improved', 'PosReg', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('H3K18Ac', 'Var', (14, 21))	('early', 'Disease', (78, 83))	('stage tumors', 'Disease', (84, 96))
39884	22507242	Polycomb group proteins (PcG) have emerged as critical epigenetic mediators of pluripotency and differentiation of stem cells, as well as aberrant gene repression during malignant transformation.	('aberrant gene repression', 'Var', (138, 162))	('pluripotency', 'Disease', (79, 91))	('PcG', 'Gene', (25, 28))	('pluripotency', 'Disease', 'None', (79, 91))
39887	22507242	observed polycomb-mediated repression of Dickkopf-1 (Dkk-1), which encodes a secreted antagonist of Wnt signaling in normal human small airway epithelial and lung cancer cells exposed to cigarette smoke.	('Dkk-1', 'Gene', (53, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Dickkopf-1', 'Gene', (41, 51))	('Dickkopf-1', 'Gene', '22943', (41, 51))	('repression', 'NegReg', (27, 37))	('Dkk-1', 'Gene', '22943', (53, 58))	('polycomb-mediated', 'Var', (9, 26))
39888	22507242	Knock-down of KMT6 inhibited proliferation and tumorigenicity of lung cancer cells.	('KMT6', 'Gene', (14, 18))	('inhibited', 'NegReg', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('KMT6', 'Gene', '2146', (14, 18))	('Knock-down', 'Var', (0, 10))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('tumorigenicity', 'CPA', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))
39889	22507242	Furthermore, several micro-RNAs such as miR-101 and miR-26a, and miR98 which target the 3' UTR of EZH2 are down-regulated in aerodigestive tract cancers.	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('EZH2', 'Gene', (98, 102))	('miR-26a', 'Gene', '407015', (52, 59))	('tract cancers', 'Disease', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('miR98', 'Gene', '407054', (65, 70))	('tract cancers', 'Disease', 'MESH:D014571', (139, 152))	('down-regulated', 'NegReg', (107, 121))	('miR-101', 'Var', (40, 47))	('miR-26a', 'Gene', (52, 59))	('miR98', 'Gene', (65, 70))
39894	22507242	Aberrant expression of EZH2 correlated with larger, more invasive tumors, distant metastases and shorter disease free survival.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Aberrant expression', 'Var', (0, 19))	('invasive tumors', 'Disease', (57, 72))	('distant metastases', 'CPA', (74, 92))	('invasive tumors', 'Disease', 'MESH:D009369', (57, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('disease free survival', 'CPA', (105, 126))	('shorter', 'NegReg', (97, 104))	('more', 'PosReg', (52, 56))	('EZH2', 'Gene', (23, 27))
39895	22507242	The effects of PRC-2 knock-down were recapitulated by the nucleoside analog, 3-deazaneplanocin A (DZNep), which has been shown recently to deplete PRC-2 components in cancer cells.	('DZNep', 'Chemical', 'MESH:C048460', (98, 103))	('PRC-2', 'Gene', (147, 152))	('knock-down', 'Var', (21, 31))	('3-deazaneplanocin A', 'Chemical', 'MESH:C048460', (77, 96))	('deplete', 'NegReg', (139, 146))	('nucleoside', 'Chemical', 'MESH:D009705', (58, 68))	('PRC-2', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
39896	22507242	Alterations in chromatin structure secondary to aberrant expression/function of epigenetic regulators of gene expression in thoracic malignancies result in silencing of numerous tumor suppressor genes via polycomb and DNA hypermethylation mechanisms with paradoxical de-repression of CT genes in thoracic malignancies.	('numerous tumor', 'Disease', 'MESH:D009369', (169, 183))	('silencing', 'NegReg', (156, 165))	('polycomb', 'Var', (205, 213))	('aberrant', 'Var', (48, 56))	('numerous tumor', 'Disease', (169, 183))	('expression/function', 'MPA', (57, 76))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Alterations', 'Reg', (0, 11))	('chromatin', 'MPA', (15, 24))	('de-repression', 'NegReg', (267, 280))
39904	22507242	Nearly one quarter of all patients exhibited expression of p16, MAGE-3, or NY-ESO-1 in post-treatment tumor biopsies.	('p16', 'Var', (59, 62))	('expression', 'MPA', (45, 55))	('MAGE-3', 'Gene', '4102', (64, 70))	('MAGE-3', 'Gene', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('NY-ESO-1', 'Gene', (75, 83))
39910	22507242	In an ongoing phase I dose-escalation trial at the NCI, 22 patients have received sequential Romidepsin/Flavopiridol infusions, based on preclinical studies demonstrating that abrogation of p21 induction by Flavopiridol (a synthetic cdk inhibitor that also destabilizes RNA) markedly enhances DP-mediated apoptosis in cultured lung and esophageal cancer and MPM cells.	('abrogation', 'Var', (176, 186))	('Flavopiridol', 'Chemical', 'MESH:C077990', (104, 116))	('Flavopiridol', 'Chemical', 'MESH:C077990', (207, 219))	('enhances', 'PosReg', (284, 292))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('DP-mediated apoptosis', 'CPA', (293, 314))	('p21', 'Gene', (190, 193))
39949	30574021	The extracted information in each study included: the first author's name, the year of publication, region of the population enrolled, tumor type, sample size (high/low), follow-up time, type of sample detected, the endpoints, high or low expression accounting for poor prognosis, cut-off value, methods of obtaining HRs (directly or indirectly), survival analysis method and Newcastle-Ottawa Scale (NOS) score.	('expression', 'MPA', (239, 249))	('OS', 'Chemical', '-', (401, 403))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('high', 'Var', (227, 231))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
39961	30574021	The pooled HR for OS of patients with high CXCR7 level compared with low expression was 1.72 (95% CI 1.49-1.99, p < 0.001), indicating that high CXCR7 level was markedly related to reduced OS of cancer patients (Fig.	('CXCR7', 'Gene', (43, 48))	('OS', 'Chemical', '-', (189, 191))	('CXCR7', 'Gene', '57007', (145, 150))	('high', 'Var', (140, 144))	('OS', 'Chemical', '-', (18, 20))	('patients', 'Species', '9606', (202, 210))	('patients', 'Species', '9606', (24, 32))	('reduced OS of cancer', 'Disease', 'MESH:C567932', (181, 201))	('reduced OS of cancer', 'Disease', (181, 201))	('CXCR7', 'Gene', '57007', (43, 48))	('CXCR7', 'Gene', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
39988	30574021	The subgroup analyses indicated that the significant association between high CXCR7 expression level and poor OS of tumor patients was not changed by region, sample size, type of cancer, paper quality, source of HR or follow-up time.	('CXCR7', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('OS of tumor', 'Disease', (110, 121))	('type of cancer', 'Disease', 'MESH:D009369', (171, 185))	('OS of tumor', 'Disease', 'MESH:C567932', (110, 121))	('patients', 'Species', '9606', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('CXCR7', 'Gene', '57007', (78, 83))	('high', 'Var', (73, 77))	('type of cancer', 'Disease', (171, 185))
40015	30574021	The high expression of CXCR7 could act as a risk factor for shorter OS, PFS, RFS and DFS in cancer patients based on the current published data.	('DFS', 'Disease', (85, 88))	('cancer', 'Disease', (92, 98))	('CXCR7', 'Gene', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('PFS', 'Disease', (72, 75))	('shorter OS', 'Disease', (60, 70))	('patients', 'Species', '9606', (99, 107))	('CXCR7', 'Gene', '57007', (23, 28))	('high', 'Var', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('OS', 'Chemical', '-', (68, 70))	('RFS', 'Disease', (77, 80))
40094	29126387	However, these refinements also are associated with a significant decrease in blood loss, from 174 mL in the early period to 94.2 mL in the late period, and a significant increase in the number of intrathoracic and total lymph nodes dissected.	('blood loss', 'Disease', 'MESH:D006473', (78, 88))	('decrease', 'NegReg', (66, 74))	('increase', 'PosReg', (171, 179))	('blood loss', 'Disease', (78, 88))	('refinements', 'Var', (15, 26))
40117	28771997	Epac1 acts as a cAMP dependent downstream protein and plays an important role in the progression of the cell cycle.1 Studies have shown that cAMP/Epac1/Rapl signaling pathways are involved in the regulation of various cellular functions, including cell proliferation.2 PDE4 is responsible for the degradation of cAMP.3 Changes in cAMP concentrations can activate different cAMP-dependent proteins and protein kinases, namely, Epac1, AKAP95, and PKC.	('Epac1', 'Gene', (0, 5))	('cAMP', 'Chemical', 'MESH:D000242', (312, 316))	('protein kinases', 'Enzyme', (401, 416))	('activate', 'PosReg', (354, 362))	('PDE4', 'Gene', (269, 273))	('AKAP95', 'Gene', (433, 439))	('cAMP', 'Chemical', 'MESH:D000242', (373, 377))	('cAMP-dependent proteins', 'Enzyme', (373, 396))	('Epac1', 'Gene', '10411', (426, 431))	('Epac1', 'Gene', '10411', (146, 151))	('PKC', 'Gene', '112476', (445, 448))	('AKAP95', 'Gene', '10270', (433, 439))	('Epac1', 'Gene', (426, 431))	('Epac1', 'Gene', (146, 151))	('Changes', 'Var', (319, 326))	('cAMP', 'Chemical', 'MESH:D000242', (16, 20))	('PKC', 'Gene', (445, 448))	('cAMP', 'Chemical', 'MESH:D000242', (330, 334))	('cAMP', 'Chemical', 'MESH:D000242', (141, 145))	('Epac1', 'Gene', '10411', (0, 5))	('PDE4', 'Gene', '5141', (269, 273))
40264	26943443	Collectively, the tumor was diagnosed as primary EACC, T1bN0M0 according to "Japanese Classification of Esophageal Cancer 10th edition."	('tumor', 'Disease', (18, 23))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (104, 121))	('T1bN0M0', 'Var', (55, 62))	('EACC', 'Chemical', '-', (49, 53))	('Cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('Esophageal Cancer', 'Disease', (104, 121))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
40330	25767603	Conclusions: Our data suggested that deregulation of TCF4 isoforms may contribute to the tumorigenesis of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('contribute', 'Reg', (71, 81))	('ESCC', 'Disease', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('TCF4', 'Gene', (53, 57))	('deregulation', 'Var', (37, 49))	('TCF4', 'Gene', '6925', (53, 57))	('tumor', 'Disease', (89, 94))
40357	25767603	As mentioned above, aberrant expression of Wnt/beta-catenin signal pathway components was found in ESCC, the alterative splicing of TCF4 may contribute to carcinogenesis and tumor progress.	('tumor', 'Disease', (174, 179))	('beta-catenin', 'Gene', '1499', (47, 59))	('found', 'Reg', (90, 95))	('TCF4', 'Gene', '6925', (132, 136))	('TCF4', 'Gene', (132, 136))	('ESCC', 'Disease', (99, 103))	('alterative splicing', 'Var', (109, 128))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('carcinogenesis', 'Disease', 'MESH:D063646', (155, 169))	('expression', 'Species', '29278', (29, 39))	('beta-catenin', 'Gene', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('expression', 'MPA', (29, 39))	('contribute', 'Reg', (141, 151))	('carcinogenesis', 'Disease', (155, 169))
40383	25767603	However, it was not clear whether TCF4N variants also occur in human cell types.	('variants', 'Var', (40, 48))	('TCF4N', 'Chemical', '-', (34, 39))	('TCF4N', 'Gene', (34, 39))	('human', 'Species', '9606', (63, 68))
40384	25767603	We first analyzed the TCF4N variant ESCC cells.	('variant', 'Var', (28, 35))	('TCF4N', 'Chemical', '-', (22, 27))	('TCF4N', 'Gene', (22, 27))	('ESCC', 'Disease', (36, 40))
40387	25767603	Moreover, sequencing analysis showed that TCF4N variant was expressed in human ESCC cells (Fig.	('TCF4N', 'Chemical', '-', (42, 47))	('TCF4N', 'Gene', (42, 47))	('variant', 'Var', (48, 55))	('human', 'Species', '9606', (73, 78))
40388	25767603	To exactly identify all the transcript variants spanning exon 3 to exons 17 in EC109 cells, primer pair located in exon 3(P1F) and exon 17(P3R) was applied to amplify the main body of all the transcript variants, which generate a chief product (Fig.S1C).	('variants', 'Var', (203, 211))	('EC109', 'CellLine', 'CVCL:6898', (79, 84))	('variants', 'Var', (39, 47))
40407	25767603	In order to determine its effects on cell growth in EC109 cells, gene expression of TCF4E knockdown by RNAi with different target site.	('EC109', 'CellLine', 'CVCL:6898', (52, 57))	('knockdown', 'Var', (90, 99))	('expression', 'Species', '29278', (70, 80))	('TCF4', 'Gene', (84, 88))	('TCF4', 'Gene', '6925', (84, 88))
40410	25767603	Simultaneously, cell cycle distribution was also altered by TCF4E knockdown, with decreased S-phase and increased G2 phase (Fig.3C and Supplementary Material: Fig.S3).	('G2 phase', 'CPA', (114, 122))	('altered', 'Reg', (49, 56))	('increased', 'PosReg', (104, 113))	('cell cycle distribution', 'CPA', (16, 39))	('S-phase', 'CPA', (92, 99))	('TCF4', 'Gene', (60, 64))	('TCF4', 'Gene', '6925', (60, 64))	('knockdown', 'Var', (66, 75))	('decreased', 'NegReg', (82, 91))
40432	25767603	Moreover, its splicing was found to be associated with type 2 diabetes.	('associated with', 'Reg', (39, 54))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (55, 70))	('splicing', 'Var', (14, 22))	('diabetes', 'Disease', (62, 70))	('diabetes', 'Disease', 'MESH:D003920', (62, 70))
40439	25767603	Moreover, we convinced the existence of TCF4N variant in human cells, as this isoform has only been reported in mouse but not in human cells.	('variant', 'Var', (46, 53))	('TCF4N', 'Chemical', '-', (40, 45))	('TCF4N', 'Gene', (40, 45))	('human', 'Species', '9606', (129, 134))	('mouse', 'Species', '10090', (112, 117))	('human', 'Species', '9606', (57, 62))
40441	25767603	As it lacks the HMG-box, TCF4N inhibits the activation of beta-catenin-dependent promoter.	('beta-catenin', 'Gene', (58, 70))	('inhibits', 'NegReg', (31, 39))	('beta-catenin', 'Gene', '1499', (58, 70))	('HMG', 'Chemical', 'MESH:D008596', (16, 19))	('TCF4N', 'Chemical', '-', (25, 30))	('TCF4N', 'Var', (25, 30))	('activation', 'MPA', (44, 54))
40444	25767603	According to recent nomenclature of TCF4 variants, the protein products are classified as 3 groups: TCF4E, TCF4M and TCF4S.	('variants', 'Var', (41, 49))	('TCF4', 'Gene', (100, 104))	('TCF4', 'Gene', '6925', (100, 104))	('TCF4', 'Gene', (117, 121))	('TCF4', 'Gene', '6925', (117, 121))	('TCF4', 'Gene', (107, 111))	('TCF4', 'Gene', '6925', (107, 111))	('TCF4', 'Gene', (36, 40))	('TCF4', 'Gene', '6925', (36, 40))
40446	25767603	The protein products encoded by the splicing variants in this study are grouped as TCF4E and TCF4M, which was coincident with the result of Western blotting in EC109 cells (Fig.1).	('TCF4', 'Gene', '6925', (83, 87))	('TCF4', 'Gene', (83, 87))	('variants', 'Var', (45, 53))	('TCF4', 'Gene', (93, 97))	('TCF4', 'Gene', '6925', (93, 97))	('EC109', 'CellLine', 'CVCL:6898', (160, 165))
40458	25767603	The gene functions of splicing isoform TCF4E and TCF4M were analyzed in EC109 cells, and TCF4 potential binding proteins were preliminarily identified by MS. Our data suggested that deregulation of TCF4 isoform may contribute to the tumorigenesis of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('deregulation', 'Var', (182, 194))	('EC109', 'CellLine', 'CVCL:6898', (72, 77))	('TCF4', 'Gene', (89, 93))	('contribute', 'Reg', (215, 225))	('tumor', 'Disease', (233, 238))	('TCF4', 'Gene', '6925', (89, 93))	('TCF4', 'Gene', (49, 53))	('ESCC', 'Disease', (250, 254))	('TCF4', 'Gene', '6925', (49, 53))	('TCF4', 'Gene', (198, 202))	('TCF4', 'Gene', '6925', (198, 202))	('TCF4', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('TCF4', 'Gene', '6925', (39, 43))
40480	25621278	This mechanistic evidence leads us once more to believe that conjugated BA (bile salts), rather than secondary BA, are more likely to induce intestinal metaplasia.	('induce', 'Reg', (134, 140))	('bile salts', 'Chemical', 'MESH:D001647', (76, 86))	('BA', 'Chemical', 'MESH:D001647', (72, 74))	('intestinal metaplasia', 'Disease', (141, 162))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (141, 162))	('BA', 'Chemical', 'MESH:D001647', (111, 113))	('conjugated', 'Var', (61, 71))
40494	25621278	Overall, we believe that the PPI-induced increase of the intra-gastric pH to >4 could promote higher levels of conjugated BA to reach the esophagus.	('PPI-induced', 'Var', (29, 40))	('promote higher', 'PosReg', (86, 100))	('increase', 'PosReg', (41, 49))	('BA', 'Chemical', 'MESH:D001647', (122, 124))
40503	25621278	Interestingly, non-selective NSAID (nsNSAID) - especially aspirin (irreversible COX-1/2 inhibitor) - are strongly associated with decreased risk of EAC in patients with BE.	('EAC', 'Disease', (148, 151))	('aspirin', 'Chemical', 'MESH:D001241', (58, 65))	('BE', 'Phenotype', 'HP:0100580', (169, 171))	('non-selective', 'Var', (15, 28))	('COX-1', 'Gene', '4512', (80, 85))	('COX-1', 'Gene', (80, 85))	('patients', 'Species', '9606', (155, 163))	('EAC', 'Phenotype', 'HP:0011459', (148, 151))	('decreased', 'NegReg', (130, 139))
40505	25621278	Importantly, PGs derived from COX-1, but not COX-2, exert inhibitory effects on acid secretion.	('COX-2', 'Gene', '5743', (45, 50))	('PGs', 'Chemical', 'MESH:D010715', (13, 16))	('acid secretion', 'MPA', (80, 94))	('inhibitory effects', 'MPA', (58, 76))	('PGs', 'Var', (13, 16))	('COX-1', 'Gene', '4512', (30, 35))	('COX-1', 'Gene', (30, 35))	('COX-2', 'Gene', (45, 50))
40506	25621278	Thus, inhibition by non-specific NSAIDs may theoretically increase acid secretion in patients on PPI therapy, thereby countering the acid suppression effect of PPIs and promoting an intra-gastric pH 2-4.	('increase', 'PosReg', (58, 66))	('intra-gastric pH 2-4', 'MPA', (182, 202))	('promoting', 'PosReg', (169, 178))	('patients', 'Species', '9606', (85, 93))	('acid secretion', 'MPA', (67, 81))	('PPI', 'Var', (97, 100))
40525	33605536	In endoscopic core ESCC biopsies taken from 61 patients who underwent neoadjuvant chemotherapy (NAC) (5-fluorouracil and cisplatin), low MRE11A and high UBQLN4 protein levels were associated with reduced pathological response to NAC (P < 0.001 and P < 0.001, respectively).	('low', 'NegReg', (133, 136))	('NAC', 'Chemical', '-', (96, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (102, 116))	('patients', 'Species', '9606', (47, 55))	('MRE11A', 'MPA', (137, 143))	('UBQLN4 protein levels', 'MPA', (153, 174))	('NAC', 'Chemical', '-', (229, 232))	('high', 'Var', (148, 152))	('reduced', 'NegReg', (196, 203))
40526	33605536	Multivariable analysis of surgically resected ESCC tissues from 59 patients revealed low MRE11A and high UBLQN4 expression as independent factors that can predict shorter overall survival [P = 0.01, hazard ratio (HR) = 5.11, 95% confidence interval (CI), 1.45-18.03; P = 0.02, HR = 3.74, 95% CI, 1.19-11.76, respectively].	('UBLQN4', 'Gene', (105, 111))	('patients', 'Species', '9606', (67, 75))	('low', 'NegReg', (85, 88))	('high', 'Var', (100, 104))	('shorter', 'NegReg', (163, 170))	('MRE11A', 'Gene', (89, 95))	('overall survival', 'MPA', (171, 187))	('expression', 'MPA', (112, 122))
40533	33605536	Binding of ubiquilin-4 (UBQLN4) to ubiquitinated-MRE11A increased MRE11A degradation, thereby promoting cisplatin resistance.	('UBQLN4', 'Var', (24, 30))	('MRE11A degradation', 'MPA', (66, 84))	('increased', 'PosReg', (56, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('promoting', 'PosReg', (94, 103))	('cisplatin resistance', 'MPA', (104, 124))	('ubiquilin-4', 'Gene', '56893', (11, 22))	('ubiquilin-4', 'Gene', (11, 22))	('Binding', 'Interaction', (0, 7))
40551	33605536	However, there is no evidence showing whether UBQLN4 has a role in reducing genotoxic stress in ESCC tumor cells during chemotherapy treatment and how that affects the tumor sensitivity to chemotherapy.	('affects', 'Reg', (156, 163))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('genotoxic stress', 'Disease', 'MESH:D000079225', (76, 92))	('genotoxic stress', 'Disease', (76, 92))	('UBQLN4', 'Var', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('reducing', 'NegReg', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
40576	33605536	TE-8 and TE-10 cell lines were transfected with 50 nm pool siRNA MRE11A or nontargeting Pool (L-009271-00-0005 and D-001810-10-05, respectively; Dharmacon) using jetPRIME Polyplus transfection.	('TE', 'Chemical', 'MESH:D013691', (9, 11))	('D-001810-10-05', 'Var', (115, 129))	('TE', 'Chemical', 'MESH:D013691', (0, 2))	('L-009271-00-0005', 'Var', (94, 110))
40602	33605536	Normal adjacent esophageal epithelia showed lower H-score values for MRE11A (n = 7, H-score = 29.9 +- 14.5) compared to primary ESCC tumors (n = 59, H-score = 163.4 +- 75.3, P < 0.0001, Fig.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('lower', 'NegReg', (44, 49))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (16, 36))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('H-score', 'MPA', (50, 57))	('ESCC tumors', 'Disease', (128, 139))	('MRE11A', 'Var', (69, 75))	('ESCC tumors', 'Disease', 'MESH:D004938', (128, 139))
40609	33605536	MRE11A knockdown promoted cisplatin resistance in ESCC cell lines (Fig.	('MRE11A', 'Gene', (0, 6))	('promoted', 'PosReg', (17, 25))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('knockdown', 'Var', (7, 16))	('cisplatin resistance', 'MPA', (26, 46))
40610	33605536	Conversely, MRE11A-OV enhanced cisplatin sensitivity in ESCC cell lines (Fig.	('enhanced', 'PosReg', (22, 30))	('cisplatin sensitivity', 'MPA', (31, 52))	('MRE11A-OV', 'Var', (12, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))
40616	33605536	The results showed that cisplatin-resistant cell lines with MRE11A knockdown were even more resistant to cisplatin compared to the respective parental cell lines (Fig.	('knockdown', 'Var', (67, 76))	('resistant to', 'MPA', (92, 104))	('MRE11A', 'Gene', (60, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))
40619	33605536	MRE11A-OV in cisplatin-resistant cell lines restored the sensitivity to cisplatin (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('MRE11A-OV', 'Var', (0, 9))	('restored', 'PosReg', (44, 52))	('sensitivity to cisplatin', 'MPA', (57, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
40622	33605536	Ectopic OV of GFP-tagged UBQLN4 (UBQLN4-OV) or an EV was performed for TE-8 and TE-10 ESCC cell lines.	('UBQLN4', 'Gene', (25, 31))	('TE', 'Chemical', 'MESH:D013691', (80, 82))	('EV', 'Chemical', '-', (50, 52))	('TE', 'Chemical', 'MESH:D013691', (71, 73))	('GFP-tagged', 'Var', (14, 24))
40630	33605536	Ubiquitinated-MRE11A levels were increased in ESCC cell lines treated with cisplatin in the presence of MG-132 compared to absence of MG-132 (Fig.	('MG-132', 'Chemical', 'MESH:C072553', (104, 110))	('MG-132', 'Var', (104, 110))	('Ubiquitinated-MRE11A levels', 'MPA', (0, 27))	('increased', 'PosReg', (33, 42))	('MG-132', 'Chemical', 'MESH:C072553', (134, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))
40636	33605536	A significant decrease was observed for MRE11A protein levels in UBQLN4-OV compared to the control EV cell lines (Fig.	('UBQLN4-OV', 'Var', (65, 74))	('decrease', 'NegReg', (14, 22))	('MRE11A protein levels', 'MPA', (40, 61))	('EV', 'Chemical', '-', (99, 101))
40641	33605536	The Cancer Genome Atlas database analysis revealed that UBQLN4 was highly expressed (mRNA z-score >= 1.5) in about 24% (23 of 95) and decreased in only 2% (mRNA z-score <= 1.5) of ESCC patients (Fig.	('decreased', 'NegReg', (134, 143))	('UBQLN4', 'Var', (56, 62))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('patients', 'Species', '9606', (185, 193))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('ESCC', 'Disease', (180, 184))
40654	33605536	Next, UBQLN4-OV and control EV cell lines were assessed for cell proliferation and cisplatin resistance.	('cell proliferation', 'CPA', (60, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('UBQLN4-OV', 'Var', (6, 15))	('cisplatin resistance', 'MPA', (83, 103))	('EV', 'Chemical', '-', (28, 30))
40655	33605536	In drug sensitivity assays, UBQLN4-OV cell lines presented cisplatin resistance compared to control EV cell lines (Fig.	('UBQLN4-OV', 'Var', (28, 37))	('cisplatin resistance', 'MPA', (59, 79))	('drug sensitivity', 'Phenotype', 'HP:0020174', (3, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('EV', 'Chemical', '-', (100, 102))
40657	33605536	Since UBQLN4 expression determines resistance to cisplatin in ESCC cell lines, we assumed that UBQLN4 may reduce the DNA damage after cisplatin treatment.	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('reduce', 'NegReg', (106, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('UBQLN4', 'Var', (95, 101))	('DNA damage', 'MPA', (117, 127))
40661	33605536	Then, gamma-H2AX was analyzed by IF in si-Ctrl or si-UBQLN4 TE-4 cell lines cisplatin-treated or untreated.	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('gamma-H2AX', 'Gene', '15270', (6, 16))	('gamma-H2AX', 'Gene', (6, 16))	('si-UBQLN4', 'Var', (50, 59))	('TE', 'Chemical', 'MESH:D013691', (60, 62))
40662	33605536	Consistently, TE-4 cell lines transfected with si-UBQLN4 showed an enhancement in gamma-H2AX activation (Fig.	('gamma-H2AX', 'Gene', '15270', (82, 92))	('enhancement', 'PosReg', (67, 78))	('TE', 'Chemical', 'MESH:D013691', (14, 16))	('gamma-H2AX', 'Gene', (82, 92))	('si-UBQLN4', 'Var', (47, 56))
40664	33605536	Finally, we determined whether knockdown of MRE11A also modified the levels of DNA damage induced by cisplatin.	('levels of DNA damage induced', 'MPA', (69, 97))	('modified', 'Reg', (56, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('MRE11A', 'Gene', (44, 50))	('knockdown', 'Var', (31, 40))
40666	33605536	In order to demonstrate that UBQLN4 localized to DNA damage areas, gamma-H2AX and UBQLN4 were analyzed by IF in si-UBQLN4 and si-Ctrl TE-4 cell lines cisplatin-treated or untreated.	('si-UBQLN4', 'Var', (112, 121))	('si-Ctrl', 'Var', (126, 133))	('gamma-H2AX', 'Gene', (67, 77))	('gamma-H2AX', 'Gene', '15270', (67, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('TE', 'Chemical', 'MESH:D013691', (134, 136))
40671	33605536	However, in certain cancer types, loss of MRE11A and other components of the MRN complex promote a resistant phenotype in response to DNA damage [23, 24, 25].	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('loss', 'Var', (34, 38))	('promote', 'PosReg', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('MRE11A', 'Gene', (42, 48))	('resistant phenotype in response to DNA damage', 'MPA', (99, 144))
40675	33605536	Additionally, our in vitro results demonstrated that UBQLN4 OV alleviated DNA damage induced by cisplatin, while UBQLN4 knockdown caused the opposite effects.	('alleviated', 'NegReg', (63, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('UBQLN4', 'Var', (53, 59))	('DNA damage', 'MPA', (74, 84))
40678	33605536	These results validated our previous observations demonstrating that UBQLN4 and ubiquitinated-MRE11A accumulate at the DSB after inducing DNA damage in other solid tumors [29].	('DNA damage', 'MPA', (138, 148))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('UBQLN4', 'Var', (69, 75))	('accumulate', 'PosReg', (101, 111))	('inducing', 'Reg', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('ubiquitinated-MRE11A', 'Var', (80, 100))
40679	33605536	In addition, we previously demonstrated that high UBQLN4 protein levels activate alternative DDR pathways to overcome MRE11A loss and DNA damage induced by cisplatin and other DNA damage drugs; however, further studies are needed to address this and identify those oncogenic pathways reducing DNA damage in ESCC.	('loss', 'NegReg', (125, 129))	('DDR pathways', 'Pathway', (93, 105))	('MRE11A', 'Gene', (118, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('DDR', 'Chemical', '-', (93, 96))	('high', 'Var', (45, 49))
40683	33605536	Further, we demonstrated that UBQLN4 targets ubiquitinated-MRE11A for degradation and reduced the genotoxic stress.	('UBQLN4', 'Var', (30, 36))	('degradation', 'MPA', (70, 81))	('reduced', 'NegReg', (86, 93))	('genotoxic stress', 'Disease', 'MESH:D000079225', (98, 114))	('ubiquitinated-MRE11A', 'MPA', (45, 65))	('genotoxic stress', 'Disease', (98, 114))
40802	31511230	2258 participants seropositive for antibodies to H pylori were randomly assigned to H pylori treatment, vitamin supplementation, garlic supplementation, or their placebos in a 2x2x2 factorial design, and 1107 H pylori seronegative participants were randomly assigned to vitamin supplementation, garlic supplementation, or their placebos in a 2x2 factorial design.	('participants', 'Species', '9606', (231, 243))	('men', 'Species', '9606', (142, 145))	('participants', 'Species', '9606', (5, 17))	('H pylori', 'Species', '210', (209, 217))	('vitamin', 'Chemical', 'MESH:C059630', (104, 111))	('H pylori', 'Species', '210', (49, 57))	('men', 'Species', '9606', (118, 121))	('men', 'Species', '9606', (284, 287))	('garlic', 'Species', '4682', (295, 301))	('antibodies', 'Var', (35, 45))	('men', 'Species', '9606', (308, 311))	('H pylori', 'Disease', (84, 92))	('men', 'Species', '9606', (98, 101))	('vitamin', 'Chemical', 'MESH:C059630', (270, 277))	('garlic', 'Species', '4682', (129, 135))	('H pylori', 'Species', '210', (84, 92))
40827	31511230	A total of 2258 participants who were seropositive for antibodies to H pylori, as determined by IgG serology from enzyme linked immunoassay in 1994, were randomly assigned to three interventions (H pylori treatment with amoxicillin and omeprazole for two weeks, and/or garlic supplementation for 7.3 years, and/or vitamin supplementation for 7.3 years) or their placebos in a 2x2x2 factorial design.	('men', 'Species', '9606', (210, 213))	('H pylori', 'Gene', (196, 204))	('amoxicillin', 'Chemical', 'MESH:D000658', (220, 231))	('H pylori', 'Species', '210', (196, 204))	('H pylori', 'Gene', (69, 77))	('garlic', 'Species', '4682', (269, 275))	('men', 'Species', '9606', (282, 285))	('H pylori', 'Species', '210', (69, 77))	('vitamin', 'Chemical', 'MESH:C059630', (314, 321))	('antibodies', 'Var', (55, 65))	('men', 'Species', '9606', (328, 331))	('omeprazole', 'Chemical', 'MESH:D009853', (236, 246))	('participants', 'Species', '9606', (16, 28))
40879	31511230	In secondary analyses (table 3), vitamin supplementation was marginally associated with decreased all cause mortality (hazard ratio 0.87, 0.76 to 1.01, P=0.07).	('vitamin supplementation', 'Var', (33, 56))	('all cause', 'CPA', (98, 107))	('decreased', 'NegReg', (88, 97))	('men', 'Species', '9606', (47, 50))	('vitamin', 'Chemical', 'MESH:C059630', (33, 40))
40904	31511230	The Maastricht V/Florence consensus report stated that H pylori eradication results in a clear improvement of gastritis and gastric atrophy but not of intestinal metaplasia.	('gastritis', 'Disease', (110, 119))	('gastric atrophy', 'Disease', 'MESH:D013274', (124, 139))	('H pylori', 'Species', '210', (55, 63))	('improvement', 'PosReg', (95, 106))	('gastritis', 'Disease', 'MESH:D005756', (110, 119))	('gastritis', 'Phenotype', 'HP:0005263', (110, 119))	('men', 'Species', '9606', (102, 105))	('eradication', 'Var', (64, 75))	('gastric atrophy', 'Disease', (124, 139))
40905	31511230	A trial also showed that eradication of H pylori did not reduce the incidence of intestinal metaplasia or decrease its histological severity.	('intestinal metaplasia', 'Disease', (81, 102))	('eradication', 'Var', (25, 36))	('H pylori', 'Species', '210', (40, 48))	('H pylori', 'Disease', (40, 48))	('histological', 'MPA', (119, 131))
40906	31511230	However, the consensus report also recognized that the progression of intestinal metaplasia can be halted by eradicationof H pylori, as supported by our intervention trial.	('eradicationof', 'Var', (109, 122))	('intestinal metaplasia', 'Disease', (70, 91))	('H pylori', 'Disease', (123, 131))	('H pylori', 'Species', '210', (123, 131))
40926	31511230	After 22.3 years, garlic supplementation led to a non-statistically significant reduction in gastric cancer incidence and a statistically significant reduction in gastric cancer mortality, confirming favorable, but non-statistically significant trends seen at 14.7 years.	('gastric cancer', 'Disease', (163, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('reduction', 'NegReg', (80, 89))	('men', 'Species', '9606', (31, 34))	('garlic', 'Species', '4682', (18, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('reduction', 'NegReg', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('garlic', 'Var', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('gastric cancer', 'Disease', (93, 107))
40955	31511230	Multiyear vitamin supplementation yielded statistically significant reductions in gastric cancer incidence and mortality.	('mortality', 'CPA', (111, 120))	('men', 'Species', '9606', (24, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('vitamin', 'Chemical', 'MESH:C059630', (10, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('gastric cancer', 'Disease', (82, 96))	('reductions', 'NegReg', (68, 78))	('supplementation', 'Var', (18, 33))
40956	31511230	Garlic supplementation also yielded a statistically significant decrease in gastric cancer mortality and a promising, but not statistically significant, decrease in gastric cancer incidence.	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('decrease', 'NegReg', (64, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (165, 179))	('Garlic', 'Species', '4682', (0, 6))	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('supplementation', 'Var', (7, 22))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('decrease', 'NegReg', (153, 161))	('gastric cancer', 'Disease', (165, 179))	('men', 'Species', '9606', (13, 16))	('gastric cancer', 'Disease', (76, 90))
41062	29623265	Multivariate Cox proportional hazards analysis showed that pre-LWL group had a significantly better 3-year overall survival than pre-HWL group (P = 0.027, HR = 1.89, and 95% CI = 1.07-3.32).	('overall survival', 'CPA', (107, 123))	('Cox', 'Gene', (13, 16))	('pre-LWL', 'Var', (59, 66))	('better', 'PosReg', (93, 99))	('Cox', 'Gene', '1351', (13, 16))
41068	29623265	have demonstrated that high BMI has a distinctly adverse impact on the long-term survival of esophageal squamous cell carcinoma patients after esophagectomy.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 127))	('high BMI', 'Var', (23, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal squamous cell carcinoma', 'Disease', (93, 127))	('adverse', 'NegReg', (49, 56))
41082	28458309	Hemorrhaging from esophagogastric varices remains a major cause of morbidity and mortality in patients with portal hypertension, and rupture of IGVs is associated with an increased mortality rate (45-50%).	('Hemorrhaging', 'Disease', (0, 12))	('patients', 'Species', '9606', (94, 102))	('esophagogastric varices', 'Disease', (18, 41))	('rupture', 'Var', (133, 140))	('Hemorrhaging', 'Disease', 'MESH:D006470', (0, 12))	('gastric varices', 'Phenotype', 'HP:0030169', (26, 41))	('hypertension', 'Disease', 'MESH:D006973', (115, 127))	('esophagogastric varices', 'Phenotype', 'HP:0002040', (18, 41))	('portal hypertension', 'Phenotype', 'HP:0001409', (108, 127))	('hypertension', 'Disease', (115, 127))	('hypertension', 'Phenotype', 'HP:0000822', (115, 127))
41111	28458309	One advantage of SO-EIS over BRTO is that SO-EIS achieves thrombosis of the IGVs themselves and the afferent veins without occlusion of the major shunt, resulting in no increase in the pressure of the portal vein.	('thrombosis', 'Disease', 'MESH:D013927', (58, 68))	('SO-EIS', 'Var', (42, 48))	('pressure of the portal vein', 'MPA', (185, 212))	('BRTO', 'Chemical', '-', (29, 33))	('thrombosis', 'Disease', (58, 68))
41131	28458309	In addition, cyanoacrylate injection also carries a risk of pulmonary embolization, multiple systemic embolization such as splenic infarction, and cerebral infarction, all of which rarely occur but can be fatal.	('pulmonary embolization', 'Disease', 'MESH:D011655', (60, 82))	('splenic infarction', 'Disease', (123, 141))	('splenic infarction', 'Disease', 'MESH:D013159', (123, 141))	('pulmonary embolization', 'Disease', (60, 82))	('cerebral infarction', 'Disease', 'MESH:D002544', (147, 166))	('cyanoacrylate', 'Var', (13, 26))	('cyanoacrylate', 'Chemical', 'MESH:D003487', (13, 26))	('cerebral infarction', 'Disease', (147, 166))	('pulmonary embolization', 'Phenotype', 'HP:0002204', (60, 82))
41153	28036326	The methylation of the TIP30 promoter is also associated with tumor prognosis.	('TIP30', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('methylation', 'Var', (4, 15))	('TIP30', 'Gene', '10553', (23, 28))	('associated', 'Reg', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
41157	28036326	A significant association was observed between high expression of TIP30 in patients with cancer with a good overall survival (hazard ratio = 0.53, 95% confidence interval: 0.41-0.69), and good recurrence-free survival or disease free survival (hazard ratio = 0.49, 95% confidence interval: 0.37-0.66).	('disease free survival', 'CPA', (221, 242))	('high', 'Var', (47, 51))	('TIP30', 'Gene', '10553', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('TIP30', 'Gene', (66, 71))	('recurrence-free survival', 'CPA', (193, 217))
41168	28036326	The methylation of the TIP30 promoter may also be associated with tumor prognosis, but there are conflicting results from another study.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('TIP30', 'Gene', (23, 28))	('tumor', 'Disease', (66, 71))	('methylation', 'Var', (4, 15))	('TIP30', 'Gene', '10553', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('associated', 'Reg', (50, 60))
41179	28036326	In addition to the expression of TIP30, two articles explored the HR between methylation of the TIP30 promoter and OS or DFS of cancer patients.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('methylation', 'Var', (77, 88))	('patients', 'Species', '9606', (135, 143))	('TIP30', 'Gene', (33, 38))	('TIP30', 'Gene', '10553', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TIP30', 'Gene', '10553', (33, 38))	('TIP30', 'Gene', (96, 101))	('cancer', 'Disease', (128, 134))
41183	28036326	This suggests that high expression of TIP30 might be associated with a prolonged overall survival time of cancer patients (random effect model HR = 0.53, 95% CI: 0.41-0.69), but significant heterogeneity was detected among studies (Chi2 = 30.69, df = 10, p = 0.0007, I2 = 67%) (Fig 2).	('TIP30', 'Gene', '10553', (38, 43))	('high expression', 'Var', (19, 34))	('patients', 'Species', '9606', (113, 121))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('overall survival time', 'CPA', (81, 102))	('TIP30', 'Gene', (38, 43))	('cancer', 'Disease', (106, 112))	('prolonged', 'PosReg', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
41189	28036326	It has been suggested that high expression of TIP30 might be associated with a prolonged RFS and DFS for cancer patients (random model HR = 0.49, 95%CI: 0.37-0.66), but some heterogeneity was detected among the studies (Chi2 = 9.15, df = 5, p = 0.10, I2 = 45%) (Fig 4).	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('prolonged', 'PosReg', (79, 88))	('patients', 'Species', '9606', (112, 120))	('TIP30', 'Gene', '10553', (46, 51))	('high expression', 'Var', (27, 42))	('RFS', 'MPA', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('DFS', 'MPA', (97, 100))	('TIP30', 'Gene', (46, 51))
41190	28036326	The subgroup DFS and RFS analysis indicated that high expression of TIP30 could both prolong RFS (random effect model HR = 0.49 with 95% CI: 0.34-0.70) and DFS (random effect model HR = 0.46 with 95% CI: 0.26-0.84).	('DFS', 'MPA', (156, 159))	('TIP30', 'Gene', '10553', (68, 73))	('RFS', 'MPA', (93, 96))	('TIP30', 'Gene', (68, 73))	('high expression', 'Var', (49, 64))	('prolong', 'PosReg', (85, 92))
41191	28036326	However, the subgroup analysis of TIP30 high expression and promoter methylation indicated that methylation of the TIP30 promoter was not significantly associated with a prolonged DFS for tumor patients (random model HR = 0.62, 95% CI: 0.19-2.02) (Figs 4 and 5).	('tumor', 'Disease', (188, 193))	('TIP30', 'Gene', '10553', (34, 39))	('patients', 'Species', '9606', (194, 202))	('TIP30', 'Gene', '10553', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('methylation', 'Var', (96, 107))	('TIP30', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('DFS', 'MPA', (180, 183))	('TIP30', 'Gene', (115, 120))
41193	28036326	We detected a significant association between high expression of TIP30 and a good OS of patients with esophageal carcinoma (HR = 0.50, 95% CI: 0.29-0.86), laryngeal carcinoma (HR = 0.38, 95% CI: 0.23-0.65), pancreatic adenocarcinoma (HR = 0.60, 95% CI: 0.39-0.92), gastric cancer (HR = 0.18, 95% CI: 0.05-0.65), and gallbladder adenocarcinoma (HR = 0.40, 95% CI: 0.23-0.70).	('gastric cancer', 'Disease', 'MESH:D013274', (265, 279))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (102, 122))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (207, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('pancreatic adenocarcinoma', 'Disease', (207, 232))	('esophageal carcinoma', 'Disease', (102, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('TIP30', 'Gene', '10553', (65, 70))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (316, 342))	('gastric cancer', 'Phenotype', 'HP:0012126', (265, 279))	('TIP30', 'Gene', (65, 70))	('laryngeal carcinoma', 'Disease', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (102, 122))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (207, 232))	('gastric cancer', 'Disease', (265, 279))	('high expression', 'Var', (46, 61))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (155, 174))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('gallbladder adenocarcinoma', 'Disease', (316, 342))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (155, 174))
41197	28036326	Moreover, high expression of TIP30 was closely associated with a good OS of tumor patients in the subgroups based on sample size (more than 110 or less than 110), and the pooled HRs were 0.68 (95% CI: 0.51-0.91) and 0.48 (95% CI: 0.38-0.61), respectively.	('TIP30', 'Gene', (29, 34))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('high expression', 'Var', (10, 25))	('TIP30', 'Gene', '10553', (29, 34))	('associated', 'Reg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
41212	28036326	It has been suggested that high expression of TIP30 is associated with prolonged overall survival time and disease free survival time for tumor patients.	('tumor', 'Disease', (138, 143))	('disease free survival time', 'CPA', (107, 133))	('overall survival time', 'CPA', (81, 102))	('high expression', 'Var', (27, 42))	('TIP30', 'Gene', '10553', (46, 51))	('patients', 'Species', '9606', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('prolonged', 'PosReg', (71, 80))	('TIP30', 'Gene', (46, 51))
41213	28036326	The DNA methylation status of TIP30 gene may be associated with this and affect the sensitivity of tumor cells to chemotherapy.	('TIP30', 'Gene', '10553', (30, 35))	('tumor', 'Disease', (99, 104))	('affect', 'Reg', (73, 79))	('associated', 'Reg', (48, 58))	('TIP30', 'Gene', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('DNA methylation status', 'Var', (4, 26))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
41215	28036326	This might be confusing since previous studies have suggested that methylation of TIP30 could down-regulate its expression.	('expression', 'MPA', (112, 122))	('TIP30', 'Gene', (82, 87))	('TIP30', 'Gene', '10553', (82, 87))	('down-regulate', 'NegReg', (94, 107))	('methylation', 'Var', (67, 78))
41216	28036326	Still, other epigenetic alterations such as gene mutations or loss of heterozygosity might also affect the expression of TIP30.	('affect', 'Reg', (96, 102))	('loss of heterozygosity', 'Var', (62, 84))	('TIP30', 'Gene', '10553', (121, 126))	('expression', 'MPA', (107, 117))	('gene mutations', 'Var', (44, 58))	('TIP30', 'Gene', (121, 126))
41220	28036326	In subgroup analysis, high expression of TIP30 had a significant association with longer OS for esophageal carcinoma, laryngeal carcinoma, pancreatic adenocarcinoma, gastric cancer, and gallbladder adenocarcinoma patients.	('gastric cancer', 'Disease', (166, 180))	('longer OS', 'Disease', (82, 91))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (96, 116))	('gallbladder adenocarcinoma', 'Disease', (186, 212))	('patients', 'Species', '9606', (213, 221))	('laryngeal carcinoma', 'Disease', (118, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (139, 164))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (118, 137))	('TIP30', 'Gene', '10553', (41, 46))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (96, 116))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (186, 212))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('TIP30', 'Gene', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('high expression', 'Var', (22, 37))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (118, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('esophageal carcinoma', 'Disease', (96, 116))	('pancreatic adenocarcinoma', 'Disease', (139, 164))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (139, 164))
41228	28036326	In conclusion, the high expression of TIP30 is a good prognostic indicator for tumor patients, associated with a prolonged OS and DFS/RFS.	('TIP30', 'Gene', '10553', (38, 43))	('tumor', 'Disease', (79, 84))	('high expression', 'Var', (19, 34))	('DFS/RFS', 'Disease', (130, 137))	('patients', 'Species', '9606', (85, 93))	('TIP30', 'Gene', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('associated', 'Reg', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
41248	25228972	Studies have indicated RNFs play an important role in the regulation of cell differentiation, growth and transformation, and abnormal expressions of RNFs can result in certain pathological sequences including cancers.	('RNF', 'Gene', (149, 152))	('abnormal expressions', 'Var', (125, 145))	('RNF', 'Gene', '11074', (149, 152))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('cell differentiation', 'CPA', (72, 92))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('RNF', 'Gene', (23, 26))	('result in', 'Reg', (158, 167))	('cancers', 'Disease', (209, 216))	('transformation', 'CPA', (105, 119))	('abnormal expressions', 'Phenotype', 'HP:0100022', (125, 145))	('RNF', 'Gene', '11074', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
41260	25228972	cRNA gragmentation reaction system included Cy3-cRNA 1 mug, Cy5-cRNA 1 mug, 10xcontrol targets 50 muL, and RNA enzyme-free water was added to a total volume of 240 muL, and gragmentation buffer l0 muL was added and then gently mixed and incubated at 60 C for 30 minutes.	('Cy5-cRNA', 'Var', (60, 68))	('Cy3-cRNA', 'Chemical', '-', (44, 52))	('Cy3-cRNA', 'Var', (44, 52))	('Cy5', 'Chemical', 'MESH:C085321', (60, 63))	('water', 'Chemical', 'MESH:D014867', (123, 128))
41284	25228972	Results showed the expressions of RNF32, RNF121, RNF139, RNF11, RNF130, RNF24, RNF141, RNF159, RNF14 in the BE and EAC were significantly increased when compared with NE (p=0.000036, p=0.000212, p=0.0157, p=0.039, p=0.0077, p=0.037, p=0.0013, p=0.0017, and p=0.0018, differently), and the increased expressions were more obvious in EAC (p=0.000032, p=0.00018, p=0.0124, p=0.041, p=0.0089, p=0.025, p=0.00021, p=0.00012, and p=0.00012, differently).	('BE', 'Phenotype', 'HP:0100580', (108, 110))	('RNF14', 'Gene', '9604', (79, 84))	('RNF130', 'Gene', '55819', (64, 70))	('RNF11', 'Gene', (57, 62))	('p=0.0017', 'Var', (243, 251))	('RNF14', 'Gene', (95, 100))	('RNF32', 'Gene', (34, 39))	('RNF139', 'Gene', (49, 55))	('RNF24', 'Gene', '11237', (72, 77))	('RNF14', 'Gene', '9604', (95, 100))	('increased', 'PosReg', (138, 147))	('EAC', 'Phenotype', 'HP:0011459', (332, 335))	('RNF141', 'Gene', '50862', (79, 85))	('expressions', 'MPA', (299, 310))	('RNF24', 'Gene', (72, 77))	('RNF121', 'Gene', '55298', (41, 47))	('RNF159', 'Gene', '84333', (87, 93))	('RNF139', 'Gene', '11236', (49, 55))	('RNF141', 'Gene', (79, 85))	('RNF130', 'Gene', (64, 70))	('RNF159', 'Gene', (87, 93))	('RNF32', 'Gene', '140545', (34, 39))	('EAC', 'Phenotype', 'HP:0011459', (115, 118))	('expressions', 'MPA', (19, 30))	('RNF11', 'Gene', '26994', (57, 62))	('RNF14', 'Gene', (79, 84))	('RNF121', 'Gene', (41, 47))
41305	25228972	In recent years, studies reveal that the posttranslational modification by ubiquitin and ubiquitin-like proteins implicate in the regulation of several cell activites including cell cycle, signal transduction, immune recognition, cell apoptosis, cell proliferation and differentiation, protein transportation, organ development, inflammation, antigen presenting, regulation of endoplasmic reticulum, DNA repair, stress, and major histocompatibility complex regulation.	('implicate', 'Reg', (113, 122))	('posttranslational', 'Var', (41, 58))	('differentiation', 'CPA', (269, 284))	('cell apoptosis', 'CPA', (230, 244))	('inflammation', 'Disease', 'MESH:D007249', (329, 341))	('inflammation', 'Disease', (329, 341))	('cell proliferation', 'CPA', (246, 264))
41306	25228972	Increasing evidence demonstrates abnormal E3 ligase expressions in the tumorigenesis and dysregulation of these E3 ligases play crucial roles in the tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('dysregulation', 'Var', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (149, 154))	('expressions', 'MPA', (52, 63))	('E3 ligase', 'Protein', (42, 51))	('tumor', 'Disease', (71, 76))
41307	25228972	Studies also propose the abnormalities in E3 ligase expressions can be applied as a molecular marker in the diagnosis of some cancers and as a target in the treatment of these cancers.	('cancers', 'Disease', (176, 183))	('abnormalities', 'Var', (25, 38))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('expressions', 'MPA', (52, 63))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('E3 ligase', 'Protein', (42, 51))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))
41330	23792587	In the development of cancer, both genetic and epigenetic mechanisms contribute to the activation or inactivation of key signaling pathways and acquisition of the cancer phenotype "hallmarks".	('activation', 'PosReg', (87, 97))	('men', 'Species', '9606', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('epigenetic', 'Var', (47, 57))	('inactivation', 'NegReg', (101, 113))	('key signaling pathways', 'Pathway', (117, 139))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
41331	23792587	It is generally accepted that Barrett multistep carcinogenesis is characterized by genomic instability, which facilitates accumulation of lesions that target proto-oncogenes, tumor suppressor genes, mismatch repair genes, and mitotic checkpoint genes, thereby aiding tumorigenic progression.	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('carcinogenesis', 'Disease', 'MESH:D063646', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('lesions', 'Var', (138, 145))	('mismatch repair genes', 'Protein', (199, 220))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (267, 272))	('aiding', 'PosReg', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('carcinogenesis', 'Disease', (48, 62))	('mitotic checkpoint genes', 'Gene', (226, 250))
41332	23792587	Although there are no data showing that reflux causes more permanent genetic (e.g., mutations) or epigenetic alterations, recent Next Generation sequencing data show a high overall mutation rate in EAC that is only exceeded by lung cancer and melanoma, both of which are known to be largely driven by mutagens (smoking and UV light, respectively).	('lung cancer', 'Disease', (227, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (227, 238))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('melanoma', 'Disease', (243, 251))	('mutation', 'Var', (181, 189))	('EAC', 'Gene', (198, 201))	('melanoma', 'Disease', 'MESH:D008545', (243, 251))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('lung cancer', 'Disease', 'MESH:D008175', (227, 238))
41341	23792587	More promisingly, the step-wise neoplastic transformation of a hTERT immortalised, non-dysplastic Barrett cell line using the defined genetic manipulations of p53 knockdown and expression of oncogenic H-Ras (G12V) has been reported.	('p53', 'Gene', (159, 162))	('neoplastic transformation', 'CPA', (32, 57))	('knockdown', 'Var', (163, 172))	('non-dysplastic Barrett', 'Disease', (83, 105))	('non-dysplastic Barrett', 'Disease', 'MESH:D001471', (83, 105))	('H-Ras', 'Gene', '3265', (201, 206))	('H-Ras', 'Gene', (201, 206))	('G12V', 'Mutation', 'rs104894230', (208, 212))	('p53', 'Gene', '7157', (159, 162))
41348	23792587	Altered EGF expression in some cases may be due to the presence of the EGF A61G polymorphism, which is associated with an increased risk of EAC.	('EGF', 'Gene', (71, 74))	('presence', 'Var', (55, 63))	('EGF', 'Gene', '1950', (8, 11))	('A61G', 'Mutation', 'rs4444903', (75, 79))	('associated', 'Reg', (103, 113))	('EGF', 'Gene', '1950', (71, 74))	('Altered', 'Reg', (0, 7))	('EGF', 'Gene', (8, 11))	('EAC', 'Disease', (140, 143))	('expression', 'MPA', (12, 22))
41351	23792587	The gene for EGFR is also amplified in HGD and around one third of EAC, and activating mutations in exons 18 and 21 of the EGFR gene have been identified in approximately 15% of BE and EAC.	('EGFR', 'Gene', (123, 127))	('BE', 'Phenotype', 'HP:0100580', (178, 180))	('EGFR', 'Gene', '1956', (123, 127))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (87, 96))
41352	23792587	Both EGFR overexpression and mutant p53 contribute to the enrichment of a subpopulation of human esophageal epithelial cells which, after negating the oncogene-induced senescence induced by EGFR overexpression, undergo epithelial to mesenchymal transition (EMT) on TGF-beta stimulation.	('TGF-beta', 'Gene', (265, 273))	('EGFR', 'Gene', '1956', (190, 194))	('mutant', 'Var', (29, 35))	('p53', 'Gene', (36, 39))	('undergo', 'PosReg', (211, 218))	('EGFR', 'Gene', '1956', (5, 9))	('epithelial to mesenchymal transition', 'CPA', (219, 255))	('p53', 'Gene', '7157', (36, 39))	('EGFR', 'Gene', (190, 194))	('EGFR', 'Gene', (5, 9))	('men', 'Species', '9606', (64, 67))	('TGF-beta', 'Gene', '7040', (265, 273))	('human', 'Species', '9606', (91, 96))
41354	23792587	Amplification and overexpression of erbB-2 have been reported in HGD but not normal esophagus or BE with or without low grade dysplasia (LGD), suggesting that this lesion is a late stage event in BE carcinogenesis.	('Amplification', 'Var', (0, 13))	('BE', 'Phenotype', 'HP:0100580', (97, 99))	('carcinogenesis', 'Disease', 'MESH:D063646', (199, 213))	('erbB-2', 'Gene', (36, 42))	('erbB-2', 'Gene', '2064', (36, 42))	('carcinogenesis', 'Disease', (199, 213))	('low grade dysplasia', 'Disease', 'MESH:D008228', (116, 135))	('BE', 'Phenotype', 'HP:0100580', (196, 198))	('HGD', 'Disease', (65, 68))	('overexpression', 'PosReg', (18, 32))	('low grade dysplasia', 'Disease', (116, 135))
41357	23792587	This may be related to the presence of K-ras mutations, which are known to predict resistance to EGFR inhibition.	('resistance', 'MPA', (83, 93))	('mutations', 'Var', (45, 54))	('EGFR', 'Gene', '1956', (97, 101))	('K-ras', 'Gene', (39, 44))	('EGFR', 'Gene', (97, 101))	('K-ras', 'Gene', '3845', (39, 44))
41359	23792587	In contrast, targeting erbB-2 in patients with HER2+ metastatic esophago-gastric junctional adenocarcinoma has been more successful, and is being tested further in a clinical trial with earlier stage disease (RTOG-1010, National Cancer Institute, USA).	('adenocarcinoma', 'Disease', (92, 106))	('Cancer', 'Disease', 'MESH:D009369', (229, 235))	('adenocarcinoma', 'Disease', 'MESH:D000230', (92, 106))	('patients', 'Species', '9606', (33, 41))	('Cancer', 'Phenotype', 'HP:0002664', (229, 235))	('HER2', 'Gene', (47, 51))	('HER2', 'Gene', '2064', (47, 51))	('erbB-2', 'Gene', (23, 29))	('targeting', 'Var', (13, 22))	('erbB-2', 'Gene', '2064', (23, 29))	('esophago-gastric junctional adenocarcinoma', 'Phenotype', 'HP:0011459', (64, 106))	('Cancer', 'Disease', (229, 235))
41368	23792587	In addition, polymorphisms in the VEGF-A gene, which are linked with increased VEGF expression, are associated with an increased risk of EAC, particularly in smokers.	('increased', 'PosReg', (69, 78))	('VEGF', 'Gene', '7422', (34, 38))	('VEGF', 'Gene', '7422', (79, 83))	('associated with', 'Reg', (100, 115))	('increased VEGF expression', 'Phenotype', 'HP:0030269', (69, 94))	('polymorphisms', 'Var', (13, 26))	('EAC', 'Disease', (137, 140))	('expression', 'MPA', (84, 94))	('VEGF', 'Gene', (34, 38))	('VEGF', 'Gene', (79, 83))
41380	23792587	Activation of this pathway may also occur through modulation of the receptor, IGF-1R.	('IGF-1R', 'Gene', '3480', (78, 84))	('modulation', 'Var', (50, 60))	('IGF-1R', 'Gene', (78, 84))
41381	23792587	Overactivation of IGF-1R has been implicated in several cancers in which it is thought to promote cell growth, survival, and angiogenesis, possibly via heterodimerization with EGFR.	('cancers', 'Disease', (56, 63))	('IGF-1R', 'Gene', '3480', (18, 24))	('angiogenesis', 'CPA', (125, 137))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('IGF-1R', 'Gene', (18, 24))	('EGFR', 'Gene', '1956', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('heterodimerization', 'Interaction', (152, 170))	('EGFR', 'Gene', (176, 180))	('promote', 'PosReg', (90, 97))	('cell growth', 'CPA', (98, 109))	('survival', 'CPA', (111, 119))	('implicated', 'Reg', (34, 44))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('Overactivation', 'Var', (0, 14))
41383	23792587	Increased expression may be a result of posttranscriptional regulation since there is no difference in IGF-1R mRNA expression between EAC and matched normal tissue, with the exception of individuals carrying a G1013A polymorphism in the igf-1r gene, suggesting that this polymorphism may enhance transcription or stabilize the transcript.	('igf-1r', 'Gene', '3480', (237, 243))	('transcript', 'MPA', (327, 337))	('stabilize', 'MPA', (313, 322))	('transcription', 'MPA', (296, 309))	('igf-1r', 'Gene', (237, 243))	('expression', 'MPA', (10, 20))	('G1013A', 'Var', (210, 216))	('IGF-1R', 'Gene', '3480', (103, 109))	('G1013A', 'Mutation', 'rs1169461493', (210, 216))	('IGF-1R', 'Gene', (103, 109))	('enhance', 'PosReg', (288, 295))
41384	23792587	This same polymorphism increases the risk of developing BE and EAC in obese individuals by 3- and 5-fold respectively.	('EAC', 'Disease', (63, 66))	('polymorphism', 'Var', (10, 22))	('obese', 'Disease', 'MESH:D009765', (70, 75))	('BE', 'Phenotype', 'HP:0100580', (56, 58))	('obese', 'Disease', (70, 75))
41391	23792587	Overexpression of Axl in EAC is inversely associated with survival and RNAi knockdown in 2 EAC cell lines reduced in vitro invasion, migration, and anchorage-independent growth and completely abrogated in vivo engraftment in immunocompromised mice.	('RNAi', 'Gene', (71, 75))	('men', 'Species', '9606', (217, 220))	('knockdown', 'Var', (76, 85))	('migration', 'CPA', (133, 142))	('anchorage-independent growth', 'CPA', (148, 176))	('abrogated', 'NegReg', (192, 201))	('reduced', 'NegReg', (106, 113))	('mice', 'Species', '10090', (243, 247))
41392	23792587	This novel finding is intriguing given the recent development of small molecule inhibitors of Axl that have shown promising results in a mouse model of breast cancer.	('Axl', 'Protein', (94, 97))	('small molecule inhibitors', 'Var', (65, 90))	('mouse', 'Species', '10090', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('men', 'Species', '9606', (57, 60))	('inhibitors', 'Var', (80, 90))
41416	23792587	Dysregulated response to TGFbeta has been associated with a range of epithelial cancers.	('epithelial cancers', 'Disease', (69, 87))	('TGFbeta', 'Gene', '7040', (25, 32))	('associated', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('epithelial cancers', 'Disease', 'MESH:D000077216', (69, 87))	('TGFbeta', 'Gene', (25, 32))	('Dysregulated', 'Var', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
41422	23792587	Loss of heterozygosity (LOH) at chromosome 18q, location of SMAD2 and 4 genes, occurs in BE carcinogenesis and SMAD4 is mutated in approximately 8% of EAC.	('SMAD4', 'Gene', (111, 116))	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('SMAD2 and 4', 'Gene', '4087;4089', (60, 71))	('carcinogenesis', 'Disease', (92, 106))	('SMAD4', 'Gene', '4089', (111, 116))	('Loss', 'NegReg', (0, 4))	('BE', 'Phenotype', 'HP:0100580', (89, 91))	('EAC', 'Disease', (151, 154))	('mutated', 'Var', (120, 127))
41439	23792587	Polymorphisms in the genes for caspase-7 and caspase-9 are significantly associated with an increased risk of EAC, and polymorphisms in caspase-7 and Bcl-2 modify the risk of EAC in smokers.	('caspase-7', 'Gene', (136, 145))	('modify', 'Reg', (156, 162))	('caspase-7', 'Gene', '840', (136, 145))	('polymorphisms', 'Var', (119, 132))	('Polymorphisms', 'Var', (0, 13))	('caspase-9', 'Gene', '842', (45, 54))	('associated', 'Reg', (73, 83))	('caspase-7', 'Gene', (31, 40))	('caspase-7', 'Gene', '840', (31, 40))	('EAC', 'Disease', (110, 113))	('Bcl-2', 'Gene', (150, 155))	('Bcl-2', 'Gene', '596', (150, 155))	('caspase-9', 'Gene', (45, 54))
41449	23792587	Aside from the modulation of ligand/RTK activation as described above, there is evidence that alterations to these downstream mediators may also contribute to the progression of BE to EAC.	('alterations', 'Var', (94, 105))	('RTK', 'Gene', (36, 39))	('BE', 'Phenotype', 'HP:0100580', (178, 180))	('contribute', 'Reg', (145, 155))	('RTK', 'Gene', '5979', (36, 39))	('BE to EAC', 'Disease', (178, 187))
41450	23792587	Expression of mutant oncogenic ras (K-ras or H-ras) is rarely found in non-dysplastic BE but is detected in up to 40% of dysplasia and EAC samples, suggesting that acquisition of this mutation is important in progression.	('dysplasia', 'Disease', (121, 130))	('BE', 'Phenotype', 'HP:0100580', (86, 88))	('detected', 'Reg', (96, 104))	('mutant', 'Var', (14, 20))	('H-ras', 'Gene', '3265', (45, 50))	('EAC', 'Disease', (135, 138))	('dysplasia', 'Disease', 'MESH:D004476', (121, 130))	('non-dysplastic', 'Disease', 'MESH:D004416', (71, 85))	('K-ras', 'Gene', (36, 41))	('K-ras', 'Gene', '3845', (36, 41))	('non-dysplastic', 'Disease', (71, 85))	('H-ras', 'Gene', (45, 50))
41451	23792587	Mutation of BRAF, downstream of Ras, is also found at low frequency (5-10%) in dysplasia and EAC, although never in combination with Ras mutation, and thus represents an alternative mechanism for activating downstream signaling.	('dysplasia', 'Disease', (79, 88))	('EAC', 'Disease', (93, 96))	('BRAF', 'Gene', (12, 16))	('dysplasia', 'Disease', 'MESH:D004476', (79, 88))	('BRAF', 'Gene', '673', (12, 16))	('Mutation', 'Var', (0, 8))	('activating', 'PosReg', (196, 206))
41452	23792587	Introduction of H-ras together with RNAi knockdown of p53 in p16-deficient non-dysplastic BAR-T Barrett cells leads to tumorigenic transformation, demonstrating a mechanistic role for Ras activation in BE carcinogenesis.	('H-ras', 'Gene', (16, 21))	('tumor', 'Disease', (119, 124))	('carcinogenesis', 'Disease', (205, 219))	('p16', 'Gene', (61, 64))	('leads to', 'Reg', (110, 118))	('BAR-T Barrett', 'Phenotype', 'HP:0100580', (90, 103))	('p53', 'Gene', (54, 57))	('non-dysplastic', 'Disease', (75, 89))	('non-dysplastic', 'Disease', 'MESH:D004416', (75, 89))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('H-ras', 'Gene', '3265', (16, 21))	('p53', 'Gene', '7157', (54, 57))	('BE', 'Phenotype', 'HP:0100580', (202, 204))	('p16', 'Gene', '1029', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('knockdown', 'Var', (41, 50))	('carcinogenesis', 'Disease', 'MESH:D063646', (205, 219))
41454	23792587	PIK3CA, the gene that encodes for the p110alpha catalytic subunit of PI3K is mutated in approximately 6% of EAC but no activating mutations have been reported in BE.	('EAC', 'Disease', (108, 111))	('BE', 'Phenotype', 'HP:0100580', (162, 164))	('mutated', 'Var', (77, 84))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('p110alpha', 'Gene', (38, 47))	('p110alpha', 'Gene', '5290', (38, 47))
41474	23792587	Overactivation of NFkappaB has been linked to neoplasia, including EAC, through promoting cell survival, particularly in the context of chronic inflammation.	('neoplasia', 'Disease', (46, 55))	('EAC', 'Disease', (67, 70))	('promoting', 'PosReg', (80, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (46, 55))	('inflammation', 'Disease', (144, 156))	('cell survival', 'CPA', (90, 103))	('neoplasia', 'Disease', 'MESH:D009369', (46, 55))	('NFkappaB', 'Gene', (18, 26))	('linked', 'Reg', (36, 42))	('NFkappaB', 'Gene', '4790', (18, 26))	('inflammation', 'Disease', 'MESH:D007249', (144, 156))	('Overactivation', 'Var', (0, 14))
41480	23792587	Dysregulation of cell cycle mediators appears to be central to development of EAC.	('Dysregulation', 'Var', (0, 13))	('Dysregulation of cell cycle', 'Phenotype', 'HP:0011018', (0, 27))	('men', 'Species', '9606', (70, 73))	('EAC', 'Disease', (78, 81))
41483	23792587	This may be at least partly due to the G870A polymorphism in the gene, which results in protein stabilization and a longer half-life.	('G870A', 'Var', (39, 44))	('longer', 'PosReg', (116, 122))	('half-life', 'MPA', (123, 132))	('protein stabilization', 'MPA', (88, 109))	('G870A', 'Mutation', 'rs9344', (39, 44))
41487	23792587	In contrast, inactivation of p16, which indirectly negatively regulates the function of Rb, occurs frequently in non-dysplastic BE or at the non-dysplasia to LGD interface, and seems to represent one of the key early molecular events driving BE carcinogenesis.	('p16', 'Gene', (29, 32))	('dysplasia', 'Disease', (145, 154))	('inactivation', 'Var', (13, 25))	('carcinogenesis', 'Disease', (245, 259))	('negatively', 'NegReg', (51, 61))	('BE', 'Phenotype', 'HP:0100580', (128, 130))	('BE', 'Phenotype', 'HP:0100580', (242, 244))	('p16', 'Gene', '1029', (29, 32))	('dysplasia', 'Disease', 'MESH:D004476', (145, 154))	('function', 'MPA', (76, 84))	('non-dysplastic', 'Disease', (113, 127))	('non-dysplastic', 'Disease', 'MESH:D004416', (113, 127))	('regulates', 'Reg', (62, 71))	('carcinogenesis', 'Disease', 'MESH:D063646', (245, 259))
41488	23792587	In a mouse surgically induced reflux model, development of both BE and EAC are increased in p27 knockout mice compared with wild-type, demonstrating that loss of p27 can enhance Barrett carcinogenesis, possibly at an early stage.	('increased', 'PosReg', (79, 88))	('men', 'Species', '9606', (51, 54))	('development', 'CPA', (44, 55))	('Barrett carcinogenesis', 'Disease', 'MESH:D063646', (178, 200))	('Barrett carcinogenesis', 'Disease', (178, 200))	('p27', 'Gene', (162, 165))	('enhance', 'PosReg', (170, 177))	('mouse', 'Species', '10090', (5, 10))	('knockout', 'Var', (96, 104))	('BE', 'Phenotype', 'HP:0100580', (64, 66))	('mice', 'Species', '10090', (105, 109))	('loss', 'Var', (154, 158))
41492	23792587	p53 LOH and p53 gene mutations, occur in the majority of EAC cases and these lesions are associated with poor outcome.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('EAC', 'Disease', (57, 60))	('LOH', 'NegReg', (4, 7))	('mutations', 'Var', (21, 30))
41493	23792587	Mutations often result in stabilized p53 protein and increased staining for p53 has been detected in non-dysplastic BE and more frequently in dysplasia and EAC.	('stabilized', 'MPA', (26, 36))	('dysplasia', 'Disease', (142, 151))	('p53', 'Gene', (76, 79))	('EAC', 'Disease', (156, 159))	('dysplasia', 'Disease', 'MESH:D004476', (142, 151))	('p53', 'Gene', '7157', (76, 79))	('non-dysplastic', 'Disease', (101, 115))	('non-dysplastic', 'Disease', 'MESH:D004416', (101, 115))	('BE', 'Phenotype', 'HP:0100580', (116, 118))	('Mutations', 'Var', (0, 9))	('increased', 'PosReg', (53, 62))	('staining', 'MPA', (63, 71))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('result', 'Reg', (16, 22))
41500	23792587	Nuclear accumulation may be a consequence of APC LOH, which is a frequent late event in EAC, via APC promoter methylation or via upregulation of Wnt ligands and epigenetic silencing of Wnt inhibitory factor (WIF1).	('epigenetic silencing', 'Var', (161, 181))	('EAC', 'Disease', (88, 91))	('upregulation', 'PosReg', (129, 141))	('APC', 'Gene', (45, 48))	('APC', 'Gene', (97, 100))	('Wnt', 'Protein', (145, 148))	('WIF1', 'Gene', (208, 212))	('WIF1', 'Gene', '11197', (208, 212))	('APC', 'Gene', '324', (45, 48))	('APC', 'Gene', '324', (97, 100))	('Nuclear accumulation', 'MPA', (0, 20))
41523	23792587	However, activation of Notch and Hedgehog pathways, through mechanisms that include aberrant TGFbeta signaling, cdx2 activation by the bile components of the refluxate and interactions with the TNFalpha/mTOR pathway, seem increasingly important.	('activation', 'PosReg', (9, 19))	('TNFalpha', 'Gene', '7124', (194, 202))	('TGFbeta', 'Gene', (93, 100))	('cdx2', 'Gene', (112, 116))	('TGFbeta', 'Gene', '7040', (93, 100))	('cdx2', 'Gene', '1045', (112, 116))	('bile components', 'MPA', (135, 150))	('interactions', 'Interaction', (172, 184))	('TNFalpha', 'Gene', (194, 202))	('Hedgehog pathways', 'Pathway', (33, 50))	('activation', 'PosReg', (117, 127))	('aberrant', 'Var', (84, 92))	('mTOR', 'Gene', (203, 207))	('mTOR', 'Gene', '2475', (203, 207))
41527	23792587	As for other cancers, EAC research is entering an exciting era of discovery searching for associations between variations in massive scale data and disease, as exemplified by several completed and ongoing next generation sequencing (NGS) studies and the BE genome-wide association study (GWAS).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('variations', 'Var', (111, 121))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Disease', (13, 20))	('BE', 'Phenotype', 'HP:0100580', (254, 256))
41537	22240585	Whereas the skin suprabasal and superficial layers express CK1 and CK10 (ref.	('CK1', 'Species', '2498238', (67, 70))	('CK10', 'Gene', (67, 71))	('CK1', 'Var', (59, 62))	('CK1', 'Species', '2498238', (59, 62))
41552	22240585	Epithelial cells may be transformed by the introduction of a combination of oncogenes and/or inactivated tumor suppressor genes (e.g., EGFR, cyclin D1 and mutant p53), and the resulting transformed epithelial cells invade into the underlying matrix, thereby providing a platform to investigate properties of tumor cells and the cross talk between invading tumor cells and activated stromal fibroblasts.	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('tumor', 'Disease', (308, 313))	('cyclin D1', 'Gene', (141, 150))	('p53', 'Gene', (162, 165))	('cyclin D1', 'Gene', '595', (141, 150))	('EGFR', 'Gene', '1956', (135, 139))	('mutant', 'Var', (155, 161))	('p53', 'Gene', '7157', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('EGFR', 'Gene', (135, 139))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', (356, 361))
41661	22240585	Adjust the voltages on Hoechst-stained cells to optimize the SP (excitation 100 mW multiline UV, Blue fluorescence 450/20 (linear scale), red fluorescence 675LP (linear scale)), which is split by a 610SP (dichroic).	('Hoechst', 'Chemical', '-', (23, 30))	('SP', 'Chemical', '-', (201, 203))	('SP', 'Chemical', '-', (61, 63))	('Blue fluorescence 450/20', 'Var', (97, 121))	('red fluorescence 675LP', 'Var', (138, 160))
41663	22240585	Set gates for the following: esophageal epithelial cells (usually 200-400 FSC-A and 100-400 SSC-A); single cells; live cells (dead cells above PI 101.3); SP cells ('tail' of cells with Hoechst red below 300 and Hoechst blue below 400); and NSP cells (Hoechst red above 300, Hoechst blue over 400).	('Hoechst', 'Var', (274, 281))	('SP', 'Chemical', '-', (241, 243))	('Hoechst red', 'Chemical', '-', (251, 262))	('Hoechst blue', 'Chemical', '-', (211, 223))	('Hoechst red', 'Chemical', '-', (185, 196))	('Hoechst blue', 'Chemical', '-', (274, 286))	('SP', 'Chemical', '-', (154, 156))	('Hoechst red above 300', 'Var', (251, 272))
41681	22240585	Add DMEM-10% (wt/vol) FBS: 10 ml to the bottom of the wells in the Transwell carrier and 2 ml to the Transwell inserts.	('FBS', 'Disease', (22, 25))	('DMEM', 'Chemical', '-', (4, 8))	('FBS', 'Disease', 'MESH:D005198', (22, 25))	('DMEM-10', 'Var', (4, 11))
41927	30268436	A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-beta Superfamily We present an integromic analysis of gene alterations that modulate transforming growth factor beta (TGF-beta)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA).	('transforming growth factor beta', 'Gene', (187, 218))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('cancer', 'Disease', (287, 293))	('TGF-beta', 'Gene', (220, 228))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('TGF-beta', 'Gene', '7040', (98, 106))	('transforming growth factor beta', 'Gene', '7040', (187, 218))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Disease', (263, 268))	('modulate', 'Reg', (178, 186))	('TGF-beta', 'Gene', '7040', (220, 228))	('TGF-beta', 'Gene', (98, 106))	('Cancer', 'Phenotype', 'HP:0002664', (307, 313))	('alterations', 'Var', (161, 172))
41928	30268436	Focusing on genes that encode mediators and regulators of TGF-beta signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('TGF-beta', 'Gene', (58, 66))	('mutation', 'Var', (120, 128))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (216, 240))	('amplification', 'Var', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('gastrointestinal cancers', 'Disease', (216, 240))	('frequencies', 'Reg', (201, 212))	('TGF-beta', 'Gene', '7040', (58, 66))
41930	30268436	Alterations in the TGF-beta superfamily correlated positively with expression of metastasis-associated genes and with decreased survival.	('Alterations', 'Var', (0, 11))	('TGF-beta', 'Gene', '7040', (19, 27))	('metastasis-associated genes', 'Gene', (81, 108))	('decreased', 'NegReg', (118, 127))	('survival', 'CPA', (128, 136))	('expression', 'MPA', (67, 77))	('TGF-beta', 'Gene', (19, 27))
41931	30268436	Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-beta signaling in each cancer type.	('miR', 'Gene', (105, 108))	('TGF-beta', 'Gene', '7040', (153, 161))	('deletion', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('mutation', 'Var', (49, 57))	('TGF-beta', 'Gene', (153, 161))	('transcriptional activity', 'MPA', (125, 149))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('amplification', 'Var', (59, 72))	('cancer', 'Disease', (180, 186))	('miR', 'Gene', '220972', (105, 108))
41947	30268436	We analyzed multiple data types: somatic copy number variation (CNV), point mutation, DNA methylation, mRNA expression (from mRNA-seq), miRNA expression (from miRNA-seq), and, for correlative analyses, protein expression (from reverse-phase protein arrays; RPPA).	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('point mutation', 'Var', (70, 84))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', (159, 162))	('mRNA expression', 'MPA', (103, 118))
41953	30268436	Using the cBioPortal definitions, genomic alterations were classified as gene amplifications, gains (low-level amplifications), deep deletions (equivalent to homozygous deletions for non-aneuploidy cases), shallow deletions (heterozygous loss), truncating mutations, inframe mutations, or missense mutations.	('non-aneuploidy', 'Disease', (183, 197))	('truncating', 'Disease', (245, 255))	('gains', 'Disease', (94, 99))	('inframe mutations', 'Var', (267, 284))	('deep', 'Disease', (128, 132))	('missense mutations', 'Var', (289, 307))	('shallow', 'Disease', (206, 213))	('non-aneuploidy', 'Disease', 'MESH:D000782', (183, 197))
41955	30268436	Although alteration frequencies were low, 39% of the tumors contained an alteration in at least one of the 43 genes.	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('alteration', 'Var', (73, 83))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
41959	30268436	When excluding those six, cumulative mutation frequency (23%) in the TGF-beta core pathways was significantly higher than expected for a randomly selected set of 37 genes (Figure S1C, S1D).	('TGF-beta', 'Gene', '7040', (69, 77))	('higher', 'PosReg', (110, 116))	('mutation frequency', 'Var', (37, 55))	('TGF-beta', 'Gene', (69, 77))
41963	30268436	The frequency and type of genomic alteration varied widely across tumor types (Figure 2A and S2A), from no alterations in testicular germline tumors (TGCT) to all three types of alterations (mutation, deletion, and amplification) in urothelial bladder cancers (BLCA).	('deletion', 'Var', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('tumor', 'Disease', (66, 71))	('bladder cancers', 'Phenotype', 'HP:0009725', (244, 259))	('tumor', 'Disease', (142, 147))	('amplification', 'Var', (215, 228))	('urothelial bladder cancers', 'Disease', (233, 259))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('BLCA', 'Phenotype', 'HP:0009725', (261, 265))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (233, 259))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
41964	30268436	There were genomic alterations of TGF-beta pathway genes in more than 50% of samples in 12 tumor types (Figure 2A, Tables S2-S4).	('TGF-beta', 'Gene', (34, 42))	('genomic alterations', 'Var', (11, 30))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TGF-beta', 'Gene', '7040', (34, 42))	('tumor', 'Disease', (91, 96))
41966	30268436	Without adjusting for background alteration burden, among the 39% of TCGA cases that carried TGF-beta pathway gene alterations, SKCM (70%), COAD (65%), and ESCA (65%) had the highest percentages of alterations; THCA (4%), KICH (6%), and TGCT (9%) had the lowest (Table S3).	('TGF-beta', 'Gene', '7040', (93, 101))	('COAD', 'Disease', (140, 144))	('TGF-beta', 'Gene', (93, 101))	('alterations', 'Reg', (198, 209))	('alterations', 'Var', (115, 126))	('KICH', 'Disease', 'None', (222, 226))	('ESCA', 'Phenotype', 'HP:0011459', (156, 160))	('COAD', 'Disease', 'MESH:D029424', (140, 144))	('KICH', 'Disease', (222, 226))
41967	30268436	We observed non-silent SMAD4 mutations in 24% and SMAD4 deletions in 13% of pancreatic adenocarcinoma (PAAD) samples (Figure 2A, 2C; Table S4).	('SMAD4', 'Gene', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutations', 'Var', (29, 38))	('SMAD4', 'Gene', (50, 55))	('pancreatic adenocarcinoma', 'Disease', (76, 101))	('deletions', 'Var', (56, 65))	('PAAD', 'Phenotype', 'HP:0006725', (103, 107))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (76, 101))	('SMAD4', 'Gene', '4089', (23, 28))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (76, 101))	('SMAD4', 'Gene', '4089', (50, 55))
41968	30268436	Because SMAD4 is the Co-Smad required for transducing the Smad signal to downstream effectors, loss of SMAD4 in PAAD by mutation or deletion suggests a tumor-suppressive role for TGF-beta signaling in PAAD, which is consistent with other reports.	('TGF-beta', 'Gene', (179, 187))	('deletion', 'Var', (132, 140))	('SMAD4', 'Gene', (8, 13))	('a tumor', 'Disease', 'MESH:D009369', (150, 157))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('SMAD4', 'Gene', '4089', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutation', 'Var', (120, 128))	('a tumor', 'Disease', (150, 157))	('SMAD4', 'Gene', '4089', (8, 13))	('TGF-beta', 'Gene', '7040', (179, 187))	('loss', 'NegReg', (95, 99))	('SMAD4', 'Gene', (103, 108))	('PAAD', 'Disease', (201, 205))	('PAAD', 'Phenotype', 'HP:0006725', (201, 205))
41972	30268436	Diffuse large B-cell lymphoma (DLBC) had a high frequency of deletions spanning different levels of the pathway:: ligands (TGFB2, INHBB, GDF1), receptors or receptor-associated proteins (BMPR1A, ACVR1, ACVR1C, ACV2A, ACVR2B, TGFBRAP1), and Smads (SMAD9):, indicative of a tumor-suppressive role for TGF-beta signaling in these early-stage DLBC cases in the TCGA cohort.	('deletions', 'Var', (61, 70))	('TGF-beta', 'Gene', (299, 307))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (14, 29))	('TGFB2', 'Gene', '7042', (123, 128))	('ACVR1C', 'Gene', (202, 208))	('ACVR1C', 'Gene', '130399', (202, 208))	('INHBB', 'Gene', (130, 135))	('BMPR1A', 'Gene', '657', (187, 193))	('ACV', 'Gene', (195, 198))	('ACV', 'Gene', (210, 213))	('ACV', 'Gene', (202, 205))	('ACVR1', 'Gene', (195, 200))	('a tumor', 'Disease', 'MESH:D009369', (270, 277))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (14, 29))	('TGFB2', 'Gene', (123, 128))	('TGFBRAP1', 'Gene', '9392', (225, 233))	('ACV', 'Gene', '83729', (202, 205))	('ACVR2B', 'Gene', '93', (217, 223))	('GDF1', 'Gene', (137, 141))	('ACV', 'Gene', '83729', (195, 198))	('ACV', 'Gene', '83729', (210, 213))	('ACVR1', 'Gene', '90', (202, 207))	('INHBB', 'Gene', '3625', (130, 135))	('B-cell lymphoma', 'Disease', (14, 29))	('early-stage DLBC', 'Disease', (327, 343))	('ACV', 'Gene', (217, 220))	('a tumor', 'Disease', (270, 277))	('BMPR1A', 'Gene', (187, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	('ACVR1', 'Gene', (202, 207))	('ACVR1', 'Gene', '90', (195, 200))	('SMAD9', 'Gene', (247, 252))	('GDF1', 'Gene', '2657', (137, 141))	('TGF-beta', 'Gene', '7040', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('ACV', 'Gene', '83729', (217, 220))	('ACVR2B', 'Gene', (217, 223))	('SMAD9', 'Gene', '4093', (247, 252))	('TGFBRAP1', 'Gene', (225, 233))
41978	30268436	PAAD had deletions associated with 14 TGF-beta core genes, suggesting synergistic effects from ligands (BMP family), receptors (BMPR, TGFBR), and SMAD4.	('TGFBR', 'Gene', '7046;7048;7049', (134, 139))	('TGF-beta', 'Gene', (38, 46))	('BMP', 'Gene', (128, 131))	('BMP', 'Gene', (104, 107))	('TGFBR', 'Gene', (134, 139))	('SMAD4', 'Gene', '4089', (146, 151))	('PAAD', 'Phenotype', 'HP:0006725', (0, 4))	('TGF-beta', 'Gene', '7040', (38, 46))	('deletions', 'Var', (9, 18))	('BMP', 'Gene', '649', (104, 107))	('SMAD4', 'Gene', (146, 151))	('BMP', 'Gene', '649', (128, 131))
41979	30268436	Colorectal cancers (COAD and READ) were marked by SMAD4 and SMAD3 deletions.	('SMAD3', 'Gene', (60, 65))	('COAD', 'Disease', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Colorectal cancers', 'Disease', (0, 18))	('SMAD4', 'Gene', (50, 55))	('Colorectal cancers', 'Disease', 'MESH:D015179', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('COAD', 'Disease', 'MESH:D029424', (20, 24))	('deletions', 'Var', (66, 75))	('SMAD3', 'Gene', '4088', (60, 65))	('SMAD4', 'Gene', '4089', (50, 55))
41980	30268436	Deletions in genomic regions covering all ACVR genes except ACVR2B were identified as significant in DLBC.	('ACV', 'Gene', '83729', (42, 45))	('ACVR2B', 'Gene', (60, 66))	('DLBC', 'Disease', (101, 105))	('ACV', 'Gene', (42, 45))	('ACV', 'Gene', '83729', (60, 63))	('ACV', 'Gene', (60, 63))	('ACVR2B', 'Gene', '93', (60, 66))	('significant', 'Reg', (86, 97))	('Deletions', 'Var', (0, 9))
41981	30268436	To understand how gene alterations affect transcriptional output of the pathways, we analyzed the mRNA expression of 50 downstream targets of Smad signaling with defined roles as tumor promoters or tumor suppressors (Table S1).	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('alterations', 'Var', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (179, 184))
41982	30268436	Surprisingly, the directionality of target-gene change was consistent for all mutations, even for mutations in the inhibitors SMAD6/7.	('SMAD6/7', 'Gene', (126, 133))	('SMAD6/7', 'Gene', '4091;4092', (126, 133))	('mutations', 'Var', (78, 87))
41983	30268436	An explanation is that mutations in pathway activators, like TGFB1/2/3 and TGFBR1/2/3, may result in gain of function, whereas mutations in the inhibitors SMAD6 and SMAD7 may result in loss of inhibitory function.	('TGFBR1/2/3', 'Gene', (75, 85))	('TGFBR1/2/3', 'Gene', '7046;7048;7049', (75, 85))	('SMAD7', 'Gene', (165, 170))	('TGFB1/2/3', 'Gene', (61, 70))	('SMAD6', 'Gene', (155, 160))	('mutations', 'Var', (23, 32))	('SMAD7', 'Gene', '4092', (165, 170))	('SMAD6', 'Gene', '4091', (155, 160))	('TGFB1/2/3', 'Gene', '7040;7042;7043', (61, 70))	('gain of function', 'PosReg', (101, 117))	('inhibitory function', 'MPA', (193, 212))
41985	30268436	Similarly, SMAD3 was generally co-amplified with SMAD6; both are in proximal cytogenetic bands, 15q22.33 and 15q22.31, respectively.	('SMAD3', 'Gene', '4088', (11, 16))	('SMAD3', 'Gene', (11, 16))	('SMAD6', 'Gene', '4091', (49, 54))	('15q22.33', 'Var', (96, 104))	('SMAD6', 'Gene', (49, 54))	('15q22.31', 'Var', (109, 117))
41986	30268436	In support of that hypothesis, both the amplification and deletion profiles (rows in Figure 2H-I) of those gene pairs were similar, and, consequently, SMAD2 and SMAD7 are co-clustered, whereas SMAD3 and SMAD6 clustered close to each other.	('SMAD7', 'Gene', (161, 166))	('SMAD7', 'Gene', '4092', (161, 166))	('SMAD2', 'Gene', (151, 156))	('SMAD2', 'Gene', '4087', (151, 156))	('SMAD6', 'Gene', '4091', (203, 208))	('deletion', 'Var', (58, 66))	('SMAD6', 'Gene', (203, 208))	('SMAD3', 'Gene', '4088', (193, 198))	('SMAD3', 'Gene', (193, 198))
41987	30268436	The effect of TGF-beta pathway amplification events on target gene mRNA expression was similar to that of mutations (Figure 2H), suggesting that most mutations in TGF-beta pathway activators are gain of function.	('TGF-beta', 'Gene', '7040', (163, 171))	('TGF-beta', 'Gene', (14, 22))	('gain of function', 'PosReg', (195, 211))	('TGF-beta', 'Gene', (163, 171))	('mutations', 'Var', (150, 159))	('TGF-beta', 'Gene', '7040', (14, 22))
41988	30268436	HMGA2 was overexpressed in samples with either mutations or amplifications in the TGF-beta pathway genes, with the exception of tumors with amplifications in TGFB2, TGFBR2, ACVR2B, SMAD4, SMAD5, or SMAD6.	('TGFBR2', 'Gene', (165, 171))	('SMAD6', 'Gene', (198, 203))	('ACVR2B', 'Gene', '93', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TGF-beta', 'Gene', '7040', (82, 90))	('SMAD4', 'Gene', (181, 186))	('tumors', 'Disease', (128, 134))	('overexpressed', 'PosReg', (10, 23))	('HMGA2', 'Gene', '8091', (0, 5))	('SMAD5', 'Gene', (188, 193))	('mutations', 'Var', (47, 56))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('TGF-beta', 'Gene', (82, 90))	('ACVR2B', 'Gene', (173, 179))	('SMAD6', 'Gene', '4091', (198, 203))	('SMAD4', 'Gene', '4089', (181, 186))	('amplifications', 'Var', (140, 154))	('TGFB2', 'Gene', '7042', (158, 163))	('TGFBR2', 'Gene', '7048', (165, 171))	('SMAD5', 'Gene', '4090', (188, 193))	('amplifications', 'Var', (60, 74))	('TGFB2', 'Gene', (158, 163))	('HMGA2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
41993	30268436	SMAD5 amplification was associated with increased CDH2 expression; 36 other amplifications were associated with decreased CDH2 expression.	('CDH2', 'Gene', (50, 54))	('CDH2', 'Gene', '1000', (50, 54))	('expression', 'MPA', (127, 137))	('SMAD5', 'Gene', (0, 5))	('CDH2', 'Gene', (122, 126))	('expression', 'MPA', (55, 65))	('CDH2', 'Gene', '1000', (122, 126))	('SMAD5', 'Gene', '4090', (0, 5))	('increased', 'PosReg', (40, 49))	('amplification', 'Var', (6, 19))	('decreased', 'NegReg', (112, 121))
41995	30268436	Another exception was reduced HMGA2 expression in samples with amplifications of SMAD4 or TGFBR2, whereas HMGA2 expression increased in samples with mutations in SMAD4 or TGFBR2 (Figure 2G).	('increased', 'PosReg', (123, 132))	('mutations', 'Var', (149, 158))	('HMGA2', 'Gene', '8091', (30, 35))	('TGFBR2', 'Gene', (90, 96))	('SMAD4', 'Gene', '4089', (162, 167))	('TGFBR2', 'Gene', '7048', (171, 177))	('HMGA2', 'Gene', '8091', (106, 111))	('SMAD4', 'Gene', (81, 86))	('HMGA2', 'Gene', (30, 35))	('HMGA2', 'Gene', (106, 111))	('amplifications', 'Var', (63, 77))	('reduced', 'NegReg', (22, 29))	('TGFBR2', 'Gene', (171, 177))	('TGFBR2', 'Gene', '7048', (90, 96))	('SMAD4', 'Gene', (162, 167))	('expression', 'MPA', (36, 46))	('SMAD4', 'Gene', '4089', (81, 86))	('expression', 'MPA', (112, 122))
41997	30268436	The analysis identified 6genes with hotspot mutations, representing all levels of the TGF-beta pathway (Figure 3A-E).	('TGF-beta', 'Gene', '7040', (86, 94))	('TGF-beta', 'Gene', (86, 94))	('mutations', 'Var', (44, 53))
41999	30268436	Hotspot mutations of BMP5 occurred in 13 cases across 7 cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (8, 17))	('occurred', 'Reg', (26, 34))	('BMP5', 'Gene', (21, 25))	('BMP5', 'Gene', '653', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('Hotspot', 'PosReg', (0, 7))
42000	30268436	BMP5 is synthesized as a proprotein, and an R321 stop-codon mutation (4 cases) (Figure 3A) results in loss of the functional, secreted ligand.	('R321 stop-codon', 'Var', (44, 59))	('BMP5', 'Gene', '653', (0, 4))	('BMP5', 'Gene', (0, 4))	('loss', 'NegReg', (102, 106))
42001	30268436	Frameshift mutations in ACVR2A at the K437 hotspot generate the variants K437Efs*19 (7 cases in 2 cancers) and K437Rfs*5 (69 cases in 5 cancers), resulting in premature stop codons and deletion of two C-terminal helices of the 4-helix bundle (Figure 3A, 3D), which likely disrupt ACV signaling (; Yosef et al., 2017).	('ACV', 'Gene', '83729', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', (98, 105))	('K437Efs*19', 'Var', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('K437Efs', 'Mutation', 'p.K437,FSE', (73, 80))	('ACV', 'Gene', (280, 283))	('disrupt', 'NegReg', (272, 279))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('ACV', 'Gene', '83729', (280, 283))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('K437Rfs*5', 'Var', (111, 120))	('stop codons', 'MPA', (169, 180))	('ACVR2A', 'Gene', '92', (24, 30))	('ACV', 'Gene', (24, 27))	('deletion', 'Var', (185, 193))	('ACVR2A', 'Gene', (24, 30))	('K437Rfs', 'Mutation', 'p.K437,FSR', (111, 118))	('Frameshift mutations', 'Var', (0, 20))
42002	30268436	Type I receptors ACVR1B and ACVR1C have similar C-terminal frameshift mutation hotspots at R485 (6 cases) and R441 (5 cases), respectively (Figure S3).	('ACVR1B', 'Gene', '91', (17, 23))	('ACVR1B', 'Gene', (17, 23))	('R441', 'Var', (110, 114))	('ACVR1C', 'Gene', (28, 34))	('ACVR1C', 'Gene', '130399', (28, 34))	('R485', 'Var', (91, 95))
42003	30268436	TGFBR2 R553 to C or H mutations and BMPR2 N583 frameshift might disrupt interaction with other receptor subunits or binding proteins.	('BMPR2', 'Gene', '659', (36, 41))	('binding', 'Interaction', (116, 123))	('N583 frameshift', 'Var', (42, 57))	('interaction', 'Interaction', (72, 83))	('TGFBR2', 'Gene', (0, 6))	('R553 to C or H mutations', 'Var', (7, 31))	('frameshift', 'Var', (47, 57))	('TGFBR2', 'Gene', '7048', (0, 6))	('disrupt', 'NegReg', (64, 71))	('BMPR2', 'Gene', (36, 41))
42004	30268436	Hotspots in SMAD4 at R361 and D537 (two conserved sites in R-Smads) normally stabilize homo- or heterotrimer oligomerization (Figure 3C).	('SMAD4', 'Gene', (12, 17))	('stabilize', 'Reg', (77, 86))	('D537', 'Var', (30, 34))	('homo-', 'MPA', (87, 92))	('SMAD4', 'Gene', '4089', (12, 17))
42005	30268436	Those mutations could have widespread effects, because SMAD4 is a binding partner for all Smad-dependent transcriptional regulation.	('mutations', 'Var', (6, 15))	('SMAD4', 'Gene', '4089', (55, 60))	('SMAD4', 'Gene', (55, 60))
42006	30268436	Mutation at either R361 or D537 in SMAD4 correlates with metastasis and decreased survival in colon cancer.	('survival', 'CPA', (82, 90))	('colon cancer', 'Disease', (94, 106))	('decreased', 'NegReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('SMAD4', 'Gene', '4089', (35, 40))	('D537', 'Var', (27, 31))	('metastasis', 'CPA', (57, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('SMAD4', 'Gene', (35, 40))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
42007	30268436	SMAD2 exhibited 13 truncating mutations at S464 (Figure 3A).	('SMAD2', 'Gene', (0, 5))	('SMAD2', 'Gene', '4087', (0, 5))	('S464', 'Var', (43, 47))
42009	30268436	S464 is necessary for proper positioning of SMAD2 for phosphorylation at S465 and S467, both of which mediate interaction of SMAD2 with SMAD4 and dissociation of SMAD2 from TGFBR1 and the adaptor SARA (encoded by ZFYVE9).	('SARA', 'Gene', (196, 200))	('SMAD4', 'Gene', '4089', (136, 141))	('SARA', 'Gene', '9372', (196, 200))	('dissociation', 'MPA', (146, 158))	('ZFYVE9', 'Gene', '9372', (213, 219))	('TGFBR1', 'Gene', '7046', (173, 179))	('mediate', 'Reg', (102, 109))	('interaction', 'Interaction', (110, 121))	('SMAD4', 'Gene', (136, 141))	('TGFBR1', 'Gene', (173, 179))	('SMAD2', 'Gene', (162, 167))	('SMAD2', 'Gene', '4087', (125, 130))	('SMAD2', 'Gene', '4087', (162, 167))	('SMAD2', 'Gene', (125, 130))	('SMAD2', 'Gene', '4087', (44, 49))	('ZFYVE9', 'Gene', (213, 219))	('SMAD2', 'Gene', (44, 49))	('S467', 'Var', (82, 86))
42010	30268436	Hence, S464 mutations may prevent dissociation of SMAD2 from the receptor-adaptor complex, blocking the downstream signal (Figure 3E).	('SMAD2', 'Gene', (50, 55))	('S464 mutations', 'Var', (7, 21))	('downstream signal', 'MPA', (104, 121))	('blocking', 'NegReg', (91, 99))	('SMAD2', 'Gene', '4087', (50, 55))	('dissociation', 'MPA', (34, 46))	('prevent', 'NegReg', (26, 33))
42011	30268436	Of 176 mutations at hotspot sites across 6 genes, 115 (65%) were in cancers of the GI system (Figure S3): 60 in ESCA, 51 in COAD, 3 in PAAD, and 1 in LIHC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers of the GI system', 'Phenotype', 'HP:0007378', (68, 92))	('PAAD', 'Phenotype', 'HP:0006725', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('COAD', 'Disease', (124, 128))	('cancers of the GI system', 'Disease', 'MESH:D009369', (68, 92))	('cancers of the GI system', 'Disease', (68, 92))	('LIHC', 'Disease', (150, 154))	('ESCA', 'Phenotype', 'HP:0011459', (112, 116))	('LIHC', 'Disease', 'None', (150, 154))	('ESCA', 'Disease', (112, 116))	('COAD', 'Disease', 'MESH:D029424', (124, 128))	('mutations', 'Var', (7, 16))
42014	30268436	To determine if GI cancers possess a unique signature of altered TGF-beta pathway activity, we compared changes in the expression of 50 downstream genes related to mutations at hotspot sites (Figure 3B).	('TGF-beta', 'Gene', (65, 73))	('expression', 'MPA', (119, 129))	('GI cancers', 'Disease', (16, 26))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('activity', 'MPA', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (164, 173))	('TGF-beta', 'Gene', '7040', (65, 73))
42016	30268436	Notably, CDH2 exhibited an overall reduction in expression except in the context of the BMP5 hotspot mutation.	('CDH2', 'Gene', (9, 13))	('CDH2', 'Gene', '1000', (9, 13))	('BMP5', 'Gene', (88, 92))	('expression', 'MPA', (48, 58))	('BMP5', 'Gene', '653', (88, 92))	('mutation', 'Var', (101, 109))	('reduction', 'NegReg', (35, 44))
42020	30268436	Guided by the enrichment of hotspot mutations in GI cancers, we tested for enrichment of TGF-beta pathway point mutations in GI cancers.	('GI cancers', 'Disease', 'MESH:D009369', (49, 59))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('GI cancers', 'Disease', 'MESH:D009369', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (49, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (125, 134))	('tested', 'Reg', (64, 70))	('point mutations', 'Var', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TGF-beta', 'Gene', '7040', (89, 97))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('GI cancers', 'Disease', (49, 59))	('GI cancers', 'Disease', (125, 135))	('TGF-beta', 'Gene', (89, 97))
42021	30268436	Non-silent mutations were significantly more common in GI cancers (596 of 1,511) than in the non-GI cancers (1,606 of 7,614).	('GI cancers', 'Disease', 'MESH:D009369', (55, 65))	('common', 'Reg', (45, 51))	('non-GI cancers', 'Disease', 'MESH:D009369', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (55, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('Non-silent mutations', 'Var', (0, 20))	('GI cancers', 'Disease', 'MESH:D009369', (97, 107))	('GI cancers', 'Disease', (55, 65))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('non-GI cancers', 'Disease', (93, 107))
42022	30268436	Deep deletions and amplifications were also significantly enriched in GI cancers.	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('Deep deletions', 'Var', (0, 14))	('GI cancers', 'Disease', (70, 80))	('amplifications', 'Var', (19, 33))
42023	30268436	COAD, READ, and STAD had recurrent aberrations in genes at each level of the pathway (ligands, receptors, and SMADs) and all axes (TGFBR, BMPR, ACVR), whereas PAAD had frequent mutations in only SMAD4 and TGFBR2 (Figure S4A).	('TGFBR', 'Gene', (205, 210))	('COAD', 'Disease', (0, 4))	('SMAD4', 'Gene', '4089', (195, 200))	('aberrations', 'Var', (35, 46))	('TGFBR2', 'Gene', '7048', (205, 211))	('ACV', 'Gene', (144, 147))	('mutations', 'Var', (177, 186))	('BMP', 'Gene', (138, 141))	('TGFBR', 'Gene', '7046;7048;7049', (131, 136))	('TGFBR2', 'Gene', (205, 211))	('SMAD4', 'Gene', (195, 200))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('TGFBR', 'Gene', '7046;7048;7049', (205, 210))	('PAAD', 'Phenotype', 'HP:0006725', (159, 163))	('BMP', 'Gene', '649', (138, 141))	('ACV', 'Gene', '83729', (144, 147))	('TGFBR', 'Gene', (131, 136))
42024	30268436	To compare the TGF-beta pathway transcriptional signatures in GI vs. other cancers, we calculated the target gene expression signatures associated with TGF-beta pathway mutations in both groups (Figure 4A-B).	('TGF-beta', 'Gene', '7040', (152, 160))	('mutations', 'Var', (169, 178))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('TGF-beta', 'Gene', '7040', (15, 23))	('cancers', 'Disease', (75, 82))	('TGF-beta', 'Gene', (15, 23))	('TGF-beta', 'Gene', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
42026	30268436	Whereas IL6 mRNA was increased in most non-GI cancers with TGF-beta pathway mutations, IL6 upregulation was significantly greater in GI cancers than non-GI cancers (Figure S4B), and within GI cancers IL6 expression was greater in samples with alterations in the TGF-beta pathway genes than those without alterations in the TGF-beta pathway genes.	('non-GI cancers', 'Disease', (39, 53))	('GI cancers than non-GI cancers', 'Disease', 'MESH:D009369', (133, 163))	('GI cancers', 'Disease', 'MESH:D009369', (189, 199))	('non-GI cancers', 'Disease', 'MESH:D009369', (39, 53))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('TGF-beta', 'Gene', (323, 331))	('GI cancers', 'Disease', 'MESH:D009369', (43, 53))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('IL6', 'Gene', '3569', (8, 11))	('alterations', 'Var', (243, 254))	('IL6', 'Gene', '3569', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('TGF-beta', 'Gene', (59, 67))	('increased', 'PosReg', (21, 30))	('non-GI cancers', 'Disease', 'MESH:D009369', (149, 163))	('GI cancers', 'Disease', 'MESH:D009369', (153, 163))	('IL6', 'Gene', '3569', (87, 90))	('GI cancer', 'Phenotype', 'HP:0007378', (43, 52))	('IL6', 'Gene', (8, 11))	('TGF-beta', 'Gene', '7040', (262, 270))	('IL6', 'Gene', (200, 203))	('GI cancers than non-GI cancers', 'Disease', (133, 163))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('GI cancer', 'Phenotype', 'HP:0007378', (153, 162))	('upregulation', 'PosReg', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('IL6', 'Gene', (87, 90))	('expression', 'MPA', (204, 214))	('GI cancers', 'Disease', (189, 199))	('greater', 'PosReg', (122, 129))	('TGF-beta', 'Gene', '7040', (323, 331))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('mutations', 'Var', (76, 85))	('TGF-beta', 'Gene', (262, 270))	('GI cancer', 'Phenotype', 'HP:0007378', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('GI cancers', 'Disease', 'MESH:D009369', (133, 143))	('GI cancer', 'Phenotype', 'HP:0007378', (189, 198))	('TGF-beta', 'Gene', '7040', (59, 67))
42027	30268436	Notably, in non-GI cancers associated with GDF1 mutations, IL6 mRNA expression was markedly decreased, suggesting that GDF1 may play different roles in GI and non-GI cancers.	('non-GI cancers', 'Disease', 'MESH:D009369', (159, 173))	('GDF1', 'Gene', (43, 47))	('non-GI cancers', 'Disease', (159, 173))	('GDF1', 'Gene', (119, 123))	('non-GI cancers', 'Disease', (12, 26))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('GI cancer', 'Phenotype', 'HP:0007378', (163, 172))	('IL6', 'Gene', '3569', (59, 62))	('IL6', 'Gene', (59, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('decreased', 'NegReg', (92, 101))	('GDF1', 'Gene', '2657', (43, 47))	('mutations', 'Var', (48, 57))	('GDF1', 'Gene', '2657', (119, 123))
42029	30268436	In GI cancers, most TGF-beta pathway gene mutations were associated with increased FOS expression; exceptions were TGFBRAP1, SMAD7, SMAD5, GDF1, BMP5, and ACVRL1.	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('TGF-beta', 'Gene', (20, 28))	('ACVRL1', 'Gene', (155, 161))	('SMAD7', 'Gene', '4092', (125, 130))	('BMP5', 'Gene', (145, 149))	('BMP5', 'Gene', '653', (145, 149))	('TGFBRAP1', 'Gene', '9392', (115, 123))	('SMAD5', 'Gene', (132, 137))	('GDF1', 'Gene', (139, 143))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (73, 82))	('ACVRL1', 'Gene', '94', (155, 161))	('GDF1', 'Gene', '2657', (139, 143))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('SMAD5', 'Gene', '4090', (132, 137))	('FOS', 'Gene', (83, 86))	('SMAD7', 'Gene', (125, 130))	('GI cancers', 'Disease', (3, 13))	('TGF-beta', 'Gene', '7040', (20, 28))	('FOS', 'Gene', '2353', (83, 86))	('TGFBRAP1', 'Gene', (115, 123))	('mutations', 'Var', (42, 51))
42030	30268436	In non-GI cancers, only mutations in TGFBR2 were associated with increased FOS expression; all other TGF-beta pathway gene mutations were associated with decreased FOS expression.	('decreased', 'NegReg', (154, 163))	('increased', 'PosReg', (65, 74))	('FOS', 'Gene', (164, 167))	('TGF-beta', 'Gene', '7040', (101, 109))	('TGFBR2', 'Gene', '7048', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('FOS', 'Gene', '2353', (164, 167))	('TGF-beta', 'Gene', (101, 109))	('non-GI cancers', 'Disease', (3, 17))	('FOS', 'Gene', (75, 78))	('TGFBR2', 'Gene', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('mutations', 'Var', (24, 33))	('non-GI cancers', 'Disease', 'MESH:D009369', (3, 17))	('GI cancer', 'Phenotype', 'HP:0007378', (7, 16))	('FOS', 'Gene', '2353', (75, 78))
42031	30268436	To compare the transcriptional output resulting from mutations in GI and non-GI cancers, we calculated differences in expression of the 50 target genes associated with mutations in the 43 genes (Figure 4C).	('non-GI cancers', 'Disease', 'MESH:D009369', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('differences', 'Reg', (103, 114))	('expression', 'MPA', (118, 128))	('non-GI cancers', 'Disease', (73, 87))	('mutations', 'Var', (168, 177))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
42032	30268436	The analysis revealed a shift toward repression of transcriptional output in GI cancers with the most significant shifts occurring with mutations in ACVR2B, INHBA, SMAD3, or GDF2.	('GDF2', 'Gene', (174, 178))	('repression', 'NegReg', (37, 47))	('GI cancers', 'Disease', (77, 87))	('SMAD3', 'Gene', '4088', (164, 169))	('INHBA', 'Gene', '3624', (157, 162))	('ACVR2B', 'Gene', '93', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('transcriptional output', 'MPA', (51, 73))	('SMAD3', 'Gene', (164, 169))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('INHBA', 'Gene', (157, 162))	('mutations', 'Var', (136, 145))	('GI cancers', 'Disease', 'MESH:D009369', (77, 87))	('ACVR2B', 'Gene', (149, 155))	('GDF2', 'Gene', '2658', (174, 178))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
42033	30268436	In GI cancers, mutations in GDF1 were associated with significantly increased target gene transcription.	('GDF1', 'Gene', '2657', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (15, 24))	('GDF1', 'Gene', (28, 32))	('target gene transcription', 'MPA', (78, 103))	('GI cancers', 'Disease', (3, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (68, 77))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))
42034	30268436	Mutations in any of the 43 genes were associated with reduced mRNA expression in GI cancers compared with non-GI cancers for most target genes with the largest reductions found for HMGA2 and TERT.	('GI cancer', 'Phenotype', 'HP:0007378', (110, 119))	('GI cancers', 'Disease', 'MESH:D009369', (110, 120))	('GI cancers', 'Disease', (81, 91))	('HMGA2', 'Gene', '8091', (181, 186))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('non-GI cancers', 'Disease', 'MESH:D009369', (106, 120))	('non-GI cancers', 'Disease', (106, 120))	('GI cancers', 'Disease', 'MESH:D009369', (81, 91))	('mRNA expression', 'MPA', (62, 77))	('Mutations', 'Var', (0, 9))	('HMGA2', 'Gene', (181, 186))	('reduced', 'NegReg', (54, 61))	('GI cancer', 'Phenotype', 'HP:0007378', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TERT', 'Gene', (191, 195))	('TERT', 'Gene', '7015', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
42035	30268436	Compared to non-GI cancers, GI cancers had fewer genes with increased expression resulting from pathway mutations.	('non-GI cancers', 'Disease', (12, 26))	('mutations', 'Var', (104, 113))	('GI cancers', 'Disease', 'MESH:D009369', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('expression', 'MPA', (70, 80))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('GI cancers', 'Disease', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('GI cancer', 'Phenotype', 'HP:0007378', (28, 37))	('increased', 'PosReg', (60, 69))
42036	30268436	In GI cancers, mutations in any of the 43 genes were associated with a significantly increased expression of FOS, IL6, ZEB2, and ZEB1 compared to expression changes of the same genes resulting from pathway mutations in non-GI cancers.	('ZEB1', 'Gene', '6935', (129, 133))	('IL6', 'Gene', (114, 117))	('increased', 'PosReg', (85, 94))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('mutations', 'Var', (15, 24))	('non-GI cancers', 'Disease', (219, 233))	('non-GI cancers', 'Disease', 'MESH:D009369', (219, 233))	('FOS', 'Gene', (109, 112))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('GI cancers', 'Disease', 'MESH:D009369', (223, 233))	('expression', 'MPA', (95, 105))	('FOS', 'Gene', '2353', (109, 112))	('ZEB1', 'Gene', (129, 133))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (223, 232))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ZEB2', 'Gene', (119, 123))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('IL6', 'Gene', '3569', (114, 117))	('GI cancers', 'Disease', (3, 13))	('ZEB2', 'Gene', '9839', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
42037	30268436	Finally, we probed for associations between transcriptional output and TGF-beta pathway gene alterations for all cancers and the GI and non-GI subsets (Figure 4E).	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('alterations', 'Var', (93, 104))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('probed', 'Reg', (12, 18))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('TGF-beta', 'Gene', '7040', (71, 79))	('TGF-beta', 'Gene', (71, 79))
42040	30268436	To explore TGF-beta signaling pathway variation across the 33 cancers in the PanCancer cohort, we computed a "pathway activity score" based on mRNA expression of the 43 genes.	('TGF-beta', 'Gene', '7040', (11, 19))	('TGF-beta', 'Gene', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('variation', 'Var', (38, 47))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
42062	30268436	We attribute this observation to co-occurring amplifications or deletions of SMAD7 and SMAD2 and co-occurring amplifications of SMAD6 and SMAD3 (Figure 1B).	('amplifications', 'Var', (46, 60))	('SMAD7', 'Gene', (77, 82))	('SMAD6', 'Gene', (128, 133))	('SMAD2', 'Gene', '4087', (87, 92))	('SMAD3', 'Gene', '4088', (138, 143))	('deletions', 'Var', (64, 73))	('SMAD7', 'Gene', '4092', (77, 82))	('SMAD2', 'Gene', (87, 92))	('SMAD3', 'Gene', (138, 143))	('SMAD6', 'Gene', '4091', (128, 133))
42069	30268436	We analyzed the combined impact of TGF-beta target gene expression and the 43 core gene alterations on patient survival across the PanCancer cohort.	('TGF-beta', 'Gene', (35, 43))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alterations', 'Var', (88, 99))	('patient', 'Species', '9606', (103, 110))	('TGF-beta', 'Gene', '7040', (35, 43))
42070	30268436	We compared the survival of patients with 3 different cancer profiles: those with high expression of HMGA2 and alterations in any one of the 43 TGF-beta pathway genes (Figure 6C, High HMGA2/TGF-beta mutant), those with high HMGA2 expression and no alterations in any of the 43 genes (Figure 6C, High HMGA2/TGF-beta wild-type), and those with low expression of HMGA2 without considering alterations in TGF-beta pathway genes (Figure 6C, Low HMGA2 expression).	('TGF-beta', 'Gene', '7040', (306, 314))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('HMGA2', 'Gene', '8091', (360, 365))	('high', 'PosReg', (82, 86))	('HMGA2', 'Gene', '8091', (440, 445))	('HMGA2', 'Gene', '8091', (184, 189))	('HMGA2', 'Gene', (300, 305))	('TGF-beta', 'Gene', (401, 409))	('mutant', 'Var', (199, 205))	('HMGA2', 'Gene', (101, 106))	('TGF-beta', 'Gene', (306, 314))	('HMGA2', 'Gene', '8091', (224, 229))	('TGF-beta', 'Gene', '7040', (144, 152))	('patients', 'Species', '9606', (28, 36))	('TGF-beta', 'Gene', '7040', (190, 198))	('cancer', 'Disease', (54, 60))	('HMGA2', 'Gene', (360, 365))	('HMGA2', 'Gene', '8091', (300, 305))	('HMGA2', 'Gene', '8091', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('TGF-beta', 'Gene', (144, 152))	('HMGA2', 'Gene', (184, 189))	('HMGA2', 'Gene', (440, 445))	('alterations', 'Var', (111, 122))	('TGF-beta', 'Gene', (190, 198))	('TGF-beta', 'Gene', '7040', (401, 409))	('HMGA2', 'Gene', (224, 229))
42074	30268436	We saw the opposite for cancers with downregulated CDH2; the worst outcome was associated with low CDH2 expression and mutations in 43 genes (Figure S6B).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('low', 'NegReg', (95, 98))	('CDH2', 'Gene', (99, 103))	('CDH2', 'Gene', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('expression', 'MPA', (104, 114))	('CDH2', 'Gene', '1000', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('mutations', 'Var', (119, 128))	('CDH2', 'Gene', '1000', (51, 55))	('cancers', 'Disease', (24, 31))
42075	30268436	Thus, the expression profile of specific target genes and alterations in the TGF-beta superfamily genes cooperated to increase tumor aggressiveness.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor aggressiveness', 'Disease', (127, 147))	('increase', 'PosReg', (118, 126))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (127, 147))	('TGF-beta', 'Gene', '7040', (77, 85))	('aggressiveness', 'Phenotype', 'HP:0000718', (133, 147))	('TGF-beta', 'Gene', (77, 85))	('alterations', 'Var', (58, 69))
42077	30268436	Because of the association of collagen overexpression and alterations in TGF-beta pathway genes with poor survival, we hypothesize that altered signaling through the TGF-beta superfamily pathways remodels the extracellular matrix to drive metastasis in multiple cancer contexts.	('cancer', 'Disease', (262, 268))	('overexpression', 'PosReg', (39, 53))	('TGF-beta', 'Gene', '7040', (73, 81))	('TGF-beta', 'Gene', '7040', (166, 174))	('remodels', 'Reg', (196, 204))	('TGF-beta', 'Gene', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('drive', 'PosReg', (233, 238))	('TGF-beta', 'Gene', (166, 174))	('metastasis', 'CPA', (239, 249))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('alterations', 'Var', (58, 69))
42079	30268436	In the GI cohort, only ZEB2 combined with TGF-beta pathway gene alteration yielded a significant difference, with low ZEB2 expression corresponding to a survival benefit.	('ZEB2', 'Gene', '9839', (23, 27))	('ZEB2', 'Gene', (118, 122))	('expression', 'MPA', (123, 133))	('TGF-beta', 'Gene', (42, 50))	('ZEB2', 'Gene', (23, 27))	('alteration', 'Var', (64, 74))	('benefit', 'PosReg', (162, 169))	('low', 'NegReg', (114, 117))	('TGF-beta', 'Gene', '7040', (42, 50))	('ZEB2', 'Gene', '9839', (118, 122))
42080	30268436	In non-GI patients, high expression of the TGF-beta pathway target genes IL6, HMGA2, ZEB2, and FOS was associated with reduced survival particularly when combined with TGF-beta pathway mutations.	('TGF-beta', 'Gene', (168, 176))	('ZEB2', 'Gene', '9839', (85, 89))	('HMGA2', 'Gene', '8091', (78, 83))	('survival', 'MPA', (127, 135))	('expression', 'MPA', (25, 35))	('high', 'PosReg', (20, 24))	('HMGA2', 'Gene', (78, 83))	('TGF-beta', 'Gene', '7040', (43, 51))	('IL6', 'Gene', '3569', (73, 76))	('ZEB2', 'Gene', (85, 89))	('TGF-beta', 'Gene', (43, 51))	('IL6', 'Gene', (73, 76))	('FOS', 'Gene', (95, 98))	('mutations', 'Var', (185, 194))	('reduced', 'NegReg', (119, 126))	('TGF-beta', 'Gene', '7040', (168, 176))	('patients', 'Species', '9606', (10, 18))	('FOS', 'Gene', '2353', (95, 98))
42081	30268436	Thus, although TGF-beta pathway mutations may not occur as commonly in non-GI cancers, they may be important contributors to mortality.	('non-GI cancers', 'Disease', (71, 85))	('non-GI cancers', 'Disease', 'MESH:D009369', (71, 85))	('contributors', 'Reg', (109, 121))	('TGF-beta', 'Gene', '7040', (15, 23))	('TGF-beta', 'Gene', (15, 23))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('mutations', 'Var', (32, 41))	('GI cancer', 'Phenotype', 'HP:0007378', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
42099	30268436	We also identified BMPR2 and TGFBR2 as genes with hotspot sites of mutations that were common in STAD and COAD.	('COAD', 'Disease', (106, 110))	('STAD', 'Disease', (97, 101))	('COAD', 'Disease', 'MESH:D029424', (106, 110))	('mutations', 'Var', (67, 76))	('TGFBR2', 'Gene', (29, 35))	('BMPR2', 'Gene', (19, 24))	('BMPR2', 'Gene', '659', (19, 24))	('TGFBR2', 'Gene', '7048', (29, 35))
42100	30268436	The cancers with high frequencies of hotspot mutations in those two genes did not have high expression of miRNA 92a-3p, suggesting that there is little selective pressure for both mutation and downregulation by that miRNA.	('downregulation', 'NegReg', (193, 207))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (216, 219))	('miR', 'Gene', (216, 219))	('miR', 'Gene', '220972', (106, 109))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
42101	30268436	To examine the contribution of mutations, amplifications, deletions, DNA methylation and miRNAs to the pathway activity score across tumor types, we computed Pearson's correlations between the pathway activity score and (i) levels of DNA methylation or miRNA expression and (ii) percentages of mutations or CNVs in each tumor type and plotted the results in order of increasing pathway activity score (Figure 7F).	('miR', 'Gene', '220972', (253, 256))	('miR', 'Gene', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('CNVs', 'Var', (307, 311))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', (133, 138))	('mutations', 'Var', (294, 303))
42103	30268436	DNA methylation was dominant in DLBC, STAD, BRCA, and COAD.	('STAD', 'Disease', (38, 42))	('COAD', 'Disease', 'MESH:D029424', (54, 58))	('dominant', 'Reg', (20, 28))	('methylation', 'Var', (4, 15))	('DLBC', 'Disease', (32, 36))	('BRCA', 'Gene', '672', (44, 48))	('BRCA', 'Gene', (44, 48))	('COAD', 'Disease', (54, 58))
42104	30268436	Amplifications positively correlated with activity score and played a dominant role in UCS, SARC, ESCA, CHOL, and OV.	('activity score', 'MPA', (42, 56))	('CHOL', 'CellLine', 'None', (104, 108))	('Amplifications', 'Var', (0, 14))	('CHOL', 'Disease', (104, 108))	('correlated', 'Reg', (26, 36))	('UCS', 'Disease', (87, 90))	('OV', 'Phenotype', 'HP:0100615', (114, 116))	('ESCA', 'Phenotype', 'HP:0011459', (98, 102))	('SARC', 'Disease', (92, 96))	('ESCA', 'Disease', (98, 102))
42108	30268436	Some of the key findings of the study were that (i) 39% of the cancers carried TGF-beta pathway gene alterations; (ii) the genomic alterations appeared to affect expression of metastatic and EMT genes; (iii) six hotspot mutations were identified in six genes; (iv) the pathway was most frequently aberrant in GI cancers, which exhibited 115 of the 176 hotspot mutations identified; (iv) high expression of downstream target genes coupled with mutations in the TGF-beta pathway genes was associated with poor outcome, suggesting a net tumor-promoting role of the superfamily across the PanCancer cohort; (v) apparent gene silencing by DNA methylation and deletion of TGF-beta pathway genes were observed most frequently in DLBC, whereas miRNA silencing was seen most often in LAML.	('gene silencing', 'NegReg', (616, 630))	('cancers', 'Phenotype', 'HP:0002664', (312, 319))	('cancers', 'Disease', (312, 319))	('GI cancers', 'Disease', (309, 319))	('tumor', 'Disease', (534, 539))	('miR', 'Gene', (736, 739))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('tumor', 'Disease', 'MESH:D009369', (534, 539))	('DLBC', 'Disease', (722, 726))	('TGF-beta', 'Gene', '7040', (666, 674))	('TGF-beta', 'Gene', '7040', (460, 468))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('GI cancers', 'Disease', 'MESH:D009369', (309, 319))	('TGF-beta', 'Gene', '7040', (79, 87))	('cancers', 'Disease', (63, 70))	('Cancer', 'Phenotype', 'HP:0002664', (588, 594))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation', 'Var', (638, 649))	('tumor', 'Phenotype', 'HP:0002664', (534, 539))	('cancers', 'Disease', 'MESH:D009369', (312, 319))	('TGF-beta', 'Gene', (460, 468))	('TGF-beta', 'Gene', (666, 674))	('TGF-beta', 'Gene', (79, 87))	('GI cancer', 'Phenotype', 'HP:0007378', (309, 318))	('deletion', 'Var', (654, 662))	('DNA methylation', 'Var', (634, 649))	('miR', 'Gene', '220972', (736, 739))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
42110	30268436	Although 39% of the cancers had genomic alterations in at least one of the TGF-beta pathway genes, GI cancers were particularly enriched for them.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancers', 'Disease', (99, 109))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('GI cancers', 'Disease', 'MESH:D009369', (99, 109))	('genomic alterations', 'Var', (32, 51))	('TGF-beta', 'Gene', '7040', (75, 83))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('TGF-beta', 'Gene', (75, 83))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('cancers', 'Disease', (20, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
42111	30268436	GI cancers were most influenced by recurrent hotspot mutations in 6 genes, SMAD4, SMAD2, BMPR2, BMP5, TGFBR2, and ACVR2A.	('BMP5', 'Gene', (96, 100))	('SMAD2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('BMP5', 'Gene', '653', (96, 100))	('BMPR2', 'Gene', (89, 94))	('GI cancers', 'Disease', (0, 10))	('SMAD4', 'Gene', (75, 80))	('TGFBR2', 'Gene', '7048', (102, 108))	('mutations', 'Var', (53, 62))	('hotspot', 'PosReg', (45, 52))	('ACVR2A', 'Gene', '92', (114, 120))	('GI cancer', 'Phenotype', 'HP:0007378', (0, 9))	('influenced', 'Reg', (21, 31))	('GI cancers', 'Disease', 'MESH:D009369', (0, 10))	('BMPR2', 'Gene', '659', (89, 94))	('ACVR2A', 'Gene', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('SMAD4', 'Gene', '4089', (75, 80))	('SMAD2', 'Gene', '4087', (82, 87))	('TGFBR2', 'Gene', (102, 108))
42112	30268436	The hotspot mutations in BMP5 and TGFBR2 had not been identified previously, and their function in GI cancer should be explored.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancer', 'Disease', (99, 108))	('mutations', 'Var', (12, 21))	('TGFBR2', 'Gene', '7048', (34, 40))	('GI cancer', 'Disease', 'MESH:D009369', (99, 108))	('BMP5', 'Gene', (25, 29))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('TGFBR2', 'Gene', (34, 40))	('BMP5', 'Gene', '653', (25, 29))
42132	30268436	We selected the list of core TGF-beta superfamily genes used in the paper by searching for the keyword "TGF-beta" in 4 databases: (i) BIOCARTA_TGFB_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/BIOCARTA_TGFB_PATHWAY), (ii) KEGG_TGF_BETA_SIGNALING_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/KEGG_TGF_BETA_SIGNALING_PATHWAY), (iii) GO_0007179 full gene set from BioMart, and (iv) subset of GO_0007179 (filtered by "experimental evidence") from AmiGo.	('AmiGo', 'Gene', '57463', (497, 502))	('TGF-beta', 'Gene', (104, 112))	('AmiGo', 'Gene', (497, 502))	('TGF-beta', 'Gene', '7040', (29, 37))	('TGF-beta', 'Gene', (29, 37))	('TGF-beta', 'Gene', '7040', (104, 112))	('GO_0007179', 'Var', (385, 395))
42133	30268436	(ii) We then performed extensive literature searches and kept only those genes that satisfied any of the following conditions: (a) the gene had previously been implicated in cancer, or (b) the gene was involved in direct binding to and regulation of Smad function, or (c) the gene was phenotypically associated with the TGF-beta superfamily, where mutations or deletions of the gene had resulted in phenotypes similar to those from loss of function of the TGF-beta superfamily pathways.	('TGF-beta', 'Gene', '7040', (320, 328))	('TGF-beta', 'Gene', (456, 464))	('mutations', 'Var', (348, 357))	('implicated', 'Reg', (160, 170))	('TGF-beta', 'Gene', (320, 328))	('involved', 'Reg', (202, 210))	('associated', 'Reg', (300, 310))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('resulted', 'Reg', (387, 395))	('deletions', 'Var', (361, 370))	('binding', 'Interaction', (221, 228))	('TGF-beta', 'Gene', '7040', (456, 464))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
42150	30268436	Copy-number alterations (CNA) were assessed as deviations in the tumor sample from the paired normal tissue sample, so they only reflected somatic changes.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Copy-number alterations', 'Var', (0, 23))
42158	30268436	This step realigns reads at sites that potentially harbor small insertions or deletions in either the tumor or the matched normal, to decrease the number of false positive single nucleotide variations caused by misaligned reads.	('insertions', 'Var', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('deletions', 'Var', (78, 87))
42161	30268436	Firehose (http://www.broadinstitute.org/cancer/cga/Firehose) takes the BAM files for the tumor and patient- matched normal samples and performs analyses including quality control, local realignment, mutation calling, small insertion and deletion identification, rearrangement detection, coverage calculations and others as described briefly below.	('patient', 'Species', '9606', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('rearrangement', 'Var', (262, 275))	('mutation calling', 'Var', (199, 215))	('tumor', 'Disease', (89, 94))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cga', 'Gene', '1113', (47, 50))	('deletion', 'Var', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('cga', 'Gene', (47, 50))	('small insertion', 'Var', (217, 232))
42164	30268436	Each oncoprint visualizes and quantifies the somatic mutation and copy number events in 9,125 patients with 33 cancer types for each gene family in the pathway.	('patients', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('copy number', 'Var', (66, 77))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
42165	30268436	The hotspot mutations are extracted from MC3 MAF file first programmatically for any hotspot site with more than nine counts and validated through a systematic mining in the cBioPortal.	('MC3', 'Gene', '4159', (41, 44))	('mutations', 'Var', (12, 21))	('MAF', 'Gene', '4094', (45, 48))	('MAF', 'Gene', (45, 48))	('MC3', 'Gene', (41, 44))
42166	30268436	For ACVR2A and SMAD4 hotspot mutations are mapped onto the respective protein structures (pdb IDs: 4ASX for ACVR2A and 1DD1 for SMAD4) using the UCSF chimera software.	('ACVR2A', 'Gene', (108, 114))	('SMAD4', 'Gene', (15, 20))	('ACVR2A and 1DD1', 'Gene', '92', (108, 123))	('SMAD4', 'Gene', (128, 133))	('ACVR2A', 'Gene', '92', (4, 10))	('mutations', 'Var', (29, 38))	('ACVR2A', 'Gene', '92', (108, 114))	('SMAD4', 'Gene', '4089', (15, 20))	('SMAD4', 'Gene', '4089', (128, 133))	('ACVR2A', 'Gene', (4, 10))
42176	30268436	Tumor types for which few tumors have been profiled and that have infrequently occurring copy number alterations, GISTIC may fail to identify rare but important somatic events.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('copy number alterations', 'Var', (89, 112))	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
42177	30268436	As more copy number profiles become available through large-scale tumor sequencing efforts, the ability to detect these rare but significant events will increase.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('copy number', 'Var', (8, 19))
42179	30268436	The genomic alteration frequencies for copy number gains or losses and mutations are extracted from the cBioPortal and programmatically form the MC3 MAF file.	('MC3', 'Gene', '4159', (145, 148))	('MC3', 'Gene', (145, 148))	('MAF', 'Gene', '4094', (149, 152))	('losses', 'NegReg', (60, 66))	('mutations', 'Var', (71, 80))	('MAF', 'Gene', (149, 152))	('copy number gains', 'Var', (39, 56))
42181	30268436	The samples with alterations in each core gene and wild type for all TGF-beta pathway genes are extracted from the MC3 MAF file.	('MAF', 'Gene', '4094', (119, 122))	('MAF', 'Gene', (119, 122))	('TGF-beta', 'Gene', (69, 77))	('MC3', 'Gene', '4159', (115, 118))	('MC3', 'Gene', (115, 118))	('TGF-beta', 'Gene', '7040', (69, 77))	('alterations', 'Var', (17, 28))
42182	30268436	The median fold change of transcriptional changes are calculated as the ratio of expression of downstream genes among all core pathway gene mutated, amplified and deleted samples to expression levels in TGF-beta pathway wild type samples.	('TGF-beta', 'Gene', (203, 211))	('deleted', 'Var', (163, 170))	('TGF-beta', 'Gene', '7040', (203, 211))	('expression', 'MPA', (81, 91))	('mutated', 'Var', (140, 147))
42186	30268436	The enrichment of genomic TGF-beta pathway genomic alterations in the GI cancers was statistically assessed using a one tailed Fisher's exact test, where the null hypothesis was the odds ratio of alterations in GI vs other cancers was not greater than 1.	('cancers', 'Disease', (223, 230))	('cancers', 'Disease', (73, 80))	('alterations', 'Var', (51, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('TGF-beta', 'Gene', '7040', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('GI cancers', 'Disease', (70, 80))	('TGF-beta', 'Gene', (26, 34))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
42187	30268436	The transcriptional outcome of GI cancers with TGF-beta pathway disruptions were quantified using the same method and downstream target gene list as we did in the analysis of transcriptional output from all cancers.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('GI cancer', 'Phenotype', 'HP:0007378', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('GI cancers', 'Disease', 'MESH:D009369', (31, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('disruptions', 'Var', (64, 75))	('TGF-beta', 'Gene', '7040', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TGF-beta', 'Gene', (47, 55))	('cancers', 'Disease', (34, 41))	('GI cancers', 'Disease', (31, 41))
42211	30268436	We particularly focused on mRNA expression distribution of HMGA2, MMP9, collagens (COL1A1, COL1A2, COL3A1), TERT, FOXP3, CDH2 as the expression of these genes varied significantly between TGF-beta pathway mutated vs. wild type samples.	('mutated', 'Var', (205, 212))	('COL1A2', 'Gene', '1278', (91, 97))	('TERT', 'Gene', (108, 112))	('varied', 'Reg', (159, 165))	('TERT', 'Gene', '7015', (108, 112))	('CDH2', 'Gene', (121, 125))	('FOXP3', 'Gene', (114, 119))	('HMGA2', 'Gene', (59, 64))	('COL1A2', 'Gene', (91, 97))	('COL1A1', 'Gene', '1277', (83, 89))	('CDH2', 'Gene', '1000', (121, 125))	('COL3A1', 'Gene', '1281', (99, 105))	('TGF-beta', 'Gene', '7040', (188, 196))	('FOXP3', 'Gene', '50943', (114, 119))	('COL1A1', 'Gene', (83, 89))	('expression', 'MPA', (133, 143))	('MMP9', 'Gene', (66, 70))	('HMGA2', 'Gene', '8091', (59, 64))	('MMP9', 'Gene', '4318', (66, 70))	('TGF-beta', 'Gene', (188, 196))	('COL3A1', 'Gene', (99, 105))
42213	30268436	The resulting thresholds divided the cohorts into three groups as TGF-beta expression, TGF-beta mutant/high target expression, TGF-beta wt/high target expression and low target gene expression.	('TGF-beta', 'Gene', (87, 95))	('TGF-beta', 'Gene', (66, 74))	('TGF-beta', 'Gene', '7040', (127, 135))	('mutant/high', 'Var', (96, 107))	('TGF-beta', 'Gene', '7040', (87, 95))	('TGF-beta', 'Gene', (127, 135))	('TGF-beta', 'Gene', '7040', (66, 74))
42214	30268436	We merged the TGF-beta mutant/low target expression and TGF-beta wt/low expression cohorts as discriminating between these sets do not inform on the combined effect of TGF-beta mutations and target expression.	('TGF-beta', 'Gene', (168, 176))	('TGF-beta', 'Gene', '7040', (56, 64))	('TGF-beta', 'Gene', (14, 22))	('mutant/low', 'Var', (23, 33))	('mutant/low', 'NegReg', (23, 33))	('TGF-beta', 'Gene', (56, 64))	('TGF-beta', 'Gene', '7040', (14, 22))	('TGF-beta', 'Gene', '7040', (168, 176))
42318	29658006	Most comparisons of treatment outcome in the two groups did not reveal any significant differences, the only exception being the incidence and grade of radiation-induced pneumonitis, which was higher in the with-CTV arm.	('with-CTV', 'Var', (207, 215))	('pneumonitis', 'Disease', 'MESH:D011014', (170, 181))	('pneumonitis', 'Disease', (170, 181))	('higher', 'PosReg', (193, 199))
42351	29658006	The reported studies on recurrence patterns have consistently identified the GTV as the dominant site of failure, some suggesting the omission of a CTV expansion in favor of isotoxic dose escalation.	('GTV', 'Chemical', '-', (77, 80))	('CTV', 'Gene', (148, 151))	('expansion', 'Var', (152, 161))
42446	32948633	Methylation of specific CpG loci is strongly associated with cancer; these MDMs have demonstrated utility as biomarkers for early detection of cancer and pre-cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Methylation', 'Var', (0, 11))	('MDM', 'Gene', '57152', (75, 78))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('associated', 'Reg', (45, 55))	('cancer', 'Disease', (158, 164))	('MDM', 'Gene', (75, 78))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
42457	32948633	Three additional markers, EMX1, LOC645323, and VWC2, were high performing markers for other epithelial cancers of the GI tract that were validated in a separate experiment on esophageal cancer tissues; from this experiment, LMX1A and SLC32A1 were also chosen after re-analysis of this data excluding normal colonic tissue as part of the controls.	('SLC32A1', 'Gene', (234, 241))	('cancer', 'Disease', (103, 109))	('men', 'Species', '9606', (218, 221))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('VWC2', 'Gene', (47, 51))	('epithelial cancers', 'Disease', 'MESH:D009369', (92, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('men', 'Species', '9606', (167, 170))	('epithelial cancers', 'Disease', (92, 110))	('cancers of the GI tract', 'Phenotype', 'HP:0007378', (103, 126))	('SLC32A1', 'Gene', '140679', (234, 241))	('LOC645323', 'Var', (32, 41))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('EMX1', 'Gene', '2016', (26, 30))	('cancer', 'Disease', (186, 192))	('EMX1', 'Gene', (26, 30))	('LMX1A', 'Gene', (224, 229))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('VWC2', 'Gene', '375567', (47, 51))	('LMX1A', 'Gene', '4009', (224, 229))
42481	32948633	Since many of the relationships between the targeted MDM and methylated ACTB are non-linear, we elected to use GAM, a well-established statistical method of fitting non-linear relationships between two variables.	('ACTB', 'Gene', (72, 76))	('methylated', 'Var', (61, 71))	('ACTB', 'Gene', '60', (72, 76))	('MDM', 'Gene', (53, 56))	('MDM', 'Gene', '57152', (53, 56))
42536	33178606	A Comprehensive Analysis of Alterations in DNA Damage Repair Pathways Reveals a Potential Way to Enhance the Radio-Sensitivity of Esophageal Squamous Cell Cancer Esophageal squamous cell cancer (ESCC) is a common malignancy with a poor 5-year overall survival in China.	('Squamous Cell Cancer', 'Disease', 'MESH:D002294', (141, 161))	('Squamous Cell Cancer', 'Disease', (141, 161))	('squamous cell cancer', 'Disease', (173, 193))	('Enhance', 'PosReg', (97, 104))	('squamous cell cancer', 'Disease', 'MESH:D002294', (173, 193))	('malignancy', 'Disease', (213, 223))	('Cancer', 'Phenotype', 'HP:0002664', (155, 161))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (173, 193))	('Alterations', 'Var', (28, 39))	('Squamous Cell Cancer', 'Phenotype', 'HP:0002860', (141, 161))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('Esophageal', 'Disease', (130, 140))	('malignancy', 'Disease', 'MESH:D009369', (213, 223))
42539	33178606	Compared with other pathways, two DNA double-strand break (DSB) repair pathways homologous recombination (HR) and non-homologous end joining (NHEJ), carried significant gene mutations and CNVs especially gene amplifications.	('DSB', 'Chemical', '-', (59, 62))	('gene amplifications', 'Var', (204, 223))	('CNVs', 'Var', (188, 192))
42541	33178606	Amplification and high expression of DSB repair pathway genes were associated with poorer overall survival.	('Amplification', 'Var', (0, 13))	('high', 'Reg', (18, 22))	('DSB repair pathway genes', 'Gene', (37, 61))	('overall', 'MPA', (90, 97))	('poorer', 'NegReg', (83, 89))	('DSB', 'Chemical', '-', (37, 40))	('expression', 'MPA', (23, 33))
42543	33178606	Besides, we firstly demonstrated that combination of mirin and NU7441, two inhibitors for HR and NHEJ respectively, with ionizing radiation treatment significantly enhanced DSBs, reduced clonogenic cell survival, inhibited cell proliferation, and promoted cell apoptosis in ESCC cells with DSB pathway gene amplification.	('NU7441', 'Var', (63, 69))	('cell proliferation', 'CPA', (223, 241))	('clonogenic cell survival', 'CPA', (187, 211))	('enhanced', 'PosReg', (164, 172))	('cell apoptosis', 'CPA', (256, 270))	('DSBs', 'Chemical', '-', (173, 177))	('inhibited', 'NegReg', (213, 222))	('combination', 'Interaction', (38, 49))	('promoted', 'PosReg', (247, 255))	('DSB', 'Chemical', '-', (173, 176))	('DSBs', 'MPA', (173, 177))	('NU7441', 'Chemical', 'MESH:C499693', (63, 69))	('mirin', 'Chemical', 'MESH:C526365', (53, 58))	('DSB', 'Chemical', '-', (290, 293))	('reduced', 'NegReg', (179, 186))
42552	33178606	Dysregulation of DDR pathways is an important determinant of cancer risk, progression, and therapeutic response.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('DDR pathways', 'Pathway', (17, 29))
42554	33178606	Genetic variants in NER genes were linked to exert an impact on survival outcomes of Chinese ESCC patients.	('impact', 'Reg', (54, 60))	('survival outcomes', 'CPA', (64, 81))	('patients', 'Species', '9606', (98, 106))	('ESCC', 'Disease', (93, 97))	('NER genes', 'Gene', (20, 29))	('Genetic variants', 'Var', (0, 16))
42555	33178606	Moreover, genetic polymorphisms of XRCC6 and XRCC5, two genes in NHEJ pathway, were related to higher risk of ESCC.	('XRCC6', 'Gene', (35, 40))	('related', 'Reg', (84, 91))	('XRCC5', 'Gene', '7520', (45, 50))	('XRCC6', 'Gene', '2547', (35, 40))	('ESCC', 'Disease', (110, 114))	('genetic polymorphisms', 'Var', (10, 31))	('XRCC5', 'Gene', (45, 50))
42559	33178606	We finally investigated the effect of combination of mirin and NU7441 with ionizing radiation (IR) treatment on ESCC cell phenotypes, and found that mirin and NU7441 could enhance the radio-sensitivity of ESCC cells with DSB pathway gene amplification.	('mirin', 'Var', (149, 154))	('NU7441', 'Var', (159, 165))	('mirin', 'Chemical', 'MESH:C526365', (149, 154))	('enhance', 'PosReg', (172, 179))	('radio-sensitivity', 'CPA', (184, 201))	('DSB pathway', 'Pathway', (221, 232))	('NU7441', 'Chemical', 'MESH:C499693', (63, 69))	('DSB', 'Chemical', '-', (221, 224))	('NU7441', 'Chemical', 'MESH:C499693', (159, 165))	('mirin', 'Chemical', 'MESH:C526365', (53, 58))	('ESCC', 'Disease', (205, 209))
42560	33178606	These findings suggest that alterations of DSB repair pathways might be involved in ESCC radio-resistance, and mirin and NU7441 might have potential application in ESCC treatment.	('NU7441', 'Var', (121, 127))	('DSB', 'Chemical', '-', (43, 46))	('ESCC', 'Disease', (84, 88))	('alterations', 'Var', (28, 39))	('NU7441', 'Chemical', 'MESH:C499693', (121, 127))	('ESCC', 'Disease', (164, 168))	('mirin', 'Chemical', 'MESH:C526365', (111, 116))	('involved', 'Reg', (72, 80))	('DSB repair pathways', 'Pathway', (43, 62))	('radio-resistance', 'CPA', (89, 105))
42566	33178606	The clinical characteristics of 119 ESCC patients in GSE53624 were summarized in Table 1.	('patients', 'Species', '9606', (41, 49))	('GSE53624', 'Var', (53, 61))	('ESCC', 'Disease', (36, 40))
42583	33178606	There were three genes (POLB, LIG1, and LIG3) mutated in BER pathway, each of which only carried one mutation.	('LIG1', 'Gene', '3978', (30, 34))	('BER pathway', 'Pathway', (57, 68))	('LIG1', 'Gene', (30, 34))	('mutated', 'Var', (46, 53))	('LIG3', 'Gene', '3980', (40, 44))	('POLB', 'Gene', (24, 28))	('LIG3', 'Gene', (40, 44))	('POLB', 'Gene', '5423', (24, 28))
42587	33178606	We also observed that MRE11-RAD50-NBS1 (MRN) complex genes, which play important roles in the sensing, processing and repair of DSBs, were mutated in four ESCC patients.	('patients', 'Species', '9606', (160, 168))	('DSBs', 'Chemical', '-', (128, 132))	('NBS1', 'Gene', '4683', (34, 38))	('RAD50', 'Gene', (28, 33))	('RAD50', 'Gene', '10111', (28, 33))	('MRE11', 'Gene', '4361', (22, 27))	('mutated', 'Var', (139, 146))	('MRE11', 'Gene', (22, 27))	('NBS1', 'Gene', (34, 38))	('MRN) complex genes', 'Gene', (40, 58))	('ESCC', 'Disease', (155, 159))
42588	33178606	Besides, RBBP8, PALB2, WRN, and BARD1 were mutated in more than one ESCC case.	('BARD1', 'Gene', '580', (32, 37))	('PALB2', 'Gene', '79728', (16, 21))	('PALB2', 'Gene', (16, 21))	('BARD1', 'Gene', (32, 37))	('WRN', 'Gene', (23, 26))	('WRN', 'Gene', '7486', (23, 26))	('RBBP8', 'Gene', '5932', (9, 14))	('RBBP8', 'Gene', (9, 14))	('mutated', 'Var', (43, 50))
42589	33178606	In NHEJ pathway, another pathway involved in repairing DSBs, PRKDC, which encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK), carried the most frequent mutations (3.1%, 6/192).	('NHEJ', 'Gene', (3, 7))	('mutations', 'Var', (176, 185))	('DNA-PK', 'Gene', (141, 147))	('PRKDC', 'Gene', '5591', (61, 66))	('DNA-PK', 'Gene', '5591', (141, 147))	('DSBs', 'Chemical', '-', (55, 59))	('PRKDC', 'Gene', (61, 66))
42593	33178606	The result showed that the "DSB repair pathway" mutation was significantly enriched in ESCC (P = 0.009; Figure 2B).	('DSB', 'Chemical', '-', (28, 31))	('ESCC', 'Disease', (87, 91))	('mutation', 'Var', (48, 56))
42594	33178606	Both POLB and TDP1 were amplified in 10.4% (16/154) of cases and the incidence of amplification of APEX1/2 was 14.3% (22/154).	('TDP1', 'Gene', '55775', (14, 18))	('amplified', 'Var', (24, 33))	('APEX1/2', 'Gene', '328;27301', (99, 106))	('APEX1/2', 'Gene', (99, 106))	('TDP1', 'Gene', (14, 18))	('POLB', 'Gene', '5423', (5, 9))	('POLB', 'Gene', (5, 9))
42596	33178606	CUL5 had the highest deletion frequency (9.1%, 14/154), and ERCC1 and ERCC2 had the same CNV profile (3.9% of amplification and 6.5% of deletion) due to proximal genomic location.	('ERCC2', 'Gene', '2068', (70, 75))	('CUL5', 'Gene', (0, 4))	('ERCC2', 'Gene', (70, 75))	('deletion', 'Var', (21, 29))	('CUL5', 'Gene', '8065', (0, 4))	('ERCC1', 'Gene', '2067', (60, 65))	('ERCC1', 'Gene', (60, 65))
42598	33178606	We observed that XPA was amplified in 8 ESCC patients (5.2%) and deleted in 2 ESCC cases (1.3%), whereas the incidences of amplification and deletion of XPC were 1.3% (2/154) and 5.2% (8/154), respectively.	('ESCC', 'Disease', (40, 44))	('deletion', 'Var', (141, 149))	('deleted', 'Var', (65, 72))	('XPC', 'Gene', (153, 156))	('patients', 'Species', '9606', (45, 53))	('XPC', 'Gene', '7508', (153, 156))	('XPA', 'Gene', '7507', (17, 20))	('XPA', 'Gene', (17, 20))
42599	33178606	MLH1, one of the important genes in MMR process, was observed to be deleted in 5.2% (8/154) of ESCC cases.	('MLH1', 'Gene', (0, 4))	('deleted', 'Var', (68, 75))	('ESCC', 'Disease', (95, 99))	('MLH1', 'Gene', '4292', (0, 4))
42609	33178606	Additionally, FANCD2, carrying the most CNVs in FA pathway, was mainly deleted in 11% (17/154) of ESCC cases.	('FANCD2', 'Gene', '2177', (14, 20))	('FA', 'Phenotype', 'HP:0001994', (48, 50))	('FANCD2', 'Gene', (14, 20))	('ESCC', 'Disease', (98, 102))	('FA', 'Phenotype', 'HP:0001994', (14, 16))	('deleted', 'Var', (71, 78))
42612	33178606	Similarly, the main CNV type of POLH and REV1 was deletion.	('REV1', 'Gene', (41, 45))	('deletion', 'Var', (50, 58))	('REV1', 'Gene', '51455', (41, 45))
42615	33178606	Similarly, we found that ESCC patients with the "DSB repair pathway" amplification had poorer overall survival (P = 0.0956; Figure 3B).	('overall survival', 'MPA', (94, 110))	('DSB', 'Chemical', '-', (49, 52))	('patients', 'Species', '9606', (30, 38))	('poorer', 'NegReg', (87, 93))	('amplification', 'Var', (69, 82))
42617	33178606	As presented in Figure 3D, amplification of RAD54B or RAD51B was related to poorer overall survival (P = 0.0313 and P = 0.0146, respectively).	('overall', 'MPA', (83, 90))	('poorer', 'NegReg', (76, 82))	('RAD51B', 'Gene', (54, 60))	('RAD54B', 'Gene', '25788', (44, 50))	('RAD51B', 'Gene', '5890', (54, 60))	('RAD54B', 'Gene', (44, 50))	('amplification', 'Var', (27, 40))
42632	33178606	Accordingly, we assumed that inhibition of HR and NHEJ pathways might enhance the radio-sensitivity of ESCC with DSB repair pathway up-regulation.	('DSB', 'Chemical', '-', (113, 116))	('enhance', 'PosReg', (70, 77))	('up-regulation', 'PosReg', (132, 145))	('radio-sensitivity', 'CPA', (82, 99))	('ESCC', 'Disease', (103, 107))	('NHEJ pathways', 'Pathway', (50, 63))	('inhibition', 'Var', (29, 39))
42639	33178606	We firstly tested if mirin and NU7441 could induce DSBs.	('mirin', 'Chemical', 'MESH:C526365', (21, 26))	('NU7441', 'Chemical', 'MESH:C499693', (31, 37))	('DSBs', 'Disease', (51, 55))	('DSBs', 'Chemical', '-', (51, 55))	('NU7441', 'Var', (31, 37))
42641	33178606	The level of gamma-H2AX had a little increasing following 6 Gy IR treatment alone, whereas both mirin and NU7441 enhanced gamma-H2AX recruitment and combination of two inhibitors led to the higher level of gamma-H2AX (Figures 6A, B), indicating that inhibiting DSB repair pathways could enhance IR-inducing DSBs in ESCC cells.	('enhance', 'PosReg', (287, 294))	('IR-inducing', 'Disease', (295, 306))	('DSBs', 'Chemical', '-', (307, 311))	('gamma-H2AX', 'Gene', '3014', (13, 23))	('gamma-H2AX', 'Gene', (122, 132))	('DSB', 'Chemical', '-', (261, 264))	('NU7441', 'Chemical', 'MESH:C499693', (106, 112))	('mirin', 'Chemical', 'MESH:C526365', (96, 101))	('DSB', 'Chemical', '-', (307, 310))	('gamma-H2AX', 'Gene', (13, 23))	('gamma-H2AX', 'Gene', '3014', (122, 132))	('gamma-H2AX', 'Gene', (206, 216))	('enhanced', 'PosReg', (113, 121))	('DSBs', 'Disease', (307, 311))	('gamma-H2AX', 'Gene', '3014', (206, 216))	('NU7441', 'Var', (106, 112))
42643	33178606	Combining IR with mirin or NU7441 treatment showed notable reduction in clonogenic survival of ESCC cells, and combination of mirin and NU7441 with IR treatment led to the lowest number of colonies in both cells (Figures 7A, B).	('mirin', 'Chemical', 'MESH:C526365', (126, 131))	('NU7441', 'Var', (27, 33))	('NU7441', 'Chemical', 'MESH:C499693', (136, 142))	('clonogenic survival', 'CPA', (72, 91))	('mirin', 'Chemical', 'MESH:C526365', (18, 23))	('NU7441', 'Chemical', 'MESH:C499693', (27, 33))	('reduction', 'NegReg', (59, 68))	('NU7441', 'Var', (136, 142))
42645	33178606	Interestingly, we observed that combining IR with mirin or NU7441 showed significant inhibition of cell proliferation.	('mirin', 'Chemical', 'MESH:C526365', (50, 55))	('cell proliferation', 'CPA', (99, 117))	('NU7441', 'Var', (59, 65))	('inhibition', 'NegReg', (85, 95))	('NU7441', 'Chemical', 'MESH:C499693', (59, 65))
42648	33178606	The apoptosis rates were obviously increased in groups combining IR with mirin or NU7441 treatment (Figures 7D, E).	('increased', 'PosReg', (35, 44))	('apoptosis rates', 'CPA', (4, 19))	('NU7441', 'Chemical', 'MESH:C499693', (82, 88))	('mirin', 'Chemical', 'MESH:C526365', (73, 78))	('NU7441', 'Var', (82, 88))
42649	33178606	Furthermore, the synergistic effect of mirin and NU7441 dramatically promoted cell apoptosis (Figures 7D, E).	('NU7441', 'Var', (49, 55))	('cell apoptosis', 'CPA', (78, 92))	('promoted', 'PosReg', (69, 77))	('NU7441', 'Chemical', 'MESH:C499693', (49, 55))	('mirin', 'Chemical', 'MESH:C526365', (39, 44))
42652	33178606	As genomics-driven precision medicine extends beyond somatic mutations, comprehensive cancer sequencing to identify structural and copy number variations, as well as abnormal expression is becoming increasingly relevant to guide cancer therapy.	('copy number variations', 'Var', (131, 153))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Disease', (86, 92))
42656	33178606	Alterations in DDR pathways play important roles in the development of cancers.	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('Alterations', 'Var', (0, 11))	('roles', 'Reg', (43, 48))	('DDR pathways', 'Pathway', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
42658	33178606	DDR gene mutations were linked to immune-related gene expression in ovarian cancer and muscle invasive bladder cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (68, 82))	('mutations', 'Var', (9, 18))	('ovarian cancer', 'Disease', 'MESH:D010051', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (87, 117))	('ovarian cancer', 'Disease', (68, 82))	('muscle invasive bladder cancer', 'Disease', (87, 117))	('invasive bladder', 'Phenotype', 'HP:0100645', (94, 110))	('linked', 'Reg', (24, 30))	('DDR gene', 'Gene', (0, 8))
42660	33178606	Activated DDR increases nucleotide synthesis and anabolic glucose metabolism, while reduces glutamine anaplerosis.	('nucleotide synthesis', 'MPA', (24, 44))	('increases', 'PosReg', (14, 23))	('anabolic glucose metabolism', 'Disease', 'MESH:D044882', (49, 76))	('glutamine anaplerosis', 'MPA', (92, 113))	('glutamine', 'Chemical', 'MESH:D005973', (92, 101))	('reduces', 'NegReg', (84, 91))	('anabolic glucose metabolism', 'Disease', (49, 76))	('Activated DDR', 'Var', (0, 13))
42663	33178606	Mutations in DDR pathway genes are associated with human cancers.	('DDR pathway', 'Gene', (13, 24))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('associated', 'Reg', (35, 45))	('cancers', 'Disease', (57, 64))	('human', 'Species', '9606', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
42664	33178606	Polymorphisms of BER pathway genes were reported to be associated with risk of ESCC, and frequent mutations of MMR pathway genes occurred in colorectal cancer and were associated with the etiology of colorectal cancer.	('colorectal cancer', 'Disease', (200, 217))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('colorectal cancer', 'Disease', 'MESH:D015179', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('associated with', 'Reg', (168, 183))	('Polymorphisms', 'Var', (0, 13))	('MMR pathway genes', 'Gene', (111, 128))	('associated', 'Reg', (55, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('occurred', 'Reg', (129, 137))	('mutations', 'Var', (98, 107))	('ESCC', 'Disease', (79, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (200, 217))	('colorectal cancer', 'Disease', (141, 158))	('BER pathway genes', 'Gene', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
42666	33178606	Amplification of DDR pathway genes was reported to play a crucial role in cancer progression.	('Amplification', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('DDR pathway genes', 'Gene', (17, 34))
42669	33178606	We found that amplification of DSB repair pathways was associated with poorer overall survival.	('DSB repair pathways', 'Pathway', (31, 50))	('DSB', 'Chemical', '-', (31, 34))	('poorer', 'NegReg', (71, 77))	('overall', 'MPA', (78, 85))	('amplification', 'Var', (14, 27))
42674	33178606	These findings suggest that alterations in DSB repair pathways might play important roles in the development of ESCC.	('roles', 'Reg', (84, 89))	('alterations', 'Var', (28, 39))	('ESCC', 'Disease', (112, 116))	('play', 'Reg', (69, 73))	('DSB repair pathways', 'Pathway', (43, 62))	('DSB', 'Chemical', '-', (43, 46))
42681	33178606	Similarly, NU7441, a highly selective inhibitor for DNA-PK, blocked NHEJ of radiation-induced DSBs and enhanced cancer radio-sensitivity.	('DNA-PK', 'Gene', (52, 58))	('cancer', 'Disease', (112, 118))	('blocked', 'NegReg', (60, 67))	('DSBs', 'Chemical', '-', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('DNA-PK', 'Gene', '5591', (52, 58))	('NHEJ', 'Gene', (68, 72))	('enhanced', 'PosReg', (103, 111))	('NU7441', 'Chemical', 'MESH:C499693', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('NU7441', 'Var', (11, 17))
42682	33178606	However, whether mirin and NU7441 could affect the radio-sensitivity of ESCC with DSB repair pathway up-regulation is still unclear.	('NU7441', 'Var', (27, 33))	('DSB repair pathway', 'Pathway', (82, 100))	('up-regulation', 'PosReg', (101, 114))	('mirin', 'Chemical', 'MESH:C526365', (17, 22))	('NU7441', 'Chemical', 'MESH:C499693', (27, 33))	('affect', 'Reg', (40, 46))	('ESCC', 'Disease', (72, 76))	('DSB', 'Chemical', '-', (82, 85))
42683	33178606	We made the first demonstration that combination of mirin and NU7441 with IR treatment significantly enhanced the radio-sensitivity of ESCC cells with DSB repair pathway gene amplification.	('NU7441', 'Var', (62, 68))	('DSB', 'Chemical', '-', (151, 154))	('radio-sensitivity', 'CPA', (114, 131))	('combination', 'Interaction', (37, 48))	('NU7441', 'Chemical', 'MESH:C499693', (62, 68))	('mirin', 'Chemical', 'MESH:C526365', (52, 57))	('enhanced', 'PosReg', (101, 109))
42684	33178606	Nevertheless, the effect of mirin and NU7441 on xenograft tumors in mice needs to be explored in the future.	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('mirin', 'Chemical', 'MESH:C526365', (28, 33))	('NU7441', 'Chemical', 'MESH:C499693', (38, 44))	('NU7441', 'Var', (38, 44))
42685	33178606	In conclusion, this is the first report to comprehensively identify the alterations of DDR pathways in ESCC, and demonstrated that altered DSB repair pathway genes might contribute to ESCC progression.	('alterations', 'Reg', (72, 83))	('contribute', 'Reg', (170, 180))	('DSB repair pathway genes', 'Gene', (139, 163))	('DDR pathways', 'Pathway', (87, 99))	('altered', 'Var', (131, 138))	('ESCC', 'Disease', (103, 107))	('DSB', 'Chemical', '-', (139, 142))	('ESCC', 'Disease', (184, 188))
42686	33178606	We also firstly revealed two DSB repair pathway inhibitors mirin and NU7441 could obviously improve the radio-sensitivity of ESCC cells with DSB repair pathway gene amplification, showing the potential clinical application in ESCC treatment.	('improve', 'PosReg', (92, 99))	('radio-sensitivity', 'CPA', (104, 121))	('NU7441', 'Var', (69, 75))	('mirin', 'Chemical', 'MESH:C526365', (59, 64))	('DSB', 'Chemical', '-', (141, 144))	('NU7441', 'Chemical', 'MESH:C499693', (69, 75))	('ESCC', 'Disease', (125, 129))	('DSB', 'Chemical', '-', (29, 32))
42705	32541449	immunohistochemical markers:P40(+),CK5/6(+),CD56(+),Syn(-),NSE(-),Ki67(+70%).	('CD56', 'Gene', (44, 48))	('CK5/6', 'Gene', (35, 40))	('P40(+', 'Var', (28, 33))	('CD56', 'Gene', '4684', (44, 48))	('CK5/6', 'Gene', '3852', (35, 40))
42738	32541449	However, there wereclinical reports that TMZ can improve progression-free survival or increase radiation response.	('increase', 'PosReg', (86, 94))	('radiation response', 'CPA', (95, 113))	('TMZ', 'Var', (41, 44))	('improve', 'PosReg', (49, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (41, 44))	('progression-free survival', 'CPA', (57, 82))
42950	30364783	An R1/Rx resection (a common error during ESD learning) is much more detrimental in the UGI tract than in the colon; especially if high risk colon lesions are avoided during learning.	('R1/Rx resection', 'Var', (3, 18))	('colon lesions', 'Disease', 'MESH:D003108', (141, 154))	('colon lesions', 'Disease', (141, 154))	('detrimental', 'NegReg', (69, 80))
42963	30364783	Berr had suggestions for the "colon heavy-untutored/prevalence based" ESD learners based on his retrospective video analysis of his own work including avoiding: (1) wide SM injection around the lesion (which forces a "perpendicular" instead of "tangential approach"); (2) injection deep to muscle layer (lack of submucosal fluid cushion); (3) disruption of vessels leading to hematoma and loss of transparency of submucosa; (4) dissection without direct vision of the tip of the knife; (5) contact coagulation of small vessel directly on colonic proper muscle layer; and (6) mucosal incision using knife in "pullback fashion" across a haustral fold.	('disruption', 'Var', (343, 353))	('leading to', 'Reg', (365, 375))	('hematoma', 'Disease', (376, 384))	('hematoma', 'Disease', 'MESH:D006406', (376, 384))
43117	27384379	Compared to population controls, a decreased risk of GERD was observed among those with short LTL (T3 vs. T1), OR 0.57 (95% CI: 0.35-0.93) (Table 2).	('GERD', 'Disease', (53, 57))	('decreased', 'NegReg', (35, 44))	('LTL', 'Chemical', '-', (94, 97))	('short LTL', 'Var', (88, 97))	('GERD', 'Disease', 'MESH:D005764', (53, 57))
43120	27384379	When stratified by gender, an increased risk of BE was observed among men with short telomere length (T3 vs. T1) when compared to GERD controls (OR 2.16 [95% CI: 1.19-3.19]), but not compared with population-based controls (Table 3).	('GERD', 'Disease', 'MESH:D005764', (130, 134))	('short telomere length', 'Phenotype', 'HP:0031413', (79, 100))	('GERD', 'Disease', (130, 134))	('short telomere length', 'Var', (79, 100))	('men', 'Species', '9606', (70, 73))	('BE', 'Phenotype', 'HP:0100580', (48, 50))
43133	27384379	Shortening occurring early on in neoplastic progression could result in LTL being highly variable among BE patients 29.	('BE', 'Phenotype', 'HP:0100580', (104, 106))	('LTL', 'MPA', (72, 75))	('LTL', 'Chemical', '-', (72, 75))	('Shortening', 'Var', (0, 10))	('patients', 'Species', '9606', (107, 115))
43317	19272137	According to the pattern of mucin expression, four tumors were classified as MUC2 positive (Figure 3) indicating an intestinal type of tumor differentiation, while seven were MUC5AC positive tumors (Figure 4), indicating a gastric type of tumor differentiation.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('intestinal type', 'Disease', (116, 131))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (239, 244))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('MUC5AC', 'Gene', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('gastric type of tumor', 'Disease', (223, 244))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Disease', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MUC5AC', 'Gene', '4586', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('mucin', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumors', 'Disease', (51, 57))	('MUC2', 'Var', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('gastric type of tumor', 'Disease', 'MESH:D013274', (223, 244))	('mucin', 'Gene', '100508689', (28, 33))
43349	19272137	Some authors suggested that mucin histochemistry could be used to establish if a pattern of mucin staining in Barrett's esophagus may be associated with a greater risk of progression to adenocarcinoma.	('associated', 'Reg', (137, 147))	('pattern', 'Var', (81, 88))	('mucin', 'Gene', (28, 33))	('mucin', 'Gene', '100508689', (92, 97))	('adenocarcinoma', 'Disease', (186, 200))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (110, 129))	('adenocarcinoma', 'Disease', 'MESH:D000230', (186, 200))	('mucin', 'Gene', '100508689', (28, 33))	('mucin', 'Gene', (92, 97))
43427	31887810	Furthermore, modifications can be made to the clip line in terms of the devices used, and these adjustments avert the need for reinsertion of the colonoscope, while with other alteration traction points can be added during the ESD procedure as it progressed.	('clip', 'Gene', (46, 50))	('adjustments', 'Var', (96, 107))	('avert', 'NegReg', (108, 113))	('modifications', 'Var', (13, 26))	('clip', 'Gene', '6249', (46, 50))
43435	31887810	In the retrospective analysis of 1,000 colorectal ESD cases by Yoshida et al., severe fibrosis compared to non-fibrotic cases were associated with lower en bloc resection rates (78.3% vs 95.7%, p<0.001), higher discontinuation rates (12.5% vs 0.3%, p<0.001), and higher perforation rates (8.3% vs 2.6%, p=0.001).	('en bloc resection rates', 'CPA', (153, 176))	('severe', 'Var', (79, 85))	('lower', 'NegReg', (147, 152))	('colorectal ESD', 'Disease', (39, 53))	('perforation rates', 'CPA', (270, 287))	('fibrosis', 'Disease', 'MESH:D005355', (86, 94))	('fibrosis', 'Disease', (86, 94))	('discontinuation rates', 'MPA', (211, 232))	('higher', 'PosReg', (204, 210))
43525	30611753	After more than ten years of successfully following-up fifty thousand participants of the GCS, the results show that smoking opium, drinking hot tea, low intake of fruits, low intake of vegetables, tooth loss, drinking un-piped water, and exposure to indoor air pollution are all associated with increased ESCC risk in a dose-response manner.	('water', 'Chemical', 'MESH:D014867', (228, 233))	('tooth loss', 'Disease', 'MESH:D016388', (198, 208))	('increased ESCC', 'Phenotype', 'HP:0003565', (296, 310))	('low', 'NegReg', (150, 153))	('low', 'Var', (172, 175))	('tooth loss', 'Disease', (198, 208))	('tooth loss', 'Phenotype', 'HP:0006480', (198, 208))	('participants', 'Species', '9606', (70, 82))	('ESCC', 'Disease', (306, 310))
43563	32198345	AGPG is also a transcriptional target of p53; loss or mutation of TP53 triggers the marked upregulation of AGPG.	('mutation', 'Var', (54, 62))	('p53', 'Gene', '7157', (41, 44))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('upregulation', 'PosReg', (91, 103))	('AGPG', 'Chemical', '-', (0, 4))	('AGPG', 'Chemical', '-', (107, 111))	('loss', 'Disease', 'MESH:D015431', (46, 50))	('loss', 'Disease', (46, 50))	('AGPG', 'Gene', (107, 111))	('p53', 'Gene', (41, 44))
43564	32198345	Notably, inhibiting AGPG dramatically impaired tumor growth in patient-derived xenograft (PDX) models.	('AGPG', 'Chemical', '-', (20, 24))	('inhibiting', 'Var', (9, 19))	('impaired tumor', 'Disease', 'MESH:D015417', (38, 52))	('AGPG', 'Gene', (20, 24))	('patient', 'Species', '9606', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('impaired tumor', 'Disease', (38, 52))
43576	32198345	As reported, PFKFB3 inhibition is a promising modality for cancer treatment because it suppresses glycolysis, proliferation, and metastasis in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('inhibition', 'Var', (20, 30))	('glycolysis', 'MPA', (98, 108))	('PFKFB3', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('proliferation', 'CPA', (110, 123))	('PFKFB3', 'Gene', '5209', (13, 19))	('metastasis', 'CPA', (129, 139))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('suppresses', 'NegReg', (87, 97))
43588	32198345	Among these eight lncRNAs, AGPG knockdown significantly decreased cell viability and lactate production (Fig.	('F', 'Chemical', 'MESH:D005461', (105, 106))	('AGPG', 'Chemical', '-', (27, 31))	('cell viability', 'CPA', (66, 80))	('knockdown', 'Var', (32, 41))	('decreased', 'NegReg', (56, 65))	('lactate', 'Chemical', 'MESH:D019344', (85, 92))	('AGPG', 'Gene', (27, 31))	('lactate production', 'MPA', (85, 103))
43612	32198345	AGPG knockdown in KYSE150 and KYSE30 cells strikingly inhibited cell proliferation and colony formation (Fig.	('colony formation', 'CPA', (87, 103))	('inhibited', 'NegReg', (54, 63))	('F', 'Chemical', 'MESH:D005461', (105, 106))	('cell proliferation', 'CPA', (64, 82))	('AGPG', 'Chemical', '-', (0, 4))	('knockdown', 'Var', (5, 14))	('AGPG', 'Gene', (0, 4))
43614	32198345	2a, b), and AGPG knockdown blocked the G1/S cell cycle transition (Fig.	('F', 'Chemical', 'MESH:D005461', (67, 68))	('AGPG', 'Gene', (12, 16))	('G1/S cell cycle transition', 'CPA', (39, 65))	('blocked', 'NegReg', (27, 34))	('knockdown', 'Var', (17, 26))	('AGPG', 'Chemical', '-', (12, 16))
43616	32198345	We also detected key cell cycle proteins and observed that AGPG knockdown markedly increased p27 expression and decreased CDK1 expression (Fig.	('expression', 'Species', '29278', (127, 137))	('p27', 'Gene', (93, 96))	('increased', 'PosReg', (83, 92))	('expression', 'MPA', (127, 137))	('AGPG', 'Chemical', '-', (59, 63))	('CDK1', 'Gene', '983', (122, 126))	('CDK1', 'Gene', (122, 126))	('p27', 'Gene', '3429', (93, 96))	('expression', 'Species', '29278', (97, 107))	('AGPG', 'Gene', (59, 63))	('knockdown', 'Var', (64, 73))	('F', 'Chemical', 'MESH:D005461', (139, 140))	('decreased', 'NegReg', (112, 121))	('expression', 'MPA', (97, 107))
43620	32198345	We demonstrated that AGPG knockdown significantly impaired glycolysis, which was consistent with our previous screening results.	('AGPG', 'Chemical', '-', (21, 25))	('impaired', 'NegReg', (50, 58))	('AGPG', 'Gene', (21, 25))	('knockdown', 'Var', (26, 35))	('glycolysis', 'MPA', (59, 69))
43622	32198345	Metabolome analysis based on liquid chromatography and mass spectrometry (MS) showed that intracellular metabolites of glycolysis (3-phosphoglycerate, pyruvate, and lactate) were markedly decreased after AGPG knockdown, further confirming that AGPG is essential for the conversion of glucose to lactate (Fig.	('decreased', 'NegReg', (188, 197))	('3-phosphoglycerate', 'Chemical', 'MESH:C005156', (131, 149))	('lactate', 'Chemical', 'MESH:D019344', (165, 172))	('pyruvate', 'Chemical', 'MESH:D019289', (151, 159))	('AGPG', 'Gene', (204, 208))	('intracellular metabolites', 'MPA', (90, 115))	('AGPG', 'Chemical', '-', (244, 248))	('lactate', 'Chemical', 'MESH:D019344', (295, 302))	('glucose', 'Chemical', 'MESH:D005947', (284, 291))	('AGPG', 'Chemical', '-', (204, 208))	('knockdown', 'Var', (209, 218))	('pyruvate', 'MPA', (151, 159))	('F', 'Chemical', 'MESH:D005461', (304, 305))
43624	32198345	Consistently, AGPG CRISPR KO significantly inhibited ESCC cell proliferation and cell cycle progression (Supplementary Fig.	('ESCC', 'Disease', (53, 57))	('inhibited', 'NegReg', (43, 52))	('AGPG', 'Chemical', '-', (14, 18))	('F', 'Chemical', 'MESH:D005461', (119, 120))	('AGPG', 'Var', (14, 18))	('cell cycle progression', 'CPA', (81, 103))
43625	32198345	In addition, AGPG CRISPR KO led to a significant reduction in aerobic glycolysis (Supplementary Fig.	('reduction', 'NegReg', (49, 58))	('F', 'Chemical', 'MESH:D005461', (96, 97))	('aerobic glycolysis', 'MPA', (62, 80))	('AGPG CRISPR KO', 'Var', (13, 27))	('AGPG', 'Chemical', '-', (13, 17))
43629	32198345	Proteins that bound to antisense AGPG were excluded from the candidate list, and the remaining proteins were sorted by MS score, as described in previous lncRNA studies.	('AGPG', 'Chemical', '-', (33, 37))	('antisense', 'Var', (23, 32))	('Proteins', 'Protein', (0, 8))
43652	32198345	Overexpression of AGPG FL, but not a mutant lacking the T5 fragment (AGPG DeltaT5), was sufficient to prevent the phenotypes observed after AGPG knockout (KO), including glycolytic reprogramming and cell proliferation (Fig.	('knockout', 'Var', (145, 153))	('expression', 'Species', '29278', (4, 14))	('DeltaT5', 'DELETION', 'None', (74, 81))	('cell proliferation', 'CPA', (199, 217))	('F', 'Chemical', 'MESH:D005461', (219, 220))	('AGPG', 'Chemical', '-', (140, 144))	('AGPG', 'Chemical', '-', (69, 73))	('AGPG', 'Chemical', '-', (18, 22))	('glycolytic reprogramming', 'CPA', (170, 194))	('DeltaT5', 'Var', (74, 81))	('AGPG', 'Gene', (140, 144))	('F', 'Chemical', 'MESH:D005461', (23, 24))	('AGPG', 'Var', (18, 22))
43661	32198345	In addition, overexpression of this AGPG MT could not rescue the decreased glycolysis caused by AGPG KO (Supplementary Fig.	('expression', 'Species', '29278', (17, 27))	('decreased', 'NegReg', (65, 74))	('F', 'Chemical', 'MESH:D005461', (119, 120))	('AGPG', 'Chemical', '-', (96, 100))	('glycolysis', 'MPA', (75, 85))	('decreased glycolysis', 'Phenotype', 'HP:0012270', (65, 85))	('AGPG KO', 'Var', (96, 103))	('AGPG', 'Chemical', '-', (36, 40))
43669	32198345	Interestingly, AGPG knockdown mediated by shRNA significantly reduced the expression of PFKFB3 (Fig.	('expression', 'MPA', (74, 84))	('F', 'Chemical', 'MESH:D005461', (91, 92))	('F', 'Chemical', 'MESH:D005461', (89, 90))	('PFKFB3', 'Gene', '5209', (88, 94))	('F', 'Chemical', 'MESH:D005461', (96, 97))	('AGPG', 'Chemical', '-', (15, 19))	('knockdown', 'Var', (20, 29))	('expression', 'Species', '29278', (74, 84))	('PFKFB3', 'Gene', (88, 94))	('reduced', 'NegReg', (62, 69))
43671	32198345	In addition, overexpression of AGPG FL but not AGPG DeltaT5 rescued the decreased PFKFB3 level induced by AGPG deletion (Fig.	('AGPG', 'Chemical', '-', (47, 51))	('AGPG', 'Chemical', '-', (106, 110))	('F', 'Chemical', 'MESH:D005461', (85, 86))	('expression', 'Species', '29278', (17, 27))	('DeltaT5', 'Var', (52, 59))	('PFKFB3', 'Gene', (82, 88))	('decreased', 'NegReg', (72, 81))	('F', 'Chemical', 'MESH:D005461', (83, 84))	('AGPG', 'Gene', (106, 110))	('AGPG', 'Chemical', '-', (31, 35))	('F', 'Chemical', 'MESH:D005461', (121, 122))	('PFKFB3', 'Gene', '5209', (82, 88))	('DeltaT5', 'DELETION', 'None', (52, 59))	('deletion', 'Var', (111, 119))	('F', 'Chemical', 'MESH:D005461', (36, 37))
43675	32198345	In addition, AGPG knockdown had marked effects on PFKFB3 stabilization in ESCC cells, shortening the half-life of PFKFB3 (Fig.	('F', 'Chemical', 'MESH:D005461', (53, 54))	('knockdown', 'Var', (18, 27))	('PFKFB3', 'Gene', '5209', (114, 120))	('F', 'Chemical', 'MESH:D005461', (122, 123))	('PFKFB3', 'Gene', '5209', (50, 56))	('half-life', 'MPA', (101, 110))	('AGPG', 'Gene', (13, 17))	('shortening', 'NegReg', (86, 96))	('F', 'Chemical', 'MESH:D005461', (117, 118))	('F', 'Chemical', 'MESH:D005461', (51, 52))	('F', 'Chemical', 'MESH:D005461', (115, 116))	('PFKFB3', 'Gene', (114, 120))	('PFKFB3', 'Gene', (50, 56))	('AGPG', 'Chemical', '-', (13, 17))
43677	32198345	Moreover, we carried out IP assays in cells expressing FLAG-tagged PFKFB3 with an anti-FLAG antibody and detected ubiquitin levels by western blotting.	('ubiquitin levels', 'MPA', (114, 130))	('F', 'Chemical', 'MESH:D005461', (55, 56))	('FLAG-tagged', 'Var', (55, 66))	('F', 'Chemical', 'MESH:D005461', (68, 69))	('PFKFB3', 'Gene', '5209', (67, 73))	('F', 'Chemical', 'MESH:D005461', (87, 88))	('F', 'Chemical', 'MESH:D005461', (70, 71))	('PFKFB3', 'Gene', (67, 73))
43678	32198345	As shown, AGPG knockdown significantly increased the levels of ubiquitinated PFKFB3 (Fig.	('F', 'Chemical', 'MESH:D005461', (78, 79))	('levels of ubiquitinated', 'MPA', (53, 76))	('PFKFB3', 'Gene', (77, 83))	('F', 'Chemical', 'MESH:D005461', (85, 86))	('knockdown', 'Var', (15, 24))	('AGPG', 'Chemical', '-', (10, 14))	('PFKFB3', 'Gene', '5209', (77, 83))	('increased', 'PosReg', (39, 48))	('AGPG', 'Gene', (10, 14))	('F', 'Chemical', 'MESH:D005461', (80, 81))
43682	32198345	Regarding PFKFB3 enzymatic activity, AGPG CRISPR KO had a mild effect on PFKFB3 S461 phosphorylation (Supplementary Fig.	('PFKFB3', 'Gene', '5209', (73, 79))	('F', 'Chemical', 'MESH:D005461', (116, 117))	('F', 'Chemical', 'MESH:D005461', (74, 75))	('phosphorylation', 'MPA', (85, 100))	('F', 'Chemical', 'MESH:D005461', (13, 14))	('F', 'Chemical', 'MESH:D005461', (11, 12))	('PFKFB3', 'Gene', (10, 16))	('S461', 'Var', (80, 84))	('PFKFB3', 'Gene', (73, 79))	('F', 'Chemical', 'MESH:D005461', (76, 77))	('PFKFB3', 'Gene', '5209', (10, 16))	('AGPG', 'Chemical', '-', (37, 41))
43693	32198345	Because AGPG binds mainly to the C-terminal fragment of PFKFB3, we analyzed four putative ubiquitinated lysine (K) residues, namely, K292, K302, K352, and K472, in the C-terminus of PFKFB3 to identify the predominant lysine residue(s) subject to ubiquitination that is (are) affected by AGPG (Supplementary Fig.	('F', 'Chemical', 'MESH:D005461', (183, 184))	('PFKFB3', 'Gene', (56, 62))	('lysine', 'Chemical', 'MESH:D008239', (217, 223))	('AGPG', 'Chemical', '-', (287, 291))	('ubiquitination', 'MPA', (246, 260))	('K302', 'Var', (139, 143))	('PFKFB3', 'Gene', '5209', (56, 62))	('PFKFB3', 'Gene', (182, 188))	('K472', 'Var', (155, 159))	('K292', 'Var', (133, 137))	('F', 'Chemical', 'MESH:D005461', (59, 60))	('PFKFB3', 'Gene', '5209', (182, 188))	('AGPG', 'Chemical', '-', (8, 12))	('F', 'Chemical', 'MESH:D005461', (307, 308))	('lysine', 'Chemical', 'MESH:D008239', (104, 110))	('F', 'Chemical', 'MESH:D005461', (185, 186))	('K352', 'Var', (145, 149))	('K302', 'Chemical', '-', (139, 143))	('F', 'Chemical', 'MESH:D005461', (57, 58))
43695	32198345	Among the four mutants, PFKFB3 K302A showed no increase in ubiquitination in response to AGPG knockdown (Fig.	('F', 'Chemical', 'MESH:D005461', (105, 106))	('K302A', 'Var', (31, 36))	('AGPG', 'Chemical', '-', (89, 93))	('PFKFB3', 'Gene', (24, 30))	('F', 'Chemical', 'MESH:D005461', (25, 26))	('ubiquitination', 'MPA', (59, 73))	('F', 'Chemical', 'MESH:D005461', (27, 28))	('PFKFB3', 'Gene', '5209', (24, 30))	('increase', 'PosReg', (47, 55))	('K302A', 'Mutation', 'p.K302A', (31, 36))
43698	32198345	Moreover, PFKFB3 K302A, but not other mutants, significantly abrogated APC/C (Cdc27)-induced PFKFB3 ubiquitination in ESCC cells (Supplementary Fig.	('APC', 'Disease', (71, 74))	('F', 'Chemical', 'MESH:D005461', (144, 145))	('PFKFB3', 'Gene', '5209', (93, 99))	('F', 'Chemical', 'MESH:D005461', (94, 95))	('F', 'Chemical', 'MESH:D005461', (13, 14))	('ubiquitination', 'MPA', (100, 114))	('F', 'Chemical', 'MESH:D005461', (11, 12))	('PFKFB3', 'Gene', (10, 16))	('F', 'Chemical', 'MESH:D005461', (96, 97))	('PFKFB3', 'Gene', (93, 99))	('abrogated', 'NegReg', (61, 70))	('K302A', 'Mutation', 'p.K302A', (17, 22))	('PFKFB3', 'Gene', '5209', (10, 16))	('APC', 'Disease', 'MESH:D011125', (71, 74))	('K302A', 'Var', (17, 22))
43699	32198345	4j, k), further indicating that K302 is an important site for APC/C-mediated ubiquitination in PFKFB3.	('K302', 'Var', (32, 36))	('PFKFB3', 'Gene', '5209', (95, 101))	('APC', 'Disease', 'MESH:D011125', (62, 65))	('APC', 'Disease', (62, 65))	('K302', 'Chemical', '-', (32, 36))	('PFKFB3', 'Gene', (95, 101))
43700	32198345	Thus, AGPG stabilizes PFKFB3 by preventing APC/C-mediated PFKFB3 K302 ubiquitination.	('APC', 'Disease', 'MESH:D011125', (43, 46))	('K302', 'Chemical', '-', (65, 69))	('APC', 'Disease', (43, 46))	('PFKFB3', 'Gene', (58, 64))	('AGPG', 'Chemical', '-', (6, 10))	('PFKFB3', 'Gene', '5209', (22, 28))	('preventing', 'NegReg', (32, 42))	('K302', 'Var', (65, 69))	('PFKFB3', 'Gene', '5209', (58, 64))	('PFKFB3', 'Gene', (22, 28))
43701	32198345	Furthermore, to ascertain the function of K302 in regulating PFKFB3, FLAG-tagged PFKFB3 wild-type (WT) or K302A was exogenously expressed in ESCC cells; intriguingly, the PFKFB3 K302A mutant showed an extended half-life (Fig.	('K302', 'Chemical', '-', (106, 110))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('half-life', 'MPA', (210, 219))	('K302', 'Chemical', '-', (178, 182))	('K302', 'Chemical', '-', (42, 46))	('F', 'Chemical', 'MESH:D005461', (221, 222))	('PFKFB3', 'Gene', (81, 87))	('F', 'Chemical', 'MESH:D005461', (64, 65))	('F', 'Chemical', 'MESH:D005461', (174, 175))	('F', 'Chemical', 'MESH:D005461', (62, 63))	('PFKFB3', 'Gene', '5209', (81, 87))	('K302A', 'Mutation', 'p.K302A', (106, 111))	('K302A', 'Mutation', 'p.K302A', (178, 183))	('F', 'Chemical', 'MESH:D005461', (84, 85))	('K302A', 'Var', (178, 183))	('F', 'Chemical', 'MESH:D005461', (172, 173))	('F', 'Chemical', 'MESH:D005461', (69, 70))	('PFKFB3', 'Gene', (61, 67))	('PFKFB3', 'Gene', (171, 177))	('F', 'Chemical', 'MESH:D005461', (82, 83))	('PFKFB3', 'Gene', '5209', (171, 177))	('PFKFB3', 'Gene', '5209', (61, 67))
43703	32198345	4l), indicating that K302 is an important ubiquitination site responsible for PFKFB3 stability.	('K302', 'Chemical', '-', (21, 25))	('PFKFB3', 'Gene', (78, 84))	('K302', 'Var', (21, 25))	('PFKFB3', 'Gene', '5209', (78, 84))
43707	32198345	Taken together, these data show that by inhibiting PFKFB3 K302 ubiquitination, AGPG enhanced PFKFB3 stability and therefore led to the increased accumulation of PFKFB3 in cancer cells, thereby increasing F-2,6-BP synthesis and subsequently promoting cell cycle progression by regulating p27 and CDK1.	('p27', 'Gene', '3429', (287, 290))	('PFKFB3', 'Gene', '5209', (93, 99))	('p27', 'Gene', (287, 290))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('K302', 'Chemical', '-', (58, 62))	('stability', 'MPA', (100, 109))	('PFKFB3', 'Gene', (51, 57))	('PFKFB3', 'Gene', '5209', (51, 57))	('regulating', 'Reg', (276, 286))	('PFKFB3', 'Gene', (161, 167))	('F-2,6-BP', 'Chemical', 'MESH:C027652', (204, 212))	('PFKFB3', 'Gene', '5209', (161, 167))	('cell cycle progression', 'CPA', (250, 272))	('promoting', 'PosReg', (240, 249))	('AGPG', 'Chemical', '-', (79, 83))	('increased accumulation', 'PosReg', (135, 157))	('CDK1', 'Gene', '983', (295, 299))	('cancer', 'Disease', (171, 177))	('CDK1', 'Gene', (295, 299))	('ubiquitination', 'MPA', (63, 77))	('AGPG', 'Gene', (79, 83))	('K302', 'Var', (58, 62))	('enhanced', 'PosReg', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('inhibiting', 'NegReg', (40, 50))	('increasing', 'PosReg', (193, 203))	('PFKFB3', 'Gene', (93, 99))
43718	32198345	WT TP53 overexpression in KYSE150 and HCT-116 cells decreased AGPG levels, whereas TP53 knockdown increased AGPG expression, further confirming the role of p53 in regulating AGPG expression (Fig.	('TP53', 'Gene', '7157', (83, 87))	('expression', 'Species', '29278', (179, 189))	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('AGPG', 'Chemical', '-', (174, 178))	('TP53', 'Gene', (83, 87))	('decreased', 'NegReg', (52, 61))	('p53', 'Gene', (156, 159))	('knockdown', 'Var', (88, 97))	('AGPG', 'Chemical', '-', (108, 112))	('AGPG', 'Chemical', '-', (62, 66))	('p53', 'Gene', '7157', (156, 159))	('expression', 'Species', '29278', (12, 22))	('increased', 'PosReg', (98, 107))	('AGPG levels', 'MPA', (62, 73))	('AGPG expression', 'MPA', (108, 123))	('expression', 'Species', '29278', (113, 123))	('F', 'Chemical', 'MESH:D005461', (191, 192))
43727	32198345	Collectively, our data demonstrate the important regulatory role of p53 in AGPG transcription, and loss or mutation of TP53 leads to the striking upregulation of AGPG.	('TP53', 'Gene', '7157', (119, 123))	('loss', 'Disease', 'MESH:D015431', (99, 103))	('AGPG', 'Chemical', '-', (75, 79))	('loss', 'Disease', (99, 103))	('upregulation', 'PosReg', (146, 158))	('AGPG', 'Gene', (75, 79))	('AGPG', 'Chemical', '-', (162, 166))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('AGPG', 'Gene', (162, 166))	('mutation', 'Var', (107, 115))	('TP53', 'Gene', (119, 123))
43729	32198345	Expression of oncogenic KRasG12V led to AGPG upregulation and TP53 downregulation in 293 T cells (Fig.	('F', 'Chemical', 'MESH:D005461', (98, 99))	('AGPG', 'Gene', (40, 44))	('TP53', 'Gene', '7157', (62, 66))	('downregulation', 'NegReg', (67, 81))	('KRasG12V', 'Var', (24, 32))	('TP53', 'Gene', (62, 66))	('Expression', 'Species', '29278', (0, 10))	('AGPG', 'Chemical', '-', (40, 44))	('upregulation', 'PosReg', (45, 57))
43734	32198345	AGPG knockdown significantly repressed cell-based xenograft tumor growth (Fig.	('xenograft tumor', 'Disease', (50, 65))	('AGPG', 'Chemical', '-', (0, 4))	('knockdown', 'Var', (5, 14))	('repressed', 'NegReg', (29, 38))	('xenograft tumor', 'Disease', 'MESH:D009369', (50, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('AGPG', 'Gene', (0, 4))	('F', 'Chemical', 'MESH:D005461', (74, 75))
43736	32198345	As indicated by the Haemotoxylin and Eosin (HE) and immunohistochemistry (IHC) results, AGPG knockdown decreased the levels of the cell proliferation marker Ki67, as well as of PFKFB3 and CDK1, but increased p27 levels (Fig.	('knockdown', 'Var', (93, 102))	('Haemotoxylin', 'Chemical', '-', (20, 32))	('PFKFB3', 'Gene', (177, 183))	('PFKFB3', 'Gene', '5209', (177, 183))	('decreased', 'NegReg', (103, 112))	('F', 'Chemical', 'MESH:D005461', (180, 181))	('AGPG', 'Chemical', '-', (88, 92))	('levels of the', 'MPA', (117, 130))	('AGPG', 'Gene', (88, 92))	('F', 'Chemical', 'MESH:D005461', (220, 221))	('Eosin', 'Chemical', 'MESH:D004801', (37, 42))	('CDK1', 'Gene', (188, 192))	('CDK1', 'Gene', '983', (188, 192))	('F', 'Chemical', 'MESH:D005461', (178, 179))	('increased', 'PosReg', (198, 207))	('HE', 'Chemical', '-', (44, 46))	('cell proliferation', 'CPA', (131, 149))	('p27', 'Gene', '3429', (208, 211))	('p27', 'Gene', (208, 211))
43739	32198345	6f), AGPG depletion via in vivo-optimized AGPG inhibitor dramatically reduced tumor growth (Fig.	('F', 'Chemical', 'MESH:D005461', (92, 93))	('inhibitor', 'Var', (47, 56))	('reduced', 'NegReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('AGPG', 'Chemical', '-', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('AGPG', 'Chemical', '-', (5, 9))	('tumor', 'Disease', (78, 83))	('AGPG', 'Gene', (42, 46))
43742	32198345	The main component of the in vivo-optimized AGPG inhibitor used in the PDX model was antisense oligonucleotides, which exhibited a stronger knockdown effect on nuclear-localized RNAs.	('AGPG', 'Gene', (44, 48))	('oligonucleotides', 'Chemical', 'MESH:D009841', (95, 111))	('knockdown', 'MPA', (140, 149))	('AGPG', 'Chemical', '-', (44, 48))	('antisense oligonucleotides', 'Var', (85, 111))
43743	32198345	Accordingly, as shown in the HE and IHC analyses, AGPG knockdown significantly affected cell proliferation (indicated by Ki67), which might be attributed to the modulation of PFKFB3 and downstream CDK1 and p27 expression, as mentioned previously (Fig.	('HE', 'Chemical', '-', (29, 31))	('knockdown', 'Var', (55, 64))	('PFKFB3', 'Gene', (175, 181))	('CDK1', 'Gene', '983', (197, 201))	('AGPG', 'Gene', (50, 54))	('expression', 'Species', '29278', (210, 220))	('CDK1', 'Gene', (197, 201))	('p27', 'Gene', '3429', (206, 209))	('F', 'Chemical', 'MESH:D005461', (247, 248))	('F', 'Chemical', 'MESH:D005461', (178, 179))	('p27', 'Gene', (206, 209))	('PFKFB3', 'Gene', '5209', (175, 181))	('affected', 'Reg', (79, 87))	('modulation', 'Reg', (161, 171))	('cell proliferation', 'CPA', (88, 106))	('AGPG', 'Chemical', '-', (50, 54))	('F', 'Chemical', 'MESH:D005461', (176, 177))
43745	32198345	The AGPG-high group exhibited higher Ki67, PFKFB3, and CDK1 expression but lower p27 and p53 expression, whereas the AGPG-low group showed the opposite pattern (Fig.	('expression', 'MPA', (60, 70))	('PFKFB3', 'Gene', '5209', (43, 49))	('AGPG', 'Chemical', '-', (4, 8))	('p53', 'Gene', (89, 92))	('Ki67', 'MPA', (37, 41))	('lower', 'NegReg', (75, 80))	('higher', 'PosReg', (30, 36))	('expression', 'Species', '29278', (93, 103))	('expression', 'Species', '29278', (60, 70))	('F', 'Chemical', 'MESH:D005461', (46, 47))	('CDK1', 'Gene', (55, 59))	('CDK1', 'Gene', '983', (55, 59))	('p27', 'Gene', '3429', (81, 84))	('p27', 'Gene', (81, 84))	('AGPG-high', 'Var', (4, 13))	('F', 'Chemical', 'MESH:D005461', (161, 162))	('F', 'Chemical', 'MESH:D005461', (44, 45))	('AGPG', 'Chemical', '-', (117, 121))	('p53', 'Gene', '7157', (89, 92))	('PFKFB3', 'Gene', (43, 49))
43746	32198345	Collectively, we speculated that dysregulation of the p53-AGPG-PFKFB3 axis promotes ESCC development.	('dysregulation', 'Var', (33, 46))	('PFKFB3', 'Gene', '5209', (63, 69))	('ESCC', 'Disease', (84, 88))	('promotes', 'PosReg', (75, 83))	('AGPG', 'Chemical', '-', (58, 62))	('p53', 'Gene', (54, 57))	('PFKFB3', 'Gene', (63, 69))	('p53', 'Gene', '7157', (54, 57))
43749	32198345	7c, d), and high PFKFB3 expression was associated with poor outcomes in ESCC patients (Fig.	('expression', 'Species', '29278', (24, 34))	('PFKFB3', 'Gene', (17, 23))	('high', 'Var', (12, 16))	('F', 'Chemical', 'MESH:D005461', (20, 21))	('F', 'Chemical', 'MESH:D005461', (87, 88))	('F', 'Chemical', 'MESH:D005461', (18, 19))	('patients', 'Species', '9606', (77, 85))	('PFKFB3', 'Gene', '5209', (17, 23))	('ESCC', 'Disease', (72, 76))
43757	32198345	PFKFB3 is reported to be dimethylated at R131 and R134, and the regulation of PFKFB3 methylation determines directional glucose utilization.	('R131', 'Var', (41, 45))	('determines', 'Reg', (97, 107))	('PFKFB3', 'Gene', (78, 84))	('PFKFB3', 'Gene', (0, 6))	('PFKFB3', 'Gene', '5209', (78, 84))	('directional glucose utilization', 'MPA', (108, 139))	('glucose', 'Chemical', 'MESH:D005947', (120, 127))	('R134', 'Var', (50, 54))	('PFKFB3', 'Gene', '5209', (0, 6))
43769	32198345	Collectively, these findings further delineate the detailed mechanism underlying lncRNA-mediated PFKFB3 turnover and cancer metabolism remodeling.	('PFKFB3', 'Gene', '5209', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lncRNA-mediated', 'Var', (81, 96))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('PFKFB3', 'Gene', (97, 103))	('cancer', 'Disease', (117, 123))
43777	32198345	Unfortunately, over 50% of human cancers, including ESCC, have no WT TP53 function due to mutation or deletion, and multiple microenvironmental factors, including hypoxia and excessive genotoxic insults, are potential driving forces that cause TP53 mutations.	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (244, 248))	('TP53', 'Gene', (69, 73))	('cancers', 'Disease', (33, 40))	('mutations', 'Var', (249, 258))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('human', 'Species', '9606', (27, 32))	('deletion', 'Var', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('ESCC', 'Disease', (52, 56))	('hypoxia', 'Disease', 'MESH:D000860', (163, 170))	('mutation', 'Var', (90, 98))	('hypoxia', 'Disease', (163, 170))	('TP53', 'Gene', '7157', (244, 248))
43778	32198345	Therefore, dysregulation of the p53-AGPG-PFKFB3 axis leads to metabolism remodeling and cell proliferation.	('PFKFB3', 'Gene', (41, 47))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('dysregulation', 'Var', (11, 24))	('metabolism remodeling', 'CPA', (62, 83))	('cell proliferation', 'CPA', (88, 106))	('AGPG', 'Chemical', '-', (36, 40))	('PFKFB3', 'Gene', '5209', (41, 47))	('leads to', 'Reg', (53, 61))
43782	32198345	High expression of both AGPG and PFKFB3 is correlated with an even poorer prognosis, suggesting that the combination of AGPG and PFKFB3 is a potential prognostic marker for ESCC diagnosis.	('AGPG', 'Chemical', '-', (120, 124))	('expression', 'MPA', (5, 15))	('ESCC', 'Disease', (173, 177))	('PFKFB3', 'Gene', (129, 135))	('PFKFB3', 'Gene', '5209', (33, 39))	('AGPG', 'Chemical', '-', (24, 28))	('PFKFB3', 'Gene', '5209', (129, 135))	('AGPG', 'Gene', (24, 28))	('PFKFB3', 'Gene', (33, 39))	('combination', 'Var', (105, 116))	('expression', 'Species', '29278', (5, 15))
43786	32198345	KYSE30, KYSE510, KYSE150, KYSE520, KYSE70, and KYSE180 cells were obtained from German Cell Culture Collection (DSMZ, Braunschweig, Germany).	('KYSE180', 'CellLine', 'CVCL:1349;0.014871367430453558', (47, 54))	('KYSE180', 'Var', (47, 54))	('KYSE150', 'Var', (17, 24))	('KYSE70', 'Var', (35, 41))	('KYSE510', 'Var', (8, 15))	('KYSE520', 'Var', (26, 33))
43796	32198345	N-Terminal FLAG-tagged expression vectors (for expression in mammalian cells) for FL PFKFB3, truncated mutants, and site-directed mutants (K292A, K302A, K352A, and K472A) were provided by OBiO Technology (Shanghai, China).	('K352A', 'Var', (153, 158))	('PFKFB3', 'Gene', (85, 91))	('K302A', 'Mutation', 'p.K302A', (146, 151))	('F', 'Chemical', 'MESH:D005461', (82, 83))	('expression vectors', 'Species', '29278', (23, 41))	('K302A', 'Var', (146, 151))	('K292A', 'Mutation', 'p.K292A', (139, 144))	('K352A', 'Mutation', 'p.K352A', (153, 158))	('F', 'Chemical', 'MESH:D005461', (11, 12))	('K292A', 'Var', (139, 144))	('K472A', 'Var', (164, 169))	('K472A', 'Mutation', 'p.K472A', (164, 169))	('PFKFB3', 'Gene', '5209', (85, 91))	('mammalian', 'Species', '9606', (61, 70))	('F', 'Chemical', 'MESH:D005461', (86, 87))	('expression', 'Species', '29278', (47, 57))	('expression', 'Species', '29278', (23, 33))	('F', 'Chemical', 'MESH:D005461', (88, 89))
43801	32198345	Briefly, AGPG-specific sgRNAs were designed to recognize two different sites of the AGPG gene, the location of the upstream target (>hg38_refGene_NR_002929_0 range=chr1:202861697-202861719) and the location of the downstream target (>hg38_refGene_NR_002929_6 range=chr1:202876356-202876378).	('AGPG', 'Gene', (84, 88))	('chr1:202876356-202876378', 'STRUCTURAL_ABNORMALITY', 'None', (265, 289))	('>hg38_refGene_NR_002929_6', 'Var', (233, 258))	('AGPG', 'Chemical', '-', (9, 13))	('AGPG', 'Chemical', '-', (84, 88))	('>hg38_refGene_NR_002929_0', 'Var', (132, 157))	('chr1:202861697-202861719', 'STRUCTURAL_ABNORMALITY', 'None', (164, 188))
43861	32198345	R.-H.X., J.L., Z.-X.L., Q.-N.W., Y.-X.L., D.-S.W., D.-L.C., H.-Y.P., D.X., M.-S.Z., L.F., B.L., A.L., P.H., D.-X.L., and H.-Q.J.	('F', 'Chemical', 'MESH:D005461', (86, 87))	('P.H.', 'Var', (102, 106))	('M.-S.Z.', 'Var', (75, 82))	('D.-X.L.', 'Var', (108, 115))
43870	31646712	Forced expression of miR-338-5p in these cells resulted in downregulation of Id-1, and restoration of both in vitro and in vivo sensitivity to 5-FU treatment.	('5-FU', 'Chemical', 'MESH:D005472', (143, 147))	('miR-338-5p', 'Chemical', '-', (21, 31))	('miR-338-5p', 'Var', (21, 31))	('Id-1', 'Gene', (77, 81))	('restoration', 'PosReg', (87, 98))	('downregulation', 'NegReg', (59, 73))	('Id-1', 'Gene', '3397', (77, 81))	('sensitivity to 5-FU treatment', 'MPA', (128, 157))
43872	31646712	In contrast, miR-338-5p knockdown induced 5-FU resistance in chemosensitive esophageal cell lines, and knockdown of both miR-338-5p and Id-1 resensitized the cells to 5-FU.	('miR-338-5p', 'Chemical', '-', (121, 131))	('miR-338-5p', 'Var', (121, 131))	('5-FU', 'Chemical', 'MESH:D005472', (167, 171))	('resensitized', 'NegReg', (141, 153))	('5-FU', 'Chemical', 'MESH:D005472', (42, 46))	('5-FU resistance', 'MPA', (42, 57))	('Id-1', 'Gene', '3397', (136, 140))	('Id-1', 'Gene', (136, 140))	('induced', 'Reg', (34, 41))	('miR-338-5p', 'Chemical', '-', (13, 23))	('knockdown', 'Var', (103, 112))	('miR-338-5p', 'Var', (13, 23))
43873	31646712	In addition, miR-338-5p had suppressive effects on migration and invasion of ESCC cells.	('ESCC', 'Disease', (77, 81))	('invasion of', 'CPA', (65, 76))	('miR-338-5p', 'Var', (13, 23))	('miR-338-5p', 'Chemical', '-', (13, 23))	('suppressive', 'NegReg', (28, 39))
43874	31646712	Luciferase reporter assay confirmed a direct interaction between miR-338-5p and the 3'-UTR of Id-1.	('Id-1', 'Gene', (94, 98))	('miR-338-5p', 'Chemical', '-', (65, 75))	('Id-1', 'Gene', '3397', (94, 98))	('miR-338-5p', 'Var', (65, 75))	('interaction', 'Interaction', (45, 56))
43875	31646712	We also found that miR-338-5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC.	('ESCC', 'Disease', (113, 117))	('tumor', 'Disease', (65, 70))	('downregulated', 'NegReg', (48, 61))	('patients', 'Species', '9606', (99, 107))	('miR-338-5p', 'Chemical', '-', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('miR-338-5p', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
43877	31646712	In summary, we found that miR-338-5p can modulate 5-FU chemoresistance and inhibit invasion-related functions in ESCC by negatively regulating Id-1, and that serum miR-338-5p could be a novel noninvasive prognostic and predictive biomarker in ESCC.	('negatively regulating', 'NegReg', (121, 142))	('miR-338-5p', 'Var', (164, 174))	('ESCC', 'Disease', (113, 117))	('invasion-related functions', 'CPA', (83, 109))	('5-FU chemoresistance', 'MPA', (50, 70))	('ESCC', 'Disease', (243, 247))	('inhibit', 'NegReg', (75, 82))	('Id-1', 'Gene', '3397', (143, 147))	('Id-1', 'Gene', (143, 147))	('miR-338-5p', 'Var', (26, 36))	('5-FU', 'Chemical', 'MESH:D005472', (50, 54))	('modulate', 'Reg', (41, 49))	('miR-338-5p', 'Chemical', '-', (26, 36))	('miR-338-5p', 'Chemical', '-', (164, 174))
43878	31646712	We found that microRNA (miR)-338-5p was underexpressed in esophageal squamous cell carcinoma cells with acquired 5-fluorouracil (5-FU) chemoresistance, and that reexpression of miR-338-5p could resensitize them to 5-FU treatment through targeting Id-1.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (58, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('-338-5p', 'Chemical', '-', (180, 187))	('5-FU', 'Chemical', 'MESH:D005472', (214, 218))	('esophageal squamous cell carcinoma', 'Disease', (58, 92))	('miR-338-5p', 'Var', (177, 187))	('targeting', 'Reg', (237, 246))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (113, 127))	('Id-1', 'Gene', '3397', (247, 251))	('Id-1', 'Gene', (247, 251))	('miR-338-5p', 'Chemical', '-', (177, 187))	('5-FU', 'Chemical', 'MESH:D005472', (129, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('-338-5p', 'Chemical', '-', (28, 35))
43879	31646712	MicroRNA-338-5p was significantly downregulated in tumor tissue and serum of patients with esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (91, 125))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('downregulated', 'NegReg', (34, 47))	('-338-5p', 'Chemical', '-', (8, 15))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (77, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (91, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('MicroRNA-338-5p', 'Var', (0, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
43880	31646712	Low serum miR-338-5p was predictive of poor response to 5-FU/cisplatin-based neoadjuvant chemoradiotherapy.	('miR-338-5p', 'Protein', (10, 20))	('miR-338-5p', 'Chemical', '-', (10, 20))	('5-FU', 'Chemical', 'MESH:D005472', (56, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('Low', 'Var', (0, 3))
43885	31646712	Herein, we present data based on in vitro and in vivo functional experiments, as well as analyses of clinical samples, to show that miR-338-5p is downregulated in ESCC, and that it regulates chemoresistance and invasion-related functions in ESCC cells by negatively regulating Id-1.	('ESCC', 'Disease', (163, 167))	('Id-1', 'Gene', (277, 281))	('regulates', 'Reg', (181, 190))	('chemoresistance', 'CPA', (191, 206))	('miR-338-5p', 'Var', (132, 142))	('miR-338-5p', 'Chemical', '-', (132, 142))	('Id-1', 'Gene', '3397', (277, 281))	('downregulated', 'NegReg', (146, 159))	('invasion-related functions', 'CPA', (211, 237))	('negatively regulating', 'NegReg', (255, 276))
43904	31646712	For in vitro experiments, the mean Ct values of miR-338-5p were normalized to that of the internal reference gene or endogenous control to obtain DeltaCt, and then to that of the corresponding control or parental cell line to obtain the 2-DeltaDeltaCt value as fold change.	('miR-338-5p', 'Var', (48, 58))	('DeltaCt', 'MPA', (146, 153))	('miR-338-5p', 'Chemical', '-', (48, 58))
43928	31646712	The prediction results showed that there were 2 putative binding sites for miR-338-5p within the 3'-UTR of Id-1 (Figure 1A).	('Id-1', 'Gene', (107, 111))	('binding', 'Interaction', (57, 64))	('Id-1', 'Gene', '3397', (107, 111))	('miR-338-5p', 'Var', (75, 85))	('miR-338-5p', 'Chemical', '-', (75, 85))
43929	31646712	The luciferase reporter vectors containing WT and Mut Id-1 3'-UTR were then constructed accordingly (Figure 1A), and dual-luciferase reporter assay was carried out to confirm the direct binding of miR-338-5p to the Id-1 3'-UTR.	('Id-1', 'Gene', '3397', (215, 219))	('Id-1', 'Gene', (215, 219))	('Id-1', 'Gene', (54, 58))	('Id-1', 'Gene', '3397', (54, 58))	('miR-338-5p', 'Var', (197, 207))	('miR-338-5p', 'Chemical', '-', (197, 207))	('binding', 'Interaction', (186, 193))
43930	31646712	Cotransfection of miR-338-5p and the WT psiCHECK-Id-1 3'-UTR into KYSE150 cells led to a significant decrease (P = .004) of the luciferase signal when compared with scrambled miRNA control (Figure 1B).	('Id-1', 'Gene', '3397', (49, 53))	('decrease', 'NegReg', (101, 109))	('miR-338-5p', 'Chemical', '-', (18, 28))	('WT psiCHECK', 'Disease', (37, 48))	('miR-338-5p', 'Var', (18, 28))	('WT psiCHECK', 'Disease', 'MESH:C536751', (37, 48))	('Id-1', 'Gene', (49, 53))	('luciferase', 'Enzyme', (128, 138))
43931	31646712	This inhibitory effect was rescued by mutating the 2 predicted miR-338-5p binding sites (Figure 1B).	('miR-338-5p', 'Chemical', '-', (63, 73))	('mutating', 'Var', (38, 46))	('miR-338-5p', 'Gene', (63, 73))	('binding', 'Interaction', (74, 81))
43932	31646712	These data indicated that Id-1 3'-UTR is a direct target of miR-338-5p.	('Id-1', 'Gene', '3397', (26, 30))	('Id-1', 'Gene', (26, 30))	('miR-338-5p', 'Chemical', '-', (60, 70))	('miR-338-5p', 'Var', (60, 70))
43933	31646712	We determined the miR-338-5p expression level in 42 pairs of esophageal tumor and nonneoplastic tissues (Set B samples), which were previously analyzed for Id-1 protein expression.15 Pearson's correlation analysis showed an inverse relationship (r = -0.214, P = .050) between miR-338-5p and Id-1 (Figure 1C).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Id-1', 'Gene', (156, 160))	('miR-338-5p', 'Chemical', '-', (18, 28))	('esophageal tumor', 'Disease', (61, 77))	('Id-1', 'Gene', '3397', (156, 160))	('esophageal tumor', 'Phenotype', 'HP:0100751', (61, 77))	('miR-338-5p', 'Chemical', '-', (276, 286))	('Id-1', 'Gene', '3397', (291, 295))	('miR-338-5p', 'Var', (276, 286))	('Id-1', 'Gene', (291, 295))	('esophageal tumor', 'Disease', 'MESH:D004938', (61, 77))
43934	31646712	Our group previously reported that Id-1 can induce chemoresistance in ESCC.14, 15 We therefore speculated that targeting Id-1 using miR-338-5p could help ESCC cancer cells overcome 5-FU resistance.	('Id-1', 'Gene', (121, 125))	('cancer', 'Disease', (159, 165))	('5-FU', 'Chemical', 'MESH:D005472', (181, 185))	('Id-1', 'Gene', '3397', (121, 125))	('Id-1', 'Gene', '3397', (35, 39))	('Id-1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ESCC', 'Disease', (154, 158))	('miR-338-5p', 'Chemical', '-', (132, 142))	('miR-338-5p', 'Var', (132, 142))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('chemoresistance', 'CPA', (51, 66))
43935	31646712	We found that miR-338-5p was downregulated, whereas Id-1 was upregulated, in KYSE410FR and KYSE150FR cells in comparison with their parental ESCC cell lines (Figure 2A,B).	('Id-1', 'Gene', '3397', (52, 56))	('upregulated', 'PosReg', (61, 72))	('Id-1', 'Gene', (52, 56))	('miR-338-5p', 'Gene', (14, 24))	('KYSE150FR', 'Var', (91, 100))	('miR-338-5p', 'Chemical', '-', (14, 24))	('downregulated', 'NegReg', (29, 42))	('KYSE410FR', 'Var', (77, 86))
43936	31646712	We then undertook miR-338-5p knockdown in parental ESCC cell lines using miRZip-338-5p (Figure 2C) and found elevation of Id-1 protein expression levels in both cell lines (Figure 2D).	('miR-338-5p', 'Chemical', '-', (18, 28))	('elevation', 'PosReg', (109, 118))	('-338-5p', 'Chemical', '-', (21, 28))	('Id-1', 'Gene', '3397', (122, 126))	('Id-1', 'Gene', (122, 126))	('miRZip-338-5p', 'Var', (73, 86))	('-338-5p', 'Chemical', '-', (79, 86))
43937	31646712	In contrast, stable miR-338-5p overexpression decreased Id-1 protein levels in KYSE410FR and KYSE150FR cells when compared with their corresponding control cell lines (Figure 2E,F), thus indicating that miR-338-5p can modulate Id-1 function in 5-FU-resistant ESCC cells.	('function', 'MPA', (232, 240))	('Id-1', 'Gene', (227, 231))	('miR-338-5p', 'Var', (203, 213))	('miR-338-5p', 'Chemical', '-', (20, 30))	('Id-1', 'Gene', '3397', (56, 60))	('Id-1', 'Gene', (56, 60))	('miR-338-5p', 'Chemical', '-', (203, 213))	('Id-1', 'Gene', '3397', (227, 231))	('5-FU', 'Chemical', 'MESH:D005472', (244, 248))	('protein levels', 'MPA', (61, 75))	('modulate', 'Reg', (218, 226))	('KYSE410FR', 'Var', (79, 88))	('decreased', 'NegReg', (46, 55))	('KYSE150FR', 'Var', (93, 102))	('miR-338-5p', 'Var', (20, 30))
43939	31646712	The results of MTT cell viability assays showed that overexpression of miR-338-5p sensitized KYSE410FR and KYSE150FR cells to 5-FU treatment, and that this effect was abolished by overexpression of Id-1 (Figure 3A).	('5-FU', 'Chemical', 'MESH:D005472', (126, 130))	('overexpression', 'PosReg', (53, 67))	('Id-1', 'Gene', (198, 202))	('miR-338-5p', 'Var', (71, 81))	('5-FU treatment', 'MPA', (126, 140))	('Id-1', 'Gene', '3397', (198, 202))	('miR-338-5p', 'Chemical', '-', (71, 81))	('KYSE410FR', 'Var', (93, 102))	('KYSE150FR', 'Var', (107, 116))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('sensitized', 'Reg', (82, 92))
43940	31646712	Western blot analyses showed that miR-338-5p expression increased the sensitivity of KYSE410FR and KYSE150FR cells to 5-FU-induced apoptosis, as indicated by the increase in cleaved caspase-3 and cleaved PARP; overexpression of Id-1 reversed this effect (Figure 3B).	('increase', 'PosReg', (162, 170))	('increased', 'PosReg', (56, 65))	('Id-1', 'Gene', (228, 232))	('caspase-3', 'Gene', '836', (182, 191))	('PARP', 'Gene', '142', (204, 208))	('sensitivity', 'MPA', (70, 81))	('Id-1', 'Gene', '3397', (228, 232))	('miR-338-5p', 'Chemical', '-', (34, 44))	('caspase-3', 'Gene', (182, 191))	('5-FU', 'Chemical', 'MESH:D005472', (118, 122))	('PARP', 'Gene', (204, 208))	('miR-338-5p expression', 'Var', (34, 55))
43942	31646712	In contrast, data from MTT assays showed that knockdown of miR-338-5p increased the viability of the 5-FU-sensitive parental esophageal cell lines under 5-FU treatment, and that this effect could be abolished by Id-1 knockdown (Figure 3D).	('MTT', 'Chemical', 'MESH:C070243', (23, 26))	('miR-338-5p', 'Chemical', '-', (59, 69))	('viability', 'CPA', (84, 93))	('increased', 'PosReg', (70, 79))	('miR-338-5p', 'Var', (59, 69))	('5-FU', 'Chemical', 'MESH:D005472', (101, 105))	('Id-1', 'Gene', '3397', (212, 216))	('5-FU', 'Chemical', 'MESH:D005472', (153, 157))	('Id-1', 'Gene', (212, 216))
43943	31646712	Western blot analysis of cleaved caspase-3 and cleaved PARP, and flow cytometric analysis of the sub-G1 apoptotic cell population, indicated that knockdown of miR-338-5p made the parental esophageal cells more resistant to 5-FU-induced apoptosis, whereas knockdown of Id-1 could restore 5-FU sensitivity (Figure 3E,F).	('knockdown', 'Var', (146, 155))	('PARP', 'Gene', '142', (55, 59))	('Id-1', 'Gene', '3397', (268, 272))	('miR-338-5p', 'Var', (159, 169))	('resistant', 'CPA', (210, 219))	('caspase-3', 'Gene', (33, 42))	('5-FU', 'Chemical', 'MESH:D005472', (223, 227))	('miR-338-5p', 'Chemical', '-', (159, 169))	('caspase-3', 'Gene', '836', (33, 42))	('PARP', 'Gene', (55, 59))	('more', 'PosReg', (205, 209))	('5-FU', 'Chemical', 'MESH:D005472', (287, 291))	('Id-1', 'Gene', (268, 272))
43944	31646712	Collectively, these data showed that miR-338-5p can modulate 5-FU chemoresistance by downregulating Id-1.	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('miR-338-5p', 'Var', (37, 47))	('5-FU chemoresistance', 'MPA', (61, 81))	('miR-338-5p', 'Chemical', '-', (37, 47))	('downregulating', 'NegReg', (85, 99))	('Id-1', 'Gene', '3397', (100, 104))	('Id-1', 'Gene', (100, 104))	('modulate', 'Reg', (52, 60))
43945	31646712	Tumor xenograft experiments were undertaken to determine whether miR-338-5p overexpression could render ESCC tumors more sensitive to 5-FU treatment in vivo (Figure 4A).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('5-FU', 'Chemical', 'MESH:D005472', (134, 138))	('miR-338-5p', 'Chemical', '-', (65, 75))	('more', 'PosReg', (116, 120))	('miR-338-5p', 'Var', (65, 75))	('ESCC tumors', 'Disease', (104, 115))	('sensitive to 5-FU treatment', 'MPA', (121, 148))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ESCC tumors', 'Disease', 'MESH:D004938', (104, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
43946	31646712	Comparison of tumor size showed that miR-338-5p overexpression in KYSE150FR cells significantly increased the sensitivity of the tumors to 5-FU therapy, and that concomitant overexpression of Id-1 significantly restored the 5-FU resistance (Figure 4B,C).	('tumors', 'Disease', (129, 135))	('miR-338-5p', 'Chemical', '-', (37, 47))	('Id-1', 'Gene', '3397', (192, 196))	('Id-1', 'Gene', (192, 196))	('5-FU', 'Chemical', 'MESH:D005472', (139, 143))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('5-FU', 'Chemical', 'MESH:D005472', (224, 228))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('miR-338-5p', 'Var', (37, 47))	('sensitivity', 'MPA', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('5-FU resistance', 'MPA', (224, 239))	('restored', 'PosReg', (211, 219))	('increased', 'PosReg', (96, 105))	('tumor', 'Disease', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
43947	31646712	Several studies reported that overexpression of Id-1 is associated with tumor invasion and metastasis in different cancer types, including ESCC.20, 23, 24 As our data showed that miR-338-5p could downregulate Id-1, we further speculated that miR-338-5p might play a role in regulating invasion and migration of ESCC cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('downregulate', 'NegReg', (196, 208))	('overexpression', 'PosReg', (30, 44))	('associated', 'Reg', (56, 66))	('Id-1', 'Gene', '3397', (209, 213))	('Id-1', 'Gene', (209, 213))	('miR-338-5p', 'Chemical', '-', (179, 189))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ESCC.20', 'Disease', (139, 146))	('miR-338-5p', 'Chemical', '-', (242, 252))	('miR-338-5p', 'Var', (179, 189))	('Id-1', 'Gene', (48, 52))	('Id-1', 'Gene', '3397', (48, 52))	('tumor', 'Disease', (72, 77))	('metastasis', 'CPA', (91, 101))	('invasion', 'CPA', (285, 293))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
43948	31646712	The results of the Transwell cell invasion assay indicated that forced expression of miR-338-5p significantly inhibited the invasive activity of ESCC cells in vitro (Figure 5A).	('invasive activity of', 'CPA', (124, 144))	('inhibited', 'NegReg', (110, 119))	('miR-338-5p', 'Chemical', '-', (85, 95))	('miR-338-5p', 'Var', (85, 95))	('ESCC', 'Disease', (145, 149))
43949	31646712	MicroRNA-338-5p also reduced the migration activity of ESCC cells, as shown by the wound healing assay (Figure 5B).	('reduced', 'NegReg', (21, 28))	('ESCC cells', 'CPA', (55, 65))	('-338-5p', 'Chemical', '-', (8, 15))	('migration activity', 'CPA', (33, 51))	('MicroRNA-338-5p', 'Var', (0, 15))
43950	31646712	Reoverexpression of Id-1 attenuated these effects (Figure 5A,B).	('Id-1', 'Gene', (20, 24))	('Reoverexpression', 'Var', (0, 16))	('Id-1', 'Gene', '3397', (20, 24))
43951	31646712	Conversely, silencing miR-338-5p increased the abilities of KYSE270 and T.Tn cells to migrate and invade, and the effects were ameliorated by Id-1 knockdown (Figure 5C,D).	('Id-1', 'Gene', '3397', (142, 146))	('Id-1', 'Gene', (142, 146))	('miR-338-5p', 'Protein', (22, 32))	('silencing', 'Var', (12, 21))	('miR-338-5p', 'Chemical', '-', (22, 32))	('increased', 'PosReg', (33, 42))
43952	31646712	These findings suggest that miR-338-5p has metastasis-inhibiting functions that are mediated by downregulating Id-1.	('miR-338-5p', 'Var', (28, 38))	('Id-1', 'Gene', (111, 115))	('downregulating', 'NegReg', (96, 110))	('metastasis-inhibiting', 'CPA', (43, 64))	('Id-1', 'Gene', '3397', (111, 115))	('miR-338-5p', 'Chemical', '-', (28, 38))
43954	31646712	Among the 30 ESCC samples in Set A, 19 (approximately 63%) had lower expression of miR-338-5p relative to their corresponding nonneoplastic tissues (Figure 6A, upper panel).	('miR-338-5p', 'Chemical', '-', (83, 93))	('miR-338-5p', 'Var', (83, 93))	('lower', 'NegReg', (63, 68))	('expression', 'MPA', (69, 79))
43955	31646712	Similarly, analysis of Set B samples showed that 29 of 42 cases (approximately 69%) had lower expression of miR-338-5p in tumors than in their corresponding nontumor tissues (Figure 6A, lower panel).	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('miR-338-5p', 'Chemical', '-', (108, 118))	('miR-338-5p', 'Var', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('expression', 'MPA', (94, 104))	('lower', 'NegReg', (88, 93))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', (122, 127))
43957	31646712	We also analyzed miR-338-5p expression in other cancers of the gastrointestinal tract using public sources including TCGA database and GEO datasets.	('miR-338-5p', 'Var', (17, 27))	('cancers', 'Disease', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (48, 85))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('miR-338-5p', 'Chemical', '-', (17, 27))
43958	31646712	In TCGA data, the expression level of miR-338-5p in the ESCA data cohort was significantly lower than that in nontumor tissues (Figure S1A).	('lower', 'NegReg', (91, 96))	('tumor', 'Disease', (113, 118))	('miR-338-5p', 'Chemical', '-', (38, 48))	('expression level', 'MPA', (18, 34))	('ESCA', 'Disease', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('miR-338-5p', 'Var', (38, 48))
43960	31646712	Taken together, these results suggest an association between miR-338-5p dysregulation and esophageal cancer.	('miR-338-5p dysregulation', 'Var', (61, 85))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miR-338-5p', 'Chemical', '-', (61, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))
43961	31646712	In the GEO datasets, lower expression of miR-338-5p was also found in other gastrointestinal cancers (Figure S1C-F).	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (76, 100))	('miR-338-5p', 'Chemical', '-', (41, 51))	('miR-338-5p', 'Var', (41, 51))	('lower', 'NegReg', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('expression', 'MPA', (27, 37))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('gastrointestinal cancers', 'Disease', (76, 100))
43962	31646712	Analysis of TCGA-ESCA data showed that ESCA patients with high miR-338-5p expression in their tumors had longer overall survival time (Figure S1G).	('longer', 'PosReg', (105, 111))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('miR-338-5p', 'Chemical', '-', (63, 73))	('overall survival time', 'CPA', (112, 133))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('high miR-338-5p expression', 'Var', (58, 84))	('ESCA', 'Disease', (39, 43))
43963	31646712	To determine whether circulating miR-338-5p could serve as a noninvasive serum biomarker, we analyzed the expression level of miR-338-5p in admission/pretreatment serum samples of 104 patients with ESCC and 50 healthy individuals.	('ESCC', 'Disease', (198, 202))	('patients', 'Species', '9606', (184, 192))	('miR-338-5p', 'Chemical', '-', (33, 43))	('miR-338-5p', 'Chemical', '-', (126, 136))	('miR-338-5p', 'Var', (126, 136))
43970	31646712	The patients with high serum miR-338-5p expression had significantly (P = .013) better survival rates (median survival = 58.00 months) than those with low miR-338-5p expression (median survival = 21.57 months) (Figure 6D).	('miR-338-5p', 'Chemical', '-', (155, 165))	('miR-338-5p expression', 'Var', (29, 50))	('miR-338-5p', 'Chemical', '-', (29, 39))	('high', 'Var', (18, 22))	('better', 'PosReg', (80, 86))	('patients', 'Species', '9606', (4, 12))	('survival rates', 'CPA', (87, 101))
43972	31646712	Correlation with clinicopathologic parameters showed that expression levels of miR-338-5p in pretreatment serum were inversely correlated with posttherapy pathologic ypT-stage (P = .034), ypM-stage (P = .014), overall pathologic stage (ypTNM; P = .017), and histologic grade (P = .026) (Table 1).	('miR-338-5p', 'Chemical', '-', (79, 89))	('miR-338-5p', 'Var', (79, 89))	('expression', 'MPA', (58, 68))	('ypT-stage', 'Disease', (166, 175))	('ypM-stage', 'Disease', (188, 197))	('inversely', 'NegReg', (117, 126))
43973	31646712	Furthermore, high serum miR-338-5p expression was associated with lower percentage of residual viable cells in the primary tumor collected during surgery, and with complete response to therapy (Table 1), which indicated that higher pretreatment serum miR-338-5p level could predict a better response to chemoradiotherapy.	('miR-338-5p', 'Chemical', '-', (24, 34))	('tumor', 'Disease', (123, 128))	('high', 'Var', (13, 17))	('lower', 'NegReg', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('miR-338-5p', 'Chemical', '-', (251, 261))
43975	31646712	Despite 5-FU being an antimetabolic agent widely used in treating gastrointestinal cancers, the response rate of esophageal carcinoma to 5-FU is only 15%.26, 27, 28 Emerging evidence indicates that miRNAs are associated with chemoresistance, but relatively few miRNAs were experimentally validated to have the ability to regulate the sensitivity of ESCC cells to 5-FU treatment.10, 11, 12, 29, 30, 31 Our present study found that miR-338-5p was underexpressed in 5-FU-resistant ESCC cells, and that ectopic overexpression of miR-338-5p in these cells could increase their sensitivity to 5-FU treatment both in vitro and in vivo.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (113, 133))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (66, 90))	('5-FU', 'Chemical', 'MESH:D005472', (137, 141))	('sensitivity to 5-FU treatment', 'MPA', (572, 601))	('5-FU', 'Chemical', 'MESH:D005472', (463, 467))	('gastrointestinal cancers', 'Disease', (66, 90))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (113, 133))	('5-FU', 'Chemical', 'MESH:D005472', (587, 591))	('miR-338-5p', 'Chemical', '-', (525, 535))	('5-FU', 'Chemical', 'MESH:D005472', (8, 12))	('esophageal carcinoma', 'Disease', (113, 133))	('miR-338-5p', 'Chemical', '-', (430, 440))	('5-FU', 'Chemical', 'MESH:D005472', (363, 367))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('overexpression', 'PosReg', (507, 521))	('increase', 'PosReg', (557, 565))	('miR-338-5p', 'Var', (525, 535))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
43976	31646712	We further established that miR-338-5p inhibits 5-FU chemoresistance as well as decreases the invasive and migratory potential of ESCC cells through targeting Id-1.	('miR-338-5p', 'Var', (28, 38))	('5-FU', 'Protein', (48, 52))	('Id-1', 'Gene', (159, 163))	('ESCC', 'Disease', (130, 134))	('Id-1', 'Gene', '3397', (159, 163))	('5-FU', 'Chemical', 'MESH:D005472', (48, 52))	('decreases', 'NegReg', (80, 89))	('inhibits', 'NegReg', (39, 47))	('targeting', 'Reg', (149, 158))	('miR-338-5p', 'Chemical', '-', (28, 38))
43978	31646712	Although miR-338-5p had been reported to be downregulated in non-small-cell lung carcinoma36 and glioblastoma,37, 38 we have found that its expression was reduced in the majority of ESCC.	('downregulated', 'NegReg', (44, 57))	('expression', 'MPA', (140, 150))	('reduced', 'NegReg', (155, 162))	('lung carcinoma36', 'Disease', 'MESH:D008171', (76, 92))	('miR-338-5p', 'Chemical', '-', (9, 19))	('miR-338-5p', 'Var', (9, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('ESCC', 'Disease', (182, 186))	('small-cell lung carcinoma36', 'Phenotype', 'HP:0030357', (65, 92))	('non-small-cell lung carcinoma36', 'Phenotype', 'HP:0030358', (61, 92))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))	('lung carcinoma36', 'Disease', (76, 92))
43979	31646712	Analysis of GEO datasets showed the same phenomenon in gastric, colon, and rectal cancers, thus suggesting that miR-338-5p has tumor suppressor functions in the gastrointestinal tract.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (127, 132))	('colon', 'Disease', (64, 69))	('rectal cancer', 'Phenotype', 'HP:0100743', (75, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('gastric', 'Disease', (55, 62))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('miR-338-5p', 'Chemical', '-', (112, 122))	('miR-338-5p', 'Var', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('colon', 'Disease', 'MESH:D003110', (64, 69))
43981	31646712	Our results showed that low miR-338-5p levels in serum on admission was significantly associated with poorer survival and advanced posttherapy pathologic staging.	('miR-338-5p', 'Var', (28, 38))	('poorer', 'NegReg', (102, 108))	('low', 'NegReg', (24, 27))	('survival', 'CPA', (109, 117))	('miR-338-5p', 'Chemical', '-', (28, 38))
44026	31114372	Patients who fulfilled the following inclusion criteria were selected: i)histologically confirmed ESCC patients with no distant metastases except supraclavicular lymph node metastasis; ii)Eastern Cooperative Oncology Group (ECOG) performance status <=2; iii)treated initially with CRT without neoadjuvant chemotherapy and/or salvage surgery; and iv)computed tomography (CT) and barium esophagography images available for defining clinical stage and evaluating tumor regression, from pre-CRT, at completion of CRT, and every 1-3 months subsequently.	('Oncology', 'Phenotype', 'HP:0002664', (208, 216))	('metastases', 'Disease', (128, 138))	('<=2', 'Var', (249, 252))	('CR', 'Chemical', 'MESH:D002857', (509, 511))	('ESCC', 'Disease', (98, 102))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (460, 465))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (460, 465))	('CR', 'Chemical', 'MESH:D002857', (487, 489))	('patients', 'Species', '9606', (103, 111))	('barium', 'Chemical', 'MESH:D001464', (378, 384))	('tumor', 'Disease', (460, 465))	('CR', 'Chemical', 'MESH:D002857', (281, 283))
44181	28790843	Aberrant lncRNA expression participates in carcinogenesis by disrupting the major biological processes, and could also serve as a potential diagnostic or prognostic biomarker for diverse human malignancies.	('malignancies', 'Disease', (193, 205))	('major biological processes', 'CPA', (76, 102))	('disrupting', 'NegReg', (61, 71))	('carcinogenesis', 'Disease', 'MESH:D063646', (43, 57))	('Aberrant', 'Var', (0, 8))	('carcinogenesis', 'Disease', (43, 57))	('lncRNA expression', 'Protein', (9, 26))	('human', 'Species', '9606', (187, 192))	('participates', 'Reg', (27, 39))	('malignancies', 'Disease', 'MESH:D009369', (193, 205))
44189	28790843	Our study demonstrates that the transcriptional dysregulation is the critical cause of ESCC tumorigenesis, and the two-lncRNA signature may be regarded as a novel prognostic molecular marker, which is better than traditional biomarkers.	('cause', 'Reg', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('transcriptional', 'MPA', (32, 47))	('dysregulation', 'Var', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('ESCC', 'Disease', (87, 91))	('tumor', 'Disease', (92, 97))
44190	28790843	All of patients in GSE53624 and GSE53622 were followed up for 5 years at least.	('GSE53624', 'Var', (19, 27))	('GSE53622', 'Var', (32, 40))	('patients', 'Species', '9606', (7, 15))
44191	28790843	The median follow-up time of patients in GSE53624 and GSE53622 was 32.2 and 39.5 months, respectively.	('GSE53622', 'Var', (54, 62))	('patients', 'Species', '9606', (29, 37))	('GSE53624', 'Var', (41, 49))
44222	28790843	Next, DRLs were divided into five types according to the changes of the regulation efficacy in the tumor compared with the normal cells, "loss-of-regulation" (42.66%), "gain-of-regulation" (24%), "reverse-of-regulation" (20.11%), "weaken-of-regulation" (9.15%) and "strengthen-of-regulation" (4.08%) (Figure 2A).	('regulation', 'MPA', (72, 82))	('tumor', 'Disease', (99, 104))	('reverse-of-regulation', 'Var', (197, 218))	('strengthen-of-regulation', 'PosReg', (266, 290))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('weaken-of-regulation', 'NegReg', (231, 251))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('loss-of-regulation', 'NegReg', (138, 156))	('gain-of-regulation', 'PosReg', (169, 187))
44226	28790843	A two-lncRNA combination, ADAMTS9-AS1 (ENSG00000241158.5) and AP000696.2 (ENSG00000231324.1), was identified as the optimal combination for predicting the survival of ESCC patients (Figure 3).	('ADAMTS9', 'Gene', '56999', (26, 33))	('ADAMTS9', 'Gene', (26, 33))	('ESCC', 'Disease', (167, 171))	('ENSG00000231324.1', 'Var', (74, 91))	('patients', 'Species', '9606', (172, 180))	('AS1', 'Gene', '5729', (34, 37))	('AS1', 'Gene', (34, 37))
44238	28790843	ADAMTS9-AS1 and AP000696.2 were two novel lncR-NAs without any functional annotations, except another ADAMTS9 antisense transcript.	('AS1', 'Gene', '5729', (8, 11))	('AP000696.2', 'Var', (16, 26))	('ADAMTS9', 'Gene', '56999', (102, 109))	('ADAMTS9', 'Gene', '56999', (0, 7))	('ADAMTS9', 'Gene', (102, 109))	('ADAMTS9', 'Gene', (0, 7))	('AS1', 'Gene', (8, 11))
44255	28790843	A lot of TP53 mutants can lead to the loss of its DNA-binding activity and affect its role as a TF.	('mutants', 'Var', (14, 21))	('DNA-binding', 'Interaction', (50, 61))	('TP53', 'Gene', '7157', (9, 13))	('affect', 'Reg', (75, 81))	('TP53', 'Gene', (9, 13))	('loss', 'NegReg', (38, 42))
44280	28367244	DNA methylation is the most extensively studied epigenetic modification of mammalian DNA.	('mammalian', 'Species', '9606', (75, 84))	('DNA', 'Disease', (0, 3))	('methylation', 'Var', (4, 15))
44284	28367244	By analyzing the mRNA and methylation profiles, we identified a possible correlation between Sall2 demethylation and its upregulated expression in radioresistant cells.	('expression', 'MPA', (133, 143))	('Sall2', 'Gene', (93, 98))	('demethylation', 'Var', (99, 112))	('Sall2', 'Gene', '6297', (93, 98))	('upregulated', 'PosReg', (121, 132))
44331	28367244	Table 2 and Supplementary 2 summarize the methylation frequency of each gene in the TE-1/R cells and their corresponding parent TE-1 cells.	('methylation', 'Var', (42, 53))	('TE-1/R', 'Gene', '9524', (84, 90))	('TE-1/R', 'Gene', (84, 90))
44356	28367244	Tumor suppressor DOK1 is repressed in multiple types of human tumors as a result of hypermethylation of its promoter region.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('DOK1', 'Gene', (17, 21))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('DOK1', 'Gene', '1796', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('human', 'Species', '9606', (56, 61))	('hypermethylation', 'Var', (84, 100))
44359	28367244	Epigenetics has recently emerged as one of the most exciting frontiers in the study of radioresistance of cancer cells.	('cancer', 'Disease', (106, 112))	('Epigenetics', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
44361	28367244	miR-24 was negatively regulated by hypermethylation of its precursor promoter in nasopharyngeal carcinoma radioresistance.	('hypermethylation', 'Var', (35, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('negatively', 'NegReg', (11, 21))	('miR-24', 'Gene', (0, 6))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (81, 105))	('nasopharyngeal carcinoma', 'Disease', (81, 105))	('miR-24', 'Chemical', '-', (0, 6))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (81, 105))
44362	28367244	Hypermethylation of TOPO2A is involved in the radioresistance of human laryngeal squamous cell carcinoma.	('human', 'Species', '9606', (65, 70))	('involved', 'Reg', (30, 38))	('Hypermethylation', 'Var', (0, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('TOPO2A', 'Gene', (20, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('squamous cell carcinoma', 'Disease', (81, 104))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 104))	('radioresistance', 'CPA', (46, 61))
44363	28367244	The methylation status of ERCC1 is associated with radiosensitivity in glioma cell lines.	('radiosensitivity', 'Disease', (51, 67))	('glioma', 'Disease', (71, 77))	('associated', 'Reg', (35, 45))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('ERCC1', 'Gene', '2067', (26, 31))	('ERCC1', 'Gene', (26, 31))	('methylation status', 'Var', (4, 22))
44368	28367244	Cells with deletion of Sall2 (Sall2-/- MEFs) showed reduced apoptosis with increased cell viability in response to genotoxic stress.	('Sall2', 'Gene', (30, 35))	('reduced', 'NegReg', (52, 59))	('Sall2', 'Gene', '6297', (30, 35))	('Sall2-/- MEFs', 'Gene', '6297', (30, 43))	('Sall2-/- MEFs', 'Gene', (30, 43))	('Sall2', 'Gene', (23, 28))	('deletion', 'Var', (11, 19))	('increased', 'PosReg', (75, 84))	('cell viability', 'CPA', (85, 99))	('Sall2', 'Gene', '6297', (23, 28))
44371	28367244	Moreover, restoration of Sall2 expression in cells derived from a human ovarian carcinoma suppresses growth of the cells in immunodeficient mice.	('suppresses', 'NegReg', (90, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('mice', 'Species', '10090', (140, 144))	('Sall2', 'Gene', (25, 30))	('ovarian carcinoma', 'Disease', (72, 89))	('restoration', 'Var', (10, 21))	('human', 'Species', '9606', (66, 71))	('growth of the cells in', 'CPA', (101, 123))	('expression', 'MPA', (31, 41))	('Sall2', 'Gene', '6297', (25, 30))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (72, 89))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (72, 89))
44383	28367244	Our present findings illustrate the mRNA and epigenetic changes during the radioresistance of ESCC and the important role of Sall2 in ESCC malignancy.	('radioresistance', 'CPA', (75, 90))	('mRNA', 'MPA', (36, 40))	('Sall2', 'Gene', (125, 130))	('malignancy', 'Disease', 'MESH:D009369', (139, 149))	('Sall2', 'Gene', '6297', (125, 130))	('malignancy', 'Disease', (139, 149))	('ESCC', 'Disease', (94, 98))	('epigenetic', 'Var', (45, 55))
44393	26192915	Historically studies have focused on mutation, methylation and/or loss of heterozygosity of specific target genes, most commonly p16 and TP53, to try to understand the natural history of Barrett's esophagus and to predict patients at high-risk of cancer.	('loss of', 'NegReg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (187, 206))	('p16', 'Gene', (129, 132))	('methylation', 'Var', (47, 58))	('patients', 'Species', '9606', (222, 230))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('p16', 'Gene', '1029', (129, 132))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', (137, 141))
44394	26192915	One model formulated by Maley and colleagues proposed that a mutation (most commonly inactivation of p16), that confers a selective advantage to a cell will sweep across the Barrett's segment resulting in this mutation being present in the majority of the cells in that Barrett's segment, a so-called selective sweep.	('p16', 'Gene', '1029', (101, 104))	('p16', 'Gene', (101, 104))	('mutation', 'Var', (61, 69))	('mutation', 'Var', (210, 218))
44396	26192915	This results in a cancer with a serial accumulation of mutations, including drivers and hitchhikers, a proportion of which would be present in all Barrett's epithelium.	('mutations', 'Var', (55, 64))	('results in', 'Reg', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
44398	26192915	Recent DNA sequencing studies have demonstrated a high mutational burden within EAC, and described distinct mutational signatures observed within this cancer type.	('mutational', 'Var', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('EAC', 'Disease', (80, 83))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
44400	26192915	In a study using exome sequencing data from two matched Barrett's and EAC samples, Agrawal and colleagues found that approximately 80% of the cancer mutations were already present in DNA from the adjacent Barrett's epithelium.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (149, 158))	('cancer', 'Disease', (142, 148))
44402	26192915	We recently demonstrated that putative esophageal driver genes, such as ARID1A and SMARCA4, were also recurrently mutated in patients with a very stable phenotype who had never shown any evidence of dysplasia within their Barrett's segment over multiple years of follow-up (median 58 months).	('mutated', 'Var', (114, 121))	('dysplasia', 'Disease', 'MESH:D004476', (199, 208))	('SMARCA4', 'Gene', (83, 90))	('ARID1A', 'Gene', '8289', (72, 78))	('SMARCA4', 'Gene', '6597', (83, 90))	('ARID1A', 'Gene', (72, 78))	('esophageal driver genes', 'Gene', (39, 62))	('dysplasia', 'Disease', (199, 208))	('patients', 'Species', '9606', (125, 133))
44404	26192915	In contrast, TP53 and SMAD4 mutations were highly specific to patients with HGD and EAC, respectively.	('HGD', 'Disease', (76, 79))	('TP53', 'Gene', (13, 17))	('SMAD4', 'Gene', (22, 27))	('EAC', 'Disease', (84, 87))	('SMAD4', 'Gene', '4089', (22, 27))	('TP53', 'Gene', '7157', (13, 17))	('patients', 'Species', '9606', (62, 70))	('mutations', 'Var', (28, 37))
44414	26192915	Of note, the Barrett's esophagus samples with dysplasia (either LGD, HGD or indefinite for dysplasia called by two independent expert pathologists), did not have significantly more mutations than the Barrett's esophagus samples with no dysplasia (Mann Whitney test, p=0.271).	('dysplasia', 'Disease', (46, 55))	('dysplasia', 'Disease', 'MESH:D004476', (46, 55))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (13, 32))	('dysplasia', 'Disease', (236, 245))	('dysplasia', 'Disease', (91, 100))	('mutations', 'Var', (181, 190))	('dysplasia', 'Disease', 'MESH:D004476', (91, 100))	('dysplasia', 'Disease', 'MESH:D004476', (236, 245))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (200, 219))
44417	26192915	Barrett's esophagus samples harbored TP53 mutations less commonly (9/23 (39.1%) of which 5 were dysplastic).	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (0, 19))	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('TP53', 'Gene', '7157', (37, 41))
44419	26192915	Other previously reported putative EAC driver genes, such as EYS, ARID1A and ABCB1, were mutated less commonly (<=30%) and if mutated within a patient's tissue (either Barrett's esophagus or EAC), were seldom shared (21/73, (28.8%)) between the paired Barrett's and EAC samples (Figure 1c).	('EAC', 'Disease', (35, 38))	('patient', 'Species', '9606', (143, 150))	('ABCB1', 'Gene', (77, 82))	('ABCB1', 'Gene', '5243', (77, 82))	('ARID1A', 'Gene', '8289', (66, 72))	('ARID1A', 'Gene', (66, 72))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (168, 187))	('mutated', 'Var', (89, 96))	('EYS', 'Gene', '346007', (61, 64))	('EYS', 'Gene', (61, 64))
44434	26192915	Three SNVs, all occurring in non-coding regions and representing the most-recent common ancestor (chr4:33658353 T>C, chr13:88285478_A>C and chr18:11483749_A>C), were found in all six clones providing evidence for an initial clonal sweep of the patient's Barrett's segment.	('88285478_A>C', 'Mutation', 'g.88285478A>C', (123, 135))	('chr4:33658353', 'Var', (98, 111))	('33658353 T>C', 'Mutation', 'g.33658353T>C', (103, 115))	('patient', 'Species', '9606', (244, 251))	('chr18:11483749_A', 'Var', (140, 156))	('11483749_A>C', 'Mutation', 'g.11483749A>C', (146, 158))
44435	26192915	Clone 3 had 9p LOH, a common event observed in non-dysplastic Barrett's esophagus and one that has been previously shown to impart selective advantage to Barrett's esophagus cells, however this clone did not appear to seed further clones within this patient's Barrett's segment (Figure 5c).	('9p LOH', 'Var', (12, 18))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (47, 81))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (154, 173))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (62, 81))	("non-dysplastic Barrett's esophagus", 'Disease', (47, 81))	('patient', 'Species', '9606', (250, 257))
44438	26192915	In addition to multiple regions of Barrett's esophagus with no dysplasia, patient AHM1051 has multiple areas with cellular abnormalities which were graded according to the degree of dysplasia by consensus review by two expert gastrointestinal pathologists.	('dysplasia', 'Disease', (182, 191))	('patient', 'Species', '9606', (74, 81))	('dysplasia', 'Disease', 'MESH:D004476', (182, 191))	('dysplasia', 'Disease', 'MESH:D004476', (63, 72))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (35, 54))	('AHM1051', 'Var', (82, 89))	('dysplasia', 'Disease', (63, 72))
44443	26192915	Given the pathogenic importance of TP53, in a more targeted approach we also mapped mutations at this locus within this patient's Barrett's segment.	('mutations', 'Var', (84, 93))	('patient', 'Species', '9606', (120, 127))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))
44444	26192915	TP53 sequencing on the Cytosponge sample, identified a dominant TP53 mutation (chr17:7577538 C>T) which was also identified in the WGS.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('7577538 C>T', 'Mutation', 'rs11540652', (85, 96))	('chr17:7577538', 'Var', (79, 92))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))
44445	26192915	This particular TP53 mutation established itself in Clone 2 (VAF between 0.28 - 0.56) and was therefore also present in all the daughter clones (i.e.	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))	('mutation', 'Var', (21, 29))
44446	26192915	The presence of a TP53 mutation in non-dysplastic Barrett's esophagus from a patient with early cancer is similar to that seen in the WGS data which showed that 4/17 (23.5%) non-dysplastic Barrett's samples taken adjacent to EAC contained TP53 mutations.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (50, 69))	('TP53', 'Gene', '7157', (18, 22))	('mutation', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	("non-dysplastic Barrett's esophagus", 'Disease', (35, 69))	('TP53', 'Gene', (18, 22))	('TP53', 'Gene', '7157', (239, 243))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (244, 253))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (35, 69))	('patient', 'Species', '9606', (77, 84))	('cancer', 'Disease', (96, 102))	('TP53', 'Gene', (239, 243))	('contained', 'Reg', (229, 238))
44447	26192915	These data from patients who have progressed to cancer should not be confused with studies that look at the TP53 mutation prevalence in non-dysplastic Barrett's esophagus from patients who never progress to dysplasia and/or EAC .	('patients', 'Species', '9606', (176, 184))	('mutation', 'Var', (113, 121))	("non-dysplastic Barrett's esophagus", 'Disease', (136, 170))	('TP53', 'Gene', '7157', (108, 112))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (136, 170))	('TP53', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (16, 24))	('dysplasia', 'Disease', (207, 216))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (151, 170))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('dysplasia', 'Disease', 'MESH:D004476', (207, 216))	('EAC', 'Disease', (224, 227))
44477	26192915	Identification of somatic single nucleotide variants (SNVs) and somatic small indels (<50bp) was performed by Strelka in the 12 Barrett's esophagus samples from patient AHM1051 using the duodenum sample as the matching normal sample and in both cancer and Barrett's esophagus samples using the matched normal for the patients with EAC.	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('patient', 'Species', '9606', (161, 168))	('Barrett', 'Disease', (128, 135))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (256, 275))	('cancer', 'Disease', (245, 251))	('single nucleotide variants', 'Var', (26, 52))	('patient', 'Species', '9606', (317, 324))	('patients', 'Species', '9606', (317, 325))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (128, 147))
44503	26218285	Recently, several lines of evidence revealed that miRNAs may influence the patients' response to chemotherapy.	('influence', 'Reg', (61, 70))	('miRNAs', 'Var', (50, 56))	('patients', 'Species', '9606', (75, 83))	('response to chemotherapy', 'CPA', (85, 109))
44556	26218285	To determine whether modulation of let-7a expression impacts the epirubicin response, we enhanced let-7a expression in the SK-3rd sphere cell line.	('modulation', 'Var', (21, 31))	('epirubicin', 'Chemical', 'MESH:D015251', (65, 75))	('let-7a', 'Gene', (98, 104))	('impacts', 'Reg', (53, 60))	('SK-3', 'Gene', (123, 127))	('enhanced', 'PosReg', (89, 97))	('let-7a', 'Gene', (35, 41))	('let-7a', 'Chemical', '-', (35, 41))	('epirubicin response', 'MPA', (65, 84))	('let-7a', 'Chemical', '-', (98, 104))	('expression', 'MPA', (105, 115))	('SK-3', 'Gene', '3782', (123, 127))
44557	26218285	Using the MTT assay, we found that let-7a upregulation in the epirubicin-resistant SK-3rd sphere cell line sensitized this cell line to epirubicin because the IC50 for epirubicin in the let-7a transfected cells and the non-transfected cells was 1.53+-0.07 mug/mL and 2.25+-0.11 mug/mL, respectively (P<0.01) (Fig 4).	('let-7a', 'Var', (186, 192))	('epirubicin', 'Chemical', 'MESH:D015251', (62, 72))	('MTT', 'Chemical', '-', (10, 13))	('SK-3', 'Gene', '3782', (83, 87))	('let-7a', 'Gene', (35, 41))	('let-7a', 'Chemical', '-', (35, 41))	('let-7a', 'Chemical', '-', (186, 192))	('epirubicin', 'Chemical', 'MESH:D015251', (136, 146))	('transfected', 'Var', (193, 204))	('SK-3', 'Gene', (83, 87))	('epirubicin', 'Chemical', 'MESH:D015251', (168, 178))	('upregulation', 'PosReg', (42, 54))
44574	26218285	In esophageal cancer cells, let-7 expression may modulate the chemosensitivity to genotoxic chemotherapy in esophageal cancer cells through the IL-6/STAT3 pathway.	('STAT3', 'Gene', '6774', (149, 154))	('esophageal cancer', 'Disease', (3, 20))	('STAT3', 'Gene', (149, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('chemosensitivity', 'CPA', (62, 78))	('esophageal cancer', 'Disease', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('expression', 'Var', (34, 44))	('let-7', 'Chemical', '-', (28, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('let-7', 'Gene', (28, 33))	('IL-6', 'Gene', (144, 148))	('modulate', 'Reg', (49, 57))	('IL-6', 'Gene', '3569', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
44578	26218285	In the present study, we found that upregulating the expression of let-7a can enhance apoptosis and reduce the survival of SK-3rd sphere cells exposed to epirubicin, and let-7a miRNA was subsequently found to enhance the chemosensitivity of SK-3rd sphere cells.	('enhance', 'PosReg', (78, 85))	('enhance', 'PosReg', (209, 216))	('SK-3', 'Gene', (123, 127))	('let-7a', 'Var', (170, 176))	('let-7a', 'Chemical', '-', (67, 73))	('SK-3', 'Gene', '3782', (241, 245))	('reduce', 'NegReg', (100, 106))	('let-7a', 'Chemical', '-', (170, 176))	('epirubicin', 'Chemical', 'MESH:D015251', (154, 164))	('survival', 'CPA', (111, 119))	('SK-3', 'Gene', (241, 245))	('expression', 'MPA', (53, 63))	('upregulating', 'PosReg', (36, 48))	('let-7a', 'Gene', (67, 73))	('apoptosis', 'CPA', (86, 95))	('SK-3', 'Gene', '3782', (123, 127))
44581	26218285	Second, we did not investigate the mechanisms of let-7a that are involved in inducing apoptosis in SK-3rd sphere cells.	('SK-3', 'Gene', '3782', (99, 103))	('SK-3', 'Gene', (99, 103))	('let-7a', 'Chemical', '-', (49, 55))	('let-7a', 'Var', (49, 55))
44634	25389033	Subsequent stimulation with NGF caused rapid phosphorylation of tyrosine residues Tyr674/675 in the catalytic domain of NTRK1 (Figure 5A, B, pNTRK1 panel), as well as increased phosphorylation of ERK1/2 (Figure 5B, pERK1/2 panel) in IL-13-treated cells.	('Tyr674', 'Chemical', '-', (82, 88))	('phosphorylation', 'MPA', (45, 60))	('increased', 'PosReg', (167, 176))	('Tyr674/675', 'Var', (82, 92))	('pERK', 'Gene', '9451', (215, 219))	('tyrosine', 'Chemical', 'MESH:D014443', (64, 72))	('pERK', 'Gene', (215, 219))	('NTRK1', 'Gene', (120, 125))	('phosphorylation', 'MPA', (177, 192))	('ERK1/2', 'Protein', (196, 202))
44649	25389033	We further hypothesized that inhibition of NTRK1 kinase activity will prevent induction of EGR genes following NGF stimulation.	('induction', 'MPA', (78, 87))	('EGR', 'Gene', (91, 94))	('prevent', 'NegReg', (70, 77))	('NTRK1', 'Gene', (43, 48))	('inhibition', 'Var', (29, 39))	('EGR', 'Gene', '13653', (91, 94))
44671	25389033	Epigenetics is considered as a possible mechanism involved in the development of many disorders, including allergic diseases .	('allergic diseases', 'Disease', 'MESH:D004342', (107, 124))	('allergic diseases', 'Disease', (107, 124))	('Epigenetics', 'Var', (0, 11))	('involved', 'Reg', (50, 58))
44674	25389033	Among the 90 RTKs identified in the human genome , NTRK1 was the only one induced both transcriptionally and epigenetically by IL-13 in esophageal epithelial cells.	('IL-13', 'Gene', (127, 132))	('RTK', 'Gene', '5979', (13, 16))	('epigenetically', 'Var', (109, 123))	('NTRK1', 'Gene', (51, 56))	('induced', 'Reg', (74, 81))	('RTK', 'Gene', (13, 16))	('human', 'Species', '9606', (36, 41))
44682	25389033	The increasingly recognized link between NTRK1 signaling and cancer progression  as well as the critical role of NTRK1 in pain sensitivity  has stimulated development of highly specific NTRK1 inhibitors, such as AR-786, AR-256 and AR-618 .	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('AR-786', 'Var', (212, 218))	('cancer', 'Disease', (61, 67))	('NTRK1', 'Gene', (186, 191))	('pain', 'Phenotype', 'HP:0012531', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('pain', 'Disease', 'MESH:D010146', (122, 126))	('pain', 'Disease', (122, 126))
44692	25389033	Tyrosine kinase inhibitors crizotinib (PZ0191) and lestaurtinib (CEP-701 hydrate, C7869) were purchased from Sigma-Aldrich (Sigma-Aldrich Corp. St. Louis, MO) and were dissolved in DMSO to stock concentration of 10 mM.	('rat', 'Species', '10116', (76, 79))	('CEP-701', 'Chemical', 'MESH:C119379', (65, 72))	('Sigma-Aldrich Corp', 'Disease', 'MESH:D014923', (124, 142))	('lestaurtinib', 'Chemical', 'MESH:C119379', (51, 63))	('PZ0191', 'Chemical', '-', (39, 45))	('Sigma-Aldrich Corp', 'Disease', (124, 142))	('Tyrosine kinase', 'Gene', (0, 15))	('DMSO', 'Chemical', 'MESH:D004121', (181, 185))	('crizotinib', 'Chemical', 'MESH:D000077547', (27, 37))	('Tyrosine kinase', 'Gene', '7294', (0, 15))	('rat', 'Species', '10116', (202, 205))	('PZ0191', 'Var', (39, 45))
44693	25389033	Rabbit antibodies against TrkA (14G6) (#2508), phospho-TrkA (Tyr674/675)/TrkB (Tyr706/707) (#C50F3); phospho-p44/42 MAPK (ERK1/2) (Thr202/Tyr204) (#9101), p44/42 MAPK (ERK1/2) (137F5) (#4695); phospho-STAT6 (Tyr641) (C11A12); EGR1 (44D5) (#4154); EGR3 (#2559), p38 MAPK (D13E1) XP  (#8690); mouse monoclonal antibody against p44/42 MAPK (Erk1/2) (3A7, #9107) and anti-rabbit IgG, HRP-linked (#7074) were purchased from Cell Signaling (Cell Signaling Technology, MA).	('#7074', 'Var', (392, 397))	('p44', 'Gene', '10561', (155, 158))	('Erk1/2', 'Gene', '5595;5594', (338, 344))	('TrkA', 'Gene', '4914', (26, 30))	('p38', 'Gene', '5594', (261, 264))	('TrkA', 'Gene', '4914', (55, 59))	('TrkB', 'Gene', '4915', (73, 77))	('rabbit', 'Species', '9986', (368, 374))	('mouse', 'Species', '10090', (291, 296))	('Rabbit', 'Species', '9986', (0, 6))	('TrkB', 'Gene', (73, 77))	('Tyr674', 'Chemical', '-', (61, 67))	('p44', 'Gene', (325, 328))	('TrkA', 'Gene', (26, 30))	('p44', 'Gene', '10561', (325, 328))	('Erk1/2', 'Gene', (338, 344))	('TrkA', 'Gene', (55, 59))	('p38', 'Gene', (261, 264))	('p44', 'Gene', (109, 112))	('p44', 'Gene', '10561', (109, 112))	('p44', 'Gene', (155, 158))
44768	25584171	Studies showed that eradication of H.pylori has been successful in reducing gastric cancer risk.	('reducing gastric cancer', 'Phenotype', 'HP:0006753', (67, 90))	('reducing', 'NegReg', (67, 75))	('eradication', 'Var', (20, 31))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('H.pylori', 'Gene', (35, 43))	('H.pylori', 'Species', '210', (35, 43))	('gastric cancer', 'Disease', (76, 90))
44801	24216130	The A549 cell line transfected with the miR-10b exhibited significantly increased proliferation, migration, and invasion capacities when compared with the control cells (P < 0.05).	('A549', 'CellLine', 'CVCL:0023', (4, 8))	('migration', 'CPA', (97, 106))	('increased', 'PosReg', (72, 81))	('invasion capacities', 'CPA', (112, 131))	('proliferation', 'CPA', (82, 95))	('miR-10b', 'Var', (40, 47))
44803	24216130	In this study, we found that miR-10b is a tumor enhancer in NSCLC.	('enhancer', 'PosReg', (48, 56))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('NSCLC', 'Disease', (60, 65))	('miR-10b', 'Var', (29, 36))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
44808	24216130	Recently, an increasing number of reports have shown that non-coding small RNAs may be involved in NSCLC pathogenesis, providing new insights into disease biology.	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('non-coding small RNAs', 'Var', (58, 79))	('involved', 'Reg', (87, 95))	('NSCLC', 'Disease', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
44809	24216130	The miRNAs are endogenous small non-coding RNAs of 21 to 24 nucleotides that regulate gene expression by base pairing with target mRNAs in the 3'-untranslated region (3'-UTR), leading to mRNA cleavage or translational repression.	('base pairing', 'Var', (105, 117))	('regulate', 'Reg', (77, 85))	('miR', 'Gene', (4, 7))	('translational repression', 'MPA', (204, 228))	('miR', 'Gene', '220972', (4, 7))	('gene expression', 'MPA', (86, 101))	('mRNA cleavage', 'MPA', (187, 200))
44812	24216130	Dysregulation of miRNAs may lead to alterations in cellular differentiation, proliferation, and apoptotic processes of cancer.	('Dysregulation', 'Var', (0, 13))	('cellular differentiation', 'CPA', (51, 75))	('miR', 'Gene', (17, 20))	('miR', 'Gene', '220972', (17, 20))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('lead to alterations', 'Reg', (28, 47))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('proliferation', 'CPA', (77, 90))	('apoptotic processes', 'CPA', (96, 115))
44813	24216130	Indeed, deregulation of miRNAs is closely associated with tumor initiation, promotion, and progression through the regulation of key oncogenes or tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor initiation', 'Disease', 'MESH:D009369', (58, 74))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('associated', 'Reg', (42, 52))	('promotion', 'PosReg', (76, 85))	('tumor', 'Disease', (146, 151))	('tumor initiation', 'Disease', (58, 74))	('deregulation', 'Var', (8, 20))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
44818	24216130	Silencing of miR-10b significantly decreases miR-10b levels and increases the levels of HOXD10 to inhibit metastasis.	('HOXD10', 'Gene', (88, 94))	('decreases', 'NegReg', (35, 44))	('miR-10b', 'Gene', (13, 20))	('inhibit', 'NegReg', (98, 105))	('HOXD10', 'Gene', '3236', (88, 94))	('miR-10b levels', 'MPA', (45, 59))	('metastasis', 'CPA', (106, 116))	('Silencing', 'Var', (0, 9))	('increases', 'PosReg', (64, 73))
44822	24216130	In this study, we focused on the expression and roles of miR-10b in the A549 cell line, and found that miR-10b promotes the proliferation and invasion of A549 cells in vitro.	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('proliferation', 'CPA', (124, 137))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('miR-10b', 'Var', (103, 110))	('promotes', 'PosReg', (111, 119))	('invasion', 'CPA', (142, 150))
44833	24216130	Cells were collected after miR-10b transfection for 72 hours, and the translocation of phosphatidylserine in treated cells was detected using the Annexin-V-FLUOS Staining Kit (Roche Applied Science, Mannheim, Germany).	('Annexin-V', 'Gene', '308', (146, 155))	('transfection', 'Var', (35, 47))	('Annexin-V', 'Gene', (146, 155))	('translocation', 'MPA', (70, 83))
44847	24216130	The results of this assay showed that miR-10b could enhance the A549 cell growth remarkably (Figure 2A) and also in H1299 cells (Figure 2B), and provides evidence that miR-10b plays a key role in promoting the development of lung cancer.	('promoting', 'PosReg', (196, 205))	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('miR-10b', 'Var', (168, 175))	('miR-10b', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('lung cancer', 'Disease', 'MESH:D008175', (225, 236))	('H1299', 'CellLine', 'CVCL:0060', (116, 121))	('enhance', 'PosReg', (52, 59))	('A549', 'CellLine', 'CVCL:0023', (64, 68))	('A549 cell growth', 'CPA', (64, 80))	('lung cancer', 'Disease', (225, 236))
44848	24216130	To test whether miR-10b affected the behavior of A549 cells, we detected the cell cycle of A549 cells with miR-10b or anti-miR-10b transfection.	('anti-miR-10b transfection', 'Var', (118, 143))	('miR-10b', 'Gene', (107, 114))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('detected', 'Reg', (64, 72))	('transfection', 'Var', (131, 143))	('A549', 'CellLine', 'CVCL:0023', (91, 95))	('cell cycle', 'CPA', (77, 87))
44849	24216130	Compared with the cells transfected with the negative control miRNA, the proliferation of A549 cells transfected with anti-miR-10b was significantly decreased (Figure 2C), while A549 cell growth increased in miR-10b transfection, indicating that miR-10b may increase A549 cell proliferation.	('miR', 'Gene', (208, 211))	('increase', 'PosReg', (258, 266))	('A549', 'CellLine', 'CVCL:0023', (178, 182))	('proliferation', 'CPA', (73, 86))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (123, 126))	('miR', 'Gene', (62, 65))	('transfection', 'Var', (216, 228))	('A549', 'CellLine', 'CVCL:0023', (90, 94))	('miR', 'Gene', '220972', (208, 211))	('decreased', 'NegReg', (149, 158))	('A549', 'CellLine', 'CVCL:0023', (267, 271))	('increased', 'PosReg', (195, 204))	('miR', 'Gene', '220972', (246, 249))	('miR', 'Gene', (246, 249))
44851	24216130	MiR-10b was significantly overexpressed after transfection of the miR-10b.	('MiR-10b', 'Gene', '406903', (0, 7))	('MiR-10b', 'Gene', (0, 7))	('miR-10b', 'Gene', (66, 73))	('transfection', 'Var', (46, 58))	('overexpressed', 'PosReg', (26, 39))
44852	24216130	As shown in Figure 3, the number of invading A549 and H1299 cells transfected with the miR-10b was greater than the control group (P < 0.05).	('greater', 'PosReg', (99, 106))	('A549', 'CellLine', 'CVCL:0023', (45, 49))	('miR-10b', 'Var', (87, 94))	('H1299', 'CellLine', 'CVCL:0060', (54, 59))
44855	24216130	A549 cells transfected with the miR-10b or anti-miR-10b were applied to wound healing assays.	('anti-miR-10b', 'Var', (43, 55))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('miR-10b', 'Var', (32, 39))
44856	24216130	The results showed that miR-10b significantly increased the migration of A549 cells, whereas anti-miR-10b decreased the migration of A549 cells (Figure 4).	('decreased', 'NegReg', (106, 115))	('anti-miR-10b', 'Var', (93, 105))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('increased', 'PosReg', (46, 55))	('miR-10b', 'Var', (24, 31))	('migration', 'CPA', (60, 69))	('A549', 'CellLine', 'CVCL:0023', (133, 137))
44858	24216130	After successful transfection of miR-10b and anti-miR-10b, we found that overexpression of miR-10b did not significantly inhibit the early and late apoptosis, and total apoptotic cell death in A549 cells (Figure 5).	('inhibit', 'NegReg', (121, 128))	('transfection', 'Var', (17, 29))	('A549', 'CellLine', 'CVCL:0023', (193, 197))	('miR-10b', 'Var', (91, 98))	('death', 'Disease', 'MESH:D003643', (184, 189))	('death', 'Disease', (184, 189))	('anti-miR-10b', 'Var', (45, 57))	('miR-10b', 'Var', (33, 40))
44860	24216130	Western blot analysis showed that the KLF4 protein expression levels were significantly increased after miR-10b transfection; in contrast, the anti-miR-10b transfection effectively downregulated the KLF4 protein expression levels as examined by western blot analysis (Figure 6), which indicated that the KLF4 gene was not the indirect target of miR-10b.	('KLF4', 'Gene', (304, 308))	('transfection', 'Var', (112, 124))	('downregulated', 'NegReg', (181, 194))	('KLF4', 'Gene', '9314', (304, 308))	('KLF4', 'Gene', (38, 42))	('KLF4', 'Gene', '9314', (38, 42))	('KLF4', 'Gene', '9314', (199, 203))	('increased', 'PosReg', (88, 97))	('KLF4', 'Gene', (199, 203))	('anti-miR-10b', 'Var', (143, 155))	('miR-10b', 'Gene', (104, 111))	('transfection', 'Var', (156, 168))
44861	24216130	In recent years, molecular genetic studies have shown that abnormalities in non-coding miRNAs represent the most recent class of epigenetic mechanisms, which can also contribute to the different steps of tumor development by regulating genes that control cellular processes such as the cell cycle and apoptosis.	('apoptosis', 'CPA', (301, 310))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('genes', 'Gene', (236, 241))	('cell cycle', 'CPA', (286, 296))	('contribute', 'Reg', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('abnormalities', 'Var', (59, 72))	('regulating', 'Reg', (225, 235))
44863	24216130	Upregulation of miR-10b expression has been detected in metastatic breast cancer, esophageal cancer, malignant glioma, pancreatic cancer, and others, and miR-10b can positively regulate migration and invasion in both breast cancer and esophageal cancer cell lines.	('esophageal cancer', 'Disease', (235, 252))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('pancreatic cancer', 'Disease', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('esophageal cancer', 'Disease', (82, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('miR-10b', 'Var', (154, 161))	('malignant glioma', 'Disease', (101, 117))	('malignant glioma', 'Disease', 'MESH:D005910', (101, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (119, 136))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('miR-10b', 'Gene', (16, 23))	('breast cancer', 'Disease', (67, 80))	('Upregulation', 'PosReg', (0, 12))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('regulate', 'Reg', (177, 185))	('breast cancer', 'Disease', (217, 230))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (235, 252))	('pancreatic cancer', 'Disease', 'MESH:D010190', (119, 136))
44866	24216130	We showed that transfected miR-10b was associated with growth promotion and invasiveness of A549 cells, and these findings are consistent with a previous study.	('invasiveness of A549 cells', 'CPA', (76, 102))	('growth promotion', 'CPA', (55, 71))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('miR-10b', 'Gene', (27, 34))	('transfected', 'Var', (15, 26))
44867	24216130	showed that miR-10b decreased the expression of HOXD10, resulting in increased expression of RhoC.	('expression', 'MPA', (34, 44))	('expression', 'MPA', (79, 89))	('decreased', 'NegReg', (20, 29))	('increased', 'PosReg', (69, 78))	('HOXD10', 'Gene', '3236', (48, 54))	('RhoC', 'Gene', (93, 97))	('RhoC', 'Gene', '389', (93, 97))	('HOXD10', 'Gene', (48, 54))	('miR-10b', 'Var', (12, 19))
44874	24216130	In conclusion, we found that miR-10b is a tumor enhancer in NSCLC.	('enhancer', 'PosReg', (48, 56))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('NSCLC', 'Disease', (60, 65))	('miR-10b', 'Var', (29, 36))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
44881	24967419	Changes in serum IL-2 and IFN-gamma concentrations were further associated with increased risks of acute hematologic toxicity and acute organ toxicity of the esophagus, lung, and skin.	('associated', 'Reg', (64, 74))	('hematologic toxicity', 'Disease', (105, 125))	('toxicity', 'Disease', 'MESH:D064420', (142, 150))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))	('toxicity', 'Disease', (142, 150))	('toxicity', 'Disease', (117, 125))	('hematologic toxicity', 'Disease', 'MESH:D006402', (105, 125))	('Changes', 'Var', (0, 7))	('IFN-gamma', 'Gene', '3458', (26, 35))	('IFN-gamma', 'Gene', (26, 35))	('IL-2', 'Gene', (17, 21))	('IL-2', 'Gene', '3558', (17, 21))
44932	24967419	As shown in Figure 2, we also found that serum IL-2 and IFN-gamma concentrations in the CR + PR group were both higher than the corresponding concentrations in the SD + PD group at the same time during radiotherapy.	('IFN-gamma', 'Gene', '3458', (56, 65))	('IFN-gamma', 'Gene', (56, 65))	('higher', 'PosReg', (112, 118))	('CR + PR', 'Var', (88, 95))	('SD', 'Chemical', '-', (164, 166))	('IL-2', 'Gene', '3558', (47, 51))	('PD', 'Disease', 'MESH:D010300', (169, 171))	('IL-2', 'Gene', (47, 51))
44935	24967419	Our results suggest that changes in serum IL-2 and IFN-gamma concentrations are associated with an increased probability of acute hematologic toxicity.	('IFN-gamma', 'Gene', '3458', (51, 60))	('IFN-gamma', 'Gene', (51, 60))	('IL-2', 'Gene', '3558', (42, 46))	('IL-2', 'Gene', (42, 46))	('hematologic toxicity', 'Disease', (130, 150))	('changes', 'Var', (25, 32))	('hematologic toxicity', 'Disease', 'MESH:D006402', (130, 150))
44936	24967419	Further, the results suggest that changes in serum IFN-gamma concentrations are associated with an increased probability of acute organ toxicity of the esophagus and that changes in serum IFN-gamma concentrations are associated with an increased probability of acute organ toxicity of the lung or skin.	('IFN-gamma', 'Gene', '3458', (51, 60))	('IFN-gamma', 'Gene', (51, 60))	('toxicity', 'Disease', 'MESH:D064420', (136, 144))	('toxicity', 'Disease', (136, 144))	('IFN-gamma', 'Gene', '3458', (188, 197))	('toxicity of the lung', 'Disease', (273, 293))	('changes', 'Var', (171, 178))	('changes', 'Var', (34, 41))	('toxicity', 'Disease', 'MESH:D064420', (273, 281))	('toxicity of the lung', 'Disease', 'MESH:D008171', (273, 293))	('toxicity', 'Disease', (273, 281))	('IFN-gamma', 'Gene', (188, 197))
44955	24967419	Further, changes in the IL-2 and IFN-gamma serum concentrations were associated with increased probabilities of acute hematologic toxicity and acute organ toxicity of the esophagus, lung, and skin.	('IL-2', 'Gene', '3558', (24, 28))	('changes', 'Var', (9, 16))	('toxicity', 'Disease', 'MESH:D064420', (130, 138))	('IL-2', 'Gene', (24, 28))	('toxicity', 'Disease', (130, 138))	('hematologic toxicity', 'Disease', 'MESH:D006402', (118, 138))	('IFN-gamma', 'Gene', '3458', (33, 42))	('IFN-gamma', 'Gene', (33, 42))	('toxicity', 'Disease', (155, 163))	('toxicity', 'Disease', 'MESH:D064420', (155, 163))	('hematologic toxicity', 'Disease', (118, 138))
44962	23667679	It has also been reported that inactive ALDH2*1/*2 and less-active ADH1B*1/*1, and smoking, are risk factors for esophageal SCC.	('ALDH2', 'Gene', (40, 45))	('ADH1B', 'Gene', (67, 72))	('ADH1B', 'Gene', '125', (67, 72))	('inactive', 'Var', (31, 39))	('esophageal SCC', 'Disease', (113, 127))	('esophageal SCC', 'Disease', 'MESH:D004941', (113, 127))	('ALDH2', 'Gene', '217', (40, 45))
44969	23667679	Telomere shortening may not generate cancer directly, but may create conditions under which SCC can develop more easily, depending on subsequent exposure to carcinogens.	('Telomere shortening', 'Phenotype', 'HP:0031413', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('SCC', 'Gene', '6317', (92, 95))	('Telomere shortening', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('SCC', 'Gene', (92, 95))
45039	23667679	Both the mean and median NTCRs were significantly smaller in the group with multiple DIULs than in the group without multiple DIULs (p = 0.0403, and 0.0275, respectively) (Fig.	('NTCRs', 'CPA', (25, 30))	('DIULs', 'Chemical', '-', (126, 131))	('DIULs', 'Chemical', '-', (85, 90))	('NTCR', 'Chemical', '-', (25, 29))	('multiple DIULs', 'Var', (76, 90))	('smaller', 'NegReg', (50, 57))
45070	23667679	Like p53 alterations, shortening of telomere length represents a very common molecular process in human neoplastic initiation and progression, and reflects the DIULs per se rather than the causative impact of ALDH2 and ADH1B genotype on the development of DIULs.	('shortening of telomere', 'Phenotype', 'HP:0031413', (22, 44))	('men', 'Species', '9606', (248, 251))	('neoplastic initiation', 'Disease', (104, 125))	('ALDH2', 'Gene', '217', (209, 214))	('ALDH2', 'Gene', (209, 214))	('alterations', 'Var', (9, 20))	('DIULs', 'Chemical', '-', (160, 165))	('shortening', 'Var', (22, 32))	('ADH1B', 'Gene', (219, 224))	('p53', 'Gene', (5, 8))	('neoplastic initiation', 'Disease', 'MESH:D007319', (104, 125))	('DIULs', 'Chemical', '-', (256, 261))	('p53', 'Gene', '7157', (5, 8))	('telomere length', 'MPA', (36, 51))	('ADH1B', 'Gene', '125', (219, 224))	('human', 'Species', '9606', (98, 103))
45071	23667679	In any event, telomere shortening may not cause cancer directly, but may create conditions in which SCC can develop more easily, if subsequent exposure to carcinogens occurs.	('SCC', 'Gene', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('telomere shortening', 'Var', (14, 33))	('SCC', 'Gene', '6317', (100, 103))	('create', 'Reg', (73, 79))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('telomere shortening', 'Phenotype', 'HP:0031413', (14, 33))
45084	33519139	In vivo assays showed circAKT3 knockdown inhibited growth of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('growth', 'CPA', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('circAKT3', 'Gene', '10000', (22, 30))	('inhibited', 'NegReg', (41, 50))	('circAKT3', 'Gene', (22, 30))	('esophageal cancer', 'Disease', (61, 78))	('knockdown', 'Var', (31, 40))
45093	33519139	In tumor tissues and cell lines, the aberrant expression of circRNAs is involved in the regulation of malignant phenotypes of tumor cells.	('tumor', 'Disease', (3, 8))	('circRNAs', 'Gene', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('involved', 'Reg', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('aberrant', 'Var', (37, 45))	('tumor', 'Disease', (126, 131))
45137	33519139	Next, siRNAs against circAKT3 were transfected into TE-1 cells, and qRT-PCR analysis revealed a marked efficiency of circAKT3 knockdown (Figure 1C).	('circAKT3', 'Gene', (21, 29))	('circAKT3', 'Gene', '10000', (117, 125))	('circAKT3', 'Gene', (117, 125))	('TE-1', 'CellLine', 'CVCL:1759', (52, 56))	('circAKT3', 'Gene', '10000', (21, 29))	('knockdown', 'Var', (126, 135))
45141	33519139	We also found that circAKT3 knockdown suppressed migration and invasion of TE-1 cells, while circAKT3 overexpression exerted the opposite role by conducting the wound healing assay and Transwell assay, respectively (Figure 1G and 1H).	('TE-1', 'CellLine', 'CVCL:1759', (75, 79))	('circAKT3', 'Gene', '10000', (93, 101))	('wound healing assay', 'CPA', (161, 180))	('circAKT3', 'Gene', (19, 27))	('circAKT3', 'Gene', (93, 101))	('suppressed', 'NegReg', (38, 48))	('circAKT3', 'Gene', '10000', (19, 27))	('knockdown', 'Var', (28, 37))	('invasion of TE-1 cells', 'CPA', (63, 85))
45172	33519139	Finally, we found circAKT3 knockdown inhibited growth of esophageal cancer in vivo.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('circAKT3', 'Gene', '10000', (18, 26))	('knockdown', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('inhibited', 'NegReg', (37, 46))	('circAKT3', 'Gene', (18, 26))	('esophageal cancer', 'Disease', (57, 74))	('growth', 'CPA', (47, 53))
45174	33519139	A recent study reported that circZNF292 is upregulated in the esophageal cancer cell line Eca-109, and inhibition of circZNF292 enhanced the expression of miR-206 to limit the proliferative, migratory, and invasive ability of Eca-109 cells.	('proliferative', 'CPA', (176, 189))	('upregulated', 'PosReg', (43, 54))	('circZNF292', 'Gene', (117, 127))	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('miR-206', 'Gene', (155, 162))	('enhanced', 'PosReg', (128, 136))	('circZNF292', 'Gene', (29, 39))	('limit', 'NegReg', (166, 171))	('expression', 'MPA', (141, 151))	('inhibition', 'Var', (103, 113))	('miR-206', 'Gene', '406989', (155, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('invasive ability of Eca-109', 'CPA', (206, 233))
45188	33519139	The in vitro and in vivo experiments manifest that RHOC enhanced the proliferative and invasive capacity of esophageal cancer cells.	('invasive capacity', 'CPA', (87, 104))	('esophageal cancer', 'Disease', (108, 125))	('enhanced', 'PosReg', (56, 64))	('RHOC', 'Var', (51, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('proliferative', 'CPA', (69, 82))
45284	32372963	It has been shown that regulation of Treg cells can increase immune protection from tumor-associated antigens that are expressed as self-antigens.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Treg', 'Chemical', '-', (37, 41))	('increase', 'PosReg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('regulation', 'Var', (23, 33))	('tumor', 'Disease', (84, 89))	('immune protection', 'CPA', (61, 78))
45293	32372963	It was found that FZQJ could alleviate chemotherapy induced stresses including white blood cell and platelet destruction, and reduction of CD3+ and CD4+ T lymphocytes.	('stresses', 'Disease', 'MESH:D000079225', (60, 68))	('white', 'CPA', (79, 84))	('FZQJ', 'Var', (18, 22))	('platelet destruction', 'CPA', (100, 120))	('stresses', 'Disease', (60, 68))	('reduction', 'NegReg', (126, 135))	('CD3', 'Gene', (139, 142))	('CD3', 'Gene', '12503', (139, 142))
45294	32372963	FZQJ could also help maintain the concentration of hemoglobin, prevent the loss of body weight, and increase serum TNF-alpha and IL-2 levels, thus alleviating the side effects of chemotherapy (in this case cyclophosphamide or CTX).	('concentration', 'MPA', (34, 47))	('body weight', 'MPA', (83, 94))	('serum TNF-alpha', 'MPA', (109, 124))	('FZQJ', 'Var', (0, 4))	('cyclophosphamide', 'MPA', (206, 222))	('CTX', 'Gene', (226, 229))	('alleviating', 'NegReg', (147, 158))	('IL-2', 'Gene', '3558', (129, 133))	('prevent', 'NegReg', (63, 70))	('CTX', 'Gene', '1593', (226, 229))	('loss', 'NegReg', (75, 79))	('IL-2', 'Gene', (129, 133))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (206, 222))	('increase', 'PosReg', (100, 108))
45295	32372963	Interestingly, while FZQJ was able to inhibit the development of tumors on its own, its effects were more pronounced when used with CTX.	('FZQJ', 'Var', (21, 25))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('CTX', 'Gene', (132, 135))	('inhibit', 'NegReg', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('CTX', 'Gene', '1593', (132, 135))
45307	32372963	XIAO AI PING was also found to increase the infiltration of cytotoxic T lymphocytes CD8+ T cells.	('CD8', 'Gene', (84, 87))	('CD8', 'Gene', '925', (84, 87))	('XIAO', 'Var', (0, 4))	('increase', 'PosReg', (31, 39))
45325	32372963	Li also noted that in their studies XIAOJI increased lung cancer cell apoptosis, and inhibited tumor cell growth and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('inhibited', 'NegReg', (85, 94))	('XIAOJI', 'Var', (36, 42))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('increased', 'PosReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('tumor', 'Disease', (95, 100))
45334	32372963	More recent studies demonstrated that LBP significantly increased CD4+ and CD8+ as compared with the control groups to reduce immunosuppression in H22-bearing mice, and that LBP can enhance the immune system and inhibit tumor growth.	('immune system', 'CPA', (194, 207))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('enhance', 'PosReg', (182, 189))	('CD8', 'Gene', '925', (75, 78))	('increased', 'PosReg', (56, 65))	('tumor', 'Disease', (220, 225))	('inhibit', 'NegReg', (212, 219))	('immunosuppression', 'MPA', (126, 143))	('mice', 'Species', '10090', (159, 163))	('CD4+', 'MPA', (66, 70))	('CD8', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('LBP', 'Var', (174, 177))
45338	32372963	found that DGBXT could also inhibit colorectal cancer (CT-26) through autophagic processes, or cell degradation.	('colorectal cancer', 'Disease', (36, 53))	('DGBXT', 'Var', (11, 16))	('cell degradation', 'CPA', (95, 111))	('CT-26', 'CellLine', 'CVCL:7254', (55, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))	('autophagic processes', 'CPA', (70, 90))	('inhibit', 'NegReg', (28, 35))
45354	32372963	This activation of CD4+ and CD8+ increased cytokine production, specifically IL-2, IL-6, IL-7, and decreased TNF-alpha levels.	('IL-7', 'Gene', (89, 93))	('decreased', 'NegReg', (99, 108))	('IL-6', 'Gene', '3569', (83, 87))	('IL-7', 'Gene', '16196', (89, 93))	('cytokine', 'Gene', (43, 51))	('increased cytokine', 'Phenotype', 'HP:0031407', (33, 51))	('cytokine', 'Gene', '943', (43, 51))	('CD8', 'Gene', (28, 31))	('increased', 'PosReg', (33, 42))	('TNF-alpha levels', 'MPA', (109, 125))	('IL-6', 'Gene', (83, 87))	('CD8', 'Gene', '925', (28, 31))	('IL-2', 'Gene', (77, 81))	('IL-2', 'Gene', '3558', (77, 81))	('CD4+', 'Var', (19, 23))
45363	32372963	The study showed that the immune response was able to significantly delay tumor development in colon cancer-bearing murine models, and indicates that ACML-55 increases the antitumor response of both our adaptive immune system, and our innate immune system.	('ACML-55', 'Var', (150, 157))	('ACML-55', 'Chemical', '-', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (95, 107))	('colon cancer', 'Disease', 'MESH:D015179', (95, 107))	('delay', 'NegReg', (68, 73))	('tumor', 'Disease', (176, 181))	('murine', 'Species', '10090', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('colon cancer', 'Disease', (95, 107))	('tumor', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('increases', 'PosReg', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
45412	32372963	In a meta-analysis and systematic review, found that XBJ could inhibit inflammation through the regulation of Tregs and Th17, and reduced inflammatory cytokines TNF-alpha and IL-6.	('Th1', 'Gene', (120, 123))	('Tregs', 'Chemical', '-', (110, 115))	('XBJ', 'Var', (53, 56))	('reduced inflammatory cytokines', 'Phenotype', 'HP:0012648', (130, 160))	('cytokine', 'Gene', (151, 159))	('inflammation', 'Disease', 'MESH:D007249', (71, 83))	('IL-6', 'Gene', (175, 179))	('cytokine', 'Gene', '943', (151, 159))	('Tregs', 'Protein', (110, 115))	('reduced', 'NegReg', (130, 137))	('Th1', 'Gene', '51497', (120, 123))	('IL-6', 'Gene', '3569', (175, 179))	('inflammation', 'Disease', (71, 83))	('inhibit', 'NegReg', (63, 70))
45413	32372963	In another study, identified the constituents by which the inflammatory process was downregulated via the NF-kB pathway by senkyunolide I, safflor yellow A, oxypaeoniflorin, and benzoylpaeoniflori.	('downregulated', 'NegReg', (84, 97))	('NF-kB pathway', 'Pathway', (106, 119))	('inflammatory process', 'CPA', (59, 79))	('safflor yellow A', 'Chemical', '-', (139, 155))	('senkyunolide I', 'Chemical', 'MESH:C576743', (123, 137))	('oxypaeoniflorin', 'Var', (157, 172))	('senkyunolide', 'Var', (123, 135))	('benzoylpaeoniflori', 'Var', (178, 196))
45417	32372963	found in a clinical trial of post-treatment breast cancer patients that yunzhi-danshen decoction could significantly elevate CD4+ T cells along with B-lymphocytes after just 6 months of oral administration.	('yunzhi-danshen', 'Var', (72, 86))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('elevate CD4+ T', 'Phenotype', 'HP:0005407', (117, 131))	('breast cancer', 'Disease', (44, 57))	('elevate', 'PosReg', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('yunzhi-danshen', 'Chemical', '-', (72, 86))	('patients', 'Species', '9606', (58, 66))	('CD4+ T cells', 'MPA', (125, 137))
45438	32372963	Interestingly, Trichosanthes kirilowi has been shown to augment Th2 cells, and to induce HLA-associated immune suppression in bone marrow derived cells, and to decrease CD3+CD8+ T cells in the lymph nodes and spleen of naive mice although Cai et al.	('CD8', 'Gene', '925', (173, 176))	('decrease', 'NegReg', (160, 168))	('Trichosanthes', 'Var', (15, 28))	('HLA-associated immune suppression', 'MPA', (89, 122))	('augment', 'PosReg', (56, 63))	('CD3', 'Gene', (169, 172))	('CD8', 'Gene', (173, 176))	('CD3', 'Gene', '12503', (169, 172))	('mice', 'Species', '10090', (225, 229))	('Th2', 'Gene', (64, 67))	('Th2', 'Gene', '15111', (64, 67))
45489	31417631	In addition, the multivariate Cox regression analysis also suggested that BLUT was an independent prognostic factor for ESCC patients (P=0.003), as shown in Table 6.	('Cox', 'Gene', (30, 33))	('ESCC', 'Disease', (120, 124))	('BLUT', 'Var', (74, 78))	('BLUT', 'Chemical', '-', (74, 78))	('Cox', 'Gene', '1351', (30, 33))	('patients', 'Species', '9606', (125, 133))
45513	31417631	Furthermore, in the univariate Cox analysis, the HRs and 95% Cis for Mckeown approach and Ivor-Lewis approach were 0.491(0.281-0.860) and 0.353(0.632-1.178) compared with Sweet approach, while there were no statistically significant results for these surgical approaches in the multivariate analysis.	('Cox', 'Gene', '1351', (31, 34))	('Cox', 'Gene', (31, 34))	('0.491', 'Var', (115, 120))	('0.353', 'Var', (138, 143))
45599	28086198	However, in this case, no intestinal metaplasia was found histologically and the presence of EGM raised the possibility of a different pathway of carcinogenesis in this tumour.	('carcinogenesis', 'Disease', (146, 160))	('tumour', 'Disease', (169, 175))	('EGM', 'Protein', (93, 96))	('presence of EGM raised', 'Phenotype', 'HP:0003496', (81, 103))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('presence', 'Var', (81, 89))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))
45661	27826199	Effect of VEGF-C siRNA and endostatin on ring formation and proliferation of esophageal squamous cell carcinoma lymphatic endothelial cells To study the effects of vascular endothelial growth factor C small interfering RNA and endostatin on esophageal squamous cell carcinoma-related ring formation in vitro and proliferation of lymphatic endothelial cells.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (241, 275))	('endostatin', 'Gene', (227, 237))	('VEGF-C', 'Gene', (10, 16))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('vascular endothelial growth factor C', 'Gene', '7424', (164, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('endostatin', 'Gene', '80781', (27, 37))	('vascular endothelial growth factor C', 'Gene', (164, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (252, 275))	('esophageal squamous cell carcinoma', 'Disease', (241, 275))	('endostatin', 'Gene', '80781', (227, 237))	('VEGF-C', 'Gene', '7424', (10, 16))	('small interfering', 'Var', (201, 218))	('endostatin', 'Gene', (27, 37))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))
45667	27826199	Both vascular endothelial growth factor C small interfering RNA and endostatin could inhibit ring formation in esophageal squamous cell carcinoma and proliferation of lymphatic endothelial cells.	('ring formation', 'CPA', (93, 107))	('vascular endothelial growth factor C', 'Gene', '7424', (5, 41))	('proliferation of lymphatic endothelial cells', 'CPA', (150, 194))	('small interfering RNA', 'Var', (42, 63))	('vascular endothelial growth factor C', 'Gene', (5, 41))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (111, 145))	('endostatin', 'Gene', '80781', (68, 78))	('inhibit', 'NegReg', (85, 92))	('endostatin', 'Gene', (68, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('esophageal squamous cell carcinoma', 'Disease', (111, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
45809	27076841	Furthermore, p16INK4A positivity has been detected in 16.4 % of HPV-positive patients with ESCC, which is lower than previously published data reporting a range of prevalence between 20 % and 86.2 % .	('SCC', 'Phenotype', 'HP:0002860', (92, 95))	('ESCC', 'Disease', (91, 95))	('p16INK4A', 'Gene', (13, 21))	('HPV-positive', 'Gene', (64, 76))	('patients', 'Species', '9606', (77, 85))	('p16INK4A', 'Gene', '1029', (13, 21))	('positivity', 'Var', (22, 32))	('HPV', 'Species', '10566', (64, 67))	('detected', 'Reg', (42, 50))
45819	27076841	Rb1 alterations and subsequent p16 INK4A overexpression have also been described in non-HPV-driven tumors [.	('INK4A', 'Gene', '1029', (35, 40))	('p16', 'Gene', '1029', (31, 34))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('alterations', 'Var', (4, 15))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('INK4A', 'Gene', (35, 40))	('p16', 'Gene', (31, 34))	('HPV', 'Species', '10566', (88, 91))	('Rb1', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('overexpression', 'PosReg', (41, 55))	('tumors', 'Disease', (99, 105))
45822	27076841	p53 expression may be regarded as an indicator of p53 gene mutation.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('expression', 'MPA', (4, 14))	('p53', 'Gene', (50, 53))	('mutation', 'Var', (59, 67))	('p53', 'Gene', '7157', (50, 53))
45824	27076841	However, p53 shows nuclear staining because of the accumulation of mutant p53, which is resistant to degradation.	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (74, 77))	('accumulation', 'PosReg', (51, 63))	('mutant', 'Var', (67, 73))	('p53', 'Gene', '7157', (74, 77))
45830	27076841	HPV-associated oropharyngeal SCCs generally show a low level of p53 protein because of degradation through viral E6 protein, whereas HPV-negative tumors show absent or high p53 protein level because of nonsense or missense p53 mutations.	('E6 protein', 'Protein', (113, 123))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('HPV', 'Species', '10566', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('p53', 'Gene', (173, 176))	('degradation', 'MPA', (87, 98))	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('oropharyngeal SCCs', 'Disease', (15, 33))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('p53', 'Gene', '7157', (173, 176))	('low', 'NegReg', (51, 54))	('nonsense', 'Var', (202, 210))	('tumors', 'Disease', (146, 152))	('p53', 'Gene', (64, 67))	('SCC', 'Phenotype', 'HP:0002860', (29, 32))	('HPV', 'Species', '10566', (133, 136))	('p53', 'Gene', '7157', (64, 67))
45902	22807150	The samples were analyzed by liquid chromatography-tandem mass spectrometry with selected reaction monitoring for m/z 178   m/z 148 for NNN and m/z 184   m/z 154 for [13C6]NNN.	('NNN', 'Chemical', 'MESH:C008655', (172, 175))	('NNN', 'Chemical', 'MESH:C008655', (136, 139))	('m/z 178   m/z 148', 'Var', (114, 131))	('m/z 184   m/z 154', 'Var', (144, 161))
45935	22807150	The difference in susceptibility can be mediated by several mechanisms, one of which may be the previously described polymorphisms of CYP1A1, GSTM1, and GSTT1 enzymes that result in activation of PAH.	('GSTT1', 'Gene', (153, 158))	('PAH', 'Chemical', 'MESH:D011084', (196, 199))	('polymorphisms', 'Var', (117, 130))	('CYP1A1', 'Gene', (134, 140))	('PAH', 'CPA', (196, 199))	('activation', 'PosReg', (182, 192))
45938	22807150	Our data demonstrating elevated NNN in those smokers with HNSCC compared with smokers without HNSCC, is interesting given that NNN has been shown to induce esophageal and nasal cavity tumors in rats.	('esophageal', 'Disease', 'MESH:D004941', (156, 166))	('elevated', 'PosReg', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('NNN', 'MPA', (32, 35))	('NNN', 'Chemical', 'MESH:C008655', (32, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('tumors', 'Disease', (184, 190))	('induce', 'Reg', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('esophageal', 'Disease', (156, 166))	('NNN', 'Chemical', 'MESH:C008655', (127, 130))	('NNN', 'Var', (127, 130))	('rats', 'Species', '10116', (194, 198))	('HNSCC', 'Phenotype', 'HP:0012288', (58, 63))
45948	22807150	In smokers, urinary total NNN was found to be strongly associated with the risk of developing esophageal cancer in a prospective study based on a cohort of 18,244 Chinese men in Shanghai, China.	('urinary', 'Var', (12, 19))	('esophageal cancer', 'Disease', (94, 111))	('associated', 'Reg', (55, 65))	('NNN', 'Chemical', 'MESH:C008655', (26, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('men', 'Species', '9606', (171, 174))
45975	21672255	The genotypes for CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 allele genes were identified in blood samples collected from all participants.	('MTHFR', 'Gene', (46, 51))	('MPO', 'Gene', (59, 62))	('ALDH2', 'Gene', (74, 79))	('hOGG1', 'Gene', (33, 38))	('MTHFR', 'Gene', '4524', (46, 51))	('CYP2E1', 'Gene', (18, 24))	('MPO', 'Gene', '4353', (59, 62))	('C326G', 'Var', (39, 44))	('C677T', 'Mutation', 'rs1801133', (52, 57))	('G463A', 'Mutation', 'rs1199277582', (63, 68))	('hOGG1', 'Gene', '4968', (33, 38))	('ALDH2', 'Gene', '217', (74, 79))	('C677T', 'Var', (52, 57))	('G1259C', 'Mutation', 'rs753863502', (25, 31))	('participants', 'Species', '9606', (145, 157))	('C326G', 'Mutation', 'c.326C>G', (39, 44))	('CYP2E1', 'Gene', '1571', (18, 24))
45976	21672255	The alleles ALDH2 and MTHFR C677T were critical for determining individual susceptibility to esophageal cancer.	('ALDH2', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('MTHFR', 'Gene', (22, 27))	('esophageal cancer', 'Disease', (93, 110))	('C677T', 'Mutation', 'rs1801133', (28, 33))	('C677T', 'Var', (28, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('MTHFR', 'Gene', '4524', (22, 27))	('ALDH2', 'Gene', '217', (12, 17))
45978	21672255	However, the TT genotype of MTHFR C677T only increased the risk of ESCC.	('MTHFR', 'Gene', '4524', (28, 33))	('ESCC', 'Disease', (67, 71))	('C677T', 'Var', (34, 39))	('C677T', 'Mutation', 'rs1801133', (34, 39))	('ESCC', 'Phenotype', 'HP:0011459', (67, 71))	('MTHFR', 'Gene', (28, 33))
45979	21672255	Further analysis revealed that the combination of the high-risk genotypes 2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T increased the risk of BCH by 4.0 fold, of ESCD by 3.7 fold, and ESSC by 8.72 fold.	('BCH', 'Chemical', '-', (139, 142))	('increased', 'PosReg', (117, 126))	('MTHFR', 'Gene', (105, 110))	('BCH', 'Disease', (139, 142))	('ALDH 2', 'Gene', (85, 91))	('C677T', 'Mutation', 'rs1801133', (111, 116))	('C677T', 'Var', (111, 116))	('MTHFR', 'Gene', '4524', (105, 110))	('ESCD', 'Disease', (159, 163))	('ALDH 2', 'Gene', '217', (85, 91))	('ESSC', 'Disease', (181, 185))
45993	21672255	In addition to endoscopic evaluation for various types of esophageal lesions, the multi-genotype polymorphisms of CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 genes were identified for each individual subject.	('ALDH2', 'Gene', (170, 175))	('MPO', 'Gene', (155, 158))	('G1259C', 'Var', (121, 127))	('MTHFR', 'Gene', (142, 147))	('CYP2E1', 'Gene', '1571', (114, 120))	('ALDH2', 'Gene', '217', (170, 175))	('hOGG1', 'Gene', '4968', (129, 134))	('C677T', 'Mutation', 'rs1801133', (148, 153))	('G1259C', 'Mutation', 'rs753863502', (121, 127))	('esophageal lesions', 'Disease', 'MESH:D004935', (58, 76))	('hOGG1', 'Gene', (129, 134))	('C326G', 'Var', (135, 140))	('CYP2E1', 'Gene', (114, 120))	('esophageal lesions', 'Disease', (58, 76))	('MTHFR', 'Gene', '4524', (142, 147))	('MPO', 'Gene', '4353', (155, 158))	('C326G', 'Mutation', 'c.326C>G', (135, 140))	('C677T', 'Var', (148, 153))	('G463A', 'Mutation', 'rs1199277582', (159, 164))
46008	21672255	According to the actual sample sizes in the study, the posterior powers (1-beta), were 0.735, 0.796, 0.808 and 0.769 for the above four groups of ESCC, ESLD, BCH and controls, respectively.	('ESLD', 'Disease', 'None', (152, 156))	('ESCC', 'Phenotype', 'HP:0011459', (146, 150))	('BCH', 'Disease', (158, 161))	('BCH', 'Chemical', '-', (158, 161))	('ESLD', 'Disease', (152, 156))	('0.769', 'Var', (111, 116))	('ESCC', 'Disease', (146, 150))
46012	21672255	The PCR product of the MPO G463A gene digested by an AciI restriction enzyme yielding three possible genotypes which were defined by three distinct banding patterns: A/A 289 and 61bp fragments, A/G 289, 169, 120, and 6lbp fragments, and G/G 169, 120, and 6lbp fragments.	('A/G 289', 'Mutation', 'rs1401606459', (194, 201))	('MPO', 'Gene', '4353', (23, 26))	('A/G 289', 'Var', (194, 201))	('MPO', 'Gene', (23, 26))	('G463A', 'Mutation', 'rs1199277582', (27, 32))	('G/G 169', 'Var', (237, 244))
46013	21672255	The PCR product of CYP2E1 G1259C gene was digested with PstI restriction endonuclease for 8 hours at 37 C. Three possible genotypes were defined by three distinct banding patterns: C1/C1 410bp fragment, C1/C2 410, 290 and 120 bp fragments, and C2/C2 290- and 120-bp fragments.	('G1259C', 'Mutation', 'rs753863502', (26, 32))	('C1/C2 410', 'Gene', (203, 212))	('C1/C2 410', 'Gene', '6966', (203, 212))	('C1/C1 410bp fragment', 'Var', (181, 201))	('PstI', 'Gene', '6690', (56, 60))	('CYP2E1', 'Gene', '1571', (19, 25))	('C2/C2 290- and 120-bp', 'Gene', '717', (244, 265))	('CYP2E1', 'Gene', (19, 25))	('PstI', 'Gene', (56, 60))
46014	21672255	F1 and R1 were used to amplify the ALDH2*1 allele (296bp), and F2 and R2 to amplify the ALDH2*2 allele (203bp).	('ALDH2', 'Gene', (88, 93))	('F2 and R2', 'Gene', '2147', (63, 72))	('ALDH2', 'Gene', (35, 40))	('ALDH2', 'Gene', '217', (35, 40))	('203bp', 'Var', (104, 109))	('ALDH2', 'Gene', '217', (88, 93))
46017	21672255	If one showed 296 bp band and the other showed no band, the corresponding genotype was ALDH2*1/2*1 (G/G); if one showed 296 bp band and the other showed 203 bp band, the corresponding genotype was ALDH2*1/2*2 (G/A); and if one showed 203 bp band and the other showed no band, the corresponding genotype was ALDH2*2/2*2 (A/A).	('ALDH2', 'Gene', (307, 312))	('ALDH2', 'Gene', (197, 202))	('296 bp', 'Var', (120, 126))	('ALDH2', 'Gene', '217', (87, 92))	('ALDH2', 'Gene', (87, 92))	('ALDH2', 'Gene', '217', (307, 312))	('ALDH2', 'Gene', '217', (197, 202))
46019	21672255	The PCR product of hOGG1 C326G gene is digested by Fnu4HI on the polyacrylamide gels showed C/C genotype is a band at 200bp, G/G genotype is a band at 100bp, and C/G genotype is two bands at 200bp and 100bp.	('polyacrylamide', 'Chemical', 'MESH:C016679', (65, 79))	('hOGG1', 'Gene', (19, 24))	('C326G', 'Mutation', 'c.326C>G', (25, 30))	('C/C', 'Var', (92, 95))	('hOGG1', 'Gene', '4968', (19, 24))
46024	21672255	The frequency distribution of CYP2E1 G1259C, MPO G463A, MTHFR C677T, hOGG1 C326G, and ALDH2 genotypes are shown in Table 3.	('G463A', 'Mutation', 'rs1199277582', (49, 54))	('MPO', 'Gene', (45, 48))	('G1259C', 'Mutation', 'rs753863502', (37, 43))	('hOGG1', 'Gene', '4968', (69, 74))	('MTHFR', 'Gene', '4524', (56, 61))	('ALDH2', 'Gene', '217', (86, 91))	('CYP2E1', 'Gene', '1571', (30, 36))	('MPO', 'Gene', '4353', (45, 48))	('C677T', 'Mutation', 'rs1801133', (62, 67))	('C326G', 'Var', (75, 80))	('C677T', 'Var', (62, 67))	('hOGG1', 'Gene', (69, 74))	('G463A', 'Var', (49, 54))	('MTHFR', 'Gene', (56, 61))	('ALDH2', 'Gene', (86, 91))	('CYP2E1', 'Gene', (30, 36))	('C326G', 'Mutation', 'c.326C>G', (75, 80))
46025	21672255	As shown in Table 4 after adjusting for the potential confounders gender, age, school years, income per year, smoking index, alcohol drinking status, and family history of esophageal cancer, we found that polymorphism of the ALDH2 genotype was associated with BCH, ESCD, and ESCC.	('esophageal cancer', 'Disease', (172, 189))	('BCH', 'Chemical', '-', (260, 263))	('polymorphism', 'Var', (205, 217))	('BCH', 'Disease', (260, 263))	('ESCC', 'Disease', (275, 279))	('esophageal cancer', 'Disease', 'MESH:D004938', (172, 189))	('associated', 'Reg', (244, 254))	('ALDH2', 'Gene', '217', (225, 230))	('alcohol drinking', 'Phenotype', 'HP:0030955', (125, 141))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('ESCD', 'Disease', (265, 269))	('ESCC', 'Phenotype', 'HP:0011459', (275, 279))	('ALDH2', 'Gene', (225, 230))	('alcohol', 'Chemical', 'MESH:D000438', (125, 132))
46027	21672255	Furthermore, the TT genotype of MTHFR C677T increased the relative risk in the ESCC group, while the GG genotype of hOGG1 C326G increased the risk in the ESCD group.	('ESCC', 'Phenotype', 'HP:0011459', (79, 83))	('C326G', 'Mutation', 'c.326C>G', (122, 127))	('MTHFR', 'Gene', (32, 37))	('hOGG1', 'Gene', (116, 121))	('increased', 'PosReg', (128, 137))	('C677T', 'Mutation', 'rs1801133', (38, 43))	('C677T', 'Var', (38, 43))	('ESCC', 'Disease', (79, 83))	('C326G', 'Var', (122, 127))	('increased', 'PosReg', (44, 53))	('MTHFR', 'Gene', '4524', (32, 37))	('hOGG1', 'Gene', '4968', (116, 121))
46028	21672255	Based on the values of ORG, only the MTHFR C677T genotype (ORG = 1.16; 95%CI: 1.00-1.35) and ALDH 2 (ORG = 1.52; 95%CI: 1.30-1.77) genotype showed significant genetic association with the risk of carcinogenic progression of the esophagus.	('MTHFR', 'Gene', (37, 42))	('C677T', 'Mutation', 'rs1801133', (43, 48))	('C677T', 'Var', (43, 48))	('carcinogenic', 'Disease', 'MESH:D063646', (196, 208))	('ALDH 2', 'Gene', (93, 99))	('carcinogenic', 'Disease', (196, 208))	('ALDH 2', 'Gene', '217', (93, 99))	('MTHFR', 'Gene', '4524', (37, 42))
46029	21672255	Subjects with either homozygous or heterozygous variant alleles (2*2 or 1*2) of ALDH 2 had increased risk of developing BCH, ESCD, and ESCC compared to those who had wild type ALDH 2 (Table 4).	('ESCC', 'Disease', (135, 139))	('ALDH 2', 'Gene', (176, 182))	('ESCC', 'Phenotype', 'HP:0011459', (135, 139))	('ALDH 2', 'Gene', (80, 86))	('ALDH 2', 'Gene', '217', (176, 182))	('ESCD', 'Disease', (125, 129))	('ALDH 2', 'Gene', '217', (80, 86))	('BCH', 'Chemical', '-', (120, 123))	('BCH', 'Disease', (120, 123))	('variant', 'Var', (48, 55))
46030	21672255	Furthermore, TT and CT genotypes of MTHFR C677T were found to enhanced susceptibility to ESCC compared to the CC genotype.	('MTHFR', 'Gene', (36, 41))	('enhanced', 'PosReg', (62, 70))	('C677T', 'Mutation', 'rs1801133', (42, 47))	('susceptibility', 'MPA', (71, 85))	('C677T', 'Var', (42, 47))	('ESCC', 'Disease', (89, 93))	('ESCC', 'Phenotype', 'HP:0011459', (89, 93))	('MTHFR', 'Gene', '4524', (36, 41))
46031	21672255	The frequencies of the various combinations of the susceptible genotypes of ALDH 2 and MTHFR C677T genes were calculated and analyzed for their associated risks of diseases (Tables 5 and 6).	('ALDH 2', 'Gene', (76, 82))	('MTHFR', 'Gene', '4524', (87, 92))	('ALDH 2', 'Gene', '217', (76, 82))	('C677T', 'Mutation', 'rs1801133', (93, 98))	('C677T', 'Var', (93, 98))	('MTHFR', 'Gene', (87, 92))
46033	21672255	For example, after adjusting for the aforementioned seven potential confounders, the combinations of ALDH 2 2*2/1*2 and MTHFR TT/TC genotypes were associated with significantly increased risks for BCH, ESCD, and ESCC compared to patients with the 1*1 ALDH 2 and CC MTHFR C677T genotype.	('patients', 'Species', '9606', (229, 237))	('BCH', 'Chemical', '-', (197, 200))	('combinations', 'Var', (85, 97))	('ALDH 2', 'Gene', '217', (251, 257))	('ESCD', 'Disease', (202, 206))	('MTHFR', 'Gene', (120, 125))	('BCH', 'Disease', (197, 200))	('ESCC', 'Disease', (212, 216))	('MTHFR', 'Gene', '4524', (265, 270))	('TT/TC', 'Var', (126, 131))	('increased', 'PosReg', (177, 186))	('C677T', 'Mutation', 'rs1801133', (271, 276))	('MTHFR', 'Gene', (265, 270))	('ALDH 2', 'Gene', (101, 107))	('ESCC', 'Phenotype', 'HP:0011459', (212, 216))	('ALDH 2', 'Gene', '217', (101, 107))	('MTHFR', 'Gene', '4524', (120, 125))	('ALDH 2', 'Gene', (251, 257))
46053	21672255	Associational studies linking polymorphisms of the MTHFR C677T genotype with ESCC risk have yielded inconsistent result.	('C677T', 'Mutation', 'rs1801133', (57, 62))	('C677T', 'Var', (57, 62))	('ESCC', 'Disease', (77, 81))	('MTHFR', 'Gene', '4524', (51, 56))	('ESCC', 'Phenotype', 'HP:0011459', (77, 81))	('MTHFR', 'Gene', (51, 56))
46054	21672255	A meta-analysis of studies examined the association of the MTHFR C667T polymorphism with risk of esophageal cancer.	('MTHFR', 'Gene', '4524', (59, 64))	('esophageal cancer', 'Disease', (97, 114))	('C667T', 'Mutation', 'rs1801133', (65, 70))	('MTHFR', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('C667T', 'Var', (65, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('association', 'Interaction', (40, 51))
46056	21672255	When folic acid intake is sufficient, individuals with the MTHFR CT or TT genotypes may actually have a decreased risk of esophageal lesions because the lower MTHFR activity of the 677TT allele may lead to an elevation in 5, 10-methylenetetrahydrofolate, facilitating DNA synthesis.	('folic acid', 'Chemical', 'MESH:D005492', (5, 15))	('MTHFR', 'Gene', '4524', (59, 64))	('esophageal lesions', 'Disease', (122, 140))	('5, 10-methylenetetrahydrofolate', 'Chemical', 'MESH:C013123', (222, 253))	('decreased', 'NegReg', (104, 113))	('MTHFR', 'Gene', '4524', (159, 164))	('MTHFR', 'Gene', (59, 64))	('elevation', 'PosReg', (209, 218))	('677TT', 'Var', (181, 186))	('lower', 'NegReg', (153, 158))	('esophageal lesions', 'Disease', 'MESH:D004935', (122, 140))	('DNA synthesis', 'MPA', (268, 281))	('MTHFR', 'Gene', (159, 164))
46057	21672255	In contrast, both impaired DNA methylation and DNA synthesis/repair may become the primary mechanisms of carcinogenesis in the presence of low folic acid intake.	('carcinogenesis', 'Disease', 'MESH:D063646', (105, 119))	('low folic acid', 'Phenotype', 'HP:0100507', (139, 153))	('low', 'Var', (139, 142))	('folic acid', 'Chemical', 'MESH:D005492', (143, 153))	('carcinogenesis', 'Disease', (105, 119))	('DNA methylation', 'MPA', (27, 42))	('impaired', 'NegReg', (18, 26))
46060	21672255	The combination of the two high-risk genotypes 2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T resulted in a 4-fold higher risk of developing BCH, a 3.7-fold increased risk of ESCD, and a 8.72 times higher ESSC risk.	('C677T', 'Var', (84, 89))	('ALDH 2', 'Gene', (58, 64))	('ESCD', 'Disease', (171, 175))	('MTHFR', 'Gene', (78, 83))	('ESSC', 'Disease', (201, 205))	('ALDH 2', 'Gene', '217', (58, 64))	('BCH', 'Chemical', '-', (137, 140))	('BCH', 'Disease', (137, 140))	('higher', 'PosReg', (111, 117))	('MTHFR', 'Gene', '4524', (78, 83))	('C677T', 'Mutation', 'rs1801133', (84, 89))	('developing', 'MPA', (126, 136))
46061	21672255	The ALDH 2 and MTHFR C677T genes showed a significant association with ESCC in our population.	('ALDH 2', 'Gene', (4, 10))	('MTHFR', 'Gene', (15, 20))	('ESCC', 'Disease', (71, 75))	('ALDH 2', 'Gene', '217', (4, 10))	('ESCC', 'Phenotype', 'HP:0011459', (71, 75))	('C677T', 'Var', (21, 26))	('C677T', 'Mutation', 'rs1801133', (21, 26))	('MTHFR', 'Gene', '4524', (15, 20))
46062	21672255	In contrast to ALDH 2 and MTHFR, polymorphisms of CYP2E1 G1259C, MPO G463A, and hOGG1 C326G genes were not associated with BCH, ESCD, or ESCC risk in this study.	('MTHFR', 'Gene', (26, 31))	('C326G', 'Mutation', 'c.326C>G', (86, 91))	('ALDH 2', 'Gene', (15, 21))	('BCH', 'Disease', (123, 126))	('ESCC', 'Phenotype', 'HP:0011459', (137, 141))	('G463A', 'Mutation', 'rs1199277582', (69, 74))	('CYP2E1', 'Gene', '1571', (50, 56))	('ESCC', 'Disease', (137, 141))	('MPO', 'Gene', '4353', (65, 68))	('ESCD', 'Disease', (128, 132))	('MPO', 'Gene', (65, 68))	('G1259C', 'Mutation', 'rs753863502', (57, 63))	('associated', 'Reg', (107, 117))	('CYP2E1', 'Gene', (50, 56))	('MTHFR', 'Gene', '4524', (26, 31))	('C326G', 'Var', (86, 91))	('hOGG1', 'Gene', '4968', (80, 85))	('BCH', 'Chemical', '-', (123, 126))	('ALDH 2', 'Gene', '217', (15, 21))	('hOGG1', 'Gene', (80, 85))
46065	21672255	Compared with the ALDH 1*1 genotype, the ALHD 2*2 genotype was associated with significantly increased risks for BCH, ESCD, and ESCC, while the TT genotype of MTHFR C677T increased the risk of ESCC.	('ESCC', 'Disease', (193, 197))	('ESCC', 'Phenotype', 'HP:0011459', (128, 132))	('ESCC', 'Phenotype', 'HP:0011459', (193, 197))	('BCH', 'Chemical', '-', (113, 116))	('C677T', 'Mutation', 'rs1801133', (165, 170))	('C677T', 'Var', (165, 170))	('ALDH 1', 'Gene', '216', (18, 24))	('BCH', 'Disease', (113, 116))	('MTHFR', 'Gene', '4524', (159, 164))	('ALDH 1', 'Gene', (18, 24))	('ESCC', 'Disease', (128, 132))	('ESCD', 'Disease', (118, 122))	('MTHFR', 'Gene', (159, 164))
46066	21672255	Further analysis revealed that the combination of these high-risk genotypes (2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T) significantly increased susceptibility for BCH, ESCD, and ESSC (by 4.0, 3.7 and 8.72 fold, respectively).	('ESSC', 'Disease', (179, 183))	('ALDH 2', 'Gene', (88, 94))	('MTHFR', 'Gene', '4524', (108, 113))	('increased', 'PosReg', (135, 144))	('BCH', 'Disease', (164, 167))	('susceptibility', 'Reg', (145, 159))	('BCH', 'Chemical', '-', (164, 167))	('ALDH 2', 'Gene', '217', (88, 94))	('MTHFR', 'Gene', (108, 113))	('ESCD', 'Disease', (169, 173))	('C677T', 'Mutation', 'rs1801133', (114, 119))	('C677T', 'Var', (114, 119))
46168	29439548	A recent meta-analysis reported an overall prevalence of HPV in ESCC of 19.8% in Africa and 27.7% worldwide, with HPV16 being the most prevalent HPV type.	('HPV16', 'Var', (114, 119))	('ESCC', 'Disease', (64, 68))	('HPV', 'Species', '10566', (114, 117))	('HPV', 'Species', '10566', (145, 148))	('HPV', 'Species', '10566', (57, 60))	('HPV16', 'Species', '333760', (114, 119))
46181	29439548	The weakness of that study, however, was that the integration data was based on E2/E6 ratios, which provide only indirect evidence for HPV-integration.	('weakness', 'Disease', 'MESH:D018908', (4, 12))	('weakness', 'Disease', (4, 12))	('E2/E6 ratios', 'Var', (80, 92))	('HPV', 'Species', '10566', (135, 138))
46201	29439548	Moreover, expression of p16INK4a in tumor cells can be lost in the cells due to molecular events, such as promotor methylation or loss of heterozygosity.	('expression', 'MPA', (10, 20))	('lost', 'NegReg', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('p16INK4a', 'Gene', (24, 32))	('loss', 'Var', (130, 134))	('tumor', 'Disease', (36, 41))	('p16INK4a', 'Gene', '1029', (24, 32))
46211	29439548	This is followed by the inactivation of Rb, which facilitates disease progression.	('disease progression', 'CPA', (62, 81))	('Rb', 'Phenotype', 'HP:0009919', (40, 42))	('Rb', 'Gene', '5925', (40, 42))	('inactivation', 'Var', (24, 36))	('facilitates', 'PosReg', (50, 61))
46212	29439548	Second, loss of Rb yields oncogenic stress, which induces p16INK4a.	('p16INK4a', 'Gene', '1029', (58, 66))	('Rb', 'Phenotype', 'HP:0009919', (16, 18))	('Rb', 'Gene', '5925', (16, 18))	('oncogenic stress', 'CPA', (26, 42))	('loss', 'Var', (8, 12))	('p16INK4a', 'Gene', (58, 66))	('induces', 'Reg', (50, 57))
46230	29439548	beta-HPVs in keratinocyte carcinoma are suggested to play a role during the early stages of carcinogenesis, by promoting the accumulation of UV-induced mutations and oncogenic transformation.	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('mutations', 'Var', (152, 161))	('carcinogenesis', 'Disease', (92, 106))	('promoting', 'PosReg', (111, 120))	('carcinoma', 'Disease', 'MESH:D002277', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('UV-induced', 'Gene', (141, 151))	('HPV', 'Species', '10566', (5, 8))	('oncogenic transformation', 'CPA', (166, 190))	('carcinoma', 'Disease', (26, 35))
46236	29439548	Indeed, 47.4% of ESCC display somatic TP53 mutations, which would be in line with a "hit and run" mechanism.	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', '7157', (38, 42))
46252	29439548	Reaction mix 1 detects HPV16, 18, 31, and 45, and reaction mix 2 detects HPV33, 52, 58, and beta-globin.	('HPV16', 'Species', '333760', (23, 28))	('HPV33', 'Var', (73, 78))	('HPV16', 'Var', (23, 28))	('HPV', 'Species', '10566', (73, 76))	('beta-globin', 'Protein', (92, 103))	('HPV', 'Species', '10566', (23, 26))
46253	29439548	The PCR primers targeted the LCR/E6/E7 regions of the HPV genomes and the PCR products were detected by the corresponding TaqMan probes.	('PCR', 'Gene', (4, 7))	('LCR/E6/E7', 'Var', (29, 38))	('HPV', 'Gene', (54, 57))	('HPV', 'Species', '10566', (54, 57))
46294	29552204	Blocking signal transduction from RAS inhibits the activation of the Ras/Raf/MEK/ERK signaling pathway, and consequently affects the proliferation and malignant transformation of cells, as well as the development and progression of cancer.	('affects', 'Reg', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('Blocking signal transduction', 'Var', (0, 28))	('RAS', 'Gene', (34, 37))	('malignant transformation of cells', 'CPA', (151, 184))	('cancer', 'Disease', (232, 238))	('Ras/Raf/MEK/ERK signaling pathway', 'Pathway', (69, 102))	('inhibits', 'NegReg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('proliferation', 'CPA', (133, 146))	('development', 'CPA', (201, 212))
46296	29552204	A study by Wang et al determined that kinases in the Raf/MEK/ERK signaling pathway were abnormally activated in various tissues of PAQR3 gene knockout mice.	('kinases', 'Enzyme', (38, 45))	('mice', 'Species', '10090', (151, 155))	('activated', 'PosReg', (99, 108))	('PAQR3', 'Gene', (131, 136))	('Raf/MEK/ERK signaling pathway', 'Pathway', (53, 82))	('knockout', 'Var', (142, 150))
46314	29552204	The G418-resistant colonies were pooled together and used for colony formation and tumorigenic studies.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('G418-resistant', 'Var', (4, 18))	('tumor', 'Disease', (83, 88))	('G418', 'Chemical', 'MESH:C010680', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
46392	27575711	Variables that were selected a priori as adjustment factors included age (<50, 50-<60, 60-<70, >=70 years), sex (except for NDB which included only males), highest level of education (school only, tech/diploma, university), smoking status (never, former, current) and body mass index (BMI; <25, 25-29.9, >=30 kg/m2).	('never', 'Var', (240, 245))	('diploma', 'Disease', (202, 209))	('diploma', 'Disease', 'None', (202, 209))
46450	27839769	In other tumor sites, concurrent ATR inhibition has been shown in vitro to improve the response to cisplatin and radiation, both of which are key therapeutics in the treatment of esophageal cancer.	('esophageal cancer', 'Disease', (179, 196))	('inhibition', 'Var', (37, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('ATR', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('improve', 'PosReg', (75, 82))	('response to cisplatin', 'MPA', (87, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))
46452	27839769	Esophageal cancers have a high incidence of p53 mutations (~89.9% in SCC of the esophagus and ~72% in ACA).	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('SCC', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('Esophageal cancers', 'Disease', (0, 18))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('SCC', 'Gene', '6317', (69, 72))	('Esophageal cancers', 'Disease', 'MESH:D004938', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('ACA', 'Disease', (102, 105))	('mutations', 'Var', (48, 57))
46477	27839769	Alternatively sections were stained for 53BP1 (NB100-904, Novus Biologicals) or ATR-T1989 (ABE462, Millipore), all followed by HRP-conjugated secondary antibody incubation.	('NB100-904', 'Var', (47, 56))	('53BP1', 'Gene', '7158', (40, 45))	('ATR-T1989', 'Var', (80, 89))	('53BP1', 'Gene', (40, 45))
46482	27839769	As expected an increase in phosphorylated Chk1 at both residues S317 and S345 was observed in response to hypoxia and this was decreased in the presence of VX-970.	('decreased', 'NegReg', (127, 136))	('phosphorylated', 'MPA', (27, 41))	('increase', 'PosReg', (15, 23))	('hypoxia', 'Disease', (106, 113))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('S345', 'Var', (73, 77))	('Chk1', 'Gene', (42, 46))	('VX-970', 'Chemical', 'MESH:C000598331', (156, 162))	('Chk1', 'Gene', '1111', (42, 46))
46486	27839769	VX-970 decreased the levels of the ATR-Chk1 dependent phosphorylation site S473 on KAP-1 while not effecting S824 (a site phosphorylated predominantly by ATM) (Fig.	('Chk1', 'Gene', (39, 43))	('VX-970', 'Chemical', 'MESH:C000598331', (0, 6))	('decreased', 'NegReg', (7, 16))	('ATM', 'Gene', (154, 157))	('Chk1', 'Gene', '1111', (39, 43))	('KAP-1', 'Gene', (83, 88))	('KAP-1', 'Gene', '10155', (83, 88))	('ATM', 'Gene', '472', (154, 157))	('S473', 'Var', (75, 79))	('levels', 'MPA', (21, 27))	('phosphorylation', 'MPA', (54, 69))
46521	27839769	Our study also suggests that ATR-T1989 and KAP1-S473 should be further investigated as potential biomarkers for inhibition of ATR.	('ATR-T1989', 'Var', (29, 38))	('KAP1', 'Gene', (43, 47))	('KAP1', 'Gene', '10155', (43, 47))
46523	27839769	The only biomarker driven therapy in clinical practice to date is trastuzumab, a humanized monoclonal antibody against HER2 which is amplified in 15-25% of adenocarcinomas of the esophagus; future treatment strategies should increasingly incorporate drugs that exploit aberrations in specific signaling pathways (in this case, ATR inhibition in a p53 mutated tumor).	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('p53', 'Gene', (347, 350))	('adenocarcinomas of the esophagus', 'Disease', 'MESH:C562730', (156, 188))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('mutated', 'Var', (351, 358))	('p53', 'Gene', '7157', (347, 350))	('HER2', 'Gene', (119, 123))	('trastuzumab', 'Chemical', 'MESH:D000068878', (66, 77))	('tumor', 'Disease', (359, 364))	('HER2', 'Gene', '2064', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('adenocarcinomas of the esophagus', 'Disease', (156, 188))
46575	27738541	It has been shown that SATB2 germline deletion mutation in both mice and humans leads to dysregulation of osteoblasts.	('humans', 'Species', '9606', (73, 79))	('SATB2', 'Gene', (23, 28))	('germline deletion mutation', 'Var', (29, 55))	('dysregulation', 'MPA', (89, 102))	('mice', 'Species', '10090', (64, 68))
46625	26426603	The possibility of EAC-free group is 1.00, whereas the possibilities of incident EAC patients are 0.6239, 0.3250, 0.3151, and 0.2331 in AS-BE, IAS-BE, NS-BE, and NS-NBE groups, respectively.	('BE', 'Phenotype', 'HP:0100580', (139, 141))	('EAC', 'Gene', '1540', (19, 22))	('EAC', 'Gene', '1540', (81, 84))	('EAC', 'Gene', (19, 22))	('EAC', 'Gene', (81, 84))	('BE', 'Phenotype', 'HP:0100580', (154, 156))	('BE', 'Phenotype', 'HP:0100580', (147, 149))	('0.3151', 'Var', (114, 120))	('patients', 'Species', '9606', (85, 93))	('IAS', 'Disease', 'None', (143, 146))	('NS-NBE', 'Disease', 'MESH:D009404', (162, 168))	('IAS', 'Disease', (143, 146))	('0.3250', 'Var', (106, 112))	('NS-BE', 'Chemical', '-', (151, 156))	('AS-BE', 'Chemical', '-', (136, 141))	('EAC', 'Phenotype', 'HP:0011459', (81, 84))	('EAC', 'Phenotype', 'HP:0011459', (19, 22))	('NS-NBE', 'Disease', (162, 168))	('AS-BE', 'Chemical', '-', (144, 149))	('0.2331', 'Var', (126, 132))	('BE', 'Phenotype', 'HP:0100580', (166, 168))
46657	26426603	In addition, the post genome-wide association analysis in the Barrett's and Esophageal Adenocarcinoma Consortium genome-wide association study did not find any common genetic variants within components of the miRNA biogenesis core pathway to likely modulate susceptibility to esophgeal adenocarcinoma or BE.	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (76, 101))	('variants', 'Var', (175, 183))	('Esophageal Adenocarcinoma', 'Disease', (76, 101))	('esophgeal adenocarcinoma', 'Disease', 'MESH:D000230', (276, 300))	('modulate', 'Reg', (249, 257))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('BE', 'Phenotype', 'HP:0100580', (304, 306))	('esophgeal adenocarcinoma', 'Phenotype', 'HP:0011459', (276, 300))	('esophgeal adenocarcinoma', 'Disease', (276, 300))
46661	26426603	Radiofrequency ablation of BE with confirmed LGD can reduce risk of developing HGD and adenocarcinoma.	('reduce', 'NegReg', (53, 59))	('BE', 'Phenotype', 'HP:0100580', (27, 29))	('Radiofrequency', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('adenocarcinoma', 'Disease', (87, 101))	('adenocarcinoma', 'Disease', 'MESH:D000230', (87, 101))
46674	25885227	More over, knockdown of ESCCAL-1 expression increases esophageal cancer cell apoptosis and reduces the invasion in vitro.	('ESCCAL-1', 'Gene', (24, 32))	('increases esophageal cancer', 'Disease', (44, 71))	('ESCCAL-1', 'Gene', '101805492', (24, 32))	('invasion in vitro', 'CPA', (103, 120))	('increases esophageal cancer', 'Disease', 'MESH:D004938', (44, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('reduces', 'NegReg', (91, 98))	('knockdown', 'Var', (11, 20))
46686	25885227	Detection of aberrant expression of lncRNAs in various tissue origin of cancers could serve as novel biomarkers for cancer diagnosis and prognosis.	('cancer', 'Disease', (116, 122))	('lncRNAs', 'Gene', (36, 43))	('aberrant expression', 'Var', (13, 32))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cancer', 'Disease', (72, 78))
46726	25885227	HoxA11-AS1 is evolutionary conservation and tissue-specific expression, It was proposed that HOXA11 antisense represses HOXA11 expression by competing for transcription of the common gene, rather than by sense/antisense interaction.	('competing', 'NegReg', (141, 150))	('HoxA11', 'Gene', (0, 6))	('antisense', 'Var', (100, 109))	('HOXA11', 'Gene', '3207', (93, 99))	('expression', 'MPA', (127, 137))	('HoxA11', 'Gene', '3207', (0, 6))	('HOXA11', 'Gene', (93, 99))	('transcription', 'MPA', (155, 168))	('AS1', 'Gene', '5729', (7, 10))	('AS1', 'Gene', (7, 10))	('HOXA11', 'Gene', '3207', (120, 126))	('HOXA11', 'Gene', (120, 126))
46734	25885227	We want to know how esophageal cancer cell behavior changes if knocking down the expression of ESCCAL-1 lncRNA, we therefore designed three small interfering RNAs targeting various region of ESCCAL-1 sequencing.	('esophageal cancer', 'Disease', (20, 37))	('knocking', 'Var', (63, 71))	('ESCCAL-1 lncRNA', 'Gene', (95, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ESCCAL-1', 'Gene', (191, 199))	('ESCCAL-1 lncRNA', 'Gene', '101805492', (95, 110))	('ESCCAL-1', 'Gene', (95, 103))	('ESCCAL-1', 'Gene', '101805492', (191, 199))	('ESCCAL-1', 'Gene', '101805492', (95, 103))	('changes', 'Reg', (52, 59))	('expression', 'MPA', (81, 91))
46739	25885227	Core signaling pathways may be disrupted by these aberrant lncRNA expressions, such as WNT pathway is activated by HOTAIR over expression, TGFbeta1 pathway is inhibited by ANRIL.	('HOTAIR', 'Gene', (115, 121))	('TGFbeta1', 'Gene', '7040', (139, 147))	('TGFbeta1', 'Gene', (139, 147))	('ANRIL', 'Gene', '100048912', (172, 177))	('activated', 'PosReg', (102, 111))	('HOTAIR', 'Gene', '100124700', (115, 121))	('disrupted', 'Reg', (31, 40))	('WNT pathway', 'Pathway', (87, 98))	('Core signaling pathways', 'Pathway', (0, 23))	('ANRIL', 'Gene', (172, 177))	('aberrant', 'Var', (50, 58))	('inhibited', 'NegReg', (159, 168))
46742	25885227	The knockdown of ESCCAL-1 expression increases apoptosis and decrease invasion in intro.	('ESCCAL-1', 'Gene', (17, 25))	('ESCCAL-1', 'Gene', '101805492', (17, 25))	('decrease', 'NegReg', (61, 69))	('invasion in intro', 'CPA', (70, 87))	('apoptosis', 'CPA', (47, 56))	('increases', 'PosReg', (37, 46))	('knockdown', 'Var', (4, 13))
46744	21070776	An association between a variation in the PSCA gene and upper gastrointestinal cancer in Caucasians An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen (PSCA) gene has been reported for several Asian populations.	('PSCA', 'Gene', '8000', (210, 214))	('upper gastrointestinal cancer', 'Disease', (56, 85))	('association', 'Interaction', (3, 14))	('PSCA', 'Gene', '8000', (42, 46))	('upper gastrointestinal cancer', 'Disease', 'MESH:D004067', (56, 85))	('prostate stem cell antigen', 'Gene', '8000', (182, 208))	('prostate stem cell antigen', 'Gene', (182, 208))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('PSCA', 'Gene', (210, 214))	('rs2294008 (C>T', 'Var', (146, 160))	('rs2294008', 'Mutation', 'rs2294008', (146, 155))	('gastric cancer', 'Disease', (123, 137))	('variation', 'Var', (25, 34))	('PSCA', 'Gene', (42, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (62, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))
46749	21070776	Carriage of the risk allele (T) of rs2294008 in PSCA was associated with chronic atrophic gastritis (adjusted odds ratio [OR] = 1.5; 95% confidence interval [CI], 1.1-1.9) and non-cardia gastric cancer (OR = 1.9; 95% CI, 1.3- 2.8).	('chronic atrophic gastritis', 'Phenotype', 'HP:0002582', (73, 99))	('rat', 'Species', '10116', (115, 118))	('rs2294008', 'Var', (35, 44))	('chronic atrophic gastritis', 'Disease', 'MESH:D005757', (73, 99))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (81, 99))	('rs2294008', 'Mutation', 'rs2294008', (35, 44))	('PSCA', 'Gene', (48, 52))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (176, 201))	('gastric cancer', 'Phenotype', 'HP:0012126', (187, 201))	('chronic atrophic gastritis', 'Disease', (73, 99))	('gastritis', 'Phenotype', 'HP:0005263', (90, 99))	('non-cardia gastric cancer', 'Disease', (176, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
46750	21070776	An inverse association was observed between carriage of the risk allele and gastric cardia cancer (OR = 0.5; 95% CI, 0.3-0.9), esophageal adenocarcinoma (OR = 0.5; 95% CI, 0.3-0.9), and esophageal squamous cell carcinoma (OR = 0.4; 95% CI, 0.2-0.9).	('gastric cardia cancer', 'Disease', (76, 97))	('carriage', 'Var', (44, 52))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (186, 220))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('inverse', 'NegReg', (3, 10))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (127, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('esophageal adenocarcinoma', 'Disease', (127, 152))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (76, 97))	('esophageal squamous cell carcinoma', 'Disease', (186, 220))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (127, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))
46751	21070776	The rs2294008 polymorphism in PSCA increases the risk of non-cardia gastric cancer and its precursors in Caucasians but protects against proximal cancers.	('rs2294008', 'Var', (4, 13))	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('proximal cancers', 'Disease', 'MESH:D009369', (137, 153))	('protects', 'NegReg', (120, 128))	('increases', 'PosReg', (35, 44))	('PSCA', 'Gene', (30, 34))	('rs2294008', 'Mutation', 'rs2294008', (4, 13))	('proximal cancers', 'Disease', (137, 153))	('non-cardia gastric cancer', 'Disease', (57, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (57, 82))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
46756	21070776	We, and other authors, have previously reported an increased risk of gastric cancer and its precursors (gastric atrophy and hypochlorhydria) in association with polymorphisms in pro-inflammatory cytokine genes (IL-1B, IL-1RN, TNFA and IL-10), and genes involved in the innate immune response (TLR4).	('TNFA', 'Gene', (226, 230))	('gastric cancer', 'Disease', (69, 83))	('IL-10', 'Gene', (235, 240))	('IL-1RN', 'Gene', (218, 224))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('polymorphisms', 'Var', (161, 174))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (51, 83))	('TLR4', 'Gene', (293, 297))	('IL-1B', 'Gene', (211, 216))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gastric atrophy and hypochlorhydria', 'Disease', 'MESH:D000126', (104, 139))
46757	21070776	Recently, genome wide association studies (GWAS) have permitted the identification of novel, high prevalence, low penetrance genetic polymorphisms associated with complex human traits, including sporadic cancer risk.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('polymorphisms', 'Var', (133, 146))	('associated', 'Reg', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('human', 'Species', '9606', (171, 176))
46758	21070776	Indeed, the mechanism of action of many GWAS-identified genetic variants remains unknown, and the ability to stratify individual cancer risk on the basis of these variants is limited.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('rat', 'Species', '10116', (111, 114))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('variants', 'Var', (64, 72))
46759	21070776	Recently, the Study Group of the Millennium Genome Project for Cancer published findings of a two-stage GWAS, which demonstrated an association between the rs2294008 single nucleotide polymorphism (SNP) in the prostate stem cell antigen gene (PSCA), and the risk of gastric cancer in Japanese.	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('PSCA', 'Gene', (243, 247))	('gastric cancer', 'Disease', 'MESH:D013274', (266, 280))	('rs2294008 single nucleotide polymorphism', 'Var', (156, 196))	('gastric cancer', 'Disease', (266, 280))	('prostate stem cell antigen', 'Gene', '8000', (210, 236))	('prostate stem cell antigen', 'Gene', (210, 236))	('rat', 'Species', '10116', (123, 126))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Cancer', 'Disease', (63, 69))	('rs2294008', 'Mutation', 'rs2294008', (156, 165))	('Cancer', 'Disease', 'MESH:D009369', (63, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (266, 280))
46762	21070776	The finding of an association between gastric cancer and rs2294008 has now been replicated in several, independent, Asian case-control studies, and was also confirmed in a recent gastric cancer GWAS in a Chinese population.	('gastric cancer', 'Phenotype', 'HP:0012126', (179, 193))	('gastric cancer', 'Phenotype', 'HP:0012126', (38, 52))	('gastric cancer', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('gastric cancer', 'Disease', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (179, 193))	('gastric cancer', 'Disease', 'MESH:D013274', (38, 52))	('rs2294008', 'Var', (57, 66))	('rs2294008', 'Mutation', 'rs2294008', (57, 66))
46763	21070776	Limited functional data exist on the effect of the rs2294008 C>T transition, however results from a reporter assay suggest that the T allele reduces upstream PSCA transcriptional activity.	('rs2294008 C>T', 'Var', (51, 64))	('upstream PSCA transcriptional activity', 'MPA', (149, 187))	('reduces', 'NegReg', (141, 148))	('rs2294008', 'Mutation', 'rs2294008', (51, 60))
46764	21070776	Whether the rs2294008 polymorphism confers increased risk of gastric cancer in Caucasian populations has not yet been established.	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('rs2294008', 'Var', (12, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('rs2294008', 'Mutation', 'rs2294008', (12, 21))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (43, 75))
46765	21070776	Furthermore, it is not known at what stage in gastric carcinogenesis the PSCA polymorphism exerts its effect.	('gastric carcinogenesis', 'Disease', (46, 68))	('PSCA', 'Gene', (73, 77))	('polymorphism', 'Var', (78, 90))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (46, 68))
46767	21070776	To determine whether the rs2294008 polymorphism is associated with the risk of premalignant change in the stomach, we employed two case-control studies of chronic atrophic gastritis (CAG).	('rs2294008', 'Var', (25, 34))	('chronic atrophic gastritis', 'Disease', 'MESH:D005757', (155, 181))	('CAG', 'Phenotype', 'HP:0002582', (183, 186))	('rs2294008', 'Mutation', 'rs2294008', (25, 34))	('gastritis', 'Phenotype', 'HP:0005263', (172, 181))	('associated', 'Reg', (51, 61))	('chronic atrophic gastritis', 'Phenotype', 'HP:0002582', (155, 181))	('chronic atrophic gastritis', 'Disease', (155, 181))	('premalignant change in the stomach', 'Disease', (79, 113))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (163, 181))
46778	21070776	In order to investigate the influence of the rs2294008 polymorphism on upper GI cancer risk in Caucasians, two independent, population-based, case-control studies were utilized.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('rs2294008', 'Var', (45, 54))	('GI cancer', 'Disease', 'MESH:D009369', (77, 86))	('rs2294008', 'Mutation', 'rs2294008', (45, 54))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('GI cancer', 'Disease', (77, 86))
46787	21070776	In both the German and Scottish study populations, an association was observed between the risk allele (T) of rs2294008 and CAG (Table 1).	('CAG', 'Disease', (124, 127))	('CAG', 'Phenotype', 'HP:0002582', (124, 127))	('rs2294008', 'Var', (110, 119))	('rs2294008', 'Mutation', 'rs2294008', (110, 119))	('association', 'Interaction', (54, 65))
46788	21070776	In the Scottish study, the T allele conferred increased risk of atrophy and hypochlorhydria, with the T/T genotype yielding an OR of 4.1 (95% CI, 1.3-12.7) in a recessive model (Table 1).	('T/T', 'Var', (102, 105))	('atrophy', 'Disease', 'MESH:D001284', (64, 71))	('hypochlorhydria', 'Disease', (76, 91))	('atrophy', 'Disease', (64, 71))	('hypochlorhydria', 'Disease', 'MESH:D000126', (76, 91))
46789	21070776	Analysis of the German and Scottish study populations did not reveal an association between rs2294008 and the risk of H pylori infection (data not shown).	('rs2294008', 'Mutation', 'rs2294008', (92, 101))	('H pylori infection', 'Disease', 'MESH:D016481', (118, 136))	('H pylori infection', 'Phenotype', 'HP:0005202', (118, 136))	('H pylori infection', 'Disease', (118, 136))	('rs2294008', 'Var', (92, 101))
46790	21070776	A positive association was observed between the rs2294008 risk allele and non-cardia gastric cancer in the US study population, and all-site gastric cancer in the Polish study population (Table 2).	('rs2294008', 'Var', (48, 57))	('non-cardia gastric cancer', 'Disease', (74, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rs2294008', 'Mutation', 'rs2294008', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))	('gastric cancer', 'Disease', (141, 155))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (74, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))
46794	21070776	In the US study population, the association between the rs2294008 risk allele and non-cardia cancer, and diffuse histological-type, was only significant in recessive models, yielding an OR of 1.9 in both cases (95% CI, 1.2-3.0 and 1.1-3.5 respectively).	('non-cardia cancer', 'Disease', (82, 99))	('non-cardia cancer', 'Disease', 'MESH:D004938', (82, 99))	('rs2294008', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rs2294008', 'Mutation', 'rs2294008', (56, 65))
46796	21070776	Additionally, no relationship was detected between rs2294008 and risk of H pylori infection in either the US or Polish study populations (data not shown).	('H pylori infection', 'Phenotype', 'HP:0005202', (73, 91))	('H pylori infection', 'Disease', 'MESH:D016481', (73, 91))	('H pylori infection', 'Disease', (73, 91))	('rs2294008', 'Var', (51, 60))	('rs2294008', 'Mutation', 'rs2294008', (51, 60))
46797	21070776	An inverse association was observed between the rs2294008 polymorphism and proximal cancers of the upper gastrointestinal tract in the US study (Table 2; US study).	('proximal cancers', 'Disease', 'MESH:D009369', (75, 91))	('rs2294008', 'Var', (48, 57))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('proximal cancers', 'Disease', (75, 91))	('cancers of the upper gastrointestinal tract', 'Disease', (84, 127))	('inverse', 'NegReg', (3, 10))	('cancers of the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (84, 127))	('rs2294008', 'Mutation', 'rs2294008', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
46800	21070776	In the present study, we demonstrate that the rs2294008 polymorphism in the PSCA gene, previously described as a risk factor for gastric cancer in Asians, is associated with gastric cancer and its precursors (gastric atrophy and hypochlorhydria) in Caucasian populations.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (174, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('associated with', 'Reg', (158, 173))	('rat', 'Species', '10116', (32, 35))	('gastric cancer', 'Disease', (129, 143))	('rs2294008', 'Var', (46, 55))	('gastric atrophy and hypochlorhydria', 'Disease', 'MESH:D000126', (209, 244))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('gastric cancer', 'Disease', (174, 188))	('rs2294008', 'Mutation', 'rs2294008', (46, 55))	('PSCA', 'Gene', (76, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (174, 188))
46802	21070776	We also report the additional novel findings of divergent effects of the polymorphism on cardia and non-cardia gastric cancers, and an inverse association with esophageal cancer of both squamous and adenocarcinoma histotypes.	('gastric cancers', 'Phenotype', 'HP:0012126', (111, 126))	('cardia', 'Disease', (104, 110))	('inverse', 'NegReg', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('cardia', 'Disease', 'MESH:D004938', (104, 110))	('esophageal cancer of both squamous and adenocarcinoma', 'Disease', 'MESH:D004938', (160, 213))	('polymorphism', 'Var', (73, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('non-cardia gastric cancers', 'Disease', 'MESH:D013274', (100, 126))	('non-cardia gastric cancers', 'Disease', (100, 126))	('cardia', 'Disease', 'MESH:D004938', (89, 95))	('cardia', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
46809	21070776	The inverse association between rs2294008 and gastric cardia cancer was only observed in the US study; however the number of Polish cardia cases may well have been too small to detect a similar effect.	('gastric cardia cancer', 'Disease', (46, 67))	('cardia', 'Disease', (132, 138))	('cardia', 'Disease', 'MESH:D004938', (132, 138))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (46, 67))	('cardia', 'Disease', 'MESH:D004938', (54, 60))	('cardia', 'Disease', (54, 60))	('inverse', 'NegReg', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('rs2294008', 'Var', (32, 41))	('rs2294008', 'Mutation', 'rs2294008', (32, 41))
46810	21070776	found no overall association between rs2294008 and gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (51, 65))	('rs2294008', 'Var', (37, 46))	('rs2294008', 'Mutation', 'rs2294008', (37, 46))	('gastric cancer', 'Disease', (51, 65))
46811	21070776	Sub-group analysis, however, revealed a positive association between rs2294008 and non-cardia gastric cancer, yet no association with cardia cancer.	('positive', 'PosReg', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs2294008', 'Var', (69, 78))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (83, 108))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rs2294008', 'Mutation', 'rs2294008', (69, 78))	('cardia cancer', 'Disease', 'MESH:D004938', (134, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('cardia cancer', 'Disease', (134, 147))	('non-cardia gastric cancer', 'Disease', (83, 108))
46813	21070776	Given that cardia cancer itself appears to be an etiologically heterogeneous condition, the opposing effect of rs2294008 on cardia and non-cardia cancer risk observed in our Caucasian population is at least biologically plausible.	('cardia', 'Disease', (11, 17))	('cardia cancer', 'Disease', 'MESH:D004938', (139, 152))	('cardia', 'Disease', 'MESH:D004938', (11, 17))	('cardia cancer', 'Disease', (11, 24))	('cardia', 'Disease', 'MESH:D004938', (124, 130))	('rs2294008', 'Var', (111, 120))	('cardia', 'Disease', (124, 130))	('cardia', 'Disease', 'MESH:D004938', (139, 145))	('cardia', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('rs2294008', 'Mutation', 'rs2294008', (111, 120))	('cardia cancer', 'Disease', 'MESH:D004938', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('non-cardia cancer', 'Disease', (135, 152))	('non-cardia cancer', 'Disease', 'MESH:D004938', (135, 152))
46814	21070776	Interestingly, in per-genotype analyses, the inverse risk for proximal cancers was only significant in C/T heterozygotes.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('proximal cancers', 'Disease', 'MESH:D009369', (62, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('proximal cancers', 'Disease', (62, 78))	('C/T', 'Var', (103, 106))
46816	21070776	Assuming that the divergent effect of the rs2294008 polymorphism on cancer risk at different anatomic sites is genuine, it is not necessarily all that surprising.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs2294008', 'Var', (42, 51))	('rs2294008', 'Mutation', 'rs2294008', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))
46821	21070776	From a genetic standpoint, similar opposing effects have been described for other GWAS-identified SNPs such as rs6983267, which confers risk for prostate cancer and smoking-related oropharyngeal cancers, but is inversely associated with bladder cancer.	('oropharyngeal cancers', 'Disease', (181, 202))	('rs6983267', 'Var', (111, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (145, 160))	('bladder cancer', 'Phenotype', 'HP:0009725', (237, 251))	('prostate cancer', 'Disease', (145, 160))	('prostate cancer', 'Phenotype', 'HP:0012125', (145, 160))	('oropharyngeal cancers', 'Disease', 'MESH:D009959', (181, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('rs6983267', 'Mutation', 'rs6983267', (111, 120))	('bladder cancer', 'Disease', 'MESH:D001749', (237, 251))	('bladder cancer', 'Disease', (237, 251))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
46831	21070776	In vitro studies have shown that PSCA influences survival in gastric cancer cells, where transfection of PSCA into PSCA-negative cells leads to reduced cell proliferation.	('reduced', 'NegReg', (144, 151))	('influences', 'Reg', (38, 48))	('transfection', 'Var', (89, 101))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('survival', 'CPA', (49, 57))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('rat', 'Species', '10116', (164, 167))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('cell proliferation', 'CPA', (152, 170))
46832	21070776	In contrast, knockdown of PSCA in a bladder cancer cell line results in induction of inflammatory gene expression, accompanied by a reduction in cell grown.	('PSCA', 'Gene', (26, 30))	('bladder cancer', 'Phenotype', 'HP:0009725', (36, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (36, 50))	('cell grown', 'CPA', (145, 155))	('reduction', 'NegReg', (132, 141))	('inflammatory gene expression', 'MPA', (85, 113))	('bladder cancer', 'Disease', (36, 50))	('induction', 'PosReg', (72, 81))	('knockdown', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
46836	21070776	observed that misexpressing PSCA during chick ciliary ganglion development lead to allosteric antagonism of alpha7 subunit-containing nicotinic acetylcholine receptors (alpha7-nAChRs), and rescued a neuronal subpopulation from programmed cell death.	('programmed cell death', 'CPA', (227, 248))	('alpha7 subunit-containing', 'Protein', (108, 133))	('misexpressing', 'Var', (14, 27))	('neuronal subpopulation', 'CPA', (199, 221))	('nAChR', 'Gene', '1137', (176, 181))	('allosteric antagonism', 'MPA', (83, 104))	('PSCA', 'Gene', (28, 32))	('chick', 'Species', '9031', (40, 45))	('rescued', 'PosReg', (189, 196))	('nAChR', 'Gene', (176, 181))	('ciliary ganglion', 'Phenotype', 'HP:3000025', (46, 62))	('acetylcholine', 'Chemical', 'MESH:D000109', (144, 157))
46839	21070776	In addition, mutations in SLURP-1 have been implicated in the inflammatory skin disorder Mal de Meleda, suggesting that SLURP-1 has a role in epidermal homeostasis.	('inflammatory skin', 'Phenotype', 'HP:0011123', (62, 79))	('SLURP-1', 'Gene', '57152', (120, 127))	('implicated', 'Reg', (44, 54))	('inflammatory skin disorder Mal de Meleda', 'Disease', (62, 102))	('SLURP-1', 'Gene', '57152', (26, 33))	('inflammatory skin disorder Mal de Meleda', 'Disease', 'MESH:D007645', (62, 102))	('skin disorder', 'Phenotype', 'HP:0000951', (75, 88))	('SLURP-1', 'Gene', (26, 33))	('role', 'Reg', (134, 138))	('mutations', 'Var', (13, 22))	('SLURP-1', 'Gene', (120, 127))
46843	21070776	It is plausible therefore that PSCA might interact with alpha7-nAChRs in humans, and that the rs2294008 polymorphism may influence the balance of pro-inflammatory and anti-inflammatory signals present in the gastric mucosa.	('humans', 'Species', '9606', (73, 79))	('nAChR', 'Gene', '1137', (63, 68))	('rs2294008', 'Var', (94, 103))	('rs2294008', 'Mutation', 'rs2294008', (94, 103))	('interact', 'Reg', (42, 50))	('nAChR', 'Gene', (63, 68))	('influence', 'Reg', (121, 130))	('PSCA', 'Disease', (31, 35))
46855	20538426	The sham operated animals, received an average esophagitis score of 0.1 +- 0.1, this increased significantly in EDA -CD animals to 1.8 +- 0.14 (p< 0.001 vs SH-CD) and in EDA-BRB group to 1.7 +- 0.06 (p< 0.001 vs SH-CD), with BE changes also present.	('esophagitis', 'Disease', (47, 58))	('esophagitis', 'Disease', 'MESH:D004941', (47, 58))	('rat', 'Species', '10116', (12, 15))	('SH-CD', 'Chemical', '-', (156, 161))	('EDA', 'Phenotype', 'HP:0100628', (170, 173))	('BE', 'Phenotype', 'HP:0100580', (225, 227))	('SH-CD', 'Chemical', '-', (212, 217))	('EDA-BRB', 'Chemical', '-', (170, 177))	('EDA', 'Phenotype', 'HP:0100628', (112, 115))	('EDA -CD', 'Chemical', '-', (112, 119))	('increased', 'PosReg', (85, 94))	('esophagitis', 'Phenotype', 'HP:0100633', (47, 58))	('EDA -CD', 'Var', (112, 119))
46871	20538426	Although, these facts suggests that the two main types of esophageal cancers may differ considerably in their etiology, the low intake of fruits and vegetables is the only risk factor consistently associated with both SCC and EAC.	('SCC', 'Phenotype', 'HP:0002860', (218, 221))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('SCC', 'Disease', (218, 221))	('esophageal cancers', 'Disease', (58, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('low intake', 'Var', (124, 134))	('esophageal cancers', 'Disease', 'MESH:D004938', (58, 76))	('EAC', 'Phenotype', 'HP:0011459', (226, 229))	('EAC', 'Disease', (226, 229))	('associated', 'Reg', (197, 207))
46875	20538426	A relevant early biomarker for esophageal carcinogenesis is Manganese Superoxide Dismutase (MnSOD), whose levels and activity are significantly reduced 4-weeks after EDA surgery, replacement of which results in reduced EAC incidence.	('reduced', 'NegReg', (144, 151))	('replacement', 'Var', (179, 190))	('activity', 'MPA', (117, 125))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (31, 56))	('EDA', 'Phenotype', 'HP:0100628', (166, 169))	('EDA', 'Chemical', '-', (166, 169))	('esophageal carcinogenesis', 'Disease', (31, 56))	('reduced', 'NegReg', (211, 218))	('men', 'Species', '9606', (186, 189))	('MnSOD', 'Gene', '24787', (92, 97))	('EAC', 'Phenotype', 'HP:0011459', (219, 222))	('EAC', 'Disease', (219, 222))	('MnSOD', 'Gene', (92, 97))	('levels', 'MPA', (106, 112))
46904	20538426	Animals that underwent EDA surgery, regardless of the diet, had significant weight loss 1 week following surgery (Figure 1A) and also had significantly lower feed intake (Figure 1B).	('surgery', 'Var', (27, 34))	('weight loss', 'Disease', 'MESH:D015431', (76, 87))	('weight loss', 'Phenotype', 'HP:0001824', (76, 87))	('feed intake', 'MPA', (158, 169))	('weight loss', 'Disease', (76, 87))	('EDA', 'Phenotype', 'HP:0100628', (23, 26))	('lower', 'NegReg', (152, 157))	('EDA', 'Disease', (23, 26))	('EDA', 'Chemical', '-', (23, 26))
46921	20538426	Once again, the MnSOD activity mimicked the expression level and there was a slight reduction in MnSOD activity for EDA-BRB groups compared to the other 2 (Figure 4B).	('MnSOD', 'Gene', '24787', (97, 102))	('reduction', 'NegReg', (84, 93))	('EDA-BRB', 'Var', (116, 123))	('MnSOD', 'Gene', '24787', (16, 21))	('MnSOD', 'Gene', (97, 102))	('EDA', 'Phenotype', 'HP:0100628', (116, 119))	('MnSOD', 'Gene', (16, 21))	('EDA-BRB', 'Chemical', '-', (116, 123))
46924	20538426	In fact, 4 weeks after EDA-surgery, EDA-PD group had a lower lipid peroxidation level than SH-PD.	('EDA', 'Chemical', '-', (23, 26))	('EDA-PD', 'Var', (36, 42))	('PD', 'Chemical', 'MESH:D010165', (40, 42))	('EDA', 'Phenotype', 'HP:0100628', (36, 39))	('SH-PD', 'Chemical', '-', (91, 96))	('EDA', 'Phenotype', 'HP:0100628', (23, 26))	('EDA', 'Chemical', '-', (36, 39))	('lower', 'NegReg', (55, 60))	('lipid peroxidation level', 'MPA', (61, 85))	('PD', 'Chemical', 'MESH:D010165', (94, 96))	('lipid', 'Chemical', 'MESH:D008055', (61, 66))
46925	20538426	BRB supplementation significantly increased the measured MDA concentration compared to EDA-PD at 2 weeks (p <0.05), but had no effect at 4 weeks (Figure 5).	('EDA', 'Phenotype', 'HP:0100628', (87, 90))	('men', 'Species', '9606', (10, 13))	('PD', 'Chemical', 'MESH:D010165', (91, 93))	('EDA', 'Chemical', '-', (87, 90))	('BRB', 'Chemical', '-', (0, 3))	('BRB', 'Gene', (0, 3))	('rat', 'Species', '10116', (68, 71))	('MDA concentration', 'MPA', (57, 74))	('supplementation', 'Var', (4, 19))	('increased', 'PosReg', (34, 43))
46962	19014523	Deoxycholic acid induces the overexpression of intestinal mucin, MUC2, via NF-kB signaling pathway in human esophageal adenocarcinoma cells Mucin alterations are a common feature of esophageal neoplasia, and alterations in MUC2 mucin have been associated with tumor progression in the esophagus.	('tumor', 'Disease', (260, 265))	('Deoxycholic acid', 'Chemical', 'MESH:D003840', (0, 16))	('overexpression', 'PosReg', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('MUC2', 'Gene', (65, 69))	('MUC2', 'Gene', '4583', (223, 227))	('mucin', 'Gene', (58, 63))	('mucin', 'Gene', '100508689', (58, 63))	('MUC2', 'Gene', (223, 227))	('esophageal neoplasia', 'Disease', (182, 202))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (182, 202))	('neoplasia', 'Phenotype', 'HP:0002664', (193, 202))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('human', 'Species', '9606', (102, 107))	('Mucin', 'Gene', (140, 145))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (108, 133))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (108, 133))	('alterations', 'Var', (208, 219))	('mucin', 'Gene', (228, 233))	('esophageal adenocarcinoma', 'Disease', (108, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (182, 202))	('MUC2', 'Gene', '4583', (65, 69))	('Mucin', 'Gene', '100508689', (140, 145))	('mucin', 'Gene', '100508689', (228, 233))	('associated with', 'Reg', (244, 259))
47061	19014523	A previous study found that specific inhibitors of MAP kinase, U0126 and PD98059, inhibited the induction of MUC2 by bile acids.	('inhibited', 'NegReg', (82, 91))	('bile acids', 'Chemical', 'MESH:D001647', (117, 127))	('PD98059', 'Var', (73, 80))	('U0126', 'Var', (63, 68))	('MUC2', 'Gene', (109, 113))	('MUC2', 'Gene', '4583', (109, 113))	('PD98059', 'Chemical', 'MESH:C093973', (73, 80))	('U0126', 'Chemical', 'MESH:C113580', (63, 68))
47064	19014523	To further investigate the effection of MAPK on the induction of MUC2 and NF-kappaB, we used U0126 and PD98059 to selectively block the activity of MAPK, we found that these inhibitors did not block the DCA-dependent increase in MUC2 protein and NF-kappaB protein, although both U0126 and PD98059 did suppress phosphorylation of ERK1/2, JNK, and P38.	('DCA', 'Chemical', 'MESH:D003840', (203, 206))	('U0126', 'Chemical', 'MESH:C113580', (93, 98))	('MUC2', 'Gene', (65, 69))	('phosphorylation', 'MPA', (310, 325))	('MUC2', 'Gene', '4583', (229, 233))	('PD98059', 'Chemical', 'MESH:C093973', (289, 296))	('P38', 'Gene', (346, 349))	('NF-kappaB', 'Gene', (246, 255))	('PD98059', 'Var', (289, 296))	('MUC2', 'Gene', (229, 233))	('NF-kappaB', 'Gene', '4790', (246, 255))	('suppress', 'NegReg', (301, 309))	('ERK1/2', 'Protein', (329, 335))	('PD98059', 'Chemical', 'MESH:C093973', (103, 110))	('JNK', 'Gene', (337, 340))	('U0126', 'Chemical', 'MESH:C113580', (279, 284))	('NF-kappaB', 'Gene', (74, 83))	('JNK', 'Gene', '5599', (337, 340))	('MUC2', 'Gene', '4583', (65, 69))	('P38', 'Gene', '5594', (346, 349))	('NF-kappaB', 'Gene', '4790', (74, 83))
47071	19014523	Our data indicate that CAPE, an inhibitor of NF-kappaB translocation, it reduced endogenous as well as bile acid up-regulated MUC2 transcription, in addition NF-kappaB expression and transcription activity coincided with MUC2 induction, and inhibition of NF-kappaB expression and activity efficiently suppressed bile acid-mediated up-regulation of MUC2, indicating that NF-kappaB is involved in MUC2 transcription induced by bile acid.	('CAPE', 'Gene', (23, 27))	('inhibition', 'Var', (241, 251))	('NF-kappaB', 'Gene', (255, 264))	('MUC2', 'Gene', '4583', (221, 225))	('bile acid', 'Chemical', 'MESH:D001647', (312, 321))	('suppressed', 'NegReg', (301, 311))	('MUC2', 'Gene', '4583', (395, 399))	('MUC2', 'Gene', '4583', (126, 130))	('reduced', 'NegReg', (73, 80))	('NF-kappaB', 'Gene', (158, 167))	('NF-kappaB', 'Gene', '4790', (255, 264))	('MUC2', 'Gene', (221, 225))	('MUC2', 'Gene', '4583', (348, 352))	('MUC2', 'Gene', (395, 399))	('bile acid-mediated', 'MPA', (312, 330))	('NF-kappaB', 'Gene', '4790', (158, 167))	('MUC2', 'Gene', (126, 130))	('bile acid', 'Chemical', 'MESH:D001647', (103, 112))	('bile acid up-regulated', 'MPA', (103, 125))	('NF-kappaB', 'Gene', (370, 379))	('MUC2', 'Gene', (348, 352))	('NF-kappaB', 'Gene', (45, 54))	('endogenous', 'MPA', (81, 91))	('NF-kappaB', 'Gene', '4790', (370, 379))	('CAPE', 'Gene', '10592', (23, 27))	('NF-kappaB', 'Gene', '4790', (45, 54))	('bile acid', 'Chemical', 'MESH:D001647', (425, 434))
47115	33623071	The lung V5 and V20 as well as the mean lung dose were significantly and positively associated (r = 0.996, 0.974, 0.999, p < 0.001) with the lung V5_VBA (Fig.	('associated', 'Interaction', (84, 94))	('lung V5_VBA', 'Var', (141, 152))	('VBA', 'Chemical', '-', (149, 152))	('V20', 'Var', (16, 19))
47120	33623071	The mean lung dose and V5 were highly related to the risk of radiation pneumonitis, i.e., 3% and 38% within 1 year for V5 < 42% and V5 > 42% respectively.	('V5 > 42%', 'Var', (132, 140))	('V5 < 42%', 'Var', (119, 127))	('radiation pneumonitis', 'Disease', 'MESH:D017564', (61, 82))	('radiation pneumonitis', 'Disease', (61, 82))
47121	33623071	In summary, the incidence of radiation pneumonitis was positively correlated with the mean lung dose, V20, V10, and V5.	('radiation pneumonitis', 'Disease', (29, 50))	('V20', 'Var', (102, 105))	('radiation pneumonitis', 'Disease', 'MESH:D017564', (29, 50))	('V10', 'Var', (107, 110))
47213	31969127	Although several studies have reported poor long-term prognosis associated with high baseline SUVmax its prognostic value for the individual patient remains limited, as great variability is seen in the suggested cutoffs (ranging from 3 to 9 g/mL).	('to 9', 'Species', '1214577', (236, 240))	('high', 'Var', (80, 84))	('patient', 'Species', '9606', (141, 148))	('SUVmax', 'MPA', (94, 100))
47221	31969127	The added value of our study lies in the identification of SUVmax > 12.7 g/mL as an independent predictor of early tumor recurrence, within the 1st postoperative year.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('> 12.7 g/mL', 'Var', (66, 77))
47224	31969127	previously reported worse DFS for patients with baseline SUVmax > 3.67 g/mL, although no correlation with overall survival was found in that study either.	('DFS', 'MPA', (26, 29))	('worse', 'NegReg', (20, 25))	('patients', 'Species', '9606', (34, 42))	('> 3.67 g/mL', 'Var', (64, 75))
47235	31969127	18F- FDG PET/CT derived parameters SUVmax > 8.25 g/mL, TLG > 41.7 g and MTV > 10.70 cm3 were significantly associated with locally advanced cT3/4 stage and a baseline SUVmax > 12.7 g/mL with early tumor recurrence and poor disease-free survival, particularly for squamous cell cancer.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('associated', 'Reg', (107, 117))	('squamous cell cancer', 'Disease', (263, 283))	('FDG', 'Gene', '23583', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('SUVmax', 'MPA', (167, 173))	('FDG', 'Gene', (5, 8))	('TLG', 'Disease', 'MESH:C564972', (55, 58))	('squamous cell cancer', 'Disease', 'MESH:D018307', (263, 283))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (263, 283))	('cT3/4', 'Gene', '27120;285782', (140, 145))	('cT3/4', 'Gene', (140, 145))	('tumor', 'Disease', (197, 202))	('> 8.25', 'Var', (42, 48))	('TLG', 'Disease', (55, 58))
47246	29157271	Fifty-one patients (31 patients treated with CDDP/5FU and 20 patients treated with Carb/TAX) were evaluated for the intention-to-treat (ITT) analysis and 44 patients (26 patients treated with CDDP/5FU and 18 patients treated with Carb/TAX) were evaluated for the PP analysis.	('patients', 'Species', '9606', (170, 178))	('CDDP', 'Chemical', 'MESH:D002945', (45, 49))	('patients', 'Species', '9606', (208, 216))	('CDDP', 'Chemical', 'MESH:D002945', (192, 196))	('Carb', 'Gene', '9482', (230, 234))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (61, 69))	('Carb', 'Gene', '9482', (83, 87))	('5FU', 'Chemical', 'MESH:D005472', (197, 200))	('5FU', 'Chemical', 'MESH:D005472', (50, 53))	('patients', 'Species', '9606', (157, 165))	('Carb', 'Gene', (230, 234))	('CDDP/5FU', 'Var', (45, 53))	('patients', 'Species', '9606', (10, 18))	('Carb', 'Gene', (83, 87))
47251	29157271	Patients treated with CDDP/5FU developed significantly more cumulative hematologic III  (CTCAE) toxicities (58% vs 20%; p = 0.010) than patients treated with Carb/TAX.	('toxicities', 'Disease', (96, 106))	('CDDP/5FU', 'Var', (22, 30))	('Carb', 'Gene', '9482', (158, 162))	('hematologic', 'CPA', (71, 82))	('CDDP', 'Chemical', 'MESH:D002945', (22, 26))	('toxicities', 'Disease', 'MESH:D064420', (96, 106))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (136, 144))	('Carb', 'Gene', (158, 162))	('5FU', 'Chemical', 'MESH:D005472', (27, 30))
47253	29157271	In this retrospective analysis, no significant difference was seen for OS and FFR between nCRT with CDDP/5FU and nCRT with Carb/TAX.	('Carb', 'Gene', '9482', (123, 127))	('CDDP', 'Chemical', 'MESH:D002945', (100, 104))	('Carb', 'Gene', (123, 127))	('5FU', 'Chemical', 'MESH:D005472', (105, 108))	('FFR', 'Gene', (78, 81))	('OS', 'Chemical', '-', (71, 73))	('CDDP/5FU', 'Var', (100, 108))	('FFR', 'Gene', '738', (78, 81))
47254	29157271	However, the application of CDDP/5FU was associated with significantly more hematologic III - toxicities compared to Carb/TAX.	('more', 'PosReg', (71, 75))	('toxicities', 'Disease', (94, 104))	('CDDP', 'Chemical', 'MESH:D002945', (28, 32))	('5FU', 'Chemical', 'MESH:D005472', (33, 36))	('Carb', 'Gene', '9482', (117, 121))	('CDDP/5FU', 'Var', (28, 36))	('toxicities', 'Disease', 'MESH:D064420', (94, 104))	('Carb', 'Gene', (117, 121))
47267	29157271	In the mentioned study, patients treated with CDDP/5FU had more hematological toxicities, whereas there was no significant difference for overall survival.	('CDDP/5FU', 'Var', (46, 54))	('CDDP', 'Chemical', 'MESH:D002945', (46, 50))	('hematological toxicities', 'Disease', (64, 88))	('patients', 'Species', '9606', (24, 32))	('5FU', 'Chemical', 'MESH:D005472', (51, 54))	('hematological toxicities', 'Disease', 'MESH:D006402', (64, 88))
47307	29157271	Regarding hematologic parameters significantly more grade III toxicities were seen in patients treated with CDDP/5FU (58%) compared to patients treated analogue to the CROSS-protocol (20%) (p = 0.010).	('patients', 'Species', '9606', (135, 143))	('CDDP', 'Chemical', 'MESH:D002945', (108, 112))	('toxicities', 'Disease', 'MESH:D064420', (62, 72))	('OS', 'Chemical', '-', (170, 172))	('toxicities', 'Disease', (62, 72))	('5FU', 'Chemical', 'MESH:D005472', (113, 116))	('CDDP/5FU', 'Var', (108, 116))	('patients', 'Species', '9606', (86, 94))
47310	29157271	In patients treated per protocol, significantly higher rates of leukopenia were seen in patients who received CDDP/5FU than in patients who were treated with Carb/TAX (I : 15% vs. 17%, II : 19% vs. 56%, III : 50% vs. 17%, IV : 8% vs. 0%; p = 0.048).	('leukopenia', 'Disease', 'MESH:D007970', (64, 74))	('CDDP', 'Chemical', 'MESH:D002945', (110, 114))	('Carb', 'Gene', '9482', (158, 162))	('patients', 'Species', '9606', (88, 96))	('5FU', 'Chemical', 'MESH:D005472', (115, 118))	('leukopenia', 'Phenotype', 'HP:0001882', (64, 74))	('patients', 'Species', '9606', (127, 135))	('higher', 'PosReg', (48, 54))	('Carb', 'Gene', (158, 162))	('patients', 'Species', '9606', (3, 11))	('CDDP/5FU', 'Var', (110, 118))	('leukopenia', 'Disease', (64, 74))
47327	29157271	While there were no differences regarding overall survival and freedom from relapse for the two treatment regimes, significantly more hematologic III  toxicities were observed in patients treated with CDDP/5FU.	('more', 'PosReg', (129, 133))	('hematologic III  toxicities', 'Disease', 'MESH:D006402', (134, 161))	('CDDP', 'Chemical', 'MESH:D002945', (201, 205))	('5FU', 'Chemical', 'MESH:D005472', (206, 209))	('patients', 'Species', '9606', (179, 187))	('CDDP/5FU', 'Var', (201, 209))	('hematologic III  toxicities', 'Disease', (134, 161))
47330	29157271	No significant differences were seen for OS, but as in our study, patients treated with CDDP/5FU had a significantly higher risk of developing any grade III toxicity than patients treated with the CROSS-regime (41% vs. 25%).	('OS', 'Chemical', '-', (199, 201))	('OS', 'Chemical', '-', (41, 43))	('CDDP/5FU', 'Var', (88, 96))	('5FU', 'Chemical', 'MESH:D005472', (93, 96))	('toxicity', 'Disease', (157, 165))	('toxicity', 'Disease', 'MESH:D064420', (157, 165))	('patients', 'Species', '9606', (171, 179))	('CDDP', 'Chemical', 'MESH:D002945', (88, 92))	('patients', 'Species', '9606', (66, 74))
47331	29157271	Thereby, the most common >= III  toxicity was leukopenia, which was observed in 24% of patients treated with CDDP/5FU and 10% of patients treated with the CROSS-regime.	('CDDP/5FU', 'Var', (109, 117))	('toxicity', 'Disease', 'MESH:D064420', (33, 41))	('5FU', 'Chemical', 'MESH:D005472', (114, 117))	('leukopenia', 'Phenotype', 'HP:0001882', (46, 56))	('patients', 'Species', '9606', (129, 137))	('leukopenia', 'Disease', (46, 56))	('CDDP', 'Chemical', 'MESH:D002945', (109, 113))	('leukopenia', 'Disease', 'MESH:D007970', (46, 56))	('patients', 'Species', '9606', (87, 95))	('toxicity', 'Disease', (33, 41))	('OS', 'Chemical', '-', (157, 159))
47334	29157271	Nonetheless, toxicity results for patients treated with CDDP/5FU match with the results by Tepper et al.	('toxicity', 'Disease', 'MESH:D064420', (13, 21))	('toxicity', 'Disease', (13, 21))	('CDDP', 'Chemical', 'MESH:D002945', (56, 60))	('patients', 'Species', '9606', (34, 42))	('5FU', 'Chemical', 'MESH:D005472', (61, 64))	('CDDP/5FU', 'Var', (56, 64))
47337	29157271	As in other studies leukopenia was the most common hematologic toxicity and our analysis showed a strong trend for higher grades of leukopenia in patients treated with CDDP/5FU in the ITT-analysis and significantly higher grades of leukopenia in patients treated with CDDP/5FU in the PP population.	('leukopenia', 'Disease', 'MESH:D007970', (20, 30))	('hematologic toxicity', 'Disease', 'MESH:D006402', (51, 71))	('5FU', 'Chemical', 'MESH:D005472', (173, 176))	('leukopenia', 'Phenotype', 'HP:0001882', (232, 242))	('leukopenia', 'Phenotype', 'HP:0001882', (132, 142))	('patients', 'Species', '9606', (246, 254))	('CDDP', 'Chemical', 'MESH:D002945', (268, 272))	('CDDP', 'Chemical', 'MESH:D002945', (168, 172))	('leukopenia', 'Disease', (232, 242))	('leukopenia', 'Disease', (132, 142))	('5FU', 'Chemical', 'MESH:D005472', (273, 276))	('leukopenia', 'Phenotype', 'HP:0001882', (20, 30))	('leukopenia', 'Disease', 'MESH:D007970', (232, 242))	('hematologic toxicity', 'Disease', (51, 71))	('CDDP/5FU', 'Var', (168, 176))	('leukopenia', 'Disease', 'MESH:D007970', (132, 142))	('leukopenia', 'Disease', (20, 30))	('patients', 'Species', '9606', (146, 154))
47371	29157271	Because nCRT with CDDP/5FU was only used until 2014 and nCRT with Carb/TAX was only used since then, follow-up for patients treated with CDDP/5FU is obviously longer than for patient treated with Carb/PTAX, which can affect OS and FFR.	('patients', 'Species', '9606', (115, 123))	('5FU', 'Chemical', 'MESH:D005472', (142, 145))	('Carb', 'Gene', '9482', (196, 200))	('OS', 'Chemical', '-', (224, 226))	('CDDP/5FU', 'Var', (137, 145))	('FFR', 'Gene', (231, 234))	('patient', 'Species', '9606', (175, 182))	('CDDP', 'Chemical', 'MESH:D002945', (18, 22))	('Carb', 'Gene', '9482', (66, 70))	('Carb', 'Gene', (196, 200))	('FFR', 'Gene', '738', (231, 234))	('5FU', 'Chemical', 'MESH:D005472', (23, 26))	('patient', 'Species', '9606', (115, 122))	('PTAX', 'Chemical', '-', (201, 205))	('affect', 'Reg', (217, 223))	('Carb', 'Gene', (66, 70))	('CDDP', 'Chemical', 'MESH:D002945', (137, 141))
47381	28086222	Leukocytosis and neutrophilia were defined as a leukocyte or neutrophil count over 10 G/L and 7 G/L, respectively.	('10 G/L', 'Var', (83, 89))	('7 G/L', 'SUBSTITUTION', 'None', (94, 99))	('Leukocytosis and neutrophilia', 'Disease', 'MESH:D007964', (0, 29))	('7 G/L', 'Var', (94, 99))	('10 G/L', 'SUBSTITUTION', 'None', (83, 89))	('Leukocytosis', 'Phenotype', 'HP:0001974', (0, 12))	('neutrophilia', 'Phenotype', 'HP:0011897', (17, 29))
47479	28086222	Leukocytosis and neutrophilia, defining biological inflammation, were defined as blood count over 10 G/L and 7 G/L, respectively.	('10 G/L', 'SUBSTITUTION', 'None', (98, 104))	('inflammation', 'Disease', (51, 63))	('Leukocytosis', 'Phenotype', 'HP:0001974', (0, 12))	('Leukocytosis and neutrophilia', 'Disease', 'MESH:D007964', (0, 29))	('7 G/L', 'SUBSTITUTION', 'None', (109, 114))	('10 G/L', 'Var', (98, 104))	('neutrophilia', 'Phenotype', 'HP:0011897', (17, 29))	('7 G/L', 'Var', (109, 114))	('inflammation', 'Disease', 'MESH:D007249', (51, 63))
47480	28086222	Anemia was defined as hemoglobin count below 12.0 g/dL; thrombocytosis as platelet count over 400,000 /mm3; lymphopenia as lymphocyte count below 1,000 /mm3; and monocytosis as monocyte count over 1,000 /mm3.	('below', 'NegReg', (140, 145))	('thrombocytosis', 'Disease', (56, 70))	('platelet count', 'MPA', (74, 88))	('below', 'Var', (39, 44))	('lymphopenia', 'Disease', 'MESH:D008231', (108, 119))	('lymphopenia', 'Phenotype', 'HP:0001888', (108, 119))	('thrombocytosis', 'Phenotype', 'HP:0001894', (56, 70))	('monocytosis', 'Phenotype', 'HP:0012311', (162, 173))	('Anemia', 'Phenotype', 'HP:0001903', (0, 6))	('Anemia', 'Disease', (0, 6))	('monocytosis', 'Disease', (162, 173))	('Anemia', 'Disease', 'MESH:D000740', (0, 6))	('lymphopenia', 'Disease', (108, 119))	('thrombocytosis', 'Disease', 'MESH:D013922', (56, 70))	('hemoglobin', 'Disease', (22, 32))
47491	26925372	Association between microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 polymorphisms and esophageal cancer risk: A meta-analysis Many observational studies have found that microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 are associated with esophageal cancer risk.	('rs11614913', 'Var', (35, 45))	('esophageal cancer', 'Disease', (117, 134))	('esophageal cancer', 'Disease', (299, 316))	('rs6505162', 'Mutation', 'rs6505162', (269, 278))	('rs11614913', 'Mutation', 'rs11614913', (35, 45))	('Association', 'Interaction', (0, 11))	('rs2910164', 'Mutation', 'rs2910164', (241, 250))	('microRNA-423', 'Gene', (256, 268))	('microRNA-196a2 rs11614913', 'Var', (200, 225))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('rs11614913', 'Var', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('associated', 'Reg', (283, 293))	('rs11614913', 'Mutation', 'rs11614913', (215, 225))	('microRNA-423', 'Gene', '494335', (76, 88))	('rs6505162', 'Mutation', 'rs6505162', (89, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (299, 316))	('rs2910164', 'Mutation', 'rs2910164', (61, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('microRNA-423', 'Gene', (76, 88))	('microRNA-423', 'Gene', '494335', (256, 268))	('microRNA-146a rs2910164', 'Var', (227, 250))
47492	26925372	We conducted a meta-analysis to assess the relationship between the polymorphisms of three microRNAs and esophageal cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal cancer', 'Disease', (105, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('polymorphisms', 'Var', (68, 81))
47494	26925372	A total of 6 case-control studies on microRNA-196a2 rs11614913, 4 studies on microRNA-146a rs2910164, and 4 studies on microRNA-423 rs6505162 were considered eligible in the meta-analysis.	('microRNA-423', 'Gene', (119, 131))	('microRNA-196a2', 'Gene', (37, 51))	('rs11614913', 'Var', (52, 62))	('rs6505162', 'Mutation', 'rs6505162', (132, 141))	('rs2910164', 'Var', (91, 100))	('microRNA-423', 'Gene', '494335', (119, 131))	('rs2910164', 'Mutation', 'rs2910164', (91, 100))	('rs11614913', 'Mutation', 'rs11614913', (52, 62))
47495	26925372	No statistical association was found between microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 polymorphisms and esophageal cancer susceptibility in any genetic model.	('rs2910164', 'Mutation', 'rs2910164', (86, 95))	('rs2910164', 'Var', (86, 95))	('esophageal cancer', 'Disease', (142, 159))	('rs11614913', 'Mutation', 'rs11614913', (60, 70))	('rs6505162', 'Mutation', 'rs6505162', (114, 123))	('rs6505162', 'Var', (114, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (142, 159))	('microRNA-423', 'Gene', '494335', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('microRNA-196a2', 'Gene', (45, 59))	('microRNA-423', 'Gene', (101, 113))	('rs11614913', 'Var', (60, 70))
47496	26925372	In summary, based on the currently limited proof, no association exists between microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 polymorphism and esophageal cancer risk.	('microRNA-423', 'Gene', '494335', (136, 148))	('rs2910164', 'Var', (121, 130))	('esophageal cancer', 'Disease', (176, 193))	('microRNA-423', 'Gene', (136, 148))	('rs11614913', 'Mutation', 'rs11614913', (95, 105))	('rs6505162', 'Mutation', 'rs6505162', (149, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (176, 193))	('rs6505162', 'Var', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('rs11614913', 'Var', (95, 105))	('microRNA-196a2', 'Gene', (80, 94))	('rs2910164', 'Mutation', 'rs2910164', (121, 130))
47502	26925372	In recent years, many studies have demonstrated that deregulation of microRNAs may play crucial role in malignant transformation of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('malignant transformation', 'CPA', (104, 128))	('esophageal cancer', 'Disease', (132, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('microRNAs', 'Protein', (69, 78))	('deregulation', 'Var', (53, 65))
47505	26925372	As of this writing, a number of epidemiological studies have been conducted to examine the association between microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 polymorphisms and esophageal cancer risk.	('rs2910164', 'Mutation', 'rs2910164', (152, 161))	('rs2910164', 'Var', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('microRNA-423', 'Gene', (167, 179))	('rs11614913', 'Mutation', 'rs11614913', (126, 136))	('rs6505162', 'Mutation', 'rs6505162', (180, 189))	('rs6505162', 'Var', (180, 189))	('esophageal cancer', 'Disease', (208, 225))	('microRNA-423', 'Gene', '494335', (167, 179))	('rs11614913', 'Var', (126, 136))	('microRNA-196a2', 'Gene', (111, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('association', 'Interaction', (91, 102))
47509	26925372	Studies were considered eligible in the meta-analysis if they met the following criteria: (1) an evaluation of the association between microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 polymorphisms and esophageal cancer susceptibility (with full text); (2) a case-control study; (3) and detailed genotype data were available for calculating ORs and the corresponding 95% CIs.	('rs2910164', 'Var', (176, 185))	('association', 'Interaction', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('rs11614913', 'Mutation', 'rs11614913', (150, 160))	('rs6505162', 'Mutation', 'rs6505162', (204, 213))	('microRNA-423', 'Gene', '494335', (191, 203))	('esophageal cancer', 'Disease', (232, 249))	('microRNA-423', 'Gene', (191, 203))	('rs11614913', 'Var', (150, 160))	('rs2910164', 'Mutation', 'rs2910164', (176, 185))	('microRNA-196a2', 'Gene', (135, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (232, 249))
47511	26925372	The overall ORs were summarized to assess the strength of the association between the microRNAs 196a2/146a/423 and esophageal cancer susceptibility.	('microRNAs 196a2/146a/423', 'Var', (86, 110))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('esophageal cancer', 'Disease', (115, 132))
47513	26925372	The included studies involving 2,071 cases and 2,547 controls for microRNA-196a2 C > T rs11614913, 1,494 cases and 1,538 controls for microRNA-146a C > G rs2910164 and 2,048 cases and 2,995 controls for microRNA-423 C > A rs2910164 were considered eligible in the meta-analysis.	('rs2910164', 'DBSNP_MENTION', 'None', (154, 163))	('microRNA-423', 'Gene', '494335', (203, 215))	('C > T rs11614913', 'Var', (81, 97))	('rs2910164', 'Mutation', 'rs2910164', (222, 231))	('microRNA-423', 'Gene', (203, 215))	('rs2910164', 'DBSNP_MENTION', 'None', (222, 231))	('rs2910164', 'Var', (222, 231))	('microRNA-196a2', 'Gene', (66, 80))	('rs2910164', 'Var', (154, 163))	('rs2910164', 'Mutation', 'rs2910164', (154, 163))	('rs11614913', 'Mutation', 'rs11614913', (87, 97))
47514	26925372	Genotype frequencies of microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 were reported in one study.	('rs11614913', 'Mutation', 'rs11614913', (39, 49))	('rs6505162', 'Mutation', 'rs6505162', (93, 102))	('microRNA-423', 'Gene', (80, 92))	('rs6505162', 'Var', (93, 102))	('rs11614913', 'Var', (39, 49))	('microRNA-196a2', 'Gene', (24, 38))	('microRNA-423', 'Gene', '494335', (80, 92))	('microRNA-146a', 'Gene', (51, 64))	('rs2910164', 'Mutation', 'rs2910164', (65, 74))	('rs2910164', 'Var', (65, 74))
47515	26925372	In two studies, the genotype frequencies of microRNA-196a2 rs11614913 and microRNA-146a rs2910164 were reported.	('rs11614913', 'Var', (59, 69))	('rs2910164', 'Var', (88, 97))	('microRNA-196a2', 'Gene', (44, 58))	('rs2910164', 'Mutation', 'rs2910164', (88, 97))	('rs11614913', 'Mutation', 'rs11614913', (59, 69))
47516	26925372	Genotype frequencies of microRNA-423 rs6505162 were presented separately in one study; thus, each of the abovementioned studies were considered separately.	('rs6505162', 'Var', (37, 46))	('microRNA-423', 'Gene', '494335', (24, 36))	('microRNA-423', 'Gene', (24, 36))	('rs6505162', 'Mutation', 'rs6505162', (37, 46))
47519	26925372	Among the studies on microRNA-423 C > A rs6505162, two studies involved Asian subjects, whereas African subjects were included in the other two studies.	('rs6505162', 'Var', (40, 49))	('microRNA-423', 'Gene', (21, 33))	('rs6505162', 'DBSNP_MENTION', 'None', (40, 49))	('microRNA-423', 'Gene', '494335', (21, 33))
47522	26925372	In addition, three studies reported the hsa-microRNA-196a2 rs11614913 polymorphism, and the pooled estimates suggested that the association between hsa-microRNA-196a2 rs11614913 polymorphism and esophageal cancer in Chinese Han population was not detected in all genetic models (Table 2).	('esophageal cancer', 'Disease', (195, 212))	('rs11614913', 'Var', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('rs11614913', 'Mutation', 'rs11614913', (167, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('rs11614913', 'Var', (167, 177))	('rs11614913', 'Mutation', 'rs11614913', (59, 69))	('hsa-microRNA-196a2', 'Gene', (148, 166))
47525	26925372	Four studies examined the association between microRNA-146a C > G rs2910164 and esophageal cancer risk.	('examined', 'Reg', (13, 21))	('esophageal cancer', 'Disease', (80, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('microRNA-146a', 'Gene', (46, 59))	('rs2910164', 'Mutation', 'rs2910164', (66, 75))	('C > G rs2910164', 'Var', (60, 75))	('rs2910164', 'Var', (66, 75))
47527	26925372	Four studies contained data on microRNA-423 C > A rs6505162.	('microRNA-423', 'Gene', (31, 43))	('microRNA-423', 'Gene', '494335', (31, 43))	('rs6505162', 'DBSNP_MENTION', 'None', (50, 59))	('rs6505162', 'Var', (50, 59))
47528	26925372	No publication bias for the association between microRNA-196a2 C > T rs11614913 polymorphism and esophageal cancer susceptibility was detected by Begg's funnel plot (allele model G vs. C, P = 1.00) or by Egger's regression test (allele model G vs. C, P = 0.75) (Fig.	('rs11614913', 'Var', (69, 79))	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('C > T rs11614913', 'Var', (63, 79))	('microRNA-196a2', 'Gene', (48, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('rs11614913', 'Mutation', 'rs11614913', (69, 79))
47529	26925372	Publication bias was not assessed for the association between microRNA-146a C > G rs2910164 and microRNA-423 C > A rs6505162 and esophageal cancer susceptibility because of the limited number of studies included in each analysis.	('microRNA-423', 'Gene', '494335', (96, 108))	('microRNA-146a', 'Var', (62, 75))	('rs6505162', 'Var', (115, 124))	('microRNA-423', 'Gene', (96, 108))	('rs2910164', 'Mutation', 'rs2910164', (82, 91))	('rs2910164', 'Var', (82, 91))	('esophageal cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('rs6505162', 'DBSNP_MENTION', 'None', (115, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
47530	26925372	To the best of our knowledge, this meta-analysis is the first to evaluate the association between microRNA-196a2 C > T rs11614913, microRNA-146a C > G rs2910164, and microRNA-423 C > A rs6505162 and esophageal cancer risk.	('microRNA-196a2', 'Gene', (98, 112))	('esophageal cancer', 'Disease', (199, 216))	('esophageal cancer', 'Disease', 'MESH:D004938', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('C > T rs11614913', 'Var', (113, 129))	('C > G rs2910164', 'Var', (145, 160))	('rs11614913', 'Mutation', 'rs11614913', (119, 129))	('microRNA-423', 'Gene', '494335', (166, 178))	('rs6505162', 'Var', (185, 194))	('rs6505162', 'DBSNP_MENTION', 'None', (185, 194))	('microRNA-423', 'Gene', (166, 178))	('rs2910164', 'Mutation', 'rs2910164', (151, 160))	('association', 'Interaction', (78, 89))
47531	26925372	In this meta-analysis, 6 eligible case-control studies involving 2,071 cases and 2,547 controls for microRNA-196a2 C > T rs11614913, 4 studies including 1,494 cases and 1,538 controls for microRNA-146a C > G rs2910164, and 4 studies involving 2,048 cases and 2,995 controls for microRNA-423 C > A rs6505162 were analyzed.	('C > T rs11614913', 'Var', (115, 131))	('rs11614913', 'Var', (121, 131))	('rs2910164', 'Mutation', 'rs2910164', (208, 217))	('rs6505162', 'DBSNP_MENTION', 'None', (297, 306))	('rs2910164', 'Var', (208, 217))	('rs6505162', 'Var', (297, 306))	('microRNA-423', 'Gene', '494335', (278, 290))	('microRNA-423', 'Gene', (278, 290))	('rs11614913', 'Mutation', 'rs11614913', (121, 131))	('microRNA-196a2', 'Gene', (100, 114))
47532	26925372	The major finding of the present meta-analysis suggested that no significant association between microRNA-196a2/146a/423 polymorphisms and esophageal cancer susceptibility was observed in all genetic models.	('microRNA-196a2/146a/423', 'Gene', (97, 120))	('esophageal cancer', 'Disease', (139, 156))	('polymorphisms', 'Var', (121, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
47533	26925372	Among studies on Hsa-microRNA-196a2, three studies demonstrated that Hsa-microRNA-196a2 was associated with increased esophageal cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('increased', 'PosReg', (108, 117))	('Hsa-microRNA-196a2', 'Var', (69, 87))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))
47537	26925372	The three studies discussed the association between microRNA-26a-1 C > T rs7372209 and microRNA-499 T > C rs3746444 and esophageal cancer susceptibility, and the pooled estimates suggested that no significant association was detected.	('microRNA-499', 'Gene', (87, 99))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('rs3746444', 'DBSNP_MENTION', 'None', (106, 115))	('rs7372209', 'DBSNP_MENTION', 'None', (73, 82))	('microRNA-26a-1', 'Gene', '407015', (52, 66))	('microRNA-26a-1', 'Gene', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('microRNA-499', 'Gene', '574501', (87, 99))	('rs7372209', 'Var', (73, 82))	('rs3746444', 'Var', (106, 115))	('esophageal cancer', 'Disease', (120, 137))	('association', 'Interaction', (32, 43))
47540	26925372	It may be explained that the conflicting results with respect to microRNA-196a2 polymorphisms and esophageal cancer risk between Caucasian and Asian population.	('esophageal cancer', 'Disease', (98, 115))	('polymorphisms', 'Var', (80, 93))	('microRNA-196a2', 'Gene', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
47542	26925372	First, this is the first meta-analysis to investigate the association between and esophageal cancer susceptibility and microRNA-196a2, microRNA-146a, and microRNA-423.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('microRNA-423', 'Gene', '494335', (154, 166))	('microRNA-423', 'Gene', (154, 166))	('microRNA-196a2', 'Var', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('microRNA-146a', 'Var', (135, 148))	('esophageal cancer', 'Disease', (82, 99))
47548	26925372	In conclusion, the current available evidence suggested that the microRNA-196a2, microRNA-146a, and microRNA-423 are unlikely to have any important effects on the risk of esophageal cancer, except on Caucasian subjects.	('microRNA-423', 'Gene', '494335', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('microRNA-423', 'Gene', (100, 112))	('microRNA-196a2', 'Var', (65, 79))	('microRNA-146a', 'Var', (81, 94))	('esophageal cancer', 'Disease', (171, 188))
47602	25907360	Both tumor and nodal stage had a significant influence on OS, with patients harbouring T1/2 tumors or N0-status achieving a median OS of 25.9 and 29.6 months, respectively.	('OS', 'Chemical', '-', (58, 60))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('N0-status', 'Var', (102, 111))	('OS', 'Chemical', '-', (131, 133))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
47683	25699038	Alternative splicing is also an important characteristic of the HLA-G gene.	('Alternative splicing', 'Var', (0, 20))	('HLA-G', 'Gene', (64, 69))	('HLA-G', 'Gene', '3135', (64, 69))
47688	25699038	Although there is no consensus regarding where the HLA-G transcription starts, the polymorphisms at the 5' upstream regulatory region (5'URR) have been considered to influence HLA-G expression, mainly because of the fact that polymorphic sites coincides with, or are close to, known transcription factor binding sites (Figure 1) [Reviewed at Ref.	('expression', 'MPA', (182, 192))	('HLA-G', 'Gene', (176, 181))	('HLA-G', 'Gene', (51, 56))	('HLA-G', 'Gene', '3135', (176, 181))	('HLA-G', 'Gene', '3135', (51, 56))	('polymorphisms', 'Var', (83, 96))	('influence', 'Reg', (166, 175))
47689	25699038	Likewise, haplotypes at the HLA-G 3'UTR segment have been considered influencing HLA-G expression, mainly because the fact that some polymorphic sites (such as the one at position +3142) may influence the binding of specific microRNAs or may influence mRNA stability (such as the one at position +3187) and alternative splicing (such as the 14-bp polymorphism) (Figure 2).	('HLA-G', 'Gene', '3135', (81, 86))	('alternative splicing', 'MPA', (307, 327))	('influence', 'Reg', (242, 251))	('microRNAs', 'Protein', (225, 234))	('HLA-G', 'Gene', (28, 33))	('HLA-G', 'Gene', '3135', (28, 33))	('influence', 'Reg', (191, 200))	('specific microRNAs', 'Protein', (216, 234))	('polymorphic', 'Var', (133, 144))	('binding', 'Interaction', (205, 212))	('mRNA stability', 'MPA', (252, 266))	('HLA-G', 'Gene', (81, 86))
47690	25699038	The HLA-G coding region presents mainly synonymous or intronic variation sites.	('intronic variation', 'Var', (54, 72))	('HLA-G', 'Gene', '3135', (4, 9))	('HLA-G', 'Gene', (4, 9))
47695	25699038	In the present review, we report some diseases that have been associated with the modulation of the HLA-G expression, with the presence of specific HLA-G gene variation sites or both, and whenever known, the mechanisms underlying such associations are discussed.	('modulation', 'Var', (82, 92))	('variation sites', 'Var', (159, 174))	('HLA-G', 'Gene', (100, 105))	('HLA-G', 'Gene', '3135', (100, 105))	('HLA-G', 'Gene', (148, 153))	('HLA-G', 'Gene', '3135', (148, 153))	('diseases', 'Disease', (38, 46))	('presence', 'Var', (127, 135))
47715	25699038	In breast cancer patients, the 14-bpDEL allele and 14-bpDEL/DEL genotype were associated with susceptibility to breast cancer in Southeastern Iranian and Korean patients; however, no association has been reported for Brazilians.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (112, 125))	('14-bpDEL/DEL', 'Var', (51, 63))	('14-bpDEL', 'Chemical', '-', (31, 39))	('14-bpDEL', 'Chemical', '-', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('14-bpDEL', 'Var', (31, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (17, 25))	('susceptibility', 'Reg', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
47717	25699038	A meta-analysis evaluating the role of the 14-bpINS/DEL polymorphism in breast cancer reports an overall cancer risk in Asian populations.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('14-bpINS/DEL polymorphism', 'Var', (43, 68))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
47718	25699038	The 14-bpDEL allele was associated with susceptibility to hepatocellular carcinoma in Brazilian and Chinese patients, but not in Korean patients.	('hepatocellular carcinoma', 'Disease', (58, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('14-bpDEL', 'Chemical', '-', (4, 12))	('14-bpDEL', 'Var', (4, 12))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (108, 116))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
47719	25699038	In addition, Chinese patients exhibiting the 14-bpDEL/DEL genotype presented increased HLA-G expression in hepatocellular carcinoma specimens.	('14-bpDEL/DEL', 'Var', (45, 57))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (107, 131))	('14-bpDEL', 'Chemical', '-', (45, 53))	('hepatocellular carcinoma', 'Disease', (107, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (107, 131))	('HLA-G', 'Gene', (87, 92))	('HLA-G', 'Gene', '3135', (87, 92))	('patients', 'Species', '9606', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('increased', 'PosReg', (77, 86))
47720	25699038	The 14-bpINS/DEL genotype was associated with decreased risk for childhood neuroblastoma development in Australian and New Zealand patients.	('patients', 'Species', '9606', (131, 139))	('14-bpINS/DEL', 'Var', (4, 16))	('neuroblastoma', 'Disease', 'MESH:D009447', (75, 88))	('neuroblastoma', 'Disease', (75, 88))	('decreased', 'NegReg', (46, 55))	('child', 'Species', '9606', (65, 70))	('neuroblastoma', 'Phenotype', 'HP:0003006', (75, 88))
47722	25699038	Considering the HLA-G coding segment, the +755C/A (non-synonymous Leu/Ile substitution at codon 110, which defines the HLA-G*01:04 protein group) was associated with protection against more severe nasopharyngeal carcinoma tumor stages.	('Leu', 'Chemical', 'MESH:D007930', (66, 69))	('+755C/A', 'Mutation', 'c.+755C>A', (42, 49))	('HLA-G', 'Gene', (119, 124))	('HLA-G', 'Gene', '3135', (119, 124))	('+755C/A', 'Var', (42, 49))	('carcinoma tumor', 'Disease', (212, 227))	('carcinoma tumor', 'Disease', 'MESH:D009369', (212, 227))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (197, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('nasopharyngeal carcinoma', 'Disease', (197, 221))	('HLA-G', 'Gene', (16, 21))	('HLA-G', 'Gene', '3135', (16, 21))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (197, 221))
47726	25699038	No association has been observed for: (i) HLA-G coding region alleles in South Korean and Brazilian breast cancer patients; (ii) 14-bpINS/DEL polymorphism in Italian patients presenting thyroid cancer; (iii) HLA-G*01:03 allele and HLA-G*01:05N null allele in Tunisian patients with nasopharyngeal carcinoma; (iv) HLA-G*01:05N null allele with susceptibility to esophagus carcinoma development in Chinese patients; (v) 14-bp INS/DEL polymorphic site in Brazilian bladder TCC patients; and (vi) +292A/T, +755C/A, and +1799C/T in Australian and New Zealand childhood neuroblastoma patients.	('thyroid cancer', 'Disease', (186, 200))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (282, 306))	('patients', 'Species', '9606', (404, 412))	('HLA-G', 'Gene', '3135', (313, 318))	('patients', 'Species', '9606', (268, 276))	('patients', 'Species', '9606', (474, 482))	('+292A/T', 'Mutation', 'c.+292A>T', (493, 500))	('esophagus carcinoma', 'Phenotype', 'HP:0011459', (361, 380))	('esophagus carcinoma', 'Disease', 'MESH:D004938', (361, 380))	('HLA-G', 'Gene', '3135', (42, 47))	('neuroblastoma', 'Disease', (564, 577))	('+755C/A', 'Mutation', 'c.+755C>A', (502, 509))	('+755C/A', 'Var', (502, 509))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (282, 306))	('patients', 'Species', '9606', (578, 586))	('HLA-G', 'Gene', '3135', (231, 236))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('thyroid cancer', 'Disease', 'MESH:D013964', (186, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (371, 380))	('neuroblastoma', 'Phenotype', 'HP:0003006', (564, 577))	('HLA-G', 'Gene', '3135', (208, 213))	('patients', 'Species', '9606', (114, 122))	('+1799C/T', 'Mutation', 'c.+1799C>T', (515, 523))	('neuroblastoma', 'Disease', 'MESH:D009447', (564, 577))	('child', 'Species', '9606', (554, 559))	('HLA-G', 'Gene', (313, 318))	('thyroid cancer', 'Phenotype', 'HP:0002890', (186, 200))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('esophagus carcinoma', 'Disease', (361, 380))	('breast cancer', 'Disease', (100, 113))	('+292A/T', 'Var', (493, 500))	('HLA-G', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('nasopharyngeal carcinoma', 'Disease', (282, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('HLA-G', 'Gene', (231, 236))	('HLA-G', 'Gene', (208, 213))	('patients', 'Species', '9606', (166, 174))
47739	25699038	Regarding the typing of HLA-G 3'UTR polymorphic sites in HCV- and HBV-infected patients, the +3142C allele and 14-bpDEL/+3142C haplotype were underrepresented in Brazilian HCV-infected patients presenting sickle cells disease compared with HCV-negative group.	('HBV-infected', 'Disease', (66, 78))	('HCV-infected', 'Disease', 'MESH:D006526', (172, 184))	('HBV-infected', 'Disease', 'MESH:D006509', (66, 78))	('14-bpDEL/+3142C', 'Var', (111, 126))	('HLA-G', 'Gene', (24, 29))	('HLA-G', 'Gene', '3135', (24, 29))	('HCV-infected', 'Disease', (172, 184))	('sickle cells disease', 'Disease', (205, 225))	('underrepresented', 'NegReg', (142, 158))	('14-bpDEL', 'Chemical', '-', (111, 119))	('+3142C', 'Var', (93, 99))	('patients', 'Species', '9606', (79, 87))	('patients', 'Species', '9606', (185, 193))
47748	25699038	A family based association study performed on individuals from Niakhar, Senegal, reported that the +3187G allele was associated with higher transmission to children and lower level of parasite density during asymptomatic P. falciparum infection.	('children', 'Species', '9606', (156, 164))	('falciparum infection', 'Disease', (224, 244))	('+3187G', 'Var', (99, 105))	('higher', 'PosReg', (133, 139))	('falciparum infection', 'Disease', 'MESH:D016778', (224, 244))	('transmission', 'MPA', (140, 152))	('P. falciparum', 'Species', '5833', (221, 234))	('lower', 'NegReg', (169, 174))
47750	25699038	A second family based association study also conducted on Senegalese population has tested the association of HLA-G 3'UTR variants with acquired anti-malarial humoral immunity.	('association', 'Interaction', (95, 106))	('tested', 'Reg', (84, 90))	('variants', 'Var', (122, 130))	('malaria', 'Disease', 'MESH:D008288', (150, 157))	('HLA-G', 'Gene', (110, 115))	('malaria', 'Disease', (150, 157))	('HLA-G', 'Gene', '3135', (110, 115))
47751	25699038	The +3010G and +3142C alleles were overtransmitted to children with increased total IgG and IgG1 antibodies levels against glutamate-rich protein (GLURP) of P. falciparum, and the +3196G allele had a preferential transmission to children with a lower IgG3 response against merozoite surface protein 2 (MSP2).	('IgG3', 'Gene', '3502', (251, 255))	('P. falciparum', 'Species', '5833', (157, 170))	('IgG3', 'Gene', (251, 255))	('+3196G', 'Var', (180, 186))	('children', 'Species', '9606', (229, 237))	('children', 'Species', '9606', (54, 62))	('increased', 'PosReg', (68, 77))	('transmission', 'MPA', (213, 225))	('IgG1', 'Gene', (92, 96))	('+3142C', 'Var', (15, 21))	('+3010G', 'Var', (4, 10))
47752	25699038	The HLA-G 3'UTR-2 haplotype was associated with a decreased IgG3 response against MSP2, suggesting a role of HLA-G on the regulation of immune humoral response during P. falciparum infection.	('HLA-G', 'Gene', '3135', (109, 114))	('HLA-G', 'Gene', (4, 9))	('HLA-G', 'Gene', '3135', (4, 9))	('P. falciparum', 'Species', '5833', (167, 180))	('decreased IgG3', 'Phenotype', 'HP:0032137', (50, 64))	('UTR-2', 'Gene', (12, 17))	('IgG3', 'Gene', (60, 64))	('decreased', 'NegReg', (50, 59))	('falciparum infection', 'Disease', (170, 190))	('haplotype', 'Var', (18, 27))	('IgG3', 'Gene', '3502', (60, 64))	('falciparum infection', 'Disease', 'MESH:D016778', (170, 190))	('UTR-2', 'Gene', '2837', (12, 17))	('HLA-G', 'Gene', (109, 114))
47754	25699038	Although no studies are available regarding HLA-G expression, genetic studies report associations of HLA-G gene single nucleotide variation sites with the disease.	('single nucleotide variation sites', 'Var', (112, 145))	('HLA-G', 'Gene', (101, 106))	('HLA-G', 'Gene', '3135', (101, 106))	('HLA-G', 'Gene', (44, 49))	('HLA-G', 'Gene', '3135', (44, 49))	('associations', 'Interaction', (85, 97))
47755	25699038	A family based association study reported that the HLA-G 3'UTR-14-bpINS and +3196G alleles had a preferential transmission from heterozygote parents to children and were associated with susceptibility to human African trypanosomiasis (HAT) development.	('children', 'Species', '9606', (152, 160))	('+3196G', 'Var', (76, 82))	('HLA-G', 'Gene', (51, 56))	('HLA-G', 'Gene', '3135', (51, 56))	('preferential', 'PosReg', (97, 109))	('human', 'Species', '9606', (204, 209))	('associated with susceptibility', 'Reg', (170, 200))	('trypanosomiasis', 'Disease', (218, 233))	('trypanosomiasis', 'Disease', 'MESH:D014352', (218, 233))
47756	25699038	In contrast, the HLA-G 3'UTR +3003C, +3010G, and +3187G alleles showed lower transmission from parents to children and were associated with decreased risk of developing the disease.	('decreased', 'NegReg', (140, 149))	('HLA-G', 'Gene', (17, 22))	('HLA-G', 'Gene', '3135', (17, 22))	('+3010G', 'Var', (37, 43))	('transmission', 'MPA', (77, 89))	('children', 'Species', '9606', (106, 114))	('+3187G', 'Var', (49, 55))	('lower', 'NegReg', (71, 76))
47757	25699038	Regarding HLA-G 3'UTR haplotypes, UTR-2 and UTR-5 haplotypes were associated with higher susceptibility to HAT development, whereas the HLA-G UTR-4 haplotype was associated with decreased risk for HAT development.	('susceptibility', 'Reg', (89, 103))	('haplotypes', 'Var', (22, 32))	('HAT development', 'CPA', (107, 122))	('HLA-G', 'Gene', (10, 15))	('HLA-G', 'Gene', '3135', (10, 15))	('haplotypes', 'Var', (50, 60))	('UTR-2', 'Gene', '2837', (34, 39))	('UTR-5', 'Gene', (44, 49))	('UTR-2', 'Gene', (34, 39))	('HLA-G', 'Gene', (136, 141))	('HLA-G', 'Gene', '3135', (136, 141))
47763	25699038	The +3003T allele and +3003TT and +3187GG genotypes were overrepresented, whereas the +3003C allele and +3003CT, +3010GC, and +3042GC genotypes were underrepresented in symptomatic patients.	('+3003T', 'Var', (4, 10))	('+3042GC', 'Var', (126, 133))	('+3003TT', 'Var', (22, 29))	('patients', 'Species', '9606', (181, 189))	('+3010GC', 'Var', (113, 120))	('+3003CT', 'Var', (104, 111))	('+3003C', 'Var', (86, 92))
47764	25699038	In addition, the +3027CC and +3035CC genotypes, and the +3027C and +3035C alleles were associated with the digestive form of Chagas disease.	('Chagas disease', 'Disease', 'MESH:D014355', (125, 139))	('associated', 'Reg', (87, 97))	('+3027CC', 'Var', (17, 24))	('+3035CC', 'Var', (29, 36))	('+3035C', 'Var', (67, 73))	('Chagas disease', 'Disease', (125, 139))	('+3027C', 'Var', (56, 62))
47765	25699038	Regarding HLA-G 3'UTR haplotypes, decreased UTR-4 and UTR-7 frequencies were associated with symptomatic patients and with the digestive form, respectively.	('patients', 'Species', '9606', (105, 113))	('decreased', 'NegReg', (34, 43))	('haplotypes', 'Var', (22, 32))	('HLA-G', 'Gene', (10, 15))	('HLA-G', 'Gene', '3135', (10, 15))	('digestive form', 'Disease', (127, 141))	('UTR-4', 'Gene', (44, 49))	('UTR-7', 'Gene', (54, 59))
47774	25699038	Theoretically, polymorphic sites observed along the coding region may modify the encoded protein and consequently the interaction with HLA-G receptors and the formation of HLA-G dimers that may more efficiently bind to HLA-G receptors.	('HLA-G', 'Gene', (219, 224))	('HLA-G', 'Gene', (172, 177))	('HLA-G', 'Gene', '3135', (219, 224))	('HLA-G', 'Gene', '3135', (172, 177))	('bind', 'Interaction', (211, 215))	('HLA-G', 'Gene', (135, 140))	('HLA-G', 'Gene', '3135', (135, 140))	('interaction', 'Interaction', (118, 129))	('polymorphic sites', 'Var', (15, 32))	('modify', 'Reg', (70, 76))	('protein', 'Protein', (89, 96))
47776	25699038	On the other hand, polymorphic sites observed along the HLA-G promoter and 3'UTR gene segments may modify gene expression, accounting for disease morbidity.	('HLA-G', 'Gene', (56, 61))	('HLA-G', 'Gene', '3135', (56, 61))	('modify', 'Reg', (99, 105))	('gene expression', 'MPA', (106, 121))	('polymorphic sites', 'Var', (19, 36))
47785	32308943	Among these are expansions to the colon or small bowel, as well as cutaneous metastases.	('expansions', 'Var', (16, 26))	('colon', 'Disease', (34, 39))	('cutaneous metastases', 'CPA', (67, 87))	('colon', 'Disease', 'MESH:D003110', (34, 39))
47821	31638253	Accumulating evidence has revealed that dysregulated long non-coding RNAs (lncRNAs) play a number of key biological roles in the progression of various types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('long non-coding RNAs', 'Protein', (53, 73))	('dysregulated', 'Var', (40, 52))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))
47822	31638253	An increasing number of studies have suggested that aberrant expression of lncRNAs in ESCC is closely associated with histological type, tumor-node-metastasis (TNM) stage, lymph node metastasis and prognosis.	('lncRNAs', 'Protein', (75, 82))	('associated', 'Reg', (102, 112))	('ESCC', 'Disease', 'MESH:C562729', (86, 90))	('TNM', 'Disease', (160, 163))	('TNM', 'Disease', 'MESH:D009362', (160, 163))	('tumor-node-metastasis', 'Disease', (137, 158))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (137, 158))	('aberrant expression', 'Var', (52, 71))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ESCC', 'Disease', (86, 90))	('lymph node metastasis', 'CPA', (172, 193))
47827	31638253	Currently, high-throughput RNA sequencing technologies are being widely used for the detection of lncRNA alterations in carcinogenesis and screening for potential biomarkers of numerous diseases.	('lncRNA', 'Gene', (98, 104))	('alterations', 'Var', (105, 116))	('carcinogenesis', 'Disease', (120, 134))	('carcinogenesis', 'Disease', 'MESH:D063646', (120, 134))
47839	31638253	The RNA sequencing datasets of patients with ESCC were downloaded from the GSE23400 (208 tissue samples: ), GSE26886 (69 tissue samples: ), GSE45670 (38 tissue samples: ), GSE97049 (14 tissue samples: ), GSE6188 (257 tissue samples: ) and GSE55856 (216 tissue samples: ) datasets.	('ESCC', 'Disease', 'MESH:C562729', (45, 49))	('GSE97049', 'Var', (172, 180))	('GSE26886', 'Var', (108, 116))	('GSE97049', 'CellLine', 'CVCL:6F81', (172, 180))	('GSE45670', 'Var', (140, 148))	('ESCC', 'Disease', (45, 49))	('patients', 'Species', '9606', (31, 39))
47844	31638253	In order to enhance the comparability of the GEO database RNA sequencing data, the signature values of the GSE23400, GSE26886, GSE45670, GSE97049, GSE6188 and GSE55856 RNA sequencing datasets were downloaded and converted to new comparable transcripts.	('GSE97049', 'CellLine', 'CVCL:6F81', (137, 145))	('GSE26886', 'Var', (117, 125))	('GSE55856', 'Var', (159, 167))	('GSE45670', 'Var', (127, 135))	('GSE97049', 'Var', (137, 145))	('GSE23400', 'Var', (107, 115))	('GSE6188', 'Var', (147, 154))
47906	31638253	A multiple subset analysis and integrated bioinformatics approach was applied in order to identify dysregulated RNAs in ESCC in the present study.	('ESCC', 'Disease', 'MESH:C562729', (120, 124))	('ESCC', 'Disease', (120, 124))	('dysregulated', 'Var', (99, 111))	('RNAs', 'Gene', (112, 116))
47933	30998992	High-fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via IL8 and Alterations to the Gut Microbiome Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC).	('Mouse', 'Species', '10090', (46, 51))	('adenocarcinoma', 'Disease', (181, 195))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (170, 195))	('BE', 'Phenotype', 'HP:0100580', (148, 150))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (127, 146))	('IL8', 'Gene', (85, 88))	('Carcinogenesis', 'CPA', (26, 40))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (61, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (181, 195))	('Alterations', 'Var', (93, 104))	('Accelerates', 'PosReg', (14, 25))	('IL8', 'Gene', '20309', (85, 88))	('EAC', 'Phenotype', 'HP:0011459', (197, 200))
47943	30998992	Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC).	('increased', 'PosReg', (62, 71))	('mouse', 'Species', '10090', (147, 152))	('CXCL1', 'Gene', '14825', (125, 130))	('dysplasias', 'Disease', (13, 23))	('levels of cytokines', 'MPA', (72, 91))	('mice', 'Species', '10090', (35, 39))	('CXCL1', 'Gene', (125, 130))	('dysplasias', 'Disease', 'MESH:C536170', (13, 23))	('L2-IL1B', 'Var', (27, 34))
47945	30998992	BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 mRNAs (epithelial progenitors) compared to mice fed control diets.	('Cxcr2', 'Gene', '12765', (133, 138))	('mice', 'Species', '10090', (24, 28))	('mice', 'Species', '10090', (62, 66))	('L2-IL1B', 'Var', (16, 23))	('myeloid cells', 'CPA', (98, 111))	('mice', 'Species', '10090', (191, 195))	('Lgr5', 'Gene', '14160', (143, 147))	('increased', 'PosReg', (77, 86))	('Cxcr2', 'Gene', (133, 138))	('Lgr5', 'Gene', (143, 147))	('BE', 'Phenotype', 'HP:0100580', (0, 2))	('L2-IL1B/IL8', 'Var', (50, 61))
47947	30998992	In a mouse model of BE, we found that a HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.	('promoted', 'PosReg', (44, 52))	('obesity', 'Disease', (197, 204))	('gut microbiome', 'Species', '749906', (111, 125))	('dysplasia', 'Disease', 'MESH:C536170', (53, 62))	('altering', 'Reg', (66, 74))	('inflammation', 'Disease', (144, 156))	('dysplasia', 'Disease', (53, 62))	('inducing', 'Reg', (135, 143))	('HFD', 'Var', (40, 43))	('mouse', 'Species', '10090', (5, 10))	('inflammation', 'Disease', 'MESH:D007249', (144, 156))	('obesity', 'Phenotype', 'HP:0001513', (197, 204))	('BE', 'Phenotype', 'HP:0100580', (20, 22))	('esophageal microenvironment', 'MPA', (79, 106))	('obesity', 'Disease', 'MESH:D009765', (197, 204))	('stem cell expansion', 'CPA', (161, 180))
47958	30998992	We demonstrate that HFD leads to global changes in the gut microbiome that mirror closely those observed in BE patients, and facilitates the establishment of an inflammatory pro-carcinogenic microenvironment at the GEJ accelerating disease progression.	('BE', 'Phenotype', 'HP:0100580', (108, 110))	('HFD', 'Var', (20, 23))	('changes', 'Reg', (40, 47))	('gut microbiome', 'Species', '749906', (55, 69))	('disease progression', 'CPA', (232, 251))	('facilitates', 'PosReg', (125, 136))	('gut microbiome', 'MPA', (55, 69))	('inflammatory pro-carcinogenic microenvironment', 'MPA', (161, 207))	('establishment', 'MPA', (141, 154))	('patients', 'Species', '9606', (111, 119))
47971	30998992	Compared to Chow fed L2-IL1B mice, a significant increase in macroscopic tumor burden at the SCJ and in the esophagus was observed in L2-IL1B mice on HFD at 9 and 12 months (Fig.	('increase', 'PosReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mice', 'Species', '10090', (142, 146))	('tumor', 'Disease', (73, 78))	('L2-IL1B', 'Var', (134, 141))	('mice', 'Species', '10090', (29, 33))
47973	30998992	However, HFD-treated L2-IL1B mice exhibited a significant increase in proliferation only at the age of 12 months (Fig.	('mice', 'Species', '10090', (29, 33))	('increase', 'PosReg', (58, 66))	('proliferation', 'CPA', (70, 83))	('L2-IL1B', 'Var', (21, 28))
47977	30998992	In contrast to HFD-induced obesity in WT mice (48% weight gain (p<0.001)), HFD-fed L2-IL1B mice did not gain body weight (p<0.001) (Fig.	('mice', 'Species', '10090', (91, 95))	('weight gain', 'Disease', 'MESH:D015430', (51, 62))	('weight gain', 'Disease', (51, 62))	('L2-IL1B', 'Var', (83, 90))	('mice', 'Species', '10090', (41, 45))	('obesity', 'Phenotype', 'HP:0001513', (27, 34))	('obesity', 'Disease', 'MESH:D009765', (27, 34))	('obesity', 'Disease', (27, 34))	('weight gain', 'Phenotype', 'HP:0004324', (51, 62))
47978	30998992	Both fat and lean mass were lower in L2-IL1B mice on HFD relative to WT mice on HFD (Suppl.	('lower', 'NegReg', (28, 33))	('mice', 'Species', '10090', (72, 76))	('mice', 'Species', '10090', (45, 49))	('L2-IL1B', 'Var', (37, 44))
47981	30998992	In contrast to L2-IL1B mice on a HFD, Mc4rhet; L2-IL1B mice showed an absence of disease acceleration, with no increase in the level of inflammation, metaplasia or dysplasia (Suppl.	('Mc4r', 'Gene', '17202', (38, 42))	('metaplasia or dysplasia', 'Disease', (150, 173))	('metaplasia or dysplasia', 'Disease', 'MESH:D008679', (150, 173))	('mice', 'Species', '10090', (55, 59))	('Mc4r', 'Gene', (38, 42))	('inflammation', 'Disease', 'MESH:D007249', (136, 148))	('inflammation', 'Disease', (136, 148))	('L2-IL1B', 'Var', (47, 54))	('mice', 'Species', '10090', (23, 27))
47984	30998992	These data suggest that genetic obesity does not promote BE progression, and HFD accelerates the phenotype independent of body weight.	('obesity', 'Disease', (32, 39))	('accelerates', 'PosReg', (81, 92))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('HFD', 'Var', (77, 80))	('obesity', 'Phenotype', 'HP:0001513', (32, 39))	('obesity', 'Disease', 'MESH:D009765', (32, 39))
47986	30998992	Thus, we postulated that the enhancement of dysplasia in L2-IL1B mice by HFD might be due primarily to a change of systemic and esophageal inflammation profiles.	('inflammation', 'Disease', 'MESH:D007249', (139, 151))	('mice', 'Species', '10090', (65, 69))	('enhancement', 'PosReg', (29, 40))	('inflammation', 'Disease', (139, 151))	('dysplasia', 'Disease', 'MESH:C536170', (44, 53))	('dysplasia', 'Disease', (44, 53))	('L2-IL1B', 'Var', (57, 64))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (128, 151))	('change', 'Reg', (105, 111))
47987	30998992	Although our tissue inflammation metric was not significantly altered in HFD L2 mice compared with chow fed L2 mice (Fig.	('mice', 'Species', '10090', (111, 115))	('inflammation', 'Disease', 'MESH:D007249', (20, 32))	('mice', 'Species', '10090', (80, 84))	('HFD L2', 'Var', (73, 79))	('inflammation', 'Disease', (20, 32))
47989	30998992	aSMA+ myofibroblasts within the SJC region were significantly increased in HFD fed L2-IL1B mice (Fig.	('mice', 'Species', '10090', (91, 95))	('increased', 'PosReg', (62, 71))	('L2-IL1B', 'Var', (83, 90))	('aSMA', 'Gene', '11475', (0, 4))	('aSMA', 'Gene', (0, 4))
47995	30998992	Importantly, the functional mouse homolog of IL8, KC or CXCL1, was among those cytokines in the chemokine array (Fig 2B), and was also upregulated 6-fold in esophagus tissue lysates from L2-IL1B mice on HFD for 12 months (Fig.	('mice', 'Species', '10090', (195, 199))	('mouse', 'Species', '10090', (28, 33))	('CXCL1', 'Gene', '14825', (56, 61))	('L2-IL1B', 'Var', (187, 194))	('IL8', 'Gene', (45, 48))	('CXCL1', 'Gene', (56, 61))	('upregulated', 'PosReg', (135, 146))
47996	30998992	Cytokine arrays of SCJ and esophageal tissue in Chow and HFD fed WT mice did not show any major changes; nevertheless, serum from WT-HFD showed a mainly obesity related phenotype, compared to chow fed WT mice, whereas HFD fed L2-IL1B mice showed an accelerated inflammatory phenotype compared to Chow fed L2-IL1B mice (Suppl.	('mice', 'Species', '10090', (68, 72))	('accelerated', 'PosReg', (249, 260))	('inflammatory phenotype', 'MPA', (261, 283))	('mice', 'Species', '10090', (234, 238))	('mice', 'Species', '10090', (313, 317))	('obesity', 'Phenotype', 'HP:0001513', (153, 160))	('mice', 'Species', '10090', (204, 208))	('obesity', 'Disease', 'MESH:D009765', (153, 160))	('L2-IL1B', 'Var', (226, 233))	('obesity', 'Disease', (153, 160))
47998	30998992	Consistent with these earlier clinical observations, levels of the functional mouse IL8 homologue, KC or CXCL1, were significantly increased in the esophagus of HFD fed L2-IL1B mice (Fig.	('levels of the functional', 'MPA', (53, 77))	('increased', 'PosReg', (131, 140))	('CXCL1', 'Gene', (105, 110))	('L2-IL1B', 'Var', (169, 176))	('CXCL1', 'Gene', '14825', (105, 110))	('mouse', 'Species', '10090', (78, 83))	('mice', 'Species', '10090', (177, 181))
48002	30998992	L2-IL1B/IL8Tg mice showed an accelerated phenotype, remarkably similar to that of L2-IL1B HFD mice (Fig.	('mice', 'Species', '10090', (14, 18))	('L2-IL1B/IL8Tg', 'Var', (0, 13))	('mice', 'Species', '10090', (94, 98))	('accelerated', 'PosReg', (29, 40))
48005	30998992	Utilizing gene expression data from L2-IL1B/IL8Tg compared to L2-IL1B mice, we generated an IL8 specific gene set including 150 upregulated and 110 downregulated genes.	('mice', 'Species', '10090', (70, 74))	('downregulated', 'NegReg', (148, 161))	('upregulated', 'PosReg', (128, 139))	('L2-IL1B/IL8Tg', 'Var', (36, 49))
48006	30998992	Genes stimulated by IL8 pathway activity were enriched in HFD fed WT and L2-IL1B mice compared to Chow fed mice (Fig.	('mice', 'Species', '10090', (81, 85))	('L2-IL1B', 'Var', (73, 80))	('activity', 'MPA', (32, 40))	('IL8 pathway', 'Pathway', (20, 31))	('mice', 'Species', '10090', (107, 111))	('stimulated', 'PosReg', (6, 16))
48012	30998992	Relative to lean serum treatment, obese serum resulted in higher levels of L2-IL1B/IL8Tg mouse epithelial cell derived IL8 in the supernatant (Fig.	('levels', 'MPA', (65, 71))	('obese', 'Disease', 'MESH:D009765', (34, 39))	('higher', 'PosReg', (58, 64))	('obese', 'Disease', (34, 39))	('L2-IL1B/IL8Tg', 'Var', (75, 88))	('mouse', 'Species', '10090', (89, 94))
48016	30998992	Additionally, we observed a significant decrease in NK cells in HFD compared to chow fed mice (Fig.	('HFD', 'Var', (64, 67))	('mice', 'Species', '10090', (89, 93))	('decrease', 'NegReg', (40, 48))	('NK cells', 'CPA', (52, 60))
48017	30998992	We also found increased neutrophils in esophageal tissue of L2-IL1B/IL8Tg mice (Fig.	('increased', 'PosReg', (14, 23))	('neutrophils', 'CPA', (24, 35))	('increased neutrophils', 'Phenotype', 'HP:0011897', (14, 35))	('mice', 'Species', '10090', (74, 78))	('L2-IL1B/IL8Tg', 'Var', (60, 73))
48018	30998992	Importantly, a significant increase of immune cells expressing IL8 receptor CXCR2 was observed in L2-IL1B HFD and L2-IL1B/IL8-Tg mice compared to L2-IL1B mice (Fig.	('mice', 'Species', '10090', (154, 158))	('CXCR2', 'Gene', '12765', (76, 81))	('L2-IL1B/IL8-Tg', 'Var', (114, 128))	('L2-IL1B', 'Var', (98, 105))	('mice', 'Species', '10090', (129, 133))	('CXCR2', 'Gene', (76, 81))	('increase', 'PosReg', (27, 35))
48022	30998992	Previous studies by our group and others have pointed to the gastric SCJ as the origin of BE and EAC, with expansion of SCJ progenitor cells into the esophagus in response to chronic inflammation, thus giving rise to metaplastic and dysplastic lesions.	('giving rise to', 'Reg', (202, 216))	('inflammation', 'Disease', (183, 195))	('BE', 'Phenotype', 'HP:0100580', (90, 92))	('dysplastic lesions', 'Disease', 'MESH:D004416', (233, 251))	('dysplastic lesions', 'Disease', (233, 251))	('expansion', 'Var', (107, 116))	('EAC', 'Phenotype', 'HP:0011459', (97, 100))	('inflammation', 'Disease', 'MESH:D007249', (183, 195))	('SCJ', 'Gene', (120, 123))
48023	30998992	In situ hybridization revealed a significant increase of the naturally present Lgr5+ progenitor cells in areas of BE at the SCJ in L2-IL1B mice on HFD, compared to Chow, and in L2-IL1B/IL8Tg mice (Fig.	('Lgr5', 'Gene', '14160', (79, 83))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('L2-IL1B', 'Var', (131, 138))	('mice', 'Species', '10090', (191, 195))	('mice', 'Species', '10090', (139, 143))	('Lgr5', 'Gene', (79, 83))	('increase', 'PosReg', (45, 53))
48027	30998992	Additionally, analysis of BE specimens from 12-month old L2-IL1B HFD and L2-IL1B/IL8Tg mice showed significantly more crypt fission compared to age-matched L2-IL1B chow fed mice (Fig.	('more', 'PosReg', (113, 117))	('crypt fission', 'CPA', (118, 131))	('L2-IL1B/IL8Tg', 'Var', (73, 86))	('mice', 'Species', '10090', (87, 91))	('BE', 'Phenotype', 'HP:0100580', (26, 28))	('L2-IL1B', 'Var', (57, 64))	('mice', 'Species', '10090', (173, 177))
48037	30998992	To investigate whether the gut microbiota in general influenced inflammation and tumor development in the L2-IL1B HFD mouse model, we re-derived L2-IL1B mice as germfree (GF) and found a marked reduction of inflammation, metaplasia and dysplasia, with an increase in goblet-like cells (Fig.	('L2-IL1B', 'Var', (145, 152))	('inflammation', 'Disease', 'MESH:D007249', (207, 219))	('inflammation', 'Disease', (207, 219))	('inflammation', 'Disease', 'MESH:D007249', (64, 76))	('metaplasia and dysplasia', 'Disease', 'MESH:D008679', (221, 245))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('inflammation', 'Disease', (64, 76))	('mouse', 'Species', '10090', (118, 123))	('mice', 'Species', '10090', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('reduction of inflammation', 'Disease', 'MESH:D007022', (194, 219))	('increase', 'PosReg', (255, 263))	('goblet-like cells', 'CPA', (267, 284))	('tumor', 'Disease', (81, 86))	('reduction of inflammation', 'Disease', (194, 219))
48040	30998992	When transferring bedding including feces from L2-IL1B mice on HFD to cages of L2-IL1B mice on Control diet over 9 months, the tumor phenotype could be transmitted, suggesting that the fecal microbial community is at least partly responsible for the SCJ phenotype (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('mice', 'Species', '10090', (87, 91))	('mice', 'Species', '10090', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('L2-IL1B', 'Var', (47, 54))
48042	30998992	Clustering KEGG data showed that in L2-IL1B mice, HFD differentiated microbial function from Chow and Control diet (Fig.	('differentiated', 'Reg', (54, 68))	('mice', 'Species', '10090', (44, 48))	('L2-IL1B', 'Var', (36, 43))	('microbial function', 'CPA', (69, 87))
48045	30998992	GSEAs revealed an upregulation of the inflammatory response to LPS and Toll-Like Receptor (TLR) signaling in the SCJ of L2-IL1B HFD mice, suggesting that such gut microbiota changes are likely influenced through TLR signaling (Fig.	('upregulation', 'PosReg', (18, 30))	('GSEAs', 'Chemical', '-', (0, 5))	('HFD', 'Var', (128, 131))	('inflammatory response to LPS', 'MPA', (38, 66))	('L2-IL1B HFD', 'Var', (120, 131))	('mice', 'Species', '10090', (132, 136))
48050	30998992	The absence of weight gain in L2-IL1B mice on HFD was likely due to systemic effects of IL1B, but also raises the question as to whether increased body fat alone contributes to BE/EAC.	('weight gain', 'Disease', 'MESH:D015430', (15, 26))	('weight gain', 'Phenotype', 'HP:0004324', (15, 26))	('mice', 'Species', '10090', (38, 42))	('BE', 'Phenotype', 'HP:0100580', (177, 179))	('weight gain', 'Disease', (15, 26))	('L2-IL1B', 'Var', (30, 37))	('IL1B', 'Gene', (88, 92))	('EAC', 'Phenotype', 'HP:0011459', (180, 183))
48055	30998992	The IL8/CXCL1 chemokine family is an additional well-defined downstream target of IL1B, and we observed elevated levels of the functional murine homolog CXCL1 at the SCJ of HFD treated L2-IL1B mice.	('CXCL1', 'Gene', (8, 13))	('levels of', 'MPA', (113, 122))	('L2-IL1B', 'Var', (185, 192))	('CXCL1', 'Gene', '14825', (153, 158))	('mice', 'Species', '10090', (193, 197))	('CXCL1', 'Gene', '14825', (8, 13))	('murine', 'Species', '10090', (138, 144))	('IL1B', 'Gene', (82, 86))	('elevated', 'PosReg', (104, 112))	('CXCL1', 'Gene', (153, 158))
48059	30998992	Indeed, reconstitution of the human IL8 gene in the BE mouse model resulted in acceleration of dysplasia, mimicking the HFD phenotype, confirming the importance of local IL-8 expression.	('acceleration', 'PosReg', (79, 91))	('human', 'Species', '9606', (30, 35))	('IL-8', 'Gene', (170, 174))	('BE', 'Phenotype', 'HP:0100580', (52, 54))	('IL8', 'Gene', (36, 39))	('reconstitution', 'Var', (8, 22))	('IL-8', 'Gene', '20309', (170, 174))	('dysplasia', 'Disease', 'MESH:C536170', (95, 104))	('mouse', 'Species', '10090', (55, 60))	('dysplasia', 'Disease', (95, 104))
48062	30998992	Although we cannot prove directly in our work that a specific microbial species is activating IL8 signaling in the esophagus, we provide evidence in our KEGG analysis: The bacterial community profile associated with LPS biosynthesis, known to activate TLR signaling, was upregulated in the SCJ of L2-IL1B HFD mice.	('bacterial community profile', 'MPA', (172, 199))	('LPS', 'Gene', (216, 219))	('mice', 'Species', '10090', (309, 313))	('L2-IL1B', 'Gene', (297, 304))	('HFD', 'Var', (305, 308))	('upregulated', 'PosReg', (271, 282))
48064	30998992	In HFD fed L2-IL1B and L2-IL1B/IL8Tg mice, we observed an accumulation of CXCR2+ IMCs and neutrophils.	('L2-IL1B', 'Var', (11, 18))	('accumulation', 'PosReg', (58, 70))	('neutrophils', 'CPA', (90, 101))	('L2-IL1B/IL8Tg', 'Var', (23, 36))	('CXCR2', 'Gene', (74, 79))	('CXCR2', 'Gene', '12765', (74, 79))	('mice', 'Species', '10090', (37, 41))
48067	30998992	Of note, bile acid treated L2-IL1B mice also exhibit a granulocytic shift, along with acceleration of dysplasia at the SCJ region pointing to the importance of neutrophils.	('acceleration', 'PosReg', (86, 98))	('granulocytic shift', 'CPA', (55, 73))	('dysplasia', 'Disease', 'MESH:C536170', (102, 111))	('bile acid', 'Gene', (9, 18))	('mice', 'Species', '10090', (35, 39))	('dysplasia', 'Disease', (102, 111))	('bile acid', 'Gene', '230101', (9, 18))	('L2-IL1B', 'Var', (27, 34))
48074	30998992	Although there are clearly limitations to studies of inflammation in a pro-inflammatory mouse model of BE, the findings suggest that an altered neutrophils to NK ratio may portend a poor prognosis, as shown in other cancers.	('BE', 'Phenotype', 'HP:0100580', (103, 105))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('inflammation', 'Disease', 'MESH:D007249', (53, 65))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('inflammation', 'Disease', (53, 65))	('mouse', 'Species', '10090', (88, 93))	('cancers', 'Disease', (216, 223))	('altered', 'Var', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('neutrophils to NK ratio', 'MPA', (144, 167))
48075	30998992	Apart from IL8 effects on the esophageal inflammatory niche, we observed an epithelial effect of the IL8/CXCL1 chemokine family, with an expansion in the gastric SCJ of Cxcr2 expressing Lgr5+ progenitor cells with accelerated dysplasia.	('epithelial', 'MPA', (76, 86))	('expansion', 'Var', (137, 146))	('CXCL1', 'Gene', (105, 110))	('Lgr5', 'Gene', '14160', (186, 190))	('Lgr5', 'Gene', (186, 190))	('Cxcr2', 'Gene', (169, 174))	('dysplasia', 'Disease', 'MESH:C536170', (226, 235))	('CXCL1', 'Gene', '14825', (105, 110))	('dysplasia', 'Disease', (226, 235))	('Cxcr2', 'Gene', '12765', (169, 174))
48086	30998992	In accordance, we found only modest changes in the microbiota at the SCJ in L2-IL1B mice, while microbial composition in the colon was changed upon feeding HFD, with an altered Firmicutes:Bacteroidetes ratio that correlated with BE progression.	('altered', 'Reg', (169, 176))	('changed', 'Reg', (135, 142))	('L2-IL1B', 'Var', (76, 83))	('BE', 'Phenotype', 'HP:0100580', (229, 231))	('microbial composition', 'MPA', (96, 117))	('Firmicutes:Bacteroidetes ratio', 'MPA', (177, 207))	('mice', 'Species', '10090', (84, 88))
48088	30998992	Changes in gut microbiota may account for the inflammatory phenotype observed in HFD L2-IL1B mice and importantly, can induce an increased cancer phenotype, if transferred to L2-IL1B mice on chow diet.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mice', 'Species', '10090', (183, 187))	('HFD L2-IL1B', 'Var', (81, 92))	('mice', 'Species', '10090', (93, 97))	('L2-IL1B', 'Var', (85, 92))	('induce', 'Reg', (119, 125))	('cancer', 'Disease', (139, 145))
48160	30254401	SRER or extensive EMR can cause bleeding in 2.4% to 25% cases.	('SRER', 'Var', (0, 4))	('bleeding', 'Disease', 'MESH:D006470', (32, 40))	('cause', 'Reg', (26, 31))	('bleeding', 'Disease', (32, 40))	('extensive EMR', 'CPA', (8, 21))
48200	30254401	Its utility in the management of ESCC is mainly limited to T1a and T1b lesions which are not amenable to endoscopic therapy due to underlying comorbidities.	('SCC', 'Gene', (34, 37))	('SCC', 'Gene', '6317', (34, 37))	('T1b', 'Var', (67, 70))	('T1a', 'Gene', '10630', (59, 62))	('T1a', 'Gene', (59, 62))
48271	28658150	Kim et al reported that patients with ypT0N1 disease had lower 5-year survival than complete response in the primary esophageal carcinoma and lymph nodes (ypT0N0) patients, and similar to pathologic TNM stage II.	('5-year survival', 'MPA', (63, 78))	('patients', 'Species', '9606', (163, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal carcinoma', 'Disease', (117, 137))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (117, 137))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (117, 137))	('ypT0N1 disease', 'Var', (38, 52))	('patients', 'Species', '9606', (24, 32))	('lower', 'NegReg', (57, 62))
48281	28658150	In the present meta-analysis that included 8 studies, a total of 837 patients that performed neoadjuvant therapy and surgery in patients with ypT0 esophageal carcinoma.	('ypT0', 'Var', (142, 146))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (147, 167))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (147, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (128, 136))	('esophageal carcinoma', 'Disease', (147, 167))
48287	28658150	The pooled OR and 95% CI by comparing the ypT0N1 and ypT0N0 on 3-year and 5-year OS were 3.08 (95% CI = 2.07-4.57; P < .001) and 4.27 (95% CI = 2.76-6.59; P < .001) (Fig.	('OS', 'Chemical', '-', (81, 83))	('ypT0N1', 'Var', (42, 48))	('ypT0N0', 'Var', (53, 59))
48288	28658150	2), indicating that patients with ypT0N0 have better overall survival than patients with ypT0N1.	('patients', 'Species', '9606', (75, 83))	('overall survival', 'MPA', (53, 69))	('patients', 'Species', '9606', (20, 28))	('better', 'PosReg', (46, 52))	('ypT0N0', 'Var', (34, 40))
48307	28658150	Our data in the present study suggested that the group of ypT0N1 was associated with worse survival outcomes (OS and DFS) compared with ypT0N0 group.	('survival', 'CPA', (91, 99))	('ypT0N1', 'Var', (58, 64))	('OS', 'Chemical', '-', (110, 112))
48315	28658150	Future modifications should consider patients after neoadjuvant therapy and ypT0N1 should be included in the modified staging system of esophageal cancer.	('esophageal cancer', 'Disease', (136, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('patients', 'Species', '9606', (37, 45))	('ypT0N1', 'Var', (76, 82))
48321	28038457	Sym004 treatments were more effective at inducing EGFR internalization and degradation than the two other anti-EGFR antibodies.	('inducing', 'Reg', (41, 49))	('EGFR', 'Gene', '1956', (111, 115))	('Sym004', 'Var', (0, 6))	('internalization', 'MPA', (55, 70))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', (111, 115))	('degradation', 'MPA', (75, 86))	('EGFR', 'Gene', (50, 54))
48322	28038457	Sym004 was more sensitive significantly to cell lines with EGFR gene amplification than those without amplification (P = 0.002).	('amplification', 'Var', (69, 82))	('EGFR', 'Gene', '1956', (59, 63))	('EGFR', 'Gene', (59, 63))
48323	28038457	Growth inhibition of Sym004 was greater than in that of cetuximab or panitumumab in vitro and in vivo.	('Growth', 'MPA', (0, 6))	('panitumumab', 'Chemical', 'MESH:D000077544', (69, 80))	('cetuximab', 'Chemical', 'MESH:D000068818', (56, 65))	('Sym004', 'Var', (21, 27))
48333	28038457	Although considerable in vitro and in vivo preclinical evidence suggests that Sym004 is superior to cetuximab and panitumumab in a several types of cancer, its efficacy has not yet been demonstrated in ESCC.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cetuximab', 'Chemical', 'MESH:D000068818', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('ESCC', 'Disease', (202, 206))	('panitumumab', 'Chemical', 'MESH:D000077544', (114, 125))	('Sym004', 'Var', (78, 84))
48337	28038457	Seven of 48 cell lines were 50% inhibited by Sym004 at 1 mug/mL, whereas only 3 cell lines were 50% inhibited by cetuximab and panitumumab at this dose.	('inhibited', 'NegReg', (32, 41))	('cetuximab', 'Chemical', 'MESH:D000068818', (113, 122))	('Sym004', 'Var', (45, 51))	('panitumumab', 'Chemical', 'MESH:D000077544', (127, 138))
48338	28038457	Although the effects of these antibody preparations were similar in KYSE960 cell, the anti-proliferative activity of Sym004 was more potent than those of the two commercially available anti-EGFR antibodies in OE-21, KYSE590, and KYSE220 cells (Figure 1B).	('KYSE220', 'CellLine', 'CVCL:1359', (229, 236))	('Sym004', 'Var', (117, 123))	('EGFR', 'Gene', '1956', (190, 194))	('potent', 'PosReg', (133, 139))	('EGFR', 'Gene', (190, 194))	('anti-proliferative activity', 'CPA', (86, 113))
48339	28038457	The IC 50 values of Sym004 were significantly lower than those of cetuximab and panitumumab in OE-21, KYSE220 cells (Figure 1C).	('cetuximab', 'Chemical', 'MESH:D000068818', (66, 75))	('Sym004', 'Var', (20, 26))	('KYSE220', 'CellLine', 'CVCL:1359', (102, 109))	('lower', 'NegReg', (46, 51))	('panitumumab', 'Chemical', 'MESH:D000077544', (80, 91))	('IC 50', 'MPA', (4, 9))
48341	28038457	In these experiments, EGFR amplification was found in 9 cell lines (18.7%) including OE21, KYSE590, and KYSE960 and mutations of oncogenes MET, PIK3CA, KRAS, and HRAS were detected in 8.3%, 8.3%, and 6.3% of cell lines, respectively.	('KYSE590', 'Var', (91, 98))	('HRAS', 'Gene', '3265', (162, 166))	('PIK3CA', 'Gene', (144, 150))	('KYSE960', 'Var', (104, 111))	('PIK3CA', 'Gene', '5290', (144, 150))	('KRAS', 'Gene', (152, 156))	('KRAS', 'Gene', '3845', (152, 156))	('HRAS', 'Gene', (162, 166))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))	('MET', 'Gene', (139, 142))
48342	28038457	Cell lines with EGFR amplification showed significantly greater (P = 0.002) sensitivity to Sym004 than those without EGFR amplifications (Figure 3A).	('sensitivity to Sym004', 'MPA', (76, 97))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('greater', 'PosReg', (56, 63))	('EGFR', 'Gene', '1956', (16, 20))	('amplification', 'Var', (21, 34))	('EGFR', 'Gene', (16, 20))
48343	28038457	However, no difference in the sensitivity was observed between cells with mutations in PIK3CA and RAS and those without mutation (Figure 3B and 3C).	('PIK3CA', 'Gene', '5290', (87, 93))	('mutations', 'Var', (74, 83))	('RAS', 'Gene', (98, 101))	('PIK3CA', 'Gene', (87, 93))
48345	28038457	In almost cell lines tested, Sym004 was sufficiently internalized into the cytoplasm even after 1h incubation.	('Sym004', 'Var', (29, 35))	('1h', 'Chemical', '-', (96, 98))	('internalized', 'MPA', (53, 65))
48348	28038457	EGFR levels were dramatically decreased by Sym004 in all three cell lines, whereas small decrease in EGFR level was observed by cetuximab or panitumumab (Figure 5A).	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('cetuximab', 'Chemical', 'MESH:D000068818', (128, 137))	('panitumumab', 'Chemical', 'MESH:D000077544', (141, 152))	('Sym004', 'Var', (43, 49))	('EGFR', 'Gene', '1956', (0, 4))	('decreased', 'NegReg', (30, 39))
48349	28038457	Quantification of band intensities showed that Sym004 reduced the total EGFR level by 60 to 80% within 24 h in the four cell lines (Figure 5B).	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', (72, 76))	('reduced', 'NegReg', (54, 61))	('Sym004', 'Var', (47, 53))
48350	28038457	In OE21 cells and KYSE220, reduction of EGFR protein by Sym004 was significantly more effective than cetuximab (P = 0.027 and P = 0.009, respectively) and panitumumab (P = 0.014 and P = 0.001, respectively).	('cetuximab', 'Chemical', 'MESH:D000068818', (101, 110))	('Sym004', 'Var', (56, 62))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('panitumumab', 'Chemical', 'MESH:D000077544', (155, 166))	('KYSE220', 'CellLine', 'CVCL:1359', (18, 25))	('reduction', 'NegReg', (27, 36))
48352	28038457	In the presence and absence of ligand, Sym004 treatment led to a more potent blockade of EGFR phosphorylation at the Tyr1068 compared with panitumumab (P = 0.012) in OE-21 cells (Figure 5D).	('EGFR', 'Gene', (89, 93))	('panitumumab', 'Chemical', 'MESH:D000077544', (139, 150))	('Tyr1068', 'Var', (117, 124))	('Tyr1068', 'Chemical', '-', (117, 124))	('phosphorylation', 'MPA', (94, 109))	('Sym004', 'Var', (39, 45))	('blockade', 'NegReg', (77, 85))	('EGFR', 'Gene', '1956', (89, 93))
48354	28038457	Sym004 was also more potent than cetuximab at inhibiting phosphorylation of AKT in the KYSE220 cell line.	('inhibiting', 'NegReg', (46, 56))	('AKT', 'Gene', '207', (76, 79))	('Sym004', 'Var', (0, 6))	('AKT', 'Gene', (76, 79))	('cetuximab', 'Chemical', 'MESH:D000068818', (33, 42))	('phosphorylation', 'MPA', (57, 72))	('KYSE220', 'CellLine', 'CVCL:1359', (87, 94))
48355	28038457	The tumor growth of KYSE960 cells was significantly suppressed by all groups treated with anti-EGFR antibodies compared with the group treated with saline (P < 0.001) (Figure 6A).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('saline', 'Chemical', 'MESH:D012965', (148, 154))	('suppressed', 'NegReg', (52, 62))	('EGFR', 'Gene', '1956', (95, 99))	('antibodies', 'Var', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('EGFR', 'Gene', (95, 99))
48364	28038457	Sym004 is a mixture of anti-EGFR mAb 992 and 1024 that targets non-overlapping epitopes (epitope 992 vs. 1024) in EGFR extracellular domain III.	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (114, 118))	('epitope 992', 'Var', (89, 100))	('EGFR', 'Gene', (114, 118))
48367	28038457	In the present study, Sym004 exerted more potent growth inhibition than cetuximab or panitumumab in a panel of 48 ESCC cell lines.	('cetuximab', 'Chemical', 'MESH:D000068818', (72, 81))	('panitumumab', 'Chemical', 'MESH:D000077544', (85, 96))	('growth', 'MPA', (49, 55))	('Sym004', 'Var', (22, 28))
48368	28038457	Interestingly, ESCC cell lines with EGFR amplification tended to be more sensitive to Sym004 in in vitro cell proliferation assays (Figure 3A).	('more', 'PosReg', (68, 72))	('EGFR', 'Gene', '1956', (36, 40))	('sensitive', 'MPA', (73, 82))	('amplification', 'Var', (41, 54))	('EGFR', 'Gene', (36, 40))
48371	28038457	The clinicopathological analysis of ESCC showed that EGFR amplification occurred in 24%-28% of ESCC patients and were significantly associated with high-level overexpression of EGFR.	('overexpression', 'PosReg', (159, 173))	('amplification', 'Var', (58, 71))	('ESCC', 'Disease', (95, 99))	('patients', 'Species', '9606', (100, 108))	('EGFR', 'Gene', '1956', (177, 181))	('EGFR', 'Gene', '1956', (53, 57))	('associated', 'Reg', (132, 142))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', (177, 181))
48372	28038457	In our study, EGFR amplification was observed more frequently in EGFR relative high expression cell lines (Figure 2).	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('amplification', 'Var', (19, 32))	('observed', 'Reg', (37, 45))
48373	28038457	High EGFR gene copy number or EGFR amplification is correlated with advanced pathologic stage and more number of the metastatic lymph nodes in ESCC.	('amplification', 'Var', (35, 48))	('EGFR', 'Gene', (30, 34))	('High', 'Var', (0, 4))	('ESCC', 'Disease', (143, 147))	('EGFR', 'Gene', '1956', (5, 9))	('EGFR', 'Gene', (5, 9))	('EGFR', 'Gene', '1956', (30, 34))
48376	28038457	KRAS mutations in the exon 2 are reportedly predictive of resistance to anti-EGFR mAb therapy, and a retrospective analysis of RAS mutations in specimens from a randomized trial of combination chemotherapy for metastatic colorectal cancer (the PRIME trial) indicated that, similar to KRAS exon 2, mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4 were negative predictive factors to panitumumab.	('panitumumab', 'Chemical', 'MESH:D000077544', (392, 403))	('NRAS', 'Gene', '4893', (333, 337))	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('KRAS', 'Gene', '3845', (284, 288))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', (310, 314))	('mutations', 'Var', (297, 306))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', (284, 288))	('KRAS', 'Gene', '3845', (310, 314))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('EGFR', 'Gene', '1956', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('NRAS', 'Gene', (333, 337))	('negative', 'NegReg', (361, 369))	('colorectal cancer', 'Disease', (221, 238))	('EGFR', 'Gene', (77, 81))	('KRAS', 'Gene', '3845', (0, 4))
48378	28038457	In HNSCC, HRAS mutations are more common than KRAS mutations and this mutation exhibited de novo resistance to cetuximab-based therapy.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('HRAS', 'Gene', (10, 14))	('cetuximab', 'Chemical', 'MESH:D000068818', (111, 120))	('mutations', 'Var', (15, 24))	('KRAS', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (46, 50))	('common', 'Reg', (34, 40))	('HNSCC', 'Disease', (3, 8))	('HRAS', 'Gene', '3265', (10, 14))
48380	28038457	Similarly, relationships between PIK3CA mutations and responses to anti-EGFR mAb remain controversial, and the present data showed no differences in Sym004 sensitivity between PIK3CA mutant and wild-type cancer cells.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('PIK3CA', 'Gene', '5290', (176, 182))	('PIK3CA', 'Gene', '5290', (33, 39))	('EGFR', 'Gene', '1956', (72, 76))	('mutant', 'Var', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('PIK3CA', 'Gene', (176, 182))	('EGFR', 'Gene', (72, 76))	('PIK3CA', 'Gene', (33, 39))
48381	28038457	The lack of statistically significant difference between Sym004 and the cetuximab or panitumumab in the KYSE960 xenograft model was not surprising, because in vitro result showeds that Sym004 and the other anti-EGFR mAb were equally effective in the growth of KYSE960 cells.	('cetuximab', 'Chemical', 'MESH:D000068818', (72, 81))	('panitumumab', 'Chemical', 'MESH:D000077544', (85, 96))	('Sym004', 'Var', (185, 191))	('EGFR', 'Gene', '1956', (211, 215))	('growth', 'CPA', (250, 256))	('EGFR', 'Gene', (211, 215))
48383	28038457	Sym004 was significantly more potent in tumor growth inhibition than cetuximab or panitumumab, respectively.	('cetuximab', 'Chemical', 'MESH:D000068818', (69, 78))	('Sym004', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('panitumumab', 'Chemical', 'MESH:D000077544', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
48389	28038457	Antibodies against EGFR (D38B1), phosphorylated EGFR (Tyr1068), Akt, phosphorylated-Akt (Ser473), ERK1/2, phosphorylated-ERK1/2 (Thr202/Thr204) and beta-actin were purchased from Cell Signaling Technology (Beverly, MA).	('ERK1/2', 'Gene', (121, 127))	('EGFR', 'Gene', '1956', (48, 52))	('ERK1/2', 'Gene', '5595;5594', (121, 127))	('Akt', 'Gene', '207', (64, 67))	('EGFR', 'Gene', (19, 23))	('ERK1/2', 'Gene', (98, 104))	('ERK1/2', 'Gene', '5595;5594', (98, 104))	('beta-actin', 'Gene', (148, 158))	('Thr204', 'Chemical', '-', (136, 142))	('Akt', 'Gene', (84, 87))	('Ser473', 'Var', (89, 95))	('Ser473', 'Chemical', '-', (89, 95))	('Tyr1068', 'Var', (54, 61))	('Akt', 'Gene', '207', (84, 87))	('EGFR', 'Gene', (48, 52))	('EGFR', 'Gene', '1956', (19, 23))	('Thr202', 'Chemical', '-', (129, 135))	('beta-actin', 'Gene', '728378', (148, 158))	('Tyr1068', 'Chemical', '-', (54, 61))	('Akt', 'Gene', (64, 67))
48394	28038457	Antibodies were used at the following dilutions: against EGF Receptor (1:200), phosphorylated EGFR (1:200), Akt (1:200), phosphorylated-Akt (1:400), ERK1/2 (1:200) and phosphorylated-ERK1/2 (1:400) as indicated.	('EGF Receptor', 'Gene', '1956', (57, 69))	('Akt', 'Gene', (108, 111))	('1:200', 'Var', (113, 118))	('ERK1/2', 'Gene', (149, 155))	('EGFR', 'Gene', '1956', (94, 98))	('EGF Receptor', 'Gene', (57, 69))	('EGFR', 'Gene', (94, 98))	('ERK1/2', 'Gene', (183, 189))	('ERK1/2', 'Gene', '5595;5594', (183, 189))	('Akt', 'Gene', '207', (136, 139))	('ERK1/2', 'Gene', '5595;5594', (149, 155))	('Akt', 'Gene', '207', (108, 111))	('1:200', 'Var', (100, 105))	('Akt', 'Gene', (136, 139))
48409	28038457	Sym004 exhibited significant tumor growth inhibition in a subset of ESCC cell lines in vitro and in vivo with pronounced activities in comparison with other anti-EGFR monoclonal antibodies, cetuximab and panitumumab.	('activities', 'MPA', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('Sym004', 'Var', (0, 6))	('cetuximab', 'Chemical', 'MESH:D000068818', (190, 199))	('EGFR', 'Gene', (162, 166))	('EGFR', 'Gene', '1956', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('panitumumab', 'Chemical', 'MESH:D000077544', (204, 215))
48410	28038457	These analyses suggest that EGFR amplification may be a potential predictive biomarker to Sym004 in clinical implication to ESCC.	('amplification', 'Var', (33, 46))	('ESCC', 'Disease', (124, 128))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))
48454	25452775	The aim of this study was to explore the expression of multiple types of 5-HT receptor (5-HT1AR, 5-HT2AR, 5-HT3AR, 5-HT4R, 5-HT5AR, 5-HT6R and 5-HT7R) in sling and clasp fibers from the human lower esophageal sphincter (LES).	('5-HT5A', 'Gene', (123, 129))	('5-HT5A', 'Gene', '3361', (123, 129))	('5-HT1A', 'Gene', (88, 94))	('5-HT1A', 'Gene', '3350', (88, 94))	('5-HT2A', 'Gene', '3356', (97, 103))	('5-HT3AR', 'Var', (106, 113))	('5-HT6R', 'Gene', '3362', (132, 138))	('human', 'Species', '9606', (186, 191))	('esophageal sphincter', 'Disease', (198, 218))	('esophageal sphincter', 'Disease', 'MESH:D009122', (198, 218))	('5-HT6R', 'Gene', (132, 138))	('5-HT2A', 'Gene', (97, 103))
48456	25452775	At the mRNA level, the expression levels were highest for 5-HT3AR and 5-HT4R, and lowest for 5-HT5AR, 5-HT6R and 5-HT7R.	('5-HT3AR', 'Var', (58, 65))	('5-HT4R', 'Var', (70, 76))	('5-HT6R', 'Gene', (102, 108))	('5-HT5A', 'Gene', '3361', (93, 99))	('5-HT6R', 'Gene', '3362', (102, 108))	('5-HT5A', 'Gene', (93, 99))	('expression levels', 'MPA', (23, 40))	('highest', 'Reg', (46, 53))
48457	25452775	At the protein level, the expression levels were highest for 5-HT3AR and 5-HT4R, followed by 5-HT1AR and 5-HT2AR; 5-HT7R was also detected at a low level.	('5-HT1A', 'Gene', (93, 99))	('5-HT2A', 'Gene', (105, 111))	('5-HT1A', 'Gene', '3350', (93, 99))	('5-HT2A', 'Gene', '3356', (105, 111))	('5-HT3AR', 'Var', (61, 68))	('highest', 'Reg', (49, 56))	('5-HT4R', 'Var', (73, 79))	('expression levels', 'MPA', (26, 43))
48466	25452775	Abnormalities in the LES are closely associated with dysfunction in gastrointestinal motility disorders such as achalasia and gastroesophageal reflux disease (GERD).	('achalasia', 'Phenotype', 'HP:0002571', (112, 121))	('Abnormalities', 'Var', (0, 13))	('achalasia', 'Disease', (112, 121))	('gastrointestinal motility disorders', 'Phenotype', 'HP:0030895', (68, 103))	('gastroesophageal reflux disease', 'Disease', (126, 157))	('dysfunction in gastrointestinal motility disorders', 'Disease', 'MESH:D005767', (53, 103))	('dysfunction in gastrointestinal motility disorders', 'Disease', (53, 103))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (126, 157))	('associated', 'Reg', (37, 47))	('GERD', 'Disease', 'MESH:D005764', (159, 163))	('achalasia', 'Disease', 'MESH:D004931', (112, 121))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (126, 149))	('GERD', 'Disease', (159, 163))
48502	25452775	However, the primer pairs for the 5-HT7R, 5-HT5AR and 5-HT6R mRNA produced relatively weak bands (Fig.	('5-HT5A', 'Gene', '3361', (42, 48))	('5-HT5A', 'Gene', (42, 48))	('weak', 'NegReg', (86, 90))	('5-HT6R', 'Gene', (54, 60))	('5-HT6R', 'Gene', '3362', (54, 60))	('5-HT7R', 'Var', (34, 40))
48503	25452775	The rank order of expression was as follows: 5-HT3AR = 5-HT4R > 5-HT1AR = 5-HT2AR > 5-HT5AR = 5-HT6R = 5-HT7R.	('5-HT6R', 'Gene', (94, 100))	('5-HT2A', 'Gene', (74, 80))	('5-HT1A', 'Gene', (64, 70))	('5-HT6R', 'Gene', '3362', (94, 100))	('5-HT1A', 'Gene', '3350', (64, 70))	('5-HT5A', 'Gene', '3361', (84, 90))	('5-HT2A', 'Gene', '3356', (74, 80))	('5-HT5A', 'Gene', (84, 90))	('5-HT3AR', 'Var', (45, 52))
48505	25452775	The rank order of the IOD values was as follows: 5-HT3AR = 5-HT4R > 5-HT1AR = 5-HT2AR > 5-HT7R.	('5-HT2A', 'Gene', (78, 84))	('5-HT2A', 'Gene', '3356', (78, 84))	('5-HT1A', 'Gene', '3350', (68, 74))	('5-HT4R', 'Var', (59, 65))	('5-HT3AR', 'Var', (49, 56))	('5-HT1A', 'Gene', (68, 74))
48521	25452775	5-HT5 and 5-HT6 receptors mainly exist in the central nervous system and are associated with memory, mood, pain and cognition.	('memory', 'Disease', (93, 99))	('pain', 'Phenotype', 'HP:0012531', (107, 111))	('5-HT6', 'Var', (10, 15))	('cognition', 'Disease', (116, 125))	('pain', 'Disease', 'MESH:D010146', (107, 111))	('pain', 'Disease', (107, 111))	('mood', 'Disease', (101, 105))	('associated', 'Reg', (77, 87))
48532	25452775	Yang et al concluded that a 5-HT signaling pathway disorder may be a major factor in the pathogenesis of gastroesophageal reflux and reflux esophagitis in experiments on rats.	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (105, 128))	('5-HT signaling pathway', 'Pathway', (28, 50))	('reflux esophagitis', 'Disease', 'MESH:D005764', (133, 151))	('reflux esophagitis', 'Disease', (133, 151))	('rats', 'Species', '10116', (170, 174))	('disorder', 'Var', (51, 59))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (105, 128))	('gastroesophageal reflux', 'Disease', (105, 128))	('esophagitis', 'Phenotype', 'HP:0100633', (140, 151))
48653	23663216	Within the BE and COL groups, nocturnal GERD was associated with BQ+ status, although the rate of nocturnal GERD was low (23%) among BQ+ subjects in the COL group.	('BQ+', 'Chemical', '-', (65, 68))	('associated', 'Reg', (49, 59))	('BQ+', 'Chemical', '-', (133, 136))	('nocturnal GERD', 'Disease', (30, 44))	('BQ+ status', 'Var', (65, 75))
48677	23663216	LCC was supported by an NIH Postdoctoral Training Grant in Digestive Diseases (T32-DK61917), NIH Paul Calabresi Award for Clinical Oncology (K12 CA076917), and Case SPORE in GI Malignancies (P50 CA150964).	('GI Malignancies', 'Disease', (174, 189))	('Digestive Diseases', 'Phenotype', 'HP:0011024', (59, 77))	('T32-DK61917', 'Var', (79, 90))	('GI Malignancies', 'Disease', 'MESH:D009369', (174, 189))	('Digestive Diseases', 'Disease', (59, 77))	('K12 CA076917', 'Var', (141, 153))	('P50 CA150964', 'Var', (191, 203))	('Oncology', 'Phenotype', 'HP:0002664', (131, 139))
48689	22488081	Cancers in Barrett's esophagus are thought to evolve through a sequence of genetic and epigenetic alterations that endow cells with growth advantages and cause histological changes in the metaplastic epithelium that pathologists recognize as dysplasia.	('Cancers', 'Disease', (0, 7))	('dysplasia', 'Disease', (242, 251))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (11, 30))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('dysplasia', 'Disease', 'MESH:D004476', (242, 251))	('growth advantages', 'CPA', (132, 149))	('alterations', 'Var', (98, 109))
48727	22488081	Among the 12 studies that reported the depth of mucosal tumor invasion as m1/m2/m3, there were a total of 170 patients with m3 lesions, 8 of whom (4.7%) had lymph node metastases.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('lymph node metastases', 'Disease', 'MESH:D009362', (157, 178))	('mucosal tumor', 'Disease', 'MESH:D052016', (48, 61))	('lymph node metastases', 'Disease', (157, 178))	('m3 lesions', 'Var', (124, 134))	('mucosal tumor', 'Disease', (48, 61))	('patients', 'Species', '9606', (110, 118))
48759	22488081	Histological evaluation of the esophagus resected for dysplasia or cancer in Barrett's esophagus has revealed duplication of the muscularis mucosae in up to 92% of cases.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('dysplasia', 'Disease', (54, 63))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (77, 96))	('dysplasia', 'Disease', 'MESH:D004476', (54, 63))	('duplication', 'Var', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
48760	22488081	This finding is important because duplication of the muscularis mucosae can result in errors in the staging of superficial adenocarcinomas.	('adenocarcinomas', 'Disease', (123, 138))	('staging', 'MPA', (100, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('duplication', 'Var', (34, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('result in errors', 'Reg', (76, 92))	('adenocarcinomas', 'Disease', 'MESH:D000230', (123, 138))
48825	23199089	In the stomach hereditary cancer is also rare and caused by a germline mutation of the regulatory gene (16q) encoding E-cadherin.	('16q', 'Gene', (104, 107))	('caused by', 'Reg', (50, 59))	('E-cadherin', 'Gene', (118, 128))	('E-cadherin', 'Gene', '999', (118, 128))	('stomach hereditary cancer', 'Disease', (7, 32))	('stomach hereditary cancer', 'Disease', 'MESH:D013274', (7, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('germline mutation', 'Var', (62, 79))
48858	23199089	The assessment of a precursor as a "preneoplastic" lesion depends upon the presence of reliable histological criteria and of molecular markers: the most common molecular alterations are mutations in the suppressor gene TP53 (17p13), encoding p53, inactivation of P16/CDKN2A (9p22), encoding p16, amplification of CCND1, encoding Cyclin D1, and overexpression of proto-oncogenes such as the EGF receptor or c-Myc.	('p16', 'Gene', (291, 294))	('P16', 'Gene', '1029', (263, 266))	('CDKN2A', 'Gene', '1029', (267, 273))	('c-Myc', 'Gene', (406, 411))	('p16', 'Gene', '1029', (291, 294))	('EGF receptor', 'Gene', '1956', (390, 402))	('P16', 'Gene', (263, 266))	('men', 'Species', '9606', (10, 13))	('TP53', 'Gene', (219, 223))	('c-Myc', 'Gene', '4609', (406, 411))	('overexpression', 'PosReg', (344, 358))	('amplification', 'Var', (296, 309))	('inactivation', 'Var', (247, 259))	('EGF receptor', 'Gene', (390, 402))	('p53', 'Gene', '7157', (242, 245))	('TP53', 'Gene', '7157', (219, 223))	('CDKN2A', 'Gene', (267, 273))	('mutations', 'Var', (186, 195))	('CCND1', 'Gene', '595', (313, 318))	('p53', 'Gene', (242, 245))	('Cyclin D1', 'Gene', '595', (329, 338))	('Cyclin D1', 'Gene', (329, 338))	('CCND1', 'Gene', (313, 318))
48876	23199089	Until recently, it was assumed that all colorectal neoplastic lesions developed through the single sequence of polypoid adenoma cancer with mutations involving APC inactivation, KRAS mutation and TP53 inactivation in the sequence.	('TP53', 'Gene', (196, 200))	('KRAS', 'Gene', (178, 182))	('APC', 'Gene', '324', (160, 163))	('KRAS', 'Gene', '3845', (178, 182))	('polypoid adenoma cancer', 'Disease', 'MESH:D000236', (111, 134))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (51, 69))	('colorectal neoplastic lesions', 'Disease', 'MESH:D015179', (40, 69))	('polypoid adenoma cancer', 'Disease', (111, 134))	('developed', 'Reg', (70, 79))	('mutations', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('APC', 'Gene', (160, 163))	('colorectal neoplastic lesions', 'Disease', (40, 69))	('TP53', 'Gene', '7157', (196, 200))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (51, 68))
48905	23199089	In the columnar lined esophagus superficial premalignant lesions and adenocarcinomas are suspected on the basis of slight surface irregularities, spots with color change, or variations in the network of superficial vessels.	('variations', 'Var', (174, 184))	('superficial premalignant lesions', 'Phenotype', 'HP:0031190', (32, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('adenocarcinomas', 'Disease', 'MESH:D000230', (69, 84))	('columnar lined esophagus', 'Disease', (7, 31))	('adenocarcinomas', 'Disease', (69, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))
48981	21869822	We developed two mouse models of esophageal cancer by inoculating immunocompetent mice with syngeneic esophageal cell lines transformed by cyclin-D1 or mutant HRASG12V and loss of p53.	('mice', 'Species', '10090', (82, 86))	('loss', 'NegReg', (172, 176))	('S', 'Chemical', 'MESH:D013455', (162, 163))	('mouse', 'Species', '10090', (17, 22))	('p53', 'Gene', (180, 183))	('HRASG12V', 'Gene', (159, 167))	('mutant', 'Var', (152, 158))	('esophageal cancer', 'Disease', (33, 50))	('syngeneic esophageal', 'Disease', (92, 112))	('syngeneic esophageal', 'Disease', 'MESH:D004941', (92, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
48985	21869822	Mechanistic studies suggested that AdV-tk/GCV mediated a direct cytotoxic effect and an increased intra-tumoral trafficking of CD8 T cells (8.15% vs 14.89%, P=0.02).	('P', 'Chemical', 'MESH:D010758', (157, 158))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('intra-tumoral', 'Disease', 'MESH:D009369', (98, 111))	('increased', 'PosReg', (88, 97))	('AdV-tk/GCV', 'Var', (35, 45))	('intra-tumoral', 'Disease', (98, 111))	('GCV', 'Chemical', 'MESH:D015774', (42, 45))
48997	21869822	In addition to its enzymatic effects, AdV-tk/GCV (adenoviral vector carrying the herpes simplex virus thymidine kinase gene in combination with the prodrug ganciclovir) treatment stimulates a strong local and systemic immune response characterized by a T-helper type 1 cytokine cascade that manifests with increased interleukin-2, tumor necrosis factor-alpha, interferon-gamma and interleukin-12 production.	('ganciclovir', 'Chemical', 'MESH:D015774', (156, 167))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('stimulates', 'PosReg', (179, 189))	('increased', 'PosReg', (306, 315))	('men', 'Species', '9606', (174, 177))	('increased interleukin-', 'Phenotype', 'HP:0030783', (306, 328))	('AdV-tk/GCV', 'Var', (38, 48))	('interferon-gamma', 'Gene', '15978', (360, 376))	('interleukin-12 production', 'MPA', (381, 406))	('interleukin-2, tumor necrosis factor-alpha', 'Gene', '16183;21926', (316, 358))	('herpes simplex', 'Phenotype', 'HP:0012302', (81, 95))	('T-helper type 1 cytokine cascade', 'Pathway', (253, 285))	('interferon-gamma', 'Gene', (360, 376))	('local and', 'CPA', (199, 208))	('GCV', 'Chemical', 'MESH:D015774', (45, 48))
48998	21869822	AdV-tk/GCV increases cytotoxic T-lymphocyte infiltration and increased tumor immunogenicity.	('cytotoxic T-lymphocyte infiltration', 'CPA', (21, 56))	('increases', 'PosReg', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('increased', 'PosReg', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('AdV-tk/GCV', 'Var', (0, 10))	('GCV', 'Chemical', 'MESH:D015774', (7, 10))	('tumor', 'Disease', (71, 76))
49025	21869822	A549 is a human non-small-cell lung cancer (NSCLC) that we used as a control for in vitro assays.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('human', 'Species', '9606', (10, 15))	('A549', 'Var', (0, 4))	('lung cancer', 'Disease', (31, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('NSCLC', 'Disease', (44, 49))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))
49082	21869822	Increasing concentrations of cis/5-FU were toxic to animals, and did not significantly alter tumor growth kinetics (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cis/5-FU', 'Var', (29, 37))	('tumor', 'Disease', (93, 98))	('alter', 'Reg', (87, 92))	('5-FU', 'Chemical', 'MESH:D005472', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
49108	21869822	These data provide evidence that AdV-tk/GCV is directly cytotoxic and potentially useful in the treatment of human esophageal carcinomas.	('esophageal carcinomas', 'Disease', 'MESH:D004938', (115, 136))	('human', 'Species', '9606', (109, 114))	('AdV-tk/GCV', 'Var', (33, 43))	('GCV', 'Chemical', 'MESH:D015774', (40, 43))	('men', 'Species', '9606', (101, 104))	('esophageal carcinomas', 'Disease', (115, 136))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (115, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (115, 135))
49114	21869822	AdV-tk/GCV significantly inhibited tumor growth in this model; at day 26, the mean tumor volume of control mice was 1016 vs 338 mm3 in mice receiving AdV-tk/GCV; P=0.004 (Figures 3a and b).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (35, 40))	('mice', 'Species', '10090', (107, 111))	('AdV-tk/GCV', 'Var', (0, 10))	('P', 'Chemical', 'MESH:D010758', (162, 163))	('mice', 'Species', '10090', (135, 139))	('inhibited', 'NegReg', (25, 34))	('GCV', 'Chemical', 'MESH:D015774', (157, 160))	('GCV', 'Chemical', 'MESH:D015774', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
49120	21869822	As shown in Figure 3c, all tumors containing AdV-tk-transduced cells demonstrated strong regression as compared to tumors consisting of uninfected AKR cells.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('regression', 'CPA', (89, 99))	('AdV-tk-transduced cells', 'Var', (45, 68))
49122	21869822	These experiments show that a strong cytotoxic bystander effect is operative in adenovirus-transduced AKR tumors in vivo.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('men', 'Species', '9606', (12, 15))	('adenovirus-transduced', 'Var', (80, 101))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
49124	21869822	To more precisely define this role in our AKR model and AdV-tk system, mice bearing established AKR flank tumors were randomized to four groups: (1) Ad.LacZ/GCV treatment (control); (2) Ad.LacZ/GCV with CD8 T-cell depletion; (3) AdV-tk/GCV; or (4) AdV-tk/GCV with CD8 T-cell depletion.	('mice', 'Species', '10090', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('GCV', 'Chemical', 'MESH:D015774', (236, 239))	('Ad.LacZ/GCV', 'Var', (149, 160))	('GCV', 'Chemical', 'MESH:D015774', (194, 197))	('men', 'Species', '9606', (166, 169))	('Ad.LacZ/GCV', 'Var', (186, 197))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('GCV', 'Chemical', 'MESH:D015774', (157, 160))	('GCV', 'Chemical', 'MESH:D015774', (255, 258))	('flank tumors', 'Disease', (100, 112))	('flank tumors', 'Disease', 'MESH:D021501', (100, 112))
49125	21869822	Although mice receiving AdV-tk/GCV had smaller nodules after 26 days of tumor growth, effects were negated in the presence of CD8 T-cell depletion (Figures 3e and f).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('nodules', 'MPA', (47, 54))	('AdV-tk/GCV', 'Var', (24, 34))	('mice', 'Species', '10090', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('GCV', 'Chemical', 'MESH:D015774', (31, 34))	('smaller', 'NegReg', (39, 46))
49126	21869822	In fact, mice randomized to CD8 T-cell depletion protocols were observed to have more rapid growth, regardless of administration of AdV-tk/GCV and experienced more rapid growth (Figure 3e).	('CD8', 'Var', (28, 31))	('rapid growth', 'MPA', (86, 98))	('more', 'PosReg', (81, 85))	('GCV', 'Chemical', 'MESH:D015774', (139, 142))	('mice', 'Species', '10090', (9, 13))
49128	21869822	These experiments demonstrate in vivo evidence that AdV-tk/GCV therapy provides benefit with regard to tumor reduction in murine models of esophageal carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('murine', 'Species', '10090', (122, 128))	('men', 'Species', '9606', (12, 15))	('reduction', 'NegReg', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('esophageal carcinoma', 'Disease', (139, 159))	('AdV-tk/GCV', 'Var', (52, 62))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (139, 159))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (139, 159))	('GCV', 'Chemical', 'MESH:D015774', (59, 62))
49137	21869822	All mice undergoing surgery were observed to have a local recurrence; however, recurrent tumor volumes in the group receiving AdV-tk/GCV were significantly reduced postoperatively (Figures 4a and b).	('mice', 'Species', '10090', (4, 8))	('GCV', 'Chemical', 'MESH:D015774', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('AdV-tk/GCV', 'Var', (126, 136))	('reduced', 'NegReg', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
49143	21869822	We hypothesized that AdV-tk/GCV followed by surgery and cis/5-FU would similarly provide superior effects in limiting postoperative recurrences with minimal additional toxicity.	('toxicity', 'Disease', 'MESH:D064420', (168, 176))	('toxicity', 'Disease', (168, 176))	('postoperative', 'CPA', (118, 131))	('limiting', 'NegReg', (109, 117))	('AdV-tk/GCV', 'Var', (21, 31))	('5-FU', 'Chemical', 'MESH:D005472', (60, 64))	('GCV', 'Chemical', 'MESH:D015774', (28, 31))
49148	21869822	Following completion of AdV-tk/GCV or Ad.LacZ/GCV therapy, surgery was performed, leaving approximately 10% of tumor volume.	('Ad.LacZ/GCV', 'Var', (38, 49))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('GCV', 'Chemical', 'MESH:D015774', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('GCV', 'Chemical', 'MESH:D015774', (31, 34))
49150	21869822	As in the single-agent studies described above, we observed a modest reduction in tumor progression in animals receiving AdV-tk/GCV or chemotherapy as monotherapy.	('GCV', 'Chemical', 'MESH:D015774', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('AdV-tk/GCV', 'Var', (121, 131))	('reduction', 'NegReg', (69, 78))	('tumor', 'Disease', (82, 87))
49153	21869822	Although no mice were cured in any treatment groups, we observed almost a twofold increase in postoperative median survival in mice receiving combination therapy vs those receiving monotherapy (Figure 5c).	('mice', 'Species', '10090', (127, 131))	('combination', 'Var', (142, 153))	('postoperative median survival', 'CPA', (94, 123))	('men', 'Species', '9606', (40, 43))	('increase', 'PosReg', (82, 90))	('mice', 'Species', '10090', (12, 16))
49163	21869822	Immunohistochemical CD8 staining demonstrated an increased intratumoral CD8 T-cell trafficking in mice receiving AdV-tk/GCV therapy vs those receiving Ad.LacZ/GCV; 13.6 vs 4.2 cells per high power field (P=0.009) (Figure 6a).	('tumor', 'Disease', (64, 69))	('increased', 'PosReg', (49, 58))	('AdV-tk/GCV', 'Var', (113, 123))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('GCV', 'Chemical', 'MESH:D015774', (120, 123))	('P', 'Chemical', 'MESH:D010758', (204, 205))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('GCV', 'Chemical', 'MESH:D015774', (159, 162))	('mice', 'Species', '10090', (98, 102))
49166	21869822	We noted that mice receiving AdV-tk/GCV had a significant increase in the percentage of CD8 immunocytes (8.15% vs 14.89% P=0.02) of CD8 cells (Figure 6b).	('increase', 'PosReg', (58, 66))	('AdV-tk/GCV', 'Var', (29, 39))	('GCV', 'Chemical', 'MESH:D015774', (36, 39))	('mice', 'Species', '10090', (14, 18))	('P', 'Chemical', 'MESH:D010758', (121, 122))
49170	21869822	We found that CD8 T cells obtained from mice receiving both neoadjuvant AdV-tk/GCV and postoperative chemotherapy were better able to neutralize AKR cells as compared to mice receiving either monotherapy alone (P=0.02) (Figure 6c).	('mice', 'Species', '10090', (170, 174))	('mice', 'Species', '10090', (40, 44))	('AdV-tk/GCV', 'Var', (72, 82))	('GCV', 'Chemical', 'MESH:D015774', (79, 82))	('P', 'Chemical', 'MESH:D010758', (211, 212))	('neutralize AKR cells', 'MPA', (134, 154))
49183	21869822	Our AKR model incorporates both genetic (cyclin-D1 overexpression and p53 deletion) and physiological (resistance to standard platinum-based chemotherapy regimen) similarities to human esophageal carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('human', 'Species', '9606', (179, 184))	('esophageal carcinomas', 'Disease', (185, 206))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (185, 206))	('p53', 'Gene', (70, 73))	('deletion', 'Var', (74, 82))	('men', 'Species', '9606', (158, 161))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (185, 205))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (185, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('platinum', 'Chemical', 'MESH:D010984', (126, 134))	('overexpression', 'PosReg', (51, 65))
49197	21869822	We also present initial in vitro evidence supporting the notion that a human response will mirror (and potentially supersede) our murine preclinical findings, as the human esophageal cancer cells were more susceptible to AdV-tk-mediated killing than murine tumor cells.	('tumor', 'Disease', (257, 262))	('esophageal cancer', 'Disease', (172, 189))	('murine', 'Species', '10090', (250, 256))	('murine', 'Species', '10090', (130, 136))	('human', 'Species', '9606', (166, 171))	('susceptible', 'MPA', (206, 217))	('esophageal cancer', 'Disease', 'MESH:D004938', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('human', 'Species', '9606', (71, 76))	('AdV-tk-mediated', 'Var', (221, 236))
49343	29979428	To ensure the accuracy of periodontitis diagnosis in our study cohort, we selected subjects who had received additional procedure codes corresponding to periodontitis (91006C, 91007C, 91008C, 91009B, 91010B, 92013C, and 92014C).	('91006C', 'Var', (168, 174))	('periodontitis', 'Disease', (153, 166))	('91008C', 'Var', (184, 190))	('91009B', 'Var', (192, 198))	('periodontitis', 'Disease', 'MESH:D010518', (26, 39))	('periodontitis', 'Phenotype', 'HP:0000704', (153, 166))	('periodontitis', 'Phenotype', 'HP:0000704', (26, 39))	('periodontitis', 'Disease', (26, 39))	('91010B', 'Var', (200, 206))	('92013C', 'Var', (208, 214))	('92014C', 'Var', (220, 226))	('91007C', 'Var', (176, 182))	('periodontitis', 'Disease', 'MESH:D010518', (153, 166))
49386	29979428	In a large European prospective cohort study, individuals with high levels of antibodies (>200 ng/mL) for Porphyromonas gingivalis, which is one of the major periodontal pathogens, had a 2-fold higher risk of developing pancreatic cancer, compared with those with lower levels of antibodies.	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('Porphyromonas gingivalis', 'Gene', (106, 130))	('antibodies', 'Var', (78, 88))	('Porphyromonas gingivalis', 'Species', '837', (106, 130))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('pancreatic cancer', 'Disease', (220, 237))
49421	29922071	Knockout of MCM10 significantly suppressed the proliferation, colony formation, and migration capacity of EC109 ESCC cells, compared to control cells harboring wild-type MCM10.	('colony formation', 'CPA', (62, 78))	('EC109 ESCC', 'CellLine', 'CVCL:6898', (106, 116))	('Knockout', 'Var', (0, 8))	('MCM10', 'Gene', (12, 17))	('proliferation', 'CPA', (47, 60))	('migration capacity', 'CPA', (84, 102))	('suppressed', 'NegReg', (32, 42))
49422	29922071	Mechanistically, MCM10 depletion markedly reduced the phosphorylation of Akt.	('reduced', 'NegReg', (42, 49))	('Akt', 'Gene', (73, 76))	('MCM10', 'Gene', (17, 22))	('depletion', 'Var', (23, 32))	('Akt', 'Gene', '207', (73, 76))	('phosphorylation', 'MPA', (54, 69))
49432	29922071	For example, high expression of MCM3 is associated with epithelial-mesenchymal transition and invasion in prostate cancer.	('invasion', 'CPA', (94, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('high', 'Var', (13, 17))	('MCM3', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MCM3', 'Gene', '4172', (32, 36))	('prostate cancer', 'Disease', (106, 121))	('epithelial-mesenchymal transition', 'CPA', (56, 89))	('associated with', 'Reg', (40, 55))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))
49449	29922071	K520, K510, K410, K30, K180, HKESC1, EC7906, EC18, and EC109 ESCC cells were kindly provided by Professor Srivastava (University of Hong Kong).	('HKESC1', 'CellLine', 'CVCL:D568', (29, 35))	('EC109 ESCC', 'CellLine', 'CVCL:6898', (55, 65))	('K410', 'Var', (12, 16))	('EC7906', 'CellLine', 'CVCL:5V07', (37, 43))	('K180', 'Var', (23, 27))	('K520', 'Var', (0, 4))	('K30', 'Var', (18, 21))	('K510', 'Var', (6, 10))
49462	29922071	EC109 cell clones expressing wild-type and mutant MCM10 were seeded onto six-well plates (1,000 cells/well) and cultured for 3 weeks.	('MCM10', 'Gene', (50, 55))	('mutant', 'Var', (43, 49))	('EC109', 'CellLine', 'CVCL:6898', (0, 5))
49469	29922071	The membranes were incubated with anti-Akt (#9272, Cell Signaling Technology, Danvers, MA, USA; 1:500 dilution), anti-phospho-Akt (#9271, Cell signaling; 1:300 dilution), and anti-beta-actin (Santa Cruz Biotechnology, Santa Cruz, CA, USA; 1:2,000 dilution).	('#9271', 'Var', (131, 136))	('Akt', 'Gene', '207', (39, 42))	('Akt', 'Gene', '207', (126, 129))	('Akt', 'Gene', (39, 42))	('beta-actin', 'Gene', '728378', (180, 190))	('beta-actin', 'Gene', (180, 190))	('Akt', 'Gene', (126, 129))
49472	29922071	It was found that MCM10 was predominantly detected in the cytoplasm of tumor cells (Figure 1A).	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('MCM10', 'Var', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
49479	29922071	Western blot analysis revealed that MCM10 depletion led to a marked inhibition of Akt phosphorylation on Ser473 in EC109 cells (Figure 5A).	('Akt', 'Gene', '207', (82, 85))	('EC109', 'CellLine', 'CVCL:6898', (115, 120))	('Ser473', 'Chemical', '-', (105, 111))	('depletion', 'Var', (42, 51))	('inhibition', 'NegReg', (68, 78))	('Akt', 'Gene', (82, 85))	('MCM10 depletion', 'Var', (36, 51))
49480	29922071	However, the phosphorylation levels of nuclear factor kappa B (NF-kappaB), extracellular signal-regulated kinase (ERK), and p38 protein were not altered by MCM10 depletion (data not shown).	('p38', 'Gene', (124, 127))	('ERK', 'Gene', (114, 117))	('nuclear factor kappa B', 'Gene', (39, 61))	('nuclear factor kappa B', 'Gene', '4790', (39, 61))	('NF-kappaB', 'Gene', '4790', (63, 72))	('phosphorylation levels', 'MPA', (13, 35))	('NF-kappaB', 'Gene', (63, 72))	('extracellular signal-regulated kinase', 'Gene', '5594', (75, 112))	('depletion', 'Var', (162, 171))	('extracellular signal-regulated kinase', 'Gene', (75, 112))	('p38', 'Gene', '5594', (124, 127))	('MCM10 depletion', 'Var', (156, 171))	('ERK', 'Gene', '5594', (114, 117))
49481	29922071	To confirm the role of Akt signaling in the action of MCM10, we performed rescue experiments in the Clone 5 subline using constitutively active Akt (Figure 5B).	('Akt', 'Gene', (144, 147))	('Akt', 'Gene', '207', (23, 26))	('men', 'Species', '9606', (87, 90))	('MCM10', 'Var', (54, 59))	('Akt', 'Gene', (23, 26))	('Akt', 'Gene', '207', (144, 147))
49487	29922071	Inhibition of Akt phosphorylation can restrain cell growth (Figure 6B) and cell migration capacity (Figure 6C) in MCM10-overexpressed cells.	('Akt', 'Gene', (14, 17))	('cell migration capacity', 'CPA', (75, 98))	('restrain', 'NegReg', (38, 46))	('cell growth', 'CPA', (47, 58))	('Inhibition', 'Var', (0, 10))	('Akt', 'Gene', '207', (14, 17))
49496	29922071	Of note, knockout of MCM10 significantly impaired the growth and colony formation of EC109 cells.	('MCM10', 'Gene', (21, 26))	('knockout', 'Var', (9, 17))	('EC109', 'CellLine', 'CVCL:6898', (85, 90))	('impaired', 'NegReg', (41, 49))
49497	29922071	Moreover, MCM10 knockout suppressed the anchorage-independent growth of EC109 cells on soft agar.	('anchorage-independent growth', 'CPA', (40, 68))	('agar', 'Chemical', 'MESH:D000362', (92, 96))	('MCM10', 'Gene', (10, 15))	('EC109', 'CellLine', 'CVCL:6898', (72, 77))	('knockout', 'Var', (16, 24))	('suppressed', 'NegReg', (25, 35))
49499	29922071	MCM10 is implicated in MCM2-7 remodeling and cell-cycle progression and its functional deletion causes S phase defects, which may explain the reduced growth in MCM10-null EC109 cells.	('S phase defects', 'CPA', (103, 118))	('reduced', 'NegReg', (142, 149))	('growth', 'MPA', (150, 156))	('MCM2-7', 'Gene', '4171;4172;4173;4174;4175;4176', (23, 29))	('cell-cycle', 'CPA', (45, 55))	('MCM2-7', 'Gene', (23, 29))	('deletion', 'Var', (87, 95))	('EC109', 'CellLine', 'CVCL:6898', (171, 176))	('MCM10', 'Gene', (0, 5))
49501	29922071	Another study showed that MCM7 knockdown hinders the migration of KYSE510 and EC9706 cells in vitro.	('MCM7', 'Gene', (26, 30))	('EC9706', 'CellLine', 'CVCL:E307', (78, 84))	('migration', 'CPA', (53, 62))	('MCM7', 'Gene', '4176', (26, 30))	('hinders', 'NegReg', (41, 48))	('knockdown', 'Var', (31, 40))
49509	29922071	Ongoing studies are designed to address the effect of targeted ablation of MCM10 on tumor growth and metastasis in mouse models inoculated with multiple ESCC cell lines.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mouse', 'Species', '10090', (115, 120))	('metastasis', 'CPA', (101, 111))	('tumor', 'Disease', (84, 89))	('MCM10', 'Gene', (75, 80))	('ablation', 'Var', (63, 71))
49517	27903976	It is universally acknowledged that dysregulation of the cell cycle is closely correlated with proliferation of cancer cells, and is a hallmark of human carcinomas.	('dysregulation', 'Var', (36, 49))	('human', 'Species', '9606', (147, 152))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('carcinomas', 'Disease', 'MESH:D002277', (153, 163))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (36, 67))	('carcinomas', 'Disease', (153, 163))	('correlated', 'Reg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cell cycle', 'CPA', (57, 67))
49523	27903976	Deregulation of cyclin B1 can result in unrestricted cell-cycle progression and malignant transformation.	('Deregulation', 'Var', (0, 12))	('malignant transformation', 'CPA', (80, 104))	('unrestricted cell-cycle progression', 'CPA', (40, 75))	('result in', 'Reg', (30, 39))	('cyclin B1', 'Gene', '891', (16, 25))	('cyclin B1', 'Gene', (16, 25))
49568	27903976	A growing body of research indicates that dysregulated expression of cyclin B1 is a common event in cancer cells.	('cyclin B1', 'Gene', '891', (69, 78))	('cyclin B1', 'Gene', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('expression', 'MPA', (55, 65))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('dysregulated', 'Var', (42, 54))
49622	27853736	The number of inflammatory cells infiltrating into esophageal ulcer sites was much lower in pigs that underwent transplantation than in control and EBD-treated pigs.	('esophageal ulcer', 'Disease', 'MESH:D014456', (51, 67))	('esophageal ulcer', 'Disease', (51, 67))	('esophageal ulcer', 'Phenotype', 'HP:0004791', (51, 67))	('transplantation', 'Var', (112, 127))	('lower', 'NegReg', (83, 88))
49641	25326863	When the ATC sequence context is disrupted by mutations, SATB1 binding is abolished.	('mutations', 'Var', (46, 55))	('binding', 'Interaction', (63, 70))	('abolished', 'NegReg', (74, 83))	('SATB1', 'Gene', (57, 62))	('SATB1', 'Gene', '6304', (57, 62))
49648	25326863	SATB1 expression in gastric cancer has previously been examined in two studies on Chinese populations, both indicating that SATB1 expression is independently associated with worse prognosis.	('associated', 'Reg', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('SATB1', 'Gene', (0, 5))	('SATB1', 'Gene', '6304', (0, 5))	('expression', 'Var', (130, 140))	('gastric cancer', 'Disease', (20, 34))	('SATB1', 'Gene', '6304', (124, 129))	('gastric cancer', 'Disease', 'MESH:D013274', (20, 34))	('SATB1', 'Gene', (124, 129))	('gastric cancer', 'Phenotype', 'HP:0012126', (20, 34))
49660	25326863	Western blot analyses were performed according to standard protocols on SATB1 and SATB2 overexpression lysates co-expressed with a C-terminal myc-DDK tag (~3.1 kDa) in mammalian HEK293T cells (LY427355 and LY414656, respectively, Origene Technologies, Rockville, MD, USA).	('mammalian', 'Species', '9606', (168, 177))	('tag', 'Gene', '404663', (150, 153))	('SATB2', 'Gene', (82, 87))	('LY414656', 'Var', (206, 214))	('LY427355', 'Var', (193, 201))	('LY414656', 'Chemical', '-', (206, 214))	('tag', 'Gene', (150, 153))	('SATB1', 'Gene', '6304', (72, 77))	('SATB2', 'Gene', '23314', (82, 87))	('HEK293T', 'CellLine', 'CVCL:0063', (178, 185))	('SATB1', 'Gene', (72, 77))	('LY427355', 'Chemical', '-', (193, 201))
49683	25326863	Overall survival (OS) rates and recurrence-free survival (RFS) time according to SATB1 negativity versus SATB1 positivity were calculated using Kaplan-Meier analysis.	('SATB1', 'Gene', '6304', (105, 110))	('SATB1', 'Gene', (81, 86))	('SATB1', 'Gene', '6304', (81, 86))	('RFS', 'Disease', (58, 61))	('OS', 'Chemical', '-', (18, 20))	('RFS', 'Disease', 'MESH:D005198', (58, 61))	('negativity', 'Var', (87, 97))	('SATB1', 'Gene', (105, 110))
49706	25326863	In the entire cohort, SATB1 positivity was not significantly associated with overall survival but with a significantly shorter RFS in unadjusted (HR = 1.68; 95 % CI 1.04-2.71, p = 0.032) but not in adjusted analysis (data not shown).	('shorter', 'NegReg', (119, 126))	('SATB1', 'Gene', (22, 27))	('RFS', 'Disease', (127, 130))	('positivity', 'Var', (28, 38))	('RFS', 'Disease', 'MESH:D005198', (127, 130))	('SATB1', 'Gene', '6304', (22, 27))
49714	25326863	These results are in line with several previous studies indicating that SATB1 expression correlates with a more aggressive phenotype and worse prognosis in several types of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('expression', 'Var', (78, 88))	('SATB1', 'Gene', '6304', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('SATB1', 'Gene', (72, 77))
49720	25326863	We also confirm that expression of SATB1in a limited fraction of the tumor cells already confers poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('SATB1', 'Gene', (35, 40))	('SATB1', 'Gene', '6304', (35, 40))	('expression', 'Var', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
49755	25336972	Patients with ALI <18 had a significantly poorer 5-year CSS compared to ALI >=18 (21.7% versus 43.4%, P<0.001).	('ALI', 'Chemical', '-', (72, 75))	('ALI <18', 'Var', (14, 21))	('CSS', 'Chemical', '-', (56, 59))	('poorer', 'NegReg', (42, 48))	('CSS', 'CPA', (56, 59))	('Patients', 'Species', '9606', (0, 8))	('ALI', 'Chemical', '-', (14, 17))
49791	25336972	Patients with ALI <18 had a significantly poor 5-year CSS compared to ALI >=18 (21.7% versus 43.4%, P<0.001) (Figure 1).	('ALI <18', 'Var', (14, 21))	('CSS', 'MPA', (54, 57))	('CSS', 'Chemical', '-', (54, 57))	('Patients', 'Species', '9606', (0, 8))	('ALI', 'Chemical', '-', (14, 17))	('poor', 'NegReg', (42, 46))	('ALI', 'Chemical', '-', (70, 73))
49793	25336972	On multivariate analysis, we showed that ALI was a significant predictive factor of CSS (P=0.024) (Table 2).	('CSS', 'Disease', (84, 87))	('ALI', 'Var', (41, 44))	('ALI', 'Chemical', '-', (41, 44))	('CSS', 'Chemical', '-', (84, 87))
49796	25336972	ALI <18 had a hazard ratio (HR) of 1.433 (95% confidence interval [CI]: 1.048-1.959; P=0.024) for CSS.	('CSS', 'Disease', (98, 101))	('ALI', 'Chemical', '-', (0, 3))	('ALI <18', 'Var', (0, 7))	('CSS', 'Chemical', '-', (98, 101))
50009	19473205	Using multivariate logistic regression, we found that being diagnosed at <=30 years of age was strongly associated with Kalenjin ethnicity (OR (95%CI) 5.68 (2.13-15.11)), but not with residence within the traditional catchment area (OR (95%CI) 1.01 (0.48-2.14)).	('men', 'Species', '9606', (222, 225))	('associated', 'Interaction', (104, 114))	('Kalenjin ethnicity', 'Var', (120, 138))
50056	33392080	Furthermore, patients with non-B blood types had a significantly shorter DFS (HR=1.22, 95%CI:1.07-1.38, P=0.002) and OS (HR=1.22, 95%CI:1.07-1.38, P=0.003) than patients with blood type B, and patients with non-O blood types had a significantly better DFS (HR=0.86, 95%CI:0.77-0.96, P=0.006) and OS (HR=0.86, 95%CI:0.77-0.96, P=0.007) than patients with blood type O. Subgroup analyses found that blood type B had a better DFS and OS than non-B in patients who were male, younger, early pathological stages and had squamous-cell carcinomas (ESCC).	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (65, 72))	('better', 'PosReg', (416, 422))	('non-O', 'Gene', '4841', (207, 212))	('non-O', 'Gene', (207, 212))	('blood type B', 'Var', (397, 409))	('patients', 'Species', '9606', (448, 456))	('carcinomas', 'Phenotype', 'HP:0030731', (529, 539))	('patients', 'Species', '9606', (161, 169))	('squamous-cell carcinomas', 'Disease', 'MESH:D002294', (515, 539))	('patients', 'Species', '9606', (340, 348))	('DFS', 'MPA', (423, 426))	('squamous-cell carcinomas', 'Disease', (515, 539))	('carcinoma', 'Phenotype', 'HP:0030731', (529, 538))	('squamous-cell carcinomas', 'Phenotype', 'HP:0002860', (515, 539))
50067	33392080	showed that blood type AB was not associated with OS for all patients, but was independently associated with worse OS compared to non-AB in patients with lymph node-negative.	('patients', 'Species', '9606', (61, 69))	('blood type AB', 'Var', (12, 25))	('associated', 'Reg', (93, 103))	('patients', 'Species', '9606', (140, 148))	('non-A', 'Species', '12440', (130, 135))
50068	33392080	The other study, only including 181 Japanese patients, reported that patients with blood type B had a significantly better OS than those with non-B.	('patients', 'Species', '9606', (69, 77))	('blood type B', 'Var', (83, 95))	('patients', 'Species', '9606', (45, 53))	('better', 'Reg', (116, 122))
50100	33392080	Additionally, patients with blood type B had significantly better DFS (P=0.001,  Figure 2A ) and OS (P=0.001,  Figure 2B ) than those with non-B blood types.	('DFS', 'MPA', (66, 69))	('patients', 'Species', '9606', (14, 22))	('better', 'PosReg', (59, 65))	('blood type B', 'Var', (28, 40))
50101	33392080	Moreover, patients with blood type O had a significantly shorter DFS (P=0.027,  Figure 2C ) and OS (P=0.017,  Figure 2D ) compared to patients with non-O blood types.	('non-O', 'Gene', '4841', (148, 153))	('non-O', 'Gene', (148, 153))	('patients', 'Species', '9606', (134, 142))	('blood type O', 'Var', (24, 36))	('DFS', 'MPA', (65, 68))	('patients', 'Species', '9606', (10, 18))	('shorter', 'NegReg', (57, 64))
50107	33392080	The analyses revealed that the association of blood type B with longer DFS and OS was observed in male patients, younger patients, patients with esophageal squamous-cell carcinomas (ESCC), and patients in the early pathological stage (P<0.05,  Table 4 ,  Figure 3A ).	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (193, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('squamous-cell carcinomas', 'Phenotype', 'HP:0002860', (156, 180))	('esophageal squamous-cell carcinomas', 'Disease', 'MESH:D000077277', (145, 180))	('association', 'Interaction', (31, 42))	('blood type', 'Var', (46, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('patients', 'Species', '9606', (103, 111))	('esophageal squamous-cell carcinomas', 'Disease', (145, 180))	('patients', 'Species', '9606', (121, 129))
50109	33392080	Moreover, the association between blood type O and shorter DFS and OS was observed in male patients, younger patients, and patients with ESCC (P<0.05,  Table 4 ,  Figure 3B ).	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (109, 117))	('shorter', 'NegReg', (51, 58))	('ESCC', 'Disease', (137, 141))	('patients', 'Species', '9606', (123, 131))	('blood type O', 'Var', (34, 46))	('DFS', 'MPA', (59, 62))
50118	33392080	One study showed that blood type AB was not associated with OS for all patients, but was independently associated with worse OS compared to non-AB in subgroup of patients with lymph node-negative.	('patients', 'Species', '9606', (162, 170))	('associated', 'Reg', (103, 113))	('patients', 'Species', '9606', (71, 79))	('blood type AB', 'Var', (22, 35))	('non-A', 'Species', '12440', (140, 145))
50120	33392080	Thus, we examined the impact of each ABO blood type on survival and found that patients with non-B blood types had a 22% higher risk of disease progression and a 22% higher risk of death, compared to patients with blood type B.	('patients', 'Species', '9606', (200, 208))	('death', 'Disease', 'MESH:D003643', (181, 186))	('death', 'Disease', (181, 186))	('disease progression', 'CPA', (136, 155))	('patients', 'Species', '9606', (79, 87))	('non-B blood types', 'Var', (93, 110))	('ABO', 'Gene', '28', (37, 40))	('ABO', 'Gene', (37, 40))
50122	33392080	These findings suggested that blood type B is a favorable prognostic factor and blood type O is an adverse prognostic factor for survival in patients with esophageal cancer.	('blood type B', 'Var', (30, 42))	('esophageal cancer', 'Disease', (155, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('blood type O', 'Var', (80, 92))	('patients', 'Species', '9606', (141, 149))
50124	33392080	In addition, we found that in subgroup of patients with male, younger, esophageal squamous cell carcinomas, and early pathological stage (I-II), blood type B was associated with better DFS and OS compared to non-B.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('DFS', 'CPA', (185, 188))	('better', 'PosReg', (178, 184))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (82, 106))	('blood type B', 'Var', (145, 157))	('esophageal squamous cell carcinomas', 'Disease', (71, 106))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (71, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('patients', 'Species', '9606', (42, 50))
50126	33392080	Moreover, the association between blood type O and worse DFS and OS was observed in subgroup of patients who were male, younger, and esophageal squamous cell carcinomas, but not in subgroup of patients who were female, old, had adenocarcinoma, or were in early or advanced pathological stages.	('patients', 'Species', '9606', (193, 201))	('adenocarcinoma', 'Disease', 'MESH:D000230', (228, 242))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('patients', 'Species', '9606', (96, 104))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (144, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('blood type', 'Var', (34, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('esophageal squamous cell carcinomas', 'Disease', (133, 168))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (133, 168))	('adenocarcinoma', 'Disease', (228, 242))
50128	33392080	It has been shown that the modified expression of blood group antigens on tumor cells may alter cell motility, resistance to apoptosis, and immune escape.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('resistance to apoptosis', 'CPA', (111, 134))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('modified', 'Var', (27, 35))	('tumor', 'Disease', (74, 79))	('cell motility', 'CPA', (96, 109))	('immune escape', 'CPA', (140, 153))	('alter', 'Reg', (90, 95))
50132	33392080	The proportion of tumors associated with elevated pretreatment serum CEA and SCCA was significantly higher in patients with blood type O than in patients with other blood types, while the proportion associated with elevated serum CEA and SCCA was significantly lower in patients with blood type B than in patients with other blood types.	('patients', 'Species', '9606', (145, 153))	('CEA', 'Gene', (69, 72))	('elevated pretreatment serum CEA', 'Phenotype', 'HP:0031029', (41, 72))	('CEA', 'Gene', '1084', (69, 72))	('patients', 'Species', '9606', (270, 278))	('elevated serum CEA', 'Phenotype', 'HP:0031029', (215, 233))	('SCCA', 'MPA', (77, 81))	('patients', 'Species', '9606', (305, 313))	('tumors', 'Disease', (18, 24))	('elevated', 'PosReg', (41, 49))	('blood type O', 'Var', (124, 136))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('higher', 'PosReg', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('CEA', 'Gene', (230, 233))	('patients', 'Species', '9606', (110, 118))	('CEA', 'Gene', '1084', (230, 233))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
50136	33392080	Our study implicated that ABO blood group might serve as a useful biomarker to independently predict prognosis of patients with esophageal cancer, adjuvant therapy and close follow-up after surgery are more necessary as patients with blood type O were identified to have higher risk of recurrence and poorer prognosis than others.	('esophageal cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('ABO blood group', 'Gene', (26, 41))	('blood type O', 'Var', (234, 246))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('patients', 'Species', '9606', (220, 228))	('patients', 'Species', '9606', (114, 122))	('ABO blood group', 'Gene', '28', (26, 41))
50163	32728182	In addition, a previous study reported that CKI limited cancer pain both directly by blocking TRPV1 signalling and indirectly by reducing tumour growth.	('TRPV1', 'Gene', (94, 99))	('cancer pain', 'Disease', 'MESH:D000072716', (56, 67))	('TRPV1', 'Gene', '7442', (94, 99))	('pain', 'Phenotype', 'HP:0012531', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('cancer pain', 'Disease', (56, 67))	('CKI', 'Var', (44, 47))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('blocking', 'NegReg', (85, 93))	('reducing', 'NegReg', (129, 137))	('tumour', 'Disease', (138, 144))
50177	32728182	Adenine mainly forms two hydrogen bonds with the TYR-801 and ASN-808 residues on the EGFR protein, and a total of 6 residues are bound to the protein by hydrophobic interaction.	('EGFR', 'Gene', (85, 89))	('TYR-801', 'Var', (49, 56))	('Adenine', 'Chemical', 'MESH:D000225', (0, 7))	('hydrogen', 'Chemical', 'MESH:D006859', (25, 33))	('hydrogen', 'Protein', (25, 33))	('ASN', 'Chemical', 'MESH:D001216', (61, 64))	('ASN-808', 'Gene', (61, 68))	('EGFR', 'Gene', '1956', (85, 89))	('bound', 'Interaction', (129, 134))	('TYR', 'Chemical', 'MESH:D014443', (49, 52))
50178	32728182	In addition, the same EGFR protein formed two hydrogen bonds with residues LYS-852 and ARG-776 in addition to 7 hydrophobic bonds.	('hydrophobic bonds', 'MPA', (112, 129))	('ARG', 'Chemical', 'MESH:D001120', (87, 90))	('hydrogen bonds', 'MPA', (46, 60))	('ARG-776', 'Var', (87, 94))	('LYS-852', 'Var', (75, 82))	('EGFR', 'Gene', '1956', (22, 26))	('LYS', 'Chemical', 'MESH:D008239', (75, 78))	('hydrogen', 'Chemical', 'MESH:D006859', (46, 54))	('EGFR', 'Gene', (22, 26))
50194	32728182	EGFR is overexpressed or mutated in most tumours, resulting in dysregulation of the signal transduction pathway, uncontrolled cell growth, and inhibition of cancer cell apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('EGFR', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('overexpressed', 'PosReg', (8, 21))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('dysregulation', 'MPA', (63, 76))	('signal transduction pathway', 'Pathway', (84, 111))	('cancer', 'Disease', (157, 163))	('uncontrolled', 'MPA', (113, 125))	('tumours', 'Disease', (41, 48))	('inhibition', 'NegReg', (143, 153))	('EGFR', 'Gene', '1956', (0, 4))	('mutated', 'Var', (25, 32))
50197	32728182	In addition, high expression of EGFR is closely related to the proliferation, infiltration and poor prognosis of ESCA cells.	('high', 'Var', (13, 17))	('EGFR', 'Gene', '1956', (32, 36))	('infiltration', 'CPA', (78, 90))	('EGFR', 'Gene', (32, 36))	('ESCA', 'Disease', (113, 117))	('related', 'Reg', (48, 55))
50198	32728182	Thus, abnormal EGFR expression is one of the serious pathogenic factors of ESCA.	('ESCA', 'Disease', (75, 79))	('abnormal', 'Var', (6, 14))	('expression', 'MPA', (20, 30))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))
50203	32728182	Hoffmann proposed a diagnostic method to detect ErbB2 amplification in single disseminated cancer cells, demonstrating that ErbB2 amplification in esophageal cancer patients is significantly correlated with short-term survival.	('ErbB2', 'Gene', '2064', (124, 129))	('short-term survival', 'CPA', (207, 226))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('ErbB2', 'Gene', (48, 53))	('amplification', 'Var', (130, 143))	('cancer', 'Disease', (158, 164))	('ErbB2', 'Gene', (124, 129))	('patients', 'Species', '9606', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ErbB2', 'Gene', '2064', (48, 53))	('correlated with', 'Reg', (191, 206))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
50212	32728182	Genome-wide screening revealed that the amplification of cyclin D1 is one of many genetic changes in ESCC.	('cyclin D1', 'Gene', '595', (57, 66))	('ESCC', 'Disease', (101, 105))	('amplification', 'Var', (40, 53))	('cyclin D1', 'Gene', (57, 66))
50226	32728182	Abnormal activation of pathways caused by abnormal expression of these proteins is a critical factor affecting the progression of esophageal cancer.	('activation', 'PosReg', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('abnormal', 'Var', (42, 50))	('expression', 'MPA', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('pathways', 'Pathway', (23, 31))
50252	32494154	Moreover, the aberrant expression of SLC39A4 was positively correlated with clinical stage, T categories and lymph node metastasis.	('clinical stage', 'CPA', (76, 90))	('lymph node metastasis', 'CPA', (109, 130))	('T categories', 'CPA', (92, 104))	('aberrant expression', 'Var', (14, 33))	('correlated', 'Reg', (60, 70))	('SLC39A4', 'Gene', (37, 44))	('SLC39A4', 'Gene', '55630', (37, 44))
50254	32494154	Furthermore, the in vitro experiments showed that SLC39A4 knockdown not only impaired the proliferation and motility capacities of ESCC cells but also enhanced the sensitivity to cisplatin treatment.	('sensitivity to cisplatin treatment', 'MPA', (164, 198))	('enhanced', 'PosReg', (151, 159))	('proliferation', 'CPA', (90, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('impaired', 'NegReg', (77, 85))	('motility capacities', 'CPA', (108, 127))	('SLC39A4', 'Gene', '55630', (50, 57))	('SLC39A4', 'Gene', (50, 57))	('knockdown', 'Var', (58, 67))
50282	32494154	The primer pairs of target mRNAs were as follows: SLC39A4, F: 5'- CGAGGTCCCTATGACGCTG-3' and R: 5'-CACTCAGGCATACCGTGTCC-3', GAPDH, F: 5'-TGCACCACCAACTGCTTAGC-3' and R: 5'-GGCATGGACTGTGGTCATGAG-3'.	('GAPDH', 'Gene', '2597', (124, 129))	("R: 5'-CACTCAGGCATACCGTGTCC-3", 'Var', (93, 121))	('GAPDH', 'Gene', (124, 129))	('SLC39A4', 'Gene', '55630', (50, 57))	('SLC39A4', 'Gene', (50, 57))
50306	32494154	In the meanwhile, mining five accessible datasets of gene expression profiling (GSE17351, GSE20347, GSE23400, GSE38129 and GSE100942) in GEO also confirmed that SLC39A4 was elevated in ESCC tissues (Figure 1B).	('SLC39A4', 'Gene', '55630', (161, 168))	('SLC39A4', 'Gene', (161, 168))	('elevated', 'PosReg', (173, 181))	('GSE100942', 'Var', (123, 132))	('GSE20347', 'Var', (90, 98))	('GSE23400', 'Var', (100, 108))	('ESCC', 'Disease', (185, 189))	('GSE38129', 'Var', (110, 118))	('GSE17351', 'Var', (80, 88))
50310	32494154	Kaplan-Meier survival analysis revealed that aberrant expression of SLC39A4 predicted poor prognosis of patients with ESCC (HR=2.017, P=0.0126, Figure 1E).	('SLC39A4', 'Gene', '55630', (68, 75))	('ESCC', 'Disease', (118, 122))	('aberrant expression', 'Var', (45, 64))	('patients', 'Species', '9606', (104, 112))	('SLC39A4', 'Gene', (68, 75))
50313	32494154	Besides, knockdown of SLC39A4 significantly reduced both the size and number of colonies in TE-1 and TE-10 cells (Figure 2D).	('knockdown', 'Var', (9, 18))	('size', 'CPA', (61, 65))	('TE-10', 'CellLine', 'CVCL:1760', (101, 106))	('reduced', 'NegReg', (44, 51))	('SLC39A4', 'Gene', '55630', (22, 29))	('SLC39A4', 'Gene', (22, 29))
50315	32494154	As shown in Figure 2G and H, we observed that cell cycle was arrested at G1 phase in both TE-1 and TE-10 cells transfected with siRNAs against SLC39A4.	('arrest', 'Disease', (61, 67))	('TE-10', 'CellLine', 'CVCL:1760', (99, 104))	('SLC39A4', 'Gene', (143, 150))	('siRNAs', 'Var', (128, 134))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('cell cycle', 'CPA', (46, 56))	('SLC39A4', 'Gene', '55630', (143, 150))
50320	32494154	Similar inhibitory effect was also observed in TE-10 cells with deficient SLC39A4 (Figure 3A, lower panels).	('SLC39A4', 'Gene', '55630', (74, 81))	('deficient', 'Var', (64, 73))	('TE-10', 'CellLine', 'CVCL:1760', (47, 52))	('SLC39A4', 'Gene', (74, 81))
50321	32494154	As shown in Figure 3B, elevated SLC39A4 significantly promoted migration and invasion of ESCC cells in vitro.	('promoted', 'PosReg', (54, 62))	('invasion of ESCC cells', 'CPA', (77, 99))	('elevated', 'Var', (23, 31))	('SLC39A4', 'Gene', '55630', (32, 39))	('SLC39A4', 'Gene', (32, 39))	('migration', 'CPA', (63, 72))
50324	32494154	The results of immunoblotting showed that SLC39A4 knockdown led to an increase of E-cadherin, while the levels of N-cadherin, Vimentin and Snail were reduced (Figure 3C), suggesting that suppression of SLC39A4 reversed EMT process.	('SLC39A4', 'Gene', '55630', (202, 209))	('increase', 'PosReg', (70, 78))	('SLC39A4', 'Gene', (202, 209))	('Vimentin', 'Gene', '7431', (126, 134))	('SLC39A4', 'Gene', (42, 49))	('knockdown', 'Var', (50, 59))	('SLC39A4', 'Gene', '55630', (42, 49))	('E-cadherin', 'Gene', (82, 92))	('N-cadherin', 'Gene', (114, 124))	('Snail', 'Gene', '6615', (139, 144))	('E-cadherin', 'Gene', '999', (82, 92))	('reduced', 'NegReg', (150, 157))	('Snail', 'Gene', (139, 144))	('Vimentin', 'Gene', (126, 134))	('N-cadherin', 'Gene', '1000', (114, 124))
50331	32494154	Furthermore, SLC39A4 silencing and TPEN treatment both remarkably decreased the IC50 to CDDP in TE-1 and TE-10 cells (Figure 4C and D), suggesting the cells became more sensitive to drugs.	('SLC39A4', 'Gene', '55630', (13, 20))	('TPEN', 'Chemical', 'MESH:C044387', (35, 39))	('SLC39A4', 'Gene', (13, 20))	('TE-10', 'CellLine', 'CVCL:1760', (105, 110))	('decreased', 'NegReg', (66, 75))	('CDDP', 'Chemical', '-', (88, 92))	('silencing', 'Var', (21, 30))	('IC50 to CDDP', 'MPA', (80, 92))
50336	32494154	The zinc concentration in tumor cells is much higher than that in normal cells, which may be partially caused by the aberrant expression of SLC39A4.	('SLC39A4', 'Gene', (140, 147))	('higher', 'PosReg', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('aberrant', 'Var', (117, 125))	('zinc concentration', 'MPA', (4, 22))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('SLC39A4', 'Gene', '55630', (140, 147))
50349	32494154	The results of CCK-8 assay and clonogenicity assay demonstrated that knockdown of SLC39A4 by specific siRNAs significantly impaired ESCC cells growth, probably caused by siSLC39A4-induced downregulation of Cyclin D1 and cell cycle arrest.	('SLC39A4', 'Gene', '55630', (172, 179))	('Cyclin D1', 'Gene', (206, 215))	('SLC39A4', 'Gene', (172, 179))	('CCK-8', 'Chemical', 'MESH:D012844', (15, 20))	('downregulation', 'NegReg', (188, 202))	('SLC39A4', 'Gene', '55630', (82, 89))	('arrest', 'Disease', 'MESH:D006323', (231, 237))	('impaired', 'NegReg', (123, 131))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (220, 237))	('Cyclin D1', 'Gene', '595', (206, 215))	('arrest', 'Disease', (231, 237))	('ESCC', 'Disease', (132, 136))	('knockdown', 'Var', (69, 78))	('SLC39A4', 'Gene', (82, 89))
50354	32494154	In this study, we found that SLC39A4 blockage increased the expression of the epithelial marker E-cadherin, but reduced the level of mesenchymal markers, including N-cadherin and Vimentin.	('expression', 'MPA', (60, 70))	('Vimentin', 'Gene', (179, 187))	('N-cadherin', 'Gene', (164, 174))	('Vimentin', 'Gene', '7431', (179, 187))	('increased', 'PosReg', (46, 55))	('level of mesenchymal markers', 'MPA', (124, 152))	('blockage', 'Var', (37, 45))	('N-cadherin', 'Gene', '1000', (164, 174))	('SLC39A4', 'Gene', (29, 36))	('reduced', 'NegReg', (112, 119))	('E-cadherin', 'Gene', (96, 106))	('SLC39A4', 'Gene', '55630', (29, 36))	('E-cadherin', 'Gene', '999', (96, 106))
50357	32494154	In nasopharyngeal carcinoma, inhibition of SLC39A4 enhances the tumor cell sensitivity to radiotherapy, the main therapeutic strategy for nasopharyngeal carcinoma.	('SLC39A4', 'Gene', '55630', (43, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('tumor', 'Disease', (64, 69))	('carcinoma', 'Disease', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (138, 162))	('carcinoma', 'Disease', (153, 162))	('carcinoma', 'Disease', 'MESH:D009369', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('enhances', 'PosReg', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('inhibition', 'Var', (29, 39))	('SLC39A4', 'Gene', (43, 50))	('carcinoma', 'Disease', 'MESH:D009369', (153, 162))
50358	32494154	Here, we confirmed that siSLC39A4 could significantly sensitize ESCC cells to CDDP in vitro, the standard chemotherapy regimen for ESCC, suggesting SLC39A4 knockdown may increase the response rate and decrease the side effect caused by chemotherapy.	('knockdown', 'Var', (156, 165))	('side effect', 'CPA', (214, 225))	('response rate', 'CPA', (183, 196))	('increase', 'PosReg', (170, 178))	('SLC39A4', 'Gene', (148, 155))	('SLC39A4', 'Gene', '55630', (148, 155))	('CDDP', 'Chemical', '-', (78, 82))	('SLC39A4', 'Gene', (26, 33))	('SLC39A4', 'Gene', '55630', (26, 33))	('decrease', 'NegReg', (201, 209))
50442	30165050	In a multivariable analysis BE/IM was associated with better survival independent of age, sex, stage and tumor location and length (adjusted HR: 0.66, 95% CI: 0.5-0.88, P=0.005).	('BE', 'Phenotype', 'HP:0100580', (28, 30))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('survival', 'MPA', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('BE/IM', 'Var', (28, 33))	('tumor', 'Disease', (105, 110))	('better', 'PosReg', (54, 60))
50499	30165050	35% (n=501) of tumors were classified as spanning the esophagogastric (Siewert Type II), with 33% (n=213) in the BE/IM group compared with 36% (n=288) in the non-BE/IM group.	('tumors', 'Disease', (15, 21))	('BE', 'Phenotype', 'HP:0100580', (162, 164))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('BE/IM', 'Var', (113, 118))	('BE', 'Phenotype', 'HP:0100580', (113, 115))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
50511	30165050	In patients with tumors classed as either Siewert I (n=226, HR=0.38, 95% CI: 0.27-0.54, P<0.001) or Siewert II (n=166, HR=0.5, 95% CI: 0.33-0.77, P=0.002) the BE/IM group showed better survival indicating that the effect of BE/IM is independent of esophageal location (Figure 2A).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('BE', 'Phenotype', 'HP:0100580', (159, 161))	('Siewert', 'Var', (100, 107))	('better', 'PosReg', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (17, 23))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('survival', 'MPA', (185, 193))	('BE', 'Phenotype', 'HP:0100580', (224, 226))
50516	30165050	BE/IM was associated with superior survival compared to non-BE/IM HR: 0.65 (95%: 0.44 - 0.96, P=0.03) adjusting for age, sex, tumor location and length and TNM stage.	('BE/IM', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('TNM', 'Gene', '10178', (156, 159))	('BE', 'Phenotype', 'HP:0100580', (60, 62))	('superior', 'PosReg', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BE', 'Phenotype', 'HP:0100580', (0, 2))	('TNM', 'Gene', (156, 159))	('tumor', 'Disease', (126, 131))
50560	29391589	In the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS), the survival of patients with clinical stage T1N1 or T2-3N0-1 could be enhanced with the implementation of neoadjuvant chemoradiotherapy compared to surgery alone.	('T2-3N0-1', 'Var', (136, 144))	('enhanced', 'PosReg', (154, 162))	('patients', 'Species', '9606', (99, 107))	('survival', 'CPA', (87, 95))	('T1N1', 'Var', (128, 132))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Oesophageal Cancer', 'Disease', 'MESH:D009369', (29, 47))	('Oesophageal Cancer', 'Disease', (29, 47))
50585	29391589	Whereas the "relatively good prognosis advanced cancer" included T3N0 and T1-3N1 stages, the "most advanced cancer" referred to T4, N2-3, and M1 stages.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('T3N0', 'Var', (65, 69))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
50594	29391589	In other words, 22.3% (161/723) of patients with clinical T3N0 and T1-3N1 tumors were found to have pathological T1-2N0 tumors.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('T1-3N1 tumors', 'Disease', (67, 80))	('T1-3N1 tumors', 'Disease', 'MESH:D009369', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('T3N0', 'Var', (58, 62))	('T1-2N0 tumors', 'Disease', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('patients', 'Species', '9606', (35, 43))	('T1-2N0 tumors', 'Disease', 'MESH:D009369', (113, 126))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
50597	29391589	In our cohort, 53.5% (387/723) of patients with clinical T3N0 and T1-3N1 tumors had similar pathological stages, and their survival, with the use of adjuvant CRT, was non-inferior to the neoadjuvant chemoradiation protocol.	('T1-3N1 tumors', 'Disease', 'MESH:D009369', (66, 79))	('T3N0', 'Var', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('patients', 'Species', '9606', (34, 42))	('T1-3N1 tumors', 'Disease', (66, 79))
50598	29391589	Finally, 24.2% (175/723) of patients with clinical T3N0 and T1-3N1 tumors were actually with the most advanced cancer, which means pT4, pN2-3, and pM1 stages.	('pM1', 'Gene', '8834', (147, 150))	('pM1', 'Gene', (147, 150))	('T1-3N1 tumors', 'Disease', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('T1-3N1 tumors', 'Disease', 'MESH:D009369', (60, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('T3N0', 'Var', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (28, 36))
50623	29391589	In the current study, nearly one-fourth of patients with clinical T3N0 and T1-3N1 tumors actually had the most advanced cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('T1-3N1 tumors', 'Disease', (75, 88))	('patients', 'Species', '9606', (43, 51))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('T1-3N1 tumors', 'Disease', 'MESH:D009369', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('T3N0', 'Var', (66, 70))
50682	28587538	Kaplan-Meier analysis indicated that the overall survival of patients with a high plasma miR-9 level was significantly shorter than those with a low plasma miR-9 level (log-rank test, P < 0.001) (Figure 1(b)).	('shorter', 'NegReg', (119, 126))	('high', 'Var', (77, 81))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('patients', 'Species', '9606', (61, 69))	('miR', 'Gene', '220972', (156, 159))	('miR', 'Gene', (156, 159))
50695	28587538	Overall survival of patients with high plasma miR-9 expression was dramatically shorter than in patients with low plasma miR-9 expression.	('miR', 'Gene', (46, 49))	('high plasma', 'Var', (34, 45))	('shorter', 'NegReg', (80, 87))	('patients', 'Species', '9606', (20, 28))	('patients', 'Species', '9606', (96, 104))	('Overall', 'MPA', (0, 7))	('expression', 'Var', (52, 62))	('miR', 'Gene', (121, 124))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', '220972', (46, 49))
50698	28587538	Dysregulated circulating miR-9 expression has been reported in patients with other types of tumors and diseases, such as OSCC, osteosarcoma, and acute ischemic stroke.	('OSCC', 'Disease', (121, 125))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (127, 139))	('reported', 'Reg', (51, 59))	('osteosarcoma', 'Disease', 'MESH:D012516', (127, 139))	('ischemic stroke', 'Disease', 'MESH:D002544', (151, 166))	('miR', 'Gene', '220972', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('miR', 'Gene', (25, 28))	('ischemic stroke', 'Phenotype', 'HP:0002140', (151, 166))	('expression', 'MPA', (31, 41))	('Dysregulated', 'Var', (0, 12))	('ischemic stroke', 'Disease', (151, 166))	('patients', 'Species', '9606', (63, 71))	('stroke', 'Phenotype', 'HP:0001297', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('osteosarcoma', 'Disease', (127, 139))
50726	27840406	Pathological findings: The depth of tumor invasion was T1a-EP (Tis) with ly0 and v0.	('T1a-EP', 'Var', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (36, 41))
50732	27840406	Pathological findings revealed the depth of tumor invasion was T1a-EP (Tis) with ly0 and v0.	('T1a-EP', 'Var', (63, 69))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
50741	27840406	Pathological findings revealed the depth of tumors invasion were T2 and T1a-EP (Tis) with ly0 and v0.	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('T1a-EP', 'Var', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
50748	27840406	Pathological findings showed that the depth of tumors invasion were T1a-EP (Tis) with ly0 and v0.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('T1a-EP', 'Var', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
50856	26000630	Anovulation reduces the risk of ovarian cancer and may explain the borderline significant deficit seen for this cancer in our study.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('Anovulation', 'Var', (0, 11))	('ovarian cancer', 'Disease', (32, 46))	('cancer', 'Disease', (40, 46))	('reduces', 'NegReg', (12, 19))	('ovarian cancer', 'Phenotype', 'HP:0100615', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ovarian cancer', 'Disease', 'MESH:D010051', (32, 46))
50882	25884389	In addition, synthetic let-7a mimics suppressed NPC cells migration, invasion and EMT process and knockdown of HMGA2 was consistent with the effects of let-7a in NPC cells.	('let-7', 'Gene', '266952', (23, 28))	('NPC', 'Phenotype', 'HP:0100630', (48, 51))	('let-7', 'Gene', (23, 28))	('NPC', 'Phenotype', 'HP:0100630', (162, 165))	('EMT process', 'CPA', (82, 93))	('knockdown', 'Var', (98, 107))	('invasion', 'CPA', (69, 77))	('HMGA2', 'Gene', '8091', (111, 116))	('HMGA2', 'Gene', (111, 116))	('let-7', 'Gene', (152, 157))	('NPC cells migration', 'CPA', (48, 67))	('let-7', 'Gene', '266952', (152, 157))	('suppressed', 'NegReg', (37, 47))
50891	25884389	Moreover, recent evidence indicated that miRNAs can function either as tumor suppressors or oncogenes in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('miRNAs', 'Var', (41, 47))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (105, 110))
50909	25884389	Meanwhile, knockdown of HMGA2 was consistent with the effects of let-7a in NPC cells, but no influence on the expression of let-7a.	('let-7', 'Gene', '266952', (65, 70))	('HMGA2', 'Gene', '8091', (24, 29))	('NPC', 'Phenotype', 'HP:0100630', (75, 78))	('effects', 'Reg', (54, 61))	('let-7', 'Gene', (65, 70))	('HMGA2', 'Gene', (24, 29))	('let-7', 'Gene', '266952', (124, 129))	('knockdown', 'Var', (11, 20))	('let-7', 'Gene', (124, 129))
50944	25884389	We observed that the expression level of let-7a was positively correlated with the status of clinical stage (I-II vs. III-IV, P = 0.014), T classification (T1-T2 vs. T3-T4, P = 0.009), and N classification (N0-N1 vs. N2-N3, P = 0.039) in NPC patients.	('correlated', 'Reg', (63, 73))	('NPC', 'Phenotype', 'HP:0100630', (238, 241))	('T1-T2', 'Var', (156, 161))	('clinical', 'Species', '191496', (93, 101))	('let-7', 'Gene', (41, 46))	('NPC', 'Disease', (238, 241))	('let-7', 'Gene', '266952', (41, 46))	('expression level', 'MPA', (21, 37))	('patients', 'Species', '9606', (242, 250))
50963	25884389	However, we found that knock-down HMGA2 had no effect on the let-7a expression at CNE-2 and 5-8F cells (Figure 3C).	('knock-down', 'Var', (23, 33))	('let-7', 'Gene', '266952', (61, 66))	('expression', 'MPA', (68, 78))	('let-7', 'Gene', (61, 66))	('HMGA2', 'Gene', '8091', (34, 39))	('HMGA2', 'Gene', (34, 39))	('CNE-2', 'CellLine', 'CVCL:6889', (82, 87))
50972	25884389	HMGA2 silencing has no effect on NPC cell growth (Figure 5A), but significantly decreased the migration and invasion of CNE-2 and 5-F8 cells (Figure 5B-C), which was similar to the phenotype of migration and invasion induced by let-7a (Figure 4B-C).	('let-7', 'Gene', '266952', (228, 233))	('let-7', 'Gene', (228, 233))	('HMGA2', 'Gene', '8091', (0, 5))	('NPC', 'Phenotype', 'HP:0100630', (33, 36))	('decreased', 'NegReg', (80, 89))	('HMGA2', 'Gene', (0, 5))	('silencing', 'Var', (6, 15))	('CNE-2', 'CellLine', 'CVCL:6889', (120, 125))
50978	25884389	Similarly, knocking down endogenous HMGA2 expression suppressed the activation of MMP2, MMP9 and EMT-marker genes including Snail, Slug, and Vimentin and increased E-cadherin and Zo-1 expression, and elevated the expression of E-cadherin and Zo-1 (Figure 6C, Additional file 2: Figure S1C).	('HMGA2', 'Gene', '8091', (36, 41))	('knocking down', 'Var', (11, 24))	('Slug', 'Gene', '6591', (131, 135))	('E-cadherin', 'Gene', (164, 174))	('E-cadherin', 'Gene', '999', (164, 174))	('Snail', 'Gene', (124, 129))	('expression', 'MPA', (184, 194))	('E-cadherin', 'Gene', (227, 237))	('E-cadherin', 'Gene', '999', (227, 237))	('MMP2', 'Gene', (82, 86))	('Zo-1', 'Gene', (179, 183))	('Vimentin', 'Gene', '7431', (141, 149))	('Zo-1', 'Gene', (242, 246))	('increased', 'PosReg', (154, 163))	('suppressed', 'NegReg', (53, 63))	('activation', 'MPA', (68, 78))	('elevated', 'PosReg', (200, 208))	('expression', 'MPA', (213, 223))	('Vimentin', 'Gene', (141, 149))	('MMP2', 'Gene', '4313', (82, 86))	('HMGA2', 'Gene', (36, 41))	('Zo-1', 'Gene', '7082', (179, 183))	('Slug', 'Gene', (131, 135))	('Snail', 'Gene', '6615', (124, 129))	('EMT-marker', 'Gene', (97, 107))	('Zo-1', 'Gene', '7082', (242, 246))	('MMP9', 'Gene', (88, 92))	('MMP9', 'Gene', '4318', (88, 92))
50981	25884389	Moreover, there were two studies shown the dysregulation of let-7a expression was involved in NPC cell proliferation and apoptosis, but little is known about the function and mechanism of let-7a involving in NPC metastasis.	('NPC metastasis', 'Disease', (208, 222))	('dysregulation', 'Var', (43, 56))	('involved', 'Reg', (82, 90))	('let-7', 'Gene', '266952', (60, 65))	('NPC', 'Phenotype', 'HP:0100630', (208, 211))	('let-7', 'Gene', (60, 65))	('let-7', 'Gene', '266952', (188, 193))	('NPC metastasis', 'Disease', 'MESH:D052556', (208, 222))	('NPC', 'Disease', (94, 97))	('let-7', 'Gene', (188, 193))	('apoptosis', 'CPA', (121, 130))	('NPC', 'Phenotype', 'HP:0100630', (94, 97))
50986	25884389	In our study, synthetic let-7a mimics inhibited NPC cells migration and invasion and knockdown of HMGA2 was consistent with the effects of let-7a in NPC cells.	('let-7', 'Gene', (139, 144))	('NPC', 'Phenotype', 'HP:0100630', (48, 51))	('HMGA2', 'Gene', '8091', (98, 103))	('NPC', 'Phenotype', 'HP:0100630', (149, 152))	('HMGA2', 'Gene', (98, 103))	('inhibited', 'NegReg', (38, 47))	('let-7', 'Gene', '266952', (24, 29))	('let-7', 'Gene', (24, 29))	('knockdown', 'Var', (85, 94))	('NPC cells migration', 'CPA', (48, 67))	('invasion', 'CPA', (72, 80))	('let-7', 'Gene', '266952', (139, 144))
50996	25884389	However, our results revealed knockdown of HMGA2 has no effect on the let-7a expression.	('expression', 'MPA', (77, 87))	('HMGA2', 'Gene', '8091', (43, 48))	('HMGA2', 'Gene', (43, 48))	('knockdown', 'Var', (30, 39))	('let-7', 'Gene', (70, 75))	('let-7', 'Gene', '266952', (70, 75))
51005	25884389	Consistent with the effect of let-7a mimics, knockdown of HMGA2 also suppressed EMT in NPC cells.	('NPC', 'Phenotype', 'HP:0100630', (87, 90))	('let-7', 'Gene', '266952', (30, 35))	('let-7', 'Gene', (30, 35))	('HMGA2', 'Gene', '8091', (58, 63))	('suppressed', 'NegReg', (69, 79))	('HMGA2', 'Gene', (58, 63))	('EMT in NPC cells', 'CPA', (80, 96))	('knockdown', 'Var', (45, 54))
51009	25026173	DADS Suppresses Human Esophageal Xenograft Tumors through RAF/MEK/ERK and Mitochondria-Dependent Pathways Diallyl disulfide (DADS) is a natural organosulfur compound isolated from garlic.	('RAF', 'Gene', '22882', (58, 61))	('Tumors', 'Phenotype', 'HP:0002664', (43, 49))	('MEK', 'Gene', (62, 65))	('Esophageal Xenograft Tumors', 'Disease', (22, 49))	('DADS', 'Chemical', 'MESH:C028009', (0, 4))	('MEK', 'Gene', '5609', (62, 65))	('garlic', 'Species', '4682', (180, 186))	('DADS', 'Chemical', 'MESH:C028009', (125, 129))	('DADS', 'Var', (0, 4))	('Suppresses', 'NegReg', (5, 15))	('organosulfur', 'Chemical', '-', (144, 156))	('Diallyl disulfide', 'Chemical', 'MESH:C028009', (106, 123))	('Esophageal Xenograft Tumors', 'Disease', 'MESH:D004938', (22, 49))	('ERK', 'Gene', '5594', (66, 69))	('Tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Human', 'Species', '9606', (16, 21))	('RAF', 'Gene', (58, 61))	('ERK', 'Gene', (66, 69))
51012	25026173	In this study, MTT assay showed that DADS significantly reduced cell viability in human esophageal carcinoma ECA109 cells, but was relatively less toxic in normal liver cells.	('DADS', 'Var', (37, 41))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (88, 108))	('cell viability', 'CPA', (64, 78))	('reduced', 'NegReg', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('esophageal carcinoma', 'Disease', (88, 108))	('DADS', 'Chemical', 'MESH:C028009', (37, 41))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('human', 'Species', '9606', (82, 87))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (88, 108))
51030	25026173	Moreover, in human breast cancer MCF-7 cells, the apoptotic effect of DADS is even superior to chemotherapy agents such as 5F-dUMP (5-Fu) and cyclophosphamide (CTX).	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (142, 158))	('human', 'Species', '9606', (13, 18))	('5F-dUMP', 'Chemical', '-', (123, 130))	('DADS', 'Chemical', 'MESH:C028009', (70, 74))	('5-Fu', 'Chemical', '-', (132, 136))	('DADS', 'Var', (70, 74))	('apoptotic effect', 'CPA', (50, 66))	('CTX', 'Disease', 'MESH:D019294', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('MCF-7', 'CellLine', 'CVCL:0031', (33, 38))	('CTX', 'Disease', (160, 163))	('breast cancer', 'Disease', (19, 32))
51039	25026173	In addition, we detected the difference of ECA109 cells incubated with DADS and cis-diammminedichloroplatinum (DDP) for 24 h. Our data showed that DADS obviously inhibited cell viability in a dose-dependent manner at concentrations of 10-60 mug/mL for 24 h (p < 0.05, Figure 1).	('DADS', 'Var', (147, 151))	('cell viability', 'CPA', (172, 186))	('cis-diammminedichloroplatinum', 'Chemical', '-', (80, 109))	('DDP', 'Chemical', '-', (111, 114))	('inhibited', 'NegReg', (162, 171))	('DADS', 'Chemical', 'MESH:C028009', (71, 75))	('DADS', 'Chemical', 'MESH:C028009', (147, 151))
51043	25026173	Membrane blebbing and formation of apoptotic bodies were found in 20 and 40 mug/mL DADS groups, while cellular shrinkage, poor adherence and floating shapes were found in the 80 mug/mL DADS group (Figure 3a).	('poor adherence', 'CPA', (122, 136))	('DADS', 'Chemical', 'MESH:C028009', (185, 189))	('DADS', 'Chemical', 'MESH:C028009', (83, 87))	('cellular shrinkage', 'CPA', (102, 120))	('DADS', 'Var', (83, 87))	('formation of apoptotic bodies', 'CPA', (22, 51))	('Membrane blebbing', 'CPA', (0, 17))	('floating shapes', 'CPA', (141, 156))
51046	25026173	These results revealed that DADS induced the apoptosis of ECA109 cells in a dose-dependent manner (p < 0.05, Figure 3c).	('apoptosis', 'CPA', (45, 54))	('DADS', 'Var', (28, 32))	('DADS', 'Chemical', 'MESH:C028009', (28, 32))
51057	25026173	At the end of the study, DADS decreased tumor volume from 292.02 +- 27.08 mm3 per mouse in the negative control group to 211.95 +- 20.14, 179.08 +- 15.95 and 122.64 +- 12.62 mm3 per mouse in 20 mg/kg DADS group (p < 0.05, Figure 4b), 40 mg/kg DADS group and DDP positive control group (p < 0.01, Figure 4b) respectively.	('mouse', 'Species', '10090', (182, 187))	('DADS', 'Var', (25, 29))	('DDP', 'Chemical', '-', (258, 261))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('DADS', 'Chemical', 'MESH:C028009', (200, 204))	('decreased', 'NegReg', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('DADS', 'Chemical', 'MESH:C028009', (243, 247))	('mouse', 'Species', '10090', (82, 87))	('DADS', 'Chemical', 'MESH:C028009', (25, 29))
51058	25026173	In addition, there was no sign of possible changes of body weight in the DADS groups compared with the negative control group (p > 0.05, Figure 4c).	('body weight', 'CPA', (54, 65))	('DADS', 'Var', (73, 77))	('DADS', 'Chemical', 'MESH:C028009', (73, 77))
51059	25026173	However, the data showed that there was significant loss of body weight in DDP positive control group compared with the negative control group and DADS therapy groups (p < 0.05, Figure 4c).	('DDP', 'Chemical', '-', (75, 78))	('DDP', 'Var', (75, 78))	('loss of body weight', 'Disease', 'MESH:D015431', (52, 71))	('DADS', 'Chemical', 'MESH:C028009', (147, 151))	('loss of body weight', 'Disease', (52, 71))
51062	25026173	However, more caspase-3 immunoreactive cells were observed in the DADS groups than the negative control group (Figure 5a).	('caspase-3', 'Protein', (14, 23))	('DADS', 'Chemical', 'MESH:C028009', (66, 70))	('more', 'PosReg', (9, 13))	('DADS', 'Var', (66, 70))
51065	25026173	Our results from qPCR indicated that the levels of cytochrome C, caspase-9 and caspase-3 were stimulated in DADS groups (p < 0.01, Figure 6a).	('stimulated', 'PosReg', (94, 104))	('cytochrome C', 'Gene', '54205', (51, 63))	('DADS', 'Chemical', 'MESH:C028009', (108, 112))	('DADS', 'Var', (108, 112))	('caspase-9', 'Gene', '842', (65, 74))	('caspase-3', 'MPA', (79, 88))	('cytochrome C', 'Gene', (51, 63))	('caspase-9', 'Gene', (65, 74))
51066	25026173	Moreover, DADS significantly increased the expression levels of active caspase-3 and active caspase-9 in total proteins, as well as the expression levels of cytochrome C in cytoplasm proteins in 20 and 40 mg/kg DADS groups by western blot analysis (p < 0.01, Figure 6c,e-g).	('DADS', 'Chemical', 'MESH:C028009', (10, 14))	('DADS', 'Var', (10, 14))	('caspase-9', 'Gene', (92, 101))	('increased', 'PosReg', (29, 38))	('DADS', 'Chemical', 'MESH:C028009', (211, 215))	('cytochrome C', 'Gene', (157, 169))	('caspase-9', 'Gene', '842', (92, 101))	('DADS', 'Var', (211, 215))	('cytochrome C', 'Gene', '54205', (157, 169))	('expression levels', 'MPA', (43, 60))	('expression levels', 'MPA', (136, 153))
51069	25026173	Our results of qPCR showed that the expression levels of Bcl-2 decreased in the DADS groups (p < 0.05, Figure 6a), whereas the expression level of Bax increased only in the 40 mg/kg DADS group (p < 0.01, Figure 6a).	('Bax', 'Gene', '581', (147, 150))	('DADS', 'Chemical', 'MESH:C028009', (182, 186))	('expression', 'MPA', (127, 137))	('decreased', 'NegReg', (63, 72))	('DADS', 'Chemical', 'MESH:C028009', (80, 84))	('Bax', 'Gene', (147, 150))	('Bcl-2', 'Gene', (57, 62))	('DADS', 'Var', (80, 84))	('Bcl-2', 'Gene', '596', (57, 62))	('expression levels', 'MPA', (36, 53))
51075	25026173	These results suggested that DADS had a profound effect on the apoptosis in ECA109 xenograft tumor, which might be correlated with the RAF/MEK/ERK pathway.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('RAF', 'Gene', (135, 138))	('RAF', 'Gene', '22882', (135, 138))	('ERK', 'Gene', '5594', (143, 146))	('DADS', 'Chemical', 'MESH:C028009', (29, 33))	('apoptosis', 'CPA', (63, 72))	('DADS', 'Var', (29, 33))	('MEK', 'Gene', (139, 142))	('ERK', 'Gene', (143, 146))	('MEK', 'Gene', '5609', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
51088	25026173	Although we did not find a stronger anti-cancer effect of DADS compared to the traditional chemotherapy agent DDP, our study indicated that DADS could suppress the growth of ECA109 xenograft tumor effectively and had fewer side effects than DDP.	('growth', 'CPA', (164, 170))	('DADS', 'Chemical', 'MESH:C028009', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('DDP', 'Chemical', '-', (241, 244))	('DADS', 'Var', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('DADS', 'Chemical', 'MESH:C028009', (58, 62))	('DDP', 'Chemical', '-', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('suppress', 'NegReg', (151, 159))
51089	25026173	Moreover, our data showed that DADS decreased the expression of tumor proliferation biomarker PCNA in the 20 and 40 mg/kg DADS groups (Figure 5a,b).	('DADS', 'Chemical', 'MESH:C028009', (122, 126))	('DADS', 'Var', (122, 126))	('tumor', 'Disease', (64, 69))	('DADS', 'Chemical', 'MESH:C028009', (31, 35))	('DADS', 'Var', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PCNA', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('expression', 'MPA', (50, 60))	('decreased', 'NegReg', (36, 45))
51096	25026173	First, under light microscope, we observed morphology changes of apoptosis, such as membrane blebbing and formation of apoptotic bodies in the 20 and 40 mug/mL DADS groups, and cellular shrinkage, poor adherence and floating shapes in the 80 mug/mL DADS group (Figure 3a).	('membrane blebbing', 'CPA', (84, 101))	('cellular shrinkage', 'CPA', (177, 195))	('DADS', 'Chemical', 'MESH:C028009', (160, 164))	('DADS', 'Var', (160, 164))	('DADS', 'Chemical', 'MESH:C028009', (249, 253))	('floating shapes', 'CPA', (216, 231))	('poor adherence', 'CPA', (197, 211))
51099	25026173	In addition, the study indicated that DADS might inhibit the viability of ECA109 cells by promoting apoptosis.	('DADS', 'Chemical', 'MESH:C028009', (38, 42))	('DADS', 'Var', (38, 42))	('promoting', 'PosReg', (90, 99))	('inhibit', 'NegReg', (49, 56))	('apoptosis', 'CPA', (100, 109))	('viability', 'CPA', (61, 70))
51112	25026173	DADS induces apoptosis and promotes the activities of caspase-8 and caspase-9 in human colon cancer cell line (COLO 205).	('colon cancer', 'Disease', (87, 99))	('DADS', 'Chemical', 'MESH:C028009', (0, 4))	('caspase-9', 'Gene', '842', (68, 77))	('DADS', 'Var', (0, 4))	('promotes', 'PosReg', (27, 35))	('apoptosis', 'CPA', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('caspase-8', 'Gene', (54, 63))	('caspase-9', 'Gene', (68, 77))	('colon cancer', 'Phenotype', 'HP:0003003', (87, 99))	('activities', 'MPA', (40, 50))	('caspase-8', 'Gene', '841', (54, 63))	('COLO', 'Species', '307630', (111, 115))	('human', 'Species', '9606', (81, 86))	('colon cancer', 'Disease', 'MESH:D015179', (87, 99))
51114	25026173	Hence, these data suggested that the apoptosis effect induced by DADS on ECA109 cells was caspase-dependent in vitro as well as in vivo.	('DADS', 'Chemical', 'MESH:C028009', (65, 69))	('DADS', 'Var', (65, 69))	('apoptosis effect', 'CPA', (37, 53))	('caspase', 'Gene', '835;839;841;842;843', (90, 97))	('caspase', 'Gene', (90, 97))
51115	25026173	In addition, our results indicated that one central mechanism of the apoptosis inducing by DADS in esophageal xenograft tumor was the activation of the mitochondrial pathway, but not the death receptor pathway.	('DADS', 'Var', (91, 95))	('mitochondrial pathway', 'Pathway', (152, 173))	('esophageal xenograft tumor', 'Disease', (99, 125))	('activation', 'PosReg', (134, 144))	('esophageal xenograft tumor', 'Disease', 'MESH:D004938', (99, 125))	('apoptosis', 'CPA', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('DADS', 'Chemical', 'MESH:C028009', (91, 95))
51119	25026173	Bcl-2, an antiapoptotic protein, is able to bind and inactivate Bax to modulate tumor cells responding apoptosis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Bax', 'Gene', (64, 67))	('bind', 'Interaction', (44, 48))	('tumor', 'Disease', (80, 85))	('modulate', 'Reg', (71, 79))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))	('inactivate', 'Var', (53, 63))	('Bax', 'Gene', '581', (64, 67))
51122	25026173	DADS could up-regulate the p53 level to take part in the apoptotic processes of melanoma in the B16F-10 cell line and human cervical cancer Ca Ski cell line.	('DADS', 'Chemical', 'MESH:C028009', (0, 4))	('up-regulate', 'PosReg', (11, 22))	('p53 level', 'MPA', (27, 36))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('apoptotic processes', 'CPA', (57, 76))	('human', 'Species', '9606', (118, 123))	('B16F', 'Var', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Ca Ski', 'CellLine', 'CVCL:1100', (140, 146))	('B16F', 'SUBSTITUTION', 'None', (96, 100))
51127	25026173	P53 has been found to mutate in 83% esophageal squamous cell carcinomas, while p53 is highly expressed in the ECA109 cell line.	('mutate', 'Var', (22, 28))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (47, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('P53', 'Gene', (0, 3))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('P53', 'Gene', '7157', (0, 3))	('esophageal squamous cell carcinomas', 'Disease', (36, 71))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (36, 71))
51138	25026173	Although some studies have indicated that DADS inhibits the phosphorylation of ERK1/2 during the apoptotic processes of the human leukemia HL-60 cell line and human colon cancer COLO 205 cell line, other studies have shown that DADS activates ERK1/2 in human non-small cell lung cancer H1299 cell line and human nasopharyngeal carcinoma CNE2 cell line.	('carcinoma', 'Phenotype', 'HP:0030731', (327, 336))	('leukemia', 'Disease', (130, 138))	('H1299', 'CellLine', 'CVCL:0060', (286, 291))	('leukemia', 'Disease', 'MESH:D007938', (130, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('carcinoma', 'Disease', (327, 336))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (259, 285))	('colon cancer', 'Disease', (165, 177))	('inhibits', 'NegReg', (47, 55))	('ERK1/2', 'Protein', (79, 85))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (263, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('human', 'Species', '9606', (159, 164))	('DADS', 'Chemical', 'MESH:C028009', (228, 232))	('human', 'Species', '9606', (253, 258))	('carcinoma', 'Disease', 'MESH:D002277', (327, 336))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (259, 285))	('CNE2', 'CellLine', 'CVCL:6889', (337, 341))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (312, 336))	('HL-60', 'CellLine', 'CVCL:0002', (139, 144))	('colon cancer', 'Phenotype', 'HP:0003003', (165, 177))	('activates', 'PosReg', (233, 242))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('DADS', 'Var', (228, 232))	('phosphorylation', 'MPA', (60, 75))	('ERK1/2', 'Enzyme', (243, 249))	('leukemia', 'Phenotype', 'HP:0001909', (130, 138))	('DADS', 'Chemical', 'MESH:C028009', (42, 46))	('non-small cell lung cancer', 'Disease', (259, 285))	('colon cancer', 'Disease', 'MESH:D015179', (165, 177))	('human', 'Species', '9606', (124, 129))	('human', 'Species', '9606', (306, 311))	('COLO', 'Species', '307630', (178, 182))
51140	25026173	In the present study, our western blot results showed that the expression levels of RAF1, phosphor-MEK1 (p-MEK1), ERK1/2 and p-ERK1/2 were inhibited in both the 20 and 40 mg/kg DADS groups (Figure 7a,b,d-f), and that the expression level of MEK1 was down-regulated in the 40 mg/kg DADS group (Figure 7a,c).	('expression levels', 'MPA', (63, 80))	('RAF1', 'Gene', (84, 88))	('down-regulated', 'NegReg', (250, 264))	('RAF1', 'Gene', '5894', (84, 88))	('DADS', 'Chemical', 'MESH:C028009', (281, 285))	('MEK1', 'Gene', '5604', (99, 103))	('ERK1/2', 'Gene', (114, 120))	('MEK1', 'Gene', (99, 103))	('MEK1', 'Gene', '5604', (241, 245))	('MEK1', 'Gene', (241, 245))	('DADS', 'Chemical', 'MESH:C028009', (177, 181))	('expression', 'MPA', (221, 231))	('MEK1', 'Gene', '5604', (107, 111))	('DADS', 'Var', (177, 181))	('inhibited', 'NegReg', (139, 148))	('MEK1', 'Gene', (107, 111))
51141	25026173	Based on these findings, it seemed that the down-regulation of the RAF/MEK/ERK signaling pathway contributed to the apoptosis induced by DADS in the ECA109 xenograft tumor.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('ERK', 'Gene', '5594', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('apoptosis', 'CPA', (116, 125))	('down-regulation', 'NegReg', (44, 59))	('ERK', 'Gene', (75, 78))	('tumor', 'Disease', (166, 171))	('RAF', 'Gene', '22882', (67, 70))	('RAF', 'Gene', (67, 70))	('MEK', 'Gene', (71, 74))	('DADS', 'Chemical', 'MESH:C028009', (137, 141))	('MEK', 'Gene', '5609', (71, 74))	('DADS', 'Var', (137, 141))
51173	25026173	In summary, the present study demonstrated that DADS suppresses esophageal tumors without any apparent signs of toxicity, which is in agreement with a strong increase of apoptosis both in vitro and in vivo.	('esophageal tumors', 'Disease', 'MESH:D004938', (64, 81))	('suppresses', 'NegReg', (53, 63))	('toxicity', 'Disease', (112, 120))	('DADS', 'Chemical', 'MESH:C028009', (48, 52))	('esophageal tumors', 'Disease', (64, 81))	('esophageal tumors', 'Phenotype', 'HP:0100751', (64, 81))	('DADS', 'Var', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))
51175	25026173	Moreover, DADS induces apoptosis by activating the mitochondria-dependent pathway executed by caspase-3, increasing p53 expression level and the Bax/Bcl-2 ratio, and down-regulating the RAF/MEK/ERK pathway in ECA109 xenograft tumors.	('apoptosis', 'CPA', (23, 32))	('DADS', 'Var', (10, 14))	('Bcl-2', 'Gene', (149, 154))	('ERK', 'Gene', '5594', (194, 197))	('Bax', 'Gene', '581', (145, 148))	('RAF', 'Gene', (186, 189))	('mitochondria-dependent pathway', 'Pathway', (51, 81))	('MEK', 'Gene', (190, 193))	('ECA109 xenograft tumors', 'Disease', (209, 232))	('Bcl-2', 'Gene', '596', (149, 154))	('ERK', 'Gene', (194, 197))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('ECA109 xenograft tumors', 'Disease', 'MESH:D009369', (209, 232))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('activating', 'PosReg', (36, 46))	('DADS', 'Chemical', 'MESH:C028009', (10, 14))	('increasing', 'PosReg', (105, 115))	('down-regulating', 'NegReg', (166, 181))	('RAF', 'Gene', '22882', (186, 189))	('Bax', 'Gene', (145, 148))	('p53 expression level', 'MPA', (116, 136))	('MEK', 'Gene', '5609', (190, 193))
51245	22848173	In this study, FA-M(PTX) were constructed from two amphiphilic block copolymers, ie, MPEG-b-P(LA-co-DHP/FA) and MPEG-b-P(LA-co-MCC/PTX), with a mass ratio of 1:9, as previously described in our laboratory.	('DHP', 'Gene', (100, 103))	('copolymers', 'Chemical', '-', (69, 79))	('PTX', 'Chemical', '-', (20, 23))	('DHP', 'Gene', '1807', (100, 103))	('MPEG-b-P', 'Chemical', '-', (85, 93))	('LA-co-MCC', 'Chemical', '-', (121, 130))	('PTX', 'Chemical', '-', (131, 134))	('MPEG-b-P', 'Var', (112, 120))	('MPEG-b-P', 'Chemical', '-', (112, 120))	('MPEG-b-P', 'Var', (85, 93))
51249	22848173	It is noteworthy that folic acid was conjugated with the hydrophobic segment of the block copolymer, which was based on the following considerations: conjugation of folic acid on the hydrophobic segment may reduce the nonspecific uptake of micelles by normal tissue or cells during circulation in the blood; poly(ethylene glycol) (PEG) surface conjugation of folic acid to some extent may perturb the PEG conformation in water and thus reduce the stability of micelles; and the statistically inevitable distributions of folic acid on the micellar interface have been demonstrated to be able to increase endocytosis efficiency by target cell lines in our previous publications.	('folic acid', 'Chemical', 'MESH:D005492', (22, 32))	('reduce', 'NegReg', (207, 213))	('mice', 'Species', '10090', (460, 464))	('stability', 'MPA', (447, 456))	('PEG conformation in water', 'MPA', (401, 426))	('mice', 'Species', '10090', (240, 244))	('PEG', 'Chemical', 'MESH:D011092', (331, 334))	('perturb', 'NegReg', (389, 396))	('folic acid', 'Chemical', 'MESH:D005492', (165, 175))	('folic acid', 'Chemical', 'MESH:D005492', (520, 530))	('nonspecific uptake of micelles', 'MPA', (218, 248))	('folic acid', 'Chemical', 'MESH:D005492', (359, 369))	('increase endocytosis efficiency', 'Disease', (594, 625))	('reduce', 'NegReg', (436, 442))	('PEG', 'Chemical', 'MESH:D011092', (401, 404))	('mice', 'Species', '10090', (538, 542))	('increase endocytosis efficiency', 'Disease', 'MESH:D019586', (594, 625))	('poly', 'Var', (308, 312))
51292	22848173	As shown in Figure 7, the gray values of Bax, caspase 3, and Bcl2 indicate a statistically significant difference between FA-M(PTX) and the other two drug groups, which is in agreement with the results of flow cytometry and TUNEL, as well as the tumor volume and weight measurement.	('PTX', 'Chemical', '-', (127, 130))	('Bcl2', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('caspase 3', 'Gene', (46, 55))	('FA-M', 'Var', (122, 126))	('significant difference', 'Reg', (91, 113))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (246, 251))
51299	22848173	In this study, the ratio of Bcl2/Bax is decreased, which is concurrent with the increased apoptosis of EC9706 xenografts in mice when treated with paclitaxel and the micelles, indicating that apoptosis may be mediated via downregulated expression of Bcl2 and upregulated expression of Bax.	('EC9706', 'Var', (103, 109))	('upregulated', 'PosReg', (259, 270))	('downregulated', 'NegReg', (222, 235))	('expression', 'MPA', (271, 281))	('mice', 'Species', '10090', (124, 128))	('EC9706', 'CellLine', 'CVCL:E307', (103, 109))	('decreased', 'NegReg', (40, 49))	('mice', 'Species', '10090', (166, 170))	('Bcl2', 'Gene', (250, 254))	('Bax', 'Gene', (285, 288))	('paclitaxel', 'Chemical', 'MESH:D017239', (147, 157))
51300	22848173	Furthermore, significant upregulation of caspase 3 expression in EC9706 xenografts in mice in the drug treatment groups compared with the control group was clear, in accordance with prolonged survival of the mice.	('EC9706', 'Var', (65, 71))	('caspase 3', 'Protein', (41, 50))	('mice', 'Species', '10090', (86, 90))	('EC9706', 'CellLine', 'CVCL:E307', (65, 71))	('expression', 'MPA', (51, 61))	('mice', 'Species', '10090', (208, 212))	('upregulation', 'PosReg', (25, 37))
51301	22848173	Immunohistochemistry examination indicated that treatment with paclitaxel led to upregulation of Bax and caspase 3 and downregulation of Bcl2, and the extent of downregulation or upregulation caused by FA-M(PTX) was greater than that caused by paclitaxel and M(PTX).	('PTX', 'Chemical', '-', (261, 264))	('paclitaxel', 'Chemical', 'MESH:D017239', (63, 73))	('caspase', 'Protein', (105, 112))	('Bcl2', 'MPA', (137, 141))	('paclitaxel', 'Chemical', 'MESH:D017239', (244, 254))	('downregulation', 'NegReg', (119, 133))	('downregulation', 'NegReg', (161, 175))	('upregulation', 'PosReg', (81, 93))	('FA-M', 'Var', (202, 206))	('PTX', 'Chemical', '-', (207, 210))	('Bax', 'Protein', (97, 100))	('upregulation', 'PosReg', (179, 191))
51304	22848173	As shown in Figure 8, the areas of tissue necrosis (indicated by straight arrows) significantly increased in the FA-M(PTX) group compared with the others, which further demonstrated the enhanced antitumor efficacy of micelles containing the folic acid ligand.	('tumor', 'Disease', (199, 204))	('increased', 'PosReg', (96, 105))	('FA-M', 'Var', (113, 117))	('necrosis', 'Disease', (42, 50))	('mice', 'Species', '10090', (217, 221))	('PTX', 'Chemical', '-', (118, 121))	('folic acid', 'Chemical', 'MESH:D005492', (241, 251))	('necrosis', 'Disease', 'MESH:D009336', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('enhanced', 'PosReg', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tissue necrosis', 'Phenotype', 'HP:0010885', (35, 50))
51317	22848173	At a dose of 20 mg/kg, FA-M(PTX) showed the best tumor inhibition efficacy in vivo compared with pure paclitaxel and M(PTX), which was mainly suggested by significantly inhibited growth of subcutaneous EC9706 xenografts and extended survival rate in tumor-bearing nude mice.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PTX', 'Chemical', '-', (28, 31))	('survival rate', 'CPA', (233, 246))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('growth', 'CPA', (179, 185))	('FA-M', 'Var', (23, 27))	('EC9706', 'CellLine', 'CVCL:E307', (202, 208))	('nude mice', 'Species', '10090', (264, 273))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('extended', 'PosReg', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('PTX', 'Chemical', '-', (119, 122))	('paclitaxel', 'Chemical', 'MESH:D017239', (102, 112))	('inhibited', 'NegReg', (169, 178))
51318	22848173	This enhanced efficacy of FA-M(PTX) is most probably attributable to the targeted effect of folic acid on the micelles, verified by the preferential uptake of FA-M(RhB) compared with M(RhB) in EC9706 cells in folic acid-free medium, which could be competitively inhibited by free folic acid.	('FA-M', 'Var', (159, 163))	('RhB', 'Chemical', 'MESH:C029773', (164, 167))	('PTX', 'Chemical', '-', (31, 34))	('RhB', 'Chemical', 'MESH:C029773', (185, 188))	('folic acid', 'Chemical', 'MESH:D005492', (209, 219))	('mice', 'Species', '10090', (110, 114))	('EC9706', 'CellLine', 'CVCL:E307', (193, 199))	('enhanced', 'PosReg', (5, 13))	('efficacy', 'MPA', (14, 22))	('folic acid', 'Chemical', 'MESH:D005492', (92, 102))	('folic acid', 'Chemical', 'MESH:D005492', (280, 290))
51320	21586140	Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma: a retrospective cohort study of the Eastern Cooperative Oncology Group Recent data in esophageal cancer suggests the variant allele of a single-nucleotide polymorphism (SNP) in XRCC1 may be associated with resistance to radiochemotherapy.	('esophageal cancer', 'Disease', (191, 208))	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('esophageal adenocarcinoma', 'Disease', (78, 103))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (78, 103))	('Oncology', 'Phenotype', 'HP:0002664', (161, 169))	('single-nucleotide polymorphism', 'Var', (242, 272))	('DNA-repair pathways', 'Pathway', (21, 40))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (78, 103))	('variant', 'Var', (222, 229))	('XRCC1', 'Gene', (282, 287))	('associated', 'Reg', (295, 305))
51326	21586140	Using germline DNA from 60 subjects, we examined the base-excision repair SNP, XRCC1 Arg399Gln, and 4 other SNPs in nucleotide excision (XPD Lys751Gln and Asp312Asn, ERCC1 3' flank) and double-stranded break (XRCC2 5' flank) repair pathways, and correlated genotype with pCR rate.	('base-excision', 'MPA', (53, 66))	('XPD', 'Gene', (137, 140))	('Arg399Gln', 'SUBSTITUTION', 'None', (85, 94))	('XPD', 'Gene', '2068', (137, 140))	('Asp312Asn', 'Var', (155, 164))	('XRCC1', 'Gene', (79, 84))	('Asp312Asn', 'SUBSTITUTION', 'None', (155, 164))	('Lys751Gln', 'SUBSTITUTION', 'None', (141, 150))	('ERCC1 3', 'Pathway', (166, 173))	('double-stranded break', 'Pathway', (186, 207))	('Lys751Gln', 'Var', (141, 150))	('Arg399Gln', 'Var', (85, 94))
51346	21586140	SNPs in the XRCC1 gene (Arg399Gln) and XPD gene (Lys751Gln) have been associated with increased DNA damage.	('XPD', 'Gene', '2068', (39, 42))	('increased', 'PosReg', (86, 95))	('Arg399Gln', 'Var', (24, 33))	('Arg399Gln', 'SUBSTITUTION', 'None', (24, 33))	('associated', 'Reg', (70, 80))	('Lys751Gln', 'SUBSTITUTION', 'None', (49, 58))	('XPD', 'Gene', (39, 42))	('DNA damage', 'MPA', (96, 106))	('Lys751Gln', 'Var', (49, 58))	('XRCC1', 'Gene', (12, 17))
51348	21586140	found that the XRCC1 Arg399Gln SNP (BER) was associated with pCR in esophageal cancer patients treated with cisplatin-based RCT and surgery.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('Arg399Gln', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (86, 94))	('Arg399Gln', 'SUBSTITUTION', 'None', (21, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('associated', 'Reg', (45, 55))	('pCR', 'Disease', (61, 64))	('esophageal cancer', 'Disease', (68, 85))	('XRCC1', 'Gene', (15, 20))
51359	21586140	Other eligibility criteria included: locally advanced stage (i.e., T2-3N0M0, T1-3 N1M0 or T1-3N0-1M1a), surgically resectable disease (T1-3 but not T4), ECOG performance status 0-1, and staging by endoscopic ultrasound with esophagogastroduodenoscopy and CT of the chest and abdomen.	('locally advanced stage', 'CPA', (37, 59))	('men', 'Species', '9606', (279, 282))	('T1-3 N1M0', 'Var', (77, 86))	('T2-3N0M0', 'Var', (67, 75))	('T1-3N0-1M1a', 'Var', (90, 101))	('esophagogastroduodenoscopy', 'Disease', (224, 250))
51362	21586140	The primary endpoint of E1201 as well as the current study was pCR - i.e., the complete absence of tumor in the resected specimen subsequent to RCT; pCR was assessed by local geographic sites during E1201, not by central review.	('men', 'Species', '9606', (126, 129))	('tumor', 'Disease', (99, 104))	('E1201', 'Var', (24, 29))	('absence', 'NegReg', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
51369	21586140	DNA was extracted from macrodissected specimens using the Qiagen QIAamp DNA FFPE Tissue Kit (Valencia, CA) following manufacturer's instructions The Arg399Gln SNP within the X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) gene was chosen based on its prior association with complete pathologic response in esophageal cancer patients treated with RCT.	('patients', 'Species', '9606', (355, 363))	('esophageal cancer', 'Disease', (337, 354))	('men', 'Species', '9606', (193, 196))	('X-ray repair complementing defective repair in Chinese hamster cells 1', 'Gene', '7515', (174, 244))	('esophageal cancer', 'Disease', 'MESH:D004938', (337, 354))	('Arg399Gln', 'Var', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('men', 'Species', '9606', (43, 46))	('Arg399Gln', 'SUBSTITUTION', 'None', (149, 158))	('XRCC1', 'Gene', (246, 251))
51371	21586140	Four additional SNPs were identified in 3 genes: excision repair cross-complementing rodent repair deficiency, complementation group 2 (XPD/ERCC2, Lys751Gln and Asp312Asn); excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1 3' flank, also known as "C8092A"); X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2 5' flank, also known as "-7985T > C").	('X-ray repair complementing defective repair in Chinese hamster cells 2', 'Gene', '7516', (301, 371))	('XPD/ERCC2', 'Gene', '100689272', (136, 145))	('Asp312Asn', 'SUBSTITUTION', 'None', (161, 170))	('excision repair cross-complementing rodent repair deficiency, complementation group 2', 'Gene', '100689272', (49, 134))	('-7985T > C', 'Mutation', 'c.-7985T>C', (404, 414))	('Lys751Gln', 'SUBSTITUTION', 'None', (147, 156))	('XPD/ERCC2', 'Gene', (136, 145))	('Lys751Gln', 'Var', (147, 156))	('C8092A', 'Mutation', 'rs3212986', (291, 297))	('excision repair cross-complementing rodent repair deficiency, complementation group 1', 'Gene', '100689377', (173, 258))	('Asp312Asn', 'Var', (161, 170))
51372	21586140	MALDITOF was used to determine allelic imbalance at the XRCC1 Arg399Gln loci by dividing the allele frequency ratio of the tumor sample by the allele frequency ratio of the corresponding normal sample.	('tumor', 'Disease', (123, 128))	('Arg399Gln', 'Var', (62, 71))	('Arg399Gln', 'SUBSTITUTION', 'None', (62, 71))	('imbalance', 'Phenotype', 'HP:0002172', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('XRCC1', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
51376	21586140	Baseline clinicopathologic traits were: median age 57 years (38-76); male 88%; white 93%, black 2%, Hispanic 2%, Asian 3%; node-negative (T2-3N0M0) 28%, node-positive (T1-3 N1M0 or T1-3N0-1M1a) 72%; ECOG performance status 0 (65%) and 1 (35%); mid- (2%) and lower thoracic (45%) esophagus, gastroesophageal junction (48%), esophagus not otherwise specified (3%), and unknown (2%).	('esophagus not otherwise specified', 'Disease', (323, 356))	('T1-3 N1M0', 'Var', (168, 177))	('mid-', 'Disease', (244, 248))	('gastroesophageal junction', 'Disease', (290, 315))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (290, 315))
51384	21586140	In this study we found that 52% of EAC subjects had the variant 399Gln allele in XRCC1, and that subjects with the variant allele had five times higher odds of failing to achieve pCR after cisplatin-based RCT, compared to subjects without the variant allele.	('failing', 'MPA', (160, 167))	('XRCC1', 'Gene', (81, 86))	('variant 399Gln', 'Var', (56, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))
51389	21586140	To our knowledge, this is the first reported assessment of AI specifically in XRCC1 in EAC.	('AI specifically', 'Var', (59, 74))	('XRCC1', 'Gene', (78, 83))	('EAC', 'Disease', (87, 90))	('men', 'Species', '9606', (51, 54))
51392	21586140	In addition, XRCC1 is a key player in BER, the major repair pathway for nonbulky damaged bases, abasic sites, and DNA single-stranded breaks after treatment with ionizing radiation.	('abasic sites', 'Var', (96, 108))	('nonbulky damaged bases', 'MPA', (72, 94))	('DNA single-stranded breaks', 'Var', (114, 140))	('men', 'Species', '9606', (152, 155))
51393	21586140	Prior reports in human populations suggested the 399Gln variant of XRCC1 was associated with greater DNA and chromosomal damage.	('XRCC1', 'Gene', (67, 72))	('human', 'Species', '9606', (17, 22))	('greater', 'PosReg', (93, 100))	('399Gln', 'Var', (49, 55))	('chromosomal damage', 'CPA', (109, 127))
51394	21586140	Worsened pCR and survival related to the variant may be due to increased genetic instability and the development of multiple clonal populations, given the substantial data linking chromosomal aberrations and poor prognosis.	('increased', 'PosReg', (63, 72))	('genetic instability', 'Disease', 'MESH:D030342', (73, 92))	('survival', 'CPA', (17, 25))	('men', 'Species', '9606', (108, 111))	('pCR', 'Disease', (9, 12))	('genetic instability', 'Disease', (73, 92))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (180, 203))	('Worsened', 'NegReg', (0, 8))	('variant', 'Var', (41, 48))
51396	21586140	Also consistent with our findings, the 399Gln variant allele was associated with decreased tumor response (and worse survival) in patients with stage III-IV non-small cell lung cancer (NSCLC) and metastatic colorectal cancer, respectively, treated with platinum chemotherapy.	('colorectal cancer', 'Disease', 'MESH:D015179', (207, 224))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (157, 183))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (157, 183))	('decreased tumor', 'Disease', 'MESH:D009369', (81, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('non-small cell lung cancer', 'Disease', (157, 183))	('platinum', 'Chemical', 'MESH:D010984', (253, 261))	('patients', 'Species', '9606', (130, 138))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('decreased tumor', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (161, 183))	('colorectal cancer', 'Disease', (207, 224))	('399Gln', 'Var', (39, 45))	('NSCLC', 'Disease', (185, 190))
51397	21586140	By contrast, the variant allele was associated with favorable OS in patients with stage IV squamous cell carcinoma of the head and neck (SCCHN) treated with cisplatin-based chemotherapy or RCT.	('patients', 'Species', '9606', (68, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('variant', 'Var', (17, 24))	('squamous cell carcinoma', 'Disease', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 114))
51405	21586140	The parent and/or translational study were supported by an American Society of Clinical Oncology Young Investigator Award and Paul Calabresi Program in Clinical Translational Research CA90628-08U (both H.H.Y), and in part by Public Health Service Grants CA23318, CA66636, CA21115, CA13650, CA16116, CA49883, CA17145, CA39229 from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services.	('Cancer', 'Disease', (343, 349))	('CA17145', 'Var', (308, 315))	('Human', 'Species', '9606', (425, 430))	('CA23318', 'Var', (254, 261))	('Oncology', 'Phenotype', 'HP:0002664', (88, 96))	('Cancer', 'Disease', 'MESH:D009369', (343, 349))	('CA66636', 'Var', (263, 270))	('CA90628-08U', 'Var', (184, 195))	('CA39229', 'Var', (317, 324))	('Cancer', 'Phenotype', 'HP:0002664', (343, 349))	('CA21115', 'Var', (272, 279))	('CA16116', 'Var', (290, 297))	('men', 'Species', '9606', (406, 409))	('CA49883', 'Var', (299, 306))	('CA13650', 'Var', (281, 288))
51481	33477274	Although NBI increased the sensitivity by magnifying the features of neoplasm, NBI might also decrease the specificity through over-diagnosis.	('NBI', 'Var', (79, 82))	('neoplasm', 'Disease', (69, 77))	('neoplasm', 'Disease', 'MESH:D009369', (69, 77))	('neoplasm', 'Phenotype', 'HP:0002664', (69, 77))	('magnifying', 'PosReg', (42, 52))	('sensitivity', 'MPA', (27, 38))	('features', 'MPA', (57, 65))	('specificity', 'MPA', (107, 118))	('over-diagnosis', 'MPA', (127, 141))	('increased', 'PosReg', (13, 22))	('decrease', 'NegReg', (94, 102))
51501	33477274	A total of 936 images were collected for training images, including 162 images of a normal esophagus, 165 images of low-grade squamous dysplasia, 282 images of high-grade squamous dysplasia, and 327 images of esophageal cancer (SCC).	('esophageal cancer', 'Disease', (209, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('squamous dysplasia', 'Disease', (126, 144))	('squamous dysplasia', 'Disease', (171, 189))	('squamous dysplasia', 'Disease', 'MESH:D002294', (171, 189))	('esophageal cancer', 'Disease', 'MESH:D004938', (209, 226))	('squamous dysplasia', 'Disease', 'MESH:D002294', (126, 144))	('low-grade', 'Var', (116, 125))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (126, 144))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (171, 189))
51528	32276377	PIs form just a minor fraction of the total phospholipid content in eukaryotic cell membranes.	('phospholipid content', 'MPA', (44, 64))	('PIs', 'Var', (0, 3))	('PIs', 'Chemical', 'MESH:D010716', (0, 3))	('phospholipid', 'Chemical', 'MESH:D010743', (44, 56))
51568	32276377	Additionally, PLCgamma was demonstrated to be activated via phosphorylation of tyrosine 1253 and tyrosine 783 residues in the nuclei of cells from early breast cancer patients, indicating a role of PLCgamma in the nuclear PI cycle.	('phosphorylation', 'MPA', (60, 75))	('tyrosine', 'Chemical', 'MESH:D014443', (79, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('tyrosine 1253', 'Var', (79, 92))	('activated', 'PosReg', (46, 55))	('tyrosine', 'Chemical', 'MESH:D014443', (97, 105))	('tyrosine 783 residues', 'Var', (97, 118))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rat', 'Species', '10116', (34, 37))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('PLCgamma', 'Gene', (14, 22))	('breast cancer', 'Disease', (153, 166))
51569	32276377	The PLCdelta sub-family is composed of three different isoforms: PLCdelta1, with variants 1a and 1b; PLCdelta3, and PLCdelta4, with variants 4a, 4b, and 4c.	('PLCdelta4', 'Gene', (116, 125))	('PLCdelta3', 'Gene', '113026', (101, 110))	('PLCdelta3', 'Gene', (101, 110))	('variants', 'Var', (81, 89))	('PLCdelta4', 'Gene', '84812', (116, 125))
51597	32276377	Interestingly, alterations in both PLCbeta1 and PI3K/Akt/mTOR pathways have been associated with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).	('MDS', 'Disease', (124, 127))	('PLCbeta1', 'Gene', (35, 43))	('acute myeloid leukemia', 'Disease', (133, 155))	('mTOR', 'Gene', (57, 61))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('MDS', 'Phenotype', 'HP:0002863', (124, 127))	('AML', 'Disease', 'MESH:D015470', (157, 160))	('mTOR', 'Gene', '2475', (57, 61))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (133, 155))	('AML', 'Phenotype', 'HP:0004808', (157, 160))	('AML', 'Disease', (157, 160))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (97, 122))	('myelodysplastic syndromes', 'Disease', (97, 122))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (139, 155))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (133, 155))	('MDS', 'Disease', 'MESH:D009190', (124, 127))	('alterations', 'Var', (15, 26))	('PLCbeta1', 'Gene', '9180', (35, 43))	('rat', 'Species', '10116', (19, 22))	('associated', 'Reg', (81, 91))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (97, 122))
51600	32276377	Our group showed that monoallelic deletion of PLCbeta1 gene in MDS patients showed worse clinical outcomes with an increased probability of evolving into AML.	('MDS', 'Disease', (63, 66))	('monoallelic deletion', 'Var', (22, 42))	('MDS', 'Disease', 'MESH:D009190', (63, 66))	('MDS', 'Phenotype', 'HP:0002863', (63, 66))	('patients', 'Species', '9606', (67, 75))	('AML', 'Disease', 'MESH:D015470', (154, 157))	('evolving', 'MPA', (140, 148))	('AML', 'Disease', (154, 157))	('PLCbeta1', 'Gene', (46, 54))	('AML', 'Phenotype', 'HP:0004808', (154, 157))	('PLCbeta1', 'Gene', '9180', (46, 54))
51605	32276377	This may indicate that alterations in PLCbeta1 expression and Akt activation in MDS may deregulate the cell cycle of MDS cells, resulting in the inhibition of apoptotic mechanisms and promotion of cell survival of MDS cells.	('MDS', 'Disease', (117, 120))	('PLCbeta1', 'Gene', (38, 46))	('promotion', 'PosReg', (184, 193))	('apoptotic mechanisms', 'CPA', (159, 179))	('activation', 'PosReg', (66, 76))	('cell cycle', 'CPA', (103, 113))	('MDS', 'Phenotype', 'HP:0002863', (80, 83))	('MDS', 'Phenotype', 'HP:0002863', (214, 217))	('MDS', 'Phenotype', 'HP:0002863', (117, 120))	('MDS', 'Disease', 'MESH:D009190', (80, 83))	('PLCbeta1', 'Gene', '9180', (38, 46))	('rat', 'Species', '10116', (27, 30))	('MDS', 'Disease', 'MESH:D009190', (214, 217))	('inhibition', 'NegReg', (145, 155))	('MDS', 'Disease', 'MESH:D009190', (117, 120))	('MDS', 'Disease', (80, 83))	('MDS', 'Disease', (214, 217))	('alterations', 'Var', (23, 34))	('cell survival', 'CPA', (197, 210))	('deregulate', 'Reg', (88, 98))	('Akt', 'Gene', (62, 65))
51608	32276377	Using a dominant negative PLCgamma mutant and PLCgamma inhibitors in NIH-3T3 cells resulted in the inhibition of Akt phosphorylation on serine 473 but not on threonine 308.	('negative', 'NegReg', (17, 25))	('mutant', 'Var', (35, 41))	('inhibition', 'NegReg', (99, 109))	('PLCgamma', 'Gene', (26, 34))	('Akt', 'Pathway', (113, 116))	('NIH-3T3', 'CellLine', 'CVCL:0594', (69, 76))	('threonine', 'Chemical', 'MESH:D013912', (158, 167))	('serine', 'Chemical', 'MESH:D012694', (136, 142))
51618	32276377	In line with this microarray study is a recent functional study reporting that the knockdown of PLCbeta2 expression in melanoma cells negatively affects cell viability and promotes cell apoptosis by altering p53 and pro-apoptotic proteins, caspase 3 and Bcl-2-associated X (Bax).	('caspase 3', 'Gene', '836', (240, 249))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('cell viability', 'CPA', (153, 167))	('melanoma', 'Disease', (119, 127))	('p53', 'Gene', '7157', (208, 211))	('Bcl-2-associated X', 'Gene', '581', (254, 272))	('knockdown', 'Var', (83, 92))	('promotes', 'PosReg', (172, 180))	('p53', 'Gene', (208, 211))	('affects', 'Reg', (145, 152))	('Bcl-2-associated X', 'Gene', (254, 272))	('cell apoptosis', 'CPA', (181, 195))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('negatively', 'NegReg', (134, 144))	('PLCbeta2', 'Gene', '133396', (96, 104))	('PLCbeta2', 'Gene', (96, 104))	('altering', 'Reg', (199, 207))	('Bax', 'Gene', (274, 277))	('Bax', 'Gene', '581', (274, 277))	('caspase 3', 'Gene', (240, 249))
51629	32276377	As for other PLCs, in a mutant mice model, Xiao and colleagues demonstrated that the loss of PLCbeta3 can promote tumor development and growth.	('loss', 'Var', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('rat', 'Species', '10116', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PLCbeta3', 'Gene', (93, 101))	('promote', 'PosReg', (106, 113))	('tumor', 'Disease', (114, 119))	('mice', 'Species', '10090', (31, 35))	('growth', 'CPA', (136, 142))
51632	32276377	The authors suggested that PLCbeta3 knockout led to an increase of hematopoietic stem cells (HSCs) and a decrease of STAT5, although the full mechanism of action is unknown.	('knockout', 'Var', (36, 44))	('increase', 'PosReg', (55, 63))	('hematopoietic stem cells', 'CPA', (67, 91))	('STAT5', 'Gene', (117, 122))	('PLCbeta3', 'Gene', (27, 35))	('STAT5', 'Gene', '6776', (117, 122))	('decrease', 'NegReg', (105, 113))
51644	32276377	Similarly, PLCgamma1-mediated hydrolysis of PtdIns(4,5)P2 induces the release of actin-modifying proteins such as gelsolin, which promotes actin reorganization behind the leading edge.	('release of actin-modifying proteins', 'MPA', (70, 105))	('gelsolin', 'Gene', '2934', (114, 122))	('promotes', 'PosReg', (130, 138))	('hydrolysis', 'Var', (30, 40))	('gelsolin', 'Gene', (114, 122))	('PtdIns(4,5)P2', 'Chemical', '-', (44, 57))	('actin reorganization', 'MPA', (139, 159))
51646	32276377	Importantly, gelsolin is bound to PtdIns(4,5)P2 in its resting state and becomes active in cell migration only after PtdIns(4,5)P2 hydrolysis by PLCgamma1.	('gelsolin', 'Gene', (13, 21))	('PtdIns(4,5)P2', 'Chemical', '-', (117, 130))	('PtdIns', 'Var', (117, 123))	('rat', 'Species', '10116', (99, 102))	('gelsolin', 'Gene', '2934', (13, 21))	('PtdIns(4,5)P2', 'Chemical', '-', (34, 47))	('active', 'MPA', (81, 87))	('cell migration', 'CPA', (91, 105))
51658	32276377	Moreover, U73122, which is a potent inhibitor of PLCgamma activity, blocked glioma cell motility and invasion in fetal rat brain aggregates.	('U73122', 'Chemical', 'MESH:C060229', (10, 16))	('invasion in fetal rat', 'CPA', (101, 122))	('blocked', 'NegReg', (68, 75))	('rat', 'Species', '10116', (119, 122))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('U73122', 'Var', (10, 16))	('glioma cell motility', 'Disease', (76, 96))	('glioma cell motility', 'Disease', 'MESH:D005910', (76, 96))
51659	32276377	In addition, metastasis was reduced in an in vivo prostate carcinoma model expressing a dominant negative fragment of PLCgamma, with similar observations in an in vitro model of the neck and squamous cell carcinoma (HNSCC) upon PLCgamma inhibition.	('PLCgamma', 'Gene', (118, 126))	('reduced', 'NegReg', (28, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (191, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('squamous cell carcinoma', 'Disease', (191, 214))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (191, 214))	('prostate carcinoma', 'Disease', (50, 68))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (50, 68))	('negative', 'NegReg', (97, 105))	('metastasis', 'CPA', (13, 23))	('fragment', 'Var', (106, 114))	('HNSCC', 'CellLine', 'CVCL:5985', (216, 221))	('prostate carcinoma', 'Disease', 'MESH:D011471', (50, 68))
51661	32276377	U73122 was used to inhibit PLCgamma1 whereas the Src family inhibitor AZD0530 was used to inhibit c-Src.	('inhibit', 'NegReg', (90, 97))	('AZD0530', 'Chemical', 'MESH:C515233', (70, 77))	('inhibit', 'NegReg', (19, 26))	('c-Src', 'Gene', (98, 103))	('Src', 'Gene', (100, 103))	('Src', 'Gene', '6714', (100, 103))	('U73122', 'Var', (0, 6))	('c-Src', 'Gene', '6714', (98, 103))	('Src', 'Gene', (49, 52))	('Src', 'Gene', '6714', (49, 52))	('PLCgamma1', 'Protein', (27, 36))	('U73122', 'Chemical', 'MESH:C060229', (0, 6))
51668	32276377	reported that knocking down PLCepsilon in prostate cancer cells significantly reduces the phosphorylation levels of Twist1 proteins through MAPK signaling.	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('knocking down', 'Var', (14, 27))	('Twist1', 'Gene', '7291', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PLCepsilon in prostate cancer', 'Disease', 'MESH:D011471', (28, 57))	('Twist1', 'Gene', (116, 122))	('PLCepsilon in prostate cancer', 'Disease', (28, 57))	('phosphorylation levels', 'MPA', (90, 112))	('reduces', 'NegReg', (78, 85))	('MAPK', 'MPA', (140, 144))
51676	32276377	However, inhibiting PLCgamma disrupts the invasion of glioblastoma cells into normal brain tissues, regardless of the combined signaling effects of PDGFR, NGF, IGF-1, and EGFR upregulation.	('EGFR', 'Gene', (171, 175))	('PDGFR', 'Gene', (148, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('PDGFR', 'Gene', '5159', (148, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('IGF-1', 'Gene', '3479', (160, 165))	('inhibiting', 'Var', (9, 19))	('IGF-1', 'Gene', (160, 165))	('invasion', 'CPA', (42, 50))	('EGFR', 'Gene', '1956', (171, 175))	('PLCgamma', 'Protein', (20, 28))	('disrupts', 'NegReg', (29, 37))	('glioblastoma', 'Disease', (54, 66))
51686	32276377	Conversely, knocking down PLCdelta1 reactivates the ERK1/2/beta-catenin/MMP pathway and induces cell migration.	('induces', 'Reg', (88, 95))	('ERK1/2', 'Gene', (52, 58))	('ERK1/2', 'Gene', '5595;5594', (52, 58))	('cell migration', 'CPA', (96, 110))	('beta-catenin', 'Gene', '1499', (59, 71))	('reactivates', 'PosReg', (36, 47))	('MMP', 'Gene', '4316', (72, 75))	('MMP', 'Gene', (72, 75))	('knocking down', 'Var', (12, 25))	('PLCdelta1', 'Gene', (26, 35))	('beta-catenin', 'Gene', (59, 71))	('rat', 'Species', '10116', (104, 107))
51765	30667557	Kusano et al.16 reported that mucosal elevation formed by injection of 0.6% SA was significantly higher than that formed by 0.4% SH over 30 min after injection in a test system using excised porcine stomach.	('mucosal elevation', 'MPA', (30, 47))	('SH', 'Chemical', 'MESH:D006820', (129, 131))	('higher', 'PosReg', (97, 103))	('0.6% SA', 'Var', (71, 78))
51773	30667557	Analysis and interpretation of data: I.O., Y.S., H.O., J.F., N.M., K.O., N.Y., T.Y., H.T., M.I.	('N.Y.', 'Var', (73, 77))	('T.Y.', 'Var', (79, 83))	('K.O.', 'Var', (67, 71))	('H.T', 'Disease', (85, 88))	('H.T', 'Disease', 'MESH:D000848', (85, 88))
51809	30893904	To determine the effect of arecoline in ESCC cells, two ESCC cell lines, CE81T/VGH and OE21, which represented Asians (with betel nut chewing) and Caucasians (without betel nut chewing), were treated with a two-fold serial dilution of arecoline from 1000 muM to 3.9 muM for 72 h. High concentrations of arecoline elicited a cytotoxic effect on both cell lines and the half-maximal inhibitory concentration (IC50) of arecoline on CE81T/VGH and OE21 was 578.5 muM and 494.3 muM, respectively (Figure 1A).	('muM', 'Gene', (266, 269))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('CE81T/VGH', 'Var', (429, 438))	('arecoline', 'Chemical', 'MESH:D001115', (235, 244))	('nut', 'Gene', (173, 176))	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('muM', 'Gene', '56925', (255, 258))	('SCC', 'Gene', '6317', (41, 44))	('muM', 'Gene', (255, 258))	('SCC', 'Gene', (41, 44))	('SCC', 'Gene', '6317', (57, 60))	('nut', 'Gene', '256646', (130, 133))	('arecoline', 'Chemical', 'MESH:D001115', (416, 425))	('muM', 'Gene', '56925', (458, 461))	('arecoline', 'Chemical', 'MESH:D001115', (27, 36))	('arecoline', 'Chemical', 'MESH:D001115', (303, 312))	('cytotoxic effect', 'CPA', (324, 340))	('muM', 'Gene', (458, 461))	('SCC', 'Gene', (57, 60))	('muM', 'Gene', '56925', (472, 475))	('nut', 'Gene', (130, 133))	('muM', 'Gene', '56925', (266, 269))	('muM', 'Gene', (472, 475))	('nut', 'Gene', '256646', (173, 176))
51822	30893904	Consistent with the findings from others, EGCG or N-acetyl-L-cysteine (NAC) significantly reduced the arecoline-induced ROS production (Figure 2A).	('arecoline', 'Chemical', 'MESH:D001115', (102, 111))	('N-acetyl-L-cysteine', 'Chemical', 'MESH:D000111', (50, 69))	('reduced', 'NegReg', (90, 97))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('NAC', 'Chemical', 'MESH:D000111', (71, 74))	('arecoline-induced ROS production', 'MPA', (102, 134))	('EGCG', 'Chemical', 'MESH:C045651', (42, 46))	('N-acetyl-L-cysteine', 'Var', (50, 69))
51831	30893904	Treatment of MK2206, a selective inhibitor of Akt1, Akt2 and Akt3, completely diminished arecoline-induced Akt phosphorylation (Figure 3A).	('MK2206', 'Chemical', 'MESH:C548887', (13, 19))	('Akt', 'Gene', (46, 49))	('Akt3', 'Gene', (61, 65))	('Akt', 'Gene', '207', (46, 49))	('MK2206', 'Var', (13, 19))	('Akt1', 'Gene', (46, 50))	('Akt', 'Gene', (61, 64))	('Akt2', 'Gene', (52, 56))	('Akt2', 'Gene', '208', (52, 56))	('Akt', 'Gene', (107, 110))	('Akt', 'Gene', (52, 55))	('Akt', 'Gene', '207', (61, 64))	('Akt3', 'Gene', '10000', (61, 65))	('Akt', 'Gene', '207', (107, 110))	('Akt', 'Gene', '207', (52, 55))	('Akt1', 'Gene', '207', (46, 50))	('arecoline', 'Chemical', 'MESH:D001115', (89, 98))	('diminished', 'NegReg', (78, 88))	('men', 'Species', '9606', (5, 8))
51833	30893904	Ten minutes before the proliferation assay, MK2206 was applied into the culture medium, and the cell proliferation was monitored by cell counting.	('nut', 'Gene', '256646', (6, 9))	('MK2206', 'Var', (44, 50))	('nut', 'Gene', (6, 9))	('MK2206', 'Chemical', 'MESH:C548887', (44, 50))
51834	30893904	Blockage of Akt phosphorylation by MK2206 reduced cell proliferation of the vehicle:and arecoline-treated OE21 cells (Figure 3B).	('Akt', 'Gene', '207', (12, 15))	('reduced', 'NegReg', (42, 49))	('Akt', 'Gene', (12, 15))	('MK2206', 'Chemical', 'MESH:C548887', (35, 41))	('arecoline', 'Chemical', 'MESH:D001115', (88, 97))	('MK2206', 'Var', (35, 41))	('Blockage', 'NegReg', (0, 8))	('cell proliferation', 'CPA', (50, 68))
51835	30893904	On the other hand, the treatment of MK2206 also decreased arecoline-promoted colony formation (Figure 3C).	('men', 'Species', '9606', (28, 31))	('MK2206', 'Var', (36, 42))	('arecoline-promoted colony formation', 'CPA', (58, 93))	('decreased', 'NegReg', (48, 57))	('arecoline', 'Chemical', 'MESH:D001115', (58, 67))	('MK2206', 'Chemical', 'MESH:C548887', (36, 42))
51837	30893904	Interestingly, although PD98059 decreased the arecoline-induced ERK1/2 phosphorylation (Figure 3D), it did not affect the cell proliferation and soft-agar colony formation of the vehicle and arecoline-pretreated OE21 cells (Figure 3E,F).	('phosphorylation', 'MPA', (71, 86))	('soft-agar colony formation', 'CPA', (145, 171))	('agar', 'Chemical', 'MESH:D000362', (150, 154))	('ERK1/2', 'Gene', '5595;5594', (64, 70))	('arecoline', 'Chemical', 'MESH:D001115', (191, 200))	('PD98059', 'Var', (24, 31))	('arecoline', 'Chemical', 'MESH:D001115', (46, 55))	('PD98059', 'Chemical', 'MESH:C093973', (24, 31))	('ERK1/2', 'Gene', (64, 70))	('cell proliferation', 'CPA', (122, 140))	('decreased', 'NegReg', (32, 41))	('arecoline-induced', 'MPA', (46, 63))
51840	30893904	Our in vitro studies further indicated that EGCG could attenuate the oncogenic property of ESCC cells after low-concentration, long-term arecoline treatment.	('arecoline', 'Chemical', 'MESH:D001115', (137, 146))	('EGCG', 'Chemical', 'MESH:C045651', (44, 48))	('SCC', 'Gene', '6317', (92, 95))	('EGCG', 'Var', (44, 48))	('men', 'Species', '9606', (152, 155))	('attenuate', 'NegReg', (55, 64))	('SCC', 'Gene', (92, 95))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))
51846	30893904	For example, EGCG could reduce liver cell injury caused by oxidative stress from ethanol in vitro.	('reduce liver cell', 'Phenotype', 'HP:0001410', (24, 41))	('EGCG', 'Chemical', 'MESH:C045651', (13, 17))	('liver cell injury', 'Disease', 'MESH:D056486', (31, 48))	('reduce', 'NegReg', (24, 30))	('EGCG', 'Var', (13, 17))	('oxidative stress', 'Phenotype', 'HP:0025464', (59, 75))	('ethanol', 'Chemical', 'MESH:D000431', (81, 88))	('oxidative stress', 'MPA', (59, 75))	('liver cell injury', 'Disease', (31, 48))
51850	30893904	However, arecoline-induced Akt and ERK1/2 phosphorylation activation could only be inhibited by EGCG, not by NAC, suggesting a ROS-independent pathway that differs from previous OSCC studies.	('ROS', 'Chemical', 'MESH:D017382', (127, 130))	('SCC', 'Gene', (179, 182))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('ERK1/2', 'Gene', (35, 41))	('phosphorylation', 'MPA', (42, 57))	('Akt', 'Gene', (27, 30))	('NAC', 'Chemical', 'MESH:D000111', (109, 112))	('ERK1/2', 'Gene', '5595;5594', (35, 41))	('Akt', 'Gene', '207', (27, 30))	('inhibited', 'NegReg', (83, 92))	('SCC', 'Gene', '6317', (179, 182))	('arecoline', 'Chemical', 'MESH:D001115', (9, 18))	('EGCG', 'Chemical', 'MESH:C045651', (96, 100))	('activation', 'PosReg', (58, 68))	('EGCG', 'Var', (96, 100))
51859	30893904	For the CE81T/VGH cell line, arecoline exposure induced Akt and ERK1/2 phosphorylation in 10 min, and a second-phase Akt phosphorylation was observed after 60 min of arecoline treatment.	('ERK1/2', 'Gene', '5595;5594', (64, 70))	('Akt', 'Gene', (117, 120))	('Akt', 'Gene', (56, 59))	('men', 'Species', '9606', (181, 184))	('arecoline', 'Chemical', 'MESH:D001115', (166, 175))	('Akt', 'Gene', '207', (117, 120))	('Akt', 'Gene', '207', (56, 59))	('ERK1/2', 'Gene', (64, 70))	('CE81T/VGH', 'Var', (8, 17))	('arecoline', 'Chemical', 'MESH:D001115', (29, 38))	('phosphorylation', 'CPA', (71, 86))
51865	30893904	EGCG can also selectively inhibit multiple epidermal growth factor-dependent kinases to inhibit cell proliferation.	('epidermal growth factor-dependent kinases', 'Pathway', (43, 84))	('inhibit', 'NegReg', (26, 33))	('inhibit', 'NegReg', (88, 95))	('cell proliferation', 'CPA', (96, 114))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGCG', 'Var', (0, 4))
51885	30893904	Both culture medium were supplemented with 10% fetal bovine serum (FBS; Cat: 1600044, Gibco, Waltham, MA, USA) and 1% antibiotic-antimycotic (Cat: 15240062, Gibco, Waltham, MA, USA), and additional 1% MEM non-essential amino acids solution (Cat: 11140035, Gibco) for CE81T/VGH.	('Cat: 11140035', 'Var', (241, 254))	('men', 'Species', '9606', (31, 34))	('Cat: 15240062', 'Var', (142, 155))	('FBS', 'Disease', (67, 70))	('bovine', 'Species', '9913', (53, 59))	('FBS', 'Disease', 'MESH:D005198', (67, 70))
51887	30893904	EGCG, PD98059, and N-Acetyl-L-cysteine were obtained from Sigma Aldrich (Cat: 50299, P215, and A9165, St. Louis, MS, USA).	('A9165', 'Var', (95, 100))	('PD98059', 'Chemical', 'MESH:C093973', (6, 13))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('N-Acetyl-L-cysteine', 'Chemical', 'MESH:D000111', (19, 38))	('P215', 'Var', (85, 89))
51911	30893904	The following are available online at , Figure S1: EGCG reduced the numbers and size of arecoline induced cell colonies, Figure S2: DCFH-DA intracellular ROS level quantification in OE21 after treating arecoline for 8 h.	('reduced', 'NegReg', (56, 63))	('arecoline induced cell colonies', 'CPA', (88, 119))	('DCFH-DA', 'Chemical', 'MESH:C029569', (132, 139))	('arecoline', 'Chemical', 'MESH:D001115', (202, 211))	('EGCG', 'Chemical', 'MESH:C045651', (51, 55))	('EGCG', 'Var', (51, 55))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('arecoline', 'Chemical', 'MESH:D001115', (88, 97))
51956	29608256	In the patients with NRI >=100 before RT had better OS (P = 0.012) and DMFS (P = 0.011) than the patients with NRI < 100, and NLR >= 2.5 before RT was associated with bad OS (P < 0.001) and LRFFS (P = 0.002).	('NRI >=100', 'Var', (21, 30))	('LRFFS', 'CPA', (190, 195))	('better', 'PosReg', (45, 51))	('DMFS', 'CPA', (71, 75))	('bad OS', 'Disease', (167, 173))	('DMFS', 'Chemical', '-', (71, 75))	('patients', 'Species', '9606', (7, 15))	('patients', 'Species', '9606', (97, 105))
52044	24133666	Also, for follow-up period, the heart rate in Group GVO+BB was lower than that in Group GVO (53.4+-10.6 vs. 75.4+-11.3 beats per minute, P=0.001).	('heart rate', 'MPA', (32, 42))	('GVO+BB', 'Var', (52, 58))	('GV', 'Phenotype', 'HP:0030169', (88, 90))	('lower', 'NegReg', (63, 68))	('GVO', 'Chemical', '-', (52, 55))	('GV', 'Phenotype', 'HP:0030169', (52, 54))	('GVO+', 'Chemical', '-', (52, 56))	('GVO', 'Chemical', '-', (88, 91))
52073	24133666	Also, this study showed that rebleeding of EV was a relatively large number in group GVO+BB than in group GVO.	('GVO', 'Chemical', '-', (85, 88))	('GV', 'Phenotype', 'HP:0030169', (85, 87))	('EV', 'Phenotype', 'HP:0002040', (43, 45))	('GVO', 'Chemical', '-', (106, 109))	('GVO+', 'Chemical', '-', (85, 89))	('GV', 'Phenotype', 'HP:0030169', (106, 108))	('bleeding', 'Disease', 'MESH:D006470', (31, 39))	('bleeding', 'Disease', (31, 39))	('GVO+BB', 'Var', (85, 91))
52202	22751462	Focal amplifications were substantially more prevalent in gastric/esophageal adenocarcinomas than colorectal tumors.	('prevalent', 'Reg', (45, 54))	('gastric/esophageal adenocarcinomas than colorectal tumors', 'Disease', 'MESH:D013274', (58, 115))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (66, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Focal amplifications', 'Var', (0, 20))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
52203	22751462	We identified 64 regions of significant recurrent amplification and deletion, some shared and others unique to the adenocarcinoma types examined.	('amplification', 'Var', (50, 63))	('deletion', 'Var', (68, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('adenocarcinoma', 'Disease', (115, 129))	('adenocarcinoma', 'Disease', 'MESH:D000230', (115, 129))
52205	22751462	Amplified loci implicated genes with known involvement in carcinogenesis but also pointed to regions harboring potentially novel cancer genes, including a recurrent deletion found in 15% of esophageal tumors where the Runt transcription factor subunit RUNX1 was implicated, including by functional experiments in tissue culture.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('esophageal tumors', 'Disease', (190, 207))	('esophageal tumor', 'Phenotype', 'HP:0100751', (190, 206))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('carcinogenesis', 'Disease', (58, 72))	('RUNX1', 'Gene', (252, 257))	('deletion', 'Var', (165, 173))	('RUNX1', 'Gene', '861', (252, 257))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('esophageal tumors', 'Disease', 'MESH:D004938', (190, 207))	('esophageal tumors', 'Phenotype', 'HP:0100751', (190, 207))
52208	22751462	Colorectal cancer (CRC) genomes have been studied extensively; the value of this information is realized by persuasive evidence that KRAS and BRAF mutations in CRC predict lack of response to cetuximab.	('BRAF', 'Gene', '673', (142, 146))	('mutations', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('lack', 'NegReg', (172, 176))	('KRAS', 'Gene', (133, 137))	('CRC', 'Gene', (160, 163))	('response to cetuximab', 'MPA', (180, 201))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('Colorectal cancer', 'Disease', (0, 17))	('KRAS', 'Gene', '3845', (133, 137))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('cetuximab', 'Chemical', 'MESH:D000068818', (192, 201))	('BRAF', 'Gene', (142, 146))
52214	22751462	Two challenges exist in the somatic genetic analysis of cancer: 1) distinguishing 'driver' alterations that contribute to tumor development, maintenance, or proliferation from random 'passenger' alterations that do not contribute to the neoplastic process, and 2) identifying the specific genes that mediate tumor progression.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('neoplastic process', 'Phenotype', 'HP:0002664', (237, 255))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('alterations', 'Var', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Disease', (56, 62))	('tumor', 'Disease', (308, 313))	('tumor', 'Disease', (122, 127))
52215	22751462	Both challenges must be confronted in analysis of somatic copy-number alterations (SCNAs) as tumors often harbor many such alterations, each of which often encompasses up to thousands of genes.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('alterations', 'Var', (123, 134))
52226	22751462	We analyzed a cohort of 363 new and 123 publically available genome array profiles from primary untreated gut adenocarcinomas including EA (186), GC (110), and CRC (190) (Table S1).	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('adenocarcinomas', 'Disease', 'MESH:D000230', (110, 125))	('CRC (190', 'Var', (160, 168))	('adenocarcinomas', 'Disease', (110, 125))
52232	22751462	Upper gut adenocarcinomas exhibited an even greater excess of higher-level, multi-copy focal amplifications (Fig.	('adenocarcinomas', 'Disease', 'MESH:D000230', (10, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('adenocarcinomas', 'Disease', (10, 25))	('multi-copy focal amplifications', 'Var', (76, 107))
52236	22751462	Fewer arm-level deletions were seen in GC than other gut adenocarcinomas (Fig.	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('deletions', 'Var', (16, 25))	('Fewer', 'NegReg', (0, 5))	('adenocarcinomas', 'Disease', 'MESH:D000230', (57, 72))	('adenocarcinomas', 'Disease', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
52239	22751462	Arm-level deletions were more variable across tumor types.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Disease', (46, 51))	('deletions', 'Var', (10, 19))
52240	22751462	Loss of arms 8p, 14q, and 15q were of higher significance in CRC, whereas loss of 5q, 9p, and 21q were particularly significant among EAs.	('CRC', 'Disease', (61, 64))	('Loss', 'Var', (0, 4))	('EAs', 'Chemical', '-', (134, 137))
52242	22751462	Unique significant losses of 9p and 21q in EA are notable because these arms respectively contain the known and putative tumor suppressors CDKN2A and RUNX1, both targets of focal deletion in EA (discussed below).	('CDKN2A', 'Gene', '1029', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('losses', 'NegReg', (19, 25))	('RUNX1', 'Gene', (150, 155))	('deletion', 'Var', (179, 187))	('RUNX1', 'Gene', '861', (150, 155))	('CDKN2A', 'Gene', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
52245	22751462	We next evaluated focal SCNAs across all 486 tumors and identified 33 regions subject to significant (q<0.01) focal amplification (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('focal', 'Var', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (45, 51))
52252	22751462	Prior studies suggest that such regions often lie in "fragile sites" or areas of low gene density where deletion may be tolerated, and may not harbor functional tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('deletion', 'Var', (104, 112))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (161, 166))
52258	22751462	For example, the 1p36.11 deletion narrowed from 89 genes in the EA set to only 11 genes in the combined dataset, including the chromatin-modifying enzyme ARID1A, a recently identified target of frequent mutation in clear cell ovarian and gastric adenocarcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (251, 261))	('ARID1A', 'Gene', '8289', (154, 160))	('ARID1A', 'Gene', (154, 160))	('narrowed', 'NegReg', (34, 42))	('clear cell ovarian', 'Disease', (215, 233))	('deletion', 'Var', (25, 33))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (238, 261))	('gastric adenocarcinomas', 'Disease', (238, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
52259	22751462	After correcting for multiple hypothesis testing and tissue type, the only significant (Bonferroni-corrected p-value >=0.05) findings were correlations of amplifications of CCNE1 with each of two peaks with unknown targets: a deletion peak at 6p25.3 and amplification of 1q42.3.	('CCNE1', 'Gene', '898', (173, 178))	('CCNE1', 'Gene', (173, 178))	('deletion', 'Var', (226, 234))
52262	22751462	Highlighting the similarities and differences among digestive tract cancers, only three amplifications were significant in all tumor types: 8q24.21 (containing MYC), 17q12 (containing ERBB2), and 18q11.2 (containing GATA6).	('ERBB2', 'Gene', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('MYC', 'Gene', '4609', (160, 163))	('17q12', 'Var', (166, 171))	('tumor', 'Disease', (127, 132))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('18q11.2', 'Var', (196, 203))	('cancers', 'Disease', (68, 75))	('GATA6', 'Gene', (216, 221))	('MYC', 'Gene', (160, 163))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('GATA6', 'Gene', '2627', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('ERBB2', 'Gene', '2064', (184, 189))	('8q24.21', 'Var', (140, 147))
52280	22751462	The presence of FGFR2 amplifications in EA suggests a potential new therapeutic target for these tumors, similar to in GC.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FGFR2', 'Gene', (16, 21))	('FGFR2', 'Gene', '2263', (16, 21))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('amplifications', 'Var', (22, 36))
52282	22751462	These results indicate FGFR2 amplification may serve as a biomarker for the use of FGFR2-directed therapy in EA in addition to GC.	('FGFR2', 'Gene', '2263', (83, 88))	('FGFR2', 'Gene', (83, 88))	('amplification', 'Var', (29, 42))	('FGFR2', 'Gene', (23, 28))	('FGFR2', 'Gene', '2263', (23, 28))
52287	22751462	Only 10% of tumors had concurrent amplifications of RTKs and KRAS.	('amplifications', 'Var', (34, 48))	('RTKs', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('KRAS', 'Gene', (61, 65))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('KRAS', 'Gene', '3845', (61, 65))
52293	22751462	HMGA2 amplifications on chromosome 12 are notably absent in GI tumors, despite the presence of chromosome 12 amplification at MDM2 in both GI and non-GI carcinomas.	('non-GI carcinomas', 'Disease', 'MESH:D002289', (146, 163))	('HMGA2', 'Gene', '8091', (0, 5))	('GI carcinomas', 'Phenotype', 'HP:0002672', (150, 163))	('non-GI carcinomas', 'Disease', (146, 163))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('MDM2', 'Gene', '4193', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('MDM2', 'Gene', (126, 130))	('amplification', 'Var', (109, 122))	('HMGA2', 'Gene', (0, 5))	('GI tumors', 'Phenotype', 'HP:0007378', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('GI tumors', 'Disease', (60, 69))	('GI tumors', 'Disease', 'MESH:D009369', (60, 69))
52301	22751462	Among the 30 deletion peaks in the composite tumor set (Table 2), 15 were also significant in the non-GI adenocarcinoma study (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('non-GI adenocarcinoma', 'Disease', 'MESH:D000230', (98, 119))	('GI adenocarcinoma', 'Phenotype', 'HP:0002672', (102, 119))	('tumor', 'Disease', (45, 50))	('deletion', 'Var', (13, 21))	('non-GI adenocarcinoma', 'Disease', (98, 119))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
52303	22751462	One of the latter peaks contains the effector caspase gene CASP3, suggesting that deletion of an effector caspase, CASP3 or CASP7, may mark GI adenocarcinomas more generally and not CRC alone.	('CASP3', 'Gene', '836', (59, 64))	('CASP3', 'Gene', (59, 64))	('GI adenocarcinomas', 'Disease', 'MESH:D000230', (140, 158))	('CASP7', 'Gene', '840', (124, 129))	('CASP3', 'Gene', '836', (115, 120))	('mark', 'Reg', (135, 139))	('GI adenocarcinoma', 'Phenotype', 'HP:0002672', (140, 157))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('deletion', 'Var', (82, 90))	('CASP7', 'Gene', (124, 129))	('CASP3', 'Gene', (115, 120))	('GI adenocarcinomas', 'Disease', (140, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
52307	22751462	We observed highly focal RUNX1 deletions at 21q22.12 in 15% of EAs, also noted in a recent report (Fig.	('RUNX1', 'Gene', (25, 30))	('RUNX1', 'Gene', '861', (25, 30))	('EAs', 'Chemical', '-', (63, 66))	('EAs', 'Disease', (63, 66))	('deletions', 'Var', (31, 40))
52308	22751462	RUNX1 behaves as a tumor suppressor in leukemia, where translocations and mutations disrupt gene function.	('leukemia', 'Disease', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('translocations', 'Var', (55, 69))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('disrupt', 'NegReg', (84, 91))	('RUNX1', 'Gene', (0, 5))	('tumor', 'Disease', (19, 24))	('leukemia', 'Phenotype', 'HP:0001909', (39, 47))	('leukemia', 'Disease', 'MESH:D007938', (39, 47))	('gene function', 'MPA', (92, 105))	('RUNX1', 'Gene', '861', (0, 5))
52309	22751462	We therefore evaluated a possible tumor suppressor function for RUNX1 in EA by reintroducing it into the EA cell line OE33, which carries a focal RUNX1 deletion (Fig.	('deletion', 'Var', (152, 160))	('tumor', 'Disease', (34, 39))	('RUNX1', 'Gene', '861', (146, 151))	('RUNX1', 'Gene', (146, 151))	('RUNX1', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('RUNX1', 'Gene', '861', (64, 69))
52315	22751462	Notably, the genomes of EA and GC cancers contain alterations selected for their contributions to the process of both intestinal metaplasia and malignant transformation to adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (118, 139))	('adenocarcinoma', 'Disease', (172, 186))	('alterations', 'Var', (50, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('intestinal metaplasia', 'Disease', (118, 139))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('adenocarcinoma', 'Disease', 'MESH:D000230', (172, 186))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))
52323	22751462	The presence of ERBB2 amplifications in 6% of CRCs suggests that ERBB2-directed therapy may benefit select CRC patients.	('CRC', 'Disease', (107, 110))	('ERBB2', 'Gene', (16, 21))	('ERBB2', 'Gene', '2064', (16, 21))	('ERBB2', 'Gene', (65, 70))	('ERBB2', 'Gene', '2064', (65, 70))	('CRCs', 'Disease', (46, 50))	('amplifications', 'Var', (22, 36))	('patients', 'Species', '9606', (111, 119))
52324	22751462	Additionally, based on evidence that KRAS mutation negatively predicts cetuximab response, highly prevalent KRAS amplification in upper GI tumors may similarly impact clinical decisions.	('KRAS', 'Gene', (108, 112))	('impact', 'Reg', (160, 166))	('upper GI tumors', 'Disease', (130, 145))	('negatively', 'NegReg', (51, 61))	('KRAS', 'Gene', '3845', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('KRAS', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('cetuximab', 'Chemical', 'MESH:D000068818', (71, 80))	('amplification', 'Var', (113, 126))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('GI tumors', 'Phenotype', 'HP:0007378', (136, 145))	('cetuximab response', 'MPA', (71, 89))	('KRAS', 'Gene', '3845', (37, 41))	('predicts', 'Reg', (62, 70))	('upper GI tumors', 'Disease', 'MESH:D009369', (130, 145))
52334	22751462	Moreover, as evidenced by the selective deletion of RUNX1 in EA, clear genomic differences exist between EA and GC.	('deletion', 'Var', (40, 48))	('RUNX1', 'Gene', '861', (52, 57))	('RUNX1', 'Gene', (52, 57))
52345	32103779	The cumulative incidence of pericardial effusion of any grade was higher in patients with mean heart dose > 23.45 Gy (p = 0.00018), heart V30 > 33.55% (p = 0.00015), mean pericardium dose > 20.33 Gy (p = 0.00027), and pericardium V20 > 42.55% (p = 0.00018).	('patients', 'Species', '9606', (76, 84))	('pericardial effusion', 'Disease', (28, 48))	('pericardial effusion', 'Disease', 'MESH:D010490', (28, 48))	('higher', 'PosReg', (66, 72))	('heart V30 >', 'Var', (132, 143))	('pericardial effusion', 'Phenotype', 'HP:0001698', (28, 48))
52347	32103779	The cumulative incidence of pericardial effusion >= grade 3 was higher in patients with pericardium V30 > 65.80% (p = 0.00028), V40 > 55.35% (p < 0.0001), and V60 > 24.70% (p = 0.0021).	('V60 >', 'Var', (159, 164))	('V40 > 55.35', 'Var', (128, 139))	('pericardial effusion', 'Disease', (28, 48))	('higher', 'PosReg', (64, 70))	('patients', 'Species', '9606', (74, 82))	('V30 > 65.80', 'Var', (100, 111))	('pericardial effusion', 'Disease', 'MESH:D010490', (28, 48))	('pericardial effusion', 'Phenotype', 'HP:0001698', (28, 48))
52372	32103779	Normal tissue-dose constraints included spinal cord (50 Gy to 5 cm), heart (50 Gy to one-third of the heart volume, V50 < 33%), lung (20 Gy to one-third of the lung volume, V20 < 33%), stomach (55 Gy to any part of the stomach volume, Dmax < 50 Gy), and liver (35 Gy to one-half of the liver volume, V35 < 50%).	('V35', 'Gene', '28474', (300, 303))	('V50 < 33%', 'Var', (116, 125))	('V35', 'Gene', (300, 303))
52394	32103779	The cumulative incidence of pericardial effusion >= grade 3 was higher in patients with heart V60 > 26.00% (p = 0.0073, Fig.	('pericardial effusion', 'Disease', (28, 48))	('patients', 'Species', '9606', (74, 82))	('higher', 'PosReg', (64, 70))	('heart V60 > 26.00', 'Var', (88, 105))	('pericardial effusion', 'Disease', 'MESH:D010490', (28, 48))	('pericardial effusion', 'Phenotype', 'HP:0001698', (28, 48))
52395	32103779	Multivariate analyses showed pericardium V30, V40, and V60 were independent predictors of pericardial effusion >= grade 3 (Table 3 and Additional file 5: Table S4).	('V30', 'Var', (41, 44))	('pericardial effusion', 'Disease', (90, 110))	('V60', 'Var', (55, 58))	('pericardial effusion', 'Disease', 'MESH:D010490', (90, 110))	('V40', 'Var', (46, 49))	('pericardial effusion', 'Phenotype', 'HP:0001698', (90, 110))
52424	32103779	For example, pericardium V30 > 46% and V20 were identified as the important parameters associated with pericardial effusion of any grade by other groups.	('pericardial effusion', 'Phenotype', 'HP:0001698', (103, 123))	('pericardial effusion', 'Disease', (103, 123))	('V20', 'Var', (39, 42))	('pericardial effusion', 'Disease', 'MESH:D010490', (103, 123))	('V30', 'Var', (25, 28))
52425	32103779	In the present study, pericardium V30 > 33.35% and V20 > 42.55% correlated with the higher cumulative incidence of pericardial effusion of any grade.	('V30 > 33.35', 'Var', (34, 45))	('pericardial effusion', 'Phenotype', 'HP:0001698', (115, 135))	('pericardial effusion', 'Disease', (115, 135))	('V20 >', 'Var', (51, 56))	('pericardial effusion', 'Disease', 'MESH:D010490', (115, 135))
52427	32103779	Based on the values of hazard ratios in multivariate analyses, we suggested mean heart dose <=23.45 Gy, heart V30 <= 33.55%, mean pericardium dose <=20.33 Gy, and pericardium V20 <= 42.55% as representative dose-volume constraints to reduce the risk of pericardial effusion after CCRT in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (288, 305))	('pericardial effusion', 'Disease', 'MESH:D010490', (253, 273))	('pericardial effusion', 'Phenotype', 'HP:0001698', (253, 273))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('reduce', 'NegReg', (234, 240))	('<=23.45', 'Var', (92, 99))	('pericardial effusion', 'Disease', (253, 273))	('esophageal cancer', 'Disease', (288, 305))
52434	32103779	In the present study, multivariate analyses showed pericardium V30 > 65.8%, V40 > 55.35%, and V60 > 24.7% served as risk factors for pericardial effusion >= grade 3 after CCRT in esophageal cancer.	('esophageal cancer', 'Disease', (179, 196))	('pericardial effusion', 'Disease', 'MESH:D010490', (133, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('V30', 'Var', (63, 66))	('pericardial effusion', 'Phenotype', 'HP:0001698', (133, 153))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('pericardial effusion', 'Disease', (133, 153))	('V40 > 55.35', 'Var', (76, 87))	('V60 > 24.7', 'Var', (94, 104))
52626	31423180	For example, RNASEN, which has previously been reported as a biomarker of worse prognosis in patients with ESCC, was also demonstrated to be associated with worse prognosis by OSescc in the TCGA dataset; however, the prognosis analysis based on the GSE53625 dataset was not statistically significant (Fig.	('OS', 'Chemical', '-', (176, 178))	('OSescc', 'Var', (176, 182))	('RNASEN', 'Gene', (13, 19))	('ESCC', 'Disease', (107, 111))	('patients', 'Species', '9606', (93, 101))	('RNASEN', 'Gene', '29102', (13, 19))
52653	27738428	The depth of field for the GIF-H260Z and EG-L590ZW endoscope was 7 to 100  mm and 6 to 100 mm, respectively.	('H260Z', 'Var', (31, 36))	('H260Z', 'SUBSTITUTION', 'None', (31, 36))	('EG-L590ZW', 'Var', (41, 50))
52716	27279758	The overall median survival was significantly higher in patients receiving both stent and EBRT than in patients with stents alone.	('patients', 'Species', '9606', (56, 64))	('higher', 'PosReg', (46, 52))	('EBRT', 'Var', (90, 94))	('EBRT', 'Chemical', '-', (90, 94))	('patients', 'Species', '9606', (103, 111))	('median survival', 'MPA', (12, 27))
52877	19184473	However, Hispanic women had an almost threefold higher risk of vagina/vulva cancer compared to the general population (SIR = 2.71, 95% CI: 1.48, 4.55).	('vulva cancer', 'Phenotype', 'HP:0030416', (70, 82))	('Hispanic', 'Var', (9, 17))	('SIR = 2', 'Gene', '23411', (119, 126))	('SIR = 2', 'Gene', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('vagina/vulva cancer', 'Disease', 'MESH:D014846', (63, 82))	('women', 'Species', '9606', (18, 23))	('His', 'Chemical', 'MESH:D006639', (9, 12))	('vagina/vulva cancer', 'Disease', (63, 82))
52947	19903418	Disorders in a number of these pathways can lead to gastric acid hypersecretion (Table 1) including ones, which primarily mediate the hypersecretion by causing hypergastrinemia, causing hyperhistaminemia or by an unknown etiology.	('Disorders', 'Var', (0, 9))	('lead to', 'Reg', (44, 51))	('hypergastrinemia', 'Disease', (160, 176))	('hypergastrinemia', 'Disease', 'None', (160, 176))	('causing', 'Reg', (152, 159))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (160, 176))	('hyperhistaminemia', 'Disease', 'None', (186, 203))	('gastric acid hypersecretion', 'MPA', (52, 79))	('hyperhistaminemia', 'Disease', (186, 203))	('causing', 'Reg', (178, 185))
52951	19903418	In addition to PUD/GERD the acid hypersecretion can result in diarrhea and malabsorption of nutrients, particularly vitamin B12 and iron.	('acid hypersecretion', 'Var', (28, 47))	('iron', 'Chemical', 'MESH:D007501', (132, 136))	('diarrhea', 'Phenotype', 'HP:0002014', (62, 70))	('malabsorption', 'Phenotype', 'HP:0002024', (75, 88))	('diarrhea', 'Disease', (62, 70))	('iron', 'MPA', (132, 136))	('diarrhea', 'Disease', 'MESH:D003967', (62, 70))	('malabsorption', 'Disease', 'MESH:D008286', (75, 88))	('malabsorption', 'Disease', (75, 88))	('result in', 'Reg', (52, 61))	('vitamin B12', 'Chemical', 'MESH:D014805', (116, 127))
53003	19903418	Alterations in common oncogenes or tumor suppressor genes are uncommon in these tumors.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Alterations', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (80, 85))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))
53005	19903418	MEN1 is due to mutations in the MEN1 gene on chromosome11q13, which encodes for a 610 amino acid protein, menin, a nuclear protein, which binds to numerous transcription factors.	('MEN1', 'Gene', '4221', (0, 4))	('mutations', 'Var', (15, 24))	('menin', 'Gene', '4221', (106, 111))	('MEN1', 'Gene', (32, 36))	('MEN1', 'Gene', '4221', (32, 36))	('menin', 'Gene', (106, 111))	('due to', 'Reg', (8, 14))	('MEN1', 'Gene', (0, 4))
53006	19903418	Sporadic PETs show a loss of heterozygosity at 11q13 in 20-90% and 27-39% have an MEN1 gene mutation.	('PETs', 'Phenotype', 'HP:0030405', (9, 13))	('MEN1', 'Gene', (82, 86))	('mutation', 'Var', (92, 100))	('MEN1', 'Gene', '4221', (82, 86))
53011	19903418	MEN1 patients, who have a defect in the MEN1 gene on 11q13, characteristically develop tumors or hyperplasia of multiple endocrine and non-endocrine tissues.	('MEN1', 'Gene', '4221', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('patients', 'Species', '9606', (5, 13))	('hyperplasia', 'Disease', (97, 108))	('develop', 'PosReg', (79, 86))	('MEN1', 'Gene', (40, 44))	('defect', 'Var', (26, 32))	('MEN1', 'Gene', '4221', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('hyperplasia', 'Disease', 'MESH:D006965', (97, 108))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('MEN1', 'Gene', (0, 4))
53034	19903418	In particular no evidence of an increased incidence of gastric carcinoids due to the PPI usage in ZES has been seen or of other cancers which has been seen in experimental and/or animal studies.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('ZES', 'Phenotype', 'HP:0002044', (98, 101))	('cancers', 'Disease', (128, 135))	('PPI', 'Var', (85, 88))	('gastric carcinoids', 'Disease', (55, 73))	('carcinoids', 'Phenotype', 'HP:0100570', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric carcinoids', 'Disease', 'MESH:D002276', (55, 73))
53078	19903418	Evidence has been provided that the mechanism of the rebound hypersecretion post use of PPIs was, at least in part, mediated by the hypergastrinemia that occurred as result of the marked inhibition of the acid secretion by the PPI.	('hypergastrinemia', 'Disease', 'None', (132, 148))	('inhibition', 'NegReg', (187, 197))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (132, 148))	('acid secretion', 'MPA', (205, 219))	('PPI', 'Var', (227, 230))	('hypergastrinemia', 'Disease', (132, 148))
53079	19903418	The PPI-induced hypergastrinemia stimulates an increase in parietal cell mass leading to an increased maximal acid output, an increased ECL cell mass and ECL activity.	('parietal cell', 'MPA', (59, 72))	('hypergastrinemia', 'Disease', (16, 32))	('ECL cell mass', 'MPA', (136, 149))	('hypergastrinemia', 'Disease', 'None', (16, 32))	('PPI-induced', 'Var', (4, 15))	('ECL activity', 'MPA', (154, 166))	('maximal acid output', 'MPA', (102, 121))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (16, 32))	('increased', 'PosReg', (92, 101))	('increase', 'PosReg', (47, 55))	('increased', 'PosReg', (126, 135))
53193	32422875	Increased Endotoxin Activity Is Associated with the Risk of Developing Acute-on-Chronic Liver Failure Acute-on-chronic liver failure (ACLF) leads to systematic inflammatory response syndrome and multiple organ failure.	('chronic liver failure', 'Phenotype', 'HP:0100626', (111, 132))	('leads to', 'Reg', (140, 148))	('Liver Failure Acute', 'Phenotype', 'HP:0006554', (88, 107))	('multiple organ failure', 'Disease', (195, 217))	('Liver Failure', 'Disease', (88, 101))	('systematic inflammatory response syndrome', 'MPA', (149, 190))	('Acute-on-chronic liver failure', 'Phenotype', 'HP:0006554', (102, 132))	('Liver Failure', 'Phenotype', 'HP:0001399', (88, 101))	('liver failure', 'Phenotype', 'HP:0001399', (119, 132))	('Endotoxin', 'Protein', (10, 19))	('Liver Failure', 'Disease', 'MESH:D017093', (88, 101))	('liver failure', 'Disease', (119, 132))	('liver failure', 'Disease', 'MESH:D017093', (119, 132))	('Chronic Liver Failure', 'Phenotype', 'HP:0100626', (80, 101))	('multiple organ failure', 'Disease', 'MESH:D009102', (195, 217))	('Acute-on-chronic', 'Var', (102, 118))
53260	32422875	The cumulative incidence of ACLF in patients with low (<0.4) and high (>=0.4) EA are shown in Figure 2a; it indicates that the risk of ACLF development was significantly higher in patients with high EA than in those with low EA (p < 0.05).	('high', 'Var', (194, 198))	('low EA', 'Disease', 'MESH:D009800', (221, 227))	('higher', 'PosReg', (170, 176))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (180, 188))	('low EA', 'Disease', (221, 227))	('ACLF development', 'CPA', (135, 151))	('men', 'Species', '9606', (147, 150))
53263	32422875	CRP was higher in patients with rifaximin treatment than in those without (p < 0.05).	('CRP', 'Gene', (0, 3))	('men', 'Species', '9606', (47, 50))	('patients', 'Species', '9606', (18, 26))	('rifaximin', 'Var', (32, 41))	('rifaximin', 'Chemical', 'MESH:D000078262', (32, 41))	('higher', 'PosReg', (8, 14))	('CRP', 'Gene', '1401', (0, 3))
53264	32422875	The cumulative incidence of ACLF with and without rifaximin treatment during the observation period (Figure 2b) shows that the risk of ACLF development was significantly decreased by rifaximin (p < 0.05).	('ACLF', 'Disease', (135, 139))	('men', 'Species', '9606', (65, 68))	('rifaximin', 'Var', (183, 192))	('decreased', 'NegReg', (170, 179))	('rifaximin', 'Chemical', 'MESH:D000078262', (183, 192))	('rifaximin', 'Chemical', 'MESH:D000078262', (50, 59))	('men', 'Species', '9606', (147, 150))
53272	32422875	In a rat model of endotoxemia, injection of LPS in the mesenteric vein increased vascular permeability and resulted in ascites.	('ascites', 'Disease', (119, 126))	('ascites', 'Phenotype', 'HP:0001541', (119, 126))	('endotoxemia', 'Disease', 'MESH:D019446', (18, 29))	('resulted in', 'Reg', (107, 118))	('ascites', 'Disease', 'MESH:D001201', (119, 126))	('endotoxemia', 'Disease', (18, 29))	('vascular permeability', 'MPA', (81, 102))	('rat', 'Species', '10116', (5, 8))	('increased', 'PosReg', (71, 80))	('LPS', 'Var', (44, 47))
53273	32422875	In this study, the presence of ascites increased the risk of ACLF development, which is in line with previous findings of increased Et in cirrhotic patients.	('patients', 'Species', '9606', (148, 156))	('men', 'Species', '9606', (73, 76))	('ascites', 'Disease', (31, 38))	('ascites', 'Phenotype', 'HP:0001541', (31, 38))	('presence', 'Var', (19, 27))	('ascites', 'Disease', 'MESH:D001201', (31, 38))	('ACLF development', 'Disease', (61, 77))
53288	32422875	In this study, the fibrosis markers 4COL7S, P3P, and M2BpGi were increased in patients who developed ACLF.	('ACLF', 'Disease', (101, 105))	('fibrosis', 'Disease', (19, 27))	('increased', 'PosReg', (65, 74))	('fibrosis', 'Disease', 'MESH:D005355', (19, 27))	('patients', 'Species', '9606', (78, 86))	('P3P', 'MPA', (44, 47))	('4COL7S', 'MPA', (36, 42))	('M2BpGi', 'Var', (53, 59))
53289	32422875	4COL7S and M2BpGi have been shown to increase in ALF patients during HSC activation and extracellular matrix remodeling, and the levels of fibrosis markers have been related to ALF prognosis.	('ALF', 'Disease', 'MESH:D017114', (49, 52))	('related', 'Reg', (166, 173))	('ALF', 'Disease', 'MESH:D017114', (177, 180))	('patients', 'Species', '9606', (53, 61))	('ALF', 'Disease', (177, 180))	('M2BpGi', 'Var', (11, 17))	('increase', 'PosReg', (37, 45))	('levels', 'MPA', (129, 135))	('4COL7S', 'Var', (0, 6))	('fibrosis', 'Disease', 'MESH:D005355', (139, 147))	('fibrosis', 'Disease', (139, 147))	('ALF', 'Disease', (49, 52))
53306	31861383	We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin.	('increased', 'PosReg', (17, 26))	('tumor', 'Disease', (63, 68))	('reduced', 'NegReg', (55, 62))	('E-cadherin', 'Protein', (225, 235))	('ZEB1', 'Protein', (192, 196))	('migration', 'CPA', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('miR-142-5p', 'Chemical', '-', (27, 37))	('reduction', 'NegReg', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('increase', 'PosReg', (213, 221))	('miR-142-5p level', 'Var', (27, 43))	('SREBP1', 'Protein', (201, 207))	('tumor', 'Disease', (109, 114))
53322	31861383	The presence of the Snai11 (snail family transcriptional repressor 1) gene is indispensable for EMT, and knockout of Slug (snail family transcriptional repressor 2, Snail2) strongly reduces invasion and metastases in EC.	('snail family transcriptional repressor 2', 'Gene', '6591', (123, 163))	('metastases', 'Disease', 'MESH:D009362', (203, 213))	('snail family transcriptional repressor 1', 'Gene', '6615', (28, 68))	('reduces', 'NegReg', (182, 189))	('knockout', 'Var', (105, 113))	('snail family transcriptional repressor 2', 'Gene', (123, 163))	('Slug', 'Gene', '6591', (117, 121))	('Slug', 'Gene', (117, 121))	('Snail2', 'Gene', (165, 171))	('Snail2', 'Gene', '6591', (165, 171))	('metastases', 'Disease', (203, 213))	('snail family transcriptional repressor 1', 'Gene', (28, 68))
53337	31861383	SurvExpress software was used to calculate the overall survival rate of EC patients with high versus low SREPB1 expression.	('high', 'Var', (89, 93))	('patients', 'Species', '9606', (75, 83))	('low', 'NegReg', (101, 104))	('SREPB1', 'Gene', (105, 111))
53373	31861383	Subsequently, we identified that SREBP1 is a target of tumor suppressor miR-142-5p (as one of the top-ranking miRs); miR-142-5p level was negatively associated with SREBP1 expression in ESCC patient cohort (N = 162, TCGA ESCA database) (Figure 1D).	('miR-142-5p', 'Chemical', '-', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miR-142-5p', 'Chemical', '-', (72, 82))	('SREBP1', 'Gene', (165, 171))	('negatively', 'NegReg', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('miR-142-5p', 'Var', (117, 127))	('tumor', 'Disease', (55, 60))	('expression', 'MPA', (172, 182))	('patient', 'Species', '9606', (191, 198))
53378	31861383	From our bioinformatics analysis of clinical cohorts of ESCC patients, a negative correlation exists between the level of tumor suppressor miR-142-5p and SREBP1.	('SREBP1', 'Gene', (154, 160))	('patients', 'Species', '9606', (61, 69))	('miR-142-5p', 'Chemical', '-', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('negative', 'NegReg', (73, 81))	('miR-142-5p', 'Var', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
53380	31861383	Using different target prediction software, we found that miR-142-5p could target both SREBP1 and ZEB1 (Figure 3B), as demonstrated by the potential 3'UTR binding of both genes with miR-142-5p.	('miR-142-5p', 'Var', (58, 68))	('miR-142-5p', 'Var', (182, 192))	('binding', 'Interaction', (155, 162))	('SREBP1', 'Gene', (87, 93))	('miR-142-5p', 'Chemical', '-', (182, 192))	('miR-142-5p', 'Chemical', '-', (58, 68))
53383	31861383	Consistently, the higher level of miR-142-5p by mimic molecules led to a significantly suppressed migratory ability of both OE21 and OE33 cells, whereas miR-142-5p-silenced OE21 and OE33 cells showed significantly increased migratory ability (Figure 3D).	('migratory ability', 'CPA', (98, 115))	('miR-142-5p', 'Chemical', '-', (153, 163))	('migratory ability', 'CPA', (224, 241))	('increased', 'PosReg', (214, 223))	('suppressed', 'NegReg', (87, 97))	('miR-142-5p', 'Chemical', '-', (34, 44))	('miR-142-5p', 'Var', (34, 44))
53384	31861383	Notably, we also found that the self-renewal ability (by tumor sphere formation assay) was significantly suppressed in both cell lines transfected with miR-142-5p mimic molecules (Figure 3E).	('suppressed', 'NegReg', (105, 115))	('miR-142-5p mimic molecules', 'Var', (152, 178))	('miR-142-5p', 'Chemical', '-', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('self-renewal ability', 'CPA', (32, 52))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
53385	31861383	These observations provided the inverse relationship between the expression levels of miR-142-5p (tumor suppressor) and SREBP1 and established that miR-142-5p functioned to suppress esophageal tumorigenesis via the expression of both SREBP1 and ZEB1.	('ZEB1', 'Gene', (245, 249))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('SREBP1', 'Gene', (234, 240))	('suppress', 'NegReg', (173, 181))	('miR-142-5p', 'Chemical', '-', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('miR-142-5p', 'Var', (148, 158))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (193, 198))	('miR-142-5p', 'Chemical', '-', (86, 96))
53389	31861383	In addition, fatostatin treatment (10 muM, 24 h) suppressed the percentage of CD133+ population in both OE21 and OE33 spheres (Figure 4B).	('OE21', 'Var', (104, 108))	('OE33', 'Var', (113, 117))	('CD133+ population', 'CPA', (78, 95))	('suppressed', 'NegReg', (49, 59))	('fatostatin', 'Chemical', 'MESH:C545733', (13, 23))
53396	31861383	In addition, flow cytometric analysis of tumor cells harvested from the control and fatostatin mice indicated that fatostatin-treated tumor cells contained a lower percentage of CD133+ cells (Figure 5D) and higher miR-142-5p level (Figure 5E).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mice', 'Species', '10090', (95, 99))	('miR-142-5p level', 'MPA', (214, 230))	('lower', 'NegReg', (158, 163))	('tumor', 'Disease', (41, 46))	('miR-142-5p', 'Chemical', '-', (214, 224))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('fatostatin', 'Chemical', 'MESH:C545733', (115, 125))	('CD133+ cells', 'MPA', (178, 190))	('fatostatin-treated', 'Var', (115, 133))	('fatostatin', 'Chemical', 'MESH:C545733', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (134, 139))	('higher', 'PosReg', (207, 213))
53397	31861383	Together, these observations provided support for our hypothesis, whereby inhibition of SREBP1 resulted in the suppression of ESCC tumorigenesis and stemness.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('inhibition', 'Var', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('suppression', 'NegReg', (111, 122))	('tumor', 'Disease', (131, 136))	('ESCC', 'Disease', (126, 130))	('SREBP1', 'Gene', (88, 94))
53402	31861383	We showed that the expression of SREBP1 was associated with the tumorigenic properties where it was associated with the EMT makers.	('associated', 'Reg', (44, 54))	('tumor', 'Disease', (64, 69))	('expression', 'Var', (19, 29))	('associated', 'Reg', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('SREBP1', 'Gene', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
53406	31861383	Firstly, we identified both SREBP1 and ZEB1 as the silencing targets of miR-142-5p using multiple algorithms, and the negative correlation between their expression levels was found in the public databases of EC (Figure 3).	('miR-142-5p', 'Var', (72, 82))	('miR-142-5p', 'Chemical', '-', (72, 82))	('silencing', 'NegReg', (51, 60))
53407	31861383	Second, miR-142-5p has been demonstrated to serve as a tumor suppressor in different cancer types.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('miR-142-5p', 'Chemical', '-', (8, 18))	('tumor', 'Disease', (55, 60))	('miR-142-5p', 'Var', (8, 18))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
53408	31861383	For instance, a higher level of miR-142-5p-induced apoptosis was found in osteosarcoma via suppression of Erk-associated signaling.	('osteosarcoma', 'Disease', 'MESH:D012516', (74, 86))	('miR-142-5p-induced', 'Var', (32, 50))	('Erk', 'Gene', '2048', (106, 109))	('miR-142-5p', 'Chemical', '-', (32, 42))	('suppression', 'NegReg', (91, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (74, 86))	('Erk', 'Gene', (106, 109))	('osteosarcoma', 'Disease', (74, 86))
53409	31861383	In another example, miR-142-5p targeted several antiapoptotic genes, including baculoviral IAP repeat-containing 3 (BIRC3), B-cell lymphoma-2 (BCL2), BCL2-like 2 (BCL2L2), and myeloid cell leukemia sequence 1 (MCL1), and could improve cisplatin-mediated anticancer function in ovarian cancer.	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (176, 197))	('BCL2L2', 'Gene', '599', (163, 169))	('BCL2', 'Gene', (150, 154))	('BCL2', 'Gene', '596', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('MCL1', 'Gene', (210, 214))	('myeloid cell leukemia sequence 1', 'Gene', '4170', (176, 208))	('miR-142-5p', 'Chemical', '-', (20, 30))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (124, 139))	('leukemia', 'Phenotype', 'HP:0001909', (189, 197))	('B-cell lymphoma-2', 'Gene', (124, 141))	('MCL1', 'Gene', '4170', (210, 214))	('BCL2', 'Gene', (163, 167))	('baculoviral IAP repeat-containing 3', 'Gene', '330', (79, 114))	('cancer', 'Disease', (285, 291))	('BCL2', 'Gene', '596', (143, 147))	('BIRC3', 'Gene', '330', (116, 121))	('baculoviral IAP repeat-containing 3', 'Gene', (79, 114))	('ovarian cancer', 'Disease', 'MESH:D010051', (277, 291))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cisplatin', 'Chemical', 'MESH:D002945', (235, 244))	('improve', 'PosReg', (227, 234))	('BCL2L2', 'Gene', (163, 169))	('cancer', 'Disease', (258, 264))	('myeloid cell leukemia sequence 1', 'Gene', (176, 208))	('BCL2', 'Gene', '596', (150, 154))	('miR-142-5p', 'Var', (20, 30))	('antiapoptotic genes', 'Gene', (48, 67))	('BCL2', 'Gene', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('BCL2-like 2', 'Gene', '599', (150, 161))	('ovarian cancer', 'Disease', (277, 291))	('BIRC3', 'Gene', (116, 121))	('BCL2-like 2', 'Gene', (150, 161))	('B-cell lymphoma-2', 'Gene', '596', (124, 141))	('ovarian cancer', 'Phenotype', 'HP:0100615', (277, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
53410	31861383	Our observations, where miR-142-5p targeted both SREBP1 and ZEB1 in ESCC cells, provide additional support to its role as a tumor suppressor.	('miR-142-5p', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('targeted', 'Reg', (35, 43))	('ZEB1', 'Gene', (60, 64))	('tumor', 'Disease', (124, 129))	('SREBP1', 'Gene', (49, 55))	('miR-142-5p', 'Chemical', '-', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
53411	31861383	More importantly, our results also provide a potential link between miR-142-5p and the self-renewal ability of ESCC cells where exogenous miR-142-5p led to a decreased ability to generate tumor spheres in both OE21 and OE33 cells.	('tumor', 'Disease', (188, 193))	('miR-142-5p', 'Chemical', '-', (138, 148))	('decreased', 'NegReg', (158, 167))	('self-renewal ability', 'CPA', (87, 107))	('miR-142-5p', 'Var', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('miR-142-5p', 'Chemical', '-', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
53412	31861383	A recent study indicated that miR-142-5p functioned to suppress cell migration by targeting VCAM-1 in bone marrow-derived mesenchymal stem cells.	('targeting', 'Reg', (82, 91))	('cell migration', 'CPA', (64, 78))	('miR-142-5p', 'Chemical', '-', (30, 40))	('VCAM-1', 'Gene', (92, 98))	('VCAM-1', 'Gene', '7412', (92, 98))	('miR-142-5p', 'Var', (30, 40))	('suppress', 'NegReg', (55, 63))
53415	31861383	Together, the results from others and this study have provided evidence for the role of miR-142-5p as a tumor suppressor, while the decreased level of miR-142-5p was linked to the EMT and stemness of ESCC.	('miR-142-5p', 'Chemical', '-', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('stemness', 'CPA', (188, 196))	('EMT', 'CPA', (180, 183))	('miR-142-5p', 'Chemical', '-', (88, 98))	('tumor', 'Disease', (104, 109))	('miR-142-5p', 'Var', (151, 161))	('linked', 'Reg', (166, 172))	('level', 'MPA', (142, 147))	('miR-142-5p', 'Var', (88, 98))	('decreased', 'NegReg', (132, 141))	('ESCC', 'Disease', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
53425	31861383	This is supported by a previous study where ectopic expression of SREBP1 resulted in increased levels of lipogenic genes, such as fatty acid synthase (FASN), stearoyl CoA desaturase (SCD), and acetyl-CoA carboxylase-1 (ACC), and augmented lipogenesis and sphere formation in MCF10A stem-like cells.	('lipogenesis', 'MPA', (239, 250))	('FASN', 'Gene', (151, 155))	('FASN', 'Gene', '2194', (151, 155))	('SREBP1', 'Gene', (66, 72))	('MCF10', 'CellLine', 'CVCL:5555', (275, 280))	('levels of lipogenic genes', 'MPA', (95, 120))	('fatty acid synthase', 'Gene', '2194', (130, 149))	('stearoyl CoA desaturase', 'Gene', '6319', (158, 181))	('acetyl-CoA carboxylase-1', 'Gene', '31', (193, 217))	('augmented', 'PosReg', (229, 238))	('ectopic expression', 'Var', (44, 62))	('sphere formation', 'CPA', (255, 271))	('SCD', 'Gene', (183, 186))	('increased', 'PosReg', (85, 94))	('SCD', 'Gene', '6319', (183, 186))	('acetyl-CoA carboxylase-1', 'Gene', (193, 217))	('stearoyl CoA desaturase', 'Gene', (158, 181))	('fatty acid synthase', 'Gene', (130, 149))
53427	31861383	Our results from in vivo experiments using fatostatin also supported this hypothesis that fatostatin-treated mice showed a significantly lower tumor burden and better survival rate as compared to the vehicle control counterparts.	('tumor', 'Disease', (143, 148))	('lower', 'NegReg', (137, 142))	('fatostatin-treated', 'Var', (90, 108))	('fatostatin', 'Chemical', 'MESH:C545733', (43, 53))	('fatostatin', 'Chemical', 'MESH:C545733', (90, 100))	('mice', 'Species', '10090', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('better', 'PosReg', (160, 166))	('survival rate', 'CPA', (167, 180))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
53429	31861383	Consistently, a significantly higher level of miR-142-5p was also detected in the tumor cells harvested from the fatostatin-treated group.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('miR-142-5p', 'Chemical', '-', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('miR-142-5p', 'Var', (46, 56))	('tumor', 'Disease', (82, 87))	('fatostatin', 'Chemical', 'MESH:C545733', (113, 123))
53449	31598423	Besides, patients with low COL6A5 expression or high COL18A1 expression showed poor survival.	('patients', 'Species', '9606', (9, 17))	('COL6A5', 'Gene', (27, 33))	('expression', 'MPA', (34, 44))	('low', 'NegReg', (23, 26))	('COL6A5', 'Gene', '256076', (27, 33))	('high', 'Var', (48, 52))	('COL18A1', 'Gene', (53, 60))	('COL18A1', 'Gene', '80781', (53, 60))	('expression', 'MPA', (61, 71))
53532	31598423	In addition, the aberrant expression of a few collagen family genes has also been reported to be significantly associated with the prognosis of ESCC patients.	('patients', 'Species', '9606', (149, 157))	('ESCC', 'Disease', 'MESH:C562729', (144, 148))	('associated', 'Reg', (111, 121))	('aberrant expression', 'Var', (17, 36))	('ESCC', 'Disease', (144, 148))	('collagen family genes', 'Gene', (46, 67))
53543	31598423	In this study, ESCC patients with low COL6A5 expression or high COL18A1 expression showed poor overall survival (Figs.	('COL18A1', 'Gene', (64, 71))	('ESCC', 'Disease', (15, 19))	('poor', 'NegReg', (90, 94))	('COL18A1', 'Gene', '80781', (64, 71))	('COL6A5', 'Gene', '256076', (38, 44))	('expression', 'MPA', (72, 82))	('low', 'NegReg', (34, 37))	('expression', 'MPA', (45, 55))	('overall survival', 'MPA', (95, 111))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (20, 28))	('ESCC', 'Disease', 'MESH:C562729', (15, 19))	('COL6A5', 'Gene', (38, 44))
53545	31598423	Moreover, the variations that affect the expression of COL6A5 and COL18A1 possibly have effects on the progression of ESCC.	('COL6A5', 'Gene', (55, 61))	('ESCC', 'Disease', (118, 122))	('COL18A1', 'Gene', (66, 73))	('COL18A1', 'Gene', '80781', (66, 73))	('variations', 'Var', (14, 24))	('COL6A5', 'Gene', '256076', (55, 61))	('ESCC', 'Disease', 'MESH:C562729', (118, 122))	('effects', 'Reg', (88, 95))
53546	31598423	Activating COL6A5 or inhibiting COL18A1 might improve the therapeutic efficiency and the life-span of ESCC patients.	('COL18A1', 'Gene', '80781', (32, 39))	('patients', 'Species', '9606', (107, 115))	('life-span', 'CPA', (89, 98))	('therapeutic efficiency', 'CPA', (58, 80))	('ESCC', 'Disease', (102, 106))	('inhibiting', 'NegReg', (21, 31))	('COL6A5', 'Gene', '256076', (11, 17))	('Activating', 'Var', (0, 10))	('COL18A1', 'Gene', (32, 39))	('COL6A5', 'Gene', (11, 17))	('ESCC', 'Disease', 'MESH:C562729', (102, 106))	('improve', 'PosReg', (46, 53))
53555	31598423	Earlier studies proved that enhanced expression of ectopic p53 in dermal fibroblasts inhibited basal and TGF-beta-stimulated collagen gene expression, and the absence of cellular p53 was correlated with increased transcriptional activity of the Type I collagen gene (COL1A2) and collagen synthesis.	('p53', 'Gene', (59, 62))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('p53', 'Gene', '7157', (59, 62))	('transcriptional activity', 'MPA', (213, 237))	('inhibited', 'NegReg', (85, 94))	('enhanced', 'PosReg', (28, 36))	('COL1A2', 'Gene', (267, 273))	('COL1A2', 'Gene', '1278', (267, 273))	('collagen synthesis', 'CPA', (279, 297))	('basal and', 'MPA', (95, 104))	('expression', 'MPA', (37, 47))	('absence', 'Var', (159, 166))	('increased', 'PosReg', (203, 212))
53566	31598423	ROBO2 has been identified as a candidate tumor suppressor, and the alteration of its expression might play a role in malignant tumors of digestive tract including gastric and colorectal cancers.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('role', 'Reg', (109, 113))	('ROBO2', 'Gene', (0, 5))	('malignant tumors', 'Disease', (117, 133))	('malignant tumors', 'Disease', 'MESH:D009369', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('alteration', 'Var', (67, 77))	('colorectal cancers', 'Disease', 'MESH:D015179', (175, 193))	('play', 'Reg', (102, 106))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('expression', 'MPA', (85, 95))	('colorectal cancers', 'Disease', (175, 193))	('tumor', 'Disease', (127, 132))	('ROBO2', 'Gene', '6092', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('gastric', 'Disease', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
53617	31572795	Specifically, in the parakeratinized swine esophageal epithelium, keratinocytes in the prickle layer demonstrated a cytoplasmic intensity of (3.34 +- 0.19) x 10-6, which is significantly higher than that of the intermediate layer ([2.05 +- 0.13] x 10-6; Figure 8c; one-way analysis of variation [ANOVA], p < .01).	('NOV', 'Gene', (297, 300))	('rat', 'Species', '10116', (108, 111))	('3.34', 'Var', (142, 146))	('cytoplasmic', 'MPA', (116, 127))	('swine', 'Species', '9823', (37, 42))	('rat', 'Species', '10116', (68, 71))	('rat', 'Species', '10116', (27, 30))	('NOV', 'Gene', '100154395', (297, 300))	('higher', 'PosReg', (187, 193))
53693	30100738	As for miRNA biomarkers, miR-196a, miR-25, miR-93, and miR-221/222 are considered as oncogenic miRNAs in EAC, while the combination of expression of miR-133a-3p, miR-382-5p, and miR-451a in plasma is thought to be an effective method to distinguish EAC from controls.	('miR-133a-3p', 'Var', (149, 160))	('miR-451a', 'Gene', (178, 186))	('EAC', 'Phenotype', 'HP:0011459', (249, 252))	('miR-221', 'Gene', (55, 62))	('miR-451a', 'Gene', '574411', (178, 186))	('EAC', 'Disease', (105, 108))	('miR-382', 'Gene', '494331', (162, 169))	('miR-196a', 'Var', (25, 33))	('EAC', 'Phenotype', 'HP:0011459', (105, 108))	('EAC', 'Disease', (249, 252))	('miR-93', 'Gene', '407051', (43, 49))	('miR-25', 'Gene', '407014', (35, 41))	('miR-221', 'Gene', '407006', (55, 62))	('miR-382', 'Gene', (162, 169))	('miR-93', 'Gene', (43, 49))	('miR-25', 'Gene', (35, 41))
53702	30100738	In total, 2,669, 4,548, and 2,371 DEGs were identified from GSE1420, GSE26886, and GSE92396, respectively.	('GSE1420', 'Var', (60, 67))	('GSE26886', 'Var', (69, 77))	('GSE92396', 'Var', (83, 91))	('GSE1420', 'Chemical', '-', (60, 67))
53721	30100738	The ECM regulates tissue homeostasis, and its dysregulation contributes to tumor progression by directing cell growth, survival, and migration, and modulating immune function and vascular development.	('survival', 'CPA', (119, 127))	('contributes', 'Reg', (60, 71))	('immune function', 'CPA', (159, 174))	('directing', 'PosReg', (96, 105))	('tissue homeostasis', 'MPA', (18, 36))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('migration', 'CPA', (133, 142))	('vascular development', 'CPA', (179, 199))	('modulating', 'Reg', (148, 158))	('cell growth', 'CPA', (106, 117))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('dysregulation', 'Var', (46, 59))	('tumor', 'Disease', (75, 80))
53724	30100738	Type I collagen increases in various types of tumor, such as pancreatic carcinoma, breast cancer, and medulloblastoma, and fragments of type I collagen produced as a result of matrix metalloproteinase cleavage may promote tumor invasion, metastasis, and survival.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('metastasis', 'CPA', (238, 248))	('survival', 'CPA', (254, 262))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('medulloblastoma', 'Disease', 'MESH:D008527', (102, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('medulloblastoma', 'Phenotype', 'HP:0002885', (102, 117))	('cleavage', 'Var', (201, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('medulloblastoma', 'Disease', (102, 117))	('promote', 'PosReg', (214, 221))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('tumor', 'Disease', (46, 51))	('breast cancer', 'Disease', (83, 96))	('tumor', 'Disease', (222, 227))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (61, 81))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('pancreatic carcinoma', 'Disease', (61, 81))
53727	30100738	The loss of collagen IV alpha5 contributes toward delaying tumor progression and decreasing DDR1.	('tumor', 'Disease', (59, 64))	('decreasing', 'NegReg', (81, 91))	('collagen IV alpha5', 'Protein', (12, 30))	('DDR1', 'Gene', '780', (92, 96))	('DDR1', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('delaying', 'NegReg', (50, 58))	('loss', 'Var', (4, 8))
53732	30100738	In addition, RAB15 was significantly upregulated by early growth factor-4 overexpression, which plays a critical role in cell proliferation in small cell lung cancer, while knocking down RAB15 contributes to significant suppression of cell proliferation in small cell lung cancer.	('suppression', 'NegReg', (220, 231))	('cell proliferation', 'CPA', (235, 253))	('RAB15', 'Gene', (13, 18))	('upregulated', 'PosReg', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (268, 279))	('small cell lung cancer', 'Disease', (143, 165))	('RAB15', 'Gene', '376267', (13, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (257, 279))	('small cell lung cancer', 'Disease', (257, 279))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('knocking down', 'Var', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('RAB15', 'Gene', '376267', (187, 192))	('RAB15', 'Gene', (187, 192))	('small cell lung cancer', 'Disease', 'MESH:D055752', (257, 279))	('small cell lung cancer', 'Disease', 'MESH:D055752', (143, 165))
53753	28579811	Prenzel et al assessed the presence of NSM in 128 patients with resectable EC and revealed that the 5-year survival rate was higher in patients with NSM than in those with continuous metastasis (53% vs 15%, P<0.0001).	('NSM', 'Var', (149, 152))	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (50, 58))	('higher', 'PosReg', (125, 131))
53815	28579811	The prevalence of NSM is influenced by T stage and N stage, and the presence of NSM is associated with a negative prognosis of ESCC.	('SCC', 'Gene', (128, 131))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('presence', 'Var', (68, 76))	('SCC', 'Gene', '6317', (128, 131))	('NSM', 'Disease', (18, 21))
53882	28210086	The present study provides more evidence that regular use of PPI should not be recommended to all patients with cirrhosis who are at risk of GFV bleeding; the PPI group had increased short- and long-term mortality rates and a significantly lower overall survival rate than did the non-PPI group.	('cirrhosis', 'Phenotype', 'HP:0001394', (112, 121))	('GFV', 'Chemical', '-', (141, 144))	('bleeding', 'Disease', (145, 153))	('lower', 'NegReg', (240, 245))	('cirrhosis', 'Disease', 'MESH:D005355', (112, 121))	('patients', 'Species', '9606', (98, 106))	('overall', 'MPA', (246, 253))	('increased', 'PosReg', (173, 182))	('PPI', 'Var', (159, 162))	('cirrhosis', 'Disease', (112, 121))	('bleeding', 'Disease', 'MESH:D006470', (145, 153))
53886	28210086	Additionally, PPI themselves might have direct adverse effects on patients with GFV bleeding.	('bleeding', 'Disease', 'MESH:D006470', (84, 92))	('bleeding', 'Disease', (84, 92))	('GFV', 'Chemical', '-', (80, 83))	('PPI', 'Var', (14, 17))	('patients', 'Species', '9606', (66, 74))
53899	28147304	Multiple studies with large clinic-based cohorts revealed that variations of the phospholipase C epsilon (PLCE1) gene were associated with esophageal cancer susceptibility.	('associated', 'Reg', (123, 133))	('variations', 'Var', (63, 73))	('PLCE1', 'Gene', (106, 111))	('esophageal cancer', 'Disease', (139, 156))	('phospholipase C epsilon', 'Gene', '5334', (81, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('phospholipase C epsilon', 'Gene', (81, 104))
53901	28147304	Our results showed that loss of PLCE1 dramatically decreased the invasion and proliferation capacity of esophageal carcinoma cells in vitro.	('loss', 'Var', (24, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('esophageal carcinoma', 'Disease', (104, 124))	('PLCE1', 'Gene', (32, 37))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (104, 124))	('decreased', 'NegReg', (51, 60))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (104, 124))
53904	28147304	Our further transcriptomic data revealed that deficient cells were significantly decreased in expression of genes enriched as targets of Snail.	('decreased', 'NegReg', (81, 90))	('expression of genes', 'MPA', (94, 113))	('Snail', 'Gene', '6615', (137, 142))	('Snail', 'Gene', (137, 142))	('deficient', 'Var', (46, 55))
53908	28147304	Therefore, our functional experiments showed the essential roles of PLCE1 in esophageal carcinoma cells and provided evidences that targeting PLCE1 and its downstream molecules could be effective therapies for esophageal cancer.	('PLCE1', 'Gene', (142, 147))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (77, 97))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (77, 97))	('esophageal cancer', 'Disease', (210, 227))	('roles', 'Reg', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (210, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('PLCE1', 'Gene', (68, 73))	('esophageal carcinoma', 'Disease', (77, 97))	('targeting', 'Var', (132, 141))
53924	28147304	Cell line authentication utilizing Short Tandem Repeat (STR) profiling were performed with PowerPlex  21 System (Promega, USA) which allowed for detection of 21 loci, including D1S1656, D2S1338, D3S1358, D5S818, D6S1043, D7S820, D8S1179, D12S391, D13S317, D16S539, D18S51, D19S433, D21S11, Amelogenin, CSF1PO, FGA, Penta D, Penta E, TH01, TPOX and vWA (Supplementary Figure 1, A and B).	('D3S1358', 'Var', (195, 202))	('D5S818', 'Var', (204, 210))	('FGA', 'Gene', (310, 313))	('D6S1043', 'Var', (212, 219))	('D2S1338', 'Var', (186, 193))	('D21S11', 'Var', (282, 288))	('D13S317', 'Var', (247, 254))	('D18S51', 'Var', (265, 271))	('D16S539', 'Var', (256, 263))	('D1S1656', 'Var', (177, 184))	('D19S433', 'Var', (273, 280))	('D12S391', 'Var', (238, 245))	('D7S820', 'Var', (221, 227))	('D8S1179', 'Var', (229, 236))	('Short Tandem Repeat', 'Disease', 'MESH:D000647', (35, 54))	('FGA', 'Gene', '2243', (310, 313))	('Short Tandem Repeat', 'Disease', (35, 54))
53931	28147304	Cells in each well were transfected with 5 mug of plasmid px330-sgRNA2 and px330-sgRNA3, respectively, using Lipofectamine  3000 Transfection Reagent (ThermoFisher L3000-001) according to the manufacturer's protocol.	('px330-sgRNA3', 'Var', (75, 87))	('px330-sgRNA2', 'Var', (58, 70))	('Lipofectamine', 'Chemical', 'MESH:C086724', (109, 122))
53932	28147304	EC9706 and Eca109 cells transfected with plasmid px330-sgRNA2 or px330-sgRNA3 were incubated for 48 hours and then cloned by limiting dilution as previously described.	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('px330-sgRNA2', 'Var', (49, 61))	('px330-sgRNA3', 'Var', (65, 77))
53933	28147304	For the migration assay, 7.5 x 104 EC9706 and control cells were seeded in serum-free medium in the upper chamber.	('EC9706', 'CellLine', 'CVCL:E307', (35, 41))	('migration', 'CPA', (8, 17))	('EC9706', 'Var', (35, 41))
53934	28147304	For the invasion assay, 1 x 105 mutant EC9706 and control cells were added to the top chamber coated with matrigel (Biocoat, USA).	('mutant', 'Var', (32, 38))	('EC9706', 'CellLine', 'CVCL:E307', (39, 45))	('EC9706', 'Gene', (39, 45))
53937	28147304	To measure the Mean fluorescent intensity (MFI) of cytoplasm proteins, control and PLCE1 inactivated mutant cells were fixed in 4% paraformaldehyde for 20 min on ice, washed with FACS buffer (1 x PBS, 2% bovine serum, 2 mM EDTA), and permeablized with 90% methyl alcohol.	('methyl alcohol', 'Chemical', 'MESH:D000432', (256, 270))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (131, 147))	('PBS', 'Chemical', 'MESH:D007854', (196, 199))	('mutant', 'Var', (101, 107))	('bovine', 'Species', '9913', (204, 210))	('PLCE1', 'Gene', (83, 88))	('EDTA', 'Chemical', 'MESH:D004492', (223, 227))
53965	28147304	In order to identify the functional role of PLCE1 in ESCC cells, we performed genetic inactivation of the gene in EC9706 cells derived from esophageal squamous cell carcinoma as used in previous studies.	('genetic inactivation', 'Var', (78, 98))	('esophageal squamous cell carcinoma', 'Disease', (140, 174))	('EC9706', 'CellLine', 'CVCL:E307', (114, 120))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (140, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
53969	28147304	We first observed significant declination in the tumor graft weight between the PLCE1 mutant and control groups, and further analyzed the cell proliferation at two time points, in every 24 hours post the cell seeding in culture medium.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PLCE1', 'Gene', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutant', 'Var', (86, 92))	('tumor', 'Disease', (49, 54))
53970	28147304	The results from three independent experiments showed that there was a significant decrease of proliferation in both PLCE1 inactivated EC9706 and Eca109 cells (Figure 2G, Supplementary Figure 2D).	('EC9706', 'Var', (135, 141))	('decrease', 'NegReg', (83, 91))	('EC9706', 'CellLine', 'CVCL:E307', (135, 141))	('proliferation', 'CPA', (95, 108))	('PLCE1', 'Gene', (117, 122))
53972	28147304	Sizes of the tumor grafts from mutant and control cells were analyzed for their growth kinetics for 30 days.	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (13, 18))	('mutant', 'Var', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
53975	28147304	The weight of tumor xenografts originating from the PLCE1 deficient cells was less than half of those from control cells (Figure 2J).	('PLCE1', 'Gene', (52, 57))	('tumor', 'Disease', (14, 19))	('less', 'NegReg', (78, 82))	('deficient', 'Var', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
53976	28147304	Inactivation of PLCE1 caused significant change in cell migration and invasion, and also resulted in retarded proliferation in ESCC cells.	('retarded', 'Disease', 'MESH:D008607', (101, 109))	('ESCC', 'Disease', (127, 131))	('change', 'Reg', (41, 47))	('PLCE1', 'Gene', (16, 21))	('cell migration', 'CPA', (51, 65))	('proliferation', 'CPA', (110, 123))	('retarded', 'Disease', (101, 109))	('Inactivation', 'Var', (0, 12))	('invasion', 'CPA', (70, 78))
53978	28147304	172 genes were significantly down-regulated in the mutant group with Log Fold change <=-2.0, and such genes were significantly enriched in multiple tumor associated pathways (Figure 3A), including top enriched pathways of cell adhesion.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('mutant', 'Var', (51, 57))	('down-regulated', 'NegReg', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
53980	28147304	Based on the alteration of migratory phenotype observed in the mutant cells and results of transcriptomic analysis, we screened the activity of EMT a critical process for cancer cell invasion driven by Snail.	('mutant', 'Var', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('Snail', 'Gene', '6615', (202, 207))	('Snail', 'Gene', (202, 207))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
53981	28147304	Six out of nine markers were significantly decreased in the mutant cells, while E-Cadherin, N-Cadherin and Claudin-1 were not changed in protein expression (Figure 4, A and B, Supplementary Figure 3, A and B).	('N-Cadherin', 'Gene', (92, 102))	('Claudin-1', 'Gene', '9076', (107, 116))	('N-Cadherin', 'Gene', '1000', (92, 102))	('E-Cadherin', 'Gene', '999', (80, 90))	('E-Cadherin', 'Gene', (80, 90))	('Claudin-1', 'Gene', (107, 116))	('mutant', 'Var', (60, 66))	('decreased', 'NegReg', (43, 52))
53982	28147304	Among these markers Snail and ZO-1 were found significantly decreased in mutant cells, which was shown in both FACS and immunoblotting analyses of three different mutant clones involving both EC9706 and Eca109 cells (Figure 4C, Supplementary Figure 2E).	('decreased', 'NegReg', (60, 69))	('Snail', 'Gene', (20, 25))	('EC9706', 'CellLine', 'CVCL:E307', (192, 198))	('ZO-1', 'Gene', (30, 34))	('Snail', 'Gene', '6615', (20, 25))	('mutant', 'Var', (73, 79))	('ZO-1', 'Gene', '7082', (30, 34))
53986	28147304	To visualize Snail distribution in the nucleus, confocal cell staining was performed and we found that PLCE1 depletion decreases Snail signal in both cytosol and nuclear (Figure 4E).	('decreases', 'NegReg', (119, 128))	('Snail', 'Gene', (129, 134))	('Snail', 'Gene', '6615', (129, 134))	('Snail', 'Gene', '6615', (13, 18))	('Snail', 'Gene', (13, 18))	('depletion', 'Var', (109, 118))	('PLCE1', 'Gene', (103, 108))
53991	28147304	We transfected the PLCE1 inactivated mutant cells with Snail over-expression vector or empty vector both of which were engineered with GFP expressing and puromycin selection cassettes.	('PLCE1', 'Gene', (19, 24))	('mutant', 'Var', (37, 43))	('Snail', 'Gene', '6615', (55, 60))	('Snail', 'Gene', (55, 60))	('puromycin', 'Chemical', 'MESH:D011691', (154, 163))	('over-expression', 'PosReg', (61, 76))
53993	28147304	It was notable that intracellular staining showed decrease of Snail in PLCE1 inactivated mutant cells, which was completely rescued by transfection of Snail over-expression lentiviral vector (Figure 5, A and B).	('PLCE1', 'Gene', (71, 76))	('Snail', 'Gene', '6615', (62, 67))	('Snail', 'Gene', (151, 156))	('Snail', 'Gene', (62, 67))	('Snail', 'Gene', '6615', (151, 156))	('mutant', 'Var', (89, 95))	('decrease', 'NegReg', (50, 58))
53994	28147304	The PLCE1 inactivated mutant cells re-expressing Snail via lentiviral vector were analyzed in parallel with the Snail deficient PLCE1 inactivated cells.	('Snail', 'Gene', '6615', (112, 117))	('Snail', 'Gene', (112, 117))	('mutant', 'Var', (22, 28))	('Snail', 'Gene', '6615', (49, 54))	('Snail', 'Gene', (49, 54))
53996	28147304	In the wound healing assay, by 48 h the PLCE1 inactivated cells transfected with Snail over-expression vector reached complete closure which was even faster than the EC9706 control cells indicating critical role of Snail in compensating PLCE1 deficiency (Figure 5, C and D).	('Snail', 'Gene', '6615', (215, 220))	('Snail', 'Gene', (215, 220))	('vector', 'Var', (103, 109))	('Snail', 'Gene', (81, 86))	('deficiency', 'Var', (243, 253))	('Snail', 'Gene', '6615', (81, 86))	('EC9706', 'CellLine', 'CVCL:E307', (166, 172))	('faster', 'PosReg', (150, 156))	('PLCE1', 'Gene', (237, 242))
53997	28147304	We also observed that expression of Snail rescued completely the invasiveness and proliferation of PLCE1 inactivated cells (Figure 5, E, F and G, Supplementary Figure 4, A and B).	('Snail', 'Gene', '6615', (36, 41))	('expression', 'Var', (22, 32))	('Snail', 'Gene', (36, 41))	('PLCE1', 'Gene', (99, 104))	('proliferation', 'CPA', (82, 95))	('invasiveness', 'CPA', (65, 77))
53999	28147304	As determined in ESCC cells that PLCE1 inactivation regulated invasion and proliferation by restraining Snail, we further explored to delineate the clinical relevance of PLCE1 expression on tumor invasion and Snail signaling.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('Snail', 'Gene', (209, 214))	('PLCE1', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('clinical', 'Species', '191496', (148, 156))	('Snail', 'Gene', '6615', (209, 214))	('restraining', 'NegReg', (92, 103))	('tumor', 'Disease', (190, 195))	('Snail', 'Gene', (104, 109))	('invasion', 'CPA', (62, 70))	('inactivation', 'Var', (39, 51))	('Snail', 'Gene', '6615', (104, 109))	('regulated', 'Reg', (52, 61))
54010	28147304	In this study, we used two independent esophageal squamous carcinoma derived cell lines and targeted 2 loci which led to frame-shift and absence of protein production.	('squamous carcinoma', 'Phenotype', 'HP:0002860', (50, 68))	('protein production', 'MPA', (148, 166))	('absence', 'NegReg', (137, 144))	('frame-shift', 'Var', (121, 132))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (39, 68))	('esophageal squamous carcinoma', 'Disease', (39, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (39, 68))
54011	28147304	Loss of PLCE1 is not lethal both in ESCC cell lines and in the mouse, therefore complete inactivation using CRISPR/Cas9 tool is necessary and desirable for elucidation of its function.	('mouse', 'Species', '10090', (63, 68))	('Loss', 'Var', (0, 4))	('PLCE1', 'Gene', (8, 13))
54013	28147304	In humans, mutations in PLCE1 were found to be responsible for a recessive nephrotic syndrome with diffuse mesangial sclerosis or focal segmental glomerulosclerosis.	('glomerulosclerosis', 'Disease', 'MESH:D005921', (146, 164))	('mutations', 'Var', (11, 20))	('focal segmental glomerulosclerosis', 'Phenotype', 'HP:0000097', (130, 164))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (146, 164))	('diffuse mesangial sclerosis', 'Disease', 'MESH:C537346', (99, 126))	('diffuse mesangial sclerosis', 'Phenotype', 'HP:0001967', (99, 126))	('diffuse mesangial sclerosis', 'Disease', (99, 126))	('recessive nephrotic syndrome', 'Disease', 'MESH:D009404', (65, 93))	('responsible', 'Reg', (47, 58))	('humans', 'Species', '9606', (3, 9))	('glomerulosclerosis', 'Disease', (146, 164))	('PLCE1', 'Gene', (24, 29))	('nephrotic syndrome', 'Phenotype', 'HP:0000100', (75, 93))	('recessive nephrotic syndrome', 'Disease', (65, 93))
54019	28147304	In our study, it was difficult to make assessment in vivo whether PLCE1 inactivation could impair the metastasis of tumor grafts, as subcutaneous tumor graft of both mutant and control cells did not embark on metastasis in the mouse model.	('PLCE1', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mouse', 'Species', '10090', (227, 232))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mutant', 'Var', (166, 172))	('inactivation', 'Var', (72, 84))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (133, 151))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('impair', 'NegReg', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
54030	28147304	In our study, PLCE1 inactivation significantly reduced Snail expression, which was accompanied by down-regulation of mesenchymal markers, however we did not find change of E-cadherin.	('mesenchymal markers', 'CPA', (117, 136))	('inactivation', 'Var', (20, 32))	('down-regulation', 'NegReg', (98, 113))	('Snail', 'Gene', '6615', (55, 60))	('Snail', 'Gene', (55, 60))	('PLCE1', 'Gene', (14, 19))	('E-cadherin', 'Gene', (172, 182))	('E-cadherin', 'Gene', '999', (172, 182))	('reduced', 'NegReg', (47, 54))
54032	28147304	Over-expression of Snail in PLCE1 inactivated cells also did not change E-cadherin level (data not shown).	('change', 'Reg', (65, 71))	('Over-expression', 'Var', (0, 15))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))	('Snail', 'Gene', '6615', (19, 24))	('Snail', 'Gene', (19, 24))
54049	27172796	Increasing evidence, including the detection of AJUBA mutations in multiple human cancers such as ESCC, cutaneous squamous cell carcinoma and head and neck squamous cell carcinomas, suggests a role for AJUBA in tumorigenesis.	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('tumor', 'Disease', (211, 216))	('cutaneous squamous cell carcinoma', 'Disease', (104, 137))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (156, 180))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('mutations', 'Var', (54, 63))	('ESCC', 'Disease', (98, 102))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 137))	('AJUBA', 'Gene', (48, 53))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (142, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('neck squamous cell carcinomas', 'Disease', (151, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (104, 137))	('human', 'Species', '9606', (76, 81))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (151, 180))
54063	27172796	Furthermore, patients with high AJUBA expression had poorer differentiation and a higher tumor grade (Table 1).	('patients', 'Species', '9606', (13, 21))	('higher', 'PosReg', (82, 88))	('high', 'Var', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('poorer', 'NegReg', (53, 59))	('differentiation', 'CPA', (60, 75))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('AJUBA', 'Protein', (32, 37))
54064	27172796	KYSE450, KYSE510 and KYSE180 ESCC cell lines with relatively higher levels of AJUBA expression were used in further RNA interference studies.	('KYSE510', 'CellLine', 'CVCL:1354', (9, 16))	('KYSE510', 'Var', (9, 16))	('KYSE180', 'Var', (21, 28))	('KYSE180', 'CellLine', 'CVCL:1349', (21, 28))
54067	27172796	The size (Figure 2E and 2F) and weight (Figure 2G) of tumors were significantly reduced in AJUBA knockdown mice compared with the control group (P < 0.05, paired t-tests).	('knockdown', 'Var', (97, 106))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('reduced', 'NegReg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mice', 'Species', '10090', (107, 111))	('AJUBA', 'Gene', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
54071	27172796	The flow cytometric analyses showed that after 24 hours of cisplatin treatment, AJUBA knockdown significantly enhanced the apoptosis of KYSE450 and KYSE510 cells (Figure 3C).	('KYSE510', 'CellLine', 'CVCL:1354', (148, 155))	('knockdown', 'Var', (86, 95))	('enhanced', 'PosReg', (110, 118))	('apoptosis', 'CPA', (123, 132))	('AJUBA', 'Protein', (80, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))
54073	27172796	These data suggested that regulation of AJUBA expression might sensitize the ESCC cell response to chemotherapeutic drugs, such as cisplatin.	('AJUBA', 'Protein', (40, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('regulation', 'Var', (26, 36))	('ESCC', 'Disease', (77, 81))	('sensitize', 'Reg', (63, 72))
54074	27172796	The results of wound-healing and Transwell assays showed that AJUBA depletion significantly inhibited the migration and invasion of KYSE450 and KYSE510 cells (Figures 4A-4D).	('KYSE510', 'CellLine', 'CVCL:1354', (144, 151))	('migration', 'CPA', (106, 115))	('inhibited', 'NegReg', (92, 101))	('depletion', 'Var', (68, 77))
54078	27172796	RNA sequencing was used to identify the altered gene expression profiles following AJUBA knockdown in KYSE450, KYSE510 and KYSE180 cells.	('KYSE510', 'CellLine', 'CVCL:1354', (111, 118))	('KYSE180', 'CellLine', 'CVCL:1349', (123, 130))	('altered', 'Reg', (40, 47))	('knockdown', 'Var', (89, 98))	('gene expression profiles', 'MPA', (48, 72))
54085	27172796	The Western blot analysis showed that the level of phosphorylated ERK1/2, but not p38 MAPK, was dramatically decreased in ESCC cells with AJUBA knockdown and increased in ESCC cells with AJUBA overexpression (Figure 6D and Supplementary Figure S3).	('decreased', 'NegReg', (109, 118))	('p38', 'Gene', '5594', (82, 85))	('MAPK', 'Gene', '5595;5594;5595', (86, 90))	('knockdown', 'Var', (144, 153))	('MAPK', 'Gene', (86, 90))	('p38', 'Gene', (82, 85))	('increased', 'PosReg', (158, 167))
54087	27172796	Treatment with U0126, which largely decreased the level of phosphorylated ERK1/2, reduced MMP10 and MMP13 expression in KYSE450 and KYSE510 cells (Figure 6E).	('MMP13', 'Gene', '4322', (100, 105))	('KYSE510', 'CellLine', 'CVCL:1354', (132, 139))	('U0126', 'Var', (15, 20))	('ERK1/2', 'Protein', (74, 80))	('level of phosphorylated', 'MPA', (50, 73))	('U0126', 'Chemical', 'MESH:C113580', (15, 20))	('MMP10', 'Gene', (90, 95))	('reduced', 'NegReg', (82, 89))	('MMP10', 'Gene', '4319', (90, 95))	('MMP13', 'Gene', (100, 105))	('decreased', 'NegReg', (36, 45))
54088	27172796	In addition, U0126 attenuated the effect of AJUBA overexpression on the upregulation of MMP10 and MMP13.	('upregulation', 'PosReg', (72, 84))	('MMP10', 'Gene', '4319', (88, 93))	('MMP13', 'Gene', (98, 103))	('MMP13', 'Gene', '4322', (98, 103))	('U0126', 'Var', (13, 18))	('attenuated', 'NegReg', (19, 29))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))	('MMP10', 'Gene', (88, 93))
54094	27172796	In line with these clinical data, AJUBA knockdown effectively inhibited cell growth, colony formation, and tumor formation.	('cell growth', 'CPA', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('knockdown', 'Var', (40, 49))	('clinical', 'Species', '191496', (19, 27))	('inhibited', 'NegReg', (62, 71))	('colony formation', 'CPA', (85, 101))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
54095	27172796	Platinum-based chemotherapy is the first-line agent for patients with advanced ESCC, and apoptosis-related genes, such as TP53, are ubiquitously mutated in ESCC.	('patients', 'Species', '9606', (56, 64))	('Platinum', 'Chemical', 'MESH:D010984', (0, 8))	('TP53', 'Gene', (122, 126))	('mutated', 'Var', (145, 152))	('apoptosis-related genes', 'Gene', (89, 112))	('TP53', 'Gene', '7157', (122, 126))	('ESCC', 'Disease', (156, 160))
54102	27172796	MAPK/ERK1/2 pathways play critical roles in cell growth, apoptosis and metastasis, and several studies reported that MMP activities could be affected by the level of p-ERK1/2 in ESCC.	('MAPK', 'Gene', '5595;5594;5595', (0, 4))	('MMP activities', 'CPA', (117, 131))	('MAPK', 'Gene', (0, 4))	('p-ERK1/2', 'Var', (166, 174))	('affected', 'Reg', (141, 149))
54104	27172796	Recently, AJUBA mutations were found in many types of tumors.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('found', 'Reg', (31, 36))	('tumors', 'Disease', (54, 60))
54105	27172796	Truncations and subcellular localization can have distinct effects on the function of AJUBA and on the cellular activities of tumor cells.	('effects', 'Reg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Truncations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('function', 'MPA', (74, 82))	('tumor', 'Disease', (126, 131))
54112	27172796	The deletion of AJUBA decreased the resistance of ESCC cells to cisplatin, which could serve as a new strategy for ESCC treatment.	('resistance', 'MPA', (36, 46))	('AJUBA', 'Gene', (16, 21))	('deletion', 'Var', (4, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('decreased', 'NegReg', (22, 31))
54113	27172796	The esophageal cancer cell lines KYSE30, KYSE70, KYSE140, KYSE180, KYSE410, KYSE450 and KYSE510 were grown in RMPI 1640 medium (HyClone, Logan, UT, USA).	('KYSE410', 'Var', (67, 74))	('KYSE510', 'Var', (88, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('KYSE510', 'CellLine', 'CVCL:1354', (88, 95))	('KYSE180', 'CellLine', 'CVCL:1349', (58, 65))	('KYSE180', 'Var', (58, 65))	('KYSE450', 'Var', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal cancer', 'Disease', (4, 21))
54179	27050369	Of the 154 patients with TIMCs, CTLA-4 expression in TIMCs was scored as absent [0] in 23 patients (14.9%), focal in 42 patients (27.3%), mild in 53 patients (34.4%), moderate in 20 patients (13.0%) and severe in 16 patients (10.4%; Figure 1E-H).	('patients', 'Species', '9606', (149, 157))	('CTLA-4', 'Gene', (32, 38))	('absent', 'NegReg', (73, 79))	('patients', 'Species', '9606', (216, 224))	('TIMC', 'Chemical', '-', (53, 57))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (182, 190))	('mild', 'Var', (138, 142))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (90, 98))	('TIMC', 'Chemical', '-', (25, 29))
54185	27050369	Patients were divided into four subgroups according to their profiles of tumor cell CTLA-4 expression and CTLA-4+ TIMC density: Group 1 (CTLA-4high tumor cells, densityhigh CTLA-4+ TIMCs), Group 2 (CTLA-4high tumor cells, densitylowCTLA-4+ TIMCs), Group 3 (CTLA-4low tumor cells, densityhighCTLA-4+ TIMCs), and Group 4 (CTLA-4lowtumor cells, densitylowCTLA-4+ TIMCs).	('TIMC', 'Chemical', '-', (360, 364))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TIMC', 'Chemical', '-', (114, 118))	('tumor', 'Disease', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('TIMC', 'Chemical', '-', (181, 185))	('TIMC', 'Chemical', '-', (299, 303))	('tumor', 'Disease', (73, 78))	('CTLA-4high', 'Var', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('TIMC', 'Chemical', '-', (240, 244))
54207	27050369	Cellular and murine models have been used to demonstrate that CTLA-4 blockade augments endogenous responses to several tumor types, leading to tumor cell death when utilized alone or in combination other therapeutic interventions.	('CTLA-4', 'Gene', (62, 68))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (143, 148))	('augments', 'PosReg', (78, 86))	('murine', 'Species', '10090', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('blockade', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
54210	27050369	However, although aberrant CTLA-4 expression is strongly implicated in immune dysfunction in ESCC, it is likely that multiple other host factors also contribute.	('CTLA-4', 'Gene', (27, 33))	('immune dysfunction', 'Disease', 'MESH:D007154', (71, 89))	('implicated', 'Reg', (57, 67))	('aberrant', 'Var', (18, 26))	('immune dysfunction', 'Disease', (71, 89))	('ESCC', 'Disease', (93, 97))
54261	26594591	If the locations of the residual MAVs can be identified with the high FDG uptake subvolumes on the pre-therapy PET/CT scans, SIB to these subvolumes may improve clinical outcomes.	('FDG', 'Gene', (70, 73))	('clinical', 'MPA', (161, 169))	('FDG', 'Chemical', 'MESH:D019788', (70, 73))	('improve', 'PosReg', (153, 160))	('SIB', 'Var', (125, 128))
54278	26594591	Similarly, a total of seven MAVs pre-CRT and four MAVs post-CRT with high FDG uptakes were defined using thresholds of SUV 2.5 (original MAV), SUV 5.0, 34%, 40%, 50%, 60%, and 70% of the maximal SUV (SUVmax) pre-CRT, and SUV 2.5 (residual MAV), 70%, 80% and 90% of SUVmax post-CRT, respectively.	('SUV 2.5', 'Var', (221, 228))	('FDG', 'Chemical', 'MESH:D019788', (74, 77))	('SUV', 'Var', (143, 146))
54287	26594591	There were no statistically significant difference in the volume of the original MAVs (47.1 vs. 43.7 cm3), or pre-CRT SUVmax (10.7 vs. 7.8), or decrease in SUVmax (4.5 vs. 6.4) between patients (n=6) with local residual MAVs and patients (n=14) without local residual MAVs (Wilcoxon test, p=0.84, 0.18, and 0.49, respectively).	('patients', 'Species', '9606', (229, 237))	('MAVs', 'Var', (220, 224))	('decrease', 'NegReg', (144, 152))	('SUVmax', 'MPA', (156, 162))	('patients', 'Species', '9606', (185, 193))
54499	21847566	This finding is consistent with another study done to assess the risk factors for developing ESCC, in which they found that low income, moderate to heavy alcohol drinking and tobacco use is associated with almost all cases of ESCC in whites (98%) and blacks (99%).	('low income', 'Var', (124, 134))	('moderate to heavy alcohol drinking', 'Var', (136, 170))	('alcohol', 'Chemical', 'MESH:D000438', (154, 161))	('ESCC', 'Disease', (226, 230))	('alcohol drinking', 'Phenotype', 'HP:0030955', (154, 170))	('tobacco', 'Species', '4097', (175, 182))
54535	22076207	At the MD Anderson Cancer Center in the USA, the positive rate was 10.2% in cases of T1~T4b (n=381).	('Cancer', 'Disease', 'MESH:D009369', (19, 25))	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Cancer', 'Disease', (19, 25))	('T1~T4b', 'Var', (85, 91))
54598	20871187	Following a long-term debate, transhiatal esophagectomy has been found to be associated with fewer postoperative pulmonary complications and subsequently long-term benefit in patients with resectable esophageal cancer.	('benefit', 'PosReg', (164, 171))	('fewer', 'NegReg', (93, 98))	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (99, 136))	('pulmonary complications', 'Phenotype', 'HP:0006532', (113, 136))	('postoperative pulmonary complications', 'Disease', (99, 136))	('patients', 'Species', '9606', (175, 183))	('esophageal cancer', 'Disease', (200, 217))	('transhiatal', 'Var', (30, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
54696	33717744	Infrequently, sigmoid dolichomegaesopahagus can cause an acute airway obstruction from the regurgitation of food and present clinically as asthma, pneumonia, or a lung abscess requiring urgent treatment.	('regurgitation of food', 'MPA', (91, 112))	('pneumonia', 'Disease', (147, 156))	('lung abscess', 'Disease', (163, 175))	('pneumonia', 'Disease', 'MESH:D011014', (147, 156))	('airway obstruction', 'Disease', 'MESH:D000402', (63, 81))	('asthma', 'Disease', (139, 145))	('cause', 'Reg', (48, 53))	('asthma', 'Disease', 'MESH:D001249', (139, 145))	('sigmoid dolichomegaesopahagus', 'Var', (14, 43))	('airway obstruction', 'Phenotype', 'HP:0002781', (63, 81))	('lung abscess', 'Phenotype', 'HP:0025044', (163, 175))	('asthma', 'Phenotype', 'HP:0002099', (139, 145))	('abscess', 'Phenotype', 'HP:0025615', (168, 175))	('pneumonia', 'Phenotype', 'HP:0002090', (147, 156))	('airway obstruction', 'Disease', (63, 81))
54769	28188229	Mechanisms include RNAi pathways, nonsense mediated decay via up-frame shift 1 (UPF1), and antiviral proteins like apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) cytidine deaminase, Moloney leukemia virus 10 (MOV10), and zinc-finger antiviral protein (ZAP).	('up-frame shift 1', 'Gene', '5976', (62, 78))	('Moloney leukemia virus 10', 'Gene', (206, 231))	('UPF1', 'Gene', '5976', (80, 84))	('up-frame shift 1', 'Gene', (62, 78))	('cytidine deaminase', 'Gene', '978', (186, 204))	('apolipoprotein B', 'Protein', (115, 131))	('MOV10', 'Gene', '4343', (233, 238))	('zinc-finger antiviral protein', 'Gene', '56829', (245, 274))	('Moloney leukemia virus 10', 'Gene', '4343', (206, 231))	('leukemia', 'Phenotype', 'HP:0001909', (214, 222))	('zinc-finger antiviral protein', 'Gene', (245, 274))	('MOV10', 'Gene', (233, 238))	('ZAP', 'Gene', (276, 279))	('cytidine deaminase', 'Gene', (186, 204))	('RNAi pathways', 'Pathway', (19, 32))	('UPF1', 'Gene', (80, 84))	('nonsense mediated decay', 'Var', (34, 57))	('ZAP', 'Gene', '56829', (276, 279))
54770	28188229	It is important to note that while many tumor suppressor gene promoters are methylated in tumors, whole genome methylation and LINE-1 methylation specifically tend to be reduced in malignancies.	('malignancies', 'Disease', 'MESH:D009369', (181, 193))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('reduced', 'NegReg', (170, 177))	('tumors', 'Disease', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('malignancies', 'Disease', (181, 193))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('methylation', 'Var', (111, 122))
54772	28188229	In non-small cell lung cancer, LINE-1 promoter hypomethylation is common and is associated with genomic instability and poor prognosis.	('LINE-1', 'Gene', (31, 37))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('genomic', 'MPA', (96, 103))	('promoter hypomethylation', 'Var', (38, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('associated', 'Reg', (80, 90))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('non-small cell lung cancer', 'Disease', (3, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
54773	28188229	In colon cancer, LINE-1 hypomethylation appears to be an early event also associated with poor outcomes.	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('hypomethylation', 'Var', (24, 39))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('colon cancer', 'Disease', (3, 15))
54775	28188229	LINE-1 hypomethylation is more pronounced in colon cancer liver metastases compared to matched primary tumors.	('primary tumors', 'Disease', (95, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('hypomethylation', 'Var', (7, 22))	('primary tumors', 'Disease', 'MESH:D009369', (95, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('colon cancer liver metastases', 'Disease', 'MESH:D009362', (45, 74))	('colon cancer liver metastases', 'Disease', (45, 74))
54776	28188229	In breast cancer, LINE-1 hypomethylation has been reported in preneoplastic phases of epithelial atypia with persistently low LINE-1 promoter methylation seen in in situ and invasive lesions.	('LINE-1', 'Gene', (18, 24))	('hypomethylation', 'Var', (25, 40))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('preneoplastic phases of epithelial atypia', 'Disease', (62, 103))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('low', 'NegReg', (122, 125))	('promoter methylation', 'MPA', (133, 153))	('LINE-1', 'Gene', (126, 132))	('reported', 'Reg', (50, 58))
54778	28188229	In prostate cancers, LINE-1 hypomethylation is also reported, particularly in association with chromosome 8 abnormalities; it appears more pronounced in metastatic lesions than in primary tumors.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('metastatic', 'Disease', (153, 163))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('hypomethylation', 'Var', (28, 43))	('prostate cancers', 'Phenotype', 'HP:0012125', (3, 19))	('abnormalities', 'Var', (108, 121))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('pronounced', 'Reg', (139, 149))	('prostate cancers', 'Disease', (3, 19))	('primary tumors', 'Disease', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('primary tumors', 'Disease', 'MESH:D009369', (180, 194))	('prostate cancers', 'Disease', 'MESH:D011471', (3, 19))
54779	28188229	In hepatocellular carcinoma, several groups have associated LINE-1 hypomethylation with poor clinical outcomes, including disease recurrence after resection.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('LINE-1', 'Gene', (60, 66))	('hypomethylation', 'Var', (67, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
54780	28188229	In epithelial ovarian cancers, LINE-1 hypomethylation is correlated with more aggressive histology, poorer progression-free intervals, and poorer survival.	('LINE-1', 'Gene', (31, 37))	('hypomethylation', 'Var', (38, 53))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (3, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('poorer', 'NegReg', (100, 106))	('progression-free intervals', 'CPA', (107, 133))	('ovarian cancers', 'Phenotype', 'HP:0100615', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('epithelial ovarian cancers', 'Disease', (3, 29))
54781	28188229	Finally, in esophageal squamous cell carcinomas, LINE-1 hypomethylation is also recognized and associated with poorer survival.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (23, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('poorer', 'NegReg', (111, 117))	('hypomethylation', 'Var', (56, 71))	('esophageal squamous cell carcinomas', 'Disease', (12, 47))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (12, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))
54782	28188229	Evidence of aberrant LINE-1 hypomethylation is less frequently reported for hematolymphoid neoplasias.	('hypomethylation', 'Var', (28, 43))	('hematolymphoid neoplasias', 'Disease', (76, 101))	('aberrant', 'Var', (12, 20))	('neoplasias', 'Phenotype', 'HP:0002664', (91, 101))	('neoplasia', 'Phenotype', 'HP:0002664', (91, 100))	('hematolymphoid neoplasias', 'Disease', 'MESH:D009369', (76, 101))
54783	28188229	A meta-analysis of LINE-1 hypomethylation as a marker for cancer risk revealed that tissue-based DNA assays fairly consistently reveal LINE-1 hypomethylation in cancers compared to controls.	('cancer', 'Disease', (161, 167))	('LINE-1', 'Gene', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('reveal', 'Reg', (128, 134))	('cancers', 'Disease', (161, 168))	('hypomethylation', 'Var', (142, 157))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Disease', (58, 64))
54786	28188229	However, very recent work suggests that more personalized approaches are likely to yield new insight, and add nuance to the overly simplistic model that relating cancerous histopathology or poor outcomes with LINE-1 hypomethylation.	('person', 'Species', '9606', (45, 51))	('hypomethylation', 'Var', (216, 231))	('cancerous', 'Disease', 'MESH:D009369', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancerous', 'Disease', (162, 171))
54809	28188229	The group reported detecting LINE-1 ORF1p in embryonal carcinoma cells (Ntera2), teratocarcinoma cells (2102Ep), and choriocarcinoma cells (JEG-3).	('Ntera2', 'CellLine', 'CVCL:0034', (72, 78))	('choriocarcinoma', 'Disease', (117, 132))	('ORF1p', 'Gene', '55354', (36, 41))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (117, 132))	('embryonal carcinoma', 'Disease', (45, 64))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (45, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('ORF1p', 'Gene', (36, 41))	('teratocarcinoma', 'Disease', 'MESH:D018243', (81, 96))	('choriocarcinoma', 'Disease', 'MESH:D002822', (117, 132))	('teratocarcinoma', 'Disease', (81, 96))	('LINE-1', 'Var', (29, 35))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (45, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
54820	28188229	The group reported positivity in 99% of breast cancers, but as well, expression in a significant proportion of bladder cancers, prostate cancers, colorectal cancers, ileal carcinoids, and pancreatic neuroendocrine tumors.	('bladder cancers', 'Disease', (111, 126))	('prostate cancers', 'Disease', 'MESH:D011471', (128, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('ileal carcinoids', 'Disease', 'MESH:D007077', (166, 182))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('colorectal cancers', 'Disease', 'MESH:D015179', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (128, 143))	('ileal carcinoids', 'Disease', (166, 182))	('prostate cancers', 'Phenotype', 'HP:0012125', (128, 144))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('prostate cancers', 'Disease', (128, 144))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (188, 220))	('carcinoids', 'Phenotype', 'HP:0100570', (172, 182))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('bladder cancers', 'Phenotype', 'HP:0009725', (111, 126))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('colorectal cancers', 'Disease', (146, 164))	('breast cancers', 'Disease', 'MESH:D001943', (40, 54))	('pancreatic neuroendocrine tumors', 'Disease', (188, 220))	('breast cancers', 'Disease', (40, 54))	('positivity', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (199, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('bladder cancers', 'Disease', 'MESH:D001749', (111, 126))	('breast cancers', 'Phenotype', 'HP:0003002', (40, 54))
54822	28188229	Nuclear immunoreactivity was associated with increased incidence of local recurrence, distant metastases, and poorer overall survival.	('metastases', 'Disease', (94, 104))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('local recurrence', 'CPA', (68, 84))	('Nuclear immunoreactivity', 'Var', (0, 24))
54832	28188229	Genomic LINE-1 hypomethylation, increases in LINE-1 RNA transcription, and ORF1p accumulation seem to be features of malignant cells more so than adjacent normal tissues.	('ORF1p', 'Gene', '55354', (75, 80))	('ORF1p', 'Gene', (75, 80))	('LINE-1 RNA', 'Gene', (45, 55))	('hypomethylation', 'Var', (15, 30))	('increases', 'PosReg', (32, 41))	('RNA', 'Gene', (52, 55))	('accumulation', 'PosReg', (81, 93))
54837	28188229	Aberrant LINE-1 ORF1p expression is a hallmark of epithelial tumors more than, for example, hematolymphoid malignancies.	('hematolymphoid malignancies', 'Disease', (92, 119))	('ORF1p', 'Gene', '55354', (16, 21))	('Aberrant', 'Var', (0, 8))	('ORF1p', 'Gene', (16, 21))	('hematolymphoid malignancies', 'Disease', 'MESH:D009369', (92, 119))	('hallmark of epithelial tumors', 'Disease', (38, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('hallmark of epithelial tumors', 'Disease', 'MESH:D002277', (38, 67))	('expression', 'MPA', (22, 32))
54849	27737537	Definitive chemoradiotherapy (CRT) has been recommended as the optimal treatment for patients who are medically inoperable or have an unresectable tumor based on the results of the Radiation Therapy Oncology Group (RTOG) 85-01 trial, which showed a statistically significant survival benefit with CRT compared to radiotherapy (RT) alone (5-year overall survival [OS], 26% vs. 0%, respectively).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('CRT', 'Var', (297, 300))	('CR', 'Chemical', '-', (297, 299))	('patients', 'Species', '9606', (85, 93))	('Oncology', 'Phenotype', 'HP:0002664', (199, 207))	('CR', 'Chemical', '-', (30, 32))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('OS', 'Chemical', '-', (363, 365))
54909	27737537	The results of the current study suggest that patients who received a total dose >= 60 Gy of RT had significantly better LRC, PFS, and OS than patients receiving < 60 Gy when treated with concurrent chemotherapy.	('>= 60 Gy', 'Var', (81, 89))	('patients', 'Species', '9606', (46, 54))	('LRC', 'CPA', (121, 124))	('PFS', 'CPA', (126, 129))	('OS', 'Chemical', '-', (135, 137))	('patients', 'Species', '9606', (143, 151))	('better', 'PosReg', (114, 120))
54915	27737537	A total of 236 patients with locally advanced esophageal cancer were randomly selected to receive a combined therapy consisting of FP chemotherapy concurrently with high-dose (64.8 Gy) versus standard-dose (50.4 Gy) RT.	('patients', 'Species', '9606', (15, 23))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('64.8', 'Var', (176, 180))
54932	27737537	Radiation dose to the heart was recently reported to have adverse effects on survival, with mean heart dose noted in patients with breast cancer and with V5 and V30 noted in lung cancer patients in the RTOG 0617 trial.	('lung cancer', 'Disease', (174, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('heart', 'MPA', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('breast cancer', 'Disease', (131, 144))	('patients', 'Species', '9606', (117, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('V30', 'Var', (161, 164))	('patients', 'Species', '9606', (186, 194))
54946	26893678	The expression of EGFR was detected in the human EC1 or EC9706 esophageal squamous cell carcinoma cell line using immunohistochemistry.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('EC9706', 'Var', (56, 62))	('EGFR', 'Gene', '1956', (18, 22))	('EC1', 'Gene', '4819', (49, 52))	('EC1', 'Gene', (49, 52))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('EGFR', 'Gene', (18, 22))	('EC9706', 'CellLine', 'CVCL:E307', (56, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('detected', 'Reg', (27, 35))	('human', 'Species', '9606', (43, 48))
54967	26893678	Human EC1 and EC9706 esophageal squamous cell carcinoma cells were provided by the Cancer Retroviral Molecular Biology Laboratory, Xinxiang Medical University (Xinxiang, China).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (21, 55))	('EC9706', 'Var', (14, 20))	('Human', 'Species', '9606', (0, 5))	('EC1', 'Gene', '4819', (6, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('EC1', 'Gene', (6, 9))	('esophageal squamous cell carcinoma', 'Disease', (21, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', (83, 89))	('EC9706', 'CellLine', 'CVCL:E307', (14, 20))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))
54995	26893678	The number of EC9706-positive cells was 91.22+-4.65% (+++), indicating that EC9706 cells were highly expressed in EGFR (Figs.. 1 and 2).	('EGFR', 'Gene', '1956', (114, 118))	('EC9706', 'CellLine', 'CVCL:E307', (76, 82))	('EC9706', 'CellLine', 'CVCL:E307', (14, 20))	('EGFR', 'Gene', (114, 118))	('EC9706 cells', 'Var', (76, 88))
55007	26893678	The rate of apoptosis between single use of DDP, 5-FU or the combination with h-R3 group with the control group was statistically significant (P<0.05).	('DDP', 'Chemical', 'MESH:D002945', (44, 47))	('h-R3', 'Chemical', '-', (78, 82))	('5-FU', 'Chemical', 'MESH:D005472', (49, 53))	('DDP', 'Var', (44, 47))	('apoptosis', 'CPA', (12, 21))
55008	26893678	However, the EC9706 esophageal carcinoma cell apoptotic rate between the drug treatment and control groups was statistically different (P<0.05).	('EC9706', 'CellLine', 'CVCL:E307', (13, 19))	('esophageal carcinoma', 'Disease', (20, 40))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (20, 40))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (20, 40))	('EC9706', 'Var', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
55010	26893678	The apoptotic rate of DDP and 5-FU single use therapy or combination with the h-R3 compared to the control group showed a statistically significant difference (P<0.05).	('5-FU', 'Chemical', 'MESH:D005472', (30, 34))	('combination', 'Interaction', (57, 68))	('h-R3', 'Chemical', '-', (78, 82))	('apoptotic rate', 'CPA', (4, 18))	('DDP', 'Var', (22, 25))	('DDP', 'Chemical', 'MESH:D002945', (22, 25))
55011	26893678	The difference in the apoptotic rate of EC9706 esophageal cancer cells between the control and h-R3 groups was statistically significant (P<0.05).	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('EC9706', 'Var', (40, 46))	('h-R3', 'Chemical', '-', (95, 99))	('esophageal cancer', 'Disease', (47, 64))	('apoptotic rate', 'CPA', (22, 36))	('EC9706', 'CellLine', 'CVCL:E307', (40, 46))
55017	26893678	Through comparison of two types of human squamous cell carcinoma of esophagus, our in vitro experiment results show that the sensitization effect in EC9706 cells with a high expression of EGFR is better than that in EC1 cells with a low expression of EGFR.	('high', 'Var', (169, 173))	('EC1', 'Gene', (216, 219))	('EGFR', 'Gene', (251, 255))	('sensitization', 'MPA', (125, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('squamous cell carcinoma of esophagus', 'Disease', 'MESH:D002294', (41, 77))	('human', 'Species', '9606', (35, 40))	('better', 'PosReg', (196, 202))	('EC1', 'Gene', '4819', (216, 219))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (55, 77))	('EC9706', 'CellLine', 'CVCL:E307', (149, 155))	('EGFR', 'Gene', '1956', (188, 192))	('squamous cell carcinoma of esophagus', 'Disease', (41, 77))	('EGFR', 'Gene', (188, 192))	('EGFR', 'Gene', '1956', (251, 255))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
55024	26893678	Investigation of the EGFR monoclonal antibody demonstrated that C225 ligand can induce EGFR to migrate into the nucleus.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (87, 91))	('C225 ligand', 'Var', (64, 75))	('EGFR', 'Gene', (87, 91))	('migrate into the nucleus', 'CPA', (95, 119))
55025	26893678	Previous findings have confirmed that C225 is directly associated with chemotherapy resistance, which means nuclear EGFR is possibly associated with EGFR-targeted therapy effect.	('C225', 'Var', (38, 42))	('associated', 'Reg', (55, 65))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'Gene', (149, 153))	('chemotherapy resistance', 'Disease', (71, 94))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('associated', 'Reg', (133, 143))
55030	26893678	The effect of h-R3 on chemotherapy sensitization is positively associated with a high expression of EGFR.	('EGFR', 'Gene', '1956', (100, 104))	('high', 'Var', (81, 85))	('EGFR', 'Gene', (100, 104))	('h-R3', 'Protein', (14, 18))	('h-R3', 'Chemical', '-', (14, 18))	('chemotherapy sensitization', 'CPA', (22, 48))
55046	24281085	In the C-terminal half of human MK, two heparin-binding clusters, namely cluster I (K79, R81 and K102) and cluster II (K86, K87 and R89), have been identified.	('K86', 'Var', (119, 122))	('human', 'Species', '9606', (26, 31))	('heparin', 'Chemical', 'MESH:D006493', (40, 47))	('K87', 'Var', (124, 127))	('heparin-binding', 'MPA', (40, 55))	('R81', 'Var', (89, 92))	('K79', 'Var', (84, 87))	('R89', 'Var', (132, 135))	('K102', 'Var', (97, 101))
55082	24281085	Furthermore, angiogenic role of midkine has been shown by the observation that MK transfection into the breast carcinoma line, MCF-7, accelerated tumor growth, and increased tumor vascularity after implantation of the cells in nude mice.	('tumor', 'Disease', (174, 179))	('nude mice', 'Species', '10090', (227, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('transfection', 'Var', (82, 94))	('MCF-7', 'CellLine', 'CVCL:0031', (127, 132))	('accelerated', 'PosReg', (134, 145))	('tumor', 'Disease', (146, 151))	('breast carcinoma', 'Disease', 'MESH:D001943', (104, 120))	('breast carcinoma', 'Disease', (104, 120))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('MK transfection', 'Var', (79, 94))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('breast carcinoma', 'Phenotype', 'HP:0003002', (104, 120))	('increased', 'PosReg', (164, 173))
55095	24281085	Many prognostic studies have identified several tumor markers associated with overall or disease-free survival, including MYCN copy number, tyrosine kinase A (TrkA) expression level, ploidy, and deletion or loss of heterozygosity of chromosome 1p and gain of chromosome 17q.	('MYCN', 'Gene', (122, 126))	('tyrosine kinase A', 'Gene', (140, 157))	('TrkA', 'Gene', (159, 163))	('MYCN', 'Gene', '4613', (122, 126))	('TrkA', 'Gene', '4914', (159, 163))	('tumor', 'Disease', (48, 53))	('loss', 'NegReg', (207, 211))	('deletion', 'Var', (195, 203))	('ploidy', 'Var', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('expression level', 'MPA', (165, 181))	('tyrosine kinase A', 'Gene', '4914', (140, 157))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('gain', 'PosReg', (251, 255))
55140	24281085	In addition, cancer detection rates based on MK levels were higher than those based on three conventional markers including CEA, carbohydrate antigen 15-3 (CA15-3), and Nation Cancer Center-Stomach-439 (NCC-ST-439).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('higher', 'PosReg', (60, 66))	('carbohydrate antigen 15-3 (CA15-3', 'Gene', '4582', (129, 162))	('cancer', 'Disease', (13, 19))	('Cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('CEA', 'Gene', '1048', (124, 127))	('MK levels', 'Var', (45, 54))	('Cancer', 'Disease', 'MESH:D009369', (176, 182))	('CEA', 'Gene', (124, 127))
55155	24281085	Indeed, antisense MK oligodeoxyribonucleotides show anti-tumor activity for neurofibroma derived-cells and mouse rectal carcinoma cells.	('rectal carcinoma', 'Disease', (113, 129))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (113, 129))	('mouse', 'Species', '10090', (107, 112))	('neurofibroma', 'Phenotype', 'HP:0001067', (76, 88))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('neurofibroma', 'Disease', (76, 88))	('neurofibroma', 'Disease', 'MESH:D009455', (76, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('rectal carcinoma', 'Disease', 'MESH:D012004', (113, 129))	('antisense MK', 'Var', (8, 20))
55216	20934723	Within Het-1A cells, inhibition of PKC was shown to block bile salt-induced increases in surface expression of CD95 (Figure 3a).	('bile salt-induced', 'MPA', (58, 75))	('PKC', 'Gene', (35, 38))	('block', 'NegReg', (52, 57))	('PKC', 'Gene', '112476', (35, 38))	('increases', 'PosReg', (76, 85))	('inhibition', 'Var', (21, 31))	('bile salt', 'Chemical', 'MESH:D001647', (58, 67))	('surface expression', 'MPA', (89, 107))
55252	33757572	Silencing ATAD2 significantly suppressed ESCC cell migration and invasion in vitro, and inhibited tumor growth and lung metastasis in vivo.	('ATAD2', 'Gene', (10, 15))	('inhibited', 'NegReg', (88, 97))	('tumor', 'Disease', (98, 103))	('suppressed', 'NegReg', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('ESCC', 'Disease', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('invasion', 'CPA', (65, 73))	('Silencing', 'Var', (0, 9))
55271	33757572	Subsequently, ATAD2 was found overexpressed in various cancer types such as prostate cancer, hepatocellular carcinoma, lung cancer, breast cancer, gastric cancer and ovarian cancer and high expression of ATAD2 was approved as an indicator of poor prognosis and had a critical part in cell proliferation, apoptosis, invasion and migration.	('lung cancer', 'Disease', (119, 130))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (93, 117))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (93, 117))	('cancer', 'Disease', (174, 180))	('high expression', 'Var', (185, 200))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('ovarian cancer', 'Disease', 'MESH:D010051', (166, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('cancer', 'Disease', (55, 61))	('apoptosis', 'CPA', (304, 313))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('hepatocellular carcinoma', 'Disease', (93, 117))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (85, 91))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('gastric cancer', 'Disease', (147, 161))	('migration', 'CPA', (328, 337))	('breast cancer', 'Disease', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', (139, 145))	('ovarian cancer', 'Disease', (166, 180))	('cell proliferation', 'CPA', (284, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('ATAD2', 'Gene', (14, 19))	('cancer', 'Disease', (124, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('ATAD2', 'Gene', (204, 209))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('prostate cancer', 'Disease', (76, 91))	('overexpressed', 'PosReg', (30, 43))
55280	33757572	ESCC cell lines TE-1 and EC109 were purchased from the CellBank of the Chinese Academy of Sciences (Shanghai), KYSE140, KYSE510, EC9706, KYSE30 and KYSE180 were generously provided by Professor Guan from SYSUCC.	('EC9706', 'CellLine', 'CVCL:E307', (129, 135))	('EC109', 'CellLine', 'CVCL:6898', (25, 30))	('KYSE510', 'Var', (120, 127))	('KYSE30', 'Var', (137, 143))	('EC9706', 'Var', (129, 135))	('KYSE140', 'Var', (111, 118))
55281	33757572	All of the cell lines were cultured in RPMI-1640 media with 10% fetal bovine serum (FBS, GIBCO) and maintained in a humidified incubator under 5% CO2 at 37  C. Antibodies used in this study are listed as follows: anti-ATAD2 (#ab176319, Abcam), anti-TGF-beta1 (#sc-130348, Santa Cruz Biotechnology), anti-Smad2/3 (#8685, Cell Signaling Technology), anti-Smad4 (#46535, Cell Signaling Technology), anti-Phospho-Smad2 (Ser465/467)/Smad3 (Ser423/425) (#8828, Cell Signaling Technology), anti-Phospho-Smad2(Ser465/467) (#18338, Cell Signaling Technology), anti-Phospho-Smad3(Ser465/467) (#ab52903, Abcam), anti-Snail (#3879, Cell Signaling Technology), anti-E-Cadherin (#3195, Cell Signaling Technology), anti-N-Cadherin (#13116, Cell Signaling Technology), anti-Vimentin (#5761, Cell Signaling Technology), anti-beta-actin (#64132, Bioworld), anti-Lamin B1 (#66095-1-Ig, Proteintech), anti-C/EBPbeta (#sc-7962, Santa Cruz Biotechnology), anti-C/EBPbeta (#3087, Cell Signaling Technology).	('E-Cadherin', 'Gene', '999', (653, 663))	('Smad4', 'Gene', '4089', (353, 358))	('beta-actin', 'Gene', (808, 818))	('Smad2', 'Gene', (496, 501))	('Smad2', 'Gene', (304, 309))	('Smad2/3', 'Gene', (304, 311))	('Smad3', 'Gene', '4088', (564, 569))	('TGF-beta1', 'Gene', '7040', (249, 258))	('Snail', 'Gene', (606, 611))	('Smad3', 'Gene', '4088', (428, 433))	('Smad3', 'Gene', (564, 569))	('#66095-1-Ig', 'Var', (854, 865))	('C/EBPbeta', 'Gene', '1050', (886, 895))	('Smad3', 'Gene', (428, 433))	('C/EBPbeta', 'Gene', '1050', (939, 948))	('Smad2/3', 'Gene', '4087;4088', (304, 311))	('Lamin B1', 'Gene', (844, 852))	('E-Cadherin', 'Gene', (653, 663))	('Vimentin', 'Gene', '7431', (758, 766))	('Smad4', 'Gene', (353, 358))	('beta-actin', 'Gene', '728378', (808, 818))	('Lamin B1', 'Gene', '4001', (844, 852))	('Smad2', 'Gene', '4087', (409, 414))	('Vimentin', 'Gene', (758, 766))	('N-Cadherin', 'Gene', (705, 715))	('Snail', 'Gene', '6615', (606, 611))	('N-Cadherin', 'Gene', '1000', (705, 715))	('Smad2', 'Gene', '4087', (496, 501))	('Smad2', 'Gene', '4087', (304, 309))	('C/EBPbeta', 'Gene', (886, 895))	('#sc-7962', 'Var', (897, 905))	('TGF-beta1', 'Gene', (249, 258))	('Smad2', 'Gene', (409, 414))	('C/EBPbeta', 'Gene', (939, 948))	('CO2', 'Chemical', 'MESH:D002245', (146, 149))	('RPMI-1640 media', 'Chemical', '-', (39, 54))
55282	33757572	The small-molecule TGF-beta1 receptor inhibitors LY2157299 and SB525334 were purchased from Selleck Biochemicals.	('SB525334', 'Chemical', 'MESH:C521813', (63, 71))	('TGF-beta1', 'Gene', '7040', (19, 28))	('TGF-beta1', 'Gene', (19, 28))	('LY2157299', 'Chemical', 'MESH:C557799', (49, 58))	('LY2157299', 'Var', (49, 58))
55307	33757572	After 16 h (KYSE30) or 36 h (KYSE510) of migration and 24 h (KYSE30) or 48 h (KYSE510) of invasion, cells remained on the upper surface of the chamber were cleaned, whereas the migrated or invaded cells were fixed in 4% paraformaldehyde and stained with crystal violet.	('KYSE510', 'Var', (78, 85))	('migration', 'CPA', (41, 50))	('KYSE30', 'Var', (61, 67))	('crystal violet', 'Chemical', 'MESH:D005840', (254, 268))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (220, 236))	('KYSE30', 'Var', (12, 18))	('KYSE510', 'Var', (29, 36))	('invasion', 'CPA', (90, 98))
55321	33757572	Univariate Cox regression analysis showed that high expression of ATAD2 (hazard ratio [HR] 1.63, P = 0.015) along with advanced clinical stage and poor histological differentiation were significantly related to poor overall survival in ESCC patients (Table S2).	('related', 'Reg', (200, 207))	('poor', 'NegReg', (211, 215))	('ATAD2', 'Gene', (66, 71))	('high', 'Var', (47, 51))	('ESCC', 'Disease', (236, 240))	('overall survival', 'MPA', (216, 232))	('patients', 'Species', '9606', (241, 249))
55326	33757572	Consistent with in vitro assays, tumor growth was significantly decreased in ATAD2 knockdown group compared with control group (P < 0.01), and the group with ectopic expression of ATAD2 grew larger tumors compared with the ATAD2 knockdown group (P < 0.05) (Fig.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('ATAD2', 'Gene', (180, 185))	('larger', 'PosReg', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('ectopic expression', 'Var', (158, 176))	('tumor', 'Disease', (33, 38))	('tumors', 'Disease', (198, 204))	('tumor', 'Disease', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('ATAD2', 'Gene', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('knockdown', 'Var', (83, 92))	('decreased', 'NegReg', (64, 73))
55329	33757572	The lung metastatic nodules were significantly decreased in mice injected with ATAD2 knockdown cells compared with the control group (P < 0.05) and mice injected with ATAD2 restored cells grew significantly more lung metastatic nodules than the ATAD2 knockdown group (P < 0.05) (Fig.	('mice', 'Species', '10090', (60, 64))	('lung metastatic nodules', 'CPA', (212, 235))	('lung metastatic nodules', 'CPA', (4, 27))	('mice', 'Species', '10090', (148, 152))	('knockdown', 'Var', (85, 94))	('more', 'PosReg', (207, 211))	('decreased', 'NegReg', (47, 56))
55330	33757572	To elucidate the molecular mechanism of ATAD2 in promoting tumor metastasis in ESCC, we performed RNA sequencing on KYSE510 cells infected with two validated shRNAs targeting ATAD2 and a control shRNA.	('infected', 'Disease', 'MESH:D007239', (130, 138))	('tumor metastasis', 'Disease', 'MESH:D009362', (59, 75))	('promoting', 'PosReg', (49, 58))	('infected', 'Disease', (130, 138))	('targeting', 'Var', (165, 174))	('tumor metastasis', 'Disease', (59, 75))	('ESCC', 'Disease', (79, 83))	('ATAD2', 'Gene', (40, 45))	('ATAD2', 'Gene', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
55337	33757572	5A and B, ectopic expression of ATAD2 significantly promoted KYSE510 and KYSE30 cells migration and invasion, whereas they were significantly inhibited after TGF-beta1 receptor blocking, inferring that the pro- metastatic effect of ATAD2 is at least in part depending on TGF-beta signaling in ESCC.	('TGF-beta1', 'Gene', '7040', (158, 167))	('TGF-beta1', 'Gene', (158, 167))	('ATAD2', 'Gene', (32, 37))	('inhibited', 'NegReg', (142, 151))	('ectopic expression', 'Var', (10, 28))	('promoted', 'PosReg', (52, 60))
55338	33757572	Meanwhile, after knocking down of ATAD2 expression, western blot analysis showed a significantly upregulation of epithelial marker E-cadherin as well as down-regulation of mesenchymal markers (Snail, Vimentin and N-cadherin) both in KYSE510 and KYSE30 cells (Fig.	('Snail', 'Gene', '6615', (193, 198))	('Snail', 'Gene', (193, 198))	('upregulation', 'PosReg', (97, 109))	('ATAD2', 'Gene', (34, 39))	('E-cadherin', 'Gene', '999', (131, 141))	('down-regulation', 'NegReg', (153, 168))	('N-cadherin', 'Gene', (213, 223))	('Vimentin', 'Gene', (200, 208))	('N-cadherin', 'Gene', '1000', (213, 223))	('Vimentin', 'Gene', '7431', (200, 208))	('mesenchymal', 'CPA', (172, 183))	('epithelial', 'CPA', (113, 123))	('E-cadherin', 'Gene', (131, 141))	('knocking down', 'Var', (17, 30))
55342	33757572	The results demonstrated that in addition to TGF-beta1, only p-Smad3 was downregulated in ATAD2 knockdown cells and upregulated when ATAD2 expression was restored (Fig.	('knockdown', 'Var', (96, 105))	('Smad3', 'Gene', '4088', (63, 68))	('TGF-beta1', 'Gene', '7040', (45, 54))	('TGF-beta1', 'Gene', (45, 54))	('ATAD2', 'Gene', (90, 95))	('upregulated', 'PosReg', (116, 127))	('Smad3', 'Gene', (63, 68))	('downregulated', 'NegReg', (73, 86))	('expression', 'MPA', (139, 149))
55347	33757572	Intriguingly, decreased activation of Smad3 induced by ATAD2 knockdown did not affect the nuclear translocation of Smad4 (Fig.	('Smad3', 'Gene', '4088', (38, 43))	('Smad4', 'Gene', (115, 120))	('Smad4', 'Gene', '4089', (115, 120))	('activation', 'MPA', (24, 34))	('ATAD2', 'Gene', (55, 60))	('nuclear', 'MPA', (90, 97))	('knockdown', 'Var', (61, 70))	('Smad3', 'Gene', (38, 43))
55351	33757572	PCR analysis demonstrated a significantly downregulation of TGF-beta1 mRNA expression in ATAD2 knockdown KYSE510 and KYSE30 cells (Fig.	('ATAD2', 'Gene', (89, 94))	('knockdown', 'Var', (95, 104))	('downregulation', 'NegReg', (42, 56))	('mRNA expression', 'MPA', (70, 85))	('TGF-beta1', 'Gene', '7040', (60, 69))	('TGF-beta1', 'Gene', (60, 69))
55362	33757572	Since neither whole C/EBPbeta mRNA nor protein expression was altered in ATAD2 knockdown KYSE510 and KYSE30 cells (Figure S1E, F), we separated proteins in nuclear and cytoplasm to detect the nuclear translocation alteration of C/EBPbeta.	('C/EBPbeta', 'Gene', (20, 29))	('C/EBPbeta', 'Gene', '1050', (228, 237))	('ATAD2', 'Gene', (73, 78))	('knockdown', 'Var', (79, 88))	('C/EBPbeta', 'Gene', (228, 237))	('C/EBPbeta', 'Gene', '1050', (20, 29))
55374	33757572	In this regard, we examined the association between ATAD2 expression and patients outcome and discovered that high level of ATAD2 was significantly correlated with poor overall survival of ESCC patients especially those with advanced stage.	('overall survival', 'MPA', (169, 185))	('patients', 'Species', '9606', (194, 202))	('high level', 'Var', (110, 120))	('ATAD2', 'Gene', (124, 129))	('ESCC', 'Disease', (189, 193))	('poor', 'NegReg', (164, 168))	('patients', 'Species', '9606', (73, 81))
55375	33757572	Further multivariate Cox regression model showed that high expression of ATAD2 was an independent prognostic marker for advanced ESCC patients, which suggested that ATAD2 may be used as a hopeful therapeutic target.	('ATAD2', 'Gene', (73, 78))	('patients', 'Species', '9606', (134, 142))	('high', 'Var', (54, 58))
55397	33375021	Co-Occurrence of Hotspot Point Mutation and Novel Deletion Mutation of TERT Promoter in Solid Variant Papillary Thyroid Carcinoma in a Patient with Synchronous Esophageal Cancer (1) Introduction: Telomerase reverse transcriptase (TERT) promoter mutations are associated with unfavorable clinical outcomes in papillary thyroid carcinomas (PTCs).	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (318, 336))	('TERT', 'Gene', (71, 75))	('Cancer', 'Disease', (171, 177))	('TERT', 'Gene', '7015', (71, 75))	('Patient', 'Species', '9606', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('carcinomas', 'Phenotype', 'HP:0030731', (326, 336))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (308, 336))	('mutations', 'Var', (245, 254))	('Papillary Thyroid Carcinoma', 'Disease', 'MESH:D000077273', (102, 129))	('Cancer', 'Disease', 'MESH:D009369', (171, 177))	('Telomerase reverse transcriptase', 'Gene', '7015', (196, 228))	('Deletion Mutation', 'Var', (50, 67))	('associated', 'Reg', (259, 269))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (308, 335))	('Telomerase reverse transcriptase', 'Gene', (196, 228))	('Thyroid Carcinoma', 'Phenotype', 'HP:0002890', (112, 129))	('PTCs', 'Phenotype', 'HP:0002895', (338, 342))	('PTC', 'Phenotype', 'HP:0002895', (338, 341))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Papillary Thyroid Carcinoma', 'Disease', (102, 129))	('TERT', 'Gene', (230, 234))	('TERT', 'Gene', '7015', (230, 234))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (318, 335))	('papillary thyroid carcinomas', 'Disease', (308, 336))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (308, 336))	('Papillary Thyroid Carcinoma', 'Phenotype', 'HP:0002895', (102, 129))
55398	33375021	Two substitution mutations, C228T (c.1-124C>T) and C250T (c.1-146C>T), make up most of the mutations and occur in a mutually exclusive manner.	('c.1-146C>T', 'SUBSTITUTION', 'None', (58, 68))	('C250T', 'SUBSTITUTION', 'None', (51, 56))	('c.1-124C>T', 'SUBSTITUTION', 'None', (35, 45))	('c.1-124C>T', 'Var', (35, 45))	('c.1-146C>T', 'Var', (58, 68))	('C250T', 'Var', (51, 56))	('C228T', 'SUBSTITUTION', 'None', (28, 33))	('C228T', 'Var', (28, 33))
55401	33375021	Sanger sequencing using DNA from the thyroid tumor showed an indel mutation, c.1-132_1-124delinsT, composed of a deletion (c.1-132_1-125del) as well as a hotspot mutation (c.1-124C>T(C228T)) in the TERT promoter.	('c.1-124C>T', 'SUBSTITUTION', 'None', (172, 182))	('C228T', 'SUBSTITUTION', 'None', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('c.1-132_1-125del', 'Var', (123, 139))	('TERT', 'Gene', '7015', (198, 202))	('c.1-132_1-124delinsT', 'DELETION_INSERTION', 'None', (77, 97))	('c.1-124C>T', 'Var', (172, 182))	('C228T', 'Var', (183, 188))	('thyroid tumor', 'Disease', (37, 50))	('thyroid tumor', 'Phenotype', 'HP:0100031', (37, 50))	('c.1-132_1-125del', 'DELETION', 'None', (123, 139))	('thyroid tumor', 'Disease', 'MESH:D013964', (37, 50))	('TERT', 'Gene', (198, 202))
55402	33375021	(3) Conclusions: This is the first report of PTC harboring a novel deletion along with a hotspot mutation in the TERT promoter in a patient with synchronous esophageal squamous cell carcinoma.	('TERT', 'Gene', '7015', (113, 117))	('deletion', 'Var', (67, 75))	('synchronous esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (145, 191))	('synchronous esophageal squamous cell carcinoma', 'Disease', (145, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('patient', 'Species', '9606', (132, 139))	('PTC', 'Phenotype', 'HP:0002895', (45, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))	('TERT', 'Gene', (113, 117))
55405	33375021	In an effort to finding a biomarker that indicates aggressive biological behavior of the tumor, telomerase reverse transcriptase (TERT) promoter mutations have been suggested as a useful prognostic indicator of clinical aggressiveness and poor outcome in differentiated thyroid carcinomas.	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (51, 81))	('telomerase reverse transcriptase', 'Gene', (96, 128))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (270, 288))	('TERT', 'Gene', (130, 134))	('aggressiveness', 'Disease', 'MESH:D001523', (220, 234))	('thyroid carcinomas', 'Disease', (270, 288))	('mutations', 'Var', (145, 154))	('TERT', 'Gene', '7015', (130, 134))	('telomerase reverse transcriptase', 'Gene', '7015', (96, 128))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (270, 288))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('aggressiveness', 'Disease', (220, 234))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (270, 287))	('aggressiveness', 'Phenotype', 'HP:0000718', (220, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('tumor', 'Disease', (89, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (278, 288))
55408	33375021	Two of the most recurrent non-coding mutations, C228T (c.1-124G>A) and C250T (c.1-146G>A), create a de novo binding site (GGAA) for the E26 transformation-specific (ETS) family of transcription factors, specifically the multimeric GA-binding protein (GABP) in the TERT promoter.	('C228T', 'Var', (48, 53))	('c.1-146G>A', 'Var', (78, 88))	('binding', 'Interaction', (108, 115))	('C250T', 'SUBSTITUTION', 'None', (71, 76))	('c.1-124G>A', 'Var', (55, 65))	('TERT', 'Gene', (264, 268))	('TERT', 'Gene', '7015', (264, 268))	('C228T', 'SUBSTITUTION', 'None', (48, 53))	('c.1-124G>A', 'SUBSTITUTION', 'None', (55, 65))	('C250T', 'Var', (71, 76))	('c.1-146G>A', 'SUBSTITUTION', 'None', (78, 88))
55410	33375021	Among three major variants of PTC, the tall cell variant shows highest prevalence of TERT promoter mutation, followed by conventional and follicular variants.	('PTC', 'Phenotype', 'HP:0002895', (30, 33))	('TERT', 'Gene', (85, 89))	('TERT', 'Gene', '7015', (85, 89))	('mutation', 'Var', (99, 107))
55413	33375021	Here, we first report the co-occurrence of a novel deletion and hotspot mutation in the TERT promoter in solid variant PTC found in a patient with synchronous primary esophageal cancer.	('hotspot', 'PosReg', (64, 71))	('synchronous primary esophageal cancer', 'Disease', 'MESH:D004938', (147, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('TERT', 'Gene', '7015', (88, 92))	('PTC', 'Phenotype', 'HP:0002895', (119, 122))	('mutation', 'Var', (72, 80))	('synchronous primary esophageal cancer', 'Disease', (147, 184))	('deletion', 'Var', (51, 59))	('patient', 'Species', '9606', (134, 141))	('TERT', 'Gene', (88, 92))
55433	33375021	We carried out Sanger sequencing to identify TERT promoter mutations using a set of primers 5'-AGTGGATTCGCGGGCACAGA-3' (forward) and 5'-AGCACCTCGCGGTAGTGG-3' (reverse).	('TERT', 'Gene', (45, 49))	('TERT', 'Gene', '7015', (45, 49))	('mutations', 'Var', (59, 68))
55434	33375021	The analysis revealed a novel indel mutation, c.1-132_1-124delinsT, composed of a deletion (c.1-132_c.1-125) along with the well-known substitution mutation (c.1-124(G>A)(C228T)) (Figure 3).	('c.1-124', 'Var', (158, 165))	('C228T', 'SUBSTITUTION', 'None', (171, 176))	('c.1-132_c.1-125', 'Var', (92, 107))	('C228T', 'Var', (171, 176))	('c.1-132_1-124delinsT', 'DELETION_INSERTION', 'None', (46, 66))
55436	33375021	TERT promoter mutations are identified in various types of cancers with different frequencies.	('identified', 'Reg', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('mutations', 'Var', (14, 23))
55438	33375021	As a result of its rarity, the frequency of TERT promoter mutations in SVPTC has not been well known, and only a few studies compared the genetic alterations among subvariants of PTC including SVPTC.	('mutations', 'Var', (58, 67))	('PTC', 'Phenotype', 'HP:0002895', (73, 76))	('TERT', 'Gene', (44, 48))	('TERT', 'Gene', '7015', (44, 48))	('PTC', 'Phenotype', 'HP:0002895', (195, 198))	('PTC', 'Phenotype', 'HP:0002895', (179, 182))
55443	33375021	Two mutations of the TERT core promoter, which cause a cytidine-to-thymidine (CT) dipyrimidine transition at chromosome 5 1,295,228 and 1,295,250 (-124 and -146bp from the ATG), c.1-124C>T(C228T) and c.1-146C>T(C250T), respectively, predominantly occur regardless of tumor type.	('c.1-146C>T', 'Var', (200, 210))	('c.1-124C>T', 'Var', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('TERT', 'Gene', (21, 25))	('c.1-146C>T', 'SUBSTITUTION', 'None', (200, 210))	('cytidine-to-thymidine', 'MPA', (55, 76))	('cytidine', 'Chemical', 'MESH:D003562', (55, 63))	('TERT', 'Gene', '7015', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('C250T', 'SUBSTITUTION', 'None', (211, 216))	('C228T', 'SUBSTITUTION', 'None', (189, 194))	('tumor', 'Disease', (267, 272))	('thymidine', 'Chemical', 'MESH:D013936', (67, 76))	('c.1-124C>T', 'SUBSTITUTION', 'None', (178, 188))	('dipyrimidine', 'Chemical', '-', (82, 94))	('C228T', 'Var', (189, 194))	('C250T', 'Var', (211, 216))
55444	33375021	The C228T mutation is more prevalent than C250T among various malignancies including thyroid cancer.	('C250T', 'SUBSTITUTION', 'None', (42, 47))	('malignancies', 'Disease', (62, 74))	('C250T', 'Var', (42, 47))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('C228T', 'SUBSTITUTION', 'None', (4, 9))	('thyroid cancer', 'Phenotype', 'HP:0002890', (85, 99))	('thyroid cancer', 'Disease', (85, 99))	('C228T', 'Var', (4, 9))	('prevalent', 'Reg', (27, 36))	('thyroid cancer', 'Disease', 'MESH:D013964', (85, 99))
55445	33375021	Multiple studies provide evidence that the presence of C228T or C250T mutations promotes telomerase activity both in vivo and in vitro.	('C250T', 'Var', (64, 69))	('C228T', 'Var', (55, 60))	('C250T', 'SUBSTITUTION', 'None', (64, 69))	('telomerase', 'Enzyme', (89, 99))	('C228T', 'SUBSTITUTION', 'None', (55, 60))	('promotes', 'PosReg', (80, 88))
55446	33375021	These mutations generate a de novo binding site for activating the ETS family of transcription factors, including GA-binding proteins (GABP), thereby activating TERT transcription and telomerase activity.	('telomerase', 'CPA', (184, 194))	('activating', 'PosReg', (150, 160))	('ETS', 'Gene', (67, 70))	('TERT', 'Gene', (161, 165))	('activating', 'PosReg', (52, 62))	('TERT', 'Gene', '7015', (161, 165))	('mutations', 'Var', (6, 15))
55447	33375021	Although not a promoter lesion, one previous study reviewing 173 Hurthle cell carcinomas of thyroid cases found a 24 bp deletion in the 5' UTR of exon 1 (c.-53_-29delAGCGCTGCGTCCTGCTGCGCACGT) of TERT in one sample.	('c.-53_-29delAGCGCTGCGTCCTGCTGCGCACGT', 'DELETION', 'None', (154, 190))	('TERT', 'Gene', (195, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Hurthle cell carcinomas of thyroid', 'Phenotype', 'HP:0006781', (65, 99))	('TERT', 'Gene', '7015', (195, 199))	('carcinomas of thyroid', 'Disease', (78, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('c.-53_-29delAGCGCTGCGTCCTGCTGCGCACGT', 'Var', (154, 190))	('carcinomas of thyroid', 'Disease', 'MESH:D013964', (78, 99))
55448	33375021	A recent study identified two additional novel mutations in the thyroid tumor: c.-332C>T in one medullary thyroid carcinoma and c.-104_-83dup in one PTC.	('thyroid tumor', 'Phenotype', 'HP:0100031', (64, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('c.-104_-83dup', 'Var', (128, 141))	('c.-332C>T', 'Var', (79, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('PTC', 'Phenotype', 'HP:0002895', (149, 152))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (106, 123))	('c.-332C>T', 'SUBSTITUTION', 'None', (79, 88))	('thyroid tumor', 'Disease', (64, 77))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (106, 123))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (96, 123))	('thyroid tumor', 'Disease', 'MESH:D013964', (64, 77))	('c.-104_-83dup', 'DUPLICATION', 'None', (128, 141))	('thyroid carcinoma', 'Disease', (106, 123))
55450	33375021	Instead, the mutation deletes the Specificity Protein 1 (SP1) binding site (Figure 4).	('mutation', 'Var', (13, 21))	('Specificity Protein 1', 'Gene', '6667', (34, 55))	('Specificity Protein 1', 'Gene', (34, 55))	('deletes', 'NegReg', (22, 29))
55453	33375021	In a previous study, the authors observed that hotspot mutant promoter activity fluctuated depending on the distance from the native ETS sites, and there was peak activity when two locations were separated by full helical turns of DNA, suggesting that TERT promoter mutation cooperates with native ETSs to recruit GABP.	('TERT', 'Gene', (252, 256))	('TERT', 'Gene', '7015', (252, 256))	('mutant', 'Var', (55, 61))	('mutation', 'Var', (266, 274))	('promoter activity', 'MPA', (62, 79))
55454	33375021	In order to confirm the overall effects of deletion and point mutation of the TERT gene promoter, further studies should be performed through luciferase reporter assay.	('deletion', 'Var', (43, 51))	('point mutation', 'Var', (56, 70))	('TERT', 'Gene', '7015', (78, 82))	('TERT', 'Gene', (78, 82))
55455	33375021	The co-occurrence of different substitution mutations of the TERT promoter has previously been reported.	('substitution', 'Var', (31, 43))	('TERT', 'Gene', '7015', (61, 65))	('TERT', 'Gene', (61, 65))
55456	33375021	One previous PTC cohort study reported that mutations C229T (c.-125C>T) and C232T (c.-128C>T) were simultaneously found in one PTC sample.	('found', 'Reg', (114, 119))	('c.-128C>T', 'SUBSTITUTION', 'None', (83, 92))	('c.-128C>T', 'Var', (83, 92))	('C229T', 'SUBSTITUTION', 'None', (54, 59))	('c.-125C>T', 'SUBSTITUTION', 'None', (61, 70))	('C229T', 'Var', (54, 59))	('C232T', 'SUBSTITUTION', 'None', (76, 81))	('PTC', 'Phenotype', 'HP:0002895', (13, 16))	('c.-125C>T', 'Var', (61, 70))	('PTC', 'Phenotype', 'HP:0002895', (127, 130))	('C232T', 'Var', (76, 81))
55458	33375021	The rs2853669 common allele, a common T>C polymorphism at the -245 bp position from the ATG site, disrupts the pre-existing non-canonical ETS2 binding site in the proximal region of the TERT promoter, reducing the transcriptional activity of TERT.	('TERT', 'Gene', (242, 246))	('binding', 'Interaction', (143, 150))	('disrupts', 'NegReg', (98, 106))	('ETS2', 'Gene', (138, 142))	('rs2853669', 'Var', (4, 13))	('TERT', 'Gene', '7015', (242, 246))	('ETS2', 'Gene', '2114', (138, 142))	('reducing', 'NegReg', (201, 209))	('rs2853669', 'DBSNP_MENTION', 'None', (4, 13))	('TERT', 'Gene', (186, 190))	('transcriptional activity', 'MPA', (214, 238))	('TERT', 'Gene', '7015', (186, 190))
55459	33375021	Several studies reported that the prognostic effect of TERT promoter mutations was modified by the SNP in the TERT promoter.	('mutations', 'Var', (69, 78))	('prognostic', 'MPA', (34, 44))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (110, 114))	('TERT', 'Gene', '7015', (55, 59))	('SNP', 'Var', (99, 102))	('modified', 'Reg', (83, 91))
55460	33375021	In the presence of a somatic TERT promoter mutation in the tumor, patients with the rs2853669 common allele showed poor prognosis in bladder cancer and glioma, although conflicting evidence has been found for the latter.	('TERT', 'Gene', '7015', (29, 33))	('poor', 'NegReg', (115, 119))	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('glioma', 'Disease', (152, 158))	('rs2853669', 'DBSNP_MENTION', 'None', (84, 93))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('patients', 'Species', '9606', (66, 74))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('bladder cancer', 'Disease', (133, 147))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('rs2853669', 'Var', (84, 93))	('TERT', 'Gene', (29, 33))
55462	33375021	A previous study evaluating two hotspot TERT promoter mutations in 313 esophageal squamous cell carcinoma samples identified 1.6% occurrence, showing the extremely low frequency compared to that of thyroid cancer (15-50%).	('TERT', 'Gene', '7015', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('thyroid cancer', 'Phenotype', 'HP:0002890', (198, 212))	('thyroid cancer', 'Disease', (198, 212))	('mutations', 'Var', (54, 63))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('thyroid cancer', 'Disease', 'MESH:D013964', (198, 212))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('TERT', 'Gene', (40, 44))
55463	33375021	Some studies identified a germline mutation in TERT, c.-57T>G in only two melanoma families worldwide, indicating that this inherited mutation is extremely rare.	('TERT', 'Gene', (47, 51))	('c.-57T>G', 'Var', (53, 61))	('TERT', 'Gene', '7015', (47, 51))	('c.-57T>G', 'SUBSTITUTION', 'None', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))
55472	33375021	In conclusion, this is the first report to describe the co-existing deletion and hotspot TERT promoter mutation of SVPTC in a patient with synchronous esophageal squamous cell carcinoma.	('PTC', 'Phenotype', 'HP:0002895', (117, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('SVPTC', 'Gene', (115, 120))	('patient', 'Species', '9606', (126, 133))	('TERT', 'Gene', (89, 93))	('deletion', 'Var', (68, 76))	('TERT', 'Gene', '7015', (89, 93))	('synchronous esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (139, 185))	('synchronous esophageal squamous cell carcinoma', 'Disease', (139, 185))	('mutation', 'Var', (103, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
55532	32252507	Endoscopic treatments of SESCC have better prognoses when the depth of invasion is shallow, and unlike gastric cancer, SESCC invading the muscularis mucosa poses a risk of lymph node metastasis.	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('SESCC', 'Var', (119, 124))	('gastric cancer', 'Disease', (103, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('lymph node metastasis', 'CPA', (172, 193))
55646	32252507	In another Korean study on 15 cases of extra-gastric recurrence published in 2017, 66.7% (4/6) of expanded criteria lesions and 83.3% (5/6) of out-of-indication lesions showed extra-gastric recurrences on CT without any intragastric recurrences, demonstrating the need for follow-up CT in patients with expanded criteria lesions.	('extra-gastric recurrences', 'CPA', (176, 201))	('lesions', 'Var', (116, 123))	('patients', 'Species', '9606', (289, 297))
55661	32252507	Intermediate-to-high grade tumor budding is associated with an increased risk of lymph node metastasis According to some meta-analyses, the presence of tumor budding increases the OR of lymph node metastasis by 3.26-7.74 fold.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('lymph node metastasis', 'CPA', (186, 207))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (152, 157))	('increases', 'PosReg', (166, 175))	('lymph node metastasis', 'CPA', (81, 102))	('presence', 'Var', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
55669	32252507	In addition, studies comparing endoscopic resection and surgical resection for submucosal colorectal cancer reported local recurrence rates of 2.3%-6.4% for endoscopic resection and relatively low local recurrence rates of 0.9%-1.87% for surgical resection.	('submucosal colorectal cancer', 'Disease', 'MESH:D015179', (79, 107))	('submucosal colorectal cancer', 'Disease', (79, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('endoscopic', 'Var', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
55672	32252507	reported a high five-year recurrence-free survival rate of 98% for lowrisk submucosal colorectal cancer.	('submucosal colorectal cancer', 'Disease', 'MESH:D015179', (75, 103))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lowrisk', 'Var', (67, 74))	('submucosal colorectal cancer', 'Disease', (75, 103))
55753	31771653	However, as described below, while EC cells battle with the immune system, mutations and/or other alterations in EC cells may endow them with the ability of immune evasion.	('EC', 'Disease', 'MESH:D004938', (35, 37))	('endow', 'NegReg', (126, 131))	('immune evasion', 'MPA', (157, 171))	('EC', 'Disease', 'MESH:D004938', (113, 115))	('mutations', 'Var', (75, 84))
55769	31771653	The overexpression or hyperactivation of TGF-beta can be detected in a high proportion of EC patients, and more importantly, blockade of TGF-beta enhances the efficiency of PD-L1/PD-1 inhibition, inducing MAGE-A3+ specific CD8+ T-cell response in ESCC.	('enhances', 'PosReg', (146, 154))	('MAGE-A3', 'Gene', '4102', (205, 212))	('EC', 'Disease', 'MESH:D004938', (90, 92))	('MAGE-A3', 'Gene', (205, 212))	('TGF-beta', 'Gene', '7040', (41, 49))	('ESCC', 'Disease', (247, 251))	('ESCC', 'Disease', 'MESH:C562729', (247, 251))	('TGF-beta', 'Gene', (41, 49))	('TGF-beta', 'Gene', '7040', (137, 145))	('CD8', 'Gene', (223, 226))	('CD8', 'Gene', '925', (223, 226))	('TGF-beta', 'Gene', (137, 145))	('inducing', 'PosReg', (196, 204))	('patients', 'Species', '9606', (93, 101))	('blockade', 'Var', (125, 133))
55809	31771653	In studies with a relatively small series of patients, PD-L1/2 expression in ESCC was associated with poor prognosis.	('ESCC', 'Disease', (77, 81))	('patients', 'Species', '9606', (45, 53))	('PD-L1/2 expression', 'Var', (55, 73))	('ESCC', 'Disease', 'MESH:C562729', (77, 81))
55810	31771653	However, in other studies with larger series of ESCC patients, the high expression of PD-L1 was associated with a well-differentiated disease status, early tumor stage, and increased survival benefits.	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (53, 61))	('ESCC', 'Disease', 'MESH:C562729', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('survival benefits', 'CPA', (183, 200))	('increased', 'PosReg', (173, 182))	('tumor', 'Disease', (156, 161))	('ESCC', 'Disease', (48, 52))	('PD-L1', 'Gene', (86, 91))
55815	31771653	showed that an objective response to PD-L1/PD-1 blockade was more common in patients with PD-L1-positive ESCC than in those with PD-L1-negative ESCC.	('PD-L1-positive', 'Var', (90, 104))	('patients', 'Species', '9606', (76, 84))	('ESCC', 'Disease', (105, 109))	('ESCC', 'Disease', 'MESH:C562729', (144, 148))	('ESCC', 'Disease', (144, 148))	('ESCC', 'Disease', 'MESH:C562729', (105, 109))
55817	31771653	In this study, CTLA-4 expression in either cancer cells or TIICs was associated with shortened overall survival (OS) in ESCC patients, and the OS of patients with CTLA-4-positive epithelial cells was similar to that of patients with CTLA-4-positive TIICs.	('ESCC', 'Disease', 'MESH:C562729', (120, 124))	('shortened', 'NegReg', (85, 94))	('patients', 'Species', '9606', (149, 157))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('expression', 'Var', (22, 32))	('cancer', 'Disease', (43, 49))	('ESCC', 'Disease', (120, 124))	('overall survival', 'MPA', (95, 111))	('CTLA-4', 'Gene', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('patients', 'Species', '9606', (219, 227))	('patients', 'Species', '9606', (125, 133))
55818	31771653	Interestingly, the co-expression of tumor cell-derived CTLA-4 and TIIC-derived CTLA-4 can predict the outcomes of ESCC patients more accurately than each marker alone.	('co-expression', 'Var', (19, 32))	('ESCC', 'Disease', (114, 118))	('CTLA-4', 'Gene', (79, 85))	('CTLA-4', 'Gene', (55, 61))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ESCC', 'Disease', 'MESH:C562729', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
55819	31771653	IDO1 expression is associated with decreased OS, poor pathologic response, and increased recurrence in both ESCCs and EACs.	('IDO1', 'Gene', (0, 4))	('EAC', 'Disease', (118, 121))	('ESCC', 'Disease', 'MESH:C562729', (108, 112))	('expression', 'Var', (5, 15))	('EAC', 'Disease', 'MESH:D004941', (118, 121))	('decreased', 'NegReg', (35, 44))	('IDO1', 'Gene', '3620', (0, 4))	('ESCC', 'Disease', (108, 112))	('EAC', 'Phenotype', 'HP:0011459', (118, 121))
55821	31771653	Moreover, the co-expression of IDO1 and PD-L1 is better for the prediction of EC patient outcomes than either alone.	('patient', 'Species', '9606', (81, 88))	('IDO1', 'Gene', (31, 35))	('PD-L1', 'Gene', (40, 45))	('co-expression', 'Var', (14, 27))	('EC', 'Disease', 'MESH:D004938', (78, 80))	('IDO1', 'Gene', '3620', (31, 35))
55823	31771653	showed that the expression of VISTA was associated with prolonged OS in EAC patients with stage pT1/2 tumor.	('VISTA', 'Gene', (30, 35))	('patients', 'Species', '9606', (76, 84))	('expression', 'Var', (16, 26))	('EAC', 'Disease', 'MESH:D004941', (72, 75))	('EAC', 'Disease', (72, 75))	('pT1/2', 'Gene', (96, 101))	('pT1/2', 'Gene', '58492', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('prolonged OS', 'Disease', (56, 68))	('VISTA', 'Gene', '64115', (30, 35))	('EAC', 'Phenotype', 'HP:0011459', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('associated', 'Reg', (40, 50))
55839	31771653	In EC, increased CD8+ TILs are always detected in PD-L1-positive tumors, whereas the levels of cytotoxic T cells are low in PD-L1-negative ones, suggesting that enhanced PD-L1 expression in tumors may be caused by increased TILs.	('enhanced', 'PosReg', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PD-L1-positive', 'Var', (50, 64))	('tumors', 'Disease', (65, 71))	('expression', 'MPA', (176, 186))	('tumors', 'Disease', (190, 196))	('T cells are low', 'Phenotype', 'HP:0005403', (105, 120))	('TIL', 'Gene', '7096', (224, 227))	('CD8', 'Gene', (17, 20))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('EC', 'Disease', 'MESH:D004938', (3, 5))	('TIL', 'Gene', '7096', (22, 25))	('TIL', 'Gene', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('PD-L1', 'Gene', (170, 175))	('CD8', 'Gene', '925', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('TIL', 'Gene', (22, 25))
55846	31771653	The expression of IDO1 was associated with that of PD-L1, and patients with co-expression of IDO1 and PD-L1 had significantly lower therapeutic response and higher recurrence rate than those with either one or none expression in ESCC.	('ESCC', 'Disease', (229, 233))	('lower', 'NegReg', (126, 131))	('recurrence rate', 'CPA', (164, 179))	('IDO1', 'Gene', (93, 97))	('PD-L1', 'Gene', (102, 107))	('IDO1', 'Gene', (18, 22))	('therapeutic response', 'CPA', (132, 152))	('higher', 'PosReg', (157, 163))	('ESCC', 'Disease', 'MESH:C562729', (229, 233))	('co-expression', 'Var', (76, 89))	('patients', 'Species', '9606', (62, 70))	('IDO1', 'Gene', '3620', (93, 97))	('IDO1', 'Gene', '3620', (18, 22))
55887	31771653	A clinical trial has demonstrated the safety and efficacy of a combined therapy with anti-CTLA-4 antibodies (ipilimumab) and anti-PD-1 antibodies (nivolumab) in advanced EC (Table 2), showing that the outcome of patients receiving combined therapy was better than that of those receiving nivolumab monotherapy.	('anti-CTLA-4', 'Var', (85, 96))	('anti-PD-1', 'Var', (125, 134))	('patients', 'Species', '9606', (212, 220))	('anti-CTLA-4', 'Gene', (85, 96))	('EC', 'Disease', 'MESH:D004938', (170, 172))
55888	31771653	However, the adverse events in patients treated with CTLA4 inhibitors were more common and more serious than those with PD-1 inhibitors.	('patients', 'Species', '9606', (31, 39))	('CTLA4', 'Gene', '1493', (53, 58))	('CTLA4', 'Gene', (53, 58))	('inhibitors', 'Var', (59, 69))
55889	31771653	Therefore, the development of effective strategies to reduce the adverse events of CTLA-4 inhibitors is required for immunotherapy targeting CTLA-4 in EC.	('CTLA-4', 'Gene', (83, 89))	('CTLA-4', 'Gene', (141, 147))	('inhibitors', 'Var', (90, 100))	('EC', 'Disease', 'MESH:D004938', (151, 153))
55941	31771653	This work was supported by grants from the National Key R&D Program of China (2017YFA0503900), the National Natural Science Foundation of China (81372583 and 81772957), the Science and Technology Program of Guangdong Province in China (2019B030301009) and the Industry and Information Technology Foundation of Shenzhen (20180309100135860).	('China', 'Var', (71, 76))	('2019B030301009', 'Chemical', 'MESH:C101407', (236, 250))	('2017YFA0503900', 'Chemical', 'MESH:C587222', (78, 92))	('China', 'Var', (138, 143))
55946	30643460	Then, independent microarray data of GSE6188, GSE89102, and GSE92396 and correlation analysis were used to validate molecular biomarkers in the initial ceRNet.	('GSE92396', 'Var', (60, 68))	('GSE89102', 'Var', (46, 54))	('GSE6188', 'Var', (37, 44))	('GSE6188', 'Chemical', '-', (37, 44))
55963	30643460	Microarray data of GSE6188, GSE89102, and GSE92396 and correlation analysis were used to identify oncocers.	('GSE92396', 'Var', (42, 50))	('GSE89102', 'Var', (28, 36))	('GSE6188', 'Chemical', '-', (19, 26))
55967	30643460	We then validated the elements of the initial ceRNet from three independent data sets (GSE6188, GSE89102, and GSE92396) and acquired a validated ceRNet.	('GSE6188', 'Chemical', '-', (87, 94))	('GSE92396', 'Var', (110, 118))	('GSE89102', 'Var', (96, 104))	('GSE6188', 'Var', (87, 94))
56009	30643460	PVT1 has been reported to inhibit the expression of miR200a, miR200b, miR199a5p, miR497, miR152, miR186, and miR214 by acting as a ceRNA and also promoted cell invasion.	('PVT1', 'Gene', (0, 4))	('cell invasion', 'CPA', (155, 168))	('miR152', 'Gene', (89, 95))	('PVT1', 'Gene', '5820', (0, 4))	('miR152', 'Gene', '406943', (89, 95))	('miR200a', 'Gene', (52, 59))	('miR200a', 'Gene', '406983', (52, 59))	('miR497', 'Gene', '574456', (81, 87))	('miR200b', 'Gene', '406984', (61, 68))	('miR200b', 'Gene', (61, 68))	('expression', 'MPA', (38, 48))	('miR199a5p', 'Var', (70, 79))	('promoted', 'PosReg', (146, 154))	('miR186', 'Gene', (97, 103))	('miR497', 'Gene', (81, 87))	('inhibit', 'NegReg', (26, 33))	('miR186', 'Gene', '406962', (97, 103))	('miR214', 'Gene', '406996', (109, 115))	('miR214', 'Gene', (109, 115))
56126	29378603	All the patients had stage IA disease (pT1aN0M0 or pT1bN0M0), according to the Seventh Edition of the International Union against Cancer TNM classification system.	('Cancer', 'Disease', (130, 136))	('pT1bN0M0', 'Var', (51, 59))	('Cancer', 'Disease', 'MESH:D009369', (130, 136))	('T1a', 'Gene', '10630', (40, 43))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('T1a', 'Gene', (40, 43))	('TNM', 'Gene', (137, 140))	('stage IA disease', 'Disease', 'MESH:C536041', (21, 37))	('stage IA disease', 'Disease', (21, 37))	('TNM', 'Gene', '10178', (137, 140))	('patients', 'Species', '9606', (8, 16))
56263	24223792	Patients with high expression of survivin in EAC tumor had an increased risk of death.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('survivin', 'Gene', '11799', (33, 41))	('tumor', 'Disease', (49, 54))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('survivin', 'Gene', (33, 41))	('death', 'Disease', 'MESH:D003643', (80, 85))	('death', 'Disease', (80, 85))
56265	24223792	Cell line evaluation demonstrated that inhibition of survivin resulted in an increase in apoptosis.	('survivin', 'Gene', (53, 61))	('inhibition', 'Var', (39, 49))	('apoptosis', 'CPA', (89, 98))	('survivin', 'Gene', '11799', (53, 61))
56267	24223792	Inhibition of survivin in EAC cell lines further showed increased apoptosis, supporting the potential benefits of therapeutic strategies targeted to this marker.	('increased', 'PosReg', (56, 65))	('survivin', 'Gene', (14, 22))	('apoptosis', 'CPA', (66, 75))	('Inhibition', 'Var', (0, 10))	('survivin', 'Gene', '11799', (14, 22))
56279	24223792	In fact agents targeting survivin are currently in phase I and phase II clinical trials in patients with advanced cancer where methods of inhibition include antisense oligonucleotides (ASOs), transcriptional repressors, and immunotherapy.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('patients', 'Species', '9606', (91, 99))	('survivin', 'Gene', (25, 33))	('oligonucleotides', 'Chemical', 'MESH:D009841', (167, 183))	('survivin', 'Gene', '11799', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('antisense oligonucleotides', 'Var', (157, 183))	('cancer', 'Disease', (114, 120))
56301	24223792	PCR was performed in a total volume of 20 ul using 600 ng cDNA, 1x Taqman PCR universal mastermix (Invitrogen, Grand Island, NY, 4304437), and 1x Survivin or GAPDH primer (Applied Biosystems, Carlsbad, CA hs03043576_m1 and hs99999905_m1) for each reaction.	('GAPDH', 'Gene', '2597', (158, 163))	('GAPDH', 'Gene', (158, 163))	('hs99999905_m1', 'Var', (223, 236))	('Survivin', 'Gene', '11799', (146, 154))	('Survivin', 'Gene', (146, 154))
56303	24223792	qRT-PCR was performed with the One-step qRT-PCR Kit (Life Technologies, Carlsbad, CA 4310299) according to manufacturer's instructions in a total volume of 20 ul using 2 ul of tissue lysate and 1x Survivin or 1x GAPDH primer (Life Technologies, Carlsbad, CA hs03043576_m1 and hs99999905_m1) for each reaction.	('GAPDH', 'Gene', (212, 217))	('hs99999905_m1', 'Var', (276, 289))	('Survivin', 'Gene', '11799', (197, 205))	('GAPDH', 'Gene', '2597', (212, 217))	('Survivin', 'Gene', (197, 205))
56345	24223792	The probability of a patient in the high-risk tumor survivin group experiencing death was 5.23 times greater than that of a patient categorized in the low risk group (p<.05).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patient', 'Species', '9606', (21, 28))	('tumor', 'Disease', (46, 51))	('survivin', 'Gene', (52, 60))	('greater', 'PosReg', (101, 108))	('high-risk', 'Var', (36, 45))	('patient', 'Species', '9606', (124, 131))	('death', 'Disease', 'MESH:D003643', (80, 85))	('death', 'Disease', (80, 85))	('survivin', 'Gene', '11799', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
56361	24223792	Moreover, as evidenced from prior studies, each tumor exhibits significant heterogeneity with intra-tumor variations in somatic mutations, allelic composition, tumor suppressor and oncogenic dysregulation.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (48, 53))	('intra-tumor', 'Disease', (94, 105))	('tumor', 'Disease', (100, 105))	('variations', 'Var', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('intra-tumor', 'Disease', 'MESH:D009369', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (160, 165))	('oncogenic dysregulation', 'CPA', (181, 204))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
56366	24223792	Cell line analysis in the present study confirmed clear inhibition of survivin through transfection with siRNA.	('transfection', 'Var', (87, 99))	('survivin', 'Gene', '11799', (70, 78))	('survivin', 'Gene', (70, 78))	('inhibition', 'NegReg', (56, 66))
56367	24223792	Survivin was effectively downregulated and cleaved caspase 3 was consumed in the reaction leading to upregulation of cleaved PARP, indicating that inhibition of survivin leads to activation of the apoptotic pathway.	('PARP', 'Gene', '142', (125, 129))	('survivin', 'Gene', (161, 169))	('caspase 3', 'Gene', (51, 60))	('upregulation', 'PosReg', (101, 113))	('Survivin', 'Gene', '11799', (0, 8))	('caspase 3', 'Gene', '836', (51, 60))	('Survivin', 'Gene', (0, 8))	('survivin', 'Gene', '11799', (161, 169))	('downregulated', 'NegReg', (25, 38))	('inhibition', 'Var', (147, 157))	('PARP', 'Gene', (125, 129))	('apoptotic pathway', 'Pathway', (197, 214))	('activation', 'PosReg', (179, 189))
56371	24223792	Additionally we also demonstrated that inhibition of survivin in EAC cell lines leads to upregulation of apoptosis supporting further evaluation of therapeutic strategies targeted to this marker.	('inhibition', 'Var', (39, 49))	('apoptosis', 'CPA', (105, 114))	('survivin', 'Gene', '11799', (53, 61))	('upregulation', 'PosReg', (89, 101))	('survivin', 'Gene', (53, 61))
56375	20007561	Telomeres were causally connected to human disease when mutations in the DKC1 gene were detected in a rare inherited form of bone marrow failure.	('mutations', 'Var', (56, 65))	('DKC1', 'Gene', '1736', (73, 77))	('bone marrow failure', 'Phenotype', 'HP:0005528', (125, 144))	('bone marrow failure', 'Disease', (125, 144))	('bone marrow failure', 'Disease', 'MESH:D000080983', (125, 144))	('detected', 'Reg', (88, 96))	('connected', 'Reg', (24, 33))	('human', 'Species', '9606', (37, 42))	('DKC1', 'Gene', (73, 77))
56377	20007561	Telomeres are short in many patients with inherited or apparently acquired aplastic anemia, and mutations affecting telomerase have been identified in these forms of aplastic anemia; telomerase mutations also have been associated with fibrosis of the lungs and the liver.	('aplastic anemia', 'Disease', (166, 181))	('identified', 'Reg', (137, 147))	('associated with', 'Reg', (219, 234))	('fibrosis of the lungs', 'Phenotype', 'HP:0002206', (235, 256))	('aplastic anemia', 'Disease', (75, 90))	('mutations', 'Var', (194, 203))	('fibrosis', 'Disease', 'MESH:D005355', (235, 243))	('aplastic anemia', 'Phenotype', 'HP:0001915', (166, 181))	('aplastic anemia', 'Phenotype', 'HP:0001915', (75, 90))	('anemia', 'Phenotype', 'HP:0001903', (84, 90))	('aplastic anemia', 'Disease', 'MESH:D000741', (166, 181))	('patients', 'Species', '9606', (28, 36))	('aplastic anemia', 'Disease', 'MESH:D000741', (75, 90))	('anemia', 'Phenotype', 'HP:0001903', (175, 181))	('telomerase', 'Gene', (183, 193))	('fibrosis', 'Disease', (235, 243))
56378	20007561	Moreover, the telomerase gene is a susceptibility locus for cancer, and short telomeres may be risk factors for cardiovascular disease.	('cardiovascular disease', 'Phenotype', 'HP:0001626', (112, 134))	('cardiovascular disease', 'Disease', 'MESH:D002318', (112, 134))	('short', 'Var', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('susceptibility', 'Reg', (35, 49))	('cancer', 'Disease', (60, 66))	('cardiovascular disease', 'Disease', (112, 134))	('telomerase', 'Gene', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('short telomeres', 'Phenotype', 'HP:0031413', (72, 87))
56391	20007561	Hematopoietic dysfunction caused by defective telomere structure and repair has a broad clinical spectrum.	('defective', 'Var', (36, 45))	('telomere structure', 'Protein', (46, 64))	('Hematopoietic dysfunction', 'Disease', 'MESH:D019337', (0, 25))	('Hematopoietic dysfunction', 'Disease', (0, 25))
56401	20007561	After the discovery of DKC1 mutations, very short telomeres were detected in all patients with dyskeratosis congenita.	('detected', 'Reg', (65, 73))	('DKC1', 'Gene', (23, 27))	('patients', 'Species', '9606', (81, 89))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (95, 117))	('short telomeres', 'Phenotype', 'HP:0031413', (44, 59))	('DKC1', 'Gene', '1736', (23, 27))	('dyskeratosis congenita', 'Disease', (95, 117))	('mutations', 'Var', (28, 37))
56402	20007561	Genetic screening revealed heterozygous mutations in TERC, homozygous mutations in NOP10 and NHP2 (genes encoding proteins that, like dyskerin, associate with the complex), and in TERT.	('NHP2', 'Gene', (93, 97))	('TERC', 'Gene', (53, 57))	('NOP10', 'Gene', (83, 88))	('associate', 'Interaction', (144, 153))	('TERC', 'Gene', '7012', (53, 57))	('NOP10', 'Gene', '55505', (83, 88))	('mutations', 'Var', (40, 49))	('TERT', 'Gene', (180, 184))	('TERT', 'Gene', '7015', (180, 184))	('NHP2', 'Gene', '55651', (93, 97))
56403	20007561	Recently, mutated TINF2 was detected in autosomal dominant dyskeratosis congenita; loss of this protein in the shelterin complex causes extremely short telomeres.	('autosomal dominant dyskeratosis congenita', 'Disease', 'MESH:D019871', (40, 81))	('TINF2', 'Gene', (18, 23))	('causes', 'Reg', (129, 135))	('loss', 'Var', (83, 87))	('short telomeres', 'Phenotype', 'HP:0031413', (146, 161))	('TINF2', 'Gene', '26277', (18, 23))	('autosomal dominant dyskeratosis congenita', 'Disease', (40, 81))
56414	20007561	Pedigree interpretation occasionally can be complicated by mosaicism, and girls and women may have a mild phenotype with a single X-linked DKC1 mutation.	('women', 'Species', '9606', (84, 89))	('DKC1', 'Gene', (139, 143))	('DKC1', 'Gene', '1736', (139, 143))	('mutation', 'Var', (144, 152))	('girls', 'Species', '9606', (74, 79))
56419	20007561	Measurements of telomere length in hematopoietic cells preceded the discovery of the mutations in dyskeratosis.	('dyskeratosis', 'Disease', (98, 110))	('mutations', 'Var', (85, 94))	('dyskeratosis', 'Disease', 'MESH:D019871', (98, 110))
56425	20007561	Bone marrow transplantation from a histocompatible sibling with an unrecognized TERC mutation culminated in early death from graft failure in one patient; this led to the selection of an unrelated donor rather than a sibling donor in a second patient.	('donor', 'Species', '9606', (225, 230))	('TERC', 'Gene', '7012', (80, 84))	('patient', 'Species', '9606', (243, 250))	('graft failure', 'Disease', (125, 138))	('donor', 'Species', '9606', (197, 202))	('mutation', 'Var', (85, 93))	('graft failure', 'Disease', 'MESH:D055589', (125, 138))	('death', 'Disease', 'MESH:D003643', (114, 119))	('patient', 'Species', '9606', (146, 153))	('death', 'Disease', (114, 119))	('TERC', 'Gene', (80, 84))
56426	20007561	Mutations in TERT were first discovered in patients with aplastic anemia.	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('patients', 'Species', '9606', (43, 51))	('anemia', 'Phenotype', 'HP:0001903', (66, 72))	('aplastic anemia', 'Phenotype', 'HP:0001915', (57, 72))	('Mutations', 'Var', (0, 9))	('aplastic anemia', 'Disease', 'MESH:D000741', (57, 72))	('aplastic anemia', 'Disease', (57, 72))
56430	20007561	Overall, mutations in telomerase genes (but not in DKC1) appear to explain the short telomeres detected in about 10% of patients with aplastic anemia.	('short telomeres', 'Phenotype', 'HP:0031413', (79, 94))	('short telomeres', 'MPA', (79, 94))	('anemia', 'Phenotype', 'HP:0001903', (143, 149))	('aplastic anemia', 'Disease', (134, 149))	('mutations', 'Var', (9, 18))	('DKC1', 'Gene', (51, 55))	('patients', 'Species', '9606', (120, 128))	('aplastic anemia', 'Phenotype', 'HP:0001915', (134, 149))	('aplastic anemia', 'Disease', 'MESH:D000741', (134, 149))	('DKC1', 'Gene', '1736', (51, 55))
56431	20007561	Mutations are associated with short telomere length (adjusted for the patient's age) of blood leukocytes.	('patient', 'Species', '9606', (70, 77))	('associated', 'Reg', (14, 24))	('Mutations', 'Var', (0, 9))	('short telomere length', 'MPA', (30, 51))	('short telomere length', 'Phenotype', 'HP:0031413', (30, 51))
56432	20007561	As in dyskeratosis congenita, heterozygosity causes disease by means of a dominant mechanism of haploinsufficiency.	('dyskeratosis congenita', 'Disease', (6, 28))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (6, 28))	('haploinsufficiency', 'Disease', (96, 114))	('heterozygosity', 'Var', (30, 44))	('causes', 'Reg', (45, 51))	('haploinsufficiency', 'Disease', 'MESH:D058495', (96, 114))
56437	20007561	These associations led to the discovery of telomerase mutations in about 15% of patients with familial idiopathic pulmonary fibrosis.	('familial idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (94, 132))	('patients', 'Species', '9606', (80, 88))	('mutations', 'Var', (54, 63))	('familial idiopathic pulmonary fibrosis', 'Disease', (94, 132))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (114, 132))	('telomerase', 'Protein', (43, 53))
56440	20007561	Telomerase mutations are also sometimes present in patients with sporadic idiopathic pulmonary fibrosis.	('mutations', 'Var', (11, 20))	('Telomerase', 'Protein', (0, 10))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (85, 103))	('sporadic idiopathic pulmonary fibrosis', 'Disease', (65, 103))	('patients', 'Species', '9606', (51, 59))	('present', 'Reg', (40, 47))	('sporadic idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (65, 103))
56444	20007561	We have observed that many relatives of patients with aplastic anemia and a telomerase mutation have liver disease.	('liver disease', 'Phenotype', 'HP:0001392', (101, 114))	('aplastic anemia', 'Disease', (54, 69))	('anemia', 'Phenotype', 'HP:0001903', (63, 69))	('liver disease', 'Disease', (101, 114))	('patients', 'Species', '9606', (40, 48))	('aplastic anemia', 'Phenotype', 'HP:0001915', (54, 69))	('telomerase', 'Gene', (76, 86))	('liver disease', 'Disease', 'MESH:D008107', (101, 114))	('mutation', 'Var', (87, 95))	('aplastic anemia', 'Disease', 'MESH:D000741', (54, 69))
56446	20007561	The genetic basis of the peculiar familial association of bone marrow, liver, and lung disease is telomere erosion and telomerase mutations.	('liver', 'Disease', (71, 76))	('telomerase', 'Gene', (119, 129))	('lung disease', 'Disease', (82, 94))	('bone marrow', 'Disease', (58, 69))	('mutations', 'Var', (130, 139))	('lung disease', 'Disease', 'MESH:D008171', (82, 94))	('lung disease', 'Phenotype', 'HP:0002088', (82, 94))	('telomere', 'Var', (98, 106))
56451	20007561	In late-generation Terc-knockout mice, short telomeres cause chromosomal instability through end-to-end fusions.	('chromosomal', 'MPA', (61, 72))	('short telomeres', 'Var', (39, 54))	('end-to-end fusions', 'CPA', (93, 111))	('Terc', 'Gene', '21748', (19, 23))	('short telomeres', 'Phenotype', 'HP:0031413', (39, 54))	('Terc', 'Gene', (19, 23))	('mice', 'Species', '10090', (33, 37))	('cause', 'Reg', (55, 60))	('chromosomal instability', 'Phenotype', 'HP:0040012', (61, 84))
56452	20007561	Thus, in Terc-/- mice that are also deficient in p53, a variety of cancers develop in association with nonreciprocal translocations, mimicking human malignant conditions.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('human', 'Species', '9606', (143, 148))	('p53', 'Gene', (49, 52))	('mice', 'Species', '10090', (17, 21))	('cancers', 'Disease', (67, 74))	('deficient', 'Var', (36, 45))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('Terc', 'Gene', (9, 13))	('p53', 'Gene', '22060', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('develop', 'PosReg', (75, 82))	('Terc', 'Gene', '21748', (9, 13))
56467	20007561	In small studies, telomere length has been associated with the risk of leukemic transformation from myelodysplasia after chemotherapy and autologous hematopoietic-cell transplantation, and short telomeres of blast cells have been correlated with chromosomal abnormalities.	('myelodysplasia', 'Disease', (100, 114))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (246, 271))	('myelodysplasia', 'Disease', 'MESH:D009190', (100, 114))	('leukemic', 'Disease', (71, 79))	('myelodysplasia', 'Phenotype', 'HP:0002863', (100, 114))	('short telomeres', 'Var', (189, 204))	('associated', 'Reg', (43, 53))	('leukemic', 'Disease', 'MESH:D007938', (71, 79))	('correlated', 'Reg', (230, 240))	('telomere', 'Protein', (18, 26))	('chromosomal abnormalities', 'Disease', (246, 271))	('short telomeres', 'Phenotype', 'HP:0031413', (189, 204))
56468	20007561	Genomewide association studies have shown polymorphisms in the TERT gene at a higher frequency than normal in patients with cancer.	('cancer', 'Disease', (124, 130))	('patients', 'Species', '9606', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('polymorphisms', 'Var', (42, 55))	('TERT', 'Gene', (63, 67))	('TERT', 'Gene', '7015', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
56471	20007561	Similar statistical associations have been reproducible for lung cancer in genomewide association studies involving large European populations and in Chinese patients, in whom risk was also linked to short telomeres.	('lung cancer', 'Disease', (60, 71))	('short telomeres', 'Phenotype', 'HP:0031413', (200, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('linked', 'Reg', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('short telomeres', 'Var', (200, 215))	('patients', 'Species', '9606', (158, 166))
56472	20007561	TERT-locus polymorphisms have been associated with susceptibility to gliomas and renal-cell carcinoma; they have also been associated with relative resistance to melanoma and breast cancer.	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('associated', 'Reg', (123, 133))	('gliomas', 'Disease', (69, 76))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('melanoma', 'Disease', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('breast cancer', 'Disease', (175, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('TERT', 'Gene', (0, 4))	('polymorphisms', 'Var', (11, 24))	('renal-cell carcinoma', 'Disease', 'MESH:C538614', (81, 101))	('TERT', 'Gene', '7015', (0, 4))	('renal-cell carcinoma', 'Disease', (81, 101))
56473	20007561	In summary, telomere shortening can be related to the risk of cancer, ranging from high rates of specific cancers in dyskeratosis congenita to modest contributions to oncogenesis in general.	('telomere shortening', 'Phenotype', 'HP:0031413', (12, 31))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (117, 139))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('related', 'Reg', (39, 46))	('dyskeratosis congenita', 'Disease', (117, 139))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (106, 113))	('cancer', 'Disease', (62, 68))	('telomere shortening', 'Var', (12, 31))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
56474	20007561	In some specific inflammatory and immune diseases, telomere attrition may be the critical factor in promoting the development of cancer (Fig.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('telomere', 'Var', (51, 59))	('promoting', 'PosReg', (100, 109))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
56477	20007561	In one of many epidemiologic surveys, people with short leukocyte telomeres were at risk for coronary disease, which appeared to be attenuated by statin therapy.	('coronary disease', 'Phenotype', 'HP:0001677', (93, 109))	('coronary disease', 'Disease', 'MESH:D003324', (93, 109))	('short leukocyte telomeres', 'Phenotype', 'HP:0031413', (50, 75))	('short', 'Var', (50, 55))	('coronary disease', 'Disease', (93, 109))	('people', 'Species', '9606', (38, 44))
56478	20007561	In the Cardiovascular Health Study, shortened telomeres corresponded with a risk of myocardial infarction among younger patients that was three times as high as the risk among older patients, and in the Heart and Soul Study, shorter-than-normal telomeres were a biomarker for the risk of death in patients with stable coronary artery disease.	('coronary artery disease', 'Disease', 'MESH:D003324', (318, 341))	('myocardial infarction', 'Phenotype', 'HP:0001658', (84, 105))	('death', 'Disease', 'MESH:D003643', (288, 293))	('patients', 'Species', '9606', (297, 305))	('death', 'Disease', (288, 293))	('coronary artery disease', 'Disease', (318, 341))	('myocardial infarction', 'Disease', (84, 105))	('shortened telomeres', 'Phenotype', 'HP:0031413', (36, 55))	('myocardial infarction', 'Disease', 'MESH:D009203', (84, 105))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (182, 190))	('shorter-than-normal', 'Var', (225, 244))	('shortened', 'NegReg', (36, 45))
56481	20007561	Telomerase defects affect yeast viability and replication and account for the shortened life span of knockout mice.	('defects', 'Var', (11, 18))	('Telomerase', 'Protein', (0, 10))	('yeast viability', 'CPA', (26, 41))	('yeast', 'Species', '4932', (26, 31))	('mice', 'Species', '10090', (110, 114))	('affect', 'Reg', (19, 25))	('replication', 'CPA', (46, 57))
56483	20007561	Proteins that are released from dysfunctional cells because of telomere shortening have been proposed as biomarkers of aging and age-dependent degenerative diseases.	('degenerative diseases', 'Disease', (143, 164))	('telomere shortening', 'Var', (63, 82))	('dysfunctional', 'Disease', (32, 45))	('dysfunctional', 'Disease', 'MESH:D006331', (32, 45))	('telomere shortening', 'Phenotype', 'HP:0031413', (63, 82))	('Proteins', 'Protein', (0, 8))	('degenerative diseases', 'Disease', 'MESH:D019636', (143, 164))
56610	31786484	KIT-positive melanomas represent a significant diagnostic pitfall; KIT mutations are seen in ~10% melanomas arising at mucosal, acral, and chronically sun-exposed sites, and these tumors tend to overexpress KIT.	('KIT', 'Gene', '3815', (207, 210))	('KIT', 'Gene', (67, 70))	('melanomas', 'Disease', (13, 22))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('overexpress', 'PosReg', (195, 206))	('KIT', 'Gene', '3815', (0, 3))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanomas', 'Disease', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('mutations', 'Var', (71, 80))	('tumors', 'Disease', (180, 186))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('KIT', 'Gene', '3815', (67, 70))	('KIT', 'Gene', (207, 210))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('KIT', 'Gene', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))
56627	31786484	Often, the diagnostic challenge lies in successfully identifying scant tumor and then distinguishing the deceptively bland glands from reactive change (not the subject of this review, though mutant-pattern p53 staining is useful in this setting).	('p53', 'Gene', (206, 209))	('p53', 'Gene', '7157', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mutant-pattern', 'Var', (191, 205))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
56629	31786484	Loss of SMAD4/DPC4 is seen in up to 60% of pancreatic ductal carcinomas (Figure 11), and, although it is less well-studied, is probably seen in no more than 15% of primary small intestinal adenocarcinomas.	('SMAD4', 'Gene', (8, 13))	('DPC4', 'Gene', '4089', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('DPC4', 'Gene', (14, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('pancreatic ductal carcinomas', 'Disease', 'MESH:D021441', (43, 71))	('intestinal adenocarcinomas', 'Phenotype', 'HP:0040273', (178, 204))	('intestinal adenocarcinomas', 'Disease', 'MESH:D000230', (178, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('SMAD4', 'Gene', '4089', (8, 13))	('pancreatic ductal carcinomas', 'Disease', (43, 71))	('Loss', 'Var', (0, 4))	('intestinal adenocarcinomas', 'Disease', (178, 204))
56698	31786484	When faced with diagnostic uncertainty on the initial H&E, it is best to start by trying to assign the broad tumor class with screening markers such as pankeratin, S100 or SOX10, and CD20 or CD45.	('H&E', 'Chemical', '-', (54, 57))	('CD45', 'Gene', (191, 195))	('S100', 'Gene', (164, 168))	('CD20', 'Gene', '54474', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CD20', 'Gene', (183, 187))	('and', 'Var', (179, 182))	('CD45', 'Gene', '5788', (191, 195))	('SOX10', 'Gene', '6663', (172, 177))	('pankeratin', 'Chemical', '-', (152, 162))	('S100', 'Gene', '6271', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('SOX10', 'Gene', (172, 177))	('tumor', 'Disease', (109, 114))
56764	32869505	reported five genes that have a connection with overall or relapse-free survival.16 However, the credibility of the result which shows the identification of DEGs in mRNA expression profiling data sets GSE1420, GSE26886, and GSE92396 was not high as the three data sets come from different platforms (GSE1420 from GPL96, GSE26886 from GPL570, GSE92396 from GPL6244).	('GSE26886', 'Var', (320, 328))	('DEGs', 'Gene', '8560', (157, 161))	('GSE92396', 'Var', (342, 350))	('GSE1420', 'Var', (300, 307))	('DEGs', 'Gene', (157, 161))
56781	32443386	Recently, cancer microarrays and high-throughput sequencing technologies have been frequently used to explore common biomarkers associated with cancer, as well as drugs that are directly used in cancer treatment, diagnosis, and prognosis, revealing key genetic or epigenetic variations in tumorigenesis.	('genetic', 'Var', (253, 260))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (289, 294))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('epigenetic variations', 'Var', (264, 285))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
56813	32443386	When an abnormality occurs in AURKA, it often leads to the functional defect of the centrosome in mitosis and the disorder of the bipolar spindle, which conduces to the asymmetric separation of chromosomes during division, induces chromosomal instability, forms aneuploidy, and causes abnormal mutations in cells.	('aneuploidy', 'Disease', (262, 272))	('chromosomal instability', 'Phenotype', 'HP:0040012', (231, 254))	('abnormal mutations', 'CPA', (285, 303))	('aneuploidy', 'Disease', 'MESH:D000782', (262, 272))	('causes', 'Reg', (278, 284))	('functional', 'MPA', (59, 69))	('chromosomal instability', 'CPA', (231, 254))	('mitosis and the disorder of the bipolar', 'Disease', 'MESH:D001714', (98, 137))	('induces', 'Reg', (223, 230))	('abnormality', 'Var', (8, 19))	('AURKA', 'Gene', '6790', (30, 35))	('leads to', 'Reg', (46, 54))	('AURKA', 'Gene', (30, 35))
56825	32443386	It has been experimentally proven that knocking down ASPM can inhibit tumor growth and lead to apoptosis.	('ASPM', 'Gene', '259266', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('apoptosis', 'CPA', (95, 104))	('knocking down', 'Var', (39, 52))	('ASPM', 'Gene', (53, 57))	('lead to', 'Reg', (87, 94))	('inhibit', 'NegReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
56830	32443386	Studies have shown that improper expression of TPX2 leads to chromosomal instability, resulting in centrosome expansion and development into aneuploidy which is highly correlated with the occurrence and development of various tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('aneuploidy', 'Disease', (141, 151))	('chromosomal instability', 'MPA', (61, 84))	('improper', 'Var', (24, 32))	('TPX2', 'Gene', (47, 51))	('tumors', 'Disease', (226, 232))	('centrosome expansion', 'CPA', (99, 119))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('leads to', 'Reg', (52, 60))	('aneuploidy', 'Disease', 'MESH:D000782', (141, 151))	('TPX2', 'Gene', '22974', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('chromosomal instability', 'Phenotype', 'HP:0040012', (61, 84))	('development', 'Reg', (124, 135))
56832	32443386	Furthermore, different kinds of experiments have confirmed that the high expression of CEPNF is a prognostic indicator of survival and metastasis in ESCA patients.	('metastasis', 'CPA', (135, 145))	('high', 'Var', (68, 72))	('patients', 'Species', '9606', (154, 162))	('ESCA', 'Disease', (149, 153))	('CEPNF', 'Gene', (87, 92))
57005	30903323	Within the group of AJCC 6th edition users, over 75% of respondents resected stations 7, 8M and 8L in cases of proximal SCC.	('SCC', 'Gene', '6317', (120, 123))	('resected', 'Var', (68, 76))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', (120, 123))
57008	30903323	Over 80% of users of the JSED 9th edition indicated they resected stations 105, 108, 110, 106R and 107 in cases of proximal SCC; all respondents resected stations 108, 110, 107, 3 and 7 in middle-esophageal SCC.	('middle-esophageal SCC', 'Disease', (189, 210))	('SCC', 'Gene', (124, 127))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('SCC', 'Gene', (207, 210))	('SCC', 'Phenotype', 'HP:0002860', (207, 210))	('SCC', 'Gene', '6317', (124, 127))	('resected', 'Var', (145, 153))	('SCC', 'Gene', '6317', (207, 210))	('middle-esophageal SCC', 'Disease', 'MESH:D020244', (189, 210))
57158	26510908	Epigenetic silencing of HIC1 promotes epithelial-mesenchymal transition and drives progression in esophageal squamous cell carcinoma Downregulation of the novel tumor suppressor gene HIC1 (hypermethylated in cancer 1) occurs frequently in various tumors where it causes tumor progression and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('esophageal squamous cell carcinoma', 'Disease', (98, 132))	('tumors', 'Disease', (247, 253))	('HIC1', 'Gene', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', (161, 166))	('promotes', 'PosReg', (29, 37))	('HIC1', 'Gene', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('hypermethylated in cancer 1', 'Gene', '3090', (189, 216))	('HIC1', 'Gene', '3090', (183, 187))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (98, 132))	('Downregulation', 'NegReg', (133, 147))	('tumor', 'Disease', (247, 252))	('HIC1', 'Gene', '3090', (24, 28))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', (270, 275))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('epithelial-mesenchymal transition', 'CPA', (38, 71))	('hypermethylated in cancer 1', 'Gene', (189, 216))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
57164	26510908	Together, loss of the regulation of EphA2 pathway through HIC1 epigenetic silencing could be an important mechanism in the ESCC progression.	('EphA2', 'Gene', '1969', (36, 41))	('epigenetic silencing', 'Var', (63, 83))	('ESCC', 'Disease', (123, 127))	('HIC1', 'Gene', (58, 62))	('EphA2', 'Gene', (36, 41))	('regulation', 'MPA', (22, 32))	('HIC1', 'Gene', '3090', (58, 62))	('loss', 'NegReg', (10, 14))
57171	26510908	It has been proved that this region is frequently affected by genetic alterations such as deletion and epigenetic modifications like hypermethylation in human cancers, including the p53 tumor suppressor gene at 17p13.1.	('cancers', 'Disease', (159, 166))	('deletion', 'Var', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('p53', 'Gene', '7157', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (186, 191))	('human', 'Species', '9606', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('hypermethylation', 'Var', (133, 149))	('p53', 'Gene', (182, 185))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
57172	26510908	Accumulating dada showed HIC1 is epigenetically silenced in various types of common human cancers such as prostate cancers, hepatocellular carcinoma, pancreatic cancer, hyperparathyroid tumors, renal cell carcinoma, et al.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('cancers', 'Disease', (90, 97))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (124, 148))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Disease', (115, 122))	('HIC1', 'Gene', (25, 29))	('pancreatic cancer', 'Disease', (150, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (124, 148))	('HIC1', 'Gene', '3090', (25, 29))	('renal cell carcinoma', 'Disease', (194, 214))	('prostate cancers', 'Phenotype', 'HP:0012125', (106, 122))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (194, 214))	('prostate cancers', 'Disease', (106, 122))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('hyperparathyroid tumors', 'Disease', 'MESH:D006961', (169, 192))	('hepatocellular carcinoma', 'Disease', (124, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('hyperparathyroid tumors', 'Disease', (169, 192))	('human', 'Species', '9606', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (194, 214))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('epigenetically', 'Var', (33, 47))	('prostate cancers', 'Disease', 'MESH:D011471', (106, 122))
57175	26510908	These findings suggest that epigenetic HIC1 silencing predisposes tissues to tumorigenesis.	('HIC1', 'Gene', '3090', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('predisposes', 'Reg', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('epigenetic', 'Var', (28, 38))	('silencing', 'Var', (44, 53))	('tumor', 'Disease', (77, 82))	('HIC1', 'Gene', (39, 43))
57176	26510908	However, the status and role of HIC1 by epigenetic modification in ESCC have never been analyzed in detail and thus still remain unsettled.	('HIC1', 'Gene', '3090', (32, 36))	('HIC1', 'Gene', (32, 36))	('epigenetic modification', 'Var', (40, 63))	('ESCC', 'Gene', (67, 71))
57185	26510908	These findings indicate that HIC1 by hypermethylation may play a critical role in facilitating ESCC progression.	('HIC1', 'Gene', (29, 33))	('ESCC', 'Disease', (95, 99))	('HIC1', 'Gene', '3090', (29, 33))	('hypermethylation', 'Var', (37, 53))
57187	26510908	Downregulation of HIC1 was detected in all six ESCC cell lines (KYSE180, KYSE410, KYSE1170, EC1, EC18 and EC109), while the normal expression of HIC1 was detected in human normal esophageal epithelial cell line HEEC (Figure 1A and 1B).	('EC1', 'Gene', '4819', (92, 95))	('EC1', 'Gene', (106, 109))	('EC1', 'Gene', '4819', (106, 109))	('Downregulation', 'NegReg', (0, 14))	('human', 'Species', '9606', (166, 171))	('HIC1', 'Gene', (18, 22))	('KYSE180', 'Var', (64, 71))	('HIC1', 'Gene', '3090', (18, 22))	('EC1', 'Gene', '4819', (97, 100))	('EC1', 'Gene', (97, 100))	('HIC1', 'Gene', (145, 149))	('KYSE1170', 'Var', (82, 90))	('EC1', 'Gene', (92, 95))	('HIC1', 'Gene', '3090', (145, 149))	('HEEC', 'CellLine', 'None', (211, 215))	('KYSE410', 'Var', (73, 80))
57188	26510908	Restoration of HIC1 expression was revealed by 5-Aza-CdR treatment in six ESCC lines (Figure 1B), accompanied by demethylation of HIC1 promoter, while no change in HEEC cells (Figure 1D and 1E), indicating that HIC1 is transcriptionally silenced in these cells by DNA hypermethylation.	('HIC1', 'Gene', (130, 134))	('expression', 'MPA', (20, 30))	('HIC1', 'Gene', '3090', (130, 134))	('demethylation', 'Var', (113, 126))	('HEEC', 'CellLine', 'None', (164, 168))	('HIC1', 'Gene', (15, 19))	('HIC1', 'Gene', '3090', (211, 215))	('HIC1', 'Gene', (211, 215))	('HIC1', 'Gene', '3090', (15, 19))
57192	26510908	The western blot analysis using KYSE410 and HEEC cells, as a model, confirmed the upregulation of HIC1 proteins following the 5-Aza-CdR and 5-Aza-CdR/TSA treatments in KYSE410 cells, while no change in HEEC cells (Figure 1E).	('TSA', 'Chemical', 'MESH:C012589', (150, 153))	('HIC1', 'Gene', '3090', (98, 102))	('HIC1', 'Gene', (98, 102))	('HEEC', 'CellLine', 'None', (44, 48))	('proteins', 'Protein', (103, 111))	('HEEC', 'CellLine', 'None', (202, 206))	('5-Aza-CdR', 'Var', (126, 135))	('upregulation', 'PosReg', (82, 94))
57194	26510908	As shown in Figure 2A, 84.2% (64/76) of ESCCs was methylated, while only 7.9% (6/76) of its corresponding para-cancerous histological normal tissues (PCHNTs) was methylated, showing partial methylation.	('methylated', 'Var', (50, 60))	('ESCCs', 'Disease', (40, 45))	('para-cancerous', 'Disease', 'MESH:D009369', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('PCHNTs', 'Chemical', '-', (150, 156))	('para-cancerous', 'Disease', (106, 120))
57195	26510908	The percentage of HIC1 non-methylation, partial methylation, and complete methylation in 76 ESCC tissues was 15.8% (12/76), 75% (57/76) and 9.2% (7/76), respectively.	('HIC1', 'Gene', (18, 22))	('HIC1', 'Gene', '3090', (18, 22))	('partial methylation', 'Var', (40, 59))	('methylation', 'MPA', (74, 85))	('non-methylation', 'Var', (23, 38))
57196	26510908	The frequency of HIC1 methylation in ESCC tissues was significantly higher as compared with that in paired PCHNTs (P = 0.000).	('HIC1', 'Gene', '3090', (17, 21))	('HIC1', 'Gene', (17, 21))	('higher', 'PosReg', (68, 74))	('PCHNTs', 'Chemical', '-', (107, 113))	('methylation', 'Var', (22, 33))
57202	26510908	Correspondingly, the frequency of HIC1 methylation in all non-cancer controls was very low, even lower than that in adjacent normal tissues.	('methylation', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('HIC1', 'Gene', '3090', (34, 38))	('HIC1', 'Gene', (34, 38))	('non-cancer', 'Disease', (58, 68))	('non-cancer', 'Disease', 'MESH:D009369', (58, 68))
57208	26510908	Downregulation of HIC1 at mRNA and protein level by methylation was associated with late stage, vascular invasion and lymph node metastasis, respectively (Table 1, all P < 0.05).	('vascular invasion', 'CPA', (96, 113))	('Downregulation', 'NegReg', (0, 14))	('lymph node metastasis', 'CPA', (118, 139))	('HIC1', 'Gene', (18, 22))	('late stage', 'CPA', (84, 94))	('HIC1', 'Gene', '3090', (18, 22))	('methylation', 'Var', (52, 63))
57213	26510908	Kaplan-Meier analysis demonstrated that no significant correlation was found between patients' OS and HIC1 protein downexpression, or HIC1 mRNA downexpression, or HIC1 methylation.	('HIC1', 'Gene', (102, 106))	('HIC1', 'Gene', (134, 138))	('mRNA', 'MPA', (139, 143))	('HIC1', 'Gene', '3090', (102, 106))	('HIC1', 'Gene', '3090', (134, 138))	('methylation', 'Var', (168, 179))	('patients', 'Species', '9606', (85, 93))	('protein', 'Protein', (107, 114))	('downexpression', 'NegReg', (144, 158))	('HIC1', 'Gene', '3090', (163, 167))	('HIC1', 'Gene', (163, 167))	('downexpression', 'NegReg', (115, 129))
57225	26510908	As analyzed by MTT assay, the cell proliferation rate of KYSE410 cells was significantly inhibited by HIC1 overexpression (Figure 6A).	('HIC1', 'Gene', (102, 106))	('HIC1', 'Gene', '3090', (102, 106))	('inhibited', 'NegReg', (89, 98))	('KYSE410', 'Var', (57, 64))	('overexpression', 'PosReg', (107, 121))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('cell proliferation rate', 'CPA', (30, 53))
57242	26510908	This inactivation of HIC1 might impel cancer cells to alter survival and signaling pathways or lineage-specific transcription factors during the early stages of tumorigenesis.	('HIC1 might impel cancer', 'Disease', (21, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('alter', 'Reg', (54, 59))	('HIC1 might impel cancer', 'Disease', 'MESH:D009369', (21, 44))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('inactivation', 'Var', (5, 17))	('lineage-specific', 'Gene', (95, 111))	('tumor', 'Disease', (161, 166))
57251	26510908	Emerging evidence suggests that HIC1 is frequently hypermethylated as a result of silence or low level in a variety of solid tumors.	('HIC1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('solid tumors', 'Disease', 'MESH:D009369', (119, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('HIC1', 'Gene', '3090', (32, 36))	('low', 'NegReg', (93, 96))	('silence', 'Var', (82, 89))	('solid tumors', 'Disease', (119, 131))
57253	26510908	Here, we showed that the CpG sites in the HIC1 promoter were mostly hypermethylated in primary ESCC tumors and cell lines, whereas those in normal esophageal mucosal tissues remained non-methylated.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('HIC1', 'Gene', '3090', (42, 46))	('HIC1', 'Gene', (42, 46))	('primary ESCC tumors', 'Disease', 'MESH:D004938', (87, 106))	('primary ESCC tumors', 'Disease', (87, 106))	('hypermethylated', 'Var', (68, 83))
57254	26510908	We concluded that the inactivation mediated by promoter methylation might be the major cause of the frequent HIC1 downregulation in ESCC cells.	('inactivation', 'NegReg', (22, 34))	('promoter methylation', 'Var', (47, 67))	('HIC1', 'Gene', '3090', (109, 113))	('HIC1', 'Gene', (109, 113))	('downregulation', 'NegReg', (114, 128))
57259	26510908	Results showed that both HIC1 hypermethylation and HIC1 downregulation both at mRNA and protein level were significantly correlated with vascular invasion, lymph node metastasis and clinical stage, respectively (all P < 0.05), suggesting that frequent dysfunction of HIC1 through its promoter methylation might play crucial roles in malignant progression of human esophageal cancer and might have a important impact on the metastasis and poor survival of ESCC patients.	('HIC1', 'Gene', '3090', (267, 271))	('esophageal cancer', 'Disease', (364, 381))	('HIC1', 'Gene', (25, 29))	('HIC1', 'Gene', '3090', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('play', 'Reg', (311, 315))	('promoter', 'MPA', (284, 292))	('impact', 'Reg', (409, 415))	('ESCC', 'Disease', (455, 459))	('HIC1', 'Gene', '3090', (25, 29))	('human', 'Species', '9606', (358, 363))	('malignant progression', 'CPA', (333, 354))	('hypermethylation', 'Var', (30, 46))	('HIC1', 'Gene', (267, 271))	('roles', 'Reg', (324, 329))	('esophageal cancer', 'Disease', 'MESH:D004938', (364, 381))	('HIC1', 'Gene', (51, 55))	('downregulation', 'NegReg', (56, 70))	('patients', 'Species', '9606', (460, 468))	('dysfunction', 'Var', (252, 263))
57260	26510908	It was reported that the loss of suppressive function of HIC1 by promoter hypermethylation was responsible for prostate cancer progression and invasion.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (111, 126))	('suppressive function', 'NegReg', (33, 53))	('HIC1', 'Gene', '3090', (57, 61))	('invasion', 'CPA', (143, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('loss', 'NegReg', (25, 29))	('promoter hypermethylation', 'Var', (65, 90))	('HIC1', 'Gene', (57, 61))
57261	26510908	Recently, Eggers H, et al pinpointed that HIC1 hypermethylation was associated with reduced recurrence-free survival in renal cell carcinoma (RCC), suggesting that HIC1 could be seen as a possible marker to improve individualized therapy and risk stratification.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('HIC1', 'Gene', (164, 168))	('recurrence-free survival', 'CPA', (92, 116))	('HIC1', 'Gene', '3090', (164, 168))	('HIC1', 'Gene', '3090', (42, 46))	('reduced', 'NegReg', (84, 91))	('HIC1', 'Gene', (42, 46))	('renal cell carcinoma', 'Disease', (120, 140))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('hypermethylation', 'Var', (47, 63))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 140))
57266	26510908	The abnormal regulation of Eph pathway via HIC1 epigenetic silencing could be an important mechanism in the pathogenesis of epithelial cancers.	('Eph pathway', 'Pathway', (27, 38))	('regulation', 'Reg', (13, 23))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('epithelial cancers', 'Disease', (124, 142))	('HIC1', 'Gene', '3090', (43, 47))	('epigenetic silencing', 'Var', (48, 68))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('epithelial cancers', 'Disease', 'MESH:D000077216', (124, 142))	('HIC1', 'Gene', (43, 47))
57291	26510908	The primers used in PCR are listed as follows: HIC1 sense 5'-cga cga cta caa gag cag cag c-3', and antisense 5'-cag gtt gtc acc gaa gct ctc-3'.	('HIC1', 'Gene', '3090', (47, 51))	('HIC1', 'Gene', (47, 51))	('gaa', 'Gene', (128, 131))	('gag', 'Chemical', 'MESH:D006025', (77, 80))	("antisense 5'-cag", 'Var', (99, 115))	('gaa', 'Gene', '2548', (128, 131))
57292	26510908	EphA2 sense 5'-tgt gcc agg cag gct acg-3', and antisense 5'-ctc caa gca ggg gct ctc a-3'.	('EphA2', 'Gene', '1969', (0, 5))	("antisense 5'-ctc", 'Var', (47, 63))	('EphA2', 'Gene', (0, 5))
57297	26510908	The specific primers for detection of HIC1 CpG island methylation and unmethylation were designed according to previous report.	('methylation', 'Var', (54, 65))	('HIC1', 'Gene', '3090', (38, 42))	('HIC1', 'Gene', (38, 42))
57311	26880967	MSCs also inhibit primary tumour growth and metastasis formation in mice resulting in prolonged survival.	('mice', 'Species', '10090', (68, 72))	('survival', 'CPA', (96, 104))	('prolonged', 'PosReg', (86, 95))	('MSCs', 'Var', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('inhibit', 'NegReg', (10, 17))
57338	26880967	Antibodies to CD44-FITC, CD45-FITC, CD73-FITC, CD90-FITC, and CD105-FITC (Abcam, USA) were used to mark cell surface epitopes.	('FITC', 'Chemical', 'MESH:D016650', (52, 56))	('FITC', 'Chemical', 'MESH:D016650', (19, 23))	('CD44-FITC', 'Var', (14, 23))	('FITC', 'Chemical', 'MESH:D016650', (68, 72))	('CD73-FITC', 'Var', (36, 45))	('CD90-FITC', 'Var', (47, 56))	('FITC', 'Chemical', 'MESH:D016650', (30, 34))	('CD105-FITC', 'Chemical', '-', (62, 72))	('CD105-FITC', 'Var', (62, 72))	('CD45-FITC', 'Var', (25, 34))	('FITC', 'Chemical', 'MESH:D016650', (41, 45))
57348	26880967	p21 knockdown was also associated with the reversal of fd-ECM-mediated downregulation of PCNA and BCL-2 mRNA levels in both WHCO1 and MDA MB 231 cells.	('downregulation', 'NegReg', (71, 85))	('BCL-2', 'Gene', (98, 103))	('p21', 'Gene', (0, 3))	('BCL-2', 'Gene', '596', (98, 103))	('knockdown', 'Var', (4, 13))
57384	21372352	High platelet counts were found to be associated with tumor progression and poor survival in esophageal cancer.	('High platelet count', 'Phenotype', 'HP:0001894', (0, 19))	('poor', 'NegReg', (76, 80))	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('High platelet counts', 'Phenotype', 'HP:0001894', (0, 20))	('tumor', 'Disease', (54, 59))
57412	21372352	Additionally, TP inhibition suppresses tumor growth by increasing the proportion of apoptotic cells and probably inhibiting angiogenesis.	('TP', 'Gene', '1890', (14, 16))	('inhibiting', 'NegReg', (113, 123))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('inhibition', 'Var', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('suppresses', 'NegReg', (28, 38))	('tumor', 'Disease', (39, 44))	('increasing', 'PosReg', (55, 65))	('angiogenesis', 'CPA', (124, 136))
57429	19407849	RNA interference-mediated knockdown of p21WAF1 enhances anti-tumor cell activity of oncolytic adenoviruses The ability of oncolytic adenoviruses to replicate in and lyse cancer cells offers a potential therapeutic approach.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('enhances', 'PosReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('knockdown', 'Var', (26, 35))	('p21WAF1', 'Gene', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
57430	19407849	In this study, we present that loss of p21WAF1 promotes adenovirus replication and more effective cell killing.	('cell killing', 'CPA', (98, 110))	('adenovirus', 'Protein', (56, 66))	('promotes', 'PosReg', (47, 55))	('loss', 'Var', (31, 35))	('p21', 'Gene', (39, 42))	('p21', 'Gene', '1026', (39, 42))	('more', 'PosReg', (83, 87))
57431	19407849	To test our hypothesis, we took HCT116 colon cancer cell lines carrying deletions of either p21WAF1 or p53, and infected these cell lines with wild-type adenovirus (WtD) or the oncolytic adenoviruses, ONYX-015 and Delta-24.	('p53', 'Gene', (103, 106))	('colon cancer', 'Disease', 'MESH:D015179', (39, 51))	('colon cancer', 'Phenotype', 'HP:0003003', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Delta-24', 'Chemical', '-', (214, 222))	('colon cancer', 'Disease', (39, 51))	('p21', 'Gene', '1026', (92, 95))	('deletions', 'Var', (72, 81))	('p21', 'Gene', (92, 95))	('HCT116', 'CellLine', 'CVCL:0291', (32, 38))
57432	19407849	We found that WtD, ONYX-015 and Delta-24 induced stronger cytopathic effects in HCT116 p21-/- cells compared with HCT116-WT cells.	('cytopathic effects', 'CPA', (58, 76))	('p21', 'Gene', '1026', (87, 90))	('p21', 'Gene', (87, 90))	('Delta-24', 'Chemical', '-', (32, 40))	('stronger', 'PosReg', (49, 57))	('HCT116', 'CellLine', 'CVCL:0291', (80, 86))	('HCT116', 'CellLine', 'CVCL:0291', (114, 120))	('Delta-24', 'Var', (32, 40))
57438	19407849	One strategy for achieving tumor selectivity is to mutate or partially delete E1 genes that are required for viral replication in normal cells but are dispensable in cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('E1 genes', 'Gene', (78, 86))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', (27, 32))	('delete', 'NegReg', (71, 77))	('mutate', 'Var', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
57440	19407849	Although indeed aberrations within the p53 pathway seem to contribute to ONYX-015's selectivity, it is now clear that additional, p53-independent effects are important for its tumor selectivity.	('selectivity', 'MPA', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('aberrations', 'Var', (16, 27))	('p53 pathway', 'Pathway', (39, 50))	('contribute', 'Reg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
57441	19407849	Another oncolytic adenovirus, Delta-24, contains a 24-bp deletion in the viral E1A gene, which prevents binding of E1A to the RB protein.	('prevents', 'NegReg', (95, 103))	('deletion', 'Var', (57, 65))	('E1A', 'Protein', (115, 118))	('RB', 'Chemical', 'MESH:D012413', (126, 128))	('binding', 'Interaction', (104, 111))	('E1A', 'Gene', (79, 82))	('RB protein', 'Protein', (126, 136))	('Delta-24', 'Chemical', '-', (30, 38))
57450	19407849	HCT116 wild-type (HCT116-WT) cells and their derivatives, HCT116 p21-/- and HCT116 p53-/- (clone 379.2), carrying homozygous deletions of p21 and p53, respectively, were kindly provided by Dr Bert Vogelstein (John Hopkins Cancer Center, Baltimore, MD).	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('p21', 'Gene', '1026', (65, 68))	('p21', 'Gene', '1026', (138, 141))	('p21', 'Gene', (65, 68))	('p21', 'Gene', (138, 141))	('John Hopkins Cancer', 'Disease', 'MESH:D010283', (209, 228))	('p53', 'Gene', (146, 149))	('HCT116', 'CellLine', 'CVCL:0291', (58, 64))	('HCT116', 'CellLine', 'CVCL:0291', (0, 6))	('HCT116', 'CellLine', 'CVCL:0291', (76, 82))	('deletions', 'Var', (125, 134))	('HCT116', 'CellLine', 'CVCL:0291', (18, 24))	('John Hopkins Cancer', 'Disease', (209, 228))
57457	19407849	Viruses included wild-type adenovirus (WtD), the E1B-55K-deficient adenovirus mutant ONYX-015 and Delta-24, which carries a 24-bp deletion in the viral E1A gene (kindly provided by Dr Juan Fueyo, University of Texas MD Anderson Cancer Center, Houston, TX).	('E1B', 'Gene', '6080', (49, 52))	('Texas MD Anderson Cancer', 'Disease', 'MESH:C535460', (210, 234))	('E1B', 'Gene', (49, 52))	('Texas MD Anderson Cancer', 'Disease', (210, 234))	('deletion', 'Var', (130, 138))	('Cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Delta-24', 'Chemical', '-', (98, 106))	('E1A', 'Gene', (152, 155))
57464	19407849	For p21WAF1, 30 n of CDKN1A cat # J-003471-11 and J-003471-12 (oligonucleotides (oligos) #11, #12 hereafter) and for p27KIP1 30 n of CDKN1B cat # J-003472-05 and J-003472-08 (oligos #5, #8 hereafter) were used.	('p21', 'Gene', (4, 7))	('p27KIP1', 'Gene', '1027', (117, 124))	('CDKN1B', 'Gene', (133, 139))	('p27KIP1', 'Gene', (117, 124))	('CDKN1B', 'Gene', '1027', (133, 139))	('CDKN1A', 'Gene', (21, 27))	('CDKN1A', 'Gene', '1026', (21, 27))	('oligonucleotides', 'Chemical', 'MESH:D009841', (63, 79))	('p21', 'Gene', '1026', (4, 7))	('J-003471-12', 'Var', (50, 61))
57477	19407849	Primary mouse monoclonal antibodies used were anti-p21 (sc-6246, Santa Cruz Biotechnology, Inc., Santa Cruz, CA), anti-p53 (sc-126, Santa Cruz Biotechnology) and anti-beta-actin (Sigma-Aldrich).	('p21', 'Gene', '1026', (51, 54))	('beta-actin', 'Gene', '728378', (167, 177))	('p21', 'Gene', (51, 54))	('beta-actin', 'Gene', (167, 177))	('mouse', 'Species', '10090', (8, 13))	('anti-p53', 'Var', (114, 122))
57487	19407849	As the increase in killing of HCT116 p21-/- cells could have been a result of enhanced apoptosis and not of virus-mediated cell lysis, we examined the ability of adenovirus to replicate and to produce viable progeny in HCT116-WT, HCT116 p21-/- and HCT116 p53-/- cells.	('increase', 'PosReg', (7, 15))	('HCT116', 'CellLine', 'CVCL:0291', (30, 36))	('p21', 'Gene', (237, 240))	('HCT116', 'CellLine', 'CVCL:0291', (230, 236))	('HCT116', 'CellLine', 'CVCL:0291', (219, 225))	('p21', 'Gene', '1026', (37, 40))	('HCT116', 'Var', (30, 36))	('apoptosis', 'CPA', (87, 96))	('HCT116', 'CellLine', 'CVCL:0291', (248, 254))	('p21', 'Gene', (37, 40))	('p21', 'Gene', '1026', (237, 240))	('enhanced', 'PosReg', (78, 86))
57493	19407849	We found that the number of copies of adenovirus fiber taken up by the cells was the same for both cell lines after 24 and 48 h after infection (data not shown), thus indicating that loss of p21WAF1 does not affect adenoviral entry into these cell lines.	('p21', 'Gene', '1026', (191, 194))	('loss', 'Var', (183, 187))	('p21', 'Gene', (191, 194))	('adenoviral entry', 'CPA', (215, 231))
57494	19407849	To determine if indeed the loss of p21WAF1 promotes adenovirus-mediated cell killing and is not an artifact related to the HCT116 p21-/- cell line, we silenced p21WAF1 in HCT116-WT cells and evaluated whether cell killing and virus production were also enhanced in this system.	('loss', 'Var', (27, 31))	('p21', 'Gene', (130, 133))	('HCT116', 'CellLine', 'CVCL:0291', (171, 177))	('promotes', 'PosReg', (43, 51))	('silenced', 'Var', (151, 159))	('p21', 'Gene', (35, 38))	('cell killing', 'CPA', (209, 221))	('HCT116', 'CellLine', 'CVCL:0291', (123, 129))	('p21', 'Gene', '1026', (160, 163))	('p21', 'Gene', (160, 163))	('adenovirus-mediated cell killing', 'CPA', (52, 84))	('p21', 'Gene', '1026', (35, 38))	('p21', 'Gene', '1026', (130, 133))	('enhanced', 'PosReg', (253, 261))
57495	19407849	As p21WAF1 is functionally related to p27KIP1, we expanded our analysis also by knockdown of p27KIP1.	('knockdown', 'Var', (80, 89))	('p27KIP1', 'Gene', '1027', (93, 100))	('p27KIP1', 'Gene', (38, 45))	('p27KIP1', 'Gene', (93, 100))	('p21', 'Gene', '1026', (3, 6))	('p27KIP1', 'Gene', '1027', (38, 45))	('p21', 'Gene', (3, 6))
57501	19407849	Similarly to WtD, the oncolytic effect of ONYX-015 increased when p21WAF1 was silenced (Figure 3f), although p27KIP1 knockdown showed no effect on cell killing by ONYX-015 (Figure 3f).	('p27KIP1', 'Gene', (109, 116))	('p21', 'Gene', (66, 69))	('increased', 'PosReg', (51, 60))	('p27KIP1', 'Gene', '1027', (109, 116))	('knockdown', 'Var', (117, 126))	('oncolytic effect', 'MPA', (22, 38))	('p21', 'Gene', '1026', (66, 69))
57513	19407849	These results suggest that p53 plays an important role in virus replication and oncolytic effect after knockdown of p21WAF1 and p27KIP1.	('p21', 'Gene', (116, 119))	('p27KIP1', 'Gene', '1027', (128, 135))	('virus replication', 'CPA', (58, 75))	('p21', 'Gene', '1026', (116, 119))	('p27KIP1', 'Gene', (128, 135))	('oncolytic effect', 'CPA', (80, 96))	('knockdown', 'Var', (103, 112))
57516	19407849	To find out whether the observed effects resulting from p21WAF1 knockdown on adenovirus replication are specific for HCT116 cells, we expanded our analysis to TE7 cells, an esophageal carcinoma cell line, as this tumor type is a possible target for adenoviral therapies.	('tumor', 'Disease', (213, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('p21', 'Gene', '1026', (56, 59))	('p21', 'Gene', (56, 59))	('esophageal carcinoma', 'Disease', (173, 193))	('HCT116', 'CellLine', 'CVCL:0291', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (173, 193))	('knockdown', 'Var', (64, 73))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (173, 193))
57517	19407849	Viability of this cell decreases to 28, 71 and 59% after p21WAF1 knockdown (oligo #12) and adenovirus WtD, ONYX-015 and Delta-24 infection, respectively, compared with untreated cells (Figures 5a and b).	('Viability', 'CPA', (0, 9))	('Delta-24', 'Chemical', '-', (120, 128))	('p21', 'Gene', '1026', (57, 60))	('decreases', 'NegReg', (23, 32))	('knockdown', 'Var', (65, 74))	('p21', 'Gene', (57, 60))
57518	19407849	To address the role of p53 in cells lacking functional p53 expression, we used H1299, p53 null, and DU-145, non-functional p53.	('DU-145', 'CellLine', 'CVCL:0105', (100, 106))	('H1299', 'CellLine', 'CVCL:0060', (79, 84))	('H1299', 'Var', (79, 84))	('p53', 'Gene', (86, 89))
57520	19407849	For H1299 cells infected with oncolytic adenoviruses, ONYX-015, no increase in cell-killing effect was observed, although there was an increased viruses production after p21WAF1 knockdown (oligo #12) (Figures 5c and 6).	('p21', 'Gene', '1026', (170, 173))	('increased', 'PosReg', (135, 144))	('viruses production', 'MPA', (145, 163))	('p21', 'Gene', (170, 173))	('knockdown', 'Var', (178, 187))	('H1299', 'CellLine', 'CVCL:0060', (4, 9))
57521	19407849	For DU-145 cells, a slightly decrease in the viability and increase in virus production were observed after p21WAF1 knockdown (oligo #12) and infection of ONYX-015 and Delta-24 (Figures 5d and c).	('Delta-24', 'Chemical', '-', (168, 176))	('p21', 'Gene', '1026', (108, 111))	('p21', 'Gene', (108, 111))	('knockdown', 'Var', (116, 125))	('DU-145', 'CellLine', 'CVCL:0105', (4, 10))	('virus production', 'MPA', (71, 87))	('decrease', 'NegReg', (29, 37))	('increase', 'PosReg', (59, 67))
57524	19407849	For example, H101, a variant of ONYX-015, has been approved for the use in head-and-neck cancer by the Chinese authorities.	('head-and-neck cancer', 'Phenotype', 'HP:0012288', (75, 95))	('H101', 'Var', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
57526	19407849	Our data show that loss of p21WAF1 promotes adenovirus replication and more effective cell killing compared with cells expressing p21WAF1.	('p21', 'Gene', (27, 30))	('p21', 'Gene', (130, 133))	('more', 'PosReg', (71, 75))	('p21', 'Gene', '1026', (27, 30))	('promotes', 'PosReg', (35, 43))	('p21', 'Gene', '1026', (130, 133))	('cell killing', 'CPA', (86, 98))	('loss', 'Var', (19, 23))	('adenovirus', 'Protein', (44, 54))
57527	19407849	We took advantage of a derivative of the human HCT116 colon cancer cell line harboring a homozygous deletion of p21-/-, and found that wild-type adenovirus and ONYX-015 replicate more efficiently in tumor cells lacking p21WAF1 expression compared with wild-type cells (Figure 1).	('tumor', 'Disease', (199, 204))	('HCT116', 'CellLine', 'CVCL:0291', (47, 53))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('p21', 'Gene', (219, 222))	('human', 'Species', '9606', (41, 46))	('colon cancer', 'Disease', (54, 66))	('replicate', 'MPA', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('p21', 'Gene', '1026', (112, 115))	('deletion', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('p21', 'Gene', '1026', (219, 222))	('p21', 'Gene', (112, 115))
57538	19407849	We expanded our studies using two different cell lines with non-functioning p53, H1299 and DU-145, and we found that again virus production but not cell-killing effect were enhanced after p21 knockdown in cells infected with oncolytic adenoviruses, ONYX-015 or Delta-24.	('DU-145', 'CellLine', 'CVCL:0105', (91, 97))	('cell-killing effect', 'CPA', (148, 167))	('Delta-24', 'Chemical', '-', (261, 269))	('H1299', 'CellLine', 'CVCL:0060', (81, 86))	('virus production', 'MPA', (123, 139))	('p21', 'Gene', '1026', (188, 191))	('enhanced', 'PosReg', (173, 181))	('p21', 'Gene', (188, 191))	('knockdown', 'Var', (192, 201))
57540	19407849	reported that wild-type p53 was associated with increased anti-tumor activity of ONYX-015 in human malignant glioma xenografts.	('tumor', 'Disease', (63, 68))	('increased', 'PosReg', (48, 57))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('human', 'Species', '9606', (93, 98))	('ONYX-015', 'Gene', (81, 89))	('malignant glioma', 'Disease', 'MESH:D005910', (99, 115))	('malignant glioma', 'Disease', (99, 115))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('wild-type', 'Var', (14, 23))	('p53', 'Var', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
57544	19407849	Delta-24 carries a deletion within the CR2 region of E1A, a region necessary for interaction with and inactivation of RB.	('deletion', 'Var', (19, 27))	('Delta-24', 'Gene', (0, 8))	('CR2', 'Species', '2498238', (39, 42))	('RB', 'Chemical', 'MESH:D012413', (118, 120))	('Delta-24', 'Chemical', '-', (0, 8))
57546	19407849	This finding also confirms that expression of p21WAF1 decreases the cytophatic effects of the Delta-24 adenovirus.	('Delta-24', 'Var', (94, 102))	('expression', 'Var', (32, 42))	('p21', 'Gene', '1026', (46, 49))	('Delta-24', 'Chemical', '-', (94, 102))	('decreases', 'NegReg', (54, 63))	('p21', 'Gene', (46, 49))	('cytophatic effects', 'MPA', (68, 86))
57556	19407849	Interestingly, antisense oligonucleotides directed against human p21WAF1 have been described as a means of improving cancer radiotherapy.	('human', 'Species', '9606', (59, 64))	('p21', 'Gene', '1026', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('p21', 'Gene', (65, 68))	('oligonucleotides', 'Chemical', 'MESH:D009841', (25, 41))	('antisense oligonucleotides', 'Var', (15, 41))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('improving', 'PosReg', (107, 116))
57570	18941749	Overexpression of RR2M is associated with increased cell proliferation and malignant potential in certain cancers and inhibition of RRM2 reduces cellular proliferation in vitro and in vivo.	('increased', 'PosReg', (42, 51))	('cellular proliferation', 'CPA', (145, 167))	('reduces', 'NegReg', (137, 144))	('cell proliferation', 'CPA', (52, 70))	('RR2M', 'Gene', '6241', (18, 22))	('RRM2', 'Gene', '6241', (132, 136))	('RR2M', 'Gene', (18, 22))	('RRM2', 'Gene', (132, 136))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('Overexpression', 'Var', (0, 14))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('malignant potential', 'CPA', (75, 94))	('inhibition', 'Var', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
57572	18941749	Therefore, inhibition of RRM2 is a potential therapeutic target for new anticancer agents.	('RRM2', 'Gene', '6241', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('inhibition', 'Var', (11, 21))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('RRM2', 'Gene', (25, 29))
57595	18941749	The mean CV in the Ct values for RRM2 over this time ranged from 0.32% (range 0.09-0.68%) for the 400 ng standard to 1.47% (range 0.66-2.84%) for the 0.128 ng standard.	('0.128 ng', 'Var', (150, 158))	('RRM2', 'Gene', (33, 37))	('RRM2', 'Gene', '6241', (33, 37))
57628	18941749	Gandera and colleagues recently reported preliminary findings suggesting inhibition of RRM2 gene expression was associated with clinical response to the antisense agent GTI-2040 targeting RRM2.	('RRM2', 'Gene', '6241', (87, 91))	('inhibition', 'Var', (73, 83))	('RRM2', 'Gene', (87, 91))	('associated', 'Reg', (112, 122))	('RRM2', 'Gene', '6241', (188, 192))	('GTI-2040', 'Chemical', 'MESH:C464617', (169, 177))	('RRM2', 'Gene', (188, 192))
57680	20037711	However, fast transit in the dilated small intestine in Chagas disease has been associated with bacteria overgrowth with chronic diarrhea, malabsorption, steatorrhea and hypocalcemia that improved with oral antibiotic therapy.	('malabsorption', 'Disease', (139, 152))	('fast', 'Var', (9, 13))	('associated', 'Reg', (80, 90))	('chronic diarrhea', 'Phenotype', 'HP:0002028', (121, 137))	('diarrhea', 'Phenotype', 'HP:0002014', (129, 137))	('malabsorption', 'Phenotype', 'HP:0002024', (139, 152))	('bacteria overgrowth', 'Disease', (96, 115))	('Chagas disease', 'Disease', 'MESH:D014355', (56, 70))	('steatorrhea', 'Disease', (154, 165))	('hypocalcemia', 'Disease', (170, 182))	('Chagas disease', 'Disease', (56, 70))	('hypocalcemia', 'Phenotype', 'HP:0002901', (170, 182))	('diarrhea', 'Disease', (129, 137))	('steatorrhea', 'Phenotype', 'HP:0002570', (154, 165))	('malabsorption', 'Disease', 'MESH:D008286', (139, 152))	('diarrhea', 'Disease', 'MESH:D003967', (129, 137))	('overgrowth', 'Phenotype', 'HP:0001548', (105, 115))	('steatorrhea', 'Disease', 'MESH:D045602', (154, 165))	('hypocalcemia', 'Disease', 'MESH:D006996', (170, 182))
57688	20037711	Alteration of the rectoanal inhibitory reflex in most of the chagasic patients with megacolon was demonstrated by several researchers and can be justified by the destruction of enteric motor innervations.	('patients', 'Species', '9606', (70, 78))	('Alteration', 'Var', (0, 10))	('inhibitory reflex', 'Phenotype', 'HP:0001265', (28, 45))	('megacolon', 'Phenotype', 'HP:0002251', (84, 93))	('megacolon', 'Disease', (84, 93))	('rectoanal inhibitory reflex', 'MPA', (18, 45))
57698	20037711	Despite the controversy regarding the pathogenic role of defects in the interstitial cells of Cajal in idiopathic constipation and other gastrointestinal motor disorders, changes in the distribution of the interstitial cells of Cajal have been reported in various conditions, such as achalasia, chronic intestinal pseudo-obstruction, infantile hypertrophic pyloric stenosis, Hirschsprung's disease, inflammatory bowel disease and slow transit constipation.	('hypertrophic pyloric stenosis', 'Disease', (344, 373))	('hypertrophic pyloric stenosis', 'Disease', 'MESH:D046248', (344, 373))	('gastrointestinal motor disorders', 'Disease', 'MESH:D005767', (137, 169))	('achalasia', 'Disease', (284, 293))	('idiopathic constipation', 'Disease', (103, 126))	("Hirschsprung's disease", 'Phenotype', 'HP:0002251', (375, 397))	('achalasia', 'Phenotype', 'HP:0002571', (284, 293))	('idiopathic constipation', 'Disease', 'MESH:D003248', (103, 126))	('constipation', 'Disease', 'MESH:D003248', (443, 455))	('constipation', 'Phenotype', 'HP:0002019', (114, 126))	("Hirschsprung's disease", 'Disease', (375, 397))	("Hirschsprung's disease", 'Disease', 'MESH:D006627', (375, 397))	('changes', 'Var', (171, 178))	('chronic intestinal pseudo-obstruction', 'Disease', (295, 332))	('pyloric stenosis', 'Phenotype', 'HP:0002021', (357, 373))	('constipation', 'Disease', 'MESH:D003248', (114, 126))	('gastrointestinal motor disorders', 'Disease', (137, 169))	('constipation', 'Disease', (443, 455))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (399, 425))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (399, 425))	('inflammatory bowel disease', 'Disease', (399, 425))	('reported', 'Reg', (244, 252))	('achalasia', 'Disease', 'MESH:D004931', (284, 293))	('constipation', 'Disease', (114, 126))	('intestinal pseudo-obstruction', 'Phenotype', 'HP:0004389', (303, 332))	('constipation', 'Phenotype', 'HP:0002019', (443, 455))
57706	20037711	Chagas disease is related to several chronic gastrointestinal disorders resulting from damage to both excitatory and inhibitory enteric motor innervations, leading to megaesophagus, megacolon, megasmall intestine, megagallbladder, megacholedochus, achalasia of the cardia, changes in gastric receptive relaxation, fast gastric emptying of liquid meals, delayed gastric emptying of solid meals, altered small intestine transit and impairment of colon and gallbladder motility.	('megasmall intestine', 'Disease', (193, 212))	('small intestine transit', 'CPA', (402, 425))	('gastric emptying', 'Phenotype', 'HP:0002578', (361, 377))	('Chagas disease', 'Disease', 'MESH:D014355', (0, 14))	('gastric receptive relaxation', 'MPA', (284, 312))	('gastrointestinal disorders', 'Phenotype', 'HP:0011024', (45, 71))	('delayed gastric emptying', 'Phenotype', 'HP:0002578', (353, 377))	('megagallbladder', 'Disease', (214, 229))	('achalasia of the cardia', 'Disease', (248, 271))	('megacolon', 'Disease', (182, 191))	('Chagas disease', 'Disease', (0, 14))	('impairment of colon and gallbladder motility', 'Disease', 'MESH:D015835', (430, 474))	('fast gastric emptying', 'CPA', (314, 335))	('gastrointestinal disorders', 'Disease', 'MESH:D005767', (45, 71))	('achalasia of the cardia', 'Disease', 'MESH:D004931', (248, 271))	('altered', 'Reg', (394, 401))	('gastric emptying', 'Phenotype', 'HP:0002578', (319, 335))	('megacolon', 'Phenotype', 'HP:0002251', (182, 191))	('delayed gastric emptying', 'CPA', (353, 377))	('megaesophagus', 'Disease', (167, 180))	('changes', 'Reg', (273, 280))	('achalasia', 'Phenotype', 'HP:0002571', (248, 257))	('gastrointestinal disorders', 'Disease', (45, 71))	('damage', 'Var', (87, 93))	('megacholedochus', 'Disease', (231, 246))
57711	34022910	This study aimed to explore the role and molecular mechanism of circ_0006168 in Taxol resistance of ESCC.	('circ_0006168', 'Var', (64, 76))	('circ_0006168', 'Chemical', '-', (64, 76))	('Taxol resistance', 'MPA', (80, 96))	('Taxol', 'Chemical', 'MESH:D017239', (80, 85))
57718	34022910	Functionally, knockdown of circ_0006168 or JMJD1C increased Taxol sensitivity of ESCC in vitro via inhibiting cell proliferation, migration and invasion, and promoting apoptosis.	('inhibiting', 'NegReg', (99, 109))	('Taxol', 'Chemical', 'MESH:D017239', (60, 65))	('increased', 'PosReg', (50, 59))	('Taxol sensitivity', 'MPA', (60, 77))	('apoptosis', 'CPA', (168, 177))	('circ_0006168', 'Var', (27, 39))	('cell proliferation', 'CPA', (110, 128))	('JMJD1C', 'Gene', (43, 49))	('promoting', 'PosReg', (158, 167))	('circ_0006168', 'Chemical', '-', (27, 39))
57719	34022910	Moreover, circ_0006168 could directly bind to miR-194-5p and JMJD1C was verified as a direct target of miR-194-5p.	('bind', 'Interaction', (38, 42))	('miR-194-5p', 'Protein', (46, 56))	('circ_0006168', 'Var', (10, 22))	('circ_0006168', 'Chemical', '-', (10, 22))
57721	34022910	Furthermore, JMJD1C overexpression reversed the promotive effect of circ_0006168 knockdown on Taxol sensitivity.	('Taxol sensitivity', 'MPA', (94, 111))	('promotive effect', 'MPA', (48, 64))	('Taxol', 'Chemical', 'MESH:D017239', (94, 99))	('knockdown', 'Var', (81, 90))	('circ_0006168', 'Gene', (68, 80))	('circ_0006168', 'Chemical', '-', (68, 80))
57723	34022910	Circ_0006168 facilitated Taxol resistance in ESCC by regulating miR-194-5p/JMJD1C axis, providing a promising therapeutic target for ESCC chemotherapy.	('regulating', 'Reg', (53, 63))	('Taxol resistance', 'MPA', (25, 41))	('Circ_0006168', 'Var', (0, 12))	('facilitated', 'PosReg', (13, 24))	('Taxol', 'Chemical', 'MESH:D017239', (25, 30))	('miR-194-5p/JMJD1C axis', 'MPA', (64, 86))
57733	34022910	Moreover, hsa_circ_0030998 suppressed lung cancer tumorigenesis and Taxol resistance by sponging miR-558.	('lung cancer', 'Disease', (38, 49))	('miR-558', 'Gene', '693143', (97, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('hsa_circ_0030998', 'Var', (10, 26))	('suppressed', 'NegReg', (27, 37))	('Taxol', 'Chemical', 'MESH:D017239', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('miR-558', 'Gene', (97, 104))	('Taxol resistance', 'CPA', (68, 84))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
57734	34022910	In addition, hsa_circ_0002483 inhibited the progression and enhanced the Taxol sensitivity of non-small cell lung cancer via regulating miR-182-5p.	('Taxol', 'Chemical', 'MESH:D017239', (73, 78))	('miR-182', 'Gene', (136, 143))	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('progression', 'MPA', (44, 55))	('inhibited', 'NegReg', (30, 39))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('miR-182', 'Gene', '406958', (136, 143))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('regulating', 'Reg', (125, 135))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('enhanced', 'PosReg', (60, 68))	('hsa_circ_0002483', 'Var', (13, 29))	('Taxol sensitivity', 'MPA', (73, 90))
57737	34022910	MiR-194-5p, an endogenous miRNA with low expression in many cancers, was shown to suppress ESCC cell progression.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('ESCC', 'Disease', (91, 95))	('MiR-194-5p', 'Var', (0, 10))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('MiR-194-5p', 'Chemical', '-', (0, 10))	('suppress', 'NegReg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
57738	34022910	Moreover, miR-194-5p downregulation induced Taxol resistance in ovarian cancer cells via affecting MDM2 expression.	('miR-194-5p', 'Var', (10, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (64, 78))	('MDM2', 'Gene', '4193', (99, 103))	('affecting', 'Reg', (89, 98))	('MDM2', 'Gene', (99, 103))	('Taxol', 'Chemical', 'MESH:D017239', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('downregulation', 'NegReg', (21, 35))	('Taxol resistance', 'MPA', (44, 60))	('expression', 'MPA', (104, 114))	('induced', 'PosReg', (36, 43))	('ovarian cancer', 'Disease', (64, 78))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))
57740	34022910	Base on the analysis of bioinformatics software (Circinteractome and TargetScan), we found that circ_0006168 and JMJD1C had complementary binding sequence for miR-194-5p, which stimulated us to assume the ceRNA regulatory network of circ_0006168/ miR-194-5p/JMJD1C in Taxol resistance of ESCC.	('Taxol', 'Chemical', 'MESH:D017239', (268, 273))	('circ_0006168', 'Chemical', '-', (96, 108))	('Taxol resistance', 'MPA', (268, 284))	('circ_0006168', 'Chemical', '-', (233, 245))	('circ_0006168/ miR-194-5p/JMJD1C', 'Var', (233, 264))
57741	34022910	In this work, the abundance of circ_0006168, miR-194-5p and JMJD1C in ESCC tissues, ESCC cells, and Taxol-resistant cells was determined.	('miR-194-5p', 'Gene', (45, 55))	('JMJD1C', 'Gene', (60, 66))	('circ_0006168', 'Chemical', '-', (31, 43))	('Taxol', 'Chemical', 'MESH:D017239', (100, 105))	('circ_0006168', 'Var', (31, 43))
57742	34022910	Then we investigated the biological roles of circ_0006168 in Taxol-resistant cell growth, migration, invasion, and apoptosis.	('circ_0006168', 'Chemical', '-', (45, 57))	('circ_0006168', 'Var', (45, 57))	('Taxol', 'Chemical', 'MESH:D017239', (61, 66))	('investigated', 'Reg', (8, 20))
57771	34022910	For migration, transfected cells (Eca109/Taxol and KYSE150/Taxol) suspended in serum-free RPMI-1640 (0.2 mL) were seeded into the top chamber of the 24-well transwell plates (Costar, Corning, NY, USA).	('Taxol', 'Chemical', 'MESH:D017239', (59, 64))	('KYSE150/Taxol', 'Var', (51, 64))	('Taxol', 'Chemical', 'MESH:D017239', (41, 46))	('KYSE150', 'Chemical', '-', (51, 58))	('migration', 'CPA', (4, 13))	('RPMI-1640', 'Chemical', '-', (90, 99))
57777	34022910	Meanwhile, their mutated-type reporter vectors (circ_0006168-mut and JMJD1C-mut) without binding sites were constructed in the same way.	('circ_0006168-mut', 'Var', (48, 64))	('JMJD1C-mut', 'Var', (69, 79))	('circ_0006168', 'Chemical', '-', (48, 60))
57786	34022910	These membranes were incubated for 12 h at 4C using primary antibody against JMJD1C (ab130922, 1:2000, Abcam, Cambridge, UK) or GAPDH (ab37168, 1:1000, Abcam) after blocking with 5% non-fat milk.	('ab130922', 'Var', (85, 93))	('JMJD1C', 'Gene', (77, 83))	('GAPDH', 'Gene', '2597', (128, 133))	('GAPDH', 'Gene', (128, 133))	('ab37168', 'Var', (135, 142))
57790	34022910	All mice would be sacrificed after injection for 5 weeks, and the tumor tissues were excised, weighed and harvested for detecting the abundance of circ_0006168, miR-194-5p and JMJD1C.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('JMJD1C', 'Var', (176, 182))	('mice', 'Species', '10090', (4, 8))	('tumor', 'Disease', (66, 71))	('circ_0006168', 'Var', (147, 159))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('circ_0006168', 'Chemical', '-', (147, 159))	('miR-194-5p', 'Var', (161, 171))
57791	34022910	To explore the potential roles of circ_0006168 in ESCC, the expression of circ_0006168 was detected by qRT-PCR in ESCC tissues and cells.	('circ_0006168', 'Chemical', '-', (34, 46))	('circ_0006168', 'Chemical', '-', (74, 86))	('ESCC', 'Disease', (114, 118))	('circ_0006168', 'Var', (74, 86))
57793	34022910	Likewise, compared with HET-1A cells, the expression of circ_0006168 level was also increased in ESCC cells (Eca109, KYSE450, KYSE150, and KYSE30), especially in Eca109 and KYSE150 cells (Fig.	('KYSE450', 'Enzyme', (117, 124))	('KYSE150', 'Var', (173, 180))	('expression', 'MPA', (42, 52))	('circ_0006168', 'Chemical', '-', (56, 68))	('KYSE150', 'Chemical', '-', (126, 133))	('increased', 'PosReg', (84, 93))	('KYSE150', 'Var', (126, 133))	('KYSE150', 'Chemical', '-', (173, 180))	('KYSE30', 'Var', (139, 145))	('ESCC', 'Disease', (97, 101))
57799	34022910	These results suggested that circ_0006168 might play an important role in Taxol resistance.	('Taxol resistance', 'MPA', (74, 90))	('circ_0006168', 'Chemical', '-', (29, 41))	('Taxol', 'Chemical', 'MESH:D017239', (74, 79))	('circ_0006168', 'Var', (29, 41))
57802	34022910	Transfection of si-circ_0006168 could specifically knock down the expression of circ_0006168 in Eca109/Taxol and KYSE150/Taxol (Fig.	('KYSE150', 'Chemical', '-', (113, 120))	('si-circ_0006168', 'Var', (16, 31))	('knock down', 'NegReg', (51, 61))	('si-circ_0006168', 'Chemical', '-', (16, 31))	('expression', 'MPA', (66, 76))	('circ_0006168', 'Gene', (80, 92))	('circ_0006168', 'Chemical', '-', (80, 92))	('Taxol', 'Chemical', 'MESH:D017239', (103, 108))	('circ_0006168', 'Chemical', '-', (19, 31))	('Taxol', 'Chemical', 'MESH:D017239', (121, 126))
57806	34022910	We found that circ_0006168 overexpression increased the IC50 value of Taxol in Eca109 and KYSE150 cells (Additional file 2: Fig.	('overexpression increased', 'PosReg', (27, 51))	('KYSE150', 'Chemical', '-', (90, 97))	('circ_0006168', 'Chemical', '-', (14, 26))	('IC50 value of Taxol', 'MPA', (56, 75))	('Taxol', 'Chemical', 'MESH:D017239', (70, 75))	('circ_0006168', 'Var', (14, 26))
57807	34022910	Meanwhile, CCK-8 assay and colony formation assay indicated that cell viability and colony-forming ability were was impaired by silencing circ_0006168 in Eca109/Taxol and KYSE150/Taxol cells (Fig.	('CCK-8', 'Chemical', '-', (11, 16))	('circ_0006168', 'Gene', (138, 150))	('Taxol', 'Chemical', 'MESH:D017239', (161, 166))	('circ_0006168', 'Chemical', '-', (138, 150))	('KYSE150', 'Chemical', '-', (171, 178))	('cell viability', 'CPA', (65, 79))	('silencing', 'Var', (128, 137))	('impaired', 'NegReg', (116, 124))	('Taxol', 'Chemical', 'MESH:D017239', (179, 184))	('colony-forming ability', 'CPA', (84, 106))
57808	34022910	2C, D), suggesting that circ_0006168 silence suppressed proliferation of Eca109/Taxol and KYSE150/Taxol cells.	('circ_0006168', 'Chemical', '-', (24, 36))	('Taxol', 'Chemical', 'MESH:D017239', (98, 103))	('proliferation', 'CPA', (56, 69))	('suppressed', 'NegReg', (45, 55))	('circ_0006168 silence', 'Var', (24, 44))	('KYSE150', 'Chemical', '-', (90, 97))	('Taxol', 'Chemical', 'MESH:D017239', (80, 85))
57809	34022910	Transwell assay demonstrated that interference of circ_0006168 could reduce migration and invasion of Eca109/Taxol and KYSE150/Taxol cells (Fig.	('migration', 'CPA', (76, 85))	('KYSE150', 'Chemical', '-', (119, 126))	('circ_0006168', 'Var', (50, 62))	('Taxol', 'Chemical', 'MESH:D017239', (109, 114))	('Taxol', 'Chemical', 'MESH:D017239', (127, 132))	('circ_0006168', 'Chemical', '-', (50, 62))	('reduce', 'NegReg', (69, 75))	('invasion', 'CPA', (90, 98))
57810	34022910	In addition, flow cytometry analysis indicated that circ_0006168 downregulation prominently increased apoptosis of Eca109/Taxol and KYSE150/Taxol cells (Fig.	('KYSE150', 'Chemical', '-', (132, 139))	('circ_0006168', 'Var', (52, 64))	('apoptosis', 'CPA', (102, 111))	('Taxol', 'Chemical', 'MESH:D017239', (122, 127))	('circ_0006168', 'Chemical', '-', (52, 64))	('Taxol', 'Chemical', 'MESH:D017239', (140, 145))	('increased', 'PosReg', (92, 101))	('downregulation', 'NegReg', (65, 79))
57811	34022910	These data illustrated that circ_0006168 sensitized Eca109/Taxol and KYSE150/Taxol cells to Taxol.	('Taxol', 'Chemical', 'MESH:D017239', (92, 97))	('sensitized', 'Reg', (41, 51))	('circ_0006168', 'Chemical', '-', (28, 40))	('Taxol', 'Chemical', 'MESH:D017239', (77, 82))	('Taxol', 'Chemical', 'MESH:D017239', (59, 64))	('KYSE150', 'Chemical', '-', (69, 76))	('circ_0006168', 'Var', (28, 40))
57813	34022910	Results showed that there were potential binding sites between circ_0006168 and miR-194-5p (Fig.	('circ_0006168', 'Chemical', '-', (63, 75))	('binding', 'Interaction', (41, 48))	('miR-194-5p', 'Var', (80, 90))	('circ_0006168', 'Var', (63, 75))
57814	34022910	3A), indicating that circ_0006168 might interact with miR-194-5p.	('interact', 'Interaction', (40, 48))	('circ_0006168', 'Var', (21, 33))	('circ_0006168', 'Chemical', '-', (21, 33))
57815	34022910	Moreover, knockdown of circ_0006168 enhance the expression of miR-194-5p (Fig.	('miR-194-5p', 'Var', (62, 72))	('expression', 'MPA', (48, 58))	('enhance', 'PosReg', (36, 43))	('circ_0006168', 'Chemical', '-', (23, 35))	('circ_0006168', 'Gene', (23, 35))	('knockdown', 'Var', (10, 19))
57817	34022910	We constructed dual-luciferase reporter assay, RIP assay and RNA pull-down assay to verify interaction between circ_0006168 and miR-194-5p.	('interaction', 'Interaction', (91, 102))	('circ_0006168', 'Chemical', '-', (111, 123))	('miR-194-5p', 'Var', (128, 138))	('circ_0006168', 'Gene', (111, 123))
57818	34022910	The results indicated that the luciferase activity of circ_0006168-wt was reduced by overexpression of miR-194-5p, but the luciferase activity of circ_0006168-mut was not changed (Fig.	('miR-194-5p', 'Var', (103, 113))	('activity', 'MPA', (42, 50))	('overexpression', 'PosReg', (85, 99))	('circ_0006168', 'Chemical', '-', (146, 158))	('circ_0006168', 'Chemical', '-', (54, 66))	('luciferase', 'Enzyme', (31, 41))	('reduced', 'NegReg', (74, 81))
57819	34022910	RIP assay revealed that both circ_0006168 and miR-194-5p were immunoprecipitated in Ago2 group instead of IgG group (Fig.	('circ_0006168', 'Var', (29, 41))	('Ago2', 'Gene', '27161', (84, 88))	('miR-194-5p', 'Var', (46, 56))	('circ_0006168', 'Chemical', '-', (29, 41))	('Ago2', 'Gene', (84, 88))
57820	34022910	Moreover, a considerable amount of circ_0006168 was detected in bio-miR-194-5p group by RNA pull-down assay compared with the bio-NC group (Fig.	('circ_0006168', 'Chemical', '-', (35, 47))	('detected', 'Reg', (52, 60))	('circ_0006168', 'Var', (35, 47))	('bio-miR-194-5p', 'Var', (64, 78))
57821	34022910	3F), suggesting that miR-194-5p could pull down circ_0006168.	('circ_0006168', 'Gene', (48, 60))	('miR-194-5p', 'Var', (21, 31))	('circ_0006168', 'Chemical', '-', (48, 60))
57823	34022910	Moreover, miR-194-5p expression was reduced in Eca109/Taxol and KYSE150/Taxol relative to HET-1A cells, and miR-194-5p expression was further decreased in Eca109/Taxol and KYSE150/Taxol (Fig.	('miR-194-5p expression', 'MPA', (10, 31))	('Taxol', 'Chemical', 'MESH:D017239', (72, 77))	('Taxol', 'Chemical', 'MESH:D017239', (54, 59))	('KYSE150/Taxol', 'Var', (172, 185))	('Eca109/Taxol', 'Var', (47, 59))	('decreased', 'NegReg', (142, 151))	('KYSE150', 'Chemical', '-', (64, 71))	('miR-194-5p expression', 'MPA', (108, 129))	('reduced', 'NegReg', (36, 43))	('Eca109/Taxol', 'Var', (155, 167))	('KYSE150', 'Chemical', '-', (172, 179))	('Taxol', 'Chemical', 'MESH:D017239', (162, 167))	('Taxol', 'Chemical', 'MESH:D017239', (180, 185))	('KYSE150/Taxol', 'Var', (64, 77))
57824	34022910	The results of dual-luciferase reporter assay showed that overexpression of miR-194-5p distinctly degraded the luciferase activity of JMJD1C-wt, but had no significant effect on the luciferase activity of JMJD1C-mut in Eca109/Taxol and KYSE150/Taxol cells (Fig.	('miR-194-5p', 'Var', (76, 86))	('KYSE150', 'Chemical', '-', (236, 243))	('Taxol', 'Chemical', 'MESH:D017239', (226, 231))	('activity', 'MPA', (122, 130))	('luciferase', 'Enzyme', (182, 192))	('Taxol', 'Chemical', 'MESH:D017239', (244, 249))	('degraded', 'NegReg', (98, 106))	('luciferase', 'Enzyme', (111, 121))
57825	34022910	Furthermore, RIP assay showed that JMJD1C and miR-194-5p were remarkably enriched in the Ago2 immunoprecipitation compared with the IgG immunoprecipitation (Fig.	('miR-194-5p', 'Var', (46, 56))	('JMJD1C', 'Var', (35, 41))	('Ago2', 'Gene', '27161', (89, 93))	('Ago2', 'Gene', (89, 93))
57826	34022910	Additionally, bio-miR-194-5p led to higher JMJD1C level than treatment of bio-NC group in Eca109/Taxol and KYSE150/Taxol cells (Fig.	('KYSE150', 'Chemical', '-', (107, 114))	('higher', 'PosReg', (36, 42))	('JMJD1C level', 'MPA', (43, 55))	('Taxol', 'Chemical', 'MESH:D017239', (115, 120))	('bio-miR-194-5p', 'Var', (14, 28))	('Taxol', 'Chemical', 'MESH:D017239', (97, 102))
57827	34022910	Transfection of inhibitor-miR-194-5p reduced the expression of miR-194-5p in Eca109/Taxol and KYSE150/Taxol cells (Fig.	('miR-194-5p', 'Gene', (63, 73))	('Taxol', 'Chemical', 'MESH:D017239', (102, 107))	('expression', 'MPA', (49, 59))	('inhibitor-miR-194-5p', 'Var', (16, 36))	('reduced', 'NegReg', (37, 44))	('KYSE150', 'Chemical', '-', (94, 101))	('Taxol', 'Chemical', 'MESH:D017239', (84, 89))
57829	34022910	Western blot assay revealed that knockdown of circ_0006168 downregulated the protein expression of JMJD1C, which was restored by downregulating miR-194-5p (Fig.	('circ_0006168', 'Var', (46, 58))	('downregulated', 'NegReg', (59, 72))	('circ_0006168', 'Chemical', '-', (46, 58))	('protein expression', 'MPA', (77, 95))	('JMJD1C', 'Gene', (99, 105))	('downregulating', 'NegReg', (129, 143))	('miR-194-5p', 'Var', (144, 154))
57832	34022910	Moreover, JMJD1C protein expression was enhanced in Eca109 and KYSE150 cells compared with HET-1A cells, and its expression was markedly higher in Eca109/Taxol and KYSE150/Taxol than that in HET-1A cells (Fig.	('expression', 'MPA', (113, 123))	('protein', 'Protein', (17, 24))	('expression', 'MPA', (25, 35))	('KYSE150/Taxol', 'Var', (164, 177))	('higher', 'PosReg', (137, 143))	('Eca109/Taxol', 'Var', (147, 159))	('JMJD1C', 'Gene', (10, 16))	('Taxol', 'Chemical', 'MESH:D017239', (154, 159))	('KYSE150', 'Chemical', '-', (164, 171))	('KYSE150', 'Chemical', '-', (63, 70))	('Eca109', 'Var', (52, 58))	('Taxol', 'Chemical', 'MESH:D017239', (172, 177))	('enhanced', 'PosReg', (40, 48))	('KYSE150', 'Var', (63, 70))
57834	34022910	CCK-8 results showed that JMJD1C knockdown decreased the IC50 value of Taxol in Eca109/Taxol and KYSE150/Taxol cells (Fig.	('KYSE150', 'Chemical', '-', (97, 104))	('Taxol', 'Chemical', 'MESH:D017239', (71, 76))	('knockdown', 'Var', (33, 42))	('Taxol', 'Chemical', 'MESH:D017239', (105, 110))	('Taxol', 'Chemical', 'MESH:D017239', (87, 92))	('IC50 value of Taxol', 'MPA', (57, 76))	('JMJD1C', 'Gene', (26, 32))	('decreased', 'NegReg', (43, 52))	('CCK-8', 'Chemical', '-', (0, 5))
57836	34022910	In addition, JMJD1C knockdown suppressed cell migration and invasion and increased apoptosis of Eca109/Taxol and KYSE150/Taxol cells (Fig.	('increased', 'PosReg', (73, 82))	('JMJD1C', 'Gene', (13, 19))	('Taxol', 'Chemical', 'MESH:D017239', (103, 108))	('invasion', 'CPA', (60, 68))	('KYSE150', 'Chemical', '-', (113, 120))	('cell migration', 'CPA', (41, 55))	('suppressed', 'NegReg', (30, 40))	('apoptosis', 'CPA', (83, 92))	('knockdown', 'Var', (20, 29))	('Taxol', 'Chemical', 'MESH:D017239', (121, 126))
57840	34022910	Moreover, the effect of circ_0006168 downregulation on reduction of IC50 value of Taxol was abolished by elevating JMJD1C in Eca109/Taxol and KYSE150/Taxol cells (Fig.	('downregulation', 'NegReg', (37, 51))	('Taxol', 'Chemical', 'MESH:D017239', (132, 137))	('reduction', 'MPA', (55, 64))	('JMJD1C', 'MPA', (115, 121))	('circ_0006168', 'Chemical', '-', (24, 36))	('Taxol', 'Chemical', 'MESH:D017239', (82, 87))	('Taxol', 'Chemical', 'MESH:D017239', (150, 155))	('elevating', 'PosReg', (105, 114))	('IC50 value of Taxol', 'MPA', (68, 87))	('circ_0006168', 'Var', (24, 36))	('KYSE150', 'Chemical', '-', (142, 149))
57842	34022910	Furthermore, JMJD1C upregulation attenuated si-circ_0006168-induced apoptosis in Eca109/Taxol and KYSE150/Taxol cells (Fig.	('JMJD1C', 'Gene', (13, 19))	('Taxol', 'Chemical', 'MESH:D017239', (88, 93))	('KYSE150', 'Chemical', '-', (98, 105))	('Taxol', 'Chemical', 'MESH:D017239', (106, 111))	('apoptosis', 'CPA', (68, 77))	('attenuated', 'NegReg', (33, 43))	('si-circ_0006168', 'Chemical', '-', (44, 59))	('upregulation', 'PosReg', (20, 32))	('si-circ_0006168-induced', 'Var', (44, 67))
57843	34022910	These results indicated that circ_0006168 exerted its functions by regulating JMJD1C in ESCC cells.	('regulating', 'Reg', (67, 77))	('circ_0006168', 'Chemical', '-', (29, 41))	('JMJD1C', 'Gene', (78, 84))	('circ_0006168', 'Var', (29, 41))
57845	34022910	Knockdown of circ_0006168 inhibited tumor volume and weight in Eca109/Taxol and KYSE150/Taxol xenograft models (Fig.	('Taxol', 'Chemical', 'MESH:D017239', (88, 93))	('KYSE150', 'Chemical', '-', (80, 87))	('inhibited', 'NegReg', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('circ_0006168', 'Var', (13, 25))	('Taxol', 'Chemical', 'MESH:D017239', (70, 75))	('tumor', 'Disease', (36, 41))	('circ_0006168', 'Chemical', '-', (13, 25))
57846	34022910	Moreover, the expression levels of circ_0006168, miR-194-5p and JMJD1C were measured in tumor tissues.	('miR-194-5p', 'Var', (49, 59))	('circ_0006168', 'Chemical', '-', (35, 47))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('circ_0006168', 'Gene', (35, 47))	('expression', 'MPA', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('JMJD1C', 'Var', (64, 70))	('tumor', 'Disease', (88, 93))
57848	34022910	In addition, JMJD1C protein expression was decreased in sh-circ_0006168 group compared with that in sh-control group (Fig.	('JMJD1C', 'Gene', (13, 19))	('sh-circ_0006168 group', 'Var', (56, 77))	('circ_0006168', 'Chemical', '-', (59, 71))	('protein', 'Protein', (20, 27))	('decreased', 'NegReg', (43, 52))
57854	34022910	Herein, we investigated the roles and regulatory mechanism of circ_0006168 in Taxol resistance of ESCC.	('circ_0006168', 'Var', (62, 74))	('Taxol', 'Chemical', 'MESH:D017239', (78, 83))	('circ_0006168', 'Chemical', '-', (62, 74))	('investigated', 'Reg', (11, 23))	('Taxol resistance', 'MPA', (78, 94))
57855	34022910	declared that circ_0006168 was overexpressed in EC tumors and cells, and inhibition of circ_0006168 attenuated cell growth migration, invasion, and glycolysis in EC via modulating miR-384/RBBP7 axis.	('circ_0006168', 'Var', (87, 99))	('glycolysis', 'MPA', (148, 158))	('RBBP7', 'Gene', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('circ_0006168', 'Chemical', '-', (14, 26))	('circ_0006168', 'Chemical', '-', (87, 99))	('attenuated', 'NegReg', (100, 110))	('miR-384', 'Gene', '494333', (180, 187))	('RBBP7', 'Gene', '5931', (188, 193))	('invasion', 'CPA', (134, 142))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('EC tumors', 'CellLine', 'CVCL:5V07', (48, 57))	('modulating', 'Reg', (169, 179))	('miR-384', 'Gene', (180, 187))	('cell growth migration', 'CPA', (111, 132))	('inhibition', 'Var', (73, 83))
57856	34022910	also declared that high level of circ_0006168 level was positively correlated with TNM stage and lymph node metastasis in the patients with ESCC, and circ_0006168 facilitated the growth and metastasis of ESCC cells via sponging miR-100 and regulating mTOR.	('ESCC', 'Disease', (204, 208))	('lymph node metastasis', 'CPA', (97, 118))	('growth', 'CPA', (179, 185))	('TNM', 'Gene', '10178', (83, 86))	('miR-100', 'Gene', (228, 235))	('miR-100', 'Gene', '406892', (228, 235))	('patients', 'Species', '9606', (126, 134))	('circ_0006168', 'Var', (150, 162))	('mTOR', 'Gene', (251, 255))	('circ_0006168', 'Chemical', '-', (33, 45))	('mTOR', 'Gene', '2475', (251, 255))	('TNM', 'Gene', (83, 86))	('facilitated', 'PosReg', (163, 174))	('circ_0006168', 'Chemical', '-', (150, 162))
57860	34022910	Taken together, these findings implicated that circ_0006168 promoted Taxol resistance in ESCC.	('circ_0006168', 'Chemical', '-', (47, 59))	('Taxol resistance', 'MPA', (69, 85))	('promoted', 'PosReg', (60, 68))	('circ_0006168', 'Var', (47, 59))	('Taxol', 'Chemical', 'MESH:D017239', (69, 74))
57862	34022910	For instance, hsa_circ_0030018 served as a miR-599 sponge to facilitate EC progression through upregulating ENAH expression.	('upregulating', 'PosReg', (95, 107))	('expression', 'MPA', (113, 123))	('miR-599', 'Gene', '693184', (43, 50))	('miR-599', 'Gene', (43, 50))	('ENAH', 'Gene', (108, 112))	('facilitate', 'PosReg', (61, 71))	('hsa_circ_0030018', 'Var', (14, 30))	('ENAH', 'Gene', '55740', (108, 112))
57864	34022910	In this research, we confirmed that miR-194-5p directly bound to circ_0006168, which was a key miRNA that targeted multiple genes.	('circ_0006168', 'Chemical', '-', (65, 77))	('miR-194-5p', 'Var', (36, 46))	('bound', 'Interaction', (56, 61))	('circ_0006168', 'Gene', (65, 77))
57865	34022910	MiR-194-5p was reported to be involved in regulating chemoresistance, including Taxol resistance.	('MiR-194-5p', 'Chemical', '-', (0, 10))	('chemoresistance', 'CPA', (53, 68))	('MiR-194-5p', 'Var', (0, 10))	('Taxol resistance', 'MPA', (80, 96))	('Taxol', 'Chemical', 'MESH:D017239', (80, 85))
57866	34022910	Previous studies have proven that miR-194-5p payed a tumor-suppressive role and downregulated in many cancers, including ESCC.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('ESCC', 'Disease', (121, 125))	('tumor', 'Disease', (53, 58))	('downregulated', 'NegReg', (80, 93))	('miR-194-5p', 'Var', (34, 44))	('cancers', 'Disease', (102, 109))
57867	34022910	Consistent with these reports, we uncovered that miR-194-5p was obviously reduced in ESCC tissues, ESCC cells, and Taxol-resistant cells.	('Taxol', 'Chemical', 'MESH:D017239', (115, 120))	('reduced', 'NegReg', (74, 81))	('miR-194-5p', 'Var', (49, 59))	('ESCC', 'Disease', (85, 89))
57868	34022910	We revealed that JMJD1C acted as a downstream target of miR-194-5p, and circ_0006168 could positively modulate JMJD1C expression via sponging miR-194-5p.	('circ_0006168', 'Var', (72, 84))	('miR-194-5p', 'Var', (56, 66))	('JMJD1C', 'Gene', (111, 117))	('circ_0006168', 'Chemical', '-', (72, 84))	('modulate', 'Reg', (102, 110))	('miR-194-5p', 'MPA', (142, 152))	('expression', 'MPA', (118, 128))
57870	34022910	proved that JMJD1C level was positively correlated with the TNM stage, and knockdown of JMJD1C inhibited EC cell proliferation by regulating YAP1 signaling.	('regulating', 'Reg', (130, 140))	('TNM', 'Gene', (60, 63))	('inhibited', 'NegReg', (95, 104))	('knockdown', 'Var', (75, 84))	('YAP1', 'Gene', (141, 145))	('YAP1', 'Gene', '10413', (141, 145))	('JMJD1C', 'Gene', (88, 94))	('TNM', 'Gene', '10178', (60, 63))	('EC cell proliferation', 'CPA', (105, 126))
57874	34022910	Rescue assays proved that JMJD1C overexpression countervailed the promotive role of Taxol sensitivity caused by circ_0006168 knockdown, suggesting that circ_0006168 contributed to Taxol resistance of ESCC cells by upregulating JMJD1C.	('contributed', 'Reg', (165, 176))	('circ_0006168', 'Var', (152, 164))	('JMJD1C', 'Gene', (227, 233))	('Taxol resistance', 'MPA', (180, 196))	('circ_0006168', 'Chemical', '-', (152, 164))	('circ_0006168', 'Chemical', '-', (112, 124))	('Taxol', 'Chemical', 'MESH:D017239', (180, 185))	('upregulating', 'PosReg', (214, 226))	('Taxol', 'Chemical', 'MESH:D017239', (84, 89))
57875	34022910	In addition, in vivo experiments revealed that circ_0006168 deficiency suppressed tumor growth by increasing miR-194-5p and decreasing JMJD1C, implying that circ_0006168 silence might improve Taxol sensitivity in vivo.	('circ_0006168', 'Chemical', '-', (47, 59))	('deficiency', 'Var', (60, 70))	('JMJD1C', 'MPA', (135, 141))	('increasing', 'PosReg', (98, 108))	('decreasing', 'NegReg', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('circ_0006168', 'Chemical', '-', (157, 169))	('Taxol sensitivity', 'MPA', (192, 209))	('Taxol', 'Chemical', 'MESH:D017239', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('improve', 'PosReg', (184, 191))	('miR-194-5p', 'MPA', (109, 119))	('circ_0006168', 'Gene', (47, 59))	('suppressed', 'NegReg', (71, 81))
57876	34022910	Although circ_0006168 knockdown inhibits tumor growth in vivo, this effect does not necessarily translate into meaningful clinical benefits.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('circ_0006168', 'Var', (9, 21))	('tumor', 'Disease', (41, 46))	('knockdown', 'Var', (22, 31))	('circ_0006168', 'Chemical', '-', (9, 21))	('inhibits', 'NegReg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
57878	34022910	Moreover, the circRNAs/miRNAs/mRNAs regulatory networks are very complicated, thus, the detailed physiological mechanisms for the effects of circ_0006168 in ESCC and Taxol resistance need further exploration.	('circ_0006168', 'Chemical', '-', (141, 153))	('circ_0006168', 'Var', (141, 153))	('Taxol', 'Chemical', 'MESH:D017239', (166, 171))	('ESCC', 'Disease', (157, 161))
57879	34022910	In conclusion, interference of circ_0006168 restrained cell proliferation, invasion and migration and accelerated apoptosis of Taxol-resistant cells in vitro, and inhibited tumor growth in vivo via sponging miR-194-5p and regulating JMJD1C (Fig.	('JMJD1C', 'Gene', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('circ_0006168', 'Gene', (31, 43))	('invasion', 'CPA', (75, 83))	('interference', 'Var', (15, 27))	('circ_0006168', 'Chemical', '-', (31, 43))	('miR-194-5p', 'Gene', (207, 217))	('accelerated', 'PosReg', (102, 113))	('migration', 'CPA', (88, 97))	('tumor', 'Disease', (173, 178))	('cell proliferation', 'CPA', (55, 73))	('Taxol', 'Chemical', 'MESH:D017239', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('restrained', 'NegReg', (44, 54))	('inhibited', 'NegReg', (163, 172))	('apoptosis', 'CPA', (114, 123))	('regulating', 'Reg', (222, 232))
57901	33671026	However, there are many candidate genes, including silencing mutations of the p53 gene (Tp53).	('Tp53', 'Gene', '7157', (88, 92))	('p53', 'Gene', (78, 81))	('p53', 'Gene', (89, 92))	('Tp53', 'Gene', (88, 92))	('silencing mutations', 'Var', (51, 70))	('p53', 'Gene', '7157', (89, 92))	('p53', 'Gene', '7157', (78, 81))
57903	33671026	Alterations in p53 expression are often elevated, even in benign conditions such as esophagitis, which later leads to overt malignancy in the minority of patients.	('expression', 'MPA', (19, 29))	('Alterations', 'Var', (0, 11))	('elevated', 'PosReg', (40, 48))	('esophagitis', 'Disease', 'MESH:D004938', (84, 95))	('patients', 'Species', '9606', (154, 162))	('p53', 'Gene', (15, 18))	('malignancy', 'Disease', 'MESH:D009369', (124, 134))	('p53', 'Gene', '7157', (15, 18))	('malignancy', 'Disease', (124, 134))	('esophagitis', 'Phenotype', 'HP:0100633', (84, 95))	('esophagitis', 'Disease', (84, 95))
57905	33671026	Changes to p53 protein expression is also higher in patients predisposed to other risk factors.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('higher', 'PosReg', (42, 48))	('Changes', 'Var', (0, 7))	('protein', 'Protein', (15, 22))	('patients', 'Species', '9606', (52, 60))
57906	33671026	A higher frequency of p53 mutations is reported in patients with confirmed cancerous lesions and alcohol, smoking and a high oral intake of nitrosamine compounds found in chilies, spiced foods, and hot tea.	('nitrosamine', 'Chemical', 'MESH:D009602', (140, 151))	('p53', 'Gene', (22, 25))	('cancerous lesions', 'Disease', 'MESH:D009369', (75, 92))	('mutations', 'Var', (26, 35))	('p53', 'Gene', '7157', (22, 25))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancerous lesions', 'Disease', (75, 92))	('alcohol', 'Chemical', 'MESH:D000438', (97, 104))
57911	33671026	This suggests that p53 and p53-independent genetic mutations might be an initial step in the interaction between lifestyle and genetic factors to mediate the development of ESCC.	('mutations', 'Var', (51, 60))	('p53', 'Gene', '7157', (27, 30))	('ESCC', 'Disease', (173, 177))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('p53', 'Gene', (27, 30))
57912	33671026	Loss of heterozygosity (LOH) is a common genetic event in cancer development.	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('Loss of heterozygosity', 'Var', (0, 22))
57913	33671026	LOH is strongly associated with the loss of the wild-type allele in patients who carry a germline mutation and have an inherited cancer syndrome.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('inherited', 'Disease', (119, 128))	('cancer syndrome', 'Disease', 'MESH:D009369', (129, 144))	('patients', 'Species', '9606', (68, 76))	('germline mutation', 'Var', (89, 106))	('LOH', 'Disease', (0, 3))	('cancer syndrome', 'Disease', (129, 144))
57915	33671026	Allelic loss on chromosomes 2q, 3p, 4p, 4q, 5p, 5q, 6q, 8p, 9p, 9q, 11p, 13q, 14q, 15q, 17p, 17q, and 18q has been reported previously in esophageal cancer.	('Allelic loss', 'Var', (0, 12))	('esophageal cancer', 'Disease', (138, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))
57916	33671026	Allelic loss on chromosome 17p has been reported frequently in esophageal squamous cell carcinoma, as in many human tumors, and generally encompasses the p53 locus at 17p13.	('tumors', 'Disease', (116, 122))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('Allelic loss', 'Var', (0, 12))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('human', 'Species', '9606', (110, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
57917	33671026	For example, allelic loss at D6S1027 (6q21) and D9S910 (9q22.3-q31) was more frequent in tumors that had metastasized, so there may be a role for these genes in modulating the metastatic process.	('D9S910', 'Var', (48, 54))	('tumors', 'Disease', (89, 95))	('modulating', 'Reg', (161, 171))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('S910', 'CellLine', 'CVCL:N671', (50, 54))	('metastatic process', 'CPA', (176, 194))	('allelic', 'Var', (13, 20))	('D6S1027', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
57918	33671026	Meanwhile, LOH at locus D4S2361 (4q21.3-q22) was inversely associated with tumor grade.	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('D4S2361', 'Var', (24, 31))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
57923	33671026	show that gain-of-function mutations in RHBDF2 gene leads to sustained EGFR signalling within the cells, which in turn, leads to a hyperproliferative epithelium and dysregulated wound healing seen in ESCC.	('mutations', 'Var', (27, 36))	('leads to', 'Reg', (120, 128))	('hyperproliferative epithelium', 'CPA', (131, 160))	('RHBDF2', 'Gene', (40, 46))	('dysregulated wound healing', 'Phenotype', 'HP:0001058', (165, 191))	('gain-of-function', 'PosReg', (10, 26))	('RHBDF2', 'Gene', '79651', (40, 46))	('EGFR', 'Gene', '1956', (71, 75))	('dysregulated wound healing', 'CPA', (165, 191))	('EGFR', 'Gene', (71, 75))	('ESCC', 'Disease', (200, 204))
57927	33671026	For example, polymorphisms of LPM2-60 and LMP7-145 have been shown to generate functional alterations in how tumor antigens are processed in colorectal and gastric cancers.	('LPM2-60', 'Gene', (30, 37))	('alterations', 'Reg', (90, 101))	('gastric cancers', 'Phenotype', 'HP:0012126', (156, 171))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('polymorphisms', 'Var', (13, 26))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (141, 171))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('LMP7-145', 'Gene', (42, 50))	('tumor', 'Disease', (109, 114))
57929	33671026	showed that certain polymorphisms of LMP proteins (rs17587 and rs2071543 polymorphisms) were associated with an increased cancer risk in the recessive and homozygote models.	('rs2071543', 'Mutation', 'rs2071543', (63, 72))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('associated', 'Reg', (93, 103))	('rs17587', 'Var', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('rs17587', 'Mutation', 'rs17587', (51, 58))	('LMP proteins', 'Gene', (37, 49))	('rs2071543', 'Var', (63, 72))
57934	33671026	Similarly, NAT2 is involved in the metabolism of aromatic amines, a major class of tobacco smoke carcinogens, and variant alleles in NAT2 result in slow clearance of aromatic amines.	('involved', 'Reg', (19, 27))	('aromatic amines', 'Chemical', '-', (166, 181))	('smoke carcinogens', 'Disease', (91, 108))	('smoke carcinogens', 'Disease', 'MESH:D000074607', (91, 108))	('slow', 'NegReg', (148, 152))	('NAT2', 'Gene', (133, 137))	('NAT2', 'Gene', '10', (11, 15))	('tobacco', 'Species', '4097', (83, 90))	('NAT2', 'Gene', '10', (133, 137))	('variant alleles', 'Var', (114, 129))	('clearance of aromatic amines', 'MPA', (153, 181))	('NAT2', 'Gene', (11, 15))	('aromatic amines', 'Chemical', '-', (49, 64))
57939	33671026	In contrast, miR-143-3p is a tumor suppressor that can decrease cellular proliferation and prevents metastasis but is usually downregulated in ESCC cells.	('prevents', 'NegReg', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('miR-143-3p', 'Chemical', '-', (13, 23))	('cellular proliferation', 'CPA', (64, 86))	('decrease', 'NegReg', (55, 63))	('tumor', 'Disease', (29, 34))	('miR-143-3p', 'Var', (13, 23))	('metastasis', 'CPA', (100, 110))
57940	33671026	The deactivation of miR-29c often results in resistance to chemotherapy and radiotherapy.	('results in', 'Reg', (34, 44))	('miR-29c', 'Gene', '407026', (20, 27))	('deactivation', 'Var', (4, 16))	('miR-29c', 'Gene', (20, 27))
57992	33671026	Polycyclic aromatic hydrocarbons are the major component of biomass fuels which has independently been associated with an increased risk of ESCC.	('Polycyclic', 'Var', (0, 10))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (0, 32))	('ESCC', 'Disease', (140, 144))	('associated', 'Reg', (103, 113))
58002	33671026	The macroscopic findings concurred with molecular analysis which showed mutations in p53, p21, p16, and EGFR.	('mutations', 'Var', (72, 81))	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'Gene', (104, 108))	('p21', 'Gene', (90, 93))	('p16', 'Gene', '1029', (95, 98))	('p21', 'Gene', '644914', (90, 93))	('p53', 'Gene', (85, 88))	('p53', 'Gene', '7157', (85, 88))	('p16', 'Gene', (95, 98))
58034	33562316	In 2011, a wide meta-analysis comparing multimodal treatments for esophageal cancer suggested significant improvement using neoadjuvant therapies, with NACRT having the lowest association with all-cause mortality (hazard ratio (HR): 0.78; 95% confidence interval (CI): 0.70-0.88) compared with chemotherapy (HR: 0.87; 95% CI: 0.79-0.96).	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('NACRT', 'Var', (152, 157))	('mortality', 'Disease', 'MESH:D003643', (203, 212))	('NACRT', 'Chemical', '-', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mortality', 'Disease', (203, 212))	('lowest', 'NegReg', (169, 175))
58052	33562316	The 50-month DFS for these two groups of patients was 11% and 8%, respectively, for ypN0 and ypN+, and time to relapse was significantly longer for the ypN0 group (p = 0.005) (Figure 5).	('ypN0', 'Var', (152, 156))	('ypN0', 'Var', (84, 88))	('longer', 'PosReg', (137, 143))	('ypN+', 'Var', (93, 97))	('patients', 'Species', '9606', (41, 49))
58067	33562316	However, the DFS of patients with an SRC component is significantly better after NACRT compared to NACT, demonstrating the importance of a local therapy effect in this subset of patients with negative prognosis.	('NACT', 'Gene', (99, 103))	('better', 'PosReg', (68, 74))	('DFS', 'MPA', (13, 16))	('patients', 'Species', '9606', (178, 186))	('NACT', 'Gene', '284111', (99, 103))	('NACRT', 'Var', (81, 86))	('patients', 'Species', '9606', (20, 28))	('SRC', 'Disease', (37, 40))	('NACRT', 'Chemical', '-', (81, 86))
58073	33562316	In our analysis, 11% of patients had a cT4 neoplasm and this could negatively influence the long-term oncological outcomes, particularly for DFS.	('neoplasm', 'Phenotype', 'HP:0002664', (43, 51))	('influence', 'Reg', (78, 87))	('cT4', 'Var', (39, 42))	('patients', 'Species', '9606', (24, 32))	('DFS', 'Disease', (141, 144))	('negatively', 'NegReg', (67, 77))	('neoplasm', 'Disease', (43, 51))	('neoplasm', 'Disease', 'MESH:D009369', (43, 51))
58082	33562316	It is interesting to note that, although the numbers are small and with short actuarial analysis of DFS (median follow-up of 14 months), patients with yp Stage IIIA and IIIB nonetheless have a higher rate of distant relapse in comparison to earlier pathological stages.	('yp Stage IIIA', 'Var', (151, 164))	('distant relapse', 'CPA', (208, 223))	('IIIB', 'Var', (169, 173))	('patients', 'Species', '9606', (137, 145))
58115	30933965	Overexpression of TRAF4 in ESCC was also associated with high expression of ki-67 and p53 (P<0.05).	('p53', 'Gene', '7157', (86, 89))	('expression', 'MPA', (62, 72))	('TRAF4', 'Gene', (18, 23))	('TRAF4', 'Gene', '9618', (18, 23))	('Overexpression', 'Var', (0, 14))	('ki-67', 'Protein', (76, 81))	('p53', 'Gene', (86, 89))
58116	30933965	We also found that patients with high expression of TRAF4 had significantly lower OS than in patients with low TRAF4 expression (P<0.05).	('TRAF4', 'Gene', '9618', (52, 57))	('patients', 'Species', '9606', (19, 27))	('high expression', 'Var', (33, 48))	('lower', 'NegReg', (76, 81))	('TRAF4', 'Gene', (52, 57))	('TRAF4', 'Gene', (111, 116))	('low TRAF4', 'Phenotype', 'HP:0040209', (107, 116))	('patients', 'Species', '9606', (93, 101))	('TRAF4', 'Gene', '9618', (111, 116))
58117	30933965	Overexpression of TRAF4 was an independent risk factor affecting the prognosis of patients (P<0.05).	('patients', 'Species', '9606', (82, 90))	('TRAF4', 'Gene', '9618', (18, 23))	('TRAF4', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))
58119	30933965	Overexpression of TRAF4 was an independent risk factor affecting the overall prognosis of patients.	('TRAF4', 'Gene', '9618', (18, 23))	('patients', 'Species', '9606', (90, 98))	('TRAF4', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))
58178	30933965	We found that the overall survival (OS) of patients with high expression of TRAF4 was significantly lower than that of patients with low expression of TRAF4 by Kaplan-Meier survival analysis and log-rank statistical test (95%CI 23.337-37.763 vs. 44.409-78.546, P<0.01, Figure 5A).	('overall survival', 'MPA', (18, 34))	('TRAF4', 'Gene', '9618', (76, 81))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (119, 127))	('lower', 'NegReg', (100, 105))	('TRAF4', 'Gene', (151, 156))	('TRAF4', 'Gene', (76, 81))	('TRAF4', 'Gene', '9618', (151, 156))	('high expression', 'Var', (57, 72))
58199	30933965	A high ki-67-positive rate is often accompanied by accelerated tumor growth, poor tissue differentiation, and poor prognosis.	('tumor', 'Disease', (63, 68))	('ki-67-positive', 'Var', (7, 21))	('tissue differentiation', 'CPA', (82, 104))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('accelerated', 'PosReg', (51, 62))
58202	30933965	Therefore, high expression of TRAF4 may lead to the poor prognosis of patients by promoting the growth and proliferation of tumor cells and by inhibiting cell apoptosis.	('patients', 'Species', '9606', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('TRAF4', 'Gene', (30, 35))	('TRAF4', 'Gene', '9618', (30, 35))	('growth', 'CPA', (96, 102))	('inhibiting', 'NegReg', (143, 153))	('cell apoptosis', 'CPA', (154, 168))	('tumor', 'Disease', (124, 129))	('high expression', 'Var', (11, 26))	('promoting', 'PosReg', (82, 91))	('lead', 'Reg', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
58208	30933965	Yao also found that silencing TRAF4 inhibits osteosarcoma cell growth in vivo and in vitro, consistent with these findings.	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('TRAF4', 'Gene', (30, 35))	('osteosarcoma', 'Disease', (45, 57))	('TRAF4', 'Gene', '9618', (30, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('inhibits', 'NegReg', (36, 44))	('silencing', 'Var', (20, 29))
58212	30933965	Through further Kaplan-Meier and log-rank statistical tests, we found that the overall survival (OS) of patients with high expression of TRAF4 in the cytosol was significantly lower than that of patients with low expression of TRAF4, and the Cox multivariate analysis suggests that TRAF4 is an independent risk factor affecting overall patient survival.	('overall survival', 'CPA', (79, 95))	('patient', 'Species', '9606', (336, 343))	('TRAF4', 'Gene', (137, 142))	('patient', 'Species', '9606', (195, 202))	('patients', 'Species', '9606', (104, 112))	('lower', 'NegReg', (176, 181))	('TRAF4', 'Gene', (282, 287))	('TRAF4', 'Gene', '9618', (137, 142))	('TRAF4', 'Gene', (227, 232))	('TRAF4', 'Gene', '9618', (227, 232))	('patients', 'Species', '9606', (195, 203))	('patient', 'Species', '9606', (104, 111))	('high expression', 'Var', (118, 133))	('Cox', 'Gene', '1351', (242, 245))	('TRAF4', 'Gene', '9618', (282, 287))	('Cox', 'Gene', (242, 245))
58215	30933965	Targeted silencing of TRAF4 may benefit patients with advanced esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('TRAF4', 'Gene', (22, 27))	('TRAF4', 'Gene', '9618', (22, 27))	('patients', 'Species', '9606', (40, 48))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('benefit', 'PosReg', (32, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('Targeted silencing', 'Var', (0, 18))
58216	30933965	In the future, TRAF4 gene knockout and inhibition of TRAF4 expression may promote apoptosis of esophageal cells, and inhibit proliferation and distant metastasis.	('TRAF4', 'Gene', '9618', (15, 20))	('TRAF4', 'Gene', '9618', (53, 58))	('apoptosis', 'CPA', (82, 91))	('promote', 'PosReg', (74, 81))	('gene knockout', 'Var', (21, 34))	('inhibition', 'NegReg', (39, 49))	('knockout', 'Var', (26, 34))	('expression', 'MPA', (59, 69))	('TRAF4', 'Gene', (53, 58))	('inhibit', 'NegReg', (117, 124))	('TRAF4', 'Gene', (15, 20))
58221	30933965	Patients with high expression of TRAF4 had significantly lower OS than patients with low TRAF4 expression.	('TRAF4', 'Gene', '9618', (33, 38))	('low TRAF4', 'Phenotype', 'HP:0040209', (85, 94))	('TRAF4', 'Gene', (89, 94))	('patients', 'Species', '9606', (71, 79))	('TRAF4', 'Gene', '9618', (89, 94))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('TRAF4', 'Gene', (33, 38))	('lower', 'NegReg', (57, 62))
58222	30933965	Overexpression of TRAF4 was an independent risk factor affecting the prognosis of patients, indicating that TRAF4 may become a new target for the treatment of ESCC in the future.	('men', 'Species', '9606', (151, 154))	('patients', 'Species', '9606', (82, 90))	('TRAF4', 'Gene', (18, 23))	('TRAF4', 'Gene', '9618', (108, 113))	('TRAF4', 'Gene', (108, 113))	('Overexpression', 'Var', (0, 14))	('TRAF4', 'Gene', '9618', (18, 23))	('affecting', 'Reg', (55, 64))	('ESCC', 'Disease', (159, 163))
58241	30762735	Thoracic epidural anesthesia and/or analgesia have been reported to inhibit the stress response and immune system dysfunction, enhance the microcirculation of the gastric tube, decrease postoperative opioid use, shorten the stay in the intensive care unit (ICU) or hospital and reduce the incidences of pneumonia, postoperative respiratory failure, chronic post-thoracotomy pain syndrome, and anastomotic leakage, although not all studies agree with the latter finding.	('respiratory failure', 'Phenotype', 'HP:0002878', (328, 347))	('enhance', 'PosReg', (127, 134))	('gastric tube', 'Disease', 'MESH:D013274', (163, 175))	('gastric tube', 'Disease', (163, 175))	('stay', 'MPA', (224, 228))	('pneumonia', 'Phenotype', 'HP:0002090', (303, 312))	('system dysfunction', 'Disease', 'MESH:D007154', (107, 125))	('pneumonia', 'Disease', 'MESH:D011014', (303, 312))	('pain syndrome', 'Disease', (374, 387))	('anastomotic leakage', 'Disease', (393, 412))	('pain syndrome', 'Disease', 'MESH:D010146', (374, 387))	('system dysfunction', 'Disease', (107, 125))	('pain', 'Phenotype', 'HP:0012531', (374, 378))	('thoracotomy pain', 'Phenotype', 'HP:0100749', (362, 378))	('postoperative respiratory failure', 'Disease', (314, 347))	('pneumonia', 'Disease', (303, 312))	('postoperative opioid use', 'MPA', (186, 210))	('inhibit', 'NegReg', (68, 75))	('shorten', 'NegReg', (212, 219))	('postoperative respiratory failure', 'Disease', 'MESH:D012131', (314, 347))	('decrease', 'NegReg', (177, 185))	('immune', 'CPA', (100, 106))	('stress', 'MPA', (80, 86))	('reduce', 'NegReg', (278, 284))	('Thoracic epidural anesthesia', 'Var', (0, 28))
58289	30762735	Furthermore, the VAS pain scores in the TIVA/PCEA group were significantly lower than those in the TIVA/PCIA group at all time points, both at rest and during coughing (P <.05; Table 4).	('pain', 'Disease', 'MESH:D010146', (21, 25))	('lower', 'NegReg', (75, 80))	('pain', 'Disease', (21, 25))	('VAS', 'CPA', (17, 20))	('TIVA', 'Chemical', '-', (40, 44))	('coughing', 'Phenotype', 'HP:0012735', (159, 167))	('TIVA/PCEA', 'Var', (40, 49))	('TIVA', 'Chemical', '-', (99, 103))	('pain', 'Phenotype', 'HP:0012531', (21, 25))	('VAS pain', 'Phenotype', 'HP:0025637', (17, 25))	('PCEA', 'Chemical', '-', (45, 49))
58300	30762735	Furthermore, the level of postoperative pain was lower in patients given PCEA than in those provided with PCIA.	('pain', 'Phenotype', 'HP:0012531', (40, 44))	('lower', 'NegReg', (49, 54))	('postoperative pain', 'Disease', 'MESH:D010149', (26, 44))	('PCEA', 'Var', (73, 77))	('patients', 'Species', '9606', (58, 66))	('postoperative pain', 'Disease', (26, 44))	('PCEA', 'Chemical', '-', (73, 77))
58324	30762735	Interestingly, a previous investigation found that PCEA enhanced the microcirculation of the gastric tube after surgery.	('gastric tube', 'Disease', 'MESH:D013274', (93, 105))	('gastric tube', 'Disease', (93, 105))	('PCEA', 'Var', (51, 55))	('enhanced', 'PosReg', (56, 64))	('PCEA', 'Chemical', '-', (51, 55))
58329	30762735	This is in agreement with other published studies reporting that PCEA could reduce the length of stay in the ICU or hospital.	('length of stay in the ICU or hospital', 'MPA', (87, 124))	('reduce', 'NegReg', (76, 82))	('PCEA', 'Var', (65, 69))	('PCEA', 'Chemical', '-', (65, 69))
58332	30762735	The incidences of postoperative nausea/vomiting and pruritus were higher in patients receiving PCEA than in those given PCIA.	('patients', 'Species', '9606', (76, 84))	('postoperative nausea/vomiting', 'Disease', (18, 47))	('pruritus', 'Phenotype', 'HP:0000989', (52, 60))	('PCEA', 'Var', (95, 99))	('higher', 'PosReg', (66, 72))	('PCEA', 'Chemical', '-', (95, 99))	('pruritus', 'Disease', 'MESH:D011537', (52, 60))	('pruritus', 'Disease', (52, 60))	('nausea', 'Phenotype', 'HP:0002018', (32, 38))	('nausea/vomiting', 'Phenotype', 'HP:0002017', (32, 47))	('vomiting', 'Phenotype', 'HP:0002013', (39, 47))	('postoperative nausea/vomiting', 'Disease', 'MESH:D020250', (18, 47))
58353	30219035	Dual luciferase assay demonstrated that TUSC2P 3'UTR decoyed miR-17-5p, miR-520a-3p, miR-608, miR-661 from binding to TUSC2.	('miR-661', 'Gene', (94, 101))	('miR-608', 'Gene', '693193', (85, 92))	('miR-661', 'Gene', '724031', (94, 101))	('TUSC2', 'Gene', (118, 123))	('TUSC2P', 'Gene', (40, 46))	('TUSC2P', 'Gene', '11334', (40, 46))	('miR-520a-3p', 'Var', (72, 83))	('TUSC2', 'Gene', (40, 45))	('TUSC2', 'Gene', '11334', (118, 123))	('TUSC2', 'Gene', '11334', (40, 45))	('binding', 'Interaction', (107, 114))	('miR-17-5p', 'Gene', '406952', (61, 70))	('miR-608', 'Gene', (85, 92))	('decoyed', 'NegReg', (53, 60))	('miR-17-5p', 'Gene', (61, 70))
58360	30219035	TUSC2 was firstly reported in a study analyzing frequent deletions in the short arm of chromosome 3p.	('TUSC2', 'Gene', '11334', (0, 5))	('deletions', 'Var', (57, 66))	('TUSC2', 'Gene', (0, 5))	('short arm', 'Phenotype', 'HP:0009824', (74, 83))
58361	30219035	Frequent deletions in the short arm of chromosome 3p occurs in a wide variety of cancers.	('occurs', 'Reg', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('short arm', 'Phenotype', 'HP:0009824', (26, 35))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('deletions', 'Var', (9, 18))
58366	30219035	In addition, they shared binding sites of many miRNAs, including miRNA-17-5p, miRNA-608, miRNA-661, miRNA-520a-3p.	('binding', 'Interaction', (25, 32))	('miRNA-520a-3p', 'Var', (100, 113))	('miRNA-661', 'Var', (89, 98))	('miRNA-17', 'Gene', (65, 73))	('miRNA-608', 'Var', (78, 87))	('miRNA-17', 'Gene', '406952', (65, 73))
58371	30219035	The fragment of 3'UTR of TUSC2 and TUSC2P which contained potential binding sites of miRNA-17-5p, miRNA-608, miRNA-661, miR-520a-3p were synthesized.	('TUSC2', 'Gene', (25, 30))	('miR-520a-3p', 'Var', (120, 131))	('binding', 'Interaction', (68, 75))	('TUSC2', 'Gene', (35, 40))	('TUSC2', 'Gene', '11334', (25, 30))	('miRNA-661', 'Var', (109, 118))	('TUSC2', 'Gene', '11334', (35, 40))	('miRNA-17', 'Gene', (85, 93))	('TUSC2P', 'Gene', '11334', (35, 41))	('miRNA-17', 'Gene', '406952', (85, 93))	('miRNA-608', 'Var', (98, 107))	('TUSC2P', 'Gene', (35, 41))
58373	30219035	To obtain a negative control, the corresponding fragments of 3'UTR of TUSC2 and TUSC2P 3'UTR of which the miRNAs binding sites were mutated was synthesized and cloned to psiCHECK -2 luciferase vector to obtain corresponding mutant luciferase constructs.	('TUSC2', 'Gene', (70, 75))	('mutant', 'Var', (224, 230))	('TUSC2', 'Gene', (80, 85))	('TUSC2', 'Gene', '11334', (70, 75))	('TUSC2', 'Gene', '11334', (80, 85))	('TUSC2P', 'Gene', (80, 86))	('TUSC2P', 'Gene', '11334', (80, 86))
58388	30219035	Cells were cultured at 37  C for 24 h, TUSC2 and TUSC2P luciferase constructs or corresponding mutant constructs were co-transfected with miRNA mimics, or miRNAs controls, respectively using Lipofectamine 2000.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (191, 209))	('TUSC2', 'Gene', '11334', (49, 54))	('TUSC2', 'Gene', (39, 44))	('TUSC2', 'Gene', '11334', (39, 44))	('mutant', 'Var', (95, 101))	('TUSC2P', 'Gene', (49, 55))	('TUSC2P', 'Gene', '11334', (49, 55))	('TUSC2', 'Gene', (49, 54))
58399	30219035	When analyzing the sequence of the TUSC2P and TUSC2 3'UTR, miRNA-17-5p, miRNA-608, miRNA-661, miRNA-520a-3p were found to poss conserved binding sites for TUSC2P and TUSC2 (Fig.	('poss', 'NegReg', (122, 126))	('TUSC2', 'Gene', (155, 160))	('TUSC2', 'Gene', '11334', (155, 160))	('miRNA-608', 'Var', (72, 81))	('TUSC2P', 'Gene', '11334', (35, 41))	('miRNA-17', 'Gene', '406952', (59, 67))	('TUSC2P', 'Gene', (35, 41))	('TUSC2', 'Gene', (35, 40))	('miRNA-661', 'Var', (83, 92))	('TUSC2', 'Gene', '11334', (35, 40))	('miRNA-17', 'Gene', (59, 67))	('TUSC2', 'Gene', (46, 51))	('TUSC2', 'Gene', (166, 171))	('TUSC2', 'Gene', '11334', (46, 51))	('TUSC2', 'Gene', '11334', (166, 171))	('miRNA-520a-3p', 'Var', (94, 107))	('binding sites', 'Interaction', (137, 150))	('TUSC2P', 'Gene', '11334', (155, 161))	('TUSC2P', 'Gene', (155, 161))
58437	30219035	Accumulating evidence showed that pseudogenes usually expressed in a cancer specific pattern.	('pseudogenes', 'Var', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('expressed', 'Reg', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
58439	30219035	However, more and more pseudogenes have been identified, and they exhibit cancer specific expression pattern and are proven to be related to cancer.	('pseudogenes', 'Var', (23, 34))	('related', 'Reg', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('expression', 'MPA', (90, 100))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (141, 147))
58443	30219035	In light of this, pseudogenes can not only play structural and functional roles in the tumorigenesis, but also in disease diagnosis and prognosis.	('pseudogenes', 'Var', (18, 29))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
58461	29348896	Emerging evidence has indicated that dysregulation of lncRNAs is often associated with a variety of human diseases including cancer.	('dysregulation', 'Var', (37, 50))	('lncRNAs', 'Protein', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('human', 'Species', '9606', (100, 105))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('associated', 'Reg', (71, 81))
58469	29348896	Recent studies indicated that down-regulation of PVT1 expression inhibited non-small cell lung cancer cells proliferation, migration and invasion through epigenetically regulating large tumor suppressor 2 (LATS2) expression.	('large tumor suppressor 2', 'Gene', '26524', (180, 204))	('non-small cell lung cancer', 'Disease', (75, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('large tumor suppressor 2', 'Gene', (180, 204))	('invasion', 'CPA', (137, 145))	('down-regulation', 'NegReg', (30, 45))	('inhibited', 'NegReg', (65, 74))	('LATS2', 'Gene', (206, 211))	('LATS2', 'Gene', '26524', (206, 211))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (79, 101))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (75, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('expression', 'MPA', (213, 223))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('migration', 'CPA', (123, 132))	('epigenetically regulating', 'Var', (154, 179))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (75, 101))	('PVT1', 'Gene', (49, 53))	('PVT1', 'Gene', '5820', (49, 53))
58474	29348896	Moreover, dysregulation of PVT1 expression is significantly correlated with certain clinicopathological characteristics of cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('dysregulation', 'Var', (10, 23))	('PVT1', 'Gene', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('correlated', 'Reg', (60, 70))	('cancer', 'Disease', (123, 129))	('PVT1', 'Gene', '5820', (27, 31))	('expression', 'MPA', (32, 42))
58485	29348896	Furthermore, the negative effect of PVT1 overexpression on predicting poor OS was found in studies with sample size < 100 (HR = 2.40, 95% CI: 1.56-3.23) as well as those with sample size > 100 (HR = 1.35, 95% CI: 1.151.54) (Supplementary Figure 1).	('poor OS', 'Disease', (70, 77))	('PVT1', 'Gene', '5820', (36, 40))	('negative', 'NegReg', (17, 25))	('< 100', 'Var', (116, 121))	('overexpression', 'PosReg', (41, 55))	('PVT1', 'Gene', (36, 40))
58486	29348896	There was a significant relationship between PVT1 overexpression and poor OS in studies with NOS < 6 (HR = 2.28, 95% CI: 1.05-3.51) and NOS > 6 (HR = 1.38, 95% CI: 1.19-1.57) (Supplementary Figure 2).	('NOS > 6', 'Var', (136, 143))	('poor', 'Disease', (69, 73))	('overexpression', 'PosReg', (50, 64))	('PVT1', 'Gene', (45, 49))	('PVT1', 'Gene', '5820', (45, 49))
58489	29348896	We found a negative significant relationship between high PVT1 expression and poor DFS (pooled HR = 1.83, 95% CI: 1.39-2.27) with no heterogeneity (I2 = 0.0%, P = 0.965) (Figure 3).	('high', 'Var', (53, 57))	('expression', 'MPA', (63, 73))	('PVT1', 'Gene', (58, 62))	('poor', 'Disease', (78, 82))	('PVT1', 'Gene', '5820', (58, 62))
58516	29348896	In recent years, numerous studies have demonstrated that high PVT1 expression significantly correlated with poor prognosis of patients with nearly all types of cancers.	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('high', 'Var', (57, 61))	('cancers', 'Disease', (160, 167))	('correlated', 'Reg', (92, 102))	('PVT1', 'Gene', (62, 66))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('expression', 'MPA', (67, 77))	('PVT1', 'Gene', '5820', (62, 66))
58524	29348896	Although they found no statistically significance of PVT1 as a predictor of HCC patients' survival, HCC patients with high level of PVT1 expression demonstrated a trend for poor prognosis.	('PVT1', 'Gene', '5820', (132, 136))	('PVT1', 'Gene', (53, 57))	('expression', 'MPA', (137, 147))	('patients', 'Species', '9606', (80, 88))	('PVT1', 'Gene', '5820', (53, 57))	('high level', 'Var', (118, 128))	('PVT1', 'Gene', (132, 136))	('patients', 'Species', '9606', (104, 112))
58525	29348896	Other research group demonstrated that PVT1 promotes cell proliferation, cell cycling, and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein, and HCC patients with high PVT1 expression had a poor prognosis.	('promotes', 'PosReg', (44, 52))	('PVT1', 'Gene', (39, 43))	('stem cell-like properties', 'CPA', (110, 135))	('PVT1', 'Gene', '5820', (205, 209))	('NOP2', 'Gene', (164, 168))	('acquisition', 'PosReg', (95, 106))	('PVT1', 'Gene', '5820', (39, 43))	('PVT1', 'Gene', (205, 209))	('NOP2', 'Gene', '4839', (164, 168))	('cell proliferation', 'CPA', (53, 71))	('high', 'Var', (200, 204))	('stabilizing', 'NegReg', (152, 163))	('patients', 'Species', '9606', (186, 194))	('cell cycling', 'CPA', (73, 85))
58527	29348896	The pooled analysis incorporation the hypothetical studies continued to show a statistically significant association between PVT1 expression on overall survival, and this results indicated that the correction for potential publication bias had an effect on the stability of the results.	('significant association', 'Reg', (93, 116))	('expression', 'Var', (130, 140))	('PVT1', 'Gene', (125, 129))	('overall survival', 'MPA', (144, 160))	('PVT1', 'Gene', '5820', (125, 129))
58535	29348896	Other study reported that PVT1 promotes cell proliferation through epigenetically regulating p15 and p16, and higher PVT1 expression in gastric cancer was positively correlated with deeper invasion depth and advanced TNM stage.	('expression', 'MPA', (122, 132))	('PVT1', 'Gene', (26, 30))	('p16', 'Gene', '1029', (101, 104))	('PVT1', 'Gene', '5820', (26, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('higher', 'PosReg', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PVT1', 'Gene', (117, 121))	('cell proliferation', 'CPA', (40, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('PVT1', 'Gene', '5820', (117, 121))	('TNM', 'Gene', '10178', (217, 220))	('p15', 'Gene', (93, 96))	('TNM', 'Gene', (217, 220))	('epigenetically regulating', 'Var', (67, 92))	('deeper invasion depth', 'CPA', (182, 203))	('promotes', 'PosReg', (31, 39))	('gastric cancer', 'Disease', (136, 150))	('p15', 'Gene', '1030', (93, 96))	('p16', 'Gene', (101, 104))
58554	29348896	According to the above inclusion and exclusion criteria, the following items were extracted: first author, publication date, country, ethnicity, tumor type, sample size, detection method of PVT1 expression, follow-up period, cut-off value, the number of high and low PVT1 expression, the number of patients with lymph node metastasis, adjuvant therapy before surgery, survival analysis methodology, HRs with corresponding 95% CIs for OS, RFS or DFS, and other patient data such as age, gentle, tumor size, differentiation, TNM staging and distant metastasis.	('expression', 'MPA', (272, 282))	('high', 'Var', (254, 258))	('PVT1', 'Gene', (190, 194))	('low', 'NegReg', (263, 266))	('PVT1', 'Gene', '5820', (190, 194))	('patient', 'Species', '9606', (460, 467))	('patients', 'Species', '9606', (298, 306))	('distant metastasis', 'CPA', (539, 557))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (494, 499))	('PVT1', 'Gene', (267, 271))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('PVT1', 'Gene', '5820', (267, 271))	('tumor', 'Disease', 'MESH:D009369', (494, 499))	('patient', 'Species', '9606', (298, 305))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TNM', 'Gene', '10178', (523, 526))	('tumor', 'Phenotype', 'HP:0002664', (494, 499))	('TNM', 'Gene', (523, 526))
58593	23591281	Esophageal cancer included topography codes C15.0-C15.9, and was categorized as ESCC and EAC by histology codes.	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('EAC', 'Phenotype', 'HP:0011459', (89, 92))	('C15.0-C15.9', 'Var', (44, 55))	('EAC', 'Disease', (89, 92))	('Esophageal cancer', 'Disease', (0, 17))	('ESCC', 'Disease', (80, 84))
58617	23591281	In this study, we observed that participants with a higher adherence to HEI-2005 had a reduced risk of ESCC and EAC, and those adhering to aMED had a reduced risk of ESCC, highlighting the effect of adherence to dietary guidance in prevention of esophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('reduced', 'NegReg', (87, 94))	('EAC', 'Disease', (112, 115))	('higher', 'PosReg', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('esophageal cancers', 'Disease', (246, 264))	('ESCC', 'Disease', (103, 107))	('esophageal cancers', 'Disease', 'MESH:D004938', (246, 264))	('ESCC', 'Disease', (166, 170))	('participants', 'Species', '9606', (32, 44))	('HEI-2005', 'Var', (72, 80))
58632	23591281	We observed that persons with higher HEI-2005 or aMED score tended to drink less, suggesting that confounding by heavy alcohol intake was of potential concern.	('less', 'NegReg', (76, 80))	('persons', 'Species', '9606', (17, 24))	('HEI-2005', 'Var', (37, 45))	('alcohol', 'Chemical', 'MESH:D000438', (119, 126))	('heavy alcohol intake', 'Phenotype', 'HP:0030955', (113, 133))	('drink', 'MPA', (70, 75))	('aMED score', 'Gene', (49, 59))
58646	23497461	NQO1 C609T polymorphism and esophageal cancer risk: a HuGE review and meta-analysis Many studies have been carried out to test the hypothesis that the NQO1 C609T polymorphism might be associated with the risk of esophageal cancer.	('C609T', 'Mutation', 'rs1800566', (156, 161))	('esophageal cancer', 'Disease', (28, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('C609T', 'Mutation', 'rs1800566', (5, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('C609T', 'Var', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('NQO1', 'Gene', (0, 4))	('NQO1', 'Gene', (151, 155))	('associated', 'Reg', (184, 194))	('NQO1', 'Gene', '1728', (151, 155))	('esophageal cancer', 'Disease', (212, 229))	('NQO1', 'Gene', '1728', (0, 4))
58648	23497461	Our study included eight published case-control studies about the NQO1 C609T polymorphism and esophageal cancer, including a total of 1,217 esophageal cancer patients and 1,560 controls.	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('esophageal cancer', 'Disease', (94, 111))	('C609T', 'Var', (71, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('C609T', 'Mutation', 'rs1800566', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (158, 166))	('esophageal cancer', 'Disease', (140, 157))	('NQO1', 'Gene', (66, 70))
58649	23497461	Overall, a significant association was found between the NQO1 C609T variant and esophageal cancer under a recessive model (OR = 1.647; 95% CI = 1.233-2.200).	('NQO1', 'Gene', (57, 61))	('esophageal cancer', 'Disease', (80, 97))	('C609T', 'Mutation', 'rs1800566', (62, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('C609T', 'Var', (62, 67))
58651	23497461	The meta-analysis suggests that the NQO1 C609T polymorphism considerably increases the risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('NQO1', 'Gene', (36, 40))	('increases', 'PosReg', (73, 82))	('C609T', 'Mutation', 'rs1800566', (41, 46))	('esophageal cancer', 'Disease', (95, 112))	('C609T', 'Var', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
58659	23497461	However, the activity of the NQO1 enzyme may be influenced by a major polymorphism involving a single C to T substitution at nucleotide 609 of exon 6 in the NQO1 cDNA that causes a Pro187Ser amino acid change.	('NQO1', 'Gene', (29, 33))	('Pro187Ser amino acid change', 'MPA', (181, 208))	('C to T substitution', 'Var', (102, 121))	('C to T substitution at nucleotide 609', 'Mutation', 'rs1800566', (102, 139))	('causes', 'Reg', (172, 178))	('Pro187Ser', 'Chemical', '-', (181, 190))	('NQO1', 'Gene', (157, 161))	('activity', 'MPA', (13, 21))	('influenced by', 'Reg', (48, 61))
58660	23497461	The NQO1 C609T polymorphism has been associated with the risk of various cancers such as renal, lung, esophageal, colorectal, and head and neck.	('C609T', 'Var', (9, 14))	('cancers', 'Disease', (73, 80))	('colorectal', 'Disease', (114, 124))	('renal', 'Disease', (89, 94))	('esophageal', 'Disease', (102, 112))	('lung', 'Disease', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('C609T', 'Mutation', 'rs1800566', (9, 14))	('associated', 'Reg', (37, 47))	('NQO1', 'Gene', (4, 8))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('colorectal', 'Disease', 'MESH:D015179', (114, 124))
58661	23497461	However, the results of some studies on the effect of the NQO1 C609T polymorphism on esophageal cancer are debatable.	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('C609T', 'Mutation', 'rs1800566', (63, 68))	('C609T', 'Var', (63, 68))	('NQO1', 'Gene', (58, 62))	('esophageal cancer', 'Disease', (85, 102))
58662	23497461	Therefore, a meta-analysis of these studies was undertaken to investigate the association of the NQO1 C609T polymorphism with susceptibility to esophageal cancer.	('C609T', 'Mutation', 'rs1800566', (102, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('C609T', 'Var', (102, 107))	('NQO1', 'Gene', (97, 101))	('esophageal cancer', 'Disease', (144, 161))
58663	23497461	All original studies published in English on the NQO1 C609T polymorphism and esophageal cancer were considered in our meta-analysis.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('C609T', 'Mutation', 'rs1800566', (54, 59))	('C609T', 'Var', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('NQO1', 'Gene', (49, 53))	('esophageal cancer', 'Disease', (77, 94))
58665	23497461	Included studies had to fit the following criteria: (1) sufficient data regarding allele frequency; (2) an association analysis between the NQO1 C609T polymorphism and esophageal cancer risk; and (3) independent case-control studies.	('esophageal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('C609T', 'Mutation', 'rs1800566', (145, 150))	('association', 'Interaction', (107, 118))	('NQO1', 'Gene', (140, 144))	('C609T', 'Var', (145, 150))
58667	23497461	If OR1 > OR2 > 1 and OR1 > OR3 > 1(or OR1 < OR2 < 1 and OR1 < OR3 < 1), the codominant model was adopted.	('OR1 > OR3 > 1', 'Var', (21, 34))	('OR1 < OR2 < 1 and OR1 < OR3 < 1', 'Gene', '389090', (38, 69))	('OR1 > OR2 > 1', 'Var', (3, 16))
58668	23497461	Ten relevant studies describing the association between NQO1 C609T and esophageal cancer were identified.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('NQO1', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('C609T', 'Var', (61, 66))	('esophageal cancer', 'Disease', (71, 88))	('C609T', 'Mutation', 'rs1800566', (61, 66))
58672	23497461	The prevalence rates of TT in C609T variants were 19.1% in the controls of Asian descent and 4.1% in the controls of Caucasian descent.	('C609T', 'Var', (30, 35))	('Asian descent', 'Disease', (75, 88))	('C609T', 'Mutation', 'rs1800566', (30, 35))
58674	23497461	The results of the included studies regarding the association between the NQO1 C609T polymorphism and esophageal cancer were conflicting, as seen in Table 1.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('C609T', 'Mutation', 'rs1800566', (79, 84))	('NQO1', 'Gene', (74, 78))	('C609T', 'Var', (79, 84))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
58679	23497461	The summary result showed a significant relationship between the NQO1 C609T polymorphism and esophageal cancer (Figure 1) from the meta-analysis of the phenotype studies.	('C609T', 'Var', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('C609T', 'Mutation', 'rs1800566', (70, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('NQO1', 'Gene', (65, 69))
58680	23497461	Six case-control articles reporting an association between the NQO1 C609T polymorphism and the histological type of esophageal cancer were included in our research, but their results were debatable.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('C609T', 'Mutation', 'rs1800566', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('C609T', 'Var', (68, 73))	('NQO1', 'Gene', (63, 67))	('esophageal cancer', 'Disease', (116, 133))
58682	23497461	The summary result from the meta-analysis of the phenotype studies indicated a significant relationship between the NQO1 C609T polymorphism and the histological type of esophageal cancer (Figure 2).	('C609T', 'Var', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('C609T', 'Mutation', 'rs1800566', (121, 126))	('NQO1', 'Gene', (116, 120))	('esophageal cancer', 'Disease', (169, 186))	('esophageal cancer', 'Disease', 'MESH:D004938', (169, 186))
58686	23497461	NQO1 gene mutations are linked to tardive dyskinesia, which increases the risk of hematotoxicity after exposure to benzene, and susceptibility to various forms of cancer.	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('tardive dyskinesia', 'Phenotype', 'HP:0040141', (34, 52))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('NQO1', 'Gene', (0, 4))	('tardive dyskinesia', 'Disease', 'MESH:D004409', (34, 52))	('hematotoxicity', 'Disease', 'MESH:D006402', (82, 96))	('tardive dyskinesia', 'Disease', (34, 52))	('mutations', 'Var', (10, 19))	('benzene', 'Chemical', 'MESH:D001554', (115, 122))	('linked', 'Reg', (24, 30))	('cancer', 'Disease', (163, 169))	('hematotoxicity', 'Disease', (82, 96))	('dyskinesia', 'Phenotype', 'HP:0100660', (42, 52))
58687	23497461	Many studies have been carried out to test the hypothesis that the NQO1 C609T polymorphism might be linked to the risk of esophageal cancer, but the results are controversial.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('NQO1', 'Gene', (67, 71))	('linked', 'Reg', (100, 106))	('C609T', 'Mutation', 'rs1800566', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('C609T', 'Var', (72, 77))
58688	23497461	This meta-analysis, involving a total of 1,217 esophageal cancer patients and 1,560 controls from eight case-control studies, examined the association of one polymorphisms of the NQO1 gene with esophageal cancer risk.	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('polymorphisms', 'Var', (158, 171))	('esophageal cancer', 'Disease', (194, 211))	('NQO1', 'Gene', (179, 183))	('patients', 'Species', '9606', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('association', 'Interaction', (139, 150))	('esophageal cancer', 'Disease', (47, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))
58689	23497461	In addition, significant evidence was found for a correlation between the NQO1 C609T variant and esophageal cancer under the recessive model (OR = 1.647; 95%CI = 1.233-2.200).	('C609T', 'Mutation', 'rs1800566', (79, 84))	('NQO1', 'Gene', (74, 78))	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('C609T', 'Var', (79, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('correlation', 'Interaction', (50, 61))
58691	23497461	Marjani et al observed that NQO1 expression in esophageal tumor tissue was related to the NOQ1C609T genotype, with its expression elevated when the T allele appeared in the NOQ1C609T genotype.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('expression', 'MPA', (119, 129))	('NOQ1C609T', 'Var', (173, 182))	('esophageal tumor', 'Disease', (47, 63))	('C609T', 'Mutation', 'rs1800566', (94, 99))	('elevated', 'PosReg', (130, 138))	('esophageal tumor', 'Phenotype', 'HP:0100751', (47, 63))	('NOQ1C609T', 'Var', (90, 99))	('expression', 'MPA', (33, 43))	('NQO1', 'Gene', (28, 32))	('C609T', 'Mutation', 'rs1800566', (177, 182))	('esophageal tumor', 'Disease', 'MESH:D004938', (47, 63))
58692	23497461	Traver et al confirmed that the NQO1 homozygous variant (TT) had very little or no quinine reductase activity; however, compared to the homozygote (CC), the heterozygote variant (CT) showed approximately one-third of the enzymatic activity.	('quinine', 'Species', '50278', (83, 90))	('quinine reductase activity', 'MPA', (83, 109))	('NQO1', 'Gene', (32, 36))	('variant', 'Var', (48, 55))
58693	23497461	Two to 4% of the global human population carry both mutant alleles and are deficient in NQO1.	('NQO1', 'Gene', (88, 92))	('deficient', 'NegReg', (75, 84))	('human', 'Species', '9606', (24, 29))	('mutant', 'Var', (52, 58))
58695	23497461	Delwin et al showed that loss of NQO1 caused mycloid hyperplasia of the bone marrow and significant increases in blood neutrophils, eosinophils and basophils in NQO1-null mice.	('loss', 'Var', (25, 29))	('NQO1', 'Gene', (33, 37))	('mice', 'Species', '10090', (171, 175))	('increases', 'PosReg', (100, 109))	('mycloid hyperplasia of the bone marrow', 'Disease', (45, 83))	('mycloid hyperplasia of the bone marrow', 'Disease', 'MESH:D001855', (45, 83))	('blood neutrophils', 'MPA', (113, 130))
58696	23497461	In the racial subgroups, there was a statistically significant asssociation between the NQO1 polymorphism and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('NQO1', 'Gene', (88, 92))	('polymorphism', 'Var', (93, 105))	('esophageal cancer', 'Disease', (110, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('significant', 'Reg', (51, 62))
58699	23497461	Third, we only considered the NQO1 C609T polymorphism in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('C609T', 'Var', (35, 40))	('C609T', 'Mutation', 'rs1800566', (35, 40))	('NQO1', 'Gene', (30, 34))	('esophageal cancer', 'Disease', (57, 74))
58700	23497461	However, there may be a possible interaction between the NQO1 C609T polymorphism and other environmental factors.	('NQO1', 'Gene', (57, 61))	('C609T', 'Var', (62, 67))	('C609T', 'Mutation', 'rs1800566', (62, 67))	('interaction', 'Reg', (33, 44))
58701	23497461	In summary, the present meta-analysis provides information that the NQO1 C609T polymorphism considerably increases susceptibility to or prognosis of esophageal cancer, especially in ESCC patients.	('patients', 'Species', '9606', (187, 195))	('C609T', 'Var', (73, 78))	('NQO1', 'Gene', (68, 72))	('esophageal cancer', 'Disease', (149, 166))	('ESCC', 'Disease', (182, 186))	('C609T', 'Mutation', 'rs1800566', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('increases', 'PosReg', (105, 114))
58750	21490865	Oncogenesis is not completely elucidated, but some immunohistological reports using an electron microscope have indicated point mutation in a p53 gene.	('p53', 'Gene', (142, 145))	('point mutation', 'Var', (122, 136))	('p53', 'Gene', '7157', (142, 145))	('indicated', 'Reg', (112, 121))
58829	33485350	However, transhiatal surgery would result in reduced pulmonary complications and a shortened hospital stay.	('reduced', 'NegReg', (45, 52))	('pulmonary complications', 'Phenotype', 'HP:0006532', (53, 76))	('pulmonary complications', 'Disease', (53, 76))	('transhiatal', 'Var', (9, 20))	('pulmonary complications', 'Disease', 'MESH:D008171', (53, 76))
58853	32872659	Meanwhile, STAT3beta, a STAT3 splicing isoform, is related to the inhibition of tumor growth and chemosensitivity.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('chemosensitivity', 'CPA', (97, 113))	('tumor', 'Disease', (80, 85))	('STAT3beta', 'Var', (11, 20))	('inhibition', 'NegReg', (66, 76))
58869	32872659	While STAT3 deficiency causes early embryonic lethality, STAT3beta itself can rescue the embryonic lethality.	('embryonic lethality', 'Disease', 'MESH:D020964', (89, 108))	('embryonic lethality', 'Disease', (89, 108))	('early embryonic lethality', 'Disease', (30, 55))	('early embryonic lethality', 'Disease', 'MESH:D020964', (30, 55))	('STAT3', 'Gene', (6, 11))	('deficiency', 'Var', (12, 22))	('embryonic lethality', 'Disease', 'MESH:D020964', (36, 55))
58873	32872659	The development of small-molecule inhibitors has significantly improved progression-free survival against receptor tyrosine kinases (RTKs), but disappointing outcomes remain due to the emergence of drug resistance (Figure 2).	('receptor tyrosine kinase', 'Gene', (106, 130))	('drug resistance', 'Phenotype', 'HP:0020174', (198, 213))	('receptor tyrosine kinase', 'Gene', '5979', (106, 130))	('improved', 'PosReg', (63, 71))	('small-molecule', 'Var', (19, 33))	('progression-free survival', 'CPA', (72, 97))
58874	32872659	Interestingly, erlotinib, as an RTK inhibitor, increases STAT3 phosphorylation (Tyr705) in EGFR-mutant ono-small-cell lung cancer (NSCLC) cells through an autocrine loop, whereas knockdown of STAT3 decreases erlotinib-resistant colony numbers in the presence of erlotinib.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('erlotinib', 'Chemical', 'MESH:D000069347', (15, 24))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('NSCLC', 'Disease', (131, 136))	('erlotinib', 'Chemical', 'MESH:D000069347', (208, 217))	('Tyr705', 'Chemical', '-', (80, 86))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))	('EGFR-mutant', 'Var', (91, 102))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('lung cancer', 'Disease', (118, 129))	('increases', 'PosReg', (47, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('EGFR-mutant', 'Gene', (91, 102))	('erlotinib', 'Chemical', 'MESH:D000069347', (262, 271))
58877	32872659	MEK blockage has poor clinical outcome in KRAS-mutant (KRASMT) colorectal cancer cells, and siRNA-mediated knockdown of macrophage inhibitory factor (MIF) restored sensitivity to refametinib by decreasing STAT3 phosphorylation.	('sensitivity', 'MPA', (164, 175))	('MIF', 'Gene', '4282', (150, 153))	('refametinib', 'Chemical', 'MESH:C544830', (179, 190))	('rectal cancer', 'Phenotype', 'HP:0100743', (67, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('MEK', 'Gene', (0, 3))	('macrophage inhibitory factor', 'Gene', '4282', (120, 148))	('macrophage inhibitory factor', 'Gene', (120, 148))	('MEK', 'Gene', '5609', (0, 3))	('restored', 'PosReg', (155, 163))	('STAT3 phosphorylation', 'MPA', (205, 226))	('colorectal cancer', 'Disease', (63, 80))	('MIF', 'Gene', (150, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('blockage', 'Var', (4, 12))	('decreasing', 'NegReg', (194, 204))
58897	32872659	These reports indicate that miRNA-dependent regulation of the STAT3 axis could provide a chance to overcoming the chemoresistance of cancer patients.	('chemoresistance', 'CPA', (114, 129))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('miRNA-dependent', 'Var', (28, 43))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
58898	32872659	In addition, STAT3 on Tyr705 correlates with Burkitt lymphoma (BL) chemoresistance.	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('Tyr705', 'Var', (22, 28))	('BL', 'Phenotype', 'HP:0030080', (63, 65))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (45, 61))	('Burkitt lymphoma', 'Disease', (45, 61))	('Tyr705', 'Chemical', '-', (22, 28))	('correlates', 'Reg', (29, 39))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (45, 61))
58902	32872659	Radiotherapy causes DNA damage directly or indirectly through generation of ROS and induces various forms of cancer cell death, including apoptosis, autography, mitotic catastrophe, necrosis and senescence.	('necrosis', 'Disease', (182, 190))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('Radiotherapy', 'Var', (0, 12))	('cancer', 'Disease', (109, 115))	('mitotic catastrophe', 'CPA', (161, 180))	('necrosis', 'Disease', 'MESH:D009336', (182, 190))	('senescence', 'CPA', (195, 205))	('apoptosis', 'CPA', (138, 147))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('ROS', 'Protein', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('rat', 'Species', '10116', (66, 69))	('autography', 'CPA', (149, 159))	('induces', 'Reg', (84, 91))
58904	32872659	STAT3 Y705 activation occurs in a dose- and time-dependent manner upon radiation, mediates hepatobiliary malignancies and maintains stem cell self-renewal and tumorigenic potential.	('malignancies', 'Disease', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('stem cell self-renewal', 'CPA', (132, 154))	('STAT3 Y705', 'Var', (0, 10))	('tumor', 'Disease', (159, 164))	('Y705', 'Chemical', '-', (6, 10))	('mediates', 'Reg', (82, 90))	('maintains', 'PosReg', (122, 131))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))	('activation', 'PosReg', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
58908	32872659	STAT3 antisense oligonucleotide (ASO) inhibited the phosphorylation of STAT3.	('inhibited', 'NegReg', (38, 47))	('STAT3', 'Protein', (71, 76))	('ASO', 'Chemical', 'MESH:D016376', (33, 36))	('oligonucleotide', 'Chemical', 'MESH:D009841', (16, 31))	('antisense', 'Var', (6, 15))	('STAT3', 'Gene', (0, 5))	('phosphorylation', 'MPA', (52, 67))
58910	32872659	Constitutive phosphorylation of STAT3 Tyr705 is present in B-1 lymphocytes and contributes to radioresistance.	('STAT3 Tyr705', 'Var', (32, 44))	('radioresistance', 'CPA', (94, 109))	('Tyr705', 'Chemical', '-', (38, 44))	('contributes', 'Reg', (79, 90))
58912	32872659	STAT3 Ser727 phosphorylation is also associated with radioresistance and has been reported to correlate with shortened overall survival and progression-free survival of GBM (glioblastoma) patients.	('shortened', 'NegReg', (109, 118))	('glioblastoma', 'Disease', (174, 186))	('glioblastoma', 'Disease', 'MESH:D005909', (174, 186))	('progression-free', 'CPA', (140, 156))	('Ser727', 'Chemical', '-', (6, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (174, 186))	('phosphorylation', 'Var', (13, 28))	('patients', 'Species', '9606', (188, 196))	('associated', 'Reg', (37, 47))	('overall survival', 'CPA', (119, 135))	('radioresistance', 'CPA', (53, 68))	('STAT3 Ser727 phosphorylation', 'Var', (0, 28))
58913	32872659	IL6/STAT3/TWIST signaling pathway activation mediates esophageal squamous carcinoma EMT, whereas inactivation of STAT3 by an IL-6 inhibitor or siRNA-mediated downregulation of Twist enhances cancer cell apoptosis and reverses radiation-induced EMT.	('IL-6', 'Gene', '3569', (125, 129))	('downregulation', 'NegReg', (158, 172))	('activation', 'PosReg', (34, 44))	('IL-6', 'Gene', (125, 129))	('cancer', 'Disease', (191, 197))	('IL6', 'Gene', '3569', (0, 3))	('esophageal squamous carcinoma EMT', 'Disease', (54, 87))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Twist', 'Gene', (176, 181))	('IL6', 'Gene', (0, 3))	('inactivation', 'Var', (97, 109))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (54, 83))	('enhances', 'PosReg', (182, 190))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (65, 83))	('TWIST', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Twist', 'Gene', '7291', (176, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('STAT3', 'Gene', (113, 118))	('TWIST', 'Gene', '7291', (10, 15))	('esophageal squamous carcinoma EMT', 'Disease', 'MESH:D000077277', (54, 87))
58917	32872659	Lip-FLLL32 sensitized pancreatic CSCs to chemotherapy and radiotherapy both in vitro and in vivo.	('pancreatic CSCs', 'Disease', (22, 37))	('Lip-FLLL32', 'Var', (0, 10))	('sensitized', 'Reg', (11, 21))	('FLLL32', 'Chemical', 'MESH:C548902', (4, 10))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (22, 37))
58923	32872659	Both STAT3 Y705 and S727 are potential targets for overcoming clinical radioresistance.	('STAT3 Y705', 'Var', (5, 15))	('S727', 'Var', (20, 24))	('Y705', 'Chemical', '-', (11, 15))
58929	32872659	STAT3 has been shown to significantly enhance Bcl-2 and Bcl-xL promoter activity.	('Bcl-2', 'Gene', (46, 51))	('Bcl-xL', 'Gene', '598', (56, 62))	('enhance', 'PosReg', (38, 45))	('STAT3', 'Var', (0, 5))	('Bcl-2', 'Gene', '596', (46, 51))	('Bcl-xL', 'Gene', (56, 62))
58932	32872659	Thus, aberrant activation of STAT3 can activate Bcl-2 family proteins in various cancer cells.	('Bcl-2', 'Gene', (48, 53))	('activation', 'PosReg', (15, 25))	('Bcl-2', 'Gene', '596', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('aberrant', 'Var', (6, 14))	('cancer', 'Disease', (81, 87))	('STAT3', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('activate', 'PosReg', (39, 47))
58935	32872659	For cisplatin-induced mitochondrial-related apoptosis, knockdown of STAT3, by using siRNA, attenuated the expression of anti-apoptotic proteins Bcl-xL and Bcl-2 and increased the release of cytochrome C and the expression of Bax.	('knockdown', 'Var', (55, 64))	('Bcl-2', 'Gene', (155, 160))	('release of cytochrome C', 'MPA', (179, 202))	('Bax', 'Gene', (225, 228))	('Bcl-xL', 'Gene', '598', (144, 150))	('Bcl-2', 'Gene', '596', (155, 160))	('Bax', 'Gene', '581', (225, 228))	('expression', 'MPA', (106, 116))	('Bcl-xL', 'Gene', (144, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('attenuated', 'NegReg', (91, 101))	('STAT3', 'Gene', (68, 73))	('increased', 'PosReg', (165, 174))	('expression', 'MPA', (211, 221))
58945	32872659	However, (-)-gossypol also increases the expression levels of Mcl-1, which may result in drug resistance.	('expression levels', 'MPA', (41, 58))	('(-)-gossypol', 'Chemical', 'MESH:D006072', (9, 21))	('increases', 'PosReg', (27, 36))	('Mcl-1', 'Gene', '4170', (62, 67))	('drug resistance', 'MPA', (89, 104))	('Mcl-1', 'Gene', (62, 67))	('result in', 'Reg', (79, 88))	('-)-gossypol', 'Var', (10, 21))	('drug resistance', 'Phenotype', 'HP:0020174', (89, 104))
58965	32872659	Moreover, the blockage of STAT3/Slug also improves survival in GBM-R2I2 xenografts.	('blockage', 'Var', (14, 22))	('GBM-R2I2', 'Gene', (63, 71))	('survival', 'CPA', (51, 59))	('Slug', 'Gene', '6591', (32, 36))	('improves', 'PosReg', (42, 50))	('Slug', 'Gene', (32, 36))
58979	32872659	Inhibition of the IL6/STAT3/Twist signaling pathway could be a useful strategy to reverse radiation -induced EMT and radioresistance in ESCC.	('rat', 'Species', '10116', (72, 75))	('Twist', 'Gene', '7291', (28, 33))	('ESCC', 'Disease', (136, 140))	('IL6', 'Gene', '3569', (18, 21))	('radioresistance', 'CPA', (117, 132))	('Twist', 'Gene', (28, 33))	('IL6', 'Gene', (18, 21))	('Inhibition', 'Var', (0, 10))
58983	32872659	Survivin is an inhibitor of the apoptosis protein family, and its aberrant expression correlates with a poor prognosis and contributes to chemo(radio)resistance.	('Survivin', 'Gene', '11799', (0, 8))	('chemo', 'CPA', (138, 143))	('Survivin', 'Gene', (0, 8))	('aberrant expression', 'Var', (66, 85))	('contributes to', 'Reg', (123, 137))
58986	32872659	Survivin inhibitor MX106 effectively overcomes paclitaxel resistance in ovarian cancer cells.	('overcomes', 'NegReg', (37, 46))	('MX106', 'Var', (19, 24))	('Survivin', 'Gene', '11799', (0, 8))	('MX106', 'Chemical', '-', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('Survivin', 'Gene', (0, 8))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('paclitaxel resistance', 'MPA', (47, 68))	('paclitaxel', 'Chemical', 'MESH:D017239', (47, 57))	('ovarian cancer', 'Disease', (72, 86))
58992	32872659	Furthermore, using an inhibitor of JAK2, which is upstream of STAT3, affected survivin expression and sensitized lung cancer to radiation in vitro and in vivo.	('sensitized', 'Reg', (102, 112))	('inhibitor', 'Var', (22, 31))	('JAK2', 'Gene', (35, 39))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('survivin', 'Gene', '11799', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('affected', 'Reg', (69, 77))	('expression', 'MPA', (87, 97))	('JAK2', 'Gene', '3717', (35, 39))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('survivin', 'Gene', (78, 86))
58997	32872659	Several studies reported that inhibition of the STAT3 signaling pathway reduced the expression of cyclin D1 and enhanced the drug sensitivity of the cancer cells, including gastric carcinoma, cholangiocarcinoma, bladder cancer and hepatocellular carcinoma.	('cyclin D1', 'Gene', '595', (98, 107))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('hepatocellular carcinoma', 'Disease', (231, 255))	('drug sensitivity', 'CPA', (125, 141))	('enhanced', 'PosReg', (112, 120))	('reduced', 'NegReg', (72, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (192, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('gastric carcinoma', 'Disease', 'MESH:D013274', (173, 190))	('cholangiocarcinoma', 'Disease', (192, 210))	('cancer', 'Disease', (149, 155))	('gastric carcinoma', 'Disease', (173, 190))	('drug sensitivity', 'Phenotype', 'HP:0020174', (125, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (192, 210))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (231, 255))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (173, 190))	('bladder cancer', 'Disease', 'MESH:D001749', (212, 226))	('bladder cancer', 'Disease', (212, 226))	('cancer', 'Disease', (220, 226))	('expression', 'MPA', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('inhibition', 'Var', (30, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('bladder cancer', 'Phenotype', 'HP:0009725', (212, 226))	('cyclin D1', 'Gene', (98, 107))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (231, 255))	('STAT3 signaling pathway', 'Pathway', (48, 71))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
58998	32872659	An antisense cyclin D1 sequence in head and neck squamous cell carcinoma (HSNCC) cells inhibits cell growth, induces apoptosis and enhances sensitivity to chemotherapeutic agents both in vitro and in vivo.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (44, 72))	('sensitivity to chemotherapeutic agents', 'MPA', (140, 178))	('enhances', 'PosReg', (131, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('cyclin D1', 'Gene', (13, 22))	('inhibits', 'NegReg', (87, 95))	('antisense', 'Var', (3, 12))	('apoptosis', 'CPA', (117, 126))	('cyclin D1', 'Gene', '595', (13, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('neck squamous cell carcinoma', 'Disease', (44, 72))	('cell growth', 'CPA', (96, 107))	('induces', 'Reg', (109, 116))
59000	32872659	The researchers also demonstrated that a dominant-negative STAT3 strongly enhanced the cellular sensitivity of HNSCC cells to 5-FU and radiation.	('5-FU', 'Chemical', 'MESH:D005472', (126, 130))	('dominant-negative', 'Var', (41, 58))	('cellular sensitivity', 'MPA', (87, 107))	('STAT3', 'Gene', (59, 64))	('enhanced', 'PosReg', (74, 82))	('rat', 'Species', '10116', (28, 31))
59002	32872659	Inhibition of cyclin D1 using siRNA can inhibit the LDIR-associated anti-apoptotic response and eliminate LDIR-induced adaptive radioresistance.	('adaptive radioresistance', 'CPA', (119, 143))	('eliminate', 'NegReg', (96, 105))	('inhibit', 'NegReg', (40, 47))	('LDIR-associated', 'Disease', (52, 67))	('anti-apoptotic response', 'CPA', (68, 91))	('Inhibition', 'Var', (0, 10))	('cyclin D1', 'Gene', '595', (14, 23))	('cyclin D1', 'Gene', (14, 23))
59004	32872659	Inhibition of cyclin D1 by using siRNA significantly decreased the cell proliferation rate and resulted in G0/G1 arrest, and it also enhanced sensitivity to radiation and reversed EMT.	('arrest', 'Disease', (113, 119))	('cell proliferation rate', 'CPA', (67, 90))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (142, 166))	('cyclin D1', 'Gene', '595', (14, 23))	('enhanced sensitivity to radiation', 'Phenotype', 'HP:0011133', (133, 166))	('reversed EMT', 'CPA', (171, 183))	('Inhibition', 'Var', (0, 10))	('sensitivity', 'CPA', (142, 153))	('arrest', 'Disease', 'MESH:D006323', (113, 119))	('rat', 'Species', '10116', (79, 82))	('decreased', 'NegReg', (53, 62))	('rat', 'Species', '10116', (86, 89))	('enhanced', 'PosReg', (133, 141))	('cyclin D1', 'Gene', (14, 23))
59007	32872659	Cyclin D1 knockdown using shRNA resulted in a radiation-dose dependent precipitous decline in clonogenic survival.	('decline', 'NegReg', (83, 90))	('Cyclin D1', 'Gene', '595', (0, 9))	('clonogenic survival', 'CPA', (94, 113))	('Cyclin D1', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))
59010	32872659	Moreover, controlling cyclin D1 by knocking down insulinoma-associated protein1 enhanced the sensitivity of NPC cells to radiation both in vitro and in vivo.	('NPC', 'Phenotype', 'HP:0100630', (108, 111))	('insulinoma-associated protein1', 'Gene', (49, 79))	('knocking down', 'Var', (35, 48))	('cyclin D1', 'Gene', '595', (22, 31))	('sensitivity', 'MPA', (93, 104))	('cyclin D1', 'Gene', (22, 31))	('enhanced', 'PosReg', (80, 88))	('insulinoma-associated protein1', 'Gene', '3642', (49, 79))	('insulinoma', 'Phenotype', 'HP:0012197', (49, 59))
59012	32872659	Yu's study showed that blocking STAT3 signaling with STAT3beta or antisense STAT3 oligonucleotide activated dendritic cells (DCs) by inducing the proinflammatory mediators IL-6, regulated upon activation normal T cell expressed and secreted factor (RANTES) and interferon-inducible protein-10 (IP-10) in tumor cells.	('RANTES', 'Gene', (249, 255))	('interferon-inducible protein-10', 'Gene', (261, 292))	('IL-6', 'Gene', '3569', (172, 176))	('IP-10', 'Gene', (294, 299))	('regulated upon activation normal T cell expressed and secreted factor', 'Gene', '6352', (178, 247))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('RANTES', 'Gene', '6352', (249, 255))	('IP-10', 'Gene', '3627', (294, 299))	('interferon-inducible protein-10', 'Gene', '3627', (261, 292))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('blocking', 'NegReg', (23, 31))	('inducing', 'PosReg', (133, 141))	('tumor', 'Disease', (304, 309))	('IL-6', 'Gene', (172, 176))	('antisense', 'Var', (66, 75))	('oligonucleotide', 'Chemical', 'MESH:D009841', (82, 97))
59026	32872659	Suppressor of cytokine signaling 3 (SOCS3)-deficient CD4+ T cells have a lower type 2 T helper cell (Th2) immune response and considerably increase the expression level of IL-10 and TGF-beta for Th3-like differentiation via the enhanced recruitment of STAT3 to their promoters.	('TGF-beta', 'Gene', (182, 190))	('CD4', 'Gene', '920', (53, 56))	('Suppressor of cytokine signaling 3', 'Gene', (0, 34))	('SOCS3', 'Gene', (36, 41))	('expression level', 'MPA', (152, 168))	('TGF-beta', 'Gene', '7039', (182, 190))	('deficient CD4+ T', 'Phenotype', 'HP:0005407', (43, 59))	('increase', 'PosReg', (139, 147))	('lower', 'NegReg', (73, 78))	('CD4', 'Gene', (53, 56))	('SOCS3', 'Gene', '9021', (36, 41))	('-deficient', 'Var', (42, 52))	('recruitment', 'MPA', (237, 248))	('enhanced', 'PosReg', (228, 236))	('Suppressor of cytokine signaling 3', 'Gene', '9021', (0, 34))
59030	32872659	Recently, Ong and colleagues found that a novel STAT3 mutation (p.D427H, E616G, p.E616K and p.E696K) increased phosphorylation of STAT3 at Tyr705 in STAT3 mutants.	('STAT3', 'Gene', (48, 53))	('p.D427H', 'Mutation', 'p.D427H', (64, 71))	('mutants', 'Var', (155, 162))	('increased', 'PosReg', (101, 110))	('STAT3', 'Gene', (149, 154))	('p.E616K', 'Var', (80, 87))	('p.D427H', 'Var', (64, 71))	('E616G', 'Var', (73, 78))	('p.E696K', 'Mutation', 'p.E696K', (92, 99))	('Tyr705', 'Chemical', '-', (139, 145))	('p.E616K', 'Mutation', 'p.E616K', (80, 87))	('STAT3', 'Protein', (130, 135))	('E616G', 'Mutation', 'p.E616G', (73, 78))	('phosphorylation', 'MPA', (111, 126))	('p.E696K', 'Var', (92, 99))
59031	32872659	Further, p.E616K regulated programmed death-ligand 1(PD-L1) expression via the binding of STAT3 to the promoter of PD-L1 in NK/T-cell lymphoma (NKTL).	('expression', 'MPA', (60, 70))	('PD-L1', 'Gene', (53, 58))	('p.E616K', 'Var', (9, 16))	('PD-L1', 'Gene', (115, 120))	('PD-L1', 'Gene', '29126', (115, 120))	('PD-L1', 'Gene', '29126', (53, 58))	('binding', 'Interaction', (79, 86))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (127, 142))	('lymphoma', 'Phenotype', 'HP:0002665', (134, 142))	('cell lymphoma', 'Phenotype', 'HP:0012191', (129, 142))	('p.E616K', 'Mutation', 'p.E616K', (9, 16))	('regulated', 'Reg', (17, 26))	('NK/T-cell lymphoma', 'Disease', 'MESH:D054391', (124, 142))	('NK/T-cell lymphoma', 'Disease', (124, 142))
59032	32872659	The team suggested that inhibitors of STAT3 and PD-L1 might be a promising therapeutic strategy for NKTL.	('PD-L1', 'Gene', '29126', (48, 53))	('NKTL', 'Disease', (100, 104))	('rat', 'Species', '10116', (89, 92))	('inhibitors', 'Var', (24, 34))	('PD-L1', 'Gene', (48, 53))	('STAT3', 'Gene', (38, 43))
59034	32872659	Silencing STAT3 signaling can reverse the level of PD-L1 and enhance the susceptibility of CRPC cells to NK cell immunity.	('enhance', 'PosReg', (61, 68))	('susceptibility', 'MPA', (73, 87))	('PD-L1', 'Gene', '29126', (51, 56))	('STAT3', 'Protein', (10, 15))	('Silencing', 'Var', (0, 9))	('PD-L1', 'Gene', (51, 56))
59038	32872659	However, STAT3beta significantly inhibited cell growth in soft agar in a dose-dependent manner, while cell-specific STAT3beta expression in macrophages reduced the invasion and cell mobility of breast cancer cells and significantly suppressed breast tumor growth.	('breast cancer', 'Disease', (194, 207))	('breast tumor', 'Phenotype', 'HP:0100013', (243, 255))	('STAT3beta', 'Var', (116, 125))	('agar', 'Chemical', 'MESH:D000362', (63, 67))	('reduced', 'NegReg', (152, 159))	('breast tumor', 'Disease', 'MESH:D001943', (243, 255))	('cell growth in soft agar', 'CPA', (43, 67))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast tumor', 'Disease', (243, 255))	('inhibited', 'NegReg', (33, 42))	('suppressed', 'NegReg', (232, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
59041	32872659	Cooperating with c-Jun, STAT3beta increases Fas expression and the sensitization of melanoma cells to Fas ligand-induced apoptosis.	('c-Jun', 'Gene', (17, 22))	('Fas ligand', 'Gene', '356', (102, 112))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('sensitization', 'CPA', (67, 80))	('melanoma', 'Disease', (84, 92))	('Fas', 'Protein', (44, 47))	('expression', 'MPA', (48, 58))	('STAT3beta', 'Var', (24, 33))	('rat', 'Species', '10116', (5, 8))	('c-Jun', 'Gene', '3725', (17, 22))	('Fas ligand', 'Gene', (102, 112))	('increases', 'PosReg', (34, 43))
59042	32872659	Zammarchi and colleagues revealed that the STAT3beta switch leads to tumor regression in vivo.	('STAT3beta', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))
59046	32872659	In breast cancer cells, STAT3beta mediates cells' growth inhibition and leads to cell cycle arrest and apoptosis.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (81, 98))	('STAT3beta', 'Var', (24, 33))	('arrest', 'Disease', 'MESH:D006323', (92, 98))	('leads to', 'Reg', (72, 80))	('apoptosis', 'CPA', (103, 112))	('arrest', 'Disease', (92, 98))
59048	32872659	Intriguingly, the expression of STAT3beta can rescue the embryonic lethality of STAT3 deficient mice and induce the expression of specific STAT3 target genes.	('induce', 'PosReg', (105, 111))	('expression', 'MPA', (116, 126))	('mice', 'Species', '10090', (96, 100))	('STAT3beta', 'Gene', (32, 41))	('rescue', 'PosReg', (46, 52))	('embryonic lethality', 'Disease', 'MESH:D020964', (57, 76))	('embryonic lethality', 'Disease', (57, 76))	('expression', 'Var', (18, 28))
59049	32872659	STAT3beta has gained attention as a potent tumor suppressor and a favorable prognostic factor in ESCC with or without chemoradiotherapy, and it strongly correlates with longer overall survival and recurrence-free survival.	('recurrence-free survival', 'CPA', (197, 221))	('overall survival', 'CPA', (176, 192))	('STAT3beta', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('longer', 'PosReg', (169, 175))	('ESCC', 'Disease', (97, 101))
59050	32872659	Recently, it has been found that STAT3beta correlates with a favorable prognosis and prolonged survival, and also has a tumor-suppressive effect in acute myeloid leukemia via the regulation of its target gene, SELL.	('acute myeloid leukemia', 'Disease', (148, 170))	('SELL', 'Gene', (210, 214))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (148, 170))	('SELL', 'Gene', '6402', (210, 214))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (154, 170))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (120, 125))	('leukemia', 'Phenotype', 'HP:0001909', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (148, 170))	('STAT3beta', 'Var', (33, 42))
59056	32872659	The splicing reprogramming offers an effective therapeutic approach for cancer.	('splicing', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
59067	32872659	Furthermore, ST3-H2A2 (LDTRYLEQLHKLY) bound to both phosphorylated and unphosphorylated STAT3 in prostate cancer cells, decreased STAT3 DNA binding ability and induced apoptotic cell death.	('decreased', 'NegReg', (120, 129))	('bound', 'Interaction', (38, 43))	('induced', 'Reg', (160, 167))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('STAT3 DNA binding', 'Interaction', (130, 147))	('apoptotic cell death', 'CPA', (168, 188))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('ST3-H2A2', 'Var', (13, 21))	('prostate cancer', 'Disease', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
59072	32872659	showed that it acts as a cysteine reactive inhibitor and binds to one or more cysteines in STAT3 (Cys-367, Cys-468, Cys-542).	('Cys-468', 'Var', (107, 114))	('Cys-367', 'Var', (98, 105))	('cysteines', 'Chemical', 'MESH:D003545', (78, 87))	('Cys', 'Chemical', 'MESH:D003545', (98, 101))	('Cys', 'Chemical', 'MESH:D003545', (116, 119))	('Cys-542', 'Var', (116, 123))	('cysteine', 'Chemical', 'MESH:D003545', (78, 86))	('binds', 'Interaction', (57, 62))	('cysteine', 'Chemical', 'MESH:D003545', (25, 33))	('Cys', 'Chemical', 'MESH:D003545', (107, 110))
59073	32872659	Recently, it was shown to suppress the resistance of prostate cancer cells to enzalutamide, and its analogs SG-1709 (Figure 3b) and SG-1721 (Figure 3c) exhibited even greater effectiveness in blocking STAT3 signaling and inducing apoptosis.	('SG-1721', 'Var', (132, 139))	('prostate cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('resistance', 'MPA', (39, 49))	('apoptosis', 'CPA', (230, 239))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('inducing', 'Reg', (221, 229))	('blocking', 'NegReg', (192, 200))	('suppress', 'NegReg', (26, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('STAT3', 'MPA', (201, 206))	('enzalutamide', 'Chemical', 'MESH:C540278', (78, 90))	('SG-1709', 'Gene', (108, 115))
59089	32872659	found that C48 is a STAT3 inhibitor that selectively binds to Cys468 of STAT3 and blocks phosphorylation of STAT3 to inhibit tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('phosphorylation', 'MPA', (89, 104))	('STAT3', 'Gene', (72, 77))	('C48', 'Gene', (11, 14))	('blocks', 'NegReg', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Cys468', 'Chemical', '-', (62, 68))	('tumor', 'Disease', (125, 130))	('binds', 'Interaction', (53, 58))	('C48', 'Gene', '55755', (11, 14))	('Cys468', 'Var', (62, 68))	('inhibit', 'NegReg', (117, 124))
59092	32872659	From an analysis by matrix-assisted laser desorption/ionization-mass spectrometry, Cys550 was found to be an important residue for crosslinking between STAT3 and BPMB.	('BPMB', 'Chemical', '-', (162, 166))	('STAT3', 'Gene', (152, 157))	('Cys550', 'Chemical', '-', (83, 89))	('BPMB', 'Gene', (162, 166))	('Cys550', 'Var', (83, 89))	('crosslinking', 'MPA', (131, 143))
59104	32872659	CJ-1383 induced breast cancer cell apoptosis in a dose-dependent manner, while inhibition of tumor growth by the phosphopeptide mimetic PM-73G occurred without apoptosis or changes in the expression of cyclin D1 or survivin in xenograft models.	('cyclin D1', 'Gene', (202, 211))	('breast cancer', 'Disease', (16, 29))	('PM', 'Chemical', 'MESH:D011399', (136, 138))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('survivin', 'Gene', '11799', (215, 223))	('CJ-1383', 'CellLine', 'CVCL:8044', (0, 7))	('tumor', 'Disease', (93, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))	('survivin', 'Gene', (215, 223))	('phosphopeptide', 'Chemical', 'MESH:D010748', (113, 127))	('CJ-1383', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cyclin D1', 'Gene', '595', (202, 211))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
59106	32872659	Another study demonstrated that Stattic enhanced radiosensitivity.	('Stattic', 'Var', (32, 39))	('radiosensitivity', 'CPA', (49, 65))	('rat', 'Species', '10116', (21, 24))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (40, 65))	('enhanced', 'PosReg', (40, 48))
59107	32872659	STA-21 (Figure 3g), a natural product analog of tetrangomycin, was discovered via structure-based virtual screening to bind to the SH2 domain and form hydrogen bonds with Arg595, Arg609 and Ile634.	('Ile634', 'Var', (190, 196))	('Arg595', 'Var', (171, 177))	('Arg609', 'Chemical', '-', (179, 185))	('Arg595', 'Chemical', '-', (171, 177))	('form', 'Reg', (146, 150))	('Arg609', 'Var', (179, 185))	('hydrogen', 'Chemical', 'MESH:D006859', (151, 159))	('STA-21', 'Chemical', 'MESH:C500947', (0, 6))	('bind', 'Interaction', (119, 123))	('Ile634', 'Chemical', '-', (190, 196))	('tetrangomycin', 'Chemical', 'MESH:C103671', (48, 61))	('hydrogen', 'Interaction', (151, 159))
59113	32872659	S3I-201 (NSC 74859, Figure 3k) is a selective chemical probe inhibitor of STAT3 and binds to the STAT3 phosphotyrosine peptide (PY*LKT) with the potential to become a radiosensitizer for esophageal cancer radiotherapy.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (103, 118))	('binds', 'Interaction', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('S3I-201', 'Var', (0, 7))
59114	32872659	S3I-201 alkylates multiple Cys residues of STAT3 (Cys 108, 259, 367, 542 and 687), and is identified as a non-selective alkylating agent due to its leaving group O-tosyl.	('Cys', 'Chemical', 'MESH:D003545', (27, 30))	('alkylates', 'Reg', (8, 17))	('Cys', 'Chemical', 'MESH:D003545', (50, 53))	('S3I-201', 'Var', (0, 7))
59115	32872659	Molecular modeling, using S3I-201 as the lead compound, led to S3I-1757, which could interact with Y705 in the binding site of the SH2 domain and decrease nuclear phosphotyrosine STAT3 levels.	('phosphotyrosine', 'Chemical', 'MESH:D019000', (163, 178))	('nuclear phosphotyrosine STAT3 levels', 'MPA', (155, 191))	('Y705', 'Chemical', '-', (99, 103))	('binding', 'Interaction', (111, 118))	('S3I-1757', 'Var', (63, 71))	('Y705', 'Var', (99, 103))	('decrease', 'NegReg', (146, 154))
59116	32872659	synthesized a large set of S3I-201 analogs, among which SF-1-066 (known as S3I-201.1066, Figure 3l) and SF-1-121 showed impressive potency in whole-cell viability assays, and SF-1-066 also induced an antitumor response in breast tumor xenografts.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('breast tumor', 'Phenotype', 'HP:0100013', (222, 234))	('SF-1-066', 'Chemical', 'MESH:C000595191', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('breast tumor', 'Disease', 'MESH:D001943', (222, 234))	('SF-1-066', 'Var', (175, 183))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', (204, 209))	('induced', 'Reg', (189, 196))	('breast tumor', 'Disease', (222, 234))	('SF-1-066', 'Chemical', 'MESH:C000595191', (175, 183))
59117	32872659	Further improvement of the parent compound SF-1-066 led to BP-5-087 (Figure 3m), a highly potent and selective STAT3 SH2 domain inhibitor, and when used in combination with imatinib, it could reverse TKI-resistant CML.	('BP-5-087', 'Var', (59, 67))	('imatinib', 'Chemical', 'MESH:D000068877', (173, 181))	('SF-1-066', 'Chemical', 'MESH:C000595191', (43, 51))	('TKI-resistant CML', 'Disease', (200, 217))	('BP-5-087', 'Chemical', 'MESH:C000597560', (59, 67))
59121	32872659	To reduce the pharmacokinetic lability of BP-1-102, SH-4-54 was designed as a STAT3 SH2 domain inhibitor, which showed better therapeutic efficacy than BP-1-102, and exhibited blood-brain barrier permeability and controlled glioma tumor growth.	('BP-1-102', 'Chemical', 'MESH:C000595192', (152, 160))	('SH-4-54', 'Var', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('pharmacokinetic lability', 'MPA', (14, 38))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('glioma tumor', 'Disease', (224, 236))	('BP-1-102', 'Chemical', 'MESH:C000595192', (42, 50))	('glioma tumor', 'Disease', 'MESH:D005910', (224, 236))
59123	32872659	They interact with the SH2 domain of STAT3 with high affinity and inhibit STAT3 Y705 and S727 phosphorylation.	('S727', 'Var', (89, 93))	('Y705', 'Chemical', '-', (80, 84))	('Y705', 'Var', (80, 84))	('interact', 'Interaction', (5, 13))	('inhibit', 'NegReg', (66, 73))	('STAT3', 'MPA', (74, 79))
59124	32872659	Computational docking and molecular dynamics simulations were used to examine the binding of OPB-31121 to STAT3, and OPB-31121 bound to S636 and V637 residues without overlapping with other STAT3 inhibitors.	('bound', 'Interaction', (127, 132))	('OPB-31121', 'Chemical', '-', (117, 126))	('V637', 'Var', (145, 149))	('OPB-31121', 'Var', (117, 126))	('OPB-31121', 'Chemical', '-', (93, 102))	('S636', 'Var', (136, 140))	('binding', 'Interaction', (82, 89))	('OPB-31121', 'Gene', (93, 102))
59125	32872659	OPB-51602 can directly interfere with mitochondrial STAT3 and induce the formation of STAT3 proteotoxic aggregates that are lethal to cancer cells.	('STAT3 proteotoxic aggregates', 'MPA', (86, 114))	('OPB-51602', 'Var', (0, 9))	('induce', 'Reg', (62, 68))	('interfere', 'NegReg', (23, 32))	('formation', 'MPA', (73, 82))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mitochondrial STAT3', 'MPA', (38, 57))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('OPB-51602', 'Chemical', '-', (0, 9))
59128	32872659	These include a Phase I clinical trial for OPB-31121 in advanced cancer and solid tumor in Korea (NCT00657176, 18 April 2008) and the USA (NCT00955812, 12 February 2013), a Phase I/II trial in patients with progressive hepatocellular carcinoma (NCT01406574, 8 June 2015), and a Phase I OPB-51602 clinical trial for hematological malignancies in Japan (NCT01344876, 8 June 2015) and for refractory solid tumors (NCT01184807, 26 March 2014).	('tumor', 'Disease', 'MESH:D009369', (403, 408))	('hematological malignancies', 'Disease', 'MESH:D019337', (315, 341))	('OPB-51602', 'Chemical', '-', (286, 295))	('progressive hepatocellular carcinoma', 'Disease', (207, 243))	('tumors', 'Phenotype', 'HP:0002664', (403, 409))	('hematological malignancies', 'Phenotype', 'HP:0004377', (315, 341))	('tumor', 'Disease', (82, 87))	('cancer', 'Disease', (65, 71))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (219, 243))	('OPB-31121', 'Chemical', '-', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (403, 408))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('progressive hepatocellular carcinoma', 'Disease', 'MESH:D006528', (207, 243))	('tumors', 'Disease', (403, 409))	('patients', 'Species', '9606', (193, 201))	('hematological malignancies', 'Disease', (315, 341))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('NCT00657176', 'Var', (98, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('NCT01344876', 'Var', (352, 363))	('NCT01406574', 'Var', (245, 256))	('tumors', 'Disease', 'MESH:D009369', (403, 409))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Disease', (403, 408))	('NCT00955812', 'Var', (139, 150))
59129	32872659	Aberrant STAT3 activation is related to cell malignant transformation, tumor proliferation, differentiation and anti-apoptosis.	('activation', 'PosReg', (15, 25))	('cell malignant transformation', 'CPA', (40, 69))	('Aberrant', 'Var', (0, 8))	('STAT3', 'Gene', (9, 14))	('rat', 'Species', '10116', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('anti-apoptosis', 'CPA', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('differentiation', 'CPA', (92, 107))
59136	32872659	The team confirmed that K116 both inhibited STAT3 Tyr705 and promoted apoptosis in a dose-dependent manner.	('promoted', 'PosReg', (61, 69))	('inhibited', 'NegReg', (34, 43))	('STAT3 Tyr705', 'MPA', (44, 56))	('apoptosis', 'CPA', (70, 79))	('Tyr705', 'Chemical', '-', (50, 56))	('K116', 'Var', (24, 28))	('K116', 'Chemical', '-', (24, 28))
59137	32872659	In summary, small-molecule STAT3 inhibitors have antitumor activities and inhibit STAT3 phosphorylation but are yet to be approved for clinical cancer therapy.	('small-molecule', 'Var', (12, 26))	('STAT3', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('inhibit', 'NegReg', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Disease', (144, 150))	('tumor', 'Disease', (53, 58))	('STAT3 phosphorylation', 'MPA', (82, 103))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
59145	32872659	As mentioned above, STAT3beta functions as a tumor suppressor and sensitizes cancer cells and ESCC patients to chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Disease', (45, 50))	('STAT3beta', 'Var', (20, 29))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('sensitizes', 'Reg', (66, 76))
59147	32872659	Interestingly, the ratio of STAT3alpha/STAT3beta impacts the fate of a tumor.	('STAT3alpha/STAT3beta', 'Var', (28, 48))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('impacts', 'Reg', (49, 56))	('tumor', 'Disease', (71, 76))
59206	31929362	In applying the above-mentioned software for quantitative analysis and identification of the various types of tissue, the average SVM output value was 0.846 +- 0.220 for cancerous lesions, 0.381 +- 0.349 for reddened lesions, and 0.219 +- 0.277 for surrounding tissue, with the SVM output value for cancerous lesions being significantly greater than that for reddened lesions or surrounding tissue.	('cancerous lesions', 'Disease', 'MESH:D009369', (299, 316))	('cancerous lesions', 'Disease', 'MESH:D009369', (170, 187))	('cancerous lesions', 'Disease', (299, 316))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('greater', 'PosReg', (337, 344))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancerous lesions', 'Disease', (170, 187))	('0.381 +-', 'Var', (189, 197))
59354	30759966	Subgroup analysis showed that the subdistribution hazard ratio was higher in patients with high volume index in non-alcoholic cirrhosis (5.05; 95% confidence interval [CI], 2.14 to 11.90; p < 0.001), but the volume index was not significant predictor in alcoholic cirrhosis (1.19; 95% CI, 0.33 to 4.28; p = 0.788).	('high volume index', 'Var', (91, 108))	('alcoholic cirrhosis', 'Phenotype', 'HP:0002613', (254, 273))	('non-alcoholic cirrhosis', 'Disease', (112, 135))	('higher', 'PosReg', (67, 73))	('alcoholic cirrhosis', 'Disease', 'MESH:D008104', (254, 273))	('cirrhosis', 'Phenotype', 'HP:0001394', (126, 135))	('non-alcoholic cirrhosis', 'Disease', 'MESH:D008104', (112, 135))	('patients', 'Species', '9606', (77, 85))	('alcoholic cirrhosis', 'Phenotype', 'HP:0002613', (116, 135))	('alcoholic cirrhosis', 'Disease', (254, 273))	('cirrhosis', 'Phenotype', 'HP:0001394', (264, 273))	('alcoholic cirrhosis', 'Disease', 'MESH:D008104', (116, 135))
59372	30759966	There have been concerns regarding the use of NSBB in decompensated cirrhosis with ascites, advocating the concept of "window hypothesis for beta-blockers": NSBB may be harmful in the end-stage cirrhosis with refractory ascites.	('cirrhosis', 'Disease', 'MESH:D005355', (194, 203))	('cirrhosis', 'Phenotype', 'HP:0001394', (68, 77))	('ascites', 'Disease', (83, 90))	('ascites', 'Disease', 'MESH:D001201', (220, 227))	('cirrhosis', 'Disease', (194, 203))	('NSBB', 'Var', (157, 161))	('ascites', 'Disease', (220, 227))	('cirrhosis', 'Disease', 'MESH:D005355', (68, 77))	('ascites', 'Disease', 'MESH:D001201', (83, 90))	('ascites', 'Phenotype', 'HP:0001541', (220, 227))	('ascites', 'Phenotype', 'HP:0001541', (83, 90))	('cirrhosis', 'Disease', (68, 77))	('cirrhosis', 'Phenotype', 'HP:0001394', (194, 203))
59373	30759966	However, contradicting results exist and recent meta-analyses indicate that NSBB does not increase mortality in decompensated cirrhosis.	('cirrhosis', 'Disease', 'MESH:D005355', (126, 135))	('cirrhosis', 'Disease', (126, 135))	('cirrhosis', 'Phenotype', 'HP:0001394', (126, 135))	('NSBB', 'Var', (76, 80))
59450	30655068	Multivariable analysis showed that advanced clinical stage remained important (HR 1.86, p=0.085), but poor tumor differentiation once again was the only independent predictor for developing a recurrence (HR 2.39, p=0.018) (Table 4).	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('poor', 'Var', (102, 106))	('tumor', 'Disease', (107, 112))
59456	30655068	Here, we demonstrate that poor tumor differentiation grade is an independent predictor of recurrence, particularly in the subgroup of patients with EAC where there was adequate statistical power to detect this result.	('EAC', 'Gene', '1540', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('poor', 'Var', (26, 30))	('tumor', 'Disease', (31, 36))	('EAC', 'Gene', (148, 151))	('patients', 'Species', '9606', (134, 142))	('recurrence', 'Disease', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
59487	28702078	Anticancer activities and mechanisms of heat-clearing and detoxicating traditional Chinese herbal medicine In traditional Chinese medicine (TCM) theory, pathogenic heat and toxins, which are akin to the inflammatory factors, are the causes of cancer and could promote its virulent development.	('promote', 'PosReg', (260, 267))	('pathogenic heat', 'Var', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('causes', 'Reg', (233, 239))	('cancer', 'Disease', (243, 249))	('virulent development', 'CPA', (272, 292))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', (4, 10))
59536	28702078	CR supplementation significantly attenuated weight loss in tumor-bearing nude mice without changing food intake or tumor growth, and maintained good nutritional status in these mice.	('changing food', 'Disease', 'MESH:D005517', (91, 104))	('changing food', 'Disease', (91, 104))	('weight loss', 'Disease', (44, 55))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('weight loss', 'Phenotype', 'HP:0001824', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (115, 120))	('supplementation', 'Var', (3, 18))	('attenuated', 'NegReg', (33, 43))	('nutritional status', 'MPA', (149, 167))	('weight loss', 'Disease', 'MESH:D015431', (44, 55))	('mice', 'Species', '10090', (177, 181))	('CR', 'Chemical', '-', (0, 2))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('mice', 'Species', '10090', (78, 82))	('nude mice', 'Species', '10090', (73, 82))
59572	28702078	A more recent report revealed that DHA activates the autophagy program by suppressing the nuclear translocation of NF-kappaB.	('suppressing', 'NegReg', (74, 85))	('DHA', 'Var', (35, 38))	('activates', 'PosReg', (39, 48))	('nuclear translocation', 'MPA', (90, 111))	('NF-kappaB', 'Gene', '4790', (115, 124))	('autophagy program', 'CPA', (53, 70))	('NF-kappaB', 'Gene', (115, 124))	('DHA', 'Chemical', 'MESH:C039060', (35, 38))
59577	28702078	For instance, DHA sensitized human ovarian cancer cells to carboplatin therapy and synergistically enhanced the anticancer effect of gemcitabine on human lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('carboplatin', 'Chemical', 'MESH:D016190', (59, 70))	('enhanced', 'PosReg', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (35, 49))	('DHA', 'Chemical', 'MESH:C039060', (14, 17))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ovarian cancer', 'Disease', (35, 49))	('lung cancer', 'Disease', (154, 165))	('cancer', 'Disease', (116, 122))	('DHA', 'Var', (14, 17))	('human', 'Species', '9606', (148, 153))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('human', 'Species', '9606', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('gemcitabine', 'Chemical', 'MESH:C056507', (133, 144))	('cancer', 'Disease', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
59597	28702078	Methylanthraquinone also caused apoptosis in human leukemic U937 cells by decreasing phospho-ERK1/2 and increasing phospho-p38 MAPKs.	('leukemic', 'Disease', 'MESH:D007938', (51, 59))	('Methylanthraquinone', 'Var', (0, 19))	('p38', 'Gene', '5594', (123, 126))	('decreasing', 'NegReg', (74, 84))	('ERK1/2', 'Gene', (93, 99))	('ERK1/2', 'Gene', '5595;5594', (93, 99))	('human', 'Species', '9606', (45, 50))	('Methylanthraquinone', 'Chemical', '-', (0, 19))	('p38', 'Gene', (123, 126))	('leukemic', 'Disease', (51, 59))	('U937', 'CellLine', 'CVCL:0007', (60, 64))	('increasing', 'PosReg', (104, 114))
59622	28702078	Further studies on benign smooth muscle cell tumor model demonstrated that SBH could induce differentiation and apoptosis in uterine smooth muscle cells.	('induce', 'PosReg', (85, 91))	('SBH', 'Chemical', '-', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('apoptosis', 'CPA', (112, 121))	('SBH', 'Var', (75, 78))	('tumor', 'Disease', (45, 50))	('differentiation', 'CPA', (92, 107))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
59668	28702078	Moreover, EE-JXY inhibits angiogenesis in chick chorioallantoic membrane and decreases microvessel density in the xenograft tumor.	('inhibits', 'NegReg', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('angiogenesis in chick chorioallantoic membrane', 'CPA', (26, 72))	('EE-JXY', 'Var', (10, 16))	('chick', 'Species', '9031', (42, 47))	('decreases', 'NegReg', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
59675	28702078	Although PHY906 alone has little antitumor effect, it was developed to be an effective TCM recipe for the relief of gastrointestinal toxicity and improvement of the antitumor efficacy of chemotherapeutic drugs, which has been proven both in preclinical animal models and in clinical studies.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('improvement', 'PosReg', (146, 157))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PHY906', 'Var', (9, 15))	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (116, 141))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (169, 174))	('gastrointestinal toxicity', 'Disease', (116, 141))
59676	28702078	In a phase I clinical study, it was found that PHY906 could increase the therapeutic outcomes of capecitabine by reducing side effects such as diarrhea in patients with advanced pancreatic cancer, colon cancer, cholangiocarcinoma, or esophageal cancer.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (211, 229))	('diarrhea', 'Disease', 'MESH:D003967', (143, 151))	('colon cancer', 'Disease', (197, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (234, 251))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (178, 195))	('capecitabine', 'Chemical', 'MESH:D000069287', (97, 109))	('patients', 'Species', '9606', (155, 163))	('cholangiocarcinoma', 'Disease', (211, 229))	('esophageal cancer', 'Disease', (234, 251))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (211, 229))	('increase', 'PosReg', (60, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('PHY906', 'Var', (47, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (197, 209))	('diarrhea', 'Phenotype', 'HP:0002014', (143, 151))	('pancreatic cancer', 'Disease', 'MESH:D010190', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('colon cancer', 'Disease', 'MESH:D015179', (197, 209))	('pancreatic cancer', 'Disease', (178, 195))	('diarrhea', 'Disease', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('therapeutic outcomes', 'MPA', (73, 93))	('side effects', 'MPA', (122, 134))	('reducing', 'NegReg', (113, 121))
59677	28702078	In a phase II study, combination administration of PHY906 and capecitabine for patients with advanced pancreatic cancer resulted in a well tolerate and response of the treatment and improved indices of quality of life, including fatigue, loss of appetite, nausea, impaired sense of well-being, and diarrhea.	('diarrhea', 'Phenotype', 'HP:0002014', (298, 306))	('loss of appetite', 'Disease', 'MESH:D001068', (238, 254))	('PHY906', 'Var', (51, 57))	('fatigue', 'Disease', (229, 236))	('nausea', 'Disease', (256, 262))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('fatigue', 'Phenotype', 'HP:0012378', (229, 236))	('response', 'MPA', (152, 160))	('diarrhea', 'Disease', (298, 306))	('nausea', 'Disease', 'MESH:D009325', (256, 262))	('diarrhea', 'Disease', 'MESH:D003967', (298, 306))	('improved', 'PosReg', (182, 190))	('impaired sense of well-being', 'CPA', (264, 292))	('capecitabine', 'Chemical', 'MESH:D000069287', (62, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('loss of appetite', 'Disease', (238, 254))	('patients', 'Species', '9606', (79, 87))	('nausea', 'Phenotype', 'HP:0002018', (256, 262))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
59678	28702078	Studies revealed that PHY906 possessed a wide range of pharmacological activities due to its multiple components and mechanisms, including inhibitory activities on multi-drug resistant protein (MDR) and CYP450 which could result in enhancement of cellular uptake of chemotherapeutic agents, inhibitory activities on NF-kappaB and matrix metalloproteases which could inhibit angiogenesis and enhance the antitumor effect of chemotherapeutic agents, and inhibition of tachykinin NK-1, opiate delta receptors and acetylcholine esterase which may contribute to the improvement of quality of life.	('inhibition', 'NegReg', (452, 462))	('inhibitory', 'Var', (139, 149))	('improvement', 'PosReg', (561, 572))	('angiogenesis', 'CPA', (374, 386))	('tumor', 'Disease', (407, 412))	('NF-kappaB', 'Gene', (316, 325))	('cellular uptake', 'CPA', (247, 262))	('opiate delta receptors', 'Enzyme', (483, 505))	('tumor', 'Disease', 'MESH:D009369', (407, 412))	('inhibitory', 'MPA', (291, 301))	('NF-kappaB', 'Gene', '4790', (316, 325))	('PHY906', 'Var', (22, 28))	('CYP450', 'Gene', (203, 209))	('enhance', 'PosReg', (391, 398))	('inhibit', 'NegReg', (366, 373))	('enhancement', 'PosReg', (232, 243))	('tumor', 'Phenotype', 'HP:0002664', (407, 412))	('acetylcholine esterase', 'Enzyme', (510, 532))	('tachykinin NK-1', 'Enzyme', (466, 481))
59679	28702078	Although PHY906 does not directly protect the initial impairment of intestine caused by irinotecan, it can effectively ameliorate inflammatory responses through inhibiting multiple inflammation related targets, including TNF-alpha-induced NF-kappaB-mediated transcriptional activity and COX-2 and iNOS enzyme activity.	('iNOS enzyme', 'Enzyme', (297, 308))	('irinotecan', 'Chemical', 'MESH:D000077146', (88, 98))	('NF-kappaB', 'Gene', (239, 248))	('activity', 'MPA', (309, 317))	('TNF-alpha', 'Gene', '7124', (221, 230))	('ameliorate', 'PosReg', (119, 129))	('PHY906', 'Var', (9, 15))	('inhibiting', 'NegReg', (161, 171))	('TNF-alpha', 'Gene', (221, 230))	('COX-2', 'Gene', (287, 292))	('COX-2', 'Gene', '5743', (287, 292))	('inflammatory responses', 'CPA', (130, 152))	('NF-kappaB', 'Gene', '4790', (239, 248))	('inflammation', 'Disease', 'MESH:D007249', (181, 193))	('inflammation', 'Disease', (181, 193))
59724	27455080	Comorbidities included alcohol-related disorders (ICD-9-CM codes 291, 303, 305.00-305.03, and 571.0-571.3), HCC (ICD-9-CM code 155.0), RFI (ICD-9-CM codes 584, 585, 586, 572.4, or other procedure codes related to renal failure), hepatic encephalopathy (ICD-9-CM code 572.2), ascites (ICD-9-CM code 789.5 or ICD-9 v3 Procedure Code 54.91), bacterial infections including pneumonia (ICD-9-CM codes 481-487, without 484), liver abscess (ICD-9-CM code 572.0), necrotizing fasciitis (ICD-9-CM code 728.86), empyema (ICD-9-CM code 510), cellulitis (ICD-9-CM codes 681 or 682), central nervous system infection (including bacterial meningitis or brain abscess, ICD-9-CM codes 324 or 320), sepsis (ICD-9-CM codes 038 or 790.7), infective endocarditis (ICD-9-CM code 421), biliary tract infection or acute cholecystitis (ICD-9-CM codes 576.1, 575.0, 574.00, 574.01, 574.30, 574.31, 574.60, 574.61, 574.80, or 574.81), urinary tract infection (ICD-9-CM codes 590.1, 595.0, 595.9 or 599.0), septic arthritis, (ICD-9-CM code 711), perianal abscess (ICD-9-CM code 566), or spontaneous bacterial peritonitis.	('perianal abscess', 'Phenotype', 'HP:0009789', (1019, 1035))	('urinary tract infection', 'Disease', (909, 932))	('infective endocarditis', 'Phenotype', 'HP:0006689', (720, 742))	('bacterial infections', 'Disease', 'MESH:D001424', (339, 359))	('infective endocarditis', 'Disease', (720, 742))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (229, 251))	('hepatic encephalopathy', 'Disease', (229, 251))	('ascites', 'Disease', 'MESH:D001201', (275, 282))	('brain abscess', 'Disease', (639, 652))	('liver abscess', 'Phenotype', 'HP:0100523', (419, 432))	('septic arthritis', 'Disease', (980, 996))	('pneumonia', 'Disease', (370, 379))	('central nervous system infection', 'Disease', (571, 603))	('cellulitis', 'Disease', (531, 541))	('peritonitis', 'Phenotype', 'HP:0002586', (1082, 1093))	('encephalopathy', 'Phenotype', 'HP:0001298', (237, 251))	('renal failure', 'Phenotype', 'HP:0000083', (213, 226))	('empyema', 'Disease', 'MESH:D004653', (502, 509))	('sepsis', 'Phenotype', 'HP:0100806', (682, 688))	('empyema', 'Disease', (502, 509))	('sepsis', 'Disease', 'MESH:D018805', (682, 688))	('acute cholecystitis', 'Disease', (791, 810))	('bacterial peritonitis', 'Disease', (1072, 1093))	('alcohol', 'Chemical', 'MESH:D000438', (23, 30))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (229, 251))	('liver abscess', 'Disease', (419, 432))	('biliary tract infection', 'Disease', (764, 787))	('necrotizing fasciitis', 'Disease', (456, 477))	('renal failure', 'Disease', 'MESH:D051437', (213, 226))	('ascites', 'Phenotype', 'HP:0001541', (275, 282))	('meningitis', 'Phenotype', 'HP:0001287', (625, 635))	('renal failure', 'Disease', (213, 226))	('bacterial infection', 'Phenotype', 'HP:0002718', (339, 358))	('acute cholecystitis', 'Disease', 'MESH:D041881', (791, 810))	('cellulitis', 'Disease', 'MESH:D002481', (531, 541))	('sepsis', 'Disease', (682, 688))	('HCC', 'Gene', '619501', (108, 111))	('septic arthritis', 'Phenotype', 'HP:0003095', (980, 996))	('septic arthritis', 'Disease', 'MESH:D001170', (980, 996))	('infective endocarditis', 'Disease', 'MESH:D004696', (720, 742))	('cellulitis', 'Phenotype', 'HP:0100658', (531, 541))	('abscess', 'Phenotype', 'HP:0025615', (1028, 1035))	('HCC', 'Phenotype', 'HP:0001402', (108, 111))	('brain abscess', 'Phenotype', 'HP:0030049', (639, 652))	('liver abscess', 'Disease', 'MESH:D008100', (419, 432))	('biliary tract infection', 'Disease', 'MESH:D001661', (764, 787))	('HCC', 'Gene', (108, 111))	('arthritis', 'Phenotype', 'HP:0001369', (987, 996))	('central nervous system infection', 'Disease', 'MESH:D002494', (571, 603))	('bacterial infections', 'Disease', (339, 359))	('bacterial meningitis', 'Disease', 'MESH:D016920', (615, 635))	('abscess', 'Phenotype', 'HP:0025615', (425, 432))	('bacterial meningitis', 'Disease', (615, 635))	('urinary tract infection', 'Disease', 'MESH:D014552', (909, 932))	('endocarditis', 'Phenotype', 'HP:0100584', (730, 742))	('fasciitis', 'Phenotype', 'HP:0100537', (468, 477))	('necrotizing fasciitis', 'Disease', 'MESH:D019115', (456, 477))	('central nervous system infection', 'Phenotype', 'HP:0011450', (571, 603))	('ICD-9-CM code 711', 'Var', (999, 1016))	('urinary tract infection', 'Phenotype', 'HP:0000010', (909, 932))	('ascites', 'Disease', (275, 282))	('pneumonia', 'Phenotype', 'HP:0002090', (370, 379))	('bacterial peritonitis', 'Disease', 'MESH:D010534', (1072, 1093))	('perianal abscess', 'Disease', (1019, 1035))	('abscess', 'Phenotype', 'HP:0025615', (645, 652))	('bacterial infections', 'Phenotype', 'HP:0002718', (339, 359))	('cholecystitis', 'Phenotype', 'HP:0001082', (797, 810))	('pneumonia', 'Disease', 'MESH:D011014', (370, 379))
59751	27455080	There were no significant differences in the 30-day mortality rate between patients treated with terlipressin versus those treated with somatostatin.	('somatostatin', 'Gene', '6750', (136, 148))	('patients', 'Species', '9606', (75, 83))	('terlipressin', 'Var', (97, 109))	('somatostatin', 'Gene', (136, 148))
59763	27455080	RFI is a strong indicator of liver dysfunction and the presence of RFI is sufficient to predict a poor outcome.	('presence', 'Var', (55, 63))	('liver dysfunction', 'Disease', (29, 46))	('liver dysfunction', 'Phenotype', 'HP:0001410', (29, 46))	('liver dysfunction', 'Disease', 'MESH:D017093', (29, 46))
59927	20412959	Yoshikawa and colleagues found that HDAC inhibition suppressed TGF-beta1-induced EMT responsible for tubulointerstitial fibrosis of the kidney and that this suppression of EMT was associated with increased E-cadherin transcription.	('TGF-beta1', 'Gene', '7040', (63, 72))	('increased', 'PosReg', (196, 205))	('TGF-beta1', 'Gene', (63, 72))	('fibrosis of the kidney', 'Disease', (120, 142))	('transcription', 'MPA', (217, 230))	('HDAC', 'Gene', (36, 40))	('HDAC', 'Gene', '9734', (36, 40))	('tubulointerstitial fibrosis', 'Phenotype', 'HP:0005576', (101, 128))	('inhibition', 'Var', (41, 51))	('suppressed', 'NegReg', (52, 62))	('EMT', 'CPA', (81, 84))	('fibrosis of the kidney', 'Phenotype', 'HP:0030760', (120, 142))	('fibrosis of the kidney', 'Disease', 'MESH:D005355', (120, 142))	('E-cadherin', 'Gene', (206, 216))	('E-cadherin', 'Gene', '999', (206, 216))
59928	20412959	In addition, HDAC inhibition was found to suppress metastasis in pancreatic cancer.	('suppress', 'NegReg', (42, 50))	('metastasis', 'CPA', (51, 61))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('pancreatic cancer', 'Disease', (65, 82))	('HDAC', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('inhibition', 'Var', (18, 28))	('HDAC', 'Gene', '9734', (13, 17))
59940	20412959	Previously published work and the results of this study suggest that one mechanism through which this combined therapy inhibits metastasis may be synergistic re-expression of CDH1.	('CDH1', 'Gene', '999', (175, 179))	('metastasis', 'CPA', (128, 138))	('re-expression', 'Var', (158, 171))	('CDH1', 'Gene', (175, 179))	('inhibits', 'NegReg', (119, 127))
59945	20412959	In conclusion, combined HDAC and proteasome inhibition attenuates esophageal cancer EMT by upregulating E-cadherin expression in human esophageal cancer cell lines.	('HDAC', 'Gene', '9734', (24, 28))	('E-cadherin', 'Gene', (104, 114))	('inhibition', 'Var', (44, 54))	('attenuates', 'NegReg', (55, 65))	('esophageal cancer', 'Disease', (66, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('esophageal cancer', 'Disease', (135, 152))	('expression', 'MPA', (115, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('upregulating', 'PosReg', (91, 103))	('human', 'Species', '9606', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('HDAC', 'Gene', (24, 28))	('E-cadherin', 'Gene', '999', (104, 114))
59953	23777267	Overexpression of HSPA2 was significantly associated with primary tumor, TNM stage, lymph node metastases and recurrence, respectively (all, P <0.05).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('HSPA2', 'Gene', (18, 23))	('tumor', 'Disease', (66, 71))	('associated', 'Reg', (42, 52))	('TNM', 'Gene', '10178', (73, 76))	('metastases', 'Disease', (95, 105))	('Overexpression', 'Var', (0, 14))	('metastases', 'Disease', 'MESH:D009362', (95, 105))	('TNM', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('recurrence', 'CPA', (110, 120))
59963	23777267	Aberrant expression of HSPA2 in testes induced primary spermatocytes to arrest in meiosis I and undergo apoptosis, which was leading to male infertility .	('arrest', 'CPA', (72, 78))	('leading to', 'Reg', (125, 135))	('Aberrant expression', 'Var', (0, 19))	('meiosis I', 'Disease', (82, 91))	('infertility', 'Phenotype', 'HP:0000789', (141, 152))	('induced', 'Reg', (39, 46))	('infertility', 'Disease', (141, 152))	('male infertility', 'Phenotype', 'HP:0003251', (136, 152))	('meiosis I', 'Disease', 'MESH:C536875', (82, 91))	('HSPA2', 'Gene', (23, 28))	('apoptosis', 'CPA', (104, 113))	('infertility', 'Disease', 'MESH:D007247', (141, 152))
59965	23777267	Some level of the HSPA2 gene activity was also observed in cell lines derived from several human cancers , while silencing of the HSPA2 gene in cancer cells led to growth arrest and decrease in tumorigenic potential .	('growth arrest', 'CPA', (164, 177))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('growth arrest', 'Phenotype', 'HP:0001510', (164, 177))	('cancers', 'Disease', (97, 104))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('decrease', 'NegReg', (182, 190))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (194, 199))	('silencing', 'Var', (113, 122))	('HSPA2', 'Gene', (130, 135))	('human', 'Species', '9606', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
59966	23777267	A HSPA2 mutation was recognized by cytotoxic T lymphocyte (CTL) on a human renal cell carcinoma .	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('renal cell carcinoma', 'Disease', (75, 95))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (75, 95))	('human', 'Species', '9606', (69, 74))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (75, 95))	('HSPA2', 'Gene', (2, 7))	('mutation', 'Var', (8, 16))
59967	23777267	Furthermore, polymorphism in the HSPA2 gene is associated with an increase in the risk of developing type 1 diabetes , non-Hodgkin's lymphoma , lung cancer , systemic lupus erythematosus (SLE) , rheumatoid arthritis  and inflammatory bowel diseases .	('polymorphism', 'Var', (13, 25))	('arthritis', 'Phenotype', 'HP:0001369', (206, 215))	('inflammatory bowel diseases', 'Disease', 'MESH:D015212', (221, 248))	('inflammatory bowel diseases', 'Disease', (221, 248))	('diabetes', 'Disease', 'MESH:D003920', (108, 116))	('systemic lupus erythematosus', 'Disease', (158, 186))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (119, 141))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (101, 116))	('rheumatoid arthritis', 'Disease', (195, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (119, 141))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (123, 141))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (158, 186))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (195, 215))	("non-Hodgkin's lymphoma", 'Disease', (119, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('diabetes', 'Disease', (108, 116))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (158, 186))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('inflammatory bowel diseases', 'Phenotype', 'HP:0002037', (221, 248))	('HSPA2', 'Gene', (33, 38))	('SLE', 'Disease', 'MESH:D008180', (188, 191))	('SLE', 'Disease', (188, 191))	('SLE', 'Phenotype', 'HP:0002725', (188, 191))	('lung cancer', 'Disease', (144, 155))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (195, 215))
59968	23777267	Overexpression of HSPA2 is correlated with increased cell proliferation, poor differentiation and lymph node metastases in human breast cancer, cervical cancer and bladder urothelial cancer .	('breast cancer', 'Disease', (129, 142))	('poor differentiation', 'CPA', (73, 93))	('HSPA2', 'Gene', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cervical cancer', 'Disease', 'MESH:D002583', (144, 159))	('human', 'Species', '9606', (123, 128))	('bladder urothelial cancer', 'Disease', (164, 189))	('metastases', 'Disease', (109, 119))	('cervical cancer', 'Disease', (144, 159))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Overexpression', 'Var', (0, 14))	('increased', 'PosReg', (43, 52))	('cell proliferation', 'CPA', (53, 71))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('metastases', 'Disease', 'MESH:D009362', (109, 119))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (164, 189))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
60010	23777267	Overexpression of HSPA2 was significantly associated with primary tumor, TNM stage, lymph node metastases and recurrence respectively (all, P <0.05).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('associated', 'Reg', (42, 52))	('TNM', 'Gene', '10178', (73, 76))	('metastases', 'Disease', (95, 105))	('Overexpression', 'Var', (0, 14))	('metastases', 'Disease', 'MESH:D009362', (95, 105))	('TNM', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('recurrence', 'CPA', (110, 120))	('HSPA2', 'Protein', (18, 23))
60014	23777267	Kaplan-Meier curves of survival analysis demonstrated that patients with HSPA2-positive expression had a shorter overall survival than patients with HSPA2-negative expression (survival rate: 18.9% versus 66.7%, P <0.001) (Figure  3).	('patients', 'Species', '9606', (135, 143))	('HSPA2-positive expression', 'Var', (73, 98))	('overall survival', 'MPA', (113, 129))	('patients', 'Species', '9606', (59, 67))	('shorter', 'NegReg', (105, 112))
60019	23777267	The polymorphism of HSPA2 at position 1267 has been suggested to be associated with carcinogenesis in many malignant cancer tissues .	('HSPA2', 'Gene', (20, 25))	('associated', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('polymorphism', 'Var', (4, 16))
60022	23777267	Silencing the expression of the HSPA2 gene by RNA interference suggests that HSPA2 increases the growth rate and tumorigenic potential not only in the cell culture but also in tumor xenograft in mice .	('tumor', 'Disease', (113, 118))	('increases', 'PosReg', (83, 92))	('mice', 'Species', '10090', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('RNA', 'MPA', (46, 49))	('growth rate', 'CPA', (97, 108))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('HSPA2', 'Gene', (32, 37))	('HSPA2', 'Gene', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
60025	23777267	During meiosis, spermatogenic cells synthesize HSPA2, knockout of HSPA2 in HSPA2 (-/-) male mice testes induce primary spermatocytes to arrest in meiosis I and undergo a dramatic increase in spermatocyte apoptosis, which was leading to male infertility .	('HSPA2', 'Gene', (66, 71))	('knockout', 'Var', (54, 62))	('male infertility', 'Phenotype', 'HP:0003251', (236, 252))	('meiosis I', 'Disease', 'MESH:C536875', (146, 155))	('infertility', 'Phenotype', 'HP:0000789', (241, 252))	('infertility', 'Disease', (241, 252))	('leading to', 'Reg', (225, 235))	('meiosis I', 'Disease', (146, 155))	('HSPA2', 'Gene', (75, 80))	('increase', 'PosReg', (179, 187))	('mice', 'Species', '10090', (92, 96))	('spermatocyte apoptosis', 'CPA', (191, 213))	('infertility', 'Disease', 'MESH:D007247', (241, 252))
60027	23777267	The mechanism of a mutated HSPA2 chaperone has a dominant effect in tumor cells by triggering the G2/M phase transition during the mitotic cell cycle, which could explain the HSPA2 abnormal expression in somatic tumors.	('tumor', 'Disease', (68, 73))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('HSPA2', 'Protein', (27, 32))	('mutated', 'Var', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('G2/M phase transition during the', 'CPA', (98, 130))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('triggering', 'Reg', (83, 93))	('tumor', 'Disease', (212, 217))
60046	23777267	Overexpression of HSPA2 is correlated with poor therapeutic outcomes in human breast cancer, cervical cancer and bladder urothelial cancer; furthermore, it is now a valuable prognostic marker for breast cancer patients .	('cervical cancer', 'Disease', (93, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('bladder urothelial cancer', 'Disease', (113, 138))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (113, 138))	('breast cancer', 'Disease', (196, 209))	('human', 'Species', '9606', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cervical cancer', 'Disease', 'MESH:D002583', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('HSPA2', 'Protein', (18, 23))	('breast cancer', 'Disease', (78, 91))
60047	23777267	The polymorphism of HSPA2 acts as an attractive susceptibility marker and independent prognostic indicator in Kangri cancer patients .	('HSPA2', 'Gene', (20, 25))	('Kangri cancer', 'Disease', (110, 123))	('Kangri cancer', 'Disease', 'MESH:D009369', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (124, 132))	('polymorphism', 'Var', (4, 16))
60055	17192185	Primary cervical tumors of four HLA-A*0201 allele patients were typed for HPV and their CTL's stimulated in vitro with the T2 cell line previously loaded with 50 muM of the HPV peptides.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('HLA-A', 'Gene', (32, 37))	('HPV', 'Disease', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('cervical tumors', 'Phenotype', 'HP:0030159', (8, 23))	('patients', 'Species', '9606', (50, 58))	('Primary cervical tumors', 'Disease', (0, 23))	('T2', 'CellLine', 'CVCL:0042', (123, 125))	('cervical tumor', 'Phenotype', 'HP:0030159', (8, 22))	('typed', 'Var', (64, 69))	('Primary cervical tumors', 'Disease', 'MESH:D002583', (0, 23))	('HLA-A', 'Gene', '3105', (32, 37))
60057	17192185	Valproic acid and hydralazine/valproic acid up-regulated the constitutive HLA class-I expression as evaluated by flow cytometry and RT-PCR despite constitutive promoter demethylation at these loci.	('valproic acid', 'Chemical', 'MESH:D014635', (30, 43))	('expression', 'MPA', (86, 96))	('up-regulated', 'PosReg', (44, 56))	('hydralazine', 'Chemical', 'MESH:D006830', (18, 29))	('Valproic acid', 'Chemical', 'MESH:D014635', (0, 13))	('hydralazine/valproic acid', 'Var', (18, 43))	('constitutive', 'MPA', (61, 73))
60063	17192185	Current research demonstrates that epigenetic defects are involved in at least some mechanisms that preclude mounting a successful host-antitumor response, involving the HLA system, tumor-associated antigens, and accessory/co-stimulatory molecules.	('tumor', 'Disease', (182, 187))	('involved', 'Reg', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('epigenetic defects', 'Var', (35, 53))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', (140, 145))
60064	17192185	Genetic alterations in antigen processing and presentation are commonly observed in malignancies, thus, complete HLA loss is a common event in several murine and human tumors.	('malignancies', 'Disease', (84, 96))	('Genetic alterations', 'Var', (0, 19))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('loss', 'NegReg', (117, 121))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('human', 'Species', '9606', (162, 167))	('HLA', 'Protein', (113, 116))	('murine', 'Species', '10090', (151, 157))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
60066	17192185	showed down-regulation of HLA class-I antigens in esophageal carcinoma as a common mechanism for transcriptional inactivation caused primarily by DNA hypermethylation, as well as in melanoma, where 5-aza-2'-deoxycytidine significantly enhances the constitutive expression of HLA class-I antigens, of HLA-A1 and -A2 alleles, and of the co-stimulatory molecule, intercellular adhesion molecule-1, and lymphocyte function-associated antigen-3.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (50, 70))	('constitutive expression', 'MPA', (248, 271))	('lymphocyte function-associated antigen-3', 'Gene', '965', (399, 439))	('enhances', 'PosReg', (235, 243))	('lymphocyte function-associated antigen-3', 'Gene', (399, 439))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (198, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('esophageal carcinoma', 'Disease', (50, 70))	('HLA-A', 'Gene', '3105', (300, 305))	('hypermethylation', 'Var', (150, 166))	('down-regulation', 'NegReg', (7, 22))	('HLA-A', 'Gene', (300, 305))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanoma', 'Disease', (182, 190))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (50, 70))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
60071	17192185	Its ability to inhibit deacetylase activity in solid tumors has recently been demonstrated in cervical cancer patients, and when used in combination, these epigenetic agents show inhibitory growth effect in vitro and in vivo, and a synergistic effect upon global gene expression.	('deacetylase', 'Enzyme', (23, 34))	('inhibitory growth effect', 'MPA', (179, 203))	('solid tumors', 'Disease', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('epigenetic', 'Var', (156, 166))	('inhibit', 'NegReg', (15, 22))	('solid tumors', 'Disease', 'MESH:D009369', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cervical cancer', 'Disease', 'MESH:D002583', (94, 109))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('cervical cancer', 'Disease', (94, 109))	('patients', 'Species', '9606', (110, 118))
60107	17192185	To determine whether these epigenetic agents enhance the constitutive expression of HLA class-I molecules, the expression analysis of the HLA-A2 allele and total HLA class-I molecules was carried out by using PA2.1 and W6/32 MAbs.	('enhance', 'PosReg', (45, 52))	('HLA-A', 'Gene', '3105', (138, 143))	('constitutive expression', 'MPA', (57, 80))	('HLA-A', 'Gene', (138, 143))	('epigenetic', 'Var', (27, 37))
60110	17192185	In CasKi cells, a similar pattern of increased expression was observed in HLA-A2 allele and total HLA class-I molecules expression by these drugs and combinations except for hydralazine alone treatment.	('HLA-A', 'Gene', (74, 79))	('expression', 'MPA', (120, 130))	('combinations', 'Var', (150, 162))	('hydralazine', 'Chemical', 'MESH:D006830', (174, 185))	('expression', 'MPA', (47, 57))	('increased', 'PosReg', (37, 46))	('HLA-A', 'Gene', '3105', (74, 79))	('HLA class-I molecules', 'Gene', (98, 119))
60112	17192185	Of note the effect seen on CasKi cells in HLA-A2 allele and total HLA class-I molecules by these drugs and combinations was almost identical in the MS751 cells.	('HLA-A', 'Gene', '3105', (42, 47))	('combinations', 'Var', (107, 119))	('HLA', 'Protein', (66, 69))	('HLA-A', 'Gene', (42, 47))
60118	17192185	Previous studies have demonstrated that epigenetic mechanisms are main regulators of the expression of this class of molecules and that both DNA methylation and HDAC inhibitors demethylate and reactivate their expression.	('demethylate', 'NegReg', (177, 188))	('expression', 'MPA', (210, 220))	('demethylate', 'Chemical', '-', (177, 188))	('methylation', 'Var', (145, 156))	('inhibitors', 'Var', (166, 176))	('reactivate', 'MPA', (193, 203))
60120	17192185	As shown in figure 3b, chromatin immunoprecipitation assay showed that the combination of H/VA but no IFN-gamma led to H4 hyperacetylation at the HLA-class-I promoter.	('IFN-gamma', 'Gene', '3458', (102, 111))	('H/VA', 'Var', (90, 94))	('IFN-gamma', 'Gene', (102, 111))	('VA', 'Chemical', 'MESH:D014635', (92, 94))
60122	17192185	We found that the SW480 colon carcinoma cell line had methylated the HLA-B locus.	('HLA-B', 'Gene', '3106', (69, 74))	('HLA-B', 'Gene', (69, 74))	('colon carcinoma', 'Disease', 'MESH:D015179', (24, 39))	('colon carcinoma', 'Disease', (24, 39))	('SW480', 'CellLine', 'CVCL:0546', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('methylated', 'Var', (54, 64))
60123	17192185	When this cell line was treated with H, VA and H/VA, like to that observed for cervical cancer cell lines, VA and H/VA led to small but clear increase in expression level of the three loci, however, neither H nor 5-aza'-2'-deoxycytidine demethylated the HLA-B locus (Figure 3c and 3d).	('HLA-B', 'Gene', '3106', (254, 259))	('HLA-B', 'Gene', (254, 259))	('increase', 'PosReg', (142, 150))	('VA', 'Chemical', 'MESH:D014635', (107, 109))	('VA', 'Chemical', 'MESH:D014635', (49, 51))	('VA', 'Chemical', 'MESH:D014635', (40, 42))	('VA', 'Chemical', 'MESH:D014635', (116, 118))	('H/VA', 'Var', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	("5-aza'-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (213, 236))	('cervical cancer', 'Disease', (79, 94))	('cervical cancer', 'Disease', 'MESH:D002583', (79, 94))	('demethylate', 'Chemical', '-', (237, 248))	('expression level', 'MPA', (154, 170))
60149	17192185	Besides the well demonstrated antitumor effects of epigenetic therapies achieved by restoring the expression of key genes responsible of the malignant phenotype, the restoration of the defective expression of distinct components of the "tumor recognition complex" through epigenetic targeting of cancer cells results in their efficient recognition and lysis by antigen-specific CTL.	('recognition', 'Interaction', (336, 347))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('lysis', 'CPA', (352, 357))	('epigenetic targeting', 'Var', (272, 292))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('cancer', 'Disease', (296, 302))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
60163	17192185	In addition, this combination of epigenetic agents may also help to avoid immune evasion strategy of tumors by up-regulating the expression of the major histocompatibility complex, class-I-related, a powerful NKG2D ligand for NK cell-mediated antitumor immunity as we have observed it in a colon carcinoma cell line treated with hydralazine and valproate.	('valproate', 'Chemical', 'MESH:D014635', (345, 354))	('up-regulating', 'PosReg', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('expression', 'MPA', (129, 139))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', (247, 252))	('epigenetic', 'Var', (33, 43))	('immune', 'MPA', (74, 80))	('tumor', 'Disease', (101, 106))	('hydralazine', 'Chemical', 'MESH:D006830', (329, 340))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('colon carcinoma', 'Disease', 'MESH:D015179', (290, 305))	('colon carcinoma', 'Disease', (290, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
60165	17192185	The results of this study suggest that use of epigenetic drugs such as hydralazine and valproic acid could improve immune interventions in clinical trials based on E6 and E7 peptides, due to their up-regulating effect on HLA class-I molecules.	('up-regulating effect', 'PosReg', (197, 217))	('E7 peptides', 'Var', (171, 182))	('epigenetic', 'Var', (46, 56))	('valproic acid', 'Chemical', 'MESH:D014635', (87, 100))	('immune interventions', 'MPA', (115, 135))	('clinical', 'Species', '191496', (139, 147))	('improve', 'PosReg', (107, 114))	('HLA class-I molecules', 'Protein', (221, 242))	('hydralazine', 'Chemical', 'MESH:D006830', (71, 82))
60172	33961658	cytokeratin+/CD45-) in 8/29 (27.6%) of patients with esophageal adenocarcinoma, of whom 50% had early stage (I-II) disease.	('cytokeratin+/CD45-', 'Var', (0, 18))	('patients', 'Species', '9606', (39, 47))	('esophageal adenocarcinoma', 'Disease', (53, 78))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (53, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (53, 78))
60190	33961658	Approval from the ethical committee was confirmed and written informed consent was obtained from the study patients (reference numbers: B670201628319, B670201628317).	('patients', 'Species', '9606', (107, 115))	('B670201628317', 'Var', (151, 164))	('B670201628319', 'Var', (136, 149))
60192	33961658	Parsortix procedures on Cell-free DNA BCT-collected blood samples were performed with HEPES buffered saline using PX2_PF, PX2_S99F, PX2_CT2 and PX2_H programs consequently with the 6.5 mum cassettes.	('HEPES', 'Chemical', 'MESH:D006531', (86, 91))	('S99F', 'Mutation', 'p.S99F', (126, 130))	('PX2_CT2', 'Var', (132, 139))	('PX2_S99F', 'Var', (122, 130))
60269	33887608	Using knockdown of APE1 with reconstitution of wild-type and a redox-deficient mutant (C65A) of APE1, as well as pharmacologic APE1 redox inhibitor (E3330), we demonstrated that APE1 regulated NRF2 in a redox-dependent manner.	('APE1', 'Gene', '328', (96, 100))	('E3330', 'Chemical', 'MESH:C075569', (149, 154))	('APE1', 'Gene', '328', (178, 182))	('APE1', 'Gene', (19, 23))	('C65A', 'Var', (87, 91))	('APE1', 'Gene', (127, 131))	('APE1', 'Gene', '328', (19, 23))	('NRF2', 'Gene', (193, 197))	('C65A', 'SUBSTITUTION', 'None', (87, 91))	('rat', 'Species', '10116', (167, 170))	('APE1', 'Gene', '328', (127, 131))	('APE1', 'Gene', (96, 100))	('APE1', 'Gene', (178, 182))
60270	33887608	Mechanistically, we found that APE1 is required for phosphorylation and inactivation of GSK-3beta, an important player in the NRF2 degradation pathway.	('APE1', 'Gene', (31, 35))	('APE1', 'Gene', '328', (31, 35))	('GSK-3beta', 'Gene', '2931', (88, 97))	('GSK-3beta', 'Gene', (88, 97))	('inactivation', 'Var', (72, 84))
60309	33887608	The E3330, an APE1 redox inhibitor, was obtained from Novus Biologicals (NBP1-49581, Centennial, CO, USA) and GSK-3beta inhibitors; lithium chloride (Calbiochem) and CHIR-98014 (Selleck chemicals).	('S', 'Chemical', 'MESH:D013455', (111, 112))	('GSK-3beta', 'Gene', '2931', (110, 119))	('NBP1', 'Gene', (73, 77))	('lithium chloride', 'Chemical', 'MESH:D018021', (132, 148))	('GSK-3beta', 'Gene', (110, 119))	('E3330', 'Var', (4, 9))	('E3330', 'Chemical', 'MESH:C075569', (4, 9))	('NBP1', 'Gene', '51606', (73, 77))	('S', 'Chemical', 'MESH:D013455', (102, 103))	('APE1', 'Gene', (14, 18))	('S', 'Chemical', 'MESH:D013455', (178, 179))	('APE1', 'Gene', '328', (14, 18))
60315	33887608	The FLAG-tagged coding sequence of APE1 and its mutant C65A were cloned into pcDNA3.1 mammalian expression plasmid (Invitrogen, Carlsbad, CA USA).	('C65A', 'SUBSTITUTION', 'None', (55, 59))	('APE1', 'Gene', (35, 39))	('S', 'Chemical', 'MESH:D013455', (142, 143))	('mammalian', 'Species', '9606', (86, 95))	('expression', 'Species', '29278', (96, 106))	('APE1', 'Gene', '328', (35, 39))	('C65A', 'Var', (55, 59))
60346	33887608	Upon stress, CM-H2DCFDA passively diffuses into cells, where its acetate groups are cleaved by intracellular esterase and its thiol-reactive chloromethyl group reacts with intracellular glutathione and other thiols.	('acetate groups', 'MPA', (65, 79))	('CM-H2DCFDA', 'Chemical', '-', (13, 23))	('thiol', 'Chemical', 'MESH:D013438', (208, 213))	('thiols', 'Chemical', 'MESH:D013438', (208, 214))	('thiol', 'Chemical', 'MESH:D013438', (126, 131))	('acetate', 'Chemical', 'MESH:D000085', (65, 72))	('reacts', 'Reg', (160, 166))	('glutathione', 'Chemical', 'MESH:D005978', (186, 197))	('CM-H2DCFDA', 'Var', (13, 23))
60362	33887608	By using CM-H2DCFDA, an intracellular ROS indicator, we found that silencing of APE1 significantly increased the ROS production in OE33 cells and promoted ROS generation in response to ABS treatment (P < 0.05) (Fig.	('ROS production', 'MPA', (113, 127))	('rat', 'Species', '10116', (163, 166))	('P', 'Chemical', 'MESH:D010758', (81, 82))	('APE1', 'Gene', (80, 84))	('response to ABS treatment', 'MPA', (173, 198))	('ABS', 'Chemical', '-', (185, 188))	('ROS', 'Chemical', 'MESH:D017382', (155, 158))	('ROS', 'Chemical', 'MESH:D017382', (38, 41))	('APE1', 'Gene', '328', (80, 84))	('CM-H2DCFDA', 'Chemical', '-', (9, 19))	('ROS generation', 'MPA', (155, 169))	('silencing', 'Var', (67, 76))	('increased', 'PosReg', (99, 108))	('P', 'Chemical', 'MESH:D010758', (200, 201))	('promoted', 'PosReg', (146, 154))	('ROS', 'Chemical', 'MESH:D017382', (113, 116))
60365	33887608	Next, we investigated the levels of 8-OxoG following APE1 knockdown (si-APE1) and exposure to ABS, or H2O2, as a positive control.	('APE1', 'Gene', (72, 76))	('APE1', 'Gene', '328', (72, 76))	('ABS', 'Chemical', '-', (94, 97))	('8-OxoG', 'Chemical', 'MESH:C024829', (36, 42))	('APE1', 'Gene', '328', (53, 57))	('APE1', 'Gene', (53, 57))	('H2O2', 'Chemical', 'MESH:D006861', (102, 106))	('knockdown', 'Var', (58, 67))
60367	33887608	We detected a significant increase in 8-OxoG immunostaining following exposure to ABS or H2O2 in APE1 knockdown conditions, as compared with controls (P < 0.05) (Fig.	('8-OxoG immunostaining', 'MPA', (38, 59))	('P', 'Chemical', 'MESH:D010758', (98, 99))	('APE1', 'Gene', (97, 101))	('APE1', 'Gene', '328', (97, 101))	('knockdown', 'Var', (102, 111))	('P', 'Chemical', 'MESH:D010758', (151, 152))	('8-OxoG', 'Chemical', 'MESH:C024829', (38, 44))	('increase', 'PosReg', (26, 34))	('H2O2', 'Chemical', 'MESH:D006861', (89, 93))	('H2O2', 'Var', (89, 93))	('ABS', 'Chemical', '-', (82, 85))
60368	33887608	By using gamma-H2AX (gamma-H2AX, p-H2AX (s139)), a maker of DNA double-strand DNA breaks, we detected a significant increase in gamma-H2AX immunostaining following exposure to ABS or H2O2 in conditions of APE1 knockdown, as compared to controls (P < 0.05) (Fig.	('knockdown', 'Var', (210, 219))	('P', 'Chemical', 'MESH:D010758', (246, 247))	('APE1', 'Gene', (205, 209))	('H2AX', 'Gene', '3014', (35, 39))	('H2O2', 'Chemical', 'MESH:D006861', (183, 187))	('H2AX', 'Gene', '3014', (15, 19))	('APE1', 'Gene', '328', (205, 209))	('immunostaining', 'MPA', (139, 153))	('P', 'Chemical', 'MESH:D010758', (206, 207))	('H2AX', 'Gene', (35, 39))	('ABS', 'Chemical', '-', (176, 179))	('H2AX', 'Gene', (15, 19))	('H2AX', 'Gene', '3014', (134, 138))	('increase', 'PosReg', (116, 124))	('H2AX', 'Gene', '3014', (27, 31))	('H2AX', 'Gene', (27, 31))	('H2AX', 'Gene', (134, 138))
60369	33887608	In line with this, the knockdown of APE1 significantly sensitized esophageal neoplastic cells to ABS-induced genotoxic stresses.	('genotoxic stresses', 'Disease', (109, 127))	('esophageal neoplastic cells', 'CPA', (66, 93))	('APE1', 'Gene', (36, 40))	('knockdown', 'Var', (23, 32))	('sensitized', 'Reg', (55, 65))	('ABS', 'Chemical', '-', (97, 100))	('APE1', 'Gene', '328', (36, 40))	('genotoxic stresses', 'Disease', 'MESH:D000079225', (109, 127))
60370	33887608	APE1 knockdown promoted cell death, as evidenced by flow cytometry of Annexin V and Western blotting of cleaved PARP (Fig.	('promoted', 'PosReg', (15, 23))	('PARP', 'Gene', '1302', (112, 116))	('PARP', 'Gene', (112, 116))	('knockdown', 'Var', (5, 14))	('cell death', 'CPA', (24, 34))	('Annexin V', 'Gene', '308', (70, 79))	('Annexin V', 'Gene', (70, 79))	('APE1', 'Gene', (0, 4))	('APE1', 'Gene', '328', (0, 4))
60373	33887608	In addition to apoptosis, bile acid exposure may also induce other cell death types, such as necroptosis, and ferroptosis, which require further investigations in the future.	('necroptosis', 'Disease', (93, 104))	('bile acid', 'Var', (26, 35))	('bile acid', 'Chemical', 'MESH:D001647', (26, 35))	('ferroptosis', 'Disease', (110, 121))	('induce', 'Reg', (54, 60))
60383	33887608	Using an ARE luciferase reporter assay as a measure of NRF2 transcription activity, we detected a significant increase in transcriptional activity of NRF2 (P < 0.01) in cells treated with bile salts, as compared with control cells (Fig.	('increase', 'PosReg', (110, 118))	('NRF2', 'Gene', (150, 154))	('transcriptional activity', 'MPA', (122, 146))	('bile', 'Var', (188, 192))	('P', 'Chemical', 'MESH:D010758', (156, 157))	('bile salts', 'Chemical', 'MESH:D001647', (188, 198))
60397	33887608	To investigate the mechanistic relationship between APE1 and NRF2, we knocked down APE1 using transient siRNA (si-APE1) and stable lentiviral shRNA (sh-APE1).	('APE1', 'Gene', '328', (52, 56))	('APE1', 'Gene', (52, 56))	('APE1', 'Gene', '328', (83, 87))	('APE1', 'Gene', (152, 156))	('APE1', 'Gene', (114, 118))	('APE1', 'Gene', '328', (152, 156))	('APE1', 'Gene', '328', (114, 118))	('knocked', 'Var', (70, 77))	('APE1', 'Gene', (83, 87))
60398	33887608	Western blot analyses revealed that knockdown of APE1 decreased the level of NRF2 in CPB, OE33, and FLO1 cells, compared to scrambled controls (si-Ctrl and sh-Ctrl) (Fig.	('APE1', 'Gene', '328', (49, 53))	('level', 'MPA', (68, 73))	('knockdown', 'Var', (36, 45))	('P', 'Chemical', 'MESH:D010758', (86, 87))	('NRF2', 'MPA', (77, 81))	('decreased', 'NegReg', (54, 63))	('APE1', 'Gene', (49, 53))	('P', 'Chemical', 'MESH:D010758', (50, 51))
60399	33887608	However, the levels of KEAP-1 were not significantly changed in APE1 knockdown cells as compared with controls.	('KEAP-1', 'Gene', '9817', (23, 29))	('APE1', 'Gene', (64, 68))	('APE1', 'Gene', '328', (64, 68))	('KEAP-1', 'Gene', (23, 29))	('knockdown', 'Var', (69, 78))
60401	33887608	Indeed, the knockdown of APE1 significantly reduced NRF2 transcriptional activity in CPB, OE33, and FLO1 cells (P < 0.001), as compared with control cells (si-Ctrl) (Fig.	('P', 'Chemical', 'MESH:D010758', (112, 113))	('P', 'Chemical', 'MESH:D010758', (26, 27))	('NRF2', 'Gene', (52, 56))	('knockdown', 'Var', (12, 21))	('P', 'Chemical', 'MESH:D010758', (86, 87))	('reduced', 'NegReg', (44, 51))	('APE1', 'Gene', (25, 29))	('APE1', 'Gene', '328', (25, 29))	('transcriptional activity', 'MPA', (57, 81))
60402	33887608	Moreover, the knockdown of APE1 blocked bile salts-induced increase in ARE transcriptional activity (Fig.	('blocked', 'NegReg', (32, 39))	('APE1', 'Gene', (27, 31))	('bile salts', 'Chemical', 'MESH:D001647', (40, 50))	('knockdown', 'Var', (14, 23))	('ARE transcriptional activity', 'MPA', (71, 99))	('APE1', 'Gene', '328', (27, 31))	('bile salts-induced', 'MPA', (40, 58))	('increase', 'PosReg', (59, 67))
60403	33887608	Consequently, ABS-induced upregulation of NRF2 downstream target genes, HO-1 and TRXND1, were blocked in APE1 knockdown cells as compared to that in control cells (Fig.	('knockdown', 'Var', (110, 119))	('ABS', 'Chemical', '-', (14, 17))	('HO-1', 'Gene', (72, 76))	('NRF2', 'Gene', (42, 46))	('APE1', 'Gene', (105, 109))	('APE1', 'Gene', '328', (105, 109))	('upregulation', 'PosReg', (26, 38))	('HO-1', 'Gene', '3162', (72, 76))	('TRXND1', 'Gene', (81, 87))	('blocked', 'NegReg', (94, 101))
60405	33887608	Overexpression of APE1 led to an increase in NRF2 protein level and its downstream HO-1 level (Supplementary Fig.	('HO-1', 'Gene', (83, 87))	('APE1', 'Gene', (18, 22))	('NRF2', 'Protein', (45, 49))	('expression', 'Species', '29278', (4, 14))	('APE1', 'Gene', '328', (18, 22))	('HO-1', 'Gene', '3162', (83, 87))	('increase', 'PosReg', (33, 41))	('Overexpression', 'Var', (0, 14))	('S', 'Chemical', 'MESH:D013455', (95, 96))
60414	33887608	To determine the role of APE1 in regulating nuclear NRF2, cells were transfected with si-APE1 for 48 h. Immunoblot analysis displayed a significant decrease in NRF2 protein levels in a nuclear fraction in APE1 knockdown cells (Fig.	('knockdown', 'Var', (210, 219))	('APE1', 'Gene', (205, 209))	('APE1', 'Gene', '328', (205, 209))	('APE1', 'Gene', (89, 93))	('NRF2', 'Gene', (160, 164))	('APE1', 'Gene', (25, 29))	('decrease', 'NegReg', (148, 156))	('protein levels', 'MPA', (165, 179))	('APE1', 'Gene', '328', (25, 29))	('APE1', 'Gene', '328', (89, 93))
60416	33887608	APE1 knockdown downregulated NRF2 protein and its target gene HO-1 levels.	('HO-1', 'Gene', '3162', (62, 66))	('knockdown', 'Var', (5, 14))	('protein', 'Protein', (34, 41))	('NRF2 protein', 'Protein', (29, 41))	('APE1', 'Gene', (0, 4))	('downregulated', 'NegReg', (15, 28))	('HO-1', 'Gene', (62, 66))	('APE1', 'Gene', '328', (0, 4))
60423	33887608	Next, we investigated if APE1 played a role in regulating NRF2 protein stability using APE1 knockdown.	('APE1', 'Gene', (87, 91))	('APE1', 'Gene', '328', (87, 91))	('knockdown', 'Var', (92, 101))	('NRF2', 'Protein', (58, 62))	('APE1', 'Gene', (25, 29))	('stability', 'MPA', (71, 80))	('APE1', 'Gene', '328', (25, 29))
60424	33887608	Indeed, NRF2 protein degraded much faster in APE1 knockdown cells than control cells (Fig.	('APE1', 'Gene', '328', (45, 49))	('degraded', 'NegReg', (21, 29))	('knockdown', 'Var', (50, 59))	('NRF2', 'Gene', (8, 12))	('APE1', 'Gene', (45, 49))	('protein', 'Protein', (13, 20))
60425	33887608	To validate whether APE1 played a role in NRF2 stability under ABS conditions, we transfected OE33 cells with si-Ctrl or si-APE1 and treated cells with ABS (100muM/20 min) followed by recovery in regular media in the presence of CHX.	('APE1', 'Gene', '328', (20, 24))	('APE1', 'Gene', (124, 128))	('CHX', 'Chemical', 'MESH:D003513', (229, 232))	('ABS', 'Chemical', '-', (63, 66))	('si-Ctrl', 'Var', (110, 117))	('APE1', 'Gene', '328', (124, 128))	('ABS', 'Chemical', '-', (152, 155))	('APE1', 'Gene', (20, 24))
60426	33887608	Cells treated with ABS showed an increase in NRF2 stability in control cells (si-Ctrl), whereas APE1 knockdown cells (si-APE1) showed a reduction in NRF2 stability (Supplementary Fig S8).	('stability', 'MPA', (154, 163))	('S', 'Chemical', 'MESH:D013455', (21, 22))	('APE1', 'Gene', (121, 125))	('APE1', 'Gene', '328', (96, 100))	('NRF2', 'Protein', (45, 49))	('APE1', 'Gene', '328', (121, 125))	('S', 'Chemical', 'MESH:D013455', (183, 184))	('increase', 'PosReg', (33, 41))	('stability', 'MPA', (50, 59))	('reduction', 'NegReg', (136, 145))	('S', 'Chemical', 'MESH:D013455', (165, 166))	('ABS', 'Chemical', '-', (19, 22))	('APE1', 'Gene', (96, 100))	('knockdown', 'Var', (101, 110))
60436	33887608	At the same time, the knockdown of APE1 blocked ABS-induced phosphorylation of GSK-3beta (S9) with a decrease in NRF2 levels in these cells (Fig.	('phosphorylation', 'MPA', (60, 75))	('NRF2 levels', 'MPA', (113, 124))	('APE1', 'Gene', (35, 39))	('GSK-3beta', 'Gene', (79, 88))	('blocked', 'NegReg', (40, 47))	('S', 'Chemical', 'MESH:D013455', (90, 91))	('ABS', 'Chemical', '-', (48, 51))	('S', 'Chemical', 'MESH:D013455', (80, 81))	('APE1', 'Gene', '328', (35, 39))	('knockdown', 'Var', (22, 31))	('S', 'Chemical', 'MESH:D013455', (50, 51))	('GSK-3beta', 'Gene', '2931', (79, 88))	('decrease', 'NegReg', (101, 109))
60437	33887608	These results suggested that the inactivation of GSK-3beta by phosphorylation might mediate the increase in NRF2 protein stability.	('GSK-3beta', 'Gene', '2931', (49, 58))	('GSK-3beta', 'Gene', (49, 58))	('NRF2', 'Protein', (108, 112))	('phosphorylation', 'Var', (62, 77))	('protein stability', 'MPA', (113, 130))	('inactivation', 'Var', (33, 45))	('increase', 'PosReg', (96, 104))
60447	33887608	Cells treated with CHIR-98014 displayed higher levels of NRF2 (Supplementary Fig S9).	('S', 'Chemical', 'MESH:D013455', (63, 64))	('higher', 'PosReg', (40, 46))	('levels', 'MPA', (47, 53))	('NRF2', 'MPA', (57, 61))	('S', 'Chemical', 'MESH:D013455', (81, 82))	('CHIR-98014', 'Var', (19, 29))
60448	33887608	Collectively, our findings indicated that inactivation of GSK-3beta played a role in APE1-mediated accumulation of NRF2.	('APE1', 'Gene', '328', (85, 89))	('GSK-3beta', 'Gene', '2931', (58, 67))	('GSK-3beta', 'Gene', (58, 67))	('inactivation', 'Var', (42, 54))	('APE1', 'Gene', (85, 89))	('NRF2', 'Protein', (115, 119))	('accumulation', 'PosReg', (99, 111))
60449	33887608	To determine if the APE1 redox function is required for the proper regulation of GSK-3beta, we first applied (E)-3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-nonyl propenoic acid (E3330), a known APE1 redox function inhibitor.	('APE1', 'Gene', '328', (20, 24))	('(E)-3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-nonyl propenoic acid', 'Chemical', '-', (109, 184))	('GSK-3beta', 'Gene', '2931', (81, 90))	('APE1', 'Gene', (202, 206))	('E3330', 'Var', (186, 191))	('APE1', 'Gene', (20, 24))	('GSK-3beta', 'Gene', (81, 90))	('APE1', 'Gene', '328', (202, 206))	('E3330', 'Chemical', 'MESH:C075569', (186, 191))
60450	33887608	Treatment of CPB, FLO1, and OE33 cells with E3330 led to a significant decrease in the transcriptional activity of NRF2, as measured by the ARE-luciferase reporter assay (P < 0.05) (Fig.	('P', 'Chemical', 'MESH:D010758', (171, 172))	('E3330', 'Var', (44, 49))	('decrease', 'NegReg', (71, 79))	('E3330', 'Chemical', 'MESH:C075569', (44, 49))	('P', 'Chemical', 'MESH:D010758', (14, 15))	('transcriptional activity', 'MPA', (87, 111))	('NRF2', 'Gene', (115, 119))
60451	33887608	Western blot analyses demonstrated that NRF2 and p-GSK-3beta (S9) induction by ABS exposure was diminished in cells treated with E3330 (Fig.	('S', 'Chemical', 'MESH:D013455', (52, 53))	('E3330', 'Var', (129, 134))	('GSK-3beta', 'Gene', (51, 60))	('ABS', 'Chemical', '-', (79, 82))	('E3330', 'Chemical', 'MESH:C075569', (129, 134))	('rat', 'Species', '10116', (29, 32))	('diminished', 'NegReg', (96, 106))	('NRF2', 'Gene', (40, 44))	('induction', 'MPA', (66, 75))	('S', 'Chemical', 'MESH:D013455', (81, 82))	('GSK-3beta', 'Gene', '2931', (51, 60))	('S', 'Chemical', 'MESH:D013455', (62, 63))
60453	33887608	To validate this result, we transfected OE33 cells (with relatively low APE1) with wild type APE1 (Flag-APE1) or redox-defective APE1 mutant (C65A).	('APE1', 'Gene', '328', (104, 108))	('APE1', 'Gene', (93, 97))	('C65A', 'SUBSTITUTION', 'None', (142, 146))	('APE1', 'Gene', (72, 76))	('APE1', 'Gene', '328', (93, 97))	('APE1', 'Gene', '328', (72, 76))	('APE1', 'Gene', (129, 133))	('C65A', 'Var', (142, 146))	('APE1', 'Gene', '328', (129, 133))	('Flag-APE1', 'Gene', '328', (99, 108))	('APE1', 'Gene', (104, 108))	('Flag-APE1', 'Gene', (99, 108))
60454	33887608	7F, overexpression of wild type APE1 increased NRF2 and p-GSK-3beta (S9), while overexpression of mutant APE1 (C65A) did not.	('C65A', 'SUBSTITUTION', 'None', (111, 115))	('GSK-3beta', 'Gene', (58, 67))	('APE1', 'Gene', (32, 36))	('APE1', 'Gene', (105, 109))	('S', 'Chemical', 'MESH:D013455', (69, 70))	('APE1', 'Gene', '328', (32, 36))	('APE1', 'Gene', '328', (105, 109))	('expression', 'Species', '29278', (8, 18))	('C65A', 'Var', (111, 115))	('expression', 'Species', '29278', (84, 94))	('increased', 'PosReg', (37, 46))	('GSK-3beta', 'Gene', '2931', (58, 67))	('NRF2', 'Protein', (47, 51))	('S', 'Chemical', 'MESH:D013455', (59, 60))
60456	33887608	The reconstitution of wild-type APE1 (Flag-APE1) restored NRF2 and p-GSK-3beta (S9) expression in APE1 knockdown cells, whereas reconstitution of mutant APE1 (C65A) failed to rescue the p-GSK-3beta (S9) level (Fig.	('S', 'Chemical', 'MESH:D013455', (70, 71))	('GSK-3beta', 'Gene', (69, 78))	('expression', 'Species', '29278', (84, 94))	('GSK-3beta', 'Gene', (188, 197))	('NRF2', 'MPA', (58, 62))	('APE1', 'Gene', '328', (43, 47))	('APE1', 'Gene', '328', (98, 102))	('Flag-APE1', 'Gene', '328', (38, 47))	('C65A', 'SUBSTITUTION', 'None', (159, 163))	('APE1', 'Gene', (43, 47))	('APE1', 'Gene', '328', (32, 36))	('APE1', 'Gene', '328', (153, 157))	('APE1', 'Gene', (98, 102))	('expression', 'MPA', (84, 94))	('S', 'Chemical', 'MESH:D013455', (199, 200))	('GSK-3beta', 'Gene', '2931', (69, 78))	('Flag-APE1', 'Gene', (38, 47))	('APE1', 'Gene', (32, 36))	('S', 'Chemical', 'MESH:D013455', (80, 81))	('APE1', 'Gene', (153, 157))	('GSK-3beta', 'Gene', '2931', (188, 197))	('C65A', 'Var', (159, 163))	('S', 'Chemical', 'MESH:D013455', (189, 190))
60457	33887608	These data demonstrated that APE1 redox function was required for dysfunction of GSK-3beta and NRF2 protein stability (see Fig.	('rat', 'Species', '10116', (18, 21))	('dysfunction', 'Var', (66, 77))	('APE1', 'Gene', (29, 33))	('APE1', 'Gene', '328', (29, 33))	('GSK-3beta', 'Gene', '2931', (81, 90))	('GSK-3beta', 'Gene', (81, 90))	('NRF2', 'Gene', (95, 99))
60470	33887608	Herein, we demonstrated that knockdown of APE1 significantly increased intracellular ROS levels in esophageal cells, particularly in neoplastic esophageal cells, exposed to reflux conditions.	('APE1', 'Gene', (42, 46))	('rat', 'Species', '10116', (18, 21))	('knockdown', 'Var', (29, 38))	('APE1', 'Gene', '328', (42, 46))	('increased intracellular ROS', 'Phenotype', 'HP:0025464', (61, 88))	('intracellular ROS levels', 'MPA', (71, 95))	('increased', 'PosReg', (61, 70))	('ROS', 'Chemical', 'MESH:D017382', (85, 88))
60471	33887608	Consequently, the knockdown of APE1 led to a significant increase in oxidative DNA damage and double-strand breaks and promoted more cell death upon exposure to reflux conditions.	('APE1', 'Gene', (31, 35))	('knockdown', 'Var', (18, 27))	('oxidative DNA damage', 'MPA', (69, 89))	('APE1', 'Gene', '328', (31, 35))	('double-strand breaks', 'MPA', (94, 114))	('cell death', 'CPA', (133, 143))	('promoted', 'PosReg', (119, 127))	('increase', 'PosReg', (57, 65))
60479	33887608	We found that GSk-3beta phosphorylation was abrogated in APE1 knockdown cells, suggesting that APE1 was required for proper phosphorylation of GSK-3beta.	('GSk-3beta', 'Gene', (14, 23))	('APE1', 'Gene', (57, 61))	('GSk-3beta', 'Gene', '2931', (14, 23))	('APE1', 'Gene', (95, 99))	('phosphorylation', 'MPA', (24, 39))	('APE1', 'Gene', '328', (57, 61))	('GSK-3beta', 'Gene', '2931', (143, 152))	('APE1', 'Gene', '328', (95, 99))	('abrogated', 'NegReg', (44, 53))	('GSK-3beta', 'Gene', (143, 152))	('knockdown', 'Var', (62, 71))
60480	33887608	Further studies using APE1 specific redox function inhibitor, E3330 and reconstitution of wild-type or redox-defective APE1 mutant (C65A) demonstrated that APE1 redox function was required for proper phosphorylation of GSK-3beta and activation of NRF2.	('C65A', 'SUBSTITUTION', 'None', (132, 136))	('APE1', 'Gene', (156, 160))	('GSK-3beta', 'Gene', '2931', (219, 228))	('mutant', 'Var', (124, 130))	('APE1', 'Gene', '328', (156, 160))	('C65A', 'Var', (132, 136))	('APE1', 'Gene', (119, 123))	('APE1', 'Gene', (22, 26))	('phosphorylation', 'MPA', (200, 215))	('APE1', 'Gene', '328', (119, 123))	('APE1', 'Gene', '328', (22, 26))	('NRF2', 'Gene', (247, 251))	('E3330', 'Chemical', 'MESH:C075569', (62, 67))	('rat', 'Species', '10116', (145, 148))	('GSK-3beta', 'Gene', (219, 228))
60484	33887608	Based on these findings, approaches that modulate APE1-NRF2 using specific inhibitors of APE1 and/or NRF2 in EAC may have clinical therapeutic benefit, which warrants further investigation.	('inhibitors', 'Var', (75, 85))	('EAC', 'Phenotype', 'HP:0011459', (109, 112))	('NRF2', 'Gene', (101, 105))	('APE1', 'Gene', (50, 54))	('EAC', 'Disease', (109, 112))	('APE1', 'Gene', '328', (50, 54))	('modulate', 'Var', (41, 49))	('APE1', 'Gene', (89, 93))	('APE1', 'Gene', '328', (89, 93))
60533	33061807	Moreover, lnc-MCEI knockdown significantly improved the chemosensitivity of ESCC to cisplatin (DDP) both in vivo and in vitro.	('knockdown', 'Var', (19, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('improved', 'PosReg', (43, 51))	('lnc-MCEI', 'Gene', (10, 18))	('chemosensitivity', 'MPA', (56, 72))	('DDP', 'Chemical', 'MESH:D002945', (95, 98))
60536	33061807	These data suggested that lnc-MCEI was an oncogenic lncRNA and lnc-MCEI knockdown enhanced chemosensitivity of ESCC cells to cisplatin by targeting miR-6759-5p /IGF2/PI3K/AKT axis.	('miR-6759', 'Gene', '102466729', (148, 156))	('enhanced', 'PosReg', (82, 90))	('knockdown', 'Var', (72, 81))	('chemosensitivity', 'MPA', (91, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('miR-6759', 'Gene', (148, 156))	('AKT', 'Gene', '207', (171, 174))	('IGF2', 'Gene', '3481', (161, 165))	('targeting', 'Reg', (138, 147))	('IGF2', 'Gene', (161, 165))	('AKT', 'Gene', (171, 174))	('lnc-MCEI', 'Gene', (63, 71))
60548	33061807	In addition, studies showed that lncRNA DUXAP10 promotes tumorigenesis of ESCC by epigenetically silencing p21.	('DUXAP10', 'Gene', (40, 47))	('epigenetically silencing', 'Var', (82, 106))	('ESCC', 'Disease', (74, 78))	('DUXAP10', 'Gene', '503639', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('p21', 'Gene', (107, 110))	('promotes', 'PosReg', (48, 56))	('p21', 'Gene', '644914', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
60566	33061807	Wild-type (WT) or mutant (MUT) 3'-UTR of lnc-MCEI and IGF2 were cloned into the firefly-tagged pGL3 promoter luciferase vector (Promega, Madison, WI, USA) and then were co-transfected into HEK-293 cells with the Renilla control luciferase vector (Promega).	('HEK-293', 'CellLine', 'CVCL:0045', (189, 196))	('pGL3', 'Gene', '6391', (95, 99))	('IGF2', 'Gene', '3481', (54, 58))	('mutant', 'Var', (18, 24))	('IGF2', 'Gene', (54, 58))	('lnc-MCEI', 'Gene', (41, 49))	('pGL3', 'Gene', (95, 99))
60587	33061807	The results suggested that cell proliferation and clone formation of KYSE-30 and EC109 cells with lnc-MCEI knockdown were significantly suppressed compared to the negative controls (NC; Figure 2B-D).	('knockdown', 'Var', (107, 116))	('suppressed', 'NegReg', (136, 146))	('cell proliferation', 'CPA', (27, 45))	('clone formation of KYSE-30', 'CPA', (50, 76))	('lnc-MCEI', 'Gene', (98, 106))	('EC109', 'CellLine', 'CVCL:6898', (81, 86))
60588	33061807	Next, to determine the effect of lnc-MCEI on chemosensitivity, KYSE-30 and EC109 cells were treated with cisplatin (DDP) combined with lnc-MCEI knockdown or not.	('DDP', 'Chemical', 'MESH:D002945', (116, 119))	('lnc-MCEI', 'Gene', (135, 143))	('knockdown', 'Var', (144, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('EC109', 'CellLine', 'CVCL:6898', (75, 80))
60590	33061807	More importantly, the results of MTT assays and colony formation assays indicated that DDP treatments combined with lnc-MCEI knockdown significantly enhanced the chemosensitivity of KYSE-30 and EC109 cells to DDP (Figure 3C and 3D).	('men', 'Species', '9606', (96, 99))	('knockdown', 'Var', (125, 134))	('DDP', 'Chemical', 'MESH:D002945', (209, 212))	('chemosensitivity', 'CPA', (162, 178))	('EC109', 'CellLine', 'CVCL:6898', (194, 199))	('lnc-MCEI', 'Gene', (116, 124))	('enhanced', 'PosReg', (149, 157))	('DDP', 'Chemical', 'MESH:D002945', (87, 90))	('MTT', 'Chemical', 'MESH:C070243', (33, 36))
60592	33061807	All these data suggested that lnc-MCEI knockdown sensitizes ESCC cells to DDP.	('DDP', 'Chemical', 'MESH:D002945', (74, 77))	('DDP', 'Disease', (74, 77))	('ESCC', 'Disease', (60, 64))	('knockdown', 'Var', (39, 48))	('lnc-MCEI', 'Gene', (30, 38))	('sensitizes', 'Reg', (49, 59))
60603	33061807	What's more, lnc-MCEI knockdown significantly decreased the protein expression IGF2 and phosphorylated AKT (p-AKT) but this effect was rescued by miR-6759-5p inhibitor in both KYSE-30 and EC109 cells (Figure 6A and 6B).	('AKT', 'Gene', '207', (103, 106))	('miR-6759', 'Gene', (146, 154))	('miR-6759', 'Gene', '102466729', (146, 154))	('IGF2', 'Gene', (79, 83))	('AKT', 'Gene', (110, 113))	('AKT', 'Gene', (103, 106))	('knockdown', 'Var', (22, 31))	('lnc-MCEI', 'Gene', (13, 21))	('IGF2', 'Gene', '3481', (79, 83))	('decreased', 'NegReg', (46, 55))	('EC109', 'CellLine', 'CVCL:6898', (188, 193))	('protein expression', 'MPA', (60, 78))	('AKT', 'Gene', '207', (110, 113))
60604	33061807	In addition, MTT assays suggested that IGF2 overexpression rescued the inhibitory effect of the combination of lnc-MCEI knockdown and DDP whereas the effect of IGF2 overexpression was then abolished by the PI3K inhibitor LY294002 in KYSE-30 cells (Figure 6C).	('IGF2', 'Gene', '3481', (160, 164))	('LY294002', 'Chemical', 'MESH:C085911', (221, 229))	('MTT', 'Chemical', 'MESH:C070243', (13, 16))	('IGF2', 'Gene', '3481', (39, 43))	('lnc-MCEI', 'Gene', (111, 119))	('IGF2', 'Gene', (160, 164))	('DDP', 'Chemical', 'MESH:D002945', (134, 137))	('inhibitory effect', 'MPA', (71, 88))	('knockdown', 'Var', (120, 129))	('IGF2', 'Gene', (39, 43))
60607	33061807	To further confirm the role of miR-6759-5p and IGF2 in the lnc-MCEI-mediated ESCC progression and chemoresistance, colony formation assays were performed and the data indicated that miR-6759-5p inhibitor or IGF2 overexpression rescued the inhibitory effect of the combination of lnc-MCEI knockdown and DDP (Figure 7A).	('DDP', 'Chemical', 'MESH:D002945', (302, 305))	('IGF2', 'Gene', (207, 211))	('IGF2', 'Gene', '3481', (207, 211))	('IGF2', 'Gene', '3481', (47, 51))	('inhibitory effect', 'MPA', (239, 256))	('rescued', 'PosReg', (227, 234))	('knockdown', 'Var', (288, 297))	('IGF2', 'Gene', (47, 51))	('miR-6759', 'Gene', '102466729', (31, 39))	('miR-6759', 'Gene', '102466729', (182, 190))	('miR-6759', 'Gene', (31, 39))	('miR-6759', 'Gene', (182, 190))
60608	33061807	Furthermore, the combination of lnc-MCEI knockdown and DDP significantly induced the apoptosis of KYSE-30 and EC109 cells but the effect was abolished by the miR-6759-5p inhibitor or IGF2 overexpression (Figure 7B).	('induced', 'Reg', (73, 80))	('IGF2', 'Gene', (183, 187))	('EC109', 'CellLine', 'CVCL:6898', (110, 115))	('lnc-MCEI', 'Gene', (32, 40))	('DDP', 'Gene', (55, 58))	('apoptosis', 'CPA', (85, 94))	('DDP', 'Chemical', 'MESH:D002945', (55, 58))	('IGF2', 'Gene', '3481', (183, 187))	('miR-6759', 'Gene', '102466729', (158, 166))	('knockdown', 'Var', (41, 50))	('miR-6759', 'Gene', (158, 166))
60609	33061807	These data suggested that the miR-6759-5p inhibitor or IGF2 overexpression restores the effect of lnc-MCEI knockdown on chemotherapy.	('IGF2', 'Gene', (55, 59))	('knockdown', 'Var', (107, 116))	('effect', 'MPA', (88, 94))	('restores', 'PosReg', (75, 83))	('miR-6759', 'Gene', '102466729', (30, 38))	('lnc-MCEI', 'Gene', (98, 106))	('miR-6759', 'Gene', (30, 38))	('IGF2', 'Gene', '3481', (55, 59))
60612	33061807	The results disclosed that tumor volume and tumor weight were significantly decreased in the sh-MCEI and DDP groups and the combination of sh-MCEI and DDP exhibited a more significant suppressive effect on the tumorigenesis (Figure 8A-C).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('DDP', 'Chemical', 'MESH:D002945', (105, 108))	('suppressive', 'NegReg', (184, 195))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (27, 32))	('sh-MCEI', 'Var', (93, 100))	('DDP', 'Chemical', 'MESH:D002945', (151, 154))	('tumor', 'Disease', (210, 215))	('decreased', 'NegReg', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('DDP', 'Var', (105, 108))	('sh-MCEI', 'Var', (139, 146))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
60613	33061807	Moreover, the positive rate of Ki67 was also lower in the sh-MCEI + DDP group than the sh-MCEI or DDP group (Figure 8D).	('positive', 'MPA', (14, 22))	('DDP', 'Chemical', 'MESH:D002945', (98, 101))	('DDP', 'Chemical', 'MESH:D002945', (68, 71))	('lower', 'NegReg', (45, 50))	('Ki67', 'Var', (31, 35))	('sh-MCEI + DDP', 'Var', (58, 71))
60618	33061807	Lnc-MCEI knockdown significantly inhibits the malignant biological behaviors of ESCC cells and sensitizes ESCC cells to DDP.	('malignant biological behaviors of ESCC cells', 'CPA', (46, 90))	('knockdown', 'Var', (9, 18))	('DDP', 'Chemical', 'MESH:D002945', (120, 123))	('sensitizes', 'Reg', (95, 105))	('inhibits', 'NegReg', (33, 41))	('Lnc-MCEI', 'Gene', (0, 8))
60619	33061807	Further mechanism disclosed that lnc-MCEI functioned as a competing endogenous RNA (ceRNA) via sponging miR-6759-5p and lnc-MCEI mediated the chemosensitivity of ESCC by targeting miR-6759-5p/IGF2/PI3K/AKT axis.	('miR-6759', 'Gene', (104, 112))	('miR-6759', 'Gene', (180, 188))	('AKT', 'Gene', (202, 205))	('IGF2', 'Gene', '3481', (192, 196))	('lnc-MCEI', 'Var', (120, 128))	('AKT', 'Gene', '207', (202, 205))	('chemosensitivity', 'MPA', (142, 158))	('IGF2', 'Gene', (192, 196))	('miR-6759', 'Gene', '102466729', (104, 112))	('miR-6759', 'Gene', '102466729', (180, 188))	('targeting', 'Reg', (170, 179))
60623	33061807	Further in-vivo and in-vitro biological experiments in our study confirm that lnc-MCEI promotes the malignant biological properties and inhibition of lnc-MCEI sensitizes ESCC cells to DDP.	('malignant biological properties', 'CPA', (100, 131))	('inhibition', 'Var', (136, 146))	('men', 'Species', '9606', (46, 49))	('lnc-MCEI', 'Gene', (78, 86))	('promotes', 'PosReg', (87, 95))	('lnc-MCEI', 'Gene', (150, 158))	('DDP', 'Chemical', 'MESH:D002945', (184, 187))	('ESCC', 'Disease', (170, 174))
60633	33061807	Moreover, the epigenetically changes of IGF2 was associated with prognosis of ESCC.	('IGF2', 'Gene', '3481', (40, 44))	('epigenetically changes', 'Var', (14, 36))	('ESCC', 'Disease', (78, 82))	('associated', 'Reg', (49, 59))	('IGF2', 'Gene', (40, 44))
60638	33061807	Taken together, the beneficial effect of lnc-MCEI knockdown on the malignant biological behaviors of ESCC cells and chemosensitivity of ESCC cells to DDP was verified in the present study.	('DDP', 'Chemical', 'MESH:D002945', (150, 153))	('knockdown', 'Var', (50, 59))	('beneficial', 'PosReg', (20, 30))	('lnc-MCEI', 'Gene', (41, 49))	('malignant biological behaviors of ESCC cells', 'CPA', (67, 111))
60746	32035477	Especially for patients with ASA physical status >=3, high BMI, obstructive sleep apnea and severe comorbidities, the presence of an anesthesiologist is recommended.	('sleep apnea', 'Phenotype', 'HP:0010535', (76, 87))	('patients', 'Species', '9606', (15, 23))	('apnea', 'Phenotype', 'HP:0002104', (82, 87))	('ASA', 'Disease', (29, 32))	('high BMI', 'Var', (54, 62))	('obstructive sleep apnea', 'Disease', (64, 87))	('obstructive sleep apnea', 'Phenotype', 'HP:0002870', (64, 87))	('obstructive sleep apnea', 'Disease', 'MESH:D020181', (64, 87))
60810	31324603	Immunohistochemical staining confirmed that positive CDCA5 expression was associated with advanced TNM staging and a shorter overall survival rate (45.59% vs 28.00% for CDCA5-/+ subjects, P = 1.86 x 10-3).	('TNM', 'Gene', (99, 102))	('overall', 'MPA', (125, 132))	('shorter', 'NegReg', (117, 124))	('CDCA5', 'Gene', (53, 58))	('TNM', 'Gene', '10178', (99, 102))	('positive', 'Var', (44, 52))
60811	31324603	H3K27 acetylation in CDCA5 promoter might lead to the activation of CDCA5 during ESCC tumorigenesis.	('K27', 'Gene', '342574', (2, 5))	('ESCC tumor', 'Disease', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('K27', 'Gene', (2, 5))	('acetylation', 'Var', (6, 17))	('CDCA5', 'Gene', (68, 73))	('ESCC tumor', 'Disease', 'MESH:D004938', (81, 91))	('activation', 'PosReg', (54, 64))
60813	31324603	Moreover, in vivo assay showed that silenced CDCA5 could inhibit tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('inhibit', 'NegReg', (57, 64))	('CDCA5', 'Gene', (45, 50))	('silenced', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
60814	31324603	Mechanistically, CDCA5 knockdown led to an arrest in G2/M phase and changes in the expression of factors that played fundamental roles in the cell cycle pathway.	('knockdown', 'Var', (23, 32))	('CDCA5', 'Gene', (17, 22))	('G2/M phase', 'CPA', (53, 63))	('changes', 'Reg', (68, 75))	('expression of factors', 'MPA', (83, 104))	('arrest', 'Disease', 'MESH:D006323', (43, 49))	('arrest', 'Disease', (43, 49))
60821	31324603	Furthermore, knockdown of CDCA5 inhibited tumor growth both in vitro and in vivo through the cell cycle pathway.	('CDCA5', 'Gene', (26, 31))	('tumor', 'Disease', (42, 47))	('inhibited', 'NegReg', (32, 41))	('cell', 'Pathway', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('knockdown', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
60831	31324603	Nevertheless, ESCC might be excellent candidate disease for immunotherapy, in light of the abundant somatic mutations found in tumors, which might make the cancer cells more susceptible to recognition by the immune system due to neoepitope presentation on their surfaces that enhances tumor immunogenicity.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('enhances', 'PosReg', (276, 284))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('cancer', 'Disease', (156, 162))	('tumors', 'Disease', (127, 133))	('tumor', 'Disease', (127, 132))	('mutations', 'Var', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (285, 290))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('ESCC', 'Disease', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('neoepitope', 'Var', (229, 239))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
60866	31324603	KYSE150 cells, which have a low CDCA5 expression, were transfected with pcDNA-CDCA5 (seq: 5'-GAGGATCCCCGGGTACCGGTCGCCACCATGTCTGGGAGGCGAACGCG-3', named OE) or a negative control (named NC) sequence as before.	('pcDNA-CDCA5', 'Var', (72, 83))	('CDCA5', 'Gene', (32, 37))	('KYSE150', 'CellLine', 'CVCL:1348', (0, 7))
60880	31324603	A total of 4 x 106 KYSE30 or Eca109 cells (in which CDCA5 was stably expressed or knocked down, respectively) in 0.1 ml phosphate-buffered saline were subcutaneously injected into the right or left oxter of female BALB/c nude mice at 4 weeks of age (SLAC Laboratory Animal Co., Ltd., Shanghai, China).	('CDCA5', 'Gene', (52, 57))	('knocked', 'Var', (82, 89))	('phosphate-buffered saline', 'Chemical', '-', (120, 145))	('nude mice', 'Species', '10090', (221, 230))
60906	31324603	The disease-free survival rate was 44% for the CDCA5- subjects, while 23.2% for the CDCA5+ patients.	('CDCA5-', 'Var', (47, 53))	('disease-free survival', 'CPA', (4, 25))	('patients', 'Species', '9606', (91, 99))
60911	31324603	Epigenetic modifications such as methylation, acetylation and phosphorylation were one of the most common mechanisms of regulation of the CTGs expression.	('acetylation', 'MPA', (46, 57))	('methylation', 'Var', (33, 44))	('CTGs', 'Chemical', '-', (138, 142))	('phosphorylation', 'MPA', (62, 77))	('CTGs', 'Gene', (138, 142))
60913	31324603	As we expected, the anti-H3K27Ac levels in both KYSE30 (Student's t-test, P < .01) and Eca109 (Student's t-test, P < .05) cells were significantly higher than that in Het-1A cells.	('K27', 'Gene', '342574', (27, 30))	('KYSE30', 'Var', (48, 54))	('K27', 'Gene', (27, 30))	('Het-1A', 'CellLine', 'CVCL:3702', (167, 173))	('higher', 'PosReg', (147, 153))
60915	31324603	2e), suggesting that the knockdown of CDCA5 could induce cell cycle arrest in ESCC.	('arrest', 'Disease', (68, 74))	('ESCC', 'Disease', (78, 82))	('CDCA5', 'Gene', (38, 43))	('induce', 'Reg', (50, 56))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('knockdown', 'Var', (25, 34))
60921	31324603	Furthermore, CDCA5 knockdown cells treated with DDP showed a significantly reduced cell viability than CDCA5 knockdown cells or DDP culture cells alone (both KYSE30 and Eca109 cells, Student's t-test, P < .001).	('DDP', 'Var', (48, 51))	('cell viability', 'CPA', (83, 97))	('reduced', 'NegReg', (75, 82))	('DDP', 'Chemical', 'MESH:D002945', (48, 51))	('DDP', 'Chemical', 'MESH:D002945', (128, 131))
60922	31324603	This finding suggested that CDCA5 could induce cisplatin resistance and that the inhibition of CDCA5 could enhance the sensitivity of ESCC cells to cisplatin.	('CDCA5', 'Gene', (95, 100))	('cisplatin resistance', 'MPA', (47, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('inhibition', 'Var', (81, 91))	('enhance', 'PosReg', (107, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('induce', 'PosReg', (40, 46))	('sensitivity', 'MPA', (119, 130))
60924	31324603	4d-e, tumor size was measured every three days and the CDCA5-KD group (both KYSE30 and ECA109 cells) had smaller tumor size than the NC or Vector group (Student's t-test, P < .01).	('tumor', 'Disease', (113, 118))	('CDCA5-KD', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('smaller', 'NegReg', (105, 112))	('tumor', 'Disease', (6, 11))
60925	31324603	Similarly, tumor weight in CDCA5-KD group was significantly lower compared with that in NC or Vector group (Student's t-test, P < .01).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('CDCA5-KD', 'Var', (27, 35))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('lower', 'NegReg', (60, 65))
60927	31324603	All these findings suggested that knockdown of CDCA5 could inhibit tumor growth in vivo and CDCA5 might be a potential therapeutic target for the treatment of ESCC.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ESCC', 'Disease', (159, 163))	('knockdown', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('inhibit', 'NegReg', (59, 66))	('CDCA5', 'Gene', (47, 52))
60953	31324603	What's more, CDCA5 knockdown enhanced the chemosensitivity of ESCC cells to cisplatin and led to a significant reduction in the tumor volumes and weights of mice tumors.	('reduction', 'NegReg', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CDCA5', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mice', 'Species', '10090', (157, 161))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('knockdown', 'Var', (19, 28))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('chemosensitivity', 'MPA', (42, 58))	('tumors', 'Disease', (162, 168))	('tumor', 'Disease', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('enhanced', 'PosReg', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
60954	31324603	Recent evidence indicates that the regulation of the cell cycle is extremely important to the cell because a dysregulated cell cycle leads the cell to grow autonomously, which is thought to be a fundamental hallmark of cancer, especially the checkpoint pathways.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('grow autonomously', 'CPA', (151, 168))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('dysregulated', 'Var', (109, 121))	('cancer', 'Disease', (219, 225))	('cell cycle', 'CPA', (122, 132))
60955	31324603	In this study, we present the first evidence that CDCA5 knockdown induced G2/M phases arrest and apoptosis in ESCC.	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('arrest', 'Disease', (86, 92))	('ESCC', 'Disease', (110, 114))	('apoptosis', 'CPA', (97, 106))	('knockdown', 'Var', (56, 65))	('CDCA5', 'Gene', (50, 55))
60957	31324603	Consistent with this finding, in vitro experiments revealed that inhibition of CDCA5 significantly suppressed the expression of CCNA2, CCNB1, CDC25A and PCNA, and these genes appear to function with cell cycle pathway to govern ESCC development.	('CDC25A', 'Gene', '993', (142, 148))	('CCNB1', 'Gene', (135, 140))	('ESCC development', 'CPA', (228, 244))	('suppressed', 'NegReg', (99, 109))	('CCNB1', 'Gene', '891', (135, 140))	('CDCA5', 'Gene', (79, 84))	('PCNA', 'Gene', '5111', (153, 157))	('CCNA2', 'Gene', (128, 133))	('inhibition', 'Var', (65, 75))	('expression', 'MPA', (114, 124))	('CDC25A', 'Gene', (142, 148))	('PCNA', 'Gene', (153, 157))	('CCNA2', 'Gene', '890', (128, 133))	('function', 'Reg', (185, 193))
60963	31324603	He were involved in material and technical support; X. Pan, H. Wei, Y. Zhu, Y.	('Pan', 'Gene', (55, 58))	('Pan', 'Gene', '51816', (55, 58))	('H. Wei', 'Var', (60, 66))	('Y. Zhu', 'Var', (68, 74))
61043	28410201	Programmed death ligand-1 (PD-L1) was reported as a potential biomarker for the prognosis of ESCC, and the high expression indicated a poor prognosis.	('Programmed death ligand-1', 'Gene', '29126', (0, 25))	('Programmed death ligand-1', 'Gene', (0, 25))	('PD-L1', 'Gene', (27, 32))	('high', 'Var', (107, 111))	('ESCC', 'Disease', (93, 97))	('PD-L1', 'Gene', '29126', (27, 32))
61063	28410201	The SEER database was searched to identify patients whose primary tumor sites were coded as C15.0-C15.9 (esophagus) and whose cancers were diagnosed from 1998 to 2013.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('primary tumor', 'Disease', (58, 71))	('patients', 'Species', '9606', (43, 51))	('primary tumor', 'Disease', 'MESH:D009369', (58, 71))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('SE', 'Disease', 'None', (4, 6))	('C15.0-C15.9', 'Var', (92, 103))
61064	28410201	We included only histological codes for adenocarcinomas (8140-8573) and squamous cell cancers (8050-8082).	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('adenocarcinomas', 'Disease', (40, 55))	('squamous cell cancers', 'Disease', (72, 93))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (72, 93))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('8050-8082', 'Var', (95, 104))	('squamous cell cancers', 'Disease', 'MESH:D002294', (72, 93))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('adenocarcinomas', 'Disease', 'MESH:D000230', (40, 55))	('8140-8573', 'Var', (57, 66))
61091	27004256	All of the procedures were performed with an upper gastrointestinal endoscope (GIF-Q260J; Olympus, Tokyo, Japan) that was fitted with a transparent cap (D-201-11804; Olympus).	('Q260J', 'SUBSTITUTION', 'None', (83, 88))	('Q260J', 'Var', (83, 88))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (45, 77))	('upper gastrointestinal endoscope', 'Disease', (45, 77))
61092	27004256	A 0.75 % iodine solution was used to delineate the tumor margin, and marker dots were placed circumferentially outside the tumor margins with a flush knife (DK2618JN; Fujifilm Medical, Tokyo, Japan) or hook knife (KD-620LR; Olympus, Tokyo, Japan).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('DK2618JN;', 'Var', (157, 166))	('flush', 'Phenotype', 'HP:0031284', (144, 149))	('iodine', 'Chemical', 'MESH:D007455', (9, 15))	('flush', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('flush', 'Disease', 'MESH:D005483', (144, 149))
61182	26937932	The bleeding-free survival rate was significantly better in patients who had been administered PPIs compared with those who were not administered PPIs (P < 0.001), and in those patients who did not have gastric varices compared with those who had gastric varices (P = 0.010) (Figure 2); bleeding events occurred in 3 of 359 patients who received PPIs and in 11 of 146 patients who did not receive PPIs, and they occurred in 7 of 110 patients who had gastric varices and in 7 of 395 patients who did not have gastric varices.	('patients', 'Species', '9606', (324, 332))	('gastric varices', 'Phenotype', 'HP:0030169', (247, 262))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (60, 68))	('gastric', 'Disease', (450, 457))	('patients', 'Species', '9606', (482, 490))	('bleeding', 'Disease', 'MESH:D006470', (287, 295))	('bleeding', 'Disease', (287, 295))	('PPIs', 'Var', (346, 350))	('bleeding', 'Disease', 'MESH:D006470', (4, 12))	('patients', 'Species', '9606', (433, 441))	('bleeding', 'Disease', (4, 12))	('gastric varices', 'Phenotype', 'HP:0030169', (450, 465))	('patients', 'Species', '9606', (368, 376))	('gastric varices', 'Phenotype', 'HP:0030169', (203, 218))	('better', 'PosReg', (50, 56))	('gastric varices', 'Phenotype', 'HP:0030169', (508, 523))
61187	26937932	The bleeding-free survival rate was significantly better in patients who were administered PPIs compared with those who were not administered PPIs (P < 0.001) (Figure 3); bleeding events occurred in 2 of 338 patients who received PPIs and in 9 of 143 patients who did not receive PPIs.	('patients', 'Species', '9606', (208, 216))	('occurred', 'Reg', (187, 195))	('patients', 'Species', '9606', (60, 68))	('bleeding', 'Disease', 'MESH:D006470', (171, 179))	('bleeding', 'Disease', (171, 179))	('patients', 'Species', '9606', (251, 259))	('bleeding', 'Disease', 'MESH:D006470', (4, 12))	('PPIs', 'Var', (230, 234))	('bleeding', 'Disease', (4, 12))	('better', 'PosReg', (50, 56))
61196	26937932	A randomized trial performed in 42 subjects after elective EVL treated with either pantoprazole or placebo showed that patients receiving pantoprazole had significantly smaller post-banding ulcers than those receiving placebo.	('pantoprazole', 'Var', (138, 150))	('EVL', 'Chemical', '-', (59, 62))	('ulcers', 'Disease', (190, 196))	('patients', 'Species', '9606', (119, 127))	('ulcers', 'Disease', 'MESH:D014456', (190, 196))	('pantoprazole', 'Chemical', 'MESH:D000077402', (138, 150))	('smaller', 'NegReg', (169, 176))	('pantoprazole', 'Chemical', 'MESH:D000077402', (83, 95))
61201	26937932	In the present study, we evaluated effect of PPIs on post-EVL ulcer bleeding in a large number of patients, and the bleeding-free survival rate during 8 weeks after EVL was significantly better in patients who received PPI therapy.	('patients', 'Species', '9606', (197, 205))	('EVL', 'Chemical', '-', (165, 168))	('ulcer bleeding', 'Disease', 'MESH:D014456', (62, 76))	('bleeding', 'Disease', 'MESH:D006470', (116, 124))	('bleeding', 'Disease', 'MESH:D006470', (68, 76))	('patients', 'Species', '9606', (98, 106))	('PPI', 'Var', (219, 222))	('bleeding', 'Disease', (68, 76))	('bleeding', 'Disease', (116, 124))	('better', 'PosReg', (187, 193))	('ulcer bleeding', 'Disease', (62, 76))	('EVL', 'Chemical', '-', (58, 61))
61209	26937932	In the present study, a significant association between high Child-Turcott-Pugh or MELD score and an increased risk of bleeding after primary EVL was observed in univariate analysis, but the effect was not confirmed after correcting for confounding factors in multivariate analysis.	('Child', 'Species', '9606', (61, 66))	('EVL', 'Chemical', '-', (142, 145))	('bleeding', 'Disease', 'MESH:D006470', (119, 127))	('bleeding', 'Disease', (119, 127))	('MELD score', 'Gene', (83, 93))	('high', 'Var', (56, 60))
61229	33392180	The function of circ-ZDHHC5 was determined by siRNA-mediated knockout of circ-ZDHHC5 in in vitro proliferation, migration, and invasion.	('ZDHHC5', 'Gene', '25921', (21, 27))	('ZDHHC5', 'Gene', (78, 84))	('invasion', 'CPA', (127, 135))	('knockout', 'Var', (61, 69))	('ZDHHC5', 'Gene', (21, 27))	('migration', 'CPA', (112, 121))	('ZDHHC5', 'Gene', '25921', (78, 84))
61242	33392180	In accordance with Shi Y and colleagues, hsa_circ_0006168 is likely to control the Mammalian Target expression of Rapamycin (mTOR) by sponging miR-100 in ESCC.	('miR-100', 'Gene', (143, 150))	('Mammalian', 'MPA', (83, 92))	('mTOR', 'Gene', '2475', (125, 129))	('mTOR', 'Gene', (125, 129))	('miR-100', 'Gene', '406892', (143, 150))	('Mammalian', 'Species', '9606', (83, 92))	('sponging', 'NegReg', (134, 142))	('hsa_circ_0006168', 'Var', (41, 57))	('control', 'PosReg', (71, 78))
61300	33392180	The clone formation experiment and the CCK-8 experiment showed that after knockdown of circ-ZDHHC5, the proliferation ability of TE-10 and TE-12 cells was noticeably decreased (Figures 2E-G).	('ZDHHC5', 'Gene', (92, 98))	('knockdown', 'Var', (74, 83))	('proliferation ability', 'CPA', (104, 125))	('decreased', 'NegReg', (166, 175))	('TE-12', 'CellLine', 'CVCL:1762', (139, 144))	('ZDHHC5', 'Gene', '25921', (92, 98))	('CCK-8', 'Chemical', '-', (39, 44))
61301	33392180	The wound healing experiment revealed that silencing circ-ZDHHC5 noticeably decreased the cell mobility (Figure 2H).	('decreased', 'NegReg', (76, 85))	('silencing', 'Var', (43, 52))	('ZDHHC5', 'Gene', (58, 64))	('cell mobility', 'CPA', (90, 103))	('ZDHHC5', 'Gene', '25921', (58, 64))
61320	33392180	Kaplan-Meier Plotter results showed that more significant ZEB1 expression was associated with shorter OS in comparison with lower expression (Figure 4E).	('ZEB1', 'Gene', (58, 62))	('shorter OS', 'Disease', (94, 104))	('ZEB1', 'Gene', '6935', (58, 62))	('expression', 'Var', (63, 73))
61328	33392180	For instance, studied a group of 51 patients and reported that hsa_circ_0067934 showed noticeable over-expression in ESCC tissues in contrast to paired adjacent normal tissues.	('hsa_circ_0067934', 'Var', (63, 79))	('over-expression', 'PosReg', (98, 113))	('ESCC', 'Disease', (117, 121))	('patients', 'Species', '9606', (36, 44))
61329	33392180	The high hsa_circ_0067934 expression showed relationships to I-II TNM stage, I-II T stage, and poor differentiation.	('I-II T stage', 'Disease', (77, 89))	('TNM', 'Gene', '10178', (66, 69))	('hsa_circ_0067934', 'Gene', (9, 25))	('high', 'Var', (4, 8))	('TNM', 'Gene', (66, 69))
61343	33392180	We first found that knocking down circ-ZDHHC5, which suppresses the ESCC progression by modulating miR-217 and ZEB1 expression, could effectively inhibit the proliferation, invasion, and metastasis of ESCC cells.	('inhibit', 'NegReg', (146, 153))	('ZEB1', 'Gene', (111, 115))	('expression', 'MPA', (116, 126))	('ZDHHC5', 'Gene', (39, 45))	('suppresses', 'NegReg', (53, 63))	('invasion', 'CPA', (173, 181))	('ZEB1', 'Gene', '6935', (111, 115))	('ESCC', 'Disease', (68, 72))	('miR-217', 'Gene', '406999', (99, 106))	('ZDHHC5', 'Gene', '25921', (39, 45))	('miR-217', 'Gene', (99, 106))	('modulating', 'Reg', (88, 98))	('proliferation', 'CPA', (158, 171))	('knocking down', 'Var', (20, 33))
61349	33392180	Destruction of the junction between ZEB1 and the mentioned chromatin-modifying enzymes may represent an effective method of treating cancer.	('ZEB1', 'Gene', '6935', (36, 40))	('ZEB1', 'Gene', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('Destruction', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
61367	32131475	Both uptake ratios decreased on PET4 compared to PET3, but, were still higher compared to PET1.	('higher', 'PosReg', (71, 77))	('PET1', 'Gene', '54738', (90, 94))	('uptake ratios', 'MPA', (5, 18))	('PET1', 'Gene', (90, 94))	('decreased', 'NegReg', (19, 28))	('PET4', 'Var', (32, 36))
61431	32131475	The myocardium-to-blood pool uptake ratios on PET2, PET3, and PET4 tended to show slightly higher values than that on PET1 in both patient groups.	('myocardium-to-blood pool uptake ratios', 'MPA', (4, 42))	('higher', 'PosReg', (91, 97))	('PET1', 'Gene', '54738', (118, 122))	('PET1', 'Gene', (118, 122))	('PET3', 'Var', (52, 56))	('PET4', 'Var', (62, 66))	('PET2', 'Var', (46, 50))	('patient', 'Species', '9606', (131, 138))
61432	32131475	However, in pairwise comparisons, the myocardium-to-blood pool uptake ratio on PET3 showed no significant difference from that on PET1 in both patients with left and right breast cancers (p > 0.05; Figure 3).	('right breast cancers', 'Disease', (166, 186))	('myocardium-to-blood pool uptake ratio', 'MPA', (38, 75))	('breast cancers', 'Phenotype', 'HP:0003002', (172, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PET3', 'Var', (79, 83))	('patients', 'Species', '9606', (143, 151))	('PET1', 'Gene', '54738', (130, 134))	('PET1', 'Gene', (130, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('right breast cancers', 'Disease', 'MESH:D001943', (166, 186))	('left and', 'Disease', (157, 165))
61433	32131475	Furthermore, on repeated measures ANOVA, there were no significant differences in the myocardium-to-blood pool uptake ratios among PET1, PET2, and PET3 and among PET1, PET3, and PET4 in both patient groups (p > 0.05 for all; Figure 3).	('PET1', 'Gene', '54738', (162, 166))	('PET2', 'Var', (137, 141))	('PET1', 'Gene', (162, 166))	('PET1', 'Gene', '54738', (131, 135))	('PET3', 'Var', (147, 151))	('PET1', 'Gene', (131, 135))	('myocardium-to-blood pool uptake ratios', 'MPA', (86, 124))	('patient', 'Species', '9606', (191, 198))
61440	32131475	In the pairwise comparison between PET1 and PET3, the 30 Gy uptake ratio on PET3 was significantly higher than that on PET1 (p < 0.001; Figure 4A), and 51 patients (92.7%) showed higher 30 Gy uptake ratios on PET3 than on PET1.	('PET1', 'Gene', '54738', (35, 39))	('30 Gy uptake ratios', 'MPA', (186, 205))	('PET1', 'Gene', (35, 39))	('higher', 'PosReg', (99, 105))	('30 Gy uptake ratio', 'MPA', (54, 72))	('patients', 'Species', '9606', (155, 163))	('PET1', 'Gene', '54738', (222, 226))	('PET1', 'Gene', '54738', (119, 123))	('PET1', 'Gene', (222, 226))	('PET1', 'Gene', (119, 123))	('PET3', 'Var', (76, 80))	('higher', 'PosReg', (179, 185))
61441	32131475	On repeated measures ANOVA, there were significant differences in the 30 Gy uptake ratio among PET1, PET2, and PET3 and among PET1, PET3, and PET4 (p < 0.001 for all; Figure 4B).	('30 Gy uptake ratio', 'MPA', (70, 88))	('differences', 'Reg', (51, 62))	('PET3', 'Var', (111, 115))	('PET1', 'Gene', (95, 99))	('PET1', 'Gene', '54738', (95, 99))	('PET1', 'Gene', '54738', (126, 130))	('PET1', 'Gene', (126, 130))
61442	32131475	On post-hoc pairwise comparisons between PET1, PET2, and PET3 with Bonferroni correction, the 30 Gy uptake ratio on PET3 was significantly higher than that on PET1 (p < 0.001) and PET 2 (p < 0.001), whereas there was no significant difference between PET1 and PET2 (p > 0.999).	('PET3', 'Var', (116, 120))	('PET1', 'Gene', '54738', (159, 163))	('PET1', 'Gene', (159, 163))	('PET1', 'Gene', '54738', (41, 45))	('PET1', 'Gene', '54738', (251, 255))	('30 Gy uptake ratio', 'MPA', (94, 112))	('PET1', 'Gene', (41, 45))	('PET1', 'Gene', (251, 255))	('higher', 'PosReg', (139, 145))
61443	32131475	On post-hoc comparisons between PET1, PET3, and PET4, the 30 Gy uptake ratio significantly decreased on PET4 as compared with PET3 (p = 0.022).	('PET1', 'Gene', '54738', (32, 36))	('PET1', 'Gene', (32, 36))	('30 Gy uptake ratio', 'MPA', (58, 76))	('PET4', 'Var', (104, 108))	('decreased', 'NegReg', (91, 100))
61446	32131475	In the pairwise comparison, the 47.5 Gy uptake ratio on PET3 was significantly higher than that on PET1 (p < 0.001; Figure 4C), and 95.7% of patients (45 of 47 patients) showed an increased uptake ratio on PET3.	('patients', 'Species', '9606', (160, 168))	('increased', 'PosReg', (180, 189))	('PET1', 'Gene', '54738', (99, 103))	('PET3', 'Var', (56, 60))	('PET1', 'Gene', (99, 103))	('higher', 'PosReg', (79, 85))	('uptake ratio', 'MPA', (190, 202))	('patients', 'Species', '9606', (141, 149))
61447	32131475	On repeated measures ANOVA, there were significant differences in the 47.5 Gy uptake ratio among PET1, PET2, and PET3 and among PET1, PET3, and PET4 (p < 0.001 for all; Figure 4D).	('PET1', 'Gene', (128, 132))	('PET1', 'Gene', '54738', (128, 132))	('PET1', 'Gene', (97, 101))	('47.5', 'MPA', (70, 74))	('differences', 'Reg', (51, 62))	('PET1', 'Gene', '54738', (97, 101))	('PET3', 'Var', (113, 117))
61448	32131475	On post-hoc pairwise comparisons between PET1, PET2, and PET3, the 47.5 Gy uptake ratio on PET3 was significantly higher than that on PET1 (p < 0.001) and PET 2 (p < 0.001), whereas there was no significant difference between PET1 and PET2 (p = 0.269).	('PET3', 'Var', (91, 95))	('47.5 Gy uptake ratio', 'MPA', (67, 87))	('PET1', 'Gene', '54738', (134, 138))	('PET1', 'Gene', '54738', (226, 230))	('PET1', 'Gene', (226, 230))	('PET1', 'Gene', '54738', (41, 45))	('PET1', 'Gene', (41, 45))	('PET1', 'Gene', (134, 138))	('higher', 'PosReg', (114, 120))
61449	32131475	On post-hoc comparisons between PET1, PET3, and PET4, a decreased 47.5 Gy uptake ratio was observed on PET4 compared with PET3, but with borderline significance (p = 0.051), and the 47.5 Gy uptake ratio on PET4 was still significantly higher than that on PET1 (p < 0.001).	('47.5 Gy uptake ratio', 'MPA', (66, 86))	('PET1', 'Gene', '54738', (32, 36))	('higher', 'PosReg', (235, 241))	('PET1', 'Gene', (32, 36))	('decreased', 'NegReg', (56, 65))	('PET4', 'Var', (103, 107))	('PET1', 'Gene', '54738', (255, 259))	('PET1', 'Gene', (255, 259))
61460	32131475	These mitochondrial damages can cause impairment of myocardial oxidative metabolism and a transition to anaerobic metabolism with upregulated glycolysis.	('upregulated', 'PosReg', (130, 141))	('damages', 'Var', (20, 27))	('glycolysis', 'MPA', (142, 152))	('impairment of myocardial oxidative metabolism', 'Disease', (38, 83))	('impairment of myocardial oxidative metabolism', 'Disease', 'MESH:D009202', (38, 83))	('transition', 'MPA', (90, 100))	('cause', 'Reg', (32, 37))
61478	32131475	In the present study, the myocardial-to-blood pool uptake ratios on PET2 showed higher values than those on PET1 both in patients with left and with right breast cancer.	('PET1', 'Gene', (108, 112))	('right breast cancer', 'Disease', 'MESH:D001943', (149, 168))	('myocardial-to-blood pool uptake ratios', 'MPA', (26, 64))	('right breast cancer', 'Disease', (149, 168))	('higher values', 'PosReg', (80, 93))	('left', 'Disease', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('PET2', 'Var', (68, 72))	('PET1', 'Gene', '54738', (108, 112))	('patients', 'Species', '9606', (121, 129))
61677	31058437	Therefore, in retrospect, we think that probe insertion can increase the vulnerability of the esophagus to edema in mice for irradiation.	('edema', 'Phenotype', 'HP:0000969', (107, 112))	('probe insertion', 'Var', (40, 55))	('mice', 'Species', '10090', (116, 120))	('edema', 'Disease', (107, 112))	('increase', 'PosReg', (60, 68))	('vulnerability', 'MPA', (73, 86))	('edema', 'Disease', 'MESH:D004487', (107, 112))
61769	29854808	One recent study in small cell lung cancer also demonstrated that osteopontin increased chemoresistance to cisplatin in SBC-3 cells by suppressing bcl-2 protein downregulation.	('osteopontin', 'Var', (66, 77))	('small cell lung cancer', 'Disease', (20, 42))	('chemoresistance', 'CPA', (88, 103))	('bcl-2', 'Gene', (147, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('increased', 'PosReg', (78, 87))	('small cell lung cancer', 'Disease', 'MESH:D055752', (20, 42))	('bcl-2', 'Gene', '596', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('suppressing', 'NegReg', (135, 146))
61772	29854808	Furthermore, inhibition of osteopontin can sensitize esophageal cancer cells to cisplatin.	('sensitize', 'Reg', (43, 52))	('inhibition', 'Var', (13, 23))	('esophageal cancer', 'Disease', (53, 70))	('osteopontin', 'Protein', (27, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
61817	27125498	We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150.	('N-cadherin', 'Gene', '1000', (173, 183))	('elongated spindle shape', 'CPA', (65, 88))	('KYSE-150R', 'Var', (9, 18))	('up-regulated', 'PosReg', (141, 153))	('E-cadherin', 'Gene', (126, 136))	('down-regulated', 'NegReg', (93, 107))	('E-cadherin', 'Gene', '999', (126, 136))	('mesenchymal', 'CPA', (154, 165))	('N-cadherin', 'Gene', (173, 183))
61818	27125498	Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice.	('sphere formation', 'CPA', (146, 162))	('stemness', 'Disease', 'MESH:D020295', (43, 51))	('stemness', 'Disease', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('mice', 'Species', '10090', (193, 197))	('growth promotion', 'CPA', (103, 119))	('KYSE-150R', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
61837	27125498	Down-regulation of WISP1 expression in KYSE-150R significantly reversed EMT-associated radioresistance.	('WISP1', 'Gene', (19, 24))	('KYSE-150R', 'Var', (39, 48))	('expression', 'MPA', (25, 35))	('Down-regulation', 'NegReg', (0, 15))	('reversed', 'NegReg', (63, 71))	('EMT-associated radioresistance', 'CPA', (72, 102))	('WISP1', 'Gene', '8840', (19, 24))
61873	27125498	The results showed that epithelial marker E-cadherin was significantly down-regulated and mesenchymal marker N-cadherin was significantly up-regulated in KYSE-150R compared with in KYSE-150 (Fig.	('down-regulated', 'NegReg', (71, 85))	('mesenchymal', 'CPA', (90, 101))	('up-regulated', 'PosReg', (138, 150))	('N-cadherin', 'Gene', '1000', (109, 119))	('KYSE-150R', 'Var', (154, 163))	('E-cadherin', 'Gene', (42, 52))	('E-cadherin', 'Gene', '999', (42, 52))	('N-cadherin', 'Gene', (109, 119))
61874	27125498	Moreover, we found KYSE-150R also possessed increased translocation of beta-catenin from the cell membrane into the nucleus when compared with KYSE-150 using immunofluorescence analysis (Fig.	('KYSE-150R', 'Var', (19, 28))	('increased', 'PosReg', (44, 53))	('beta-catenin', 'Gene', (71, 83))	('beta-catenin', 'Gene', '1499', (71, 83))	('translocation', 'MPA', (54, 67))
61877	27125498	The results showed that the mRNA level of WISP1 was most significantly changed among the CCN family, with an expression increase of more than 12-fold in KYSE-150R cells compared with in KYSE-150 cells (Fig.	('KYSE-150R', 'Var', (153, 162))	('mRNA level', 'MPA', (28, 38))	('expression', 'MPA', (109, 119))	('WISP1', 'Gene', '8840', (42, 47))	('changed', 'Reg', (71, 78))	('WISP1', 'Gene', (42, 47))	('increase', 'PosReg', (120, 128))
61906	27125498	There was no macroscopically detectable tumorigenesis for either KYSE-150 or KYSE-150R at cell numbers of 102 or 103.	('KYSE-150R', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('KYSE-150', 'Var', (65, 73))
61907	27125498	Furthermore, in comparison with KYSE-150, KYSE-150R showed significantly greater capability for sphere formation, another known stemness-like property (Fig.	('greater', 'PosReg', (73, 80))	('stemness', 'Disease', 'MESH:D020295', (128, 136))	('sphere formation', 'CPA', (96, 112))	('stemness', 'Disease', (128, 136))	('KYSE-150R', 'Var', (42, 51))
61920	27125498	However, the precise mechanisms by which high expression of WISP1 resulted in poor prognosis of ESCC patients have remained poorly elucidated.	('WISP1', 'Gene', '8840', (60, 65))	('patients', 'Species', '9606', (101, 109))	('WISP1', 'Gene', (60, 65))	('high expression', 'Var', (41, 56))	('ESCC patients', 'Disease', (96, 109))
61926	27125498	In a previous study by Guanyu Wang et al., Bmi-1 was demonstrated to be significantly up-regulated in KYSE-150R cells compared with in their parental KYSE-150 cells.	('Bmi-1', 'Gene', (43, 48))	('Bmi-1', 'Gene', '648', (43, 48))	('KYSE-150R', 'Var', (102, 111))	('up-regulated', 'PosReg', (86, 98))
61931	27125498	Since stemness is a recognized cell survival mechanism through preferential activation of the DNA damage response following ionizing radiation, those stemness-like properties observed in KYSE-150R are at least partially responsible for EMT-associated radioresistance.	('KYSE-150R', 'Var', (187, 196))	('stemness', 'Disease', 'MESH:D020295', (150, 158))	('stemness', 'Disease', (150, 158))	('stemness', 'Disease', 'MESH:D020295', (6, 14))	('stemness', 'Disease', (6, 14))	('DNA damage response', 'MPA', (94, 113))	('activation', 'PosReg', (76, 86))
61990	26018527	For multivariate analysis the following parameters were derived from the dose-volume histogram for each patient: mean esophageal dose (MED), Vx (volume receiving at least dose x) in 2.5 Gy steps from V20 to V70, Dmax, size of the tumor PTV, doses to the tumor, lymph nodes, and elective lymph drainage.	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', (254, 259))	('Dmax', 'MPA', (212, 216))	('esophageal dose', 'MPA', (118, 133))	('V20', 'Var', (200, 203))	('patient', 'Species', '9606', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('PTV', 'Chemical', '-', (236, 239))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
62012	26018527	Therefore, the following variables were included in the forward stepwise regression (Cox Regression): age, loss of weight, KPS, sex, T, N, tumor location (peripheral versus central), lymph node dose, elective dose, V20 to V70 in 2.5 Gy steps, MED, maximum esophagus dose (Dmax), V38.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('loss of weight', 'Phenotype', 'HP:0001824', (107, 121))	('V20 to V70', 'Var', (215, 225))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('V38', 'Var', (279, 282))
62013	26018527	In the first step (= univariate analysis), tumor location, N-stage, and the Vx from V30 to V57.5 and V65 as well as V38 were significant (p < 0.05).	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('V38', 'Var', (116, 119))	('V30', 'Var', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('V57.5', 'Var', (91, 96))	('V65', 'Var', (101, 104))	('tumor', 'Disease', (43, 48))
62023	26018527	In a review of 18 studies including 2173 patients, six parameters (V20, V30, V40, V45, V50, MED) were significantly related with AE in at least two thirds of the studies.	('V40', 'Var', (77, 80))	('V50', 'Var', (87, 90))	('V20', 'Var', (67, 70))	('V30', 'Var', (72, 75))	('V45', 'Var', (82, 85))	('related', 'Reg', (116, 123))	('patients', 'Species', '9606', (41, 49))	('MED', 'Disease', (92, 95))
62029	26018527	Since on multivariate analysis, including a range of patient related parameters, the statistically most significant factor for AE prediction was V38, we believe that a specific dose given to the esophagus is more predictive than patient and tumor related parameters.	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('V38', 'Var', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('patient', 'Species', '9606', (53, 60))	('patient', 'Species', '9606', (229, 236))
62043	24243830	Aberrant chimeric RNA GOLM1-MAK10 encoding a secreted fusion protein as a molecular signature for human esophageal squamous cell carcinoma It is increasingly recognized that chimeric RNAs may exert a novel layer of cellular complexity that contributes to oncogenesis and cancer progression, and could be utilized as molecular biomarkers and therapeutic targets.	('MAK10', 'Gene', (28, 33))	('chimeric', 'Var', (9, 17))	('GOLM1', 'Gene', '51280', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (104, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('contributes', 'Reg', (240, 251))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('oncogenesis', 'CPA', (255, 266))	('chimeric', 'Var', (174, 182))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('MAK10', 'Gene', '60560', (28, 33))	('human', 'Species', '9606', (98, 103))	('esophageal squamous cell carcinoma', 'Disease', (104, 138))	('cancer', 'Disease', (271, 277))	('GOLM1', 'Gene', (22, 27))
62047	24243830	Furthermore, we demonstrate that chimera GOLM1-MAK10 encodes a secreted fusion protein.	('MAK10', 'Gene', '60560', (47, 52))	('chimera', 'Var', (33, 40))	('GOLM1', 'Gene', (41, 46))	('MAK10', 'Gene', (47, 52))	('GOLM1', 'Gene', '51280', (41, 46))
62053	24243830	It is increasingly recognized that chimeric RNAs may exert a novel layer of cellular complexity that contributes to oncogenesis and cancer progression.	('cancer', 'Disease', (132, 138))	('oncogenesis', 'CPA', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('contributes', 'Reg', (101, 112))	('chimeric', 'Var', (35, 43))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('RNAs', 'Protein', (44, 48))
62054	24243830	With the aid of high-throughput RNA sequencing technology and bioinformatics analysis, transcriptome sequencing has uncovered a large number of chimeric RNAs across different human tissues and diseases.	('RNAs', 'Protein', (153, 157))	('chimeric', 'Var', (144, 152))	('human', 'Species', '9606', (175, 180))
62059	24243830	Despite their importance, chimeric RNAs are largely under-investigated and mostly unknown in esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal carcinoma', 'Disease', (93, 113))	('chimeric', 'Var', (26, 34))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (93, 113))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (93, 113))
62060	24243830	In this study, we investigated a set of 32 highly recurrent chimeric RNAs recently identified in prostate cancer, and characterized their presence in multiple ESCC and non-neoplastic cell lines, in addition to a large cohort of clinical ESCC patient samples.	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('chimeric', 'Var', (60, 68))	('RNAs', 'Protein', (69, 73))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('patient', 'Species', '9606', (242, 249))	('prostate cancer', 'Disease', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
62062	24243830	Importantly, the expression of the chimera is markedly elevated in cancer cells within patients' tumor and nearly undetectable in esophageal tissue from subjects without esophageal neoplasia.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (170, 190))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('esophageal neoplasia', 'Disease', (170, 190))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (170, 190))	('cancer', 'Disease', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'MPA', (17, 27))	('patients', 'Species', '9606', (87, 95))	('tumor', 'Disease', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('elevated', 'PosReg', (55, 63))	('chimera', 'Var', (35, 42))	('neoplasia', 'Phenotype', 'HP:0002664', (181, 190))
62063	24243830	The aberrant chimera closely correlated with tumor differetiation and lymph node metastasis.	('lymph node metastasis', 'CPA', (70, 91))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('correlated', 'Reg', (29, 39))	('tumor', 'Disease', (45, 50))	('aberrant', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
62064	24243830	Moreover, we showed that the chimera GOLM1-MAK10 led to the translation of a fusion protein that was secreted into the cell-culture media.	('GOLM1', 'Gene', '51280', (37, 42))	('chimera', 'Var', (29, 36))	('led to', 'Reg', (49, 55))	('translation', 'MPA', (60, 71))	('MAK10', 'Gene', '60560', (43, 48))	('GOLM1', 'Gene', (37, 42))	('MAK10', 'Gene', (43, 48))
62065	24243830	Our results thus suggest that the aberrant chimeric RNA GOLM1-MAK10 is abundant and may represent a novel molecular alteration in ESCC that could have important implications in understanding the mechanism and early detection of ESCC.	('MAK10', 'Gene', (62, 67))	('ESCC', 'Disease', (130, 134))	('chimeric', 'Var', (43, 51))	('aberrant chimeric', 'Var', (34, 51))	('GOLM1', 'Gene', (56, 61))	('GOLM1', 'Gene', '51280', (56, 61))	('MAK10', 'Gene', '60560', (62, 67))
62066	24243830	A set of 32 cancer-enriched and recurrent chimeric RNAs we recently discovered was chosen for initial screening.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('RNAs', 'Gene', (51, 55))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('chimeric', 'Var', (42, 50))
62069	24243830	RT-PCR showed that out of the 32 chimeric RNAs, 18 displayed varying degrees of expression in cancer vs. matched benign tissue (Figure 2).	('RNAs', 'Gene', (42, 46))	('chimeric', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('expression', 'MPA', (80, 90))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
62076	24243830	The data hence suggest the association of the chimeric GOLM1-MAK10 with ESCC.	('chimeric', 'Var', (46, 54))	('MAK10', 'Gene', '60560', (61, 66))	('association', 'Interaction', (27, 38))	('GOLM1', 'Gene', (55, 60))	('MAK10', 'Gene', (61, 66))	('GOLM1', 'Gene', '51280', (55, 60))	('ESCC', 'Disease', (72, 76))
62079	24243830	Abberant GOLM1-MAK10 was associated with histologic differentiation and lymph node metastasis (p=0.013 & 0.023 respectively, Table 1), but not statistically signifcant with any other clinicopathological indicators.	('histologic differentiation', 'CPA', (41, 67))	('MAK10', 'Gene', '60560', (15, 20))	('associated', 'Reg', (25, 35))	('Abberant', 'Var', (0, 8))	('MAK10', 'Gene', (15, 20))	('GOLM1', 'Gene', (9, 14))	('GOLM1', 'Gene', '51280', (9, 14))	('lymph node metastasis', 'CPA', (72, 93))
62082	24243830	The analysis revealed that non-neoplastic tissue from subjects without esophageal neoplasia expressed near undetectable level of chimera, as compared to the remarkably high level in ESCC tissue (p=3.7e-07, Figure 4).	('neoplastic tissue', 'Phenotype', 'HP:0002664', (31, 48))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (71, 91))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (71, 91))	('esophageal neoplasia', 'Disease', (71, 91))	('chimera', 'Var', (129, 136))	('neoplasia', 'Phenotype', 'HP:0002664', (82, 91))
62086	24243830	Our analysis indicated that GOLM1-MAK10 could result in the substitution of the last 25 amino acids of GOLM1 by 26 new amino acids and a new 3' UTR from MAK10 (Figure 5A).	('MAK10', 'Gene', '60560', (153, 158))	('result in', 'Reg', (46, 55))	('substitution', 'Var', (60, 72))	('GOLM1', 'Gene', (28, 33))	('GOLM1', 'Gene', (103, 108))	('MAK10', 'Gene', (153, 158))	('MAK10', 'Gene', '60560', (34, 39))	('GOLM1', 'Gene', '51280', (103, 108))	('GOLM1', 'Gene', '51280', (28, 33))	('MAK10', 'Gene', (34, 39))
62101	24243830	Recurrent fusion genes have been described in many hematological cancers and solid tumors, and subsequently provided new insights into the molecular subtypes of cancers and pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('hematological cancers', 'Disease', 'MESH:D009369', (51, 72))	('solid tumors', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('fusion genes', 'Var', (10, 22))	('hematological cancers', 'Disease', (51, 72))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('described', 'Reg', (33, 42))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('solid tumors', 'Disease', 'MESH:D009369', (77, 89))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (161, 168))	('cancers', 'Disease', (65, 72))
62104	24243830	In prostate cancer, the chimeric RNA SLC45A3-ELK4 is present in urine at detectable levels.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('ELK4', 'Gene', '2005', (45, 49))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('ELK4', 'Gene', (45, 49))	('SLC45A3', 'Gene', (37, 44))	('SLC45A3', 'Gene', '85414', (37, 44))	('chimeric', 'Var', (24, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
62106	24243830	Interestingly, our cell culture results demonstrated that chimera GOLM1-MAK10 identified in ESCC led to the translation of potentially functional fusion protein in human cells.	('human', 'Species', '9606', (164, 169))	('ESCC', 'Gene', (92, 96))	('MAK10', 'Gene', (72, 77))	('GOLM1', 'Gene', (66, 71))	('chimera', 'Var', (58, 65))	('GOLM1', 'Gene', '51280', (66, 71))	('MAK10', 'Gene', '60560', (72, 77))
62112	24243830	Our observation revealed a close correlation between aberrant GOLM1-MAK10 and lymph node metastasis as well as tumor differentiation, implying a potential function in ESCC.	('MAK10', 'Gene', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('ESCC', 'Disease', (167, 171))	('lymph node metastasis', 'CPA', (78, 99))	('tumor', 'Disease', (111, 116))	('GOLM1', 'Gene', (62, 67))	('MAK10', 'Gene', '60560', (68, 73))	('GOLM1', 'Gene', '51280', (62, 67))	('aberrant', 'Var', (53, 61))
62115	24243830	Our findings that the aberrant chimera GOLM1-MAK10 was enriched in ESCC, and that GOLM1-MAK10 produced a secreted fusion protein, suggests the possibility of a unique protein signature detectable by standard non-invasive ELISA assays.	('GOLM1', 'Gene', (82, 87))	('aberrant', 'Var', (22, 30))	('GOLM1', 'Gene', '51280', (39, 44))	('GOLM1', 'Gene', '51280', (82, 87))	('ESCC', 'Disease', (67, 71))	('MAK10', 'Gene', '60560', (88, 93))	('MAK10', 'Gene', (45, 50))	('MAK10', 'Gene', (88, 93))	('MAK10', 'Gene', '60560', (45, 50))	('GOLM1', 'Gene', (39, 44))
62116	24243830	Intriguingly, approximately 18 of the 32 recurrent chimeric RNAs identified in prostate cancer were also present in ESCC (Figure 2), suggesting that similarity exists between the two cancer types.	('chimeric RNAs', 'Var', (51, 64))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('ESCC', 'Disease', (116, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('prostate cancer', 'Disease', (79, 94))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
62120	24243830	For example, the expression of both chimeric TMPRSS2-ERG and SLC45A3-ELK4 are androgen-regulated in prostate cancer, a male and androgen-sensitive cancer.	('ELK4', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('chimeric', 'Var', (36, 44))	('ELK4', 'Gene', '2005', (69, 73))	('ERG', 'Gene', (53, 56))	('TMPRSS2', 'Gene', '7113', (45, 52))	('expression', 'MPA', (17, 27))	('TMPRSS2', 'Gene', (45, 52))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('ERG', 'Gene', '2078', (53, 56))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('SLC45A3', 'Gene', (61, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('prostate cancer', 'Disease', (100, 115))	('cancer', 'Disease', (147, 153))	('SLC45A3', 'Gene', '85414', (61, 68))
62121	24243830	Given that ESCC occurs predominantly in males and that sex steroid pathways such as androgen signaling may be involved in ESCC, we hypothesized that the expression of chimeric GOLM1-MAK10 may also be modulated by androgen.	('modulated', 'Reg', (200, 209))	('MAK10', 'Gene', (182, 187))	('MAK10', 'Gene', '60560', (182, 187))	('steroid', 'Chemical', 'MESH:D013256', (59, 66))	('chimeric', 'Var', (167, 175))	('GOLM1', 'Gene', (176, 181))	('involved', 'Reg', (110, 118))	('GOLM1', 'Gene', '51280', (176, 181))	('expression', 'MPA', (153, 163))	('ESCC', 'Disease', (11, 15))
62123	24243830	The possibly hormone-dependent regulation of chimeric RNAs, once further elucidated, may better our understanding of molecular mechanisms responsible for ESCC carcinogenesis and potentially provides novel target pathways for therapeutic intervention.	('carcinogenesis', 'Disease', (159, 173))	('ESCC', 'Disease', (154, 158))	('chimeric', 'Var', (45, 53))	('RNAs', 'Gene', (54, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))
62124	24243830	In summary, this investigation shows that chimeric RNA, previously unknown in esophageal carcinoma, is prevalent in ESCC, and identified GOLM1-MAK10 as important molecular signature of ESCC.	('prevalent', 'Reg', (103, 112))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (78, 98))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (78, 98))	('ESCC', 'Disease', (116, 120))	('GOLM1', 'Gene', (137, 142))	('GOLM1', 'Gene', '51280', (137, 142))	('MAK10', 'Gene', '60560', (143, 148))	('ESCC', 'Disease', (185, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal carcinoma', 'Disease', (78, 98))	('chimeric', 'Var', (42, 50))	('MAK10', 'Gene', (143, 148))
62259	32839439	Currently, nuclear receptors represent one of the largest transcription factor families, and nuclear receptor signaling dysregulation contributes to various human diseases, such as cancer.	('contributes', 'Reg', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('dysregulation', 'Var', (120, 133))	('nuclear', 'MPA', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('human diseases', 'Disease', (157, 171))	('human', 'Species', '9606', (157, 162))
62286	32839439	When NRIP3 was knocked down, the cells were arrested at the G1/S checkpoint (Fig.	('NRIP3', 'Gene', (5, 10))	('knocked down', 'Var', (15, 27))	('arrest', 'Disease', 'MESH:D006323', (44, 50))	('arrest', 'Disease', (44, 50))
62293	32839439	Notably, NRIP3-overexpressing cells displayed reduced ceramide (Cer) levels by up to 50% (Fig.	('Cer', 'Chemical', 'MESH:D002518', (64, 67))	('reduced', 'NegReg', (46, 53))	('ceramide', 'Chemical', 'MESH:D002518', (54, 62))	('NRIP3-overexpressing', 'Var', (9, 29))	('ceramide', 'MPA', (54, 62))
62301	32839439	We next investigated damage signaling in cells with NRIP3 overexpression or knockdown.	('NRIP3', 'Gene', (52, 57))	('knockdown', 'Var', (76, 85))	('investigated', 'Reg', (8, 20))	('overexpression', 'PosReg', (58, 72))	('age', 'Gene', (24, 27))	('age', 'Gene', '5973', (24, 27))
62302	32839439	NRIP3-KD cells showed elevated levels of phosphorylation of ATR (Ser428), Chk1 (Ser296), Cdc25C (Ser216), and gammaH2AX as well as decreased Rb phosphorylation (Ser795) following aphidicolin treatment.	('ATR', 'Gene', '545', (60, 63))	('elevated', 'PosReg', (22, 30))	('gammaH2AX', 'Gene', (110, 119))	('phosphorylation', 'MPA', (41, 56))	('Cdc25C', 'Gene', (89, 95))	('Ser296', 'Chemical', '-', (80, 86))	('Ser216', 'Chemical', '-', (97, 103))	('Rb', 'Chemical', 'MESH:D012413', (141, 143))	('Ser428', 'Var', (65, 71))	('Ser428', 'Chemical', '-', (65, 71))	('Rb phosphorylation', 'MPA', (141, 159))	('Ser296', 'Var', (80, 86))	('Chk1', 'Gene', (74, 78))	('ATR', 'Gene', (60, 63))	('Chk1', 'Gene', '1111', (74, 78))	('aphidicolin', 'Chemical', 'MESH:D016590', (179, 190))	('Ser216', 'Var', (97, 103))	('decreased', 'NegReg', (131, 140))	('Ser795', 'Chemical', '-', (161, 167))	('Cdc25C', 'Gene', '995', (89, 95))
62303	32839439	Likewise, overexpression of NRIP3 suppressed the phosphorylation of ATR (Ser428), Chk1 (Ser296), and Cdc25C (Ser16) and gammaH2AX as well as increased Rb phosphorylation (Ser795) in KYSE30 cells following aphidicolin treatment (Fig.	('Ser795', 'Var', (171, 177))	('increased', 'PosReg', (141, 150))	('ATR', 'Gene', '545', (68, 71))	('phosphorylation', 'MPA', (49, 64))	('Rb', 'Chemical', 'MESH:D012413', (151, 153))	('Rb phosphorylation', 'MPA', (151, 169))	('aphidicolin', 'Chemical', 'MESH:D016590', (205, 216))	('Ser296', 'Var', (88, 94))	('Ser428', 'Chemical', '-', (73, 79))	('Ser795', 'Chemical', '-', (171, 177))	('Chk1', 'Gene', (82, 86))	('gammaH2AX', 'Protein', (120, 129))	('ATR', 'Gene', (68, 71))	('Cdc25C', 'Gene', '995', (101, 107))	('Chk1', 'Gene', '1111', (82, 86))	('Ser16', 'Var', (109, 114))	('NRIP3', 'Gene', (28, 33))	('Cdc25C', 'Gene', (101, 107))	('suppressed', 'NegReg', (34, 44))	('Ser16', 'Chemical', '-', (109, 114))	('Ser296', 'Chemical', '-', (88, 94))
62312	32839439	Because gene set enrichment analysis revealed that NRIP3 knockdown resulted in the enrichment of genes related to the PPARalpha pathway (Fig.	('PPARalpha', 'Gene', (118, 127))	('PPARalpha', 'Gene', '5465', (118, 127))	('knockdown', 'Var', (57, 66))	('NRIP3', 'Gene', (51, 56))
62325	32839439	In addition, we found that NRIP3-overexpressing cells exhibited resistance to carboplatin, another commonly used platinum salt, compared to vector control cells (Fig.	('NRIP3-overexpressing', 'Var', (27, 47))	('carboplatin', 'Chemical', 'MESH:D016190', (78, 89))	('platinum salt', 'Chemical', '-', (113, 126))	('resistance', 'MPA', (64, 74))
62328	32839439	Consistently, tail moment increased in NRIP3-KD cells treated with cisplatin or IR (Fig.	('cisplatin', 'Var', (67, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('increased', 'PosReg', (26, 35))	('IR', 'Gene', '3643', (80, 82))	('tail moment', 'MPA', (14, 25))
62329	32839439	In addition, western blotting results showed significant changes of phosphorylation of ATR (Ser428), Cdc25C (Ser216), Chk1 (Ser345 and Ser296), and gammaH2AX in NRIP3-KD cells when cells were treated with IR (Fig.	('Chk1', 'Gene', '1111', (118, 122))	('Ser428', 'Var', (92, 98))	('phosphorylation', 'MPA', (68, 83))	('Ser216', 'Var', (109, 115))	('Cdc25C', 'Gene', (101, 107))	('gammaH2AX', 'Gene', (148, 157))	('Ser428', 'Chemical', '-', (92, 98))	('changes', 'Reg', (57, 64))	('IR', 'Gene', '3643', (205, 207))	('Ser345', 'Chemical', '-', (124, 130))	('Cdc25C', 'Gene', '995', (101, 107))	('Ser345', 'Var', (124, 130))	('Ser216', 'Chemical', '-', (109, 115))	('ATR', 'Gene', '545', (87, 90))	('ATR', 'Gene', (87, 90))	('Ser296', 'Chemical', '-', (135, 141))	('Chk1', 'Gene', (118, 122))	('Ser296', 'Var', (135, 141))
62344	32839439	Consistent with this finding, we observed decreased cell proliferation and G1/S arrest in NRIP3 knockdown cells.	('knockdown', 'Var', (96, 105))	('S arrest', 'Disease', (78, 86))	('NRIP3', 'Gene', (90, 95))	('decreased', 'NegReg', (42, 51))	('S arrest', 'Disease', 'MESH:D006323', (78, 86))	('cell proliferation', 'CPA', (52, 70))
62346	32839439	The Cer decreased in NRIP3-overexpressing cells and it increased in NRIP3-KD cells, leading us to wonder whether NRIP3 could protect cells from DNA damage.	('NRIP3-overexpressing', 'Var', (21, 41))	('age', 'Gene', (151, 154))	('increased', 'PosReg', (55, 64))	('Cer', 'Chemical', 'MESH:D002518', (4, 7))	('Cer', 'MPA', (4, 7))	('age', 'Gene', '5973', (151, 154))	('decreased', 'NegReg', (8, 17))
62352	32839439	Based on the previous studies and our observations, we believe that the relevant DNA damage types in the context of NRIP3 manipulations are: SSBs, DSBs, and covalent cross-links between DNA bases.	('covalent cross-links', 'Var', (157, 177))	('manipulations', 'Var', (122, 135))	('age', 'Gene', '5973', (88, 91))	('DSBs', 'Disease', (147, 151))	('NRIP3', 'Gene', (116, 121))	('SSBs', 'Chemical', '-', (141, 145))	('DSBs', 'Chemical', '-', (147, 151))	('SSBs', 'Disease', (141, 145))	('age', 'Gene', (88, 91))
62358	32839439	Exploring the mechanism by which NRIP3 induces an increase in the protein level of DDI1, we detected a decrease in PPARalpha in NRIP3-KD cells and an increase in PPARalpha in NRIP3-overexpressing cells.	('PPARalpha', 'Gene', (162, 171))	('PPARalpha', 'Gene', (115, 124))	('protein level', 'MPA', (66, 79))	('NRIP3', 'Var', (33, 38))	('increase', 'PosReg', (50, 58))	('DDI1', 'Gene', '414301', (83, 87))	('PPARalpha', 'Gene', '5465', (162, 171))	('PPARalpha', 'Gene', '5465', (115, 124))	('decrease', 'NegReg', (103, 111))	('DDI1', 'Gene', (83, 87))
62364	32839439	Our results suggest a model that NRIP3 upregulation increases DDI1 at least partly via PPARalpha; NRIP3, DDI1, and RTF2 form a complex and facilitate RTF2 removal by proteosomal degradation of RTF2, thereby restarting the replication fork when cells are in replicative stress (Fig.	('removal', 'NegReg', (155, 162))	('DDI1', 'Gene', '414301', (105, 109))	('NRIP3', 'Gene', (33, 38))	('DDI1', 'Gene', (105, 109))	('DDI1', 'Gene', '414301', (62, 66))	('PPARalpha', 'Gene', '5465', (87, 96))	('RTF2', 'MPA', (150, 154))	('facilitate', 'PosReg', (139, 149))	('upregulation', 'PosReg', (39, 51))	('NRIP3', 'Var', (98, 103))	('restarting', 'PosReg', (207, 217))	('DDI1', 'Gene', (62, 66))	('PPARalpha', 'Gene', (87, 96))	('replication fork', 'MPA', (222, 238))
62413	32256815	In addition, overexpression of ectopic ENO1 promoted cell proliferation and survival in lung cancer cell lines, which was not the case in other cells, including an esophageal cell line.	('promoted', 'PosReg', (44, 52))	('lung cancer', 'Disease', (88, 99))	('expression', 'Species', '29278', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('ENO1', 'Gene', (39, 43))	('overexpression', 'PosReg', (13, 27))	('ectopic', 'Var', (31, 38))	('survival', 'CPA', (76, 84))	('cell proliferation', 'CPA', (53, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
62417	32256815	There are three different ENO isoforms in higher eukaryotes, including ENO1 or alpha-ENO, ENO2 or gamma-ENO and ENO3 or beta-ENO.	('gamma-ENO', 'Var', (98, 107))	('ENO3', 'Gene', '2027', (112, 116))	('ENO2', 'Gene', '2026', (90, 94))	('ENO3', 'Gene', (112, 116))	('ENO2', 'Gene', (90, 94))
62422	32256815	In addition, abnormally upregulated ENO1 is associated with poor survival and prognosis in patients with mammary carcinoma.	('patients', 'Species', '9606', (91, 99))	('ENO1', 'Gene', (36, 40))	('poor', 'NegReg', (60, 64))	('carcinoma', 'Disease', 'MESH:D009369', (113, 122))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (105, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinoma', 'Disease', (113, 122))	('abnormally', 'Var', (13, 23))
62423	32256815	Furthermore, overexpression of ectopic ENO1 promotes tumor formation or enhances cell transformation in gastric cancer, lung cancer, pancreatic cancer, colorectal cancer and glioma and promotes chemoresistance in gastric and breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('lung cancer', 'Disease', (120, 131))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('overexpression', 'PosReg', (13, 27))	('cell transformation', 'CPA', (81, 100))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('pancreatic cancer', 'Disease', (133, 150))	('colorectal cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('promotes', 'PosReg', (44, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('ectopic', 'Var', (31, 38))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('breast cancers', 'Disease', 'MESH:D001943', (225, 239))	('enhances', 'PosReg', (72, 80))	('breast cancers', 'Disease', (225, 239))	('gastric', 'Disease', (213, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('promotes', 'PosReg', (185, 193))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('chemoresistance', 'CPA', (194, 209))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('glioma', 'Disease', (174, 180))	('breast cancers', 'Phenotype', 'HP:0003002', (225, 239))	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('expression', 'Species', '29278', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ENO1', 'Gene', (39, 43))	('tumor', 'Disease', (53, 58))	('pancreatic cancer', 'Disease', 'MESH:D010190', (133, 150))	('gastric cancer', 'Disease', (104, 118))
62450	32256815	Regarding RNA interference, the shRNAs packed in lentivirus and provided by the National RNAi core facility (Institute of Molecular Biology, Academia Sinica, Taiwan, R.O.C), were employed to infect cells in the presence of 8 microg/ml polybrene, which notably stimulates infection rate.	('stimulates', 'PosReg', (260, 270))	('polybrene', 'Chemical', 'MESH:D006583', (235, 244))	('infection', 'Disease', (271, 280))	('polybrene', 'Var', (235, 244))	('infection', 'Disease', 'MESH:D007239', (271, 280))
62467	32256815	2B) FBS, including kidney epithelium (293T and 293), liver cancer (HepG2), cervical cancer (HeLa), lung cancer (H1299, H460 and A549) and esophageal cancer (TE12).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('H1299', 'Var', (112, 117))	('293T', 'CellLine', 'CVCL:0063', (38, 42))	('A549', 'CellLine', 'CVCL:0023', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('liver cancer', 'Phenotype', 'HP:0002896', (53, 65))	('cancer', 'Disease', (104, 110))	('liver cancer', 'Disease', (53, 65))	('kidney epithelium', 'Disease', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (149, 155))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('HepG2', 'CellLine', 'CVCL:0027', (67, 72))	('HeLa', 'CellLine', 'CVCL:0030', (92, 96))	('H1299', 'CellLine', 'CVCL:0060', (112, 117))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('cancer', 'Disease', (59, 65))	('liver cancer', 'Disease', 'MESH:D006528', (53, 65))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
62468	32256815	The results demonstrated that overexpression of ectopic ENO1 stimulated the proliferation of two lung cancer cell lines H1299 and H460, but had no effect on other cell line proliferation, including the esophageal cell line TE12.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ENO1', 'Gene', (56, 60))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('overexpression', 'PosReg', (30, 44))	('stimulated', 'PosReg', (61, 71))	('proliferation', 'CPA', (76, 89))	('H1299', 'CellLine', 'CVCL:0060', (120, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('lung cancer', 'Disease', (97, 108))	('ectopic', 'Var', (48, 55))	('expression', 'Species', '29278', (34, 44))
62469	32256815	Consistently with the results from overexpression, ENO1 knockdown inhibited cell proliferation in H1299 and H460 cell proliferation (Fig.	('expression', 'Species', '29278', (39, 49))	('H1299', 'CellLine', 'CVCL:0060', (98, 103))	('inhibited', 'NegReg', (66, 75))	('cell proliferation in H1299', 'CPA', (76, 103))	('knockdown', 'Var', (56, 65))	('ENO1', 'Gene', (51, 55))
62477	32256815	Furthermore, overexpression of exogenous ENO1 promoted cell proliferation and enhanced cell survival in lung cancer cell lines, but not in esophageal cell lines.	('promoted', 'PosReg', (46, 54))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('expression', 'Species', '29278', (17, 27))	('cell survival', 'CPA', (87, 100))	('lung cancer', 'Disease', (104, 115))	('cell proliferation', 'CPA', (55, 73))	('overexpression', 'PosReg', (13, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('enhanced', 'PosReg', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ENO1', 'Gene', (41, 45))	('exogenous', 'Var', (31, 40))
62479	32256815	The results demonstrated that exogenous ENO1 induced the increase in p38 and p-AKT protein levels and the decrease in cell growth suppressive p-c-Raf protein level in H1299 cells (Fig.	('AKT', 'Gene', (79, 82))	('ENO1', 'Gene', (40, 44))	('decrease', 'NegReg', (106, 114))	('p38', 'Gene', '1432', (69, 72))	('H1299', 'CellLine', 'CVCL:0060', (167, 172))	('increase', 'PosReg', (57, 65))	('AKT', 'Gene', '207', (79, 82))	('exogenous', 'Var', (30, 39))	('c-Raf', 'Gene', '5894', (144, 149))	('c-Raf', 'Gene', (144, 149))	('p38', 'Gene', (69, 72))
62485	32256815	In addition, consistent with the aforementioned results, exogenous ENO1 preferentially stimulated cell proliferation of the lung cancer cell lines H1299 and H460, but not of the esophageal TE12, liver cancer HepG2 and cervical cancer HeLa cell lines.	('cell proliferation', 'CPA', (98, 116))	('stimulated', 'PosReg', (87, 97))	('HepG2', 'CellLine', 'CVCL:0027', (208, 213))	('liver cancer', 'Disease', 'MESH:D006528', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('liver cancer', 'Phenotype', 'HP:0002896', (195, 207))	('liver cancer', 'Disease', (195, 207))	('exogenous', 'Var', (57, 66))	('ENO1', 'Gene', (67, 71))	('lung cancer', 'Disease', (124, 135))	('H1299', 'CellLine', 'CVCL:0060', (147, 152))	('men', 'Species', '9606', (38, 41))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cervical cancer HeLa', 'Disease', 'MESH:D002583', (218, 238))	('cervical cancer HeLa', 'Disease', (218, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('preferentially', 'PosReg', (72, 86))
62487	32256815	Furthermore, ENO1 overexpression only activated AKT to a certain extent, as full activation of AKT requires phosphorylation at T308 and T473, and only stimulated the increase of AKT-thr308.	('AKT', 'Gene', (178, 181))	('AKT', 'Gene', (48, 51))	('AKT', 'Gene', '207', (95, 98))	('T473', 'Var', (136, 140))	('AKT', 'Gene', (95, 98))	('phosphorylation', 'MPA', (108, 123))	('AKT', 'Gene', '207', (178, 181))	('expression', 'Species', '29278', (22, 32))	('AKT', 'Gene', '207', (48, 51))	('thr308', 'Chemical', '-', (182, 188))
62488	32256815	In addition, ectopic ENO1 accelerated G1 progression and upregulated CDK6, rather than G1 cyclins, including cyclins A, B, D or E. Furthermore, the growth suppressor protein c-Raf was decreased following ENO1 overexpression.	('expression', 'Species', '29278', (213, 223))	('cyclins A, B, D or E', 'Gene', '890', (109, 129))	('accelerated', 'PosReg', (26, 37))	('G1 progression', 'CPA', (38, 52))	('ectopic', 'Var', (13, 20))	('CDK6', 'Gene', (69, 73))	('decreased', 'NegReg', (184, 193))	('CDK6', 'Gene', '1021', (69, 73))	('c-Raf', 'Gene', '5894', (174, 179))	('c-Raf', 'Gene', (174, 179))	('ENO1', 'Gene', (21, 25))	('upregulated', 'PosReg', (57, 68))
62491	32256815	Since H1299 and H460 are non-small lung cancer cell lines, ENO1 may therefore activate AKT via the FAK pathway.	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('ENO1', 'Gene', (59, 63))	('FAK', 'Gene', (99, 102))	('AKT', 'Gene', (87, 90))	('FAK', 'Gene', '5747', (99, 102))	('small lung', 'Phenotype', 'HP:0002089', (29, 39))	('H1299', 'Var', (6, 11))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('H1299', 'CellLine', 'CVCL:0060', (6, 11))	('AKT', 'Gene', '207', (87, 90))	('activate', 'PosReg', (78, 86))
62493	32256815	The results of the present study, which demonstrated that ENO1 failed to promote the proliferation of the lung cancer cell line A549, were inconsistent with the study from Fu et al, which demonstrated that ENO1 can enhance cell proliferation, colony formation and cell migration in A549 cell line.	('cell proliferation', 'CPA', (223, 241))	('lung cancer', 'Disease', (106, 117))	('cell migration', 'CPA', (264, 278))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('A549', 'CellLine', 'CVCL:0023', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('colony formation', 'CPA', (243, 259))	('A549', 'CellLine', 'CVCL:0023', (282, 286))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('enhance', 'PosReg', (215, 222))	('ENO1', 'Var', (206, 210))
62495	32256815	Long-term incubation of A549 cells with exogenous ENO1 may offer additional advantages to lung cancer cell proliferation.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('ENO1', 'Gene', (50, 54))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('exogenous', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('advantages', 'PosReg', (76, 86))
62599	31205568	concluded that signal transduction of IL-35 does overlap with IL-12 and IL-27 transduction as it relays the signals using IL-12Rbeta2 and gp130, which corresponds with IL-12 and IL-27 respectively.	('gp130', 'Gene', '3572', (138, 143))	('gp130', 'Gene', (138, 143))	('relays', 'MPA', (97, 103))	('IL-12Rbeta2', 'Var', (122, 133))
62601	31205568	Though conversion of conventional T cells into iTr35 require the phosphorylation of both STAT1 and STAT4 from gp130 chain and IL-12Rbeta2 chain respectively.	('STAT4', 'Gene', '6775', (99, 104))	('STAT1', 'Gene', '6772', (89, 94))	('gp130', 'Gene', (110, 115))	('gp130', 'Gene', '3572', (110, 115))	('phosphorylation', 'MPA', (65, 80))	('IL-12Rbeta2 chain', 'Var', (126, 143))	('STAT4', 'Gene', (99, 104))	('STAT1', 'Gene', (89, 94))
62604	31205568	Hetrodiamerization of STAT1 and STAT4 leads to upregulation of EBI3 or P35 which ultimately helps convert conventional T cells into iTr35.	('Hetrodiamerization', 'Var', (0, 18))	('STAT4', 'Gene', (32, 37))	('upregulation', 'PosReg', (47, 59))	('P35', 'Gene', '3592', (71, 74))	('EBI3', 'Protein', (63, 67))	('STAT1', 'Gene', (22, 27))	('STAT1', 'Gene', '6772', (22, 27))	('P35', 'Gene', (71, 74))	('STAT4', 'Gene', '6775', (32, 37))
62617	31205568	According to the study the injection of J558-IL-35 cells (mouse plasmacytoma cells expressing IL-35) in BALB/c mice drastically increased the tumor size as compared to control.	('plasmacytoma', 'Phenotype', 'HP:0011857', (64, 76))	('mouse', 'Species', '10090', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('J558-IL-35 cells', 'Var', (40, 56))	('tumor', 'Disease', (142, 147))	('increased', 'PosReg', (128, 137))	('mice', 'Species', '10090', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
62619	31205568	IL-35 neutralizing mAb was co-injected with J558-IL-35 cells in Rag2-/-BALB/c mice (mice that lack T and B lymohocytes), to know whether tumor progression was IL-35 specific.	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('J558-IL-35', 'Var', (44, 54))	('Rag2', 'Gene', '19374', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mice', 'Species', '10090', (78, 82))	('mice', 'Species', '10090', (84, 88))	('Rag2', 'Gene', (64, 68))
62620	31205568	Intriguingly study found the abrogation of tumor growth in the presence of IL-35 neutralizing mAb compared to control.	('neutralizing', 'Var', (81, 93))	('mAb', 'Protein', (94, 97))	('abrogation', 'NegReg', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('IL-35', 'Gene', (75, 80))	('tumor', 'Disease', (43, 48))
62623	31205568	A mathematical model was developed followed by in-silico experiments to evaluate the extent to which blocking IL-35 can reduce tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('reduce', 'NegReg', (120, 126))	('tumor', 'Disease', (127, 132))	('IL-35', 'Protein', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('blocking', 'Var', (101, 109))
62625	31205568	One of the type consisted of tumor cells that were transfected with IL-35 to raise the amount of IL-35 into TME while second used normal plasmacytoma cells that produced very small amount of IL-35.	('amount of IL-35 into TME', 'MPA', (87, 111))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('plasmacytoma', 'Phenotype', 'HP:0011857', (137, 149))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('transfected', 'Var', (51, 62))	('tumor', 'Disease', (29, 34))	('raise', 'PosReg', (77, 82))	('IL-35', 'Gene', (68, 73))
62630	31205568	In the research of Pylayeva-Gupta's group, they use a mouse model of pancreatic cancer demonstrated that IL-35+ Bregs are directly recruited to the tumor cell vicinity via a chemokine gradient of CXCL13 and promote tumorigenesis in IL-35 dependent manner.	('promote', 'PosReg', (207, 214))	('pancreatic cancer', 'Disease', (69, 86))	('CXCL13', 'Gene', '55985', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('IL-35+', 'Var', (105, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('mouse', 'Species', '10090', (54, 59))	('CXCL13', 'Gene', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
62661	31205568	Study findings manifested that neutralization of IL-35 resulted in improved tumor control in Wild-type C57BL/6 mice as compared to control mice.	('neutralization', 'Var', (31, 45))	('IL-35', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mice', 'Species', '10090', (111, 115))	('mice', 'Species', '10090', (139, 143))	('improved', 'PosReg', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
62667	31205568	Theoretically, EBI3 knockout would stall IL-35 production from Tregs which would result in raised CTL and improved tumor protection.	('EBI3', 'Gene', (15, 19))	('improved', 'PosReg', (106, 114))	('CTL', 'CPA', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('IL-35 production', 'MPA', (41, 57))	('tumor', 'Disease', (115, 120))	('raised', 'PosReg', (91, 97))	('knockout', 'Var', (20, 28))	('stall', 'NegReg', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
62698	31205568	Ectopic expression of IL-35 in pancreatic beta cells prevents development of diabetes mellitus in NOD mice.	('mice', 'Species', '10090', (102, 106))	('prevents', 'NegReg', (53, 61))	('pancreatic', 'Disease', (31, 41))	('IL-35', 'Gene', (22, 27))	('Ectopic expression', 'Var', (0, 18))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (77, 94))	('diabetes mellitus', 'Disease', (77, 94))	('pancreatic', 'Disease', 'MESH:D010195', (31, 41))	('diabetes mellitus', 'Disease', 'MESH:D003920', (77, 94))
62703	31205568	For instance, Corona virus-induced encephalomyelitis and experimental autoimmune encephalomyelitis (EAE) were worsened in EBI3-/- mice.	('mice', 'Species', '10090', (130, 134))	('encephalomyelitis', 'Disease', 'MESH:D004679', (81, 98))	('encephalomyelitis', 'Disease', (81, 98))	('induced encephalomyelitis', 'Phenotype', 'HP:0002383', (27, 52))	('EBI3-/-', 'Var', (122, 129))	('worsened', 'PosReg', (110, 118))	('autoimmune encephalomyelitis', 'Disease', (70, 98))	('encephalomyelitis', 'Disease', 'MESH:D004679', (35, 52))	('encephalomyelitis', 'Disease', (35, 52))	('autoimmune encephalomyelitis', 'Disease', 'MESH:D004681', (70, 98))
62720	28500305	NSAIDs are related to a significantly reduced risk of metastasis development, regardless of pre-diagnostic or post-diagnostic use.	('men', 'Species', '9606', (72, 75))	('metastasis development', 'CPA', (54, 76))	('NSAIDs', 'Var', (0, 6))	('reduced', 'NegReg', (38, 45))
62729	28500305	While some studies found no significant association between NSAID use and cancer metastasis, other studies have demonstrated that NSAIDs are associated with reduced risk of metastasis and even with reduced cancer incidence.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer metastasis', 'Disease', (74, 91))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('metastasis', 'CPA', (173, 183))	('NSAIDs', 'Var', (130, 136))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('reduced', 'NegReg', (198, 205))	('cancer', 'Disease', (206, 212))	('cancer metastasis', 'Disease', 'MESH:D009362', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('reduced', 'NegReg', (157, 164))
62742	28500305	Among the eleven studies, ten studies reported the negative association between NSAIDs and cancer metastasis, although the results from two studies were not statistically significant.	('cancer metastasis', 'Disease', 'MESH:D009362', (91, 108))	('NSAIDs', 'Var', (80, 86))	('negative', 'NegReg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer metastasis', 'Disease', (91, 108))
62748	28500305	In prostate cancer, the summarized results suggested a negative association between NSAIDs and prostate cancer metastasis with a considerable heterogeneity (RR = 0.817, 95% CI 0.74-00.902, p = 0.006, I2 = 70.9%).	('prostate cancer metastasis', 'Disease', (95, 121))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('NSAIDs', 'Var', (84, 90))	('prostate cancer metastasis', 'Disease', 'MESH:D009362', (95, 121))	('negative', 'NegReg', (55, 63))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (95, 110))	('prostate cancer', 'Phenotype', 'HP:0012125', (95, 110))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
62757	28500305	A negative relationship between NSAIDs and LN metastasis was detected in the summarized studies, although the results were not statically significant (RR = 0.958, 95% CI 0.913-1.004, p = 0.075, I2 = 34.8) (Supplementary Dataset 7).	('LN metastasis', 'CPA', (43, 56))	('negative', 'NegReg', (2, 10))	('NSAIDs', 'Var', (32, 38))	('men', 'Species', '9606', (212, 215))
62782	28500305	Disordered COX2/PGE pathway is involved in multi-cancer processes, including carcinogenesis, proliferation, and metastatic spread; additionally, inhibition of COX2/PGE pathway with NSAIDs can restrain cancer cell lines and xenograft models.	('multi-cancer', 'Disease', 'MESH:D009369', (43, 55))	('cancer', 'Disease', (201, 207))	('multi-cancer', 'Disease', (43, 55))	('carcinogenesis', 'Disease', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('inhibition', 'Var', (145, 155))	('cancer', 'Disease', (49, 55))	('COX2', 'Gene', '4513', (159, 163))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('involved', 'Reg', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PGE', 'Chemical', 'MESH:D011458', (16, 19))	('Disordered COX2', 'Disease', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('Disordered COX2', 'Disease', 'MESH:D030342', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('COX2', 'Gene', (11, 15))	('PGE', 'Chemical', 'MESH:D011458', (164, 167))	('COX2', 'Gene', '4513', (11, 15))	('COX2', 'Gene', (159, 163))
62830	27432467	Dysfunction in the apoptotic process contributes to the pathogenesis of a variety of malignant tumors, and it is considered to be the key reason for their occurrence and development, being closely associated with tumor drug resistance.	('tumor', 'Disease', (213, 218))	('contributes', 'Reg', (37, 48))	('drug resistance', 'Phenotype', 'HP:0020174', (219, 234))	('Dysfunction', 'Var', (0, 11))	('malignant tumors', 'Disease', (85, 101))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('malignant tumors', 'Disease', 'MESH:D018198', (85, 101))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('apoptotic process', 'CPA', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (95, 100))
62880	27432467	As summarized in Table I, the high expression of Apollon was significantly associated with the TNM stage (P<0.001) and lymph node (N classification) metastasis (P<0.001).	('Apollon', 'Gene', (49, 56))	('high expression', 'Var', (30, 45))	('Apollon', 'Gene', '57448', (49, 56))	('TNM', 'Disease', (95, 98))	('associated', 'Reg', (75, 85))
62886	27432467	Patients with ESCC who had high Apollon expression also had shorter disease-free survival rates (median survival time: 22 vs. >60 months, P<0.001; Fig.	('disease-free survival rates', 'CPA', (68, 95))	('high', 'Var', (27, 31))	('Apollon', 'Gene', (32, 39))	('ESCC', 'Disease', (14, 18))	('Apollon', 'Gene', '57448', (32, 39))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (60, 67))
62903	27432467	The results revealed that patients with high Apollon expression/more lymph node metastasis (N2) had shorter overall and disease-free survival times compared with patients with neither.	('high', 'Var', (40, 44))	('patients', 'Species', '9606', (162, 170))	('Apollon', 'Gene', (45, 52))	('Apollon', 'Gene', '57448', (45, 52))	('shorter', 'NegReg', (100, 107))	('patients', 'Species', '9606', (26, 34))	('lymph node metastasis', 'CPA', (69, 90))
62908	27432467	Notably, abundant previous research has demonstrated that a high level of Apollon expression is associated with poor chemotherapeutic outcomes in various carcinomas, including colon cancer, acute leukemia, prostate cancer and melanoma, whereas silencing Apollon may improve patient sensitivity to chemotherapy.	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('colon cancer', 'Phenotype', 'HP:0003003', (176, 188))	('silencing', 'Var', (244, 253))	('leukemia', 'Phenotype', 'HP:0001909', (196, 204))	('Apollon', 'Gene', (254, 261))	('Apollon', 'Gene', '57448', (254, 261))	('acute leukemia', 'Disease', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('colon cancer', 'Disease', 'MESH:D015179', (176, 188))	('carcinomas', 'Disease', (154, 164))	('improve', 'PosReg', (266, 273))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('prostate cancer', 'Disease', 'MESH:D011471', (206, 221))	('prostate cancer', 'Phenotype', 'HP:0012125', (206, 221))	('acute leukemia', 'Disease', 'MESH:D015470', (190, 204))	('prostate cancer', 'Disease', (206, 221))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))	('patient', 'Species', '9606', (274, 281))	('colon cancer', 'Disease', (176, 188))	('acute leukemia', 'Phenotype', 'HP:0002488', (190, 204))	('Apollon', 'Gene', (74, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('carcinomas', 'Disease', 'MESH:D002277', (154, 164))	('Apollon', 'Gene', '57448', (74, 81))
62993	26346864	Previous work suggests that when utilizing the Seattle protocol, q1cm four quadrant biopsies detect more dysplasia than q2cm regimens, a finding replicated in our simulation.	('dysplasia', 'Disease', 'MESH:D004476', (105, 114))	('q1cm', 'Var', (65, 69))	('dysplasia', 'Disease', (105, 114))
63013	26346864	However, differences in the performance of EGD or the quality of the histological grading of dysplasia have the potential to change both the test characteristics of surveillance endoscopy, and, potentially, the findings we report here.	('dysplasia', 'Disease', (93, 102))	('test', 'MPA', (141, 145))	('dysplasia', 'Disease', 'MESH:D004476', (93, 102))	('change', 'Reg', (125, 131))	('differences', 'Var', (9, 20))
63030	19268726	Stratified by BE length, nonadherence was associated with significantly decreased dysplasia detection (summary OR 0.53, 95% CI 0.35- 0.82).	('nonadherence', 'Var', (25, 37))	('decreased dysplasia', 'Disease', (72, 91))	('BE', 'Phenotype', 'HP:0100580', (14, 16))	('decreased dysplasia', 'Disease', 'MESH:D012021', (72, 91))
63031	19268726	Adherence to BE biopsy guidelines in the community is low, and nonadherence is associated with significantly decreased dysplasia detection.	('BE', 'Phenotype', 'HP:0100580', (13, 15))	('nonadherence', 'Var', (63, 75))	('decreased dysplasia', 'Disease', 'MESH:D012021', (109, 128))	('decreased dysplasia', 'Disease', (109, 128))
63080	19268726	When stratified by length of BE and excluding patients with a history of dysplasia, nonadherence was associated with significantly decreased odds of detection of dysplasia (Mantel-Haenszel summary OR, 0.53; 95% CI, 0.35- 0.82) (Figure 4).	('patients', 'Species', '9606', (46, 54))	('dysplasia', 'Disease', 'MESH:D004476', (73, 82))	('dysplasia', 'Disease', (162, 171))	('BE', 'Phenotype', 'HP:0100580', (29, 31))	('dysplasia', 'Disease', 'MESH:D004476', (162, 171))	('decreased', 'NegReg', (131, 140))	('nonadherence', 'Var', (84, 96))	('dysplasia', 'Disease', (73, 82))
63113	19268726	Patients with shorter segments of BE were possibly less likely to have intestinal metaplasia successfully detected, and therefore a lower proportion of true short segment BE (compared with long segment) would be captured in our cohort.	('intestinal metaplasia', 'Disease', 'MESH:D008679', (71, 92))	('short segment BE', 'Var', (157, 173))	('men', 'Species', '9606', (166, 169))	('men', 'Species', '9606', (197, 200))	('Patients', 'Species', '9606', (0, 8))	('BE', 'Phenotype', 'HP:0100580', (34, 36))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('intestinal metaplasia', 'Disease', (71, 92))	('men', 'Species', '9606', (25, 28))
63124	32550750	Importance of investigating high-risk human papillomavirus in lymph node metastasis of esophageal adenocarcinoma High-risk human papillomavirus has been suggested as a risk factor for esophageal adenocarcinoma.	('adenocarcinoma', 'Disease', (98, 112))	('esophageal adenocarcinoma', 'Disease', (184, 209))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (87, 112))	('human papillomavirus', 'Species', '10566', (123, 143))	('adenocarcinoma', 'Disease', (195, 209))	('adenocarcinoma', 'Disease', 'MESH:D000230', (98, 112))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (184, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (87, 112))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (184, 209))	('adenocarcinoma', 'Disease', 'MESH:D000230', (195, 209))	('human papillomavirus', 'Species', '10566', (38, 58))	('High-risk', 'Var', (113, 122))	('esophageal adenocarcinoma', 'Disease', (87, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
63150	32550750	Mechanisms reported include immune evasion due to functional suppression of cytotoxic T-lymphocytes by DNA methylation in MHC class I phenotype esophageal cancers and hypercoagulation.	('DNA methylation', 'Var', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('immune evasion', 'MPA', (28, 42))	('hypercoagulation', 'Disease', (167, 183))	('hypercoagulation', 'Disease', 'MESH:D019851', (167, 183))	('MHC class I', 'Gene', (122, 133))	('suppression', 'NegReg', (61, 72))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers', 'Disease', (155, 162))
63152	32550750	The presence of HPV DNA in the RLNs has been associated with disease recurrence and early signs of metastasis.	('HPV DNA', 'Gene', (16, 23))	('HPV', 'Species', '10566', (16, 19))	('associated', 'Reg', (45, 55))	('presence', 'Var', (4, 12))	('disease recurrence', 'CPA', (61, 79))
63172	32550750	Later in 2013, they provided world first evidence for a strong association of transcriptionally active hr-HPV with EAC.	('EAC', 'Disease', (115, 118))	('hr-HPV', 'Gene', (103, 109))	('transcriptionally active', 'Var', (78, 102))	('EAC', 'Phenotype', 'HP:0011459', (115, 118))	('HPV', 'Species', '10566', (106, 109))
63184	32550750	Increasing hr-HPV viral load and integration status has been linked with more severe disease along the Barrett metaplasia-dysplasia-adenocarcinoma sequence.	('Increasing', 'PosReg', (0, 10))	('hr-HPV', 'Protein', (11, 17))	('HPV', 'Species', '10566', (14, 17))	('integration status', 'Var', (33, 51))	('Barrett metaplasia-dysplasia-adenocarcinoma', 'Disease', (103, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('linked', 'Reg', (61, 67))	('Barrett metaplasia-dysplasia-adenocarcinoma', 'Disease', 'MESH:D001471', (103, 146))
63186	32550750	The presence of HPV oncogene E6/7 mRNA was also observed in the BD and EAC (Figure 2).	('HPV', 'Gene', (16, 19))	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('HPV', 'Species', '10566', (16, 19))	('E6/7 mRNA', 'Var', (29, 38))
63223	32550750	Cervical LNM in oropharyngeal squamous cell carcinoma (OSCC) has been linked to regional recurrence and decreased overall survival.	('Cervical LNM', 'Var', (0, 12))	('decreased', 'NegReg', (104, 113))	('overall', 'MPA', (114, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('OSCC', 'Phenotype', 'HP:0012182', (55, 59))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 53))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (16, 53))	('squamous cell carcinoma', 'Disease', (30, 53))
63227	32550750	HPV driven HNSCCs have considerably superior prognosis and superior chemo- and radio-sensitivity than the typical non-HPV related HNSCC.	('HNSCCs', 'Disease', (11, 17))	('superior', 'PosReg', (36, 44))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Var', (0, 3))	('HPV', 'Species', '10566', (118, 121))	('superior', 'PosReg', (59, 67))
63228	32550750	Normally, HNSCC is keratinizing and is usually caused by genetic alterations; whereas, HPV-associated HNSCC is non-keratinizing and is triggered by inactivation of tumor suppressor genes (e.g.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('alterations', 'Var', (65, 76))	('tumor', 'Disease', (164, 169))	('HNSCC', 'Disease', (10, 15))	('HPV', 'Species', '10566', (87, 90))	('HNSCC', 'Disease', (102, 107))	('inactivation', 'Var', (148, 160))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('triggered by', 'Reg', (135, 147))	('caused', 'Reg', (47, 53))
63234	32550750	Cancer free lymph nodes with high viral load could indicate occult metastasis.	('Cancer', 'Disease', (0, 6))	('high viral load', 'Var', (29, 44))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
63243	32550750	These studies found that EBV positive gastric cancer was negatively associated with lymph node metastasis, resulting in better prognosis.	('gastric cancer', 'Phenotype', 'HP:0012126', (38, 52))	('better', 'PosReg', (120, 126))	('lymph node metastasis', 'CPA', (84, 105))	('EBV positive', 'Var', (25, 37))	('gastric cancer', 'Disease', (38, 52))	('negatively', 'NegReg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (38, 52))	('EBV', 'Species', '10376', (25, 28))
63253	32550750	Studies have demonstrated an association of transcriptionally active HPV with esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('esophageal adenocarcinoma', 'Disease', (78, 103))	('HPV', 'Species', '10566', (69, 72))	('HPV', 'Gene', (69, 72))	('transcriptionally active', 'Var', (44, 68))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (78, 103))	('association', 'Interaction', (29, 40))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (78, 103))
63254	32550750	Through this review, we propose that HPV detection should be undertaken in LNM of EAC tissue samples which test positive for HPV infection in the primary tumor, using PCR, DNA ISH, RT-PCR, E6-E7 mRNA ISH and p16INK4A.	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('E6-E7 mRNA', 'Var', (189, 199))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('p16INK4A', 'Gene', '1029', (208, 216))	('HPV infection', 'Disease', 'MESH:D030361', (125, 138))	('HPV', 'Species', '10566', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('p16INK4A', 'Gene', (208, 216))	('HPV infection', 'Disease', (125, 138))	('HPV', 'Species', '10566', (37, 40))	('tumor', 'Disease', (154, 159))
63263	32308431	In both xenograft models, STA-9090 substantially inhibited the growth of MYC-positive ESCC tumors in vivo.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('STA-9090', 'Var', (26, 34))	('ESCC tumors', 'Disease', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('growth', 'MPA', (63, 69))	('ESCC tumors', 'Disease', 'MESH:D004938', (86, 97))	('inhibited', 'NegReg', (49, 58))
63264	32308431	In contrast, STA-9090 treatment demonstrated no beneficial effects in mice with low-MYC expressing ESCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ESCC tumors', 'Disease', 'MESH:D004938', (99, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('mice', 'Species', '10090', (70, 74))	('low-MYC', 'Var', (80, 87))	('ESCC tumors', 'Disease', (99, 110))
63277	32308431	Inhibition of HSP90 leads to the degradation of client proteins and induces cell cycle arrest or apoptosis.	('induces', 'Reg', (68, 75))	('degradation of client proteins', 'MPA', (33, 63))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('arrest', 'Disease', 'MESH:D006323', (87, 93))	('HSP90', 'Protein', (14, 19))	('arrest', 'Disease', (87, 93))	('Inhibition', 'Var', (0, 10))	('apoptosis', 'CPA', (97, 106))
63337	32308431	We found that STA-9090 treatment significantly induced p21 and p15 mRNA expression in STA-9090 sensitive cells KYSE-150 and Eca-109 (Figure 2E), while TE-1 cells exhibited decreased expression levels.	('induced', 'PosReg', (47, 54))	('p21', 'Gene', (55, 58))	('TE-1', 'CellLine', 'CVCL:1759', (151, 155))	('p15', 'Gene', (63, 66))	('p15', 'Gene', '1030', (63, 66))	('STA-9090', 'Var', (86, 94))	('KYSE', 'Chemical', '-', (111, 115))	('p21', 'Gene', '1026', (55, 58))
63338	32308431	Our results showed that STA-9090 inhibited tumor cell proliferation, ultimately causing cell cycle arrest in ESCC cells.	('inhibited', 'NegReg', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (88, 105))	('STA-9090', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('causing', 'Reg', (80, 87))	('arrest', 'Disease', 'MESH:D006323', (99, 105))	('tumor', 'Disease', (43, 48))	('arrest', 'Disease', (99, 105))
63341	32308431	We tested the treatment outcome of STA-9090 by intraperitoneal injection of vehicle control or STA-9090 (25 mg/kg) every three days for 21 days, a relevant dose in human cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('human', 'Species', '9606', (164, 169))	('tested', 'Reg', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('STA-9090', 'Var', (95, 103))
63352	32308431	Treatments were initiated when tumor volume reached 5 mm and STA-9090 strongly inhibited tumor growth (Figure 6D).	('STA-9090', 'Var', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('inhibited', 'NegReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
63364	32308431	As reported, STA-9090 inhibited cell growth by inducing cell cycle arrest in some cancers, including thyroid cancer, gastric cancer and ovarian cancer.	('STA-9090', 'Var', (13, 21))	('inhibited', 'NegReg', (22, 31))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('thyroid cancer', 'Disease', (101, 115))	('cancers', 'Disease', (82, 89))	('gastric cancer', 'Disease', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ovarian cancer', 'Disease', 'MESH:D010051', (136, 150))	('cell growth', 'CPA', (32, 43))	('thyroid cancer', 'Disease', 'MESH:D013964', (101, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('arrest', 'Disease', (67, 73))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('thyroid cancer', 'Phenotype', 'HP:0002890', (101, 115))	('ovarian cancer', 'Disease', (136, 150))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('inducing', 'NegReg', (47, 55))
63366	32308431	Importantly, cell cycle analysis revealed that STA-9090 induces G0/G1 phase arrest in ESCC cells.	('arrest', 'Disease', 'MESH:D006323', (76, 82))	('STA-9090', 'Var', (47, 55))	('arrest', 'Disease', (76, 82))
63367	32308431	The fact that, in our experiments, inhibition of ESCC cell proliferation after treatment with STA-9090 was achieved through G0/G1 cell cycle arrest, is consistent with previously reported results in melanoma.	('arrest', 'Disease', 'MESH:D006323', (141, 147))	('inhibition', 'NegReg', (35, 45))	('arrest', 'Disease', (141, 147))	('STA-9090', 'Var', (94, 102))	('ESCC cell proliferation', 'CPA', (49, 72))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (130, 147))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('melanoma', 'Disease', (199, 207))
63368	32308431	We also found that in addition to cell cycle arrest, STA-9090 induced significant apoptosis in MYC-overexpressed ESCC cells, including increased BAX expression and reduced BCL-2 expression.	('BAX expression', 'MPA', (145, 159))	('arrest', 'Disease', (45, 51))	('BCL-2 expression', 'MPA', (172, 188))	('increased', 'PosReg', (135, 144))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (34, 51))	('reduced', 'NegReg', (164, 171))	('STA-9090', 'Var', (53, 61))	('arrest', 'Disease', 'MESH:D006323', (45, 51))
63369	32308431	An important finding of our study was that STA-9090 showed very strong in vivo antitumor activity against ESCC in both ESCC xenograft mice and human ESCC PDX models (p<0.01, p=0.0017 in KYSE-150 induced tumors, and p=0.0045 in PDX model), indicating its potential therapeutic application in the treatment of ESCC.	('STA-9090', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('human', 'Species', '9606', (143, 148))	('mice', 'Species', '10090', (134, 138))	('tumors', 'Disease', (203, 209))	('tumor', 'Disease', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('ESCC', 'Disease', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('KYSE', 'Chemical', '-', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
63380	32308431	In summary, our study provides data to support that inhibited/reduced expression of MYC in ESCC cells suppresses proliferation and promotes ESCC apoptosis/cell death in vivo and in vitro.	('inhibited/reduced', 'NegReg', (52, 69))	('death', 'Disease', 'MESH:D003643', (160, 165))	('death', 'Disease', (160, 165))	('inhibited/reduced', 'Var', (52, 69))	('ESCC', 'Disease', (140, 144))	('apoptosis/cell', 'CPA', (145, 159))	('suppresses', 'NegReg', (102, 112))	('expression', 'MPA', (70, 80))	('proliferation', 'CPA', (113, 126))	('MYC', 'Gene', (84, 87))	('promotes', 'PosReg', (131, 139))
63382	32308431	Although the use of other HSP90 inhibitors in cancer patients has not shown impressive clinical activity at present, it is possible that STA-9090 is an agent with high antitumor efficacy against MYC overexpressing ESCC, i.e.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('ESCC', 'Disease', (214, 218))	('STA-9090', 'Var', (137, 145))	('patients', 'Species', '9606', (53, 61))	('cancer', 'Disease', (46, 52))	('tumor', 'Disease', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('MYC', 'Disease', (195, 198))
63396	31427966	These disorders include inherited mutations in the APC gene in FAP, those related to mismatch DNA repair in Lynch syndrome, or the presence of inflammatory bowel disease.	('Lynch syndrome', 'Disease', (108, 122))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (143, 169))	('inflammatory bowel disease', 'Disease', (143, 169))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (143, 169))	('Lynch syndrome', 'Disease', 'MESH:D003123', (108, 122))	('APC', 'Disease', 'MESH:D011125', (51, 54))	('APC', 'Disease', (51, 54))	('mutations', 'Var', (34, 43))	('FAP', 'Disease', (63, 66))
63398	31427966	In addition, other factors include reduced physical activity, an unbalanced diet like those rich in saturated fats, low fiber, red and processed meat, overweight or obesity, alcohol consumption, or smoking, which have been associated with chronic low-grade inflammation (parainflammation) and increased cancer risk too.	('reduced', 'NegReg', (35, 42))	('alcohol', 'Chemical', 'MESH:D000438', (174, 181))	('inflammation', 'Disease', 'MESH:D007249', (257, 269))	('obesity', 'Disease', 'MESH:D009765', (165, 172))	('reduced physical activity', 'Phenotype', 'HP:0003546', (35, 60))	('overweight', 'Disease', (151, 161))	('inflammation', 'Disease', (275, 287))	('low fiber', 'Var', (116, 125))	('physical activity', 'CPA', (43, 60))	('cancer', 'Disease', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('overweight', 'Phenotype', 'HP:0025502', (151, 161))	('inflammation', 'Disease', (257, 269))	('obesity', 'Phenotype', 'HP:0001513', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('fats', 'Chemical', 'MESH:D005223', (110, 114))	('inflammation', 'Disease', 'MESH:D007249', (275, 287))	('obesity', 'Disease', (165, 172))	('rat', 'Species', '10116', (104, 107))
63412	31427966	Synthetic RvD supplementation has shown to improve colitis activity index and reduce body weight loss, colonic damage, PMN infiltration, colonic cytokine levels for TNF-alpha, IL-1beta, MIP-2, CXCL1/KC, and NF-kappaB phosphorylation, as well as mRNA expression of NF-kappaB and the adhesion molecules VCAM-1, ICAM-1, and LFA-1 in both models.	('MIP-2', 'Gene', (186, 191))	('weight loss', 'Disease', 'MESH:D015431', (90, 101))	('TNF-alpha', 'Gene', (165, 174))	('NF-kappaB', 'Gene', '4790', (264, 273))	('PMN infiltration', 'MPA', (119, 135))	('weight loss', 'Phenotype', 'HP:0001824', (90, 101))	('supplementation', 'Var', (14, 29))	('reduce', 'NegReg', (78, 84))	('NF-kappaB', 'Gene', (207, 216))	('weight loss', 'Disease', (90, 101))	('colonic damage', 'Disease', 'MESH:D003108', (103, 117))	('VCAM-1', 'Gene', (301, 307))	('colitis', 'Phenotype', 'HP:0002583', (51, 58))	('LFA-1', 'Gene', '3683', (321, 326))	('men', 'Species', '9606', (20, 23))	('NF-kappaB', 'Gene', '4790', (207, 216))	('colonic damage', 'Disease', (103, 117))	('ICAM-1', 'Gene', (309, 315))	('ICAM-1', 'Gene', '3383', (309, 315))	('reduce body weight', 'Phenotype', 'HP:0004325', (78, 96))	('LFA-1', 'Gene', (321, 326))	('CXCL1', 'Gene', '2919', (193, 198))	('mRNA expression', 'MPA', (245, 260))	('colitis', 'Disease', (51, 58))	('improve', 'PosReg', (43, 50))	('MIP-2', 'Gene', '2920', (186, 191))	('CXCL1', 'Gene', (193, 198))	('rat', 'Species', '10116', (129, 132))	('NF-kappaB', 'Gene', (264, 273))	('VCAM-1', 'Gene', '7412', (301, 307))	('TNF-alpha', 'Gene', '7124', (165, 174))	('colitis', 'Disease', 'MESH:D003092', (51, 58))
63413	31427966	AT-RvD1 showed greater potency than its precursor 17R-HDHA and RvD2 ( Table 1 ).	('potency', 'MPA', (23, 30))	('AT-RvD1', 'Var', (0, 7))	('DHA', 'Chemical', '-', (55, 58))
63417	31427966	Exogenous administration of synthesized PD1n-3DPA or RvD5n-3DPA reduced inflammation and improved the score of disease in the DSS model too, through a mechanism that implies regulation of neutrophil-endothelial interaction and reduction of granulocyte trafficking.	('improved', 'PosReg', (89, 97))	('rat', 'Species', '10116', (18, 21))	('PD1n-3DPA', 'Var', (40, 49))	('inflammation', 'Disease', (72, 84))	('DSS', 'Chemical', '-', (126, 129))	('score of disease', 'MPA', (102, 118))	('inflammation', 'Disease', 'MESH:D007249', (72, 84))	('RvD5n-3DPA', 'Var', (53, 63))	('granulocyte trafficking', 'CPA', (240, 263))	('RvD5n-3DPA', 'Chemical', '-', (53, 63))	('reduced', 'NegReg', (64, 71))	('PD1n-3DPA', 'Chemical', '-', (40, 49))	('reduction', 'NegReg', (227, 236))
63418	31427966	The impact of PD1n-3DPA in pro-inflammatory cytokines (TNF-alpha, IL-6, and IL-1beta) was bigger, and RvD5n-3DPA causes only a partial decrease of IL-1beta.	('IL-6', 'Gene', '3569', (66, 70))	('RvD5n-3DPA', 'Chemical', '-', (102, 112))	('RvD5n-3DPA', 'Var', (102, 112))	('PD1n-3DPA', 'Var', (14, 23))	('TNF-alpha', 'Gene', '7124', (55, 64))	('TNF-alpha', 'Gene', (55, 64))	('IL-1beta', 'MPA', (147, 155))	('PD1n-3DPA', 'Chemical', '-', (14, 23))	('IL-6', 'Gene', (66, 70))
63436	31427966	A study including 68,109 Washington residents found dependence of sex and anatomic subsite, with reduced risk by fish oil supplementation only in men and in colon cancer but not in rectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('dependence of sex', 'Phenotype', 'HP:0030214', (52, 69))	('rectal cancer', 'Disease', 'MESH:D012004', (181, 194))	('colon cancer', 'Phenotype', 'HP:0003003', (157, 169))	('rectal cancer', 'Disease', (181, 194))	('men', 'Species', '9606', (128, 131))	('men', 'Species', '9606', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colon cancer', 'Disease', 'MESH:D015179', (157, 169))	('rectal cancer', 'Phenotype', 'HP:0100743', (181, 194))	('supplementation', 'Var', (122, 137))	('colon cancer', 'Disease', (157, 169))
63438	31427966	Although controversial results have been found between PUFAs intake and risk of CRC in prospective studies evaluating fish intake, supplementation with fish oil rich in omega3-PUFAs has shown to reduce cell proliferation in rectal mucosa of patients with sporadic CR adenomas and/or to increased mucosal apoptosis.	('PUFAs', 'Chemical', 'MESH:D005231', (176, 181))	('PUFAs', 'Chemical', 'MESH:D005231', (55, 60))	('reduce', 'NegReg', (195, 201))	('mucosal apoptosis', 'CPA', (296, 313))	('adenomas', 'Disease', 'MESH:D000236', (267, 275))	('cell proliferation', 'CPA', (202, 220))	('increased', 'PosReg', (286, 295))	('adenomas', 'Disease', (267, 275))	('rat', 'Species', '10116', (214, 217))	('omega3-PUFAs', 'Chemical', 'MESH:D015525', (169, 181))	('men', 'Species', '9606', (137, 140))	('supplementation', 'Var', (131, 146))	('patients', 'Species', '9606', (241, 249))
63442	31427966	Finally, beneficial effects of EPA supplementation have also been found in patients undergoing liver resection for CRC liver metastases, showing reduced vascularity and increased overall survival during the first 18 months after resection, although without changes in recurrence rate ( Figure 1 ).	('vascularity', 'MPA', (153, 164))	('overall survival', 'CPA', (179, 195))	('reduced', 'NegReg', (145, 152))	('increased', 'PosReg', (169, 178))	('EPA', 'Chemical', 'MESH:D015118', (31, 34))	('patients', 'Species', '9606', (75, 83))	('CRC liver metastases', 'Disease', (115, 135))	('CRC liver metastases', 'Disease', 'MESH:D009362', (115, 135))	('supplementation', 'Var', (35, 50))	('men', 'Species', '9606', (41, 44))	('rat', 'Species', '10116', (279, 282))
63589	30885279	Although station 14v is not within the routine scope of D2 lymphadenectomy in the 3rd edition of the Japanese Gastric Cancer Treatment Guidelines, it has been observed that D2+ station 14v lymph node dissection may improve overall survival (OS) in clinically staged III/IV patients with middle- and lower-third gastric cancer.	('OS', 'Gene', '17451', (241, 243))	('Gastric Cancer', 'Disease', (110, 124))	('improve', 'PosReg', (215, 222))	('patients', 'Species', '9606', (273, 281))	('Gastric Cancer', 'Disease', 'MESH:D013274', (110, 124))	('Cancer', 'Phenotype', 'HP:0002664', (118, 124))	('D2+ station 14v', 'Var', (173, 188))	('gastric cancer', 'Disease', (311, 325))	('gastric cancer', 'Disease', 'MESH:D013274', (311, 325))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('III/IV', 'Disease', (266, 272))	('gastric cancer', 'Phenotype', 'HP:0012126', (311, 325))	('overall survival', 'MPA', (223, 239))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (110, 124))
63610	30885279	Adjuvant chemotherapy may reduce the risk of metastasis in the following groups of patients: high-risk T2N0 patients, younger age (< 40 years old), high histological grade or poorly differentiated lesions, and those with nervous, vascular, or lymphatic invasion.	('metastasis', 'CPA', (45, 55))	('reduce', 'NegReg', (26, 32))	('patients', 'Species', '9606', (83, 91))	('vascular', 'CPA', (230, 238))	('high histological', 'Var', (148, 165))	('nervous', 'CPA', (221, 228))	('T2N0', 'Gene', (103, 107))	('patients', 'Species', '9606', (108, 116))	('lymphatic invasion', 'CPA', (243, 261))	('poorly differentiated lesions', 'CPA', (175, 204))
63617	30885279	The present recommendations for preoperative chemotherapy include epirubicin + cisplatin + 5-FU (ECF), cisplatin + 5-FU (PF), modified ECF (mECF), oxaliplatin + capecitabine (XELOX), oxaliplatin + 5-FU (FOLFOX), and oxaliplatin + S-1 (SOX).	('capecitabine', 'Chemical', 'MESH:D000069287', (161, 173))	('5-FU', 'Chemical', 'MESH:D005472', (91, 95))	('S-1', 'Gene', '5707', (230, 233))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (216, 227))	('PF', 'Chemical', 'MESH:C002997', (121, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (183, 194))	('modified', 'Var', (126, 134))	('S-1', 'Gene', (230, 233))	('mECF', 'Chemical', '-', (140, 144))	('XELOX', 'Chemical', '-', (175, 180))	('5-FU', 'Chemical', 'MESH:D005472', (115, 119))	('5-FU', 'Chemical', 'MESH:D005472', (197, 201))	('epirubicin', 'Chemical', 'MESH:D015251', (66, 76))	('FOLFOX', 'Chemical', '-', (203, 209))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (147, 158))
63664	30885279	In addition, the stomach is an important digestive organ where the primary lesion may directly affect the nutritional status, leading to complications such as bleeding, digestive tract obstruction, and/or perforation.	('digestive tract obstruction', 'Disease', (169, 196))	('nutritional status', 'MPA', (106, 124))	('digestive tract obstruction', 'Phenotype', 'HP:0004796', (169, 196))	('leading to', 'Reg', (126, 136))	('affect', 'Reg', (95, 101))	('bleeding', 'Disease', 'MESH:D006470', (159, 167))	('perforation', 'Disease', (205, 216))	('bleeding', 'Disease', (159, 167))	('lesion', 'Var', (75, 81))
63700	30885279	A phase III clinical study which enrolled 273 patients who had treatment failure after using second-line/subsequent-lines chemotherapeutic regimens showed that apatinib, compared with the placebo, could prolong the median progression-free survival (mPFS) (2.6 vs. 1.8 months, P < 0.001) and increase the disease control rate (42.05% vs. 8.79%, P < 0.001).	('prolong', 'PosReg', (203, 210))	('patients', 'Species', '9606', (46, 54))	('apatinib', 'Var', (160, 168))	('apatinib', 'Chemical', 'MESH:C553458', (160, 168))	('PF', 'Chemical', 'MESH:C002997', (250, 252))	('progression-free survival', 'CPA', (222, 247))	('increase', 'PosReg', (291, 299))	('disease control', 'CPA', (304, 319))
63722	30885279	Both the results of retrospective studies and meta-analysis have shown that the survival of patients undergoing liver surgery was longer than those patients not receiving liver surgery (mOS: 22-26 months vs. 3-7 months, respectively, P < 0.001).	('patients', 'Species', '9606', (148, 156))	('longer', 'PosReg', (130, 136))	('liver surgery', 'Var', (112, 125))	('patients', 'Species', '9606', (92, 100))	('mOS', 'Gene', (186, 189))	('mOS', 'Gene', '17451', (186, 189))	('survival', 'CPA', (80, 88))
63725	30885279	Retrospective studies have shown that, compared with systemic chemotherapy, RFA could significantly prolong the mOS of patients with metachronous liver metastasis (25 months vs. 12 months, P = 0.015).	('prolong', 'PosReg', (100, 107))	('mOS', 'Gene', '17451', (112, 115))	('RFA', 'Var', (76, 79))	('patients', 'Species', '9606', (119, 127))	('metachronous liver metastasis', 'Disease', 'MESH:D009362', (133, 162))	('mOS', 'Gene', (112, 115))	('metachronous liver metastasis', 'Disease', (133, 162))
63735	30885279	The results of CCOG0301 study demonstrated that CY1 patients could benefit from S-1 as adjuvant chemotherapy after radical gastrectomy, and it was further reported that their mOS could reach up to 22.3 months.	('S-1', 'Gene', (80, 83))	('mOS', 'Gene', '17451', (175, 178))	('CY1', 'Var', (48, 51))	('S-1', 'Gene', '5707', (80, 83))	('mOS', 'Gene', (175, 178))	('patients', 'Species', '9606', (52, 60))
63736	30885279	Selected P0CY1 gastric cancer patients may benefit from systemic chemotherapy in combination with surgery.	('gastric cancer', 'Disease', (15, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (15, 29))	('P0CY1', 'Var', (9, 14))	('patients', 'Species', '9606', (30, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
63737	30885279	CY1 gastric cancer patients may benefit from preoperative chemotherapy.	('CY1', 'Var', (0, 3))	('patients', 'Species', '9606', (19, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('gastric cancer', 'Disease', (4, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (4, 18))
63740	30885279	Another study has reported that CY1 patients treated with HIPEC (paclitaxel used as intraperitoneal perfusion) combined with S-1 and paclitaxel as systemic chemotherapy, providing that their exfoliative cytology changed to negative and they could undergo radical surgery, their OS was observed to increase from 14.3 (without surgery) to 30.5 months (with radical surgery).	('HIPEC', 'Chemical', '-', (58, 63))	('OS', 'Gene', '17451', (278, 280))	('S-1', 'Gene', (125, 128))	('patients', 'Species', '9606', (36, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (65, 75))	('exfoliative', 'MPA', (191, 202))	('CY1', 'Var', (32, 35))	('S-1', 'Gene', '5707', (125, 128))	('paclitaxel', 'Chemical', 'MESH:D017239', (133, 143))
63743	30885279	Overall, some highly selected gastric cancer patients with P0CY1 disease can benefit from surgery combined with intraoperative chemotherapy or systemic chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('gastric cancer', 'Disease', 'MESH:D013274', (30, 44))	('P0CY1', 'Var', (59, 64))	('gastric cancer', 'Disease', (30, 44))	('patients', 'Species', '9606', (45, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (30, 44))
63759	30885279	A systematic review of 39 retrospective studies found that the resection of liver metastasis could significantly improve prognosis (hazard ratio [HR] = 0.50; P < 0.001), especially for those with solitary liver metastasis and in the Eastern population.	('resection', 'Var', (63, 72))	('prognosis', 'MPA', (121, 130))	('solitary liver metastasis', 'Disease', (196, 221))	('solitary liver metastasis', 'Disease', 'MESH:D009362', (196, 221))	('improve', 'PosReg', (113, 120))
63777	30885279	They are only recommended for suspected recurrence when there is no clear evidence from conventional imaging examinations (CT or ultrasound) despite a continuous elevation of blood tumor markers (e.g., CEA and CA19-9).	('CEA', 'Gene', '5670', (202, 205))	('blood tumor', 'Phenotype', 'HP:0004377', (175, 186))	('blood tumor', 'Disease', 'MESH:D009383', (175, 186))	('CA19-9', 'Var', (210, 216))	('elevation', 'PosReg', (162, 171))	('CEA', 'Gene', (202, 205))	('blood tumor', 'Disease', (175, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
63784	29863160	Therefore, conventional transhiatal esophagectomy is associated with increased recurrent laryngeal nerve injury and inadequate mediastinal lymph dissection.11, 12 For transhiatal esophagectomy to be a feasible surgery for esophageal malignancies, it should preserve an adequate surgical view of the upper mediastinum.	('esophageal malignancies', 'Disease', 'MESH:D004938', (222, 245))	('mediastinal lymph dissection', 'Phenotype', 'HP:0100721', (127, 155))	('esophageal malignancies', 'Disease', (222, 245))	('laryngeal nerve injury', 'Disease', (89, 111))	('laryngeal nerve injury', 'Disease', 'MESH:D061224', (89, 111))	('transhiatal', 'Var', (167, 178))	('esophageal malignancies', 'Phenotype', 'HP:0100751', (222, 245))
63785	29863160	Tasks of VATCMD were: (i) en bloc retrieval of lymph nodes in the following stations: upper paraesophageal (#105 nodes), left recurrent laryngeal nerve (#106recL nodes) and left tracheobronchial stations (#106tbL nodes); (ii) complete mobilization of the upper thoracic esophagus; and (iii) division of small vessels at the lateral and dorsal side of the middle esophagus.	('#105', 'Var', (108, 112))	('#106tbL nodes', 'Var', (205, 218))	('left tracheobronchial stations', 'Disease', (173, 203))	('#106recL', 'Var', (153, 161))	('left tracheobronchial stations', 'Disease', 'MESH:C566362', (173, 203))
63803	29581778	The anti-tumor effects of dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A on inducing autophagy in esophageal squamous cell carcinoma The effect and regulation of autophagy-related proteins Beclin-1 and LC3 in esophageal squamous cell carcinoma have not been fully studied.	('esophageal squamous cell carcinoma', 'Disease', (132, 166))	('mTOR', 'Gene', '2475', (36, 40))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (243, 277))	('LC3', 'Gene', (236, 239))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('autophagy', 'CPA', (119, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (254, 277))	('BEZ235', 'Var', (51, 57))	('Trichostatin A', 'Chemical', 'MESH:C012589', (92, 106))	('tumor', 'Disease', (9, 14))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (132, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('inhibitor BEZ235', 'Var', (41, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('inducing', 'PosReg', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('LC3', 'Gene', '84557', (236, 239))	('Beclin-1', 'Gene', '8678', (223, 231))	('esophageal squamous cell carcinoma', 'Disease', (243, 277))	('mTOR', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Beclin-1', 'Gene', (223, 231))	('BEZ235', 'Chemical', 'MESH:C531198', (51, 57))
63812	29581778	In Vitro co-treatment with BEZ235 and TSA showed a synergistic effect on inhibition of ESCC cell viability and induction of autophagy with the increasing expressions of Beclin-1, LC3-II and the ratio of LC3-II/LC3-I.	('LC3', 'Gene', '84557', (179, 182))	('LC3', 'Gene', '84557', (210, 213))	('LC3', 'Gene', '84557', (203, 206))	('inhibition', 'NegReg', (73, 83))	('TSA', 'Chemical', 'MESH:C012589', (38, 41))	('increasing', 'PosReg', (143, 153))	('LC3-II', 'Gene', (179, 185))	('men', 'Species', '9606', (17, 20))	('BEZ235', 'Var', (27, 33))	('LC3-II', 'Gene', '84557', (179, 185))	('induction', 'Reg', (111, 120))	('Beclin-1', 'Gene', '8678', (169, 177))	('expressions', 'MPA', (154, 165))	('LC3', 'Gene', (210, 213))	('autophagy', 'CPA', (124, 133))	('LC3', 'Gene', (203, 206))	('LC3', 'Gene', (179, 182))	('ESCC', 'Disease', (87, 91))	('Beclin-1', 'Gene', (169, 177))	('LC3-II', 'Gene', (203, 209))	('BEZ235', 'Chemical', 'MESH:C531198', (27, 33))	('LC3-II', 'Gene', '84557', (203, 209))
63814	29581778	The co-treatment of BEZ235 and TSA significantly induced autophagy and enhanced anti-tumor activities, provided a new effective therapeutic target in ESCCs.	('tumor', 'Disease', (85, 90))	('enhanced', 'PosReg', (71, 79))	('BEZ235', 'Var', (20, 26))	('BEZ235', 'Chemical', 'MESH:C531198', (20, 26))	('induced', 'PosReg', (49, 56))	('ESCCs', 'Disease', (150, 155))	('men', 'Species', '9606', (12, 15))	('TSA', 'Chemical', 'MESH:C012589', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('autophagy', 'CPA', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
63821	29581778	Both the disturbances of signal transduction pathways and the dysfunction of programmed cell death machinery have been demonstrated to be critical for cancer cells to survive and metastasis.	('disturbances', 'Var', (9, 21))	('dysfunction', 'Var', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('signal transduction pathways', 'Pathway', (25, 53))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('programmed cell death machinery', 'Pathway', (77, 108))
63833	29581778	Histone deacetylases (HDACs) plays a critical role in the regulation of gene expression and has been shown to contribute to carcinogenesis by inducing the aberrant transcription of key genes regulating important cellular functions such as cell proliferation, cell-cycle regulation and PCD.	('PCD', 'Disease', 'MESH:D007619', (285, 288))	('cell proliferation', 'CPA', (239, 257))	('inducing', 'PosReg', (142, 150))	('transcription', 'MPA', (164, 177))	('contribute', 'Reg', (110, 120))	('aberrant', 'Var', (155, 163))	('HDAC', 'Gene', (22, 26))	('cell-cycle regulation', 'CPA', (259, 280))	('HDAC', 'Gene', '9734', (22, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (124, 138))	('regulation', 'MPA', (58, 68))	('PCD', 'Disease', (285, 288))	('carcinogenesis', 'Disease', (124, 138))
63834	29581778	Inhibitors of HDACs exert anticancer activity by promoting acetylation of histones as well as by promoting acetylation of non-histone protein substrates, and represent promising potential targets for esophageal cancer treatment.	('HDAC', 'Gene', (14, 18))	('HDAC', 'Gene', '9734', (14, 18))	('men', 'Species', '9606', (223, 226))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('promoting', 'PosReg', (49, 58))	('promoting', 'PosReg', (97, 106))	('cancer', 'Disease', (211, 217))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Disease', (30, 36))	('histones', 'Protein', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('esophageal cancer', 'Disease', (200, 217))	('acetylation', 'MPA', (59, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('acetylation', 'MPA', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
63851	29581778	The antibodies against Beclin-1, LC3, p-Akt (Ser473), Akt, p-mTOR (Ser2448), mTOR, Bcl-2, p70S6K, p-p70S6K, Caspase-3, cleaved Caspase-3 and beta-actin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).	('Beclin-1', 'Gene', (23, 31))	('Akt', 'Gene', '207', (40, 43))	('LC3', 'Gene', (33, 36))	('mTOR', 'Gene', '2475', (77, 81))	('Akt', 'Gene', (54, 57))	('p70S6K', 'Gene', '6198', (100, 106))	('mTOR', 'Gene', '2475', (61, 65))	('Bcl-2', 'Gene', (83, 88))	('Akt', 'Gene', '207', (54, 57))	('Caspase-3, cleaved Caspase-3', 'Gene', '836', (108, 136))	('p70S6K', 'Gene', '6198', (90, 96))	('LC3', 'Gene', '84557', (33, 36))	('beta-actin', 'Gene', '728378', (141, 151))	('Bcl-2', 'Gene', '596', (83, 88))	('Ser2448', 'Chemical', '-', (67, 74))	('p70S6K', 'Gene', (100, 106))	('Ser2448', 'Var', (67, 74))	('Beclin-1', 'Gene', '8678', (23, 31))	('Akt', 'Gene', (40, 43))	('p70S6K', 'Gene', (90, 96))	('mTOR', 'Gene', (77, 81))	('mTOR', 'Gene', (61, 65))	('beta-actin', 'Gene', (141, 151))	('Ser473', 'Chemical', '-', (45, 51))
63888	29581778	Meanwhile, univariate survival analysis for disease-free survival (DFS) also showed similar results, patients with a high expression of Beclin-1 (54.3 % vs. 34.2%, p=0.023) or LC3 (58.6 % vs. 34.1%, p=0.014) had a better 5-year DFS rate.	('patients', 'Species', '9606', (101, 109))	('Beclin-1', 'Gene', (136, 144))	('Beclin-1', 'Gene', '8678', (136, 144))	('DFS', 'CPA', (228, 231))	('LC3', 'Gene', '84557', (176, 179))	('LC3', 'Gene', (176, 179))	('high', 'Var', (117, 121))	('better', 'PosReg', (214, 220))
63892	29581778	As shown in Figure 3, the cell viability was significantly decreased after treatment with BEZ235 or TSA in both Eca-109 and TE-1 cells, indicating that both BEZ235 and TSA had dose dependent anti-tumor effects.	('BEZ235', 'Var', (157, 163))	('TSA', 'Chemical', 'MESH:C012589', (168, 171))	('tumor', 'Disease', (196, 201))	('decreased', 'NegReg', (59, 68))	('BEZ235', 'Chemical', 'MESH:C531198', (157, 163))	('TSA', 'Chemical', 'MESH:C012589', (100, 103))	('men', 'Species', '9606', (80, 83))	('TE-1', 'CellLine', 'CVCL:1759', (124, 128))	('BEZ235', 'Chemical', 'MESH:C531198', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('cell viability', 'CPA', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
63898	29581778	The western blot results showed that BEZ235 inhibited the expression of p-mTOR, p-AKT and p-p70S6K in Eca-109 cells (P<0.05).	('p70S6K', 'Gene', '6198', (92, 98))	('p70S6K', 'Gene', (92, 98))	('expression', 'MPA', (58, 68))	('inhibited', 'NegReg', (44, 53))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('AKT', 'Gene', '207', (82, 85))	('BEZ235', 'Var', (37, 43))	('AKT', 'Gene', (82, 85))	('BEZ235', 'Chemical', 'MESH:C531198', (37, 43))
63902	29581778	After the combination with BEZ235 and TSA, it significantly inhibited the phosphorylation of mTOR, AKT and p70S6K in both Eca-109 and TE-1 cells relative to single drug.	('phosphorylation', 'MPA', (74, 89))	('BEZ235', 'Var', (27, 33))	('mTOR', 'Gene', (93, 97))	('TE-1', 'CellLine', 'CVCL:1759', (134, 138))	('mTOR', 'Gene', '2475', (93, 97))	('AKT', 'Gene', '207', (99, 102))	('BEZ235', 'Chemical', 'MESH:C531198', (27, 33))	('TSA', 'Chemical', 'MESH:C012589', (38, 41))	('inhibited', 'NegReg', (60, 69))	('p70S6K', 'Gene', (107, 113))	('AKT', 'Gene', (99, 102))	('p70S6K', 'Gene', '6198', (107, 113))	('combination', 'Interaction', (10, 21))
63907	29581778	These results suggested that co-treatment with BEZ235 and TSA synergistically induced apoptosis through both the mitochondrial pathway and the caspase-dependent pathway for cell death in ESCC cells.	('BEZ235', 'Chemical', 'MESH:C531198', (47, 53))	('caspase-dependent pathway', 'Pathway', (143, 168))	('TSA', 'Chemical', 'MESH:C012589', (58, 61))	('induced', 'Reg', (78, 85))	('men', 'Species', '9606', (37, 40))	('mitochondrial pathway', 'Pathway', (113, 134))	('BEZ235', 'Var', (47, 53))	('apoptosis', 'CPA', (86, 95))
63908	29581778	Compared with treatment with either drug alone, the apoptotic relative proteins LC3-I, LC3-II and Beclin-1 were detected and immunoblotting analysis found co-treatment with BEZ235 and TSA significantly increased the expression of both LC3-II and Beclin-1 in ESCC cells, but the effect on the expression of LC3-I was no obvious (Figure 6).	('Beclin-1', 'Gene', (246, 254))	('LC3', 'Gene', '84557', (306, 309))	('LC3', 'Gene', (87, 90))	('LC3', 'Gene', (80, 83))	('LC3-II', 'Gene', '84557', (235, 241))	('men', 'Species', '9606', (19, 22))	('Beclin-1', 'Gene', '8678', (98, 106))	('expression', 'MPA', (216, 226))	('BEZ235', 'Chemical', 'MESH:C531198', (173, 179))	('LC3', 'Gene', (235, 238))	('increased', 'PosReg', (202, 211))	('Beclin-1', 'Gene', (98, 106))	('LC3', 'Gene', '84557', (87, 90))	('LC3', 'Gene', '84557', (80, 83))	('LC3', 'Gene', (306, 309))	('LC3-II', 'Gene', (87, 93))	('TSA', 'Chemical', 'MESH:C012589', (184, 187))	('men', 'Species', '9606', (163, 166))	('Beclin-1', 'Gene', '8678', (246, 254))	('LC3-II', 'Gene', '84557', (87, 93))	('BEZ235', 'Var', (173, 179))	('LC3', 'Gene', '84557', (235, 238))	('LC3-II', 'Gene', (235, 241))
63910	29581778	Our finding indicated that co-treatment with BEZ235 and TSA exhibited anti-cancer effects through not only autophagy but also apoptosis pathways in ESCC cells.	('men', 'Species', '9606', (35, 38))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('autophagy', 'CPA', (107, 116))	('BEZ235', 'Var', (45, 51))	('cancer', 'Disease', (75, 81))	('BEZ235', 'Chemical', 'MESH:C531198', (45, 51))	('TSA', 'Chemical', 'MESH:C012589', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ESCC', 'Disease', (148, 152))	('apoptosis pathways', 'CPA', (126, 144))
63912	29581778	Abnormal regulation of PCD is associated with a wide variety of human diseases, including cancer.	('associated', 'Reg', (30, 40))	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PCD', 'Disease', (23, 26))	('PCD', 'Disease', 'MESH:D007619', (23, 26))	('Abnormal', 'Var', (0, 8))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
63922	29581778	Yang et al found the high expression of Beclin-1 in colorectal cancer and was correlated with histological grade and clinical stage and patients with a high Beclin-1 expression had a better OS and DFS.	('expression', 'MPA', (26, 36))	('Beclin-1', 'Gene', '8678', (40, 48))	('high', 'Var', (152, 156))	('OS', 'Chemical', 'MESH:D009992', (190, 192))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('better', 'PosReg', (183, 189))	('Beclin-1', 'Gene', (157, 165))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('Beclin-1', 'Gene', '8678', (157, 165))	('patients', 'Species', '9606', (136, 144))	('correlated', 'Reg', (78, 88))	('DFS', 'CPA', (197, 200))	('colorectal cancer', 'Disease', (52, 69))	('expression', 'MPA', (166, 176))	('Beclin-1', 'Gene', (40, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
63929	29581778	Patients with a high expression of Beclin-1 or LC3 had a better OS or DFS.	('high expression', 'Var', (16, 31))	('LC3', 'Gene', '84557', (47, 50))	('LC3', 'Gene', (47, 50))	('DFS', 'CPA', (70, 73))	('Beclin-1', 'Gene', (35, 43))	('Patients', 'Species', '9606', (0, 8))	('Beclin-1', 'Gene', '8678', (35, 43))	('better', 'PosReg', (57, 63))	('OS', 'Chemical', 'MESH:D009992', (64, 66))
63932	29581778	The PI3K/mTOR pathway dysregulation has been found in various tumors and plays a crucial role in regulation of cell proliferation, apoptosis and autophagy.	('dysregulation', 'Var', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('mTOR', 'Gene', (9, 13))	('autophagy', 'CPA', (145, 154))	('mTOR', 'Gene', '2475', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cell proliferation', 'CPA', (111, 129))	('apoptosis', 'CPA', (131, 140))
63935	29581778	Our study found BEZ235, the dual inhibitor of mTOR and PI3K can reduce viability of ESCC cells in a dose-dependent manner caused by the significant reduction in p-Akt, p-mTOR and p-p70S6K activity on Eca-109 and TE-1 cells.	('TE-1', 'CellLine', 'CVCL:1759', (212, 216))	('reduction', 'NegReg', (148, 157))	('Akt', 'Gene', (163, 166))	('reduce', 'NegReg', (64, 70))	('mTOR', 'Gene', '2475', (46, 50))	('mTOR', 'Gene', (170, 174))	('BEZ235', 'Chemical', 'MESH:C531198', (16, 22))	('BEZ235', 'Var', (16, 22))	('mTOR', 'Gene', (46, 50))	('PI3K', 'Var', (55, 59))	('p70S6K', 'Gene', (181, 187))	('mTOR', 'Gene', '2475', (170, 174))	('activity', 'MPA', (188, 196))	('p70S6K', 'Gene', '6198', (181, 187))	('viability', 'CPA', (71, 80))	('Akt', 'Gene', '207', (163, 166))
63936	29581778	After BEZ235 intervention, the autophagy or apoptosis-related proteins beclin-1, LC3-II, ratio of LC3-II/LC3-I and cleaved caspase-3 were increased as well as caspase-3 and BCL-2 decreased.	('BEZ235', 'Var', (6, 12))	('caspase-3', 'Gene', '836', (159, 168))	('LC3', 'Gene', '84557', (105, 108))	('ratio of', 'MPA', (89, 97))	('LC3', 'Gene', '84557', (81, 84))	('LC3', 'Gene', '84557', (98, 101))	('LC3-II', 'Gene', (81, 87))	('increased', 'PosReg', (138, 147))	('caspase-3', 'Gene', (159, 168))	('autophagy', 'CPA', (31, 40))	('LC3-II', 'Gene', (98, 104))	('apoptosis-related', 'CPA', (44, 61))	('LC3-II', 'Gene', '84557', (81, 87))	('beclin-1', 'Gene', '8678', (71, 79))	('LC3-II', 'Gene', '84557', (98, 104))	('BEZ235', 'Chemical', 'MESH:C531198', (6, 12))	('BCL-2', 'Gene', '596', (173, 178))	('LC3', 'Gene', (105, 108))	('BCL-2', 'Gene', (173, 178))	('LC3', 'Gene', (81, 84))	('LC3', 'Gene', (98, 101))	('beclin-1', 'Gene', (71, 79))	('decreased', 'NegReg', (179, 188))	('caspase-3', 'Gene', '836', (123, 132))	('caspase-3', 'Gene', (123, 132))
63937	29581778	The study reveals that BEZ235 inhibits the PI3K/mTOR pathway and induces the autophagy and apoptosis in human esophageal cancer cells.	('mTOR', 'Gene', '2475', (48, 52))	('BEZ235', 'Chemical', 'MESH:C531198', (23, 29))	('mTOR', 'Gene', (48, 52))	('apoptosis', 'CPA', (91, 100))	('induces', 'PosReg', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (104, 109))	('esophageal cancer', 'Disease', (110, 127))	('autophagy', 'CPA', (77, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('BEZ235', 'Var', (23, 29))	('inhibits', 'NegReg', (30, 38))
63938	29581778	Epigenetic mechanisms, such as modifications of DNA-structure or histone modification play particularly important roles in controlling PCD, such as autophagy, apoptosis and necroptosis in tumor cells.	('tumor', 'Disease', (188, 193))	('DNA-structure', 'Protein', (48, 61))	('PCD', 'Disease', (135, 138))	('modifications', 'Var', (31, 44))	('autophagy', 'CPA', (148, 157))	('PCD', 'Disease', 'MESH:D007619', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('necroptosis', 'CPA', (173, 184))	('histone', 'Protein', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('apoptosis', 'CPA', (159, 168))
63940	29581778	HDAC inhibitors cause changes in the acetylation status of chromatin and other non-histone proteins, resulting in changes in gene expression, induction of apoptosis and inhibition of angiogenesis and metastasis.	('HDAC', 'Gene', (0, 4))	('inhibition', 'NegReg', (169, 179))	('changes', 'Reg', (22, 29))	('HDAC', 'Gene', '9734', (0, 4))	('inhibitors', 'Var', (5, 15))	('induction', 'Reg', (142, 151))	('acetylation status', 'MPA', (37, 55))	('gene expression', 'MPA', (125, 140))	('apoptosis', 'CPA', (155, 164))	('changes', 'Reg', (114, 121))
63943	29581778	Chen et al found co-treatment with BEZ235 and TSA enhanced autophagic cell death and blocked tumor growth without noticeable side effects in breast cancer.	('autophagic cell death', 'CPA', (59, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('BEZ235', 'Var', (35, 41))	('tumor', 'Disease', (93, 98))	('blocked', 'NegReg', (85, 92))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('BEZ235', 'Chemical', 'MESH:C531198', (35, 41))	('breast cancer', 'Disease', (141, 154))	('enhanced', 'PosReg', (50, 58))	('TSA', 'Chemical', 'MESH:C012589', (46, 49))	('men', 'Species', '9606', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
63947	29581778	Our recently study found co-treatment with BEZ235 and TSA could inhibit the growth and visibility in human esophageal cancer Eca-109 and TE-1 cells and enhanced autophagic cell death by up-regulating the expression of LC3-II and Beclin-1.	('up-regulating', 'PosReg', (186, 199))	('TE-1', 'CellLine', 'CVCL:1759', (137, 141))	('inhibit', 'NegReg', (64, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('LC3-II', 'Gene', '84557', (218, 224))	('enhanced', 'PosReg', (152, 160))	('BEZ235', 'Var', (43, 49))	('esophageal cancer', 'Disease', (107, 124))	('men', 'Species', '9606', (33, 36))	('autophagic cell death', 'CPA', (161, 182))	('Beclin-1', 'Gene', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('human', 'Species', '9606', (101, 106))	('expression', 'MPA', (204, 214))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))	('Beclin-1', 'Gene', '8678', (229, 237))	('growth', 'CPA', (76, 82))	('LC3-II', 'Gene', (218, 224))	('TSA', 'Chemical', 'MESH:C012589', (54, 57))
63948	29581778	Meanwhile, co-treatment with BEZ235 and TSA can increase the expression of cleaved caspase-3 and decrease the expression of caspase-3 and BCL-2.	('caspase-3', 'Gene', (124, 133))	('caspase-3', 'Gene', '836', (83, 92))	('BCL-2', 'Gene', '596', (138, 143))	('TSA', 'Chemical', 'MESH:C012589', (40, 43))	('BEZ235', 'Chemical', 'MESH:C531198', (29, 35))	('BEZ235', 'Var', (29, 35))	('BCL-2', 'Gene', (138, 143))	('caspase-3', 'Gene', '836', (124, 133))	('expression', 'MPA', (110, 120))	('men', 'Species', '9606', (19, 22))	('decrease', 'NegReg', (97, 105))	('caspase-3', 'Gene', (83, 92))	('expression', 'MPA', (61, 71))	('increase', 'PosReg', (48, 56))
63955	29581778	Co-treatment with BEZ235 and TSA is more effective than single drug in inhibiting the viability of ESCC cells in Vitro through inducing apoptosis and autophagy, which can be a new effective therapeutic target in ESCCs.	('inhibiting', 'NegReg', (71, 81))	('apoptosis', 'CPA', (136, 145))	('men', 'Species', '9606', (8, 11))	('BEZ235', 'Var', (18, 24))	('viability', 'CPA', (86, 95))	('BEZ235', 'Chemical', 'MESH:C531198', (18, 24))	('autophagy', 'CPA', (150, 159))	('inducing', 'NegReg', (127, 135))	('TSA', 'Chemical', 'MESH:C012589', (29, 32))
63959	27756887	In colorectal cancers, a splicing variant of FIR that lacks exon2 (FIRDeltaexon2) is overexpressed as a dominant negative form of FIR.	('lacks', 'NegReg', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('colorectal cancers', 'Disease', 'MESH:D015179', (3, 21))	('exon2', 'MPA', (60, 65))	('FIR', 'Gene', (45, 48))	('FIR', 'Gene', '22827', (45, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('splicing variant', 'Var', (25, 41))	('FIR', 'Gene', (67, 70))	('FIR', 'Gene', '22827', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancers', 'Disease', (3, 21))	('overexpressed', 'PosReg', (85, 98))	('FIR', 'Gene', (130, 133))	('FIR', 'Gene', '22827', (130, 133))
63964	27756887	Furthermore, the area under the curve of receiver operating characteristic for anti-FIRs antibodies was significantly larger (0.85) than that for anti-p53 antibodies or CA19-9.	('antibodies', 'Var', (89, 99))	('FIR', 'Gene', (84, 87))	('FIR', 'Gene', '22827', (84, 87))	('p53', 'Gene', (151, 154))	('p53', 'Gene', '7157', (151, 154))
63967	27756887	On the contrary, the far-upstream element (FUSE)-binding protein-interacting repressor (FIR), splicing variant of PUF60 lacking exon5, have been reported to be overexpressed in various malignant tumors, such as colorectal cancers, hepatocellular carcinomas, T-cell acute lymphoblastic leukemia,and non-small cell lung cancer.	('leukemia', 'Phenotype', 'HP:0001909', (285, 293))	('colorectal cancer', 'Phenotype', 'HP:0003003', (211, 228))	('FUSE', 'Gene', (43, 47))	('FUSE', 'Gene', '2522', (43, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (313, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('non-small cell lung cancer', 'Disease', (298, 324))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (231, 256))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (231, 256))	('carcinomas', 'Phenotype', 'HP:0030731', (246, 256))	('overexpressed', 'PosReg', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('malignant tumors', 'Disease', 'MESH:D018198', (185, 201))	('hepatocellular carcinomas', 'Disease', (231, 256))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (258, 293))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (302, 324))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (298, 324))	('PUF60', 'Gene', '22827', (114, 119))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (265, 293))	('colorectal cancers', 'Disease', (211, 229))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (231, 255))	('malignant tumors', 'Disease', (185, 201))	('FIR', 'Gene', (88, 91))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (258, 293))	('PUF60', 'Gene', (114, 119))	('T-cell acute lymphoblastic leukemia', 'Disease', (258, 293))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (298, 324))	('splicing variant', 'Var', (94, 110))	('FIR', 'Gene', '22827', (88, 91))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (271, 293))	('colorectal cancers', 'Disease', 'MESH:D015179', (211, 229))
63992	27756887	The sensitivity of anti-FIRDeltaexon2 antibodies was significantly higher than that of controls in colorectal (p < 0.0001) and esophageal cancer patients (p < 0.0027) (Figure 2D) detected by purified FIRDeltaexon2 proteins (Supplementary Figure S3).	('patients', 'Species', '9606', (145, 153))	('FIR', 'Gene', (24, 27))	('higher', 'PosReg', (67, 73))	('esophageal cancer', 'Disease', (127, 144))	('colorectal', 'Disease', 'MESH:D015179', (99, 109))	('FIR', 'Gene', '22827', (24, 27))	('sensitivity', 'MPA', (4, 15))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('antibodies', 'Var', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('FIR', 'Gene', (200, 203))	('FIR', 'Gene', '22827', (200, 203))	('colorectal', 'Disease', (99, 109))
64027	27756887	The detection rates of colon cancer by anti-FIRs antibodies were almost the same rate as reported in meningioma cases by detecting the splicing variant of MGEA6/11 (41.7%).	('colon cancer', 'Phenotype', 'HP:0003003', (23, 35))	('MGEA6/11', 'Gene', (155, 163))	('meningioma', 'Phenotype', 'HP:0002858', (101, 111))	('colon cancer', 'Disease', 'MESH:D015179', (23, 35))	('colon cancer', 'Disease', (23, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('meningioma', 'Disease', 'MESH:D008577', (101, 111))	('MGEA6/11', 'Gene', '4253', (155, 163))	('FIR', 'Gene', (44, 47))	('FIR', 'Gene', '22827', (44, 47))	('splicing variant', 'Var', (135, 151))	('detecting', 'Reg', (121, 130))	('meningioma', 'Disease', (101, 111))
64090	27556090	Most endoscopic examinations were carried out using a magnifying endoscope with narrow-band imaging (NBI) (GIF-Q240Z or GIF-H260Z; Olympus Optical Co Ltd, Tokyo, Japan) fitted with a soft black hood attachment (MB-162 for GIF-Q240Z, or MB-46 for GIF-H260Z; Olympus) on its top.	('H260Z', 'Var', (250, 255))	('H260Z', 'SUBSTITUTION', 'None', (250, 255))	('Q240Z', 'SUBSTITUTION', 'None', (111, 116))	('Q240Z', 'Var', (226, 231))	('Q240Z', 'Var', (111, 116))	('H260Z', 'Var', (124, 129))	('H260Z', 'SUBSTITUTION', 'None', (124, 129))	('Q240Z', 'SUBSTITUTION', 'None', (226, 231))
64172	23244191	Epidermal growth factor receptor (EGFR) mutations and expression in squamous cell carcinoma of the esophagus in central Asia Esophageal squamous cell carcinoma (ESCC) shows geographic variations in incidence, with high incidences (>50/105 person-years) in central Asia, including North Eastern Iran (Golestan) and Northern India (Kashmir).	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (82, 108))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (68, 108))	('EGFR', 'Gene', (34, 38))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('Esophageal squamous cell carcinoma', 'Disease', (125, 159))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (125, 159))	('mutations', 'Var', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('person', 'Species', '9606', (239, 245))	('EGFR', 'Gene', '1956', (34, 38))	('squamous cell carcinoma of the esophagus', 'Disease', (68, 108))
64174	23244191	In this study 152 cases of histologically confirmed ESCC from Iran (Tehran and Golestan Province) and North India (Kashmir Valley) have been analyzed for EGFR mutation by direct sequencing of exons 18-21.	('EGFR', 'Gene', (154, 158))	('EGFR', 'Gene', '1956', (154, 158))	('mutation', 'Var', (159, 167))	('ESCC', 'Disease', (52, 56))
64175	23244191	Egfr protein expression was evaluated by immunohistochemistry in 34 samples from Tehran and HER2 mutations were analyzed in 54 cases from Kashmir.	('mutations', 'Var', (97, 106))	('Egfr', 'Gene', '1956', (0, 4))	('HER2', 'Gene', '2064', (92, 96))	('HER2', 'Gene', (92, 96))	('Egfr', 'Gene', (0, 4))
64176	23244191	A total of 14 (9.2%) EGFR variations were detected, including seven variations in exons.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('variations', 'Var', (26, 36))
64179	23244191	Overall, EGFR mutations appear to be a rare event in ESCC in high incidence areas of central Asia, although a very small proportion of cases may harbor mutations predicting sensitivity to anti-Egfr drugs.	('Egfr', 'Gene', (193, 197))	('ESCC', 'Disease', (53, 57))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('Egfr', 'Gene', '1956', (193, 197))	('mutations', 'Var', (14, 23))
64187	23244191	Independent of geographic origin, molecular changes in ESCC include frequent loss of alleles at chromosomes 3p, 5q, 9p and q, 13q, 17p, 17q or 18q, mutations in tumor suppressor genes such as TP53, and genetic and/or epigenetic alterations in CDKN2a, CCDN1, MYC1 FHIT, FEZ1, DLC1, Annexin-1, CCNB1, TP63, TP73 or DCC.	('alleles', 'MPA', (85, 92))	('FHIT', 'Gene', '2272', (263, 267))	('CCNB1', 'Gene', (292, 297))	('loss', 'NegReg', (77, 81))	('tumor', 'Disease', (161, 166))	('FEZ1', 'Gene', (269, 273))	('CDKN2a', 'Gene', (243, 249))	('DCC', 'Gene', '1630', (313, 316))	('FEZ1', 'Gene', '9638', (269, 273))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('epigenetic alterations', 'Var', (217, 239))	('TP63', 'Gene', (299, 303))	('DCC', 'Gene', (313, 316))	('TP53', 'Gene', (192, 196))	('mutations', 'Var', (148, 157))	('CCNB1', 'Gene', '891', (292, 297))	('CCDN1', 'Gene', (251, 256))	('CDKN2a', 'Gene', '1029', (243, 249))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('TP73', 'Gene', '7161', (305, 309))	('ESCC', 'Disease', (55, 59))	('TP63', 'Gene', '8626', (299, 303))	('FHIT', 'Gene', (263, 267))	('DLC1', 'Gene', '10395', (275, 279))	('Annexin-1', 'Gene', (281, 290))	('Annexin-1', 'Gene', '301', (281, 290))	('DLC1', 'Gene', (275, 279))	('TP73', 'Gene', (305, 309))	('TP53', 'Gene', '7157', (192, 196))
64188	23244191	Increased expression of Epidermal Growth factor Receptor (Egfr), sometimes associated with amplification of EGFR gene, has been observed in a subset of ESCC .	('Egfr', 'Gene', (58, 62))	('Epidermal Growth factor Receptor', 'Gene', (24, 56))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('ESCC', 'Disease', (152, 156))	('Egfr', 'Gene', '1956', (58, 62))	('amplification', 'Var', (91, 104))	('expression', 'MPA', (10, 20))	('Increased', 'PosReg', (0, 9))	('Epidermal Growth factor Receptor', 'Gene', '1956', (24, 56))	('observed', 'Reg', (128, 136))
64190	23244191	Mutations in the RTK domain of EGFR activate the kinase activity by a ligand-independent mechanism.	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (31, 35))	('Mutations', 'Var', (0, 9))	('activate', 'PosReg', (36, 44))	('kinase activity', 'MPA', (49, 64))
64191	23244191	Such mutations are common in adenocarcinomas arising in never-smokers, particularly in women and in patients of Asian origin, and are associated with therapeutic sensitivity to drugs inhibiting the tyrosine kinase (TKIs) .	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('associated', 'Reg', (134, 144))	('adenocarcinomas', 'Disease', (29, 44))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (100, 108))	('women', 'Species', '9606', (87, 92))	('adenocarcinomas', 'Disease', 'MESH:D000230', (29, 44))	('inhibiting', 'NegReg', (183, 193))
64192	23244191	However, only few studies have evaluated EGFR mutations in esophageal adenocarcinoma  or ESCC .	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (59, 84))	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('ESCC', 'Disease', (89, 93))	('esophageal adenocarcinoma', 'Disease', (59, 84))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (59, 84))	('EGFR', 'Gene', '1956', (41, 45))
64193	23244191	Overall, these reports have identified only rare mutations, with the exception of a recent study focusing on basaloid squamous cell carcinoma subtype in Japanese patients, which reported EGFR mutations in 14% of the cases .	('patients', 'Species', '9606', (162, 170))	('basaloid squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('basaloid squamous cell carcinoma', 'Disease', (109, 141))	('EGFR', 'Gene', '1956', (187, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('basaloid squamous cell carcinoma', 'Phenotype', 'HP:0002671', (109, 141))	('squamous cell carcinoma subtype', 'Disease', 'MESH:D002294', (118, 149))	('EGFR', 'Gene', (187, 191))	('basaloid squamous cell carcinoma subtype', 'Phenotype', 'HP:0002671', (109, 149))	('squamous cell carcinoma subtype', 'Disease', (118, 149))	('mutations', 'Var', (192, 201))
64194	23244191	Here we have analyzed EGFR mutations in EGFR TK domain (exons 18 to 21) in a total number of 152 ESCC from Iran and India (Kashmir), two areas of the "Asian Esophageal Cancer Belt" where smoking and alcohol drinking are not significant risk factors at population level.	('mutations', 'Var', (27, 36))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (157, 174))	('Esophageal Cancer', 'Disease', (157, 174))	('alcohol', 'Chemical', 'MESH:D000438', (199, 206))	('alcohol drinking', 'Phenotype', 'HP:0030955', (199, 215))	('EGFR', 'Gene', '1956', (40, 44))	('Cancer', 'Phenotype', 'HP:0002664', (168, 174))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
64195	23244191	We hypothesized that, similar to lung cancers of non-smokers, EGFR mutations might be more common in this etiological context than in ESCC occurring in the "Western" context of heavy combined tobacco and alcohol use.	('alcohol', 'Chemical', 'MESH:D000438', (204, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('EGFR', 'Gene', '1956', (62, 66))	('lung cancers', 'Disease', 'MESH:D008175', (33, 45))	('lung cancers', 'Phenotype', 'HP:0100526', (33, 45))	('tobacco', 'Species', '4097', (192, 199))	('EGFR', 'Gene', (62, 66))	('alcohol use', 'Phenotype', 'HP:0030955', (204, 215))	('mutations', 'Var', (67, 76))	('common', 'Reg', (91, 97))	('lung cancers', 'Disease', (33, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))
64199	23244191	They were all analyzed for EGFR mutations.	('EGFR', 'Gene', '1956', (27, 31))	('mutations', 'Var', (32, 41))	('analyzed', 'Reg', (14, 22))	('EGFR', 'Gene', (27, 31))
64201	23244191	Resected specimens from Tehran were analyzed for EGFR mutations and immunohistochemical detection of Egfr.	('EGFR', 'Gene', '1956', (49, 53))	('Egfr', 'Gene', (101, 105))	('men', 'Species', '9606', (14, 17))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('Egfr', 'Gene', '1956', (101, 105))
64204	23244191	This series was analyzed for EGFR and HER2 mutations.	('mutations', 'Var', (43, 52))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('HER2', 'Gene', (38, 42))	('HER2', 'Gene', '2064', (38, 42))
64218	23244191	A total of 14 (9.2%) different variations were detected, eight (5.3%) have been reported as known polymorphisms, including a common polymorphism at codon 787 (rs1050171, c.2361 G>A), occurring with a global allelic frequency of 0.417.	('rs1050171', 'Var', (159, 168))	('c.2361 G>A', 'Mutation', 'rs1050171', (170, 180))	('c.2361 G>A', 'Var', (170, 180))	('rs1050171', 'Mutation', 'rs1050171', (159, 168))
64219	23244191	Four variations (2.6%) were identical to potential or demonstrated activating mutations in EGFR TK domain already reported in other cancers, in particular NSCLC (http://www.sanger.ac.uk/genetics/CGP/cosmic/) (Table 4) and two variations (1.3%) have never been reported in any available database (a one-bp deletion in exon 20 (c.2373) and an intronic one (c.2625+68)) (Table 3).	('cancers', 'Disease', (132, 139))	('EGFR', 'Gene', (91, 95))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('NSCLC', 'Disease', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('c.2625+68', 'Var', (355, 364))	('EGFR', 'Gene', '1956', (91, 95))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('c.2373', 'Var', (326, 332))
64220	23244191	These 10 variations were not considered as potential activating EGFR mutations.	('variations', 'Var', (9, 19))	('mutations', 'Var', (69, 78))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', '1956', (64, 68))
64224	23244191	Of the four cases with potential activating EGFR mutations, two also carried a mutation in TP53 (V173G in the case from Tehran; R175H in the case from Kashmir with the G719D EGFR mutation).	('EGFR', 'Gene', (174, 178))	('TP53', 'Gene', (91, 95))	('V173G', 'Mutation', 'rs1057519747', (97, 102))	('mutations', 'Var', (49, 58))	('R175H', 'Mutation', 'rs28934578', (128, 133))	('R175H', 'Var', (128, 133))	('G719D', 'Mutation', 'rs121913428', (168, 173))	('EGFR', 'Gene', '1956', (44, 48))	('activating', 'PosReg', (33, 43))	('EGFR', 'Gene', (44, 48))	('TP53', 'Gene', '7157', (91, 95))	('G719D', 'Var', (168, 173))	('EGFR', 'Gene', '1956', (174, 178))
64225	23244191	The series from Kashmir was also analyzed for mutations in exons 19 and 20 of HER2, encoding a tyrosine kinase receptor closely related to EGFR.	('mutations in', 'Var', (46, 58))	('HER2', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (139, 143))	('HER2', 'Gene', '2064', (78, 82))	('EGFR', 'Gene', (139, 143))
64227	23244191	Among mutated cases, only the one with L730P EGFR mutation showed Egfr over-expression and was scored as 2+ (Figure 1).	('L730P', 'Mutation', 'rs771995749', (39, 44))	('L730P', 'Var', (39, 44))	('EGFR', 'Gene', (45, 49))	('Egfr', 'Gene', '1956', (66, 70))	('over-expression', 'PosReg', (71, 86))	('EGFR', 'Gene', '1956', (45, 49))	('Egfr', 'Gene', (66, 70))
64228	23244191	Mutations in EGFR have attracted attention because of their common occurrence in lung cancers of non-smokers (in particular in adenocarcinoma, women, and patients of Asian origin) and because of their significance as predictors of response to therapeutic tyrosine kinase inhibitors .	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung cancers', 'Disease', (81, 93))	('adenocarcinoma', 'Disease', (127, 141))	('lung cancers', 'Disease', 'MESH:D008175', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('patients', 'Species', '9606', (154, 162))	('lung cancers', 'Phenotype', 'HP:0100526', (81, 93))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('adenocarcinoma', 'Disease', 'MESH:D000230', (127, 141))	('women', 'Species', '9606', (143, 148))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('occurrence', 'Reg', (67, 77))
64229	23244191	In lung cancer, EGFR mutations cluster in exons 18 to 21, encoding the domain of the tyrosine kinase that contains the ATP binding pocket.	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('EGFR', 'Gene', '1956', (16, 20))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
64231	23244191	These mutations modify the geometry of the ATP binding cleft in the tyrosine kinase, resulting in a hyperactive form of the receptor.	('ATP', 'Chemical', 'MESH:D000255', (43, 46))	('hyperactive', 'PosReg', (100, 111))	('modify', 'Reg', (16, 22))	('mutations', 'Var', (6, 15))
64233	23244191	Mutations are infrequent in other cancer pathologies analyzed to date .	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))
64234	23244191	Based on the hypothesis that these mutations may preferentially occur in a context of non-tobacco dependent carcinogenesis, we investigated whether EGFR mutations could be detected in three series of ESCC from central Asia (two high incidence areas in Northern Iran (Golestan) and Northern India (Kashmir) and one low incidence area in Iran (Tehran).	('mutations', 'Var', (153, 162))	('EGFR', 'Gene', '1956', (148, 152))	('tobacco', 'Species', '4097', (90, 97))	('EGFR', 'Gene', (148, 152))
64236	23244191	Sequencing of exons 18 to 21 of EGFR in a total of 152 ESCC cases detected 14 variations (9.2%).	('Sequencing', 'Var', (0, 10))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (32, 36))	('ESCC', 'Disease', (55, 59))
64237	23244191	Comparison with COSMIC database indicates that four of these variations are known activating mutations in EGFR TK domain (2.6%), including a common deletion (p.Q746_A750del; 560 occurrences in the COSMIC database) and three less common missense mutations.	('activating', 'PosReg', (82, 92))	('p.Q746_A750del', 'Mutation', 'p.746,750delA', (158, 172))	('EGFR', 'Gene', '1956', (106, 110))	('p.Q746_A750del;', 'Var', (158, 173))	('EGFR', 'Gene', (106, 110))
64238	23244191	The other variations identified in this study are known polymorphisms except for two unknown never reported variations which is not clear whether they may activate the tyrosine kinase in the same way as well-characterized EGFR activating mutations.	('activate', 'PosReg', (155, 163))	('variations', 'Var', (10, 20))	('variations', 'Var', (108, 118))	('EGFR', 'Gene', '1956', (222, 226))	('EGFR', 'Gene', (222, 226))	('tyrosine', 'Enzyme', (168, 176))
64239	23244191	Previous studies have shown that EGFR activating mutations were rare in ESCC.	('EGFR', 'Gene', '1956', (33, 37))	('mutations', 'Var', (49, 58))	('ESCC', 'Disease', (72, 76))	('EGFR', 'Gene', (33, 37))
64240	23244191	reported three EGFR mutations, including a truncating mutation at E872 and two silent mutations at G873 and P753 .	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('E872', 'Var', (66, 70))	('P753', 'Var', (108, 112))
64241	23244191	In another series of 40 cases (15 of which with amplification of Egfr), Hanawa et al.	('Egfr', 'Gene', '1956', (65, 69))	('Egfr', 'Gene', (65, 69))	('amplification', 'Var', (48, 61))
64242	23244191	To our knowledge, the only study in which a significant proportion of cases contained EGFR mutation (14%) was focused on a rare variant form, basaloid squamous cell carcinoma, suggesting that aberrations in EGFR may be involved in this particularly aggressive form of the disease .	('basaloid squamous cell carcinoma', 'Phenotype', 'HP:0002671', (142, 174))	('mutation', 'Var', (91, 99))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', '1956', (207, 211))	('involved', 'Reg', (219, 227))	('EGFR', 'Gene', (86, 90))	('EGFR', 'Gene', (207, 211))	('basaloid squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('aberrations', 'Var', (192, 203))	('basaloid squamous cell carcinoma', 'Disease', (142, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
64243	23244191	Notably, the series analyzed here does not include basaloid forms of ESCC but comprises cases from Golestan, an area in which we have previously reported an extremely high rate of TP53 mutations (90%), suggestive of the role of diverse mutagens in esophageal carcinogenesis .	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (248, 273))	('TP53', 'Gene', '7157', (180, 184))	('TP53', 'Gene', (180, 184))	('esophageal carcinogenesis', 'Disease', (248, 273))	('mutations', 'Var', (185, 194))
64244	23244191	Thus, contrary to our hypothesis, and regardless of involvement of environmental mutagens in ESCC from Golestan, EGFR mutations in non-smoking ESCC patients appears to be a rare event which may not play a significant role in the pathogenesis of ESCC.	('patients', 'Species', '9606', (148, 156))	('ESCC', 'Disease', (245, 249))	('mutations', 'Var', (118, 127))	('EGFR', 'Gene', '1956', (113, 117))	('men', 'Species', '9606', (74, 77))	('EGFR', 'Gene', (113, 117))	('men', 'Species', '9606', (59, 62))
64245	23244191	Further studies are needed to determine such EGFR mutations tend to occur at higher frequency in specific groups of ESCC patients.	('EGFR', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('ESCC', 'Disease', (116, 120))	('patients', 'Species', '9606', (121, 129))	('EGFR', 'Gene', '1956', (45, 49))
64246	23244191	Despite infrequent mutations in EGFR, over expression of the protein, with or without gene amplification, is a relatively frequent event in ESCC .	('EGFR', 'Gene', '1956', (32, 36))	('ESCC', 'Disease', (140, 144))	('over expression', 'PosReg', (38, 53))	('mutations', 'Var', (19, 28))	('EGFR', 'Gene', (32, 36))
64249	23244191	The only case with known EGFR activating mutation expressed Egfr at moderate levels.	('EGFR', 'Gene', (25, 29))	('Egfr', 'Gene', (60, 64))	('mutation', 'Var', (41, 49))	('EGFR', 'Gene', '1956', (25, 29))	('Egfr', 'Gene', '1956', (60, 64))
64251	23244191	A phase II study of Gefinitib, an Egfr tyrosine kinase inhibitor, in second-line treatment of advanced esophageal cancer, reported that a significantly higher disease control rate (response plus stable disease) was observed in patients with ESCC histology or with high Egfr expression .	('higher', 'PosReg', (152, 158))	('Gefinitib', 'Chemical', '-', (20, 29))	('men', 'Species', '9606', (86, 89))	('Egfr', 'Gene', (269, 273))	('esophageal cancer', 'Disease', (103, 120))	('Egfr', 'Gene', '1956', (34, 38))	('expression', 'Var', (274, 284))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('Egfr', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('high', 'Var', (264, 268))	('Egfr', 'Gene', '1956', (269, 273))	('ESCC', 'Disease', (241, 245))	('patients', 'Species', '9606', (227, 235))	('disease control rate', 'CPA', (159, 179))
64255	23244191	These results suggest that further efforts should be developed to determine whether EGFR mutations occur in specific groups of ESCC patients and whether these esophageal cancer patients may benefit from Egfr-targeted therapies.	('ESCC', 'Disease', (127, 131))	('patients', 'Species', '9606', (177, 185))	('Egfr', 'Gene', '1956', (203, 207))	('esophageal cancer', 'Disease', (159, 176))	('EGFR', 'Gene', '1956', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (89, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('EGFR', 'Gene', (84, 88))	('Egfr', 'Gene', (203, 207))	('patients', 'Species', '9606', (132, 140))
64273	21105043	Iodine deficiency can give rise to multiple health problems, including developmental delays and goiter.	('Iodine', 'Chemical', 'MESH:D007455', (0, 6))	('developmental delays', 'Phenotype', 'HP:0001263', (71, 91))	('developmental delays', 'Disease', 'MESH:D002658', (71, 91))	('deficiency can give rise', 'Disease', 'MESH:D009798', (7, 31))	('Iodine', 'Var', (0, 6))	('goiter', 'Phenotype', 'HP:0000853', (96, 102))	('goiter', 'Disease', 'MESH:D006042', (96, 102))	('developmental delays', 'Disease', (71, 91))	('goiter', 'Disease', (96, 102))	('deficiency can give rise', 'Disease', (7, 31))
64306	21105043	Consistent with previous studies of UGI cancers in Linxian, age (years), history of smoking (yes or no), alcohol consumption (yes or no in the past 12 months), H pylori seropositivity, and the PGI/II ratio (>4, yes or no) were considered as potential confounders.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('alcohol', 'Chemical', 'MESH:D000438', (105, 112))	('UGI cancers', 'Disease', 'MESH:D009369', (36, 47))	('UGI cancers', 'Disease', (36, 47))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (162, 183))	('H pylori', 'Species', '210', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('PGI/II', 'Chemical', '-', (193, 199))	('seropositivity', 'Var', (169, 183))
64343	21105043	Also, drinking water contaminants such as nitrates and polycyclic aromatic hydrocarbons are known to be goitrogenic and may be associated with UGI cancers.	('goitrogenic', 'Disease', 'None', (104, 115))	('nitrates', 'Var', (42, 50))	('associated', 'Reg', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('polycyclic aromatic hydrocarbons', 'Var', (55, 87))	('goitrogenic', 'Disease', (104, 115))	('nitrates', 'Chemical', 'MESH:D009566', (42, 50))	('UGI cancers', 'Disease', 'MESH:D009369', (143, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (55, 87))	('UGI cancers', 'Disease', (143, 154))	('water', 'Chemical', 'MESH:D014867', (15, 20))
64359	33339860	The development and progression of CRC are triggered in a stepwise-manner by many genetic mutations in cancer cells as well as host-tumor interactions within the tumor microenvironment (TME).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutations', 'Var', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CRC', 'Phenotype', 'HP:0003003', (35, 38))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('genetic mutations', 'Var', (82, 99))	('tumor', 'Disease', (132, 137))	('triggered', 'Reg', (43, 52))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('CRC', 'Disease', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
64363	33339860	Although the infiltration of T lymphocytes is correlated with improved outcomes in CRC, the degree of T lymphocyte infiltration is determined by tumor antigens and tumor molecular characteristics such as microsatellite instability (MSI).	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('improved', 'PosReg', (62, 70))	('microsatellite instability', 'Var', (204, 230))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('CRC', 'Disease', (83, 86))
64381	33339860	Positive staining for CD8 (ab4055, Abcam, Cambridge, UK), CD45RO (ab23, Abcam) and PD1 (ab52587, Abcam) was defined as staining in the cytoplasm or membranous intratumoral TILs by microscopy (Olympus BX53, Tokyo, Japan).	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('CD45RO', 'Gene', '5788', (58, 64))	('TIL', 'Gene', '7096', (172, 175))	('CD45RO', 'Gene', (58, 64))	('TIL', 'Gene', (172, 175))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('CD8', 'Gene', (22, 25))	('ab4055', 'Var', (27, 33))	('CD8', 'Gene', '925', (22, 25))
64390	33339860	To evaluate the status of mismatch repair (MMR), MMR proficiency was defined the expression of 4 proteins: MLH1 (ab92312, Abcam), MSH2 (ab92372, Abcam), MSH6 (ab92471, Abcam) and PMS2 (ab110638, Abcam), while MMR-deficient tumors were defined as those lacking at least one of these four markers by IHC.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('ab92372', 'Var', (136, 143))	('MSH2', 'Gene', (130, 134))	('PMS2', 'Gene', (179, 183))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (209, 229))	('MSH2', 'Gene', '4436', (130, 134))	('PMS2', 'Gene', '5395', (179, 183))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('MMR-deficient tumors', 'Disease', (209, 229))	('ab110638', 'Var', (185, 193))	('MSH6', 'Gene', (153, 157))	('MLH1', 'Gene', '4292', (107, 111))	('MSH6', 'Gene', '2956', (153, 157))	('ab92312', 'Var', (113, 120))	('MLH1', 'Gene', (107, 111))	('ab92471', 'Var', (159, 166))
64407	33339860	However, KM curves and log-rank tests revealed that high expression of tumor PD-L2 was associated with a remarkably longer 5-year OS than low expression of tumor PD-L2 in advanced stage patients (57% vs 40%, p < 0.001, Fig.	('longer', 'PosReg', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('PD-L2', 'Gene', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (156, 161))	('high expression', 'Var', (52, 67))	('tumor', 'Disease', (71, 76))	('patients', 'Species', '9606', (186, 194))
64413	33339860	Classifying advanced stage colon carcinoma patients into subgroups based on stage and postoperative chemotherapy regimen, we found that stage III or IV patients with elevated tumor PD-L2 tended to have better 5-year OS than those with low tumor PD-L2 (Fig.	('elevated tumor', 'Disease', (166, 180))	('stage colon carcinoma', 'Disease', (21, 42))	('low tumor', 'Disease', 'MESH:D009800', (235, 244))	('patients', 'Species', '9606', (43, 51))	('PD-L2', 'Var', (181, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('better', 'PosReg', (202, 208))	('5-year OS', 'CPA', (209, 218))	('low tumor', 'Disease', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patients', 'Species', '9606', (152, 160))	('stage colon carcinoma', 'Disease', 'MESH:D003110', (21, 42))	('elevated tumor', 'Disease', 'MESH:D006973', (166, 180))
64414	33339860	Patients with advanced stage colon cancer who received postoperative chemotherapy with high tumor PD-L2 had more favorable 5-year OS than those with low tumor PD-L2 (Fig.	('colon cancer', 'Phenotype', 'HP:0003003', (29, 41))	('colon cancer', 'Disease', 'MESH:D015179', (29, 41))	('PD-L2', 'Var', (98, 103))	('high tumor', 'Disease', (87, 97))	('low tumor', 'Disease', 'MESH:D009800', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('colon cancer', 'Disease', (29, 41))	('high tumor', 'Disease', 'MESH:D009369', (87, 97))	('low tumor', 'Disease', (149, 158))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
64417	33339860	Multiverse analysis adjusted with clinicopathologic parameters suggested that tumor PD-L2 may be an independent prognostic factor for advanced stage colon carcinoma patients, especially for patients who receive postoperative chemotherapy (Stage III: HR 1.575, 95% CI 1.098-2.259, p = 0.045, Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('patients', 'Species', '9606', (190, 198))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (165, 173))	('stage colon carcinoma', 'Disease', 'MESH:D003110', (143, 164))	('stage colon carcinoma', 'Disease', (143, 164))	('PD-L2', 'Var', (84, 89))
64454	33339860	also showed that high tumor PD-L2 led to decreased expression of immune gene signatures within the TME via the beta-catenin/Wnt and PI3K pathways in adenoid cystic carcinoma (ACC).	('adenoid cystic carcinoma', 'Disease', (149, 173))	('beta-catenin', 'Gene', (111, 123))	('high tumor', 'Disease', 'MESH:D009369', (17, 27))	('decreased', 'NegReg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PD-L2', 'Var', (28, 33))	('beta-catenin', 'Gene', '1499', (111, 123))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (149, 173))	('PI3K pathways', 'Pathway', (132, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('high tumor', 'Disease', (17, 27))	('expression of immune gene signatures', 'MPA', (51, 87))
64455	33339860	These results suggest that tumor PD-L2 expression may inhibit anti-cancer immunity against colon carcinoma, implying that tumor PD-L2 might be upregulated by other mechanisms, such as hypoxia.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('hypoxia', 'Disease', (184, 191))	('hypoxia', 'Disease', 'MESH:D000860', (184, 191))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('inhibit', 'NegReg', (54, 61))	('expression', 'Var', (39, 49))	('cancer', 'Disease', (67, 73))	('PD-L2', 'Gene', (33, 38))	('tumor', 'Disease', (27, 32))	('colon carcinoma', 'Disease', 'MESH:D003110', (91, 106))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('colon carcinoma', 'Disease', (91, 106))	('tumor', 'Disease', (122, 127))
64460	33339860	Several studies reported that high PD-L2 expression was associated with poor patient survival, including studies in esophageal cancer, pancreatic ductal adenocarcinoma and colorectal cancer, and high tumor PD-L2 expression was associated with a favorable survival outcome in melanoma and colorectal cancer.	('colorectal cancer', 'Disease', (288, 305))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (135, 167))	('high tumor', 'Disease', (195, 205))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('high tumor', 'Disease', 'MESH:D009369', (195, 205))	('cancer', 'Disease', (183, 189))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('cancer', 'Disease', (127, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (288, 305))	('patient', 'Species', '9606', (77, 84))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('melanoma', 'Disease', (275, 283))	('PD-L2', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (135, 167))	('high', 'Var', (30, 34))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('poor', 'NegReg', (72, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('pancreatic ductal adenocarcinoma', 'Disease', (135, 167))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('colorectal cancer', 'Disease', (172, 189))	('colorectal cancer', 'Disease', 'MESH:D015179', (288, 305))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))	('PD-L2', 'Gene', (206, 211))	('patient survival', 'CPA', (77, 93))
64463	33339860	reported that 78% of stromal cells expressed PD-L2, and 51.6% of tumor cells expressed PD-L2, while Guo et al.	('tumor', 'Disease', (65, 70))	('PD-L2', 'Protein', (45, 50))	('PD-L2', 'Var', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
64464	33339860	indicated 17.4% of immune cells expressed PD-L2 and 19.3% of tumor cells expressed PD-L2 in CRC.	('CRC', 'Phenotype', 'HP:0003003', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('PD-L2', 'Var', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
64470	33339860	Second, based on our results, we speculate that tumor PD-L2 may inhibit intratumoral T cell infiltration.	('tumor', 'Disease', (48, 53))	('PD-L2', 'Var', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('inhibit', 'NegReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
64482	32790041	Patients with pathologically staged T1-4N0M0 esophageal cancer were divided into two treatment groups: (i) neoadjuvant radiotherapy followed by surgery; and (ii) upfront esophagectomy followed by adjuvant radiotherapy.	('esophageal cancer', 'Disease', (45, 62))	('T1-4N0M0', 'Var', (36, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Patients', 'Species', '9606', (0, 8))
64513	32790041	Patients who received NRT + S tended to have a significantly larger total tumor size, younger age and more localized disease.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('larger', 'PosReg', (61, 67))	('localized disease', 'Disease', (107, 124))	('NRT + S', 'Var', (22, 29))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', (74, 79))	('localized disease', 'Disease', 'MESH:D012594', (107, 124))
64514	32790041	Conversely, patients in the S + RT group were older and had a smaller total tumor size, earlier pT stage disease compared with patients in the NRT + S group.	('earlier', 'PosReg', (88, 95))	('patients', 'Species', '9606', (12, 20))	('S + RT', 'Var', (28, 34))	('pT stage disease', 'CPA', (96, 112))	('smaller', 'NegReg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('patients', 'Species', '9606', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
64518	32790041	Taking into account for all matched patients, there were still survival benefits for neoadjuvant radiotherapy in OS (five-year survival 63.2% vs. 46.5%; P = 0.019) and CSS (five-year survival 77.2% vs. 58.4%; P = 0.019) than that of adjuvant treatment (Fig 3).	('CSS', 'Disease', (168, 171))	('benefits', 'PosReg', (72, 80))	('patients', 'Species', '9606', (36, 44))	('neoadjuvant', 'Var', (85, 96))
64521	32790041	On subgroup analysis, neoadjuvant radiation was not associated with improved overall survival (five-year survival 72.5% vs. 54.9%; P = 0.181) and cancer-specific survival (five-year survival 80.4% vs. 73.5%; P = 0.619) for pT1-2N0 (early-staged) disease, even for pT3-4N0 (localized) disease only with a modest but not statistically significant increase in overall survival (five-year survival 69.5% vs. 43.2%; P = 0.060).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('pT3', 'Gene', '7694', (264, 267))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('pT3', 'Gene', (264, 267))	('pT1-2N0', 'Var', (223, 230))
64538	32790041	created a decision analysis mode for cT2N0 esophageal cancer, which estimated 6% patients in this model to represent the proportion of patients who underwent chemoradiation and were no longer operative candidates because of progression of disease, patient preference, toxicity of chemotherapy, or decline in health making them medically unfit for surgery.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('patient', 'Species', '9606', (135, 142))	('patients', 'Species', '9606', (135, 143))	('patient', 'Species', '9606', (81, 88))	('2N0 esophageal cancer', 'Phenotype', 'HP:0011459', (39, 60))	('patients', 'Species', '9606', (81, 89))	('toxicity', 'Disease', 'MESH:D064420', (268, 276))	('toxicity', 'Disease', (268, 276))	('cT2N0', 'Var', (37, 42))	('esophageal cancer', 'Disease', (43, 60))	('patient', 'Species', '9606', (248, 255))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
64540	32790041	9 ,  10  Therefore, the identification of higher-risk pN0 esophageal cancer patients for neoadjuvant therapy would be expected to yield better results than taking a uniform approach to this group.	('patients', 'Species', '9606', (76, 84))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('pN0 esophageal cancer', 'Phenotype', 'HP:0011459', (54, 75))	('pN0', 'Var', (54, 57))
64541	32790041	The prognosis for patients with pN0 esophageal cancer is modulated by T status and histologic grade.	('esophageal cancer', 'Disease', 'MESH:D004938', (36, 53))	('pN0 esophageal cancer', 'Phenotype', 'HP:0011459', (32, 53))	('modulated', 'Reg', (57, 66))	('pN0', 'Var', (32, 35))	('patients', 'Species', '9606', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancer', 'Disease', (36, 53))
64547	32790041	In this study, neoadjuvant radiotherapy along with esophagectomy did not improve survival for pT1-2N0 esophageal cancer in pathologically node-negative disease compared with the adjuvant approach.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('2N0 esophageal cancer', 'Phenotype', 'HP:0011459', (98, 119))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('pT1-2N0', 'Var', (94, 101))
64556	32790041	Finally, limitation inherent to the database does not provide data on other factors that may influence survival, including surgical margin status, patient comorbidities, performance status, lymphovascular invasion, type of lymphadenectomy and gene mutations, which may contribute to a list of unknown confounders affecting outcomes.	('influence', 'Reg', (93, 102))	('lymphovascular', 'Disease', (190, 204))	('patient', 'Species', '9606', (147, 154))	('gene mutations', 'Var', (243, 257))
64558	32579544	Germline BRCA2 Truncating Mutation in Familial Esophageal Squamous Cell Carcinoma: A Case Controlled Study in China Germline mutations of BRCA2 have been reported in various malignancies.	('mutations', 'Var', (125, 134))	('BRCA2', 'Gene', (9, 14))	('Familial Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (38, 81))	('Familial Esophageal Squamous Cell Carcinoma', 'Disease', (38, 81))	('BRCA2', 'Gene', '675', (138, 143))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('malignancies', 'Disease', (174, 186))	('BRCA2', 'Gene', '675', (9, 14))	('Carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('BRCA2', 'Gene', (138, 143))	('malignancies', 'Disease', 'MESH:D009369', (174, 186))
64561	32579544	Multiple BRCA2 mutations including one novel splice variant, c.426-2A>G were identified.	('BRCA2', 'Gene', (9, 14))	('c.426-2A>G', 'Mutation', 'rs398122779', (61, 71))	('c.426-2A>G', 'Var', (61, 71))	('BRCA2', 'Gene', '675', (9, 14))
64564	32579544	BRCA2 germline mutation in ESCC patients may play a role in genetic susceptibility to familial ESCC.	('BRCA2', 'Gene', '675', (0, 5))	('patients', 'Species', '9606', (32, 40))	('germline mutation', 'Var', (6, 23))	('BRCA2', 'Gene', (0, 5))	('play', 'Reg', (45, 49))	('familial ESCC', 'Disease', (86, 99))
64565	32579544	Genetic analysis of BRCA2 in patients with familial ESCC could provide opportunities for targeted therapies.	('BRCA2', 'Gene', '675', (20, 25))	('patients', 'Species', '9606', (29, 37))	('familial ESCC', 'Disease', (43, 56))	('Genetic analysis', 'Var', (0, 16))	('BRCA2', 'Gene', (20, 25))
64571	32579544	There is growing evidence in the literature that supports an important role for genetic and epigenetic predisposition in the carcinogenesis of ESCC, in addition to the environmental factors, particularly in the areas with a high-risk population.	('carcinogenesis', 'Disease', (125, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('epigenetic', 'Var', (92, 102))	('ESCC', 'Disease', (143, 147))
64575	32579544	In addition to breast cancer, as was originally identified, germline mutations in the BRCA2 gene have been associated with increased risk of various other cancers such as ovarian cancer, melanoma, and cancers of the pancreas and liver.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('cancers', 'Disease', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('ovarian cancer', 'Disease', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers of the pancreas', 'Disease', 'MESH:D010190', (201, 224))	('breast cancer', 'Disease', (15, 28))	('cancers of the pancreas', 'Disease', (201, 224))	('ovarian cancer', 'Phenotype', 'HP:0100615', (171, 185))	('cancers of the pancreas', 'Phenotype', 'HP:0002894', (201, 224))	('BRCA2', 'Gene', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('associated', 'Reg', (107, 117))	('germline mutations', 'Var', (60, 78))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancers', 'Disease', (155, 162))	('ovarian cancer', 'Disease', 'MESH:D010051', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('BRCA2', 'Gene', '675', (86, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
64576	32579544	In the current study, we evaluated family clusters with ESCC for possible germline mutations in BRCA2 and identified a novel BRCA2 variant in a family, one with multiple primary cancers, as well as several other mutations with unknown clinical significance and polymorphisms in BRCA2 gene.	('BRCA2', 'Gene', (278, 283))	('BRCA2', 'Gene', (125, 130))	('variant', 'Var', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mul', 'Gene', '4591', (161, 164))	('BRCA2', 'Gene', '675', (96, 101))	('mul', 'Gene', (161, 164))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('BRCA2', 'Gene', '675', (278, 283))	('BRCA2', 'Gene', '675', (125, 130))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('BRCA2', 'Gene', (96, 101))
64579	32579544	Five families with affected probands were analyzed for BRCA2 mutations in germline DNA by whole gene sequencing in accordance to previously published protocol.	('BRCA2', 'Gene', (55, 60))	('BRCA2', 'Gene', '675', (55, 60))	('mutations', 'Var', (61, 70))
64591	32579544	Sequencing revealed that mutation at the splice site leads to exon 5 skipping and disrupted the coding reading frame in exon 6, which in turn created a frameshift with a premature stop codon in exon 6 and subsequent truncation of the in BRCA2 protein.	('exon 5', 'MPA', (62, 68))	('disrupted', 'NegReg', (82, 91))	('BRCA2', 'Gene', '675', (237, 242))	('mutation', 'Var', (25, 33))	('frameshift', 'Var', (152, 162))	('truncation', 'MPA', (216, 226))	('skipping', 'NegReg', (69, 77))	('BRCA2', 'Gene', (237, 242))	('protein', 'Protein', (243, 250))	('created', 'Reg', (142, 149))	('coding reading frame', 'MPA', (96, 116))
64600	32579544	In this study, we report a novel BRCA2 germline mutation at the splicing site c.426-2A>G in familial ESCC and concomitant breast cancer in one of the patients.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('c.426-2A>G', 'Mutation', 'rs398122779', (78, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('BRCA2', 'Gene', (33, 38))	('familial ESCC', 'Disease', (92, 105))	('c.426-2A>G', 'Var', (78, 88))	('patients', 'Species', '9606', (150, 158))	('BRCA2', 'Gene', '675', (33, 38))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
64606	32579544	reported loss of heterozygosity (LOH) in chromosome 13 of patients with ESCC and later, for the first time, reported germline (Cys315Ser, Pro3300Ser, and Arg118His) and somatic mutations of BRCA2 in patients with familial as well as sporadic esophageal cancer.	('Arg118His', 'Var', (154, 163))	('heterozygosity', 'MPA', (17, 31))	('BRCA2', 'Gene', (190, 195))	('Pro3300Ser', 'Var', (138, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (242, 259))	('familial', 'Disease', (213, 221))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('Cys315Ser', 'SUBSTITUTION', 'None', (127, 136))	('loss', 'NegReg', (9, 13))	('BRCA2', 'Gene', '675', (190, 195))	('Pro3300Ser', 'Chemical', '-', (138, 148))	('esophageal cancer', 'Disease', (242, 259))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (58, 66))	('Cys315Ser', 'Var', (127, 136))	('Arg118His', 'SUBSTITUTION', 'None', (154, 163))	('ESCC', 'Disease', (72, 76))
64610	32579544	reported germline mutations in sporadic ESCC from an area with low risk of esophageal cancer in China.	('ESCC', 'Disease', (40, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('esophageal cancer', 'Disease', (75, 92))	('germline mutations', 'Var', (9, 27))
64613	32579544	They also detected k3326X mutation in 8 familial ESCC patients, as the most frequent mutation associated with genetic susceptibility to familial ESCC.	('familial ESCC', 'Disease', (136, 149))	('k3326X', 'Var', (19, 25))	('patients', 'Species', '9606', (54, 62))	('familial ESCC', 'Disease', (40, 53))
64614	32579544	A robust association between k3326X mutation and upper aerodigestive tract cancers was demonstrated by Delahaye-Sourdeix et al.	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('k3326X', 'Var', (29, 35))
64617	32579544	His372Asn is a common polymorphism (rs144848) that was found in all the studied familial ESCC patients, and it has been shown to be associated with increased risk of non-Hodgkin lymphoma in a meta-analysis.	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (170, 186))	('patients', 'Species', '9606', (94, 102))	('rs144848', 'Var', (36, 44))	('His372Asn', 'Var', (0, 9))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (166, 186))	('lymphoma', 'Phenotype', 'HP:0002665', (178, 186))	('non-Hodgkin lymphoma', 'Disease', (166, 186))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (166, 186))	('His372Asn', 'Mutation', 'rs144848', (0, 9))	('rs144848', 'Mutation', 'rs144848', (36, 44))	('associated', 'Reg', (132, 142))
64618	32579544	Phe599Ser is another single nucleotide variant which was observed in all the familial ESCC tested and has not been widely studied but has been considered to likely be pathogenic.	('familial ESCC', 'Disease', (77, 90))	('Phe599Ser', 'SUBSTITUTION', 'None', (0, 9))	('observed', 'Reg', (57, 65))	('Phe599Ser', 'Var', (0, 9))
64626	32579544	Genetic analysis of BRCA2 in patients with familial ESCC should be considered and could identify family members at higher risk, both for esophageal cancer and future risk for breast cancer.	('BRCA2', 'Gene', '675', (20, 25))	('patients', 'Species', '9606', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Genetic analysis', 'Var', (0, 16))	('BRCA2', 'Gene', (20, 25))	('esophageal cancer', 'Disease', (137, 154))
64627	32579544	Moreover, genetic alterations of BRCA2 have potential therapeutic significance with recent advancements in PARP inhibitors in BRCA2 related tumors.	('genetic alterations', 'Var', (10, 29))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('BRCA2', 'Gene', (33, 38))	('PARP', 'Gene', '1302', (107, 111))	('BRCA2', 'Gene', (126, 131))	('BRCA2', 'Gene', '675', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('PARP', 'Gene', (107, 111))	('BRCA2', 'Gene', '675', (126, 131))
64628	32579544	Screening for BRCA2 mutations in familial esophageal cancer patients could provide opportunities for targeted therapies.	('familial esophageal cancer', 'Disease', (33, 59))	('BRCA2', 'Gene', '675', (14, 19))	('patients', 'Species', '9606', (60, 68))	('familial esophageal cancer', 'Disease', 'MESH:D004938', (33, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BRCA2', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
64714	30945395	The causal factors of aberrant portal hemodynamics, including BCS, have yet to be clarified.	('aberrant', 'Var', (22, 30))	('BCS', 'Phenotype', 'HP:0002639', (62, 65))	('BCS', 'Disease', 'MESH:D006502', (62, 65))	('BCS', 'Disease', (62, 65))
64821	30871493	In line, NSCLC patients treated with pembrolizumab showed longer PFS (HR 0.56 [95% CI 0.34-0.91], p = 0.019) and increased OS (HR 0.58 [95% CI 0.36-0.94], p = 0.026) if they had received any radiotherapy as compared to non-radiated patients.	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (232, 240))	('NSCLC', 'Disease', (9, 14))	('PFS', 'MPA', (65, 68))	('pembrolizumab', 'Chemical', 'MESH:C582435', (37, 50))	('longer', 'PosReg', (58, 64))	('NSCLC', 'Disease', 'MESH:D002289', (9, 14))	('pembrolizumab', 'Var', (37, 50))	('increased', 'PosReg', (113, 122))	('OS', 'Chemical', '-', (123, 125))
64832	30871493	As the CheckMate Trial 214 revealed grade 3 and 4 toxicities in up to 46% of the patients with advanced renal cell carcinoma treated with nivolumab and ipilimumab, we consider the RAMONA dosage treatment scheme with longer intervals of ipilimumab administration to provide better tolerability (CheckMate 214 ipilimumab Q3W as compared to Q6W in our study).	('ipilimumab Q3W', 'Var', (308, 322))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (104, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('CheckMate', 'Chemical', 'MESH:C049437', (294, 303))	('patients', 'Species', '9606', (81, 89))	('toxicities', 'Disease', (50, 60))	('CheckMate', 'Chemical', 'MESH:C049437', (7, 16))	('ipilimumab', 'Chemical', 'MESH:D000074324', (152, 162))	('ipilimumab', 'Chemical', 'MESH:D000074324', (236, 246))	('nivolumab', 'Chemical', 'MESH:D000077594', (138, 147))	('Q3W', 'Var', (319, 322))	('ipilimumab', 'Chemical', 'MESH:D000074324', (308, 318))	('renal cell carcinoma', 'Disease', (104, 124))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (104, 124))	('toxicities', 'Disease', 'MESH:D064420', (50, 60))
64848	30390388	ENST00000508406.1 was significantly associated with T, N, and tumor node metastasis stages, and NR_037652.1 was significantly associated with N stage.	('associated', 'Reg', (126, 136))	('NR_037652.1', 'Var', (96, 107))	('ENST00000508406.1', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor node metastasis', 'Disease', 'MESH:D009362', (62, 83))	('tumor node metastasis', 'Disease', (62, 83))	('associated', 'Reg', (36, 46))
64881	30390388	Genome-wide analysis of lncRNAs allows the identification of dysregulated lncRNAs in ESCC to obtain novel and tumor-specific lncRNAs for the prediction of ESCC invasion and lymphatic metastasis.	('invasion', 'CPA', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('ESCC', 'Disease', (85, 89))	('dysregulated', 'Var', (61, 73))	('ESCC', 'Disease', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
64883	30390388	Further KEGG pathway analysis identified at least six main signaling pathways associated with the carcinogenesis, invasion, and metastasis of cancer, especially transcriptional misregulation in the cancer (hsa05202) pathway, which is associated with many solid tumors and contributes to the tumorigenic process.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('metastasis of cancer', 'Disease', 'MESH:D009362', (128, 148))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('tumor', 'Disease', (291, 296))	('cancer', 'Disease', (198, 204))	('carcinogenesis', 'Disease', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', (142, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('solid tumors', 'Disease', (255, 267))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('misregulation', 'Var', (177, 190))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('metastasis of cancer', 'Disease', (128, 148))	('tumor', 'Disease', (261, 266))	('solid tumors', 'Disease', 'MESH:D009369', (255, 267))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
64886	29617662	Driver Fusions and Their Implications in the Development and Treatment of Human Cancers Gene fusions represent an important class of somatic alterations in cancer.	('Gene fusions', 'Var', (88, 100))	('Human Cancers', 'Disease', (74, 87))	('Human Cancers', 'Disease', 'MESH:D009369', (74, 87))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cancers', 'Phenotype', 'HP:0002664', (80, 87))
64888	29617662	Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect.	('oncogenes', 'Gene', (104, 113))	('tumor', 'Disease', (178, 183))	('expression', 'MPA', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('increased', 'PosReg', (130, 139))	('fusions', 'Var', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
64894	29617662	To date, many studies have focused on determining the landscape of SNPs, insertions, deletions, and copy number alterations in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deletions', 'Var', (85, 94))	('copy number alterations', 'Var', (100, 123))	('SNPs', 'Var', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('insertions', 'Var', (73, 83))	('cancer', 'Disease', (127, 133))
64895	29617662	Although such genomic alterations make up a large fraction of the typical tumor mutation burden, gene fusions also play a critical role in oncogenesis.	('alterations', 'Var', (22, 33))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
64897	29617662	Gene fusions function as diagnostic markers for specific cancer types.	('cancer', 'Disease', (57, 63))	('Gene fusions', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))
64898	29617662	For example, a frequent translocation between chromosomes 11 and 22 creates a fusion between EWSR1 and FLI1 in Ewing's sarcoma.	('fusion', 'Var', (78, 84))	('translocation', 'Var', (24, 37))	('FLI1', 'Gene', (103, 107))	('EWSR1', 'Gene', (93, 98))	('FLI1', 'Gene', '2313', (103, 107))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (111, 126))	('EWSR1', 'Gene', '2130', (93, 98))	("Ewing's sarcoma", 'Disease', (111, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (111, 126))
64905	29617662	performed breakpoint analysis on exon microarrays across 974 cancer samples and identified 198 candidate fusions in annotated cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('fusions', 'Var', (105, 112))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
64907	29617662	Some studies focus on important classes of genes, such as kinase fusions, which may have particular structural properties that are selected for during oncogenesis and cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('kinase fusions', 'Var', (58, 72))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))
64921	29617662	Fusion events may be associated with altered expression of one or both of the fusion gene partners, a well-known example being multiple myeloma tumors in which translocation t(4;14) fuses the highly expressed IGH locus with the tyrosine protein kinase FGFR3.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('FGFR3', 'Gene', (252, 257))	('myeloma tumors', 'Disease', 'MESH:D009101', (136, 150))	('IGH', 'Gene', '3492', (209, 212))	('IGH', 'Gene', (209, 212))	('myeloma tumors', 'Disease', (136, 150))	('multiple myeloma', 'Phenotype', 'HP:0006775', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('FGFR3', 'Gene', '2261', (252, 257))	('translocation t', 'Var', (160, 175))
64923	29617662	Figure 2A shows that between 6% (mesothelioma [MESO]) and 28% (KIRP) of kinase fusions displayed outlier overexpression of the kinase partner.	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('fusions', 'Var', (79, 86))	('mesothelioma', 'Disease', (33, 45))	('overexpression', 'PosReg', (105, 119))
64924	29617662	Oncogenes tended to show higher likelihoods of overexpression, whereas TSGs displayed lower likelihoods.	('Oncogenes', 'Var', (0, 9))	('TSG', 'Gene', '57045', (71, 74))	('overexpression', 'MPA', (47, 61))	('TSG', 'Gene', (71, 74))
64925	29617662	Between 3% (breast invasive carcinoma [BRCA]) and 38% (PCPG) of TSG fusions showed outlier underexpression, generally higher than both oncogenes and kinases.	('BRCA', 'Gene', (39, 43))	('fusions', 'Var', (68, 75))	('TSG', 'Gene', (64, 67))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (12, 37))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (12, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('breast invasive carcinoma', 'Disease', (12, 37))	('BRCA', 'Gene', '672', (39, 43))	('underexpression', 'NegReg', (91, 106))	('TSG', 'Gene', '57045', (64, 67))
64927	29617662	Samples with fusions involving oncogenes, such as EGFR, ERBB2, and RET, showed increased expression of those genes relative to samples without fusions across cancer types.	('increased', 'PosReg', (79, 88))	('expression', 'MPA', (89, 99))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('RET', 'Gene', '5979', (67, 70))	('EGFR', 'Gene', '1956', (50, 54))	('fusions', 'Var', (13, 20))	('cancer', 'Disease', (158, 164))	('ERBB2', 'Gene', '2064', (56, 61))	('EGFR', 'Gene', (50, 54))	('ERBB2', 'Gene', (56, 61))	('RET', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
64931	29617662	For example, TP53 is affected by mutations rather than fusions in most cancer types.	('TP53', 'Gene', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('mutations', 'Var', (33, 42))	('affected', 'Reg', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TP53', 'Gene', '7157', (13, 17))
64932	29617662	However, in sarcoma (SARC), both fusions and mutations affecting TP53 were detected.	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (65, 69))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('TP53', 'Gene', (65, 69))	('sarcoma', 'Disease', (12, 19))	('fusions', 'Var', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('detected', 'Reg', (75, 83))
64933	29617662	In acute myeloid leukemia (LAML), several CBFB fusions but no mutations were observed, yet other cancer types also exhibited CBFB mutations (Table S3; Figure S2).	('CBFB', 'Gene', '865', (125, 129))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('cancer', 'Disease', (97, 103))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))	('CBFB', 'Gene', (42, 46))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('exhibited', 'Reg', (115, 124))	('CBFB', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('fusions', 'Var', (47, 54))	('mutations', 'Var', (130, 139))	('acute myeloid leukemia', 'Disease', (3, 25))	('CBFB', 'Gene', '865', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
64937	29617662	Recurrent CBFB-MYH11 fusions in LAML are significantly associated with decreased expression of the tumor suppressor CBFB, which functions as a transcriptional regulator (Figure 2D).	('tumor', 'Disease', (99, 104))	('CBFB', 'Gene', (10, 14))	('MYH11', 'Gene', '4629', (15, 20))	('MYH11', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CBFB', 'Gene', '865', (116, 120))	('fusions', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CBFB', 'Gene', '865', (10, 14))	('decreased', 'NegReg', (71, 80))	('expression', 'MPA', (81, 91))	('CBFB', 'Gene', (116, 120))
64938	29617662	In breast cancer, copy number amplification is a well-known mechanism of ERBB2 overexpression, and treatment of these HER2+ patients with trastuzumab is an established and effective targeted therapy.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('copy number amplification', 'Var', (18, 43))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('HER2', 'Gene', (118, 122))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('HER2', 'Gene', '2064', (118, 122))	('trastuzumab', 'Chemical', 'MESH:D000068878', (138, 149))	('overexpression', 'PosReg', (79, 93))	('ERBB2', 'Gene', (73, 78))	('ERBB2', 'Gene', '2064', (73, 78))	('patients', 'Species', '9606', (124, 132))
64939	29617662	Interestingly, three of four samples with ERBB2 fusions and two samples without a called fusion showed HPV integration within 1 Mb of ERBB2.	('fusions', 'Var', (48, 55))	('ERBB2', 'Gene', '2064', (134, 139))	('ERBB2', 'Gene', (134, 139))	('ERBB2', 'Gene', '2064', (42, 47))	('ERBB2', 'Gene', (42, 47))	('HPV integration', 'CPA', (103, 118))
64942	29617662	Comparison of kinase fusions across different cancer types indicated that kinase fusions are significantly enriched in THCA (35.6%, Fisher's exact test, p < 2.2e-16) (Figure 3B).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('THCA', 'Disease', (119, 123))	('kinase fusions', 'Var', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
64946	29617662	For example, there are more TK fusions in THCA and GBM, more CK1 fusions in uterine corpus endometrial carcinoma (UCEC), colon adenocarcinoma (COAD), and esophageal carcinoma (ESCA) and more AGC fusions in liver hepatocellular carcinoma (LIHC).	('colon adenocarcinoma', 'Disease', (121, 141))	('TK fusions', 'Var', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (154, 174))	('COAD', 'Disease', (143, 147))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (206, 236))	('CK1', 'Gene', (61, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('esophageal carcinoma', 'Disease', (154, 174))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('LIHC', 'Disease', (238, 242))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (121, 141))	('corpus endometrial carcinoma', 'Disease', (84, 112))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (84, 112))	('fusions', 'Var', (65, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('CK1', 'Species', '2498238', (61, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (154, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('liver hepatocellular carcinoma', 'Disease', (206, 236))	('LIHC', 'Disease', 'None', (238, 242))	('COAD', 'Disease', 'MESH:D029424', (143, 147))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (212, 236))
64947	29617662	Across different cancer types, we found an enrichment of TK and TKL kinase fusions for 3'-kinases but no strong preference for 5'-kinases (Figure S3).	('TKL', 'Gene', (64, 67))	('fusions', 'Var', (75, 82))	("3'-kinases", 'MPA', (87, 97))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('TKL', 'Gene', '7294', (64, 67))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
64949	29617662	As expected, fusions in the FGFR kinase family (FGFR2 and FGFR3) are the most frequent 5'-kinase fusions, given their high recurrence in individual cancer types (Figure 3C).	('cancer', 'Disease', (148, 154))	('FGFR2', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('FGFR2', 'Gene', '2263', (48, 53))	('FGFR3', 'Gene', '2261', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('FGFR3', 'Gene', (58, 63))	('fusions', 'Var', (13, 20))
64959	29617662	For example, we found a TRABD-DDR2 fusion in one head and neck squamous cell carcinoma (HNSC) sample, which fused the stronger TRABD promoter with DDR2, resulting in its overexpression (Figure 4D).	('neck squamous cell carcinoma', 'Disease', (58, 86))	('DDR2', 'Gene', (30, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('DDR2', 'Gene', '4921', (147, 151))	('DDR2', 'Gene', '4921', (30, 34))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (58, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('fusion', 'Var', (35, 41))	('DDR2', 'Gene', (147, 151))	('overexpression', 'PosReg', (170, 184))
64961	29617662	DDR2 fusions were also detected in another nine samples from five different cancer types, which could be treated similarly given sufficient DDR2 overexpression (Table S1).	('fusions', 'Var', (5, 12))	('DDR2', 'Gene', '4921', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DDR2', 'Gene', '4921', (140, 144))	('DDR2', 'Gene', (140, 144))	('cancer', 'Disease', (76, 82))	('DDR2', 'Gene', (0, 4))	('overexpression', 'PosReg', (145, 159))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
64962	29617662	Although mutations in oncogenes or TSGs may lead to tumorigenesis, fusions involving those genes are also an important class of cancer driver events.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('lead to', 'Reg', (44, 51))	('tumor', 'Disease', (52, 57))	('TSG', 'Gene', '57045', (35, 38))	('mutations', 'Var', (9, 18))	('oncogenes', 'Gene', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('TSG', 'Gene', (35, 38))	('cancer', 'Disease', (128, 134))
64964	29617662	We characterized patients as having a driver mutation, a mutation in a driver gene, and/or a driver fusion (fusion involving a driver gene).	('mutation', 'Var', (57, 65))	('driver fusion', 'Disease', (93, 106))	('driver gene', 'Gene', (71, 82))	('driver', 'Disease', (38, 44))	('patients', 'Species', '9606', (17, 25))
64965	29617662	Although the majority of cancer cases have known driver mutations (48.6%, mean 6.8 mutations) or mutations in driver genes (28.1%, mean 4.2 mutations), we found that 8.3% have both driver mutations and driver fusion events (mean 5.5 mutations and 1.2 fusions), 6.4% have both mutations and fusions in driver genes (mean 4.2 mutations and 1.3 fusions), and 1.8% have driver fusions only (mean 1.1 fusions) (Figure 5A).	('mutations', 'Var', (97, 106))	('mutations', 'Var', (56, 65))	('mutations', 'Var', (324, 333))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (276, 285))	('fusions', 'Var', (290, 297))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
64967	29617662	The significant decrease in the numbers of mutations (Mann-Whitney U test, p < 2.2e-16) reflects the functionality of fusions across multiple cancer types.	('multiple cancer', 'Disease', (133, 148))	('decrease', 'NegReg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (43, 52))	('multiple cancer', 'Disease', 'MESH:D009369', (133, 148))
64968	29617662	Moreover, within cancer types, we observed a range of 0.2% (HNSC) to 14.0% (LAML) of tumors with fusions but no driver gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('fusions', 'Var', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
64977	29617662	Several Food and Drug Administration (FDA)-approved drugs exist to target ALK fusions in lung and other cancer types.	('ALK', 'Gene', (74, 77))	('lung', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('fusions', 'Var', (78, 85))	('ALK', 'Gene', '238', (74, 77))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
64979	29617662	In most cases, fusion status corresponded to copy number neutral overexpression of ALK (Figure 6D).	('ALK', 'Gene', '238', (83, 86))	('copy number neutral', 'Var', (45, 64))	('corresponded', 'Reg', (29, 41))	('overexpression', 'PosReg', (65, 79))	('ALK', 'Gene', (83, 86))
64982	29617662	We detected ESR1 fusions in 16 samples from five different cancer types (9 samples from BRCA).	('ESR1', 'Gene', '2099', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('fusions', 'Var', (17, 24))	('BRCA', 'Gene', '672', (88, 92))	('ESR1', 'Gene', (12, 16))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('BRCA', 'Gene', (88, 92))	('detected', 'Reg', (3, 11))
64984	29617662	We observed strict mutual exclusivity between ESR1 mutations and fusions (Figure 5C).	('ESR1', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))	('ESR1', 'Gene', '2099', (46, 50))
64989	29617662	Similarly, ESR1 expression is higher when ESR1 is mutated in BRCA, CESC, and UCEC, which are all hormone receptor-related cancer types.	('ESR1', 'Gene', '2099', (11, 15))	('higher', 'PosReg', (30, 36))	('ESR1', 'Gene', (42, 46))	('UCEC', 'Disease', (77, 81))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('CESC', 'Disease', (67, 71))	('hormone receptor', 'Gene', (97, 113))	('ESR1', 'Gene', (11, 15))	('mutated', 'Var', (50, 57))	('hormone receptor', 'Gene', '3164', (97, 113))	('ESR1', 'Gene', '2099', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BRCA', 'Gene', '672', (61, 65))	('expression', 'MPA', (16, 26))	('BRCA', 'Gene', (61, 65))
64990	29617662	Further functional study to determine the mechanism of ESR1 fusions could suggest drug development directions.	('ESR1', 'Gene', (55, 59))	('ESR1', 'Gene', '2099', (55, 59))	('fusions', 'Var', (60, 67))
64993	29617662	However, patients with known driver fusions may be poor candidates for immunotherapy because of their reduced mutational burden, especially without clear evidence of immune cell infiltration and overall immunogenicity.	('patients', 'Species', '9606', (9, 17))	('reduced', 'NegReg', (102, 109))	('mutational burden', 'MPA', (110, 127))	('fusions', 'Var', (36, 43))
65001	29617662	When comparing fusion events with the remainder of the cancer cohort, fusions involving oncogenes such as EGFR, ERBB2, and RET had increased expression.	('ERBB2', 'Gene', '2064', (112, 117))	('increased', 'PosReg', (131, 140))	('ERBB2', 'Gene', (112, 117))	('RET', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('expression', 'MPA', (141, 151))	('EGFR', 'Gene', '1956', (106, 110))	('RET', 'Gene', '5979', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('fusions', 'Var', (70, 77))	('cancer', 'Disease', (55, 61))	('EGFR', 'Gene', (106, 110))
65003	29617662	In addition to well-known recurrent fusions such as FGFR3-TACC3, we also detected 245 kinases with recurrent fusions to different partner genes, which may ultimately prove to be successful drug targets.	('TACC3', 'Gene', '10460', (58, 63))	('FGFR3', 'Gene', '2261', (52, 57))	('TACC3', 'Gene', (58, 63))	('fusions', 'Var', (109, 116))	('FGFR3', 'Gene', (52, 57))
65004	29617662	We showed that a meaningful percentage of patients (1.8%) harbor fusions involving cancer driver genes but have no driver gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('patients', 'Species', '9606', (42, 50))	('fusions', 'Var', (65, 72))	('cancer', 'Disease', (83, 89))
65007	29617662	The significant decrease in mutational burden observed in patients with fusions in driver genes points toward a reduced efficacy of immunotherapy in these patients, despite fusion peptides themselves potentially being good immunogenic targets.	('decrease', 'NegReg', (16, 24))	('efficacy of immunotherapy', 'CPA', (120, 145))	('patients', 'Species', '9606', (155, 163))	('mutational burden', 'MPA', (28, 45))	('reduced', 'NegReg', (112, 119))	('patients', 'Species', '9606', (58, 66))	('fusions', 'Var', (72, 79))
65009	29617662	We sought to prioritize fusions relevant to cancer by highlighting their associations with gene expression, potential for targeted therapy, and roles in cancer hallmark pathways.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('gene expression', 'MPA', (91, 106))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('associations', 'Interaction', (73, 85))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('fusions', 'Var', (24, 31))
65011	29617662	Fusions play an increasingly appreciated role in tumorigenesis and progression and represent an important source of improved treatment options.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('progression', 'CPA', (67, 78))	('Fusions', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
65026	29617662	The percentage of kinase genes in each group across different cancer types was defined as the number of kinase genes with fusions in each group divided by their sum, denoted as pg.	('fusions', 'Var', (122, 129))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
65031	29617662	For TCGA tumor samples where both MC3 (Key Resources Table) mutation calls and gene fusion calls were available, we obtained the genetic alteration events, including fusion, inframe deletion, inframe insertion, missense mutation, nonsense mutation, nonstop mutation, splice site mutation, and translation start site mutation in 299 driver genes.	('nonstop', 'Disease', (249, 256))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('splice', 'MPA', (267, 273))	('nonsense mutation', 'Var', (230, 247))	('missense mutation', 'Var', (211, 228))	('tumor', 'Disease', (9, 14))	('inframe insertion', 'Var', (192, 209))	('MC3', 'Gene', (34, 37))	('fusion', 'Var', (166, 172))	('MC3', 'Gene', '4159', (34, 37))
65033	29617662	Highly recurrent fusions were found in prostate, bladder, breast, and lung cancers Expression increased in oncogene fusions but decreased in tumor suppressor genes Thyroid carcinoma showed significantly higher rates of kinase fusions Tumors with fusion events tend to have lower mutational burden	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('increased', 'PosReg', (94, 103))	('Tumors', 'Disease', 'MESH:D009369', (234, 240))	('Expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('prostate', 'Disease', (39, 47))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (164, 181))	('fusions', 'Var', (116, 123))	('decreased', 'NegReg', (128, 137))	('breast', 'Disease', (58, 64))	('oncogene', 'Gene', (107, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('Tumors', 'Phenotype', 'HP:0002664', (234, 240))	('lung cancers', 'Disease', 'MESH:D008175', (70, 82))	('bladder', 'Disease', (49, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('lung cancers', 'Disease', (70, 82))	('tumor', 'Disease', (141, 146))	('Tumors', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancers', 'Phenotype', 'HP:0100526', (70, 82))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (164, 181))	('Thyroid carcinoma', 'Disease', (164, 181))
65039	29661174	The pooled RRR indicated DM women was associated with an increased risk of GC (RRR: 1.14; 95%CI: 1.06-1.22; p < 0.001), while the risk of HCC was lower (RRR: 0.88; 95%CI: 0.79-0.99; p = 0.031) as compared with DM men.	('HCC', 'Phenotype', 'HP:0001402', (138, 141))	('DM', 'Phenotype', 'HP:0000819', (25, 27))	('RRR', 'Var', (11, 14))	('DM', 'Disease', 'MESH:D009223', (25, 27))	('DM', 'Phenotype', 'HP:0000819', (210, 212))	('DM', 'Disease', 'MESH:D009223', (210, 212))	('HCC', 'Gene', (138, 141))	('CC', 'Phenotype', 'HP:0002664', (139, 141))	('GC', 'Phenotype', 'HP:0012126', (75, 77))	('women', 'Species', '9606', (28, 33))	('men', 'Species', '9606', (30, 33))	('RRR: 1', 'Gene', '147906', (79, 85))	('HCC', 'Gene', '619501', (138, 141))	('men', 'Species', '9606', (213, 216))	('RRR: 1', 'Gene', (79, 85))
65087	29661174	Finally, men and women with DM were correlated with greater risk of PC based on SIR/SMR or RR/OR/HR.	('men', 'Species', '9606', (19, 22))	('SMR', 'Gene', (84, 87))	('men', 'Species', '9606', (9, 12))	('DM', 'Phenotype', 'HP:0000819', (28, 30))	('PC', 'Phenotype', 'HP:0002894', (68, 70))	('RR/OR/HR', 'Var', (91, 99))	('DM', 'Disease', 'MESH:D009223', (28, 30))	('women', 'Species', '9606', (17, 22))	('SMR', 'Gene', '147719', (84, 87))
65107	29661174	This conclusion was consistent whether the summary results were based on SIR/SMR (RRR: 0.96; 95%CI: 0.91-1.01; p = 0.107) or RR/OR/HR (RRR: 1.04; 95%CI: 0.97-1.11; p = 0.244).	('SMR', 'Gene', (77, 80))	('RR/OR/HR', 'Var', (125, 133))	('SMR', 'Gene', '147719', (77, 80))	('RRR: 1', 'Gene', '147906', (135, 141))	('RRR: 1', 'Gene', (135, 141))
65175	29661174	(3) Heavy alcohol intake was associated with higher risk of EC, GC, CRC, HCC, and PC, which might bias the relation between DM and gastrointestinal cancer.	('HCC', 'Gene', '619501', (73, 76))	('Heavy alcohol', 'Var', (4, 17))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (131, 154))	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('CC', 'Phenotype', 'HP:0002664', (74, 76))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (131, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CRC', 'Disease', (68, 71))	('PC', 'Phenotype', 'HP:0002894', (82, 84))	('DM', 'Phenotype', 'HP:0000819', (124, 126))	('alcohol', 'Chemical', 'MESH:D000438', (10, 17))	('HCC', 'Gene', (73, 76))	('DM', 'Disease', 'MESH:D009223', (124, 126))	('gastrointestinal cancer', 'Disease', (131, 154))	('RC', 'Phenotype', 'HP:0100743', (69, 71))	('GC', 'Phenotype', 'HP:0012126', (64, 66))
65199	29863129	was able to demonstrate the feasibility of carrying out para-aortic dissection on top of D2 lymphadenectomy for gastric cancer, although there was no benefit to the 5-year overall survival.24, 25 Most recently, Sano et al.26 showed that splenectomy for patients with proximal gastric cancer that does not involve the greater curvature was associated with increased morbidity without improving the overall 5-year survival.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('splenectomy', 'Var', (237, 248))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('gastric cancer', 'Disease', (276, 290))	('gastric cancer', 'Disease', (112, 126))	('patients', 'Species', '9606', (253, 261))	('gastric cancer', 'Disease', 'MESH:D013274', (276, 290))	('aortic dissection', 'Phenotype', 'HP:0002647', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))
65282	26923327	Like other GI tract cancers, initial studies on molecular mechanisms underlying esophageal cancer have focused on tumor cell-intrinsic features, namely the activation of oncogenes (cyclin D1 and EGFR) and inactivation of tumor suppressor genes (TP53, p120catenin, E-cadherin) .	('EGFR', 'Gene', (195, 199))	('activation', 'PosReg', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('p120catenin', 'Gene', (251, 262))	('GI tract cancers', 'Disease', 'MESH:D004067', (11, 27))	('TP53', 'Gene', '7157', (245, 249))	('p120catenin', 'Gene', '1500', (251, 262))	('tumor', 'Disease', (114, 119))	('E-cadherin', 'Gene', (264, 274))	('cyclin D1', 'Gene', (181, 190))	('E-cadherin', 'Gene', '999', (264, 274))	('EGFR', 'Gene', '1956', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('GI tract cancers', 'Disease', (11, 27))	('tumor', 'Disease', (221, 226))	('cyclin D1', 'Gene', '595', (181, 190))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('esophageal cancer', 'Disease', (80, 97))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TP53', 'Gene', (245, 249))	('inactivation', 'Var', (205, 217))
65295	26923327	First, aberrant Sonic hedgehog (SHH) signaling between the injured epithelium and adjacent stroma triggers transcription of genes responsible for columnar metaplasia .	('SHH', 'Gene', '6469', (32, 35))	('Sonic hedgehog', 'Gene', '6469', (16, 30))	('Sonic hedgehog', 'Gene', (16, 30))	('aberrant', 'Var', (7, 15))	('transcription', 'MPA', (107, 120))	('triggers', 'Reg', (98, 106))	('columnar metaplasia', 'Disease', (146, 165))	('SHH', 'Gene', (32, 35))	('columnar metaplasia', 'Disease', 'MESH:D008679', (146, 165))
65296	26923327	Second, damage to the existing esophageal epithelium can actually make way for migration of epithelial cells from the forestomach, which have a columnar morphology .	('migration', 'CPA', (79, 88))	('make', 'Reg', (66, 70))	('damage', 'Var', (8, 14))	('rat', 'Species', '10116', (82, 85))
65297	26923327	On the other hand, ROS production causes direct DNA damage leading to tumor-initiating mutations .	('direct DNA damage', 'MPA', (41, 58))	('ROS', 'Protein', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('mutations', 'Var', (87, 96))	('ROS', 'Chemical', 'MESH:D017382', (19, 22))
65299	26923327	Furthermore, ROS can activate a number of cancer-associated signaling pathways such as PI3K/Akt, ERK1/2, and NF-kappaB .	('ROS', 'Var', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('activate', 'PosReg', (21, 29))	('ERK1/2', 'Gene', (97, 103))	('Akt', 'Gene', '207', (92, 95))	('ERK1/2', 'Gene', '5595;5594', (97, 103))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('Akt', 'Gene', (92, 95))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))	('NF-kappaB', 'Pathway', (109, 118))
65316	26923327	Disruption of this relationship, termed dysbiosis, may lead to GI carcinogenesis by disrupting epithelial barriers, triggering inflammation, and inducing subsequent DNA damage or pro-oncogenic signaling .	('DNA damage', 'MPA', (165, 175))	('pro-oncogenic signaling', 'CPA', (179, 202))	('dysbiosis', 'Disease', 'MESH:D064806', (40, 49))	('GI carcinogenesis', 'Disease', (63, 80))	('triggering', 'Reg', (116, 126))	('GI carcinogenesis', 'Disease', 'MESH:D063646', (63, 80))	('epithelial barriers', 'CPA', (95, 114))	('Disruption', 'Var', (0, 10))	('inducing', 'Reg', (145, 153))	('inflammation', 'Disease', 'MESH:D007249', (127, 139))	('dysbiosis', 'Disease', (40, 49))	('inflammation', 'Disease', (127, 139))	('lead to', 'Reg', (55, 62))	('disrupting', 'NegReg', (84, 94))
65361	26923327	In addition, inhibition of IL-8 and IL-1beta reduces tumor invasiveness as well as tumor-induced immunosuppression .	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('IL-1beta', 'Gene', '3553', (36, 44))	('tumor', 'Disease', (83, 88))	('reduces', 'NegReg', (45, 52))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('IL-8', 'Gene', '3576', (27, 31))	('tumor invasiveness', 'Disease', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('IL-8', 'Gene', (27, 31))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor invasiveness', 'Disease', 'MESH:D009369', (53, 71))	('IL-1beta', 'Gene', (36, 44))
65366	26923327	High COX-2 expression in ESCC was also associated with poor prognosis and chemotherapy resistance .	('chemotherapy resistance', 'CPA', (74, 97))	('poor prognosis', 'CPA', (55, 69))	('High', 'Var', (0, 4))	('COX-2', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('COX-2', 'Gene', '5743', (5, 10))	('associated', 'Reg', (39, 49))
65368	26923327	Several studies have demonstrated that both selective and nonselective COX-2 inhibitors suppress inflammation and cell growth while inducing apoptosis in BE and EAC .	('inhibitors', 'Var', (77, 87))	('inflammation', 'Disease', 'MESH:D007249', (97, 109))	('BE', 'Chemical', 'MESH:D001608', (154, 156))	('cell growth', 'CPA', (114, 125))	('EAC', 'Phenotype', 'HP:0011459', (161, 164))	('inflammation', 'Disease', (97, 109))	('COX-2', 'Gene', (71, 76))	('suppress', 'NegReg', (88, 96))	('inducing', 'Reg', (132, 140))	('COX-2', 'Gene', '5743', (71, 76))	('apoptosis', 'CPA', (141, 150))	('rat', 'Species', '10116', (28, 31))
65369	26923327	In ESCC, COX-2 inhibition leads to decreased cell proliferation, PGE2 production and overall tumor progression in vitro and in vivo .	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('COX-2', 'Gene', (9, 14))	('tumor', 'Disease', (93, 98))	('cell proliferation', 'CPA', (45, 63))	('COX-2', 'Gene', '5743', (9, 14))	('decreased', 'NegReg', (35, 44))	('PGE2', 'Chemical', 'MESH:D015232', (65, 69))	('rat', 'Species', '10116', (57, 60))	('PGE2 production', 'MPA', (65, 80))	('inhibition', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
65376	26923327	MDSCs suppress anti-tumor immunity by several mechanisms:direct inhibition of T cell activation , inhibition of NK cell cytotoxicity , depletion of the amino acids arginine and cysteine , and the induction of regulatory T cells .	('induction', 'Reg', (196, 205))	('MDSCs', 'Var', (0, 5))	('DS', 'Chemical', 'MESH:D003871', (1, 3))	('cytotoxicity', 'Disease', 'MESH:D064420', (120, 132))	('cytotoxicity', 'Disease', (120, 132))	('inhibition', 'NegReg', (98, 108))	('arginine', 'Chemical', 'MESH:D001120', (164, 172))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('inhibition', 'NegReg', (64, 74))	('T cell activation', 'CPA', (78, 95))	('cysteine', 'Chemical', 'MESH:D003545', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('regulatory T cells', 'CPA', (209, 227))	('suppress', 'NegReg', (6, 14))	('tumor', 'Disease', (20, 25))
65382	26923327	CD38 expression was driven by factors such as IL-6, IFN-gamma, TNF-alpha, IGFBP-3 and CXCL16, and crosslinking of CD38 with a monoclonal antibody daratumumab (now FDA-approved for treatment of multiple myeloma ) decreased esophageal tumor growth in vivo .	('daratumumab', 'Chemical', 'MESH:C556306', (146, 157))	('CD38', 'Gene', (114, 118))	('IGFBP-3', 'Gene', (74, 81))	('CD38', 'Gene', (0, 4))	('esophageal tumor', 'Disease', (222, 238))	('esophageal tumor', 'Phenotype', 'HP:0100751', (222, 238))	('IGFBP-3', 'Gene', '3486', (74, 81))	('multiple myeloma', 'Phenotype', 'HP:0006775', (193, 209))	('decreased', 'NegReg', (212, 221))	('IFN-gamma', 'Gene', '3458', (52, 61))	('IFN-gamma', 'Gene', (52, 61))	('multiple myeloma', 'Disease', 'MESH:D009101', (193, 209))	('crosslinking', 'Var', (98, 110))	('CXCL16', 'Gene', '58191', (86, 92))	('TNF-alpha', 'Gene', '7124', (63, 72))	('CD38', 'Gene', '952', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('esophageal tumor', 'Disease', 'MESH:D004938', (222, 238))	('TNF-alpha', 'Gene', (63, 72))	('CXCL16', 'Gene', (86, 92))	('CD38', 'Gene', '952', (0, 4))	('multiple myeloma', 'Disease', (193, 209))
65433	26923327	Moreover, the presence of CAFs in ESCC patients was associated with increased microvessel density, increased TAMs, and EMT, which is vital to cancer progression and metastasis .	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('presence', 'Var', (14, 22))	('patients', 'Species', '9606', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TAMs', 'CPA', (109, 113))	('CAFs', 'Gene', (26, 30))	('ESCC', 'Disease', (34, 38))	('increased', 'PosReg', (99, 108))	('TAMs', 'Chemical', '-', (109, 113))	('EMT', 'CPA', (119, 122))	('increased', 'PosReg', (68, 77))	('microvessel density', 'CPA', (78, 97))	('cancer', 'Disease', (142, 148))
65435	26923327	observed that CAF conditioned media supported EAC cell growth despite the presence of cisplatin and 5-FU and led to a twofold increase in EAC cell invasion in OTC compared to normal fibroblast conditioned media .	('5-FU', 'Var', (100, 104))	('5-FU', 'Chemical', 'MESH:D005472', (100, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('EAC cell growth', 'CPA', (46, 61))	('EAC cell invasion', 'CPA', (138, 155))	('EAC', 'Phenotype', 'HP:0011459', (138, 141))	('increase', 'PosReg', (126, 134))	('EAC', 'Phenotype', 'HP:0011459', (46, 49))	('cisplatin', 'Var', (86, 95))
65441	26923327	Whereas TGF-beta downregulation by DACH1 methylation or decreased Smad4 expression were associated with increased depth of invasion, later tumor stage and poor differentiation , TGF-beta downregulation by proteasomal degradation actually suppressed growth and invasion in vivo .	('Smad4', 'Gene', '4089', (66, 71))	('tumor', 'Disease', (139, 144))	('TGF-beta', 'Gene', (178, 186))	('suppressed', 'NegReg', (238, 248))	('TGF-beta', 'Gene', '7040', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('decreased', 'NegReg', (56, 65))	('expression', 'MPA', (72, 82))	('depth of invasion', 'CPA', (114, 131))	('poor differentiation', 'CPA', (155, 175))	('downregulation', 'NegReg', (187, 201))	('Smad4', 'Gene', (66, 71))	('TGF-beta', 'Gene', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('DACH1', 'Gene', (35, 40))	('increased', 'PosReg', (104, 113))	('methylation', 'Var', (41, 52))	('downregulation', 'NegReg', (17, 31))	('TGF-beta', 'Gene', '7040', (178, 186))	('DACH1', 'Gene', '1602', (35, 40))
65448	26923327	Together, these changes allow TGF-beta to promote tumor progression and eventual metastasis via EMT.	('changes', 'Var', (16, 23))	('EMT', 'CPA', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('promote', 'PosReg', (42, 49))	('metastasis', 'CPA', (81, 91))	('TGF-beta', 'Gene', '7040', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('TGF-beta', 'Gene', (30, 38))
65471	26923327	In ESCC, siRNA knockdown of CXCR4 suppressed proliferation, invasion, and metastasis of KYSE-150 and TE-13 cell lines in vitro and in vivo .	('rat', 'Species', '10116', (52, 55))	('knockdown', 'Var', (15, 24))	('invasion', 'CPA', (60, 68))	('proliferation', 'CPA', (45, 58))	('suppressed', 'NegReg', (34, 44))
65480	26923327	For example, our laboratory previously showed that periostin (POSTN), a matricellular protein secreted by fibroblasts in response to TGF-beta , cooperates with mutant p53 to induce STAT1 activation and facilitate ESCC cell invasion .	('rat', 'Species', '10116', (149, 152))	('induce', 'PosReg', (174, 180))	('facilitate', 'PosReg', (202, 212))	('activation', 'PosReg', (187, 197))	('STAT1', 'Gene', '6772', (181, 186))	('TGF-beta', 'Gene', '7040', (133, 141))	('ESCC cell invasion', 'CPA', (213, 231))	('POSTN', 'Gene', (62, 67))	('mutant', 'Var', (160, 166))	('rat', 'Species', '10116', (21, 24))	('periostin', 'Gene', '10631', (51, 60))	('p53', 'Gene', '7157', (167, 170))	('TGF-beta', 'Gene', (133, 141))	('periostin', 'Gene', (51, 60))	('POSTN', 'Gene', '10631', (62, 67))	('STAT1', 'Gene', (181, 186))	('p53', 'Gene', (167, 170))
65481	26923327	Intriguingly, both shRNA-mediated knockdown of POSTN and restoration of wildtype p53 decreased STAT1 activation and tumor invasion in vivo .	('STAT1', 'Gene', '6772', (95, 100))	('decreased', 'NegReg', (85, 94))	('rat', 'Species', '10116', (62, 65))	('POSTN', 'Gene', '10631', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('POSTN', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('knockdown', 'Var', (34, 43))	('STAT1', 'Gene', (95, 100))	('tumor', 'Disease', (116, 121))
65485	26923327	Subsequent study of DS in vitro showed that knockdown of iduronic acid, a component of DS, led to decreased migration and invasion of ESCC cells and was correlated with decreased HGF binding and pERK1/2 activity .	('ERK1/2', 'Gene', (196, 202))	('ERK1/2', 'Gene', '5595;5594', (196, 202))	('migration', 'CPA', (108, 117))	('rat', 'Species', '10116', (111, 114))	('HGF', 'Gene', (179, 182))	('invasion', 'CPA', (122, 130))	('DS', 'Chemical', 'MESH:D003871', (20, 22))	('HGF', 'Gene', '3082', (179, 182))	('knockdown', 'Var', (44, 53))	('decreased', 'NegReg', (169, 178))	('iduronic acid', 'Chemical', 'MESH:D007067', (57, 70))	('decreased', 'NegReg', (98, 107))	('DS', 'Chemical', 'MESH:D003871', (87, 89))	('activity', 'MPA', (203, 211))
65487	26923327	Importantly, inhibition of HA synthesis by either 4-methylumbelliferone or lentiviral knockdown of HA-synthase suppressed tumor progression and promoted a more differentiated phenotype in ESCC xenografts .	('knockdown', 'Var', (86, 95))	('HA-synthase', 'Gene', (99, 110))	('ESCC', 'Disease', (188, 192))	('HA', 'Chemical', 'MESH:D006820', (27, 29))	('HA', 'Chemical', 'MESH:D006820', (99, 101))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('promoted', 'PosReg', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('suppressed', 'NegReg', (111, 121))	('inhibition', 'NegReg', (13, 23))	('4-methylumbelliferone', 'Chemical', 'MESH:D006923', (50, 71))	('more differentiated phenotype', 'CPA', (155, 184))	('tumor', 'Disease', (122, 127))
65493	26923327	On the whole, disruption of these components in preclinical studies restored sensitivity to chemoradiation, suggesting considerable promise for TME-directed therapeutics in combination with tumor cell-directed agents.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('sensitivity to chemoradiation', 'MPA', (77, 106))	('tumor', 'Disease', (190, 195))	('disruption', 'Var', (14, 24))	('restored', 'PosReg', (68, 76))
65518	26240633	Our experience has shown that E-VAC may significantly improve the morbidity and mortality rate.	('morbidity', 'CPA', (66, 75))	('tal', 'Gene', (83, 86))	('tal', 'Gene', '6888', (83, 86))	('E-VAC', 'Chemical', '-', (30, 35))	('E-VAC', 'Var', (30, 35))	('improve', 'PosReg', (54, 61))
65578	26240633	The closure rate was significantly higher in patients treated with E-VAC than SEMS/SEPS (84.4% vs. 53.8%).	('closure', 'MPA', (4, 11))	('SEPS', 'Chemical', '-', (83, 87))	('E-VAC', 'Chemical', '-', (67, 72))	('patients', 'Species', '9606', (45, 53))	('E-VAC', 'Var', (67, 72))	('higher', 'PosReg', (35, 41))
65579	26240633	In addition, more strictures were found in the stent group in comparison to the E-VAC group (28.2% vs. 9.4%, p < 0.05).	('strictures', 'CPA', (18, 28))	('E-VAC', 'Chemical', '-', (80, 85))	('stent', 'Var', (47, 52))
65612	26240633	In-hospital mortality was significantly lower in the E-VAC group (12%; 2 patients) in comparison to the surgical treatment group (50%; 9 patients) and stent treatment group (42%; 5 patients).	('E-VAC', 'Chemical', '-', (53, 58))	('tal', 'Gene', (8, 11))	('patients', 'Species', '9606', (137, 145))	('tal', 'Gene', (15, 18))	('tal', 'Gene', '6888', (8, 11))	('patients', 'Species', '9606', (181, 189))	('E-VAC', 'Var', (53, 58))	('tal', 'Gene', '6888', (15, 18))	('patients', 'Species', '9606', (73, 81))	('lower', 'NegReg', (40, 45))
65613	26240633	The survival rate in the E-VAC group was significantly superior to the surgically and stent treated patients (p = 0.011 and p = 0.00014).	('E-VAC', 'Chemical', '-', (25, 30))	('E-VAC', 'Var', (25, 30))	('survival', 'CPA', (4, 12))	('patients', 'Species', '9606', (100, 108))	('superior', 'PosReg', (55, 63))
65677	26240633	Time of wound healing was significantly accelerated in the E-VAC group as compared to the group treated with transrectal lavage.	('E-VAC', 'Var', (59, 64))	('accelerated', 'PosReg', (40, 51))	('tal', 'Gene', (117, 120))	('tal', 'Gene', '6888', (117, 120))	('Time of wound healing', 'CPA', (0, 21))	('E-VAC', 'Chemical', '-', (59, 64))
65678	26240633	In-hospital time was shortened in the E-VAC group.	('E-VAC', 'Var', (38, 43))	('shortened', 'NegReg', (21, 30))	('tal', 'Gene', (8, 11))	('tal', 'Gene', '6888', (8, 11))	('E-VAC', 'Chemical', '-', (38, 43))
65817	19327567	Known biological processes such as methylation have been shown to play a role in the pathogenesis of both squamous and adenocarcinoma.	('role', 'Reg', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('squamous and adenocarcinoma', 'Disease', 'MESH:D002294', (106, 133))	('methylation', 'Var', (35, 46))	('play', 'Reg', (66, 70))
65911	19327567	This study also showed that nodularity on endoscopy was associated with a 2.5-fold increased risk of EAC.	('EAC', 'Gene', '1540', (101, 104))	('nodularity', 'Var', (28, 38))	('EAC', 'Gene', (101, 104))
65939	19327567	More recently, different sets of probes were assessed for the detection of dysplasia and adenocarcinoma in patients with BE and the study showed a probe set consisting of probes to 8q24, 9p21, 17q11.2, and 20q13.2 had a sensitivity and specificity, respectively, of 70% and 89% for low-grade dysplasia, 84% and 93% for high-grade dysplasia, and 94% and 93% for esophageal adenocarcinoma.	('dysplasia', 'Disease', (330, 339))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (361, 386))	('patients', 'Species', '9606', (107, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (377, 386))	('dysplasia and adenocarcinoma', 'Disease', 'MESH:D000230', (75, 103))	('esophageal adenocarcinoma', 'Disease', (361, 386))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('dysplasia', 'Disease', 'MESH:D004476', (292, 301))	('9p21', 'Var', (187, 191))	('probes', 'Var', (171, 177))	('dysplasia', 'Disease', 'MESH:D004476', (330, 339))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (361, 386))	('dysplasia', 'Disease', (75, 84))	('dysplasia', 'Disease', 'MESH:D004476', (75, 84))	('17q11.2', 'Var', (193, 200))	('dysplasia', 'Disease', (292, 301))	('BE', 'Phenotype', 'HP:0100580', (121, 123))
65965	19327567	It was shown that cyclooxygenase (COX)-2 inhibitor suppressed proliferation in Barrett's esophageal cells and proliferation was restored by prostaglandin.	('cyclooxygenase (COX)-2', 'Gene', (18, 40))	('cyclooxygenase (COX)-2', 'Gene', '4513', (18, 40))	('prostaglandin', 'Chemical', 'MESH:D011453', (140, 153))	('proliferation', 'CPA', (62, 75))	('inhibitor', 'Var', (41, 50))	('suppressed', 'NegReg', (51, 61))	("Barrett's esophageal cells", 'Phenotype', 'HP:0100580', (79, 105))
66057	23248752	compared the MIS TLIF in 10 patients vs. open TLIF in 12 patients, they found that although the MIS TLIF patients demonstrated significantly lower intraoperative transfusion rates, required fewer drains over shorter time periods, and ambulated earlier, they " tended to have a higher rate of complications, which might have been associated with the learning curve."	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (57, 65))	('rat', 'Species', '10116', (284, 287))	('rat', 'Species', '10116', (121, 124))	('MIS TLIF', 'Var', (96, 104))	('lower', 'NegReg', (141, 146))	('rat', 'Species', '10116', (174, 177))	('rat', 'Species', '10116', (155, 158))	('patients', 'Species', '9606', (28, 36))	('intraoperative transfusion rates', 'MPA', (147, 179))
66090	23248752	Cessation of anticoagulants or anti-platelet aggregants prior to spine surgery increase the risk of stroke carrying a 27.3% risk of in-hospital mortality.	('stroke', 'Disease', 'MESH:D020521', (100, 106))	('Cessation', 'Var', (0, 9))	('stroke', 'Disease', (100, 106))	('stroke', 'Phenotype', 'HP:0001297', (100, 106))
66102	23248752	Their retrospective analysis assessed the adverse impact of morbid obesity on morbidity/mortality for 4 types of spinal fusions: Anterior Cervical Fusion (ICD-9-CM procedure code 810.2), Posterior Cervical Fusion (810.3), Anterior Lumbar Fusion (810.6), and Posterior Lumbar Fusion (810.8).	('Anterior Cervical Fusion', 'Disease', (129, 153))	('obesity', 'Disease', 'MESH:D009765', (67, 74))	('spinal fusion', 'Phenotype', 'HP:0002948', (113, 126))	('Cervical Fusion', 'Phenotype', 'HP:0002949', (138, 153))	('obesity', 'Disease', (67, 74))	('obesity', 'Phenotype', 'HP:0001513', (67, 74))	('Anterior Lumbar Fusion', 'Disease', (222, 244))	('spinal fusions', 'Phenotype', 'HP:0002948', (113, 127))	('Cervical Fusion', 'Phenotype', 'HP:0002949', (197, 212))	('Posterior Lumbar Fusion', 'Phenotype', 'HP:0005626', (258, 281))	('Lumbar Fusion', 'Phenotype', 'HP:0030040', (231, 244))	('Posterior Cervical Fusion', 'Disease', (187, 212))	('morbid obesity', 'Phenotype', 'HP:0012743', (60, 74))	('Anterior Lumbar Fusion', 'Phenotype', 'HP:0004557', (222, 244))	('Posterior Lumbar Fusion', 'Disease', (258, 281))	('810.3', 'Var', (214, 219))	('Lumbar Fusion', 'Phenotype', 'HP:0030040', (268, 281))
66112	23248752	IAPs increased disproportionately for the morbidly obese Group 3 patients, thereby increasing EBL: Group I (IAP-7.8 mmHg), Group 2 (IAP-8.2 mmHg), and Group 3 (IAP-10.4 mmHg).	('IAP-8.2', 'Var', (132, 139))	('IAP-7.8', 'Var', (108, 115))	('patients', 'Species', '9606', (65, 73))	('obese', 'Disease', 'MESH:D009765', (51, 56))	('EBL', 'MPA', (94, 97))	('increasing', 'PosReg', (83, 93))	('obese', 'Disease', (51, 56))
66119	23248752	The malabsorption of calcium and vitamin D resulted in decreased hip and bone densities.	('malabsorption', 'Var', (4, 17))	('vitamin D', 'Chemical', 'MESH:D014807', (33, 42))	('decreased', 'NegReg', (55, 64))	('malabsorption', 'Phenotype', 'HP:0002024', (4, 17))	('calcium', 'Chemical', 'MESH:D002118', (21, 28))
66125	23248752	Vitamin E, which may be taken separately or as part of a multivitamin complex, or ingested in high concentrations in nuts-almonds are an increased source of Vitamin E. Vitamin E has not only an anti-platelet aggregant effect, but may also inhibit platelet procoagulant activity.	('Vitamin E', 'Var', (168, 177))	('inhibit', 'NegReg', (239, 246))	('platelet procoagulant activity', 'MPA', (247, 277))	('Vitamin E', 'Chemical', 'MESH:D014810', (157, 166))	('almonds', 'Species', '3755', (122, 129))	('Vitamin E', 'Chemical', 'MESH:D014810', (0, 9))	('rat', 'Species', '10116', (106, 109))	('anti-platelet aggregant effect', 'CPA', (194, 224))	('Vitamin E', 'Chemical', 'MESH:D014810', (168, 177))	('rat', 'Species', '10116', (34, 37))
66130	23248752	"The molecular pathology of Type 2 and 3 VWD is now comprehensively documented and involves rare sequence variants at the Von Willebrand Factor (VWF) locus."	('Von Willebrand Factor', 'Gene', (122, 143))	('VWD', 'Disease', 'MESH:D056729', (41, 44))	('variants', 'Var', (106, 114))	('VWF', 'Gene', '7450', (145, 148))	('VWF', 'Gene', (145, 148))	('Von Willebrand Factor', 'Gene', '7450', (122, 143))	('VWD', 'Disease', (41, 44))
66134	23248752	Surgical prophylaxis for factor VIII (FVIII) deficiency is often considered the optimal treatment for managing patients about to undergo spinal surgery, as hemophilia poses an increased risk of intraoperative/postoperative hemorrhagic complications.	('hemophilia', 'Disease', 'MESH:D006467', (156, 166))	('intraoperative/postoperative hemorrhagic complications', 'Disease', 'MESH:D019106', (194, 248))	('FVIII', 'Gene', '2157', (38, 43))	('factor VIII', 'Gene', '2157', (25, 36))	('factor VIII', 'Gene', (25, 36))	('deficiency', 'Var', (45, 55))	('hemophilia', 'Disease', (156, 166))	('FVIII', 'Gene', (38, 43))	('patients', 'Species', '9606', (111, 119))
66149	23248752	Intrinsic disorders include deficiencies of anticoagulation proteins (antithrombin III, protein C, protein S), Factor V Leiden Mutation, Thrombophilia, or dysfibrinogenaemia, a deficiency of natural activators of fibrinolysis or increased activity of their inhibitors, and homocystinuria.	('activity', 'MPA', (239, 247))	('antithrombin III', 'Gene', '462', (70, 86))	('antithrombin III', 'Gene', (70, 86))	('homocystinuria', 'Disease', (273, 287))	('deficiency', 'NegReg', (177, 187))	('Factor V Leiden', 'Gene', '2153', (111, 126))	('antithrombin III', 'Phenotype', 'HP:0001976', (70, 86))	('protein S', 'Protein', (99, 108))	('dysfibrinogenaemia', 'Disease', (155, 173))	('Factor V Leiden', 'Gene', (111, 126))	('anticoagulation', 'MPA', (44, 59))	('Thrombophilia', 'Disease', (137, 150))	('protein C', 'Protein', (88, 97))	('deficiencies', 'Var', (28, 40))	('homocystinuria', 'Disease', 'MESH:D006712', (273, 287))	('Thrombophilia', 'Disease', 'MESH:D019851', (137, 150))	('dysfibrinogenaemia', 'Phenotype', 'HP:0011901', (155, 173))	('dysfibrinogenaemia', 'Disease', 'None', (155, 173))	('Mutation', 'Var', (127, 135))	('increased', 'PosReg', (229, 238))	('Thrombophilia', 'Phenotype', 'HP:0100724', (137, 150))	('homocystinuria', 'Phenotype', 'HP:0002156', (273, 287))
66150	23248752	Other acquired hypercoagulation syndromes include anticardiolipin antibodies (lupus anticoagulants), pregnancy, the use of oral contraceptives, malignancy, nephrotic syndrome, postoperative conditions, diabetes mellitus, and other diseases.	('anticardiolipin', 'Var', (50, 65))	('diabetes mellitus', 'Disease', (202, 219))	('malignancy', 'Disease', (144, 154))	('hypercoagulation syndromes', 'Disease', (15, 41))	('diabetes mellitus', 'Disease', 'MESH:D003920', (202, 219))	('postoperative conditions', 'Disease', 'MESH:D010149', (176, 200))	('nephrotic syndrome', 'Disease', 'MESH:D009404', (156, 174))	('hypercoagulation syndromes', 'Disease', 'MESH:D019851', (15, 41))	('nephrotic syndrome', 'Disease', (156, 174))	('lupus anticoagulants', 'Phenotype', 'HP:0025343', (78, 98))	('hypercoagulation syndrome', 'Phenotype', 'HP:0100724', (15, 40))	('postoperative conditions', 'Disease', (176, 200))	('nephrotic syndrome', 'Phenotype', 'HP:0000100', (156, 174))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (202, 219))	('malignancy', 'Disease', 'MESH:D009369', (144, 154))	('pregnancy', 'Disease', (101, 110))
66210	23248752	reviewed 25 studies regarding the timing for cessation of smoking prior to spine surgery they found: (1) respiratory complications were comparable for patients who did not stop smoking or who quit within <2-4 weeks preoperatively, (2) cessation of smoking at least 3-4 weeks before surgery improved wound healing, and (3) for those who quit smoking >4-8 weeks preoperatively, the risk of respiratory complications was reduced.	('rat', 'Species', '10116', (110, 113))	('respiratory complications', 'Phenotype', 'HP:0011947', (388, 413))	('rat', 'Species', '10116', (393, 396))	('wound healing', 'CPA', (299, 312))	('rat', 'Species', '10116', (221, 224))	('patients', 'Species', '9606', (151, 159))	('cessation', 'Var', (235, 244))	('rat', 'Species', '10116', (366, 369))	('improved', 'PosReg', (290, 298))	('respiratory complications', 'Phenotype', 'HP:0011947', (105, 130))	('improved wound healing', 'Phenotype', 'HP:0001058', (290, 312))	('respiratory complications', 'Disease', (388, 413))
66250	23248752	They found that 291 (0.0043) CHG patients developed a BSI over 67,775 patient-days vs. 557 (0.008) control patients over 69,617 catheter-days.	('patient', 'Species', '9606', (33, 40))	('patients', 'Species', '9606', (33, 41))	('CHG', 'Chemical', 'MESH:C010882', (29, 32))	('CHG', 'Var', (29, 32))	('patient', 'Species', '9606', (70, 77))	('BSI', 'MPA', (54, 57))	('patient', 'Species', '9606', (107, 114))	('patients', 'Species', '9606', (107, 115))
66264	23248752	SSI occurred in only 1.3% of patients receiving cefuroxime vs. 2.8% in the placebo group.	('cefuroxime', 'Chemical', 'MESH:D002444', (48, 58))	('patients', 'Species', '9606', (29, 37))	('cefuroxime', 'Var', (48, 58))	('SSI', 'Disease', (0, 3))
66331	23248752	Summary: Microdiscectomy significantly improve pain-associated depression, somatic anxiety, and mental well-being in patients with herniated lumbar disc.	('improve', 'PosReg', (39, 46))	('herniated lumbar disc', 'Phenotype', 'HP:0008441', (131, 152))	('depression', 'Disease', 'MESH:D000275', (63, 73))	('depression', 'Phenotype', 'HP:0000716', (63, 73))	('somatic anxiety', 'Disease', 'MESH:D001008', (75, 90))	('Microdiscectomy', 'Var', (9, 24))	('anxiety', 'Phenotype', 'HP:0000739', (83, 90))	('herniated lumbar disc', 'Disease', (131, 152))	('mental well-being', 'CPA', (96, 113))	('somatic anxiety', 'Disease', (75, 90))	('depression', 'Disease', (63, 73))	('pain', 'Phenotype', 'HP:0012531', (47, 51))	('pain', 'Disease', 'MESH:D010146', (47, 51))	('pain', 'Disease', (47, 51))	('patients', 'Species', '9606', (117, 125))
66339	20960497	Combined Modality Therapy of cT2N0M0 Esophageal Cancer: UT M. D. Anderson Cancer Center Experience Treatment strategy for patients with adequately staged cT2N0M0 carcinoma of the thoracic esophagus is a subject of debate.	('Esophageal Cancer', 'Disease', (37, 54))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))	('men', 'Species', '9606', (104, 107))	('cT2N0M0', 'Var', (154, 161))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('carcinoma of the thoracic esophagus', 'Disease', 'MESH:D004938', (162, 197))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Disease', (48, 54))	('patients', 'Species', '9606', (122, 130))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (37, 54))	('carcinoma of the thoracic esophagus', 'Disease', (162, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
66340	20960497	We analyzed the largest series of consecutive cT2N0M0 esophageal cancer patients treated with preoperative chemoradiotherapy.	('cT2N0M0', 'Var', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('patients', 'Species', '9606', (72, 80))
66356	20960497	Therapy options available to patients with localized >=cT1b esophageal cancer located in the thoracic cavity include primary surgery, preoperative therapy, or definitive chemoradiation therapy.	('patients', 'Species', '9606', (29, 37))	('esophageal cancer', 'Disease', (60, 77))	('>=cT1b', 'Var', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
66365	20960497	Clearly, cT2N0M0 esophageal cancer is not a common entity and there is no agreement as to how these patients should be treated.	('men', 'Species', '9606', (79, 82))	('cT2N0M0', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('esophageal cancer', 'Disease', (17, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (17, 34))	('patients', 'Species', '9606', (100, 108))
66404	20960497	Our study also demonstrates that the actuarial 10-year survival rate of patients with cT2N0M0 adenocarcinoma is 60% and although our results cannot be compared to those by others, they are encouraging.	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('cT2N0M0', 'Var', (86, 93))	('adenocarcinoma', 'Disease', (94, 108))	('adenocarcinoma', 'Disease', 'MESH:D000230', (94, 108))	('patients', 'Species', '9606', (72, 80))
66407	20960497	Our study cannot resolve the issue of what would be the best therapy for patients with adequately staged cT2N0M0 esophageal cancer but suggests that a prospective evaluation may be warranted.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('cT2N0M0', 'Var', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal cancer', 'Disease', (113, 130))	('patients', 'Species', '9606', (73, 81))
66409	20960497	In conclusion, our study demonstrates that cT2N0M0 patients treated with preoperative chemoradiation have an excellent overall survival and disease-free survival.	('patients', 'Species', '9606', (51, 59))	('cT2N0M0', 'Var', (43, 50))	('disease-free survival', 'CPA', (140, 161))
66440	32225025	Herein, we have investigated the effect of nc886 on cell proliferation to provide a clue as to how nc886 silencing promotes ESCC carcinogenesis.	('nc886', 'Gene', (43, 48))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('nc886', 'Gene', (99, 104))	('nc886', 'Gene', '100126299', (43, 48))	('carcinogenesis', 'Disease', (129, 143))	('nc886', 'Gene', '100126299', (99, 104))	('silencing', 'Var', (105, 114))	('promotes', 'PosReg', (115, 123))
66446	32225025	Antibodies against phospho-AKT at Ser473 (cat # 9271), total AKT (cat # 4691), phospho-FOXO3 at Thr32 (cat # 9464), total FOXO3 (cat # 2497), and GAPDH (cat # 2118) were purchased from Cell Signaling Technology (CST, Beverly, MA).	('Thr32', 'Chemical', '-', (96, 101))	('GAPDH', 'Gene', '2597', (146, 151))	('FOXO3', 'Gene', (122, 127))	('GAPDH', 'Gene', (146, 151))	('FOXO3', 'Gene', '2309', (122, 127))	('FOXO3', 'Gene', (87, 92))	('Ser473', 'Chemical', '-', (34, 40))	('cat # 4691', 'Var', (66, 76))	('FOXO3', 'Gene', '2309', (87, 92))	('cat # 9464', 'Var', (103, 113))
66455	32225025	Anti-oligos ("anti-nc886" and "anti-control") used in this study were the same as our previous study (therein named "anti886 75-56" and "anti-vt 21-2" respectively).	('anti886', 'Var', (117, 124))	('nc886', 'Gene', '100126299', (19, 24))	('nc886', 'Gene', (19, 24))
66458	32225025	For nc886 KD in Het-1A cells and ESCC patients, array data had been generated in our previous studies and deposited to the Gene Expression Omnibus database (GSE66258 for ESCC samples and GSE51732 for Het-1A) in the National Center for Biotechnology Information.	('nc886', 'Gene', (4, 9))	('nc886', 'Gene', '100126299', (4, 9))	('GSE51732', 'Var', (187, 195))	('patients', 'Species', '9606', (38, 46))
66468	32225025	Palbociclib was added at eleven different concentrations (0, 0.15625, 0.3125, 0.625, 1.25, 2.5, 5, 10, 20, 40, and 80 microM) at 37  C. After 48 h incubation, the cells were washed with fresh media and were grown in palbociclib-free media for an additional 24 h, until MTT assays were done as specified by the manufacturer's instructions.	('MTT', 'Chemical', 'MESH:C070243', (269, 272))	('0.625', 'Var', (78, 83))	('palbociclib', 'Chemical', 'MESH:C500026', (216, 227))	('0.3125', 'Var', (70, 76))
66480	32225025	nc886 expression has become low or epigenetically silenced in ESCC cells (nc886- cells) and we attempted to construct an isogenic nc886+ ESCC cell line from them.	('nc886', 'Gene', '100126299', (74, 79))	('nc886', 'Gene', '100126299', (130, 135))	('nc886', 'Gene', (130, 135))	('nc886', 'Gene', (0, 5))	('nc886', 'Gene', '100126299', (0, 5))	('epigenetically', 'Var', (35, 49))	('nc886', 'Gene', (74, 79))
66500	32225025	At 12 h, nc886- cells progressed further to the S phase and this progression was delayed in the case of nc886+ cells (the 293T-U6 and 293T-U6:nc886 pair in Figure 2; the 293T-GFP and 293T-GFP/nc886 pair in Figure S3).	('nc886', 'Gene', '100126299', (9, 14))	('293T', 'CellLine', 'CVCL:0063', (122, 126))	('293T', 'CellLine', 'CVCL:0063', (134, 138))	('293T', 'CellLine', 'CVCL:0063', (183, 187))	('293T-GFP', 'Var', (170, 178))	('nc886', 'Gene', (192, 197))	('nc886', 'Gene', '100126299', (142, 147))	('nc886', 'Gene', '100126299', (104, 109))	('293T', 'CellLine', 'CVCL:0063', (170, 174))	('nc886', 'Gene', '100126299', (192, 197))	('293T-U6', 'CellLine', 'CVCL:0063', (134, 141))	('nc886', 'Gene', (142, 147))	('nc886', 'Gene', (9, 14))	('nc886', 'Gene', (104, 109))	('293T-U6', 'CellLine', 'CVCL:0063', (122, 129))
66542	32225025	In our RPPA data, phosphorylation of AKT1 at Thr308 and Ser473 was increased, with the total AKT1 being relatively unchanged (Figure 5A).	('AKT1', 'Gene', (37, 41))	('Ser473', 'Chemical', '-', (56, 62))	('Thr308', 'Chemical', '-', (45, 51))	('AKT1', 'Gene', '207', (93, 97))	('increased', 'PosReg', (67, 76))	('phosphorylation', 'MPA', (18, 33))	('AKT1', 'Gene', (93, 97))	('AKT1', 'Gene', '207', (37, 41))	('Thr308', 'Var', (45, 51))	('Ser473', 'Var', (56, 62))
66569	32225025	In all three curves, a higher prognostic score was proportional to a shorter survival; patients with score 4 (advanced stages III and IV, low nc886, high AKT signature score, and high cell cycle score) survived the worst, whereas those with score 0 (vice versa) survived the best.	('high', 'Var', (149, 153))	('AKT', 'Pathway', (154, 157))	('nc886', 'Gene', '100126299', (142, 147))	('nc886', 'Gene', (142, 147))	('low', 'NegReg', (138, 141))	('patients', 'Species', '9606', (87, 95))
66578	32225025	In line with the IC50 data, the apoptosis rate was highest in TT and higher in TE-8, as compare to TE-1 (Figure 7E).	('TE-8', 'Var', (79, 83))	('TE', 'Chemical', 'MESH:D013691', (99, 101))	('apoptosis rate', 'CPA', (32, 46))	('TE', 'Chemical', 'MESH:D013691', (79, 81))
66589	32225025	When nc886 silencing occurs in a neoplastic cell, it will lead to AKT activation and promotion of the G1-S transition.	('silencing', 'Var', (11, 20))	('G1-S transition', 'CPA', (102, 117))	('nc886', 'Gene', '100126299', (5, 10))	('AKT', 'Pathway', (66, 69))	('promotion', 'PosReg', (85, 94))	('activation', 'PosReg', (70, 80))	('nc886', 'Gene', (5, 10))
66602	32225025	AKT has been shown to inhibit the E2F activity and E2F has been shown to activate CDKN2A and CDKN2C.	('activity', 'MPA', (38, 46))	('inhibit', 'NegReg', (22, 29))	('E2F', 'Var', (51, 54))	('CDKN2A', 'Gene', (82, 88))	('CDKN2C', 'Gene', '1031', (93, 99))	('activate', 'PosReg', (73, 81))	('CDKN2A', 'Gene', '1029', (82, 88))	('CDKN2C', 'Gene', (93, 99))
66606	32225025	As cyclin D1-CDK4/6 is crucial for G1 cell cycle progression and generation of neoplastic cells, targeting CDK4/6 could be effective for ESCC patients.	('CDK4/6', 'Gene', '1019;1021', (13, 19))	('cyclin D1', 'Gene', '595', (3, 12))	('ESCC', 'Disease', (137, 141))	('CDK4/6', 'Gene', (13, 19))	('CDK4/6', 'Gene', '1019;1021', (107, 113))	('patients', 'Species', '9606', (142, 150))	('targeting', 'Var', (97, 106))	('CDK4/6', 'Gene', (107, 113))	('cyclin D1', 'Gene', (3, 12))
66613	32225025	); by grants from the National Cancer Center, Korea (NCC-1810070 to Y.S.L.	('NCC-1810070', 'Var', (53, 64))	('Cancer', 'Disease', (31, 37))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Cancer', 'Disease', 'MESH:D009369', (31, 37))
66616	30945310	We downloaded genomic profiles of GSE781, GSE6244, GSE53757, and GSE66271 from the Gene Expression Omnibus (GEO) database.	('GSE6244', 'Var', (42, 49))	('Ge', 'Chemical', 'MESH:D005857', (83, 85))	('GSE66271', 'Var', (65, 73))	('GSE53757', 'Var', (51, 59))
66627	30945310	(2009) found no relationship between VHL mutations/deletions and prognosis in ccRCC patients.	('VHL', 'Disease', (37, 40))	('patients', 'Species', '9606', (84, 92))	('ccRCC', 'Disease', (78, 83))	('ccRCC', 'Disease', 'MESH:D002292', (78, 83))	('mutations/deletions', 'Var', (41, 60))	('VHL', 'Disease', 'MESH:D006623', (37, 40))
66657	30945310	Cell proliferation in GNG7 knockdown was carried out as previously described (Xu et al., 2016).	('knockdown', 'Var', (27, 36))	('GNG7', 'Gene', '2788', (22, 26))	('GNG7', 'Gene', (22, 26))
66681	30945310	We found that the distribution curves tended to be "bumpy" in phenotype in GNG7 expression high-group enrichment when compared to the enrichment plot of GNG7 low expression group (Figure S3).	('men', 'Species', '9606', (140, 143))	('GNG7', 'Gene', (153, 157))	('men', 'Species', '9606', (108, 111))	('GNG7', 'Gene', (75, 79))	('GNG7', 'Gene', '2788', (153, 157))	('high-group', 'Var', (91, 101))	('GNG7', 'Gene', '2788', (75, 79))
66684	30945310	These results reveal that repressed GNG7 was associated with increased cell proliferation and viability in ccRCC progression.	('GNG7', 'Gene', (36, 40))	('repressed', 'Var', (26, 35))	('increased', 'PosReg', (61, 70))	('viability', 'CPA', (94, 103))	('ccRCC', 'Disease', (107, 112))	('GNG7', 'Gene', '2788', (36, 40))	('ccRCC', 'Disease', 'MESH:D002292', (107, 112))	('cell proliferation', 'CPA', (71, 89))
66690	30945310	To determine the mechanism of cell growth inhibition in by GNG7, cell-cycle assay was performed in A498 and 786-O cells after knocking down GNG7 for 48 hr (Figure 7e).	('knocking down', 'Var', (126, 139))	('GNG7', 'Gene', '2788', (59, 63))	('GNG7', 'Gene', '2788', (140, 144))	('GNG7', 'Gene', (140, 144))	('GNG7', 'Gene', (59, 63))
66701	30945310	These findings are consistent with the previous reports showing that loss of GNG7 was related to large tumor and tumor invasion and aggressiveness in squamous cell carcinoma of head and neck and esophageal cancer (S. Wu, F. Wu, & Jiang, 2017; Ohta et al., 2008), respectively.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('aggressiveness', 'Phenotype', 'HP:0000718', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('loss', 'Var', (69, 73))	('tumor', 'Disease', (103, 108))	('GNG7', 'Gene', (77, 81))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (164, 190))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('related', 'Reg', (86, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('GNG7', 'Gene', '2788', (77, 81))	('tumor invasion and aggressiveness in squamous cell carcinoma of head and neck and esophageal cancer', 'Disease', 'MESH:C535575', (113, 212))
66704	30945310	Moreover, GNG7 gene mutation was found in almost all ccRCC patients in this study, further validating the TCGA data set (Figure 3a).	('ccRCC', 'Disease', (53, 58))	('found', 'Reg', (33, 38))	('GNG7', 'Gene', '2788', (10, 14))	('ccRCC', 'Disease', 'MESH:D002292', (53, 58))	('mutation', 'Var', (20, 28))	('GNG7', 'Gene', (10, 14))	('patients', 'Species', '9606', (59, 67))
66705	30945310	This result indicates that GNG7 gene methylation and high CG sit may be responsible for GNG7 gene inactivation in ccRCC progression.	('ccRCC', 'Disease', (114, 119))	('GNG7', 'Gene', '2788', (27, 31))	('ccRCC', 'Disease', 'MESH:D002292', (114, 119))	('GNG7', 'Gene', (88, 92))	('methylation', 'Var', (37, 48))	('CG sit', 'CPA', (58, 64))	('GNG7', 'Gene', (27, 31))	('GNG7', 'Gene', '2788', (88, 92))	('inactivation', 'NegReg', (98, 110))
66717	30945310	GNG7 gene was strongly suppressed in ccRCC tumor tissues as a result of promoter methylation and frequent gene mutation.	('ccRCC', 'Disease', (37, 42))	('suppressed', 'NegReg', (23, 33))	('GNG7', 'Gene', '2788', (0, 4))	('ccRCC', 'Disease', 'MESH:D002292', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('GNG7', 'Gene', (0, 4))	('mutation', 'Var', (111, 119))	('tumor', 'Disease', (43, 48))
66823	30444988	We focused on tumor response, perioperative morbidity and mortality, and overall survival within three dosage groups that were defined for this study: low-dose (30-40Gy), standard-dose (40-50.4Gy), or high-dose (>50.4-70Gy).	('tumor', 'Disease', (14, 19))	('40-50.4Gy', 'Var', (186, 195))	('30-40Gy', 'Var', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('>50.4-70Gy', 'Var', (212, 222))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
66828	30444988	Patients were excluded if they had clinical distant metastatic disease, underwent laryngectomy, had an interval between the start of induction and surgery >6 months, the esophagus was not the site of radiation administration, or radiation dose was <30Gy or >70Gy.	('Patients', 'Species', '9606', (0, 8))	('laryngectomy', 'Disease', (82, 94))	('<30Gy', 'Var', (248, 253))
66829	30444988	Based on common clinical practice and histogram analysis, patients were classified as receiving low-dose (30-40Gy), standard-dose (40-50.4Gy), or high-dose (>50.4-70Gy) induction radiation (Figure 1).	('patients', 'Species', '9606', (58, 66))	('40-50.4Gy', 'Var', (131, 140))	('>50.4-70Gy', 'Var', (157, 167))
66831	30444988	The following variables were abstracted as covariates: age, sex, race (white vs non-white), insurance status (public vs private), median income by zip code (lowest quartile of <$38,000 vs >$38,000), population by zip code (>250,000 vs <250,000), treatment center (academic vs non-academic), Charlson Deyo Score (0, 1, >=2), tumor size, histology (squamous cell vs adenocarcinoma), clinically positive lymph nodes (cN0 vs cN1-3), receipt of neoadjuvant chemotherapy (considered concurrent if started within two weeks), and the interval between the start of induction radiation and surgery (categorized by quartile).	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('zip', 'Gene', (213, 216))	('adenocarcinoma', 'Disease', (364, 378))	('tumor', 'Disease', (324, 329))	('zip', 'Gene', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('>250,000', 'Var', (223, 231))	('adenocarcinoma', 'Disease', 'MESH:D000230', (364, 378))	('zip', 'Gene', '1613', (213, 216))	('tumor', 'Disease', 'MESH:D009369', (324, 329))	('zip', 'Gene', '1613', (147, 150))
66852	30444988	Cox proportional hazards modeling demonstrated a trend towards worse survival for non-standard radiation doses in squamous cell patients (low-dose HR 1.19, 95%CI: 0.99-1.43 and high-dose HR 1.22, 95%CI: 0.95-1.58, p=0.07), whereas there was not a significant trend for adenocarcinoma patients (p=0.2).	('worse', 'NegReg', (63, 68))	('squamous cell', 'Disease', (114, 127))	('patients', 'Species', '9606', (284, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('adenocarcinoma', 'Disease', (269, 283))	('patients', 'Species', '9606', (128, 136))	('adenocarcinoma', 'Disease', 'MESH:D000230', (269, 283))	('high-dose HR', 'Var', (177, 189))
66854	30444988	Current dosing is extrapolated primarily from non-operative populations: Herskovic et al demonstrated in a randomized controlled trial that improved survival was seen in patients getting concurrent chemoradiation with 5-FU, cisplatin, and 50Gy of radiation versus high-dose radiation of 64Gy alone.	('5-FU', 'Chemical', 'MESH:D005472', (218, 222))	('50Gy of', 'Var', (239, 246))	('improved', 'PosReg', (140, 148))	('patients', 'Species', '9606', (170, 178))	('survival', 'MPA', (149, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (224, 233))
66859	30444988	This study examined radiation dose in the surgical population and demonstrated that doses between 40-50.4Gy optimally maximize tumor response to induction therapy without increasing operative risk.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('maximize', 'PosReg', (118, 126))	('tumor', 'Disease', (127, 132))	('doses', 'Var', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
66877	29580149	A novel BRCA2 mutation in prostate cancer sensitive to combined radiotherapy and androgen deprivation therapy Genetic factors contribute to more than 40% of prostate cancer risk, and mutations in BRCA1 and BRCA2 are well-established risk factors.	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('BRCA1', 'Gene', '672', (196, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('BRCA2', 'Gene', '675', (206, 211))	('BRCA2', 'Gene', (8, 13))	('prostate cancer', 'Disease', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BRCA1', 'Gene', (196, 201))	('contribute', 'Reg', (126, 136))	('mutation', 'Var', (14, 22))	('BRCA2', 'Gene', '675', (8, 13))	('prostate cancer', 'Disease', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('BRCA2', 'Gene', (206, 211))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))
66878	29580149	By using target capture-based deep sequencing to identify potential pathogenic germline mutations, followed by Sanger sequencing to determine the loci of the mutations, we identified a novel pathogenic BRCA2 mutation caused by a cytosine-to-guanine base substitution at position 4211, resulting in protein truncation (p.Ser1404Ter), which was confirmed by immunohistochemistry.	('guanine', 'Chemical', 'MESH:D006147', (241, 248))	('mutation', 'Var', (208, 216))	('cytosine', 'Chemical', 'MESH:D003596', (229, 237))	('pathogenic', 'Reg', (191, 201))	('BRCA2', 'Gene', '675', (202, 207))	('p.Ser1404Ter', 'Mutation', 'rs41293489', (318, 330))	('caused by', 'Reg', (217, 226))	('protein truncation', 'MPA', (298, 316))	('BRCA2', 'Gene', (202, 207))
66879	29580149	Analysis of peripheral blood also identified benign polymorphisms in BRCA2 (c.7397T>C, p.Val2466Ala) and SRD5A2 (c.87G>C, p.Lys29Asn).	('c.87G>C', 'Mutation', 'c.87G>C', (113, 120))	('BRCA2', 'Gene', '675', (69, 74))	('SRD5A2', 'Gene', '6716', (105, 111))	('c.7397T>C', 'Mutation', 'rs169547', (76, 85))	('p.Val2466Ala', 'Mutation', 'rs169547', (87, 99))	('c.7397T>C', 'Var', (76, 85))	('p.Lys29Asn', 'Mutation', 'p.K29N', (122, 132))	('BRCA2', 'Gene', (69, 74))	('p.Lys29Asn', 'Var', (122, 132))	('SRD5A2', 'Gene', (105, 111))	('p.Val2466Ala', 'Var', (87, 99))	('c.87G>C', 'Var', (113, 120))
66880	29580149	Analysis of tumor tissues revealed seven somatic mutations in prostate tumor tissue and nine somatic mutations in esophageal squamous carcinoma tissue (single nucleotide polymorphisms, insertions, and deletions).	('tumor', 'Disease', (12, 17))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (114, 143))	('insertions', 'Var', (185, 195))	('prostate tumor', 'Disease', 'MESH:D011471', (62, 76))	('esophageal squamous carcinoma', 'Disease', (114, 143))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('prostate tumor', 'Phenotype', 'HP:0100787', (62, 76))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (114, 143))	('single nucleotide polymorphisms', 'Var', (152, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('prostate tumor', 'Disease', (62, 76))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (125, 143))	('deletions', 'Var', (201, 210))	('tumor', 'Disease', (71, 76))
66882	29580149	To our knowledge, we are the first to report the germline BRCA2 mutation c.4211C>G (p.Ser1404Ter) in prostate cancer.	('BRCA2', 'Gene', '675', (58, 63))	('prostate cancer', 'Disease', (101, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('c.4211C>G', 'Mutation', 'rs41293489', (73, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('c.4211C>G', 'Var', (73, 82))	('p.Ser1404Ter', 'Mutation', 'rs41293489', (84, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))	('BRCA2', 'Gene', (58, 63))
66883	29580149	Combined ADT and radiotherapy may be effective in treating other patients with prostate cancer caused by this or similar mutations.	('mutations', 'Var', (121, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('caused by', 'Reg', (95, 104))	('ADT', 'Chemical', '-', (9, 12))	('patients', 'Species', '9606', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('prostate cancer', 'Disease', (79, 94))
66886	29580149	Mutations in the tumor suppressor genes BRCA1 and BRCA2 are well-known genetic risk factors for this cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', (17, 22))	('cancer', 'Disease', (101, 107))	('BRCA2', 'Gene', (50, 55))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA1', 'Gene', '672', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('BRCA2', 'Gene', '675', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BRCA1', 'Gene', (40, 45))
66887	29580149	BRCA1 and BRCA2 mutations are associated with an increased risk for many cancers including breast, ovarian, pancreatic, stomach, laryngeal, and fallopian tube cancer, as well as PCa.	('PCa', 'Phenotype', 'HP:0012125', (178, 181))	('fallopian tube cancer', 'Disease', (144, 165))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', (73, 80))	('PCa', 'Disease', (178, 181))	('BRCA2', 'Gene', '675', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('fallopian tube cancer', 'Phenotype', 'HP:0030394', (144, 165))	('BRCA1', 'Gene', '672', (0, 5))	('associated', 'Reg', (30, 40))	('fallopian tube cancer', 'Disease', 'MESH:D005185', (144, 165))	('BRCA1', 'Gene', (0, 5))	('stomach', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('breast, ovarian, pancreatic', 'Disease', 'MESH:D010051', (91, 118))	('man', 'Species', '9606', (68, 71))	('laryngeal', 'Disease', (129, 138))	('BRCA2', 'Gene', (10, 15))
66888	29580149	The increased cancer risk in carriers of the BRCA1/BRCA2 mutations is predominantly in breast cancer and ovarian cancer for women and PCa for men.	('BRCA2', 'Gene', (51, 56))	('PCa', 'Disease', (134, 137))	('BRCA1', 'Gene', '672', (45, 50))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Disease', (113, 119))	('BRCA1', 'Gene', (45, 50))	('mutations', 'Var', (57, 66))	('breast cancer', 'Disease', (87, 100))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ovarian cancer', 'Disease', 'MESH:D010051', (105, 119))	('BRCA2', 'Gene', '675', (51, 56))	('cancer', 'Disease', (94, 100))	('men', 'Species', '9606', (142, 145))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('ovarian cancer', 'Disease', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('women', 'Species', '9606', (124, 129))	('cancer', 'Disease', (14, 20))	('men', 'Species', '9606', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('PCa', 'Phenotype', 'HP:0012125', (134, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
66889	29580149	Germline BRCA2 and BRCA1 mutations are present in 1.2% and 0.44% of PCa tumors, respectively.	('PCa tumors', 'Disease', 'MESH:D009369', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutations', 'Var', (25, 34))	('BRCA2', 'Gene', (9, 14))	('PCa', 'Phenotype', 'HP:0012125', (68, 71))	('PCa tumors', 'Disease', (68, 78))	('BRCA2', 'Gene', '675', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('BRCA1', 'Gene', '672', (19, 24))	('BRCA1', 'Gene', (19, 24))
66890	29580149	Compared with the general population, the relative risk of PCa is 3.8 for carriers of BRCA1 mutations up to 65 years of age and 5 to 7 for carriers of BRCA2 mutations.	('to 7', 'Species', '1214577', (130, 134))	('BRCA1', 'Gene', '672', (86, 91))	('BRCA2', 'Gene', '675', (151, 156))	('PCa', 'Disease', (59, 62))	('BRCA1', 'Gene', (86, 91))	('mutations', 'Var', (92, 101))	('PCa', 'Phenotype', 'HP:0012125', (59, 62))	('BRCA2', 'Gene', (151, 156))
66891	29580149	Male BRCA mutation carriers with localized PCa are at substantially higher risk of dying from PCa than their non-mutation-carrying counterparts.	('PCa', 'Disease', (43, 46))	('PCa', 'Phenotype', 'HP:0012125', (43, 46))	('mutation', 'Var', (10, 18))	('PCa', 'Disease', (94, 97))	('BRCA', 'Gene', '672', (5, 9))	('BRCA', 'Gene', (5, 9))	('PCa', 'Phenotype', 'HP:0012125', (94, 97))
66892	29580149	Moreover, BRCA2 contributes to early onset, with 1.2% patients younger than 65 years old carrying germline BRCA2 mutations.	('BRCA2', 'Gene', '675', (10, 15))	('BRCA2', 'Gene', '675', (107, 112))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (113, 122))	('BRCA2', 'Gene', (10, 15))	('BRCA2', 'Gene', (107, 112))
66893	29580149	BRCA1/2 mutations are also associated with higher Gleason scores, and germline BRCA1/2 mutations confer a more aggressive phenotype with a higher probability of nodal involvement, distant metastasis, and shorter survival.	('BRCA1/2', 'Gene', (79, 86))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('higher', 'PosReg', (43, 49))	('Gleason scores', 'MPA', (50, 64))	('BRCA1/2', 'Gene', '672;675', (79, 86))	('mutations', 'Var', (8, 17))	('shorter', 'NegReg', (204, 211))	('men', 'Species', '9606', (174, 177))	('nodal involvement', 'CPA', (161, 178))	('BRCA1/2', 'Gene', (0, 7))	('mutations', 'Var', (87, 96))	('distant metastasis', 'CPA', (180, 198))
66894	29580149	Tumors in BRCA mutation carriers that have defects in homologous recombination can be treated with radiotherapy, cisplatin, anthracyclines, or poly(ADP-ribose) polymerase inhibitors.	('mutation', 'Var', (15, 23))	('BRCA', 'Gene', '672', (10, 14))	('BRCA', 'Gene', (10, 14))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('anthracyclines', 'Chemical', 'MESH:D018943', (124, 138))
66895	29580149	In addition, radical local therapy (e.g., radical prostatectomy or radiotherapy) can be effective when performed early for PCa with BRCA2 mutations.	('BRCA2', 'Gene', (132, 137))	('PCa', 'Phenotype', 'HP:0012125', (123, 126))	('BRCA2', 'Gene', '675', (132, 137))	('PCa', 'Disease', (123, 126))	('mutations', 'Var', (138, 147))
66896	29580149	For metastatic castration-resistant PCa with biallelic inactivation of BRCA2, chemotherapy with platinum agents has been suggested.	('metastatic castration-resistant PCa', 'Disease', (4, 39))	('PCa', 'Phenotype', 'HP:0012125', (36, 39))	('biallelic inactivation', 'Var', (45, 67))	('BRCA2', 'Gene', (71, 76))	('BRCA2', 'Gene', '675', (71, 76))
66897	29580149	reported that poly(ADP-ribose) polymerase inhibitors are efficacious in cancers with homologous recombination defects in tumors deficient in BRCA1 and BRCA2 but not in tumors with functional BRCA1 or BRCA2 proteins.	('BRCA2', 'Gene', (200, 205))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BRCA2', 'Gene', '675', (200, 205))	('tumors deficient', 'Disease', (121, 137))	('BRCA2', 'Gene', (151, 156))	('defects', 'Var', (110, 117))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('BRCA1', 'Gene', '672', (191, 196))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('tumors deficient', 'Disease', 'MESH:D009369', (121, 137))	('BRCA1', 'Gene', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('BRCA2', 'Gene', '675', (151, 156))	('BRCA1', 'Gene', '672', (141, 146))	('tumors', 'Disease', (121, 127))	('BRCA1', 'Gene', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
66899	29580149	Here we report a patient with locally advanced PCa carrying a novel germline BRCA2 mutation.	('PCa', 'Disease', (47, 50))	('PCa', 'Phenotype', 'HP:0012125', (47, 50))	('patient', 'Species', '9606', (17, 24))	('BRCA2', 'Gene', (77, 82))	('mutation', 'Var', (83, 91))	('BRCA2', 'Gene', '675', (77, 82))
66904	29580149	Immunohistochemistry results showed positive staining for Ki-67, p504S, and PSA, and negative results for p63 and 34betaE2.	('p63', 'Gene', (106, 109))	('Ki-67', 'Var', (58, 63))	('PSA', 'Gene', '354', (76, 79))	('PSA', 'Gene', (76, 79))	('p63', 'Gene', '8626', (106, 109))	('p504S', 'Var', (65, 70))
66909	29580149	1B) showed that the pelvic lymph nodes and tumor had shrunk (2.1 x 2.7 cm), presumably as a result of ADT.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ADT', 'Var', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('ADT', 'Chemical', '-', (102, 105))
66918	29580149	To identify potential pathogenic mutations, we screened a panel of seven genes (BRCA2, CHEK2, ELAC2, HSD17B3, HSD3B2, RNASEL, and SRD5A2) using the patient's peripheral blood and identified a novel germline BRCA2 mutation: Ser1404Ter caused by a C>G point mutation at position 4211 (Fig.	('HSD3B2', 'Gene', '3284', (110, 116))	('SRD5A2', 'Gene', '6716', (130, 136))	('HSD17B3', 'Gene', '3293', (101, 108))	('RNASEL', 'Gene', (118, 124))	('HSD17B3', 'Gene', (101, 108))	('BRCA2', 'Gene', (80, 85))	('BRCA2', 'Gene', (207, 212))	('SRD5A2', 'Gene', (130, 136))	('Ser1404Ter', 'SUBSTITUTION', 'None', (223, 233))	('HSD3B2', 'Gene', (110, 116))	('CHEK2', 'Gene', (87, 92))	('BRCA2', 'Gene', '675', (80, 85))	('Ser1404Ter', 'Var', (223, 233))	('BRCA2', 'Gene', '675', (207, 212))	('patient', 'Species', '9606', (148, 155))	('CHEK2', 'Gene', '11200', (87, 92))	('ELAC2', 'Gene', '60528', (94, 99))	('C>G point mutation at', 'Var', (246, 267))	('ELAC2', 'Gene', (94, 99))	('caused by', 'Reg', (234, 243))	('RNASEL', 'Gene', '6041', (118, 124))
66919	29580149	We also identified two germline mutations in BRCA2 (c.7397T>C, p.Val2466Ala) and SRD5A2 (c.87G>C, p.Lys29Asn) that resulted in benign polymorphisms (data not shown).	('SRD5A2', 'Gene', (81, 87))	('BRCA2', 'Gene', (45, 50))	('p.Val2466Ala', 'Mutation', 'rs169547', (63, 75))	('c.87G>C', 'Mutation', 'c.87G>C', (89, 96))	('BRCA2', 'Gene', '675', (45, 50))	('c.7397T>C', 'Var', (52, 61))	('SRD5A2', 'Gene', '6716', (81, 87))	('p.Lys29Asn', 'Mutation', 'p.K29N', (98, 108))	('c.7397T>C', 'Mutation', 'rs169547', (52, 61))	('p.Lys29Asn', 'Var', (98, 108))	('p.Val2466Ala', 'Var', (63, 75))	('c.87G>C', 'Var', (89, 96))	('polymorphisms', 'MPA', (134, 147))
66920	29580149	The following seven somatic single nucleotide polymorphism/indel mutations were identified in PCa tumor tissue: TP53 (c.1049T>C, p.L350P), PIK3CB (c.2527G>C, p.A843P), MLL (c.2806T>A, p.S936T), PTCH1 (c.2075>A, p.V692E), and TERT (c.-58-u5148C>A; c.-58-u3620G>A; c.-58-u1324T>C).	('p.L350P', 'Mutation', 'rs201174718', (129, 136))	('MLL', 'Gene', '4297', (168, 171))	('MLL', 'Gene', (168, 171))	('c.1049T>C', 'Var', (118, 127))	('c.-58-u5148C>A', 'Var', (231, 245))	('TP53', 'Gene', '7157', (112, 116))	('c.-58-u1324T>C', 'Mutation', 'c.-58,1324T>C', (263, 277))	('p.A843P', 'Mutation', 'p.A843P', (158, 165))	('PTCH1', 'Gene', '5727', (194, 199))	('c.-58-u3620G>A', 'Mutation', 'c.-58,3620G>A', (247, 261))	('c.2806T>A', 'Mutation', 'c.2806T>A', (173, 182))	('c.2075>A', 'Var', (201, 209))	('PIK3CB', 'Gene', (139, 145))	('PIK3CB', 'Gene', '5291', (139, 145))	('p.V692E', 'Mutation', 'p.V692E', (211, 218))	('c.2806T>A', 'Var', (173, 182))	('TERT', 'Gene', (225, 229))	('TERT', 'Gene', '7015', (225, 229))	('PCa tumor', 'Disease', (94, 103))	('c.1049T>C', 'Mutation', 'rs201174718', (118, 127))	('c.2527G>C', 'Mutation', 'c.2527G>C', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PCa tumor', 'Disease', 'MESH:D009369', (94, 103))	('c.2527G>C', 'Var', (147, 156))	('PTCH1', 'Gene', (194, 199))	('c.-58-u1324T>C', 'Var', (263, 277))	('PCa', 'Phenotype', 'HP:0012125', (94, 97))	('TP53', 'Gene', (112, 116))	('c.-58-u3620G>A; c.-58-u1324T>C', 'Var', (247, 277))	('p.S936T', 'Mutation', 'p.S936T', (184, 191))	('c.-58-u5148C>A', 'SUBSTITUTION', 'None', (231, 245))
66921	29580149	The following nine somatic single nucleotide polymorphism/indel mutations were identified in esophageal squamous carcinoma tissue: TP53 (c.743G>A, p.R248Q; c.713G>C, p.C238S), PIK3CA (c.1636C>A, p.Q546K), PTPRD (c.5083G>A, p.E1695K), MLL3 (c.4093-2A>G; c.10249C>A, p.Q3417K), OR4C6 (c.541C>A, p.Q181K), MSH6 (c.124C>G, p.P42A), and TMPRSS2 (c.589G>A, p.V197M).	('p.R248Q', 'Mutation', 'rs11540652', (147, 154))	('OR4C6', 'Gene', (276, 281))	('esophageal squamous carcinoma', 'Disease', (93, 122))	('c.124C>G', 'Mutation', 'rs730881815', (309, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('c.589G>A', 'Mutation', 'rs12329760', (341, 349))	('TMPRSS2', 'Gene', '7113', (332, 339))	('MLL3', 'Gene', '58508', (234, 238))	('c.589G>A', 'Var', (341, 349))	('p.Q546K', 'Mutation', 'rs121913286', (195, 202))	('c.124C>G', 'Var', (309, 317))	('c.541C>A', 'Mutation', 'rs587782596', (283, 291))	('TMPRSS2', 'Gene', (332, 339))	('PIK3CA', 'Gene', (176, 182))	('TP53', 'Gene', (131, 135))	('PTPRD', 'Gene', (205, 210))	('p.Q3417K', 'Mutation', 'p.Q3417K', (265, 273))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (93, 122))	('c.10249C>A', 'Mutation', 'c.10249C>A', (253, 263))	('c.743G>A', 'Mutation', 'rs11540652', (137, 145))	('c.5083G>A', 'Mutation', 'c.5083G>A', (212, 221))	('OR4C6', 'Gene', '219432', (276, 281))	('MLL3', 'Gene', (234, 238))	('c.1636C>A', 'Var', (184, 193))	('c.713G>C', 'Mutation', 'rs730882005', (156, 164))	('p.E1695K', 'Mutation', 'p.E1695K', (223, 231))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (104, 122))	('PTPRD', 'Gene', '5789', (205, 210))	('MSH6', 'Gene', (303, 307))	('c.10249C>A', 'Var', (253, 263))	('p.C238S', 'Mutation', 'rs730882005', (166, 173))	('c.4093-2A>G', 'Mutation', 'c.4093-2A>G', (240, 251))	('p.P42A', 'Mutation', 'rs34014629', (319, 325))	('p.Q181K', 'Mutation', 'rs1323987464', (293, 300))	('c.5083G>A', 'Var', (212, 221))	('c.743G', 'Var', (137, 143))	('TP53', 'Gene', '7157', (131, 135))	('MSH6', 'Gene', '2956', (303, 307))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (93, 122))	('c.1636C>A', 'Mutation', 'rs121913286', (184, 193))	('PIK3CA', 'Gene', '5290', (176, 182))	('c.541C>A', 'Var', (283, 291))	('p.V197M', 'Mutation', 'rs12329760', (351, 358))
66922	29580149	To determine whether the patient's BRCA2 mutation resulted in a truncated protein, we analyzed prostate and esophageal tumor tissues by immunohistochemistry.	('resulted in', 'Reg', (50, 61))	('truncated', 'MPA', (64, 73))	('BRCA2', 'Gene', '675', (35, 40))	('mutation', 'Var', (41, 49))	('patient', 'Species', '9606', (25, 32))	('esophageal tumor', 'Disease', 'MESH:D004938', (108, 124))	('esophageal tumor', 'Disease', (108, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('esophageal tumor', 'Phenotype', 'HP:0100751', (108, 124))	('BRCA2', 'Gene', (35, 40))
66925	29580149	Levels of full-length BRCA2 in the patient's tumor tissues were considerably lower than those of control tissues, presumably due to the heterozygosity of the BRCA2 mutation expressing the truncated protein.	('lower', 'NegReg', (77, 82))	('Levels', 'MPA', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('BRCA2', 'Gene', (22, 27))	('patient', 'Species', '9606', (35, 42))	('mutation', 'Var', (164, 172))	('BRCA2', 'Gene', '675', (22, 27))	('BRCA2', 'Gene', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('BRCA2', 'Gene', '675', (158, 163))
66926	29580149	Truncated BRCA2 protein was detected primarily in the cytoplasm, whereas full-length BRCA2 protein was detected primarily in the nucleus (Fig.	('BRCA2', 'Gene', '675', (10, 15))	('BRCA2', 'Gene', (85, 90))	('protein', 'Protein', (16, 23))	('Truncated', 'Var', (0, 9))	('BRCA2', 'Gene', (10, 15))	('BRCA2', 'Gene', '675', (85, 90))
66928	29580149	To the best of our knowledge, this is the first description of PCa caused by a germline BRCA2 mutation in a Chinese patient, and the first report of the BRCA mutation c.4211C>G, which results in a truncated protein (p.Ser1404Ter).	('truncated', 'MPA', (197, 206))	('results in', 'Reg', (184, 194))	('c.4211C>G', 'Var', (167, 176))	('patient', 'Species', '9606', (116, 123))	('mutation', 'Var', (94, 102))	('caused by', 'Reg', (67, 76))	('c.4211C>G', 'Mutation', 'rs41293489', (167, 176))	('BRCA2', 'Gene', (88, 93))	('PCa', 'Disease', (63, 66))	('protein', 'Protein', (207, 214))	('BRCA', 'Gene', '672', (153, 157))	('PCa', 'Phenotype', 'HP:0012125', (63, 66))	('BRCA', 'Gene', '672', (88, 92))	('BRCA2', 'Gene', '675', (88, 93))	('BRCA', 'Gene', (153, 157))	('BRCA', 'Gene', (88, 92))	('p.Ser1404Ter', 'Mutation', 'rs41293489', (216, 228))
66929	29580149	We also demonstrated that PCa associated with this mutation is sensitive to ADT combined with radiotherapy.	('PCa', 'Disease', (26, 29))	('ADT', 'Chemical', '-', (76, 79))	('mutation', 'Var', (51, 59))	('PCa', 'Phenotype', 'HP:0012125', (26, 29))
66931	29580149	As a component of the double-strand break (DSB) repair machinery, BRCA2 interacts with RAD51 through the BRC repeats and the RAD51-binding domain at its C-terminus (residues 3196-3232).	('BRCA2', 'Gene', (66, 71))	('RAD51', 'Gene', (87, 92))	('RAD51', 'Gene', (125, 130))	('RAD51', 'Gene', '5888', (87, 92))	('BRCA2', 'Gene', '675', (66, 71))	('BRC', 'Protein', (105, 108))	('RAD51', 'Gene', '5888', (125, 130))	('residues 3196-3232', 'Var', (165, 183))	('interacts', 'Interaction', (72, 81))
66932	29580149	Analysis of previously reported BRCA2 mutations suggests that truncation producing a protein smaller than 3308 amino acids severely affects protein function.	('affects', 'Reg', (132, 139))	('BRCA2', 'Gene', (32, 37))	('protein function', 'MPA', (140, 156))	('smaller', 'NegReg', (93, 100))	('BRCA2', 'Gene', '675', (32, 37))	('mutations', 'Var', (38, 47))	('truncation', 'Var', (62, 72))
66934	29580149	Previous studies have described BRCA2 mutations associated with esophagus cancer, including the mutations c.203G>A, c.10462A>G (p.Ile3412Val), c.8415G>T (p.Lys2729Asn), and c.10204A>T (p.Lys3326Ter).	('c.10462A>G', 'Var', (116, 126))	('c.8415G>T', 'Var', (143, 152))	('c.10462A>G', 'Mutation', 'rs1801426', (116, 126))	('p.Ile3412Val', 'Mutation', 'rs1801426', (128, 140))	('p.Lys2729Asn', 'Mutation', 'rs80359065', (154, 166))	('associated', 'Reg', (48, 58))	('BRCA2', 'Gene', (32, 37))	('esophagus cancer', 'Disease', (64, 80))	('p.Lys3326Ter', 'Mutation', 'rs11571833', (185, 197))	('c.10204A>T', 'Var', (173, 183))	('c.8415G>T', 'Mutation', 'rs80359065', (143, 152))	('c.10204A>T', 'Mutation', 'rs11571833', (173, 183))	('BRCA2', 'Gene', '675', (32, 37))	('c.203G>A', 'Mutation', 'c.203G>A', (106, 114))	('esophagus cancer', 'Disease', 'MESH:D004938', (64, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('c.203G>A', 'Var', (106, 114))
66935	29580149	The mutation identified in this case (C.4211C>G, p.Ser1404Ter) also appears increase the risk of esophageal cancer, suggesting that special attention should be paid to patients with germline mutations of BRCA2 during examination of the upper aero-digestive tract.	('4211C>G', 'Mutation', 'g.4211C>G', (40, 47))	('BRCA2', 'Gene', (204, 209))	('C.4211C>G', 'Var', (38, 47))	('increase', 'PosReg', (76, 84))	('p.Ser1404Ter', 'Mutation', 'rs41293489', (49, 61))	('esophageal cancer', 'Disease', (97, 114))	('BRCA2', 'Gene', '675', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('patients', 'Species', '9606', (168, 176))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('p.Ser1404Ter', 'Var', (49, 61))
66936	29580149	This mutation may also increase the risk of other cancers, given the important role of BRCA2 in DNA repair.	('increase', 'Reg', (23, 31))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('BRCA2', 'Gene', '675', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('mutation', 'Var', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('BRCA2', 'Gene', (87, 92))
66938	29580149	Thus, accumulation of acquired and uncorrected somatic mutations is expected in individuals with germline BRCA2 mutations.	('mutations', 'Var', (112, 121))	('BRCA2', 'Gene', '675', (106, 111))	('BRCA2', 'Gene', (106, 111))
66939	29580149	Indeed, whole exome sequencing revealed multiple somatic mutations in our patient's prostate and esophageal tumor tissues.	('patient', 'Species', '9606', (74, 81))	('esophageal tumor', 'Phenotype', 'HP:0100751', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('revealed', 'Reg', (31, 39))	('mutations', 'Var', (57, 66))	('esophageal tumor', 'Disease', 'MESH:D004938', (97, 113))	('esophageal tumor', 'Disease', (97, 113))
66940	29580149	Misrepair or inefficient repair of DSBs can lead to genetic instability and ultimately carcinogenesis.	('DSBs', 'Gene', (35, 39))	('lead to', 'Reg', (44, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('DSBs', 'Chemical', 'MESH:C007563', (35, 39))	('Misrepair', 'Var', (0, 9))	('carcinogenesis', 'Disease', (87, 101))	('genetic', 'MPA', (52, 59))	('inefficient', 'Var', (13, 24))
66943	29580149	Consistent with the finding that most cancer-causing somatic mutations are associated with chromatin remodeling and DNA repair, we found that both tumors in our patient had mutations in the tumor protein p53 (TP53), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3C), and mixed lineage leukemia (MLL) pathways.	('patient', 'Species', '9606', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (216, 253))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', (38, 44))	('leukemia', 'Phenotype', 'HP:0001909', (290, 298))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('TP53', 'Gene', (209, 213))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('mutations', 'Var', (61, 70))	('p53', 'Gene', '7157', (204, 207))	('mutations', 'Var', (173, 182))	('tumor', 'Disease', (190, 195))	('MLL', 'Gene', (300, 303))	('MLL', 'Gene', '4297', (300, 303))	('leukemia', 'Disease', 'MESH:D007938', (290, 298))	('leukemia', 'Disease', (290, 298))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumors', 'Disease', (147, 153))	('p53', 'Gene', (204, 207))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('TP53', 'Gene', '7157', (209, 213))
66945	29580149	Most PCa patients carrying BRCA2 mutations are treated with radical local therapy with or without adjuvant ADT.	('patients', 'Species', '9606', (9, 17))	('BRCA2', 'Gene', '675', (27, 32))	('PCa', 'Phenotype', 'HP:0012125', (5, 8))	('ADT', 'Chemical', '-', (107, 110))	('mutations', 'Var', (33, 42))	('BRCA2', 'Gene', (27, 32))	('PCa', 'Disease', (5, 8))
66946	29580149	Here we assessed the effect of initial ADT and subsequent radiotherapy on PCa associated with a BRCA2 mutation.	('associated', 'Reg', (78, 88))	('PCa', 'Phenotype', 'HP:0012125', (74, 77))	('mutation', 'Var', (102, 110))	('BRCA2', 'Gene', '675', (96, 101))	('ADT', 'Chemical', '-', (39, 42))	('PCa', 'Disease', (74, 77))	('BRCA2', 'Gene', (96, 101))
66954	29580149	On the other hand, cancer cells expressing truncated BRCA2 are expected to be more responsive to radiotherapy.	('more', 'PosReg', (78, 82))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('BRCA2', 'Gene', (53, 58))	('responsive', 'Reg', (83, 93))	('cancer', 'Disease', (19, 25))	('BRCA2', 'Gene', '675', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('truncated', 'Var', (43, 52))
66955	29580149	Polymorphisms in genes such as XRCC3 and RAD51 are also associated with radiosensitivity, but whether the SRD5A2 mutation (c.87G>C, p.Lys29Asn) identified in our patient plays a role in radiosensitivity is unclear.	('c.87G>C', 'Var', (123, 130))	('SRD5A2', 'Gene', (106, 112))	('c.87G>C', 'Mutation', 'c.87G>C', (123, 130))	('RAD51', 'Gene', (41, 46))	('p.Lys29Asn', 'Mutation', 'p.K29N', (132, 142))	('XRCC3', 'Gene', '7517', (31, 36))	('RAD51', 'Gene', '5888', (41, 46))	('radiosensitivity', 'Disease', (72, 88))	('associated', 'Reg', (56, 66))	('SRD5A2', 'Gene', '6716', (106, 112))	('p.Lys29Asn', 'Var', (132, 142))	('patient', 'Species', '9606', (162, 169))	('XRCC3', 'Gene', (31, 36))
66957	29580149	In conclusion, we believe we are the first to describe this germline mutation of BRCA2 (c.4211C>G, p.Ser1404Ter) in a patient with PCa, which was effectively treated with ADT and radiotherapy.	('c.4211C>G', 'Mutation', 'rs41293489', (88, 97))	('c.4211C>G', 'Var', (88, 97))	('p.Ser1404Ter', 'Var', (99, 111))	('BRCA2', 'Gene', (81, 86))	('BRCA2', 'Gene', '675', (81, 86))	('p.Ser1404Ter', 'Mutation', 'rs41293489', (99, 111))	('patient', 'Species', '9606', (118, 125))	('PCa', 'Phenotype', 'HP:0012125', (131, 134))	('ADT', 'Chemical', '-', (171, 174))
66961	29580149	In addition, total DNA purified from the patient's peripheral blood was analyzed by target capture-based deep sequencing (BGI Health, China) to identify potential mutations in the following genes: BRCA2, CHEK2, ELAC2, HSD17B3, HSD3B2, RNASEL, and SRD5A2.	('SRD5A2', 'Gene', (247, 253))	('mutations', 'Var', (163, 172))	('ELAC2', 'Gene', (211, 216))	('RNASEL', 'Gene', '6041', (235, 241))	('HSD17B3', 'Gene', (218, 225))	('BRCA2', 'Gene', (197, 202))	('CHEK2', 'Gene', '11200', (204, 209))	('HSD17B3', 'Gene', '3293', (218, 225))	('patient', 'Species', '9606', (41, 48))	('BRCA2', 'Gene', '675', (197, 202))	('SRD5A2', 'Gene', '6716', (247, 253))	('CHEK2', 'Gene', (204, 209))	('ELAC2', 'Gene', '60528', (211, 216))	('RNASEL', 'Gene', (235, 241))	('HSD3B2', 'Gene', (227, 233))	('HSD3B2', 'Gene', '3284', (227, 233))
66965	29580149	Goat serum (ZSGB-BIO, China) was used to block nonspecific interactions before incubating the sections at 4 C with specific primary antibodies against the BRCA2 C-terminus (amino acids 2587-2601, Abcam ab53887, Cambridge, MA, USA) and BRCA2 N-terminus (amino acids 100-150 amino acids, Proteintech 19791-1-ap, Rosemont, IL, USA).	('amino acids 2587-2601', 'Var', (173, 194))	('BRCA2', 'Gene', '675', (155, 160))	('Goat', 'Species', '9925', (0, 4))	('BRCA2', 'Gene', (235, 240))	('BRCA2', 'Gene', '675', (235, 240))	('BRCA2', 'Gene', (155, 160))
66976	27799787	Furthermore, the risk of death due to low BMI would be significantly increased in never smokers.	('low BMI', 'Var', (38, 45))	('death', 'Disease', 'MESH:D003643', (25, 30))	('death', 'Disease', (25, 30))	('low BMI', 'Phenotype', 'HP:0045082', (38, 45))
66981	27799787	In 2011, Yoon et al reported their data on esophageal adenocarcinoma and found that the unfavorable prognostic impact of high BMI was limited to never smokers.	('esophageal adenocarcinoma', 'Disease', (43, 68))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (43, 68))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (43, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('high', 'Var', (121, 125))
66995	27799787	Patients were categorized by BMI into three subsets: underweight (<18.5 kg/m2), normal weight (18.5-24.99 kg/m2), and overweight or obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (132, 137))	('<18.5 kg/m2', 'Var', (66, 77))	('obese', 'Disease', (132, 137))	('Patients', 'Species', '9606', (0, 8))	('18.5-24.99', 'Var', (95, 105))	('overweight', 'Phenotype', 'HP:0025502', (118, 128))
67032	27799787	Smoking status was found to modify the association between 15q25 variant of CHRNA5-CHRNA3-CHRNB4 gene and BMI, providing reliable evidence that smoking exposure reduces the BMI.	('15q25', 'Var', (59, 64))	('reduces', 'NegReg', (161, 168))	('CHRNA5-CHRNA3-CHRNB4', 'Disease', 'None', (76, 96))	('BMI', 'CPA', (173, 176))	('CHRNA5-CHRNA3-CHRNB4', 'Disease', (76, 96))	('BMI', 'Disease', (106, 109))	('association', 'Interaction', (39, 50))
67087	22328562	Whole genome tiling-path array CGH was used to identify significant regions of copy number (CN) alteration in 20 EACs and 10 matching BE tissues.	('EAC', 'Phenotype', 'HP:0011459', (113, 116))	('BE', 'Phenotype', 'HP:0100580', (134, 136))	('alteration', 'Var', (96, 106))	('CGH', 'Gene', (31, 34))	('CGH', 'Gene', '3342', (31, 34))
67089	22328562	CN gains were detected in other cancer types and RFC3 knockdown inhibited proliferation and anchorage-independent growth of cancer cells with increased CN, but had little effect on those without.	('cancer', 'Disease', (124, 130))	('anchorage-independent growth', 'CPA', (92, 120))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('knockdown', 'Var', (54, 63))	('cancer', 'Disease', (32, 38))	('RFC3', 'Gene', (49, 53))	('inhibited', 'NegReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('proliferation', 'CPA', (74, 87))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
67090	22328562	Moreover, high RFC3 expression was associated with poor patient outcome in multiple cancer types.	('expression', 'MPA', (20, 30))	('multiple cancer', 'Disease', 'MESH:D009369', (75, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('RFC3', 'Gene', (15, 19))	('high', 'Var', (10, 14))	('patient', 'Species', '9606', (56, 63))	('multiple cancer', 'Disease', (75, 90))
67091	22328562	RFC3 DNA amplification is also prevalent in other epithelial cancer types and RFC3 expression could serve as a prognostic marker.	('prevalent', 'Reg', (31, 40))	('RFC3', 'Gene', (0, 4))	('epithelial cancer', 'Phenotype', 'HP:0031492', (50, 67))	('epithelial cancer', 'Disease', (50, 67))	('epithelial cancer', 'Disease', 'MESH:D000077216', (50, 67))	('DNA amplification', 'Var', (5, 22))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
67094	22328562	To discover genes involved in cancer progression, we identified recurrent genetic alterations in EAC tumors and assessed their presence in BE.	('BE', 'Phenotype', 'HP:0100580', (139, 141))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('EAC tumors', 'Disease', (97, 107))	('genetic alterations', 'Var', (74, 93))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('EAC', 'Phenotype', 'HP:0011459', (97, 100))	('EAC tumors', 'Disease', 'MESH:C536611', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
67097	22328562	Furthermore, we showed that RFC3 gain is prevalent in several types of cancer, knockdown of RFC3 has an anti-proliferative effect, and that RFC3 expression is associated with poor prognosis in multiple patient cohorts, which collectively suggests an oncogenic role for RFC3.	('RFC3', 'Gene', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('RFC3', 'Gene', (28, 32))	('patient', 'Species', '9606', (202, 209))	('anti-proliferative effect', 'CPA', (104, 129))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('gain', 'PosReg', (33, 37))	('RFC3', 'Gene', (92, 96))	('knockdown', 'Var', (79, 88))
67101	22328562	The EAC profiles were analyzed using the GISTIC (Genomic Identification of Significant Targets in Cancer) algorithm for copy number alteration frequency and amplitude, using the following parameters: q-value threshold of 0.10, refgene file Hg18, amplification threshold 0.1, deletion threshold 0.1, join segment size = 2.	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (98, 104))	('EAC', 'Phenotype', 'HP:0011459', (4, 7))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('deletion', 'Var', (275, 283))
67104	22328562	Esophageal adenocarcinoma cell lines, OE33 (Sigma-Aldrich 96070808-1VL) and OE19 (Sigma-Aldrich 96071721-1VL), and breast ductal adenocarcinoma cell line, HCC1395 (ATCC CRL-2324), were cultured in RPMI-1640 media supplemented with 10% fetal bovine serum and 0.1% Penicillin-Streptomycin (Invitrogen).	('HCC1395', 'CellLine', 'CVCL:1249', (155, 162))	('Esophageal adenocarcinoma', 'Disease', (0, 25))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (0, 25))	('Sigma-Aldrich', 'Var', (82, 95))	('bovine', 'Species', '9913', (241, 247))	('breast ductal adenocarcinoma', 'Disease', 'MESH:D018270', (115, 143))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('Streptomycin', 'Chemical', 'MESH:D013307', (274, 286))	('breast ductal adenocarcinoma', 'Disease', (115, 143))	('RPMI-1640 media', 'Chemical', '-', (197, 212))	('Penicillin', 'Chemical', 'MESH:D010406', (263, 273))	('HCC', 'Phenotype', 'HP:0001402', (155, 158))
67121	22328562	Although both amplifications and deletions are known to be important in cancer development, the gain-of-function effect of gene amplifications makes them ideal targets for the development of biomarkers and strategies for therapeutic intervention.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gain-of-function', 'PosReg', (96, 112))	('amplifications', 'Var', (128, 142))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('deletions', 'Var', (33, 42))	('cancer', 'Disease', (72, 78))
67124	22328562	Matched copy number and gene expression data for 11 of the 20 discovery set EAC tumors were integrated to determine whether PDS5B, KL, STARD13, or RFC3 exhibited elevated gene expression as a consequence of DNA amplification.	('elevated', 'PosReg', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('EAC tumors', 'Disease', (76, 86))	('DNA', 'Var', (207, 210))	('STARD13', 'Gene', (135, 142))	('gene expression', 'MPA', (171, 186))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('PDS5B', 'Gene', (124, 129))	('EAC tumors', 'Disease', 'MESH:C536611', (76, 86))	('PDS5B', 'Gene', '23047', (124, 129))	('STARD13', 'Gene', '90627', (135, 142))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))
67126	22328562	Expression of both genes was significantly higher in tumors with DNA copy number gain as opposed to those without (p=0.01), providing further evidence that amplification of STARD13 and RFC3 is a mechanism of gene deregulation in EAC tumors (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('EAC', 'Phenotype', 'HP:0011459', (229, 232))	('STARD13', 'Gene', (173, 180))	('amplification', 'Var', (156, 169))	('EAC tumors', 'Disease', 'MESH:C536611', (229, 239))	('tumors', 'Disease', (233, 239))	('higher', 'PosReg', (43, 49))	('RFC3', 'Gene', (185, 189))	('Expression', 'MPA', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('EAC tumors', 'Disease', (229, 239))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('STARD13', 'Gene', '90627', (173, 180))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('DNA copy number', 'Var', (65, 80))	('tumors', 'Disease', (53, 59))
67139	22328562	RFC3 copy number gain (defined as >2 copies) was detected in 14% of all cases in 23 tissue types, while 6% of all malignancies harbored gains of >3 copies.	('malignancies', 'Disease', 'MESH:D009369', (114, 126))	('malignancies', 'Disease', (114, 126))	('copy number gain', 'Var', (5, 21))	('RFC3', 'Gene', (0, 4))
67142	22328562	Similar to EAC tumors, cell lines harboring RFC3 copy number gains showed higher expression than those without gain (p<0.0001) (Supplemental Figure 3B).	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('EAC tumors', 'Disease', (11, 21))	('copy number gains', 'Var', (49, 66))	('higher', 'PosReg', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('EAC', 'Phenotype', 'HP:0011459', (11, 14))	('EAC tumors', 'Disease', 'MESH:C536611', (11, 21))	('RFC3', 'Gene', (44, 48))	('expression', 'MPA', (81, 91))
67146	22328562	To determine if RFC3 functions as a putative oncogene in other cancer types, we also inhibited RFC3 in the breast cancer cell line, HCC1395, which harbored RFC3 DNA copy number gain (Supplemental Figure 4B).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('RFC3', 'Gene', (95, 99))	('HCC1395', 'CellLine', 'CVCL:1249', (132, 139))	('inhibited', 'NegReg', (85, 94))	('RFC3 DNA copy number gain', 'Var', (156, 181))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('HCC', 'Phenotype', 'HP:0001402', (132, 135))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', (114, 120))
67148	22328562	These cell experiments supported our hypothesis, demonstrating a significant biological effect of RFC3 knockdown in cancer cells, consistent with an oncogenic role for RFC3 in cancer.	('RFC3', 'Gene', (98, 102))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('knockdown', 'Var', (103, 112))
67150	22328562	Moreover, these genes were enriched for involvement in the Wntbeta-catenin signaling pathway.	('involvement', 'Reg', (40, 51))	('beta-catenin', 'Gene', '1499', (62, 74))	('beta-catenin', 'Gene', (62, 74))	('genes', 'Var', (16, 21))
67158	22328562	Since the small sample size of EAC tumors may have prevented a significant association with patient survival in EAC and we observed RFC3 amplification in other cancer types including lung and breast, we interrogated five additional datasets to determine whether RFC3 expression was associated with patient survival.	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('lung', 'Disease', (183, 187))	('EAC', 'Phenotype', 'HP:0011459', (31, 34))	('EAC tumors', 'Disease', (31, 41))	('cancer', 'Disease', (160, 166))	('amplification', 'Var', (137, 150))	('RFC3', 'Gene', (132, 136))	('EAC', 'Disease', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('EAC tumors', 'Disease', 'MESH:C536611', (31, 41))	('association', 'Interaction', (75, 86))	('associated', 'Reg', (282, 292))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('breast', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('patient', 'Species', '9606', (298, 305))	('patient', 'Species', '9606', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('prevented', 'NegReg', (51, 60))
67159	22328562	Comparison of survival times in patients with high versus low expression in 295 breast cancers and four independent sets of lung adenocarcinoma (n=58, n=82, n=107 and n=92) revealed survival was significantly worse in patients with high RFC3 expression in the breast cancer (p=0.0027) and two of four lung adenocarcinoma sets (p=0.0079 and p=0.0102) (Figure 6B-D).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (301, 320))	('high', 'Var', (232, 236))	('lung adenocarcinoma', 'Disease', (124, 143))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('RFC3', 'Gene', (237, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('worse', 'NegReg', (209, 214))	('breast cancer', 'Disease', (260, 273))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung adenocarcinoma', 'Disease', (301, 320))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('breast cancers', 'Disease', 'MESH:D001943', (80, 94))	('breast cancers', 'Disease', (80, 94))	('survival', 'MPA', (182, 190))	('patients', 'Species', '9606', (32, 40))	('breast cancers', 'Phenotype', 'HP:0003002', (80, 94))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (301, 320))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('expression', 'MPA', (242, 252))
67169	22328562	Our analysis detected a discrete, minimal common region of DNA amplification in an EAC tumor and matched BE sample encompassing only four genes.	('EAC', 'Disease', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('DNA amplification', 'Var', (59, 76))	('tumor', 'Disease', (87, 92))	('BE', 'Phenotype', 'HP:0100580', (105, 107))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))
67174	22328562	In human cells, RFC3 protein was found associated with the mitogenic transcription factor, MYC, which suggests RFC3 could have an integral role in driving cell proliferation in human cells as well and could explain the anti-proliferative knockdown effect we observed in cancer cells.	('RFC3', 'Var', (111, 115))	('MYC', 'Gene', '4609', (91, 94))	('human', 'Species', '9606', (3, 8))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cell proliferation', 'CPA', (155, 173))	('MYC', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('human', 'Species', '9606', (177, 182))
67183	22328562	RFC4 up-regulation was discovered in hepatocellular carcinoma (HCC) tissues relative to non-malignant liver tissue, and knockdown of endogenous RFC4 decreased cellular proliferation, increased apoptosis, and enhanced the chemosensitivity of the HCC cell line HepG2.	('cellular proliferation', 'CPA', (159, 181))	('RFC4', 'Gene', (144, 148))	('RFC4', 'Gene', (0, 4))	('chemosensitivity of the HCC cell line HepG2', 'CPA', (221, 264))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (37, 61))	('HCC', 'Phenotype', 'HP:0001402', (63, 66))	('enhanced', 'PosReg', (208, 216))	('HCC', 'Phenotype', 'HP:0001402', (245, 248))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (37, 61))	('RFC4', 'Gene', '5984', (144, 148))	('RFC4', 'Gene', '5984', (0, 4))	('HepG2', 'CellLine', 'CVCL:0027', (259, 264))	('up-regulation', 'PosReg', (5, 18))	('knockdown', 'Var', (120, 129))	('hepatocellular carcinoma', 'Disease', (37, 61))	('decreased', 'NegReg', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('apoptosis', 'CPA', (193, 202))	('increased', 'PosReg', (183, 192))
67188	22328562	Interestingly, a recent study reported frequent loss of function mutations and down-regulation of RFC3 in gastric and colorectal cancers.	('RFC3', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('gastric', 'Disease', (106, 113))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('colorectal cancers', 'Disease', (118, 136))	('colorectal cancers', 'Disease', 'MESH:D015179', (118, 136))	('loss of function', 'NegReg', (48, 64))	('down-regulation', 'NegReg', (79, 94))	('mutations', 'Var', (65, 74))
67190	22328562	We validated the biological effect of RFC3 up-regulation in cell model experiments by showing that RFC3 suppression impedes cell proliferation and anchorage independent growth exclusively in cancer cell lines with copy gain, an observation consistent with our oncogene hypothesis.	('RFC3', 'Gene', (99, 103))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('copy gain', 'Var', (214, 223))	('suppression impedes', 'NegReg', (104, 123))	('cell proliferation', 'CPA', (124, 142))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
67195	22328562	Lastly, we demonstrated that RFC3 DNA copy number alterations are not restricted to EAC but are also prevalent in other cancers (Supplemental Figure 3A).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('copy number alterations', 'Var', (38, 61))	('prevalent', 'Reg', (101, 110))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('EAC', 'Disease', (84, 87))	('RFC3 DNA', 'Gene', (29, 37))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
67196	22328562	Moreover, high RFC3 expression was associated with poor patient survival in multiple lung and breast adenocarcinoma datasets, as well as in EACs.	('lung', 'Disease', (85, 89))	('expression', 'MPA', (20, 30))	('breast adenocarcinoma', 'Disease', (94, 115))	('EAC', 'Phenotype', 'HP:0011459', (140, 143))	('patient survival', 'CPA', (56, 72))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (94, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('RFC3', 'Gene', (15, 19))	('poor', 'NegReg', (51, 55))	('high', 'Var', (10, 14))	('patient', 'Species', '9606', (56, 63))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (94, 115))
67201	22328562	We identified RFC3 as a candidate oncogene activated by DNA amplification in ~25% of EAC patients.	('EAC', 'Phenotype', 'HP:0011459', (85, 88))	('RFC3', 'Gene', (14, 18))	('DNA amplification', 'Var', (56, 73))	('patients', 'Species', '9606', (89, 97))	('EAC', 'Disease', (85, 88))
67203	22328562	Furthermore, high RFC3 expression was associated with poor patient outcome in multiple epithelial cancer types.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('epithelial cancer', 'Disease', (87, 104))	('RFC3', 'Gene', (18, 22))	('high', 'Var', (13, 17))	('epithelial cancer', 'Disease', 'MESH:D000077216', (87, 104))	('patient', 'Species', '9606', (59, 66))	('epithelial cancer', 'Phenotype', 'HP:0031492', (87, 104))	('expression', 'MPA', (23, 33))
67267	30323626	The EBV-positive tumors showed a high frequency of DNA hypermethylation as well as amplifications of JAK-2, PD-L1, and PD-L2.	('PD-L1', 'Gene', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('amplifications', 'Var', (83, 97))	('DNA', 'MPA', (51, 54))	('PD-L2', 'Gene', (119, 124))	('JAK-2', 'Gene', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('EBV', 'Species', '10376', (4, 7))
67270	30323626	PD-L1 positivity is more frequent in EBV-positive and MSI-H tumors.	('positivity', 'Var', (6, 16))	('MSI-H tumors', 'Disease', 'MESH:D009369', (54, 66))	('frequent', 'Reg', (25, 33))	('PD-L1', 'Gene', (0, 5))	('EBV', 'Species', '10376', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MSI-H tumors', 'Disease', (54, 66))	('EBV-positive', 'Disease', (37, 49))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
67357	30323626	Analyses of KEYNOTE-042, a Phase III trial of pembrolizumab vs platinum doublet chemotherapy in treatment-naive NSCLC patients, showed that baseline-to-week 15 change in European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30) Global Health Status (GHS)/QoLscore was 6.9 (95% CI 3.3-10.6) for pembrolizumab and -0.9 (-4.8 to 3.0) for chemotherapy, for a difference of 7.8 (2.9-12.8; two-sided nominal P=0.0020).	('pembrolizumab', 'Var', (361, 374))	('Cancer', 'Disease', (226, 232))	('pembrolizumab', 'Chemical', 'MESH:C582435', (46, 59))	('pembrolizumab', 'Chemical', 'MESH:C582435', (361, 374))	('men', 'Species', '9606', (101, 104))	('Cancer', 'Disease', 'MESH:D009369', (226, 232))	('Cancer', 'Phenotype', 'HP:0002664', (226, 232))	('platinum', 'Chemical', 'MESH:D010984', (63, 71))	('NSCLC', 'Disease', (112, 117))	('men', 'Species', '9606', (218, 221))	('patients', 'Species', '9606', (118, 126))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
67358	30323626	Time to deterioration (TTD) was also significantly longer with pembrolizumab than with chemotherapy.	('longer', 'PosReg', (51, 57))	('pembrolizumab', 'Var', (63, 76))	('Time', 'MPA', (0, 4))	('pembrolizumab', 'Chemical', 'MESH:C582435', (63, 76))
67359	30323626	A Health-related Quality of Life (HRQoL) analysis of KEYNOTE-045 study comparing pembrolizumab to investigator's choice chemotherapy in previously treated urothelial cancer patients showed that pembrolizumab delayed the TTD in QoL scores as compared to chemotherapy (median 3.5 months vs 2.3 months; HR 0.72; P=0.004).	('urothelial cancer', 'Disease', 'MESH:D014523', (155, 172))	('patients', 'Species', '9606', (173, 181))	('pembrolizumab', 'Chemical', 'MESH:C582435', (194, 207))	('pembrolizumab', 'Var', (194, 207))	('urothelial cancer', 'Disease', (155, 172))	('pembrolizumab', 'Chemical', 'MESH:C582435', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('TTD in QoL scores', 'MPA', (220, 237))
67367	30323626	Does PD-L1 positivity capture all patients who seem to derive the most benefit from this treatment?	('PD-L1', 'Gene', (5, 10))	('positivity', 'Var', (11, 21))	('men', 'Species', '9606', (94, 97))	('patients', 'Species', '9606', (34, 42))
67369	30323626	Although patients with PD-L1 positivity have better ORR than those with PD-L1-negative tumors, responses - and sometimes CR - are noted in PD-L1-negative patients.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CR', 'Chemical', '-', (121, 123))	('patients', 'Species', '9606', (154, 162))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('ORR', 'MPA', (52, 55))	('positivity', 'Var', (29, 39))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
67432	29181066	All subgroups analyzed in the study (patients with EC, ESCC and AC) were divided into the following groups: depending on tumor stage (I + II, III, and IV), depth of tumor invasion (T1 + T2, T3, and T4), the presence of lymph node metastasis (N0 and N1) and distant metastasis (M0 and M1) as well as histological grade of tumor (G1, G2 and G3).	('M0', 'Var', (277, 279))	('T1', 'Var', (181, 183))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('M1', 'Var', (284, 286))	('T4', 'Var', (198, 200))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (321, 326))	('distant metastasis', 'CPA', (257, 275))	('lymph node metastasis', 'CPA', (219, 240))	('tumor', 'Disease', (165, 170))
67439	29181066	The reference cut-off values for SCF (1285.0 pg/ml) and CEA (4.0 ng/ml) concentrations (the 95th percentile) corresponded to the highest accuracy (minimal false-negative and false-positive results).	('CEA', 'Gene', (56, 59))	('CEA', 'Gene', '1084', (56, 59))	('SCF', 'Gene', (33, 36))	('SCF', 'Gene', '4254', (33, 36))	('1285.0', 'Var', (38, 44))
67509	28408841	After CIK/DC-CIK immunotherapy, lymphocyte percentages of CD3+ and CD3-CD56+ subsets (P<0.01) and cytokines levels of IFN-gamma, -2, TNF-alpha and IL-12 (P<0.00001) were significantly increased, and the percentage of cluster of differentiation (CD)4+CD25+CD127- subset was significantly decreased, whereas analysis of CD4+, CD8+, CD4+/CD8+ and CD3+CD56+ did not show significant difference (P>0.05).	('CD4', 'Gene', '920', (330, 333))	('cytokines levels', 'MPA', (98, 114))	('decreased', 'NegReg', (287, 296))	('CD56', 'Gene', '4684', (71, 75))	('CD8', 'Gene', '925', (324, 327))	('CD56', 'Gene', (348, 352))	('CD4', 'Gene', (330, 333))	('CD8', 'Gene', (335, 338))	('CD25', 'Gene', (250, 254))	('cluster of differentiation', 'CPA', (217, 243))	('CD56', 'Gene', '4684', (348, 352))	('IFN-gamma', 'Gene', '3458', (118, 127))	('IFN-gamma', 'Gene', (118, 127))	('CIK/DC-CIK', 'Var', (6, 16))	('increased', 'PosReg', (184, 193))	('CD8', 'Gene', (324, 327))	('CD25', 'Gene', '3559', (250, 254))	('TNF-alpha', 'Gene', (133, 142))	('CD127', 'Gene', (255, 260))	('CD4', 'Gene', '920', (318, 321))	('CD8', 'Gene', '925', (335, 338))	('CD127', 'Gene', '3575', (255, 260))	('lymphocyte percentages', 'CPA', (32, 54))	('TNF-alpha', 'Gene', '7124', (133, 142))	('CD4', 'Gene', (318, 321))	('CD56', 'Gene', (71, 75))
67522	28408841	On the one hand, the cytotoxicity of CIK cells is not affected by immune inhibitors such as cyclosporin A (CsA) and FK506.	('cytotoxicity', 'Disease', (21, 33))	('FK506', 'Chemical', 'MESH:D016559', (116, 121))	('FK506', 'Var', (116, 121))	('CsA', 'Chemical', 'MESH:D016572', (107, 110))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('cyclosporin A', 'Chemical', 'MESH:D016572', (92, 105))
67531	28408841	The immune function of EC patients before and after treatment was determined by the status of the lymphocyte subsets (CD3+, CD4+, CD8+, CD3-CD56+, CD3+CD56+ and CD4+CD25+CD127-) and cytokine secretion (IFN-gamma, IL-2, TNF-alpha and IL-12).	('CD3+', 'Var', (118, 122))	('CD4', 'Gene', '920', (124, 127))	('CD127', 'Gene', (170, 175))	('CD25', 'Gene', '3559', (165, 169))	('TNF-alpha', 'Gene', '7124', (219, 228))	('IL-2', 'Gene', '3558', (213, 217))	('CD8', 'Gene', (130, 133))	('TNF-alpha', 'Gene', (219, 228))	('CD4', 'Gene', (124, 127))	('CD56', 'Gene', (140, 144))	('CD127', 'Gene', '3575', (170, 175))	('CD56', 'Gene', '4684', (140, 144))	('CD4', 'Gene', '920', (161, 164))	('IFN-gamma', 'Gene', '3458', (202, 211))	('CD4', 'Gene', (161, 164))	('IFN-gamma', 'Gene', (202, 211))	('IL-2', 'Gene', (213, 217))	('CD25', 'Gene', (165, 169))	('CD56', 'Gene', (151, 155))	('patients', 'Species', '9606', (26, 34))	('CD8', 'Gene', '925', (130, 133))	('CD56', 'Gene', '4684', (151, 155))
67537	28408841	This analysis indicated that OS, ORR and DCR were significantly improved in patients who underwent combination therapy compared to those treated by conventional therapy alone (Figure 3, 1-year OS: OR =2.59, 95% CI =1.52-4.40, P=0.0005; ORR: OR =2.18, 95% CI =1.57-3.02, P<0.00001; DCR: OR =3.83, 95% CI =2.47-5.92, P<0.00001).	('patients', 'Species', '9606', (76, 84))	('DCR', 'CPA', (41, 44))	('improved', 'PosReg', (64, 72))	('ORR', 'CPA', (33, 36))	('combination', 'Var', (99, 110))
67541	28408841	On the other hand, patients' cytokines levels were also significantly increased after CIK/DC-CIK therapy (Figure 6, IFN-gamma: OR =36.30, 95% CI =31.54-41.06, P<0.00001; IL-2: OR =13.00, 95% CI =9.88-16.12, P<0.00001; TNF-alpha: OR =15.10, 95% CI =12.31-17.89, P<0.00001; IL-12: OR =56.30, 95% CI =51.32-61.28, P<0.00001).	('CIK/DC-CIK', 'Var', (86, 96))	('patients', 'Species', '9606', (19, 27))	('increased', 'PosReg', (70, 79))	('TNF-alpha', 'Gene', '7124', (218, 227))	('IL-2', 'Gene', (170, 174))	('IL-2', 'Gene', '3558', (170, 174))	('cytokines levels', 'MPA', (29, 45))	('TNF-alpha', 'Gene', (218, 227))	('IFN-gamma', 'Gene', '3458', (116, 125))	('IFN-gamma', 'Gene', (116, 125))
67553	28408841	The antitumor activity of CIK/DC-CIK is mainly attributed to CD3-CD56+ and CD3+CD56+ cells.	('CD56', 'Gene', '4684', (65, 69))	('CD56', 'Gene', '4684', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('CD56', 'Gene', (65, 69))	('CD56', 'Gene', (79, 83))	('tumor', 'Disease', (8, 13))	('CIK/DC-CIK', 'Var', (26, 36))
67554	28408841	Our analysis indicated that the proportions of CD3+, CD3-CD56+ and CD3+CD56+ T cells were increased after CIK/DC-CIK treatment, although the percentages of CD3+CD56+ T cells did not reach statistical significance.	('T cells were increased', 'Phenotype', 'HP:0100828', (77, 99))	('CD56', 'Gene', (57, 61))	('increased', 'PosReg', (90, 99))	('CD56', 'Gene', '4684', (57, 61))	('CD56', 'Gene', '4684', (160, 164))	('CD56', 'Gene', '4684', (71, 75))	('CD56', 'Gene', (160, 164))	('CIK/DC-CIK', 'Var', (106, 116))	('CD56', 'Gene', (71, 75))
67560	28408841	Our analysis showed that after CIK/DC-CIK immunotherapy, the levels of Th1 cytokines, including IFN-gamma, IL-2, TNF-alpha and IL-12, were significantly increased (P<0.00001), indicating a strong association between Th1 cytokines and efficacy of CIK/DC-CIK immunotherapy.	('CIK/DC-CIK', 'Var', (31, 41))	('Th1', 'Gene', (216, 219))	('IFN-gamma', 'Gene', '3458', (96, 105))	('IFN-gamma', 'Gene', (96, 105))	('Th1', 'Gene', '51497', (71, 74))	('increased', 'PosReg', (153, 162))	('IL-2', 'Gene', (107, 111))	('IL-2', 'Gene', '3558', (107, 111))	('levels', 'MPA', (61, 67))	('Th1', 'Gene', (71, 74))	('Th1', 'Gene', '51497', (216, 219))	('TNF-alpha', 'Gene', '7124', (113, 122))	('IL-12', 'MPA', (127, 132))	('TNF-alpha', 'Gene', (113, 122))
67561	28408841	Although our results indicated that CIK/DC-CIK immunotherapy enhanced the immune function in EC patients, the exact underlying mechanism of action of CIK/DC-CIK immunotherapy on hosts' immune system remains unclear, which requires further studies on its mechanism.	('enhanced', 'PosReg', (61, 69))	('CIK/DC-CIK', 'Var', (36, 46))	('immune function', 'CPA', (74, 89))	('patients', 'Species', '9606', (96, 104))
67582	26788152	It has been reported previously that tumor-associated factors derived from homogenates of EC9706 human ESCC cells may induce iDCs to differentiate into ELCs.	('iDCs', 'Disease', (125, 129))	('EC9706', 'Var', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('human', 'Species', '9606', (97, 102))	('EC9706', 'CellLine', 'CVCL:E307', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('ELCs', 'Disease', (152, 156))	('induce', 'PosReg', (118, 124))
67596	26788152	The anti-p-JAK2 (Tyr 1007/Tyr 1008) primary antibody (1:100; cat no.	('JAK2', 'Gene', (11, 15))	('Tyr 1007/Tyr 1008', 'Var', (17, 34))	('JAK2', 'Gene', '3717', (11, 15))	('Tyr', 'Chemical', 'MESH:D014443', (26, 29))	('Tyr', 'Chemical', 'MESH:D014443', (17, 20))
67604	26788152	Immature DCs induced by KYSE450 or KYSE70 supernatant for 4 days appeared round, with a similar form to control DCs.	('KYSE450', 'Chemical', '-', (24, 31))	('KYSE450', 'Var', (24, 31))	('KYSE70', 'Var', (35, 41))
67605	26788152	However, following induction of 8 days, the KYSE450 group cells exhibited a fusiform shape, and a number of cells from the KYSE70 group was arranged in cord-like structures, a typical appearance of ECs (Fig.	('ECs', 'Disease', (198, 201))	('fusiform shape', 'CPA', (76, 90))	('KYSE70', 'Var', (123, 129))	('KYSE450', 'Chemical', '-', (44, 51))	('KYSE450', 'Var', (44, 51))	('exhibited', 'Reg', (64, 73))
67606	26788152	The protein expression levels of EC markers were significantly increased in cells induced by KYSE450 or KYSE70 supernatant, compared with the control DCs (n=4, P<0.001).	('increased', 'PosReg', (63, 72))	('KYSE450', 'Chemical', '-', (93, 100))	('KYSE450', 'Var', (93, 100))	('protein expression levels', 'MPA', (4, 29))	('KYSE70', 'Var', (104, 110))
67607	26788152	The immunostaining intensity of the two EC markers was greater in the poorly differentiated ESCC group (KYSE70) compared with the highly differentiated group (KYSE450; Fig.	('KYSE450', 'Chemical', '-', (159, 166))	('ESCC', 'Disease', (92, 96))	('greater', 'PosReg', (55, 62))	('immunostaining intensity', 'MPA', (4, 28))	('KYSE70', 'Var', (104, 110))
67608	26788152	RT-qPCR analysis demonstrated enhanced expression of vWF and CD144 mRNA in the KYSE450 and KYSE70 groups compared to the control DCs (n=3, P<0.01, P<0.001).	('enhanced', 'PosReg', (30, 38))	('KYSE70', 'Var', (91, 97))	('vWF', 'Gene', (53, 56))	('KYSE450', 'Chemical', '-', (79, 86))	('KYSE450', 'Var', (79, 86))	('vWF', 'Gene', '7450', (53, 56))	('CD144', 'Chemical', '-', (61, 66))	('expression', 'MPA', (39, 49))	('CD144', 'Gene', (61, 66))
67609	26788152	Furthermore, the mRNA expression levels of vWF and CD144 in the KYSE70 group were enhanced significantly in comparison to the KYSE450 group (Fig.	('CD144', 'MPA', (51, 56))	('enhanced', 'PosReg', (82, 90))	('KYSE70', 'Var', (64, 70))	('CD144', 'Chemical', '-', (51, 56))	('mRNA expression levels', 'MPA', (17, 39))	('vWF', 'Gene', '7450', (43, 46))	('KYSE450', 'Chemical', '-', (126, 133))	('vWF', 'Gene', (43, 46))
67612	26788152	By contrast, in the current study, the cells induced by KYSE450 or KYSE70 supernatant exhibited a strong uptake of Dil-Ac-LDL compared to the control DCs (n=4, P<0.001).	('KYSE70', 'Var', (67, 73))	('Dil-Ac-LDL', 'Chemical', '-', (115, 125))	('KYSE450', 'Chemical', '-', (56, 63))	('uptake', 'MPA', (105, 111))	('KYSE450', 'Var', (56, 63))
67613	26788152	Additionally, the KYSE70 group cells demonstrated a stronger uptake compared to the KYSE450 group (Fig.	('uptake', 'CPA', (61, 67))	('stronger', 'PosReg', (52, 60))	('KYSE450', 'Chemical', '-', (84, 91))	('KYSE70', 'Var', (18, 24))
67614	26788152	The above results demonstrated that iDCs induced by KYSE450 and KYSE70 supernatant differentiate towards an EC phenotype, and the KYSE70 supernatant induced a greater effect during this transition.	('iDCs', 'Disease', (36, 40))	('KYSE450', 'Chemical', '-', (52, 59))	('KYSE450', 'Var', (52, 59))	('KYSE70', 'Var', (64, 70))
67616	26788152	The results showed that the mRNA expression levels of JAK and STAT3 increased in the KYSE450 and KYSE70 groups in comparison to the control DCs (Fig.	('STAT3', 'Gene', (62, 67))	('JAK', 'Gene', (54, 57))	('JAK', 'Gene', '3717', (54, 57))	('mRNA expression levels', 'MPA', (28, 50))	('KYSE450', 'Chemical', '-', (85, 92))	('KYSE450', 'Var', (85, 92))	('STAT3', 'Gene', '6774', (62, 67))	('increased', 'PosReg', (68, 77))	('KYSE70', 'Var', (97, 103))
67617	26788152	Furthermore, the KYSE70 group exhibited slightly increased mRNA levels of JAK and STAT3 compared with the KYSE450 group, however this difference was not statistically significant (n=3, P=0.054, P=0.617, respectively).	('JAK', 'Gene', (74, 77))	('increased', 'PosReg', (49, 58))	('KYSE70', 'Var', (17, 23))	('STAT3', 'Gene', '6774', (82, 87))	('JAK', 'Gene', '3717', (74, 77))	('STAT3', 'Gene', (82, 87))	('KYSE450', 'Chemical', '-', (106, 113))
67619	26788152	VEGF-A and IL-6 mRNA levels increased significantly in the KYSE450 and KYSE70 groups compared to the control DCs (P<0.01 for VEGF-A; P<0.001 for IL-6), with a significantly higher level of expression in the KYSE70 group than KYSE450 (Fig.	('increased', 'PosReg', (28, 37))	('KYSE70', 'Var', (71, 77))	('IL-6', 'Gene', '3569', (11, 15))	('IL-6', 'Gene', (145, 149))	('KYSE450', 'Var', (59, 66))	('mRNA levels', 'MPA', (16, 27))	('VEGF-A', 'Gene', (0, 6))	('IL-6', 'Gene', '3569', (145, 149))	('VEGF-A', 'Gene', '7422', (125, 131))	('VEGF-A', 'Gene', '7422', (0, 6))	('KYSE450', 'Chemical', '-', (225, 232))	('expression', 'MPA', (189, 199))	('VEGF-A', 'Gene', (125, 131))	('KYSE450', 'Chemical', '-', (59, 66))	('higher', 'PosReg', (173, 179))	('IL-6', 'Gene', (11, 15))
67621	26788152	Immunocytochemical analysis demonstrated that JAK and STAT3 were phosphorylated at higher levels in the KYSE450 and KYSE70 groups compared with the control DCs, and the fluorescence intensity in the KYSE70 group was stronger than that in the KYSE450 group (Fig.3B; n=3; P<0.001).	('JAK', 'Gene', (46, 49))	('KYSE450', 'Chemical', '-', (104, 111))	('KYSE450', 'Chemical', '-', (242, 249))	('JAK', 'Gene', '3717', (46, 49))	('stronger', 'PosReg', (216, 224))	('STAT3', 'Gene', '6774', (54, 59))	('KYSE70', 'Var', (199, 205))	('KYSE450', 'Var', (104, 111))	('STAT3', 'Gene', (54, 59))	('fluorescence intensity', 'MPA', (169, 191))	('higher', 'PosReg', (83, 89))
67622	26788152	AG490 (AG) is an inhibitor of JAK.	('JAK', 'Gene', (30, 33))	('JAK', 'Gene', '3717', (30, 33))	('AG490', 'Var', (0, 5))	('AG490', 'Chemical', 'MESH:C095512', (0, 5))
67624	26788152	Following 8 days of incubation, the mRNA expression levels of vWF and CD144 had significantly decreased in the KYSE450 + AG and KYSE70 + AG groups (Fig.	('vWF', 'Gene', (62, 65))	('CD144', 'Chemical', '-', (70, 75))	('mRNA expression levels', 'MPA', (36, 58))	('CD144', 'Gene', (70, 75))	('KYSE70 + AG', 'Var', (128, 139))	('KYSE450', 'Chemical', '-', (111, 118))	('decreased', 'NegReg', (94, 103))	('KYSE450 + AG', 'Var', (111, 123))	('vWF', 'Gene', '7450', (62, 65))
67625	26788152	Furthermore, the levels of these proteins were significantly decreased, as demonstrated by a reduction in the fluorescence intensity of CD144 and vWF in the KYSE450 + AG and KYSE70+AG groups compared with the control KYSE450 group or KYSE70 group (Fig.	('KYSE450', 'Chemical', '-', (157, 164))	('reduction', 'NegReg', (93, 102))	('vWF', 'Gene', '7450', (146, 149))	('KYSE70+AG', 'Var', (174, 183))	('levels of', 'MPA', (17, 26))	('vWF', 'Gene', (146, 149))	('fluorescence intensity', 'MPA', (110, 132))	('decreased', 'NegReg', (61, 70))	('CD144', 'Gene', (136, 141))	('CD144', 'Chemical', '-', (136, 141))	('KYSE450', 'Chemical', '-', (217, 224))	('KYSE450 + AG', 'Var', (157, 169))
67626	26788152	Additionally, Dil-Ac-LDL uptake was significantly reduced in the KYSE450 and KYSE70 groups incubated with AG490 (Fig.	('Dil-Ac-LDL', 'Chemical', '-', (14, 24))	('KYSE70', 'Var', (77, 83))	('AG490', 'Var', (106, 111))	('Dil-Ac-LDL uptake', 'MPA', (14, 31))	('KYSE450', 'Var', (65, 72))	('AG490', 'Chemical', 'MESH:C095512', (106, 111))	('reduced', 'NegReg', (50, 57))	('KYSE450', 'Chemical', '-', (65, 72))
67627	26788152	In summary, the results demonstrated the JAK/STAT3 signaling pathway promotes the ELD of iDCs induced by KYSE450 and KYSE70 supernatant, and blocking JAK/STAT3 signaling inhibits the ELD of iDCs.	('STAT3', 'Gene', (45, 50))	('JAK', 'Gene', (150, 153))	('STAT3', 'Gene', '6774', (154, 159))	('promotes', 'PosReg', (69, 77))	('ELD', 'Disease', (82, 85))	('inhibits', 'NegReg', (170, 178))	('JAK', 'Gene', '3717', (150, 153))	('KYSE450', 'Chemical', '-', (105, 112))	('ELD', 'MPA', (183, 186))	('JAK', 'Gene', (41, 44))	('blocking', 'Var', (141, 149))	('JAK', 'Gene', '3717', (41, 44))	('STAT3', 'Gene', (154, 159))	('iDCs', 'Disease', (89, 93))	('STAT3', 'Gene', '6774', (45, 50))
67632	26788152	The results demonstrate that iDCs induced by the KYSE70 supernatant appeared with fusiform shapes and were arranged into cord-like structures in the KYSE70 and KYSE450 groups.	('iDCs', 'Disease', (29, 33))	('KYSE70', 'Gene', (49, 55))	('KYSE70', 'Var', (149, 155))	('KYSE450', 'Chemical', '-', (160, 167))
67633	26788152	Additionally, the KYSE70- induced group expressed higher levels of the EC markers vWF and CD144, and exhibited stronger Dil-Ac-LDL uptake in comparison with the KYSE450-induced group.	('CD144', 'MPA', (90, 95))	('higher', 'PosReg', (50, 56))	('Dil-Ac-LDL uptake', 'MPA', (120, 137))	('CD144', 'Chemical', '-', (90, 95))	('Dil-Ac-LDL', 'Chemical', '-', (120, 130))	('levels', 'MPA', (57, 63))	('KYSE70- induced', 'Var', (18, 33))	('stronger', 'PosReg', (111, 119))	('vWF', 'Gene', '7450', (82, 85))	('KYSE450', 'Chemical', '-', (161, 168))	('vWF', 'Gene', (82, 85))
67635	26788152	This may be due to increased IL-6 and VEGF protein expression in the KYSE70 group, a hypothesis that is supported by our previous findings showing VEGF can induce the ELD of iDCs.	('VEGF', 'Gene', '7422', (38, 42))	('IL-6', 'Gene', (29, 33))	('VEGF', 'Gene', '7422', (147, 151))	('IL-6', 'Gene', '3569', (29, 33))	('increased', 'PosReg', (19, 28))	('expression', 'MPA', (51, 61))	('ELD', 'Disease', (167, 170))	('KYSE70', 'Var', (69, 75))	('VEGF', 'Gene', (38, 42))	('VEGF', 'Gene', (147, 151))
67639	26788152	The results of the current study revealed the JAK/STAT3 signaling pathway was activated during the ELD of iDCs, and the cells in the KYSE70 group exhibited higher levels of p-JAK and p-STAT3, compared with the cells in the KYSE450 group.	('JAK', 'Gene', (46, 49))	('higher', 'PosReg', (156, 162))	('KYSE450', 'Chemical', '-', (223, 230))	('activated', 'PosReg', (78, 87))	('levels', 'MPA', (163, 169))	('STAT3', 'Gene', '6774', (50, 55))	('KYSE70', 'Var', (133, 139))	('JAK', 'Gene', '3717', (46, 49))	('JAK', 'Gene', (175, 178))	('STAT3', 'Gene', (50, 55))	('STAT3', 'Gene', '6774', (185, 190))	('JAK', 'Gene', '3717', (175, 178))	('STAT3', 'Gene', (185, 190))
67640	26788152	AG490 is the inhibitor of the JAK/STAT3 signaling pathway, and not only inhibited the activation of JAK signaling, but also inhibited the differentiation of iDCs to ELCs.	('JAK', 'Gene', '3717', (100, 103))	('STAT3', 'Gene', (34, 39))	('JAK', 'Gene', (30, 33))	('differentiation', 'CPA', (138, 153))	('activation', 'MPA', (86, 96))	('AG490', 'Var', (0, 5))	('AG490', 'Chemical', 'MESH:C095512', (0, 5))	('STAT3', 'Gene', '6774', (34, 39))	('JAK', 'Gene', '3717', (30, 33))	('JAK', 'Gene', (100, 103))	('inhibited', 'NegReg', (72, 81))	('iDCs', 'Disease', (157, 161))	('inhibited', 'NegReg', (124, 133))
67642	26409826	Integrative genomics analysis of genes with biallelic loss and its relation to the expression of mRNA and micro-RNA in esophageal squamous cell carcinoma Genomic instability plays an important role in human cancers.	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('esophageal squamous cell carcinoma', 'Disease', (119, 153))	('cancers', 'Disease', (207, 214))	('biallelic loss', 'Var', (44, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('human', 'Species', '9606', (201, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (119, 153))
67643	26409826	We previously characterized genomic instability in esophageal squamous cell carcinomas (ESCC) in terms of loss of heterozygosity (LOH) and copy number (CN) changes in tumors.	('copy number', 'Var', (139, 150))	('esophageal squamous cell carcinomas', 'Disease', (51, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (51, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (62, 86))	('heterozygosity', 'MPA', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('loss', 'NegReg', (106, 110))	('tumors', 'Disease', (167, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
67645	26409826	(iii) The relation of biallelic loss to miRNA expression was less clear but appeared to favor higher miRNA levels: of 60 miRNA-target gene pairs, 34 pairs (57 %) had higher miRNA expression with biallelic loss than without, while 26 pairs (43 %) had lower miRNA expression.	('higher', 'PosReg', (166, 172))	('miR', 'Gene', '220972', (256, 259))	('miR', 'Gene', (256, 259))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('loss', 'NegReg', (205, 209))	('biallelic', 'Var', (195, 204))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('miR', 'Gene', '220972', (173, 176))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (173, 176))	('miR', 'Gene', (101, 104))
67646	26409826	(iv) Finally, the effect of biallelic loss on the relation between miRNA and mRNA expression was complex.	('mRNA expression', 'MPA', (77, 92))	('miR', 'Gene', '220972', (67, 70))	('biallelic loss', 'Var', (28, 42))	('miR', 'Gene', (67, 70))
67647	26409826	Biallelic loss was most commonly associated with a pattern of elevated miRNA and reduced mRNA (43 %), but a pattern of both reduced miRNA and mRNA was also common (35 %).	('miR', 'Gene', (71, 74))	('elevated', 'PosReg', (62, 70))	('miR', 'Gene', '220972', (71, 74))	('mRNA', 'MPA', (89, 93))	('miR', 'Gene', '220972', (132, 135))	('reduced', 'NegReg', (81, 88))	('Biallelic', 'Var', (0, 9))	('miR', 'Gene', (132, 135))	('loss', 'NegReg', (10, 14))	('mRNA', 'MPA', (142, 146))
67648	26409826	The effect of biallelic loss on miRNA expression and on the relation between miRNA and mRNA expressions was complex.	('miR', 'Gene', (32, 35))	('miR', 'Gene', (77, 80))	('biallelic', 'Var', (14, 23))	('loss', 'NegReg', (24, 28))	('miR', 'Gene', '220972', (32, 35))	('miR', 'Gene', '220972', (77, 80))
67654	26409826	Genomic instability is one of several mechanisms that can lead to gene dysregulation and has been thought to play an important role in the etiology of human cancers, including both histologic types of esophageal cancer, esophageal adenocarcinoma and ESCC.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('human', 'Species', '9606', (151, 156))	('ESCC', 'Disease', (250, 254))	('esophageal cancer', 'Disease', (201, 218))	('lead to', 'Reg', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('Genomic instability', 'Var', (0, 19))	('esophageal adenocarcinoma', 'Disease', (220, 245))	('cancers', 'Disease', (157, 164))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (220, 245))	('esophageal cancer', 'Disease', 'MESH:D004938', (201, 218))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (220, 245))	('gene dysregulation', 'MPA', (66, 84))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
67655	26409826	These studies identified over 20 common LOH regions, frequent copy number alterations (both gain and loss), as well as numerous copy number neutral regions, which suggests that this cancer is characterized by genomic instability.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('copy number alterations', 'Var', (62, 85))	('loss', 'NegReg', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))
67656	26409826	In addition, somatic mutations in several genes with critical roles in carcinogenesis (e.g., TP53, CDKN2A, and BRCA2) have been identified in ESCC patients with LOH in regions that include the genes, indicating that a wide variety of DNA alterations in numerous genes occur in the development of this tumor.	('BRCA2', 'Gene', (111, 116))	('CDKN2A', 'Gene', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('carcinogenesis', 'Disease', (71, 85))	('TP53', 'Gene', '7157', (93, 97))	('BRCA2', 'Gene', '675', (111, 116))	('TP53', 'Gene', (93, 97))	('CDKN2A', 'Gene', '1029', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('patients', 'Species', '9606', (147, 155))	('tumor', 'Disease', (301, 306))	('ESCC', 'Disease', (142, 146))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))	('mutations', 'Var', (21, 30))
67661	26409826	Further, dysregulation of some miRNAs has been related to patient survival in some cancers, including ESCC.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('ESCC', 'Disease', (102, 106))	('patient', 'Species', '9606', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('miR', 'Gene', '220972', (31, 34))	('related', 'Reg', (47, 54))	('miR', 'Gene', (31, 34))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('dysregulation', 'Var', (9, 22))	('cancers', 'Disease', (83, 90))
67662	26409826	Biallelic loss is thought to play a critical role in tumor pathogenesis, especially because of its influence on expression of affected genes (mRNA) and related miRNA, however, these relations have not been well studied in ESCC.	('miR', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Biallelic loss', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('miR', 'Gene', '220972', (160, 163))	('expression', 'MPA', (112, 122))
67665	26409826	Of the molecular genetic changes that occur during the development of human cancer, alterations in SNPs are likely among the earliest or even the initial events that lead to genomic instability.	('genomic', 'MPA', (174, 181))	('SNPs', 'Gene', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('alterations', 'Var', (84, 95))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
67666	26409826	While studying large changes (eg, big deletions, inversions, and translocations at the chromosomal level) in tumor cells is informative, knowledge of the more numerous small alterations that occur at the nucleotide sequence level are equally or more critical to our understanding of the detailed process of carcinogenesis, particularly at its earliest stages.	('carcinogenesis', 'Disease', (307, 321))	('inversions', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('carcinogenesis', 'Disease', 'MESH:D063646', (307, 321))	('tumor', 'Disease', (109, 114))
67667	26409826	In the present study, we performed global profiling of alterations in DNA as well as expression of mRNA and miRNA in tumors and their matched normal tissues from 30 ESCC cases.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('alterations', 'Var', (55, 66))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('ESCC', 'Disease', (165, 169))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))	('DNA', 'MPA', (70, 73))
67692	26409826	Biallelic loss, including loss of both alleles in heterozygotes as well as homozygous deletions, was determined based on comparison of matched tumor versus germline DNA.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (143, 148))	('deletions', 'Var', (86, 95))
67701	26409826	The criteria used to call an miRNA dysregulated were fold changes >= 2 or <= 0.5.	('<= 0.5', 'Var', (74, 80))	('miR', 'Gene', '220972', (29, 32))	('fold changes', 'Var', (53, 65))	('miR', 'Gene', (29, 32))
67707	26409826	However, such alterations could be more severe and consequently might have greater impact on tumorigenesis.	('alterations', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('impact', 'Reg', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
67708	26409826	We also checked for microdeletions or biallelic loss regions on chromosomes (eg, 3p14) caused by continuous SNPs with biallelic loss, but were unable to identify any.	('p14', 'Gene', '1029', (82, 85))	('biallelic', 'Var', (118, 127))	('p14', 'Gene', (82, 85))	('biallelic', 'Var', (38, 47))
67709	26409826	Among the 77 genes with biallelic loss, 52 had probes represented on the Affymetrix Hu 133 array with signals in both tumor and normal tissues.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('genes', 'Gene', (13, 18))	('biallelic loss', 'Var', (24, 38))	('tumor', 'Disease', (118, 123))
67710	26409826	For example, the mean fold change in MTAP expression was 0.83 in cases with biallelic loss versus 1.11 in cases with no biallelic loss (P = 0.009).	('MTAP', 'Gene', (37, 41))	('MTAP', 'Gene', '4507', (37, 41))	('biallelic loss', 'Var', (76, 90))
67711	26409826	As an example, the median fold change for expression of ADAMTS9 was 1.35 in cases with biallelic loss compared to 1.0 in cases without biallelic loss (Additional file 2: Table S1).	('expression', 'MPA', (42, 52))	('ADAMTS9', 'Gene', (56, 63))	('biallelic loss', 'Var', (87, 101))	('ADAMTS9', 'Gene', '56999', (56, 63))
67713	26409826	The ratio of miRNA expression in target genes with biallelic loss (versus without) was greater than one for 34 of 60 (57 %) miRNAs and less than one in 26 of 60 (43 %).	('expression', 'MPA', (19, 29))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('loss', 'NegReg', (61, 65))	('miR', 'Gene', (124, 127))	('biallelic', 'Var', (51, 60))	('miR', 'Gene', '220972', (124, 127))
67719	26409826	Overall, in the 35 genes with biallelic loss that were evaluable, miRNA expression levels were more often elevated (fold change > 1.0) than mRNA expression levels (69 % versus 14 %, respectively).	('loss', 'NegReg', (40, 44))	('miR', 'Gene', (66, 69))	('biallelic', 'Var', (30, 39))	('miR', 'Gene', '220972', (66, 69))	('elevated', 'PosReg', (106, 114))
67726	26409826	In the present study, we took an integrative approach by evaluating genes in relation to biallelic loss and expression of both mRNA and miRNA in ESCC cases using profiling data generated from arrays.	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('biallelic', 'Var', (89, 98))	('loss', 'NegReg', (99, 103))	('ESCC', 'Disease', (145, 149))
67727	26409826	Third, although the relation was less clear than for mRNA, biallelic loss also appeared to affect miRNA expression.	('affect', 'Reg', (91, 97))	('miR', 'Gene', '220972', (98, 101))	('biallelic loss', 'Var', (59, 73))	('miR', 'Gene', (98, 101))
67728	26409826	More informative future studies will need larger sample sizes so as to have more heterozygous SNPs for evaluation, and appropriate coverage of promoter regions, to confirm and expand our findings here regarding relations between SNPs with biallelic loss and expression of mRNA and miRNA.	('SNPs', 'Var', (229, 233))	('miR', 'Gene', '220972', (281, 284))	('expression', 'MPA', (258, 268))	('miR', 'Gene', (281, 284))	('biallelic loss', 'Var', (239, 253))	('mRNA', 'Protein', (272, 276))
67729	26409826	Distributions of miRNA expressions were generally higher in cases with biallelic loss than in cases without loss.	('higher', 'PosReg', (50, 56))	('miR', 'Gene', '220972', (17, 20))	('biallelic', 'Var', (71, 80))	('miR', 'Gene', (17, 20))	('Distributions', 'MPA', (0, 13))	('loss', 'NegReg', (81, 85))
67730	26409826	Of 60 miRNA-target gene pairs, 34 pairs (57 %) had higher miRNA expression with biallelic loss than without, while 26 pairs (43 %) had lower miRNA expression.	('loss', 'NegReg', (90, 94))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('miR', 'Gene', '220972', (6, 9))	('miR', 'Gene', (6, 9))	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', (141, 144))	('higher', 'PosReg', (51, 57))	('biallelic', 'Var', (80, 89))
67731	26409826	Finally, the effect of biallelic loss on the relation between miRNA and mRNA expression was complex.	('biallelic loss', 'Var', (23, 37))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('mRNA expression', 'MPA', (72, 87))
67733	26409826	For example, biallelic loss of CHL1 (3p26.3) affected six of 78 SNPs, and the expression level of CHL1 was reduced in cases with biallelic loss but elevated in cases without biallelic loss (Additional file 2: Table S1), while miRNA-10a and miRNA-10b expression levels, which both target CHL1, were higher in cases with biallelic loss than those without (Additional file 3: Table S2).	('elevated', 'PosReg', (148, 156))	('miRNA-10a', 'Gene', (226, 235))	('biallelic', 'Var', (129, 138))	('miRNA-10b', 'Gene', '406903', (240, 249))	('reduced', 'NegReg', (107, 114))	('miRNA-10b', 'Gene', (240, 249))	('CHL1', 'Gene', (287, 291))	('CHL1', 'Gene', (98, 102))	('expression level', 'MPA', (78, 94))	('higher', 'PosReg', (298, 304))	('CHL1', 'Gene', '10752', (31, 35))	('miRNA-10a', 'Gene', '406902', (226, 235))	('biallelic', 'Var', (13, 22))	('CHL1', 'Gene', (31, 35))	('expression levels', 'MPA', (250, 267))	('CHL1', 'Gene', '10752', (287, 291))	('CHL1', 'Gene', '10752', (98, 102))
67743	26409826	In addition, most of the SNPs identified with biallelic loss were in introns of genes, and our small sample size precluded detailed assessment of interactions among DNA, RNA, and miRNA.	('biallelic', 'Var', (46, 55))	('loss', 'NegReg', (56, 60))	('miR', 'Gene', '220972', (179, 182))	('miR', 'Gene', (179, 182))	('interactions', 'Interaction', (146, 158))
67746	26409826	SNP Single nucleotide polymorphism ESCC Esophageal squamous cell carcinoma FC Fold change	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('Single nucleotide polymorphism', 'Var', (4, 34))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (40, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('ESCC', 'Gene', (35, 39))	('Esophageal squamous cell carcinoma', 'Disease', (40, 74))
67750	22767218	Here, we show that 80% of tumors and cell lines featuring amplified ERBB2 display an aberrantly activated eIF4F.	('amplified', 'Var', (58, 67))	('eIF4F', 'Gene', (106, 111))	('ERBB2', 'Gene', '2064', (68, 73))	('eIF4F', 'Gene', '1981', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('ERBB2', 'Gene', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
67760	22767218	Overexpression of ERBB2 through gene amplification leads to homodimerization of the ERBB2 receptor resulting in a constitutively active state triggering aberrant signaling of major RAS/MAPK and PI3K/AKT pathways which activate the mammalian target of rapamycin (mTOR) where these oncogenic pathways converge.	('ERBB2', 'Gene', (84, 89))	('mammalian target of rapamycin', 'Gene', (231, 260))	('mammalian target of rapamycin', 'Gene', '2475', (231, 260))	('AKT', 'Gene', (199, 202))	('mTOR', 'Gene', '2475', (262, 266))	('mTOR', 'Gene', (262, 266))	('ERBB2', 'Gene', '2064', (18, 23))	('constitutively active state', 'MPA', (114, 141))	('ERBB2', 'Gene', (18, 23))	('AKT', 'Gene', '207', (199, 202))	('triggering', 'Reg', (142, 152))	('gene amplification', 'Var', (32, 50))	('ERBB2', 'Gene', '2064', (84, 89))	('aberrant signaling', 'MPA', (153, 171))	('homodimerization', 'MPA', (60, 76))
67783	22767218	Recent studies on proteasome-dependent proteolysis of ubiquitinated eIF4E revealed that while ubiquitinated eIF4E retains its cap binding ability, eIF4E phosphorylation and eIF4G binding are reduced.	('cap binding ability', 'MPA', (126, 145))	('eIF4E', 'Gene', (147, 152))	('eIF4E', 'Gene', (108, 113))	('binding', 'Interaction', (179, 186))	('cap', 'Chemical', '-', (126, 129))	('ubiquitinated', 'Var', (94, 107))	('reduced', 'NegReg', (191, 198))	('eIF4E', 'Gene', '1977', (68, 73))	('eIF4G', 'Gene', (173, 178))	('eIF4E', 'Gene', '1977', (147, 152))	('eIF4E', 'Gene', '1977', (108, 113))	('phosphorylation', 'MPA', (153, 168))	('eIF4E', 'Gene', (68, 73))	('eIF4G', 'Gene', '1981', (173, 178))
67786	22767218	Thus, presumably, targeting UPS in ERBB2-positive cancers with aberrantly activated eIF4F might be a novel and more efficient therapeutic strategy compared to a standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway.	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('aberrantly activated', 'Var', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))	('eIF4F', 'Gene', (84, 89))	('eIF4F', 'Gene', '1981', (84, 89))
67787	22767218	A corollary of our concept is that disruption of aberrantly activated eIF4F function downstream of amplified ERBB2 will be an effective anti-cancer strategy; and that targeting the UPS could increase the efficacy of therapeutics targeting cap-dependent translation.	('increase', 'PosReg', (191, 199))	('ERBB2', 'Gene', '2064', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('cap-dependent', 'MPA', (239, 252))	('ERBB2', 'Gene', (109, 114))	('eIF4F', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('disruption', 'Var', (35, 45))	('eIF4F', 'Gene', '1981', (70, 75))	('aberrantly', 'Var', (49, 59))	('cap', 'Chemical', '-', (239, 242))
67789	22767218	Our studies show that aberrantly activated eIF4F and the deregulated proteasome system collaborate as part of the molecular strategy adopted by esophageal cancer cells to maintain neoplastic growth; and identify interruption of this pro-oncogenic cooperation as a novel therapeutic approach.	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('maintain', 'PosReg', (171, 179))	('eIF4F', 'Gene', '1981', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('aberrantly', 'Var', (22, 32))	('eIF4F', 'Gene', (43, 48))	('neoplastic growth', 'CPA', (180, 197))	('esophageal cancer', 'Disease', (144, 161))
67811	22767218	Here we explored whether inhibition of ERBB2 with herceptin (Trastuzumab), an FDA approved therapeutic monoclonal antibody for ERBB2 protein overexpressing metastatic breast cancer, alters ERBB2-positive EAC cell growth and the expression of two major mTOR targets regulating mRNA translation: p70S6K and 4E-BP1 (Figures 1b-d).	('breast cancer', 'Disease', (167, 180))	('p70S6K and 4E-BP1', 'Gene', '6198;1978', (294, 311))	('mTOR', 'Gene', '2475', (252, 256))	('ERBB2', 'Gene', (39, 44))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (61, 72))	('herceptin', 'Chemical', 'MESH:D000068878', (50, 59))	('ERBB2', 'Gene', (127, 132))	('ERBB2', 'Gene', (189, 194))	('inhibition', 'Var', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('ERBB2', 'Gene', '2064', (39, 44))	('EAC', 'Phenotype', 'HP:0011459', (204, 207))	('ERBB2', 'Gene', '2064', (189, 194))	('ERBB2', 'Gene', '2064', (127, 132))	('expression', 'MPA', (228, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('alters', 'Reg', (182, 188))	('mTOR', 'Gene', (252, 256))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
67816	22767218	The effect of a PI3K inhibitor, LY294002, on p-AKT expression was more pronounced.	('AKT', 'Gene', (47, 50))	('AKT', 'Gene', '207', (47, 50))	('LY294002', 'Var', (32, 40))	('expression', 'MPA', (51, 61))	('LY294002', 'Chemical', 'MESH:C085911', (32, 40))
67817	22767218	The combination of herceptin and LY294002 was synergistic and resulted in complete abrogation of p-AKT expression.	('LY294002', 'Chemical', 'MESH:C085911', (33, 41))	('abrogation', 'NegReg', (83, 93))	('herceptin', 'Chemical', 'MESH:D000068878', (19, 28))	('AKT', 'Gene', '207', (99, 102))	('AKT', 'Gene', (99, 102))	('LY294002', 'Var', (33, 41))
67824	22767218	'ERBB2-specific targets', would be altered upon ErbB2 knockdown with siRNA.	('knockdown', 'Var', (54, 63))	('ErbB2', 'Gene', (48, 53))	('ErbB2', 'Gene', '2064', (48, 53))	('ERBB2', 'Gene', (1, 6))	('ERBB2', 'Gene', '2064', (1, 6))
67846	22767218	This result suggests uncoupling of growth--factor signaling and regulation of capdependent translation in cells with high level of ErbB2 amplification.	('cap', 'Chemical', '-', (78, 81))	('capdependent translation', 'MPA', (78, 102))	('ErbB2', 'Gene', '2064', (131, 136))	('amplification', 'Var', (137, 150))	('ErbB2', 'Gene', (131, 136))
67866	22767218	Moreover, western blot analysis revealed activation of MAPK in OE19 cells as reflected by its phosphorylation on Thr202/Tyr 204 sites.	('Thr202/Tyr', 'Var', (113, 123))	('MAPK', 'Gene', (55, 59))	('Thr202/Tyr', 'SUBSTITUTION', 'None', (113, 123))	('activation', 'PosReg', (41, 51))	('OE19', 'CellLine', 'CVCL:1622', (63, 67))
67870	22767218	Previous reports on breast cancers show that overexpression of ErbB2 as a result of gene amplification leads to aberrant signaling downstream of major RAS/MAPK and PI3K/AKT/mTOR oncogenic signaling pathways, presumably modulating the level of mRNA translation.	('breast cancers', 'Phenotype', 'HP:0003002', (20, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancers', 'Disease', 'MESH:D001943', (20, 34))	('breast cancers', 'Disease', (20, 34))	('ErbB2', 'Gene', (63, 68))	('aberrant signaling', 'MPA', (112, 130))	('AKT', 'Gene', (169, 172))	('mTOR', 'Gene', '2475', (173, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('gene amplification', 'Var', (84, 102))	('mTOR', 'Gene', (173, 177))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('ErbB2', 'Gene', '2064', (63, 68))	('overexpression', 'PosReg', (45, 59))	('AKT', 'Gene', '207', (169, 172))
67873	22767218	To directly target eIF4F integrity, we used a vector encoding a double phosphorylation site mutant form of 4E-BP1 gene (4E-BP1 A36/A47, designated 'TTAA') that resists inactivation by hyperphosphorylation through the PI3K/Akt/mTOR cascade and compared its effect to a vector encoding wild type 4E-BP1 (WT) and an empty vector control.	('4E-BP1', 'Gene', '1978', (294, 300))	('4E-BP1', 'Gene', (107, 113))	('4E-BP1', 'Gene', '1978', (120, 126))	('eIF4F', 'Gene', '1981', (19, 24))	('Akt', 'Gene', '207', (222, 225))	('4E-BP1', 'Gene', '1978', (107, 113))	('4E-BP1', 'Gene', (294, 300))	('Akt', 'Gene', (222, 225))	('4E-BP1', 'Gene', (120, 126))	('mutant', 'Var', (92, 98))	('mTOR', 'Gene', (226, 230))	('mTOR', 'Gene', '2475', (226, 230))	('eIF4F', 'Gene', (19, 24))	('TTAA', 'Chemical', '-', (148, 152))
67882	22767218	Decrease in translation of renilla luciferase in both, TTAA-OE33 and TTAA-OE19 cells, compared to vector control also indicated TTAA 4E-BP1 was an effective translational repressor.	('translation', 'MPA', (12, 23))	('TTAA', 'Var', (128, 132))	('OE19', 'CellLine', 'CVCL:1622', (74, 78))	('Decrease', 'NegReg', (0, 8))	('4E-BP1', 'Gene', '1978', (133, 139))	('renilla luciferase', 'Enzyme', (27, 45))	('TTAA', 'Chemical', '-', (69, 73))	('4E-BP1', 'Gene', (133, 139))	('TTAA', 'Chemical', '-', (55, 59))	('TTAA', 'Chemical', '-', (128, 132))
67885	22767218	Moreover, mutant forms of 4E-BP1, including TTAA, which cannot be inactivated by hyperphosphorylation, stimulate apoptosis and inhibit tumorigenicity when expressed in human breast carcinoma cells.	('human', 'Species', '9606', (168, 173))	('breast carcinoma', 'Disease', 'MESH:D001943', (174, 190))	('breast carcinoma', 'Disease', (174, 190))	('mutant', 'Var', (10, 16))	('apoptosis', 'CPA', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('TTAA', 'Chemical', '-', (44, 48))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('4E-BP1', 'Gene', (26, 32))	('breast carcinoma', 'Phenotype', 'HP:0003002', (174, 190))	('stimulate', 'PosReg', (103, 112))	('inhibit', 'NegReg', (127, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('4E-BP1', 'Gene', '1978', (26, 32))
67894	22767218	Accordingly, inhibition of the 20S proteasome core activity with UPS specific inhibitors prevents cleavage and stabilizes eIF4E and eIF4G1, decreases amount of cap-bound eIF4G1 and as a result differentially affects translation of different mRNAs.	('cleavage', 'MPA', (98, 106))	('eIF4G1', 'Gene', (132, 138))	('eIF4G1', 'Gene', (170, 176))	('affects', 'Reg', (208, 215))	('inhibition', 'Var', (13, 23))	('stabilizes', 'MPA', (111, 121))	('eIF4E', 'Gene', '1977', (122, 127))	('prevents', 'NegReg', (89, 97))	('translation of different mRNAs', 'MPA', (216, 246))	('eIF4E', 'Gene', (122, 127))	('eIF4G1', 'Gene', '1981', (132, 138))	('amount', 'MPA', (150, 156))	('cap', 'Chemical', '-', (160, 163))	('eIF4G1', 'Gene', '1981', (170, 176))	('decreases', 'NegReg', (140, 149))
67901	22767218	Examination of clonogenic growth revealed that inhibition of cap-dependent translation via both, genetic (TTAA) or pharmacological (rapamycin) targeting, and inhibition of the UPS (bortezomib) results in suppression of anchorage-dependent colony formation.	('rapamycin', 'Chemical', 'MESH:D020123', (132, 141))	('anchorage-dependent colony formation', 'CPA', (219, 255))	('inhibition', 'Var', (47, 57))	('suppression', 'NegReg', (204, 215))	('bortezomib', 'Chemical', 'MESH:D000069286', (181, 191))	('TTAA', 'Chemical', '-', (106, 110))	('cap-dependent translation', 'MPA', (61, 86))	('cap', 'Chemical', '-', (61, 64))
67905	22767218	Here we show that co-targeting 2 crucial steps of the post-transcriptional control, the cap-dependent translation initiation complex (eIF4F) and the ubiquitin-proteasome system (UPS) synergistically attenuates the esophageal adenocarcinoma (EAC) phenotype.	('attenuates', 'NegReg', (199, 209))	('eIF4F', 'Gene', (134, 139))	('esophageal adenocarcinoma', 'Disease', (214, 239))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (214, 239))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (214, 239))	('eIF4F', 'Gene', '1981', (134, 139))	('co-targeting', 'Var', (18, 30))	('EAC', 'Phenotype', 'HP:0011459', (241, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('cap', 'Chemical', '-', (88, 91))
67906	22767218	Our results demonstrate that cap-dependent mRNA translation, a step near the apex of the post-transcriptional control, is activated in most tested EAC cell lines and tumors (Figures 1 and 2), and that targeted disruption of eIF4F abrogates the malignant phenotype (Figures 3-5).	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('activated', 'PosReg', (122, 131))	('EAC', 'Phenotype', 'HP:0011459', (147, 150))	('cap-dependent mRNA translation', 'MPA', (29, 59))	('abrogates', 'NegReg', (230, 239))	('eIF4F', 'Gene', (224, 229))	('malignant phenotype', 'CPA', (244, 263))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('eIF4F', 'Gene', '1981', (224, 229))	('cap', 'Chemical', '-', (29, 32))	('targeted disruption', 'Var', (201, 220))
67916	22767218	We show that expression of constitutively active mutant form of the translational repressor TTAA not only effectively reduces translation in rapamycin resistant cells, but also efficiently alleviates basic cancer-associated features, including cell growth, proliferation, colony formation, and in OE33 cells also resistance to apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('mutant', 'Var', (49, 55))	('proliferation', 'CPA', (257, 270))	('TTAA', 'Chemical', '-', (92, 96))	('TTAA', 'Gene', (92, 96))	('rapamycin', 'Chemical', 'MESH:D020123', (141, 150))	('reduces', 'NegReg', (118, 125))	('translation', 'MPA', (126, 137))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('colony formation', 'CPA', (272, 288))	('alleviates', 'NegReg', (189, 199))	('cell growth', 'CPA', (244, 255))	('resistance to apoptosis', 'CPA', (313, 336))
67926	22767218	After this current manuscript was accepted for publication, our collaborators have brilliantly established the mechanistic basis underlying the putative potency of combinatory treatment with bortezomib and antisense eIF4E as anti-cancer regimen.	('bortezomib', 'Chemical', 'MESH:D000069286', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('eIF4E', 'Gene', '1977', (216, 221))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('eIF4E', 'Gene', (216, 221))	('antisense', 'Var', (206, 215))
67932	22767218	To date, this strategy has not been completely validated mainly due to the ability of cancer cells to rapidly adapt to inhibition of signal suppression (inactivation of a particular pathway frequently leads to activation of pro-oncogenic collateral signaling circuits).	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('inactivation', 'Var', (153, 165))	('pro-oncogenic collateral', 'MPA', (224, 248))	('activation', 'PosReg', (210, 220))	('cancer', 'Disease', (86, 92))
68025	22824179	However, because the esophageal surface area irradiated (1-4 cm2 vs 3-9 cm2) and the total laser irradiation dose (100-300 J vs 225-675 J) were quite different between each study, the toxicity related with laser irradiation should be evaluated in the next phase II study.	('toxicity', 'Disease', (184, 192))	('toxicity', 'Disease', 'MESH:D064420', (184, 192))	('100-300', 'Var', (115, 122))
68050	19147768	Poly E inhibited the proliferation of immortalized Barrett's cells as well as various adenocarcinoma cells, and this was associated with the down-regulation of cyclin D1 protein expression.	('proliferation', 'CPA', (21, 34))	('adenocarcinoma cell', 'Disease', 'MESH:C538614', (86, 105))	('adenocarcinoma cell', 'Disease', (86, 105))	('Poly E', 'Var', (0, 6))	('Poly E', 'Chemical', 'MESH:C472086', (0, 6))	('inhibited', 'NegReg', (7, 16))	('protein', 'Protein', (170, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('down-regulation', 'NegReg', (141, 156))	('cyclin D1 protein', 'Protein', (160, 177))
68051	19147768	Inhibition of cyclin D1 led to dephosphorylation of the retinoblastoma protein in a dose-dependent manner; these changes were associated with G1 cell cycle arrest.	('cyclin D1', 'Protein', (14, 23))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (145, 162))	('dephosphorylation of the retinoblastoma', 'Disease', (31, 70))	('retinoblastoma', 'Phenotype', 'HP:0009919', (56, 70))	('G1 cell cycle arrest', 'CPA', (142, 162))	('Inhibition', 'Var', (0, 10))	('dephosphorylation of the retinoblastoma', 'Disease', 'MESH:D012175', (31, 70))
68052	19147768	Poly E down-regulated cyclin D1 promoter activity and mRNA expression, suggesting transcriptional repression, and this correlated with decreased nuclear beta-catenin and beta-catenin/TCF4 transcriptional activity.	('mRNA expression', 'MPA', (54, 69))	('down-regulated', 'NegReg', (7, 21))	('nuclear beta-catenin', 'MPA', (145, 165))	('Poly E', 'Var', (0, 6))	('beta-catenin/TCF4', 'Protein', (170, 187))	('Poly E', 'Chemical', 'MESH:C472086', (0, 6))	('decreased', 'NegReg', (135, 144))	('cyclin D1', 'Protein', (22, 31))	('transcriptional activity', 'MPA', (188, 212))
68053	19147768	MG132, an inhibitor of 26S proteosome, blocked the Poly E-induced down-regulation of cyclin D1, and Poly E promoted cyclin D1 polyubiquitination, suggesting that Poly E also inhibits cyclin D1 expression by promoting its degradation.	('Poly E', 'Chemical', 'MESH:C472086', (162, 168))	('Poly', 'Var', (100, 104))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('degradation', 'MPA', (221, 232))	('cyclin D1', 'Gene', (183, 192))	('Poly', 'Gene', (51, 55))	('cyclin', 'Protein', (85, 91))	('Poly E', 'Chemical', 'MESH:C472086', (100, 106))	('promoting', 'PosReg', (207, 216))	('Poly E', 'Chemical', 'MESH:C472086', (51, 57))	('cyclin D1 polyubiquitination', 'MPA', (116, 144))	('expression', 'MPA', (193, 203))	('promoted', 'PosReg', (107, 115))	('inhibits', 'NegReg', (174, 182))	('down-regulation', 'NegReg', (66, 81))
68054	19147768	Poly E inhibits growth of transformed aerodigestive epithelial cells by suppressing cyclin D1 expression through both transcriptional and post-translational mechanisms.	('inhibits', 'NegReg', (7, 15))	('cyclin D1', 'Gene', (84, 93))	('Poly E', 'Var', (0, 6))	('growth', 'CPA', (16, 22))	('Poly E', 'Chemical', 'MESH:C472086', (0, 6))	('suppressing', 'NegReg', (72, 83))	('expression', 'MPA', (94, 104))
68055	19147768	These results provide insight into the mechanisms by which Poly E inhibits growth of Barrett's and adenocarcinoma cells, and provides a rationale for using this agent as a potential chemopreventive and therapeutic strategy for esophageal adenocarcinoma and its precursor, Barrett's esophagus.	('adenocarcinoma cell', 'Disease', 'MESH:C538614', (99, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (227, 252))	('adenocarcinoma cell', 'Disease', (99, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (227, 252))	('inhibits', 'NegReg', (66, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (272, 291))	('Poly E', 'Var', (59, 65))	('Poly E', 'Chemical', 'MESH:C472086', (59, 65))	('growth', 'CPA', (75, 81))	('esophageal adenocarcinoma', 'Disease', (227, 252))
68061	19147768	We believe that these results provide insight into the mechanisms by which polyphenon E may function as a potential chemopreventive and therapeutic agent for esophageal adenocarcinoma and its precursor Barrett's esophagus.	('polyphenon E', 'Chemical', 'MESH:C472086', (75, 87))	('esophageal adenocarcinoma', 'Disease', (158, 183))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (202, 221))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (158, 183))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (158, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('polyphenon', 'Var', (75, 85))
68071	19147768	Shimizu et alfound that EGCG inhibits the activation of EGF receptor, the receptors HER2 and HER3, and their downstream signaling pathways (including ERK, COX-2, cyclin D1, and BCL-XL) in human colon, breast, and head and neck cancer cell lines.	('head and neck cancer', 'Phenotype', 'HP:0012288', (213, 233))	('HER2', 'Gene', (84, 88))	('activation', 'PosReg', (42, 52))	('EGCG', 'Chemical', 'MESH:C045651', (24, 28))	('BCL-XL', 'Gene', '598', (177, 183))	('HER3', 'Gene', '2065', (93, 97))	('EGF receptor', 'Protein', (56, 68))	('head and neck cancer', 'Disease', 'MESH:D006258', (213, 233))	('inhibits', 'NegReg', (29, 37))	('cyclin D1', 'MPA', (162, 171))	('COX-2', 'Gene', (155, 160))	('HER2', 'Gene', '2064', (84, 88))	('ERK', 'Gene', (150, 153))	('COX-2', 'Gene', '4513', (155, 160))	('human', 'Species', '9606', (188, 193))	('HER3', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('ERK', 'Gene', '2048', (150, 153))	('EGCG', 'Var', (24, 28))	('BCL-XL', 'Gene', (177, 183))
68076	19147768	Shimizu et al recently reported that Poly E has efficacy similar to EGCG in inhibiting human colon cancer cell growth, and activation of the EGF receptor and HER2 in human colon cancer cells.	('colon cancer', 'Disease', (93, 105))	('Poly E', 'Chemical', 'MESH:C472086', (37, 43))	('colon cancer', 'Disease', (172, 184))	('HER2', 'Gene', '2064', (158, 162))	('colon cancer', 'Phenotype', 'HP:0003003', (172, 184))	('EGCG', 'Chemical', 'MESH:C045651', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('human', 'Species', '9606', (87, 92))	('human', 'Species', '9606', (166, 171))	('HER2', 'Gene', (158, 162))	('inhibiting', 'NegReg', (76, 86))	('activation', 'PosReg', (123, 133))	('EGF receptor', 'Protein', (141, 153))	('colon cancer', 'Disease', 'MESH:D015179', (172, 184))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('Poly E', 'Var', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colon cancer', 'Disease', 'MESH:D015179', (93, 105))
68078	19147768	Using the A/J mouse model, Yan et al reported that Poly E in the diet (2% wt/wt) reduced tumor multiplicity by 46% and tumor load by 94% in the benzo[a]pyrene-induced lung tumorigenesis model.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (119, 124))	('mouse', 'Species', '10090', (14, 19))	('tumor', 'Disease', (172, 177))	('pyrene', 'Chemical', 'MESH:C030984', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Poly E', 'Var', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Poly E', 'Chemical', 'MESH:C472086', (51, 57))	('reduced', 'NegReg', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('benzo', 'CPA', (144, 149))
68082	19147768	Increased cyclin D1 expression or activity as a result of gene amplification or translocation is common in many human cancers, including breast, esophagus, lung, head and neck, colon, and prostate cancer.	('activity', 'MPA', (34, 42))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('esophagus', 'Disease', (145, 154))	('human', 'Species', '9606', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('colon', 'Disease', (177, 182))	('cancers', 'Disease', (118, 125))	('cyclin D1', 'Protein', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lung', 'Disease', (156, 160))	('Increased', 'PosReg', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('prostate cancer', 'Disease', 'MESH:D011471', (188, 203))	('breast', 'Disease', (137, 143))	('prostate cancer', 'Phenotype', 'HP:0012125', (188, 203))	('expression', 'MPA', (20, 30))	('gene amplification', 'Var', (58, 76))	('common', 'Reg', (97, 103))	('prostate cancer', 'Disease', (188, 203))	('translocation', 'Var', (80, 93))
68087	19147768	We found that Poly E inhibits the growth of these cells by down-regulating cyclin D1 expression via both transcriptional and post-translational mechanisms.	('expression', 'MPA', (85, 95))	('inhibits', 'NegReg', (21, 29))	('Poly E', 'Var', (14, 20))	('cyclin D1', 'Gene', (75, 84))	('growth of these cells', 'CPA', (34, 55))	('Poly E', 'Chemical', 'MESH:C472086', (14, 20))	('down-regulating', 'NegReg', (59, 74))
68088	19147768	These results provide novel insights into the mechanisms of Poly E inhibition of EA cell growth and provide the rationale for using this agent as a potential chemopreventive and therapeutic strategy for treating EA and its precursor, BE.	('Poly E', 'Var', (60, 66))	('inhibition', 'NegReg', (67, 77))	('EA', 'Phenotype', 'HP:0011459', (212, 214))	('Poly E', 'Chemical', 'MESH:C472086', (60, 66))	('EA cell growth', 'CPA', (81, 95))	('BE', 'Phenotype', 'HP:0100580', (234, 236))	('EA', 'Phenotype', 'HP:0011459', (81, 83))
68117	19147768	To determine whether the treated cells underwent apoptosis, cells treated with up to 100 mug/ml Poly E for 36 hours were washed in PBS, resuspended in 100 mul of binding buffer containing fluorescein isothiocyanate-conjugated Annexin V, and analyzed by flow cytometry to determine the apoptosis index.	('PBS', 'Chemical', '-', (131, 134))	('Annexin V', 'Gene', (226, 235))	('Poly E', 'Var', (96, 102))	('fluorescein isothiocyanate', 'Chemical', 'MESH:D016650', (188, 214))	('Poly E', 'Chemical', 'MESH:C472086', (96, 102))	('Annexin V', 'Gene', '308', (226, 235))
68125	19147768	Cyclin D1 and phospho-Rb were detected with 1 mug/ml anti-cyclin D1 and anti-phospho-Rb antibody, respectively.	('anti-cyclin', 'Var', (53, 64))	('Cyclin D1', 'Gene', (0, 9))	('Cyclin D1', 'Gene', '595', (0, 9))	('detected', 'Reg', (30, 38))
68137	19147768	To determine the fold-change in RNA targets, real-time RT-PCR was performed on the ABI Prism 7900 (Applied Biosystems, Foster City, CA) using the commercially available gene expression assay for cyclin D1, CCND1 (Hs00277039_m1), and the cyclophilin A Vic-labeled predeveloped assay reagent (4326316E; Applied Biosystems) without multiplexing.	('C', 'Chemical', 'MESH:D002244', (59, 60))	('C', 'Chemical', 'MESH:D002244', (206, 207))	('Hs00277039_m1', 'Var', (213, 226))	('CCND1', 'Gene', '595', (206, 211))	('C', 'Chemical', 'MESH:D002244', (207, 208))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('CCND1', 'Gene', (206, 211))	('C', 'Chemical', 'MESH:D002244', (126, 127))
68142	19147768	We determined the effects of Poly E on the growth of two BE cells and several aerodigestive adenocarcinoma cell lines by using a nonradioactive MTS cell proliferation assay, and observed a dose- and time-dependent decrease in the rate of proliferation in SEG-1, BIC-1, SKGT-4, and BE3 esophageal adenocarcinoma cells and CP-A, CP-C immortalized Barrett's cells (Figs.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (285, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('CP-A', 'Gene', (321, 325))	('esophageal adenocarcinoma', 'Disease', (285, 310))	('CP-A', 'Gene', '1357', (321, 325))	('adenocarcinoma cell', 'Disease', (92, 111))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('adenocarcinoma cell', 'Disease', (296, 315))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('Poly', 'Var', (29, 33))	('BE', 'Phenotype', 'HP:0100580', (281, 283))	('BIC', 'Chemical', 'MESH:C100119', (262, 265))	('SKGT-4', 'CellLine', 'CVCL:2195', (269, 275))	('CP-C', 'Chemical', 'MESH:C015101', (327, 331))	('adenocarcinoma cell', 'Disease', 'MESH:C538614', (92, 111))	('adenocarcinoma cell', 'Disease', 'MESH:C538614', (296, 315))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (285, 310))	('Poly E', 'Chemical', 'MESH:C472086', (29, 35))	('decrease', 'NegReg', (214, 222))
68146	19147768	Poly E can induce the arrest of the cell cycle at the G1 phase and induce apoptosis in human HT29 colon cancer cells.	('apoptosis', 'CPA', (74, 83))	('HT29', 'CellLine', 'CVCL:0320', (93, 97))	('induce', 'Reg', (11, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('human', 'Species', '9606', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('arrest', 'CPA', (22, 28))	('Poly E', 'Var', (0, 6))	('colon cancer', 'Disease', (98, 110))	('induce', 'Reg', (67, 73))	('Poly E', 'Chemical', 'MESH:C472086', (0, 6))
68148	19147768	When SEG-1 cells were treated with 20 or 40 mug/ml Poly E for up to 72 hours, the percentage of cells in the G0/G1 phase increased in a dose- and time-dependent manner and was associated with a concomitant decrease of cells in the S phase (Fig.	('increased', 'PosReg', (121, 130))	('decrease', 'NegReg', (206, 214))	('Poly E', 'Var', (51, 57))	('Poly E', 'Chemical', 'MESH:C472086', (51, 57))	('cells in the S phase', 'CPA', (218, 238))
68150	19147768	Furthermore, treatment with Poly E for 36 hours induced apoptosis in SEG-1 and SKGT-4 cells, as indicated by a dose-dependent increase in the apoptosis index using Annexin V and propidium iodide (Fig.	('Annexin V', 'Gene', '308', (164, 173))	('men', 'Species', '9606', (18, 21))	('SKGT-4', 'CellLine', 'CVCL:2195', (79, 85))	('Annexin V', 'Gene', (164, 173))	('Poly', 'Var', (28, 32))	('propidium iodide', 'Chemical', 'MESH:D011419', (178, 194))	('Poly E', 'Chemical', 'MESH:C472086', (28, 34))	('increase', 'PosReg', (126, 134))	('apoptosis index', 'MPA', (142, 157))
68154	19147768	3A, 3B).These findings were not cell line specific since Poly E also reduced cyclin D1 expression in other transformed esophageal cell lines, including CP-A and CP-C derived from Barrett's epithelium (Fig.	('cyclin', 'MPA', (77, 83))	('Poly E', 'Chemical', 'MESH:C472086', (57, 63))	('reduced', 'NegReg', (69, 76))	('CP-C', 'Chemical', 'MESH:C015101', (161, 165))	('expression', 'MPA', (87, 97))	('CP-A', 'Gene', '1357', (152, 156))	('Poly E', 'Var', (57, 63))	('CP-A', 'Gene', (152, 156))
68156	19147768	Immunohistochemical staining of cyclin D1 in cytospin slides confirmed that Poly E dramatically decreased nuclear cyclin D1 staining in SEG-1 and CP-A cells without changes in morphology (Fig.	('decreased', 'NegReg', (96, 105))	('CP-A', 'Gene', '1357', (146, 150))	('nuclear cyclin D1 staining', 'MPA', (106, 132))	('Poly E', 'Var', (76, 82))	('CP-A', 'Gene', (146, 150))	('Poly E', 'Chemical', 'MESH:C472086', (76, 82))
68158	19147768	We therefore determined whether Poly E affects Rb phosphorylation in BE and EA cell lines.	('BE', 'Phenotype', 'HP:0100580', (69, 71))	('phosphorylation', 'MPA', (50, 65))	('Poly E', 'Chemical', 'MESH:C472086', (32, 38))	('affects', 'Reg', (39, 46))	('EA', 'Phenotype', 'HP:0011459', (76, 78))	('Poly E', 'Var', (32, 38))
68159	19147768	Poly E dephosphorylated Rb in a time-dependent manner in SEG-1, BIC-1, SKGT-4 and BE3 EA cells and in CP-A and CP-C immortalized Barrett's epithelial cells (Fig.4A).	('CP-A', 'Gene', '1357', (102, 106))	('CP-A', 'Gene', (102, 106))	('Poly E', 'Var', (0, 6))	('EA', 'Phenotype', 'HP:0011459', (86, 88))	('BE', 'Phenotype', 'HP:0100580', (82, 84))	('Poly E', 'Chemical', 'MESH:C472086', (0, 6))	('SKGT-4', 'CellLine', 'CVCL:2195', (71, 77))	('BE3 EA', 'CellLine', 'CVCL:E575', (82, 88))	('CP-C', 'Chemical', 'MESH:C015101', (111, 115))	('BIC', 'Chemical', 'MESH:C100119', (64, 67))
68161	19147768	These findings suggest that poly E inhibits the growth of BE and aerodigestive adenocarcinoma cells at least in part, by down-regulating cyclin D1 and that is accompanied by dephosphorylation of Rb.	('growth', 'CPA', (48, 54))	('dephosphorylation', 'MPA', (174, 191))	('poly E', 'Chemical', '-', (28, 34))	('BE', 'Phenotype', 'HP:0100580', (58, 60))	('inhibits', 'NegReg', (35, 43))	('poly E', 'Var', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinoma cell', 'Disease', 'MESH:C538614', (79, 98))	('adenocarcinoma cell', 'Disease', (79, 98))	('down-regulating', 'NegReg', (121, 136))	('cyclin D1', 'Protein', (137, 146))
68162	19147768	We next sought to define the mechanisms by which Poly E down-regulates cyclin-D1 expression.	('cyclin-D1', 'Gene', '595', (71, 80))	('cyclin-D1', 'Gene', (71, 80))	('down-regulates', 'NegReg', (56, 70))	('Poly E', 'Var', (49, 55))	('Poly E', 'Chemical', 'MESH:C472086', (49, 55))	('expression', 'MPA', (81, 91))
68163	19147768	We first explored the possibility that Poly E decreases cyclin D1 expression by altering transcription.	('Poly E', 'Chemical', 'MESH:C472086', (39, 45))	('transcription', 'MPA', (89, 102))	('cyclin D1', 'Protein', (56, 65))	('expression', 'MPA', (66, 76))	('decreases', 'NegReg', (46, 55))	('altering', 'Reg', (80, 88))	('Poly E', 'Var', (39, 45))
68166	19147768	We then explored whether Poly E affects cyclin D1 expression by affecting its promoter activity.	('affects', 'Reg', (32, 39))	('expression', 'MPA', (50, 60))	('promoter activity', 'MPA', (78, 95))	('affecting', 'Reg', (64, 73))	('Poly E', 'Var', (25, 31))	('Poly E', 'Chemical', 'MESH:C472086', (25, 31))	('cyclin D1', 'Protein', (40, 49))
68168	19147768	Poly E decreased cyclin D1 reporter activity in a dose-dependent manner in SEG-1 and SKGT-4 cells (Fig.	('decreased', 'NegReg', (7, 16))	('Poly E', 'Var', (0, 6))	('Poly E', 'Chemical', 'MESH:C472086', (0, 6))	('SKGT-4', 'CellLine', 'CVCL:2195', (85, 91))	('cyclin D1 reporter activity', 'MPA', (17, 44))
68169	19147768	These results suggest that Poly E down-regulates cyclin D1 expression at least in part by suppressing its transcription.	('cyclin D1', 'Gene', (49, 58))	('down-regulates', 'NegReg', (34, 48))	('Poly E', 'Var', (27, 33))	('suppressing', 'NegReg', (90, 101))	('expression', 'MPA', (59, 69))	('Poly E', 'Chemical', 'MESH:C472086', (27, 33))	('transcription', 'MPA', (106, 119))
68171	19147768	Treatment of SEG-1 and SKGT-4 cells with Poly E for 24 hours decreased nuclear level of beta-catenin in a dose-dependent fashion that corresponded with the decreased cyclin D1 expression (Fig.	('cyclin D1 expression', 'MPA', (166, 186))	('Poly E', 'Var', (41, 47))	('Poly E', 'Chemical', 'MESH:C472086', (41, 47))	('decreased', 'NegReg', (156, 165))	('nuclear level of beta-catenin', 'MPA', (71, 100))	('men', 'Species', '9606', (5, 8))	('decreased', 'NegReg', (61, 70))	('SKGT-4', 'CellLine', 'CVCL:2195', (23, 29))
68175	19147768	Poly E inhibited TCF4 activity in a dose-dependent manner (Fig.	('TCF4', 'Enzyme', (17, 21))	('Poly E', 'Var', (0, 6))	('Poly E', 'Chemical', 'MESH:C472086', (0, 6))	('inhibited', 'NegReg', (7, 16))	('activity', 'MPA', (22, 30))
68176	19147768	These results suggest that Poly E inhibits nuclear beta-catenin and beta-catenin/TCF4 transcriptional activity which may mediate down-regulation of cyclin D1.	('cyclin D1', 'Gene', (148, 157))	('inhibits', 'NegReg', (34, 42))	('transcriptional activity', 'MPA', (86, 110))	('down-regulation', 'NegReg', (129, 144))	('Poly E', 'Var', (27, 33))	('Poly E', 'Chemical', 'MESH:C472086', (27, 33))	('beta-catenin/TCF4', 'Protein', (68, 85))	('nuclear beta-catenin', 'Protein', (43, 63))
68177	19147768	Since cyclin D1 undergoes ubiquitin dependent proteosomal degradation, it is possible that poly E could down-regulate cyclin D1 by enhancing its degradation.	('poly E', 'Var', (91, 97))	('degradation', 'MPA', (145, 156))	('ubiquitin dependent proteosomal degradation', 'MPA', (26, 69))	('cyclin D1', 'Gene', (118, 127))	('enhancing', 'PosReg', (131, 140))	('down-regulate', 'NegReg', (104, 117))	('poly E', 'Chemical', '-', (91, 97))
68180	19147768	MG132 prevented the decrease in cyclin D1 associated with Poly E treatment in SEG-1, BIC-1 and SKGT-4 cells (Fig.	('MG132', 'Var', (0, 5))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('cyclin D1', 'MPA', (32, 41))	('Poly', 'Var', (58, 62))	('men', 'Species', '9606', (70, 73))	('decrease', 'NegReg', (20, 28))	('Poly E', 'Chemical', 'MESH:C472086', (58, 64))	('BIC', 'Chemical', 'MESH:C100119', (85, 88))	('SKGT-4', 'CellLine', 'CVCL:2195', (95, 101))
68182	19147768	In order to explore the possibility that Poly E enhances cyclin D1 polyubiquitination and facilitates its degradation by proteosomes, we performed immunoprecipitation using anti-cyclin D1 antibody and immunoblotting with anti-ubiquitin antibody.	('polyubiquitination', 'MPA', (67, 85))	('facilitates', 'PosReg', (90, 101))	('Poly E', 'Var', (41, 47))	('Poly E', 'Chemical', 'MESH:C472086', (41, 47))	('cyclin D1', 'Protein', (57, 66))	('enhances', 'PosReg', (48, 56))	('degradation', 'MPA', (106, 117))
68184	19147768	6B), and MG132 further enhanced this polyubiquitination (Fig.	('enhanced', 'PosReg', (23, 31))	('MG132', 'Chemical', 'MESH:C072553', (9, 14))	('polyubiquitination', 'MPA', (37, 55))	('MG132', 'Var', (9, 14))
68186	19147768	These results suggest that Poly E enhances cyclin D1 proteolysis by facilitating cyclin D1 polyubiquitination and its subsequent degradation.	('cyclin', 'MPA', (81, 87))	('polyubiquitination', 'MPA', (91, 109))	('cyclin D1 proteolysis', 'MPA', (43, 64))	('Poly E', 'Var', (27, 33))	('enhances', 'PosReg', (34, 42))	('Poly E', 'Chemical', 'MESH:C472086', (27, 33))	('degradation', 'MPA', (129, 140))
68187	19147768	Green tea has been shown to be chemopreventive in several animal models of tumorigenesis, We have demonstrated that Poly E, a well-standardized green tea catechin mixture, potently inhibits the proliferation of aerodigestive adenocarcinoma cells and immortalized Barrett's epithelial cells and that this inhibition correlates with the down-regulation of cyclin D1 protein, dephosphorylation of Rb, and changes associated with cell cycle arrest at the G1 phase.	('dephosphorylation', 'MPA', (373, 390))	('Poly E', 'Var', (116, 122))	('catechin', 'Chemical', 'MESH:D002392', (154, 162))	('inhibits', 'NegReg', (181, 189))	('Poly E', 'Chemical', 'MESH:C472086', (116, 122))	('down-regulation', 'NegReg', (335, 350))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cell cycle arrest at the G1 phase', 'CPA', (426, 459))	('proliferation', 'CPA', (194, 207))	('changes', 'Reg', (402, 409))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('cyclin D1 protein', 'Protein', (354, 371))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (426, 443))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('adenocarcinoma cell', 'Disease', (225, 244))	('tumor', 'Disease', (75, 80))	('adenocarcinoma cell', 'Disease', 'MESH:C538614', (225, 244))
68188	19147768	Our data suggest that Poly E down-regulates cyclin D1 by inhibiting its transcription, which correlates with Poly E-induced decreases in nuclear beta-catenin levels and decreased beta-catenin/TCF4 transcriptional activity.	('inhibiting', 'NegReg', (57, 67))	('nuclear beta-catenin levels', 'MPA', (137, 164))	('cyclin D1', 'Gene', (44, 53))	('Poly E', 'Chemical', 'MESH:C472086', (22, 28))	('Poly E', 'Chemical', 'MESH:C472086', (109, 115))	('decreases', 'NegReg', (124, 133))	('transcription', 'MPA', (72, 85))	('beta-catenin/TCF4', 'Enzyme', (179, 196))	('transcriptional activity', 'MPA', (197, 221))	('decreased', 'NegReg', (169, 178))	('Poly', 'Var', (109, 113))	('down-regulates', 'NegReg', (29, 43))	('Poly E', 'Var', (22, 28))
68189	19147768	In addition, Poly E promotes the ubiquitinition of cyclin D1 and its subsequent degradation.	('degradation', 'MPA', (80, 91))	('Poly E', 'Var', (13, 19))	('cyclin D1', 'Protein', (51, 60))	('promotes', 'PosReg', (20, 28))	('Poly E', 'Chemical', 'MESH:C472086', (13, 19))	('ubiquitinition', 'MPA', (33, 47))
68193	19147768	Our data indicate that Poly E inhibits the phosphorylation of Rb and cellular arrested in G1, mediated through the down-regulation of cyclin D1.	('phosphorylation', 'MPA', (43, 58))	('Poly E', 'Var', (23, 29))	('down-regulation', 'NegReg', (115, 130))	('cellular arrested', 'CPA', (69, 86))	('Poly E', 'Chemical', 'MESH:C472086', (23, 29))	('cyclin D1', 'Protein', (134, 143))	('inhibits', 'NegReg', (30, 38))
68194	19147768	Our results suggest that there are at least two mechanisms by which Poly E down-regulates cyclin D1.	('cyclin D1', 'Protein', (90, 99))	('Poly E', 'Chemical', 'MESH:C472086', (68, 74))	('down-regulates', 'NegReg', (75, 89))	('Poly E', 'Var', (68, 74))
68195	19147768	The first mechanism involves transcriptional repression: cyclin D1 mRNA and promoter activity were down-regulated by Poly E, suggesting transcriptional repression.	('down-regulated', 'NegReg', (99, 113))	('cyclin', 'MPA', (57, 63))	('Poly E', 'Var', (117, 123))	('Poly E', 'Chemical', 'MESH:C472086', (117, 123))	('promoter activity', 'MPA', (76, 93))
68196	19147768	Nuclear beta-catenin level was suppressed by Poly E, which correlated with cyclin D1 down-regulation.	('Nuclear beta-catenin level', 'MPA', (0, 26))	('Poly E', 'Var', (45, 51))	('down-regulation', 'NegReg', (85, 100))	('cyclin D1', 'Gene', (75, 84))	('Poly E', 'Chemical', 'MESH:C472086', (45, 51))	('suppressed', 'NegReg', (31, 41))
68197	19147768	Suppression of beta-catenin/TCF4 promoter activity by Poly E was also observed, suggesting that the Wnt pathway mediates transcriptional down-regulation of cyclin D1 by Poly E. These data are consistent with those of Ju et al, who reported that EGCG decreases levels of nuclear beta-catenin and its target gene c-myc in HT29 human colon cancer cells and small intestinal tumor tissues.	('colon cancer', 'Disease', 'MESH:D015179', (331, 343))	('c-myc', 'Gene', (311, 316))	('EGCG', 'Var', (245, 249))	('c-myc', 'Gene', '4609', (311, 316))	('EGCG', 'Chemical', 'MESH:C045651', (245, 249))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('Poly E', 'Chemical', 'MESH:C472086', (54, 60))	('colon cancer', 'Disease', (331, 343))	('small intestinal tumor', 'Phenotype', 'HP:0100833', (354, 376))	('intestinal tumor', 'Disease', 'MESH:D007414', (360, 376))	('colon cancer', 'Phenotype', 'HP:0003003', (331, 343))	('HT29 human', 'CellLine', 'CVCL:3285', (320, 330))	('levels of nuclear beta-catenin', 'MPA', (260, 290))	('intestinal tumor', 'Disease', (360, 376))	('decreases', 'NegReg', (250, 259))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('Poly E', 'Chemical', 'MESH:C472086', (169, 175))
68199	19147768	We were unable to demonstrate a similar affect on HBP1 protein levels by Poly E in the cell lines employed in our study (data not shown).	('Poly E', 'Var', (73, 79))	('HBP1', 'Gene', (50, 54))	('HBP1', 'Gene', '26959', (50, 54))	('Poly E', 'Chemical', 'MESH:C472086', (73, 79))
68203	19147768	Poly E also promoted cyclin D1 polyubiquitination in a dose-dependent manner further suggesting that Poly E down-regulates cyclin D1 by promoting its polyubiquitination and subsequently its proteosomal degradation.	('promoted', 'PosReg', (12, 20))	('Poly E', 'Var', (101, 107))	('Poly E', 'Chemical', 'MESH:C472086', (101, 107))	('proteosomal degradation', 'MPA', (190, 213))	('cyclin', 'MPA', (21, 27))	('Poly E', 'Chemical', 'MESH:C472086', (0, 6))	('down-regulates', 'NegReg', (108, 122))	('promoting', 'PosReg', (136, 145))	('cyclin D1', 'Gene', (123, 132))
68204	19147768	In conclusion, our results demonstrated that Poly E, a green tea derivative, potently inhibits the growth of human aerodigestive adenocarcinoma cells as well as Barrett's cells by down-regulating cyclin D1 expression via both transcriptional and post-translational mechanisms.	('cyclin D1', 'Gene', (196, 205))	('human', 'Species', '9606', (109, 114))	('adenocarcinoma cell', 'Disease', (129, 148))	('adenocarcinoma cell', 'Disease', 'MESH:C538614', (129, 148))	('down-regulating', 'NegReg', (180, 195))	('growth', 'MPA', (99, 105))	('expression', 'MPA', (206, 216))	('Poly E', 'Var', (45, 51))	('inhibits', 'NegReg', (86, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('Poly E', 'Chemical', 'MESH:C472086', (45, 51))
68290	32978845	1,2-DCP 1,2-dichloropropane AFB1 aflatoxin B1 AL aristolactam amu atomic mass unit HRAM high resolution accurate mass LC liquid chromatography LPO lipid peroxidation product MGT nanosized magnetite MS mass spectrometry NOC N-nitroso compound NPIP N-nitrosopiperidine PCA principal component analysis SBS single-base-substitution THP-dG N 2-(3,4,5,6-tetrahydro-2H-pyran-2-yl) deoxyguanosine Environmental factors contribute substantially to cancer development.	('aflatoxin B1', 'Chemical', 'MESH:D016604', (33, 45))	('cancer', 'Phenotype', 'HP:0002664', (440, 446))	('LPO', 'Gene', '4025', (143, 146))	('lipid', 'Chemical', 'MESH:D008055', (147, 152))	('1,2-DCP', 'Chemical', '-', (0, 7))	('1,2-dichloropropane', 'Chemical', 'MESH:C004765', (8, 27))	('amu', 'Chemical', 'MESH:C066068', (62, 65))	('NPIP', 'Gene', (242, 246))	('cancer', 'Disease', 'MESH:D009369', (440, 446))	('cancer', 'Disease', (440, 446))	('NOC', 'Gene', '25819', (219, 222))	('N-nitrosopiperidine', 'Chemical', 'MESH:C002743', (247, 266))	('rat', 'Species', '10116', (108, 111))	('THP-dG', 'Gene', (329, 335))	('N-nitroso compound', 'Chemical', '-', (223, 241))	('single-base-substitution', 'Var', (304, 328))	('N 2-(3,4,5,6-tetrahydro-2H-pyran-2-yl) deoxyguanosine', 'Chemical', '-', (336, 389))	('LPO', 'Gene', (143, 146))	('AL', 'Chemical', 'MESH:D000535', (46, 48))	('NPIP', 'Gene', '730153', (242, 246))	('NOC', 'Gene', (219, 222))
68310	32978845	As most of these major contributors coincided with oxidative stress and inflammation-related DNA adducts, 15  inflammation responses might contribute to the increased prevalence of mutations in the MGT-treated group.	('inflammation', 'Disease', (110, 122))	('inflammation', 'Disease', (72, 84))	('oxidative', 'MPA', (51, 60))	('oxidative stress', 'Phenotype', 'HP:0025464', (51, 67))	('mutations', 'Var', (181, 190))	('inflammation', 'Disease', 'MESH:D007249', (110, 122))	('inflammation', 'Disease', 'MESH:D007249', (72, 84))
68338	32978845	Cancer arises from the sequential accumulation of mutations in driver genes.	('mutations', 'Var', (50, 59))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
68340	32978845	27  Approximately one-third of these 49 signatures have unknown etiology; the remaining two-thirds are attributed to DNA repair deficiency, environmental exposure to chemical compounds, or cancer chemotherapy.	('DNA repair', 'Protein', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('deficiency', 'Var', (128, 138))	('cancer', 'Disease', (189, 195))
68341	32978845	Of these, four signatures, SBS11, SBS22, SBS24, and SBS42, are well-characterized and the underlying etiology has been clearly linked to environmental exposure or cancer treatment (Figure 3).	('linked', 'Reg', (127, 133))	('SBS11', 'Chemical', '-', (27, 32))	('SBS22', 'Var', (34, 39))	('SBS42', 'Var', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('SBS24', 'Var', (41, 46))	('SBS11', 'Var', (27, 32))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
68352	32978845	31  Taken together, these findings provide strong evidence for the involvement of aristolochic acids in the etiology of human urothelial cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('human', 'Species', '9606', (120, 125))	('involvement', 'Reg', (67, 78))	('urothelial cancers', 'Disease', 'MESH:D014523', (126, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('urothelial cancers', 'Disease', (126, 144))	('aristolochic acids', 'Chemical', 'MESH:D034341', (82, 100))	('aristolochic acids', 'Var', (82, 100))
68361	32978845	The identification of characteristic mutational signatures for AFB1 and aristolochic acids provided strong evidence for the contribution of these compounds to human cancer etiology.	('aristolochic acids', 'Chemical', 'MESH:D034341', (72, 90))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('aristolochic acids', 'Var', (72, 90))	('mutational', 'Var', (37, 47))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('AFB1', 'Gene', (63, 67))
68373	32978845	Furthermore, efforts are ongoing to examine the association between levels of THP-dG in the blood and risk of esophageal cancer in a nested case-control study.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('THP-dG', 'Var', (78, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('esophageal cancer', 'Disease', (110, 127))
68377	32978845	An integrated approach that combines data from epidemiologic studies, experimental models, next-generation sequencing, and mathematical analysis of mutations would be crucial to identify and quantitate the causative agents of mutational signatures of unknown etiology.	('mutational', 'Var', (226, 236))	('rat', 'Species', '10116', (8, 11))	('mutations', 'Var', (148, 157))	('rat', 'Species', '10116', (100, 103))
68387	32701250	The abundance of miR-143-3p was lower in esophageal cancer tissues and cells than that in paring normal tissues and normal esophageal mucosal cells Het-1A.	('miR-143-3p', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('esophageal cancer', 'Disease', (41, 58))	('miR-143-3p', 'Chemical', '-', (17, 27))	('abundance', 'MPA', (4, 13))	('lower', 'NegReg', (32, 37))
68388	32701250	MiR-143-3p could be induced by DEX treatment in esophageal cancer cells, and miR-143-3p also suppressed the development of esophageal cancer.	('MiR-143-3p', 'Chemical', '-', (0, 10))	('esophageal cancer', 'Disease', (123, 140))	('esophageal cancer', 'Disease', (48, 65))	('miR-143-3p', 'Chemical', '-', (77, 87))	('MiR-143-3p', 'Gene', (0, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('DEX', 'Chemical', 'MESH:D020927', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('miR-143-3p', 'Var', (77, 87))	('suppressed', 'NegReg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('development of', 'CPA', (108, 122))
68389	32701250	EPS8 was a functional target of miR-143-3p, and it played an oncogenic role in esophageal cancer.	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('miR-143-3p', 'Var', (32, 42))	('EPS8', 'Gene', '2059', (0, 4))	('EPS8', 'Gene', (0, 4))	('miR-143-3p', 'Chemical', '-', (32, 42))
68402	32701250	MiR-143-3p suppressed the progression of many cancers, including triple-negative breast cancer (TNBC), ovarian cancer, osteosarcoma and esophageal squamous cell carcinoma (ESCC).	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('breast cancer', 'Disease', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))	('MiR-143-3p', 'Chemical', '-', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('MiR-143-3p', 'Var', (0, 10))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('TNBC', 'Disease', 'None', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('osteosarcoma and esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (119, 170))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('ovarian cancer', 'Disease', (103, 117))	('TNBC', 'Disease', (96, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('suppressed', 'NegReg', (11, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
68403	32701250	claimed that the enhancement of miR-143-3p suppressed TNBC progression through reducing the abundance of LIM domain kinase 1.	('LIM domain kinase 1', 'Gene', '3984', (105, 124))	('reducing', 'NegReg', (79, 87))	('TNBC', 'Disease', 'None', (54, 58))	('miR-143-3p', 'Var', (32, 42))	('abundance', 'MPA', (92, 101))	('TNBC', 'Disease', (54, 58))	('enhancement', 'PosReg', (17, 28))	('LIM domain kinase 1', 'Gene', (105, 124))	('miR-143-3p', 'Chemical', '-', (32, 42))	('suppressed', 'NegReg', (43, 53))
68404	32701250	demonstrated that the growth and metastasis of ovarian cancer cells were restrained with the overexpression of miR-143-3p.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('restrained', 'NegReg', (73, 83))	('miR-143-3p', 'Var', (111, 121))	('metastasis of ovarian cancer', 'Disease', (33, 61))	('miR-143-3p', 'Chemical', '-', (111, 121))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (33, 61))	('overexpression', 'PosReg', (93, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
68405	32701250	demonstrated that miR-143-3p suppressed the development of osteosarcoma partly through FOSL2.	('osteosarcoma', 'Phenotype', 'HP:0002669', (59, 71))	('osteosarcoma', 'Disease', (59, 71))	('development', 'CPA', (44, 55))	('miR-143-3p', 'Var', (18, 28))	('osteosarcoma', 'Disease', 'MESH:D012516', (59, 71))	('FOSL2', 'Gene', '2355', (87, 92))	('miR-143-3p', 'Chemical', '-', (18, 28))	('FOSL2', 'Gene', (87, 92))	('suppressed', 'NegReg', (29, 39))
68406	32701250	proved that miR-143-3p inhibited the proliferation, metastasis and epithelial-mesenchymal transition of ESCC cells through reducing the level of QKI-5.	('reducing', 'NegReg', (123, 131))	('level', 'MPA', (136, 141))	('metastasis', 'CPA', (52, 62))	('inhibited', 'NegReg', (23, 32))	('QKI-5', 'MPA', (145, 150))	('miR-143-3p', 'Var', (12, 22))	('miR-143-3p', 'Chemical', '-', (12, 22))	('epithelial-mesenchymal transition', 'CPA', (67, 100))
68413	32701250	In this article, we investigated the function of DEX on the growth, apoptosis and metastasis of esophageal cancer cells, and then we explored the signal network by which DEX inhibiting the proliferation and metastasis while promoting the apoptosis of esophageal cancer cells.	('apoptosis', 'CPA', (238, 247))	('promoting', 'PosReg', (224, 233))	('inhibiting', 'NegReg', (174, 184))	('esophageal cancer', 'Disease', (251, 268))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (251, 268))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('DEX', 'Chemical', 'MESH:D020927', (49, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('DEX', 'Chemical', 'MESH:D020927', (170, 173))	('DEX', 'Var', (170, 173))
68427	32701250	In order to detect the abundance of EPS8 and miR-143-3p in patients, 25 esophageal cancer tissues and their matching control tissues were gathered from sufferers who had undergone resection in The Second Affiliated Hospital of Fujian Medical University.	('EPS8', 'Gene', '2059', (36, 40))	('miR-143-3p', 'Var', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('EPS8', 'Gene', (36, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('patients', 'Species', '9606', (59, 67))	('miR-143-3p', 'Chemical', '-', (45, 55))
68433	32701250	The abundance of EPS8 and miR-143-3p was detected by 2-DeltaDeltaCt method.	('EPS8', 'Gene', (17, 21))	('miR-143-3p', 'Chemical', '-', (26, 36))	('miR-143-3p', 'Var', (26, 36))	('EPS8', 'Gene', '2059', (17, 21))
68439	32701250	The 3' UTR of EPS8 was amplified, including wild-type or mutant-type binding sites, and embedded to the luciferase reporter vector, generating WT-EPS8 or MUT-EPS8.	('EPS8', 'Gene', (158, 162))	('EPS8', 'Gene', '2059', (146, 150))	('EPS8', 'Gene', (14, 18))	('EPS8', 'Gene', (146, 150))	('mutant-type', 'Var', (57, 68))	('binding', 'Interaction', (69, 76))	('EPS8', 'Gene', '2059', (158, 162))	('EPS8', 'Gene', '2059', (14, 18))
68444	32701250	The levels of miR-143-3p and EPS8 were detected in tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('miR-143-3p', 'Var', (14, 24))	('EPS8', 'Gene', '2059', (29, 33))	('tumor', 'Disease', (51, 56))	('EPS8', 'Gene', (29, 33))	('miR-143-3p', 'Chemical', '-', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
68455	32701250	2c, the level of miR-143-3p was positively modulated by DEX in KYSE150 and ECA-109 cells.	('modulated', 'Reg', (43, 52))	('miR-143-3p', 'Chemical', '-', (17, 27))	('DEX', 'Chemical', 'MESH:D020927', (56, 59))	('DEX', 'Var', (56, 59))	('KYSE150', 'Chemical', '-', (63, 70))
68456	32701250	To illustrate whether miR-143-3p was involved in DEX-mediated proliferation, apoptosis and metastasis of esophageal cancer cells, we conducted the following experiments.	('miR-143-3p', 'Chemical', '-', (22, 32))	('metastasis', 'CPA', (91, 101))	('DEX', 'Chemical', 'MESH:D020927', (49, 52))	('miR-143-3p', 'Var', (22, 32))	('esophageal cancer', 'Disease', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('involved', 'Reg', (37, 45))
68457	32701250	The knockdown efficiency of anti-miR-143-3p was measured in KYSE150 and ECA-109 cells, and the abundance of miR-143-3p was notably decreased by the transfection of anti-miR-143-3p in KYSE150 and ECA-109 cells (Fig.	('miR-143-3p', 'Chemical', '-', (33, 43))	('KYSE150', 'Chemical', '-', (60, 67))	('decreased', 'NegReg', (131, 140))	('anti-miR-143-3p', 'Var', (164, 179))	('abundance', 'MPA', (95, 104))	('miR-143-3p', 'Chemical', '-', (169, 179))	('miR-143-3p', 'Chemical', '-', (108, 118))	('KYSE150', 'Chemical', '-', (183, 190))
68459	32701250	Flow cytometry results revealed that miR-143-3p depletion reversed the promoting impact of DEX treatment on the apoptosis of esophageal cancer cells (Fig.	('apoptosis', 'CPA', (112, 121))	('esophageal cancer', 'Disease', (125, 142))	('miR-143-3p', 'Var', (37, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('DEX', 'Chemical', 'MESH:D020927', (91, 94))	('miR-143-3p', 'Chemical', '-', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
68461	32701250	Besides, Western blot assay also revealed that miR-143-3p depletion counteracted the suppressive effects of DEX treatment on the proliferation and metastasis of esophageal cancer cells and the promoting impact on the apoptosis of esophageal cancer cells (Fig.	('miR-143-3p depletion', 'Var', (47, 67))	('miR-143-3p', 'Chemical', '-', (47, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('esophageal cancer', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('esophageal cancer', 'Disease', 'MESH:D004938', (230, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('apoptosis', 'CPA', (217, 226))	('DEX', 'Chemical', 'MESH:D020927', (108, 111))	('promoting', 'PosReg', (193, 202))	('depletion', 'Var', (58, 67))	('esophageal cancer', 'Disease', (230, 247))	('metastasis', 'CPA', (147, 157))
68463	32701250	EPS8 was predicted as a target of miR-143-3p by Starbase online software (Fig.	('EPS8', 'Gene', '2059', (0, 4))	('miR-143-3p', 'Chemical', '-', (34, 44))	('miR-143-3p', 'Var', (34, 44))	('EPS8', 'Gene', (0, 4))
68464	32701250	4a), and the combination between EPS8 and miR-143-3p was then confirmed by dual-luciferase reporter assay.	('miR-143-3p', 'Var', (42, 52))	('EPS8', 'Gene', '2059', (33, 37))	('EPS8', 'Gene', (33, 37))	('miR-143-3p', 'Chemical', '-', (42, 52))
68467	32701250	The luciferase activity was significantly decreased in KYSE150 and ECA-109 cells cotransfected with miR-143-3p and WT-EPS8 plasmid, whereas it remained unchanged in cells cotransfected with miR-143-3p and MUT-EPS8, demonstrating that miR-143-3p directly bound to EPS8 in KYSE150 and ECA-109 cells (Fig.	('miR-143-3p', 'Var', (100, 110))	('decreased', 'NegReg', (42, 51))	('EPS8', 'Gene', '2059', (118, 122))	('EPS8', 'Gene', (209, 213))	('activity', 'MPA', (15, 23))	('EPS8', 'Gene', '2059', (263, 267))	('miR-143-3p', 'Chemical', '-', (234, 244))	('EPS8', 'Gene', (118, 122))	('EPS8', 'Gene', (263, 267))	('KYSE150', 'Chemical', '-', (271, 278))	('EPS8', 'Gene', '2059', (209, 213))	('miR-143-3p', 'Chemical', '-', (100, 110))	('luciferase', 'Enzyme', (4, 14))	('KYSE150', 'Chemical', '-', (55, 62))	('miR-143-3p', 'Chemical', '-', (190, 200))
68473	32701250	Collectively, EPS8 was a direct target of miR-143-3p and was inversely modulated by miR-143-3p and DEX.	('miR-143-3p', 'Var', (42, 52))	('EPS8', 'Gene', (14, 18))	('DEX', 'Chemical', 'MESH:D020927', (99, 102))	('miR-143-3p', 'Var', (84, 94))	('miR-143-3p', 'Chemical', '-', (42, 52))	('EPS8', 'Gene', '2059', (14, 18))	('miR-143-3p', 'Chemical', '-', (84, 94))
68474	32701250	The interference of EPS8 attenuates the promoting effects of miR-143-3p inhibition on the proliferation and metastasis of esophageal cancer cells and the inhibitory impact on the apoptosis of esophageal cancer cells treated with DEX The mRNA and protein expression of EPS8 were prominently reduced by the transfection of si-EPS8 in KYSE150 and ECA-109 cells (Fig.	('KYSE150', 'Chemical', '-', (332, 339))	('miR-143-3p', 'Gene', (61, 71))	('EPS8', 'Gene', '2059', (268, 272))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (192, 209))	('EPS8', 'Gene', '2059', (324, 328))	('apoptosis', 'CPA', (179, 188))	('EPS8', 'Gene', '2059', (20, 24))	('esophageal cancer', 'Disease', (192, 209))	('esophageal cancer', 'Disease', (122, 139))	('miR-143-3p', 'Chemical', '-', (61, 71))	('metastasis', 'CPA', (108, 118))	('attenuates', 'NegReg', (25, 35))	('si-EPS8', 'Gene', (321, 328))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('EPS8', 'Gene', (268, 272))	('transfection', 'Var', (305, 317))	('EPS8', 'Gene', (324, 328))	('reduced', 'NegReg', (290, 297))	('si-EPS8', 'Gene', '2059', (321, 328))	('DEX', 'Chemical', 'MESH:D020927', (229, 232))	('EPS8', 'Gene', (20, 24))
68476	32701250	The intervention of EPS8 reversed the promoting effect of miR-143-3p inhibition on the proliferation of esophageal cancer cells (Fig.	('proliferation', 'CPA', (87, 100))	('miR-143-3p', 'Chemical', '-', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('EPS8', 'Gene', '2059', (20, 24))	('EPS8', 'Gene', (20, 24))	('miR-143-3p', 'Var', (58, 68))
68478	32701250	The apoptosis of esophageal cancer cells was inhibited with miR-143-3p inhibition and was recovered with the addition of si-EPS8 (Fig.	('miR-143-3p', 'Chemical', '-', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('esophageal cancer', 'Disease', (17, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (17, 34))	('apoptosis', 'CPA', (4, 13))	('si-EPS8', 'Gene', '2059', (121, 128))	('inhibition', 'NegReg', (71, 81))	('si-EPS8', 'Gene', (121, 128))	('miR-143-3p', 'Var', (60, 70))	('inhibited', 'NegReg', (45, 54))
68479	32701250	5f and g, the knockdown of EPS8 counteracted the promoting effects of miR-143-3p inhibition on the metastasis of esophageal cancer cells.	('EPS8', 'Gene', (27, 31))	('metastasis of', 'CPA', (99, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('EPS8', 'Gene', '2059', (27, 31))	('knockdown', 'Var', (14, 23))	('esophageal cancer', 'Disease', (113, 130))	('miR-143-3p', 'Chemical', '-', (70, 80))
68485	32701250	6a and b, tumor volume and weight were less in the DEX group compared with that in the negative control group.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('less', 'NegReg', (39, 43))	('DEX', 'Chemical', 'MESH:D020927', (51, 54))	('DEX', 'Var', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
68494	32701250	MiR-143-3p was a tumor suppressor in multiple cancers.	('MiR-143-3p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('multiple cancers', 'Disease', (37, 53))	('MiR-143-3p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('multiple cancers', 'Disease', 'MESH:D009369', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
68495	32701250	reported that the enrichment of miR-143-3p was downregulated in ESCC tissues, and the low expression of miR-143-3p was related to the poor prognosis of ESCC patients.	('ESCC', 'Disease', (64, 68))	('downregulated', 'NegReg', (47, 60))	('miR-143-3p', 'Var', (104, 114))	('related', 'Reg', (119, 126))	('patients', 'Species', '9606', (157, 165))	('miR-143-3p', 'Gene', (32, 42))	('expression', 'MPA', (90, 100))	('enrichment', 'MPA', (18, 28))	('low', 'NegReg', (86, 89))	('miR-143-3p', 'Chemical', '-', (104, 114))	('ESCC', 'Disease', (152, 156))	('miR-143-3p', 'Chemical', '-', (32, 42))
68496	32701250	Consistent with the above results, the abundance of miR-143-3p was decreased in esophageal cancer tissues and cells compared with that in normal tissues and normal esophageal mucosal cells Het-1A.	('miR-143-3p', 'Var', (52, 62))	('esophageal cancer', 'Disease', (80, 97))	('miR-143-3p', 'Chemical', '-', (52, 62))	('abundance', 'MPA', (39, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('decreased', 'NegReg', (67, 76))
68501	32701250	The depletion of miR-143-3p alleviated the inhibitory effects of DEX treatment on the proliferation and metastasis of esophageal cancer cells and the promoting impact on the apoptosis of esophageal cancer cells.	('miR-143-3p', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('metastasis', 'CPA', (104, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('apoptosis', 'CPA', (174, 183))	('DEX', 'Chemical', 'MESH:D020927', (65, 68))	('miR-143-3p', 'Chemical', '-', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', (187, 204))	('depletion', 'MPA', (4, 13))	('promoting', 'PosReg', (150, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('alleviated', 'NegReg', (28, 38))
68505	32701250	As mentioned above, the expression of miR-143-3p was declined in esophageal cancer tissues and cells, showing an inverse trend with the expression of EPS8.	('esophageal cancer', 'Disease', (65, 82))	('declined', 'NegReg', (53, 61))	('expression', 'MPA', (24, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('miR-143-3p', 'Chemical', '-', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('EPS8', 'Gene', '2059', (150, 154))	('EPS8', 'Gene', (150, 154))	('miR-143-3p', 'Var', (38, 48))
68506	32701250	There was a negative correlation between the expression of EPS8 and the enrichment of miR-143-3p.	('miR-143-3p', 'Var', (86, 96))	('enrichment', 'MPA', (72, 82))	('miR-143-3p', 'Chemical', '-', (86, 96))	('negative', 'NegReg', (12, 20))	('EPS8', 'Gene', '2059', (59, 63))	('EPS8', 'Gene', (59, 63))
68510	32701250	demonstrated that PTK6 facilitated cell growth and migration by phosphorylating EPS8.	('EPS8', 'Gene', '2059', (80, 84))	('phosphorylating', 'Var', (64, 79))	('EPS8', 'Gene', (80, 84))	('facilitated', 'PosReg', (23, 34))	('PTK6', 'Gene', (18, 22))	('PTK6', 'Gene', '5753', (18, 22))	('cell growth', 'CPA', (35, 46))
68529	28875961	Although many risk factors contribute to the development of cancer, including genetic variants, obesity, smoking, poor diet, physical inactivity, and reproductive factors (including lower parity and higher age at first birth), such risk factors account for only a small proportion of cancer cases.	('genetic variants', 'Var', (78, 94))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('obesity', 'Phenotype', 'HP:0001513', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (284, 290))	('obesity', 'Disease', 'MESH:D009765', (96, 103))	('cancer', 'Disease', (60, 66))	('obesity', 'Disease', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('poor diet', 'Phenotype', 'HP:0011968', (114, 123))
68560	28875961	To the best of our knowledge, the current study represents the most comprehensive and up-to-date meta-analysis (39 case-control studies) of the association between high spicy food intake and cancer risk.	('cancer', 'Disease', (191, 197))	('association', 'Interaction', (144, 155))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('high', 'Var', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
68563	28875961	Interestingly, in terms of cancer subtypes, high spicy food intake was only found to be associated with gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('high spicy', 'Var', (44, 54))	('cancer', 'Disease', (27, 33))	('associated', 'Reg', (88, 98))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('gastric cancer', 'Disease', (104, 118))
68572	28875961	We believe that these results are credible because the pooled ORs from 39 articles and subgroup analyses indicated a significantly positive association between high spicy food intake and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('high spicy food', 'Var', (160, 175))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('positive', 'PosReg', (131, 139))
68677	27957293	P16 could prevent cell cycle development and encourages apoptosis or growth arrest.	('encourages', 'PosReg', (45, 55))	('growth arrest', 'Disease', (69, 82))	('cell cycle development', 'CPA', (18, 40))	('prevent', 'NegReg', (10, 17))	('growth arrest', 'Disease', 'MESH:D006323', (69, 82))	('apoptosis', 'CPA', (56, 65))	('P16', 'Var', (0, 3))	('growth arrest', 'Phenotype', 'HP:0001510', (69, 82))
68683	26386145	Tumor genomes with TP53 mutations were significantly more unstable than those without TP53 mutations.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', (86, 90))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))
68684	26386145	In terms of the landscape of genomic alterations, deletion of 9p21.3 covering CDKN2A/2B (30.9%), amplification of 11q13.3 covering CCND1 (30.9%), and TP53 point mutation (50.9%) occurred in two-thirds of the cases.	('CCND1', 'Gene', (131, 136))	('TP53', 'Gene', (150, 154))	('deletion', 'Var', (50, 58))	('CDKN2A/2B', 'Gene', (78, 87))	('CCND1', 'Gene', '595', (131, 136))	('amplification of', 'Var', (97, 113))	('TP53', 'Gene', '7157', (150, 154))	('CDKN2A/2B', 'Gene', '1029', (78, 87))
68685	26386145	With the high correlation of TP53 mutation and genomic instability in ESCC, the amplification of CCND1, the deletion of CDKN2A/2B, and the somatic mutation of TP53 appear to play pivotal roles via G1 deregulation and therefore helps to classify this cancer into different genomic subtypes.	('CCND1', 'Gene', (97, 102))	('CDKN2A/2B', 'Gene', '1029', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('genomic instability', 'MPA', (47, 66))	('CCND1', 'Gene', '595', (97, 102))	('cancer', 'Disease', (250, 256))	('mutation', 'Var', (34, 42))	('CDKN2A/2B', 'Gene', (120, 129))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (159, 163))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('ESCC', 'Disease', (70, 74))	('deletion', 'Var', (108, 116))
68691	26386145	A comprehensive description of various types of genetic alterations in ESCC and their correlation with clinical outcome would be a great step forward in our understanding of the mechanism involved in ESCC development, and could be applied to improve the survival rate of patients.	('ESCC', 'Gene', (71, 75))	('improve', 'PosReg', (242, 249))	('patients', 'Species', '9606', (271, 279))	('genetic alterations', 'Var', (48, 67))
68694	26386145	Interruption of G1 control by TP53 somatic mutation and copy number alterations (CNAs) was found in over 65% of ESCC cases.	('TP53', 'Gene', (30, 34))	('copy number alterations', 'Var', (56, 79))	('ESCC', 'Disease', (112, 116))	('Interruption', 'NegReg', (0, 12))	('TP53', 'Gene', '7157', (30, 34))
68695	26386145	Furthermore, for the first time we have identified a significant correlation between copy number aberrations in three minimal common regions (MCRs), i.e., amplification of 7p11.2, deletion of 3p12.1, and deletion of 9p21.3, and lymph node metastases in ESCC (P < 0.05).	('amplification', 'Var', (155, 168))	('deletion', 'Var', (180, 188))	('ESCC', 'Disease', (253, 257))	('deletion', 'Var', (204, 212))	('3p12.1', 'Protein', (192, 198))	('7p11.2', 'Gene', (172, 178))	('metastases', 'Disease', (239, 249))	('metastases', 'Disease', 'MESH:D009362', (239, 249))
68697	26386145	The non-synonymous somatic mutations (NSSMs, present in tumor but absent in blood samples) identified by exome sequencing were validated using either Sequenom MassARRAY or Sanger sequencing in both tumor and blood samples.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('non-synonymous', 'Var', (4, 18))
68701	26386145	Both FBXL4 and DMD were mutated in two tumor samples.	('mutated', 'Var', (24, 31))	('DMD', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('FBXL4', 'Gene', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('FBXL4', 'Gene', '26235', (5, 10))	('DMD', 'Gene', '1756', (15, 18))	('tumor', 'Disease', (39, 44))
68705	26386145	50% of the validated samples (23/46) were found to carry at least one NSSM in TP53.	('NSSM', 'Var', (70, 74))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))
68707	26386145	Notably, at least one TP53 mutation in each of the 23 patients was predicted to be deleterious.	('mutation', 'Var', (27, 35))	('patients', 'Species', '9606', (54, 62))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
68708	26386145	Only one of the 26 somatic mutations in TP53 was reported in dbSNP, a database of single nucleotide polymorphisms, with a very low frequency (rs201382018, identified in patient 109596, the allele frequency is 0.02% or 1/5008, accordingly).	('rs201382018', 'Mutation', 'rs201382018', (142, 153))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('patient', 'Species', '9606', (169, 176))	('rs201382018', 'Var', (142, 153))
68710	26386145	Despite the fact that there was no particular hot spot identified, most somatic mutations were localized in exons 4-8 of TP53.	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('mutations', 'Var', (80, 89))
68719	26386145	Among these seven missense mutations, six mutations were predicted by SIFT and PolyPhen 2 to have a deleterious effect on the protein function (Table S3), suggesting that there is a frequent disruption of the chromatin modification processes in the pathogenesis of ESCC.	('ESCC', 'Disease', (265, 269))	('SIFT', 'Disease', (70, 74))	('missense', 'Var', (18, 26))	('disruption', 'Reg', (191, 201))	('SIFT', 'Disease', 'None', (70, 74))	('chromatin modification processes', 'MPA', (209, 241))
68720	26386145	Considering that mutations of chromatin remodeling genes have been highlighted in several cancer studies, we then conducted Sanger sequencing for all the coding regions of these seven genes in different validation sets (samples for validation were selected randomly, however, due to limited volume of DNA samples of each patient, we cannot test all genes in a single validation set).	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('mutations', 'Var', (17, 26))	('patient', 'Species', '9606', (321, 328))
68723	26386145	On the other hand, the remaining 6 tumor samples showed many regions of allelic imbalance, including a few large regions.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('imbalance', 'Phenotype', 'HP:0002172', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('allelic imbalance', 'Var', (72, 89))
68726	26386145	As shown in Table S6, the fraction of genomic instability, including copy number gain, copy number loss, and CNNLOH, ranged from 0.001 to 0.97 (median, 0.557) among the 55 tumor samples.	('gain', 'PosReg', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('CNNLOH', 'Disease', (109, 115))	('copy number', 'Var', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('copy number loss', 'Var', (87, 103))
68728	26386145	Moreover, 30 of the 55 tumors (54.5%) had genome-wide alteration fractions higher than 0.5 (Table S6), suggesting severe genomic instability in those ESCC samples.	('alteration', 'Var', (54, 64))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
68730	26386145	Regarding the type of genomic alterations in ESCC, the median fraction of CNNLOH across the entire genome in all 55 samples was 0.29 (in the range 0-0.67), suggesting frequent occurrences of acquired uniparental disomy during mitosis.	('uniparental disomy', 'Disease', (200, 218))	('alterations', 'Var', (30, 41))	('mitosis', 'Disease', (226, 233))	('ESCC', 'Gene', (45, 49))	('uniparental disomy', 'Disease', 'MESH:D024182', (200, 218))	('mitosis', 'Disease', 'None', (226, 233))
68733	26386145	This resulted in the amplification of several oncogenes, including CCND1, FGF3, FGF4, and FGF19, and the deletion of the tumor suppressor genes CDKN2A and CDKN2B.	('CDKN2B', 'Gene', '1030', (155, 161))	('deletion', 'Var', (105, 113))	('FGF4', 'Gene', '2249', (80, 84))	('resulted in', 'Reg', (5, 16))	('FGF3', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('CCND1', 'Gene', (67, 72))	('CDKN2A', 'Gene', (144, 150))	('CCND1', 'Gene', '595', (67, 72))	('amplification', 'MPA', (21, 34))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('FGF19', 'Gene', '9965', (90, 95))	('FGF3', 'Gene', '2248', (74, 78))	('FGF4', 'Gene', (80, 84))	('CDKN2A', 'Gene', '1029', (144, 150))	('FGF19', 'Gene', (90, 95))	('CDKN2B', 'Gene', (155, 161))
68736	26386145	About 2/3 of the samples carried TP53 somatic mutations or focal CNAs that make a large contribution to damaging cell cycle regulation.	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (33, 37))	('focal CNAs', 'Var', (59, 69))	('cell', 'MPA', (113, 117))	('damaging', 'Reg', (104, 112))
68737	26386145	As demonstrated in Figure 4, the most affected nodes are at p16INK4A/p15INK4B, cyclin D1, and p53, which were caused by focal deletion of CDKN2A/2B (30.9%), focal amplification of CCND1 (30.9%), and point mutations in TP53 (50.9%), respectively.	('p15INK4B', 'Gene', (69, 77))	('cyclin D1', 'Gene', (79, 88))	('p53', 'Gene', '7157', (94, 97))	('focal deletion', 'Var', (120, 134))	('CDKN2A/2B', 'Gene', '1029', (138, 147))	('p15INK4B', 'Gene', '1030', (69, 77))	('affected', 'Reg', (38, 46))	('TP53', 'Gene', (218, 222))	('cyclin D1', 'Gene', '595', (79, 88))	('p53', 'Gene', (94, 97))	('CCND1', 'Gene', '595', (180, 185))	('CDKN2A/2B', 'Gene', (138, 147))	('CCND1', 'Gene', (180, 185))	('caused by', 'Reg', (110, 119))	('p16INK4A', 'Gene', (60, 68))	('focal amplification', 'Var', (157, 176))	('TP53', 'Gene', '7157', (218, 222))	('point mutations', 'Var', (199, 214))	('p16INK4A', 'Gene', '1029', (60, 68))
68740	26386145	We found a high correlation of TP53 mutations with genome instability.	('TP53', 'Gene', '7157', (31, 35))	('genome instability', 'MPA', (51, 69))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))
68741	26386145	As depicted in Figure 5, the median fractions of copy number gain, copy number loss, and CNNLOH in samples with TP53 mutations were 0.13, 0.11, and 0.35, respectively.	('loss', 'NegReg', (79, 83))	('mutations', 'Var', (117, 126))	('CNNLOH', 'CPA', (89, 95))	('copy number', 'Var', (49, 60))	('TP53', 'Gene', '7157', (112, 116))	('copy number', 'Var', (67, 78))	('gain', 'PosReg', (61, 65))	('TP53', 'Gene', (112, 116))
68743	26386145	In particular, 75% of the patients with TP53 mutations had severe genomic instability, while only 33% of the patients with wild-type TP53 had severe genomic instability (P = 0.002).	('mutations', 'Var', (45, 54))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (26, 34))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('genomic instability', 'MPA', (66, 85))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))
68749	26386145	Moreover, among the six MCRs identified, three regions were significantly correlated with lymph node metastasis, including the amplification of 7p11.2 (P = 0.042), deletion of 3p12.1 (P = 0.030), and deletion of 9p21.3 (P = 0.033) (Figure 2; Table S12).	('lymph node metastasis', 'CPA', (90, 111))	('deletion', 'Var', (200, 208))	('7p11.2', 'Gene', (144, 150))	('S12', 'Gene', (248, 251))	('correlated', 'Reg', (74, 84))	('S12', 'Gene', '6268', (248, 251))	('deletion', 'Var', (164, 172))	('amplification', 'Var', (127, 140))	('3p12.1', 'Gene', (176, 182))
68750	26386145	On the other hand, although non-synonymous TP53 mutations occurred more frequently, we observed no correlation between these mutations and clinical outcome (data not shown).	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
68755	26386145	Other potential driver genes defined by these studies mutated only in ~20% samples at most, which were identified as singleton in our exome sequencing study, for instance somatic frameshift indel identified in ADAM29 from patient 101919.	('ADAM29', 'Gene', (210, 216))	('frameshift indel', 'Var', (179, 195))	('ADAM29', 'Gene', '11086', (210, 216))	('patient', 'Species', '9606', (222, 229))
68758	26386145	A number of in vitro and in vivo experiments have demonstrated the key role of cell cycle deregulation in tumorigenesis.	('cell cycle', 'CPA', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('deregulation', 'Var', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
68761	26386145	Somatic mutations in TP53 plus two MCRs (deletion of CDKN2A/2B and amplification of CCND1) point primarily to cell cycle deregulation in over 65% of the cases examined.	('TP53', 'Gene', (21, 25))	('point', 'Reg', (91, 96))	('CDKN2A/2B', 'Gene', (53, 62))	('CCND1', 'Gene', (84, 89))	('amplification', 'Var', (67, 80))	('deletion', 'Var', (41, 49))	('CCND1', 'Gene', '595', (84, 89))	('cell cycle deregulation', 'CPA', (110, 133))	('CDKN2A/2B', 'Gene', '1029', (53, 62))	('TP53', 'Gene', '7157', (21, 25))
68762	26386145	Therefore, TP53 mutations, which disrupt cell cycle check points at the G1/S and G2/M transitions, and the amplification of an oncogene (CCND1) or the deletion of suppressor genes (CDKN2A/2B) strongly suggest that the disruption of G1 control is a key event in the development of ESCC (Figure 4).	('ESCC', 'Disease', (280, 284))	('CCND1', 'Gene', '595', (137, 142))	('CDKN2A/2B', 'Gene', '1029', (181, 190))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('CDKN2A/2B', 'Gene', (181, 190))	('mutations', 'Var', (16, 25))	('CCND1', 'Gene', (137, 142))
68763	26386145	Although the high rate of TP53 mutation and the complex DNA alterations have been observed in ESCC and other cancers, to our knowledge this is the first analysis on a large sample size that pinpoints the high frequency of G1 control deregulation caused by genomic alterations in ESCC.	('TP53', 'Gene', (26, 30))	('TP53', 'Gene', '7157', (26, 30))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('mutation', 'Var', (31, 39))	('cancers', 'Disease', (109, 116))	('deregulation', 'NegReg', (233, 245))	('G1 control', 'MPA', (222, 232))	('ESCC', 'Disease', (279, 283))	('genomic alterations', 'Var', (256, 275))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ESCC', 'Disease', (94, 98))
68765	26386145	In tumors with a genomic instability fraction <0.10, only 1 out of 14 samples had a mutated TP53.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumors', 'Disease', (3, 9))	('mutated', 'Var', (84, 91))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
68766	26386145	Conversely, in samples with fraction >0.90 for structural alteration, six out of seven samples had TP53 mutations.	('TP53', 'Gene', '7157', (99, 103))	('TP53', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))
68767	26386145	One assumption is that the TP53 mutations and genomic alteration may occur independently and that TP53 mutations result in a failure to undergo apoptosis in cells carrying genomic abnormalities.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('mutations', 'Var', (103, 112))	('TP53', 'Gene', '7157', (98, 102))	('TP53', 'Gene', (98, 102))
68768	26386145	On the other hand, TP53 has also been proposed to be the "genome guardian" and mutations in this gene may therefore directly cause other genomic alterations.	('cause', 'Reg', (125, 130))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('mutations', 'Var', (79, 88))
68769	26386145	In our ESCC cases, despite the high mutation rate of TP53, we found no significant association between TP53 mutation and tumor stage, whereas genomic instability correlated with lymph node metastasis.	('TP53', 'Gene', '7157', (103, 107))	('TP53', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('TP53', 'Gene', (103, 107))	('tumor', 'Disease', (121, 126))	('genomic', 'MPA', (142, 149))	('TP53', 'Gene', '7157', (53, 57))	('mutation', 'Var', (108, 116))	('lymph node metastasis', 'CPA', (178, 199))	('correlated', 'Reg', (162, 172))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
68776	26386145	Therefore, although CCND1 was considered as the major player in this MCR, the amplification of other genes may also contribute to ESCC development.	('amplification', 'Var', (78, 91))	('contribute', 'Reg', (116, 126))	('CCND1', 'Gene', (20, 25))	('ESCC development', 'Disease', (130, 146))	('CCND1', 'Gene', '595', (20, 25))
68784	26386145	In this study, we found a ~50% prevalence of TP53 mutations in ESCC, and the somatic mutation of TP53 is highly correlated with genomic instability.	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (97, 101))	('mutations', 'Var', (50, 59))	('correlated', 'Reg', (112, 122))	('TP53', 'Gene', (97, 101))	('ESCC', 'Disease', (63, 67))	('TP53', 'Gene', '7157', (45, 49))	('genomic instability', 'MPA', (128, 147))
68785	26386145	The amplification of CCND1 and the deletion of CDKN2A/2B, together with TP53 mutations, may play pivotal roles in ESCC by deregulating G1 cell cycle signaling, which classify this cancer into different groups.	('CDKN2A/2B', 'Gene', '1029', (47, 56))	('ESCC', 'Disease', (114, 118))	('CDKN2A/2B', 'Gene', (47, 56))	('TP53', 'Gene', '7157', (72, 76))	('CCND1', 'Gene', '595', (21, 26))	('deregulating', 'Reg', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('CCND1', 'Gene', (21, 26))	('TP53', 'Gene', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('amplification', 'Var', (4, 17))	('deletion', 'Var', (35, 43))	('G1 cell', 'MPA', (135, 142))	('cancer', 'Disease', (180, 186))
68797	26386145	In order to identify and further increase the specificity of somatic mutation calls, we applied the following post-processing filters: (1) only loci with >=10x coverage in both tumor and normal samples were used for variant calling; (2) at least 20% of mutant alleles in reads from tumor samples had a Phred quality score >=20; and (3) no mutant alleles were detected in reads from the blood samples.	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('mutant', 'Var', (253, 259))	('tumor', 'Disease', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
68801	26386145	With a window size of 50 SNPs, a window was considered to be a region undergoing somatic alteration if more than 70% of the SNPs had a significantly-different MAF in the tumor and blood samples.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('significantly-different', 'Reg', (135, 158))	('SNPs', 'Var', (124, 128))	('MAF', 'MPA', (159, 162))
68805	26386145	To identify common regions with copy number gain and loss across samples, the Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was utilized.	('copy number', 'Var', (32, 43))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Cancer', 'Disease', (127, 133))	('loss', 'NegReg', (53, 57))	('Cancer', 'Disease', 'MESH:D009369', (127, 133))
68811	25473069	The EnR, CR, and CuR rates were significantly greater in the endoscopic submucosal dissection group when compared to those in the endoscopic resection group.	('CuR rates', 'CPA', (17, 26))	('endoscopic submucosal dissection', 'Var', (61, 93))	('CR', 'Chemical', '-', (9, 11))	('EnR', 'CPA', (4, 7))	('greater', 'PosReg', (46, 53))
68897	21991535	On the other hand, alkalis cause liquefaction necrosis, are more viscous, and tend to adhere to the esophageal mucosa with only a relatively small amount reaching the stomach.	('liquefaction necrosis', 'Disease', (33, 54))	('esophageal mucosa', 'Disease', (100, 117))	('esophageal mucosa', 'Disease', 'MESH:D004941', (100, 117))	('liquefaction necrosis', 'Phenotype', 'HP:0010885', (33, 54))	('alkalis', 'Var', (19, 26))
68898	21991535	The extent of esophageal damage is greater with alkalis than acids.	('esophageal damage', 'Disease', (14, 31))	('esophageal damage', 'Disease', 'MESH:D004935', (14, 31))	('alkalis', 'Var', (48, 55))
68946	19545449	Esophageal adenocarcinomas was defined as ICDO codes 81403, 81443, 81903, 82103, 82113, 82553, 82603, 82613, 82623, 82633, 83103, 83233, 84103, 84803, 84813, and 84903.	('84903', 'Var', (162, 167))	('Esophageal adenocarcinomas', 'Disease', (0, 26))	('81903', 'Var', (67, 72))	('82553', 'Var', (88, 93))	('83103', 'Var', (123, 128))	('84813', 'Var', (151, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('81443', 'Var', (60, 65))	('82623', 'Var', (109, 114))	('84803', 'Var', (144, 149))	('84103', 'Var', (137, 142))	('82103', 'Var', (74, 79))	('82603', 'Var', (95, 100))	('83233', 'Var', (130, 135))	('82633', 'Var', (116, 121))	('82613', 'Var', (102, 107))	('82113', 'Var', (81, 86))	('Esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (0, 26))
68947	19545449	Squamous cell carcinoma was defined as ICDO codes 80763, 80713, 80723, 80733, 80743, 80753, and 80763.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('80763', 'Var', (96, 101))	('80733', 'Var', (71, 76))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('80753', 'Var', (85, 90))	('80743', 'Var', (78, 83))	('Squamous cell carcinoma', 'Disease', (0, 23))	('80763', 'Var', (50, 55))	('80713', 'Var', (57, 62))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 23))	('80723', 'Var', (64, 69))
69011	33772105	PP-VATS-E was less invasive and an independent risk factor for postoperative pulmonary complications.	('PP-VATS-E', 'Var', (0, 9))	('pulmonary complications', 'Phenotype', 'HP:0006532', (77, 100))	('postoperative pulmonary complications', 'Disease', (63, 100))	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (63, 100))
69033	33772105	The ventilator settings at the end of the artificial pneumothorax were TV < 8 mL/kg-1, PEEP 5 cm H2O, and respiratory rate 10-12 breaths/min-1.	('pneumothorax', 'Disease', 'MESH:D011030', (53, 65))	('pneumothorax', 'Disease', (53, 65))	('H2O', 'Chemical', '-', (97, 100))	('pneumothorax', 'Phenotype', 'HP:0002107', (53, 65))	('PEEP', 'Var', (87, 91))
69070	33772105	In addition to the fact that the alveoli were directly exposed to CO2 due to the effect of artificial pneumothorax with CO2, EtCO2 was significantly higher.	('pneumothorax', 'Disease', 'MESH:D011030', (102, 114))	('CO2', 'Chemical', 'MESH:D002245', (127, 130))	('pneumothorax', 'Disease', (102, 114))	('CO2', 'Chemical', 'MESH:D002245', (120, 123))	('CO2', 'Chemical', 'MESH:D002245', (66, 69))	('CO2', 'Var', (120, 123))	('higher', 'PosReg', (149, 155))	('pneumothorax', 'Phenotype', 'HP:0002107', (102, 114))	('EtCO2', 'Chemical', '-', (125, 130))
69072	33772105	Regarding the respiratory setting in this study, we found a tendency to respond to elevated EtCO2 by increasing respiratory frequency and decreasing PEEP, suggesting that further increases in airway resistance and shortening of expiratory time may contribute to the high CO2 levels.	('increases', 'PosReg', (179, 188))	('increasing', 'PosReg', (101, 111))	('EtCO2', 'Chemical', '-', (92, 97))	('elevated', 'Var', (83, 91))	('CO2 levels', 'MPA', (271, 281))	('EtCO2', 'Gene', (92, 97))	('CO2', 'Chemical', 'MESH:D002245', (271, 274))	('airway resistance', 'MPA', (192, 209))	('PEEP', 'MPA', (149, 153))	('CO2', 'Chemical', 'MESH:D002245', (94, 97))	('respiratory frequency', 'MPA', (112, 133))	('decreasing', 'NegReg', (138, 148))
69075	33772105	PP-VATS-E in which artificial pneumothorax two-lung ventilation was performed was predicted to be difficult to manage due to worsening of the ventilatory blood flow ratio and alveolar hypoventilation.	('PP-VATS-E', 'Var', (0, 9))	('pneumothorax', 'Disease', 'MESH:D011030', (30, 42))	('alveolar hypoventilation', 'Disease', (175, 199))	('ventilatory blood flow ratio', 'MPA', (142, 170))	('worsening', 'PosReg', (125, 134))	('pneumothorax', 'Disease', (30, 42))	('lung ventilation', 'Phenotype', 'HP:0002107', (47, 63))	('alveolar hypoventilation', 'Phenotype', 'HP:0002791', (175, 199))	('alveolar hypoventilation', 'Disease', 'MESH:C536281', (175, 199))	('pneumothorax', 'Phenotype', 'HP:0002107', (30, 42))
69109	32884042	Each tumor-organoid pair had a different TP53 mutation (Supplementary Fig.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('mutation', 'Var', (46, 54))
69110	32884042	Outside of TP53, other mutations shared with the EAC driver gene list included MUC6 (EDO 74 and 82), CDKN2A (EDO 70) and ARID1B (EDO74 and 92) (Fig.	('ARID1B', 'Gene', (121, 127))	('CDKN2A', 'Gene', (101, 107))	('MUC6', 'Gene', (79, 83))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('CDKN2A', 'Gene', '1029', (101, 107))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('mutations', 'Var', (23, 32))	('MUC6', 'Gene', '4588', (79, 83))	('ARID1B', 'Gene', '57492', (121, 127))
69111	32884042	When we looked at all SNV, we discovered previously undescribed mutations shared between tumor-organoid pairs, such as AHNAK2 and LAMA1 (shared between EDO 74 and 82) and LILBR2 (shared between EDO 92 and 74) (Supplementary Fig.	('AHNAK2', 'Gene', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('LILBR2', 'Gene', (171, 177))	('LAMA1', 'Gene', '284217', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('AHNAK2', 'Gene', '113146', (119, 125))	('mutations', 'Var', (64, 73))	('LAMA1', 'Gene', (130, 135))	('tumor', 'Disease', (89, 94))
69140	32884042	More troublesome is also the fact that dysplastic BE is known to harbor mutations similar to bona fide EAC.	('mutations', 'Var', (72, 81))	('dysplastic', 'Disease', (39, 49))	('dysplastic', 'Disease', 'MESH:D004416', (39, 49))	('EAC', 'Phenotype', 'HP:0011459', (103, 106))	('BE', 'Chemical', 'MESH:D001608', (50, 52))
69141	32884042	In terms of immunohistochemistry, EDO77 was positive for P53 and faintly stained positive for CK7, similar to the endoscopic biopsy (Fig.	('CK7', 'Gene', (94, 97))	('CK7', 'Gene', '3855', (94, 97))	('P53', 'Gene', (57, 60))	('P53', 'Gene', '7157', (57, 60))	('EDO77', 'Var', (34, 39))	('positive', 'Reg', (44, 52))
69155	32884042	Indeed, shared mutations between the organoid and tumor showed a much higher allele frequency in the organoid, suggesting a purer cell population following organoid culture.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
69157	32884042	We attempted to mitigate this computationally by comparing high confidence organoid SNV calls to tumor SNV calls, as heterogeneity of the tumor may have reduced the SNV frequency below the confidence filter.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('reduced', 'NegReg', (153, 160))	('heterogeneity', 'Var', (117, 130))	('tumor', 'Disease', (97, 102))	('SNV', 'MPA', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
69158	32884042	There were only 32 genes which were recurrently mutated in both the tumor and organoid in 2 or more pairs and 5 which were recurrently mutated in 3 or more pairs.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutated', 'Var', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
69185	32884042	Endoscopic biopsies at the time of diagnosis were collected and stored in PBS containing Penicillin-Streptomycin, Neomycin, Anti-Anti (Gibco, USA) and Primocin (Invivogen, USA) (PBS PNP).	('PBS PNP', 'Chemical', '-', (178, 185))	('PBS', 'Chemical', 'MESH:D007854', (74, 77))	('Streptomycin', 'Chemical', 'MESH:D013307', (100, 112))	('Penicillin', 'Chemical', 'MESH:D010406', (89, 99))	('Primocin', 'Chemical', '-', (151, 159))	('Anti-Anti', 'Var', (124, 133))	('PBS', 'Chemical', 'MESH:D007854', (178, 181))	('Neomycin', 'Chemical', 'MESH:D009355', (114, 122))	('Primocin', 'Var', (151, 159))
69214	31859933	It is currently advocated that the presence of this bacterium in the gastric mucosa may trigger a protective effect for patients with gastroesophageal reflux disease (GERD), both for esophagitis and for the development of EB and esophageal adenocarcinoma.	('GERD', 'Disease', (167, 171))	('presence', 'Var', (35, 43))	('esophageal adenocarcinoma', 'Disease', (229, 254))	('GERD', 'Disease', 'MESH:D005764', (167, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('gastroesophageal reflux disease', 'Disease', (134, 165))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (229, 254))	('esophagitis', 'Phenotype', 'HP:0100633', (183, 194))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (134, 157))	('esophagitis', 'Disease', (183, 194))	('protective effect', 'CPA', (98, 115))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (134, 165))
69228	31859933	The cardia is an area where both H pylori and abnormal GERD exert their damaging potential, inducing inflammation and its consequences, such as intestinal metaplasia.	('intestinal metaplasia', 'Disease', (144, 165))	('GERD', 'Gene', (55, 59))	('inflammation', 'Disease', (101, 113))	('abnormal', 'Var', (46, 54))	('H pylori', 'Species', '210', (33, 41))	('H pylori', 'Disease', (33, 41))	('inducing', 'Reg', (92, 100))
69229	28288140	MicroRNA-377 suppresses initiation and progression of esophageal cancer by inhibiting CD133 and VEGF Esophageal cancer is one of the most lethal cancers worldwide with poor survival and limited therapeutic options.	('cancers', 'Disease', (145, 152))	('inhibiting', 'NegReg', (75, 85))	('CD133', 'Gene', (86, 91))	('Esophageal cancer', 'Disease', (101, 118))	('CD133', 'Gene', '8842', (86, 91))	('progression', 'CPA', (39, 50))	('VEGF', 'CPA', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('initiation', 'CPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('suppresses', 'NegReg', (13, 23))	('MicroRNA-377', 'Var', (0, 12))	('esophageal cancer', 'Disease', (54, 71))	('Esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Disease', 'MESH:D009369', (145, 152))
69238	28288140	Collectively, our study established that miR-377 plays a functional and significant role in suppressing tumor initiation and progression, and may represent a promising non-invasive diagnostic and prognostic biomarker and therapeutic strategy for patients with ESCC.	('suppressing', 'NegReg', (92, 103))	('tumor initiation', 'Disease', 'MESH:D009369', (104, 120))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('patients', 'Species', '9606', (246, 254))	('tumor initiation', 'Disease', (104, 120))	('ESCC', 'Disease', (260, 264))	('miR-377', 'Var', (41, 48))	('ESCC', 'Phenotype', 'HP:0011459', (260, 264))
69257	28288140	Analysis of gene expression profiles of several cohorts of patients from Gene Expression Omnibus (GEO) database showed that miR-377 was also significantly reduced in colon, ovarian, and breast cancers (Supplementary Figure S2a).	('Supplementary Figure S2a', 'Disease', 'MESH:D017034', (202, 226))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('colon', 'Disease', 'MESH:D015179', (166, 171))	('reduced', 'NegReg', (155, 162))	('breast cancers', 'Phenotype', 'HP:0003002', (186, 200))	('ovarian', 'Disease', (173, 180))	('colon', 'Disease', (166, 171))	('Supplementary Figure S2a', 'Disease', (202, 226))	('patients', 'Species', '9606', (59, 67))	('breast cancers', 'Disease', 'MESH:D001943', (186, 200))	('breast cancers', 'Disease', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('miR-377', 'Var', (124, 131))
69258	28288140	Furthermore, although no significant correlation was found between clinicopathological parameters and tumor miR-377 expression level in the 30 ESCC patients who had upfront surgery (Supplementary Table S1), patients with low miR-377 expression in their tumor had significantly shorter survival (median survival=14.33 months) than the patients with higher tumor miR-377 expression (median survival=20.85 months; Figure 1c).	('patients', 'Species', '9606', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (355, 360))	('survival', 'MPA', (285, 293))	('patients', 'Species', '9606', (207, 215))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Disease', (355, 360))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('shorter', 'NegReg', (277, 284))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('ESCC', 'Phenotype', 'HP:0011459', (143, 147))	('tumor', 'Disease', (253, 258))	('patients', 'Species', '9606', (334, 342))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('low', 'NegReg', (221, 224))	('miR-377 expression', 'Var', (225, 243))
69266	28288140	Given that ESCC patients with lower serum miR-377 level were less responsive to chemoradiotherapy (Figure 1e), we next examined the effects of miR-377 on chemoresistance and the results showed that ectopic miR-377 expression significantly enhanced the sensitivity of ESCC cells to 5-FU and DDP, which are two commonly used chemotherapeutic drugs for treating esophageal cancer (Figure 2a).	('ESCC', 'Disease', (267, 271))	('5-FU', 'Chemical', 'MESH:D005472', (281, 285))	('ESCC', 'Phenotype', 'HP:0011459', (11, 15))	('ectopic', 'Var', (198, 205))	('patients', 'Species', '9606', (16, 24))	('esophageal cancer', 'Disease', (359, 376))	('DDP', 'Gene', '1678', (290, 293))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('ESCC', 'Phenotype', 'HP:0011459', (267, 271))	('esophageal cancer', 'Disease', 'MESH:D004938', (359, 376))	('sensitivity', 'MPA', (252, 263))	('miR-377', 'Gene', (206, 213))	('DDP', 'Gene', (290, 293))	('enhanced', 'PosReg', (239, 247))
69267	28288140	Furthermore, because our data from clinical sample analysis strongly suggest that miR-377 is a tumor suppressor in ESCC, we examined its function in tumor initiation.	('ESCC', 'Disease', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('ESCC', 'Phenotype', 'HP:0011459', (115, 119))	('tumor initiation', 'Disease', 'MESH:D009369', (149, 165))	('miR-377', 'Var', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (149, 154))	('tumor initiation', 'Disease', (149, 165))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
69268	28288140	We found that sphere-forming ESCC cells had lower miR-377 expression compared with the differentiated adherent counterparts (Figure 2b), and that ESCC cells with ectopic miR-377 expression had significantly reduced sphere formation ability (Figure 2c), which suggest that miR-377 has a regulatory role in tumor initiation.	('lower', 'NegReg', (44, 49))	('tumor initiation', 'Disease', (305, 321))	('miR-377', 'Var', (170, 177))	('sphere formation ability', 'CPA', (215, 239))	('ESCC', 'Phenotype', 'HP:0011459', (146, 150))	('miR-377', 'Protein', (50, 57))	('ectopic miR-377', 'Var', (162, 177))	('expression', 'MPA', (58, 68))	('ESCC', 'Phenotype', 'HP:0011459', (29, 33))	('reduced', 'NegReg', (207, 214))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumor initiation', 'Disease', 'MESH:D009369', (305, 321))
69270	28288140	Interestingly, although a dramatic effect was observed in the group of mice inoculated with KYSE270-miR-377 cells, as indicated by the almost complete suppression of tumor growth in nude mice, ectopic miR-377 expression exerted only a modest inhibitory effect on the tumorigenic potential of KYSE150 cells (Figure 2d).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('mice', 'Species', '10090', (71, 75))	('suppression', 'NegReg', (151, 162))	('ectopic', 'Var', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('miR-377', 'Gene', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('mice', 'Species', '10090', (187, 191))	('tumor', 'Disease', (267, 272))	('nude mice', 'Species', '10090', (182, 191))
69272	28288140	Interestingly, CD133, one of the most commonly used marker for TICs, but not CD90 and CD44, was identified as a potential target of miR-377.	('CD44', 'Gene', (86, 90))	('TIC', 'Phenotype', 'HP:0100033', (63, 66))	('CD133', 'Gene', (15, 20))	('TICs', 'Phenotype', 'HP:0100033', (63, 67))	('CD90', 'Gene', '7070', (77, 81))	('CD44', 'Gene', '960', (86, 90))	('CD90', 'Gene', (77, 81))	('miR-377', 'Var', (132, 139))
69273	28288140	This difference suggests that miR-377 can suppress tumor formation by targeting CD133 expression, and may explain the discrepancy of anti-tumor effect of miR-377 between KYSE150 and KYSE270 (Figure 2d).	('suppress', 'NegReg', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (138, 143))	('KYSE150', 'Var', (170, 177))	('KYSE270', 'Var', (182, 189))	('CD133', 'Gene', (80, 85))	('tumor', 'Disease', (51, 56))	('expression', 'MPA', (86, 96))	('targeting', 'Reg', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
69274	28288140	Western blot data showed that transfection of miR-377 mimic or miR-377-expressing plasmid reduced CD133 expression dose dependently in two ESCC cell lines, as well as in colorectal and liver cancer cell lines (Figure 3c and Supplementary Figure S3).	('miR-377', 'Var', (46, 53))	('reduced', 'NegReg', (90, 97))	('liver cancer', 'Phenotype', 'HP:0002896', (185, 197))	('colorectal and liver cancer', 'Disease', 'MESH:D015179', (170, 197))	('ESCC', 'Phenotype', 'HP:0011459', (139, 143))	('expression', 'MPA', (104, 114))	('CD133', 'Gene', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
69275	28288140	Ectopic expression of miR-377 in HEK293 cells resulted in a significant dose-dependent decrease in the relative luciferase activity of CD133 3'-UTR (Figure 3e left panel), but there was no inhibition of luciferase activity when the cells were co-transfected with miR-377 and mutant CD133 3'-UTR (Figure 3e, right panel), thus confirming that miR-377 can directly bind to and repress CD133.	('miR-377', 'Var', (22, 29))	('CD133', 'Gene', (383, 388))	('mutant', 'Var', (275, 281))	('repress', 'NegReg', (375, 382))	('bind', 'Interaction', (363, 367))	('relative', 'MPA', (103, 111))	('decrease', 'NegReg', (87, 95))	('activity', 'MPA', (123, 131))	('HEK293', 'CellLine', 'CVCL:0045', (33, 39))
69277	28288140	The significantly higher CD133 (Figures 3f and g) and lower miR-377 expression (Figure 3h) in tumor tissues compared with normal esophageal tissue suggest that CD133 has an oncogenic role whereas miR-377 has tumor suppressive function in ESCC.	('ESCC', 'Disease', (238, 242))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('CD133', 'Gene', (25, 30))	('expression', 'MPA', (68, 78))	('CD133', 'Var', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('ESCC', 'Phenotype', 'HP:0011459', (238, 242))	('tumor', 'Disease', (94, 99))	('miR-377', 'Gene', (60, 67))	('oncogenic', 'CPA', (173, 182))	('tumor', 'Disease', (208, 213))	('higher', 'PosReg', (18, 24))	('lower', 'NegReg', (54, 59))
69280	28288140	We also found a positive correlation between CD133 expression and chemoresistance, which is another important property of TICs, amongst several ESCC cell lines: the CD133-rich KYSE270 and T.Tn cells were more resistant to 5-FU and DDP, compared with CD133-low KYSE150 and HKESC-1 cells (Figure 4b).	('T.Tn', 'Var', (188, 192))	('5-FU', 'Chemical', 'MESH:D005472', (222, 226))	('TICs', 'Phenotype', 'HP:0100033', (122, 126))	('TIC', 'Phenotype', 'HP:0100033', (122, 125))	('DDP', 'Gene', '1678', (231, 234))	('chemoresistance', 'CPA', (66, 81))	('ESCC', 'Phenotype', 'HP:0011459', (144, 148))	('CD133-rich KYSE270', 'Var', (165, 183))	('resistant', 'CPA', (209, 218))	('DDP', 'Gene', (231, 234))
69282	28288140	The sorted CD133+ and CD133- KYSE410 cells were subcutaneously injected into the left and right flanks of nude mice, respectively, for comparison of tumor-initiating ability.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('CD133+', 'Var', (11, 17))	('nude mice', 'Species', '10090', (106, 115))	('CD133- KYSE410', 'Var', (22, 36))	('tumor', 'Disease', (149, 154))	('KYSE410', 'CellLine', 'CVCL:1352', (29, 36))
69284	28288140	Higher capacity for tumorigenicity was also found in sorted CD133+ KYSE270 cells in NOD/SCID mice, compared with CD133- cells (Figure 4d and Supplementary Table S3).	('CD133+ KYSE270', 'Var', (60, 74))	('NOD', 'Gene', '1822', (84, 87))	('SCID', 'Gene', '19090', (88, 92))	('SCID', 'Gene', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('mice', 'Species', '10090', (93, 97))	('Higher', 'PosReg', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('NOD', 'Gene', (84, 87))	('tumor', 'Disease', (20, 25))
69286	28288140	The primary tumor xenografts derived from CD133+ KYSE270 cells were excised from the NOD/SCID mice, re-sorted into CD133+ and CD133- cells, and re-injected into secondary mouse recipients.	('CD133+ KYSE270', 'Var', (42, 56))	('KYSE270', 'Var', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('NOD', 'Gene', '1822', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mice', 'Species', '10090', (94, 98))	('SCID', 'Gene', '19090', (89, 93))	('tumor', 'Disease', (12, 17))	('mouse', 'Species', '10090', (171, 176))	('NOD', 'Gene', (85, 88))	('SCID', 'Gene', (89, 93))
69287	28288140	Consistently, only CD133+ but not CD133- ESCC cells formed tumors with the same histological morphology as the primary tumors (Figure 4d and Supplementary Table S3), thus providing direct evidence for self-renewal capacity of CD133+ ESCC cells in vivo.	('CD133+', 'Var', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('primary tumors', 'Disease', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('ESCC', 'Phenotype', 'HP:0011459', (41, 45))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('primary tumors', 'Disease', 'MESH:D009369', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ESCC', 'Phenotype', 'HP:0011459', (233, 237))	('self-renewal', 'CPA', (201, 213))
69288	28288140	With respect to resistance to conventional chemotherapeutic drugs, we found that CD133+ ESCC cells were more resistant to 5-FU and DDP than CD133- cells (Figure 4f).	('5-FU', 'Chemical', 'MESH:D005472', (122, 126))	('DDP', 'Gene', '1678', (131, 134))	('CD133+ ESCC', 'Var', (81, 92))	('ESCC', 'Phenotype', 'HP:0011459', (88, 92))	('DDP', 'Gene', (131, 134))	('resistant to 5-FU', 'MPA', (109, 126))
69289	28288140	We also examined whether CD133+ cells preferentially express the stem cell-associated genes crucial for maintenance of stem cell properties, and found higher expression levels of sox2 and LIN28 in CD133+ ESCC cells (Figure 4h).	('CD133+', 'Var', (197, 203))	('expression levels', 'MPA', (158, 175))	('LIN28', 'Gene', (188, 193))	('ESCC', 'Phenotype', 'HP:0011459', (204, 208))	('higher', 'PosReg', (151, 157))	('sox2', 'Gene', '6657', (179, 183))	('sox2', 'Gene', (179, 183))
69291	28288140	We found that CD133-knockdown reduced the expression levels of sox2 and LIN28, compared with the scrambled shRNA control (shCON) (Supplementary Figure S5a).	('sox2', 'Gene', '6657', (63, 67))	('expression levels', 'MPA', (42, 59))	('LIN28', 'Gene', (72, 77))	('reduced', 'NegReg', (30, 37))	('sox2', 'Gene', (63, 67))	('CD133-knockdown', 'Var', (14, 29))
69292	28288140	In vivo assay showed that at a cell dose of 2 x 104, only two out of six (33.3%) mice injected with KYSE270-shCD133 cells developed tumor whereas KYSE270-shCON cells produced tumors in all of the six nude mice (100%) examined (Supplementary Figure S5b and Supplementary Table S4).	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', (175, 180))	('nude mice', 'Species', '10090', (200, 209))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('mice', 'Species', '10090', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('mice', 'Species', '10090', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('KYSE270-shCD133', 'Var', (100, 115))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
69294	28288140	When a larger number of cells (1 x 105) were injected, both KYSE270-shCD133 and KYSE270-shCON cell lines formed tumors in all the mice in the respective groups (n=6), but the KYSE270-shCD133 tumors were significantly smaller (Supplementary Figure S5c) and with decreased expression levels of Sox2 and LIN28 (Supplementary Figure S5d).	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('mice', 'Species', '10090', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('smaller', 'NegReg', (217, 224))	('Sox2', 'Gene', (292, 296))	('LIN28', 'Protein', (301, 306))	('KYSE270-shCD133', 'Var', (60, 75))	('decreased', 'NegReg', (261, 270))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('KYSE270-shCD133', 'Var', (175, 190))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('Sox2', 'Gene', '20674', (292, 296))	('tumors', 'Disease', (112, 118))	('expression levels of', 'MPA', (271, 291))
69295	28288140	We also found that CD133-knockdown significantly enhanced the sensitivity of esophageal tumor xenografts to 5-FU and DDP in vivo (Supplementary Figure S5f).	('esophageal tumor', 'Disease', 'MESH:D004938', (77, 93))	('esophageal tumor', 'Disease', (77, 93))	('enhanced', 'PosReg', (49, 57))	('sensitivity', 'MPA', (62, 73))	('CD133-knockdown', 'Var', (19, 34))	('esophageal tumor', 'Phenotype', 'HP:0100751', (77, 93))	('5-FU', 'Chemical', 'MESH:D005472', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('DDP', 'Gene', (117, 120))	('DDP', 'Gene', '1678', (117, 120))
69298	28288140	Interestingly, histologic comparison of the tumor xenografts demonstrated significantly lower microvessel density (MVD), as determined by CD31-immunostaining, in the miR-377-overexpressing tumor xenografts, compared with tumors that expressed control vector, suggesting that miR-377 may affect tumor angiogenesis (Figure 5a).	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('microvessel density', 'CPA', (94, 113))	('miR-377', 'Var', (275, 282))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (44, 49))	('miR-377-overexpressing', 'PosReg', (166, 188))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumors', 'Disease', (221, 227))	('lower', 'NegReg', (88, 93))	('CD31', 'Gene', '5175', (138, 142))	('affect', 'Reg', (287, 293))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', (294, 299))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('CD31', 'Gene', (138, 142))	('miR-377-overexpressing', 'Gene', (166, 188))
69299	28288140	Moreover, conditioned medium (CM) from ESCC cells expressing miR-377 remarkably reduced the tube formation and migration ability of human umbilical vein endothelial cells (HUVECs) while knockdown of miR-377 in ESCC resulted in increased tube formation and migration of HUVECs (Figures 5b and c).	('tube formation', 'CPA', (237, 251))	('knockdown', 'Var', (186, 195))	('increased', 'PosReg', (227, 236))	('miR-377', 'Var', (61, 68))	('reduced', 'NegReg', (80, 87))	('miR-377', 'Var', (199, 206))	('ESCC', 'Phenotype', 'HP:0011459', (39, 43))	('tube formation', 'CPA', (92, 106))	('migration ability', 'CPA', (111, 128))	('human', 'Species', '9606', (132, 137))	('migration of HUVECs', 'CPA', (256, 275))	('ESCC', 'Phenotype', 'HP:0011459', (210, 214))	('CM', 'Disease', 'MESH:D009202', (30, 32))
69300	28288140	In the mouse model, we also observed a reduction of VEGF in the tumor xenografts established by ESCC cells expressing miR-377, compared with vector control (Figure 5d).	('tumor', 'Disease', (64, 69))	('mouse', 'Species', '10090', (7, 12))	('reduction', 'NegReg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('VEGF', 'MPA', (52, 56))	('ESCC', 'Phenotype', 'HP:0011459', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('miR-377', 'Var', (118, 125))
69302	28288140	ESCC cell lines that stably overexpressed miR-377 showed downregulation of VEGF in both cell lysates and CM, as determined using western blot and Enzyme-Linked Immunosorbent Assay (ELISA), respectively (Figure 5f).	('downregulation', 'NegReg', (57, 71))	('miR-377', 'Var', (42, 49))	('ESCC', 'Phenotype', 'HP:0011459', (0, 4))	('CM', 'Disease', 'MESH:D009202', (105, 107))	('VEGF', 'Protein', (75, 79))
69303	28288140	Analysis of 50 primary ESCC tumors and matched normal esophageal tissue samples showed upregulation of VEGF in the majority of tumor samples, and an inverse correlation between miR-377 and VEGF expressions (Figure 5h).	('ESCC tumors', 'Disease', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('expressions', 'MPA', (194, 205))	('tumor', 'Disease', (28, 33))	('VEGF', 'Protein', (103, 107))	('tumor', 'Disease', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('ESCC tumors', 'Disease', 'MESH:D004938', (23, 34))	('ESCC', 'Phenotype', 'HP:0011459', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('inverse', 'NegReg', (149, 156))	('miR-377', 'Var', (177, 184))	('upregulation', 'PosReg', (87, 99))
69304	28288140	To examine the importance of CD133 and VEGF in the functional roles of miR-377 in cancer stemness and angiogenesis, the expression levels of CD133 and VEGF in the miR-377-knockdown cells were inhibited with the corresponding siRNAs (Figure 6a).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('CD133', 'Gene', (141, 146))	('cancer stemness', 'Disease', 'MESH:D009369', (82, 97))	('inhibited', 'NegReg', (192, 201))	('miR-377-knockdown', 'Var', (163, 180))	('cancer stemness', 'Disease', (82, 97))	('expression levels', 'MPA', (120, 137))
69309	28288140	Taken together, these data suggest that miR-377 plays a role in inhibiting tumor invasion and metastasis.	('miR-377', 'Var', (40, 47))	('inhibiting', 'NegReg', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
69312	28288140	The results showed that systemic delivery of miR-377 oligonucleotide resulted in a significant decrease in tumor burden as compared with treatment with miR-CON or vehicle (Figure 8a).	('decrease', 'NegReg', (95, 103))	('miR-377 oligonucleotide', 'Var', (45, 68))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
69313	28288140	The anti-tumor effect of systemically delivered miR-377 was more pronounced for KYSE270 than KYSE150 xenografts, which was consistent with that of ectopic miR-377 expression (Figure 2d).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('KYSE270', 'Var', (80, 87))	('miR-377', 'Var', (48, 55))
69315	28288140	Systemic miR-377 treatment reduced VEGF expression level in KYSE150 and KYSE270 tumors, as well as CD133 level in the CD133+ KYSE270 tumors (Figure 8c).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('reduced', 'NegReg', (27, 34))	('CD133 level', 'MPA', (99, 110))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('KYSE270', 'Var', (72, 79))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('VEGF expression level', 'MPA', (35, 56))	('KYSE150', 'Var', (60, 67))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))
69321	28288140	Our study was prompted by the discrepancy in the anti-tumorigenic response of KYSE270 and KYSE150 cells to ectopic miR-377 expression, with the former cell line showing complete abolition of tumorigenicity in nude mice but only a modest effect was observed in the latter (Figure 2d).	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('nude mice', 'Species', '10090', (209, 218))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('abolition', 'NegReg', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', (54, 59))	('miR-377', 'Var', (115, 122))
69326	28288140	Third, overexpression and knockdown of miR-377 in cancer cells decreased and increased CD133 expression, respectively, in transient and stable expression experiments.	('CD133', 'Gene', (87, 92))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('decreased', 'NegReg', (63, 72))	('miR-377', 'Gene', (39, 46))	('expression', 'MPA', (93, 103))	('knockdown', 'Var', (26, 35))	('increased', 'PosReg', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
69328	28288140	It was also reported that CD133 silencing can induce cancer cell cycle arrest by inhibiting expression of cytokinesis-related genes.	('inhibiting', 'NegReg', (81, 91))	('cancer', 'Disease', (53, 59))	('cytokinesis-related genes', 'Gene', (106, 131))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('silencing', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CD133', 'Gene', (26, 31))	('induce', 'PosReg', (46, 52))	('expression', 'MPA', (92, 102))
69329	28288140	Likewise, whether CD133 has any advantage compared with CD44 or CD90 as a TIC marker for ESCC, and whether a combination of cell surface markers should be used to identify esophageal TICs merit further investigations.	('CD44', 'Gene', (56, 60))	('CD90', 'Gene', '7070', (64, 68))	('TICs', 'Phenotype', 'HP:0100033', (183, 187))	('ESCC', 'Disease', (89, 93))	('TIC', 'Phenotype', 'HP:0100033', (183, 186))	('TIC', 'Phenotype', 'HP:0100033', (74, 77))	('CD90', 'Gene', (64, 68))	('CD133', 'Var', (18, 23))	('esophageal TICs', 'Disease', (172, 187))	('ESCC', 'Phenotype', 'HP:0011459', (89, 93))	('CD44', 'Gene', '960', (56, 60))	('esophageal TICs', 'Disease', 'MESH:D020323', (172, 187))
69332	28288140	This was likely to be attributed to the inhibitory effect of miR-377 on VEGF, which plays a predominant role in tumor angiogenesis.	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('miR-377', 'Var', (61, 68))
69339	28288140	It is possible that by targeting VEGF, miR-377 may impact on the function of VEGF-responsive non-tumor cells and deter the establishment of pre-metastatic niches at distant sites.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('miR-377', 'Var', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('function', 'MPA', (65, 73))	('deter', 'NegReg', (113, 118))	('VEGF', 'Gene', (33, 37))	('tumor', 'Disease', (97, 102))	('impact', 'Reg', (51, 57))
69343	28288140	For example, a recent study suggests that treatment with miR-200 members into the tumor endothelium resulted in marked reductions in metastasis and angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('reductions', 'NegReg', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('miR-200 members', 'Var', (57, 72))	('tumor', 'Disease', (82, 87))	('angiogenesis', 'CPA', (148, 160))
69345	28288140	Human ESCC cell lines KYSE30, KYSE70, KYSE150, KYSE270, KYSE410 (DSMZ, Braunschweig, Germany), HKESC-1 and T.Tn were maintained in RPMI 1640 (Sigma, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (FBS, Invitrogen, Gaithersburg, MD, USA) at 37  C in 5% CO2.	('KYSE270', 'Var', (47, 54))	('Human', 'Species', '9606', (0, 5))	('CO2', 'Chemical', '-', (266, 269))	('KYSE70', 'Var', (30, 36))	('KYSE410', 'CellLine', 'CVCL:1352', (56, 63))	('FBS', 'Disease', (211, 214))	('FBS', 'Disease', 'MESH:D005198', (211, 214))	('ESCC', 'Phenotype', 'HP:0011459', (6, 10))	('bovine', 'Species', '9913', (197, 203))	('KYSE410', 'Var', (56, 63))	('KYSE150', 'Var', (38, 45))
69360	28288140	The expression level of miR-377 in tumor and serum samples was compared with that in normal tissues and healthy control serum, respectively, using t-test.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('miR-377', 'Var', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))
69371	28740634	The results show a strong relationship between HPV infection especially high-risk HPV type 16 and GI cancers in Iranian population.	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('HPV infection', 'Disease', (47, 60))	('high-risk', 'Var', (72, 81))	('HPV type 16', 'Gene', (82, 93))	('GI cancers', 'Disease', (98, 108))	('GI cancer', 'Phenotype', 'HP:0007378', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('HPV infection', 'Disease', 'MESH:D030361', (47, 60))
69377	28740634	Mucosal low-risk HPV such as HPV6 and HPV11 create genital warts, while high-risk types like HPV16 and HPV 18 can lead to squamous intraepithelial lesions which can progress to invasive squamous cell carcinoma stage.	('HPV11', 'Species', '10580', (38, 43))	('HPV 18', 'Var', (103, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('invasive squamous cell carcinoma', 'Disease', (177, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('HPV11', 'Var', (38, 43))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (177, 209))	('genital warts', 'Disease', (51, 64))	('genital warts', 'Phenotype', 'HP:0032301', (51, 64))	('HPV16', 'Species', '333760', (93, 98))	('warts', 'Phenotype', 'HP:0200043', (59, 64))	('squamous intraepithelial', 'Disease', (122, 146))	('HPV16', 'Var', (93, 98))	('HPV6', 'Var', (29, 33))	('progress', 'Reg', (165, 173))	('lead to', 'Reg', (114, 121))
69381	28740634	Multiple risk factors are involved in the development of these malignancies such as family history, smoking, consumption of alcohol and hot foods, genetic mutations and infections.	('genetic mutations', 'Var', (147, 164))	('infections', 'Disease', (169, 179))	('infections', 'Disease', 'MESH:D007239', (169, 179))	('alcohol', 'Chemical', 'MESH:D000438', (124, 131))
69390	28740634	investigated the association between HPV-16 and esophageal cancer in Chinese population and reported that being infected with HPV-16 increases the chance of esophageal squamous cell carcinoma more than six folds.	('HPV-16', 'Gene', (126, 132))	('infected', 'Var', (112, 120))	('esophageal squamous cell carcinoma', 'Disease', (157, 191))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('increases', 'PosReg', (133, 142))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (157, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))
69400	28790844	Kaplan-Meier survival analysis indicated that high FA score and low PNI were associated with poor progression-free survival (PFS; for the FA score, P<0.001; for PNI, P=0.001) and overall survival (OS; for the FA score, P<0.001; for PNI, P=0.013), respectively.	('overall survival', 'CPA', (179, 195))	('progression-free survival', 'CPA', (98, 123))	('high', 'Var', (46, 50))	('low', 'NegReg', (64, 67))	('OS', 'Chemical', '-', (197, 199))	('PNI', 'Gene', (68, 71))	('poor', 'NegReg', (93, 97))
69462	28790844	In the analysis of SCC patients (Figure 2), high FA score was significantly associated with poor PFS (P=0.022) and OS (P=0.004).	('SCC', 'Gene', '6317', (19, 22))	('patients', 'Species', '9606', (23, 31))	('OS', 'Chemical', '-', (115, 117))	('SCC', 'Gene', (19, 22))	('high FA', 'Var', (44, 51))
69463	28790844	Patients with high PNI exhibited superior PFS (P=0.003) and OS (P=0.007).	('superior', 'PosReg', (33, 41))	('PFS', 'CPA', (42, 45))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (60, 62))	('high PNI', 'Var', (14, 22))
69470	28790844	For OS, the AUC was 0.662 for FA score (P<0.001, 95% CI, 0.583-0.742) and 0.560 for PNI (P=0.166, 95% CI, 0.476-0.644).	('FA score', 'Disease', (30, 38))	('PNI', 'Gene', (84, 87))	('0.560', 'Var', (74, 79))	('OS', 'Chemical', '-', (4, 6))
69498	28790844	Low albumin commonly reflects malnutrition, which could impair anatomic barriers, immunity, and other defense mechanisms.	('malnutrition', 'Disease', (30, 42))	('impair', 'NegReg', (56, 62))	('albumin', 'Gene', (4, 11))	('malnutrition', 'Disease', 'MESH:D044342', (30, 42))	('albumin', 'Gene', '213', (4, 11))	('anatomic barriers', 'CPA', (63, 80))	('Low albumin', 'Phenotype', 'HP:0003073', (0, 11))	('malnutrition', 'Phenotype', 'HP:0004395', (30, 42))	('immunity', 'CPA', (82, 90))	('Low', 'Var', (0, 3))
69505	28790844	Studies have confirmed that NSCLC patients with low PNI experienced poor clinical outcomes, but the optimal cutoff value was controversial.	('PNI', 'Gene', (52, 55))	('NSCLC', 'Disease', (28, 33))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('patients', 'Species', '9606', (34, 42))	('low', 'Var', (48, 51))
69509	28790844	In our analysis, patients with low lymphocyte count tended to develop lymph node metastasis and demonstrated advanced TNM stage.	('lymph node metastasis', 'CPA', (70, 91))	('develop', 'PosReg', (62, 69))	('TNM stage', 'CPA', (118, 127))	('low lymphocyte count', 'Phenotype', 'HP:0001888', (31, 51))	('patients', 'Species', '9606', (17, 25))	('low', 'Var', (31, 34))
69516	28790844	ROC curves of FA score showed that the AUC was 0.636 (P=0.001) for PFS and 0.662 (P<0.001) for OS, which were superior to PNI.	('0.662', 'Var', (75, 80))	('PFS', 'Disease', (67, 70))	('OS', 'Chemical', '-', (95, 97))
69541	28435467	Although the proof is outside of the scope of this review, the relationship between Young's modulus E and shear modulus G is as follows: Given the high-water content of soft tissue, the Poisson's ratio v is near 0.5 of an incompressible medium, and E = 3G.	('water', 'Chemical', 'MESH:D014867', (152, 157))	('E = 3G', 'Var', (249, 255))	('high-water', 'MPA', (147, 157))
69709	28435467	They showed that using benign SWI signs (homogeneity and Rperilesion < 4.32), to selectively downgrade B-mode US classified BI-RADS 4a (low suspicion for malignancy) and BI-RADS 4b (intermediate suspicion for malignancy) lesions improved specificity of US (13% to 51%) without loss in sensitivity (100%) (Table 3,).	('malignancy', 'Disease', (209, 219))	('downgrade', 'NegReg', (93, 102))	('RADS 4b', 'Phenotype', 'HP:0500055', (173, 180))	('malignancy', 'Disease', 'MESH:D009369', (209, 219))	('improved', 'PosReg', (229, 237))	('BI-RADS', 'Var', (170, 177))	('specificity', 'MPA', (238, 249))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('malignancy', 'Disease', (154, 164))
69754	28435467	SE was shown to be useful for predicting fibrosis in renal transplant patients, mainly for F2-F3 cases, with overall accuracy of 95%.	('patients', 'Species', '9606', (70, 78))	('fibrosis in renal transplant', 'Phenotype', 'HP:0030760', (41, 69))	('F2-F3', 'Var', (91, 96))	('fibrosis', 'Disease', 'MESH:D005355', (41, 49))	('fibrosis', 'Disease', (41, 49))	('SE', 'Chemical', '-', (0, 2))
69756	28435467	They found the mean strain index value of renal parenchyma in CKD patients (1.81+-0.88) was significantly higher than in healthy individuals (0.42+-0.30) (p<0.001).	('renal parenchyma', 'Disease', 'MESH:D007674', (42, 58))	('strain index value', 'MPA', (20, 38))	('higher', 'PosReg', (106, 112))	('CKD', 'Var', (62, 65))	('renal parenchyma', 'Disease', (42, 58))	('patients', 'Species', '9606', (66, 74))
69759	28435467	The majority of studies using SWI to evaluate CKD (Table 4,) have shown that the shear wave velocity of the renal parenchyma of CKD patients was significantly lower than in normal patients.	('renal parenchyma', 'Disease', 'MESH:D007674', (108, 124))	('CKD', 'Var', (128, 131))	('lower', 'NegReg', (159, 164))	('renal parenchyma', 'Disease', (108, 124))	('shear wave velocity', 'MPA', (81, 100))	('patients', 'Species', '9606', (132, 140))	('patients', 'Species', '9606', (180, 188))
69771	28435467	In a study comparing strain imaging in 28 AMLs and 19 RCCs, strain ratios measured in AMLs by two radiologists (0.15 +- 0.06 and 0.18 +- 0.09, respectively) were significantly lower compared to RCCs (0.64 +- 0.15 and 0.63 +- 0.19), with the best cut-off value of 0.3 (sensitivity = 95%, specificity = 100%) (Table 3,).	('AML', 'Disease', (86, 89))	('AML', 'Disease', (42, 45))	('0.18 +- 0.09', 'Var', (129, 141))	('RCC', 'Disease', (54, 57))	('0.15 +- 0.06', 'Var', (112, 124))	('RCC', 'Disease', (194, 197))	('strain ratios', 'MPA', (60, 73))	('lower', 'NegReg', (176, 181))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('AML', 'Disease', 'MESH:D015470', (86, 89))	('AML', 'Disease', 'MESH:D015470', (42, 45))
69831	28435467	In particular with EUS-FNA, sampling is relatively contraindicated if the primary tumor blocks access to the suspicious lymph node, as traversal of the primary tumor by the sampling needle may lead to track seeding.	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('track seeding', 'CPA', (201, 214))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', (82, 87))	('traversal', 'Var', (135, 144))	('lead to', 'Reg', (193, 200))
69864	24944678	The median survival time (MST) of all patients with T3-4M0 esophageal cancer who received CCRT was demonstrated to be only 16 months.	('esophageal cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CRT', 'Gene', '799', (91, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('T3-4M0', 'Var', (52, 58))	('patients', 'Species', '9606', (38, 46))	('CRT', 'Gene', (91, 94))
69923	24944678	However, other previous studies have also demonstrated that EGFR amplification or overexpression significantly correlates with lymph node metastasis.	('overexpression', 'PosReg', (82, 96))	('correlates', 'Reg', (111, 121))	('EGFR', 'Gene', '1956', (60, 64))	('lymph node metastasis', 'CPA', (127, 148))	('amplification', 'Var', (65, 78))	('EGFR', 'Gene', (60, 64))
69928	24944678	Previously, hyperexpression of HER-2 in the tumor has been found to correlate with ESCC progression and is significantly more common in patients developing early local relapses or distant metastases following surgery, however, this correlation has not been found in EGFR, as shown in the current study.	('HER-2', 'Gene', (31, 36))	('ESCC', 'Disease', (83, 87))	('EGFR', 'Gene', '1956', (266, 270))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('patients', 'Species', '9606', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('EGFR', 'Gene', (266, 270))	('common', 'Reg', (126, 132))	('hyperexpression', 'Var', (12, 27))	('metastases', 'Disease', (188, 198))	('HER-2', 'Gene', '2064', (31, 36))	('tumor', 'Disease', (44, 49))	('metastases', 'Disease', 'MESH:D009362', (188, 198))
69942	24944678	In the present study, the tumor tissue of 10 patients was investigated for mutation status, but no mutations were found and the incidence of EGFR mutations in patients with ESCC was extremely low.	('mutations', 'Var', (146, 155))	('ESCC', 'Disease', (173, 177))	('EGFR', 'Gene', '1956', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('EGFR', 'Gene', (141, 145))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('patients', 'Species', '9606', (159, 167))
69961	19937795	As predicted by Warburg, the capacity to sustain high rates of glycolysis under aerobic conditions appears to be an important feature of rapidly growing tumors, and impaired mitochondrial oxidative function may be a factor in increased glucose utilization of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('mitochondrial oxidative function', 'MPA', (174, 206))	('impaired mitochondrial oxidative function', 'Phenotype', 'HP:0003287', (165, 206))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('impaired', 'Var', (165, 173))	('tumor', 'Disease', (153, 158))	('glucose', 'Chemical', 'MESH:D005947', (236, 243))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', (259, 264))	('increased glucose', 'Phenotype', 'HP:0003074', (226, 243))	('increased', 'PosReg', (226, 235))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('glycolysis', 'MPA', (63, 73))
69964	19937795	Upregulation of glucose turn-over via the pentose phosphate pathway leads to enhanced expression of HIF-1alpha G6PD, p-Akt, LDH and carbonic anhydrase enzyme activity.	('Upregulation', 'PosReg', (0, 12))	('enhanced', 'PosReg', (77, 85))	('activity', 'MPA', (158, 166))	('HIF-1alpha', 'Gene', (100, 110))	('pentose phosphate', 'Chemical', 'MESH:D010428', (42, 59))	('glucose', 'Chemical', 'MESH:D005947', (16, 23))	('Akt', 'Gene', '207', (119, 122))	('carbonic anhydrase enzyme', 'Enzyme', (132, 157))	('LDH', 'Gene', (124, 127))	('expression', 'MPA', (86, 96))	('pentose phosphate pathway', 'Pathway', (42, 67))	('Akt', 'Gene', (119, 122))	('HIF-1alpha', 'Gene', '3091', (100, 110))	('G6PD', 'Var', (111, 115))	('glucose turn-over', 'MPA', (16, 33))
69966	19937795	Alteration in the bioenergetic phenotype, which results in dysfunctional mitochondria in mammalian cells, is a hallmark of many solid tumors including breast, gastric, lung and esophageal cancers.	('esophageal cancers', 'Disease', 'MESH:D004938', (177, 195))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('breast', 'Disease', (151, 157))	('lung', 'Disease', (168, 172))	('Alteration', 'Var', (0, 10))	('hallmark of many solid tumors', 'Disease', 'MESH:D009369', (111, 140))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (59, 85))	('gastric', 'Disease', (159, 166))	('bioenergetic', 'MPA', (18, 30))	('dysfunctional mitochondria', 'Disease', (59, 85))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('results in', 'Reg', (48, 58))	('mammalian', 'Species', '9606', (89, 98))	('esophageal cancers', 'Disease', (177, 195))	('hallmark of many solid tumors', 'Disease', (111, 140))
69971	19937795	Seven ESCC cell lines (TE1, TE2, TE4, KYSE70, KYSE140, KYSE150, and KYSE410) were obtained from the Cell Response Center for Biomedical Research Institute, Department of Aging and Cancer, Tohoku University (TE series) and kindly provided by Dr. Shimada in the Department of Surgery, Kyoto University (KYSE series).	('KYSE150', 'Var', (55, 62))	('KYSE410', 'Var', (68, 75))	('TE2', 'Gene', '8260', (28, 31))	('KYSE70', 'Var', (38, 44))	('Cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Cancer', 'Disease', (180, 186))	('TE2', 'Gene', (28, 31))	('Cancer', 'Disease', 'MESH:D009369', (180, 186))
70002	19937795	All antibodies were purchased from Cell Signaling Technologies (Beverly, MA) except for the anti-vimentin (BD Pharmingen, San Jose, CA), anti-PK-M2 (Abnova, Walnut, CA), anti-PDK1 (Stressgen, British Colombis, Canada), anti-PFK (Abcam, Cambridge, MA ), and anti-beta-actin (Sigma, St. Louis, MO) antibodies.	('vimentin', 'Gene', '7431', (97, 105))	('anti-PFK', 'Var', (219, 227))	('PDK1', 'Gene', '5163', (175, 179))	('vimentin', 'Gene', (97, 105))	('PDK1', 'Gene', (175, 179))	('PK-M2', 'Gene', '5315', (142, 147))	('beta-actin', 'Gene', '728378', (262, 272))	('beta-actin', 'Gene', (262, 272))	('PK-M2', 'Gene', (142, 147))
70010	19937795	Cellular oxygen consumption and ATP production were significantly decreased by 0.25% MSE or 0.5% SSE treatment, (Supplemental Fig.	('SSE', 'Gene', (97, 100))	('0.25% MSE', 'Var', (79, 88))	('decreased', 'NegReg', (66, 75))	('ATP production', 'CPA', (32, 46))	('MSE', 'Var', (85, 88))	('oxygen', 'Chemical', 'MESH:D010100', (9, 15))	('0.5%', 'Var', (92, 96))	('Cellular oxygen consumption', 'CPA', (0, 27))	('ATP', 'Chemical', 'MESH:D000255', (32, 35))
70011	19937795	Consistent results were observed in Het-1A cells resistant to MSE or SSE; MSE- and SSE-Het-1A cells consumed more glucose, and thus produced more lactate than sensitive cells (Fig.	('produced', 'MPA', (132, 140))	('consumed', 'MPA', (100, 108))	('SSE-Het-1A', 'Var', (83, 93))	('lactate', 'MPA', (146, 153))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('lactate', 'Chemical', 'MESH:D019344', (146, 153))	('MSE-', 'Var', (74, 78))	('glucose', 'MPA', (114, 121))	('more', 'PosReg', (141, 145))	('more', 'PosReg', (109, 113))
70034	19937795	In vivo and in vitro studies have shown that exposure to tobacco smoke, including mainstream and sidestream, or their mixture, causes DNA single-strand breaks, aromatic adducts and oxidative damage to DNA, chromosome aberrations, and micronuclei.	('DNA', 'Gene', (134, 137))	('chromosome aberrations', 'CPA', (206, 228))	('tobacco', 'Species', '4097', (57, 64))	('aromatic adducts', 'MPA', (160, 176))	('oxidative damage', 'CPA', (181, 197))	('micronuclei', 'CPA', (234, 245))	('single-strand breaks', 'Var', (138, 158))
70047	19937795	We observed an increase of invasive activity in MSE- or SSE-Het-1A cells which produced a higher level of lactate than control-Het-1A cells.	('MSE-', 'Var', (48, 52))	('increase', 'PosReg', (15, 23))	('invasive activity', 'CPA', (27, 44))	('lactate', 'Chemical', 'MESH:D019344', (106, 113))	('higher', 'PosReg', (90, 96))
70059	19937795	The underlying mechanism of MSE or SSE-induced glycolysis and mitochondrial dysfunction involves up-regulation of glycolytic enzymes and reciprocally down-regulation of mitochondrial genes.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (62, 87))	('up-regulation', 'PosReg', (97, 110))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (62, 87))	('mitochondrial', 'MPA', (169, 182))	('glycolytic enzymes', 'MPA', (114, 132))	('glycolysis', 'MPA', (47, 57))	('mitochondrial dysfunction', 'Disease', (62, 87))	('down-regulation', 'NegReg', (150, 165))	('MSE', 'Var', (28, 31))
70161	33543230	constructed the network of lncRNA, miRNA, and mRNA and found eight lncRNAs including WDFY3-AS2, CASC8, UGDH-AS1, RAP2C-AS1, AC007128.1, AC016205.1, AC092803.2, and AC079949.2 correlated with overall survival of the patients with ESCA.	('AC079949.2', 'Var', (164, 174))	('patients', 'Species', '9606', (215, 223))	('RAP2C-AS1', 'Gene', '101928578', (113, 122))	('WDFY3', 'Gene', '23001', (85, 90))	('CASC8', 'Gene', (96, 101))	('CASC8', 'Gene', '727677', (96, 101))	('correlated with', 'Reg', (175, 190))	('UGDH-AS1', 'Gene', (103, 111))	('AC016205.1', 'Var', (136, 146))	('overall', 'MPA', (191, 198))	('ESCA', 'Phenotype', 'HP:0011459', (229, 233))	('ESCA', 'Disease', (229, 233))	('UGDH-AS1', 'Gene', '100885776', (103, 111))	('RAP2C-AS1', 'Gene', (113, 122))	('WDFY3', 'Gene', (85, 90))
70162	33543230	built the regulatory networks of miRNA-TF and miRNA-gene and identified the top five miRNAs (miRNA-93, miRNA-21, miRNA-4746, miRNA-196a-1, and miRNA-196a-2) with diagnostic value.	('miRNA-196a-1', 'Var', (125, 137))	('miRNA-gene', 'Gene', (46, 56))	('miRNA-21', 'Gene', (103, 111))	('miRNA-4746', 'Var', (113, 123))	('miRNA-196a-2', 'Var', (143, 155))	('miRNA-93', 'Gene', (93, 101))	('miRNA-21', 'Gene', '406991', (103, 111))	('miRNA-93', 'Gene', '407051', (93, 101))
70216	33543230	These results suggest the major variations in ESCA were involved in the remodeling of the tumor microenvironment (TME) and cell differentiation.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Th', 'Chemical', '-', (0, 2))	('involved', 'Reg', (56, 64))	('cell differentiation', 'CPA', (123, 143))	('variations', 'Var', (32, 42))	('ESCA', 'Phenotype', 'HP:0011459', (46, 50))	('ESCA', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
70248	31881015	Hsa_circ_0006948 enhances cancer progression and epithelial-mesenchymal transition through the miR-490-3p/HMGA2 axis in esophageal squamous cell carcinoma Increasing studies have indicated that circular RNAs (circRNAs) are important in cancer progression.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('miR', 'Gene', '220972', (95, 98))	('Hsa_circ_0006948', 'Var', (0, 16))	('miR', 'Gene', (95, 98))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('cancer', 'Disease', (26, 32))	('epithelial-mesenchymal transition', 'CPA', (49, 82))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('cancer', 'Disease', (236, 242))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (120, 154))	('HMGA2', 'Gene', '8091', (106, 111))	('enhances', 'PosReg', (17, 25))	('HMGA2', 'Gene', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))
70250	31881015	In this study, we aimed to identify whether hsa_circ_0006948 promotes ESCC cell EMT and explore its biological mechanisms.	('ESCC', 'Disease', (70, 74))	('hsa_circ_0006948', 'Var', (44, 60))	('promotes', 'PosReg', (61, 69))	('ESCC', 'Disease', 'MESH:C562729', (70, 74))
70254	31881015	In conclusion, hsa_circ_0006948 was overexpressed in ESCC tissues and promoted cancer progression, and it could induce EMT by enhancing HMGA2 by sponging miR-490-3p, suggesting that hsa_circ_0006948 could be a biomarker for ESCC.	('ESCC', 'Disease', 'MESH:C562729', (224, 228))	('ESCC', 'Disease', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('enhancing', 'PosReg', (126, 135))	('miR-490', 'Gene', (154, 161))	('HMGA2', 'Gene', '8091', (136, 141))	('miR-490', 'Gene', '574443', (154, 161))	('HMGA2', 'Gene', (136, 141))	('ESCC', 'Disease', (224, 228))	('EMT', 'CPA', (119, 122))	('ESCC', 'Disease', 'MESH:C562729', (53, 57))	('promoted', 'PosReg', (70, 78))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('induce', 'PosReg', (112, 118))	('hsa_circ_0006948', 'Var', (15, 31))
70262	31881015	In this study, using a circRNA microarray profiling, we identified that hsa_circ_0006948, which originates from exons 2, 3 and 4 of the FNDC3B gene, was up-regulated in ESCC tissues and cell lines.	('FNDC3B', 'Gene', (136, 142))	('ESCC', 'Disease', (169, 173))	('up-regulated', 'PosReg', (153, 165))	('ESCC', 'Disease', 'MESH:C562729', (169, 173))	('hsa_circ_0006948', 'Var', (72, 88))	('FNDC3B', 'Gene', '64778', (136, 142))
70263	31881015	Further studies suggested that hsa_circ_0006948 promoted proliferation, migration and invasion, and induced EMT in ESCC cells by sponging miR-490-3p.	('ESCC', 'Disease', (115, 119))	('EMT', 'CPA', (108, 111))	('migration', 'CPA', (72, 81))	('induced', 'PosReg', (100, 107))	('hsa_circ_0006948', 'Var', (31, 47))	('ESCC', 'Disease', 'MESH:C562729', (115, 119))	('miR-490', 'Gene', '574443', (138, 145))	('proliferation', 'CPA', (57, 70))	('miR-490', 'Gene', (138, 145))	('promoted', 'PosReg', (48, 56))	('invasion', 'CPA', (86, 94))
70264	31881015	In summary, this study indicated that hsa_circ_0006948 may play an important regulatory role in the EMT process of ESCC cells.	('ESCC', 'Disease', (115, 119))	('hsa_circ_0006948', 'Var', (38, 54))	('ESCC', 'Disease', 'MESH:C562729', (115, 119))
70268	31881015	The results showed that hsa_circ_0006948 was significantly lower than housekeeping mRNA GAPDH, however, it was abundant as the linear FNDC3B (linFNDC3B) (Figure 1D).	('lower', 'NegReg', (59, 64))	('hsa_circ_0006948', 'Var', (24, 40))	('FNDC3B', 'Gene', '64778', (145, 151))	('FNDC3B', 'Gene', (145, 151))	('GAPDH', 'Gene', '2597', (88, 93))	('GAPDH', 'Gene', (88, 93))	('FNDC3B', 'Gene', '64778', (134, 140))	('FNDC3B', 'Gene', (134, 140))
70272	31881015	We examined hsa_circ_0006948 expression in 153 pairs of ESCC tissues and adjacent normal tissues using qRT-PCR analysis and found that hsa_circ_0006948 was significantly higher in cancer tissues than in normal tissues (Figure 2A).	('ESCC', 'Disease', (56, 60))	('higher', 'PosReg', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('ESCC', 'Disease', 'MESH:C562729', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('hsa_circ_0006948', 'Var', (135, 151))	('cancer', 'Disease', (180, 186))
70273	31881015	Additionally, hsa_circ_0006948 expression was high in 83.6% of ESCC patients (128 of 153) (Figure 2B).	('hsa_circ_0006948', 'Var', (14, 30))	('ESCC', 'Disease', 'MESH:C562729', (63, 67))	('patients', 'Species', '9606', (68, 76))	('ESCC', 'Disease', (63, 67))
70276	31881015	Briefly, high hsa_circ_0006948 was positively correlated with lymphatic metastasis (Figure 2D), and no significant correlation was observed for other clinicopathological features, including age, T stage, sex, blood type, tumor location and differentiation.	('lymphatic metastasis', 'CPA', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('correlated', 'Reg', (46, 56))	('high hsa_circ_0006948', 'Var', (9, 30))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
70277	31881015	Kaplan-Meier survival curves showed that patients with higher hsa_circ_0006948 expression had a significantly shorter OS than patients with low expression (P=0.0009) (Figure 2E).	('patients', 'Species', '9606', (41, 49))	('hsa_circ_0006948 expression', 'Var', (62, 89))	('shorter', 'NegReg', (110, 117))	('patients', 'Species', '9606', (126, 134))
70279	31881015	We found that the expression of hsa_circ_0006948 was an independent prognostic factor for ESCC prognosis (HR = 1.94; 95% CI 1.11-3.39; P = 0.021).	('hsa_circ_0006948', 'Var', (32, 48))	('ESCC', 'Disease', (90, 94))	('ESCC', 'Disease', 'MESH:C562729', (90, 94))
70283	31881015	Compared to the negative control conditions, knockdown of hsa_circ_0006948 significantly inhibited ESCC cell proliferation (Figure 3D, Additional file 1: Supplementary Figure 1D).	('inhibited', 'NegReg', (89, 98))	('ESCC', 'Disease', 'MESH:C562729', (99, 103))	('knockdown', 'Var', (45, 54))	('ESCC', 'Disease', (99, 103))
70285	31881015	The transwell assay results showed that hsa_circ_0006948 downregulation inhibited ESCC cell migratory and invasion abilities.	('ESCC', 'Disease', (82, 86))	('downregulation inhibited', 'NegReg', (57, 81))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))	('hsa_circ_0006948', 'Var', (40, 56))
70286	31881015	Overexpression of hsa_circ_0006948 in ESCC cells promoted the proliferation and increased the migratory and invasion abilities in ESCC cells (Figure 3F-H, Additional file 1: Supplementary Figure 1F-1H).	('ESCC', 'Disease', 'MESH:C562729', (38, 42))	('proliferation', 'CPA', (62, 75))	('ESCC', 'Disease', (130, 134))	('increased', 'PosReg', (80, 89))	('ESCC', 'Disease', (38, 42))	('hsa_circ_0006948', 'Var', (18, 34))	('promoted', 'PosReg', (49, 57))	('ESCC', 'Disease', 'MESH:C562729', (130, 134))
70288	31881015	Therefore, we assessed whether hsa_circ_0006948 could induce EMT in ESCC cells, and EMT markers were assessed by Western blot in the present study.	('ESCC', 'Disease', (68, 72))	('EMT in', 'CPA', (61, 67))	('hsa_circ_0006948', 'Var', (31, 47))	('ESCC', 'Disease', 'MESH:C562729', (68, 72))	('induce', 'PosReg', (54, 60))
70289	31881015	Western blot analysis demonstrated that knockdown of hsa_circ_0006948 led to the upregulated expression of the epithelial marker E-cadherin and downregulated expression of the mesenchymal markers vimentin and N-cadherin.	('upregulated', 'PosReg', (81, 92))	('hsa_circ_0006948', 'Var', (53, 69))	('N-cadherin', 'Gene', (209, 219))	('expression', 'MPA', (158, 168))	('downregulated', 'NegReg', (144, 157))	('N-cadherin', 'Gene', '1000', (209, 219))	('E-cadherin', 'Gene', (129, 139))	('E-cadherin', 'Gene', '999', (129, 139))	('expression', 'MPA', (93, 103))	('vimentin', 'Gene', '7431', (196, 204))	('vimentin', 'Gene', (196, 204))
70290	31881015	On the other hand, the expression of E-cadherin was decreased, whereas that of vimentin and N-cadherin was increased in ESCC cells overexpressing hsa_circ_0006948 (Figure 3I).	('ESCC', 'Disease', 'MESH:C562729', (120, 124))	('vimentin', 'Gene', (79, 87))	('E-cadherin', 'Gene', (37, 47))	('N-cadherin', 'Gene', '1000', (92, 102))	('increased', 'PosReg', (107, 116))	('decreased', 'NegReg', (52, 61))	('E-cadherin', 'Gene', '999', (37, 47))	('ESCC', 'Disease', (120, 124))	('expression', 'MPA', (23, 33))	('hsa_circ_0006948', 'Var', (146, 162))	('vimentin', 'Gene', '7431', (79, 87))	('N-cadherin', 'Gene', (92, 102))
70291	31881015	These results implied that hsa_circ_0006948 promotes ESCC cell EMT.	('ESCC', 'Disease', 'MESH:C562729', (53, 57))	('promotes', 'PosReg', (44, 52))	('ESCC', 'Disease', (53, 57))	('hsa_circ_0006948', 'Var', (27, 43))
70293	31881015	Given that FISH showed that hsa_circ_0006948 was localized mainly in the cytoplasm, we speculated that hsa_circ_0006948 could sponge miRNAs to inhibit their function.	('miR', 'Gene', '220972', (133, 136))	('function', 'MPA', (157, 165))	('miR', 'Gene', (133, 136))	('hsa_circ_0006948', 'Var', (103, 119))	('inhibit', 'NegReg', (143, 150))
70297	31881015	Therefore, we hypothesized that hsa_circ_0006948 could induce EMT by enhancing HMGA2 by sponging miR-490-3p.	('miR-490', 'Gene', (97, 104))	('enhancing', 'PosReg', (69, 78))	('HMGA2', 'Gene', '8091', (79, 84))	('HMGA2', 'Gene', (79, 84))	('induce', 'PosReg', (55, 61))	('hsa_circ_0006948', 'Var', (32, 48))	('EMT', 'CPA', (62, 65))	('miR-490', 'Gene', '574443', (97, 104))
70302	31881015	The results of qRT-PCR showed that hsa_circ_0006948 was significantly enriched in AGO2-containing beads samples compared to control IgG immunoprecipitates, suggesting miR-490-3p targets directly hsa_circ_0006948 in an AGO2-dependent manner (Figure 4E, 4F).	('AGO2', 'Gene', (218, 222))	('hsa_circ_0006948', 'Var', (195, 211))	('AGO2', 'Gene', (82, 86))	('miR-490', 'Gene', '574443', (167, 174))	('miR-490', 'Gene', (167, 174))	('4F', 'Chemical', 'MESH:C006011', (252, 254))	('AGO2', 'Gene', '27161', (218, 222))	('AGO2', 'Gene', '27161', (82, 86))
70303	31881015	These results indicated that hsa_circ_0006948 may function as a competitive endogenous RNA by sponging miR-490-3p.	('miR-490', 'Gene', '574443', (103, 110))	('miR-490', 'Gene', (103, 110))	('sponging', 'NegReg', (94, 102))	('hsa_circ_0006948', 'Var', (29, 45))
70316	31881015	Next, we tried to analyze whether hsa_circ_0006948 exerts its cancerous effect on ESCC by sponging miR-490-3p, and a "rescue" experiment was performed to assess the functional interaction of "hsa_circ_0006948/miR-490-3p".	('miR-490', 'Gene', (209, 216))	('ESCC', 'Disease', (82, 86))	('miR-490', 'Gene', '574443', (99, 106))	('hsa_circ_0006948', 'Var', (34, 50))	('miR-490', 'Gene', (99, 106))	('miR-490', 'Gene', '574443', (209, 216))	('cancerous', 'Disease', 'MESH:D009369', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('sponging', 'MPA', (90, 98))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))	('cancerous', 'Disease', (62, 71))
70317	31881015	Compared with the migratory and invasive abilities of ESCC cells transfected with empty vector and miR-490-3p mimics, those of upregulated hsa_circ_0006948 cells transfected with miR-490-3p mimics significantly increased, suggesting that hsa_circ0006948 promotes ESCC progression and partly reverses the tumor suppressive effect of miR-490-3p (Figure 6A 6B).	('miR-490', 'Gene', '574443', (99, 106))	('miR-490', 'Gene', (99, 106))	('miR-490', 'Gene', (179, 186))	('miR-490', 'Gene', '574443', (179, 186))	('ESCC', 'Disease', 'MESH:C562729', (263, 267))	('tumor', 'Disease', (304, 309))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('increased', 'PosReg', (211, 220))	('ESCC', 'Disease', 'MESH:C562729', (54, 58))	('invasive abilities', 'CPA', (32, 50))	('ESCC', 'Disease', (263, 267))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('progression', 'CPA', (268, 279))	('reverses', 'NegReg', (291, 299))	('ESCC', 'Disease', (54, 58))	('miR-490', 'Gene', '574443', (332, 339))	('miR-490', 'Gene', (332, 339))	('promotes', 'PosReg', (254, 262))	('hsa_circ0006948', 'Var', (238, 253))	('migratory', 'CPA', (18, 27))
70318	31881015	Further Western blot analysis indicated that knockdown of hsa_circ_0006948 could induce downregulation of HMGA2, vimentin and N-cadherin while increasing E-cadherin.	('N-cadherin', 'Gene', (126, 136))	('downregulation', 'NegReg', (88, 102))	('HMGA2', 'Gene', '8091', (106, 111))	('hsa_circ_0006948', 'Gene', (58, 74))	('increasing', 'PosReg', (143, 153))	('N-cadherin', 'Gene', '1000', (126, 136))	('E-cadherin', 'Gene', (154, 164))	('E-cadherin', 'Gene', '999', (154, 164))	('vimentin', 'Gene', '7431', (113, 121))	('HMGA2', 'Gene', (106, 111))	('vimentin', 'Gene', (113, 121))	('knockdown', 'Var', (45, 54))
70323	31881015	Cell proliferation assay indicated that hsa_circ_0006948 promoted cell viability of ESCC cells, while downregulation of HMGA2 reversed this effect (Figure 7A, 7B).	('HMGA2', 'Gene', '8091', (120, 125))	('ESCC', 'Disease', (84, 88))	('promoted', 'PosReg', (57, 65))	('downregulation', 'NegReg', (102, 116))	('cell viability', 'CPA', (66, 80))	('HMGA2', 'Gene', (120, 125))	('ESCC', 'Disease', 'MESH:C562729', (84, 88))	('hsa_circ_0006948', 'Var', (40, 56))
70324	31881015	Additionally, transwell invasion assays showed that cell invasion ability was enhanced by hsa_circ_0006948, but was restored by transfection of si-HMGA2 (Figure 7C).	('HMGA2', 'Gene', '8091', (147, 152))	('hsa_circ_0006948', 'Var', (90, 106))	('HMGA2', 'Gene', (147, 152))	('cell invasion ability', 'CPA', (52, 73))	('enhanced', 'PosReg', (78, 86))
70325	31881015	Moreover, knockdown of HMGA2 abrogated hsa_circ_0006948-induced increase on HMGA2, vimentin and N-cadherin, and decrease on E-cadherin (Figure 7D).	('HMGA2', 'Gene', (76, 81))	('vimentin', 'Gene', (83, 91))	('decrease', 'NegReg', (112, 120))	('HMGA2', 'Gene', (23, 28))	('abrogated', 'NegReg', (29, 38))	('HMGA2', 'Gene', '8091', (23, 28))	('N-cadherin', 'Gene', (96, 106))	('vimentin', 'Gene', '7431', (83, 91))	('increase', 'PosReg', (64, 72))	('hsa_circ_0006948-induced', 'Gene', (39, 63))	('N-cadherin', 'Gene', '1000', (96, 106))	('HMGA2', 'Gene', '8091', (76, 81))	('knockdown', 'Var', (10, 19))	('E-cadherin', 'Gene', (124, 134))	('E-cadherin', 'Gene', '999', (124, 134))
70327	31881015	To further assess whether hsa_circ_0006948 exerts a tumor-promoting effect in vivo, a xenograft mouse model was established by subcutaneously injecting TE-1 cells (n=5 for each group).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mouse', 'Species', '10090', (96, 101))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('hsa_circ_0006948', 'Var', (26, 42))
70328	31881015	After 12 days, negative control, si-hsa_circ_0006948 and combined si-hsa_circ_0006948 and agomiR-490-3p were injected intratumorally every two days for two weeks.	('tumor', 'Disease', (123, 128))	('si-hsa_circ_0006948', 'Var', (66, 85))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('miR-490', 'Gene', '574443', (93, 100))	('miR-490', 'Gene', (93, 100))
70329	31881015	The results indicated that the tumor weight and growth rates were significantly lower in the si-hsa_circ_0006948 group than in the control group.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('growth rates', 'CPA', (48, 60))	('tumor', 'Disease', (31, 36))	('lower', 'NegReg', (80, 85))	('si-hsa_circ_0006948', 'Var', (93, 112))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
70330	31881015	Importantly, the tumor volume and weight were lower in the combined si-hsa_circ_0006948 and agomiR-490-3p group than in the si-hsa_circ_0006948 group alone.	('tumor', 'Disease', (17, 22))	('si-hsa_circ_0006948', 'Var', (68, 87))	('miR-490', 'Gene', '574443', (95, 102))	('miR-490', 'Gene', (95, 102))	('lower', 'NegReg', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
70332	31881015	The IHC results showed that the expression levels of HMGA2, N-cadherin and vimentin were significantly inhibited in the combined si-hsa_circ_0006948 and agomiR-490-3p group compared with those in control group or si- hsa_circ_0006948 group alone, which implied that silencing hsa_circ_0006948 combined with miR-490-3p overexpression exhibits an additive inhibitory effect on ESCC growth in xenograft animal models (Figure 8).	('miR-490', 'Gene', (156, 163))	('N-cadherin', 'Gene', (60, 70))	('si-hsa_circ_0006948', 'Var', (129, 148))	('miR-490', 'Gene', '574443', (307, 314))	('HMGA2', 'Gene', (53, 58))	('miR-490', 'Gene', '574443', (156, 163))	('N-cadherin', 'Gene', '1000', (60, 70))	('ESCC', 'Disease', (375, 379))	('silencing', 'Var', (266, 275))	('inhibited', 'NegReg', (103, 112))	('ESCC', 'Disease', 'MESH:C562729', (375, 379))	('vimentin', 'Gene', '7431', (75, 83))	('vimentin', 'Gene', (75, 83))	('expression levels', 'MPA', (32, 49))	('miR-490', 'Gene', (307, 314))	('HMGA2', 'Gene', '8091', (53, 58))
70336	31881015	In this study, we identified a novel circular RNA termed hsa_circ_0006948 that was up-regulated in ESCC cells and tissues, and higher expression of hsa_circ_0006948 was associated with poor survival and lymph metastasis.	('ESCC', 'Disease', 'MESH:C562729', (99, 103))	('expression', 'MPA', (134, 144))	('up-regulated', 'PosReg', (83, 95))	('poor survival', 'CPA', (185, 198))	('ESCC', 'Disease', (99, 103))	('higher', 'PosReg', (127, 133))	('hsa_circ_0006948', 'Var', (148, 164))	('lymph metastasis', 'CPA', (203, 219))
70337	31881015	Therefore, hsa_circ_0006948 might be a promising biomarker for the prognosis of ESCC.	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('ESCC', 'Disease', (80, 84))	('hsa_circ_0006948', 'Var', (11, 27))
70342	31881015	In the present study, we screened dysregulated circRNAs through microarray analysis and identified that hsa_circ_0006948 promotes proliferation, migration and invasion in vitro and induces tumor growth in vivo, and hsa_circ_0006948 was further confirmed to be an EMT-related circRNA, suggesting its tumor-aggressive effect.	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('tumor', 'Disease', (299, 304))	('induces', 'PosReg', (181, 188))	('migration', 'CPA', (145, 154))	('hsa_circ_0006948', 'Var', (104, 120))	('promotes', 'PosReg', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('invasion', 'CPA', (159, 167))	('proliferation', 'CPA', (130, 143))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('hsa_circ_0006948', 'Var', (215, 231))
70345	31881015	In the present study, hsa_circ_0006948 was confirmed to harbor miRNA-binding site predicted by bioinformatics and was located mainly in the cytoplasm.	('miR', 'Gene', (63, 66))	('miR', 'Gene', '220972', (63, 66))	('hsa_circ_0006948', 'Var', (22, 38))
70348	31881015	Further "rescue" assays suggested that the tumor suppressive roles of miR-490-3p could be partially reversed by hsa_circ_0006948, suggesting that hsa_circ_0006948 functions as a miR-490-3p sponge in ESCC.	('ESCC', 'Disease', 'MESH:C562729', (199, 203))	('miR-490', 'Gene', '574443', (178, 185))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('miR-490', 'Gene', (178, 185))	('hsa_circ_0006948', 'Var', (146, 162))	('miR-490', 'Gene', '574443', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('miR-490', 'Gene', (70, 77))	('ESCC', 'Disease', (199, 203))	('tumor', 'Disease', (43, 48))
70363	31881015	In addition, the effects of hsa_circ_0006948 on E-cadherin, vimentin and N-cadherin were reversed by overexpression of miR-490-3p in ESCC cells.	('N-cadherin', 'Gene', '1000', (73, 83))	('ESCC', 'Disease', (133, 137))	('miR-490', 'Gene', '574443', (119, 126))	('miR-490', 'Gene', (119, 126))	('hsa_circ_0006948', 'Var', (28, 44))	('vimentin', 'Gene', '7431', (60, 68))	('N-cadherin', 'Gene', (73, 83))	('E-cadherin', 'Gene', (48, 58))	('vimentin', 'Gene', (60, 68))	('E-cadherin', 'Gene', '999', (48, 58))	('ESCC', 'Disease', 'MESH:C562729', (133, 137))
70364	31881015	Furthermore, knockdown of HMGA2 could reverse hsa_circ_0006948-induced increase on vimentin and N-cadherin expression.	('hsa_circ_0006948-induced', 'Var', (46, 70))	('vimentin', 'Gene', (83, 91))	('HMGA2', 'Gene', '8091', (26, 31))	('N-cadherin', 'Gene', (96, 106))	('HMGA2', 'Gene', (26, 31))	('increase', 'PosReg', (71, 79))	('N-cadherin', 'Gene', '1000', (96, 106))	('knockdown', 'Var', (13, 22))	('vimentin', 'Gene', '7431', (83, 91))
70367	31881015	In summary, hsa_circ_0006948 was up-regulated in ESCC tissues and cells, and we found that increased hsa_circ_0006948 was associated with poor survival in ESCC patients.	('patients', 'Species', '9606', (160, 168))	('ESCC', 'Disease', 'MESH:C562729', (155, 159))	('ESCC', 'Disease', 'MESH:C562729', (49, 53))	('up-regulated', 'PosReg', (33, 45))	('ESCC', 'Disease', (49, 53))	('increased', 'PosReg', (91, 100))	('hsa_circ_0006948', 'Var', (101, 117))	('hsa_circ_0006948', 'Gene', (12, 28))	('ESCC', 'Disease', (155, 159))
70368	31881015	Furthermore, our data indicated that overexpression of hsa_circ_0006948 promotes the cancer progression and could induce EMT by enhancing HMGA2 by sponging miR-490-3p.	('miR-490', 'Gene', (156, 163))	('miR-490', 'Gene', '574443', (156, 163))	('EMT', 'CPA', (121, 124))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('hsa_circ_0006948', 'Var', (55, 71))	('cancer', 'Disease', (85, 91))	('HMGA2', 'Gene', '8091', (138, 143))	('promotes', 'PosReg', (72, 80))	('induce', 'PosReg', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('enhancing', 'PosReg', (128, 137))	('HMGA2', 'Gene', (138, 143))
70369	31881015	Our results suggested that hsa_circ_0006948 could be a vital biomarker for ESCC progression.	('ESCC', 'Disease', (75, 79))	('hsa_circ_0006948', 'Var', (27, 43))	('ESCC', 'Disease', 'MESH:C562729', (75, 79))
70383	31881015	Hsa_circ_0006948 sequences (or HMGA2-3'UTR sequences) containing wild-type or mutated miR-490-3p binding sites were synthesized and inserted into luciferase vectors respectively.	('miR-490', 'Gene', '574443', (86, 93))	('HMGA2-3', 'Gene', (31, 38))	('miR-490', 'Gene', (86, 93))	('mutated', 'Var', (78, 85))	('HMGA2-3', 'Gene', '8091', (31, 38))
70386	31881015	After being electrophoresed by SDS-PAGE, the samples were transferred to nitrocellulose membranes and incubated with primary antibodies specific for E-cadherin (diluted 1:1000, Proteintech, USA), vimentin (diluted 1:1000, ABclonal, China), N-cadherin (diluted 1:1000, ABclonal, China), HMGA2 (diluted 1:1000, ABclonal, China) and GAPDH (diluted 1:1000, ABclonal, China) at 4  C overnight.	('GAPDH', 'Gene', '2597', (330, 335))	('GAPDH', 'Gene', (330, 335))	('diluted', 'Var', (252, 259))	('N-cadherin', 'Gene', (240, 250))	('HMGA2', 'Gene', '8091', (286, 291))	('vimentin', 'Gene', '7431', (196, 204))	('SDS', 'Chemical', 'MESH:C032259', (31, 34))	('N-cadherin', 'Gene', '1000', (240, 250))	('vimentin', 'Gene', (196, 204))	('HMGA2', 'Gene', (286, 291))	('E-cadherin', 'Gene', (149, 159))	('E-cadherin', 'Gene', '999', (149, 159))
70388	31881015	After 12 days, the mice were treated with intertumoral injection of negative control, si-hsa_circ_0006948 and combined si-hsa_circ_0006948 and agomiR-490-3p every two days, respectively.	('tumor', 'Disease', (47, 52))	('si-hsa_circ_0006948', 'Var', (119, 138))	('si-hsa_circ_0006948', 'Var', (86, 105))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('miR-490', 'Gene', '574443', (146, 153))	('mice', 'Species', '10090', (19, 23))	('miR-490', 'Gene', (146, 153))
70454	30157855	In an independent study using this model to examine the tumor phenotype of a tumor-related protein kinase AKT, an obvious tumor-suppressing effect was found associated with the knockdown of AKT, such that a reduced growth rate of orthotopic tumors was readily detected.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('AKT', 'Gene', (190, 193))	('AKT', 'Gene', '207', (106, 109))	('tumor', 'Disease', (122, 127))	('orthotopic tumor', 'Disease', (230, 246))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('reduced', 'NegReg', (207, 214))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('growth rate', 'CPA', (215, 226))	('orthotopic tumor', 'Disease', 'MESH:D009369', (230, 246))	('reduced growth rate', 'Phenotype', 'HP:0001510', (207, 226))	('AKT', 'Gene', '207', (190, 193))	('tumor', 'Disease', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('knockdown', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('AKT', 'Gene', (106, 109))	('tumors', 'Disease', (241, 247))	('tumor', 'Disease', (77, 82))
70456	30157855	A comprehensive study pointed out the involvement of a cell surface molecule CD44H on tumor invasion based on the invasive patterns observed between orthotopic tumors derived from T.T ESCC cells and the invasive counterpart T.T-1 ESCC cells.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('T.T', 'Var', (180, 183))	('tumor', 'Disease', (86, 91))	('T-1', 'CellLine', 'CVCL:M858', (226, 229))	('T.T ESCC', 'CellLine', 'CVCL:R804', (180, 188))	('orthotopic tumor', 'Disease', 'MESH:D009369', (149, 165))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('involvement', 'Reg', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('orthotopic tumor', 'Disease', (149, 165))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
70480	30157855	established a panel of patient-derived tumor xenograft models and well characterized them for common genetic aberrations frequently detected in ESCC, such as HER2 expression and mutations of EGFR (epidermal growth factor receptor), K-ras, B-raf and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha).	('PIK3CA', 'Gene', (249, 255))	('HER2', 'Gene', '2064', (158, 162))	('epidermal growth factor receptor', 'Gene', '1956', (197, 229))	('PIK3CA', 'Gene', '5290', (249, 255))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('epidermal growth factor receptor', 'Gene', (197, 229))	('K-ras', 'Gene', (232, 237))	('K-ras', 'Gene', '3845', (232, 237))	('EGFR', 'Gene', (191, 195))	('ESCC', 'Disease', (144, 148))	('EGFR', 'Gene', '1956', (191, 195))	('HER2', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('mutations', 'Var', (178, 187))	('B-raf', 'Gene', (239, 244))	('B-raf', 'Gene', '673', (239, 244))	('patient', 'Species', '9606', (23, 30))
70485	30157855	Further treatment of these HER2-positive and PIK3CA-mutated tumor xenografts with AKT inhibitor AZD5363 subsequently rendered the xenografts to be responsive to trastuzumab treatment again.	('trastuzumab', 'Chemical', 'MESH:D000068878', (161, 172))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('PIK3CA', 'Gene', (45, 51))	('AKT', 'Gene', '207', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('PIK3CA', 'Gene', '5290', (45, 51))	('AZD5363', 'Chemical', 'MESH:C575618', (96, 103))	('HER2', 'Gene', (27, 31))	('tumor', 'Disease', (60, 65))	('AZD5363', 'Var', (96, 103))	('AKT', 'Gene', (82, 85))	('HER2', 'Gene', '2064', (27, 31))
70510	29531469	Chronic GER after EA repair might lead to mucosal damage, esophageal stricturing, Barrett's esophagus and eventually esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (117, 142))	('esophageal stricturing', 'Phenotype', 'HP:0002043', (58, 80))	('esophageal stricturing', 'Disease', (58, 80))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (82, 101))	("Barrett's esophagus", 'Disease', (82, 101))	('mucosal damage', 'Disease', (42, 56))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (82, 101))	('EA', 'Phenotype', 'HP:0002032', (18, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('lead to', 'Reg', (34, 41))	('Chronic GER', 'Var', (0, 11))	('esophageal adenocarcinoma', 'Disease', (117, 142))	('GER', 'Phenotype', 'HP:0002020', (8, 11))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (117, 142))	('mucosal damage', 'Disease', 'MESH:D009059', (42, 56))
70521	29531469	Chronic GER after EA repair might lead to mucosal damage, esophageal stricturing, Barrett's esophagus and eventually esophageal adenocarcinoma (EAC).	('EA', 'Phenotype', 'HP:0002032', (144, 146))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (117, 142))	('esophageal stricturing', 'Phenotype', 'HP:0002043', (58, 80))	('esophageal stricturing', 'Disease', (58, 80))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (82, 101))	("Barrett's esophagus", 'Disease', (82, 101))	('mucosal damage', 'Disease', (42, 56))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (82, 101))	('EA', 'Phenotype', 'HP:0002032', (18, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('lead to', 'Reg', (34, 41))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('Chronic GER', 'Var', (0, 11))	('esophageal adenocarcinoma', 'Disease', (117, 142))	('GER', 'Phenotype', 'HP:0002020', (8, 11))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (117, 142))	('mucosal damage', 'Disease', 'MESH:D009059', (42, 56))
70590	29531469	Chronic GER might lead to gastric and intestinal metaplasia of the squamous epithelium in the esophagus, known as Barrett's esophagus, which predisposes to dysplasia and EAC.	('EAC', 'Phenotype', 'HP:0011459', (170, 173))	('GER', 'Phenotype', 'HP:0002020', (8, 11))	('dysplasia', 'Disease', (156, 165))	('EAC', 'Disease', (170, 173))	('dysplasia', 'Disease', 'MESH:D004476', (156, 165))	('EA', 'Phenotype', 'HP:0002032', (170, 172))	('gastric', 'Disease', (26, 33))	('Chronic GER', 'Var', (0, 11))	('lead to', 'Reg', (18, 25))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (114, 133))	("Barrett's esophagus", 'Disease', (114, 133))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (114, 133))
70712	26664422	It has been shown that low intake of micronutrients, vitamins, and minerals can increase the esophageal cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('increase', 'PosReg', (80, 88))	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('low intake', 'Var', (23, 33))
70725	26664422	The inclusion criteria were as follows: Resectable T2-T3 N0-N1 disease, lack of distant metastases including celiac and supraclavicular lymph nodes, maximum age 70, Karnosfsky performance status of 70 or more, creatinine clearance >=60 mL/min, normal liver function and blood biochemistry tests, and adequate baseline hematologic parameter including neutrophil count >1500 mul and platelet count >10 x 105/mL.	('metastases', 'Disease', (88, 98))	('creatinine', 'Chemical', 'MESH:D003404', (210, 220))	('>=60', 'Var', (231, 235))	('creatinine clearance', 'MPA', (210, 230))	('neutrophil count', 'MPA', (350, 366))	('T2-T3', 'Disease', (51, 56))	('metastases', 'Disease', 'MESH:D009362', (88, 98))	('normal liver function', 'Phenotype', 'HP:0001410', (244, 265))
70728	26664422	The patients received the second course of chemotherapy if they had the neutrophil count >=1500 mul and platelet count >=10 x 105/mL, mucosal toxicity <= Grade 2, and creatinine clearance >=60 mL/min.	('>=10', 'Var', (119, 123))	('creatinine clearance', 'MPA', (167, 187))	('mucosal toxicity', 'Disease', (134, 150))	('neutrophil count', 'CPA', (72, 88))	('patients', 'Species', '9606', (4, 12))	('creatinine', 'Chemical', 'MESH:D003404', (167, 177))	('mucosal toxicity', 'Disease', 'MESH:D052016', (134, 150))
70813	19320537	ALDH2 eficiency resulting from the ALDH2 Lys487 allele contributes to both the alcohol flushing response and an elevated risk of squamous cell esophageal cancer from alcohol consumption.	('Lys487', 'Var', (41, 47))	('alcohol flushing', 'Disease', 'MESH:D005483', (79, 95))	('flushing', 'Phenotype', 'HP:0031284', (87, 95))	('ALDH2', 'Gene', (0, 5))	('ALDH2', 'Gene', '217', (35, 40))	('squamous cell esophageal cancer', 'Disease', (129, 160))	('alcohol', 'Chemical', 'MESH:D000438', (166, 173))	('alcohol', 'Chemical', 'MESH:D000438', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('squamous cell esophageal cancer', 'Disease', 'MESH:D002294', (129, 160))	('Lys487', 'Chemical', '-', (41, 47))	('flush', 'Phenotype', 'HP:0031284', (87, 92))	('alcohol flushing', 'Disease', (79, 95))	('ALDH2', 'Gene', (35, 40))	('ALDH2', 'Gene', '217', (0, 5))
70819	19320537	In East Asian populations there are two main variants of ALDH2, resulting from the replacement of glutamate (Glu) at position 487 with lysine (Lys).	('Lys', 'Chemical', 'MESH:D008239', (143, 146))	('men', 'Species', '9606', (90, 93))	('lysine', 'Chemical', 'MESH:D008239', (135, 141))	('ALDH2', 'Gene', (57, 62))	('replacement', 'Var', (83, 94))	('lysine', 'MPA', (135, 141))	('Glu', 'Chemical', 'MESH:D018698', (109, 112))	('glutamate', 'Chemical', 'MESH:D018698', (98, 107))	('glutamate', 'Protein', (98, 107))	('ALDH2', 'Gene', '217', (57, 62))
70821	19320537	As a result, Lys/Lys homozygotes have no detectable ALDH2 activity.	('activity', 'MPA', (58, 66))	('ALDH2', 'Gene', '217', (52, 57))	('Lys', 'Chemical', 'MESH:D008239', (13, 16))	('ALDH2', 'Gene', (52, 57))	('Lys/Lys', 'Var', (13, 20))	('Lys', 'Chemical', 'MESH:D008239', (17, 20))
70822	19320537	Because the Lys allele acts in a semi-dominant manner, ALDH2 Lys/Glu heterozygotes have far less than half of the ALDH2 activity of Glu/Glu homozygotes; in fact, the reduction in ALDH2 activity in heterozygotes is more than 100-fold.	('ALDH2', 'Gene', '217', (179, 184))	('activity', 'MPA', (185, 193))	('Glu', 'Chemical', 'MESH:D018698', (136, 139))	('reduction', 'NegReg', (166, 175))	('Glu', 'Chemical', 'MESH:D018698', (65, 68))	('less', 'NegReg', (92, 96))	('Glu', 'Chemical', 'MESH:D018698', (132, 135))	('ALDH2', 'Gene', (179, 184))	('Lys', 'Chemical', 'MESH:D008239', (12, 15))	('ALDH2', 'Gene', '217', (55, 60))	('ALDH2', 'Gene', '217', (114, 119))	('Lys/Glu', 'Var', (61, 68))	('Lys', 'Chemical', 'MESH:D008239', (61, 64))	('activity', 'MPA', (120, 128))	('ALDH2', 'Gene', (55, 60))	('ALDH2', 'Gene', (114, 119))
70825	19320537	Because of the intensity of this unpleasant response, ALDH2 Lys/Lys homozygotes are unable to consume significant amounts of alcohol.	('ALDH2', 'Gene', (54, 59))	('Lys', 'Chemical', 'MESH:D008239', (60, 63))	('Lys/Lys', 'Var', (60, 67))	('Lys', 'Chemical', 'MESH:D008239', (64, 67))	('ALDH2', 'Gene', '217', (54, 59))	('alcohol', 'Chemical', 'MESH:D000438', (125, 132))
70828	19320537	ALDH2 Lys/Glu heterozygotes experience a less severe manifestation of the flushing response due to residual but low ALDH2 enzyme activity in their cells.	('Lys', 'Chemical', 'MESH:D008239', (6, 9))	('Glu', 'Chemical', 'MESH:D018698', (10, 13))	('flushing', 'Phenotype', 'HP:0031284', (74, 82))	('flush', 'Phenotype', 'HP:0031284', (74, 79))	('flushing', 'Disease', (74, 82))	('ALDH2', 'Gene', (116, 121))	('low', 'NegReg', (112, 115))	('ALDH2', 'Gene', (0, 5))	('ALDH2', 'Gene', '217', (0, 5))	('flushing', 'Disease', 'MESH:D005483', (74, 82))	('activity', 'MPA', (129, 137))	('ALDH2', 'Gene', '217', (116, 121))	('Lys/Glu', 'Var', (6, 13))
70830	19320537	Therefore, paradoxically, it is the more common low-activity ALDH2 heterozygous genotype that is associated with greatest risk of esophageal cancer from drinking alcohol.	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('alcohol', 'Chemical', 'MESH:D000438', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ALDH2', 'Gene', (61, 66))	('ALDH2', 'Gene', '217', (61, 66))	('low-activity', 'Var', (48, 60))	('associated', 'Reg', (97, 107))	('esophageal cancer', 'Disease', (130, 147))
70831	19320537	Following the first study, which was conducted in the Japanese population, case control studies in Japan and Taiwan have consistently demonstrated a strong link between the risk of esophageal squamous cell carcinoma (Figure 3) and alcohol consumption in low-activity ALDH2 heterozygotes, with odds ratios (ORs) ranging from 3.7 to 18.1 after adjustment for alcohol consumption.	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('ALDH2', 'Gene', (267, 272))	('alcohol', 'Chemical', 'MESH:D000438', (231, 238))	('esophageal squamous cell carcinoma', 'Disease', (181, 215))	('men', 'Species', '9606', (348, 351))	('alcohol', 'Chemical', 'MESH:D000438', (357, 364))	('low-activity', 'Var', (254, 266))	('ALDH2', 'Gene', '217', (267, 272))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (181, 215))
70832	19320537	In the Japanese and Taiwanese studies, a strikingly high proportion (58%-69%) of the excessive risk for esophageal cancer is attributable to drinking by low-activity ALDH2 heterozygous individuals.	('low-activity', 'Var', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('ALDH2', 'Gene', '217', (166, 171))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('ALDH2', 'Gene', (166, 171))
70833	19320537	Consistent with the results of case control studies, prospective studies in cancer-free alcoholics have also shown that the relative hazard for future upper aerodigestive tract (UADT) cancers in low-activity ALDH2 heterozygotes is approximately 12 times higher than in individuals with active ALDH2.	('cancer', 'Disease', (184, 190))	('ALDH2', 'Gene', (293, 298))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('upper aerodigestive tract', 'Disease', (151, 176))	('ALDH2', 'Gene', (208, 213))	('cancers', 'Disease', (184, 191))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('alcohol', 'Chemical', 'MESH:D000438', (88, 95))	('higher', 'PosReg', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('low-activity', 'Var', (195, 207))	('UADT', 'Chemical', '-', (178, 182))	('ALDH2', 'Gene', '217', (293, 298))	('ALDH2', 'Gene', '217', (208, 213))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
70835	19320537	In addition, alcohol consumption in low-activity ALDH2 heterozygotes has been associated with other cancer-related outcomes, including the presence of multiple areas of esophageal dysplasia (i.e., premalignant lesions) and multiple independent UADT cancers.	('associated', 'Reg', (78, 88))	('low-activity', 'Var', (36, 48))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (169, 189))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('UADT cancers', 'Disease', (244, 256))	('alcohol', 'Chemical', 'MESH:D000438', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (249, 255))	('ALDH2', 'Gene', '217', (49, 54))	('UADT cancers', 'Disease', 'MESH:D006258', (244, 256))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('esophageal dysplasia', 'Disease', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('ALDH2', 'Gene', (49, 54))
70838	19320537	In rural areas of China, where there is a high rate of esophageal cancer but alcohol drinking plays a less important role than in Japan and Taiwan, there is a more modest positive association (ORs, 1.7 to 3.1) between low-activity ALDH2 heterozygotes and esophageal cancer risk (e.g.,).	('alcohol', 'Chemical', 'MESH:D000438', (77, 84))	('low-activity', 'Var', (218, 230))	('alcohol drinking', 'Phenotype', 'HP:0030955', (77, 93))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (255, 272))	('esophageal cancer', 'Disease', (55, 72))	('ALDH2', 'Gene', '217', (231, 236))	('esophageal cancer', 'Disease', 'MESH:D004938', (255, 272))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('ALDH2', 'Gene', (231, 236))
70846	19320537	Yoshida et al., 1984 Identification of the amino acid variant responsible for ALDH deficiency.	('amino acid variant', 'Var', (43, 61))	('ALDH deficiency', 'Disease', 'MESH:D007153', (78, 93))	('ALDH deficiency', 'Disease', (78, 93))
70860	19320537	In a more recent study, approximately 26% of heavy drinking (consuming more than about 400 g of ethanol per week) men in Tokyo were ALDH2 Lys487 heterozygotes.	('ALDH2', 'Gene', (132, 137))	('men', 'Species', '9606', (114, 117))	('Lys487', 'Var', (138, 144))	('ALDH2', 'Gene', '217', (132, 137))	('ethanol', 'Chemical', 'MESH:D000431', (96, 103))	('Lys487', 'Chemical', '-', (138, 144))
70878	19320537	The sensitivity, specificity, and positive predictive value for inactive ALDH2 are more than 90% in Japanese youth.	('ALDH2', 'Gene', (73, 78))	('ALDH2', 'Gene', '217', (73, 78))	('inactive', 'Var', (64, 72))
71009	30242913	Cell proliferation significantly increased or decreased in ECA109 and EC9706 (another ESCC-originating cell line) cells transfected with a PADI4-expressing plasmid or anti-PADI4 siRNA, respectively.	('EC9706', 'Var', (70, 76))	('EC9706', 'CellLine', 'CVCL:E307', (70, 76))	('increased', 'PosReg', (33, 42))	('decreased', 'NegReg', (46, 55))	('Cell proliferation', 'CPA', (0, 18))
71012	30242913	This enzymatic activity is referred as citrullination or, alternatively, as deamination.1, 2, 3, 4 An increasing amount of evidence suggests that peptidylarginine deiminase isoform 4 (PADI4), a PAD family member, is involved in tumor progression.5, 6, 7, 8, 9 We and others have demonstrated marked PADI4 overexpression in many human cancers, including cervical squamous cell carcinoma, gastric carcinoma, lung cancer, ovarian serous papillary adenocarcinoma, and papillary carcinoma of the thyroid.10, 11 Studies have shown that arginine residues R2, R8, R17, and R26 in the Histone 3 tail and the R3 residue in the Histone 4 tail can be deiminated by PADI4.	('His', 'Chemical', 'MESH:D006639', (617, 620))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('squamous cell carcinoma', 'Disease', (362, 385))	('PAD', 'Gene', (653, 656))	('cancers', 'Phenotype', 'HP:0002664', (334, 341))	('PAD', 'Gene', (184, 187))	('PAD', 'Gene', (194, 197))	('cancers', 'Disease', (334, 341))	('papillary carcinoma of the thyroid', 'Disease', (464, 498))	('gastric carcinoma', 'Disease', 'MESH:D013274', (387, 404))	('His', 'Chemical', 'MESH:D006639', (576, 579))	('R26', 'Var', (565, 568))	('arginine', 'Var', (530, 538))	('lung cancer', 'Disease', 'MESH:D008175', (406, 417))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('arginine', 'Chemical', 'MESH:D001120', (154, 162))	('gastric carcinoma', 'Disease', (387, 404))	('PAD', 'Gene', '23569', (299, 302))	('peptidylarginine deiminase isoform 4', 'Gene', '23569', (146, 182))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('ovarian serous papillary adenocarcinoma', 'Disease', 'MESH:D000231', (419, 458))	('papillary adenocarcinoma', 'Phenotype', 'HP:0006774', (434, 458))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (387, 404))	('carcinoma', 'Phenotype', 'HP:0030731', (395, 404))	('carcinoma', 'Phenotype', 'HP:0030731', (474, 483))	('lung cancer', 'Phenotype', 'HP:0100526', (406, 417))	('R17', 'Var', (556, 559))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (362, 385))	('PAD', 'Gene', (299, 302))	('peptidylarginine deiminase isoform 4', 'Gene', (146, 182))	('cancers', 'Disease', 'MESH:D009369', (334, 341))	('PAD', 'Gene', '23569', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('papillary carcinoma of the thyroid', 'Disease', 'MESH:D000077273', (464, 498))	('ovarian serous papillary adenocarcinoma', 'Disease', (419, 458))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (362, 385))	('PAD', 'Gene', '23569', (653, 656))	('carcinoma', 'Phenotype', 'HP:0030731', (449, 458))	('tumor', 'Disease', (228, 233))	('human', 'Species', '9606', (328, 333))	('PAD', 'Gene', '23569', (184, 187))	('arginine', 'Chemical', 'MESH:D001120', (530, 538))	('ovarian serous papillary', 'Phenotype', 'HP:0012887', (419, 443))	('lung cancer', 'Disease', (406, 417))
71021	30242913	The primary antibodies used in this study were against the following proteins: PADI4 (ab128086, Abcam, Cambridge, UK); GAPDH (ab181603, Abcam, Cambridge, UK); carbonic anhydrase 9 (CA9) (ab15086, Abcam); angiopoietin 1 (ANGPT1) (ab102015, Abcam); tyrosine-protein kinase receptor TIE2 (TEK) (NBP1-69753SS, NovusBiologicals, Littleton, CO); and His-tag (12698S, CST, Danvers, MA).	('NBP1', 'Gene', (292, 296))	('GAPDH', 'Gene', (119, 124))	('GAPDH', 'Gene', '2597', (119, 124))	('carbonic anhydrase 9', 'Gene', '768', (159, 179))	('His', 'Chemical', 'MESH:D006639', (344, 347))	('ab15086', 'Var', (187, 194))	('angiopoietin 1', 'Gene', '284', (204, 218))	('angiopoietin 1', 'Gene', (204, 218))	('carbonic anhydrase 9', 'Gene', (159, 179))	('12698S', 'Var', (353, 359))	('TIE2', 'Gene', '7010', (280, 284))	('NBP1', 'Gene', '4682', (292, 296))	('TIE2', 'Gene', (280, 284))
71058	30242913	Tumor weight was significantly increased in the tumors injected with PADI4-overexpressing ECA109 cells compared with that in the tumors that were established with RFP-expressing ECA109 cells (P = 0.0124) (Figure 2).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('increased', 'PosReg', (31, 40))	('tumors', 'Disease', (48, 54))	('ECA109', 'Var', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Tumor weight', 'CPA', (0, 12))	('PADI4-overexpressing ECA109', 'Var', (69, 96))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
71062	30242913	ECA109 and EC9706 cells were also transfected with anti-PADI4 siRNA, and PADI4 expression at molecular weight of 74 kDa was subsequently down-regulated in these two cell lines.	('expression', 'MPA', (79, 89))	('PADI4', 'Gene', (73, 78))	('down-regulated', 'NegReg', (137, 151))	('EC9706', 'CellLine', 'CVCL:E307', (11, 17))	('anti-PADI4', 'Var', (51, 61))
71063	30242913	The cell proliferation of ECA109 (P = 0.0144) and EC9706 (P = 0.0276) cells transfected with anti-PADI4 siRNA was significantly decreased compared with that of cells transfected with Allstars siRNA for 48 h (Figure 3B).	('EC9706', 'CellLine', 'CVCL:E307', (50, 56))	('cell proliferation', 'CPA', (4, 22))	('decreased', 'NegReg', (128, 137))	('anti-PADI4', 'Var', (93, 103))
71066	30242913	qRT-PCR detected up-regulated ANGPT1 (P = 0.0394), CA9 (P = 0.0097), and TEK (P = 0.0226) expression in the animal tumors established with a PADI4-expressing pHBLV-CMV lentivirus compared with that in the tumors established an RFP-expressing lentivirus (P < 0.0001).	('pHBLV-CMV', 'Var', (158, 167))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('ANGPT1', 'Gene', (30, 36))	('CA9', 'Gene', (51, 54))	('tumors', 'Disease', (115, 121))	('TEK', 'Gene', (73, 76))	('expression', 'MPA', (90, 100))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumors', 'Disease', (205, 211))	('up-regulated', 'PosReg', (17, 29))
71073	30242913	Tumor size and weight were significantly increased in the tumors from PADI4-overexpressing ECA109 cell injections compared with those of tumors established with cells transfected with blank lentivirus.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (137, 143))	('increased', 'PosReg', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('injections', 'Var', (103, 113))	('ECA109', 'Gene', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
71074	30242913	This observation demonstrates that PADI4 expression stimulates tumor growth in a mouse model under in vivo conditions.	('tumor', 'Disease', (63, 68))	('PADI4', 'Gene', (35, 40))	('mouse', 'Species', '10090', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('stimulates', 'PosReg', (52, 62))	('expression', 'Var', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
71076	30242913	After 24 and 48 h of incubation, cell proliferation was significantly increased in both ECA109 and EC9706 cells compared with that in cells transfected with a plasmid expressing RFP alone.	('cell proliferation', 'CPA', (33, 51))	('EC9706', 'Var', (99, 105))	('EC9706', 'CellLine', 'CVCL:E307', (99, 105))	('increased', 'PosReg', (70, 79))
71081	30242913	Meanwhile, qRT-PCR and Western blot analyses revealed a marked decrease in CA9 expression in cells transfected with anti-PADI4 siRNA, as well as the up-regulation of CA9 in mouse tumors that were established with PADI4-expressing lentivirus.	('anti-PADI4 siRNA', 'Var', (116, 132))	('expression', 'MPA', (79, 89))	('up-regulation', 'PosReg', (149, 162))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('decrease', 'NegReg', (63, 71))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('mouse', 'Species', '10090', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('CA9', 'Gene', (75, 78))
71086	30242913	McIntyre et al20 reported that CA9 promotes tumor growth in a colon cancer (HT29) and a glioblastoma (U87) cell line; Parks et al21 reported that CA9 knock down dramatically reduced growth in hypoxic conditions.	('glioblastoma', 'Disease', (88, 100))	('U87', 'CellLine', 'CVCL:0022', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('hypoxic conditions', 'Disease', (192, 210))	('colon cancer', 'Disease', (62, 74))	('HT29', 'CellLine', 'CVCL:0320', (76, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('promotes', 'PosReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('hypoxic conditions', 'Disease', 'MESH:D009135', (192, 210))	('colon cancer', 'Disease', 'MESH:D015179', (62, 74))	('CA9', 'Gene', (146, 149))	('knock down', 'Var', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('colon cancer', 'Phenotype', 'HP:0003003', (62, 74))	('reduced', 'NegReg', (174, 181))	('tumor', 'Disease', (44, 49))
71105	31096699	Moreover, earlier detection and improved prognosis have the potential to reduce the overall mortality burden from GI cancers.. Epigenetic changes, including aberrant DNA methylation, are common events in GC initiation and progression.	('GI cancers', 'Disease', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('GI cancers', 'Disease', 'MESH:D009369', (114, 124))	('GC', 'Phenotype', 'HP:0007378', (204, 206))	('aberrant DNA methylation', 'Var', (157, 181))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))
71107	31096699	Other epigenetic alterations include histone modifications, histone variants, loss of genome imprinting, chromatin remodeling and the activity of non-coding RNAs, all of which are broadly associated with carcinogenesis in humans.	('variants', 'Var', (68, 76))	('carcinogenesis', 'Disease', (204, 218))	('associated', 'Reg', (188, 198))	('histone modifications', 'CPA', (37, 58))	('chromatin remodeling', 'CPA', (105, 125))	('humans', 'Species', '9606', (222, 228))	('loss', 'NegReg', (78, 82))	('carcinogenesis', 'Disease', 'MESH:D063646', (204, 218))	('histone variants', 'Var', (60, 76))	('activity', 'MPA', (134, 142))
71109	31096699	Such variants have important roles in regulating stem cell lineage commitment and reprogramming somatic cells to a state of pluripotency.	('pluripotency', 'Disease', (124, 136))	('men', 'Species', '9606', (73, 76))	('pluripotency', 'Disease', 'None', (124, 136))	('regulating', 'Reg', (38, 48))	('variants', 'Var', (5, 13))	('reprogramming', 'CPA', (82, 95))	('stem cell lineage commitment', 'CPA', (49, 77))
71110	31096699	Changes in histone variant deposition onto chromatin affect tumorigenesis by modulating chromatin plasticity, genomic instability and cellular senescence, and triggering cancer-promoting gene expression pathways.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cellular senescence', 'CPA', (134, 153))	('cancer', 'Disease', (170, 176))	('genomic instability', 'CPA', (110, 129))	('affect', 'Reg', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('variant', 'Var', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('histone', 'Protein', (11, 18))	('triggering', 'Reg', (159, 169))	('Changes', 'Reg', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('modulating', 'Reg', (77, 87))	('chromatin', 'MPA', (88, 97))
71115	31096699	and H3.Y) variants have been identified in human somatic cells, and H2B variants (H2BFWT and TSH2B) have been identified in germ cells.	('H2B', 'Gene', '8349', (95, 98))	('H2B', 'Gene', (82, 85))	('variants', 'Var', (10, 18))	('H2BFWT', 'Gene', (82, 88))	('H2B', 'Gene', '8349', (82, 85))	('H2B', 'Gene', '8349', (68, 71))	('H2BFWT', 'Gene', '158983', (82, 88))	('H2B', 'Gene', (95, 98))	('human', 'Species', '9606', (43, 48))	('H2B', 'Gene', (68, 71))
71123	31096699	This finding could be because loss of macroH2A1 enhances stem-like properties in cancer cells, as observed in the bladder.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('enhances', 'PosReg', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('loss', 'Var', (30, 34))	('macroH2A1', 'Gene', (38, 47))
71125	31096699	In fact, this variant is downregulated in many cancer types, and this down-regulation is associated with a poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('downregulated', 'NegReg', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('down-regulation', 'NegReg', (70, 85))	('variant', 'Var', (14, 21))
71150	31096699	In the context of obesity and NAFLD, epigenetic events have a role in chromatin remodeling and plasticity in hepatocytes, as discussed below.	('plasticity', 'CPA', (95, 105))	('obesity', 'Disease', (18, 25))	('epigenetic events', 'Var', (37, 54))	('obesity', 'Phenotype', 'HP:0001513', (18, 25))	('chromatin', 'MPA', (70, 79))	('obesity', 'Disease', 'MESH:D009765', (18, 25))
71155	31096699	Silencing macroH2A1 led to global chromatin decondensation, indicating that this protein is required for stabilizing the chromatin architecture in mouse liver cells.	('Silencing', 'Var', (0, 9))	('mouse', 'Species', '10090', (147, 152))	('macroH2A1', 'Gene', (10, 19))	('global chromatin decondensation', 'MPA', (27, 58))
71163	31096699	We recently reported that C57BL/6 macroH2A1 KO mice fed a HFD exhibited ~10% reduced weight gain compared to wild-type (WT) mice, due to a decrease in body-fat mass.	('weight gain', 'Disease', 'MESH:D015430', (85, 96))	('reduced weight', 'Phenotype', 'HP:0004325', (77, 91))	('body-fat mass', 'MPA', (151, 164))	('mice', 'Species', '10090', (124, 128))	('weight gain', 'Phenotype', 'HP:0004324', (85, 96))	('reduced weight gain', 'Phenotype', 'HP:0001508', (77, 96))	('weight gain', 'Disease', (85, 96))	('reduced', 'NegReg', (77, 84))	('C57BL/6', 'Var', (26, 33))	('macroH2A1', 'Gene', (34, 43))	('mice', 'Species', '10090', (47, 51))	('decrease', 'NegReg', (139, 147))
71166	31096699	These findings diverge somewhat from those of earlier studies that rather showed that loss of macroH2A1 worsens lipid metabolism, reviewed in Reference.	('macroH2A1', 'Gene', (94, 103))	('loss', 'Var', (86, 90))	('lipid metabolism', 'MPA', (112, 128))	('worsens lipid metabolism', 'Phenotype', 'HP:0003077', (104, 128))	('worsens', 'NegReg', (104, 111))	('lipid', 'Chemical', 'MESH:D008055', (112, 117))
71168	31096699	A mild effect due to the lack of macroH2A1 was reported in several organ systems; in particular, KO mice displayed an enlarged spleen with increased lymphocyte infiltration, and mild inflammation of various tissues.	('spleen', 'CPA', (127, 133))	('increased lymphocyte', 'Phenotype', 'HP:0100827', (139, 159))	('inflammation', 'Disease', (183, 195))	('mice', 'Species', '10090', (100, 104))	('increased', 'PosReg', (139, 148))	('macroH2A1', 'Gene', (33, 42))	('lack', 'Var', (25, 29))	('enlarged', 'PosReg', (118, 126))	('lymphocyte infiltration', 'CPA', (149, 172))	('enlarged spleen', 'Phenotype', 'HP:0001744', (118, 133))	('inflammation', 'Disease', 'MESH:D007249', (183, 195))
71173	31096699	The researchers noted that loss of macroH2A1 correlated with Tbg up-regulation, leading to altered lipid metabolism and lipid accumulation in female mice during hepatic steatosis development.	('lipid', 'Chemical', 'MESH:D008055', (120, 125))	('loss', 'Var', (27, 31))	('lipid metabolism', 'MPA', (99, 115))	('macroH2A1', 'Gene', (35, 44))	('Tbg', 'Gene', '331535', (61, 64))	('lipid', 'Chemical', 'MESH:D008055', (99, 104))	('Tbg', 'Gene', (61, 64))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (161, 178))	('men', 'Species', '9606', (186, 189))	('altered', 'Reg', (91, 98))	('steatosis', 'Phenotype', 'HP:0001397', (169, 178))	('mice', 'Species', '10090', (149, 153))	('hepatic steatosis', 'Disease', (161, 178))	('hepatic steatosis', 'Disease', 'MESH:D005234', (161, 178))	('lipid accumulation', 'MPA', (120, 138))	('up-regulation', 'PosReg', (65, 78))
71181	31096699	They showed that macroH2A1.1 levels increased during adipogenesis, while macroH2A1.1 knockdown inhibited adipogenesis.	('macroH2A1.1', 'Gene', '9555', (17, 28))	('macroH2A1.1', 'Gene', (73, 84))	('inhibited', 'NegReg', (95, 104))	('adipogenesis', 'MPA', (105, 117))	('macroH2A1.1', 'Gene', '9555', (73, 84))	('increased', 'PosReg', (36, 45))	('knockdown', 'Var', (85, 94))	('adipogenesis', 'MPA', (53, 65))	('macroH2A1.1', 'Gene', (17, 28))
71187	31096699	Conversely, knockdown of the whole H2AFY transcript by siRNA resulted in the down-regulation of genes involved in FFA intake, including FATP2 and FATP4, and lipogenic genes, including SCD, FASN, and VLDLr.	('lipogenic genes', 'Gene', (157, 172))	('FATP4', 'Gene', '26569', (146, 151))	('H2AFY', 'Gene', (35, 40))	('down-regulation', 'NegReg', (77, 92))	('FASN', 'Gene', (189, 193))	('knockdown', 'Var', (12, 21))	('genes', 'MPA', (96, 101))	('FATP2', 'Gene', (136, 141))	('FASN', 'Gene', '14104', (189, 193))	('VLDLr', 'Gene', (199, 204))	('H2AFY', 'Gene', '26914', (35, 40))	('SCD', 'Gene', '20249', (184, 187))	('FATP2', 'Gene', '26458', (136, 141))	('VLDLr', 'Gene', '22359', (199, 204))	('SCD', 'Gene', (184, 187))	('FFA', 'Chemical', 'MESH:D005230', (114, 117))	('FATP4', 'Gene', (146, 151))
71195	31096699	Furthermore, macroH2A1.1, but not macroH2A1.2, knockdown inhibited adipogenesis.	('macroH2A1.1', 'Gene', '9555', (13, 24))	('inhibited', 'NegReg', (57, 66))	('knockdown', 'Var', (47, 56))	('macroH2A1.1', 'Gene', (13, 24))	('adipogenesis', 'MPA', (67, 79))
71197	31096699	This contradiction could be because this histone variant might have distinct tissue-specific functions in the liver and adipose tissue, and the lipid content in the liver is dependent on obesity/BMI, and hence the amount of lipids in excess that are mobilized from the adipose tissue.	('obesity', 'Disease', 'MESH:D009765', (187, 194))	('lipids', 'Chemical', 'MESH:D008055', (224, 230))	('lipid', 'Chemical', 'MESH:D008055', (144, 149))	('obesity', 'Disease', (187, 194))	('dependent', 'Reg', (174, 183))	('lipid', 'Chemical', 'MESH:D008055', (224, 229))	('obesity', 'Phenotype', 'HP:0001513', (187, 194))	('variant', 'Var', (49, 56))	('lipid content', 'MPA', (144, 157))
71202	31096699	For example, when macroH2A is deleted on a CB57Bl/6 background, the transgenic mice show impaired reproductive capacity and increased rate of peri-natal death that is not evident on a 129/S6 background.	('peri-natal death', 'CPA', (142, 158))	('increased', 'PosReg', (124, 133))	('macroH2A', 'Gene', (18, 26))	('transgenic mice', 'Species', '10090', (68, 83))	('reproductive capacity', 'CPA', (98, 119))	('impaired', 'NegReg', (89, 97))	('deleted', 'Var', (30, 37))
71203	31096699	Conversely, 129/S6, but not CB57Bl/6 KO, mice show signs of bilaterally increased palpebral fissure, eyelid inflammation, and a darker back compared to WT littermate controls.	('eyelid inflammation', 'Phenotype', 'HP:0000498', (101, 120))	('palpebral fissure', 'Disease', 'MESH:C537734', (82, 99))	('increased', 'PosReg', (72, 81))	('mice', 'Species', '10090', (41, 45))	('eyelid inflammation', 'Disease', 'MESH:D007249', (101, 120))	('palpebral fissure', 'Disease', (82, 99))	('129/S6', 'Var', (12, 18))	('eyelid inflammation', 'Disease', (101, 120))
71209	31096699	Molecular analyses have identified altered epigenetic processes in HCC, namely promoter-specific hypermethylation and global DNA hypomethylation.	('global DNA hypomethylation', 'MPA', (118, 144))	('promoter-specific', 'MPA', (79, 96))	('HCC', 'Gene', '619501', (67, 70))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('epigenetic processes', 'MPA', (43, 63))	('hypermethylation', 'Var', (97, 113))	('HCC', 'Gene', (67, 70))
71213	31096699	Moreover, we detected DNA hypomethylation along the whole liver disease spectrum, with a correlation between epigenetic changes occurring in HCC and macroH2A1 isoform expression.	('liver disease', 'Phenotype', 'HP:0001392', (58, 71))	('macroH2A1', 'Gene', (149, 158))	('HCC', 'Phenotype', 'HP:0001402', (141, 144))	('liver disease', 'Disease', 'MESH:D008107', (58, 71))	('HCC', 'Gene', (141, 144))	('detected', 'Reg', (13, 21))	('hypomethylation', 'Var', (26, 41))	('HCC', 'Gene', '619501', (141, 144))	('liver disease', 'Disease', (58, 71))
71216	31096699	The researchers went on to show that HCC cells over-expressing macroH2A1.1 or macroH2A1.2 developed resistance to decitabine-induced senescence through a pathway depending on p38 mitogen-activated protein kinase/interleukin (MAPK/IL8) signaling.	('macroH2A1.1', 'Gene', (63, 74))	('p38', 'Gene', '26416', (175, 178))	('IL8', 'Gene', '20309', (230, 233))	('macroH2A1.1', 'Gene', '9555', (63, 74))	('decitabine', 'Chemical', 'MESH:D000077209', (114, 124))	('HCC', 'Gene', '619501', (37, 40))	('HCC', 'Phenotype', 'HP:0001402', (37, 40))	('resistance to decitabine-induced senescence', 'MPA', (100, 143))	('IL8', 'Gene', (230, 233))	('p38', 'Gene', (175, 178))	('macroH2A1.2', 'Var', (78, 89))	('HCC', 'Gene', (37, 40))
71222	31096699	Next, to deeply understand the role of macroH2A1 in tumor differentiation, we inoculated female athymic nude mice with control (CTL), macroH2A1 knock-down (KD), or macroH2A1.1 or macroH2A1.2 over-expressing HepG2 cells.	('macroH2A1.1', 'Gene', '9555', (164, 175))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('knock-down', 'Var', (144, 154))	('tumor', 'Disease', (52, 57))	('HepG2', 'CellLine', 'CVCL:0027', (207, 212))	('macroH2A1', 'Gene', (134, 143))	('macroH2A1.1', 'Gene', (164, 175))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('nude mice', 'Species', '10090', (104, 113))
71224	31096699	On the other hand, tumor cells over-expressing macroH2A1.1 or macroH2A1.2 reached a smaller size compared to WT cells, supporting the idea that macroH2A1 expression is associated with HCC differentiation.	('macroH2A1', 'Var', (144, 153))	('macroH2A1.1', 'Gene', '9555', (47, 58))	('associated', 'Reg', (168, 178))	('HCC', 'Gene', '619501', (184, 187))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('HCC', 'Phenotype', 'HP:0001402', (184, 187))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('macroH2A1.1', 'Gene', (47, 58))	('HCC', 'Gene', (184, 187))
71226	31096699	Finally, we showed that the CSC phenotype was achieved through nuclear factor kappa-light-chain-enhancer of activated B cells nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB)p65 phosphorylation at Ser536, an oncogenic driver involved in the development of several tumors.	('p65', 'Gene', (200, 203))	('tumors', 'Disease', (290, 296))	('p65', 'Gene', '19697', (200, 203))	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('men', 'Species', '9606', (274, 277))	('Ser536', 'Var', (223, 229))	('Ser536', 'Chemical', '-', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))
71237	31096699	Using a double knock-out (DKO) macroH2A1 mouse, the researchers found that loss of macroH2A1 in the epithelium caused an increased number of ISCs compared to WT mice.	('mice', 'Species', '10090', (161, 165))	('increased', 'PosReg', (121, 130))	('mouse', 'Species', '10090', (41, 46))	('ISCs', 'Disease', (141, 145))	('loss', 'Var', (75, 79))	('macroH2A1', 'Gene', (83, 92))
71246	31096699	Nevertheless, increasing evidence suggests that macroH2A1 might instead function as a potential barrier to CRC development.	('CRC development', 'CPA', (107, 122))	('macroH2A1', 'Var', (48, 57))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('men', 'Species', '9606', (118, 121))
71252	31096699	Silencing both ZEB1 and DKK1 led to macroH2A1 up-regulation.	('up-regulation', 'PosReg', (46, 59))	('ZEB1', 'Gene', (15, 19))	('DKK1', 'Gene', (24, 28))	('DKK1', 'Gene', '13380', (24, 28))	('ZEB1', 'Gene', '21417', (15, 19))	('macroH2A1', 'Gene', (36, 45))	('Silencing', 'Var', (0, 9))
71257	31096699	H19 knockdown in HCT116 CRC cells decreased cell proliferation, with a significant reduction of cells in S phase, and an accumulation of cells in G1 phase.	('H19', 'Gene', (0, 3))	('cells in G1 phase', 'CPA', (137, 154))	('cell proliferation', 'CPA', (44, 62))	('decreased', 'NegReg', (34, 43))	('CRC', 'Phenotype', 'HP:0003003', (24, 27))	('HCT116 CRC', 'CellLine', 'CVCL:0291', (17, 27))	('accumulation', 'PosReg', (121, 133))	('cells in S phase', 'CPA', (96, 112))	('reduction', 'NegReg', (83, 92))	('knockdown', 'Var', (4, 13))
71274	31096699	MacroH2A1.1 knockdown in FET cells, a cell model obtained from an early stage human colon cancer, led to a phenotype of enhanced cell proliferation and DNA replication.	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('cell proliferation', 'CPA', (129, 147))	('colon cancer', 'Disease', 'MESH:D015179', (84, 96))	('enhanced', 'PosReg', (120, 128))	('MacroH2A1.1', 'Gene', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon cancer', 'Disease', (84, 96))	('knockdown', 'Var', (12, 21))	('DNA replication', 'CPA', (152, 167))	('MacroH2A1.1', 'Gene', '9555', (0, 11))	('human', 'Species', '9606', (78, 83))
71276	31096699	Knockdown of macroH2A1.2 led to a similar phenotype, explained by concomitant decrease in macroH2A1.1 levels following macroH2A1.2 knockdown.	('macroH2A1.1', 'Gene', (90, 101))	('macroH2A1.1', 'Gene', '9555', (90, 101))	('knockdown', 'Var', (131, 140))	('decrease', 'NegReg', (78, 86))
71277	31096699	Similar results were obtained in a murine model of lung cancer in which tumor senescence was induced by K-RasG12V.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('K-RasG12V', 'Var', (104, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('murine', 'Species', '10090', (35, 41))
71287	31096699	In conclusion, macroH2A2 expression is a predictor of a better survival rate in patients with AIN and SSC, thus, its expression may be assayed as a prognostic marker of anal neoplasm progression (Figure 2).	('neoplasm', 'Disease', 'MESH:D009369', (174, 182))	('neoplasm', 'Phenotype', 'HP:0002664', (174, 182))	('AIN', 'Phenotype', 'HP:0032187', (94, 97))	('patients', 'Species', '9606', (80, 88))	('anal neoplasm', 'Phenotype', 'HP:0032186', (169, 182))	('macroH2A2', 'Gene', (15, 24))	('better', 'PosReg', (56, 62))	('neoplasm', 'Disease', (174, 182))	('expression', 'Var', (25, 35))	('SSC', 'Disease', (102, 105))	('AIN', 'Disease', (94, 97))	('survival', 'MPA', (63, 71))
71288	31096699	This review has summarized the current knowledge regarding the roles of the histone variants macroH2A1 (with its 2 isoforms macroH2A1.1 and macroH2A1.2) and macroH2A2 as tumor suppressors or oncogenes in the GI tract.	('macroH2A1', 'Gene', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('macroH2A1.1', 'Gene', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('macroH2A1.1', 'Gene', '9555', (124, 135))	('variants', 'Var', (84, 92))
71405	30099818	Furthermore, tumors can acquire resistance to anti-EGFR antibody therapy through mutation of the EGFR antibody-binding epitopes.	('tumors', 'Disease', (13, 19))	('EGFR', 'Gene', (51, 55))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('EGFR', 'Gene', '1956', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutation', 'Var', (81, 89))	('EGFR', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('resistance', 'CPA', (32, 42))	('EGFR', 'Gene', '1956', (51, 55))
71408	30099818	This combination was selected following systematic testing of antibody combinations for the ability to inhibit cancer cell growth in vivo and in vitro.16 Unlike cetuximab and panitumumab, Sym004 can induce rapid internalization and degradation of EGFR.17 This leads to inhibition of both ligand-dependent and ligand-independent EGFR activity.	('Sym004', 'Var', (188, 194))	('internalization', 'MPA', (212, 227))	('ligand-dependent', 'Interaction', (288, 304))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('inhibition', 'NegReg', (269, 279))	('degradation', 'MPA', (232, 243))	('panitumumab', 'Chemical', 'MESH:D000077544', (175, 186))	('EGFR', 'Gene', '1956', (328, 332))	('cetuximab', 'Chemical', 'MESH:D000068818', (161, 170))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('EGFR', 'Gene', '1956', (247, 251))	('EGFR', 'Gene', (247, 251))	('EGFR', 'Gene', (328, 332))	('activity', 'MPA', (333, 341))
71456	30099818	Following the first dose and multiple doses of Sym004, dose-normalized exposure measures for the constituent antibodies mAb992 and mAb1024 were consistent among patients in Part A and Part B, indicating reasonable dose proportionality.	('mAb992', 'Gene', (120, 126))	('patients', 'Species', '9606', (161, 169))	('mAb1024', 'Var', (131, 138))
71474	30099818	We hypothesize that Sym004 may be superior to other anti-EGFR therapies tested in ESCC because Sym004 is a mixture of 2 anti-EGFR monoclonal antibodies targeting different epitopes, providing the specificity of a monoclonal antibody therapy combined with a degree of diversity.	('ESCC', 'Disease', (82, 86))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (125, 129))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', (57, 61))	('Sym004', 'Var', (95, 101))
71476	30099818	Further trials are needed to establish whether Sym004 can provide significantly greater benefit to patients with ESCC and other types of tumor compared to currently available therapies.	('ESCC', 'Disease', (113, 117))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('patients', 'Species', '9606', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('benefit', 'MPA', (88, 95))	('Sym004', 'Var', (47, 53))
71487	29757528	The median survival of patients with high HOXA13 expression was significantly shorter than those with low expression (P = 0.027).	('high', 'Var', (37, 41))	('HOXA13', 'Gene', '3209', (42, 48))	('HOXA13', 'Gene', (42, 48))	('patients', 'Species', '9606', (23, 31))	('expression', 'MPA', (49, 59))	('shorter', 'NegReg', (78, 85))
71489	29757528	Low HOXA13 expressed cells decreased the half-maximal inhibitory concentration of cisplatin (P < 0.05), increased cisplatin-induced apoptosis (P < 0.05), and decreased EMT (P < 0.05) compared with high HOXA13 expressed cells.	('HOXA13', 'Gene', (202, 208))	('decreased', 'NegReg', (158, 167))	('decreased EMT', 'Phenotype', 'HP:0032198', (158, 171))	('increased', 'PosReg', (104, 113))	('HOXA13', 'Gene', (4, 10))	('decreased', 'NegReg', (27, 36))	('HOXA13', 'Gene', '3209', (202, 208))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('HOXA13', 'Gene', '3209', (4, 10))	('cisplatin-induced apoptosis', 'MPA', (114, 141))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('half-maximal inhibitory concentration of cisplatin', 'MPA', (41, 91))	('EMT', 'CPA', (168, 171))	('Low', 'Var', (0, 3))
71492	29757528	High HOXA13 expression was associated with inferior tumor regression grade and poor overall survival in ESCC patients treated with neoadjuvant chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('inferior tumor', 'Disease', (43, 57))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (109, 117))	('ESCC', 'Disease', (104, 108))	('overall', 'MPA', (84, 91))	('HOXA13', 'Gene', (5, 11))	('expression', 'MPA', (12, 22))	('poor', 'NegReg', (79, 83))	('inferior tumor', 'Disease', 'MESH:D001932', (43, 57))	('HOXA13', 'Gene', '3209', (5, 11))
71498	29757528	HOXA10 controls migration and EMT in oral squamous cell carcinoma.16 HOXB5 promotes EMT in breast cancer cells and non-small cell lung cancer.17, 18 In addition, several markers of EMT are associated with chemoresistance, such as Snail and E-cadherin.19, 20, 21, 22 However, the relationship between HOXA13 dysregulation and chemoresistance or EMT in ESCC is not well understood.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('non-small cell lung cancer', 'Disease', (115, 141))	('HOXB5', 'Gene', (69, 74))	('HOXA10', 'Gene', '3206', (0, 6))	('Snail', 'Gene', '6615', (230, 235))	('HOXA13', 'Gene', '3209', (300, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HOXB5', 'Gene', '3215', (69, 74))	('HOXA13', 'Gene', (300, 306))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('Snail', 'Gene', (230, 235))	('HOXA10', 'Gene', (0, 6))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (119, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('E-cadherin', 'Gene', (240, 250))	('E-cadherin', 'Gene', '999', (240, 250))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (115, 141))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 65))	('breast cancer', 'Disease', (91, 104))	('oral squamous cell carcinoma', 'Disease', (37, 65))	('dysregulation', 'Var', (307, 320))
71516	29757528	Human ESCC cell lines KYSE70, KYSE150, KYSE180, KYSE450, and KYSE510 were purchased from the Cancer Hospital of the Chinese Academy of Medical Sciences (Beijing, China).	('Human', 'Species', '9606', (0, 5))	('KYSE510', 'Var', (61, 68))	('KYSE150', 'Var', (30, 37))	('KYSE180', 'Var', (39, 46))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Cancer', 'Disease', (93, 99))	('Cancer', 'Disease', 'MESH:D009369', (93, 99))
71540	29757528	RT-PCR and WB were used to determine HOXA13 expression in KYSE510 and KYSE510-HOXA13.	('HOXA13', 'Gene', (78, 84))	('HOXA13', 'Gene', '3209', (78, 84))	('expression', 'MPA', (44, 54))	('KYSE510', 'Var', (58, 65))	('HOXA13', 'Gene', (37, 43))	('HOXA13', 'Gene', '3209', (37, 43))
71541	29757528	We suspended 1 x 105 KYSE70, KYSE70-siHOXA13, KYSE510, and KYSE510-HOXA13 in 200 mul of serum-free medium.	('HOXA13', 'Gene', (38, 44))	('HOXA13', 'Gene', '3209', (38, 44))	('HOXA13', 'Gene', (67, 73))	('HOXA13', 'Gene', '3209', (67, 73))	('KYSE510', 'Var', (46, 53))
71557	29757528	The baseline expression levels of HOXA13 were determined by RT-PCR and WB in several human ESCC cell lines, including KYSE70, KYSE150, KYSE180, KYSE450, and KYSE510 (Fig 2a,b).	('HOXA13', 'Gene', (34, 40))	('HOXA13', 'Gene', '3209', (34, 40))	('KYSE510', 'Var', (157, 164))	('KYSE450', 'Var', (144, 151))	('KYSE180', 'Var', (135, 142))	('KYSE150', 'Var', (126, 133))	('KYSE70', 'Var', (118, 124))	('human', 'Species', '9606', (85, 90))
71558	29757528	KYSE70 and KYSE510 were selected for further analysis because HOXA13 expression was highest in KYSE70 and lowest in KYSE510 of the five ESCC cell lines.	('highest', 'Reg', (84, 91))	('KYSE510', 'Var', (116, 123))	('KYSE70', 'Var', (95, 101))	('HOXA13', 'Gene', (62, 68))	('HOXA13', 'Gene', '3209', (62, 68))	('lowest', 'NegReg', (106, 112))	('expression', 'MPA', (69, 79))
71561	29757528	We then tested whether HOXA13 was involved in cisplatin-induced apoptosis in KYSE70 and KYSE510.	('tested', 'Reg', (8, 14))	('HOXA13', 'Gene', (23, 29))	('HOXA13', 'Gene', '3209', (23, 29))	('KYSE510', 'Var', (88, 95))	('involved', 'Reg', (34, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))
71562	29757528	Indeed, knockdown of HOXA13 sensitized KYSE70 to cisplatin-induced apoptosis, and flow cytometry analysis demonstrated that cisplatin-induced apoptosis was significantly increased in KYSE70-siHOXA13 (Fig 3c).	('cisplatin-induced', 'MPA', (124, 141))	('HOXA13', 'Gene', (192, 198))	('HOXA13', 'Gene', '3209', (192, 198))	('knockdown', 'Var', (8, 17))	('HOXA13', 'Gene', (21, 27))	('HOXA13', 'Gene', '3209', (21, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('increased', 'PosReg', (170, 179))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))
71569	29757528	Interestingly, we found that low HOXA13 expression decreased the ability of cell invasion (Fig 4c,d).	('expression', 'MPA', (40, 50))	('low', 'Var', (29, 32))	('decreased', 'NegReg', (51, 60))	('HOXA13', 'Gene', '3209', (33, 39))	('HOXA13', 'Gene', (33, 39))
71579	29757528	To further explore the role of HOXA13 in ESCC cisplatin-chemoresistance, we knocked down HOXA13 expression by HOXA13 siRNA in KYSE70 and overexpressed HOXA13 in KYSE510.	('HOXA13', 'Gene', (89, 95))	('knocked', 'Var', (76, 83))	('HOXA13', 'Gene', (31, 37))	('HOXA13', 'Gene', (151, 157))	('HOXA13', 'Gene', '3209', (89, 95))	('HOXA13', 'Gene', '3209', (151, 157))	('expression', 'MPA', (96, 106))	('HOXA13', 'Gene', '3209', (31, 37))	('HOXA13', 'Gene', (110, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('HOXA13', 'Gene', '3209', (110, 116))	('overexpressed', 'PosReg', (137, 150))
71580	29757528	The evaluation of cisplatin-induced inhibition and apoptosis in ESCC cells revealed that low HOXA13 expression increased KYSE70 and KYSE510 sensitivity to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (18, 27))	('increased', 'PosReg', (111, 120))	('KYSE510 sensitivity to cisplatin', 'MPA', (132, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('KYSE70', 'MPA', (121, 127))	('low', 'Var', (89, 92))	('HOXA13', 'Gene', (93, 99))	('HOXA13', 'Gene', '3209', (93, 99))
71581	29757528	Furthermore, we found that the depletion of HOXA13 promoted cisplatin-induced apoptosis in KYSE70 and KYSE510.	('KYSE70', 'Var', (91, 97))	('KYSE510', 'Var', (102, 109))	('cisplatin-induced', 'MPA', (60, 77))	('HOXA13', 'Gene', '3209', (44, 50))	('promoted', 'PosReg', (51, 59))	('depletion', 'Var', (31, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('HOXA13', 'Gene', (44, 50))
71587	29757528	Transwell analysis indicated that the ability of EMT was decreased in KYSE70 and KYSE510 with low HOXA13 expression.	('KYSE510', 'Var', (81, 88))	('HOXA13', 'Gene', (98, 104))	('HOXA13', 'Gene', '3209', (98, 104))	('KYSE70', 'Var', (70, 76))	('low', 'NegReg', (94, 97))	('expression', 'MPA', (105, 115))	('decreased', 'NegReg', (57, 66))
71595	29757528	In conclusion, high HOXA13 expression was associated with inferior TRG and poor overall survival in ESCC patients treated with neoadjuvant chemotherapy.	('high', 'Var', (15, 19))	('HOXA13', 'Gene', (20, 26))	('TRG', 'Gene', '7195', (67, 70))	('patients', 'Species', '9606', (105, 113))	('TRG', 'Gene', (67, 70))	('overall survival', 'MPA', (80, 96))	('HOXA13', 'Gene', '3209', (20, 26))	('poor', 'NegReg', (75, 79))	('expression', 'MPA', (27, 37))	('inferior', 'NegReg', (58, 66))	('ESCC', 'Disease', (100, 104))
71596	29757528	Moreover, high expression enhances cisplatin-chemoresistance and promotes EMT in ESCC cell lines.	('EMT in ESCC cell lines', 'CPA', (74, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('high expression', 'Var', (10, 25))	('enhances', 'PosReg', (26, 34))	('promotes', 'PosReg', (65, 73))	('cisplatin-chemoresistance', 'MPA', (35, 60))
71658	27445460	To distinguish the influence of clinical stage, we compared the survival of different chemotherapy regimens and radiation doses among all the patients with stage III disease and showed that OS was significantly better in patients treated with the cisplatinum/paclitaxel regimen than cisplatinum/5-FU regimen (median OS, 36.0 versus 26.9 months, P=0.004).	('cisplatinum', 'Chemical', 'MESH:D002945', (247, 258))	('patients', 'Species', '9606', (221, 229))	('5-FU', 'Chemical', 'MESH:D005472', (295, 299))	('OS', 'Chemical', '-', (316, 318))	('paclitaxel', 'Chemical', 'MESH:D017239', (259, 269))	('OS', 'Chemical', '-', (190, 192))	('cisplatinum/paclitaxel', 'Var', (247, 269))	('cisplatinum', 'Chemical', 'MESH:D002945', (283, 294))	('patients', 'Species', '9606', (142, 150))	('better', 'PosReg', (211, 217))
71683	27445460	Scheer et al found that median survival times for patients with pathological CR were significantly longer than patients with residual tumor (P=0.011).	('longer', 'PosReg', (99, 105))	('patients', 'Species', '9606', (50, 58))	('pathological', 'Var', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('CR', 'Chemical', '-', (77, 79))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('patients', 'Species', '9606', (111, 119))
71721	23716126	In fact, 66 % of patients with small-bowel varices had undergone abdominal or pelvic surgery, suggesting that postoperative adhesions between an incision in the abdominal wall and the small bowel may result in the formation of collaterals drained by the systemic venous circulation.	('result in', 'Reg', (200, 209))	('small-bowel', 'Disease', 'MESH:D015212', (31, 42))	('adhesions', 'Var', (124, 133))	('patients', 'Species', '9606', (17, 25))	('small-bowel', 'Disease', (31, 42))
71735	23716126	He did not develop hemorrhages from ectopic varices, although the obliteration of a collateral vein can induce the development of other varices.	('hemorrhages', 'Disease', (19, 30))	('obliteration', 'Var', (66, 78))	('hemorrhages', 'Disease', 'MESH:D006470', (19, 30))	('collateral vein', 'Phenotype', 'HP:0025154', (84, 99))
71758	22646266	Some data indicate that HER2/neu positivity may be associated with advanced disease, suggesting a significant prognostic value of HER2/neu-status.	('HER2/neu', 'Gene', (24, 32))	('associated', 'Reg', (51, 61))	('HER2/neu', 'Gene', '2064', (130, 138))	('positivity', 'Var', (33, 43))	('advanced disease', 'Disease', (67, 83))	('HER2/neu', 'Gene', '2064', (24, 32))	('HER2/neu', 'Gene', (130, 138))
71877	32294323	4-000-100) P1000, P200, and P20 pipettor (Thermo Fisher Scientific, Cat.	('Cat', 'Gene', (68, 71))	('P20', 'Gene', (18, 21))	('Cat', 'Gene', '847', (68, 71))	('P20', 'Gene', '51673', (28, 31))	('P20', 'Gene', (28, 31))	('P20', 'Gene', '51673', (18, 21))	('P1000', 'Var', (11, 16))
71878	32294323	FA10006MTG, FA10005MTG, and FA10004MTG) Forceps (VWR, Cat.	('Cat', 'Gene', (54, 57))	('FA10004MTG', 'Var', (28, 38))	('Cat', 'Gene', '847', (54, 57))	('FA10006MTG', 'Var', (0, 10))	('FA10005MTG', 'Var', (12, 22))
71888	32294323	P1237-200) 20-muL barrier pipette tips (GeneMate, cat.	('P1237-200', 'Var', (0, 9))	('muL', 'Gene', '4591', (14, 17))	('cat', 'Gene', (50, 53))	('muL', 'Gene', (14, 17))	('cat', 'Gene', '847', (50, 53))
71902	32294323	S1049) Reconstituted Y-27632 2 HCl in DPBS, stored in aliquots at -20 C. Dissolve 1 mg or Y-27632 (MW=320.26) into 320 muL DPBS, dispense into 50 muL aliquots and store at -20 C. Thaw at room temperature prior to use.	('muL', 'Gene', (146, 149))	('muL', 'Gene', '4591', (119, 122))	('DPBS', 'Chemical', '-', (38, 42))	('Y-27632', 'Chemical', 'MESH:C108830', (21, 28))	('HCl', 'Chemical', 'MESH:D006851', (31, 34))	('Y-27632', 'Var', (90, 97))	('muL', 'Gene', (119, 122))	('Y-27632', 'Chemical', 'MESH:C108830', (90, 97))	('muL', 'Gene', '4591', (146, 149))	('DPBS', 'Chemical', '-', (123, 127))
71905	32294323	HBSS-DFCY (optional): HBSS-DF supplemented with Collagenase IV and Y-27632 Add Collagenase IV and Y-27632 into HBSS-DF to the final concentration of 20 mg/mL and 10 muM, respectively.	('HBSS-DF', 'Chemical', '-', (0, 7))	('Y-27632', 'Chemical', 'MESH:C108830', (98, 105))	('mL', 'Gene', '21832', (155, 157))	('HBSS-DF', 'Chemical', '-', (111, 118))	('HBSS-DFCY', 'Chemical', '-', (0, 9))	('Y-27632', 'Var', (67, 74))	('HBSS-DF', 'Chemical', '-', (22, 29))	('Y-27632', 'Var', (98, 105))	('Y-27632', 'Chemical', 'MESH:C108830', (67, 74))
71906	32294323	To prepare a working solution for 2 tumor sample, add 200 muL Collagenase IV (200 mg/mL) and 2 muL Y-27632 (10 mM) into 1.8 mL HBSS-DF in 15-mL conical sterile polypropylene centrifuge tube.	('muL', 'Gene', '4591', (58, 61))	('muL', 'Gene', (95, 98))	('mL', 'Gene', '21832', (141, 143))	('mL HBSS-DF', 'Disease', 'MESH:C562593', (124, 134))	('muL', 'Gene', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('Y-27632', 'Chemical', 'MESH:C108830', (99, 106))	('mL HBSS-DF', 'Disease', (124, 134))	('polypropylene', 'Chemical', 'MESH:D011126', (160, 173))	('mL', 'Gene', '21832', (124, 126))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('muL', 'Gene', '4591', (95, 98))	('Y-27632', 'Var', (99, 106))	('tumor', 'Disease', (36, 41))	('mL', 'Gene', '21832', (85, 87))
71914	32294323	T10282) Tissue specimen kept at 4 C (or on wet-ice) in a 15-mL polypropylene tube containing Basal Medium (Table 1) Transfer a tumor tissue with sterile forceps into a 60-mm cell culture dish.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('ice', 'Chemical', 'MESH:D007053', (47, 50))	('T10282', 'Chemical', '-', (0, 6))	('tumor', 'Disease', (127, 132))	('polypropylene', 'Chemical', 'MESH:D011126', (63, 76))	('mL', 'Gene', '21832', (60, 62))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('T10282', 'Var', (0, 6))
71916	32294323	Incubate for 10 min at 37 C with simultaneous mixing at 800 rpm in Thermomixer C. Optional: Collagenase IV and Y-27632 may be added into HBSS-DF (HBSS-DFCY) with an extended incubation time period for ~45 min to increase single cell yields.	('mix', 'Gene', (73, 76))	('mix', 'Gene', '83881', (46, 49))	('mix', 'Gene', (46, 49))	('mul', 'Gene', '4591', (35, 38))	('HBSS-DF', 'Chemical', '-', (146, 153))	('Y-27632', 'Var', (111, 118))	('mul', 'Gene', (35, 38))	('Y-27632', 'Chemical', 'MESH:C108830', (111, 118))	('mix', 'Gene', '83881', (73, 76))	('increase', 'PosReg', (212, 220))	('HBSS-DF', 'Chemical', '-', (137, 144))	('HBSS-DFCY', 'Chemical', '-', (146, 155))	('single cell yields', 'CPA', (221, 239))
71955	32294323	Take a necessary volume (mL) of cell suspension according to the following formula: 6x104 [cell number needed] / [cell density (/mL) from Basic Protocol 2 step 13] Transfer 6x104 cells into a 1.7-mL tube Centrifuge at 500 x g (2,300 rpm on Eppendorf 5424R) for 3 min at room temperature to pellet cells.	('mul', 'Gene', '4591', (78, 81))	('mL', 'Gene', '21832', (129, 131))	('mul', 'Gene', (78, 81))	('mL', 'Gene', '21832', (196, 198))	('6x104', 'Var', (173, 178))	('mL', 'Gene', '21832', (25, 27))
71974	32294323	Optional: for EAC PDO, supplementation of 100 ng/mL FGF-10 (Table 3) in the first week dramatically increases recovery after cryopreservation.	('supplementation', 'Var', (23, 38))	('increases', 'PosReg', (100, 109))	('mL', 'Gene', '21832', (49, 51))	('EAC', 'Phenotype', 'HP:0011459', (14, 17))	('FGF-10', 'Gene', (52, 58))	('FGF-10', 'Gene', '2255', (52, 58))	('recovery', 'MPA', (110, 118))
71983	32294323	4A): a 200-muL pipette tip modified to have a wide opening Use clean dissecting scissors and cut off ~9 mm the pointed end of 200-muL tips to make their opening wider.	('muL', 'Gene', '4591', (130, 133))	('muL', 'Gene', '4591', (11, 14))	('muL', 'Gene', (130, 133))	('muL', 'Gene', (11, 14))	('cut', 'Var', (93, 96))
71997	32294323	Add 500 muL of cold DPBS into each well, dislodge and disrupt the Matrigel mechanically by pipetting up and down 3-4 times with a P1000 pipettor with a 1,250-muL tip.	('muL', 'Gene', '4591', (158, 161))	('disrupt', 'Reg', (54, 61))	('muL', 'Gene', '4591', (8, 11))	('muL', 'Gene', (158, 161))	('dislodge', 'Var', (41, 49))	('muL', 'Gene', (8, 11))	('DPBS', 'Chemical', '-', (20, 24))
72018	32294323	SE1M179M6) Fluorescence-activated cell sorting (FACS) buffer: DPBS supplemented with 1% bovine serum albumin (BSA).	('serum albumin', 'Gene', (95, 108))	('SE1M179M6', 'Var', (0, 9))	('serum albumin', 'Gene', '213', (95, 108))	('DPBS', 'Chemical', '-', (62, 66))
72081	32294323	P-600-100) pCMVR8.74, 2nd generation lentiviral packaging plasmid (Addgene, cat.	('cat', 'Gene', (76, 79))	('P-600-100', 'Var', (0, 9))	('cat', 'Gene', '847', (76, 79))
72090	32294323	0309604) PES Syringe filter (0.45mum, 30mm, Sterile, CellTreat Scientific Products, cat.	('0.45mum', 'Var', (29, 36))	('cat', 'Gene', '847', (84, 87))	('cat', 'Gene', (84, 87))
72143	32294323	utilize advanced DMEM/F12 where they supplement CHIR99021 (GSK3beta inhibitor), FGF2, FGF10, Prostaglandin E, and forskolin that we do not use.	('FGF10', 'Gene', (86, 91))	('CHIR99021', 'Var', (48, 57))	('FGF2', 'Gene', '2247', (80, 84))	('DMEM/F12', 'Gene', '2161', (17, 25))	('Prostaglandin E', 'Chemical', 'MESH:D011458', (93, 108))	('DMEM/F12', 'Gene', (17, 25))	('FGF2', 'Gene', (80, 84))	('forskolin', 'Chemical', 'MESH:D005576', (114, 123))	('FGF10', 'Gene', '2255', (86, 91))	('GSK3beta', 'Gene', (59, 67))	('GSK3beta', 'Gene', '2931', (59, 67))
72176	32294323	Upregulation of dysfunctional tumor suppressor TP53 protein is common in both ESCC and EAC via mutant TP53 stabilization; however, some tumors display TP53 downregulation via other mechanisms (e.g.	('tumors', 'Disease', (136, 142))	('TP53', 'Gene', (102, 106))	('EAC', 'Phenotype', 'HP:0011459', (87, 90))	('TP53', 'Gene', '7157', (151, 155))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('TP53', 'Gene', '7157', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutant', 'Var', (95, 101))	('TP53', 'Gene', '7157', (102, 106))	('dysfunctional tumor', 'Disease', (16, 35))	('dysfunctional tumor', 'Disease', 'MESH:D009369', (16, 35))	('EAC', 'Disease', (87, 90))	('downregulation', 'NegReg', (156, 170))	('Upregulation', 'PosReg', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('ESCC', 'Disease', (78, 82))	('TP53', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('TP53', 'Gene', (47, 51))
72249	27013591	Predictive value of EGFR overexpression and gene amplification on icotinib efficacy in patients with advanced esophageal squamous cell carcinoma This study aimed to search for a molecular marker for targeted epithelial growth factor receptor (EGFR) inhibitor Icotinib by analyzing protein expression and amplification of EGFR proto-oncogene in esophageal squamous cell carcinoma (ESCC) patients.	('Icotinib', 'Chemical', 'MESH:C531470', (259, 267))	('EGFR', 'Gene', (20, 24))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (110, 144))	('icotinib', 'Chemical', 'MESH:C531470', (66, 74))	('esophageal squamous cell carcinoma', 'Disease', (344, 378))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (355, 378))	('EGFR', 'Gene', (321, 325))	('patients', 'Species', '9606', (386, 394))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('amplification', 'Var', (304, 317))	('EGFR', 'Gene', '1956', (243, 247))	('EGFR', 'Gene', '1956', (20, 24))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (344, 378))	('EGFR', 'Gene', '1956', (321, 325))	('esophageal squamous cell carcinoma', 'Disease', (110, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('EGFR', 'Gene', (243, 247))	('patients', 'Species', '9606', (87, 95))
72255	27013591	Among the 62 patients who received icotinib, the response rate was 17.6% for patients with high EGFR-expressing tumors, which was markedly higher than the rate (0%) for patients with low to moderate EGFR-expressing tumors (p=0.341).	('EGFR', 'Gene', '1956', (96, 100))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('patients', 'Species', '9606', (169, 177))	('EGFR', 'Gene', (199, 203))	('EGFR', 'Gene', (96, 100))	('high', 'Var', (91, 95))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', (112, 118))	('icotinib', 'Chemical', 'MESH:C531470', (35, 43))	('patients', 'Species', '9606', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', (215, 221))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('higher', 'PosReg', (139, 145))	('EGFR', 'Gene', '1956', (199, 203))
72264	27013591	EGFR expression was usually associated with more advanced tumor stage as well as reduced overall survival for patients with esophageal and esophagogastric junction adenocarcinomas.	('esophageal and esophagogastric junction adenocarcinomas', 'Disease', 'MESH:D004938', (124, 179))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EGFR', 'Gene', (0, 4))	('associated', 'Reg', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('expression', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('overall survival', 'MPA', (89, 105))	('reduced', 'NegReg', (81, 88))	('EGFR', 'Gene', '1956', (0, 4))	('patients', 'Species', '9606', (110, 118))
72279	27013591	According to the EGFR FISH analysis, gene amplification was present in 26 patients (13.5%), high polysomy in 21 (10.9%) and other conditions in 146 (75.6%).	('patients', 'Species', '9606', (74, 82))	('high polysomy', 'Var', (92, 105))	('EGFR', 'Gene', '1956', (17, 21))	('gene amplification', 'Var', (37, 55))	('EGFR', 'Gene', (17, 21))
72298	27013591	Among the 61 patients evaluated for EGFR FISH, 39 cases (63.9%) were FISH negative, and 22 cases (36.1%) were FISH positive, including 9 cases with high polysomy and 13 cases with gene amplification.	('high polysomy', 'Var', (148, 161))	('patients', 'Species', '9606', (13, 21))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (36, 40))
72300	27013591	Two of the four cases with partial response were identified as high polysomy of EGFR gene, whereas the other two were amplification of EGFR gene.	('EGFR', 'Gene', '1956', (135, 139))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('EGFR', 'Gene', (135, 139))	('high polysomy', 'Var', (63, 76))
72305	27013591	Our study reported the response rate was 17.6% for ESCC patients with high EGFR-expressing tumors, which was markedly higher than the rate (0%) for patients with low to moderate EGFR-expressing tumors.	('higher', 'PosReg', (118, 124))	('tumors', 'Disease', (91, 97))	('patients', 'Species', '9606', (148, 156))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('patients', 'Species', '9606', (56, 64))	('EGFR', 'Gene', '1956', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('EGFR', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('ESCC', 'Disease', (51, 55))	('EGFR', 'Gene', '1956', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('high', 'Var', (70, 74))	('tumors', 'Disease', (194, 200))	('EGFR', 'Gene', (75, 79))
72315	27013591	Compared with previous studies, our study retrospectively analyzed the association between EGFR overexpression and gene amplification in a larger number of ESCC patients, including metastatic cases being firstly analyzed.	('EGFR', 'Gene', (91, 95))	('gene amplification', 'Var', (115, 133))	('patients', 'Species', '9606', (161, 169))	('EGFR', 'Gene', '1956', (91, 95))	('ESCC', 'Disease', (156, 160))
72317	27013591	In their study, 9 patients with high EGFR expression (IHC 3+) demonstrated a significantly better disease control rate than the remaining 15 patients (66.7% vs. 6.7%, P=0.002).	('high', 'Var', (32, 36))	('better', 'PosReg', (91, 97))	('disease control', 'CPA', (98, 113))	('EGFR', 'Gene', '1956', (37, 41))	('patients', 'Species', '9606', (18, 26))	('EGFR', 'Gene', (37, 41))	('patients', 'Species', '9606', (141, 149))
72329	27013591	reported that K-ras mutation was identified in two (8.7%) of 23 esophageal cancer patients treated with gefitinib and was associated with early disease progression.	('K-ras', 'Gene', '3845', (14, 19))	('patients', 'Species', '9606', (82, 90))	('gefitinib', 'Chemical', 'MESH:D000077156', (104, 113))	('mutation', 'Var', (20, 28))	('associated with', 'Reg', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('K-ras', 'Gene', (14, 19))
72331	27013591	Interestingly, significantly improved survival was observed in the subgroup of patients with high EGFR/low Akt expression but not in the EGFR high/Akt high patients, suggesting that the aberrant activation of Akt (as evidenced by its high expression) by other signals may result in resistance to EGFR-targeted therapy.	('EGFR', 'Gene', (98, 102))	('EGFR', 'Gene', (137, 141))	('patients', 'Species', '9606', (156, 164))	('EGFR', 'Gene', (296, 300))	('Akt', 'Gene', (209, 212))	('result in', 'Reg', (272, 281))	('high', 'Var', (93, 97))	('Akt', 'Gene', (147, 150))	('Akt', 'Gene', (107, 110))	('Akt', 'Gene', '207', (209, 212))	('Akt', 'Gene', '207', (147, 150))	('improved', 'PosReg', (29, 37))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'Gene', '1956', (137, 141))	('Akt', 'Gene', '207', (107, 110))	('EGFR', 'Gene', '1956', (296, 300))	('aberrant', 'Var', (186, 194))	('activation', 'PosReg', (195, 205))	('patients', 'Species', '9606', (79, 87))
72332	27013591	Furthermore, the aberrant activation of several bypass pathways, including HER-2, HER-3 and C-MET pathways, also plays an important role in inducing resistance to EGFR TKI therapy.	('aberrant', 'Var', (17, 25))	('inducing', 'Reg', (140, 148))	('C-MET', 'Gene', '4233', (92, 97))	('HER-3', 'Gene', '2065', (82, 87))	('HER-3', 'Gene', (82, 87))	('HER-2', 'Gene', '2064', (75, 80))	('EGFR', 'Gene', '1956', (163, 167))	('bypass pathways', 'Pathway', (48, 63))	('activation', 'PosReg', (26, 36))	('HER-2', 'Gene', (75, 80))	('EGFR', 'Gene', (163, 167))	('C-MET', 'Gene', (92, 97))	('resistance', 'MPA', (149, 159))
72346	27013591	According to the criteria which were reported previously, signals from at least 100 cancer cell nuclei were counted and the EGFR gene copy number was classified into six subgroups: (1) disomy (2 or less copies in more than 90% of cells); (2) low trisomy (2 or less copies in 40% or more of cells, 3 copies in 10%-40% of cells, 4 or more copies in less than 10% of cells); (3) high trisomy (2 or less copies in 40% or more of cells, 3 copies in 40% or more of cells, 4 or more copies in less than 10% of cells); (4) low polysomy (4 or more copies in 10%-40% of cells); (5) high polysomy (4 or more copies in 40% or more of cells); (6) gene amplification (defined by the presence of tight EGFR gene clusters and a ratio of EGFR genes to chromosome of 2 or more, or 15 or more copies of EGFR per cell in 10% or more of the cells analyzed).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('EGFR', 'Gene', '1956', (124, 128))	('cancer', 'Disease', (84, 90))	('EGFR', 'Gene', '1956', (687, 691))	('EGFR', 'Gene', (687, 691))	('EGFR', 'Gene', (721, 725))	('gene', 'MPA', (634, 638))	('EGFR', 'Gene', '1956', (784, 788))	('high polysomy', 'Var', (572, 585))	('EGFR', 'Gene', '1956', (721, 725))	('EGFR', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('EGFR', 'Gene', (784, 788))
72347	27013591	EGFR FISH positivity was considered as high polysomy or gene amplification.	('gene amplification', 'Var', (56, 74))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
72357	22439934	Moreover, elimination of S6K1 activation by mTOR pathway inhibitor enhances the killing effects of the hedgehog pathway inhibitor.	('S6K1', 'Gene', (25, 29))	('elimination', 'Var', (10, 21))	('enhances', 'PosReg', (67, 75))	('S6K1', 'Gene', '6198', (25, 29))	('hedgehog pathway', 'Pathway', (103, 119))	('activation', 'PosReg', (30, 40))	('killing effects', 'CPA', (80, 95))
72371	22439934	Inhibition of PTCH1 releases the G-coupled receptor-like signal transducer Smoothened (SMO).	('SMO', 'Gene', '6608', (87, 90))	('Smoothened', 'Gene', '6608', (75, 85))	('PTCH1', 'Gene', (14, 19))	('SMO', 'Gene', (87, 90))	('G-coupled receptor-like signal transducer', 'MPA', (33, 74))	('Inhibition', 'Var', (0, 10))	('Smoothened', 'Gene', (75, 85))	('PTCH1', 'Gene', '5727', (14, 19))
72388	22439934	Similarly, knockdown of SMO did not inhibit the TNFalpha-induced Gli activity (Figure S1B).	('SMO', 'Gene', '6608', (24, 27))	('TNFalpha', 'Gene', (48, 56))	('inhibit', 'NegReg', (36, 43))	('SMO', 'Gene', (24, 27))	('TNFalpha', 'Gene', '7124', (48, 56))	('knockdown', 'Var', (11, 20))
72393	22439934	To further evaluate this possibility, we overexpressed wild-type mTOR or a rapamycin-resistant mTOR (mTORS2035T) in EAC cells followed by treatment of TNFalpha alone or plus rapamycin.	('mTORS2035T', 'Var', (101, 111))	('overexpressed', 'PosReg', (41, 54))	('TNFalpha', 'Gene', (151, 159))	('EAC', 'Phenotype', 'HP:0011459', (116, 119))	('rapamycin', 'Chemical', 'MESH:D020123', (75, 84))	('TNFalpha', 'Gene', '7124', (151, 159))	('rapamycin', 'Chemical', 'MESH:D020123', (174, 183))
72394	22439934	Western blot results confirmed that rapamycin blocked activation of mTOR pathway in mTOR-overexpressed cells but not in mTORS2035T-overexpressed cells (Figure S1D).	('rapamycin', 'Chemical', 'MESH:D020123', (36, 45))	('mTOR-overexpressed', 'Var', (84, 102))	('mTOR pathway', 'Pathway', (68, 80))
72397	22439934	Although Gli1, Gli2, and Gli3 all can regulate the expression of the Gli reporter, only Gli1 knock-down impaired the TNFalpha-stimulated expression of Gli reporter (Figure S1E), which suggests that TNFalpha selectively activated Gli1.	('Gli2', 'Gene', (15, 19))	('impaired', 'NegReg', (104, 112))	('Gli3', 'Gene', (25, 29))	('expression', 'MPA', (137, 147))	('TNFalpha', 'Gene', (117, 125))	('Gli1', 'Gene', (88, 92))	('Gli2', 'Gene', '2736', (15, 19))	('TNFalpha', 'Gene', '7124', (117, 125))	('expression', 'MPA', (51, 61))	('TNFalpha', 'Gene', (198, 206))	('regulate', 'Reg', (38, 46))	('Gli reporter', 'Gene', (69, 81))	('knock-down', 'Var', (93, 103))	('Gli3', 'Gene', '2737', (25, 29))	('TNFalpha', 'Gene', '7124', (198, 206))
72416	22439934	The results indicated that the TNFalpha-stimulated Gli1 activity and expression of Gli target genes were impeded by S6K1 knock-down (Figure 2F and 2G).	('S6K1', 'Gene', '6198', (116, 120))	('Gli1', 'Gene', (51, 55))	('TNFalpha', 'Gene', (31, 39))	('S6K1', 'Gene', (116, 120))	('impeded', 'NegReg', (105, 112))	('TNFalpha', 'Gene', '7124', (31, 39))	('expression', 'MPA', (69, 79))	('knock-down', 'Var', (121, 131))
72423	22439934	We identified 79-KKRALS-84 (Figure S3A), which is highly conserved from fruit fly to human (Figure 3C), as one potential S6K1-recognizing motif (K/RxRxxS/T) in Gli1F1.	('K/RxRxxS/T', 'Var', (145, 155))	('fruit fly', 'Species', '7227', (72, 81))	('S6K1', 'Gene', (121, 125))	('S6K1', 'Gene', '6198', (121, 125))	('Gli1F1', 'Gene', (160, 166))	('human', 'Species', '9606', (85, 90))
72424	22439934	When Ser84 was mutated to alanine (Gli1S84A), phosphorylation of Gli1 by S6K1 disappeared (Figure 3D), suggesting that the Ser84 in Gli1 is the site phosphorylated by S6K1 in vitro.	('S6K1', 'Gene', '6198', (167, 171))	('Ser84', 'Chemical', '-', (123, 128))	('Ser84', 'Var', (5, 10))	('disappeared', 'NegReg', (78, 89))	('Ser84 was mutated to alanine', 'Mutation', 'p.S84A', (5, 33))	('S6K1', 'Gene', (73, 77))	('S6K1', 'Gene', '6198', (73, 77))	('Ser84', 'Chemical', '-', (5, 10))	('phosphorylation', 'MPA', (46, 61))	('S6K1', 'Gene', (167, 171))
72428	22439934	To further investigate endogenous Gli1 phosphorylation by TNFalpha or S6K1, we developed a mouse polyclonal antibody that specifically recognizes phosphorylated Ser84 of Gli1 (p-Gli1S84).	('Ser84', 'Chemical', '-', (161, 166))	('TNFalpha', 'Gene', (58, 66))	('TNFalpha', 'Gene', '7124', (58, 66))	('Ser84', 'Var', (161, 166))	('S6K1', 'Gene', (70, 74))	('S6K1', 'Gene', '6198', (70, 74))	('mouse', 'Species', '10090', (91, 96))
72430	22439934	Using this antibody, we found that TNFalpha stimulation or S6K1 ectopic expression effectively induced Gli1 Ser84 phosphorylation (Figure 3E), which was diminished by the addition of rapamycin (Figure 3E).	('rapamycin', 'Chemical', 'MESH:D020123', (183, 192))	('S6K1', 'Gene', (59, 63))	('induced', 'Reg', (95, 102))	('TNFalpha', 'Gene', (35, 43))	('S6K1', 'Gene', '6198', (59, 63))	('Ser84', 'Chemical', '-', (108, 113))	('Gli1', 'Protein', (103, 107))	('TNFalpha', 'Gene', '7124', (35, 43))	('ectopic expression', 'Var', (64, 82))
72431	22439934	The TNFalpha-stimulated phosphorylation of Gli1 was largely inhibited when S6K1 was knocked down by siRNA targeting 3'UTR, but could be effectively rescued by exogenous S6K1 (Figure 3G).	('S6K1', 'Gene', '6198', (75, 79))	('TNFalpha', 'Gene', (4, 12))	('TNFalpha', 'Gene', '7124', (4, 12))	('inhibited', 'NegReg', (60, 69))	('knocked down', 'Var', (84, 96))	('phosphorylation', 'MPA', (24, 39))	('Gli1', 'Gene', (43, 47))	('S6K1', 'Gene', (169, 173))	('S6K1', 'Gene', '6198', (169, 173))	('S6K1', 'Gene', (75, 79))
72434	22439934	We detected clear signals of p-Gli1S84 in BE3 and OE33 (Figure S3D) and knock-down of Gli1 impaired the TNFalpha-stimulated as well as S6K1 ectopic expression-increased cell viability, proliferation, and invasion (Figure S3E and S3F).	('proliferation', 'CPA', (185, 198))	('invasion', 'CPA', (204, 212))	('TNFalpha', 'Gene', (104, 112))	('impaired', 'NegReg', (91, 99))	('Gli1', 'Gene', (86, 90))	('BE', 'Chemical', 'MESH:D001608', (42, 44))	('p-Gli1S84', 'Var', (29, 38))	('cell viability', 'CPA', (169, 183))	('rat', 'Species', '10116', (192, 195))	('knock-down', 'Var', (72, 82))	('TNFalpha', 'Gene', '7124', (104, 112))	('expression-increased', 'PosReg', (148, 168))	('S6K1', 'Gene', (135, 139))	('S6K1', 'Gene', '6198', (135, 139))
72443	22439934	Although knock-down of mTOR or raptor impaired the TNFalpha-mediated Gli1 phosphorylation and activation, knock-down of rictor did not (Figure 3H and S3I), indicating that only mTORC1 plays a role in the regulation of Gli1.	('phosphorylation', 'MPA', (74, 89))	('raptor', 'Gene', '57521', (31, 37))	('mTORC1', 'Gene', (177, 183))	('mTORC1', 'Gene', '382056', (177, 183))	('TNFalpha', 'Gene', (51, 59))	('activation', 'MPA', (94, 104))	('mTOR', 'Gene', (23, 27))	('TNFalpha', 'Gene', '7124', (51, 59))	('knock-down', 'Var', (9, 19))	('raptor', 'Gene', (31, 37))	('impaired', 'NegReg', (38, 46))
72445	22439934	We established BE3 stable clones with Gli1 knock-down (Figure 4A), and as expected, transcription of Gli1 target genes decreased with Gli1 knock-down (Figure 4B).	('decreased', 'NegReg', (119, 128))	('transcription', 'MPA', (84, 97))	('Gli1', 'Gene', (134, 138))	('knock-down', 'Var', (139, 149))	('Gli1', 'Gene', (38, 42))	('knock-down', 'Var', (43, 53))	('BE', 'Chemical', 'MESH:D001608', (15, 17))
72446	22439934	Moreover, Gli1 knock-down also decreased cell proliferation (Figure 4C and 4D), migration (Figure S4A), invasion (Figure S4B), and anchorage-independent growth ability (Figure S4C).	('rat', 'Species', '10116', (83, 86))	('Gli1', 'Gene', (10, 14))	('anchorage-independent growth ability', 'CPA', (131, 167))	('cell proliferation', 'CPA', (41, 59))	('migration', 'CPA', (80, 89))	('decreased', 'NegReg', (31, 40))	('rat', 'Species', '10116', (53, 56))	('knock-down', 'Var', (15, 25))	('invasion', 'CPA', (104, 112))
72447	22439934	Then, to understand the effects of Ser84 phosphorylation on Gli1 function, we generated stable clones of BE3 cells expressing wild-type Gli1 (BE3/Gli1), Gli1S84A (BE3/S84A), Gli1S84E (BE3/S84E), or with the empty vector (BE3/EV).	('BE', 'Chemical', 'MESH:D001608', (105, 107))	('BE3/Gli1', 'Gene', (142, 150))	('S84A', 'Mutation', 'p.S84A', (167, 171))	('S84E', 'Mutation', 'p.S84E', (188, 192))	('S84A', 'Mutation', 'p.S84A', (157, 161))	('Ser84', 'Chemical', '-', (35, 40))	('Gli1S84A', 'Var', (153, 161))	('BE3/Gli1', 'Gene', '2735', (142, 150))	('BE', 'Chemical', 'MESH:D001608', (184, 186))	('S84E', 'Mutation', 'p.S84E', (178, 182))	('Gli1S84E', 'Var', (174, 182))	('BE', 'Chemical', 'MESH:D001608', (163, 165))	('rat', 'Species', '10116', (82, 85))	('BE', 'Chemical', 'MESH:D001608', (142, 144))	('BE', 'Chemical', 'MESH:D001608', (221, 223))
72448	22439934	For Gli1S84E, Ser84 was mutated into glutamine to mimic constitutive phosphorylation of Gli1 at Ser84.	('mutated', 'Var', (24, 31))	('Ser84 was mutated into glutamine', 'Mutation', 'p.S84Q', (14, 46))	('Ser84', 'Chemical', '-', (14, 19))	('Ser84', 'Chemical', '-', (96, 101))	('Ser84', 'Var', (14, 19))
72449	22439934	We found that with similar Gli1 expression levels, BE3/S84E bore much higher Gli1 transcriptional activity and mRNA levels of Gli1 target genes among all the stable clones (Figure 5A and 5B).	('mRNA levels', 'MPA', (111, 122))	('BE', 'Chemical', 'MESH:D001608', (51, 53))	('BE3/S84E', 'Var', (51, 59))	('Gli1', 'Gene', (77, 81))	('S84E', 'Mutation', 'p.S84E', (55, 59))	('higher', 'PosReg', (70, 76))	('transcriptional activity', 'MPA', (82, 106))
72450	22439934	Consistently, the immunofluorescence staining showed that the level of nuclear Gli1 was much higher in BE3/S84E cells than BE3/Gli1 and BE3/S84A (Figure 5C).	('higher', 'PosReg', (93, 99))	('BE', 'Chemical', 'MESH:D001608', (136, 138))	('BE', 'Chemical', 'MESH:D001608', (123, 125))	('BE', 'Chemical', 'MESH:D001608', (103, 105))	('S84A', 'Mutation', 'p.S84A', (140, 144))	('BE3/S84E', 'Var', (103, 111))	('S84E', 'Mutation', 'p.S84E', (107, 111))	('BE3/Gli1', 'Gene', '2735', (123, 131))	('BE3/Gli1', 'Gene', (123, 131))
72451	22439934	To further confirm that the functional difference was due to the mutations of Gli1, we treated these cells with TNFalpha alone or together with rapamycin and found that TNFalpha markedly induced the Gli1 transcriptional activity in BE3/Gli1, which was inhibited by co-treatment of rapamycin, but did not affect the Gli1 activity in BE3/S84E and BE3/S84A (Figure S5A).	('Gli1', 'Gene', (199, 203))	('TNFalpha', 'Gene', '7124', (169, 177))	('BE', 'Chemical', 'MESH:D001608', (332, 334))	('TNFalpha', 'Gene', '7124', (112, 120))	('S84E', 'Mutation', 'p.S84E', (336, 340))	('S84A', 'Mutation', 'p.S84A', (349, 353))	('rapamycin', 'Chemical', 'MESH:D020123', (144, 153))	('rapamycin', 'Chemical', 'MESH:D020123', (281, 290))	('BE', 'Chemical', 'MESH:D001608', (345, 347))	('induced', 'PosReg', (187, 194))	('BE3/Gli1', 'Gene', (232, 240))	('TNFalpha', 'Gene', (169, 177))	('TNFalpha', 'Gene', (112, 120))	('BE3/Gli1', 'Gene', '2735', (232, 240))	('mutations', 'Var', (65, 74))	('BE', 'Chemical', 'MESH:D001608', (232, 234))
72452	22439934	The results suggest that both S84E and S84A mutants were insensitive to TNFalpha stimulation.	('S84A', 'Mutation', 'p.S84A', (39, 43))	('S84E', 'Mutation', 'p.S84E', (30, 34))	('TNFalpha', 'Gene', (72, 80))	('TNFalpha', 'Gene', '7124', (72, 80))	('S84E', 'Var', (30, 34))	('S84A', 'Var', (39, 43))
72453	22439934	The immunofluorescence staining also showed that in BE3/Gli1 was Gli1 nuclear localization induced by TNFalpha, but in BE3/S84E or BE3/S84A, Gli1 distribution was not obviously changed by TNFalpha (Figure 5C and Figure S5B).	('BE3/S84E', 'Var', (119, 127))	('S84E', 'Mutation', 'p.S84E', (123, 127))	('induced', 'Reg', (91, 98))	('BE3/S84A', 'Var', (131, 139))	('TNFalpha', 'Gene', '7124', (102, 110))	('TNFalpha', 'Gene', '7124', (188, 196))	('BE', 'Chemical', 'MESH:D001608', (119, 121))	('BE3/Gli1', 'Gene', '2735', (52, 60))	('BE3/Gli1', 'Gene', (52, 60))	('BE', 'Chemical', 'MESH:D001608', (52, 54))	('Gli1 nuclear localization', 'MPA', (65, 90))	('BE', 'Chemical', 'MESH:D001608', (131, 133))	('TNFalpha', 'Gene', (188, 196))	('TNFalpha', 'Gene', (102, 110))	('S84A', 'Mutation', 'p.S84A', (135, 139))
72454	22439934	Moreover, the p-Gli1S84 level also increased with TNFalpha stimulation but gradually decreased with increased rapamycin dose (Figure S5C).	('rapamycin', 'Chemical', 'MESH:D020123', (110, 119))	('increased', 'PosReg', (35, 44))	('TNFalpha', 'Gene', '7124', (50, 58))	('p-Gli1S84 level', 'MPA', (14, 29))	('TNFalpha', 'Gene', (50, 58))	('stimulation', 'Var', (59, 70))
72455	22439934	Taken together, TNFalpha-stimulated S84 phosphorylation increases Gli1 nuclear localization and transcriptional activity, and S84E and S84A mutants, mimicking phosphorylated and non-phosphorylated Gli1, respectively, are no longer sensitive to TNFalpha.	('transcriptional activity', 'CPA', (96, 120))	('TNFalpha', 'Gene', '7124', (16, 24))	('increases', 'PosReg', (56, 65))	('S84', 'Var', (36, 39))	('TNFalpha', 'Gene', (244, 252))	('Gli1', 'Protein', (66, 70))	('nuclear localization', 'MPA', (71, 91))	('S84E', 'Mutation', 'p.S84E', (126, 130))	('S84A', 'Var', (135, 139))	('TNFalpha', 'Gene', '7124', (244, 252))	('TNFalpha', 'Gene', (16, 24))	('S84E', 'Var', (126, 130))	('S84A', 'Mutation', 'p.S84A', (135, 139))
72457	22439934	Gli1S84E and wild-type Gli1, but not Gli1S84A, increased cell proliferation (Figure S5D).	('S84A', 'Mutation', 'p.S84A', (41, 45))	('cell proliferation', 'CPA', (57, 75))	('increased', 'PosReg', (47, 56))	('rat', 'Species', '10116', (69, 72))	('Gli1S84E', 'Var', (0, 8))
72458	22439934	The Gli1S84E stable clones also exhibited the highest level of colony formation activity in soft-agar assay (Figure S5E).	('Gli1S84E', 'Var', (4, 12))	('agar', 'Chemical', 'MESH:D000362', (97, 101))	('colony formation activity', 'CPA', (63, 88))
72459	22439934	BE3/S84E exhibited much higher invasive ability than BE3/Gli1 and BE3/S84A (Figure S5F).	('BE', 'Chemical', 'MESH:D001608', (0, 2))	('BE3/S84E', 'Var', (0, 8))	('BE', 'Chemical', 'MESH:D001608', (66, 68))	('higher', 'PosReg', (24, 30))	('S84E', 'Mutation', 'p.S84E', (4, 8))	('S84A', 'Mutation', 'p.S84A', (70, 74))	('BE3/Gli1', 'Gene', (53, 61))	('BE3/Gli1', 'Gene', '2735', (53, 61))	('invasive ability', 'CPA', (31, 47))	('BE', 'Chemical', 'MESH:D001608', (53, 55))
72460	22439934	These results support that the phosphorylation of Gli1 at Ser84 enhances Gli1 function.	('Ser84', 'Chemical', '-', (58, 63))	('enhances', 'PosReg', (64, 72))	('Gli1', 'Gene', (50, 54))	('Gli1', 'CPA', (73, 77))	('Ser84', 'Var', (58, 63))	('phosphorylation', 'Var', (31, 46))	('function', 'MPA', (78, 86))
72466	22439934	Consistent with our in vitro data, BE3/S84E had the strongest tumorigenicity among all stable cells.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('S84E', 'Mutation', 'p.S84E', (39, 43))	('tumor', 'Disease', (62, 67))	('BE', 'Chemical', 'MESH:D001608', (35, 37))	('BE3/S84E', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
72468	22439934	BE3/EV and BE3/S84A induced only small tumor formation (Figure 5D and Figure S5J).	('BE3/S84A', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('BE', 'Chemical', 'MESH:D001608', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('BE', 'Chemical', 'MESH:D001608', (11, 13))	('tumor', 'Disease', (39, 44))	('BE3/EV', 'Var', (0, 6))	('S84A', 'Mutation', 'p.S84A', (15, 19))
72471	22439934	We therefore investigated whether Gli1 Ser84 phosphorylation affects its binding with SuFu.	('SuFu', 'Gene', '51684', (86, 90))	('Ser84', 'Var', (39, 44))	('SuFu', 'Gene', (86, 90))	('binding', 'Interaction', (73, 80))	('Ser84', 'Chemical', '-', (39, 44))
72472	22439934	Co-immunoprecipitation experiment showed that the interaction between SuFu and Gli1 was markedly decreased in BE3/S84E compared with BE3/Gli1 and BE3/S84A at similar total level of SuFu (Figure 5E), which suggested that the Ser84 phosphorylation in Gli1 possibly reduced its binding to SuFu.	('binding', 'Interaction', (275, 282))	('Ser84', 'Chemical', '-', (224, 229))	('BE3/S84E', 'Var', (110, 118))	('decreased', 'NegReg', (97, 106))	('BE', 'Chemical', 'MESH:D001608', (110, 112))	('SuFu', 'Gene', (286, 290))	('BE', 'Chemical', 'MESH:D001608', (133, 135))	('S84A', 'Mutation', 'p.S84A', (150, 154))	('Ser84 phosphorylation', 'Var', (224, 245))	('reduced', 'NegReg', (263, 270))	('BE3/Gli1', 'Gene', '2735', (133, 141))	('BE3/Gli1', 'Gene', (133, 141))	('SuFu', 'Gene', (181, 185))	('SuFu', 'Gene', '51684', (286, 290))	('SuFu', 'Gene', (70, 74))	('interaction', 'Interaction', (50, 61))	('SuFu', 'Gene', '51684', (181, 185))	('BE', 'Chemical', 'MESH:D001608', (146, 148))	('Gli1', 'Gene', (79, 83))	('SuFu', 'Gene', '51684', (70, 74))	('S84E', 'Mutation', 'p.S84E', (114, 118))
72474	22439934	Furthermore, both TNFalpha treatment and S6K1 ectopic expression decreased the binding between SuFu and Gli1, which was fully reversed by rapamycin administration (Figure 5F).	('rat', 'Species', '10116', (156, 159))	('S6K1', 'Gene', (41, 45))	('S6K1', 'Gene', '6198', (41, 45))	('decreased', 'NegReg', (65, 74))	('TNFalpha', 'Gene', (18, 26))	('ectopic expression', 'Var', (46, 64))	('binding', 'Interaction', (79, 86))	('SuFu', 'Gene', '51684', (95, 99))	('TNFalpha', 'Gene', '7124', (18, 26))	('SuFu', 'Gene', (95, 99))	('rapamycin', 'Chemical', 'MESH:D020123', (138, 147))
72485	22439934	All p-Gli1-positive tissues are also Gli1-positive, and among the Gli1-positive tissues, there is also a strong positive correlation between p-Gli1 and p-S6K1 (Figure 6G).	('S6K1', 'Gene', (154, 158))	('p-Gli1', 'Var', (141, 147))	('S6K1', 'Gene', '6198', (154, 158))	('p-Gli1-positive', 'Var', (4, 19))
72491	22439934	As expected, the IC50 value of cyclopamine or GDC-0449 in BE3/S84E was much higher than that for BE3/EV, BE3/Gli1, and BE3/S84A (Figure 7C).	('BE', 'Chemical', 'MESH:D001608', (105, 107))	('BE', 'Chemical', 'MESH:D001608', (119, 121))	('BE', 'Chemical', 'MESH:D001608', (58, 60))	('S84A', 'Mutation', 'p.S84A', (123, 127))	('GDC-0449', 'Gene', (46, 54))	('BE3/S84E', 'Var', (58, 66))	('BE3/Gli1', 'Gene', '2735', (105, 113))	('BE3/Gli1', 'Gene', (105, 113))	('S84E', 'Mutation', 'p.S84E', (62, 66))	('IC50 value', 'MPA', (17, 27))	('BE', 'Chemical', 'MESH:D001608', (97, 99))	('cyclopamine', 'Chemical', 'MESH:C000541', (31, 42))	('higher', 'PosReg', (76, 82))	('GDC-0449', 'Chemical', 'MESH:C538724', (46, 54))
72492	22439934	Moreover, TNFalpha treatment increased the resistance of BE3/Gli1, but not BE3/S84A, to cyclopamine or GDC-0449 (Figure 7D), suggesting that Gli1S84 phosphorylation enhances cell resistance to SMO inhibitors.	('TNFalpha', 'Gene', (10, 18))	('cyclopamine', 'Chemical', 'MESH:C000541', (88, 99))	('Gli1S84 phosphorylation', 'Var', (141, 164))	('resistance', 'MPA', (43, 53))	('SMO', 'Gene', '6608', (193, 196))	('SMO', 'Gene', (193, 196))	('increased', 'PosReg', (29, 38))	('BE', 'Chemical', 'MESH:D001608', (75, 77))	('S84A', 'Mutation', 'p.S84A', (79, 83))	('enhances', 'PosReg', (165, 173))	('TNFalpha', 'Gene', '7124', (10, 18))	('GDC-0449', 'Chemical', 'MESH:C538724', (103, 111))	('BE3/Gli1', 'Gene', '2735', (57, 65))	('BE3/Gli1', 'Gene', (57, 65))	('BE', 'Chemical', 'MESH:D001608', (57, 59))	('phosphorylation', 'Var', (149, 164))
72496	22439934	Moreover, knock-down of SMO also inhibited cell viability, and rapamycin treatment further enhanced the inhibitory effect (Figure S7C).	('SMO', 'Gene', '6608', (24, 27))	('inhibitory effect', 'MPA', (104, 121))	('inhibited', 'NegReg', (33, 42))	('SMO', 'Gene', (24, 27))	('knock-down', 'Var', (10, 20))	('rapamycin', 'Chemical', 'MESH:D020123', (63, 72))	('cell viability', 'CPA', (43, 57))	('enhanced', 'PosReg', (91, 99))
72499	22439934	For further examining the crosstalk of mTOR and HH pathways in vivo, we performed an in vivo combination therapy using GDC-0449 and another mTOR inhibitor, RAD-001, which is widely used in combination with other anti-tumor drugs in clinical trials.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('GDC-0449', 'Chemical', 'MESH:C538724', (119, 127))	('GDC-0449', 'Var', (119, 127))	('RAD-001', 'Disease', 'MESH:C535729', (156, 163))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('RAD-001', 'Disease', (156, 163))
72500	22439934	We subcutaneously inoculated mice with BE3 cells and treated them with GDC-0449, RAD-001, or both, and found that though low dose RAD001 did not inhibit tumor growth, it enhanced the tumor-inhibitory effect of GDC-0449 (Figure 7G).	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('RAD-001', 'Disease', (81, 88))	('GDC-0449', 'Chemical', 'MESH:C538724', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('RAD001', 'Var', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('GDC-0449', 'Chemical', 'MESH:C538724', (210, 218))	('enhanced', 'PosReg', (170, 178))	('RAD-001', 'Disease', 'MESH:C535729', (81, 88))	('tumor', 'Disease', (183, 188))	('BE', 'Chemical', 'MESH:D001608', (39, 41))	('mice', 'Species', '10090', (29, 33))
72504	22439934	Through ectopic expression of AKT or ERK, we found that Gli1 activity increased, which could be blocked by rapamycin (Figure S8).	('ectopic expression', 'Var', (8, 26))	('increased', 'PosReg', (70, 79))	('ERK', 'Gene', '5594', (37, 40))	('Gli1', 'Gene', (56, 60))	('ERK', 'Gene', (37, 40))	('AKT', 'Gene', '207', (30, 33))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('activity', 'MPA', (61, 69))	('AKT', 'Gene', (30, 33))	('rapamycin', 'Chemical', 'MESH:D020123', (107, 116))
72506	22439934	However, AKT and ERK lost the ability to induce Gli1 phosphorylation when S6K1 was knocked down (Figure 8B).	('S6K1', 'Gene', '6198', (74, 78))	('AKT', 'Gene', '207', (9, 12))	('lost', 'NegReg', (21, 25))	('ability', 'MPA', (30, 37))	('induce Gli1 phosphorylation', 'MPA', (41, 68))	('knocked down', 'Var', (83, 95))	('ERK', 'Gene', '5594', (17, 20))	('AKT', 'Gene', (9, 12))	('ERK', 'Gene', (17, 20))	('S6K1', 'Gene', (74, 78))
72515	22439934	Function-loss-mutation of SuFu has been shown to result in tumorigenesis due to the aberrant activation of the HH pathway.	('Function-loss-mutation', 'Var', (0, 22))	('activation', 'PosReg', (93, 103))	('tumor', 'Disease', (59, 64))	('SuFu', 'Gene', (26, 30))	('SuFu', 'Gene', '51684', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('HH pathway', 'Pathway', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
72519	22439934	In fact, SMO inhibitors, such as cyclopamine and GDC-0449, had little effects on the mTOR/S6K1-mediated Gli1 activation.	('cyclopamine', 'Chemical', 'MESH:C000541', (33, 44))	('SMO', 'Gene', '6608', (9, 12))	('activation', 'PosReg', (109, 119))	('mTOR/S6K1', 'Gene', '21977;72508', (85, 94))	('GDC-0449', 'Chemical', 'MESH:C538724', (49, 57))	('SMO', 'Gene', (9, 12))	('GDC-0449', 'Var', (49, 57))	('mTOR/S6K1', 'Gene', (85, 94))
72523	22439934	Our data showed that the administration of GDC-0449 indeed decreased the EAC tumor size, supporting that GDC-0449 could also be used for treating EAC (Figure 7G).	('EAC', 'Disease', (73, 76))	('EAC', 'Disease', (146, 149))	('GDC-0449', 'Chemical', 'MESH:C538724', (43, 51))	('decreased', 'NegReg', (59, 68))	('GDC-0449', 'Var', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('rat', 'Species', '10116', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('EAC', 'Phenotype', 'HP:0011459', (73, 76))	('tumor', 'Disease', (77, 82))	('EAC', 'Phenotype', 'HP:0011459', (146, 149))	('GDC-0449', 'Chemical', 'MESH:C538724', (105, 113))
72530	22439934	It is worthwhile to mention that many inhibitors targeting these two pathways are being tested in clinical trials, such as GDC-0449 and IPI-926, targeting the hedgehog pathway, and RAD001 and AP23573, targeting the mTOR pathway.	('GDC-0449', 'Chemical', 'MESH:C538724', (123, 131))	('hedgehog pathway', 'Pathway', (159, 175))	('AP23573', 'Var', (192, 199))	('RAD001', 'Var', (181, 187))	('IPI-926', 'Chemical', 'MESH:C541444', (136, 143))	('mTOR pathway', 'Pathway', (215, 227))
72531	22439934	Although SMO inhibitors are known to inhibit several types of cancer and have shown hopeful tumor-inhibitory effects, the development of resistance has been reported due to the constitutive activation mutation of SMO or overactivation of PI3K/AKT pathway.	('activation', 'PosReg', (190, 200))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('AKT', 'Gene', '207', (243, 246))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('SMO', 'Gene', '6608', (9, 12))	('inhibit', 'NegReg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('SMO', 'Gene', (213, 216))	('overactivation', 'PosReg', (220, 234))	('SMO', 'Gene', (9, 12))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', (92, 97))	('mutation', 'Var', (201, 209))	('SMO', 'Gene', '6608', (213, 216))	('AKT', 'Gene', (243, 246))
72543	22439934	Purified GST protein or GST fusion proteins were incubated with purified HA-S6K1 or HA-S6K1 mutants in the presence of 50 mM ATP in a kinase buffer for 30 min at 30 C. Reaction products were subjected to SDS PA GE gel and then blotted with phosphor-Thr/Ser antibody.	('Thr', 'Chemical', 'MESH:D013912', (249, 252))	('SDS PA', 'Chemical', '-', (204, 210))	('S6K1', 'Gene', (87, 91))	('S6K1', 'Gene', '6198', (87, 91))	('S6K1', 'Gene', (76, 80))	('mutants', 'Var', (92, 99))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('S6K1', 'Gene', '6198', (76, 80))	('Ser', 'Chemical', 'MESH:D012694', (253, 256))
72544	22439934	Cells were seeded in 96-well plates at the density of 5000 cells/well, and after overnight growth, the cells were exposed to increasing concentrations ranging from 1 nM to 100 muM for cyclopamine or GDC-0449, with or without 10 nM rapamycin, for 48 hr.	('rapamycin', 'Chemical', 'MESH:D020123', (231, 240))	('muM', 'Gene', '56925', (176, 179))	('GDC-0449', 'Chemical', 'MESH:C538724', (199, 207))	('rat', 'Species', '10116', (143, 146))	('GDC-0449', 'Var', (199, 207))	('muM', 'Gene', (176, 179))	('cyclopamine', 'Chemical', 'MESH:C000541', (184, 195))
72559	22439934	Therefore, the combination of the inhibitors against mTOR/S6K1 and Hedgehog pathways may be more effective in cancer target therapy.	('cancer', 'Disease', (110, 116))	('mTOR/S6K1', 'Gene', '21977;72508', (53, 62))	('inhibitors', 'Var', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mTOR/S6K1', 'Gene', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('Hedgehog pathways', 'Pathway', (67, 84))
72587	19932903	Malnutrition resulting from surgical manipulation of the alimentary tract is inherent to these animal models and thus a potentially confounding effect of these results.	('Malnutrition', 'Phenotype', 'HP:0004395', (0, 12))	('Malnutrition', 'Disease', (0, 12))	('men', 'Species', '9606', (60, 63))	('surgical manipulation', 'Var', (28, 49))
72590	19932903	In studies that investigate the role of dietary components in the prevention of cancer, purified component diets such as AIN-76A and AIN-93M are commonly used due to better quality control.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('AIN-93M', 'Var', (133, 140))	('cancer', 'Disease', (80, 86))
72614	19932903	Regardless of the type of diet, the body weight of EDA-operated animals was significantly lower than their sham-operated counterparts at each time point starting at 2 weeks after surgery (Figure 1, p<0.001), suggesting that EDA-surgery by itself slows weight gain in these animals.	('EDA', 'Chemical', '-', (51, 54))	('EDA', 'Chemical', '-', (224, 227))	('rat', 'Species', '10116', (115, 118))	('weight gain', 'Disease', 'MESH:D015430', (252, 263))	('weight gain', 'Phenotype', 'HP:0004324', (252, 263))	('EDA-surgery', 'Var', (224, 235))	('lower', 'NegReg', (90, 95))	('weight gain', 'Disease', (252, 263))	('slows', 'NegReg', (246, 251))	('rat', 'Species', '10116', (58, 61))	('slows weight gain', 'Phenotype', 'HP:0001508', (246, 263))	('EDA-operated', 'Var', (51, 63))	('body weight', 'CPA', (36, 47))
72625	19932903	Although it appeared that the esophageal tumor incidence was slightly lower in EDA-PD animals (3 of 11; 27%) compared to EDA-RD animals (4 of 10; 40%), this difference was not statistically significant.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('esophageal tumor', 'Disease', 'MESH:D004938', (30, 46))	('EDA', 'Chemical', '-', (79, 82))	('EDA-PD', 'Chemical', '-', (79, 85))	('EDA', 'Chemical', '-', (121, 124))	('esophageal tumor', 'Disease', (30, 46))	('lower', 'NegReg', (70, 75))	('esophageal tumor', 'Phenotype', 'HP:0100751', (30, 46))	('EDA-PD', 'Var', (79, 85))
72629	19932903	Further, we show a difference in tumor incidence in EDA-RD (4/10-40%) compared to the EDA-PD (3/11-27%).	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('EDA', 'Chemical', '-', (86, 89))	('EDA-RD', 'Var', (52, 58))	('EDA', 'Chemical', '-', (52, 55))	('EDA-PD', 'Chemical', '-', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
72647	19932903	However, the same investigators report a lack of malnutrition in a study using AIN-93M diet in the esophagogastroduodenal anastomosis (EGDA) animal model in which the stomach is fully functional.	('malnutrition', 'Disease', (49, 61))	('esophagogastroduodenal anastomosis', 'Disease', (99, 133))	('malnutrition', 'Disease', 'MESH:D044342', (49, 61))	('AIN-93M', 'Var', (79, 86))	('malnutrition', 'Phenotype', 'HP:0004395', (49, 61))	('esophagogastroduodenal anastomosis', 'Phenotype', 'HP:0100628', (99, 133))
72669	33922189	Eps15 Homology Domain-Containing Protein 3 Hypermethylation as a Prognostic and Predictive Marker for Colorectal Cancer Colorectal cancer (CRC) arises from chromosomal instability, resulting from aberrant hypermethylation in tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Eps15', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Eps15', 'Gene', '2060', (0, 5))	('tumor', 'Disease', (225, 230))	('Colorectal cancer', 'Disease', (120, 137))	('aberrant hypermethylation', 'Var', (196, 221))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('Colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('CRC', 'Phenotype', 'HP:0003003', (139, 142))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (102, 119))	('chromosomal instability', 'Phenotype', 'HP:0040012', (156, 179))	('rectal cancer', 'Phenotype', 'HP:0100743', (124, 137))	('Colorectal Cancer', 'Disease', (102, 119))
72672	33922189	Furthermore, EHD3 hypermethylation was detected in other gastrointestinal cancers.	('hypermethylation', 'Var', (18, 34))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (57, 80))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('gastrointestinal cancers', 'Disease', (57, 81))	('EHD3', 'Gene', '30845', (13, 17))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (57, 81))	('detected', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('EHD3', 'Gene', (13, 17))
72674	33922189	Multivariate Cox proportional-hazards survival analysis revealed that hypermethylation in women and low mRNA expression were associated with overall survival.	('overall survival', 'MPA', (141, 157))	('hypermethylation', 'Var', (70, 86))	('low', 'NegReg', (100, 103))	('mRNA expression', 'MPA', (104, 119))	('women', 'Species', '9606', (90, 95))
72675	33922189	In the Western CRC cohort, EHD3 hypermethylation was also connected to overall survival and lower chemotherapy and antimetabolite response rates.	('EHD3', 'Gene', (27, 31))	('hypermethylation', 'Var', (32, 48))	('EHD3', 'Gene', '30845', (27, 31))	('CRC', 'Phenotype', 'HP:0003003', (15, 18))	('lower', 'NegReg', (92, 97))
72676	33922189	In conclusion, EHD3 hypermethylation contributes to the development of CRC in both Asian and Western populations.	('men', 'Species', '9606', (63, 66))	('contributes', 'Reg', (37, 48))	('hypermethylation', 'Var', (20, 36))	('EHD3', 'Gene', '30845', (15, 19))	('CRC', 'Disease', (71, 74))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('EHD3', 'Gene', (15, 19))
72679	33922189	Multiple genetic and epigenetic modifications result in the silencing of tumor suppressor genes (TSGs) and activation of oncogenes, which transform normal colonic epithelial cells into adenocarcinoma cells in CRC.	('TSG', 'Gene', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('epigenetic modifications', 'Var', (21, 45))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TSG', 'Gene', '57045', (97, 100))	('tumor', 'Disease', (73, 78))	('silencing', 'NegReg', (60, 69))	('CRC', 'Phenotype', 'HP:0003003', (209, 212))	('modifications', 'Var', (32, 45))	('transform', 'Reg', (138, 147))	('oncogenes', 'Gene', (121, 130))	('activation', 'PosReg', (107, 117))
72680	33922189	In gene promoter regions, aberrant DNA methylation can inactivate TSGs, contributing to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('TSG', 'Gene', '57045', (66, 69))	('contributing', 'Reg', (72, 84))	('aberrant DNA methylation', 'Var', (26, 50))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('inactivate', 'NegReg', (55, 65))	('tumor', 'Disease', (88, 93))	('TSG', 'Gene', (66, 69))
72685	33922189	For instance, detection of Septin 9 hypermethylation DNA in plasma has been approved by the US Food and Drug Administration for CRC screening.	('Septin 9', 'Gene', (27, 35))	('CRC', 'Phenotype', 'HP:0003003', (128, 131))	('hypermethylation DNA', 'Var', (36, 56))	('Septin 9', 'Gene', '10801', (27, 35))
72695	33922189	Aberrant DNA methylation was previously found in esophageal squamous cell carcinoma.	('Aberrant', 'Var', (0, 8))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (49, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('DNA', 'Protein', (9, 12))	('found', 'Reg', (40, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('esophageal squamous cell carcinoma', 'Disease', (49, 83))
72697	33922189	We assumed responsibility for discovering the exact relationship between alteration of EHD3 and colorectal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('EHD3', 'Gene', (87, 91))	('colorectal tumorigenesis', 'Disease', (96, 120))	('colorectal tumorigenesis', 'Disease', 'MESH:D015179', (96, 120))	('alteration', 'Var', (73, 83))	('EHD3', 'Gene', '30845', (87, 91))
72725	33922189	EHD3 hypermethylation was observed in most Western alimentary canal cancers compared with paired adjacent normal tissues (Figure 1C), such as colon cancer (68.4%, 26/38), esophageal cancer (60.0%, 9/15), liver cancer (33.3%, 4/12), gastric cancer (2/2, 100%), pancreatic cancer (10.0%, 1/10), and rectal cancer (42.9%, 3/7).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colon cancer', 'Disease', (142, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('gastric cancer', 'Disease', 'MESH:D013274', (232, 246))	('cancer', 'Disease', (304, 310))	('observed', 'Reg', (26, 34))	('liver cancer', 'Phenotype', 'HP:0002896', (204, 216))	('cancer', 'Disease', (240, 246))	('cancer', 'Disease', (271, 277))	('liver cancer', 'Disease', (204, 216))	('esophageal cancer', 'Disease', (171, 188))	('pancreatic cancer', 'Disease', 'MESH:D010190', (260, 277))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (232, 246))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('EHD3', 'Gene', '30845', (0, 4))	('pancreatic cancer', 'Disease', (260, 277))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('hypermethylation', 'Var', (5, 21))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('men', 'Species', '9606', (54, 57))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('cancer', 'Disease', (148, 154))	('gastric cancer', 'Disease', (232, 246))	('EHD3', 'Gene', (0, 4))	('rectal cancer', 'Phenotype', 'HP:0100743', (297, 310))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Disease', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (260, 277))	('cancer', 'Disease', (68, 74))	('liver cancer', 'Disease', 'MESH:D006528', (204, 216))	('cancer', 'Disease', (210, 216))
72726	33922189	In the Taiwanese cohort, EHD3 hypermethylation was detected in 73.1% (19/26) of patients with CRC and 18.8% (3/16) of patients with esophageal cancer compared with matched normal tissues (Figure 2A and Figure S2).	('detected', 'Reg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('patients', 'Species', '9606', (80, 88))	('esophageal cancer', 'Disease', (132, 149))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('EHD3', 'Gene', '30845', (25, 29))	('hypermethylation', 'Var', (30, 46))	('patients', 'Species', '9606', (118, 126))	('CRC', 'Disease', (94, 97))	('EHD3', 'Gene', (25, 29))
72736	33922189	EHD3 hypermethylation plays a role in vascular invasion and high microsatellite instability in patients with CRC (Table 1, p = 0.005 and p = 0.047).	('EHD3', 'Gene', (0, 4))	('patients', 'Species', '9606', (95, 103))	('CRC', 'Disease', (109, 112))	('high microsatellite instability', 'MPA', (60, 91))	('hypermethylation', 'Var', (5, 21))	('EHD3', 'Gene', '30845', (0, 4))	('vascular invasion', 'CPA', (38, 55))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))
72740	33922189	Whether EHD3 hypermethylation affects mRNA expression remains unknown.	('affects', 'Reg', (30, 37))	('EHD3', 'Gene', '30845', (8, 12))	('mRNA expression', 'MPA', (38, 53))	('EHD3', 'Gene', (8, 12))	('hypermethylation', 'Var', (13, 29))
72746	33922189	Female patients with EHD3 hypermethylation had poor prognosis results (Figure 3C, p = 0.046).	('hypermethylation', 'Var', (26, 42))	('EHD3', 'Gene', (21, 25))	('EHD3', 'Gene', '30845', (21, 25))	('patients', 'Species', '9606', (7, 15))
72747	33922189	Multivariate Cox proportional-hazards survival analysis revealed that EHD3 hypermethylation in women was independently and significantly associated with poor overall survival and recurrence-free survival, even after adjustment for age, location, tumor differentiation, and cancer stage (Table 2, p = 0.020 and p = 0.020).	('associated', 'Reg', (137, 147))	('EHD3', 'Gene', '30845', (70, 74))	('cancer', 'Disease', (273, 279))	('poor', 'NegReg', (153, 157))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('men', 'Species', '9606', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('EHD3', 'Gene', (70, 74))	('women', 'Species', '9606', (95, 100))	('overall survival', 'CPA', (158, 174))	('recurrence-free survival', 'CPA', (179, 203))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('men', 'Species', '9606', (222, 225))	('tumor', 'Disease', (246, 251))	('hypermethylation', 'Var', (75, 91))
72756	33922189	Prognoses were poorer in patients exhibiting hypermethylation than in those exhibiting low methylation of EHD3 promoter probe 4 (Figure 4B, p = 0.046).	('EHD3', 'Gene', (106, 110))	('EHD3', 'Gene', '30845', (106, 110))	('patients', 'Species', '9606', (25, 33))	('hypermethylation', 'Var', (45, 61))
72757	33922189	Multivariate Cox proportional-hazards survival analysis indicated that EHD3 hypermethylation was independently and significantly associated with overall survival after adjustment for age, location, tumor size, lymph invasion, and metastasis (Table S2, p = 0.039).	('associated', 'Reg', (129, 139))	('overall survival', 'MPA', (145, 161))	('hypermethylation', 'Var', (76, 92))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('EHD3', 'Gene', '30845', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('men', 'Species', '9606', (174, 177))	('EHD3', 'Gene', (71, 75))
72760	33922189	As a result, EHD3 promoter (cg01163837) hypermethylation was significantly associated with poor treatment response to chemotherapy and antimetabolites (p = 0.017 and p = 0.039, Table 3).	('men', 'Species', '9606', (101, 104))	('EHD3', 'Gene', '30845', (13, 17))	('hypermethylation', 'Var', (40, 56))	('cg01163837) hypermethylation', 'Var', (28, 56))	('EHD3', 'Gene', (13, 17))
72761	33922189	The silencing of TSGs could be caused by hypermethylation of CpG islands, resulting in tumorigenesis.	('hypermethylation', 'Var', (41, 57))	('TSG', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TSG', 'Gene', '57045', (17, 20))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('silencing', 'NegReg', (4, 13))	('CpG islands', 'Protein', (61, 72))
72763	33922189	Furthermore, QMSP confirmed EHD3 hypermethylation in CRC tissues compared with normal tissues.	('CRC', 'Phenotype', 'HP:0003003', (53, 56))	('EHD3', 'Gene', '30845', (28, 32))	('hypermethylation', 'Var', (33, 49))	('EHD3', 'Gene', (28, 32))
72766	33922189	Caucasian patients with CRC and high EHD3 promoter methylation (Figure 4B) or low EHD3 protein expression (Figure 4C) also had poor prognosis.	('high', 'Var', (32, 36))	('CRC', 'Phenotype', 'HP:0003003', (24, 27))	('low', 'NegReg', (78, 81))	('EHD3', 'Gene', '30845', (37, 41))	('EHD3', 'Gene', '30845', (82, 86))	('EHD3', 'Gene', (82, 86))	('patients', 'Species', '9606', (10, 18))	('EHD3', 'Gene', (37, 41))	('CRC', 'Disease', (24, 27))
72767	33922189	Vascular invasion and lymphatic invasion, both poor prognostic factors for CRC, were observed in patients with CRC with high EHD3 methylation and low EHD3 mRNA expression (Table 1).	('low', 'NegReg', (146, 149))	('methylation', 'Var', (130, 141))	('CRC', 'Disease', (111, 114))	('EHD3', 'Gene', '30845', (125, 129))	('EHD3', 'Gene', (125, 129))	('CRC', 'Disease', (75, 78))	('high', 'Var', (120, 124))	('Vascular invasion', 'CPA', (0, 17))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('lymphatic invasion', 'CPA', (22, 40))	('EHD3', 'Gene', '30845', (150, 154))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('EHD3', 'Gene', (150, 154))	('patients', 'Species', '9606', (97, 105))
72769	33922189	A previous study suggested that EHD3 polymorphism explains why women are more prone to major depressive disorder than men are.	('depressive disorder', 'Phenotype', 'HP:0000716', (93, 112))	('men', 'Species', '9606', (65, 68))	('EHD3', 'Gene', '30845', (32, 36))	('depressive disorder', 'Disease', (93, 112))	('men', 'Species', '9606', (118, 121))	('EHD3', 'Gene', (32, 36))	('prone', 'Reg', (78, 83))	('women', 'Species', '9606', (63, 68))	('depressive disorder', 'Disease', 'MESH:D000275', (93, 112))	('polymorphism', 'Var', (37, 49))
72777	33922189	Therefore, we speculated that the loss of EHD3 expression in colon cells occurs through the same mechanism and increases cell growth and tumorigenesis.	('loss', 'Var', (34, 38))	('tumor', 'Disease', (137, 142))	('EHD3', 'Gene', (42, 46))	('increases', 'PosReg', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cell growth', 'CPA', (121, 132))	('EHD3', 'Gene', '30845', (42, 46))
72778	33922189	EHD3 promoter hypermethylation likely plays a vital role in gastrointestinal cancers, such as esophageal and gastric cancer, in Western populations (Figure 1C).	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('EHD3', 'Gene', (0, 4))	('gastrointestinal cancers', 'Disease', (60, 84))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (60, 84))	('promoter hypermethylation', 'Var', (5, 30))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (60, 83))	('esophageal', 'Disease', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('EHD3', 'Gene', '30845', (0, 4))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))
72782	33922189	To summarize, gastrointestinal cancers are often accompanied by EHD3 promoter hypermethylation, especially in regions involved in food transport, including the esophagus, stomach, colon, and rectum.	('accompanied', 'Reg', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('EHD3', 'Gene', '30845', (64, 68))	('esophagus', 'Disease', (160, 169))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (14, 38))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (14, 37))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('gastrointestinal cancers', 'Disease', (14, 38))	('EHD3', 'Gene', (64, 68))	('promoter hypermethylation', 'Var', (69, 94))
72784	33922189	The chemotherapy response rate was significantly higher in patients with low EHD3 methylation levels (p = 0.017, Table 3).	('chemotherapy response rate', 'CPA', (4, 30))	('methylation levels', 'MPA', (82, 100))	('EHD3', 'Gene', '30845', (77, 81))	('patients', 'Species', '9606', (59, 67))	('higher', 'PosReg', (49, 55))	('low', 'Var', (73, 76))	('EHD3', 'Gene', (77, 81))
72785	33922189	Antimetabolites are recommended for patients without EHD3 promoter hypermethylation (p = 0.039, Table 3) for postoperative chemotherapy.	('patients', 'Species', '9606', (36, 44))	('EHD3', 'Gene', '30845', (53, 57))	('EHD3', 'Gene', (53, 57))	('promoter hypermethylation', 'Var', (58, 83))	('men', 'Species', '9606', (25, 28))
72790	33922189	Similarly, patients with EHD3 hypermethylation have poor overall survival and response to chemotherapy.	('overall', 'MPA', (57, 64))	('EHD3', 'Gene', '30845', (25, 29))	('patients', 'Species', '9606', (11, 19))	('hypermethylation', 'Var', (30, 46))	('poor', 'NegReg', (52, 56))	('EHD3', 'Gene', (25, 29))
72794	33922189	EHD3 hypermethylation promotes the development of CRC and other gastrointestinal cancers in both Asian and Western populations and can be developed as a prognostic marker or a target for precision medicine.	('promotes', 'PosReg', (22, 30))	('men', 'Species', '9606', (42, 45))	('EHD3', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('gastrointestinal cancers', 'Disease', (64, 88))	('CRC', 'Disease', (50, 53))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (64, 88))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (64, 87))	('hypermethylation', 'Var', (5, 21))	('CRC', 'Phenotype', 'HP:0003003', (50, 53))	('EHD3', 'Gene', '30845', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
72795	33922189	The following are available online at , Figure S1: Methylation heatmap of EHD3 in paired breast cancer, lung adenocarcinoma, and squamous cell lung cancer tissues.	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (129, 154))	('lung adenocarcinoma', 'Disease', (104, 123))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('Methylation', 'Var', (51, 62))	('breast cancer', 'Disease', (89, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('EHD3', 'Gene', '30845', (74, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('EHD3', 'Gene', (74, 78))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))	('squamous cell lung cancer', 'Disease', (129, 154))
72807	32022229	Results showed that pyrotinib inhibited HER2 activation and exerted an anti-proliferative effect in TE-1 and KYSE30 cells.	('HER2', 'Gene', (40, 44))	('anti-proliferative effect', 'CPA', (71, 96))	('HER2', 'Gene', '2064', (40, 44))	('inhibited', 'NegReg', (30, 39))	('activation', 'MPA', (45, 55))	('pyrotinib', 'Chemical', 'MESH:C000622954', (20, 29))	('pyrotinib', 'Var', (20, 29))
72809	32022229	Our results indicated that pyrotinib sensitivitied HER2 positive esophageal cancer cells to radiation treatment through various mechanisms.	('sensitivitied', 'Reg', (37, 50))	('esophageal cancer', 'Disease', (65, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('pyrotinib', 'Chemical', 'MESH:C000622954', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('HER2', 'Gene', (51, 55))	('pyrotinib', 'Var', (27, 36))	('HER2', 'Gene', '2064', (51, 55))
72831	32022229	The dosage for pyrotinib was determined by cell viability assay that showed that pyrotinib produced a cytotoxic effect on TE-1 cells with IC50 = 3.32 (Supplementary Figure S1A,B) and on KYSE30 cells with IC50 = 4.294 (Supplementary Figure S1C,D).	('pyrotinib', 'Chemical', 'MESH:C000622954', (81, 90))	('cytotoxic effect', 'CPA', (102, 118))	('pyrotinib', 'Chemical', 'MESH:C000622954', (15, 24))	('pyrotinib', 'Var', (81, 90))
72834	32022229	The membranes were blocked by 5% skimmed milk for 2 h and then incubated with following primary antibodies at 4 C overnight: anti-EGFR (1:1000, Cell Signaling), anti-HER2 (1:1000, Cell Signaling), anti-phospho-HER2 (1:1000, Cell Signaling), anti-cyclin D1 (1:500, Abcam), anti-CDK4 (1:800, Abcam),anti-AKT (1:600, Cell Signaling), anti-pAKT (1:600, Cell Signaling), anti gamma-H2AX (1:200, Cell Signaling), or anti-GAPDH (as internal control, 1:800, Abcam).	('AKT', 'Gene', '207', (337, 340))	('HER2', 'Gene', (166, 170))	('GAPDH', 'Gene', (415, 420))	('GAPDH', 'Gene', '2597', (415, 420))	('HER2', 'Gene', '2064', (166, 170))	('CDK4', 'Gene', (277, 281))	('HER2', 'Gene', '2064', (210, 214))	('AKT', 'Gene', (337, 340))	('cyclin D1', 'Gene', '595', (246, 255))	('1:600', 'Var', (342, 347))	('AKT', 'Gene', (302, 305))	('CDK4', 'Gene', '1019', (277, 281))	('cyclin D1', 'Gene', (246, 255))	('HER2', 'Gene', (210, 214))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('AKT', 'Gene', '207', (302, 305))
72846	32022229	In both TE-1 and KYSE30 cells, pyrotinib treatment reduced the protein levels of phosphorylated HER2 in a dose-dependent manner.	('protein levels', 'MPA', (63, 77))	('reduced', 'NegReg', (51, 58))	('HER2', 'Gene', (96, 100))	('pyrotinib', 'Chemical', 'MESH:C000622954', (31, 40))	('HER2', 'Gene', '2064', (96, 100))	('pyrotinib', 'Var', (31, 40))
72848	32022229	As shown in Figure 3, pyrotinib inhibited the colony formation of TE-1 and KYSE30 cells, in dose-dependent manners.	('inhibited', 'NegReg', (32, 41))	('pyrotinib', 'Chemical', 'MESH:C000622954', (22, 31))	('pyrotinib', 'Var', (22, 31))
72849	32022229	In TE-1 cells, pyrotinib at higher doses significantly reduced colony formation, resulting in ~40% colony formation at 3 mug/ml and ~10% colony formation at 6 mug/ml, compared with control group (Figure 3A, B).	('pyrotinib', 'Var', (15, 24))	('pyrotinib', 'Chemical', 'MESH:C000622954', (15, 24))	('reduced', 'NegReg', (55, 62))	('colony formation', 'CPA', (99, 115))	('colony formation', 'CPA', (137, 153))	('colony formation', 'CPA', (63, 79))
72850	32022229	Pyrotinib inhibited colony formation of KYSE30 cells at all doses, resulting in ~80 colony formation at 2 mug/ml, ~30% colony formation at 4 mug/ml and <10% colony formation at 8 mug/ml, compared with control group (Figure 3C, D).	('Pyrotinib', 'Var', (0, 9))	('colony formation', 'CPA', (84, 100))	('inhibited', 'NegReg', (10, 19))	('colony formation', 'CPA', (119, 135))	('Pyrotinib', 'Chemical', 'MESH:C000622954', (0, 9))	('colony formation', 'CPA', (20, 36))
72851	32022229	Compared with radiation treatment alone, cells treated with radiation combined with pyrotinib showed significantly reduced colony formation, indicating that pyrotinib enhanced the inhibitory effect of radiation on colony formation in these two human esophageal cancer cell lines.	('esophageal cancer', 'Disease', 'MESH:D004938', (250, 267))	('pyrotinib', 'Chemical', 'MESH:C000622954', (84, 93))	('enhanced', 'PosReg', (167, 175))	('human', 'Species', '9606', (244, 249))	('colony formation', 'CPA', (214, 230))	('pyrotinib', 'Var', (157, 166))	('reduced', 'NegReg', (115, 122))	('pyrotinib', 'Chemical', 'MESH:C000622954', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('colony formation', 'CPA', (123, 139))	('esophageal cancer', 'Disease', (250, 267))
72852	32022229	Treatment with pyrotinib significantly decreased the percentage of G2/M cells while increased the percentage of G0/G1 cells compared with Radiation group (Figure 5A-D).	('pyrotinib', 'Var', (15, 24))	('pyrotinib', 'Chemical', 'MESH:C000622954', (15, 24))	('G2/M cells', 'CPA', (67, 77))	('increased', 'PosReg', (84, 93))	('G0/G1 cells', 'CPA', (112, 123))	('decreased', 'NegReg', (39, 48))
72853	32022229	Meanwhile, pyrotinib could also cause G0/G1 arrest and reduce G2/M phase in the cells without irradiation (Figure 5A-D).	('G2/M phase', 'CPA', (62, 72))	('pyrotinib', 'Chemical', 'MESH:C000622954', (11, 20))	('reduce', 'NegReg', (55, 61))	('pyrotinib', 'Var', (11, 20))	('G0/G1 arrest', 'CPA', (38, 50))	('cause', 'Reg', (32, 37))
72854	32022229	The expression of two important cell cycle-regulating proteins, cyclin D1 and CDK4 was decreased following treatment with pyrotinib (Figure 6).	('decreased', 'NegReg', (87, 96))	('CDK4', 'Gene', (78, 82))	('pyrotinib', 'Var', (122, 131))	('expression', 'MPA', (4, 14))	('pyrotinib', 'Chemical', 'MESH:C000622954', (122, 131))	('CDK4', 'Gene', '1019', (78, 82))	('cyclin D1', 'Gene', '595', (64, 73))	('cyclin D1', 'Gene', (64, 73))
72855	32022229	Pyrotinib could also decrease the cyclin D1 and CDK4 expression in irradiation treated TE-1 and KYSE30 cells (Figure 6).	('CDK4', 'Gene', '1019', (48, 52))	('Pyrotinib', 'Var', (0, 9))	('decrease', 'NegReg', (21, 29))	('Pyrotinib', 'Chemical', 'MESH:C000622954', (0, 9))	('cyclin D1', 'Gene', '595', (34, 43))	('expression', 'MPA', (53, 63))	('cyclin D1', 'Gene', (34, 43))	('CDK4', 'Gene', (48, 52))
72861	32022229	Tyrosine residues in the cytoplasmic domain of this receptor can be auto-phosphorylated by dimerization, resulting in activation of various signaling pathways related to cell proliferation and tumorigenesis.	('activation', 'PosReg', (118, 128))	('signaling pathways', 'Pathway', (140, 158))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cell proliferation', 'CPA', (170, 188))	('Tyrosine', 'Chemical', 'MESH:D014443', (0, 8))	('tumor', 'Disease', (193, 198))	('Tyrosine residues', 'Var', (0, 17))
72864	32022229	Here, we found that pyrotinib significantly reduced HER2 phosphorylation, resulting in reduced cell proliferation of TE-1 and KYSE30 cells.	('HER2', 'Gene', '2064', (52, 56))	('reduced', 'NegReg', (87, 94))	('pyrotinib', 'Chemical', 'MESH:C000622954', (20, 29))	('reduced', 'NegReg', (44, 51))	('pyrotinib', 'Var', (20, 29))	('phosphorylation', 'MPA', (57, 72))	('HER2', 'Gene', (52, 56))
72865	32022229	This effect was in accordance with a previous report that pyrotinib reduced HER2 phosphorylation in lung cancer patient-derived xenografts and inhibit cell growth of dissociated organoid cells.	('HER2', 'Gene', (76, 80))	('phosphorylation', 'MPA', (81, 96))	('cell growth of dissociated organoid cells', 'CPA', (151, 192))	('patient', 'Species', '9606', (112, 119))	('HER2', 'Gene', '2064', (76, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('inhibit', 'NegReg', (143, 150))	('pyrotinib', 'Chemical', 'MESH:C000622954', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('reduced', 'NegReg', (68, 75))	('pyrotinib', 'Var', (58, 67))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
72866	32022229	Our findings indicated that pyrotinib could inhibit cell proliferation of HER2-positiveesophageal cancer cells by inhibiting HER2 phosphorylation.	('HER2', 'Gene', (125, 129))	('phosphorylation', 'MPA', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HER2', 'Gene', '2064', (125, 129))	('esophageal cancer', 'Disease', (87, 104))	('inhibit', 'NegReg', (44, 51))	('HER2', 'Gene', (74, 78))	('cell proliferation', 'CPA', (52, 70))	('pyrotinib', 'Chemical', 'MESH:C000622954', (28, 37))	('HER2', 'Gene', '2064', (74, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('pyrotinib', 'Var', (28, 37))	('inhibiting', 'NegReg', (114, 124))
72867	32022229	Radiation resistance in esophageal cancer patients may cause radiation therapy failure and lead to a less promising prognosis.	('lead to', 'Reg', (91, 98))	('esophageal cancer', 'Disease', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Radiation resistance', 'Var', (0, 20))	('failure', 'Disease', (79, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('cause', 'Reg', (55, 60))	('patients', 'Species', '9606', (42, 50))	('failure', 'Disease', 'MESH:D017093', (79, 86))
72873	32022229	As G2 arrest plays a critical role in DNA repair and G2 arrest was considered to play a role in cell survival after radiation, pyrotinib might enhance radiation-induced cell damage by reducing G2 duration.	('enhance', 'PosReg', (143, 150))	('radiation-induced cell damage', 'CPA', (151, 180))	('G2 duration', 'MPA', (193, 204))	('pyrotinib', 'Var', (127, 136))	('pyrotinib', 'Chemical', 'MESH:C000622954', (127, 136))	('reducing', 'NegReg', (184, 192))
72875	32022229	Although pyrotinib treatment did not further increase gamma-H2AX expression, we found that pyrotinib enhanced the radiation-induced decrease in p-Akt expression.	('Akt', 'Gene', (146, 149))	('pyrotinib', 'Var', (91, 100))	('pyrotinib', 'Chemical', 'MESH:C000622954', (91, 100))	('Akt', 'Gene', '207', (146, 149))	('decrease', 'NegReg', (132, 140))	('pyrotinib', 'Chemical', 'MESH:C000622954', (9, 18))
72877	32022229	Our results suggested that pyrotinib enhance the effect of radiation on esophageal cancer cells via reducing DNA repair.	('DNA repair', 'MPA', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('reducing', 'NegReg', (100, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('pyrotinib', 'Var', (27, 36))	('effect', 'MPA', (49, 55))	('pyrotinib', 'Chemical', 'MESH:C000622954', (27, 36))	('enhance', 'PosReg', (37, 44))
72878	32022229	On the other hand, we found that pyrotinib increased the duration of G0/G1 phase.	('pyrotinib', 'Var', (33, 42))	('pyrotinib', 'Chemical', 'MESH:C000622954', (33, 42))	('increased', 'PosReg', (43, 52))	('duration', 'MPA', (57, 65))
72881	32022229	Consistently, we found that pyrotinib could reduce cyclin D1 and CDK4 levels in esophageal cancer cells.	('cyclin D1', 'Gene', (51, 60))	('reduce', 'NegReg', (44, 50))	('esophageal cancer', 'Disease', (80, 97))	('pyrotinib', 'Chemical', 'MESH:C000622954', (28, 37))	('pyrotinib', 'Var', (28, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('CDK4', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cyclin D1', 'Gene', '595', (51, 60))	('CDK4', 'Gene', '1019', (65, 69))
72882	32022229	Our results suggested that pyrotinib could enhance the anti-proliferation effect of radiation by increasing G0/G1 arrest, via regulating cell cycle related proteins.	('G0/G1 arrest', 'CPA', (108, 120))	('regulating', 'Reg', (126, 136))	('pyrotinib', 'Var', (27, 36))	('increasing', 'PosReg', (97, 107))	('anti-proliferation effect', 'CPA', (55, 80))	('cell', 'Protein', (137, 141))	('pyrotinib', 'Chemical', 'MESH:C000622954', (27, 36))	('enhance', 'PosReg', (43, 50))
72884	32022229	Pyrotinib inhibitd HER2 activation and exerted anti-proliferative effect in human esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('HER2', 'Gene', (19, 23))	('anti-proliferative effect', 'CPA', (47, 72))	('Pyrotinib', 'Var', (0, 9))	('activation', 'MPA', (24, 34))	('HER2', 'Gene', '2064', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Pyrotinib', 'Chemical', 'MESH:C000622954', (0, 9))	('human', 'Species', '9606', (76, 81))	('inhibitd', 'NegReg', (10, 18))	('esophageal cancer', 'Disease', (82, 99))
72956	32010243	The G0/G1-phase population of KYSE410 and TE-13 cells with up-regulated miR-940 expression was significantly increased (P<0.01), while the proportions of cells in the G2/M- and S-phase were evidently decreased (P<0.05), indicating that overexpression of miR-940 caused cell cycle arrest of ESCC cells at the G0/G1 phase.	('up-regulated', 'PosReg', (59, 71))	('TE-13', 'CellLine', 'CVCL:4463', (42, 47))	('ESCC', 'Disease', (290, 294))	('G0/G1-phase population', 'CPA', (4, 26))	('KYSE410', 'Var', (30, 37))	('miR-940', 'Gene', '100126328', (254, 261))	('cell cycle arrest', 'CPA', (269, 286))	('miR-940', 'Gene', (72, 79))	('miR-940', 'Gene', '100126328', (72, 79))	('miR-940', 'Gene', (254, 261))	('expression', 'MPA', (80, 90))	('increased', 'PosReg', (109, 118))	('ESCC', 'Disease', 'MESH:C562729', (290, 294))
72958	32010243	The apoptotic rates of KYSE410 and TE-13 cells with overexpression of miR-940 were evidently elevated (P<0.01), indicating that miR-940 mimics promote apoptosis of ESCC cells.	('ESCC', 'Disease', 'MESH:C562729', (164, 168))	('TE-13', 'CellLine', 'CVCL:4463', (35, 40))	('apoptotic rates', 'CPA', (4, 19))	('KYSE410', 'Var', (23, 30))	('miR-940', 'Gene', '100126328', (70, 77))	('promote', 'PosReg', (143, 150))	('ESCC', 'Disease', (164, 168))	('miR-940', 'Gene', (70, 77))	('miR-940', 'Gene', '100126328', (128, 135))	('apoptosis', 'CPA', (151, 160))	('elevated', 'PosReg', (93, 101))	('miR-940', 'Gene', (128, 135))
72981	32010243	However, it has also been indicated that high expression of miR-940 is associated with poor prognosis in patients with gastric cancer.	('miR-940', 'Gene', (60, 67))	('miR-940', 'Gene', '100126328', (60, 67))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('high expression', 'Var', (41, 56))	('gastric cancer', 'Disease', (119, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))
72982	32010243	In the present study, post-operative follow-up was performed, the results of which indicated that patients in the low miR-940 expression group had a shorter OS and that low miR-940 levels are therefore associated with poor prognosis.	('low', 'Var', (114, 117))	('miR-940', 'Gene', (173, 180))	('expression', 'MPA', (126, 136))	('patients', 'Species', '9606', (98, 106))	('miR-940', 'Gene', '100126328', (173, 180))	('miR-940', 'Gene', (118, 125))	('miR-940', 'Gene', '100126328', (118, 125))
72987	32010243	The flow cytometric cell cycle analysis performed in the present study indicated that miR-940 mimics made the cells stay at G0 phase or blocked the cell cycle progression from G1- to S-phase.	('blocked', 'NegReg', (136, 143))	('miR-940', 'Gene', (86, 93))	('miR-940', 'Gene', '100126328', (86, 93))	('mimics', 'Var', (94, 100))	('cell cycle progression from G1- to S-phase', 'CPA', (148, 190))
72989	32010243	Finally, cell apoptosis was also detected through Annexin V-FITC/PI double-staining, and the results suggested that miR-940 mimics increased apoptosis of ESCC cells.	('ESCC', 'Disease', 'MESH:C562729', (154, 158))	('increased', 'PosReg', (131, 140))	('miR-940', 'Gene', '100126328', (116, 123))	('ESCC', 'Disease', (154, 158))	('miR-940', 'Gene', (116, 123))	('Annexin V', 'Gene', '308', (50, 59))	('Annexin V', 'Gene', (50, 59))	('mimics', 'Var', (124, 130))	('apoptosis', 'CPA', (141, 150))
72996	31258791	The miRNA-27 family consists of miR-27a and miR-27b, which are transcribed from different chromosomes and different in nucleotide at the 3' end.	('miR-27a', 'Var', (32, 39))	('miR-27b', 'Gene', '407019', (44, 51))	('miR-27b', 'Gene', (44, 51))	('miRNA-27', 'Gene', (4, 12))
72999	31258791	Apart from it, miR-27a could affect drug sensitivity, treatment of cancer and patients prognosis.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('treatment', 'Disease', (54, 63))	('cancer', 'Disease', (67, 73))	('affect', 'Reg', (29, 35))	('drug sensitivity', 'Phenotype', 'HP:0020174', (36, 52))	('drug sensitivity', 'MPA', (36, 52))	('patients', 'Species', '9606', (78, 86))	('miR-27a', 'Var', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients prognosis', 'CPA', (78, 96))
73006	31258791	The miRNA-27 family consists of miR-27a and miR-27b, and the former plays a vital role in tumor development.	('miR-27b', 'Gene', '407019', (44, 51))	('miR-27a', 'Var', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('miR-27b', 'Gene', (44, 51))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('plays', 'Reg', (68, 73))	('miRNA-27', 'Gene', (4, 12))
73007	31258791	Increasing evidence has confirmed that miR-27a plays a vital role in tumor biology, including polymorphisms, tumorigenesis, proliferation, apoptosis, invasion, migration and angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('migration', 'CPA', (160, 169))	('tumor', 'Disease', (69, 74))	('miR-27a', 'Gene', (39, 46))	('angiogenesis', 'CPA', (174, 186))	('proliferation', 'CPA', (124, 137))	('invasion', 'CPA', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('polymorphisms', 'Var', (94, 107))	('apoptosis', 'CPA', (139, 148))	('tumor', 'Disease', (109, 114))
73009	31258791	In recent studies, miR-27a, was significantly dysregulated in various cancers, such as NSCLC, liver cancer and prostate cancer, and acted as an oncogene.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (111, 126))	('NSCLC', 'Disease', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('miR-27a', 'Var', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('liver cancer', 'Phenotype', 'HP:0002896', (94, 106))	('liver cancer', 'Disease', 'MESH:D006528', (94, 106))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('liver cancer', 'Disease', (94, 106))	('cancers', 'Disease', (70, 77))	('dysregulated', 'Reg', (46, 58))
73012	31258791	Single-nucleotide polymorphisms (SNPs) in miRNA genes were a novel class of genetic variations in the human genome.	('miRNA', 'Gene', (42, 47))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('human', 'Species', '9606', (102, 107))
73013	31258791	Increasing studies revealed pre-miR-27a (rs895819) or miR-27a gene (rs11671784) may be associated with cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rs895819', 'Var', (41, 49))	('rs11671784', 'DBSNP_MENTION', 'None', (68, 78))	('miR-27a', 'Gene', (54, 61))	('associated', 'Reg', (87, 97))	('rs895819', 'Mutation', 'rs895819', (41, 49))	('rs11671784', 'Var', (68, 78))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
73014	31258791	They demonstrated that the SNPs could not only enhance or reduce the cancer risk but also exert a vital function in chemo-sensitivity.	('enhance', 'PosReg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('chemo-sensitivity', 'CPA', (116, 133))	('reduce', 'NegReg', (58, 64))	('SNPs', 'Var', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
73016	31258791	found that a common polymorphism (rs895819) could act as a vital factor in cell susceptibility via modulating miR-27a and ZBTB10 levels.	('modulating', 'Reg', (99, 109))	('rs895819', 'Var', (34, 42))	('miR-27a', 'MPA', (110, 117))	('rs895819', 'Mutation', 'rs895819', (34, 42))	('ZBTB10', 'Gene', (122, 128))	('ZBTB10', 'Gene', '65986', (122, 128))
73017	31258791	also indicated that in gastric cancer, it has been reported that the variant genotypes of rs895819 located at miR-27a conferred a 48% increased risk of developing gastric cancer in the Chinese population.	('gastric cancer', 'Disease', (163, 177))	('variant', 'Var', (69, 76))	('miR-27a', 'Gene', (110, 117))	('rs895819', 'Mutation', 'rs895819', (90, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('gastric cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (23, 37))	('increased risk of developing gastric cancer', 'Phenotype', 'HP:0006753', (134, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('rs895819', 'Var', (90, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
73018	31258791	Similar to the study by Renata Hezova et al., there was a finding also revealed in Chinese population, individuals with rs895819 G variants exhibited significantly increased risk of gastric cancer.	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (164, 196))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('rs895819', 'Mutation', 'rs895819', (120, 128))	('rs895819 G', 'Var', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('gastric cancer', 'Disease', (182, 196))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))
73020	31258791	also indicated that the G/A polymorphism in miR-27a gene (rs11671784) decreased miR-27a expression and reduced gastric cancer risk.	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('miR-27a expression', 'MPA', (80, 98))	('reduced', 'NegReg', (103, 110))	('miR-27a', 'Gene', (44, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('decreased', 'NegReg', (70, 79))	('G/A', 'Var', (24, 27))	('rs11671784', 'DBSNP_MENTION', 'None', (58, 68))	('reduced gastric cancer', 'Phenotype', 'HP:0006753', (103, 125))	('rs11671784', 'Var', (58, 68))	('gastric cancer', 'Disease', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
73021	31258791	And in NSCLC, there was a study proved this SNP (rs895819) was an independently unfavorable factor for the prognosis of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('NSCLC', 'Disease', (7, 12))	('NSCLC', 'Disease', 'MESH:D002289', (7, 12))	('rs895819', 'Var', (49, 57))	('rs895819', 'Mutation', 'rs895819', (49, 57))	('NSCLC', 'Disease', (120, 125))
73022	31258791	The authors demonstrated that the variant allele G of rs895819 within pre-miR-27a was associated with a significantly increased risk of deaths for NSCLC.	('NSCLC', 'Disease', (147, 152))	('rs895819', 'Mutation', 'rs895819', (54, 62))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('associated', 'Reg', (86, 96))	('pre-miR-27a', 'Gene', (70, 81))	('deaths', 'Disease', (136, 142))	('rs895819', 'Var', (54, 62))
73023	31258791	Moreover, they also found a significantly decreased response rate to platinum-based chemotherapy in advanced NSCLC patients with AG/GG genotype.	('patients', 'Species', '9606', (115, 123))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('decreased', 'NegReg', (42, 51))	('response rate', 'MPA', (52, 65))	('platinum', 'Chemical', 'MESH:D010984', (69, 77))	('AG/GG', 'Var', (129, 134))	('NSCLC', 'Disease', (109, 114))
73024	31258791	According to the study of Ma et al, allele G, allele G carrier (AG/GG) and genotype GG of rs895819 could be used as susceptible factors in NSCLC.	('rs895819', 'Mutation', 'rs895819', (90, 98))	('rs895819', 'Var', (90, 98))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('NSCLC', 'Disease', (139, 144))
73025	31258791	Furthermore, they also reported that rs895819 was strongly associated with NSCLC carcinogenesis, but not with NSCLC progression in Chinese Han population.	('rs895819', 'Var', (37, 45))	('NSCLC', 'Disease', (110, 115))	('NSCLC carcinogenesis', 'Disease', (75, 95))	('associated with', 'Reg', (59, 74))	('rs895819', 'Mutation', 'rs895819', (37, 45))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('NSCLC', 'Disease', (75, 80))	('NSCLC carcinogenesis', 'Disease', 'MESH:D063646', (75, 95))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
73026	31258791	found that the SNP rs895819 may act as a risk factor for breast cancer.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('rs895819', 'Mutation', 'rs895819', (19, 27))	('SNP rs895819', 'Var', (15, 27))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
73027	31258791	However it has been demonstrated that G allele of rs895819 was also related to reduced German familial breast cancer risk.	('familial breast cancer', 'Disease', 'MESH:D001943', (94, 116))	('reduced', 'NegReg', (79, 86))	('rs895819', 'Mutation', 'rs895819', (50, 58))	('familial breast cancer', 'Disease', (94, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('rs895819', 'Var', (50, 58))
73028	31258791	also found that the G-allele of rs895819, located in the terminal loop of the pre-miR27a oncogene, could reduce familial breast cancer risk strongly.	('rs895819', 'Mutation', 'rs895819', (32, 40))	('miR27a', 'Gene', '407018', (82, 88))	('reduce', 'NegReg', (105, 111))	('familial breast cancer', 'Disease', 'MESH:D001943', (112, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('familial breast cancer', 'Disease', (112, 134))	('miR27a', 'Gene', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('rs895819', 'Var', (32, 40))
73029	31258791	revealed that the G allele of rs895819 could not enhance or decrease risk of breast cancer in the Italian population.	('breast cancer', 'Disease', (77, 90))	('rs895819', 'Var', (30, 38))	('decrease', 'NegReg', (60, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('enhance', 'PosReg', (49, 56))	('rs895819', 'Mutation', 'rs895819', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
73031	31258791	reported that Rs895819 in miR-27a improved the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity.	('fluoropyrimidine', 'Chemical', '-', (120, 136))	('improved', 'PosReg', (34, 42))	('predictive value', 'MPA', (47, 63))	('Rs895819', 'Mutation', 'Rs895819', (14, 22))	('toxicity', 'Disease', 'MESH:D064420', (148, 156))	('miR-27a', 'Gene', (26, 33))	('DPYD', 'Gene', (67, 71))	('variants', 'Var', (72, 80))	('Rs895819', 'Var', (14, 22))	('DPYD', 'Gene', '1806', (67, 71))	('toxicity', 'Disease', (148, 156))	('patients', 'Species', '9606', (93, 101))
73032	31258791	However, the association between rs11671784 and fluoropyrimidine-associated toxicity was not quite clear.	('rs11671784', 'DBSNP_MENTION', 'None', (33, 43))	('fluoropyrimidine', 'Chemical', '-', (48, 64))	('rs11671784', 'Var', (33, 43))	('toxicity', 'Disease', 'MESH:D064420', (76, 84))	('toxicity', 'Disease', (76, 84))
73033	31258791	In southern Chinese women, miR-27a rs895819 polymorphism could reduce risk of cervical cancer, especially T allele and CT or TT genotype, compared with C and CC respectively.	('rs895819 polymorphism', 'Var', (35, 56))	('cervical cancer', 'Disease', 'MESH:D002583', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('women', 'Species', '9606', (20, 25))	('cervical cancer', 'Disease', (78, 93))	('polymorphism', 'Var', (44, 56))	('reduce', 'NegReg', (63, 69))	('rs895819', 'Mutation', 'rs895819', (35, 43))	('miR-27a', 'Gene', (27, 34))
73034	31258791	In addition to rs895819 polymorphism, it has been reported that compared to A allele, rs11671784 G allele has significantly stronger effect in promoting chemo-sensitivity in bladder cancer.	('promoting', 'PosReg', (143, 152))	('rs11671784', 'Var', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('chemo-sensitivity', 'CPA', (153, 170))	('rs895819', 'Mutation', 'rs895819', (15, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (174, 188))	('stronger', 'PosReg', (124, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (174, 188))	('bladder cancer', 'Disease', (174, 188))	('rs11671784', 'DBSNP_MENTION', 'None', (86, 96))
73035	31258791	Furthermore, RUNX-1, a novel direct target of miR-27a, could play a vital role in the regulation of chemo-sensitivity in bladder cancer.	('bladder cancer', 'Disease', (121, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('miR-27a', 'Var', (46, 53))	('bladder cancer', 'Phenotype', 'HP:0009725', (121, 135))	('RUNX-1', 'Gene', '861', (13, 19))	('play', 'Reg', (61, 65))	('bladder cancer', 'Disease', 'MESH:D001749', (121, 135))	('RUNX-1', 'Gene', (13, 19))
73037	31258791	In addition, they also showed that rs895819 was associated with age and hypertension.	('associated', 'Reg', (48, 58))	('rs895819', 'Var', (35, 43))	('hypertension', 'Disease', 'MESH:D006973', (72, 84))	('hypertension', 'Phenotype', 'HP:0000822', (72, 84))	('hypertension', 'Disease', (72, 84))	('rs895819', 'Mutation', 'rs895819', (35, 43))	('age', 'Disease', (64, 67))
73038	31258791	Furthermore, the miR-27a polymorphism was found not to affect the survival of RCC cells in their study.	('RCC', 'Disease', (78, 81))	('polymorphism', 'Var', (25, 37))	('miR-27a', 'Gene', (17, 24))	('RCC', 'Disease', 'MESH:C538614', (78, 81))
73040	31258791	They showed that the hsa-miR-27a rs895819 polymorphism did not correlate with overall cancer risk in the general population, however, the rs895819 AG genotype may play a protective role in the development of human cancer in white people.	('people', 'Species', '9606', (230, 236))	('cancer', 'Disease', (214, 220))	('rs895819', 'Mutation', 'rs895819', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('rs895819 AG', 'Var', (138, 149))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('rs895819', 'Mutation', 'rs895819', (138, 146))	('human', 'Species', '9606', (208, 213))	('cancer', 'Disease', (86, 92))
73042	31258791	Therefore, miR-27a may directly affect tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('affect', 'Reg', (32, 38))	('tumor', 'Disease', (39, 44))	('miR-27a', 'Var', (11, 18))
73045	31258791	also reported that miR-27a could function as a suppressor in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('miR-27a', 'Var', (19, 26))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
73047	31258791	Apart from the studies above which suggesting miR-27a could play a vital role in repressing many tumors growth, there were evidences illustrating that it also acted as an enhancer in the angiogenesis of tumors.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('miR-27a', 'Var', (46, 53))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('repressing', 'NegReg', (81, 91))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('enhancer', 'PosReg', (171, 179))
73050	31258791	In addition, recent studies demonstrated that miR-27a and EGFR functioned as downstream effector of mutant p53 and miR-27a/EGFR/ERK1/2 axis driven by p53-273H could play a vital role in promoting human tumor formation.	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', '1956', (58, 62))	('tumor', 'Disease', (202, 207))	('mutant', 'Var', (100, 106))	('p53', 'Gene', (107, 110))	('promoting', 'PosReg', (186, 195))	('EGFR', 'Gene', (58, 62))	('ERK1/2', 'Gene', (128, 134))	('human', 'Species', '9606', (196, 201))	('p53', 'Gene', '7157', (107, 110))	('ERK1/2', 'Gene', '5595;5594', (128, 134))	('p53', 'Gene', (150, 153))	('p53', 'Gene', '7157', (150, 153))	('EGFR', 'Gene', '1956', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
73055	31258791	But surprisingly, over-expression of miR-27a suppressed the expression of AGGF1 which may promote tumorigenesis of cancer cells.	('expression', 'MPA', (60, 70))	('cancer', 'Disease', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('AGGF1', 'Gene', (74, 79))	('over-expression', 'PosReg', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('suppressed', 'NegReg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('promote', 'PosReg', (90, 97))	('miR-27a', 'Var', (37, 44))	('tumor', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('AGGF1', 'Gene', '55109', (74, 79))
73056	31258791	More and more studies have proved that miR-27a was associated with proliferation and apoptosis which were important parts of tumor cell growth.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('miR-27a', 'Var', (39, 46))	('apoptosis', 'CPA', (85, 94))	('tumor', 'Disease', (125, 130))	('associated', 'Reg', (51, 61))	('proliferation', 'CPA', (67, 80))
73058	31258791	described that in colorectal cancer, miR-27a could not only inhibit cell proliferation, enhance apoptosis, but also attenuate cancer cell migration via targeting SGPP1 and Smad2, which were inversely correlated with miR-27a.	('cell proliferation', 'CPA', (68, 86))	('colorectal cancer', 'Disease', (18, 35))	('attenuate', 'NegReg', (116, 125))	('cancer', 'Disease', (126, 132))	('SGPP1', 'Gene', '81537', (162, 167))	('targeting', 'Reg', (152, 161))	('miR-27a', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (29, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('inhibit', 'NegReg', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Smad2', 'Gene', '4087', (172, 177))	('SGPP1', 'Gene', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('apoptosis', 'CPA', (96, 105))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('Smad2', 'Gene', (172, 177))	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))	('enhance', 'PosReg', (88, 95))
73060	31258791	In vivo, miR-27a inhibited colon cancer cell growth in tumor-bearing mice.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miR-27a', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('colon cancer', 'Phenotype', 'HP:0003003', (27, 39))	('tumor', 'Disease', (55, 60))	('mice', 'Species', '10090', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('inhibited', 'NegReg', (17, 26))	('colon cancer', 'Disease', 'MESH:D015179', (27, 39))	('colon cancer', 'Disease', (27, 39))
73062	31258791	Moreover, miR-27a could reduce its downstream gene cyclin D1, CDK2, and up-regulate the expression of the CDK inhibitor p27 to inhibit proliferation and induces apoptosis in 786-O cells.	('cyclin D1', 'Gene', (51, 60))	('p27', 'Gene', (120, 123))	('CDK2', 'Gene', (62, 66))	('reduce', 'NegReg', (24, 30))	('up-regulate', 'PosReg', (72, 83))	('induces', 'PosReg', (153, 160))	('cyclin D1', 'Gene', '595', (51, 60))	('apoptosis', 'CPA', (161, 170))	('proliferation', 'CPA', (135, 148))	('inhibit', 'NegReg', (127, 134))	('p27', 'Gene', '51014', (120, 123))	('CDK2', 'Gene', '1017', (62, 66))	('expression', 'MPA', (88, 98))	('miR-27a', 'Var', (10, 17))
73063	31258791	And in vivo, they found that miR-27a attenuated RCC tumor growth in mouse xeno-graft models.	('attenuated RCC tumor', 'Disease', 'MESH:C538614', (37, 57))	('mouse', 'Species', '10090', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('attenuated RCC tumor', 'Disease', (37, 57))	('miR-27a', 'Var', (29, 36))
73064	31258791	Consistent with this discovery, miR-27a, significantly lower in ESCC cells, could inhibit esophageal squamous cell carcinoma cells proliferation via a direct target: KRAS.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (90, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('miR-27a', 'Var', (32, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('inhibit', 'NegReg', (82, 89))	('lower', 'NegReg', (55, 60))	('esophageal squamous cell carcinoma', 'Disease', (90, 124))
73067	31258791	It also reported that miR-27a, which was own-regulated, could significantly up-regulate the expression of p21; while in the expression of pglycoprotein as well as cyclin D1, it could exert opposite biological effects.	('cyclin D1', 'Gene', '595', (163, 172))	('pglycoprotein', 'Protein', (138, 151))	('cyclin D1', 'Gene', (163, 172))	('p21', 'Gene', '644914', (106, 109))	('miR-27a', 'Var', (22, 29))	('expression', 'MPA', (92, 102))	('up-regulate', 'PosReg', (76, 87))	('expression', 'MPA', (124, 134))	('p21', 'Gene', (106, 109))
73068	31258791	Furthermore, it was also reported that stable lentiviral transduction of anti-miRNAs targeted miR-27a in U87 glioma cells, and anti-miR-27a reduced the viability as well as invasiveness, and increased apoptosis of U87 cells.	('anti-miR-27a', 'Var', (127, 139))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('viability', 'CPA', (152, 161))	('invasiveness', 'CPA', (173, 185))	('increased', 'PosReg', (191, 200))	('glioma', 'Disease', (109, 115))	('anti-miRNAs', 'Gene', (73, 84))	('apoptosis', 'CPA', (201, 210))	('U87', 'CellLine', 'CVCL:0022', (105, 108))	('U87', 'CellLine', 'CVCL:0022', (214, 217))	('miR-27a', 'Gene', (94, 101))	('reduced', 'NegReg', (140, 147))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
73069	31258791	In glioblastoma cell lines, miR-27a antagonists reduce cell proliferation and invasion.	('invasion', 'CPA', (78, 86))	('glioblastoma', 'Disease', (3, 15))	('cell proliferation', 'CPA', (55, 73))	('antagonists', 'Var', (36, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('reduce', 'NegReg', (48, 54))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('miR-27a', 'Gene', (28, 35))
73070	31258791	However, recent reports have shown that miR-27a promoted cell proliferation in GBM cell lines by directly targeting MXI1.	('MXI1', 'Gene', (116, 120))	('targeting', 'Reg', (106, 115))	('miR-27a', 'Var', (40, 47))	('promoted', 'PosReg', (48, 56))	('cell proliferation', 'CPA', (57, 75))	('MXI1', 'Gene', '4601', (116, 120))
73071	31258791	reported that MET and EGFR in NSCLC could be regulated by miR-27a.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('MET', 'Var', (14, 17))	('EGFR', 'Gene', '1956', (22, 26))	('miR-27a', 'Gene', (58, 65))	('regulated', 'Reg', (45, 54))	('NSCLC', 'Disease', (30, 35))	('EGFR', 'Gene', (22, 26))
73076	31258791	Apart from inhibiting cancer cell proliferation activities, it was also found that miR-27a could play a crucial role in multiple tumors.	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('multiple tumors', 'Disease', (120, 135))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('multiple tumors', 'Disease', 'MESH:D009369', (120, 135))	('cancer', 'Disease', (22, 28))	('inhibiting', 'NegReg', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('miR-27a', 'Var', (83, 90))
73078	31258791	Meanwhile, miR-27a could enhance the G1/S cell cycle transition by significantly decreasing the cell cycle inhibitors p21 and p27, as well as increasing cell cycle regulator cyclin D1.	('enhance', 'PosReg', (25, 32))	('p27', 'Gene', (126, 129))	('decreasing', 'NegReg', (81, 91))	('p21', 'Gene', (118, 121))	('G1/S cell cycle transition', 'CPA', (37, 63))	('cyclin D1', 'Gene', '595', (174, 183))	('p21', 'Gene', '644914', (118, 121))	('miR-27a', 'Var', (11, 18))	('p27', 'Gene', '51014', (126, 129))	('cyclin D1', 'Gene', (174, 183))	('increasing', 'PosReg', (142, 152))
73086	31258791	described that miR-27a could function as a tumor suppressor in renal cell carcinoma, but Peng et al.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (63, 83))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (63, 83))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('miR-27a', 'Var', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('renal cell carcinoma', 'Disease', (63, 83))	('tumor', 'Disease', (43, 48))
73090	31258791	also revealed that up-regulation of miR-27a could not only enhance the malignant transformation but also promote cell proliferation activity of human bronchial epithelial cells induced by SV40 small T antigen, via targeting and negatively regulating Fbxw7.	('Fbxw7', 'Gene', (250, 255))	('targeting', 'Reg', (214, 223))	('promote', 'PosReg', (105, 112))	('human', 'Species', '9606', (144, 149))	('enhance', 'PosReg', (59, 66))	('negatively regulating', 'NegReg', (228, 249))	('miR-27a', 'Gene', (36, 43))	('Fbxw7', 'Gene', '55294', (250, 255))	('up-regulation', 'PosReg', (19, 32))	('malignant transformation', 'CPA', (71, 95))	('SV40', 'Var', (188, 192))	('small T antigen', 'Protein', (193, 208))
73094	31258791	has revealed miR-27a acted as a tumor suppressor by targeting SGPP1 and Smad2 to attenuate cell migration in colorectal cancer.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('attenuate', 'NegReg', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('SGPP1', 'Gene', '81537', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('targeting', 'Reg', (52, 61))	('SGPP1', 'Gene', (62, 67))	('miR-27a', 'Var', (13, 20))	('Smad2', 'Gene', '4087', (72, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('tumor', 'Disease', (32, 37))	('cell migration', 'CPA', (91, 105))	('Smad2', 'Gene', (72, 77))
73095	31258791	It was shown that miR-27a-3p transfection could significantly decrease the invasive ability of OSCC cell lines and YAP1 (Yes-associated protein-1) was a direct target gene of miR-27a-3p.	('Yes-associated protein-1', 'Gene', '10413', (121, 145))	('OSCC', 'Phenotype', 'HP:0002860', (95, 99))	('decrease', 'NegReg', (62, 70))	('YAP1', 'Gene', (115, 119))	('YAP1', 'Gene', '10413', (115, 119))	('OS', 'Chemical', '-', (95, 97))	('miR-27a-3p transfection', 'Var', (18, 41))	('Yes-associated protein-1', 'Gene', (121, 145))	('invasive ability of OSCC cell lines', 'CPA', (75, 110))
73096	31258791	Moreover, increasing the expression of miR-27a-3p could significantly decrease the expression level of YAP1 and several epithelial to mesenchymal transition (EMT) related molecules in OSCC cell lines, including Twist and Snail.	('OSCC', 'Phenotype', 'HP:0002860', (184, 188))	('expression level', 'MPA', (83, 99))	('expression', 'MPA', (25, 35))	('OS', 'Chemical', '-', (184, 186))	('YAP1', 'Gene', (103, 107))	('YAP1', 'Gene', '10413', (103, 107))	('increasing', 'PosReg', (10, 20))	('decrease', 'NegReg', (70, 78))	('miR-27a-3p', 'Var', (39, 49))
73098	31258791	COUP-TFII was negatively regulated by miR-101 and miR-27a, and loss of miRNA promoted metastasis by inducing COUP-TFII.	('loss', 'Var', (63, 67))	('promoted', 'PosReg', (77, 85))	('inducing', 'Reg', (100, 108))	('miRNA', 'Protein', (71, 76))	('COUP-TFII', 'Gene', (0, 9))	('COUP-TFII', 'Gene', (109, 118))	('COUP-TFII', 'Gene', '7026', (0, 9))	('COUP-TFII', 'Gene', '7026', (109, 118))	('metastasis', 'CPA', (86, 96))	('miR-101', 'Chemical', '-', (38, 45))
73100	31258791	These inhibitory effects on migration and invasion were revealed in oral squamous cell carcinoma (OSCC); a study showed that miR-27a, negatively correlated with the MCPH1 protein level, could target MCPH1 inhibiting cell invasion.	('inhibiting', 'NegReg', (205, 215))	('MCPH1', 'Gene', (165, 170))	('MCPH1', 'Gene', (199, 204))	('cell invasion', 'CPA', (216, 229))	('miR-27a', 'Var', (125, 132))	('MCPH1', 'Gene', '79648', (165, 170))	('MCPH1', 'Gene', '79648', (199, 204))	('oral squamous cell carcinoma', 'Disease', (68, 96))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('OSCC', 'Phenotype', 'HP:0002860', (98, 102))	('target', 'Reg', (192, 198))	('OS', 'Chemical', '-', (98, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
73106	31258791	Meanwhile, instead of the stability of B4GALT3 miRNA and protein, miR-27a increased the transcription of B4GALT3.	('increased', 'PosReg', (74, 83))	('B4GALT3', 'Gene', '8703', (105, 112))	('B4GALT3', 'Gene', '8703', (39, 46))	('transcription', 'MPA', (88, 101))	('B4GALT3', 'Gene', (105, 112))	('miR-27a', 'Var', (66, 73))	('B4GALT3', 'Gene', (39, 46))
73107	31258791	They also detected the effects induced by miR-27a could be abolished via knock-downing B4GALT3 in cervical cancer cells.	('miR-27a', 'Var', (42, 49))	('B4GALT3', 'Gene', '8703', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('knock-downing', 'Var', (73, 86))	('cervical cancer', 'Disease', 'MESH:D002583', (98, 113))	('cervical cancer', 'Disease', (98, 113))	('B4GALT3', 'Gene', (87, 94))
73108	31258791	Similarly, it was reported that in osteosarcoma, CBFA2T3, which was negatively related to miR-27a expression, was a target of miR-27a, and miR-27a co-over-expression promoted metastatic properties of SAOS2.	('OS', 'Chemical', '-', (202, 204))	('metastatic properties', 'CPA', (175, 196))	('CBFA2T3', 'Gene', (49, 56))	('co-over-expression', 'Var', (147, 165))	('osteosarcoma', 'Phenotype', 'HP:0002669', (35, 47))	('osteosarcoma', 'Disease', (35, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (35, 47))	('miR-27a co-over-expression', 'Var', (139, 165))	('promoted', 'PosReg', (166, 174))	('CBFA2T3', 'Gene', '863', (49, 56))
73109	31258791	Furthermore, miR-27a inactivation by sponges reduced metastatic properties in HOS and KHOS osteosarcoma cells.	('KHOS osteosarcoma', 'Disease', 'MESH:D012516', (86, 103))	('inactivation', 'Var', (21, 33))	('reduced', 'NegReg', (45, 52))	('HOS', 'Disease', (87, 90))	('HOS', 'Disease', 'MESH:C535326', (78, 81))	('KHOS osteosarcoma', 'Disease', (86, 103))	('miR-27a', 'Gene', (13, 20))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('HOS', 'Disease', (78, 81))	('HOS', 'Disease', 'MESH:C535326', (87, 90))
73115	31258791	demonstrated that high levels of miR-27a strongly promoted the invasion of RCC cells, whereas low expression of miR-27a had an opposite effect.	('RCC', 'Disease', (75, 78))	('miR-27a', 'Var', (33, 40))	('promoted', 'PosReg', (50, 58))	('RCC', 'Disease', 'MESH:C538614', (75, 78))
73118	31258791	Increasing numbers of studies revealed that miR-27a played a crucial role in enhancing or inhibiting the tumor angiogenesis.	('miR-27a', 'Var', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('inhibiting', 'NegReg', (90, 100))	('tumor', 'Disease', (105, 110))	('enhancing', 'PosReg', (77, 86))
73125	31258791	Similarly, in the study of Zhao et al., miR-27a-3p deregulation could contribute to vasculogenic mimicry (VM) and metastasis by directly targeting VE-cadherin.	('targeting', 'Reg', (137, 146))	('metastasis', 'CPA', (114, 124))	('deregulation', 'Var', (51, 63))	('miR-27a-3p', 'Gene', (40, 50))	('VE-cadherin', 'Gene', (147, 158))	('contribute', 'Reg', (70, 80))	('VE-cadherin', 'Gene', '1003', (147, 158))	('vasculogenic mimicry', 'Disease', (84, 104))
73131	31258791	Similar to the studies above, miR-27a, acted as an angiogenesis promoter, could directly target and down-regulate calreticulin affecting MHC class I exposure to affect cell proliferation and angiogenesis in vitro.	('angiogenesis', 'CPA', (191, 203))	('calreticulin', 'Gene', '811', (114, 126))	('cell proliferation', 'CPA', (168, 186))	('miR-27a', 'Var', (30, 37))	('calreticulin', 'Gene', (114, 126))	('down-regulate', 'NegReg', (100, 113))	('affect', 'Reg', (161, 167))
73132	31258791	In recent years, various studies have been reported that miR-27a could regulate other related molecules to affect tumorigenesis.	('affect', 'Reg', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('regulate', 'Reg', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('miR-27a', 'Var', (57, 64))
73140	31258791	SPRY2 was a directly targeted of miR-27a and recognized as an inhibitor of the p44/42 MAPK signaling pathway, hence, miR-27a could target SPRY2 to regulate p44/42 MAPK signaling pathway.	('SPRY2', 'Gene', '10253', (0, 5))	('p44', 'Gene', '10561', (79, 82))	('p44', 'Gene', (156, 159))	('SPRY2', 'Gene', '10253', (138, 143))	('p44', 'Gene', '10561', (156, 159))	('regulate', 'Reg', (147, 155))	('p44', 'Gene', (79, 82))	('SPRY2', 'Gene', (0, 5))	('SPRY2', 'Gene', (138, 143))	('miR-27a', 'Var', (117, 124))
73141	31258791	Apart from this, miR-27a could also affect the cell cycle to regulate tumor cell activity.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('affect', 'Reg', (36, 42))	('cell cycle', 'CPA', (47, 57))	('miR-27a', 'Var', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
73142	31258791	For example, miR-27a could enhance the G1/S cell cycle transition by significantly decreasing the cell cycle inhibitors p21 and p27, as well as increasing cell cycle regulator cyclin D1 to promote proliferation.	('decreasing', 'NegReg', (83, 93))	('p27', 'Gene', '51014', (128, 131))	('p21', 'Gene', '644914', (120, 123))	('enhance', 'PosReg', (27, 34))	('increasing', 'PosReg', (144, 154))	('G1/S cell cycle transition', 'CPA', (39, 65))	('promote', 'PosReg', (189, 196))	('p27', 'Gene', (128, 131))	('miR-27a', 'Var', (13, 20))	('proliferation', 'CPA', (197, 210))	('cyclin D1', 'Gene', '595', (176, 185))	('p21', 'Gene', (120, 123))	('cyclin D1', 'Gene', (176, 185))
73146	31258791	Mutant p53 was different with p53 and promoted the tumor development.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('p53', 'Gene', '7157', (7, 10))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('promoted', 'PosReg', (38, 46))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
73147	31258791	Mutant p53, targeting and down-regulating directly miR-27a, could bind to the miR-27a promoter region and repress the expression of miR-27a.	('repress', 'NegReg', (106, 113))	('miR-27a', 'Gene', (132, 139))	('bind', 'Interaction', (66, 70))	('down-regulating', 'NegReg', (26, 41))	('p53', 'Gene', '7157', (7, 10))	('Mutant', 'Var', (0, 6))	('expression', 'MPA', (118, 128))	('miR-27a', 'Gene', (51, 58))	('p53', 'Gene', (7, 10))
73167	31258791	Besides, miR-27a-3p, as one of the vital upstream molecules, could influence EMT-related inducers Snail and Twist through YAP1-OCT4/Sox2 signal axis.	('Sox2', 'Gene', '6657', (132, 136))	('influence', 'Reg', (67, 76))	('Twist', 'CPA', (108, 113))	('Sox2', 'Gene', (132, 136))	('OCT4', 'Gene', '5460', (127, 131))	('OCT4', 'Gene', (127, 131))	('YAP1', 'Gene', '10413', (122, 126))	('miR-27a-3p', 'Var', (9, 19))	('Snail', 'CPA', (98, 103))	('YAP1', 'Gene', (122, 126))
73171	31258791	Additionally, there was a study reported that miR-331-5p and miR-27a could increase the sensitivity of K562/DOX and HL60/DOX cells to DOX.	('DOX', 'Chemical', 'MESH:D004317', (134, 137))	('-331-5p', 'Chemical', '-', (49, 56))	('DOX', 'Chemical', 'MESH:D004317', (108, 111))	('DOX', 'Chemical', 'MESH:D004317', (121, 124))	('miR-331', 'Gene', '442903', (46, 53))	('miR-27a', 'Var', (61, 68))	('K562', 'CellLine', 'CVCL:0004', (103, 107))	('miR-331', 'Gene', (46, 53))	('K562/DOX', 'MPA', (103, 111))	('increase', 'PosReg', (75, 83))	('HL60', 'CellLine', 'CVCL:0002', (116, 120))	('sensitivity', 'MPA', (88, 99))
73174	31258791	Interestingly, it was also revealed that miR-27a and miR-451, being in up-regulated, could promote expression level of MDR1 in human ovarian cancer cell and cervix carcinoma cell.	('miR-451', 'Gene', '574411', (53, 60))	('promote', 'PosReg', (91, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('human', 'Species', '9606', (127, 132))	('cervix carcinoma', 'Phenotype', 'HP:0030079', (157, 173))	('MDR1', 'Gene', (119, 123))	('cervix carcinoma', 'Disease', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('MDR1', 'Gene', '5243', (119, 123))	('ovarian cancer', 'Disease', 'MESH:D010051', (133, 147))	('miR-451', 'Gene', (53, 60))	('ovarian cancer', 'Disease', (133, 147))	('expression level', 'MPA', (99, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('cervix carcinoma', 'Disease', 'MESH:D002583', (157, 173))	('miR-27a', 'Var', (41, 48))
73175	31258791	Therefore, miR-27a may have a promising future in the treatment of DOX resistance.	('DOX', 'Chemical', 'MESH:D004317', (67, 70))	('miR-27a', 'Var', (11, 18))	('DOX resistance', 'Disease', (67, 81))
73176	31258791	Similar to the effect of repressing the cell drug resistance, the gene of BAK may play a vital role of functional target of miR-27a in breast cancer.	('miR-27a', 'Var', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('drug resistance', 'Phenotype', 'HP:0020174', (45, 60))	('BAK', 'Gene', (74, 77))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('BAK', 'Gene', '578', (74, 77))
73177	31258791	Moreover, knockdown of miR-27a increased the sensitivity of cancer cells to cisplatin treatment by BAK-SMAC/DIABLO-XIAP pathway.	('DIABLO', 'Gene', (108, 114))	('increased', 'PosReg', (31, 40))	('SMAC', 'Gene', (103, 107))	('sensitivity', 'MPA', (45, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('miR-27a', 'Gene', (23, 30))	('cancer', 'Disease', (60, 66))	('XIAP', 'Gene', (115, 119))	('DIABLO', 'Gene', '56616', (108, 114))	('XIAP', 'Gene', '331', (115, 119))	('SMAC', 'Gene', '56616', (103, 107))	('BAK', 'Gene', (99, 102))	('knockdown', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('BAK', 'Gene', '578', (99, 102))
73178	31258791	The effect of DOX, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)), and 5-FU to cancer could also be promoted by miR-27a.	('tumor necrosis factor-related apoptosis-inducing ligand', 'Gene', '8743', (26, 81))	('TRAIL', 'Gene', '8743', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('DOX', 'Chemical', 'MESH:D004317', (14, 17))	('TRAIL', 'Gene', (83, 88))	('5-FU', 'Chemical', 'MESH:D005472', (96, 100))	('TRAIL', 'Gene', '8743', (19, 24))	('miR-27a', 'Var', (137, 144))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('TRAIL', 'Gene', (19, 24))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('promoted', 'PosReg', (125, 133))
73180	31258791	It was possible that GBM patients with high miR-27a expression levels may respond better to certain chemotherapeutic agents, but the specific underlying mechanisms were not quite clear in this study.	('high', 'Var', (39, 43))	('better', 'PosReg', (82, 88))	('miR-27a', 'Gene', (44, 51))	('expression', 'MPA', (52, 62))	('patients', 'Species', '9606', (25, 33))
73183	31258791	They also found that when compared to A allele, rs11671784 G allele has a significantly stronger effect in promoting chemo-sensitivity in bladder cancer partially through reducing P-gp expression.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('reducing', 'NegReg', (171, 179))	('promoting', 'PosReg', (107, 116))	('P-gp', 'Gene', '5243', (180, 184))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('rs11671784', 'DBSNP_MENTION', 'None', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('chemo-sensitivity', 'CPA', (117, 134))	('P-gp', 'Gene', (180, 184))	('rs11671784', 'Var', (48, 58))
73184	31258791	Apart from the role of inhibiting the cell drug resistance, miR-27a could exert an opposite effect in many tumors.	('inhibiting', 'NegReg', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('miR-27a', 'Var', (60, 67))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('cell drug resistance', 'CPA', (38, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (43, 58))
73190	31258791	showed that in prostate cancer, COUP-TFII was negatively regulated by miR-101 and miR-27a, and loss of miRNA promoted metastasis by inducing COUP-TFII.	('miRNA', 'Protein', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('promoted', 'PosReg', (109, 117))	('COUP-TFII', 'Gene', (141, 150))	('prostate cancer', 'Disease', (15, 30))	('metastasis', 'CPA', (118, 128))	('COUP-TFII', 'Gene', '7026', (141, 150))	('miR-101', 'Gene', (70, 77))	('COUP-TFII', 'Gene', (32, 41))	('inducing', 'Reg', (132, 140))	('prostate cancer', 'Disease', 'MESH:D011471', (15, 30))	('COUP-TFII', 'Gene', '7026', (32, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (15, 30))	('miR-101', 'Chemical', '-', (70, 77))	('loss', 'Var', (95, 99))
73192	31258791	Therefore, miR-101 or miR-27a would act as a promising target in therapy.	('miR-101', 'Chemical', '-', (11, 18))	('miR-27a', 'Gene', (22, 29))	('miR-101', 'Var', (11, 18))
73193	31258791	Similar to studies above, miR-27a/b could convert NOF to CAF-like fibroblasts (miR-27a/b-induced CAF) and indirectly affect chemo-sensitivity of esophageal cancer cells.	('CAF', 'Chemical', '-', (97, 100))	('miR-27a/b', 'Var', (26, 35))	('esophageal cancer', 'Disease', (145, 162))	('CAF', 'Chemical', '-', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('miR-27a/b-induced', 'Var', (79, 96))	('chemo-sensitivity', 'CPA', (124, 141))	('affect', 'Reg', (117, 123))
73218	31258791	In the drug resistance or therapy of the cancer, miR-27a has been played a vital role and significantly affects the patient's prognosis.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('patient', 'Species', '9606', (116, 123))	('drug resistance', 'Phenotype', 'HP:0020174', (7, 22))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('affects', 'Reg', (104, 111))	('miR-27a', 'Var', (49, 56))
73219	31258791	Accordingly, miR-27a may be a potential biomarker for cancer patients' prognoses.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Disease', (54, 60))	('miR-27a', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
73220	31258791	The expression level of a combination of miR-27a or miR-331-5p could suggest clinical relapse or poor prognosis.	('miR-331', 'Gene', '442903', (52, 59))	('clinical relapse', 'CPA', (77, 93))	('-331-5p', 'Chemical', '-', (55, 62))	('miR-331', 'Gene', (52, 59))	('poor prognosis', 'CPA', (97, 111))	('expression', 'MPA', (4, 14))	('miR-27a', 'Var', (41, 48))
73221	31258791	For example, the patients with relapsed lymphocytic leukaemia or myeloid leukaemia, the expression of miR-27a or miR-331-5p was low but untreated patients was high.	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (65, 82))	('miR-27a', 'Var', (102, 109))	('-331-5p', 'Chemical', '-', (116, 123))	('miR-331', 'Gene', '442903', (113, 120))	('lymphocytic leukaemia or myeloid leukaemia', 'Disease', (40, 82))	('patients', 'Species', '9606', (17, 25))	('miR-331', 'Gene', (113, 120))	('low', 'NegReg', (128, 131))	('lymphocytic leukaemia or myeloid leukaemia', 'Disease', 'MESH:D007938', (40, 82))	('expression', 'MPA', (88, 98))	('patients', 'Species', '9606', (146, 154))	('relapsed lymphocytic leukaemia', 'Phenotype', 'HP:0005550', (31, 61))
73222	31258791	Apart from it, it was possible that GBM patients with high miR-27a expression levels may respond better to certain chemotherapeutic agents.	('high', 'Var', (54, 58))	('patients', 'Species', '9606', (40, 48))	('better', 'PosReg', (97, 103))	('expression', 'MPA', (67, 77))	('miR-27a', 'Gene', (59, 66))
73223	31258791	And the study also revealed that in GBM patients whose miR-27a expression levels were high would have a better outcome, while the GBM patients whose miR-27a expression levels were low may have a poor prognosis.	('patients', 'Species', '9606', (40, 48))	('expression levels', 'MPA', (63, 80))	('patients', 'Species', '9606', (134, 142))	('miR-27a', 'Var', (55, 62))
73226	31258791	The obese liver cancer patients with high miR-27a levels would tend to promote liver cancer proliferation when compared to those with low miR-27a levels.	('miR-27a', 'Var', (42, 49))	('promote', 'PosReg', (71, 78))	('liver cancer', 'Phenotype', 'HP:0002896', (79, 91))	('liver cancer', 'Phenotype', 'HP:0002896', (10, 22))	('patients', 'Species', '9606', (23, 31))	('liver cancer', 'Disease', 'MESH:D006528', (79, 91))	('liver cancer', 'Disease', 'MESH:D006528', (10, 22))	('liver cancer', 'Disease', (79, 91))	('obese liver cancer', 'Disease', (4, 22))	('obese liver cancer', 'Disease', 'MESH:D009765', (4, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('high miR-27a', 'Var', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
73227	31258791	Hence, miR-27a may suggest that the obese liver cancer patients may have poor prognosis in the future.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('liver cancer', 'Phenotype', 'HP:0002896', (42, 54))	('obese liver cancer', 'Disease', 'MESH:D009765', (36, 54))	('obese liver cancer', 'Disease', (36, 54))	('miR-27a', 'Var', (7, 14))	('patients', 'Species', '9606', (55, 63))
73230	31258791	Accordingly, these results above indicated that miR-27a may have a promising prognostic value of osteosarcoma patients prognosis.	('miR-27a', 'Var', (48, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (97, 109))	('osteosarcoma', 'Disease', (97, 109))	('osteosarcoma', 'Disease', 'MESH:D012516', (97, 109))	('patients', 'Species', '9606', (110, 118))
73237	31258791	In tumor biology, it could have the polymorphisms and significantly influence tumor cells tumorigenesis, proliferation, apoptosis, invasion, migration and angiogenesis.	('migration', 'CPA', (141, 150))	('tumor', 'Disease', (3, 8))	('invasion', 'CPA', (131, 139))	('polymorphisms', 'Var', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('apoptosis', 'CPA', (120, 129))	('influence', 'Reg', (68, 77))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('proliferation', 'CPA', (105, 118))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Disease', (78, 83))	('angiogenesis', 'CPA', (155, 167))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
73238	31258791	And in clinical significance, miR-27a could affect clinical therapy, drug sensitivity of patients and patient's prognosis.	('patient', 'Species', '9606', (89, 96))	('patient', 'Species', '9606', (102, 109))	('miR-27a', 'Var', (30, 37))	('patients', 'Species', '9606', (89, 97))	('affect', 'Reg', (44, 50))	('clinical therapy', 'MPA', (51, 67))	('drug sensitivity', 'Phenotype', 'HP:0020174', (69, 85))	('drug sensitivity', 'MPA', (69, 85))
73240	31258791	In conclusion, miR-27a participated in tumor biology and affected the clinical treatment, therefore, we suggested that miR-27a acted as a promising biomarker and potential therapeutic target in various tumors.	('affected', 'Reg', (57, 65))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('miR-27a', 'Var', (119, 126))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('participated', 'Reg', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
73267	27759060	All 14 comparisons from 11 articles included reported the relationship between dietary consumption of choline and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('dietary', 'Var', (79, 86))	('choline', 'Chemical', 'MESH:D002794', (102, 109))	('relationship', 'Interaction', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
73293	27759060	Therefore, in case that this pathway of one-carbon metabolism gets disrupted, it will exert an influence over the process of DNA synthesis and repair, as well as the genetic expression regulation by means of methylation, and consequently promotes carcinogenesis.	('carbon', 'Chemical', 'MESH:D002244', (44, 50))	('disrupted', 'Var', (67, 76))	('influence', 'Reg', (95, 104))	('carcinogenesis', 'Disease', 'MESH:D063646', (247, 261))	('carcinogenesis', 'Disease', (247, 261))	('promotes', 'PosReg', (238, 246))	('methylation', 'MPA', (208, 219))
73394	26934001	Subsequent studies showed that miR-92b exerted its inhibitory function through suppressing the expression of integrin alphaV (ITGAV), which further reduced phosphrylated FAK and impaired Rac1 activation.	('Rac1', 'Gene', (187, 191))	('FAK', 'Gene', (170, 173))	('FAK', 'Gene', '5747', (170, 173))	('reduced', 'NegReg', (148, 155))	('integrin alphaV (ITGAV)', 'Gene', '3685', (109, 132))	('miR-92b', 'Var', (31, 38))	('integrin alphaV (ITGAV', 'Gene', (109, 131))	('suppressing', 'NegReg', (79, 90))	('impaired', 'NegReg', (178, 186))	('Rac1', 'Gene', '5879', (187, 191))	('expression', 'MPA', (95, 105))
73399	26934001	In breast cancer cells, miR-10b decreased HOXD10 level to enhance metastasis and miR-335 inhibited SOX4 expression to suppress epithelial-mesenchymal transition (EMT) are examples of the first mode.	('enhance', 'PosReg', (58, 65))	('miR-335', 'Gene', '442904', (81, 88))	('suppress', 'NegReg', (118, 126))	('epithelial-mesenchymal transition', 'CPA', (127, 160))	('HOXD10', 'Gene', '3236', (42, 48))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('miR-10b', 'Var', (24, 31))	('inhibited', 'NegReg', (89, 98))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('HOXD10', 'Gene', (42, 48))	('SOX4', 'Gene', (99, 103))	('miR-335', 'Gene', (81, 88))	('SOX4', 'Gene', '6659', (99, 103))	('decreased', 'NegReg', (32, 41))	('metastasis', 'CPA', (66, 76))
73408	26934001	Mechanistically, overexpression of miR-92b or silence of ITGAV led to decreased phosphrylated focal adhesion kinase (FAK) and reduced activation of Rac1, both of which were essential mediators of cellular motility in ESCC cells.	('Rac1', 'Gene', (148, 152))	('miR-92b', 'Var', (35, 42))	('decreased', 'NegReg', (70, 79))	('activation', 'PosReg', (134, 144))	('focal adhesion kinase', 'Gene', '5747', (94, 115))	('silence', 'Var', (46, 53))	('ITGAV', 'Gene', (57, 62))	('Rac1', 'Gene', '5879', (148, 152))	('overexpression', 'PosReg', (17, 31))	('focal adhesion kinase', 'Gene', (94, 115))	('FAK', 'Gene', (117, 120))	('FAK', 'Gene', '5747', (117, 120))	('reduced', 'NegReg', (126, 133))
73413	26934001	Additionally, miR-92b retarded the healing velocity of 30-D cells within 24 hours (Supplementary Figure S2C).	('retarded', 'Disease', (22, 30))	('healing velocity of 30-D cells', 'CPA', (35, 65))	('miR-92b', 'Var', (14, 21))	('retarded', 'Disease', 'MESH:D008607', (22, 30))
73417	26934001	We found that 2 out of 7 mice implanted with miR-92b tumors were free of invasion (IS0), whereas all mock tumors invaded muscle to different extents (p = 0.021, Figure 2D), showing that the control cells manifested more aggressive invasion than the miR-92b- transfected counterparts did.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('mice', 'Species', '10090', (25, 29))	('mock tumors', 'Disease', (101, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('miR-92b', 'Var', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('aggressive invasion', 'CPA', (220, 239))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', (53, 59))	('mock tumors', 'Disease', 'MESH:D009369', (101, 112))
73418	26934001	We then examined whether miR-92b impeded pulmonary arrest of ESCC cells.	('pulmonary arrest', 'Disease', (41, 57))	('impeded', 'NegReg', (33, 40))	('miR-92b', 'Var', (25, 32))	('pulmonary arrest', 'Disease', 'MESH:D006323', (41, 57))
73420	26934001	As interactions among transmembrane molecules of circulating tumor cells and endothelia as well as tumor cell size contribute to microvasculature arrest, we tested whether miR-92b would diminish bulk of the transfected cells.	('microvasculature arrest', 'Disease', (129, 152))	('tumor', 'Disease', (99, 104))	('miR-92b', 'Var', (172, 179))	('diminish', 'NegReg', (186, 194))	('interactions', 'Interaction', (3, 15))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tested', 'Reg', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('contribute', 'Reg', (115, 125))	('tumor', 'Disease', (61, 66))	('microvasculature arrest', 'Disease', 'MESH:D006323', (129, 152))
73421	26934001	Lastly, we evaluated whether miR-92b could impair overt metastases formation in lung.	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('metastases', 'Disease', (56, 66))	('impair', 'NegReg', (43, 49))	('miR-92b', 'Var', (29, 36))
73426	26934001	Luciferase reporter assay excluded the possibility of JMY, SOX4, TOB1, USP28, and WASL as targets of miR-92b (Supplementary Figure S5B).	('USP28', 'Gene', '57646', (71, 76))	('JMY', 'Gene', '133746', (54, 57))	('TOB1', 'Gene', (65, 69))	('miR-92b', 'Var', (101, 108))	('SOX4', 'Gene', (59, 63))	('S5B', 'Gene', '5711', (131, 134))	('TOB1', 'Gene', '10140', (65, 69))	('USP28', 'Gene', (71, 76))	('WASL', 'Gene', (82, 86))	('S5B', 'Gene', (131, 134))	('JMY', 'Gene', (54, 57))	('SOX4', 'Gene', '6659', (59, 63))	('WASL', 'Gene', '8976', (82, 86))
73429	26934001	Additionally, silence of endogenous miR-92b in 30-D, KYSE450, and KYSE510 cells could enhance luciferase activity, further confirming that miR-92b suppressed ITGAV expression by directly binding to 3'UTR of this integrin (Supplementary Figure S5F).	('ITGAV', 'Protein', (158, 163))	('miR-92b', 'Gene', (36, 43))	('silence', 'Var', (14, 21))	('enhance', 'PosReg', (86, 93))	('expression', 'MPA', (164, 174))	('KYSE510', 'Var', (66, 73))	('suppressed', 'NegReg', (147, 157))	('activity', 'MPA', (105, 113))	('binding', 'Interaction', (187, 194))	('KYSE510', 'CellLine', 'CVCL:1354', (66, 73))	('miR-92b', 'Var', (139, 146))	('luciferase', 'Enzyme', (94, 104))
73431	26934001	Moreover, we found that silence of ITGAV, resembling miR-92b function in pulmonary arrest, attenuated adhesion of 30-D cells to pulmonary capillaries (p = 0.007, Figure 5A and Supplementary Figure S7A), and reduction in ITGAV did not influence cell size either (Supplementary Figure S7B).	('silence', 'Var', (24, 31))	('ITGAV', 'Gene', (35, 40))	('pulmonary arrest', 'Disease', 'MESH:D006323', (73, 89))	('attenuated', 'NegReg', (91, 101))	('pulmonary capillaries', 'Disease', (128, 149))	('adhesion', 'MPA', (102, 110))	('pulmonary arrest', 'Disease', (73, 89))	('pulmonary capillaries', 'Disease', 'MESH:C535861', (128, 149))
73434	26934001	To begin with, silence of FAK undermined migration and invasion of 30-D cells in vitro (Figure 6A, Supplementary Figure S10A and S10B).	('S10A', 'Var', (120, 124))	('FAK', 'Gene', (26, 29))	('FAK', 'Gene', '5747', (26, 29))	('S10B', 'Var', (129, 133))	('S10A', 'SUBSTITUTION', 'None', (120, 124))	('S10B', 'SUBSTITUTION', 'None', (129, 133))	('undermined', 'NegReg', (30, 40))	('silence', 'Var', (15, 22))
73435	26934001	Thereafter, we detected the level of phosphorylated FAK and P130/Cas at indicated time points, showing that elevated miR-92b in 30-D cells decreased the abundance of p-FAK (Y397, Y576/577, Y861 and Y925) and p-P130/Cas (Y165, Y249, and Y410) (Figure 6B).	('p-P130/Cas', 'Gene', '9564', (208, 218))	('P130/Cas', 'Gene', '9564;22930', (210, 218))	('P130/Cas', 'Gene', (60, 68))	('P130/Cas', 'Gene', (210, 218))	('FAK', 'Gene', (52, 55))	('Y576/577', 'Var', (179, 187))	('FAK', 'Gene', (168, 171))	('elevated', 'PosReg', (108, 116))	('FAK', 'Gene', '5747', (52, 55))	('miR-92b', 'Protein', (117, 124))	('Y861', 'Var', (189, 193))	('FAK', 'Gene', '5747', (168, 171))	('Y249', 'Var', (226, 230))	('Y165', 'Var', (220, 224))	('p-P130/Cas', 'Gene', (208, 218))	('Y410', 'Var', (236, 240))	('Y925', 'Var', (198, 202))	('decreased', 'NegReg', (139, 148))	('P130/Cas', 'Gene', '9564;22930', (60, 68))
73436	26934001	Paxillin phosphorylation is a critical event during focal adhesion formation; in our system, we also observed decreased level of p-Paxillin (Y118) in miR-92b-transfected cells (Figure 6B).	('Paxillin', 'Gene', '5829', (0, 8))	('decreased', 'NegReg', (110, 119))	('Y118', 'Chemical', '-', (141, 145))	('Paxillin', 'Gene', (0, 8))	('Paxillin', 'Gene', '5829', (131, 139))	('Y118', 'Var', (141, 145))	('Paxillin', 'Gene', (131, 139))
73440	26934001	As expected, both silence of Rac1 and pharmaceutical inhibition using NSC23667 could significantly inhibit invasion of 30-D cells (Figure 6C, Supplementary Figure S10D and S10E).	('Rac1', 'Gene', (29, 33))	('S10E', 'Mutation', 'p.S10E', (172, 176))	('silence', 'Var', (18, 25))	('inhibit', 'NegReg', (99, 106))	('NSC23667', 'Var', (70, 78))	('S10D', 'Var', (163, 167))	('S10D', 'SUBSTITUTION', 'None', (163, 167))	('Rac1', 'Gene', '5879', (29, 33))	('invasion of 30-D cells', 'CPA', (107, 129))
73441	26934001	Besides, we found that miR-92b or ITGAV depletion reduced the amount of activated Rac1 without influencing activation of total Rho and Cdc42 (Figure 6D and Supplementary Figure S10F).	('depletion', 'Var', (40, 49))	('Rac1', 'Gene', (82, 86))	('Rac1', 'Gene', '5879', (82, 86))	('activated', 'MPA', (72, 81))	('Cdc42', 'Gene', '998', (135, 140))	('Cdc42', 'Gene', (135, 140))	('reduced', 'NegReg', (50, 57))	('miR-92b', 'Var', (23, 30))	('S10F', 'Mutation', 'p.S10F', (177, 181))	('amount', 'MPA', (62, 68))
73442	26934001	Moreover, re-expression of ITGAV could rescue Rac1 activation and increase the level of p-FAK (Y397) in 30-D cells pre-transfected miR-92b mimics (Figure 6E).	('ITGAV', 'Gene', (27, 32))	('increase', 'PosReg', (66, 74))	('Rac1', 'Gene', (46, 50))	('activation', 'MPA', (51, 61))	('rescue', 'PosReg', (39, 45))	('re-expression', 'Var', (10, 23))	('FAK', 'Gene', (90, 93))	('FAK', 'Gene', '5747', (90, 93))	('Rac1', 'Gene', '5879', (46, 50))
73443	26934001	Accumulating evidence has corroborated that integrin alphavbeta5 and alphavbeta3 were involved in tumor metastasis, we therefore detected the membrane expression of these two integrin heterodimers in 30-D cells, showing negative expression of alphavbeta3 but dramatically decreased alphavbeta5 responding to elevated miR-92b (Supplementary Figure S11A).	('in a', 'Gene', (50, 54))	('tumor metastasis', 'Disease', 'MESH:D009362', (98, 114))	('miR-92b', 'MPA', (317, 324))	('tumor metastasis', 'Disease', (98, 114))	('decreased', 'NegReg', (272, 281))	('elevated', 'PosReg', (308, 316))	('S11A', 'Var', (347, 351))	('in a', 'Gene', '9118', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('involved', 'Reg', (86, 94))	('alphavbeta5 responding', 'MPA', (282, 304))	('S11A', 'SUBSTITUTION', 'None', (347, 351))
73444	26934001	Further knockdown of ITGB5 attenuated motility of 30-D cells, partially demonstrating that integrin alphavbeta5 was probably important in invasion-metastasis cascade of ESCC (Supplementary Figure S11B).	('S11B', 'Var', (196, 200))	('attenuated', 'NegReg', (27, 37))	('motility of 30-D cells', 'CPA', (38, 60))	('ESCC', 'Disease', (169, 173))	('ITGB5', 'Gene', '3693', (21, 26))	('S11B', 'SUBSTITUTION', 'None', (196, 200))	('in a', 'Gene', '9118', (97, 101))	('knockdown', 'Var', (8, 17))	('in a', 'Gene', (97, 101))	('ITGB5', 'Gene', (21, 26))
73447	26934001	Previous reports from glioblastoma and non-small cell lung cancer indicated that miR-92b promoted growth and metastasis of neoplastic cells; whereas absence ofmiR-92b contributed to transformation of normal human B lymphocytes through epigenetic mechanisms.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (39, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('miR-92b', 'Gene', (81, 88))	('non-small cell lung cancer', 'Disease', (39, 65))	('glioblastoma', 'Disease', (22, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (43, 65))	('growth and metastasis of neoplastic cells', 'CPA', (98, 139))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('promoted', 'PosReg', (89, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('human', 'Species', '9606', (207, 212))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (39, 65))	('absence', 'Var', (149, 156))
73453	26934001	In our study, integrin alphaVbeta5, not alphaVbeta3 was detected in 30-D cells and membrane expression of integrin alphaVbeta5 dropped dramatically upon transfection of miR-92b mimic.	('integrin alphaV', 'Gene', (14, 29))	('membrane expression', 'MPA', (83, 102))	('dropped', 'NegReg', (127, 134))	('miR-92b', 'Var', (169, 176))	('integrin alphaV', 'Gene', '3685', (106, 121))	('integrin alphaV', 'Gene', '3685', (14, 29))	('integrin alphaV', 'Gene', (106, 121))
73454	26934001	Responding to variant stimulus integrins activate or suppress different signaling pathways, among which FAK is one critical signal hub.	('activate', 'PosReg', (41, 49))	('suppress', 'NegReg', (53, 61))	('signaling pathways', 'Pathway', (72, 90))	('FAK', 'Gene', '5747', (104, 107))	('FAK', 'Gene', (104, 107))	('variant', 'Var', (14, 21))
73455	26934001	We found that miR-92b decreased the level of p-FAKs and relevant scaffold proteins such as p-paxillin and p-p130/Cas.	('p-p130/Cas', 'Gene', (106, 116))	('paxillin', 'Gene', (93, 101))	('in a', 'Gene', (99, 103))	('FAK', 'Gene', '5747', (47, 50))	('miR-92b', 'Var', (14, 21))	('p-p130/Cas', 'Gene', '9564', (106, 116))	('FAK', 'Gene', (47, 50))	('in a', 'Gene', '9118', (99, 103))	('paxillin', 'Gene', '5829', (93, 101))	('decreased', 'NegReg', (22, 31))
73457	26934001	We found that knockdown of ITGB1 or ITGB5 retarded motility of 30-D cells respectively.	('ITGB1', 'Gene', (27, 32))	('ITGB5', 'Gene', (36, 41))	('ITGB5', 'Gene', '3693', (36, 41))	('knockdown', 'Var', (14, 23))	('ITGB1', 'Gene', '3688', (27, 32))	('retarded motility', 'Disease', 'MESH:D015835', (42, 59))	('retarded motility', 'Disease', (42, 59))
73458	26934001	Moreover, ITGB1 depletion also reduced p-FAKs but failed to cause pulmonary arrest (data not shown).	('reduced', 'NegReg', (31, 38))	('ITGB1', 'Gene', (10, 15))	('depletion', 'Var', (16, 25))	('pulmonary arrest', 'Disease', 'MESH:D006323', (66, 82))	('FAK', 'Gene', (41, 44))	('FAK', 'Gene', '5747', (41, 44))	('ITGB1', 'Gene', '3688', (10, 15))	('pulmonary arrest', 'Disease', (66, 82))
73474	26934001	When HEK293T cells grew to 80-90% confluence, fresh DMEM with 10% FBS was added in culture dishes and after around 24 hr the culture medium was collected, centrifuged (4.5x103 g, 4 C), filtered (0.45 mum pores) and stored in -80 C refrigerator in aliquots.	('in a', 'Gene', '9118', (244, 248))	('FBS', 'Disease', (66, 69))	('HEK293T', 'CellLine', 'CVCL:0063', (5, 12))	('DMEM', 'Chemical', '-', (52, 56))	('HEK293T', 'Var', (5, 12))	('in a', 'Gene', (244, 248))	('FBS', 'Disease', 'MESH:D005198', (66, 69))
73490	26934001	In the lower chambers were added RPMI1640 with 20% FBS.	('RPMI1640', 'Var', (33, 41))	('RPMI1640', 'Chemical', '-', (33, 41))	('FBS', 'Disease', (51, 54))	('FBS', 'Disease', 'MESH:D005198', (51, 54))
73497	26934001	The pISO plasmid containing wild type or mutated miR-92b recognized sites was co-transfected with a Renilla luciferase vector and miR-92b or negative control oligos into 30-D, KYSE450, or KYSE510 cells, which were maintained in 96-well plates, in quadruplicate respectively.	('KYSE510', 'CellLine', 'CVCL:1354', (188, 195))	('mutated', 'Var', (41, 48))	('miR-92b', 'Gene', (49, 56))
73525	26924648	Specifically, coexisting CKD and DM increased the 42-day and one-year mortality with respective HRs of 1.99 (95%CI, 1.03-3.84) and 1.84 (95%CI, 1.14-2.98) compared with those without CKD and DM.	('CKD', 'Phenotype', 'HP:0012622', (25, 28))	('increased', 'PosReg', (36, 45))	('DM', 'Phenotype', 'HP:0000819', (191, 193))	('CKD', 'Phenotype', 'HP:0012622', (183, 186))	('DM', 'Phenotype', 'HP:0000819', (33, 35))	('DM', 'Disease', 'MESH:D009223', (33, 35))	('42-day', 'MPA', (50, 56))	('CKD', 'Var', (25, 28))	('DM', 'Disease', 'MESH:D009223', (191, 193))
73539	26924648	How DM and/or CKD per se, is/are independent mortality risk factors, and how they further increase the risk of mortality is still unclear.	('CKD', 'Var', (14, 17))	('increase', 'PosReg', (90, 98))	('DM', 'Phenotype', 'HP:0000819', (4, 6))	('DM', 'Disease', 'MESH:D009223', (4, 6))	('CKD', 'Phenotype', 'HP:0012622', (14, 17))
73563	26924648	In Model 4, the HRs for male and female diabetic patients with CKD were 2.84 (95 % CI, 1.31-6.14) and 2.42 (95 % CI, 1.28-4.57), respectively.	('CKD', 'Var', (63, 66))	('diabetic', 'Disease', (40, 48))	('CKD', 'Phenotype', 'HP:0012622', (63, 66))	('patients', 'Species', '9606', (49, 57))	('diabetic', 'Disease', 'MESH:D003920', (40, 48))
73586	26924648	This implied that CKD may be associated with poor clearance of circulatory neurotoxic substances that increases the susceptibility to mortality in cirrhotic patients with hepatic encephalopathy.	('neurotoxic', 'Disease', (75, 85))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (171, 193))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (171, 193))	('patients', 'Species', '9606', (157, 165))	('hepatic encephalopathy', 'Disease', (171, 193))	('poor', 'NegReg', (45, 49))	('CKD', 'Phenotype', 'HP:0012622', (18, 21))	('encephalopathy', 'Phenotype', 'HP:0001298', (179, 193))	('neurotoxic', 'Disease', 'MESH:D020258', (75, 85))	('CKD', 'Var', (18, 21))
73591	26924648	CKD and DM have many long-term complications such as increased immunocompromised status, as well as increased risk of metabolic disorders and cardiovascular events.	('metabolic disorders', 'Disease', (118, 137))	('cardiovascular events', 'Phenotype', 'HP:0001626', (142, 163))	('increased immunocompromised status', 'Phenotype', 'HP:0005387', (53, 87))	('CKD', 'Phenotype', 'HP:0012622', (0, 3))	('increased', 'PosReg', (53, 62))	('DM', 'Phenotype', 'HP:0000819', (8, 10))	('metabolic disorders', 'Disease', 'MESH:D008659', (118, 137))	('DM', 'Disease', 'MESH:D009223', (8, 10))	('CKD', 'Var', (0, 3))
73610	26924648	In a cross-sectional community study that included 11.4 % (372/3,260) individuals with elevated alanine aminotransferase (ALT), NAFLD was the most common cause of ALT elevation with a prevalence of 33.6 %, and followed by HBV (28.5 %), unexplained cause (21.8 %), HCV (13.2 %), both HBV and HCV (2.2 %), and excess alcohol consumption (0.8 %).	('NAFLD', 'Var', (128, 133))	('alcohol', 'Chemical', 'MESH:D000438', (315, 322))	('elevation', 'PosReg', (167, 176))	('alanine aminotransferase', 'Gene', (96, 120))	('ALT', 'MPA', (163, 166))	('excess alcohol consumption', 'Phenotype', 'HP:0030955', (308, 334))	('alanine aminotransferase', 'Gene', '2875', (96, 120))	('elevated alanine aminotransferase', 'Phenotype', 'HP:0031964', (87, 120))	('elevated alanine', 'Phenotype', 'HP:0003348', (87, 103))	('ALT elevation', 'Phenotype', 'HP:0031964', (163, 176))
73620	26924648	This study provides evidence that coexistence of CKD and DM has a higher impact on 42-day and one-year mortality than DM or CKD individually.	('CKD', 'Var', (49, 52))	('CKD', 'Phenotype', 'HP:0012622', (49, 52))	('42-day', 'MPA', (83, 89))	('DM', 'Phenotype', 'HP:0000819', (118, 120))	('CKD', 'Phenotype', 'HP:0012622', (124, 127))	('DM', 'Disease', 'MESH:D009223', (118, 120))	('DM', 'Phenotype', 'HP:0000819', (57, 59))	('DM', 'Disease', 'MESH:D009223', (57, 59))	('one-year mortality', 'CPA', (94, 112))
73677	26819634	The median time period to dysphagia improvement for at least one point was 26 weeks for patients who were treated with EBRT +- BT and 16 weeks for patients who were treated with BT alone (Fig.	('dysphagia', 'Disease', 'MESH:D003680', (26, 35))	('EBRT +- BT', 'Var', (119, 129))	('patients', 'Species', '9606', (88, 96))	('improvement', 'PosReg', (36, 47))	('patients', 'Species', '9606', (147, 155))	('dysphagia', 'Disease', (26, 35))	('EBRT +- BT', 'Chemical', '-', (119, 129))	('dysphagia', 'Phenotype', 'HP:0002015', (26, 35))
73857	25383653	In particular, as for short-term tumor growth analysis, the treatment of colorectal carcinoma with ONCOFID-P improves mice survival at a comparable extent to ONCOFID-S, which carry the on-label, widely used CPT-11 metabolite.	('improves', 'PosReg', (109, 117))	('CPT-11', 'Chemical', 'MESH:D000077146', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (73, 93))	('ONCOFID-P', 'Chemical', 'MESH:C560640', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mice survival', 'CPA', (118, 131))	('-S', 'Chemical', 'MESH:D013455', (165, 167))	('tumor', 'Disease', (33, 38))	('mice', 'Species', '10090', (118, 122))	('ONCOFID-P', 'Var', (99, 108))	('colorectal carcinoma', 'Disease', (73, 93))
73859	23536563	Loss of TGF-beta Adaptor beta2SP Activates Notch Signaling and SOX9 Expression in Esophageal Adenocarcinoma TGF-beta and Notch signaling pathways play important roles in regulating self-renewal of stem cells and gastrointestinal carcinogenesis.	('TGF-beta', 'Gene', '7040', (108, 116))	('TGF-beta', 'Gene', '7040', (8, 16))	('TGF-beta', 'Gene', (108, 116))	('Expression', 'MPA', (68, 78))	('SOX9', 'Gene', (63, 67))	('TGF-beta', 'Gene', (8, 16))	('Notch Signaling', 'MPA', (43, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (82, 107))	('gastrointestinal carcinogenesis', 'Disease', (212, 243))	('Esophageal Adenocarcinoma', 'Disease', (82, 107))	('SOX9', 'Gene', '6662', (63, 67))	('gastrointestinal carcinogenesis', 'Disease', 'MESH:D063646', (212, 243))	('Activates', 'PosReg', (33, 42))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (82, 107))	('Loss', 'Var', (0, 4))	('self-renewal of stem cells', 'CPA', (181, 207))
73860	23536563	Loss of TGF-beta signaling components activates Notch signaling in esophageal adenocarcinoma, but the basis for this effect has been unclear.	('TGF-beta', 'Gene', '7040', (8, 16))	('esophageal adenocarcinoma', 'Disease', (67, 92))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (67, 92))	('TGF-beta', 'Gene', (8, 16))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (67, 92))	('activates', 'PosReg', (38, 47))	('Loss', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('Notch signaling', 'MPA', (48, 63))
73861	23536563	Here we report that loss of TGF-beta adapter beta2SP (SPNB2) activates Notch signaling and its target SOX9 in primary fibroblasts or esophageal adenocarcinoma cells.	('loss', 'Var', (20, 24))	('TGF-beta', 'Gene', (28, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (133, 158))	('esophageal adenocarcinoma', 'Disease', (133, 158))	('Notch signaling', 'MPA', (71, 86))	('activates', 'PosReg', (61, 70))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (133, 158))	('SPNB2', 'Gene', (54, 59))	('TGF-beta', 'Gene', '7040', (28, 36))
73863	23536563	In contrast, reintroduction into esophageal adenocarcinoma cells of beta2SP and a dominant-negative mutant of the Notch coactivator mastermind-like (dnMAN) decreased SOX9 promoter activity.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('beta2SP', 'Protein', (68, 75))	('esophageal adenocarcinoma', 'Disease', (33, 58))	('mutant', 'Var', (100, 106))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (33, 58))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (33, 58))	('decreased', 'NegReg', (156, 165))	('SOX9 promoter activity', 'MPA', (166, 188))
73865	23536563	Conversely, SOX9 silencing rescued the phenotype of esophageal adenocarcinoma cells with loss of beta2SP.	('esophageal adenocarcinoma', 'Disease', (52, 77))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (52, 77))	('rescued', 'PosReg', (27, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('SOX9', 'Gene', (12, 16))	('beta2SP', 'Protein', (97, 104))	('silencing', 'Var', (17, 26))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (52, 77))	('loss', 'NegReg', (89, 93))
73866	23536563	Interaction between Smad3 and ICN1 via Smad3 MH1 domain was also observed, with loss of beta2SP increasing the binding between these proteins, inducing expression of Notch targets SOX9 and C-MYC, and decreasing expression of TGF-beta targets p21(CDKN1A), p27 (CDKN1B), and E-cadherin.	('TGF-beta', 'Gene', '7040', (225, 233))	('p21', 'Gene', '1026', (242, 245))	('loss', 'Var', (80, 84))	('Smad3', 'Gene', '4088', (39, 44))	('Smad3', 'Gene', (39, 44))	('E-cadherin', 'Gene', (273, 283))	('E-cadherin', 'Gene', '999', (273, 283))	('TGF-beta', 'Gene', (225, 233))	('CDKN1B', 'Gene', '1027', (260, 266))	('inducing', 'PosReg', (143, 151))	('expression', 'MPA', (152, 162))	('p27', 'Gene', '51014', (255, 258))	('decreasing', 'NegReg', (200, 210))	('CDKN1A', 'Gene', (246, 252))	('Smad3', 'Gene', '4088', (20, 25))	('Interaction', 'Interaction', (0, 11))	('CDKN1A', 'Gene', '1026', (246, 252))	('Smad3', 'Gene', (20, 25))	('p21', 'Gene', (242, 245))	('C-MYC', 'Gene', '4609', (189, 194))	('beta2SP', 'Protein', (88, 95))	('expression', 'MPA', (211, 221))	('C-MYC', 'Gene', (189, 194))	('p27', 'Gene', (255, 258))	('binding', 'Interaction', (111, 118))	('increasing', 'PosReg', (96, 106))	('CDKN1B', 'Gene', (260, 266))
73867	23536563	Taken together, our findings suggest that loss of beta2SP switches TGF-beta signaling from tumor suppression to tumor promotion by engaging Notch signaling and activating SOX9.	('tumor', 'Disease', (112, 117))	('SOX9', 'Gene', (171, 175))	('loss', 'Var', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('TGF-beta', 'Gene', '7040', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TGF-beta', 'Gene', (67, 75))	('Notch signaling', 'MPA', (140, 155))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('engaging', 'PosReg', (131, 139))	('beta2SP', 'Protein', (50, 57))	('activating', 'PosReg', (160, 170))	('tumor', 'Disease', (91, 96))
73872	23536563	Deregulation of these pathways along with improper interactions between them may represent key events for esophageal adenocarcinoma carcinogenesis.	('Deregulation', 'Var', (0, 12))	('interactions', 'Interaction', (51, 63))	('esophageal adenocarcinoma carcinogenesis', 'Disease', (106, 146))	('esophageal adenocarcinoma carcinogenesis', 'Disease', 'MESH:D063646', (106, 146))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (106, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
73874	23536563	Dysfunction of TGF-beta signaling is widely associated with many tumors.	('associated', 'Reg', (44, 54))	('Dysfunction', 'Var', (0, 11))	('TGF-beta', 'Gene', '7040', (15, 23))	('TGF-beta', 'Gene', (15, 23))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
73877	23536563	Interestingly, 40% of mice with heterozygous deletion of beta2SP developed hepatocellular carcinoma and 90% of beta2SP+/-/Smad4+/- mice developed gastric cancer and other gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('gastric cancer', 'Disease', 'MESH:D013274', (146, 160))	('gastric cancer', 'Disease', (146, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (171, 195))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('gastrointestinal cancers', 'Disease', (171, 195))	('hepatocellular carcinoma', 'Disease', (75, 99))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (75, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (146, 160))	('mice', 'Species', '10090', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('beta2SP', 'Gene', (57, 64))	('deletion', 'Var', (45, 53))	('mice', 'Species', '10090', (22, 26))
73878	23536563	Dysfunctional TGF-beta signaling has been reported in esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (54, 79))	('TGF-beta', 'Gene', (14, 22))	('esophageal adenocarcinoma', 'Disease', (54, 79))	('reported', 'Reg', (42, 50))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (54, 79))	('TGF-beta', 'Gene', '7040', (14, 22))	('Dysfunctional', 'Var', (0, 13))
73881	23536563	Aberrant Notch signaling has been implicated in a variety of tumors including colon cancer, glioma, and T-cell leukemia, etc.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('Aberrant', 'Var', (0, 8))	('colon cancer', 'Disease', 'MESH:D015179', (78, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (78, 90))	('glioma', 'Disease', (92, 98))	('T-cell leukemia', 'Disease', 'MESH:D015458', (104, 119))	('colon cancer', 'Disease', (78, 90))	('Notch signaling', 'Gene', (9, 24))	('implicated', 'Reg', (34, 44))	('leukemia', 'Phenotype', 'HP:0001909', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('T-cell leukemia', 'Disease', (104, 119))
73889	23536563	Here, we provide evidence that loss of beta2SP directly activates Notch signaling and increased expression of its target SOX9 at the level of transcription through interactions between Smad3 and ICN1 at Smad3 MH1 domain.	('activates', 'PosReg', (56, 65))	('Smad3', 'Gene', '4088', (185, 190))	('increased', 'PosReg', (86, 95))	('Smad3', 'Gene', '4088', (203, 208))	('loss', 'Var', (31, 35))	('interactions', 'Interaction', (164, 176))	('expression', 'MPA', (96, 106))	('SOX9', 'Gene', (121, 125))	('Smad3', 'Gene', (185, 190))	('ICN1', 'Gene', (195, 199))	('Smad3', 'Gene', (203, 208))	('Notch signaling', 'MPA', (66, 81))	('beta2SP', 'Protein', (39, 46))
73890	23536563	Our study for the first time provides evidence that loss of beta2SP in TGF-beta signaling may switch Smad3 function from tumor suppression to tumor promotion by engaging Notch signaling and increasing expression of SOX9.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('engaging', 'PosReg', (161, 169))	('Notch signaling', 'MPA', (170, 185))	('expression', 'MPA', (201, 211))	('beta2SP', 'Protein', (60, 67))	('SOX9', 'Protein', (215, 219))	('tumor', 'Disease', (121, 126))	('Smad3', 'Gene', '4088', (101, 106))	('Smad3', 'Gene', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('loss', 'Var', (52, 56))	('tumor', 'Disease', (142, 147))	('TGF-beta', 'Gene', '7040', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('function', 'MPA', (107, 115))	('switch', 'Reg', (94, 100))	('increasing', 'PosReg', (190, 200))	('TGF-beta', 'Gene', (71, 79))
73908	23536563	Esophageal adenocarcinoma cells with genetically knockdown beta2SP or/and shSOX9 and control cells were subcutaneously injected with 2 x 106 cells in nude mice.	('knockdown', 'Var', (49, 58))	('Esophageal adenocarcinoma', 'Disease', (0, 25))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (0, 25))	('beta2SP', 'Protein', (59, 66))	('nude mice', 'Species', '10090', (150, 159))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('shSOX9', 'Gene', (74, 80))
73915	23536563	1C) indicated that high levels of nuclear SOX9 expression was associated with poor survival in esophageal adenocarcinoma patients in univariate analysis (P < 0.05).	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('poor', 'NegReg', (78, 82))	('esophageal adenocarcinoma', 'Disease', (95, 120))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (95, 120))	('nuclear SOX9', 'Protein', (34, 46))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (95, 120))	('high levels', 'Var', (19, 30))	('patients', 'Species', '9606', (121, 129))	('expression', 'MPA', (47, 57))	('survival', 'MPA', (83, 91))
73917	23536563	To determine if SOX9 upregulation is because of loss of TGF-beta signaling, we found that Hes1 and SOX9 expression increased by 15- and 40-fold, respectively, in MEFs-/- (Fig.	('Hes1', 'Gene', '3280', (90, 94))	('TGF-beta', 'Gene', '7040', (56, 64))	('SOX9', 'Gene', (99, 103))	('increased', 'PosReg', (115, 124))	('TGF-beta', 'Gene', (56, 64))	('expression', 'MPA', (104, 114))	('upregulation', 'PosReg', (21, 33))	('MEFs', 'CellLine', 'CVCL:9115', (162, 166))	('MEFs-/-', 'Var', (162, 169))	('Hes1', 'Gene', (90, 94))
73921	23536563	Furthermore, beta2SP-/- MEFs grew faster, showed mesenchymal phenotype, and acted like immortalized cells, whereas wt MEFs grew slowly had an epithelial phenotype (Fig.	('MEFs', 'CellLine', 'CVCL:9115', (118, 122))	('mesenchymal phenotype', 'CPA', (49, 70))	('beta2SP-/- MEFs', 'Var', (13, 28))	('grew', 'CPA', (29, 33))	('MEFs', 'CellLine', 'CVCL:9115', (24, 28))	('faster', 'PosReg', (34, 40))
73922	23536563	Correspondingly, expression of EMT transcription factor Twist as well as Slug and Snail was increased in beta2SP-/- MEFs compared with beta2SP wt MEFs cells (Fig.	('Snail', 'Gene', (82, 87))	('Slug', 'Gene', '20583', (73, 77))	('beta2SP-/- MEFs', 'Var', (105, 120))	('MEFs', 'CellLine', 'CVCL:9115', (116, 120))	('expression', 'MPA', (17, 27))	('increased', 'PosReg', (92, 101))	('Slug', 'Gene', (73, 77))	('MEFs', 'CellLine', 'CVCL:9115', (146, 150))	('Snail', 'Gene', '20613', (82, 87))
73926	23536563	Notch target Hes-1 and its ligand Jagged1 promoter activities were increased because of knockdown beta2SP (Supplementary Fig.	('beta2SP', 'Protein', (98, 105))	('Hes-1', 'Gene', '3280', (13, 18))	('knockdown', 'Var', (88, 97))	('Jagged1', 'Gene', '182', (34, 41))	('increased', 'PosReg', (67, 76))	('Hes-1', 'Gene', (13, 18))	('Jagged1', 'Gene', (34, 41))
73929	23536563	4A show that the mRNA level of SOX9 was increased by beta2SP knockdown in both SKGT-4 and BE3 cells.	('SKGT-4', 'CellLine', 'CVCL:2195', (79, 85))	('knockdown', 'Var', (61, 70))	('increased', 'PosReg', (40, 49))	('mRNA level of SOX9', 'MPA', (17, 35))	('beta2SP', 'Protein', (53, 60))
73930	23536563	Using transient transfection of a SOX9 luciferase promoter into esophageal adenocarcinoma cells, we found that loss of beta2SP increased SOX9 promoter luciferase activities in both SKGT-4 and BE3 esophageal adenocarcinoma cells (Fig.	('SOX9 promoter luciferase', 'Enzyme', (137, 161))	('increased', 'PosReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('SKGT-4', 'CellLine', 'CVCL:2195', (181, 187))	('esophageal adenocarcinoma', 'Disease', (64, 89))	('loss', 'Var', (111, 115))	('activities', 'MPA', (162, 172))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (64, 89))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (196, 221))	('esophageal adenocarcinoma', 'Disease', (196, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (64, 89))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (196, 221))	('beta2SP', 'Protein', (119, 126))
73931	23536563	4C, left) into SKGT-4 cells with or without beta2SP knockdown.	('knockdown', 'Var', (52, 61))	('SKGT-4', 'CellLine', 'CVCL:2195', (15, 21))	('beta2SP', 'Protein', (44, 51))
73932	23536563	SOX9 promoter activity was reduced dramatically with deletion of both the Notch-RBP-Jkappa and Smad3 SBE-binding sites in the promoter and the responsiveness to loss of beta2SP on SOX9 promoter activity was greatly reduced as well (-218 construct).	('Smad3', 'Gene', '4088', (95, 100))	('reduced', 'NegReg', (27, 34))	('RBP-Jkappa', 'Gene', '3516', (80, 90))	('SOX9', 'Gene', (0, 4))	('promoter activity', 'MPA', (5, 22))	('deletion', 'Var', (53, 61))	('Smad3', 'Gene', (95, 100))	('beta2SP', 'Protein', (169, 176))	('RBP-Jkappa', 'Gene', (80, 90))	('reduced', 'NegReg', (215, 222))	('loss', 'NegReg', (161, 165))
73933	23536563	Conversely, 3 other SOX9 promoter constructs (-718, -839, and -1,034) kept the high responsiveness to loss of beta2SP because they maintained intact binding sites for both RBP-Jkappa and Smad3.	('Smad3', 'Gene', (187, 192))	('RBP-Jkappa', 'Gene', (172, 182))	('binding sites', 'Interaction', (149, 162))	('beta2SP', 'Protein', (110, 117))	('responsiveness', 'MPA', (84, 98))	('-718', 'Var', (46, 50))	('Smad3', 'Gene', '4088', (187, 192))	('loss', 'NegReg', (102, 106))	('RBP-Jkappa', 'Gene', '3516', (172, 182))
73937	23536563	To determine the exact mechanisms by which loss of beta2SP increased SOX9, we proposed that interaction between Smad3 and active Notch intracellular domain (ICN1) may mediate induction of SOX9.	('SOX9', 'MPA', (69, 73))	('Smad3', 'Gene', (112, 117))	('beta2SP', 'Protein', (51, 58))	('Smad3', 'Gene', '4088', (112, 117))	('loss', 'Var', (43, 47))	('increased', 'PosReg', (59, 68))	('interaction', 'Interaction', (92, 103))
73943	23536563	Interestingly, when transfection with Flag-Smad3 and pull-down with anti-Flag antibody in these cell lysate, stronger bindings were found in esophageal adenocarcinoma cells with knockdown of beta2SP (Fig.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (141, 166))	('bindings', 'Interaction', (118, 126))	('Smad3', 'Gene', (43, 48))	('Smad3', 'Gene', '4088', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('knockdown', 'Var', (178, 187))	('beta2SP', 'Protein', (191, 198))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (141, 166))	('stronger', 'PosReg', (109, 117))	('esophageal adenocarcinoma', 'Disease', (141, 166))
73945	23536563	In addition, Smad3 DNA-binding ability was increased in shRNA beta2SP knockdown esophageal adenocarcinoma cells compared with control cells as assessed by gel shift assay (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (80, 105))	('Smad3', 'Gene', '4088', (13, 18))	('knockdown', 'Var', (70, 79))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('DNA-binding', 'Interaction', (19, 30))	('Smad3', 'Gene', (13, 18))	('increased', 'PosReg', (43, 52))	('shRNA beta2SP', 'Gene', (56, 69))	('esophageal adenocarcinoma', 'Disease', (80, 105))
73952	23536563	Expression of OCT3/4 and Lgr5 was increased in shbeta2SP SKTG4 cells compared to its control (Supplementary Fig.	('Expression', 'MPA', (0, 10))	('Lgr5', 'Gene', '8549', (25, 29))	('OCT3/4', 'Gene', '5460', (14, 20))	('shbeta2SP', 'Var', (47, 56))	('SKTG4', 'CellLine', 'CVCL:7377', (57, 62))	('OCT3/4', 'Gene', (14, 20))	('increased', 'PosReg', (34, 43))	('Lgr5', 'Gene', (25, 29))
73954	23536563	Furthermore, knockdown SOX9 in the background of depleted beta2SP or Notch inhibitor GSI decreased the capacities of tumor sphere formation and invasion (Fig.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('beta2SP', 'Protein', (58, 65))	('tumor', 'Disease', (117, 122))	('invasion', 'CPA', (144, 152))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('GSI', 'Gene', (85, 88))	('decreased', 'NegReg', (89, 98))
73956	23536563	The expression of stem cell markers as well as active form of Notch1 (ICN1) were increased in mice tumors with knockdown beta2SP (Supplementary Fig.	('Notch1', 'Gene', (62, 68))	('knockdown', 'Var', (111, 120))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('expression', 'MPA', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('beta2SP', 'Protein', (121, 128))	('mice', 'Species', '10090', (94, 98))	('active', 'MPA', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('increased', 'PosReg', (81, 90))	('tumors', 'Disease', (99, 105))
73957	23536563	This indicates loss of beta2SP in tumor cells enhances oncogenic properties of esophageal adenocarcinoma cells, which may be because of activating Notch signaling and its target SOX9, whereas knockdown SOX9 or blocking Notch signaling by GSI rescued the phenotype of loss of beta2SP.	('enhances', 'PosReg', (46, 54))	('beta2SP', 'Protein', (23, 30))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('activating', 'PosReg', (136, 146))	('tumor', 'Disease', (34, 39))	('oncogenic properties', 'CPA', (55, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('loss', 'Var', (15, 19))	('Notch signaling', 'MPA', (147, 162))	('esophageal adenocarcinoma', 'Disease', (79, 104))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
73960	23536563	7E illustrates the proposed model by which loss of TGF-beta signaling adaptor beta2SP engages and activates Notch signaling and increases the expression of SOX9.	('Notch signaling', 'MPA', (108, 123))	('TGF-beta', 'Gene', (51, 59))	('activates', 'PosReg', (98, 107))	('increases', 'PosReg', (128, 137))	('SOX9', 'Gene', (156, 160))	('expression', 'MPA', (142, 152))	('loss', 'Var', (43, 47))	('TGF-beta', 'Gene', '7040', (51, 59))
73961	23536563	Loss of beta2SP disrupts canonical Smad3 complex with beta2SP, Smad4 and leads to reduced expression of p27, p21, and E-cadherin.	('p27', 'Gene', '51014', (104, 107))	('E-cadherin', 'Gene', (118, 128))	('E-cadherin', 'Gene', '999', (118, 128))	('p21', 'Gene', (109, 112))	('p27', 'Gene', (104, 107))	('Smad3', 'Gene', '4088', (35, 40))	('expression', 'MPA', (90, 100))	('complex', 'Interaction', (41, 48))	('p21', 'Gene', '1026', (109, 112))	('beta2SP', 'Protein', (8, 15))	('reduced', 'NegReg', (82, 89))	('Loss', 'Var', (0, 4))	('Smad3', 'Gene', (35, 40))	('disrupts', 'NegReg', (16, 24))
73967	23536563	A direct interaction between Smad3 and ICN1 via Smad3 MH1 domain was observed and loss of beta2SP increases the binding of Smad3 with ICN1 and induces Notch targets SOX9.	('binding', 'Interaction', (112, 119))	('Smad3', 'Gene', (29, 34))	('induces', 'Reg', (143, 150))	('Smad3', 'Gene', '4088', (48, 53))	('Smad3', 'Gene', '4088', (123, 128))	('Notch targets SOX9', 'MPA', (151, 169))	('increases', 'PosReg', (98, 107))	('beta2SP', 'Protein', (90, 97))	('Smad3', 'Gene', (123, 128))	('Smad3', 'Gene', (48, 53))	('Smad3', 'Gene', '4088', (29, 34))	('loss', 'Var', (82, 86))
73968	23536563	Our findings suggest that loss of beta2SP may switch TGF-beta signaling function from tumor suppression to tumor promotion by engaging Notch signaling and increasing the expression of SOX9 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('engaging', 'PosReg', (126, 134))	('tumor', 'Disease', (107, 112))	('Notch signaling', 'MPA', (135, 150))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('beta2SP', 'Protein', (34, 41))	('TGF-beta', 'Gene', '7040', (53, 61))	('SOX9', 'Gene', (184, 188))	('increasing', 'PosReg', (155, 165))	('function', 'MPA', (72, 80))	('loss', 'Var', (26, 30))	('TGF-beta', 'Gene', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('expression', 'MPA', (170, 180))
73972	23536563	In this study, we show that loss of beta2SP in TGF-beta signaling directly gives rise to activation in Notch signaling exemplified by increased Notch1 receptor and nuclear ICN1 expression in both MEFs and esophageal adenocarcinoma cells.	('nuclear', 'MPA', (164, 171))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (205, 230))	('loss', 'Var', (28, 32))	('TGF-beta', 'Gene', (47, 55))	('Notch signaling', 'MPA', (103, 118))	('esophageal adenocarcinoma', 'Disease', (205, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('MEFs', 'CellLine', 'CVCL:9115', (196, 200))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (205, 230))	('ICN1', 'Gene', (172, 176))	('activation', 'PosReg', (89, 99))	('TGF-beta', 'Gene', '7040', (47, 55))	('Notch1 receptor', 'Protein', (144, 159))	('beta2SP', 'Protein', (36, 43))	('increased', 'PosReg', (134, 143))	('expression', 'MPA', (177, 187))
73974	23536563	This suggests that loss of beta2SP mainly increased Notch1 activation in esophageal adenocarcinoma cells; and this may occur downstream of the cleavage of Notch1 receptor by gamma-secretase complex through increased binding between Smad3 and ICN1 and prevent its degradation and facilitate its translocation to the nucleus.	('increased', 'PosReg', (42, 51))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (73, 98))	('binding', 'Interaction', (216, 223))	('Smad3', 'Gene', '4088', (232, 237))	('Notch1', 'Gene', (52, 58))	('increased', 'PosReg', (206, 215))	('Smad3', 'Gene', (232, 237))	('prevent', 'NegReg', (251, 258))	('facilitate', 'PosReg', (279, 289))	('translocation to the nucleus', 'MPA', (294, 322))	('beta2SP', 'Protein', (27, 34))	('loss', 'Var', (19, 23))	('degradation', 'MPA', (263, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (73, 98))	('activation', 'PosReg', (59, 69))	('esophageal adenocarcinoma', 'Disease', (73, 98))
73978	23536563	For the first time, we showed that loss of beta2SP leads to an increase of SOX9 expression at the transcriptional level by the coordination among Smad3, ICN1, and RBP-Jkappa in the promotion of SOX9 upon loss of beta2SP.	('SOX9', 'Gene', (75, 79))	('beta2SP', 'Protein', (43, 50))	('increase', 'PosReg', (63, 71))	('beta2SP', 'Protein', (212, 219))	('RBP-Jkappa', 'Gene', '3516', (163, 173))	('Smad3', 'Gene', (146, 151))	('loss', 'Var', (35, 39))	('loss', 'NegReg', (204, 208))	('RBP-Jkappa', 'Gene', (163, 173))	('Smad3', 'Gene', '4088', (146, 151))	('expression', 'MPA', (80, 90))	('promotion', 'PosReg', (181, 190))
73980	23536563	Our findings suggest loss of beta2SP may permit Smad3 to recruit ICN1 as its coactivator and binds more avidly to its SBE and RBP-Jkappa sites in the form of a complex with ICN1 and activate Notch signaling target SOX9.	('loss', 'Var', (21, 25))	('complex', 'Interaction', (160, 167))	('RBP-Jkappa', 'Gene', (126, 136))	('binds', 'Interaction', (93, 98))	('Smad3', 'Gene', '4088', (48, 53))	('activate', 'PosReg', (182, 190))	('ICN1', 'Gene', (65, 69))	('Smad3', 'Gene', (48, 53))	('RBP-Jkappa', 'Gene', '3516', (126, 136))	('beta2SP', 'Protein', (29, 36))
73981	23536563	Dysfunctional TGF-beta signaling via loss of beta2SP has the potential to increase the putative cancer stem cell proportion and significantly enhance tumor sphere formation and invasive capacities, which are critical for their malignancy.	('malignancy', 'Disease', 'MESH:D009369', (227, 237))	('TGF-beta', 'Gene', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('malignancy', 'Disease', (227, 237))	('cancer', 'Disease', (96, 102))	('increase', 'PosReg', (74, 82))	('beta2SP', 'Protein', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('loss', 'NegReg', (37, 41))	('enhance', 'PosReg', (142, 149))	('invasive capacities', 'CPA', (177, 196))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('Dysfunctional', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('TGF-beta', 'Gene', '7040', (14, 22))	('tumor', 'Disease', (150, 155))
73985	23536563	In conclusion, this study provides evidence for the first time loss of beta2SP directly activates Notch signaling and increased the expression of SOX9 by the interplay between Smad3 MH1 domain and ICN1.	('loss', 'Var', (63, 67))	('activates', 'PosReg', (88, 97))	('Smad3', 'Gene', '4088', (176, 181))	('interplay', 'Interaction', (158, 167))	('increased', 'PosReg', (118, 127))	('SOX9', 'Gene', (146, 150))	('Notch signaling', 'Pathway', (98, 113))	('expression', 'MPA', (132, 142))	('Smad3', 'Gene', (176, 181))	('beta2SP', 'Protein', (71, 78))
73992	23354948	Under-expression of EHD2 increased the motility property of ESCC cell TE1 in vitro by wound-healing assays and transwell migration assays, and it was concurrent with the decreased expression of epithelial marker E-cadherin.	('Under-expression', 'Var', (0, 16))	('increased', 'PosReg', (25, 34))	('EHD2', 'Gene', (20, 24))	('motility property', 'CPA', (39, 56))	('EHD2', 'Gene', '30846', (20, 24))	('expression', 'MPA', (180, 190))	('decreased', 'NegReg', (170, 179))	('E-cadherin', 'Gene', (212, 222))	('E-cadherin', 'Gene', '999', (212, 222))
73993	23354948	Under-expression of EHD2 in TE1 can cause resistance to cisplatin.	('EHD2', 'Gene', (20, 24))	('Under-expression', 'Var', (0, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('cause', 'Reg', (36, 41))	('EHD2', 'Gene', '30846', (20, 24))	('resistance to cisplatin', 'MPA', (42, 65))
74005	23354948	EHD2 has also been implicated as a tumor suppressor gene candidate mapping to a 1.6 Mb 19q region of deletion in glioma tumors.	('glioma tumors', 'Disease', 'MESH:D005910', (113, 126))	('deletion', 'Var', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('EHD2', 'Gene', (0, 4))	('EHD2', 'Gene', '30846', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('glioma tumors', 'Disease', (113, 126))	('tumor', 'Disease', (120, 125))
74049	23354948	These results indicate that low expression of EHD2 inhibits the migration of ESCC TE1 cells.	('inhibits', 'NegReg', (51, 59))	('low expression', 'Var', (28, 42))	('migration of ESCC TE1 cells', 'CPA', (64, 91))	('EHD2', 'Gene', '30846', (46, 50))	('EHD2', 'Gene', (46, 50))
74050	23354948	We speculated that under-expression of EHD2 reduced chemosensitivity in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('EHD2', 'Gene', '30846', (39, 43))	('tumor', 'Disease', (72, 77))	('reduced', 'NegReg', (44, 51))	('under-expression', 'Var', (19, 35))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('EHD2', 'Gene', (39, 43))
74052	23354948	TE1 cells were transfected with siEHD2 plasmid and were treated with various concentrations of cisplatin for 48 h. The result of the Cell Counting Kit-8 (CCK8) assay indicated that the transfection of siEHD2 significantly increased cell viability compared with mock transfection.	('EHD2', 'Gene', (34, 38))	('EHD2', 'Gene', '30846', (34, 38))	('EHD2', 'Gene', (203, 207))	('EHD2', 'Gene', '30846', (203, 207))	('transfection', 'Var', (185, 197))	('cell viability', 'CPA', (232, 246))	('increased', 'PosReg', (222, 231))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))
74063	23354948	And we discovered that under-expression of EHD2 was closely related with metastasis of ESCC.	('EHD2', 'Gene', (43, 47))	('metastasis', 'CPA', (73, 83))	('related', 'Reg', (60, 67))	('ESCC', 'Disease', (87, 91))	('under-expression', 'Var', (23, 39))	('EHD2', 'Gene', '30846', (43, 47))
74075	23354948	Our data showed that cells migration increased with EHD2 under-expression which might foreshadowed cells morphology changed by transcytosis cytoskeletal molecules.	('EHD2', 'Gene', '30846', (52, 56))	('EHD2', 'Gene', (52, 56))	('cells migration', 'CPA', (21, 36))	('increased', 'PosReg', (37, 46))	('under-expression', 'Var', (57, 73))
74082	23354948	Disorder of EHD2 expression in tumor tissue may cause esophageal squamous cell structure to change and obtain the migration ability.	('obtain', 'PosReg', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('EHD2', 'Gene', '30846', (12, 16))	('tumor', 'Disease', (31, 36))	('cause', 'Reg', (48, 53))	('esophageal squamous', 'Disease', (54, 73))	('Disorder', 'Var', (0, 8))	('migration ability', 'CPA', (114, 131))	('esophageal squamous', 'Disease', 'MESH:D000077277', (54, 73))	('EHD2', 'Gene', (12, 16))	('change', 'Reg', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
74189	18250021	Changes in 18F-FDG-PET, however, may predict disease-free and overall survival after induction therapy and resection in patients with esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('overall survival', 'CPA', (62, 78))	('disease-free', 'Disease', (45, 57))	('18F-FDG', 'Chemical', 'MESH:D019788', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Changes', 'Var', (0, 7))	('patients', 'Species', '9606', (120, 128))	('predict', 'Reg', (37, 44))	('esophageal cancer', 'Disease', (134, 151))	('18F-FDG-PET', 'Gene', (11, 22))
74203	33840743	For individuals with a family history of esophageal cancer (EC), high TC, and LDL-C were associated with a significantly increased risk of having malignant lesions (odds ratio [OR]High vs. Low TC = 2.22, 95% confidence interval [CI]: 1.14-4.35; ORHigh vs. Low LDL-C = 1.93, 95% CI: 1.01-3.65).	('high TC', 'Var', (65, 72))	('TC', 'Chemical', '-', (193, 195))	('malignant lesions', 'Disease', 'MESH:D009369', (146, 163))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Low LDL', 'Phenotype', 'HP:0003563', (256, 263))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('LDL-C', 'Gene', (78, 83))	('TC', 'Chemical', '-', (70, 72))	('LDL-C', 'Gene', '22796', (78, 83))	('malignant lesions', 'Disease', (146, 163))	('LDL-C', 'Gene', '22796', (260, 265))	('LDL-C', 'Gene', (260, 265))	('ORHigh', 'Var', (245, 251))	('esophageal cancer', 'Disease', (41, 58))
74204	33840743	However, a negative association was observed in participants without an EC family history (ORHigh vs. Low TC = 0.69, 95% CI: 0.48-0.98, Pinteraction = 0.002; ORHigh vs. Low LDL-C = 0.50, 95% CI: 0.34-0.76, Pinteraction < 0.001).	('ORHigh', 'Var', (158, 164))	('LDL-C', 'Gene', (173, 178))	('TC', 'Chemical', '-', (106, 108))	('LDL-C', 'Gene', '22796', (173, 178))	('participants', 'Species', '9606', (48, 60))	('Low LDL', 'Phenotype', 'HP:0003563', (169, 176))
74207	33840743	Abnormalities in lipid and lipoprotein metabolism are associated with various diseases.	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('associated', 'Reg', (54, 64))	('Abnormalities', 'Var', (0, 13))
74253	33840743	For individuals with a family history, high-level group of TC (>=200 mg/dL) and LDL-C (>=110 mg/dL) were accompanied by a significantly increased risk of malignant lesions (TC: ORHigh vs. Low = 2.22, 95% CI: 1.14-4.35; LDL-C: ORHigh vs. Low = 1.93, 95% CI: 1.01-3.65).	('LDL-C', 'Gene', (80, 85))	('malignant lesions', 'Disease', (154, 171))	('LDL-C', 'Gene', '22796', (80, 85))	('>=200 mg/dL', 'Var', (63, 74))	('malignant lesions', 'Disease', 'MESH:D009369', (154, 171))	('TC', 'Chemical', '-', (173, 175))	('TC', 'Chemical', '-', (59, 61))	('>=110 mg/dL', 'Var', (87, 98))	('LDL-C', 'Gene', '22796', (219, 224))	('LDL-C', 'Gene', (219, 224))
74278	33840743	This explanation was supported by two studies evaluating the association of single-nucleotide polymorphisms (SNPs), the main contributor to genetic susceptibility to cancer, and ESCC according to the status of family history.	('single-nucleotide polymorphisms', 'Var', (76, 107))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('ESCC', 'Disease', (178, 182))	('association', 'Interaction', (61, 72))
74280	33840743	Another genome-wide association study compared genetic alterations in familial and non-familial ESCC, and the rs79747906 locus was found to be associated with a family history of EC.	('rs79747906', 'Var', (110, 120))	('associated', 'Reg', (143, 153))	('rs79747906', 'Mutation', 'rs79747906', (110, 120))	('ESCC', 'Disease', (96, 100))
74281	33840743	This variant is associated with metabolic traits by alteration of the expression of LPIN2, which is an important enzyme in triglyceride metabolism.	('alteration', 'Reg', (52, 62))	('metabolic traits', 'Disease', (32, 48))	('variant', 'Var', (5, 12))	('expression', 'MPA', (70, 80))	('triglyceride', 'Chemical', 'MESH:D014280', (123, 135))	('LPIN2', 'Gene', (84, 89))	('associated', 'Reg', (16, 26))	('LPIN2', 'Gene', '9663', (84, 89))
74282	33840743	These studies altogether suggested that genetic alternations were different between familiar and non-familiar ESCC, and a certain proportion of these genetic alternations might be located in lipids metabolism pathways and cause discrepancies in lipid profiles.	('discrepancies', 'MPA', (228, 241))	('lipids metabolism pathways', 'Pathway', (191, 217))	('genetic alternations', 'Var', (150, 170))	('located', 'Reg', (180, 187))	('lipids', 'Chemical', 'MESH:D008055', (191, 197))	('lipid', 'Chemical', 'MESH:D008055', (245, 250))	('alternations', 'Var', (158, 170))	('lipid profiles', 'MPA', (245, 259))	('lipid', 'Chemical', 'MESH:D008055', (191, 196))	('cause', 'Reg', (222, 227))
74286	33840743	We conclude that high levels of TC or LDL-C were associated with an increased risk of malignant esophageal lesions in subjects with a family history of EC but were associated with decreased risk for subjects with no family history of EC.	('TC', 'Chemical', '-', (32, 34))	('high', 'Var', (17, 21))	('malignant esophageal lesions', 'Disease', (86, 114))	('LDL-C', 'Gene', '22796', (38, 43))	('LDL-C', 'Gene', (38, 43))
74308	32793446	A total of 366 patients with cT1N1 or T2-T3N0-N1 SCC or ADC were randomly assigned to receive either surgery alone or NACRT (41.4 Gy with concurrent weekly carboplatin plus paclitaxel) and surgery.	('patients', 'Species', '9606', (15, 23))	('SCC', 'Gene', (49, 52))	('T2-T3N0-N1', 'Var', (38, 48))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('paclitaxel', 'Chemical', 'MESH:D017239', (173, 183))	('ADC', 'Disease', (56, 59))	('SCC', 'Gene', '6317', (49, 52))	('cT1N1', 'Var', (29, 34))	('NACRT', 'Chemical', '-', (118, 123))	('carboplatin', 'Chemical', 'MESH:D016190', (156, 167))
74309	32793446	The trial found that the R0 resection rate was higher in the NACRT group than in the surgery alone group (92% versus 69%, p<0.001).	('R0 resection rate', 'CPA', (25, 42))	('higher', 'PosReg', (47, 53))	('NACRT', 'Var', (61, 66))	('NACRT', 'Chemical', '-', (61, 66))
74311	32793446	The median overall survival (OS) was also shown to be significantly higher in the NACRT group than in the surgery alone group (49 months versus 24 months, p=0.003; hazard ratio [HR], 0.657) and the 5-year OS was 47% in the NACRT group and 34% in the surgery alone group.	('overall', 'MPA', (11, 18))	('NACRT', 'Chemical', '-', (223, 228))	('higher', 'PosReg', (68, 74))	('NACRT', 'Var', (82, 87))	('NACRT', 'Chemical', '-', (82, 87))
74320	32793446	Postoperative mortality was also shown to be significantly higher in the NACRT group than in the surgery alone group (11.1% versus 3.4%, p=0.049).	('mortality', 'Disease', 'MESH:D003643', (14, 23))	('NACRT', 'Var', (73, 78))	('NACRT', 'Chemical', '-', (73, 78))	('higher', 'PosReg', (59, 65))	('mortality', 'Disease', (14, 23))
74326	32793446	The trial showed that the R0 resection rate was higher in the NACRT group than the surgery alone group (98.4% versus 91.2%, p=0.002) and that the pCR rate after NACRT was 43.2%.	('NACRT', 'Var', (62, 67))	('NACRT', 'Chemical', '-', (62, 67))	('higher', 'PosReg', (48, 54))	('NACRT', 'Chemical', '-', (161, 166))	('R0 resection rate', 'CPA', (26, 43))
74327	32793446	Moreover, the median OS was shown to be significantly higher in the NACRT group than in the surgery alone group (100.1 months versus 66.5 months; HR, 0.71; p=0.025).	('NACRT', 'Chemical', '-', (68, 73))	('NACRT', 'Var', (68, 73))	('higher', 'PosReg', (54, 60))
74328	32793446	Additionally, NACRT did not increase postoperative mortality (2.2% in the NACRT group versus 0.4% in the surgery alone group, p=0.212).	('mortality', 'Disease', (51, 60))	('NACRT', 'Chemical', '-', (14, 19))	('NACRT', 'Var', (74, 79))	('mortality', 'Disease', 'MESH:D003643', (51, 60))	('NACRT', 'Chemical', '-', (74, 79))
74345	32793446	Moreover, 5-year OS was improved in the NAC group when compared to the surgery group (23% versus 17%; HR, 0.84; p=0.03).	('NAC', 'Var', (40, 43))	('NAC', 'Chemical', '-', (40, 43))	('improved', 'PosReg', (24, 32))
74357	32793446	Notably, the 5-year OS was higher in the NAC group than in the adjuvant chemotherapy group (55% versus 43%; HR, 0.73; p=0.04).	('NAC', 'Var', (41, 44))	('NAC', 'Chemical', '-', (41, 44))	('higher', 'PosReg', (27, 33))
74360	32793446	The results of the trial showed that the pCR rate was higher in the NACRT group than in the NAC group (28% versus 9%), but found no significant difference in the 3-year OS (49% in NAC versus 47% in NACRT, p=0.77).	('NACRT', 'Chemical', '-', (68, 73))	('NAC', 'Chemical', '-', (68, 71))	('pCR rate', 'CPA', (41, 49))	('higher', 'PosReg', (54, 60))	('NAC', 'Chemical', '-', (180, 183))	('NACRT', 'Chemical', '-', (198, 203))	('NAC', 'Chemical', '-', (198, 201))	('NACRT', 'Var', (68, 73))	('NAC', 'Chemical', '-', (92, 95))
74416	32793446	Moreover, in a population-based study, IMRT led to significantly lower all-cause mortality and cardiac mortality rates in patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mortality', 'Disease', 'MESH:D003643', (81, 90))	('IMRT', 'Var', (39, 43))	('lower', 'NegReg', (65, 70))	('mortality', 'Disease', 'MESH:D003643', (103, 112))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('mortality', 'Disease', (81, 90))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Disease', (147, 153))	('mortality', 'Disease', (103, 112))
74418	32793446	reported that in patients treated with NACRT followed by surgery, there was a significant increase in pulmonary complications for 3D-CRT (odds ratio [OR], 9.13; 95% CI, 1.83-45.42) and an increasing trend for IMRT (OR, 2.23; 95% CI, 0.86-5.76) compared to that for proton therapy.	('increase', 'PosReg', (90, 98))	('pulmonary complications', 'Phenotype', 'HP:0006532', (102, 125))	('patients', 'Species', '9606', (17, 25))	('NACRT', 'Var', (39, 44))	('3D-CRT', 'Var', (130, 136))	('NACRT', 'Chemical', '-', (39, 44))	('pulmonary complications', 'CPA', (102, 125))
74459	32370142	In the context of genetic alterations, the most frequent and mutually exclusive genetic changes in PTCs are BRAF V600E, RAS, and RET/PTC rearrangement, leading to constitutive activation of the signaling pathway of mitogen-activated kinases (MAPK) (Figure 1).	('RET', 'Gene', (129, 132))	('RAS', 'Gene', (120, 123))	('PTC', 'Gene', (99, 102))	('PTC', 'Gene', (133, 136))	('signaling pathway of mitogen-activated kinases', 'Pathway', (194, 240))	('PTC', 'Gene', '5979', (99, 102))	('PTC', 'Gene', '5979', (133, 136))	('V600E', 'Mutation', 'rs113488022', (113, 118))	('BRAF', 'Gene', '673', (108, 112))	('RET', 'Gene', '5979', (129, 132))	('activation', 'PosReg', (176, 186))	('BRAF', 'Gene', (108, 112))	('rearrangement', 'Var', (137, 150))
74460	32370142	BRAF occurs in 45% of PTCs, and in the majority, it is a substitution at the second position of codon 600 (V600E; GTG > GAG), c.1799 T > A) resulting in an amino acid change from valine to glutamic acid that leading to constitutive activation of serine/threonine kinase BRAF.	('PTC', 'Gene', (22, 25))	('BRAF', 'Gene', (270, 274))	('BRAF', 'Gene', '673', (270, 274))	('glutamic acid', 'Chemical', 'MESH:D018698', (189, 202))	('constitutive', 'MPA', (219, 231))	('activation', 'PosReg', (232, 242))	('V600E;', 'Var', (107, 113))	('GAG', 'Chemical', 'MESH:D006025', (120, 123))	('PTC', 'Gene', '5979', (22, 25))	('c.1799 T > A', 'Mutation', 'rs113488022', (126, 138))	('GTG', 'Gene', '2678', (114, 117))	('BRAF', 'Gene', '673', (0, 4))	('valine', 'Chemical', 'MESH:D014633', (179, 185))	('BRAF', 'Gene', (0, 4))	('c.1799 T > A', 'Var', (126, 138))	('serine', 'Chemical', 'MESH:D012694', (246, 252))	('V600E', 'Mutation', 'rs113488022', (107, 112))	('GTG', 'Gene', (114, 117))
74461	32370142	The RAS gene encodes a family of three highly homologous oncogenes: NRAS, HRAS, and KRAS, in which mutations occur in 10%-20% of PTCs.	('occur', 'Reg', (109, 114))	('RAS', 'Gene', (4, 7))	('PTC', 'Gene', (129, 132))	('NRAS', 'Gene', (68, 72))	('PTC', 'Gene', '5979', (129, 132))	('KRAS', 'Gene', (84, 88))	('mutations', 'Var', (99, 108))	('HRAS', 'Gene', '3265', (74, 78))	('KRAS', 'Gene', '3845', (84, 88))	('NRAS', 'Gene', '4893', (68, 72))	('HRAS', 'Gene', (74, 78))
74464	32370142	In contrast, the characteristic genetic modifications that are mutually exclusive in FTC are changes in the RAS, PTEN, and PIK3CA genes, as well as rearrangement of PAX8-PPARgamma, activating the 3-phosphatidylinositol kinase PI kinase (PI3K/Protein Kinase B-AKT).	('PAX8', 'Gene', '7849', (165, 169))	('activating', 'PosReg', (181, 191))	('PPARgamma', 'Gene', '5468', (170, 179))	('PAX8', 'Gene', (165, 169))	('AKT', 'Gene', '207', (259, 262))	('RAS', 'Gene', (108, 111))	('PIK3CA', 'Gene', (123, 129))	('Protein Kinase B', 'Gene', (242, 258))	('PIK3CA', 'Gene', '5290', (123, 129))	('PTEN', 'Gene', (113, 117))	('rearrangement', 'Var', (148, 161))	('AKT', 'Gene', (259, 262))	('PTEN', 'Gene', '5728', (113, 117))	('modifications', 'Var', (40, 53))	('Protein Kinase B', 'Gene', '2185', (242, 258))	('PPARgamma', 'Gene', (170, 179))
74465	32370142	The RAS mutations were observed in approximately 40%-50% of FTC cases, and the modification was predominantly found in the NRAS codon 61, which positively associated with distant metastases of FTC.	('FTC', 'Disease', (193, 196))	('mutations', 'Var', (8, 17))	('NRAS', 'Gene', (123, 127))	('associated with', 'Reg', (155, 170))	('NRAS', 'Gene', '4893', (123, 127))	('metastases', 'Disease', (179, 189))	('metastases', 'Disease', 'MESH:D009362', (179, 189))
74466	32370142	Following, the mutation or deletion of the tumor suppressor gene - PTEN (phosphatase and tensin homolog) and PIK3CA transcript (coding the p110alpha catalytic subunit of PI3K) are the classical genetic alterations that activate the PI3K-AKT pathway in ~10% and 10%-30% of FTC cases, respectively.	('AKT', 'Gene', (237, 240))	('mutation', 'Var', (15, 23))	('PIK3CA', 'Gene', (109, 115))	('PIK3CA', 'Gene', '5290', (109, 115))	('activate', 'PosReg', (219, 227))	('p110alpha', 'Gene', (139, 148))	('p110alpha', 'Gene', '5290', (139, 148))	('phosphatase and tensin homolog', 'Gene', '5728', (73, 103))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('deletion', 'Var', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PTEN', 'Gene', (67, 71))	('AKT', 'Gene', '207', (237, 240))	('PTEN', 'Gene', '5728', (67, 71))	('tumor', 'Disease', (43, 48))	('FTC', 'Disease', (272, 275))
74468	32370142	The PAX8/PPAR fusion results in significant increases in expression of PAX8/PPAR chimeric protein and, as a result, inhibits the tumor suppressor activity of PPAR.	('expression', 'MPA', (57, 67))	('PAX8', 'Gene', (71, 75))	('inhibits', 'NegReg', (116, 124))	('PAX8', 'Gene', '7849', (4, 8))	('PPAR', 'Gene', (76, 80))	('chimeric protein', 'Protein', (81, 97))	('PPAR', 'Gene', '5465', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('PPAR', 'Gene', (9, 13))	('PAX8', 'Gene', (4, 8))	('fusion', 'Var', (14, 20))	('PPAR', 'Gene', '5465', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PAX8', 'Gene', '7849', (71, 75))	('tumor', 'Disease', (129, 134))	('PPAR', 'Gene', (158, 162))	('increases', 'PosReg', (44, 53))	('PPAR', 'Gene', '5465', (9, 13))
74473	32370142	Additionally, through whole-genome sequencing, in many malignant THC cases, the mutations in the promoter region of telomerase reverse transcriptase (TERT) were found, contrary to the early stages of thyroid tumors.	('thyroid tumors', 'Disease', 'MESH:D013964', (200, 214))	('mutations in', 'Var', (80, 92))	('TERT', 'Gene', (150, 154))	('found', 'Reg', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('TERT', 'Gene', '7015', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('thyroid tumors', 'Disease', (200, 214))	('thyroid tumor', 'Phenotype', 'HP:0100031', (200, 213))	('THC', 'Disease', (65, 68))	('telomerase reverse transcriptase', 'Gene', (116, 148))	('telomerase reverse transcriptase', 'Gene', '7015', (116, 148))
74475	32370142	Two main TERT mutations: 1 295 228 C>T (C228T) and 1 295 250 C>T(C250T) can increase the TERT transcriptional activities.	('increase', 'PosReg', (76, 84))	('228 C>T', 'Var', (31, 38))	('C228T', 'Mutation', 'rs1361898625', (40, 45))	('C250T', 'Mutation', 'c.250C>T', (65, 70))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', '7015', (89, 93))	('228 C>T', 'SUBSTITUTION', 'None', (31, 38))	('295 250 C>T', 'Mutation', 'g.295250C>T', (53, 64))	('1 295 250 C>T', 'Var', (51, 64))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
74476	32370142	Particularly prevalent in THC is the C228T variant, which appeared in Liu X. et al.	('C228T', 'Mutation', 'rs1361898625', (37, 42))	('C228T', 'Var', (37, 42))	('prevalent', 'Reg', (13, 22))	('THC', 'Disease', (26, 29))
74478	32370142	Moreover, the coexistence of TERT with BRAF or RAS alterations had a synergistic effect on poor clinicopathologic outcomes of PTCs, such as disease recurrence and patient mortality.	('TERT', 'Gene', '7015', (29, 33))	('alterations', 'Var', (51, 62))	('BRAF', 'Gene', '673', (39, 43))	('mortality', 'Disease', 'MESH:D003643', (171, 180))	('BRAF', 'Gene', (39, 43))	('PTC', 'Gene', (126, 129))	('disease recurrence', 'Disease', (140, 158))	('patient', 'Species', '9606', (163, 170))	('mortality', 'Disease', (171, 180))	('PTC', 'Gene', '5979', (126, 129))	('RAS', 'Gene', (47, 50))	('TERT', 'Gene', (29, 33))
74479	32370142	All data suggest that TERT promoter mutations may play a role in the THC de-differentiation, progression, and aggressive behavior.	('TERT', 'Gene', (22, 26))	('aggressive behavior', 'Phenotype', 'HP:0000718', (110, 129))	('play', 'Reg', (50, 54))	('TERT', 'Gene', '7015', (22, 26))	('mutations', 'Var', (36, 45))	('aggressive behavior', 'CPA', (110, 129))	('THC', 'Disease', (69, 72))	('progression', 'CPA', (93, 104))
74483	32370142	The human PROX1 transcript is located on chromosome 1q32.2-q32.3 composed of five exons and four introns and produces two variants: NM_002763 and NM_001270616, both encoding the same protein product, but the NM_002763 transcript is longer by 322 nucleotides.	('NM_001270616', 'Var', (146, 158))	('human', 'Species', '9606', (4, 9))	('NM_002763', 'Var', (132, 141))	('NM_002763', 'Var', (208, 217))
74496	32370142	RNA editing occurs through base modification, by deamination of cytidine (C) to uridine (U) or by deamination of adenosine (A) to inosine (I), in nuclear mRNA.	('deamination', 'Var', (98, 109))	('deamination', 'MPA', (49, 60))	('inosine', 'Chemical', 'MESH:D007288', (130, 137))	('uridine', 'Chemical', 'MESH:D014529', (80, 87))	('base modification', 'MPA', (27, 44))	('adenosine', 'Chemical', 'MESH:D000241', (113, 122))	('cytidine', 'Chemical', 'MESH:D003562', (64, 72))
74497	32370142	Uridine and inosine are recognized by translational apparatus as thymidine and guanosine, respectively, so the net effects are changes in C-to-T and A-to-G.	('inosine', 'Chemical', 'MESH:D007288', (12, 19))	('thymidine', 'Chemical', 'MESH:D013936', (65, 74))	('Uridine', 'Chemical', 'MESH:D014529', (0, 7))	('C-to-T', 'Disease', (138, 144))	('changes', 'Reg', (127, 134))	('A-to-G', 'Var', (149, 155))	('guanosine', 'Chemical', 'MESH:D006151', (79, 88))
74498	32370142	In this context, the A-to-G mutation affects PROX1 function in human specimens of pancreatic, colon, and esophageal cancers and A to I in esophageal cancer.	('esophageal cancers', 'Disease', (105, 123))	('esophageal cancers', 'Disease', 'MESH:D004938', (105, 123))	('cancer', 'Disease', (149, 155))	('PROX1', 'Enzyme', (45, 50))	('human', 'Species', '9606', (63, 68))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('affects', 'Reg', (37, 44))	('function', 'MPA', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('pancreatic', 'Disease', 'MESH:D010195', (82, 92))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('colon', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pancreatic', 'Disease', (82, 92))	('A-to-G mutation', 'Var', (21, 36))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
74499	32370142	Importantly, several single nucleotide polymorphisms (SNPs) present in intronic regions of PROX1 were suggested to modulate PROX1 expression levels with potential involvement in the pathogenesis of type 2 diabetes.	('single nucleotide polymorphisms', 'Var', (21, 52))	('modulate', 'Reg', (115, 123))	('PROX1', 'Gene', (91, 96))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (198, 213))	('diabetes', 'Disease', (205, 213))	('PROX1 expression levels', 'MPA', (124, 147))	('diabetes', 'Disease', 'MESH:D003920', (205, 213))	('involvement', 'Reg', (163, 174))
74502	32370142	It is commonly known that inactivation of specific tumor suppressor genes occurs as a consequence of hypermethylation within the promoter regions, and numerous studies have demonstrated a broad range of genes silenced by DNA methylation in different cancer types.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('DNA', 'Var', (221, 224))	('cancer', 'Disease', (250, 256))	('tumor', 'Disease', (51, 56))	('hypermethylation', 'Var', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('silenced', 'NegReg', (209, 217))	('inactivation', 'NegReg', (26, 38))
74503	32370142	Epigenetic silencing is one of the mechanisms responsible for PROX1 inactivation in tumors.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Epigenetic silencing', 'Var', (0, 20))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('PROX1', 'Gene', (62, 67))	('inactivation', 'NegReg', (68, 80))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
74504	32370142	For example, hypermethylation of CpG islands was identified as a mechanism for PROX1 inactivation in breast, biliary system, and squamous cell carcinomas.	('inactivation', 'NegReg', (85, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('squamous cell carcinomas', 'Disease', (129, 153))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (129, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('PROX1', 'Gene', (79, 84))	('biliary system', 'Disease', (109, 123))	('breast', 'Disease', (101, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('hypermethylation', 'Var', (13, 29))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (129, 153))
74511	32370142	According to the miRDB database , for example, miR-10527-5p, miR-6867-5p, miR-4262, miR-4668-5p, and miR-3148 may still regulate PROX1 mRNA and thus can be the future research aim, especially in THC cases, due to the lack of published data.	('PROX1 mRNA', 'MPA', (129, 139))	('miR-4668', 'Gene', '100616114', (84, 92))	('regulate', 'Reg', (120, 128))	('miR-4262', 'Gene', (74, 82))	('miR-10527-5p', 'Var', (47, 59))	('miR-4262', 'Gene', '100422996', (74, 82))	('miR-3148', 'Gene', (101, 109))	('THC cases', 'Disease', (195, 204))	('miR-6867', 'Gene', '102465523', (61, 69))	('miR-6867', 'Gene', (61, 69))	('miR-4668', 'Gene', (84, 92))	('miR-3148', 'Gene', '100422876', (101, 109))
74514	32370142	In detail, knockdown of PROX1-AS1 significantly inhibited proliferation, colony formation, migration, and invasion of PTC cells.	('colony formation', 'CPA', (73, 89))	('proliferation', 'CPA', (58, 71))	('PTC', 'Gene', '5979', (118, 121))	('AS1', 'Gene', '5729', (30, 33))	('AS1', 'Gene', (30, 33))	('inhibited', 'NegReg', (48, 57))	('migration', 'CPA', (91, 100))	('knockdown', 'Var', (11, 20))	('PTC', 'Gene', (118, 121))
74532	32370142	The downregulation of PROX1 in PTC-derived cells was a consequence of aberrantly activated Notch signaling.	('Notch signaling', 'Pathway', (91, 106))	('downregulation', 'NegReg', (4, 18))	('PROX1', 'Protein', (22, 27))	('PTC', 'Gene', (31, 34))	('aberrantly', 'Var', (70, 80))	('PTC', 'Gene', '5979', (31, 34))
74533	32370142	Moreover, in PTC cells after transgenic PROX1 reexpression enhanced Wnt/beta-catenin signaling was observed, coupled with and regulation of thyroid cancer 1 (TC-1) protein, Serpina 1, and Fatty acid-binding protein 4 (FABP4), that are known to be associated with PTC.	('TC-1', 'Gene', '56892', (158, 162))	('FABP4', 'Gene', '2167', (218, 223))	('TC-1', 'Gene', (158, 162))	('PTC', 'Gene', (263, 266))	('beta-catenin', 'Gene', (72, 84))	('Fatty acid-binding protein 4', 'Gene', (188, 216))	('PTC', 'Gene', '5979', (263, 266))	('Serpina 1', 'Gene', '5265', (173, 182))	('beta-catenin', 'Gene', '1499', (72, 84))	('thyroid cancer', 'Phenotype', 'HP:0002890', (140, 154))	('Fatty acid-binding protein 4', 'Gene', '2167', (188, 216))	('transgenic', 'Var', (29, 39))	('thyroid cancer 1', 'Gene', (140, 156))	('PTC', 'Gene', (13, 16))	('PTC', 'Gene', '5979', (13, 16))	('FABP4', 'Gene', (218, 223))	('thyroid cancer 1', 'Gene', '56892', (140, 156))	('Serpina 1', 'Gene', (173, 182))	('PROX1', 'Gene', (40, 45))	('enhanced', 'PosReg', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
74534	32370142	Additionally, notch-induced PROX1 inactivation significantly promoted the malignant phenotype of thyroid cancer cells.	('malignant phenotype of', 'CPA', (74, 96))	('inactivation', 'Var', (34, 46))	('thyroid cancer', 'Disease', (97, 111))	('promoted', 'PosReg', (61, 69))	('thyroid cancer', 'Phenotype', 'HP:0002890', (97, 111))	('thyroid cancer', 'Disease', 'MESH:D013964', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
74535	32370142	Furthermore, PROX1 knockdown increased the angiogenic potential of FTC- and SCT-derived cells by modulating the expression of genes involved in the angiogenic signaling pathway and was regulated in the opposite direction than pro-angiogenic factor FGF2.	('angiogenic', 'Pathway', (148, 158))	('expression of', 'MPA', (112, 125))	('FGF2', 'Gene', '2247', (248, 252))	('knockdown', 'Var', (19, 28))	('PROX1', 'Gene', (13, 18))	('increased', 'PosReg', (29, 38))	('FGF2', 'Gene', (248, 252))	('angiogenic potential', 'CPA', (43, 63))	('modulating', 'Reg', (97, 107))
74536	32370142	We can hypothesize that the discrepancy between the regulation of PTC and FTC and SCT by PROX1 may result from differences in the origin of cancer cells, mutations, as well as signaling pathways involved.	('result', 'Reg', (99, 105))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('PTC', 'Gene', (66, 69))	('mutations', 'Var', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PTC', 'Gene', '5979', (66, 69))
74538	32370142	Further, all molecular changes were rigorously confirmed in biological testing where cells after PROX1 knockdown revealed changed actin organization, showed the lower motility, increased invasive potential, and changed the tubularization of human umbilical endothelial cells cultivated in medium conditioned using CGTH-W-1 cells transfected with siPROX1.	('lower', 'NegReg', (161, 166))	('actin', 'MPA', (130, 135))	('CGTH-W-1', 'CellLine', 'CVCL:1120', (314, 322))	('human', 'Species', '9606', (241, 246))	('PROX1', 'Gene', (97, 102))	('changed', 'Reg', (211, 218))	('increased', 'PosReg', (177, 186))	('tubularization', 'CPA', (223, 237))	('motility', 'CPA', (167, 175))	('invasive potential', 'CPA', (187, 205))	('changed', 'Reg', (122, 129))	('knockdown', 'Var', (103, 112))
74553	32370142	Furthermore, defects in the transcription factor SOX18 cause lymphatic dysfunction in the human syndrome hypotrichosis-lymphoedema-telangiectasia.	('telangiectasia', 'Phenotype', 'HP:0001009', (131, 145))	('lymphoedema', 'Phenotype', 'HP:0001004', (119, 130))	('cause', 'Reg', (55, 60))	('SOX18', 'Gene', '54345', (49, 54))	('lymphatic dysfunction in the human syndrome hypotrichosis-lymphoedema-telangiectasia', 'Disease', 'MESH:D013684', (61, 145))	('hypotrichosis', 'Phenotype', 'HP:0001006', (105, 118))	('defects', 'Var', (13, 20))	('SOX18', 'Gene', (49, 54))
74561	32370142	In the PTC-derived cells, PDPN silencing reduces migration, invasion, and adhesion of tested cells through regulating the expression of the ezrin, radixin, and moesin proteins, MMP9 and MMP2 proteins.	('expression', 'MPA', (122, 132))	('invasion', 'CPA', (60, 68))	('migration', 'CPA', (49, 58))	('MMP2', 'Gene', (186, 190))	('PDPN', 'Gene', '10630', (26, 30))	('radixin', 'Protein', (147, 154))	('silencing', 'Var', (31, 40))	('reduces', 'NegReg', (41, 48))	('regulating', 'Reg', (107, 117))	('ezrin', 'Protein', (140, 145))	('PTC', 'Gene', (7, 10))	('PTC', 'Gene', '5979', (7, 10))	('MMP2', 'Gene', '4313', (186, 190))	('adhesion', 'CPA', (74, 82))	('PDPN', 'Gene', (26, 30))	('moesin', 'Gene', (160, 166))	('MMP9', 'Gene', '4318', (177, 181))	('MMP9', 'Gene', (177, 181))	('moesin', 'Gene', '4478', (160, 166))
74570	32370142	Still, further experiments are required to understand how the PROX1 epigenetic regulation and relation with other vascular molecules translate into a tumor setting and development.	('epigenetic regulation', 'Var', (68, 89))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PROX1', 'Gene', (62, 67))	('tumor', 'Disease', (150, 155))
74594	31728250	A week after finishing the course of neoadjuvant chemoradiotherapy, however, his fever changed from intermittent low-grade to persistent high-grade (>101 F or >38.3 C) requiring hospitalization.	('fever', 'Disease', (81, 86))	('>101 F', 'Var', (149, 155))	('fever', 'Phenotype', 'HP:0001945', (81, 86))	('fever', 'Disease', 'MESH:D005334', (81, 86))
74642	30603736	Through deep-sequencing of 74 cancer genes in 234 biopsies isolated from the eyelids of four different individuals, 3760 somatic mutations were identified, largely occurring in the ultraviolet mutational signature context.	('mutations', 'Var', (129, 138))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
74643	30603736	Strong positive selection was observed within the skin samples, evidenced by an increased ratio of nonsynomous (protein-altering) mutations versus synonymous (background) mutations in six genes, including NOTCH1 and TP53.	('NOTCH1', 'Gene', (205, 211))	('TP53', 'Gene', (216, 220))	('mutations', 'Var', (130, 139))	('NOTCH1', 'Gene', '4851', (205, 211))
74645	30603736	Mutational processes either from exogenous or endogenous origin, can potentially contribute to the development of pre-cancerous clones.	('cancer', 'Disease', (118, 124))	('contribute', 'Reg', (81, 91))	('Mutational', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
74647	30603736	Observations of multifocal patches of clonal populations with cancer-related genetic aberrations are not restricted to the skin, but have amongst others also been found in lung epithelium, breast epithelium and intestinal epithelium in patients with ileocolitis (Figure 1).	('ileocolitis', 'Disease', 'MESH:D003424', (250, 261))	('found', 'Reg', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('patients', 'Species', '9606', (236, 244))	('genetic aberrations', 'Var', (77, 96))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('ileocolitis', 'Disease', (250, 261))
74650	30603736	More recent studies have also implicated epigenetic dysregulation of cancer cells in the process of field cancerization in the colon and esophagus.	('colon', 'Disease', 'MESH:D015179', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('colon', 'Disease', (127, 132))	('epigenetic dysregulation', 'Var', (41, 65))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
74651	30603736	Epigenetic changes induced in dermal fibroblasts by exposure to ultraviolet light may also contribute to field cancerization, through dysregulating local release of factors including cytokines and matrix-remodelling enzymes.	('dysregulating local release of factors', 'MPA', (134, 172))	('contribute', 'Reg', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('Epigenetic changes', 'Var', (0, 18))
74653	30603736	as "the preconditioning of an area of epithelium to tumor growth, either as the result of a clonal proliferation of mutant cells through the epithelium without causing neoplasia or because of consistent changes to cells in the stromal compartment".	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('neoplasia', 'Disease', 'MESH:D009369', (168, 177))	('tumor', 'Disease', (52, 57))	('neoplasia', 'Phenotype', 'HP:0002664', (168, 177))	('changes', 'Reg', (203, 210))	('mutant', 'Var', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('neoplasia', 'Disease', (168, 177))
74658	30603736	For example, patients with familial adenomatous polyposis (FAP) have germline APC mutations, which causes a field defect in the colon even though the mutation is present in every cell.	('APC', 'Gene', (78, 81))	('causes', 'Reg', (99, 105))	('FAP', 'Disease', (59, 62))	('adenoma', 'Disease', (36, 43))	('patients', 'Species', '9606', (13, 21))	('colon', 'Disease', 'MESH:D015179', (128, 133))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (36, 57))	('FAP', 'Disease', 'MESH:C567782', (59, 62))	('mutations', 'Var', (82, 91))	('adenoma', 'Disease', 'MESH:D000236', (36, 43))	('colon', 'Disease', (128, 133))	('field defect', 'MPA', (108, 120))
74673	30603736	For example, patients who do not progress to EAC have relatively stable somatic chromosomal aberrations including localised CDKN2A deletions, 9p loss and copy number neutral loss of heterozygosity.	('CDKN2A', 'Gene', (124, 130))	('copy number neutral', 'Var', (154, 173))	('CDKN2A', 'Gene', '1029', (124, 130))	('patients', 'Species', '9606', (13, 21))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (80, 103))	('deletions', 'Var', (131, 140))	('loss', 'NegReg', (174, 178))
74674	30603736	In contrast patients who do progress to EAC develop chromosome instability, genomic diversity and selection of somatic copy number alterations including amplifications and genome doublings events.	('patients', 'Species', '9606', (12, 20))	('chromosome instability', 'CPA', (52, 74))	('genomic diversity', 'CPA', (76, 93))	('EAC', 'Disease', (40, 43))	('amplifications', 'Var', (153, 167))	('chromosome instability', 'Phenotype', 'HP:0040012', (52, 74))	('genome doublings events', 'Var', (172, 195))	('develop', 'Reg', (44, 51))
74675	30603736	Four unrelated BE segments contained homozygous CDKN2A deletions, whereas the EACs that developed in these patients lacked these alterations.	('CDKN2A', 'Gene', '1029', (48, 54))	('CDKN2A', 'Gene', (48, 54))	('patients', 'Species', '9606', (107, 115))	('deletions', 'Var', (55, 64))
74677	30603736	Given these findings, perhaps BE clones with early CDKN2A deletion are able to tolerate mutagenesis induced by an acidic environment through avoiding apoptosis.	('CDKN2A', 'Gene', '1029', (51, 57))	('avoiding', 'NegReg', (141, 149))	('apoptosis', 'CPA', (150, 159))	('deletion', 'Var', (58, 66))	('CDKN2A', 'Gene', (51, 57))
74678	30603736	On the other hand, clones that acquire early TP53 mutations, permissive for tolerance of DNA damage and ongoing genomic instability, undergo genome doubling and diversification acquiring further tumor suppressor gene inactivation and oncogene amplification events.	('tumor', 'Disease', (195, 200))	('TP53', 'Gene', (45, 49))	('undergo', 'Reg', (133, 140))	('mutations', 'Var', (50, 59))	('genome doubling', 'CPA', (141, 156))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
74679	30603736	In support of this theory, TP53 is recurrently mutated in dysplastic-BE, which is associated with occult EAC in up to 40% of cases, yet rarely mutated in non-dysplastic BE segments, which only progress to EAC in approximately 1 in 300 patients.	('TP53', 'Gene', (27, 31))	('dysplastic', 'Disease', 'MESH:D004416', (58, 68))	('associated', 'Reg', (82, 92))	('dysplastic', 'Disease', 'MESH:D004416', (158, 168))	('dysplastic', 'Disease', (158, 168))	('dysplastic', 'Disease', (58, 68))	('non-dysplastic', 'Disease', 'MESH:D004416', (154, 168))	('patients', 'Species', '9606', (235, 243))	('mutated', 'Var', (47, 54))	('non-dysplastic', 'Disease', (154, 168))
74680	30603736	Furthermore, there is evidence to suggest TP53 mutations facilitate the transition toward genomic instability in EAC carcinogenesis.	('facilitate', 'PosReg', (57, 67))	('TP53', 'Gene', (42, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (117, 131))	('mutations', 'Var', (47, 56))	('transition', 'MPA', (72, 82))	('carcinogenesis', 'Disease', (117, 131))
74688	30603736	Colorectal carcinomas have been demonstrated to be more chromosomally instable than adenomas by whole genome single nucleotide polymorphism arrays and separate analyses of genomic imbalances in the adenoma and carcinoma components present in "malignant polyps" (small adenocarcinomas arising in high grade adenomas) revealed considerably more chromosomal losses and gains within the carcinoma region as compared with the adenoma region suggesting increased chromosomal instability during tumor progression.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('chromosomal losses', 'Var', (343, 361))	('tumor', 'Disease', (488, 493))	('carcinoma', 'Phenotype', 'HP:0030731', (383, 392))	('carcinoma', 'Disease', (11, 20))	('carcinoma', 'Disease', (210, 219))	('imbalances', 'Phenotype', 'HP:0002172', (180, 190))	('adenocarcinomas', 'Disease', 'MESH:D000230', (268, 283))	('malignant polyps', 'Disease', (243, 259))	('adenocarcinomas', 'Disease', (268, 283))	('Colorectal carcinomas', 'Disease', (0, 21))	('carcinoma', 'Disease', (383, 392))	('adenoma', 'Disease', 'MESH:D000236', (306, 313))	('tumor', 'Disease', 'MESH:D009369', (488, 493))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (447, 480))	('adenoma', 'Disease', (421, 428))	('adenomas', 'Disease', 'MESH:D000236', (84, 92))	('adenomas', 'Disease', (84, 92))	('carcinoma', 'Disease', 'MESH:D002277', (273, 282))	('adenoma', 'Disease', 'MESH:D000236', (421, 428))	('carcinoma', 'Disease', 'MESH:D002277', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (488, 493))	('carcinoma', 'Disease', 'MESH:D002277', (210, 219))	('adenomas', 'Disease', 'MESH:D000236', (306, 314))	('malignant polyps', 'Disease', 'MESH:D011127', (243, 259))	('adenomas', 'Disease', (306, 314))	('adenoma', 'Disease', (198, 205))	('carcinoma', 'Disease', 'MESH:D002277', (383, 392))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))	('imbalance', 'Phenotype', 'HP:0002172', (180, 189))	('chromosomal instability', 'Phenotype', 'HP:0040012', (457, 480))	('Colorectal carcinomas', 'Disease', 'MESH:D015179', (0, 21))	('adenoma', 'Disease', 'MESH:D000236', (198, 205))	('gains within the carcinoma', 'Disease', 'MESH:D001929', (366, 392))	('adenoma', 'Disease', (84, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('carcinomas', 'Phenotype', 'HP:0030731', (273, 283))	('carcinoma', 'Disease', (273, 282))	('gains within the carcinoma', 'Disease', (366, 392))	('adenoma', 'Disease', 'MESH:D000236', (84, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('adenoma', 'Disease', (306, 313))
74698	30603736	Transgenic expression in Zebrafish melanocytes of BRAFV600E, with concomitant deletion of TP53, leads to melanoma development, however only a small number of melanocytes develop into melanomas in this model.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('melanoma', 'Disease', (183, 191))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('melanomas', 'Disease', 'MESH:D008545', (183, 192))	('melanoma', 'Disease', (105, 113))	('leads to', 'Reg', (96, 104))	('deletion', 'Var', (78, 86))	('Zebrafish', 'Species', '7955', (25, 34))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('BRAFV600E', 'Var', (50, 59))	('BRAFV600E', 'Mutation', 'rs113488022', (50, 59))	('TP53', 'Gene', (90, 94))	('melanomas', 'Disease', (183, 192))
74699	30603736	Through use of an in vivo reporter of neural crest-progenitor (NCP) state it was demonstrated that clusters of melanocytes within a BRAFV600E mutant, TP53 deficient "cancer field", regress to a NCP identity and it is these cells that display tumorigenic properties and progress to form invasive melanoma.	('TP53', 'Gene', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('invasive melanoma', 'Disease', 'MESH:D008545', (286, 303))	('BRAFV600E', 'Mutation', 'rs113488022', (132, 141))	('mutant', 'Var', (142, 148))	('deficient "cancer', 'Disease', 'MESH:D009369', (155, 172))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('deficient "cancer', 'Disease', (155, 172))	('progress', 'PosReg', (269, 277))	('tumor', 'Disease', (242, 247))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('BRAFV600E', 'Gene', (132, 141))	('invasive melanoma', 'Disease', (286, 303))
74709	30603736	The Cytosponge is a non-endoscopic device designed to acquire BE samples, analysis of Cytosponge samples using a multi-biomarker panel including TP53 mutation status can identify patients at low-risk of progression to EAC.	('EAC', 'Disease', (218, 221))	('mutation', 'Var', (150, 158))	('TP53', 'Gene', (145, 149))	('patients', 'Species', '9606', (179, 187))
74712	30603736	These include vaccination strategies and therapeutic modulation of inflammatory pathways within the tissue microenvironment that promote tumorigenesis.	('tumor', 'Disease', (137, 142))	('promote', 'PosReg', (129, 136))	('modulation', 'Var', (53, 63))	('inflammatory pathways', 'Pathway', (67, 88))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
74731	29796163	Esophageal SCC (ESCC) has frequent TP53 mutations independent of c-Myc activation.	('c-Myc', 'Gene', (65, 70))	('Esophageal SCC', 'Disease', (0, 14))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('c-Myc', 'Gene', '4609', (65, 70))
74734	29796163	Recently, DNA damage has been reported to induce alternative splicing (AS), but the significance of AS in carcinogenesis remains largely unclear.	('carcinogenesis', 'Disease', 'MESH:D063646', (106, 120))	('induce', 'Reg', (42, 48))	('carcinogenesis', 'Disease', (106, 120))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('alternative splicing', 'MPA', (49, 69))	('DNA', 'Var', (10, 13))
74749	29796163	TP53 gene variation of TE1 and TE2 was benign (wild) whereas that of YES2 and T.Tn was pathogenic, however, no significant difference of TP53 expression among these cells (Figure 1D, Supplementary Figure 2).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('variation', 'Var', (10, 19))	('YES2', 'Gene', '7526', (69, 73))	('TE2', 'Gene', '8260', (31, 34))	('TP53', 'Gene', '7157', (137, 141))	('YES2', 'Gene', (69, 73))	('TE2', 'Gene', (31, 34))	('TP53', 'Gene', (137, 141))
74750	29796163	TP53 gene mutation in YES3 generated truncated TP53 or scarce expression (Figure 1D, large arrow, Supplementary Figure 2).	('YES3', 'Gene', (22, 26))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('scarce', 'NegReg', (55, 61))	('expression', 'MPA', (62, 72))	('mutation', 'Var', (10, 18))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))	('truncated', 'MPA', (37, 46))
74754	29796163	Together, no apparent feedback reaction was observed in FBW7 expression in response to altered TP53 or Notch1 expression in ESCC cells (Figure 1D).	('FBW7', 'Gene', (56, 60))	('Notch1', 'Gene', (103, 109))	('altered', 'Var', (87, 94))	('Notch1', 'Gene', '4851', (103, 109))	('expression', 'MPA', (110, 120))	('FBW7', 'Gene', '55294', (56, 60))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
74763	29796163	Clinically, esophageal cancer patients with high FIRDeltaexon2/FIR ratio (tumor tissues/non-tumor tissues [T/N] ratio) of >= 2 had significantly higher lymph node metastases (Figure 2C).	('high', 'Var', (44, 48))	('metastases', 'Disease', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('metastases', 'Disease', 'MESH:D009362', (163, 173))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Disease', (74, 79))	('esophageal cancer', 'Disease', (12, 29))	('tumor', 'Disease', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('higher', 'PosReg', (145, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (12, 29))
74766	29796163	Therefore, antibodies against FIRDeltaexon2 can be used as a potential biomarker for esophageal cancer and a therapeutic target to reduce the lymph nodes metastasis (Figure 2E).	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('antibodies', 'Var', (11, 21))	('reduce', 'NegReg', (131, 137))	('FIRDeltaexon2', 'Gene', (30, 43))	('lymph nodes metastasis', 'CPA', (142, 164))	('esophageal cancer', 'Disease', (85, 102))
74768	29796163	If the expression of FIRs is critical for cyclin E expression, altered FIRs expression should alter its expression.	('altered', 'Var', (63, 70))	('FIRs', 'Gene', (71, 75))	('cyclin', 'Gene', '5111', (42, 48))	('expression', 'MPA', (104, 114))	('cyclin', 'Gene', (42, 48))	('alter', 'Reg', (94, 99))
74769	29796163	To explore the significance of FIRs, FIR, and FIRDeltaexon2 expression in relation to esophageal cancer progression, knockdown of FIR was challenged to esophageal cancer cells TE2 (TP53 gene variation was benign) and cyclin E expression was examined.	('TE2', 'Gene', (176, 179))	('TP53', 'Gene', (181, 185))	('esophageal cancer', 'Disease', (152, 169))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cyclin', 'Gene', '5111', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cyclin', 'Gene', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('TE2', 'Gene', '8260', (176, 179))	('variation', 'Var', (191, 200))	('TP53', 'Gene', '7157', (181, 185))
74775	29796163	Therefore, knockdown of SAP155 was also expected to decrease cyclin E and Notch1.	('Notch1', 'Gene', '4851', (74, 80))	('cyclin', 'Gene', '5111', (61, 67))	('decrease cyclin E', 'Phenotype', 'HP:0500152', (52, 69))	('cyclin', 'Gene', (61, 67))	('SAP155', 'Gene', (24, 30))	('decrease', 'NegReg', (52, 60))	('Notch1', 'Gene', (74, 80))	('knockdown', 'Var', (11, 20))	('SAP155', 'Gene', '23451', (24, 30))
74777	29796163	Remarkably, the knockdown of SAP155 by siRNA drastically decreased cyclin E, Notch1, FIR, TP53 and GSK3beta in YES2 cells with pathogenic TP53 (Figure 4A, arrows) whereas those no remarkable changes were observed in YES3 cells with scarce TP53 expression (Figure 4A, arrows).	('TP53', 'Gene', '7157', (90, 94))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('decreased cyclin E', 'Phenotype', 'HP:0500152', (57, 75))	('TP53', 'Gene', '7157', (239, 243))	('GSK3beta', 'Gene', (99, 107))	('decreased', 'NegReg', (57, 66))	('SAP155', 'Gene', (29, 35))	('TP53', 'Gene', (138, 142))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('cyclin', 'Gene', '5111', (67, 73))	('FIR', 'MPA', (85, 88))	('TP53', 'Gene', (90, 94))	('Notch1', 'Gene', (77, 83))	('TP53', 'Gene', (239, 243))	('Notch1', 'Gene', '4851', (77, 83))	('GSK3beta', 'Gene', '2932', (99, 107))	('TP53', 'Gene', '7157', (138, 142))	('cyclin', 'Gene', (67, 73))	('knockdown', 'Var', (16, 25))	('SAP155', 'Gene', '23451', (29, 35))	('YES2', 'Gene', '7526', (111, 115))	('YES2', 'Gene', (111, 115))
74778	29796163	Of note, the knockdown of SAP155 by siRNA significantly suppressed Notch1 mRNA (Figure 4B) but not cyclin E mRNA (Figure 4C).	('N', 'Chemical', 'MESH:D009584', (67, 68))	('cyclin', 'Gene', '5111', (99, 105))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('SAP155', 'Gene', (26, 32))	('cyclin', 'Gene', (99, 105))	('suppressed', 'NegReg', (56, 66))	('Notch1', 'Gene', (67, 73))	('SAP155', 'Gene', '23451', (26, 32))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('knockdown', 'Var', (13, 22))	('N', 'Chemical', 'MESH:D009584', (76, 77))	('Notch1', 'Gene', '4851', (67, 73))
74798	29796163	A crystal structure on the binding mode of SPF45 and SAP155 (PDB#: 2PEH) suggested that SAP155 used W and D residues for the binding and W338 and D339 of SAP155 made a close contact with the SPF45 LNGRYFGGRVVKA motif (Figures 5C-c, 5C-d).	('N', 'Chemical', 'MESH:D009584', (198, 199))	('SPF45', 'Gene', (43, 48))	('SPF45', 'Gene', (191, 196))	('D339', 'Var', (146, 150))	('SAP155', 'Gene', (88, 94))	('SAP155', 'Gene', (53, 59))	('W338', 'Var', (137, 141))	('SAP155', 'Gene', '23451', (88, 94))	('SAP155', 'Gene', (154, 160))	('SPF45', 'Gene', '84991', (191, 196))	('SAP155', 'Gene', '23451', (53, 59))	('SPF45', 'Gene', '84991', (43, 48))	('SAP155', 'Gene', '23451', (154, 160))
74812	29796163	Expectedly, TP53 was decreased (Figure 6A, arrows), whereas cyclin E was increased (Figures 6B, 6C, arrows) when exposed to CDDP in esophageal cancer cell lines (TE2 and TE1 with benign TP53 variation).	('increased', 'PosReg', (73, 82))	('TE2', 'Gene', (162, 165))	('CDDP', 'Chemical', '-', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cyclin', 'Gene', '5111', (60, 66))	('decreased', 'NegReg', (21, 30))	('esophageal cancer', 'Disease', (132, 149))	('TP53', 'Gene', '7157', (186, 190))	('cyclin', 'Gene', (60, 66))	('TP53', 'Gene', '7157', (12, 16))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('TP53', 'Gene', (186, 190))	('TE2', 'Gene', '8260', (162, 165))	('TP53', 'Gene', (12, 16))	('variation', 'Var', (191, 200))
74813	29796163	gammaH2AX was an indicator of DNA damage even in T.Tn cells that has pathogenic TP53 mutation ((Figure 6C, arrow).	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('pathogenic', 'Reg', (69, 79))
74821	29796163	Antibodies against FIRDeltaexon2 are potential biomarker for esophageal cancer and a therapeutic target to decrease lymph nodes metastasis (Figures 2D, 2E).	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('Antibodies', 'Var', (0, 10))	('decrease lymph', 'Phenotype', 'HP:0001888', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lymph nodes metastasis', 'CPA', (116, 138))	('decrease lymph nodes', 'Phenotype', 'HP:0002732', (107, 127))	('FIRDeltaexon2', 'Gene', (19, 32))	('decrease', 'NegReg', (107, 115))	('esophageal cancer', 'Disease', (61, 78))
74822	29796163	Moreover, knockdown of FIR by siRNA increased cyclin E expression in esophageal cancer cells (Figure 3, arrows).	('esophageal cancer', 'Disease', (69, 86))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('cyclin', 'Gene', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('increased', 'PosReg', (36, 45))	('FIR', 'Gene', (23, 26))	('knockdown', 'Var', (10, 19))	('cyclin', 'Gene', '5111', (46, 52))
74826	29796163	Since SAP155 is required for proper AS of FIR (PUF60) pre-mRNA, knockdown of SAP155 recovered FBW7 function possibly by reducing FIR/FIRDeltaexon2 expression.	('FBW7', 'Gene', (94, 98))	('function', 'MPA', (99, 107))	('expression', 'MPA', (147, 157))	('reducing', 'NegReg', (120, 128))	('PUF60', 'Gene', (47, 52))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('FIR/FIRDeltaexon2', 'Protein', (129, 146))	('SAP155', 'Gene', '23451', (6, 12))	('SAP155', 'Gene', (77, 83))	('PUF60', 'Gene', '22827', (47, 52))	('recovered', 'PosReg', (84, 93))	('knockdown', 'Var', (64, 73))	('FBW7', 'Gene', '55294', (94, 98))	('SAP155', 'Gene', '23451', (77, 83))	('SAP155', 'Gene', (6, 12))
74829	29796163	These results indicated that the expression of FIR/FIRDeltaexon2 affects degradation of cyclin E and Notch1 by FBW7 depending on the TP53 (Figure 7A).	('cyclin', 'Gene', '5111', (88, 94))	('expression', 'Var', (33, 43))	('FBW7', 'Gene', (111, 115))	('FIR/FIRDeltaexon2', 'Gene', (47, 64))	('cyclin', 'Gene', (88, 94))	('affects', 'Reg', (65, 72))	('Notch1', 'Gene', (101, 107))	('Notch1', 'Gene', '4851', (101, 107))	('FBW7', 'Gene', '55294', (111, 115))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))
74836	29796163	In case the change of mutant p53 proteins expression, it does not directly represent or surrogate the effect of RNA interference of FIR and SAP155 and the DNA-damaging agents.	('N', 'Chemical', 'MESH:D009584', (156, 157))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('expression', 'MPA', (42, 52))	('p53', 'Gene', (29, 32))	('SAP155', 'Gene', (140, 146))	('mutant', 'Var', (22, 28))	('p53', 'Gene', '7157', (29, 32))	('proteins', 'Protein', (33, 41))	('SAP155', 'Gene', '23451', (140, 146))
74843	29796163	Fascinatingly, FIR haplodeficiency promotes splicing to pyruvate kinase M2 in mice thymic lymphoma tissues, indicating disturbed splicing of FIR or a dominant negative form of FIR interferes cancer metabolism.	('lymphoma', 'Phenotype', 'HP:0002665', (90, 98))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('interferes', 'NegReg', (180, 190))	('splicing to pyruvate kinase M2', 'MPA', (44, 74))	('promotes', 'PosReg', (35, 43))	('haplodeficiency', 'Var', (19, 34))	('FIR', 'Gene', (15, 18))	('lymphoma', 'Disease', (90, 98))	('lymphoma', 'Disease', 'MESH:D008223', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mice', 'Species', '10090', (78, 82))
74846	29796163	In other words, altered FIR expression inhibits FBW7, resulting delayed DNA damage repair or elevated cyclin E expression in a c-Myc-independent manner in esophageal carcinogenesis.	('delayed', 'NegReg', (64, 71))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('c-Myc', 'Gene', (127, 132))	('FBW7', 'Gene', (48, 52))	('cyclin', 'Gene', '5111', (102, 108))	('altered', 'Var', (16, 23))	('elevated', 'PosReg', (93, 101))	('DNA damage repair', 'MPA', (72, 89))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (155, 180))	('FBW7', 'Gene', '55294', (48, 52))	('cyclin', 'Gene', (102, 108))	('esophageal carcinogenesis', 'Disease', (155, 180))	('inhibits', 'NegReg', (39, 47))	('c-Myc', 'Gene', '4609', (127, 132))	('FIR', 'Protein', (24, 27))
74848	29796163	Since FBW7 ubiquitinates c-Myc and Notch1 proteins and promotes degradation of those proteins in the proteasome system, a mutation in the FBW7 gene increases intracellular accumulation of c-Myc and Notch1 proteins.	('Notch1', 'Gene', (35, 41))	('Notch1', 'Gene', '4851', (35, 41))	('FBW7', 'Gene', '55294', (138, 142))	('intracellular accumulation', 'MPA', (158, 184))	('mutation', 'Var', (122, 130))	('c-Myc', 'Gene', (25, 30))	('Notch1', 'Gene', (198, 204))	('Notch1', 'Gene', '4851', (198, 204))	('c-Myc', 'Gene', '4609', (25, 30))	('proteins', 'Protein', (42, 50))	('FBW7', 'Gene', (6, 10))	('c-Myc', 'Gene', (188, 193))	('increases', 'PosReg', (148, 157))	('promotes', 'PosReg', (55, 63))	('proteins', 'Protein', (205, 213))	('FBW7', 'Gene', '55294', (6, 10))	('degradation', 'MPA', (64, 75))	('c-Myc', 'Gene', '4609', (188, 193))	('FBW7', 'Gene', (138, 142))
74905	29796163	The list of esophageal cancer patients and the results of their anti-FIRDeltaexon2s autoantibodies with other tumor markers are indicated (Supplementary Table 4).	('esophageal cancer', 'Disease', 'MESH:D004938', (12, 29))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('patients', 'Species', '9606', (30, 38))	('esophageal cancer', 'Disease', (12, 29))	('anti-FIRDeltaexon2s', 'Var', (64, 83))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
74917	27785073	The estimated OS (38.1 months) and PFS (13.4 months) of patients with high expression of EGFR were lower than those of patients with low expression (69.3 and 68.1 months, P<0.05).	('patients', 'Species', '9606', (56, 64))	('EGFR', 'Gene', (89, 93))	('lower', 'NegReg', (99, 104))	('patients', 'Species', '9606', (119, 127))	('PFS', 'CPA', (35, 38))	('high expression', 'Var', (70, 85))	('EGFR', 'Gene', '1956', (89, 93))
74918	27785073	The estimated OS (31.1 months) and PFS (13.1 months) of patients with high expression of B7-H3 were also lower than those of patients with low expression (69.3 and 66.6 months, P<0.05).	('lower', 'NegReg', (105, 110))	('patients', 'Species', '9606', (56, 64))	('B7-H3', 'Gene', (89, 94))	('PFS', 'CPA', (35, 38))	('high expression', 'Var', (70, 85))	('B7-H3', 'Gene', '80381', (89, 94))	('patients', 'Species', '9606', (125, 133))
74931	27785073	All of these changes can promote multidrug resistance of the tumor, thereby negatively affecting the efficacy of treatment and worsening the prognosis of ESCC patients.	('worsening', 'Reg', (127, 136))	('negatively', 'NegReg', (76, 86))	('changes', 'Var', (13, 20))	('ESCC', 'Disease', (154, 158))	('men', 'Species', '9606', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('multidrug resistance', 'MPA', (33, 53))	('promote', 'PosReg', (25, 32))	('affecting', 'Reg', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('efficacy of treatment', 'CPA', (101, 122))	('patients', 'Species', '9606', (159, 167))	('tumor', 'Disease', (61, 66))
74942	27785073	In vitro, inhibition of B7-H3 in ESCC cells suppresses their migration and invasion abilities.	('inhibition', 'Var', (10, 20))	('suppresses', 'NegReg', (44, 54))	('B7-H3', 'Gene', '80381', (24, 29))	('B7-H3', 'Gene', (24, 29))
74972	27785073	For patients with high EGFR expression, the estimated OS was 31.8 months (95% CI =26.5~37.1 months), and the estimated PFS was 13.4 months (95% CI =12.3~14.5 months).	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))
74975	27785073	For the patients with high B7-H3 expression, the estimated OS was 31.1 months (95% CI =24.9~37.3 months), and the estimated PFS was 13.1 months (95% CI =10.5~15.7 months).	('B7-H3', 'Gene', '80381', (27, 32))	('high', 'Var', (22, 26))	('B7-H3', 'Gene', (27, 32))	('patients', 'Species', '9606', (8, 16))
74982	27785073	Further, high expression of EGFR was associated with more advanced tumor infiltration and clinical staging.	('EGFR', 'Gene', '1956', (28, 32))	('clinical staging', 'CPA', (90, 106))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('EGFR', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('associated', 'Reg', (37, 47))	('tumor', 'Disease', (67, 72))	('high', 'Var', (9, 13))
74998	27358073	MiR-143-3p functions as a tumor suppressor by regulating cell proliferation, invasion and epithelial-mesenchymal transition by targeting QKI-5 in esophageal squamous cell carcinoma Dysregulation of microRNAs (miRNAs) have been demonstrated to contribute to carcinogenesis.	('targeting', 'NegReg', (127, 136))	('miR', 'Gene', '220972', (209, 212))	('QKI', 'Gene', '9444', (137, 140))	('cell proliferation', 'CPA', (57, 75))	('Dysregulation', 'Var', (181, 194))	('MiR', 'Gene', '220972', (0, 3))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (146, 180))	('QKI', 'Gene', (137, 140))	('miR', 'Gene', (209, 212))	('contribute', 'Reg', (243, 253))	('epithelial-mesenchymal transition', 'CPA', (90, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('tumor', 'Disease', (26, 31))	('carcinogenesis', 'Disease', (257, 271))	('MiR', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('carcinogenesis', 'Disease', 'MESH:D063646', (257, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('esophageal squamous cell carcinoma', 'Disease', (146, 180))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
75013	27358073	Accumulating evidence suggests that dysregulated miRNAs can function either as oncogenes or tumor suppressor genes to affect the initiation and progression of tumors, including ESCC.	('affect', 'Reg', (118, 124))	('initiation', 'CPA', (129, 139))	('ESCC', 'Disease', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (159, 164))	('dysregulated', 'Var', (36, 48))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
75020	27358073	Aberrant expression of QKI-5 is associated with the development and progression of human cancers.	('Aberrant expression', 'Var', (0, 19))	('QKI', 'Gene', (23, 26))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('QKI', 'Gene', '9444', (23, 26))	('human', 'Species', '9606', (83, 88))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('associated with', 'Reg', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
75108	27358073	5a and b), while silencing of QKI-5 expression suppressed cell growth (Fig.	('suppressed', 'NegReg', (47, 57))	('QKI', 'Gene', (30, 33))	('QKI', 'Gene', '9444', (30, 33))	('cell growth', 'CPA', (58, 69))	('silencing', 'Var', (17, 26))
75112	27358073	Meanwhile, Invasion assay demonstrated that inhibition of QKI-5 expression reduced the invasiveness of ESCC cells (Fig.	('inhibition', 'Var', (44, 54))	('invasiveness of', 'CPA', (87, 102))	('QKI', 'Gene', (58, 61))	('reduced', 'NegReg', (75, 82))	('QKI', 'Gene', '9444', (58, 61))	('ESCC', 'Disease', (103, 107))
75124	27358073	Additionally, restoration of QKI-5 promoted proliferation and significantly increased tumor volume.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('restoration', 'Var', (14, 25))	('QKI', 'Gene', (29, 32))	('increased', 'PosReg', (76, 85))	('tumor', 'Disease', (86, 91))	('QKI', 'Gene', '9444', (29, 32))	('promoted', 'PosReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('proliferation', 'CPA', (44, 57))
75132	27358073	Figure 9a and b demonstrate that both miR-143-3p overexpression and QKI-5 silening resulted in increased E-cadherin and beta-catenin protein levels and decreased of vimentin and N-cadherin protein levels.	('vimentin', 'Gene', (165, 173))	('beta-catenin', 'Gene', '1499', (120, 132))	('N-cadherin', 'Gene', (178, 188))	('silening', 'Var', (74, 82))	('QKI', 'Gene', (68, 71))	('E-cadherin', 'Gene', (105, 115))	('E-cadherin', 'Gene', '999', (105, 115))	('decreased', 'NegReg', (152, 161))	('QKI', 'Gene', '9444', (68, 71))	('miR-143', 'Gene', '406935', (38, 45))	('N-cadherin', 'Gene', '1000', (178, 188))	('miR-143', 'Gene', (38, 45))	('overexpression', 'PosReg', (49, 63))	('increased', 'PosReg', (95, 104))	('vimentin', 'Gene', '7431', (165, 173))	('beta-catenin', 'Gene', (120, 132))
75160	27358073	Disrupting QKI expression, especially the QKI-5 isoform, also inhibited ESCC cells proliferation and induced cell apoptosis in vitro.	('cell apoptosis', 'CPA', (109, 123))	('QKI', 'Gene', (11, 14))	('Disrupting', 'Var', (0, 10))	('induced', 'Reg', (101, 108))	('inhibited', 'NegReg', (62, 71))	('QKI', 'Gene', (42, 45))	('QKI', 'Gene', '9444', (11, 14))	('QKI', 'Gene', '9444', (42, 45))	('ESCC', 'Disease', (72, 76))
75162	27358073	Gene dysregulation plays a critical role in the initiation and progression of multiple human cancers.	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Gene dysregulation', 'Var', (0, 18))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
75171	27358073	Meanwhile, levels of the epithelial markers E-cadherin and beta-catenin were increased in both groups of transfected cells.	('beta-catenin', 'Gene', '1499', (59, 71))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('transfected', 'Var', (105, 116))	('increased', 'PosReg', (77, 86))	('beta-catenin', 'Gene', (59, 71))
75179	27358073	Furthermore, dysregulation of miR-143-3p is a molecular mechanisms involved in the development and progression of ESCC.	('miR-143', 'Gene', '406935', (30, 37))	('involved', 'Reg', (67, 75))	('ESCC', 'Disease', (114, 118))	('miR-143', 'Gene', (30, 37))	('dysregulation', 'Var', (13, 26))
75381	32495982	In esophageal squamous cell carcinoma (ESCC), high circular RNA LPAR3 expression is positively correlated with lymph node metastasis and advanced tumor TNM stage.	('TNM', 'Gene', (152, 155))	('LPAR3', 'Gene', '23566', (64, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('lymph node metastasis', 'CPA', (111, 132))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('high circular', 'Var', (46, 59))	('tumor', 'Disease', (146, 151))	('LPAR3', 'Gene', (64, 69))	('correlated', 'Reg', (95, 105))	('expression', 'MPA', (70, 80))	('TNM', 'Gene', '10178', (152, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
75399	32495982	The ESCC cell lines ECA109, TE-13, Kyse150, Kyse450, and Kyse510, as well as the normal esophageal epithelial HET-1A cells, were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.	('Kyse150', 'Var', (35, 42))	('TE-13', 'CellLine', 'CVCL:4463', (28, 33))	('Kyse450', 'Var', (44, 51))	('Kyse510', 'Var', (57, 64))
75418	32495982	Lipofectamine 2000 (Invitrogen) was used to cotransfect the dual-luciferase reporter gene plasmid and miR-198 mimics or miR-198 mimic-NC into Kyse450 cells.	('mimic-NC', 'Var', (128, 136))	('miR-198', 'Gene', (102, 109))	('miR-198', 'Gene', (120, 127))	('miR-198', 'Gene', '406975', (102, 109))	('miR-198', 'Gene', '406975', (120, 127))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (0, 18))	('mimics', 'Var', (110, 116))
75431	32495982	Expression of circLPAR3 in ESCC tissues was markedly higher than that in paracarcinoma tissues; in addition, the high circLPAR3 expression was correlated with LNM and advanced TNM stage, but not with age, sex, tumor infiltration depth, or tissue differentiation degree (Table 4).	('high', 'Var', (113, 117))	('LPAR3', 'Gene', '23566', (122, 127))	('higher', 'PosReg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('LPAR3', 'Gene', (122, 127))	('LNM', 'Disease', (159, 162))	('Expression', 'MPA', (0, 10))	('paracarcinoma', 'Disease', (73, 86))	('tumor infiltration depth', 'Disease', (210, 234))	('paracarcinoma', 'Disease', 'None', (73, 86))	('LPAR3', 'Gene', '23566', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('TNM', 'Gene', '10178', (176, 179))	('LPAR3', 'Gene', (18, 23))	('expression', 'MPA', (128, 138))	('correlated', 'Reg', (143, 153))	('TNM', 'Gene', (176, 179))	('tumor infiltration depth', 'Disease', 'MESH:D007222', (210, 234))
75444	32495982	Similarly, the Transwell assay showed that high circLPAR3 expression promoted the migration and invasion capacities of ESCC cells (Figure 3J).	('high', 'Var', (43, 47))	('invasion capacities', 'CPA', (96, 115))	('LPAR3', 'Gene', '23566', (52, 57))	('migration', 'CPA', (82, 91))	('LPAR3', 'Gene', (52, 57))	('promoted', 'PosReg', (69, 77))
75447	32495982	Using Arraystar's home-made software, it was predicted that 5 miRNAs had the binding sites with circLPAR3, including miR-198, miR-2682-5p, miR-4692, miR-6511a-5p, and miR-6780-5p.	('miR-6780-5p', 'Var', (167, 178))	('miR-4692', 'Gene', '100616410', (139, 147))	('LPAR3', 'Gene', '23566', (100, 105))	('binding', 'Interaction', (77, 84))	('miR-4692', 'Gene', (139, 147))	('miR-2682', 'Gene', '100616452', (126, 134))	('LPAR3', 'Gene', (100, 105))	('miR-198', 'Gene', '406975', (117, 124))	('miR-6511a-5p', 'Var', (149, 161))	('miR-2682', 'Gene', (126, 134))	('miR-198', 'Gene', (117, 124))
75452	32495982	Based on the binding site of circLPAR3 with miR-198, the circLPAR3 WT and mutant dual-luciferase reporter gene plasmids were designed and synthesized (Figure 4D), and the circLPAR3 WT or mutant plasmids were cotransfected into TE13 cells with miR-198 mimics or miR-198 mimic-NC.	('miR-198', 'Gene', '406975', (44, 51))	('LPAR3', 'Gene', (33, 38))	('miR-198', 'Gene', (44, 51))	('LPAR3', 'Gene', '23566', (175, 180))	('miR-198', 'Gene', (243, 250))	('mimic-NC', 'Var', (269, 277))	('LPAR3', 'Gene', (61, 66))	('miR-198', 'Gene', '406975', (243, 250))	('LPAR3', 'Gene', (175, 180))	('miR-198', 'Gene', (261, 268))	('miR-198', 'Gene', '406975', (261, 268))	('LPAR3', 'Gene', '23566', (33, 38))	('mutant', 'Var', (74, 80))	('LPAR3', 'Gene', '23566', (61, 66))
75458	32495982	Transwell assay indicated that overexpression of miR-198 reversed the promoting effect of high circLPAR3 expression on ESCC cell migration (Figure 5G).	('ESCC', 'Disease', (119, 123))	('LPAR3', 'Gene', (99, 104))	('miR-198', 'Gene', (49, 56))	('promoting', 'PosReg', (70, 79))	('miR-198', 'Gene', '406975', (49, 56))	('high', 'Var', (90, 94))	('LPAR3', 'Gene', '23566', (99, 104))
75462	32495982	Transfection with sh-circLPAR#3 in TE13 cells markedly downregulated the circLPAR3 expression level (Figure 6A).	('LPAR3', 'Gene', '23566', (77, 82))	('sh-circLPAR', 'Var', (18, 29))	('LPAR3', 'Gene', (77, 82))	('downregulated', 'NegReg', (55, 68))
75465	32495982	The H&E staining results of nude mouse lung tissue pathological sections indicated that the size and number of lung metastases in nude mice of low circLPAR3 group were apparently less than those in control group (Figure 6C,D).	('of low', 'Var', (140, 146))	('mouse', 'Species', '10090', (33, 38))	('apparently', 'NegReg', (168, 178))	('LPAR3', 'Gene', '23566', (151, 156))	('nude mice', 'Species', '10090', (130, 139))	('lung metastases', 'Disease', (111, 126))	('lung metastases', 'Disease', 'MESH:D009362', (111, 126))	('H&E', 'Chemical', 'MESH:D006371', (4, 7))	('LPAR3', 'Gene', (151, 156))
75466	32495982	Additionally, IHC and qRT-PCR results suggested that the c-MET and MET expression in lung metastases of nude mice with low circLPAR3 expression was also apparently lower than that in control group (Figure 6E,F).	('expression', 'MPA', (71, 81))	('low circLPAR3 expression', 'Phenotype', 'HP:0031037', (119, 143))	('LPAR3', 'Gene', '23566', (127, 132))	('lower', 'NegReg', (164, 169))	('c-MET', 'MPA', (57, 62))	('low', 'Var', (119, 122))	('LPAR3', 'Gene', (127, 132))	('MET', 'Protein', (67, 70))	('lung metastases', 'Disease', 'MESH:D009362', (85, 100))	('lung metastases', 'Disease', (85, 100))	('nude mice', 'Species', '10090', (104, 113))
75491	32495982	In vivo experiment proves that low circLPAR3 expression results in a lower risk of distant metastasis.	('LPAR3', 'Gene', (39, 44))	('LPAR3', 'Gene', '23566', (39, 44))	('low circLPAR3 expression', 'Phenotype', 'HP:0031037', (31, 55))	('expression', 'MPA', (45, 55))	('distant metastasis', 'CPA', (83, 101))	('low', 'Var', (31, 34))
75571	30923786	In the JCOG0303 trial,36 which included patients with cT4 and/or unresectable regional lymph node metastasis, grades 3-4 fistula formation occurred in 32 of 140 patients (23%) during or after dCRT.	('dCRT', 'Gene', '45841', (192, 196))	('cT4', 'Var', (54, 57))	('dCRT', 'Gene', (192, 196))	('patients', 'Species', '9606', (40, 48))	('fistula', 'Disease', 'MESH:D005402', (121, 128))	('fistula', 'Disease', (121, 128))	('patients', 'Species', '9606', (161, 169))
75577	30923786	Incidence of late toxicities as a result of dCRT was 0%-22%, although only five studies reported relevant data.12, 16, 34, 36, 37 In addition to fistula formation, the JCOG0303 study36 reported other common late toxicities, including dyspnea, dysphagia/esophagitis/odynophagia, and pneumonitis.	('pneumonitis', 'Disease', (282, 293))	('dCRT', 'Gene', (44, 48))	('late toxicities', 'Disease', 'MESH:D064420', (13, 28))	('fistula', 'Disease', 'MESH:D005402', (145, 152))	('fistula', 'Disease', (145, 152))	('late toxicities', 'Disease', (207, 222))	('dyspnea, dysphagia/esophagitis/odynophagia', 'Disease', 'MESH:D003680', (234, 276))	('pneumonitis', 'Disease', 'MESH:D011014', (282, 293))	('dyspnea', 'Phenotype', 'HP:0002094', (234, 241))	('late toxicities', 'Disease', 'MESH:D064420', (207, 222))	('dysphagia', 'Phenotype', 'HP:0002015', (243, 252))	('esophagitis', 'Phenotype', 'HP:0100633', (253, 264))	('odynophagia', 'Phenotype', 'HP:0032043', (265, 276))	('late toxicities', 'Disease', (13, 28))	('dCRT', 'Gene', '45841', (44, 48))	('JCOG0303', 'Var', (168, 176))
75623	30923786	Indeed, DCF had a strong antitumor effect for ESCC, and it is currently being used as a first-line chemotherapy regimen for ESCC.	('ESCC', 'Disease', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('DCF', 'Var', (8, 11))	('DCF', 'Chemical', '-', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))
75636	30923786	Considering that local recurrence after curative surgery tended to be lower in the DCF group than in the CRT group, DCF chemotherapy appeared to control local disease sufficiently, with or without subsequent CRT.	('DCF', 'Var', (83, 86))	('local recurrence', 'CPA', (17, 33))	('DCF', 'Chemical', '-', (83, 86))	('local', 'Disease', (153, 158))	('lower', 'NegReg', (70, 75))	('CRT', 'Gene', '45841', (105, 108))	('CRT', 'Gene', '45841', (208, 211))	('CRT', 'Gene', (105, 108))	('CRT', 'Gene', (208, 211))	('DCF', 'Chemical', '-', (116, 119))
75643	30923786	The aim of this new phase III JCOG study is to confirm that DCF chemotherapy followed by radical surgery or dCRT shows superiority in OS over the standard dCRT for patients with cT4 ESCC of the thoracic esophagus.	('cT4', 'Var', (178, 181))	('dCRT', 'Gene', '45841', (108, 112))	('dCRT', 'Gene', (155, 159))	('dCRT', 'Gene', (108, 112))	('dCRT', 'Gene', '45841', (155, 159))	('DCF', 'Chemical', '-', (60, 63))	('OS', 'Chemical', '-', (134, 136))	('patients', 'Species', '9606', (164, 172))
75664	30923786	Thus, it might be more appropriate to base treatment decisions on comorbidity and/or performance status, rather than chronological age alone.48 Although we proposed a possible treatment algorithm for cT4 esophageal cancer (Figure 1), the tolerance for each treatment should first be evaluated, considering comorbidity, performance status, and general condition, in addition to the patient's age.	('cT4', 'Var', (200, 203))	('esophageal cancer', 'Disease', (204, 221))	('patient', 'Species', '9606', (381, 388))	('esophageal cancer', 'Disease', 'MESH:D004938', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
75771	30127886	As shown in Table I, in the low expression of TNFR2 group, only 119 out of 192 cases had an invasion depth greater than the muscularis, which was much less than 187 out of 239 cases in the high expression of TNFR2 group, and the difference was statistically significant (P<0.001).	('invasion depth greater than the muscularis', 'CPA', (92, 134))	('TNFR2', 'Gene', '7133', (208, 213))	('low expression', 'Var', (28, 42))	('TNFR2', 'Gene', (46, 51))	('TNFR2', 'Gene', (208, 213))	('TNFR2', 'Gene', '7133', (46, 51))
75776	30127886	In the high expression of TNFR2 group, follow-up was performed in 113 cases.	('high expression', 'Var', (7, 22))	('TNFR2', 'Gene', '7133', (26, 31))	('TNFR2', 'Gene', (26, 31))
75779	30127886	As shown in Table II, in the low expression of TNFR2 group, only 73 out of 120 cases had an invasion depth greater than the muscularis, which was much less than 127 out of 159 cases in the high expression of TNFR2 group, and the difference was statistically significant (P=0.001).	('invasion depth greater than the muscularis', 'CPA', (92, 134))	('TNFR2', 'Gene', '7133', (208, 213))	('TNFR2', 'Gene', '7133', (47, 52))	('low expression', 'Var', (29, 43))	('TNFR2', 'Gene', (208, 213))	('TNFR2', 'Gene', (47, 52))
75782	30127886	In the high expression of TNFR2 group, follow-up was performed in 75 cases.	('high expression', 'Var', (7, 22))	('TNFR2', 'Gene', '7133', (26, 31))	('TNFR2', 'Gene', (26, 31))
75785	30127886	As shown in Table III, in the low expression of TNFR2 group, only 33 out of 72 cases had a low differentiation degree, which was much less than 52 out of 80 cases in the high expression of TNFR2 group, and the difference was statistically significant (P=0.022).	('TNFR2', 'Gene', (189, 194))	('TNFR2', 'Gene', (48, 53))	('low differentiation degree', 'CPA', (91, 117))	('TNFR2', 'Gene', '7133', (189, 194))	('TNFR2', 'Gene', '7133', (48, 53))	('low expression', 'Var', (30, 44))
75787	30127886	In the high expression of TNFR2 group, follow-up was performed in 38 cases.	('high expression', 'Var', (7, 22))	('TNFR2', 'Gene', '7133', (26, 31))	('TNFR2', 'Gene', (26, 31))
75803	30127886	Furthermore, it is well-known that CAFs can contribute to migration, invasion and metastasis, and even prevent differentiation and induce the stemness of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('contribute', 'Reg', (44, 54))	('stemness of tumor', 'Disease', (142, 159))	('differentiation', 'CPA', (111, 126))	('CAFs', 'Var', (35, 39))	('invasion', 'CPA', (69, 77))	('prevent', 'NegReg', (103, 110))	('induce', 'PosReg', (131, 137))	('stemness of tumor', 'Disease', 'MESH:D020295', (142, 159))	('migration', 'CPA', (58, 67))
75816	30127886	Otherwise, in lower thoracic ESCC patients, although the prognosis of patients in the high expression of TNFR2 group was poorer than in the low expression of TNFR2 group, the difference was not significant.	('patients', 'Species', '9606', (70, 78))	('lower thoracic ESCC', 'Disease', (14, 33))	('TNFR2', 'Gene', (158, 163))	('poorer', 'NegReg', (121, 127))	('TNFR2', 'Gene', '7133', (105, 110))	('high expression', 'Var', (86, 101))	('patients', 'Species', '9606', (34, 42))	('TNFR2', 'Gene', '7133', (158, 163))	('TNFR2', 'Gene', (105, 110))
75826	30127886	Zhao Y reported that downregulating TNFR1 could suppress growth of breast cancer cells.	('suppress', 'NegReg', (48, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('TNFR1', 'Gene', '7132', (36, 41))	('growth of', 'CPA', (57, 66))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('downregulating', 'Var', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))	('TNFR1', 'Gene', (36, 41))
75891	28375450	These included condition-specific measures for: esophageal cancer (FACT-E, EORTC QLQ-OG25, EORTC QLQ-OES18), upper aerodigestive neoplasm-attributable oropharyngeal dysphagia (MDADI), mechanical and neuromyogenic oropharyngeal dysphagia (SWAL-QOL, SSQ, SWAL-CARE), achalasia (MADS), and eosinophilic esophagitis (DSQ-EoE).	('neoplasm', 'Disease', 'MESH:D009369', (129, 137))	('dysphagia', 'Phenotype', 'HP:0002015', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('neoplasm', 'Disease', (129, 137))	('oropharyngeal dysphagia', 'Disease', 'MESH:D003680', (213, 236))	('dysphagia', 'Phenotype', 'HP:0002015', (227, 236))	('oropharyngeal dysphagia', 'Disease', (151, 174))	('oropharyngeal dysphagia', 'Disease', 'MESH:D003680', (151, 174))	('eosinophilic esophagitis', 'Disease', (287, 311))	('neoplasm', 'Phenotype', 'HP:0002664', (129, 137))	('achalasia', 'Disease', 'MESH:D004931', (265, 274))	('EORTC', 'Var', (91, 96))	('eosinophilic esophagitis', 'Disease', 'MESH:D004802', (287, 311))	('oropharyngeal dysphagia', 'Phenotype', 'HP:0200136', (213, 236))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('esophagitis', 'Phenotype', 'HP:0100633', (300, 311))	('oropharyngeal dysphagia', 'Phenotype', 'HP:0200136', (151, 174))	('achalasia', 'Disease', (265, 274))	('neuromyogenic oropharyngeal dysphagia', 'Disease', (199, 236))	('esophageal cancer', 'Disease', (48, 65))	('achalasia', 'Phenotype', 'HP:0002571', (265, 274))	('neuromyogenic oropharyngeal dysphagia', 'Disease', 'MESH:D003680', (199, 236))	('SSQ', 'Chemical', '-', (248, 251))	('eosinophilic esophagitis', 'Phenotype', 'HP:0410151', (287, 311))
75964	29142347	Further symptoms are related to the site of esophagus perforated, for example, neck pain in patients with perforation of cervical esophagus and acute abdominal or epigastric pain in those with gastroesophageal junction perforation.	('pain', 'Disease', 'MESH:D010146', (174, 178))	('pain', 'Disease', (174, 178))	('perforation', 'Var', (106, 117))	('acute abdominal', 'Disease', (144, 159))	('pain', 'Phenotype', 'HP:0012531', (84, 88))	('patients', 'Species', '9606', (92, 100))	('epigastric pain', 'Phenotype', 'HP:0410019', (163, 178))	('pain', 'Disease', 'MESH:D010146', (84, 88))	('pain', 'Disease', (84, 88))	('gastroesophageal junction', 'Disease', (193, 218))	('pain', 'Phenotype', 'HP:0012531', (174, 178))	('neck pain', 'Phenotype', 'HP:0030833', (79, 88))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (193, 218))
76109	28640831	Ribosomal DNA copy number loss and sequence variation in cancer Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('copy number', 'Var', (14, 25))	('human', 'Species', '9606', (121, 126))	('Ribosomal DNA', 'Gene', (0, 13))	('loss', 'NegReg', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('sequence variation', 'Var', (35, 53))
76118	28640831	Loss of copies occurs early and is associated with hypersensitivity to DNA damage.	('Loss', 'NegReg', (0, 4))	('copies', 'Var', (8, 14))	('hypersensitivity', 'Disease', 'MESH:D004342', (51, 67))	('hypersensitivity', 'Disease', (51, 67))
76119	28640831	Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation.	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('copy loss', 'Var', (11, 20))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
76136	28640831	Southern blotting experiments demonstrate that recombination at the rDNA is common in adult lung and colorectal cancer, suggesting the possibility that the rDNA may be affected in the cancer genome.	('cancer', 'Disease', (184, 190))	('common', 'Reg', (76, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('adult lung', 'Disease', (86, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('recombination', 'Var', (47, 60))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('colorectal cancer', 'Disease', (101, 118))
76142	28640831	Together these results suggest there may be a connection between TOR signaling and the rDNA copy number, but this has not been explored in the mammalian genome.	('mammalian', 'Species', '9606', (143, 152))	('copy number', 'Var', (92, 103))	('rDNA', 'Gene', (87, 91))
76144	28640831	Dramatically reducing the copy number in yeast does not cause reduction in rRNA levels, but causes all repeats to become active (sometimes termed "compensation") and the yeast are hypersensitive to DNA damage.	('causes', 'Reg', (92, 98))	('reducing', 'NegReg', (13, 21))	('copy number', 'Var', (26, 37))	('active', 'MPA', (121, 127))	('hypersensitive', 'Disease', 'MESH:D004342', (180, 194))	('become', 'PosReg', (114, 120))	('hypersensitive', 'Disease', (180, 194))	('yeast', 'Species', '4932', (41, 46))	('yeast', 'Species', '4932', (170, 175))
76145	28640831	In contrast, low copy compromises protein synthesis and development in the bobbed mutants in Drosophila.	('Drosophila', 'Species', '7227', (93, 103))	('compromises', 'NegReg', (22, 33))	('low copy', 'Var', (13, 21))	('protein synthesis', 'MPA', (34, 51))	('mutants', 'Var', (82, 89))	('development', 'CPA', (56, 67))
76149	28640831	Using cancer stem cells derived from a mouse model for leukemia driven by loss of Pten, we find that copy loss does not compromise proliferation, rRNA production, or protein synthesis, but cells are hypersensitive to DNA damage.	('protein synthesis', 'MPA', (166, 183))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('Pten', 'Gene', (82, 86))	('leukemia', 'Disease', 'MESH:D007938', (55, 63))	('loss', 'NegReg', (74, 78))	('copy loss', 'Var', (101, 110))	('leukemia', 'Disease', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('rRNA production', 'MPA', (146, 161))	('mouse', 'Species', '10090', (39, 44))	('hypersensitive', 'Disease', 'MESH:D004342', (199, 213))	('cancer', 'Disease', (6, 12))	('hypersensitive', 'Disease', (199, 213))
76161	28640831	The copy number variation in CD-1 is more like what has been reported in the human population.	('CD-1', 'Gene', (29, 33))	('copy number variation', 'Var', (4, 25))	('human', 'Species', '9606', (77, 82))
76174	28640831	We used the ~16,000 exons selected for normalization, which are scattered across all chromosomes, to examine whether the chromosomes with rDNA (13, 14, 15, 21, 22) are present at lower levels relative to other chromosomes in the tumor genomes, since this would indicate chromosome loss as one mechanism to lose rDNA copies.	('lose', 'NegReg', (306, 310))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('chromosome', 'Var', (270, 280))	('tumor', 'Disease', (229, 234))	('loss', 'NegReg', (281, 285))
76179	28640831	For the three genome projects with low rDNA copy number in tumor versus normal (phs000530, phs000598, phs000699) there were 353 such exons.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('phs000699', 'Var', (102, 111))	('phs000530', 'Var', (80, 89))	('phs000598', 'Var', (91, 100))	('rDNA', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
76180	28640831	We then used hierarchical clustering to identify exons with similar trends in copy number (gain or loss) in the three "positive" projects compared to the five "negative" projects.	('copy number', 'Var', (78, 89))	('gain or loss', 'Disease', 'MESH:D015430', (91, 103))	('gain or loss', 'Disease', (91, 103))
76186	28640831	We identified single nucleotide variants (SNVs) and indels in tumor and normal genomes relative to a common reference.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('indels', 'Var', (52, 58))	('single nucleotide variants', 'Var', (14, 40))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
76195	28640831	SNVs in the gene encoding 28S rRNA have the potential to affect ribosome function if the corresponding repeats are transcribed.	('28S', 'Gene', (26, 29))	('ribosome function', 'MPA', (64, 81))	('28S', 'Gene', '236598', (26, 29))	('affect', 'Reg', (57, 63))	('rRNA', 'Gene', (30, 34))	('SNVs', 'Var', (0, 4))
76197	28640831	SNVs in the transcribed non-coding regions have the potential to affect transcription and processing of rRNA but are difficult to functionally evaluate given our limited understanding of the sequence features of the human repeat.	('affect', 'Reg', (65, 71))	('rRNA', 'Protein', (104, 108))	('human', 'Species', '9606', (216, 221))	('transcription', 'MPA', (72, 85))	('SNVs', 'Var', (0, 4))	('processing', 'MPA', (90, 100))
76205	28640831	The initial publication describing the analysis of the EAC genomes reported mutational complexity with accumulated mutations including activating mutations in PIK3CA, and loss of function mutations in PTEN, PIK3R1, AKT2, and AKT3, together implicating the mTOR-PTEN pathway in some instances of this cancer.	('mutations', 'Var', (146, 155))	('loss of function', 'NegReg', (171, 187))	('AKT2', 'Gene', (215, 219))	('AKT3', 'Gene', (225, 229))	('PTEN', 'Gene', (201, 205))	('PIK3CA', 'Gene', '18706', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('PIK3R1', 'Gene', '18708', (207, 213))	('AKT3', 'Gene', '23797', (225, 229))	('activating', 'PosReg', (135, 145))	('PIK3R1', 'Gene', (207, 213))	('PIK3CA', 'Gene', (159, 165))	('mul', 'Gene', (107, 110))	('mutations', 'Var', (188, 197))	('AKT2', 'Gene', '11652', (215, 219))	('mul', 'Gene', '68729', (107, 110))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('cancer', 'Disease', (300, 306))
76209	28640831	Loss of PTEN in prostate cancer is associated with tumor aggression and poor outcome.	('prostate cancer', 'Disease', (16, 31))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('PTEN', 'Protein', (8, 12))	('aggression', 'Phenotype', 'HP:0000718', (57, 67))	('prostate cancer', 'Disease', 'MESH:D011471', (16, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (16, 31))	('tumor aggression', 'Disease', (51, 67))	('tumor aggression', 'Disease', 'MESH:D001523', (51, 67))	('Loss', 'Var', (0, 4))
76210	28640831	In fact, mutations that activate the PI3K (phosphatidylinositol-3-kinase)-mTOR pathway are frequently found in many cancers, including AIDS-related lymphomas, and esophageal cancer, as mentioned above.	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('lymphomas', 'Disease', (148, 157))	('mutations', 'Var', (9, 18))	('lymphomas', 'Disease', 'MESH:D008223', (148, 157))	('phosphatidylinositol-3-kinase', 'Gene', (43, 72))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('activate', 'PosReg', (24, 32))	('esophageal cancer', 'Disease', (163, 180))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('found', 'Reg', (102, 107))	('lymphomas', 'Phenotype', 'HP:0002665', (148, 157))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('phosphatidylinositol-3-kinase', 'Gene', '18708', (43, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('AIDS', 'Disease', (135, 139))	('AIDS', 'Disease', 'MESH:D000163', (135, 139))
76218	28640831	We verified that loss of Pten in HSCs results in a pathway signature indicative of mTOR activation, including higher levels of phosphorylated mTOR, Rps6, and S6K1 (S5 Fig).	('pathway signature', 'MPA', (51, 68))	('activation', 'PosReg', (88, 98))	('S6K1', 'Gene', (158, 162))	('mTOR', 'MPA', (83, 87))	('Rps6', 'Gene', '20104', (148, 152))	('Pten', 'Gene', (25, 29))	('Rps6', 'Gene', (148, 152))	('higher', 'PosReg', (110, 116))	('S6K1', 'Gene', '72508', (158, 162))	('loss', 'Var', (17, 21))
76219	28640831	Remarkably, the Pten-/- HSCs have significantly lower copy number compared to two different controls, tail samples from the same mice which retain Pten and matched Pten+/+ HSCs (Fig 5A and 5B).	('mice', 'Species', '10090', (129, 133))	('lower', 'NegReg', (48, 53))	('Pten-/- HSCs', 'Var', (16, 28))	('copy number', 'MPA', (54, 65))
76229	28640831	Deletion of PTEN in prostate cancer cells is associated with sensitivity to DNA damaging agents including ionizing radiation, mitomycin-C, UV, H2O2, and methyl methanesulfonate (MMS).	('prostate cancer', 'Disease', 'MESH:D011471', (20, 35))	('mitomycin-C', 'Chemical', 'MESH:D016685', (126, 137))	('methyl methanesulfonate', 'MPA', (153, 176))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('methyl methanesulfonate', 'Chemical', 'MESH:D008741', (153, 176))	('PTEN', 'Gene', (12, 16))	('associated', 'Reg', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('prostate cancer', 'Disease', (20, 35))	('H2O2', 'Chemical', 'MESH:D006861', (143, 147))	('MMS', 'Chemical', 'MESH:D008741', (178, 181))	('mitomycin-C', 'MPA', (126, 137))	('sensitivity to DNA damaging agents', 'MPA', (61, 95))	('Deletion', 'Var', (0, 8))
76234	28640831	Moreover, global protein synthesis, as measured by 35S-methionine incorporation, was significantly higher in the Pten-/- HSCs (Fig 6C), consistent with a previous study.	('35S-methionine incorporation', 'MPA', (51, 79))	('higher', 'PosReg', (99, 105))	('Pten-/- HSCs', 'Var', (113, 125))	('35S-methionine', 'Chemical', '-', (51, 65))	('global protein synthesis', 'MPA', (10, 34))
76237	28640831	First we identified a concentration of INK128 that would effectively block TOR activity in the HSCs (Fig 7A).	('TOR activity', 'MPA', (75, 87))	('INK128', 'Chemical', 'MESH:C572449', (39, 45))	('INK128', 'Var', (39, 45))	('block', 'NegReg', (69, 74))
76243	28640831	Importantly, the Pten-/- HSCs are more sensitive to bleomycin than the WT HSCs (Fig 7F), suggesting that the sensitivity is not due to differential activation of mTOR, but could derive from the lower copy number.	('Pten-/-', 'Var', (17, 24))	('bleomycin', 'Chemical', 'MESH:D001761', (52, 61))	('sensitive', 'MPA', (39, 48))
76250	28640831	It remains to be determined whether compensation occurs in the mammalian genome, and whether the absence of silenced repeats could cause DNA damage sensitivity.	('silenced', 'Protein', (108, 116))	('absence', 'Var', (97, 104))	('DNA damage sensitivity', 'MPA', (137, 159))	('cause', 'Reg', (131, 136))	('mammalian', 'Species', '9606', (63, 72))
76255	28640831	The low copy cancer genomes show concerted copy number changes in additional genes, suggesting a structural signature for these genomes.	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('copy number changes', 'Var', (43, 62))
76257	28640831	Our results suggest that copy number and sequence can change in the mammalian genome in cancer, and that loss of copies may have both costs and benefits.	('cancer', 'Disease', (88, 94))	('change', 'Reg', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('loss', 'Var', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mammalian', 'Species', '9606', (68, 77))
76275	28640831	Cancer stem cells with low copy number may be more sensitive to DNA damaging agents.	('low copy number', 'Var', (23, 38))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('sensitive', 'MPA', (51, 60))
76276	28640831	We speculate that this single copy number measurement could be used as a proxy detector for the variety of mutations that can occur in the PI3K-AKT-mTOR pathway in cancer and a predictor of whether DNA damaging drugs would selectively target the cancer stem cells.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('mutations', 'Var', (107, 116))	('AKT', 'Gene', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (246, 252))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('AKT', 'Gene', '11651', (144, 147))
76289	28640831	The Pten-/- HSC cause leukemia development after transplant.	('leukemia', 'Disease', 'MESH:D007938', (22, 30))	('Pten-/- HSC', 'Var', (4, 15))	('cause', 'Reg', (16, 21))	('leukemia', 'Disease', (22, 30))	('leukemia', 'Phenotype', 'HP:0001909', (22, 30))
76295	28640831	Secondary antibodies were HRP linked, anti-rabbit IgG (from donkey) and anti-mouse IgG (from sheep), (GE Healthcare, NA934V, NA931V, and NA935V, respectively).	('HRP linked', 'Protein', (26, 36))	('rabbit', 'Species', '9986', (43, 49))	('NA934V', 'Var', (117, 123))	('donkey', 'Species', '9793', (60, 66))	('NA931V', 'Var', (125, 131))	('mouse', 'Species', '10090', (77, 82))	('sheep', 'Species', '9940', (93, 98))	('NA935V', 'Var', (137, 143))
76325	28640831	Human RPE1 cells (hTERT-immortalized retinal pigment epithelial cell line from ATCC), at low passage number and ~70% cell confluence, were transfected by three different PTEN-siRNAs or the control siRNAs (Ambion) using Lipofectamine RNAiMAX Transfection Reagent from Thermo Fisher Scientific company.	('Human', 'Species', '9606', (0, 5))	('RPE1', 'Gene', (6, 10))	('PTEN-siRNAs', 'Var', (170, 181))	('RPE1', 'CellLine', 'CVCL:4388', (6, 10))	('Lipofectamine', 'Chemical', 'MESH:C086724', (219, 232))	('transfected', 'Reg', (139, 150))
76339	28570554	DTC increases the risk of lymph node metastasis and distant metastasis.	('DTC', 'Phenotype', 'HP:0007378', (0, 3))	('lymph node metastasis', 'Disease', 'MESH:D009362', (26, 47))	('lymph node metastasis', 'Disease', (26, 47))	('DTC', 'Var', (0, 3))	('DTC', 'Chemical', '-', (0, 3))	('distant metastasis', 'CPA', (52, 70))
76376	28570554	Moreover, MTA1 high expression is relatively association with the clinicopathological variables of GC and CRC patients (Table 5).	('high', 'Var', (15, 19))	('CRC', 'Phenotype', 'HP:0003003', (106, 109))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('MTA1', 'Gene', (10, 14))	('association', 'Reg', (45, 56))	('CRC', 'Disease', (106, 109))	('patients', 'Species', '9606', (110, 118))
76378	28570554	Similar to GI cancers, MTA1-positive expression increased the risk of death postoperatively.	('GI cancer', 'Phenotype', 'HP:0007378', (11, 20))	('rat', 'Species', '10116', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('death', 'Disease', 'MESH:D003643', (70, 75))	('GI cancers', 'Disease', (11, 21))	('death', 'Disease', (70, 75))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('GI cancers', 'Disease', 'MESH:D009369', (11, 21))	('MTA1-positive expression', 'Var', (23, 47))
76389	28570554	MTAs including MTA1, MTA2, and MTA3 are expressed indifferent isoforms (MTA1,MTA1s,MTA-ZG29p,MTA2,MTA3, and MTA3L).	('MTA3', 'Gene', (108, 112))	('MTA3', 'Gene', (31, 35))	('MTA2', 'Gene', '9219', (21, 25))	('MTA3', 'Gene', '57504', (98, 102))	('MTA2', 'Gene', (21, 25))	('MTA2', 'Gene', '9219', (93, 97))	('MTA3', 'Gene', '57504', (31, 35))	('MTA-ZG29p', 'Var', (83, 92))	('MTA3', 'Gene', (98, 102))	('MTA1s', 'Var', (77, 82))	('MTA3', 'Gene', '57504', (108, 112))	('MTA2', 'Gene', (93, 97))
76398	28570554	The results demonstrate that MTA1-positive expression increased the risk of stomach wall invasion (OR = 1.88, 95%CI: 1.05-3.37, P = 0.03), lymph node-positive metastasis (OR = 2.30, 95%CI: 1.76-3.01, P<0.001) and vascular invasion (OR = 2.02, 95%CI: 1.40-2.91, P<0.001), leading to later TNM stages (OR = 2.78, 95%CI: 1.63-4.74, P<0.001).	('TNM', 'Gene', (288, 291))	('expression', 'Var', (43, 53))	('rat', 'Species', '10116', (19, 22))	('MTA1-positive', 'Gene', (29, 42))	('stomach wall invasion', 'CPA', (76, 97))	('lymph node-positive metastasis', 'CPA', (139, 169))	('TNM', 'Gene', '10178', (288, 291))	('vascular invasion', 'CPA', (213, 230))
76426	26640385	The postoperative recurrence, invasion, and metastasis of ESCC are affected by many closely linked factors such as proto-oncogene activation, tumor-suppressor gene inactivation, and abnormal protein expression.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('inactivation', 'Var', (164, 176))	('invasion', 'CPA', (30, 38))	('affected by', 'Reg', (67, 78))	('metastasis', 'CPA', (44, 54))	('protein', 'Protein', (191, 198))	('ESCC', 'Disease', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
76429	26640385	Some scholars have suggested that a coherent understanding of the mTOR network is imperative, as its dysregulation has been implicated in diverse pathologies including cancer, diabetes, autism, and aging.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mTOR', 'Gene', (66, 70))	('implicated', 'Reg', (124, 134))	('mTOR', 'Gene', '2475', (66, 70))	('autism', 'Phenotype', 'HP:0000717', (186, 192))	('autism', 'Disease', 'MESH:D001321', (186, 192))	('diabetes', 'Disease', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('diabetes', 'Disease', 'MESH:D003920', (176, 184))	('autism', 'Disease', (186, 192))	('cancer', 'Disease', (168, 174))	('dysregulation', 'Var', (101, 114))
76430	26640385	In addition, a study has shown that disheveled, Egl-10, and pleckstrin (DEP) domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) abnormal expression may be associated with resistance to chemotherapy in breast cancer patients; these authors also highlighted the dichotomous functions of DEPTOR in modulating the proliferation and survival of triple-negative breast cancers during metastasis.	('proliferation', 'CPA', (343, 356))	('mammalian target of rapamycin', 'Gene', '2475', (95, 124))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Disease', 'MESH:D001943', (389, 402))	('DEPTOR', 'Gene', '64798', (153, 159))	('DEPTOR', 'Gene', '64798', (318, 324))	('mammalian target of rapamycin', 'Gene', (95, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('cancers', 'Phenotype', 'HP:0002664', (396, 403))	('associated', 'Reg', (188, 198))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('DEPTOR', 'Gene', (153, 159))	('DEPTOR', 'Gene', (318, 324))	('breast cancer', 'Disease', (234, 247))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('breast cancers', 'Disease', 'MESH:D001943', (389, 403))	('breast cancers', 'Disease', (389, 403))	('mTOR', 'Gene', (126, 130))	('patients', 'Species', '9606', (248, 256))	('survival', 'CPA', (361, 369))	('abnormal expression', 'Var', (161, 180))	('breast cancers', 'Phenotype', 'HP:0003002', (389, 403))	('modulating', 'Reg', (328, 338))	('breast cancer', 'Phenotype', 'HP:0003002', (389, 402))	('mTOR', 'Gene', '2475', (126, 130))
76583	25811880	This Swedish population-based study showed an association between higher education level and improved survival after esophageal cancer surgery, independent of established prognostic factors.	('higher education level', 'Var', (66, 88))	('esophageal cancer', 'Disease', (117, 134))	('improved', 'PosReg', (93, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('survival', 'MPA', (102, 110))
76728	25635388	Generally, chemotherapy and radiotherapy are considered to have cytotoxic effects on other organs and thus increase sequential cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('increase', 'PosReg', (107, 115))	('chemotherapy', 'Var', (11, 23))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('radiotherapy', 'Var', (28, 40))
76738	20197393	Interactions of the p53 protein family in cellular stress response in gastrointestinal tumors p53, p63 and p73 are members of the p53 protein family involved in regulation of cell cycle, apoptosis, differentiation and other critical cellular processes.	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('p73', 'Var', (107, 110))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('p63', 'Var', (99, 102))	('Interactions', 'Interaction', (0, 12))	('gastrointestinal tumors', 'Disease', (70, 93))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (70, 93))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (70, 93))	('p53', 'Gene', (130, 133))	('p53', 'Gene', '7157', (130, 133))
76745	20197393	p53 mutations have been described in 40-50% of colorectal carcinomas.	('p53', 'Gene', (0, 3))	('described', 'Reg', (24, 33))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (47, 68))	('colorectal carcinomas', 'Disease', (47, 68))	('mutations', 'Var', (4, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
76756	20197393	Plasmids expressing human p53, TAp73alpha, TAp73beta, DeltaNp73alpha, DeltaNp73beta, DeltaNp63alpha, and luciferase reporter constructs PG13 and MG15 have been described previously.	('DeltaNp73alpha', 'Var', (54, 68))	('TAp73', 'Gene', (31, 36))	('human', 'Species', '9606', (20, 25))	('TAp73', 'Gene', '22062', (43, 48))	('DeltaNp73beta', 'Var', (70, 83))	('DeltaNp63alpha', 'Var', (85, 99))	('TAp73', 'Gene', (43, 48))	('TAp73', 'Gene', '22062', (31, 36))	('PG13', 'Gene', (136, 140))	('PG13', 'Chemical', '-', (136, 140))
76764	20197393	DNA-protein complexes were precipitated with NeutrAvidin agarose beads (Fisher, Waltham, MA), washed, eluted, and analyzed by Western blotting with p53 (DO-1), p63 (4A4), TAp73 (Bethyl Laboratories) and DeltaNp73 (Imgenex) antibody.	('TAp73', 'Gene', (171, 176))	('p53', 'Var', (148, 151))	('agarose', 'Chemical', 'MESH:D012685', (57, 64))	('TAp73', 'Gene', '22062', (171, 176))
76771	20197393	In order to meet the assumption of normality and reduce the influence of extremely high values, the analyses were performed with log-transformed values of IC50 and PG13/MG15.	('PG13/MG15', 'Var', (164, 173))	('IC50', 'Var', (155, 159))	('PG13', 'Chemical', '-', (164, 168))
76783	20197393	Using real-time PCR, we also analyzed the expression profiles of p53, p63 and p73 mRNA in a subset of these tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('p63', 'Var', (70, 73))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('p53', 'Var', (65, 68))	('p73 mRNA', 'Var', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
76784	20197393	Similar to TMA analysis, we found elevated levels of TAp73 and DeltaNp73 mRNA compared to the average expression in non-neoplastic colon tissues.	('DeltaNp73', 'Var', (63, 72))	('TAp73', 'Gene', (53, 58))	('elevated', 'PosReg', (34, 42))	('TMA', 'Chemical', 'MESH:C071868', (11, 14))	('neoplastic colon', 'Phenotype', 'HP:0100273', (120, 136))	('TAp73', 'Gene', '22062', (53, 58))
76788	20197393	p73 and p53 proteins, and in some cases p63, are co-expressed in tumor tissues from the same patient (Fig.	('p73', 'Var', (0, 3))	('tumor', 'Disease', (65, 70))	('proteins', 'Protein', (12, 20))	('patient', 'Species', '9606', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('p53', 'Var', (8, 11))
76795	20197393	DeltaNp63alpha showed a significant induction of NOXA, p21 and FasR.	('NOXA', 'Gene', (49, 53))	('NOXA', 'Gene', '5366', (49, 53))	('p21', 'Gene', (55, 58))	('FasR', 'Disease', (63, 67))	('p21', 'Gene', '1026', (55, 58))	('DeltaNp63alpha', 'Var', (0, 14))	('induction', 'PosReg', (36, 45))
76796	20197393	DeltaNp73beta transfection was sufficient to induce NOXA expression and activate reporter.	('NOXA', 'Gene', (52, 56))	('induce', 'PosReg', (45, 51))	('reporter', 'MPA', (81, 89))	('NOXA', 'Gene', '5366', (52, 56))	('DeltaNp73beta transfection', 'Var', (0, 26))	('activate', 'PosReg', (72, 80))
76798	20197393	To evaluate the expression of the p73 and p63 isoforms, we employed colon cancer cell lines that express wild-type or mutant p53.	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('p53', 'Gene', (125, 128))	('mutant', 'Var', (118, 124))	('colon cancer', 'Disease', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
76800	20197393	Similar to primary colon tumors, colon cancer cell lines express multiple isoforms of p73 and low or undetectable levels of p63 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (33, 45))	('colon cancer', 'Disease', 'MESH:D015179', (33, 45))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('p73', 'Var', (86, 89))	('colon tumors', 'Phenotype', 'HP:0100273', (19, 31))	('colon tumors', 'Disease', 'MESH:D015179', (19, 31))	('colon cancer', 'Disease', (33, 45))	('colon tumor', 'Phenotype', 'HP:0100273', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('colon tumors', 'Disease', (19, 31))
76805	20197393	An increase of mutant p53alpha and p53beta isoforms was detected in the SW480 cell line.	('mutant', 'Var', (15, 21))	('p53beta', 'Var', (35, 42))	('SW480', 'CellLine', 'CVCL:0546', (72, 77))	('p53alpha', 'Protein', (22, 30))
76806	20197393	Notably, both TAp73alpha and TAp73beta proteins were found to be strongly up-regulated by 5-FU in all tested cells (Fig.	('TAp73', 'Gene', '22062', (29, 34))	('TAp73', 'Gene', (29, 34))	('5-FU', 'Var', (90, 94))	('up-regulated', 'PosReg', (74, 86))	('TAp73', 'Gene', '22062', (14, 19))	('5-FU', 'Chemical', 'MESH:D005472', (90, 94))	('TAp73', 'Gene', (14, 19))
76808	20197393	For instance, TE7 cells, which lack the expression of p53 and strongly activate TAp73alpha and beta, TAp63gamma and DeltaNp63alpha, displayed a significant increase in the endogenous levels of PUMA, NOXA, FasR, and BAX in response to 5-FU (Fig.	('activate', 'PosReg', (71, 79))	('BAX', 'Gene', '581', (215, 218))	('endogenous levels of PUMA', 'MPA', (172, 197))	('NOXA', 'Gene', (199, 203))	('TAp73', 'Gene', (80, 85))	('NOXA', 'Gene', '5366', (199, 203))	('increase', 'PosReg', (156, 164))	('DeltaNp63alpha', 'Var', (116, 130))	('TAp63gamma', 'Var', (101, 111))	('5-FU', 'Chemical', 'MESH:D005472', (234, 238))	('FasR', 'MPA', (205, 209))	('TAp73', 'Gene', '22062', (80, 85))	('BAX', 'Gene', (215, 218))
76812	20197393	As shown in Figure 3A, stable transfection of the p73 shRNA significantly inhibits the 5-FU-induced apoptosis in RKO (p53 +/+) colon cancer cells, which express high levels of endogenous TAp73 (Fig.	('5-FU-induced apoptosis', 'MPA', (87, 109))	('TAp73', 'Gene', (187, 192))	('RKO', 'CellLine', 'CVCL:0504', (113, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (127, 139))	('colon cancer', 'Disease', 'MESH:D015179', (127, 139))	('5-FU', 'Chemical', 'MESH:D005472', (87, 91))	('inhibits', 'NegReg', (74, 82))	('colon cancer', 'Disease', (127, 139))	('p73 shRNA', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TAp73', 'Gene', '22062', (187, 192))
76813	20197393	FasR, p21, and BAX proteins were inhibited by p73 siRNA (Fig.	('p73 siRNA', 'Var', (46, 55))	('p21', 'Gene', (6, 9))	('p21', 'Gene', '1026', (6, 9))	('BAX', 'Gene', '581', (15, 18))	('inhibited', 'NegReg', (33, 42))	('BAX', 'Gene', (15, 18))
76816	20197393	Similarly, inhibition of p73 with a dominant-negative DDp73 mutant or specific siRNA against TAp73 isoforms inhibited the cytotoxic effect of 5-FU in RKO cells (data not shown).	('DDp73', 'Gene', (54, 59))	('TAp73', 'Gene', (93, 98))	('cytotoxic effect', 'CPA', (122, 138))	('RKO', 'CellLine', 'CVCL:0504', (150, 153))	('5-FU', 'Chemical', 'MESH:D005472', (142, 146))	('TAp73', 'Gene', '22062', (93, 98))	('mutant', 'Var', (60, 66))	('inhibited', 'NegReg', (108, 117))
76820	20197393	Thus, not only p53, but also p73 and p63 are accumulated in response to chemotherapeutic treatment, induce p53 transcription targets, and significantly contribute to chemotherapeutic drug response in cancer cells.	('p53', 'Var', (15, 18))	('contribute', 'Reg', (152, 162))	('transcription targets', 'MPA', (111, 132))	('p53', 'Gene', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('p63', 'Var', (37, 40))	('induce', 'PosReg', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('p73', 'Var', (29, 32))	('cancer', 'Disease', (200, 206))
76822	20197393	TE7, TE11 and isogenic HCT116 cell lines were selected, as they express p73/p63 and have null (TE7), mutant (TE11) and wild-type (HCT116) p53.	('HCT116', 'CellLine', 'CVCL:0291', (130, 136))	('p53', 'Gene', (138, 141))	('HCT116', 'CellLine', 'CVCL:0291', (23, 29))	('TE7', 'Var', (95, 98))	('mutant', 'Var', (101, 107))	('p73/p63', 'Var', (72, 79))
76824	20197393	As controls, we generated non-specific probes: mutated PUMA (mtPUMA) with point mutations in the p53-RE and intronic sequence of p21 gene (n/s).	('p21', 'Gene', '1026', (129, 132))	('p21', 'Gene', (129, 132))	('point mutations in', 'Var', (74, 92))
76829	20197393	In both p53-null TE7 and mutant p53 TE11 cell lines, we found strong specific binding of TAp63gamma and DeltaNp63alpha as well as TAp73 to the p21 and PUMA probes (Fig.	('p21', 'Gene', (143, 146))	('binding', 'Interaction', (78, 85))	('mutant', 'Var', (25, 31))	('TAp73', 'Gene', '22062', (130, 135))	('p53', 'Gene', (32, 35))	('TAp73', 'Gene', (130, 135))	('DeltaNp63alpha', 'Protein', (104, 118))	('p21', 'Gene', '1026', (143, 146))
76832	20197393	Consistent with DAI, we found increased interactions of p53, p73 and p63 with promoters of p21 and PUMA genes after 5-FU treatment (Fig.	('p53', 'Var', (56, 59))	('5-FU', 'Chemical', 'MESH:D005472', (116, 120))	('PUMA genes', 'Gene', (99, 109))	('p21', 'Gene', '1026', (91, 94))	('p21', 'Gene', (91, 94))	('increased', 'PosReg', (30, 39))	('interactions', 'Interaction', (40, 52))	('p73', 'Var', (61, 64))	('p63', 'Var', (69, 72))
76833	20197393	Taken together, these findings show that not only p53, but also various isoforms of p63 and p73 bind to the promoters of target genes in response to chemotherapeutic treatment with 5-FU.	('bind', 'Reg', (96, 100))	('5-FU', 'Chemical', 'MESH:D005472', (181, 185))	('p73', 'Var', (92, 95))
76835	20197393	Using p53 and p73 antibodies, we found that p53 and p73 bind alongside the PUMA and p21 promoters in HCT116 cells (Fig.	('p53', 'Var', (44, 47))	('p73', 'Var', (52, 55))	('p21', 'Gene', '1026', (84, 87))	('p21', 'Gene', (84, 87))	('HCT116', 'CellLine', 'CVCL:0291', (101, 107))
76837	20197393	Using the same techniques, we also found that p63 and p73 bind together to the PUMA and p21 promoters in TE7 cells (Fig.	('p73', 'Var', (54, 57))	('p63', 'Var', (46, 49))	('p21', 'Gene', '1026', (88, 91))	('p21', 'Gene', (88, 91))
76838	20197393	In TE11 cells, which express mutant p53, p73 and p63, also simultaneously bind to the p21 and PUMA promoters suggesting that mutant p53 does not affect binding of the other members of the p53 family in these cells (Fig.	('p21', 'Gene', '1026', (86, 89))	('p21', 'Gene', (86, 89))	('mutant', 'Var', (125, 131))	('p53', 'Gene', (132, 135))	('mutant', 'Var', (29, 35))
76842	20197393	To determine the integral transcription activity we used luciferase reporter PG13-LUC because it can measure activity, not only of p53 but also p73 and p63 isoforms (Fig.	('p53', 'Var', (131, 134))	('p73', 'Var', (144, 147))	('p63', 'Var', (152, 155))	('activity', 'MPA', (109, 117))	('PG13', 'Chemical', '-', (77, 81))
76849	20197393	We showed, for the first time, that p53, p73 and p63 bind simultaneously to target gene promoters in tumor cells treated with DNA-damaging drug 5-FU.	('p73', 'Var', (41, 44))	('p53', 'Var', (36, 39))	('5-FU', 'Chemical', 'MESH:D005472', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('bind', 'Interaction', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('p63', 'Var', (49, 52))
76852	20197393	Whereas in p63 expressing esophageal cancer cells, TA isoforms of p63 and p73, as well as DeltaNp63alpha, are associated with PUMA and p21 promoters.	('esophageal cancer', 'Disease', 'MESH:D004938', (26, 43))	('p21', 'Gene', '1026', (135, 138))	('p21', 'Gene', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('p73', 'Var', (74, 77))	('associated', 'Interaction', (110, 120))	('esophageal cancer', 'Disease', (26, 43))	('p63', 'Var', (66, 69))
76853	20197393	Our data also show that p73 and p63 are expressed as a complex set of isoforms in cancer cell lines and primary tumors.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('p73', 'Var', (24, 27))	('p63', 'Var', (32, 35))	('primary tumors', 'Disease', (104, 118))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('primary tumors', 'Disease', 'MESH:D009369', (104, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
76854	20197393	In colon cancers, we found increased co-expression of TAp73 and DeltaNp73 compared to normal tissue and low levels of all analyzed p63 isoforms (Fig.	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('colon cancers', 'Phenotype', 'HP:0003003', (3, 16))	('increased', 'PosReg', (27, 36))	('DeltaNp73', 'Var', (64, 73))	('colon cancers', 'Disease', 'MESH:D015179', (3, 16))	('TAp73', 'Gene', '22062', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TAp73', 'Gene', (54, 59))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('co-expression', 'MPA', (37, 50))	('colon cancers', 'Disease', (3, 16))
76856	20197393	p73 gamma, delta, phi and epsilon isoforms were primarily detected in tumors, but not in normal tissues (Fig.	('phi', 'Gene', '2821', (18, 21))	('p73', 'Var', (0, 3))	('detected', 'Reg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('phi', 'Gene', (18, 21))
76857	20197393	Notably, mRNA expression profiles for p63 and p73 isoforms were unique for each analyzed patient (Fig.	('p73', 'Var', (46, 49))	('patient', 'Species', '9606', (89, 96))	('mRNA expression', 'MPA', (9, 24))	('p63', 'Var', (38, 41))
76859	20197393	Consistent with previous reports on other tumor types, we confirmed that p73 and p63 contribute to the up-regulation of p53 transcription targets and p53-dependent apoptosis in colon and esophageal tumors (Fig.	('up-regulation', 'PosReg', (103, 116))	('tumor', 'Disease', (42, 47))	('esophageal tumors', 'Phenotype', 'HP:0100751', (187, 204))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('p73', 'Var', (73, 76))	('p63', 'Var', (81, 84))	('apoptosis', 'CPA', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (198, 203))	('p53', 'Gene', (120, 123))	('colon and esophageal tumors', 'Disease', 'MESH:D004938', (177, 204))
76862	20197393	However, this does not exclude the inhibitory role of mutant p53 on TAp73 and TAp63 as previously reported.	('mutant', 'Var', (54, 60))	('p53', 'Gene', (61, 64))	('TAp73', 'Gene', '22062', (68, 73))	('TAp73', 'Gene', (68, 73))
76866	20197393	For instance, when DeltaNp73beta co-expresses with p53, it inhibits the p53 transcription activity, but alone it activates p53 reporter and induces p53 target genes p21, NOXA and FasR (Fig.	('p53 transcription activity', 'MPA', (72, 98))	('induces', 'PosReg', (140, 147))	('p21', 'Gene', (165, 168))	('inhibits', 'NegReg', (59, 67))	('p53 reporter', 'MPA', (123, 135))	('FasR', 'Disease', (179, 183))	('NOXA', 'Gene', (170, 174))	('activates', 'PosReg', (113, 122))	('DeltaNp73beta', 'Var', (19, 32))	('NOXA', 'Gene', '5366', (170, 174))	('p21', 'Gene', '1026', (165, 168))
76872	20197393	A recent large-scale meta-analyses in colorectal tumors also concluded that the predicting value of p53 mutations does not reach the level of clinical usefulness and fails to correlate with a treatment response.	('colorectal tumors', 'Disease', 'MESH:D015179', (38, 55))	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('colorectal tumors', 'Disease', (38, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('p53', 'Gene', (100, 103))
76931	19503761	Complications of bone deposit ablation include damage to surrounding structures such as nerve roots, bowel and bladder symptoms, formation of tumor-cutaneous fistulae, and pathological fractures.	('bowel and bladder symptoms', 'Disease', 'MESH:D001745', (101, 127))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor-cutaneous fistulae', 'Disease', 'MESH:D017577', (142, 166))	('fractures', 'Disease', (185, 194))	('tumor-cutaneous fistulae', 'Disease', (142, 166))	('ablation', 'Var', (30, 38))	('bowel and bladder symptoms', 'Phenotype', 'HP:0002607', (101, 127))	('pathological fractures', 'Phenotype', 'HP:0002756', (172, 194))	('pathological fracture', 'Phenotype', 'HP:0002756', (172, 193))	('fractures', 'Disease', 'MESH:D050723', (185, 194))
76991	19503761	The risk increases with balloon dilatation of the diseased segment before stent deployment and excessive manipulation of guidewires (especially in the presence of diverticular disease).	('diverticular disease', 'Disease', (163, 183))	('diverticular disease', 'Disease', 'MESH:D000076385', (163, 183))	('men', 'Species', '9606', (62, 65))	('men', 'Species', '9606', (86, 89))	('balloon dilatation', 'Var', (24, 42))	('dilatation', 'Phenotype', 'HP:0002617', (32, 42))
77019	19503761	Deficiencies in more than 100 physiologic factors implicated in the cascades of angiogenesis, tissue regeneration and normal wound healing have been identified in diabetic ischemic feet.	('diabetic ischemic', 'Disease', (163, 180))	('identified', 'Reg', (149, 159))	('Deficiencies', 'Var', (0, 12))	('diabetic ischemic', 'Disease', 'MESH:D003920', (163, 180))
77087	33062005	Many researchers have discovered that the abnormal expression of transcription factors is closely correlated with malignant tumor onset and development, and among these transcription factors, Snail is a classic example that shows high levels of expression in several types of solid tumors; Snail can induce epithelial-mesenchymal transition (EMT), resulting in cancer cell invasion and metastasis and, consequently, leading to death.	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer cell invasion', 'CPA', (361, 381))	('malignant tumor', 'Disease', (114, 129))	('tumors', 'Disease', (282, 288))	('induce', 'Reg', (300, 306))	('tumor', 'Disease', (282, 287))	('tumor', 'Disease', (124, 129))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('malignant tumor', 'Disease', 'MESH:D009369', (114, 129))	('metastasis', 'CPA', (386, 396))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('resulting in', 'Reg', (348, 360))	('epithelial-mesenchymal transition', 'CPA', (307, 340))	('Snail', 'Var', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
77089	33062005	Researchers presented that degree of blood stasis is closely related to the oxygen supply in tumor tissue and cells and that activating blood circulation and removing blood stasis improved hypoxia microenvironment of tumors.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('activating', 'Var', (125, 135))	('oxygen', 'Chemical', 'MESH:D010100', (76, 82))	('improved', 'PosReg', (180, 188))	('hypoxia', 'Disease', 'MESH:D000860', (189, 196))	('hypoxia', 'Disease', (189, 196))
77090	33062005	A series of basic experiments and clinical trials were conducted showing that MTD inhibited Eca109 cell proliferation and downregulated the NF-kappaB signaling pathway.	('downregulated', 'NegReg', (122, 135))	('inhibited', 'NegReg', (82, 91))	('NF-kappaB', 'Gene', '4790', (140, 149))	('NF-kappaB', 'Gene', (140, 149))	('Eca109 cell proliferation', 'CPA', (92, 117))	('MTD', 'Var', (78, 81))
77118	33062005	A new neo-clerodane diterpenoid, barbatin H, together with fifteen known analogues were isolated from Scutellaria barbata D.Don, and a study turned out that the series of neo-clerodane diterpenoids exhibited varying degrees of cytotoxic activities against the growth of tumor cell lines.	('neo-clerodane', 'Var', (171, 184))	('neo-clerodane diterpenoids', 'Chemical', '-', (171, 197))	('cytotoxic activities', 'CPA', (227, 247))	('growth of tumor cell lines', 'CPA', (260, 286))	('barbatin H', 'Chemical', '-', (33, 43))	('Scutellaria barbata D.Don', 'Species', '396367', (102, 127))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('neo-clerodane diterpenoid', 'Chemical', '-', (171, 196))	('neo-clerodane diterpenoid', 'Chemical', '-', (6, 31))
77180	31957322	Examinations were performed using Olympus endoscopes (models Q10, P20, XQ200, XQ230, Q240, Q240Z, Q260, and Q260Z in chronological order of use; Olympus Optical Co. Ltd.).	('Q260Z', 'SUBSTITUTION', 'None', (108, 113))	('P20', 'Gene', (66, 69))	('Q240Z', 'SUBSTITUTION', 'None', (91, 96))	('P20', 'Gene', '51673', (66, 69))	('Q240', 'Var', (85, 89))	('Q260Z', 'Var', (108, 113))	('Q260', 'Var', (98, 102))	('XQ230', 'Var', (78, 83))	('Q240Z', 'Var', (91, 96))
77294	30361422	Cisplatin treatment is associated with severe hematologic toxicities such as myelosuppression as well as nonhematologic toxicities including nephrotoxicity, nausea, and nephropathy, which can result in treatment disruption in patients with advanced esophageal cancer who are likely to be especially susceptible to such toxicities.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('nephropathy', 'Disease', 'MESH:D007674', (169, 180))	('nephrotoxicity', 'Disease', 'MESH:D007674', (141, 155))	('myelosuppression', 'Disease', 'MESH:D001855', (77, 93))	('nausea', 'Disease', 'MESH:D009325', (157, 163))	('toxicities', 'Disease', 'MESH:D064420', (58, 68))	('result', 'Reg', (192, 198))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (249, 266))	('toxicities', 'Disease', (58, 68))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('n', 'Chemical', 'MESH:D009584', (231, 232))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('toxicities', 'Disease', 'MESH:D064420', (120, 130))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('toxicities', 'Disease', 'MESH:D064420', (319, 329))	('hematologic toxicities', 'Disease', 'MESH:D006402', (46, 68))	('nephropathy', 'Phenotype', 'HP:0000112', (169, 180))	('n', 'Chemical', 'MESH:D009584', (17, 18))	('n', 'Chemical', 'MESH:D009584', (262, 263))	('n', 'Chemical', 'MESH:D009584', (224, 225))	('patients', 'Species', '9606', (226, 234))	('esophageal cancer', 'Disease', (249, 266))	('toxicities', 'Disease', (120, 130))	('toxicities', 'Disease', (319, 329))	('n', 'Chemical', 'MESH:D009584', (166, 167))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('n', 'Chemical', 'MESH:D009584', (190, 191))	('n', 'Chemical', 'MESH:D009584', (221, 222))	('hematologic toxicities', 'Disease', 'MESH:D006402', (108, 130))	('hematologic toxicities', 'Disease', (46, 68))	('nausea', 'Phenotype', 'HP:0002018', (157, 163))	('myelosuppression', 'Disease', (77, 93))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('n', 'Chemical', 'MESH:D009584', (244, 245))	('treatment', 'Disease', (202, 211))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('hematologic toxicities', 'Disease', (108, 130))	('nephrotoxicity', 'Disease', (141, 155))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('nausea', 'Disease', (157, 163))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('nephropathy', 'Disease', (169, 180))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('Cisplatin', 'Var', (0, 9))	('n', 'Chemical', 'MESH:D009584', (107, 108))
77488	28872613	Elucidation of the molecular cues underlying the effects of noncoding RNAs on CSCs may thus facilitate the design of effective strategies to improve radiotherapy and prevent cancer metastasis.	('noncoding RNAs', 'Var', (60, 74))	('cancer metastasis', 'Disease', (174, 191))	('radiotherapy', 'CPA', (149, 161))	('cancer metastasis', 'Disease', 'MESH:D009362', (174, 191))	('improve', 'PosReg', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
77511	28872613	Inhibition of Nrf2-Notch axis reduces EMT but enhanced radiosensitivity of NSCLC, and consequently decreases radiation-induced NSCLC invasion.	('NSCLC', 'Disease', (127, 132))	('radiation-induced', 'CPA', (109, 126))	('decreases', 'NegReg', (99, 108))	('EMT', 'CPA', (38, 41))	('Nrf2', 'Gene', '4780', (14, 18))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('radiosensitivity', 'MPA', (55, 71))	('Nrf2', 'Gene', (14, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (46, 71))	('enhanced', 'PosReg', (46, 54))	('Inhibition', 'Var', (0, 10))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('reduces', 'NegReg', (30, 37))
77523	28872613	Accordingly, silencing the expression of SNAIL and SLUG (Snail family transcriptional repressor 2), crucial EMT inducers, could sensitize cancer cells to genotoxic stress induced by chemo or radiotherapy.	('cancer', 'Disease', (138, 144))	('Snail family transcriptional repressor 2', 'Gene', (57, 97))	('sensitize', 'Reg', (128, 137))	('SLUG', 'Gene', '6591', (51, 55))	('genotoxic stress', 'MPA', (154, 170))	('Snail family transcriptional repressor 2', 'Gene', '6591', (57, 97))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('SLUG', 'Gene', (51, 55))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('SNAIL', 'Gene', '6615', (41, 46))	('SNAIL', 'Gene', (41, 46))	('silencing', 'Var', (13, 22))
77545	28872613	Additionally, the subpopulation of CD133+ colorectal or CD24+ ovarian cancer cells exhibits both properties of CSC and EMT, characterized as increased SNAIL, TWIST, and Vimentin along with decreased E-cadherin expression.	('SNAIL', 'Gene', '6615', (151, 156))	('SNAIL', 'Gene', (151, 156))	('CD24', 'Gene', (56, 60))	('increased', 'PosReg', (141, 150))	('expression', 'MPA', (210, 220))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('Vimentin', 'Gene', (169, 177))	('TWIST', 'Gene', (158, 163))	('colorectal', 'Disease', 'MESH:D015179', (42, 52))	('TWIST', 'Gene', '7291', (158, 163))	('CD133+', 'Var', (35, 41))	('CD24', 'Gene', '100133941', (56, 60))	('decreased', 'NegReg', (189, 198))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (62, 76))	('E-cadherin', 'Gene', (199, 209))	('E-cadherin', 'Gene', '999', (199, 209))	('colorectal', 'Disease', (42, 52))	('Vimentin', 'Gene', '7431', (169, 177))	('ovarian cancer', 'Disease', (62, 76))
77558	28872613	Silencing of lincRNA-p21 causes beta-catenin overexpression and leads to increased stemness and radioresistance of glioma stem cells.	('increased', 'PosReg', (73, 82))	('glioma', 'Disease', (115, 121))	('beta-catenin', 'Protein', (32, 44))	('causes', 'Reg', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('lincRNA-p21', 'Gene', (13, 24))	('radioresistance', 'CPA', (96, 111))	('stemness', 'Disease', 'MESH:D020295', (83, 91))	('stemness', 'Disease', (83, 91))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('Silencing', 'Var', (0, 9))	('overexpression', 'PosReg', (45, 59))
77560	28872613	Ultraviolet B-mediated lincRNA-p21 triggered cell cycle arrest and apoptosis in keratinocytes, and conversely, its inhibition resulted in evasion of apoptosis caused by ultraviolet B.	('inhibition', 'NegReg', (115, 125))	('apoptosis', 'MPA', (149, 158))	('apoptosis', 'CPA', (67, 76))	('arrest', 'Disease', 'MESH:D006323', (56, 62))	('arrest', 'Disease', (56, 62))	('lincRNA-p21', 'Var', (23, 34))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (45, 62))	('evasion', 'MPA', (138, 145))
77561	28872613	The lncRNA LOC285194, also termed LSAMP antisense RNA, was first identified as a p53-regulated tumor suppressor that influences the cell cycle and apoptosis by regulating VEGF receptor 1 and miR-211 in osteosarcoma.	('LSAMP', 'Gene', '4045', (34, 39))	('osteosarcoma', 'Phenotype', 'HP:0002669', (202, 214))	('regulating', 'Reg', (160, 170))	('osteosarcoma', 'Disease', (202, 214))	('osteosarcoma', 'Disease', 'MESH:D012516', (202, 214))	('influences', 'Reg', (117, 127))	('miR-211', 'Gene', '406993', (191, 198))	('miR-211', 'Gene', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('LOC285194', 'Var', (11, 20))	('LSAMP', 'Gene', (34, 39))	('cell cycle', 'CPA', (132, 142))	('apoptosis', 'CPA', (147, 156))	('VEGF receptor 1', 'Gene', (171, 186))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
77562	28872613	Recent evidence has shown decreased expression of LOC285194 in esophageal squamous cell carcinoma in relation to larger tumor size, high-grade TNM stage, lymph node and distant metastasis.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('TNM', 'Gene', (143, 146))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('LOC285194', 'Var', (50, 59))	('decreased', 'NegReg', (26, 35))	('expression', 'MPA', (36, 46))	('tumor', 'Disease', (120, 125))	('TNM', 'Gene', '10178', (143, 146))
77568	28872613	Conversely, inhibition of ANRIL expression causes repression of cellular proliferation and radioresistance via induction of apoptosis.	('radioresistance', 'CPA', (91, 106))	('inhibition', 'Var', (12, 22))	('repression', 'NegReg', (50, 60))	('cellular proliferation', 'CPA', (64, 86))	('ANRIL', 'Gene', (26, 31))	('apoptosis', 'CPA', (124, 133))	('ANRIL', 'Gene', '100048912', (26, 31))
77570	28872613	Moreover, Silencing of ANRIL upregulates the expression of the pro-apoptotic genes, BAX and SMAC (second mitochondria-derived activator of caspases), but suppresses the anti-apoptotic gene, BCL-2.	('BAX', 'Gene', '581', (84, 87))	('second mitochondria-derived activator of caspases', 'Gene', '56616', (98, 147))	('SMAC', 'Gene', '56616', (92, 96))	('upregulates', 'PosReg', (29, 40))	('second mitochondria-derived activator of caspases', 'Gene', (98, 147))	('ANRIL', 'Gene', (23, 28))	('anti-apoptotic gene', 'MPA', (169, 188))	('suppresses', 'NegReg', (154, 164))	('expression', 'MPA', (45, 55))	('BCL-2', 'Gene', '596', (190, 195))	('BAX', 'Gene', (84, 87))	('ANRIL', 'Gene', '100048912', (23, 28))	('SMAC', 'Gene', (92, 96))	('BCL-2', 'Gene', (190, 195))	('Silencing', 'Var', (10, 19))
77573	28872613	Among the 116 radiation-induced and Cur-reversed differentially expressed lncRNAs, six (AF086415, AK095147, RP1-179N16.3, MUDENG, AK056098, and AK294004) were identified.	('AF086415', 'Var', (88, 96))	('MUDENG', 'Gene', (122, 128))	('RP1-179N16.3', 'Var', (108, 120))	('AK095147', 'Var', (98, 106))	('MUDENG', 'Gene', '55745', (122, 128))	('AK294004', 'Var', (144, 152))	('AK056098', 'Var', (130, 138))
77574	28872613	Further functional studies indicated that lncRNA AK294004 directly targets Cyclin D1 and exerts a negative effect.	('AK294004', 'Var', (49, 57))	('Cyclin D1', 'Gene', (75, 84))	('Cyclin D1', 'Gene', '595', (75, 84))	('targets', 'Reg', (67, 74))
77575	28872613	In view of the finding that Cyclin D1 is an important mediator of the cellular DNA damage response and apoptosis after radiation treatment, AK294004 may be a potential lncRNA participating in radioresistance of cancer.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (211, 217))	('Cyclin D1', 'Gene', '595', (28, 37))	('AK294004', 'Var', (140, 148))	('Cyclin D1', 'Gene', (28, 37))
77578	28872613	Expression of lncRNA-ROR is increased in several cancer types and serves as a prognosis marker including colorectal cancer, and silencing its expression in CRC cells enhances sensitivity to radiotherapy via negative regulation of the p53/miR-145 axis.	('miR-145', 'Gene', (238, 245))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('silencing', 'Var', (128, 137))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('cancer', 'Disease', (49, 55))	('ROR', 'Gene', (21, 24))	('increased', 'PosReg', (28, 37))	('ROR', 'Gene', '100885779', (21, 24))	('sensitivity to radiotherapy', 'CPA', (175, 202))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('enhances', 'PosReg', (166, 174))	('cancer', 'Disease', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('expression', 'MPA', (142, 152))	('negative', 'NegReg', (207, 215))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('miR-145', 'Gene', '406937', (238, 245))	('CR', 'Chemical', '-', (156, 158))	('colorectal cancer', 'Disease', (105, 122))
77579	28872613	Importantly, combination of radiotherapy with specific knockdown of lncRNA-ROR was shown to induce significant tumor reduction in a xenograft model.	('reduction', 'NegReg', (117, 126))	('knockdown', 'Var', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('ROR', 'Gene', (75, 78))	('tumor', 'Disease', (111, 116))	('ROR', 'Gene', '100885779', (75, 78))
77584	28872613	Silencing the expression of MALAT1 sensitizes NPC cells to radiotherapy, both in vitro and in vivo.	('MALAT1', 'Gene', (28, 34))	('sensitizes', 'Reg', (35, 45))	('NPC', 'Phenotype', 'HP:0100630', (46, 49))	('Silencing', 'Var', (0, 9))	('MALAT1', 'Gene', '378938', (28, 34))
77590	28872613	Ectopic expression of MALAT1 induced an increase in CKS1 in ESCC cells and decrease in miR-145 in cervical cancer cells, and which is leading to inhibition of cancer cell apoptosis after radiation treatment.	('cancer', 'Disease', (159, 165))	('miR-145', 'Gene', '406937', (87, 94))	('decrease', 'NegReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('miR-145', 'Gene', (87, 94))	('increase', 'PosReg', (40, 48))	('Ectopic expression', 'Var', (0, 18))	('MALAT1', 'Gene', '378938', (22, 28))	('CKS1', 'Gene', '137529', (52, 56))	('cervical cancer', 'Disease', 'MESH:D002583', (98, 113))	('cervical cancer', 'Disease', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('CKS1', 'Gene', (52, 56))	('MALAT1', 'Gene', (22, 28))	('cancer', 'Disease', (107, 113))	('inhibition', 'NegReg', (145, 155))
77593	28872613	Silencing of NEAT1 expression prevents paraspeckle formation and sensitizes preneoplastic cells to DNA damage-induced cell death, preventing chemical-induced skin tumorigenesis in mice and enhancing chemotherapy-induced cytotoxicity, consistent with the theory that increased DNA damage sensitizes cells to p53 reactivation therapy.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('NEAT1', 'Gene', (13, 18))	('cytotoxicity', 'Disease', (220, 232))	('enhancing', 'PosReg', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('preventing', 'NegReg', (130, 140))	('tumor', 'Disease', (163, 168))	('mice', 'Species', '10090', (180, 184))	('cytotoxicity', 'Disease', 'MESH:D064420', (220, 232))	('Silencing', 'Var', (0, 9))
77604	28872613	Importantly, p53-mediated inhibition of LINP1 increases the sensitivity of breast tumor cells to radiotherapy.	('p53-mediated', 'Var', (13, 25))	('LINP1', 'Gene', '108570035', (40, 45))	('sensitivity', 'CPA', (60, 71))	('breast tumor', 'Phenotype', 'HP:0100013', (75, 87))	('LINP1', 'Gene', (40, 45))	('increases', 'PosReg', (46, 55))	('inhibition', 'NegReg', (26, 36))	('breast tumor', 'Disease', 'MESH:D001943', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast tumor', 'Disease', (75, 87))
77614	28872613	Notably, TUG1 expression promoted cancer cell invasion and radioresistance via triggering EMT.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'Var', (14, 24))	('EMT', 'CPA', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('triggering', 'Reg', (79, 89))	('radioresistance', 'CPA', (59, 74))	('promoted', 'PosReg', (25, 33))	('cancer', 'Disease', (34, 40))	('TUG1', 'Gene', (9, 13))
77617	28872613	Additionally, silencing of TUG1 was shown to enhance sensitivity to radiotherapy via suppression of HMGB1 (high mobility group box 1) expression.	('silencing', 'Var', (14, 23))	('TUG1', 'Gene', (27, 31))	('expression', 'MPA', (134, 144))	('enhance', 'PosReg', (45, 52))	('enhance sensitivity to radiotherapy', 'Phenotype', 'HP:0011133', (45, 80))	('suppression', 'NegReg', (85, 96))	('HMGB1', 'Gene', (100, 105))	('HMGB1', 'Gene', '3146', (100, 105))	('high mobility group box 1', 'Gene', (107, 132))	('sensitivity to radiotherapy', 'MPA', (53, 80))	('high mobility group box 1', 'Gene', '3146', (107, 132))
77620	28872613	Homeobox (HOX) transcript antisense RNA (HOTAIR) initially identified as a spliced and polyadenylated RNA participating in the promotion of carcinogenesis and cancer progression, is considered a prognosis marker for various cancer types.	('cancer', 'Disease', (159, 165))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('antisense', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('carcinogenesis', 'Disease', (140, 154))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (224, 230))
77627	28872613	Conversely, silencing of HOTAIR in CRC cells inhibits cell invasion and increases sensitivity to radiation by regulating apoptosis-related genes, such as BCL-2 and BAX.	('BCL-2', 'Gene', '596', (154, 159))	('BAX', 'Gene', '581', (164, 167))	('CR', 'Chemical', '-', (35, 37))	('inhibits', 'NegReg', (45, 53))	('BAX', 'Gene', (164, 167))	('CRC', 'Phenotype', 'HP:0003003', (35, 38))	('increases', 'PosReg', (72, 81))	('BCL-2', 'Gene', (154, 159))	('silencing', 'Var', (12, 21))	('apoptosis-related genes', 'Gene', (121, 144))	('regulating', 'Reg', (110, 120))	('HOTAIR', 'Gene', (25, 31))	('cell invasion', 'CPA', (54, 67))	('increases sensitivity to radiation', 'Phenotype', 'HP:0011133', (72, 106))	('sensitivity to', 'MPA', (82, 96))
77640	28872613	Thus, dysregulation of PARTICLE may be an important factor influencing the outcome of radiotherapy.	('PARTICLE', 'Gene', (23, 31))	('PARTICLE', 'Gene', '100630918', (23, 31))	('dysregulation', 'Var', (6, 19))
77649	28872613	Following microarray expression analysis and further validation, three novel lncRNAs, TCONS_00026506, ENST00000468960, and NR_038990, were identified, which may serve as potential therapeutic targets for radioresistant cancer cells.	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('NR_038990', 'Var', (123, 132))	('cancer', 'Disease', (219, 225))
77651	28872613	Further validation via qRT-PCR in both established radioresistant CNE-2 and 6-10B cell lines showed that three novel lncRNAs (n373932, n409627 and n386034) exhibit significant expression changes after radiation treatment.	('CR', 'Chemical', '-', (28, 30))	('n409627', 'Var', (135, 142))	('n386034', 'Var', (147, 154))	('CNE-2', 'CellLine', 'CVCL:6889', (66, 71))	('expression', 'MPA', (176, 186))	('n373932', 'Var', (126, 133))	('changes', 'Reg', (187, 194))
77652	28872613	Further examination of the expression patterns of n373932 and its associated gene, SLITRK5, in clinical specimens revealed a negative correlation between expression of n373932 and SLITRK5.	('SLITRK5', 'Gene', (180, 187))	('n373932', 'Gene', (50, 57))	('clinical', 'Species', '191496', (95, 103))	('SLITRK5', 'Gene', '26050', (83, 90))	('negative', 'NegReg', (125, 133))	('SLITRK5', 'Gene', (83, 90))	('SLITRK5', 'Gene', '26050', (180, 187))	('n373932', 'Var', (168, 175))	('expression', 'MPA', (154, 164))
77653	28872613	In view of the results, it is proposed that n373932, n409627 and n386034, and interactions between n373932 and SLITRK5 are involved in radioresistance of cancer cells.	('n409627', 'Var', (53, 60))	('involved', 'Reg', (123, 131))	('cancer', 'Disease', (154, 160))	('n386034', 'Var', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('n373932', 'Var', (99, 106))	('n373932', 'Var', (44, 51))	('SLITRK5', 'Gene', '26050', (111, 118))	('radioresistance', 'CPA', (135, 150))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('SLITRK5', 'Gene', (111, 118))	('interactions', 'Interaction', (78, 90))
77655	28872613	Further experiments demonstrated that TCONS_00018436 exhibits anti-apoptotic activity following radiotherapy and its expression is dysregulated in recurrent HSCC clinical tissue samples.	('clinical', 'Species', '191496', (162, 170))	('HSCC', 'Phenotype', 'HP:0012182', (157, 161))	('TCONS_00018436', 'Var', (38, 52))	('anti-apoptotic activity', 'CPA', (62, 85))
77657	28872613	Several studies have demonstrated that the dysregulation of lncRNAs in malignant tumors is closely related to the function of CSCs.	('dysregulation', 'Var', (43, 56))	('malignant tumors', 'Disease', (71, 87))	('lncRNAs', 'Protein', (60, 67))	('malignant tumors', 'Disease', 'MESH:D018198', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
77659	28872613	Recent studies have demonstrated that lincRNA-p21 is a potent suppressor of the stem-like traits of CSCs purified from both CRC and glioma cells.	('glioma', 'Disease', (132, 138))	('CR', 'Chemical', '-', (124, 126))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('lincRNA-p21', 'Var', (38, 49))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('stem-like traits', 'CPA', (80, 96))
77676	28872613	In breast cancer, HOTAIR enhances metastasis.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('enhances', 'PosReg', (25, 33))	('metastasis', 'CPA', (34, 44))	('HOTAIR', 'Var', (18, 24))
77682	28872613	Its silencing in CD133+ CRC cells leads to decreased cellular proliferation, metastasis and colony-forming properties as well as decreased Vimentin with enhanced E-cadherin expression.	('E-cadherin', 'Gene', '999', (162, 172))	('CR', 'Chemical', '-', (24, 26))	('CRC', 'Phenotype', 'HP:0003003', (24, 27))	('cellular proliferation', 'CPA', (53, 75))	('colony-forming properties', 'CPA', (92, 117))	('metastasis', 'CPA', (77, 87))	('Vimentin', 'Gene', (139, 147))	('Vimentin', 'Gene', '7431', (139, 147))	('expression', 'MPA', (173, 183))	('enhanced', 'PosReg', (153, 161))	('decreased', 'NegReg', (129, 138))	('decreased', 'NegReg', (43, 52))	('silencing', 'Var', (4, 13))	('E-cadherin', 'Gene', (162, 172))
77683	28872613	Additionally, CD133+ CRC cells with low HOTAIR expression show decreased capacities of tumor growth and lung metastasis in xenograft mouse models.	('CRC', 'Phenotype', 'HP:0003003', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('low', 'Var', (36, 39))	('decreased', 'NegReg', (63, 72))	('tumor', 'Disease', (87, 92))	('HOTAIR', 'Gene', (40, 46))	('mouse', 'Species', '10090', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('lung metastasis', 'CPA', (104, 119))	('CR', 'Chemical', '-', (21, 23))
77691	28872613	Moreover, Lnc34a is overexpressed in late-stage CRCs, leading to epigenetic silencing of miR-34a and regulation of CRC malignancy.	('CR', 'Chemical', '-', (48, 50))	('CRC malignancy', 'Disease', 'MESH:D015179', (115, 129))	('CR', 'Chemical', '-', (115, 117))	('epigenetic silencing', 'Var', (65, 85))	('miR-34a', 'Gene', '407040', (89, 96))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('CRC malignancy', 'Disease', (115, 129))	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('miR-34a', 'Gene', (89, 96))
77698	28872613	Silencing of this lncRNA in various cancer cell lines causes cell cycle arrest at the G1 phase and inhibits cellular proliferation.	('cellular proliferation', 'CPA', (108, 130))	('causes', 'Reg', (54, 60))	('inhibits', 'NegReg', (99, 107))	('arrest', 'Disease', 'MESH:D006323', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('arrest', 'Disease', (72, 78))	('cancer', 'Disease', (36, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Silencing', 'Var', (0, 9))
77699	28872613	Further functional analyses have revealed that inhibition of TALNEC2 triggers repression of miR-21 and miR-191, and consequently decreases the self-renewal and mesenchymal transformation of CSCs, increases radiosensitivity and prolongs the survival of xenograft mice bearing CSCs of glioma.	('prolongs', 'PosReg', (227, 235))	('radiosensitivity', 'CPA', (206, 222))	('increases', 'PosReg', (196, 205))	('inhibition', 'Var', (47, 57))	('miR-191', 'Gene', '387186', (103, 110))	('survival', 'CPA', (240, 248))	('self-renewal', 'CPA', (143, 155))	('glioma', 'Disease', (283, 289))	('miR-21', 'Gene', '387140', (92, 98))	('mice', 'Species', '10090', (262, 266))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (196, 222))	('miR-191', 'Gene', (103, 110))	('glioma', 'Disease', 'MESH:D005910', (283, 289))	('glioma', 'Phenotype', 'HP:0009733', (283, 289))	('decreases', 'NegReg', (129, 138))	('miR-21', 'Gene', (92, 98))	('repression', 'MPA', (78, 88))	('TALNEC2', 'Gene', (61, 68))
77700	28872613	Homeobox A11 antisense (HOXA11-AS) is an lncRNA located near the homeobox A11 (HOXA11) gene that is highly expressed in several cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('HOXA11', 'Gene', '3207', (79, 85))	('Homeobox A11', 'Gene', '3207', (0, 12))	('HOXA11', 'Gene', '3207', (24, 30))	('HOXA11-AS', 'Gene', (24, 33))	('HOXA11', 'Gene', (24, 30))	('HOXA11-AS', 'Gene', '221883', (24, 33))	('HOXA11', 'Gene', (79, 85))	('Homeobox A11', 'Gene', (0, 12))	('homeobox A11', 'Gene', '3207', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('antisense', 'Var', (13, 22))	('homeobox A11', 'Gene', (65, 77))	('cancer', 'Disease', (128, 134))
77703	28872613	Conversely, its knockdown suppresses these aggressive biologic features, accompanied by decreased EMT and CSC-related genes, including NANOG, OCT4, SOX2, and beta-catenin.	('aggressive biologic features', 'CPA', (43, 71))	('OCT4', 'Gene', '5460', (142, 146))	('OCT4', 'Gene', (142, 146))	('SOX2', 'Gene', '6657', (148, 152))	('SOX2', 'Gene', (148, 152))	('suppresses', 'NegReg', (26, 36))	('knockdown', 'Var', (16, 25))	('NANOG', 'Gene', '79923', (135, 140))	('EMT and', 'CPA', (98, 105))	('decreased', 'NegReg', (88, 97))	('beta-catenin', 'Protein', (158, 170))	('NANOG', 'Gene', (135, 140))	('decreased EMT', 'Phenotype', 'HP:0032198', (88, 101))
77706	28872613	Overexpression of lncRNA-Hh in breast cancer cells increases Hh signaling accompanied by elevated levels of SOX2 and OCT4 via targeting to GAS1 (growth arrest specific 1), and consequently contributes to activation of EMT, CSC maintenance and tumorigenesis of breast cancer cells.	('growth arrest', 'Phenotype', 'HP:0001510', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('tumor', 'Disease', (243, 248))	('OCT4', 'Gene', '5460', (117, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('increases', 'PosReg', (51, 60))	('lncRNA-Hh', 'Gene', (18, 27))	('breast cancer', 'Disease', (31, 44))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('GAS1', 'Gene', '2619', (139, 143))	('CSC maintenance', 'CPA', (223, 238))	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', (260, 273))	('OCT4', 'Gene', (117, 121))	('targeting', 'Var', (126, 135))	('Hh signaling', 'MPA', (61, 73))	('GAS1', 'Gene', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('elevated', 'PosReg', (89, 97))	('EMT', 'CPA', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('growth arrest specific 1', 'Gene', '2619', (145, 169))	('activation', 'PosReg', (204, 214))	('growth arrest specific 1', 'Gene', (145, 169))	('SOX2', 'Gene', '6657', (108, 112))	('SOX2', 'Gene', (108, 112))	('levels', 'MPA', (98, 104))
77713	28872613	Furthermore, linc00617 has been shown to physically bind the SOX2 promoter and activate its transcription by recruiting hnRNP-K. Conversely, silencing of linc00617 suppresses tumor progression.	('tumor', 'Disease', (175, 180))	('silencing', 'Var', (141, 150))	('linc00617', 'Gene', '100507043', (154, 163))	('hnRNP-K', 'Gene', (120, 127))	('linc00617', 'Gene', (13, 22))	('linc00617', 'Gene', '100507043', (13, 22))	('suppresses', 'NegReg', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('SOX2', 'Gene', (61, 65))	('hnRNP-K', 'Gene', '3190', (120, 127))	('SOX2', 'Gene', '6657', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('transcription', 'MPA', (92, 105))	('linc00617', 'Gene', (154, 163))
77729	28872613	In an earlier study, its knockdown in CD133+ glioma cells resulted in decreased colony formation, cell proliferation, metastasis and increased cell cycle arrest and apoptosis.	('cell proliferation', 'CPA', (98, 116))	('arrest', 'Disease', (154, 160))	('colony formation', 'CPA', (80, 96))	('metastasis', 'CPA', (118, 128))	('apoptosis', 'CPA', (165, 174))	('decreased', 'NegReg', (70, 79))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (143, 160))	('arrest', 'Disease', 'MESH:D006323', (154, 160))	('increased', 'PosReg', (133, 142))	('glioma', 'Disease', (45, 51))	('knockdown', 'Var', (25, 34))
77731	28872613	Further experiments revealed that restoration of let-7e suppresses proliferation and metastasis but promotes apoptosis in NEAT1 knockdown CSCs of glioma, which may be attributable to repression of NRAS, a direct target of let-7e known to induce tumorigenesis and stemness.	('promotes', 'PosReg', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('restoration', 'Var', (34, 45))	('glioma', 'Disease', (146, 152))	('apoptosis', 'CPA', (109, 118))	('let-7e', 'Gene', (49, 55))	('NRAS', 'Gene', '4893', (197, 201))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('suppresses', 'NegReg', (56, 66))	('let-7e', 'Gene', (222, 228))	('let-7e', 'Gene', '406887', (49, 55))	('stemness', 'Disease', 'MESH:D020295', (263, 271))	('stemness', 'Disease', (263, 271))	('let-7e', 'Gene', '406887', (222, 228))	('proliferation', 'CPA', (67, 80))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('tumor', 'Disease', (245, 250))	('repression', 'NegReg', (183, 193))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('NRAS', 'Gene', (197, 201))
77739	28872613	Overexpression of lncRNA H19 promotes metastasis, angiogenesis, and stemness in glioblastoma and cholangiocarcinoma cells through effects on EMT and is associated with poor prognosis.	('H19', 'Gene', (25, 28))	('stemness in glioblastoma', 'Disease', (68, 92))	('EMT', 'CPA', (141, 144))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (97, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('stemness in glioblastoma', 'Disease', 'MESH:D005909', (68, 92))	('angiogenesis', 'CPA', (50, 62))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('effects', 'Reg', (130, 137))	('cholangiocarcinoma', 'Disease', (97, 115))	('Overexpression', 'Var', (0, 14))	('H19', 'Gene', '283120', (25, 28))	('metastasis', 'CPA', (38, 48))	('promotes', 'PosReg', (29, 37))
77740	28872613	Furthermore, knockdown of H19 has been shown to downregulate the stem cell-related genes SOX2, OCT4, and NANOG, as well as other CSC markers in glioblastoma and embryonic carcinoma cell lines.	('SOX2', 'Gene', '6657', (89, 93))	('NANOG', 'Gene', '79923', (105, 110))	('embryonic carcinoma', 'Disease', (161, 180))	('NANOG', 'Gene', (105, 110))	('embryonic carcinoma', 'Disease', 'MESH:D018236', (161, 180))	('embryonic carcinoma', 'Phenotype', 'HP:0002898', (161, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('glioblastoma', 'Disease', (144, 156))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('H19', 'Gene', '283120', (26, 29))	('H19', 'Gene', (26, 29))	('OCT4', 'Gene', '5460', (95, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('OCT4', 'Gene', (95, 99))	('downregulate', 'NegReg', (48, 60))	('knockdown', 'Var', (13, 22))	('SOX2', 'Gene', (89, 93))
77745	28872613	Further experiments have revealed that FOXF1-AS1 physically associates with the PRC2 component, EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), and its knockdown mediates metastasis and stemness of cancer cells in the EZH2-dependent manner.	('EZH2', 'Gene', (236, 240))	('knockdown', 'Var', (170, 179))	('stemness of cancer', 'Disease', (204, 222))	('EZH2', 'Gene', '2146', (96, 100))	('FOXF1', 'Gene', '2294', (39, 44))	('mediates', 'Reg', (180, 188))	('FOXF1', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('EZH2', 'Gene', (96, 100))	('associates', 'Interaction', (60, 70))	('stemness of cancer', 'Disease', 'MESH:D009369', (204, 222))	('AS1', 'Gene', '5729', (45, 48))	('AS1', 'Gene', (45, 48))	('EZH2', 'Gene', '2146', (236, 240))	('metastasis', 'CPA', (189, 199))
77748	28872613	MALAT1 is overexpressed in CSCs of pancreatic cancer and its elimination leads to a decrease in the pancreatic CSC fraction.	('decrease', 'NegReg', (84, 92))	('pancreatic', 'Disease', (35, 45))	('pancreatic', 'Disease', (100, 110))	('overexpressed', 'PosReg', (10, 23))	('MALAT1', 'Gene', '378938', (0, 6))	('CSCs of pancreatic cancer', 'Disease', (27, 52))	('MALAT1', 'Gene', (0, 6))	('CSCs of pancreatic cancer', 'Disease', 'MESH:D010190', (27, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('pancreatic', 'Disease', 'MESH:D010195', (35, 45))	('elimination', 'Var', (61, 72))	('pancreatic', 'Disease', 'MESH:D010195', (100, 110))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (35, 52))
77761	28872613	Previous studies have suggested the crucial role of lncRNAs deregulation in cancer recurrence and prognosis.	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('deregulation', 'Var', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
77764	28872613	In the current article, several dysregulated lncRNAs involved in the regulation of radioresistance, metastasis and cancer stem cell properties, such as ANRIL, TUG1, LOC285194, LncRNA-ROR, MALAT1, NEAT1, HOTAIR, POU6F2-AS2, GAS5, HIF2PUT, H19, TALNEC2, HOXA11-AS, Linc00617, HULC, and UCA1, have been found to be associated with the outcomes of radiotherapy and act as valuable prognostic biomarkers (Table 1 and Figure 1B,C).	('associated', 'Reg', (312, 322))	('GAS5', 'Gene', '60674', (223, 227))	('UCA1', 'Gene', '652995', (284, 288))	('H19', 'Gene', (238, 241))	('UCA1', 'Gene', (284, 288))	('HULC', 'Gene', '728655', (274, 278))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('HOXA11-AS', 'Gene', (252, 261))	('POU6F2-AS2', 'Gene', '100689074;11281', (211, 221))	('H19', 'Gene', '283120', (238, 241))	('GAS5', 'Gene', (223, 227))	('Linc00617', 'Gene', '100507043', (263, 272))	('MALAT1', 'Gene', (188, 194))	('HOXA11-AS', 'Gene', '221883', (252, 261))	('LOC285194', 'Var', (165, 174))	('POU6F2-AS2', 'Gene', (211, 221))	('ANRIL', 'Gene', '100048912', (152, 157))	('MALAT1', 'Gene', '378938', (188, 194))	('cancer', 'Disease', (115, 121))	('HULC', 'Gene', (274, 278))	('ROR', 'Gene', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ROR', 'Gene', '100885779', (183, 186))	('Linc00617', 'Gene', (263, 272))	('ANRIL', 'Gene', (152, 157))
77766	28872613	To date, two major mechanisms have emerged regarding lncRNA-mediated effects on CSC activity and radioresistance via regulation of EMT, DNA repair, apoptosis and stemness: (1) epigenetic regulation of genes, particularly via recruitment of the Polycomb repressor complex (PRC2); and (2) post-transcriptionally by acting as competing endogenous RNAs (ceRNAs) for miRNAs that target genes involved in stemness and radioresistance.	('stemness', 'Disease', 'MESH:D020295', (399, 407))	('stemness', 'Disease', (399, 407))	('PRC2', 'Gene', (272, 276))	('miR', 'Gene', (362, 365))	('miR', 'Gene', '220972', (362, 365))	('stemness', 'Disease', 'MESH:D020295', (162, 170))	('stemness', 'Disease', (162, 170))	('epigenetic', 'Var', (176, 186))
77771	28872613	Dysregulated lincRNA-p21 and LINP1 are shown to influence the radiosensitivity of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('LINP1', 'Gene', (29, 34))	('cancer', 'Disease', (82, 88))	('lincRNA-p21', 'Gene', (13, 24))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Dysregulated', 'Var', (0, 12))	('influence', 'Reg', (48, 57))	('LINP1', 'Gene', '108570035', (29, 34))
77799	26991823	Four patients had stable disease (>=24 weeks in one patient with rectal cancer [100 mg] and one with esophageal cancer [125 mg]) in part 1; two patients had partial response and two had stable disease (both >=24 weeks) in part 2.	('patient', 'Species', '9606', (5, 12))	('patients', 'Species', '9606', (5, 13))	('rectal cancer', 'Disease', 'MESH:D012004', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('[100 mg]', 'Var', (79, 87))	('patient', 'Species', '9606', (144, 151))	('esophageal cancer', 'Disease', (101, 118))	('patients', 'Species', '9606', (144, 152))	('rectal cancer', 'Disease', (65, 78))	('rectal cancer', 'Phenotype', 'HP:0100743', (65, 78))	('patient', 'Species', '9606', (52, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
77839	26991823	The most common all-grade non-hematologic events were increased blood creatinine with palbociclib 100 mg and fatigue and diarrhea with palbociclib 125 mg, whether given as monotherapy or with letrozole (Table 3).	('letrozole', 'Chemical', 'MESH:D000077289', (192, 201))	('palbociclib', 'Chemical', 'MESH:C500026', (86, 97))	('blood creatinine', 'MPA', (64, 80))	('increased blood creatinine', 'Phenotype', 'HP:0003259', (54, 80))	('creatinine', 'Chemical', 'MESH:D003404', (70, 80))	('fatigue', 'Disease', 'MESH:D005221', (109, 116))	('increased', 'PosReg', (54, 63))	('diarrhea', 'Phenotype', 'HP:0002014', (121, 129))	('diarrhea', 'Disease', 'MESH:D003967', (121, 129))	('diarrhea', 'Disease', (121, 129))	('fatigue', 'Disease', (109, 116))	('palbociclib', 'Chemical', 'MESH:C500026', (135, 146))	('palbociclib', 'Var', (86, 97))	('fatigue', 'Phenotype', 'HP:0012378', (109, 116))	('palbociclib 125 mg', 'Var', (135, 153))
77845	26991823	In part 1, objective responses (CR or PR) were not reported; stable disease was observed in three of six patients (Table 7) receiving palbociclib 100 mg (one with stable disease lasting >=24 weeks; patient with rectal cancer) and in one of six patients receiving palbociclib 125 mg (stable disease lasted >=24 weeks; patient with esophageal cancer; Table 7).	('patient', 'Species', '9606', (105, 112))	('rectal cancer', 'Phenotype', 'HP:0100743', (211, 224))	('patients', 'Species', '9606', (105, 113))	('patient', 'Species', '9606', (198, 205))	('stable disease', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('esophageal cancer', 'Disease', (330, 347))	('patient', 'Species', '9606', (244, 251))	('esophageal cancer', 'Disease', 'MESH:D004938', (330, 347))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('palbociclib 100 mg', 'Var', (134, 152))	('patients', 'Species', '9606', (244, 252))	('patient', 'Species', '9606', (317, 324))	('rectal cancer', 'Disease', 'MESH:D012004', (211, 224))	('palbociclib', 'Chemical', 'MESH:C500026', (134, 145))	('rectal cancer', 'Disease', (211, 224))	('palbociclib', 'Chemical', 'MESH:C500026', (263, 274))
77881	25536077	However, CD90+ fibroblast cells were clustered around CD24+ malignant ducts, suggesting that CD90 may be involved in the tumor-stroma interactions and promote pancreatic cancer development.	('tumor-stroma', 'Disease', 'MESH:D009369', (121, 133))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (159, 176))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CD24', 'Gene', '100133941', (54, 58))	('CD24', 'Gene', (54, 58))	('pancreatic cancer', 'Disease', (159, 176))	('involved', 'Reg', (105, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('promote', 'PosReg', (151, 158))	('tumor-stroma', 'Disease', (121, 133))	('CD90', 'Var', (93, 97))
77882	25536077	Furthermore, CD90 mostly overlapped with alpha-smooth muscle actin (alphaSMA, a marker of activated pancreatic stellate cells (PSCs)) in PDAC stroma, which demonstrated that CD90+ stromal cells consist largely of activated PSCs.	('CD90+', 'Var', (174, 179))	('pancreatic stellate', 'Disease', 'MESH:D010195', (100, 119))	('pancreatic stellate', 'Disease', (100, 119))	('PDAC', 'Phenotype', 'HP:0006725', (137, 141))	('PDAC', 'Chemical', '-', (137, 141))
77893	25536077	It was predominantly co-localized with CD31, a vascular endothelial cell marker, which indicated that CD90+ glioma CSCs may reside within the endothelial niche for their self-renewal.	('CD90+', 'Var', (102, 107))	('glioma CSCs', 'Disease', 'MESH:D005910', (108, 119))	('CD31', 'Gene', (39, 43))	('CD31', 'Gene', '5175', (39, 43))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('glioma CSCs', 'Disease', (108, 119))
77898	25536077	Double immunofluorescence staining of CD90 and CD24 showed that the abundant CD90+ fibroblasts were clustered around CD24+ malignant ducts, suggesting that CD90 may be involved in the tumor-stroma interactions and promote pancreatic cancer development.	('CD24', 'Gene', (117, 121))	('CD90', 'Var', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('promote', 'PosReg', (214, 221))	('tumor-stroma', 'Disease', 'MESH:D009369', (184, 196))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('CD24', 'Gene', '100133941', (47, 51))	('CD24', 'Gene', (47, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (222, 239))	('involved', 'Reg', (168, 176))	('pancreatic cancer', 'Disease', (222, 239))	('CD24', 'Gene', '100133941', (117, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (222, 239))	('tumor-stroma', 'Disease', (184, 196))
77944	25536077	Abundant CD90+ fibroblasts were present in all stages, which were found around/related to malignant ducts, as well as blood vessels and pancreatic lobules.	('pancreatic lobules', 'Disease', 'MESH:D000069337', (136, 154))	('CD90+', 'Var', (9, 14))	('pancreatic lobules', 'Disease', (136, 154))
77968	25536077	These results suggest that CD90 may serve as a promising marker for pancreatic adenocarcinoma and CD90+ cells might be associated with distant metastasis.	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (68, 93))	('distant metastasis', 'CPA', (135, 153))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (68, 93))	('CD90', 'MPA', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('CD90+ cells', 'Var', (98, 109))	('pancreatic adenocarcinoma', 'Disease', (68, 93))	('associated', 'Reg', (119, 129))
77982	25536077	7A), suggesting that CD90+ PSCs may play an important role in tumor-stroma interactions in PDAC and modulation of fibroblast proliferation.	('PDAC', 'Chemical', '-', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CD90+ PSCs', 'Var', (21, 31))	('PDAC', 'Disease', (91, 95))	('PDAC', 'Phenotype', 'HP:0006725', (91, 95))	('tumor-stroma', 'Disease', (62, 74))	('fibroblast proliferation', 'CPA', (114, 138))	('tumor-stroma', 'Disease', 'MESH:D009369', (62, 74))
77987	25536077	Our study revealed the colocalization of staining for collagen, CD90, and alphaSMA, which indicates that CD90+ PSCs may play an important role in the desmoplastic reaction in PDAC.	('PDAC', 'Chemical', '-', (175, 179))	('desmoplastic reaction', 'Disease', 'MESH:D004342', (150, 171))	('desmoplastic reaction', 'Disease', (150, 171))	('play', 'Reg', (120, 124))	('PDAC', 'Disease', (175, 179))	('PDAC', 'Phenotype', 'HP:0006725', (175, 179))	('CD90+ PSCs', 'Var', (105, 115))
78010	25536077	CD90+ CSCs not only displayed tumorigenic capacity to initiate tumor and self-renewal, but also conferred an enhanced metastatic potential.	('tumor', 'Disease', (63, 68))	('metastatic potential', 'CPA', (118, 138))	('CD90+ CSCs', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('enhanced', 'PosReg', (109, 117))	('tumor', 'Disease', (30, 35))
78018	25536077	Abundant CD90+ fibroblasts were present in all stages, which were found closely localized to malignant ducts, as well as blood vessels and pancreatic lobules.	('CD90+', 'Var', (9, 14))	('pancreatic lobules', 'Disease', (139, 157))	('pancreatic lobules', 'Disease', 'MESH:D000069337', (139, 157))
78026	25536077	has reported that CD90+ cells in esophageal cancer possessed enhanced ability to both invade and migrate.	('enhanced', 'PosReg', (61, 69))	('CD90+', 'Var', (18, 23))	('migrate', 'CPA', (97, 104))	('esophageal cancer', 'Disease', (33, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
78027	25536077	The presence of CD90+ cells has been associated with a high incidence of distant organ metastasis in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (101, 125))	('CD90+ cells', 'Var', (16, 27))	('hepatocellular carcinoma', 'Disease', (101, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (101, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('associated', 'Reg', (37, 47))	('distant organ metastasis', 'CPA', (73, 97))
78033	25536077	However, CD90+ cells were found clustered around CD24+ malignant ducts, which further suggests that CD90 may be involved in the tumor-stroma interactions and play a role in cancer-associated fibroblasts to promote pancreatic tumorigenesis and development.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumor', 'Disease', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CD24', 'Gene', '100133941', (49, 53))	('CD90', 'Var', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('involved', 'Reg', (112, 120))	('promote', 'PosReg', (206, 213))	('pancreatic', 'Disease', 'MESH:D010195', (214, 224))	('cancer', 'Disease', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CD24', 'Gene', (49, 53))	('tumor', 'Disease', (128, 133))	('tumor-stroma', 'Disease', (128, 140))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor-stroma', 'Disease', 'MESH:D009369', (128, 140))	('development', 'CPA', (243, 254))	('pancreatic', 'Disease', (214, 224))
78039	25536077	The CD90+ stromal cells were clustered around malignant pancreatic ductal cells, indicating that CD90 may be involved in the tumor-stroma interaction and establish a favorable environment that promotes tumor progression.	('CD90', 'Var', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor-stroma', 'Disease', 'MESH:D009369', (125, 137))	('tumor', 'Disease', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('pancreatic duct', 'Disease', (56, 71))	('pancreatic duct', 'Disease', 'MESH:D021441', (56, 71))	('tumor', 'Disease', (125, 130))	('promotes', 'PosReg', (193, 201))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor-stroma', 'Disease', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
78040	25536077	To isolate CD90+ stromal cells from PDAC by flow cytometry or immunostaining-directed laser capture microdissection (iLCM) could facilitate better understanding of the mechanisms by which CD90+ fibrotic stroma promotes tumor growth in pancreatic adenocarcinoma.	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (235, 260))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('PDAC', 'Phenotype', 'HP:0006725', (36, 40))	('CD90+', 'Var', (188, 193))	('tumor', 'Disease', (219, 224))	('promotes', 'PosReg', (210, 218))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (235, 260))	('PDAC', 'Chemical', '-', (36, 40))	('pancreatic adenocarcinoma', 'Disease', (235, 260))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
78041	24909518	MiningABs: mining associated biomarkers across multi-connected gene expression datasets Human disease often arises as a consequence of alterations in a set of associated genes rather than alterations to a set of unassociated individual genes.	('rat', 'Species', '10116', (176, 179))	('rat', 'Species', '10116', (139, 142))	('rat', 'Species', '10116', (192, 195))	('alterations', 'Var', (135, 146))	('Human disease', 'Disease', (88, 101))	('Human', 'Species', '9606', (88, 93))
78048	24909518	Synthetic lethality, where cell death is observed when two genes are mutated but not when only one of the pair is mutated, is a classic example of genetic interaction.	('mutated', 'Var', (69, 76))	('Synthetic lethality', 'CPA', (0, 19))	('death', 'Disease', 'MESH:D003643', (32, 37))	('death', 'Disease', (32, 37))
78049	24909518	showed that two associated SNPs in the non-coding region of CFH (complement factor H) were linked to age-related macular degeneration.	('complement factor H', 'Gene', '3075', (65, 84))	('CFH', 'Gene', (60, 63))	('complement factor H', 'Gene', (65, 84))	('age-related macular degeneration', 'Disease', (101, 133))	('linked to', 'Reg', (91, 100))	('SNPs', 'Var', (27, 31))	('CFH', 'Gene', '3075', (60, 63))	('rat', 'Species', '10116', (127, 130))	('macular degeneration', 'Phenotype', 'HP:0000608', (113, 133))
78058	24909518	integrated one-sided permutation t-test p-values for each gene that is present in all collected prostate cancer gene expression profiles.	('p-values', 'Var', (40, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('rat', 'Species', '10116', (5, 8))	('prostate cancer', 'Disease', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
78092	24909518	Assuming EI = {PF 1 -P 1 -G 1 , PF 3 -P 2 -G 3 }, a c-LM will be introduced to the algorithm c-LM identification (Figure 2).	('PF 1', 'Gene', '57649', (15, 19))	('PF 3 -P 2 -G 3 }', 'Var', (32, 48))	('PF 1', 'Gene', (15, 19))	('PF 3 -P', 'Chemical', '-', (32, 39))
78093	24909518	The examining identifiers in sk-LMs for DS 1 , DS 2  and DS 3  will be {PF 1 -P 1 -G 1 , PF 1 -P 3 -G 3 }, {PF 2 -P 1 -G 1 , PF 2 -P 2 -G 2 } and {PF 3 -P 1 -G 2 , PF 3 -P 2 -G 3 } respectively.	('PF 2 -P 2 -G 2 }', 'Var', (125, 141))	('DS 1', 'Gene', (40, 44))	('PF 2 -P', 'Chemical', '-', (108, 115))	('PF 1', 'Gene', '57649', (72, 76))	('PF 3 -P', 'Chemical', '-', (164, 171))	('PF 2 -P', 'Chemical', '-', (125, 132))	('PF 1', 'Gene', (89, 93))	('DS 1', 'Gene', '3396', (40, 44))	('PF 3 -P', 'Chemical', '-', (147, 154))	('{PF 2 -P 1 -G 1', 'Var', (107, 122))	('PF 1', 'Gene', '57649', (89, 93))	('PF 1', 'Gene', (72, 76))
78129	24909518	reported that both CAP2 and HSP70 (heat shock protein 70) were molecular markers for early HCC detection, CDKN2A has been shown as a diagnostic and prognostic molecular marker through its epigenetic alteration in HCC, and ECM1 was identified as a prognostic factor associated with metastatic potential of HCC.	('HSP70', 'Gene', (28, 33))	('HCC', 'Gene', (213, 216))	('HCC', 'Gene', '619501', (305, 308))	('HCC', 'Gene', '619501', (91, 94))	('epigenetic alteration', 'Var', (188, 209))	('heat shock protein 70', 'Gene', (35, 56))	('ECM1', 'Gene', (222, 226))	('HCC', 'Gene', '619501', (213, 216))	('CDKN2A', 'Gene', (106, 112))	('shock', 'Phenotype', 'HP:0031273', (40, 45))	('HSP70', 'Gene', '3308', (28, 33))	('ECM1', 'Gene', '1893', (222, 226))	('CDKN2A', 'Gene', '1029', (106, 112))	('metastatic potential', 'CPA', (281, 301))	('heat shock protein 70', 'Gene', '3308', (35, 56))	('rat', 'Species', '10116', (203, 206))	('HCC', 'Gene', (305, 308))	('HCC', 'Gene', (91, 94))
78176	24805924	In a previous study performed with125 siRNAs, we further illustrated that the cleavage of double-stranded RNAs occurred mainly at two sites, 5'-C/A-3' (5'-U/G-3' on complementary strand) and 5'-U/A-3' dinucleotide sites.	('RNAs', 'Protein', (106, 110))	('cleavage', 'MPA', (78, 86))	('dinucleotide', 'Chemical', 'MESH:D015226', (201, 213))	('double-stranded', 'Var', (90, 105))	('C/A-3', 'Mutation', 'c.-3C>A', (144, 149))
78239	24805924	The extinction coefficient was also measured at 260 nm, resulting in 140860 L/(mol*cm) for the FAM-labeled RNA oligonucleotide and 156900 L/(mol*cm) for the TAMRA-labeled RNA oligonucleotide.	('oligonucleotide', 'Chemical', 'MESH:D009841', (175, 190))	('156900 L/', 'Var', (131, 140))	('oligonucleotide', 'Chemical', 'MESH:D009841', (111, 126))	('TAMRA', 'Chemical', 'MESH:C005358', (157, 162))	('140860 L/', 'Var', (69, 78))
78282	24281163	N-nitroso compounds have been demonstrated to be carcinogenic for esophageal cancer in animal studies, but evidence of their importance in the etiology of SCC from epidemiologic studies is conflicting.	('N-nitroso', 'Chemical', '-', (0, 9))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('N-nitroso', 'Var', (0, 9))	('esophageal cancer', 'Disease', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
78288	24281163	A more recent study, which included 226 patients post cardiomyotomy and partial fundoplication with 18.3 years average follow-up, found an increased risk of SCC only in men with a standardized mortality ratio of 11.01.	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('SCC only', 'Disease', (157, 165))	('cardiomyotomy', 'Disease', 'None', (54, 67))	('partial', 'Var', (72, 79))	('cardiomyotomy', 'Disease', (54, 67))
78295	24281163	Acetaldehyde has been demonstrated to be carcinogenic and therefore genetic variations resulting in functional differences in ADH and ALDH activity which lead to increased levels of acetaldehyde in drinkers may be important.	('increased', 'PosReg', (162, 171))	('increased levels of acetaldehyde', 'Phenotype', 'HP:0003533', (162, 194))	('ALDH', 'Gene', (134, 138))	('variations', 'Var', (76, 86))	('activity', 'MPA', (139, 147))	('ADH', 'Gene', (126, 129))	('levels of acetaldehyde', 'MPA', (172, 194))	('Acetaldehyde', 'Chemical', 'MESH:D000079', (0, 12))
78298	24281163	A comprehensive Japanese two-step genome wide association study including 1070 SCC cases and 2836 controls identified significant associations of SCC with single nucleotide polymorphisms (SNP) in ADH1B and ALDH2 with odds rations of 1.85 (95% CI 1.03-3.34) and 1.66 (1.11-2.50) respectively.	('single nucleotide polymorphisms', 'Var', (155, 186))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('ADH1B', 'Gene', (196, 201))	('associations', 'Interaction', (130, 142))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('ADH1B', 'Gene', '125', (196, 201))	('ALDH2', 'Gene', (206, 211))	('SCC', 'Disease', (146, 149))
78299	24281163	Polymorphic variation in the DNA repair capacity genes XPD and MGMT as well as ALD2 have been associated with increased esophageal SCC susceptibility in a Chinese population study.	('MGMT', 'Gene', '4255', (63, 67))	('MGMT', 'Gene', (63, 67))	('increased', 'PosReg', (110, 119))	('XPD', 'Gene', (55, 58))	('Polymorphic variation', 'Var', (0, 21))	('XPD', 'Gene', '2068', (55, 58))	('ALD2', 'Gene', (79, 83))	('associated', 'Reg', (94, 104))	('esophageal SCC', 'Disease', (120, 134))	('SCC', 'Phenotype', 'HP:0002860', (131, 134))
78302	24281163	However, a recent meta-analysis investigating GSTM1 and CYP1A1 polymorphisms found that CYP1A1 exon 7 polymorphism was associated with increased risk in Asians only but that GSTM1 polymorphism was not associated with SCC risk.	('polymorphism', 'Var', (102, 114))	('CYP1A1', 'Gene', (56, 62))	('CYP1A1', 'Gene', '1543', (56, 62))	('SCC', 'Phenotype', 'HP:0002860', (217, 220))	('CYP1A1', 'Gene', (88, 94))	('Asians only', 'Disease', (153, 164))	('CYP1A1', 'Gene', '1543', (88, 94))
78313	24281163	The host inflammatory response modulated by pro-inflammatory polymorphisms in IL-1beta and TNFalpha are two factors that have been found to distinguish between subjects who will develop the hypochlorhydric atrophic phenotype in response to H pylori and those who manage to limit the infection to a smaller area and offer better protection of their corpus function.	('polymorphisms', 'Var', (61, 74))	('IL-1beta', 'Gene', (78, 86))	('hypochlorhydric atrophic', 'Disease', (190, 214))	('H pylori', 'Species', '210', (240, 248))	('hypochlorhydric atrophic', 'Disease', 'MESH:D020966', (190, 214))	('TNFalpha', 'Gene', (91, 99))	('develop', 'PosReg', (178, 185))
78414	22740464	Identifying cancer biomarkers by mass spectrometry-based glycomics Correlations between aberrant glycosylation and cancer have been established for decades.	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (88, 110))	('aberrant', 'Var', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
78421	22740464	Moreover, aberrant glycosylation has been implicated in many mammalian diseases, such as hereditary disorders, immune deficiencies, cardiovascular disease, and cancer These associations between disease development/progression and alterations in glycosylation have prompted a plethora of research activities directed toward the possible utilization of these changes to provide reliable diagnostic information.	('immune deficiencies', 'Phenotype', 'HP:0002721', (111, 130))	('hereditary disorders', 'Disease', (89, 109))	('glycosylation', 'MPA', (19, 32))	('aberrant', 'Var', (10, 18))	('implicated', 'Reg', (42, 52))	('cancer', 'Disease', (160, 166))	('mammalian', 'Species', '9606', (61, 70))	('hereditary disorders', 'Disease', 'MESH:D030342', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('man', 'Species', '9606', (56, 59))	('immune deficiencies', 'Disease', (111, 130))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (10, 32))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (132, 154))	('cardiovascular disease', 'Disease', 'MESH:D002318', (132, 154))	('alterations', 'Var', (230, 241))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('immune deficiencies', 'Disease', 'MESH:D007153', (111, 130))	('cardiovascular disease', 'Disease', (132, 154))	('associations', 'Interaction', (173, 185))	('plethora', 'Phenotype', 'HP:0001050', (275, 283))	('men', 'Species', '9606', (209, 212))
78434	22740464	Moreover, the sensitive detection of released glycans is often enhanced through labeling with a fluorophore or methylation prior to analysis employing several methods, including HPLC, CE, MS, and LC-MS.	('enhanced', 'PosReg', (63, 71))	('glycans', 'Chemical', 'MESH:D011134', (46, 53))	('sensitive detection', 'MPA', (14, 33))	('methylation', 'Var', (111, 122))
78446	22740464	The authors attributed such difference in glycan profiles to the fact that the BT 474 is a ductal carcinoma cell line and is more precancerous than the other three.	('ductal carcinoma', 'Disease', (91, 107))	('glycan', 'Chemical', 'MESH:D011134', (42, 48))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (91, 107))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cancer', 'Disease', (133, 139))	('BT 474', 'Var', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('ductal carcinoma', 'Disease', 'MESH:D044584', (91, 107))
78450	22740464	This study demonstrated a direct correlation between alteration in O-glycosylation and breast cancer invasiveness.	('alteration', 'Var', (53, 63))	('breast cancer invasiveness', 'Disease', (87, 113))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer invasiveness', 'Disease', 'MESH:D001943', (87, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('O-glycosylation', 'Protein', (67, 82))
78454	22740464	This study also reported the glycomic profile of blood serum collected from four patients previously tested for CA27-29 and four disease-free subjects (Supporting Information Table S1).	('CA27-29', 'Var', (112, 119))	('glycomic profile', 'MPA', (29, 45))	('patients', 'Species', '9606', (81, 89))	('tested', 'Reg', (101, 107))
78462	22740464	The chemistry used allows the selective amidation of only alpha2,6-linked sialic acids, thus permethylation would convert the two hydrogen atoms of the amide nitrogen with two methyl groups.	('two hydrogen atoms of', 'MPA', (126, 147))	('amide', 'Chemical', 'MESH:D000577', (152, 157))	('convert', 'Reg', (114, 121))	('alpha2,6-linked sialic acids', 'Chemical', '-', (58, 86))	('hydrogen', 'Chemical', 'MESH:D006859', (130, 138))	('permethylation', 'Var', (93, 107))	('nitrogen', 'Chemical', 'MESH:D009584', (158, 166))
78493	22740464	The levels of all of these individual glycans and total sLex, except A2F1G1 alone, were significantly higher in breast cancer patients with CTCs >5/7.5 mL relative to patients with CTCs <5/7.5 mL.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('glycans', 'Chemical', 'MESH:D011134', (38, 45))	('levels', 'MPA', (4, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('patients', 'Species', '9606', (167, 175))	('higher', 'PosReg', (102, 108))	('patients', 'Species', '9606', (126, 134))	('sLex', 'MPA', (56, 60))	('>5/7.5', 'Var', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
78494	22740464	Glycans containing one sLex epitope and more antennae were more prevalent in breast cancer patients with CTCs >= 5/7.5 mL (A4F1G1 > A3F1G1 > A2F1G1).	('breast cancer', 'Disease', (77, 90))	('patients', 'Species', '9606', (91, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('antennae', 'MPA', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('A4F1G1 > A3F1G1 > A2F1G1', 'Var', (123, 147))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('Glycans', 'Chemical', 'MESH:D011134', (0, 7))
78501	22740464	Breast cancer development and progression can be monitored through glycomic profiling of native, labeled, or permethylated O- and N-glycans.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('O- and N-glycans', 'Chemical', '-', (123, 139))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('permethylated', 'Var', (109, 122))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Breast cancer', 'Disease', (0, 13))	('men', 'Species', '9606', (21, 24))
78511	22740464	However, the presence of four molecular ions at m/z values of 1836, 2082, 2286, and 2327 with monosaccharide compositions correspond to Hex3-4HexNAc4-6DeoxyHex was significantly higher in differentiated cells (Supporting Information Table S1).	('monosaccharide', 'Chemical', 'MESH:D009005', (94, 108))	('higher', 'PosReg', (178, 184))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('differentiated cells', 'CPA', (188, 208))	('Hex3-4HexNAc4-6DeoxyHex', 'Var', (136, 159))
78523	22740464	The decrease in the relative intensities of the m/z values of 2244 (fucosylated biantennary), 2040 (fucosylated biantennary with only one terminal galactose), and 2227 (monosialylated fucosylated biantennary with only one terminal galactose) predicted EAC with 94% sensitivity and better than 60% specificity as determined by receiver operating characteristic (ROC) analysis (Supporting Information Table S1).	('galactose', 'Chemical', 'MESH:D005690', (231, 240))	('2227', 'Var', (163, 167))	('EAC', 'Disease', (252, 255))	('decrease', 'NegReg', (4, 12))	('galactose', 'Chemical', 'MESH:D005690', (147, 156))
78536	22740464	A combination of three selected N-glycans (disialylated triantennary, monosialylated triantennary with terminal galactose, and trisialylated tetraantennary) was sufficient to classify HCC with 90% sensitivity and 89% specificity in an independent validation set of patients with chronic liver disease.	('chronic liver disease', 'Disease', (279, 300))	('HCC', 'Gene', '619501', (184, 187))	('chronic liver disease', 'Disease', 'MESH:D058625', (279, 300))	('galactose', 'Chemical', 'MESH:D005690', (112, 121))	('HCC', 'Phenotype', 'HP:0001402', (184, 187))	('liver disease', 'Phenotype', 'HP:0001392', (287, 300))	('monosialylated triantennary', 'Var', (70, 97))	('patients', 'Species', '9606', (265, 273))	('N-glycans', 'Chemical', '-', (32, 41))	('HCC', 'Gene', (184, 187))	('trisialylated', 'Var', (127, 140))
78547	22740464	Similar analyses of other glycans (and a series of controls) lead us to conclude that the behavior associated with the [NeuNAc1Hex5HexNac4 +3Na]3+ ion arises because of the existence of multiple isomers.	('[NeuNAc1Hex5HexNac4 +3Na]', 'Var', (119, 144))	('behavior', 'MPA', (90, 98))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('glycans', 'Chemical', 'MESH:D011134', (26, 33))	('N', 'Chemical', 'MESH:D009584', (141, 142))
78571	22740464	Glycans isolated from apolipoprotein B-100 (517 kDa) consisted of small, specific O-glycans, while the glycans associated with fibronectin (250 kDa) and immunoglobulin A1 (163 kDa) consisted of both Oand N-glycans that were sufficiently different than the glycans obtained from the corresponding protein band present in the normal serum samples.	('apolipoprotein B-100', 'Gene', (22, 42))	('glycans', 'Chemical', 'MESH:D011134', (103, 110))	('O-glycans', 'Chemical', '-', (82, 91))	('apolipoprotein B-100', 'Gene', '338', (22, 42))	('fibronectin', 'Gene', '2335', (127, 138))	('glycans', 'Chemical', 'MESH:D011134', (256, 263))	('250', 'Var', (140, 143))	('glycans', 'Chemical', 'MESH:D011134', (84, 91))	('N-glycans', 'Chemical', '-', (204, 213))	('Glycans', 'Chemical', 'MESH:D011134', (0, 7))	('glycans', 'Chemical', 'MESH:D011134', (206, 213))	('fibronectin', 'Gene', (127, 138))
78669	32793450	Several retrospective studies demonstrated the dosimetric superiority of PBT to 3D-CRT and IMRT, demonstrating actual reductions in cardiopulmonary toxicity with PBT.	('PBT', 'Var', (162, 165))	('actual reductions in cardiopulmonary toxicity', 'Disease', (111, 156))	('actual reductions in cardiopulmonary toxicity', 'Disease', 'MESH:D007674', (111, 156))
78672	32793450	However, these local procedures alone are not considered sufficient for SEC in terms of oncologic safety in cases of extensive T1a, positive (close) margin, T1b, or lymphatic invasion.	('lymphatic invasion', 'CPA', (165, 183))	('T1a', 'Gene', (127, 130))	('T1a', 'Gene', '10630', (127, 130))	('T1b', 'Var', (157, 160))
78689	32793450	EFRT did not increase the risk of grade >=2 acute esophagitis compared with IFRT (28% after EFRT versus 63% after IFRT, p=0.092).	('EFRT', 'Chemical', '-', (92, 96))	('esophagitis', 'Disease', 'MESH:D004938', (50, 61))	('esophagitis', 'Phenotype', 'HP:0100633', (50, 61))	('EFRT', 'Chemical', '-', (0, 4))	('esophagitis', 'Disease', (50, 61))	('EFRT', 'Var', (92, 96))
78700	32793450	After adjusting for confounding factors, pulmonary and GI complications were significantly more common in patients treated with 3D-CRT than in those treated with IMRT (odds ratio [OR], 2.018; 95% confidence interval [CI], 1.104-3.688; OR, 1.704; 95% CI, 1.03-2.82, respectively) or PBT (OR, 3.154; 95% CI, 1.365-7.289; OR, 1.55; 95% CI, 0.78-3.08, respectively).	('common', 'Reg', (96, 102))	('more', 'PosReg', (91, 95))	('3D-CRT', 'Var', (128, 134))	('patients', 'Species', '9606', (106, 114))	('GI complications', 'CPA', (55, 71))
78706	32793450	3E, PBT can effectively reduce the lung dose (V20-lung: 3D-CRT versus IMRT versus PBT, 25.9% versus 18.0% versus 9.2%), heart dose (mean heart dose, MHD: 3D-CRT versus IMRT versus PBT, 35.8 Gy versus 29.3 Gy versus 18.6 Gy), as well as the integral dose (data not shown) compared to 3D-CRT and IMRT for LA-EC.	('integral dose', 'MPA', (240, 253))	('MHD', 'Disease', 'None', (149, 152))	('MHD', 'Disease', (149, 152))	('reduce', 'NegReg', (24, 30))	('heart dose', 'MPA', (120, 130))	('LA-EC', 'Chemical', '-', (303, 308))	('lung dose', 'MPA', (35, 44))	('PBT', 'Var', (4, 7))
78707	32793450	Because lymphocytes are exquisitely radiosensitive at low doses, PBT is more beneficial than 3D-CRT and IMRT in terms of both immunological and cardiopulmonary toxicity.	('cardiopulmonary toxicity', 'Disease', (144, 168))	('PBT', 'Var', (65, 68))	('cardiopulmonary toxicity', 'Disease', 'MESH:D006323', (144, 168))
78709	32793450	PBT patients had grade 4 neutropenia markedly less frequently than IMRT patients (17.6% versus 40.34%, p< 0.0001).	('neutropenia', 'Disease', (25, 36))	('less', 'NegReg', (46, 50))	('neutropenia', 'Disease', 'MESH:D009503', (25, 36))	('neutropenia', 'Phenotype', 'HP:0001875', (25, 36))	('patients', 'Species', '9606', (4, 12))	('PBT', 'Var', (0, 3))	('patients', 'Species', '9606', (72, 80))
78710	32793450	In a multivariate analysis, PBT was found to be an independent predictor of grade 4 lymphopenia (OR, 0.29; 95% CI, 0.16-0.52; p<0.0001).	('PBT', 'Var', (28, 31))	('lymphopenia', 'Disease', (84, 95))	('grade', 'Disease', (76, 81))	('lymphopenia', 'Phenotype', 'HP:0001888', (84, 95))	('lymphopenia', 'Disease', 'MESH:D008231', (84, 95))
78713	32793450	In particular, PBT has the additional advantage of causing less severe lymphopenia compared to X-ray RT, which is promising for the treatment of LA-EC.	('lymphopenia', 'Disease', (71, 82))	('PBT', 'Var', (15, 18))	('LA-EC', 'Chemical', '-', (145, 150))	('lymphopenia', 'Phenotype', 'HP:0001888', (71, 82))	('lymphopenia', 'Disease', 'MESH:D008231', (71, 82))	('LA-EC', 'Disease', (145, 150))
78750	31737655	On the contrary, it is well established that the most frequent alterations in both ESCC and EAC are the mutations in the tumor suppressor gene TP53 (tumor protein p53) that is present in about 70-80% of EC cases.	('TP53', 'Gene', (143, 147))	('mutations', 'Var', (104, 113))	('ESCC', 'Disease', 'MESH:C562729', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('TP53', 'Gene', '7157', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('p53', 'Gene', (163, 166))	('p53', 'Gene', '7157', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (121, 126))	('EAC', 'Disease', (92, 95))	('tumor', 'Disease', (149, 154))	('EAC', 'Disease', 'MESH:D004941', (92, 95))	('ESCC', 'Disease', (83, 87))	('EC', 'Disease', 'MESH:D004938', (203, 205))	('alterations', 'Reg', (63, 74))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
78787	31737655	In this sense, some molecular alterations frequently found in GC occur almost exclusively in one of the subtypes: for instance, amplification of EGFR, ERBB-2, and MET and TP53 mutations occur predominantly in the intestinal subtype, whereas CDH1 and RHOA mutations are mainly detected in the diffuse subtype.	('TP53', 'Gene', (171, 175))	('mutations', 'Var', (176, 185))	('GC', 'Phenotype', 'HP:0012126', (62, 64))	('CDH1', 'Gene', (241, 245))	('RHOA', 'Gene', '387', (250, 254))	('EGFR', 'Gene', '1956', (145, 149))	('CDH1', 'Gene', '999', (241, 245))	('ERBB-2', 'Gene', '2064', (151, 157))	('EGFR', 'Gene', (145, 149))	('GC', 'Disease', 'MESH:D013274', (62, 64))	('ERBB-2', 'Gene', (151, 157))	('RHOA', 'Gene', (250, 254))	('amplification', 'MPA', (128, 141))	('TP53', 'Gene', '7157', (171, 175))
78788	31737655	On the other hand, GC evolution has been classically associated with a multistep sequence of histopathological alterations, which include the development of gastritis, atrophic gastritis, and intraepithelial neoplasia.	('evolution', 'Var', (22, 31))	('gastritis', 'Phenotype', 'HP:0005263', (157, 166))	('men', 'Species', '9606', (149, 152))	('gastritis', 'Disease', (177, 186))	('atrophic gastritis', 'Disease', (168, 186))	('gastritis', 'Disease', (157, 166))	('neoplasia', 'Phenotype', 'HP:0002664', (208, 217))	('intraepithelial neoplasia', 'Disease', (192, 217))	('GC', 'Disease', 'MESH:D013274', (19, 21))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (192, 217))	('gastritis', 'Disease', 'MESH:D005756', (177, 186))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (168, 186))	('GC', 'Phenotype', 'HP:0012126', (19, 21))	('gastritis', 'Phenotype', 'HP:0005263', (177, 186))	('associated with', 'Reg', (53, 68))	('intraepithelial neoplasia', 'Disease', 'MESH:D018290', (192, 217))	('atrophic gastritis', 'Disease', 'MESH:D005757', (168, 186))	('gastritis', 'Disease', 'MESH:D005756', (157, 166))
78791	31737655	As a matter of fact, Let7 microRNA expression deregulation has been related with the development of several cancer types, including GC.	('Let7', 'Gene', (21, 25))	('GC', 'Disease', 'MESH:D013274', (132, 134))	('related', 'Reg', (68, 75))	('deregulation', 'Var', (46, 58))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('GC', 'Phenotype', 'HP:0012126', (132, 134))	('men', 'Species', '9606', (92, 95))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
78798	31737655	In addition, the relationship between HMGA2 and nitrosamine compounds might be even deeper, once HMGA2 was demonstrated to be a key player in DNA damage repair induced by N-methyl-N-nitrosourea (MNU).	('MNU', 'Chemical', 'MESH:D008770', (195, 198))	('N-methyl-N-nitrosourea', 'Var', (171, 193))	('HMGA2', 'Gene', '8091', (38, 43))	('nitrosamine', 'Chemical', 'MESH:D009602', (48, 59))	('HMGA2', 'Gene', '8091', (97, 102))	('HMGA2', 'Gene', (38, 43))	('N-methyl-N-nitrosourea', 'Chemical', 'MESH:D008770', (171, 193))	('HMGA2', 'Gene', (97, 102))
78800	31737655	However, HMGA2 overexpression could also be figured as a potential prognostic biomarker for GC progression, since the deregulation of its expression has been associated with several clinical pathological parameters which include vasculogenic mimicry during GC progression and disease recurrence.	('HMGA2', 'Gene', (9, 14))	('associated', 'Reg', (158, 168))	('GC', 'Phenotype', 'HP:0012126', (257, 259))	('deregulation', 'Var', (118, 130))	('GC', 'Disease', 'MESH:D013274', (92, 94))	('expression', 'MPA', (138, 148))	('HMGA2', 'Gene', '8091', (9, 14))	('GC', 'Disease', 'MESH:D013274', (257, 259))	('GC', 'Phenotype', 'HP:0012126', (92, 94))	('vasculogenic', 'Disease', (229, 241))
78801	31737655	In this sense, a recent meta-analysis reported a significant association between increased levels of HMGA2 and later tumor stage, lymph node metastasis, vascular invasion, and diminished overall survival of gastric cancer patients, thus pointing out its potential role as a prognostic biomarker for gastric tumors.	('gastric cancer', 'Disease', (207, 221))	('patients', 'Species', '9606', (222, 230))	('tumor', 'Disease', (307, 312))	('gastric tumors', 'Disease', (299, 313))	('diminished', 'NegReg', (176, 186))	('HMGA2', 'Gene', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('gastric cancer', 'Disease', 'MESH:D013274', (207, 221))	('overall survival', 'CPA', (187, 203))	('tumors', 'Phenotype', 'HP:0002664', (307, 313))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('diminished overall survival of gastric cancer', 'Phenotype', 'HP:0006753', (176, 221))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('vascular invasion', 'CPA', (153, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (207, 221))	('gastric tumors', 'Disease', 'MESH:D013274', (299, 313))	('HMGA2', 'Gene', '8091', (101, 106))	('increased', 'PosReg', (81, 90))	('gastric tumors', 'Phenotype', 'HP:0006753', (299, 313))	('tumor', 'Disease', (117, 122))	('lymph node metastasis', 'CPA', (130, 151))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('levels', 'Var', (91, 97))
78809	31737655	Therefore, the chromosomal instability (CIN) group is the most representative one and responds for nearly 85% of all CRC cases, being particularly characterized by the presence of mutations in the tumor suppressors TP53 and APC.	('mutations', 'Var', (180, 189))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('presence', 'Reg', (168, 176))	('APC', 'Disease', 'MESH:D011125', (224, 227))	('TP53', 'Gene', '7157', (215, 219))	('CRC', 'Disease', 'MESH:D015179', (117, 120))	('CIN', 'Phenotype', 'HP:0040012', (40, 43))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('APC', 'Disease', (224, 227))	('TP53', 'Gene', (215, 219))	('tumor', 'Disease', (197, 202))	('chromosomal instability', 'Phenotype', 'HP:0040012', (15, 38))	('CRC', 'Disease', (117, 120))
78816	31737655	In addition, it was observed that aberrant expression of HMGA2 could also be efficiently detected in the blood of CRC patients, compared to healthy individuals.	('HMGA2', 'Gene', '8091', (57, 62))	('aberrant expression', 'Var', (34, 53))	('HMGA2', 'Gene', (57, 62))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('CRC', 'Disease', 'MESH:D015179', (114, 117))	('patients', 'Species', '9606', (118, 126))	('CRC', 'Disease', (114, 117))	('detected', 'Reg', (89, 97))
78821	31737655	Therefore, as well demonstrated for HMGA1, it seems that the aberrant expression of HMGA2 might be involved in the early steps of CRC development.	('aberrant', 'Var', (61, 69))	('men', 'Species', '9606', (141, 144))	('CRC', 'Disease', 'MESH:D015179', (130, 133))	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('HMGA2', 'Gene', (84, 89))	('involved', 'Reg', (99, 107))	('CRC', 'Disease', (130, 133))	('HMGA2', 'Gene', '8091', (84, 89))
78827	31737655	Therefore, it is known that HMGA1 expression impairs adipocyte differentiation, while HMGA2 expression induces adipocyte differentiation, being these effects due to a down- or upregulation exerted by HMGA1/HMGA2 on key genes involved in adipogenesis.	('down-', 'NegReg', (167, 172))	('upregulation', 'PosReg', (176, 188))	('adipocyte', 'MPA', (111, 120))	('expression', 'Var', (34, 44))	('HMGA2', 'Gene', '8091', (206, 211))	('HMGA1', 'Gene', (28, 33))	('impairs', 'NegReg', (45, 52))	('adipocyte differentiation', 'CPA', (53, 78))	('HMGA2', 'Gene', '8091', (86, 91))	('HMGA2', 'Gene', (206, 211))	('HMGA2', 'Gene', (86, 91))
78960	29788321	In patients who received transhiatal esophagectomy, several abnormal swallowing biomechanics were reported: vocal fold immobility (25.0%-33.0%), delayed onset of swallowing, reduced hyolaryngeal elevation during swallowing, and reduced maximum anterior-posterior diameter of the UES during swallowing.	('transhiatal', 'Var', (25, 36))	('hyolaryngeal elevation', 'MPA', (182, 204))	('vocal fold', 'Disease', (108, 118))	('abnormal swallowing', 'Phenotype', 'HP:0002015', (60, 79))	('reduced', 'NegReg', (228, 235))	('patients', 'Species', '9606', (3, 11))	('reduced', 'NegReg', (174, 181))	('delayed onset of swallowing', 'Phenotype', 'HP:0002015', (145, 172))
78986	29788321	The studies reviewed found a wide range of vocal fold immobility rates between 25.0% and 33.0% for patients who underwent transhiatal esophagectomy, and between 12.7% and 76.0% for patients who underwent transthoracic esophagectomy.	('patients', 'Species', '9606', (99, 107))	('transhiatal', 'Var', (122, 133))	('patients', 'Species', '9606', (181, 189))	('vocal fold immobility', 'CPA', (43, 64))
79007	28900507	Moreover, excellent outcomes for biochemical relapse-free survival were obtained from carbon ion RT in high-risk CaP compared with the photon or proton radiation.	('biochemical relapse-free survival', 'CPA', (33, 66))	('carbon ion', 'Var', (86, 96))	('carbon', 'Chemical', 'MESH:D002244', (86, 92))
79009	28900507	However, it was found that the high-dose RT (74-80 Gy) is associated with an increased risk of late grade 2 or higher gastrointestinal toxicity compared with lower doses of RT (64-70.2 Gy).	('gastrointestinal toxicity', 'Disease', (118, 143))	('late grade 2', 'MPA', (95, 107))	('74-80 Gy', 'Var', (45, 53))	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (118, 143))
79013	28900507	Radioresistance may arise from many biological processes including mutations of oncogenes and/or tumor suppressors, deregulated signalling pathways, abnormal DDR, as well as disordered cell death and cell cycle checkpoint.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('DDR', 'Chemical', '-', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('arise', 'Reg', (20, 25))	('disordered cell death', 'Disease', 'MESH:D003643', (174, 195))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', (97, 102))	('abnormal', 'Var', (149, 157))	('disordered cell death', 'Disease', (174, 195))	('deregulated', 'Reg', (116, 127))	('Radioresistance', 'Disease', (0, 15))	('DDR', 'MPA', (158, 161))	('signalling pathways', 'Pathway', (128, 147))
79022	28900507	As such, dysfunction of miRNAs is known to disrupt the expression of mRNAs and proteins, and has been found to be involved in various human cancers, including CaP.	('proteins', 'Protein', (79, 87))	('CaP', 'Disease', (159, 162))	('human', 'Species', '9606', (134, 139))	('expression', 'MPA', (55, 65))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('miR', 'Gene', '220972', (24, 27))	('cancers', 'Disease', (140, 147))	('involved', 'Reg', (114, 122))	('miR', 'Gene', (24, 27))	('dysfunction', 'Var', (9, 20))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('disrupt', 'NegReg', (43, 50))
79023	28900507	It was found that about 26% (12 out of 47) long-range epigenetic silencing contained miRNA genes in 4 CaP cell lines (LNCaP, DU145, PC3 and MDA-2A).	('PC3', 'Gene', (132, 135))	('miR', 'Gene', '220972', (85, 88))	('LNCaP', 'CellLine', 'CVCL:0395', (118, 123))	('miR', 'Gene', (85, 88))	('epigenetic', 'Var', (54, 64))	('MDA-2A', 'CellLine', 'CVCL:0062', (140, 146))	('PC3', 'Gene', '3853', (132, 135))	('DU145', 'CellLine', 'CVCL:0105', (125, 130))
79035	28900507	Introduction of ectopic miR-145 in 22Rv1 CaP cells generated an inhibitory effect on the AR at both transcript and protein levels as well as its activity and downstream targets PSA, hence reduce the transformation to the deadly CRPC.	('inhibitory', 'NegReg', (64, 74))	('transformation', 'MPA', (199, 213))	('activity', 'MPA', (145, 153))	('AR', 'Gene', '367', (89, 91))	('reduce', 'NegReg', (188, 194))	('22Rv1 CaP', 'CellLine', 'CVCL:1045', (35, 44))	('miR-145', 'Gene', '406937', (24, 31))	('miR-145', 'Gene', (24, 31))	('ectopic', 'Var', (16, 23))
79072	28900507	In CaP, it was found that siRNA-mediated knockdown of SGPP1 ugregulated phospho-Akt levels in PC-3 CaP cells and conferred increased radiation resistance in PC-3 and DU145 CaP cells, phenocopying that seen in miR-95-overexpressing PC-3 and DU145 CaP cell lines.	('PC-3', 'Gene', (231, 235))	('Akt', 'Gene', (80, 83))	('radiation', 'MPA', (133, 142))	('DU145 CaP', 'CellLine', 'CVCL:0105', (240, 249))	('Akt', 'Gene', '207', (80, 83))	('PC-3', 'Gene', (157, 161))	('PC-3 CaP', 'CellLine', 'CVCL:5573', (94, 102))	('PC-3', 'Gene', '3853', (231, 235))	('increased', 'PosReg', (123, 132))	('PC-3', 'Gene', (94, 98))	('DU145 CaP', 'CellLine', 'CVCL:0105', (166, 175))	('SGPP1', 'Gene', (54, 59))	('miR-95', 'Gene', (209, 215))	('conferred', 'Reg', (113, 122))	('miR-95', 'Gene', '407052', (209, 215))	('knockdown', 'Var', (41, 50))	('PC-3', 'Gene', '3853', (157, 161))	('ugregulated', 'PosReg', (60, 71))	('PC-3', 'Gene', '3853', (94, 98))
79091	28900507	At the level of transducers, ATM and ATR (ATM-Rad3-related) are proximal kinases in the central of the entire DDR and can be used to detect various forms of damaged DNA and trigger the downstream DDR cascades.	('DDR', 'Chemical', '-', (196, 199))	('ATR', 'Gene', '545', (37, 40))	('ATR', 'Gene', (37, 40))	('ATM', 'Gene', '472', (42, 45))	('ATM', 'Gene', (29, 32))	('DDR cascades', 'Pathway', (196, 208))	('ATM-Rad3-related', 'Gene', (42, 58))	('DDR', 'Chemical', '-', (110, 113))	('ATM', 'Gene', '472', (29, 32))	('ATM-Rad3-related', 'Gene', '545', (42, 58))	('ATM', 'Gene', (42, 45))	('damaged', 'Var', (157, 164))	('trigger', 'Reg', (173, 180))
79104	28900507	A recent genomic analysis revealed that inactivating mutations in BRCA1 or BRCA2 or other genes involved in the HR pathway of DNA repair collectively occur in as much as 20-25% of advanced CaP, indicating that BRCA1 and BRCA2 play an essential role in DNA damage repair pathways, specifically the HR pathway.	('advanced CaP', 'Disease', (180, 192))	('BRCA1', 'Gene', '672', (66, 71))	('BRCA2', 'Gene', '675', (220, 225))	('BRCA1', 'Gene', '672', (210, 215))	('BRCA1', 'Gene', (66, 71))	('BRCA2', 'Gene', (75, 80))	('BRCA1', 'Gene', (210, 215))	('BRCA2', 'Gene', '675', (75, 80))	('inactivating mutations', 'Var', (40, 62))	('BRCA2', 'Gene', (220, 225))
79105	28900507	A synthetic lethal therapeutic approach using PARP inhibitor has been developed for BRCA mutant- and HR deficient-related cancers including metastatic CRPC and is being investigated in multiple Phase I and Phase II clinical trials (NCT01972217, NCT02861573 and NCT01682772).	('metastatic CRPC', 'Disease', (140, 155))	('BRCA', 'Gene', (84, 88))	('PARP', 'Gene', '142', (46, 50))	('HR deficient-related cancers', 'Disease', 'MESH:D009369', (101, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('mutant-', 'Var', (89, 96))	('PARP', 'Gene', (46, 50))	('HR deficient-related cancers', 'Disease', (101, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
79107	28900507	It was also found that the transcripts of HR factors including BRCA1, BRCA2 and RAD51 can be targeted by miR-1255b, miR-148b* and miR-193b*, and inhibiting these miRNAs increased expression of BRCA1/BRCA2/RAD51, specifically in the G1-phase, which blocked NHEJ impairing DSB repair in MDA-MB-231 breast cancer cell line in vitro .	('miR', 'Gene', '220972', (116, 119))	('miR-193b', 'Gene', '574455', (130, 138))	('BRCA2', 'Gene', (199, 204))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', '220972', (105, 108))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (116, 119))	('RAD51', 'Gene', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('RAD51', 'Gene', '5888', (80, 85))	('BRCA1', 'Gene', '672', (193, 198))	('BRCA2', 'Gene', (70, 75))	('BRCA1', 'Gene', '672', (63, 68))	('miR', 'Gene', (162, 165))	('BRCA1', 'Gene', (193, 198))	('miR', 'Gene', (105, 108))	('BRCA2', 'Gene', '675', (199, 204))	('impairing', 'NegReg', (261, 270))	('BRCA1', 'Gene', (63, 68))	('increased', 'PosReg', (169, 178))	('miR', 'Gene', (130, 133))	('RAD51', 'Gene', (205, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (296, 309))	('miR-148b', 'Gene', '442892', (116, 124))	('RAD51', 'Gene', '5888', (205, 210))	('miR-193b', 'Gene', (130, 138))	('miR-148b', 'Gene', (116, 124))	('expression', 'MPA', (179, 189))	('BRCA2', 'Gene', '675', (70, 75))	('DSB repair', 'CPA', (271, 281))	('inhibiting', 'Var', (145, 155))	('breast cancer', 'Disease', 'MESH:D001943', (296, 309))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (285, 295))	('breast cancer', 'Disease', (296, 309))
79118	28900507	It was reported that miR-29c was found to be frequently down-regulated in 5 esophageal squamous cell carcinoma cell lines (KYSE150, KYSE410, KYSE450, KYSE510 and EC9706) in vitro and 60 advanced human esophageal squamous cell carcinoma tissue samples.	('human', 'Species', '9606', (195, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (201, 235))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (76, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('EC9706', 'Var', (162, 168))	('KYSE450', 'Var', (141, 148))	('down-regulated', 'NegReg', (56, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('miR-29c', 'Gene', (21, 28))	('miR-29c', 'Gene', '407026', (21, 28))	('KYSE150', 'Var', (123, 130))	('EC9706', 'CellLine', 'CVCL:E307', (162, 168))	('esophageal squamous cell carcinoma', 'Disease', (201, 235))	('esophageal squamous cell carcinoma', 'Disease', (76, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (212, 235))	('KYSE410', 'Var', (132, 139))	('KYSE510', 'Var', (150, 157))
79119	28900507	Overexpression of miR-29c suppressed EC9706 and KYSE150 esophageal squamous cell carcinoma cell growth in vitro by inducing cell cycle G1/G0 arrest mainly through modulating Cyclin-E expression.	('miR-29c', 'Gene', (18, 25))	('Cyclin', 'Gene', '5111', (174, 180))	('miR-29c', 'Gene', '407026', (18, 25))	('KYSE150', 'Var', (48, 55))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (56, 90))	('suppressed', 'NegReg', (26, 36))	('cell cycle G1/G0 arrest', 'CPA', (124, 147))	('EC9706', 'Var', (37, 43))	('inducing', 'PosReg', (115, 123))	('Cyclin', 'Gene', (174, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('expression', 'MPA', (183, 193))	('modulating', 'Reg', (163, 173))	('esophageal squamous cell carcinoma', 'Disease', (56, 90))	('EC9706', 'CellLine', 'CVCL:E307', (37, 43))
79131	28900507	While the cell cycle arrest driven by CDC25A is transient, the more long-term arrest effect is achieved by p53.	('cell cycle arrest', 'CPA', (10, 27))	('CDC25A', 'Gene', (38, 44))	('CDC25A', 'Gene', '993', (38, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (10, 27))	('p53', 'Var', (107, 110))
79174	28900507	Inhibition of HIF-1alpha suppressed glycolysis and re-sensitized the cancer cells to radiation, whereas the recovery of HIF-1alpha in RR cells resulted in recovery of radioresistance.	('HIF-1alpha', 'Gene', (14, 24))	('HIF-1alpha', 'Gene', '3091', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('glycolysis', 'MPA', (36, 46))	('suppressed', 'NegReg', (25, 35))	('radioresistance', 'CPA', (167, 182))	('Inhibition', 'Var', (0, 10))	('HIF-1alpha', 'Gene', '3091', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('HIF-1alpha', 'Gene', (120, 130))	('cancer', 'Disease', (69, 75))
79178	28900507	It is also known the down-regulation of miR-210 by antisense lentiviral vectors in hypoxic human hepatocarcinoma led to increased radiosensitivity, both in SMMC-7721, HepG2 and HuH7 cell lines in vitro  and SMMC-7721 mouse model in vivo .	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (120, 146))	('mouse', 'Species', '10090', (217, 222))	('miR-210', 'Gene', (40, 47))	('hypoxic human hepatocarcinoma', 'Disease', 'MESH:D015658', (83, 112))	('hypoxic human hepatocarcinoma', 'Disease', (83, 112))	('miR-210', 'Gene', '406992', (40, 47))	('HepG2', 'CellLine', 'CVCL:0027', (167, 172))	('HuH7', 'CellLine', 'CVCL:0336', (177, 181))	('down-regulation', 'NegReg', (21, 36))	('increased', 'PosReg', (120, 129))	('radiosensitivity', 'CPA', (130, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('antisense', 'Var', (51, 60))
79219	28900507	found that patients diagnosed with high-Gleason score tumors and higher expression levels of miR-221 have an early CRPC compared to patients with lower miR-221 expression levels (10 vs. 46 months, log-rank test P = 0.012) and observed a significantly lower overall survival in patients with higher peripheral whole-blood expression levels of miR-7 (28 vs. 116 months, log-rank test P = 0.001).	('lower', 'NegReg', (251, 256))	('miR-221', 'Gene', (152, 159))	('patients', 'Species', '9606', (277, 285))	('miR-7', 'Gene', '10859', (342, 347))	('miR-221', 'Gene', '407006', (152, 159))	('patients', 'Species', '9606', (132, 140))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('expression', 'MPA', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('miR-221', 'Gene', (93, 100))	('high-Gleason score', 'Var', (35, 53))	('overall survival', 'MPA', (257, 273))	('patients', 'Species', '9606', (11, 19))	('miR-221', 'Gene', '407006', (93, 100))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('miR-7', 'Gene', (342, 347))	('higher', 'PosReg', (65, 71))	('expression', 'MPA', (321, 331))
79230	28900507	These modern treatment approaches include the use of small molecule inhibitors, miRNA vectors, miRNA mimics, miRNA sponges, the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 technology, antisense oligonucleotides and miR-mask oligonucleotides.	('miR', 'Gene', '220972', (80, 83))	('miR', 'Gene', (80, 83))	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (109, 112))	('miR', 'Gene', (95, 98))	('miR', 'Gene', '220972', (109, 112))	('antisense oligonucleotides', 'Var', (211, 237))	('miR', 'Gene', '220972', (242, 245))	('miR', 'Gene', (242, 245))
79239	28900507	Similarly, intratumoral injection of miRNA mimics may prove beneficial in controlling tumor growth, for example, reconstitution of miR-15a and miR-16-1 expression results in growth arrest, apoptosis and marked regression of LNCaP CaP orthotopic xenografts in vivo .	('miR', 'Gene', '220972', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('apoptosis', 'CPA', (189, 198))	('miR', 'Gene', '220972', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR', 'Gene', (37, 40))	('miR-15a', 'Gene', (131, 138))	('growth arrest', 'Phenotype', 'HP:0001510', (174, 187))	('miR', 'Gene', (131, 134))	('regression', 'CPA', (210, 220))	('miR', 'Gene', '220972', (143, 146))	('growth arrest', 'Disease', 'MESH:D006323', (174, 187))	('LNCaP CaP orthotopic xenografts', 'CPA', (224, 255))	('reconstitution', 'Var', (113, 127))	('tumor', 'Disease', (16, 21))	('miR-16-1', 'Gene', '406950', (143, 151))	('LNCaP CaP', 'CellLine', 'CVCL:0395', (224, 233))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('miR-15a', 'Gene', '406948', (131, 138))	('tumor', 'Disease', (86, 91))	('miR', 'Gene', (143, 146))	('growth arrest', 'Disease', (174, 187))	('miR-16-1', 'Gene', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
79248	28900507	The expression of miRNAs is regulated by radiation, and in turn, altered miRNAs play an important role in changing radiation sensitivity via multiple cellular signalling pathways as well as a diverse range of biological processes.	('altered', 'Var', (65, 72))	('changing', 'Reg', (106, 114))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))	('radiation sensitivity', 'CPA', (115, 136))
79259	26632887	According to Kaplan-Meier analyses, the number of metastatic LNs was a good predictor for the prognosis of patients with esophageal squamous carcinoma and the dissection of >=29 LNs during thoracic surgery significantly improved patient survival (P = 0.011).	('improved', 'PosReg', (220, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (132, 150))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (121, 150))	('esophageal squamous carcinoma', 'Disease', (121, 150))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (121, 150))	('dissection', 'Var', (159, 169))	('patient survival', 'CPA', (229, 245))	('patient', 'Species', '9606', (107, 114))	('patients', 'Species', '9606', (107, 115))	('patient', 'Species', '9606', (229, 236))
79300	26632887	Rizk et al analyzed 4627 patients from the Worldwide Esophageal Cancer Collaboration database, and suggested that the extent of lymphadenectomy was positively associated with survival among all patients with pN0 and pN(+) cancers, and recommended more LN dissections for patients with higher T status.	('patients', 'Species', '9606', (194, 202))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('associated with', 'Reg', (159, 174))	('pN0', 'Var', (208, 211))	('cancers', 'Disease', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (271, 279))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (53, 70))	('survival', 'MPA', (175, 183))	('Esophageal Cancer', 'Disease', (53, 70))
79333	25526438	Sustained virologic response is the required end point of treatment and its rate is considerably high in patients infected with HCV genotypes 2 and 3 (~80%), however, sustained virologic response rates are lower in those patients infected with genotypes 1 and 4 (~50%).	('HCV', 'Gene', (128, 131))	('men', 'Species', '9606', (63, 66))	('Sustained', 'MPA', (0, 9))	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (221, 229))	('HCV', 'Species', '11103', (128, 131))	('genotypes', 'Var', (132, 141))
79373	25526438	Moreover, it was recently reported that the presence of certain single nucleotide polymorphisms of the estrogen receptor alpha can enable females to attain either spontenous clearance or or persistent infection of HCV.	('single nucleotide polymorphisms', 'Var', (64, 95))	('estrogen', 'Protein', (103, 111))	('enable', 'PosReg', (131, 137))	('spontenous clearance', 'CPA', (163, 183))	('presence', 'Var', (44, 52))	('infection', 'Disease', (201, 210))	('infection', 'Disease', 'MESH:D007239', (201, 210))	('HCV', 'Species', '11103', (214, 217))	('persistent infection', 'Phenotype', 'HP:0031035', (190, 210))
79383	25526438	From the virological factors are the NS5A mutations specifically a region named interferon ribavirin resistance determining region (IRRDR) in HCV-4; mutations in IRRDR>4 were correlated with a positive treatment response.	('mutations', 'Var', (149, 158))	('HCV', 'Species', '11103', (142, 145))	('men', 'Species', '9606', (207, 210))	('IRRDR>', 'Gene', (162, 168))	('NS5A', 'Gene', (37, 41))	('ribavirin', 'Chemical', 'MESH:D012254', (91, 100))	('positive', 'PosReg', (193, 201))	('mutations', 'Var', (42, 51))
79384	25526438	Host factors as the single nucleotide polymorphisms near the IL28 region were correlated with the treatment response.	('IL28', 'Gene', '282617', (61, 65))	('treatment response', 'CPA', (98, 116))	('men', 'Species', '9606', (103, 106))	('IL28', 'Gene', (61, 65))	('correlated', 'Reg', (78, 88))	('single nucleotide polymorphisms', 'Var', (20, 51))
79406	25526438	Since, HCV-4 shows a higher resistance against Interferon therapy and the progression to cirrhosis appear to be faster in HCV-4 especially when co-infected with schistosomiasis and given the long incubation period of HCV and the high infection rate in Egypt, so peak morbidity and mortality is yet to come.	('HCV', 'Species', '11103', (122, 125))	('infection', 'Disease', (234, 243))	('infection', 'Disease', 'MESH:D007239', (234, 243))	('HCV', 'Species', '11103', (217, 220))	('cirrhosis', 'Phenotype', 'HP:0001394', (89, 98))	('HCV-4', 'Var', (122, 127))	('schistosomiasis', 'Disease', (161, 176))	('cirrhosis', 'Disease', 'MESH:D005355', (89, 98))	('higher', 'PosReg', (21, 27))	('resistance', 'MPA', (28, 38))	('faster', 'PosReg', (112, 118))	('schistosomiasis', 'Disease', 'MESH:D012552', (161, 176))	('cirrhosis', 'Disease', (89, 98))	('HCV', 'Species', '11103', (7, 10))
79419	24824854	We demonstrate a high level of uptake of the fluorescent nanoparticles by myeloid-derived suppressor cells (MDSCs) in the esophagus and spleen of L2Cre;p120ctnflox/flox mice.	('p120ctn', 'Gene', '12388', (152, 159))	('mice', 'Species', '10090', (169, 173))	('uptake', 'MPA', (31, 37))	('p120ctn', 'Gene', (152, 159))	('rat', 'Species', '10116', (10, 13))	('L2Cre', 'Var', (146, 151))
79428	24824854	MDSCs have also been shown to enhance inflammation-associated carcinogenesis.	('MDSCs', 'Var', (0, 5))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))	('inflammation', 'Disease', 'MESH:D007249', (38, 50))	('enhance', 'PosReg', (30, 37))	('carcinogenesis', 'Disease', (62, 76))	('inflammation', 'Disease', (38, 50))
79432	24824854	Disruption of this complex is a hallmark feature of many epithelially derived cancers.	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Disruption', 'Var', (0, 10))
79434	24824854	There is a marked increase in splenic, circulating, and esophageal MDSCs in the L2Cre;p120ctnflox/flox mouse, making it well suited for the study of imaging this component of the immune infiltrate given our previous findings that the recruitment of MDSCs occurs early and is highly predictive of later cancer development.	('increase', 'PosReg', (18, 26))	('p120ctn', 'Gene', '12388', (86, 93))	('L2Cre', 'Var', (80, 85))	('splenic', 'MPA', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('mouse', 'Species', '10090', (103, 108))	('p120ctn', 'Gene', (86, 93))	('rat', 'Species', '10116', (192, 195))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('cancer', 'Disease', (302, 308))
79472	24824854	The following antibodies were used for immunophenotyping: CD45 (clone 30-F11), CD19 (clone 6D5), CD3E (clone 145-2C11), CD49b (clone DX5), CD11c (clone N418), F4/80 (clone CI:A3-1), Gr-1 (clone RB6-8C5), and CD11b (clone M1/70), all from BioLegend (San Diego, CA).	('DX5', 'Gene', (133, 136))	('M1/70', 'Gene', (221, 226))	('CD3E', 'Gene', '12501', (97, 101))	('CD19', 'Gene', '12478', (79, 83))	('CD49b', 'Gene', (120, 125))	('F4/80', 'Gene', '13733', (159, 164))	('F4/80', 'Gene', (159, 164))	('CD45', 'Gene', (58, 62))	('CD3E', 'Gene', (97, 101))	('CD11b', 'Var', (208, 213))	('CD49b', 'Gene', '16398', (120, 125))	('Gr-1', 'Gene', '546644', (182, 186))	('M1/70', 'Gene', '22238', (221, 226))	('CD19', 'Gene', (79, 83))	('CD11c', 'Var', (139, 144))	('Gr-1', 'Gene', (182, 186))	('CD45', 'Gene', '19264', (58, 62))	('DX5', 'Gene', '16398', (133, 136))
79502	24824854	To determine the utility of CyAL5.5-conjugated nanoparticles for imaging Gr-1+ CD11b+ MDSCs, we performed flow cytometric immunophenotyping of splenocytes from 9-month-old L2-Cre;p120flox/flox mice following nanoparticle injection.	('p120', 'Gene', '12388', (179, 183))	('mice', 'Species', '10090', (193, 197))	('Gr-1', 'Gene', '546644', (73, 77))	('p120', 'Gene', (179, 183))	('L2-Cre', 'Var', (172, 178))	('Gr-1', 'Gene', (73, 77))
79503	24824854	Spleens were isolated at 180 minutes following nanoparticle injection, and leukocytes were sorted for fluorochrome (CyAL5.5) expression and stained for CD11b+ and Gr-1+.	('Gr-1', 'Gene', '546644', (163, 167))	('Gr-1', 'Gene', (163, 167))	('CD11b+', 'Var', (152, 158))
79511	24824854	In line with the flow cytometry findings, multichannel upper gastrointestinal endoscopy showed significantly higher NIR signal in the esophagus of 9-month-old L2-Cre;p120flox/flox mice treated with PBS (Figure 4, A-C, PBS group) compared to dexamethasone-treated animals (Figure 4, E-G, dexamethasone group).	('p120', 'Gene', (166, 170))	('dexamethasone', 'Chemical', 'MESH:D003907', (287, 300))	('higher', 'PosReg', (109, 115))	('PBS', 'Chemical', '-', (198, 201))	('NIR signal', 'MPA', (116, 126))	('PBS', 'Var', (198, 201))	('PBS', 'Chemical', '-', (218, 221))	('dexamethasone', 'Chemical', 'MESH:D003907', (241, 254))	('mice', 'Species', '10090', (180, 184))	('p120', 'Gene', '12388', (166, 170))	('L2-Cre', 'Var', (159, 165))
79578	32041673	Epigenetic silencing of IGFBPL1 promotes esophageal cancer growth by activating PI3K-AKT signaling There are seven insulin-like growth factor binding proteins (IGFBPs) that bind insulin-like growth factors (IGFs).	('insulin', 'Gene', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('insulin', 'Gene', '3630', (115, 122))	('insulin', 'Gene', (178, 185))	('PI3K-AKT signaling', 'MPA', (80, 98))	('activating', 'PosReg', (69, 79))	('insulin', 'Gene', '3630', (178, 185))	('Epigenetic silencing', 'Var', (0, 20))	('IGFBPL1', 'Gene', (24, 31))	('IGFBPL1', 'Gene', '347252', (24, 31))	('promotes', 'PosReg', (32, 40))	('IGFBPs', 'Gene', '3484;3485;3486;3487;3488;3489;3490', (160, 166))	('IGFBPs', 'Gene', (160, 166))	('esophageal cancer', 'Disease', (41, 58))
79585	32041673	Restoration of IGFBPL1 expression was found in KYSE150 and KYSE410 cells and the expression of IGFBPL1 was increased in Bic1, KYSE140, KYSE450, KYSE520, and COLO680N cells, after 5-AZA-2'-deoxycytidine treatment.	('IGFBPL1', 'Gene', (95, 102))	('KYSE140', 'Var', (126, 133))	('IGFBPL1', 'Gene', (15, 22))	('KYSE410', 'CellLine', 'CVCL:1352', (59, 66))	('increased', 'PosReg', (107, 116))	("5-AZA-2'-deoxycytidine", 'Chemical', 'MESH:C000589260', (179, 201))	('expression', 'MPA', (81, 91))	('expression', 'MPA', (23, 33))
79586	32041673	IGFBPL1 was methylated in 47.3% (53/114) of esophageal dysplasia and 49.1% (246/501) of human primary esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (102, 136))	('ESCC', 'Disease', 'MESH:C562729', (138, 142))	('IGFBPL1', 'Gene', (0, 7))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (44, 64))	('human', 'Species', '9606', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('ESCC', 'Disease', (138, 142))	('methylated', 'Var', (12, 22))	('esophageal dysplasia', 'Disease', (44, 64))
79587	32041673	Methylation of IGFBPL1 was significantly associated with TNM stage (p = 0.012), and tumor size (p = 0.009).	('TNM', 'Gene', '10178', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('associated', 'Reg', (41, 51))	('IGFBPL1', 'Gene', (15, 22))	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TNM', 'Gene', (57, 60))	('tumor', 'Disease', (84, 89))
79589	32041673	Further study found that IGFBPL1 is involved in PI3K-AKT signaling and IGFBPL1 suppressed human ESCC xenografts growth in mice.	('ESCC', 'Disease', 'MESH:C562729', (96, 100))	('mice', 'Species', '10090', (122, 126))	('suppressed', 'NegReg', (79, 89))	('AKT', 'Gene', '207', (53, 56))	('human', 'Species', '9606', (90, 95))	('ESCC', 'Disease', (96, 100))	('IGFBPL1', 'Var', (71, 78))	('AKT', 'Gene', (53, 56))
79599	32041673	Interestingly, inactivating mutations of NOTCH1 were identified in 21% of ESCCs but not in EACs.	('ESCC', 'Disease', (74, 78))	('EAC', 'Gene', '1540', (91, 94))	('inactivating mutations', 'Var', (15, 37))	('EAC', 'Gene', (91, 94))	('NOTCH1', 'Gene', '4851', (41, 47))	('NOTCH1', 'Gene', (41, 47))	('ESCC', 'Disease', 'MESH:C562729', (74, 78))
79600	32041673	Notably, NOTCH1 mutations were more frequent in North American ESCCs (11 of 53) compared to ESCCs from China (1 of 48 cases) according to Sanger sequencing validation.	('ESCC', 'Disease', (92, 96))	('ESCC', 'Disease', 'MESH:C562729', (63, 67))	('mutations', 'Var', (16, 25))	('ESCC', 'Disease', (63, 67))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))	('NOTCH1', 'Gene', '4851', (9, 15))	('NOTCH1', 'Gene', (9, 15))
79603	32041673	In addition to NOTCH1 mutations, Hu et al.	('NOTCH1', 'Gene', '4851', (15, 21))	('mutations', 'Var', (22, 31))	('NOTCH1', 'Gene', (15, 21))
79604	32041673	revealed frequent mutations in PIK3CA and PTEN in ESCC.	('PTEN', 'Gene', (42, 46))	('PTEN', 'Gene', '5728', (42, 46))	('PIK3CA', 'Gene', (31, 37))	('ESCC', 'Disease', 'MESH:C562729', (50, 54))	('PIK3CA', 'Gene', '5290', (31, 37))	('ESCC', 'Disease', (50, 54))	('mutations', 'Var', (18, 27))
79607	32041673	Aberrant DNA methylation has been reported in genes involved in cell cycle, DNA damage repair, Wnt, TGF-beta, and NF-kappaB pathways.	('TGF-beta', 'Gene', (100, 108))	('TGF-beta', 'Gene', '7039', (100, 108))	('reported', 'Reg', (34, 42))	('Aberrant', 'Var', (0, 8))
79616	32041673	Eight esophageal cancer cell lines were employed in this study, including Bic1, KYSE140, KYSE410, KYSE450, KYSE150, KYSE520, KYSE510, and COLO680N cells.	('esophageal cancer', 'Disease', (6, 23))	('KYSE520', 'Var', (116, 123))	('KYSE410', 'Var', (89, 96))	('KYSE150', 'Var', (107, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (6, 23))	('KYSE410', 'CellLine', 'CVCL:1352', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('KYSE510', 'CellLine', 'CVCL:1354', (125, 132))
79636	32041673	Before and after the knockdown of IGFBPL1, KYSE510 cells were seeded in 6-well plates at a density of 400 cells per well.	('KYSE510', 'CellLine', 'CVCL:1354', (43, 50))	('IGFBPL1', 'Gene', (34, 41))	('knockdown', 'Var', (21, 30))
79641	32041673	The same method was used to analyze KYSE510 cells before and after IGFBPL1 knockdown.	('knockdown', 'Var', (75, 84))	('IGFBPL1', 'Gene', (67, 74))	('KYSE510', 'CellLine', 'CVCL:1354', (36, 43))
79655	32041673	High-level expression of IGFBPL1 was detected in KYSE510 cells, while the expression of IGFBPL1 was absent in KYSE410 and KYSE150 cells (Fig.	('KYSE410', 'CellLine', 'CVCL:1352', (110, 117))	('expression', 'MPA', (11, 21))	('IGFBPL1', 'Gene', (25, 32))	('KYSE510', 'Var', (49, 56))	('KYSE510', 'CellLine', 'CVCL:1354', (49, 56))
79661	32041673	Taken together, these results suggested that the expression of IGFBPL1 is regulated by promoter region methylation in esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('regulated', 'Reg', (74, 83))	('expression', 'MPA', (49, 59))	('IGFBPL1', 'Gene', (63, 70))	('esophageal cancer', 'Disease', (118, 135))	('methylation', 'Var', (103, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))
79663	32041673	IGFBPL1 methylation was detected by MSP in 114 cases of dysplasia, 501 cases of primary ESCC, and 5 cases of normal esophageal mucosa.	('ESCC', 'Disease', (88, 92))	('detected', 'Reg', (24, 32))	('IGFBPL1', 'Gene', (0, 7))	('ESCC', 'Disease', 'MESH:C562729', (88, 92))	('dysplasia', 'Disease', (56, 65))	('dysplasia', 'Disease', 'MESH:D015792', (56, 65))	('methylation', 'Var', (8, 19))
79664	32041673	IGFBPL1 was methylated in 47.3% (53/114) of esophageal dysplasia and 49.1% (246/501) of human primary ESCC, while no methylation was found in normal esophageal mucosa (Fig.	('ESCC', 'Disease', (102, 106))	('ESCC', 'Disease', 'MESH:C562729', (102, 106))	('IGFBPL1', 'Gene', (0, 7))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (44, 64))	('human', 'Species', '9606', (88, 93))	('methylated', 'Var', (12, 22))	('esophageal dysplasia', 'Disease', (44, 64))
79665	32041673	Methylation of IGFBPL1 was significantly associated with TNM stage (p = 0.012) and tumor size (p = 0.009) (Table 1), whereas it was not associated with age, gender, lymph node metastasis, tumor cell differentiation, cancer embolus, distal metastasis, smoking, alcohol consumption, or family history (all p > 0.05).	('tumor', 'Disease', (188, 193))	('TNM', 'Gene', '10178', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('associated', 'Reg', (41, 51))	('IGFBPL1', 'Gene', (15, 22))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('TNM', 'Gene', (57, 60))	('alcohol', 'Chemical', 'MESH:D000431', (260, 267))	('cancer embolus', 'Disease', (216, 230))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer embolus', 'Disease', 'MESH:D009369', (216, 230))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
79668	32041673	These results further suggested that the expression of IGFBPL1 is regulated by promoter region methylation in human esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('methylation', 'Var', (95, 106))	('expression', 'MPA', (41, 51))	('human', 'Species', '9606', (110, 115))	('IGFBPL1', 'Gene', (55, 62))	('regulated', 'Reg', (66, 75))	('esophageal cancer', 'Disease', (116, 133))
79670	32041673	The OD values were 0.9607 +- 0.0603 vs. 0.6034 +- 0.0299 in KYSE150 cells (t test, p < 0.01) and 0.8575 +- 0.0820 vs. 0.6167 +- 0.0108 (t test, p < 0.01) in KYSE410 cells before and after the restoration of IGFBPL1 expression (Fig.	('KYSE410', 'CellLine', 'CVCL:1352', (157, 164))	('0.9607 +- 0.0603', 'Var', (19, 35))	('IGFBPL1', 'Gene', (207, 214))	('0.8575 +- 0.0820 vs.', 'Var', (97, 117))	('expression', 'MPA', (215, 225))
79671	32041673	The OD values were 1.3924 +- 0.0304 vs. 1.6345 +- 0.0652 (t test, p < 0.001) in KYSE510 before and after the knockdown of IGFBPL1 (Fig.	('knockdown', 'Var', (109, 118))	('KYSE510', 'CellLine', 'CVCL:1354', (80, 87))	('IGFBPL1', 'Gene', (122, 129))
79674	32041673	The clone numbers were 8 +- 1.3 vs.18 +- 3.0 (t test, p < 0.001) in KYSE510 cells before and after the knockdown of IGFBPL1 (Fig.	('KYSE510', 'CellLine', 'CVCL:1354', (68, 75))	('knockdown', 'Var', (103, 112))	('IGFBPL1', 'Gene', (116, 123))
79677	32041673	The proportion of apoptotic cells increased significantly after re-expression of IGFBPL1 in KYSE150 and KYSE410 cells.	('IGFBPL1', 'Gene', (81, 88))	('re-expression', 'Var', (64, 77))	('KYSE410', 'CellLine', 'CVCL:1352', (104, 111))	('apoptotic cells', 'CPA', (18, 33))	('increased', 'PosReg', (34, 43))
79678	32041673	The percentage of apoptotic cells before and after knockdown of IGFBPL1 in KYSE510 cells was 30.06 +- 0.12% vs. 18.87 +- 0.14% (t test, p < 0.01, Fig.	('IGFBPL1', 'Gene', (64, 71))	('apoptotic cells', 'CPA', (18, 33))	('KYSE510', 'CellLine', 'CVCL:1354', (75, 82))	('knockdown', 'Var', (51, 60))
79681	32041673	Meanwhile, the levels of caspase-3 and Bcl-2 increased and the levels of cleaved-caspase-3 decreased after knockdown of the IGFBPL1 in KYSE510 cells (Fig.	('knockdown', 'Var', (107, 116))	('caspase-3', 'Gene', '836', (81, 90))	('increased', 'PosReg', (45, 54))	('decreased', 'NegReg', (91, 100))	('KYSE510', 'CellLine', 'CVCL:1354', (135, 142))	('caspase-3', 'Gene', '836', (25, 34))	('Bcl-2', 'Gene', '596', (39, 44))	('caspase-3', 'Gene', (81, 90))	('Bcl-2', 'Gene', (39, 44))	('IGFBPL1', 'Gene', (124, 131))	('caspase-3', 'Gene', (25, 34))
79684	32041673	The G0/G1 phase cells increased significantly, whereas the S phase cells decreased significantly after re-expression of IGFBPL1 in KYSE410 cells (Fig.	('decreased', 'NegReg', (73, 82))	('IGFBPL1', 'Gene', (120, 127))	('increased', 'PosReg', (22, 31))	('KYSE410', 'CellLine', 'CVCL:1352', (131, 138))	('G0/G1 phase cells', 'CPA', (4, 21))	('S phase cells', 'CPA', (59, 72))	('re-expression', 'Var', (103, 116))
79685	32041673	The effect of IGFBPL1 on cell cycle was further validated by knocking down IGFBPL1 in IGFBPL1 highly expressed KYSE510 cells.	('IGFBPL1', 'Gene', (86, 93))	('IGFBPL1', 'Gene', (75, 82))	('KYSE510', 'CellLine', 'CVCL:1354', (111, 118))	('knocking down', 'Var', (61, 74))
79688	32041673	The effect of knocking down IGFBPL1 on cyclinE1, cyclinA2, and cyclinD1 expression was verified in KYSE510 cells as well.	('cyclinD1', 'Gene', (63, 71))	('knocking down', 'Var', (14, 27))	('cyclinD1', 'Gene', '595', (63, 71))	('KYSE510', 'CellLine', 'CVCL:1354', (99, 106))	('cyclinA2', 'Gene', (49, 57))	('IGFBPL1', 'Gene', (28, 35))	('cyclinA2', 'Gene', '890', (49, 57))	('cyclinE1', 'Gene', (39, 47))	('cyclinE1', 'Gene', '898', (39, 47))
79689	32041673	The levels of cyclinE1, cyclinA2, and cyclinD1 increased after knockdown of IGFBPL1 (Fig.	('levels', 'MPA', (4, 10))	('cyclinD1', 'Gene', (38, 46))	('cyclinE1', 'Gene', (14, 22))	('cyclinE1', 'Gene', '898', (14, 22))	('cyclinD1', 'Gene', '595', (38, 46))	('increased', 'PosReg', (47, 56))	('cyclinA2', 'Gene', (24, 32))	('cyclinA2', 'Gene', '890', (24, 32))	('knockdown', 'Var', (63, 72))	('IGFBPL1', 'Gene', (76, 83))
79693	32041673	4a, the levels of PI3K, p-AKT, mTOR, p-mTOR, and MYC were decreased and the levels of AKT were increased after re-expression of IGFBPL1 in KYSE150 and KYSE410 cells, while the levels of PI3K, p-AKT, mTOR, p-mTOR, and MYC were increased and the levels of AKT were reduced after knockdown of IGFBPL1 in KYSE510 cells.	('AKT', 'Gene', '207', (194, 197))	('AKT', 'Gene', (86, 89))	('KYSE510', 'CellLine', 'CVCL:1354', (301, 308))	('AKT', 'Gene', (254, 257))	('mTOR', 'Gene', '2475', (31, 35))	('AKT', 'Gene', '207', (26, 29))	('levels', 'MPA', (8, 14))	('decreased', 'NegReg', (58, 67))	('KYSE410', 'CellLine', 'CVCL:1352', (151, 158))	('MYC', 'Gene', (49, 52))	('mTOR', 'Gene', (207, 211))	('MYC', 'Gene', (217, 220))	('IGFBPL1', 'Gene', (290, 297))	('reduced', 'NegReg', (263, 270))	('AKT', 'Gene', '207', (86, 89))	('AKT', 'Gene', '207', (254, 257))	('mTOR', 'Gene', (199, 203))	('levels', 'MPA', (76, 82))	('levels', 'MPA', (244, 250))	('mTOR', 'Gene', '2475', (207, 211))	('mTOR', 'Gene', (39, 43))	('AKT', 'Gene', (194, 197))	('AKT', 'Gene', (26, 29))	('MYC', 'Gene', '4609', (49, 52))	('MYC', 'Gene', '4609', (217, 220))	('IGFBPL1', 'Gene', (128, 135))	('mTOR', 'Gene', '2475', (199, 203))	('mTOR', 'Gene', (31, 35))	('knockdown', 'Var', (277, 286))	('mTOR', 'Gene', '2475', (39, 43))	('increased', 'PosReg', (95, 104))
79696	32041673	The OD values in KYSE510 cells were 0.658 +- 0.021 in the control group, 0.611 +- 0.016 in control plus NVP-BEZ235 treatment group, 0.993 +- 0.022 in siIGFBPL1 group, and 0.529 +- 0.014 in siIGFBPL1 plus NVP-BEZ235 treatment group.	('0.611', 'Var', (73, 78))	('KYSE510', 'CellLine', 'CVCL:1354', (17, 24))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (104, 114))	('0.993 +- 0.022', 'Var', (132, 146))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (204, 214))
79698	32041673	4b), and the OD value decreased significantly in siIGFBPL1 plus NVP-BEZ235 group compared to siIGFBPL1 group (p < 0.01, Fig.	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (64, 74))	('OD value', 'MPA', (13, 21))	('siIGFBPL1', 'Var', (49, 58))	('decreased', 'NegReg', (22, 31))
79701	32041673	The levels of PI3K, p-AKT, mTOR, p-mTOR, and MYC were decreased after NVP-BEZ235 treatment in KYSE510 cells.	('levels', 'MPA', (4, 10))	('NVP-BEZ235', 'Var', (70, 80))	('mTOR', 'Gene', (35, 39))	('MYC', 'Gene', (45, 48))	('AKT', 'Gene', '207', (22, 25))	('mTOR', 'Gene', '2475', (35, 39))	('KYSE510', 'CellLine', 'CVCL:1354', (94, 101))	('AKT', 'Gene', (22, 25))	('decreased', 'NegReg', (54, 63))	('MYC', 'Gene', '4609', (45, 48))	('PI3K', 'Pathway', (14, 18))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (70, 80))
79702	32041673	The levels of PI3K, p-AKT, mTOR, p-mTOR, and MYC were increased after siIGFBPL1 knockdown KYSE510 cells (Fig.	('knockdown', 'Var', (80, 89))	('levels', 'MPA', (4, 10))	('AKT', 'Gene', '207', (22, 25))	('mTOR', 'Gene', (35, 39))	('MYC', 'Gene', (45, 48))	('siIGFBPL1', 'Gene', (70, 79))	('mTOR', 'Gene', '2475', (35, 39))	('increased', 'PosReg', (54, 63))	('AKT', 'Gene', (22, 25))	('MYC', 'Gene', '4609', (45, 48))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))	('KYSE510', 'CellLine', 'CVCL:1354', (90, 97))
79703	32041673	The levels of PI3K, p-AKT, mTOR, p-mTOR, and MYC were reduced after NVP-BEZ235 treatment in siIGFBPL1 KYSE510 cells (Fig.	('levels', 'MPA', (4, 10))	('AKT', 'Gene', '207', (22, 25))	('mTOR', 'Gene', (35, 39))	('MYC', 'Gene', (45, 48))	('PI3K', 'Var', (14, 18))	('mTOR', 'Gene', '2475', (35, 39))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (68, 78))	('KYSE510', 'CellLine', 'CVCL:1354', (102, 109))	('reduced', 'NegReg', (54, 61))	('AKT', 'Gene', (22, 25))	('MYC', 'Gene', '4609', (45, 48))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))
79726	32041673	To date, no cancers have been attributed to IGFBP mutation.	('IGFBP', 'Gene', (44, 49))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutation', 'Var', (50, 58))
79728	32041673	The IGFBPL1 gene was reported to be frequently methylated in human breast cancer and regulated by promoter region methylation, and methylation of IGFBPL1 was associated with poor prognosis.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('associated', 'Reg', (158, 168))	('IGFBPL1', 'Gene', (4, 11))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('IGFBPL1', 'Gene', (146, 153))	('human', 'Species', '9606', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))	('methylation', 'Var', (131, 142))
79731	32041673	Methylation of IGFBPL1 is associated with tumor size and TNM stage and therefore may serve as an esophageal cancer early detection marker.	('TNM', 'Gene', '10178', (57, 60))	('tumor', 'Disease', (42, 47))	('IGFBPL1', 'Gene', (15, 22))	('Methylation', 'Var', (0, 11))	('esophageal cancer', 'Disease', (97, 114))	('TNM', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('associated', 'Reg', (26, 36))
79736	32041673	Thus, methylation of IGFBPL1 may activate PI3K-AKT signaling in ESCC.	('AKT', 'Gene', (47, 50))	('ESCC', 'Disease', (64, 68))	('IGFBPL1', 'Gene', (21, 28))	('AKT', 'Gene', '207', (47, 50))	('methylation', 'Var', (6, 17))	('ESCC', 'Disease', 'MESH:C562729', (64, 68))	('activate', 'PosReg', (33, 41))
79737	32041673	These results suggest IGFBPL1 methylation may serve as a predictive marker for PI3K-targeted therapy in ESCC.	('ESCC', 'Disease', 'MESH:C562729', (104, 108))	('ESCC', 'Disease', (104, 108))	('IGFBPL1', 'Gene', (22, 29))	('methylation', 'Var', (30, 41))
79739	32041673	Methylation of IGFBPL1 is associated with tumor size and TNM stage.	('TNM', 'Gene', '10178', (57, 60))	('tumor', 'Disease', (42, 47))	('IGFBPL1', 'Gene', (15, 22))	('Methylation', 'Var', (0, 11))	('TNM', 'Gene', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('associated', 'Reg', (26, 36))
79740	32041673	Methylation of IGFBPL1 is a potential esophageal cancer early detection marker and a predictive marker for PI3K-targeted therapy in ESCC.	('esophageal cancer', 'Disease', (38, 55))	('IGFBPL1', 'Gene', (15, 22))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('ESCC', 'Disease', 'MESH:C562729', (132, 136))	('ESCC', 'Disease', (132, 136))
79747	31739546	Deregulation of epigenetic mechanisms, including aberrant DNA methylation and histone modifications, have emerged as critical factors in cancer development and progression.	('DNA', 'Protein', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('aberrant', 'Var', (49, 57))	('histone', 'Protein', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))
79749	31739546	Thus, further insight into hypoxia-induced epigenetic alterations in EC may allow the identification of novel therapeutic targets and predictive biomarkers, impacting on patient survival and quality of life.	('impacting', 'Reg', (157, 166))	('epigenetic alterations', 'Var', (43, 65))	('hypoxia', 'Disease', (27, 34))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('patient', 'Species', '9606', (170, 177))
79766	31739546	Furthermore, epigenetic alterations are a recognized cancer hallmark owing to its role in altered chromatin organization and consequent transcriptional gene deregulation.	('cancer', 'Disease', (53, 59))	('chromatin organization', 'MPA', (98, 120))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('altered', 'Reg', (90, 97))	('epigenetic alterations', 'Var', (13, 35))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
79768	31739546	In radioresistant tumor cells, a phenotypic switch occurs during the course of radiation delivery, associated with both genetic and epigenetic changes.	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('epigenetic', 'Var', (132, 142))
79769	31739546	Thus, the aim of this review is to summarize published evidence on the role of hypoxia-induced epigenetic alterations which might impact on RT resistance in EC.	('impact', 'Reg', (130, 136))	('epigenetic alterations', 'Var', (95, 117))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('RT resistance', 'MPA', (140, 153))	('hypoxia', 'Disease', (79, 86))
79774	31739546	Repair of sublethal DNA damage is more effective in normal than tumor cells, as observed from cell recovery after exposure to ionizing radiation (IR).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('sublethal', 'Var', (10, 19))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
79775	31739546	Radiation randomly interacts with several cellular molecules, with DNA being the main target for the biological effects of radiation, including cell killing, carcinogenesis and mutation.	('mutation', 'Var', (177, 185))	('interacts', 'Reg', (19, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (158, 172))	('cell killing', 'CPA', (144, 156))	('carcinogenesis', 'Disease', (158, 172))
79806	31739546	The most studied histone modifications are arginine's and lysine's methylation, acetylation and phosphorylation.	('arginine', 'Chemical', 'MESH:D001120', (43, 51))	('lysine', 'MPA', (58, 64))	('phosphorylation', 'MPA', (96, 111))	('arginine', 'Var', (43, 51))	('methylation', 'MPA', (67, 78))	('acetylation', 'MPA', (80, 91))	('lysine', 'Chemical', 'MESH:D008239', (58, 64))
79807	31739546	Several epigenetic alterations, including aberrant DNA methylation and histone onco-modifications, found in several cancers and associated with oncogene activation and tumor suppressor gene silencing, have emerged as potential cancer biomarkers.	('aberrant DNA methylation', 'Var', (42, 66))	('histone', 'Protein', (71, 78))	('tumor', 'Disease', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Disease', (227, 233))	('cancers', 'Disease', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
79809	31739546	Remarkably, histone methylation is a frequent event in cancer, and its dynamic transition plays a critical role in transcriptional regulation and subsequently in signaling pathways related with cell cycle, tumor metabolism and overall tumor aggressiveness capacities.	('histone', 'Protein', (12, 19))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (235, 255))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('plays', 'Reg', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('methylation', 'Var', (20, 31))	('tumor metabolism', 'Disease', (206, 222))	('tumor aggressiveness', 'Disease', (235, 255))	('aggressiveness', 'Phenotype', 'HP:0000718', (241, 255))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor metabolism', 'Disease', 'MESH:D008659', (206, 222))	('cancer', 'Disease', (55, 61))
79812	31739546	Briefly, HDAC6 overexpression induced higher proliferation and migration in ESCC cancer cell lines.	('proliferation', 'CPA', (45, 58))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('HDAC6', 'Gene', '10013', (9, 14))	('overexpression', 'Var', (15, 29))	('higher', 'PosReg', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ESCC', 'Disease', (76, 80))	('migration', 'CPA', (63, 72))	('HDAC6', 'Gene', (9, 14))
79820	31739546	Another extensively studied epigenetic alteration occurring in cancer cells is aberrant DNA methylation.	('DNA', 'MPA', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('aberrant', 'Var', (79, 87))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
79823	31739546	Specifically, CDKN2A, MGMT, APC, RUNX3, TIMP-3 and CRBP1 hypermethylation have been frequently reported in EC.	('CRBP1', 'Gene', '5947', (51, 56))	('CDKN2A', 'Gene', '1029', (14, 20))	('TIMP-3', 'Gene', (40, 46))	('TIMP-3', 'Gene', '7078', (40, 46))	('CRBP1', 'Gene', (51, 56))	('MGMT', 'Gene', (22, 26))	('APC', 'Disease', 'MESH:D011125', (28, 31))	('RUNX3', 'Gene', (33, 38))	('MGMT', 'Gene', '4255', (22, 26))	('RUNX3', 'Gene', '864', (33, 38))	('reported', 'Reg', (95, 103))	('hypermethylation', 'Var', (57, 73))	('APC', 'Disease', (28, 31))	('CDKN2A', 'Gene', (14, 20))
79843	31739546	Moreover, the KDM4 subfamily, particularly KDM4C/JMJD2C, which target methylated H3K9 and H3K36 histone marks, contributes to cancer initiation and development, and is associated with hypoxic status in breast cancer, whereas, in renal cell carcinoma cell lines, KDM3A, KDM4B and KDM5B were shown to be regulated by HIF family.	('associated', 'Reg', (168, 178))	('KDM4B', 'Gene', '23030', (269, 274))	('KDM3A', 'Gene', (262, 267))	('H3K36', 'Var', (90, 95))	('KDM5B', 'Gene', '10765', (279, 284))	('JMJD2C', 'Gene', '23081', (49, 55))	('hypoxic status in breast cancer', 'Disease', 'MESH:D001943', (184, 215))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (126, 132))	('methylated', 'Var', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (229, 249))	('KDM3A', 'Gene', '55818', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('KDM4C', 'Gene', '23081', (43, 48))	('KDM4C', 'Gene', (43, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('development', 'CPA', (148, 159))	('contributes', 'Reg', (111, 122))	('KDM4B', 'Gene', (269, 274))	('KDM5B', 'Gene', (279, 284))	('H3K9', 'Protein', (81, 85))	('renal cell carcinoma', 'Disease', (229, 249))	('hypoxic status in breast cancer', 'Disease', (184, 215))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (229, 249))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', (209, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('JMJD2C', 'Gene', (49, 55))
79845	31739546	The involvement of these main JmjC-KDMs highlight the importance of HIF-1alpha-dependent epigenetic regulation in hypoxia, leading to several molecular changes, like cell cycle arrest and DNA repair, which contribute to cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('DNA repair', 'CPA', (188, 198))	('HIF-1alpha', 'Gene', '3091', (68, 78))	('JmjC-KDMs', 'Disease', 'None', (30, 39))	('arrest', 'Disease', 'MESH:D006323', (177, 183))	('cancer', 'Disease', (220, 226))	('arrest', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('leading to', 'Reg', (123, 133))	('epigenetic regulation', 'Var', (89, 110))	('JmjC-KDMs', 'Disease', (30, 39))	('contribute', 'Reg', (206, 216))	('hypoxia', 'Disease', (114, 121))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))	('HIF-1alpha', 'Gene', (68, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (166, 183))
79847	31739546	Considering that both hypoxia and epigenetic alterations are common features in EC, however, its relevance in this particular cancer type is very likely.	('hypoxia', 'Disease', 'MESH:D000860', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hypoxia', 'Disease', (22, 29))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('epigenetic alterations', 'Var', (34, 56))
79853	31739546	Recently, dysregulated epigenetic control through DNA methylation was associated with tumors' radiation resistance.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('epigenetic control', 'MPA', (23, 41))	('dysregulated', 'Var', (10, 22))	('tumors', 'Disease', (86, 92))	('associated', 'Reg', (70, 80))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('DNA', 'Protein', (50, 53))
79858	31739546	RUNX3, a tumor suppressor mediating TGF-beta-dependent apoptosis pathway was reported to be hypermethylated and downregulated in radioresistant EC cells.	('downregulated', 'NegReg', (112, 125))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('radioresistant EC', 'Disease', (129, 146))	('hypermethylated', 'Var', (92, 107))	('TGF-beta', 'Gene', (36, 44))	('tumor', 'Disease', (9, 14))	('TGF-beta', 'Gene', '7039', (36, 44))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
79887	31739546	Overall, according to the premise that epigenetic modulation promotes radiation resistance under hypoxic microenvironment, additional pre-clinical and clinical trials are required to confirm the efficacy and safety of new epigenetic drugs that may increase cancer cells' radiosensitivity, particularly in hypoxic microenvironment.	('radiosensitivity', 'CPA', (271, 287))	('increase', 'PosReg', (248, 256))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('promotes', 'PosReg', (61, 69))	('cancer', 'Disease', (257, 263))	('epigenetic modulation', 'Var', (39, 60))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('epigenetic drugs', 'Var', (222, 238))	('radiation resistance', 'CPA', (70, 90))	("increase cancer cells' radiosensitivity", 'Phenotype', 'HP:0010997', (248, 287))
79897	31815134	Furthermore, RNAi-mediated knockdown of genes in the flavoprotein signature led to decreased proliferation and migration of ESCC cells.	('knockdown', 'Var', (27, 36))	('proliferation', 'CPA', (93, 106))	('ESCC', 'Disease', 'MESH:C562729', (124, 128))	('decreased', 'NegReg', (83, 92))	('flavoprotein', 'Gene', (53, 65))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('ESCC', 'Disease', (124, 128))
79919	31815134	A number of recent studies indicate that abnormal expression of flavoproteins and their interacting proteins lead to a variety of clinical abnormalities, which range from degenerative changes in the skin lesions, to the growth retardation, or nervous system and peripheral neuropathy; it also affects the proliferation and mobility of various cancer cells.	('lead to', 'Reg', (109, 116))	('cancer', 'Disease', (343, 349))	('growth retardation', 'Disease', 'MESH:D006130', (220, 238))	('peripheral neuropathy', 'Disease', (262, 283))	('growth retardation', 'Disease', (220, 238))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (262, 283))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('degenerative changes', 'Phenotype', 'HP:0002180', (171, 191))	('mobility', 'CPA', (323, 331))	('nervous system', 'Disease', (243, 257))	('affects', 'Reg', (293, 300))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (262, 283))	('expression', 'Var', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('skin lesions', 'Disease', 'MESH:D012871', (199, 211))	('proliferation', 'CPA', (305, 318))	('growth retardation', 'Phenotype', 'HP:0001510', (220, 238))	('abnormal expression', 'Var', (41, 60))	('flavoproteins', 'Protein', (64, 77))	('skin lesions', 'Disease', (199, 211))
79933	31815134	In brief, KYSE150 and KYSE510 esophageal carcinoma cells were grown in RPMI 1640 medium (Thermo Fisher Scientific) supplemented with 10% fetal bovine serum (GIBCO), penicillin-G (100 units/mL), and streptomycin (100 mug/mL).	('KYSE510', 'Var', (22, 29))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (30, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (30, 50))	('bovine', 'Species', '9913', (143, 149))	('KYSE510', 'CellLine', 'CVCL:1354', (22, 29))	('penicillin-G', 'Chemical', 'MESH:D010400', (165, 177))	('streptomycin', 'Chemical', 'MESH:D013307', (198, 210))	('esophageal carcinoma', 'Disease', (30, 50))
79964	31815134	Figure 2(a) shows that the relative mRNA expression of the flavoprotein signature in KYSE150 cells and KYSE510 cells in the si-flavoprotein signature group was lower than the si-negative control (NC) group (P < 0.01).	('KYSE510', 'CellLine', 'CVCL:1354', (103, 110))	('mRNA expression', 'MPA', (36, 51))	('si-flavoprotein', 'Var', (124, 139))	('N', 'Chemical', 'MESH:D009584', (196, 197))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('KYSE510', 'Var', (103, 110))	('flavoprotein signature', 'MPA', (59, 81))	('lower', 'NegReg', (160, 165))
79965	31815134	Colony formation assay showed that knockdown of the flavoprotein signature genes significantly inhibited the growth of KYSE150 cells and KYSE510 cells (Figure 2(b)).	('knockdown', 'Var', (35, 44))	('inhibited', 'NegReg', (95, 104))	('KYSE510', 'CellLine', 'CVCL:1354', (137, 144))	('flavoprotein signature genes', 'Gene', (52, 80))	('growth of KYSE150 cells and', 'CPA', (109, 136))
79966	31815134	Compared with the siNC group, ESCC cell growth in the si-flavoprotein signature group was generally suppressed (P < 0.0001, one-way ANOVA).	('N', 'Chemical', 'MESH:D009584', (133, 134))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('ESCC', 'Disease', (30, 34))	('suppressed', 'NegReg', (100, 110))	('si-flavoprotein', 'Var', (54, 69))	('ESCC', 'Disease', 'MESH:C562729', (30, 34))
79968	31815134	As shown in Figures 3 and 4, siRNA-mediated knockdown of CTTN, GGH, GPD2, PYROXD2, SRC, or SYNJ2BP in KYSE150 cells and KYSE510 cells conferred reduced migration, compared with the siNC group (P < 0.01, one-way ANOVA).	('SRC', 'Gene', (83, 86))	('SYNJ2BP', 'Gene', '55333', (91, 98))	('KYSE510', 'CellLine', 'CVCL:1354', (120, 127))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('PYROXD2', 'Gene', '84795', (74, 81))	('CTTN', 'Gene', (57, 61))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('GGH', 'Gene', '8836', (63, 66))	('GPD2', 'Gene', (68, 72))	('knockdown', 'Var', (44, 53))	('reduced', 'NegReg', (144, 151))	('GPD2', 'Gene', '2820', (68, 72))	('GGH', 'Gene', (63, 66))	('SRC', 'Gene', '6714', (83, 86))	('N', 'Chemical', 'MESH:D009584', (183, 184))	('migration', 'CPA', (152, 161))	('SYNJ2BP', 'Gene', (91, 98))	('N', 'Chemical', 'MESH:D009584', (32, 33))	('CTTN', 'Gene', '2017', (57, 61))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('PYROXD2', 'Gene', (74, 81))
79970	31815134	And six genes also play different roles in KYSE150 and KYSE510 cells.	('KYSE150', 'Var', (43, 50))	('KYSE510', 'Var', (55, 62))	('play', 'Reg', (19, 23))	('KYSE510', 'CellLine', 'CVCL:1354', (55, 62))
79971	31815134	After knocking down the PYROXD2 gene in KYSE150 cells, the cell proliferation ability was most significantly reduced (P < 0.0001, one-way ANOVA), while wound healing and transwell assay showed that knockdown of the PYROXD2 gene in KYSE150 cells had the least effect on cell migration compared to other genes (P < 0.01, one-way ANOVA).	('N', 'Chemical', 'MESH:D009584', (139, 140))	('PYROXD2', 'Gene', (24, 31))	('N', 'Chemical', 'MESH:D009584', (328, 329))	('PYROXD2', 'Gene', '84795', (215, 222))	('knockdown', 'Var', (198, 207))	('cell migration', 'CPA', (269, 283))	('cell proliferation ability', 'CPA', (59, 85))	('PYROXD2', 'Gene', '84795', (24, 31))	('PYROXD2', 'Gene', (215, 222))	('reduced', 'NegReg', (109, 116))	('knocking down', 'Var', (6, 19))
79972	31815134	In KYSE510 cells, the significant effect of inhibiting cell proliferation is knocking down the SYNJ2BP gene (P < 0.0001, one-way ANOVA).	('inhibiting', 'NegReg', (44, 54))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('SYNJ2BP', 'Gene', (95, 102))	('cell proliferation', 'CPA', (55, 73))	('SYNJ2BP', 'Gene', '55333', (95, 102))	('KYSE510', 'CellLine', 'CVCL:1354', (3, 10))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('knocking', 'Var', (77, 85))
79973	31815134	In KYSE150 and KYSE510 cells, the effect of GGH on cell proliferation was minimal compared to other genes (P < 0.01, one-way ANOVA).	('minimal', 'NegReg', (74, 81))	('GGH', 'Gene', (44, 47))	('KYSE510', 'CellLine', 'CVCL:1354', (15, 22))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('KYSE510', 'Var', (15, 22))	('cell proliferation', 'CPA', (51, 69))	('GGH', 'Gene', '8836', (44, 47))	('KYSE150', 'Var', (3, 10))
79974	31815134	However, after knockdown of GGH, wound healing and transwell assay showed that the GGH gene has a great influence on the mobility of ESCC cells (P < 0.0001, one-way ANOVA).	('knockdown', 'Var', (15, 24))	('ESCC', 'Disease', (133, 137))	('GGH', 'Gene', '8836', (83, 86))	('ESCC', 'Disease', 'MESH:C562729', (133, 137))	('mobility', 'CPA', (121, 129))	('GGH', 'Gene', '8836', (28, 31))	('GGH', 'Gene', (28, 31))	('influence', 'Reg', (104, 113))	('GGH', 'Gene', (83, 86))	('N', 'Chemical', 'MESH:D009584', (166, 167))
79999	31815134	confirmed the effect of PYROXD2 polymorphisms on trimethylamine metabolism.	('polymorphisms', 'Var', (32, 45))	('PYROXD2', 'Gene', (24, 31))	('effect', 'Reg', (14, 20))	('PYROXD2', 'Gene', '84795', (24, 31))	('trimethylamine metabolism', 'MPA', (49, 74))	('trimethylamine', 'Chemical', 'MESH:C023336', (49, 63))
80011	31815134	Similar to knockdown of CTTN and SRC, ESCC cell growth and motility are significantly reduced following knockdown of GGH, GPD2, PYROXD2, and SYNJ2BP.	('motility', 'CPA', (59, 67))	('reduced', 'NegReg', (86, 93))	('ESCC', 'Disease', 'MESH:C562729', (38, 42))	('CTTN', 'Gene', '2017', (24, 28))	('SYNJ2BP', 'Gene', '55333', (141, 148))	('GPD2', 'Gene', '2820', (122, 126))	('SRC', 'Gene', '6714', (33, 36))	('GGH', 'Gene', '8836', (117, 120))	('SRC', 'Gene', (33, 36))	('PYROXD2', 'Gene', (128, 135))	('ESCC', 'Disease', (38, 42))	('GPD2', 'Gene', (122, 126))	('PYROXD2', 'Gene', '84795', (128, 135))	('SYNJ2BP', 'Gene', (141, 148))	('CTTN', 'Gene', (24, 28))	('GGH', 'Gene', (117, 120))	('knockdown', 'Var', (104, 113))
80012	31815134	Among these genes, GPD2 knockdown has the most significant effect on inhibiting the proliferation and migration of ESCC cells.	('ESCC', 'Disease', (115, 119))	('ESCC', 'Disease', 'MESH:C562729', (115, 119))	('GPD2', 'Gene', (19, 23))	('inhibiting', 'NegReg', (69, 79))	('knockdown', 'Var', (24, 33))	('GPD2', 'Gene', '2820', (19, 23))
80020	31815134	Furthermore, abnormal expression of the flavoprotein signature promotes proliferation and migration of ESCC cells.	('flavoprotein signature', 'Gene', (40, 62))	('ESCC', 'Disease', 'MESH:C562729', (103, 107))	('migration', 'CPA', (90, 99))	('proliferation', 'CPA', (72, 85))	('promotes', 'PosReg', (63, 71))	('ESCC', 'Disease', (103, 107))	('abnormal', 'Var', (13, 21))	('expression', 'MPA', (22, 32))
80039	31248382	Research demonstrated that ZEB-1 promotes the process of EMT through regulation of the relevant protein binding domains, such as the p300-P/CAF binding domain, Smad interaction domain, and C-terminal-binding protein interaction domain.	('C-terminal-binding protein interaction', 'MPA', (189, 227))	('promotes', 'PosReg', (33, 41))	('protein', 'Protein', (96, 103))	('p300-P/CAF', 'Var', (133, 143))	('Smad interaction', 'Protein', (160, 176))	('ZEB-1', 'Gene', (27, 32))	('EMT', 'CPA', (57, 60))	('CAF', 'Chemical', '-', (140, 143))	('ZEB-1', 'Gene', '6935', (27, 32))	('regulation', 'MPA', (69, 79))
80042	31248382	suggested that aberrant expression of ZEB-1in gastric cancer was associated with tumor stage, depth of invasion and poor differentiation.	('aberrant expression', 'Var', (15, 34))	('gastric cancer', 'Disease', (46, 60))	('ZEB-1', 'Gene', (38, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('associated', 'Reg', (65, 75))	('poor differentiation', 'CPA', (116, 136))	('depth of invasion', 'CPA', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ZEB-1', 'Gene', '6935', (38, 43))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', (81, 86))
80064	31248382	The results indicated a negative effect of high ZEB-1 expression on OS (univariable analysis) in patients with colorectal cancer (pooled HR: 1.80; 95% CI: 1.28-2.54) (Fig.	('expression', 'MPA', (54, 64))	('high', 'Var', (43, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('ZEB-1', 'Gene', (48, 53))	('negative', 'NegReg', (24, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('ZEB-1', 'Gene', '6935', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('OS', 'Chemical', '-', (68, 70))	('patients', 'Species', '9606', (97, 105))
80076	31248382	revealed that high expression of ZEB-1 may have an impact on cell-cell interactions resulting in endometrial cancer cell invasion and metastasis.	('cell-cell interactions', 'CPA', (61, 83))	('endometrial cancer', 'Disease', (97, 115))	('metastasis', 'CPA', (134, 144))	('high expression', 'Var', (14, 29))	('endometrial cancer', 'Disease', 'MESH:D016889', (97, 115))	('endometrial cancer', 'Phenotype', 'HP:0012114', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('impact', 'Reg', (51, 57))	('ZEB-1', 'Gene', (33, 38))	('ZEB-1', 'Gene', '6935', (33, 38))
80078	31248382	Knockdown of ZEB-1 may induce cell apoptosis, while high ZEB-1 expression may drastically suppress lung cancer cells, as shown through soft agar colony formation assays.	('ZEB-1', 'Gene', (57, 62))	('lung cancer', 'Disease', (99, 110))	('Knockdown', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ZEB-1', 'Gene', (13, 18))	('suppress', 'NegReg', (90, 98))	('cell apoptosis', 'CPA', (30, 44))	('ZEB-1', 'Gene', '6935', (57, 62))	('expression', 'MPA', (63, 73))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('ZEB-1', 'Gene', '6935', (13, 18))	('high', 'Var', (52, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
80084	31248382	In vitro, high expression of ZEB-1 was associated with poor OS in patients with esophageal squamous cell carcinoma.	('OS', 'Chemical', '-', (60, 62))	('ZEB-1', 'Gene', '6935', (29, 34))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (80, 114))	('poor OS', 'Disease', (55, 62))	('high expression', 'Var', (10, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('associated', 'Reg', (39, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('ZEB-1', 'Gene', (29, 34))	('esophageal squamous cell carcinoma', 'Disease', (80, 114))	('patients', 'Species', '9606', (66, 74))
80086	31248382	identified that high level of ZEB-1 expression was associated with recurrence, lymph node metastasis, worse pathologic grading and low survival rates in oral cavity carcinoma.	('carcinoma', 'Disease', (165, 174))	('ZEB-1', 'Gene', (30, 35))	('recurrence', 'CPA', (67, 77))	('expression', 'MPA', (36, 46))	('ZEB-1', 'Gene', '6935', (30, 35))	('associated', 'Reg', (51, 61))	('high level', 'Var', (16, 26))	('carcinoma', 'Disease', 'MESH:D002277', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('lymph node metastasis', 'CPA', (79, 100))	('low', 'NegReg', (131, 134))
80091	31248382	Regarding the types of tumors, our study indicated that high expression of ZEB-1 was also significantly associated with worse OS in colorectal cancer, esophageal squamous cell carcinoma, pancreatic cancer, gastric cancer and hepatocellular carcinoma.	('ZEB-1', 'Gene', (75, 80))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (151, 185))	('ZEB-1', 'Gene', '6935', (75, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (187, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('associated', 'Reg', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('gastric cancer', 'Disease', (206, 220))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (225, 249))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('pancreatic cancer', 'Disease', 'MESH:D010190', (187, 204))	('OS', 'Chemical', '-', (126, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (23, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('pancreatic cancer', 'Disease', (187, 204))	('esophageal squamous cell carcinoma', 'Disease', (151, 185))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (225, 249))	('colorectal cancer', 'Disease', (132, 149))	('high expression', 'Var', (56, 71))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('hepatocellular carcinoma', 'Disease', (225, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
80168	29091952	Evaluation of miRNA-196a2 and apoptosis-related target genes: ANXA1, DFFA and PDCD4 expression in gastrointestinal cancer patients: A pilot study Previous reports have suggested the significant association of miRNAs aberrant expression with tumor initiation, progression and metastasis in cancer, including gastrointestinal (GI) cancers.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('aberrant', 'Var', (216, 224))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (98, 121))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('gastrointestinal cancer', 'Disease', (98, 121))	('ANXA1', 'Gene', '301', (62, 67))	('miRNAs', 'Gene', (209, 215))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (98, 121))	('DFFA', 'Gene', '1676', (69, 73))	('expression', 'MPA', (225, 235))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('PDCD4', 'Gene', (78, 83))	('metastasis in cancer', 'Disease', 'MESH:D009362', (275, 295))	('patients', 'Species', '9606', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('progression', 'CPA', (259, 270))	('gastrointestinal (GI) cancers', 'Disease', 'MESH:D004067', (307, 336))	('ANXA1', 'Gene', (62, 67))	('PDCD4', 'Gene', '27250', (78, 83))	('cancers', 'Phenotype', 'HP:0002664', (329, 336))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('metastasis in cancer', 'Disease', (275, 295))	('DFFA', 'Gene', (69, 73))
80173	29091952	Taken together, aberrant expression of miR-196a2 and the selected apoptosis-related biomarkers might be involved in GI cancer development and progression and could have potential diagnostic and prognostic roles in these types of cancer; particularly colorectal cancer, provided the results experimentally validated and confirmed in larger multi-center studies.	('colorectal cancer', 'Disease', (250, 267))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('GI cancer', 'Disease', 'MESH:D009369', (116, 125))	('miR-196a2', 'Gene', '406973', (39, 48))	('involved', 'Reg', (104, 112))	('GI cancer', 'Phenotype', 'HP:0007378', (116, 125))	('miR-196a2', 'Gene', (39, 48))	('expression', 'MPA', (25, 35))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (261, 267))	('colorectal cancer', 'Phenotype', 'HP:0003003', (250, 267))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('aberrant', 'Var', (16, 24))	('cancer', 'Disease', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('GI cancer', 'Disease', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('colorectal cancer', 'Disease', 'MESH:D015179', (250, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))
80177	29091952	Several reports have suggested the significant association of miRNAs aberrant expression with tumor initiation, progression and metastasis in cancer, including gastrointestinal (GI) cancers.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('progression', 'CPA', (112, 123))	('gastrointestinal (GI) cancers', 'Disease', 'MESH:D004067', (160, 189))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('metastasis in cancer', 'Disease', 'MESH:D009362', (128, 148))	('tumor', 'Disease', (94, 99))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('aberrant expression', 'Var', (69, 88))	('metastasis in cancer', 'Disease', (128, 148))	('miRNAs', 'Gene', (62, 68))	('association', 'Interaction', (47, 58))
80202	29091952	The complementary DNA (cDNA) was prepared from total RNA using TaqMan MicroRNA Reverse Transcription (RT) kit (P/N 4366596; Applied Biosystems, Foster City, CA, USA), miRNA-196a2 specific stem-loop primer (assay ID 478230_mir), and the endogenous control RNU6B primer (assay ID 001093) as previously described in details.	('P/N 4366596', 'Var', (111, 122))	('RNU6B', 'Gene', '26826', (255, 260))	('RNU6B', 'Gene', (255, 260))	('P/N 4366596', 'SUBSTITUTION', 'None', (111, 122))
80205	29091952	Extracted mRNAs were converted to cDNA using "High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, P/N 4368814)" and quantified via Real Time PCR technology system using the TaqMan  assay (Applied Biosystems, assay ID Hs00167549_m1 for ANXA1, Hs00189336_m1 for DFFA, and Hs00377253_m1 for PDCD4), TaqMan  Endogenous control assay for GAPDH (Applied Biosystems, catalogue no Hs402869), and (2x) Taqman  Universal PCR master mix II, No UNG (Applied Biosystems, P/N 4440043).	('UNG', 'Gene', '7374', (447, 450))	('ANXA1', 'Gene', (249, 254))	('UNG', 'Gene', (447, 450))	('Hs00377253_m1', 'Var', (284, 297))	('P/N 4440043', 'SUBSTITUTION', 'None', (472, 483))	('P/N 4368814', 'SUBSTITUTION', 'None', (112, 123))	('ANXA1', 'Gene', '301', (249, 254))	('P/N 4368814', 'Var', (112, 123))	('P/N 4440043', 'Var', (472, 483))
80229	29091952	In colorectal cancer, over-expression levels of miR-196a were negatively correlated with annexin A1 protein expression (r = -0.738, P < 0.001).	('annexin A1', 'Gene', '301', (89, 99))	('negatively', 'NegReg', (62, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('annexin A1', 'Gene', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('over-expression', 'PosReg', (22, 37))	('miR-196a', 'Var', (48, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
80246	29091952	Disturbances in the apoptotic pathway promote uncontrolled cell growth, which is a key event in tumor development and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Disturbances', 'Var', (0, 12))	('tumor', 'Disease', (96, 101))	('promote', 'PosReg', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('uncontrolled cell growth', 'CPA', (46, 70))	('apoptotic pathway', 'Pathway', (20, 37))
80248	29091952	Deregulation could be caused by chromosomal abnormalities, single nucleotide polymorphisms (SNPs), epigenetic changes, and defects in miRNA biogenesis pathways.	('miRNA biogenesis pathways', 'Pathway', (134, 159))	('epigenetic changes', 'Var', (99, 117))	('single nucleotide polymorphisms', 'Var', (59, 90))	('defects', 'NegReg', (123, 130))	('caused', 'Reg', (22, 28))	('chromosomal abnormalities', 'Disease', (32, 57))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (32, 57))
80251	29091952	Furthermore, within MIR-196A2 gene, a genetic variant rs11614913 (C/T) was identified in the stem region of the secondary precursor that have a significant impact on miRNA expression.	('impact', 'Reg', (156, 162))	('miRNA expression', 'MPA', (166, 182))	('rs11614913', 'Mutation', 'rs11614913', (54, 64))	('MIR-196A2', 'Gene', '406973', (20, 29))	('MIR-196A2', 'Gene', (20, 29))	('rs11614913', 'Var', (54, 64))
80253	29091952	reported higher risk of gaining somatic mutations during malignant transformation among C allele carriers of that particular SNP (rs11614913).	('gaining', 'PosReg', (24, 31))	('rs11614913', 'Var', (130, 140))	('rs11614913', 'Mutation', 'rs11614913', (130, 140))
80255	29091952	Fragile sites are considered preferential sites of "sister chromatid exchange, deletion, amplification, translocation, or insertion" of tumor-associated viruses.	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('translocation', 'Var', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('amplification', 'Var', (89, 102))	('deletion', 'Var', (79, 87))	('tumor', 'Disease', (136, 141))
80256	29091952	Silencing of the CpG island upstream of the MIR196A2 gene by hypermethylation was associated with reduced breast cancer risk, and DNA hypomethylation of the gene was associated with over-expression in various tumor types.	('MIR196A2', 'Gene', (44, 52))	('tumor', 'Disease', (209, 214))	('breast cancer', 'Disease', (106, 119))	('over-expression', 'PosReg', (182, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('Silencing', 'NegReg', (0, 9))	('hypermethylation', 'Var', (61, 77))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('reduced', 'NegReg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('MIR196A2', 'Gene', '406973', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
80257	29091952	Additionally, the current results revealed that miR-196a2, ANXA1, and annexin A1 deregulation were associated with unfavorable prognosis in colorectal carcinoma patients.	('miR-196a2', 'Gene', '406973', (48, 57))	('miR-196a2', 'Gene', (48, 57))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (140, 160))	('ANXA1', 'Gene', '301', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('annexin A1', 'Gene', (70, 80))	('ANXA1', 'Gene', (59, 64))	('patients', 'Species', '9606', (161, 169))	('annexin A1', 'Gene', '301', (70, 80))	('colorectal carcinoma', 'Disease', (140, 160))	('associated', 'Reg', (99, 109))	('deregulation', 'Var', (81, 93))
80271	29091952	Additionally, gastric cell lines with low ANXA1 expression showed higher potency for cell growth and invasion than that with high ANXA1 expression via regulating COX-2 (cyclooxygenase-2) expression.	('ANXA1', 'Gene', '301', (130, 135))	('cyclooxygenase-2', 'Gene', (169, 185))	('low', 'Var', (38, 41))	('ANXA1', 'Gene', '301', (42, 47))	('cyclooxygenase-2', 'Gene', '5743', (169, 185))	('expression', 'MPA', (187, 197))	('COX-2', 'Gene', '5743', (162, 167))	('cell growth', 'CPA', (85, 96))	('invasion', 'CPA', (101, 109))	('ANXA1', 'Gene', (130, 135))	('higher', 'PosReg', (66, 72))	('regulating', 'Reg', (151, 161))	('potency', 'MPA', (73, 80))	('expression', 'Var', (48, 58))	('ANXA1', 'Gene', (42, 47))	('COX-2', 'Gene', (162, 167))
80278	29091952	DFFA (-/-) mice were associated with tumor progression and severe genomic instability in colon epithelial cells.	('genomic instability', 'CPA', (66, 85))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('DFFA', 'Var', (0, 4))	('mice', 'Species', '10090', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
80294	29091952	PDCD4 suppressed carbonic anhydrase II (CAII) in human embryonic kidney, delayed cell cycle transition from G1 to S phase in glioma cancer cell, inhibited colon cancer cell invasion through suppressing MAP4K1, and phosphorylated the specificity protein transcription factors in colorectal cells, thus promoting essential events important in driving invasion and metastasis.	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('carbonic anhydrase II', 'Gene', '760', (17, 38))	('PDCD4', 'Var', (0, 5))	('colon cancer', 'Disease', (155, 167))	('colorectal', 'Disease', (278, 288))	('glioma cancer', 'Disease', (125, 138))	('carbonic anhydrase II', 'Gene', (17, 38))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('human', 'Species', '9606', (49, 54))	('delayed', 'NegReg', (73, 80))	('CAII', 'Gene', '760', (40, 44))	('inhibited', 'NegReg', (145, 154))	('embryonic kidney', 'Disease', (55, 71))	('MAP4K1', 'Gene', (202, 208))	('colorectal', 'Disease', 'MESH:D015179', (278, 288))	('suppressed', 'NegReg', (6, 16))	('colon cancer', 'Phenotype', 'HP:0003003', (155, 167))	('phosphorylated', 'Var', (214, 228))	('glioma cancer', 'Disease', 'MESH:D005910', (125, 138))	('cell cycle transition', 'CPA', (81, 102))	('MAP4K1', 'Gene', '11184', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('promoting', 'PosReg', (301, 310))	('embryonic kidney', 'Disease', 'MESH:D007674', (55, 71))	('colon cancer', 'Disease', 'MESH:D015179', (155, 167))	('CAII', 'Gene', (40, 44))	('suppressing', 'NegReg', (190, 201))
80306	28637022	CDKN2A methylation in esophageal cancer: a meta-analysis CDKN2A is a tumor suppressor gene and is frequently inactivated in human cancers by hypermethylation of its promoter.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('CDKN2A', 'Gene', (57, 63))	('tumor', 'Disease', (69, 74))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('hypermethylation', 'Var', (141, 157))	('CDKN2A', 'Gene', '1029', (57, 63))	('human', 'Species', '9606', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('CDKN2A', 'Gene', (0, 6))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))	('esophageal cancer', 'Disease', (22, 39))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('inactivated', 'NegReg', (109, 120))	('CDKN2A', 'Gene', '1029', (0, 6))
80307	28637022	However, the role and diagnostic value of CDKN2A methylation in esophageal cancer (EC) remains controversial.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CDKN2A', 'Gene', (42, 48))	('methylation', 'Var', (49, 60))	('CDKN2A', 'Gene', '1029', (42, 48))	('esophageal cancer', 'Disease', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
80309	28637022	A significant increase in the frequency of CDKN2A methylation was identified during EC carcinogenesis: cancer vs. controls, odds ratio (OR) = 12.60 (95 % CI, 8.90-17.85); cancer vs. precancerous lesions, OR = 2.89 (95% CI, 2.20-3.79); and precancerous lesions vs. controls, OR = 7.38, 95% (CI, 4.31-12.66).	('CDKN2A', 'Gene', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('EC carcinogenesis', 'Disease', (84, 101))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', (185, 191))	('increase', 'PosReg', (14, 22))	('EC carcinogenesis', 'Disease', 'MESH:D063646', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('CDKN2A', 'Gene', '1029', (43, 49))	('precancerous lesions', 'Disease', (239, 259))	('precancerous lesions', 'Disease', (182, 202))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('methylation', 'Var', (50, 61))	('cancer', 'Disease', (242, 248))	('precancerous lesions', 'Disease', 'MESH:D011230', (239, 259))	('precancerous lesions', 'Disease', 'MESH:D011230', (182, 202))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
80310	28637022	CDKN2A promoter methylation was associated with EC tumor grade (OR = 1.79; 95% CI, 1.20-2.67) and clinical stage (OR = 2.56; 95% CI, 1.33-4.92).	('EC tumor', 'Disease', 'MESH:D009369', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('EC tumor', 'Disease', (48, 56))	('associated', 'Reg', (32, 42))	('CDKN2A', 'Gene', (0, 6))	('methylation', 'Var', (16, 27))	('CDKN2A', 'Gene', '1029', (0, 6))
80311	28637022	Additionally, the sensitivity, specificity, and area under the summary receiver operating characteristic curve (AUC) for diagnosis of EC based on CDKN2A methylation were 0.52 (95% CI, 0.44-0.59), 0.96 (95% CI, 0.93-0.98), and 0.83 (95% CI, 0.79-0.86), respectively.	('CDKN2A', 'Gene', (146, 152))	('methylation', 'Var', (153, 164))	('CDKN2A', 'Gene', '1029', (146, 152))
80312	28637022	Our findings indicate that CDKN2A methylation has a vital role in EC tumorigenesis and could be a biomarker for early diagnosis of EC.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('EC tumor', 'Disease', 'MESH:D009369', (66, 74))	('methylation', 'Var', (34, 45))	('EC tumor', 'Disease', (66, 74))	('CDKN2A', 'Gene', (27, 33))	('CDKN2A', 'Gene', '1029', (27, 33))
80317	28637022	Abnormal methylation in the promoter region of tumor suppressor genes is one of the most common mechanisms of modification, and results in target gene transcriptional silencing.	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Abnormal', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('methylation', 'MPA', (9, 20))	('tumor', 'Disease', (47, 52))	('transcriptional', 'MPA', (151, 166))
80318	28637022	Moreover, with the introduction of precise and convenient methods of detection, DNA methylation has become a credible potential biomarker for early detection and diagnosis of cancer.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('methylation', 'Var', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
80320	28637022	Hypermethylation of the CDKN2A gene promoter region, resulting in its inactivation, has been reported in several types of malignancy, including lung, head and neck, hepatocellular, breast, and esophageal cancers.	('lung', 'Disease', (144, 148))	('malignancy', 'Disease', (122, 132))	('breast', 'Disease', (181, 187))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('inactivation', 'MPA', (70, 82))	('Hypermethylation', 'Var', (0, 16))	('hepatocellular', 'Disease', (165, 179))	('reported', 'Reg', (93, 101))	('CDKN2A', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('CDKN2A', 'Gene', '1029', (24, 30))	('esophageal cancers', 'Disease', (193, 211))	('malignancy', 'Disease', 'MESH:D009369', (122, 132))	('esophageal cancers', 'Disease', 'MESH:D004938', (193, 211))
80322	28637022	For example, one study reported that the methylation rate at the CDKN2A promoter was similar in EC patients and healthy controls; however, another investigation identified a differential frequency of CDKN2A promoter methylation between these two groups.	('CDKN2A', 'Gene', '1029', (65, 71))	('CDKN2A', 'Gene', '1029', (200, 206))	('methylation', 'Var', (216, 227))	('patients', 'Species', '9606', (99, 107))	('CDKN2A', 'Gene', (65, 71))	('CDKN2A', 'Gene', (200, 206))
80323	28637022	In addition, the value for EC diagnosis of testing for CDKN2A methylation, particularly using blood samples, has been less intensely investigated.	('CDKN2A', 'Gene', '1029', (55, 61))	('CDKN2A', 'Gene', (55, 61))	('methylation', 'Var', (62, 73))
80324	28637022	Here, we performed a meta-analysis to generate a quantitative estimate of the association of CDKN2A methylation with EC risk and its role in EC carcinogenesis.	('CDKN2A', 'Gene', (93, 99))	('EC carcinogenesis', 'Disease', 'MESH:D063646', (141, 158))	('CDKN2A', 'Gene', '1029', (93, 99))	('EC carcinogenesis', 'Disease', (141, 158))	('methylation', 'Var', (100, 111))	('association', 'Interaction', (78, 89))
80325	28637022	Furthermore, we assessed whether there were associations between CDKN2A promoter methylation and the clinical characteristics of EC patients.	('CDKN2A', 'Gene', '1029', (65, 71))	('methylation', 'Var', (81, 92))	('associations', 'Interaction', (44, 56))	('CDKN2A', 'Gene', (65, 71))	('patients', 'Species', '9606', (132, 140))
80328	28637022	Additionally, all subgroups showed that CDKN2A hypermethylation was significantly associated with EC.	('CDKN2A', 'Gene', '1029', (40, 46))	('CDKN2A', 'Gene', (40, 46))	('hypermethylation', 'Var', (47, 63))	('associated', 'Reg', (82, 92))
80330	28637022	In the absence of heterogeneity (I2 = 25%, P = 0.183), a fixed-effects model was applied to evaluate the association of between methylation of CDKN2A in EC and precancerous lesions.	('precancerous lesions', 'Disease', 'MESH:D011230', (160, 180))	('precancerous lesions', 'Disease', (160, 180))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CDKN2A', 'Gene', (143, 149))	('methylation', 'Var', (128, 139))	('CDKN2A', 'Gene', '1029', (143, 149))	('association', 'Interaction', (105, 116))
80332	28637022	The results of a sensitivity analysis indicated the authenticity of our results (Figure 3B) and a Begg's test for publication bias was not statistically significant (P = 0.74; Figure 4B) The analysis of the association between methylated CDKN2A and esophageal precancerous lesions included 612 precancerosis samples and 381 healthy controls from 14 studies.	('CDKN2A', 'Gene', (238, 244))	('cancer', 'Disease', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('CDKN2A', 'Gene', '1029', (238, 244))	('cancer', 'Disease', (263, 269))	('esophageal precancerous lesions', 'Disease', (249, 280))	('methylated', 'Var', (227, 237))	('association', 'Interaction', (207, 218))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (249, 280))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))
80334	28637022	A total of 1313 ECs from 16 studies were used to evaluate the relationships between CDKN2A methylation and clinicopathological features, including age, gender, smoking behavior, alcohol consumption, tumor location, tumor diameter, differentiation grade, tumor stage, clinical stage, and lymph node metastasis (Table 4).	('lymph node metastasis', 'Disease', (287, 308))	('tumor', 'Disease', (199, 204))	('methylation', 'Var', (91, 102))	('tumor', 'Disease', (254, 259))	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('alcohol', 'Chemical', 'MESH:D000438', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', (215, 220))	('lymph node metastasis', 'Disease', 'MESH:D009362', (287, 308))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
80335	28637022	Our findings demonstrated that CDKN2A methylation was significantly associated with differentiation grade (poor vs. well and moderate: OR = 1.79; 95% CI, 1.20-2.67; P < 0.01) and clinical stage (advanced vs. early: OR = 2.56; 95% CI, 1.33-4.92; P < 0.01).	('associated', 'Reg', (68, 78))	('methylation', 'Var', (38, 49))	('differentiation grade', 'CPA', (84, 105))	('CDKN2A', 'Gene', (31, 37))	('clinical stage', 'CPA', (179, 193))	('CDKN2A', 'Gene', '1029', (31, 37))
80336	28637022	However, there were no associations between other clinicopathological characteristics and CDKN2A promoter methylation in EC.	('CDKN2A', 'Gene', '1029', (90, 96))	('CDKN2A', 'Gene', (90, 96))	('methylation', 'Var', (106, 117))	('associations', 'Interaction', (23, 35))
80337	28637022	In the current analysis, the diagnostic value of methylated CDKN2A for EC diagnosis was assessed using data from 41 eligible case-control studies.	('methylated', 'Var', (49, 59))	('CDKN2A', 'Gene', '1029', (60, 66))	('CDKN2A', 'Gene', (60, 66))
80338	28637022	As shown in the Figure 6, Fagan plot analysis demonstrated that the probabilities of a patient being diagnosed with EC were 82%, 93%, and 98% following a positive result for methylation of CDKN2A, where the pretest probabilities of being diagnosed with EC were set to 25%, 50%, and 75%, respectively; when the test was negative, the probabilities of diagnosis with EC reduced to 14%, 33%, and 60%, respectively.	('methylation', 'Var', (174, 185))	('patient', 'Species', '9606', (87, 94))	('CDKN2A', 'Gene', (189, 195))	('CDKN2A', 'Gene', '1029', (189, 195))
80340	28637022	DNA methylation is a relatively early molecular change that is a candidate biomarker in several carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('carcinomas', 'Disease', 'MESH:D002277', (96, 106))	('carcinomas', 'Disease', (96, 106))	('methylation', 'Var', (4, 15))	('DNA', 'Disease', (0, 3))
80341	28637022	Increasing evidence demonstrates that methylation of the promoter of CDKN2A, an important negative regulator of cell growth and proliferation, is involved in the tumorigenesis and progression of various tumors, including pancreatic, gastric, and prostate cancers.	('tumor', 'Disease', (203, 208))	('gastric', 'Disease', (233, 240))	('methylation', 'Var', (38, 49))	('tumor', 'Disease', (162, 167))	('pancreatic', 'Disease', (221, 231))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('prostate cancers', 'Disease', 'MESH:D011471', (246, 262))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('CDKN2A', 'Gene', '1029', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('prostate cancers', 'Phenotype', 'HP:0012125', (246, 262))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('prostate cancers', 'Disease', (246, 262))	('tumors', 'Disease', (203, 209))	('pancreatic', 'Disease', 'MESH:D010195', (221, 231))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('involved', 'Reg', (146, 154))	('CDKN2A', 'Gene', (69, 75))
80342	28637022	Although there have been several reports that the frequency of CDKN2A promoter methylation is higher in EC samples than those from cancer-free controls, the association and the role of CDKN2A promoter methylation in EC remain controversial.	('cancer', 'Disease', (131, 137))	('CDKN2A', 'Gene', '1029', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('CDKN2A', 'Gene', '1029', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('methylation', 'Var', (79, 90))	('CDKN2A', 'Gene', (185, 191))	('CDKN2A', 'Gene', (63, 69))	('higher', 'PosReg', (94, 100))
80347	28637022	This evidence supports the association of methylated CDKN2A with EC carcinogenesis.	('EC carcinogenesis', 'Disease', (65, 82))	('CDKN2A', 'Gene', (53, 59))	('methylated', 'Var', (42, 52))	('association', 'Interaction', (27, 38))	('CDKN2A', 'Gene', '1029', (53, 59))	('EC carcinogenesis', 'Disease', 'MESH:D063646', (65, 82))
80348	28637022	In our results, the OR of the association with CDKN2A methylation for the EAC subgroup was greater than that for the ESCC subgroup, indicating that this molecular feature may be more relevant in EAC.	('EAC', 'Phenotype', 'HP:0011459', (74, 77))	('methylation', 'Var', (54, 65))	('CDKN2A', 'Gene', (47, 53))	('EAC', 'Disease', (74, 77))	('EAC', 'Phenotype', 'HP:0011459', (195, 198))	('CDKN2A', 'Gene', '1029', (47, 53))	('association', 'Interaction', (30, 41))
80349	28637022	The subgroup analysis by ethnicity showed that CDKN2A promoter methylation was associated with an increased risk of EC in Asian and Caucasian, as well as African population, with the Caucasian population showing a higher OR than the Asian and African population, suggesting that the Caucasian population may be more susceptible to CDKN2A promoter methylation.	('CDKN2A', 'Gene', (331, 337))	('CDKN2A', 'Gene', (47, 53))	('CDKN2A', 'Gene', '1029', (331, 337))	('CDKN2A', 'Gene', '1029', (47, 53))	('methylation', 'Var', (63, 74))
80350	28637022	The subgroup analysis of sample source presented a significant correlation between hypermethylated CDKN2A and EC in both tissue and blood samples, and the pooled OR of blood samples was remarkably higher than that of tissue samples, which suggested that hypermethylated CDKN2A may be a useful noninvasive biomarker for blood detection.	('CDKN2A', 'Gene', (99, 105))	('higher', 'PosReg', (197, 203))	('CDKN2A', 'Gene', (270, 276))	('CDKN2A', 'Gene', '1029', (99, 105))	('correlation', 'Interaction', (63, 74))	('CDKN2A', 'Gene', '1029', (270, 276))	('hypermethylated', 'Var', (83, 98))	('hypermethylated', 'Var', (254, 269))
80352	28637022	A previous systematic review reported that there was a trend towards increased frequency of CDKN2A methylation according to EC differentiation grade; however, the association was not statistically significant.	('methylation', 'Var', (99, 110))	('CDKN2A', 'Gene', '1029', (92, 98))	('CDKN2A', 'Gene', (92, 98))	('increased', 'PosReg', (69, 78))
80353	28637022	In contrast, our results indicate that methylation of the CDKN2A promoter is significantly more common among patients with poorly differentiated tumors and advanced clinical stage, compared with those with well/moderately differentiated tumors and early stage disease.	('common', 'Reg', (96, 102))	('methylation', 'Var', (39, 50))	('patients', 'Species', '9606', (109, 117))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('CDKN2A', 'Gene', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('poorly', 'Disease', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('CDKN2A', 'Gene', '1029', (58, 64))
80354	28637022	Together, these results support the hypothesis that hypermethylation of the CDKN2A promoter is involved in the progression of EC.	('CDKN2A', 'Gene', '1029', (76, 82))	('CDKN2A', 'Gene', (76, 82))	('involved', 'Reg', (95, 103))	('hypermethylation', 'Var', (52, 68))
80355	28637022	We further assessed the diagnostic potential of CDKN2A promoter methylation for EC, based on data from 41 eligible case-control studies.	('CDKN2A', 'Gene', '1029', (48, 54))	('CDKN2A', 'Gene', (48, 54))	('methylation', 'Var', (64, 75))
80356	28637022	The pooled sensitivity and specificity for all included studies were 0.52 and 0.96, respectively, indicating that CDKN2A promoter methylation could be a useful biomarker for diagnosis of EC.	('methylation', 'Var', (130, 141))	('CDKN2A', 'Gene', '1029', (114, 120))	('CDKN2A', 'Gene', (114, 120))
80357	28637022	The AUC calculated from all studies included in the current analysis was 0.83, indicating that CDKN2A promoter methylation is an extremely useful biomarker for EC diagnosis.	('CDKN2A', 'Gene', '1029', (95, 101))	('CDKN2A', 'Gene', (95, 101))	('methylation', 'Var', (111, 122))
80358	28637022	In addition, there is increasing evidence that abnormal DNA methylation in body fluid samples is a promising biomarker for cancer screening and diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('DNA', 'Protein', (56, 59))	('methylation', 'Var', (60, 71))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('abnormal', 'Var', (47, 55))
80363	28637022	It has been reported that tumor-derived somatic alterations in DNA can be detected in ctDNA with broad clinical application, high sensitivity, and specificity.	('alterations', 'Var', (48, 59))	('DNA', 'Gene', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('detected', 'Reg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('ctDNA', 'Disease', (86, 91))
80364	28637022	All these above indicated that testing for CDKN2A methylation in blood samples has potential as a noninvasive tool for the diagnosis of EC.	('CDKN2A', 'Gene', '1029', (43, 49))	('methylation', 'Var', (50, 61))	('CDKN2A', 'Gene', (43, 49))
80366	28637022	The results demonstrated that, when the pre-test probabilities were assumed to be 25%, 50%, and 75%, a corresponding 82%, 93%, and 98% of patients would be correctly diagnosed with EC following positive CDKN2A methylation tests; moreover, a diagnosis of EC could be ruled out for 86%, 67%, and 40% of patients following negative results.	('patients', 'Species', '9606', (301, 309))	('CDKN2A', 'Gene', (203, 209))	('methylation', 'Var', (210, 221))	('CDKN2A', 'Gene', '1029', (203, 209))	('patients', 'Species', '9606', (138, 146))
80367	28637022	These analyses suggest that methylated CDKN2A has good diagnostic power to discriminate patients with EC from healthy individuals.	('methylated', 'Var', (28, 38))	('patients', 'Species', '9606', (88, 96))	('CDKN2A', 'Gene', '1029', (39, 45))	('CDKN2A', 'Gene', (39, 45))
80369	28637022	In conclusion, our findings provide strong evidence that CDKN2A methylation is involved in the carcinogenesis and progression of EC and that it is a promising biomarker for the diagnosis of EC, especially by screening of blood samples.	('methylation', 'Var', (64, 75))	('carcinogenesis', 'Disease', 'MESH:D063646', (95, 109))	('CDKN2A', 'Gene', (57, 63))	('carcinogenesis', 'Disease', (95, 109))	('CDKN2A', 'Gene', '1029', (57, 63))	('involved', 'Reg', (79, 87))
80370	28637022	Future large-scale studies are necessary to support or add to our findings, especially regarding the role of CDKN2A methylation in the prediction of prognosis, and to support the clinical application of our findings for the benefit of patients with EC.	('methylation', 'Var', (116, 127))	('CDKN2A', 'Gene', '1029', (109, 115))	('CDKN2A', 'Gene', (109, 115))	('patients', 'Species', '9606', (235, 243))
80371	28637022	The following search terms, and various combinations of them, were used: "p16," "p16INK4a," "p14arf", "p14", "CDKN2A (p16 and p14)," "cyclin-dependent kinase inhibitor 2A," "methylation," "DNA methylation," "promoter methylation," "esophageal carcinoma," "esophagus cancer," "esophageal tumor," and "esophageal malignancy."	('p14', 'Gene', (126, 129))	('methylation', 'Var', (174, 185))	('esophagus cancer', 'Disease', (256, 272))	('CDKN2A', 'Gene', '1029', (110, 116))	('p14', 'Gene', (93, 96))	('p16INK4a', 'Gene', '1029', (81, 89))	('p14"', 'Gene', (103, 107))	('esophageal tumor', 'Disease', (276, 292))	('p16', 'Gene', (81, 84))	('esophageal malignancy', 'Disease', (300, 321))	('p16', 'Gene', (74, 77))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (232, 252))	('esophageal tumor', 'Phenotype', 'HP:0100751', (276, 292))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (134, 170))	('p16', 'Gene', '1029', (81, 84))	('p16', 'Gene', '1029', (74, 77))	('esophagus cancer', 'Disease', 'MESH:D004938', (256, 272))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (134, 170))	('esophageal malignancy', 'Disease', 'MESH:D004938', (300, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('p14', 'Gene', '1029', (103, 106))	('esophageal malignancy', 'Phenotype', 'HP:0100751', (300, 321))	('esophageal tumor', 'Disease', 'MESH:D004938', (276, 292))	('p16', 'Gene', (118, 121))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (232, 252))	('CDKN2A', 'Gene', (110, 116))	('p14arf', 'Gene', '1029', (93, 99))	('p14"', 'Gene', '1029', (103, 107))	('p16', 'Gene', '1029', (118, 121))	('p16INK4a', 'Gene', (81, 89))	('p14arf', 'Gene', (93, 99))	('p14', 'Gene', '1029', (126, 129))	('p14', 'Gene', (103, 106))	('p14', 'Gene', '1029', (93, 96))	('promoter', 'MPA', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('esophageal carcinoma', 'Disease', (232, 252))
80372	28637022	We collected all eligible articles that addressed the association between CDKN2A methylation and EC.	('CDKN2A', 'Gene', (74, 80))	('association', 'Interaction', (54, 65))	('CDKN2A', 'Gene', '1029', (74, 80))	('methylation', 'Var', (81, 92))
80376	28637022	Overall odds ORs and corresponding 95% CIs were calculated to evaluate the strengths of the associations between CDKN2A methylation and different EC pathological processes (cancer vs. healthy control, cancer vs. precancerous lesion, precancerous lesion vs. healthy control), as well as clinicopathological features.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (201, 207))	('methylation', 'Var', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', (215, 221))	('CDKN2A', 'Gene', (113, 119))	('precancerous lesion', 'Disease', (212, 231))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CDKN2A', 'Gene', '1029', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('precancerous lesion', 'Disease', (233, 252))	('precancerous lesion', 'Disease', 'MESH:D011230', (212, 231))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('associations', 'Interaction', (92, 104))	('precancerous lesion', 'Disease', 'MESH:D011230', (233, 252))
80377	28637022	Pooled sensitivity and specificity were used to estimate the diagnostic efficacy of testing for CDKN2A promoter methylation.	('CDKN2A', 'Gene', '1029', (96, 102))	('CDKN2A', 'Gene', (96, 102))	('testing', 'Reg', (84, 91))	('methylation', 'Var', (112, 123))
80378	28637022	Two indicators, the SROC and AUC, were also calculated to evaluate the stability and accuracy of the diagnostic capacity of CDKN2A promoter methylation for EC.	('CDKN2A', 'Gene', '1029', (124, 130))	('CDKN2A', 'Gene', (124, 130))	('methylation', 'Var', (140, 151))
80379	28637022	Fagan plot analysis was performed with 25%, 50%, and 75% pre-test probability to assess the diagnostic power of CDKN2A promoter methylation in clinical practice.	('methylation', 'Var', (128, 139))	('CDKN2A', 'Gene', '1029', (112, 118))	('CDKN2A', 'Gene', (112, 118))
80393	28533917	Substances with extremes of pH (less than 2 or greater than 12) are very corrosive and can create severe injury and burns in the upper gastrointestinal tract.	('create', 'Reg', (91, 97))	('less than 2', 'Var', (32, 43))	('injury and burns in the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (105, 157))
80399	28533917	Conversely, alkalis cause more injury to the esophagus.	('injury to the esophagus', 'Disease', (31, 54))	('alkalis', 'Var', (12, 19))	('injury to the esophagus', 'Disease', 'MESH:D004938', (31, 54))
80416	28533917	For alkaline ingestion in particular, subsequent development of squamous cell carcinoma has been reported to occur approximately 40 years after injury.	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('alkaline', 'Var', (4, 12))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 87))	('alkaline ingestion', 'Phenotype', 'HP:0001948', (4, 22))	('squamous cell carcinoma', 'Disease', (64, 87))
80463	28533917	In a study of 16 patients treated with endoscopic topical application of mitomycin-C, a decrease in the number of dilatations and apparent relief of dysphagia were achieved compared to triamcinolone.	('triamcinolone', 'Chemical', 'MESH:D014221', (185, 198))	('decrease', 'NegReg', (88, 96))	('mitomycin-C', 'Var', (73, 84))	('dysphagia', 'Disease', (149, 158))	('mitomycin-C', 'Chemical', 'MESH:D016685', (73, 84))	('dilatation', 'Phenotype', 'HP:0002617', (114, 124))	('dysphagia', 'Phenotype', 'HP:0002015', (149, 158))	('patients', 'Species', '9606', (17, 25))	('dilatations', 'Phenotype', 'HP:0002617', (114, 125))	('number of dilatations', 'MPA', (104, 125))	('dysphagia', 'Disease', 'MESH:D003680', (149, 158))
80468	28533917	Up to 70% of patients with grade IIB and more than 90% of patients with grade III injury are likely to develop esophageal stricture.	('III injury', 'Disease', (78, 88))	('esophageal stricture', 'Disease', (111, 131))	('develop', 'PosReg', (103, 110))	('grade IIB', 'Var', (27, 36))	('to 7', 'Species', '1214577', (3, 7))	('patients', 'Species', '9606', (13, 21))	('III injury', 'Disease', 'MESH:D061220', (78, 88))	('esophageal stricture', 'Phenotype', 'HP:0002043', (111, 131))	('patients', 'Species', '9606', (58, 66))
80506	26788548	Commercially available TMAs were obtained from following vendors: (i) US Biomax, Inc. (Rockville, MD; Catalog numbers ES1201, ES1202, and ES801) consisting of 160 ESCC cases with matched adjacent normal esophageal epithelia.	('TMAs', 'Chemical', '-', (23, 27))	('ESCC', 'Disease', (163, 167))	('ES1201', 'Var', (118, 124))	('esophageal epithelia', 'Disease', (203, 223))	('esophageal epithelia', 'Disease', 'MESH:D004941', (203, 223))	('ES801', 'Var', (138, 143))	('ES1202', 'Var', (126, 132))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (203, 223))
80549	26788548	However, disruption of this process leads to dedifferentiation of epithelial cells resulting in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (96, 110))	('dedifferentiation', 'CPA', (45, 62))	('leads to', 'Reg', (36, 44))	('carcinogenesis', 'Disease', (96, 110))	('epithelia', 'Disease', 'None', (66, 75))	('epithelia', 'Disease', (66, 75))	('disruption', 'Var', (9, 19))
80552	26788548	In addition, S100A9 knockdown resulted in impaired apoptosis mediated by TP53.	('TP53', 'Gene', '7157', (73, 77))	('S100A9', 'Gene', (13, 19))	('TP53', 'Gene', (73, 77))	('impaired apoptosis', 'Disease', (42, 60))	('impaired apoptosis', 'Disease', 'MESH:D009422', (42, 60))	('knockdown', 'Var', (20, 29))	('S100A9', 'Gene', '6280', (13, 19))
80558	26788548	This results in mutation of TP53, which regulates S100A9 expression; hence S100A9 is frequently downregulated in ESCC.	('expression', 'MPA', (57, 67))	('ESCC', 'Disease', (113, 117))	('regulates', 'Reg', (40, 49))	('mutation', 'Var', (16, 24))	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('results in', 'Reg', (5, 15))	('S100A9', 'Gene', (75, 81))	('downregulated', 'NegReg', (96, 109))	('S100A9', 'Gene', '6280', (50, 56))	('S100A9', 'Gene', '6280', (75, 81))	('S100A9', 'Gene', (50, 56))
80586	24820097	The activation of EGFR leads to the activation of one or more intermediate signaling network branches which regulate cell motility, such as the extracellular-regulated kinase (ERK) pathway, the phosphoinositide 3-OH kinase (PI3K) pathway, the Janus kinase (Jak) pathway, the c-Jun NH2 terminal kinase (JNK) pathway, and the p38 pathway.	('c-Jun NH2 terminal kinase', 'Gene', '5599', (275, 300))	('JNK', 'Gene', (302, 305))	('p38', 'Gene', (324, 327))	('EGFR', 'Gene', '1956', (18, 22))	('ERK', 'Gene', (176, 179))	('c-Jun NH2 terminal kinase', 'Gene', (275, 300))	('phosphoinositide 3-OH kinase', 'Gene', '5293', (194, 222))	('activation', 'Var', (4, 14))	('JNK', 'Gene', '5599', (302, 305))	('activation', 'PosReg', (36, 46))	('EGFR', 'Gene', (18, 22))	('cell motility', 'CPA', (117, 130))	('p38', 'Gene', '5594', (324, 327))	('extracellular-regulated kinase', 'Gene', (144, 174))	('extracellular-regulated kinase', 'Gene', '5594', (144, 174))	('ERK', 'Gene', '5594', (176, 179))	('phosphoinositide 3-OH kinase', 'Gene', (194, 222))
80598	24820097	For example, the phosphorylation of Akt (p-Akt, S473 and T308 residues) was induced between 5 min and 1 h following EGF stimulation in EC109 cells and TT cells.	('S473', 'Var', (48, 52))	('Akt', 'Gene', '207', (43, 46))	('EC109', 'CellLine', 'CVCL:6898', (135, 140))	('T308', 'Chemical', '-', (57, 61))	('phosphorylation', 'MPA', (17, 32))	('Akt', 'Gene', (36, 39))	('EGF', 'Gene', (116, 119))	('Akt', 'Gene', (43, 46))	('EGF', 'Gene', '1950', (116, 119))	('T308 residues', 'Var', (57, 70))	('Akt', 'Gene', '207', (36, 39))	('induced', 'Reg', (76, 83))
80608	24820097	In the case of  Figure 3a , the MEK inhibitor U0126 suppressed the EGF-induced phosphorylation of ERK (p-ERK) by more than 50%.	('EGF', 'Gene', '1950', (67, 70))	('ERK', 'Gene', '5594', (105, 108))	('U0126', 'Chemical', 'MESH:C113580', (46, 51))	('ERK', 'Gene', '5594', (98, 101))	('ERK', 'Gene', (105, 108))	('ERK', 'Gene', (98, 101))	('suppressed', 'NegReg', (52, 62))	('MEK', 'Gene', (32, 35))	('MEK', 'Gene', '5609', (32, 35))	('U0126', 'Var', (46, 51))	('EGF', 'Gene', (67, 70))
80610	24820097	In the case of  Figure 3b , the PI3K inhibitor LY294002 increased EGF-induced c-Fos expression by more than 50%.	('c-Fos', 'Gene', (78, 83))	('increased', 'PosReg', (56, 65))	('c-Fos', 'Gene', '2353', (78, 83))	('LY294002', 'Chemical', 'MESH:C085911', (47, 55))	('EGF', 'Gene', (66, 69))	('LY294002', 'Var', (47, 55))	('EGF', 'Gene', '1950', (66, 69))
80612	24820097	In the case of  Figure 3c , the GSK-3 inhibitor SB415286 increased c-Jun expression without EGF stimulation.	('SB415286', 'Var', (48, 56))	('EGF', 'Gene', (92, 95))	('c-Jun', 'Gene', '3725', (67, 72))	('EGF', 'Gene', '1950', (92, 95))	('c-Jun', 'Gene', (67, 72))	('GSK-3', 'Gene', (32, 37))	('increased', 'PosReg', (57, 66))	('SB415286', 'Chemical', 'MESH:C417520', (48, 56))
80619	24820097	We also found that MEK regulated expression levels of c-Fos and p21, and that PI3K suppressed the expression levels of c-Fos in the three cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('p21', 'Gene', '644914', (64, 67))	('cancer', 'Disease', (138, 144))	('MEK', 'Gene', '5609', (19, 22))	('c-Fos', 'Gene', (54, 59))	('c-Fos', 'Gene', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('c-Fos', 'Gene', '2353', (54, 59))	('expression levels', 'MPA', (33, 50))	('c-Fos', 'Gene', '2353', (119, 124))	('expression levels', 'MPA', (98, 115))	('MEK', 'Gene', (19, 22))	('suppressed', 'NegReg', (83, 93))	('PI3K', 'Var', (78, 82))	('p21', 'Gene', (64, 67))
80662	24820097	MAPK activation consequently induces RhoA activation and epithelial-mesenchymal-transition, while PI3K activation suppresses RhoA activity in colon cancer.	('activation', 'Var', (5, 15))	('induces', 'Reg', (29, 36))	('RhoA', 'Gene', (125, 129))	('colon cancer', 'Disease', (142, 154))	('RhoA', 'Gene', '387', (125, 129))	('MAPK', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('RhoA', 'Gene', (37, 41))	('epithelial-mesenchymal-transition', 'CPA', (57, 90))	('activation', 'PosReg', (42, 52))	('RhoA', 'Gene', '387', (37, 41))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('suppresses', 'NegReg', (114, 124))
80664	24820097	This could involve PI3K-induced Rac1 activation, because E-cadherin-stimulated actin cytoskeletal reorganization requires Rac activation and PI3P-activated GEF Tiam1.	('Rac1', 'Gene', (32, 36))	('Rac', 'Gene', '207', (32, 35))	('E-cadherin', 'Gene', (57, 67))	('E-cadherin', 'Gene', '999', (57, 67))	('Rac', 'Gene', (32, 35))	('PI3P-activated', 'Var', (141, 155))	('Tiam1', 'Gene', (160, 165))	('Rac', 'Gene', '207', (122, 125))	('Tiam1', 'Gene', '7074', (160, 165))	('Rac', 'Gene', (122, 125))	('Rac1', 'Gene', '5879', (32, 36))
80673	24820097	AG1478 (EGFR inhibitor), rapamycin (mTOR inhibitor), and Y27632 (ROCK inhibitor) were purchased from Calbiochem.	('Y27632', 'Var', (57, 63))	('Y27632', 'Chemical', 'MESH:C108830', (57, 63))	('mTOR', 'Gene', (36, 40))	('AG1478', 'Chemical', 'MESH:C101044', (0, 6))	('mTOR', 'Gene', '2475', (36, 40))	('EGFR', 'Gene', '1956', (8, 12))	('EGFR', 'Gene', (8, 12))	('rapamycin', 'Chemical', 'MESH:D020123', (25, 34))
80675	24820097	AA861 (5-lipoxygenase inhibitor), Actinomycin D (Transcription inhibitor), Cycloheximide (Translation inhibitor), LY294002 (PI3K inhibitor), Mevastatin (HMG-CoA reductase inhibitor), MG132 (Proteasome inhibitor), SB203580 (p38 inhibitor), SB415286 (GSK-3 inhibitor), SP600125 (JNK inhibitor), U0126 (MEK inhibitor), and Epidermal Growth Factor (EGF) were purchased from Sigma.	('5-lipoxygenase', 'Gene', '240', (7, 21))	('LY294002', 'Var', (114, 122))	('SB203580', 'Var', (213, 221))	('SP600125', 'Var', (267, 275))	('U0126', 'Chemical', 'MESH:C113580', (293, 298))	('p38', 'Gene', '5594', (223, 226))	('MEK', 'Gene', '5609', (300, 303))	('HMG-CoA reductase', 'Gene', (153, 170))	('EGF', 'Gene', '1950', (345, 348))	('JNK', 'Gene', (277, 280))	('SB415286', 'Chemical', 'MESH:C417520', (239, 247))	('MEK', 'Gene', (300, 303))	('JNK', 'Gene', '5599', (277, 280))	('LY294002', 'Chemical', 'MESH:C085911', (114, 122))	('5-lipoxygenase', 'Gene', (7, 21))	('Epidermal Growth Factor', 'Gene', (320, 343))	('EGF', 'Gene', (345, 348))	('p38', 'Gene', (223, 226))	('Epidermal Growth Factor', 'Gene', '1950', (320, 343))	('HMG-CoA reductase', 'Gene', '3156', (153, 170))
80682	24820097	This rule includes three simple assumptions that are commonly used in chemical biology: a) That there exists a positive regulation from molecule X to molecule Y when the level of molecule Y in the presence of both EGF and an inhibitor of X is more than 50% lower than in the EGF-treated condition; b) There exists a negative regulation from molecule X to molecule Y when the level of molecule Y in the presence of both EGF and inhibitor of X is more than 50% higher than in EGF-treated condition; c) There exists a negative regulation from molecule X to molecule Y when the level of molecule Y in the presence of inhibitor of X is higher than the half of the level in EGF-treated condition.	('EGF', 'Gene', '1950', (474, 477))	('EGF', 'Gene', (668, 671))	('EGF', 'Gene', (214, 217))	('EGF', 'Gene', (275, 278))	('EGF', 'Gene', '1950', (668, 671))	('EGF', 'Gene', '1950', (214, 217))	('EGF', 'Gene', (474, 477))	('EGF', 'Gene', (419, 422))	('inhibitor of', 'Var', (613, 625))	('EGF', 'Gene', '1950', (419, 422))	('EGF', 'Gene', '1950', (275, 278))
80822	21826111	Buried metaplasia developed at a similar rate in both groups (30% in the PDT group and 33% in the control group, P=NS).	('PDT', 'Var', (73, 76))	('metaplasia', 'Disease', (7, 17))	('Buried', 'Disease', (0, 6))	('metaplasia', 'Disease', 'MESH:D008679', (7, 17))
80833	21826111	conducted a secondary analysis of biopsy specimens taken during the AIM dysplasia trial, and found that there was no significant difference in the frequency of esophageal squamous biopsy samples that included lamina propria between patients who received RFA (78.4% of biopsy samples included lamina propria) and those who received sham ablation (79.1% , P=NS).	('RFA', 'Var', (254, 257))	('patients', 'Species', '9606', (232, 240))	('esophageal squamous', 'Disease', 'MESH:D000077277', (160, 179))	('esophageal squamous', 'Disease', (160, 179))	('AIM dysplasia', 'Disease', 'MESH:D004476', (68, 81))	('AIM dysplasia', 'Disease', (68, 81))
80921	33023117	The 5-year cause-specific survival rates of the m1/m2, m3/sm1, and sm2 groups were 98%, 93%, and 100%, respectively.	('sm1', 'Gene', (58, 61))	('m1/m2', 'Var', (48, 53))	('sm1', 'Gene', '7911', (58, 61))	('sm2', 'Gene', (67, 70))	('sm2', 'Gene', '53366', (67, 70))
80929	33023117	The 5-year overall survival rates of the m1/m2, m3/sm1, and sm2 groups were 95%, 84%, and 75%, respectively.	('sm2', 'Gene', (60, 63))	('sm1', 'Gene', (51, 54))	('sm2', 'Gene', '53366', (60, 63))	('m1/m2', 'Var', (41, 46))	('sm1', 'Gene', '7911', (51, 54))
80987	31157290	From the 20 years of medical records, we included all patients with superficial clinical tumors who underwent ER for therapeutic purposes and a histopathologic diagnosis of T1b-SM1 and T1b-SM2, as assessed by the Japanese Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus by the Japan Esophageal Society.	('T1b-SM1', 'Var', (173, 180))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('Carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('T1b-SM2', 'Var', (185, 192))	('Carcinoma of the Esophagus', 'Disease', (264, 290))	('Carcinoma of the Esophagus', 'Disease', 'MESH:D004938', (264, 290))	('Carcinoma of the Esophagus', 'Phenotype', 'HP:0011459', (264, 290))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
81025	24892336	(4)  Comparison between RapidArc (Varian Medical Systems, Palo Alto, CA) and fixed-field IMRT in cervical esophageal cancer also demonstrated that RapidArc could achieve similar tumor coverage and OARs sparing with shorter delivery time and fewer MUs.	('tumor', 'Disease', (178, 183))	('RapidArc', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('sparing', 'NegReg', (202, 209))	('cervical esophageal cancer', 'Disease', (97, 123))	('cervical esophageal cancer', 'Disease', 'MESH:D004938', (97, 123))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
81079	24892336	For even more complicated target of head and neck cancer, numerous studies had confirmed the superiority of IMRT in target coverage compared to CRT.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('head and neck cancer', 'Phenotype', 'HP:0012288', (36, 56))	('IMRT', 'Var', (108, 112))	('neck cancer', 'Disease', 'MESH:D006258', (45, 56))	('neck cancer', 'Disease', (45, 56))
81086	24892336	(18)  Similar to the study of Vivekanandan et al., the V30 of lung was greatly decreased with IMRT and VMAT compared to CRT.	('VMAT', 'Disease', (103, 107))	('decreased', 'NegReg', (79, 88))	('V30', 'MPA', (55, 58))	('VMAT', 'Disease', 'None', (103, 107))	('IMRT', 'Var', (94, 98))
81094	24892336	(20)  indicated that the complexity of the target volume determined whether single arc VMAT was equivalent to IMRT.	('VMAT', 'Disease', 'None', (87, 91))	('single arc', 'Var', (76, 86))	('VMAT', 'Disease', (87, 91))
81135	28706536	It is a condition in which disruption of the swallowing process interferes with a patient's ability to eat but also can result in aspiration pneumonia, malnutrition, dehydration, weight loss, and airway obstruction.	('patient', 'Species', '9606', (82, 89))	('ability', 'MPA', (92, 99))	('disruption of the swallowing process', 'Phenotype', 'HP:0002015', (27, 63))	('airway obstruction', 'Phenotype', 'HP:0002781', (196, 214))	('weight loss', 'Phenotype', 'HP:0001824', (179, 190))	('aspiration pneumonia', 'Disease', (130, 150))	('weight loss', 'Disease', (179, 190))	('aspiration', 'Phenotype', 'HP:0002835', (130, 140))	('interferes', 'NegReg', (64, 74))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (130, 150))	('dehydration', 'Phenotype', 'HP:0001944', (166, 177))	('dehydration', 'Disease', 'MESH:D003681', (166, 177))	('malnutrition', 'Phenotype', 'HP:0004395', (152, 164))	('result in', 'Reg', (120, 129))	('disruption', 'Var', (27, 37))	('malnutrition', 'Disease', (152, 164))	('airway obstruction', 'Disease', 'MESH:D000402', (196, 214))	('pneumonia', 'Phenotype', 'HP:0002090', (141, 150))	('dehydration', 'Disease', (166, 177))	('airway obstruction', 'Disease', (196, 214))	('weight loss', 'Disease', 'MESH:D015431', (179, 190))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (130, 150))	('malnutrition', 'Disease', 'MESH:D044342', (152, 164))
81275	28706536	Moreover, gold compounds (intramuscular and oral), penicillamine, sulfasalazine, methotrexate, and other cytotoxic drugs can cause oral ulcers and other lesions to oral mucosa.	('sulfasalazine', 'Chemical', 'MESH:D012460', (66, 79))	('lesions to oral', 'Phenotype', 'HP:0100649', (153, 168))	('lesions', 'Disease', (153, 160))	('penicillamine', 'Chemical', 'MESH:D010396', (51, 64))	('oral ulcers', 'Disease', (131, 142))	('cause', 'Reg', (125, 130))	('oral ulcers', 'Disease', 'MESH:D019226', (131, 142))	('methotrexate', 'Var', (81, 93))	('methotrexate', 'Chemical', 'MESH:D008727', (81, 93))	('oral ulcers', 'Phenotype', 'HP:0000155', (131, 142))
81281	28706536	The presence of changes of pressure in the LES with consequent incontinence produces a continuous exposure to gastric acid fluids, evolving in reflux esophagitis up to typical GERD findings has been described.	('changes', 'Var', (16, 23))	('reflux esophagitis up', 'Phenotype', 'HP:0002020', (143, 164))	('consequent incontinence', 'Phenotype', 'HP:0002607', (52, 75))	('incontinence', 'Disease', (63, 75))	('reflux esophagitis', 'Disease', (143, 161))	('reflux esophagitis', 'Disease', 'MESH:D005764', (143, 161))	('incontinence', 'Disease', 'MESH:D014549', (63, 75))	('esophagitis', 'Phenotype', 'HP:0100633', (150, 161))	('exposure to gastric acid fluids', 'MPA', (98, 129))	('evolving', 'Reg', (131, 139))
81293	28596684	After adjustment for body mass index, tobacco use, and alcohol intake, the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma (P = 0.0150).	('correlated', 'Reg', (121, 131))	('molar difference', 'Var', (75, 91))	('IGFBP3', 'Gene', '3486', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('IGF1', 'Gene', (102, 106))	('tobacco', 'Species', '4097', (38, 45))	('esophageal carcinoma', 'Disease', (149, 169))	('IGF1', 'Gene', '3479', (102, 106))	('alcohol', 'Chemical', 'MESH:D000438', (55, 62))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (149, 169))	('IGFBP3', 'Gene', (95, 101))	('inversely', 'NegReg', (111, 120))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (149, 169))
81337	28596684	IGF1 tertile values for tertiles 1, 2, and 3 were < 120; 120-150; and > 150.0 ng/mL, respectively.	('IGF1', 'Gene', '3479', (0, 4))	('IGF1', 'Gene', (0, 4))	('> 150.0 ng/mL', 'Var', (70, 83))
81359	28596684	However, we found no association between free IGFBP3 and the risk of esophageal cancer in the female population (P = 0.517), as the number of cases was too low.	('IGFBP3', 'Gene', '3486', (46, 52))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('IGFBP3', 'Gene', (46, 52))	('free', 'Var', (41, 45))
81373	28596684	Analyses of non-elderly or male subgroups might confirm that a high molar difference of (IGFBP3-IGF1) showed a low risk of esophageal tumors.	('IGFBP3', 'Gene', (89, 95))	('IGF1', 'Gene', '3479', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('IGFBP3', 'Gene', '3486', (89, 95))	('esophageal tumor', 'Phenotype', 'HP:0100751', (123, 139))	('IGF1', 'Gene', (96, 100))	('esophageal tumors', 'Disease', 'MESH:D004938', (123, 140))	('esophageal tumors', 'Phenotype', 'HP:0100751', (123, 140))	('high molar difference', 'Var', (63, 84))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('esophageal tumors', 'Disease', (123, 140))
81375	28596684	Moreover, we have reported that free IGFBP3 showed a reversed risk for hepatic cancer.	('IGFBP3', 'Gene', '3486', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hepatic cancer', 'Disease', (71, 85))	('free', 'Var', (32, 36))	('hepatic cancer', 'Disease', 'MESH:D008113', (71, 85))	('hepatic cancer', 'Phenotype', 'HP:0002896', (71, 85))	('IGFBP3', 'Gene', (37, 43))
81379	28596684	Although our current study did not collect data about visceral obesity, free IGFBP3 was inversely associated with the risk of esophageal cancer after adjustment including BMI.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('inversely', 'NegReg', (88, 97))	('free', 'Var', (72, 76))	('IGFBP3', 'Gene', '3486', (77, 83))	('visceral obesity', 'Disease', 'MESH:D056128', (54, 70))	('associated', 'Reg', (98, 108))	('visceral obesity', 'Disease', (54, 70))	('obesity', 'Phenotype', 'HP:0001513', (63, 70))	('IGFBP3', 'Gene', (77, 83))	('visceral obesity', 'Phenotype', 'HP:0012743', (54, 70))	('esophageal cancer', 'Disease', (126, 143))
81380	28596684	In a population-based case-control study, three polymorphisms in IGF and related genes such as IGF1 (CA)17 185-bp allele and two single-nucleotide polymorphisms, IGF1 rs6214 and growth hormone receptor rs6898743, were associated with EAC or its precursors, including reflux esophagitis and Barrett esophagus.	('rs6898743', 'Mutation', 'rs6898743', (202, 211))	('rs6898743', 'Var', (202, 211))	('rs6214', 'Var', (167, 173))	('reflux esophagitis', 'Disease', (267, 285))	('rs6214', 'Mutation', 'rs6214', (167, 173))	('reflux esophagitis', 'Disease', 'MESH:D005764', (267, 285))	('IGF1', 'Gene', '3479', (162, 166))	('Barrett esophagus', 'Disease', (290, 307))	('IGF1', 'Gene', (95, 99))	('EAC', 'Phenotype', 'HP:0011459', (234, 237))	('esophagitis', 'Phenotype', 'HP:0100633', (274, 285))	('IGF', 'Gene', (65, 68))	('associated', 'Reg', (218, 228))	('IGF1', 'Gene', (162, 166))	('IGF1', 'Gene', '3479', (95, 99))	('EAC', 'Disease', (234, 237))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (290, 307))
81402	25229459	The prevalence of lymph node involvement, tumor size (T1-T2 vs T3-T4) and histological grade was significantly greater in RUNX3-negative cases (RUNX3 unmethylated groups) than in RUNX3-positive cases (OR = 0.25, CI = 0.14-0.43, P<0.00001).	('T3-T4', 'Var', (63, 68))	('RUNX3', 'Gene', (144, 149))	('RUNX3', 'Gene', '864', (179, 184))	('RUNX3', 'Gene', '864', (144, 149))	('tumor', 'Disease', (42, 47))	('T1-T2', 'Var', (54, 59))	('histological grade', 'CPA', (74, 92))	('greater', 'PosReg', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('lymph node involvement', 'CPA', (18, 40))	('RUNX3', 'Gene', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('RUNX3', 'Gene', '864', (122, 127))	('RUNX3', 'Gene', (179, 184))
81405	25229459	The results of this meta-analysis suggest that RUNX3 methylation is associated with an increased risk, progression as well as worse survival in esophageal cancer.	('associated', 'Reg', (68, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('esophageal cancer', 'Disease', (144, 161))	('RUNX3', 'Gene', '864', (47, 52))	('RUNX3', 'Gene', (47, 52))	('methylation', 'Var', (53, 64))
81406	25229459	RUNX3 methylation, which induces the inactivation of RUNX3 gene, plays an important role in esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (92, 117))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (92, 117))	('role', 'Reg', (84, 88))	('methylation', 'Var', (6, 17))	('inactivation', 'MPA', (37, 49))	('RUNX3', 'Gene', (53, 58))	('RUNX3', 'Gene', '864', (53, 58))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
81413	25229459	Inactivation of RUNX3 by promoter methylation has been found to play an important role during normal tissue development and in tumorigenesis in esophagus.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('promoter methylation', 'Var', (25, 45))	('play', 'Reg', (64, 68))	('RUNX3', 'Gene', (16, 21))	('RUNX3', 'Gene', '864', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Inactivation', 'Var', (0, 12))	('esophagus', 'Disease', (144, 153))
81420	25229459	The following information was recorded for each study: the first author name, year of publication, sample source, number of cases, clinicopathological parameters, cancer with tumor node metastasis (TNM) stage, RUNX3 methylation and/or expression, and patient survival.	('expression', 'MPA', (235, 245))	('tumor node metastasis', 'Disease', 'MESH:D009362', (175, 196))	('patient', 'Species', '9606', (251, 258))	('RUNX3', 'Gene', (210, 215))	('RUNX3', 'Gene', '864', (210, 215))	('methylation', 'Var', (216, 227))	('tumor node metastasis', 'Disease', (175, 196))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
81425	25229459	The pooled OR from 6 studies including 347 esophageal cancers and 246 normal squamous mucosa was shown in Figure 2 (OR = 2.85, CI = 2.01-4.05, P<0.00001), which indicated that RUNX3 inactivation through methylation plays an important role in the pathogenesis of esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('esophageal cancers', 'Disease', (262, 280))	('RUNX3', 'Gene', (176, 181))	('RUNX3', 'Gene', '864', (176, 181))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('esophageal cancers', 'Disease', 'MESH:D004938', (43, 61))	('methylation', 'Var', (203, 214))	('esophageal cancers', 'Disease', 'MESH:D004938', (262, 280))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('esophageal cancers', 'Disease', (43, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('inactivation', 'NegReg', (182, 194))
81426	25229459	We analyzed 263 patients pooled in 4 studies to assess whether the aberrant RUNX3 methylation/expression in serum/cancer tissues DNA was associated with advanced stage, including tumor size (T1-T2 vs T3-T4), lymph node involvement, lymph and blood vessels metastasis, and recurrence in esophageal carcinomas.	('associated', 'Reg', (137, 147))	('lymph node involvement', 'CPA', (208, 230))	('patients', 'Species', '9606', (16, 24))	('RUNX3', 'Gene', '864', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (286, 307))	('methylation/expression', 'MPA', (82, 104))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (286, 306))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (286, 307))	('esophageal carcinomas', 'Disease', (286, 307))	('RUNX3', 'Gene', (76, 81))	('methylation/expression', 'Var', (82, 104))	('cancer', 'Disease', (114, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('carcinomas', 'Phenotype', 'HP:0030731', (297, 307))	('aberrant', 'Var', (67, 75))	('tumor', 'Disease', (179, 184))
81428	25229459	The prevalence of lymph node involvement, tumor size (T1-T2 vs T3-T4) and histological grade was significantly greater in RUNX3-negative cases (RUNX3 unmethylated groups) than in RUNX3-positive cases (Figure 3), with OR = 0.25, CI = 0.14-0.43, P<0.00001.	('T3-T4', 'Var', (63, 68))	('RUNX3', 'Gene', (144, 149))	('RUNX3', 'Gene', '864', (179, 184))	('RUNX3', 'Gene', '864', (144, 149))	('tumor', 'Disease', (42, 47))	('T1-T2', 'Var', (54, 59))	('histological grade', 'CPA', (74, 92))	('greater', 'PosReg', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('lymph node involvement', 'CPA', (18, 40))	('RUNX3', 'Gene', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('RUNX3', 'Gene', '864', (122, 127))	('RUNX3', 'Gene', (179, 184))
81429	25229459	These results suggest that epigenetic silencing of RUNX3 gene expression by promoter hypermethylation may play an important role in esophageal cancer progression and development.	('role', 'Reg', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('epigenetic silencing', 'Var', (27, 47))	('esophageal cancer', 'Disease', (132, 149))	('RUNX3', 'Gene', (51, 56))	('RUNX3', 'Gene', '864', (51, 56))	('play', 'Reg', (106, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))
81433	25229459	RUNX3 hypermethylation is an independent risk factor for progression of BE to high-grade dysplasia of esophagus and EAC.	('dysplasia of esophagus', 'Disease', (89, 111))	('hypermethylation', 'Var', (6, 22))	('dysplasia of esophagus', 'Phenotype', 'HP:0002032', (89, 111))	('dysplasia of esophagus', 'Disease', 'MESH:D004938', (89, 111))	('EAC', 'Disease', (116, 119))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
81434	25229459	No heterogeneity was observed in the analysis of RUNX3 methylation/low expression in normal samples and esophageal patient samples (P = 0.81), in BE and EAC patients (P = 0.88).	('expression', 'MPA', (71, 81))	('patient', 'Species', '9606', (157, 164))	('RUNX3', 'Gene', '864', (49, 54))	('RUNX3', 'Gene', (49, 54))	('patients', 'Species', '9606', (157, 165))	('methylation/low', 'NegReg', (55, 70))	('patient', 'Species', '9606', (115, 122))	('esophageal', 'Disease', (104, 114))	('methylation/low', 'Var', (55, 70))
81436	25229459	Four studies included investigated the relationship between OS and RUNX3 methylation/expression.	('RUNX3', 'Gene', '864', (67, 72))	('investigated', 'Reg', (22, 34))	('RUNX3', 'Gene', (67, 72))	('methylation/expression', 'Var', (73, 95))
81440	25229459	RUNX3 inactivation is a crucial factor to determine cancer pathogenesis and clinical outcome in a variety of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('inactivation', 'Var', (6, 18))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
81441	25229459	The different modes of RUNX3 inactivation in various tumor types include hemizygous deletion, mutations, hypermethylation, histone modifications and cytoplasmic mislocalization.	('mutations', 'Var', (94, 103))	('cytoplasmic', 'Disease', (149, 160))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('hemizygous deletion', 'Disease', (73, 92))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inactivation', 'NegReg', (29, 41))	('RUNX3', 'Gene', '864', (23, 28))	('hypermethylation', 'Var', (105, 121))	('tumor', 'Disease', (53, 58))	('RUNX3', 'Gene', (23, 28))	('histone', 'MPA', (123, 130))
81443	25229459	We conducted a meta-analysis to evaluate the correlation between RUNX3 promoter methylation/low expression and esophageal cancer.	('RUNX3', 'Gene', (65, 70))	('RUNX3', 'Gene', '864', (65, 70))	('promoter methylation/low', 'Var', (71, 95))	('esophageal cancer', 'Disease', (111, 128))	('expression', 'MPA', (96, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
81446	25229459	Although these two esophageal cancers are different in pathogenesis, epidemiology, tumor biology, prognosis and therapeutic strategies among the pooled patients in this meta analysis, RUNX3 methylation/low expression was associated with the pathogenesis of both types of esophageal cancer, indicating that RUNX3 might be responsible for different patterns of tumorigenesis.	('tumor', 'Disease', (83, 88))	('methylation/low', 'Var', (190, 205))	('RUNX3', 'Gene', '864', (306, 311))	('esophageal cancers', 'Disease', 'MESH:D004938', (19, 37))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (19, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (271, 288))	('tumor', 'Disease', (359, 364))	('RUNX3', 'Gene', '864', (184, 189))	('associated', 'Reg', (221, 231))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('esophageal cancer', 'Disease', (271, 288))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('RUNX3', 'Gene', (306, 311))	('patients', 'Species', '9606', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('methylation/low', 'NegReg', (190, 205))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('RUNX3', 'Gene', (184, 189))	('esophageal cancers', 'Disease', (19, 37))
81450	25229459	It was accepted that BE is a precancerous tissue, and that aberrant promoter methylation occurs early in metaplasia before histological evidence of progression to cancer.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('metaplasia', 'Disease', 'MESH:D008679', (105, 115))	('cancer', 'Disease', (32, 38))	('aberrant', 'Var', (59, 67))	('metaplasia', 'Disease', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('promoter methylation', 'MPA', (68, 88))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
81451	25229459	Some underlying mechanisms for aberrant DNA methylation in Barrett's metaplasia have been noted.	('aberrant', 'Var', (31, 39))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (59, 79))	("Barrett's metaplasia", 'Disease', (59, 79))	('DNA', 'Protein', (40, 43))
81454	25229459	In other words, the aberrant methylation of RUNX3 gene is an early event, which most probably occurs independently of EAC.	('methylation', 'MPA', (29, 40))	('aberrant', 'Var', (20, 28))	('RUNX3', 'Gene', (44, 49))	('RUNX3', 'Gene', '864', (44, 49))
81458	25229459	Sakakura et al found that frequent silencing of RUNX3 by promoter hypermethylation in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis.	('silencing', 'NegReg', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('RUNX3', 'Gene', (48, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('RUNX3', 'Gene', '864', (48, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('esophageal squamous cell carcinomas', 'Disease', (86, 121))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (86, 121))	('associated', 'Reg', (125, 135))	('promoter hypermethylation', 'Var', (57, 82))	('radioresistance', 'CPA', (141, 156))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (97, 121))
81469	25229459	In addition, RUNX3 methylation is associated with an increased risk and worse survival in esophageal cancer patients.	('RUNX3', 'Gene', (13, 18))	('RUNX3', 'Gene', '864', (13, 18))	('methylation', 'Var', (19, 30))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (108, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))
81474	25229459	Conventional chemotherapy can induce resistance to chemotherapeutic agents, and tumor regrowth mediated by CSCs, therefore targeting RUNX3 gene and its related signaling pathways could be another mechanism for therapeutic approaches for cancer treatment aiming at CSC elimination.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('targeting', 'Var', (123, 132))	('RUNX3', 'Gene', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('RUNX3', 'Gene', '864', (133, 138))	('resistance', 'CPA', (37, 47))	('cancer', 'Disease', (237, 243))
81478	22264787	The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency.	('EAC', 'Phenotype', 'HP:0011459', (26, 29))	('IL-6 deficiency', 'Phenotype', 'HP:0030783', (110, 125))	('accelerated', 'PosReg', (34, 45))	('rat', 'Species', '10116', (40, 43))	('BE', 'Phenotype', 'HP:0100580', (19, 21))	('nitrosamines', 'MPA', (79, 91))	('development', 'CPA', (4, 15))	('deficiency', 'Var', (115, 125))	('nitrosamines', 'Chemical', 'MESH:D009602', (79, 91))	('inhibited', 'NegReg', (97, 106))	('bile acids', 'Chemical', 'MESH:D001647', (61, 71))	('bile acids', 'MPA', (61, 71))
81489	22264787	However, prior to the development of IM, a regenerative intestinal-like columnar cell lineage appears in the esophagus that expresses TFF2, K8, K20, Notch and Cdx2.	('K20', 'Gene', (144, 147))	('Notch', 'Var', (149, 154))	('Cdx2', 'Gene', (159, 163))	('TFF2', 'Gene', (134, 138))	('rat', 'Species', '10116', (49, 52))	('K20', 'Gene', '66809', (144, 147))
81498	22264787	L2-IL-1beta mice developed splenomegaly (Figure S1c) that correlated with age dependent IL-1beta expression levels (Figure 1b), consistent with a systemic inflammatory reaction and at least 10-fold elevated (p<0.05) circulating levels of IL-1beta, TNFalpha (Figure S1d), and IL-6 (Figure 1d).	('splenomegaly', 'Disease', 'MESH:D013163', (27, 39))	('IL-1beta expression', 'MPA', (88, 107))	('TNFalpha', 'Gene', (248, 256))	('elevated', 'PosReg', (198, 206))	('splenomegaly', 'Phenotype', 'HP:0001744', (27, 39))	('splenomegaly', 'Disease', (27, 39))	('mice', 'Species', '10090', (12, 16))	('TNFalpha', 'Gene', '21926', (248, 256))	('L2-IL-1beta', 'Var', (0, 11))
81504	22264787	In 100% (10/10) of the 6-month-old L2-IL-1beta mice, we observed moderate inflammation and profound epithelial hyperplasia (Figure 1f) that was never observed in age-matched WT mice.	('L2-IL-1beta', 'Var', (35, 46))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('inflammation', 'Disease', (74, 86))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (100, 122))	('epithelial hyperplasia', 'Disease', (100, 122))	('mice', 'Species', '10090', (177, 181))	('rat', 'Species', '10116', (69, 72))	('mice', 'Species', '10090', (47, 51))
81510	22264787	At 20-22 months of age, 20% (2/9) of L2-IL-1beta mice developed high-grade dysplasia (HGD) or intramucosal EAC (Figure 1e-g).	('mice', 'Species', '10090', (49, 53))	('dysplasia', 'Disease', (75, 84))	('L2-IL-1beta', 'Var', (37, 48))	('EAC', 'Phenotype', 'HP:0011459', (107, 110))	('dysplasia', 'Disease', 'MESH:D004476', (75, 84))
81524	22264787	Sixty percent (6/10) of 9-month-old BA-treated L2-IL-1beta mice showed metaplastic changes at the SCJ, with higher overall metaplasia scores compared to untreated L2-IL-1beta mice (2.7 vs. 1.8 p<0.05) (Figure 3a, S3c), indicating a significant acceleration by BA of Barrett's-like metaplasia.	('metaplastic changes', 'CPA', (71, 90))	('BA', 'Chemical', 'MESH:D001647', (260, 262))	('acceleration', 'PosReg', (244, 256))	('mice', 'Species', '10090', (175, 179))	('mice', 'Species', '10090', (59, 63))	('metaplasia', 'Disease', 'MESH:D008679', (281, 291))	('rat', 'Species', '10116', (250, 253))	('metaplasia', 'Disease', 'MESH:D008679', (123, 133))	('metaplasia', 'Disease', (281, 291))	("Barrett's-like", 'Disease', (266, 280))	('L2-IL-1beta', 'Var', (47, 58))	('metaplasia', 'Disease', (123, 133))	('higher', 'PosReg', (108, 114))	('BA', 'Chemical', 'MESH:D001647', (36, 38))
81525	22264787	Moreover, we observed more severe metaplasia and dysplasia in BA-treated L2-IL-1beta mice compared to untreated L2-IL-1beta mice at both 12 months (dysplasia score 2.1 vs. 1.0 p<0.05) and 15 months (dysplasia score 2.4 vs. 1.4 p<0.01) (Figure 3a, S3c).	('mice', 'Species', '10090', (85, 89))	('L2-IL-1beta', 'Var', (73, 84))	('dysplasia', 'Disease', (148, 157))	('BA', 'Chemical', 'MESH:D001647', (62, 64))	('dysplasia', 'Disease', (49, 58))	('dysplasia', 'Disease', 'MESH:D004476', (148, 157))	('metaplasia and dysplasia', 'Disease', 'MESH:D008679', (34, 58))	('mice', 'Species', '10090', (124, 128))	('dysplasia', 'Disease', 'MESH:D004476', (49, 58))	('dysplasia', 'Disease', (199, 208))	('dysplasia', 'Disease', 'MESH:D004476', (199, 208))
81533	22264787	The esophagi of L2-IL-1beta mice showed circumferential erythema and edema with inflammatory exudates compared to the normal esophagus (Figure 3c), changes that were increased in BA-treated L2-IL-1beta mice.	('edema', 'Phenotype', 'HP:0000969', (69, 74))	('erythema', 'Disease', 'MESH:D004890', (56, 64))	('BA', 'Chemical', 'MESH:D001647', (179, 181))	('mice', 'Species', '10090', (202, 206))	('erythema', 'Disease', (56, 64))	('mice', 'Species', '10090', (28, 32))	('L2-IL-1beta', 'Var', (16, 27))	('edema', 'Disease', (69, 74))	('edema', 'Disease', 'MESH:D004487', (69, 74))	('erythema', 'Phenotype', 'HP:0010783', (56, 64))
81540	22264787	At 9, 12, and 15-months, there was an even greater accumulation in L2-IL-1beta mice of CD11b+Gr1+ cells in the esophagus (Figure 4c) and spleen (not shown) associated with chronic esophagitis and metaplasia.	('CD11b+Gr1+', 'Var', (87, 97))	('mice', 'Species', '10090', (79, 83))	('accumulation', 'PosReg', (51, 63))	('esophagitis', 'Phenotype', 'HP:0100633', (180, 191))	('esophagitis', 'Disease', (180, 191))	('esophagitis', 'Disease', 'MESH:D004941', (180, 191))	('metaplasia', 'Disease', 'MESH:D008679', (196, 206))	('metaplasia', 'Disease', (196, 206))
81542	22264787	Inflammatory cytokines were increased (Figure 1a-d and S1d) and the L2-IL-1beta mice developed splenomegaly, likely due to an accumulation of immature splenic myeloid cells (Figure S1c).	('increased', 'PosReg', (28, 37))	('splenomegaly', 'Phenotype', 'HP:0001744', (95, 107))	('accumulation', 'PosReg', (126, 138))	('Inflammatory cytokines', 'MPA', (0, 22))	('splenomegaly', 'Disease', (95, 107))	('L2-IL-1beta', 'Var', (68, 79))	('mice', 'Species', '10090', (80, 84))	('splenomegaly', 'Disease', 'MESH:D013163', (95, 107))	('developed', 'PosReg', (85, 94))
81552	22264787	Notch inhibition by systemic treatment with a gamma-secretase inhibitor (DBZ), as reported previously, markedly increased both PAS+ cells and Alcian-Blue(+) goblet-like cells (Figure 5b, c), suggesting that inhibition of Notch signaling is associated with IM.	('inhibition', 'Var', (207, 217))	('Alcian-Blue', 'Chemical', 'MESH:D000423', (142, 153))	('DBZ', 'Gene', '216049', (73, 76))	('increased', 'PosReg', (112, 121))	('DBZ', 'Gene', (73, 76))	('Notch', 'MPA', (0, 5))
81554	22264787	These findings suggest that Notch signaling might contribute to the development of dysplasia, whereas inhibition of Notch signaling results in goblet cell differentiation and may prevent malignant transformation, although in theory both processes could occur simultaneously in different regions of the metaplastic epithelium.	('contribute', 'Reg', (50, 60))	('results in', 'Reg', (132, 142))	('malignant transformation', 'CPA', (187, 211))	('dysplasia', 'Disease', 'MESH:D004476', (83, 92))	('prevent', 'NegReg', (179, 186))	('inhibition', 'Var', (102, 112))	('Notch signaling', 'Gene', (116, 131))	('goblet cell differentiation', 'CPA', (143, 170))	('dysplasia', 'Disease', (83, 92))	('Notch', 'Var', (28, 33))
81561	22264787	Overall, Notch activation appears to be associated with decreased goblet cell differentiation, as suggested by a lack of goblet cells in adjacent tissue of human EAC samples (unpublished data) and a review of the literature (Table S2).	('goblet cell differentiation', 'CPA', (66, 93))	('decreased', 'NegReg', (56, 65))	('Notch activation', 'Var', (9, 25))	('EAC', 'Phenotype', 'HP:0011459', (162, 165))	('human', 'Species', '9606', (156, 161))	('rat', 'Species', '10116', (217, 220))
81565	22264787	LCM was applied to typical metaplastic lesions in L2-IL-1beta mice (with or without BA), and to the squamous epithelium of WT mice (Figure 6a).	('metaplastic lesions', 'CPA', (27, 46))	('mice', 'Species', '10090', (126, 130))	('L2-IL-1beta', 'Var', (50, 61))	('mice', 'Species', '10090', (62, 66))	('BA', 'Chemical', 'MESH:D001647', (84, 86))
81590	22264787	IL-1beta is upstream of IL-6 and TNF-alpha, which are both upregulated in our models (Figure S1d) and overexpression of IL-1beta has been shown to induce tumorigenesis of the stomach.	('TNF-alpha', 'Gene', '21926', (33, 42))	('induce', 'PosReg', (147, 153))	('IL-1beta', 'Gene', (120, 128))	('upregulated', 'PosReg', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('TNF-alpha', 'Gene', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumorigenesis of the stomach', 'Phenotype', 'HP:0006753', (154, 182))	('overexpression', 'Var', (102, 116))	('tumor', 'Disease', (154, 159))
81592	22264787	We observed elevated IL-6 protein levels in the serum and the SCJ of L2-IL-1beta mice (Figure 1d), and IL-6 could be upregulated further by BA treatment (Figure 8a).	('BA', 'Chemical', 'MESH:D001647', (140, 142))	('L2-IL-1beta', 'Var', (69, 80))	('elevated', 'PosReg', (12, 20))	('mice', 'Species', '10090', (81, 85))	('elevated IL-6', 'Phenotype', 'HP:0030783', (12, 25))	('IL-6', 'Protein', (21, 25))
81598	22264787	When we crossed L2-IL-1beta mice with IL-6-/- mice we observed a complete abolishment of the metaplastic and dysplastic phenotype in homozygous L2-IL-1beta/IL-6-/- mice, and a partly diminished phenotype with little metaplasia and no dysplasia in heterozygous L2-IL-1beta/IL-6-/+ mice (Figure 8f).	('dysplastic', 'Disease', (109, 119))	('dysplasia', 'Disease', 'MESH:D004476', (234, 243))	('L2-IL-1beta/IL-6-/-', 'Var', (144, 163))	('abolishment', 'NegReg', (74, 85))	('mice', 'Species', '10090', (164, 168))	('mice', 'Species', '10090', (28, 32))	('metaplasia', 'Disease', 'MESH:D008679', (216, 226))	('mice', 'Species', '10090', (46, 50))	('mice', 'Species', '10090', (280, 284))	('dysplasia', 'Disease', (234, 243))	('metaplasia', 'Disease', (216, 226))	('dysplastic', 'Disease', 'MESH:D004416', (109, 119))
81599	22264787	In L2-IL-1beta/IL-6-/- mice, we observed only a minor inflammatory response, which was increased in L2-IL-1beta/IL-6-/+ mice, but no increase in pSTAT3+ cells could be detected (data not shown).	('increased', 'PosReg', (87, 96))	('mice', 'Species', '10090', (120, 124))	('L2-IL-1beta/IL-6-/-', 'Var', (3, 22))	('STAT3', 'Gene', (146, 151))	('L2-IL-1beta/IL-6-/+', 'Var', (100, 119))	('inflammatory response', 'CPA', (54, 75))	('STAT3', 'Gene', '20848', (146, 151))	('mice', 'Species', '10090', (23, 27))
81613	22264787	IL-6 levels were systemically elevated in L2-IL-1beta mice, and the addition of IL-6 deficiency completely abrogated the IL-1beta induced phenotype, indicating the importance of systemic immune activation in the development of neoplasia.	('deficiency', 'Var', (85, 95))	('IL-6', 'Gene', (80, 84))	('abrogated', 'NegReg', (107, 116))	('IL-6 deficiency', 'Phenotype', 'HP:0030783', (80, 95))	('neoplasia', 'Disease', 'MESH:D009369', (227, 236))	('neoplasia', 'Phenotype', 'HP:0002664', (227, 236))	('elevated', 'PosReg', (30, 38))	('mice', 'Species', '10090', (54, 58))	('neoplasia', 'Disease', (227, 236))
81657	33364828	Subgroup analysis demonstrated that Siewert type III (HR= 3.20, 95% CI: 1.45-7.06) was associated with worse DSS, but not Siewert type I/II (HR= 1.46, 95% CI: 0.94-2.31, P-interaction=0.047).	('DSS', 'Chemical', '-', (109, 112))	('DSS', 'Disease', (109, 112))	('Siewert type III', 'Var', (36, 52))
81690	33364828	Adjustment variables included age, sex, tumor size, Siewert type, degree of differentiation, pT stage, pN stage, lymph node ratio, Her2 expression, Ki67%, preoperative and postoperative chemotherapy and surgical approach, all of which might have been correlated with tumor prognosis.	('pN stage', 'Disease', (103, 111))	('Her2', 'Gene', (131, 135))	('Her2', 'Gene', '2064', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('Ki67', 'Var', (148, 152))	('pT stage', 'Disease', (93, 101))	('tumor', 'Disease', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
81711	33364828	Subgroup analysis according to Siewert type demonstrated that Siewert type III (HR= 3.20, 95% CI: 1.45-7.06) was associated with worse DSS, but not Siewert type I/II (HR= 1.46, 95% CI: 0.94-2.31, P-interaction=0.047).	('Siewert', 'Var', (62, 69))	('DSS', 'Chemical', '-', (135, 138))	('DSS', 'Disease', (135, 138))
81722	33364828	The risk of developing LVI in Siewert type III AEG was 2.08 times higher than in Siewert type I/II (OR 2.08, 95% CI: 1.02-4.25).	('Siewert type III', 'Var', (30, 46))	('LVI', 'Chemical', '-', (23, 26))	('LVI', 'Disease', (23, 26))	('AEG', 'Chemical', '-', (47, 50))
81854	33314747	Nevertheless, in the KEYNOTE-181 trial, pembrolizumab significantly prolonged OS compared with chemotherapy in the subgroup of patients with a PD-L1 CPS >= 10, while in the intent-to-treat population, the OS was similar [32].	('CPS', 'Chemical', '-', (149, 152))	('prolonged', 'PosReg', (68, 77))	('patients', 'Species', '9606', (127, 135))	('PD-L1', 'Gene', (143, 148))	('pembrolizumab', 'Chemical', 'MESH:C582435', (40, 53))	('pembrolizumab', 'Var', (40, 53))	('PD-L1', 'Gene', '29126', (143, 148))
81987	32039021	Finally, previous studies have shown that gene events such as ZNF750 mutations were associated with metastasis in patients with ESCC.	('mutations', 'Var', (69, 78))	('ZNF750', 'Gene', (62, 68))	('ZNF750', 'Gene', '79755', (62, 68))	('ESCC', 'Disease', 'MESH:C562729', (128, 132))	('associated', 'Reg', (84, 94))	('ESCC', 'Disease', (128, 132))	('patients', 'Species', '9606', (114, 122))	('metastasis', 'CPA', (100, 110))
82012	29947767	Several studies have demonstrated favorable clinical outcomes for C-ion RT, especially in X-ray-resistant tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('C-ion', 'Var', (66, 71))	('C', 'Chemical', 'MESH:D002244', (66, 67))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
82051	29947767	Because HMGB1 stimulates DCs to activate immature T lymphocytes, the present study suggests that high-LET irradiation may induce more efficient specific anti-tumor immunity than low-LET irradiation, even if the iso-survival dose is administered.	('HMGB1', 'Gene', '3146', (8, 13))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('HMGB1', 'Gene', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('high-LET', 'Var', (97, 105))
82065	29947767	A recent study showed that checkpoint kinase 1, which coordinates the DNA damage and cell cycle checkpoint responses, is activated by ~3-fold after C-ion irradiation compared with after an equal physical dose of X-rays.	('cell cycle', 'CPA', (85, 95))	('C', 'Chemical', 'MESH:D002244', (148, 149))	('checkpoint kinase 1', 'Enzyme', (27, 46))	('C-ion irradiation', 'Var', (148, 165))	('rays', 'Species', '255564', (214, 218))	('activated', 'PosReg', (121, 130))	('DNA damage', 'MPA', (70, 80))
82166	29021969	Instead, cancer occurs at the DNA level via somatic alterations in the genome structure.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('alterations', 'Var', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
82167	29021969	A common type of somatic mutations found in cancer is due to single nucleotide variations (SNVs) or alterations to single bases in the genome, which accumulate through the lifespan of the cancer via imperfect DNA replication during cell division or spontaneous cytosine deamination, or due to exposures to chemical insults or ultraviolet radiation, etc.	('mutations', 'Var', (25, 34))	('single nucleotide variations', 'Var', (61, 89))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('imperfect', 'Var', (199, 208))	('cytosine', 'Chemical', 'MESH:D003596', (261, 269))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('alterations', 'Var', (100, 111))
82237	29021969	14 through 20 of, Sig1, Sig2, Sig4 and Sig7 are precisely the cancer signatures that have "peaks" (or "spikes" - "tall mountain landscapes"), whereas Sig3, Sig5 and Sig6 do not have such "peaks" ("flat" or "rolling hills landscapes").	('Sig4', 'Var', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Sig1', 'Var', (18, 22))	('Sig2', 'Var', (24, 28))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Sig7', 'Gene', (39, 43))
82252	29021969	Instead, via aggregating a large number of k-means clusterings and statistical examination of the occurrence counts of such aggregations, *K-means takes a mess of myriad vanilla k-means clusterings and systematically reduces randomness and indeterminism without ad hoc initial "guesswork".	('reduces', 'NegReg', (217, 224))	('randomness', 'Disease', 'MESH:C562757', (225, 235))	('randomness', 'Disease', (225, 235))	('indeterminism', 'MPA', (240, 253))	('*K-means', 'Var', (138, 146))
82277	29021969	20 of, we see that its "peaks" for the C > G mutations are essentially the same as in Cl-1.	('Cl-1', 'Gene', '9201', (86, 90))	('C > G mutations', 'Var', (39, 54))	('Cl-1', 'Gene', (86, 90))
82300	28501229	In three studies of functional dyspepsia that included patients with GERD symptoms, those receiving STW 5 were more likely to have improvement in symptoms than those receiving placebo.	('STW 5', 'Chemical', '-', (100, 105))	('functional dyspepsia', 'Disease', (20, 40))	('STW 5', 'Var', (100, 105))	('improvement', 'PosReg', (131, 142))	('dyspepsia', 'Phenotype', 'HP:0410281', (31, 40))	('functional dyspepsia', 'Disease', 'MESH:D004415', (20, 40))	('patients', 'Species', '9606', (55, 63))	('symptoms', 'MPA', (146, 154))
82309	28501229	Weight loss (obesity increases the risk of GERD) and elevating the head of the bed can help decrease symptoms.	('obesity', 'Phenotype', 'HP:0001513', (13, 20))	('Weight loss', 'Phenotype', 'HP:0001824', (0, 11))	('obesity increases', 'Disease', 'MESH:D009765', (13, 30))	('Weight loss', 'Disease', (0, 11))	('Weight loss', 'Disease', 'MESH:D015431', (0, 11))	('obesity increases', 'Disease', (13, 30))	('elevating', 'Var', (53, 62))
82310	28501229	There is good evidence for acupuncture, raft-forming agents, Iberogast, weight loss, and elevating the head of the bed for reducing GERD-related symptoms.	('reducing', 'NegReg', (123, 131))	('weight loss', 'Disease', 'MESH:D015431', (72, 83))	('elevating', 'Var', (89, 98))	('weight loss', 'Disease', (72, 83))	('GERD-related symptoms', 'Disease', (132, 153))	('acupuncture', 'Var', (27, 38))	('weight loss', 'Phenotype', 'HP:0001824', (72, 83))
82368	28501229	A recent meta-analysis of 6 RCTs and 16 non-randomized studies showed that a low FODMAP diet was associated with reduced abdominal pain, bloating and improvement in overall symptom score.	('low', 'Var', (77, 80))	('bloating', 'Disease', (137, 145))	('bloating', 'Phenotype', 'HP:0003270', (137, 145))	('abdominal pain', 'Phenotype', 'HP:0002027', (121, 135))	('pain', 'Phenotype', 'HP:0012531', (131, 135))	('abdominal pain', 'Disease', (121, 135))	('improvement', 'PosReg', (150, 161))	('symptom score', 'MPA', (173, 186))	('reduced', 'NegReg', (113, 120))	('abdominal pain', 'Disease', 'MESH:D015746', (121, 135))
82411	28501229	There is good evidence for weight loss, silymarin (140 mg/day) combined with vitamin E, and probiotics for patients with NAFLD.	('weight loss', 'Disease', (27, 38))	('silymarin', 'Chemical', 'MESH:D012838', (40, 49))	('140', 'Var', (51, 54))	('weight loss', 'Phenotype', 'HP:0001824', (27, 38))	('patients', 'Species', '9606', (107, 115))	('vitamin E', 'Chemical', 'MESH:D014810', (77, 86))	('weight loss', 'Disease', 'MESH:D015431', (27, 38))
82429	28501229	A Cochrane review of nine trials (6 RCTs and 3 controlled clinical trials) concluded that isopropyl alcohol was more effective than saline for post-operative nausea but less effective than standard anti-emetics.	('nausea', 'Phenotype', 'HP:0002018', (158, 164))	('post-operative', 'Disease', (143, 157))	('nausea', 'Disease', (158, 164))	('nausea', 'Disease', 'MESH:D009325', (158, 164))	('isopropyl alcohol', 'Chemical', 'MESH:D019840', (90, 107))	('saline', 'Chemical', 'MESH:D012965', (132, 138))	('isopropyl alcohol', 'Var', (90, 107))
82444	28068934	Concordance between PIK3CA mutations in endoscopic biopsy and surgically resected specimens of esophageal squamous cell carcinoma PIK3CA mutations are expected to be potential therapeutic targets for esophageal squamous cell carcinoma (ESCC).	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (130, 136))	('esophageal squamous cell carcinoma', 'Disease', (95, 129))	('PIK3CA', 'Gene', '5290', (130, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('PIK3CA', 'Gene', (20, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('PIK3CA', 'Gene', '5290', (20, 26))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (200, 234))	('mutations', 'Var', (137, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (95, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('esophageal squamous cell carcinoma', 'Disease', (200, 234))
82445	28068934	We examined five hotspot mutations in the PIK3CA gene (E542K, E545K, E546K, H1047R, and H1047L) in formalin-fixed and paraffin-embedded tissue sections of paired endoscopic biopsy and surgically resected specimens from 181 patients undergoing curative resection for ESCC between 2000 and 2011 using a Luminex technology-based multiplex gene mutation detection kit.	('E542K', 'Var', (55, 60))	('ESCC', 'Disease', (266, 270))	('PIK3CA', 'Gene', (42, 48))	('H1047R', 'Mutation', 'rs121913279', (76, 82))	('paraffin', 'Chemical', 'MESH:D010232', (118, 126))	('E545K', 'Mutation', 'rs104886003', (62, 67))	('E542K', 'Mutation', 'rs121913273', (55, 60))	('E545K', 'Var', (62, 67))	('H1047L', 'Mutation', 'rs121913279', (88, 94))	('E546K', 'Var', (69, 74))	('H1047L', 'Var', (88, 94))	('formalin', 'Chemical', 'MESH:D005557', (99, 107))	('patient', 'Species', '9606', (223, 230))	('patients', 'Species', '9606', (223, 231))	('H1047R', 'Var', (76, 82))	('E546K', 'Mutation', 'rs752742313', (69, 74))
82446	28068934	There were three cases with a discordant mutation status between the types of specimens (PIK3CA mutation in surgically resected specimen and wild-type in biopsy specimen in two cases, and the opposite pattern in one case), suggesting possible intratumoral heterogeneity in the PIK3CA mutation status.	('tumor', 'Disease', (248, 253))	('PIK3CA', 'Gene', (89, 95))	('mutation', 'Var', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
82447	28068934	The PIK3CA mutation status was highly concordant between endoscopic biopsy and surgically resected specimens from the same patient, suggesting that endoscopic biopsy specimens can be clinically used to detect PIK3CA mutations in patients with ESCC.	('clinical', 'Species', '191496', (183, 191))	('mutations', 'Var', (216, 225))	('PIK3CA', 'Gene', (209, 215))	('ESCC', 'Disease', (243, 247))
82450	28068934	The phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway plays a pivotal role in cancer cell proliferation, and mutations in the PIK3CA gene are commonly found in various cancers regardless of histological subtypes.	('phosphoinositide 3-kinase', 'Gene', '5290', (4, 29))	('mammalian', 'Species', '9606', (41, 50))	('mTOR', 'Gene', '2475', (72, 76))	('mutations', 'Var', (141, 150))	('PIK3CA', 'Gene', (158, 164))	('found', 'Reg', (183, 188))	('Akt', 'Gene', '207', (37, 40))	('mTOR', 'Gene', (72, 76))	('phosphoinositide 3-kinase', 'Gene', (4, 29))	('cancers', 'Disease', (200, 207))	('PI3', 'Gene', '5266', (31, 34))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('Akt', 'Gene', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('PI3', 'Gene', (31, 34))
82451	28068934	More than 80% of PIK3CA mutations occur in two major regions: the helical domain (exon 9), and the kinase domain (exon 20); moreover, three mutations (E542K, E545K, and H1047R) have been regarded as hotspot mutations.	('E542K', 'SUBSTITUTION', 'None', (151, 156))	('H1047R', 'Var', (169, 175))	('H1047R', 'SUBSTITUTION', 'None', (169, 175))	('PIK3CA', 'Gene', (17, 23))	('E545K', 'Var', (158, 163))	('E545K', 'SUBSTITUTION', 'None', (158, 163))	('E542K', 'Var', (151, 156))
82452	28068934	In addition, PIK3CA mutations have been suggested to be a potential predictive biomarker for PI3K-Akt-mTOR inhibitors in a review of early phase clinical trials for the testing of such agents in various solid cancers.	('PIK3CA', 'Gene', (13, 19))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('solid cancers', 'Disease', (203, 216))	('solid cancers', 'Disease', 'MESH:D009369', (203, 216))	('mutations', 'Var', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
82453	28068934	In this report, a case with squamous cell head and neck carcinoma, which is genetically similar to ESCC, harboring a PIK3CA mutation (H1047R) demonstrated a partial response to a PI3K-Akt-mTOR inhibitor.	('H1047R', 'Var', (134, 140))	('PIK3CA', 'Gene', (117, 123))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (42, 65))	('H1047R', 'SUBSTITUTION', 'None', (134, 140))	('neck carcinoma', 'Disease', (51, 65))	('neck carcinoma', 'Disease', 'MESH:D006258', (51, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
82454	28068934	The frequency of PIK3CA mutations in ESCC has been reported to range from 2.2 to 21%, whereas mutations in genes in the RAS-RAF pathway are very rare.	('RAF', 'Gene', (124, 127))	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', (17, 23))	('RAF', 'Gene', '22882', (124, 127))
82455	28068934	Previous studies investigating the frequency of PIK3CA mutations in ESCC used available clinical samples obtained from either surgically resected specimens or biopsy specimens.	('ESCC', 'Disease', (68, 72))	('PIK3CA', 'Gene', (48, 54))	('clinical samples', 'Species', '191496', (88, 104))	('mutations', 'Var', (55, 64))
82456	28068934	Among 352 previously untreated patients with ESCC who underwent a curative-intent transthoracic esophagectomy with extended lymphadenectomy at the National Cancer Center Hospital East, Kashiwa, Japan, between January 2000 and December 2011, a total of 181 patients were enrolled according to the following selection criteria: (i) pathological T factor of at least T1b, (ii) availability of paired samples of endoscopic biopsy and surgically resected specimens, (iii) patient age of <=75 years, (iv) absence of past or concurrent history of cancer, (v) adequate organ function, and (vi) absence of in-hospital death following surgery.	('death', 'Disease', (609, 614))	('Cancer', 'Disease', 'MESH:D009369', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (540, 546))	('extended lymphadenectomy', 'Phenotype', 'HP:0002716', (115, 139))	('T1b', 'Var', (364, 367))	('death', 'Disease', 'MESH:D003643', (609, 614))	('Cancer', 'Disease', (156, 162))
82459	28068934	PIK3CA mutations were detected using a Luminex (xMAP) technology-based multiplex gene mutation detection kit (GENOSEARCH Mu-PACK; MBL, Nagoya, Japan), which was developed prior to the present study; an optimal concordance between the kit and the conventional direct sequencing method was confirmed previously.	('MBL', 'Gene', (130, 133))	('PIK3CA', 'Gene', (0, 6))	('MBL', 'Gene', '50639', (130, 133))	('mutations', 'Var', (7, 16))
82460	28068934	A total of five PIK3CA mutations, including codon 542 (E542K), codon 545 (E545K), and codon 546 (E546K) in exon 9 and codon 1047 (H1047R, H1047L) in exon 20, were investigated.	('E542K', 'Var', (55, 60))	('H1047L', 'SUBSTITUTION', 'None', (138, 144))	('E542K', 'SUBSTITUTION', 'None', (55, 60))	('E546K', 'SUBSTITUTION', 'None', (97, 102))	('H1047R', 'SUBSTITUTION', 'None', (130, 136))	('H1047R', 'Var', (130, 136))	('E545K', 'SUBSTITUTION', 'None', (74, 79))	('H1047L', 'Var', (138, 144))	('E546K', 'Var', (97, 102))	('PIK3CA', 'Gene', (16, 22))	('E545K', 'Var', (74, 79))
82463	28068934	Among the endoscopic biopsy specimens, there were 11 cases with PIK3CA mutations: two with E542K, three with E545K, five with H1047R, and one with H1047L.	('PIK3CA', 'Gene', (64, 70))	('H1047L', 'Var', (147, 153))	('E545K', 'Var', (109, 114))	('E542K', 'Var', (91, 96))	('H1047R', 'Var', (126, 132))	('E542K', 'SUBSTITUTION', 'None', (91, 96))	('H1047R', 'SUBSTITUTION', 'None', (126, 132))	('E545K', 'SUBSTITUTION', 'None', (109, 114))	('H1047L', 'SUBSTITUTION', 'None', (147, 153))
82464	28068934	Among the surgically resected specimens, there were 12 cases with PIK3CA mutations: one with E542K, four with E545K, six with H1047R, and one with H1047L.	('E542K', 'SUBSTITUTION', 'None', (93, 98))	('H1047L', 'Var', (147, 153))	('E545K', 'SUBSTITUTION', 'None', (110, 115))	('PIK3CA', 'Gene', (66, 72))	('H1047R', 'Var', (126, 132))	('H1047R', 'SUBSTITUTION', 'None', (126, 132))	('E545K', 'Var', (110, 115))	('H1047L', 'SUBSTITUTION', 'None', (147, 153))	('E542K', 'Var', (93, 98))
82465	28068934	Figure 1 shows micrographs of the ESCC case that harbored a PIK3CA mutation (H1047R) in both the biopsy and the surgically resected specimens.	('H1047R', 'SUBSTITUTION', 'None', (77, 83))	('H1047R', 'Var', (77, 83))	('PIK3CA', 'Gene', (60, 66))
82466	28068934	132, NGS revealed a PIK3CA mutation in H1047R with a mutant allele frequency of 4.5% in the surgically resected specimen; no PIK3CA mutations were detected in the endoscopic biopsy specimen.	('PIK3CA', 'Gene', (20, 26))	('H1047R', 'SUBSTITUTION', 'None', (39, 45))	('H1047R', 'Var', (39, 45))
82467	28068934	Among the five hotspot mutations assessed in the present study, E542K, E545K and E546K are located in exon 9, corresponding to the helical domain, and H1047R and H1047L are located in exon 20, corresponding to the kinase domain.	('E545K', 'Var', (71, 76))	('E546K', 'Var', (81, 86))	('H1047L', 'SUBSTITUTION', 'None', (162, 168))	('E545K', 'SUBSTITUTION', 'None', (71, 76))	('E546K', 'SUBSTITUTION', 'None', (81, 86))	('H1047R', 'Var', (151, 157))	('E542K', 'Var', (64, 69))	('H1047L', 'Var', (162, 168))	('H1047R', 'SUBSTITUTION', 'None', (151, 157))	('E542K', 'SUBSTITUTION', 'None', (64, 69))
82469	28068934	In colorectal cancer, the concordance rate of the KRAS mutation status between endoscopic biopsy and surgically resected specimens is high, similar to that of the PIK3CA mutation status in ESCC demonstrated in the present study, and endoscopic biopsy specimens are used for the molecular analysis of KRAS mutations to evaluate the clinical indications for anti-epidermal growth factor receptor antibody therapy.	('KRAS', 'Gene', (300, 304))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('KRAS', 'Gene', '3845', (300, 304))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('KRAS', 'Gene', (50, 54))	('KRAS', 'Gene', '3845', (50, 54))	('colorectal cancer', 'Disease', (3, 20))	('mutation', 'Var', (55, 63))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
82470	28068934	Obtaining multiple endoscopic biopsy samples from primary tumors may improve the likelihood of detecting a mutation and may minimize potential mutational discordances.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('minimize', 'NegReg', (124, 132))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('improve', 'PosReg', (69, 76))	('mutation', 'Var', (107, 115))
82471	28068934	Among these agents, the clinical efficacy of buparlisib (BKM120), a pan-PI3K inhibitor, has been demonstrated in breast cancer patients in a phase 3 trial, and the presence of a PIK3CA mutation was shown to predict a response to this agent.	('BKM120', 'Chemical', 'MESH:C571178', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', (113, 126))	('PIK3CA', 'Gene', (178, 184))	('predict', 'Reg', (207, 214))	('buparlisib', 'Chemical', 'MESH:C571178', (45, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('presence', 'Var', (164, 172))
82476	27050145	Furthermore, increase of PRSS8 led to the inhibition of colorectal cancer cell proliferation, knockdown of PRSS8 accelerated cell proliferation in vitro, and overexpressing PRSS8 retarded cancer cell growth in nude mice.	('knockdown', 'Var', (94, 103))	('PRSS8', 'Gene', (25, 30))	('nude mice', 'Species', '10090', (210, 219))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('retarded cancer', 'Disease', 'MESH:D009369', (179, 194))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('accelerated', 'PosReg', (113, 124))	('cell proliferation', 'CPA', (125, 143))	('colorectal cancer', 'Disease', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('increase', 'PosReg', (13, 21))	('retarded cancer', 'Disease', (179, 194))	('inhibition', 'NegReg', (42, 52))	('PRSS8', 'Gene', (107, 112))
82480	27050145	Several decades effort have revealed that the development and progression of colorectal cancer is linked to the inactivation or downregulation of tumor suppressors, and activation or upregulation of oncogenes, leading to oncogenic signaling activation such as Wnt/beta-catenin, inflammatory signaling, etc.	('inactivation', 'Var', (112, 124))	('colorectal cancer', 'Disease', (77, 94))	('upregulation', 'PosReg', (183, 195))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('inflammatory signaling', 'Disease', (278, 300))	('oncogenic signaling', 'MPA', (221, 240))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('oncogenes', 'Gene', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('activation', 'PosReg', (241, 251))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('downregulation', 'NegReg', (128, 142))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
82485	27050145	Moreover, recent studies have also demonstrated tumor suppressive roles of PRSS8 on prostate, breast, bladder and gastric cancers, in which PRSS8 expression was reduced in prostate, breast, bladder and gastric cancers, due to the hypermethylation of PRSS8.	('breast', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('bladder', 'Disease', (190, 197))	('gastric cancers', 'Disease', 'MESH:D013274', (202, 217))	('breast', 'Disease', (94, 100))	('gastric cancers', 'Disease', (202, 217))	('gastric cancers', 'Phenotype', 'HP:0012126', (202, 217))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('bladder', 'Disease', (102, 109))	('PRSS8', 'Gene', (250, 255))	('gastric cancers', 'Disease', 'MESH:D013274', (114, 129))	('gastric cancers', 'Disease', (114, 129))	('expression', 'MPA', (146, 156))	('gastric cancers', 'Phenotype', 'HP:0012126', (114, 129))	('hypermethylation', 'Var', (230, 246))	('reduced', 'NegReg', (161, 168))	('prostate', 'Disease', (84, 92))	('tumor', 'Disease', (48, 53))	('prostate', 'Disease', (172, 180))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('PRSS8', 'Gene', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
82489	27050145	The results generated from these experiments strongly suggested that PRSS8 is a tumor suppressor in colorectal cancer, which is through inhibiting Sphk1/S1P/Stat3 signaling pathways.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('inhibiting', 'NegReg', (136, 146))	('S1P', 'Gene', '13609', (153, 156))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('S1P', 'Gene', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (80, 85))	('colorectal cancer', 'Disease', (100, 117))	('PRSS8', 'Var', (69, 74))
82512	27050145	MTT assay showed that increasing PRSS8 expression inhibited cancer cell proliferation at 24 and 48 hours in both SW480 and HCT116 cell lines (Figure 2C, 2D, p<0.05), compared to the cells transfected with empty vector.	('SW480', 'CellLine', 'CVCL:0546', (113, 118))	('increasing', 'PosReg', (22, 32))	('expression', 'Var', (39, 49))	('HCT116', 'CellLine', 'CVCL:0291', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('PRSS8', 'Gene', (33, 38))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('inhibited', 'NegReg', (50, 59))
82515	27050145	MTT results showed that knockdown of PRSS8 significantly promoted cell proliferation (Figure 2E and 2F).	('promoted', 'PosReg', (57, 65))	('cell proliferation', 'CPA', (66, 84))	('PRSS8', 'Gene', (37, 42))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('knockdown', 'Var', (24, 33))
82520	27050145	In contrast, knockdown of PRSS8 upregulated the expression of Sgpp1, p-Stat3 and p-Akt in HCT8 and Caco2 cell lines (Figure 2H).	('p-Stat3', 'Protein', (69, 76))	('HCT8', 'CellLine', 'CVCL:2478', (90, 94))	('Akt', 'Gene', (83, 86))	('expression', 'MPA', (48, 58))	('Sgpp1', 'Gene', (62, 67))	('PRSS8', 'Gene', (26, 31))	('Sgpp1', 'Gene', '81537', (62, 67))	('Akt', 'Gene', '207', (83, 86))	('knockdown', 'Var', (13, 22))	('upregulated', 'PosReg', (32, 43))
82521	27050145	Interestingly, knockdown of PRSS8 could cause Sphk1 upregulation in HCT8 cells (Figure 3A).	('upregulation', 'PosReg', (52, 64))	('knockdown', 'Var', (15, 24))	('HCT8', 'CellLine', 'CVCL:2478', (68, 72))	('Sphk1', 'Gene', (46, 51))	('PRSS8', 'Gene', (28, 33))
82522	27050145	Moreover, increasing expression of Sphk1 in HCT8 cells led to the downregulation of PRSS8 (Figure 3B), and vice versa, knockdown of Sphk1 by small interfering RNA targeting Sphk1 in HCT116 and SW480 cells led to the upregulation of PRSS8 (Figure 3C).	('SW480', 'CellLine', 'CVCL:0546', (193, 198))	('Sphk1', 'Gene', (173, 178))	('PRSS8', 'Gene', (84, 89))	('HCT116', 'CellLine', 'CVCL:0291', (182, 188))	('small interfering RNA', 'Var', (141, 162))	('HCT8', 'CellLine', 'CVCL:2478', (44, 48))	('PRSS8', 'Gene', (232, 237))	('knockdown', 'Var', (119, 128))	('downregulation', 'NegReg', (66, 80))	('increasing', 'PosReg', (10, 20))	('Sphk1', 'Gene', (35, 40))	('upregulation', 'PosReg', (216, 228))	('Sphk1', 'Gene', (132, 137))
82524	27050145	As shown in Figure 3D, PRSS8 expression was increased in the colon of Sphk1-/- mice, compared to Sphk1+/+ mice, assayed by immunohistochemical staining.	('mice', 'Species', '10090', (106, 110))	('PRSS8', 'Gene', (23, 28))	('mice', 'Species', '10090', (79, 83))	('Sphk1-/-', 'Var', (70, 78))	('increased', 'PosReg', (44, 53))	('expression', 'MPA', (29, 39))
82533	27050145	Results showed that PRSS8 was overexpressed in HCT116 tumor cells which were transfected with PRSS8 plasmid, and that PRSS8 was almost undetectable in the tumor cells that were transfected with empty vector (Figure 4B).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('HCT116', 'CellLine', 'CVCL:0291', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PRSS8', 'Gene', (20, 25))	('tumor', 'Disease', (54, 59))	('PRSS8', 'Var', (94, 99))	('overexpressed', 'PosReg', (30, 43))
82534	27050145	Consistent with the effects of PRSS8 on oncogenic signaling pathways in vitro, in the HCT116 cell xenografts PRSS8 also suppressed Sphk1/S1P/Stat3/Akt signaling (Figure 4C).	('suppressed', 'NegReg', (120, 130))	('PRSS8', 'Var', (109, 114))	('S1P', 'Gene', '13609', (137, 140))	('Akt', 'Gene', '207', (147, 150))	('S1P', 'Gene', (137, 140))	('HCT116', 'CellLine', 'CVCL:0291', (86, 92))	('Akt', 'Gene', (147, 150))
82540	27050145	Mechanistic studies showed that PRSS8 inhibited Sphk1/S1P/Stat3 signaling.	('S1P', 'Gene', (54, 57))	('S1P', 'Gene', '13609', (54, 57))	('PRSS8', 'Var', (32, 37))	('inhibited', 'NegReg', (38, 47))
82541	27050145	Reduced expression of tumor suppressor genes by inactivation or silencing is frequently observed in late stage of colorectal cancer, and it may be a result of tumor progression, not a driver.	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Reduced', 'NegReg', (0, 7))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('inactivation', 'Var', (48, 60))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (159, 164))	('expression', 'MPA', (8, 18))	('tumor', 'Disease', (22, 27))	('colorectal cancer', 'Disease', (114, 131))	('silencing', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
82542	27050145	In this study, using five sets of variant TMAs, including colorectal, esophageal, liver, prostate, and breast cancers, we have found that PRSS8 expression was reduced in all of the five types of cancer tissues, and poorly differentiated cancers exhibited less or absent expression of PRSS8.	('PRSS8', 'Gene', (138, 143))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('esophageal', 'Disease', (70, 80))	('variant', 'Var', (34, 41))	('TMAs', 'Chemical', 'MESH:C071868', (42, 46))	('expression', 'MPA', (144, 154))	('reduced', 'NegReg', (159, 166))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (237, 244))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', (110, 116))	('cancers', 'Disease', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('breast cancers', 'Disease', 'MESH:D001943', (103, 117))	('breast cancers', 'Disease', (103, 117))	('cancer', 'Disease', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('breast cancers', 'Phenotype', 'HP:0003002', (103, 117))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('colorectal', 'Disease', (58, 68))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
82555	27050145	In conclusion, we have identified PRSS8 as a tumor suppressor in colorectal cancer formation and progression, and PRSS8 might be one of the key elements that suppress Sphk1/S1p/Stat3/Akt inflammatory signaling during colorectal carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('Akt', 'Gene', (183, 186))	('tumor', 'Disease', (45, 50))	('Akt', 'Gene', '207', (183, 186))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (217, 242))	('colorectal cancer', 'Disease', (65, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('S1p', 'Gene', '5707', (173, 176))	('S1p', 'Gene', (173, 176))	('colorectal carcinogenesis', 'Disease', (217, 242))	('PRSS8', 'Var', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('suppress', 'NegReg', (158, 166))
82578	27050145	The immunocomplex was separated on 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunoblotting was used to detect PRSS8 with anti-flag and to detect Sphk1 with anti-Sphk1 antibody, respectively.	('polyacrylamide', 'Chemical', 'MESH:C016679', (62, 76))	('sodium dodecyl sulfate', 'Chemical', 'MESH:D012967', (39, 61))	('anti-flag', 'Var', (147, 156))	('Sphk1', 'Gene', (171, 176))	('PRSS8', 'Gene', (136, 141))	('detect', 'Reg', (129, 135))
82579	27050145	For co-localization analysis, the cells grown on a chamber slide (BD Biosciences, San Jose, CA) were co-transfected with pEGFP-PRSS8 and pEX-6-Sphk1 plasmids.	('pEGFP-PRSS8', 'Var', (121, 132))	('pEX-6', 'Gene', '5190', (137, 142))	('pEX-6', 'Gene', (137, 142))
82584	27050145	Sphk1-deficient mice (Sphk1-/-) and wild-type (Sphk1+/+) sibling mice were generated by mating Sphk1+/- mice (in C57BL/6 background), as described recently.	('Sphk1+/-', 'Var', (95, 103))	('Sphk1-deficient', 'Disease', (0, 15))	('mice', 'Species', '10090', (104, 108))	('mice', 'Species', '10090', (65, 69))	('Sphk1-deficient', 'Disease', 'MESH:D007153', (0, 15))	('mice', 'Species', '10090', (16, 20))
82588	27385979	China-specific BMI cut-offs (underweight < 18.5, healthy >= 18.5 to <24, overweight >= 24 to <28, and obese >= 28) and quartile categories were used to define BMI subgroups.	('overweight', 'Disease', (73, 83))	('obese', 'Disease', 'MESH:D009765', (102, 107))	('obese', 'Disease', (102, 107))	('underweight < 18.5', 'Var', (29, 47))	('overweight', 'Phenotype', 'HP:0025502', (73, 83))
82620	27385979	Underweight participants were generally older, reported relatively less alcohol use, and were more likely to have ESCC.	('ESCC', 'Disease', (114, 118))	('alcohol use', 'MPA', (72, 83))	('alcohol use', 'Phenotype', 'HP:0030955', (72, 83))	('less', 'NegReg', (67, 71))	('alcohol', 'Chemical', 'MESH:D000438', (72, 79))	('Underweight', 'Var', (0, 11))	('participants', 'Species', '9606', (12, 24))
82748	31208348	Overall, BBR reduced tumor volume (SMD =3.72, 95% CI: 2.89, 4.56, Z = 8.73, p < 0.00001) and tumor weight (SMD =2.35, 95% CI: 1.51, 3.19, Z = 5.50, p < 0.00001) in a linear The dose-response relationship (Pearson r = - 0.6717, p < 0.0001 in tumor volume analysis; Pearson r = - 0.7704, p < 0.0005 in tumor weight analysis).	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('BBR', 'Chemical', 'MESH:D001599', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', (300, 305))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('reduced', 'NegReg', (13, 20))	('BBR', 'Var', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
82825	31208348	Single-drug BBR has an obvious inhibitory effect on lung cancer cells; BBR can inhibit doxorubicin (DOX)-mediated STAT3 activation and sensitize lung cancer cells to the cytotoxic effects of DOX treatment.	('BBR', 'Chemical', 'MESH:D001599', (12, 15))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('inhibit', 'NegReg', (79, 86))	('cytotoxic effects', 'CPA', (170, 187))	('DOX', 'Chemical', 'MESH:D004317', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))	('BBR', 'Chemical', 'MESH:D001599', (71, 74))	('sensitize', 'Reg', (135, 144))	('STAT3', 'Gene', '20848', (114, 119))	('lung cancer', 'Disease', (52, 63))	('lung cancer', 'Disease', (145, 156))	('BBR', 'Var', (71, 74))	('DOX', 'Chemical', 'MESH:D004317', (100, 103))	('STAT3', 'Gene', (114, 119))
82829	31208348	Latest research shows that the combination of the second generation Hsp90 inhibitor NVP-AUY922 and BBR therapy could inhibit a variety of oncogenic signaling pathways of colorectal cancer.	('Hsp90', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('oncogenic signaling pathways', 'Pathway', (138, 166))	('colorectal cancer', 'Disease', 'MESH:D015179', (170, 187))	('BBR', 'Chemical', 'MESH:D001599', (99, 102))	('rat', 'Species', '10116', (61, 64))	('Hsp90', 'Gene', '111042', (68, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (170, 187))	('NVP-AUY922', 'Var', (84, 94))	('colorectal cancer', 'Disease', (170, 187))	('inhibit', 'NegReg', (117, 124))
82834	31208348	However, studies have shown that BBR could induce weight loss in rodents and humans.	('BBR', 'Var', (33, 36))	('weight loss', 'Phenotype', 'HP:0001824', (50, 61))	('BBR', 'Chemical', 'MESH:D001599', (33, 36))	('humans', 'Species', '9606', (77, 83))	('weight loss', 'Disease', 'MESH:D015431', (50, 61))	('weight loss', 'Disease', (50, 61))
82860	30483549	Previously, we reported that GFV did not recur in any of the patients who had received successful B-RTO procedures in a long-term follow-up study of 154 patients.7 As a secondary benefit of treatment for GFV, B-RTO procedures have been shown to improve liver function; serum ammonia levels decreased after B-RTO because of the increase in the portal blood flow after the occlusion of splenorenal shunts,8, 9, 10, 11, 12 whereas TIPS procedures aggravate hepatic encephalopathy through decreasing the portal blood flow.	('decreased', 'NegReg', (290, 299))	('GFV', 'Phenotype', 'HP:0030169', (204, 207))	('portal blood flow', 'MPA', (500, 517))	('GFV', 'Phenotype', 'HP:0030169', (29, 32))	('-RTO', 'Chemical', '-', (307, 311))	('procedures', 'Var', (433, 443))	('improve liver function', 'Phenotype', 'HP:0001410', (245, 267))	('-RTO', 'Chemical', '-', (210, 214))	('patients', 'Species', '9606', (61, 69))	('GFV', 'Chemical', '-', (204, 207))	('GFV', 'Chemical', '-', (29, 32))	('aggravate', 'PosReg', (444, 453))	('serum ammonia levels', 'MPA', (269, 289))	('ammonia', 'Chemical', 'MESH:D000641', (275, 282))	('portal blood flow', 'MPA', (343, 360))	('-RTO', 'Chemical', '-', (99, 103))	('decreasing', 'NegReg', (485, 495))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (454, 476))	('hepatic encephalopathy', 'Disease', (454, 476))	('patients', 'Species', '9606', (153, 161))	('increase', 'PosReg', (327, 335))	('encephalopathy', 'Phenotype', 'HP:0001298', (462, 476))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (454, 476))
82894	30483549	The percentage of patients with a splenorenal shunt was higher among those undergoing a B-RTO procedure for the treatment of GFV (92.3%) than among those undergoing the procedure for the improvement of liver function (71.4%, including two patients with both splenorenal and azygos shunts).	('improvement of liver function', 'Phenotype', 'HP:0001410', (187, 216))	('GFV', 'Chemical', '-', (125, 128))	('patients', 'Species', '9606', (239, 247))	('-RTO', 'Chemical', '-', (89, 93))	('patients', 'Species', '9606', (18, 26))	('GFV', 'Phenotype', 'HP:0030169', (125, 128))	('splenorenal', 'Disease', (34, 45))	('B-RTO', 'Var', (88, 93))
82905	30483549	Consequently, the Child-Pugh scores were decreased from 8.6 +- 1.3 to 6.6 +- 1.3 (P < 0.001) after the B-RTO procedures in the latter patients, while they remained unchanged in the former patients (from 6.4 +- 1.1 to 6.2 +- 1.5).	('decreased', 'NegReg', (41, 50))	('Child', 'Species', '9606', (18, 23))	('patients', 'Species', '9606', (134, 142))	('patients', 'Species', '9606', (188, 196))	('Child-Pugh scores', 'CPA', (18, 35))	('-RTO', 'Chemical', '-', (104, 108))	('procedures', 'Var', (109, 119))
82919	30483549	The extents of the attenuations in the deranged serum levels of ammonia and albumin were smaller in patients undergoing B-RTO procedures for the treatment of GFV than in those undergoing the procedures for the improvement of liver function.	('B-RTO', 'Var', (120, 125))	('albumin', 'MPA', (76, 83))	('GFV', 'Phenotype', 'HP:0030169', (158, 161))	('-RTO', 'Chemical', '-', (121, 125))	('patients', 'Species', '9606', (100, 108))	('improvement of liver function', 'Phenotype', 'HP:0001410', (210, 239))	('GFV', 'Chemical', '-', (158, 161))	('deranged serum levels of ammonia', 'MPA', (39, 71))	('ammonia', 'Chemical', 'MESH:D000641', (64, 71))	('smaller', 'NegReg', (89, 96))
82939	30123356	An aberrant exaltation of the serum SCC antigen level is an effective predictor of advanced esophageal cancer correlative to poor survival after esophagostomy.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aberrant exaltation', 'Var', (3, 22))	('SCC', 'Gene', (36, 39))	('esophageal cancer', 'Disease', (92, 109))	('SCC', 'Gene', '6317', (36, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
82952	30123356	Studies that reported dysregulated microRNAs in ESCC cases compared with healthy controls, together with the corresponding AUC and sensitivity and specificity for the very microRNA, were enrolled in the meta-analysis.	('SCC', 'Gene', (49, 52))	('SCC', 'Gene', '6317', (49, 52))	('microRNAs', 'MPA', (35, 44))	('dysregulated', 'Var', (22, 34))
82953	30123356	The overall pooled sensitivity, specificity and AUC of all the 43 microRNAs in the diagnosis of ESCC were 0.794 (95%CI: 0.765 - 0.820), 0.779 (95%CI: 0.746 - 0.808) and 0.86 (95%CI: 0.82 - 0.88), respectively.	('SCC', 'Gene', (97, 100))	('0.779', 'Var', (136, 141))	('SCC', 'Gene', '6317', (97, 100))
83052	29973636	Several studies indicated an association between high blood glucose and an increased risk of cancer overall.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('high blood', 'Var', (49, 59))	('glucose', 'Chemical', 'MESH:D005947', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('high blood glucose', 'Phenotype', 'HP:0003074', (49, 67))
83141	28357082	ROS, such as the superoxide radical, the hydroxyl radical and H2O2 or RNS, such as peroxynitrites and nitrogen oxides, are toxic metabolic secondary products that pose a significant threat by damaging DNA, lipids, proteins and other macromolecules.	('H2O2', 'Chemical', 'MESH:D006861', (62, 66))	('lipids', 'Chemical', 'MESH:D008055', (206, 212))	('h', 'Gene', '9421', (41, 42))	('h', 'Gene', '9421', (8, 9))	('h', 'Gene', '9421', (159, 160))	('h', 'Gene', '9421', (229, 230))	('nitrogen oxides', 'Chemical', 'MESH:D009589', (102, 117))	('h', 'Gene', '9421', (183, 184))	('h', 'Gene', '9421', (78, 79))	('H2O2', 'Var', (62, 66))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('damaging', 'NegReg', (192, 200))	('h', 'Gene', '9421', (38, 39))	('h', 'Gene', '9421', (14, 15))	('lipids', 'MPA', (206, 212))	('superoxide radical', 'Chemical', 'MESH:D013481', (17, 35))	('peroxynitrites', 'Chemical', 'MESH:D030421', (83, 97))	('hydroxyl radical', 'Chemical', 'MESH:D017665', (41, 57))	('proteins', 'Protein', (214, 222))	('DNA', 'MPA', (201, 204))	('RNS', 'Chemical', 'MESH:D026361', (70, 73))
83146	28357082	Aberrant ROS levels are able to drive cancer initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('progression', 'CPA', (60, 71))	('Aberrant', 'Var', (0, 8))	('ROS levels', 'MPA', (9, 19))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('cancer initiation', 'Disease', 'MESH:D009369', (38, 55))	('cancer initiation', 'Disease', (38, 55))	('drive', 'Reg', (32, 37))
83162	28357082	Its cellular expression is controlled at the transcriptional level by nuclear factor (erythroid-derived 2)-related factor 2 (NRF2), and at the post-transcriptional level, through degradation and deadenylation/polyadenylation processes.	('h', 'Gene', '9421', (140, 141))	('cellular', 'MPA', (4, 12))	('deadenylation/polyadenylation', 'Var', (195, 224))	('NRF2', 'Gene', '2551', (125, 129))	('h', 'Gene', '9421', (172, 173))	('h', 'Gene', '9421', (42, 43))	('NRF2', 'Gene', (125, 129))	('h', 'Gene', '9421', (90, 91))	('h', 'Gene', '9421', (177, 178))
83163	28357082	A tumor suppressor function of PRDX1 was first demonstrated in a knockout-mouse model, where its deficiency generated mice suffering from hemolytic anemia and multiple tumors, including mammary carcinomas.	('hemolytic anemia', 'Disease', (138, 154))	('PRDX1', 'Gene', (31, 36))	('mice', 'Species', '10090', (118, 122))	('multiple tumors', 'Disease', (159, 174))	('carcinomas', 'Disease', (194, 204))	('tumor', 'Disease', (2, 7))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('h', 'Gene', '9421', (138, 139))	('anemia', 'Phenotype', 'HP:0001903', (148, 154))	('mouse', 'Species', '10090', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('hemolytic anemia', 'Disease', 'MESH:D000743', (138, 154))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (138, 154))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('multiple tumors', 'Disease', 'MESH:D009369', (159, 174))	('carcinomas', 'Disease', 'MESH:D002277', (194, 204))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('h', 'Gene', '9421', (88, 89))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('deficiency', 'Var', (97, 107))
83165	28357082	In particular, PRDX1 exerts its protective effect by oxidation of the Cys residue located within the active site of PTEN phosphatase, thereby reducing the predisposition of PRDX1-deficient mice to develop Ras-induced mammary tumors.	('Cys', 'Chemical', 'MESH:D003545', (70, 73))	('mice', 'Species', '10090', (189, 193))	('PRDX1-deficient', 'Disease', (173, 188))	('h', 'Gene', '9421', (135, 136))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('h', 'Gene', '9421', (152, 153))	('PRDX1-deficient', 'Disease', 'MESH:D007153', (173, 188))	('h', 'Gene', '9421', (126, 127))	('reducing', 'NegReg', (142, 150))	('develop', 'PosReg', (197, 204))	('h', 'Gene', '9421', (93, 94))	('oxidation', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('h', 'Gene', '9421', (67, 68))	('h', 'Gene', '9421', (98, 99))	('h', 'Gene', '9421', (122, 123))	('PRDX1', 'Gene', (15, 20))	('tumors', 'Disease', (225, 231))
83176	28357082	Decreased PRDX1 levels in papillary thyroid carcinomas (PTCs) correlate with the presence of the BRAF V600E mutation and of lymph node metastasis, suggesting that PRDX1 reduction may be caused by mutated BRAF, and this is associated with a more aggressive clinical outcome of PTCs.	('h', 'Gene', '9421', (128, 129))	('mutated', 'Var', (196, 203))	('h', 'Gene', '9421', (159, 160))	('V600E', 'Var', (102, 107))	('h', 'Gene', '9421', (78, 79))	('h', 'Gene', '9421', (215, 216))	('Decreased', 'NegReg', (0, 9))	('papillary thyroid carcinomas', 'Disease', (26, 54))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (26, 54))	('PRDX1', 'Gene', (163, 168))	('h', 'Gene', '9421', (94, 95))	('BRAF', 'Gene', (97, 101))	('h', 'Gene', '9421', (37, 38))	('h', 'Gene', '9421', (236, 237))	('BRAF', 'Gene', '673', (204, 208))	('reduction', 'NegReg', (169, 178))	('BRAF', 'Gene', (204, 208))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (26, 54))	('h', 'Gene', '9421', (75, 76))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (36, 54))	('V600E', 'Mutation', 'rs113488022', (102, 107))	('PRDX1 levels', 'MPA', (10, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('BRAF', 'Gene', '673', (97, 101))
83220	28357082	As described above for the other PRDXs, modifications in PRDX4 levels have been associated with invasion, recurrence, prognosis, and other characteristics of cancer.	('PRDX4', 'Gene', '10549', (57, 62))	('prognosis', 'CPA', (118, 127))	('PRDX4', 'Gene', (57, 62))	('h', 'Gene', '9421', (140, 141))	('h', 'Gene', '9421', (24, 25))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('invasion', 'CPA', (96, 104))	('recurrence', 'CPA', (106, 116))	('associated', 'Reg', (80, 90))	('modifications', 'Var', (40, 53))	('h', 'Gene', '9421', (70, 71))	('h', 'Gene', '9421', (135, 136))	('h', 'Gene', '9421', (94, 95))	('h', 'Gene', '9421', (29, 30))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
83256	28357082	However, preliminary studies in breast cancer have demonstrated that the survival of carriers of the PRDX6 SNPs, rs4916362 and rs7314, was consistently less favorable.	('breast cancer', 'Disease', (32, 45))	('h', 'Gene', '9421', (98, 99))	('less', 'NegReg', (152, 156))	('rs4916362', 'Mutation', 'rs4916362', (113, 122))	('PRDX6', 'Gene', '9588', (101, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('rs4916362', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('rs7314', 'Var', (127, 133))	('h', 'Gene', '9421', (70, 71))	('h', 'Gene', '9421', (65, 66))	('PRDX6', 'Gene', (101, 106))	('h', 'Gene', '9421', (46, 47))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('rs7314', 'Mutation', 'rs7314', (127, 133))
83286	27043676	Moreover, T (17%), N (5%), and M (5%) stage of the disease, cancer histology (11%), TLG70 (5%) at the end of chemioradioterapy, and DeltaTLG50-70 (17%-5%) were positively associated with patient outcome.	('DeltaTLG50-70', 'Var', (132, 145))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('TLG', 'Chemical', '-', (84, 87))	('associated with', 'Reg', (171, 186))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('TLG', 'Chemical', '-', (137, 140))	('cancer', 'Disease', (60, 66))	('patient', 'Species', '9606', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('TLG70', 'Gene', (84, 89))
83322	27043676	At logistic univariate analysis, among clinical and tomographic data, only PET/CT parameters TLG40-50-70 at the end of the treatment, DeltaSUVmax, DeltaSUL, and DeltaTLG40-50-70 resulted predictive of patient survival (P < 0.05).	('TLG40-50-70', 'Gene', (93, 104))	('DeltaSUVmax', 'MPA', (134, 145))	('DeltaTLG40-50-70', 'Var', (161, 177))	('patient survival', 'CPA', (201, 217))	('DeltaSUL', 'MPA', (147, 155))	('patient', 'Species', '9606', (201, 208))	('TLG', 'Chemical', '-', (93, 96))	('predictive', 'Reg', (187, 197))	('TLG', 'Chemical', '-', (166, 169))
83326	27043676	Among the other studied variables, TNM stage of the disease (T 17.6%; N 5.8%; M 5.8%), adenocarcinoma histology (11.7%), TLG70 at the end of chemioradioterapy (5.8%), and DeltaTLG50-70 (17.6% and 5.8%, respectively) were positively associated with patient outcome.	('TLG', 'Chemical', '-', (176, 179))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('TLG70', 'Var', (121, 126))	('adenocarcinoma', 'Disease', (87, 101))	('DeltaTLG50-70', 'Var', (171, 184))	('TLG', 'Chemical', '-', (121, 124))	('patient', 'Species', '9606', (248, 255))	('adenocarcinoma', 'Disease', 'MESH:D000230', (87, 101))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('associated with', 'Reg', (232, 247))
83338	27043676	A decrease of the tumor metabolic activity, measured as variations in SUV from the pretherapy to the end of the treatment, has been shown to be predictive of histopathologic response and the outcome of the patient.	('decrease', 'NegReg', (2, 10))	('tumor', 'Disease', (18, 23))	('patient', 'Species', '9606', (206, 213))	('variations', 'Var', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('SUV', 'MPA', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
83364	24700175	Imbalances in the composition of gut microorganisms and induced changes in their interaction with the human host have been associated with the development of obesity, diabetes, and other diseases.	('diabetes', 'Disease', (167, 175))	('associated', 'Reg', (123, 133))	('diabetes', 'Disease', 'MESH:D003920', (167, 175))	('composition', 'MPA', (18, 29))	('Imbalances', 'Phenotype', 'HP:0002172', (0, 10))	('changes', 'Reg', (64, 71))	('obesity', 'Disease', 'MESH:D009765', (158, 165))	('Imbalances', 'Var', (0, 10))	('obesity', 'Disease', (158, 165))	('obesity', 'Phenotype', 'HP:0001513', (158, 165))	('interaction', 'Interaction', (81, 92))	('human', 'Species', '9606', (102, 107))
83366	24700175	Inflammatory responses to H. pylori, however, sometimes result in the destruction of the cells that secrete acid into the stomach, leading to a condition known as chronic atrophic gastritis.	('leading to', 'Reg', (131, 141))	('H. pylori', 'Species', '210', (26, 35))	('chronic atrophic gastritis', 'Phenotype', 'HP:0002582', (163, 189))	('chronic atrophic gastritis', 'Disease', 'MESH:D005757', (163, 189))	('H. pylori', 'Var', (26, 35))	('chronic atrophic gastritis', 'Disease', (163, 189))	('gastritis', 'Phenotype', 'HP:0005263', (180, 189))	('result in', 'Reg', (56, 65))
83413	24700175	Subjects with a low PGI/II ratio, however, are at high risk for chronic atrophic gastritis, a condition in which the stomach can no longer secrete normal amounts of acid.	('chronic atrophic gastritis', 'Disease', 'MESH:D005757', (64, 90))	('gastritis', 'Phenotype', 'HP:0005263', (81, 90))	('low', 'Var', (16, 19))	('chronic atrophic gastritis', 'Disease', (64, 90))	('secrete', 'MPA', (139, 146))	('chronic atrophic gastritis', 'Phenotype', 'HP:0002582', (64, 90))	('PGI/II ratio', 'Gene', (20, 32))	('PGI/II ratio', 'Gene', '633', (20, 32))
83425	33061640	EphA5 Silencing Increases the Radiosensitivity of ESCC Cells Through ATM-Dependent Pathway Radiotherapy is one of the most important treatments for esophageal squamous cell carcinoma (ESCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('Silencing', 'Var', (6, 15))	('ATM', 'Gene', '472', (69, 72))	('Radiosensitivity', 'MPA', (30, 46))	('Increases', 'PosReg', (16, 25))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (148, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('EphA5', 'Gene', (0, 5))	('EphA5', 'Gene', '2044', (0, 5))	('ATM', 'Gene', (69, 72))	('esophageal squamous cell carcinoma', 'Disease', (148, 182))
83434	33061640	The defective activation of ATM resulted in a decrease of p-Chk2, p-p53 and p21 expression.	('Chk2', 'Gene', '11200', (60, 64))	('defective', 'Var', (4, 13))	('Chk2', 'Gene', (60, 64))	('p21', 'Gene', (76, 79))	('p53', 'Gene', (68, 71))	('p21', 'Gene', '644914', (76, 79))	('p53', 'Gene', '7157', (68, 71))	('decrease', 'NegReg', (46, 54))	('si', 'Chemical', 'MESH:D012825', (86, 88))
83435	33061640	In conclusion, these results indicate that EphA5 silencing increases radiosensitivity in ESCC cells through ATM-dependent pathway, which provides a potential target for the radiotherapy in ESCC.	('silencing', 'Var', (49, 58))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (59, 85))	('ATM-dependent pathway', 'Pathway', (108, 129))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('radiosensitivity', 'MPA', (69, 85))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('EphA5', 'Protein', (43, 48))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('increases', 'PosReg', (59, 68))
83451	33061640	Moreover, cell cycle checkpoints and DNA damage repair induced by ionizing radiation (IR) can be regulated by EphA5 in human lung cancer, which indicated that EphA5 was associated with the radiosensitivity of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('DNA damage repair', 'MPA', (37, 54))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('radiosensitivity of lung', 'Phenotype', 'HP:0010997', (189, 213))	('lung cancer', 'Disease', (209, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('si', 'Chemical', 'MESH:D012825', (197, 199))	('cell cycle checkpoints', 'CPA', (10, 32))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('associated', 'Reg', (169, 179))	('EphA5', 'Var', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('regulated', 'Reg', (97, 106))	('human', 'Species', '9606', (119, 124))
83482	33061640	And the EphA5 expression of the cells transfected with the siRNA1 was lower than the siRNA2 (Figure 1).	('siRNA1', 'Var', (59, 65))	('lower', 'NegReg', (70, 75))	('EphA5', 'Protein', (8, 13))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('si', 'Chemical', 'MESH:D012825', (59, 61))
83483	33061640	Therefore, in the subsequent experiments, we selected siRNA1 (replace with si-EphA5 later) for transfection of esophageal cancer cells to knockdown the EphA5 expression.	('knockdown', 'Var', (138, 147))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('cancer', 'Disease', (122, 128))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('EphA5', 'Gene', (152, 157))
83485	33061640	Transfection of si-EphA5 could remarkably deplete EphA5 expression in KYSE150 and KYSE450 cells.	('deplete', 'NegReg', (42, 49))	('si-EphA5', 'Var', (16, 24))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('EphA5', 'Protein', (50, 55))	('si', 'Chemical', 'MESH:D012825', (62, 64))
83489	33061640	The results revealed that EphA5 silencing obviously reduced the number of colonies in KYSE450 and KYSE150 cells after different doses of irradiation (Figure 2E-H).	('silencing', 'Var', (32, 41))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('EphA5', 'Protein', (26, 31))	('reduced', 'NegReg', (52, 59))
83490	33061640	After transfected with si-EphA5, the SER (sensitization enhancement ratio) of KYSE150 and KYSE450 cells was 1.56 and 1.21, respectively.	('si-EphA5', 'Var', (23, 31))	('SER', 'MPA', (37, 40))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('SER', 'Chemical', '-', (37, 40))	('si', 'Chemical', 'MESH:D012825', (45, 47))
83492	33061640	Having confirmed that after irradiation ESCC cells proliferation and clonal formation ability were suppressed by EphA5 silencing, we wondered whether these were caused by cell apoptosis and cell cycle arrest.	('suppressed', 'NegReg', (99, 109))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (190, 207))	('arrest', 'Disease', 'MESH:D006323', (201, 207))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('EphA5', 'Protein', (113, 118))	('arrest', 'Disease', (201, 207))	('si', 'Chemical', 'MESH:D012825', (182, 184))	('silencing', 'Var', (119, 128))	('clonal formation ability', 'CPA', (69, 93))
83500	33061640	Thus, we conclude that EphA5 silencing leads to a defective G1/S cell cycle checkpoint in ESCC cells after IR.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('silencing', 'Var', (29, 38))	('EphA5', 'Protein', (23, 28))	('G1/S cell cycle checkpoint', 'CPA', (60, 86))	('defective', 'NegReg', (50, 59))
83501	33061640	Since EphA5 silencing could increase radiotherapy sensitivity of ESCC cells, phosphorylated histone H2AX (gamma-H2AX), a marker of DNA double strand breaks (DSBs), was analyzed by immunofluorescence.	('si', 'Chemical', 'MESH:D012825', (53, 55))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('histone H2AX', 'Gene', '3014', (92, 104))	('histone H2AX', 'Gene', (92, 104))	('silencing', 'Var', (12, 21))	('DSBs', 'Chemical', '-', (157, 161))	('gamma-H2AX', 'Gene', (106, 116))	('radiotherapy sensitivity', 'CPA', (37, 61))	('EphA5', 'Protein', (6, 11))	('increase', 'PosReg', (28, 36))	('gamma-H2AX', 'Gene', '3014', (106, 116))
83508	33061640	The results indicated that the activation of ATM was impaired in the EphA5-silenced cells.	('EphA5-silenced', 'Var', (69, 83))	('impaired', 'NegReg', (53, 61))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('activation', 'MPA', (31, 41))
83515	33061640	Immunoblotting assay showed that EphA5 silencing could downregulate the p21 levels in comparison with the negative groups after irradiation (Figure 6A).	('si', 'Chemical', 'MESH:D012825', (39, 41))	('EphA5', 'Protein', (33, 38))	('p21', 'Gene', (72, 75))	('silencing', 'Var', (39, 48))	('downregulate', 'NegReg', (55, 67))	('p21', 'Gene', '644914', (72, 75))
83518	33061640	As Figure 6A shows, irradiation-induced phosphorylation of Chk2 was impaired in EphA5-silenced cells after irradiation for 0.5 h. These data suggest that EphA5 silencing causes an impairment of G1/S cell cycle checkpoint activation.	('EphA5', 'Var', (154, 159))	('G1/S cell cycle checkpoint activation', 'CPA', (194, 231))	('silencing', 'NegReg', (160, 169))	('si', 'Chemical', 'MESH:D012825', (160, 162))	('Chk2', 'Gene', '11200', (59, 63))	('Chk2', 'Gene', (59, 63))	('si', 'Chemical', 'MESH:D012825', (86, 88))
83520	33061640	To investigate whether EphA5 silencing influenced G2/M checkpoint, Cdc2/cyclinB1 complex as a key regulator in G2/M phase was checked by immunoblotting.	('Cdc2', 'Gene', (67, 71))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('silencing', 'Var', (29, 38))	('influenced', 'Reg', (39, 49))	('cyclinB1', 'Gene', (72, 80))	('cyclinB1', 'Gene', '891', (72, 80))	('Cdc2', 'Gene', '983', (67, 71))
83524	33061640	In colorectal carcinoma, EphA5 was associated with depth of wall invasion, tumor differentiation and lymph node metastasis.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('lymph node metastasis', 'CPA', (101, 122))	('associated', 'Reg', (35, 45))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (3, 23))	('EphA5', 'Var', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('colorectal carcinoma', 'Disease', (3, 23))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('si', 'Chemical', 'MESH:D012825', (69, 71))
83530	33061640	For example, Li et al found that EphA5 could inhibit the ability of invasion and migration in prostate cancer cell.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('prostate cancer', 'Disease', 'MESH:D011471', (94, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('inhibit', 'NegReg', (45, 52))	('EphA5', 'Var', (33, 38))	('prostate cancer', 'Disease', (94, 109))
83540	33061640	Both single- and double-strand DNA breaks can be induced by ionizing radiation.	('double-strand DNA', 'Var', (17, 34))	('single-', 'Var', (5, 12))	('si', 'Chemical', 'MESH:D012825', (5, 7))
83543	33061640	We did not find that EphA5 silencing could promote apoptosis after irradiation compared with the negative groups.	('silencing', 'Var', (27, 36))	('promote', 'PosReg', (43, 50))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('apoptosis', 'CPA', (51, 60))	('EphA5', 'Protein', (21, 26))	('si', 'Chemical', 'MESH:D012825', (27, 29))
83548	33061640	But our present study did not find that EphA5 silencing could result in cell cycle arrest in the nonirradiated cells.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('silencing', 'Var', (46, 55))	('arrest', 'Disease', (83, 89))	('EphA5', 'Protein', (40, 45))
83550	33061640	DNA double-strand breaks (DSBs), which is the most hazardous form of DNA lesion, can result in cell death and genomic instability.	('double-strand breaks', 'Var', (4, 24))	('genomic instability', 'CPA', (110, 129))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('DSBs', 'Chemical', '-', (26, 30))	('result in', 'Reg', (85, 94))	('death', 'Disease', (100, 105))	('death', 'Disease', 'MESH:D003643', (100, 105))
83562	33061640	It reveals that EphA5 silencing results in a decrease of phosphorylated p53 in irradiated cells, with p21 expression down-regulated as a consequence.	('p21', 'Gene', '644914', (102, 105))	('expression', 'MPA', (106, 116))	('p53', 'Gene', (72, 75))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('EphA5', 'Protein', (16, 21))	('down-regulated', 'NegReg', (117, 131))	('p53', 'Gene', '7157', (72, 75))	('silencing', 'Var', (22, 31))	('decrease', 'NegReg', (45, 53))	('phosphorylated', 'MPA', (57, 71))	('p21', 'Gene', (102, 105))
83569	33061640	Nonetheless, the present study indicates that EphA5 silencing increases radiosensitivity in ESCC cells through ATM-dependent pathway in response to DSBs.	('ATM-dependent pathway', 'Pathway', (111, 132))	('DSBs', 'Chemical', '-', (148, 152))	('silencing', 'Var', (52, 61))	('increases', 'PosReg', (62, 71))	('EphA5', 'Protein', (46, 51))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (62, 88))	('radiosensitivity', 'MPA', (72, 88))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('si', 'Chemical', 'MESH:D012825', (80, 82))
83664	31269908	Among the 16 patients with triploid of chromosome 8, 4 patients benefit, and of the 63 patients with non-triploid, 54 patients benefit.	('patients', 'Species', '9606', (13, 21))	('triploid', 'Var', (27, 35))	('patients', 'Species', '9606', (55, 63))	('benefit', 'PosReg', (64, 71))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (118, 126))	('benefit', 'PosReg', (127, 134))
83678	31269908	The phenotype and karyotyping analysis of CTC subtypes in patients with gastric cancer showed that CTCs with cytokeratins 18-negative/triploidy of chromosome 8 show endogenous resistance to cis-platinum, and CTCs with cytokeratins 18-positive/tetraploidy or over tetraploidy of chromosome 8 show endogenous acquired resistance to cis-platinum.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('cis-platinum', 'Chemical', 'MESH:D002945', (190, 202))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('endogenous', 'MPA', (296, 306))	('cytokeratins', 'Var', (109, 121))	('endogenous', 'MPA', (165, 175))	('tetraploid', 'Disease', (263, 273))	('tetraploid', 'Disease', 'MESH:D057891', (263, 273))	('tetraploid', 'Disease', (243, 253))	('tetraploid', 'Disease', 'MESH:D057891', (243, 253))	('patients', 'Species', '9606', (58, 66))	('acquired resistance to cis-platinum', 'MPA', (307, 342))	('gastric cancer', 'Disease', (72, 86))	('cis-platinum', 'Chemical', 'MESH:D002945', (330, 342))
83680	31269908	Recently, it has been reported that the increased copy number of chromosome 8 is significantly correlated with esophageal cancer and lymph node metastasis, but the relationship between CTC karyotype and therapeutic effect and prognosis of esophageal cancer has not been further elaborated.	('copy number', 'Var', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('lymph node metastasis', 'Disease', 'MESH:D009362', (133, 154))	('esophageal cancer', 'Disease', (111, 128))	('correlated', 'Reg', (95, 105))	('esophageal cancer', 'Disease', (239, 256))	('increased', 'PosReg', (40, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))	('lymph node metastasis', 'Disease', (133, 154))
83695	31269908	1, triploidy, tetraploidy, pentaploidy or greater than pentaploidy copies of chromosome 8 in CTCs were observed in esophageal cancer patients, indicating heterogeneous polysomic of chromosome 8 exist in CTCs.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tetraploid', 'Disease', (14, 24))	('tetraploid', 'Disease', 'MESH:D057891', (14, 24))	('patients', 'Species', '9606', (133, 141))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('pentaploidy', 'Var', (27, 38))	('observed', 'Reg', (103, 111))	('triploidy', 'Var', (3, 12))
83700	31269908	The results showed that of these 16 triploid genotype patients, 10 were no-benefit group (PD), 6 were benefit group (PR and SD), and of these 63 non-triploid genotype patients, 9 were no-benefit group, 54 were benefit group (Table 2).	('no-benefit', 'NegReg', (72, 82))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (167, 175))	('triploid', 'Var', (36, 44))	('PD', 'Disease', 'MESH:D010300', (90, 92))
83710	31269908	Chemotherapeutic efficacy of non-triploid patients displayed significantly higher than triploid patients.	('Chemotherapeutic efficacy', 'CPA', (0, 25))	('higher', 'PosReg', (75, 81))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (42, 50))	('non-triploid', 'Var', (29, 41))
83716	30302893	Framework for microRNA variant annotation and prioritization using human population and disease datasets MicroRNA (miRNA) expression is frequently deregulated in human disease, in contrast, disease-associated miRNA mutations are understudied.	('variant', 'Var', (23, 30))	('human', 'Species', '9606', (67, 72))	('deregulated', 'PosReg', (147, 158))	('human', 'Species', '9606', (162, 167))
83720	30302893	In addition to known somatic miR-142 mutations in hematologic cancers, we describe novel somatic miR-21 mutations in esophageal cancers impacting downstream miRNA targets.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mutations', 'Var', (104, 113))	('miRNA targets', 'MPA', (157, 170))	('cancers', 'Disease', (128, 135))	('impacting', 'Reg', (136, 145))	('miR-21', 'Gene', '406991', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancers', 'Disease', (117, 135))	('esophageal cancers', 'Disease', 'MESH:D004938', (117, 135))	('miR-21', 'Gene', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('miR-142', 'Gene', '406934', (29, 36))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('miR-142', 'Gene', (29, 36))	('cancers', 'Disease', (62, 69))
83722	30302893	Dysregulation of miRNAs leads to altered expression of their downstream target genes as seen in a wide variety of human diseases such as cancer, cardiovascular and developmental diseases.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cardiovascular and developmental diseases', 'Disease', 'MESH:D002318', (145, 186))	('expression', 'MPA', (41, 51))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('miRNAs', 'Gene', (17, 23))	('altered', 'Reg', (33, 40))	('cancer', 'Disease', (137, 143))	('human', 'Species', '9606', (114, 119))
83724	30302893	Ablation of the miRNA repertoire in Dicer1-/- mutant zebrafish and mice leads to lethality in model organisms and heterozygous loss leads to cancer predisposition in humans.	('humans', 'Species', '9606', (166, 172))	('mice', 'Species', '10090', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Ablation', 'Var', (0, 8))	('miRNA', 'Protein', (16, 21))	('leads to', 'Reg', (132, 140))	('Dicer1', 'Gene', '324724', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('lethality', 'CPA', (81, 90))	('zebrafish', 'Species', '7955', (53, 62))	('Dicer1', 'Gene', (36, 42))	('cancer', 'Disease', (141, 147))
83726	30302893	Three out of the four known Mendelian disorders shown to be caused by mutations in miRNAs (OMIM (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University) are due to seed domain mutations: miR-96 in hearing loss, miR-184 in familial keratoconus, and miR-204 in inherited retinal dystrophy.	('inherited retinal dystrophy', 'Disease', (277, 304))	('miR-204', 'Gene', (266, 273))	('mutations', 'Var', (70, 79))	('Mendelian disorders', 'Disease', (28, 47))	('hearing loss', 'Disease', (215, 227))	('familial keratoconus', 'Disease', (240, 260))	('miR-96', 'Gene', '407053', (205, 211))	('keratoconus', 'Phenotype', 'HP:0000563', (249, 260))	('miR-96', 'Gene', (205, 211))	('miR-184', 'Gene', (229, 236))	('retinal dystrophy', 'Phenotype', 'HP:0000556', (287, 304))	('due', 'Reg', (175, 178))	('miR-184', 'Gene', '406960', (229, 236))	('miR-204', 'Gene', '406987', (266, 273))	('caused', 'Reg', (60, 66))	('miRNAs', 'Gene', (83, 89))	('hearing loss', 'Phenotype', 'HP:0000365', (215, 227))
83728	30302893	Most of these variants ascribed to cancer predisposition or somatic mechanisms are primary or precursor miRNA transcript variants and alter the expression levels of mature miRNAs by interfering with the miRNA processing.	('interfering', 'NegReg', (182, 193))	('miRNA processing', 'MPA', (203, 219))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('alter', 'Reg', (134, 139))	('variants', 'Var', (14, 22))	('expression levels of mature miRNAs', 'MPA', (144, 178))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
83732	30302893	Annotation of variants within protein-coding genes utilize several criteria including but not limited to, predicted protein truncations, change in the amino acid code, evolutionary conservation and/or on sequence constraint metrics such as those developed using large human population datasets of protein-coding sequences like ExAC.	('truncations', 'NegReg', (124, 135))	('human', 'Species', '9606', (268, 273))	('variants', 'Var', (14, 22))	('protein', 'Protein', (116, 123))
83744	30302893	We used BEDTools intersect tool to subset the whole exome germline variant calls to the miRNA regions that corresponded to the mature and precursor miRNA sequences (miRBase v21).	('variant', 'Var', (67, 74))	('v21', 'Gene', (173, 176))	('v21', 'Gene', '28809', (173, 176))
83752	30302893	On average, 55% of all miRNAs listed in miRBase v21 (>90% precursor bases in capture bed file) were targeted either directly, as per the miRBase release at the time of capture design, or indirectly as a result of miRNAs overlapping the protein-coding exons.	('v21', 'Gene', '28809', (48, 51))	('protein-coding', 'Protein', (236, 250))	('miRNAs', 'Var', (213, 219))	('v21', 'Gene', (48, 51))
83755	30302893	The majority of mature miRNAs contain 0-2 variants in the entire gnomAD WGS dataset, with a few outlier miRNAs accumulating relatively high sequence variation (Figure 5 D).	('gnomAD WGS dataset', 'Disease', (65, 83))	('variants', 'Var', (42, 50))	('gnomAD WGS dataset', 'Disease', 'None', (65, 83))
83763	30302893	Among the mature miRNA variants, 1,267 were rare germline variants (as defined by ExAC nonTCGA AF <0.1%) found in approximately 11% of all PanCancerAtlas samples and 1,492 were somatic mutations in 8% of all samples (Table 2).	('variants', 'Var', (23, 31))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PanCancerAtlas', 'Disease', (139, 153))	('AF', 'Disease', 'MESH:D001281', (95, 97))
83764	30302893	We first analyzed those variants found in miRNAs in the KEGG pathway 'MicroRNAs in Cancer' that catalogues differentially expressed miRNAs across 10 cancer types.	('cancer type', 'Disease', 'MESH:D009369', (149, 160))	('variants', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer type', 'Disease', (149, 160))	('KEGG', 'Pathway', (56, 60))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))
83766	30302893	miR-10, let-7, miR-17, miR-30, and miR-15 harbor frequent somatic and rare germline variants in the above mentioned 10 cancer types as well as some other cancer types in the PanCancerAtlas dataset, (Figure 8).	('Cancer', 'Phenotype', 'HP:0002664', (177, 183))	('let-7', 'Gene', (8, 13))	('cancer type', 'Disease', (119, 130))	('miR-10', 'Gene', '10288', (0, 6))	('cancer type', 'Disease', 'MESH:D009369', (154, 165))	('miR-17', 'Gene', (15, 21))	('cancer type', 'Disease', 'MESH:D009369', (119, 130))	('miR-30', 'Gene', (23, 29))	('miR-10', 'Gene', (0, 6))	('variants', 'Var', (84, 92))	('miR-17', 'Gene', '406952', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('miR-15', 'Gene', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer type', 'Disease', (154, 165))
83769	30302893	There were 1,267 rare germline variants spread among 631 miRNAs, however, variation within many miRNAs did not significantly cluster within one tumor type (Supplementary Data).	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('variants', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
83774	30302893	Overall, our analysis of rare germline miRNA variants in the TCGA PanCancerAtlas Dataset compared with gnomAD suggests that rare germline variation plays little to no role in predisposition to the most common histologic types of adult cancers, however, this does not preclude smaller effects of common variants, or miRNA variation in other tumors types or histopathologic subtypes.	('tumors', 'Disease', (340, 346))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('variants', 'Var', (45, 53))	('tumors', 'Disease', 'MESH:D009369', (340, 346))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('variation', 'Var', (138, 147))	('cancers', 'Disease', (235, 242))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
83776	30302893	We identified the 10 most frequently mutated miRNAs within each cancer type (Figure 9 A).	('cancer type', 'Disease', 'MESH:D009369', (64, 75))	('mutated', 'Var', (37, 44))	('cancer type', 'Disease', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
83777	30302893	We found that the majority of miRNAs were mutated in <1% of samples in the respective cancer type.	('mutated', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('miRNAs', 'Gene', (30, 36))	('cancer type', 'Disease', (86, 97))	('cancer type', 'Disease', 'MESH:D009369', (86, 97))
83779	30302893	The tumor types with at least 1% somatic mutation in a specific miRNA (Figure 9 A) included diffuse large B-cell lymphoma (DLBC) and acute myeloid leukemia (LAML) with miR-142 mutations, 6.2%, and 1.3% respectively.	('tumor', 'Disease', (4, 9))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (139, 155))	('B-cell lymphoma', 'Disease', (106, 121))	('mutations', 'Var', (176, 185))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('miR-142', 'Gene', (168, 175))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (133, 155))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('acute myeloid leukemia', 'Disease', (133, 155))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (133, 155))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('miR-142', 'Gene', '406934', (168, 175))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (106, 121))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (106, 121))
83781	30302893	This result is consistent with the previously reported association of somatic mutations of miR-142 (miR142) mutations in hematologic malignancies, lymphoma (20% DLBC) and leukemia (2% LAML) (Figure 9 B).	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('leukemia', 'Disease', 'MESH:D007938', (171, 179))	('mutations', 'Var', (108, 117))	('leukemia', 'Disease', (171, 179))	('miR-142', 'Gene', '406934', (91, 98))	('miR142', 'Gene', '406934', (100, 106))	('miR142', 'Gene', (100, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (147, 155))	('miR-142', 'Gene', (91, 98))	('hematologic malignancies, lymphoma', 'Disease', 'MESH:D019337', (121, 155))
83785	30302893	Indeed, expression of 5 miR-21 target genes, APAF1, BASP1, PDCD4, RASA1, and RASGRP1, show significantly altered expression in mutated samples as compared to the rest of the samples in this cancer type (Wilcoxon test p<0.05) suggesting the miRNA variants impact miR-21 function (Figure 9 C).	('RASA1', 'Gene', (66, 71))	('miR-21', 'Gene', (262, 268))	('PDCD4', 'Gene', '27250', (59, 64))	('expression', 'MPA', (113, 123))	('APAF1', 'Gene', '317', (45, 50))	('miR-21', 'Gene', '406991', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('expression', 'MPA', (8, 18))	('impact', 'Reg', (255, 261))	('BASP1', 'Gene', (52, 57))	('APAF1', 'Gene', (45, 50))	('BASP1', 'Gene', '10409', (52, 57))	('RASGRP1', 'Gene', '10125', (77, 84))	('function', 'MPA', (269, 277))	('variants', 'Var', (246, 254))	('cancer type', 'Disease', (190, 201))	('RASGRP1', 'Gene', (77, 84))	('miR-21', 'Gene', '406991', (262, 268))	('RASA1', 'Gene', '5921', (66, 71))	('miR-21', 'Gene', (24, 30))	('cancer type', 'Disease', 'MESH:D009369', (190, 201))	('PDCD4', 'Gene', (59, 64))	('altered', 'Reg', (105, 112))
83787	30302893	Overall, somatic mutations in miRNAs appear to play an important role in a small number of the most common forms of adult cancers.	('role', 'Reg', (65, 69))	('miRNAs', 'Gene', (30, 36))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('somatic mutations', 'Var', (9, 26))
83793	30302893	Despite this difference in the genomic environment, we found comparable variant AF distribution of intragenic and intergenic miRNA genes and similar conservation profiles of the mature miRNA sequence.	('AF', 'Disease', 'MESH:D001281', (80, 82))	('variant', 'Var', (72, 79))	('miRNA genes', 'Gene', (125, 136))
83802	30302893	Further study is needed to determine the potential role of germline variants in miRNA genes in rare pathologic subtypes, other rare adult cancers, pediatric cancers and those miRNAs not effectively sequenced by WES.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('germline variants', 'Var', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('miRNA genes', 'Gene', (80, 91))	('cancers', 'Disease', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
83803	30302893	Genome-wide association approaches could also be explored by focusing on the common miRNAs variants (AF >5%) described here, as some of these common variants are predicted to alter miRNA target gene expression.	('expression', 'MPA', (199, 209))	('alter', 'Reg', (175, 180))	('variants', 'Var', (149, 157))	('AF', 'Disease', 'MESH:D001281', (101, 103))	('variants', 'Var', (91, 99))
83804	30302893	Analysis of somatic mutations in miRNAs demonstrated higher specificity with cancer type including the previously described association of miR-142 somatic mutations in hematologic malignancies such as lymphoma (DLBC) and leukemia (LAML).	('lymphoma', 'Phenotype', 'HP:0002665', (201, 209))	('mutations', 'Var', (155, 164))	('cancer type', 'Disease', 'MESH:D009369', (77, 88))	('leukemia', 'Disease', 'MESH:D007938', (221, 229))	('association', 'Interaction', (124, 135))	('miR-142', 'Gene', '406934', (139, 146))	('hematologic malignancies', 'Disease', 'MESH:D019337', (168, 192))	('lymphoma', 'Disease', (201, 209))	('leukemia', 'Phenotype', 'HP:0001909', (221, 229))	('miR-142', 'Gene', (139, 146))	('lymphoma', 'Disease', 'MESH:D008223', (201, 209))	('hematologic malignancies', 'Disease', (168, 192))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer type', 'Disease', (77, 88))	('leukemia', 'Disease', (221, 229))
83841	30042826	AQP1 depletion significantly increased early apoptosis (Annexin V positive/PI negative) in TE5 and TE15 cell lines at 72 h after siRNA transfection (Figure 5B).	('depletion', 'Var', (5, 14))	('early apoptosis', 'CPA', (39, 54))	('Annexin V', 'Gene', '308', (56, 65))	('increased', 'PosReg', (29, 38))	('Annexin V', 'Gene', (56, 65))	('AQP1', 'Gene', (0, 4))
83842	30042826	These findings indicated that the expression of AQP1 suppresses apoptosis according to the type of ESCC cells, especially where AQP1 expression was predominantly in the cytoplasm.	('SCC', 'Gene', (100, 103))	('suppresses', 'NegReg', (53, 63))	('apoptosis', 'CPA', (64, 73))	('SCC', 'Gene', '6317', (100, 103))	('expression', 'Var', (34, 44))	('ESCC', 'Phenotype', 'HP:0011459', (99, 103))	('AQP1', 'Gene', (48, 52))
83845	30042826	An ingenuity pathway analysis (IPA) showed that "Cancer" was the top-ranked disease and that "Cellular Movement", "Cellular Development", and "Cellular Growth and Proliferation" were some of the top-ranked biological functions related to the depletion of AQP1 (Supplementary Table 2).	('depletion', 'Var', (242, 251))	('Cellular Movement', 'CPA', (94, 111))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('AQP1', 'Gene', (255, 259))	('Cancer', 'Disease', (49, 55))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('Development', 'CPA', (124, 135))
83848	30042826	These results were consistent with the microarray results and suggested that knockdown of AQP1 suppresses Death receptor signaling in ESCC cells.	('Death receptor signaling', 'MPA', (106, 130))	('suppresses', 'NegReg', (95, 105))	('knockdown', 'Var', (77, 86))	('SCC', 'Gene', (135, 138))	('ESCC', 'Phenotype', 'HP:0011459', (134, 138))	('AQP1', 'Gene', (90, 94))	('SCC', 'Gene', '6317', (135, 138))
83865	30042826	indicated that targeted AQP1 gene disruption of melanoma cells reduced angiogenesis in vivo.	('melanoma', 'Disease', (48, 56))	('reduced', 'NegReg', (63, 70))	('angiogenesis', 'CPA', (71, 83))	('gene disruption', 'Var', (29, 44))	('AQP1', 'Gene', (24, 28))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
83867	30042826	In the present study, cell cycle analysis indicated that the knockdown of AQP1 with siRNA increased the component of sub G1 phase in TE5 and TE15, ESCC cell lines.	('AQP1', 'Gene', (74, 78))	('increased', 'PosReg', (90, 99))	('component', 'MPA', (104, 113))	('knockdown', 'Var', (61, 70))	('SCC', 'Gene', (148, 151))	('ESCC', 'Phenotype', 'HP:0011459', (147, 151))	('SCC', 'Gene', '6317', (148, 151))
83868	30042826	Furthermore, apoptosis analysis revealed that depleted-AQP1 ESCC cells were induced to undergo apoptosis.	('ESCC', 'Phenotype', 'HP:0011459', (60, 64))	('depleted-AQP1', 'Var', (46, 59))	('SCC', 'Gene', (61, 64))	('SCC', 'Gene', '6317', (61, 64))
83881	30042826	The results of the present study indicated the gene expression of factors that activate the Death receptor signaling pathway, such as FASL, cleaved caspase-3, FLIP, XIAP, and p-JNK was changed by the knockdown of AQP1, suggesting that AQP1 suppresses this pathway in ESCC cells.	('changed', 'Reg', (185, 192))	('knockdown', 'Var', (200, 209))	('JNK', 'Gene', (177, 180))	('XIAP', 'Gene', '331', (165, 169))	('AQP1', 'Var', (235, 239))	('SCC', 'Gene', (268, 271))	('activate', 'PosReg', (79, 87))	('JNK', 'Gene', '5599', (177, 180))	('caspase-3', 'Gene', '836', (148, 157))	('cleaved', 'MPA', (140, 147))	('AQP1', 'Gene', (213, 217))	('ESCC', 'Phenotype', 'HP:0011459', (267, 271))	('SCC', 'Gene', '6317', (268, 271))	('suppresses', 'NegReg', (240, 250))	('Death receptor signaling pathway', 'Pathway', (92, 124))	('FLIP', 'MPA', (159, 163))	('XIAP', 'Gene', (165, 169))	('caspase-3', 'Gene', (148, 157))
83894	30042826	Cells were detached from the flasks with trypsin-EDTA 48 and 72 h after siRNA transfection and were counted using a hemocytometer.	('EDTA', 'Chemical', 'MESH:D004492', (49, 53))	('transfection', 'Var', (78, 90))	('siRNA', 'Gene', (72, 77))
83896	30042826	Expression levels were measured for the following genes: AQP1 (Hs01028916_m1), FASL (Hs00181225_m1), XIAP (Hs00745222_s1), FLIP (Hs01117851_m1), and BCL-2 (Hs00608023_m1) (Applied Biosystems).	('XIAP', 'Gene', (101, 105))	('Expression levels', 'MPA', (0, 17))	('Hs01028916_m1', 'Var', (63, 76))	('Hs00745222_s1', 'Var', (107, 120))	('Hs00181225_m1', 'Var', (85, 98))	('Hs00608023_m1', 'Var', (156, 169))	('XIAP', 'Gene', '331', (101, 105))	('BCL-2', 'Gene', '596', (149, 154))	('Hs01117851_m1', 'Var', (129, 142))	('BCL-2', 'Gene', (149, 154))
83924	28693209	Frequent aberrant p53 and Fhit expression in endoscopically resected superficial hypopharyngeal cancer and esophageal cancer In the last decade, the incidence rate of detection rate of superficial head, neck and esophageal squamous cell carcinomas has increased with the development of endoscopic imaging techniques.	('p53', 'Gene', '7157', (18, 21))	('esophageal squamous cell carcinomas', 'Disease', (212, 247))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (81, 102))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (212, 247))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('aberrant', 'Var', (9, 17))	('p53', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Fhit', 'Gene', (26, 30))	('esophageal cancer', 'Disease', (107, 124))	('Fhit', 'Gene', '2272', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('carcinomas', 'Phenotype', 'HP:0030731', (237, 247))	('superficial head', 'Disease', (185, 201))	('men', 'Species', '9606', (278, 281))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('hypopharyngeal cancer', 'Disease', (81, 102))	('rat', 'Species', '10116', (177, 180))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (223, 247))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))	('rat', 'Species', '10116', (159, 162))
83934	28693209	These results suggested that aberrant p53 and Fhit expression was involved in the development of HPSCC and their DESCC, and that their expression may be used for the prediction of DESCC development in patients with HPSCC, thereby acting as a biomarker of field cancerization.	('DESCC', 'Disease', (113, 118))	('patients', 'Species', '9606', (201, 209))	('HPSCC', 'Disease', (97, 102))	('p53', 'Gene', (38, 41))	('Fhit', 'Gene', (46, 50))	('p53', 'Gene', '7157', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('DESCC', 'Disease', (180, 185))	('men', 'Species', '9606', (193, 196))	('Fhit', 'Gene', '2272', (46, 50))	('involved', 'Reg', (66, 74))	('aberrant', 'Var', (29, 37))	('men', 'Species', '9606', (89, 92))
83949	28693209	Modulation of the FHIT gene, which is located in the most active human fragile region, FRA3B, and of Fhit protein expression, has also been linked to ESCC and cigarette smoking.	('Modulation', 'Var', (0, 10))	('protein', 'Protein', (106, 113))	('human', 'Species', '9606', (65, 70))	('Fhit', 'Gene', '2272', (101, 105))	('cigarette smoking', 'Disease', (159, 176))	('FRA3B', 'Gene', '2272', (87, 92))	('ESCC', 'Disease', (150, 154))	('FRA3B', 'Gene', (87, 92))	('FHIT', 'Gene', (18, 22))	('linked', 'Reg', (140, 146))	('Fhit', 'Gene', (101, 105))	('FHIT', 'Gene', '2272', (18, 22))
83954	28693209	The purpose of the present study was to test the field cancerization hypothesis at the molecular level by identifying aberrant tumor-related protein expression in superficial HPSCCs and ESCCs arising in the same patient.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patient', 'Species', '9606', (212, 219))	('tumor-related protein', 'Gene', '49860', (127, 148))	('tumor-related protein', 'Gene', (127, 148))	('ESCCs', 'Disease', (186, 191))	('aberrant', 'Var', (118, 126))	('expression', 'MPA', (149, 159))	('HPSCCs', 'Phenotype', 'HP:0012182', (175, 181))	('superficial HPSCCs', 'Disease', (163, 181))
83969	28693209	Flushing responses are clinically useful as a simple, cost-effective and non-invasive method for identification of aldehyde dehydrogenase-2 (ALDH2) deficient patients.	('aldehyde dehydrogenase-2', 'Gene', (115, 139))	('Flushing', 'Phenotype', 'HP:0031284', (0, 8))	('Flushing', 'Disease', 'MESH:D005483', (0, 8))	('ALDH2', 'Gene', '217', (141, 146))	('patients', 'Species', '9606', (158, 166))	('Flushing', 'Disease', (0, 8))	('deficient', 'Var', (148, 157))	('ALDH2', 'Gene', (141, 146))	('aldehyde dehydrogenase-2', 'Gene', '217', (115, 139))
83999	28693209	Aberrant E-cadherin and AID expression was identified in 4 (44%) and 6 (67%) of the 9 HPSCCs and in 4 (44%) and 4 (44%) of the 9 DESCCs, respectively (Table III).	('AID', 'Gene', '57379', (24, 27))	('AID', 'Gene', (24, 27))	('HPSCCs', 'Phenotype', 'HP:0012182', (86, 92))	('E-cadherin', 'Gene', '999', (9, 19))	('Aberrant', 'Var', (0, 8))	('E-cadherin', 'Gene', (9, 19))
84000	28693209	Aberrant expression of p53 and Fhit was identified in 7 tumors out of 9 HPSCCs and in 7 tumors out of their DESCCs (Table IV).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Aberrant', 'Var', (0, 8))	('HPSCCs', 'Disease', (72, 78))	('Fhit', 'Gene', '2272', (31, 35))	('HPSCCs', 'Phenotype', 'HP:0012182', (72, 78))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('Fhit', 'Gene', (31, 35))
84006	28693209	A high frequency of aberrant p53 and Fhit expression was observed in HPSCCs and DESCCs.	('HPSCCs', 'Phenotype', 'HP:0012182', (69, 75))	('aberrant', 'Var', (20, 28))	('Fhit', 'Gene', (37, 41))	('HPSCCs', 'Disease', (69, 75))	('DESCCs', 'Disease', (80, 86))	('p53', 'Gene', (29, 32))	('Fhit', 'Gene', '2272', (37, 41))	('p53', 'Gene', '7157', (29, 32))
84009	28693209	It has been demonstrated for East Asian drinkers that there is a strong association between inactive ALDH2 and the risk of HNC and esophageal cancer.	('HNC', 'Disease', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('inactive', 'Var', (92, 100))	('ALDH2', 'Gene', '217', (101, 106))	('esophageal cancer', 'Disease', (131, 148))	('rat', 'Species', '10116', (19, 22))	('HNC', 'Phenotype', 'HP:0012288', (123, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('ALDH2', 'Gene', (101, 106))
84012	28693209	Alterations in the p53 and FHIT genes and their expression have been reported in a variety of epithelial tumors and premalignant lesions including in HNC and esophageal cancer.	('epithelial tumors', 'Disease', (94, 111))	('epithelial tumors', 'Disease', 'MESH:D002277', (94, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('reported', 'Reg', (69, 77))	('Alterations', 'Var', (0, 11))	('expression', 'MPA', (48, 58))	('HNC', 'Phenotype', 'HP:0012288', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('FHIT', 'Gene', (27, 31))	('p53', 'Gene', (19, 22))	('FHIT', 'Gene', '2272', (27, 31))	('p53', 'Gene', '7157', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HNC', 'Disease', (150, 153))	('rat', 'Species', '10116', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('esophageal cancer', 'Disease', (158, 175))
84013	28693209	In the present study, a high frequency of aberrant p53 and Fhit expression in HPSCCs and in their DESCCs was observed.	('Fhit', 'Gene', '2272', (59, 63))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('expression', 'MPA', (64, 74))	('aberrant', 'Var', (42, 50))	('HPSCCs', 'Phenotype', 'HP:0012182', (78, 84))	('Fhit', 'Gene', (59, 63))	('HPSCCs', 'Disease', (78, 84))
84016	28693209	The frequency of aberrant p53 and Fhit expression was increased compared with what has been observed in previous reports.	('Fhit', 'Gene', '2272', (34, 38))	('aberrant', 'Var', (17, 25))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('Fhit', 'Gene', (34, 38))
84019	28693209	Therefore, the p53 and Fhit alterations observed in patients clearly associated with field cancerization may frequently occur in the early stages of head, neck and esophageal carcinogenesis.	('occur', 'Reg', (120, 125))	('field cancerization', 'Disease', (85, 104))	('alterations', 'Var', (28, 39))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (164, 189))	('rat', 'Species', '10116', (32, 35))	('Fhit', 'Gene', (23, 27))	('associated', 'Reg', (69, 79))	('esophageal carcinogenesis', 'Disease', (164, 189))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('Fhit', 'Gene', '2272', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('patients', 'Species', '9606', (52, 60))
84025	28693209	Aberrant AID expression induces p53 gene mutation in Helicobacter pylori infected gastric epithelial cells and is associated with the development of precancerous lesions and the progression of malignant tumors.	('precancerous lesions', 'Disease', 'MESH:D011230', (149, 169))	('men', 'Species', '9606', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('malignant tumors', 'Disease', 'MESH:D018198', (193, 209))	('Aberrant', 'Var', (0, 8))	('precancerous lesions', 'Disease', (149, 169))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('AID', 'Gene', (9, 12))	('p53', 'Gene', (32, 35))	('mutation', 'Var', (41, 49))	('Helicobacter pylori', 'Species', '210', (53, 72))	('associated with', 'Reg', (114, 129))	('AID', 'Gene', '57379', (9, 12))	('p53', 'Gene', '7157', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('malignant tumors', 'Disease', (193, 209))
84034	28693209	In conclusion, the frequency and pattern of aberrant p53, Fhit, E-cadherin, and AID expression in the examined superficial HPSCCs and their DESCCs was consistent with the field theory of cancerization.	('Fhit', 'Gene', '2272', (58, 62))	('E-cadherin', 'Gene', (64, 74))	('AID', 'Gene', (80, 83))	('AID', 'Gene', '57379', (80, 83))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('E-cadherin', 'Gene', '999', (64, 74))	('HPSCCs', 'Phenotype', 'HP:0012182', (123, 129))	('expression', 'MPA', (84, 94))	('Fhit', 'Gene', (58, 62))	('aberrant', 'Var', (44, 52))
84063	26962818	The following International Classification of Disease for Oncology site codes were used to identify eligible patients: C15.0, C15.1, C15.2, C15.3, C15.4, C15.5, C15.8, and C15.9 as well as codes 8052, 8070, 8071, 8072, 8073, 8074, 8076, 8077, 8083, and 8044.	('8044', 'Var', (253, 257))	('8077', 'Var', (237, 241))	('C15.3', 'Var', (140, 145))	('patients', 'Species', '9606', (109, 117))	('8073', 'Var', (219, 223))	('C15.2', 'Var', (133, 138))	('C15.0', 'Var', (119, 124))	('C15.5', 'Var', (154, 159))	('8072', 'Var', (213, 217))	('C15.9', 'Var', (172, 177))	('C15.8', 'Var', (161, 166))	('C15.4', 'Var', (147, 152))	('Oncology', 'Phenotype', 'HP:0002664', (58, 66))	('C15.1', 'Var', (126, 131))	('8083', 'Var', (243, 247))	('8076', 'Var', (231, 235))	('8074', 'Var', (225, 229))
84105	26962818	Motoori et al enrolled 173 patients with clinical T1bN0M0 squamous cell carcinoma of thoracic esophagus.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('patients', 'Species', '9606', (27, 35))	('squamous cell carcinoma of thoracic esophagus', 'Disease', 'MESH:D002294', (58, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('squamous cell carcinoma of thoracic esophagus', 'Disease', (58, 103))	('T1bN0M0', 'Var', (50, 57))
84135	26962818	Javidfar et al enrolled 3125 patients with pathologic T1-3N0-1M0 esophageal cancer from 2003 to 2006 in the National Cancer Data Base into analysis and found positive surgical margin are associated with poor survival.	('patients', 'Species', '9606', (29, 37))	('esophageal cancer', 'Disease', (65, 82))	('positive', 'Var', (158, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Cancer', 'Disease', (117, 123))	('T1-3N0-1M0', 'Var', (54, 64))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))
84179	26229436	Also displayed in Figure 3, MMP-7 protein expression in EC patients with invasive grade T3-4 was higher than that in patients with invasive grade T1-2 (OR 3.47, 95% CI 2.32-5.19; P<0.001).	('invasive grade T3-4', 'Var', (73, 92))	('higher', 'PosReg', (97, 103))	('T1-2', 'Gene', (146, 150))	('MMP-7', 'Gene', (28, 33))	('patients', 'Species', '9606', (59, 67))	('MMP-7', 'Gene', '4316', (28, 33))	('T1-2', 'Gene', '923;921;292', (146, 150))	('patients', 'Species', '9606', (117, 125))
84183	26229436	In addition, subgroup analysis based on country found that MMP-7 protein was more highly expressed in EC patients with invasive grade T3-4 than in patients with invasive grade T1-2 in both the Chinese (OR 2.00, 95% CI 1.58-2.53; P<0.001) and Japanese populations (OR 1.48, 95% CI 1.06-2.07; P=0.022; Figure 4).	('patients', 'Species', '9606', (105, 113))	('MMP-7', 'Gene', (59, 64))	('T1-2', 'Gene', (176, 180))	('invasive grade T3-4', 'Var', (119, 138))	('patients', 'Species', '9606', (147, 155))	('MMP-7', 'Gene', '4316', (59, 64))	('T1-2', 'Gene', '923;921;292', (176, 180))	('highly expressed', 'PosReg', (82, 98))
84188	26229436	Furthermore, subgroup analysis by detection method showed that by using both SP and non-SP methods, the relationship between high MMP-7 protein expression in EC patients and LN metastasis existed (P<0.001, Figure 4).	('LN metastasis', 'CPA', (174, 187))	('MMP-7', 'Gene', (130, 135))	('expression', 'MPA', (144, 154))	('MMP-7', 'Gene', '4316', (130, 135))	('patients', 'Species', '9606', (161, 169))	('SP', 'Chemical', '-', (77, 79))	('SP', 'Chemical', '-', (88, 90))	('protein', 'Protein', (136, 143))	('high', 'Var', (125, 129))
84203	26229436	In summary, partly in line with previous studies, our results showed that the high expression of MMP-7 could affect the EC clinicopathological features, showing MMP-7 could be an independent biomarker for the diagnosis of EC and thus improving the survival rate of EC patients.	('MMP-7', 'Gene', '4316', (97, 102))	('high', 'Var', (78, 82))	('MMP-7', 'Gene', (161, 166))	('survival rate', 'CPA', (248, 261))	('MMP-7', 'Gene', '4316', (161, 166))	('improving', 'PosReg', (234, 243))	('affect', 'Reg', (109, 115))	('MMP-7', 'Gene', (97, 102))	('patients', 'Species', '9606', (268, 276))
84216	25994132	Its overexpression induces an aggressive phenotype in many cancers and aberrant expression of homeotic HOX transcription factors, especially HOXD10, that regulate differentiation and tissue homeostasis.	('HOXD10', 'Gene', '3236', (141, 147))	('aberrant', 'Var', (71, 79))	('cancers', 'Disease', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('expression', 'MPA', (80, 90))	('overexpression', 'PosReg', (4, 18))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('HOXD10', 'Gene', (141, 147))	('induces', 'Reg', (19, 26))	('aggressive phenotype', 'CPA', (30, 50))
84232	25994132	These findings call for the delineation of the mechanisms regulating normal and aberrant differentiation in the urothelium in order to improve prognostic classification and to develop new strategies for targeting the tumor-initiating cell populations as a driving force of progression, metastasis and recurrence.	('aberrant', 'Var', (80, 88))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))
84245	25994132	Subsequent to modulation of HOTAIR expression by knockdown or ectopic overexpression, we did not observe the same effects on HOTAIR target genes among the posterior HOXD genes as previously reported for other cancer types.	('knockdown', 'Var', (49, 58))	('HOTAIR', 'Gene', '100124700', (28, 34))	('HOTAIR', 'Gene', '100124700', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('HOXD', 'Gene', '3230', (165, 169))	('cancer', 'Disease', (209, 215))	('HOXD', 'Gene', (165, 169))	('HOTAIR', 'Gene', (28, 34))	('modulation', 'Reg', (14, 24))	('HOTAIR', 'Gene', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
84293	25994132	Of these, 2835 genes were common to both cell lines, but only 784 of these were downregulated, indicating that also transcription activating chromatin modifications may be mediated by HOTAIR.	('HOTAIR', 'Gene', '100124700', (184, 190))	('modifications', 'Var', (151, 164))	('transcription', 'MPA', (116, 129))	('HOTAIR', 'Gene', (184, 190))
84296	25994132	Downregulated genes in VM-CUB1_HOTAIR cells encoded cytokeratins (KRT5, 6A/B, 13, 14, 19, 80), E-Cadherin and negative cell cycle regulators.	('6A/B', 'Var', (72, 76))	('HOTAIR', 'Gene', '100124700', (31, 37))	('E-Cadherin', 'Gene', (95, 105))	('6A/B', 'SUBSTITUTION', 'None', (72, 76))	('E-Cadherin', 'Gene', '999', (95, 105))	('Downregulated', 'NegReg', (0, 13))	('KRT5', 'Gene', (66, 70))	('HOTAIR', 'Gene', (31, 37))
84343	25994132	Moreover, by using the same siRNA-technique as previous authors we achieved the same degree of HOTAIR knockdown, but no induction of HOXD10 expression in UC cell lines.	('HOXD10', 'Gene', '3236', (133, 139))	('HOTAIR', 'Gene', (95, 101))	('knockdown', 'Var', (102, 111))	('HOXD10', 'Gene', (133, 139))	('HOTAIR', 'Gene', '100124700', (95, 101))
84346	25994132	Considering the data from ectopic overexpression and the report of a lack of HOXD10 induction after HOTAIR knockdown in ovarian cancer cells, our finding strongly argues that HOTAIR target genes are tissue-specific.	('knockdown', 'Var', (107, 116))	('HOXD10', 'Gene', (77, 83))	('lack', 'NegReg', (69, 73))	('ovarian cancer', 'Disease', 'MESH:D010051', (120, 134))	('HOTAIR', 'Gene', '100124700', (100, 106))	('ovarian cancer', 'Disease', (120, 134))	('HOTAIR', 'Gene', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HOTAIR', 'Gene', '100124700', (175, 181))	('HOXD10', 'Gene', '3236', (77, 83))	('HOTAIR', 'Gene', (100, 106))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
84354	25994132	Similarly, modulation of HOTAIR expression by ectopic expression or depletion resulted in changes in migration and invasion capacity in esophageal cancer, lung cancer cells and one bladder cancer cell line (T-24).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('ectopic expression', 'Var', (46, 64))	('invasion capacity', 'CPA', (115, 132))	('depletion', 'MPA', (68, 77))	('HOTAIR', 'Gene', '100124700', (25, 31))	('modulation', 'Var', (11, 21))	('migration', 'CPA', (101, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (181, 195))	('lung cancer', 'Disease', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('HOTAIR', 'Gene', (25, 31))	('bladder cancer', 'Disease', (181, 195))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('bladder cancer', 'Phenotype', 'HP:0009725', (181, 195))	('changes', 'Reg', (90, 97))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('esophageal cancer', 'Disease', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))
84362	25994132	Due to mutational inactivation of both pRB1 and p53, 5637 cells are unable to undergo regular senescence, but a partial senescence induction accompanied by SASP could account for the observed slower proliferation of HOTAIR-overexpressing 5637 cells.	('pRB1', 'Gene', '5542', (39, 43))	('p53', 'Gene', (48, 51))	('slower proliferation', 'CPA', (192, 212))	('HOTAIR', 'Gene', '100124700', (216, 222))	('p53', 'Gene', '7157', (48, 51))	('SASP', 'Gene', (156, 160))	('SASP', 'Gene', '7295', (156, 160))	('partial senescence induction', 'MPA', (112, 140))	('mutational inactivation', 'Var', (7, 30))	('pRB1', 'Gene', (39, 43))	('HOTAIR', 'Gene', (216, 222))
84367	25994132	In addition, DeltaNp63, a likely regulator of stemness in genitourinary epithelia, was differentially expressed indicating that aberrant HOTAIR expression may be involved in the establishment of aberrant differentiation states in bladder cancer.	('DeltaNp63', 'Gene', (13, 22))	('bladder cancer', 'Phenotype', 'HP:0009725', (230, 244))	('stemness in genitourinary epithelia', 'Disease', (46, 81))	('bladder cancer', 'Disease', 'MESH:D001749', (230, 244))	('aberrant', 'Var', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('HOTAIR', 'Gene', (137, 143))	('bladder cancer', 'Disease', (230, 244))	('involved', 'Reg', (162, 170))	('HOTAIR', 'Gene', '100124700', (137, 143))	('stemness in genitourinary epithelia', 'Disease', 'MESH:D014564', (46, 81))
84369	25994132	on HOTAIR transfected MDA-MB-231 cells revealed only four HOX genes (HOXA4, C8, D10, D13) with increased PRC2 occupancy, although none appeared to gain the repressive H3K27me chromatin mark.	('HOXA4', 'Gene', '3201', (69, 74))	('H3K27me', 'Var', (167, 174))	('gain', 'PosReg', (147, 151))	('HOXA4', 'Gene', (69, 74))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (22, 32))	('H3', 'Chemical', 'MESH:C012616', (167, 169))	('HOTAIR', 'Gene', (3, 9))	('HOTAIR', 'Gene', '100124700', (3, 9))
84418	25994132	The antibodies used for immunoprecipitation were H3K4me3 (#39915, Active Motif), H3K27me3 (#39535, Active Motif) and H3K9me3 (ab-8898, abcam).	('H3K4me3', 'Protein', (49, 56))	('#39915', 'Var', (58, 64))	('H3', 'Chemical', 'MESH:C012616', (81, 83))	('H3K9me3', 'Var', (117, 124))	('#39535', 'Var', (91, 97))	('H3', 'Chemical', 'MESH:C012616', (117, 119))	('H3', 'Chemical', 'MESH:C012616', (49, 51))
84432	25133495	Further analysis revealed that survival was significantly better in the CCRT group than in the RT alone group for patients <= 72 years.	('better', 'PosReg', (58, 64))	('CR', 'Chemical', '-', (73, 75))	('patients', 'Species', '9606', (114, 122))	('survival', 'MPA', (31, 39))	('CCRT', 'Var', (72, 76))
84485	25133495	Patients treated with CCRT developed more grade >= 2 esophagitis and pneumonitis than patients who received RT alone (52.1% vs. 34.5%, p = 0.005).	('pneumonitis', 'Disease', (69, 80))	('CCRT', 'Var', (22, 26))	('pneumonitis', 'Disease', 'MESH:D011014', (69, 80))	('grade', 'Disease', (42, 47))	('Patients', 'Species', '9606', (0, 8))	('esophagitis', 'Phenotype', 'HP:0100633', (53, 64))	('esophagitis', 'Disease', (53, 64))	('CR', 'Chemical', '-', (23, 25))	('esophagitis', 'Disease', 'MESH:D004941', (53, 64))	('patients', 'Species', '9606', (86, 94))
84490	25133495	The 3-year PFS rate of the CCRT group was also significantly higher than that for the RT alone group (27.2% vs. 16.3%, p = 0.004).	('PFS', 'CPA', (11, 14))	('higher', 'PosReg', (61, 67))	('CR', 'Chemical', '-', (28, 30))	('CCRT', 'Var', (27, 31))
84495	25133495	2, for patients <= 72 years, OS and PFS were significantly better in the CCRT group than in the RT alone group (p =  0.003, 0.042).	('PFS', 'CPA', (36, 39))	('better', 'PosReg', (59, 65))	('CCRT', 'Var', (73, 77))	('CR', 'Chemical', '-', (74, 76))	('patients', 'Species', '9606', (7, 15))
84559	27713364	Macrophages generate a great amount of inflammatory mediators which react with DNA and cause mutations in proliferating epithelial and stroma cells.	('rat', 'Species', '10116', (16, 19))	('rat', 'Species', '10116', (113, 116))	('mutations', 'Var', (93, 102))	('cause', 'Reg', (87, 92))
84603	27713364	Additionally, increased prostanoid generation due to COX-2 overexpression specifically inhibits Fas-mediated apoptosis.	('increased', 'PosReg', (14, 23))	('Fas-mediated apoptosis', 'CPA', (96, 118))	('overexpression', 'Var', (59, 73))	('COX-2', 'Gene', (53, 58))	('prostanoid generation', 'MPA', (24, 45))	('inhibits', 'NegReg', (87, 95))	('rat', 'Species', '10116', (39, 42))	('Fas', 'Chemical', 'MESH:C038178', (96, 99))	('prostanoid', 'Chemical', 'MESH:D011453', (24, 34))
84604	27713364	In vivo, both non-selective and selective COX-2 inhibitors stimulate apoptosis in APC-deficient cells that have not yet undergone malignant transformation.	('stimulate', 'PosReg', (59, 68))	('APC-deficient', 'Disease', (82, 95))	('inhibitors', 'Var', (48, 58))	('apoptosis', 'CPA', (69, 78))	('COX-2', 'Gene', (42, 47))	('APC-deficient', 'Disease', 'MESH:D011125', (82, 95))
84607	27713364	In contrast, selective COX-2 inhibitors stimulate apoptosis and suppress growth in many carcinomas, including cultured human cancers of the stomach, esophagus, colon, and pancreas.	('cancers of the stomach', 'Phenotype', 'HP:0006753', (125, 147))	('COX-2', 'Gene', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('carcinomas', 'Disease', 'MESH:D002277', (88, 98))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('pancreas', 'Disease', (171, 179))	('stimulate', 'PosReg', (40, 49))	('suppress', 'NegReg', (64, 72))	('growth', 'CPA', (73, 79))	('apoptosis', 'CPA', (50, 59))	('human', 'Species', '9606', (119, 124))	('inhibitors', 'Var', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophagus', 'Disease', (149, 158))	('carcinomas', 'Disease', (88, 98))	('colon', 'Disease', (160, 165))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))
84614	27713364	Both non-selective and selective COX-2 inhibitors inhibit angiogenesis through a combined inhibition of angiogenic growth factors production, response to angiogenic factor and impairment of endothelial cell survival and migration.	('inhibitors', 'Var', (39, 49))	('inhibition', 'NegReg', (90, 100))	('impairment', 'NegReg', (176, 186))	('response to angiogenic factor', 'MPA', (142, 171))	('angiogenic growth factors production', 'MPA', (104, 140))	('inhibit', 'NegReg', (50, 57))	('COX-2', 'Gene', (33, 38))	('endothelial cell survival', 'CPA', (190, 215))	('angiogenesis', 'CPA', (58, 70))	('rat', 'Species', '10116', (223, 226))
84615	27713364	Inhibition of COX-2 activity in endothelial cells by COX-2 inhibitors resulted in a diminished integrine alphaVbeta3-dependent activation Cdc42 and Rac, two members of the Rho family of GTPases that regulate cytoskeletal organization and cell migration, resulting in FGF-2-induced angiogenesis in vivo.	('Cdc42', 'Gene', (138, 143))	('FGF-2', 'Gene', '2247', (267, 272))	('Rac', 'Gene', '207', (148, 151))	('rat', 'Species', '10116', (246, 249))	('FGF-2', 'Gene', (267, 272))	('Rac', 'Gene', (148, 151))	('COX-2', 'Gene', (53, 58))	('angiogenesis', 'CPA', (281, 293))	('Cdc42', 'Gene', '998', (138, 143))	('inhibitors', 'Var', (59, 69))	('activation', 'PosReg', (127, 137))	('diminished', 'NegReg', (84, 94))	('integrine alphaVbeta3-dependent', 'MPA', (95, 126))
84621	27713364	COX-2 selective inhibitors restore the tumour induced imbalance between Th1 and Th2 and promote antineoplastic responses in lung cancer and metastatic spread of CRC.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('CRC', 'Phenotype', 'HP:0003003', (161, 164))	('inhibitors', 'Var', (16, 26))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', (39, 45))	('promote', 'PosReg', (88, 95))	('imbalance', 'Phenotype', 'HP:0002172', (54, 63))	('restore', 'PosReg', (27, 34))	('antineoplastic responses', 'CPA', (96, 120))	('Th1', 'Gene', (72, 75))	('metastatic spread', 'CPA', (140, 157))	('lung cancer', 'Disease', (124, 135))	('COX-2', 'Gene', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('Th1', 'Gene', '51497', (72, 75))
84641	27713364	Overexpression of COX-2 also was associated with increased levels of bcl-2, a proapoptotic protein that induced resistance to apoptosis.	('increased', 'PosReg', (49, 58))	('bcl-2', 'Gene', (69, 74))	('Overexpression', 'Var', (0, 14))	('bcl-2', 'Gene', '596', (69, 74))	('COX-2', 'Gene', (18, 23))
84642	27713364	Therefore, selective COX-2 inhibitors may up-regulate the expression of Fas receptors on the cell surface in subjects with Barrett dysplasia and have an inhibiting role in esophageal carcinogenesis by influencing apoptosis and cellular proliferation.	('Fas receptors', 'Protein', (72, 85))	('Fas', 'Chemical', 'MESH:C038178', (72, 75))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (172, 197))	('expression', 'MPA', (58, 68))	('inhibiting', 'NegReg', (153, 163))	('esophageal carcinogenesis', 'Disease', (172, 197))	('up-regulate', 'PosReg', (42, 53))	('Barrett dysplasia', 'Disease', (123, 140))	('Barrett dysplasia', 'Disease', 'MESH:D001471', (123, 140))	('rat', 'Species', '10116', (243, 246))	('inhibitors', 'Var', (27, 37))	('apoptosis', 'CPA', (213, 222))	('cellular proliferation', 'CPA', (227, 249))	('COX-2', 'Gene', (21, 26))	('influencing', 'NegReg', (201, 212))
84652	27713364	Furthermore, in a study carried out using a carcinogen-induced rodent model, selective COX-2 inhibitors have been reported to prevent the development of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('COX-2', 'Enzyme', (87, 92))	('prevent', 'NegReg', (126, 133))	('esophageal cancer', 'Disease', (153, 170))	('inhibitors', 'Var', (93, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
84671	27713364	The blockade of COX-2 was also associated with a decrease in the serum level of proinflammatory cytokines IL-8 and TNFalpha being also involved in the gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (151, 173))	('IL-8', 'Gene', '3576', (106, 110))	('blockade', 'Var', (4, 12))	('IL-8', 'Gene', (106, 110))	('decrease', 'NegReg', (49, 57))	('COX-2', 'Gene', (16, 21))	('TNFalpha', 'Gene', (115, 123))	('TNFalpha', 'Gene', '7124', (115, 123))	('gastric carcinogenesis', 'Disease', (151, 173))
84686	27713364	According to this adenoma-carcinoma sequence model, carcinogenesis proceeds through the accumulation of series of epigenetic and genetic alterations involving several tumour-suppressor genes (i.e., APC and p53) and oncogenes (i.e., k-ras).	('p53', 'Gene', (206, 209))	('p53', 'Gene', '7157', (206, 209))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('epigenetic', 'Var', (114, 124))	('APC', 'Disease', 'MESH:D011125', (198, 201))	('tumour', 'Disease', (167, 173))	('APC', 'Disease', (198, 201))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (18, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (52, 66))	('adenoma-carcinoma', 'Disease', (18, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('carcinogenesis', 'Disease', (52, 66))	('rat', 'Species', '10116', (141, 144))
84689	27713364	They induced COX-2 mutations in ApcDelta716 knockout mice, which led to the development of numerous polyps in the intestine.	('led to', 'Reg', (65, 71))	('Apc', 'Gene', (32, 35))	('numerous polyps', 'Disease', (91, 106))	('mutations', 'Var', (19, 28))	('numerous polyps', 'Disease', 'MESH:D011127', (91, 106))	('COX-2', 'Gene', (13, 18))	('polyps in the intestine', 'Phenotype', 'HP:0200008', (100, 123))	('Apc', 'Gene', '324', (32, 35))	('mice', 'Species', '10090', (53, 57))
84690	27713364	In COX-2-/- ApcDelta716 and COX-2+/- ApcDelta716 mice, the number of polyps dramatically decreased by 86% and 66%, in comparison to that in the littermate COX-2+/+ ApcDelta716 mice.	('Apc', 'Gene', '324', (37, 40))	('Apc', 'Gene', (12, 15))	('Apc', 'Gene', '324', (164, 167))	('Apc', 'Gene', (37, 40))	('mice', 'Species', '10090', (49, 53))	('mice', 'Species', '10090', (176, 180))	('polyps', 'Disease', (69, 75))	('COX-2+/-', 'Var', (28, 36))	('Apc', 'Gene', (164, 167))	('polyps', 'Disease', 'MESH:D011127', (69, 75))	('Apc', 'Gene', '324', (12, 15))	('decreased', 'NegReg', (89, 98))
84704	27713364	Colony formation of cultured HCA-7 cells also was inhibited by SC-58125.	('SC-58125', 'Chemical', 'MESH:C090859', (63, 71))	('HCA-7', 'CellLine', 'CVCL:0289', (29, 34))	('Colony formation', 'CPA', (0, 16))	('inhibited', 'NegReg', (50, 59))	('SC-58125', 'Var', (63, 71))
84705	27713364	On the other hand, SC-58125 had no effect on HCT-116 implants in nude mice or colony formation in culture.	('HCT-116', 'Gene', (45, 52))	('colony formation', 'CPA', (78, 94))	('SC-58125', 'Var', (19, 27))	('SC-58125', 'Chemical', 'MESH:C090859', (19, 27))	('nude mice', 'Species', '10090', (65, 74))	('HCT-116', 'CellLine', 'CVCL:0291', (45, 52))
84709	27713364	After 6 months, the patients receiving celecoxib 400 mg twice/day had a 28.0% reduction in the mean number of colorectal polyps (p = 0.003) and a 30.7% reduction in the polyp size (p = 0.001), as compared with reductions of 4.5% and 4.9%, respectively, in the placebo group.	('colorectal polyps', 'Phenotype', 'HP:0200063', (110, 127))	('celecoxib', 'Var', (39, 48))	('reduction', 'NegReg', (78, 87))	('colorectal polyps', 'Disease', 'MESH:D003111', (110, 127))	('celecoxib', 'Chemical', 'MESH:D000068579', (39, 48))	('colorectal polyps', 'Disease', (110, 127))	('patients', 'Species', '9606', (20, 28))	('polyp', 'Disease', (121, 126))	('polyp', 'Disease', 'MESH:D011127', (121, 126))	('polyp', 'Disease', (169, 174))	('reduction', 'NegReg', (152, 161))	('polyp', 'Disease', 'MESH:D011127', (169, 174))
84721	27713364	in a five-years efficacy and safety analysis of the adenoma prevention with celecoxib trial, found an inhibitory effect of celecoxib in colorectal adenoma formation but they reported an elevated risk for cardiovascular and thrombotic adverse events [6% (RR, 1.6; 95% CI, 1.0-2.5) and 7.5% (RR, 1.9; 95% CI, 1.2-3.1) in celecoxib 200 and 400 mg twice daily users, respectively compared to 3.8% in placebo group.	('adenoma', 'Disease', 'MESH:D000236', (147, 154))	('celecoxib', 'Chemical', 'MESH:D000068579', (319, 328))	('cardiovascular', 'Disease', (204, 218))	('thrombotic adverse', 'Disease', 'MESH:D013927', (223, 241))	('colorectal adenoma', 'Disease', 'MESH:D015179', (136, 154))	('adenoma', 'Disease', (147, 154))	('thrombotic adverse', 'Disease', (223, 241))	('celecoxib', 'Chemical', 'MESH:D000068579', (123, 132))	('celecoxib', 'Chemical', 'MESH:D000068579', (76, 85))	('colorectal adenoma', 'Disease', (136, 154))	('adenoma', 'Disease', 'MESH:D000236', (52, 59))	('cardiovascular', 'Disease', 'MESH:D002318', (204, 218))	('adenoma', 'Disease', (52, 59))	('celecoxib 200', 'Var', (319, 332))
84732	27713364	demonstrated that deficiency of either COX-1 and COX-2 caused similar reduction in intestinal tumourigenesis in Min mice having a mutation in the APC gene and spontaneously developing intestinal adenomas .	('tumour', 'Disease', (94, 100))	('mice', 'Species', '10090', (116, 120))	('reduction', 'NegReg', (70, 79))	('mutation', 'Var', (130, 138))	('intestinal adenomas', 'Disease', 'MESH:D000236', (184, 203))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('rat', 'Species', '10116', (7, 10))	('APC', 'Disease', 'MESH:D011125', (146, 149))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('APC', 'Disease', (146, 149))	('intestinal adenomas', 'Disease', (184, 203))
84742	27713364	There are many reasons to be optimistic that tumour formation mediated by abnormal COX-2 activity can be effectively and safely targeted by chemoprevention regimens.	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('COX-2', 'Protein', (83, 88))	('abnormal', 'Var', (74, 82))	('tumour', 'Disease', (45, 51))	('activity', 'MPA', (89, 97))
84754	23155448	The Association between Four Genetic Variants in MicroRNAs (rs11614913, rs2910164, rs3746444, rs2292832) and Cancer Risk: Evidence from Published Studies MicroRNAs (miRNAs) participate in diverse biological pathways and may act as either tumor suppressor genes or oncogenes.	('Cancer', 'Disease', (109, 115))	('rs11614913', 'Mutation', 'rs11614913', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('miR', 'Gene', (165, 168))	('MicroRNAs', 'Gene', (49, 58))	('rs2910164', 'Var', (72, 81))	('rs3746444', 'Var', (83, 92))	('rs2292832', 'Mutation', 'rs2292832', (94, 103))	('Cancer', 'Disease', 'MESH:D009369', (109, 115))	('rs2292832', 'Var', (94, 103))	('rs2910164', 'Mutation', 'rs2910164', (72, 81))	('participate', 'Reg', (173, 184))	('tumor', 'Disease', (238, 243))	('Association', 'Interaction', (4, 15))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('rs3746444', 'Mutation', 'rs3746444', (83, 92))	('miR', 'Gene', '220972', (165, 168))	('rs11614913', 'Var', (60, 70))
84755	23155448	Single nucleotide polymorphisms (SNPs) in miRNA may contribute to cancer development with changes in the microRNA's properties and/or maturation.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('microRNA', 'MPA', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('maturation', 'CPA', (134, 144))	('miR', 'Gene', (42, 45))	('miR', 'Gene', '220972', (42, 45))	('contribute', 'Reg', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('changes', 'Reg', (90, 97))	('cancer', 'Disease', (66, 72))
84756	23155448	Polymorphisms in miRNAs have been suggested in predisposition to cancer risk; however, accumulated studies have shown inconsistent conslusionss.	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('Polymorphisms', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('predisposition', 'Reg', (47, 61))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
84757	23155448	To further validate determine whether there is any potential association between the four common SNPs (miR-196a2C>T, rs11614913; miR-146aG>C, rs2910164; miR-499A>G, rs3746444; miR-149C>T, rs2292832) and the risk for developing risk, a meta-analysis was performed according to the 40 published case-control studies.	('miR-196a2', 'Gene', '406973', (103, 112))	('miR-146a', 'Gene', (129, 137))	('rs3746444', 'Mutation', 'rs3746444', (165, 174))	('rs2292832', 'Var', (188, 197))	('miR-499A', 'Gene', '574501', (153, 161))	('miR-146a', 'Gene', '406938', (129, 137))	('rs2292832', 'Mutation', 'rs2292832', (188, 197))	('rs11614913', 'Mutation', 'rs11614913', (117, 127))	('miR-196a2', 'Gene', (103, 112))	('miR-499A', 'Gene', (153, 161))	('miR-149', 'Gene', (176, 183))	('rs2910164', 'Mutation', 'rs2910164', (142, 151))	('miR-149', 'Gene', '406941', (176, 183))
84758	23155448	The results demonstrated that the rs11614913TT genotype was significantly associated with a decreased cancer risk, in particular with a decreased risk for colorectal cancer and lung cancer, or for Asian population subgroup.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('rs11614913', 'Mutation', 'rs11614913', (34, 44))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('decreased', 'NegReg', (136, 145))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('lung cancer', 'Disease', (177, 188))	('decreased', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs11614913TT', 'Var', (34, 46))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('colorectal cancer', 'Disease', (155, 172))
84759	23155448	In addition, the rs2910164C allele was associated with decreased risk for esophageal cancer, cervical cancer, prostate cancer, and hepatocellular carcinoma (HCC), in particular in Asian population subgroup.	('cervical cancer', 'Disease', (93, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (131, 155))	('hepatocellular carcinoma', 'Disease', (131, 155))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (131, 155))	('decreased', 'NegReg', (55, 64))	('esophageal cancer', 'Disease', (74, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('HCC', 'Phenotype', 'HP:0001402', (157, 160))	('rs2910164', 'Mutation', 'rs2910164', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cervical cancer', 'Disease', 'MESH:D002583', (93, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('prostate cancer', 'Disease', (110, 125))	('rs2910164C', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
84760	23155448	Similarly, the rs3746444G allele was observed as a risk factor for cancers in the Asian population.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('rs3746444G', 'Var', (15, 25))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('risk', 'Reg', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs3746444', 'Mutation', 'rs3746444', (15, 24))
84761	23155448	It is concluded that two SNPs prsent in miRNAs(rs11614913TT, and rs2910164C) may protect against the pathogenesis of some cancers, and that the rs3746444 may increase risk for cancer.	('rs2910164C', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('protect', 'Reg', (81, 88))	('rs11614913TT', 'Var', (47, 59))	('rs2910164', 'Mutation', 'rs2910164', (65, 74))	('cancers', 'Disease', (122, 129))	('increase', 'PosReg', (158, 166))	('rs3746444', 'Mutation', 'rs3746444', (144, 153))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('miR', 'Gene', '220972', (40, 43))	('rs11614913', 'Mutation', 'rs11614913', (47, 57))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('rs3746444', 'Var', (144, 153))	('miR', 'Gene', (40, 43))	('cancer', 'Disease', (122, 128))	('pathogenesis', 'CPA', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (176, 182))
84764	23155448	SNPs in miRNA genes are regarded to affect function by three ways: first, through the transcription of the primary transcript; second, through pri-miRNA and pre-miRNA processing; and third, through effects on miRNA-mRNA interactions.	('function', 'MPA', (43, 51))	('miR', 'Gene', '220972', (209, 212))	('miR', 'Gene', (209, 212))	('miR', 'Gene', '220972', (161, 164))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (161, 164))	('transcription', 'MPA', (86, 99))	('miR', 'Gene', (147, 150))	('affect', 'Reg', (36, 42))	('SNPs', 'Var', (0, 4))	('effects', 'Reg', (198, 205))	('miR', 'Gene', '220972', (8, 11))	('miR', 'Gene', (8, 11))
84766	23155448	For example, four SNPs - miR-196a2C>T (or rs11614913), miR-146aG>C (rs2910164), miR-499A>G (rs3746444), and miR-149C>T (rs2292832) - identified in the pre-miRNA regions of miR-146a, miR-149, miR-196a2, and miR-499, respectively, have been reported to be associated with cancer risk.	('miR', 'Gene', (80, 83))	('miR-196a2', 'Gene', '406973', (25, 34))	('miR-499', 'Gene', (206, 213))	('associated', 'Reg', (254, 264))	('miR-196a2', 'Gene', '406973', (191, 200))	('miR-146a', 'Gene', (55, 63))	('rs11614913', 'Mutation', 'rs11614913', (42, 52))	('miR', 'Gene', (172, 175))	('rs3746444', 'Var', (92, 101))	('rs2910164', 'Mutation', 'rs2910164', (68, 77))	('miR', 'Gene', (155, 158))	('miR', 'Gene', (108, 111))	('miR-196a2', 'Gene', (25, 34))	('miR-499', 'Gene', (80, 87))	('miR-499', 'Gene', '574501', (80, 87))	('miR-146a', 'Gene', '406938', (55, 63))	('miR-196a2', 'Gene', (191, 200))	('miR-149', 'Gene', (182, 189))	('cancer', 'Disease', (270, 276))	('miR', 'Gene', '220972', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('miR', 'Gene', '220972', (191, 194))	('miR', 'Gene', '220972', (182, 185))	('miR-146a', 'Gene', (172, 180))	('miR', 'Gene', '220972', (206, 209))	('miR', 'Gene', (25, 28))	('miR-149', 'Gene', (108, 115))	('miR', 'Gene', '220972', (55, 58))	('miR-149', 'Gene', '406941', (182, 189))	('rs3746444', 'Mutation', 'rs3746444', (92, 101))	('miR-499A', 'Gene', (80, 88))	('miR-146a', 'Gene', '406938', (172, 180))	('miR', 'Gene', (191, 194))	('miR', 'Gene', '220972', (80, 83))	('rs2292832) -', 'Var', (120, 132))	('miR-499', 'Gene', '574501', (206, 213))	('miR-499A', 'Gene', '574501', (80, 88))	('miR', 'Gene', (182, 185))	('miR', 'Gene', '220972', (172, 175))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('miR', 'Gene', (206, 209))	('rs2292832', 'Mutation', 'rs2292832', (120, 129))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (55, 58))	('miR-149', 'Gene', '406941', (108, 115))
84772	23155448	All the studies were included if they met the following criteria: (i) about the rs11614913, rs2910164, rs3746444, and rs2292832 polymorphisms and cancer risk, (ii) from a case-control designed study, and (iii) genotype frequencies available.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('rs3746444', 'Var', (103, 112))	('rs11614913', 'Var', (80, 90))	('rs2292832', 'Mutation', 'rs2292832', (118, 127))	('rs2910164', 'Mutation', 'rs2910164', (92, 101))	('rs3746444', 'Mutation', 'rs3746444', (103, 112))	('rs2910164', 'Var', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('rs11614913', 'Mutation', 'rs11614913', (80, 90))	('rs2292832', 'Var', (118, 127))
84778	23155448	Moreover, stratified analyses were also performed by ethnicity (Asian, and Caucasian), cancer type (if only one cancer type contained fewer than two individual studies it was combined into the 'Other Cancers' group) and source of control for rs11614913 and rs2910164.	('rs11614913', 'Mutation', 'rs11614913', (242, 252))	('cancer', 'Disease', (87, 93))	('rs2910164', 'Var', (257, 266))	('Cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rs11614913', 'Var', (242, 252))	('Cancers', 'Disease', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('Cancers', 'Phenotype', 'HP:0002664', (200, 207))	('rs2910164', 'Mutation', 'rs2910164', (257, 266))
84779	23155448	Stratified analyses were performed by ethnicity for rs2292382, and by ethnicity and cancer type for rs3746444, respectively.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('rs3746444', 'Var', (100, 109))	('rs3746444', 'Mutation', 'rs3746444', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rs2292382', 'Var', (52, 61))	('rs2292382', 'Mutation', 'rs2292382', (52, 61))
84780	23155448	A total of 40 eligible studies met the prespecified inclusion criteria (See Figure S1), in which 27, 26, 13, and 6 studies were pooleded for the analyses of the rs11614913, rs2910164, rs37464444, and rs2292832, respectively (Table 1).	('rs11614913', 'Var', (161, 171))	('rs2292832', 'Mutation', 'rs2292832', (200, 209))	('rs2910164', 'Mutation', 'rs2910164', (173, 182))	('rs2910164', 'Var', (173, 182))	('rs11614913', 'Mutation', 'rs11614913', (161, 171))	('rs2292832', 'Var', (200, 209))	('rs37464444', 'Mutation', 'rs37464444', (184, 194))	('rs37464444', 'Var', (184, 194))
84782	23155448	For rs11614913 polymorphism, significant differences were observed for the comparison of TT vs. CC and TT vs. CC+CT.	('differences', 'Reg', (41, 52))	('rs11614913', 'Mutation', 'rs11614913', (4, 14))	('CT', 'Chemical', 'MESH:D002251', (113, 115))	('rs11614913', 'Var', (4, 14))
84789	23155448	Similarly, a decreased risk was observed for the comparison of GC vs. GG in the cervical cancer (OR = 0.71, 95% CI: 0.51-0.99, P h = 0.254), CC+GC vs. GG in esophageal cancer (OR = 0.79, 95% CI: 0.65-0.96, P h = 0.195), and CC vs. GG+GC in prostate cancer (OR = 0.65, 95% CI: 0.44-0.96, P h = 0.699) and esophageal cancer (OR = 0.64, 95% CI: 0.41-0.98, P h = 0.079).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('decreased', 'NegReg', (13, 22))	('prostate cancer', 'Disease', 'MESH:D011471', (240, 255))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('prostate cancer', 'Phenotype', 'HP:0012125', (240, 255))	('CC vs. GG+GC', 'Var', (224, 236))	('cervical cancer', 'Disease', (80, 95))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('esophageal cancer', 'Disease', (304, 321))	('cervical cancer', 'Disease', 'MESH:D002583', (80, 95))	('prostate cancer', 'Disease', (240, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('CC+GC vs. GG', 'Var', (141, 153))	('esophageal cancer', 'Disease', (157, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (304, 321))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
84791	23155448	For the rs3746444 polymorphism, there was no significant risk association observed for the overall pooled analysis of cancer risk.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs3746444', 'Var', (8, 17))	('rs3746444', 'Mutation', 'rs3746444', (8, 17))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
84793	23155448	There was significant heterogeneity across the studies of the rs11614913, rs2910164, rs3746444, and thus the source of heterogeneity was further explored by the heterozygote comparison.	('rs3746444', 'Mutation', 'rs3746444', (85, 94))	('rs11614913', 'Var', (62, 72))	('rs2910164', 'Var', (74, 83))	('rs2910164', 'Mutation', 'rs2910164', (74, 83))	('rs11614913', 'Mutation', 'rs11614913', (62, 72))	('rs3746444', 'Var', (85, 94))
84794	23155448	For the rs11614913, cancer type (chi2 = 23.68, df = 5, P = 0.000) and source of control (chi2 = 5.63, df = 1, P = 0.018) were the source of the heterogeneity.	('rs11614913', 'Mutation', 'rs11614913', (8, 18))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('rs11614913', 'Var', (8, 18))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))
84795	23155448	For rs2910164 polymorphism, cancer type (chi2 = 27.65, df = 6, P = 0.000) and ethnicity (chi2 = 15.52, df = 3, P = 0.000) contributed substantially to the heterogeneity.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('rs2910164', 'Var', (4, 13))	('rs2910164', 'Mutation', 'rs2910164', (4, 13))	('cancer', 'Disease', (28, 34))
84799	23155448	Similarly, heterogeneity of the rs2910164 (CC+GC vs. GG: P h = 0.060, I 2 = 33.5%) and rs3746444 (GG+GA vs. AA: P h = 0.092, I 2 = 39.8%) were decreased when the four and the three independent studies removed, respectively.	('rs3746444', 'Mutation', 'rs3746444', (87, 96))	('rs2910164', 'Mutation', 'rs2910164', (32, 41))	('rs3746444', 'Var', (87, 96))	('rs2910164', 'Var', (32, 41))
84800	23155448	The results also did not show any evidence of publication bias (rs11614913: t = 0.25, P =  0.806, rs2910164: t = -0.70, P = 0.489, rs37464444: t = 1.88, P = 0.087, and rs2292832: t = 1.14, P = 0.318 for dominant model.	('rs2910164', 'Mutation', 'rs2910164', (98, 107))	('rs2910164', 'Var', (98, 107))	('rs11614913:', 'Var', (64, 75))	('rs11614913', 'Mutation', 'rs11614913', (64, 74))	('rs2292832', 'Var', (168, 177))	('rs37464444', 'Var', (131, 141))	('rs2292832', 'Mutation', 'rs2292832', (168, 177))	('rs37464444', 'Mutation', 'rs37464444', (131, 141))
84801	23155448	In this meta-analysis, an association between the four common SNPs in microRNAs (rs11614913, rs2910164, rs3746444, and rs2292832) and cancer risk was evaluated by the pooled results from 40 published studies.	('rs2910164', 'Var', (93, 102))	('rs11614913', 'Mutation', 'rs11614913', (81, 91))	('rs2292832', 'Var', (119, 128))	('rs3746444', 'Var', (104, 113))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('rs3746444', 'Mutation', 'rs3746444', (104, 113))	('rs11614913', 'Var', (81, 91))	('rs2292832', 'Mutation', 'rs2292832', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('rs2910164', 'Mutation', 'rs2910164', (93, 102))
84802	23155448	The results demonstrated that the rs11614913TT genotype was associated with a decreased risk for developing cancer, in particular for colorectal cancer and lung cancer, or in the Asian population, and that the rs2910164C allele was associated with a decreased risk for developing esophageal cancer, cervical cancer, prostate cancer and HCC, in particular in the Asian population.	('cancer', 'Disease', (145, 151))	('rs11614913', 'Mutation', 'rs11614913', (34, 44))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (161, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (280, 297))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('rs2910164', 'Mutation', 'rs2910164', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', (325, 331))	('esophageal cancer', 'Disease', (280, 297))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('decreased', 'NegReg', (78, 87))	('cervical cancer', 'Disease', 'MESH:D002583', (299, 314))	('lung cancer', 'Disease', (156, 167))	('cervical cancer', 'Disease', (299, 314))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('colorectal cancer', 'Disease', (134, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (316, 331))	('cancer', 'Disease', (291, 297))	('prostate cancer', 'Phenotype', 'HP:0012125', (316, 331))	('cancer', 'Disease', (308, 314))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('prostate cancer', 'Disease', (316, 331))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('rs2910164C', 'Var', (210, 220))	('cancer', 'Disease', (108, 114))	('rs11614913TT', 'Var', (34, 46))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('HCC', 'Disease', (336, 339))	('HCC', 'Phenotype', 'HP:0001402', (336, 339))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('decreased', 'NegReg', (250, 259))
84803	23155448	Contrary to the above, the rs3746444G allele was observed as a risk factor for cancer in the Asian population; however, the rs2292832 polymorphism was not associated with cancer risk.	('rs2292832', 'Mutation', 'rs2292832', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('rs3746444', 'Mutation', 'rs3746444', (27, 36))	('rs2292832', 'Var', (124, 133))	('rs3746444G', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
84804	23155448	The rs11614913 polymorphism present in the miR-196a2 has significantly greater impact on miR-196a expression and is associated with various carcinogenesis.	('associated with', 'Reg', (116, 131))	('rs11614913', 'Var', (4, 14))	('miR-196a2', 'Gene', (43, 52))	('miR', 'Gene', (43, 46))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('carcinogenesis', 'Disease', (140, 154))	('rs11614913', 'Mutation', 'rs11614913', (4, 14))	('miR-196a2', 'Gene', '406973', (43, 52))	('greater impact', 'PosReg', (71, 85))	('expression', 'MPA', (98, 108))
84805	23155448	Although there were studies reporting no direct association between rs11614913 and the expression of miR-196a, previous, meta-analysis studies have suggested an association between rs11614913 and risk of cancers, This updated meta-analysis further support the rs11614913 TT genotype was associated with a decreased risk for cancer.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', (324, 330))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('association', 'Interaction', (161, 172))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('rs11614913', 'Mutation', 'rs11614913', (260, 270))	('rs11614913', 'Mutation', 'rs11614913', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('rs11614913', 'Mutation', 'rs11614913', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('decreased', 'NegReg', (305, 314))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('rs11614913', 'Var', (260, 270))	('rs11614913', 'Var', (181, 191))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (101, 104))
84806	23155448	In contrast to the published pooled results, this updated pooled results revealed that the rs116114913 TT could be a protective factor against colorectal cancer and lung cancer.	('colorectal cancer', 'Disease', (143, 160))	('lung cancer', 'Disease', (165, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('rs116114913', 'Var', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('rs116114913', 'Mutation', 'rs116114913', (91, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))
84810	23155448	In contrast to the published results, this study revealed the different association between rs2910164 polymorphism and cancer risk among ethnicity and the cancer types.	('rs2910164', 'Mutation', 'rs2910164', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('rs2910164', 'Var', (92, 101))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
84811	23155448	The rs2910164 CC genotype was associated with decreased risk for esophageal cancer, cervical cancer, prostate cancer, and HCC in the Asian population, suggesting a difference in genetic background and the environment, and pathogenesis of different tumor sites.	('esophageal cancer', 'Disease', (65, 82))	('tumor', 'Disease', (248, 253))	('cervical cancer', 'Disease', 'MESH:D002583', (84, 99))	('prostate cancer', 'Disease', (101, 116))	('cervical cancer', 'Disease', (84, 99))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('HCC', 'Disease', (122, 125))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))	('decreased', 'NegReg', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('rs2910164 CC', 'Var', (4, 16))	('rs2910164', 'Mutation', 'rs2910164', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
84812	23155448	The rs2910164 in the miR-146aG>C gene is located in the stem region opposite to the mature miR-146 sequence and results in a change from G:U pair to C:U mismatch in the stem structure of miR-146a precursor.	('miR', 'Gene', (91, 94))	('stem structure', 'MPA', (169, 183))	('miR-146a', 'Gene', '406938', (187, 195))	('results in', 'Reg', (112, 122))	('miR', 'Gene', '220972', (21, 24))	('miR-146a', 'Gene', (21, 29))	('miR', 'Gene', (21, 24))	('change', 'Reg', (125, 131))	('rs2910164', 'Var', (4, 13))	('miR-146a', 'Gene', (187, 195))	('miR', 'Gene', (187, 190))	('miR-146a', 'Gene', '406938', (21, 29))	('rs2910164', 'Mutation', 'rs2910164', (4, 13))	('miR', 'Gene', '220972', (187, 190))	('miR', 'Gene', '220972', (91, 94))
84814	23155448	The rs3746444 polymorphism present in the miR-499 would target to SOX6 and Rod1 genes important roles for the etiology of cancers.	('rs3746444', 'Var', (4, 13))	('miR-499', 'Gene', (42, 49))	('SOX6', 'Gene', (66, 70))	('rs3746444', 'Mutation', 'rs3746444', (4, 13))	('SOX6', 'Gene', '55553', (66, 70))	('miR-499', 'Gene', '574501', (42, 49))	('Rod1', 'Gene', (75, 79))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('Rod1', 'Gene', '9991', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('target', 'Reg', (56, 62))
84815	23155448	The pooled results from 13 studies revealed that rs3746444G allele was associated with an increased risk for developing cancer in the Asian population.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('rs3746444', 'Mutation', 'rs3746444', (49, 58))	('rs3746444G', 'Var', (49, 59))
84816	23155448	To our knowledge, this is the first meta-analysisabout the association of rs3746444 of cancer from 11 Asian population studies and two Caucasian population studies.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('association', 'Interaction', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rs3746444', 'Var', (74, 83))	('rs3746444', 'Mutation', 'rs3746444', (74, 83))
84818	23155448	Thus far, few epidemiologic studies have investigated the association of rs2292832 polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rs2292832', 'Var', (73, 82))	('cancer', 'Disease', (100, 106))	('rs2292832', 'Mutation', 'rs2292832', (73, 82))
84819	23155448	The heterogeneity were observed across the studies for the polymorphisms of rs11614913, rs2910164, rs3746444, the source of the heterogeneity were mainly from the cancer type, such as glioma, gallbladder, bladder, and papillary thyroid carcinoma and cervical cancer, suggesting polymorphisms in miRNAs may play different roles according the cancer type.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('rs3746444', 'Mutation', 'rs3746444', (99, 108))	('bladder', 'Disease', (205, 212))	('rs2910164', 'Var', (88, 97))	('cancer', 'Disease', (341, 347))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('glioma', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (228, 245))	('rs2910164', 'Mutation', 'rs2910164', (88, 97))	('glioma', 'Disease', 'MESH:D005910', (184, 190))	('rs3746444', 'Var', (99, 108))	('cancer', 'Disease', (259, 265))	('gallbladder', 'Disease', (192, 203))	('cervical cancer', 'Disease', 'MESH:D002583', (250, 265))	('miR', 'Gene', '220972', (295, 298))	('cervical cancer', 'Disease', (250, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (218, 245))	('cancer', 'Disease', (163, 169))	('rs11614913', 'Var', (76, 86))	('papillary thyroid carcinoma', 'Disease', (218, 245))	('miR', 'Gene', (295, 298))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (218, 245))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('rs11614913', 'Mutation', 'rs11614913', (76, 86))
84820	23155448	Furthermore, different risk of polymorphisms in miRNAs was also the source of the heterogeneity, significant associations were observed in the most studies for Asian populations.	('miR', 'Gene', (48, 51))	('miR', 'Gene', '220972', (48, 51))	('polymorphisms', 'Var', (31, 44))	('associations', 'Interaction', (109, 121))
84822	23155448	In summary, this meta-analysis suggested that the rs11614913TT genotype was associated with a decreased cancer risk, especially for colorectal cancer and lung cancer, that the rs2910164C allele was a protective factor for esophageal cancer, cervical cancer, prostate cancer and HCC, and that the rs11614913, rs2910164, and rs3746444 SNPs were risk factors for cancer in the Asian population.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('rs11614913', 'Var', (296, 306))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('prostate cancer', 'Disease', 'MESH:D011471', (258, 273))	('rs3746444', 'Var', (323, 332))	('prostate cancer', 'Phenotype', 'HP:0012125', (258, 273))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('rs11614913', 'Mutation', 'rs11614913', (296, 306))	('HCC', 'Disease', (278, 281))	('cancer', 'Disease', (104, 110))	('prostate cancer', 'Disease', (258, 273))	('rs2910164', 'Mutation', 'rs2910164', (176, 185))	('HCC', 'Phenotype', 'HP:0001402', (278, 281))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('rs11614913', 'Mutation', 'rs11614913', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs2910164', 'Var', (308, 317))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', (154, 165))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('cancer', 'Disease', (267, 273))	('rs2910164', 'Mutation', 'rs2910164', (308, 317))	('rs11614913TT', 'Var', (50, 62))	('decreased', 'NegReg', (94, 103))	('rs3746444', 'Mutation', 'rs3746444', (323, 332))	('cervical cancer', 'Disease', (241, 256))	('colorectal cancer', 'Disease', (132, 149))	('cervical cancer', 'Disease', 'MESH:D002583', (241, 256))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (222, 239))	('rs2910164C', 'Var', (176, 186))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', (360, 366))	('cancer', 'Disease', (233, 239))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('esophageal cancer', 'Disease', (222, 239))
84824	31410110	However, the role of ZNF545 in the tumorigenesis of esophageal cancer cells expressing loss-of-function mutant p53 has not been elucidated.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('ZNF545', 'Gene', '284406', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutant', 'Var', (104, 110))	('esophageal cancer', 'Disease', (52, 69))	('p53', 'Gene', (111, 114))	('loss-of-function', 'NegReg', (87, 103))	('tumor', 'Disease', (35, 40))	('p53', 'Gene', '7157', (111, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('ZNF545', 'Gene', (21, 27))
84827	31410110	Methylated ZNF545 was detected in 76.6% of tumor tissues compared with 28.1% of adjacent normal tissues.	('ZNF545', 'Gene', '284406', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ZNF545', 'Gene', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Methylated', 'Var', (0, 10))	('detected', 'Reg', (22, 30))	('tumor', 'Disease', (43, 48))
84831	31410110	In addition, tumor-specific methylation of ZNF545 may represent an epigenetic diagnostic biomarker and a therapeutic target in patients with esophageal cancer.	('tumor', 'Disease', (13, 18))	('ZNF545', 'Gene', (43, 49))	('esophageal cancer', 'Disease', (141, 158))	('patients', 'Species', '9606', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('ZNF545', 'Gene', '284406', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('methylation', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
84835	31410110	Aberrant inactivation of tumor suppressor genes by promoter methylation is frequently involved in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('Aberrant inactivation', 'Var', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('involved', 'Reg', (86, 94))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('promoter methylation', 'Var', (51, 71))
84836	31410110	In particular, there has been accumulating evidence reveling a close association between methylated tumor suppressor-encoding genes and the development and progression of malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (181, 186))	('development', 'CPA', (140, 151))	('methylated', 'Var', (89, 99))	('tumor', 'Disease', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('malignant tumors', 'Disease', (171, 187))	('malignant tumors', 'Disease', 'MESH:D018198', (171, 187))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
84837	31410110	A Kruppel-associated box zinc-finger protein, ZFP82/ZNF545/KIAA1948 is considered to be a novel tumor suppressive gene that is frequently downregulated and methylated in multiple carcinomas including in breast and gastric cancer.	('ZNF545', 'Gene', '284406', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('multiple carcinomas', 'Disease', 'MESH:C537656', (170, 189))	('downregulated', 'NegReg', (138, 151))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('ZFP82', 'Gene', (46, 51))	('multiple carcinomas', 'Disease', (170, 189))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (203, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('gastric cancer', 'Phenotype', 'HP:0012126', (214, 228))	('ZNF545', 'Gene', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('methylated', 'Var', (156, 166))	('ZFP82', 'Gene', '284406', (46, 51))
84841	31410110	Frequent point mutations in the tumor suppressor gene p53 have been identified in both primary ESCCs and in ESCC cell lines.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('ESCCs', 'Disease', (95, 100))	('p53', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('p53', 'Gene', '7157', (54, 57))	('tumor', 'Disease', (32, 37))	('identified', 'Reg', (68, 78))	('point mutations', 'Var', (9, 24))
84842	31410110	Point mutations in this gene may occur at early stages of ESCC and correlate with tumor progression, indicating that they may serve an important role in ESCC.	('correlate', 'Reg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ESCC', 'Disease', (58, 62))	('Point mutations', 'Var', (0, 15))	('tumor', 'Disease', (82, 87))	('ESCC', 'Disease', (153, 157))
84858	31410110	PCR products were amplified with 32 cycles for ZNF545 and 23 cycles for beta-actin using the following temperature protocol: Initial denaturation at 95 C for 10 min, denaturation at 95 C for 30 sec, annealing at 55 C for 30 sec, elongation at 72 C for 30 sec and final extension at 25 C for 10 min.	('ZNF545', 'Gene', (47, 53))	('denaturation', 'Var', (166, 178))	('beta-actin', 'Gene', '728378', (72, 82))	('ZNF545', 'Gene', '284406', (47, 53))	('beta-actin', 'Gene', (72, 82))
84886	31410110	ZNF545 expression was also restored following the pharmacologic treatment of Aza and TSA in KYSE150 (Fig.	('TSA', 'Chemical', 'MESH:C012589', (85, 88))	('Aza', 'Chemical', 'MESH:D001379', (77, 80))	('ZNF545', 'Gene', '284406', (0, 6))	('restored', 'PosReg', (27, 35))	('expression', 'MPA', (7, 17))	('ZNF545', 'Gene', (0, 6))	('KYSE150', 'Var', (92, 99))	('KYSE150', 'CellLine', 'CVCL:1348', (92, 99))
84888	31410110	ZNF545 promoter methylation was observed in 76.6% (49/64) of primary tumors, compared with only 28.1% (28/64) of adjacent normal tissues (P<0.001; Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('promoter', 'MPA', (7, 15))	('observed', 'Reg', (32, 40))	('ZNF545', 'Gene', '284406', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('ZNF545', 'Gene', (0, 6))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('methylation', 'Var', (16, 27))
84892	31410110	The total number of colonies was significantly decreased in cells stably transfected with the ZNF545 vector (P<0.001) compared with those transfected with the control vector (Fig.	('ZNF545', 'Gene', '284406', (94, 100))	('vector', 'Var', (101, 107))	('ZNF545', 'Gene', (94, 100))	('decreased', 'NegReg', (47, 56))
84896	31410110	In a previous study, ZNF545 was identified as a novel tumor suppressor that inhibited cell proliferation and colony formation, and induced apoptosis via TP53 reactivation in multiple myeloma.	('reactivation', 'Var', (158, 170))	('ZNF545', 'Gene', '284406', (21, 27))	('apoptosis', 'CPA', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('TP53', 'Gene', '7157', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('induced', 'PosReg', (131, 138))	('ZNF545', 'Gene', (21, 27))	('TP53', 'Gene', (153, 157))	('multiple myeloma', 'Phenotype', 'HP:0006775', (174, 190))	('tumor', 'Disease', (54, 59))	('inhibited', 'NegReg', (76, 85))	('multiple myeloma', 'Disease', 'MESH:D009101', (174, 190))	('multiple myeloma', 'Disease', (174, 190))
84898	31410110	RT-qPCR analysis revealed that ectopic ZNF545 expression in KYSE150 cells upregulated p53 mRNA expression when compared with those transfected with the control vector (P<0.05; Fig.	('ZNF545', 'Gene', (39, 45))	('upregulated', 'PosReg', (74, 85))	('p53', 'Gene', '7157', (86, 89))	('ZNF545', 'Gene', '284406', (39, 45))	('ectopic', 'Var', (31, 38))	('KYSE150', 'CellLine', 'CVCL:1348', (60, 67))	('p53', 'Gene', (86, 89))
84900	31410110	The protein expression levels of two downstream effectors of the p53 pathway, Bax and p21, were increased in KYSE150 p53-mutant cells transfected with ZNF545; whereas the expression of Akt was not affected by ZNF545 transfection (Fig.	('p21', 'Gene', '1026', (86, 89))	('ZNF545', 'Gene', '284406', (209, 215))	('increased', 'PosReg', (96, 105))	('p21', 'Gene', (86, 89))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('ZNF545', 'Gene', '284406', (151, 157))	('Bax', 'Gene', (78, 81))	('ZNF545', 'Gene', (209, 215))	('KYSE150', 'Var', (109, 116))	('protein expression levels', 'MPA', (4, 29))	('ZNF545', 'Gene', (151, 157))	('Akt', 'Gene', '207', (185, 188))	('KYSE150', 'CellLine', 'CVCL:1348', (109, 116))	('Akt', 'Gene', (185, 188))	('Bax', 'Gene', '581', (78, 81))
84902	31410110	Furthermore, upregulating p21 and Bax expression via p53-independent signaling pathways in tumor cells with mutant p53 is another possibility (Fig.	('upregulating', 'PosReg', (13, 25))	('Bax', 'Gene', '581', (34, 37))	('expression', 'MPA', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('mutant', 'Var', (108, 114))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('p21', 'Gene', '1026', (26, 29))	('Bax', 'Gene', (34, 37))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('p21', 'Gene', (26, 29))	('tumor', 'Disease', (91, 96))
84905	31410110	The present study provides novel evidence for an association between ZNF545 and mutant p53 in ESCC.	('mutant', 'Var', (80, 86))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('ZNF545', 'Gene', '284406', (69, 75))	('ZNF545', 'Gene', (69, 75))	('ESCC', 'Disease', (94, 98))
84906	31410110	To assess ZNF545 methylation as a potential epigenetic biomarker, its relevance in relation to the clinicopathological features of ESCC was also evaluated, as aberrant DNA methylation has been reported to mediate tumor suppressor gene silencing and consequent tumorigenesis.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', (260, 265))	('ZNF545', 'Gene', '284406', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('silencing', 'NegReg', (235, 244))	('aberrant', 'Var', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('ZNF545', 'Gene', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('ESCC', 'Disease', (131, 135))
84907	31410110	As demonstrated by MSP analysis in the present study, ZNF545 methylation was detected in 76.6% of ESCC tissues when compared with 28.1% of adjacent normal tissues.	('methylation', 'Var', (61, 72))	('ZNF545', 'Gene', (54, 60))	('ESCC', 'Disease', (98, 102))	('detected', 'Reg', (77, 85))	('ZNF545', 'Gene', '284406', (54, 60))
84908	31410110	However, no significant association between the clinicopathological features of patients with ESCC and the methylation status of ZNF545 was observed.	('patients', 'Species', '9606', (80, 88))	('ZNF545', 'Gene', (129, 135))	('ZNF545', 'Gene', '284406', (129, 135))	('methylation', 'Var', (107, 118))	('ESCC', 'Disease', (94, 98))
84911	31410110	A previous study demonstrated that ZNF545 methylation was associated with survival in patients with ESCC, and poor survival in gastric and hepatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('associated', 'Reg', (58, 68))	('ZNF545', 'Gene', '284406', (35, 41))	('hepatic cancer', 'Phenotype', 'HP:0002896', (139, 153))	('ESCC', 'Disease', (100, 104))	('ZNF545', 'Gene', (35, 41))	('gastric and hepatic cancer', 'Disease', 'MESH:D013274', (127, 153))	('methylation', 'Var', (42, 53))	('patients', 'Species', '9606', (86, 94))
84912	31410110	The present study also revealed that ectopic ZNF545 expression inhibited cell growth by significantly suppressing colony formation and inducing apoptosis in ESCC cells.	('cell growth', 'CPA', (73, 84))	('ZNF545', 'Gene', '284406', (45, 51))	('ectopic', 'Var', (37, 44))	('suppressing', 'NegReg', (102, 113))	('inducing', 'NegReg', (135, 143))	('apoptosis', 'CPA', (144, 153))	('ZNF545', 'Gene', (45, 51))	('inhibited', 'NegReg', (63, 72))	('colony formation', 'CPA', (114, 130))
84918	31410110	However, p53 mutations are more commonly observed in malignancies involving organs compared with their hematological counterparts.	('malignancies', 'Disease', (53, 65))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('observed', 'Reg', (41, 49))	('mutations', 'Var', (13, 22))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('organs', 'Disease', (76, 82))
84919	31410110	Strategies targeting mutant p53, and altered signaling pathways exhibited in p53-mutant cells have been evaluated with the aim of uncovering novel treatments for malignancies associated with mutant p53.	('p53', 'Gene', (28, 31))	('mutant', 'Var', (21, 27))	('p53', 'Gene', '7157', (28, 31))	('malignancies', 'Disease', 'MESH:D009369', (162, 174))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('mutant', 'Var', (191, 197))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('malignancies', 'Disease', (162, 174))
84921	31410110	As the functional status of p53 in KYSE150 cells is unknown, these observations indicate that mutant p53 proteins in ESCC may retain the ability to activate p21, but also suggests that ZNF545-mediated tumor suppression may be independent of p53, thus providing insights into a potentially novel tumorigenic mechanism in ESCC.	('p53', 'Gene', (28, 31))	('ZNF545', 'Gene', '284406', (185, 191))	('activate', 'PosReg', (148, 156))	('proteins', 'Protein', (105, 113))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', (295, 300))	('p21', 'Gene', (157, 160))	('KYSE150', 'CellLine', 'CVCL:1348', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('mutant', 'Var', (94, 100))	('p53', 'Gene', '7157', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('p53', 'Gene', '7157', (241, 244))	('p53', 'Gene', '7157', (28, 31))	('p53', 'Gene', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('ZNF545', 'Gene', (185, 191))	('p21', 'Gene', '1026', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('ESCC', 'Disease', (117, 121))	('p53', 'Gene', (241, 244))
84924	31410110	One hypothesis is that the function of mutant p53 could be restored by specific DNA binding or transcriptional transactivation via a p53-dependent pathway.	('transcriptional transactivation', 'MPA', (95, 126))	('p53', 'Gene', (46, 49))	('function', 'MPA', (27, 35))	('DNA binding', 'Interaction', (80, 91))	('p53', 'Gene', '7157', (133, 136))	('p53', 'Gene', '7157', (46, 49))	('mutant', 'Var', (39, 45))	('p53', 'Gene', (133, 136))
84928	31410110	In addition, activation of these potential signaling pathways during tumorigenesis may be inhibited by ZNF545 methylation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ZNF545', 'Gene', '284406', (103, 109))	('tumor', 'Disease', (69, 74))	('methylation', 'Var', (110, 121))	('ZNF545', 'Gene', (103, 109))	('inhibited', 'NegReg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
84929	31410110	Tumor-specific methylation of ZNF545 may be a potential epigenetic biomarker for the early diagnosis of ESCC.	('methylation', 'Var', (15, 26))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ZNF545', 'Gene', (30, 36))	('ESCC', 'Disease', (104, 108))	('ZNF545', 'Gene', '284406', (30, 36))
84936	31114367	Methods: Expression profile datasets for mRNAs (GSE92396, GSE13898, GSE26886 and GSE1420) and miRNAs (GSE16456) were downloaded from the GEO database.	('GSE92396', 'Var', (48, 56))	('GSE1420', 'Chemical', '-', (81, 88))	('GSE1420', 'Var', (81, 88))	('GSE13898', 'Var', (58, 66))	('GSE26886', 'Var', (68, 76))
84954	31114367	The GSE92396, GSE13898, GSE26886 and GSE1420 datasets were used for mRNA, while the GSE16456 dataset was used for miRNA.	('GSE13898', 'Var', (14, 22))	('GSE26886', 'Var', (24, 32))	('GSE92396', 'Var', (4, 12))	('GSE1420', 'Chemical', '-', (37, 44))
84985	31114367	Intriguingly, the key genes were enriched in the TNF signaling pathway, transcriptional misregulation in cancer and pathways in cancer, which further verified that the key genes were associated with misregulation of TFs leading to tumorigenesis.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('TFs', 'Gene', (216, 219))	('misregulation', 'Var', (199, 212))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (128, 134))
85005	31114367	Additionally, inhibition of miR-191 decreases HCC cell proliferation and tumor growth, and miR-191 has been found to be closely correlated with TNM stage, metastasis and poor prognosis in pancreatic cancer.	('metastasis', 'Disease', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('miR-191', 'Gene', '406966', (91, 98))	('pancreatic cancer', 'Disease', (188, 205))	('HCC cell proliferation', 'CPA', (46, 68))	('miR-191', 'Gene', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('miR-191', 'Gene', '406966', (28, 35))	('HCC', 'Phenotype', 'HP:0001402', (46, 49))	('miR-191', 'Gene', (28, 35))	('decreases', 'NegReg', (36, 45))	('correlated', 'Reg', (128, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('TNM', 'Gene', '10178', (144, 147))	('HCC', 'CellLine', 'CVCL:0C54', (46, 49))	('TNM', 'Gene', (144, 147))	('inhibition', 'Var', (14, 24))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))
85095	30365605	For example, anti-CTLA4 antibodies seem to have little, if any, activity in these tumors.	('CTLA4', 'Gene', '1493', (18, 23))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('CTLA4', 'Gene', (18, 23))	('antibodies', 'Var', (24, 34))	('activity', 'MPA', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
85106	30365605	In a post hoc analysis, patients who developed an anti-G17DT response experienced longer overall survival times than those who did not develop this response.	('anti-G17DT', 'Var', (50, 60))	('patients', 'Species', '9606', (24, 32))	('overall', 'MPA', (89, 96))	('longer', 'PosReg', (82, 88))
85128	30365605	In a phase 1 study, 14 patients with pancreatic cancer were treated with the anti-PD-L1 antibody BMS-936559, but no responses were observed.	('PD-L1', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (23, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('PD-L1', 'Gene', '29126', (82, 87))	('pancreatic cancer', 'Disease', (37, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))	('BMS-936559', 'Var', (97, 107))
85135	30365605	Finally, the presence of certain bacteria has been shown to facilitate the development of pancreatic cancer, possibly by inducing an inflammatory state.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('inducing', 'Reg', (121, 129))	('pancreatic cancer', 'Disease', (90, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('presence', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('facilitate', 'PosReg', (60, 70))
85164	30365605	This subgroup is heterogeneous and comprises NETs with a high ki67 index and poorly differentiated neuroendocrine carcinomas (NECs).	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('ki67 index', 'Var', (62, 72))	('NETs', 'Phenotype', 'HP:0100634', (45, 49))	('NECs', 'Phenotype', 'HP:0100634', (126, 130))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (99, 124))	('neuroendocrine carcinomas', 'Disease', (99, 124))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (99, 124))
85171	30365605	Similarly, heterogeneity in tumor PD-L1 expression may hamper the correlation of PD-L1 expression with clinical benefit from immunotherapy.	('tumor', 'Disease', (28, 33))	('hamper', 'NegReg', (55, 61))	('PD-L1', 'Gene', (81, 86))	('correlation', 'Interaction', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('heterogeneity', 'Var', (11, 24))	('PD-L1', 'Gene', (34, 39))	('PD-L1', 'Gene', '29126', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('PD-L1', 'Gene', '29126', (34, 39))
85364	22537613	In defining early cancer, we chose T1sm1 as being the extent of early cancer, as beyond this point metastases increases from ~1% to >10% for T1sm2.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('T1sm2', 'Var', (141, 146))	('sm1', 'Gene', '7911', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('metastases', 'Disease', (99, 109))	('cancer', 'Disease', (70, 76))	('sm1', 'Gene', (37, 40))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('metastases', 'Disease', 'MESH:D009362', (99, 109))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
85443	28168111	We used the multivariable Coxph regression model to fit the survival trend of patients with T3N0-3 status and T1-4N0 status in the two different tumor length groups (tumor length <=3 cm versus >3 cm).	('T1-4N0', 'Var', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('T3N0-3 status', 'Var', (92, 105))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('patients', 'Species', '9606', (78, 86))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (145, 150))	('Cox', 'Gene', '1351', (26, 29))	('Cox', 'Gene', (26, 29))
85481	24945674	Genetic Variants of EGF and VEGF Predict Prognosis of Patients with Advanced Esophageal Squamous Cell Carcinoma To investigate the association between genetic polymorphisms of growth factor-related genes and prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC).	('EGF', 'Gene', (29, 32))	('patients', 'Species', '9606', (221, 229))	('VEGF', 'Gene', (28, 32))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (244, 278))	('Carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('Patients', 'Species', '9606', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('Advanced Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (68, 111))	('esophageal squamous cell carcinoma', 'Disease', (244, 278))	('Variants', 'Var', (8, 16))	('VEGF', 'Gene', '7422', (28, 32))	('EGF', 'Gene', '1950', (29, 32))	('EGF', 'Gene', (20, 23))	('Predict', 'Reg', (33, 40))	('EGF', 'Gene', '1950', (20, 23))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('Advanced Esophageal Squamous Cell Carcinoma', 'Disease', (68, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
85483	24945674	The genotypes of 14 candidate single nucleotide polymorphisms (SNPs) involved in growth factor-related functions were analyzed using iPLEX Gold technology from the genomic DNA of peripheral leukocytes, and were correlated with the clinical outcome of patients.	('single nucleotide polymorphisms', 'Var', (30, 61))	('patients', 'Species', '9606', (251, 259))	('correlated', 'Reg', (211, 221))
85484	24945674	The genetic polymorphisms of EGF:rs4444903, EGF:rs2237051 and VEGF:rs2010963 showed significant associations with overall survival (OS) of advanced ESCC patients (A/A+ A/G vs. GG, [HR = 0.77, 95% CI = 0.60-0.99, P = 0.039 for rs4444903; A/G+ G/G vs. A/A, [HR = 0.74, 95% CI = 0.58-0.95, P = 0.019 for rs2237051; G/G+G/C vs. C/C, [HR] inves = 0.69, 95% CI = 0.50-0.95, P = 0.023 for rs2010963).	('EGF', 'Gene', (29, 32))	('patients', 'Species', '9606', (153, 161))	('rs2237051; G/G+G/C vs.', 'Var', (301, 323))	('rs4444903', 'Var', (33, 42))	('rs2010963', 'Mutation', 'rs2010963', (382, 391))	('rs4444903', 'Mutation', 'rs4444903', (33, 42))	('overall', 'MPA', (114, 121))	('rs2237051', 'Mutation', 'rs2237051', (48, 57))	('VEGF', 'Gene', '7422', (62, 66))	('rs4444903', 'Var', (226, 235))	('rs2010963', 'Mutation', 'rs2010963', (67, 76))	('rs4444903', 'Mutation', 'rs4444903', (226, 235))	('rs2237051', 'Var', (48, 57))	('ESCC', 'Disease', (148, 152))	('VEGF', 'Gene', (62, 66))	('associations', 'Interaction', (96, 108))	('rs2237051', 'Mutation', 'rs2237051', (301, 310))
85485	24945674	EGFR:rs2227983 and 3 SNPs of PIK3CA also showed borderline significant correlation with OS of advanced ESCC patients (P = 0.058 for rs2227983; P = 0.069, 0.091 and 0.067 for rs6443624, rs7651265 and rs7621329 of PIK3CA respectively).	('rs6443624', 'Mutation', 'rs6443624', (174, 183))	('PIK3CA', 'Gene', '5290', (29, 35))	('rs2227983', 'Var', (132, 141))	('EGFR', 'Gene', (0, 4))	('rs2227983', 'Var', (5, 14))	('rs7651265', 'Var', (185, 194))	('patients', 'Species', '9606', (108, 116))	('PIK3CA', 'Gene', (212, 218))	('rs2227983', 'Mutation', 'rs2227983', (132, 141))	('rs2227983', 'Mutation', 'rs2227983', (5, 14))	('rs7621329', 'Var', (199, 208))	('rs6443624', 'Var', (174, 183))	('PIK3CA', 'Gene', '5290', (212, 218))	('advanced ESCC patients', 'Disease', (94, 116))	('PIK3CA', 'Gene', (29, 35))	('EGFR', 'Gene', '1956', (0, 4))	('rs7651265', 'Mutation', 'rs7651265', (185, 194))	('rs7621329', 'Mutation', 'rs7621329', (199, 208))
85500	24945674	Genetic variants of EGFR have also been shown to influence clinical outcome of many different types of cancer including non-small-cell lung cancer (NSCLC), prostate cancer, metastatic colorectal cancer (mCRC), and pancreatic cancer.	('prostate cancer', 'Disease', (156, 171))	('EGFR', 'Gene', (20, 24))	('colorectal cancer', 'Disease', 'MESH:D015179', (184, 201))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('pancreatic cancer', 'Disease', (214, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('colorectal cancer', 'Disease', (184, 201))	('cancer', 'Disease', (103, 109))	('influence', 'Reg', (49, 58))	('non-small-cell lung cancer', 'Disease', (120, 146))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (120, 146))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('NSCLC', 'Disease', (148, 153))	('variants', 'Var', (8, 16))	('EGFR', 'Gene', '1956', (20, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (214, 231))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', (140, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (184, 201))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (124, 146))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (120, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('pancreatic cancer', 'Disease', 'MESH:D010190', (214, 231))
85501	24945674	Most studies have focused on the R497K (rs2227983) and the CA repeat polymorphisms within intron 1, as EGFR R497K is known to attenuate the binding of the ligand EGF while the CA repeat polymorphism appears to significantly influence the transcription of EGFR .	('EGFR', 'Gene', '1956', (255, 259))	('EGFR', 'Gene', (255, 259))	('R497K', 'Var', (108, 113))	('ligand', 'Interaction', (155, 161))	('attenuate', 'NegReg', (126, 135))	('EGF', 'Protein', (162, 165))	('EGFR', 'Gene', '1956', (103, 107))	('binding', 'Interaction', (140, 147))	('rs2227983', 'Var', (40, 49))	('EGFR', 'Gene', (103, 107))	('rs2227983', 'Mutation', 'rs2227983', (40, 49))	('R497K', 'Mutation', 'rs2227983', (108, 113))	('influence', 'Reg', (224, 233))	('R497K', 'Mutation', 'rs2227983', (33, 38))	('transcription', 'MPA', (238, 251))
85502	24945674	The interaction of EGFR R497K with EGF at the +61A/G (rs4444903) polymorphism has been shown to enhance the risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('R497K', 'Mutation', 'rs2227983', (24, 29))	('interaction', 'Interaction', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs4444903', 'Var', (54, 63))	('rs4444903', 'Mutation', 'rs4444903', (54, 63))	('enhance', 'PosReg', (96, 103))	('EGFR', 'Gene', '1956', (19, 23))	('R497K', 'Var', (24, 29))	('+61A/G', 'Mutation', 'rs4444903', (46, 52))	('EGFR', 'Gene', (19, 23))	('esophageal cancer', 'Disease', (116, 133))
85503	24945674	We also found that the polymorphism in EGFR intron 1 was able to predict the prognosis of our patients with esophageal cancer after chemoradiation and surgery previously.	('predict', 'Reg', (65, 72))	('patients', 'Species', '9606', (94, 102))	('esophageal cancer', 'Disease', (108, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('EGFR', 'Gene', '1956', (39, 43))	('polymorphism', 'Var', (23, 35))	('EGFR', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
85510	24945674	The genetic polymorphisms of the insulin-related pathway are associated with the risk of colorectal cancer and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('prostate cancer', 'Disease', (111, 126))	('insulin', 'Gene', (33, 40))	('insulin', 'Gene', '3630', (33, 40))	('colorectal cancer', 'Disease', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('genetic polymorphisms', 'Var', (4, 25))	('associated', 'Reg', (61, 71))
85513	24945674	The SNPs of the genes involved in the PI3K/PTEN/AKT/mTOR pathway have recently been demonstrated to be associated with treatment outcome in esophageal cancer patients who have undergone surgery and chemoradiotherapy.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('AKT', 'Gene', (48, 51))	('men', 'Species', '9606', (124, 127))	('PTEN', 'Gene', (43, 47))	('SNPs', 'Var', (4, 8))	('associated with', 'Reg', (103, 118))	('PTEN', 'Gene', '5728', (43, 47))	('AKT', 'Gene', '207', (48, 51))	('patients', 'Species', '9606', (158, 166))	('esophageal cancer', 'Disease', (140, 157))
85515	24945674	Two SNPs within the genes AKT2 and FRAP1 (encoding mTOR) were correlated with poor treatment response, while a better response was associated with heterozygosity for AKT1 rs3803304.	('mTOR', 'Gene', (51, 55))	('AKT2', 'Gene', '208', (26, 30))	('AKT1', 'Gene', '207', (166, 170))	('FRAP1', 'Gene', '2475', (35, 40))	('AKT2', 'Gene', (26, 30))	('treatment response', 'CPA', (83, 101))	('men', 'Species', '9606', (88, 91))	('rs3803304', 'Var', (171, 180))	('rs3803304', 'Mutation', 'rs3803304', (171, 180))	('mTOR', 'Gene', '2475', (51, 55))	('AKT1', 'Gene', (166, 170))	('FRAP1', 'Gene', (35, 40))
85516	24945674	Growing reports revealed the significant prognostic relevance of the SNPs among the genes involved in growth factor-mediated pathways in cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Disease', (137, 144))	('SNPs', 'Var', (69, 73))
85546	24945674	To select potential prognostically relevant SNPs, we randomly selected 95 subjects to conduct a pre-test by analyzing 26 growth-factor related SNPs, including 8 SNPs in EGFR; 2 SNPs in EGF; 2 SNPs in IGF1R; 2 SNPs in IGF; 4 SNPs in VEGF; 3 SNPs in PIK3CA; and a single SNP in AKT1, AKT2, FRAP1 and PTEN (Table S1).	('IGF1R', 'Gene', (200, 205))	('AKT2', 'Gene', (282, 286))	('AKT2', 'Gene', '208', (282, 286))	('PTEN', 'Gene', '5728', (298, 302))	('IGF1R', 'Gene', '3480', (200, 205))	('SNPs', 'Var', (177, 181))	('PIK3CA', 'Gene', '5290', (248, 254))	('EGFR', 'Gene', '1956', (169, 173))	('AKT1', 'Gene', '207', (276, 280))	('SNPs', 'Var', (192, 196))	('VEGF', 'Gene', (232, 236))	('FRAP1', 'Gene', (288, 293))	('PTEN', 'Gene', (298, 302))	('PIK3CA', 'Gene', (248, 254))	('EGFR', 'Gene', (169, 173))	('AKT1', 'Gene', (276, 280))	('VEGF', 'Gene', '7422', (232, 236))	('FRAP1', 'Gene', '2475', (288, 293))
85549	24945674	Both SNPs in EGF, rs4444903 and rs2237051, exhibited significance for overall survival (Table 2).	('rs4444903', 'Var', (18, 27))	('rs4444903', 'Mutation', 'rs4444903', (18, 27))	('rs2237051', 'Var', (32, 41))	('rs2237051', 'Mutation', 'rs2237051', (32, 41))
85550	24945674	Patients carrying major allele A in EGF:rs4444903 exhibited obvious reduced risk for death ([HR] = 0.77, 95% CI = 0.60-0.99, P = 0.039; Table 2), whereas patients with the minor allele G in EGF:rs2237051 showed significantly better survival ([HR] = 0.74, 95% CI = 0.58-0.95, P = 0.019, Table 2).	('death', 'Disease', 'MESH:D003643', (85, 90))	('death', 'Disease', (85, 90))	('rs4444903', 'Var', (40, 49))	('patients', 'Species', '9606', (154, 162))	('rs4444903', 'Mutation', 'rs4444903', (40, 49))	('Patients', 'Species', '9606', (0, 8))	('rs2237051', 'Mutation', 'rs2237051', (194, 203))	('reduced', 'NegReg', (68, 75))	('better', 'PosReg', (225, 231))	('EGF', 'Gene', (36, 39))
85551	24945674	The wildtype genotype of VEGF:rs2010963 was also significantly associated with improved survival ([HR] = 0.69, 95% CI = 0.50-0.95, P = 0.023; Table 2).	('survival', 'CPA', (88, 96))	('improved', 'PosReg', (79, 87))	('rs2010963', 'Var', (30, 39))	('VEGF', 'Gene', '7422', (25, 29))	('VEGF', 'Gene', (25, 29))	('rs2010963', 'Mutation', 'rs2010963', (30, 39))
85552	24945674	EGFR:rs2227983 and 3 SNPs in PIK3CA also exhibited borderline significant correlation with survival (P = 0.058 for EGFR:rs2227983; P = 0.069 for PIK3CA:rs6443624; P = 0.091 for PIK3CA:rs7651265; P = 0.067 for PIK3CA:rs7621329; Table 2).	('PIK3CA', 'Gene', '5290', (177, 183))	('rs2227983', 'Var', (5, 14))	('EGFR', 'Gene', (115, 119))	('rs7651265', 'Mutation', 'rs7651265', (184, 193))	('rs6443624', 'Mutation', 'rs6443624', (152, 161))	('PIK3CA', 'Gene', (209, 215))	('rs2227983', 'Mutation', 'rs2227983', (120, 129))	('PIK3CA', 'Gene', (145, 151))	('rs7651265', 'Var', (184, 193))	('PIK3CA', 'Gene', (177, 183))	('PIK3CA', 'Gene', '5290', (29, 35))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (115, 119))	('rs2227983', 'Mutation', 'rs2227983', (5, 14))	('PIK3CA', 'Gene', '5290', (209, 215))	('rs6443624', 'Var', (152, 161))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (145, 151))	('EGFR', 'Gene', '1956', (0, 4))	('rs7621329', 'Mutation', 'rs7621329', (216, 225))
85553	24945674	Even though none of these genetic polymorphisms significantly predicted tumor recurrence among these patients, EGFR:rs2227983, VEGF:rs2010963, and EGF:rs2237051 showed borderline significance for disease progression (P = 0.058 for EGFR:rs2227983, P = 0.073 for VEGF:rs2010963, and P = 0.104 for EGF:rs2237051; Table 2).	('VEGF', 'Gene', (261, 265))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('EGFR', 'Gene', '1956', (111, 115))	('rs2227983', 'Var', (116, 125))	('rs2010963', 'Mutation', 'rs2010963', (132, 141))	('rs2237051', 'Mutation', 'rs2237051', (151, 160))	('rs2237051', 'Mutation', 'rs2237051', (299, 308))	('rs2010963', 'Mutation', 'rs2010963', (266, 275))	('patients', 'Species', '9606', (101, 109))	('EGFR', 'Gene', (231, 235))	('VEGF', 'Gene', '7422', (127, 131))	('tumor', 'Disease', (72, 77))	('EGFR', 'Gene', (111, 115))	('VEGF', 'Gene', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('VEGF', 'Gene', '7422', (261, 265))	('EGFR', 'Gene', '1956', (231, 235))	('rs2227983', 'Mutation', 'rs2227983', (116, 125))	('rs2227983', 'Mutation', 'rs2227983', (236, 245))
85555	24945674	These two EGF SNPs separately analyzed in combination with VEGF:rs2010963 resulted in more significant joint effects.	('joint effects', 'CPA', (103, 116))	('VEGF', 'Gene', '7422', (59, 63))	('rs2010963', 'Var', (64, 73))	('VEGF', 'Gene', (59, 63))	('rs2010963', 'Mutation', 'rs2010963', (64, 73))
85556	24945674	Patients with both unfavorable genotypes of VEGF:rs2010963 and either EGF:rs4444903 or EGF:rs2237051 had an approximately 1.7-fold increased risk of death ([HR] = 1.70, 95% CI = 1.06-2.72, P = 0.027, P trend = 0.003 for EGF:rs4444903 with VEGF:rs2010963; [HR] = 1.74, 95% CI = 1.09-2.80, P = 0.022, P trend = 0.002 for EGF:rs2237051 with VEGF:rs2010963; Table 4).	('VEGF', 'Gene', (338, 342))	('rs4444903', 'Mutation', 'rs4444903', (74, 83))	('VEGF', 'Gene', (44, 48))	('rs2237051', 'Mutation', 'rs2237051', (323, 332))	('rs4444903', 'Mutation', 'rs4444903', (224, 233))	('rs4444903', 'Var', (74, 83))	('Patients', 'Species', '9606', (0, 8))	('rs2010963', 'Var', (49, 58))	('rs2010963', 'Mutation', 'rs2010963', (343, 352))	('death', 'Disease', (149, 154))	('VEGF', 'Gene', '7422', (239, 243))	('rs2237051', 'Mutation', 'rs2237051', (91, 100))	('rs2010963', 'Mutation', 'rs2010963', (49, 58))	('VEGF', 'Gene', (239, 243))	('EGF', 'Var', (70, 73))	('rs2010963', 'Mutation', 'rs2010963', (244, 253))	('VEGF', 'Gene', '7422', (338, 342))	('VEGF', 'Gene', '7422', (44, 48))	('death', 'Disease', 'MESH:D003643', (149, 154))
85557	24945674	The cumulative effect of VEGF:rs2010963 with either EGF:rs4444903 or EGF:rs2010963 is better than the effect of all the 3 SNPs combined (P = 0.075).	('rs4444903', 'Mutation', 'rs4444903', (56, 65))	('rs2010963', 'Mutation', 'rs2010963', (73, 82))	('VEGF', 'Gene', '7422', (25, 29))	('rs2010963', 'Var', (30, 39))	('better', 'PosReg', (86, 92))	('VEGF', 'Gene', (25, 29))	('rs2010963', 'Mutation', 'rs2010963', (30, 39))
85558	24945674	We further jointly analyzed EGFR:rs2227983 and PIK3CA:rs6443624.	('PIK3CA', 'Gene', (47, 53))	('EGFR', 'Gene', '1956', (28, 32))	('rs2227983', 'Var', (33, 42))	('PIK3CA', 'Gene', '5290', (47, 53))	('rs2227983', 'Mutation', 'rs2227983', (33, 42))	('EGFR', 'Gene', (28, 32))	('rs6443624', 'Mutation', 'rs6443624', (54, 63))	('rs6443624', 'Var', (54, 63))
85559	24945674	The hazard for death further increased to 3.29 or 3.14-fold in patients carrying the four unfavorable genotypes of VEGF, EGFR, PIK3CA and either EGF:rs2237051 or EGF:rs4444903 ([HR] = 3.29, 95% CI = 1.36-7.96, P = 0.008 and [HR] = 3.14, 95% CI = 1.12-8.19, P = 0.008, respectively; Table 4).	('rs4444903', 'Mutation', 'rs4444903', (166, 175))	('EGFR', 'Gene', '1956', (121, 125))	('VEGF', 'Gene', (115, 119))	('EGF', 'Var', (145, 148))	('PIK3CA', 'Gene', (127, 133))	('EGFR', 'Gene', (121, 125))	('PIK3CA', 'Gene', '5290', (127, 133))	('rs2237051', 'Mutation', 'rs2237051', (149, 158))	('patients', 'Species', '9606', (63, 71))	('VEGF', 'Gene', '7422', (115, 119))	('death', 'Disease', 'MESH:D003643', (15, 20))	('death', 'Disease', (15, 20))
85562	24945674	Compared with those carrying favorable genotypes, patients with the adverse genotypes had a significantly reduced survival duration (MST = 12.53 vs. 8.62 months, log-rank P = 0.025 for EGF:rs4444903, Fig.	('patients', 'Species', '9606', (50, 58))	('EGF', 'Var', (185, 188))	('survival duration', 'CPA', (114, 131))	('rs4444903', 'Mutation', 'rs4444903', (189, 198))	('reduced', 'NegReg', (106, 113))
85564	24945674	Overall survival also differed significantly among the group of advanced ESCC patients according to the accumulated number of unfavorable genotypes within EGF, VEGF, EGFR and PIK3CA (log-rank P = 0.013 in EGF:rs4444903-containing set, and log-rank P = 0.007 in EGF:rs2237051-containing set, Fig.	('PIK3CA', 'Gene', (175, 181))	('differed', 'Reg', (22, 30))	('VEGF', 'Gene', (160, 164))	('PIK3CA', 'Gene', '5290', (175, 181))	('rs4444903-containing', 'Var', (209, 229))	('EGFR', 'Gene', (166, 170))	('rs2237051', 'Mutation', 'rs2237051', (265, 274))	('patients', 'Species', '9606', (78, 86))	('EGFR', 'Gene', '1956', (166, 170))	('rs4444903', 'Mutation', 'rs4444903', (209, 218))	('VEGF', 'Gene', '7422', (160, 164))
85565	24945674	Patients carrying all of the unfavorable genotypes exhibited significantly increased risk of death compared with those carrying none of the adverse genotypes (MST = 17.51 vs. 5.21 months in EGF:rs4444903-containing set, and MST = 14.72 vs. 5.21 months in EGF:rs2237051-containing set, Fig.	('rs2237051', 'Mutation', 'rs2237051', (259, 268))	('rs4444903', 'Mutation', 'rs4444903', (194, 203))	('death', 'Disease', 'MESH:D003643', (93, 98))	('Patients', 'Species', '9606', (0, 8))	('death', 'Disease', (93, 98))	('rs4444903-containing', 'Var', (194, 214))
85568	24945674	The rs4444903 SNP, localized at position 61 in the 5'-untranslated region (5'UTR) of EGF, has been found to be correlated with production level of EGF measured in peripheral-blood mononuclear cells in-vitro .	('rs4444903 SNP', 'Var', (4, 17))	('production level', 'MPA', (127, 143))	('correlated', 'Reg', (111, 121))	('EGF', 'Gene', (85, 88))	('rs4444903', 'Mutation', 'rs4444903', (4, 13))
85569	24945674	Meanwhile, rs2010963 at the 5'-UTR of VEGF has also been suggested to modulate VEGF level.	('modulate', 'Reg', (70, 78))	('rs2010963', 'Mutation', 'rs2010963', (11, 20))	('VEGF', 'Gene', '7422', (38, 42))	('VEGF', 'Gene', '7422', (79, 83))	('rs2010963', 'Var', (11, 20))	('VEGF', 'Gene', (38, 42))	('VEGF', 'Gene', (79, 83))
85573	24945674	As expected, homozygous GG carriers of rs4444903 showed a trend of increased EGF level compared with AA carriers (Fig.	('rs4444903', 'Var', (39, 48))	('rs4444903', 'Mutation', 'rs4444903', (39, 48))	('increased', 'PosReg', (67, 76))	('increased EGF level', 'Phenotype', 'HP:0003496', (67, 86))	('EGF level', 'MPA', (77, 86))
85574	24945674	However, we did not find an association between the genotypes of rs2010963 and serum VEGF level (Fig.	('rs2010963', 'Mutation', 'rs2010963', (65, 74))	('VEGF', 'Gene', (85, 89))	('rs2010963', 'Var', (65, 74))	('VEGF', 'Gene', '7422', (85, 89))
85577	24945674	Kaplan-Meier survival analysis revealed that the group with detectable levels of EGF had a significantly increased risk of death compared to the group with undetectable levels (MST = 36.92 vs. 9.12 months, log-rank P = 0.010, Fig.	('death', 'Disease', (123, 128))	('death', 'Disease', 'MESH:D003643', (123, 128))	('detectable levels', 'Var', (60, 77))	('EGF', 'Gene', (81, 84))
85581	24945674	A growing body of research shows a significant association between SNPs of the genes involved in growth factor mediated pathways and prognosis of esophageal adenocarcinoma cancer.	('esophageal adenocarcinoma cancer', 'Disease', 'MESH:D004938', (146, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('esophageal adenocarcinoma cancer', 'Disease', (146, 178))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (146, 171))	('SNPs', 'Var', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
85582	24945674	We here have demonstrated that the genetic polymorphisms rs4444903 and rs2237051 in EGF and rs2010963 in VEGF were significantly correlated with the clinical outcome of patients with advanced ESCC (Table 2).	('patients', 'Species', '9606', (169, 177))	('rs2237051', 'Var', (71, 80))	('correlated with', 'Reg', (129, 144))	('ESCC', 'Disease', (192, 196))	('VEGF', 'Gene', (105, 109))	('rs4444903', 'Var', (57, 66))	('rs4444903', 'Mutation', 'rs4444903', (57, 66))	('rs2010963', 'Mutation', 'rs2010963', (92, 101))	('VEGF', 'Gene', '7422', (105, 109))	('rs2237051', 'Mutation', 'rs2237051', (71, 80))	('rs2010963', 'Var', (92, 101))
85583	24945674	Meanwhile, the SNPs in EGFR and PIK3CA also showed a borderline significant effect for prognosis.	('PIK3CA', 'Gene', '5290', (32, 38))	('SNPs', 'Var', (15, 19))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('PIK3CA', 'Gene', (32, 38))
85587	24945674	The G/G genotype of the EGF +61A/G polymorphism has been observed to correlate with a greater risk of esophageal adenocarcinoma and increased levels of EGF in gastroesophageal reflux disease patients compared with A/A or A/G.	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (159, 190))	('patients', 'Species', '9606', (191, 199))	('levels', 'MPA', (142, 148))	('EGF +61A/G', 'Gene', (24, 34))	('G/G', 'Var', (4, 7))	('esophageal adenocarcinoma', 'Disease', (102, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (102, 127))	('increased', 'PosReg', (132, 141))	('+61A/G', 'Mutation', 'rs4444903', (28, 34))	('EGF', 'MPA', (152, 155))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))	('gastroesophageal reflux disease', 'Disease', (159, 190))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (159, 182))
85589	24945674	In the current study, we demonstrated that the G/G genotype of rs4444903 was significantly associated with increased risk of adverse clinical outcomes in ESCC patients with advanced tumor stages.	('G/G', 'Var', (47, 50))	('tumor', 'Disease', (182, 187))	('ESCC', 'Disease', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('patients', 'Species', '9606', (159, 167))	('rs4444903', 'Var', (63, 72))	('rs4444903', 'Mutation', 'rs4444903', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
85590	24945674	We also observed that G/G showed a trend to correlate with elevated serum EGF levels in these patients.	('serum EGF levels', 'MPA', (68, 84))	('G/G', 'Var', (22, 25))	('elevated', 'PosReg', (59, 67))	('patients', 'Species', '9606', (94, 102))
85593	24945674	It is released by its precursor prepro-EGF by cleavage of Arg-Asn and Arg-His bonds.	('Asn', 'Chemical', 'MESH:D001216', (62, 65))	('Arg', 'Chemical', 'MESH:D001120', (70, 73))	('Arg-His bonds', 'Protein', (70, 83))	('Arg-Asn', 'Protein', (58, 65))	('cleavage', 'Var', (46, 54))	('Arg', 'Chemical', 'MESH:D001120', (58, 61))	('His', 'Chemical', 'MESH:D006639', (74, 77))
85594	24945674	The EGF:rs2237051, I708M, is located within one of eight EGF-like repeat domains of prepro-EGF encoded by exons 6, 7, 8, 9, 15, 17, 18 and 19.	('rs2237051', 'Var', (8, 17))	('I708M', 'Var', (19, 24))	('I708M', 'Mutation', 'rs2237051', (19, 24))	('rs2237051', 'Mutation', 'rs2237051', (8, 17))
85595	24945674	The variant carriers of EGF:rs2237051 have been reported to be associated with a markedly decreased risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('rs2237051', 'Mutation', 'rs2237051', (28, 37))	('decreased', 'NegReg', (90, 99))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('EGF', 'Gene', (24, 27))	('rs2237051', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
85596	24945674	In our results, we also demonstrated that the variant allele G of EGF:rs2237051 was associated with favorable prognosis in advanced ESCC patients.	('patients', 'Species', '9606', (137, 145))	('EGF', 'Gene', (66, 69))	('rs2237051', 'Mutation', 'rs2237051', (70, 79))	('ESCC', 'Disease', (132, 136))	('rs2237051', 'Var', (70, 79))
85598	24945674	Whether or not the genetic variants of EGF:rs2237051 correlated with the function of prepro-EGF needs further investigation.	('correlated', 'Reg', (53, 63))	('rs2237051', 'Mutation', 'rs2237051', (43, 52))	('EGF', 'Gene', (39, 42))	('rs2237051', 'Var', (43, 52))
85599	24945674	The association of the SNPs of VEGF at -460T/C (rs833061), 405G/C (rs2010963 or -634G/C), and 936C/T (rs3025039) with clinical outcome of patients with esophageal cancer has been investigated previously.	('VEGF', 'Gene', (31, 35))	('405G/C', 'Var', (59, 65))	('rs3025039', 'Mutation', 'rs3025039', (102, 111))	('esophageal cancer', 'Disease', (152, 169))	('936C/T', 'Mutation', 'rs3025039', (94, 100))	('-634G/C', 'Mutation', 'rs2010963', (80, 87))	('rs833061', 'Var', (48, 56))	('VEGF', 'Gene', '7422', (31, 35))	('rs2010963', 'Mutation', 'rs2010963', (67, 76))	('405G/C', 'SUBSTITUTION', 'None', (59, 65))	('rs833061', 'Mutation', 'rs833061', (48, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('-460T/C', 'Mutation', 'rs833061', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('patients', 'Species', '9606', (138, 146))	('rs2010963 or -634G/C', 'Var', (67, 87))
85601	24945674	The combined CGC haplotype of the three VEGF SNPs (-460T/C, 405G/C, and 936C/T) was associated with worse overall survival of esophageal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('405G/C', 'SUBSTITUTION', 'None', (60, 66))	('overall', 'MPA', (106, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('CG', 'Chemical', 'MESH:C028505', (13, 15))	('936C/T', 'Mutation', 'rs3025039', (72, 78))	('VEGF', 'Gene', (40, 44))	('-460T/C', 'Var', (51, 58))	('worse', 'NegReg', (100, 105))	('patients', 'Species', '9606', (144, 152))	('936C/T', 'Var', (72, 78))	('VEGF', 'Gene', '7422', (40, 44))	('405G/C', 'Var', (60, 66))	('esophageal cancer', 'Disease', (126, 143))	('-460T/C', 'Mutation', 'rs833061', (51, 58))
85602	24945674	In the current study, we demonstrated that VEGF rs2010963 independently correlated with prognosis of patients with advanced ESCC.	('patients', 'Species', '9606', (101, 109))	('correlated', 'Reg', (72, 82))	('rs2010963', 'Mutation', 'rs2010963', (48, 57))	('VEGF', 'Gene', (43, 47))	('rs2010963', 'Var', (48, 57))	('ESCC', 'Disease', (124, 128))	('VEGF', 'Gene', '7422', (43, 47))
85603	24945674	VEGF rs2010963 405G/C has been found to correlate with VEGF protein production stimulated by lipopolysaccharide.	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (93, 111))	('VEGF', 'Gene', (55, 59))	('405G/C', 'SUBSTITUTION', 'None', (15, 21))	('VEGF', 'Gene', '7422', (0, 4))	('rs2010963', 'DBSNP_MENTION', 'None', (5, 14))	('VEGF', 'Gene', '7422', (55, 59))	('405G/C', 'Var', (15, 21))	('stimulated', 'PosReg', (79, 89))	('VEGF', 'Gene', (0, 4))	('rs2010963', 'Var', (5, 14))	('lipopolysaccharide', 'MPA', (93, 111))
85604	24945674	However, we did not find an association between the genotypes of rs2010963 and serum VEGF levels in patients with ESCC (Fig.	('rs2010963', 'Mutation', 'rs2010963', (65, 74))	('ESCC', 'Disease', (114, 118))	('VEGF', 'Gene', '7422', (85, 89))	('rs2010963', 'Var', (65, 74))	('patients', 'Species', '9606', (100, 108))	('VEGF', 'Gene', (85, 89))
85605	24945674	Because the sera were collected before patients received treatment, we suggest that the genotypes of rs2010963 may be associated with post-treatment expression of VEGF and thereby influence the survival outcome of patients.	('men', 'Species', '9606', (62, 65))	('survival', 'CPA', (194, 202))	('men', 'Species', '9606', (144, 147))	('patients', 'Species', '9606', (214, 222))	('patients', 'Species', '9606', (39, 47))	('rs2010963', 'Mutation', 'rs2010963', (101, 110))	('VEGF', 'Gene', (163, 167))	('rs2010963', 'Var', (101, 110))	('expression', 'MPA', (149, 159))	('associated', 'Reg', (118, 128))	('VEGF', 'Gene', '7422', (163, 167))	('influence', 'Reg', (180, 189))
85606	24945674	Even though EGF:rs4444903, EGF:rs2237051 and VEGF:rs2010963 were each significantly associated with a better prognosis of advanced ESCC, we found the cumulative effect of VEGF:rs2010963 with either EGF:rs4444903 or EGF:rs2010963 to be even better than the cumulative effect of these 3 SNPs combined (Table 4).	('rs2010963', 'Mutation', 'rs2010963', (219, 228))	('EGF', 'Var', (27, 30))	('VEGF', 'Gene', '7422', (171, 175))	('rs4444903', 'Mutation', 'rs4444903', (202, 211))	('better', 'PosReg', (102, 108))	('rs2010963', 'Mutation', 'rs2010963', (176, 185))	('VEGF', 'Gene', '7422', (45, 49))	('rs4444903', 'Mutation', 'rs4444903', (16, 25))	('rs2237051', 'Mutation', 'rs2237051', (31, 40))	('rs2010963', 'Mutation', 'rs2010963', (50, 59))	('EGF', 'Var', (12, 15))	('VEGF', 'Gene', (171, 175))	('VEGF', 'Gene', (45, 49))	('ESCC', 'Disease', (131, 135))
85607	24945674	Joint analysis of EGFR:rs2227983 and the SNPs of the downstream signaling factor PIK3CA, revealed strong cumulative effects for both increased risk of death and for recurrence with increasing numbers of unfavorable genotypes in both EGF:rs2237051 and EGF:rs4444903 sets (Table 4).	('PIK3CA', 'Gene', (81, 87))	('EGFR', 'Gene', '1956', (18, 22))	('PIK3CA', 'Gene', '5290', (81, 87))	('rs2227983', 'Var', (23, 32))	('rs2237051', 'Mutation', 'rs2237051', (237, 246))	('rs2227983', 'Mutation', 'rs2227983', (23, 32))	('EGFR', 'Gene', (18, 22))	('EGF', 'Gene', (233, 236))	('death', 'Disease', 'MESH:D003643', (151, 156))	('death', 'Disease', (151, 156))	('rs4444903', 'Mutation', 'rs4444903', (255, 264))
85608	24945674	The minor allele frequencies of the 3 SNPs of PIK3CA, rs6333624, rs7651263 and rs7621329 were similar (1.5%) in our study population.	('rs7651263', 'Var', (65, 74))	('PIK3CA', 'Gene', '5290', (46, 52))	('rs7621329', 'Mutation', 'rs7621329', (79, 88))	('rs7651263', 'Mutation', 'rs7651263', (65, 74))	('rs6333624', 'Mutation', 'rs6333624', (54, 63))	('rs6333624', 'Var', (54, 63))	('rs7621329', 'Var', (79, 88))	('PIK3CA', 'Gene', (46, 52))
85609	24945674	In a previous study, the minor allele homozygous AA of PIK3CA:rs6443624 was associated with risk of recurrence, but none of these PIK3CA SNPs were found to correlate with recurrence in esophageal cancer patients.	('PIK3CA', 'Gene', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('esophageal cancer', 'Disease', (185, 202))	('PIK3CA', 'Gene', '5290', (130, 136))	('rs6443624', 'Mutation', 'rs6443624', (62, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (185, 202))	('associated', 'Reg', (76, 86))	('patients', 'Species', '9606', (203, 211))	('rs6443624', 'Var', (62, 71))	('PIK3CA', 'Gene', (55, 61))	('PIK3CA', 'Gene', '5290', (55, 61))
85611	24945674	Meanwhile, the minor allele of PIK3CA:rs6443624 had a cumulative effect with the unfavorable genotypes of EGF, VEGF and EGFR.	('VEGF', 'Gene', (111, 115))	('rs6443624', 'Mutation', 'rs6443624', (38, 47))	('PIK3CA', 'Gene', (31, 37))	('rs6443624', 'Var', (38, 47))	('PIK3CA', 'Gene', '5290', (31, 37))	('VEGF', 'Gene', '7422', (111, 115))	('EGFR', 'Gene', '1956', (120, 124))	('EGF', 'Disease', (106, 109))	('EGFR', 'Gene', (120, 124))
85612	24945674	The role of EGFR:rs2227983 (G to A, R497K) in cancer has been extensively investigated.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('EGFR', 'Gene', '1956', (12, 16))	('rs2227983', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('rs2227983', 'Mutation', 'rs2227983', (17, 26))	('EGFR', 'Gene', (12, 16))	('R497K', 'Mutation', 'rs2227983', (36, 41))
85613	24945674	EGFR with an argnine-to-lysine substitution has been reported to exhibit a significantly reduced growth response to EGF and TGF-alpha.	('TGF-alpha', 'Gene', (124, 133))	('EGFR', 'Gene', (0, 4))	('argnine-to-lysine substitution', 'Var', (13, 43))	('argnine', 'Chemical', '-', (13, 20))	('TGF-alpha', 'Gene', '7039', (124, 133))	('lysine', 'Chemical', 'MESH:D008239', (24, 30))	('reduced', 'NegReg', (89, 96))	('EGFR', 'Gene', '1956', (0, 4))	('growth', 'MPA', (97, 103))
85614	24945674	The homozygous argnine allele has been suggested to associate with favorable prognosis in patients with colorectal carcinoma, whereas it has no evident effect on the outcome of esophageal cancer patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('esophageal cancer', 'Disease', (177, 194))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (104, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('argnine', 'Var', (15, 22))	('patients', 'Species', '9606', (195, 203))	('colorectal carcinoma', 'Disease', (104, 124))	('patients', 'Species', '9606', (90, 98))	('argnine', 'Chemical', '-', (15, 22))
85615	24945674	R497K alone does not significantly associate with risks of esophageal cancer and gastric cancer; however, the arginine allele has shown a cumulative effect of increasing hazard of death in combination with other SNPs.	('esophageal cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('arginine', 'Var', (110, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('R497K', 'Var', (0, 5))	('gastric cancer', 'Disease', (81, 95))	('arginine', 'Chemical', 'MESH:D001120', (110, 118))	('death', 'Disease', 'MESH:D003643', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('death', 'Disease', (180, 185))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('R497K', 'Mutation', 'rs2227983', (0, 5))
85616	24945674	We found, unexpectedly, that patients carrying the lysine allele (GA or AA genotypes) showed an increased trend of risk for death and disease recurrence, though without reaching statistical significance (P = 0.058, Table 2).	('lysine', 'Chemical', 'MESH:D008239', (51, 57))	('patients', 'Species', '9606', (29, 37))	('disease recurrence', 'CPA', (134, 152))	('lysine', 'Var', (51, 57))	('death', 'Disease', 'MESH:D003643', (124, 129))	('death', 'Disease', (124, 129))
85618	24945674	The function of R497K in ESCC cells is not clear and merits further investigation.	('R497K', 'Var', (16, 21))	('ESCC', 'Disease', (25, 29))	('R497K', 'Mutation', 'rs2227983', (16, 21))
85627	24945674	However, unlike non-small cell lung cancer (NSCLC), where useful markers such as EGFR gene mutation have already been established, the molecular markers regulating sensitivity to EGF/EGFR as well as those targeting VEGF/VEGFR in ESCC are hardly known.	('mutation', 'Var', (91, 99))	('EGFR', 'Gene', '1956', (221, 225))	('cell lung cancer', 'Disease', 'MESH:D008175', (26, 42))	('EGFR', 'Gene', (183, 187))	('VEGFR', 'Gene', '3791', (220, 225))	('VEGF', 'Gene', '7422', (215, 219))	('VEGFR', 'Gene', (220, 225))	('cell lung cancer', 'Disease', (26, 42))	('EGFR', 'Gene', (81, 85))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('VEGF', 'Gene', (215, 219))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('EGFR', 'Gene', (221, 225))	('NSCLC', 'Disease', (44, 49))	('EGFR', 'Gene', '1956', (183, 187))	('VEGF', 'Gene', '7422', (220, 224))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('VEGF', 'Gene', (220, 224))	('EGFR', 'Gene', '1956', (81, 85))
85868	23152702	The spectrum of T1b-3, N1-3, M0 esophageal cancer should receive multimodality combination therapy.	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('M0 esophageal cancer', 'Phenotype', 'HP:0011459', (29, 49))	('N1-3', 'Var', (23, 27))	('T1b-3', 'Var', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('esophageal cancer', 'Disease', (32, 49))
85892	23152702	While patients with T1b, N1, or T2 or higher with any regional node involvement are best treated with multimodality therapy, proceeding directly to esophagectomy once the diagnosis of localized esophageal cancer is made is acceptable.	('localized esophageal cancer', 'Disease', (184, 211))	('localized esophageal cancer', 'Disease', 'MESH:D004938', (184, 211))	('T1b', 'Var', (20, 23))	('patients', 'Species', '9606', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))
86037	20652463	The purpose of this study was to evaluate the feasibility, acceptability, and efficacy of a web-based alcohol intervention incorporating genetic feedback and risk information specific to ALDH2 genotype.	('ALDH2', 'Gene', (187, 192))	('alcohol', 'Chemical', 'MESH:D000438', (102, 109))	('ALDH2', 'Gene', '217', (187, 192))	('genotype', 'Var', (193, 201))
86038	20652463	The ALDH2*2 variant is associated with partial protection against alcohol dependence but confers significantly increased risk for alcohol-related cancers as a function of alcohol exposure.	('cancers', 'Disease', (146, 153))	('ALDH2', 'Gene', '217', (4, 9))	('variant', 'Var', (12, 19))	('alcohol', 'Chemical', 'MESH:D000438', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('alcohol dependence', 'Disease', 'MESH:D000437', (66, 84))	('alcohol dependence', 'Phenotype', 'HP:0030955', (66, 84))	('alcohol dependence', 'Disease', (66, 84))	('ALDH2', 'Gene', (4, 9))	('alcohol', 'Chemical', 'MESH:D000438', (171, 178))	('alcohol', 'Chemical', 'MESH:D000438', (66, 73))	('increased', 'Reg', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
86042	20652463	Results provide initial evidence of the feasibility, acceptability, and brief efficacy of web-based genetic feedback for reducing alcohol-related health risks associated with ALDH2 genotype.	('alcohol', 'Chemical', 'MESH:D000438', (130, 137))	('ALDH2', 'Gene', '217', (175, 180))	('reducing', 'NegReg', (121, 129))	('ALDH2', 'Gene', (175, 180))	('alcohol-related health risks', 'Disease', (130, 158))	('genotype', 'Var', (181, 189))
86045	20652463	In one study, the addition of GSTM1 feedback to a multicomponent intervention resulted in greater abstinence rates 6 months (but not 12 months) later.	('abstinence rates', 'MPA', (98, 114))	('addition', 'Var', (18, 26))	('greater', 'PosReg', (90, 97))	('GSTM1', 'Gene', '2944', (30, 35))	('GSTM1', 'Gene', (30, 35))
86050	20652463	A study evaluating feedback about the L-myc EcoR1 polymorphism found no overall effect on smoking rates.	('L-myc', 'Gene', (38, 43))	('smoking', 'MPA', (90, 97))	('L-myc', 'Gene', '4610', (38, 43))	('polymorphism', 'Var', (50, 62))
86051	20652463	Finally, providing smokers with genotype-specific feedback about risk for alpha-1 antitrypsin deficiency, a genetic condition that increases risk for emphysema, was associated with greater cessation rates among those at higher genetic risk.	('alpha-1 antitrypsin deficiency', 'Phenotype', 'HP:0032025', (74, 104))	('greater', 'PosReg', (181, 188))	('emphysema', 'Disease', (150, 159))	('alpha-1 antitrypsin', 'Gene', (74, 93))	('emphysema', 'Disease', 'MESH:D004646', (150, 159))	('alpha-1 antitrypsin', 'Gene', '5265', (74, 93))	('deficiency', 'Var', (94, 104))	('emphysema', 'Phenotype', 'HP:0002097', (150, 159))	('cessation rates', 'MPA', (189, 204))
86056	20652463	Genetic variations are demonstrated to influence the catalytic properties of these enzymes, leading to differences in rates of acetaldehyde production or elimination.	('influence', 'Reg', (39, 48))	('elimination', 'MPA', (154, 165))	('catalytic properties', 'MPA', (53, 73))	('acetaldehyde', 'Chemical', 'MESH:D000079', (127, 139))	('acetaldehyde production', 'MPA', (127, 150))	('rates', 'MPA', (118, 123))	('Genetic variations', 'Var', (0, 18))	('differences', 'Reg', (103, 114))
86057	20652463	Variations in alcohol metabolizing genes are demonstrated to moderate risk for alcohol-related cancers.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('Variations', 'Var', (0, 10))	('alcohol', 'Chemical', 'MESH:D000438', (14, 21))	('alcohol', 'Chemical', 'MESH:D000438', (79, 86))	('risk', 'Reg', (70, 74))
86076	20652463	The current study evaluated the feasibility, acceptability, and short-term efficacy of brief, web-based intervention incorporating personalized feedback and risk information specific to ALDH2 genotype.	('ALDH2', 'Gene', '217', (186, 191))	('genotype', 'Var', (192, 200))	('ALDH2', 'Gene', (186, 191))
86099	20652463	This section also described the functional significance of ALDH2, the role of the aldehyde dehydrogenase enzyme in acetaldehyde elimination, the functional significance of ALDH2 variants (i.e., *1 and *2 alleles), and population differences in genotype frequencies.	('variants', 'Var', (178, 186))	('ALDH2', 'Gene', '217', (59, 64))	('ALDH2', 'Gene', '217', (172, 177))	('acetaldehyde elimination', 'MPA', (115, 139))	('ALDH2', 'Gene', (59, 64))	('ALDH2', 'Gene', (172, 177))	('acetaldehyde', 'Chemical', 'MESH:D000079', (115, 127))
86105	20652463	These individuals learned that their genotype is associated with rates of alcohol dependence that are 4- to 5-fold higher than ALDH2*1/*2 individuals and 8- to 9-fold higher than ALDH2*2/*2 individuals.	('alcohol dependence', 'Phenotype', 'HP:0030955', (74, 92))	('ALDH2', 'Gene', '217', (179, 184))	('alcohol dependence', 'Disease', (74, 92))	('higher', 'PosReg', (167, 173))	('genotype', 'Var', (37, 45))	('ALDH2', 'Gene', '217', (127, 132))	('ALDH2', 'Gene', (179, 184))	('ALDH2', 'Gene', (127, 132))	('to 9', 'Species', '1214577', (157, 161))	('alcohol dependence', 'Disease', 'MESH:D000437', (74, 92))	('higher', 'PosReg', (115, 121))
86145	20652463	2, ALDH2*1/*2 participants who received genetic feedback showed significantly greater baseline to posttest decreases in drinking quantity and frequency than attention-control feedback participants.	('participants', 'Species', '9606', (184, 196))	('genetic feedback', 'Var', (40, 56))	('ALDH2', 'Gene', '217', (3, 8))	('decreases', 'NegReg', (107, 116))	('ALDH2', 'Gene', (3, 8))	('participants', 'Species', '9606', (14, 26))
86146	20652463	Within the ALDH2*1/*1 group, genetic feedback participants showed significantly greater increases in risk perception and intentions to change drinking behavior, as well as greater fear arousal, compared to attention-control feedback participants (Tables 1 and 2).	('genetic feedback', 'Var', (29, 45))	('risk perception', 'MPA', (101, 116))	('fear arousal', 'Phenotype', 'HP:0000739', (180, 192))	('greater', 'PosReg', (172, 179))	('intentions to change drinking behavior', 'MPA', (121, 159))	('ALDH2', 'Gene', '217', (11, 16))	('participants', 'Species', '9606', (233, 245))	('ALDH2', 'Gene', (11, 16))	('increases', 'PosReg', (88, 97))	('participants', 'Species', '9606', (46, 58))	('fear arousal', 'MPA', (180, 192))
86147	20652463	Within the ALDH2*1/*2 group, genetic feedback predicted greater baseline to posttest increases in risk perception compared to attention-control feedback.	('genetic feedback', 'Var', (29, 45))	('ALDH2', 'Gene', '217', (11, 16))	('risk perception', 'MPA', (98, 113))	('ALDH2', 'Gene', (11, 16))	('increases', 'PosReg', (85, 94))
86148	20652463	Among ALDH2*1/*2 participants, the genetic feedback group reported significant reductions in their evaluations of "positive" alcohol expectancies following the intervention compared to those receiving attention-control feedback.	('ALDH2', 'Gene', '217', (6, 11))	('ALDH2', 'Gene', (6, 11))	('participants', 'Species', '9606', (17, 29))	('genetic feedback', 'Var', (35, 51))	('reductions', 'NegReg', (79, 89))	('evaluations of "positive" alcohol expectancies', 'MPA', (99, 145))	('alcohol', 'Chemical', 'MESH:D000438', (125, 132))
86152	20652463	This study evaluated a brief, web-based intervention incorporating personalized genetic feedback and risk information specific to ALDH2 genotype.	('ALDH2', 'Gene', (130, 135))	('genotype', 'Var', (136, 144))	('ALDH2', 'Gene', '217', (130, 135))
86154	20652463	Genetic feedback also predicted significant increases in risk perception (for ALDH2*1/*1 and ALDH2*1/*2 individuals) and intentions to reduce drinking (for ALDH2*1/*1 individuals).	('risk perception', 'MPA', (57, 72))	('ALDH2', 'Gene', (78, 83))	('ALDH2', 'Gene', (156, 161))	('Genetic', 'Var', (0, 7))	('ALDH2', 'Gene', '217', (93, 98))	('ALDH2', 'Gene', (93, 98))	('ALDH2', 'Gene', '217', (78, 83))	('ALDH2', 'Gene', '217', (156, 161))	('increases', 'PosReg', (44, 53))	('intentions', 'MPA', (121, 131))
86167	20652463	Whereas associations of individual genetic variants with substance use behavior are usually small, focusing on ALDH2 allowed for the communication of relatively large effect sizes (i.e., odds ratios) with respect to alcohol-related health outcomes.	('ALDH2', 'Gene', (111, 116))	('associations', 'Interaction', (8, 20))	('alcohol', 'Chemical', 'MESH:D000438', (216, 223))	('ALDH2', 'Gene', '217', (111, 116))	('variants', 'Var', (43, 51))	('substance use', 'Disease', (57, 70))
86168	20652463	It is also noteworthy that genetic feedback appears capable of promoting health protective behaviors irrespective of whether participants have the higher-or lower-risk genotype or whether preventative measures exist for the disorder in question.	('participants', 'Species', '9606', (125, 137))	('health protective behaviors', 'CPA', (73, 100))	('genetic', 'Var', (27, 34))	('promoting', 'PosReg', (63, 72))
86188	34007331	In cervical cancer, enhancer of zeste homolog 2 (EZH2) promotes cell proliferation and tumor formation in cervical cancer through activation of the Wnt/beta-catenin pathway via GSK-3beta- and TP53-mediated epigenetic silencing.	('enhancer of zeste homolog 2', 'Gene', (20, 47))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('EZH2', 'Gene', '2146', (49, 53))	('epigenetic silencing', 'Var', (206, 226))	('activation', 'PosReg', (130, 140))	('beta-catenin', 'Gene', (152, 164))	('EZH2', 'Gene', (49, 53))	('beta-catenin', 'Gene', '1499', (152, 164))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('GSK-3beta', 'Gene', '2931', (177, 186))	('TP53', 'Gene', (192, 196))	('cell proliferation', 'CPA', (64, 82))	('tumor', 'Disease', (87, 92))	('GSK-3beta', 'Gene', (177, 186))	('enhancer of zeste homolog 2', 'Gene', '2146', (20, 47))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (12, 18))	('promotes', 'PosReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('TP53', 'Gene', '7157', (192, 196))
86191	34007331	EZH2 promotes cancer formation and progression through epigenetic activation of oncogenic signaling cascades and inhibition of pro-differentiation pathways.	('cancer', 'Disease', (14, 20))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('oncogenic signaling cascades', 'Pathway', (80, 108))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('epigenetic activation', 'Var', (55, 76))	('inhibition', 'NegReg', (113, 123))	('pro-differentiation pathways', 'Pathway', (127, 155))	('progression', 'CPA', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('promotes', 'PosReg', (5, 13))
86265	34007331	A previous study analyzed data from the ESCC survival database and the results indicated that patients with ESCC, high MTA1 expression exhibited a significant association with tumor metastasis and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('high', 'Var', (114, 118))	('patients', 'Species', '9606', (94, 102))	('MTA1', 'Gene', (119, 123))	('expression', 'MPA', (124, 134))	('tumor metastasis', 'Disease', (176, 192))	('MTA1', 'Gene', '9112', (119, 123))	('ESCC', 'Disease', (108, 112))	('tumor metastasis', 'Disease', 'MESH:D009362', (176, 192))
86275	34007331	Its mechanism is independent of the canonical TGF-beta signaling effector SMAD4, since short hairpin RNA-mediated ablation of SMAD4 did not substantially affect SOX4 expression in NMuMG cells.	('SMAD4', 'Gene', (74, 79))	('NMuMG', 'CellLine', 'CVCL:0075', (180, 185))	('SMAD4', 'Gene', (126, 131))	('SMAD4', 'Gene', '17128', (74, 79))	('SMAD4', 'Gene', '17128', (126, 131))	('SOX4', 'Gene', (161, 165))	('expression', 'MPA', (166, 176))	('ablation', 'Var', (114, 122))
86276	34007331	Li et al demonstrated that both SOX4 and MTA1 were downstream effectors of TGF-beta, whereas the deletion of either one substantially impaired the ability of TGF-beta to induce metastasis and invasion.	('ability', 'MPA', (147, 154))	('invasion', 'CPA', (192, 200))	('metastasis', 'CPA', (177, 187))	('impaired', 'NegReg', (134, 142))	('MTA1', 'Gene', (41, 45))	('MTA1', 'Gene', '9112', (41, 45))	('induce', 'PosReg', (170, 176))	('deletion', 'Var', (97, 105))
86282	34007331	Previous studies have indicated that EZH2 is one of the direct transcriptional targets of SOX4 and that ablation of EZH2 function affects SOX4 expression.	('EZH2', 'Gene', (116, 120))	('EZH2', 'Gene', '2146', (116, 120))	('SOX4', 'Gene', (90, 94))	('expression', 'MPA', (143, 153))	('affects', 'Reg', (130, 137))	('EZH2', 'Gene', '2146', (37, 41))	('EZH2', 'Gene', (37, 41))	('ablation', 'Var', (104, 112))	('SOX4', 'Gene', (138, 142))
86304	30627375	H2O2 resulted in the increased nuclear and cytoplasmatic expression of beta-catenin, reduced p-GSK3beta expression, up-regulated ROS content, and induced oxidative DNA damage in Eca109 cells.	('ROS content', 'MPA', (129, 140))	('increased', 'PosReg', (21, 30))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('GSK3beta', 'Gene', (95, 103))	('GSK3beta', 'Gene', '2932', (95, 103))	('beta-catenin', 'Protein', (71, 83))	('oxidative DNA damage', 'MPA', (154, 174))	('up-regulated', 'PosReg', (116, 128))	('reduced', 'NegReg', (85, 92))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('H2O2', 'Var', (0, 4))	('induced', 'Reg', (146, 153))
86305	30627375	Moreover, Eca109 cells treated with H2O2 alone had enhanced cell proliferation and metastasis but decreased cell apoptosis, as compared with those without any treatment; meanwhile, the declined Cyt C, Bax, and cleaved caspase-3, as well as the elevated Bcl-2 were also observed in Eca109 cells in the H2O2 group, which were reversed by Propofol or Dkk1.	('Bax', 'Gene', (201, 204))	('cell proliferation', 'CPA', (60, 78))	('Cyt C', 'Gene', (194, 199))	('Bax', 'Gene', '581', (201, 204))	('H2O2', 'Chemical', 'MESH:D006861', (36, 40))	('Bcl-2', 'Gene', '596', (253, 258))	('H2O2', 'Var', (301, 305))	('elevated', 'PosReg', (244, 252))	('H2O2', 'Var', (36, 40))	('Cyt C', 'Gene', '54205', (194, 199))	('Propofol', 'Chemical', 'MESH:D015742', (336, 344))	('caspase-3', 'Gene', '836', (218, 227))	('cleaved', 'MPA', (210, 217))	('metastasis', 'CPA', (83, 93))	('caspase-3', 'Gene', (218, 227))	('enhanced', 'PosReg', (51, 59))	('Bcl-2', 'Gene', (253, 258))	('H2O2', 'Chemical', 'MESH:D006861', (301, 305))	('declined', 'NegReg', (185, 193))	('decreased', 'NegReg', (98, 107))	('cell apoptosis', 'CPA', (108, 122))
86327	30627375	The resolved proteins were transferred to polyvinylidene difluoride (PVDF) membrane at 120 V for 3 hr, which was placed in 5% bovine serum albumin (BSA) for 1 hr at room temperature, followed by the addition of primary antibodies (Abcam, Cambridge, CA, USA) for overnight incubation at 4  C, including anti-beta-Catenin (ab16051, 0.25 microg/ml dilution), anti-phosphor-GSK3beta (ab75745, 1/500 dilution), anti-GSK3beta (ab32391, 1/10000 dilution), anti-Cytochrome C (ab13575, 1 microg/ml dilution), anti-Bax (ab32503, 1/2000 dilution), anti-active Caspase-3 (ab2302, 1 microg/ml dilution), anti-Bcl-2 (ab32124, 1/1000 dilution), anti-lamin B1 (ab16048, 1/1000 dilution), and anti-beta-actin (ab8226, 1 microg/ml dilution).	('Cytochrome C', 'Gene', '54205', (454, 466))	('beta-actin', 'Gene', (681, 691))	('Bcl-2', 'Gene', '596', (596, 601))	('ab16048', 'Var', (645, 652))	('lamin B1', 'Gene', (635, 643))	('Caspase-3', 'Gene', (549, 558))	('GSK3beta', 'Gene', '2932', (411, 419))	('lamin B1', 'Gene', '4001', (635, 643))	('GSK3beta', 'Gene', '2932', (370, 378))	('serum albumin (BSA) for 1', 'Gene', (133, 158))	('beta-Catenin', 'Gene', '1499', (307, 319))	('beta-actin', 'Gene', '728378', (681, 691))	('bovine', 'Species', '9913', (126, 132))	('serum albumin (BSA) for 1', 'Gene', '213', (133, 158))	('GSK3beta', 'Gene', (411, 419))	('Bax', 'Gene', (505, 508))	('beta-Catenin', 'Gene', (307, 319))	('Cytochrome C', 'Gene', (454, 466))	('Caspase-3', 'Gene', '836', (549, 558))	('Bax', 'Gene', '581', (505, 508))	('Bcl-2', 'Gene', (596, 601))	('GSK3beta', 'Gene', (370, 378))
86347	30627375	Propofol blocked the Wnt/beta-catenin pathway in H 2 O 2 -induced Eca109 cells  According to the results of Western blotting demonstrated in Figure 1, H2O2 significantly up-regulated the nuclear and cytoplasmatic expressions of beta-catenin, but down-regulated the p-GSK3beta expression (all P<0.05).	('Propofol', 'Chemical', 'MESH:D015742', (0, 8))	('GSK3beta', 'Gene', (267, 275))	('Wnt', 'Gene', (21, 24))	('up-regulated', 'PosReg', (170, 182))	('beta-catenin', 'Protein', (228, 240))	('GSK3beta', 'Gene', '2932', (267, 275))	('Wnt', 'Gene', '114487', (21, 24))	('H2O2', 'Chemical', 'MESH:D006861', (151, 155))	('H2O2', 'Var', (151, 155))	('down-regulated', 'NegReg', (246, 260))
86348	30627375	However, propofol could apparently restore beta-catenin nuclear accumulation, but elevate p-GSK3beta in H2O2-induced Eca109 cells, which was similar to Dkk1 (all P<0.05).	('restore', 'PosReg', (35, 42))	('GSK3beta', 'Gene', (92, 100))	('beta-catenin', 'Protein', (43, 55))	('propofol', 'Chemical', 'MESH:D015742', (9, 17))	('GSK3beta', 'Gene', '2932', (92, 100))	('O2-', 'Chemical', '-', (106, 109))	('H2O2-induced', 'Var', (104, 116))	('H2O2', 'Chemical', 'MESH:D006861', (104, 108))	('elevate', 'PosReg', (82, 89))
86349	30627375	Although the nuclear and cytoplasmatic expressions of beta-catenin were lower and p-GSK3beta was higher in the Dkk1 + H2O2 group (all P<0.05), there was no difference from the propofol + H2O2 group (all P>0.05).	('higher', 'PosReg', (97, 103))	('H2O2', 'Chemical', 'MESH:D006861', (187, 191))	('H2O2', 'Chemical', 'MESH:D006861', (118, 122))	('beta-catenin', 'Protein', (54, 66))	('lower', 'NegReg', (72, 77))	('GSK3beta', 'Gene', (84, 92))	('GSK3beta', 'Gene', '2932', (84, 92))	('propofol', 'Chemical', 'MESH:D015742', (176, 184))	('Dkk1 + H2O2', 'Var', (111, 122))
86353	30627375	Besides, in terms of the ROS content in Eca109 cells, the H2O2 group showed no significant difference with the propofol + LiCl + H2O2 group (all P>0.05, Figure 2).	('H2O2', 'Chemical', 'MESH:D006861', (58, 62))	('H2O2', 'Var', (58, 62))	('LiCl', 'Chemical', 'MESH:D018021', (122, 126))	('ROS content', 'MPA', (25, 36))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('H2O2', 'Chemical', 'MESH:D006861', (129, 133))	('propofol', 'Chemical', 'MESH:D015742', (111, 119))
86354	30627375	Moreover, H2O2 presented an obvious oxidative DNA damage in Eca109 cells when compared with the Control group (all P<0.05).	('H2O2', 'Var', (10, 14))	('oxidative DNA damage', 'MPA', (36, 56))	('H2O2', 'Chemical', 'MESH:D006861', (10, 14))
86357	30627375	Effect of propofol-mediated Wnt/beta-catenin pathway on the proliferation and apoptosis of H 2 O 2 -induced Eca109 cells  The H2O2 group had increased cell proliferation (24, 48, and 72 hr) and decreased cell apoptosis as compared with the Control group (all P<0.05).	('cell apoptosis', 'CPA', (204, 218))	('Wnt', 'Gene', '114487', (28, 31))	('apoptosis', 'CPA', (78, 87))	('increased', 'PosReg', (141, 150))	('propofol', 'Chemical', 'MESH:D015742', (10, 18))	('cell proliferation', 'CPA', (151, 169))	('decreased', 'NegReg', (194, 203))	('Wnt', 'Gene', (28, 31))	('H2O2', 'Chemical', 'MESH:D006861', (126, 130))	('H2O2', 'Var', (126, 130))
86358	30627375	After treated with propofol or Dkk1, the proliferation was inhibited while the apoptosis was enhanced in H2O2-induced Eca109 cells (both P<0.05).	('O2-', 'Chemical', '-', (107, 110))	('inhibited', 'NegReg', (59, 68))	('H2O2', 'Chemical', 'MESH:D006861', (105, 109))	('apoptosis', 'CPA', (79, 88))	('Dkk1', 'Var', (31, 35))	('enhanced', 'PosReg', (93, 101))	('proliferation', 'CPA', (41, 54))	('propofol', 'Chemical', 'MESH:D015742', (19, 27))
86360	30627375	Additionally, we found that H2O2 could effectively suppress the expressions of cytochrome c (Cyt C), Bax, and cleaved caspase-3, but promote the Bcl-2 expression in Eca109 cells (all P<0.05), which were reversed by propofol or Dkk1 (all P<0.05).	('Bax', 'Gene', (101, 104))	('suppress', 'NegReg', (51, 59))	('H2O2', 'Var', (28, 32))	('Cyt C', 'Gene', (93, 98))	('expressions', 'MPA', (64, 75))	('caspase-3', 'Gene', (118, 127))	('Bcl-2', 'Gene', (145, 150))	('Bcl-2', 'Gene', '596', (145, 150))	('H2O2', 'Chemical', 'MESH:D006861', (28, 32))	('promote', 'PosReg', (133, 140))	('cytochrome c', 'Gene', '54205', (79, 91))	('expression', 'MPA', (151, 161))	('Cyt C', 'Gene', '54205', (93, 98))	('Bax', 'Gene', '581', (101, 104))	('caspase-3', 'Gene', '836', (118, 127))	('propofol', 'Chemical', 'MESH:D015742', (215, 223))	('cytochrome c', 'Gene', (79, 91))
86362	30627375	Propofol inhibited the migration and invasion of H 2 O 2 -induced Eca109 cells through mediating the Wnt/beta-catenin pathway   As shown in Figure 5, it is obvious that H2O2 could induce the migration and invasion of Eca109 cells in comparison with Controls (all P<0.05).	('Wnt', 'Gene', (101, 104))	('inhibited', 'NegReg', (9, 18))	('invasion', 'CPA', (205, 213))	('invasion', 'CPA', (37, 45))	('Propofol', 'Chemical', 'MESH:D015742', (0, 8))	('Wnt', 'Gene', '114487', (101, 104))	('H2O2', 'Chemical', 'MESH:D006861', (169, 173))	('H2O2', 'Var', (169, 173))	('migration', 'CPA', (191, 200))	('induce', 'PosReg', (180, 186))	('migration', 'CPA', (23, 32))
86363	30627375	Besides, both propofol and Dkk1 markedly reduced the metastasis of H2O2-induced Eca109 cells (all P<0.05), and Dkk1 slightly but not statistically decreased the migration and invasion of H2O2-induced Eca109 cells when compared with propofol (all P>0.05).	('reduced', 'NegReg', (41, 48))	('O2-', 'Chemical', '-', (69, 72))	('H2O2', 'Chemical', 'MESH:D006861', (187, 191))	('decreased', 'NegReg', (147, 156))	('metastasis', 'CPA', (53, 63))	('propofol', 'Chemical', 'MESH:D015742', (14, 22))	('invasion', 'CPA', (175, 183))	('H2O2', 'Chemical', 'MESH:D006861', (67, 71))	('Dkk1', 'Var', (27, 31))	('migration', 'CPA', (161, 170))	('Dkk1', 'Var', (111, 115))	('propofol', 'Chemical', 'MESH:D015742', (232, 240))	('O2-', 'Chemical', '-', (189, 192))
86364	30627375	In addition, Propofol + LiCl + H2O2 and H2O2 groups were not statistically different from each other regarding the cell abilities of migration and invasion (all P>0.05).	('H2O2', 'Chemical', 'MESH:D006861', (31, 35))	('Propofol', 'Chemical', 'MESH:D015742', (13, 21))	('H2O2', 'Chemical', 'MESH:D006861', (40, 44))	('H2O2', 'Var', (40, 44))	('LiCl', 'Chemical', 'MESH:D018021', (24, 28))	('invasion', 'CPA', (147, 155))	('cell abilities of migration', 'CPA', (115, 142))
86367	30627375	H2O2, an important relatively stable non-radical ROS, is usually used in the investigation of oxidative stress, since it can diffuse freely to the nucleus to induce DNA base damage and strand breakage.	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('strand breakage', 'CPA', (185, 200))	('DNA base damage', 'MPA', (165, 180))	('oxidative stress', 'Phenotype', 'HP:0025464', (94, 110))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))	('induce', 'Reg', (158, 164))
86369	30627375	Researchers also found H2O2 could sequentially activate the ERK2 MAPK, NF-kappaB1 p50, and NOX5-S, and enhance the production of ROS, thus increasing the proliferation of EAC cells.	('activate', 'PosReg', (47, 55))	('ERK2', 'Gene', (60, 64))	('enhance', 'PosReg', (103, 110))	('H2O2', 'Var', (23, 27))	('NOX5', 'Gene', (91, 95))	('NF-kappaB', 'Gene', (71, 80))	('EAC cells', 'CPA', (171, 180))	('NF-kappaB', 'Gene', '4790', (71, 80))	('increasing', 'PosReg', (139, 149))	('EAC', 'Phenotype', 'HP:0011459', (171, 174))	('p50', 'Gene', '4790', (82, 85))	('production', 'MPA', (115, 125))	('proliferation', 'CPA', (154, 167))	('NOX5', 'Gene', '79400', (91, 95))	('p50', 'Gene', (82, 85))	('ROS', 'MPA', (129, 132))	('H2O2', 'Chemical', 'MESH:D006861', (23, 27))	('ERK2', 'Gene', '5594', (60, 64))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))
86371	30627375	From our models, we found that H2O2 significantly increased the ROS content and caused oxidative DNA damage of Eca109 cells with elevated cell proliferation and metastasis, as well as decreased cell apoptosis, showing the successful construction of oxidative cell damage models in our research.	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('H2O2', 'Chemical', 'MESH:D006861', (31, 35))	('H2O2', 'Var', (31, 35))	('cell apoptosis', 'CPA', (194, 208))	('caused', 'Reg', (80, 86))	('elevated', 'PosReg', (129, 137))	('oxidative DNA damage', 'MPA', (87, 107))	('increased', 'PosReg', (50, 59))	('decreased', 'NegReg', (184, 193))	('cell proliferation', 'CPA', (138, 156))	('ROS content', 'MPA', (64, 75))	('metastasis', 'CPA', (161, 171))
86377	30627375	Worth mentioning, our study also revealed that propofol could remarkably alleviate the oxidative stress and DNA damage in Eca109 cells induced by H2O2.	('oxidative stress', 'MPA', (87, 103))	('DNA damage', 'MPA', (108, 118))	('H2O2', 'Chemical', 'MESH:D006861', (146, 150))	('H2O2', 'Var', (146, 150))	('oxidative stress', 'Phenotype', 'HP:0025464', (87, 103))	('alleviate', 'NegReg', (73, 82))	('propofol', 'Chemical', 'MESH:D015742', (47, 55))
86385	30627375	Not surprisingly, H2O2 in our study could activate the Wnt/beta-catenin pathway in Eca109 cells.	('Wnt', 'Gene', '114487', (55, 58))	('H2O2', 'Chemical', 'MESH:D006861', (18, 22))	('H2O2', 'Var', (18, 22))	('activate', 'PosReg', (42, 50))	('Wnt', 'Gene', (55, 58))
86386	30627375	As we know, oxidative stress generated by treatment of cells with H2O2 can activate the expressions of Foxo transcription factors (like Foxo1, Foxo3a, and Foxo4), which may interact with beta-catenin to inhibit the apoptosis of cancer cells.	('H2O2', 'Var', (66, 70))	('expressions', 'MPA', (88, 99))	('Foxo4', 'Gene', '4303', (155, 160))	('activate', 'PosReg', (75, 83))	('cancer', 'Disease', (228, 234))	('Foxo3a', 'Gene', '2309', (143, 149))	('H2O2', 'Chemical', 'MESH:D006861', (66, 70))	('Foxo3a', 'Gene', (143, 149))	('Foxo transcription factors', 'Gene', (103, 129))	('Foxo4', 'Gene', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('interact', 'Interaction', (173, 181))	('oxidative stress', 'Phenotype', 'HP:0025464', (12, 28))	('Foxo1', 'Gene', '2308', (136, 141))	('inhibit', 'NegReg', (203, 210))	('Foxo1', 'Gene', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
86389	30627375	Actually, our study also observed the promoted proliferation and inhibited apoptosis of Eca109 cells treated by H2O2 with the decreased expression of Cyt C, Bax, and cleaved caspase-3, and the increased expression of Bax.	('decreased', 'NegReg', (126, 135))	('Bax', 'Gene', '581', (157, 160))	('expression', 'MPA', (136, 146))	('caspase-3', 'Gene', '836', (174, 183))	('Cyt C', 'Gene', '54205', (150, 155))	('apoptosis', 'CPA', (75, 84))	('expression', 'MPA', (203, 213))	('Bax', 'Gene', '581', (217, 220))	('Bax', 'Gene', (157, 160))	('caspase-3', 'Gene', (174, 183))	('inhibited', 'NegReg', (65, 74))	('increased', 'PosReg', (193, 202))	('promoted', 'PosReg', (38, 46))	('H2O2', 'Var', (112, 116))	('Bax', 'Gene', (217, 220))	('H2O2', 'Chemical', 'MESH:D006861', (112, 116))	('Cyt C', 'Gene', (150, 155))	('cleaved', 'MPA', (166, 173))
86390	30627375	Moreover, consistent with the findings of a previous study, H2O2 could facilitate the abilities of migration and invasion of Eca109 cells in our study, which indicated the possibility that H2O2 could activate the Wnt/beta-catenin signaling pathway and promote the epithelial-mesenchymal transition (EMT), thereby promoting metastasis of EC cells.	('promoting', 'PosReg', (313, 322))	('H2O2', 'Var', (189, 193))	('metastasis of EC cells', 'CPA', (323, 345))	('promote', 'PosReg', (252, 259))	('H2O2', 'Chemical', 'MESH:D006861', (189, 193))	('invasion', 'CPA', (113, 121))	('Wnt', 'Gene', (213, 216))	('epithelial-mesenchymal transition', 'CPA', (264, 297))	('Wnt', 'Gene', '114487', (213, 216))	('facilitate', 'PosReg', (71, 81))	('H2O2', 'Chemical', 'MESH:D006861', (60, 64))	('activate', 'PosReg', (200, 208))	('migration', 'CPA', (99, 108))
86497	30450163	Specific cancer-associated biomarkers were chosen based on knowledge that GERD remains the strongest risk factor for BE and EAC and is known to be linked to increased Inflammation, oxidative stress, aberrant activation of transcription factors and reduced antioxidant defence mechanisms.	('cancer', 'Disease', (9, 15))	('antioxidant defence mechanisms', 'MPA', (256, 286))	('activation', 'PosReg', (208, 218))	('reduced', 'NegReg', (248, 255))	('GERD', 'Var', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('transcription factors', 'MPA', (222, 243))	('EA', 'Chemical', 'MESH:D004610', (124, 126))	('oxidative stress', 'Phenotype', 'HP:0025464', (181, 197))	('increased', 'PosReg', (157, 166))	('EAC', 'Phenotype', 'HP:0011459', (124, 127))	('oxidative stress', 'MPA', (181, 197))	('Inflammation', 'MPA', (167, 179))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('BE', 'Phenotype', 'HP:0100580', (117, 119))	('EAC', 'Disease', (124, 127))
86533	30450163	Adherence to the World Cancer Research Fund (WCRF) guidelines on lifestyle and cancer has recently been identified as a significant and independent protective factor against BE progression to EAC (OR 0.51, 95% CI 0.37-0.67).	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Adherence', 'Var', (0, 9))	('EA', 'Chemical', 'MESH:D004610', (192, 194))	('EAC', 'Phenotype', 'HP:0011459', (192, 195))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('EAC', 'Disease', (192, 195))	('BE', 'Phenotype', 'HP:0100580', (174, 176))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
86630	29257318	Multiple studies have reported that aberrant LI-cadherin expression is a sensitive marker for detection of various metaplastic diseases such as gastric intestinal metaplasia and BE.	('LI-cadherin', 'Gene', (45, 56))	('gastric intestinal metaplasia', 'Disease', (144, 173))	('LI-cadherin', 'Gene', '1015', (45, 56))	('aberrant', 'Var', (36, 44))	('BE', 'Phenotype', 'HP:0100580', (178, 180))	('gastric intestinal metaplasia', 'Disease', 'MESH:D013274', (144, 173))
86655	29290767	HIF-1 activity in tumors depends on availability of the HIF-1a subunit, the levels of which increase under hypoxic conditions and through activation of oncogenes and/or inactivation of tumor suppressor genes.	('hypoxic conditions', 'Disease', (107, 125))	('HIF-1', 'Gene', '3091', (0, 5))	('tumors', 'Disease', (18, 24))	('oncogenes', 'Gene', (152, 161))	('activation', 'PosReg', (138, 148))	('HIF-1', 'Gene', '3091', (56, 61))	('tumor', 'Disease', (185, 190))	('HIF-1', 'Gene', (0, 5))	('tumor', 'Disease', (18, 23))	('HIF-1a', 'Gene', (56, 62))	('HIF-1', 'Gene', (56, 61))	('increase', 'PosReg', (92, 100))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('activity', 'MPA', (6, 14))	('hypoxic conditions', 'Disease', 'MESH:D009135', (107, 125))	('inactivation', 'Var', (169, 181))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('HIF-1a', 'Gene', '3091', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))
86660	29290767	Inhibiting PKM2 can result in the decreased intacellular ATP and increased intake of anticarcinogen, and further promotes therapeutic sensentivity.	('promotes', 'PosReg', (113, 121))	('increased', 'PosReg', (65, 74))	('intake of anticarcinogen', 'MPA', (75, 99))	('therapeutic', 'MPA', (122, 133))	('Inhibiting', 'Var', (0, 10))	('decreased', 'NegReg', (34, 43))	('ATP', 'Chemical', 'MESH:D000255', (57, 60))	('PKM2', 'Gene', (11, 15))	('intacellular ATP', 'MPA', (44, 60))	('PKM2', 'Gene', '5315', (11, 15))
86696	29290767	(Fig.1A,B) Moreover, the expression of PKM2 and HIF1alpha was examined by Western blot in Human Esophageal Epithelial Cells(HECC), EC109 and EC9706.	('PKM2', 'Gene', '5315', (39, 43))	('EC9706', 'CellLine', 'CVCL:E307', (141, 147))	('HIF1alpha', 'Gene', (48, 57))	('HIF1alpha', 'Gene', '3091', (48, 57))	('Human', 'Species', '9606', (90, 95))	('PKM2', 'Gene', (39, 43))	('EC9706', 'Var', (141, 147))
86697	29290767	Our results displayed that the expression of PKM2 and HIF1alpha rose significantly in the EC109 and EC9706 compared with Human Esophageal Epithelial Cells (HECC).	('EC9706', 'Var', (100, 106))	('HIF1alpha', 'Gene', '3091', (54, 63))	('PKM2', 'Gene', (45, 49))	('EC9706', 'CellLine', 'CVCL:E307', (100, 106))	('PKM2', 'Gene', '5315', (45, 49))	('Human', 'Species', '9606', (121, 126))	('expression', 'MPA', (31, 41))	('rose', 'PosReg', (64, 68))	('HIF1alpha', 'Gene', (54, 63))
86700	29290767	The results displayed that shikonin decreased the viability of EC109 and EC9706 in a dose and time-dependent.	('shikonin', 'Chemical', 'MESH:C016101', (27, 35))	('EC9706', 'Var', (73, 79))	('EC109', 'Var', (63, 68))	('EC9706', 'CellLine', 'CVCL:E307', (73, 79))	('viability', 'CPA', (50, 59))	('decreased', 'NegReg', (36, 45))
86702	29290767	We found that shikonin induced cell cycle arrest in EC109 and EC9706.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (31, 48))	('shikonin', 'Chemical', 'MESH:C016101', (14, 22))	('EC9706', 'CellLine', 'CVCL:E307', (62, 68))	('cell cycle arrest', 'CPA', (31, 48))	('EC9706', 'Var', (62, 68))
86712	29290767	The results showed that overexpression PKM2 increased shikonin resistance in esophageal cancer cells.	('PKM2', 'Gene', '5315', (39, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('esophageal cancer', 'Disease', (77, 94))	('shikonin resistance', 'MPA', (54, 73))	('shikonin', 'Chemical', 'MESH:C016101', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('increased', 'PosReg', (44, 53))	('PKM2', 'Gene', (39, 43))	('overexpression', 'Var', (24, 38))
86730	29290767	Previous studies have proved that inhibiting PKM2 can decrease intracellular ATP, and then suppress the proliferation of cancer cells.	('inhibiting', 'Var', (34, 44))	('ATP', 'Chemical', 'MESH:D000255', (77, 80))	('decrease', 'NegReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PKM2', 'Gene', (45, 49))	('suppress', 'NegReg', (91, 99))	('PKM2', 'Gene', '5315', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('intracellular ATP', 'MPA', (63, 80))
86736	29290767	PI3K is an important downstream molecular of EGFR.	('PI3K', 'Var', (0, 4))	('EGFR', 'Gene', '1956', (45, 49))	('EGFR', 'Gene', (45, 49))
86741	29290767	In the current study, we found that shikonin decreased the expression of cylcinD1, indicating that shikonin reduced the esophageal cancer cells proliferation by suppression HIF1alpha / PKM2/cyclin D1 pathway.	('cyclin D1', 'Gene', '595', (190, 199))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('shikonin', 'Chemical', 'MESH:C016101', (99, 107))	('cyclin D1', 'Gene', (190, 199))	('HIF1alpha', 'Gene', '3091', (173, 182))	('reduced', 'NegReg', (108, 115))	('shikonin', 'Var', (99, 107))	('PKM2', 'Gene', (185, 189))	('decreased', 'NegReg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('PKM2', 'Gene', '5315', (185, 189))	('shikonin', 'Chemical', 'MESH:C016101', (36, 44))	('esophageal cancer', 'Disease', (120, 137))	('HIF1alpha', 'Gene', (173, 182))	('suppression', 'NegReg', (161, 172))
86767	27284426	In addition, there have been numerous studies demonstrating the association between an aberrant expression level of miR-200c and the prognosis of various human malignancies, including endometrial cancer, gastric cancer, ovarian cancer, clear cell renal cell carcinoma (ccRCC), breast cancer, colorectal cancer, non-small cell lung cancer (NSCLC), prostate cancer, esophageal cancer, diffuse large B-cell lymphoma, bladder cancer and pancreatic cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (414, 428))	('bladder cancer', 'Disease', (414, 428))	('lymphoma', 'Disease', 'MESH:D008223', (404, 412))	('human', 'Species', '9606', (154, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('esophageal cancer', 'Disease', (364, 381))	('colorectal cancer', 'Phenotype', 'HP:0003003', (292, 309))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (311, 337))	('miR-200c', 'Gene', '406985', (116, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (414, 428))	('malignancies', 'Disease', 'MESH:D009369', (160, 172))	('ovarian cancer', 'Disease', (220, 234))	('gastric cancer', 'Disease', (204, 218))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('malignancies', 'Disease', (160, 172))	('NSCLC', 'Disease', 'MESH:D002289', (339, 344))	('breast cancer', 'Disease', (277, 290))	('pancreatic cancer', 'Disease', 'MESH:D010190', (433, 450))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (236, 267))	('expression', 'MPA', (96, 106))	('ovarian cancer', 'Phenotype', 'HP:0100615', (220, 234))	('aberrant', 'Var', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('miR-200c', 'Gene', (116, 124))	('non-small cell lung cancer', 'Disease', (311, 337))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (247, 267))	('colorectal cancer', 'Disease', 'MESH:D015179', (292, 309))	('NSCLC', 'Disease', (339, 344))	('gastric cancer', 'Disease', 'MESH:D013274', (204, 218))	('prostate cancer', 'Disease', 'MESH:D011471', (347, 362))	('prostate cancer', 'Phenotype', 'HP:0012125', (347, 362))	('lymphoma', 'Phenotype', 'HP:0002665', (404, 412))	('pancreatic cancer', 'Disease', (433, 450))	('lung cancer', 'Phenotype', 'HP:0100526', (326, 337))	('clear cell renal cell carcinoma', 'Disease', (236, 267))	('colorectal cancer', 'Disease', (292, 309))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('endometrial cancer', 'Phenotype', 'HP:0012114', (184, 202))	('prostate cancer', 'Disease', (347, 362))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (311, 337))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('endometrial cancer', 'Disease', (184, 202))	('esophageal cancer', 'Disease', 'MESH:D004938', (364, 381))	('gastric cancer', 'Phenotype', 'HP:0012126', (204, 218))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (397, 412))	('endometrial cancer', 'Disease', 'MESH:D016889', (184, 202))	('ovarian cancer', 'Disease', 'MESH:D010051', (220, 234))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (433, 450))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (315, 337))	('lymphoma', 'Disease', (404, 412))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (236, 267))	('association', 'Interaction', (64, 75))
86785	27284426	2B and C. First, in the subgroup analysis of patients from Europe and America, the pooled outcome demonstrated that a high expression level of miR-200c was significantly associated with worse OS (HR=1.85, 95% CI: 1.27, 2.69).	('high', 'Var', (118, 122))	('miR-200c', 'Gene', (143, 151))	('worse OS', 'Disease', (186, 194))	('miR-200c', 'Gene', '406985', (143, 151))	('patients', 'Species', '9606', (45, 53))	('associated', 'Reg', (170, 180))
86794	27284426	In the studies of CSS/OS and RFS/PFS/DFS, our sensitivity analyses did not reveal any alterations in the results due to the inclusion of any individual study (Fig.	('RFS/PFS/DFS', 'Var', (29, 40))	('CSS/OS', 'Gene', '55907', (18, 24))	('CSS/OS', 'Gene', (18, 24))
86798	27284426	Conversely, inhibition of the miR-200 family would induce mesenchymal-like spindle morphology, which promotes cancer metastasis.	('inhibition', 'Var', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer metastasis', 'Disease', (110, 127))	('induce', 'PosReg', (51, 57))	('cancer metastasis', 'Disease', 'MESH:D009362', (110, 127))	('promotes', 'PosReg', (101, 109))	('miR-200 family', 'Gene', (30, 44))	('mesenchymal-like spindle morphology', 'CPA', (58, 93))	('miR-200', 'Chemical', '-', (30, 37))
86818	27284426	In addition, using a linear combination of the microRNA cycle threshold values and Cox regression coefficients as weights, Berghmans et al revealed that a certain microRNA signature (miR-200c, miR-124, miR-29c and miR-424) is of prognostic value for OS in patients with NSCLC.	('miR-424', 'Gene', '494336', (214, 221))	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('miR-200c', 'Gene', '406985', (183, 191))	('patients', 'Species', '9606', (256, 264))	('Cox', 'Gene', '1351', (83, 86))	('miR-424', 'Gene', (214, 221))	('miR-29c', 'Gene', (202, 209))	('Cox', 'Gene', (83, 86))	('miR-29c', 'Gene', '407026', (202, 209))	('NSCLC', 'Disease', (270, 275))	('miR-124', 'Var', (193, 200))	('miR-200c', 'Gene', (183, 191))
86868	25184951	Accordingly, miRNAs, such as mir-21-5p and let-7f-5p, were highly expressed, whereas mir-9-3p and mir-9-5p were lowly expressed (Figure 4).	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('mir-9-3p', 'Gene', '407051', (85, 93))	('let-7f-5p', 'Var', (43, 52))	('mir-9-5p', 'Gene', '407052', (98, 106))	('mir-21-5p', 'Gene', (29, 38))	('mir-21-5p', 'Gene', '406997', (29, 38))	('mir-9-5p', 'Gene', (98, 106))	('mir-9-3p', 'Gene', (85, 93))
86869	25184951	Utilizing the isolated miRNA from EC9706 and their corresponding exosomes, we profiled the miRNAs and found 342 known miRNAs in the cells, 48 of which were detected in the exosomes.	('miR', 'Gene', (91, 94))	('EC9706', 'CellLine', 'CVCL:E307', (34, 40))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('EC9706', 'Var', (34, 40))	('miR', 'Gene', '220972', (118, 121))	('miR', 'Gene', (118, 121))	('miR', 'Gene', '220972', (91, 94))
86870	25184951	Figure 6 shows the number of shared and specific miRNAs between the EC9706-derived exosomes and cells.	('EC9706-derived', 'Var', (68, 82))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))
86929	25184951	In the present study, has-miR-21, has-let-7 family, miR-26a and miR-27b were abundant in EC9706 cells and their corresponding exosomes.	('EC9706', 'CellLine', 'CVCL:E307', (89, 95))	('miR-27b', 'Gene', '407019', (64, 71))	('has-let-7 family', 'Gene', (34, 50))	('miR-26a', 'Gene', '407015', (52, 59))	('miR-27b', 'Gene', (64, 71))	('miR-26a', 'Gene', (52, 59))	('has-miR-21', 'Var', (22, 32))
86934	25184951	found, through locked nucleic acid silencing combined with microarray technology, that miR-21 knockdown can inhibit the growth and migration of breast cells in vitro and tumor growth in nude mice.	('nude mice', 'Species', '10090', (186, 195))	('knockdown', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('miR-21', 'Gene', (87, 93))	('rat', 'Species', '10116', (134, 137))	('inhibit', 'NegReg', (108, 115))
86943	25184951	found that the PPARalpha protein level in the human hepatocellular carcinoma cell line HuH7 significantly decreases when the levels of miR-21 or miR-27b are over-expressed and inhibited, respectively.	('miR-27b', 'Gene', (145, 152))	('HuH7', 'Gene', (87, 91))	('over-expressed', 'PosReg', (157, 171))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (52, 76))	('PPARalpha', 'Gene', (15, 24))	('hepatocellular carcinoma', 'Disease', (52, 76))	('HuH7', 'Gene', '284424', (87, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (52, 76))	('miR-21', 'Var', (135, 141))	('human', 'Species', '9606', (46, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('miR-27b', 'Gene', '407019', (145, 152))	('inhibited', 'NegReg', (176, 185))	('PPARalpha', 'Gene', '5465', (15, 24))	('decreases', 'NegReg', (106, 115))
86952	25184951	Most isomiRs showed variability at their 5' and/or 3' ends, likely resulting from the variability in either Dicer or Drosha cleavage positions within the pre-miRNA hairpin; an example of which is given in Figure 8, which shows sequenced isomiRs for miR-21 with high read counts in cells and exosomes.	('miR', 'Gene', '220972', (249, 252))	('Dicer', 'Gene', '23405', (108, 113))	('miR', 'Gene', (249, 252))	('Dicer', 'Gene', (108, 113))	('miR', 'Gene', (158, 161))	('Drosha', 'Gene', '29102', (117, 123))	('miR', 'Gene', '220972', (158, 161))	('miR', 'Gene', '220972', (8, 11))	('resulting', 'Reg', (67, 76))	('miR', 'Gene', '220972', (240, 243))	('variability', 'Var', (86, 97))	('miR', 'Gene', (240, 243))	('Drosha', 'Gene', (117, 123))	('miR', 'Gene', (8, 11))
86953	25184951	This result indicates that the majority of esophageal cancer-derived miRNA nucleotide variants resulted from post-transcriptional modifications.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('miRNA nucleotide variants', 'Var', (69, 94))	('miRNA nucleotide', 'Chemical', '-', (69, 85))	('resulted from', 'Reg', (95, 108))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
87132	20559544	O*, O1*, O2a*, and O2a1, the four common haplogroups in the southern East Asians, were more frequent in the CSP and HTMP than in the FJP (2-sided X 2 = 8.355, p = 0.015).	('O2a1', 'Var', (19, 23))	('O2a*', 'Var', (9, 13))	('O1*', 'Gene', (4, 7))	('O1*', 'Gene', '28878', (4, 7))
87144	20559544	As shown in Table 4, the distribution of O3e*, O2a*, and O1 is opposite with PC1 and PC2.	('PC1', 'Gene', '3868', (77, 80))	('O2a*', 'Var', (47, 51))	('PC1', 'Gene', (77, 80))	('PC2', 'Gene', '3854', (85, 88))	('PC2', 'Gene', (85, 88))	('O3', 'Gene', '28879', (41, 43))
87146	20559544	O2a* and O1 were positively correlated with PC2, but O3e* was negatively correlated.	('correlated', 'Interaction', (28, 38))	('O3', 'Gene', '28879', (53, 55))	('PC2', 'Gene', '3854', (44, 47))	('PC2', 'Gene', (44, 47))	('O2a*', 'Var', (0, 4))
87161	20559544	O3* is the ancestral haplogroup of the M122C alleles, whereas O3e* and O3e1* are the 2 derived haplogroups with additional mutations, M134 and M117, respectively.	('M122C', 'Var', (39, 44))	('M134', 'Var', (134, 138))	('O3*', 'Gene', '28879', (0, 3))	('O3', 'Gene', '28879', (71, 73))	('O3*', 'Gene', (0, 3))	('M117', 'Var', (143, 147))	('O3', 'Gene', '28879', (0, 2))	('O3', 'Gene', '28879', (62, 64))	('M122C', 'SUBSTITUTION', 'None', (39, 44))
87165	19690180	AhR gene expression was detectable in 85 (58%) of the samples, and was more than 9-fold higher in those with a FH of UGI Ca (median expression (IQR) -1964 (-18000, -610) versus -18000 (-18000, -1036) Wilcoxon P = 0.02).	('higher', 'PosReg', (88, 94))	('-18000', 'Var', (156, 162))	('expression', 'MPA', (9, 19))	('AhR', 'Gene', (0, 3))	('AhR', 'Gene', '196', (0, 3))
87175	19690180	These include not only associations between a family history of upper gastrointestinal cancer and esophageal cancer risk, but also associations between family history of these cancers and chromosomal aberrations (frequency of allelic loss) or gene-environment interactions.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (188, 211))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('associations', 'Interaction', (131, 143))	('gene-environment', 'Var', (243, 259))	('esophageal cancer', 'Disease', (98, 115))	('upper gastrointestinal cancer', 'Disease', 'MESH:D004067', (64, 93))	('associations', 'Interaction', (23, 35))	('upper gastrointestinal cancer', 'Disease', (64, 93))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (70, 93))	('men', 'Species', '9606', (255, 258))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))	('chromosomal aberrations', 'Var', (188, 211))
87236	19690180	One such example is the association between tobacco use and specific Cytochrome P450-related enzyme genotypes that predispose the esophagus of smokers to an even higher risk for DNA damage or cancer.	('tobacco', 'Species', '4097', (44, 51))	('predispose', 'Reg', (115, 125))	('association', 'Interaction', (24, 35))	('genotypes', 'Var', (100, 109))	('DNA damage', 'Disease', (178, 188))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('Cytochrome P450', 'Gene', '4051', (69, 84))	('esophagus', 'Disease', (130, 139))	('Cytochrome P450', 'Gene', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
87326	19737949	Seven miRNAs were potentially important in the progression from HGD to EAC, and all of them were down-regulated in EAC, including four members of the let-7 miRNA family (hsa-let-7b, hsa-let-7a, hsa-let-7c, hsa-let-7f), hsa-miR-345, hsa-miR-494, and hsa-miR-193a.	('miR', 'Gene', (236, 239))	('miR', 'Gene', (253, 256))	('hsa-miR-494', 'Gene', '574452', (232, 243))	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('hsa-miR-345', 'Gene', (219, 230))	('EAC', 'Disease', (115, 118))	('hsa-let-7b', 'Gene', '406884', (170, 180))	('miR', 'Gene', (6, 9))	('down-regulated', 'NegReg', (97, 111))	('miR', 'Gene', (156, 159))	('miR-193a', 'Gene', (253, 261))	('miR-193a', 'Gene', '406968', (253, 261))	('hsa-let-7c', 'Gene', (194, 204))	('hsa-let-7c', 'Gene', '406885', (194, 204))	('miR', 'Gene', '220972', (223, 226))	('EAC', 'Phenotype', 'HP:0011459', (115, 118))	('miR', 'Gene', '220972', (253, 256))	('miR', 'Gene', '220972', (236, 239))	('hsa-let-7b', 'Gene', (170, 180))	('hsa-miR-345', 'Gene', '442910', (219, 230))	('miR', 'Gene', '220972', (6, 9))	('hsa-let-7f', 'Var', (206, 216))	('miR', 'Gene', (223, 226))	('hsa-miR-494', 'Gene', (232, 243))	('miR', 'Gene', '220972', (156, 159))
87420	33276430	Among the 36 SCC, 7/36 (19%) tumors were poorly differentiated; LVI was observed in 9/36 (25%) tumors; the depth of tumor invasion was T1am3 in 7/36 (19%) tumors, superficial submucosal invasion (<200 microm) in 4/36 (11%) tumors, and deep submucosal invasion (>200 microm) in 25/36 (70%) tumors.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('T1a', 'Gene', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumors', 'Disease', (223, 229))	('<200 microm', 'Var', (196, 207))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('deep submucosal invasion', 'CPA', (235, 259))	('tumor', 'Disease', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Disease', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', (223, 228))	('SCC', 'Phenotype', 'HP:0002860', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('tumors', 'Disease', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Disease', (95, 100))	('SCC', 'Gene', '6317', (13, 16))	('T1a', 'Gene', '10630', (135, 138))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', (289, 295))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('SCC', 'Gene', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
87428	33276430	Among these patients, five had poorly differentiated tumors; LVI was observed in eight patients; and the depth of tumor invasion in SCC was: T1a m3 in one patient, superficial submucosal invasion (<200 microm) in three patients, and deep submucosal invasion (>200 microm) in 22 patients.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('SCC', 'Gene', (132, 135))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('patients', 'Species', '9606', (12, 20))	('deep submucosal invasion', 'CPA', (233, 257))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (114, 119))	('patient', 'Species', '9606', (87, 94))	('patient', 'Species', '9606', (278, 285))	('patients', 'Species', '9606', (219, 227))	('tumors', 'Disease', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('patient', 'Species', '9606', (219, 226))	('patient', 'Species', '9606', (155, 162))	('SCC', 'Phenotype', 'HP:0002860', (132, 135))	('patient', 'Species', '9606', (12, 19))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('T1a', 'Gene', '10630', (141, 144))	('SCC', 'Gene', '6317', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (53, 58))	('patients', 'Species', '9606', (278, 286))	('<200 microm', 'Var', (197, 208))	('patients', 'Species', '9606', (87, 95))	('T1a', 'Gene', (141, 144))
87441	33276430	Most importantly, esophagectomy with lymphadenectomy does not prevent late tumor recurrences, and 5-year survival after esophagectomy for T1N1 esophageal cancer does not exceed 40%.	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('late tumor', 'Disease', (70, 80))	('T1N1', 'Var', (138, 142))	('late tumor', 'Disease', 'MESH:D009369', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('esophageal cancer', 'Disease', (143, 160))
87454	33276430	In this study, the 5-year CSS was 98 and 85.7% for T1a m3 and T1b sm respectively.	('T1b', 'Var', (62, 65))	('T1a', 'Gene', '10630', (51, 54))	('T1a', 'Gene', (51, 54))
87476	32372150	In esophageal cancer patients with curative treatment intention, we observed a higher hazard for death among patients who received carboplatin-fluorouracil compared to patients who received cisplatin-fluorouracil, corresponding to a HR of 2.18 (95% CI 1.09-4.37).	('fluorouracil', 'Chemical', 'MESH:D005472', (200, 212))	('men', 'Species', '9606', (49, 52))	('patients', 'Species', '9606', (109, 117))	('esophageal cancer', 'Disease', (3, 20))	('carboplatin', 'Chemical', 'MESH:D016190', (131, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('death', 'Disease', 'MESH:D003643', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (190, 199))	('patients', 'Species', '9606', (21, 29))	('fluorouracil', 'Chemical', 'MESH:D005472', (143, 155))	('patients', 'Species', '9606', (168, 176))	('carboplatin-fluorouracil', 'Var', (131, 155))	('death', 'Disease', (97, 102))
87477	32372150	Conversely, in patients with cancer in the gastroesophageal junction who had a curative treatment intention at diagnosis, we observed a reduced hazard for death among those who received fluorouracil-oxaliplatin, compared to patients who received cisplatin-fluorouracil (HR 0.28; 95% CI 0.08-0.96).	('fluorouracil', 'Chemical', 'MESH:D005472', (186, 198))	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (15, 23))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (199, 210))	('men', 'Species', '9606', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('fluorouracil', 'Chemical', 'MESH:D005472', (256, 268))	('reduced', 'NegReg', (136, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (246, 255))	('death', 'Disease', 'MESH:D003643', (155, 160))	('patients', 'Species', '9606', (224, 232))	('death', 'Disease', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('fluorouracil-oxaliplatin', 'Var', (186, 210))
87478	32372150	Among patients with esophageal cancer who received treatment with curative intention, cisplatin-fluorouracil was associated with better survival compared to carboplatin-fluorouracil, while patients with gastroesophageal junction cancer who were treated with cisplatin-fluorouracil had worse survival compared to fluorouracil-oxaliplatin.	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('fluorouracil', 'Chemical', 'MESH:D005472', (312, 324))	('fluorouracil', 'Chemical', 'MESH:D005472', (96, 108))	('patients', 'Species', '9606', (6, 14))	('gastroesophageal junction cancer', 'Disease', (203, 235))	('patients', 'Species', '9606', (189, 197))	('cisplatin-fluorouracil', 'Var', (86, 108))	('esophageal cancer', 'Disease', (20, 37))	('fluorouracil', 'Chemical', 'MESH:D005472', (169, 181))	('better', 'PosReg', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('men', 'Species', '9606', (56, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('gastroesophageal junction cancer', 'Disease', 'MESH:D009369', (203, 235))	('fluorouracil', 'Chemical', 'MESH:D005472', (268, 280))	('cisplatin', 'Chemical', 'MESH:D002945', (258, 267))	('carboplatin', 'Chemical', 'MESH:D016190', (157, 168))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (325, 336))
87507	32372150	We adjusted for potential confounding factors such as age (continuous), sex (men/women), and tumor stage (T1 + 2/T3 + 4, missing/N-/N+, missing/M-/M+) in a minimally adjusted model and added radiotherapy (unknown or missing/yes), comorbidity (0/1-5), marital status (missing/married/unmarried or divorced or widowed), education (missing/high and medium level/low level), income (missing/below median/equal to or above median), and country of birth (Sweden/other) in the fully adjusted model.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('women', 'Species', '9606', (81, 86))	('men', 'Species', '9606', (83, 86))	('missing/M-/M+', 'Var', (136, 149))	('tumor', 'Disease', (93, 98))	('missing/high', 'Var', (329, 341))	('men', 'Species', '9606', (77, 80))	('T1 + 2/T3 + 4', 'Gene', '923', (106, 119))	('missing/N-/N+', 'Var', (121, 134))	('T1 + 2/T3 + 4', 'Gene', (106, 119))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
87526	32372150	In the fully adjusted Cox regression model for the curative group, we could demonstrate a higher HR for death of 2.18 (95% CI 1.09-4.37) for patients with cancer in the esophagus who received carboplatin-fluorouracil compared to the reference group (cisplatin-fluorouracil).	('fluorouracil', 'Chemical', 'MESH:D005472', (204, 216))	('carboplatin-fluorouracil', 'Var', (192, 216))	('carboplatin', 'Chemical', 'MESH:D016190', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('patients', 'Species', '9606', (141, 149))	('fluorouracil', 'Chemical', 'MESH:D005472', (260, 272))	('Cox', 'Gene', '1351', (22, 25))	('death', 'Disease', 'MESH:D003643', (104, 109))	('death', 'Disease', (104, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (250, 259))	('Cox', 'Gene', (22, 25))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
87579	32372150	We conclude that esophageal cancer patients who received carboplatin-fluorouracil had a twofold higher HR for death compared to patients treated with cisplatin-fluorouracil in Stockholm/Gotland 2008-2013.	('carboplatin-fluorouracil', 'Var', (57, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('fluorouracil', 'Chemical', 'MESH:D005472', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('esophageal cancer', 'Disease', (17, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (17, 34))	('death', 'Disease', 'MESH:D003643', (110, 115))	('carboplatin', 'Chemical', 'MESH:D016190', (57, 68))	('death', 'Disease', (110, 115))	('patients', 'Species', '9606', (128, 136))	('higher', 'PosReg', (96, 102))	('fluorouracil', 'Chemical', 'MESH:D005472', (69, 81))	('patients', 'Species', '9606', (35, 43))
87580	32372150	Moreover, patients with cancer in the gastroesophageal junction treated with fluorouracil-oxaliplatin had a reduced HR for death compared to patients treated with cisplatin-fluorouracil.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (90, 101))	('reduced', 'NegReg', (108, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('fluorouracil', 'Chemical', 'MESH:D005472', (173, 185))	('fluorouracil', 'Chemical', 'MESH:D005472', (77, 89))	('death', 'Disease', 'MESH:D003643', (123, 128))	('death', 'Disease', (123, 128))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (141, 149))	('fluorouracil-oxaliplatin', 'Var', (77, 101))
87604	30841855	In addition, APC gene mutation leads to familiar adenomatous polyposis (FAP), a disease with hundreds of colorectal adenomas with obligatory progression to carcinoma even at a young age.	('carcinoma', 'Disease', 'MESH:D002277', (156, 165))	('mutation', 'Var', (22, 30))	('APC', 'Gene', (13, 16))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (49, 70))	('FAP', 'Disease', (72, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('leads to', 'Reg', (31, 39))	('APC', 'Gene', '324', (13, 16))	('carcinoma', 'Disease', (156, 165))	('colorectal adenomas', 'Disease', (105, 124))	('FAP', 'Disease', 'MESH:C567782', (72, 75))	('colorectal adenomas', 'Disease', 'MESH:D015179', (105, 124))	('adenomatous polyposis', 'Disease', (49, 70))	('APC', 'Phenotype', 'HP:0005227', (13, 16))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (49, 70))
87605	30841855	Hepatocellular carcinoma (HCC), hepatoblastoma and hepatocellular adenoma often show mutations of beta-catenin.	('hepatocellular adenoma', 'Disease', 'MESH:D018248', (51, 73))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (0, 24))	('HCC', 'Gene', '619501', (26, 29))	('hepatocellular adenoma', 'Disease', (51, 73))	('hepatoblastoma', 'Disease', 'MESH:D018197', (32, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('HCC', 'Phenotype', 'HP:0001402', (26, 29))	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (51, 73))	('mutations', 'Var', (85, 94))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (32, 46))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('beta-catenin', 'Gene', (98, 110))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))	('hepatoblastoma', 'Disease', (32, 46))	('beta-catenin', 'Gene', '1499', (98, 110))	('HCC', 'Gene', (26, 29))
87606	30841855	Overall, hepatocellular adenomas with beta-catenin mutation have a higher risk of malignant transformation.	('beta-catenin', 'Gene', (38, 50))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (9, 32))	('beta-catenin', 'Gene', '1499', (38, 50))	('hepatocellular adenomas', 'Disease', (9, 32))	('mutation', 'Var', (51, 59))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (9, 32))	('malignant transformation', 'CPA', (82, 106))	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (9, 31))
87607	30841855	AXIN1 gene mutation leads to inhibition of the degradation complex with resulting beta-catenin accumulation.	('beta-catenin', 'Gene', '1499', (82, 94))	('inhibition', 'NegReg', (29, 39))	('degradation complex', 'MPA', (47, 66))	('mutation', 'Var', (11, 19))	('beta-catenin', 'Gene', (82, 94))	('AXIN1', 'Gene', '8312', (0, 5))	('AXIN1', 'Gene', (0, 5))
87629	30841855	Originating from esophageal adenocarcinomas, OE33 (ECACC-96070808) and OE19 (ECACC-96071721), cells were acquired from Sigma-Aldrich (Taufkirchen, Germany).	('esophageal adenocarcinomas', 'Disease', (17, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (17, 43))	('ECACC-96071721', 'Var', (77, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (17, 42))
87648	30841855	Diluted 1:50 in 1% BSA in PBS, the monoclonal primary antibody against WNT3A (AM09053PU-N, OriGene Technologies GmbH, Herford, Germany) was incubated over night at 4  C. Detecting bound antibody, a biotin-SP conjugated goat anti-mouse (Jackson Immuno Research, Suffolk, UK) and a peroxidase conjugated Streptavidin (Jackson Immuno Research, Suffolk, UK), both diluted 1:1000 in 1% BSA in PBS, were utilized for 1 h at room temperature.	('AM09053PU-N', 'Var', (78, 89))	('WNT3A', 'Gene', (71, 76))	('goat', 'Species', '9925', (219, 223))	('mouse', 'Species', '10090', (229, 234))	('PBS', 'Gene', (26, 29))	('PBS', 'Gene', '1131', (26, 29))	('PBS', 'Gene', (388, 391))	('PBS', 'Gene', '1131', (388, 391))	('WNT3A', 'Gene', '89780', (71, 76))
87684	30841855	Only OE33 showed significant increased levels of Axin2 expression levels compared to controls.	('Axin2', 'Gene', (49, 54))	('OE33', 'Var', (5, 9))	('Axin2', 'Gene', '8313', (49, 54))	('levels', 'MPA', (39, 45))	('increased', 'PosReg', (29, 38))
87689	30841855	Only OE33 responded with an increased phosphorylation of beta-catenin (Fig.	('increased', 'PosReg', (28, 37))	('OE33', 'Var', (5, 9))	('phosphorylation', 'MPA', (38, 53))	('beta-catenin', 'Gene', (57, 69))	('beta-catenin', 'Gene', '1499', (57, 69))
87698	30841855	Aberrations in Wnt-signaling had been observed in many malignancies, including colon cancer, hepatocellular carcinomas, non-small cell lung cancer, and esophageal adenocarcinoma.	('colon cancer', 'Disease', (79, 91))	('esophageal adenocarcinoma', 'Disease', (152, 177))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (124, 146))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (120, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('malignancies', 'Disease', 'MESH:D009369', (55, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('non-small cell lung cancer', 'Disease', (120, 146))	('malignancies', 'Disease', (55, 67))	('observed', 'Reg', (38, 46))	('Aberrations', 'Var', (0, 11))	('Wnt-signaling', 'Pathway', (15, 28))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (93, 118))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (120, 146))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (152, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (93, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (152, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('hepatocellular carcinomas', 'Disease', (93, 118))
87709	30841855	The intracellular Wnt-signaling is mediated via GSK3beta phosphorylation, which leads to a cytoplasmic accumulation of beta-catenin.	('beta-catenin', 'Gene', '1499', (119, 131))	('GSK3beta', 'Gene', '2932', (48, 56))	('phosphorylation', 'Var', (57, 72))	('cytoplasmic accumulation', 'MPA', (91, 115))	('leads to', 'Reg', (80, 88))	('beta-catenin', 'Gene', (119, 131))	('GSK3beta', 'Gene', (48, 56))
87711	30841855	4d), whereas phosphorylation of beta-catenin at Ser552 was decreased in the more advanced cell lines CP-B, OE33 and OE19 (Fig.	('phosphorylation', 'MPA', (13, 28))	('decreased', 'NegReg', (59, 68))	('beta-catenin', 'Gene', (32, 44))	('beta-catenin', 'Gene', '1499', (32, 44))	('CP-B', 'Gene', '1360', (101, 105))	('Ser552', 'Chemical', '-', (48, 54))	('CP-B', 'Gene', (101, 105))	('Ser552', 'Var', (48, 54))
87725	30841855	However, loss-of-function or epigenetic alterations have not been described for beta-catenin or APC, so far.	('epigenetic alterations', 'Var', (29, 51))	('APC', 'Phenotype', 'HP:0005227', (96, 99))	('APC', 'Gene', (96, 99))	('beta-catenin', 'Gene', (80, 92))	('beta-catenin', 'Gene', '1499', (80, 92))	('APC', 'Gene', '324', (96, 99))	('loss-of-function', 'NegReg', (9, 25))
87735	30419865	The purpose of this study was to assess the prevalence and clinical significance of altered RBM3 expression in esophageal cancer.	('esophageal cancer', 'Disease', (111, 128))	('altered', 'Var', (84, 91))	('RBM3', 'Gene', '5935', (92, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('expression', 'MPA', (97, 107))	('RBM3', 'Gene', (92, 96))
87751	30419865	Using immunohistochemistry, dysregulated RBM3 expression has been suggested as prognostic biomarker in several cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('RBM3', 'Gene', '5935', (41, 45))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('dysregulated', 'Var', (28, 40))	('RBM3', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))
87764	30419865	For statistical analyses, the staining results were categorized in two groups: low and high RBM3 immunostaining.	('high', 'Var', (87, 91))	('RBM3', 'Gene', '5935', (92, 96))	('RBM3', 'Gene', (92, 96))
87772	30419865	Figure 1 shows representative pictures of RBM3 immunostaining in esophageal cancers and benign squamous esophageal tissue.	('RBM3', 'Gene', '5935', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('benign squamous esophageal', 'Disease', 'MESH:D000077277', (88, 114))	('RBM3', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('esophageal cancers', 'Disease', (65, 83))	('benign squamous esophageal', 'Disease', (88, 114))	('esophageal cancers', 'Disease', 'MESH:D004938', (65, 83))	('immunostaining', 'Var', (47, 61))
87779	30419865	The data from this study show, that altered RBM3 expression - a strong prognostic feature in several cancer types - is statistically linked to adverse tumor features in oesophageal cancer but does not have an obvious impact on clinical outcome.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('adverse tumor', 'Disease', (143, 156))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('adverse tumor', 'Disease', 'MESH:D064420', (143, 156))	('cancer', 'Disease', (101, 107))	('oesophageal cancer', 'Disease', 'MESH:D009369', (169, 187))	('expression', 'MPA', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('RBM3', 'Gene', '5935', (44, 48))	('oesophageal cancer', 'Disease', (169, 187))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('altered', 'Var', (36, 43))	('cancer', 'Disease', (181, 187))	('linked', 'Reg', (133, 139))	('RBM3', 'Gene', (44, 48))
87804	30419865	In general, the pathogenesis of esophageal carcinoma is highly complex, involving an accumulation of genetic modifications resulting in invasive carcinoma.	('resulting in', 'Reg', (123, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (32, 52))	('invasive carcinoma', 'Disease', 'MESH:D009361', (136, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('esophageal carcinoma', 'Disease', (32, 52))	('modifications', 'Var', (109, 122))	('invasive carcinoma', 'Disease', (136, 154))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (32, 52))
87805	30419865	Genetic mutations within the tumour suppressor gene, TP53, which is involved in DNA repair and cell cycle arrest, is one of the most frequently genetic abnormalities in cancers.	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('tumour', 'Disease', (29, 35))	('cancers', 'Disease', (169, 176))	('genetic abnormalities', 'Disease', 'MESH:D030342', (144, 165))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('genetic abnormalities', 'Disease', (144, 165))	('TP53', 'Gene', '7157', (53, 57))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('Genetic mutations', 'Var', (0, 17))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('TP53', 'Gene', (53, 57))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
87827	27525243	The pathology of the lesion indicated T2N0M0 squamous cell carcinoma, and no adjuvant treatment was applied.	('T2N0M0', 'Var', (38, 44))	('squamous cell carcinoma', 'Disease', (45, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))
87850	25212528	Induction chemoradiation therapy prior to esophagectomy is associated with superior long-term survival for esophageal cancer The purpose of this study was to examine the role of induction chemoradiation in the treatment of potentially-resectable locally advanced (T2-3N0 and T1-3N+) esophageal cancer utilizing a large national database.	('T2-3N0', 'Var', (264, 270))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', (283, 300))	('T1-3N+', 'Var', (275, 281))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (283, 300))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
87851	25212528	The National Cancer Data Base (NCDB) was queried for all patients undergoing esophagectomy for clinical T2-3N0 and T1-3N+ esophageal cancer of the mid- or lower-esophagus.	('esophageal cancer', 'Disease', (122, 139))	('T2-3N0', 'Var', (104, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('Cancer', 'Disease', (13, 19))	('patients', 'Species', '9606', (57, 65))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('T1-3N+', 'Var', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
87857	25212528	The purpose of this study was to supplement the available evidence that guides esophageal cancer treatment by utilizing a large national cancer database to examine the role of induction chemoradiation in the treatment of potentially resectable locally advanced (clinical T2-3N0 and T1-3N+) esophageal cancer, among whom induction therapy is recommended as an appropriate option by NCCN guidelines.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('cancer', 'Disease', (301, 307))	('T1-3N+', 'Var', (282, 288))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('esophageal cancer', 'Disease', (290, 307))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (290, 307))
87876	25212528	Of a total of 93,164 patients with mid- or lower-third esophageal cancer in the NCDB, there were 16,601 patients who met study criteria based on having clinical stage of T2-3N0 or cT1-3N+ adenocarcinoma or squamous cell carcinoa.	('squamous cell carcinoa', 'Phenotype', 'HP:0002860', (206, 228))	('cT1', 'Gene', (180, 183))	('adenocarcinoma', 'Disease', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('T2-3N0', 'Var', (170, 176))	('esophageal cancer', 'Disease', (55, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (188, 202))	('squamous cell carcinoa', 'Disease', 'MESH:D002294', (206, 228))	('patients', 'Species', '9606', (21, 29))	('squamous cell carcinoa', 'Disease', (206, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('cT1', 'Gene', '1489', (180, 183))	('patients', 'Species', '9606', (104, 112))
87886	25212528	Patients in the induction therapy group were much more likely to be ypT0, ypN0 and overall ypStage 0 compared to their surgery-first counterparts.	('ypT0', 'Disease', (68, 72))	('ypN0', 'Var', (74, 78))	('ypStage 0', 'Var', (91, 100))	('Patients', 'Species', '9606', (0, 8))
87970	32705312	In one study, patients with LSM > 4.44 kPa had a higher incidence of HCC occurrence (36.4% vs. 9.5%) than patients with LSM < 4.44 kPa.	('HCC occurrence', 'Disease', (69, 83))	('LSM > 4.44 kPa', 'Var', (28, 42))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (14, 22))	('HCC', 'Phenotype', 'HP:0001402', (69, 72))
87978	32705312	For practical purposes, a high LSM, particularly > 5 kPa, is associated with increased risk of portal hypertension and esophageal varices.	('hypertension', 'Disease', 'MESH:D006973', (102, 114))	('hypertension', 'Disease', (102, 114))	('hypertension', 'Phenotype', 'HP:0000822', (102, 114))	('esophageal varices', 'Phenotype', 'HP:0002040', (119, 137))	('portal hypertension', 'Phenotype', 'HP:0001409', (95, 114))	('> 5 kPa', 'Var', (49, 56))	('esophageal varices', 'Disease', (119, 137))
87989	32705312	In a study comparing 2D-MRE and clinical prediction rules for NAFLD for diagnosing advanced fibrosis, it was shown that 2D-MRE had significantly better AUROC versus clinical prediction rules.	('fibrosis', 'Disease', 'MESH:D005355', (92, 100))	('fibrosis', 'Disease', (92, 100))	('AUROC', 'MPA', (152, 157))	('2D-MRE', 'Var', (120, 126))	('better', 'PosReg', (145, 151))
88009	32705312	A pooled meta-analysis showed equivalent performance of SE-EPIMRE and 2D-GREMRE for detection and staging of liver fibrosis.	('liver fibrosis', 'Disease', (109, 123))	('liver fibrosis', 'Disease', 'MESH:D008103', (109, 123))	('SE-EPI', 'Chemical', '-', (56, 62))	('liver fibrosis', 'Phenotype', 'HP:0001395', (109, 123))	('SE-EPIMRE', 'Var', (56, 65))
88035	32705312	showed that mean LSM was higher in patients with malignant nodules compared to those with benign nodules.	('LSM', 'MPA', (17, 20))	('patients', 'Species', '9606', (35, 43))	('malignant nodules', 'Var', (49, 66))	('higher', 'PosReg', (25, 31))
88038	32705312	A LSM > 5 kPa is associated with bridging fibrosis and cirrhosis.	('cirrhosis', 'Disease', 'MESH:D005355', (55, 64))	('associated', 'Reg', (17, 27))	('cirrhosis', 'Disease', (55, 64))	('fibrosis', 'Disease', 'MESH:D005355', (42, 50))	('fibrosis', 'Disease', (42, 50))	('LSM > 5 kPa', 'Var', (2, 13))	('cirrhosis', 'Phenotype', 'HP:0001394', (55, 64))
88064	33363149	In the present study, we found that the poor outcome of ESCC patients receiving platinum-based regimens was associated with co-expression of Shh and Sox2.	('ESCC', 'Disease', (56, 60))	('Sox2', 'Gene', '6657', (149, 153))	('Shh', 'Gene', '6469', (141, 144))	('platinum', 'Chemical', 'MESH:D010984', (80, 88))	('patients', 'Species', '9606', (61, 69))	('Sox2', 'Gene', (149, 153))	('co-expression', 'Var', (124, 137))	('Shh', 'Gene', (141, 144))
88066	33363149	Manipulating of Shh expression markedly changed the sensitivity of ESCC cells to platinum.	('Shh', 'Gene', (16, 19))	('Manipulating', 'Var', (0, 12))	('platinum', 'Chemical', 'MESH:D010984', (81, 89))	('sensitivity', 'MPA', (52, 63))	('changed', 'Reg', (40, 47))	('Shh', 'Gene', '6469', (16, 19))
88086	33363149	DHA exerts anti-tumor effects in a multi-specific manner, in which it inhibits important tumor-related signaling pathways, such as Wnt/beta-catenin, AMPK, PI3K/AKT, and so on.	('AMPK', 'Gene', (149, 153))	('DHA', 'Var', (0, 3))	('AMPK', 'Gene', '5564', (149, 153))	('AKT', 'Gene', '207', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('beta-catenin', 'Gene', (135, 147))	('inhibits', 'NegReg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('beta-catenin', 'Gene', '1499', (135, 147))	('tumor', 'Disease', (16, 21))	('AKT', 'Gene', (160, 163))	('DHA', 'Chemical', 'MESH:C039060', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
88162	33363149	These results indicate that continuous exposure of ESCC cells to cisplatin lead to the activation of Shh signaling and the accumulation of ESCC stem cells.	('accumulation', 'PosReg', (123, 135))	('activation', 'PosReg', (87, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('Shh', 'Gene', (101, 104))	('ESCC stem cells', 'CPA', (139, 154))	('Shh', 'Gene', '6469', (101, 104))	('cisplatin', 'Var', (65, 74))
88164	33363149	We treated TE-1 cells with DHA and found that it significantly inhibited nuclear translocation of Gli1 (Figure 4B) and downregulated the transcription of the Shh target genes PTCH1 and MDR1 (Figure 4C).	('PTCH1', 'Gene', (175, 180))	('nuclear translocation', 'MPA', (73, 94))	('DHA', 'Var', (27, 30))	('downregulated', 'NegReg', (119, 132))	('TE-1', 'CellLine', 'CVCL:1759', (11, 15))	('Shh', 'Gene', (158, 161))	('MDR1', 'Gene', (185, 189))	('PTCH1', 'Gene', '5727', (175, 180))	('inhibited', 'NegReg', (63, 72))	('MDR1', 'Gene', '5243', (185, 189))	('DHA', 'Chemical', 'MESH:C039060', (27, 30))	('Gli1', 'Gene', (98, 102))	('Shh', 'Gene', '6469', (158, 161))	('Gli1', 'Gene', '2735', (98, 102))	('transcription', 'MPA', (137, 150))
88198	33363149	As shown in Figure 7A, cisplatin or DHA single administration resulted in a moderate inhibition of tumor growth, with inhibition rates of 56.8 and 43.6%, respectively.	('tumor', 'Disease', (99, 104))	('DHA', 'Chemical', 'MESH:C039060', (36, 39))	('cisplatin', 'Var', (23, 32))	('inhibition', 'NegReg', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
88200	33363149	Additionally, the gross toxicity data showed that cisplatin group had a significant decrease in the body weights of the mice, whereas DHA group had not, as compared to control group.	('decrease', 'NegReg', (84, 92))	('mice', 'Species', '10090', (120, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('toxicity', 'Disease', 'MESH:D064420', (24, 32))	('toxicity', 'Disease', (24, 32))	('body weights', 'CPA', (100, 112))	('DHA', 'Chemical', 'MESH:C039060', (134, 137))	('cisplatin', 'Var', (50, 59))
88208	33363149	However, accumulating evidence now suggests that malignant cells continuously exposed to cisplatin will activate adaptive responses that render them less susceptible to the antiproliferative and cytotoxic effects of the drug, and will eventually resume proliferation.	('resume', 'PosReg', (246, 252))	('less', 'NegReg', (149, 153))	('adaptive responses', 'CPA', (113, 131))	('cisplatin', 'Var', (89, 98))	('activate', 'PosReg', (104, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))
88213	33363149	Interestingly, continuous treatment of ESCC cells with cisplatin also resulted in the activation of Shh signaling along with the enhanced cancer stem cell property.	('enhanced', 'PosReg', (129, 137))	('cancer', 'Disease', (138, 144))	('Shh', 'Gene', '6469', (100, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Shh', 'Gene', (100, 103))	('activation', 'PosReg', (86, 96))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cisplatin', 'Var', (55, 64))
88217	33363149	reported that IGF signaling, together with the MAPK or PI3K/AKT signaling pathways, was activated in cisplatin-resistant ESCC patients, and inhibition of the IGF or/and MAPK and PI3K/AKT signaling pathways could sensitize ESCC cells to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('inhibition', 'Var', (140, 150))	('activated', 'PosReg', (88, 97))	('AKT', 'Gene', (183, 186))	('ESCC', 'Disease', (222, 226))	('AKT', 'Gene', '207', (60, 63))	('IGF signaling', 'Pathway', (14, 27))	('MAPK', 'Pathway', (47, 51))	('patients', 'Species', '9606', (126, 134))	('AKT', 'Gene', (60, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (236, 245))	('ESCC', 'Disease', (121, 125))	('AKT', 'Gene', '207', (183, 186))
88218	33363149	Based on clinical pathological and in vitro data, demonstrated that the interleukin-6/STAT3 prosurvival pathway was activated in ESCC cells by cisplatin treatment, and inhibition of that feedback pathway by let-7c restored sensitivity to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('STAT3', 'Gene', (86, 91))	('sensitivity', 'MPA', (223, 234))	('activated', 'PosReg', (116, 125))	('let-7c', 'Gene', (207, 213))	('cisplatin', 'Chemical', 'MESH:D002945', (238, 247))	('inhibition', 'Var', (168, 178))	('interleukin-6', 'Gene', (72, 85))	('let-7c', 'Gene', '406885', (207, 213))	('interleukin-6', 'Gene', '3569', (72, 85))	('restored', 'PosReg', (214, 222))	('STAT3', 'Gene', '6774', (86, 91))
88219	33363149	Here, we found for the first time that the Shh signaling pathway was activated in cells continuously exposed to cisplatin compared to the parental cells, and this activation resulted in an enhanced migratory capability and cancer stem cell characteristics, which suggests a novel biological role of the Shh signaling pathway in cisplatin resistance.	('cisplatin', 'Chemical', 'MESH:D002945', (328, 337))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cisplatin', 'Var', (112, 121))	('enhanced', 'PosReg', (189, 197))	('Shh', 'Gene', (43, 46))	('Shh', 'Gene', '6469', (43, 46))	('Shh', 'Gene', '6469', (303, 306))	('migratory capability', 'CPA', (198, 218))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('activated', 'PosReg', (69, 78))	('cancer', 'Disease', (223, 229))	('Shh', 'Gene', (303, 306))
88230	33363149	Our results indicated that DHA inhibits the nuclear translocation of Gli1, one of the key transcription factors in the Shh signaling pathway, and suppresses the transcription of PTCH and MDR1 which are target genes of the Shh pathway.	('suppresses', 'NegReg', (146, 156))	('MDR1', 'Gene', '5243', (187, 191))	('Shh', 'Gene', '6469', (119, 122))	('transcription', 'MPA', (161, 174))	('Gli1', 'Gene', (69, 73))	('inhibits', 'NegReg', (31, 39))	('DHA', 'Var', (27, 30))	('Shh', 'Gene', (222, 225))	('Shh', 'Gene', (119, 122))	('Gli1', 'Gene', '2735', (69, 73))	('PTCH', 'Gene', '5727', (178, 182))	('PTCH', 'Gene', (178, 182))	('MDR1', 'Gene', (187, 191))	('DHA', 'Chemical', 'MESH:C039060', (27, 30))	('Shh', 'Gene', '6469', (222, 225))	('nuclear translocation', 'MPA', (44, 65))
88233	33363149	Consistent with the Shh activity data, our functional studies also indicated that DHA reduced the expression level of cancer stem cell transcription factors and inhibited ALDH activity, which is recognized as an ESCC stem cell marker.	('DHA', 'Var', (82, 85))	('cancer', 'Disease', (118, 124))	('reduced', 'NegReg', (86, 93))	('Shh', 'Gene', '6469', (20, 23))	('inhibited', 'NegReg', (161, 170))	('ALDH', 'Protein', (171, 175))	('activity', 'MPA', (176, 184))	('DHA', 'Chemical', 'MESH:C039060', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Shh', 'Gene', (20, 23))	('expression level', 'MPA', (98, 114))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
88316	32808454	The oral cavity is adjacent to the esophagus, and the changes in it may predict lesions of the upper digestive tract to some extent, which may explain why OL could increase the risk of esophageal cancer deaths.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('esophageal cancer deaths', 'Disease', (185, 209))	('changes', 'Var', (54, 61))	('esophageal cancer deaths', 'Disease', 'MESH:D004938', (185, 209))	('OL', 'Phenotype', 'HP:0002745', (155, 157))	('lesions', 'Disease', (80, 87))	('increase', 'PosReg', (164, 172))
88326	32808454	A relationship between low SES and increased risk of cancer has been reported in previous studies.	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('low SES', 'Var', (23, 30))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))
88390	31358543	However, in the training cohort, high intratumoral F. nucleatum levels were associated with higher T category (p=0.03) and in patients who received preoperative treatment (p=0.03).	('high', 'Var', (33, 37))	('higher', 'PosReg', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('F. nucleatum', 'Species', '851', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('patients', 'Species', '9606', (126, 134))	('T category', 'MPA', (99, 109))	('tumor', 'Disease', (43, 48))
88391	31358543	Similarly, high levels of intratumoral F. nucleatum were significantly associated with larger tumor size (p=0.004), higher T category (p<0.001), higher TNM stage (p=0.03), and in patients who underwent preoperative treatment (p=0.01) in the validation cohort (Table 1).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('larger', 'PosReg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('higher', 'PosReg', (116, 122))	('T category', 'CPA', (123, 133))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (94, 99))	('patients', 'Species', '9606', (179, 187))	('high', 'Var', (11, 15))	('F. nucleatum', 'Species', '851', (39, 51))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('higher', 'PosReg', (145, 151))	('TNM stage', 'CPA', (152, 161))
88393	31358543	Considering that presence of F. nucleatum in cancer cells is associated with advanced disease, we were curious to interrogate its relationship with tumor recurrence in ESCC patients.	('advanced disease', 'Disease', (77, 93))	('F. nucleatum', 'Species', '851', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('patients', 'Species', '9606', (173, 181))	('tumor', 'Disease', (148, 153))	('associated', 'Reg', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('presence', 'Var', (17, 25))	('cancer', 'Disease', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
88449	31358543	reported that F. nucleatum activates autophagy-related pathways in colorectal cancer through modulation of TLR4 and MYD88 innate signaling, along with certain miRNAs which subsequently promote chemoresistance.	('activates', 'PosReg', (27, 36))	('chemoresistance', 'CPA', (193, 208))	('autophagy-related', 'CPA', (37, 54))	('modulation', 'Var', (93, 103))	('TLR4', 'Gene', (107, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('F. nucleatum', 'Species', '851', (14, 26))	('promote', 'PosReg', (185, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('MYD88', 'Gene', (116, 121))	('colorectal cancer', 'Disease', (67, 84))
88479	31289565	Abnormalities in histone lysine methylation are frequently observed in various cancers.	('cancers', 'Disease', (79, 86))	('Abnormalities', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('histone', 'Protein', (17, 24))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('observed', 'Reg', (59, 67))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('lysine', 'Chemical', 'MESH:D008239', (25, 31))
88482	31289565	In the present study, we focused on the mechanisms underlying how demethylated Lys4 of H3 influences the gene expressions in ESCC cells.	('demethylated Lys4', 'Var', (66, 83))	('influences', 'Reg', (90, 100))	('gene expressions', 'MPA', (105, 121))	('Lys4', 'Chemical', '-', (79, 83))	('ESCC', 'Disease', (125, 129))
88502	31289565	We used a cDNA microarray to identify genes induced by LSD1 exposure in ESCC.	('LSD1', 'Gene', (55, 59))	('LSD1', 'Gene', '23028', (55, 59))	('ESCC', 'Disease', (72, 76))	('exposure', 'Var', (60, 68))
88505	31289565	When we compared the findings with control cells (without LSD1 inhibitor), we identified up-regulated peaks in 468 and 814 demethylated Lys4 of H3-specific modification sites in T.Tn and TE2 cells, respectively (Fig.	('LSD1', 'Gene', (58, 62))	('TE2', 'Gene', (187, 190))	('LSD1', 'Gene', '23028', (58, 62))	('814', 'Var', (119, 122))	('Lys4', 'Chemical', '-', (136, 140))	('468', 'Var', (111, 114))	('demethylated Lys4', 'MPA', (123, 140))	('TE2', 'Gene', '8260', (187, 190))	('up-regulated', 'PosReg', (89, 101))
88506	31289565	We also identified down-regulated peaks in 532 and 612 demethylated Lys4 of H3-specific modification sites in T.Tn and TE2 cells, respectively (Fig.	('Lys4', 'Chemical', '-', (68, 72))	('TE2', 'Gene', '8260', (119, 122))	('532', 'Var', (43, 46))	('H3-specific', 'Gene', (76, 87))	('TE2', 'Gene', (119, 122))	('down-regulated', 'NegReg', (19, 33))
88507	31289565	The expression of some of these genes whose promoters were detected as candidates for targets of demethylated Lys4 of H3 were markedly changed according to the microarray data (Table II).	('Lys4', 'Chemical', '-', (110, 114))	('demethylated Lys4', 'Var', (97, 114))	('expression', 'MPA', (4, 14))	('changed', 'Reg', (135, 142))
88511	31289565	Some LSD1 inhibitors have shown potent anti-cancer effects, and their pharmacological mechanisms have been elucidated.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('LSD1', 'Gene', (5, 9))	('LSD1', 'Gene', '23028', (5, 9))	('inhibitors', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
88512	31289565	ORY-1001 is an LSD1 inhibitor that was shown to selectively inhibit KDM1A in clinical trials and is currently being assessed for its utility in treating patients with leukemia and solid tumors.	('leukemia', 'Disease', 'MESH:D007938', (167, 175))	('leukemia', 'Disease', (167, 175))	('inhibit', 'NegReg', (60, 67))	('patients', 'Species', '9606', (153, 161))	('solid tumors', 'Disease', 'MESH:D009369', (180, 192))	('ORY-1001', 'Chemical', '-', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('KDM1A', 'Gene', '23028', (68, 73))	('LSD1', 'Gene', (15, 19))	('LSD1', 'Gene', '23028', (15, 19))	('solid tumors', 'Disease', (180, 192))	('ORY-1001', 'Var', (0, 8))	('KDM1A', 'Gene', (68, 73))	('leukemia', 'Phenotype', 'HP:0001909', (167, 175))
88518	31289565	Also, the expression of BRAFV 600 E oncoprotein, which has mutations in BRAF that are not sensitive to feedback inhibition, changes the function of DUSP 5 to become an inhibitor of the entire cell of ERK, and that the cell avoids hyperactivation and aging of ERK.	('ERK', 'Gene', '5594', (200, 203))	('function', 'MPA', (136, 144))	('BRAF', 'Gene', (72, 76))	('ERK', 'Gene', '5594', (259, 262))	('ERK', 'Gene', (200, 203))	('ERK', 'Gene', (259, 262))	('BRAF', 'Gene', (24, 28))	('mutations', 'Var', (59, 68))	('DUSP 5', 'Gene', '1847', (148, 154))	('BRAF', 'Gene', '673', (24, 28))	('BRAFV 600 E', 'Mutation', 'rs113488022', (24, 35))	('changes', 'Reg', (124, 131))	('DUSP 5', 'Gene', (148, 154))	('BRAF', 'Gene', '673', (72, 76))
88524	31289565	It is thought that p53 reactivation and mass apoptosis induction (PRIMA-1), a low-molecular compound, restores the function of mutant TP53 to the function of wild-type TP53 and induces p53-mediated apoptosis.	('mutant', 'Var', (127, 133))	('p53', 'Gene', (185, 188))	('p53', 'Gene', '7157', (185, 188))	('TP53', 'Gene', (134, 138))	('TP53', 'Gene', (168, 172))	('PRIMA-1', 'Gene', '145270', (66, 73))	('TP53', 'Gene', '7157', (168, 172))	('restores', 'PosReg', (102, 110))	('induces', 'PosReg', (177, 184))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('PRIMA-1', 'Gene', (66, 73))	('function', 'MPA', (115, 123))	('TP53', 'Gene', '7157', (134, 138))
88527	31289565	Also in ESCC, Furukawa et al reported that PRIMA-1 may restore the function of mutant TP 53 in ESCC with a TP 50 missense mutation, due to the enhanced expression of Noxa.	('Noxa', 'Gene', '5366', (166, 170))	('enhanced', 'PosReg', (143, 151))	('mutant', 'Var', (79, 85))	('TP 53', 'Gene', (86, 91))	('PRIMA-1', 'Gene', (43, 50))	('TP 53', 'Gene', '7157', (86, 91))	('expression', 'MPA', (152, 162))	('PRIMA-1', 'Gene', '145270', (43, 50))	('function', 'MPA', (67, 75))	('Noxa', 'Gene', (166, 170))
88538	31289565	Conversely, it has been found that in oral squamous cell carcinoma, high expression of PHLDA1 is associated with more advanced stage.	('PHLDA1', 'Gene', (87, 93))	('PHLDA1', 'Gene', '22822', (87, 93))	('high', 'Var', (68, 72))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('oral squamous cell carcinoma', 'Disease', (38, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('associated', 'Reg', (97, 107))
88555	31289565	The results in this study suggest that the large number of genes affected by demethylation of H3 in ESCC Lys4 may be greatly implicated in the development of ESCC cancer.	('demethylation', 'Var', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Lys4', 'Chemical', '-', (105, 109))	('ESCC cancer', 'Disease', 'MESH:D004938', (158, 169))	('ESCC cancer', 'Disease', (158, 169))	('ESCC', 'Gene', (100, 104))	('implicated', 'Reg', (125, 135))
88558	30701347	The aim of this prospective study was to evaluate the efficacy of 4DST PET/CT for predicting responses to neoadjuvant therapy in patients with esophageal cancer comparing with FDG PET/CT.	('FDG', 'Gene', (176, 179))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('patients', 'Species', '9606', (129, 137))	('4DST', 'Var', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('esophageal cancer', 'Disease', (143, 160))	('FDG', 'Gene', '23583', (176, 179))
88577	30701347	have reported that 4DST PET shows a higher prognostic value in patients with head and neck carcinoma compared to FDG PET.	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (77, 100))	('4DST PET', 'Var', (19, 27))	('FDG', 'Gene', '23583', (113, 116))	('FDG', 'Gene', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('patients', 'Species', '9606', (63, 71))	('neck carcinoma', 'Disease', 'MESH:D006258', (86, 100))	('neck carcinoma', 'Disease', (86, 100))
88656	30701347	DeltaSUVmax and postSUVmax in 4DST PET can provide great diagnostic value for discriminating responders from non-responders in patients with esophageal cancer.	('postSUVmax', 'Var', (16, 26))	('esophageal cancer', 'Disease', (141, 158))	('DeltaSUVmax', 'MPA', (0, 11))	('patients', 'Species', '9606', (127, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
88665	28665042	We conducted a retrospective analysis to assess the long-term survival and toxicity of esophageal cancer patients treated with ENI versus conventional-field irradiation (CFI).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ENI', 'Chemical', '-', (127, 130))	('patients', 'Species', '9606', (105, 113))	('ENI', 'Var', (127, 130))	('toxicity of esophageal cancer', 'Disease', (75, 104))	('toxicity of esophageal cancer', 'Disease', 'MESH:D004938', (75, 104))	('CFI', 'Chemical', '-', (170, 173))
88669	28665042	For the per-protocol population, the patients in the ENI group significantly improved in terms of their 10-year disease-specific overall survival (43.1% vs 10.5%, P = 0.019), 10-year disease-free survival (36.7% vs 10.2%, P = 0.040) and 10-year local recurrence-free survival (47.2% vs 17.2%, P = 0.018) compared with the CFI group.	('CFI', 'Chemical', '-', (322, 325))	('ENI', 'Var', (53, 56))	('patients', 'Species', '9606', (37, 45))	('local recurrence-free', 'CPA', (245, 266))	('ENI', 'Chemical', '-', (53, 56))	('disease-free survival', 'CPA', (183, 204))	('improved', 'PosReg', (77, 85))
88740	28665042	In the present study, 13 (31.4%) of 51 patients in the ENI group had severe (grade >=3) radiation esophagitis vs 5 (13.2%) of 38 patients in the CFI group (P = 0.035).	('radiation esophagitis', 'Disease', (88, 109))	('esophagitis', 'Phenotype', 'HP:0100633', (98, 109))	('patients', 'Species', '9606', (39, 47))	('patients', 'Species', '9606', (129, 137))	('radiation esophagitis', 'Disease', 'MESH:D004194', (88, 109))	('ENI', 'Chemical', '-', (55, 58))	('CFI', 'Chemical', '-', (145, 148))	('ENI', 'Var', (55, 58))
88741	28665042	Other severe acute toxicities were similar between the ENI group and the CFI group.	('toxicities', 'Disease', 'MESH:D064420', (19, 29))	('ENI', 'Chemical', '-', (55, 58))	('ENI', 'Var', (55, 58))	('CFI', 'Chemical', '-', (73, 76))	('toxicities', 'Disease', (19, 29))
88758	28665042	However, the ENI group had a significantly higher LRFS than the CFI group.	('LRFS', 'CPA', (50, 54))	('ENI', 'Var', (13, 16))	('higher', 'PosReg', (43, 49))	('ENI', 'Chemical', '-', (13, 16))	('CFI', 'Chemical', '-', (64, 67))
88759	28665042	For the per-protocol population, the ENI group significantly improved in regards to 5-year and 10-year disease-specific OS, DFS and LRFS compared with the CFI group.	('improved', 'PosReg', (61, 69))	('LRFS', 'Disease', (132, 136))	('CFI', 'Chemical', '-', (155, 158))	('disease-specific OS', 'Disease', (103, 122))	('DFS', 'Disease', (124, 127))	('ENI', 'Chemical', '-', (37, 40))	('ENI', 'Var', (37, 40))
88760	28665042	These results suggest that ENI improved both disease-specific OS and local-regional control in patients with inoperable esophageal cancer receiving per-protocol treatment.	('improved', 'PosReg', (31, 39))	('local-regional control', 'CPA', (69, 91))	('ENI', 'Chemical', '-', (27, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('ENI', 'Var', (27, 30))	('disease-specific', 'MPA', (45, 61))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('esophageal cancer', 'Disease', (120, 137))
88764	28665042	In our study, ENI was associated with a higher rate of >= grade 3 radiation-induced esophagitis compared with CFI.	('esophagitis', 'Disease', 'MESH:D004941', (84, 95))	('ENI', 'Chemical', '-', (14, 17))	('CFI', 'Chemical', '-', (110, 113))	('ENI', 'Var', (14, 17))	('esophagitis', 'Phenotype', 'HP:0100633', (84, 95))	('esophagitis', 'Disease', (84, 95))
88788	28134308	For chemotherapy regimen during CCRT, cisplatin/5-fluorouracil had significantly more grade 3-4 mucositis/esophagitis and neutropenia than weekly cisplatin.	('esophagitis', 'Phenotype', 'HP:0100633', (106, 117))	('cisplatin/5-fluorouracil', 'Var', (38, 62))	('mucositis', 'Disease', (96, 105))	('neutropenia', 'Disease', 'MESH:D009503', (122, 133))	('esophagitis', 'Disease', (106, 117))	('esophagitis', 'Disease', 'MESH:D004941', (106, 117))	('mucositis', 'Disease', 'MESH:D052016', (96, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('neutropenia', 'Phenotype', 'HP:0001875', (122, 133))	('neutropenia', 'Disease', (122, 133))	('men', 'Species', '9606', (21, 24))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (48, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))
88839	28134308	In addition, patients in the cisplatin/5-fluorouracil group had higher grade 3-4 radiation mucositis/esophagitis compared with patients in the weekly cisplatin group, but it only reached a marginal trend toward significance (39% versus 9%, P = 0.059).	('radiation mucositis/esophagitis', 'Disease', (81, 112))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (39, 53))	('higher', 'PosReg', (64, 70))	('patients', 'Species', '9606', (13, 21))	('radiation mucositis/esophagitis', 'Disease', 'MESH:D004194', (81, 112))	('esophagitis', 'Phenotype', 'HP:0100633', (101, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('patients', 'Species', '9606', (127, 135))	('cisplatin/5-fluorouracil', 'Var', (29, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))
88934	27854242	CPI are being investigated in a number of malignancies, including squamous cell carcinoma of the head and neck and esophageal cancer, with a plan to isolate specific markers that might predict response and survival benefits to specific cancer populations such as the microsatellite instable colon and gastrointestinal malignancies.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 89))	('malignancies', 'Disease', 'MESH:D009369', (42, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('malignancies', 'Disease', (42, 54))	('malignancies', 'Disease', 'MESH:D009369', (318, 330))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous cell carcinoma', 'Disease', (66, 89))	('malignancies', 'Disease', (318, 330))	('cancer', 'Disease', (126, 132))	('esophageal cancer', 'Disease', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (80, 110))	('CPI', 'Chemical', '-', (0, 3))	('cancer', 'Disease', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('colon and gastrointestinal malignancies', 'Disease', 'MESH:D005767', (291, 330))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('microsatellite', 'Var', (267, 281))
89044	25575253	E2202 is a two-stage, phase II National Cancer Institute (NCI) sponsored study that was coordinated by the Eastern Cooperative Oncology Group (ECOG) and also included participation of credentialed surgeons from the Cancer and Leukemia Group B (CALGB) and the American College of Surgeons Oncology Group (ACOSOG).	('E2202', 'Var', (0, 5))	('Cancer', 'Disease', 'MESH:D009369', (215, 221))	('Oncology', 'Phenotype', 'HP:0002664', (288, 296))	('Cancer', 'Disease', (40, 46))	('Leukemia', 'Disease', 'MESH:D007938', (226, 234))	('Cancer', 'Phenotype', 'HP:0002664', (215, 221))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Cancer', 'Disease', 'MESH:D009369', (40, 46))	('Oncology', 'Phenotype', 'HP:0002664', (127, 135))	('Leukemia', 'Disease', (226, 234))	('Leukemia', 'Phenotype', 'HP:0001909', (226, 234))	('Cancer', 'Disease', (215, 221))
89114	25575253	Despite this, morbidity was significantly less in the MIE group (25% versus 74%; p=0.014).	('MIE', 'Chemical', '-', (54, 57))	('less', 'NegReg', (42, 46))	('MIE', 'Var', (54, 57))
89121	25575253	In one systematic review of over 1000 patients, MIE was found to be associated with lesser overall complication rates, and a shorter ICU and hospital stay.	('MIE', 'Chemical', '-', (48, 51))	('MIE', 'Var', (48, 51))	('complication rates', 'CPA', (99, 117))	('patients', 'Species', '9606', (38, 46))	('lesser', 'NegReg', (84, 90))
89126	25575253	The hospital length of stay was shorter in patients who underwent MIE (11 days vs. 14 days), and there were fewer pulmonary infections in the MIE group (9% within 2 weeks of MIE vs. 29% after open esophagectomy).	('pulmonary infections', 'Disease', (114, 134))	('MIE', 'Var', (66, 69))	('pulmonary infections', 'Phenotype', 'HP:0006532', (114, 134))	('MIE', 'Chemical', '-', (142, 145))	('pulmonary infections', 'Disease', 'MESH:D008171', (114, 134))	('patients', 'Species', '9606', (43, 51))	('fewer', 'NegReg', (108, 113))	('shorter', 'NegReg', (32, 39))	('MIE', 'Chemical', '-', (174, 177))	('MIE', 'Chemical', '-', (66, 69))
89156	27625896	A 55-year-old man diagnosed with clinical T3N0M0 overall Stage IIb Her2-amplified distal esophageal.	('esophageal', 'Disease', (89, 99))	('Her2', 'Gene', (67, 71))	('T3N0M0', 'Var', (42, 48))	('man', 'Species', '9606', (14, 17))	('Her2', 'Gene', '2064', (67, 71))	('esophageal', 'Disease', 'MESH:D004941', (89, 99))
89185	27625896	To our knowledge, there is no preclinical or clinical evidence that Her2 amplification is associated with increased radiation risk.	('associated', 'Reg', (90, 100))	('Her2', 'Gene', '2064', (68, 72))	('Her2', 'Gene', (68, 72))	('amplification', 'Var', (73, 86))
89303	25826075	These data included demographic data (age and gender), length of hospitalization, tumor site and size, clinical presentation, pathological parameters (mitotic index, mutation status, morphological variant, etc.	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutation status', 'Var', (166, 181))
89304	25826075	), IM duration, drug toxicity (evaluated on the basis of Common Terminology Criteria for Adverse Events version 3.0), Eastern Cooperative Oncology Group (ECOG) performance status, and analysis of immunohistochemical staining (CD117, CD34, Dog-1, S-100, SMA, and desmin).	('CD117', 'Gene', (226, 231))	('drug toxicity', 'Disease', (16, 29))	('desmin', 'Gene', '497091', (262, 268))	('drug toxicity', 'Disease', 'MESH:D064420', (16, 29))	('desmin', 'Gene', (262, 268))	('Dog', 'Species', '9615', (239, 242))	('Oncology', 'Phenotype', 'HP:0002664', (138, 146))	('CD117', 'Gene', '3815', (226, 231))	('CD34', 'Var', (233, 237))
89376	24642729	However, subjects with asymptomatic erosive esophagitis still have significantly higher SUVmax in esophagogastric junction than those without erosive esophagitis whether they were symptomatic or not (2.97+-0.63 vs. 2.57+-0.51 and 2.44+-0.53, P = .001 and .027, respectively).	('higher', 'PosReg', (81, 87))	('esophagitis', 'Disease', (44, 55))	('SUVmax in esophagogastric junction', 'MPA', (88, 122))	('esophagitis', 'Disease', 'MESH:D004941', (150, 161))	('esophagitis', 'Phenotype', 'HP:0100633', (44, 55))	('esophagitis', 'Phenotype', 'HP:0100633', (150, 161))	('esophagitis', 'Disease', (150, 161))	('erosive', 'Var', (36, 43))	('esophagitis', 'Disease', 'MESH:D004941', (44, 55))
89413	24642729	Obesity, especially central obesity, could lead to changes in gastroesophageal anatomy and physiology, such as reduced lower esophageal sphincter pressure, hiatal hernia, increased frequency of transient lower esophageal sphincter relaxation, esophageal motor abnormalities, elevated intragastric pressure and disorders of gastric accommodations, all of which could promote the gastroesophageal reflux.	('promote', 'PosReg', (366, 373))	('sphincter relaxation', 'Phenotype', 'HP:0002839', (221, 241))	('hiatal hernia', 'Phenotype', 'HP:0002036', (156, 169))	('obesity', 'Disease', (28, 35))	('motor abnormalities', 'Phenotype', 'HP:0001270', (254, 273))	('increased', 'PosReg', (171, 180))	('lower esophageal sphincter pressure', 'MPA', (119, 154))	('intragastric', 'MPA', (284, 296))	('disorders', 'Var', (310, 319))	('sphincter pressure', 'Phenotype', 'HP:0002839', (136, 154))	('obesity', 'Disease', 'MESH:D009765', (28, 35))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (378, 401))	('esophageal motor abnormalities', 'Disease', 'MESH:D004935', (243, 273))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('reduced', 'NegReg', (111, 118))	('changes', 'Reg', (51, 58))	('gastroesophageal reflux', 'Disease', (378, 401))	('hiatal hernia', 'Disease', 'MESH:D006551', (156, 169))	('obesity', 'Phenotype', 'HP:0001513', (28, 35))	('hiatal hernia', 'Disease', (156, 169))	('central obesity', 'Phenotype', 'HP:0012743', (20, 35))	('esophageal motor abnormalities', 'Disease', (243, 273))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (378, 401))	('hernia', 'Phenotype', 'HP:0100790', (163, 169))	('elevated', 'PosReg', (275, 283))	('elevated intragastric pressure', 'Phenotype', 'HP:0007906', (275, 305))
89435	23390063	A Sequence Variant in the Phospholipase C Epsilon C2 Domain Is Associated With Esophageal Carcinoma and Esophagitis A single-nucleotide polymorphism (rs2274223: A5780G:His1927Arg) in the phospholipase C epsilon gene (PLCepsilon) was recently identified as a susceptibility locus for esophageal cancer in Chinese subjects.	('A5780G', 'Mutation', 'rs2274223', (161, 167))	('Phospholipase C Epsilon', 'Gene', (26, 49))	('Associated', 'Reg', (63, 73))	('PLCepsilon', 'Gene', (217, 227))	('Phospholipase C Epsilon', 'Gene', '5334', (26, 49))	('PLCepsilon', 'Gene', '74055', (217, 227))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (79, 99))	('rs2274223', 'Mutation', 'rs2274223', (150, 159))	('Esophageal Carcinoma and Esophagitis', 'Disease', 'MESH:D004938', (79, 115))	('esophageal cancer', 'Disease', (283, 300))	('phospholipase C epsilon', 'Gene', '5334', (187, 210))	('rs2274223: A5780G:His1927Arg', 'Var', (150, 178))	('Carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('Esophagitis', 'Phenotype', 'HP:0100633', (104, 115))	('phospholipase C epsilon', 'Gene', (187, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (283, 300))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
89440	23390063	In conclusion, the PLCepsilon gene, particularly the 5780G allele, might play a pivotal role in esophageal carcinogenesis via upregulating PLCepsilon mRNA, protein, and enzyme activity, and augmenting inflammatory process in esophageal epithelium.	('PLCepsilon', 'Gene', '74055', (19, 29))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (96, 121))	('upregulating', 'PosReg', (126, 138))	('inflammatory process', 'CPA', (201, 221))	('augmenting', 'NegReg', (190, 200))	('enzyme activity', 'MPA', (169, 184))	('esophageal carcinogenesis', 'Disease', (96, 121))	('protein', 'Protein', (156, 163))	('PLCepsilon', 'Gene', (139, 149))	('PLCepsilon', 'Gene', '74055', (139, 149))	('PLCepsilon', 'Gene', (19, 29))	('5780G', 'Var', (53, 58))
89441	23390063	Thus, 5780G allele may constitute a promising biomarker for esophageal squamous cell carcinoma risk stratification, early detection, and progression prediction.	('esophageal squamous cell carcinoma', 'Disease', (60, 94))	('5780G', 'Var', (6, 11))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (60, 94))
89447	23390063	A more recent report also showed that inhibition of intestinal tumorigenesis in ApcMin/+ mice by loss of PLCepsilon occurs via reducing cytokine-mediated inflammation in local tissue.	('PLCepsilon', 'Gene', '74055', (105, 115))	('reducing', 'NegReg', (127, 135))	('loss', 'Var', (97, 101))	('mice', 'Species', '10090', (89, 93))	('inflammation', 'Disease', 'MESH:D007249', (154, 166))	('intestinal', 'Disease', (52, 62))	('PLCepsilon', 'Gene', (105, 115))	('inflammation', 'Disease', (154, 166))
89450	23390063	These previous data showed that a G at position 5780 in the C2 domain of PLCepsilon was associated with an increased risk of both squamous cell carcinoma (SCC) and esophagus-cardia gastric adenocarcinoma (ECA).	('esophagus-cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (164, 203))	('SCC', 'Gene', (155, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('PLCepsilon', 'Gene', '74055', (73, 83))	('esophagus-cardia gastric adenocarcinoma', 'Disease', (164, 203))	('PLCepsilon', 'Gene', (73, 83))	('SCC', 'Gene', '6317', (155, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('squamous cell carcinoma', 'Disease', (130, 153))	('associated', 'Reg', (88, 98))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (130, 153))	('G at position 5780', 'Var', (34, 52))
89451	23390063	In the current report, we demonstrate that the presence of the G allele at this locus leads to increased PLCepsilon mRNA and protein expression and enzyme activity in esophageal cancer cells in vitro, and that A:G allelic imbalance is strongly associated with esophageal malignancy in primary human tissues.	('esophageal cancer', 'Disease', (167, 184))	('activity', 'MPA', (155, 163))	('PLCepsilon', 'Gene', '74055', (105, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('esophageal malignancy', 'Phenotype', 'HP:0100751', (260, 281))	('PLCepsilon', 'Gene', (105, 115))	('associated with', 'Reg', (244, 259))	('esophageal malignancy', 'Disease', (260, 281))	('imbalance', 'Phenotype', 'HP:0002172', (222, 231))	('presence', 'Var', (47, 55))	('human', 'Species', '9606', (293, 298))	('esophageal malignancy', 'Disease', 'MESH:D004938', (260, 281))	('increased', 'PosReg', (95, 104))	('enzyme', 'Enzyme', (148, 154))	('A:G', 'Var', (210, 213))
89452	23390063	Interestingly, we show that the presence of the G allele is also strongly associated with moderate to severe esophagitis in non-cancer subjects from the areas of high-incidence of esophageal cancer in China.	('esophageal cancer', 'Disease', (180, 197))	('presence', 'Var', (32, 40))	('esophagitis in non-cancer', 'Disease', (109, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('esophagitis in non-cancer', 'Disease', 'MESH:D004938', (109, 134))	('esophagitis', 'Phenotype', 'HP:0100633', (109, 120))	('associated with', 'Reg', (74, 89))
89470	23390063	To investigate whether the G allele of the PLCepsilon gene SNP at position 5780 alters PLCepsilon expression, we determined PLCepsilon genotypes and mRNA levels in 13 human esophageal squamous cancer cell lines (TE-1, TE-2, TE-7, TE-8, TE-12, G5, HCE4, HCE7, EC171, EC8712, EC109, EC9706, SHEEC).	('EC9706', 'CellLine', 'CVCL:E307', (281, 287))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (173, 199))	('squamous cancer', 'Phenotype', 'HP:0002860', (184, 199))	('PLCepsilon', 'Gene', '74055', (87, 97))	('PLCepsilon', 'Gene', (43, 53))	('esophageal squamous cancer', 'Disease', (173, 199))	('PLCepsilon', 'Gene', (87, 97))	('PLCepsilon', 'Gene', (124, 134))	('EC9706', 'Var', (281, 287))	('EC171', 'CellLine', 'CVCL:G573', (259, 264))	('PLCepsilon', 'Gene', '74055', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('alters', 'Reg', (80, 86))	('human', 'Species', '9606', (167, 172))	('PLCepsilon', 'Gene', '74055', (43, 53))	('EC8712', 'CellLine', 'CVCL:E314', (266, 272))
89471	23390063	Six SCC cell lines (G5, TE-8, TE-12, HCE4, EC171, EC8712) were AA, while the remaining 7 (TE-1, TE-2, TE-7, HCE7, EC109, EC9706, SHEEC) were AG for PLCepsilon at position 5780.	('SCC', 'Gene', (4, 7))	('EC8712', 'CellLine', 'CVCL:E314', (50, 56))	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('SCC', 'Gene', '6317', (4, 7))	('EC9706', 'CellLine', 'CVCL:E307', (121, 127))	('PLCepsilon', 'Gene', (148, 158))	('PLCepsilon', 'Gene', '74055', (148, 158))	('EC8712', 'Var', (50, 56))	('EC9706', 'Var', (121, 127))	('EC171', 'CellLine', 'CVCL:G573', (43, 48))
89480	23390063	Similarly, the expression of G protein alpha-subunits Galpha 12 and Galpha 13 resulted in PLCepsilon-dependent accumulation of inositol phosphates.	('expression', 'Var', (15, 25))	('Galpha 12', 'Gene', '2768', (54, 63))	('Galpha 13', 'Gene', (68, 77))	('resulted in', 'Reg', (78, 89))	('Galpha 12', 'Gene', (54, 63))	('inositol phosphates', 'Chemical', 'MESH:D007295', (127, 146))	('G protein alpha-subunits', 'Protein', (29, 53))	('PLCepsilon', 'Gene', (90, 100))	('PLCepsilon', 'Gene', '74055', (90, 100))	('Galpha 13', 'Gene', '10672', (68, 77))
89484	23390063	As a consequence, the lack of fully activated PLCepsilon enzyme could cause epithelial cells to produce more PLCepsilon mRNA and protein as a compensatory response through a feedback mechanism.	('PLCepsilon', 'Gene', '74055', (109, 119))	('lack', 'Var', (22, 26))	('more', 'PosReg', (104, 108))	('PLCepsilon', 'Gene', (46, 56))	('PLCepsilon', 'Gene', '74055', (46, 56))	('PLCepsilon', 'Gene', (109, 119))
89485	23390063	From analysis of homology modeling of the PLCepsilon C2 domain structure, we observed that changing His1927 to Arg in the C2 domain may affect protein-protein interaction and/or lipid recognition, but is unlikely to have an impact on ion binding by this enzyme (Supplementary Figure 1).	('PLCepsilon', 'Gene', (42, 52))	('lipid', 'Chemical', 'MESH:D008055', (178, 183))	('lipid recognition', 'MPA', (178, 195))	('PLCepsilon', 'Gene', '74055', (42, 52))	('His1927 to Arg', 'Var', (100, 114))	('His1927 to Arg', 'Mutation', 'rs2274223', (100, 114))	('affect', 'Reg', (136, 142))	('protein-protein interaction', 'MPA', (143, 170))
89497	23390063	To investigate any possible association between A5780G and esophageal inflammation, we correlated SNP genotypes with presence or absence of esophagitis in individuals with cancer (SCC) and without cancer (non-SCC).	('esophageal inflammation', 'Disease', (59, 82))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('SCC', 'Gene', '6317', (209, 212))	('SCC', 'Gene', (180, 183))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('A5780G', 'Var', (48, 54))	('esophageal inflammation', 'Disease', 'MESH:D007249', (59, 82))	('SCC', 'Gene', (209, 212))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (59, 82))	('esophagitis', 'Disease', (140, 151))	('esophagitis', 'Disease', 'MESH:D004941', (140, 151))	('cancer', 'Disease', (197, 203))	('SCC', 'Phenotype', 'HP:0002860', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (172, 178))	('esophagitis', 'Phenotype', 'HP:0100633', (140, 151))	('SCC', 'Phenotype', 'HP:0002860', (209, 212))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('A5780G', 'Mutation', 'rs2274223', (48, 54))	('SCC', 'Gene', '6317', (180, 183))
89499	23390063	Importantly, the severity of esophagitis was associated with the AG/GG allele in these SCC patients.	('AG/GG', 'Var', (65, 70))	('patients', 'Species', '9606', (91, 99))	('SCC', 'Gene', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('associated', 'Reg', (45, 55))	('esophagitis', 'Phenotype', 'HP:0100633', (29, 40))	('SCC', 'Gene', '6317', (87, 90))	('esophagitis', 'Disease', (29, 40))	('esophagitis', 'Disease', 'MESH:D004941', (29, 40))
89501	23390063	However, when non-SCC individuals with esophagitis were classified into high- or low-incidence areas for esophageal cancer, a significant association between severe esophagitis and the G allele of the PLCepsilon gene was observed: 77% of the severe esophagitis individuals in high-incidence areas had AG/GG genotypes (Figure 3B), versus only 37% of these subjects in low-incidence areas (Figure 3C) (OR 6.03 with 95% CI 1.59-22.9 vs. OR 0.74 with 95% CI 0.33-1.64; P = 0.008; Table 1).	('esophagitis', 'Phenotype', 'HP:0100633', (165, 176))	('PLCepsilon', 'Gene', (201, 211))	('esophagitis', 'Disease', (165, 176))	('esophagitis', 'Disease', 'MESH:D004941', (249, 260))	('PLCepsilon', 'Gene', '74055', (201, 211))	('esophagitis', 'Phenotype', 'HP:0100633', (39, 50))	('SCC', 'Gene', (18, 21))	('esophagitis', 'Disease', 'MESH:D004941', (165, 176))	('SCC', 'Phenotype', 'HP:0002860', (18, 21))	('SCC', 'Gene', '6317', (18, 21))	('esophageal cancer', 'Disease', (105, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('esophagitis', 'Phenotype', 'HP:0100633', (249, 260))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophagitis', 'Disease', (249, 260))	('AG/GG', 'Var', (301, 306))	('esophagitis', 'Disease', (39, 50))	('esophagitis', 'Disease', 'MESH:D004941', (39, 50))
89504	23390063	In conclusion, PLCepsilon is likely to play a pivotal role in esophageal carcinogenesis: the presence of the 5780G allele may not only predict a high risk of future esophageal cancer development, but may also participate in esophageal cancer growth and progression by upregulating levels of PLCepsilon mRNA, protein, and enzyme activity, ultimately leading to augmentation of the inflammatory process in esophageal epithelium.	('esophageal cancer', 'Disease', (165, 182))	('enzyme', 'Enzyme', (321, 327))	('5780G', 'Var', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('esophageal carcinogenesis', 'Disease', (62, 87))	('inflammatory process', 'CPA', (380, 400))	('PLCepsilon', 'Gene', (291, 301))	('PLCepsilon', 'Gene', '74055', (15, 25))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (62, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (224, 241))	('protein', 'Protein', (308, 315))	('PLCepsilon', 'Gene', '74055', (291, 301))	('esophageal cancer', 'Disease', (224, 241))	('presence', 'Var', (93, 101))	('augmentation', 'PosReg', (360, 372))	('levels', 'MPA', (281, 287))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('PLCepsilon', 'Gene', (15, 25))	('growth', 'CPA', (242, 248))	('upregulating', 'PosReg', (268, 280))	('participate', 'Reg', (209, 220))	('activity', 'MPA', (328, 336))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
89505	23390063	Thus, the 5780G allele in PLCepsilon may constitute a promising biomarker for esophageal squamous carcinoma risk stratification, early detection, and progression prediction.	('PLCepsilon', 'Gene', '74055', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('5780G', 'Var', (10, 15))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (89, 107))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (78, 107))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (78, 107))	('esophageal squamous carcinoma', 'Disease', (78, 107))	('PLCepsilon', 'Gene', (26, 36))
89535	17407558	Among routinely assayed tumor markers in the laboratory, CA-125 is more sensitive for HCC than AFP but far less specific.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('AFP', 'Gene', (95, 98))	('tumor', 'Disease', (24, 29))	('CA-125', 'Var', (57, 63))	('AFP', 'Gene', '174', (95, 98))	('HCC', 'Gene', (86, 89))	('HCC', 'Gene', '619501', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
89590	17407558	Among them, expression analysis of UHRF1, ATP7A, and aldehyde oxidase 1 in combination could potentially provide a useful additional diagnostic tool for fine-needle aspirated or cytological specimens obtained during endoscopic investigations.	('aldehyde oxidase 1', 'Gene', (53, 71))	('ATP7A', 'Gene', '538', (42, 47))	('expression analysis', 'Var', (12, 31))	('men', 'Species', '9606', (195, 198))	('aldehyde oxidase 1', 'Gene', '316', (53, 71))	('UHRF1', 'Gene', (35, 40))	('UHRF1', 'Gene', '29128', (35, 40))	('ATP7A', 'Gene', (42, 47))
89612	17407558	These changes reveal an underlying mechanism of colorectal tumorigenesis in which the roles of impaired tricarboxylic acid cycle and Warburg effect may be critical.	('tumor', 'Disease', (59, 64))	('tricarboxylic acid cycle', 'MPA', (104, 128))	('impaired tricarboxylic acid cycle', 'Phenotype', 'HP:0000816', (95, 128))	('changes', 'Var', (6, 13))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (104, 122))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
89627	17407558	These findings indicated that amplification of alpha-actinin and its localization to the leading pseudopodium were potential biomarkers of cancer progression to a more metastatic phenotype.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('localization', 'MPA', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('amplification', 'Var', (30, 43))	('alpha-actinin', 'Gene', '87', (47, 60))	('alpha-actinin', 'Gene', (47, 60))	('cancer', 'Disease', (139, 145))
89665	17407558	The presence of progesterone receptor (PR) in estrogen receptor (ER) positive breast cancer is associated with a good prognosis, and indicates that tumors are likely to respond to tamoxifen.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ER', 'Gene', '2099', (65, 67))	('progesterone receptor', 'Gene', '5241', (16, 37))	('PR', 'Gene', '5241', (39, 41))	('estrogen receptor', 'Gene', (46, 63))	('progesterone receptor', 'Gene', (16, 37))	('estrogen receptor', 'Gene', '2099', (46, 63))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('presence', 'Var', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tamoxifen', 'Chemical', 'MESH:D013629', (180, 189))	('breast cancer', 'Disease', (78, 91))
89686	17407558	Analyzed by peptide fragment matching and MS/MS, cisplatin caused notably increase expressions of some proteins in ovarian cancer, including tropomyosin family, actin family, triosephosphate isomerase family, and Hsp60, while expressions of some proteins in the enolase family decreased.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('men', 'Species', '9606', (24, 27))	('Hsp60', 'Gene', '3329', (213, 218))	('ovarian cancer', 'Disease', (115, 129))	('proteins', 'Protein', (103, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('increase', 'PosReg', (74, 82))	('expressions', 'MPA', (83, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (115, 129))	('Hsp60', 'Gene', (213, 218))	('cisplatin', 'Var', (49, 58))
89703	17407558	The human proteome, due to the enormity of post-translational permutations that result in large numbers of isoforms, is much more complex than the genome and alterations in cancer which can occur in ways that are not predictable by translational analysis alone.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('human', 'Species', '9606', (4, 9))	('cancer', 'Disease', (173, 179))	('isoforms', 'MPA', (107, 115))	('post-translational permutations', 'Var', (43, 74))	('permutations', 'Var', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('result', 'Reg', (80, 86))
89737	33879806	Dysregulation of miRNAs is reportedly involved in EC tumorigenesis and progression.	('Dysregulation', 'Var', (0, 13))	('miRNAs', 'Protein', (17, 23))	('involved', 'Reg', (38, 46))	('EC tumor', 'Disease', 'MESH:D009369', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('EC tumor', 'Disease', (50, 58))
89816	30086241	However, nonspecific or excessive heating might result in normal tissues being damaged and sometimes rather enhance tissue hyperplasia after the stent placement.	('nonspecific', 'Var', (9, 20))	('hyperplasia', 'Disease', 'MESH:D006965', (123, 134))	('rat', 'Species', '10116', (101, 104))	('enhance', 'PosReg', (108, 115))	('result', 'Reg', (48, 54))	('hyperplasia', 'Disease', (123, 134))
89937	30086241	IF staining was performed with Ki67 (1:250; Abcam) and BrdU (1:250; Abcam) antibodies overnight at 4  C followed by washing with phosphate-buffered saline containing 0.1% Tween 20.	('Tween 20', 'Chemical', 'MESH:D011136', (171, 179))	('BrdU', 'Gene', (55, 59))	('BrdU', 'Chemical', 'MESH:D001973', (55, 59))	('1:250;', 'Var', (61, 67))	('phosphate-buffered saline', 'Chemical', '-', (129, 154))
89952	31888440	conducted a case-control study based on their own patients and provided the first evidence that RANK rs1805034 T>C polymorphism was associated with susceptibility of ESCA.	('patients', 'Species', '9606', (50, 58))	('rs1805034 T>C', 'Var', (101, 114))	('ESCA', 'Phenotype', 'HP:0011459', (166, 170))	('ESCA', 'Disease', (166, 170))	('rs1805034', 'Mutation', 'rs1805034', (101, 110))	('associated', 'Reg', (132, 142))	('susceptibility', 'Reg', (148, 162))
89964	31888440	Genetic variations in ESR1 were associated with an increased risk of ESCA.	('ESCA', 'Phenotype', 'HP:0011459', (69, 73))	('ESR1', 'Gene', '2099', (22, 26))	('ESCA', 'Disease', (69, 73))	('associated', 'Reg', (32, 42))	('Genetic variations', 'Var', (0, 18))	('ESR1', 'Gene', (22, 26))
89998	31488217	Moreover, hypoxic exosomes significantly enhanced the tumor growth and lung metastasis compared with normoxic exosomes in nude mice models.	('enhanced', 'PosReg', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('lung metastasis', 'CPA', (71, 86))	('nude mice', 'Species', '10090', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('hypoxic', 'Var', (10, 17))	('tumor', 'Disease', (54, 59))
90048	31488217	Western blotting analysis demonstrated that specific exosome markers (CD9 and TSG101) were enriched in purified extracellular vesicles from the supernatant of both ECA109 and KYSE410 (Fig.	('ECA109', 'Var', (164, 170))	('KYSE410', 'Var', (175, 182))	('TSG101', 'Gene', (78, 84))	('CD9', 'Gene', '928', (70, 73))	('CD9', 'Gene', (70, 73))	('TSG101', 'Gene', '7251', (78, 84))
90074	31488217	However, exosome release inhibitor, GW4869, suppressed ESCC tumor proliferation or angiogenesis in situ or distant lung metastasis notably in both ECA109 and KYSE410 mice xenograft model.	('suppressed', 'NegReg', (44, 54))	('distant lung metastasis', 'CPA', (107, 130))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('GW4869', 'Chemical', 'MESH:C468773', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('angiogenesis in situ', 'CPA', (83, 103))	('mice', 'Species', '10090', (166, 170))	('ESCC', 'Gene', (55, 59))	('tumor', 'Disease', (60, 65))	('GW4869', 'Var', (36, 42))
90083	31488217	7a, these genes were significantly enriched in cancer-related GO terms, such as cell proliferation (GO: 0008283), cell cycle (GO: 0007049), migration (GO: 0016477) and angiogenesis (GO: 0001525).	('GO: 0007049', 'Var', (126, 137))	('GO: 0016477', 'Var', (151, 162))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('GO: 0001525', 'Var', (182, 193))	('GO: 0008283', 'Var', (100, 111))	('cancer', 'Disease', (47, 53))	('cell proliferation', 'CPA', (80, 98))	('cell cycle', 'CPA', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('angiogenesis', 'CPA', (168, 180))	('migration', 'CPA', (140, 149))
90084	31488217	Moreover, KEGG signaling pathways analysis showed that dysregulated mRNAs also play a role in cancer-related pathways such as cell cycle (has: 04110) and NOD-like receptor signaling pathway (hsa:04621) (Fig.	('cell cycle', 'CPA', (126, 136))	('dysregulated', 'Var', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mRNAs', 'Gene', (68, 73))	('NOD-like receptor signaling pathway', 'Pathway', (154, 189))	('play', 'Reg', (79, 83))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
90108	31488217	Previous studies demonstrated that exosomes destroyed endothelial barriers and increased vascular permeability which provide an escape route for the tumor cells to enter the circulation.	('increased', 'PosReg', (79, 88))	('endothelial barriers', 'CPA', (54, 74))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('destroyed', 'NegReg', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('vascular permeability', 'MPA', (89, 110))	('tumor', 'Disease', (149, 154))	('exosomes', 'Var', (35, 43))
90115	31488217	Silence of AURKA inhibits tumor growth by inducing apoptosis and G2/M cell cycle arrest in human osteosarcoma and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('osteosarcoma', 'Phenotype', 'HP:0002669', (97, 109))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('AURKA', 'Gene', '6790', (11, 16))	('inducing', 'PosReg', (42, 50))	('AURKA', 'Gene', (11, 16))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('osteosarcoma', 'Disease', (97, 109))	('osteosarcoma', 'Disease', 'MESH:D012516', (97, 109))	('apoptosis', 'CPA', (51, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('arrest', 'Disease', (81, 87))	('Silence', 'Var', (0, 7))	('inhibits', 'NegReg', (17, 25))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('breast cancer', 'Disease', (114, 127))	('human', 'Species', '9606', (91, 96))
90153	30339710	Molecular studies of ESCC have revealed that genetic alterations such as mutation of Tp53, loss of p16 and an increased expression of CDKN2A play a role in the development of ESCC.	('p16', 'Gene', (99, 102))	('Tp53', 'Gene', (85, 89))	('expression', 'MPA', (120, 130))	('Tp53', 'Gene', '7157', (85, 89))	('increased', 'PosReg', (110, 119))	('CDKN2A', 'Gene', (134, 140))	('p16', 'Gene', '1029', (99, 102))	('ESCC', 'Disease', (175, 179))	('CDKN2A', 'Gene', '1029', (134, 140))	('loss', 'NegReg', (91, 95))	('mutation', 'Var', (73, 81))	('men', 'Species', '9606', (167, 170))
90162	30339710	Overexpression of COX-2 was associated with aggressive nature of the tumor and showed reduced survival in many studies.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('reduced', 'NegReg', (86, 93))	('COX-2', 'Gene', '5743', (18, 23))	('associated', 'Reg', (28, 38))	('tumor', 'Disease', (69, 74))	('survival', 'MPA', (94, 102))	('Overexpression', 'Var', (0, 14))	('COX-2', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
90210	30339710	High expression of COX-2 was seen in 65% user of naswar and 70% among non-users, though the results are statistically insignificant (Table 4).	('naswar', 'Var', (49, 55))	('COX-2', 'Gene', (19, 24))	('COX-2', 'Gene', '5743', (19, 24))
90240	30339710	In some studies, it was revealed that a high expression of COX-2 was associated with tumor proliferation and carcinogenesis.	('high', 'Var', (40, 44))	('tumor', 'Disease', (85, 90))	('COX-2', 'Gene', '5743', (59, 64))	('carcinogenesis', 'CPA', (109, 123))	('associated', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('COX-2', 'Gene', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
90275	30339710	Over-expression of COX-2 is positively associated with ESCC.	('ESCC', 'Disease', (55, 59))	('COX-2', 'Gene', (19, 24))	('COX-2', 'Gene', '5743', (19, 24))	('associated', 'Reg', (39, 49))	('Over-expression', 'Var', (0, 15))
90279	28611669	The importance of cyclooxygenase-2 (COX-2) in carcinogenesis has been previously established and the use of COX-2 inhibitors as celecoxib has been shown to exert antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('cyclooxygenase-2', 'Gene', (18, 34))	('COX-2', 'Gene', (108, 113))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('cyclooxygenase-2', 'Gene', '5743', (18, 34))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('carcinogenesis', 'Disease', (46, 60))	('COX-2', 'Gene', '5743', (108, 113))	('tumor', 'Disease', (166, 171))	('COX-2', 'Gene', (36, 41))	('COX-2', 'Gene', '5743', (36, 41))	('celecoxib', 'Chemical', 'MESH:D000068579', (128, 137))	('inhibitors', 'Var', (114, 124))
90281	28611669	OE19 and OE33 EAC cells surviving 5-FU exposure exhibited an increase in CSC markers CD24 and ABCG2 and also an increased resistance to apoptosis.	('ABCG2', 'Gene', (94, 99))	('5-FU', 'Chemical', 'MESH:D005472', (34, 38))	('resistance to apoptosis', 'CPA', (122, 145))	('CD24', 'Gene', (85, 89))	('CD24', 'Gene', '100133941', (85, 89))	('EAC', 'Phenotype', 'HP:0011459', (14, 17))	('increased', 'PosReg', (112, 121))	('ABCG2', 'Gene', '9429', (94, 99))	('increase', 'PosReg', (61, 69))	('OE33', 'Var', (9, 13))
90329	28611669	BCLL2 expression was significantly increased in 5-FU treated cells (102% in OE19 cells, p = 0.001 and 51% in OE33 cells, p = 0.002) vs. untreated cells.	('increased', 'PosReg', (35, 44))	('5-FU', 'Var', (48, 52))	('expression', 'MPA', (6, 16))	('5-FU', 'Chemical', 'MESH:D005472', (48, 52))	('BCLL2', 'Gene', (0, 5))
90332	28611669	Although levels of ABCG2 mRNA were increased in 5-FU-treated OE19 cells (123% vs. control cells, p = 0.001), no difference in expression was observed in OE33 cells (Figure 2C).	('increased', 'PosReg', (35, 44))	('levels', 'MPA', (9, 15))	('5-FU', 'Chemical', 'MESH:D005472', (48, 52))	('ABCG2', 'Gene', (19, 24))	('ABCG2', 'Gene', '9429', (19, 24))	('5-FU-treated', 'Var', (48, 60))
90336	28611669	Cells surviving treatment with 5-FU exhibited a significant increase of CD24 mRNA expression (87% in OE19 cells, p = 0.04 and 66% in OE33 cells, p = 0.001) and a moderate increase of ESA mRNA expression (40% in OE19 cells, p = 0.004 and 27% in OE33 cells, p = 0.005) compared with untreated cells.	('5-FU', 'Var', (31, 35))	('ESA', 'Gene', (183, 186))	('increase', 'PosReg', (60, 68))	('5-FU', 'Chemical', 'MESH:D005472', (31, 35))	('ESA', 'Gene', '5444', (183, 186))	('increase', 'PosReg', (171, 179))	('CD24', 'Gene', '100133941', (72, 76))	('CD24', 'Gene', (72, 76))
90338	28611669	The level of CD44 mRNA was slightly increased (18%, p = 0.027) in 5-FU treated OE33 cells (Figures 2D,E).	('5-FU', 'Var', (66, 70))	('CD44', 'Gene', '960', (13, 17))	('5-FU', 'Chemical', 'MESH:D005472', (66, 70))	('increased', 'PosReg', (36, 45))	('CD44', 'Gene', (13, 17))
90342	28611669	Flow cytometry revealed that the intensity of CD24 expression, measured as mean fluorescence units (MFI) was significantly higher in 5-FU-treated cells than in control cells in both cell lines (OE19 cells p = 0.046; OE33 cells p = 0.035; Figures 4A-E).	('CD24', 'Gene', '100133941', (46, 50))	('CD24', 'Gene', (46, 50))	('5-FU', 'Chemical', 'MESH:D005472', (133, 137))	('higher', 'PosReg', (123, 129))	('5-FU-treated', 'Var', (133, 145))	('expression', 'MPA', (51, 61))
90354	28611669	However, when cells were co-treated with 5-FU and 40 muM celecoxib, we found that celecoxib significantly attenuated 5-FU-induced CD24 expression (p = 0.017).	('celecoxib', 'Chemical', 'MESH:D000068579', (82, 91))	('celecoxib', 'Chemical', 'MESH:D000068579', (57, 66))	('5-FU-induced', 'MPA', (117, 129))	('muM', 'Gene', (53, 56))	('attenuated', 'NegReg', (106, 116))	('celecoxib', 'Var', (82, 91))	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('CD24', 'Gene', '100133941', (130, 134))	('CD24', 'Gene', (130, 134))	('5-FU', 'Chemical', 'MESH:D005472', (117, 121))	('muM', 'Gene', '56925', (53, 56))
90364	28611669	In our experiments we observed that treatment with 5-FU induced an increase in mRNA levels of CSC markers CD24 and ESA, but only increased levels of CD24 protein expression were observed, which could be probably due to post-transcriptional mechanisms.	('CD24', 'Gene', '100133941', (149, 153))	('CD24', 'Gene', (149, 153))	('5-FU', 'Var', (51, 55))	('CD24', 'Gene', '100133941', (106, 110))	('CD24', 'Gene', (106, 110))	('5-FU', 'Chemical', 'MESH:D005472', (51, 55))	('ESA', 'Gene', (115, 118))	('increase', 'PosReg', (67, 75))	('ESA', 'Gene', '5444', (115, 118))
90384	28611669	On one hand, there is clear evidence that COX-2 inhibition downregulates important proteins involved in cancer progression and dissemination, and many of the COX-2- regulated genes may determine tumor chemosensitivity (Dannenberg and Subbaramaiah,; Tuynman et al.,; Tsujii,).	('COX-2', 'Gene', '5743', (42, 47))	('determine', 'Reg', (185, 194))	('proteins', 'Protein', (83, 91))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('downregulates', 'NegReg', (59, 72))	('inhibition', 'Var', (48, 58))	('COX-2', 'Gene', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('COX-2', 'Gene', (42, 47))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('COX-2', 'Gene', '5743', (158, 163))
90392	28611669	In OE33 sphere cultures, celecoxib was unable to prevent the initiation of tumor spheres at all of the tested doses; however, celecoxib disaggregated esophageal cancer cell spheres after 7 days of treatment, suggesting a potential role of celecoxib in the cancer stem model.	('esophageal cancer', 'Disease', (150, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('celecoxib', 'Chemical', 'MESH:D000068579', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Disease', (256, 262))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('celecoxib', 'Chemical', 'MESH:D000068579', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('celecoxib', 'Var', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', (161, 167))	('celecoxib', 'Chemical', 'MESH:D000068579', (239, 248))	('tumor', 'Disease', (75, 80))
90395	28611669	Our observations demonstrate that administration of the chemotherapeutic 5-FU leads to an increase in CD24 marker expression in esophageal adenocarcinoma cell lines, which may be related to the stem cell phenotype, as suggested by its increased expression in esophageal cancer spheres.	('increase', 'PosReg', (90, 98))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (128, 153))	('CD24', 'Gene', '100133941', (102, 106))	('5-FU', 'Var', (73, 77))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (128, 153))	('5-FU', 'Chemical', 'MESH:D005472', (73, 77))	('CD24', 'Gene', (102, 106))	('esophageal cancer', 'Disease', (259, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('expression', 'MPA', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('esophageal adenocarcinoma', 'Disease', (128, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (259, 276))
90399	25164006	Using patient derived xenograft models we demonstrate that inhibition of Notch by gamma-secretase inhibitors (GSI) is efficacious in downsizing tumor growth.	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('patient', 'Species', '9606', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('inhibition', 'Var', (59, 69))	('downsizing', 'NegReg', (133, 143))	('GSI', 'Chemical', '-', (110, 113))
90401	25164006	Therefore, this study provides a proof of concept that inhibition of Notch activity will have efficacy in treating EAC, offering a rationale to lay the foundation for a clinical trial to evaluate the efficacy of GSI in EAC treatment.	('EAC', 'Disease', (115, 118))	('Notch', 'Gene', (69, 74))	('GSI', 'Chemical', '-', (212, 215))	('EAC', 'Phenotype', 'HP:0011459', (219, 222))	('inhibition', 'Var', (55, 65))	('EAC', 'Phenotype', 'HP:0011459', (115, 118))
90409	25164006	Using patient derived xenograft models we demonstrate that inhibition of Notch signaling by gamma-secretase inhibitors (GSI) is efficacious in downsizing tumor growth.	('downsizing', 'NegReg', (143, 153))	('Notch signaling', 'MPA', (73, 88))	('patient', 'Species', '9606', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('GSI', 'Chemical', '-', (120, 123))	('inhibition', 'Var', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
90411	25164006	Therefore, it appears that Notch signaling is driving resistance to chemotherapy by maintaining a robust population of CSC and that inhibition of Notch depletes the CSC population and sensitizes cells to chemotherapeutic agents which should lead to a better and more durable response to neoadjuvant chemotherapy (NAC).	('depletes', 'NegReg', (152, 160))	('sensitizes', 'Reg', (184, 194))	('Notch', 'Gene', (146, 151))	('NAC', 'Chemical', '-', (313, 316))	('inhibition', 'Var', (132, 142))
90457	25164006	There was a significant reduction in the proliferation and colony formation of OE33 cells with CSL knock down compared to control cells (Fig.	('CSL', 'Gene', '1444', (95, 98))	('CSL', 'Gene', (95, 98))	('knock down', 'Var', (99, 109))	('reduction', 'NegReg', (24, 33))	('colony formation', 'CPA', (59, 75))	('proliferation', 'CPA', (41, 54))
90478	25164006	Similar to cell line-based xenografts, inhibition of Notch signaling by DAPT in the PDX model lead to significantly stunted growth and a reduction in proliferation and increased apoptosis as compared to vehicle group (Fig.	('inhibition', 'Var', (39, 49))	('DAPT', 'Gene', (72, 76))	('Notch signaling', 'MPA', (53, 68))	('stunted', 'NegReg', (116, 123))	('growth', 'CPA', (124, 130))	('reduction', 'NegReg', (137, 146))	('apoptosis', 'CPA', (178, 187))	('stunted growth', 'Phenotype', 'HP:0001510', (116, 130))	('DAPT', 'Chemical', '-', (72, 76))	('proliferation', 'CPA', (150, 163))
90480	25164006	The experiment shown in Figure 4F indicates that inhibition of Notch signaling in the xenograft models is selectively targeting the CSC population of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Notch signaling', 'Gene', (63, 78))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CSC population', 'CPA', (132, 146))	('inhibition', 'Var', (49, 59))	('tumor', 'Disease', (154, 159))
90489	25164006	Inhibition of the Notch pathway caused a significant decrease in transcription (p<0.001) of several stem cell marker genes, including ALDH CD24, LGR5, SOX2 and TWIST1 (Fig.	('decrease', 'NegReg', (53, 61))	('CD24', 'Gene', (139, 143))	('transcription', 'MPA', (65, 78))	('SOX2', 'Gene', '6657', (151, 155))	('LGR5', 'Gene', (145, 149))	('Inhibition', 'Var', (0, 10))	('TWIST1', 'Gene', (160, 166))	('TWIST1', 'Gene', '7291', (160, 166))	('LGR5', 'Gene', '8549', (145, 149))	('Notch pathway', 'Pathway', (18, 31))	('CD24', 'Gene', '100133941', (139, 143))	('SOX2', 'Gene', (151, 155))
90513	25164006	Using patient derived xenograft models we clearly demonstrate that inhibition of Notch signaling by gamma-secretase inhibitors is efficacious in downsizing tumor growth.	('inhibition', 'Var', (67, 77))	('downsizing', 'NegReg', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('Notch signaling', 'MPA', (81, 96))	('patient', 'Species', '9606', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))
90517	25164006	Therefore, inhibition of Notch depletes the CSC population and sensitizes cells to chemotherapeutic agents, which should lead to a better and more durable response to NAC.	('Notch', 'Gene', (25, 30))	('CSC population', 'MPA', (44, 58))	('inhibition', 'Var', (11, 21))	('depletes', 'NegReg', (31, 39))	('lead to', 'Reg', (121, 128))	('sensitizes', 'Reg', (63, 73))	('NAC', 'Chemical', '-', (167, 170))
90521	25191856	ERCC1 Single Nucleotide Polymorphism C8092A, but Not Its Expression Is Associated with Survival of Esophageal Squamous Cell Carcinoma Patients from Fujian Province, China Esophageal carcinoma is one of the world's deadliest cancers.	('C8092A', 'Var', (37, 43))	('deadliest cancers', 'Disease', (214, 231))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (171, 191))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (171, 191))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('ERCC1', 'Gene', '2067', (0, 5))	('Single Nucleotide Polymorphism', 'Var', (6, 36))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (99, 133))	('C8092A', 'Mutation', 'rs3212986', (37, 43))	('Carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('Esophageal carcinoma', 'Disease', (171, 191))	('ERCC1', 'Gene', (0, 5))	('Esophageal Squamous Cell Carcinoma', 'Disease', (99, 133))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('Patients', 'Species', '9606', (134, 142))	('deadliest cancers', 'Disease', 'MESH:D009369', (214, 231))	('Associated', 'Reg', (71, 81))
90524	25191856	Evidence suggests polymorphisms in genes encoding excision repair cross-complementing group 1 (ERCC1), a protein involved in nuclear excision repair (NER), may help predict response to cisplatin and other platinum-based chemotherapeutics.	('ERCC1', 'Gene', '2067', (95, 100))	('ERCC1', 'Gene', (95, 100))	('response', 'MPA', (173, 181))	('platinum', 'Chemical', 'MESH:D010984', (205, 213))	('excision repair cross-complementing group 1', 'Gene', '2067', (50, 93))	('polymorphisms', 'Var', (18, 31))	('excision repair cross-complementing group 1', 'Gene', (50, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('help predict', 'Reg', (160, 172))
90525	25191856	Multiple ERCC1 single nucleotide polymorphisms (SNPs) have been associated with platinum chemotherapy response.	('associated', 'Reg', (64, 74))	('platinum chemotherapy response', 'CPA', (80, 110))	('platinum', 'Chemical', 'MESH:D010984', (80, 88))	('ERCC1', 'Gene', (9, 14))	('ERCC1', 'Gene', '2067', (9, 14))	('single nucleotide polymorphisms', 'Var', (15, 46))
90526	25191856	Two common SNPs occur at the C8092A and C118T loci.	('C118T', 'Mutation', 'rs11615', (40, 45))	('C118T', 'Var', (40, 45))	('C8092A', 'Var', (29, 35))	('C8092A', 'Mutation', 'rs3212986', (29, 35))
90532	25191856	Interestingly, C8092A SNP showed significant association with patient survival (P = 0.01), with patients homozygous for the mutant allele showing the most significantly reduced survival (P = 0.04) compared to those homozygous for the dominant allele (CC).	('patient survival', 'CPA', (62, 78))	('C8092A', 'Var', (15, 21))	('patient', 'Species', '9606', (62, 69))	('patient', 'Species', '9606', (96, 103))	('reduced', 'NegReg', (169, 176))	('survival', 'MPA', (177, 185))	('patients', 'Species', '9606', (96, 104))	('C8092A', 'Mutation', 'rs3212986', (15, 21))
90541	25191856	In non-small cell lung cancer (NSCLC), ERCC1 SNP has been linked to reduced survival time and increased risk of comorbid complications in specific populations of chemotherapy patients.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('SNP', 'Var', (45, 48))	('NSCLC', 'Disease', (31, 36))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('patients', 'Species', '9606', (175, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('ERCC1', 'Gene', (39, 44))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('survival time', 'CPA', (76, 89))	('reduced', 'NegReg', (68, 75))	('ERCC1', 'Gene', '2067', (39, 44))	('non-small cell lung cancer', 'Disease', (3, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
90543	25191856	Single nucleotide polymorphisms (SNP) of ERCC1 could affect potential for genetic repair, which highly influences the efficacy and individual sensitivity to these chemotherapeutic agents.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('influences', 'Reg', (103, 113))	('ERCC1', 'Gene', '2067', (41, 46))	('affect', 'Reg', (53, 59))	('ERCC1', 'Gene', (41, 46))	('potential for genetic repair', 'CPA', (60, 88))
90544	25191856	Evidence suggests that the ERCC1 C118T SNP could affect mRNA and protein expression of ERCC1, therefore altering sensitivity to platinum-based therapeutics.	('affect', 'Reg', (49, 55))	('ERCC1', 'Gene', (27, 32))	('platinum', 'Chemical', 'MESH:D010984', (128, 136))	('ERCC1', 'Gene', (87, 92))	('altering', 'Reg', (104, 112))	('C118T SNP', 'Var', (33, 42))	('ERCC1', 'Gene', '2067', (27, 32))	('ERCC1', 'Gene', '2067', (87, 92))	('C118T', 'Mutation', 'rs11615', (33, 38))	('sensitivity to', 'MPA', (113, 127))
90545	25191856	Meta-analysis suggests that certain ERCC1 SNPs may also be predictive of cancer susceptibility, further highlighting potential importance of this genetic alteration in cancer detection and therapeutics.	('ERCC1', 'Gene', '2067', (36, 41))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('SNPs', 'Var', (42, 46))	('ERCC1', 'Gene', (36, 41))
90546	25191856	Although the link between platinum-based chemotherapeutics and ERCC1 is debatable, the predictive aspect of assessing ERCC1 polymorphisms is attractive for assessing risk of cancer development in esophageal cancer due to the high latency of detection and resulting poor outcomes in this disease.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('ERCC1', 'Gene', '2067', (63, 68))	('ERCC1', 'Gene', (63, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('platinum', 'Chemical', 'MESH:D010984', (26, 34))	('polymorphisms', 'Var', (124, 137))	('ERCC1', 'Gene', '2067', (118, 123))	('ERCC1', 'Gene', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('esophageal cancer', 'Disease', (196, 213))
90578	25191856	In brief, allelic frequencies of C8092A and C118T polymorphisms were entered into a software calculator based on the equation, p2+2pq+q2 = 1, where p represents the major allele, q the minor allele, and pq the heterozygous condition.	('C8092A', 'Var', (33, 39))	('C8092A', 'Mutation', 'rs3212986', (33, 39))	('C118T', 'Mutation', 'rs11615', (44, 49))	('C118T', 'Var', (44, 49))
90591	25191856	For ERCC1 polymorphism C8092A, approximately 40% of patients were homozygous for the major allele (CC = 40.7%) or heterozygous (CA = 41.7%) while only 17.6% were homozygous for the recessive allele (AA).	('ERCC1', 'Gene', '2067', (4, 9))	('ERCC1', 'Gene', (4, 9))	('C8092A', 'Var', (23, 29))	('C8092A', 'Mutation', 'rs3212986', (23, 29))	('patients', 'Species', '9606', (52, 60))
90594	25191856	No significant relationship was identified between ERCC1 staining and allelic distribution of SNP C8092A (P = 0.56) (Table 2).	('C8092A', 'Mutation', 'rs3212986', (98, 104))	('SNP', 'Gene', (94, 97))	('ERCC1', 'Gene', '2067', (51, 56))	('C8092A', 'Var', (98, 104))	('ERCC1', 'Gene', (51, 56))
90599	25191856	Ultimately, statistical analysis revealed no significant association between ERCC1 status and allelic distribution for polymorphism C118T (P = 0.37) (Table 2).	('ERCC1', 'Gene', (77, 82))	('ERCC1', 'Gene', '2067', (77, 82))	('C118T', 'Var', (132, 137))	('C118T', 'Mutation', 'rs11615', (132, 137))
90600	25191856	Unlike ERCC1 histological classification, genotype analysis for the C8092A polymorphism exhibited a significant association with patient outcomes and overall and progression-free (PFS) survival.	('C8092A', 'Mutation', 'rs3212986', (68, 74))	('patient outcomes', 'CPA', (129, 145))	('ERCC1', 'Gene', (7, 12))	('ERCC1', 'Gene', '2067', (7, 12))	('C8092A', 'Var', (68, 74))	('progression-free', 'CPA', (162, 178))	('patient', 'Species', '9606', (129, 136))
90603	25191856	There was also no significant trend observed for SNP allele variations of C118T concerning association with overall survival (P = 0.78) or PFS (chi-square  = 0.15, P = 0.93).	('PFS', 'Disease', (139, 142))	('C118T', 'Mutation', 'rs11615', (74, 79))	('C118T', 'Var', (74, 79))
90604	25191856	Kaplan-Meier survival curves for C8092A are illustrated in Figure 6A & B, and C118T in Figure 6C & D. Platinum-based chemotherapeutics target and damage DNA, advancing cell death of affected tumorigenic, as well as normal cells.	('DNA', 'PosReg', (153, 156))	('and', 'Var', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('C8092A', 'Var', (33, 39))	('C8092A', 'Mutation', 'rs3212986', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('Platinum', 'Chemical', 'MESH:D010984', (102, 110))	('C118T', 'Mutation', 'rs11615', (78, 83))
90607	25191856	Polymorphisms in ERCC1 gene affect mRNA expression and have received much attention as potential predictors of cisplatin and platinum adjuvant therapy outcome, and patient prognosis in lung cancer, melanoma, bladder cancer, in addition to esophageal cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (208, 222))	('bladder cancer', 'Disease', (208, 222))	('mRNA expression', 'MPA', (35, 50))	('bladder cancer', 'Phenotype', 'HP:0009725', (208, 222))	('affect', 'Reg', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('ERCC1', 'Gene', '2067', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Polymorphisms', 'Var', (0, 13))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))	('ERCC1', 'Gene', (17, 22))	('patient', 'Species', '9606', (164, 171))	('esophageal cancer', 'Disease', (239, 256))	('platinum', 'Chemical', 'MESH:D010984', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('lung cancer', 'Disease', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
90618	25191856	Contrary to what we observed for ERCC1 H-score classification and adjuvant therapy, some polymorphic ERCC1 influence on overall patient survival was identified.	('polymorphic', 'Var', (89, 100))	('ERCC1', 'Gene', '2067', (101, 106))	('ERCC1', 'Gene', (101, 106))	('ERCC1', 'Gene', '2067', (33, 38))	('ERCC1', 'Gene', (33, 38))	('patient', 'Species', '9606', (128, 135))	('influence', 'Reg', (107, 116))
90619	25191856	Two commonly studied ERCC1 SNPs occur at loci C8092A and C118T, and both have been suggested to predict treatment response or patient outcome in esophageal cancer.	('ERCC1', 'Gene', (21, 26))	('C8092A', 'Var', (46, 52))	('ERCC1', 'Gene', '2067', (21, 26))	('patient', 'Species', '9606', (126, 133))	('C118T', 'Var', (57, 62))	('esophageal cancer', 'Disease', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('C8092A', 'Mutation', 'rs3212986', (46, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('C118T', 'Mutation', 'rs11615', (57, 62))	('predict', 'Reg', (96, 103))
90620	25191856	Of the two, the C8092A SNP showed a significant association with overall and progression-free patient survival.	('C8092A', 'Var', (16, 22))	('progression-free patient survival', 'CPA', (77, 110))	('patient', 'Species', '9606', (94, 101))	('C8092A', 'Mutation', 'rs3212986', (16, 22))	('overall', 'CPA', (65, 72))
90621	25191856	It is documented that polymorphisms that disrupt DNA base repair increase risk of ESCC.	('SCC', 'Gene', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('polymorphisms', 'Var', (22, 35))
90622	25191856	In our study, the C   A mutation at ERCC1 residue 8092 appears to diminish overall survival and PFS, which is reasonable if this mutation is associated with increased risk of ESCC development.	('ERCC1', 'Gene', '2067', (36, 41))	('C   A mutation at', 'Var', (18, 35))	('PFS', 'CPA', (96, 99))	('SCC', 'Gene', (176, 179))	('overall survival', 'CPA', (75, 91))	('ERCC1', 'Gene', (36, 41))	('SCC', 'Gene', '6317', (176, 179))	('diminish', 'NegReg', (66, 74))
90625	25191856	Upon review of the literature, many recent studies investigating polymorphic variations in ERCC1 and the predictive potential for patient and platinum-based treatment effects take place in Europe or the United States where ESCC is far less common than esophageal adenocarcinoma.	('patient', 'Species', '9606', (130, 137))	('platinum', 'Chemical', 'MESH:D010984', (142, 150))	('SCC', 'Gene', (224, 227))	('esophageal adenocarcinoma', 'Disease', (252, 277))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (252, 277))	('polymorphic variations', 'Var', (65, 87))	('SCC', 'Gene', '6317', (224, 227))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (252, 277))	('ERCC1', 'Gene', (91, 96))	('ERCC1', 'Gene', '2067', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))
90629	25191856	One recent study explored ERCC1-C8092A polymorphic predictive value of ESCC susceptibility in North Xinjiang, China.	('polymorphic', 'Var', (39, 50))	('SCC', 'Gene', (72, 75))	('C8092A', 'Mutation', 'rs3212986', (32, 38))	('SCC', 'Gene', '6317', (72, 75))	('ERCC1', 'Gene', '2067', (26, 31))	('ERCC1', 'Gene', (26, 31))
90632	25191856	Here, when all three allelic combinations were statistically compared, those with the AA genotype showed a trend in reduced overall survival, and when two homozygous allelic combinations (AA vs. CC) were compared there was a clear significant influence on survival, with patients homozygous for the mutant allele (AA) exhibiting reduced overall survival than those homozygous for the dominant allele, CC (P = 0.07, Hazard Ratio  = 4.496, 95%CI  = 1.507 to 13.42).	('overall survival', 'MPA', (337, 353))	('overall', 'MPA', (124, 131))	('mutant', 'Var', (299, 305))	('patients', 'Species', '9606', (271, 279))	('reduced', 'NegReg', (329, 336))	('reduced', 'NegReg', (116, 123))
90634	25191856	Similar to our findings, the recessive mutant allele (A) in their study was directly related to overall patient survival in both the homozygous mutant (AA) and heterozygous (CA) genotypes.	('mutant', 'Var', (144, 150))	('related to', 'Reg', (85, 95))	('patient', 'Species', '9606', (104, 111))
90636	25191856	As such, the C   A mutation decreases overall survival in our study patient population, but actual ERCC1 expression level within analyzed tumor tissue was not associated with any genotypic variation at this loci.	('decreases', 'NegReg', (28, 37))	('mutation', 'Var', (19, 27))	('ERCC1', 'Gene', '2067', (99, 104))	('tumor', 'Disease', (138, 143))	('patient', 'Species', '9606', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('overall survival', 'MPA', (38, 54))	('C   A mutation', 'Var', (13, 27))	('ERCC1', 'Gene', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
90649	25191856	In line with these findings, Yang and Xian performed a meta-analysis on clinical studies of various ERCC1 SNPs including C118T in non-small cell lung cancer and found overall reduced survival in ERCC1+ patients, as well as reduced sensitivity to platinum-based chemotherapy.	('C118T', 'Var', (121, 126))	('ERCC1', 'Gene', (195, 200))	('reduced', 'NegReg', (175, 182))	('survival', 'MPA', (183, 191))	('ERCC1', 'Gene', '2067', (195, 200))	('reduced', 'NegReg', (223, 230))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (130, 156))	('ERCC1', 'Gene', '2067', (100, 105))	('ERCC1', 'Gene', (100, 105))	('platinum', 'Chemical', 'MESH:D010984', (246, 254))	('C118T', 'Mutation', 'rs11615', (121, 126))	('patients', 'Species', '9606', (202, 210))	('non-small cell lung cancer', 'Disease', (130, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (134, 156))	('sensitivity', 'MPA', (231, 242))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (130, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
90651	25191856	To our knowledge this is the first clinical analysis of ERCC1 expression and polymorphic variation in esophageal cancer patients in Fujian Province.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('ERCC1', 'Gene', '2067', (56, 61))	('ERCC1', 'Gene', (56, 61))	('polymorphic variation', 'Var', (77, 98))	('patients', 'Species', '9606', (120, 128))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
90652	25191856	Only two other studies from this province have involved examination of ERCC1 polymorphisms and cancer, however these were focused on colorectal and liver cancer.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('polymorphisms', 'Var', (77, 90))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('liver cancer', 'Phenotype', 'HP:0002896', (148, 160))	('colorectal and liver cancer', 'Disease', 'MESH:D015179', (133, 160))	('ERCC1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ERCC1', 'Gene', '2067', (71, 76))
90654	25191856	Few studies have targeted tumor cell-specific expression of ERCC1 as a potential correlate for the progression of squamous cell carcinoma of the esophagus, and our findings yield interesting potential associations between ERCC1 SNP C8092A and survival of patients with this disease.	('SNP C8092A', 'Var', (228, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('C8092A', 'Var', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('squamous cell carcinoma of the esophagus', 'Disease', (114, 154))	('associations', 'Interaction', (201, 213))	('patients', 'Species', '9606', (255, 263))	('tumor', 'Disease', (26, 31))	('C8092A', 'Mutation', 'rs3212986', (232, 238))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (114, 154))	('ERCC1', 'Gene', '2067', (222, 227))	('ERCC1', 'Gene', (222, 227))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (128, 154))	('ERCC1', 'Gene', '2067', (60, 65))	('ERCC1', 'Gene', (60, 65))
90655	25191856	This might prove valuable for assessment of other allelic variations or SNPs of ERCC1 in regards to treatment response and survival outcomes in this form of the disease.	('ERCC1', 'Gene', '2067', (80, 85))	('ERCC1', 'Gene', (80, 85))	('SNPs', 'Var', (72, 76))
90657	25191856	This is the first study to investigate this regional population of Chinese with ESCC, and linked ERCC1 polymorphism to esophageal carcinoma in these patients that impacted overall survival.	('SCC', 'Gene', '6317', (81, 84))	('patients', 'Species', '9606', (149, 157))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (119, 139))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (119, 139))	('polymorphism', 'Var', (103, 115))	('ERCC1', 'Gene', (97, 102))	('impacted', 'Reg', (163, 171))	('ERCC1', 'Gene', '2067', (97, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('SCC', 'Gene', (81, 84))	('esophageal carcinoma', 'Disease', (119, 139))
90699	21470796	Relative to the IMRT plan, the IMPT (AP/PA) would have delivered roughly the same mean cardiac dose (19.9 vs 21.2 Gy) and cardiac V20, V30, V40, and V50 (Table 1), although the cardiac V10 was slightly lower with the IMPT AP./PA plan (66% vs 79%, p<0.0342).	('V50', 'Var', (149, 152))	('cardiac V20', 'MPA', (122, 133))	('V40', 'Var', (140, 143))	('lower', 'NegReg', (202, 207))	('PA', 'Chemical', 'MESH:D011478', (40, 42))	('cardiac', 'MPA', (177, 184))	('V30', 'Var', (135, 138))	('cardiac dose', 'MPA', (87, 99))	('PA', 'Chemical', 'MESH:D011478', (226, 228))
90700	21470796	Both the maximum dose to 1cm3 of the spinal cord and the maximum point dose were both markedly lower in the AP/PA IMPT plan than in the IMRT plan (p=0.004 and p=0.01) (Fig.	('PA', 'Chemical', 'MESH:D011478', (111, 113))	('lower', 'NegReg', (95, 100))	('AP/PA IMPT', 'Var', (108, 118))
90705	21470796	Both the maximum dose to 1cm3 of the spinal cord and the maximum point dose were both markedly lower in the AP/PA IMPT plan than in the IMRT plan (p=0.0008 and p=0.002) (Table 1).	('PA', 'Chemical', 'MESH:D011478', (111, 113))	('lower', 'NegReg', (95, 100))	('AP/PA IMPT', 'Var', (108, 118))
90758	24589652	Furthermore, eEF2-derived 9-mer peptides, EF786 (eEF2 786-794 aa) and EF292 (eEF2 292-300 aa), elicited cytotoxic T lymphocyte (CTL) responses in PBMCs from an HLA-A*24:02- and an HLA-A*02:01-positive healthy donors, respectively, in an HLA-A-restricted manner.	('EF292', 'CellLine', 'CVCL:V764', (70, 75))	('eEF2', 'Gene', '1938', (49, 53))	('EF292', 'Var', (70, 75))	('eEF2', 'Gene', (49, 53))	('HLA-A', 'Gene', (160, 165))	('HLA-A', 'Gene', (180, 185))	('HLA-A', 'Gene', '3105', (237, 242))	('HLA-A', 'Gene', '3105', (180, 185))	('HLA-A', 'Gene', (237, 242))	('peptides', 'Chemical', 'MESH:D010455', (32, 40))	('eEF2', 'Gene', '1938', (13, 17))	('elicited', 'Reg', (95, 103))	('eEF2', 'Gene', (77, 81))	('donor', 'Species', '9606', (209, 214))	('eEF2', 'Gene', '1938', (77, 81))	('eEF2', 'Gene', (13, 17))	('HLA-A', 'Gene', '3105', (160, 165))
90776	24589652	eEF2-H118 antibody (Santa Cruz Biotechnology) that recognized 741-858aa of eEF2 protein and Sigma-Aldrich #SAB4500695 antibody that recognized the N terminus of eEF2 protein were used as first antibodies.	('protein', 'Protein', (80, 87))	('eEF2', 'Gene', '1938', (75, 79))	('eEF2', 'Gene', (75, 79))	('741-858aa', 'Var', (62, 71))	('eEF2', 'Gene', '1938', (161, 165))	('eEF2', 'Gene', '1938', (0, 4))	('eEF2', 'Gene', (161, 165))	('eEF2', 'Gene', (0, 4))
90779	24589652	Two different shRNA vectors targeting eEF2 mRNA (shEF-1918 and shEF-2804 targeting 1918-1947 and 2804-2833 nt of eEF2 sequence, respectively) were prepared as described previously.	('eEF2', 'Gene', (38, 42))	('2804-2833 nt', 'Var', (97, 109))	('eEF2', 'Gene', '1938', (113, 117))	('eEF2', 'Gene', (113, 117))	('eEF2', 'Gene', '1938', (38, 42))
90816	24589652	To examine the role of eEF2 in cancer cell growth, either of two different shRNAs targeting eEF2 (shEF-1918 and shEF-2804) or a control shRNA targeting luciferase (shLuc) was transfected into four eEF2-expressing cells, lung cancer PC14, pancreatic cancer PCI6, fibrosarcoma HT-1080, and glioblastoma A172 and eEF2-undetectable breast cancer MCF7 cells.	('lung cancer PC14, pancreatic cancer PCI6, fibrosarcoma HT-1080', 'Disease', 'MESH:D010190', (220, 282))	('cancer', 'Disease', (225, 231))	('eEF2', 'Gene', (310, 314))	('cancer', 'Disease', (249, 255))	('cancer', 'Disease', (335, 341))	('eEF2', 'Gene', (23, 27))	('shEF-2804', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (262, 274))	('glioblastoma', 'Disease', 'MESH:D005909', (288, 300))	('eEF2', 'Gene', (197, 201))	('eEF2', 'Gene', (92, 96))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('glioblastoma', 'Disease', (288, 300))	('breast cancer', 'Phenotype', 'HP:0003002', (328, 341))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (238, 255))	('eEF2', 'Gene', '1938', (310, 314))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('glioblastoma', 'Phenotype', 'HP:0012174', (288, 300))	('MCF7', 'CellLine', 'CVCL:0031', (342, 346))	('eEF2', 'Gene', '1938', (23, 27))	('breast cancer', 'Disease', 'MESH:D001943', (328, 341))	('breast cancer', 'Disease', (328, 341))	('eEF2', 'Gene', '1938', (197, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('eEF2', 'Gene', '1938', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('A172', 'CellLine', 'CVCL:0131', (301, 305))
90821	24589652	As candidate epitope peptides that bound to HLA-A*24:02 molecules, EF78, EF786, EF701 and EF412 peptides were selected and analyzed for binding affinity to HLA-A*24:02 molecules by the MHC stabilization assay.	('HLA-A', 'Gene', '3105', (44, 49))	('HLA-A', 'Gene', '3105', (156, 161))	('peptides', 'Chemical', 'MESH:D010455', (96, 104))	('HLA-A', 'Gene', (156, 161))	('EF412', 'Var', (90, 95))	('peptides', 'Chemical', 'MESH:D010455', (21, 29))	('EF786', 'Var', (73, 78))	('HLA-A', 'Gene', (44, 49))	('EF78', 'Var', (67, 71))	('EF412', 'CellLine', 'CVCL:1V29', (90, 95))	('bound', 'Interaction', (35, 40))	('EF701', 'Var', (80, 85))	('binding', 'Interaction', (136, 143))
90824	24589652	Among the four peptides, EF786 peptide showed binding affinity higher than CMVpp65328-336, which was an exogenous cytomegalovirus antigen epitope, to the HLA-A*24:02 molecules.	('HLA-A', 'Gene', '3105', (154, 159))	('binding affinity', 'Interaction', (46, 62))	('HLA-A', 'Gene', (154, 159))	('peptides', 'Chemical', 'MESH:D010455', (15, 23))	('higher', 'PosReg', (63, 69))	('EF786 peptide', 'Var', (25, 38))
90825	24589652	As candidate peptides that bound to HLA-A*02:01 molecules, EF292, EF739, EF519 and EF671 peptides were selected and analyzed for binding affinity to HLA-A*02:01 molecules by the MHC stabilization assay.	('peptides', 'Chemical', 'MESH:D010455', (13, 21))	('HLA-A', 'Gene', '3105', (36, 41))	('peptides', 'Chemical', 'MESH:D010455', (89, 97))	('HLA-A', 'Gene', (149, 154))	('HLA-A', 'Gene', '3105', (149, 154))	('bound', 'Interaction', (27, 32))	('HLA-A', 'Gene', (36, 41))	('EF292', 'CellLine', 'CVCL:V764', (59, 64))	('EF519', 'CellLine', 'CVCL:V775', (73, 78))	('EF519', 'Var', (73, 78))	('EF671', 'Var', (83, 88))	('binding', 'Interaction', (129, 136))	('EF292', 'Var', (59, 64))	('EF739', 'Var', (66, 71))
90827	24589652	Treg-depleted PBMCs from HLA-A*24:02- or HLA-A*02:01-positive healthy donors were repeatedly stimulated with EF2 peptides (EF786 and EF292 peptides for HLA-A*24:02- and HLA-A*02:01-positive healthy donors, respectively) and pulsed irradiated autologous DCs and EF2 peptide-specific CTLs were established.	('HLA-A', 'Gene', '3105', (25, 30))	('HLA-A', 'Gene', '3105', (41, 46))	('EF292', 'CellLine', 'CVCL:V764', (133, 138))	('HLA-A', 'Gene', '3105', (169, 174))	('HLA-A', 'Gene', (152, 157))	('EF786', 'Var', (123, 128))	('HLA-A', 'Gene', (169, 174))	('EF2', 'Gene', (261, 264))	('donor', 'Species', '9606', (198, 203))	('HLA-A', 'Gene', (41, 46))	('EF2', 'Gene', (109, 112))	('HLA-A', 'Gene', (25, 30))	('EF2', 'Gene', (133, 136))	('donor', 'Species', '9606', (70, 75))	('EF2', 'Gene', '1938', (261, 264))	('EF2', 'Gene', '1938', (109, 112))	('HLA-A', 'Gene', '3105', (152, 157))	('peptides', 'Chemical', 'MESH:D010455', (139, 147))	('EF2', 'Gene', '1938', (133, 136))	('peptides', 'Chemical', 'MESH:D010455', (113, 121))
90829	24589652	4A, EF786-specific, HLA-A*24:02-restricted CTLs lysed EF786 peptide-pulsed T2-2402 cells but not unpulsed ones.	('EF786', 'Var', (54, 59))	('HLA-A', 'Gene', '3105', (20, 25))	('HLA-A', 'Gene', (20, 25))
90830	24589652	The EF786-specific CTLs lysed HLA-A*24:02-positive, eEF2-expressing SW480 cells, but not HLA-A*24:02-negative, eEF2-expressing AZ-521 and MKN28 cells.	('HLA-A', 'Gene', '3105', (30, 35))	('eEF2', 'Gene', '1938', (52, 56))	('SW480', 'CellLine', 'CVCL:0546', (68, 73))	('eEF2', 'Gene', '1938', (111, 115))	('eEF2', 'Gene', (52, 56))	('HLA-A', 'Gene', (30, 35))	('eEF2', 'Gene', (111, 115))	('HLA-A', 'Gene', (89, 94))	('HLA-A', 'Gene', '3105', (89, 94))	('EF786-specific', 'Var', (4, 18))
90831	24589652	4B, EF292 peptide-specific, HLA-A*02:01-restricted CTLs lysed EF292 peptide-pulsed T2-0201 cells but not unpulsed ones.	('EF292', 'Var', (62, 67))	('HLA-A', 'Gene', '3105', (28, 33))	('HLA-A', 'Gene', (28, 33))	('EF292', 'CellLine', 'CVCL:V764', (4, 9))	('EF292', 'CellLine', 'CVCL:V764', (62, 67))	('T2-0201', 'CellLine', 'CVCL:V460', (83, 90))
90832	24589652	Moreover, the EF292-specific CTLs lysed HLA-A*02:01-positive, eEF2-expressing TF-1 cells, but not HLA-A*02:01-negative, eEF2-expressing K562 cells and HLA-A*02:01-positive, eEF2-undetectable MCF7 cells (Fig.	('K562', 'CellLine', 'CVCL:0004', (136, 140))	('eEF2', 'Gene', '1938', (62, 66))	('HLA-A', 'Gene', '3105', (40, 45))	('HLA-A', 'Gene', (98, 103))	('HLA-A', 'Gene', (40, 45))	('eEF2', 'Gene', (62, 66))	('MCF7', 'CellLine', 'CVCL:0031', (191, 195))	('EF292', 'CellLine', 'CVCL:V764', (14, 19))	('HLA-A', 'Gene', '3105', (151, 156))	('eEF2', 'Gene', '1938', (173, 177))	('TF-1', 'CellLine', 'CVCL:0559', (78, 82))	('eEF2', 'Gene', (173, 177))	('EF292-specific', 'Var', (14, 28))	('eEF2', 'Gene', '1938', (120, 124))	('eEF2', 'Gene', (120, 124))	('HLA-A', 'Gene', (151, 156))	('HLA-A', 'Gene', '3105', (98, 103))
90843	24589652	In fact, eEF2-derived EF786 peptide showed the binding affinity higher than CMVpp65328-336, an exogenous viral antigen epitope, and elicited in vitro EF786-specific CTLs from PBMCs of HLA-A*24:02-positive healthy donors.	('HLA-A', 'Gene', (184, 189))	('EF786-specific', 'Var', (150, 164))	('higher', 'PosReg', (64, 70))	('eEF2', 'Gene', '1938', (9, 13))	('EF786', 'Gene', (22, 27))	('CTLs', 'CPA', (165, 169))	('elicited', 'Reg', (132, 140))	('donor', 'Species', '9606', (213, 218))	('eEF2', 'Gene', (9, 13))	('HLA-A', 'Gene', '3105', (184, 189))	('binding', 'Interaction', (47, 54))
90866	24589652	As shown in the present study, knockdown of eEF2 by shRNA significantly inhibited cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('eEF2', 'Gene', '1938', (44, 48))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('inhibited', 'NegReg', (72, 81))	('eEF2', 'Gene', (44, 48))	('knockdown', 'Var', (31, 40))
90868	24589652	Based on these findings showing the involvement of eEF2 in cancer cell growth, it is unlikely that antigenic loss of eEF2 could become a mechanism of tumor escape from eEF2-specific immune responses.	('eEF2', 'Gene', (51, 55))	('eEF2', 'Gene', '1938', (117, 121))	('eEF2', 'Gene', (168, 172))	('eEF2', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('loss', 'Var', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('eEF2', 'Gene', '1938', (168, 172))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', (150, 155))	('eEF2', 'Gene', '1938', (51, 55))
90880	32769441	We found that SHCBP1 depletion inhibited the proliferation and motility of ESCC cells via the transforming growth factor beta pathway and that it suppressed the growth of tumors in mice.	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('mice', 'Species', '10090', (181, 185))	('motility', 'CPA', (63, 71))	('SHCBP1', 'Gene', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('proliferation', 'CPA', (45, 58))	('inhibited', 'NegReg', (31, 40))	('transforming growth factor beta', 'Gene', '7124', (94, 125))	('depletion', 'Var', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('transforming growth factor beta', 'Gene', (94, 125))	('tumors', 'Disease', (171, 177))	('suppressed', 'NegReg', (146, 156))
90903	32769441	The 4 types of human ESCC cell lines, KYSE150, KYSE30, KYSE180, and KYSE450, were all bought from ATCC, and maintained in Dulbecco Modified Eagle Medium, supplemented with 10% of fetal bovine serum (FBS) in a 5% CO2 incubator at 37 C. The shRNAs were transfected into ESCC cells by lipofectamine 2000 (11668019; Invitrogen).	('KYSE180', 'Var', (55, 62))	('KYSE30', 'Var', (47, 53))	('Dulbecco Modified Eagle Medium', 'Chemical', '-', (122, 152))	('CO2', 'Chemical', 'MESH:D002245', (212, 215))	('lipofectamine 2000', 'Chemical', 'MESH:C086724', (282, 300))	('human', 'Species', '9606', (15, 20))	('KYSE180', 'CellLine', 'CVCL:1349', (55, 62))	('KYSE450', 'Var', (68, 75))	('KYSE150', 'Var', (38, 45))
90932	32769441	Next, we detected the mRNA levels of SHCBP1 in human normal esophageal squamous epithelial cell (Het-1A) and ESCC cell lines, including KYSE150, KYSE30, KYSE180, and KYSE450.	('SHCBP1', 'Gene', (37, 43))	('mRNA levels', 'MPA', (22, 33))	('KYSE30', 'Var', (145, 151))	('KYSE150', 'Var', (136, 143))	('human', 'Species', '9606', (47, 52))	('KYSE180', 'CellLine', 'CVCL:1349', (153, 160))
90943	32769441	The results of quantitative PCR assays showed that the transfection of SHCBP1 shRNA effectively decreased its expression level in KYSE180 cell (Fig.	('expression level', 'MPA', (110, 126))	('KYSE180', 'CellLine', 'CVCL:1349', (130, 137))	('decreased', 'NegReg', (96, 105))	('SHCBP1', 'Gene', (71, 77))	('transfection', 'Var', (55, 67))
90945	32769441	Brdu assays showed that SHCBP1 depletion resulted in a significant decreased proliferation capacity of KYSE180 cells (Fig.	('proliferation capacity', 'CPA', (77, 99))	('KYSE180', 'CellLine', 'CVCL:1349', (103, 110))	('depletion', 'Var', (31, 40))	('decreased', 'NegReg', (67, 76))	('SHCBP1', 'Gene', (24, 30))
90946	32769441	As was expected, our results revealed that SHCBP1 depletion remarkably inhibited the wound healing in KYSE180 cell (Fig.	('wound healing in KYSE180 cell', 'CPA', (85, 114))	('inhibited', 'NegReg', (71, 80))	('KYSE180', 'CellLine', 'CVCL:1349', (102, 109))	('SHCBP1', 'Gene', (43, 49))	('depletion', 'Var', (50, 59))
90947	32769441	In addition, SHCBP1 depletion markedly blocked the invasion of KYSE180 cells, with an obviously dropped cell number (Fig.	('blocked', 'NegReg', (39, 46))	('dropped', 'NegReg', (96, 103))	('depletion', 'Var', (20, 29))	('cell number', 'CPA', (104, 115))	('KYSE180', 'CellLine', 'CVCL:1349', (63, 70))	('SHCBP1', 'Gene', (13, 19))	('invasion of KYSE180 cells', 'CPA', (51, 76))
90952	32769441	Through immunoblot assays, we found that phosphorylated Smad2/3 expression was significantly reduced since SHCBP1 knockdown (Fig.	('SHCBP1', 'Gene', (107, 113))	('Smad2/3', 'Gene', (56, 63))	('expression', 'MPA', (64, 74))	('phosphorylated', 'MPA', (41, 55))	('Smad2/3', 'Gene', '4087;4088', (56, 63))	('knockdown', 'Var', (114, 123))	('reduced', 'NegReg', (93, 100))
90955	32769441	The result showed that phosphorylated ERK1/2 was dramatically reduced in the SHCBP1 knockdown group.	('ERK1/2', 'Gene', '5595;5594', (38, 44))	('knockdown', 'Var', (84, 93))	('phosphorylated', 'MPA', (23, 37))	('SHCBP1', 'Gene', (77, 83))	('ERK1/2', 'Gene', (38, 44))	('reduced', 'NegReg', (62, 69))
90956	32769441	We were, therefore, clear that ablation of SHCBP1 inhibits TGFbeta1 signaling pathway and ERK1/2 activation.	('ERK1/2', 'Gene', (90, 96))	('ERK1/2', 'Gene', '5595;5594', (90, 96))	('SHCBP1', 'Gene', (43, 49))	('TGFbeta1', 'Gene', '7040', (59, 67))	('TGFbeta1', 'Gene', (59, 67))	('inhibits', 'NegReg', (50, 58))	('ablation', 'Var', (31, 39))	('activation', 'MPA', (97, 107))
90957	32769441	According to the results mentioned above, we knew that SHCBP1 ablation led to the inhibition of ESCC cell proliferation, migration, and invasion in vitro; we then further explored the potential function of SHCBP1 in tumor growth in mice.	('tumor', 'Disease', (216, 221))	('migration', 'CPA', (121, 130))	('ESCC cell proliferation', 'CPA', (96, 119))	('SHCBP1', 'Gene', (55, 61))	('invasion', 'CPA', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('inhibition', 'NegReg', (82, 92))	('ablation', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('mice', 'Species', '10090', (232, 236))
90961	32769441	Interestingly, the volume of tumors isolated from SHCBP1 depletion groups was significantly smaller than that of the control groups (Fig.	('depletion', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('SHCBP1', 'Gene', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('smaller', 'NegReg', (92, 99))
90983	32769441	As was expected, other studies and our findings revealed that SHCBP1 depletion impaired the proliferation of cancer cells in vitro, which might be caused by the abnormal cell division.	('cell division', 'CPA', (170, 183))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('depletion', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('impaired', 'NegReg', (79, 87))	('SHCBP1', 'Gene', (62, 68))
90985	32769441	We found that SHCBP1 depletion inhibited the proliferation and motility of ESCC cells via the TGFbeta pathway, and suppressed tumor growth in mice.	('motility', 'CPA', (63, 71))	('SHCBP1', 'Gene', (14, 20))	('proliferation', 'CPA', (45, 58))	('TGFbeta pathway', 'Pathway', (94, 109))	('mice', 'Species', '10090', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('depletion', 'Var', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('suppressed', 'NegReg', (115, 125))	('inhibited', 'NegReg', (31, 40))	('tumor', 'Disease', (126, 131))
90987	32556556	p16 overexpression is also known to be induced by deregulation of RB1 in neuroendocrine carcinomas.	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (73, 98))	('neuroendocrine carcinomas', 'Disease', (73, 98))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (73, 98))	('p16', 'Gene', (0, 3))	('RB1', 'Gene', '5925', (66, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('overexpression', 'PosReg', (4, 18))	('deregulation', 'Var', (50, 62))	('p16', 'Gene', '1029', (0, 3))	('RB1', 'Gene', (66, 69))
91002	32556556	In general, CDKN2A is frequently inactivated in human malignant tumors by its gene aberrations, such as deletions or mutations, but diffuse p16 expression was also reported in various human malignancies, e.g., high-grade breast and lung cancers and/or undifferentiated pleomorphic sarcoma without significant association with its gene alteration status.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('CDKN2A', 'Gene', (12, 18))	('malignant tumors', 'Disease', 'MESH:D009369', (54, 70))	('reported', 'Reg', (164, 172))	('p16', 'Gene', (140, 143))	('human', 'Species', '9606', (184, 189))	('p16', 'Gene', '1029', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('human', 'Species', '9606', (48, 53))	('CDKN2A', 'Gene', '1029', (12, 18))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('malignancies', 'Disease', 'MESH:D009369', (190, 202))	('malignancies', 'Disease', (190, 202))	('mutations', 'Var', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('lung cancers', 'Phenotype', 'HP:0100526', (232, 244))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (252, 288))	('breast and lung cancers', 'Disease', 'MESH:D001943', (221, 244))	('deletions', 'Var', (104, 113))	('undifferentiated pleomorphic sarcoma', 'Disease', (252, 288))	('malignant tumors', 'Disease', (54, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))
91003	32556556	In these neoplasms, p16 was reported to be induced by deregulation of RB1 as positive feedback.	('RB1', 'Gene', (70, 73))	('p16', 'Gene', (20, 23))	('neoplasms', 'Disease', (9, 18))	('deregulation', 'Var', (54, 66))	('neoplasms', 'Disease', 'MESH:D009369', (9, 18))	('RB1', 'Gene', '5925', (70, 73))	('p16', 'Gene', '1029', (20, 23))	('neoplasms', 'Phenotype', 'HP:0002664', (9, 18))
91004	32556556	The p16 overexpression via RB1 alteration was on the one hand demonstrated in highly aggressive tumors, such as small-cell carcinomas of the lung and esophagus.	('overexpression', 'PosReg', (8, 22))	('small-cell carcinomas of the lung', 'Disease', 'MESH:D055752', (112, 145))	('small-cell carcinomas of the lung', 'Phenotype', 'HP:0030357', (112, 145))	('RB1', 'Gene', '5925', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('p16', 'Gene', '1029', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('p16', 'Gene', (4, 7))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('aggressive tumors', 'Disease', 'MESH:D001523', (85, 102))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (123, 145))	('alteration', 'Var', (31, 41))	('esophagus', 'Disease', (150, 159))	('aggressive tumors', 'Disease', (85, 102))	('small-cell carcinoma', 'Phenotype', 'HP:0030357', (112, 132))	('small-cell carcinomas of the lung', 'Disease', (112, 145))	('RB1', 'Gene', (27, 30))
91024	32556556	Tumors with the following conditions were excluded: (i) located at the esophagogastric junction or concomitant Barrett's esophagus and (ii) eradication of more than two thirds of the tumor with preoperative therapy.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (111, 130))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (183, 188))	('eradication', 'Var', (140, 151))
91081	32556556	CDKN2A was inactivated mostly by deletion (44-72%), occasionally by mutation (2-8%).	('inactivated', 'NegReg', (11, 22))	('deletion', 'Var', (33, 41))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))
91082	32556556	CDKN2A DNA hypermethylation could also contribute to its inactivation, and the aberrant methylation of 5' CpG islands of the CDKN2A promoter region leads to repression of its gene transcription.	('methylation', 'Var', (88, 99))	('gene transcription', 'MPA', (175, 193))	('repression', 'NegReg', (157, 167))	('inactivation', 'MPA', (57, 69))	('aberrant methylation', 'Var', (79, 99))	('CDKN2A', 'Gene', (125, 131))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (125, 131))	('CDKN2A', 'Gene', '1029', (0, 6))
91087	32556556	Although the frequency of inactivation of p16 in basaloid squamous cell carcinomas has not been fully studied at this juncture, an inactivation of the p16 gene might correlate with high-grade neoplasms.	('p16', 'Gene', '1029', (42, 45))	('inactivation', 'Var', (26, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (58, 82))	('squamous cell carcinomas', 'Disease', (58, 82))	('neoplasms', 'Disease', (192, 201))	('neoplasms', 'Disease', 'MESH:D009369', (192, 201))	('basaloid squamous cell carcinomas', 'Phenotype', 'HP:0002671', (49, 82))	('p16', 'Gene', '1029', (151, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('p16', 'Gene', (151, 154))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (58, 82))	('p16', 'Gene', (42, 45))	('inactivation', 'Var', (131, 143))	('neoplasms', 'Phenotype', 'HP:0002664', (192, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('correlate', 'Reg', (166, 175))	('basaloid squamous cell carcinoma', 'Phenotype', 'HP:0002671', (49, 81))
91088	32556556	Whether p16 immunoreactivity can serve as a predictive marker for genetic or epigenetic inactivation of CDKN2A gene is controversial, and further investigations are required for clarification at this juncture.	('CDKN2A', 'Gene', '1029', (104, 110))	('p16', 'Gene', '1029', (8, 11))	('p16', 'Gene', (8, 11))	('CDKN2A', 'Gene', (104, 110))	('epigenetic inactivation', 'Var', (77, 100))
91091	32556556	The p16 overexpression is considered as positive feedback by deregulation of RB1.	('p16', 'Gene', (4, 7))	('RB1', 'Gene', (77, 80))	('deregulation', 'Var', (61, 73))	('p16', 'Gene', '1029', (4, 7))	('RB1', 'Gene', '5925', (77, 80))
91092	32556556	An inactivation of RB1 was reported to play a pivotal role in carcinogenesis of neuroendocrine carcinomas, and Rb1 protein loss was proposed to be a characteristic in gastroenteropancreatic and pulmonary neuroendocrine carcinomas.	('Rb1', 'Gene', (111, 114))	('gastroenteropancreatic and pulmonary neuroendocrine carcinomas', 'Disease', 'MESH:C535650', (167, 229))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (80, 105))	('inactivation', 'Var', (3, 15))	('carcinogenesis of neuroendocrine carcinomas', 'Disease', (62, 105))	('protein', 'Protein', (115, 122))	('carcinogenesis of neuroendocrine carcinomas', 'Disease', 'MESH:D063646', (62, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('RB1', 'Gene', (19, 22))	('loss', 'NegReg', (123, 127))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (204, 229))	('Rb1', 'Gene', '5925', (111, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))	('RB1', 'Gene', '5925', (19, 22))
91093	32556556	In small-cell lung cancer, the mechanism has been shown that at least one allele of RB1 was affected by different genomic alterations (i.e., hemizygous deletion, loss of heterozygosity, or mutation, including rearrangements).	('affected', 'Reg', (92, 100))	('small-cell lung cancer', 'Disease', (3, 25))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (3, 25))	('RB1', 'Gene', (84, 87))	('loss of heterozygosity', 'Var', (162, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('mutation', 'Var', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('RB1', 'Gene', '5925', (84, 87))	('rearrangements', 'Var', (209, 223))
91099	32556556	However, in this study, p16 positivity in high-grade squamous cell carcinoma was not associated with tumor size, TNM stage, and patients' clinical outcome.	('p16', 'Gene', '1029', (24, 27))	('TNM', 'Gene', (113, 116))	('positivity', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('p16', 'Gene', (24, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('squamous cell carcinoma', 'Disease', (53, 76))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 76))	('patients', 'Species', '9606', (128, 136))	('TNM', 'Gene', '10178', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
91101	32556556	Interestingly, the p16 overexpression induced by dysregulation of RB1 appeared to have an association with tumor aggressiveness in high-grade squamous cell carcinoma.	('association', 'Reg', (90, 101))	('overexpression', 'PosReg', (23, 37))	('p16', 'Gene', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('aggressiveness', 'Phenotype', 'HP:0000718', (113, 127))	('squamous cell carcinoma', 'Disease', (142, 165))	('RB1', 'Gene', '5925', (66, 69))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 165))	('tumor aggressiveness', 'Disease', (107, 127))	('p16', 'Gene', '1029', (19, 22))	('dysregulation', 'Var', (49, 62))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (107, 127))	('RB1', 'Gene', (66, 69))
91109	32556556	However, p16 can be induced by dysregulation of the RB1 pathway without HPV infection.	('RB1', 'Gene', (52, 55))	('HPV infection', 'Disease', 'MESH:D030361', (72, 85))	('induced by', 'Reg', (20, 30))	('p16', 'Gene', '1029', (9, 12))	('RB1', 'Gene', '5925', (52, 55))	('dysregulation', 'Var', (31, 44))	('HPV infection', 'Disease', (72, 85))	('p16', 'Gene', (9, 12))
91130	33588854	The operative time (178.25 +- 15.41 vs 196.5 +- 21.16 min) and the gastrointestinal reconstruction time (19.3 +- 2.53 vs 34.65 +- 4.88 min) of the TULPG-SEV group were significantly less than that of the LTG group.	('TULPG-SEV', 'Var', (147, 156))	('less', 'NegReg', (182, 186))	('TULPG', 'Chemical', '-', (147, 152))	('LTG', 'Chemical', '-', (204, 207))
91134	33588854	The postoperative hemoglobin level was better in the TULPG-SEV group than in the LTG group, and the difference was most noticeable at 1 month after surgery (P = 0.024) and 3 months after surgery (P = 0.029).	('TULPG-SEV', 'Var', (53, 62))	('LTG', 'Chemical', '-', (81, 84))	('TULPG', 'Chemical', '-', (53, 58))	('hemoglobin level', 'MPA', (18, 34))	('better', 'PosReg', (39, 45))
91136	33588854	There were more patients with weight loss over 5 kg after surgery in the LTG group than in the TULPG-SEV group (P = 0.043).	('weight loss', 'Disease', (30, 41))	('weight loss', 'Phenotype', 'HP:0001824', (30, 41))	('patients', 'Species', '9606', (16, 24))	('TULPG', 'Chemical', '-', (95, 100))	('LTG', 'Var', (73, 76))	('weight loss', 'Disease', 'MESH:D015431', (30, 41))	('LTG', 'Chemical', '-', (73, 76))
91181	33588854	There were more Siewert type III patients in the LTG group than in the PG group, but the difference was not significant (P = 0.091).	('PG', 'Chemical', '-', (71, 73))	('patients', 'Species', '9606', (33, 41))	('Siewert type III', 'Disease', (16, 32))	('LTG', 'Var', (49, 52))	('LTG', 'Chemical', '-', (49, 52))
91184	33588854	The operative time (178.25 +- 15.41 vs 196.5 +- 21.16 min, P = 0.03) and the time for digestive tract reconstruction (19.3 +- 2.53 vs 34.65 +- 4.88 min, P < 0.01) in the TULPG-SEV group were significantly shorter than those in the LTG group.	('LTG', 'Chemical', '-', (231, 234))	('TULPG-SEV', 'Var', (170, 179))	('shorter', 'NegReg', (205, 212))	('TULPG', 'Chemical', '-', (170, 175))
91206	33588854	One year after surgery, hemoglobin level was still better in the TULPG-SEV group than in the LTG group, but this difference was not significant (125.3 vs 121.25 g/L; P = 0.081).	('his', 'Gene', (109, 112))	('his', 'Gene', '3034', (109, 112))	('better', 'PosReg', (51, 57))	('hemoglobin level', 'MPA', (24, 40))	('TULPG-SEV', 'Var', (65, 74))	('TULPG', 'Chemical', '-', (65, 70))	('LTG', 'Chemical', '-', (93, 96))
91209	33588854	The number of patients with weight loss over 5 kg at the sixth month after operation in the TULPG-SEV group was significantly smaller than that in the LTG group (3 vs 10, P = 0.043).	('smaller', 'NegReg', (126, 133))	('TULPG-SEV', 'Var', (92, 101))	('weight loss', 'Disease', 'MESH:D015431', (28, 39))	('TULPG', 'Chemical', '-', (92, 97))	('LTG', 'Chemical', '-', (151, 154))	('weight loss', 'Disease', (28, 39))	('weight loss', 'Phenotype', 'HP:0001824', (28, 39))	('patients', 'Species', '9606', (14, 22))
91223	33588854	(3) The division of the vagus nerve weakens gastric motility and causes persistent contraction of the pylorus, which further increases the probability of gastroesophageal reflux disease.	('increases', 'PosReg', (125, 134))	('gastric motility', 'Disease', 'MESH:D013274', (44, 60))	('gastroesophageal reflux disease', 'Disease', (154, 185))	('weakens', 'NegReg', (36, 43))	('contraction', 'MPA', (83, 94))	('division', 'Var', (8, 16))	('causes', 'Reg', (65, 71))	('gastric motility', 'Disease', (44, 60))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (154, 185))	('reflux disease', 'Phenotype', 'HP:0002020', (171, 185))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (154, 177))
91242	33588854	Our study has also confirmed that TULPG is related to high levels of hemoglobin and reduce weight loss compared to LPG.	('reduce', 'NegReg', (84, 90))	('PG', 'Chemical', '-', (37, 39))	('weight loss', 'Phenotype', 'HP:0001824', (91, 102))	('PG', 'Chemical', '-', (116, 118))	('reduce weight', 'Phenotype', 'HP:0004325', (84, 97))	('weight loss', 'Disease', 'MESH:D015431', (91, 102))	('TULPG', 'Var', (34, 39))	('TULPG', 'Chemical', '-', (34, 39))	('weight loss', 'Disease', (91, 102))
91243	33588854	The number of patients with postoperative weight loss greater than 5 kg at the sixth month after operation in TULPG group was significantly less than that in LTG group (3 vs 10, P = 0.043).	('TULPG', 'Var', (110, 115))	('TULPG', 'Chemical', '-', (110, 115))	('postoperative weight loss', 'Disease', 'MESH:D015431', (28, 53))	('LTG', 'Chemical', '-', (158, 161))	('postoperative weight loss', 'Disease', (28, 53))	('less', 'NegReg', (140, 144))	('weight loss', 'Phenotype', 'HP:0001824', (42, 53))	('patients', 'Species', '9606', (14, 22))
91258	33466296	Discovering Genotype Variants in an Infant with VACTERL through Clinical Exome Sequencing: A Support for Personalized Risk Assessment and Disease Prevention Congenital anomalies may have an increased risk of noncommunicable diseases (NCDs) We performed a clinical exome analysis in an infant affected by "Vertebral, Anorectal, Cardiac, Tracheoesophageal, Genitourinary, and Limb" (VACTERL) malformation association to identify potential biomarkers that may be helpful for preventing malignancy risk or other chronic processes.	('Variants', 'Var', (21, 29))	('NCDs', 'Disease', (234, 238))	('Congenital anomalies', 'Disease', 'MESH:D000013', (157, 177))	('NCDs', 'Disease', 'None', (234, 238))	('Congenital anomalies', 'Disease', (157, 177))	('malignancy', 'Disease', 'MESH:D009369', (483, 493))	('malignancy', 'Disease', (483, 493))
91259	33466296	The variants c.501G>C on OLR1 and c.-8C>G on PSMA6 were previously associated with myocardial infarction.	('c.501G>C', 'Var', (13, 21))	('c.-8C>G', 'Mutation', 'rs1048990', (34, 41))	('OLR1', 'Gene', (25, 29))	('myocardial infarction', 'Disease', (83, 104))	('c.501G>C', 'Mutation', 'rs11053646', (13, 21))	('myocardial infarction', 'Disease', 'MESH:D009203', (83, 104))	('c.-8C>G', 'Var', (34, 41))	('PSMA6', 'Gene', (45, 50))	('PSMA6', 'Gene', '5687', (45, 50))	('OLR1', 'Gene', '4973', (25, 29))	('myocardial infarction', 'Phenotype', 'HP:0001658', (83, 104))	('associated with', 'Reg', (67, 82))
91260	33466296	The variants c.1936A>G on AKAP10 and c.575A>G on PON1 are linked to defects in cardiac conduction and artery disease, respectively.	('c.575A>G', 'Var', (37, 45))	('AKAP10', 'Gene', (26, 32))	('AKAP10', 'Gene', '11216', (26, 32))	('PON1', 'Gene', (49, 53))	('linked', 'Reg', (58, 64))	('c.1936A>G', 'Mutation', 'rs203462', (13, 22))	('cardiac conduction and artery disease', 'Disease', 'MESH:D006331', (79, 116))	('c.575A>G', 'Mutation', 'rs662', (37, 45))	('PON1', 'Gene', '5444', (49, 53))	('cardiac conduction', 'Phenotype', 'HP:0011675', (79, 97))	('defects', 'NegReg', (68, 75))	('c.1936A>G', 'Var', (13, 22))
91261	33466296	Alterations in metabolism were also suggested by the variants c.860G>A on EPHX2 and c.214C>A on GHRL.	('c.214C>A', 'Var', (84, 92))	('GHRL', 'Gene', '51738', (96, 100))	('metabolism', 'MPA', (15, 25))	('GHRL', 'Gene', (96, 100))	('c.860G>A', 'Var', (62, 70))	('c.214C>A', 'Mutation', 'rs696217', (84, 92))	('rat', 'Species', '10116', (4, 7))	('EPHX2', 'Gene', (74, 79))	('c.860G>A', 'Mutation', 'rs751141', (62, 70))	('Alterations', 'Reg', (0, 11))	('EPHX2', 'Gene', '2053', (74, 79))
91262	33466296	In addition, three variants associated with colon cancer were discovered.	('colon cancer', 'Phenotype', 'HP:0003003', (44, 56))	('colon cancer', 'Disease', 'MESH:D015179', (44, 56))	('associated', 'Reg', (28, 38))	('colon cancer', 'Disease', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('variants', 'Var', (19, 27))
91263	33466296	Specifically, the reported variants were c.723G>A on CCND1 and c.91T>A on AURKA proto-oncogenes as well as c.827A>C in the tumor suppressor PTPRJ.	('c.827A>C', 'Mutation', 'rs1566734', (107, 115))	('c.723G>A', 'Mutation', 'rs9344', (41, 49))	('c.91T>A', 'Var', (63, 70))	('tumor', 'Disease', (123, 128))	('CCND1', 'Gene', (53, 58))	('c.91T>A', 'Mutation', 'rs2273535', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('c.723G>A', 'Var', (41, 49))	('AURKA', 'Gene', '6790', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('PTPRJ', 'Gene', '5795', (140, 145))	('AURKA', 'Gene', (74, 79))	('CCND1', 'Gene', '595', (53, 58))	('PTPRJ', 'Gene', (140, 145))	('c.827A>C', 'Var', (107, 115))
91264	33466296	A further inspection identified 15 rare variants carried by cancer genes.	('cancer', 'Disease', (60, 66))	('variants', 'Var', (40, 48))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
91265	33466296	Specifically, these mutations are located on five tumor suppressors (SDHA, RB1CC1, PTCH1, DMBT1, BCR) and eight proto-oncogenes (MERTK, CSF1R, MYB, ROS1, PCM1, FGFR2, MYH11, BRCC3) and have an allele frequency lower than 0.01 in the Genome Aggregation Database (GnomAD).	('RB1CC1', 'Gene', '9821', (75, 81))	('BCR', 'Gene', '613', (97, 100))	('DMBT1', 'Gene', '1755', (90, 95))	('PCM1', 'Gene', (154, 158))	('MYH11', 'Gene', '4629', (167, 172))	('BRCC3', 'Gene', '79184', (174, 179))	('MYH11', 'Gene', (167, 172))	('PTCH1', 'Gene', '5727', (83, 88))	('BCR', 'Gene', (97, 100))	('MERTK', 'Gene', '10461', (129, 134))	('MERTK', 'Gene', (129, 134))	('MYB', 'Gene', '4602', (143, 146))	('ROS1', 'Gene', (148, 152))	('BRCC3', 'Gene', (174, 179))	('MYB', 'Gene', (143, 146))	('tumor', 'Disease', (50, 55))	('RB1CC1', 'Gene', (75, 81))	('DMBT1', 'Gene', (90, 95))	('CSF1R', 'Gene', '1436', (136, 141))	('PTCH1', 'Gene', (83, 88))	('SDHA', 'Gene', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('CSF1R', 'Gene', (136, 141))	('FGFR2', 'Gene', (160, 165))	('SDHA', 'Gene', '6389', (69, 73))	('mutations', 'Var', (20, 29))	('PCM1', 'Gene', '5108', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('FGFR2', 'Gene', '2263', (160, 165))	('ROS1', 'Gene', '6098', (148, 152))
91288	33466296	Among them, we found two heterozygous variants described as pathogenic (rs1566734, rs72474224), one heterozygous pathogenic/risk factor (rs696217), three homozygous (rs662, rs9344, rs2273535), and four heterozygous risk factors (rs751141, rs11053646, rs1048990, rs203462) (Table 1).	('rs751141', 'Mutation', 'rs751141', (229, 237))	('rs11053646', 'Mutation', 'rs11053646', (239, 249))	('rs751141', 'Var', (229, 237))	('rs9344', 'Mutation', 'rs9344', (173, 179))	('rs696217', 'Mutation', 'rs696217', (137, 145))	('rs203462', 'Mutation', 'rs203462', (262, 270))	('rs1566734', 'Mutation', 'rs1566734', (72, 81))	('pathogenic', 'Reg', (60, 70))	('rs662', 'Mutation', 'rs662', (166, 171))	('rs1566734', 'Var', (72, 81))	('rs9344', 'Var', (173, 179))	('rs72474224', 'Var', (83, 93))	('rs2273535', 'Var', (181, 190))	('rs1048990', 'Var', (251, 260))	('rs1048990', 'Mutation', 'rs1048990', (251, 260))	('rs203462', 'Var', (262, 270))	('rs11053646', 'Var', (239, 249))	('rs662', 'Var', (166, 171))	('rs72474224', 'Mutation', 'rs72474224', (83, 93))	('rs2273535', 'Mutation', 'rs2273535', (181, 190))
91290	33466296	The only variant in our analysis affecting these genes is rs4614723, carried out by SALL1 but defined as benign.	('rs4614723', 'Var', (58, 67))	('SALL1', 'Gene', '6299', (84, 89))	('SALL1', 'Gene', (84, 89))	('rs4614723', 'Mutation', 'rs4614723', (58, 67))
91293	33466296	The only genes having variants associated with the patient were BRCA2 and PALLD for pancreatic cancer, but they are clinically identified as benign.	('BRCA2', 'Gene', '675', (64, 69))	('PALLD', 'Gene', (74, 79))	('PALLD', 'Gene', '23022', (74, 79))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('pancreatic cancer', 'Disease', (84, 101))	('patient', 'Species', '9606', (51, 58))	('BRCA2', 'Gene', (64, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('variants', 'Var', (22, 30))
91294	33466296	Furthermore, we extracted a list of proto-oncogenes and tumor suppressor genes from UniProtKB using the filters "Human" and "Reviewed" and selected only the variants carried on these genes.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Human', 'Species', '9606', (113, 118))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('variants', 'Var', (157, 165))
91295	33466296	We identified nine rare variants on eight proto-oncogenes (MERTK, CSF1R, MYB, ROS1, PCM1, FGFR2, MYH11, BRCC3) and six rare variants on five tumor suppressors (SDHA, RB1CC1, PTCH1, DMBT1, BCR), Figure 2.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('MYH11', 'Gene', '4629', (97, 102))	('RB1CC1', 'Gene', (166, 172))	('MYH11', 'Gene', (97, 102))	('MERTK', 'Gene', '10461', (59, 64))	('SDHA', 'Gene', (160, 164))	('MERTK', 'Gene', (59, 64))	('MYB', 'Gene', '4602', (73, 76))	('ROS1', 'Gene', (78, 82))	('BRCC3', 'Gene', (104, 109))	('SDHA', 'Gene', '6389', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('FGFR2', 'Gene', (90, 95))	('MYB', 'Gene', (73, 76))	('PTCH1', 'Gene', (174, 179))	('CSF1R', 'Gene', '1436', (66, 71))	('PCM1', 'Gene', '5108', (84, 88))	('BCR', 'Gene', '613', (188, 191))	('DMBT1', 'Gene', '1755', (181, 186))	('CSF1R', 'Gene', (66, 71))	('variants', 'Var', (24, 32))	('FGFR2', 'Gene', '2263', (90, 95))	('BCR', 'Gene', (188, 191))	('RB1CC1', 'Gene', '9821', (166, 172))	('PCM1', 'Gene', (84, 88))	('ROS1', 'Gene', '6098', (78, 82))	('variants', 'Var', (124, 132))	('tumor', 'Disease', (141, 146))	('DMBT1', 'Gene', (181, 186))	('PTCH1', 'Gene', '5727', (174, 179))	('BRCC3', 'Gene', '79184', (104, 109))
91302	33466296	The polymorphism c.501G>C on OLR1 gene encodes for oxidized low-density lipoprotein receptor 1, and the c.-8c>G on PSMA6 gene encodes for proteasome subunit alpha type-6.	('c.501G>C', 'Var', (17, 25))	('c.-8c>G', 'Var', (104, 111))	('oxidized low-density lipoprotein receptor 1', 'Gene', (51, 94))	('OLR1', 'Gene', '4973', (29, 33))	('proteasome subunit alpha type-6', 'Gene', '5687', (138, 169))	('c.501G>C', 'Mutation', 'rs11053646', (17, 25))	('PSMA6', 'Gene', '5687', (115, 120))	('PSMA6', 'Gene', (115, 120))	('c.-8c>G', 'Mutation', 'rs1048990', (104, 111))	('proteasome subunit alpha type-6', 'Gene', (138, 169))	('oxidized low-density lipoprotein receptor 1', 'Gene', '4973', (51, 94))	('OLR1', 'Gene', (29, 33))
91303	33466296	These two heterozygous variants are associated with myocardial infarction in ClinVar.	('myocardial infarction', 'Disease', (52, 73))	('myocardial infarction', 'Disease', 'MESH:D009203', (52, 73))	('variants', 'Var', (23, 31))	('associated with', 'Reg', (36, 51))	('myocardial infarction', 'Phenotype', 'HP:0001658', (52, 73))
91304	33466296	Specifically, c.501G>C is a missense variant that causes a change in the protein sequence of oxidized low-density lipoprotein receptor 1 and may result in reduced interaction with ligands.	('oxidized low-density lipoprotein receptor 1', 'Gene', (93, 136))	('reduced', 'NegReg', (155, 162))	('interaction', 'Interaction', (163, 174))	('c.501G>C', 'Var', (14, 22))	('change', 'Reg', (59, 65))	('c.501G>C', 'Mutation', 'rs11053646', (14, 22))	('ligands', 'Interaction', (180, 187))	('protein sequence', 'MPA', (73, 89))	('oxidized low-density lipoprotein receptor 1', 'Gene', '4973', (93, 136))
91305	33466296	observed a group of patients suffering from myocardial infarction and suggested that this variant promotes atherogenesis and coronary artery disease.	('atherogenesis', 'Disease', 'MESH:D050197', (107, 120))	('myocardial infarction', 'Disease', (44, 65))	('promotes', 'PosReg', (98, 106))	('atherogenesis', 'Disease', (107, 120))	('coronary artery disease', 'Disease', 'MESH:D003324', (125, 148))	('myocardial infarction', 'Phenotype', 'HP:0001658', (44, 65))	('myocardial infarction', 'Disease', 'MESH:D009203', (44, 65))	('patients', 'Species', '9606', (20, 28))	('coronary artery disease', 'Disease', (125, 148))	('variant', 'Var', (90, 97))
91307	33466296	found a significant association of this variant with myocardial infarction pathogenesis via the activation of inflammatory processes, and Hinoara et al.	('variant', 'Var', (40, 47))	('myocardial infarction', 'Phenotype', 'HP:0001658', (53, 74))	('association', 'Interaction', (20, 31))	('inflammatory processes', 'CPA', (110, 132))	('myocardial infarction', 'Disease', (53, 74))	('myocardial infarction', 'Disease', 'MESH:D009203', (53, 74))	('activation', 'PosReg', (96, 106))
91308	33466296	proposed a modest risk factor of the variant in coronary artery disease.	('variant', 'Var', (37, 44))	('coronary artery disease', 'Disease', 'MESH:D003324', (48, 71))	('coronary artery disease', 'Disease', (48, 71))
91309	33466296	In addition, the heterozygous variant c.1936A>G on the AKAP10 gene, which encodes for A-kinase anchoring protein 10, is associated with susceptibility to cardiac conduction defect, and the homozygous variant c.575A>G on PON1, which encodes for serum paraoxonase and arylesterase 1, is reported with susceptibility to coronary artery spasm and artery disease.	('cardiac conduction defect', 'Disease', (154, 179))	('arylesterase 1', 'Gene', '5444', (266, 280))	('PON1', 'Gene', (220, 224))	('arylesterase 1', 'Gene', (266, 280))	('coronary artery spasm and artery disease', 'Disease', 'MESH:D003324', (317, 357))	('AKAP10', 'Gene', (55, 61))	('A-kinase anchoring protein 10', 'Gene', (86, 115))	('susceptibility', 'Reg', (136, 150))	('c.575A>G', 'Mutation', 'rs662', (208, 216))	('cardiac conduction defect', 'Disease', 'OMIM:115080', (154, 179))	('c.1936A>G', 'Var', (38, 47))	('A-kinase anchoring protein 10', 'Gene', '11216', (86, 115))	('AKAP10', 'Gene', '11216', (55, 61))	('artery spasm', 'Phenotype', 'HP:0025637', (326, 338))	('cardiac conduction defect', 'Phenotype', 'HP:0011675', (154, 179))	('c.1936A>G', 'Mutation', 'rs203462', (38, 47))	('coronary artery spasm', 'Phenotype', 'HP:0025497', (317, 338))	('PON1', 'Gene', '5444', (220, 224))	('cardiac conduction', 'Phenotype', 'HP:0011675', (154, 172))	('c.575A>G', 'Var', (208, 216))
91310	33466296	found a strong correlation with c.1936A>G and aging, which, interestingly, seems to alter heart functionality.	('c.1936A>G', 'Var', (32, 41))	('c.1936A>G', 'Mutation', 'rs203462', (32, 41))	('alter', 'Reg', (84, 89))	('heart functionality', 'MPA', (90, 109))
91312	33466296	suggested that oxidative stress may be not properly suppressed when c.575A>G polymorphism occurs, facilitating the genesis of coronary spasm.	('stress', 'Disease', 'MESH:D000079225', (25, 31))	('stress', 'Disease', (25, 31))	('c.575A>G', 'Var', (68, 76))	('c.575A>G', 'Mutation', 'rs662', (68, 76))	('facilitating', 'PosReg', (98, 110))	('coronary spasm', 'Disease', (126, 140))	('coronary spasm', 'Disease', 'MESH:D003329', (126, 140))	('coronary spasm', 'Phenotype', 'HP:0025497', (126, 140))	('oxidative stress', 'Phenotype', 'HP:0025464', (15, 31))
91313	33466296	In line with these considerations, it is interesting to observe the heterozygous variants c.860G>A on EPHX2 and c.214C>A on GHRL genes that expose the patients of this study to metabolic syndrome and familial hypercholesterolemia 1, respectively.	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (209, 229))	('EPHX2', 'Gene', (102, 107))	('c.860G>A', 'Mutation', 'rs751141', (90, 98))	('EPHX2', 'Gene', '2053', (102, 107))	('familial hypercholesterolemia', 'Disease', 'MESH:D006938', (200, 229))	('rat', 'Species', '10116', (26, 29))	('c.214C>A', 'Var', (112, 120))	('GHRL', 'Gene', '51738', (124, 128))	('metabolic syndrome', 'Disease', (177, 195))	('expose', 'Reg', (140, 146))	('familial hypercholesterolemia', 'Disease', (200, 229))	('patients', 'Species', '9606', (151, 159))	('GHRL', 'Gene', (124, 128))	('c.214C>A', 'Mutation', 'rs696217', (112, 120))	('c.860G>A', 'Var', (90, 98))	('metabolic syndrome', 'Disease', 'MESH:D024821', (177, 195))
91316	33466296	suggested that this variant may lead to insulin resistance in the pathogenesis of type 2 diabetes.	('diabetes', 'Disease', (89, 97))	('lead to', 'Reg', (32, 39))	('insulin', 'Gene', (40, 47))	('diabetes', 'Disease', 'MESH:D003920', (89, 97))	('insulin', 'Gene', '3630', (40, 47))	('insulin resistance', 'Phenotype', 'HP:0000855', (40, 58))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (82, 97))	('variant', 'Var', (20, 27))
91318	33466296	proposed this variant as a risk factor for obesity, leading to an increase in body mass index.	('obesity', 'Phenotype', 'HP:0001513', (43, 50))	('increase', 'PosReg', (66, 74))	('obesity', 'Disease', 'MESH:D009765', (43, 50))	('obesity', 'Disease', (43, 50))	('body mass index', 'MPA', (78, 93))	('variant', 'Var', (14, 21))
91323	33466296	Our analysis highlights the heterozygous variant c.827A>C on the tumor suppressor gene PTPRJ and the homozygous variants c.723G>A and c.91T>A on the proto-oncogenes CCND1 and AURKA, respectively.	('PTPRJ', 'Gene', '5795', (87, 92))	('CCND1', 'Gene', '595', (165, 170))	('c.723G>A', 'Mutation', 'rs9344', (121, 129))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('PTPRJ', 'Gene', (87, 92))	('c.91T>A', 'Mutation', 'rs2273535', (134, 141))	('c.91T>A', 'Var', (134, 141))	('AURKA', 'Gene', '6790', (175, 180))	('CCND1', 'Gene', (165, 170))	('c.723G>A', 'Var', (121, 129))	('c.827A>C', 'Var', (49, 57))	('c.827A>C', 'Mutation', 'rs1566734', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('AURKA', 'Gene', (175, 180))
91324	33466296	These variants are associated with colon cancer in ClinVar.	('associated', 'Reg', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('variants', 'Var', (6, 14))	('colon cancer', 'Phenotype', 'HP:0003003', (35, 47))	('colon cancer', 'Disease', 'MESH:D015179', (35, 47))	('colon cancer', 'Disease', (35, 47))
91327	33466296	observed a highly increased risk of developing colon cancer when c.827A>C is present simultaneously with p.Arg326Gln on the same gene.	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('c.827A>C', 'Var', (65, 73))	('colon cancer', 'Disease', (47, 59))	('c.827A>C', 'Mutation', 'rs1566734', (65, 73))	('p.Arg326Gln', 'Var', (105, 116))	('p.Arg326Gln', 'Mutation', 'p.R326Q', (105, 116))
91329	33466296	studied c.723G>A and identified it as a risk factor for thyroid carcinoma even if with low penetrance, especially when it is in homozygosity, as in our study.	('risk', 'Reg', (40, 44))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (56, 73))	('c.723G>A', 'Mutation', 'rs9344', (8, 16))	('thyroid carcinoma', 'Disease', (56, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('c.723G>A', 'Var', (8, 16))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (56, 73))
91331	33466296	found a significant association between this variant and the translocation of a portion of chromosome 11, resulting in a risk factor for multiple myeloma.	('translocation', 'Var', (61, 74))	('multiple myeloma', 'Phenotype', 'HP:0006775', (137, 153))	('variant', 'Var', (45, 52))	('multiple myeloma', 'Disease', 'MESH:D009101', (137, 153))	('multiple myeloma', 'Disease', (137, 153))
91332	33466296	inspected the prognostic potential of the variant, suggesting it as a possible biomarker in colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('colon cancer', 'Disease', (92, 104))	('variant', 'Var', (42, 49))
91333	33466296	studied the c.91T>A substitution in rat models, discovering an increased association of the variant with aneuploidy in human colon tumors.	('aneuploidy', 'Disease', 'MESH:D000782', (105, 115))	('increased', 'PosReg', (63, 72))	('colon tumors', 'Phenotype', 'HP:0100273', (125, 137))	('rat', 'Species', '10116', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('c.91T>A', 'Mutation', 'rs2273535', (12, 19))	('association', 'Interaction', (73, 84))	('variant', 'Var', (92, 99))	('aneuploidy', 'Disease', (105, 115))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('colon tumors', 'Disease', (125, 137))	('colon tumors', 'Disease', 'MESH:D003110', (125, 137))	('human', 'Species', '9606', (119, 124))
91334	33466296	Indeed, the variant strengthens the binding of aurora kinase A with the E2 ubiquitin-conjugating enzyme, altering the cell cycle progression.	('variant', 'Var', (12, 19))	('aurora kinase A', 'Gene', '6790', (47, 62))	('aurora kinase A', 'Gene', (47, 62))	('cell cycle progression', 'CPA', (118, 140))	('strengthens', 'PosReg', (20, 31))	('binding', 'Interaction', (36, 43))	('altering', 'Reg', (105, 113))
91351	33466296	Mutations on MERTK are associated with autoimmune diseases, and expression alterations may have oncogenic potential.	('autoimmune diseases', 'Disease', (39, 58))	('expression', 'MPA', (64, 74))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (39, 58))	('oncogenic potential', 'CPA', (96, 115))	('Mutations', 'Var', (0, 9))	('MERTK', 'Gene', '10461', (13, 18))	('MERTK', 'Gene', (13, 18))	('autoimmune diseases', 'Disease', 'MESH:D001327', (39, 58))	('rat', 'Species', '10116', (79, 82))	('associated', 'Reg', (23, 33))
91352	33466296	The transcriptional activator Myb is encoded by MYB, which had a heterozygous missense variant in our analysis.	('MYB', 'Gene', '4602', (48, 51))	('missense variant', 'Var', (78, 94))	('MYB', 'Gene', (48, 51))	('Myb', 'Gene', '4602', (30, 33))	('Myb', 'Gene', (30, 33))
91355	33466296	It encodes for Myosin-11 and is mainly involved in muscle contraction; however, when altered, it may contribute to intestinal, gastric, and colorectal cancers and acute myeloid leukemia.	('contribute to', 'Reg', (101, 114))	('colorectal cancers', 'Disease', 'MESH:D015179', (140, 158))	('gastric', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (163, 185))	('colorectal cancers', 'Disease', (140, 158))	('intestinal', 'Disease', (115, 125))	('Myosin-11', 'Gene', (15, 24))	('Myosin-11', 'Gene', '4629', (15, 24))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (163, 185))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (169, 185))	('altered', 'Var', (85, 92))	('leukemia', 'Phenotype', 'HP:0001909', (177, 185))	('acute myeloid leukemia', 'Disease', (163, 185))
91356	33466296	PCM1 carries a heterozygous missense mutation of two close nucleotides.	('PCM1', 'Gene', '5108', (0, 4))	('missense mutation', 'Var', (28, 45))	('PCM1', 'Gene', (0, 4))
91360	33466296	Mutations of this gene have already been associated with holoprosencephaly along with several cancers such as nevoid basal cell carcinoma syndrome and medulloblastoma.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('associated', 'Reg', (41, 51))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (117, 137))	('nevoid basal cell carcinoma syndrome', 'Disease', (110, 146))	('holoprosencephaly', 'Disease', 'MESH:D016142', (57, 74))	('medulloblastoma', 'Disease', 'MESH:D008527', (151, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('nevoid basal cell carcinoma syndrome', 'Disease', 'MESH:D001478', (110, 146))	('medulloblastoma', 'Phenotype', 'HP:0002885', (151, 166))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Mutations', 'Var', (0, 9))	('holoprosencephaly', 'Disease', (57, 74))	('medulloblastoma', 'Disease', (151, 166))	('cancers', 'Disease', (94, 101))
91361	33466296	RB1CC1 carries two heterozygous variants, one missense in the coding sequence and one deletion in an intron and splice region.	('RB1CC1', 'Gene', (0, 6))	('missense', 'Var', (46, 54))	('deletion', 'Var', (86, 94))	('RB1CC1', 'Gene', '9821', (0, 6))
91366	33466296	Its rearrangement is associated with lung cancer, glioblastoma, ovarian carcinoma, sarcoma, and cholangiocarcinoma.	('lung cancer', 'Disease', (37, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('sarcoma', 'Disease', (83, 90))	('rearrangement', 'Var', (4, 17))	('associated', 'Reg', (21, 31))	('cholangiocarcinoma', 'Disease', (96, 114))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (64, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('glioblastoma, ovarian carcinoma', 'Disease', 'MESH:D010051', (50, 81))
91367	33466296	SDHA has a heterozygous frameshift variant.	('frameshift variant', 'Var', (24, 42))	('SDHA', 'Gene', '6389', (0, 4))	('SDHA', 'Gene', (0, 4))
91374	33466296	In this work, we discovered several variants in a six-month-old patient that could be responsible for the clinical complication of complex malformation.	('variants', 'Var', (36, 44))	('patient', 'Species', '9606', (64, 71))	('responsible', 'Reg', (86, 97))
91376	33466296	c.501G>C (OLR1) and c.-8C>G (PSMA6) are specifically associated with myocardial infarction, c.1936A>G (AKAP10) with cardiac conduction defects, c.575A>G (PON1) with artery disease, and c.860G>A (EPHX2) and c.214C>A (GHRL) with metabolic syndrome.	('c.-8C>G', 'Mutation', 'rs1048990', (20, 27))	('c.575A>G', 'Var', (144, 152))	('GHRL', 'Gene', (216, 220))	('cardiac conduction defects', 'Disease', 'OMIM:115080', (116, 142))	('AKAP10', 'Gene', (103, 109))	('artery disease', 'Disease', (165, 179))	('c.860G>A', 'Var', (185, 193))	('c.860G>A', 'Mutation', 'rs751141', (185, 193))	('cardiac conduction defects', 'Disease', (116, 142))	('OLR1', 'Gene', '4973', (10, 14))	('GHRL', 'Gene', '51738', (216, 220))	('PON1', 'Gene', '5444', (154, 158))	('c.501G>C', 'Mutation', 'rs11053646', (0, 8))	('OLR1', 'Gene', (10, 14))	('AKAP10', 'Gene', '11216', (103, 109))	('associated', 'Reg', (53, 63))	('cardiac conduction defect', 'Phenotype', 'HP:0011675', (116, 141))	('metabolic syndrome', 'Disease', (227, 245))	('EPHX2', 'Gene', (195, 200))	('artery disease', 'Disease', 'MESH:D000783', (165, 179))	('cardiac conduction', 'Phenotype', 'HP:0011675', (116, 134))	('myocardial infarction', 'Disease', (69, 90))	('c.575A>G', 'Mutation', 'rs662', (144, 152))	('myocardial infarction', 'Phenotype', 'HP:0001658', (69, 90))	('c.214C>A', 'Var', (206, 214))	('cardiac conduction defects', 'Phenotype', 'HP:0011675', (116, 142))	('c.214C>A', 'Mutation', 'rs696217', (206, 214))	('PON1', 'Gene', (154, 158))	('c.1936A>G', 'Var', (92, 101))	('c.501G>C', 'Var', (0, 8))	('PSMA6', 'Gene', '5687', (29, 34))	('EPHX2', 'Gene', '2053', (195, 200))	('myocardial infarction', 'Disease', 'MESH:D009203', (69, 90))	('c.-8C>G', 'Var', (20, 27))	('metabolic syndrome', 'Disease', 'MESH:D024821', (227, 245))	('PSMA6', 'Gene', (29, 34))	('c.1936A>G', 'Mutation', 'rs203462', (92, 101))
91377	33466296	In addition, the proto-oncogenes CCND1 and AURKA, along with the tumor suppressor PTPRJ, carry the variants c.723G>A, c.91T>A, and c.827A>C, respectively, which are related to colon cancer.	('c.827A>C', 'Var', (131, 139))	('c.827A>C', 'Mutation', 'rs1566734', (131, 139))	('related', 'Reg', (165, 172))	('AURKA', 'Gene', '6790', (43, 48))	('CCND1', 'Gene', '595', (33, 38))	('colon cancer', 'Phenotype', 'HP:0003003', (176, 188))	('AURKA', 'Gene', (43, 48))	('CCND1', 'Gene', (33, 38))	('tumor', 'Disease', (65, 70))	('c.91T>A', 'Mutation', 'rs2273535', (118, 125))	('PTPRJ', 'Gene', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('colon cancer', 'Disease', 'MESH:D015179', (176, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('PTPRJ', 'Gene', '5795', (82, 87))	('c.723G>A', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('colon cancer', 'Disease', (176, 188))	('c.91T>A', 'Var', (118, 125))	('c.723G>A', 'Mutation', 'rs9344', (108, 116))
91378	33466296	For the first time, we associated nine rare variants on eight proto-oncogenes (MERTK, CSF1R, MYB, ROS1, PCM1, FGFR2, MYH11, BRCC3) and six rare variants on five tumor suppressor (SDHA, RB1CC1, PTCH1, DMBT1, BCR) with VACTERL.	('DMBT1', 'Gene', '1755', (200, 205))	('FGFR2', 'Gene', '2263', (110, 115))	('BCR', 'Gene', '613', (207, 210))	('PCM1', 'Gene', (104, 108))	('tumor', 'Disease', (161, 166))	('ROS1', 'Gene', '6098', (98, 102))	('PTCH1', 'Gene', (193, 198))	('BCR', 'Gene', (207, 210))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('RB1CC1', 'Gene', '9821', (185, 191))	('associated', 'Reg', (23, 33))	('MYH11', 'Gene', '4629', (117, 122))	('BRCC3', 'Gene', '79184', (124, 129))	('variants', 'Var', (144, 152))	('DMBT1', 'Gene', (200, 205))	('VACTERL', 'Disease', (217, 224))	('MYH11', 'Gene', (117, 122))	('PTCH1', 'Gene', '5727', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MERTK', 'Gene', '10461', (79, 84))	('MERTK', 'Gene', (79, 84))	('MYB', 'Gene', '4602', (93, 96))	('SDHA', 'Gene', (179, 183))	('ROS1', 'Gene', (98, 102))	('BRCC3', 'Gene', (124, 129))	('PCM1', 'Gene', '5108', (104, 108))	('MYB', 'Gene', (93, 96))	('FGFR2', 'Gene', (110, 115))	('RB1CC1', 'Gene', (185, 191))	('CSF1R', 'Gene', '1436', (86, 91))	('SDHA', 'Gene', '6389', (179, 183))	('CSF1R', 'Gene', (86, 91))	('variants', 'Var', (44, 52))
91425	33156126	Wu et al analyzed earlier studies with ferumoxtran-10 and reported sensitivities up to 90% and specificities up to 96% for nodal involvement in several types of cancer.	('sensitivities', 'MPA', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('nodal', 'Gene', '4838', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('ferumoxtran-10', 'Var', (39, 53))	('ferumoxtran-10', 'Chemical', 'MESH:C097921', (39, 53))	('nodal', 'Gene', (123, 128))
91537	31746400	The results showed that knockdown of CHST15 inhibited TE-1 cell growth and proliferation, but induced cell apoptosis.	('CHST15', 'Gene', (37, 43))	('inhibited', 'NegReg', (44, 53))	('TE-1', 'CellLine', 'CVCL:1759', (54, 58))	('TE-1 cell growth', 'CPA', (54, 70))	('induced', 'Reg', (94, 101))	('CHST15', 'Gene', '51363', (37, 43))	('knockdown', 'Var', (24, 33))
91541	31746400	Studies have shown that certain factors are associated with increased risk of ESCC, such as alcohol and tobacco consumption, genetic mutation, diet and nutrition deficiency.	('genetic mutation', 'Var', (125, 141))	('ESCC', 'Disease', (78, 82))	('alcohol', 'Chemical', 'MESH:D000438', (92, 99))	('diet', 'Disease', (143, 147))	('nutrition deficiency', 'Disease', (152, 172))	('tobacco', 'Species', '4097', (104, 111))	('nutrition deficiency', 'Disease', 'MESH:D044342', (152, 172))
91578	31746400	TE-1 cells infected with lenti-shCtrl or lenti-shCHST15 were plated at 800 cells/well onto a 96-well plate and cultured at 37 C in a 5% CO2 incubator.	('TE-1', 'CellLine', 'CVCL:1759', (0, 4))	('infected', 'Disease', 'MESH:D007239', (11, 19))	('CO2', 'Chemical', 'MESH:D002245', (136, 139))	('hCHST15', 'Gene', (48, 55))	('infected', 'Disease', (11, 19))	('hCHST15', 'Gene', '51363', (48, 55))	('lenti-shCtrl', 'Var', (25, 37))
91583	31746400	Cell viability after CHST15 knockdown was measured using an MTT assay.	('CHST15', 'Gene', '51363', (21, 27))	('MTT', 'Chemical', 'MESH:C070243', (60, 63))	('CHST15', 'Gene', (21, 27))	('knockdown', 'Var', (28, 37))
91598	31746400	Differentially expressed genes based on the comparison of CHST15 knockdown (KD) and control cells were selected if  fold change >1.5 and the FDR was <0.05.	('CHST15', 'Gene', (58, 64))	('knockdown', 'Var', (65, 74))	('CHST15', 'Gene', '51363', (58, 64))
91614	31746400	3A and B), which indicated that deprivation of CHST15 inhibited TE-1 cell proliferation.	('inhibited', 'NegReg', (54, 63))	('TE-1 cell proliferation', 'CPA', (64, 87))	('CHST15', 'Gene', '51363', (47, 53))	('TE-1', 'CellLine', 'CVCL:1759', (64, 68))	('CHST15', 'Gene', (47, 53))	('deprivation', 'Var', (32, 43))
91633	31746400	Real-time PCR was used to detect the CHST15 knockdown efficiency.	('CHST15', 'Gene', (37, 43))	('CHST15', 'Gene', '51363', (37, 43))	('knockdown', 'Var', (44, 53))
91644	31746400	Differentially expressed genes (DEGs) identified in the CHST15 knockdown cells were analyzed according to several functional network criteria within IPA.	('CHST15', 'Gene', (56, 62))	('knockdown', 'Var', (63, 72))	('CHST15', 'Gene', '51363', (56, 62))
91651	31746400	Silencing of CHST15 inhibited TE-1 cell proliferation and promoted TE-1 cell apoptosis, suggesting that CHST15 contributes to the pathogenesis of ESCC.	('TE-1 cell proliferation', 'CPA', (30, 53))	('CHST15', 'Gene', (104, 110))	('CHST15', 'Gene', '51363', (13, 19))	('TE-1', 'CellLine', 'CVCL:1759', (30, 34))	('CHST15', 'Gene', '51363', (104, 110))	('TE-1', 'CellLine', 'CVCL:1759', (67, 71))	('inhibited', 'NegReg', (20, 29))	('promoted', 'PosReg', (58, 66))	('CHST15', 'Gene', (13, 19))	('contributes', 'Reg', (111, 122))	('Silencing', 'Var', (0, 9))	('ESCC', 'Disease', (146, 150))
91658	31746400	Overexpression or activation of ILK leads to increased tumor cell proliferation, motility and invasion; thus, ILK may be a promising therapeutic target in many types of cancer.	('invasion', 'CPA', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Disease', (169, 175))	('ILK', 'Gene', (32, 35))	('ILK', 'Gene', '3611', (32, 35))	('increased', 'PosReg', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('activation', 'Var', (18, 28))	('ILK', 'Gene', '3611', (110, 113))	('motility', 'CPA', (81, 89))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('ILK', 'Gene', (110, 113))
91661	31746400	In this study, the increased apoptosis of TE-1 cells may be attributable to activated p53 signaling induced by CHST15 knockdown.	('CHST15', 'Gene', (111, 117))	('apoptosis', 'CPA', (29, 38))	('activated', 'PosReg', (76, 85))	('knockdown', 'Var', (118, 127))	('p53', 'Gene', '7157', (86, 89))	('TE-1', 'CellLine', 'CVCL:1759', (42, 46))	('CHST15', 'Gene', '51363', (111, 117))	('p53', 'Gene', (86, 89))
91666	31746400	Tang et al demonstrated that knockdown of RABL6 upregulated retinoblastoma 1 (Rb) expression and thus downregulated Rb inhibitory downstream targets, such as cyclin A2, cyclin D1, c-Myc, and cyclin-dependent kinase 2.	('knockdown', 'Var', (29, 38))	('cyclin D1', 'Gene', (169, 178))	('cyclin-dependent kinase 2', 'Gene', (191, 216))	('RABL6', 'Gene', (42, 47))	('cyclin A2', 'Gene', '890', (158, 167))	('cyclin D1', 'Gene', '595', (169, 178))	('expression', 'MPA', (82, 92))	('downregulated', 'NegReg', (102, 115))	('retinoblastoma', 'Phenotype', 'HP:0009919', (60, 74))	('c-Myc', 'Gene', (180, 185))	('retinoblastoma 1', 'Gene', '5925', (60, 76))	('c-Myc', 'Gene', '4609', (180, 185))	('Rb', 'Gene', '5925', (116, 118))	('retinoblastoma 1', 'Gene', (60, 76))	('Rb', 'Gene', '5925', (78, 80))	('RABL6', 'Gene', '55684', (42, 47))	('cyclin A2', 'Gene', (158, 167))	('upregulated', 'PosReg', (48, 59))	('cyclin-dependent kinase 2', 'Gene', '1017', (191, 216))
91668	31746400	PMAIP1 expression was found to activate the mitochondrial apoptotic cascade and induce increased oxidative stress and calcium release, resulting in the activation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream effectors JUN N-terminal kinase (JNK) and mitogen-activated protein kinase 14 (MAPK14, also known as p38).	('JUN N-terminal kinase', 'Gene', '5599', (239, 260))	('calcium release', 'MPA', (118, 133))	('JNK', 'Gene', (262, 265))	('MAPK14', 'Gene', (308, 314))	('mitogen-activated protein kinase 14', 'Gene', (271, 306))	('MAPK14', 'Gene', '1432', (308, 314))	('JUN N-terminal kinase', 'Gene', (239, 260))	('JNK', 'Gene', '5599', (262, 265))	('p38', 'Gene', '1432', (330, 333))	('PMAIP1', 'Gene', (0, 6))	('apoptosis signal-regulating kinase 1', 'Gene', (166, 202))	('PMAIP1', 'Gene', '5366', (0, 6))	('mitogen-activated protein kinase 14', 'Gene', '1432', (271, 306))	('mitochondrial apoptotic cascade', 'Pathway', (44, 75))	('activation', 'PosReg', (152, 162))	('ASK1', 'Gene', '4217', (204, 208))	('increased', 'PosReg', (87, 96))	('calcium', 'Chemical', 'MESH:D002118', (118, 125))	('activate', 'PosReg', (31, 39))	('apoptosis signal-regulating kinase 1', 'Gene', '4217', (166, 202))	('expression', 'Var', (7, 17))	('ASK1', 'Gene', (204, 208))	('oxidative stress', 'Phenotype', 'HP:0025464', (97, 113))	('p38', 'Gene', (330, 333))
91674	31746400	ILK-mediated inhibition of GSK3beta was found to induce the expression of cyclin D1.	('expression', 'MPA', (60, 70))	('cyclin D1', 'Gene', '595', (74, 83))	('inhibition', 'Var', (13, 23))	('cyclin D1', 'Gene', (74, 83))	('induce', 'PosReg', (49, 55))	('ILK', 'Gene', (0, 3))	('ILK', 'Gene', '3611', (0, 3))	('GSK3beta', 'Gene', (27, 35))	('GSK3beta', 'Gene', '2931', (27, 35))
91771	31488173	BSCC is usually positive for immunohistochemical staining of epithelial markers, including AE1/AE3, CK5/6, CK14, CK34betaE12, p63 and p40.	('p63', 'Gene', (126, 129))	('p40', 'Gene', (134, 137))	('CK14', 'Gene', (107, 111))	('BSCC', 'Phenotype', 'HP:0002671', (0, 4))	('CK5/6', 'Gene', (100, 105))	('AE1/AE3', 'Gene', (91, 98))	('AE1/AE3', 'Gene', '6521;6508', (91, 98))	('p63', 'Gene', '8626', (126, 129))	('p40', 'Gene', '8626', (134, 137))	('CK14', 'Gene', '3861', (107, 111))	('CK34betaE12', 'Var', (113, 124))	('CK5/6', 'Gene', '3852', (100, 105))
91909	26851395	Although the exact mechanism of cisplatin-induced nephrotoxicity remains unclear, exposing proximal tubular cells to cisplatin reportedly activates complex signaling pathways and a multifactorial process that leads to tubular cell injury and death.	('death', 'Disease', (242, 247))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('leads to', 'Reg', (209, 217))	('tubular cell injury', 'Disease', (218, 237))	('tubular cell injury', 'Disease', 'MESH:D005198', (218, 237))	('nephrotoxicity', 'Disease', 'MESH:D007674', (50, 64))	('nephrotoxicity', 'Disease', (50, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('cisplatin', 'Var', (117, 126))	('activates', 'PosReg', (138, 147))	('death', 'Disease', 'MESH:D003643', (242, 247))
91914	26851395	Indeed, volume expansion remains the most effective strategy for prevention of cisplatin nephrotoxicity, though the two patients described here received sufficient drip infusion (3899 ml/day in both) and produced good urine volumes (3220 ml/day, 4830 ml/day) (Fig.	('drip infusion', 'MPA', (164, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('urine volumes', 'MPA', (218, 231))	('nephrotoxicity', 'Disease', (89, 103))	('patients', 'Species', '9606', (120, 128))	('3220 ml/day', 'Var', (233, 244))	('nephrotoxicity', 'Disease', 'MESH:D007674', (89, 103))
92003	21970688	There are only 2 reports in which plasma concentrations of 5-FU has been shown to correlate with long-term survival, but Gamelin and his co-workers conducted a phase III, multicenter, randomized trial in which pharmacokinetically guided administration of 5-FU was compared with conventional dosing in patients with metastatic colorectal cancer, and concluded that individual dose adjustments of 5-FU resulted in an improved objective response rate and fewer severe toxicities, and in a trend toward a higher survival rate.	('5-FU', 'Chemical', 'MESH:D005472', (59, 63))	('toxicities', 'Disease', 'MESH:D064420', (465, 475))	('improved', 'PosReg', (415, 423))	('5-FU', 'Chemical', 'MESH:D005472', (255, 259))	('adjustments', 'Var', (380, 391))	('5-FU', 'Chemical', 'MESH:D005472', (395, 399))	('survival rate', 'CPA', (508, 521))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('patients', 'Species', '9606', (301, 309))	('colorectal cancer', 'Disease', 'MESH:D015179', (326, 343))	('colorectal cancer', 'Phenotype', 'HP:0003003', (326, 343))	('higher', 'PosReg', (501, 507))	('toxicities', 'Disease', (465, 475))	('objective response rate', 'CPA', (424, 447))	('colorectal cancer', 'Disease', (326, 343))
92034	21970688	There was no difference of the 8-point average values of plasma concentrations of 5-FU between the 2 groups (P = 0.536), although the clinical response depended on; 0.124 +- 0.036 mug/mL for CR, 0.105 +- 0.030 mug/mL for non-CR (P = 0.043).	('5-FU', 'Chemical', 'MESH:D005472', (82, 86))	('0.105 +- 0.030 mug/mL', 'Var', (195, 216))	('CR', 'Chemical', '-', (191, 193))	('CR', 'Chemical', '-', (225, 227))	('0.124 +- 0.036 mug/mL', 'Var', (165, 186))
92045	21970688	Recently, Gamelin and his co-workers compared pharmacokinetically guided administration of 5-FU with conventional dosing in patients with metastatic colorectal cancer, and found that individual dose adjustments of 5-FU resulted in an improved objective response rate, and in a trend toward a higher survival rate.	('improved', 'PosReg', (234, 242))	('5-FU', 'Chemical', 'MESH:D005472', (91, 95))	('objective response rate', 'CPA', (243, 266))	('patients', 'Species', '9606', (124, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('higher', 'PosReg', (292, 298))	('adjustments', 'Var', (199, 210))	('colorectal cancer', 'Disease', (149, 166))	('5-FU', 'Chemical', 'MESH:D005472', (214, 218))
92048	21970688	The clinical response was determined by the 8-point average values of plasma concentrations of 5-FU; 0.124 +- 0.036 mug/mL for the patients with CR, and 0.105 +- 0.030 mug/mL for those with non-CR (P = 0.043), and therefore the survival must be associated with the concentrations.	('patients', 'Species', '9606', (131, 139))	('5-FU', 'Chemical', 'MESH:D005472', (95, 99))	('0.124 +- 0.036 mug/mL', 'Var', (101, 122))	('CR', 'Chemical', '-', (145, 147))	('CR', 'Chemical', '-', (194, 196))	('0.105 +- 0.030 mug/mL', 'Var', (153, 174))
92093	29952086	When we compared the incidence of postoperative complications with different numbers of LNs, we found that the overall incidence of postoperative complications in patients with <= 19 LNs was lower than in patients with >= 20 LNs (P = 0.04).	('lower', 'NegReg', (191, 196))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (205, 213))	('<= 19 LNs', 'Var', (177, 186))
92099	29952086	The MST of 78.0 months (95% confidence interval [CI] 71.6-84.4) in patients with T1 staging was superior to that of patients with T2 and T3 staging (P < 0.001) (Fig 1).	('patients', 'Species', '9606', (116, 124))	('MST', 'MPA', (4, 7))	('patients', 'Species', '9606', (67, 75))	('T1 staging', 'Var', (81, 91))
92191	21803982	A 10 gram increase in poultry intake (Figure 2) was associated with lower risk of liver cancer and esophageal squamous cell carcinoma, as well as laryngeal cancer in women only (Pinteraction sex= 0.01).	('women', 'Species', '9606', (166, 171))	('liver cancer', 'Disease', (82, 94))	('lower', 'NegReg', (68, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('esophageal squamous cell carcinoma', 'Disease', (99, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('laryngeal cancer', 'Disease', (146, 162))	('laryngeal cancer', 'Disease', 'MESH:D007822', (146, 162))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (146, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('poultry', 'Var', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (99, 133))	('liver cancer', 'Phenotype', 'HP:0002896', (82, 94))	('liver cancer', 'Disease', 'MESH:D006528', (82, 94))
92192	21803982	In men, poultry intake was positively associated with thyroid (Pinteraction sex= 0.03) and male breast cancer.	('male breast cancer', 'Disease', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('poultry', 'Var', (8, 15))	('associated', 'Interaction', (38, 48))	('thyroid', 'Disease', (54, 61))	('male breast cancer', 'Disease', 'MESH:D018567', (91, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('men', 'Species', '9606', (3, 6))
92199	21803982	In this large U.S. cohort, poultry and fish intake was associated with lower risk of digestive and respiratory cancers.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('respiratory cancers', 'Disease', (99, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('respiratory cancers', 'Disease', 'MESH:D012131', (99, 118))	('poultry', 'Var', (27, 34))	('lower', 'NegReg', (71, 76))
92208	21803982	Significant findings for poultry intake and lower risk of esophageal squamous cell carcinoma, liver and lung cancer in both the substitution and addition analyses suggest that other components of a high white meat diet, independent of red meat, may also be important.	('poultry', 'Var', (25, 32))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (58, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('white meat', 'Chemical', '-', (203, 213))	('esophageal squamous cell carcinoma', 'Disease', (58, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('liver and lung cancer', 'Disease', 'MESH:D006528', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
92211	21803982	Residual confounding by smoking status does not appear to have greatly influenced our findings, as poultry intake remained consistently associated with lower risk of lung cancer in analyses restricted to never smokers.	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('lower', 'NegReg', (152, 157))	('poultry', 'Var', (99, 106))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
92213	21803982	Poultry intake was also inversely associated with laryngeal cancer in women, but positively associated with thyroid and male breast cancer in men in this cohort.	('laryngeal cancer', 'Disease', 'MESH:D007822', (50, 66))	('men', 'Species', '9606', (142, 145))	('male breast cancer', 'Disease', (120, 138))	('associated', 'Interaction', (92, 102))	('men', 'Species', '9606', (72, 75))	('thyroid', 'Disease', (108, 115))	('associated', 'Interaction', (34, 44))	('laryngeal cancer', 'Disease', (50, 66))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Poultry', 'Var', (0, 7))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (50, 66))	('inversely', 'NegReg', (24, 33))	('male breast cancer', 'Disease', 'MESH:D018567', (120, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('women', 'Species', '9606', (70, 75))
92284	31652849	Dose/response curves and dose modifying factor (DMF) values highlighted an increasing radiosensitization effect in a concentration-dependent manner for both the two drugs; MCF7 cells resulted more sensitive to the combined treatment, reaching a DMF value of 1.78 using 10 microM Cur-SLN, while the MDA-MB-231 cells showed to be more sensitive to free-Cur, although a DMF value of 1.38 was obtained with the same concentration of the compound.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (298, 308))	('radiosensitization', 'MPA', (86, 104))	('Cur-SLN', 'Var', (279, 286))	('DMF', 'Chemical', 'MESH:C503868', (367, 370))	('DMF', 'Chemical', 'MESH:C503868', (48, 51))	('DMF', 'Chemical', 'MESH:C503868', (245, 248))	('N', 'Chemical', 'MESH:D009584', (285, 286))	('MCF7', 'CellLine', 'CVCL:0031', (172, 176))
92300	31652849	In this setting, the combination of 5 Gy gamma-irradiation with 50 muM of resveratrol was able to induce, both in murine cell line SW1 and human cell line WM35, a remarkable reduction of the cell survival fraction by clonogenic assays.	('murine', 'Species', '10090', (114, 120))	('WM35', 'CellLine', 'CVCL:0580', (155, 159))	('resveratrol', 'Chemical', 'MESH:C059514', (74, 85))	('muM', 'Gene', '56925', (67, 70))	('gamma-irradiation', 'Var', (41, 58))	('SW1', 'CellLine', 'CVCL:R777', (131, 134))	('muM', 'Gene', (67, 70))	('human', 'Species', '9606', (139, 144))	('reduction', 'NegReg', (174, 183))	('cell survival fraction', 'CPA', (191, 213))
92314	31652849	Through the inactivation of the PI3K-AKT pathway, DAB2IP is involved in the regulation of cell proliferation, survival and apoptosis.	('DAB2IP', 'Gene', (50, 56))	('AKT', 'Gene', '207', (37, 40))	('DAB2IP', 'Gene', '153090', (50, 56))	('AKT', 'Gene', (37, 40))	('inactivation', 'Var', (12, 24))	('involved', 'Reg', (60, 68))
92396	31652849	An interesting study about the effect of UA as a radiosensitizer was carried out on a radioresistant cell line of NSCLC obtained by transfection with a recombinant plasmid expressing a mutant form of HIF-1alpha, the H1299/M-hypoxia-inducible factor-1alpha.	('mutant', 'Var', (185, 191))	('H1299', 'CellLine', 'CVCL:0060', (216, 221))	('HIF-1alpha', 'Gene', (200, 210))	('NSCLC', 'Disease', (114, 119))	('hypoxia', 'Disease', 'MESH:D000860', (224, 231))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('hypoxia', 'Disease', (224, 231))	('HIF-1alpha', 'Gene', '3091', (200, 210))
92443	31652849	The same experimental approach was carried out using the FSa p53 mutant (Mut) murine sarcoma cell line.	('mutant', 'Var', (65, 71))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('murine', 'Species', '10090', (78, 84))	('FSa p53', 'Gene', (57, 64))	('sarcoma', 'Disease', (85, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
92445	31652849	In the CN1-E nasopharyngeal carcinoma cell line, pretreatment with 10 mg/L of GXHSWAQ-1 (a synthetic compound created on the basis of the chemical structure of Emodin) for 24 hrs before X-rays irradiation (2 Gy), caused a damage in the integrity of mitochondrial structure, with swelling and/or matrix compartments vacuole formation and a collapse in the transmembrane potential.	('matrix compartments vacuole formation', 'CPA', (295, 332))	('mitochondrial structure', 'MPA', (249, 272))	('carcinoma', 'Disease', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('collapse', 'NegReg', (339, 347))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (13, 37))	('swelling', 'Disease', (279, 287))	('swelling', 'Disease', 'MESH:D004487', (279, 287))	('carcinoma', 'Disease', 'MESH:D002277', (28, 37))	('GXHSWAQ-1', 'Var', (78, 87))	('rays', 'Species', '255564', (188, 192))	('damage', 'Reg', (222, 228))	('Emodin', 'Chemical', 'MESH:D004642', (160, 166))	('integrity', 'MPA', (236, 245))	('N', 'Chemical', 'MESH:D009584', (8, 9))
92460	31652849	The in vitro results obtained highlighted that cells treated with Flavopiridol (300 nM) for 24 hrs before or 7 h after gamma-radiation (2-6 Gy) showed greater radiosensitivity respect to the control.	('300 nM', 'Var', (80, 86))	('radiosensitivity', 'CPA', (159, 175))	('Flavopiridol', 'Chemical', 'MESH:C077990', (66, 78))
92467	31652849	A172 glioma and HeLa cervical tumor cells were stably transfected with plasmids containing mutated forms of p53 (A172/mp53) and Bcl-2 (HeLa/bcl-2) genes, respectively.	('HeLa/bcl-2', 'Gene', (135, 145))	('p53', 'Gene', (108, 111))	('cervical tumor', 'Phenotype', 'HP:0030159', (21, 35))	('Bcl-2', 'Gene', (128, 133))	('glioma', 'Disease', (5, 11))	('mutated', 'Var', (91, 98))	('HeLa cervical tumor', 'Disease', 'MESH:D002575', (16, 35))	('HeLa cervical tumor', 'Disease', (16, 35))	('HeLa/bcl-2', 'Gene', '596', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('glioma', 'Disease', 'MESH:D005910', (5, 11))	('glioma', 'Phenotype', 'HP:0009733', (5, 11))
92478	31652849	The OCA-I ovarian carcinoma cells treated with Flavopiridol (300 nM) for 24 h and gamma- radiations (1-6 Gy) exhibited an increase of the radiosensitivity compared to control.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (10, 27))	('radiosensitivity', 'CPA', (138, 154))	('300 nM', 'Var', (61, 67))	('OCA-I ovarian carcinoma', 'Disease', (4, 27))	('OCA-I ovarian carcinoma', 'Disease', 'MESH:D010051', (4, 27))	('Flavopiridol', 'Chemical', 'MESH:C077990', (47, 59))	('increase', 'PosReg', (122, 130))
92486	31652849	Indeed, the embryos treated with Flavopiridol (500 nM) before irradiation with gamma-rays (10-40 Gy) displayed reduced viability compared to the control and exhibited a morphological alteration of the dorsal tail, due to exposure to radiation.	('dorsal tail', 'Phenotype', 'HP:0002825', (201, 212))	('viability', 'CPA', (119, 128))	('500 nM', 'Var', (47, 53))	('reduced', 'NegReg', (111, 118))	('Flavopiridol', 'Chemical', 'MESH:C077990', (33, 45))	('exhibited', 'Reg', (157, 166))	('rays', 'Species', '255564', (85, 89))
92487	31652849	Moreover, the micro-injection in the embryos of the antisense hydroxylprolyl-phosphono peptide nucleic acid oligomers (0.5 pmol), which down-regulated cyclin D1, and irradiation determined not only a reduction in viability but also the manifestation of the same phenotypic characteristics observed in the embryos flavopiridol-treated.	('cyclin D1', 'Gene', (151, 160))	('cyclin D1', 'Gene', '595', (151, 160))	('down-regulated', 'NegReg', (136, 150))	('reduction', 'NegReg', (200, 209))	('viability', 'CPA', (213, 222))	('flavopiridol', 'Chemical', 'MESH:C077990', (313, 325))	('hydroxylprolyl-phosphono', 'Chemical', 'MESH:C083881', (62, 86))	('antisense', 'Var', (52, 61))
92512	31652849	Moreover, it was observed that the CNE-2 cells (NPC), treated with variable doses of Berberine (25-100 micromol/L) for 24 h and gamma-irradiation (4-8 Gy) were characterized by a decrease of the mRNA and by a down-regulation of the protein expression of Sp1, a transcription factor associated to the tumoral migration and correlated to the tumoral invasion and radioresistance in NPC patients.	('N', 'Chemical', 'MESH:D009584', (197, 198))	('Sp1', 'Gene', (254, 257))	('tumoral invasion', 'Disease', (340, 356))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('gamma-irradiation', 'Var', (128, 145))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('CNE-2', 'CellLine', 'CVCL:6889', (35, 40))	('decrease', 'NegReg', (179, 187))	('Berberine', 'Chemical', 'MESH:D001599', (85, 94))	('tumoral migration', 'Disease', 'MESH:D014085', (300, 317))	('protein expression', 'MPA', (232, 250))	('tumoral migration', 'Disease', (300, 317))	('25-100 micromol/L', 'Var', (96, 113))	('patients', 'Species', '9606', (384, 392))	('down-regulation', 'NegReg', (209, 224))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('N', 'Chemical', 'MESH:D009584', (380, 381))	('mRNA', 'MPA', (195, 199))	('tumoral invasion', 'Disease', 'MESH:D009361', (340, 356))
92522	31652849	Clinically, high levels of Survivin have been associated with a reduction in survival and an increase in relapse and resistance to therapy.	('Survivin', 'Gene', '11799', (27, 35))	('increase', 'PosReg', (93, 101))	('relapse', 'CPA', (105, 112))	('survival', 'CPA', (77, 85))	('Survivin', 'Gene', (27, 35))	('resistance to therapy', 'CPA', (117, 138))	('high levels', 'Var', (12, 23))	('reduction', 'NegReg', (64, 73))
92543	31652849	Therefore, it has been observed that these normal cells treated with Genistein were characterized by an activation of Nft2, which determined a greater synthesis of antioxidant enzymes (such as GSH) and a decrease of the apoptotic rate and the radiosensitivity.	('decrease', 'NegReg', (204, 212))	('activation', 'PosReg', (104, 114))	('Genistein', 'Chemical', 'MESH:D019833', (69, 78))	('apoptotic rate', 'CPA', (220, 234))	('Genistein', 'Var', (69, 78))	('Nft2', 'Gene', (118, 122))	('GSH', 'Chemical', 'MESH:D005978', (193, 196))	('synthesis of antioxidant enzymes', 'MPA', (151, 183))	('Nft2', 'Gene', '2551', (118, 122))	('radiosensitivity', 'CPA', (243, 259))	('greater', 'PosReg', (143, 150))
92573	31652849	ROS are not only responsible for DNA damage, but they can also oxidize almost every molecular structure within the cells, causing their death.	('ROS', 'Var', (0, 3))	('oxidize', 'MPA', (63, 70))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('causing', 'Reg', (122, 129))
92603	30558669	No significant shifts in microbial composition were observed between the original and enriched samples (Additional file 2: Figure S1B-D); however, it is worth noting that the sequencing of original samples had a low number of microbial reads (118,202-331,573 microbial reads), potentially resulting in a less accurate profiling of the microbiome.	('low', 'NegReg', (212, 215))	('S1B', 'Species', '857105', (130, 133))	('118,202-331,573', 'Var', (243, 258))
92625	30558669	Further, an increase in heme biosynthesis from glycine or uroporphyrinogen was found in GERD as compared to subjects with a normal esophagus.	('uroporphyrinogen', 'Chemical', 'MESH:D014577', (58, 74))	('GERD', 'Var', (88, 92))	('increase', 'PosReg', (12, 20))	('heme biosynthesis from glycine', 'MPA', (24, 54))	('heme', 'Chemical', 'MESH:D006418', (24, 28))	('glycine', 'Chemical', 'MESH:D005998', (47, 54))
92627	30558669	In line with the small effect of PPI on microbial composition of GERD subjects but not subjects with a normal esophagus, a higher number of individual bacterial taxa were found to be associated with PPI usage in GERD patients as compared to subjects with a normal esophagus (Additional file 2: Figure S3A, B).	('PPI', 'Var', (199, 202))	('GERD', 'Disease', (212, 216))	('patients', 'Species', '9606', (217, 225))	('higher number', 'PosReg', (123, 136))
92637	30558669	The analysis identified SNPs associated with microbiome composition across most human chromosomes (Fig.	('SNPs', 'Var', (24, 28))	('human', 'Species', '9606', (80, 85))	('associated with', 'Reg', (29, 44))	('microbiome composition', 'MPA', (45, 67))
92641	30558669	Three host SNPs [NOTCH2 rs327202, STEAP2-AS1 rs56968594, and NREP (P311) rs57227445] were validated in the allele and genotype analyses using PERMANOVA (Fig.	('rs327202', 'Var', (24, 32))	('NREP', 'Gene', (61, 65))	('rs56968594', 'Var', (45, 55))	('P311', 'Gene', '9315', (67, 71))	('STEAP2-AS1', 'Gene', (34, 44))	('rs57227445', 'Mutation', 'rs57227445', (73, 83))	('rs57227445]', 'Var', (73, 84))	('NOTCH2', 'Gene', '4853', (17, 23))	('NREP', 'Gene', '9315', (61, 65))	('P311', 'Gene', (67, 71))	('rs56968594', 'Mutation', 'rs56968594', (45, 55))	('STEAP2-AS1', 'Gene', '100874100;261729;5729', (34, 44))	('rs327202', 'Mutation', 'rs327202', (24, 32))	('NOTCH2', 'Gene', (17, 23))
92642	30558669	SNPs in LINC01822 (rs4611672; P = 0.078) and MUC19 (rs2933353; P = 0.16) did not reach significance in the validation studies (Fig.	('rs4611672', 'Mutation', 'rs4611672', (19, 28))	('rs2933353', 'Mutation', 'rs2933353', (52, 61))	('rs4611672;', 'Var', (19, 29))	('rs2933353;', 'Var', (52, 62))	('MUC19', 'Gene', (45, 50))	('MUC19', 'Gene', '283463', (45, 50))
92661	30558669	A two-step process of detecting host SNPs associated to microbiome composition using the shotgun data followed by validation using custom SNP type assays identified three host SNPs (NOTCH2 rs327202, STEAP2-AS1 rs56968594, and NREP rs57227445) to be significantly associated with microbial composition in the esophagus.	('NOTCH2', 'Gene', (182, 188))	('NREP', 'Gene', (226, 230))	('STEAP2-AS1', 'Gene', (199, 209))	('rs327202', 'Mutation', 'rs327202', (189, 197))	('rs57227445', 'Mutation', 'rs57227445', (231, 241))	('microbial', 'MPA', (279, 288))	('NOTCH2', 'Gene', '4853', (182, 188))	('NREP', 'Gene', '9315', (226, 230))	('rs56968594', 'Mutation', 'rs56968594', (210, 220))	('associated', 'Reg', (263, 273))	('STEAP2-AS1', 'Gene', '100874100;261729;5729', (199, 209))	('rs327202', 'Var', (189, 197))	('rs57227445', 'Var', (231, 241))
92662	30558669	An additional two SNPs, LINC01822 rs4611672 and MUC19 rs2933353, were found to have borderline relationships.	('MUC19', 'Gene', '283463', (48, 53))	('rs4611672', 'Var', (34, 43))	('rs2933353', 'Var', (54, 63))	('MUC19', 'Gene', (48, 53))	('rs2933353', 'Mutation', 'rs2933353', (54, 63))	('rs4611672', 'Mutation', 'rs4611672', (34, 43))
92663	30558669	The association with SNPs in NREP and NOTCH2 would suggest that the transforming growth factor beta1 (TGF-beta1) and Notch signaling pathways are linked to the esophageal microbiome, which is of interest given that both are involved in the EAC cascade.	('NOTCH2', 'Gene', (38, 44))	('transforming growth factor beta1', 'Gene', '7040', (68, 100))	('NREP', 'Gene', '9315', (29, 33))	('association', 'Interaction', (4, 15))	('Notch', 'Gene', (117, 122))	('linked', 'Reg', (146, 152))	('NOTCH2', 'Gene', '4853', (38, 44))	('Notch', 'Gene', '4853', (117, 122))	('SNPs', 'Var', (21, 25))	('transforming growth factor beta1', 'Gene', (68, 100))	('NREP', 'Gene', (29, 33))	('EAC', 'Phenotype', 'HP:0011459', (240, 243))	('TGF-beta1', 'Gene', '7040', (102, 111))	('TGF-beta1', 'Gene', (102, 111))
92665	30558669	While the association with MUC19 rs2933353 was not significant, given that MUC19 is a salivary mucin that plays a role in pathogen clearance in the oral cavity and SNPs in this gene are associated with Crohn's disease, further validation of this association in a larger cohort would be required.	("Crohn's disease", 'Phenotype', 'HP:0100280', (202, 217))	("Crohn's disease", 'Disease', 'MESH:D003424', (202, 217))	("Crohn's disease", 'Disease', (202, 217))	('rs2933353', 'Var', (33, 42))	('rs2933353', 'Mutation', 'rs2933353', (33, 42))	('MUC19', 'Gene', (27, 32))	('MUC19', 'Gene', '283463', (75, 80))	('SNPs', 'Var', (164, 168))	('associated with', 'Reg', (186, 201))	('MUC19', 'Gene', '283463', (27, 32))	('MUC19', 'Gene', (75, 80))
92683	30558669	To identify host genetic variants associated with microbiome composition, MicrobiomeGWAS was used to combine the variant file (vcf) and the Bray-Curtis dissimilarity matrix of the microbial relative abundances generated from the shotgun sequencing data by MetaPhlAn2.	('variants', 'Var', (25, 33))	('Bray-Curtis', 'Disease', 'MESH:C537936', (140, 151))	('Bray-Curtis', 'Disease', (140, 151))
92685	30558669	Briefly, 24 custom SNP assays targeting rs10433076, rs113646232, rs11564245, rs11896941, rs1900358, rs201169969, rs2933353, rs327202, rs4572690, rs4611672, rs4695217, rs4768261, rs5011360, rs56968594, rs57227445, rs62211564, rs62402964, rs73106618, rs73106620, rs73115384, rs75009827, rs7714828, rs79153215, and rs80014625 were submitted to Fluidigm for assay design.	('rs56968594', 'Var', (189, 199))	('rs7714828', 'Mutation', 'rs7714828', (285, 294))	('rs4611672', 'Mutation', 'rs4611672', (145, 154))	('rs62211564', 'Var', (213, 223))	('rs201169969', 'Var', (100, 111))	('rs79153215', 'Mutation', 'rs79153215', (296, 306))	('rs62402964', 'Var', (225, 235))	('rs10433076', 'Mutation', 'rs10433076', (40, 50))	('rs4695217', 'Var', (156, 165))	('rs2933353', 'Var', (113, 122))	('rs75009827', 'Mutation', 'rs75009827', (273, 283))	('rs4768261', 'Mutation', 'rs4768261', (167, 176))	('rs56968594', 'Mutation', 'rs56968594', (189, 199))	('rs2933353', 'Mutation', 'rs2933353', (113, 122))	('rs113646232', 'Mutation', 'rs113646232', (52, 63))	('rs73106620', 'Var', (249, 259))	('rs11896941', 'Var', (77, 87))	('rs57227445', 'Mutation', 'rs57227445', (201, 211))	('rs73115384', 'Var', (261, 271))	('rs73106618', 'Mutation', 'rs73106618', (237, 247))	('rs4768261', 'Var', (167, 176))	('rs327202', 'Var', (124, 132))	('rs79153215', 'Var', (296, 306))	('rs113646232', 'Var', (52, 63))	('rs5011360', 'Var', (178, 187))	('rs5011360', 'Mutation', 'rs5011360', (178, 187))	('rs4572690', 'Var', (134, 143))	('rs73106618', 'Var', (237, 247))	('rs7714828', 'Var', (285, 294))	('rs1900358', 'Var', (89, 98))	('rs201169969', 'Mutation', 'rs201169969', (100, 111))	('rs73115384', 'Mutation', 'rs73115384', (261, 271))	('rs4695217', 'Mutation', 'rs4695217', (156, 165))	('rs4611672', 'Var', (145, 154))	('rs62402964', 'Mutation', 'rs62402964', (225, 235))	('rs327202', 'Mutation', 'rs327202', (124, 132))	('rs73106620', 'Mutation', 'rs73106620', (249, 259))	('rs11564245', 'Mutation', 'rs11564245', (65, 75))	('rs10433076', 'Var', (40, 50))	('rs80014625', 'Var', (312, 322))	('rs57227445', 'Var', (201, 211))	('rs1900358', 'Mutation', 'rs1900358', (89, 98))	('rs80014625', 'Mutation', 'rs80014625', (312, 322))	('rs75009827', 'Var', (273, 283))	('rs11896941', 'Mutation', 'rs11896941', (77, 87))	('rs62211564', 'Mutation', 'rs62211564', (213, 223))	('rs4572690', 'Mutation', 'rs4572690', (134, 143))	('rs11564245', 'Var', (65, 75))
92808	26797530	Further inclusion criteria included: age ranged between 18 and 75 years old; Karnofsky performance status >=80; life expectancy >=3 months; adequate renal function (serum creatinine <=1.5x the upper limit of normal [ULN]), adequate hepatic function (total and direct bilirubin <=2x the ULN), ALT and AST <=5x the ULN, and alkaline phosphatase <=2x the ULN or <=5x the ULN in the setting of liver metastases; and adequate bone marrow function (absolute neutrophil count >=1500/mm3, platelets >=100 000/mm3, hemoglobin >=9 g/dL).	('platelets', 'CPA', (481, 490))	('ALT', 'MPA', (292, 295))	('>=100 000/mm3', 'Var', (491, 504))	('bone marrow function', 'CPA', (421, 441))	('liver metastases', 'Disease', (390, 406))	('hepatic function', 'MPA', (232, 248))	('alkaline phosphatase', 'MPA', (322, 342))	('liver metastases', 'Disease', 'MESH:D009362', (390, 406))
92881	26068949	We conclude that while all OPN isoforms are frequently co-overexpressed in primary EACs, isoforms OPNb and OPNc enhance invasion and dissemination through collective yet distinct mechanisms.	('OPNb', 'Chemical', '-', (98, 102))	('isoforms', 'Var', (89, 97))	('OPNc', 'Chemical', '-', (107, 111))	('OPNc', 'Gene', (107, 111))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))	('OPNb', 'Gene', (98, 102))	('enhance', 'PosReg', (112, 119))
92899	26068949	Moreover, expression of OPN at histologically-negative surgical margins has been associated with higher recurrence of oral squamous cell carcinomas and, therefore, may be useful as a prognostic marker of recurrence.	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (118, 147))	('OPN', 'Gene', (24, 27))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (123, 147))	('oral squamous cell carcinomas', 'Disease', (118, 147))	('expression', 'Species', '29278', (10, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('expression', 'Var', (10, 20))
92930	26068949	When OE33/OPN isoform stable cells were labeled with luciferase, resuspended in Matrigel solution and injected into the flanks of nude mice, OPNb cells invaded Matrigel and grew into significantly larger xenografts in mice while OPNc cells failed to produce any tumor xenografts (Figure 5B).	('OPNc', 'Chemical', '-', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('invaded Matrigel', 'CPA', (152, 168))	('OPNb', 'Var', (141, 145))	('tumor', 'Disease', (262, 267))	('grew', 'CPA', (173, 177))	('larger', 'PosReg', (197, 203))	('nude mice', 'Species', '10090', (130, 139))	('mice', 'Species', '10090', (135, 139))	('OPNb', 'Chemical', '-', (141, 145))	('mice', 'Species', '10090', (218, 222))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
92938	26068949	When OPN-null OE19 EAC cells were cultured with isoform-specific donor-media from individual Flo/OPN stable cells, OPNb-media promoted significantly more cell migration than OPNc-media (Figure S3B) consistent with the results in OPN isoform-expressing stable cells (Figure 6A).	('OPNc-media', 'Chemical', '-', (174, 184))	('EAC', 'Phenotype', 'HP:0011459', (19, 22))	('promoted', 'PosReg', (126, 134))	('OPNb-media', 'Var', (115, 125))	('OE19', 'CellLine', 'CVCL:1622', (14, 18))	('donor', 'Species', '9606', (65, 70))	('OPNb', 'Chemical', '-', (115, 119))	('more', 'PosReg', (149, 153))	('cell migration', 'CPA', (154, 168))
92949	26068949	OPNib cells also showed enhanced cell adhesion, indicating that OPNb-mediated integrin signaling alone supports increased cell adhesion (Figure 7B).	('OPNib', 'Chemical', '-', (0, 5))	('OPNib', 'Var', (0, 5))	('enhanced', 'PosReg', (24, 32))	('cell adhesion', 'CPA', (33, 46))	('cell adhesion', 'CPA', (122, 135))	('OPNb', 'Chemical', '-', (64, 68))
92952	26068949	We observed that knockdown of ERBB2 did not change the phenotype; however, silencing of MET significantly enhanced cell detachment, which was evidenced by reproducibly-increased unstained areas in culture dishes containing OPNc cells treated with siMET as compared to untreated, mock-treated, non-target siRNA-treated, or siERBB2 treated cells (Figure 8A-8B).	('enhanced', 'PosReg', (106, 114))	('cell detachment', 'CPA', (115, 130))	('ERBB2', 'Gene', '2064', (30, 35))	('ERBB2', 'Gene', (30, 35))	('silencing', 'Var', (75, 84))	('OPNc', 'Chemical', '-', (223, 227))	('siMET', 'Chemical', '-', (247, 252))	('ERBB2', 'Gene', (324, 329))	('MET', 'Gene', (88, 91))	('ERBB2', 'Gene', '2064', (324, 329))
92953	26068949	These results are consistent with the role of MET in invasive growth in that silencing of MET augments OPNc-induced cell detachment.	('augments', 'PosReg', (94, 102))	('OPNc-induced', 'Disease', (103, 115))	('silencing', 'Var', (77, 86))	('OPNc', 'Chemical', '-', (103, 107))	('MET', 'Gene', (90, 93))
92954	26068949	In addition, we found that OE33/LacZ but not OPNa or OPNb cells exhibited increased detachment upon the knockdown of MET, indicating that OPNa and OPNb enhanced cell adhesion to counteract cell detachment induced by the knockdown of MET (Figure 8B).	('cell adhesion', 'CPA', (161, 174))	('OPNb', 'Chemical', '-', (147, 151))	('MET', 'Var', (117, 120))	('enhanced', 'PosReg', (152, 160))	('OPNb', 'Chemical', '-', (53, 57))	('detachment', 'CPA', (84, 94))	('knockdown', 'Var', (104, 113))
92955	26068949	Interestingly, OPNia stable cells were more detached than OPNa cells following treatment with siMET or siMET+siERBB2 whereas detachment in OPNic cells upon silencing of MET was more similar to the detachment seen in OPNc cells without siMET treatment (Figure 8A-8C).	('siMET', 'Chemical', '-', (103, 108))	('silencing', 'Var', (156, 165))	('siMET', 'Chemical', '-', (94, 99))	('OPNc', 'Chemical', '-', (216, 220))	('siMET', 'Chemical', '-', (235, 240))	('MET', 'Gene', (169, 172))	('ERBB2', 'Gene', (111, 116))	('ERBB2', 'Gene', '2064', (111, 116))
92957	26068949	The expression and efficiency of siRNA knockdown of ERBB2 and MET were monitored by qRT-PCR.	('MET', 'Gene', (62, 65))	('expression', 'Species', '29278', (4, 14))	('knockdown', 'Var', (39, 48))	('ERBB2', 'Gene', '2064', (52, 57))	('ERBB2', 'Gene', (52, 57))
92959	26068949	While OPNa sustains cell adhesion and attachment, the presence of the CD44 domain is required to antagonize siMET-induced cell detachment.	('cell adhesion', 'CPA', (20, 33))	('attachment', 'CPA', (38, 48))	('antagonize', 'NegReg', (97, 107))	('siMET', 'Chemical', '-', (108, 113))	('CD44 domain', 'Var', (70, 81))
92977	26068949	Using conventional end-labeling quantitative RT-PCR and bioinformatic exome variant analysis of the Affymetrix array ST 2.1 in a large cohort of EACs, we showed that all five OPN isoforms are co-overexpressed in primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('variant', 'Var', (76, 83))	('OPN', 'Gene', (175, 178))	('primary tumors', 'Disease', (212, 226))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('primary tumors', 'Disease', 'MESH:D009369', (212, 226))	('EAC', 'Phenotype', 'HP:0011459', (145, 148))
92981	26068949	Silencing of MET in MET-amplified OE33/OPNc stable cells augmented OPNc-induced cell detachment, yet OPNb-enhanced cell adhesion was not affected.	('MET', 'Gene', (13, 16))	('OPNc', 'Chemical', '-', (67, 71))	('OPNc', 'Chemical', '-', (39, 43))	('OPNc-induced', 'Disease', (67, 79))	('OPNb', 'Chemical', '-', (101, 105))	('Silencing', 'Var', (0, 9))	('augmented', 'PosReg', (57, 66))
92982	26068949	While expression of both OPNb and OPNc in the transformed EAC cells significantly boosted the number of colonies formed in soft agar, blockade of integrin signaling did not affect their anchorage-independent growth.	('OPNb', 'Gene', (25, 29))	('boosted', 'PosReg', (82, 89))	('expression', 'Species', '29278', (6, 16))	('OPNb', 'Chemical', '-', (25, 29))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('OPNc', 'Chemical', '-', (34, 38))	('OPNc', 'Gene', (34, 38))	('agar', 'Chemical', 'MESH:D000362', (128, 132))	('expression', 'Var', (6, 16))
92983	26068949	RGD integrin inhibition did, however, significantly reduce OPNb stable cell proliferation in 2-D cultures.	('OPNb', 'Gene', (59, 63))	('inhibition', 'Var', (13, 23))	('OPNb', 'Chemical', '-', (59, 63))	('RGD integrin', 'Protein', (0, 12))	('reduce', 'NegReg', (52, 58))
92989	26068949	Copy number alterations were not related to SPP1/OPN overexpression.	('SPP1', 'Gene', (44, 48))	('expression', 'Species', '29278', (57, 67))	('SPP1', 'Gene', '6696', (44, 48))	('Copy number alterations', 'Var', (0, 23))
92991	26068949	Epigenetic modification of OPN has been previously reported using trichostatin A (TSA), a potent histone deacetylase (HDAC) inhibitor.	('OPN', 'Gene', (27, 30))	('TSA', 'Chemical', 'MESH:C012589', (82, 85))	('reported', 'Reg', (51, 59))	('trichostatin A', 'Chemical', 'MESH:C012589', (66, 80))	('Epigenetic modification', 'Var', (0, 23))
92997	26068949	Our data suggest that OPNc not only reduces cell motility and enhances cell detachment but is also present in primary tumors.	('cell motility', 'CPA', (44, 57))	('OPNc', 'Chemical', '-', (22, 26))	('cell detachment', 'CPA', (71, 86))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('primary tumors', 'Disease', (110, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('reduces', 'NegReg', (36, 43))	('primary tumors', 'Disease', 'MESH:D009369', (110, 124))	('enhances', 'PosReg', (62, 70))	('OPNc', 'Var', (22, 26))
93009	26068949	However, recent studies have reported that frequent, high level expression of E-cadherin is observed in colonized metastatic-cancer cells and that high expression of E-cadherin is associated with aggressive tumor growth.	('expression', 'MPA', (64, 74))	('aggressive tumor', 'Disease', (196, 212))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('aggressive tumor', 'Disease', 'MESH:D001523', (196, 212))	('high', 'Var', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('expression', 'Species', '29278', (152, 162))	('E-cadherin', 'Protein', (78, 88))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('expression', 'Species', '29278', (64, 74))	('associated with', 'Reg', (180, 195))
93069	25436011	To investigate the role of miR-27a in esophageal squamous cell carcinoma (ESCC), TargetScan software was used to predict the target gene of miR-27a.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (38, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('esophageal squamous cell carcinoma', 'Disease', (38, 72))	('miR-27a', 'Var', (140, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
93070	25436011	Kirsten rat sarcoma viral oncogene homolog (KRAS), which has been implicated as a regulator of cell proliferation, differentiation and transformation, was identified as a potential target gene of miR-27a and, thus, was the focus of the present study.	('rat', 'Species', '10116', (8, 11))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('sarcoma', 'Disease', (12, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('miR-27a', 'Var', (196, 203))	('rat', 'Species', '10116', (107, 110))
93071	25436011	Furthermore, expression levels of the K-ras protein were reduced by <=50% in cells cotransfected with an expression vector containing miR-27a and miR-27a binding sequences, when compared with the control.	('expression levels', 'MPA', (13, 30))	('expression', 'Species', '29278', (13, 23))	('miR-27a', 'Var', (134, 141))	('expression', 'Species', '29278', (105, 115))	('reduced', 'NegReg', (57, 64))	('K-ras protein', 'Protein', (38, 51))
93072	25436011	The expression level of miR-27a was significantly lower in ESCC cell lines and tissues when compared with healthy esophageal epithelial cells and tissues.	('expression level', 'MPA', (4, 20))	('lower', 'NegReg', (50, 55))	('miR-27a', 'Var', (24, 31))	('expression', 'Species', '29278', (4, 14))
93073	25436011	However, the expression level of the target gene, KRAS was upregulated and ESCC cell proliferation was significantly inhibited following miR-27a mimic or small interfering K-ras transfection.	('expression', 'Species', '29278', (13, 23))	('small interfering', 'Var', (154, 171))	('K-ras', 'Protein', (172, 177))	('transfection', 'Var', (178, 190))	('KRAS', 'Gene', (50, 54))	('upregulated', 'PosReg', (59, 70))	('rat', 'Species', '10116', (92, 95))	('expression level', 'MPA', (13, 29))	('miR-27a mimic', 'Var', (137, 150))	('inhibited', 'NegReg', (117, 126))	('ESCC cell proliferation', 'CPA', (75, 98))
93074	25436011	In conclusion, the present study demonstrated that the expression level of miR-27a was low in ESCC and that miR-27a directly targets the KRAS gene, resulting in inhibited cell proliferation in esophageal cancer.	('rat', 'Species', '10116', (183, 186))	('expression level', 'MPA', (55, 71))	('cell proliferation', 'CPA', (171, 189))	('KRAS gene', 'Gene', (137, 146))	('expression', 'Species', '29278', (55, 65))	('inhibited', 'NegReg', (161, 170))	('rat', 'Species', '10116', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('esophageal cancer', 'Disease', (193, 210))	('ESCC', 'Disease', (94, 98))	('miR-27a', 'Var', (108, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))
93083	25436011	Kirsten rat sarcoma viral oncogene homolog (KRAS), which promotes cell proliferation, was identified as a potential target gene of miR-27a and, thus, was the focus of the present study.	('rat', 'Species', '10116', (8, 11))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('miR-27a', 'Var', (131, 138))	('sarcoma', 'Disease', (12, 19))	('cell proliferation', 'CPA', (66, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('rat', 'Species', '10116', (78, 81))	('promotes', 'PosReg', (57, 65))
93085	25436011	An activating mutation can be caused by a single amino acid substitution, with the resultant transforming protein identified as an important factor in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma.	('malignancies', 'Disease', 'MESH:D009369', (159, 171))	('mucinous adenoma', 'Disease', 'MESH:D000236', (204, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('malignancies', 'Disease', (159, 171))	('ductal carcinoma of the pancreas', 'Disease', (222, 254))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (222, 238))	('colorectal carcinoma', 'Disease', (259, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (259, 279))	('ductal carcinoma of the pancreas', 'Disease', 'MESH:D021441', (222, 254))	('single amino acid substitution', 'Var', (42, 72))	('lung adenocarcinoma', 'Disease', (183, 202))	('carcinoma of the pancreas', 'Phenotype', 'HP:0002894', (229, 254))	('activating', 'PosReg', (3, 13))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (183, 202))	('mutation', 'Var', (14, 22))	('mucinous adenoma', 'Disease', (204, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (183, 202))
93106	25436011	To investigate whether miR-27a suppresses tumor progression in vivo, TE-1 cells were transfected with pEGFP-miR-27a, and G418 was added to the medium and the cells were cultured for one month.	('pEGFP-miR-27a', 'Var', (102, 115))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
93117	25436011	Furthermore, to investigate whether miR-27a affects KRAS expression at the transcriptional and translation levels, two types of expression plasmid were constructed.	('affects', 'Reg', (44, 51))	('expression', 'Species', '29278', (57, 67))	('miR-27a', 'Var', (36, 43))	('expression', 'Species', '29278', (128, 138))
93118	25436011	The expression plasmids, pcDNA3.1-Kras and pcDNA3.1-Kras/mut contain the coding regions and 3'-UTR sequence of KRAS, however, the pcDNA3.1-Kras/mut contains the mutated miR-27a binding sequences.	('expression', 'Species', '29278', (4, 14))	('Kras', 'Gene', '24525', (52, 56))	('Kras', 'Gene', '24525', (139, 143))	('Kras', 'Gene', (34, 38))	('Kras', 'Gene', '24525', (34, 38))	('Kras', 'Gene', (52, 56))	('mutated', 'Var', (161, 168))	('miR-27a', 'Protein', (169, 176))	('Kras', 'Gene', (139, 143))
93128	25436011	Thus, the results of the present study indicated that miR-27a affects KRAS expression levels.	('KRAS expression levels', 'MPA', (70, 92))	('affects', 'Reg', (62, 69))	('expression', 'Species', '29278', (75, 85))	('miR-27a', 'Var', (54, 61))
93129	25436011	To investigate whether miR-27a functions as a tumor suppressor, an MTS assay was performed to detect cell viability.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('miR-27a', 'Var', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
93131	25436011	Thus, the results of the present study indicated ectopic miR-27a expression may inhibit the proliferation of ESCC cell lines.	('ESCC cell lines', 'CPA', (109, 124))	('inhibit', 'NegReg', (80, 87))	('expression', 'Species', '29278', (65, 75))	('miR-27a', 'Gene', (57, 64))	('rat', 'Species', '10116', (99, 102))	('ectopic', 'Var', (49, 56))	('proliferation', 'CPA', (92, 105))
93136	25436011	Thus, miR-27a promotes cell proliferation by reducing the expression of KRAS in ESCC cell lines.	('expression', 'Species', '29278', (58, 68))	('KRAS', 'Gene', (72, 76))	('expression', 'MPA', (58, 68))	('rat', 'Species', '10116', (35, 38))	('reducing', 'NegReg', (45, 53))	('promotes', 'PosReg', (14, 22))	('miR-27a', 'Var', (6, 13))	('cell proliferation', 'CPA', (23, 41))
93137	25436011	Upon termination of the experiment, the tumor volume demonstrated that the tumor growth rate was substantially lower in mice implanted with the cells overexpressing miR-27a compared with the control mice (Fig.	('mice', 'Species', '10090', (120, 124))	('mice', 'Species', '10090', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('lower', 'NegReg', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('miR-27a', 'Var', (165, 172))	('tumor', 'Disease', (75, 80))
93140	25436011	miR-27a was identified to be downregulated in acute leukemia cell lines and primary samples when compared with hematopoietic stem-progenitor cells (HSPCs), which indicates that miR-27a may exert a tumor suppressor-like action in acute leukemia, possibly via the regulation of apoptosis.	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('miR-27a', 'Var', (177, 184))	('leukemia', 'Disease', (52, 60))	('acute leukemia', 'Phenotype', 'HP:0002488', (46, 60))	('leukemia', 'Disease', 'MESH:D007938', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('leukemia', 'Phenotype', 'HP:0001909', (235, 243))	('acute leukemia', 'Phenotype', 'HP:0002488', (229, 243))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('miR-27a', 'Gene', (0, 7))	('downregulated', 'NegReg', (29, 42))	('leukemia', 'Disease', (235, 243))	('leukemia', 'Disease', 'MESH:D007938', (235, 243))
93141	25436011	However, miR-27a expression was upregulated during C2C12 myoblast proliferation, indicating that miR-27a may promote myoblast proliferation by targeting myostatin.	('myoblast proliferation', 'CPA', (117, 139))	('miR-27a', 'Var', (97, 104))	('miR-27a', 'Gene', (9, 16))	('promote', 'PosReg', (109, 116))	('C2C12', 'CellLine', 'CVCL:0188', (51, 56))	('expression', 'Species', '29278', (17, 27))	('targeting', 'Reg', (143, 152))	('myostatin', 'Protein', (153, 162))	('rat', 'Species', '10116', (133, 136))	('rat', 'Species', '10116', (73, 76))	('upregulated', 'PosReg', (32, 43))
93143	25436011	The expression of miR-27a was significantly downregulated when compared with a healthy animal model and human esophageal tissues, which indicated that miR-27a may function as a tumor suppressor in ESCC.	('miR-27a', 'Var', (151, 158))	('downregulated', 'NegReg', (44, 57))	('expression', 'Species', '29278', (4, 14))	('ESCC', 'Disease', (197, 201))	('expression', 'MPA', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('human', 'Species', '9606', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))
93146	25436011	Furthermore, the proliferation of the TE-1 cell line was significantly inhibited upon siK-ras and miR-27a transfection.	('siK-ras', 'Protein', (86, 93))	('proliferation of the TE-1 cell line', 'CPA', (17, 52))	('inhibited', 'NegReg', (71, 80))	('transfection', 'Var', (106, 118))	('miR-27a transfection', 'Var', (98, 118))	('rat', 'Species', '10116', (24, 27))
93203	22440040	As our data demonstrates, week-to-week variations in absolute tidal volumes can result in changes in esophageal tumor location that were not corrected for by skeletal alignment alone during treatment set-up.	('esophageal tumor', 'Disease', (101, 117))	('esophageal tumor', 'Phenotype', 'HP:0100751', (101, 117))	('absolute tidal volumes', 'MPA', (53, 75))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('esophageal tumor', 'Disease', 'MESH:D004938', (101, 117))	('changes', 'Reg', (90, 97))	('variations', 'Var', (39, 49))
93230	23466711	Overweight and obesity are associated with metabolic dysregulation including hyperinsulinemia and insulin resistance (measured by the Homeostatic Model Assessment (HOMA) score), presence of the metabolic syndrome, and alterations in levels of adipokines, such as adiponectin and leptin, associated with increased risk of developing colon and other cancers.	('hyperinsulinemia', 'Disease', (77, 93))	('obesity', 'Disease', 'MESH:D009765', (15, 22))	('cancers', 'Disease', 'MESH:D009369', (348, 355))	('insulin', 'Gene', '3630', (98, 105))	('insulin', 'Gene', '3630', (82, 89))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('insulin resistance', 'Phenotype', 'HP:0000855', (98, 116))	('alterations', 'Var', (218, 229))	('obesity', 'Phenotype', 'HP:0001513', (15, 22))	('men', 'Species', '9606', (158, 161))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (77, 93))	('Overweight', 'Disease', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (348, 355))	('cancers', 'Disease', (348, 355))	('insulin', 'Gene', (98, 105))	('insulin', 'Gene', (82, 89))	('metabolic syndrome', 'Disease', 'MESH:D008659', (194, 212))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (77, 93))	('metabolic syndrome', 'Disease', (194, 212))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('colon', 'Disease', 'MESH:D015179', (332, 337))	('presence', 'Var', (178, 186))	('levels', 'MPA', (233, 239))	('colon', 'Disease', (332, 337))	('obesity', 'Disease', (15, 22))	('metabolic dysregulation', 'MPA', (43, 66))	('associated', 'Reg', (287, 297))
93285	23466711	Table 4 shows the associations between levels of total and HMW adiponectin, leptin, HOMA scores, presence of the metabolic syndrome and risk of developing esophageal adenocarcinoma among all participants during all years of follow up and within the first three and six years after entry into the SBES cohort.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (155, 180))	('associations', 'Interaction', (18, 30))	('presence', 'Var', (97, 105))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (155, 180))	('SBES', 'Chemical', '-', (296, 300))	('BE', 'Phenotype', 'HP:0100580', (297, 299))	('metabolic syndrome', 'Disease', 'MESH:D008659', (113, 131))	('participants', 'Species', '9606', (191, 203))	('metabolic syndrome', 'Disease', (113, 131))	('esophageal adenocarcinoma', 'Disease', (155, 180))
93288	23466711	Levels of HMW adiponectin in the second tertile were associated with a significantly reduced risk compared to the lowest tertile for all patients (HR=0.34, 95% CI 0.14-0.82), and for males only (HR=0.36 95% CI 0.15-0.88).	('reduced', 'NegReg', (85, 92))	('HMW', 'Var', (10, 13))	('patients', 'Species', '9606', (137, 145))
93319	23466711	Low levels of adiponectin are associated with increased risk for a variety of obesity-related cancers, and with risk of developing BE, though the latter reported an association only with LMW adiponectin, and not with total adiponectin.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('BE', 'Phenotype', 'HP:0100580', (131, 133))	('LMW', 'Var', (187, 190))	('LMW', 'Chemical', '-', (187, 190))	('obesity', 'Disease', 'MESH:D009765', (78, 85))	('obesity', 'Phenotype', 'HP:0001513', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('obesity', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Low levels of adiponectin', 'Phenotype', 'HP:0030685', (0, 25))	('Low levels', 'Var', (0, 10))	('cancers', 'Disease', (94, 101))
93344	23634750	Amplification of the hTERC gene appears to influence certain features associated with postoperative survival in esophageal carcinoma patients.	('Amplification', 'Var', (0, 13))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('influence', 'Reg', (43, 52))	('hTERC', 'Gene', '7012', (21, 26))	('hTERC', 'Gene', (21, 26))	('patients', 'Species', '9606', (133, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('esophageal carcinoma', 'Disease', (112, 132))
93351	23634750	Hopman and colleagues showed that both the genomic integration of oncogenic HPV and gain of the hTERC gene appeared to be important genetic events that were associated with the progression of uterine cervical dysplasia to an invasive cancer.	('cervical dysplasia', 'Disease', (200, 218))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('associated with', 'Reg', (157, 172))	('invasive cancer', 'Disease', 'MESH:D009362', (225, 240))	('genomic', 'Var', (43, 50))	('hTERC', 'Gene', '7012', (96, 101))	('hTERC', 'Gene', (96, 101))	('HPV', 'Gene', (76, 79))	('cervical dysplasia', 'Disease', 'MESH:D002575', (200, 218))	('HPV', 'Species', '10566', (76, 79))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (200, 218))	('gain', 'PosReg', (84, 88))	('invasive cancer', 'Disease', (225, 240))
93359	23634750	The isolated DNA was amplified by the HPV L1 consensus primers MY11 and MY09.	('HPV', 'Species', '10566', (38, 41))	('HPV L1', 'Gene', (38, 44))	('MY09', 'Var', (72, 76))
93360	23634750	The PCR processes were monitored through amplification of part of the human beta-actin gene in replicate tubes with related primers.	('beta-actin', 'Gene', (76, 86))	('beta-actin', 'Gene', '728378', (76, 86))	('amplification', 'Var', (41, 54))	('human', 'Species', '9606', (70, 75))
93379	23634750	The infection type included the high-risk types HPV18, HPV35, HPV51, HPV56, HPV66, HPV58, HPV68, HPV39, HPV81, HPV59 and HPV16, and the low-risk types HPV42 and HPV54.	('HPV16', 'Var', (121, 126))	('HPV', 'Species', '10566', (69, 72))	('HPV56', 'Var', (69, 74))	('HPV51', 'Var', (62, 67))	('HPV81', 'Var', (104, 109))	('HPV', 'Species', '10566', (90, 93))	('HPV', 'Species', '10566', (83, 86))	('HPV', 'Species', '10566', (76, 79))	('HPV35', 'Species', '10587', (55, 60))	('HPV39', 'Var', (97, 102))	('HPV18', 'Var', (48, 53))	('HPV16', 'Species', '333760', (121, 126))	('HPV', 'Species', '10566', (161, 164))	('HPV66', 'Var', (76, 81))	('HPV', 'Species', '10566', (104, 107))	('HPV59', 'Var', (111, 116))	('HPV', 'Species', '10566', (97, 100))	('HPV', 'Species', '10566', (121, 124))	('HPV42', 'Species', '10590', (151, 156))	('HPV58', 'Var', (83, 88))	('HPV', 'Species', '10566', (151, 154))	('HPV', 'Species', '10566', (62, 65))	('HPV', 'Species', '10566', (48, 51))	('HPV', 'Species', '10566', (55, 58))	('HPV35', 'Var', (55, 60))	('HPV68', 'Var', (90, 95))	('HPV', 'Species', '10566', (111, 114))
93381	23634750	The main infection types were found to be HPV18, HPV35 and HPV51.	('HPV', 'Species', '10566', (42, 45))	('HPV', 'Species', '10566', (59, 62))	('HPV', 'Species', '10566', (49, 52))	('HPV35', 'Var', (49, 54))	('HPV35', 'Species', '10587', (49, 54))	('HPV18', 'Var', (42, 47))	('HPV51', 'Var', (59, 64))
93407	23634750	Shen and colleagues used HPV18E6/E7 to transfect human fetal esophageal epithelial cells and found that it could induce cellular immortalization.	('cellular immortalization', 'CPA', (120, 144))	('HPV', 'Species', '10566', (25, 28))	('human', 'Species', '9606', (49, 54))	('HPV18E6/E7', 'Var', (25, 35))	('induce', 'Reg', (113, 119))
93410	23634750	Infection with HPV included the high-risk types HPV18, HPV35, HPV51, HPV56, HPV66, HPV58, HPV68, HPV39, HPV81, HPV59 and HPV16, and the low-risk types HPV42 and HPV54.	('HPV', 'Species', '10566', (69, 72))	('HPV56', 'Var', (69, 74))	('HPV51', 'Var', (62, 67))	('HPV81', 'Var', (104, 109))	('HPV', 'Species', '10566', (90, 93))	('HPV', 'Species', '10566', (83, 86))	('HPV', 'Species', '10566', (76, 79))	('HPV35', 'Species', '10587', (55, 60))	('HPV39', 'Var', (97, 102))	('HPV18', 'Var', (48, 53))	('HPV16', 'Species', '333760', (121, 126))	('HPV', 'Species', '10566', (161, 164))	('HPV66', 'Var', (76, 81))	('HPV', 'Species', '10566', (104, 107))	('HPV', 'Species', '10566', (97, 100))	('HPV', 'Species', '10566', (121, 124))	('HPV42', 'Species', '10590', (151, 156))	('HPV58', 'Var', (83, 88))	('HPV', 'Species', '10566', (151, 154))	('HPV', 'Species', '10566', (62, 65))	('HPV', 'Species', '10566', (48, 51))	('HPV', 'Species', '10566', (55, 58))	('HPV68', 'Var', (90, 95))	('HPV', 'Species', '10566', (111, 114))	('HPV', 'Species', '10566', (15, 18))
93411	23634750	The main infection types were found to be HPV18, HPV35 and HPV51, and they existed as a mixed infection.	('HPV', 'Species', '10566', (42, 45))	('HPV', 'Species', '10566', (59, 62))	('HPV', 'Species', '10566', (49, 52))	('HPV35', 'Var', (49, 54))	('HPV35', 'Species', '10587', (49, 54))	('HPV18', 'Var', (42, 47))	('HPV51', 'Var', (59, 64))
93426	23634750	Similar to observations with cervical atypical hyperplasia, hTERC gene amplification was closely associated with different grades of atypical esophageal hyperplasia.	('hTERC', 'Gene', '7012', (60, 65))	('hyperplasia', 'Disease', 'MESH:D006965', (47, 58))	('esophageal hyperplasia', 'Disease', 'MESH:D006965', (142, 164))	('hyperplasia', 'Disease', (153, 164))	('amplification', 'Var', (71, 84))	('hyperplasia', 'Disease', 'MESH:D006965', (153, 164))	('esophageal hyperplasia', 'Disease', (142, 164))	('hyperplasia', 'Disease', (47, 58))	('associated', 'Reg', (97, 107))	('hTERC', 'Gene', (60, 65))
93429	23634750	This finding might indicate that amplification of the hTERC gene is an early event in the development of esophageal cancer.	('hTERC', 'Gene', '7012', (54, 59))	('amplification', 'Var', (33, 46))	('esophageal cancer', 'Disease', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('hTERC', 'Gene', (54, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))
93459	22312520	However, whereas DFP therapy is more effective than FP therapy, DFP therapy often induces not only leukocytopenia and alopecia but also gastrointestinal symptoms such as vomiting, nausea, and/or anorexia.	('vomiting', 'Disease', (170, 178))	('induces', 'Reg', (82, 89))	('gastrointestinal symptoms', 'Disease', (136, 161))	('DFP therapy', 'Var', (64, 75))	('anorexia', 'Disease', (195, 203))	('anorexia', 'Phenotype', 'HP:0002039', (195, 203))	('leukocytopenia and alopecia but also gastrointestinal symptoms', 'Disease', 'MESH:D007970', (99, 161))	('nausea', 'Phenotype', 'HP:0002018', (180, 186))	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (136, 161))	('nausea', 'Disease', (180, 186))	('alopecia', 'Phenotype', 'HP:0001596', (118, 126))	('vomiting', 'Phenotype', 'HP:0002013', (170, 178))
93469	33080677	Three independent datasets (GSE2379, GSE20347, and GSE75241) were screened out from the Gene Expression Omnibus (GEO) database and the overlapping differentially expressed genes (DEGs) were identified using GEO2R online platform.	('GSE2379', 'Var', (28, 35))	('GSE2379', 'Chemical', '-', (28, 35))	('GSE20347', 'Var', (37, 45))	('GSE75241', 'Var', (51, 59))
93475	33080677	Finally, hsa-miR-29c-3p, hsa-miR-29a-3p, and hsa-miR-29b-3p were confirmed as the top 3 interactive miRNAs that target the most hub genes according to the interaction network of miRNAs and hub genes.	('hub', 'Gene', '1993', (128, 131))	('hub', 'Gene', '1993', (189, 192))	('hub', 'Gene', (189, 192))	('hsa-miR-29b-3p', 'Var', (45, 59))	('hub', 'Gene', (128, 131))
93495	33080677	After the rigorous screening of all relevant datasets, 3 gene expression datasets including GSE2379, GSE20347, and GSE75241 met the inclusion criteria.	('GSE2379', 'Var', (92, 99))	('GSE75241', 'Var', (115, 123))	('GSE20347', 'Var', (101, 109))	('GSE2379', 'Chemical', '-', (92, 99))
93498	33080677	The original data of 3 datasets (GSE2379, GSE20347, GSE75241) were obtained from GEO and then subjected to differential expression analysis by the GEO2R online platform.	('GSE75241', 'Var', (52, 60))	('GSE2379', 'Var', (33, 40))	('GSE2379', 'Chemical', '-', (33, 40))	('GSE20347', 'Var', (42, 50))
93499	33080677	Based on the predefined cut-off values, DEGs (254 in GSE2379, 292 in GSE20347, and 257 in GSE75241) were identified (Fig.	('GSE20347', 'Var', (69, 77))	('GSE75241', 'Var', (90, 98))	('GSE2379', 'Var', (53, 60))	('GSE2379', 'Chemical', '-', (53, 60))
93522	33080677	In addition, aberrant adhesion of tumor cells to the extracellular matrix also plays a critical role in tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (104, 109))	('adhesion', 'CPA', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('metastasis', 'CPA', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('aberrant', 'Var', (13, 21))
93542	33080677	Previous studies have demonstrated ESCC cells could produce COL1A1 endogenously, and miR-133a-3p could inhibit the ESCC cell proliferation, invasion, and migration by targeting COL1A1.	('ESCC', 'Disease', (115, 119))	('targeting', 'Reg', (167, 176))	('COL1A1', 'Gene', (177, 183))	('miR-133a-3p', 'Var', (85, 96))	('COL1A1', 'Gene', '1277', (177, 183))	('miR-133a-3p', 'Chemical', '-', (85, 96))	('invasion', 'CPA', (140, 148))	('COL1A1', 'Gene', '1277', (60, 66))	('COL1A1', 'Gene', (60, 66))	('migration', 'CPA', (154, 163))	('inhibit', 'NegReg', (103, 110))
93545	33080677	However, in other malignancies such as ovarian cancer, pancreatic cancer, and head and neck cancer, overexpressed COL1A2 was found to promote tumor cell invasion and migration.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('migration', 'CPA', (166, 175))	('malignancies', 'Disease', 'MESH:D009369', (18, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('malignancies', 'Disease', (18, 30))	('promote', 'PosReg', (134, 141))	('head and neck cancer', 'Disease', 'MESH:D006258', (78, 98))	('pancreatic cancer', 'Disease', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('ovarian cancer', 'Disease', 'MESH:D010051', (39, 53))	('tumor', 'Disease', (142, 147))	('COL1A2', 'Gene', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))	('overexpressed', 'Var', (100, 113))	('ovarian cancer', 'Disease', (39, 53))	('head and neck cancer', 'Phenotype', 'HP:0012288', (78, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))
93554	33080677	Meanwhile, POSTN has also been proven to be able to bind to multiple integrin receptors including alphavbeta3, alphavbeta5, and alpha6beta4, thereby regulating the intracellular PI3K/Akt signaling pathway.	('bind', 'Interaction', (52, 56))	('alpha6beta4', 'Var', (128, 139))	('Akt', 'Gene', (183, 186))	('Akt', 'Gene', '207', (183, 186))	('alphavbeta5', 'Protein', (111, 122))	('regulating', 'Reg', (149, 159))	('POSTN', 'Gene', '10631', (11, 16))	('alphavbeta3', 'Protein', (98, 109))	('POSTN', 'Gene', (11, 16))
93570	33080677	Meanwhile, the interaction network of miRNAs and hub genes illustrates the regulatory relationships of the hub genes and miRNA, and hsa-miR-29c-3p, hsa-miR-29a-3p, and hsa-miR-29b-3p were confirmed as the top 3 interactive miRNAs that target the most hub genes.	('hsa-miR-29a-3p', 'Var', (148, 162))	('hub', 'Gene', (107, 110))	('hsa-miR-29c-3p', 'Var', (132, 146))	('regulatory', 'MPA', (75, 85))	('hub', 'Gene', '1993', (251, 254))	('hub', 'Gene', '1993', (49, 52))	('hub', 'Gene', '1993', (107, 110))	('hub', 'Gene', (251, 254))	('hub', 'Gene', (49, 52))
93590	31027127	The cases with PPCs were defined as those with ICD-10 codes of pneumonia due to infectious organisms (J13.x-J18.x), aspiration pneumonia (J69.x), and/or postprocedural respiratory disorders (J95.8 and/or J95.9) as complications.	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (116, 136))	('pneumonia', 'Disease', (63, 72))	('respiratory disorders', 'Disease', 'MESH:D012131', (168, 189))	('pneumonia', 'Disease', 'MESH:D011014', (63, 72))	('PPCs', 'Phenotype', 'HP:0006532', (15, 19))	('respiratory disorders', 'Disease', (168, 189))	('J13.x-J18.x', 'Var', (102, 113))	('PPCs', 'Disease', (15, 19))	('J95.9', 'Var', (204, 209))	('pneumonia', 'Phenotype', 'HP:0002090', (127, 136))	('aspiration', 'Phenotype', 'HP:0002835', (116, 126))	('pneumonia', 'Phenotype', 'HP:0002090', (63, 72))	('aspiration pneumonia', 'Disease', (116, 136))	('pneumonia', 'Disease', (127, 136))	('pneumonia', 'Disease', 'MESH:D011014', (127, 136))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (116, 136))	('PPCs', 'Disease', 'MESH:D011183', (15, 19))	('postprocedural', 'Disease', (153, 167))
93716	30391577	Preliminary results of a study evaluating the optimal radiation dose during definitive chemoradiation for inoperable ESCC showed no difference in locoregional PFS, PFS, or OS in patients treated with 60-Gy radiation versus standard-dose radiation in combination with cisplatin/docetaxel.	('patients', 'Species', '9606', (178, 186))	('ESCC', 'Disease', 'MESH:C562729', (117, 121))	('cisplatin', 'Chemical', 'MESH:D002945', (267, 276))	('docetaxel', 'Chemical', 'MESH:D000077143', (277, 286))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('60-Gy', 'Var', (200, 205))	('ESCC', 'Disease', (117, 121))
93805	30006925	Some studies suggest that lipophilic statins are associated with a greater reduction in risk of cancer recurrence and improved survival , while another study found no difference in the associations between statins and cancer incidence either by their solubility or other characteristics .	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('survival', 'CPA', (127, 135))	('cancer', 'Disease', (218, 224))	('improved', 'PosReg', (118, 126))	('lipophilic', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('reduction', 'NegReg', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
93806	30006925	In our study, use of either a hydrophilic or lipophilic statin was associated with a 25% reduction in ovarian cancer risk overall.	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lipophilic', 'Var', (45, 55))	('reduction in ovarian cancer', 'Disease', (89, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))	('reduction in ovarian cancer', 'Disease', 'MESH:D010051', (89, 116))
93825	30006925	There was no indication this association is due to a confounding effect of ovarian cancer risk factors and no epidemiologic basis for proposing that high cholesterol as an indication for statin use accounts for the association.	('ovarian cancer', 'Disease', 'MESH:D010051', (75, 89))	('high', 'Var', (149, 153))	('cholesterol', 'Chemical', 'MESH:D002784', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ovarian cancer', 'Disease', (75, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (75, 89))	('high cholesterol', 'Phenotype', 'HP:0003124', (149, 165))
93905	29943286	has suggested that using the more tumor-specific tracer L-[3-18F]-alpha-methyltyrosine in an FDG-PET/CT scan may be an effective method to distinguish sarcoidosis from malignancy.	('malignancy', 'Disease', 'MESH:D009369', (168, 178))	('L-[3-18F]-alpha-methyltyrosine', 'Chemical', '-', (56, 86))	('sarcoidosis', 'Disease', 'MESH:D012507', (151, 162))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('malignancy', 'Disease', (168, 178))	('tumor', 'Disease', (34, 39))	('L-[3-18F]-alpha-methyltyrosine', 'Var', (56, 86))	('sarcoidosis', 'Disease', (151, 162))	('FDG', 'Gene', '23583', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('FDG', 'Gene', (93, 96))
93941	28927038	There were 3 cases of ECF regimen (pharmorubicin + DDP + 5-FU), 3 cases with paclitaxel and DDP or carboplatin and 3 cases of MIC regimen (mitomycin + ifosfamide + DDP).	('5-FU', 'Chemical', 'MESH:D005472', (57, 61))	('DDP', 'Gene', (92, 95))	('pharmorubicin', 'Chemical', 'MESH:D015251', (35, 48))	('DDP', 'Gene', '1678', (51, 54))	('mitomycin', 'Chemical', 'MESH:D016685', (139, 148))	('DDP', 'Gene', (164, 167))	('ifosfamide', 'Chemical', 'MESH:D007069', (151, 161))	('CF', 'Disease', 'MESH:D003550', (23, 25))	('DDP', 'Gene', (51, 54))	('pharmorubicin', 'Var', (35, 48))	('DDP', 'Gene', '1678', (92, 95))	('paclitaxel', 'Chemical', 'MESH:D017239', (77, 87))	('DDP', 'Gene', '1678', (164, 167))	('carboplatin', 'Chemical', 'MESH:D016190', (99, 110))
93972	28781952	Here, we dissect gene expression data, from a previously described KYSE150 ESCC cell line in which SMYD3 had been knocked down, by integration with the protein-protein interaction (PPI) network, to find the new potential biological roles of SMYD3 and subsequent target genes.	('SMYD3', 'Gene', (99, 104))	('KYSE150', 'CellLine', 'CVCL:1348', (67, 74))	('knocked', 'Var', (114, 121))
93975	28781952	Altered expression of SMYD3 is associated with the progression of several solid tumors, including bladder cancer 1, glioma 2, gastric cancer 3, and prostate cancer 4.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('gastric cancer', 'Disease', (126, 140))	('tumors', 'Disease', (80, 86))	('glioma 2', 'Disease', 'MESH:D005910', (116, 124))	('SMYD3', 'Gene', (22, 27))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Altered', 'Var', (0, 7))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('expression', 'MPA', (8, 18))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('glioma 2', 'Disease', (116, 124))	('associated with', 'Reg', (31, 46))	('tumor', 'Disease', (80, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (148, 163))	('prostate cancer', 'Phenotype', 'HP:0012125', (148, 163))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('prostate cancer', 'Disease', (148, 163))
93984	28781952	Nevertheless, the expression levels of these 23 proteins were not significantly changed, except for the gene mesoderm-specific transcript (MEST), which was downregulated in the mRNA profile of SMYD3 knockdown in ESCC (Fig.	('downregulated', 'NegReg', (156, 169))	('knockdown', 'Var', (199, 208))	('MEST', 'Gene', (139, 143))	('MEST', 'Gene', '4232', (139, 143))
93998	28781952	The direct role for SMYD3 in the regulation of signal pathways has been reported, as SMYD3 mediates the methylation of MAP3K2 at lysine 260, which potentiates activation of the Ras/Raf/MEK/ERK signaling module 40.	('SMYD3', 'Gene', (85, 90))	('MAP3K2', 'Gene', (119, 125))	('Raf', 'Gene', '22882', (181, 184))	('potentiates activation', 'PosReg', (147, 169))	('MEK', 'Gene', (185, 188))	('MEK', 'Gene', '5609', (185, 188))	('signal pathways', 'Pathway', (47, 62))	('Raf', 'Gene', (181, 184))	('MAP3K2', 'Gene', '10746', (119, 125))	('methylation', 'Var', (104, 115))	('ERK', 'Gene', '5594', (189, 192))	('lysine 260', 'Var', (129, 139))	('ERK', 'Gene', (189, 192))
94015	27822478	However, in patients with early stage pT2N0M0 ESCC, those with a high expression of Ku80 had a worse OS and DFS, and adjuvant radiotherapy could significantly improve survival in these patients.	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('pT2N0M0 ESCC', 'Var', (38, 50))	('Ku80', 'Gene', '7520', (84, 88))	('Ku80', 'Gene', (84, 88))	('improve', 'PosReg', (159, 166))
94056	27429973	Furthermore, miR-146a was shown to be a negative regulator of TLR-NFkappaB pathway in human periodontal ligament cells after P. gingivalis LPS stimulation, therefore being involved in inflammatory response.	('TLR-NFkappaB pathway', 'Pathway', (62, 82))	('human', 'Species', '9606', (86, 91))	('involved', 'Reg', (172, 180))	('P. gingivalis', 'Species', '837', (125, 138))	('miR-146a', 'Var', (13, 21))	('negative', 'NegReg', (40, 48))
94060	27429973	In this in vitro study THP-1 macrophages that were stimulated with LPS from Aggregatibacter actinomycetemcomitans, P.g., and also P.g.	('Aggregatibacter actinomycetemcomitans', 'Species', '714', (76, 113))	('THP-1', 'Gene', '2736', (23, 28))	('THP-1', 'Gene', (23, 28))	('P.g.', 'Var', (115, 119))
94065	27429973	In this study, 14 miRNAs displayed significant changes in expression after exposure to P.g.	('changes', 'Reg', (47, 54))	('expression', 'MPA', (58, 68))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('P.g', 'Var', (87, 90))
94112	27429973	MiR-146a and miR-155 were dominant in in vitro studies.	('MiR-146a', 'Gene', (0, 8))	('MiR-146a', 'Gene', '406938', (0, 8))	('miR-155', 'Var', (13, 20))
94181	26609350	The percentage of tumors with invasion to the adventitia (88.2%), lymph node metastasis (87.5%), and tumors which were poorly differentiated (92.9%) were higher in cyclin D1 positive tumors than in the cyclin D1 negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('adventitia', 'Disease', 'None', (46, 56))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumors', 'Disease', (183, 189))	('adventitia', 'Disease', (46, 56))	('cyclin D1', 'Protein', (164, 173))	('positive', 'Var', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (221, 227))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('higher', 'PosReg', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumors', 'Disease', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('lymph node metastasis', 'CPA', (66, 87))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
94186	26609350	CONCLUSION   The study shows that alterations of cyclin D1 and p16 play an important role in ESCC.	('alterations', 'Var', (34, 45))	('cyclin D1', 'Protein', (49, 58))	('p16', 'Gene', (63, 66))	('ESCC', 'Disease', (93, 97))	('p16', 'Gene', '1029', (63, 66))
94195	26609350	Amplification of cyclin D1 results in growth advantage for tumor cells and enhances tumorigenesis.	('Amplification', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('enhances', 'PosReg', (75, 83))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('growth advantage', 'CPA', (38, 54))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('cyclin D1', 'Gene', (17, 26))
94233	26609350	The percentage of tumors with invasion to the adventitia (88.2%), lymph node metastasis (87.5%), and tumors which were poorly differentiated (92.9%) were higher in the cyclin D1 positive tumors than in the cyclin D1 negative tumors.	('adventitia', 'Disease', 'None', (46, 56))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('adventitia', 'Disease', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('higher', 'PosReg', (154, 160))	('tumors', 'Disease', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumors', 'Disease', (101, 107))	('cyclin', 'Protein', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('positive', 'Var', (178, 186))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('lymph node metastasis', 'CPA', (66, 87))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Disease', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
94239	26609350	Overexpression of cyclin D1 is thought to override the G1 checkpoint, driving tumor cell proliferation.	('override', 'PosReg', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cyclin D1', 'Protein', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('driving', 'PosReg', (70, 77))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (78, 83))
94247	26609350	The percentage of tumors with invasion to the adventitia (88.2%), lymph node metastasis (87.5%) and tumors which were poorly differentiated (92.9%) were higher in the cyclin D1 positive tumors than in the cyclin D1 negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('adventitia', 'Disease', 'None', (46, 56))	('tumors', 'Disease', (18, 24))	('positive', 'Var', (177, 185))	('adventitia', 'Disease', (46, 56))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', (186, 192))	('cyclin D1', 'Protein', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('higher', 'PosReg', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('lymph node metastasis', 'CPA', (66, 87))
94250	26609350	However in both no significant association of cyclin D1 positivity with tumor invasion, lymph node metastasis or differentiation was observed.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('positivity', 'Var', (56, 66))	('lymph node metastasis', 'CPA', (88, 109))	('cyclin D1', 'Protein', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
94252	26609350	Alterations of p16 occur by multiple mechanisms, including mutation, loss of heterozygosity (LOH) and promoter hypermethylation.	('p16', 'Gene', (15, 18))	('Alterations', 'Var', (0, 11))	('p16', 'Gene', '1029', (15, 18))	('loss of heterozygosity', 'Var', (69, 91))	('mutation', 'Var', (59, 67))	('promoter', 'MPA', (102, 110))
94253	26609350	Immunohistochemical staining is useful for the detection and localization of aberrant p16 expressionin tumor samples.	('aberrant', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('p16', 'Gene', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('p16', 'Gene', '1029', (86, 89))
94264	26609350	The association of p16 alterations with advanced-stage ESCC suggests that p16 alterations confer tumor cells with invasiveness and aggressiveness.	('p16', 'Gene', (74, 77))	('invasiveness', 'CPA', (114, 126))	('p16', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('confer', 'Reg', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('aggressiveness', 'Disease', 'MESH:D001523', (131, 145))	('tumor', 'Disease', (97, 102))	('p16', 'Gene', '1029', (74, 77))	('p16', 'Gene', '1029', (19, 22))	('aggressiveness', 'Disease', (131, 145))	('alterations', 'Var', (78, 89))	('alterations', 'Var', (23, 34))	('aggressiveness', 'Phenotype', 'HP:0000718', (131, 145))
94268	26609350	The mechanism underlying the correlation between cyclin Dl overexpression and loss of pl6 expression has not been identified, but these results suggest that accumulation of many kinds of gene alterations occurs during oncogenesis and tumor progression.	('pl6', 'Gene', (86, 89))	('tumor', 'Disease', (234, 239))	('cyclin', 'Gene', '5111', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('alterations', 'Var', (192, 203))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('pl6', 'Gene', '11070', (86, 89))	('cyclin', 'Gene', (49, 55))
94271	26609350	In conclusion, we report that alterations of Cyclin D1 and p16 play an important role in ESCC.	('Cyclin D1', 'Gene', (45, 54))	('p16', 'Gene', '1029', (59, 62))	('alterations', 'Var', (30, 41))	('ESCC', 'Disease', (89, 93))	('p16', 'Gene', (59, 62))	('Cyclin D1', 'Gene', '595', (45, 54))
94272	26609350	The deregulated proteins confer an aggressive behavior to the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('deregulated', 'Var', (4, 15))	('proteins', 'Protein', (16, 24))	('aggressive behavior', 'Phenotype', 'HP:0000718', (35, 54))
94287	25908445	Mutations of the SOD1 gene have been linked to human diseases, such as familial amyotrophic lateral sclerosis.	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (80, 109))	('familial amyotrophic lateral sclerosis', 'Disease', (71, 109))	('Mutations', 'Var', (0, 9))	('linked', 'Reg', (37, 43))	('familial amyotrophic lateral sclerosis', 'Disease', 'MESH:C531617', (71, 109))	('human', 'Species', '9606', (47, 52))	('SOD1', 'Gene', (17, 21))
94288	25908445	SOD1-/- mice are found to have a high rate of DNA mutations that occur at an early age and have an elevated susceptibility to oxidative stress and liver tumors.	('liver tumors', 'Disease', 'MESH:D008113', (147, 159))	('mutations', 'Var', (50, 59))	('liver tumors', 'Phenotype', 'HP:0002896', (147, 159))	('liver tumors', 'Disease', (147, 159))	('oxidative stress', 'Phenotype', 'HP:0025464', (126, 142))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('susceptibility', 'Reg', (108, 122))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('DNA', 'Gene', (46, 49))	('mice', 'Species', '10090', (8, 12))
94347	25908445	As shown in Figure 1C and D, the truncated deletion of SOD1 3'UTR gradually decreased luciferase activity and deletion of any part of SOD1 3'UTR dramatically affects the reporter activity with the 87-325 fragment seemed to be most significant To understand whether the enhanced reporter gene activity is due to increased mRNA expression or protein translation, total RNA was extracted from A2780 cells 24 hours after transfection.	('activity', 'MPA', (292, 300))	('SOD1', 'Gene', (55, 59))	('reporter activity', 'MPA', (170, 187))	('activity', 'MPA', (97, 105))	('decreased', 'NegReg', (76, 85))	('affects', 'Reg', (158, 165))	('mRNA', 'MPA', (321, 325))	('enhanced', 'PosReg', (269, 277))	('luciferase', 'Enzyme', (86, 96))	('A2780', 'CellLine', 'CVCL:0134', (390, 395))	('SOD1', 'Gene', (134, 138))	('deletion', 'Var', (110, 118))
94349	25908445	As shown in Figure 2, inclusion of the SOD1 3'UTR modestly increased luciferase mRNA levels in both control and actinomycin D-treated cells, suggesting that the high luciferase activity is only partially attributed to the increased mRNA expression.	('mRNA levels', 'MPA', (80, 91))	('inclusion', 'Var', (22, 31))	("SOD1 3'UTR", 'Var', (39, 49))	('actinomycin D', 'Chemical', 'MESH:D003609', (112, 125))	('increased', 'PosReg', (59, 68))	('luciferase', 'Enzyme', (69, 79))
94354	25908445	A2780 and PANC1 cells were transfected with the wild-type SOD1 3'UTR reporter constructs or the constructs with deletion of the miRNA binding site for miR-224, miR-377 or miR-621.	('miR-224', 'Gene', '407009', (151, 158))	('miR-377', 'Gene', (160, 167))	('deletion', 'Var', (112, 120))	('miR-621', 'Gene', (171, 178))	('PANC1', 'CellLine', 'CVCL:0480', (10, 15))	('miR-621', 'Gene', '693206', (171, 178))	('miR-224', 'Gene', (151, 158))	('binding', 'Interaction', (134, 141))	('miR-377', 'Gene', '494326', (160, 167))	('A2780', 'CellLine', 'CVCL:0134', (0, 5))
94355	25908445	Interestingly, deletion of the binding site for miR-224 and miR-377, but not miR-621 in SOD1 3'UTR, significantly down-regulated luciferase reporter activity (Figure 3C), which was not in accordance with the general belief that miRNAs negatively regulate gene expression.	('miR-224', 'Gene', '407009', (48, 55))	('miR-224', 'Gene', (48, 55))	('miR-377', 'Gene', '494326', (60, 67))	('luciferase reporter', 'Enzyme', (129, 148))	('miR-621', 'Gene', '693206', (77, 84))	('deletion', 'Var', (15, 23))	('miR-621', 'Gene', (77, 84))	('miR-377', 'Gene', (60, 67))	('down-regulated', 'NegReg', (114, 128))
94357	25908445	Instead, the deletion of miR-224 and miR-377 binding sites may alter the integrity of the SOD1 3'UTR, given their close proximity to the ARE1, resulting in down-regulation of SOD1 3'UTR-driven reporter gene activity.	('ARE1', 'Gene', (137, 141))	('down-regulation', 'NegReg', (156, 171))	('miR-377', 'Gene', '494326', (37, 44))	('ARE1', 'Gene', '6293', (137, 141))	('alter', 'Reg', (63, 68))	('integrity', 'MPA', (73, 82))	('deletion', 'Var', (13, 21))	('miR-377', 'Gene', (37, 44))	("SOD1 3'UTR-driven reporter gene activity", 'MPA', (175, 215))	('miR-224', 'Gene', '407009', (25, 32))	('miR-224', 'Gene', (25, 32))
94358	25908445	Deletion of the miR-224 and miR-377 but not miR-621 remarkably changed its original structure (Figure 4B-4D).	('miR-377', 'Gene', (28, 35))	('miR-224', 'Gene', '407009', (16, 23))	('miR-224', 'Gene', (16, 23))	('miR-621', 'Gene', '693206', (44, 51))	('original structure', 'MPA', (75, 93))	('changed', 'Reg', (63, 70))	('miR-621', 'Gene', (44, 51))	('miR-377', 'Gene', '494326', (28, 35))	('Deletion', 'Var', (0, 8))
94363	25908445	We found that compared to that of HuR, knockdown of AUF-1 significantly reduces SOD1 protein expression levels (Figure 6A), which was accompanied by a corresponding decrease in SOD enzymatic activity (Figure 6B).	('SOD', 'Gene', '6647', (80, 83))	('HuR', 'Gene', '1994', (34, 37))	('AUF-1', 'Gene', '3184', (52, 57))	('SOD', 'Gene', '6647', (177, 180))	('reduces', 'NegReg', (72, 79))	('knockdown', 'Var', (39, 48))	('AUF-1', 'Gene', (52, 57))	('SOD', 'Gene', (177, 180))	('SOD', 'Gene', (80, 83))	('decrease', 'NegReg', (165, 173))	('HuR', 'Gene', (34, 37))
94365	25908445	In contrast, the reporter gene activity in cells transfected with control vector or the SOD1 3'UTR antisense vector was unaffected by AUF-1 knockdown, indicating that SOD1 3'UTR contains specific motifs for AUF-1 to interact with (Figure 6C).	('AUF-1', 'Gene', '3184', (207, 212))	('AUF-1', 'Gene', (207, 212))	('AUF-1', 'Gene', '3184', (134, 139))	('knockdown', 'Var', (140, 149))	('AUF-1', 'Gene', (134, 139))	('interact', 'Interaction', (216, 224))
94373	25908445	To determine whether AUF-1, as a SOD1 expression regulator, might affect cellular ROS levels, PANC1 and A2780 cells were transfected with siRNA control (siRNA-NC) or siRNA targeting AUF-1 (siRNA-AUF-1).	('siRNA-AUF-1', 'Gene', '3184', (189, 200))	('AUF-1', 'Gene', (195, 200))	('siRNA-AUF-1', 'Gene', (189, 200))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('AUF-1', 'Gene', (21, 26))	('affect', 'Reg', (66, 72))	('AUF-1', 'Gene', '3184', (21, 26))	('AUF-1', 'Gene', '3184', (182, 187))	('AUF-1', 'Gene', (182, 187))	('A2780', 'CellLine', 'CVCL:0134', (104, 109))	('cellular ROS levels', 'MPA', (73, 92))	('PANC1', 'CellLine', 'CVCL:0480', (94, 99))	('AUF-1', 'Gene', '3184', (195, 200))	('siRNA', 'Var', (166, 171))
94375	25908445	Transfection of siRNA-AUF-1 to PANC1 cells was found to promote basal ROS generation compared with that of siRNA-NC transfection (Figure 9A).	('basal ROS generation', 'CPA', (64, 84))	('siRNA-AUF-1', 'Gene', (16, 27))	('siRNA-AUF-1', 'Gene', '3184', (16, 27))	('Transfection', 'Var', (0, 12))	('PANC1', 'CellLine', 'CVCL:0480', (31, 36))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('promote', 'PosReg', (56, 63))
94376	25908445	Furthermore, transfection of siRNA-AUF-1 significantly enhanced radiation-induced ROS levels (Figure 9A).	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('radiation-induced ROS levels', 'MPA', (64, 92))	('transfection', 'Var', (13, 25))	('siRNA-AUF-1', 'Gene', '3184', (29, 40))	('enhanced', 'PosReg', (55, 63))	('enhanced radiation-induced ROS levels', 'Phenotype', 'HP:0025464', (55, 92))	('siRNA-AUF-1', 'Gene', (29, 40))
94377	25908445	Figure 9B shows the quantification and statistical analysis of the relative ROS levels that were significantly increased after AUF-1 knockdown in basal as well as the irradiated state of PANC1 cells.	('AUF-1', 'Gene', (127, 132))	('ROS levels', 'MPA', (76, 86))	('increased', 'PosReg', (111, 120))	('knockdown', 'Var', (133, 142))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('PANC1', 'CellLine', 'CVCL:0480', (187, 192))	('AUF-1', 'Gene', '3184', (127, 132))
94379	25908445	Because SOD1 is a superoxide dismutase, the high ROS level after AUF-1 knockdown is most likely due to an accumulation of cellular superoxides.	('AUF-1', 'Gene', '3184', (65, 70))	('superoxide', 'Chemical', 'MESH:D013481', (131, 141))	('AUF-1', 'Gene', (65, 70))	('superoxide', 'Chemical', 'MESH:D013481', (18, 28))	('high ROS level', 'Phenotype', 'HP:0025464', (44, 58))	('accumulation', 'PosReg', (106, 118))	('high', 'PosReg', (44, 48))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('knockdown', 'Var', (71, 80))	('superoxides', 'Chemical', 'MESH:D013481', (131, 142))	('ROS level', 'MPA', (49, 58))	('cellular superoxides', 'MPA', (122, 142))
94391	25908445	Given the large number of miRNAs annotated in the human genome, 30%-80% of human genes are predicted to be influenced by miRNAs.	('human', 'Species', '9606', (75, 80))	('human genes', 'Gene', (75, 86))	('influenced', 'Reg', (107, 117))	('human', 'Species', '9606', (50, 55))	('miRNAs', 'Var', (121, 127))
94393	25908445	Second, even though bioinformatics predicted the presence of miRNA binding sites for miR-621, miR-224 and miR-377, deletion of the miRNA binding site for miR-621 from the SOD1 3'UTR construct had no effect on the reporter gene activity, and deletion of miR-224 and miR-377 binding sites led to a reduction of the reporter gene activity, opposite to what was expected, which may be explained by the fact that these two adjacent miRNA binding sites are close to the ARE1 site that is important for the integrity of the SOD1 3'UTR.	('deletion', 'Var', (115, 123))	('ARE1', 'Gene', (464, 468))	('miR-621', 'Gene', (85, 92))	('miR-224', 'Gene', '407009', (253, 260))	('miR-224', 'Gene', (253, 260))	('miR-377', 'Gene', (106, 113))	('miR-621', 'Gene', (154, 161))	('miR-621', 'Gene', '693206', (85, 92))	('miR-377', 'Gene', '494326', (106, 113))	('miR-621', 'Gene', '693206', (154, 161))	('miR-377', 'Gene', '494326', (265, 272))	('ARE1', 'Gene', '6293', (464, 468))	('reporter gene activity', 'MPA', (313, 335))	('reduction', 'NegReg', (296, 305))	('miR-377', 'Gene', (265, 272))	('deletion', 'Var', (241, 249))	('miR-224', 'Gene', '407009', (94, 101))	('miR-224', 'Gene', (94, 101))
94396	25908445	Most notably, deletion of the miR-224/377 binding sites from the SOD1 3'UTR reporter construct significantly altered its secondary structure and the reporter gene activity, whereas deletion of the miR-621 binding site did not dramatically disrupt the secondary structure or the reporter gene activity.	('SOD1', 'Gene', (65, 69))	('miR-621', 'Gene', (197, 204))	('secondary structure', 'MPA', (121, 140))	('miR-621', 'Gene', '693206', (197, 204))	('miR-224', 'Gene', '407009', (30, 37))	('miR-224', 'Gene', (30, 37))	('binding', 'Interaction', (42, 49))	('altered', 'Reg', (109, 116))	('deletion', 'Var', (14, 22))	('reporter gene activity', 'MPA', (149, 171))
94400	25908445	In the present study, we found that whereas knockdown of HuR had no effect on SOD1 expression in cancer cells, knockdown of AUF-1 attenuated endogenous SOD1 expression and SOD1 3'UTR-driven reporter gene activity, indicating its involvement in regulating SOD1 gene expression via its 3'UTR.	('knockdown', 'Var', (111, 120))	('cancer', 'Disease', (97, 103))	('SOD1', 'Gene', (172, 176))	('expression', 'MPA', (157, 167))	('AUF-1', 'Gene', '3184', (124, 129))	('SOD1', 'Gene', (152, 156))	('activity', 'MPA', (204, 212))	('endogenous', 'MPA', (141, 151))	('AUF-1', 'Gene', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HuR', 'Gene', (57, 60))	('attenuated', 'NegReg', (130, 140))	('HuR', 'Gene', '1994', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
94402	25908445	AUF-1 clearly plays a role for SOD1 expression, as evidenced by attenuated SOD1 expression after AUF-1 siRNA knockdown and enhanced SOD1 expression after forced expression of AUF-1 in A2780 and PANC1 cells.	('AUF-1', 'Gene', (175, 180))	('AUF-1', 'Gene', (0, 5))	('enhanced', 'PosReg', (123, 131))	('expression', 'MPA', (137, 147))	('A2780', 'CellLine', 'CVCL:0134', (184, 189))	('SOD1', 'Gene', (132, 136))	('AUF-1', 'Gene', '3184', (97, 102))	('AUF-1', 'Gene', (97, 102))	('knockdown', 'Var', (109, 118))	('expression', 'MPA', (80, 90))	('AUF-1', 'Gene', '3184', (175, 180))	('SOD1', 'Gene', (75, 79))	('AUF-1', 'Gene', '3184', (0, 5))	('PANC1', 'CellLine', 'CVCL:0480', (194, 199))	('attenuated', 'NegReg', (64, 74))
94437	25100294	Peptides were considered legitimately identified if they achieved specific charge state and proteolytic cleavage-dependent cross-correlation (Xcorr) scores of 1.9 for [M+H]1+, 2.2 for [M+2H]2+, and 3.5 for [M+3H]3+, and a minimum delta correlation score (DeltaCn) of 0.08.	('[M+2H]2+', 'Var', (184, 192))	('2H', 'Chemical', 'MESH:D003903', (187, 189))	('[M+3H]3+', 'Var', (206, 214))	('[M+H]1+', 'Var', (167, 174))	('3H', 'Chemical', 'MESH:D014316', (209, 211))
94441	25100294	The following ELISA kits were used: alpha-1-antitrypsin (A1A), myeloperoxidase (MPO), apolipoprotein A-I (APO A1) (Immunology Consultants Laboratory, Inc., #E-80A, # E-80PX, E80AP1, Portland, OR), resistin (R and D Systems, #DRSN00, Minneapolis, MN), isoform 1 of fibronectin (Bioxys, #EF1045, Brussels, Belgium), lymphocyte cytosolic protein 1 (LCP1) (Antibodies-online.com, #ABIN415176, Atlanta GA), cathespin B (USCNK, #SEC964Hu Houston, TX), protein S-100A9/MRP14, biglycan, annexin A6, (CedarLane #CY-8062, SE9822HU, SE92345HU, Burlington, NC) and cellular fibronectin (Biohit #6030010, Helsinki, Finland).	('MRP14', 'Gene', (462, 467))	('APO A1', 'Gene', (106, 112))	('myeloperoxidase', 'Gene', (63, 78))	('lymphocyte cytosolic protein 1', 'Gene', '3936', (314, 344))	('LCP1', 'Gene', '3936', (346, 350))	('alpha-1-antitrypsin', 'Gene', '5265', (36, 55))	('apolipoprotein A-I', 'Gene', (86, 104))	('fibronectin', 'Gene', (264, 275))	('myeloperoxidase', 'Gene', '4353', (63, 78))	('MN', 'CellLine', 'CVCL:U508', (246, 248))	('SE92345HU', 'Var', (522, 531))	('alpha-1-antitrypsin', 'Gene', (36, 55))	('SE9822HU', 'Var', (512, 520))	('APO A1', 'Gene', '335', (106, 112))	('fibronectin', 'Gene', '2335', (264, 275))	('biglycan', 'Gene', '633', (469, 477))	('protein S-100A9', 'Gene', '6280', (446, 461))	('fibronectin', 'Gene', (562, 573))	('apolipoprotein A-I', 'Gene', '335', (86, 104))	('protein S-100A9', 'Gene', (446, 461))	('LCP1', 'Gene', (346, 350))	('A1A', 'Gene', (57, 60))	('SE9822HU', 'CellLine', 'CVCL:6D91', (512, 520))	('annexin A6', 'Gene', (479, 489))	('MPO', 'Gene', '4353', (80, 83))	('biglycan', 'Gene', (469, 477))	('fibronectin', 'Gene', '2335', (562, 573))	('annexin A6', 'Gene', '309', (479, 489))	('A1A', 'Gene', '5265', (57, 60))	('lymphocyte cytosolic protein 1', 'Gene', (314, 344))	('CedarLane', 'Var', (492, 501))	('MPO', 'Gene', (80, 83))	('MRP14', 'Gene', '6280', (462, 467))
94455	25100294	As expected, there are many reports citing aberrant biological processes that occur in the development of EAC, such as cell cycle abnormalities and numerous genetic and epigenetic alterations, including loss of heterozygosity, polyploidy and aneuploidy.	('polyploidy', 'Disease', (227, 237))	('loss of heterozygosity', 'Var', (203, 225))	('cell cycle abnormalities', 'CPA', (119, 143))	('polyploidy', 'Disease', 'MESH:D011123', (227, 237))	('aneuploidy', 'Disease', (242, 252))	('cell cycle abnormalities', 'Phenotype', 'HP:0011018', (119, 143))	('EAC', 'Phenotype', 'HP:0011459', (106, 109))	('EAC', 'Disease', (106, 109))	('aneuploidy', 'Disease', 'MESH:D000782', (242, 252))
94516	23171077	Furthermore, patients who were treated with a T-shaped field had a significantly higher rate of adverse events than did patients who were treated with a local field .	('patients', 'Species', '9606', (13, 21))	('adverse events', 'MPA', (96, 110))	('patients', 'Species', '9606', (120, 128))	('T-shaped field', 'Var', (46, 60))
94517	23171077	In the present study, there was no late toxicity in the gastric tube even with 60 Gy; however, there have been some reports of problems in the gastric tube caused by obstruction of blood flow , which can be induced by radiation.	('toxicity', 'Disease', 'MESH:D064420', (40, 48))	('toxicity', 'Disease', (40, 48))	('gastric tube', 'Disease', (143, 155))	('gastric tube', 'Disease', 'MESH:D013274', (56, 68))	('gastric tube', 'Disease', (56, 68))	('gastric tube caused by obstruction of blood', 'Phenotype', 'HP:0004796', (143, 186))	('gastric tube', 'Disease', 'MESH:D013274', (143, 155))	('obstruction', 'Var', (166, 177))
94549	29523224	Furthermore, aberrantly expressed miRNAs may serve as oncogenes or tumor suppressors, mainly depending on the functional roles of their target genes.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('miRNAs', 'Protein', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('aberrantly expressed', 'Var', (13, 33))	('tumor', 'Disease', (67, 72))
94578	29523224	The human ZEB2 3'-UTR containing the wild-type (Wt) or mutant (Mut) miR-377 binding sites was chemically synthesized by GenePharma, inserted downstream of the luciferase gene in the psiCHECK-2 reporter vector (Promega, Madison, WI, USA), and named psiCHECK-ZEB2-3'-UTR Wt, or psiCHECK-ZEB2-3'-UTR Mut, respectively.	('miR-377', 'Gene', '494326', (68, 75))	('human', 'Species', '9606', (4, 9))	('psiCHECK', 'Disease', 'None', (248, 256))	('psiCHECK', 'Disease', 'None', (182, 190))	('ZEB2', 'Gene', '9839', (257, 261))	('ZEB2', 'Gene', '9839', (10, 14))	('mutant', 'Var', (55, 61))	('psiCHECK', 'Disease', (182, 190))	('ZEB2', 'Gene', '9839', (285, 289))	('ZEB2', 'Gene', (257, 261))	('ZEB2', 'Gene', (10, 14))	('psiCHECK', 'Disease', (248, 256))	('psiCHECK', 'Disease', 'None', (276, 284))	('miR-377', 'Gene', (68, 75))	('ZEB2', 'Gene', (285, 289))	('psiCHECK', 'Disease', (276, 284))
94597	29523224	To examine the effect of miR-377 overexpression on cellular proliferative ability, we used CCK-8 assays to detect cell proliferation of CaSki and HeLa cells after modification of miR-377 expression.	('HeLa', 'CellLine', 'CVCL:0030', (146, 150))	('CaSki', 'CellLine', 'CVCL:1100', (136, 141))	('miR-377', 'Gene', '494326', (25, 32))	('miR-377', 'Gene', '494326', (179, 186))	('miR-377', 'Gene', (25, 32))	('cell proliferation', 'CPA', (114, 132))	('CCK-8', 'Chemical', '-', (91, 96))	('miR-377', 'Gene', (179, 186))	('modification', 'Var', (163, 175))
94640	29523224	Accumulating evidence has revealed that the aberrant expression of miR-377 plays a vital role in human cancer onset and development.	('miR-377', 'Gene', '494326', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('development', 'CPA', (120, 131))	('human', 'Species', '9606', (97, 102))	('miR-377', 'Gene', (67, 74))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('role', 'Reg', (89, 93))	('aberrant expression', 'Var', (44, 63))
94654	29523224	ZEB2 dysregulation plays crucial roles in cancer occurrence and development by regulating various pathological processes, such as cell proliferation, cell cycle, apoptosis, angiogenesis, metastasis, epithelial-mesenchymal transition, and chemoresistance.	('dysregulation', 'Var', (5, 18))	('chemoresistance', 'CPA', (238, 253))	('ZEB2', 'Gene', '9839', (0, 4))	('epithelial-mesenchymal transition', 'CPA', (199, 232))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('angiogenesis', 'CPA', (173, 185))	('metastasis', 'CPA', (187, 197))	('regulating', 'Reg', (79, 89))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('ZEB2', 'Gene', (0, 4))	('apoptosis', 'CPA', (162, 171))	('cell proliferation', 'CPA', (130, 148))	('cell cycle', 'CPA', (150, 160))
94683	24863247	In animal models, ligation of the major salivary gland arterial supply produces infarction with subsequent squamous metaplasia of the acini that is histologically identical to NSM.	('infarction', 'Disease', 'MESH:D007238', (80, 90))	('infarction', 'Disease', (80, 90))	('squamous metaplasia', 'Disease', (107, 126))	('ligation', 'Var', (18, 26))	('squamous metaplasia', 'Phenotype', 'HP:0002860', (107, 126))	('squamous metaplasia', 'Disease', 'MESH:D008679', (107, 126))
94726	24863247	In general, the epithelia of the metaplastic SMG had statistically significant decreases in staining intensity of SMA and AB-PAS, and statistically significant increases in staining intensity of CK19 and MIB-1(Table 4).	('SMA', 'Chemical', '-', (114, 117))	('CK19', 'Gene', '3880', (195, 199))	('decreases', 'NegReg', (79, 88))	('metaplastic SMG', 'Var', (33, 48))	('increases', 'PosReg', (160, 169))	('PAS', 'Chemical', 'MESH:D011478', (125, 128))	('staining intensity', 'MPA', (92, 110))	('AB-PAS', 'Protein', (122, 128))	('SMA', 'Protein', (114, 117))	('staining intensity', 'MPA', (173, 191))	('MIB-1(Table 4', 'Gene', '57534', (204, 217))	('CK19', 'Gene', (195, 199))	('SMG', 'Chemical', '-', (45, 48))
94743	24863247	The physiological implications of NSMLC are clear: destroying the SMG acini would decrease the intrinsic secretory capacity of the esophagus.	('destroying', 'Var', (51, 61))	('decrease', 'NegReg', (82, 90))	('SMG', 'Chemical', '-', (66, 69))	('SMG', 'Gene', (66, 69))	('intrinsic secretory capacity of the esophagus', 'MPA', (95, 140))
94802	33713398	Univariate analysis showed a significant correlation between poor PFS and variables including SD after dCRT, combination of fistula, no adverse event, no absence of secondary hypertension or hand-foot syndrome (p<0.05).	('hypertension', 'Disease', 'MESH:D006973', (175, 187))	('hand-foot syndrome', 'Disease', (191, 209))	('PF', 'Chemical', '-', (66, 68))	('poor', 'Var', (61, 65))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (191, 209))	('fistula', 'Disease', 'MESH:D005402', (124, 131))	('fistula', 'Disease', (124, 131))	('dCRT', 'Gene', (103, 107))	('dCRT', 'Gene', '45841', (103, 107))	('hypertension', 'Disease', (175, 187))	('hypertension', 'Phenotype', 'HP:0000822', (175, 187))
94837	33713398	The survival data reported in this study was comparable to the patients who had CR after dCRT, suggesting that maintenance therapy for those non-CR ESCC is a promising strategy to improve survival.	('dCRT', 'Gene', '45841', (89, 93))	('dCRT', 'Gene', (89, 93))	('patients', 'Species', '9606', (63, 71))	('non-CR', 'Var', (141, 147))	('survival', 'MPA', (188, 196))	('improve', 'PosReg', (180, 187))
94845	33713398	VEGF-TKI targets VEGFR2 and then decreased the release of nitric oxide from endothelial cells, leading to the constant contraction of arterial smooth muscle cells to induce hypertension.	('hypertension', 'Disease', (173, 185))	('release of nitric oxide from endothelial cells', 'MPA', (47, 93))	('VEGF', 'Gene', '7422', (17, 21))	('hypertension', 'Phenotype', 'HP:0000822', (173, 185))	('contraction', 'MPA', (119, 130))	('targets', 'Var', (9, 16))	('hypertension', 'Disease', 'MESH:D006973', (173, 185))	('VEGF', 'Gene', '7422', (0, 4))	('nitric oxide', 'Chemical', 'MESH:D009569', (58, 70))	('VEGFR2', 'Gene', (17, 23))	('leading to', 'Reg', (95, 105))	('VEGF', 'Gene', (17, 21))	('induce', 'Reg', (166, 172))	('decreased', 'NegReg', (33, 42))	('VEGF', 'Gene', (0, 4))	('VEGFR2', 'Gene', '3791', (17, 23))
94881	32533228	Combinations of radiotherapy or radiochemotherapy with newer systemic therapies such as antibodies to the epidermal growth factor receptor (EGFR) provide additional options.	('EGFR', 'Gene', (140, 144))	('epidermal growth factor receptor', 'Gene', '1956', (106, 138))	('antibodies', 'Var', (88, 98))	('EGFR', 'Gene', '1956', (140, 144))	('epidermal growth factor receptor', 'Gene', (106, 138))
94882	32533228	Overexpression of EGFR is frequent and associated with a poor prognosis in patients with squamous cell carcinoma (SCC) of the esophagus or adenocarcinoma of the gastroesophageal junction.	('adenocarcinoma', 'Disease', 'MESH:D000230', (139, 153))	('EGFR', 'Gene', '1956', (18, 22))	('SCC', 'Gene', (114, 117))	('patients', 'Species', '9606', (75, 83))	('EGFR', 'Gene', (18, 22))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('adenocarcinoma', 'Disease', (139, 153))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('squamous cell carcinoma', 'Disease', (89, 112))
94888	32533228	Stratification was based on histology (SCC vs. adenocarcinoma), Karnofsky performance score (80-100% vs. 70%), and tumor stage (T1-3N0-1 vs. T4 and/or N2 and/or M1a).	('T1-3N0-1', 'Var', (128, 136))	('SCC', 'Gene', '6317', (39, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('tumor', 'Disease', (115, 120))	('SCC', 'Phenotype', 'HP:0002860', (39, 42))	('SCC', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('adenocarcinoma', 'Disease', (47, 61))
94957	32533228	In head and neck cancer patients, interruptions of radiotherapy decrease disease control and survival.	('head and neck cancer', 'Disease', 'MESH:D006258', (3, 23))	('survival', 'CPA', (93, 101))	('interruptions', 'Var', (34, 47))	('decrease disease', 'Disease', (64, 80))	('patients', 'Species', '9606', (24, 32))	('decrease disease', 'Disease', 'MESH:D002303', (64, 80))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
94968	32533228	Additional limitations included lack of a central review, the fact that less than 20% of the patients had adenocarcinomas, no assessment of the expression of EGFR and mutations in the vast majority of the patients, and lack of standardized procedures of treatment planning and quality assurance.	('EGFR', 'Gene', (158, 162))	('patients', 'Species', '9606', (205, 213))	('adenocarcinomas', 'Disease', 'MESH:D000230', (106, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adenocarcinomas', 'Disease', (106, 121))	('mutations', 'Var', (167, 176))	('EGFR', 'Gene', '1956', (158, 162))	('patients', 'Species', '9606', (93, 101))
94983	31918742	Moreover, lncTUG1 knockdown dramatically improved the effect of radiotherapy on ESCC development both in vivo and in vitro.	('knockdown', 'Var', (18, 27))	('improved', 'PosReg', (41, 49))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('nt', 'Chemical', 'MESH:D009711', (94, 96))	('TUG1', 'Gene', '55000', (13, 17))	('TUG1', 'Gene', (13, 17))	('ESCC', 'Disease', (80, 84))
94986	31918742	Moreover, we found that knockdown of lncTUG1 enhanced the radiosensitivity of ESCC cells via the p-AKT signaling pathway.	('radiosensitivity of', 'CPA', (58, 77))	('ESCC', 'Disease', (78, 82))	('TUG1', 'Gene', '55000', (40, 44))	('AKT', 'Gene', '207', (99, 102))	('enhanced', 'PosReg', (45, 53))	('TUG1', 'Gene', (40, 44))	('AKT', 'Gene', (99, 102))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('knockdown', 'Var', (24, 33))
95028	31918742	Luciferase reporter gene vectors (pRL-TK, Promega) containing wild type (WT) or mutant (Mut) lncTUG1 and the 3'-UTR of WT or Mut MET were transfected into HEK293T cells.	('mutant', 'Var', (80, 86))	('TUG1', 'Gene', (96, 100))	('nt', 'Chemical', 'MESH:D009711', (151, 153))	('HEK293T', 'CellLine', 'CVCL:0063', (155, 162))	('nt', 'Chemical', 'MESH:D009711', (53, 55))	('nt', 'Chemical', 'MESH:D009711', (84, 86))	('TUG1', 'Gene', '55000', (96, 100))
95050	31918742	Briefly, two data series consisting of two esophageal cancer cells and their derived radioresistant cell lines were obtained from the Gene Expression Omnibus (GEO) database (i.e., GSE61620, and GSE61772).	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('GSE61620', 'Var', (180, 188))	('esophageal cancer', 'Disease', (43, 60))	('nt', 'Chemical', 'MESH:D009711', (97, 99))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
95069	31918742	In contrast, lncTUG1 knockdown increased the quantity of apoptotic cells (Fig.	('nt', 'Chemical', 'MESH:D009711', (5, 7))	('increased', 'PosReg', (31, 40))	('nt', 'Chemical', 'MESH:D009711', (48, 50))	('TUG1', 'Gene', '55000', (16, 20))	('knockdown', 'Var', (21, 30))	('TUG1', 'Gene', (16, 20))
95076	31918742	EC9706 and KYSE30 cell colonies were inhibited dramatically by lncTUG1 knockdown plus 2 Gy radiation (Fig.	('TUG1', 'Gene', '55000', (66, 70))	('inhibited', 'NegReg', (37, 46))	('TUG1', 'Gene', (66, 70))	('knockdown', 'Var', (71, 80))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))
95079	31918742	4g, the cellular survival curves of EC9706 and KYSE30 cells indicated the knockdown of lncTUG1 indeed enhance the radiosensitivity, and the relative relative radiosensitizaion effects data were shown in Table 3.	('TUG1', 'Gene', '55000', (90, 94))	('enhance', 'PosReg', (102, 109))	('radiosensitivity', 'CPA', (114, 130))	('knockdown', 'Var', (74, 83))	('TUG1', 'Gene', (90, 94))	('EC9706', 'CellLine', 'CVCL:E307', (36, 42))
95090	31918742	We further determined whether lncTUG1 affects radiosensitivity through miR-144-3p and MET.	('miR-144', 'Gene', '406936', (71, 78))	('MET', 'Var', (86, 89))	('TUG1', 'Gene', '55000', (33, 37))	('affects', 'Reg', (38, 45))	('radiosensitivity', 'MPA', (46, 62))	('TUG1', 'Gene', (33, 37))	('miR-144', 'Gene', (71, 78))
95091	31918742	6a and b, colony formation and apoptosis assays confirmed that the miR-144-3p inhibitor restored the effect of lncTUG1 knockdown on radiotherapy.	('miR-144', 'Gene', '406936', (67, 74))	('effect', 'MPA', (101, 107))	('TUG1', 'Gene', '55000', (114, 118))	('knockdown', 'Var', (119, 128))	('miR-144', 'Gene', (67, 74))	('TUG1', 'Gene', (114, 118))
95092	31918742	Moreover, MET knockdown decreased the level of EGFR and lowered the phosphorylation level of AKT (Fig.	('phosphorylation level', 'MPA', (68, 89))	('decreased', 'NegReg', (24, 33))	('level', 'MPA', (38, 43))	('AKT', 'Gene', (93, 96))	('lowered', 'NegReg', (56, 63))	('MET knockdown', 'Var', (10, 23))	('knockdown', 'Var', (14, 23))	('EGFR', 'Gene', '1956', (47, 51))	('AKT', 'Gene', '207', (93, 96))	('EGFR', 'Gene', (47, 51))
95096	31918742	The findings indicated that lncTUG1 knockdown could enhance the effect of radiotherapy on ESCC in vivo (Fig.	('TUG1', 'Gene', '55000', (31, 35))	('TUG1', 'Gene', (31, 35))	('ESCC', 'Disease', 'MESH:C562729', (90, 94))	('knockdown', 'Var', (36, 45))	('enhance', 'PosReg', (52, 59))	('ESCC', 'Disease', (90, 94))
95108	31918742	miR-144-3p and MET were found to affect the development of ESCC.	('ESCC', 'Disease', 'MESH:C562729', (59, 63))	('miR-144', 'Gene', (0, 7))	('affect', 'Reg', (33, 39))	('miR-144', 'Gene', '406936', (0, 7))	('MET', 'Var', (15, 18))	('ESCC', 'Disease', (59, 63))	('nt', 'Chemical', 'MESH:D009711', (53, 55))
95113	31918742	Moreover, numerous studies have indicated that MET is associated with activation of the AKT signaling pathway by upregulating the expression level of EGFR.	('EGFR', 'Gene', (150, 154))	('AKT', 'Gene', '207', (88, 91))	('EGFR', 'Gene', '1956', (150, 154))	('expression level', 'MPA', (130, 146))	('AKT', 'Gene', (88, 91))	('MET', 'Var', (47, 50))	('activation', 'PosReg', (70, 80))	('upregulating', 'PosReg', (113, 125))
95125	31918742	Thus, lncTUG1 knockdown potentially has significant clinical application value.	('clinical', 'Species', '191496', (52, 60))	('TUG1', 'Gene', '55000', (9, 13))	('nt', 'Chemical', 'MESH:D009711', (28, 30))	('nt', 'Chemical', 'MESH:D009711', (49, 51))	('TUG1', 'Gene', (9, 13))	('knockdown', 'Var', (14, 23))
95143	31296250	The inhibition of LEF1 might therefore be a novel therapeutic target to inactivate CSCs and inhibit tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('CSCs', 'Protein', (83, 87))	('inhibition', 'Var', (4, 14))	('inhibit', 'NegReg', (92, 99))	('inactivate', 'NegReg', (72, 82))	('LEF1', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
95152	31296250	In our previous study, we demonstrated that OV6 expression was also closely associated with the clinical outcome and prognosis of ESCC patients and contributed to tumorigenesis and chemotherapy resistance.	('patients', 'Species', '9606', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('ESCC', 'Disease', (130, 134))	('chemotherapy resistance', 'CPA', (181, 204))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('contributed to', 'Reg', (148, 162))	('rat', 'Species', '10116', (33, 36))	('associated', 'Reg', (76, 86))	('tumor', 'Disease', (163, 168))	('OV6 expression', 'Var', (44, 58))
95154	31296250	Several studies indicated that LEF1 was overexpressed in lung adenocarcinomas and oral squamous cell carcinoma, and its aberrant expression was closely associated with tumor progression and poor prognosis.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (57, 77))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('oral squamous cell carcinoma', 'Disease', (82, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('aberrant expression', 'Var', (120, 139))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('lung adenocarcinomas', 'Disease', (57, 77))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (57, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('associated', 'Reg', (152, 162))	('overexpressed', 'PosReg', (40, 53))	('LEF1', 'Gene', (31, 35))
95159	31296250	The aberrant activation of the TGF-beta signaling pathway is responsible for the self-renewal properties and drug resistance of various cancers, including hepatocellular carcinoma, esophageal squamous cell carcinoma, and colorectal cancer.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('TGF-beta', 'Gene', '7040', (31, 39))	('colorectal cancer', 'Disease', (221, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('hepatocellular carcinoma', 'Disease', (155, 179))	('esophageal squamous cell carcinoma', 'Disease', (181, 215))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('TGF-beta', 'Gene', (31, 39))	('rectal cancer', 'Phenotype', 'HP:0100743', (225, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('aberrant', 'Var', (4, 12))	('activation', 'PosReg', (13, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (181, 215))
95162	31296250	A recent study reported that the application of a TGF-beta inhibitor prevents the development of CSCs, which promotes the chemotherapeutic effect against triple-negative breast cancer.	('CSCs', 'Disease', (97, 101))	('TGF-beta', 'Gene', '7040', (50, 58))	('inhibitor', 'Var', (59, 68))	('TGF-beta', 'Gene', (50, 58))	('development of', 'CPA', (82, 96))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('prevents', 'NegReg', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', (170, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('promotes', 'PosReg', (109, 117))
95182	31296250	The lentiviral vectors were transfected into the HCC cells with a multiplicity of infection (MOI) 5 in the presence of polybrene (5 mug/ml) for 6 h. Stable Eca109 and TE-1 cells knockdown of LEF1 were generated using lentiviral constructs expressing shLEF1(shLEF11#CCCATCCCGAGAACATCAA; shLEF12#CCTCATCCAGCTATTGTAA; shLEF13#GCTACATATGCAGCTTTAT) and negative control (HeYuan Bio-technology Co., Shanghai, China), and incubated with 2 mug/ml puromycin (Sigma, St Louis, USA).	('rat', 'Species', '10116', (205, 208))	('HCC', 'CellLine', 'CVCL:0C54', (49, 52))	('shLEF13#GCTACATATGCAGCTTTAT', 'Var', (315, 342))	('shLEF12#CCTCATCCAGCTATTGTAA', 'Var', (286, 313))	('infection', 'Disease', (82, 91))	('infection', 'Disease', 'MESH:D007239', (82, 91))
95215	31296250	A Kaplan-Meier curve unveiled that patients with high expression levels of LEF1 were associated with a lower overall survival rate (Fig.	('lower', 'NegReg', (103, 108))	('LEF1', 'Gene', (75, 79))	('overall survival', 'MPA', (109, 125))	('high expression levels', 'Var', (49, 71))	('patients', 'Species', '9606', (35, 43))	('rat', 'Species', '10116', (126, 129))
95218	31296250	Our previous study reported that OV6 was a possible CSC marker for ESCC and was associated with poor prognosis in ESCC patients.	('patients', 'Species', '9606', (119, 127))	('ESCC', 'Disease', (114, 118))	('ESCC', 'Disease', (67, 71))	('OV6', 'Var', (33, 36))
95277	31296250	In addition, a significant correlation between LEF1 and ID1 expression was observed in clinical ESCC patients, strongly suggesting that LEF1 regulation of the CSC phenotype is associated with ID1 expression.	('patients', 'Species', '9606', (101, 109))	('ID1', 'Gene', (56, 59))	('LEF1', 'Var', (136, 140))	('ID1', 'Gene', '3397', (192, 195))	('ESCC', 'Disease', (96, 100))	('ID1', 'Gene', (192, 195))	('ID1', 'Gene', '3397', (56, 59))
95284	31296250	Mechanically, LEF1 overexpression in ESCC directly upregulates ID1 and activates TGF-beta pathway.	('upregulates', 'PosReg', (51, 62))	('ID1', 'Gene', (63, 66))	('activates', 'PosReg', (71, 80))	('overexpression', 'Var', (19, 33))	('ID1', 'Gene', '3397', (63, 66))	('TGF-beta', 'Gene', '7040', (81, 89))	('LEF1', 'Gene', (14, 18))	('TGF-beta', 'Gene', (81, 89))
95288	31012515	Indoleamine 2, 3-dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer Indoleamine 2, 3-dioxygenase 1 (IDO1) is a primary enzyme that generates immunosuppressive metabolites.	('IDO1', 'Gene', (157, 161))	('Indoleamine 2, 3-dioxygenase 1', 'Gene', '3620', (125, 155))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('IDO1', 'Gene', '3620', (157, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('Indoleamine 2, 3-dioxygenase 1', 'Gene', '3620', (0, 30))	('hypomethylation', 'Var', (40, 55))	('patients', 'Species', '9606', (93, 101))
95291	31012515	Recently, it has been reported that IDO1 expression is regulated by methylation of the IDO1 promoter.	('regulated', 'Reg', (55, 64))	('methylation', 'Var', (68, 79))	('expression', 'MPA', (41, 51))	('IDO1', 'Gene', '3620', (36, 40))	('IDO1', 'Gene', (87, 91))	('IDO1', 'Gene', (36, 40))	('IDO1', 'Gene', '3620', (87, 91))
95295	31012515	We treated cell lines with 5-azacytidine, and the resulting hypomethylation induced significantly higher IDO1 expression (P < .001).	('IDO1', 'Gene', '3620', (105, 109))	('5-azacytidine', 'Chemical', 'MESH:D001374', (27, 40))	('higher', 'PosReg', (98, 104))	('expression', 'MPA', (110, 120))	('IDO1', 'Gene', (105, 109))	('hypomethylation', 'Var', (60, 75))
95297	31012515	Furthermore, patients in the IDO1 promoter hypomethylation group (n = 67) had a poor prognosis compared with those in the IDO1 promoter hypermethylation group (n = 175) (overall survival, P = .011).	('IDO1', 'Gene', (122, 126))	('IDO1', 'Gene', '3620', (29, 33))	('promoter hypomethylation', 'Var', (34, 58))	('patients', 'Species', '9606', (13, 21))	('IDO1', 'Gene', (29, 33))	('IDO1', 'Gene', '3620', (122, 126))
95298	31012515	Our results showed that IDO1 promoter hypomethylation regulated IDO1 expression and was associated with a poor prognosis in esophageal cancer patients.	('regulated', 'Reg', (54, 63))	('hypomethylation', 'Var', (38, 53))	('esophageal cancer', 'Disease', (124, 141))	('IDO1', 'Gene', (24, 28))	('IDO1', 'Gene', '3620', (64, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('expression', 'MPA', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('associated', 'Reg', (88, 98))	('IDO1', 'Gene', '3620', (24, 28))	('patients', 'Species', '9606', (142, 150))	('IDO1', 'Gene', (64, 68))
95325	31012515	Because LINE-1 represents a considerable part of the human genome (approximately 17%), LINE-1 methylation levels have been considered as a surrogate marker of global DNA methylation.23 The IDO1 promoter methylation levels were also decreased by 5-AZA treatment.	('5-AZA', 'Var', (245, 250))	('IDO1', 'Gene', (189, 193))	('IDO1', 'Gene', '3620', (189, 193))	('promoter methylation levels', 'MPA', (194, 221))	('human', 'Species', '9606', (53, 58))	('5-AZA', 'Chemical', 'MESH:D001374', (245, 250))	('decreased', 'NegReg', (232, 241))
95331	31012515	These data suggest that DNA hypermethylation in the IDO1 promoter might indeed be involved in the reduction of IDO1 transcription observed in esophageal cancer.	('IDO1', 'Gene', '3620', (52, 56))	('IDO1', 'Gene', '3620', (111, 115))	('transcription', 'MPA', (116, 129))	('esophageal cancer', 'Disease', (142, 159))	('IDO1', 'Gene', (52, 56))	('IDO1', 'Gene', (111, 115))	('reduction', 'NegReg', (98, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('DNA', 'Var', (24, 27))
95340	31012515	In univariate Cox regression analysis, patients with IDO1 promoter hypomethylation showed significantly higher overall mortality than those with IDO1-negative tumors (HR 1.75; 95% confidence interval, 1.120-2.677; P = .015].	('IDO1', 'Gene', '3620', (145, 149))	('promoter hypomethylation', 'Var', (58, 82))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('IDO1', 'Gene', '3620', (53, 57))	('Cox', 'Gene', (14, 17))	('IDO1', 'Gene', (145, 149))	('tumor', 'Disease', (159, 164))	('Cox', 'Gene', '1351', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('higher', 'PosReg', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('IDO1', 'Gene', (53, 57))
95349	31012515	Furthermore, in breast cancer, it has been reported that IDO1 expression was regulated by IDO1 promoter methylation in estrogen receptor-positive cases.	('breast cancer', 'Disease', (16, 29))	('IDO1', 'Gene', '3620', (90, 94))	('regulated', 'Reg', (77, 86))	('IDO1', 'Gene', '3620', (57, 61))	('expression', 'MPA', (62, 72))	('IDO1', 'Gene', (90, 94))	('methylation', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('IDO1', 'Gene', (57, 61))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
95351	31012515	Based on past studies in other types of cancer, we considered that the most important mechanism might involve methylation of CpGs in the IDO1 promoter and therefore investigated the relationship between methylation level and IDO1 expression level.	('IDO1', 'Gene', '3620', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('IDO1', 'Gene', '3620', (137, 141))	('methylation', 'Var', (110, 121))	('IDO1', 'Gene', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('IDO1', 'Gene', (137, 141))
95352	31012515	We found that demethylation significantly induced higher expression of IDO1 in all esophageal cancer cell lines.	('expression', 'MPA', (57, 67))	('higher', 'PosReg', (50, 56))	('esophageal cancer', 'Disease', (83, 100))	('IDO1', 'Gene', '3620', (71, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('demethylation', 'Var', (14, 27))	('IDO1', 'Gene', (71, 75))
95355	31012515	Therefore, our results are evidence that epigenetic hypomethylation induces high expression of IDO1 and contributes to malignant behavior in esophageal cancer.	('esophageal cancer', 'Disease', (141, 158))	('contributes to', 'Reg', (104, 118))	('IDO1', 'Gene', '3620', (95, 99))	('malignant behavior', 'CPA', (119, 137))	('IDO1', 'Gene', (95, 99))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('epigenetic hypomethylation', 'Var', (41, 67))
95357	31012515	Most reports have concluded that mRNA, protein, and hypomethylation were associated with poor prognosis, regardless of the type of cancer.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('mRNA', 'MPA', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('hypomethylation', 'Var', (52, 67))	('poor prognosis', 'CPA', (89, 103))	('protein', 'Protein', (39, 46))
95361	31012515	The relationship between IDO1 promoter hypomethylation, preoperative therapy, and patient outcomes needs to be confirmed in independent cohorts in the future.	('IDO1', 'Gene', '3620', (25, 29))	('IDO1', 'Gene', (25, 29))	('hypomethylation', 'Var', (39, 54))	('patient', 'Species', '9606', (82, 89))
95363	31012515	Therefore, it is suggested that there are complex mechanisms that determine the influence of methylation on IDO1 protein expression, malignant behavior from IDO1, and absence of CD8+ TIL.	('IDO1', 'Gene', (157, 161))	('CD8', 'Gene', (178, 181))	('CD8', 'Gene', '925', (178, 181))	('expression', 'MPA', (121, 131))	('IDO1', 'Gene', (108, 112))	('IDO1', 'Gene', '3620', (157, 161))	('malignant behavior', 'CPA', (133, 151))	('protein', 'Protein', (113, 120))	('IDO1', 'Gene', '3620', (108, 112))	('methylation', 'Var', (93, 104))
95370	31012515	In summary, this study suggests that methylation of CpG sites in the IDO1 promoter regulated IDO1 expression levels and was associated with poor prognosis in esophageal cancer patients.	('patients', 'Species', '9606', (176, 184))	('methylation', 'Var', (37, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('IDO1', 'Gene', (69, 73))	('IDO1', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('associated', 'Reg', (124, 134))	('regulated', 'Reg', (83, 92))	('expression levels', 'MPA', (98, 115))	('IDO1', 'Gene', '3620', (93, 97))	('IDO1', 'Gene', '3620', (69, 73))	('CpG sites', 'Var', (52, 61))	('esophageal cancer', 'Disease', (158, 175))
95616	26784024	Higher uptake of 18F-FDG compared with the background activity was interpreted as abnormal, and CT images were used for anatomic landmarking.	('uptake', 'MPA', (7, 13))	('Higher', 'PosReg', (0, 6))	('18F-FDG', 'Chemical', '-', (17, 24))	('18F-FDG', 'Var', (17, 24))
95671	27488320	NK-1 receptor antagonists exert an antitumor action against GI cancer [Table 2].	('GI cancer', 'Disease', (60, 69))	('antagonists', 'Var', (14, 25))	('NK-1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('GI cancer', 'Disease', 'MESH:D009369', (60, 69))	('GI cancer', 'Phenotype', 'HP:0007378', (60, 69))	('tumor', 'Disease', (39, 44))
95688	27488320	NK-1 receptor antagonists block glycogen breakdown in tumor cells, counteracting the Warburg effect [Figure 3b].	('antagonists', 'Var', (14, 25))	('NK-1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('glycogen breakdown', 'MPA', (32, 50))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('glycogen', 'Chemical', 'MESH:D006003', (32, 40))	('tumor', 'Disease', (54, 59))	('block', 'NegReg', (26, 31))
95689	27488320	This means that NK-1 receptor antagonists produces the death of tumor cells by starvation.	('antagonists', 'Var', (30, 41))	('death of tumor', 'Disease', (55, 69))	('death of tumor', 'Disease', 'MESH:D003643', (55, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
95693	27488320	The blockade of SP induces apoptosis in colon cancer and in other types of cancers [Figure 2b and d], this effect being accompanied by a decrease in the MAPK signaling pathways.	('colon cancer', 'Phenotype', 'HP:0003003', (40, 52))	('colon cancer', 'Disease', 'MESH:D015179', (40, 52))	('decrease', 'NegReg', (137, 145))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('blockade', 'Var', (4, 12))	('colon cancer', 'Disease', (40, 52))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('MAPK', 'Gene', (153, 157))	('apoptosis', 'CPA', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('MAPK', 'Gene', '5595;5594;5595', (153, 157))
95708	27488320	Hypermethylation of the tachykinin-1 (TAC1) gene has been linked to human esophageal neoplastic transformation.	('esophageal neoplastic', 'Disease', 'MESH:D004938', (74, 95))	('linked', 'Reg', (58, 64))	('human', 'Species', '9606', (68, 73))	('TAC1', 'Gene', '6863', (38, 42))	('tachykinin-1', 'Gene', (24, 36))	('Hypermethylation', 'Var', (0, 16))	('TAC1', 'Gene', (38, 42))	('esophageal neoplastic transformation', 'Phenotype', 'HP:0100751', (74, 110))	('esophageal neoplastic', 'Disease', (74, 95))	('tachykinin-1', 'Gene', '6863', (24, 36))
95712	27488320	Myenteric denervation decreases the number and size of gastric adenocarcinomas, this decrease being more evident when denervation is associated with pyloroplasty.	('denervation', 'Var', (10, 21))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (55, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('gastric adenocarcinomas', 'Disease', (55, 78))	('decreases', 'NegReg', (22, 31))
95717	27488320	Colon cancer samples express both the full-length and the truncated forms of the NK-1 receptor [Table 1].	('Colon cancer', 'Phenotype', 'HP:0003003', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('truncated', 'Var', (58, 67))	('Colon cancer', 'Disease', (0, 12))	('NK-1 receptor', 'Gene', (81, 94))	('Colon cancer', 'Disease', 'MESH:D015179', (0, 12))
95753	27488320	It seems that the expression of NK-1 receptors and p-EGFR positivity with vitamin D receptor negativity could be used to identify areas of sporadic colorectal neoplasia.	('positivity', 'Var', (58, 68))	('vitamin D receptor', 'Gene', '7421', (74, 92))	('neoplasia', 'Phenotype', 'HP:0002664', (159, 168))	('sporadic colorectal neoplasia', 'Disease', (139, 168))	('NK-1 receptors', 'Protein', (32, 46))	('positivity with vitamin D', 'Phenotype', 'HP:0100512', (58, 83))	('vitamin D receptor', 'Gene', (74, 92))	('sporadic colorectal neoplasia', 'Disease', 'MESH:D015179', (139, 168))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))
95761	27488320	Nonpeptide NK-1 receptor antagonists include the following compounds: Perhydroisoindolones, steroids, tryptophan-based (L-732,138) [Table 2], benzylamino and benzylether quinuclidine, benzylether piperidines (L-733,060) [Table 2], and benzylamino piperidines.	('steroids', 'Chemical', 'MESH:D013256', (92, 100))	('benzylamino and benzylether quinuclidine', 'Chemical', '-', (142, 182))	('benzylamino piperidines', 'Chemical', '-', (235, 258))	('L-732', 'Chemical', '-', (120, 125))	('Perhydroisoindolones', 'Chemical', '-', (70, 90))	('benzylether piperidines', 'Chemical', '-', (184, 207))	('L-733,060', 'Chemical', 'MESH:C103788', (209, 218))	('tryptophan', 'Chemical', 'MESH:D014364', (102, 112))	('L-733,060', 'Var', (209, 218))	('L-732,138', 'Var', (120, 129))
95790	27488320	NK-1 receptor antagonists are safe and selective against tumor cells (the opposite of what happens with cytostatic drugs) [Table 3].	('NK-1', 'Gene', (0, 4))	('antagonists', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
95829	27164115	In these cells, sensitivity to the cytostatic effects of metformin can be restored via silencing ATP citrate lyase (ACL; the enzyme catalyzing the rare limiting step of acetyl-CoA production), pinpointing to the significance of future therapeutic strategies employing metformin along with ACL activity inhibition.	('silencing', 'Var', (87, 96))	('ATP citrate lyase', 'Gene', '47', (97, 114))	('metformin', 'Chemical', 'MESH:D008687', (57, 66))	('ATP citrate lyase', 'Gene', (97, 114))	('metformin', 'Chemical', 'MESH:D008687', (268, 277))
95841	27164115	Unfortunately, recent evidence suggests that the prolonged exposure of estrogen receptor (ER)-positive human breast cancer cells to metformin upregulates AKT/Snail1, suppresses ER and renders these cells tolerant to the toxicity of both metformin and tamoxifen; a phenomenon known as "cross-resistance", irrespective of AMPK stimulation.	('Snail1', 'Gene', (158, 164))	('AMPK', 'Gene', '5563', (320, 324))	('metformin', 'Var', (132, 141))	('metformin', 'Chemical', 'MESH:D008687', (132, 141))	('human', 'Species', '9606', (103, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('toxicity', 'Disease', 'MESH:D064420', (220, 228))	('AKT', 'Gene', (154, 157))	('AMPK', 'Gene', (320, 324))	('upregulates', 'PosReg', (142, 153))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('estrogen receptor', 'Gene', '2099', (71, 88))	('breast cancer', 'Disease', (109, 122))	('toxicity', 'Disease', (220, 228))	('tamoxifen', 'Chemical', 'MESH:D013629', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('renders', 'Reg', (184, 191))	('suppresses', 'NegReg', (166, 176))	('AKT', 'Gene', '207', (154, 157))	('ER', 'Gene', '2099', (90, 92))	('ER', 'Gene', '2099', (177, 179))	('Snail1', 'Gene', '6615', (158, 164))	('metformin', 'Chemical', 'MESH:D008687', (237, 246))	('estrogen receptor', 'Gene', (71, 88))	('tolerant', 'MPA', (204, 212))
95843	27164115	Consistent with data demonstrating the ability of metformin to eliminate ovarian CSCs, it was reported that low-dose metformin restrains the self-renewing capacity of CD44/CD117-positive ovarian CSCs as well as the expression of epithelial-to-mesenchymal transition (EMT) markers in vitro.	('metformin', 'Chemical', 'MESH:D008687', (50, 59))	('self-renewing capacity', 'CPA', (141, 163))	('CD44', 'Gene', '960', (167, 171))	('CD117', 'Gene', '3815', (172, 177))	('ovarian CSCs', 'Disease', 'MESH:D010051', (187, 199))	('ovarian CSCs', 'Disease', (73, 85))	('CD117', 'Gene', (172, 177))	('CD44', 'Gene', (167, 171))	('ovarian CSCs', 'Disease', (187, 199))	('metformin', 'Var', (117, 126))	('restrains', 'NegReg', (127, 136))	('metformin', 'Chemical', 'MESH:D008687', (117, 126))	('ovarian CSCs', 'Disease', 'MESH:D010051', (73, 85))
95844	27164115	Besides, irrespective of ER status, metformin exerts anti-EMT effects on 17beta-estradiol-treated human endometrial adenocarcinoma cells via engaging a betaKlotho/ERK-dependent pathway.	('endometrial adenocarcinoma', 'Disease', (104, 130))	('ERK', 'Gene', '5594', (163, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('ERK', 'Gene', (163, 166))	('metformin', 'Chemical', 'MESH:D008687', (36, 45))	('ER', 'Gene', '2099', (25, 27))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (73, 89))	('ER', 'Gene', '2099', (163, 165))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (104, 130))	('betaKlotho', 'Gene', '152831', (152, 162))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (104, 130))	('engaging', 'PosReg', (141, 149))	('human', 'Species', '9606', (98, 103))	('metformin', 'Var', (36, 45))	('anti-EMT effects', 'CPA', (53, 69))	('betaKlotho', 'Gene', (152, 162))
95857	27164115	Actually, metformin triggers apoptosis in vitro, i.e., in gastric, pancreatic, colon cancer and salivary adenocarcinoma cells.	('apoptosis', 'CPA', (29, 38))	('gastric', 'Disease', (58, 65))	('colon cancer', 'Disease', (79, 91))	('salivary adenocarcinoma', 'Disease', (96, 119))	('pancreatic', 'Disease', 'MESH:D010195', (67, 77))	('metformin', 'Var', (10, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('pancreatic', 'Disease', (67, 77))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('triggers', 'Reg', (20, 28))	('salivary adenocarcinoma', 'Disease', 'MESH:D000230', (96, 119))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
95861	27164115	Similarly, 2-DG potentiates the toxic effects of metformin in thyroid cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('thyroid cancer', 'Disease', 'MESH:D013964', (62, 76))	('potentiates', 'PosReg', (16, 27))	('toxic effects', 'MPA', (32, 45))	('metformin', 'Chemical', 'MESH:D008687', (49, 58))	('2-DG', 'Chemical', 'MESH:D003847', (11, 15))	('2-DG', 'Var', (11, 15))	('thyroid cancer', 'Phenotype', 'HP:0002890', (62, 76))	('thyroid cancer', 'Disease', (62, 76))
95866	27164115	In highly invasive C4-2B cells metformin in conjunction with simvastatin evokes necrosis, thereby circumventing the resistance to apoptosis characterizing these prostate cancer cells.	('circumventing', 'NegReg', (98, 111))	('simvastatin', 'Chemical', 'MESH:D019821', (61, 72))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('resistance to apoptosis', 'MPA', (116, 139))	('prostate cancer', 'Disease', (161, 176))	('necrosis', 'Disease', (80, 88))	('metformin', 'Var', (31, 40))	('metformin', 'Chemical', 'MESH:D008687', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('necrosis', 'Disease', 'MESH:D009336', (80, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (161, 176))	('evokes', 'Reg', (73, 79))
95867	27164115	In hepatocellular carcinoma (HCC) cells metformin functions as a radiosensitizer via increasing oxidative stress while in osteosarcoma cells metformin potentiates the cytotoxic effects of cisplatin.	('osteosarcoma', 'Disease', (122, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('osteosarcoma', 'Phenotype', 'HP:0002669', (122, 134))	('osteosarcoma', 'Disease', 'MESH:D012516', (122, 134))	('increasing', 'PosReg', (85, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('metformin', 'Chemical', 'MESH:D008687', (40, 49))	('oxidative stress', 'Phenotype', 'HP:0025464', (96, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (188, 197))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('metformin', 'Var', (141, 150))	('cytotoxic effects', 'CPA', (167, 184))	('metformin', 'Chemical', 'MESH:D008687', (141, 150))	('oxidative stress', 'MPA', (96, 112))	('potentiates', 'PosReg', (151, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
95870	27164115	The invasive and migratory potential of prostate cancer cells is also decreased by metformin in prostate cancer cell via the impairment of the insulin-like growth factor 1 receptor (IGF-1R) axis.	('insulin-like growth factor 1 receptor', 'Gene', (143, 180))	('prostate cancer', 'Disease', (40, 55))	('impairment', 'NegReg', (125, 135))	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('decreased', 'NegReg', (70, 79))	('metformin', 'Var', (83, 92))	('IGF-1R', 'Gene', '3480', (182, 188))	('metformin', 'Chemical', 'MESH:D008687', (83, 92))	('prostate cancer', 'Disease', (96, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('IGF-1R', 'Gene', (182, 188))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (143, 180))	('prostate cancer', 'Phenotype', 'HP:0012125', (40, 55))
95873	27164115	In addition, metformin dampens the proliferative as well as the invasive potential of MG63 osteosarcoma cells and counteracts their stemness.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('proliferative', 'CPA', (35, 48))	('metformin', 'Var', (13, 22))	('MG63', 'CellLine', 'CVCL:0426', (86, 90))	('dampens', 'NegReg', (23, 30))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('stemness', 'Disease', 'MESH:D020295', (132, 140))	('stemness', 'Disease', (132, 140))	('osteosarcoma', 'Disease', (91, 103))	('osteosarcoma', 'Disease', 'MESH:D012516', (91, 103))	('invasive potential', 'CPA', (64, 82))
95874	27164115	The invasiveness of B16F10 mouse melanoma cells is decreased by metformin due to up-regulation of E-cadherin expression.	('metformin', 'Var', (64, 73))	('expression', 'MPA', (109, 119))	('mouse', 'Species', '10090', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('decreased', 'NegReg', (51, 60))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('metformin', 'Chemical', 'MESH:D008687', (64, 73))	('E-cadherin', 'Protein', (98, 108))	('up-regulation', 'PosReg', (81, 94))	('B16F10', 'CellLine', 'CVCL:0159', (20, 26))
95881	27164115	Moreover, metformin prolongs the survival of murine ErbB2 transgenes and exhibits chemosensitizing properties in breast cancer cell line xenografts.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('metformin', 'Var', (10, 19))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('survival', 'MPA', (33, 41))	('transgenes', 'Var', (58, 68))	('ErbB2', 'Gene', (52, 57))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('prolongs', 'PosReg', (20, 28))	('murine', 'Species', '10090', (45, 51))
95884	27164115	In fact, metformin inhibits the growth of ESCC xenograft mouse models; an event which is molecularly associated with the upregulation of Cip/Kip family members that are known to perturb cell cycle progression.	('metformin', 'Chemical', 'MESH:D008687', (9, 18))	('perturb', 'NegReg', (178, 185))	('upregulation', 'PosReg', (121, 133))	('Cip', 'Gene', '69642', (137, 140))	('Cip', 'Gene', (137, 140))	('cell cycle progression', 'CPA', (186, 208))	('inhibits', 'NegReg', (19, 27))	('growth', 'CPA', (32, 38))	('metformin', 'Var', (9, 18))	('ESCC', 'Disease', (42, 46))	('mouse', 'Species', '10090', (57, 62))
95885	27164115	Significantly, metformin inhibits the growth of human pancreatic cancer xenografts, possibly due to the ablation of the crosstalk among an insulin receptor (IR) and G protein-coupled receptors (GPCRs), in an AMPK-dependent manner.	('crosstalk', 'Interaction', (120, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('metformin', 'Chemical', 'MESH:D008687', (15, 24))	('inhibits', 'NegReg', (25, 33))	('AMPK', 'Gene', (208, 212))	('IR', 'Gene', '3643', (157, 159))	('human', 'Species', '9606', (48, 53))	('G protein-coupled receptors', 'Protein', (165, 192))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('pancreatic cancer', 'Disease', (54, 71))	('insulin receptor', 'Gene', (139, 155))	('pancreatic cancer', 'Disease', 'MESH:D010190', (54, 71))	('metformin', 'Var', (15, 24))	('AMPK', 'Gene', '5563', (208, 212))	('growth', 'CPA', (38, 44))	('insulin receptor', 'Gene', '3643', (139, 155))
95886	27164115	In addition, in human pancreatic cancer xenografts, metformin causes tumor cells to cease proliferation and impinges on the expression of microRNAs as well as cell cycle-regulatory molecules.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cease proliferation', 'CPA', (84, 103))	('tumor', 'Disease', (69, 74))	('human', 'Species', '9606', (16, 21))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (22, 39))	('metformin', 'Var', (52, 61))	('metformin', 'Chemical', 'MESH:D008687', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('expression', 'MPA', (124, 134))	('microRNAs', 'Protein', (138, 147))	('pancreatic cancer', 'Disease', (22, 39))	('impinges', 'Reg', (108, 116))	('pancreatic cancer', 'Disease', 'MESH:D010190', (22, 39))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
95906	27164115	This is consistent with previous data demonstrating that MK886 prevents PPAR-dependent signaling.	('PPAR', 'Gene', (72, 76))	('prevents', 'NegReg', (63, 71))	('PPAR', 'Gene', '5465;5468;19016;25664', (72, 76))	('MK886', 'Var', (57, 62))	('MK886', 'Chemical', 'MESH:C060893', (57, 62))
95923	27164115	Rather, sulfonylureas and insulin have been associated with increased risk for cancer.	('associated', 'Reg', (44, 54))	('insulin', 'Gene', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('insulin', 'Gene', '3630', (26, 33))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('sulfonylureas', 'Chemical', 'MESH:D013453', (8, 21))	('sulfonylureas', 'Var', (8, 21))
95924	27164115	Retrospective studies reviewing the clinical outcome of HER2-positive breast cancer patients with diabetes suggest that metformin beneficially affects their cancer-specific survival.	('diabetes', 'Disease', 'MESH:D003920', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('metformin', 'Var', (120, 129))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (56, 83))	('patients', 'Species', '9606', (84, 92))	('metformin', 'Chemical', 'MESH:D008687', (120, 129))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('affects', 'Reg', (143, 150))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('HER2-positive breast cancer', 'Disease', (56, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('diabetes', 'Disease', (98, 106))
95938	27164115	Conceivably, it would be particularly interesting to assess whether substituting rofecoxib by another COX-2 inhibitor that has not been withdrawn in this combinational regimen yields similar benefits.	('COX-2', 'Gene', '5743', (102, 107))	('rofecoxib', 'Chemical', 'MESH:C116926', (81, 90))	('COX-2', 'Gene', (102, 107))	('substituting', 'Var', (68, 80))
96023	25303891	Lung constraints were V20 <= 12% for both lungs, and V20 <= 25% for the ipsilateral lung, which was not varied for different fraction numbers given the lack of data that fraction number affects the V20 threshold for lung toxicity in SBRT.	('lung toxicity', 'Disease', (216, 229))	('lung toxicity', 'Disease', 'MESH:D008171', (216, 229))	('V20', 'Var', (53, 56))	('V20 threshold', 'MPA', (198, 211))
96173	23828730	The rate of pneumonitis was higher for proton therapy (33%) compared to photon therapy (15%) (p=0.04).	('pneumonitis', 'Disease', (12, 23))	('proton therapy', 'Var', (39, 53))	('pneumonitis', 'Disease', 'MESH:D011014', (12, 23))
96177	23828730	Mean lobe dose ratio ( p<0.001) and SUV10-20 Gy ( p=0.046) were correlated with grade >=2 pneumonitis.	('SUV10-20 Gy', 'Var', (36, 47))	('pneumonitis', 'Disease', (90, 101))	('pneumonitis', 'Disease', 'MESH:D011014', (90, 101))
96184	23828730	One explanation for these findings is that the acute inflammation in the areas of lung receiving 0 to 10 Gy represents a relatively large volume of lung that is generally 0.5 cm or more from the esophagus.	('inflammation', 'Disease', 'MESH:D007249', (53, 65))	('0 to 10 Gy', 'Var', (97, 107))	('inflammation', 'Disease', (53, 65))
96210	33681363	regarding miR-519 through PI3K/AKT/mTOR pathway to enhance the radiosensitivity of ESCC cells.	('miR-519', 'Chemical', '-', (10, 17))	('mTOR', 'Gene', (35, 39))	('radiosensitivity', 'CPA', (63, 79))	('enhance', 'PosReg', (51, 58))	('AKT', 'Gene', (31, 34))	('mTOR', 'Gene', '2475', (35, 39))	('miR-519', 'Var', (10, 17))	('ESCC', 'Disease', (83, 87))	('AKT', 'Gene', '207', (31, 34))
96214	33681363	In Jurkat cells and human T cells, overexpressed IL-32 gamma leads to cell cycle arrest as well as cell death.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('overexpressed', 'Var', (35, 48))	('Jurkat', 'CellLine', 'CVCL:0065', (3, 9))	('cell death', 'Disease', 'MESH:D003643', (99, 109))	('IL-32 gamma', 'Gene', (49, 60))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('cell death', 'Disease', (99, 109))	('arrest', 'Disease', (81, 87))	('IL-32 gamma', 'Gene', '9235', (49, 60))
96216	33681363	As reported by Aggarwal et al., overexpressed STAT3 could increase the tolerance of head and neck squamous cell carcinoma (SCCHN) cells and nonsmall cell lung cancer (NSCLC) cells to radiation.	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('increase', 'PosReg', (58, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('tolerance', 'CPA', (71, 80))	('STAT3', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (93, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('neck squamous cell carcinoma', 'Disease', (93, 121))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('overexpressed', 'Var', (32, 45))	('nonsmall cell lung cancer', 'Disease', (140, 165))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (140, 165))	('NSCLC', 'Disease', (167, 172))
96233	33681363	Some reports also support that IL-32 inhibits the growth of colorectal cancer cells and tumor, indicating that IL-32gamma can upregulate the p32-MAPK signal to enhance TNF-alpha-mediated cell apoptosis.	('p32', 'Gene', (141, 144))	('TNF-alpha', 'Gene', '7124', (168, 177))	('p32', 'Gene', '925', (141, 144))	('TNF-alpha', 'Gene', (168, 177))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('upregulate', 'PosReg', (126, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('growth', 'CPA', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('enhance', 'PosReg', (160, 167))	('IL-32gamma', 'Var', (111, 121))	('inhibits', 'NegReg', (37, 45))	('colorectal cancer', 'Disease', (60, 77))
96278	30568392	We rescored p53 expression into three groups: weak or patchy (wild type), complete loss (nonsense, frameshift, or splice-site mutation type), and diffuse and strong (missense mutation type).	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))	('frameshift', 'Var', (99, 109))	('nonsense', 'Var', (89, 97))	('loss', 'NegReg', (83, 87))
96315	30568392	The 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging system include tumor location as a staging factor for T2-3N0M0 ESCC cases and T3N0M0 ESCC cases, respectively.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('T2-3N0M0', 'Var', (136, 144))	('tumor', 'Disease', (97, 102))	('T3N0M0', 'Var', (160, 166))
96334	30568392	We have identified certain clinicopathological features that are associated with an increased risk of tumor recurrence in pT1N0 thoracic ESCC patients after esophagectomy and thoracoabdominal two-field lymphadenectomy: (1) Patients with an upper thoracic location, ulcerative or intraluminal mass tumor type, deeper tumor invasion level, basaloid histology, angiolymphatic invasion, greater tumor thickness, greater submucosal invasion thickness, greater diameter of the largest single tongue of invasion, and/or completely negative aberrant p53 expression are at greater risk of tumor recurrence.	('intraluminal mass tumor', 'Disease', 'MESH:C536030', (279, 302))	('aberrant', 'Var', (533, 541))	('p53', 'Gene', (542, 545))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (297, 302))	('tumor', 'Disease', (391, 396))	('tumor', 'Phenotype', 'HP:0002664', (580, 585))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('pT1', 'Gene', '58492', (122, 125))	('Patients', 'Species', '9606', (223, 231))	('tumor', 'Disease', (580, 585))	('pT1', 'Gene', (122, 125))	('intraluminal mass tumor', 'Disease', (279, 302))	('expression', 'MPA', (546, 556))	('tumor', 'Disease', 'MESH:D009369', (580, 585))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('tumor', 'Disease', (102, 107))	('angiolymphatic', 'Disease', (358, 372))	('negative', 'NegReg', (524, 532))	('tumor', 'Disease', (316, 321))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('p53', 'Gene', '7157', (542, 545))	('patients', 'Species', '9606', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
96350	28356949	Association between XRCC1 and ERCC1 single-nucleotide polymorphisms and the efficacy of concurrent radiochemotherapy in patients with esophageal squamous cell carcinoma The aim of the present study was to investigate the association between single-nucleotide polymorphisms (SNPs) in X-ray repair cross-complementing 1-399 (XRCC1-399) or excision repair cross-complementation group 1-118 (ERCC1-118) and the short-term efficacy of radiochemotherapy, tumor metastasis and relapse, as well as the survival time in patients with esophageal squamous cell carcinoma (ESCC).	('ERCC1', 'Gene', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (550, 559))	('X-ray repair cross-complementing 1', 'Gene', '7515', (283, 317))	('XRCC1', 'Gene', (323, 328))	('tumor metastasis', 'Disease', (449, 465))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('esophageal squamous cell carcinoma', 'Disease', (525, 559))	('XRCC1', 'Gene', (20, 25))	('single-nucleotide polymorphisms', 'Var', (241, 272))	('X-ray repair cross-complementing 1', 'Gene', (283, 317))	('ERCC1', 'Gene', '2067', (388, 393))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (536, 559))	('XRCC1', 'Gene', '7515', (323, 328))	('esophageal squamous cell carcinoma', 'Disease', (134, 168))	('patients', 'Species', '9606', (511, 519))	('tumor', 'Phenotype', 'HP:0002664', (449, 454))	('XRCC1', 'Gene', '7515', (20, 25))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (525, 559))	('ERCC1', 'Gene', '2067', (30, 35))	('ERCC1', 'Gene', (388, 393))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('patients', 'Species', '9606', (120, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (134, 168))	('tumor metastasis', 'Disease', 'MESH:D009362', (449, 465))
96354	28356949	It was found that the short-term therapeutic efficacy (CR rate) was higher in the group of patients carrying the homozygous mutation of XRCC1-399 (A/A genotype) than in the group of patients without the XRCC1-399 mutation (G/G genotype).	('patients', 'Species', '9606', (91, 99))	('CR', 'Chemical', '-', (55, 57))	('XRCC1', 'Gene', (136, 141))	('therapeutic efficacy', 'CPA', (33, 53))	('higher', 'PosReg', (68, 74))	('XRCC1', 'Gene', (203, 208))	('mutation', 'Var', (124, 132))	('patients', 'Species', '9606', (182, 190))	('XRCC1', 'Gene', '7515', (136, 141))	('XRCC1', 'Gene', '7515', (203, 208))
96357	28356949	The mean survival time was significantly prolonged in patients carrying 1 or 2 C alleles (C/C or C/T genotype) compared with patients lacking the C allele (T/T genotype) [T/T vs. C/C, HR=12.96, 95% confidence interval (CI)=3.08-54.61, P<0.001; TT vs. C/T+C/C, HR=11.71, 95% CI=3.06-44.83, P<0.001].	('C/T+C/C', 'Var', (251, 258))	('patients', 'Species', '9606', (54, 62))	('prolonged', 'PosReg', (41, 50))	('survival time', 'CPA', (9, 22))	('patients', 'Species', '9606', (125, 133))
96359	28356949	XRCCl-399 SNP was associated with the short-term therapeutic efficacy (the CR rate) and tumor metastasis/relapse in ESCC patients who received the docetaxel plus cisplatin (TP) regimen-based concurrent radiochemotherapy.	('docetaxel', 'Chemical', 'MESH:D000077143', (147, 156))	('tumor metastasis', 'Disease', (88, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('XRCCl', 'Chemical', '-', (0, 5))	('ESCC', 'Disease', (116, 120))	('TP', 'Chemical', '-', (173, 175))	('CR', 'Chemical', '-', (75, 77))	('therapeutic efficacy', 'CPA', (49, 69))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('XRCCl-399 SNP', 'Var', (0, 13))	('patients', 'Species', '9606', (121, 129))	('tumor metastasis', 'Disease', 'MESH:D009362', (88, 104))
96360	28356949	By contrast, ERCC1-118 SNP was significantly associated with the short-term therapeutic efficacy (the CR rate) and survival time in ESCC patients who received TP regimen-based concurrent radiochemotherapy.	('ERCC1-118 SNP', 'Var', (13, 26))	('TP', 'Chemical', '-', (159, 161))	('patients', 'Species', '9606', (137, 145))	('associated', 'Reg', (45, 55))	('survival time', 'CPA', (115, 128))	('CR', 'Chemical', '-', (102, 104))	('ESCC', 'Disease', (132, 136))	('therapeutic efficacy', 'CPA', (76, 96))
96372	28356949	Inheritedor acquired defects in DNA repair genes may induce corresponding changes in the capacity of the cells to repair DNA damage and eventually affect the sensitivity of tumor cells to chemotherapy and radiation therapy.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('changes', 'Reg', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('defects', 'Var', (21, 28))	('DNA repair genes', 'Gene', (32, 48))	('capacity', 'MPA', (89, 97))	('affect', 'Reg', (147, 153))	('sensitivity', 'MPA', (158, 169))
96374	28356949	Therefore, in the present study, the novel idea concerning whether the sensitivity of tumor cells to radiochemotherapy can be predicted through the examination of SNPs in DNA repair genes was tested.	('SNPs', 'Var', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('DNA repair genes', 'Gene', (171, 187))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
96378	28356949	Currently, several studies have shown that SNPs at multiple loci of XRCC1 and ERCC1 genes are closely correlated with the susceptibility of various tumors and clinical efficacy.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SNPs', 'Var', (43, 47))	('XRCC1', 'Gene', (68, 73))	('correlated', 'Reg', (102, 112))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('ERCC1', 'Gene', (78, 83))	('XRCC1', 'Gene', '7515', (68, 73))
96402	28356949	qPCR was performed using a Stratagene Mx3000P (Agilent Technologies, Inc., Santa Clara CA, USA) as follows: The total volume of the reaction system was 20 microl, which contained 1X TaqMan PCR Master Mix (Applied Biosystems; Thermo Fisher Scientific, Inc.), 0.1 microl template DNA, 300 nM primers, 100 nM wild-type probe and 100 nM mutant probe.	('mutant', 'Var', (333, 339))	('CR', 'Chemical', '-', (190, 192))	('CR', 'Chemical', '-', (2, 4))	('Mix', 'Gene', (200, 203))	('Mix', 'Gene', '83881', (200, 203))
96419	28356949	The distribution of the three genotypes of XRCC1-399 (G/G, G/A and A/A) in the 50 ESCC patients and short-term efficacy of radiochemotherapy (which was represented by the CR rate) were compared, and the results are shown in Table II.	('XRCC1', 'Gene', (43, 48))	('ESCC', 'Disease', (82, 86))	('G/A', 'Var', (59, 62))	('XRCC1', 'Gene', '7515', (43, 48))	('patients', 'Species', '9606', (87, 95))	('G/G', 'Var', (54, 57))	('CR', 'Chemical', '-', (171, 173))
96420	28356949	The CR rate showed an upward trend in the mutated XRCC1-399 group (G/A+A/A genotypes) compared with the non-mutated XRCC1-399 group (the G/G genotype).	('upward', 'PosReg', (22, 28))	('XRCC1', 'Gene', (50, 55))	('mutated', 'Var', (42, 49))	('CR', 'Chemical', '-', (4, 6))	('XRCC1', 'Gene', (116, 121))	('XRCC1', 'Gene', '7515', (116, 121))	('XRCC1', 'Gene', '7515', (50, 55))
96423	28356949	The distribution of the three genotypes of ERCC1-118 (C/C, C/T and T/T) in the 50 ESCC patients and short-term efficacy of the radiochemotherapy (the CR rate) were compared, and the results are shown in Table III.	('ESCC', 'Disease', (82, 86))	('C/C', 'Var', (54, 57))	('CR', 'Chemical', '-', (150, 152))	('T/T', 'Var', (67, 70))	('C/T', 'Var', (59, 62))	('patients', 'Species', '9606', (87, 95))	('ERCC1-118', 'Gene', (43, 52))
96426	28356949	The distribution of the three genotypes of XRCC1-399 (G/G, G/A and A/A) among the 50 ESCC patients and occurrence of metastasis or relapse in the patients during the follow-up period was examined, and the results are summarized in Table IV.	('XRCC1', 'Gene', (43, 48))	('G/A', 'Var', (59, 62))	('ESCC', 'Disease', (85, 89))	('XRCC1', 'Gene', '7515', (43, 48))	('patients', 'Species', '9606', (90, 98))	('patients', 'Species', '9606', (146, 154))	('G/G', 'Var', (54, 57))
96429	28356949	The distribution of the three genotypes of ERCC1-118 (C/C, C/T and T/T) and occurrence of metastasis or relapse in the 50 ESCC patients were compared, and the results are summarized in Table V. No statistically significant differences were detected regarding the risk of metastasis or relapse between patients carrying one or two C alleles (C/C or C/T genotypes) and patients lacking the C allele (the T/T genotype; P>0.05).	('C/T', 'Var', (348, 351))	('patients', 'Species', '9606', (301, 309))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (367, 375))	('metastasis', 'CPA', (271, 281))	('relapse', 'CPA', (285, 292))	('ERCC1-118', 'Gene', (43, 52))
96431	28356949	Compared with the non-mutated group (G/G genotype), the survival time of patients carrying the heterozygous XRCC1-399 mutation (G/A genotype) and the homozygous mutation of XRCC1-399 (A/A genotype) was extended.	('XRCC1', 'Gene', '7515', (108, 113))	('XRCC1', 'Gene', '7515', (173, 178))	('patients', 'Species', '9606', (73, 81))	('mutation', 'Var', (118, 126))	('XRCC1', 'Gene', (108, 113))	('XRCC1', 'Gene', (173, 178))
96432	28356949	The mutated XRCC1-399 group (G/A+A/A genotypes) included patients with either G/A or A/A genotype.	('G/A', 'Var', (78, 81))	('mutated', 'Var', (4, 11))	('patients', 'Species', '9606', (57, 65))	('XRCC1', 'Gene', '7515', (12, 17))	('A/A', 'Var', (85, 88))	('XRCC1', 'Gene', (12, 17))
96435	28356949	A univariate Cox proportional hazards model was utilized to analyze the association between the survival time and several factors, including gender, age, length of the tumor, tumor location, clinical stage, radiation dose, and XRCC1-399 and ERCC1-118 gene polymorphism in ESCC patients treated with radiochemotherapy (Table VI).	('tumor', 'Disease', (175, 180))	('XRCC1', 'Gene', '7515', (227, 232))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patients', 'Species', '9606', (277, 285))	('ERCC1-118', 'Gene', (241, 250))	('XRCC1', 'Gene', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('ESCC', 'Disease', (272, 276))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('polymorphism', 'Var', (256, 268))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
96437	28356949	Subsequent to combining with univariate analysis and adjusting for confounders such as gender, tumor length and radiation dose, multivariate Cox regression analysis showed there was no statistically significant association between XRCC1-399 gene polymorphisms and survival time (P>0.05).	('polymorphisms', 'Var', (246, 259))	('XRCC1', 'Gene', '7515', (231, 236))	('survival time', 'CPA', (264, 277))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('XRCC1', 'Gene', (231, 236))	('tumor', 'Disease', (95, 100))
96438	28356949	Compared with patients lacking the C allele (T/T genotype), patients carrying one or two C alleles, consisting of the C/C (HR=12.96, 95% CI (3.08-54.61), P<0.001) or C/T (HR=11.71, 95% CI (3.06-44.83), P<0.001) genotype, experienced significantly prolonged survival.	('C/C', 'Var', (118, 121))	('prolonged', 'PosReg', (247, 256))	('patients', 'Species', '9606', (60, 68))	('survival', 'CPA', (257, 265))	('patients', 'Species', '9606', (14, 22))
96448	28356949	These results demonstrated that cells with the Gln/Gln genotype exhibit increased radiosensitivity compared with cells with other genotypes.	('increased', 'PosReg', (72, 81))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (72, 98))	('Gln/Gln', 'Var', (47, 54))	('Gln', 'Chemical', 'MESH:D005973', (47, 50))	('radiosensitivity', 'CPA', (82, 98))	('Gln', 'Chemical', 'MESH:D005973', (51, 54))
96449	28356949	Therefore, the study conducted by Cornetta et al indicates that the sensitivity to radiotherapy is associated with XRCC1 gene polymorphism.	('XRCC1', 'Gene', (115, 120))	('XRCC1', 'Gene', '7515', (115, 120))	('polymorphism', 'Var', (126, 138))	('associated', 'Reg', (99, 109))
96450	28356949	Wu et al examined XRCC1 Arg399Gln SNPs in 210 esophageal cancer patients treated with preoperative adjuvant radiochemotherapy.	('XRCC1', 'Gene', '7515', (18, 23))	('patients', 'Species', '9606', (64, 72))	('Arg399Gln', 'Var', (24, 33))	('Arg399Gln', 'SUBSTITUTION', 'None', (24, 33))	('esophageal cancer', 'Disease', (46, 63))	('XRCC1', 'Gene', (18, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
96451	28356949	This study found that the risk of mortality subsequent to radiochemotherapy was significantly increased in patients with mutant genotypes of XRCC1 Arg399Gln (G/A+A/A) compared with patients with the non-mutant genotype (G/G).	('mutant', 'Var', (121, 127))	('Arg399Gln', 'Var', (147, 156))	('XRCC1', 'Gene', '7515', (141, 146))	('increased', 'PosReg', (94, 103))	('Arg399Gln', 'SUBSTITUTION', 'None', (147, 156))	('patients', 'Species', '9606', (181, 189))	('XRCC1', 'Gene', (141, 146))	('patients', 'Species', '9606', (107, 115))
96452	28356949	The median survival times of patients with the G/A and A/A genotypes were 22.9 months and 13.7 months, respectively, while the median survival time of patients with the G/G genotype was extended to 57.4 months.	('patients', 'Species', '9606', (29, 37))	('A/A', 'Var', (55, 58))	('patients', 'Species', '9606', (151, 159))	('G/A', 'Var', (47, 50))
96453	28356949	The present study also showed that the rate of histopathological CR following radiochemotherapy was markedly reduced in patients with the G/A and A/A genotypes compared with patients with the G/G genotype.	('CR', 'Chemical', '-', (65, 67))	('A/A', 'Var', (146, 149))	('G/A', 'Var', (138, 141))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (120, 128))	('reduced', 'NegReg', (109, 116))
96454	28356949	Yoon et al conducted a retrospective cohort study to analyze the association between mutations in certain DNA repair pathway genes and the rate of histopathological remission in patients with esophageal adenocarcinoma subsequent to radiochemotherapy.	('DNA', 'Gene', (106, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('patients', 'Species', '9606', (178, 186))	('esophageal adenocarcinoma', 'Disease', (192, 217))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (192, 217))	('mutations', 'Var', (85, 94))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (192, 217))
96455	28356949	This study showed that, among the 60 esophageal adenocarcinoma specimens examined, only 6% (2/31) of the specimens with XRCC1 Arg399Gln gene mutations (Arg/Arg or Arg/Gln genotype) exhibited histopathological CR.	('Arg399Gln', 'Var', (126, 135))	('Arg399Gln', 'SUBSTITUTION', 'None', (126, 135))	('esophageal adenocarcinoma', 'Disease', (37, 62))	('XRCC1', 'Gene', (120, 125))	('Arg', 'Chemical', 'MESH:D001120', (152, 155))	('Arg', 'Chemical', 'MESH:D001120', (163, 166))	('Gln', 'Chemical', 'MESH:D005973', (132, 135))	('Arg', 'Chemical', 'MESH:D001120', (156, 159))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (37, 62))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (37, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('CR', 'Chemical', '-', (209, 211))	('Gln', 'Chemical', 'MESH:D005973', (167, 170))	('XRCC1', 'Gene', '7515', (120, 125))	('Arg', 'Chemical', 'MESH:D001120', (126, 129))	('Arg/Arg', 'Var', (152, 159))
96457	28356949	These results suggested that the Arg/Arg or Arg/Gln genotype may be negatively associated with the efficacy of radiochemotherapy.	('associated', 'Reg', (79, 89))	('Arg/Gln', 'Var', (44, 51))	('Arg/Arg', 'Var', (33, 40))	('Gln', 'Chemical', 'MESH:D005973', (48, 51))	('Arg', 'Chemical', 'MESH:D001120', (44, 47))	('Arg', 'Chemical', 'MESH:D001120', (33, 36))	('Arg', 'Chemical', 'MESH:D001120', (37, 40))	('radiochemotherapy', 'CPA', (111, 128))	('negatively', 'NegReg', (68, 78))
96458	28356949	The present study found that the mutant allele of XRCC1 Arg399Gln was present in 52% of ESCC patients.	('XRCC1', 'Gene', (50, 55))	('ESCC', 'Disease', (88, 92))	('Arg399Gln', 'Var', (56, 65))	('Arg399Gln', 'SUBSTITUTION', 'None', (56, 65))	('XRCC1', 'Gene', '7515', (50, 55))	('patients', 'Species', '9606', (93, 101))
96459	28356949	The short-term efficacy of radiochemotherapy (CR rate) was significantly higher in patients carrying the homozygous XRCC1 mutation (the A/A genotype) than in patients in the non-mutated group (G/G genotype) (P=0.014).	('XRCC1', 'Gene', (116, 121))	('mutation', 'Var', (122, 130))	('patients', 'Species', '9606', (83, 91))	('CR', 'Chemical', '-', (46, 48))	('XRCC1', 'Gene', '7515', (116, 121))	('patients', 'Species', '9606', (158, 166))	('higher', 'PosReg', (73, 79))
96460	28356949	The risk of relapse or metastasis was reduced in patients carrying the homozygous XRCC1 mutation, and the difference was also statistically significant (P=0.031).	('mutation', 'Var', (88, 96))	('relapse', 'CPA', (12, 19))	('XRCC1', 'Gene', (82, 87))	('reduced', 'NegReg', (38, 45))	('metastasis', 'CPA', (23, 33))	('XRCC1', 'Gene', '7515', (82, 87))	('patients', 'Species', '9606', (49, 57))
96474	28356949	The ERCC1/XPF heterodimer has 5' DNA endonuclease activity, which excises the damaged DNA strand 15-24 nucleotides away from the lesion.	('excises', 'MPA', (66, 73))	('damaged', 'Var', (78, 85))	('XPF', 'Gene', '2072', (10, 13))	('XPF', 'Gene', (10, 13))
96479	28356949	Several studies have shown that ERCC1-118 gene polymorphism affects cell sensitivity to platinum-based chemotherapy.	('affects', 'Reg', (60, 67))	('platinum', 'Chemical', 'MESH:D010984', (88, 96))	('cell sensitivity', 'CPA', (68, 84))	('polymorphism', 'Var', (47, 59))	('ERCC1-118', 'Gene', (32, 41))
96480	28356949	A C-to-T mutation at codon 118 of ERCC1 results in decreased sensitivity to platinum-class drugs in patients.	('ERCC1', 'Gene', (34, 39))	('sensitivity to platinum-class drugs', 'MPA', (61, 96))	('platinum', 'Chemical', 'MESH:D010984', (76, 84))	('C-to-T mutation at codon 118', 'Mutation', 'rs11615', (2, 30))	('decreased', 'NegReg', (51, 60))	('C-to-T', 'Var', (2, 8))	('patients', 'Species', '9606', (100, 108))
96482	28356949	Warnecke-Eberz et al investigated the feasibility of using ERCC1 gene polymorphisms to predict the efficacy of preoperative neoadjuvant chemotherapy for the treatment of esophageal cancer.	('ERCC1', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('esophageal cancer', 'Disease', (170, 187))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))	('polymorphisms', 'Var', (70, 83))
96483	28356949	The study found that the ERCC1 C118T genotype is associated with the efficacy of radiochemotherapy in patients with esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (102, 110))	('C118T', 'Mutation', 'rs11615', (31, 36))	('ERCC1', 'Gene', (25, 30))	('C118T', 'Var', (31, 36))	('esophageal cancer', 'Disease', (116, 133))
96484	28356949	Compared with patients with the T/T genotype, patients with the C/T genotype exhibited significantly increased histopathological responses (CR) subsequent to radiochemotherapy, most likely as the T/T genotype leads to reduced expression of ERCC1 mRNA and protein.	('histopathological responses', 'CPA', (111, 138))	('patients', 'Species', '9606', (46, 54))	('T/T', 'Var', (196, 199))	('protein', 'Protein', (255, 262))	('increased', 'PosReg', (101, 110))	('ERCC1', 'Gene', (240, 245))	('expression', 'MPA', (226, 236))	('mRNA', 'Protein', (246, 250))	('CR', 'Chemical', '-', (140, 142))	('reduced', 'NegReg', (218, 225))	('patients', 'Species', '9606', (14, 22))
96485	28356949	It found that, compared with patients lacking the ERCC1-118 C allele (T/T genotype), patients carrying one or two C alleles, consisting of the C/C (HR, 12.96; 95% CI, 3.08-54.61; P<0.001) or C/T (HR, 11.71; 95% CI, 3.06-44.83; P<0.001) genotype, were more sensitive to synchronous radiochemotherapy (P=0.040) and showed a significantly prolonged mean survival time.	('patients', 'Species', '9606', (29, 37))	('prolonged', 'PosReg', (336, 345))	('more', 'PosReg', (251, 255))	('C/C', 'Var', (143, 146))	('patients', 'Species', '9606', (85, 93))
96489	28356949	By contrast, ERCC1-118 SNP was associated with short-term therapeutic efficacy (CR rate) and survival time in ESCC patients who received TP regimen-based concurrent radiochemotherapy.	('patients', 'Species', '9606', (115, 123))	('ERCC1-118 SNP', 'Var', (13, 26))	('CR', 'Chemical', '-', (80, 82))	('survival time', 'CPA', (93, 106))	('therapeutic efficacy', 'CPA', (58, 78))	('ESCC', 'Disease', (110, 114))	('TP', 'Chemical', '-', (137, 139))
96491	28356949	XRCCl-399 SNP was associated with the short-term therapeutic efficacy (the CR rate) and tumor metastasis/relapse in ESCC patients who received the TP (docetaxel plus cisplatin) regimen-based concurrent radiochemotherapy.	('TP', 'Chemical', '-', (147, 149))	('tumor metastasis', 'Disease', (88, 104))	('docetaxel', 'Chemical', 'MESH:D000077143', (151, 160))	('XRCCl', 'Chemical', '-', (0, 5))	('ESCC', 'Disease', (116, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('CR', 'Chemical', '-', (75, 77))	('therapeutic efficacy', 'CPA', (49, 69))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('XRCCl-399 SNP', 'Var', (0, 13))	('patients', 'Species', '9606', (121, 129))	('tumor metastasis', 'Disease', 'MESH:D009362', (88, 104))
96497	28225784	To find the best candidate cell line from 7 human EAC cell lines of different origin named ESO26, OE33, ESO51, SK-GT-2, OE19, OACM5.1C and Flo-1 were injected intraperitoneally/subcutaneously into SCID mice.	('human', 'Species', '9606', (44, 49))	('mice', 'Species', '10090', (202, 206))	('SCID', 'Gene', '19090', (197, 201))	('SCID', 'Gene', (197, 201))	('ESO51', 'Var', (104, 109))	('ESO26', 'Var', (91, 96))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))
96501	28225784	Interestingly, only in the OE19 model all mice (7/7 for 5X106 and 5/5 for10X106) developed bloody ascites with liver metastasis after intraperitoneal injection.	('ascites', 'Phenotype', 'HP:0001541', (98, 105))	('bloody ascites', 'Disease', 'MESH:D001201', (91, 105))	('mice', 'Species', '10090', (42, 46))	('5X106', 'Var', (56, 61))	('liver metastasis', 'Disease', 'MESH:D009362', (111, 127))	('bloody ascites', 'Disease', (91, 105))	('liver metastasis', 'Disease', (111, 127))	('developed', 'PosReg', (81, 90))
96502	28225784	In addition, median survival was significantly increased after paclitaxel treatment compared with the control group (57 days versus 45 days, p = 0.0034) along with a significant decrease of the relative subcutaneous tumor volume (p = 0.00011).	('tumor', 'Disease', (216, 221))	('paclitaxel', 'Chemical', 'MESH:D017239', (63, 73))	('decrease', 'NegReg', (178, 186))	('paclitaxel', 'Var', (63, 73))	('increased', 'PosReg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (203, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('median survival', 'CPA', (13, 28))
96551	28225784	No peritoneal tumor was observed in mice injected with OACM5.1C even at 4 months (Figs 1A, 2A and 2B).	('tumor', 'Disease', (14, 19))	('OACM5.1C', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mice', 'Species', '10090', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
96553	28225784	Interestingly, only in the OE19 model all mice (7/7 for 5X106 and 5/5 for10X106) (Table 2) had bloody ascites (Figs 1B, 2C and 2D) with liver metastasis/implants (Fig 3) after intraperitoneal injection of cells.	('liver metastasis', 'Disease', (136, 152))	('mice', 'Species', '10090', (42, 46))	('5X106', 'Var', (56, 61))	('ascites', 'Phenotype', 'HP:0001541', (102, 109))	('bloody ascites', 'Disease', 'MESH:D001201', (95, 109))	('bloody ascites', 'Disease', (95, 109))	('liver metastasis', 'Disease', 'MESH:D009362', (136, 152))
96554	28225784	Bloody ascites within 2 months was observed in the OE19 (100% cases) and the OE33 (50% cases) models (Table 2).	('ascites', 'Disease', (7, 14))	('OE19', 'Var', (51, 55))	('ascites', 'Phenotype', 'HP:0001541', (7, 14))	('ascites', 'Disease', 'MESH:D001201', (7, 14))
96559	28225784	In this model, the animals were treated with anticancer drugs over a period of 14 days, starting 14 days after intraperitoneal injection of OE19 cells (10X106).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('10X106', 'Var', (152, 158))
96582	28225784	In our animal survival model, animal survival was significantly improved by paclitaxel and carboplatin injections, the standard anticancer agents frequently used clinically in EAC therapy.	('cancer', 'Disease', (132, 138))	('paclitaxel', 'Chemical', 'MESH:D017239', (76, 86))	('paclitaxel', 'Var', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('animal survival', 'CPA', (30, 45))	('improved', 'PosReg', (64, 72))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('EAC', 'Phenotype', 'HP:0011459', (176, 179))	('carboplatin', 'Chemical', 'MESH:D016190', (91, 102))
96679	25003602	This study showed that the presence of a long segment carried a seven fold increased risk of progression.	('men', 'Species', '9606', (49, 52))	('presence', 'Var', (27, 35))	('progression', 'CPA', (93, 104))
96681	25003602	Chromosomal instability is also associated with progression from Barrett's esophagus to esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (65, 84))	('associated', 'Reg', (32, 42))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('Chromosomal instability', 'Var', (0, 23))	("Barrett's esophagus to esophageal adenocarcinoma", 'Disease', (65, 113))	("Barrett's esophagus to esophageal adenocarcinoma", 'Disease', 'MESH:D001471', (65, 113))
96682	25003602	A biomarker panel which detects 9p LOH (inactivation p16), 17p LOH (inactivation of p53), and DNA aneuploidy and tetraploidy has shown to be superior to histology alone for risk stratification.	('p16', 'Gene', (53, 56))	('aneuploidy', 'Disease', 'MESH:D000782', (98, 108))	('tetraploidy', 'Disease', 'MESH:D057891', (113, 124))	('p16', 'Gene', '1029', (53, 56))	('p53', 'Gene', (84, 87))	('aneuploidy', 'Disease', (98, 108))	('p53', 'Gene', '7157', (84, 87))	('tetraploidy', 'Disease', (113, 124))	('inactivation', 'Var', (68, 80))
96740	25003602	Serrated lesions have been established as the precursor of colorectal cancers that exhibit methylation of CpG islands, BRAF mutations, with inactivation of MLH1, resulting in tumor microsatellite instability.	('inactivation', 'Var', (140, 152))	('tumor', 'Disease', (175, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('colorectal cancers', 'Disease', 'MESH:D015179', (59, 77))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('colorectal cancers', 'Disease', (59, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('Serrated lesions', 'Phenotype', 'HP:0032222', (0, 16))	('MLH1', 'Gene', '4292', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('MLH1', 'Gene', (156, 160))
96755	25003602	They are more likely to have microsatellite instability, CpG island methylation, and low rates of KRAS, all characteristic of the serrated pathways.	('microsatellite instability', 'MPA', (29, 55))	('KRAS', 'Gene', '3845', (98, 102))	('CpG island methylation', 'Var', (57, 79))	('KRAS', 'Gene', (98, 102))
96785	22252257	HER2 protein overexpression in the cellular membrane is induced primarily through gene amplification.	('gene amplification', 'Var', (82, 100))	('HER2', 'Gene', '2064', (0, 4))	('overexpression', 'PosReg', (13, 27))	('HER2', 'Gene', (0, 4))
96787	22252257	Recently, HER2 overexpression and/or amplification was detected in approximately 22% of advanced gastric cancers, and targeting the extracellular domain of HER2 in these patients was associated with clinical benefit compared to chemotherapy alone in a Phase III trial (ToGA).	('patients', 'Species', '9606', (170, 178))	('HER2', 'Gene', (156, 160))	('overexpression', 'PosReg', (15, 29))	('targeting the', 'Var', (118, 131))	('HER2', 'Gene', '2064', (156, 160))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('HER2', 'Gene', (10, 14))	('amplification', 'Var', (37, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('gastric cancers', 'Phenotype', 'HP:0012126', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('benefit', 'PosReg', (208, 215))	('gastric cancers', 'Disease', (97, 112))	('gastric cancers', 'Disease', 'MESH:D013274', (97, 112))	('HER2', 'Gene', '2064', (10, 14))
96789	22252257	While testing for HER2 protein overexpression or gene amplification in upper digestive cancer has become increasingly routine, the status of HER2 expression/amplification and its association with clinicopathological features and clinical outcome in esophageal adenocarcinomas remains unknown.	('cancer', 'Disease', (87, 93))	('HER2', 'Gene', (141, 145))	('HER2', 'Gene', '2064', (18, 22))	('HER2', 'Gene', '2064', (141, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (265, 275))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('gene amplification', 'Var', (49, 67))	('esophageal adenocarcinomas', 'Disease', (249, 275))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (249, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))	('protein', 'Protein', (23, 30))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('overexpression', 'PosReg', (31, 45))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (249, 275))	('HER2', 'Gene', (18, 22))
96794	22252257	Whereas HER2 positivity in breast cancer is known to be associated with adverse clinicopathologic characteristics, data are limited in EAC and results have been inconsistent.	('positivity', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('HER2', 'Gene', (8, 12))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('HER2', 'Gene', '2064', (8, 12))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('EAC', 'Phenotype', 'HP:0011459', (135, 138))
96824	22252257	Remaining cases (i.e., non-amplified IHC2+ or IHC0-1+) were considered HER2-negative.	('HER2', 'Gene', (71, 75))	('IHC2+', 'Var', (37, 42))	('HER2', 'Gene', '2064', (71, 75))
96833	22252257	In brief, all patients had adenocarcinomas; most were male (89%) and had locally advanced tumor stage (66% T3-4, 72% node-positive).	('adenocarcinomas', 'Disease', 'MESH:D000230', (27, 42))	('adenocarcinomas', 'Disease', (27, 42))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('T3-4', 'Var', (107, 111))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
96844	22252257	FISH was successfully completed in 96% (344) of 359 tumors - i.e., 93 of 99 IHC0-1+, 167 of 172 IHC2+, and 84 of 88 IHC3+ cases (Figure S1e-f).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('IHC0-1+', 'Var', (76, 83))
96846	22252257	HER2 amplification was detected in 7% (7/93) of IHC0-1+, 15% (25/167) of IHC2+, and 90% (76/84) IHC3+ cases.	('amplification', 'Var', (5, 18))	('HER2', 'Gene', (0, 4))	('detected', 'Reg', (23, 31))	('HER2', 'Gene', '2064', (0, 4))	('IHC0-1+', 'Disease', (48, 55))
96847	22252257	HER2 protein expression and gene amplification showed high agreement in the IHC0-1+ and IHC3+ groups (kappa = .83 [95% CI 0.75 to 0.91], Table 2).	('IHC0-1+', 'Var', (76, 83))	('HER2', 'Gene', (0, 4))	('IHC3+', 'Var', (88, 93))	('HER2', 'Gene', '2064', (0, 4))
96850	22252257	We defined HER2 positivity as IHC3+ or IHC2+ with gene amplification, which is the group that derived greatest benefit from trastuzumab in ToGA, and the definition approved in Europe for trastuzumab eligibility.	('IHC3+', 'Var', (30, 35))	('trastuzumab', 'Chemical', 'MESH:D000068878', (124, 135))	('IHC2+', 'Var', (39, 44))	('trastuzumab', 'Chemical', 'MESH:D000068878', (187, 198))	('gene amplification', 'Var', (50, 68))	('HER2', 'Gene', (11, 15))	('positivity', 'Var', (16, 26))	('HER2', 'Gene', '2064', (11, 15))
96865	22252257	The presence (vs absence) of adjacent BE was associated with improved DSS (HR 0.65 [95% CI 0.54 to 0.80], p<.0001) and OS (p<.0001) in univariate analysis, but not after adjustment for pathologic features (p=.94 and p=.72, respectively).	('improved', 'PosReg', (61, 69))	('DSS', 'MPA', (70, 73))	('DSS', 'Chemical', '-', (70, 73))	('BE', 'Phenotype', 'HP:0100580', (38, 40))	('presence', 'Var', (4, 12))	('OS', 'Chemical', '-', (119, 121))
96873	22252257	HER2 positivity was detected in 17% of EACs with strong agreement between protein expression on cellular membranes and gene amplification.	('detected', 'Reg', (20, 28))	('positivity', 'Var', (5, 15))	('EAC', 'Phenotype', 'HP:0011459', (39, 42))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
96875	22252257	Furthermore, HER2 positivity was associated with favorable pathological features including lower T and N stage and better tumor differentiation.	('lower', 'NegReg', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('HER2', 'Gene', (13, 17))	('positivity', 'Var', (18, 28))	('better', 'PosReg', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('HER2', 'Gene', '2064', (13, 17))	('tumor', 'Disease', (122, 127))
96879	22252257	While HER2 positivity was associated with more favorable survival in the full study cohort, it was not independent of covariates.	('positivity', 'Var', (11, 21))	('favorable', 'PosReg', (47, 56))	('HER2', 'Gene', (6, 10))	('HER2', 'Gene', '2064', (6, 10))	('survival', 'CPA', (57, 65))
96883	22252257	While not addressed in our study, metaplastic Barrett's epithelium has been shown to lack HER2 expression and/or amplification, and the frequency of HER2 expression or amplification in BE-associated dysplasia are not well understood but may increased.	('lack', 'NegReg', (85, 89))	('HER2', 'Gene', (90, 94))	('HER2', 'Gene', (149, 153))	('HER2', 'Gene', '2064', (90, 94))	('HER2', 'Gene', '2064', (149, 153))	('amplification', 'MPA', (113, 126))	('BE', 'Phenotype', 'HP:0100580', (185, 187))	('amplification', 'Var', (168, 181))	('dysplasia', 'Disease', (199, 208))	('expression', 'MPA', (95, 105))	('dysplasia', 'Disease', 'MESH:D004476', (199, 208))
96885	22252257	Our findings of higher rates of HER2 positivity in adenocarcinoma cells from patients with adjacent BE and a better prognosis in these cases suggests that BE-associated EACs are distinct biologically from non-BE-associated cancers.	('cancers', 'Disease', (223, 230))	('BE', 'Phenotype', 'HP:0100580', (100, 102))	('HER2', 'Gene', (32, 36))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('HER2', 'Gene', '2064', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('patients', 'Species', '9606', (77, 85))	('adenocarcinoma', 'Disease', (51, 65))	('BE', 'Phenotype', 'HP:0100580', (209, 211))	('EAC', 'Phenotype', 'HP:0011459', (169, 172))	('positivity', 'Var', (37, 47))	('adenocarcinoma', 'Disease', 'MESH:D000230', (51, 65))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('EACs', 'Disease', (169, 173))	('BE', 'Phenotype', 'HP:0100580', (155, 157))
96892	22252257	HER2 expression/amplification in gastric cancers has been frequently associated with intestinal-type, as compared to diffuse-type, histology.	('gastric cancers', 'Disease', 'MESH:D013274', (33, 48))	('expression/amplification', 'Var', (5, 29))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('gastric cancers', 'Disease', (33, 48))	('gastric cancers', 'Phenotype', 'HP:0012126', (33, 48))	('associated', 'Reg', (69, 79))	('intestinal-type', 'Disease', (85, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
96897	22252257	Testing for HER2 amplification in IHC0-1+ cases may have limited clinical usefulness, given that only 7% had amplification (similar to the 7.5% rate reported in the ToGA trial), and a lack of trastuzumab efficacy was seen in IHC0-1+ cases with amplification in contrast to IHC2+ cases in the ToGA trial.	('trastuzumab', 'Chemical', 'MESH:D000068878', (192, 203))	('efficacy', 'MPA', (204, 212))	('HER2', 'Gene', (12, 16))	('HER2', 'Gene', '2064', (12, 16))	('lack', 'NegReg', (184, 188))	('amplification', 'Var', (244, 257))
96900	22252257	In this context, it is important to note that, as described in the scoring criteria developed for upper digestive carcinoma, IHC2+ differs from IHC1+ only by the intensity of expression (ie, "weak to moderate" vs "faint").	('carcinoma', 'Disease', 'MESH:D002277', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('digestive carcinoma', 'Phenotype', 'HP:0002672', (104, 123))	('IHC2+', 'Var', (125, 130))	('carcinoma', 'Disease', (114, 123))
96912	22252257	In summary, we report a 17% frequency of HER2 positivity in surgically resected stage I-III EACs.	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('stage I-III EACs', 'Disease', (80, 96))	('HER2', 'Gene', (41, 45))	('HER2', 'Gene', '2064', (41, 45))	('positivity', 'Var', (46, 56))
96916	22252257	HER2 overexpression is induced mainly through gene amplification, and plays a role in the development and progression of certain human cancers.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('plays', 'Reg', (70, 75))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('overexpression', 'PosReg', (5, 19))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('role', 'Reg', (78, 82))	('HER2', 'Gene', (0, 4))	('human', 'Species', '9606', (129, 134))	('HER2', 'Gene', '2064', (0, 4))	('gene amplification', 'Var', (46, 64))
96919	22252257	HER2 positivity was detected in 17% of cases and associated with favorable pathological features.	('HER2', 'Gene', '2064', (0, 4))	('positivity', 'Var', (5, 15))	('HER2', 'Gene', (0, 4))
96924	31523512	The method allows us to infer mutational patterns and their relative frequencies in a set of tumor mutational catalogs and to compare the estimated frequencies between tumor sets.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (93, 98))	('mutational', 'Var', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
96925	31523512	We apply our method to two datasets, one containing somatic mutations in colon cancer by the time of occurrence, before or after tumor initiation, and the second containing somatic mutations in esophageal cancer by sex, age, smoking status, and tumor site.	('colon cancer', 'Disease', (73, 85))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor initiation', 'Disease', 'MESH:D009369', (129, 145))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('esophageal cancer', 'Disease', (194, 211))	('colon cancer', 'Phenotype', 'HP:0003003', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('tumor initiation', 'Disease', (129, 145))	('mutations', 'Var', (60, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))	('colon cancer', 'Disease', 'MESH:D015179', (73, 85))
96929	31523512	A variety of methods exist to discover mutational signatures from the catalog of all somatic mutations in a set of tumors, estimating the latent mutational signatures as well as the latent exposures (i.e., fraction of mutations) each signature contributes to the total catalog.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (93, 102))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
96935	31523512	However, the variation of the exposure estimates is affected by two factors, the number of mutations in the tumor and the variation in exposure frequency in the patient population.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patient', 'Species', '9606', (161, 168))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (91, 100))	('affected', 'Reg', (52, 60))
96942	31523512	Second, signature visualization methods lead to easy interpretation; an example is the common C > T substitution at CpG sites instead of the more complicated NpCpG patterns that appear when using the trinucleotide context.	('trinucleotide', 'Chemical', '-', (200, 213))	('C > T substitution', 'Var', (94, 112))	('substitution', 'Var', (100, 112))
96959	31523512	To achieve this, we classify somatic mutations into two catalogs according to time of occurrence: those that accumulated between the time of the zygote and the first tumor cell, which we call trunk mutations, and those that occur de novo during tumor growth, which we refer to as branch mutations.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', (245, 250))
96961	31523512	Tumor and adjacent normal tissue were subject to whole exome sequencing, and somatic mutations called using the GATK pipeline and MuTect (details below).	('Tumor', 'Disease', (0, 5))	('mutations', 'Var', (85, 94))	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))
96972	31523512	One tumor with microsatelite instability has more than double the number of somatic mutations (1,751 side A, 1,762 side B) than any of the remaining 30 catalogs (all <750 mutations).	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('microsatelite instability', 'Var', (15, 40))
96976	31523512	The spontaneous deamination of methylated Cs in CpGs is known to contribute to hotspots of C >T mutation in the genome.	('C >T mutation', 'Var', (91, 104))	('spontaneous deamination', 'MPA', (4, 27))	('Cs', 'Chemical', 'MESH:D002586', (42, 44))
96977	31523512	2D, involving C >T mutations at CpG sites, resembles signature 7 in (cosine similarity 0.95), where it was identified in 25 out of 30 cancer types and likely relates to the deamination of 5-methylcytosine ('aging'); the signature in the orange box in Fig.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('deamination', 'MPA', (173, 184))	('C >T mutations', 'Var', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
96978	31523512	2E, involving T>G mutations at GpGpTpG sites, is novel; the third signature, in the red box in Fig.	('GpGpTpG', 'Gene', (31, 38))	('T>G mutations', 'Var', (14, 27))	('red box', 'Species', '1226038', (84, 91))
96980	31523512	2C, it is evident that the exposures of the first ('aging') signature in trunk mutations is almost always greater than that for the matching catalog of branch mutations, which is intuitively consistent with the fact that trunk mutations may well reflect an accumulation of mutations over the life of the subject, whereas branch mutations are accumulated only after tumor initiation.	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('tumor initiation', 'Disease', 'MESH:D009369', (365, 381))	('mutations', 'Var', (273, 282))	('tumor initiation', 'Disease', (365, 381))	('mutations', 'Var', (79, 88))
96981	31523512	For the previously unseen signature, the higher exposures in branch catalogs might suggest that this signature's underlying mechanism for generating mutations might be associated with the processes occurring during tumor evolution as opposed to normal development.	('tumor', 'Disease', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('mutations', 'Var', (149, 158))
96984	31523512	We reanalyzed the 146 EAC previously studied by and recovered the same four mutational signatures, C >T at CpG (S7), C >T or A at TpC (S14), T >G or C at Cp(T >G/C)pT (S21), and a signature capturing the remaining mutations, i.e., those that do not fall into the previous three signatures.	('fall', 'Phenotype', 'HP:0002527', (249, 253))	('S14', 'Gene', (135, 138))	('EAC', 'Gene', '1540', (22, 25))	('C >T or A', 'Var', (117, 126))	('EAC', 'Gene', (22, 25))	('C >T at', 'Var', (99, 106))	('TpC', 'Gene', (130, 133))	('T >G', 'Var', (141, 145))	('S21', 'Gene', '6227', (168, 171))	('TpC', 'Gene', '8030', (130, 133))	('C at Cp', 'Var', (149, 156))	('S21', 'Gene', (168, 171))	('S14', 'Gene', '6208', (135, 138))
96999	31523512	In the analysis of the EAC data using HiLDA, we detected a statistically significant increase in the mutational exposure of S21, which is consistent with the findings of excessive fraction of A(A >C) mutations in esophagus compared to cardia/GEJ found in.	('S21', 'Gene', (124, 127))	('EAC', 'Gene', '1540', (23, 26))	('mutational', 'Var', (101, 111))	('EAC', 'Gene', (23, 26))	('cardia', 'Disease', 'MESH:D004938', (235, 241))	('S21', 'Gene', '6227', (124, 127))	('cardia', 'Disease', (235, 241))
97000	31523512	To explain, since mutational signatures features are defined in terms of substitutions by the pyrimidine (T and C), an A(A >C) transversion is equivalent to a (T >G)T transversion associated with S21.	('pyrimidine', 'Chemical', 'MESH:C030986', (94, 104))	('S21', 'Gene', (196, 199))	('S21', 'Gene', '6227', (196, 199))	('substitutions', 'Var', (73, 86))
97002	31523512	's Signature 17 has been shown to have a higher number of mutations in EAC compared to stomach cancers, which reinforces our results showing higher mutational exposures for S21 in tumors occurring in the tubular esophagus compared to those in the GEJ.	('mutations', 'Var', (58, 67))	('stomach cancers', 'Disease', 'MESH:D013274', (87, 102))	('stomach cancers', 'Disease', (87, 102))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('EAC', 'Gene', '1540', (71, 74))	('stomach cancers', 'Phenotype', 'HP:0012126', (87, 102))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('EAC', 'Gene', (71, 74))	('S21', 'Gene', (173, 176))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('S21', 'Gene', '6227', (173, 176))
97005	31523512	We note that scenarios in which the variance of the estimated exposures differs will be common if the numbers of mutations per tumor varies between the two groups (e.g., when comparing microsatellite instable vs. microsatellite stable colon tumors), leading to an inflated false-positive rate if results from the TS method are interpreted as being evidence of a difference in means.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', (127, 132))	('common', 'Reg', (88, 94))	('colon tumors', 'Phenotype', 'HP:0100273', (235, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('mutations', 'Var', (113, 122))	('colon tumors', 'Disease', 'MESH:D015179', (235, 247))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('colon tumors', 'Disease', (235, 247))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
97102	30370350	Limited-margin radiation was associated with a significant reduction in the planning target volume (PTV) size as well as the brain V25 and, importantly, with a significantly higher median postradiation ALC (1100 vs 900 cells/muL in limited- vs conventional-margin group).	('muL', 'Gene', (225, 228))	('Limited-margin', 'Var', (0, 14))	('higher', 'PosReg', (174, 180))	('brain V25', 'CPA', (125, 134))	('muL', 'Gene', '4591', (225, 228))	('reduction', 'NegReg', (59, 68))	('planning target volume', 'CPA', (76, 98))
97111	30370350	Two recent studies in pancreatic cancer have demonstrated that hypofractionated RT can considerably reduce the risk and severity of radiation-induced lymphopenia.	('lymphopenia', 'Disease', (150, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (22, 39))	('lymphopenia', 'Phenotype', 'HP:0001888', (150, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('pancreatic cancer', 'Disease', (22, 39))	('reduce', 'NegReg', (100, 106))	('lymphopenia', 'Disease', 'MESH:D008231', (150, 161))	('hypofractionated', 'Var', (63, 79))
97127	30370350	Further research is needed to definitively determine whether correcting or preventing RIL improves survival in solid tumor patients.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('patients', 'Species', '9606', (123, 131))	('RIL', 'Gene', '8572', (86, 89))	('correcting', 'Var', (61, 71))	('RIL', 'Gene', (86, 89))	('survival', 'MPA', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('improves', 'PosReg', (90, 98))
97134	29552135	Additionally, patients with positive PD-L1 expression had a lower NLR than those with negative PD-L1 expression (P=0.001).	('PD-L1', 'Gene', (37, 42))	('expression', 'Var', (43, 53))	('PD-L1', 'Gene', '29126', (37, 42))	('PD-L1', 'Gene', (95, 100))	('positive', 'Var', (28, 36))	('NLR', 'MPA', (66, 69))	('patients', 'Species', '9606', (14, 22))	('PD-L1', 'Gene', '29126', (95, 100))	('lower', 'NegReg', (60, 65))
97135	29552135	On multivariate analysis, the positive staining of PD-L1 was significantly associated with improved OS (HR, 0.6; 95% CI, 0.372-0.965; P=0.035).	('improved', 'PosReg', (91, 99))	('PD-L1', 'Gene', '29126', (51, 56))	('positive staining', 'Var', (30, 47))	('PD-L1', 'Gene', (51, 56))
97137	29552135	In summary, the present study demonstrated that positive PD-L1 expression is associated with improved survival in patients with EC treated with radical CRT, indicating that PD-L1 is a promising prognostic marker.	('PD-L1', 'Gene', (173, 178))	('improved', 'PosReg', (93, 101))	('PD-L1', 'Gene', (57, 62))	('expression', 'MPA', (63, 73))	('PD-L1', 'Gene', '29126', (173, 178))	('PD-L1', 'Gene', '29126', (57, 62))	('positive', 'Var', (48, 56))	('survival', 'MPA', (102, 110))	('patients', 'Species', '9606', (114, 122))
97182	29552135	1C and D, PD-L1 was overexpressed on the membrane or in the cytoplasm (or both) of EC cells under different magnifications (x100 and x200, respectively) in some cases, in contrast to normal esophageal epithelial tissues.	('PD-L1', 'Gene', '29126', (10, 15))	('PD-L1', 'Gene', (10, 15))	('x200', 'Var', (133, 137))	('overexpressed', 'PosReg', (20, 33))
97184	29552135	No statistically significant differences in clinical parameters were noted between the groups of positive and negative PD-L1 expression (Table II).	('positive', 'Var', (97, 105))	('PD-L1', 'Gene', '29126', (119, 124))	('negative', 'NegReg', (110, 118))	('PD-L1', 'Gene', (119, 124))
97190	29552135	The survival curve of PD-L1 demonstrated that patients with positive PD-L1 expression had increased survival times compared with patients with negative PD-L1 expression, and the median OS times were 26 and 11 months, respectively.	('PD-L1', 'Gene', '29126', (69, 74))	('patients', 'Species', '9606', (46, 54))	('PD-L1', 'Gene', '29126', (152, 157))	('survival times', 'CPA', (100, 114))	('increased', 'PosReg', (90, 99))	('PD-L1', 'Gene', (22, 27))	('patients', 'Species', '9606', (129, 137))	('PD-L1', 'Gene', '29126', (22, 27))	('PD-L1', 'Gene', (152, 157))	('PD-L1', 'Gene', (69, 74))	('positive', 'Var', (60, 68))
97219	29552135	Several studies have suggested PD-L1 expression in human tumor tissue may lead to T cell exhaustion, while the pretreatment NLR level was found to be closely associated with T cell infiltration.	('expression', 'Var', (37, 47))	('associated', 'Reg', (158, 168))	('lead to', 'Reg', (74, 81))	('PD-L1', 'Gene', '29126', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('human', 'Species', '9606', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('T cell exhaustion', 'CPA', (82, 99))	('NLR', 'MPA', (124, 127))	('tumor', 'Disease', (57, 62))	('PD-L1', 'Gene', (31, 36))
97224	29552135	Numerous reports demonstrated that patients with positive PD-L1 expression had a higher risk of mortality than patients lacking PD-L1 expression.	('PD-L1', 'Gene', '29126', (58, 63))	('PD-L1', 'Gene', (128, 133))	('PD-L1', 'Gene', '29126', (128, 133))	('expression', 'Var', (64, 74))	('PD-L1', 'Gene', (58, 63))	('patients', 'Species', '9606', (35, 43))	('mortality', 'CPA', (96, 105))	('patients', 'Species', '9606', (111, 119))
97261	29434786	It is shown that inhibition of miR-429 expression enhances the cytotoxic activity of cisplatin on endometrial endometrioid carcinoma.	('endometrial endometrioid carcinoma', 'Disease', (98, 132))	('enhances', 'PosReg', (50, 58))	('miR-429', 'Gene', '554210', (31, 38))	('inhibition', 'Var', (17, 27))	('miR-429', 'Gene', (31, 38))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (110, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('cytotoxic activity', 'CPA', (63, 81))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (98, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
97314	29434786	The data showed that BGC-823 cells transfected with miR-429 mimics had significantly higher miR-429 level than NC group (P<0.01) (Fig.	('miR-429', 'Gene', '554210', (92, 99))	('miR-429', 'Gene', (92, 99))	('mimics', 'Var', (60, 66))	('higher', 'PosReg', (85, 91))	('BGC-823', 'CellLine', 'CVCL:3360', (21, 28))	('miR-429', 'Gene', '554210', (52, 59))	('miR-429', 'Gene', (52, 59))
97318	29434786	The data showed that the absorbance of BGC-823 cells transfected with miR-429 mimics was not significantly different from that in NC group at 48 h or 72 h (P>0.05) (Fig.	('miR-429', 'Gene', '554210', (70, 77))	('mimics', 'Var', (78, 84))	('miR-429', 'Gene', (70, 77))	('BGC-823', 'CellLine', 'CVCL:3360', (39, 46))
97321	29434786	The data showed that the number of cells that crossed the chamber membrane in miR-429 mimics group was significantly lower than that in NC group (P<0.01) (Fig.	('miR-429', 'Gene', '554210', (78, 85))	('miR-429', 'Gene', (78, 85))	('mimics', 'Var', (86, 92))	('lower', 'NegReg', (117, 122))
97327	29434786	To determine the effect of silencing of HPSE on the biological functions of BGC-823 cells, Transwell assay and CCK-8 assay were carried out.	('BGC-823', 'CellLine', 'CVCL:3360', (76, 83))	('HPSE', 'Gene', (40, 44))	('silencing', 'Var', (27, 36))
97342	29434786	Uno et al show that HPSE facilitates the invasion and metastasis of esophageal cancer, and inhibition of HPSE effectively prevents the pleural metastasis of esophageal cancer.	('pleural metastasis of esophageal cancer', 'Disease', (135, 174))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('inhibition', 'Var', (91, 101))	('pleural metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (135, 174))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (143, 174))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('facilitates', 'PosReg', (25, 36))	('invasion', 'CPA', (41, 49))	('prevents', 'NegReg', (122, 130))	('metastasis of esophageal cancer', 'Disease', (54, 85))	('HPSE', 'Gene', (105, 109))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (54, 85))
97345	29434786	These studies further strengthen the fact that high expression of HPSE facilitates the invasion and metastasis of tumor cells, and reduces survival time of patients.	('patients', 'Species', '9606', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('high expression', 'Var', (47, 62))	('reduces', 'NegReg', (131, 138))	('tumor', 'Disease', (114, 119))	('HPSE', 'Gene', (66, 70))	('facilitates', 'PosReg', (71, 82))	('survival time', 'CPA', (139, 152))
97347	29434786	In addition, the invasion ability of BGC-823 cells is significantly lowered after silencing HPSE expression.	('HPSE', 'Gene', (92, 96))	('lowered', 'NegReg', (68, 75))	('invasion ability', 'CPA', (17, 33))	('BGC-823', 'CellLine', 'CVCL:3360', (37, 44))	('silencing', 'Var', (82, 91))
97356	28977909	The G2/M arrest was partially contributed by down-regulation of protein expression of Cdc-25c and up-regulation of phosphorylated Cdc-2 (Tyr15), Cyclin B1 (Ser147) and p53.	('Cdc-25c', 'Gene', (86, 93))	('G2/M arrest', 'CPA', (4, 15))	('Tyr15', 'Chemical', '-', (137, 142))	('Cyclin B1', 'Gene', '891', (145, 154))	('phosphorylated', 'MPA', (115, 129))	('Cdc-2', 'Gene', (86, 91))	('Ser147', 'Var', (156, 162))	('Cyclin B1', 'Gene', (145, 154))	('up-regulation', 'PosReg', (98, 111))	('Cdc-25c', 'Gene', '995', (86, 93))	('Cdc-2', 'Gene', '983', (130, 135))	('Ser147', 'Chemical', '-', (156, 162))	('down-regulation', 'NegReg', (45, 60))	('p53', 'Gene', (168, 171))	('Cdc-2', 'Gene', (130, 135))	('Cdc-2', 'Gene', '983', (86, 91))	('protein expression', 'MPA', (64, 82))
97368	28977909	Induction of oxidative stress and production of ROS are known to increase the rate of mutations in the cells.	('mutations', 'Var', (86, 95))	('ROS', 'Protein', (48, 51))	('oxidative stress', 'Phenotype', 'HP:0025464', (13, 29))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))
97374	28977909	The glutathionylation/deglutathionylation cycle of cysteine residues depends on the redox state of the microenvironment, and reversible S-glutathionylation may help protect proteins from irreversible thiol oxidation reactions as well as providing a mechanism to transfer redox information.	('redox', 'MPA', (271, 276))	('proteins', 'Protein', (173, 181))	('S-glutathionylation', 'Var', (136, 155))	('thiol', 'Chemical', 'MESH:D013438', (200, 205))	('cysteine', 'Chemical', 'MESH:D003545', (51, 59))
97418	28977909	2-AAPA showed no effect on protein expression of Cdc-2, Cyclin B1, p21, p-ATM (Ser1981), p-p53 (Ser15).	('Cyclin B1', 'Gene', '891', (56, 65))	('Cdc-2', 'Gene', '983', (49, 54))	('p21', 'Gene', '1026', (67, 70))	('ATM', 'Gene', (74, 77))	('Cdc-2', 'Gene', (49, 54))	('protein expression', 'MPA', (27, 45))	('Cyclin B1', 'Gene', (56, 65))	('Ser1981', 'Chemical', '-', (79, 86))	('Ser15', 'Chemical', '-', (96, 101))	('p-p53 (Ser15', 'Var', (89, 101))	('p21', 'Gene', (67, 70))	('ATM', 'Gene', '472', (74, 77))	('2-AAPA', 'Chemical', 'MESH:C503900', (0, 6))
97447	28977909	This study has shown that inhibition of GR activity is an effective way to generation of oxidative stress and suppression of cell growth in esophageal cancer cells.	('suppression', 'NegReg', (110, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cell growth', 'CPA', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('oxidative stress', 'Phenotype', 'HP:0025464', (89, 105))	('inhibition', 'Var', (26, 36))	('generation of oxidative stress', 'MPA', (75, 105))	('esophageal cancer', 'Disease', (140, 157))	('GR', 'Gene', '2936', (40, 42))
97453	28977909	In addition, p53 controls G2 checkpoints and expression of wild-type p53 can prevent G2/M transition in mouse and human cell lines.	('prevent', 'NegReg', (77, 84))	('G2/M transition', 'CPA', (85, 100))	('p53', 'Gene', (69, 72))	('mouse', 'Species', '10090', (104, 109))	('human', 'Species', '9606', (114, 119))	('expression', 'Var', (45, 55))
97464	28977909	In agreement with our findings, previously demonstrated that in some cancer cell lines proliferation inhibitors rapidly induce a substantial increase of protein S-glutathionylation levels.	('inhibitors', 'Var', (101, 111))	('increase', 'PosReg', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('protein S-glutathionylation levels', 'MPA', (153, 187))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
97469	28977909	As malfunction of microtubules can lead to in cell mitosis arrest and cell morphological changes (Figure 7), further reciprocal immunoprecipitation using anti-GSH and anti-tubulin (alpha and beta) antibodies was performed and the results showed that the S-glutathionylation increased in alpha-tubulin but not beta-tubulin by 2-AAPA treatment.	('GSH', 'Chemical', '-', (159, 162))	('cell mitosis', 'Disease', 'MESH:C538614', (46, 58))	('mitosis arrest', 'Disease', 'MESH:D006323', (51, 65))	('mitosis arrest', 'Disease', (51, 65))	('cell morphological', 'CPA', (70, 88))	('2-AAPA', 'Chemical', 'MESH:C503900', (325, 331))	('S-glutathionylation', 'MPA', (254, 273))	('alpha-tubulin', 'Gene', (287, 300))	('malfunction', 'Var', (3, 14))	('lead', 'Reg', (35, 39))	('alpha-tubulin', 'Gene', '10376', (287, 300))	('cell mitosis', 'Disease', (46, 58))	('increased', 'PosReg', (274, 283))
97476	28977909	The increased expression of p53 and phosphorylation of Cdc-2 (Tyr15) and Cyclin B1 (Ser147) which involved in G2/M phase regulation was observed.	('Cyclin B1', 'Gene', '891', (73, 82))	('Cdc-2', 'Gene', '983', (55, 60))	('Ser147', 'Var', (84, 90))	('Cdc-2', 'Gene', (55, 60))	('Cyclin B1', 'Gene', (73, 82))	('Tyr15', 'Chemical', '-', (62, 67))	('expression', 'MPA', (14, 24))	('Ser147', 'Chemical', '-', (84, 90))	('p53', 'Protein', (28, 31))	('phosphorylation', 'MPA', (36, 51))	('increased', 'PosReg', (4, 13))
97485	28977909	p-p53, p-Cdc-2, p-Cyclin B1 were from Santa Cruz Biotechnology (CA, USA).	('p-p53', 'Var', (0, 5))	('Cdc-2', 'Gene', '983', (9, 14))	('Cdc-2', 'Gene', (9, 14))	('Cyclin B1', 'Gene', (18, 27))	('Cyclin B1', 'Gene', '891', (18, 27))
97533	27225590	Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers Promoter CpG methylation is a fundamental regulatory process of gene expression.	('TET1', 'Gene', '80312', (47, 51))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('human', 'Species', '9606', (90, 95))	('TET1', 'Gene', (47, 51))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))	('Epigenetic inactivation', 'Var', (0, 23))
97534	27225590	TET proteins are active CpG demethylases converting 5-methylcytosine to 5-hydroxymethylcytosine, with loss of 5 hmC as an epigenetic hallmark of cancers, indicating critical roles of TET proteins in epigenetic tumorigenesis.	('5-methylcytosine', 'Chemical', 'MESH:D044503', (52, 68))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (72, 95))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (210, 215))	('TET', 'Chemical', '-', (0, 3))	('hallmark of cancers', 'Disease', (133, 152))	('hallmark of cancers', 'Disease', 'MESH:D009369', (133, 152))	('TET', 'Chemical', '-', (183, 186))	('loss', 'Var', (102, 106))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('mC', 'Chemical', 'MESH:D008748', (113, 115))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
97539	27225590	DNA methylation at the C5 position of cytosine (5-methylcytosine, 5-mC), known as the "fifth base", is a key epigenetic modification at CpG dinucleotides, playing critical roles in normal development and disease pathogenesis including tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (48, 64))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', (235, 240))	('cytosine', 'Chemical', 'MESH:D003596', (38, 46))	('cytosine', 'Chemical', 'MESH:D003596', (56, 64))	('5-mC', 'Chemical', '-', (66, 70))
97540	27225590	Regional promoter CpG methylation together with genome-wide hypomethylation, as a fundamental epigenetic hallmark of cancers, lead to the silencing of tumor suppressor genes (TSG) and activation of oncogenes, contributing to cancer initiation and progression.	('silencing', 'NegReg', (138, 147))	('contributing', 'Reg', (209, 221))	('activation', 'PosReg', (184, 194))	('TSG', 'Gene', '57045', (175, 178))	('cancer initiation', 'Disease', 'MESH:D009369', (225, 242))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer initiation', 'Disease', (225, 242))	('hallmark of cancers', 'Disease', (105, 124))	('tumor', 'Disease', (151, 156))	('hallmark of cancers', 'Disease', 'MESH:D009369', (105, 124))	('oncogenes', 'CPA', (198, 207))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('TSG', 'Gene', (175, 178))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('methylation', 'Var', (22, 33))
97548	27225590	Inactive mutations or deletions of TET2 with impaired catalytic activity were frequently detected in hematopoietic malignancies, along with decreased 5 hmC levels, while no somatic TET1 or TET3 mutation was found in myeloid and lymphoid tumors.	('decreased', 'NegReg', (140, 149))	('TET2', 'Gene', '54790', (35, 39))	('deletions', 'Var', (22, 31))	('catalytic activity', 'MPA', (54, 72))	('TET2', 'Gene', (35, 39))	('hematopoietic malignancies', 'Disease', (101, 127))	('lymphoid tumors', 'Disease', (228, 243))	('mC', 'Chemical', 'MESH:D008748', (153, 155))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('lymphoid tumors', 'Phenotype', 'HP:0002665', (228, 243))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('5 hmC levels', 'MPA', (150, 162))	('TET3', 'Gene', (189, 193))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (101, 127))	('lymphoid tumors', 'Disease', 'MESH:D009369', (228, 243))	('TET3', 'Gene', '200424', (189, 193))	('detected', 'Reg', (89, 97))
97562	27225590	Then by MSP, we detected TET1 promoter methylation in virtually all downregulated cell lines of nasopharyngeal, esophageal, lung, gastric, colon, breast, cervical and renal carcinomas, as well as Hodgkin (HL), non-Hodgkin (NHL) and NKTCL lymphomas, but not in immortalized normal epithelial cell lines (Fig.	('downregulated', 'NegReg', (68, 81))	('colon', 'Disease', 'MESH:D015179', (139, 144))	('NKTCL lymphomas', 'Disease', 'MESH:D008223', (232, 247))	('lymphoma', 'Phenotype', 'HP:0002665', (238, 246))	('colon', 'Disease', (139, 144))	('TET1', 'Gene', (25, 29))	('nasopharyngeal', 'Disease', (96, 110))	('renal carcinomas', 'Disease', 'MESH:C538614', (167, 183))	('methylation', 'Var', (39, 50))	('cervical', 'Disease', (154, 162))	('lymphomas', 'Phenotype', 'HP:0002665', (238, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('lung', 'Disease', (124, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('breast', 'Disease', (146, 152))	('non-Hodgkin', 'Disease', (210, 221))	('renal carcinomas', 'Disease', (167, 183))	('Hodgkin', 'Disease', (214, 221))	('renal carcinomas', 'Phenotype', 'HP:0005584', (167, 183))	('esophageal', 'Disease', (112, 122))	('Hodgkin', 'Disease', (196, 203))	('Hodgkin', 'Disease', 'MESH:D006689', (214, 221))	('Hodgkin', 'Disease', 'MESH:D006689', (196, 203))	('gastric', 'Disease', (130, 137))	('non-Hodgkin', 'Disease', 'MESH:D008228', (210, 221))	('NKTCL lymphomas', 'Disease', (232, 247))
97563	27225590	Moreover, TET1 downregulation and methylation were infrequently detected in hepatocellular (HCC) and prostate cancer cell lines but not in the bladder and melanoma cell lines examined (Suppl.	('downregulation', 'NegReg', (15, 29))	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('methylation', 'Var', (34, 45))	('prostate cancer', 'Disease', (101, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('hepatocellular', 'Disease', (76, 90))	('HCC', 'Phenotype', 'HP:0001402', (92, 95))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('TET1', 'Gene', (10, 14))	('melanoma', 'Disease', (155, 163))
97566	27225590	DNA methyltransferase inhibitor 5-aza-dC (Aza) was used or in combination with histone deacetylase (HDAC) inhibitor to treat tumor cell lines of nasopharyngeal, esophageal, colon, breast and renal, all with methylated and downregulated TET1.	('Aza', 'Chemical', 'MESH:D000077209', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('downregulated', 'NegReg', (222, 235))	('HDAC', 'Gene', '9734', (100, 104))	('colon', 'Disease', 'MESH:D015179', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('esophageal', 'Disease', (161, 171))	('breast', 'Disease', (180, 186))	('histone deacetylase', 'Gene', '9734', (79, 98))	('tumor', 'Disease', (125, 130))	('TET1', 'Gene', (236, 240))	('histone deacetylase', 'Gene', (79, 98))	('colon', 'Disease', (173, 178))	('renal', 'Disease', (191, 196))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (32, 40))	('methylated', 'Var', (207, 217))	('HDAC', 'Gene', (100, 104))
97569	27225590	In this study, we demonstrated that epigenetic silencing is a common regulatory mechanism for TET1 inactivation at the transcriptional level in multiple human cancers.	('cancers', 'Disease', (159, 166))	('TET1', 'Gene', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('human', 'Species', '9606', (153, 158))	('epigenetic silencing', 'Var', (36, 56))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('inactivation', 'NegReg', (99, 111))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
97576	27225590	Nuclear exclusion of TET1 and TET2 is significantly correlated with loss of 5mC in glioma and colon cancer.	('glioma', 'Disease', (83, 89))	('correlated', 'Reg', (52, 62))	('colon cancer', 'Disease', (94, 106))	('5mC', 'Chemical', '-', (76, 79))	('Nuclear exclusion', 'MPA', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('loss of', 'Var', (68, 75))	('TET2', 'Gene', '54790', (30, 34))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('TET2', 'Gene', (30, 34))	('TET1', 'Gene', (21, 25))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
97579	27225590	We detected frequent TET1 methylation in multiple tumors, including 55% (31/56) of NPC, 55% (30/55) of gastric, 27% (3/11) of colon, 42% (5/12) of hepatocellular, 36% (18/50) of breast and 28% (13/46) of renal tumor samples, as well as 78% of primary Hodgkin and 83% (10/12) of NKTCL lymphoma samples (Fig.	('NPC', 'Phenotype', 'HP:0100630', (83, 86))	('primary Hodgkin', 'Disease', 'MESH:D006689', (243, 258))	('multiple tumors', 'Disease', (41, 56))	('primary Hodgkin', 'Disease', (243, 258))	('hepatocellular', 'Disease', (147, 161))	('renal tumor', 'Phenotype', 'HP:0009726', (204, 215))	('NPC', 'Disease', (83, 86))	('renal tumor', 'Disease', 'MESH:D007674', (204, 215))	('NKTCL lymphoma', 'Disease', (278, 292))	('renal tumor', 'Disease', (204, 215))	('breast', 'Disease', (178, 184))	('lymphoma', 'Phenotype', 'HP:0002665', (284, 292))	('gastric', 'Disease', (103, 110))	('colon', 'Disease', 'MESH:D015179', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('TET1', 'Gene', (21, 25))	('methylation', 'Var', (26, 37))	('colon', 'Disease', (126, 131))	('multiple tumors', 'Disease', 'MESH:D009369', (41, 56))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('NKTCL lymphoma', 'Disease', 'MESH:D008223', (278, 292))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))
97581	27225590	TET1 methylation could even be detected in 50% of 16 nose swab samples from suspected NPC patients (Fig.	('detected', 'Reg', (31, 39))	('NPC', 'Phenotype', 'HP:0100630', (86, 89))	('methylation', 'Var', (5, 16))	('NPC', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))	('TET1', 'Gene', (0, 4))
97583	27225590	Further detailed BGS methylation analysis confirmed the presence of methylated promoter alleles in primary tumors but not normal tissues (Fig.	('primary tumors', 'Disease', 'MESH:D009369', (99, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('methylated', 'Var', (68, 78))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('primary tumors', 'Disease', (99, 113))
97592	27225590	TET1 methylation in colorectal cancer tissues, not TET2 and TET3, has been found as an early event in CRC tumorigenesis, thus as a valuable biomarker for metastasis prediction.	('TET2', 'Gene', (51, 55))	('TET3', 'Gene', (60, 64))	('methylation', 'Var', (5, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('colorectal cancer', 'Disease', (20, 37))	('TET3', 'Gene', '200424', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('TET2', 'Gene', '54790', (51, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('TET1', 'Gene', (0, 4))
97593	27225590	TET1 methylation appears to be tumor-specific and thus could serve as a potential epigenetic biomarker for cancer detection.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('methylation', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('TET1', 'Gene', (0, 4))
97596	27225590	Only <1% of tumor cases (most cases with <=0.25%) had detectable TET1 mutations (Fig.	('TET1', 'Gene', (65, 69))	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
97597	27225590	We also detected hemizygous deletion of TET1 in some tumor cell lines with TET1 silencing and methylation, but not in TET1-expresssing cells (Suppl.	('silencing', 'NegReg', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('TET1', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('methylation', 'Var', (94, 105))	('TET1', 'Gene', (75, 79))	('deletion', 'Var', (28, 36))
97598	27225590	Consistently, TET1 gene deletion was also observed in solid tumors by analyzing DNA copy number alterations using the Oncomine database (Suppl.	('Oncomine', 'Chemical', '-', (118, 126))	('solid tumors', 'Disease', 'MESH:D009369', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('deletion', 'Var', (24, 32))	('solid tumors', 'Disease', (54, 66))	('TET1', 'Gene', (14, 18))
97599	27225590	These results demonstrate that TET1 mutation is uncommon in human cancers, although TET1 deletion is indeed present in some tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', (124, 129))	('deletion', 'Var', (89, 97))	('TET1', 'Gene', (84, 88))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('human', 'Species', '9606', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
97607	27225590	TET1 deficiency promotes B-lineage differentiation, leading eventually to B-cell lymphoma.	('promotes', 'PosReg', (16, 24))	('leading', 'Reg', (52, 59))	('deficiency', 'Var', (5, 15))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('cell lymphoma', 'Phenotype', 'HP:0012191', (76, 89))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (74, 89))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (74, 89))	('B-cell lymphoma', 'Disease', (74, 89))	('B-lineage differentiation', 'CPA', (25, 50))	('TET1', 'Gene', (0, 4))
97620	27225590	The epigenetic alterations, especially promoter CpG methylation of TSGs, facilitate genome instability, disrupted cellular signaling and even further genetic mutations, thus are crucial to tumor initiation and progression.	('TSG', 'Gene', (67, 70))	('genome instability', 'CPA', (84, 102))	('cellular signaling', 'MPA', (114, 132))	('tumor initiation', 'Disease', (189, 205))	('facilitate', 'PosReg', (73, 83))	('genetic mutations', 'Var', (150, 167))	('epigenetic alterations', 'Var', (4, 26))	('TSG', 'Gene', '57045', (67, 70))	('promoter', 'MPA', (39, 47))	('disrupted', 'NegReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor initiation', 'Disease', 'MESH:D009369', (189, 205))
97621	27225590	Remarkably, promoter CpG methylation-mediated silencing of the CpG demethylase TET1 in human cancers, which in turn, further leads to increased 5 mC levels in tumor cells, thus forming a DNA methylation feedback loop mediated by DNMT/CpG methylation and TET1 (Fig.	('TET1', 'Gene', (79, 83))	('cancers', 'Disease', (93, 100))	('silencing', 'NegReg', (46, 55))	('DNMT', 'Gene', '1786', (229, 233))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (87, 92))	('DNMT', 'Gene', (229, 233))	('methylation-mediated', 'Var', (25, 45))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mC', 'Chemical', 'MESH:D008748', (146, 148))	('5 mC levels', 'MPA', (144, 155))	('tumor', 'Disease', (159, 164))	('forming', 'Reg', (177, 184))	('increased', 'PosReg', (134, 143))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
97642	27225590	Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('human', 'Species', '9606', (90, 95))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))	('Epigenetic inactivation', 'Var', (0, 23))
97686	25843072	The operation methods included ligation of pylorus and proximal small bowel, destruction of cardia, and different kinds of esophageal gastrointestinal anastomosis.	('small bowel', 'Disease', (64, 75))	('esophageal gastrointestinal anastomosis', 'Disease', 'MESH:D004067', (123, 162))	('small bowel', 'Disease', 'MESH:D015212', (64, 75))	('esophageal gastrointestinal anastomosis', 'Disease', (123, 162))	('cardia', 'Disease', 'MESH:D004938', (92, 98))	('rat', 'Species', '10116', (7, 10))	('cardia', 'Disease', (92, 98))	('ligation', 'Var', (31, 39))
97708	25225511	It has been demonstrated that postoperative radiotherapy can degenerate esophageal cancer cells, decrease the proliferative activity and reduce the tumor volume, thus leading to vascular thrombosis and eliminating micrometastases.	('degenerate', 'NegReg', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('micrometastases', 'CPA', (214, 229))	('radiotherapy', 'Var', (44, 56))	('esophageal', 'Disease', (72, 82))	('leading to', 'Reg', (167, 177))	('tumor volume', 'CPA', (148, 160))	('thrombosis', 'Disease', (187, 197))	('reduce', 'NegReg', (137, 143))	('decrease', 'NegReg', (97, 105))	('thrombosis', 'Disease', 'MESH:D013927', (187, 197))	('eliminating', 'NegReg', (202, 213))	('proliferative activity', 'CPA', (110, 132))
97711	25225511	NF-kappaB mainly comprises Rel (cRel) and p65 (RelA) subunits, and p65 mainly exerts functional effects.	('Rel', 'Protein', (27, 30))	('RelA', 'Gene', (47, 51))	('RelA', 'Gene', '5970', (47, 51))	('exerts', 'Reg', (78, 84))	('p65', 'Protein', (42, 45))	('NF-kappaB', 'Protein', (0, 9))	('p65', 'Var', (67, 70))
97717	25177546	Presence of TB reproducibly correlates with advanced tumor stage, frequent lymphovascular invasion, nodal, and distant metastasis.	('nodal', 'CPA', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('frequent lymphovascular invasion', 'CPA', (66, 98))	('tumor', 'Disease', (53, 58))	('TB', 'Chemical', '-', (12, 14))	('Presence', 'Var', (0, 8))	('distant metastasis', 'CPA', (111, 129))
97738	25177546	It has been suggested that tumor buds may resist both apoptosis and anoikis following the detachment from the primary tumor due to upregulation of anti-apoptotic proteins such as RAF-kinase inhibitor protein (RKIP) and caspase-3 deficiency.	('apoptosis', 'CPA', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('RKIP', 'Gene', '5037', (209, 213))	('deficiency', 'Var', (229, 239))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('resist', 'CPA', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('caspase-3', 'Gene', '836', (219, 228))	('primary tumor', 'Disease', 'MESH:D009369', (110, 123))	('caspase-3', 'Gene', (219, 228))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('RAF-kinase inhibitor protein', 'Gene', '5037', (179, 207))	('upregulation', 'PosReg', (131, 143))	('primary tumor', 'Disease', (110, 123))	('tumor', 'Disease', (118, 123))	('RKIP', 'Gene', (209, 213))	('RAF-kinase inhibitor protein', 'Gene', (179, 207))	('anoikis', 'CPA', (68, 75))
97741	25177546	Indeed, high-grade TB has been shown to be a highly specific indicator of poor response to radiotherapy in rectal cancer patients.	('TB', 'Chemical', '-', (19, 21))	('high-grade', 'Var', (8, 18))	('rectal cancer', 'Disease', 'MESH:D012004', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rectal cancer', 'Disease', (107, 120))	('rectal cancer', 'Phenotype', 'HP:0100743', (107, 120))	('patients', 'Species', '9606', (121, 129))
97743	25177546	Few studies have investigated the immunogenicity of tumor buds, but it has been suggested that loss of MHC-I expression could be a frequent feature in cancer initiating cells.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('expression', 'MPA', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', (52, 57))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('MHC-I', 'Gene', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('loss', 'Var', (95, 99))
97753	25177546	Taken together, high-grade TB in gastrointestinal carcinomas could be a general indicator of aggressive clinicopathological behavior with importance for individualized risk assessment.	('gastrointestinal carcinomas', 'Disease', (33, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('high-grade', 'Var', (16, 26))	('TB', 'Chemical', '-', (27, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (33, 60))	('gastrointestinal carcinomas', 'Disease', 'MESH:D004067', (33, 60))
97766	25177546	Further, patients with high-grade TB had a reduced 3-year survival outcome of 30.7% after esophagectomy in comparison to 72.3% in patients with low-grade budding.	('patients', 'Species', '9606', (9, 17))	('TB', 'Chemical', '-', (34, 36))	('patients', 'Species', '9606', (130, 138))	('reduced', 'NegReg', (43, 50))	('high-grade', 'Var', (23, 33))
97769	25177546	Further, high-grade TB consistently predicted more advanced T-stage and lymph node metastasis.	('lymph node metastasis', 'CPA', (72, 93))	('TB', 'Chemical', '-', (20, 22))	('high-grade', 'Var', (9, 19))
97776	25177546	Following esophagectomy, the investigators report 3-year survival rates of 48.8% for pT1 patients with high-grade TB as compared to 94.5% in the absence of this feature.	('pT1', 'Gene', (85, 88))	('high-grade', 'Var', (103, 113))	('pT1', 'Gene', '58492', (85, 88))	('patients', 'Species', '9606', (89, 97))	('TB', 'Chemical', '-', (114, 116))
97781	25177546	In a well-designed, two-center retrospective study including 287 cases of stage I-IV esophageal AC and 69 cases of SCC by Brown and associates, high-grade TB was associated with a median overall survival outcome of 15 months while patients with low-grade TB reached 31 months.	('esophageal AC', 'Disease', (85, 98))	('patients', 'Species', '9606', (231, 239))	('TB', 'Chemical', '-', (155, 157))	('TB', 'Chemical', '-', (255, 257))	('SCC', 'Gene', (115, 118))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('SCC', 'Gene', '6317', (115, 118))	('high-grade', 'Var', (144, 154))
97783	25177546	Further, high-grade TB was associated with higher overall TNM-stage and adverse clinicopathological features such as lymph node metastasis, poor tumor differentiation, and incomplete excision.	('lymph node metastasis', 'CPA', (117, 138))	('TNM', 'Gene', '10178', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('higher', 'PosReg', (43, 49))	('high-grade', 'Var', (9, 19))	('TB', 'Chemical', '-', (20, 22))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TNM', 'Gene', (58, 61))	('tumor', 'Disease', (145, 150))
97787	25177546	Survival analysis showed a trend toward poor overall survival in patients with high-grade TB but did not reach statistical significance, possibly due to the relatively small number of patients under study.	('poor', 'NegReg', (40, 44))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (65, 73))	('TB', 'Chemical', '-', (90, 92))	('high-grade', 'Var', (79, 89))
97789	25177546	In 42 patients with surgically treated pT1 AC, Nowak and colleagues demonstrate a significantly increased rate of tumor recurrence and nodal metastasis with high-grade TB.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('nodal metastasis', 'CPA', (135, 151))	('pT1', 'Gene', '58492', (39, 42))	('tumor', 'Disease', (114, 119))	('TB', 'Chemical', '-', (168, 170))	('patients', 'Species', '9606', (6, 14))	('high-grade', 'Var', (157, 167))	('pT1', 'Gene', (39, 42))
97807	25177546	While presence of TB in the surgically resected specimen of CRC may be an indicator of aggressive disease requiring adjuvant chemotherapy, esophageal cancers are commonly treated in the neo-adjuvant setting where no information on budding activity in the tumor microenvironment based on a resection specimen will be available.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('aggressive disease', 'Disease', 'MESH:D001523', (87, 105))	('esophageal cancers', 'Disease', (139, 157))	('TB', 'Chemical', '-', (18, 20))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('aggressive disease', 'Disease', (87, 105))	('esophageal cancers', 'Disease', 'MESH:D004938', (139, 157))	('presence', 'Var', (6, 14))
97830	25177546	Further, high-grade TB was associated with larger tumor size and depressive macroscopic morphology.	('depressive', 'Disease', (65, 75))	('high-grade', 'Var', (9, 19))	('TB', 'Chemical', '-', (20, 22))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('depressive', 'Disease', 'MESH:D000275', (65, 75))	('tumor', 'Disease', (50, 55))
97836	25177546	TrkB expression may promote EMT in malignant cells and has been associated with chemotherapy resistance of esophageal carcinomas.	('associated', 'Reg', (64, 74))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (107, 128))	('esophageal carcinomas', 'Disease', (107, 128))	('expression', 'Var', (5, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('EMT in malignant cells', 'CPA', (28, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('TrkB', 'Gene', '4915', (0, 4))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (107, 128))	('promote', 'PosReg', (20, 27))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (107, 127))	('TrkB', 'Gene', (0, 4))
97845	25177546	As signet cell carcinomas of the stomach also frequently display primary E-cadherin mutations, the use of this feature to characterize cells undergoing EMT is limited.	('E-cadherin', 'Gene', (73, 83))	('E-cadherin', 'Gene', '999', (73, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('carcinomas of the stomach', 'Disease', 'MESH:D013274', (15, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('display', 'Reg', (57, 64))	('mutations', 'Var', (84, 93))	('carcinomas of the stomach', 'Disease', (15, 40))	('carcinomas of the stomach', 'Phenotype', 'HP:0006753', (15, 40))	('cell carcinomas', 'Disease', 'MESH:C538614', (10, 25))	('cell carcinomas', 'Disease', (10, 25))
97850	25177546	In esophageal and gastric carcinomas, presence of TB in the resection specimen predicts unfavorable clinicopathological features and early disease recurrence.	('TB', 'Chemical', '-', (50, 52))	('presence', 'Var', (38, 46))	('gastric carcinomas', 'Disease', (18, 36))	('gastric carcinomas', 'Disease', 'MESH:D013274', (18, 36))	('esophageal', 'Disease', (3, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))
97855	25177546	In particular, some patients with pT2 esophageal cancer present with early disease recurrence following resection of the primary tumor.	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('primary tumor', 'Disease', (121, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('pT2', 'Var', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('primary tumor', 'Disease', 'MESH:D009369', (121, 134))	('patients', 'Species', '9606', (20, 28))
97870	24945256	Pri-miR-124 rs531564 and pri-miR-34b/c rs4938723 Polymorphisms Are Associated with Decreased Risk of Esophageal Squamous Cell Carcinoma in Chinese Populations MicroRNAs are a new class of small non-protein-coding RNAs that sometimes function as tumor suppressors or oncogenes.	('Esophageal Squamous Cell Carcinoma', 'Disease', (101, 135))	('rs531564', 'Var', (12, 20))	('miR-34b', 'Gene', (29, 36))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (101, 135))	('rs531564', 'Mutation', 'rs531564', (12, 20))	('rs4938723', 'Mutation', 'rs4938723', (39, 48))	('Pri-miR-124', 'Gene', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('miR-34b', 'Gene', '407041', (29, 36))	('Carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('Decreased', 'NegReg', (83, 92))	('tumor', 'Disease', (245, 250))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('rs4938723', 'Var', (39, 48))
97871	24945256	Aberrant expression and structural alteration of microRNAs have been reported to be involved in tumorigenesis and cancer development.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('structural alteration', 'CPA', (24, 45))	('Aberrant expression', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('microRNAs', 'Gene', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('involved', 'Reg', (84, 92))	('cancer', 'Disease', (114, 120))
97872	24945256	Recently, rs531564/pri-miR-124-1, rs4938723/pri-miR-34b/c, rs7372209/pri-miR-26a-1, rs895819/pre-miR-27a, and rs11134527/pri-miR-218 were reported to be associated with risks of various cancers.	('miR-34b', 'Gene', '407041', (48, 55))	('miR-26a-1', 'Gene', (73, 82))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancers', 'Disease', (186, 193))	('rs531564', 'Mutation', 'rs531564', (10, 18))	('miR-34b', 'Gene', (48, 55))	('miR-27a', 'Gene', '407018', (97, 104))	('miR-124-1', 'Gene', (23, 32))	('rs11134527', 'Mutation', 'rs11134527', (110, 120))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('miR-124-1', 'Gene', '406907', (23, 32))	('miR-26a-1', 'Gene', '407015', (73, 82))	('rs11134527/pri-miR-218', 'Var', (110, 132))	('miR-27a', 'Gene', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('rs895819', 'Mutation', 'rs895819', (84, 92))	('rs7372209', 'Mutation', 'rs7372209', (59, 68))	('rs4938723', 'Mutation', 'rs4938723', (34, 43))	('associated', 'Reg', (153, 163))
97874	24945256	We found that the GG genotype of pri-miR-124-1 rs531564 was associated to a significantly decreased risk of ESCC comparing with the CC/CG genotypes (p = 0.005; OR = 0.61, 95% CI = 0.43-0.86).	('rs531564', 'Var', (47, 55))	('decreased', 'NegReg', (90, 99))	('miR-124-1', 'Gene', '406907', (37, 46))	('CG', 'Chemical', 'MESH:C028505', (135, 137))	('miR-124-1', 'Gene', (37, 46))	('rs531564', 'Mutation', 'rs531564', (47, 55))	('ESCC', 'Disease', (108, 112))
97875	24945256	In addition, the CC genotype of pri-miR-34b/c rs4938723 was associated with a significant decreased risk of ESCC (CC VS. TT/TC: p = 0.007, OR = 0.82, 95% CI = 0.71-0.95) in Chinese population.	('miR-34b', 'Gene', (36, 43))	('miR-34b', 'Gene', '407041', (36, 43))	('rs4938723', 'Var', (46, 55))	('decreased', 'NegReg', (90, 99))	('TC', 'Chemical', 'MESH:D013667', (124, 126))	('rs4938723', 'Mutation', 'rs4938723', (46, 55))
97876	24945256	The present study provides the first evidence that pri-miR-124-1 rs531564 and pri-miR-34 rs4938723 were associated with the risk of ESCC in Chinese population.	('miR-124-1', 'Gene', '406907', (55, 64))	('rs4938723', 'Mutation', 'rs4938723', (89, 98))	('miR-124-1', 'Gene', (55, 64))	('associated', 'Reg', (104, 114))	('miR-34', 'Gene', (82, 88))	('rs531564', 'Var', (65, 73))	('rs531564', 'Mutation', 'rs531564', (65, 73))	('ESCC', 'Disease', (132, 136))	('miR-34', 'Gene', '407040', (82, 88))	('rs4938723', 'Var', (89, 98))
97882	24945256	This suggests the role of risk factors and genetic alterations in esophageal cancer carcinogenesis through gene-environment interactions.	('esophageal cancer carcinogenesis', 'Disease', 'MESH:D063646', (66, 98))	('interactions', 'Interaction', (124, 136))	('esophageal cancer carcinogenesis', 'Disease', (66, 98))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('genetic alterations', 'Var', (43, 62))
97884	24945256	SNPs or mutations in miRNA genes can influence the processing and/or target binding of miRNAs, thus resulting in diverse functional consequences and thereby possibly representing potential candidate biomarkers for cancer prognosis.	('cancer', 'Disease', (214, 220))	('influence', 'Reg', (37, 46))	('resulting in', 'Reg', (100, 112))	('functional', 'MPA', (121, 131))	('mutations', 'Var', (8, 17))	('SNPs', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('miRNA genes', 'Gene', (21, 32))	('processing', 'MPA', (51, 61))	('miRNAs', 'Protein', (87, 93))	('target binding', 'Interaction', (69, 83))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
97886	24945256	Recently, rs531564 with a G/C variation was identified in pri-miR-124-1.	('rs531564', 'Mutation', 'rs531564', (10, 18))	('miR-124-1', 'Gene', '406907', (62, 71))	('rs531564', 'Var', (10, 18))	('miR-124-1', 'Gene', (62, 71))
97891	24945256	Rs7372209/pri-miR-26a-1 decreased bladder cancer risk in women, and rs11134527/pri-miR-218 is associated with a significantly decreased risk of cervical carcinoma.	('decreased', 'NegReg', (126, 135))	('miR-26a-1', 'Gene', (14, 23))	('decreased bladder', 'Phenotype', 'HP:0005343', (24, 41))	('cervical carcinoma', 'Disease', (144, 162))	('rs11134527', 'Mutation', 'rs11134527', (68, 78))	('decreased bladder cancer', 'Disease', (24, 48))	('decreased bladder cancer', 'Disease', 'MESH:D001749', (24, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('miR-26a-1', 'Gene', '407015', (14, 23))	('rs11134527/pri-miR-218', 'Var', (68, 90))	('women', 'Species', '9606', (57, 62))	('cervical carcinoma', 'Disease', 'MESH:D002575', (144, 162))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('Rs7372209', 'Mutation', 'Rs7372209', (0, 9))
97893	24945256	We have conducted a case-control study to investigate the potential association between rs531564/pri-miR-124-1, rs4938723/pri-miR-34b/c, rs7372209/pri-miR-26a-1, rs895819/pre-miR-27a, rs11134527/pri-miR-218 and the risk of ESCC.	('miR-124-1', 'Gene', '406907', (101, 110))	('miR-27a', 'Gene', '407018', (175, 182))	('miR-26a-1', 'Gene', (151, 160))	('miR-124-1', 'Gene', (101, 110))	('rs7372209', 'Mutation', 'rs7372209', (137, 146))	('rs4938723', 'Mutation', 'rs4938723', (112, 121))	('rs531564', 'Mutation', 'rs531564', (88, 96))	('miR-34b', 'Gene', (126, 133))	('ESCC', 'Disease', (223, 227))	('miR-26a-1', 'Gene', '407015', (151, 160))	('miR-34b', 'Gene', '407041', (126, 133))	('miR-27a', 'Gene', (175, 182))	('rs11134527', 'Mutation', 'rs11134527', (184, 194))	('rs11134527/pri-miR-218', 'Var', (184, 206))	('rs895819', 'Mutation', 'rs895819', (162, 170))
97906	24945256	All papers reporting the association between the SNPs of miRNA genes and cancer risks were retrieved.	('miRNA genes', 'Gene', (57, 68))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SNPs', 'Var', (49, 53))
97910	24945256	Finally, we selected these 5 candidate SNPs in our study, which are rs531564 in pri-miR-124-1, rs4938723 in pri-miR-34b/c, rs7372209 in pri-miR-26a-1, rs895819 in pre-miR-27a, and rs11134527 in pri-miR-218.	('miR-26a-1', 'Gene', (140, 149))	('rs895819', 'Var', (151, 159))	('miR-34b', 'Gene', (112, 119))	('rs531564', 'Var', (68, 76))	('miR-124-1', 'Gene', '406907', (84, 93))	('rs4938723', 'Mutation', 'rs4938723', (95, 104))	('rs7372209', 'Mutation', 'rs7372209', (123, 132))	('rs7372209', 'Var', (123, 132))	('miR-34b', 'Gene', '407041', (112, 119))	('miR-27a', 'Gene', (167, 174))	('rs531564', 'Mutation', 'rs531564', (68, 76))	('miR-124-1', 'Gene', (84, 93))	('rs895819', 'Mutation', 'rs895819', (151, 159))	('miR-26a-1', 'Gene', '407015', (140, 149))	('rs11134527', 'Mutation', 'rs11134527', (180, 190))	('rs4938723', 'Var', (95, 104))	('rs11134527', 'Var', (180, 190))	('miR-27a', 'Gene', '407018', (167, 174))
97914	24945256	The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by univariate and multivariate logistic regression analyses to determine associations between rs531564/pri-miR-124-1, rs4938723/pri-miR-34b/c, rs7372209/pri-miR-26a-1, rs895819/pre-miR-27a, rs11134527/pri-miR-218 genotypes and the risk of ESCC.	('rs11134527/pri-miR-218', 'Var', (263, 285))	('miR-124-1', 'Gene', '406907', (180, 189))	('rs11134527', 'Mutation', 'rs11134527', (263, 273))	('miR-34b', 'Gene', '407041', (205, 212))	('miR-27a', 'Gene', '407018', (254, 261))	('miR-124-1', 'Gene', (180, 189))	('miR-26a-1', 'Gene', '407015', (230, 239))	('associations', 'Interaction', (146, 158))	('ESCC', 'Disease', (312, 316))	('rs7372209', 'Mutation', 'rs7372209', (216, 225))	('rs4938723', 'Mutation', 'rs4938723', (191, 200))	('rs531564', 'Mutation', 'rs531564', (167, 175))	('rs895819', 'Mutation', 'rs895819', (241, 249))	('miR-27a', 'Gene', (254, 261))	('miR-26a-1', 'Gene', (230, 239))	('miR-34b', 'Gene', (205, 212))
97917	24945256	The genotype frequencies of pri-miR-124-1 rs531564 C>G were 72.4% (CC), 26.6% (CG), and 1.0% (GG) in the cases and 71.4% (CC), 26.0% (CG), and 2.6% (GG) in the controls, respectively; and the difference was statistically significant (p = 0.011).	('miR-124-1', 'Gene', '406907', (32, 41))	('CG', 'Chemical', 'MESH:C028505', (79, 81))	('miR-124-1', 'Gene', (32, 41))	('rs531564 C>G', 'Var', (42, 54))	('rs531564', 'Mutation', 'rs531564', (42, 50))	('CG', 'Chemical', 'MESH:C028505', (134, 136))
97918	24945256	In the recessive model, we found that the GG genotype of rs531564 was revealed to decrease the risk of ESCC (GG VS. CC/CG, p = 0.005, OR = 0.61, 95% CI = 0.43-0.86).	('CG', 'Chemical', 'MESH:C028505', (119, 121))	('rs531564', 'Var', (57, 65))	('decrease', 'NegReg', (82, 90))	('rs531564', 'Mutation', 'rs531564', (57, 65))	('ESCC', 'Disease', (103, 107))
97920	24945256	The genotype frequencies of pri-miR-34b/c rs4938723 T>C for TT, TC and CC were 44.1%, 48.3% and 7.6% in the cases and 44.6%, 44.9% and 10.5% in the controls respectively.	('miR-34b', 'Gene', (32, 39))	('miR-34b', 'Gene', '407041', (32, 39))	('TC', 'Chemical', 'MESH:D013667', (64, 66))	('rs4938723', 'Mutation', 'rs4938723', (42, 51))	('rs4938723 T>C', 'Var', (42, 55))
97923	24945256	However, other polymorphisms, pri-miR-26-1 rs7372209 G>A, pre-miR-27a rs895819 A>G and pri-miR-218 rs11134527 T>C, did not demonstrate any associations with the risk of ESCC in the codominant, dominant, recessive or overdominant models.	('rs7372209 G>A', 'Var', (43, 56))	('ESCC', 'Disease', (169, 173))	('rs7372209', 'Mutation', 'rs7372209', (43, 52))	('miR-27a', 'Gene', '407018', (62, 69))	('rs11134527', 'Mutation', 'rs11134527', (99, 109))	('rs11134527 T>C', 'Var', (99, 113))	('rs895819 A>G', 'Var', (70, 82))	('miR-27a', 'Gene', (62, 69))	('rs895819', 'Mutation', 'rs895819', (70, 78))
97924	24945256	To further evaluate the associations between pri-miR-124-1 rs531564 C>G, pri-miR-34b/c rs4938723 T>C and ESCC risk, respectively, we performed the stratification analyses in the recessive model according to age, sex, smoking and drinking (Table 4 and Table 5).	('rs4938723 T>C', 'Var', (87, 100))	('miR-34b', 'Gene', (77, 84))	('miR-124-1', 'Gene', '406907', (49, 58))	('associations', 'Interaction', (24, 36))	('miR-124-1', 'Gene', (49, 58))	('miR-34b', 'Gene', '407041', (77, 84))	('rs4938723', 'Mutation', 'rs4938723', (87, 96))	('rs531564 C>G', 'Var', (59, 71))	('rs531564', 'Mutation', 'rs531564', (59, 67))
97925	24945256	A significantly decreased risk of ESCC was observed with pri-miR-124-1 rs531564 GG genotype from Table 4 in patients who were older than 62 years (p = 0.010, OR = 0.52, 95% CI = 0.32-0.86), no drinking (p = 0.004, OR = 0.41, 95% CI = 0.23-0.75) or no smoking (p = 0.026, OR = 0.43, 95% CI = 0.21-0.91).	('patients', 'Species', '9606', (108, 116))	('miR-124-1', 'Gene', '406907', (61, 70))	('rs531564', 'Mutation', 'rs531564', (71, 79))	('ESCC', 'Disease', (34, 38))	('miR-124-1', 'Gene', (61, 70))	('rs531564 GG', 'Var', (71, 82))	('decreased', 'NegReg', (16, 25))
97926	24945256	Female patients with miR-124-1 rs531564 GG genotype were associated with a borderline statistically decreased ESCC risk (p = 0.051, OR = 0.36, 95% CI = 0.13-1.01).	('miR-124-1', 'Gene', (21, 30))	('decreased ESCC', 'Phenotype', 'HP:0025022', (100, 114))	('rs531564 GG', 'Var', (31, 42))	('decreased', 'NegReg', (100, 109))	('ESCC', 'Disease', (110, 114))	('miR-124-1', 'Gene', '406907', (21, 30))	('rs531564', 'Mutation', 'rs531564', (31, 39))	('patients', 'Species', '9606', (7, 15))
97927	24945256	As shown in Table 5, significant associations between pri-miR-34b/c rs4938723 CC genotype and ESCC risks were found in the following subgroups, older than 62 years (p = 0.016, OR = 0.79, 95% CI = 0.65-0.96), males (p = 0.033, OR = 0.84, 95% CI = 0.71-0.99) and smokers (p = 0.026, OR = 0.81, 95% CI = 0.68-0.98).	('rs4938723', 'Mutation', 'rs4938723', (68, 77))	('miR-34b', 'Gene', (58, 65))	('miR-34b', 'Gene', '407041', (58, 65))	('ESCC', 'Disease', (94, 98))	('rs4938723 CC', 'Var', (68, 80))
97928	24945256	We found that two SNPs, rs531564 in pri-miR-124-1 and rs4938723 in pri-miR-34b/c, were associated with a significant decreased risk of ESCC.	('ESCC', 'Disease', (135, 139))	('miR-34b', 'Gene', (71, 78))	('miR-34b', 'Gene', '407041', (71, 78))	('decreased', 'NegReg', (117, 126))	('rs4938723', 'Var', (54, 63))	('miR-124-1', 'Gene', '406907', (40, 49))	('miR-124-1', 'Gene', (40, 49))	('rs531564', 'Var', (24, 32))	('rs4938723', 'Mutation', 'rs4938723', (54, 63))	('rs531564', 'Mutation', 'rs531564', (24, 32))
97929	24945256	Recent research showed that the microRNA miR-124 might play an important role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('microRNA miR-124', 'Var', (32, 48))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
97930	24945256	Some case-control studies have concentrated on the relationship between the rs531564 in pri-miR-124-1 polymorphism and the cancer risk, such as bladder cancer and esophageal cancer (mainly type is EADC).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('rs531564', 'Mutation', 'rs531564', (76, 84))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('bladder cancer', 'Disease', (144, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('cancer', 'Disease', (152, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (174, 180))	('esophageal cancer', 'Disease', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('EADC', 'Phenotype', 'HP:0011459', (197, 201))	('rs531564', 'Var', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('miR-124-1', 'Gene', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('miR-124-1', 'Gene', '406907', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', (123, 129))
97931	24945256	However, the relationship between pri-miR-124-1 rs531564 polymorphism and ESCC risk has not been reported till now.	('ESCC', 'Disease', (74, 78))	('rs531564', 'Mutation', 'rs531564', (48, 56))	('miR-124-1', 'Gene', '406907', (38, 47))	('rs531564', 'Var', (48, 56))	('miR-124-1', 'Gene', (38, 47))
97932	24945256	In this case-control study, we found that the GG genotype of the pri-miR-124-1 rs531564 polymorphism is associated with significantly decreased ESCC risk in the recessive model.	('decreased', 'NegReg', (134, 143))	('miR-124-1', 'Gene', (69, 78))	('ESCC', 'Disease', (144, 148))	('decreased ESCC', 'Phenotype', 'HP:0025022', (134, 148))	('rs531564', 'Var', (79, 87))	('miR-124-1', 'Gene', '406907', (69, 78))	('rs531564', 'Mutation', 'rs531564', (79, 87))
97933	24945256	These results suggest that the GG genotype in rs531564 is a protective factor for ESCC in the Chinese population.	('ESCC', 'Disease', (82, 86))	('rs531564', 'Var', (46, 54))	('rs531564', 'Mutation', 'rs531564', (46, 54))
97935	24945256	showed that miR-124 directly targets polypyrimidine tract-binding protein 1 (PTBP1) mRNA, which encodes a global repressor of alternative pre-mRNA splicing in non-neuronal cells.	('PTBP1', 'Gene', '5725', (77, 82))	('miR-124', 'Var', (12, 19))	('PTBP1', 'Gene', (77, 82))	('polypyrimidine tract-binding protein 1', 'Gene', (37, 75))	('polypyrimidine tract-binding protein 1', 'Gene', '5725', (37, 75))
97937	24945256	Another study demonstrated that knockdown of PTBP1 expression by siRNA impairs the growth of ovarian tumor cells and diminishes their malignant potential, indicating that overexpression of PTBP1 can be an important component of a multistep process of carcinogenesis.	('PTBP1', 'Gene', (189, 194))	('ovarian tumor', 'Disease', 'MESH:D010051', (93, 106))	('PTBP1', 'Gene', '5725', (45, 50))	('PTBP1', 'Gene', (45, 50))	('diminishes', 'NegReg', (117, 127))	('growth', 'CPA', (83, 89))	('knockdown', 'Var', (32, 41))	('carcinogenesis', 'Disease', 'MESH:D063646', (251, 265))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('carcinogenesis', 'Disease', (251, 265))	('PTBP1', 'Gene', '5725', (189, 194))	('ovarian tumor', 'Disease', (93, 106))	('ovarian tumor', 'Phenotype', 'HP:0100615', (93, 106))	('impairs', 'NegReg', (71, 78))	('malignant potential', 'CPA', (134, 153))
97938	24945256	These previous findings and the results of the present study characterize a potential mechanism of pri-miR-124-1 rs531564 in carcinogenesis as follows: First, the rs531564 GG genotype may promote the expression of miR-124, which is a cancer suppressor.	('miR-124', 'Gene', (214, 221))	('rs531564', 'Mutation', 'rs531564', (163, 171))	('miR-124-1', 'Gene', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('promote', 'PosReg', (188, 195))	('carcinogenesis', 'Disease', (125, 139))	('rs531564', 'Var', (113, 121))	('miR-124-1', 'Gene', '406907', (103, 112))	('rs531564', 'Mutation', 'rs531564', (113, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('rs531564 GG', 'Var', (163, 174))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('expression', 'MPA', (200, 210))	('cancer', 'Disease', (234, 240))
97939	24945256	Second, miR-124 may subsequently target PTBP1, which acts as an oncogene, and decrease its expression.	('expression', 'MPA', (91, 101))	('decrease', 'NegReg', (78, 86))	('PTBP1', 'Gene', '5725', (40, 45))	('miR-124', 'Var', (8, 15))	('PTBP1', 'Gene', (40, 45))	('target', 'Reg', (33, 39))
97940	24945256	We observe that pri-miR-124-1 rs531564 GG polymorphism has more significant effects on decreasing ESCC risks in subgroups of elderly persons, females, no drinking and no smoking people.	('miR-124-1', 'Gene', (20, 29))	('people', 'Species', '9606', (178, 184))	('rs531564 GG', 'Var', (30, 41))	('persons', 'Species', '9606', (133, 140))	('decreasing ESCC', 'Phenotype', 'HP:0025022', (87, 102))	('ESCC', 'Disease', (98, 102))	('rs531564', 'Mutation', 'rs531564', (30, 38))	('miR-124-1', 'Gene', '406907', (20, 29))	('decreasing', 'NegReg', (87, 97))
97941	24945256	For example, as smoking and drinking are the main risk factors for ESCC, the effect of rs531564 GG type was no longer significant in smoking or drinking group of decreasing the ESCC risks.	('ESCC', 'Disease', (177, 181))	('rs531564', 'Var', (87, 95))	('rs531564', 'Mutation', 'rs531564', (87, 95))	('ESCC', 'Disease', (67, 71))
97942	24945256	We noticed that one case-control study showed that rs531564 variant carriers have increased risks for esophageal cancer in Caucasian population.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('rs531564', 'Var', (51, 59))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('rs531564', 'Mutation', 'rs531564', (51, 59))
97943	24945256	In this study, we also checked the relationship between pri-miR-34b/c rs4938723 C/T polymorphism and the ESCC risk.	('ESCC', 'Disease', (105, 109))	('miR-34b', 'Gene', (60, 67))	('checked', 'Reg', (23, 30))	('miR-34b', 'Gene', '407041', (60, 67))	('rs4938723 C/T', 'Var', (70, 83))	('rs4938723', 'Mutation', 'rs4938723', (70, 79))
97947	24945256	The rs4938723 C/T polymorphism, located within the CpG island of pri-miR-34b/c, were reported to be associated with risks of many kinds of cancer.	('miR-34b', 'Gene', '407041', (69, 76))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('rs4938723 C/T', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('associated', 'Reg', (100, 110))	('rs4938723', 'Mutation', 'rs4938723', (4, 13))	('miR-34b', 'Gene', (69, 76))	('cancer', 'Disease', (139, 145))
97949	24945256	These findings suggest that the C allele of pri-miR-34b/c rs4938723 may be a risk factor for the development of hepatocellular carcinoma and nasopharyngeal carcinoma.	('rs4938723', 'Var', (58, 67))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (141, 165))	('miR-34b', 'Gene', '407041', (48, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('nasopharyngeal carcinoma', 'Disease', (141, 165))	('risk', 'Reg', (77, 81))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (141, 165))	('rs4938723', 'Mutation', 'rs4938723', (58, 67))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('miR-34b', 'Gene', (48, 55))	('hepatocellular carcinoma', 'Disease', (112, 136))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))
97950	24945256	However, in the current study, we found that in the recessive model, CC genotype of pri-miR-34b/c rs4938723 was associated with a significant decreased risk of ESCC.	('rs4938723', 'Mutation', 'rs4938723', (98, 107))	('miR-34b', 'Gene', (88, 95))	('miR-34b', 'Gene', '407041', (88, 95))	('decreased', 'NegReg', (142, 151))	('rs4938723', 'Var', (98, 107))
97951	24945256	Several other studies have also examined the relationship between pri-miR-34b/c rs4938723 and the cancer risk, and obtained results similar to ours.	('miR-34b', 'Gene', '407041', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs4938723', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('miR-34b', 'Gene', (70, 77))	('cancer', 'Disease', (98, 104))	('rs4938723', 'Mutation', 'rs4938723', (80, 89))	('examined', 'Reg', (32, 40))
97952	24945256	For example, compared with the TT genotype, CC genotype of pri-miR-34b/c rs4938723 was found associated with a significant decreased risk of colorectal cancer.	('rs4938723', 'Var', (73, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('decreased', 'NegReg', (123, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('rs4938723', 'Mutation', 'rs4938723', (73, 82))	('colorectal cancer', 'Disease', (141, 158))	('miR-34b', 'Gene', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('miR-34b', 'Gene', '407041', (63, 70))
97954	24945256	The possible reason for different results may be that the same variation in microRNA plays different roles in different types of cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('variation', 'Var', (63, 72))	('roles', 'Reg', (101, 106))	('microRNA', 'MPA', (76, 84))
98101	23101584	The 10 TFBSs that make these cTFBSs are determined by the following TRANSFAC identifiers V$ELK1_01, V$CETS1P54_01, V$YY1_01, V$GATA3_01, V$TAXCREB_02, V$FREAC4_01, V$AREB6_01, V$CREB_Q3, V$E2A_Q6 and V$EBOX_Q6_01.	('V$YY1_01', 'Var', (115, 123))	('GATA3', 'Gene', '2625', (127, 132))	('C4', 'Gene', '720', (157, 159))	('AREB6', 'Gene', (166, 171))	('V$ELK1_01', 'Var', (89, 98))	('CREB', 'Gene', '1385', (142, 146))	('CREB', 'Gene', (142, 146))	('CREB', 'Gene', (178, 182))	('ETS1', 'Gene', (103, 107))	('ETS1', 'Gene', '2113', (103, 107))	('V$EBOX_Q6_01', 'Var', (200, 212))	('V$E2A_Q6', 'Var', (187, 195))	('CREB', 'Gene', '1385', (178, 182))	('GATA3', 'Gene', (127, 132))	('cTFBSs', 'Chemical', '-', (29, 35))	('AREB6', 'Gene', '6935', (166, 171))
98131	23101584	"p53 signaling pathway" (hsa04115), "Bladder cancer" (hsa05219), "Small cell lung cancer" (hsa05222).	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Small cell lung cancer', 'Disease', (66, 88))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Small cell lung cancer', 'Phenotype', 'HP:0030357', (66, 88))	('hsa04115', 'Var', (25, 33))	('Bladder cancer', 'Disease', 'MESH:D001749', (37, 51))	('Bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))	('p53', 'Gene', (1, 4))	('p53', 'Gene', '7157', (1, 4))	('Bladder cancer', 'Disease', (37, 51))	('Small cell lung cancer', 'Disease', 'MESH:D055752', (66, 88))
98140	23101584	The most significant cTFBS comprised of the following TRANSFAC identifiers: V$TAXCREB_02, V$AREB6_01, V$CREB_Q3 and V$E2A_Q6.	('V$E2A_Q6', 'Var', (116, 124))	('CREB', 'Gene', (81, 85))	('AREB6', 'Gene', '6935', (92, 97))	('CREB', 'Gene', (104, 108))	('CREB', 'Gene', '1385', (81, 85))	('CREB', 'Gene', '1385', (104, 108))	('AREB6', 'Gene', (92, 97))	('cTFBS', 'Chemical', '-', (21, 26))
98155	23101584	Interestingly, one group has reported that their unbiased sequence interrogation of the genuine chromatin binding sites suggests that direct ER binding requires the presence of foxa1 binding in close proximity, as knockdown of FoxA1 expression blocked the association of ER with the chromatin and estrogen induced gene expression.	('ER', 'Gene', '2099', (271, 273))	('ER', 'Gene', '2099', (141, 143))	('knockdown', 'Var', (214, 223))	('binding', 'Interaction', (144, 151))	('FoxA1', 'Gene', '3169', (227, 232))	('foxa1', 'Gene', (177, 182))	('FoxA1', 'Gene', (227, 232))	('association', 'Interaction', (256, 267))	('blocked', 'NegReg', (244, 251))	('foxa1', 'Gene', '3169', (177, 182))
98168	23101584	Moreover, the p38 MAPK inhibitor SB202190 abrogates ERbeta activity by AKAP13 indicating that AKAP13 activates ERbeta via the p38 MAPK pathway.	('ERbeta', 'Gene', (111, 117))	('p38', 'Gene', (14, 17))	('SB202190', 'Var', (33, 41))	('activates', 'PosReg', (101, 110))	('AKAP13', 'Gene', '11214', (94, 100))	('AKAP13', 'Gene', '11214', (71, 77))	('AKAP13', 'Gene', (94, 100))	('p38', 'Gene', '1432', (126, 129))	('ERbeta', 'Gene', '2100', (52, 58))	('ERbeta', 'Gene', '2100', (111, 117))	('AKAP13', 'Gene', (71, 77))	('p38', 'Gene', '1432', (14, 17))	('SB202190', 'Chemical', 'MESH:C090942', (33, 41))	('abrogates', 'NegReg', (42, 51))	('p38', 'Gene', (126, 129))	('ERbeta', 'Gene', (52, 58))
98225	21108842	In China, a meta-analysis revealed that high percentages of cervical cancer cases mainly attributed to the 3 most frequent high-risk types of HPV (HR-HPV): HPV-16 is involved in more than half of the cervical cancer cases, and HPV-18 and -58, approximately 11.0% and 7.2%, respectively.	('cervical cancer', 'Disease', (60, 75))	('cervical cancer', 'Disease', 'MESH:D002583', (60, 75))	('HPV', 'Species', '10566', (227, 230))	('HPV', 'Species', '10566', (142, 145))	('HPV-16', 'Species', '333760', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('HPV', 'Species', '10566', (156, 159))	('HR-HPV', 'Disease', 'MESH:D030361', (147, 153))	('cervical cancer', 'Disease', (200, 215))	('HPV', 'Species', '10566', (150, 153))	('involved', 'Reg', (166, 174))	('HR-HPV', 'Disease', (147, 153))	('HPV-16', 'Var', (156, 162))	('cervical cancer', 'Disease', 'MESH:D002583', (200, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
98227	21108842	In addition, the disruption of the HPV E2 gene during viral integration, which results in a loss of its function as a regulator of viral oncogene expression and subsequent upregulation of E6/E7 gene transcription, may initiate cell transformation and immortality by deregulating the tumor suppressor gene products p53 and retinoblastoma protein.	('cell transformation', 'CPA', (227, 246))	('upregulation', 'PosReg', (172, 184))	('p53', 'Protein', (314, 317))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('transcription', 'MPA', (199, 212))	('HPV', 'Species', '10566', (35, 38))	('E6/E7', 'Gene', '25479186', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('E6/E7', 'Gene', (188, 193))	('retinoblastoma', 'Disease', (322, 336))	('immortality', 'CPA', (251, 262))	('tumor', 'Disease', (283, 288))	('disruption', 'Var', (17, 27))	('HPV E2', 'Gene', (35, 41))	('initiate', 'Reg', (218, 226))	('retinoblastoma', 'Disease', 'MESH:D012175', (322, 336))	('retinoblastoma', 'Phenotype', 'HP:0009919', (322, 336))	('deregulating', 'NegReg', (266, 278))
98269	21108842	The detection rates for total infection with HPV-16, -18 and -58 DNA in ESCC or CSCC tissue were significantly higher than those of their corresponding controls: 50.00% vs. 33.33% for ESCC, P = 0.045; and 79.48% vs. 18.52% for CSCC, P < 0.001.	('infection', 'Disease', (30, 39))	('infection', 'Disease', 'MESH:D007239', (30, 39))	('HPV-16', 'Var', (45, 51))	('HPV-16', 'Species', '333760', (45, 51))	('higher', 'PosReg', (111, 117))	('ESCC', 'Disease', (184, 188))
98277	21108842	However, ESCC patients and controls did not differ in mean ratio of E2 to E6/7 for HPV-16, -18 and -58 (0.20 +- 0.32 vs. 0.53 +- 0.33, P = 0.06, also see Table 3).	('ESCC', 'Disease', (9, 13))	('HPV-16', 'Gene', (83, 89))	('E6/7', 'Var', (74, 78))	('patients', 'Species', '9606', (14, 22))	('HPV-16', 'Species', '333760', (83, 89))
98278	21108842	Moreover, for CSCC patients, the mean ratios of E2 to E6/7 for HPV-16, -18 and -58 were 0.03 +- 0.08, 0.06 +- 0.10 and 0.12 +- 0.18, respectively, with no significant difference in HPV ratios (P = 0.229); similar results were found for ESCC patients and controls and CSCC controls.	('HPV', 'Species', '10566', (181, 184))	('patients', 'Species', '9606', (19, 27))	('HPV', 'Species', '10566', (63, 66))	('ESCC', 'Disease', (236, 240))	('HPV-16', 'Gene', (63, 69))	('CSCC', 'Disease', (14, 18))	('E6/7', 'Var', (54, 58))	('patients', 'Species', '9606', (241, 249))	('HPV-16', 'Species', '333760', (63, 69))
98311	21108842	Although the direct evidence of HPV-16 transcription and expression derived from integrated HPV DNA is still unclear, from previous studies, HPV E6- and E7-encoding cDNAs derived from integrated viral oncogene transcripts have a much stronger transforming capacity in primary cells than cDNAs derived from episome-derived transcripts.	('transforming capacity', 'CPA', (243, 264))	('HPV', 'Species', '10566', (141, 144))	('HPV-16', 'Species', '333760', (32, 38))	('HPV', 'Gene', (141, 144))	('E7-encoding', 'Var', (153, 164))	('stronger', 'PosReg', (234, 242))	('HPV', 'Species', '10566', (32, 35))	('HPV', 'Species', '10566', (92, 95))	('E6-', 'Var', (145, 148))
98349	19902005	Due to their longevity and self-renewing properties "cancer stem cells," a small subgroup of cells in malignant tumors, have a greater propensity to accumulate these carcinogenic mutations.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('malignant tumors', 'Disease', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('malignant tumors', 'Disease', 'MESH:D018198', (102, 118))	('mutations', 'Var', (179, 188))	('carcinogenic', 'Disease', 'MESH:D063646', (166, 178))	('carcinogenic', 'Disease', (166, 178))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
98381	19902005	However, given the recent focus on how k-ras mutations affect clinical outcome in metastatic colorectal cancer and anti-EGFR therapy with cetuximab, evaluation of patients for mutations in k-ras is rapidly becoming part of routine practice in clinical oncology and had so far mostly relied on formalin-fixed paraffin-embedded (FFPE) tumor tissue.	('k-ras', 'Gene', '3845', (189, 194))	('mutations', 'Var', (176, 185))	('affect', 'Reg', (55, 61))	('oncology', 'Phenotype', 'HP:0002664', (252, 260))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('k-ras', 'Gene', (39, 44))	('k-ras', 'Gene', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('formalin', 'Chemical', 'MESH:D005557', (293, 301))	('EGFR', 'Gene', (120, 124))	('patients', 'Species', '9606', (163, 171))	('cetuximab', 'Chemical', 'MESH:D000068818', (138, 147))	('colorectal cancer', 'Disease', (93, 110))	('tumor', 'Disease', (333, 338))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('k-ras', 'Gene', '3845', (39, 44))	('EGFR', 'Gene', '1956', (120, 124))	('paraffin', 'Chemical', 'MESH:D010232', (308, 316))
98382	19902005	Testing of circulating tumor DNA in peripheral blood to screen for mutations resident in the parent tumor (blood biopsy) is unencumbered by many of the factors that limit testing of FFPE-derived specimens.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('mutations', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('parent tumor', 'Disease', 'MESH:D063129', (93, 105))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('parent tumor', 'Disease', (93, 105))
98383	19902005	Accordingly, tests for circulating tumor DNA are able to screen for mutations, such as for mutations of the k-ras oncogene and are present at the time of treatment unlike tests that rely on archived tissue samples that were acquired previously.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('k-ras', 'Gene', '3845', (108, 113))	('tumor', 'Disease', (35, 40))	('k-ras', 'Gene', (108, 113))	('mutations', 'Var', (91, 100))
98388	19902005	Fifty percent of patients with R > 0.4 (R = CTC ratio of B + 3 over B0) showed tumor recurrence within 1 year after surgery, whereas the probability was only 14.3% for patients with R < 0.4 (P = .043).	('R > 0.4', 'Var', (31, 38))	('tumor', 'Disease', (79, 84))	('B + 3', 'Gene', '28908', (57, 62))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (168, 176))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('B + 3', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
98406	19902005	Furthermore, the authors found that gastric cancer patients with high levels of CEA were more likely to develop systemic disease.	('systemic disease', 'Disease', 'MESH:D034721', (112, 128))	('CEA', 'Gene', '1048', (80, 83))	('gastric cancer', 'Disease', (36, 50))	('develop', 'PosReg', (104, 111))	('systemic disease', 'Disease', (112, 128))	('high levels', 'Var', (65, 76))	('CEA', 'Gene', (80, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('patients', 'Species', '9606', (51, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
98431	31963204	Induction of apoptosis is associated with modulation of BCL-2, BAX, PARP, cytochrome c, and cleaved caspase-3, -8, and -9, while cell cycle arrest is controlled by cyclin D1, c-Myc, p21, p53, and CDK-2 and -4.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (129, 146))	('PARP', 'Gene', '142', (68, 72))	('c-Myc', 'Gene', (175, 180))	('p21', 'Gene', (182, 185))	('modulation', 'Var', (42, 52))	('PARP', 'Gene', (68, 72))	('BAX', 'Gene', (63, 66))	('BCL-2', 'Gene', '596', (56, 61))	('apoptosis', 'CPA', (13, 22))	('BAX', 'Gene', '581', (63, 66))	('cytochrome c', 'Gene', (74, 86))	('BCL-2', 'Gene', (56, 61))	('c-Myc', 'Gene', '4609', (175, 180))	('caspase-3', 'Gene', '836', (100, 109))	('p21', 'Gene', '1026', (182, 185))	('cyclin D1', 'Gene', (164, 173))	('cell cycle arrest', 'CPA', (129, 146))	('caspase-3', 'Gene', (100, 109))	('cyclin D1', 'Gene', '595', (164, 173))	('cytochrome c', 'Gene', '54205', (74, 86))
98493	31963204	Ponicidin (C20H26O6, MW: 362.42, Figure 2) was isolated from Isodon rubescens and I. japonicas, and showed cytotoxic activity against the human carcinoma cell lines K562 (leukemia), Bcap37 (breast), GC823 (gastric), BIU87 (bladder), HeLa (cervical) and PC-3 (prostate) cells.	('Bcap37', 'Gene', '11331', (182, 188))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('Bcap37', 'Gene', (182, 188))	('carcinoma', 'Disease', (144, 153))	('leukemia', 'Disease', 'MESH:D007938', (171, 179))	('C20H26O6', 'Chemical', '-', (11, 19))	('Ponicidin', 'Chemical', 'MESH:C090365', (0, 9))	('leukemia', 'Disease', (171, 179))	('human', 'Species', '9606', (138, 143))	('carcinoma', 'Disease', 'MESH:D002277', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('Isodon rubescens', 'Species', '587669', (61, 77))	('cytotoxic activity', 'CPA', (107, 125))	('C20H26O6', 'Var', (11, 19))
98497	31963204	Pharicins A (C24H34O7, MW: 434.53, Figure 2) and B (C24H34O8, MW: 450.53) were isolated from Isodon pharicus.	('Pharicins A', 'Chemical', 'MESH:C555529', (0, 11))	('Isodon pharicus', 'Species', '204134', (93, 108))	('C24H34O7', 'Chemical', '-', (13, 21))	('C24H34O8', 'Chemical', '-', (52, 60))	('C24H34O7', 'Var', (13, 21))	('C24H34O8', 'Var', (52, 60))
98498	31963204	The only structural difference between these two compounds is the position of hydroxyl group which is located at C-1 in pharicin A and at C-12 in pharicin B. Pharicin A induced mitotic arrest in leukemia cell line Jurkat and solid tumor-derived cell line raji by inhibiting auto phosphorylation activity of BubR1.	('C-1', 'Gene', '6966', (138, 141))	('auto phosphorylation activity', 'MPA', (274, 303))	('Pharicin A', 'Chemical', 'MESH:C555529', (158, 168))	('C-1', 'Gene', '6966', (113, 116))	('pharicin A', 'Chemical', 'MESH:C555529', (120, 130))	('BubR1', 'Gene', (307, 312))	('tumor', 'Disease', (231, 236))	('pharicin B', 'Chemical', 'MESH:C554739', (146, 156))	('inhibiting', 'NegReg', (263, 273))	('mitotic arrest', 'Disease', 'MESH:D006323', (177, 191))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('leukemia', 'Phenotype', 'HP:0001909', (195, 203))	('Pharicin A', 'Var', (158, 168))	('C-1', 'Gene', (138, 141))	('leukemia', 'Disease', 'MESH:D007938', (195, 203))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('leukemia', 'Disease', (195, 203))	('C-1', 'Gene', (113, 116))	('mitotic arrest', 'Disease', (177, 191))	('BubR1', 'Gene', '701', (307, 312))
98501	31963204	Moreover, pharicin B also increased ATRA-dependent transcriptional activity of RAR-alpha protein in NB4 cells, a type of promyelocytic leukemia-RAR-alpha-positive APL cell line.	('RAR-alpha', 'Gene', (144, 153))	('ATRA', 'Chemical', 'MESH:D014212', (36, 40))	('APL', 'Phenotype', 'HP:0004836', (163, 166))	('ATRA-dependent transcriptional activity', 'MPA', (36, 75))	('RAR-alpha', 'Gene', (79, 88))	('APL', 'Disease', (163, 166))	('APL', 'Disease', 'MESH:D015473', (163, 166))	('RAR-alpha', 'Gene', '5914', (144, 153))	('pharicin B', 'Chemical', 'MESH:C554739', (10, 20))	('increased', 'PosReg', (26, 35))	('pharicin', 'Var', (10, 18))	('leukemia', 'Disease', (135, 143))	('leukemia', 'Disease', 'MESH:D007938', (135, 143))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))	('RAR-alpha', 'Gene', '5914', (79, 88))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (121, 143))
98507	31963204	Jungermannenones A (C20H28O2, MW: 300.44, Figure 2) and B (C20H28O3, MW: 316.44, Figure 2) were isolated from Jungermannia fauriana, and exhibited cancer cell killing activity in multiple cell lines.	('Jungermannia fauriana', 'Disease', '-', (110, 131))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('C20H28O2', 'Var', (20, 28))	('C20H28O3', 'Chemical', '-', (59, 67))	('Jungermannenones A', 'Chemical', '-', (0, 18))	('C20H28O2', 'Chemical', '-', (20, 28))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('Jungermannia fauriana', 'Disease', (110, 131))
98516	31963204	In vivo studies found longikaurin A treatment (6 mg/kg) significantly suppressed tumor development (p < 0.01) in a SMMC-7721 xenograft mouse model study and the antitumor effect was comparable to the positive control 5-FU (fluorouracil) (10 mg/kg).	('longikaurin A', 'Chemical', 'MESH:C581034', (22, 35))	('5-FU', 'Chemical', 'MESH:D005472', (217, 221))	('longikaurin', 'Var', (22, 33))	('mouse', 'Species', '10090', (135, 140))	('suppressed', 'NegReg', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('fluorouracil', 'Chemical', 'MESH:D005472', (223, 235))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (165, 170))
98519	31963204	In nasopharyngeal carcinoma (NPC) cell lines S18 and S26, longikaurin A exerted anticancer activity and suppressed the stemness of cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('nasopharyngeal carcinoma', 'Disease', (3, 27))	('stemness', 'Disease', 'MESH:D020295', (119, 127))	('stemness', 'Disease', (119, 127))	('cancer', 'Disease', (84, 90))	('longikaurin A', 'Chemical', 'MESH:C581034', (58, 71))	('NPC', 'Phenotype', 'HP:0100630', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('suppressed', 'NegReg', (104, 114))	('longikaurin', 'Var', (58, 69))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (3, 27))
98521	31963204	At a low concentration (0.2 muM), longikaurin A induced S phase arrest while at a higher concentration (3.12 muM) it induced apoptosis in human NPC cell lines CNE1 and CNE2 cells.	('muM', 'Gene', (109, 112))	('muM', 'Gene', '56925', (28, 31))	('longikaurin A', 'Chemical', 'MESH:C581034', (34, 47))	('human', 'Species', '9606', (138, 143))	('muM', 'Gene', (28, 31))	('S phase arrest', 'MPA', (56, 70))	('apoptosis', 'CPA', (125, 134))	('longikaurin', 'Var', (34, 45))	('muM', 'Gene', '56925', (109, 112))	('induced', 'Reg', (117, 124))	('NPC', 'Phenotype', 'HP:0100630', (144, 147))
98523	31963204	In CNE2 xenograft model, longikaurin A significantly suppressed tumor growth without affecting the body weights of the mice.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mice', 'Species', '10090', (119, 123))	('tumor', 'Disease', (64, 69))	('longikaurin A', 'Chemical', 'MESH:C581034', (25, 38))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('longikaurin', 'Var', (25, 36))	('suppressed', 'NegReg', (53, 63))
98526	31963204	In MCF-7 and Hs578T breast cancer cells, glaucocalyxin A induced apoptosis, and G2/M phase arrest by increasing the expression of intrinsic apoptotic markers cleaved caspase-3, BAX, and p53, while decreasing BCL-2 expression.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('decreasing', 'NegReg', (197, 207))	('p53', 'Gene', (186, 189))	('caspase-3', 'Gene', '836', (166, 175))	('BCL-2', 'Gene', '596', (208, 213))	('glaucocalyxin A', 'Chemical', 'MESH:C055124', (41, 56))	('BCL-2', 'Gene', (208, 213))	('caspase-3', 'Gene', (166, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('G2/M phase arrest', 'CPA', (80, 97))	('expression', 'MPA', (214, 224))	('cleaved', 'Var', (158, 165))	('increasing', 'PosReg', (101, 111))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('apoptosis', 'CPA', (65, 74))	('Hs578T', 'CellLine', 'CVCL:0332;0.012232559084836017', (13, 19))	('expression', 'MPA', (116, 126))	('glaucocalyxin A', 'Gene', (41, 56))	('BAX', 'Gene', '581', (177, 180))	('BAX', 'Gene', (177, 180))
98534	31963204	Lasiodin (C22H30O7, MW: 406.48, Figure 2) was isolated from Isodon serra, and inhibited the proliferation and migration of human nasopharyngeal carcinoma cells CNE1 (IC50: ~6 muM) and CNE2 (IC50: ~5 muM) at 24 h incubation.	('muM', 'Gene', '56925', (199, 202))	('inhibited', 'NegReg', (78, 87))	('migration', 'CPA', (110, 119))	('muM', 'Gene', (175, 178))	('human', 'Species', '9606', (123, 128))	('muM', 'Gene', (199, 202))	('C22H30O7', 'Var', (10, 18))	('C22H30O7', 'Chemical', '-', (10, 18))	('Isodon serra', 'Species', '199544', (60, 72))	('Lasiodin', 'Chemical', 'MESH:C000594471', (0, 8))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (129, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('nasopharyngeal carcinoma', 'Disease', (129, 153))	('proliferation', 'CPA', (92, 105))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (129, 153))	('muM', 'Gene', '56925', (175, 178))
98557	31963204	Another study reported weisinensis B-mediated induction of apoptosis, G2/M phase arrest, and significant ROS generation in human chronic myeloid leukemia K562 cells.	('ROS', 'Chemical', 'MESH:D017382', (105, 108))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (129, 153))	('ROS generation', 'MPA', (105, 119))	('myeloid leukemia', 'Disease', 'MESH:D007951', (137, 153))	('human', 'Species', '9606', (123, 128))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (137, 153))	('apoptosis', 'CPA', (59, 68))	('G2/M phase arrest', 'CPA', (70, 87))	('leukemia', 'Phenotype', 'HP:0001909', (145, 153))	('weisinensis', 'Var', (23, 34))	('myeloid leukemia', 'Disease', (137, 153))
98562	31963204	Moreover, inhibitory effects of inflexinol on the growth of colon cancer cells were related to inactivation of NF-kappaB by modification of a cysteine residue in the p50 subunit.	('p50', 'Gene', (166, 169))	('p50', 'Gene', '4790', (166, 169))	('cysteine', 'Chemical', 'MESH:D003545', (142, 150))	('colon cancer', 'Disease', 'MESH:D015179', (60, 72))	('colon cancer', 'Phenotype', 'HP:0003003', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cysteine', 'Protein', (142, 150))	('colon cancer', 'Disease', (60, 72))	('NF-kappaB', 'Gene', '4790', (111, 120))	('inactivation', 'NegReg', (95, 107))	('modification', 'Var', (124, 136))	('inflexinol', 'Chemical', 'MESH:C530049', (32, 42))	('NF-kappaB', 'Gene', (111, 120))
98569	31963204	Henryin (C22H32O6, MW: 392.49, Figure 2) was isolated from Isodon rubescens, and inhibited the proliferation of colorectal cancer SW480 (IC50: 0.27 muM), HT-29 (IC50: 0.77 muM), and HCT-116 cells (IC50: 0.90 muM), and lung cancer A549 cells (IC50: 2.47 muM), but is slightly less toxic to normal colon cells CCD-841-CoN (IC50: 2.98 muM) and normal bronchus cells BEAS-2B (IC50: 3.55 muM).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('C22H32O6', 'Var', (9, 17))	('lung cancer', 'Disease', 'MESH:D008175', (218, 229))	('proliferation', 'CPA', (95, 108))	('colorectal cancer', 'Disease', (112, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('muM', 'Gene', '56925', (383, 386))	('muM', 'Gene', '56925', (208, 211))	('muM', 'Gene', (208, 211))	('Isodon rubescens', 'Species', '587669', (59, 75))	('muM', 'Gene', (383, 386))	('inhibited', 'NegReg', (81, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('muM', 'Gene', '56925', (253, 256))	('muM', 'Gene', '56925', (332, 335))	('lung cancer', 'Disease', (218, 229))	('muM', 'Gene', (253, 256))	('muM', 'Gene', (332, 335))	('muM', 'Gene', '56925', (172, 175))	('muM', 'Gene', '56925', (148, 151))	('muM', 'Gene', (172, 175))	('muM', 'Gene', (148, 151))
98579	31963204	JDA-202 (C21H30O5, MW: 362.47, Figure 2) was isolated from Isodon rubescens, and exhibited anticancer effects in esophageal cancer EC109 (IC50: 8.60 muM) and EC9706 (IC50: 9.40 muM) cells, yet was considerably non-toxic in normal cell lines KYSE-450 (IC50: 26.2  muM) and HET-1A (IC50: 36.1 muM) at 24 h drug incubation.	('muM', 'Gene', (291, 294))	('muM', 'Gene', '56925', (177, 180))	('EC1', 'Gene', (131, 134))	('muM', 'Gene', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('C21H30O5', 'Var', (9, 17))	('C21H30O5', 'Chemical', '-', (9, 17))	('cancer', 'Disease', (95, 101))	('EC1', 'Gene', '4819', (131, 134))	('muM', 'Gene', '56925', (263, 266))	('esophageal cancer', 'Disease', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Isodon rubescens', 'Species', '587669', (59, 75))	('muM', 'Gene', (263, 266))	('muM', 'Gene', '56925', (149, 152))	('EC9706', 'Var', (158, 164))	('muM', 'Gene', (149, 152))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('muM', 'Gene', '56925', (291, 294))
98583	31963204	Pterisolic acid G (PAG) (C20H28O6, MW: 364.44, Figure 2), isolated from Pteris semipinnata, dose- and time-dependently inhibited the growth of human colorectal cancer cell line HCT-116 with IC50 values 20.4, 16.2, and 4.07 microM for 24, 48, and 72 h, respectively.	('C20H28O6', 'Var', (25, 33))	('human', 'Species', '9606', (143, 148))	('Pterisolic acid G', 'Chemical', '-', (0, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('inhibited', 'NegReg', (119, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('PAG', 'Chemical', '-', (19, 22))	('Pteris semipinnata', 'Species', '265705', (72, 90))	('C20H28O6', 'Chemical', '-', (25, 33))	('colorectal cancer', 'Disease', (149, 166))	('growth', 'CPA', (133, 139))
98584	31963204	Mechanistic studies found that PAG reduced the expression of disheveled segment polarity protein 2 (Dvl-2), GSK-3beta, beta-catenin, cyclin D1, and c-myc in HCT-116 cells.	('beta-catenin', 'Gene', '1499', (119, 131))	('Dvl-2', 'Gene', '1856', (100, 105))	('GSK-3beta', 'Gene', '2931', (108, 117))	('Dvl-2', 'Gene', (100, 105))	('reduced', 'NegReg', (35, 42))	('cyclin D1', 'Gene', '595', (133, 142))	('PAG', 'Var', (31, 34))	('GSK-3beta', 'Gene', (108, 117))	('PAG', 'Chemical', '-', (31, 34))	('c-myc', 'Gene', '4609', (148, 153))	('cyclin D1', 'Gene', (133, 142))	('c-myc', 'Gene', (148, 153))	('beta-catenin', 'Gene', (119, 131))	('disheveled segment polarity protein 2', 'Gene', '1856', (61, 98))	('disheveled segment polarity protein 2', 'Gene', (61, 98))	('expression', 'MPA', (47, 57))
98585	31963204	Moreover, it induced apoptosis by increasing the expression of p53, puma, cleaved PARP, and cleaved caspase-3, as well as decreasing the expression of p-p65, BCL-2, and BCL-xL.	('p65', 'Gene', (153, 156))	('caspase-3', 'Gene', (100, 109))	('BCL-2', 'Gene', '596', (158, 163))	('expression', 'MPA', (137, 147))	('PARP', 'Gene', (82, 86))	('increasing', 'PosReg', (34, 44))	('BCL-2', 'Gene', (158, 163))	('decreasing', 'NegReg', (122, 132))	('expression', 'MPA', (49, 59))	('p65', 'Gene', '5970', (153, 156))	('caspase-3', 'Gene', '836', (100, 109))	('PARP', 'Gene', '142', (82, 86))	('apoptosis', 'CPA', (21, 30))	('p53', 'Var', (63, 66))	('cleaved', 'Var', (92, 99))	('BCL-xL', 'Protein', (169, 175))
98586	31963204	Rabdoternin B (C21H30O7, MW: 394.46, Figure 2) and maoecrystal I (C22H30O8, MW: 422.47, Figure 2) were isolated from the aerial parts of Isodon rosthornii and the leaves of I. xerophilus, respectively.	('C21H30O7', 'Chemical', '-', (15, 23))	('C21H30O7', 'Var', (15, 23))	('I. xerophilus', 'Species', '662931', (173, 186))	('C22H30O8', 'Var', (66, 74))	('Rabdoternin B', 'Chemical', '-', (0, 13))	('Isodon rosthornii', 'Species', '662925', (137, 154))	('C22H30O8', 'Chemical', '-', (66, 74))
98589	31963204	(2016) isolated 3alpha-cinnamoyloxy-9beta-hydroxy-ent-kaura-16-en-19-oic acid (CHKA) (C29H36O5, MW: 464.6, Figure 2) from the ethanol extract of Wedelia chinensis.	('C29H36O5', 'Var', (86, 94))	('Wedelia chinensis', 'Species', '318065', (145, 162))	('CHKA', 'Gene', '12660', (79, 83))	('ethanol', 'Chemical', 'MESH:D000431', (126, 133))	('CHKA', 'Gene', (79, 83))
98680	31475066	Patients diagnosed with T1a (m3) or T1b, i.e., tumor invasion of the muscularis mucosae or submucosal layer, respectively, require adjuvant therapy after ESD.	('T1a', 'Var', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('T1b', 'Var', (36, 39))	('tumor', 'Disease', (47, 52))
98681	31475066	In a retrospective analysis in an adjuvant treatment setting, both the 3-year relapse-free survival and overall survival rates of patients with T1a (m3) or T1b EC after ESD were significantly improved by adjuvant treatments.	('improved', 'PosReg', (192, 200))	('T1b EC', 'Var', (156, 162))	('overall', 'CPA', (104, 111))	('relapse-free survival', 'CPA', (78, 99))	('patients', 'Species', '9606', (130, 138))	('T1a', 'Var', (144, 147))
98685	31475066	Therefore, adjuvant treatments after ESD should be considered for older patients with T1a (m3) and T1b EC.	('T1b', 'Var', (99, 102))	('T1a', 'Disease', (86, 89))	('patients', 'Species', '9606', (72, 80))
98714	31134151	MiR-181a inhibitor enhanced the antitumor activity of cisplatin, which was similar with the effect of CASC2.	('MiR', 'Gene', (0, 3))	('MiR', 'Gene', '220972', (0, 3))	('CASC2', 'Gene', (102, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('CASC2', 'Gene', '255082', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('inhibitor', 'Var', (9, 18))	('tumor', 'Disease', (36, 41))	('enhanced', 'PosReg', (19, 27))
98754	31134151	The expression levels of CASC2 in Het-1A, Eca109, KYSE140, KYSE150, TE-1, and EC9706 were detected by qRT-PCR.	('EC9706', 'CellLine', 'CVCL:E307', (78, 84))	('CASC2', 'Gene', '255082', (25, 30))	('KYSE140', 'Var', (50, 57))	('KYSE150', 'Var', (59, 66))	('CASC2', 'Gene', (25, 30))
98770	31134151	CASC2 overexpression enhanced cisplatin-induced apoptosis in TE-1 and EC9706 cells, compared to the cells transfected with empty vector (Figures 3A,B).	('overexpression', 'Var', (6, 20))	('enhanced', 'PosReg', (21, 29))	('EC9706', 'CellLine', 'CVCL:E307', (70, 76))	('CASC2', 'Gene', (0, 5))	('CASC2', 'Gene', '255082', (0, 5))	('cisplatin-induced', 'MPA', (30, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))
98773	31134151	As shown in Figures 4A,B, CASC2 knockdown resisted cisplatin-induced viability reduction in TE-1 and EC9706 cells.	('cisplatin-induced viability reduction', 'MPA', (51, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('CASC2', 'Gene', (26, 31))	('resisted', 'NegReg', (42, 50))	('knockdown', 'Var', (32, 41))	('CASC2', 'Gene', '255082', (26, 31))	('EC9706', 'CellLine', 'CVCL:E307', (101, 107))
98774	31134151	CASC2 knockdown suppressed cisplatin-induced increase in LDH release in TE-1 and EC9706 cells (Figures 4C,D).	('suppressed', 'NegReg', (16, 26))	('cisplatin-induced', 'MPA', (27, 44))	('EC9706', 'CellLine', 'CVCL:E307', (81, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('CASC2', 'Gene', (0, 5))	('CASC2', 'Gene', '255082', (0, 5))	('knockdown', 'Var', (6, 15))	('LDH release', 'MPA', (57, 68))
98775	31134151	Treatment with cisplatin induced apoptosis of TE-1 and EC9706 cells, but this effect was attenuated by CASC2 knockdown (Figures 4E,F).	('apoptosis', 'CPA', (33, 42))	('CASC2', 'Gene', '255082', (103, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('knockdown', 'Var', (109, 118))	('EC9706', 'CellLine', 'CVCL:E307', (55, 61))	('CASC2', 'Gene', (103, 108))
98776	31134151	These data suggested that CASC2 knockdown attenuated the antitumor activity of cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('attenuated', 'NegReg', (42, 52))	('CASC2', 'Gene', (26, 31))	('knockdown', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CASC2', 'Gene', '255082', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
98785	31134151	We found that cisplatin exhibited antitumor activity by inhibiting cell viability, promoting LDH release, and induced apoptosis of TE-1 and EC9706 cells.	('apoptosis', 'CPA', (118, 127))	('tumor', 'Disease', (38, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('EC9706', 'CellLine', 'CVCL:E307', (140, 146))	('promoting', 'PosReg', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('inhibiting', 'NegReg', (56, 66))	('cisplatin', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cell viability', 'CPA', (67, 81))	('induced', 'Reg', (110, 117))	('LDH release', 'MPA', (93, 104))
98787	31134151	MiR-181a inhibitor enhanced the inhibitory effect of cisplatin on cell viability (Figures 6A,C).	('MiR', 'Gene', (0, 3))	('MiR', 'Gene', '220972', (0, 3))	('cell', 'CPA', (66, 70))	('inhibitory effect', 'MPA', (32, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('inhibitor', 'Var', (9, 18))	('enhanced', 'PosReg', (19, 27))
98789	31134151	Besides, apoptosis rate was significantly increased in TE-1 and EC9706 cells transfected with miR-181a inhibitor compared to that in cells transfected with inhibitor control in the presence of cisplatin (Figures 6E,F).	('increased', 'PosReg', (42, 51))	('EC9706', 'CellLine', 'CVCL:E307', (64, 70))	('apoptosis rate', 'CPA', (9, 23))	('inhibitor', 'Var', (103, 112))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))
98893	27911861	Pooled analysis showed that high levels of PKM2 was significantly associated with a poorer overall survival (HR = 1.73; 95%CI = 1.48-2.03) and DFS/ PFS/ RFS (HR = 1.90; 95%CI = 1.39-2.59) irrespective of cancer types.	('DFS/ PFS/ RFS', 'Var', (143, 156))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('PKM2', 'Gene', '5315', (43, 47))	('high levels', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('overall', 'MPA', (91, 98))	('poorer', 'NegReg', (84, 90))	('PKM2', 'Gene', (43, 47))
98895	27911861	Nevertheless, stratified by cancer type, high-expression of PKM2 was associated with an unfavorable OS in breast cancer, esophageal squamous carcinoma, hepatocellular carcinoma and gallbladder cancer; whereas was not correlated with a worse OS in pancreatic cancer and gastric cancer.	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (121, 150))	('pancreatic cancer', 'Disease', (247, 264))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('hepatocellular carcinoma', 'Disease', (152, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('gallbladder cancer', 'Disease', 'MESH:D005706', (181, 199))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('gastric cancer', 'Disease', (269, 283))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (132, 150))	('cancer', 'Disease', (277, 283))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (121, 150))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (247, 264))	('PKM2', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('gastric cancer', 'Disease', 'MESH:D013274', (269, 283))	('PKM2', 'Gene', '5315', (60, 64))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (152, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('associated', 'Reg', (69, 79))	('esophageal squamous carcinoma', 'Disease', (121, 150))	('high-expression', 'Var', (41, 56))	('cancer', 'Disease', (258, 264))	('gallbladder cancer', 'Disease', (181, 199))	('cancer', 'Disease', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('breast cancer', 'Disease', (106, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (247, 264))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (152, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (269, 283))
98907	27911861	reported that positive PKM2 expression predicted improved overall survival in pancreatic ductal adenocarcinoma patients.	('overall survival', 'MPA', (58, 74))	('PKM2', 'Gene', '5315', (23, 27))	('improved', 'PosReg', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('pancreatic ductal adenocarcinoma', 'Disease', (78, 110))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (78, 110))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (78, 110))	('positive', 'Var', (14, 22))	('PKM2', 'Gene', (23, 27))	('patients', 'Species', '9606', (111, 119))
98916	27911861	A total of 24 studies described the correlation between overall survival and PKM2 expression, while 9 datasets reported a relationship between DFS/ PFS/ RFS and PKM2 expression.	('DFS/ PFS/ RFS', 'Var', (143, 156))	('PKM2', 'Gene', (77, 81))	('PKM2', 'Gene', (161, 165))	('PKM2', 'Gene', '5315', (77, 81))	('expression', 'MPA', (82, 92))	('PKM2', 'Gene', '5315', (161, 165))	('correlation', 'Interaction', (36, 47))	('expression', 'MPA', (166, 176))
98919	27911861	In the stratified analysis by tumor type, high levels of PKM2 were significantly correlated with a poorer OS for patients with breast cancer (pooled HR = 1.85, 95%CI = 1.44-2.38), esophageal squamous cell cancer (pooled HR = 1.72, 95%CI = 1.30-2.28), gallbladder cancer (pooled HR = 2.10, 95%CI = 1.45-3.05) and hepatocellular carcinoma (pooled HR = 1.60, 95%CI = 1.40-1.83).	('carcinoma', 'Phenotype', 'HP:0030731', (327, 336))	('PKM2', 'Gene', '5315', (57, 61))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (191, 211))	('high levels', 'Var', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (312, 336))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('gallbladder cancer', 'Disease', 'MESH:D005706', (251, 269))	('patients', 'Species', '9606', (113, 121))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (180, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (312, 336))	('esophageal squamous cell cancer', 'Disease', (180, 211))	('hepatocellular carcinoma', 'Disease', (312, 336))	('tumor', 'Disease', (30, 35))	('gallbladder cancer', 'Disease', (251, 269))	('PKM2', 'Gene', (57, 61))
98925	27911861	The pooling analysis revealed high-expression of PKM2 was a negative indicator for DFS/PFS/RFS among solid cancer patients, with a pooled HR 1.90 (95%CI = 1.39-2.59) in random model and a pooled HR 1.81 (95%CI = 1.57-2.08) in fixed model.	('negative', 'NegReg', (60, 68))	('high-expression', 'Var', (30, 45))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PKM2', 'Gene', (49, 53))	('solid cancer', 'Disease', 'MESH:D009369', (101, 113))	('solid cancer', 'Disease', (101, 113))	('PKM2', 'Gene', '5315', (49, 53))	('DFS/PFS/RFS', 'Disease', (83, 94))	('patients', 'Species', '9606', (114, 122))
98926	27911861	This association was noteworthy not only in univariate models (pooled HR = 2.00, 95%CI = 1.14-3.52), but also in multivariate models (pooled HR = 1.75, 95%CI = 1.33-2.29), suggestive of a noteworthy relationship between high levels of PKM2 and unfavorable clinical outcome (Figure 5).	('PKM2', 'Gene', (235, 239))	('high', 'Var', (220, 224))	('PKM2', 'Gene', '5315', (235, 239))
98933	27911861	Individual cohorts have sporadically revealed an unfavorable impact of high PKM2 expression on clinical prognosis in certain types of cancer.	('high', 'Var', (71, 75))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('PKM2', 'Gene', (76, 80))	('PKM2', 'Gene', '5315', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
98940	27911861	With respect to ethnicity/race, increased levels of PKM2 had a negative influence on clinical outcome in the Asian group, with consistent results of OS and DFS/PFS/RFS.	('DFS/PFS/RFS', 'Var', (156, 167))	('negative', 'NegReg', (63, 71))	('PKM2', 'Gene', (52, 56))	('PKM2', 'Gene', '5315', (52, 56))	('clinical outcome', 'MPA', (85, 101))
98954	27911861	First, it shows that PKM2 expression is related to worse outcome of solid cancers, which suggests that PKM2 may be a potential prognostic indicator for solid cancer.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('PKM2', 'Gene', (21, 25))	('related', 'Reg', (40, 47))	('expression', 'Var', (26, 36))	('PKM2', 'Gene', '5315', (21, 25))	('solid cancer', 'Disease', (152, 164))	('solid cancers', 'Disease', (68, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('PKM2', 'Gene', (103, 107))	('solid cancer', 'Disease', 'MESH:D009369', (152, 164))	('PKM2', 'Gene', '5315', (103, 107))	('solid cancers', 'Disease', 'MESH:D009369', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('solid cancer', 'Disease', 'MESH:D009369', (68, 80))
99004	27082598	Patients had been defined as having dyslipidemia when hematological findings showed >=140 mg/dL of LDL-cholesterol, <40 mg/dL of HDL-cholesterol, or >=150 mg/dL of triglycerides.	('triglycerides', 'Chemical', 'MESH:D014280', (164, 177))	('HDL-cholesterol', 'Protein', (129, 144))	('>=150 mg/dL', 'Var', (149, 160))	('dyslipidemia', 'Phenotype', 'HP:0003119', (36, 48))	('cholesterol', 'Chemical', 'MESH:D002784', (133, 144))	('>=140 mg/dL', 'Var', (84, 95))	('triglycerides', 'MPA', (164, 177))	('Patients', 'Species', '9606', (0, 8))	('dyslipidemia', 'Disease', (36, 48))	('cholesterol', 'Chemical', 'MESH:D002784', (103, 114))	('dyslipidemia', 'Disease', 'MESH:D050171', (36, 48))	('LDL-cholesterol', 'MPA', (99, 114))
99026	27082598	In addition, nicotine was reported to induce radioresistance.	('radioresistance', 'CPA', (45, 60))	('nicotine', 'Chemical', 'MESH:D009538', (13, 21))	('nicotine', 'Var', (13, 21))
99052	26040563	MAPK7 was validated as a proliferative oncogenic driver by performing in vitro siRNA knockdown of MAPK7 in tumor cell lines.	('MAPK7', 'Gene', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('knockdown', 'Var', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
99055	26040563	Together, these data highlight a broader role for dysregulated MAPK7 in driving tumorigenesis within niche populations of highly prevalent tumor types, and describe current efforts in establishing a robust drug discovery screening cascade.	('driving', 'Reg', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MAPK7', 'Gene', (63, 68))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('dysregulated', 'Var', (50, 62))
99059	26040563	Under normal physiological conditions, MEK5 and ERK5 are activated by growth factors and cellular stresses and, through the use of embryonic gene knockouts of MEK5 or MAPK7, have been shown to contribute largely to blood vessel and cardiac formation during development.	('MAPK7', 'Gene', (167, 172))	('MEK5', 'Gene', '5607', (39, 43))	('MEK5', 'Gene', (159, 163))	('contribute', 'Reg', (193, 203))	('activated', 'PosReg', (57, 66))	('MEK5', 'Gene', (39, 43))	('ERK5', 'Gene', '5598', (48, 52))	('ERK5', 'Gene', (48, 52))	('knockouts', 'Var', (146, 155))	('MEK5', 'Gene', '5607', (159, 163))
99061	26040563	In the context of cancer, clinical evidence suggests a role for dysregulated MEK5/ERK5 signaling as a driver of tumorigenesis in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('MEK5', 'Gene', '5607', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('ERK5', 'Gene', (82, 86))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('ERK5', 'Gene', '5598', (82, 86))	('MEK5', 'Gene', (77, 81))	('clinical', 'Species', '191496', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('dysregulated', 'Var', (64, 76))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
99063	26040563	The ERK5 pathway also appears to play a role in mediating chemoresistance in breast cancer cells and contributes to neuregulin signaling in breast cancer cells overexpressing ErbB2.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('neuregulin signaling', 'MPA', (116, 136))	('breast cancer', 'Disease', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('breast cancer', 'Disease', (140, 153))	('play', 'Reg', (33, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('ErbB2', 'Gene', (175, 180))	('overexpressing', 'Var', (160, 174))	('ERK5', 'Gene', (4, 8))	('ERK5', 'Gene', '5598', (4, 8))	('chemoresistance', 'CPA', (58, 73))	('contributes', 'Reg', (101, 112))	('ErbB2', 'Gene', '2064', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mediating', 'Reg', (48, 57))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
99065	26040563	Furthermore, in hepatocellular carcinoma (HCC), genetic dysregulation of MAPK7 expression through amplification of 17p11 is detectable in around 50 % of primary HCC tumors.	('HCC tumors', 'Disease', (161, 171))	('expression', 'MPA', (79, 89))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('HCC tumors', 'Disease', 'MESH:D006528', (161, 171))	('amplification', 'Var', (98, 111))	('hepatocellular carcinoma', 'Disease', (16, 40))	('p11', 'Gene', (117, 120))	('dysregulation', 'Var', (56, 69))	('MAPK7', 'Gene', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('p11', 'Gene', '6281', (117, 120))
99066	26040563	In the same study, preclinical validation work using small-interfering RNA (siRNA) suppression of MAPK7 expression in amplified cell lines confirmed a role for dysregulated MAPK7 in controlling mitotic entry.	('MAPK7', 'Gene', (98, 103))	('suppression', 'NegReg', (83, 94))	('dysregulated', 'Var', (160, 172))	('mitotic entry', 'MPA', (194, 207))	('expression', 'MPA', (104, 114))	('clinical', 'Species', '191496', (22, 30))
99067	26040563	In the work reported here, we identified genetic dysregulation of MAPK7 and protein overexpression in clinical samples of non-small cell lung cancer (NSCLC) and esophageal cancer (EC) of Asian origin, using array comparative genomic hybridization (aCGH) and FISH (fluorescent in-situ hybridization) technologies.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('overexpression', 'PosReg', (84, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('protein', 'Protein', (76, 83))	('MAPK7', 'Gene', (66, 71))	('non-small cell lung cancer', 'Disease', (122, 148))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (126, 148))	('clinical samples', 'Species', '191496', (102, 118))	('dysregulation', 'Var', (49, 62))	('esophageal cancer', 'Disease', (161, 178))	('NSCLC', 'Disease', (150, 155))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (122, 148))
99070	26040563	In summary, the work here identifies and validates a novel role for dysregulated MAPK7 as a tumor driver in clinical samples of NSCLC and EC, and outlines aspects of preliminary work in developing a drug discovery programme to identify novel small molecule inhibitors of MAPK7 kinase activity.	('MAPK7', 'Gene', (81, 86))	('clinical samples', 'Species', '191496', (108, 124))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('NSCLC', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('dysregulated', 'Var', (68, 80))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('tumor', 'Disease', (92, 97))
99074	26040563	In order to test the hypothesis that dysregulation of MAPK7 signaling could drive tumor cell proliferation, we undertook a number of studies to explore the functional consequences of silencing MAPK7 gene expression in MAPK7 dysregulated tumor cell lines.	('dysregulation', 'Var', (37, 50))	('tumor', 'Disease', (237, 242))	('silencing', 'Var', (183, 192))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('MAPK7 dysregulated tumor', 'Disease', (218, 242))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('MAPK7 dysregulated tumor', 'Disease', 'MESH:D021081', (218, 242))	('drive', 'PosReg', (76, 81))	('tumor', 'Disease', (82, 87))	('MAPK7', 'Gene', (193, 198))
99077	26040563	3a), and Western blotting of lysates confirmed higher level MAPK7 protein expression in KYSE30 and SNU449, but lower levels in NCI-H1793 (Fig.	('expression', 'MPA', (74, 84))	('MAPK7', 'Gene', (60, 65))	('higher', 'PosReg', (47, 53))	('NCI-H1793', 'CellLine', 'CVCL:1496', (127, 136))	('lower', 'NegReg', (111, 116))	('SNU449', 'Var', (99, 105))
99079	26040563	Within the NCI-H1793 control cell line, knockdown of MAPK7 protein expression to around 60 % of control levels had no effect on either cell proliferation or cell death.	('protein', 'Protein', (59, 66))	('knockdown', 'Var', (40, 49))	('cell death', 'CPA', (157, 167))	('NCI-H1793', 'CellLine', 'CVCL:1496', (11, 20))	('cell proliferation', 'CPA', (135, 153))	('MAPK7', 'Gene', (53, 58))
99080	26040563	Consistent with the 'live/dead' cell assay, MAPK7 knockdown greatly reduced cell proliferation in KYS30 and SNU449 cell lines, but had no effect on NCI-H1793 (Fig.	('MAPK7', 'Gene', (44, 49))	('knockdown', 'Var', (50, 59))	('cell proliferation in', 'CPA', (76, 97))	('NCI-H1793', 'CellLine', 'CVCL:1496', (148, 157))	('KYS30', 'Chemical', '-', (98, 103))	('reduced', 'NegReg', (68, 75))
99081	26040563	Two days post-transfection, MAPK7 siRNA-transfected tumor cells failed to follow the same exponential growth dynamics of the control and scrambled siRNA treatment groups, instead displaying suppressed cell growth, and in the case of KYSE30, reductions in the degree of cell confluence consistent with the increased cell death observed in the 'live/dead'cell assay.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('cell growth', 'CPA', (201, 212))	('KYSE30', 'Var', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('suppressed', 'NegReg', (190, 200))	('cell confluence', 'CPA', (269, 284))	('reductions', 'NegReg', (241, 251))
99084	26040563	Western blot analysis demonstrated clear induction of MAPK7 Thr218/Tyr220 phosphorylation by MEK5CA, and importantly, this phosphorylation could be blocked using the commercially available and specific MAPK7 tool compound, XMD8-92 (Fig.	('MAPK7', 'Gene', (54, 59))	('MEK5CA', 'Gene', (93, 99))	('MEK5CA', 'Gene', '5607', (93, 99))	('Thr218/Tyr220', 'Var', (60, 73))	('Thr218', 'Chemical', '-', (60, 66))	('Tyr220', 'Chemical', '-', (67, 73))
99086	26040563	Further validation of this assay was performed using 2 novel small molecules, Gray#18 and Gray#21 (confirmed as MAPK7 kinase inhibitors using a biochemical kinase assay) and 2 unrelated kinase inhibitors, AZD2281 (a PARP inhibitor) and AZD3965 (an MCT1 inhibitor).	('PARP', 'Gene', '1302', (216, 220))	('PARP', 'Gene', (216, 220))	('AZD2281', 'Chemical', 'MESH:C531550', (205, 212))	('AZD3965', 'Var', (236, 243))	('MCT1', 'Gene', (248, 252))	('MCT1', 'Gene', '6566', (248, 252))	('AZD2281', 'Var', (205, 212))	('AZD3965', 'Chemical', 'MESH:C000592351', (236, 243))
99088	26040563	Compared to untreated control cells, pCDC25C (S216), pCDKN1 (T145), pMEF2A (S408) and pMEF2D (S444) all showed significant reductions with '% of control' values of 39.8, 41.9, 44.7 and 45.1, respectively (Table 2).	('MEF2D', 'Gene', '4209', (87, 92))	('MEF2A', 'Gene', '4205', (69, 74))	('CDC25C', 'Gene', (38, 44))	('CDKN1', 'Gene', (54, 59))	('MEF2A', 'Gene', (69, 74))	('MEF2D', 'Gene', (87, 92))	('reductions', 'NegReg', (123, 133))	('CDKN1', 'Gene', '1026', (54, 59))	('CDC25C', 'Gene', '995', (38, 44))	('S408', 'Var', (76, 80))
99090	26040563	Dysregulated MAPK7 signaling has been demonstrated to play key roles in uncontrolled cell proliferation across several tumor types.	('tumor', 'Disease', (119, 124))	('uncontrolled cell proliferation', 'CPA', (72, 103))	('MAPK7', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Dysregulated', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
99091	26040563	The data herein provide a first description of the identification of clinical squamous cell lung and esophageal tumor samples harbouring gene amplified and overexpressed MAPK7.	('esophageal tumor', 'Disease', (101, 117))	('esophageal tumor', 'Phenotype', 'HP:0100751', (101, 117))	('clinical', 'Species', '191496', (69, 77))	('squamous cell lung', 'Disease', (78, 96))	('gene amplified', 'Var', (137, 151))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('overexpressed', 'PosReg', (156, 169))	('esophageal tumor', 'Disease', 'MESH:D004938', (101, 117))	('MAPK7', 'Gene', (170, 175))
99092	26040563	Intriguingly, in addition to the 3 clinical cases showing a correlation between MAPK7 amplification and high level protein expression (IHC3+), we also identified a further 12 cases with IHC3+ protein staining in the absence of MAPK7 amplification, raising the question of whether MAPK7 gene amplification, protein overexpression, or both, are required for driving tumor proliferation.	('IHC3+', 'Var', (186, 191))	('tumor', 'Disease', (364, 369))	('clinical', 'Species', '191496', (35, 43))	('high level protein expression', 'MPA', (104, 133))	('MAPK7', 'Gene', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (364, 369))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('MAPK7', 'Gene', (80, 85))	('protein', 'Protein', (192, 199))
99095	26040563	Detailed exploration of the precise molecular mechanisms of MAPK7 dysregulation was outwith the scope of our work here, however our data do suggest that dysregulated MAPK7 may provide a further level of disease segmentation within squamous cell lung cancer, which crucially, is a disease with high unmet need and currently has no approved targeted therapeutics.	('lung cancer', 'Phenotype', 'HP:0100526', (245, 256))	('MAPK7 dysregulation', 'Disease', 'MESH:D021081', (60, 79))	('MAPK7 dysregulation', 'Disease', (60, 79))	('MAPK7', 'Gene', (166, 171))	('squamous cell lung cancer', 'Disease', (231, 256))	('dysregulated', 'Var', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (231, 256))
99096	26040563	Targeted siRNA knockdown of MAPK7 in two dysregulated cell lines confirmed a driving role for MAPK7 in tumor cell proliferation in vitro.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('knockdown', 'Var', (15, 24))	('tumor', 'Disease', (103, 108))	('MAPK7', 'Gene', (28, 33))	('MAPK7', 'Gene', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
99097	26040563	Importantly however, significant suppression of MAPK7 expression and a lack of any effect on cell proliferation or cell death in the non-dysregulated MAPK7 cell line, NCI-H1793, confirmed a role for dysregulated MAPK7 in driving uncontrolled cell proliferation.	('expression', 'MPA', (54, 64))	('dysregulated', 'Var', (199, 211))	('NCI-H1793', 'CellLine', 'CVCL:1496', (167, 176))	('MAPK7', 'Gene', (212, 217))	('MAPK7', 'Gene', (48, 53))	('cell proliferation', 'CPA', (93, 111))	('suppression', 'NegReg', (33, 44))	('uncontrolled cell proliferation', 'CPA', (229, 260))
99105	26040563	Taken together, our data provide the first reported incidences of dysregulated MAPK7 expression in clinical samples of squamous cell lung and esophageal carcinoma.	('expression', 'MPA', (85, 95))	('MAPK7', 'Gene', (79, 84))	('squamous cell lung', 'Disease', (119, 137))	('dysregulated', 'Var', (66, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('esophageal carcinoma', 'Disease', (142, 162))	('clinical samples', 'Species', '191496', (99, 115))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (142, 162))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (142, 162))
99106	26040563	Using MAPK7 siRNA, we validate a role for dysregulated MAPK7 in driving cell proliferation in established tumor cell lines and describe the development of a cell based ELISA assay to support screening of novel MAPK7 kinase inhibitors.	('driving', 'PosReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('MAPK7', 'Gene', (55, 60))	('cell proliferation', 'CPA', (72, 90))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('dysregulated', 'Var', (42, 54))
99112	26040563	Ninety-six h post siRNA transfection, cell lysates were collected and subjected to SDS/PAGE and transferred on to PVDF membrane.	('SDS', 'Chemical', 'MESH:D012967', (83, 86))	('transfection', 'Var', (24, 36))	('siRNA', 'Gene', (18, 23))	('PVDF', 'Chemical', 'MESH:C024865', (114, 118))
99125	19838934	Higher intakes of omega-3-fatty-acids (cases vs. population controls; OR=0.46, 95% CI 0.22-0.97, 4th vs. 1st quartiles of intake), polyunsaturated fat, total fiber (OR=0.34, 95% CI 0.15-0.76), and fiber from fruits and vegetables (OR=0.47 95% CI 0.25-0.88) were associated with a lower risk of Barrett's esophagus.	('polyunsaturated fat', 'Chemical', '-', (131, 150))	('polyunsaturated fat', 'Var', (131, 150))	('fiber', 'Chemical', 'MESH:D004043', (197, 202))	("Barrett's esophagus", 'Disease', (294, 313))	('fiber', 'Chemical', 'MESH:D004043', (158, 163))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (294, 313))	('omega-3-fatty-acids', 'Chemical', 'MESH:D015525', (18, 37))
99155	19838934	There was an inverse association between intakes of polyunsaturated fat, omega 3, and the risk of Barrett's esophagus, and the associations were stronger for long-segment Barrett's esophagus.	("long-segment Barrett's esophagus", 'Disease', (158, 190))	('polyunsaturated', 'Var', (52, 67))	("Barrett's esophagus", 'Disease', (98, 117))	('inverse', 'NegReg', (13, 20))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (171, 190))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (98, 117))	('omega 3', 'Chemical', 'MESH:D015525', (73, 80))	('polyunsaturated fat', 'Chemical', '-', (52, 71))
99156	19838934	For instance, those who consumed the highest amount of omega 3 fatty-acid were at less than half the risk of developing any Barrett's esophagus (OR=0.46; 95% CI 0.22-0.97, 4th vs. 1st quartiles), and at three times lower the risk of having long-segment Barrett's esophagus (OR=0.36; 95% CI 0.14-0.90).	('omega 3 fatty-acid', 'Var', (55, 73))	("long-segment Barrett's esophagus", 'Disease', (240, 272))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (253, 272))	('omega 3 fatty-acid', 'Chemical', 'MESH:D015525', (55, 73))	("Barrett's esophagus", 'Disease', (124, 143))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (124, 143))	('lower', 'NegReg', (215, 220))
99158	19838934	On the other hand, trans-fat, often found in highly processed food, was significantly associated with an increased risk of Barrett's esophagus when examined continuously (OR=1.11; 95% CI 1.03-1.21, any Barrett's esophagus; OR=1.15; 95%CI 1.04-1.27, for long-segment BE, per gram/day).	('trans-fat', 'Chemical', 'MESH:D044242', (19, 28))	('trans-fat', 'Var', (19, 28))	("Barrett's esophagus", 'Disease', (123, 142))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (123, 142))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (202, 221))
99173	19838934	Our data suggested that plant-based fats (e.g., polyunsaturated fat), omega 3 fatty-acids, fiber (particularly fiber from fruits and vegetables), and meat intakes were inversely associated with the risk of Barrett's esophagus, while trans-fat may be adversely associated with the disease.	('omega', 'Var', (70, 75))	('associated', 'Reg', (178, 188))	('fiber', 'Chemical', 'MESH:D004043', (91, 96))	('omega 3 fatty-acids', 'Chemical', 'MESH:D015525', (70, 89))	('fats', 'Gene', (36, 40))	('fats', 'Gene', '118611', (36, 40))	('inversely', 'NegReg', (168, 177))	("Barrett's esophagus", 'Disease', (206, 225))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (206, 225))	('trans-fat', 'Chemical', 'MESH:D044242', (233, 242))	('fiber', 'Chemical', 'MESH:D004043', (111, 116))	('polyunsaturated fat', 'Chemical', '-', (48, 67))
99184	19838934	A previous study demonstrated that Barrett's esophagus patients who were randomly assigned omega 3 fatty-acid eicosapentaenoic acid (a metabolically active omega 3 fatty-acid) experienced a significant reduction in COX-2 protein concentrations, suggesting a potential chemopreventive effect of omega 3 fatty-acid or regular consumption of oily fish.	('omega 3 fatty-acid', 'Chemical', 'MESH:D015525', (91, 109))	('omega 3 fatty-acid', 'Chemical', 'MESH:D015525', (294, 312))	('COX-2', 'Gene', '4513', (215, 220))	('COX-2', 'Gene', (215, 220))	('omega 3', 'Var', (91, 98))	('patients', 'Species', '9606', (55, 63))	('omega 3 fatty-acid', 'Chemical', 'MESH:D015525', (156, 174))	('eicosapentaenoic acid', 'Var', (110, 131))	('eicosapentaenoic acid', 'Chemical', 'MESH:D015118', (110, 131))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (35, 54))	('reduction', 'NegReg', (202, 211))
99197	19838934	In summary, in a community-based population, we found that omega 3 fatty-acid, fiber, and meat intake were inversely associated with the risk of Barrett's esophagus, while trans-fat intake may be adversely associated with risk.	('omega 3 fatty-acid', 'Var', (59, 77))	('omega 3 fatty-acid', 'Chemical', 'MESH:D015525', (59, 77))	('fiber', 'Chemical', 'MESH:D004043', (79, 84))	("Barrett's esophagus", 'Disease', (145, 164))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (145, 164))	('trans-fat', 'Chemical', 'MESH:D044242', (172, 181))	('inversely', 'NegReg', (107, 116))
99315	31348796	The glycine conjugated bile acids induced an intestinal type of metaplasia more typical for Barrett's esophagus.	('glycine', 'Var', (4, 11))	('glycine', 'Chemical', 'MESH:D005998', (4, 11))	("Barrett's esophagus", 'Disease', (92, 111))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (92, 111))	('metaplasia', 'Disease', 'MESH:D008679', (64, 74))	('metaplasia', 'Disease', (64, 74))	('induced', 'Reg', (34, 41))	('bile acids', 'Chemical', 'MESH:D001647', (23, 33))
99322	31348796	It is thought that DGERD causes damage and inflammation of the normal squamous epithelium and enhances development of columnar metaplasia "".	('enhances', 'PosReg', (94, 102))	('DGERD', 'Var', (19, 24))	('inflammation', 'Disease', 'MESH:D007249', (43, 55))	('columnar metaplasia', 'Disease', (118, 137))	('inflammation', 'Disease', (43, 55))	('columnar metaplasia', 'Disease', 'MESH:D008679', (118, 137))	('development', 'CPA', (103, 114))
99351	31348796	The mouse MLGS showed similar cytokeratin (K) expression as the human SMGD, with cells positive for squamous markers K5 and K14 in the outer layer, and for columnar markers K8 and K7 in the inner layer.	('SMG', 'Chemical', '-', (70, 73))	('mouse', 'Species', '10090', (4, 9))	('human', 'Species', '9606', (64, 69))	('K14', 'Var', (124, 127))	('MLGS', 'Disease', 'None', (10, 14))	('MLGS', 'Disease', (10, 14))
99352	31348796	Of interest is that the population of K7+ cells observed in the mice MLGS seem to mark a similar cell population situated on the inner side of the human SMGD (Fig 1A).	('MLGS', 'Disease', (69, 73))	('human', 'Species', '9606', (147, 152))	('K7+ cells', 'Var', (38, 47))	('SMG', 'Chemical', '-', (153, 156))	('MLGS', 'Disease', 'None', (69, 73))	('mice', 'Species', '10090', (64, 68))
99371	31348796	The outer layer stained positive for squamous markers K5, K14 and p63, while the inner layer stained for the columnar marker K19.	('p63', 'Gene', '22061', (66, 69))	('p63', 'Gene', (66, 69))	('K14', 'Var', (58, 61))	('positive', 'Reg', (24, 32))	('stained', 'Reg', (93, 100))	('K19', 'Gene', '16669', (125, 128))	('K19', 'Gene', (125, 128))
99373	31348796	The percentage of mice showing glands, as well as the number of glands at the SCJ, increased when acidified drinking water was combined with BAs, compared to acidified drinking water alone (Fig 2E and 2F).	('increased', 'PosReg', (83, 92))	('acidified', 'Var', (98, 107))	('mice', 'Species', '10090', (18, 22))	('drinking water', 'Chemical', 'MESH:D060766', (168, 182))	('BAs', 'Chemical', 'MESH:D001647', (141, 144))	('glands', 'CPA', (31, 37))	('drinking water', 'Chemical', 'MESH:D060766', (108, 122))
99376	31348796	Together these observations indicate that BAs from BE patients refluxates stimulate development of MLGS at the SCJ in mice, which contain cells carrying either columnar (K19+) or squamous epithelial markers (K5+, p63+).	('development', 'CPA', (84, 95))	('stimulate', 'PosReg', (74, 83))	('patients', 'Species', '9606', (54, 62))	('p63', 'Gene', '22061', (213, 216))	('MLGS', 'Disease', 'None', (99, 103))	('p63', 'Gene', (213, 216))	('mice', 'Species', '10090', (118, 122))	('BAs', 'Chemical', 'MESH:D001647', (42, 45))	('MLGS', 'Disease', (99, 103))	('K19', 'Gene', '16669', (170, 173))	('K19', 'Gene', (170, 173))	('K5+', 'Var', (208, 211))
99400	31348796	In the recent study by Jiang et al, the ectopic expression of CDX2 in K5+ basal cells resulted in expansion of a multi-layered transition zone at the SCJ resulted in intestinal-like metaplasia "".	('ectopic expression', 'Var', (40, 58))	('expansion', 'PosReg', (98, 107))	('metaplasia', 'Disease', 'MESH:D008679', (182, 192))	('metaplasia', 'Disease', (182, 192))	('CDX2', 'Gene', (62, 66))
99402	31348796	Interestingly, BA administration resulted in expansion of K5-GFP+ cells in the outer layer of the MLGS, demonstrating that the origin of these cells is from K5+ squamous progenitors.	('expansion', 'PosReg', (45, 54))	('K5-GFP+', 'Var', (58, 65))	('MLGS', 'Disease', 'None', (98, 102))	('MLGS', 'Disease', (98, 102))	('BA', 'Chemical', 'MESH:D001647', (15, 17))
99453	31348796	However, this process can be re-activated in case of mucosal damage and for instance drives the clonal expansion of mutant crypts in adenomas "".	('mucosal damage', 'Disease', (53, 67))	('mucosal damage', 'Disease', 'MESH:D009059', (53, 67))	('adenomas', 'Disease', 'MESH:D000236', (133, 141))	('adenomas', 'Disease', (133, 141))	('mutant', 'Var', (116, 122))
99483	31348796	Within several days the approximated magnets cause an esophago-jejunal fistula, while the magnets are excreted via the stools.	('fistula', 'Disease', 'MESH:D005402', (71, 78))	('fistula', 'Disease', (71, 78))	('cause', 'Reg', (45, 50))	('magnets', 'Var', (37, 44))
99550	30464518	For example, inhibiting Ras, PI3K/Akt, GSK-3/beta-catenin, and NF-kappaB signal pathways by modulating AIP1 activity can suppress tumor cell proliferation, epithelial-mesenchymal transition (EMT), and metastasis.	('suppress', 'NegReg', (121, 129))	('AIP1', 'Protein', (103, 107))	('activity', 'MPA', (108, 116))	('metastasis', 'CPA', (201, 211))	('Akt', 'Gene', (34, 37))	('NF-kappaB signal pathways', 'Pathway', (63, 88))	('GSK-3/beta-catenin', 'Gene', (39, 57))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('modulating', 'Var', (92, 102))	('Akt', 'Gene', '207', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Ras', 'Pathway', (24, 27))	('tumor', 'Disease', (130, 135))	('inhibiting', 'Var', (13, 23))
99554	30464518	Loss of AIP1 expression in vascular vessels directly stimulates tumor neovascularization, and also enhances the vascular endothelial cell VEGFR2 signaling system, thus facilitating tumor angiogenesis and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('stimulates', 'PosReg', (53, 63))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (181, 186))	('metastasis', 'CPA', (204, 214))	('VEGFR2', 'Gene', '3791', (138, 144))	('AIP1', 'Gene', (8, 12))	('VEGFR2', 'Gene', (138, 144))	('enhances', 'PosReg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('facilitating', 'PosReg', (168, 180))
99613	30464518	The abnormal methylation in the AIP1 promoter can lead to the downregulation of the gene and the loss of its tumor-suppressing function.	('abnormal methylation', 'Var', (4, 24))	('AIP1', 'Gene', (32, 36))	('loss', 'NegReg', (97, 101))	('methylation', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('downregulation', 'NegReg', (62, 76))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
99617	30464518	Moreover, studies have found that AIP1 limits tumor metastasis by inhibiting the EMT, tumor angiogenesis, and the formation of the pre-metastatic niche.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (46, 51))	('limits', 'NegReg', (39, 45))	('inhibiting', 'NegReg', (66, 76))	('EMT', 'CPA', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('AIP1', 'Var', (34, 38))	('formation of the pre-metastatic niche', 'CPA', (114, 151))
99628	30464518	MVD in tumors was associated with more malignant phenotypes, including lymph node metastasis and late clinical stages.	('MVD', 'Var', (0, 3))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('lymph node metastasis', 'CPA', (71, 92))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
99629	30464518	Some studies have shown that the absence of AIP1 in vascular endothelial cells is sufficient to enhance tumor growth and metastasis of subcutaneous melanoma and in situ in breast cancer models.	('metastasis of subcutaneous melanoma', 'Disease', (121, 156))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('absence', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('enhance', 'PosReg', (96, 103))	('tumor', 'Disease', (104, 109))	('AIP1', 'Gene', (44, 48))	('breast cancer', 'Disease', (172, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('metastasis of subcutaneous melanoma', 'Disease', 'MESH:D009362', (121, 156))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
99631	30464518	Therefore, a decrease or deletion of AIP1 expression may be an important factor that promotes angiogenesis in ESCC, and the subsequent tumor growth and metastasis.	('angiogenesis', 'CPA', (94, 106))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('decrease', 'NegReg', (13, 21))	('tumor', 'Disease', (135, 140))	('promotes', 'PosReg', (85, 93))	('AIP1', 'Gene', (37, 41))	('deletion', 'Var', (25, 33))	('ESCC', 'Disease', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
99635	30464518	The deficiency of its expression was associated with tumor angiogenesis and poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('deficiency', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('associated', 'Reg', (37, 47))	('tumor', 'Disease', (53, 58))	('expression', 'MPA', (22, 32))
99734	27072986	Missense mutations in CHN1 have been associated with variants of Duane's retraction syndrome and cranial nerve abnormalities.	('cranial nerve abnormalities', 'Disease', 'MESH:D003389', (97, 124))	('retraction syndrome', 'Disease', 'MESH:D004370', (73, 92))	('CHN1', 'Gene', '1123', (22, 26))	('cranial nerve abnormalities', 'Disease', (97, 124))	('cranial nerve abnormalities', 'Phenotype', 'HP:0001291', (97, 124))	("Duane's retraction", 'Phenotype', 'HP:0009921', (65, 83))	('CHN1', 'Gene', (22, 26))	('associated', 'Reg', (37, 47))	('variants', 'Var', (53, 61))	('retraction syndrome', 'Disease', (73, 92))	('Missense mutations', 'Var', (0, 18))
99744	26886630	We therefore meta-analyzed available observational studies with Mendelian randomization method to explore this causal association by employing IL-10 gene 3 variants (-592C>A, -819C>T, and -1082A>G) as instruments.	('IL-10', 'Gene', '3586', (143, 148))	('-1082A>G', 'Mutation', 'rs1800896', (188, 196))	('-592C>A', 'Mutation', 'rs1800872', (166, 173))	('-819C>T', 'Mutation', 'rs1800871', (175, 182))	('IL-10', 'Gene', (143, 148))	('-592C>A', 'Var', (166, 173))
99749	26886630	Our findings provided evidence for a causal role of genetically elevated IL-10 in the development of gastric cancer, especially in East Asians and for intestinal type gastric cancer.	('genetically elevated', 'Var', (52, 72))	('IL-10', 'Gene', (73, 78))	('gastric cancer', 'Disease', (101, 115))	('intestinal type gastric cancer', 'Disease', (151, 181))	('intestinal type gastric cancer', 'Disease', 'MESH:D013274', (151, 181))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('IL-10', 'Gene', '3586', (73, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
99752	26886630	For example, family members who have a mutation in a mismatch repair gene are observed to have a much higher rate of colorectal cancer than those who do not have the mutation.	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('mutation', 'Var', (39, 47))	('mismatch repair gene', 'Gene', (53, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('colorectal cancer', 'Disease', (117, 134))
99757	26886630	The genomic sequence of IL-10 gene is highly polymorphic and 3 promoter variants, viz -592C>A (rs1800872), -819C>T (rs1800871), and -1082A>G (rs1800896), in possible association with alterations of IL-10 function are well-defined from different populations with varying prevalence.	('rs1800871', 'Mutation', 'rs1800871', (116, 125))	('-819C>T', 'Mutation', 'rs1800871', (107, 114))	('IL-10', 'Gene', '3586', (24, 29))	('rs1800872', 'Var', (95, 104))	('rs1800872', 'Mutation', 'rs1800872', (95, 104))	('IL-10', 'Gene', (198, 203))	('rs1800896', 'Mutation', 'rs1800896', (142, 151))	('-592C>A', 'Mutation', 'rs1800872', (86, 93))	('IL-10', 'Gene', (24, 29))	('IL-10', 'Gene', '3586', (198, 203))	('-1082A>G', 'Mutation', 'rs1800896', (132, 140))	('rs1800871', 'Var', (116, 125))
99760	26886630	Bearing this in mind, we first meta-analyzed the association of 3 aforementioned variants in IL-10 gene with digestive cancer risk and changes of circulating IL-10 level.	('IL-10', 'Gene', '3586', (158, 163))	('IL-10', 'Gene', '3586', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('association', 'Interaction', (49, 60))	('cancer', 'Disease', (119, 125))	('IL-10', 'Gene', (158, 163))	('IL-10', 'Gene', (93, 98))	('variants', 'Var', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
99761	26886630	Second, we selected the variant(s) that can be simultaneously predictive of digestive cancers and circulating IL-10 as an instrument to explore their potential causal relevance by implementing Mendelian randomization method.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('IL-10', 'Gene', '3586', (110, 115))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('variant', 'Var', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('IL-10', 'Gene', (110, 115))
99762	26886630	A literature search for observational studies that investigated the association between IL-10 gene 3 variants (-592C>A, -819C>T, and -1082A>G) and all types of digestive cancers was conducted of PubMed and Google Scholar databases covering the period from the earliest possible year to May 1, 2015.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('IL-10', 'Gene', (88, 93))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('-1082A>G', 'Mutation', 'rs1800896', (133, 141))	('-819C>T', 'Mutation', 'rs1800871', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('-592C>A', 'Var', (111, 118))	('IL-10', 'Gene', '3586', (88, 93))	('-592C>A', 'Mutation', 'rs1800872', (111, 118))
99763	26886630	Subject terms used for the search included "interleukin 10," "interleukin-10," "IL 10," "IL-10," "gastric or stomach," "colorectal or colon or rectal," "esophageal," "liver or hepatic or hepatocellular," "pancreatic," "gallbladder or biliary," "cancer or carcinoma or tumor or sarcoma or leiomyoma," together with "polymorphism or genetic or variant or mutation or allele or genotype."	('gallbladder', 'Disease', (219, 230))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('sarcoma', 'Disease', 'MESH:D012509', (277, 284))	('pancreatic', 'Disease', (205, 215))	('IL-10', 'Gene', (89, 94))	('colorectal or colon', 'Disease', (120, 139))	('sarcoma', 'Disease', (277, 284))	('polymorphism', 'Var', (315, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('carcinoma or tumor', 'Disease', (255, 273))	('variant', 'Var', (342, 349))	('interleukin-10', 'Gene', (62, 76))	('interleukin 10,"', 'Gene', '3586', (44, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('leiomyoma', 'Disease', 'MESH:D007889', (288, 297))	('cancer', 'Disease', (245, 251))	('interleukin-10', 'Gene', '3586', (62, 76))	('carcinoma or tumor', 'Disease', 'MESH:D009369', (255, 273))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('esophageal', 'Disease', (153, 163))	('pancreatic', 'Disease', 'MESH:D010195', (205, 215))	('IL 10', 'Gene', (80, 85))	('colorectal or colon', 'Disease', 'MESH:D015179', (120, 139))	('IL 10', 'Gene', '3586', (80, 85))	('leiomyoma', 'Disease', (288, 297))	('IL-10', 'Gene', '3586', (89, 94))
99765	26886630	Data were collected on the 1st author, publication year, ethnicity of the study subjects, cancer type, study design, sample size, the genotype/allele counts of 3 examined variants between cases and controls, and the characteristics of the study subjects, if available, including age, gender, body mass index (BMI), smoking, drinking, family history of cancers, history of digestive diseases, and bacteria or virus infection status.	('cancers', 'Disease', (352, 359))	('cancers', 'Disease', 'MESH:D009369', (352, 359))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer type', 'Disease', (90, 101))	('bacteria or virus infection status', 'Disease', 'MESH:D013226', (396, 430))	('digestive diseases', 'Disease', (372, 390))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('cancer type', 'Disease', 'MESH:D009369', (90, 101))	('digestive diseases', 'Phenotype', 'HP:0011024', (372, 390))	('bacteria or virus infection status', 'Disease', (396, 430))	('cancers', 'Phenotype', 'HP:0002664', (352, 359))	('variants', 'Var', (171, 179))
99766	26886630	In this meta-analysis, the association of 3 variants in IL-10 gene with digestive cancer risk was calculated under 3 genetic models of inheritance, including allelic model, homozygous genotypic model, and dominant model.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('variants', 'Var', (44, 52))	('association', 'Interaction', (27, 38))	('IL-10', 'Gene', '3586', (56, 61))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('IL-10', 'Gene', (56, 61))
99769	26886630	Additionally, to account for the sources of heterogeneity from continuous confounders such as age, sex, BMI, smoking, drinking, family history of cancer, and Helicobacter pylori infection (only for gastric cancer studies), a set of meta-regression analyses were performed to evaluate the association of 3 examined variants with digestive cancer risk.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', (338, 344))	('gastric cancer', 'Disease', (198, 212))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('Helicobacter pylori infection', 'Disease', 'MESH:D016481', (158, 187))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('Helicobacter pylori infection', 'Disease', (158, 187))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('variants', 'Var', (314, 322))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (158, 187))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('association', 'Interaction', (288, 299))	('cancer', 'Disease', 'MESH:D009369', (338, 344))
99770	26886630	For the variant that was simultaneously associated with the significant risk of digestive cancers or its subtypes and the significant changes of circulating IL-10 level, Mendelian randomization analysis was accordingly performed.	('variant', 'Var', (8, 15))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IL-10', 'Gene', (157, 162))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('IL-10', 'Gene', '3586', (157, 162))	('associated', 'Reg', (40, 50))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
99772	26886630	The baseline characteristics of all 56 qualified studies are shown in Table 1, and the genotype distributions and allele frequencies of 3 examined variants (-592C>A, -819C>T, and -1082A>G) in IL-10 gene between cases and controls are provided in Supplementary Table 1.	('-819C>T', 'Mutation', 'rs1800871', (166, 173))	('-592C>A', 'Var', (157, 164))	('IL-10', 'Gene', '3586', (192, 197))	('-592C>A', 'Mutation', 'rs1800872', (157, 164))	('IL-10', 'Gene', (192, 197))	('-1082A>G', 'Mutation', 'rs1800896', (179, 187))
99774	26886630	Pooling 56 qualified studies together revealed no significant association between 3 examined variants (-592C>A, -819C>T, and -1082A>G) and digestive cancers under all 3 genetic models, yet there was evident heterogeneity.	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('-1082A>G', 'Mutation', 'rs1800896', (125, 133))	('-819C>T', 'Mutation', 'rs1800871', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('-592C>A', 'Var', (103, 110))	('-592C>A', 'Mutation', 'rs1800872', (103, 110))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
99775	26886630	What is more, for -592C>A and -819C>T, there was no indication of significance in subgroup analyses, except for a relatively weak association between -592C>A and biliary tract cancer (OR = 1.30; 95% CI: 1.03-1.63; P = 0.028) and between -819C>T and gastric cancer (OR = 0.87; 95% CI: 0.77-0.97; P = 0.016) under allelic model (Table S2).	('biliary tract cancer', 'Disease', (162, 182))	('-592C>A', 'Mutation', 'rs1800872', (150, 157))	('between -819C>T', 'Var', (229, 244))	('gastric cancer', 'Disease', (249, 263))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('-819C>T', 'Mutation', 'rs1800871', (30, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (249, 263))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('-819C>T', 'Mutation', 'rs1800871', (237, 244))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (162, 182))	('gastric cancer', 'Phenotype', 'HP:0012126', (249, 263))	('biliary tract cancer', 'Disease', 'MESH:D001661', (162, 182))	('-592C>A', 'Mutation', 'rs1800872', (18, 25))
99790	26886630	By meta-analyzing of the data from 56 studies and on 29,307 subjects, we investigated 3 promoter variants (-592C>A, -819C>T, and -1082A>G) in IL-10 gene and its circulating level in association with the risk of digestive cancers.	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('-1082A>G', 'Mutation', 'rs1800896', (129, 137))	('cancers', 'Disease', (221, 228))	('IL-10', 'Gene', '3586', (142, 147))	('association', 'Reg', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('-819C>T', 'Mutation', 'rs1800871', (116, 123))	('-592C>A', 'Mutation', 'rs1800872', (107, 114))	('-592C>A', 'Var', (107, 114))	('IL-10', 'Gene', (142, 147))
99791	26886630	The most noteworthy finding of this study was that genetically elevated circulating IL-10 was significantly associated with an increased risk of gastric cancer by employing -1082A>G as an instrument.	('gastric cancer', 'Disease', 'MESH:D013274', (145, 159))	('IL-10', 'Gene', (84, 89))	('-1082A>G', 'Mutation', 'rs1800896', (173, 181))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (127, 159))	('gastric cancer', 'Phenotype', 'HP:0012126', (145, 159))	('employing -1082A>G', 'Var', (163, 181))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('associated', 'Reg', (108, 118))	('IL-10', 'Gene', '3586', (84, 89))	('elevated', 'PosReg', (63, 71))	('elevated circulating IL-10', 'Phenotype', 'HP:0030783', (63, 89))	('gastric cancer', 'Disease', (145, 159))
99793	26886630	To the best of our knowledge, this is the first meta-analysis interrogating the causal relevance of circulating IL-10 and gastric cancer by implementing Mendelian randomization method.	('IL-10', 'Gene', (112, 117))	('circulating', 'Var', (100, 111))	('gastric cancer', 'Disease', (122, 136))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('IL-10', 'Gene', '3586', (112, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
99800	26886630	The IL-10 variant (-1082A>G) that investigated in the present study lies within an ETS-like recognition site and may consequently affect the binding of this transcription factor and influence IL-10 production.	('IL-10', 'Gene', '3586', (4, 9))	('-1082A>G', 'Mutation', 'rs1800896', (19, 27))	('IL-10', 'Gene', '3586', (192, 197))	('binding', 'Interaction', (141, 148))	('-1082A>G', 'Var', (19, 27))	('affect', 'Reg', (130, 136))	('IL-10', 'Gene', (4, 9))	('influence', 'Reg', (182, 191))	('IL-10', 'Gene', (192, 197))
99802	26886630	Although enormous efforts have been made to explore genetic susceptibility of IL-10 gene -1082A>G to gastric cancer risk, there has been little attention on specific subtypes of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('gastric cancer', 'Disease', (101, 115))	('IL-10', 'Gene', (78, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('gastric cancer', 'Disease', (178, 192))	('-1082A>G', 'Mutation', 'rs1800896', (89, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (178, 192))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('gene -1082A>G', 'Var', (84, 97))	('IL-10', 'Gene', '3586', (78, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (178, 192))
99811	26886630	Taken together, our findings provided evidence for a causal role of genetically elevated circulating IL-10 in the development of gastric cancer by employing IL-10 gene -1082A>G as an instrument, and the risk association of this variant with digestive cancers was more evident in patients with intestinal type gastric cancer.	('elevated circulating IL-10', 'Phenotype', 'HP:0030783', (80, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('gene -1082A>G', 'Var', (163, 176))	('intestinal type gastric cancer', 'Disease', 'MESH:D013274', (293, 323))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('-1082A>G', 'Mutation', 'rs1800896', (168, 176))	('gastric cancer', 'Disease', 'MESH:D013274', (309, 323))	('IL-10', 'Gene', '3586', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('IL-10', 'Gene', (157, 162))	('IL-10', 'Gene', '3586', (101, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))	('IL-10', 'Gene', (101, 106))	('circulating', 'MPA', (89, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (309, 323))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('cancers', 'Disease', (251, 258))	('patients', 'Species', '9606', (279, 287))	('elevated', 'PosReg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('genetically', 'Var', (68, 79))	('gastric cancer', 'Disease', (129, 143))	('intestinal type gastric cancer', 'Disease', (293, 323))
99916	25943908	This disruption elevates the bioavailability of androgen which can initiate prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('disruption', 'Var', (5, 15))	('bioavailability of androgen', 'MPA', (29, 56))	('elevates', 'Reg', (16, 24))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
99946	24886020	The correlation analysis demonstrated that PNI in ESCC was significantly correlated with tumor differentiation, infiltration depth, pN classification and stage (P < 0.05).	('correlated', 'Reg', (73, 83))	('ESCC', 'Gene', (50, 54))	('PNI', 'Var', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
99962	24886020	Moreover, PNI in N0 esophageal cancer was found to have no association with cancer-specific survival following curative esophagectomy in a univariate statistical analysis.	('esophageal cancer', 'Disease', (20, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PNI', 'Var', (10, 13))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
99988	24886020	A further correlation analysis demonstrated that the presence of PNI was significantly correlated with tumor differentiation, infiltration depth, pN classification and ESCC stage (P < 0.05, Table 1).	('infiltration depth', 'CPA', (126, 144))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('correlated', 'Reg', (87, 97))	('tumor', 'Disease', (103, 108))	('presence', 'Var', (53, 61))	('ESCC', 'Disease', (168, 172))	('PNI', 'Gene', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
99998	24886020	After controlling for patient gender, tumor differentiation, pT status, pN status and stage, the multivariate analysis confirmed that the presence of PNI was a significant independent prognostic factor for poor overall survival (hazard ratio, 1.374; 95% CI, 1.037-1.820; P = 0.027; Table 3).	('presence', 'Var', (138, 146))	('tumor', 'Disease', (38, 43))	('C', 'Chemical', 'MESH:D002244', (254, 255))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('overall survival', 'MPA', (211, 227))	('PNI', 'Gene', (150, 153))	('poor', 'NegReg', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('patient', 'Species', '9606', (22, 29))
100000	24886020	Applying Harrell's C-index to test the predictive ability of integrating PNI into the prognostic model in ESCC patients, our results showed that the PNI status improved the predictive ability when compared with the clinicopathologic model (C-indexes of 0.739 v 0.706, respectively).	('predictive ability', 'MPA', (173, 191))	('C', 'Chemical', 'MESH:D002244', (108, 109))	('ESCC', 'Disease', (106, 110))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('improved', 'PosReg', (160, 168))	('C', 'Chemical', 'MESH:D002244', (240, 241))	('PNI status', 'Var', (149, 159))	('patients', 'Species', '9606', (111, 119))
100011	24886020	A further correlation analysis revealed that the presence of PNI in ESCCs was significantly associated with tumor differentiation, infiltrate depth, pN status and stage.	('presence', 'Var', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('PNI', 'Gene', (61, 64))	('infiltrate depth', 'CPA', (131, 147))	('associated', 'Reg', (92, 102))	('pN status', 'Disease', (149, 158))
100015	24886020	Furthermore, the presence of PNI was found to be correlated with tumor size, margin status, lymph node metastasis and AJCC stage in patients with pancreatic ductal adenocarcinoma.	('correlated', 'Reg', (49, 59))	('pancreatic ductal adenocarcinoma', 'Disease', (146, 178))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (146, 178))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (146, 178))	('tumor', 'Disease', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('lymph', 'Disease', (92, 97))	('PNI', 'Gene', (29, 32))	('presence', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('patients', 'Species', '9606', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
100018	24886020	showed a significant association between the presence of PNI and the poor survival of patients with ESCC as evidenced by a univariate analysis.	('ESCC', 'Disease', (100, 104))	('poor survival', 'CPA', (69, 82))	('PNI', 'Gene', (57, 60))	('presence', 'Var', (45, 53))	('patients', 'Species', '9606', (86, 94))
100019	24886020	Other groups have reported similar results, in which PNI was a significant pathologic parameter in head and neck cancers, heralding decreased survival, increased locoregional recurrence rates and a shorter time to relapse.	('PNI', 'Var', (53, 56))	('increased', 'PosReg', (152, 161))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('neck cancers', 'Disease', (108, 120))	('head and neck cancers', 'Phenotype', 'HP:0012288', (99, 120))	('locoregional recurrence rates', 'CPA', (162, 191))	('neck cancers', 'Disease', 'MESH:D006258', (108, 120))	('decreased', 'NegReg', (132, 141))	('survival', 'CPA', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
100021	24886020	Importantly, PNI in pT3N0 rectal cancer is also found to be an independent risk predictor of a local recurrence.	('rectal cancer', 'Disease', (26, 39))	('rectal cancer', 'Phenotype', 'HP:0100743', (26, 39))	('PNI', 'Var', (13, 16))	('pT3N0', 'Var', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('local', 'CPA', (95, 100))	('rectal cancer', 'Disease', 'MESH:D012004', (26, 39))
100025	24886020	Generally, our results support the idea that the presence of PNI may improve the ability to discriminate among ESCC patients' outcomes, especially for patients who are node-negative.	('presence', 'Var', (49, 57))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (151, 159))	('PNI', 'Gene', (61, 64))	('improve', 'PosReg', (69, 76))	('ESCC', 'Disease', (111, 115))
100044	33693954	The silencing of TGIF1 by siRNA interference significantly inhibited the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process of KYSE-150 esophageal cancer cells, and promoted cell apoptosis.	('epithelial-mesenchymal transition', 'CPA', (112, 145))	('cancer', 'Disease', (183, 189))	('TGIF1', 'Gene', (17, 22))	('proliferation', 'CPA', (73, 86))	('inhibited', 'NegReg', (59, 68))	('siRNA interference', 'MPA', (26, 44))	('migration', 'CPA', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('invasion', 'CPA', (99, 107))	('promoted', 'PosReg', (201, 209))	('cell apoptosis', 'CPA', (210, 224))	('silencing', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
100045	33693954	Furthermore, the data indicated that the Wnt/beta-catenin and Akt/mammalian target of rapamycin (mTOR) signaling pathways were inhibited by TGIF1 knockdown, and were promoted by the overexpression of TGIF1.	('knockdown', 'Var', (146, 155))	('mTOR', 'Gene', '2475', (97, 101))	('Wnt', 'Gene', '7471;89780', (41, 44))	('beta-catenin', 'Gene', '1499', (45, 57))	('mTOR', 'Gene', (97, 101))	('Akt', 'Gene', '207', (62, 65))	('Wnt', 'Gene', (41, 44))	('inhibited', 'NegReg', (127, 136))	('TGIF1', 'Gene', (200, 205))	('beta-catenin', 'Gene', (45, 57))	('mammalian target of rapamycin', 'Gene', '2475', (66, 95))	('mammalian target of rapamycin', 'Gene', (66, 95))	('TGIF1', 'Gene', (140, 145))	('promoted', 'PosReg', (166, 174))	('Akt', 'Gene', (62, 65))
100046	33693954	It was also confirmed that TGIF1 knockdown reduced tumor growth, inhibited Wnt/beta-catenin and Akt/mTOR pathway activation, and reversed the TGF-beta1-mediated EMT process in a tumor xenograft model.	('reduced', 'NegReg', (43, 50))	('beta-catenin', 'Gene', (79, 91))	('TGIF1', 'Gene', (27, 32))	('Wnt', 'Gene', (75, 78))	('tumor', 'Disease', (178, 183))	('beta-catenin', 'Gene', '1499', (79, 91))	('TGF-beta1', 'Gene', (142, 151))	('tumor', 'Disease', (51, 56))	('activation', 'PosReg', (113, 123))	('inhibited', 'NegReg', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('reversed', 'NegReg', (129, 137))	('knockdown', 'Var', (33, 42))	('TGF-beta1', 'Gene', '7040', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mTOR', 'Gene', (100, 104))	('Akt', 'Gene', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('EMT process in a', 'CPA', (161, 177))	('Akt', 'Gene', '207', (96, 99))	('Wnt', 'Gene', '7471;89780', (75, 78))	('mTOR', 'Gene', '2475', (100, 104))
100057	33693954	Wang et al reported that the knockdown of TGIF inhibited the proliferation of EC-109 cells.	('proliferation of EC-109 cells', 'CPA', (61, 90))	('inhibited', 'NegReg', (47, 56))	('knockdown', 'Var', (29, 38))	('TGIF', 'Gene', '7050', (42, 46))	('TGIF', 'Gene', (42, 46))	('EC-109', 'CellLine', 'CVCL:6898', (78, 84))
100060	33693954	The data presented herein indicate that TGIF1 is significantly upregulated in esophageal cancer tissues and cells, and that TGIF1 knockdown reduces the proliferation and tumorigenicity of esophageal cancer in vivo and in vitro.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('reduces', 'NegReg', (140, 147))	('esophageal', 'Disease', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('proliferation', 'CPA', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('knockdown', 'Var', (130, 139))	('TGIF1', 'Gene', (124, 129))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumor', 'Disease', (170, 175))	('upregulated', 'PosReg', (63, 74))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (199, 205))	('TGIF1', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
100076	33693954	60004-1-lg) antibodies were obtained from Proteintech Group, Inc. Anti-cleaved caspase-3 (cat.	('caspase-3', 'Gene', (79, 88))	('caspase-3', 'Gene', '836', (79, 88))	('Anti-cleaved', 'Var', (66, 78))
100092	33693954	Five different tumor models were established: i) si-TGIF1-1#; ii) si-TGIF1-2#; iii) si-NC; iv) OE-NC; v) TGIF1-OE (n=5 per group).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('si-TGIF1-1#', 'Var', (49, 60))	('si-TGIF1-2#', 'Var', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('si-NC', 'Var', (84, 89))
100106	33693954	Subsequently, CCK-8 and colony formation assays were performed to examine the proliferative ability of the 2 esophageal cancer cells following transfection with si-TGIF1 or pcDNA3.1-TGF1 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('pcDNA3.1-TGF1', 'Var', (173, 186))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('si-TGIF1', 'Var', (161, 169))	('proliferative ability', 'CPA', (78, 99))
100109	33693954	The results indicated that the expression of N-cadherin and Snail was significantly decreased in the KYSE-150 cells transfected with si-TGIF1, while E-cadherin expression was upregulated (Fig.	('expression', 'MPA', (160, 170))	('Snail', 'Gene', (60, 65))	('si-TGIF1', 'Var', (133, 141))	('Snail', 'Gene', '6615', (60, 65))	('N-cadherin', 'Gene', (45, 55))	('upregulated', 'PosReg', (175, 186))	('expression', 'MPA', (31, 41))	('decreased', 'NegReg', (84, 93))	('N-cadherin', 'Gene', '1000', (45, 55))	('E-cadherin', 'Gene', (149, 159))	('E-cadherin', 'Gene', '999', (149, 159))
100111	33693954	Furthermore, western blot analysis revealed that the expression of the anti-apoptotic protein, Bcl-2, was significantly downregulated by si-TGIF1, whereas it was upregulated by TGIF1 overexpression.	('downregulated', 'NegReg', (120, 133))	('si-TGIF1', 'Var', (137, 145))	('upregulated', 'PosReg', (162, 173))	('expression', 'MPA', (53, 63))	('Bcl-2', 'Gene', (95, 100))	('Bcl-2', 'Gene', '596', (95, 100))
100113	33693954	Taken together, these results revealed that the silencing of TGIF1 induced the apoptosis of esophageal cancer cells by regulating the Bcl-2/Bax axis and caspase-3 activation.	('Bax', 'Gene', '581', (140, 143))	('silencing', 'Var', (48, 57))	('activation', 'PosReg', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('caspase-3', 'Gene', (153, 162))	('regulating', 'Reg', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('apoptosis', 'CPA', (79, 88))	('Bax', 'Gene', (140, 143))	('caspase-3', 'Gene', '836', (153, 162))	('Bcl-2', 'Gene', '596', (134, 139))	('TGIF1', 'Gene', (61, 66))	('cancer', 'Disease', (103, 109))	('Bcl-2', 'Gene', (134, 139))
100115	33693954	4, it was found that the silencing TGIF1 inhibited the expression of Wnt3a and beta-catenin, which was upregulated in TGIF1-overexpressing cells, suggesting that TGIF1 also promoted Wnt/beta-catenin signaling in esophageal cancer cells.	('silencing', 'Var', (25, 34))	('Wnt', 'Gene', (69, 72))	('cancer', 'Disease', (223, 229))	('beta-catenin', 'Gene', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('TGIF1', 'Gene', (35, 40))	('beta-catenin', 'Gene', '1499', (79, 91))	('Wnt3a', 'Gene', '89780', (69, 74))	('Wnt', 'Gene', '7471;89780', (182, 185))	('promoted', 'PosReg', (173, 181))	('expression', 'MPA', (55, 65))	('Wnt3a', 'Gene', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('inhibited', 'NegReg', (41, 50))	('Wnt', 'Gene', (182, 185))	('beta-catenin', 'Gene', (186, 198))	('Wnt', 'Gene', '7471;89780', (69, 72))	('beta-catenin', 'Gene', '1499', (186, 198))	('upregulated', 'PosReg', (103, 114))
100117	33693954	TGIF1 knockdown suppressed the phosphorylation of Akt, and mTOR and cyclin D1 expression in the KYSE-150 cells, while TGIF1 overexpression increased the expression of these proteins in the Eca-109 cells (Fig.	('suppressed', 'NegReg', (16, 26))	('TGIF1', 'Gene', (0, 5))	('expression', 'MPA', (78, 88))	('Akt', 'Gene', '207', (50, 53))	('increased', 'PosReg', (139, 148))	('Akt', 'Gene', (50, 53))	('phosphorylation', 'MPA', (31, 46))	('TGIF1', 'Gene', (118, 123))	('cyclin D1', 'Gene', '595', (68, 77))	('expression', 'MPA', (153, 163))	('knockdown', 'Var', (6, 15))	('mTOR', 'Gene', '2475', (59, 63))	('cyclin D1', 'Gene', (68, 77))	('mTOR', 'Gene', (59, 63))
100118	33693954	4), suggesting that TGIF1 cab promote the activation of the Akt/mTOR signaling pathway in esophageal cancer cells and that the knockdown TGIF1 arrested the cell cycle in the G1 phase.	('TGIF1', 'Gene', (20, 25))	('TGIF1', 'Gene', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('arrested', 'NegReg', (143, 151))	('cancer', 'Disease', (101, 107))	('Akt', 'Gene', '207', (60, 63))	('mTOR', 'Gene', (64, 68))	('Akt', 'Gene', (60, 63))	('mTOR', 'Gene', '2475', (64, 68))	('activation', 'PosReg', (42, 52))	('cell cycle in the G1 phase', 'CPA', (156, 182))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('knockdown', 'Var', (127, 136))
100119	33693954	To verify the effects of TGIF1 on esophageal cancer in vivo, KYSE-150 (si-NC, si-TGIF1-1#, si-TGIF1-2#) and Eca-109 (OE-NC,TGIF1-OE) subcutaneous xenograft tumor models were established using BALB/c nude mice and the relative tumor volume was measured.	('si-TGIF1-2#', 'Var', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (156, 161))	('si-TGIF1-1#', 'Var', (78, 89))	('nude mice', 'Species', '10090', (199, 208))	('cancer', 'Disease', (45, 51))	('tumor', 'Disease', (226, 231))
100120	33693954	Tumor growth was found to be markedly attenuated in the mice injected with the KYSE-150 cells and TGIF1 siRNA (si-TGIF1-1#, si-TGIF1-2#) compared with those injected with KYSE-150 cells and the negative control siRNA (si-NC; si-TGIF1-1# vs. si-NC group, P<0.05; si-TGIF1-2# vs. si-NC group, P<0.01; Fig.	('attenuated', 'NegReg', (38, 48))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('si-TGIF1-1', 'Var', (111, 121))	('mice', 'Species', '10090', (56, 60))	('TGIF1', 'Gene', (98, 103))	('Tumor growth', 'CPA', (0, 12))
100122	33693954	These data suggested that TGIF1 knockdown suppressed tumor formation and tumor growth in vivo, while the upregulation of TGIF1 enhanced tumor growth in vivo.	('enhanced', 'PosReg', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('upregulation', 'PosReg', (105, 117))	('TGIF1', 'Gene', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('knockdown', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('suppressed', 'NegReg', (42, 52))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (53, 58))	('TGIF1', 'Gene', (26, 31))	('tumor', 'Disease', (136, 141))
100124	33693954	5C and S2, the TGIF1, Snail and N-cadherin expression levels were downregulated by si-TGIF1 in the KYSE-150-derived tumor xenografts, whereas these were upregulated by TGIF1 overexpression in the Eca-109-derived tumor xenografts.	('N-cadherin', 'Gene', '1000', (32, 42))	('Snail', 'Gene', '6615', (22, 27))	('N-cadherin', 'Gene', (32, 42))	('TGIF1', 'MPA', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('downregulated', 'NegReg', (66, 79))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('si-TGIF1', 'Var', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (212, 217))	('Snail', 'Gene', (22, 27))
100126	33693954	6 and S3, the expression levels of Wnt3a and beta-catenin were inhibited by the silencing of TGIF1, whereas they were upregulated by TGIF1 overexpression.	('expression levels', 'MPA', (14, 31))	('silencing', 'Var', (80, 89))	('Wnt3a', 'Gene', '89780', (35, 40))	('TGIF1', 'Gene', (93, 98))	('beta-catenin', 'Gene', '1499', (45, 57))	('inhibited', 'NegReg', (63, 72))	('Wnt3a', 'Gene', (35, 40))	('upregulated', 'PosReg', (118, 129))	('beta-catenin', 'Gene', (45, 57))
100127	33693954	TGIF1 knockdown suppressed the phosphorylation of Akt/mTOR and Ki-67 expression in the KYSE-150-deriged tumors, while TGIF1 overexpression increased the expression of these proteins in the Eca-109-derived tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Disease', (104, 110))	('expression', 'MPA', (153, 163))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('suppressed', 'NegReg', (16, 26))	('Ki-67', 'Gene', (63, 68))	('increased', 'PosReg', (139, 148))	('phosphorylation', 'MPA', (31, 46))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))	('TGIF1', 'Gene', (0, 5))	('Akt', 'Gene', (50, 53))	('mTOR', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('Akt', 'Gene', '207', (50, 53))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('expression', 'MPA', (69, 79))	('mTOR', 'Gene', '2475', (54, 58))	('TGIF1', 'Gene', (118, 123))	('knockdown', 'Var', (6, 15))
100128	33693954	The downregulation of p-mTOR by the knockdown of TGIF1 may be the key factor of the classical Akt/mTOR signaling pathway.	('Akt', 'Gene', (94, 97))	('TGIF1', 'Gene', (49, 54))	('knockdown', 'Var', (36, 45))	('downregulation', 'NegReg', (4, 18))	('mTOR', 'Gene', '2475', (98, 102))	('Akt', 'Gene', '207', (94, 97))	('mTOR', 'Gene', (98, 102))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))
100132	33693954	Another study by Wang et al reported that TGIF1 knockdown suppressed the migration and invasion of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('TGIF1', 'Gene', (42, 47))	('breast cancer', 'Disease', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('suppressed', 'NegReg', (58, 68))	('invasion of', 'CPA', (87, 98))	('knockdown', 'Var', (48, 57))
100133	33693954	The study by Haider et al further demonstrated that the lack of TGIF1 also restricted the progression of breast cancer bone metastases.	('breast cancer bone metastases', 'Disease', (105, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('restricted', 'NegReg', (75, 85))	('breast cancer bone metastases', 'Disease', 'MESH:D001943', (105, 134))	('progression', 'CPA', (90, 101))	('lack', 'Var', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('TGIF1', 'Gene', (64, 69))
100135	33693954	Weng et al also found that the loss of TGIF1 induced the development of pancreatic cancer.	('pancreatic cancer', 'Disease', (72, 89))	('loss', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('TGIF1', 'Gene', (39, 44))	('induced', 'Reg', (45, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
100137	33693954	It has been reported that the silencing of TGIF inhibits the proliferation and tumorigenicity of EC109 cells.	('tumor', 'Disease', (79, 84))	('inhibits', 'NegReg', (48, 56))	('TGIF', 'Gene', (43, 47))	('EC109', 'CellLine', 'CVCL:6898', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('silencing', 'Var', (30, 39))	('TGIF', 'Gene', '7050', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
100143	33693954	Furthermore, the present study demonstrated that TGIF1 increased the migratory and invasive capabilities of esophageal cancer cells and regulated the expression of EMT biomarkers; TGIF1 knockdown downregulated the N-cadherin and Snail expression, and upregulated E-cadherin expression in KYSE-150 cells and tumors, indicating that TGIF1 may increase the metastatic potential of esophageal cancer cells by regulating the EMT process.	('metastatic potential', 'CPA', (354, 374))	('expression', 'MPA', (235, 245))	('expression', 'MPA', (274, 284))	('increase', 'PosReg', (341, 349))	('upregulated', 'PosReg', (251, 262))	('cancer', 'Disease', (389, 395))	('Snail', 'Gene', '6615', (229, 234))	('knockdown', 'Var', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('cancer', 'Disease', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (307, 313))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('E-cadherin', 'Gene', (263, 273))	('E-cadherin', 'Gene', '999', (263, 273))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumors', 'Disease', (307, 313))	('Snail', 'Gene', (229, 234))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('N-cadherin', 'Gene', (214, 224))	('N-cadherin', 'Gene', '1000', (214, 224))	('TGIF1', 'Gene', (180, 185))	('regulating', 'Reg', (405, 415))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('downregulated', 'NegReg', (196, 209))	('tumors', 'Disease', 'MESH:D009369', (307, 313))	('EMT process', 'CPA', (420, 431))
100150	33693954	Herein, it was found that Wnt3a and beta-catenin expression was significantly downregulated in cells and tumors in which TGIF1 was knocked down, whereas it was upregulated by TGIF1 overexpression, indicating that TGIF1 may promote the progression of esophageal cancer partly by activating the Wnt/beta-catenin signaling pathway.	('tumors', 'Disease', (105, 111))	('activating', 'PosReg', (278, 288))	('knocked down', 'Var', (131, 143))	('Wnt3a', 'Gene', '89780', (26, 31))	('Wnt', 'Gene', '7471;89780', (26, 29))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('TGIF1', 'Gene', (121, 126))	('Wnt3a', 'Gene', (26, 31))	('expression', 'MPA', (49, 59))	('cancer', 'Disease', (261, 267))	('promote', 'PosReg', (223, 230))	('downregulated', 'NegReg', (78, 91))	('Wnt', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('beta-catenin', 'Gene', (36, 48))	('Wnt', 'Gene', '7471;89780', (293, 296))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('beta-catenin', 'Gene', '1499', (36, 48))	('upregulated', 'PosReg', (160, 171))	('beta-catenin', 'Gene', (297, 309))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('TGIF1', 'Var', (213, 218))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('Wnt', 'Gene', (293, 296))	('beta-catenin', 'Gene', '1499', (297, 309))
100156	33693954	In conclusion, the present study demonstrated that the silencing of TGIF1 suppressed esophageal cancer cell proliferation, migration and invasion, and promoted apoptosis, suggesting that TGIF1 plays oncogenic role in the progression of esophageal cancer.	('apoptosis', 'CPA', (160, 169))	('TGIF1', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('suppressed', 'NegReg', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('invasion', 'CPA', (137, 145))	('silencing', 'Var', (55, 64))	('promoted', 'PosReg', (151, 159))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
100172	31632504	Moreover, siRNA-mediated knockdown of KLF5 blocked the expression of CDX2, MUC2 and villin, but transfection of a KLF5 expression vector into esophageal epithelial cells promoted their transdifferentiation into columnar-like cells, as demonstrated by increased expression of the intestinal markers CDX2, MUC2 and villin.	('increased', 'PosReg', (251, 260))	('rat', 'Species', '10116', (242, 245))	('CDX2', 'Gene', '1045', (69, 73))	('transfection', 'Var', (96, 108))	('CDX2', 'Gene', (298, 302))	('transdifferentiation', 'CPA', (185, 205))	('expression', 'MPA', (261, 271))	('CDX2', 'Gene', '1045', (298, 302))	('CDX2', 'Gene', (69, 73))	('promoted', 'PosReg', (170, 178))
100193	31632504	demonstrated that the deletion of KLF5 in the postnatal intestinal epithelium disrupted the intestinal crypt architecture and the balance between goblet and enteroendocrine cells within the colon.	('KLF5', 'Gene', (34, 38))	('disrupted', 'NegReg', (78, 87))	('deletion', 'Var', (22, 30))	('rat', 'Species', '10116', (7, 10))	('intestinal crypt architecture', 'CPA', (92, 121))
100236	31632504	Proteins were separated via SDS-PAGE, transferred to PVDF membranes (Millipore, Temecula, CA, USA), blocked with milk/BSA, and then probed with specific antibodies against KLF5 (1:1000), CDX2 (1:800), MUC2 (1:1000), villin (1:1000) (all from Abcam, Cambridge, MA, USA) and GAPDH (1:2000, Kangchen, Shanghai, China).	('rat', 'Species', '10116', (18, 21))	('CDX2', 'Gene', (187, 191))	('CDX2', 'Gene', '1045', (187, 191))	('1:1000', 'Var', (224, 230))	('SDS', 'Chemical', 'MESH:C032259', (28, 31))	('1:800', 'Var', (193, 198))	('1:1000', 'Var', (207, 213))	('PVDF', 'Chemical', 'MESH:C024865', (53, 57))	('GAPDH', 'Gene', '2597', (273, 278))	('GAPDH', 'Gene', (273, 278))	('1:1000', 'Var', (178, 184))
100253	31632504	Results showed that KLF5 siRNA transfection into Het-1A cells significantly inhibited DCA-induced KLF5 expression and reduced the expression of Cdx2, MUC2 and villin (Fig.	('Cdx2', 'Gene', (144, 148))	('expression', 'MPA', (130, 140))	('MUC2', 'Gene', (150, 154))	('DCA', 'Chemical', 'MESH:D003840', (86, 89))	('reduced', 'NegReg', (118, 125))	('transfection', 'Var', (31, 43))	('villin', 'Gene', (159, 165))	('inhibited', 'NegReg', (76, 85))	('DCA-induced KLF5 expression', 'MPA', (86, 113))
100259	31632504	KLF5 transfection up-regulated the expression of Cdx2, MUC2 and villin; conversely, KLF5 knockdown attenuated the DCA-induced expression of Cdx2, MUC2 and villin.	('DCA-induced', 'Disease', (114, 125))	('up-regulated', 'PosReg', (18, 30))	('expression', 'MPA', (126, 136))	('Cdx2', 'Gene', (49, 53))	('MUC2', 'Gene', (146, 150))	('expression', 'MPA', (35, 45))	('DCA', 'Chemical', 'MESH:D003840', (114, 117))	('knockdown', 'Var', (89, 98))	('KLF5', 'Gene', (84, 88))	('attenuated', 'NegReg', (99, 109))	('Cdx2', 'Gene', (140, 144))
100273	31632504	Transdifferentiation will occur if the combination of normally expressed transcription factors is altered during the course of regeneration due to mutation or environmental effects.	('Transdifferentiation', 'CPA', (0, 20))	('mutation', 'Var', (147, 155))	('rat', 'Species', '10116', (133, 136))	('men', 'Species', '9606', (166, 169))	('occur', 'Reg', (26, 31))
100280	31632504	We found that adenovirus-mediated over-expression of KLF5 increased CDX2, MUC2 and villin expression but that silencing of KLF5 using siRNA resulted in down-regulation of the expression of Cdx2, MUC2 and villin.	('Cdx2', 'Gene', (189, 193))	('down-regulation', 'NegReg', (152, 167))	('expression', 'MPA', (175, 185))	('MUC2', 'Gene', (195, 199))	('increased', 'PosReg', (58, 67))	('CDX2', 'Gene', (68, 72))	('silencing', 'Var', (110, 119))	('villin expression', 'MPA', (83, 100))	('villin', 'Gene', (204, 210))	('MUC2', 'MPA', (74, 78))	('CDX2', 'Gene', '1045', (68, 72))	('KLF5', 'Gene', (123, 127))	('over-expression', 'PosReg', (34, 49))
100408	30600600	For patients with IVb stage disease, the median OS was slightly better in the CCRT-2 group than in the CCRT-1 group and RT alone group.	('CCRT-2', 'Var', (78, 84))	('better', 'PosReg', (64, 70))	('patients', 'Species', '9606', (4, 12))
100416	30600600	For patients with IVb stage, PFS was slightly better in the CCRT-2 group than that in the CCRT-1 group and RT alone group.	('CCRT-2', 'Var', (60, 66))	('IVb', 'Disease', (18, 21))	('patients', 'Species', '9606', (4, 12))	('better', 'PosReg', (46, 52))	('PFS', 'MPA', (29, 32))
100421	30600600	As shown in Table 4, grade >=3 hematological toxicity was observed more frequently in the patients treated with CCRT-2 than in the patients who received CCRT-1 (42.7% vs 22.8%, P = 0.013) or patients who received RT alone (42.7% vs 5.1%, P = 0.000).	('patients', 'Species', '9606', (131, 139))	('hematological toxicity', 'Disease', (31, 53))	('patients', 'Species', '9606', (191, 199))	('CCRT-2', 'Var', (112, 118))	('patients', 'Species', '9606', (90, 98))	('hematological toxicity', 'Disease', 'MESH:D006402', (31, 53))
100422	30600600	The differences in leukocytopenia and weight loss during treatment for patients treated with CCRT-1 or CCRT-2 were statistically significant (P = 0.016 and P = 0.011, respectively).	('men', 'Species', '9606', (62, 65))	('weight loss', 'Disease', (38, 49))	('leukocytopenia', 'Disease', (19, 33))	('weight loss', 'Disease', 'MESH:D015431', (38, 49))	('patients', 'Species', '9606', (71, 79))	('weight loss', 'Phenotype', 'HP:0001824', (38, 49))	('CCRT-2', 'Var', (103, 109))	('leukocytopenia', 'Disease', 'MESH:D007970', (19, 33))
100444	30600600	In analysis of patients with IVb stage cancer, the OS and PFS were significantly different between patients who received CCRT-2 and RT alone but not between patients treated with CCRT-1 and RT alone.	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (157, 165))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('IVb stage cancer', 'Disease', 'MESH:D009085', (29, 45))	('IVb stage cancer', 'Disease', (29, 45))	('CCRT-2', 'Var', (121, 127))	('different', 'Reg', (81, 90))
100446	30600600	Furthermore, the ORR and DCR in the CCRT group were 76.7% and 96.0%, respectively, which were higher than those in the RT alone group (P = 0.006 and P = 0.184, respectively).	('ORR', 'MPA', (17, 20))	('higher', 'PosReg', (94, 100))	('DCR', 'CPA', (25, 28))	('DCR', 'Chemical', '-', (25, 28))	('CCRT', 'Var', (36, 40))
100451	30600600	However, Xu et al26 study indicated that patients received high-dose (>50 Gy) led to a improved survival compared with patients received low-dose (<=50 Gy).	('>50 Gy', 'Var', (70, 76))	('improved', 'PosReg', (87, 95))	('patients', 'Species', '9606', (119, 127))	('survival', 'CPA', (96, 104))	('patients', 'Species', '9606', (41, 49))
100455	30600600	In our study, the rate of grade 3 or 4 hematological toxicity in the CCRT group was significantly higher than that in the RT alone group (35.3% vs 5.1%).	('hematological toxicity', 'Disease', (39, 61))	('higher', 'PosReg', (98, 104))	('hematological toxicity', 'Disease', 'MESH:D006402', (39, 61))	('CCRT', 'Var', (69, 73))
100459	30600600	The results might be due to the number of chemotherapy drugs associated with an increased risk of toxicity in the elderly population with cancer,28 and aging was associated with decreased bone marrow reserve and an increased risk of myelosuppressive-associated complications from chemotherapy.29, 30 Receiving poly-chemotherapy may further enhance the myelosuppressive effect.	('enhance', 'PosReg', (340, 347))	('cancer', 'Disease', (138, 144))	('toxicity', 'Disease', 'MESH:D064420', (98, 106))	('toxicity', 'Disease', (98, 106))	('myelosuppressive effect', 'CPA', (352, 375))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('poly-chemotherapy', 'Var', (310, 327))	('decreased bone marrow', 'Phenotype', 'HP:0005528', (178, 199))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
100546	30355357	As reported, the incidence and mortality of myocardial infarction are lower among patients receiving CABG, compared with the results of noncardiac surgery after either PCI or CABG.	('myocardial infarction', 'Disease', (44, 65))	('CABG', 'Var', (101, 105))	('patients', 'Species', '9606', (82, 90))	('lower', 'NegReg', (70, 75))	('myocardial infarction', 'Phenotype', 'HP:0001658', (44, 65))	('myocardial infarction', 'Disease', 'MESH:D009203', (44, 65))
100581	24849736	In men, the supplement reduced the risk of fracture by 63% during the trial period, and this protective effect was sustained and statistically significant when analysis included both the trial period and 5 or 10 years of post-intervention follow-up (years 0-11, P=0.04, and years 0-16, P=0.02, respectively).	('men', 'Species', '9606', (18, 21))	('supplement', 'Var', (12, 22))	('fracture', 'Disease', 'MESH:D050723', (43, 51))	('reduced', 'NegReg', (23, 30))	('fracture', 'Disease', (43, 51))	('men', 'Species', '9606', (3, 6))
100598	24849736	Risk factors for osteoporosis and fractures in economically developed countries include skeletal structure, age, physical activity, calcium and vitamin D intake, low body weight, smoking, excess alcohol, falls, and genetics.	('osteoporosis', 'Disease', 'MESH:D010024', (17, 29))	('calcium', 'Chemical', 'MESH:D002118', (132, 139))	('osteoporosis', 'Disease', (17, 29))	('low body weight', 'Phenotype', 'HP:0004325', (162, 177))	('fractures', 'Disease', 'MESH:D050723', (34, 43))	('low body', 'Var', (162, 170))	('fractures', 'Disease', (34, 43))	('osteoporosis', 'Phenotype', 'HP:0000939', (17, 29))	('alcohol', 'Chemical', 'MESH:D000438', (195, 202))	('falls', 'Phenotype', 'HP:0002527', (204, 209))	('falls', 'Disease', (204, 209))	('vitamin D', 'Chemical', 'MESH:D014807', (144, 153))	('skeletal structure', 'CPA', (88, 106))
100657	24849736	Multivitamin supplementation also decreased the severity of fractures, as measured by the hospitalization rate in men over the whole study period.	('fractures', 'Disease', (60, 69))	('decreased', 'NegReg', (34, 43))	('men', 'Species', '9606', (114, 117))	('supplementation', 'Var', (13, 28))	('fractures', 'Disease', 'MESH:D050723', (60, 69))	('men', 'Species', '9606', (19, 22))	('Multivitamin', 'Protein', (0, 12))
100711	24314023	Furthermore, aberrant expression of miRNAs has been linked to the development and progression of cancer and has prognostic significance for several tumor types, including lung and esophageal squamous cell cancer, neuroblastoma and lymphocytic leukemia.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (191, 211))	('miR', 'Gene', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('leukemia', 'Phenotype', 'HP:0001909', (243, 251))	('aberrant', 'Var', (13, 21))	('neuroblastoma', 'Phenotype', 'HP:0003006', (213, 226))	('cancer', 'Disease', (205, 211))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (180, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('expression', 'MPA', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('lung', 'Disease', (171, 175))	('linked', 'Reg', (52, 58))	('tumor', 'Disease', (148, 153))	('neuroblastoma and lymphocytic leukemia', 'Disease', 'MESH:D009447', (213, 251))	('esophageal squamous cell cancer', 'Disease', (180, 211))	('miR', 'Gene', '220972', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
100749	24314023	Wild type and mutant human PTTG1 3'UTR fragments (bases 655-713, NM_004219) were created by two single-strand annealing (Sangon Biotech Co., Ltd, Shanghai).	('PTTG1', 'Gene', '9232', (27, 32))	('mutant', 'Var', (14, 20))	('human', 'Species', '9606', (21, 26))	('PTTG1', 'Gene', (27, 32))
100751	24314023	For the luciferase reporter assay, EC9706 and KYSE150 cells were transiently co-transfected with the pRL-TK Renilla plasmid (Promega, Madison, WI), matched reporter vectors (wild type reporter vectors or mutant reporter vectors), and miR-655 mimics or scrambled miR-655.	('miR-655', 'Gene', '724025', (234, 241))	('EC9706', 'Var', (35, 41))	('miR-655', 'Gene', '724025', (262, 269))	('mutant', 'Var', (204, 210))	('miR-655', 'Gene', (262, 269))	('miR-655', 'Gene', (234, 241))	('EC9706', 'CellLine', 'CVCL:E307', (35, 41))	('KYSE150', 'CellLine', 'CVCL:1348', (46, 53))
100763	24314023	A log-rank test indicated that primary ESCCs with moderate to strong PTTG1 expression (>0.7770) were associated with significantly worse survival than ESCCs with weak PTTG1 expression (<0.7770) (P < 0.05).	('>0.7770', 'Var', (87, 94))	('PTTG1', 'Gene', (167, 172))	('PTTG1', 'Gene', '9232', (167, 172))	('rat', 'Species', '10116', (54, 57))	('worse', 'NegReg', (131, 136))	('PTTG1', 'Gene', '9232', (69, 74))	('survival', 'MPA', (137, 145))	('PTTG1', 'Gene', (69, 74))
100776	24314023	To verify whether PTTG1 is a direct target of miR-655, we used a Dual-Luciferase reporter system containing either the wildtype or mutant 3' UTR of PTTG1.	('mutant', 'Var', (131, 137))	('PTTG1', 'Gene', '9232', (148, 153))	('PTTG1', 'Gene', '9232', (18, 23))	('miR-655', 'Gene', '724025', (46, 53))	('PTTG1', 'Gene', (18, 23))	('PTTG1', 'Gene', (148, 153))	('miR-655', 'Gene', (46, 53))
100781	24314023	From these results we conclude that PTTG1 expression restores the anti-migration function of miR-655.	('anti-migration function', 'CPA', (66, 89))	('PTTG1', 'Gene', (36, 41))	('restores', 'PosReg', (53, 61))	('PTTG1', 'Gene', '9232', (36, 41))	('miR-655', 'Gene', '724025', (93, 100))	('rat', 'Species', '10116', (74, 77))	('miR-655', 'Gene', (93, 100))	('expression', 'Var', (42, 52))
100890	23617935	They speculated that myenteric nerve plexus damage or direct electric damage to the muscle layer might induce atrophy of the muscle fibers.	('atrophy', 'Disease', (110, 117))	('electric damage', 'Var', (61, 76))	('induce', 'Reg', (103, 109))	('myenteric nerve plexus', 'CPA', (21, 43))	('atrophy', 'Disease', 'MESH:D001284', (110, 117))	('atrophy of the muscle', 'Phenotype', 'HP:0003202', (110, 131))
101005	19693946	Neck dissection may contribute to chronic oropharyngeal dysphagia in HNSCC patients treated with primary radiation or chemoradiation.	('HNSCC', 'Disease', (69, 74))	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('dysphagia', 'Phenotype', 'HP:0002015', (56, 65))	('HNSCC', 'Disease', 'MESH:D000077195', (69, 74))	('patients', 'Species', '9606', (75, 83))	('contribute', 'Reg', (20, 30))	('oropharyngeal dysphagia', 'Disease', (42, 65))	('oropharyngeal dysphagia', 'Disease', 'MESH:D003680', (42, 65))	('oropharyngeal dysphagia', 'Phenotype', 'HP:0200136', (42, 65))	('Neck dissection', 'Var', (0, 15))
101058	19693946	After adjusting for baseline characteristics, the 12-month frequency of feeding tube dependence was similar between patients who underwent neck dissection, and those who did not (29% vs 24%, RR 1.19, 95% CI 0.55-2.59, p=0.658).	('neck dissection', 'Var', (139, 154))	('patients', 'Species', '9606', (116, 124))	('RR 1', 'Gene', '6240', (191, 195))	('RR 1', 'Gene', (191, 195))
101068	19693946	In this study, we hypothesize that neck dissection independently exacerbates post-radiotherapy dysphagia, increasing the risk of feeding tube dependence.	('feeding tube dependence', 'Disease', (129, 152))	('exacerbates', 'PosReg', (65, 76))	('dysphagia', 'Disease', 'MESH:D003680', (95, 104))	('neck dissection', 'Var', (35, 50))	('dysphagia', 'Disease', (95, 104))	('dysphagia', 'Phenotype', 'HP:0002015', (95, 104))
101069	19693946	Measuring the effect of neck dissection on chronic dysphagia is inherently problematic as patients who undergo neck dissection potentially represent a different population than patients who do not.	('patients', 'Species', '9606', (177, 185))	('dysphagia', 'Phenotype', 'HP:0002015', (51, 60))	('chronic dysphagia', 'Disease', 'MESH:D003680', (43, 60))	('neck dissection', 'Var', (111, 126))	('chronic dysphagia', 'Disease', (43, 60))	('patients', 'Species', '9606', (90, 98))
101082	19693946	In our analysis, neck dissection was found to contribute to feeding tube dependence, regardless of whether patients with radiographically-confirmed strictures were included or not.	('feeding tube dependence', 'CPA', (60, 83))	('contribute', 'Reg', (46, 56))	('patients', 'Species', '9606', (107, 115))	('neck dissection', 'Var', (17, 32))
101098	21298375	However, only a small group of patients with EGCs are HER2 amplified, and there are other important targets/pathways which play a role in the development of these cancers that are currently being studied.	('EGCs', 'Chemical', '-', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('men', 'Species', '9606', (149, 152))	('HER2', 'Gene', (54, 58))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('HER2', 'Gene', '2064', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('patients', 'Species', '9606', (31, 39))	('EGCs', 'Var', (45, 49))	('amplified', 'Var', (59, 68))
101126	21298375	In gastric and GE junction AC, some studies have shown a correlation between HER2 amplification by FISH and increasing depth of invasion, lymph node involvement, and distant organ metastasis, as well as overall poor survival.	('gastric', 'Disease', (3, 10))	('distant organ metastasis', 'CPA', (166, 190))	('HER2', 'Gene', (77, 81))	('men', 'Species', '9606', (156, 159))	('amplification', 'Var', (82, 95))	('HER2', 'Gene', '2064', (77, 81))	('depth', 'CPA', (119, 124))	('lymph node involvement', 'CPA', (138, 160))
101154	21298375	A third study evaluated 16 patients with HER2 amplified GE junction tumors.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('GE junction tumors', 'Disease', 'MESH:D009369', (56, 74))	('GE junction tumors', 'Disease', (56, 74))	('amplified', 'Var', (46, 55))	('patients', 'Species', '9606', (27, 35))	('HER2', 'Gene', (41, 45))	('HER2', 'Gene', '2064', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
101168	21298375	Finally, in contrast to adenocarcinoma of the lung, mutations in the EGFR kinase domain are exceedingly rare in gastric and esophageal cancers.	('mutations', 'Var', (52, 61))	('EGFR', 'Gene', '1956', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('EGFR', 'Gene', (69, 73))	('adenocarcinoma of the lung', 'Disease', (24, 50))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (24, 50))	('gastric and esophageal cancers', 'Disease', 'MESH:D013274', (112, 142))
101170	21298375	Colon cancer patients with kras mutations do not seem to derive benefit from the anti-EGFR moAbs, cetuximab, or panitumumab.	('kras', 'Gene', (27, 31))	('Colon cancer', 'Phenotype', 'HP:0003003', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('EGFR', 'Gene', '1956', (86, 90))	('Colon cancer', 'Disease', (0, 12))	('patients', 'Species', '9606', (13, 21))	('moAbs', 'Chemical', 'MESH:D000911', (91, 96))	('panitumumab', 'Chemical', 'MESH:D000077544', (112, 123))	('EGFR', 'Gene', (86, 90))	('mutations', 'Var', (32, 41))	('cetuximab', 'Chemical', 'MESH:D000068818', (98, 107))	('Colon cancer', 'Disease', 'MESH:D015179', (0, 12))
101172	21298375	In one study, none of the 38 patients was found to have mutated K-ras, and in another study two of 23 patients had a mutation suggesting that mutations in kras are exceedingly rare.	('patients', 'Species', '9606', (29, 37))	('patients', 'Species', '9606', (102, 110))	('mutated', 'Var', (56, 63))	('K-ras', 'Gene', (64, 69))	('K-ras', 'Gene', '3845', (64, 69))
101206	21298375	Antacids can decrease serum concentration of erlotinib, and erlotinib may increase or decrease metabolism of CYP3A4 substrates.	('erlotinib', 'Var', (60, 69))	('CYP3A4', 'Gene', '1576', (109, 115))	('decrease', 'NegReg', (13, 21))	('increase', 'PosReg', (74, 82))	('erlotinib', 'Chemical', 'MESH:D000069347', (60, 69))	('decrease', 'NegReg', (86, 94))	('serum concentration', 'MPA', (22, 41))	('CYP3A4', 'Gene', (109, 115))	('erlotinib', 'Chemical', 'MESH:D000069347', (45, 54))
101215	21298375	Gefitinib may increase or decrease the metabolism of CYP3A4 substrates, and can enhance the anticoagulant effect of warfarin.	('CYP3A4', 'Gene', '1576', (53, 59))	('decrease', 'NegReg', (26, 34))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('metabolism', 'MPA', (39, 49))	('Gefitinib', 'Var', (0, 9))	('enhance', 'PosReg', (80, 87))	('anticoagulant effect', 'MPA', (92, 112))	('CYP3A4', 'Gene', (53, 59))	('warfarin', 'Chemical', 'MESH:D014859', (116, 124))	('increase', 'PosReg', (14, 22))
101263	21298375	A phase II study evaluated two dosing schedules for GSK1363089 (foretonib), a dual MET/VEGFR2 inhibitor in patients with metastatic gastric cancer.	('GSK1363089', 'Var', (52, 62))	('gastric cancer', 'Disease', (132, 146))	('foretonib', 'Chemical', '-', (64, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('VEGFR2', 'Gene', '3791', (87, 93))	('GSK1363089', 'Chemical', 'MESH:C544831', (52, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('VEGFR2', 'Gene', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('patients', 'Species', '9606', (107, 115))
101264	21298375	The study found that c-MET amplification in metastatic gastric cancer is rarer than anticipated (3/43 patients).	('gastric cancer', 'Disease', (55, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (102, 110))	('c-MET', 'Gene', '4233', (21, 26))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('amplification', 'Var', (27, 40))	('c-MET', 'Gene', (21, 26))
101389	32632098	In addition, PD-L1 can upregulate beta-catenin by inhibiting its degradation through PI3K/Akt signaling pathway.	('degradation', 'MPA', (65, 76))	('inhibiting', 'NegReg', (50, 60))	('Akt', 'Gene', (90, 93))	('upregulate', 'PosReg', (23, 33))	('PD-L1', 'Var', (13, 18))	('beta-catenin', 'Protein', (34, 46))	('Akt', 'Gene', '207', (90, 93))
101398	32632098	PD-L1 blockage can increase fetal resorption and Tfr cells but does not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy.	('Tfr', 'Gene', (49, 52))	('Tfr', 'Gene', (83, 86))	('fetal resorption', 'CPA', (28, 44))	('Tfr', 'Gene', '7037', (49, 52))	('increase', 'PosReg', (19, 27))	('PD-L1', 'Gene', (0, 5))	('Tfr', 'Gene', '7037', (83, 86))	('blockage', 'Var', (6, 14))
101424	32632098	The anti-p-S6 (S235/236)(4858T), anti-beta-catenin (8480S), anti-Akt (4691S), anti-p-Akt (T308)(13038T), anti-p-PDK1 (Ser241)(3438T), anti-p-GSK3beta (9323S), anti-p-P70S6K (T389) (9234T), anti-OCT4 (2750S), anti-pErk (4370S), anti-Erk (4695S), anti-CyclinD1 (2978S), anti-p-YAP (13008T), anti-Claudin-1 (13255T), and anti-Histone H3 (4499S) were purchased from Cell Signaling Technology (Danvers, MA, USA).	('Erk', 'Gene', (232, 235))	('pErk', 'Gene', (213, 217))	('Akt', 'Gene', (85, 88))	('CyclinD1', 'Gene', '595', (250, 258))	('pErk', 'Gene', '9451', (213, 217))	('P70S6K', 'Gene', (166, 172))	('Erk', 'Gene', '2048', (214, 217))	('GSK3beta', 'Gene', '2931', (141, 149))	('PDK1', 'Gene', '5163', (112, 116))	('CyclinD1', 'Gene', (250, 258))	('YAP', 'Gene', (275, 278))	('Akt', 'Gene', '207', (85, 88))	('13008T', 'Var', (280, 286))	('P70S6K', 'Gene', '6198', (166, 172))	('13255T', 'Var', (305, 311))	('OCT4', 'Gene', '5460', (194, 198))	('Erk', 'Gene', (214, 217))	('Claudin-1', 'Gene', '9076', (294, 303))	('Erk', 'Gene', '2048', (232, 235))	('YAP', 'Gene', '10413', (275, 278))	('GSK3beta', 'Gene', (141, 149))	('Akt', 'Gene', (65, 68))	('PDK1', 'Gene', (112, 116))	('OCT4', 'Gene', (194, 198))	('Akt', 'Gene', '207', (65, 68))	('Claudin-1', 'Gene', (294, 303))
101426	32632098	The anti-actin (20536-1-AP), anti-GAPDH (10494-1-AP), anti-ki67 (19972-1-AP), anti-E-cadherin (20874-1-AP), anti-N-cadherin (22018-1-AP), anti-CD44 (15675-1-AP), anti-Bax (50599-2-lg), anti-Bcl-2 (12789-1-AP), and anti-YAP (13584-1-AP) were purchased from Proteintech (Wuhan, China).	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('N-cadherin', 'Gene', (113, 123))	('GAPDH', 'Gene', (34, 39))	('YAP', 'Gene', (219, 222))	('ki67', 'Gene', (59, 63))	('N-cadherin', 'Gene', '1000', (113, 123))	('CD44', 'Gene', '960', (143, 147))	('Bcl-2', 'Gene', (190, 195))	('Bcl-2', 'Gene', '596', (190, 195))	('CD44', 'Gene', (143, 147))	('Bax', 'Gene', (167, 170))	('ki67', 'Gene', '17345', (59, 63))	('20874-1-AP', 'Var', (95, 105))	('YAP', 'Gene', '10413', (219, 222))	('GAPDH', 'Gene', '2597', (34, 39))	('Bax', 'Gene', '581', (167, 170))
101457	32632098	For xenograft tumor formation, the mice were randomly divided into four or three groups (n = 6), EV + NC, EV + shWIP, PD-L1 + NC, PD-L1 + shWIP or shCtrl, PD-L1 sh4, PD-L1 sh5.	('tumor', 'Disease', (14, 19))	('shCtrl', 'Var', (147, 153))	('PD-L1 + NC', 'Var', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mice', 'Species', '10090', (35, 39))	('PD-L1 sh4', 'Var', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('PD-L1 + shWIP', 'Var', (130, 143))	('PD-L1 sh5', 'Var', (166, 175))	('EV + shWIP', 'Var', (106, 116))
101466	32632098	The results showed that PD-L1 knockdown significantly inhibited colony formation and cell viability in H460 and H358 cells, while PD-L1 overexpression increased colony formation and cell viability in H1299 and A549 cells (Fig.	('inhibited', 'NegReg', (54, 63))	('increased', 'PosReg', (151, 160))	('H358', 'CellLine', 'CVCL:1559', (112, 116))	('H1299', 'CellLine', 'CVCL:0060', (200, 205))	('cell viability', 'CPA', (182, 196))	('A549', 'CellLine', 'CVCL:0023', (210, 214))	('colony formation', 'CPA', (64, 80))	('H460', 'CellLine', 'CVCL:0459', (103, 107))	('PD-L1', 'Gene', (130, 135))	('PD-L1', 'Gene', (24, 29))	('knockdown', 'Var', (30, 39))	('colony formation', 'CPA', (161, 177))	('cell viability', 'CPA', (85, 99))
101469	32632098	Compared with the shRNA control group, knockdown of PD-L1 by shRNA (sh4 or sh5) markedly suppressed tumor growth in mice administrated with stable PD-L1 knockdown H460 cells, resulting in significant reductions in tumor size, weight and volume (Fig.	('mice', 'Species', '10090', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('reductions', 'NegReg', (200, 210))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('suppressed', 'NegReg', (89, 99))	('tumor', 'Disease', (100, 105))	('knockdown', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('H460', 'CellLine', 'CVCL:0459', (163, 167))	('tumor', 'Disease', (214, 219))	('PD-L1', 'Gene', (52, 57))
101472	32632098	To investigate if PD-L1 was involved in tumor stemness character and cell apoptosis, we overexpressed and knocked down PD-L1 in lung cancer cells, and found that PD-L1 overexpression or knockdown did not affect the expression of the CSC-related markers (CD44, OCT4) or the apoptosis-related molecules (Bax and Bcl-2) (Supplementary Fig.	('tumor stemness', 'Disease', 'MESH:D020295', (40, 54))	('Bax', 'Gene', (302, 305))	('tumor stemness', 'Disease', (40, 54))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('Bcl-2', 'Gene', (310, 315))	('Bcl-2', 'Gene', '596', (310, 315))	('knocked down', 'Var', (106, 118))	('CD44', 'Gene', '960', (254, 258))	('PD-L1', 'Gene', (119, 124))	('Bax', 'Gene', '581', (302, 305))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('CD44', 'Gene', (254, 258))	('OCT4', 'Gene', '5460', (260, 264))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('OCT4', 'Gene', (260, 264))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('PD-L1', 'Gene', (162, 167))
101474	32632098	We next analyzed the effect of PD-L1 on NSCLC cell migration and invasion, and showed that knockdown of PD-L1 by siRNAs significantly inhibited cell migration and invasion compared with the siRNA control in H460 and H358 cells (Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('inhibited', 'NegReg', (134, 143))	('H358', 'CellLine', 'CVCL:1559', (216, 220))	('knockdown', 'Var', (91, 100))	('H460', 'CellLine', 'CVCL:0459', (207, 211))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))	('PD-L1', 'Gene', (104, 109))
101475	32632098	To further verify the role of PD-L1 in regulating cell migration and invasion, we evaluated the effect of PD-L1 on the EMT signaling, and found that PD-L1 effectively modulated the expression of the EMT-related molecules.	('PD-L1', 'Var', (149, 154))	('EMT', 'Gene', (199, 202))	('EMT', 'Gene', '3702', (119, 122))	('expression', 'MPA', (181, 191))	('EMT', 'Gene', '3702', (199, 202))	('modulated', 'Reg', (167, 176))	('EMT', 'Gene', (119, 122))
101480	32632098	PD-L1 knockdown significantly regulated the expression of 69 genes in both H460 and H358 cells (Fig.	('expression', 'MPA', (44, 54))	('H358', 'CellLine', 'CVCL:1559', (84, 88))	('H460', 'CellLine', 'CVCL:0459', (75, 79))	('PD-L1', 'Gene', (0, 5))	('regulated', 'Reg', (30, 39))	('knockdown', 'Var', (6, 15))
101481	32632098	We then confirmed the effect of PD-L1 on the expression of these genes in H460 and H358 cells by RT-PCR, and found that WIP was regulated most significantly by PD-L1 knockdown (Fig.	('knockdown', 'Var', (166, 175))	('regulated', 'Reg', (128, 137))	('PD-L1', 'Gene', (160, 165))	('WIP', 'MPA', (120, 123))	('H358', 'CellLine', 'CVCL:1559', (83, 87))	('H460', 'CellLine', 'CVCL:0459', (74, 78))
101485	32632098	To determine whether PD-L1 in lung cancer had a similar function, we analyzed the expression of p-S6 and p-P70S6K.	('p-S6', 'Var', (96, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('lung cancer', 'Disease', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('P70S6K', 'Gene', '6198', (107, 113))	('P70S6K', 'Gene', (107, 113))
101486	32632098	We found that treatment of the PI3K inhibitor LY294002 abrogated the PD-L1-mediated upregulation of S6 phosphorylation (p-S6).	('abrogated', 'NegReg', (55, 64))	('upregulation', 'PosReg', (84, 96))	('S6 phosphorylation', 'MPA', (100, 118))	('LY294002', 'Var', (46, 54))	('PD-L1-mediated', 'Gene', (69, 83))	('LY294002', 'Chemical', 'MESH:C085911', (46, 54))
101487	32632098	PD-L1 overexpression also increased the level of p-Akt (T308) (Fig.	('Akt', 'Gene', (51, 54))	('overexpression', 'Var', (6, 20))	('PD-L1', 'Gene', (0, 5))	('Akt', 'Gene', '207', (51, 54))	('increased', 'PosReg', (26, 35))
101489	32632098	To further conform the role of PI3K/AKT and Erk-signaling pathway in PD-L1 mediated proliferation in lung cancer cells, LY294002 and U0126 were used to pretreated H1299 and H358 cells, and followed by transfection with PD-L1 overexpression plasmid or PD-L1 specific siRNA.LY294002, significantly inhibited lung cancer cell proliferation, whereas inhibitor pretreatment followed by PD-L1 overexpression or knockdown did not obviously alter the proliferative promotion or inhibition in lung cancer cells, indicating the essential role of PI3K/AKT in lung cancer proliferation (Fig.	('lung cancer', 'Disease', (548, 559))	('AKT', 'Gene', '207', (541, 544))	('lung cancer', 'Disease', (484, 495))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('siRNA.LY294002', 'Var', (266, 280))	('H358', 'CellLine', 'CVCL:1559', (173, 177))	('cat', 'Gene', (507, 510))	('lung cancer', 'Disease', (306, 317))	('AKT', 'Gene', (36, 39))	('inhibited', 'NegReg', (296, 305))	('lung cancer', 'Disease', 'MESH:D008175', (548, 559))	('lung cancer', 'Disease', (101, 112))	('lung cancer', 'Disease', 'MESH:D008175', (484, 495))	('Erk', 'Gene', '2048', (44, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (548, 559))	('H1299', 'CellLine', 'CVCL:0060', (163, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (484, 495))	('cancer', 'Phenotype', 'HP:0002664', (489, 495))	('AKT', 'Gene', (541, 544))	('LY294002', 'Chemical', 'MESH:C085911', (272, 280))	('lung cancer', 'Disease', 'MESH:D008175', (306, 317))	('cat', 'Gene', '847', (507, 510))	('AKT', 'Gene', '207', (36, 39))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('LY294002', 'Chemical', 'MESH:C085911', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (553, 559))	('U0126', 'Chemical', 'MESH:C113580', (133, 138))	('Erk', 'Gene', (44, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))
101499	32632098	To investigate the relationship between PD-L1 and WIP, we performed the rescue experiments by overexpressing PD-L1 but knocking down WIP in H1299 cells, and knocking down PD-L1 but overexpressing WIP in H358 cells.	('WIP', 'MPA', (133, 136))	('PD-L1', 'Gene', (171, 176))	('H358', 'CellLine', 'CVCL:1559', (203, 207))	('PD-L1', 'Gene', (109, 114))	('H1299', 'CellLine', 'CVCL:0060', (140, 145))	('knocking', 'Var', (119, 127))	('knocking', 'Var', (157, 165))
101501	32632098	Conversely, PD-L1 knockdown suppressed WIP expression, but WIP overexpression did not changed PD-L1 expression level in H358 cells.	('suppressed', 'NegReg', (28, 38))	('knockdown', 'Var', (18, 27))	('H358', 'CellLine', 'CVCL:1559', (120, 124))	('WIP expression', 'MPA', (39, 53))
101503	32632098	5d, e), indicating that PD-L1 promoted lung cell growth partially via WIP signaling.	('cat', 'Gene', (12, 15))	('promoted', 'PosReg', (30, 38))	('lung cell growth', 'CPA', (39, 55))	('cat', 'Gene', '847', (12, 15))	('PD-L1', 'Var', (24, 29))
101506	32632098	Moreover, PD-L1 overexpression or knockdown also increased or decreased the expression of the beta-catenin targeting gene CyclinD1 (Supplementary Fig.	('decreased', 'NegReg', (62, 71))	('increased', 'PosReg', (49, 58))	('expression', 'MPA', (76, 86))	('PD-L1', 'Gene', (10, 15))	('CyclinD1', 'Gene', (122, 130))	('knockdown', 'Var', (34, 43))	('CyclinD1', 'Gene', '595', (122, 130))
101511	32632098	We first established the A549 cell lines with stable PD-L1 overexpression, or the cells with stable PD-L1 overexpression and WIP shRNA knockdown.	('overexpression', 'Var', (59, 73))	('PD-L1', 'Gene', (53, 58))	('A549', 'CellLine', 'CVCL:0023', (25, 29))
101514	32632098	Western blot analysis for tumor tissues showed that PD-L1 overexpression increased expression of beta-catenin, WIP and p-S6 (Fig.	('increased', 'PosReg', (73, 82))	('beta-catenin', 'Protein', (97, 109))	('WIP', 'Gene', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('p-S6', 'Var', (119, 123))	('expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('PD-L1', 'Gene', (52, 57))
101515	32632098	Moreover, the immunohistochemical analysis of tumor tissues similarly revealed that PD-L1 overexpression increased the expression of beta-catenin, WIP and p-S6 (Fig.	('expression', 'MPA', (119, 129))	('PD-L1', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('p-S6', 'Var', (155, 159))	('overexpression increased', 'PosReg', (90, 114))	('tumor', 'Disease', (46, 51))	('beta-catenin', 'Protein', (133, 145))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
101523	32632098	The patients with high expression of PD-L1 and WIP had short survival time compared with those with low expression of PD-L1 and WIP (p = 0.017 and 0.008, respectively) (Fig.	('high expression', 'Var', (18, 33))	('short', 'NegReg', (55, 60))	('PD-L1', 'Gene', (37, 42))	('patients', 'Species', '9606', (4, 12))
101530	32632098	NTRK1 (Neurotrophic Receptor Tyrosine Kinase 1), one of family member of RTKs, is downregulated by PD-L1 knockdown in our study.	('NTRK1', 'Gene', (0, 5))	('downregulated', 'NegReg', (82, 95))	('Neurotrophic Receptor Tyrosine Kinase 1', 'Gene', (7, 46))	('PD-L1', 'Gene', (99, 104))	('knockdown', 'Var', (105, 114))	('NTRK1', 'Gene', '4914', (0, 5))	('Neurotrophic Receptor Tyrosine Kinase 1', 'Gene', '4914', (7, 46))
101531	32632098	Whether the activation of PI3K/Akt pathway by PD-L1 is NTRK1 dependent should be further evaluated, and whether PD-1 and PD-L1 interaction is necessary for PD-L1 signaling transduction remains unclear.	('PD-L1', 'Var', (46, 51))	('PD-1', 'Gene', (112, 116))	('Akt', 'Gene', (31, 34))	('PD-1', 'Gene', '5133', (112, 116))	('NTRK1', 'Gene', (55, 60))	('Akt', 'Gene', '207', (31, 34))	('NTRK1', 'Gene', '4914', (55, 60))
101572	27863386	Univariate and multivariate analyses identified IDH1 expression as an independent prognostic factor for OS and PFS.	('IDH1', 'Gene', (48, 52))	('IDH1', 'Gene', '3417', (48, 52))	('PFS', 'Disease', (111, 114))	('expression', 'Var', (53, 63))
101598	27863386	Recent studies on IDH1 in cancers have primarily focused on the mutations of the IDH1 gene.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('IDH1', 'Gene', '3417', (18, 22))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('IDH1', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (64, 73))	('IDH1', 'Gene', '3417', (81, 85))	('IDH1', 'Gene', (18, 22))
101599	27863386	IDH1 mutations were found in low-grade glioma and secondary glioblastoma, acute myeloid leukemia, chondrosarcoma, intrahepatic cholangiocarcinoma, and melanoma.	('chondrosarcoma', 'Phenotype', 'HP:0006765', (98, 112))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('IDH1', 'Gene', (0, 4))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (80, 96))	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (114, 145))	('intrahepatic cholangiocarcinoma', 'Disease', (114, 145))	('IDH1', 'Gene', '3417', (0, 4))	('acute myeloid leukemia', 'Disease', (74, 96))	('glioma', 'Disease', (39, 45))	('mutations', 'Var', (5, 14))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('chondrosarcoma', 'Disease', 'MESH:D002813', (98, 112))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('chondrosarcoma', 'Disease', (98, 112))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (74, 96))	('found', 'Reg', (20, 25))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (74, 96))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))
101600	27863386	The aforementioned studies on the IDH1 gene indicate that IDH1 mutation may significanty affect tumorigenesis and tumor progression.	('IDH1', 'Gene', '3417', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('IDH1', 'Gene', '3417', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('affect', 'Reg', (89, 95))	('tumor', 'Disease', (96, 101))	('mutation', 'Var', (63, 71))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('IDH1', 'Gene', (34, 38))	('IDH1', 'Gene', (58, 62))
101603	27863386	Aberrant protein expression, as the primary functional gene output, complements genome initiatives and is an important phenotypic characteristic of cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('protein', 'Protein', (9, 16))
101626	27863386	With the cut-off value set to 192.084 pg/mL (Yuden index), the sensitivity and specificity of serum IDH1 were 83.3% and 67.7%, respectively.	('192.084 pg/mL', 'Var', (30, 43))	('IDH1', 'Gene', '3417', (100, 104))	('IDH1', 'Gene', (100, 104))
101639	27863386	Figure 4C and 4D show that the IDH1 protein level is also reduced in the transfection group (IDH1/beta-actin: 0.61 +- 0.02 and 0.61 +- 0.01 vs. 0.91 +- 0.02 in Eca109, P < 0.0001, respectively; 0.51 +- 0.01 and 0.56 +- 0.02 vs. 0.90 +- 0.02 in Eca9706, P < 0.0001, respectively).	('IDH1', 'Gene', (93, 97))	('IDH1', 'Gene', '3417', (31, 35))	('IDH1', 'Gene', '3417', (93, 97))	('beta-actin', 'Gene', '728378', (98, 108))	('beta-actin', 'Gene', (98, 108))	('Eca9706', 'CellLine', 'CVCL:E307', (244, 251))	('transfection', 'Var', (73, 85))	('reduced', 'NegReg', (58, 65))	('IDH1', 'Gene', (31, 35))
101640	27863386	To determine whether knockdown of IDH1 expression by shRNA can decrease the growth and proliferation of ESCC cells, CCK8 and clonal efficiency assays were conducted.	('IDH1', 'Gene', '3417', (34, 38))	('decrease', 'NegReg', (63, 71))	('ESCC', 'Disease', (104, 108))	('IDH1', 'Gene', (34, 38))	('knockdown', 'Var', (21, 30))
101642	27863386	Colony numbers of transfected Eca109 and Eca9706 cells were also significantly reduced relative to those of the control groups (all P < 0.05, Figure 5E and 5F).	('Eca9706', 'CellLine', 'CVCL:E307', (41, 48))	('Colony numbers', 'CPA', (0, 14))	('reduced', 'NegReg', (79, 86))	('transfected', 'Var', (18, 29))
101643	27863386	The status of mutant IDH1 in cancers has been revealed in recent years.	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('mutant', 'Var', (14, 20))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))	('IDH1', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (21, 25))
101644	27863386	Studies on IDH1 mutations in glioma and acute myeloid leukemia (AML) have been well developed.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (40, 62))	('glioma', 'Disease', (29, 35))	('IDH1', 'Gene', '3417', (11, 15))	('acute myeloid leukemia', 'Disease', (40, 62))	('mutations', 'Var', (16, 25))	('AML', 'Disease', 'MESH:D015470', (64, 67))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (40, 62))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('AML', 'Phenotype', 'HP:0004808', (64, 67))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('AML', 'Disease', (64, 67))	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (46, 62))	('IDH1', 'Gene', (11, 15))
101670	27863386	Moreover, siRNA knockdown of IDH1 significantly decreases the proliferative ability of the AML cell line with wild-type IDH1.	('AML', 'Disease', 'MESH:D015470', (91, 94))	('IDH1', 'Gene', (29, 33))	('decreases', 'NegReg', (48, 57))	('IDH1', 'Gene', '3417', (29, 33))	('AML', 'Disease', (91, 94))	('knockdown', 'Var', (16, 25))	('IDH1', 'Gene', (120, 124))	('AML', 'Phenotype', 'HP:0004808', (91, 94))	('IDH1', 'Gene', '3417', (120, 124))
101678	27863386	In addition, the harmful effects of radiotherapy and several anticancer drugs on the DNA of cancer cells are realized by ROS.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('ROS', 'Var', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
101693	27863386	To deactivate intrinsic peroxidase, sections were incubated with hydrogen peroxide.	('intrinsic peroxidase', 'Enzyme', (14, 34))	('deactivate', 'Var', (3, 13))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (65, 82))
101701	27863386	The IDH1 expression was calculated using the 2-DeltaDeltaCt method, where DeltaCt = CtIDH1-CtGADPH and DeltaDeltaCt = DeltaCttest -DeltaCtcontrol.	('IDH1', 'Gene', '3417', (4, 8))	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', '3417', (86, 90))	('IDH1', 'Gene', (4, 8))	('DeltaDeltaCt', 'Var', (103, 115))
101743	27766003	Genomic studies have shown that lung and esophagus squamous cell carcinomas (SCC) frequently harbor SOX2 gene amplification and aberrant expression levels.	('esophagus squamous cell carcinomas', 'Disease', 'MESH:D002294', (41, 75))	('harbor', 'Reg', (93, 99))	('esophagus squamous cell carcinomas', 'Disease', (41, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('SCC', 'Gene', '6317', (77, 80))	('SOX2 gene', 'Gene', (100, 109))	('aberrant', 'Var', (128, 136))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (51, 75))	('SCC', 'Gene', (77, 80))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))	('expression levels', 'MPA', (137, 154))
101774	27766003	Reinforcing a role of CDX2 in this carcinogenic pathway, we observed a high percentage of CDX2 positivity in dysplasia and BA.	('CDX2', 'Gene', '1045', (90, 94))	('dysplasia', 'Disease', 'MESH:D004476', (109, 118))	('CDX2', 'Gene', (22, 26))	('dysplasia', 'Disease', (109, 118))	('CDX2', 'Gene', '1045', (22, 26))	('CDX2', 'Gene', (90, 94))	('positivity', 'Var', (95, 105))
101831	26811811	As indicated, there were strong trends revealing total support significantly increased at young age, highermonthly income, higher education, increased interval after cancer occurrence and comorbid conditions.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('highermonthly income', 'Var', (101, 121))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('increased', 'PosReg', (77, 86))
101861	26811811	The results, presented in Table 6, show that QLQ-C30 global health status is negatively associated with duration after occurrence and positively correlated with household income in patients with esophagus cancer.	('correlated', 'Reg', (145, 155))	('QLQ-C30', 'Var', (45, 52))	('positively', 'PosReg', (134, 144))	('patients', 'Species', '9606', (181, 189))	('esophagus cancer', 'Disease', (195, 211))	('negatively', 'NegReg', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('esophagus cancer', 'Disease', 'MESH:D004938', (195, 211))
101864	25537505	Fibroblast growth factor receptor 1 gene amplification is associated with poor survival in patients with resected esophageal squamous cell carcinoma To investigate the frequency and the prognostic impact of fibroblast growth factor receptor 1 (FGFR1) gene amplification in 526 curatively resected esophageal squamous cell carcinoma (ESCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('esophageal squamous cell carcinoma', 'Disease', (297, 331))	('fibroblast growth factor receptor 1', 'Gene', (207, 242))	('patients', 'Species', '9606', (91, 99))	('Fibroblast growth factor receptor 1', 'Gene', (0, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (114, 148))	('FGFR1', 'Gene', (244, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (308, 331))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (297, 331))	('amplification', 'Var', (41, 54))	('fibroblast growth factor receptor 1', 'Gene', '2260', (207, 242))	('FGFR1', 'Gene', '2260', (244, 249))	('Fibroblast growth factor receptor 1', 'Gene', '2260', (0, 35))	('esophageal squamous cell carcinoma', 'Disease', (114, 148))
101867	25537505	FGFR2 and FGFR3 mutations were assessed by direct sequencing in 388 cases and no mutation was detected.	('FGFR3', 'Gene', '2261', (10, 15))	('mutations', 'Var', (16, 25))	('FGFR3', 'Gene', (10, 15))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
101868	25537505	High FGFR1 amplification had significantly shorter disease-free survival (34.0 vs 158.5 months P=0.019) and overall survival (52.2 vs not reached P=0.022) than low/no amplification group.	('shorter', 'NegReg', (43, 50))	('High', 'Var', (0, 4))	('FGFR1', 'Gene', '2260', (5, 10))	('overall survival', 'CPA', (108, 124))	('disease-free survival', 'CPA', (51, 72))	('amplification', 'Var', (11, 24))	('FGFR1', 'Gene', (5, 10))
101869	25537505	After adjusting for sex, smoking, stage, histology, and adjuvant treatment, high FGFR1 amplification had a greater risk of recurrence (adjusted hazard ratio [AHR], 1.6; P=0.029) and death (AHR, 1.53; P=0.050).	('FGFR1', 'Gene', (81, 86))	('recurrence', 'CPA', (123, 133))	('death', 'Disease', 'MESH:D003643', (182, 187))	('FGFR1', 'Gene', '2260', (81, 86))	('death', 'Disease', (182, 187))	('high', 'Var', (76, 80))	('amplification', 'Var', (87, 100))
101870	25537505	High FGFR1 amplification is a frequent oncogenic alteration and an independent poor prognostic factor in resected ESCC.	('ESCC', 'Disease', (114, 118))	('High', 'Var', (0, 4))	('FGFR1', 'Gene', '2260', (5, 10))	('amplification', 'Var', (11, 24))	('FGFR1', 'Gene', (5, 10))
101875	25537505	Amplification and overexpression of human epidermal growth factor receptor 2 (HER2; also known as ERBB2) was more frequent in EAC than ESCC and there was a strong concordance of HER2 status in primary and metastatic cancer.	('ERBB2', 'Gene', '2064', (98, 103))	('Amplification', 'Var', (0, 13))	('human epidermal growth factor receptor 2', 'Gene', (36, 76))	('ERBB2', 'Gene', (98, 103))	('human epidermal growth factor receptor 2', 'Gene', '2064', (36, 76))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('HER2', 'Gene', (78, 82))	('HER2', 'Gene', '2064', (78, 82))	('cancer', 'Disease', (216, 222))	('EAC', 'Disease', (126, 129))	('HER2', 'Gene', (178, 182))	('frequent', 'Reg', (114, 122))	('overexpression', 'PosReg', (18, 32))	('HER2', 'Gene', '2064', (178, 182))
101877	25537505	The therapeutic implication of HER2 protein overexpression or gene amplification has been demonstrated in the Trastuzumab for Gastric Cancer (ToGA) trial.	('HER2', 'Gene', '2064', (31, 35))	('gene amplification', 'Var', (62, 80))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('overexpression', 'PosReg', (44, 58))	('Gastric Cancer', 'Disease', (126, 140))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (126, 140))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (110, 121))	('Gastric Cancer', 'Disease', 'MESH:D013274', (126, 140))	('HER2', 'Gene', (31, 35))
101881	25537505	Among those, high copy number gains of cancer-associated genes, such as SOX2, PIK3CA, CCND1, and FGFR1, were more frequently observed in ESCC than in EAC, suggesting that genomic gain of these oncogenes may be therapeutic targets for ESCC.	('CCND1', 'Gene', (86, 91))	('FGFR1', 'Gene', '2260', (97, 102))	('observed', 'Reg', (125, 133))	('PIK3CA', 'Gene', (78, 84))	('SOX2', 'Gene', '6657', (72, 76))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('SOX2', 'Gene', (72, 76))	('CCND1', 'Gene', '595', (86, 91))	('ESCC', 'Disease', (137, 141))	('PIK3CA', 'Gene', '5290', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('high copy number gains', 'Var', (13, 35))	('FGFR1', 'Gene', (97, 102))
101882	25537505	Fibroblast growth factor receptor 1 (FGFR1) is a member of family of receptor tyrosine kinases (FGFR1-4), and its activation by amplification, mutation, or translocation leads to tumor cell proliferation and survival in many cancers.	('FGFR1', 'Gene', '2260', (37, 42))	('cancers', 'Disease', (225, 232))	('translocation', 'Var', (156, 169))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('FGFR1', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('activation', 'PosReg', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('Fibroblast growth factor receptor 1', 'Gene', '2260', (0, 35))	('tumor', 'Disease', (179, 184))	('FGFR1', 'Gene', (37, 42))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('Fibroblast growth factor receptor 1', 'Gene', (0, 35))	('mutation', 'Var', (143, 151))	('FGFR1', 'Gene', '2260', (96, 101))	('amplification', 'Var', (128, 141))	('leads to', 'Reg', (170, 178))	('survival', 'CPA', (208, 216))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
101883	25537505	Potentially actionable FGFR rearrangements were identified in diverse solid tumors including lung cancer, oral cancer, and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('oral cancer', 'Disease', 'MESH:D009062', (106, 117))	('FGFR', 'Gene', (23, 27))	('solid tumors', 'Disease', 'MESH:D009369', (70, 82))	('rearrangements', 'Var', (28, 42))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('oral cancer', 'Disease', (106, 117))	('breast cancer', 'Disease', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('solid tumors', 'Disease', (70, 82))	('lung cancer', 'Disease', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))
101884	25537505	FGFR1 amplification has been frequently reported in lung squamous cell carcinoma (SqCC), small cell lung cancer, and SqCC of head and neck (SCCHN), for which smoking is a clear and dominant risk factor.	('small cell lung cancer', 'Disease', (89, 111))	('SqCC', 'Phenotype', 'HP:0002860', (82, 86))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (52, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 80))	('SqCC', 'Phenotype', 'HP:0002860', (117, 121))	('small cell lung cancer', 'Disease', 'MESH:D055752', (89, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (89, 111))	('amplification', 'Var', (6, 19))	('lung squamous cell carcinoma', 'Disease', (52, 80))	('reported', 'Reg', (40, 48))
101885	25537505	Overall, the frequency of FGFR1 amplification was reported to be 5.6%-24.8% in lung SqCC and 15%-17.4% in SCCHN, suggesting that this genetic alteration mainly target squamous cell histology.	('SCCHN', 'Disease', (106, 111))	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', '2260', (26, 31))	('amplification', 'Var', (32, 45))	('lung SqCC', 'Disease', (79, 88))	('SqCC', 'Phenotype', 'HP:0002860', (84, 88))
101886	25537505	Furthermore, FGFR1 amplification has been associated with poor prognosis or unfavorable clinicopathologic parameters in lung SqCC and SCCHN.	('amplification', 'Var', (19, 32))	('FGFR1', 'Gene', (13, 18))	('lung SqCC', 'Disease', (120, 129))	('FGFR1', 'Gene', '2260', (13, 18))	('SqCC', 'Phenotype', 'HP:0002860', (125, 129))	('SCCHN', 'Disease', (134, 139))
101887	25537505	Because ESCC has risk factors in common with lung SqCC and SCCHN, we hypothesized that FGFR1 amplifications is associated with pathogenesis and poor prognosis in ESCC.	('ESCC', 'Disease', (8, 12))	('associated', 'Reg', (111, 121))	('amplifications', 'Var', (93, 107))	('FGFR1', 'Gene', (87, 92))	('FGFR1', 'Gene', '2260', (87, 92))	('ESCC', 'Disease', (162, 166))	('SqCC', 'Phenotype', 'HP:0002860', (50, 54))
101888	25537505	In this study, we sought to determine the frequency, prognostic impact and association with smoking dosage of FGFR1 amplification in surgically resected ESCC.	('FGFR1', 'Gene', '2260', (110, 115))	('amplification', 'Var', (116, 129))	('FGFR1', 'Gene', (110, 115))	('ESCC', 'Disease', (153, 157))
101889	25537505	Furthermore, we also evaluated the frequency of FGFR2 and FGFR3 mutations in ESCC.	('FGFR2', 'Gene', (48, 53))	('FGFR2', 'Gene', '2263', (48, 53))	('FGFR3', 'Gene', '2261', (58, 63))	('ESCC', 'Disease', (77, 81))	('FGFR3', 'Gene', (58, 63))	('mutations', 'Var', (64, 73))
101899	25537505	The mean FGFR1/CEN8 ratio was 2.9 (range 1.1 to 7.8), 1.5 (range, 1.0 to 1.9), and 1.3 (range, 0 to 1.6) in high, low and no amplification group, respectively.	('low', 'Var', (114, 117))	('FGFR1', 'Gene', '2260', (9, 14))	('to 7', 'Species', '1214577', (45, 49))	('CEN8', 'Chemical', '-', (15, 19))	('FGFR1', 'Gene', (9, 14))
101903	25537505	However, the incidence of high FGFR1 amplification was significantly higher in smokers than in never-smokers (P<0.001).	('high', 'Var', (26, 30))	('amplification', 'MPA', (37, 50))	('higher', 'PosReg', (69, 75))	('FGFR1', 'Gene', (31, 36))	('FGFR1', 'Gene', '2260', (31, 36))
101908	25537505	The median DFS for each of the three FGFR groups was 34.0 months in the high FGFR1 amplification, not reached (NR) in low amplification group, and 158.5 months in the no amplification group (Figure 2A).	('FGFR1', 'Gene', '2260', (77, 82))	('FGFR1', 'Gene', (77, 82))	('high', 'Var', (72, 76))
101909	25537505	By using pair-wise comparison, patients with high FGFR1 amplification showed a significantly shorter DFS than those with no amplification (34.0 vs 158.5 months in no amplification, P=0.020).	('FGFR1', 'Gene', (50, 55))	('FGFR1', 'Gene', '2260', (50, 55))	('shorter', 'NegReg', (93, 100))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('DFS', 'MPA', (101, 104))	('amplification', 'Var', (56, 69))
101910	25537505	The median OS for each of the three FGFR groups was 52.2 months in the high FGFR1 amplification, 72.0 months in the low amplification, and not reached in the no amplification (Figure 2B).	('OS', 'Chemical', '-', (11, 13))	('FGFR1', 'Gene', (76, 81))	('FGFR1', 'Gene', '2260', (76, 81))	('high', 'Var', (71, 75))
101911	25537505	By using pair-wise comparison, patients with high FGFR1 amplification showed a significantly shorter OS than those with no amplification (52.2 vs NR in no amplification, P=0.021).	('FGFR1', 'Gene', (50, 55))	('FGFR1', 'Gene', '2260', (50, 55))	('shorter', 'NegReg', (93, 100))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('OS', 'Chemical', '-', (101, 103))	('amplification', 'Var', (56, 69))
101915	25537505	The median DFS of the high FGFR1 amplification group was significantly shorter compared with that of the low/no FGFR1 amplification group (34.0 vs 158.5 months P=0.019, Figure 3A).	('FGFR1', 'Gene', (112, 117))	('FGFR1', 'Gene', '2260', (27, 32))	('FGFR1', 'Gene', '2260', (112, 117))	('high', 'Var', (22, 26))	('DFS', 'MPA', (11, 14))	('FGFR1', 'Gene', (27, 32))	('shorter', 'NegReg', (71, 78))
101916	25537505	In addition, high FGFR1 amplification group demonstrated significantly shorter OS than low/no FGFR1 amplification group (52.2 vs NR, P=0.022, Figure 3B).	('FGFR1', 'Gene', '2260', (94, 99))	('OS', 'Chemical', '-', (79, 81))	('high', 'Var', (13, 17))	('FGFR1', 'Gene', (18, 23))	('FGFR1', 'Gene', '2260', (18, 23))	('FGFR1', 'Gene', (94, 99))	('shorter', 'NegReg', (71, 78))
101917	25537505	In Cox proportional hazard model adjusted for sex, smoking history, pathologic stage, adjuvant treatment, and histologic grade, high FGFR1 amplification was significantly associated with a shorter DFS (AHR 1.61; 95% CI, 1.05-2.46; P=0.029, Table 2).	('amplification', 'Var', (139, 152))	('FGFR1', 'Gene', (133, 138))	('FGFR1', 'Gene', '2260', (133, 138))	('shorter', 'NegReg', (189, 196))	('high', 'Var', (128, 132))	('DFS', 'MPA', (197, 200))
101923	25537505	The incidences of high-level FGFR1 amplification in current, former and never-smokers were 19.0%, 2.5%, and 0.8%, respectively.	('amplification', 'Var', (35, 48))	('FGFR1', 'Gene', (29, 34))	('FGFR1', 'Gene', '2260', (29, 34))
101924	25537505	With increment of total cigarette smoking dosage, the incidence of high-level FGFR1 amplification was significantly increased (Figure 4B, Ptrend = 0.001).	('FGFR1', 'Gene', (78, 83))	('FGFR1', 'Gene', '2260', (78, 83))	('amplification', 'Var', (84, 97))	('increased', 'PosReg', (116, 125))	('high-level', 'Var', (67, 77))
101926	25537505	In this study, we investigated the frequency and the prognostic impact of FGFR1 amplification in resected ESCC.	('amplification', 'Var', (80, 93))	('FGFR1', 'Gene', '2260', (74, 79))	('ESCC', 'Disease', (106, 110))	('FGFR1', 'Gene', (74, 79))
101927	25537505	To our knowledge, this is the first report on the prognostic impact of FGFR1 amplification in the largest-ever cohort of resected ESCC patients from East Asian.	('patients', 'Species', '9606', (135, 143))	('FGFR1', 'Gene', (71, 76))	('ESCC', 'Disease', (130, 134))	('FGFR1', 'Gene', '2260', (71, 76))	('amplification', 'Var', (77, 90))
101928	25537505	Our study demonstrated high FGFR1 amplification is a common genetic alteration (8.6%) and an independent negative prognostic factor in resected ESCC.	('high', 'Var', (23, 27))	('FGFR1', 'Gene', (28, 33))	('ESCC', 'Disease', (144, 148))	('FGFR1', 'Gene', '2260', (28, 33))	('amplification', 'Var', (34, 47))
101929	25537505	The frequency of FGFR1 amplification has been reported to range from 6% to 9.4%.	('FGFR1', 'Gene', '2260', (17, 22))	('amplification', 'Var', (23, 36))	('FGFR1', 'Gene', (17, 22))	('to 9', 'Species', '1214577', (72, 76))
101931	25537505	A comparative genomic study revealed many focal DNA amplifications or losses such as SOX2, PIK3CA, CCND1, FGFR1, MYC, GATA4, and GATA6 in ESCC and EAC.	('PIK3CA', 'Gene', (91, 97))	('GATA6', 'Gene', '2627', (129, 134))	('FGFR1', 'Gene', (106, 111))	('GATA6', 'Gene', (129, 134))	('PIK3CA', 'Gene', '5290', (91, 97))	('CCND1', 'Gene', '595', (99, 104))	('GATA4', 'Gene', '2626', (118, 123))	('amplifications', 'Var', (52, 66))	('MYC', 'Gene', '4609', (113, 116))	('FGFR1', 'Gene', '2260', (106, 111))	('GATA4', 'Gene', (118, 123))	('CCND1', 'Gene', (99, 104))	('EAC', 'Disease', (147, 150))	('SOX2', 'Gene', '6657', (85, 89))	('MYC', 'Gene', (113, 116))	('SOX2', 'Gene', (85, 89))	('losses', 'NegReg', (70, 76))	('ESCC', 'Disease', (138, 142))
101932	25537505	Of note, FGFR1 was amplified in 21% of ESCC samples compare with 8% in EAC.	('FGFR1', 'Gene', '2260', (9, 14))	('FGFR1', 'Gene', (9, 14))	('ESCC', 'Disease', (39, 43))	('amplified', 'Var', (19, 28))
101933	25537505	Recently, FGFR1 amplification was reported to be 9.4% in the cohort with Western Europe.	('FGFR1', 'Gene', (10, 15))	('FGFR1', 'Gene', '2260', (10, 15))	('amplification', 'Var', (16, 29))
101935	25537505	Given the relatively high frequency of FGFR1 amplification, it may represent an attractive therapeutic target for ESCC.	('FGFR1', 'Gene', (39, 44))	('FGFR1', 'Gene', '2260', (39, 44))	('ESCC', 'Disease', (114, 118))	('amplification', 'Var', (45, 58))
101936	25537505	Given the histological similarity and common risk factors, it is not surprising that FGFR1 amplification has been reported in upper aerodigestive tract cancers such as lung SqCC, SCCHN, and small cell lung cancer.	('SCCHN', 'Disease', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tract cancers', 'Disease', (146, 159))	('reported', 'Reg', (114, 122))	('FGFR1', 'Gene', (85, 90))	('tract cancers', 'Disease', 'MESH:D014571', (146, 159))	('amplification', 'Var', (91, 104))	('small cell lung cancer', 'Disease', 'MESH:D055752', (190, 212))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (190, 212))	('FGFR1', 'Gene', '2260', (85, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('small cell lung cancer', 'Disease', (190, 212))	('lung SqCC', 'Disease', (168, 177))	('SqCC', 'Phenotype', 'HP:0002860', (173, 177))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
101937	25537505	However, the prognostic significance of FGFR1 amplification in these cancers has shown controversial results.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('amplification', 'Var', (46, 59))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
101938	25537505	In resected lung SqCC, Kim et al reported FGFR1 amplification as negative prognostic factor, whereas Heist et al observed no significant difference in OS.	('SqCC', 'Phenotype', 'HP:0002860', (17, 21))	('OS', 'Chemical', '-', (151, 153))	('lung SqCC', 'Disease', (12, 21))	('FGFR1', 'Gene', (42, 47))	('FGFR1', 'Gene', '2260', (42, 47))	('amplification', 'Var', (48, 61))
101941	25537505	Low FGFR1 amplification occurred only in 1.1% and survival outcome of low FGFR1 amplification group was similar to no amplification group.	('low', 'Var', (70, 73))	('FGFR1', 'Gene', '2260', (74, 79))	('FGFR1', 'Gene', (4, 9))	('FGFR1', 'Gene', '2260', (4, 9))	('FGFR1', 'Gene', (74, 79))
101942	25537505	Compared with low/no amplification group, high FGFR1 amplification was significantly associated with shorter DFS regardless of sex, histology, and adjuvant therapy, implying that FGFR1 amplification as an independent negative prognostic factor in curatively resected ESCC.	('ESCC', 'Disease', (267, 271))	('FGFR1', 'Gene', (47, 52))	('DFS', 'MPA', (109, 112))	('FGFR1', 'Gene', (179, 184))	('amplification', 'Var', (53, 66))	('FGFR1', 'Gene', '2260', (47, 52))	('FGFR1', 'Gene', '2260', (179, 184))	('shorter', 'NegReg', (101, 108))	('high', 'Var', (42, 46))
101943	25537505	The identification of FGFR alteration in human cancers led to rapid development of selective FGFR inhibitor such as BGJ398 and AZD4547.	('FGFR', 'Gene', (22, 26))	('AZD4547', 'Chemical', 'MESH:C572463', (127, 134))	('human', 'Species', '9606', (41, 46))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('alteration', 'Var', (27, 37))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('FGFR', 'Gene', (93, 97))	('BGJ398', 'Chemical', 'MESH:C568950', (116, 122))
101945	25537505	In another phase I study with FGFR inhibitor AZD4547, 1 partial response was also seen in lung SqCC patient with FGFR1 amplification (FGFR1/CEN8 ratio > 2.8).	('lung SqCC', 'Disease', (90, 99))	('CEN8', 'Chemical', '-', (140, 144))	('SqCC', 'Phenotype', 'HP:0002860', (95, 99))	('AZD4547', 'Chemical', 'MESH:C572463', (45, 52))	('FGFR1', 'Gene', (134, 139))	('FGFR1', 'Gene', (113, 118))	('FGFR1', 'Gene', '2260', (134, 139))	('patient', 'Species', '9606', (100, 107))	('FGFR1', 'Gene', '2260', (113, 118))	('amplification', 'Var', (119, 132))
101946	25537505	Various FGFR inhibitors are currently in clinical development for the patients with FGFR aberrations.	('patients', 'Species', '9606', (70, 78))	('FGFR', 'Gene', (8, 12))	('aberrations', 'Var', (89, 100))	('FGFR', 'Gene', (84, 88))
101947	25537505	Therefore, our study strongly suggests the therapeutic potential of FGFR inhibitor for ESCC, and future clinical trials for advanced high FGFR1 amplified ESCC are strongly warranted.	('high', 'Var', (133, 137))	('ESCC', 'Disease', (154, 158))	('FGFR1', 'Gene', (138, 143))	('ESCC', 'Disease', (87, 91))	('FGFR1', 'Gene', '2260', (138, 143))
101955	25537505	Considering clinical benefit appeared in patients with high FGFR1/CEN8 ratio in clinical trials with FGFR inhibitors, this scoring system might serve as a standardized screening tool to select patients who gain greater benefit from treatment with FGFR inhibitors.	('patients', 'Species', '9606', (193, 201))	('FGFR1', 'Gene', (60, 65))	('FGFR1', 'Gene', '2260', (60, 65))	('CEN8', 'Chemical', '-', (66, 70))	('patients', 'Species', '9606', (41, 49))	('high', 'Var', (55, 59))
101957	25537505	Accumulating evidence has shown that FGFR1 amplification correlated with smoking status in squamous cell biology.	('FGFR1', 'Gene', (37, 42))	('FGFR1', 'Gene', '2260', (37, 42))	('amplification', 'Var', (43, 56))	('correlated', 'Reg', (57, 67))	('squamous cell biology', 'Disease', (91, 112))
101958	25537505	FGFR1 amplification occurs significantly more often in the smokers of the lung SqCC, SCCHN, and small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('lung SqCC', 'Disease', (74, 83))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))	('FGFR1', 'Gene', (0, 5))	('small cell lung cancer', 'Disease', (96, 118))	('FGFR1', 'Gene', '2260', (0, 5))	('SqCC', 'Phenotype', 'HP:0002860', (79, 83))	('amplification', 'Var', (6, 19))	('often', 'Reg', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SCCHN', 'Disease', (85, 90))	('small cell lung cancer', 'Disease', 'MESH:D055752', (96, 118))
101959	25537505	The proportion of FGFR1 amplification among current smokers were reported 15.8% to 28.9% in lung SqCC and 17.7% in SCCHN in a dose dependent manner.	('lung SqCC', 'Disease', (92, 101))	('SCCHN', 'Disease', (115, 120))	('FGFR1', 'Gene', (18, 23))	('SqCC', 'Phenotype', 'HP:0002860', (97, 101))	('amplification', 'Var', (24, 37))	('FGFR1', 'Gene', '2260', (18, 23))
101961	25537505	In our study, FGFR1 amplification was significantly more likely to be smokers, and 44 out of 45 high FGFR1 amplification cases were current or former smokers.	('FGFR1', 'Gene', (14, 19))	('FGFR1', 'Gene', '2260', (14, 19))	('amplification', 'Var', (20, 33))	('FGFR1', 'Gene', (101, 106))	('FGFR1', 'Gene', '2260', (101, 106))
101962	25537505	Similar to the findings in lung SqCC and SCCHN, acquisition of FGFR1 amplification in our study was also significantly increased proportional to smoking dosage.	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('SqCC', 'Phenotype', 'HP:0002860', (32, 36))	('amplification', 'Var', (69, 82))	('increased', 'PosReg', (119, 128))
101963	25537505	Therefore, FGFR1 amplification may be an oncogenic driver mutation in tobacco-associated cancers of the aerodigestive tract.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('tobacco', 'Species', '4097', (70, 77))	('FGFR1', 'Gene', (11, 16))	('cancers', 'Disease', (89, 96))	('amplification', 'Var', (17, 30))	('FGFR1', 'Gene', '2260', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
101964	25537505	An interesting question of the role of FGFR1 amplification on the smoking-associated carcinogenesis still remained to be solved.	('FGFR1', 'Gene', (39, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('FGFR1', 'Gene', '2260', (39, 44))	('carcinogenesis', 'Disease', (85, 99))	('amplification', 'Var', (45, 58))
101966	25537505	Inhibitor-sensitive 5 mutation loci for FGFR2 and 6 mutation loci for FGFR3 were noticed in 3% of lung SqCC samples.Here, we show no FGFR2 and FGFR3 mutations in our 388 ESCC patients.	('FGFR3', 'Gene', '2261', (143, 148))	('mutations', 'Var', (149, 158))	('FGFR3', 'Gene', '2261', (70, 75))	('FGFR3', 'Gene', (143, 148))	('SqCC', 'Phenotype', 'HP:0002860', (103, 107))	('FGFR2', 'Gene', (133, 138))	('FGFR3', 'Gene', (70, 75))	('FGFR2', 'Gene', '2263', (133, 138))	('patients', 'Species', '9606', (175, 183))	('FGFR2', 'Gene', (40, 45))	('FGFR2', 'Gene', '2263', (40, 45))	('ESCC', 'Disease', (170, 174))
101969	25537505	In conclusion, we demonstrated high FGFR1 amplification is an independent poor prognostic factor in resected ESCC.	('ESCC', 'Disease', (109, 113))	('FGFR1', 'Gene', (36, 41))	('FGFR1', 'Gene', '2260', (36, 41))	('amplification', 'Var', (42, 55))	('high', 'Var', (31, 35))
101970	25537505	Patients with FGFR1 amplification were significantly more likely to be smokers and the frequency of FGFR1 amplification was also increased proportional to smoking dosage, suggesting FGFR1 amplification as an oncogenic aberration induced by smoking carcinogen.	('FGFR1', 'Gene', (14, 19))	('amplification', 'Var', (188, 201))	('FGFR1', 'Gene', (182, 187))	('smokers', 'Disease', (71, 78))	('Patients', 'Species', '9606', (0, 8))	('FGFR1', 'Gene', (100, 105))	('FGFR1', 'Gene', '2260', (14, 19))	('FGFR1', 'Gene', '2260', (182, 187))	('amplification', 'Var', (20, 33))	('FGFR1', 'Gene', '2260', (100, 105))
101971	25537505	Our finding indicates FGFR1 amplification is a promising therapeutic target in ESCC.	('FGFR1', 'Gene', '2260', (22, 27))	('ESCC', 'Disease', (79, 83))	('amplification', 'Var', (28, 41))	('FGFR1', 'Gene', (22, 27))
101986	25537505	Based on the previous study in lung SqCC, we evaluated the W290C, S320C, and K660E/K660N mutations in FGFR2, and R248C and S249C mutations in FGFR3.	('SqCC', 'Phenotype', 'HP:0002860', (36, 40))	('S249C', 'Var', (123, 128))	('W290C', 'SUBSTITUTION', 'None', (59, 64))	('S249C', 'Mutation', 'rs121913483', (123, 128))	('S320C', 'Mutation', 'rs1057519791', (66, 71))	('R248C', 'Mutation', 'rs121913482', (113, 118))	('FGFR3', 'Gene', '2261', (142, 147))	('W290C', 'Var', (59, 64))	('K660E', 'Var', (77, 82))	('K660E', 'SUBSTITUTION', 'None', (77, 82))	('K660N', 'Mutation', 'p.K660N', (83, 88))	('FGFR2', 'Gene', (102, 107))	('FGFR3', 'Gene', (142, 147))	('R248C', 'Var', (113, 118))	('S320C', 'Var', (66, 71))	('FGFR2', 'Gene', '2263', (102, 107))
101987	25537505	PCR amplification primers were designed to amplify following regions; W290C; 5'-TCCACAGTGGTCGGAGGAG-3'; 5'- AAAGTCCTCACCTTGAGAACCTTG-3', S320C; 5'-CCTGGTTGGCCGTTATATTG-3'; 5'- TGTTTTGGCAGGACAGTGAG-3', K660E/K660N; 5'- ATTCATCGAGATTTAGCAGCCAG-3'; 5'- ACATTCTGAGCCTCACCCC-3', R248C and S249C; 5'-TGGCGGTGGTGGTGAG-3'; 5'- ATTCACCTCCACGTGCTTGA-3'.	('S249C', 'Mutation', 'rs121913483', (284, 289))	('K660N', 'Mutation', 'p.K660N', (207, 212))	('S320C', 'Mutation', 'rs1057519791', (137, 142))	('R248C', 'Mutation', 'rs121913482', (274, 279))	('W290C', 'SUBSTITUTION', 'None', (70, 75))	('K660E', 'Var', (201, 206))	('S320C', 'Var', (137, 142))	('K660E', 'SUBSTITUTION', 'None', (201, 206))	('W290C', 'Var', (70, 75))	('R248C', 'Var', (274, 279))	('S249C', 'Var', (284, 289))
101988	25537505	We evaluated association between FGFR1 amplification status and clinical significance using the chi2test or Fisher's exact test and trend was analyzed using linear regression.	('FGFR1', 'Gene', '2260', (33, 38))	('amplification status', 'Var', (39, 59))	('evaluated', 'Reg', (3, 12))	('FGFR1', 'Gene', (33, 38))
101989	25537505	We also assessed whether FGFR1 amplification influenced survival outcome using Kaplan-Meier curves with a log-rank test.	('influenced', 'Reg', (45, 55))	('FGFR1', 'Gene', '2260', (25, 30))	('FGFR1', 'Gene', (25, 30))	('amplification', 'Var', (31, 44))
101999	22400064	NIR imaging with ProSense750 significantly improved upon the TBRs of esophageal tumor foci, with a TBR of 3.64+-0.14 and 4.50+-0.11 for the OE-33 and OE-19 tumors respectively, compared to 0.88+-0.04 and 0.81+-0.02 TBR for WL imaging.	('esophageal tumor foci', 'Disease', (69, 90))	('ProSense750', 'Gene', (17, 28))	('TBR', 'Chemical', '-', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('OE-19 tumors', 'Disease', 'MESH:D009369', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('TBR', 'Chemical', '-', (99, 102))	('TBRs', 'Chemical', '-', (61, 65))	('TBR', 'Chemical', '-', (61, 64))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('improved', 'PosReg', (43, 51))	('OE-33', 'Var', (140, 145))	('esophageal tumor foci', 'Disease', 'MESH:D004938', (69, 90))	('esophageal tumor', 'Phenotype', 'HP:0100751', (69, 85))	('OE-19 tumors', 'Disease', (150, 162))
102053	22400064	Analysis of the NIR and WL signal and the TBR demonstrated a several fold increase in the NIR signal in the OE-33 and OE-19 group in comparison to the controls.	('OE-19', 'Var', (118, 123))	('OE-33', 'Var', (108, 113))	('increase', 'PosReg', (74, 82))	('TBR', 'Chemical', '-', (42, 45))	('NIR signal', 'MPA', (90, 100))
102054	22400064	The NIR TBR in the OE-33 and OE-19 were 3.64+-0.14 and 4.50+-0.11, respectively, which were significantly higher compared to the control group non-elevated NIR TBR of 1.08+-0.08 (p<0.0001).	('higher', 'PosReg', (106, 112))	('OE-33', 'Var', (19, 24))	('TBR', 'Chemical', '-', (160, 163))	('TBR', 'Chemical', '-', (8, 11))
102055	22400064	The WL TBR (0.88+-0.04 and 0.81+-0.02 for OE-33 and OE-19 groups, respectively) was comparable to the WL TBR of 0.97+-0.05 for the control group.	('OE-19', 'Var', (52, 57))	('TBR', 'Chemical', '-', (7, 10))	('TBR', 'Chemical', '-', (105, 108))	('OE-33', 'Var', (42, 47))
102178	19161745	Patients thought to have T1N0M0 or T2N0M0 esophageal cancer are offered esophagogastrectomy.	('esophageal cancer', 'Disease', (42, 59))	('T2N0M0', 'Var', (35, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('esophagogastrectomy', 'Disease', (72, 91))	('T1N0M0', 'Var', (25, 31))
102179	19161745	Patients with T1N1M0, T2N1M0, T3N1M0, T3N0M0, T4N0M0, and T4N1M0 disease are offered nCRTSR, and patients with M1a disease are considered for nCRTSR.	('T4N0M0', 'Var', (46, 52))	('T3N0M0', 'Var', (38, 44))	('T4N1M0 disease', 'Var', (58, 72))	('Patients', 'Species', '9606', (0, 8))	('T2N1M0', 'Var', (22, 28))	('T1N1M0', 'Var', (14, 20))	('M1a disease', 'Disease', 'MESH:D004194', (111, 122))	('T3N1M0', 'Var', (30, 36))	('M1a disease', 'Disease', (111, 122))	('patients', 'Species', '9606', (97, 105))
102296	27656835	Multiple studies have demonstrated that alteration of the BRCA2 gene gives an increased risk factor for tumorigenesis and progression in a variety of cancers, including breast cancer, ovarian cancer, and EC.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('ovarian cancer', 'Disease', 'MESH:D010051', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('BRCA2', 'Gene', '675', (58, 63))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('risk factor', 'Reg', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('ovarian cancer', 'Disease', (184, 198))	('tumor', 'Disease', (104, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (184, 198))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))	('alteration', 'Var', (40, 50))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('BRCA2', 'Gene', (58, 63))	('breast cancer', 'Disease', (169, 182))
102298	27656835	The BRCA2 mutation has been identified as a vital risk factor in EC.	('BRCA2', 'Gene', (4, 9))	('BRCA2', 'Gene', '675', (4, 9))	('mutation', 'Var', (10, 18))
102320	27656835	Flag-tagged BRCA2 protein was generated by fusing the Flag tag to the C terminus of the BRCA2 protein.	('BRCA2', 'Gene', (12, 17))	('BRCA2', 'Gene', (88, 93))	('fusing', 'Var', (43, 49))	('BRCA2', 'Gene', '675', (12, 17))	('BRCA2', 'Gene', '675', (88, 93))
102334	27656835	Afterward, cells were incubated with primary antibodies: anti-Flag (1:500; Sigma-Aldrich), anti-BRCA2 (1:200; Calbiochem), and anti-gamma-tubulin (1:1,000; Sigma-Aldrich) for 1 h at room temperature.	('BRCA2', 'Gene', '675', (96, 101))	('BRCA2', 'Gene', (96, 101))	('anti-gamma-tubulin', 'Var', (127, 145))
102360	27656835	Studies in vitro and in vivo have demonstrated that LIMD1 interacted with retinoblastoma protein (pRB), and the loss of LIMD1 promoted lung carcinogenesis.	('LIMD1', 'Gene', '8994', (120, 125))	('pRB', 'Gene', (98, 101))	('retinoblastoma', 'Disease', 'MESH:D012175', (74, 88))	('LIMD1', 'Gene', (120, 125))	('retinoblastoma', 'Phenotype', 'HP:0009919', (74, 88))	('promoted', 'PosReg', (126, 134))	('pRB', 'Gene', '5925', (98, 101))	('lung carcinogenesis', 'Disease', (135, 154))	('LIMD1', 'Gene', '8994', (52, 57))	('loss', 'Var', (112, 116))	('retinoblastoma', 'Disease', (74, 88))	('LIMD1', 'Gene', (52, 57))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (135, 154))
102366	27656835	In mitosis, the centrosome plays a key role in the fixation of spindle and centromere, and the structure or function abnormalities of centrosome always results in abnormal nuclear division and tumorigenesis.	('abnormalities', 'Var', (117, 130))	('results in', 'Reg', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('nuclear division', 'CPA', (172, 188))	('tumor', 'Disease', (193, 198))
102370	27656835	found that BRCA2 acted as a cell cycle regulation gene, and the absence of BRCA2 causes centrosome amplification.	('BRCA2', 'Gene', '675', (11, 16))	('causes', 'Reg', (81, 87))	('BRCA2', 'Gene', (75, 80))	('absence', 'Var', (64, 71))	('centrosome amplification', 'MPA', (88, 112))	('BRCA2', 'Gene', '675', (75, 80))	('BRCA2', 'Gene', (11, 16))
102644	31143067	H. pylori may also directly damage host DNA, dysregulate DNA transcription factors such as caudal type homeobox 2 (Cdx2), and induce epithelial injury and acid secretory functions.	('induce', 'Reg', (126, 132))	('acid secretory', 'MPA', (155, 169))	('damage', 'Reg', (28, 34))	('H. pylori', 'Species', '210', (0, 9))	('DNA transcription factors', 'Gene', (57, 82))	('Cdx2', 'Gene', (115, 119))	('epithelial injury', 'Disease', 'MESH:D002277', (133, 150))	('epithelial injury', 'Disease', (133, 150))	('dysregulate', 'Var', (45, 56))
102646	31143067	Some studies suggest that H. pylori eradication could increase the serum level of ghrelin, which may lead to obesity and affect gastric emptying, subsequently initiating the risks of BE and EAC.	('EAC', 'Phenotype', 'HP:0011459', (190, 193))	('affect', 'Reg', (121, 127))	('H. pylori', 'Species', '210', (26, 35))	('BE', 'Phenotype', 'HP:0100580', (183, 185))	('ghrelin', 'Protein', (82, 89))	('obesity', 'Disease', 'MESH:D009765', (109, 116))	('gastric emptying', 'Phenotype', 'HP:0002578', (128, 144))	('obesity', 'Disease', (109, 116))	('increase', 'PosReg', (54, 62))	('gastric emptying', 'MPA', (128, 144))	('obesity', 'Phenotype', 'HP:0001513', (109, 116))	('ghrelin', 'Chemical', 'MESH:D054439', (82, 89))	('H. pylori', 'Gene', (26, 35))	('serum level', 'MPA', (67, 78))	('eradication', 'Var', (36, 47))	('lead to', 'Reg', (101, 108))
102651	31143067	The administration of PPIs could change the microbial composition in the esophagus and stomach in BE patients, which may contribute to the pathogenesis of BE, though this has not been well established.	('patients', 'Species', '9606', (101, 109))	('rat', 'Species', '10116', (12, 15))	('PPIs', 'Var', (22, 26))	('contribute', 'Reg', (121, 131))	('BE', 'Phenotype', 'HP:0100580', (98, 100))	('microbial composition', 'MPA', (44, 65))	('change', 'Reg', (33, 39))	('BE', 'Phenotype', 'HP:0100580', (155, 157))
102653	31143067	PPIs could reduce the number of gram-negative bacteria and decrease the risk for neoplasia in the esophagus.	('neoplasia in the esophagus', 'Phenotype', 'HP:0100751', (81, 107))	('reduce', 'NegReg', (11, 17))	('decrease', 'NegReg', (59, 67))	('neoplasia', 'Disease', (81, 90))	('neoplasia', 'Phenotype', 'HP:0002664', (81, 90))	('PPIs', 'Var', (0, 4))	('gram-negative', 'CPA', (32, 45))	('neoplasia', 'Disease', 'MESH:D009369', (81, 90))
102655	31143067	However, long-term PPI therapy induced hypergastrinemia, which may upregulate cyclooxygenase-2 (COX-2) expression, cell proliferation and esophageal carcinogenesis.	('COX-2', 'Gene', (96, 101))	('upregulate', 'PosReg', (67, 77))	('COX-2', 'Gene', '5743', (96, 101))	('PPI', 'Var', (19, 22))	('hypergastrinemia', 'Disease', (39, 55))	('expression', 'MPA', (103, 113))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (138, 163))	('cyclooxygenase-2', 'Gene', '5743', (78, 94))	('esophageal carcinogenesis', 'Disease', (138, 163))	('cyclooxygenase-2', 'Gene', (78, 94))	('hypergastrinemia', 'Disease', 'None', (39, 55))	('cell proliferation', 'CPA', (115, 133))	('rat', 'Species', '10116', (127, 130))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (39, 55))
102657	31143067	showed that PPIs augment anti-H. pylori activity, and H. pylori appears to exert a protective role in esophageal neoplasia.	('H. pylori', 'Species', '210', (30, 39))	('augment', 'PosReg', (17, 24))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (102, 122))	('esophageal neoplasia', 'Disease', (102, 122))	('PPIs', 'Var', (12, 16))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (102, 122))	('anti-H. pylori activity', 'MPA', (25, 48))	('neoplasia', 'Phenotype', 'HP:0002664', (113, 122))	('H. pylori', 'Species', '210', (54, 63))
102660	31143067	Antibiotics may definitively change the gastrointestinal microbiota, and alteration of the microbial abundance and/or diversity might contribute to disease pathology.	('Antibiotics', 'Var', (0, 11))	('alteration', 'Reg', (73, 83))	('rat', 'Species', '10116', (77, 80))	('contribute', 'Reg', (134, 144))	('diversity', 'CPA', (118, 127))	('change', 'Reg', (29, 35))	('gastrointestinal microbiota', 'MPA', (40, 67))	('microbial abundance', 'CPA', (91, 110))
102675	31143067	LPS could delay gastric emptying via COX1/2 and contribute to the development of GER by increasing the intra-gastric pressure.	('gastric emptying', 'CPA', (16, 32))	('GER', 'Phenotype', 'HP:0002020', (81, 84))	('intra-gastric pressure', 'MPA', (103, 125))	('LPS', 'Var', (0, 3))	('COX1/2', 'Gene', (37, 43))	('delay', 'NegReg', (10, 15))	('development', 'CPA', (66, 77))	('gastric emptying', 'Phenotype', 'HP:0002578', (16, 32))	('delay gastric emptying', 'Phenotype', 'HP:0002578', (10, 32))	('GER', 'Gene', '59330', (81, 84))	('contribute', 'Reg', (48, 58))	('GER', 'Gene', (81, 84))	('increasing', 'PosReg', (88, 98))	('COX1/2', 'Gene', '4512;4513', (37, 43))
102676	31143067	Notably, LPS could also affect the function of the lower esophageal sphincter, which may promote GER and carcinogenesis.	('GER', 'Gene', '59330', (97, 100))	('carcinogenesis', 'Disease', 'MESH:D063646', (105, 119))	('promote', 'PosReg', (89, 96))	('carcinogenesis', 'Disease', (105, 119))	('GER', 'Gene', (97, 100))	('function', 'MPA', (35, 43))	('affect', 'Reg', (24, 30))	('LPS', 'Var', (9, 12))	('GER', 'Phenotype', 'HP:0002020', (97, 100))
102724	31045824	Although TIPS is more effective than endoscopic therapy for preventing variceal bleeding, TIPS can increase the risk of hepatic encephalopathy (HE).	('HE', 'Phenotype', 'HP:0002480', (144, 146))	('TIPS', 'Var', (90, 94))	('bleeding', 'Disease', 'MESH:D006470', (80, 88))	('bleeding', 'Disease', (80, 88))	('encephalopathy', 'Phenotype', 'HP:0001298', (128, 142))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (120, 142))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (120, 142))	('hepatic encephalopathy', 'Disease', (120, 142))	('variceal', 'Disease', (71, 79))
102815	31045824	Some studies have shown that PTVE can increase portal hypertension, and result in portal hypertensive complications, including worsening non-gastric varices including bleeding from EVs.	('gastric varices', 'Phenotype', 'HP:0030169', (141, 156))	('increase', 'PosReg', (38, 46))	('PTVE', 'Var', (29, 33))	('hypertension', 'Disease', (54, 66))	('worsening', 'PosReg', (127, 136))	('hypertension', 'Phenotype', 'HP:0000822', (54, 66))	('EVs', 'Phenotype', 'HP:0002040', (181, 184))	('bleeding', 'Disease', 'MESH:D006470', (167, 175))	('portal hypertension', 'Phenotype', 'HP:0001409', (47, 66))	('portal hypertensive', 'Phenotype', 'HP:0001409', (82, 101))	('non-gastric', 'MPA', (137, 148))	('bleeding', 'Disease', (167, 175))	('hypertensive complications', 'Phenotype', 'HP:0000822', (89, 115))	('hypertensive complications', 'Disease', (89, 115))	('hypertension', 'Disease', 'MESH:D006973', (54, 66))	('result in', 'Reg', (72, 81))	('PTVE', 'Chemical', '-', (29, 33))	('hypertensive complications', 'Disease', 'MESH:D006973', (89, 115))
102829	31045824	One study by Lee et al reported that PTVE increased the risk of worsening ascites.	('ascites', 'Disease', (74, 81))	('PTVE', 'Chemical', '-', (37, 41))	('ascites', 'Phenotype', 'HP:0001541', (74, 81))	('PTVE', 'Var', (37, 41))	('ascites', 'Disease', 'MESH:D001201', (74, 81))	('PTVE increased', 'Phenotype', 'HP:0008151', (37, 51))
102832	31045824	In conclusion, the results indicate that in patients with gastric varices, PTVE offers similar survival and rebleeding-free rate compared to TIPS.	('patients', 'Species', '9606', (44, 52))	('PTVE', 'Chemical', '-', (75, 79))	('PTVE', 'Var', (75, 79))	('gastric varices', 'Disease', (58, 73))	('bleeding', 'Disease', 'MESH:D006470', (110, 118))	('gastric varices', 'Phenotype', 'HP:0030169', (58, 73))	('bleeding', 'Disease', (110, 118))
102835	31037126	Identification of miR-29c and its Target FBXO31 as a Key Regulatory Mechanism in Esophageal Cancer Chemoresistance: Functional Validation and Clinical Significance Rationale: Dysregulated microRNA (miRNA) expressions in cancer can contribute to chemoresistance.	('miR-29c', 'Gene', (18, 25))	('miR-29c', 'Gene', '407026', (18, 25))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('FBXO31', 'Gene', '79791', (41, 47))	('Esophageal Cancer', 'Disease', (81, 98))	('contribute', 'Reg', (231, 241))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('chemoresistance', 'CPA', (245, 260))	('Clinical', 'Species', '191496', (142, 150))	('FBXO31', 'Gene', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('Dysregulated', 'Var', (175, 187))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (81, 98))
102840	31037126	Bioinformatics, gain- and loss-of-function experiments, and luciferase reporter assay were performed to validate F-box only protein 31 (FBXO31) as a direct target of miR-29c, and to identify potential transcription factor binding events that control miR-29c expression.	('miR-29c', 'Gene', (250, 257))	('miR-29c', 'Var', (166, 173))	('F-box only protein 31', 'Gene', (113, 134))	('F-box only protein 31', 'Gene', '79791', (113, 134))
102843	31037126	Functional studies showed that miR-29c could override 5-FU chemoresistance in vitro and in vivo by directly interacting with the 3'UTR of FBXO31, leading to repression of FBXO31 expression and downstream activation of p38 MAPK.	('MAPK', 'Gene', (222, 226))	('activation', 'PosReg', (204, 214))	('override', 'PosReg', (45, 53))	('interacting', 'Interaction', (108, 119))	('p38', 'Gene', '1432', (218, 221))	('expression', 'MPA', (178, 188))	('FBXO31', 'Gene', (171, 177))	('repression', 'NegReg', (157, 167))	('miR-29c', 'Var', (31, 38))	('p38', 'Gene', (218, 221))	('MAPK', 'Gene', '5594', (222, 226))	('5-FU', 'Chemical', 'MESH:D005472', (54, 58))
102844	31037126	Systemically administered miR-29c dramatically improved response of 5-FU chemoresistant ESCC xenografts in vivo.	('improved', 'PosReg', (47, 55))	('response', 'MPA', (56, 64))	('5-FU', 'Chemical', 'MESH:D005472', (68, 72))	('miR-29c', 'Var', (26, 33))
102852	31037126	Our previous studies demonstrated that FBXO31 deactivates MAPK p38 and JNK signaling in ESCC cells subjected to genotoxic stresses, and that this mechanism contributes to DDP chemoresistance, but the functional role of FBXO31 in 5-FU chemoresistance and its regulatory mechanisms have not been reported.	('FBXO31', 'Var', (39, 45))	('DDP', 'Gene', (171, 174))	('MAPK', 'Gene', '5594', (58, 62))	('JNK', 'Gene', (71, 74))	('MAPK', 'Gene', (58, 62))	('p38', 'Gene', '1432', (63, 66))	('JNK', 'Gene', '5599', (71, 74))	('DDP', 'Gene', '1678', (171, 174))	('5-FU', 'Chemical', 'MESH:D005472', (229, 233))	('contributes', 'Reg', (156, 167))	('p38', 'Gene', (63, 66))	('deactivates', 'NegReg', (46, 57))
102854	31037126	Moreover, the efficacy of systemic delivery of miR-29c as cancer therapeutics was evaluated.	('cancer', 'Disease', (58, 64))	('miR-29c', 'Var', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))
102885	31037126	QuikChange Lightning Site-Directed Mutagenesis Kit (Agilent Technologies) was used to generate constructs that expressed mutated 3'UTR of FBXO31 and mutation of pGL3-miR29c-pro-WT.	('miR29c', 'Gene', (166, 172))	('pGL3', 'Gene', '6391', (161, 165))	('mutated', 'Var', (121, 128))	('miR29c', 'Gene', '407026', (166, 172))	('FBXO31', 'Gene', (138, 144))	('pGL3', 'Gene', (161, 165))	('mutation', 'Var', (149, 157))
102888	31037126	In the experiment involving systemic miR-29c treatment, KYSE410FR cells were subcutaneously injected into mice and the mice were randomized into four groups when the tumors reached ~5 mm in diameter.	('mice', 'Species', '10090', (119, 123))	('mice', 'Species', '10090', (106, 110))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('KYSE410FR', 'Var', (56, 65))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
102904	31037126	The expression level of miR-29c in tumor and serum samples was compared with that in non-tumor tissues and healthy control serum, respectively, using paired or unpaired t-test.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('non-tumor', 'Disease', 'MESH:D009369', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('miR-29c', 'Var', (24, 31))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('non-tumor', 'Disease', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
102908	31037126	The results showed that miR-29c expression was significantly lower in tumor tissues than adjacent non-tumor tissues (P < 0.001) (Figure 1A), and that downregulation was detected in 90.6% (29/32) of ESCC cases (Figure 1B).	('lower', 'NegReg', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ESCC', 'Disease', (198, 202))	('tumor', 'Disease', (70, 75))	('miR-29c', 'Var', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('non-tumor', 'Disease', (98, 107))	('non-tumor', 'Disease', 'MESH:D009369', (98, 107))	('expression', 'MPA', (32, 42))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
102910	31037126	More importantly, our results showed that miR-29c was significantly associated with overall survival of ESCC patients, with the mean survival time dropping from 36.8 months in the patients with high miR-29c expression to 17.0 months in the patients with low miR-29c expression (Figure 1C).	('dropping', 'NegReg', (147, 155))	('high miR-29c', 'Var', (194, 206))	('associated', 'Reg', (68, 78))	('patients', 'Species', '9606', (109, 117))	('miR-29c', 'Var', (199, 206))	('miR-29c', 'Var', (42, 49))	('ESCC', 'Disease', (104, 108))	('patients', 'Species', '9606', (240, 248))	('patients', 'Species', '9606', (180, 188))
102913	31037126	In the public databases, low miR-29c expression was also associated with poor prognosis in several other cancer types (Figures S2B and S3B).	('miR-29c expression', 'Var', (29, 47))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('low', 'NegReg', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
102914	31037126	We further explored the clinical relevance of miR-29c as a non-invasive marker in ESCC by comparing the expression level of miR-29c in admission serum samples of 114 ESCC patients with that in serum samples of 50 healthy individuals.	('clinical', 'Species', '191496', (24, 32))	('ESCC', 'Disease', (82, 86))	('patients', 'Species', '9606', (171, 179))	('miR-29c', 'Var', (124, 131))	('ESCC', 'Disease', (166, 170))
102916	31037126	Moreover, Kaplan- Meier survival analysis showed that the ESCC patients with high serum miR-29c expression had significantly prolonged overall survival time (Figure 1E).	('high', 'Var', (77, 81))	('miR-29c expression', 'Var', (88, 106))	('overall survival', 'MPA', (135, 151))	('prolonged', 'PosReg', (125, 134))	('patients', 'Species', '9606', (63, 71))	('ESCC', 'Disease', (58, 62))
102918	31037126	To study the role of miR-29c in ESCC chemoresistance, miR-29c was stably overexpressed in two FR sublines (KYSE150FR-miR-29c and KYSE410FR- miR-29c) (Figure S4A), and then the cells were treated with 5-FU in functional assays.	('KYSE410FR- miR-29c', 'Var', (129, 147))	('KYSE150FR-miR-29c', 'Var', (107, 124))	('overexpressed', 'PosReg', (73, 86))	('5-FU', 'Chemical', 'MESH:D005472', (200, 204))
102919	31037126	The results from MTT and colony-formation assays showed that ectopic expression of miR-29c overcame the resistance of KYSE150FR and KYSE410FR cells to 5-FU treatment (Figure 2A-B).	('resistance', 'MPA', (104, 114))	('5-FU', 'Chemical', 'MESH:D005472', (151, 155))	('MTT', 'Chemical', 'MESH:C070243', (17, 20))	('overcame', 'PosReg', (91, 99))	('miR-29c', 'Gene', (83, 90))	('KYSE410FR', 'Var', (132, 141))	('KYSE150FR', 'Var', (118, 127))
102920	31037126	Conversely, knockdown of miR-29c by miR-zip-29c (Figure S4A) markedly conferred 5-FU chemoresistance to ESCC cells (Figure 2C-D).	('zip', 'Gene', (40, 43))	('conferred', 'Reg', (70, 79))	('knockdown', 'Var', (12, 21))	('zip', 'Gene', '1613', (40, 43))	('5-FU', 'Chemical', 'MESH:D005472', (80, 84))	('5-FU', 'MPA', (80, 84))
102921	31037126	Moreover, we found that miR-29c promoted apoptosis of the 5-FU-treated cells, indicated by the increased 5-FU-induced cleaved caspase-3 expression in miR-29c-overexpressing FR cells and the decreased 5-FU-induced cleaved caspase-3 expression in miR-29c-knockdown cells (Figure 2E-F).	('promoted', 'PosReg', (32, 40))	('miR-29c', 'Var', (24, 31))	('5-FU-induced cleaved caspase-3 expression', 'MPA', (105, 146))	('5-FU', 'Chemical', 'MESH:D005472', (58, 62))	('5-FU-induced cleaved caspase-3', 'MPA', (200, 230))	('decreased', 'NegReg', (190, 199))	('apoptosis', 'CPA', (41, 50))	('5-FU', 'Chemical', 'MESH:D005472', (200, 204))	('increased', 'PosReg', (95, 104))	('5-FU', 'Chemical', 'MESH:D005472', (105, 109))	('expression', 'MPA', (231, 241))
102922	31037126	Taken together, these data demonstrated that miR-29c could enhance the sensitivity of ESCC cells to 5-FU.	('miR-29c', 'Var', (45, 52))	('5-FU', 'Chemical', 'MESH:D005472', (100, 104))	('enhance', 'PosReg', (59, 66))	('sensitivity', 'MPA', (71, 82))
102923	31037126	In addition, we determined whether miR-29c dyregulation may contribute to DDP chemoresistance.	('miR-29c dyregulation', 'Var', (35, 55))	('dyregulation', 'Var', (43, 55))	('contribute', 'Reg', (60, 70))	('DDP', 'Gene', '1678', (74, 77))	('DDP', 'Gene', (74, 77))
102924	31037126	ESCC cells with miR-29c-knockdown showed enhanced viability and colony formation ability, compared with the control cells expressing miR-zip-CON, when exposed to DDP, which suggests that miR-29c can sensitize ESCC cells to DDP treatment (Figure S5A-B).	('DDP', 'Gene', '1678', (223, 226))	('colony formation ability', 'CPA', (64, 88))	('miR-29c-knockdown', 'Var', (16, 33))	('DDP', 'Gene', '1678', (162, 165))	('zip', 'Gene', (137, 140))	('enhanced', 'PosReg', (41, 49))	('DDP', 'Gene', (223, 226))	('ESCC', 'Disease', (209, 213))	('DDP', 'Gene', (162, 165))	('viability', 'CPA', (50, 59))	('sensitize', 'Reg', (199, 208))	('zip', 'Gene', '1613', (137, 140))	('miR-29c', 'Var', (187, 194))
102925	31037126	We next investigated the mechanism by which miR-29c regulates 5-FU resistance in ESCC cells.	('5-FU resistance', 'MPA', (62, 77))	('regulates', 'Reg', (52, 61))	('5-FU', 'Chemical', 'MESH:D005472', (62, 66))	('miR-29c', 'Var', (44, 51))
102926	31037126	FBXO31, which we previously reported to have prognostic significance and regulatory function on DDP chemoresistance in ESCC, was identified as a potential target of miR-29c.	('ESCC', 'Disease', (119, 123))	('DDP', 'Gene', (96, 99))	('miR-29c', 'Var', (165, 172))	('FBXO31', 'Gene', (0, 6))	('DDP', 'Gene', '1678', (96, 99))
102927	31037126	A decrease in FBXO31 expression and an increase in p-p38 expression were observed in the FR cell lines with stable overexpression of miR-29c (Figure 3D).	('expression', 'MPA', (57, 67))	('decrease', 'NegReg', (2, 10))	('p38', 'Gene', '1432', (53, 56))	('miR-29c', 'Var', (133, 140))	('expression', 'MPA', (21, 31))	('increase', 'PosReg', (39, 47))	('p38', 'Gene', (53, 56))	('FBXO31', 'Gene', (14, 20))	('overexpression', 'PosReg', (115, 129))
102928	31037126	Conversely, expression level of FBXO31 was upregulated, whereas p-p38 expression was downregulated, in the ESCC cells with stable knockdown of miR-29c (Figure 3E).	('downregulated', 'NegReg', (85, 98))	('FBXO31', 'Gene', (32, 38))	('expression level', 'MPA', (12, 28))	('upregulated', 'PosReg', (43, 54))	('miR-29c', 'Var', (143, 150))	('expression', 'MPA', (70, 80))	('p38', 'Gene', '1432', (66, 69))	('p38', 'Gene', (66, 69))
102933	31037126	We found that knockdown of FBXO31 by stable transfection with shRNA FBXO31 (Figure S8A) significantly reduced 5-FU chemoresistance in KYSE150FR and KYSE410FR cells, as determined using MTT and colony formation assays (Figure S8B-C).	('FBXO31', 'Gene', (68, 74))	('5-FU', 'Chemical', 'MESH:D005472', (110, 114))	('MTT', 'Chemical', 'MESH:C070243', (185, 188))	('FBXO31', 'Gene', (27, 33))	('knockdown', 'Var', (14, 23))	('reduced', 'NegReg', (102, 109))	('5-FU chemoresistance', 'MPA', (110, 130))
102934	31037126	To study whether FBXO31 mediates the effect of miR-29c on 5-FU chemoresistance, the endogenous FBXO31 expression in the FR ESCC cells was first suppressed by overexpressing miR-29c, which resulted in increased phosphorylation/activation of p38 (Figure 4A).	('p38', 'Gene', (240, 243))	('expression', 'MPA', (102, 112))	('FBXO31', 'Gene', (95, 101))	('increased', 'PosReg', (200, 209))	('phosphorylation/activation', 'PosReg', (210, 236))	('suppressed', 'NegReg', (144, 154))	('5-FU', 'Chemical', 'MESH:D005472', (58, 62))	('p38', 'Gene', '1432', (240, 243))	('miR-29c', 'Var', (173, 180))	('overexpressing', 'PosReg', (158, 172))	('phosphorylation/activation', 'MPA', (210, 236))
102935	31037126	The FR cells co-overexpressing miR-29c and FBXO31 (KYSE150FR-miR-29c-FBXO31, KYSE410FR-miR-29c-FBXO31), or miR-29c alone (KYSE150FR-miR-29c-CON, KYSE410FR-miR-29c-CON), and the control cells (KYSE150-FR-miR-CON-CON, KYSE410FR-miR-CON-CON) were then treated with 10 muM 5-FU.	('muM', 'Gene', '56925', (265, 268))	('KYSE150FR-miR-29c-CON', 'Var', (122, 143))	('miR-29c', 'Var', (31, 38))	('muM', 'Gene', (265, 268))	('5-FU', 'Chemical', 'MESH:D005472', (269, 273))	('KYSE410FR-miR-29c-CON', 'Var', (145, 166))
102936	31037126	The results from MTT assay showed that overexpression of miR-29c led to a significant increased sensitivity to 5-FU, and that this effect was significantly diminished when FBXO31 expression was restored (Figure 4B).	('overexpression', 'PosReg', (39, 53))	('diminished', 'NegReg', (156, 166))	('increased', 'PosReg', (86, 95))	('miR-29c', 'Var', (57, 64))	('MTT', 'Chemical', 'MESH:C070243', (17, 20))	('5-FU', 'Chemical', 'MESH:D005472', (111, 115))	('sensitivity to 5-FU', 'MPA', (96, 115))
102939	31037126	Western blot data confirmed that miR-29c enhanced 5-FU-induced expression of cleaved caspase-3 in KYSE150FR and KYSE410 cells, whereas ectopic expression of FBXO31 significantly abrogated these effects (Figure 4C).	('miR-29c', 'Var', (33, 40))	('KYSE150FR', 'Var', (98, 107))	('enhanced', 'PosReg', (41, 49))	('5-FU-induced expression', 'MPA', (50, 73))	('cleaved caspase-3', 'MPA', (77, 94))	('5-FU', 'Chemical', 'MESH:D005472', (50, 54))
102940	31037126	On the contrary, inhibition of FBXO31 expression level with lentiviral shRNA in the miR-29c-knockdown ESCC cells (KYSE150-miR-zip- 29c-shFBXO31 and KYSE410-miR-zip-29c-shFBXO31) markedly counteracted the 5-FU chemoresistance induced by miR-29c knockdown, as indicated by Western blot and MTT assays (Figure 4D-F).	('expression level', 'MPA', (38, 54))	('zip', 'Gene', '1613', (126, 129))	('MTT', 'Chemical', 'MESH:C070243', (288, 291))	('5-FU', 'Chemical', 'MESH:D005472', (204, 208))	('miR-29c-knockdown', 'Var', (84, 101))	('zip', 'Gene', (126, 129))	('FBXO31', 'Gene', (31, 37))	('zip', 'Gene', '1613', (160, 163))	('inhibition', 'NegReg', (17, 27))	('zip', 'Gene', (160, 163))
102941	31037126	We next performed flow cytometry and the results showed that FBXO31-knockdown significantly increased 5-FU-induced apoptosis (Figure S10).	('5-FU', 'Chemical', 'MESH:D005472', (102, 106))	('FBXO31-knockdown', 'Var', (61, 77))	('increased', 'PosReg', (92, 101))	('FBXO31-knockdown', 'Gene', (61, 77))	('5-FU-induced apoptosis', 'MPA', (102, 124))
102942	31037126	We further performed in vivo experiment to validate these findings, and the results showed that ectopic miR-29c expression could override the resistance of FR tumor xenografts to 5-FU treatment in nude mice, and that overexpression of FBXO31 significantly attenuated this effect (Figure 4G-H).	('ectopic miR-29c', 'Var', (96, 111))	('5-FU', 'Chemical', 'MESH:D005472', (179, 183))	('nude mice', 'Species', '10090', (197, 206))	('resistance', 'MPA', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('miR-29c', 'Var', (104, 111))	('override', 'PosReg', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
102943	31037126	Collectively, these results demonstrated that miR-29c could sensitize ESCC cells to 5-FU treatment through downregulation of FBXO31 expression.	('miR-29c', 'Var', (46, 53))	('sensitize', 'Reg', (60, 69))	('FBXO31', 'Gene', (125, 131))	('downregulation', 'NegReg', (107, 121))	('expression', 'MPA', (132, 142))	('5-FU', 'Chemical', 'MESH:D005472', (84, 88))
102945	31037126	Gain- and loss-of-function experiments showed that STAT5A expression negatively regulated the expression of miR-29c (Figure 5A and Figure S11A).	('negatively', 'NegReg', (69, 79))	('S11A', 'Var', (138, 142))	('STAT5A', 'Gene', '6776', (51, 57))	('STAT5A', 'Gene', (51, 57))	('expression', 'MPA', (94, 104))	('S11A', 'SUBSTITUTION', 'None', (138, 142))	('miR-29c', 'Gene', (108, 115))
102946	31037126	We also compared the expression of STAT5A in parental cells and corresponding FR cells, and noted that STAT5A did increase in the FR cells (Figure S11B).	('S11B', 'Var', (147, 151))	('increase', 'PosReg', (114, 122))	('STAT5A', 'Gene', (103, 109))	('S11B', 'SUBSTITUTION', 'None', (147, 151))	('STAT5A', 'Gene', '6776', (35, 41))	('STAT5A', 'Gene', (35, 41))	('STAT5A', 'Gene', '6776', (103, 109))
102949	31037126	Site-specific mutations and luciferase assay further confirmed that only Site 3, but not the other two fragments, functions as the STAT5A-responsive element (Figure 5C).	('mutations', 'Var', (14, 23))	('STAT5A', 'Gene', '6776', (131, 137))	('STAT5A', 'Gene', (131, 137))
102950	31037126	Western blot was undertaken to determine the effect of manipulation of STAT5A expression on FBXO31, and the results indicated a positive regulation as shown in Figure S12A.	('FBXO31', 'Gene', (92, 98))	('S12A', 'SUBSTITUTION', 'None', (167, 171))	('S12A', 'Var', (167, 171))	('STAT5A', 'Gene', '6776', (71, 77))	('STAT5A', 'Gene', (71, 77))	('positive', 'PosReg', (128, 136))
102952	31037126	The data from MTT assay and colony formation assays showed that knockdown of STAT5A significantly enhanced 5-FU sensitivity (Figure S12B-C).	('5-FU sensitivity', 'MPA', (107, 123))	('enhanced', 'PosReg', (98, 106))	('S12B', 'Var', (132, 136))	('MTT', 'Chemical', 'MESH:C070243', (14, 17))	('5-FU', 'Chemical', 'MESH:D005472', (107, 111))	('S12B', 'SUBSTITUTION', 'None', (132, 136))	('knockdown', 'Var', (64, 73))	('STAT5A', 'Gene', (77, 83))	('STAT5A', 'Gene', '6776', (77, 83))
102957	31037126	Patients with low STAT5A expression had a longer survival (mean survival = 40.35 months) than the patients with high STAT5A expression (mean survival = 22.56 months) (Figure 5G).	('STAT5A', 'Gene', '6776', (117, 123))	('STAT5A', 'Gene', (117, 123))	('longer', 'PosReg', (42, 48))	('patients', 'Species', '9606', (98, 106))	('STAT5A', 'Gene', '6776', (18, 24))	('STAT5A', 'Gene', (18, 24))	('Patients', 'Species', '9606', (0, 8))	('low', 'Var', (14, 17))
102960	31037126	The data showed a markedly higher expression of STAT5A in ESCC tissues compared with non-tumor esophageal tissues (Figure S13), and a significant inverse correlation between miR-29c and STAT5A (r = -0.287, P < 0.01) (Figure 5H).	('non-tumor esophageal', 'Disease', 'MESH:D004938', (85, 105))	('expression', 'MPA', (34, 44))	('miR-29c', 'Var', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('non-tumor esophageal', 'Disease', (85, 105))	('STAT5A', 'Gene', (48, 54))	('STAT5A', 'Gene', '6776', (48, 54))	('STAT5A', 'Gene', (186, 192))	('tumor esophageal tissue', 'Phenotype', 'HP:0100751', (89, 112))	('STAT5A', 'Gene', '6776', (186, 192))	('higher', 'PosReg', (27, 33))	('ESCC', 'Disease', (58, 62))	('inverse', 'NegReg', (146, 153))
102963	31037126	We next assessed the therapeutic potential of systemically delivered miR-29c in treating 5-FU chemoresistant ESCC.	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('5-FU chemoresistant ESCC', 'Disease', (89, 113))	('miR-29c', 'Var', (69, 76))
102965	31037126	We found that administration of a combination of miR-29c oligonucleotide and 5-FU resulted in a significant decrease in tumor volume compared with 5-FU treatment alone (Figure 6A-B).	('5-FU', 'Chemical', 'MESH:D005472', (77, 81))	('5-FU', 'Chemical', 'MESH:D005472', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('miR-29c oligonucleotide', 'Var', (49, 72))	('decrease', 'NegReg', (108, 116))	('tumor', 'Disease', (120, 125))
102966	31037126	Furthermore, systemic miR-29c treatment facilitated 5-FU-induced apoptosis and suppressed proliferation of tumor cells, as indicated by increased expression of cleaved caspase-3 and p-p38 (Figure 6C) and decreased percentage of Ki-67-positive tumor cells (Figure 6D), respectively, in the tumor xenografts of mice treated with both 5-FU and miR-29c, compared with the groups treated with 5-FU or miR-29c alone.	('p38', 'Gene', '1432', (184, 187))	('tumor', 'Disease', (107, 112))	('suppressed', 'NegReg', (79, 89))	('5-FU', 'Chemical', 'MESH:D005472', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('expression', 'MPA', (146, 156))	('tumor', 'Disease', (243, 248))	('miR-29c', 'Gene', (22, 29))	('Ki-67', 'Gene', '17345', (228, 233))	('tumor', 'Disease', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('miR-29c', 'Var', (341, 348))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('facilitated', 'PosReg', (40, 51))	('p38', 'Gene', (184, 187))	('apoptosis', 'CPA', (65, 74))	('decreased', 'NegReg', (204, 213))	('Ki-67', 'Gene', (228, 233))	('increased', 'PosReg', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('5-FU', 'Chemical', 'MESH:D005472', (388, 392))	('5-FU', 'Chemical', 'MESH:D005472', (332, 336))	('proliferation', 'CPA', (90, 103))	('mice', 'Species', '10090', (309, 313))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))
102967	31037126	Notably, the administration of miR-29c did not cause toxicity to the mice, as evidenced by the lack of significant changes in body weight (Figure 6E), and blood biochemical and hematological parameters (Figure 6F).	('miR-29c', 'Var', (31, 38))	('toxicity', 'Disease', 'MESH:D064420', (53, 61))	('toxicity', 'Disease', (53, 61))	('mice', 'Species', '10090', (69, 73))
102971	31037126	showed that miRNAs, namely miR-205-5p and miR-342-3p, can cooperate to repress E2F1 and thereby decrease tumor chemoresistance.	('E2F1', 'Gene', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('decrease', 'NegReg', (96, 104))	('miR-205', 'Gene', '406988', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('miR-205', 'Gene', (27, 34))	('repress', 'NegReg', (71, 78))	('miR-342-3p', 'Var', (42, 52))	('E2F1', 'Gene', '1869', (79, 83))	('tumor', 'Disease', (105, 110))
102975	31037126	Using this approach, we have provided the first evidence of miR-29c downregulation in 5-FU resistant cancer cells, and shown that restoration of miR-29c can sensitize ESCC cells to 5-FU treatment in vitro and in vivo (Figures 2 and 4).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('5-FU', 'Chemical', 'MESH:D005472', (181, 185))	('cancer', 'Disease', (101, 107))	('ESCC', 'Disease', (167, 171))	('miR-29c', 'Gene', (60, 67))	('downregulation', 'NegReg', (68, 82))	('sensitize', 'Reg', (157, 166))	('restoration', 'Var', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('5-FU', 'Chemical', 'MESH:D005472', (86, 90))	('miR-29c', 'Gene', (145, 152))
102978	31037126	We found that the expression levels of miR-29c is significantly lower in primary ESCC tumor tissue compared with matched non-tumor tissues, and that high tumor miR-29c expression level predicts better survival.	('high', 'Var', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('non-tumor', 'Disease', (121, 130))	('expression', 'MPA', (168, 178))	('expression levels', 'MPA', (18, 35))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('lower', 'NegReg', (64, 69))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('ESCC', 'Disease', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('non-tumor', 'Disease', 'MESH:D009369', (121, 130))	('survival', 'CPA', (201, 209))	('better', 'PosReg', (194, 200))	('tumor', 'Disease', (154, 159))
102980	31037126	A previous study showed that miR-29 is repressed by NF-kB through Yin Yang 1 (YY1) and the Polycomb group, and that disruption of this regulatory circuit contributes to rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', (169, 185))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (169, 185))	('YY1', 'Gene', '7528', (78, 81))	('Yin Yang 1', 'Gene', (66, 76))	('disruption', 'Var', (116, 126))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (169, 185))	('YY1', 'Gene', (78, 81))	('Yin Yang 1', 'Gene', '7528', (66, 76))	('miR-29', 'Gene', (29, 35))	('contributes to', 'Reg', (154, 168))
102987	31037126	Our results showing that enforced expression of FBXO31 abolished the 5-FU-chemosensitizing effect of miR-29c in ESCC cells (Figure 4) revealed for the first time the key role of FBXO31 in mediating miR-29c-regulated 5-FU chemoresistance.	('5-FU', 'Chemical', 'MESH:D005472', (216, 220))	('FBXO31', 'Gene', (178, 184))	('FBXO31', 'Gene', (48, 54))	('abolished', 'NegReg', (55, 64))	('5-FU-chemosensitizing effect of', 'MPA', (69, 100))	('5-FU', 'Chemical', 'MESH:D005472', (69, 73))	('miR-29c-regulated', 'Var', (198, 215))	('5-FU chemoresistance', 'CPA', (216, 236))
102989	31037126	In conclusion, this study establishes that miR-29c can sensitize ESCC cells to 5-FU treatment through regulation of FBXO31-p38 signaling, and that the expression levels of miR-29c in the tumor and serum of ESCC patients have diagnostic and prognostic significance.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('patients', 'Species', '9606', (211, 219))	('miR-29c', 'Var', (43, 50))	('sensitize', 'Reg', (55, 64))	('miR-29c', 'Var', (172, 179))	('p38', 'Gene', '1432', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('5-FU', 'Chemical', 'MESH:D005472', (79, 83))	('tumor', 'Disease', (187, 192))	('ESCC', 'Disease', (206, 210))	('ESCC', 'Disease', (65, 69))	('p38', 'Gene', (123, 126))
102990	31037126	Our preclinical data, which proved that systemic delivery of miR-29c oligonucleotide could significantly alleviate the 5-FU chemoresistance of ESCC tumors, are strong evidence supporting the use of miR-29c as adjuvant therapy in the management of ESCC.	('miR-29c', 'Var', (61, 68))	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('alleviate', 'NegReg', (105, 114))	('ESCC tumors', 'Disease', (143, 154))	('clinical', 'Species', '191496', (7, 15))	('ESCC tumors', 'Disease', 'MESH:D004938', (143, 154))	('5-FU chemoresistance', 'MPA', (119, 139))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
103053	30546446	Therefore, the sensitivity and specificity of the diagnosis of esophageal cancer by DWI are significantly higher than those by CT scan, thus providing important information for delineating the target area.	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('higher', 'PosReg', (106, 112))	('DWI', 'Var', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
103069	30430120	The effective rate for PDT was better than that of radiotherapy or Nd:YAG laser for the treatment of middle-advanced upper gastrointestinal carcinomas [RR = 1.36; 95% confidence interval (CI): 1.13-1.65; P = 0.001].	('PDT', 'Var', (23, 26))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (123, 150))	('men', 'Species', '9606', (93, 96))	('middle-advanced upper gastrointestinal carcinomas', 'Disease', (101, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('gastrointestinal carcinoma', 'Phenotype', 'HP:0002672', (123, 149))	('middle-advanced upper gastrointestinal carcinomas', 'Disease', 'MESH:D020244', (101, 150))
103118	30430120	Lightdale et al reported that PDT was an effective method for treating esophageal cancer and that its efficacy was superior to that of Nd: YAG laser.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('PDT', 'Var', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('esophageal cancer', 'Disease', (71, 88))
103121	30430120	Li et al reported that PDT alleviated the dysphagia associated with esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('alleviated', 'NegReg', (27, 37))	('dysphagia', 'Disease', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('dysphagia', 'Phenotype', 'HP:0002015', (42, 51))	('dysphagia', 'Disease', 'MESH:D003680', (42, 51))	('esophageal cancer', 'Disease', (68, 85))	('PDT', 'Var', (23, 26))
103123	30430120	Our study showed that PDT was suitable for middle-advanced stage upper gastrointestinal carcinomas, and that it increased the significant remission rate (CR + PR) and the effective rate (CR + PR + MR) over that of Nd:YAG laser or radiotherapy alone, which is in agreement with results from studies by Lightdale and Li.	('men', 'Species', '9606', (267, 270))	('PR', 'Chemical', '-', (192, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('middle-advanced stage upper gastrointestinal carcinomas', 'Disease', 'MESH:D020244', (43, 98))	('CR', 'Chemical', '-', (187, 189))	('gastrointestinal carcinoma', 'Phenotype', 'HP:0002672', (71, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('increased', 'PosReg', (112, 121))	('CR', 'Chemical', '-', (154, 156))	('remission', 'MPA', (138, 147))	('PR', 'Chemical', '-', (159, 161))	('PDT', 'Var', (22, 25))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (71, 98))
103125	30430120	Unlike chemotherapy and radiotherapy, neither tumor DNA nor rapidly dividing tumor cells are targeted by PDT, therefore, PDT rarely induces secondary tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('PDT', 'Var', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('induces', 'Reg', (132, 139))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
103127	30430120	Unlike Nd:YAG laser, PDT selectively kills cancer cells without damaging the surrounding tissue, extending the healing time of wounds, or increasing the formation of scars after treatment, thereby reducing the possibility of posttreatment obstruction.	('healing time', 'CPA', (111, 123))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('PDT', 'Var', (21, 24))	('cancer', 'Disease', (43, 49))	('men', 'Species', '9606', (183, 186))	('scars', 'Phenotype', 'HP:0100699', (166, 171))	('extending', 'PosReg', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('reducing', 'NegReg', (197, 205))	('increasing', 'PosReg', (138, 148))	('men', 'Species', '9606', (234, 237))
103131	30430120	Our study showed that PDT combined with radiotherapy or chemotherapy significantly improved the significant remission rate, the effective rate, and the one-year survival rate for middle-advanced stage upper gastrointestinal carcinomas over rates achieved with single therapy, which is consistent with the work of Zhang and Qin.	('middle-advanced stage upper gastrointestinal carcinomas', 'Disease', 'MESH:D020244', (179, 234))	('Qin', 'Gene', (323, 326))	('improved', 'PosReg', (83, 91))	('effective', 'MPA', (128, 137))	('Qin', 'Gene', '2290', (323, 326))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('gastrointestinal carcinoma', 'Phenotype', 'HP:0002672', (207, 233))	('significant', 'Disease', (96, 107))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (207, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('PDT', 'Var', (22, 25))
103190	30045299	A significant association between PD-L1 overexpression and OS was found in 13 studies, including 11 studies linking PD-L1 expression with worse OS and 2 studies linking PD-L1 expression with better OS.	('PD-L1', 'Gene', (169, 174))	('OS', 'Chemical', '-', (59, 61))	('worse OS', 'Disease', (138, 146))	('expression', 'Var', (122, 132))	('PD-L1', 'Gene', '29126', (169, 174))	('PD-L1', 'Gene', (116, 121))	('PD-L1', 'Gene', (34, 39))	('OS', 'Chemical', '-', (198, 200))	('PD-L1', 'Gene', '29126', (116, 121))	('OS', 'Chemical', '-', (144, 146))	('PD-L1', 'Gene', '29126', (34, 39))
103210	30045299	Conversely, 2 studies included in our analysis showed PD-L1 expression to be a factor predicting favorable OS in EC.	('expression', 'Var', (60, 70))	('PD-L1', 'Gene', (54, 59))	('OS', 'Chemical', '-', (107, 109))	('PD-L1', 'Gene', '29126', (54, 59))
103212	30045299	Also, in certain circumstance, high PD-L1 expression might promote immune responses through interaction of PD-L1 with unknown receptors, resulting in T-cell proliferation and secretion of certain cytokines, which in turn activate strong antitumor effects.	('PD-L1', 'Gene', '29126', (107, 112))	('tumor', 'Disease', (241, 246))	('secretion of', 'MPA', (175, 187))	('PD-L1', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('immune responses', 'CPA', (67, 83))	('promote', 'PosReg', (59, 66))	('PD-L1', 'Gene', '29126', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('high', 'Var', (31, 35))	('PD-L1', 'Gene', (107, 112))	('activate', 'PosReg', (221, 229))	('interaction', 'Interaction', (92, 103))	('T-cell proliferation', 'CPA', (150, 170))
103279	28514311	The keywords with over 1000 usage count were identified as follows (Table 4): esophageal cancer (4674 counts), squamous cell carcinoma (2258 counts), carcinoma (1831 counts), cancer (1826 counts), adenocarcinoma (1714 counts), surgery (1311 counts), gastric cancer (1222 counts), survival (1219 counts), and chemotherapy (1016 counts).	('carcinoma', 'Disease', 'MESH:D002277', (125, 134))	('1311 counts', 'Var', (236, 247))	('carcinoma', 'Disease', (202, 211))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (89, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (250, 264))	('adenocarcinoma', 'Disease', (197, 211))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('1222 counts', 'Var', (266, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('1219 counts', 'Var', (290, 301))	('carcinoma', 'Disease', 'MESH:D002277', (202, 211))	('carcinoma', 'Disease', (150, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('gastric cancer', 'Disease', (250, 264))	('adenocarcinoma', 'Disease', 'MESH:D000230', (197, 211))	('carcinoma', 'Disease', (125, 134))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 134))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (258, 264))	('surgery', 'Disease', (227, 234))	('1826', 'Var', (183, 187))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('1831', 'Var', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('gastric cancer', 'Disease', 'MESH:D013274', (250, 264))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('squamous cell carcinoma', 'Disease', (111, 134))	('1714 counts', 'Var', (213, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('esophageal cancer', 'Disease', (78, 95))
103283	28514311	According to the top 15 journals, 13.33% of the journals, including the Journal of Clinical Oncology (IF2015, 20.982) and Gastroenterology (IF2015, 18.187) had an IF greater than 10.000; 20.00% of the journals, including Annals of Oncology (IF2015, 9.269), Gastrointestinal Endoscopy (IF2015, 6.217), and Cancer Research (IF2015, 8.556), had an IF between 5.000 and 10.000; 33.33% of the journals, including International Journal of Radiation Oncology Biology Physics (IF2015, 4.495), Annals of Surgical Oncology (IF2015, 3.655), PLoS One (IF2015, 3.057), Annals of Thoracic Surgery (IF2015, 3.021), and Journal of Gastroenterology and Hepatology (IF2015, 3.322), had an IF between 3.000 and 5.000.	('Cancer', 'Disease', (305, 311))	('Oncology', 'Phenotype', 'HP:0002664', (504, 512))	('Oncology', 'Phenotype', 'HP:0002664', (231, 239))	('Cancer', 'Disease', 'MESH:D009369', (305, 311))	('Cancer', 'Phenotype', 'HP:0002664', (305, 311))	('Oncology', 'Phenotype', 'HP:0002664', (92, 100))	('IF2015', 'Var', (514, 520))	('Oncology', 'Phenotype', 'HP:0002664', (443, 451))	('IF2015', 'Var', (648, 654))
103306	28514311	A recent study has found that Ivor-Lewis esophagogastrectomy, a new surgical approach, does not increase complication rates and perioperative mortality in Siewert type II EGJ adenocarcinoma, compared to the traditional left transthoracic approach.	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('Ivor-Lewis', 'Var', (30, 40))	('Siewert type II EGJ adenocarcinoma', 'Disease', (155, 189))	('Siewert type II EGJ adenocarcinoma', 'Disease', 'MESH:D007619', (155, 189))
103307	28514311	In addition, evidence suggests that spleen-preserving No.10 lymphadenectomy (SPL) may improve the prognosis of Siewert type III adenocarcinoma (tumor diameter >=4 cm) of the EGJ, while for patients with Siewert type II or III adenocarcinoma (tumor diameter <4 cm), SPL may be omitted without reducing the survival rate.	('tumor', 'Disease', (144, 149))	('III adenocarcinoma', 'Disease', (222, 240))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('III adenocarcinoma', 'Disease', 'MESH:D000230', (124, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('improve', 'PosReg', (86, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('Siewert type III adenocarcinoma', 'Disease', (111, 142))	('III adenocarcinoma', 'Disease', 'MESH:D000230', (222, 240))	('Siewert type III adenocarcinoma', 'Disease', 'MESH:D007619', (111, 142))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (242, 247))	('No.10', 'Var', (54, 59))	('patients', 'Species', '9606', (189, 197))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('prognosis', 'MPA', (98, 107))
103311	28514311	According to the novel target therapies, antihuman epidermal growth factor receptor 2 trastuzumab, and antivascular endothelial growth factor receptor 2 ramucirumab have proven beneficial as first-line and second-line therapies, respectively.	('antihuman', 'Var', (41, 50))	('trastuzumab', 'Chemical', 'MESH:D000068878', (86, 97))	('epidermal growth factor receptor 2', 'Gene', (51, 85))	('human', 'Species', '9606', (45, 50))	('epidermal growth factor receptor 2', 'Gene', '2064', (51, 85))
103326	28514311	GWAS is concerned with the association between single-nucleotide polymorphisms and traits such as major human diseases.	('human', 'Species', '9606', (104, 109))	('association', 'Interaction', (27, 38))	('single-nucleotide polymorphisms', 'Var', (47, 78))
103372	27421466	Considering only highquality studies, waterpipe smoking was associated with increased risk of head and neck cancer (SRR 2.97; 95 % CI 2.26-3.90), esophageal cancer (1.84; 1.42-2.38) and lung cancer (2.22; 1.24-3.97), with no evidence of heterogeneity or publication bias.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('esophageal cancer', 'Disease', (146, 163))	('waterpipe smoking', 'Var', (38, 55))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('head and neck cancer', 'Phenotype', 'HP:0012288', (94, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('water', 'Chemical', 'MESH:D014867', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('head and neck cancer', 'Disease', 'MESH:D006258', (94, 114))
103451	28176958	Literature search was conducted in databases such as PubMed, Embase, and Web of Science, using the following words "(microRNA-100 OR miR-100 OR mir100) AND (tumor OR neoplasm OR cancer OR carcinoma OR malignancy)."	('tumor', 'Disease', (157, 162))	('carcinoma OR malignancy', 'Disease', 'MESH:D009369', (188, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mir100', 'Var', (144, 150))	('carcinoma OR malignancy', 'Disease', (188, 211))	('neoplasm', 'Disease', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('miR-100', 'Gene', '406892', (133, 140))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('neoplasm', 'Disease', 'MESH:D009369', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('microRNA-100', 'Gene', '406892', (117, 129))	('miR-100', 'Gene', (133, 140))	('microRNA-100', 'Gene', (117, 129))
103463	28176958	This aberrant expression of miR-100 not only has diagnostic implications but also can predict cancer patient survival.	('predict', 'Reg', (86, 93))	('miR-100', 'Gene', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('miR-100', 'Gene', '406892', (28, 35))	('patient', 'Species', '9606', (101, 108))	('aberrant', 'Var', (5, 13))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
103468	28176958	A literature search was conducted in databases such as PubMed, Embase, and Web of Science, using the following words "(microRNA-100 OR miR-100 OR mir100) AND (tumor OR neoplasm OR cancer OR carcinoma OR malignancy)."	('miR-100', 'Gene', '406892', (135, 142))	('carcinoma OR malignancy', 'Disease', (190, 213))	('neoplasm', 'Disease', (168, 176))	('microRNA-100', 'Gene', '406892', (119, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('neoplasm', 'Disease', 'MESH:D009369', (168, 176))	('microRNA-100', 'Gene', (119, 131))	('tumor', 'Disease', (159, 164))	('miR-100', 'Gene', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('carcinoma OR malignancy', 'Disease', 'MESH:D009369', (190, 213))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cancer', 'Disease', (180, 186))	('mir100', 'Var', (146, 152))
103472	28176958	The following details of each article were recorded: publication year, first author's last name, cancer type, treatment, sample size, stage of disease, miR-100 assay, the cutoff value to discriminate high or low expression of miR-100, sample sources, follow-up time, and HR (low versus high expression).	('low', 'NegReg', (208, 211))	('miR-100', 'Gene', '406892', (152, 159))	('cancer', 'Disease', (97, 103))	('miR-100', 'Gene', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('miR-100', 'Gene', '406892', (226, 233))	('high', 'Var', (200, 204))	('miR-100', 'Gene', (226, 233))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
103498	28176958	Bi et al transfected U2OS cells (human osteo-sarcoma line) with a miR-100 construct or with an antisense of miR-100.	('miR-100', 'Gene', (66, 73))	('U2OS', 'CellLine', 'CVCL:0042', (21, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('miR-100', 'Gene', (108, 115))	('antisense', 'Var', (95, 104))	('osteo-sarcoma', 'Disease', 'MESH:D009261', (39, 52))	('human', 'Species', '9606', (33, 38))	('osteo-sarcoma', 'Phenotype', 'HP:0002669', (39, 52))	('miR-100', 'Gene', '406892', (108, 115))	('miR-100', 'Gene', '406892', (66, 73))	('osteo-sarcoma', 'Disease', (39, 52))
103551	27826196	A colony formation assay showed that pretreatment with AC-MFB decreased the survival of irradiated esophageal cancer cells, with a maximum sensitizer enhancement ratio of 1.91% and 37% survival.	('decreased', 'NegReg', (62, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('AC-MFB', 'Var', (55, 61))	('AC-MFB', 'Chemical', '-', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('survival', 'CPA', (76, 84))	('esophageal cancer', 'Disease', (99, 116))
103552	27826196	A DNA histogram study showed that AC-MFB pretreatment enhanced cell cycle arrest at the G2/M phase, the most radiosensitive phase.	('AC-MFB', 'Var', (34, 40))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('enhanced', 'PosReg', (54, 62))	('AC-MFB', 'Chemical', '-', (34, 40))	('cell cycle arrest at the G2/M phase', 'CPA', (63, 98))
103553	27826196	An immunofluorescence assay and a Western blotting assay showed that AC-MFB delayed the abrogation of gamma-H2AX, upregulated p21 expression, and attenuated the radiation-induced phosphorylation of ataxia telangiectasia-mutated kinase and checkpoint kinase 2.	('expression', 'MPA', (130, 140))	('attenuated', 'NegReg', (146, 156))	('delayed', 'NegReg', (76, 83))	('AC-MFB', 'Var', (69, 75))	('abrogation', 'MPA', (88, 98))	('ataxia telangiectasia-mutated', 'Gene', (198, 227))	('checkpoint kinase 2', 'Gene', (239, 258))	('radiation-induced', 'Pathway', (161, 178))	('upregulated', 'PosReg', (114, 125))	('p21', 'Gene', (126, 129))	('AC-MFB', 'Chemical', '-', (69, 75))	('p21', 'Gene', '644914', (126, 129))	('telangiectasia', 'Phenotype', 'HP:0001009', (205, 219))	('ataxia', 'Phenotype', 'HP:0001251', (198, 204))	('checkpoint kinase 2', 'Gene', '11200', (239, 258))	('ataxia telangiectasia-mutated', 'Gene', '472', (198, 227))	('H2AX', 'Gene', (108, 112))	('phosphorylation', 'MPA', (179, 194))	('H2AX', 'Gene', '3014', (108, 112))
103571	27826196	The cell lines used in this study included CE81T/VGH, an esophageal squamous cell line, and BE3, an adenocarcinoma (ADC) cell line.	('CE81T/VGH', 'Var', (43, 52))	('adenocarcinoma', 'Disease', (100, 114))	('esophageal squamous', 'Disease', 'MESH:D000077277', (57, 76))	('esophageal squamous', 'Disease', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('adenocarcinoma', 'Disease', 'MESH:D000230', (100, 114))
103584	27826196	Viable tumor cells (200 for CE81T/VGH and 500 for BE3) were plated onto a six-well cell culture plate and allowed to grow in DMEM/high-glucose medium containing 10% FBS at 37 C in a humidified incubator with 5% CO2.	('CO2', 'Chemical', '-', (211, 214))	('tumor', 'Disease', (7, 12))	('CE81T/VGH', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('high-glucose', 'Phenotype', 'HP:0003074', (130, 142))	('DMEM/high-glucose', 'Chemical', '-', (125, 142))
103609	27826196	After 24 to 72 hours of exposure, AC-MFB inhibited the viability of both CE81T/VGH and BE3 cells in a time- and dose-dependent manner (P<0.001).	('inhibited', 'NegReg', (41, 50))	('AC-MFB', 'Chemical', '-', (34, 40))	('viability', 'CPA', (55, 64))	('AC-MFB', 'Var', (34, 40))
103615	27826196	After 24 hours of treatment with 0.5 or 1.0 mg/mL AC-MFB, the proportion of cells in the G0/G1 phase was decreased compared with the proportion of G0/G1 cells in the untreated cells.	('AC-MFB', 'Chemical', '-', (50, 56))	('decreased', 'NegReg', (105, 114))	('AC-MFB', 'Var', (50, 56))
103619	27826196	In accordance with the changes in the DNA histogram, IR caused moderate mitotic arrest in CE-81T/VGH cells, and AC-MFB pretreatment further enhanced the accumulation of mitotically arrested cells at 24 hours (Figure 3A-D).	('AC-MFB', 'Var', (112, 118))	('enhanced', 'PosReg', (140, 148))	('mitotic arrest', 'Disease', (72, 86))	('mitotic arrest', 'Disease', 'MESH:D006323', (72, 86))	('AC-MFB', 'Chemical', '-', (112, 118))
103620	27826196	The Annexin-V assay showed that AC-MFB increased the apoptosis rate from 2.00%+-0.46% to 9.18%+-1.40% and 13.34%+-1.51% with 0.5 and 1.0 mg/mL AC-MFB, respectively (P=0.001 and P=0.0003) (Figure 3E).	('AC-MFB', 'Var', (32, 38))	('AC-MFB', 'Chemical', '-', (143, 149))	('apoptosis rate', 'CPA', (53, 67))	('AC-MFB', 'Chemical', '-', (32, 38))	('Annexin-V', 'Gene', '308', (4, 13))	('Annexin-V', 'Gene', (4, 13))	('to 9', 'Species', '1214577', (86, 90))
103621	27826196	There was also a statistically significant synergistic increase in the apoptosis rate noted from 2.64%+-1.17% to 10.11%+-0.23% with IR and 0.5 mg/mL AC-MFB and to 37.37%+-13.41% with IR and 1.0 mg/mL AC-MFB (P=0.0004 and P=0.011).	('increase', 'PosReg', (55, 63))	('apoptosis', 'CPA', (71, 80))	('AC-MFB', 'Chemical', '-', (149, 155))	('AC-MFB', 'Chemical', '-', (200, 206))	('AC-MFB', 'Var', (149, 155))
103623	27826196	The Western blot assay also showed that AC-MFB could significantly increase gamma-H2AX expression, especially at 1 hour in cells treated with AC-MFB alone; a synergistic effect was also observed with IR at 6 hours (P=0.013 and 0.008, respectively) (Figure 5).	('AC-MFB', 'Var', (40, 46))	('AC-MFB', 'Chemical', '-', (142, 148))	('H2AX', 'Gene', '3014', (82, 86))	('increase', 'PosReg', (67, 75))	('expression', 'MPA', (87, 97))	('AC-MFB', 'Chemical', '-', (40, 46))	('H2AX', 'Gene', (82, 86))
103636	27826196	The modulation of the cyclin-dependent protein kinase inhibitor p21 and the IR-induced activation of ATM and Chk2 in CE81T/VGH cells were noted.	('ATM', 'Gene', (101, 104))	('activation', 'PosReg', (87, 97))	('p21', 'Gene', '644914', (64, 67))	('Chk2', 'Gene', '11200', (109, 113))	('Chk2', 'Gene', (109, 113))	('cyclin-dependent', 'Enzyme', (22, 38))	('ATM', 'Gene', '472', (101, 104))	('CE81T/VGH', 'Var', (117, 126))	('p21', 'Gene', (64, 67))
103638	27826196	The G2/M DNA damage checkpoint serves to prevent the cell from entering mitosis (M phase) with genomic DNA damage and, therefore, the G2/M phase is the most sensitive phase to radiation.	('mitosis', 'Disease', (72, 79))	('mitosis', 'Disease', 'None', (72, 79))	('genomic DNA damage', 'Var', (95, 113))	('prevent', 'NegReg', (41, 48))
103644	27826196	Variations in the genes involved in DNA repair are important prognostic factors associated with the overall survival and progression-free survival of esophageal cancer patients treated with cisplatin.	('esophageal cancer', 'Disease', (150, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (190, 199))	('associated', 'Reg', (80, 90))	('Variations', 'Var', (0, 10))	('patients', 'Species', '9606', (168, 176))
103647	27826196	The results of our assessment of DNA double-strand breakage, as measured by the expression of gamma-H2Ax, indicate that AC-MFB may increase this lethal type of DNA damage and impair DNA repair.	('impair', 'NegReg', (175, 181))	('AC-MFB', 'Var', (120, 126))	('increase', 'PosReg', (131, 139))	('AC-MFB', 'Chemical', '-', (120, 126))	('DNA repair', 'MPA', (182, 192))	('lethal type of DNA damage', 'MPA', (145, 170))	('H2Ax', 'Gene', '3014', (100, 104))	('H2Ax', 'Gene', (100, 104))
103648	27826196	Among the complicated processes involved in DNA damage repair, we found that the phosphorylation of Chk2 and ATM induced by IR was suppressed by pretreatment with AC-MFB.	('phosphorylation', 'MPA', (81, 96))	('ATM', 'Gene', (109, 112))	('AC-MFB', 'Chemical', '-', (163, 169))	('ATM', 'Gene', '472', (109, 112))	('Chk2', 'Gene', '11200', (100, 104))	('suppressed', 'NegReg', (131, 141))	('AC-MFB', 'Var', (163, 169))	('Chk2', 'Gene', (100, 104))
103650	27826196	Given that ATM and Chk2 act as sensors and transducers of DNA damage, AC-MFB may affect DNA damage repair during an earlier phase of the cell cycle.	('Chk2', 'Gene', '11200', (19, 23))	('DNA damage repair', 'MPA', (88, 105))	('Chk2', 'Gene', (19, 23))	('AC-MFB', 'Chemical', '-', (70, 76))	('ATM', 'Gene', (11, 14))	('affect', 'Reg', (81, 87))	('AC-MFB', 'Var', (70, 76))	('ATM', 'Gene', '472', (11, 14))
103652	27826196	Taken together, these results suggest that AC-MFB may sensitize esophageal cancer cells to radiation therapy, accompanied by both the upregulation of p21 expression-induced G2/M arrest and the modulation of DNA damage repair induced by IR.	('M arrest', 'Disease', 'MESH:D006323', (176, 184))	('M arrest', 'Disease', (176, 184))	('AC-MFB', 'Var', (43, 49))	('sensitize', 'Reg', (54, 63))	('modulation', 'Reg', (193, 203))	('p21', 'Gene', '644914', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AC-MFB', 'Chemical', '-', (43, 49))	('p21', 'Gene', (150, 153))	('upregulation', 'PosReg', (134, 146))	('esophageal cancer', 'Disease', (64, 81))	('DNA damage repair', 'MPA', (207, 224))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
103657	27826196	Our in vitro results showed that AC-MFB could inhibit cell viability and enhance the effects of IR in both SCC and ADC.	('effects', 'MPA', (85, 92))	('SCC', 'Disease', (107, 110))	('inhibit', 'NegReg', (46, 53))	('enhance', 'PosReg', (73, 80))	('AC-MFB', 'Chemical', '-', (33, 39))	('ADC', 'Disease', (115, 118))	('cell viability', 'CPA', (54, 68))	('AC-MFB', 'Var', (33, 39))
103659	27826196	In the cell cycle distribution assay, pretreatment with 1.0 mg/mL AC-MFB maintained the proportion of G2/M cells at 25.9% at 24 hours and 25.2% at 48 hours, whereas the proportion decreased to 15.5% at 72 hours in CE81T/VGH cells after IR.	('AC-MFB', 'Var', (66, 72))	('G2/M cells', 'CPA', (102, 112))	('AC-MFB', 'Chemical', '-', (66, 72))
103666	27826196	Our results showed that AC-MFB may sensitize CE81T/VGH and BE3 human esophageal cancer cells to IR.	('AC-MFB', 'Chemical', '-', (24, 30))	('human', 'Species', '9606', (63, 68))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CE81T/VGH', 'Var', (45, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('sensitize', 'Reg', (35, 44))
103669	27826196	In both human CE81T/VGH squamous and BE3 ADC esophageal cancer cells, our results showed that AC-MFB pretreatment could enhance cell cycle arrest at the G2/M phase, delay the abrogation of gamma-H2AX, and attenuate the radiation-induced phosphorylation of ATM kinase and Chk2.	('esophageal cancer', 'Disease', (45, 62))	('enhance', 'PosReg', (120, 127))	('ATM', 'Gene', (256, 259))	('abrogation', 'CPA', (175, 185))	('attenuate', 'NegReg', (205, 214))	('H2AX', 'Gene', '3014', (195, 199))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (128, 145))	('phosphorylation', 'MPA', (237, 252))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('AC-MFB', 'Chemical', '-', (94, 100))	('Chk2', 'Gene', (271, 275))	('human', 'Species', '9606', (8, 13))	('cell cycle arrest at the G2/M phase', 'CPA', (128, 163))	('ATM', 'Gene', '472', (256, 259))	('ADC esophageal cancer', 'Phenotype', 'HP:0011459', (41, 62))	('delay', 'NegReg', (165, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('Chk2', 'Gene', '11200', (271, 275))	('AC-MFB', 'Var', (94, 100))	('H2AX', 'Gene', (195, 199))
103670	27826196	In addition, an in vivo study showed that AC-MFB treatment tended to have a synergistic effect with radiation on the tumor growth delay of CE81T/VGH cells in BALB/c mice.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('AC-MFB', 'Chemical', '-', (42, 48))	('mice', 'Species', '10090', (165, 169))	('tumor', 'Disease', (117, 122))	('growth delay', 'Phenotype', 'HP:0001510', (123, 135))	('CE81T/VGH', 'Var', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
103672	26148236	Disruption of Cytochrome c Oxidase Function Induces Warburg Effect and Metabolic Reprogramming Defects in mitochondrial oxidative phosphorylation complexes, altered bioenergetics and metabolic shift are often seen in cancers.	('Warburg Effect', 'CPA', (52, 66))	('bioenergetics', 'CPA', (165, 178))	('Induces', 'Reg', (44, 51))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('Cytochrome c', 'Gene', (14, 26))	('mitochondrial', 'MPA', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('Metabolic Reprogramming Defects', 'CPA', (71, 102))	('cancers', 'Disease', (217, 224))	('metabolic shift', 'CPA', (183, 198))	('Cytochrome c', 'Gene', '54205', (14, 26))	('Disruption', 'Var', (0, 10))
103673	26148236	Here we show a role for the dysfunction of electron transport chain component, cytochrome c oxidase (CcO) in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cytochrome c', 'Gene', '54205', (79, 91))	('cancer', 'Disease', (109, 115))	('CcO', 'Gene', (101, 104))	('dysfunction', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cytochrome c', 'Gene', (79, 91))
103674	26148236	We show that genetic silencing of the CcO complex by shRNA expression and loss of CcO activity in multiple cell types from the mouse and human sources resulted in metabolic shift to glycolysis, loss of anchorage dependent growth and acquired invasive phenotypes.	('invasive phenotypes', 'CPA', (242, 261))	('anchorage dependent growth', 'MPA', (202, 228))	('metabolic shift to glycolysis', 'MPA', (163, 192))	('genetic', 'Var', (13, 20))	('mouse', 'Species', '10090', (127, 132))	('human', 'Species', '9606', (137, 142))	('activity', 'MPA', (86, 94))	('loss', 'NegReg', (74, 78))	('CcO', 'Enzyme', (82, 85))	('loss', 'NegReg', (194, 198))	('shRNA', 'Gene', (53, 58))	('silencing', 'NegReg', (21, 30))
103675	26148236	Disruption of CcO complex caused loss of transmembrane potential and induction of Ca2+/Calcineurin-mediated retrograde signaling.	('induction', 'Reg', (69, 78))	('loss', 'NegReg', (33, 37))	('transmembrane potential', 'MPA', (41, 64))	('CcO complex', 'Gene', (14, 25))	('Ca2+/Calcineurin-mediated retrograde signaling', 'MPA', (82, 128))	('Ca2+', 'Chemical', 'MESH:D000069285', (82, 86))	('Disruption', 'Var', (0, 10))
103679	26148236	These results suggest that a defect in CcO complex can potentially induce tumor progression.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('defect', 'Var', (29, 35))	('CcO complex', 'Protein', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('induce', 'Reg', (67, 73))	('tumor', 'Disease', (74, 79))
103682	26148236	Epidemiological studies have proposed defective complex I as a biomarker for aggressive thyroid, breast, colon and other cancers.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('defective', 'Var', (38, 47))	('breast', 'Disease', (97, 103))	('complex I', 'Protein', (48, 57))	('colon and other cancers', 'Disease', 'MESH:D015179', (105, 128))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('defective complex I', 'Phenotype', 'HP:0011923', (38, 57))	('aggressive thyroid', 'Disease', (77, 95))
103683	26148236	Similarly mutations in Complex III and complex IV (Cytochrome c oxidase) have been reported in multiple cancers .	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('reported', 'Reg', (83, 91))	('Cytochrome c', 'Gene', (51, 63))	('multiple cancers', 'Disease', (95, 111))	('multiple cancers', 'Disease', 'MESH:D009369', (95, 111))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('mutations', 'Var', (10, 19))	('Cytochrome c', 'Gene', '54205', (51, 63))
103685	26148236	Loss of mtDNA copy number has been reported in breast, prostate, hepatocellular and lung cancers, and we have shown that partial mtDNA depletion mediates tumorigenesis by activating a Ca2+-Calcineurin dependent retrograde signaling .	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lung cancers', 'Phenotype', 'HP:0100526', (84, 96))	('mtDNA', 'Gene', (8, 13))	('prostate', 'Disease', (55, 63))	('Ca2+-Calcineurin dependent retrograde signaling', 'MPA', (184, 231))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (154, 159))	('Loss', 'NegReg', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('Ca2+', 'Chemical', 'MESH:D000069285', (184, 188))	('depletion', 'NegReg', (135, 144))	('activating', 'PosReg', (171, 181))	('hepatocellular', 'Disease', (65, 79))	('mtDNA', 'Gene', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('lung cancers', 'Disease', 'MESH:D008175', (84, 96))	('partial', 'Var', (121, 128))	('lung cancers', 'Disease', (84, 96))	('breast', 'Disease', (47, 53))
103689	26148236	Our studies and others' showed that siRNA mediated depletion of the peripheral subunits, IVi1, Vb, and VI not only affects the assembly of intact complex but also the CcO activity, culminating in respiratory dysfunction and disruption of  Psim .	('respiratory dysfunction', 'Disease', 'MESH:D012131', (196, 219))	('CcO activity', 'MPA', (167, 179))	('culminating in', 'Reg', (181, 195))	('Psim', 'MPA', (239, 243))	('disruption', 'MPA', (224, 234))	('respiratory dysfunction', 'Phenotype', 'HP:0002093', (196, 219))	('IVi1', 'Gene', (89, 93))	('depletion', 'Var', (51, 60))	('assembly of intact complex', 'MPA', (127, 153))	('respiratory dysfunction', 'Disease', (196, 219))	('affects', 'Reg', (115, 122))
103695	26148236	Similarly in cell lines derived from esophageal and breast cancers, loss of cytochrome oxidase increased invasiveness.	('breast cancers', 'Phenotype', 'HP:0003002', (52, 66))	('cytochrome oxidase', 'Enzyme', (76, 94))	('esophageal', 'Disease', 'MESH:D004941', (37, 47))	('invasiveness', 'CPA', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancers', 'Disease', 'MESH:D001943', (52, 66))	('breast cancers', 'Disease', (52, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('loss', 'Var', (68, 72))	('increased', 'PosReg', (95, 104))	('esophageal', 'Disease', (37, 47))
103698	26148236	CcOVb shRNA expressing C2C12 cells (hereafter referred to as CcO5bKD cells) had 65% reduction in Vb mRNA and protein levels (Fig.	('reduction', 'NegReg', (84, 93))	('C2C12 cells', 'Var', (23, 34))	('C2C12', 'CellLine', 'CVCL:0188', (23, 28))
103700	26148236	In C2C12 cells, silencing of neither of these subunits had an effect on mRNA levels for other subunits of ETC complexes (Fig S1A).	('mRNA levels for other subunits', 'MPA', (72, 102))	('silencing', 'Var', (16, 25))	('C2C12', 'CellLine', 'CVCL:0188', (3, 8))
103705	26148236	Mitochondrial network was also affected in CcO5bKD cells although to lesser extent compared to CcO4KD cells (Fig 2A, bottom left).	('Mito', 'Species', '262676', (0, 4))	('Mitochondrial network', 'MPA', (0, 21))	('CcO5bKD', 'Var', (43, 50))	('affected', 'Reg', (31, 39))
103706	26148236	Oxygen consumption rates (OCR) in control, CcO4KD and CcO5bKD cells were measured using an XF24 flux analyzer (Fig 3A, Left panel).	('Oxygen', 'Chemical', 'MESH:D010100', (0, 6))	('CcO5bKD', 'Var', (54, 61))	('CcO4KD', 'Var', (43, 49))	('Oxygen consumption rates', 'MPA', (0, 24))
103708	26148236	In CcO4KDshRC4 cells both ATP coupled respiration and maximum respiratory capacity were significantly recovered compared to CcO4KD cells.	('ATP', 'Chemical', 'MESH:D000255', (26, 29))	('CcO4KDshRC4', 'Var', (3, 14))	('maximum respiratory capacity', 'MPA', (54, 82))	('ATP coupled respiration', 'MPA', (26, 49))	('recovered', 'PosReg', (102, 111))
103709	26148236	However, while addition of oligomycin resulted in a significant increase in ECAR in control cells, the effect was comparatively modest in CcO5bKD cells, suggesting that in CcO5bKD cells basal glycolytic flux is closer to its maximum capacity compared to control cells (Fig 3A, Right panel).	('ECAR', 'MPA', (76, 80))	('increase', 'PosReg', (64, 72))	('basal glycolytic flux', 'MPA', (186, 207))	('oligomycin', 'Chemical', 'MESH:D009840', (27, 37))	('closer', 'PosReg', (211, 217))	('CcO5bKD', 'Var', (172, 179))
103710	26148236	Knock down of either subunit IVi1 or Vb resulted in about 25-30% increase in DCF fluorescence while it was less than 10% higher in CcO4KDshRC4 cells (Fig 3C) compared to control.	('increase', 'PosReg', (65, 73))	('IVi1', 'Gene', (29, 33))	('DCF fluorescence', 'MPA', (77, 93))	('Knock down', 'Var', (0, 10))	('DCF', 'Chemical', 'MESH:D015649', (77, 80))
103714	26148236	As seen in Fig 4A, cellular ATP levels were 15% to 20% lower in the knockdown cells.	('ATP', 'Chemical', 'MESH:D000255', (28, 31))	('knockdown', 'Var', (68, 77))	('lower', 'NegReg', (55, 60))	('cellular ATP levels', 'MPA', (19, 38))
103715	26148236	However, less than 10% ATP synthesized in CcO4KD and CcO5bKD cells were resistant to oligomycin treatment, while it was ~30% in control cells.	('ATP', 'Chemical', 'MESH:D000255', (23, 26))	('resistant', 'MPA', (72, 81))	('CcO5bKD', 'Var', (53, 60))	('oligomycin', 'Chemical', 'MESH:D009840', (85, 95))	('CcO4KD', 'Var', (42, 48))
103716	26148236	In CcO4KDshRC4 cells both total cellular ATP and oligomycin resistant ATP levels were recovered compared to CcO4KD cells (Fig 4A).	('CcO4KDshRC4', 'Var', (3, 14))	('ATP', 'Chemical', 'MESH:D000255', (41, 44))	('recovered', 'PosReg', (86, 95))	('ATP', 'Chemical', 'MESH:D000255', (70, 73))	('oligomycin resistant ATP levels', 'MPA', (49, 80))	('oligomycin', 'Chemical', 'MESH:D009840', (49, 59))
103725	26148236	BAPTA-AM reduced glucose uptake further in these cells while Wortmannin and FK506 had only marginal effect (Fig 4C).	('FK506', 'Chemical', 'MESH:D016559', (76, 81))	('BAPTA-AM', 'Var', (0, 8))	('BAPTA-AM', 'Chemical', 'MESH:C070379', (0, 8))	('reduced', 'NegReg', (9, 16))	('glucose uptake', 'MPA', (17, 31))	('glucose', 'Chemical', 'MESH:D005947', (17, 24))	('Wortmannin', 'Chemical', 'MESH:D000077191', (61, 71))
103727	26148236	Interestingly Glut1 levels were largely unaffected in both knock down cells.	('Glut1', 'Gene', (14, 19))	('Glut1', 'Gene', '6513', (14, 19))	('knock', 'Var', (59, 64))
103728	26148236	These results together show that disruption of CcO activity causes a metabolic adaptation to increased glycolysis for ATP production.	('disruption', 'Var', (33, 43))	('increased', 'PosReg', (93, 102))	('glycolysis for ATP production', 'MPA', (103, 132))	('CcO', 'Gene', (47, 50))	('metabolic adaptation', 'MPA', (69, 89))	('ATP', 'Chemical', 'MESH:D000255', (118, 121))
103729	26148236	Mitochondrial stress induced by depletion of mtDNA in C2C12 cells was shown to activate a distinctive Ca2+/Cn stress signaling, which induced the expression of many nuclear genes including those involved in tumor progression.	('mtDNA', 'Gene', (45, 50))	('depletion', 'Var', (32, 41))	('nuclear', 'MPA', (165, 172))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('Ca2+/Cn stress signaling', 'MPA', (102, 126))	('activate', 'PosReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('C2C12', 'CellLine', 'CVCL:0188', (54, 59))	('tumor', 'Disease', (207, 212))	('expression', 'MPA', (146, 156))	('Mito', 'Species', '262676', (0, 4))	('induced', 'PosReg', (134, 141))	('Ca2+', 'Chemical', 'MESH:D000069285', (102, 106))
103732	26148236	To determine the role of Ca2+/Cn in stress signaling mediated by CcO subunit knock down, cells were treated with FK506, an inhibitor of Cn and BAPTA-AM, a Ca2+ chelator.	('CcO', 'Gene', (65, 68))	('Ca2+', 'Chemical', 'MESH:D000069285', (25, 29))	('BAPTA-AM', 'Chemical', 'MESH:C070379', (143, 151))	('FK506', 'Chemical', 'MESH:D016559', (113, 118))	('knock down', 'Var', (77, 87))	('Ca2+', 'Chemical', 'MESH:D000069285', (155, 159))
103733	26148236	As shown in Fig 5B, both BAPTA-AM and FK506, significantly attenuated stress-induced expression of TGFbeta, MMP16, and Glut4 genes in CcO4KD cells.	('Glut4', 'Gene', (119, 124))	('TGFbeta', 'Gene', (99, 106))	('attenuated', 'NegReg', (59, 69))	('stress-induced expression', 'MPA', (70, 95))	('BAPTA-AM', 'Chemical', 'MESH:C070379', (25, 33))	('FK506', 'Var', (38, 43))	('MMP16', 'Gene', (108, 113))	('Glut4', 'Gene', '6517', (119, 124))	('FK506', 'Chemical', 'MESH:D016559', (38, 43))	('TGFbeta', 'Gene', '7040', (99, 106))	('MMP16', 'Gene', '4325', (108, 113))
103734	26148236	More than 100 genes were up regulated and ~ 35 genes were down regulated in CcO4KD cells compared to control C2C12 cells.	('CcO4KD', 'Var', (76, 82))	('down regulated', 'NegReg', (58, 72))	('up regulated', 'PosReg', (25, 37))	('C2C12', 'CellLine', 'CVCL:0188', (109, 114))
103740	26148236	Remarkably, both CcO4KD and CcO5bKD cells formed several distinct visible colonies on soft agar in about 3 weeks (Fig.	('CcO4KD', 'Var', (17, 23))	('agar', 'Chemical', 'MESH:D000362', (91, 95))	('CcO5bKD', 'Var', (28, 35))
103741	26148236	Notably, colony formation with CcO4KD cells was markedly inhibited by PI3-kinase inhibitor, Wortmannin, and IGF1R inhibitor Picropodophyllin, suggesting the requirement of PI3-kinase/IGF1R pathway in mediating this phenotypic transformation (Fig 7B).	('IGF1R', 'Gene', (183, 188))	('Picropodophyllin', 'Var', (124, 140))	('IGF1R', 'Gene', '3480', (108, 113))	('colony formation', 'CPA', (9, 25))	('inhibited', 'NegReg', (57, 66))	('IGF1R', 'Gene', '3480', (183, 188))	('Picropodophyllin', 'Chemical', 'MESH:C415032', (124, 140))	('Wortmannin', 'Chemical', 'MESH:D000077191', (92, 102))	('CcO4KD', 'Var', (31, 37))	('IGF1R', 'Gene', (108, 113))	('PI3-kinase', 'Enzyme', (70, 80))
103747	26148236	Immunofluorescence images in Fig 7C (bottom panel) show that Akt1 staining was significantly increased in colonies from both CcO knockdown cell lines.	('Akt1', 'Gene', (61, 65))	('Akt1', 'Gene', '207', (61, 65))	('increased', 'PosReg', (93, 102))	('knockdown', 'Var', (129, 138))	('staining', 'MPA', (66, 74))
103749	26148236	The tumorispheres formed by CcO4KD and CcO5bKD cells in 3D culture are consistent with the sarcomas suggesting the in vivo tumorigenic potential of these CcOKD cells.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (123, 128))	('CcO5bKD', 'Var', (39, 46))	('CcO4KD', 'Var', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('sarcomas', 'Disease', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
103751	26148236	The ratio of extracellular acidification to O2 consumption rates was significantly higher in knock down cells compared to corresponding control cells indicating increased glycolysis (Fig S4B).	('knock down', 'Var', (93, 103))	('glycolysis', 'MPA', (171, 181))	('O2 consumption rates', 'MPA', (44, 64))	('O2', 'Chemical', '-', (44, 46))	('extracellular acidification', 'MPA', (13, 40))	('increased', 'PosReg', (161, 170))	('higher', 'PosReg', (83, 89))
103753	26148236	The relevance of CcO disruption in cellular transformation was assessed in the hypoxic regions of human esophageal tumors and mouse xenograft sections.	('mouse', 'Species', '10090', (126, 131))	('esophageal tumors', 'Phenotype', 'HP:0100751', (104, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CcO', 'Gene', (17, 20))	('disruption', 'Var', (21, 31))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal tumors', 'Disease', 'MESH:D004938', (104, 121))	('human', 'Species', '9606', (98, 103))	('esophageal tumors', 'Disease', (104, 121))
103773	26148236	Defects in mtDNA such as mutations, deletions and reduction of copy number- all of which affect the mitochondrial ETC, have been reported in a wide variety of cancers.	('cancers', 'Disease', (159, 166))	('mutations', 'Var', (25, 34))	('deletions', 'Var', (36, 45))	('copy number-', 'MPA', (63, 75))	('mitochondrial ETC', 'MPA', (100, 117))	('reduction', 'NegReg', (50, 59))	('affect', 'Reg', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('reported', 'Reg', (129, 137))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('mtDNA', 'Gene', (11, 16))
103774	26148236	Mutations in Complex I subunit ND6 was shown to increase metastatic potential by overproducing reactive oxygen species, while a ND5 mutation promoted tumorigenesis by oxidative stress and Akt activation .	('overproducing reactive oxygen species', 'MPA', (81, 118))	('ND6', 'Gene', (31, 34))	('mutation', 'Var', (132, 140))	('Akt', 'Gene', '207', (188, 191))	('oxidative stress', 'Phenotype', 'HP:0025464', (167, 183))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (95, 118))	('ND5', 'Gene', '4540', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('metastatic potential', 'CPA', (57, 77))	('ND5', 'Gene', (128, 131))	('Mutations', 'Var', (0, 9))	('activation', 'PosReg', (192, 202))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('ND6', 'Gene', '4541', (31, 34))	('Akt', 'Gene', (188, 191))	('promoted', 'PosReg', (141, 149))	('tumor', 'Disease', (150, 155))	('increase', 'PosReg', (48, 56))
103775	26148236	Similarly, mitochondrial dysfunction resulting from mutations in nuclear DNA encoded mitochondrial proteins like SDH, FH and IDH, are also strongly associated with specific cancers.	('mutations', 'Var', (52, 61))	('SDH', 'Gene', (113, 116))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (11, 36))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (11, 36))	('cancers', 'Disease', (173, 180))	('mitochondrial dysfunction', 'Disease', (11, 36))	('IDH', 'Gene', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('FH', 'Disease', 'MESH:D006938', (118, 120))	('associated', 'Reg', (148, 158))	('SDH', 'Gene', '6390', (113, 116))	('IDH', 'Gene', '3417', (125, 128))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
103779	26148236	In the present study using multiple cell lines, we investigated the causative role of CcO dysfunction in metabolic reprogramming and tumor progression by shRNA mediated knockdown of CcO subunits IVi1 and Vb.	('CcO dysfunction', 'Disease', (86, 101))	('investigated', 'Reg', (51, 63))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('knockdown', 'Var', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('CcO dysfunction', 'Disease', 'MESH:D006331', (86, 101))
103781	26148236	Our observation that disruption of CcO activity induces a metabolic shift, and associated changes in nuclear gene expression profile and growth characteristics, has important significance in tumor progression.	('metabolic', 'MPA', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('CcO activity', 'Gene', (35, 47))	('nuclear gene expression profile', 'MPA', (101, 132))	('disruption', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('changes', 'Reg', (90, 97))	('growth characteristics', 'CPA', (137, 159))
103791	26148236	We have propagated cells from frozen stocks of the original vials that were authenticated by short tandem repeat analysis for highly polymorphic microsatellites FES/FPS, vWA31, D22S417, D10S526 and D5S592 as performed by the Cell Culture Core to validate the identity of cells by comparing cells at the earliest stocks we have and those grown >8-12 passages.	('stocks', 'Species', '3724', (37, 43))	('D10S526', 'Var', (186, 193))	('stocks', 'Species', '3724', (312, 318))	('D22S417', 'Var', (177, 184))	('D5S592', 'Var', (198, 204))	('FES/FPS', 'Gene', (161, 168))
103834	24781339	Mutations of the p53 tumor suppressor gene, as well as enhanced expression of Bcl2 and cyclin D1 have also been detected in metaplastic/pre-dysplastic BE.	('cyclin D1', 'Gene', (87, 96))	('dysplastic', 'Disease', 'MESH:D004416', (140, 150))	('expression', 'MPA', (64, 74))	('cyclin D1', 'Gene', '595', (87, 96))	('tumor', 'Disease', (21, 26))	('Bcl2', 'Gene', '596', (78, 82))	('enhanced', 'PosReg', (55, 63))	('Mutations', 'Var', (0, 9))	('detected', 'Reg', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('p53', 'Gene', (17, 20))	('Bcl2', 'Gene', (78, 82))	('dysplastic', 'Disease', (140, 150))	('p53', 'Gene', '7157', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
103836	24781339	Altogether, these genes regulate a broad range of cellular functions from cell adhesion to cell cycle checkpoints and apoptosis, illustrating the complexity of this esophageal disease and the challenges faced in modeling them in the research laboratory.	('apoptosis', 'CPA', (118, 127))	('cell', 'CPA', (74, 78))	('rat', 'Species', '10116', (246, 249))	('rat', 'Species', '10116', (135, 138))	('esophageal disease', 'Disease', (165, 183))	('esophageal disease', 'Disease', 'MESH:D004935', (165, 183))	('regulate', 'Reg', (24, 32))	('genes', 'Var', (18, 23))	('cellular', 'MPA', (50, 58))
103854	24781339	In addition, ectopic gastric expression of Cdx2 induced a gastric intestinal metaplasia (GIM) similar to human GIM .	('human', 'Species', '9606', (105, 110))	('gastric intestinal metaplasia', 'Disease', (58, 87))	('gastric intestinal metaplasia', 'Disease', 'MESH:D013274', (58, 87))	('ectopic', 'Var', (13, 20))	('Cdx2', 'Gene', (43, 47))	('ectopic gastric', 'Phenotype', 'HP:0100802', (13, 28))	('induced', 'Reg', (48, 55))
103856	24781339	These K14-Cdx2 mice were found to have significantly reduced esophageal cell proliferation, as well as diminished barrier function.	('barrier function', 'CPA', (114, 130))	('rat', 'Species', '10116', (84, 87))	('esophageal cell proliferation', 'CPA', (61, 90))	('reduced', 'NegReg', (53, 60))	('diminished', 'NegReg', (103, 113))	('K14-Cdx2', 'Var', (6, 14))	('mice', 'Species', '10090', (15, 19))
103876	24781339	In addition, using this same OTC system, we determined through a genetic approach that the onset of a true BE is a multistep process that requires increased proliferation, senescence inhibition, and epigenetic alterations.	('increased', 'PosReg', (147, 156))	('rat', 'Species', '10116', (214, 217))	('rat', 'Species', '10116', (164, 167))	('epigenetic alterations', 'Var', (199, 221))	('senescence', 'CPA', (172, 182))
103925	24781339	Additionally, mutation of Toll-like receptor 4 (TLR4), an innate immune receptor for bacterial LPS, can reduce GvHD risk whereas activation of TLR9 by bacterial DNA can enhance the risk for GvHD.	('GvHD', 'Disease', (111, 115))	('TLR4', 'Gene', (48, 52))	('TLR9', 'Gene', (143, 147))	('LPS', 'Disease', (95, 98))	('mutation', 'Var', (14, 22))	('enhance', 'PosReg', (169, 176))	('reduce', 'NegReg', (104, 110))	('Toll-like receptor 4', 'Gene', '7099', (26, 46))	('LPS', 'Disease', 'MESH:C536528', (95, 98))	('Toll-like receptor 4', 'Gene', (26, 46))	('TLR9', 'Gene', '54106', (143, 147))	('TLR4', 'Gene', '7099', (48, 52))
103939	24781339	IL-7 transgenic, IL-10 knock-out, mutant gp130 knock-in), 3) disruption of T cell homeostasis by adoptive transfer (CD45RB, CD8 transfer models), 4) congenital, spontaneous mutations (C3H/HeJBir), and 5) spontaneous (cotton-top tamarin).	('T cell homeostasis', 'MPA', (75, 93))	('IL-7', 'Gene', (0, 4))	('gp130', 'Gene', (41, 46))	('IL-7', 'Gene', '16196', (0, 4))	('cotton-top tamarin', 'Species', '9490', (217, 235))	('congenital', 'Disease', (149, 159))	('transgenic', 'Species', '10090', (5, 15))	('IL-10', 'Gene', (17, 22))	('mutant', 'Var', (34, 40))
103941	24781339	Disruption of the IL-10 gene in mice leads to spontaneous pancolitis and cecal inflammation by 2-4 months of age and histopathologically the mouse colon shows many of the same characteristics as those observed in human IBD.	('human', 'Species', '9606', (213, 218))	('colitis', 'Phenotype', 'HP:0002583', (61, 68))	('cecal', 'Disease', (73, 78))	('mouse', 'Species', '10090', (141, 146))	('mice', 'Species', '10090', (32, 36))	('pancolitis', 'Disease', (58, 68))	('IL-10', 'Gene', (18, 23))	('pancolitis', 'Disease', 'None', (58, 68))	('inflammation', 'Disease', 'MESH:D007249', (79, 91))	('inflammation', 'Disease', (79, 91))	('leads to', 'Reg', (37, 45))	('Disruption', 'Var', (0, 10))
103947	24781339	Recent evidence also supports that epithelial cell stress and abnormalities can lead to intestinal inflammation in mice following deletion in XBP1, inositol requiring enzyme 1beta (IRE1beta), caspase-8, anterior gradient 2 (AGR2), the RNA editing enzyme ADAR1, or missense mutations in MUC2.	('caspase-8', 'Gene', '12370', (192, 201))	('lead to', 'Reg', (80, 87))	('XBP1', 'Gene', (142, 146))	('IRE1beta', 'Gene', '26918', (181, 189))	('ADAR1', 'Gene', (254, 259))	('XBP1', 'Gene', '22433', (142, 146))	('intestinal inflammation', 'Disease', (88, 111))	('MUC2', 'Gene', (286, 290))	('anterior gradient 2', 'Gene', (203, 222))	('inositol requiring enzyme 1', 'Gene', (148, 175))	('mice', 'Species', '10090', (115, 119))	('intestinal inflammation', 'Disease', 'MESH:D007249', (88, 111))	('caspase-8', 'Gene', (192, 201))	('IRE1beta', 'Gene', (181, 189))	('AGR2', 'Gene', (224, 228))	('ADAR1', 'Gene', '56417', (254, 259))	('inositol requiring enzyme 1', 'Gene', '2081', (148, 175))	('AGR2', 'Gene', '23795', (224, 228))	('MUC2', 'Gene', '17831', (286, 290))	('deletion', 'Var', (130, 138))	('missense mutations', 'Var', (264, 282))	('anterior gradient 2', 'Gene', '23795', (203, 222))
104051	22853826	(Table 2) Univariate analysis (Table 3) showed that lymph node involvement (P = 0.014), 7th AJCC stages III (P = 0.004), and absence of preoperative bone scan (P = 0.009, Figure 2A) were significantly associated with inferior bone recurrence-free survival after esophagectomy.	('absence', 'Var', (125, 132))	('men', 'Species', '9606', (70, 73))	('inferior bone recurrence-free survival', 'CPA', (217, 255))	('associated with', 'Reg', (201, 216))	('lymph node involvement', 'CPA', (52, 74))
104059	22853826	Univariate analysis (Table 4) showed that T3 + 4 (P < 0.001), lymph node involvement (P < 0.001), 7th AJCC stages III (P < 0.001), and positive surgical margin (P = 0.006) were significantly associated inferior overall survival.	('overall survival', 'MPA', (211, 227))	('lymph node involvement', 'CPA', (62, 84))	('T3 + 4', 'Var', (42, 48))	('men', 'Species', '9606', (80, 83))
104063	22853826	Univariate analysis (Table 4) showed that absence of preoperative bone scan (P = 0.037, Figure 2D), lymph node involvement (P < 0.001), 7th AJCC stages III (P < 0.001), and positive surgical margin (P < 0.001) were significantly associated with inferior overall survival.	('lymph node involvement', 'CPA', (100, 122))	('overall', 'MPA', (254, 261))	('men', 'Species', '9606', (118, 121))	('absence', 'Var', (42, 49))	('inferior', 'NegReg', (245, 253))
104107	19672424	The study accrued 10 men and 5 women of median age 64 years (range: 48-80 years) and TNM stages T3N0 (n = 1), T2N1 (n = 2), T3N1 (n = 11), and T4N1 (n = 1).	('T2N1', 'Var', (110, 114))	('TNM', 'Gene', (85, 88))	('T3N1', 'Var', (124, 128))	('T4N1', 'Var', (143, 147))	('T3N0', 'Var', (96, 100))	('men', 'Species', '9606', (33, 36))	('TNM', 'Gene', '10178', (85, 88))	('men', 'Species', '9606', (21, 24))	('women', 'Species', '9606', (31, 36))
104140	19672424	Locoregional symptomatology for treatment interruption included severe esophagitis (that is, severe odynophagia or dysphagia, intolerable pain), impaired nutrition with nausea and vomiting; and dehydration requiring hospitalization.	('pain', 'Phenotype', 'HP:0012531', (138, 142))	('dehydration', 'Disease', 'MESH:D003681', (194, 205))	('esophagitis', 'Disease', (71, 82))	('nausea', 'Disease', (169, 175))	('esophagitis', 'Disease', 'MESH:D004941', (71, 82))	('vomiting', 'Disease', 'MESH:D014839', (180, 188))	('odynophagia or dysphagia', 'Disease', 'MESH:D003680', (100, 124))	('pain', 'Disease', 'MESH:D010146', (138, 142))	('dehydration', 'Disease', (194, 205))	('dysphagia', 'Phenotype', 'HP:0002015', (115, 124))	('vomiting', 'Phenotype', 'HP:0002013', (180, 188))	('esophagitis', 'Phenotype', 'HP:0100633', (71, 82))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (169, 188))	('nausea', 'Disease', 'MESH:D009325', (169, 175))	('vomiting', 'Disease', (180, 188))	('pain', 'Disease', (138, 142))	('odynophagia or dysphagia', 'Disease', (100, 124))	('men', 'Species', '9606', (37, 40))	('nausea', 'Phenotype', 'HP:0002018', (169, 175))	('odynophagia', 'Phenotype', 'HP:0032043', (100, 111))	('impaired', 'Var', (145, 153))	('dehydration', 'Phenotype', 'HP:0001944', (194, 205))
104143	19672424	The TNM stages in the group were T3N0 (n = 1), T2N1 (n = 2), T3N1 (n = 11), and T4N1 (n = 1).	('T3N0', 'Var', (33, 37))	('T4N1', 'Var', (80, 84))	('T3N1', 'Var', (61, 65))	('TNM', 'Gene', '10178', (4, 7))	('TNM', 'Gene', (4, 7))	('T2N1', 'Var', (47, 51))
104290	33544280	After allo-BMT, complete remission continued to be maintained, and the patient was discharged; however, dysphagia and saliva retention did not improve.	('saliva retention', 'Disease', (118, 134))	('dysphagia', 'Disease', (104, 113))	('dysphagia', 'Disease', 'MESH:D003680', (104, 113))	('allo-BMT', 'Var', (6, 14))	('dysphagia', 'Phenotype', 'HP:0002015', (104, 113))	('saliva retention', 'Disease', 'MESH:D016055', (118, 134))	('patient', 'Species', '9606', (71, 78))
104345	32010753	Patients were eligible if they had flat BE with low-grade dysplasia (LGD) or high-grade dysplasia (HGD) and residual BE post-endoscopic mucosal resection (EMR) for low-risk BE-related early cancer.	('LGD', 'Disease', (69, 72))	('low-grade dysplasia', 'Disease', (48, 67))	('LGD', 'Disease', 'MESH:D008228', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('high-grade', 'Var', (77, 87))	('low-grade dysplasia', 'Disease', 'MESH:D008228', (48, 67))	('BE-related early cancer', 'Disease', (173, 196))
104348	32010753	Patients were scoped with GIF-FQ260Z, GIF-H290Z or GIF-HQ290 endoscopes (Olympus, Tokyo).	('H290Z', 'SUBSTITUTION', 'None', (42, 47))	('H290Z', 'Var', (42, 47))	('GIF-HQ290', 'Var', (51, 60))	('GIF-FQ260Z', 'Var', (26, 36))
104367	30655865	Univariate analysis revealed that HDL (P=0.048), LDL (P=0.020), Pathological T-staging status (pT status) (P=0.001), Pathological N-staging status (pN status) (P=0.001) and histological differentiation (P=0.002) were significantly associated with OS.	('OS', 'Chemical', '-', (247, 249))	('LDL', 'Disease', (49, 52))	('HD', 'Disease', 'MESH:D006816', (34, 36))	('Pathological', 'Var', (117, 129))	('associated', 'Reg', (231, 241))
104422	30655865	Similar results were obtained with ECa109 cells, whereby the G1-phase proportion decreased from 63.91 to 51.83% and the total proportion of S and G2 phase cells increased from 36.09 to 48.17% in response to LDL (Fig.	('decreased', 'NegReg', (81, 90))	('ECa109', 'CellLine', 'CVCL:6898', (35, 41))	('G1-phase', 'CPA', (61, 69))	('increased', 'PosReg', (161, 170))	('LDL', 'Var', (207, 210))
104428	30655865	This predominance may be because abdominal adiposity is more common in males; abdominal adiposity increases intragastric pressure and relaxes the lower esophageal sphincter, which leads to acid reflux.	('intragastric pressure', 'MPA', (108, 129))	('acid reflux', 'Phenotype', 'HP:0002020', (189, 200))	('esophageal sphincter', 'Disease', (152, 172))	('abdominal adiposity', 'Var', (78, 97))	('relaxes', 'NegReg', (134, 141))	('leads to', 'Reg', (180, 188))	('acid reflux', 'MPA', (189, 200))	('esophageal sphincter', 'Disease', 'MESH:D009122', (152, 172))	('increases', 'PosReg', (98, 107))
104438	30655865	Several years ago, multiple studies supported the view that exogenous LDL promoted the proliferation of breast cancer and colon adenocarcinoma cells.	('promoted', 'PosReg', (74, 82))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (122, 142))	('proliferation', 'CPA', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('breast cancer', 'Disease', (104, 117))	('exogenous', 'Var', (60, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('LDL', 'Protein', (70, 73))	('colon adenocarcinoma', 'Disease', (122, 142))
104441	30655865	This observation may be attributed to the possible involvement of the LDL receptor-related protein 1 (LRP1) in regulating cancer cell survival and metastatic potential, which occurs through the ability of LDL to promote cancer cell proliferation and differentiation.	('LDL', 'Var', (205, 208))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('LRP1', 'Gene', '4035', (102, 106))	('cancer', 'Disease', (122, 128))	('promote', 'PosReg', (212, 219))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('LDL receptor-related protein 1', 'Gene', '4035', (70, 100))	('differentiation', 'CPA', (250, 265))	('LDL receptor-related protein 1', 'Gene', (70, 100))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('metastatic potential', 'CPA', (147, 167))	('cancer', 'Disease', (220, 226))	('LRP1', 'Gene', (102, 106))	('involvement', 'Reg', (51, 62))	('men', 'Species', '9606', (58, 61))
104447	30655865	Similar to the study by Montel et al, the addition of LDL cholesterol may induce activation of microvascular endothelial cells, which facilitates lymph node metastases of colon cancer cells.	('metastases of colon cancer', 'Disease', 'MESH:D009362', (157, 183))	('colon cancer', 'Phenotype', 'HP:0003003', (171, 183))	('microvascular', 'CPA', (95, 108))	('activation', 'PosReg', (81, 91))	('LDL cholesterol', 'Var', (54, 69))	('cholesterol', 'Chemical', 'MESH:D002784', (58, 69))	('metastases of colon cancer', 'Disease', (157, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('facilitates', 'PosReg', (134, 145))
104450	30655865	Furthermore, suppressive effects on the function of immune cells may be another mechanism through which a high LDL level enhances tumor metastasis.	('high', 'Var', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('LDL', 'MPA', (111, 114))	('high LDL level', 'Phenotype', 'HP:0003141', (106, 120))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('enhances', 'PosReg', (121, 129))	('tumor', 'Disease', (130, 135))	('high LDL', 'Phenotype', 'HP:0003141', (106, 114))
104457	30655865	Furthermore, to the best of our knowledge, the current study is the first to hypothesize that a high LDL level is associated with poor OS because LDL promotes lymphatic metastasis and this hypothesis has been partially confirmed in vitro.	('high LDL level', 'Phenotype', 'HP:0003141', (96, 110))	('promotes', 'PosReg', (150, 158))	('lymphatic metastasis', 'CPA', (159, 179))	('OS', 'Chemical', '-', (135, 137))	('LDL', 'MPA', (101, 104))	('LDL', 'Var', (146, 149))	('poor OS', 'Disease', (130, 137))	('high LDL', 'Phenotype', 'HP:0003141', (96, 104))
104458	30655865	81301936 and 81472811) and the Science Technology Development Project of Shandong Province (grant nos.	('81301936', 'Var', (0, 8))	('men', 'Species', '9606', (57, 60))	('81472811', 'Var', (13, 21))
104468	30412141	Overexpression of TPX2 is related to poor survival rate in most solid tumors, which indicates that the expression level of TPX2 is a significant prognostic parameter and potential therapeutic target in various solid tumors.	('solid tumors', 'Disease', (64, 76))	('survival', 'MPA', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('poor', 'NegReg', (37, 41))	('TPX2', 'Gene', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('solid tumors', 'Disease', (210, 222))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Overexpression', 'Var', (0, 14))	('solid tumors', 'Disease', 'MESH:D009369', (210, 222))	('TPX2', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
104470	30412141	Further studies indicated that TPX2 controlled MT nucleation, function, and coaction with other cell structures as an MT-associated protein (MAP), and improper expression of TPX2 lead to chromosomal instability, caused centrosome amplification, and developed aneuploidy, which highly correlated with the occurrences and developments of various tumors.	('caused', 'Reg', (212, 218))	('improper expression', 'Var', (151, 170))	('aneuploidy', 'Disease', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('lead to', 'Reg', (179, 186))	('TPX2', 'Gene', (174, 178))	('tumors', 'Disease', (344, 350))	('developed', 'PosReg', (249, 258))	('chromosomal instability', 'Phenotype', 'HP:0040012', (187, 210))	('tumors', 'Phenotype', 'HP:0002664', (344, 350))	('tumors', 'Disease', 'MESH:D009369', (344, 350))	('chromosomal', 'MPA', (187, 198))	('aneuploidy', 'Disease', 'MESH:D000782', (259, 269))	('centrosome amplification', 'CPA', (219, 243))
104489	30412141	In the following analysis of subgroups classified by different cancer types, we discovered that TPX2 expression was related to the worse 3-year OS of gastric cancer (n = 2, OR = 10.63, 95% CI: 3.41-33.15, P < .0001) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('expression', 'Var', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('gastric cancer', 'Disease', (150, 164))	('cancer', 'Disease', (158, 164))	('TPX2', 'Gene', (96, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
104492	30412141	Consistent with the results above, TPX2 expression was related to the worse 5-year OS of hepatocellular cancer (n = 2, OR = 4.25, 95% CI: 2.36-7.67, P < .00001) (Fig.	('TPX2', 'Gene', (35, 39))	('OS of hepatocellular cancer', 'Disease', (83, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('expression', 'Var', (40, 50))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (89, 110))	('OS of hepatocellular cancer', 'Disease', 'MESH:C567932', (83, 110))
104503	30412141	For instance, Yan et al found that transfection of TPX2 siRNA decreased the viability and proliferation capacity of bladder carcinoma cell lines and TPX2-depleted tumor cells obviously grew more slowly in nude mice.	('bladder carcinoma', 'Disease', (116, 133))	('bladder carcinoma', 'Disease', 'MESH:D001749', (116, 133))	('nude mice', 'Species', '10090', (205, 214))	('decreased', 'NegReg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('slowly', 'NegReg', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('transfection', 'Var', (35, 47))	('TPX2', 'Gene', (51, 55))	('viability', 'CPA', (76, 85))	('tumor', 'Disease', (163, 168))	('proliferation capacity', 'CPA', (90, 112))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (116, 133))	('grew', 'CPA', (185, 189))
104544	26989385	In a recent population-based cohort study, the presence of BE conferred a relative risk of EAC of 11.3 when compared with that of the general population (95% confidence interval (CI): 8.8-14.4).	('BE', 'Chemical', '-', (59, 61))	('EAC', 'Disease', (91, 94))	('presence', 'Var', (47, 55))
104549	26989385	Patients with long-standing or severe GERD have a much higher risk of developing EAC (odds ratio (OR) 43.5; 95% CI: 18.3-103.5) than the general population.	('GERD', 'Disease', (38, 42))	('GERD', 'Disease', 'MESH:D005764', (38, 42))	('EAC', 'Disease', (81, 84))	('Patients', 'Species', '9606', (0, 8))	('severe', 'Var', (31, 37))
104608	26083933	found that on multivariable analysis, V60 formed the best predictive model for radiation esophagitis following 3D-CRT or IMRT (for >=grade 2, OR 1.34 per 10% increase, p < 0.001; for >=grade 3, OR 1.33 per 10% increase, p < 0.001).	('esophagitis', 'Phenotype', 'HP:0100633', (89, 100))	('radiation esophagitis', 'Disease', (79, 100))	('radiation esophagitis', 'Disease', 'MESH:D004194', (79, 100))	('V60', 'Var', (38, 41))
104617	26083933	SBRT to central tumors also increases the dose to the central vascular structures, particularly the aorta.	('dose', 'MPA', (42, 46))	('SBRT', 'Chemical', '-', (0, 4))	('central tumors', 'Disease', (8, 22))	('increases', 'PosReg', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('SBRT', 'Var', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('central tumors', 'Disease', 'MESH:D016543', (8, 22))
104725	25389458	RESULTS: The 5-year CSS in patients with GPS0, 1, and 2 was 50.0%, 27.0%, and 12.5%, respectively (P < .001).	('GPS', 'Chemical', '-', (41, 44))	('patients', 'Species', '9606', (27, 35))	('GPS0', 'Var', (41, 45))	('CSS', 'MPA', (20, 23))	('CSS', 'Chemical', '-', (20, 23))
104781	25389458	Several previous studies have shown that GPS is associated with survival in various cancers, including ECs.	('GPS', 'Chemical', '-', (41, 44))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('associated', 'Reg', (48, 58))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('GPS', 'Var', (41, 44))	('ECs', 'Disease', (103, 106))
104866	31258746	Mechanistically, ERK pathway inactivation was involved in the anti-tumor functions of cordycepin.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ERK', 'Gene', '5594', (17, 20))	('cordycepin', 'Chemical', 'MESH:C058120', (86, 96))	('tumor', 'Disease', (67, 72))	('involved', 'Reg', (46, 54))	('ERK', 'Gene', (17, 20))	('cordycepin', 'Gene', (86, 96))	('inactivation', 'Var', (29, 41))
104929	31258746	We hypothesize that this was because Annexin V positivity and PI positivity can also stain senescent and dead cells and may have influenced the results.	('senescent', 'CPA', (91, 100))	('Annexin V', 'Gene', (37, 46))	('influenced', 'Reg', (129, 139))	('Annexin V', 'Gene', '308', (37, 46))	('positivity', 'Var', (47, 57))	('stain', 'Reg', (85, 90))
104934	31258746	Together, these results indicate that cordycepin induces arrest of the G2/M phase, a finding that accounts for its antiproliferative function by disturbing the level of cell cycle related proteins.	('disturbing', 'NegReg', (145, 155))	('level of cell cycle related proteins', 'MPA', (160, 196))	('arrest', 'CPA', (57, 63))	('cordycepin', 'Chemical', 'MESH:C058120', (38, 48))	('cordycepin', 'Var', (38, 48))
104955	31258746	Based on the Western blot analysis in ECA109 cells, cleaved-caspase3, cleaved-caspase9, cleaved PARP, and Bax all significantly increased.	('caspase9', 'Gene', (78, 86))	('caspase9', 'Gene', '842', (78, 86))	('PARP', 'Gene', (96, 100))	('caspase3', 'Gene', (60, 68))	('increased', 'PosReg', (128, 137))	('Bax', 'Gene', (106, 109))	('cleaved', 'Var', (88, 95))	('caspase3', 'Gene', '836', (60, 68))	('Bax', 'Gene', '581', (106, 109))	('PARP', 'Gene', '142', (96, 100))
104985	31258746	The results indicated that inactivation of the MEK/ERK pathway leads to enhanced levels of cyclinB1 and CDK-1, which contributed to G2/M stage arrest and cell death.	('G2/M stage arrest', 'CPA', (132, 149))	('ERK', 'Gene', (51, 54))	('CDK-1', 'Gene', (104, 109))	('MEK', 'Gene', (47, 50))	('inactivation', 'Var', (27, 39))	('MEK', 'Gene', '5609', (47, 50))	('cell death', 'CPA', (154, 164))	('cyclinB1', 'Gene', (91, 99))	('enhanced', 'PosReg', (72, 80))	('cyclinB1', 'Gene', '891', (91, 99))	('CDK-1', 'Gene', '983', (104, 109))	('ERK', 'Gene', '5594', (51, 54))	('contributed', 'Reg', (117, 128))
105027	28971062	The cancer sites (ICD-O code) considered in this study were: oral cavity and pharynx (C00-C14), esophagus (C15), colorectal (C18-C20), liver (C22), thyroid (C73), gall bladder (C23-C24), pancreas (C25), and larynx (C32) in both sexes; and breast (C50) in females (Table 1).	('C23', 'Gene', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('C18', 'Gene', (125, 128))	('C23', 'Gene', '4691', (177, 180))	('colorectal', 'Disease', (113, 123))	('C15', 'Gene', '51316', (107, 110))	('pancreas', 'Disease', (187, 195))	('C32', 'Gene', (215, 218))	('C73', 'Var', (157, 160))	('esophagus', 'Disease', (96, 105))	('C15', 'Gene', (107, 110))	('gall bladder', 'Disease', (163, 175))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('pancreas', 'Disease', 'MESH:D010190', (187, 195))	('C32', 'Gene', '51192', (215, 218))	('colorectal', 'Disease', 'MESH:D015179', (113, 123))	('C18', 'Gene', '27241', (125, 128))	('C00-C14', 'Var', (86, 93))	('cancer', 'Disease', (4, 10))	('gall bladder', 'Disease', 'MESH:D005705', (163, 175))
105076	28971062	To determine how much more cancers of the thyroid there may have been if the people stop taking alcohol, we computed the association between mild to moderate alcohol intake and reduced risk of thyroid cancer using a relative risk of 0.74 from meta-analyses studies.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancers of the thyroid', 'Phenotype', 'HP:0100031', (27, 49))	('alcohol', 'Chemical', 'MESH:D000438', (158, 165))	('thyroid cancer', 'Disease', (193, 207))	('reduced', 'NegReg', (177, 184))	('thyroid cancer', 'Phenotype', 'HP:0002890', (193, 207))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('thyroid cancer', 'Disease', 'MESH:D013964', (193, 207))	('people', 'Species', '9606', (77, 83))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('mild to moderate alcohol', 'Var', (141, 165))	('cancers', 'Disease', (27, 34))
105096	28971062	Other studies have suggested that gene environmental interactions could contribute to increased risk of esophageal cancer in different regions.	('interactions', 'Var', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('men', 'Species', '9606', (46, 49))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))
105184	28611969	Mobilization of the lower esophagus may risk devascularization, ischemia at the esophageal ends, and stricture formation.	('Mobilization', 'Var', (0, 12))	('ischemia', 'Disease', (64, 72))	('devascularization', 'CPA', (45, 62))	('ischemia', 'Disease', 'MESH:D007511', (64, 72))	('stricture', 'Disease', (101, 110))
105240	28611969	Iterative dilations increase the risk of complications and may cause psychological problems in children.	('cause', 'Reg', (63, 68))	('children', 'Species', '9606', (95, 103))	('complications', 'CPA', (41, 54))	('Iterative', 'Var', (0, 9))	('psychological problems', 'CPA', (69, 91))
105271	28611969	In addition to its antineoplastic properties, it has been shown that MMC may inhibit wound healing by downregulating the gene expression for extracellular matrix proteins and then it acts as an antiproliferative agent by decreasing collagen synthesis and scar formation.	('scar', 'Phenotype', 'HP:0100699', (255, 259))	('gene expression for extracellular matrix proteins', 'MPA', (121, 170))	('MMC', 'Var', (69, 72))	('decreasing', 'NegReg', (221, 231))	('inhibit', 'NegReg', (77, 84))	('scar formation', 'CPA', (255, 269))	('downregulating', 'NegReg', (102, 116))	('MMC', 'Chemical', 'MESH:D016685', (69, 72))	('decreasing collagen synthesis', 'Phenotype', 'HP:0030095', (221, 250))	('collagen synthesis', 'CPA', (232, 250))	('wound healing', 'CPA', (85, 98))
105285	28611969	El-Asmar et al., in a double-blinded, randomized, placebo-controlled trial involving children with caustic esophageal strictures, showed a significant reduction of the number of dilatation sessions needed to alleviate dysphagia in patients undergone MMC application compared to controls.	('dysphagia', 'Disease', 'MESH:D003680', (218, 227))	('esophageal strictures', 'Phenotype', 'HP:0002043', (107, 128))	('MMC', 'Chemical', 'MESH:D016685', (250, 253))	('patients', 'Species', '9606', (231, 239))	('dilatation', 'Phenotype', 'HP:0002617', (178, 188))	('MMC', 'Var', (250, 253))	('dysphagia', 'Disease', (218, 227))	('esophageal stricture', 'Phenotype', 'HP:0002043', (107, 127))	('dysphagia', 'Phenotype', 'HP:0002015', (218, 227))	('reduction', 'NegReg', (151, 160))	('children', 'Species', '9606', (85, 93))
105286	28611969	During the study period, 80% of strictures in the MMC group got completely resolved compared to only 35% in the placebo group.	('MMC', 'Var', (50, 53))	('MMC', 'Chemical', 'MESH:D016685', (50, 53))	('strictures', 'Disease', (32, 42))
105295	28611969	Potential side effects of systemic MMC include bone marrow, pulmonary, and renal toxicity; however, topical application has not been described to cause severe side effects so far.	('MMC', 'Var', (35, 38))	('pulmonary', 'CPA', (60, 69))	('renal toxicity', 'Disease', (75, 89))	('MMC', 'Chemical', 'MESH:D016685', (35, 38))	('bone marrow', 'CPA', (47, 58))	('renal toxicity', 'Disease', 'MESH:D007674', (75, 89))
105362	27749841	Half of driver mutations located on the branches targeted oncogenes, including PIK3CA, NFE2L2, MTOR, etc.	('targeted', 'Reg', (49, 57))	('mutations', 'Var', (15, 24))	('PIK3CA', 'Gene', (79, 85))	('MTOR', 'Gene', (95, 99))	('NFE2L2', 'Gene', '4780', (87, 93))	('MTOR', 'Gene', '2475', (95, 99))	('PIK3CA', 'Gene', '5290', (79, 85))	('NFE2L2', 'Gene', (87, 93))
105363	27749841	By contrast, the majority of truncal and clonal driver mutations occurred in tumor suppressor genes, including TP53, KMT2D, ZNF750, etc.	('mutations', 'Var', (55, 64))	('TP53', 'Gene', '7157', (111, 115))	('ZNF750', 'Gene', '79755', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('TP53', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ZNF750', 'Gene', (124, 130))	('KMT2D', 'Gene', '8085', (117, 122))	('KMT2D', 'Gene', (117, 122))	('tumor', 'Disease', (77, 82))	('occurred', 'Reg', (65, 73))
105374	27749841	The trunk, shared branch and private branch of the tree represented mutations in all tumor regions, in some but not all regions, and only in one region, respectively.	('tumor', 'Disease', (85, 90))	('represented', 'Reg', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mutations', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
105375	27749841	Characterization of the relative timing of mutations affecting driver genes with possible biological relevance is essential for revealing the evolutionary processes of the cancer genome, as well as further improving precision medicine strategies.	('cancer', 'Disease', (172, 178))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))
105376	27749841	To address this, we identified potential driver mutations according to recent large-scale ESCC sequencing data, COSMIC gene census and Pan-cancer analysis; this was followed by tracing them within the phylogenetic trees (See Methods).	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Pan-cancer', 'Disease', (135, 145))	('mutations', 'Var', (48, 57))	('Pan-cancer', 'Disease', 'MESH:C537931', (135, 145))
105377	27749841	This indicates that drivers are mutated as relatively early events during the evolutionary process of the tumors, which is in accordance with previous findings in other tumor types.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutated', 'Var', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
105378	27749841	We next separated putative driver mutations into those occurring either in oncogenes or tumor suppressor genes (TSGs).	('tumor', 'Disease', (88, 93))	('mutations', 'Var', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
105379	27749841	Importantly, half of the driver mutations (50.0%) that mapped to the branches were within oncogenes, including PIK3CA, KIT, NFE2L2, MTOR and FAM135B.	('NFE2L2', 'Gene', (124, 130))	('MTOR', 'Gene', (132, 136))	('MTOR', 'Gene', '2475', (132, 136))	('PIK3CA', 'Gene', (111, 117))	('FAM135B', 'Gene', (141, 148))	('mutations', 'Var', (32, 41))	('KIT', 'Gene', (119, 122))	('NFE2L2', 'Gene', '4780', (124, 130))	('PIK3CA', 'Gene', '5290', (111, 117))	('FAM135B', 'Gene', '51059', (141, 148))
105380	27749841	For example, TP53 mutations were present in twelve of the thirteen cases, and were truncal in all of the mutated cases, in agreement with recent reports.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
105381	27749841	It is worthwhile to note that potentially actionable mutations such as those targeting PIK3CA and MTOR tended to be oncogenic branch events.	('PIK3CA', 'Gene', '5290', (87, 93))	('MTOR', 'Gene', (98, 102))	('oncogenic branch events', 'CPA', (116, 139))	('mutations', 'Var', (53, 62))	('PIK3CA', 'Gene', (87, 93))	('MTOR', 'Gene', '2475', (98, 102))
105383	27749841	Several driver mutations were subclonal and possibly occurred as late events in ESCC, including MTOR, KEAP1, PTPRB and FAM135B.	('MTOR', 'Gene', '2475', (96, 100))	('KEAP1', 'Gene', (102, 107))	('PTPRB', 'Gene', '5787', (109, 114))	('mutations', 'Var', (15, 24))	('FAM135B', 'Gene', '51059', (119, 126))	('PTPRB', 'Gene', (109, 114))	('KEAP1', 'Gene', '9817', (102, 107))	('MTOR', 'Gene', (96, 100))	('ESCC', 'Disease', (80, 84))	('FAM135B', 'Gene', (119, 126))
105384	27749841	In contrast, cancer genes on the trunks, such as TP53, NOTCH1, CREBBP, KMT2D and ZNF750, were predominantly mutated in a fully clonal manner (Fig.	('mutated', 'Var', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('KMT2D', 'Gene', (71, 76))	('CREBBP', 'Gene', '1387', (63, 69))	('KMT2D', 'Gene', '8085', (71, 76))	('cancer', 'Disease', (13, 19))	('ZNF750', 'Gene', '79755', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('ZNF750', 'Gene', (81, 87))	('NOTCH1', 'Gene', '4851', (55, 61))	('NOTCH1', 'Gene', (55, 61))	('CREBBP', 'Gene', (63, 69))
105385	27749841	Of particularly noteworthy distinction, a number of driver variants detected as clonal within some individual tumor regions, were absent in others from the same individual, producing an "illusion" of clonal dominance.	('producing', 'Reg', (173, 182))	('variants', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
105386	27749841	For example, a PIK3CA hotspot mutation (M1043I) was undetectable in tumor region T2 and T3 in case ESCC13 but was clonally dominant in the other two regions.	('tumor', 'Disease', (68, 73))	('M1043I', 'Mutation', 'rs121913283', (40, 46))	('PIK3CA', 'Gene', '5290', (15, 21))	('M1043I', 'Var', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PIK3CA', 'Gene', (15, 21))
105387	27749841	Likewise, a hotspot mutation in KIT gene (E601K) was present in 100% tumor cells in regions T1 and T3 in case ESCC08, yet was absent in the rest of the tumor regions.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (69, 74))	('KIT', 'Gene', (32, 35))	('tumor', 'Disease', (152, 157))	('E601K', 'Var', (42, 47))	('E601K', 'Mutation', 'p.E601K', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
105389	27749841	Our results suggest that driver mutations can have mixed and complex intratumoral clonal status in ESCC, and that current single-sampling approach may misinterpret these critical genomic lesions because of the "illusion" of clonal dominance.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ESCC', 'Disease', (99, 103))	('mutations', 'Var', (32, 41))	('tumor', 'Disease', (74, 79))
105390	27749841	2, mutations affecting members in PI3K/MTOR pathway, KIT, AURKA and CCND2 were always late events (branched/subclonal).	('AURKA', 'Gene', (58, 63))	('MTOR', 'Gene', (39, 43))	('CCND2', 'Gene', (68, 73))	('KIT', 'Gene', (53, 56))	('MTOR', 'Gene', '2475', (39, 43))	('AURKA', 'Gene', '6790', (58, 63))	('mutations', 'Var', (3, 12))	('CCND2', 'Gene', '894', (68, 73))
105391	27749841	By contrast, variants in ERBB4, FGFR2, BRCA2, ATM and TP53, were mutated as early events (truncal/clonal), suggesting their potentials as candidate actionable targets for ESCC.	('ATM', 'Gene', (46, 49))	('variants', 'Var', (13, 21))	('TP53', 'Gene', (54, 58))	('BRCA2', 'Gene', (39, 44))	('ATM', 'Gene', '472', (46, 49))	('FGFR2', 'Gene', (32, 37))	('ERBB4', 'Gene', '2066', (25, 30))	('TP53', 'Gene', '7157', (54, 58))	('BRCA2', 'Gene', '675', (39, 44))	('FGFR2', 'Gene', '2263', (32, 37))	('ERBB4', 'Gene', (25, 30))
105392	27749841	First, recurrent copy number alterations which involve important cancer genes in ESCC were identified based on our previous results, and we confirmed that the present cohort harbored these recurrent CNAs with similar frequencies (Supplementary Fig.	('copy number alterations', 'Var', (17, 40))	('ESCC', 'Disease', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
105394	27749841	Similarly, deletions of chr9p21.3 (harboring CDKN2A/B) were ubiquitous in some cases but also occurred as heterogeneous aberrations in other samples.	('CDKN2A/B', 'Gene', (45, 53))	('occurred', 'Reg', (94, 102))	('deletions', 'Var', (11, 20))	('CDKN2A/B', 'Gene', '1029;1030', (45, 53))	('chr9p21.3', 'Gene', (24, 33))
105395	27749841	The only driver CNA found as consistently ubiquitous was the copy number gain of 11q13, which encompassed a number of oncogenes including CCND1, ANO1 and CTTN, highlighting the importance of this aberration as a founder genomic lesion in the development of ESCC.	('ANO1', 'Gene', '55107', (145, 149))	('CCND1', 'Gene', '595', (138, 143))	('ANO1', 'Gene', (145, 149))	('copy number gain', 'Var', (61, 77))	('CTTN', 'Gene', (154, 158))	('CCND1', 'Gene', (138, 143))	('CTTN', 'Gene', '2017', (154, 158))
105399	27749841	For example, ATR and TSC1 mutations, which were detected in only 2% of tumor regions (in agreement with previous results), occurred in 7.7% of cases.	('ATR', 'Gene', '545', (13, 16))	('ATR', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TSC1', 'Gene', '7248', (21, 25))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('TSC1', 'Gene', (21, 25))	('occurred', 'Reg', (123, 131))	('tumor', 'Disease', (71, 76))
105406	27749841	As with other cancers, epigenetic abnormalities have been associated with the development and pathogenesis of ESCC.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('epigenetic abnormalities', 'Var', (23, 47))	('ESCC', 'Disease', (110, 114))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
105414	27749841	We observed that a number of TSGs, including EPHA7, PCDH10, DOK1, etc, were hypermethylated at their promoters within some but not all regions of the same case, indicating that their expression might be differentially suppressed in different tumor regions.	('EPHA7', 'Gene', '2045', (45, 50))	('DOK1', 'Gene', (60, 64))	('PCDH10', 'Gene', (52, 58))	('DOK1', 'Gene', '1796', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('PCDH10', 'Gene', '57575', (52, 58))	('EPHA7', 'Gene', (45, 50))	('expression', 'MPA', (183, 193))	('tumor', 'Disease', (242, 247))	('hypermethylated', 'Var', (76, 91))
105415	27749841	Notably, some TSGs were both mutated and acquired promoter hypermethylation, such as ASXL1 and EPHA7.	('EPHA7', 'Gene', (95, 100))	('ASXL1', 'Gene', '171023', (85, 90))	('mutated', 'Var', (29, 36))	('EPHA7', 'Gene', '2045', (95, 100))	('ASXL1', 'Gene', (85, 90))	('promoter hypermethylation', 'MPA', (50, 75))
105430	27749841	For example, in case ESCC13, 282 out of 294 variants (95.9%) were compatible with the evolution model based on the topological structure of the phylogenetic tree; and only 12 mutations, including PIK3CA, were incompatible with the phylogenetic tree (Supplementary Table 6).	('PIK3CA', 'Gene', (196, 202))	('variants', 'Var', (44, 52))	('PIK3CA', 'Gene', '5290', (196, 202))	('ESCC13', 'Gene', (21, 27))
105431	27749841	This observation suggests that these driver mutations were relatively late events during tumor evolution, and contributed to the emergence of distinct subclonal expansions after the founding clones were established.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
105433	27749841	For example, ESCC13 contained branch PIK3CA mutations derived in two spatially separated tumor regions, both harboring the M1043I variant, which is a hotspot mutation.	('PIK3CA', 'Gene', '5290', (37, 43))	('M1043I', 'Mutation', 'rs121913283', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('M1043I', 'Var', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('PIK3CA', 'Gene', (37, 43))
105434	27749841	Similar parallel evolution was also observed in NFE2L2 mutations in ESCC12.	('NFE2L2', 'Gene', (48, 54))	('ESCC12', 'Gene', (68, 74))	('NFE2L2', 'Gene', '4780', (48, 54))	('mutations', 'Var', (55, 64))
105435	27749841	Interestingly, PIK3CA, KIT and NFE2L2 mutations were fully clonal in some tumor regions but were completely absent in others, showing an "illusion" of clonal dominance.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('PIK3CA', 'Gene', '5290', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('NFE2L2', 'Gene', '4780', (31, 37))	('KIT', 'Gene', (23, 26))	('tumor', 'Disease', (74, 79))	('NFE2L2', 'Gene', (31, 37))	('mutations', 'Var', (38, 47))	('PIK3CA', 'Gene', (15, 21))
105438	27749841	Although ESCC DNA methylation alterations have been profiled using single-sampling approaches, their intratumoral diversity and the relationship to genetic lesions remain unknown.	('genetic lesions', 'Disease', (148, 163))	('ESCC DNA', 'Gene', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('alterations', 'Var', (30, 41))	('methylation', 'Var', (18, 29))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('genetic lesions', 'Disease', 'MESH:D020022', (148, 163))	('tumor', 'Disease', (106, 111))
105452	27749841	For cases ESCC01 and ESCC02, whole-exome capture of gDNA was performed by the Beijing Genome Institute (BGI), using the BGI Exome Enrichment Kit, and massively parallel sequencing of captured gDNA was performed and analyzed by BGI using the Complete Genomics platform.	('ESCC01', 'Var', (10, 16))	('ESCC01', 'CellLine', 'CVCL:R804', (10, 16))	('ESCC02', 'Var', (21, 27))
105459	27749841	For mutations that have been detected from at least one tumor region, a method described by Stachler et al.	('mutations', 'Var', (4, 13))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))
105460	27749841	was used to increase the sensitivity of detecting these mutations in other tumor regions from the same individual with low VAF.	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
105464	27749841	Tumor cellularity was determined based on the VAF and segmented copy number data using ABSOLUTE, in order to determine the cancer cell fraction (CCF) of each mutation, as was previously described by McGranahan et al..	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor', 'Disease', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutation', 'Var', (158, 166))	('cancer', 'Disease', (123, 129))
105466	27749841	Next, non-silent variants in these genes were evaluated, and putative driver mutations were identified if they met one of the following requirements: i) Either the exact mutation, the same mutation site or at least three mutations located within 15 bp around the variant were found in COSMIC; ii) If the candidate gene was remarked to be recessive in COSMIC, and the variant was predicted to be deleterious, including stopgain, frameshift and splicing mutation and, had a SIFT score < 0.05 or a Polyphen score > 0.995.	('SIFT', 'Disease', 'None', (472, 476))	('splicing', 'MPA', (443, 451))	('frameshift', 'Var', (428, 438))	('stopgain', 'Disease', (418, 426))	('SIFT', 'Disease', (472, 476))
105477	27749841	As demonstrated in several TCGA marker papers, performing an analysis using only the subset of Infinium probes that are unmethylated in purified leukocyte cells, and dichotomizing/binarizing the tumor beta value of these probes with a minimum beta value cutoff, could minimize the influence of contaminating leukocytes.	('dichotomizing/binarizing', 'Var', (166, 190))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (195, 200))
105556	31886099	Radiotherapy may lead to fibrosis of the lung or of the myocardium, and thus to disorders of the conduction system and also to pericarditis.	('pericarditis', 'Phenotype', 'HP:0001701', (127, 139))	('disorders', 'Disease', (80, 89))	('fibrosis of the lung', 'Disease', 'MESH:D005355', (25, 45))	('fibrosis of the lung', 'Phenotype', 'HP:0002206', (25, 45))	('lead to', 'Reg', (17, 24))	('conduction system', 'MPA', (97, 114))	('Radiotherapy', 'Var', (0, 12))	('fibrosis of the lung', 'Disease', (25, 45))	('pericarditis', 'Disease', 'MESH:D010493', (127, 139))	('pericarditis', 'Disease', (127, 139))
105649	28778650	In a first cross-sectional prospective study, the yield of neoplasia in the AFI-targeted biopsies was significantly higher than WLE-targeted + random biopsies.	('AFI-targeted', 'Var', (76, 88))	('higher', 'PosReg', (116, 122))	('neoplasia', 'Disease', 'MESH:D009369', (59, 68))	('neoplasia', 'Disease', (59, 68))	('neoplasia', 'Phenotype', 'HP:0002664', (59, 68))
105670	28778650	Curative EMR is associated with lesions with Paris types I (polypoid), IIa (slightly elevated), IIb (flat), and IIc (slightly depressed), lesion < 20 mm, histological grades G1 and G2 and/or high-grade dysplasia in biopsy.	('dysplasia', 'Disease', (202, 211))	('high-grade', 'Disease', (191, 201))	('lesion < 20 mm', 'Var', (138, 152))	('dysplasia', 'Disease', 'MESH:D004476', (202, 211))
105678	28778650	In contrast, the risk of lymph-nodal metastasis in T1a m3 and T1b sm1 SCC i is significantly higher.	('higher', 'PosReg', (93, 99))	('lymph-nodal metastasis', 'Disease', (25, 47))	('sm1', 'Gene', (66, 69))	('SCC', 'Gene', (70, 73))	('lymph-nodal metastasis', 'Disease', 'MESH:D009362', (25, 47))	('SCC', 'Gene', '6317', (70, 73))	('T1a m3', 'Var', (51, 57))	('sm1', 'Gene', '7911', (66, 69))
105682	28778650	ESD has been studied as a resection technique to achieve en-bloc resection of BE-related neoplastic lesions, particularly with lesions > 15 mm, poorly lifting lesions, and lesions at risk for submucosal invasion.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (89, 107))	('neoplastic lesions', 'Disease', 'MESH:D051437', (89, 107))	('BE', 'Phenotype', 'HP:0100580', (78, 80))	('neoplastic lesions', 'Disease', (89, 107))	('lesions > 15 mm', 'Var', (127, 142))
105702	28778650	Importantly, RFA can significantly reduce the risk of progression of LGD and HGD to EA.	('LGD', 'Disease', (69, 72))	('HGD', 'Gene', '3081', (77, 80))	('RFA', 'Var', (13, 16))	('HGD', 'Gene', (77, 80))	('reduce', 'NegReg', (35, 41))	('EA', 'Phenotype', 'HP:0011459', (84, 86))
105725	28778650	For early ESCC, surgery may be elected in young and fit patients also for T1a m3 and T1b sm1.	('sm1', 'Gene', (89, 92))	('patients', 'Species', '9606', (56, 64))	('SCC', 'Gene', (11, 14))	('T1b', 'Var', (85, 88))	('T1a', 'Var', (74, 77))	('SCC', 'Gene', '6317', (11, 14))	('sm1', 'Gene', '7911', (89, 92))
105758	29115542	In a second step, tumor-type specific TMAs with clinical follow-up data were utilized to evaluate the clinical significance of IMP3 alterations in five selected tumor entities.	('IMP3', 'Gene', (127, 131))	('tumor', 'Disease', (18, 23))	('TMAs', 'Chemical', '-', (38, 42))	('alterations', 'Var', (132, 143))	('IMP3', 'Gene', '55272', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
105818	29115542	In earlier studies we had used multi-tumor TMAs for the evaluation of cyclin E, calretinin, KIT, ERG or copy number changes of 17q23.	('copy number changes', 'Var', (104, 123))	('TMAs', 'Chemical', '-', (43, 47))	('multi-tumor TMA', 'Disease', (31, 46))	('multi-tumor TMA', 'Disease', 'MESH:D015140', (31, 46))	('ERG', 'Gene', '2078', (97, 100))	('cyclin E', 'Protein', (70, 78))	('calretinin', 'Gene', (80, 90))	('KIT', 'Protein', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('ERG', 'Gene', (97, 100))	('calretinin', 'Gene', '794', (80, 90))
105858	25029906	Patients with abnormal TAZ or beta-catenin expression of AEG exhibited a shorter overall survival (OS) and lower overall survival rate than those with normal TAZ or beta-catenin expression (P < 0.05).	('overall survival rate', 'MPA', (113, 134))	('beta-catenin', 'Gene', '1499', (30, 42))	('abnormal', 'Var', (14, 22))	('lower', 'NegReg', (107, 112))	('beta-catenin', 'Gene', '1499', (165, 177))	('shorter', 'NegReg', (73, 80))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (81, 97))	('beta-catenin', 'Gene', (30, 42))	('AEG', 'Chemical', '-', (57, 60))	('beta-catenin', 'Gene', (165, 177))
105859	25029906	In addition, patients with abnormal expression of both TAZ and beta-catenin exhibited worst overall survival.	('beta-catenin', 'Gene', (63, 75))	('abnormal', 'Var', (27, 35))	('worst', 'NegReg', (86, 91))	('patients', 'Species', '9606', (13, 21))	('beta-catenin', 'Gene', '1499', (63, 75))	('overall', 'MPA', (92, 99))	('TAZ', 'Protein', (55, 58))
105860	25029906	In multivariate survival analysis, abnormal expression of TAZ, TAZ & beta-catenin (nuclear and membranous) and tumour differentiation were found to be independent prognostic factors related to OS of AEG patients.	('AEG', 'Chemical', '-', (199, 202))	('factors', 'Reg', (174, 181))	('abnormal', 'Var', (35, 43))	('beta-catenin', 'Gene', (69, 81))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('TAZ', 'Gene', (58, 61))	('beta-catenin', 'Gene', '1499', (69, 81))	('patients', 'Species', '9606', (203, 211))	('to OS of', 'Disease', (190, 198))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (111, 117))
105882	25029906	In some human cancers, mutation of either the APC gene or the beta-catenin gene itself leads to the accumulation of beta-catenin within the cancer cells .	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('APC', 'Phenotype', 'HP:0005227', (46, 49))	('APC', 'Disease', 'MESH:D011125', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('APC', 'Disease', (46, 49))	('human', 'Species', '9606', (8, 13))	('beta-catenin', 'Gene', (62, 74))	('cancer', 'Disease', (140, 146))	('beta-catenin', 'Gene', '1499', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('beta-catenin', 'Gene', (116, 128))	('beta-catenin', 'Gene', '1499', (116, 128))	('cancer', 'Disease', (14, 20))	('cancers', 'Disease', (14, 21))	('mutation', 'Var', (23, 31))	('accumulation', 'PosReg', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))
105890	25029906	The activated hippo pathway can reduce stability and transcriptional activity in nuclear of beta-catenin by phosphorylation of YAP and TAZ .	('YAP', 'Gene', (127, 130))	('reduce', 'NegReg', (32, 38))	('nuclear of', 'MPA', (81, 91))	('YAP', 'Gene', '10413', (127, 130))	('hippo pathway', 'Pathway', (14, 27))	('beta-catenin', 'Gene', (92, 104))	('stability', 'MPA', (39, 48))	('beta-catenin', 'Gene', '1499', (92, 104))	('transcriptional activity', 'MPA', (53, 77))	('phosphorylation', 'Var', (108, 123))
105944	25029906	The tumour sizes of abnormal expression membranous beta-catenin was 4.89 +- 1.758 centimeter and the normal one was 4.83 +- 2.059 centimeter, P = 0.863.	('abnormal', 'Var', (20, 28))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('beta-catenin', 'Gene', '1499', (51, 63))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('beta-catenin', 'Gene', (51, 63))
105946	25029906	Patients with abnormal expression tumour exhibited a shorter OS than those with normal one.	('abnormal', 'Var', (14, 22))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
105947	25029906	Moreover, patients with both TAZ and beta-catenin (nuclear and membranous) abnormal expression exhibited the worst survival (mean of 21.2 +- 3.0 months and median of 19 months).	('beta-catenin', 'Gene', (37, 49))	('abnormal expression', 'Var', (75, 94))	('beta-catenin', 'Gene', '1499', (37, 49))	('patients', 'Species', '9606', (10, 18))
105970	25029906	There was also a report that TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin .	('growth factor-independent proliferation', 'CPA', (41, 80))	('EGFR', 'Gene', '1956', (103, 107))	('TAZ', 'Var', (29, 32))	('amphiregulin', 'Gene', (115, 127))	('EGFR', 'Gene', (103, 107))	('activation', 'PosReg', (89, 99))	('amphiregulin', 'Gene', '374', (115, 127))
105979	25029906	Furthermore, abnormal expression of membranous beta-catenin was correlated with lymph node matastisis and invasion of serosa.	('beta-catenin', 'Gene', '1499', (47, 59))	('lymph node matastisis', 'Disease', (80, 101))	('lymph node matastisis', 'Disease', 'MESH:D000072717', (80, 101))	('invasion of serosa', 'CPA', (106, 124))	('beta-catenin', 'Gene', (47, 59))	('correlated', 'Reg', (64, 74))	('abnormal', 'Var', (13, 21))	('expression', 'MPA', (22, 32))
105983	25029906	We believe that the abnormal TAZ or beta-catenin expression in tumour cells promotes tumour cell EMT and, therefore, facilitates tumour cell migration and metastasis into the lymphatic vessels.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('abnormal', 'Var', (20, 28))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('metastasis into the lymphatic vessels', 'CPA', (155, 192))	('facilitates', 'PosReg', (117, 128))	('EMT', 'Gene', (97, 100))	('TAZ', 'Protein', (29, 32))	('tumour', 'Disease', (85, 91))	('beta-catenin', 'Gene', (36, 48))	('tumour', 'Disease', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('EMT', 'Gene', '3702', (97, 100))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('promotes', 'PosReg', (76, 84))	('beta-catenin', 'Gene', '1499', (36, 48))	('tumour', 'Disease', (63, 69))
105989	25029906	Consistently, in our study the Kaplan-Meier survival analysis revealed that patients with abnormal expression of TAZ or beta-catenin (nuclear or membranous) expression showed worse OS than those with normal TAZ or beta-catenin expression.	('beta-catenin', 'Gene', '1499', (120, 132))	('patients', 'Species', '9606', (76, 84))	('TAZ', 'Gene', (113, 116))	('abnormal', 'Var', (90, 98))	('beta-catenin', 'Gene', (214, 226))	('beta-catenin', 'Gene', '1499', (214, 226))	('beta-catenin', 'Gene', (120, 132))
105990	25029906	Further still, patients with abnormal expression of both TAZ and beta-catenin (nuclear and membranous) exhibited the worst overall survival.	('worst', 'NegReg', (117, 122))	('patients', 'Species', '9606', (15, 23))	('beta-catenin', 'Gene', '1499', (65, 77))	('abnormal', 'Var', (29, 37))	('TAZ', 'Protein', (57, 60))	('beta-catenin', 'Gene', (65, 77))
105997	25029906	We also provided convincing evidence that abnormal expression of TAZ or beta-catenin was correlated with the poor prognosis of patients with AEG.	('beta-catenin', 'Gene', (72, 84))	('abnormal', 'Var', (42, 50))	('AEG', 'Chemical', '-', (141, 144))	('beta-catenin', 'Gene', '1499', (72, 84))	('patients', 'Species', '9606', (127, 135))	('expression', 'MPA', (51, 61))	('correlated', 'Reg', (89, 99))	('TAZ', 'Protein', (65, 68))
105998	25029906	Moreover, abnormal expression of TAZ and TAZ & beta-catenin (nuclear and membranous) could be independent predictors of prognosis in AEG, so targeting TAZ and beta-catenin could prove to be a promising therapeutic strategy for the treatment of AEG.	('beta-catenin', 'Gene', '1499', (47, 59))	('beta-catenin', 'Gene', (159, 171))	('expression', 'MPA', (19, 29))	('abnormal', 'Var', (10, 18))	('beta-catenin', 'Gene', '1499', (159, 171))	('AEG', 'Chemical', '-', (244, 247))	('beta-catenin', 'Gene', (47, 59))	('AEG', 'Chemical', '-', (133, 136))
106012	23894350	Like other types of cancers, the development of ESCC is also believed as a multiple-step process caused by the accumulation of activation of oncogenes and inactivation of tumor suppressor genes (TSG).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('oncogenes', 'Protein', (141, 150))	('cancers', 'Disease', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('inactivation', 'Var', (155, 167))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('activation', 'PosReg', (127, 137))	('tumor', 'Disease', (171, 176))	('ESCC', 'Disease', (48, 52))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
106017	23894350	Although CRNN has been reported to be downregulated in esophageal adenocarcinoma (EAC) or ESCC, and genetic variants of CRNN appeared to interacte with tobacco smoking that contributes to the risk for ESCC, the precise mechanism underlying the involvement of CRNN in ESCC remains to be elucidated.	('interacte', 'Reg', (137, 146))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('esophageal adenocarcinoma', 'Disease', (55, 80))	('CRNN', 'Gene', (120, 124))	('CRNN', 'Protein', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('variants', 'Var', (108, 116))	('downregulated', 'NegReg', (38, 51))	('genetic variants', 'Var', (100, 116))	('ESCC', 'Disease', (201, 205))	('ESCC', 'Disease', (90, 94))	('tobacco', 'Species', '4097', (152, 159))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (55, 80))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (55, 80))
106048	23894350	CRNN-expressing clones CRNN-C2, C3 (KYSE30) or CRNN-C1 (KYSE180) were transfected with double-stranded siRNAs (Ambion, Carlsbad, CA) with lipofectamine 2000TM reagent (Invitrogen) according to the manufacturer's instructions.	('CRNN-C2', 'Disease', 'OMIM:217000', (23, 30))	('KYSE180', 'Var', (56, 63))	('CRNN-C2', 'Disease', (23, 30))	('lipofectamine 2000TM', 'Chemical', '-', (138, 158))	('CRNN-C1', 'Gene', (47, 54))	('KYSE30', 'Var', (36, 42))
106063	23894350	Stably CRNN-expressing clones from KYSE30 (CRNN-C2 and CRNN-C3) and from KYSE180 (CRNN-C1) were selected.	('KYSE30', 'Var', (35, 41))	('CRNN-C2', 'Disease', (43, 50))	('CRNN-C2', 'Disease', 'OMIM:217000', (43, 50))	('KYSE180', 'Var', (73, 80))
106066	23894350	To further explore the in vivo tumor suppressive ability of CRNN, tumor formation in nude mice was carried out by the injection of CRNN-C2 (KYSE30), CRNN-C1 (KYSE180), whereas Vec-30 and Vec-180 were used as controls.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (66, 71))	('KYSE30', 'Var', (140, 146))	('tumor', 'Disease', (31, 36))	('nude mice', 'Species', '10090', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CRNN-C2', 'Disease', 'OMIM:217000', (131, 138))	('CRNN-C2', 'Disease', (131, 138))
106075	23894350	Soft-agar assay results demonstrated that the number of colonies formed in soft agar increased in CRNN knock-down cells compared with scramble control cells (Figure 4D).	('CRNN', 'Gene', (98, 102))	('knock-down', 'Var', (103, 113))	('increased', 'PosReg', (85, 94))	('agar', 'Chemical', 'MESH:D000362', (80, 84))	('agar', 'Chemical', 'MESH:D000362', (5, 9))
106082	23894350	Loss of heterozygosity (LOH) at 1q21 region has been frequently detected in various solid tumors, including esophageal squamous cell carcinoma, breast cancer, insulinoma and esophageal adenocarcinoma.	('insulinoma and esophageal adenocarcinoma', 'Disease', 'MESH:D007340', (159, 199))	('insulinoma', 'Phenotype', 'HP:0012197', (159, 169))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('Loss of heterozygosity', 'Var', (0, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('solid tumors', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (108, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('detected', 'Reg', (64, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('solid tumors', 'Disease', (84, 96))	('esophageal squamous cell carcinoma', 'Disease', (108, 142))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (174, 199))
106083	23894350	Interestingly, loss of 1q21 has been associated with tumor malignancy and shorter overall survival.	('shorter', 'NegReg', (74, 81))	('tumor malignancy', 'Disease', 'MESH:D018198', (53, 69))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('loss of', 'Var', (15, 22))	('1q21', 'Gene', (23, 27))	('tumor malignancy', 'Disease', (53, 69))	('overall', 'MPA', (82, 89))
106093	23894350	It was reported that p53 could be activated by DNA damage in KYSE30 with mutant p53 as other ESCC cell line with wide-type p53.	('p53', 'Gene', (80, 83))	('p53', 'Gene', '7157', (21, 24))	('mutant', 'Var', (73, 79))	('p53', 'Gene', '7157', (80, 83))	('p53', 'Gene', (123, 126))	('activated', 'PosReg', (34, 43))	('p53', 'Gene', '7157', (123, 126))	('p53', 'Gene', (21, 24))
106098	23894350	Therefore, the expression of CRNN protein will presumably help maintain the barrier function in squamous epithelium in response to injury and function as a tumor suppressor.	('expression', 'Var', (15, 25))	('barrier function', 'MPA', (76, 92))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('injury', 'Disease', (131, 137))	('tumor', 'Disease', (156, 161))	('CRNN', 'Protein', (29, 33))	('injury', 'Disease', 'MESH:D058186', (131, 137))	('maintain', 'Reg', (63, 71))
106100	23894350	A better understanding of the tumor suppressive role of CRNN will significantly improve our knowledge in the development of ESCC, and may lead to a more effective management of ESCC patients with the inactivation of CRNN.	('tumor', 'Disease', (30, 35))	('improve', 'PosReg', (80, 87))	('CRNN', 'Protein', (216, 220))	('ESCC', 'Disease', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('patients', 'Species', '9606', (182, 190))	('inactivation', 'Var', (200, 212))	('lead to', 'Reg', (138, 145))	('ESCC', 'Disease', (124, 128))
106111	33652796	Currently, the definition also includes an aneurysmatic origin of an aberrant left subclavian artery from a right-sided aortic arch, and it may also be present in patients with a double aortic arch.	('patients', 'Species', '9606', (163, 171))	('aneurysmatic origin', 'Phenotype', 'HP:0002617', (43, 62))	('aberrant left subclavian artery', 'Phenotype', 'HP:0031014', (69, 100))	('right-sided aortic arch', 'Phenotype', 'HP:0012020', (108, 131))	('double aortic arch', 'Phenotype', 'HP:0011590', (179, 197))	('aberrant', 'Var', (69, 77))	('aneurysmatic', 'Disease', 'None', (43, 55))	('aneurysmatic', 'Disease', (43, 55))
106114	33652796	(Congress abstract data, American Cardiology College 2015) showed that in 863 patients who were identified with an aberrant subclavian artery, that a Kommerell's diverticulum was observed in 14% (n = 121), and of those patients 60% (n = 73) had a right-sided aortic arch and aberrant left subclavian artery.	('aberrant subclavian artery', 'Phenotype', 'HP:0031014', (115, 141))	('aberrant left subclavian artery', 'Phenotype', 'HP:0031014', (275, 306))	('aberrant', 'Var', (115, 123))	('patients', 'Species', '9606', (78, 86))	("Kommerell's diverticulum", 'Phenotype', 'HP:0011593', (150, 174))	('patients', 'Species', '9606', (219, 227))	('right-sided aortic arch', 'Phenotype', 'HP:0012020', (247, 270))	('Kommerell', 'Disease', (150, 159))
106176	33586360	The most common treatment-related adverse events of grade 3 or 4 were hypertension (17 [16%] patients), decreased appetite (6 [6%] patients), and hyponatremia (4 [4%] patients) in the anlotinib group and decreased appetite (2 [4%] patients) in the placebo group.	('patients', 'Species', '9606', (131, 139))	('hyponatremia', 'Phenotype', 'HP:0002902', (146, 158))	('appetite', 'MPA', (114, 122))	('hyponatremia', 'Disease', (146, 158))	('patients', 'Species', '9606', (231, 239))	('hyponatremia', 'Disease', 'MESH:D007010', (146, 158))	('anlotinib', 'Chemical', 'MESH:C000625192', (184, 193))	('decreased appetite', 'Phenotype', 'HP:0004396', (104, 122))	('anlotinib', 'Var', (184, 193))	('patients', 'Species', '9606', (167, 175))	('decreased', 'NegReg', (104, 113))	('decreased appetite', 'Phenotype', 'HP:0004396', (204, 222))	('hypertension', 'Disease', 'MESH:D006973', (70, 82))	('hypertension', 'Disease', (70, 82))	('patients', 'Species', '9606', (93, 101))	('hypertension', 'Phenotype', 'HP:0000822', (70, 82))
106177	33586360	Three (3%) deaths in the anlotinib group were considered as drug related, while there were no treatment-related deaths in the placebo group.	('anlotinib', 'Chemical', 'MESH:C000625192', (25, 34))	('deaths', 'Disease', 'MESH:D003643', (11, 17))	('anlotinib', 'Var', (25, 34))	('deaths', 'Disease', 'MESH:D003643', (112, 118))	('deaths', 'Disease', (112, 118))	('deaths', 'Disease', (11, 17))
106189	33586360	The Cancer Oesophagus Gefitinib (COG) trial, the first randomized phase 3 study of systemic targeted therapy in patients with advanced esophageal cancer progressing after chemotherapy, demonstrated that the overall survival did not improve by gefitinib compared to placebo.	('Gefitinib', 'Chemical', 'MESH:D000077156', (22, 31))	('gefitinib', 'Var', (243, 252))	('patients', 'Species', '9606', (112, 120))	('esophageal cancer', 'Disease', (135, 152))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('gefitinib', 'Chemical', 'MESH:D000077156', (243, 252))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('COG', 'Chemical', '-', (33, 36))
106190	33586360	5  More recently, three randomized phase 3 trials reported the promising efficacies of anti-PD-1 antibodies in second-line setting in patients with advanced esophageal cancer as compared with chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('antibodies', 'Var', (97, 107))	('patients', 'Species', '9606', (134, 142))	('esophageal cancer', 'Disease', (157, 174))	('anti-PD-1 antibodies', 'Var', (87, 107))
106193	33586360	7 ,  8  It is noteworthy that despite the longer overall survival in anti-PD-1 antibody group compared to chemotherapy group observed in these trials, only part of the patients could be benefit from the treatments.	('patients', 'Species', '9606', (168, 176))	('antibody', 'Var', (79, 87))	('longer', 'PosReg', (42, 48))	('anti-PD-1 antibody', 'Var', (69, 87))
106220	33586360	The median age of patients was 62 years in the anlotinib group and 61 years in the placebo group.	('age', 'Gene', (11, 14))	('anlotinib', 'Chemical', 'MESH:C000625192', (47, 56))	('patients', 'Species', '9606', (18, 26))	('age', 'Gene', '5973', (11, 14))	('anlotinib', 'Var', (47, 56))
106223	33586360	The proportion of patients who received previous tumor surgery was 79% in anlotinib group and 60% in placebo group.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('anlotinib', 'Chemical', 'MESH:C000625192', (74, 83))	('tumor', 'Disease', (49, 54))	('patients', 'Species', '9606', (18, 26))	('anlotinib', 'Var', (74, 83))
106229	33586360	The PFS, as assessed by investigator, was longer in patients receiving anlotinib compared to those receiving placebo (HR 0.46 [95% CI 0.32-0.66]; p < 0.001; Figure 2A).	('longer', 'PosReg', (42, 48))	('PFS', 'MPA', (4, 7))	('anlotinib', 'Chemical', 'MESH:C000625192', (71, 80))	('anlotinib', 'Var', (71, 80))	('patients', 'Species', '9606', (52, 60))
106237	33586360	The DCR was significantly higher in anlotinib group than that in placebo (70 [64%] out of 109 patients vs. 10 [18%] out of 55 patients, p < 0.001), with a higher proportion of patients achieving stable disease in the anlotinib group (62 [57%] out of 109 patients vs. eight [15%] out of 55 patients).	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (94, 102))	('higher', 'PosReg', (26, 32))	('DCR', 'Chemical', '-', (4, 7))	('anlotinib', 'Chemical', 'MESH:C000625192', (36, 45))	('patients', 'Species', '9606', (126, 134))	('anlotinib', 'Var', (36, 45))	('anlotinib', 'Chemical', 'MESH:C000625192', (217, 226))	('patients', 'Species', '9606', (254, 262))	('DCR', 'MPA', (4, 7))	('patients', 'Species', '9606', (289, 297))
106245	33586360	Grade 3 or 4 treatment-related bleeding was rare, with only two cases (2%) of hemoptysis observed in the anlotinib group and none in the placebo group.	('hemoptysis', 'Phenotype', 'HP:0002105', (78, 88))	('anlotinib', 'Var', (105, 114))	('hemoptysis', 'Disease', (78, 88))	('bleeding', 'Disease', 'MESH:D006470', (31, 39))	('anlotinib', 'Chemical', 'MESH:C000625192', (105, 114))	('bleeding', 'Disease', (31, 39))	('hemoptysis', 'Disease', 'MESH:D006469', (78, 88))
106254	33586360	Our data revealed that anlotinib might significantly prolong the PFS by 1.6 months (3.02 vs. 1.41 months) with a HR of 0.46 in patients with previously treated recurrent or metastatic ESCC.	('PFS', 'MPA', (65, 68))	('prolong', 'PosReg', (53, 60))	('anlotinib', 'Chemical', 'MESH:C000625192', (23, 32))	('patients', 'Species', '9606', (127, 135))	('anlotinib', 'Var', (23, 32))	('ESCC', 'Disease', (184, 188))
106259	33586360	6 ,  7 ,  8  The present study showed that anlotinib might lead to a median PFS of 3.0 months in patients with chemotherapy-refractory metastatic ESCC, with a clinically meaningful 1.6 months longer than that in patients given placebo.	('patients', 'Species', '9606', (212, 220))	('lead to', 'Reg', (59, 66))	('anlotinib', 'Chemical', 'MESH:C000625192', (43, 52))	('metastatic ESCC', 'Disease', (135, 150))	('PFS', 'MPA', (76, 79))	('anlotinib', 'Var', (43, 52))	('patients', 'Species', '9606', (97, 105))
106268	33586360	First of all, the ratio of patients with metastatic sites of >=2 was higher in anlotinib (85%) than that in placebo (75%).	('anlotinib', 'Var', (79, 88))	('patients', 'Species', '9606', (27, 35))	('higher', 'PosReg', (69, 75))	('anlotinib', 'Chemical', 'MESH:C000625192', (79, 88))
106273	33586360	The incidence of grade 3 or worse AEs was more frequent in the anlotinib group than that in the placebo group (39% vs. 11%).	('anlotinib', 'Var', (63, 72))	('AEs', 'Disease', (34, 37))	('anlotinib', 'Chemical', 'MESH:C000625192', (63, 72))
106306	29344243	Therefore, targeting TIM-3 could reduce the risk of adverse autoimmune-like toxicity.	('TIM-3', 'Gene', (21, 26))	('TIM-3', 'Gene', '84868', (21, 26))	('toxicity', 'Disease', 'MESH:D064420', (76, 84))	('toxicity', 'Disease', (76, 84))	('targeting', 'Var', (11, 20))
106307	29344243	In addition, it has been demonstrated that the knockdown of TIM-3 in tumor cells can weaken their proliferative and invasive ability.	('TIM-3', 'Gene', '84868', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('weaken', 'NegReg', (85, 91))	('tumor', 'Disease', (69, 74))	('knockdown', 'Var', (47, 56))	('TIM-3', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
106310	29344243	Of these ligands, TIM-3 deficiency decreased the galectin-9-mediated apoptosis of Th1 cells by ~40%, which indicates that galectin-9 has multiple target molecules in addition to TIM-3.	('TIM-3', 'Gene', (18, 23))	('TIM-3', 'Gene', '84868', (178, 183))	('TIM-3', 'Gene', (178, 183))	('galectin-9', 'Gene', '3965', (49, 59))	('TIM-3', 'Gene', '84868', (18, 23))	('galectin-9', 'Gene', (122, 132))	('deficiency', 'Var', (24, 34))	('decreased', 'NegReg', (35, 44))	('galectin-9', 'Gene', (49, 59))	('galectin-9', 'Gene', '3965', (122, 132))
106357	29344243	A study by Cao et al revealed that the migratory and invasive ability of HeLa cells was markedly reduced by the knockdown of TIM-3 expression, demonstrating that TIM-3 expression may be associated with tumor metastasis.	('TIM-3', 'Gene', (125, 130))	('tumor metastasis', 'Disease', (202, 218))	('TIM-3', 'Gene', (162, 167))	('tumor metastasis', 'Disease', 'MESH:D009362', (202, 218))	('TIM-3', 'Gene', '84868', (162, 167))	('reduced', 'NegReg', (97, 104))	('TIM-3', 'Gene', '84868', (125, 130))	('knockdown', 'Var', (112, 121))	('associated', 'Reg', (186, 196))	('HeLa', 'CellLine', 'CVCL:0030', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
106383	28454382	The tumor formation induced by 4NQO is tissue-specific.	('tumor', 'Disease', (4, 9))	('4NQO', 'Var', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('4NQO', 'Chemical', 'MESH:D015112', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
106384	28454382	Lung cancer, for example, can be induced by subcutaneous injection of 4NQO, while oral tumors can be induced by oral administration of 4NQO.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('4NQO', 'Var', (70, 74))	('oral tumors', 'Phenotype', 'HP:0100649', (82, 93))	('induced', 'Reg', (33, 40))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('oral tumors', 'Disease', 'MESH:D020820', (82, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('Lung cancer', 'Disease', (0, 11))	('4NQO', 'Chemical', 'MESH:D015112', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('4NQO', 'Chemical', 'MESH:D015112', (135, 139))	('oral tumors', 'Disease', (82, 93))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
106385	28454382	However, the study of esophageal precancerous lesions induced by 4NQO remains undetermined.	('4NQO', 'Var', (65, 69))	('esophageal precancerous lesions', 'Disease', (22, 53))	('4NQO', 'Chemical', 'MESH:D015112', (65, 69))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (22, 53))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
106387	28454382	In 2003, B7-H4, a type-I transmembrane protein, was identified by three different laboratories simultaneously, and was assigned three different names: B7-H4, B7s1 and B7x.	('B7s1', 'Gene', (158, 162))	('B7-H4', 'Var', (151, 156))	('B7s1', 'Gene', '242122', (158, 162))
106388	28454382	More recently, it was reported that B7-H4 messenger RNA was broadly expressed in human peripheral tissues, while B7-H4 protein expression was confined only to certain tumor tissues or cancer cells, including lung, ovarian, prostate, melanoma, stomach, breast and kidney cancer.	('cancer', 'Disease', (184, 190))	('ovarian', 'Disease', 'MESH:D010051', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('lung', 'Disease', (208, 212))	('prostate', 'Disease', (223, 231))	('human', 'Species', '9606', (81, 86))	('stomach', 'Disease', (243, 250))	('B7-H4', 'Var', (36, 41))	('cancer', 'Disease', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('kidney cancer', 'Phenotype', 'HP:0009726', (263, 276))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('breast and kidney cancer', 'Disease', 'MESH:D001943', (252, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ovarian', 'Disease', (214, 221))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('melanoma', 'Disease', (233, 241))
106390	28454382	In addition, it was suggested that B7-H4 was overexpressed in SCC, which was positively correlated with tumor progression and a poor prognosis, and that B7-H4 facilitated SCC cell proliferation; however, the expression of B7-H4 in esophageal precancerous conditions has not been investigated to date.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('correlated', 'Reg', (88, 98))	('SCC', 'Disease', (62, 65))	('overexpressed', 'PosReg', (45, 58))	('tumor', 'Disease', (104, 109))	('esophageal precancerous conditions', 'Disease', 'MESH:D011230', (231, 265))	('esophageal precancerous conditions', 'Disease', (231, 265))	('B7-H4', 'Var', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('facilitated', 'PosReg', (159, 170))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
106405	28454382	Sections were incubated with primary antibodies against B7-H4 (1:500; GTX62090; GeneTex, Inc., Irvine, CA, USA), CD4 (1:50; orb4241; Biorbyt, Ltd., Cambridge, UK), CD8 (1:50; orb10325; Biorbyt, Ltd.) or CD11b (1:100; cb1211; Abcam, Shanghai, China) at 4 C overnight.	('CD8', 'Gene', (164, 167))	('CD8', 'Gene', '925', (164, 167))	('CD11b (1:100; cb1211', 'Var', (203, 223))	('1:100; cb1211;', 'Var', (210, 224))
106406	28454382	The prevalence of CD4+T, CD8+T or CD11b+ macrophage cells was semi-quantitatively evaluated according to the number of each type of cells present per vision field (magnification, x400).	('CD8', 'Gene', (25, 28))	('CD8', 'Gene', '925', (25, 28))	('CD4+T', 'Var', (18, 23))	('CD11b+', 'Var', (34, 40))
106421	28454382	Firstly, with the prolongation of the time of inducing cancer, the physical conditions of 4NQO model mice became poor, and their body weight increased more slowly compared with that of control mice (Fig.	('slowly', 'NegReg', (156, 162))	('body weight', 'CPA', (129, 140))	('increased', 'PosReg', (141, 150))	('4NQO model', 'Var', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mice', 'Species', '10090', (193, 197))	('mice', 'Species', '10090', (101, 105))	('body weight increased', 'Phenotype', 'HP:0004324', (129, 150))	('4NQO', 'Chemical', 'MESH:D015112', (90, 94))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
106434	28454382	Overall, these findings indicated that 4NQO was a carcinogen able to induce SCC formation in mice, and the precancerous conditions exacerbated with increased time of induction.	('SCC formation', 'CPA', (76, 89))	('4NQO', 'Chemical', 'MESH:D015112', (39, 43))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('4NQO', 'Var', (39, 43))	('mice', 'Species', '10090', (93, 97))	('induce', 'PosReg', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
106443	28454382	Thus, the present data suggested that B7-H4 probably is important in promoting the progression of esophageal precancerous lesions, which may be attributed to its association with certain type of cytokines secreted by macrophages.	('promoting', 'PosReg', (69, 78))	('B7-H4', 'Var', (38, 43))	('esophageal precancerous lesions', 'Disease', (98, 129))	('association', 'Interaction', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (98, 129))
106449	28454382	Therefore, the present data supported the hypothesis that B7-H4 participated in the formation of esophageal precancerous lesions via interaction with the IL-6, IL-10, TGF-beta or STAT3 signal transduction pathways.	('interaction', 'Interaction', (133, 144))	('IL-10', 'Gene', '16153', (160, 165))	('participated', 'Reg', (64, 76))	('esophageal precancerous lesions', 'Disease', (97, 128))	('B7-H4', 'Var', (58, 63))	('IL-10', 'Gene', (160, 165))	('TGF-beta', 'Gene', '21803', (167, 175))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (97, 128))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('IL-6', 'Gene', (154, 158))	('STAT3', 'Gene', '20848', (179, 184))	('IL-6', 'Gene', '16193', (154, 158))	('STAT3', 'Gene', (179, 184))	('TGF-beta', 'Gene', (167, 175))
106459	28454382	Although Tang et al and Tseng et al have reported that 4NQO could induce SCC in mice, the present study is the first to profile in detail the precancerous conditions in esophageal carcinogenesis.	('cancer', 'Disease', (145, 151))	('4NQO', 'Var', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (169, 194))	('4NQO', 'Chemical', 'MESH:D015112', (55, 59))	('mice', 'Species', '10090', (80, 84))	('esophageal carcinogenesis', 'Disease', (169, 194))	('SCC', 'Disease', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
106464	28454382	Overall, the present results suggested that the function of B7-H4 in inhibiting T cell proliferation or inducing T cell apoptosis to mediate tumor escape was limited during the formation of esophageal precancerous lesions.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('B7-H4', 'Var', (60, 65))	('esophageal precancerous lesions', 'Disease', (190, 221))	('T cell proliferation', 'CPA', (80, 100))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (190, 221))	('inducing', 'Reg', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', (141, 146))	('T cell apoptosis', 'CPA', (113, 129))	('inhibiting', 'NegReg', (69, 79))
106472	28454382	In conclusion, the present study is the first to analyze the expression of B7-H4 in esophageal precancerous conditions in mice, and to provide a novel association between B7-H4 and the IL-6/STAT3 signaling pathway, which is classically recognized as an important stimulator in carcinogenesis and cancer progression.	('B7-H4', 'Var', (171, 176))	('STAT3', 'Gene', '20848', (190, 195))	('mice', 'Species', '10090', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('association', 'Interaction', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('B7-H4', 'Gene', (75, 80))	('STAT3', 'Gene', (190, 195))	('esophageal precancerous conditions', 'Disease', 'MESH:D011230', (84, 118))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('esophageal precancerous conditions', 'Disease', (84, 118))	('cancer', 'Disease', (98, 104))	('IL-6', 'Gene', (185, 189))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('IL-6', 'Gene', '16193', (185, 189))	('cancer', 'Disease', (296, 302))
106651	26158411	Studies have associated the aberrant expression of lncRNAs with the tumor progression or metastasis, for example, PCAT-1 and SChLAP1 in prostate cancer, HOTAIR in breast and colorectal cancer.	('tumor', 'Disease', (68, 73))	('HOTAIR', 'Gene', (153, 159))	('SChLAP1', 'Gene', '101669767', (125, 132))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (163, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('colorectal cancer', 'Phenotype', 'HP:0003003', (174, 191))	('prostate cancer', 'Disease', (136, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PCAT-1', 'Gene', (114, 120))	('HOTAIR', 'Gene', '100124700', (153, 159))	('aberrant', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SChLAP1', 'Gene', (125, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('metastasis', 'CPA', (89, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))	('PCAT-1', 'Gene', '100750225', (114, 120))
106680	26158411	Figure 2B-2D showed the Kaplan-Meier survival curves across the 119 ESCC patients for the up-regulated HOTAIR and two down-regulated ESCALs (linc-TMEM106A and LOC645638).	('HOTAIR', 'Gene', '100124700', (103, 109))	('TMEM106A', 'Gene', '113277', (146, 154))	('ESCC', 'Disease', (68, 72))	('up-regulated', 'PosReg', (90, 102))	('TMEM106A', 'Gene', (146, 154))	('LOC645638', 'Var', (159, 168))	('patients', 'Species', '9606', (73, 81))	('HOTAIR', 'Gene', (103, 109))
106682	26158411	It is well described that, deregulation of cell cycle, apoptosis and metastasis are critical in tumorigenesis.	('deregulation', 'Var', (27, 39))	('metastasis', 'CPA', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('cell cycle', 'CPA', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('apoptosis', 'CPA', (55, 64))
106701	26158411	However, we observed that knock-down of Epist could not significantly alter the expression of PITX1, and vice versa (Figure 4H-4I).	('knock-down', 'Var', (26, 36))	('Epist', 'Gene', '101927953', (40, 45))	('PITX1', 'Gene', '5307', (94, 99))	('Epist', 'Gene', (40, 45))	('PITX1', 'Gene', (94, 99))	('expression', 'MPA', (80, 90))
106706	26158411	The results showed that knock-down of Epist lead to an increased number of cells migrating through the membrane (Figure 5D).	('Epist', 'Gene', (38, 43))	('knock-down', 'Var', (24, 34))	('increased', 'PosReg', (55, 64))	('Epist', 'Gene', '101927953', (38, 43))
106719	26158411	Furthermore, siRNA-mediated knock-down of either PITX1 or Epist produced similar effects on the expression level of RASAL1 in TE-1 cell line (Figure 6B).	('PITX1', 'Gene', '5307', (49, 54))	('TE-1', 'CellLine', 'CVCL:1759', (126, 130))	('PITX1', 'Gene', (49, 54))	('knock-down', 'Var', (28, 38))	('Epist', 'Gene', '101927953', (58, 63))	('RASAL1', 'Gene', '8437', (116, 122))	('RASAL1', 'Gene', (116, 122))	('effects', 'Reg', (81, 88))	('Epist', 'Gene', (58, 63))	('expression level', 'MPA', (96, 112))
106729	26158411	The depth of the RNA-seq data we analyzed is comparable to that in a work identifying recurrent rearrangements of CIITA in Hodgkin lymphoma cell lines.	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (123, 139))	('rearrangements', 'Var', (96, 110))	('Hodgkin lymphoma', 'Disease', (123, 139))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (123, 139))	('CIITA', 'Gene', (114, 119))	('CIITA', 'Gene', '4261', (114, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
106744	26158411	A recent report has shown that LOC645638 (lnc-DC), which is exclusively expressed in human conventional dendritic cells, promotes the phosphorylation of STAT3 Y705 by preventing STAT3 binding to and dephosphorylation by SHP1.	('SHP1', 'Gene', (220, 224))	('dephosphorylation', 'MPA', (199, 216))	('phosphorylation', 'MPA', (134, 149))	('SHP1', 'Gene', '8431', (220, 224))	('STAT3', 'Gene', '6774', (153, 158))	('Y705', 'Var', (159, 163))	('lnc-DC', 'Gene', (42, 48))	('STAT3', 'Gene', (153, 158))	('preventing', 'NegReg', (167, 177))	('promotes', 'PosReg', (121, 129))	('LOC645638', 'Var', (31, 40))	('lnc-DC', 'Gene', '645638', (42, 48))	('STAT3', 'Gene', '6774', (178, 183))	('binding', 'Interaction', (184, 191))	('human', 'Species', '9606', (85, 90))	('STAT3', 'Gene', (178, 183))
106753	26158411	Also, the bivalent domain (a chromatin region marked by both the active mark, H3K4me3 and the repressive mark, H3K27me3) occurs at the promoter region of Epist and PITX1 in the H1-hESC cell line (ENCODE ChIP-seq data) (Figure S6C).	('H3K27me3', 'Var', (111, 119))	('Epist', 'Gene', '101927953', (154, 159))	('PITX1', 'Gene', (164, 169))	('H3K4me3', 'Var', (78, 85))	('Epist', 'Gene', (154, 159))	('PITX1', 'Gene', '5307', (164, 169))
106761	26158411	The ESCC cell lines (KYSE510, KYSE450, KYSE150, KYSE30, EC109 and TE-1) were purchased from Cell Resources Center, IBMS, CAMS/PUMC.	('EC109', 'CellLine', 'CVCL:6898', (56, 61))	('KYSE510', 'Var', (21, 28))	('TE-1', 'CellLine', 'CVCL:1759', (66, 70))	('KYSE150', 'Var', (39, 46))	('KYSE30', 'Var', (48, 54))	('KYSE450', 'Var', (30, 37))
106763	26158411	Specifically, KYSE510, KYSE450, KYSE150, KYSE30, EC109 and TE-1 cells were maintained in RPMI 1640 (Life Technology) supplemented with 10% FBS.	('TE-1', 'CellLine', 'CVCL:1759', (59, 63))	('EC109', 'CellLine', 'CVCL:6898', (49, 54))	('KYSE150', 'Var', (32, 39))	('KYSE510', 'Var', (14, 21))	('KYSE450', 'Var', (23, 30))
106767	26158411	Total RNAs were isolated from the cell lines (Het-1A, EC109, KYSE510, KYSE450, TE-1, KYSE30, KYSE150) with the Trizol reagent (Invitrogen) according to the manufacturer's instructions, and then subjected to DNaseI treatment.	('KYSE30', 'Var', (85, 91))	('KYSE150', 'Var', (93, 100))	('Trizol', 'Chemical', 'MESH:C411644', (111, 117))	('KYSE510', 'Var', (61, 68))	('KYSE450', 'Var', (70, 77))	('TE-1', 'CellLine', 'CVCL:1759', (79, 83))	('EC109', 'CellLine', 'CVCL:6898', (54, 59))
106783	26158411	Aliquots were stored at -80 C. For knock-down of Epist, KYSE30 cells were transfected with siRNA, trypsinized after 24 h, and counted with a Coulter counter.	('knock-down', 'Var', (35, 45))	('Epist', 'Gene', (49, 54))	('Epist', 'Gene', '101927953', (49, 54))
106788	19441788	Quantitative Serum Glycomics of Esophageal Adenocarcinoma, and Other Esophageal Disease Onsets Aberrant glycosylation has been implicated in various types of cancers and changes in glycosylation may be associated with signaling pathways during malignant transformation.	('changes', 'Var', (170, 177))	('Esophageal Adenocarcinoma', 'Disease', (32, 57))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (32, 57))	('associated', 'Reg', (202, 212))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (95, 117))	('cancers', 'Disease', (158, 165))	('cancer', 'Disease', (158, 164))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (32, 57))	('glycosylation', 'MPA', (104, 117))	('implicated', 'Reg', (127, 137))	('Aberrant', 'Var', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
106799	19441788	Aberrant glycosylation has been implicated in different types of cancer, with numerous glycosyl epitopes known to constitute tumor-associated antigens .	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('implicated', 'Reg', (32, 42))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', (125, 130))	('numerous glycosyl epitopes', 'Disease', 'MESH:D018981', (78, 104))	('cancer', 'Disease', (65, 71))	('glycosylation', 'MPA', (9, 22))	('numerous glycosyl epitopes', 'Disease', (78, 104))
106832	19441788	It is also observed in this study that aberrant glycosylation associated with esophagus diseases such as HGD and Barrett's, which commonly transform to esophagus adenocarcinoma, is intermediate and less pronounced relative to that observed in the case of cancer state.	('esophagus adenocarcinoma', 'Disease', (152, 176))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('HGD', 'Disease', (105, 108))	('aberrant', 'Var', (39, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('esophagus adenocarcinoma', 'Disease', 'MESH:C562730', (152, 176))	('esophagus diseases', 'Disease', (78, 96))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (39, 61))	('glycosylation', 'MPA', (48, 61))	('esophagus diseases', 'Disease', 'MESH:D004938', (78, 96))	('Barrett', 'Disease', (113, 120))	('esophagus adenocarcinoma', 'Phenotype', 'HP:0011459', (152, 176))
106838	24713797	The maximum esophageal wall thickness was significantly greater in patients with corrosive and post-radiation strictures in comparison to patients with peptic strictures.	('corrosive', 'Disease', (81, 90))	('patients', 'Species', '9606', (67, 75))	('strictures', 'Disease', (110, 120))	('greater', 'PosReg', (56, 63))	('post-radiation', 'Var', (95, 109))	('patients', 'Species', '9606', (138, 146))
106877	24713797	The maximum esophageal wall thickness was significantly greater in patients with corrosive and post-radiation strictures in comparison to patients with peptic strictures (6.55+-1.60 mm, 7.23+-1.30 mm and 3.88+-0.75 mm, respectively; p=0.0001).	('corrosive', 'Disease', (81, 90))	('patients', 'Species', '9606', (67, 75))	('strictures', 'Disease', (110, 120))	('greater', 'PosReg', (56, 63))	('post-radiation', 'Var', (95, 109))	('patients', 'Species', '9606', (138, 146))
106896	24713797	In the current study, we have demonstrated that patients with corrosive and post-radiation strictures have thicker esophageal wall in comparison to patients with peptic strictures.	('patients', 'Species', '9606', (148, 156))	('thicker', 'PosReg', (107, 114))	('strictures', 'Disease', (91, 101))	('patients', 'Species', '9606', (48, 56))	('post-radiation', 'Var', (76, 90))
107007	33628097	As occurs in breast cancer and NSCLC, ENO1 surface and nuclear forms may be involved in cancer invasion and metastasis, as well as in transcriptional repression, apparently inhibiting cell growth and accelerating apoptosis and necrosis.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('transcriptional repression', 'Var', (134, 160))	('apoptosis', 'CPA', (213, 222))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ENO1', 'Gene', '2023', (38, 42))	('cell growth', 'CPA', (184, 195))	('NSCLC', 'Disease', (31, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('accelerating', 'PosReg', (200, 212))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Disease', (13, 26))	('necrosis', 'Disease', 'MESH:D009336', (227, 235))	('cancer', 'Disease', (20, 26))	('involved', 'Reg', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('necrosis', 'Disease', (227, 235))	('inhibiting', 'NegReg', (173, 183))	('ENO1', 'Gene', (38, 42))
107128	31681567	Alternative splicing of GHRL gene transcript leads to synthesis of peptides other than native ghrelin, C-ghrelin, and Obestatin.	('GHRL', 'Gene', '51738', (24, 28))	('leads to', 'Reg', (45, 53))	('synthesis of peptides', 'MPA', (54, 75))	('Obestatin', 'Chemical', 'MESH:D054439', (118, 127))	('GHRL', 'Gene', (24, 28))	('Alternative splicing', 'Var', (0, 20))
107130	31681567	Exon 3-deleted preproghrelin apparently undergoes a processing similar to that of preproghrelin, which gives rise to native ghrelin and a unique carboxy-terminal peptide different from C-ghrelin.	('preproghrelin', 'Gene', '51738', (15, 28))	('preproghrelin', 'Gene', '51738', (82, 95))	('preproghrelin', 'Gene', (15, 28))	('carboxy', 'Chemical', 'MESH:C015732', (145, 152))	('preproghrelin', 'Gene', (82, 95))	('undergoes', 'Reg', (40, 49))	('Exon', 'Var', (0, 4))
107140	31681567	The half-life of circulating des-acylated ghrelin is consistently reported to be higher than the acylated form.	('half-life', 'MPA', (4, 13))	('des-acylated', 'Var', (29, 41))	('higher', 'PosReg', (81, 87))	('ghrelin', 'Protein', (42, 49))	('acyl', 'Chemical', 'MESH:D000214', (97, 101))	('acyl', 'Chemical', 'MESH:D000214', (33, 37))
107148	31681567	Despite diverse physiologic and pathologic functions proposed so far for des-acylated ghrelin, its cognate receptor remains to be discovered.	('ghrelin', 'Protein', (86, 93))	('acyl', 'Chemical', 'MESH:D000214', (77, 81))	('des-acylated', 'Var', (73, 85))
107157	31681567	Furthermore, exogenous ghrelin hampered systemic inflammatory response in esophageal cancer patients.	('hampered', 'NegReg', (31, 39))	('ghrelin', 'Protein', (23, 30))	('patients', 'Species', '9606', (92, 100))	('systemic inflammatory response', 'CPA', (40, 70))	('esophageal cancer', 'Disease', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('exogenous', 'Var', (13, 22))
107184	31681567	Unlike similar expression levels of full-length pre-proghrelin between benign and malignant cell lines, exon 3-deleted preproghrelin mRNA was significantly more abundant in some malignant cell lines (MDA-MB-231 and MDA-MB-435 but not MCF-7) compared to a benign cell line.	('exon 3-deleted', 'Var', (104, 118))	('preproghrelin', 'Gene', (119, 132))	('preproghrelin', 'Gene', '51738', (119, 132))	('N', 'Chemical', 'MESH:D009584', (135, 136))	('more', 'PosReg', (156, 160))
107187	31681567	In1-ghrelin variant retains the copy of intron-1 in the expression of ghrelin gene.	('variant', 'Var', (12, 19))	('In1', 'Gene', '16258', (0, 3))	('In1', 'Gene', (0, 3))	('ghrelin gene', 'Gene', (70, 82))	('expression', 'MPA', (56, 66))
107190	31681567	Expression of this variant was highly correlated with proliferation and mitotic markers, Ki-67 and cyclin D3.	('Ki-67', 'Protein', (89, 94))	('variant', 'Var', (19, 26))	('cyclin D3', 'Gene', '896', (99, 108))	('cyclin D3', 'Gene', (99, 108))	('proliferation', 'CPA', (54, 67))	('mitotic markers', 'CPA', (72, 87))	('correlated', 'Reg', (38, 48))
107193	31681567	Augmented expressions of exon 3-deleted ghrelin and In1-ghrelin in breast cancer may indicate the importance of these peptides in cancer pathophysiology.	('ghrelin', 'Protein', (40, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('expressions', 'MPA', (10, 21))	('In1', 'Gene', '16258', (52, 55))	('cancer', 'Disease', (74, 80))	('In1', 'Gene', (52, 55))	('Augmented', 'PosReg', (0, 9))	('exon 3-deleted', 'Var', (25, 39))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))	('men', 'Species', '9606', (3, 6))
107195	31681567	Although ghrelin, des-acylated ghrelin and Tamoxifen upregulated ghrelin expression in the malignant cell line, they reduced In1-ghrelin expression.	('acyl', 'Chemical', 'MESH:D000214', (22, 26))	('reduced', 'NegReg', (117, 124))	('Tamoxifen', 'Chemical', 'MESH:D013629', (43, 52))	('expression', 'MPA', (73, 83))	('ghrelin', 'Protein', (65, 72))	('In1', 'Gene', (125, 128))	('In1', 'Gene', '16258', (125, 128))	('des-acylated', 'Var', (18, 30))	('upregulated', 'PosReg', (53, 64))
107201	31681567	GOAT expression was correlated with the expression of In1-ghrelin variant to support the assumption that In1-ghrelin might be the main substrate for GOAT.	('GOAT', 'Species', '9925', (0, 4))	('GOAT', 'Species', '9925', (149, 153))	('variant', 'Var', (66, 73))	('In1', 'Gene', (105, 108))	('In1', 'Gene', '16258', (54, 57))	('In1', 'Gene', '16258', (105, 108))	('In1', 'Gene', (54, 57))
107202	31681567	Treatment by higher doses of both acylated ghrelin and des-acylated ghrelin inhibited proliferation of MCF-7 cancer cell line.	('acyl', 'Chemical', 'MESH:D000214', (34, 38))	('acyl', 'Chemical', 'MESH:D000214', (59, 63))	('MCF-7 cancer', 'Disease', (103, 115))	('MCF-7 cancer', 'Disease', 'MESH:D009369', (103, 115))	('men', 'Species', '9606', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('inhibited', 'NegReg', (76, 85))	('des-acylated', 'Var', (55, 67))
107205	31681567	A similar differential pattern was reported for exon 3-deleted pre-proghrelin mRNA among cell lines, implying a role for this ghrelin variant in the response of cancer cells to exogenous native ghrelin.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('variant', 'Var', (134, 141))	('role', 'Reg', (112, 116))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('N', 'Chemical', 'MESH:D009584', (80, 81))
107206	31681567	Both In1-ghrelin peptide treatment and its transfection into MDA-MB-231 and MCF-7 breast cancer cell-lines increased proliferation, migration, and sphere-formation.	('In1', 'Gene', (5, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('In1', 'Gene', '16258', (5, 8))	('transfection', 'Var', (43, 55))	('proliferation', 'CPA', (117, 130))	('increased', 'PosReg', (107, 116))	('migration', 'CPA', (132, 141))	('men', 'Species', '9606', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (76, 95))	('MCF-7 breast cancer', 'Disease', (76, 95))	('sphere-formation', 'CPA', (147, 163))
107208	31681567	In a nested case-control study (648 cases/659 controls), none of the tagging single-nucleotide polymorphisms (SNP) in the GHRL gene were associated with the risk of breast cancer development.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('associated', 'Reg', (137, 147))	('GHRL', 'Gene', '51738', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('GHRL', 'Gene', (122, 126))	('men', 'Species', '9606', (186, 189))	('single-nucleotide polymorphisms', 'Var', (77, 108))	('N', 'Chemical', 'MESH:D009584', (111, 112))
107209	31681567	However, another nested case-control (1,359 cases/2,389 controls) reported associations of some polymorphisms (GHRL rs171407-G allele and GHSR 2948694-GG genotype) with increased risk of breast cancer.	('rs171407-G', 'Var', (116, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('GHRL', 'Gene', '51738', (111, 115))	('rs171407', 'Mutation', 'rs171407', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('GHSR 2948694-GG', 'Var', (138, 153))	('GHRL', 'Gene', (111, 115))	('associations', 'Interaction', (75, 87))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('breast cancer', 'Disease', (187, 200))
107210	31681567	Finally, associations of Gly57Gly SNP of GHSR with increased risk, and association of some rare haplotypes of GHRL with reduced risk of breast cancer were reported.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('GHRL', 'Gene', '51738', (110, 114))	('associations', 'Interaction', (9, 21))	('Gly57Gly SNP', 'Var', (25, 37))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('GHRL', 'Gene', (110, 114))	('GHSR', 'Gene', (41, 45))	('reduced', 'NegReg', (120, 127))
107213	31681567	Positive ghrelin immune-reactivity of tumor tissue associated with better survival, independently of other putative prognostic factors such as grade and stage of the tumor (Table 2; Supplementary Table 1).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('survival', 'MPA', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Positive', 'Var', (0, 8))	('men', 'Species', '9606', (188, 191))	('better', 'PosReg', (67, 73))	('ghrelin', 'Protein', (9, 16))
107214	31681567	Likewise, ghrelin expression was associated with favorable breast cancer-specific survival in male breast cancer patients, irrespective of primary tumor size and lymph node involvement.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('favorable', 'PosReg', (49, 58))	('tumor', 'Disease', (147, 152))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('patients', 'Species', '9606', (113, 121))	('male breast cancer', 'Disease', 'MESH:D018567', (94, 112))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('men', 'Species', '9606', (180, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('ghrelin', 'Protein', (10, 17))	('male breast cancer', 'Disease', (94, 112))	('expression', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
107216	31681567	Further, ghrelin positivity of tumor cells was associated with a decreased mortality when comparing 190 patients who died of breast cancer and 190 breast cancer patients as living controls.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('decreased', 'NegReg', (65, 74))	('breast cancer', 'Disease', (147, 160))	('tumor', 'Disease', (31, 36))	('positivity', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mortality', 'MPA', (75, 84))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('patients', 'Species', '9606', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('ghrelin', 'Protein', (9, 16))
107219	31681567	Polymorphism of GHRL gene was linked to both all-cause and breast cancer-specific mortalities.	('Polymorphism', 'Var', (0, 12))	('GHRL', 'Gene', (16, 20))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('linked', 'Reg', (30, 36))	('GHRL', 'Gene', '51738', (16, 20))
107220	31681567	GHRL rs27647-GG genotype was correlated with worse all-cause mortality, whereas GHRL rs3755777-C allele conferred overall survival advantage.	('GHRL', 'Gene', (80, 84))	('rs27647-GG', 'Var', (5, 15))	('rs27647', 'Mutation', 'rs27647', (5, 12))	('all-cause mortality', 'MPA', (51, 70))	('rs3755777-C', 'Var', (85, 96))	('GHRL', 'Gene', '51738', (0, 4))	('rs3755777', 'Mutation', 'rs3755777', (85, 94))	('worse', 'NegReg', (45, 50))	('GHRL', 'Gene', (0, 4))	('GHRL', 'Gene', '51738', (80, 84))
107228	31681567	Alterations of ghrelin receptor expressions are in line with breast cancer, implying a more important role of GHSR1b in cancer biology.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ghrelin receptor', 'Gene', (15, 31))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('Alterations', 'Var', (0, 11))	('ghrelin receptor', 'Gene', '2693', (15, 31))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('expressions', 'MPA', (32, 43))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
107234	31681567	Serum ghrelin level showed an inverse association with tumor stage and was higher in patients with anti-Helicobacter pylori Ab.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('anti-Helicobacter', 'Var', (99, 116))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Ser', 'Chemical', 'MESH:C530429', (0, 3))	('higher', 'PosReg', (75, 81))	('Helicobacter pylori', 'Species', '210', (104, 123))	('tumor', 'Disease', (55, 60))	('patients', 'Species', '9606', (85, 93))	('Serum ghrelin level', 'MPA', (0, 19))
107244	31681567	The pro-proliferative effect of ghrelin was attenuated by GHSR inhibitor ([D-Lys3]-GHRP-6), dominant-negative mutation of Ras, PI3K inhibitor (LY 294002), dominant-negative mutation of Akt, or mTOR inhibitor (rapamycin).	('pro-proliferative effect', 'CPA', (4, 28))	('dominant-negative mutation', 'Var', (155, 181))	('Ras', 'Protein', (122, 125))	('LY', 'Var', (143, 145))	('GHRP', 'Gene', (83, 87))	('mTOR', 'Gene', '2475', (193, 197))	('GHRP', 'Gene', '2693', (83, 87))	('mTOR', 'Gene', (193, 197))	('LY 294002', 'Chemical', 'MESH:C085911', (143, 152))	('rapamycin', 'Chemical', 'MESH:D020123', (209, 218))	('D-Lys', 'Chemical', 'MESH:C026591', (75, 80))	('dominant-negative mutation', 'Var', (92, 118))	('Akt', 'Gene', '207', (185, 188))	('attenuated', 'NegReg', (44, 54))	('Akt', 'Gene', (185, 188))
107252	31681567	In APC-mutant mice, the deletion of ghrelin gene did not affect the size or number of tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mice', 'Species', '10090', (14, 18))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('deletion', 'Var', (24, 32))	('ghrelin', 'Gene', (36, 43))
107254	31681567	GHRL rs27647-T and rs35683-C alleles were associated with decreased risk of colorectal cancer in Czech Republic (680 cases/593 controls), but not German (569 cases/726 controls), population.	('rs35683', 'Mutation', 'rs35683', (19, 26))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('rs27647', 'Mutation', 'rs27647', (5, 12))	('GHRL', 'Gene', '51738', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('decreased', 'NegReg', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rs35683-C', 'Var', (19, 28))	('rs27647-T', 'Var', (5, 14))	('colorectal cancer', 'Disease', (76, 93))	('GHRL', 'Gene', (0, 4))
107258	31681567	GHSR agonists, HM01 and Z505 Hydrochloride, showed beneficial effects on cachexia in mouse models of colon cancer.	('HM01', 'Var', (15, 19))	('cachexia', 'Disease', (73, 81))	('mouse', 'Species', '10090', (85, 90))	('colon cancer', 'Disease', 'MESH:D015179', (101, 113))	('colon cancer', 'Disease', (101, 113))	('beneficial effects', 'PosReg', (51, 69))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cachexia', 'Phenotype', 'HP:0004326', (73, 81))	('Z505 Hydrochloride', 'Var', (24, 42))	('Hydrochloride', 'Chemical', 'MESH:C030374', (29, 42))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))	('cachexia', 'Disease', 'MESH:D002100', (73, 81))
107265	31681567	AGS cells expressed both GHS-R1a and GHS-R1b and GHS-R expression was higher in SGC7901 compared to AGS.	('GHS-R', 'Gene', (37, 42))	('AGS', 'Disease', 'MESH:C535607', (100, 103))	('GHS-R', 'Gene', '2693', (49, 54))	('GHS-R', 'Gene', '2693', (37, 42))	('GHS-R1a', 'Gene', (25, 32))	('AGS', 'Disease', (0, 3))	('expression', 'MPA', (55, 65))	('GHS-R1a', 'Gene', '208188', (25, 32))	('SGC7901', 'Var', (80, 87))	('AGS', 'Disease', (100, 103))	('GHS-R', 'Gene', (49, 54))	('higher', 'PosReg', (70, 76))	('GHS-R', 'Gene', (25, 30))	('AGS', 'Disease', 'MESH:C535607', (0, 3))	('GHS-R', 'Gene', '2693', (25, 30))
107275	31681567	Both ghrelin and des-acylated ghrelin induced proliferation of adenocarcinoma AGS cells via activation of the ERK1/2 and PI3K/Akt pathway.	('adenocarcinoma AGS', 'Disease', 'MESH:C535607', (63, 81))	('activation', 'PosReg', (92, 102))	('acyl', 'Chemical', 'MESH:D000214', (21, 25))	('ERK1/2', 'Gene', (110, 116))	('Akt', 'Gene', '207', (126, 129))	('des-acylated', 'Var', (17, 29))	('adenocarcinoma AGS', 'Disease', (63, 81))	('proliferation', 'CPA', (46, 59))	('ERK1/2', 'Gene', '5595;5594', (110, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('Akt', 'Gene', (126, 129))
107276	31681567	Different concentrations of ghrelin and des-acylated ghrelin could increase cells in the S phase of the cell cycle.	('increase', 'PosReg', (67, 75))	('cells in the S phase of the cell cycle', 'CPA', (76, 114))	('des-acylated', 'Var', (40, 52))	('acyl', 'Chemical', 'MESH:D000214', (44, 48))
107298	31681567	Likewise, exogenous ghrelin was safe and reduced post-operative systemic inflammation (duration and intensity) in esophageal cancer patients.	('reduced', 'NegReg', (41, 48))	('inflammation', 'Disease', (73, 85))	('inflammation', 'Disease', 'MESH:D007249', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('ghrelin', 'Protein', (20, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('exogenous', 'Var', (10, 19))	('patients', 'Species', '9606', (132, 140))
107299	31681567	An Australian case-control (260 OA/301 OGJA/213 OSCC cases/1,352 controls) revealed no major association between ghrelin gene SNPs and cancer incidence.	('cancer', 'Disease', (135, 141))	('SCC', 'Gene', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('N', 'Chemical', 'MESH:D009584', (127, 128))	('SCC', 'Gene', '6317', (49, 52))	('SNPs', 'Var', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('ghrelin', 'Gene', (113, 120))
107300	31681567	A modest positive association between rs696217 SNP and OA cancer was reported in cases with BMI < 25 kg/m2.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('rs696217 SNP', 'Var', (38, 50))	('rs696217', 'Mutation', 'rs696217', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('cancer', 'Disease', (58, 64))
107301	31681567	A trend of worse 1-year survival was reported in cancer patients positive vs. negative for local tumor expression of ghrelin (Table 2; Supplementary Table 4).	('patients', 'Species', '9606', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('men', 'Species', '9606', (141, 144))	('worse', 'NegReg', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('positive', 'Var', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', (97, 102))	('ghrelin', 'Protein', (117, 124))	('cancer', 'Disease', (49, 55))
107308	31681567	Furthermore, GHSR expression was linked to the activation of the MAPK/ERK and PI3K/AKT signaling and accompanied cell proliferation in Gefitinib (epidermal growth factor tyrosine kinase inhibitor)-resistant non-small cell lung cancer cell lines.	('AKT', 'Gene', '207', (83, 86))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (207, 233))	('cell proliferation', 'CPA', (113, 131))	('tyrosine', 'Chemical', 'None', (170, 178))	('ERK', 'Gene', (70, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('non-small cell lung cancer', 'Disease', (207, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('MAPK', 'Gene', (65, 69))	('AKT', 'Gene', (83, 86))	('activation', 'PosReg', (47, 57))	('MAPK', 'Gene', '5595;5594;5595', (65, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (211, 233))	('Gefitinib', 'Chemical', 'MESH:C419708', (135, 144))	('GHSR', 'Gene', (13, 17))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (207, 233))	('expression', 'Var', (18, 28))	('ERK', 'Gene', '5594', (70, 73))
107323	31681567	Both ghrelin and des-acylated ghrelin inhibited proliferation of H345 small cell lung carcinoma cell line (neuro-endocrine).	('small cell lung carcinoma', 'Disease', (70, 95))	('neu', 'Gene', (107, 110))	('neu', 'Gene', '2064', (107, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('proliferation', 'CPA', (48, 61))	('acyl', 'Chemical', 'MESH:D000214', (21, 25))	('inhibited', 'NegReg', (38, 47))	('des-acylated', 'Var', (17, 29))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (70, 95))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (70, 95))
107334	31681567	In conclusion, ghrelin alteration in patients with lung cancer seems to be a secondary systemic response to cancer-induced cachexia (Table 2).	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('cachexia', 'Phenotype', 'HP:0004326', (123, 131))	('ghrelin', 'Protein', (15, 22))	('patients', 'Species', '9606', (37, 45))	('alteration', 'Var', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('cachexia', 'Disease', 'MESH:D002100', (123, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cachexia', 'Disease', (123, 131))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
107339	31681567	Cancer cell lines consistently express acylated ghrelin, In1-ghrelin, and exon 3-deleted ghrelin.	('In1', 'Gene', '16258', (57, 60))	('ghrelin', 'Protein', (89, 96))	('acyl', 'Chemical', 'MESH:D000214', (39, 43))	('In1', 'Gene', (57, 60))	('express', 'Reg', (31, 38))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('exon 3-deleted', 'Var', (74, 88))	('acylated', 'MPA', (39, 47))
107344	31681567	In the study that investigated endogenous expression and exogenous effects of both native and In1 variant ghrelins in different prostate cancer cell lines, tumor xenograft, and human tumor samples, In1-ghrelin showed overall more impactful tumor-promoting and oncogenic effects.	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('variant', 'Var', (98, 105))	('tumor', 'Disease', (156, 161))	('human', 'Species', '9606', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('prostate cancer', 'Disease', 'MESH:D011471', (128, 143))	('prostate cancer', 'Phenotype', 'HP:0012125', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('prostate cancer', 'Disease', (128, 143))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('In1', 'Gene', '16258', (94, 97))	('tumor', 'Disease', (183, 188))	('In1', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('In1', 'Gene', '16258', (198, 201))	('In1', 'Gene', (198, 201))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('oncogenic effects', 'CPA', (260, 277))	('more', 'PosReg', (225, 229))
107366	31681567	This effect was mediated via GHS-R that induced AKt phosphorylation at Ser473 and Thr308 of PI3K/Akt pathway, which finally led to cell migration at acylated ghrelin concentrations of 180 nM.	('AKt', 'Gene', (48, 51))	('GHS-R', 'Gene', (29, 34))	('induced', 'Reg', (40, 47))	('led to', 'Reg', (124, 130))	('Akt', 'Gene', (97, 100))	('GHS-R', 'Gene', '2693', (29, 34))	('cell migration', 'CPA', (131, 145))	('AKt', 'Gene', '207', (48, 51))	('Thr308', 'Var', (82, 88))	('Ser', 'Chemical', 'MESH:C530429', (71, 74))	('acyl', 'Chemical', 'MESH:D000214', (149, 153))	('Akt', 'Gene', '207', (97, 100))
107369	31681567	Furthermore, the authors injected ghrelin knock-out 786-0 cell lines into nude-mice and found that metastatic lung nodule numbers were significantly lower in ghrelin knocked-out mice compared to the control group.	('ghrelin', 'Gene', (158, 165))	('nude-mice', 'Species', '10090', (74, 83))	('metastatic lung nodule numbers', 'CPA', (99, 129))	('mice', 'Species', '10090', (178, 182))	('mice', 'Species', '10090', (79, 83))	('knocked-out', 'Var', (166, 177))	('lower', 'NegReg', (149, 154))
107393	31681567	They observed 1,000 nM dose of exogenous acylated ghrelin enhanced cell proliferation in intact cell-lines.	('cell proliferation in intact cell-lines', 'CPA', (67, 106))	('ghrelin', 'Protein', (50, 57))	('acyl', 'Chemical', 'MESH:D000214', (41, 45))	('enhanced', 'PosReg', (58, 66))	('exogenous', 'Var', (31, 40))
107396	31681567	Accordingly, the increase in tumor size was slighter in NOD/SCID mice injected with GHSR-1a knock-out Ishikawa cell line compared to mice receiving intact Ishikawa cell line.	('mice', 'Species', '10090', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('SCID', 'Disease', 'MESH:D053632', (60, 64))	('SCID', 'Disease', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('knock-out', 'Var', (92, 101))	('mice', 'Species', '10090', (65, 69))	('GHSR-1a', 'Gene', '208188', (84, 91))	('GHSR-1a', 'Gene', (84, 91))	('tumor', 'Disease', (29, 34))	('increase', 'PosReg', (17, 25))	('N', 'Chemical', 'MESH:D009584', (56, 57))
107411	31681567	Des-acylated ghrelin has low binding affinity for this receptor, while recently found to be biologically active.	('binding', 'Interaction', (29, 36))	('Des-acylated', 'Var', (0, 12))	('acyl', 'Chemical', 'MESH:D000214', (4, 8))	('ghrelin', 'Protein', (13, 20))
107412	31681567	Many of the effects attributable to acylated or des-acylated ghrelin could be mediated by other receptors, which are yet to be characterized.	('acylated', 'Var', (36, 44))	('ghrelin', 'Protein', (61, 68))	('mediated', 'Reg', (78, 86))	('des-acylated', 'Var', (48, 60))	('acyl', 'Chemical', 'MESH:D000214', (52, 56))	('acyl', 'Chemical', 'MESH:D000214', (36, 40))
107423	31681567	Unlike GHSR1a, GHSR1b was positively associated with tumor stage.	('GHSR1b', 'Var', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('associated', 'Reg', (37, 47))	('tumor', 'Disease', (53, 58))
107432	31681567	Acylated and des-acylated ghrelins have similar local effects on human breast, lung, and gastric cancer cell lines.	('human', 'Species', '9606', (65, 70))	('lung', 'Disease', (79, 83))	('acyl', 'Chemical', 'MESH:D000214', (17, 21))	('des-acylated', 'Var', (13, 25))	('gastric cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast', 'Disease', (71, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('ghrelins', 'Protein', (26, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))
107434	31681567	These observations may also imply that two ghrelins use common, still unidentified, receptors in addition to GHSRs, because des-acylated ghrelin has much less affinity to known GHSRs.	('des-acylated', 'Var', (124, 136))	('affinity', 'MPA', (159, 167))	('acyl', 'Chemical', 'MESH:D000214', (128, 132))
107435	31681567	Exceptionally, although acylated ghrelin enhanced cell proliferation in endometrial cancer cell lines, des-acylated ghrelin did not exert proliferative effects.	('endometrial cancer', 'Disease', (72, 90))	('enhanced', 'PosReg', (41, 49))	('endometrial cancer', 'Phenotype', 'HP:0012114', (72, 90))	('acyl', 'Chemical', 'MESH:D000214', (24, 28))	('acylated', 'Var', (24, 32))	('endometrial cancer', 'Disease', 'MESH:D016889', (72, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('acyl', 'Chemical', 'MESH:D000214', (107, 111))	('cell proliferation', 'CPA', (50, 68))
107438	31681567	While the expression of full-length preproghrelin was similar between benign and malignant cell-lines, exon 3-deleted preproghrelin mRNA was significantly upregulated in malignant breast tissue and was associated with tumor grade.	('preproghrelin', 'Gene', '51738', (118, 131))	('mRNA', 'MPA', (132, 136))	('preproghrelin', 'Gene', '51738', (36, 49))	('associated', 'Reg', (202, 212))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('upregulated', 'PosReg', (155, 166))	('preproghrelin', 'Gene', (118, 131))	('tumor', 'Disease', (218, 223))	('preproghrelin', 'Gene', (36, 49))	('exon 3-deleted', 'Var', (103, 117))
107439	31681567	Upregulation of exon 3-deleted preproghrelin was also observed in some malignant cell lines, specifically those negative for ER and PR.	('Upregulation', 'PosReg', (0, 12))	('ER', 'Gene', '2099', (125, 127))	('exon 3-deleted', 'Var', (16, 30))	('PR', 'Gene', '5241', (132, 134))	('preproghrelin', 'Gene', (31, 44))	('preproghrelin', 'Gene', '51738', (31, 44))
107443	31681567	Based on these findings, authors postulated that exon 3-deleted preproghrelin and In1-ghrelin may have a more important role in breast cancer progression, compared to native ghrelin.	('In1', 'Gene', '16258', (82, 85))	('exon 3-deleted', 'Var', (49, 63))	('preproghrelin', 'Gene', '51738', (64, 77))	('In1', 'Gene', (82, 85))	('preproghrelin', 'Gene', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
107447	31681567	The prototype is gastric adenocarcinoma cell-line where a biphasic pattern for stimulatory effects of acylated and des-acylated ghrelins has been observed.	('acyl', 'Chemical', 'MESH:D000214', (119, 123))	('ghrelins', 'Protein', (128, 136))	('stimulatory effects', 'MPA', (79, 98))	('acyl', 'Chemical', 'MESH:D000214', (102, 106))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (17, 39))	('acylated', 'Var', (102, 110))	('gastric adenocarcinoma', 'Disease', (17, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))
107475	31681567	Both ghrelin and des-acylated ghrelin suppress macrophage-originated inflammatory cytokines and expression of COX-2.	('COX-2', 'Gene', '4513', (110, 115))	('COX-2', 'Gene', (110, 115))	('acyl', 'Chemical', 'MESH:D000214', (21, 25))	('expression', 'MPA', (96, 106))	('des-acylated', 'Var', (17, 29))	('macrophage-originated inflammatory cytokines', 'MPA', (47, 91))	('suppress', 'NegReg', (38, 46))
107512	31413593	We also generated subcutaneous tumors to explore whether miR-27a enhanced radiosensitivity in vivo.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (65, 90))	('enhanced', 'PosReg', (65, 73))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('miR-27a', 'Var', (57, 64))	('radiosensitivity', 'MPA', (74, 90))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (18, 37))
107514	31413593	Overexpression of miR-27a in ESCC cell lines caused a reduction of Hsp90 mRNA and protein.	('reduction', 'NegReg', (54, 63))	('miR-27a', 'Var', (18, 25))	('Hsp90', 'Gene', '3320', (67, 72))	('Hsp90', 'Gene', (67, 72))
107516	31413593	From these findings, we concluded that miR-27a may contribute to radiosensitivity by modulating Hsp90 expression.	('modulating', 'Reg', (85, 95))	('Hsp90', 'Gene', (96, 101))	('radiosensitivity', 'CPA', (65, 81))	('expression', 'MPA', (102, 112))	('miR-27a', 'Var', (39, 46))	('Hsp90', 'Gene', '3320', (96, 101))	('contribute', 'Reg', (51, 61))
107517	31413593	Moreover, miR-27a-based therapy utilized to target Hsp90 could be contemplated as a compelling alternative for sensitize ESCC to radiotherapy with fewer side effects.	('Hsp90', 'Gene', '3320', (51, 56))	('Hsp90', 'Gene', (51, 56))	('miR-27a-based', 'Var', (10, 23))
107526	31413593	Recently, several studies have investigated the important functions of miR-27a as a suppressor in cancer, and the expression level of miR-27a has been confirmed significantly reduced in ESCC cell lines and tissues.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('reduced', 'NegReg', (175, 182))	('expression level', 'MPA', (114, 130))	('miR-27a', 'Var', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('ESCC', 'Disease', (186, 190))
107530	31413593	Thus, inhibition of Hsp90 provides an approach for the simultaneous targeting of multiple proteins that can possibly serve as determinants of radiosensitivity.	('Hsp90', 'Gene', '3320', (20, 25))	('inhibition', 'Var', (6, 16))	('Hsp90', 'Gene', (20, 25))
107533	31413593	In the present study, we detected miR-27a expression in the plasma of ESCC patients.	('ESCC', 'Disease', (70, 74))	('miR-27a', 'Var', (34, 41))	('patients', 'Species', '9606', (75, 83))	('detected', 'Reg', (25, 33))
107535	31413593	The results of our study suggest that miR-27a may present a better strategy for the treatment of ESCC patients as a radiosensitizer, through downregulating Hsp90 expression and subsequently disrupting multiple radioresistant signaling pathways simultaneously.	('downregulating', 'NegReg', (141, 155))	('patients', 'Species', '9606', (102, 110))	('expression', 'MPA', (162, 172))	('ESCC patients', 'Disease', (97, 110))	('Hsp90', 'Gene', '3320', (156, 161))	('Hsp90', 'Gene', (156, 161))	('disrupting', 'NegReg', (190, 200))	('miR-27a', 'Var', (38, 45))	('radioresistant signaling pathways', 'Pathway', (210, 243))
107567	31413593	NC agomir or miR-27a agomir (RiboBio Co., Ltd, Guangzhou, China) was then directly injected into the implanted tumor at a dose of 5 nmol per mouse every 3 days for 15 days.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mouse', 'Species', '10090', (141, 146))	('tumor', 'Disease', (111, 116))	('miR-27a', 'Var', (13, 20))
107583	31413593	As shown in Figure 2A, the mRNA level of Hsp90 was significantly decreased in Eca109 (5.44+-0.27 vs 2.78+-0.18, P=0.004) and Eca9706 (3.77+-0.29 vs 1.71+-0.30, P=0.023) cells after miR-27a mimics transfection.	('decreased', 'NegReg', (65, 74))	('Hsp90', 'Gene', (41, 46))	('Hsp90', 'Gene', '3320', (41, 46))	('Eca9706', 'CellLine', 'CVCL:E307', (125, 132))	('Eca9706', 'Var', (125, 132))	('mRNA level of', 'MPA', (27, 40))
107585	31413593	What's more, miR-27a or in combination with radiation induced degradation of p-EGFR, p-Akt and p-c-Raf (Figure 2C).	('c-Raf', 'Gene', '5894', (97, 102))	('c-Raf', 'Gene', (97, 102))	('Akt', 'Gene', (87, 90))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('degradation', 'NegReg', (62, 73))	('miR-27a', 'Var', (13, 20))	('Akt', 'Gene', '207', (87, 90))
107587	31413593	Cleaved PARP is considered to be a hallmark of apoptosis.	('PARP', 'Gene', (8, 12))	('Cleaved', 'Var', (0, 7))	('PARP', 'Gene', '1302', (8, 12))
107590	31413593	As shown in Figure 3A, miR-27a significantly inhibited the proliferation of Eca109 and Eca9706 cells.	('proliferation', 'CPA', (59, 72))	('Eca9706', 'CellLine', 'CVCL:E307', (87, 94))	('miR-27a', 'Var', (23, 30))	('inhibited', 'NegReg', (45, 54))	('Eca109', 'CPA', (76, 82))
107593	31413593	The result indicated that miR-27a may be used as a radiosensitizer in the radiotherapy of ESCC patients to improve the antitumor effect of radiation.	('tumor', 'Disease', (123, 128))	('patients', 'Species', '9606', (95, 103))	('miR-27a', 'Var', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('improve', 'PosReg', (107, 114))	('ESCC', 'Disease', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
107595	31413593	The same changes of the proportion of cells in G0/G1 phase (P<0.001) and S phase (P<0.001) were observed in Eca9706, whereas no significant changes were detected in the proportion of cells in G2/M phase (Figure 5C).	('Eca9706', 'CellLine', 'CVCL:E307', (108, 115))	('S phase', 'CPA', (73, 80))	('G0/G1 phase', 'CPA', (47, 58))	('Eca9706', 'Var', (108, 115))	('changes', 'Reg', (9, 16))
107596	31413593	To explore whether miR-27a enhanced the radiosensitivity of ESCC in vivo, we generated subcutaneous tumors in nude mice using Eca109 and Eca9706 cells, and treated the mice with an intro-tumor injection of NC agomir or miR-27a agomir.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('intro-tumor', 'Disease', (181, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('miR-27a', 'Var', (19, 26))	('mice', 'Species', '10090', (168, 172))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('radiosensitivity', 'MPA', (40, 56))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (87, 106))	('intro-tumor', 'Disease', 'MESH:D009369', (181, 192))	('mice', 'Species', '10090', (115, 119))	('Eca9706', 'CellLine', 'CVCL:E307', (137, 144))	('nude mice', 'Species', '10090', (110, 119))
107598	31413593	To investigate the underlying mechanisms of miR-27a mediated radiosensitivity in ESCC xenograft models, we performed IHC to detect the expression of Hsp90, p-EGFR and cleaved PARP.	('EGFR', 'Gene', (158, 162))	('PARP', 'Gene', '1302', (175, 179))	('PARP', 'Gene', (175, 179))	('miR-27a', 'Var', (44, 51))	('Hsp90', 'Gene', (149, 154))	('Hsp90', 'Gene', '3320', (149, 154))	('EGFR', 'Gene', '1956', (158, 162))
107600	31413593	As shown in Figure 6C and D, the expression levels of Hsp90 and p-EGFR were decreased, while the expression level of cleaved PARP was increased in the tumors injected with the miR-27a agomir compared with these levels in the tumors injected with NC agomir.	('expression level', 'MPA', (97, 113))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('PARP', 'Gene', (125, 129))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('EGFR', 'Gene', (66, 70))	('tumors', 'Disease', (151, 157))	('Hsp90', 'Gene', '3320', (54, 59))	('miR-27a agomir', 'Var', (176, 190))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('increased', 'PosReg', (134, 143))	('Hsp90', 'Gene', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('EGFR', 'Gene', '1956', (66, 70))	('PARP', 'Gene', '1302', (125, 129))	('decreased', 'NegReg', (76, 85))	('expression levels', 'MPA', (33, 50))	('tumors', 'Disease', (225, 231))
107608	31413593	In our study, a significant increase in the expression of cleaved PARP, a marker of apoptosis, was observed both in vitro and in vivo.	('expression', 'MPA', (44, 54))	('PARP', 'Gene', '1302', (66, 70))	('PARP', 'Gene', (66, 70))	('cleaved', 'Var', (58, 65))	('increase', 'PosReg', (28, 36))
107613	31413593	Herein, we demonstrated that miR-27a reduced Hsp90 expression not only at the levels of translation, but also transcription.	('Hsp90', 'Gene', (45, 50))	('miR-27a', 'Var', (29, 36))	('Hsp90', 'Gene', '3320', (45, 50))	('expression', 'MPA', (51, 61))	('reduced', 'NegReg', (37, 44))
107614	31413593	To determine whether Hsp90 downregulation by miR-27a can result in weakened radiosensitivity signaling, we evaluated the expression of p-EGFR, p-Akt and p-c-Raf.	('EGFR', 'Gene', (137, 141))	('Hsp90', 'Gene', (21, 26))	('Akt', 'Gene', (145, 148))	('c-Raf', 'Gene', (155, 160))	('weakened', 'NegReg', (67, 75))	('Hsp90', 'Gene', '3320', (21, 26))	('radiosensitivity signaling', 'MPA', (76, 102))	('downregulation', 'NegReg', (27, 41))	('EGFR', 'Gene', '1956', (137, 141))	('Akt', 'Gene', '207', (145, 148))	('miR-27a', 'Var', (45, 52))	('c-Raf', 'Gene', '5894', (155, 160))
107615	31413593	Intriguingly, both Eca109 and Eca9706 cells exhibited degradation of these key client proteins associated with radioresistance.	('Eca9706', 'CellLine', 'CVCL:E307', (30, 37))	('Eca9706', 'Var', (30, 37))	('degradation', 'MPA', (54, 65))
107617	31413593	The results of our in vivo experiment also indicate that miR-27a plays as a tumor suppressor and improves the radiosensitivity in ESCC.	('radiosensitivity', 'CPA', (110, 126))	('ESCC', 'Disease', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('miR-27a', 'Var', (57, 64))	('improves', 'PosReg', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
107618	31413593	All the data indicate that the inhibition of Hsp90 by miR-27a may have broader application against ESCC radioresistance.	('inhibition', 'NegReg', (31, 41))	('Hsp90', 'Gene', (45, 50))	('ESCC', 'Disease', (99, 103))	('miR-27a', 'Var', (54, 61))	('Hsp90', 'Gene', '3320', (45, 50))
107630	31413593	In the present study,we reported a novel role for miR-27a as a key regulator of radiosensitivity and showed that miR-27a sensitized ESCC to radiation by downregulating Hsp90 expression.	('Hsp90', 'Gene', '3320', (168, 173))	('expression', 'MPA', (174, 184))	('sensitized', 'Reg', (121, 131))	('downregulating', 'NegReg', (153, 167))	('miR-27a', 'Var', (113, 120))	('ESCC', 'Disease', (132, 136))	('Hsp90', 'Gene', (168, 173))
107632	31090196	 MEIS1 knockdown may promote differentiation of esophageal squamous carcinoma cell line KYSE-30 MEIS1 (Myeloid ecotropic viral integration site 1), as a homeobox (HOX) transcription factor, has a dual function in different types of cancer.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (48, 77))	('cancer', 'Disease', (232, 238))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (48, 77))	('esophageal squamous carcinoma', 'Disease', (48, 77))	('promote', 'PosReg', (21, 28))	('differentiation', 'CPA', (29, 44))	('MEIS1', 'Gene', '4211', (96, 101))	('MEIS1', 'Gene', (96, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (59, 77))	('knockdown', 'Var', (7, 16))	('MEIS1', 'Gene', '4211', (1, 6))	('MEIS1', 'Gene', (1, 6))
107636	31090196	Retroviral transduction caused a significant underexpression of MEIS1 in GFP-hMEIS1 compared to control GFP cells approximately 5.5-fold.	('Retroviral transduction', 'Var', (0, 23))	('MEIS1', 'Gene', (64, 69))	('underexpression', 'NegReg', (45, 60))	('hMEIS1', 'Gene', '4211', (77, 83))	('hMEIS1', 'Gene', (77, 83))
107643	31090196	Abnormal expression of HOX genes, often accompanied by DNA hypermethylation, can lead to the developmental diseases and carcinogenesis.	('lead to', 'Reg', (81, 88))	('Abnormal expression', 'Var', (0, 19))	('developmental diseases', 'Disease', 'MESH:D001848', (93, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (120, 134))	('HOX genes', 'Gene', (23, 32))	('carcinogenesis', 'Disease', (120, 134))	('developmental diseases', 'Disease', (93, 115))
107648	31090196	Differentiation outcome in squamous epithelium of esophageal needs a serial activity of different specific differentiation-associated genes, and any disruption in this chain may block differentiation process leading to squamous epithelial neoplasia, although the involved molecular mechanisms remain poorly understood (Luo et al., 2014).	('block', 'NegReg', (178, 183))	('squamous epithelial neoplasia', 'Disease', (219, 248))	('epithelial neoplasia', 'Phenotype', 'HP:0031492', (228, 248))	('squamous epithelial neoplasia', 'Disease', 'MESH:D009369', (219, 248))	('neoplasia', 'Phenotype', 'HP:0002664', (239, 248))	('differentiation process', 'CPA', (184, 207))	('disruption', 'Var', (149, 159))
107649	31090196	Therefore, in the current study, we aimed to assess the impact of MEIS1 gene knockdown on the expression pattern of differentiation-associated genes including TWIST1 (twist family bHLH transcription factor 1, OMIM: 601622), EGF (epidermal growth factor, OMIM: 131530), KRT4 (Keratin 4, OMIM: 123940), and CDX2 (caudal type homeobox 2, OMIM: 600297) in human ESC cell line KYSE-30, to define probable linkage between MEIS1 and differentiation state of the cells.	('caudal type homeobox 2', 'Gene', '1045', (311, 333))	('twist', 'Gene', '7291', (167, 172))	('caudal type homeobox 2', 'Gene', (311, 333))	('twist', 'Gene', (167, 172))	('knockdown', 'Var', (77, 86))	('epidermal growth factor', 'Gene', (229, 252))	('MEIS1', 'Gene', (66, 71))	('Keratin 4', 'Gene', (275, 284))	('Keratin 4', 'Gene', '3851', (275, 284))	('epidermal growth factor', 'Gene', '1950', (229, 252))
107662	31090196	Moreover, MEIS1 knockdown inhibited DNA replication in acute lymphoblastic leukemias (ALL) through regulation of involved genes in cell cycle process (Orlovsky et al., 2011).	('acute lymphoblastic leukemias', 'Disease', 'MESH:D054198', (55, 84))	('lymphoblastic leukemias', 'Phenotype', 'HP:0005526', (61, 84))	('DNA replication', 'MPA', (36, 51))	('inhibited', 'NegReg', (26, 35))	('knockdown', 'Var', (16, 25))	('acute lymphoblastic leukemias', 'Phenotype', 'HP:0006721', (55, 84))	('acute lymphoblastic leukemias', 'Disease', (55, 84))	('leukemias', 'Phenotype', 'HP:0001909', (75, 84))	('MEIS1', 'Gene', (10, 15))	('regulation', 'Reg', (99, 109))	('leukemia', 'Phenotype', 'HP:0001909', (75, 83))
107663	31090196	On the other hand, MEIS1 ectopic expression in gastric cancer (GC) cells not only suppressed critical cancer cell properties including cell proliferation, colony formation, anchorage independent growth, epithelial mesenchymal transition (EMT), migration, and invasion, but also induced apoptosis and cell cycle arrest at G1/S transition in vitro (Song et al., 2017).	('MEIS1', 'Gene', (19, 24))	('invasion', 'CPA', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('epithelial mesenchymal transition', 'CPA', (203, 236))	('gastric cancer', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('apoptosis', 'CPA', (286, 295))	('suppressed', 'NegReg', (82, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('cell cycle arrest', 'CPA', (300, 317))	('critical cancer cell properties', 'CPA', (93, 124))	('cell proliferation', 'CPA', (135, 153))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('anchorage independent growth', 'CPA', (173, 201))	('ectopic expression', 'Var', (25, 43))	('induced', 'Reg', (278, 285))	('colony formation', 'CPA', (155, 171))	('migration', 'CPA', (244, 253))
107665	31090196	It has been illustrated that MEIS1 silencing in mouse embryonic carcinoma suppressed differentiation in neural cells, while its ectopic expression induced differentiation via expression of neural progenitor markers including GLAST, BLBP, SOX1, and Nestin (Yamada, Urano-Tashiro, Tanaka, Akiyama, & Tashiro, 2013).	('differentiation', 'CPA', (155, 170))	('suppressed', 'NegReg', (74, 84))	('mouse', 'Species', '10090', (48, 53))	('BLBP', 'Gene', (232, 236))	('SOX1', 'Gene', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('embryonic carcinoma', 'Phenotype', 'HP:0002898', (54, 73))	('SOX1', 'Gene', '20664', (238, 242))	('BLBP', 'Gene', '12140', (232, 236))	('differentiation in neural cells', 'CPA', (85, 116))	('GLAST', 'Gene', '20512', (225, 230))	('MEIS1', 'Gene', (29, 34))	('Nestin', 'Gene', '18008', (248, 254))	('silencing', 'Var', (35, 44))	('Nestin', 'Gene', (248, 254))	('embryonic carcinoma', 'Disease', (54, 73))	('induced', 'Reg', (147, 154))	('GLAST', 'Gene', (225, 230))	('embryonic carcinoma', 'Disease', 'MESH:D018236', (54, 73))
107669	31090196	It has been indicated that silencing of TWIST1 lead to increase osteoblast differentiation in mesenchymal stem cells (MSCs) by upregulation of the involved genes in FGF/ERK and BMP signaling pathways (Miraoui, Severe, Vaudin, Pages, & Marie, 2010).	('increase', 'PosReg', (55, 63))	('ERK', 'Gene', (169, 172))	('silencing', 'Var', (27, 36))	('ERK', 'Gene', '2048', (169, 172))	('increase osteoblast', 'Phenotype', 'HP:0030328', (55, 74))	('upregulation', 'PosReg', (127, 139))	('TWIST1', 'Gene', (40, 46))
107673	31090196	Ectopic expression of the intestine-specific homeobox transcription factor CDX2 cause Barrett's esophagus and gastric-intestinal metaplasia (Joo, Park, & Chun, 2016).	('CDX2', 'Gene', (75, 79))	('Ectopic expression', 'Var', (0, 18))	('gastric-intestinal metaplasia', 'Disease', 'MESH:D013274', (110, 139))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (86, 105))	("Barrett's esophagus", 'Disease', (86, 105))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (86, 105))	('cause', 'Reg', (80, 85))	('gastric-intestinal metaplasia', 'Disease', (110, 139))
107675	28415817	An updated meta-analysis of 23 case-control studies on the association between miR-34b/c polymorphism and cancer risk The association between in microRNA-34b/c gene rs4938723 polymorphisms and cancer risk remains inconclusive.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('rs4938723', 'Mutation', 'rs4938723', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('microRNA-34b', 'Gene', (145, 157))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('microRNA-34b', 'Gene', '407041', (145, 157))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('miR-34b', 'Gene', (79, 86))	('miR-34b', 'Gene', '407041', (79, 86))	('rs4938723', 'Var', (165, 174))
107676	28415817	This meta-analysis was performed to analyze the association between microRNA-34b/c rs4938723 polymorphism and risk for cancer development.	('rs4938723', 'Var', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('rs4938723', 'Mutation', 'rs4938723', (83, 92))	('microRNA-34b', 'Gene', (68, 80))	('microRNA-34b', 'Gene', '407041', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
107678	28415817	Our results indicate a significant association between the rs4938723 polymorphism and cancer risk in the overdominant model (P heterogeneity = 0.018, OR = 1.093, and 95% CI = 1.015-1.177 for CT vs. CC/TT).	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs4938723', 'Mutation', 'rs4938723', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('rs4938723', 'Var', (59, 68))	('cancer', 'Disease', (86, 92))
107679	28415817	Using a stratified subgroup analysis, rs4938723 polymorphisms were associated with an increased risk for hepatocellular carcinoma, but decreased risk for colorectal, gastric, and esophageal squamous cell cancer.	('rs4938723', 'Var', (38, 47))	('colorectal', 'Disease', 'MESH:D015179', (154, 164))	('esophageal squamous cell cancer', 'Disease', (179, 210))	('rs4938723', 'Mutation', 'rs4938723', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (105, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('hepatocellular carcinoma', 'Disease', (105, 129))	('gastric', 'Disease', (166, 173))	('colorectal', 'Disease', (154, 164))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (105, 129))	('decreased', 'NegReg', (135, 144))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (190, 210))	('increased risk for hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (86, 129))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (179, 210))
107680	28415817	These findings indicate that the rs4938723 gene is a susceptible locus for cancer.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('rs4938723', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs4938723', 'Mutation', 'rs4938723', (33, 42))
107684	28415817	Emerging evidence has revealed that genetic factors, such as single nucleotide polymorphisms (SNPs), influence cancer development, treatment efficacy, and survival time of cancer patients.	('influence', 'Reg', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('single nucleotide polymorphisms', 'Var', (61, 92))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (111, 117))	('survival time', 'CPA', (155, 168))	('treatment efficacy', 'CPA', (131, 149))
107688	28415817	The miR-34b/c gene rs4938723 has been associated with hepatocellular and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('associated', 'Reg', (38, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('rs4938723', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('miR-34b', 'Gene', (4, 11))	('miR-34b', 'Gene', '407041', (4, 11))	('hepatocellular', 'Disease', (54, 68))	('rs4938723', 'Mutation', 'rs4938723', (19, 28))
107689	28415817	However, updated, recent meta-analyses of the rs4938723 association with cancer risk have been limited.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rs4938723', 'Var', (46, 55))	('rs4938723', 'Mutation', 'rs4938723', (46, 55))
107690	28415817	In this study, we have systematically reviewed the published data, and integrated all published studies to evaluate the association between rs4938723 polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('rs4938723', 'Mutation', 'rs4938723', (140, 149))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('rs4938723', 'Var', (140, 149))
107694	28415817	In the meta-analysis of the 23 eligible studies, genotype CT was significantly associated with cancer susceptibility in the overall population (overdominant model CT versus CC/TT: PH = 0.018, OR = 1.093, and 95% CI = 1.015-1.177), as shown in Table 2 and Figure 2.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('associated with', 'Reg', (79, 94))	('genotype', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
107695	28415817	No association between rs4938723 polymorphism and cancer risk was observed in the allele, genotype, dominant, and recessive models.	('rs4938723', 'Mutation', 'rs4938723', (23, 32))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('rs4938723', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
107696	28415817	For hepatocellular carcinoma, the rs4938723 polymorphism was associated with an increased cancer risk in the comparison model (allele C versus T: PH = 0.113, OR = 1.114, and 95% CI = 1.007-1.233), genotype model (CT versus TT: PH = 0.121, OR = 1.191, and 95% CI = 1.033-1.373), and overdominant model (CT vs. CC/TT: PH = 0.195, OR = 1.157, and 95% CI = 1.010-1.324).	('rs4938723', 'Var', (34, 43))	('hepatocellular carcinoma', 'Disease', (4, 28))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('rs4938723', 'Mutation', 'rs4938723', (34, 43))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (4, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (4, 28))
107698	28415817	The rs4938723 polymorphism decreased the risk for colorectal cancer in the genotype (CC vs. TT: PH = 0.342, OR = 0.658, and 95% CI = 0.470-0.923) and recessive models (CC vs. CT/TT: PH = 0.519, OR = 0.672, and 95% CI = 0.485-0.930).	('rs4938723', 'Var', (4, 13))	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('decreased', 'NegReg', (27, 36))	('rs4938723', 'Mutation', 'rs4938723', (4, 13))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colorectal cancer', 'Disease', (50, 67))
107699	28415817	In addition, the rs4938723 polymorphism was negatively associated with gastric cancer risk in the comparison model of C versus T (PH = 0.843, OR = 0.758, and 95% CI = 0.643-0.893), CT versus TT (PH = 0.381, OR = 0.755, and 95% CI = 0.598-0.953), CC versus TT (PH = 0.400, OR = 0.584, and 95% CI = 0.405-0.842), CC/CT versus TT (PH = 0.664, OR = 0.715, and 95% CI = 0.574-0.892), and CC versus CT/TT (PH = 0.254, OR = 0.667, and 95% CI = 0.471-0.943).	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('rs4938723', 'Mutation', 'rs4938723', (17, 26))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('negatively', 'NegReg', (44, 54))	('rs4938723', 'Var', (17, 26))
107700	28415817	The rs4938723 polymorphism showed also reverse correlation with esophageal squamous cell cancer in the comparison model of CC versus TT (PH = 0.345, OR = 0.787, and 95% CI = 0.638-0.972) and CC versus CT/TT (PH = 0.164, OR = 0.774, and 95% CI = 0.633-0.947).	('rs4938723', 'Var', (4, 13))	('esophageal squamous cell cancer', 'Disease', (64, 95))	('rs4938723', 'Mutation', 'rs4938723', (4, 13))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (75, 95))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (64, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
107705	28415817	The miR-34b/c gene rs4938723 polymorphism has been investigated because of its potential association with the increased risk for cancer development; however, the results remain inconclusive.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('rs4938723', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('miR-34b', 'Gene', (4, 11))	('miR-34b', 'Gene', '407041', (4, 11))	('rs4938723', 'Mutation', 'rs4938723', (19, 28))
107706	28415817	This updated meta-analysis was performed to obtain conclusive results about the association of rs4938723 polymorphism and cancer risk.	('rs4938723', 'Mutation', 'rs4938723', (95, 104))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('association', 'Interaction', (80, 91))	('polymorphism', 'Var', (105, 117))	('rs4938723 polymorphism', 'Var', (95, 117))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
107708	28415817	An increased risk for cancer was observed for the rs4938723 polymorphism under overdominant (CT vs. CC/TT) model.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('rs4938723', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('rs4938723', 'Mutation', 'rs4938723', (50, 59))
107710	28415817	Our results indicate that the rs4938723 polymorphism is a risk factor for cancer.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('rs4938723', 'Mutation', 'rs4938723', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('risk', 'Reg', (58, 62))	('rs4938723', 'Var', (30, 39))
107711	28415817	Several meta-analyses investigated the association between miR-34b/c gene rs4938723 polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('rs4938723', 'Mutation', 'rs4938723', (74, 83))	('cancer', 'Disease', (101, 107))	('rs4938723 polymorphism', 'Var', (74, 96))	('miR-34b', 'Gene', (59, 66))	('polymorphism', 'Var', (84, 96))	('miR-34b', 'Gene', '407041', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('investigated', 'Reg', (22, 34))
107712	28415817	In the study conducted by Qiu et al., the meta-analysis included 11 studies, and indicated that allele C and genotype CT might be risk factors for hepatocellular cancer, and protective factors for colorectal cancer.	('allele C', 'Var', (96, 104))	('colorectal cancer', 'Disease', (197, 214))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (147, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (197, 214))	('hepatocellular cancer', 'Disease', (147, 168))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (147, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))
107713	28415817	included 13 studies, and indicated that the rs4938723 polymorphism was associated with an increased cancer susceptibility of the Asian population.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rs4938723', 'Mutation', 'rs4938723', (44, 53))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('rs4938723', 'Var', (44, 53))
107714	28415817	However, the polymorphism reduced susceptibility to colorectal cancer and esophageal squamous cell cancer in Asians.	('polymorphism', 'Var', (13, 25))	('esophageal squamous cell cancer', 'Disease', (74, 105))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('reduced', 'NegReg', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Disease', (52, 69))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (74, 105))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (85, 105))	('susceptibility', 'MPA', (34, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
107716	28415817	Consistent with the previous meta-analyses, we observed an increased risk for cancer that was associated with the miR-34b/c gene rs4938723 polymorphism using the overdominant model.	('miR-34b', 'Gene', (114, 121))	('miR-34b', 'Gene', '407041', (114, 121))	('rs4938723', 'Mutation', 'rs4938723', (129, 138))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('rs4938723', 'Var', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
107719	28415817	In the stratified analysis, the rs4938723 polymorphisms were associated with an increased risk of hepatocellular carcinoma, but with a decreased risk for colorectal, gastric, and esophageal squamous cell cancer.	('rs4938723', 'Mutation', 'rs4938723', (32, 41))	('colorectal', 'Disease', 'MESH:D015179', (154, 164))	('esophageal squamous cell cancer', 'Disease', (179, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('increased risk of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (80, 122))	('gastric', 'Disease', (166, 173))	('rs4938723', 'Var', (32, 41))	('colorectal', 'Disease', (154, 164))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (179, 210))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (190, 210))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('hepatocellular carcinoma', 'Disease', (98, 122))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (98, 122))
107725	28415817	In the present study, we conducted a comprehensive search of the PubMed, Embase, Web of Science, Wanfang, and CNKI databases to identify all potentially eligible studies on rs4938723 polymorphism and cancer risk.	('rs4938723', 'Mutation', 'rs4938723', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('polymorphism', 'Var', (183, 195))	('rs4938723 polymorphism', 'Var', (173, 195))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
107726	28415817	The last search was updated on December 22, 2016, by using the following search terms: (pre-mir-34b/c OR pri-miR-34b/c OR mir-34b/c OR microRNA-34b/c OR rs4938723), (gene OR polymorphism OR allele OR variation), and (cancer OR carcinoma OR tumor).	('mir-34b', 'Gene', (92, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinoma OR tumor', 'Disease', 'MESH:D009369', (227, 245))	('miR-34b', 'Gene', (109, 116))	('carcinoma OR tumor', 'Disease', (227, 245))	('mir-34b', 'Gene', (122, 129))	('microRNA-34b', 'Gene', (135, 147))	('miR-34b', 'Gene', '407041', (109, 116))	('rs4938723', 'Var', (153, 162))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('microRNA-34b', 'Gene', '407041', (135, 147))	('mir-34b', 'Gene', '407041', (92, 99))	('rs4938723', 'Mutation', 'rs4938723', (153, 162))	('mir-34b', 'Gene', '407041', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
107727	28415817	All of the selected studies in our meta-analysis conformed to all of the following criteria: (1) case-control studies; (2) evaluation of rs4938723 polymorphism and cancer risk; (3) sufficient genotype frequency data for calculating the OR and 95% CI; and (4) genotype distribution of the control group that was consistent with the HWE.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('rs4938723', 'Mutation', 'rs4938723', (137, 146))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('rs4938723', 'Var', (137, 146))
107731	28415817	The strength of the association between rs4938723 polymorphism and cancer risk was assessed by ORs and corresponding 95% CIs under five different genetic models.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('rs4938723', 'Mutation', 'rs4938723', (40, 49))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs4938723', 'Var', (40, 49))
107733	28415817	In summary, our study shows that the miR-34b/c gene rs4938723 is a susceptible locus for cancer.	('miR-34b', 'Gene', (37, 44))	('rs4938723', 'Var', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('miR-34b', 'Gene', '407041', (37, 44))	('rs4938723', 'Mutation', 'rs4938723', (52, 61))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
107734	28415817	The rs4938723 polymorphisms are associated with an increased risk for hepatocellular carcinoma, but decreased risk for colorectal, gastric, and esophageal squamous cell cancer.	('rs4938723', 'Var', (4, 13))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (155, 175))	('colorectal', 'Disease', 'MESH:D015179', (119, 129))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (70, 94))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 94))	('esophageal squamous cell cancer', 'Disease', (144, 175))	('hepatocellular carcinoma', 'Disease', (70, 94))	('rs4938723', 'Mutation', 'rs4938723', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('decreased', 'NegReg', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('gastric', 'Disease', (131, 138))	('colorectal', 'Disease', (119, 129))	('increased risk for hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (51, 94))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (144, 175))
107740	28376920	Identical TP53 mutations and homogeneously loss of heterozygosity of the TP53 locus were identified in all separated tumor regions in each of five adenocarcinomas, and in the corresponding Barrett's esophagus and tumor positive lymph node of one primary tumor.	('tumor', 'Disease', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('TP53', 'Gene', '7157', (73, 77))	('tumor', 'Disease', (254, 259))	('TP53', 'Gene', (10, 14))	('adenocarcinomas', 'Disease', 'MESH:D000230', (147, 162))	('tumor', 'Disease', (117, 122))	('mutations', 'Var', (15, 24))	('TP53', 'Gene', (73, 77))	('adenocarcinomas', 'Disease', (147, 162))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('loss', 'NegReg', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (189, 208))	('TP53', 'Gene', '7157', (10, 14))
107749	28376920	Alterations in the TP53 gene occur in the majority of EAC cases, however, only few other somatic alterations are shared between EACs, representing substantial intertumor heterogeneity.	('EAC', 'Phenotype', 'HP:0011459', (54, 57))	('tumor', 'Disease', (164, 169))	('Alterations', 'Var', (0, 11))	('EAC', 'Disease', (54, 57))	('TP53', 'Gene', '7157', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('TP53', 'Gene', (19, 23))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
107769	28376920	To demonstrate loss of heterozygosity (LOH) of the genes of interest (APC, P16, SMAD4, TP53) amplicons for single nucleotide polymorphisms (SNPs, selected from dbSNP137) in these loci were added to the custom-made cancer panel.	('TP53', 'Gene', '7157', (87, 91))	('cancer', 'Disease', (214, 220))	('P16', 'Gene', '1029', (75, 78))	('single nucleotide polymorphisms', 'Var', (107, 138))	('TP53', 'Gene', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('SMAD4', 'Gene', '4089', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('APC', 'Disease', 'MESH:D011125', (70, 73))	('APC', 'Disease', (70, 73))	('P16', 'Gene', (75, 78))	('SMAD4', 'Gene', (80, 85))
107770	28376920	For tumor DNAs, of which the normal DNA was considered heterozygous, all SNPs with variants <40 or >60% were denoted as indicative for LOH.	('variants', 'Var', (83, 91))	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
107772	28376920	In addition, identified tumor suppressor gene mutations also supplied information about possible LOH (loss of the wild type allele) by the relative frequency of the mutant DNA sequence compared to the normal wild type sequence in the tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutant', 'Var', (165, 171))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('LOH', 'NegReg', (97, 100))
107774	28376920	Homogeneity was signified by an identical mutation or the same pattern of LOH at a given gene identified in different tumor regions of the same tumor, whereas heterogeneity was signified by different mutations or various LOH patterns of a given gene in different regions of the same tumor.	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('mutation', 'Var', (42, 50))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
107782	28376920	Next-generation sequencing on the PGM and conventional Sanger sequencing revealed 21 mutations in the TP53 gene, no mutations were identified in APC, P16, and SMAD4.	('SMAD4', 'Gene', (159, 164))	('TP53', 'Gene', (102, 106))	('P16', 'Gene', (150, 153))	('P16', 'Gene', '1029', (150, 153))	('SMAD4', 'Gene', '4089', (159, 164))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('mutations', 'Var', (85, 94))	('TP53', 'Gene', '7157', (102, 106))	('APC', 'Disease', (145, 148))
107787	28376920	TP53 immunohistochemistry showed homogeneous and strong nuclear expression in all tumor regions and the BE sample of the four patients with TP53 somatic missense mutations (Fig.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('BE', 'Phenotype', 'HP:0100580', (104, 106))	('TP53', 'Gene', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('patients', 'Species', '9606', (126, 134))	('nuclear expression', 'MPA', (56, 74))	('missense mutations', 'Var', (153, 171))	('tumor', 'Disease', (82, 87))	('TP53', 'Gene', '7157', (140, 144))
107798	28376920	This analysis revealed a clonal origin of TP53 alterations: all five EACs where homogeneous with regard to TP53 mutations and LOH of the TP53 locus, in addition the same mutation and pattern of LOH in TP53 was observed in a paired TPLN of one EAC.	('TP53', 'Gene', '7157', (42, 46))	('EAC', 'Phenotype', 'HP:0011459', (243, 246))	('TP53', 'Gene', '7157', (201, 205))	('TP53', 'Gene', (42, 46))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('EAC', 'Phenotype', 'HP:0011459', (69, 72))	('TP53', 'Gene', (201, 205))	('TP53', 'Gene', '7157', (137, 141))	('alterations', 'Var', (47, 58))	('TP53', 'Gene', (137, 141))
107799	28376920	These results indicate that TP53 mutation and LOH of the TP53 locus are relatively early events in EAC tumorigenesis and clonally expand throughout the entire tumor.	('TP53', 'Gene', '7157', (28, 32))	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('mutation', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (103, 108))	('TP53', 'Gene', (28, 32))	('tumor', 'Disease', (159, 164))	('EAC', 'Disease', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('LOH', 'Var', (46, 49))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
107800	28376920	In concordance with this is the finding of the same TP53 mutation, identical pattern of LOH, and comparable strong nuclear TP53 expression in the paired primary tumor and BE case.	('mutation', 'Var', (57, 65))	('TP53', 'Gene', '7157', (52, 56))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('TP53', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('TP53', 'Gene', '7157', (123, 127))	('expression', 'MPA', (128, 138))	('tumor', 'Disease', (161, 166))	('TP53', 'Gene', (123, 127))
107803	28376920	In addition, an identical pattern of P16 locus LOH was present in the paired primary EAC and BE case, suggesting that LOH of P16 is an early alteration, clonally expanding throughout the tumor.	('P16', 'Gene', '1029', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('EAC', 'Phenotype', 'HP:0011459', (85, 88))	('P16', 'Gene', '1029', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('BE', 'Phenotype', 'HP:0100580', (93, 95))	('tumor', 'Disease', (187, 192))	('P16', 'Gene', (125, 128))	('LOH', 'Var', (118, 121))	('P16', 'Gene', (37, 40))
107805	28376920	Some EACs showed homogeneous LOH of SMAD4 and/or APC, one EAC showed no LOH of SMAD4 at all, while the remaining EACs showed different subclones: some with LOH of SMAD4 and/or APC and others without LOH of these loci.	('EAC', 'Phenotype', 'HP:0011459', (113, 116))	('SMAD4', 'Gene', (163, 168))	('SMAD4', 'Gene', '4089', (79, 84))	('EAC', 'Phenotype', 'HP:0011459', (5, 8))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('SMAD4', 'Gene', (36, 41))	('APC', 'Disease', 'MESH:D011125', (49, 52))	('SMAD4', 'Gene', '4089', (163, 168))	('SMAD4', 'Gene', (79, 84))	('APC', 'Disease', (49, 52))	('APC', 'Disease', 'MESH:D011125', (176, 179))	('APC', 'Disease', (176, 179))	('LOH', 'Var', (156, 159))	('SMAD4', 'Gene', '4089', (36, 41))	('LOH', 'Var', (29, 32))
107808	28376920	A homogeneously present TP53 mutation and LOH of the TP53 locus as well as LOH of the P16 locus in the primary tumor were also found in the adjacent BE sample, indicating that the earliest molecular alterations can already be present in the premalignant lesion (BE) and from there on clonally expand throughout the entire tumor.	('mutation', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('BE', 'Phenotype', 'HP:0100580', (262, 264))	('BE', 'Phenotype', 'HP:0100580', (149, 151))	('TP53', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('premalignant lesion', 'Disease', (241, 260))	('P16', 'Gene', (86, 89))	('tumor', 'Disease', (111, 116))	('premalignant lesion', 'Disease', 'MESH:D051437', (241, 260))	('P16', 'Gene', '1029', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('TP53', 'Gene', '7157', (53, 57))	('tumor', 'Disease', (322, 327))	('TP53', 'Gene', (53, 57))	('TP53', 'Gene', '7157', (24, 28))
107809	28376920	Alterations in TP53 were described previously in the sequential of BE (HGD) and EAC, and in addition were found to be present in a major clone, which also indicates clonal expansion of TP53 as an early alteration.	('TP53', 'Gene', (185, 189))	('BE', 'Phenotype', 'HP:0100580', (67, 69))	('Alterations', 'Var', (0, 11))	('HGD', 'Gene', '3081', (71, 74))	('HGD', 'Gene', (71, 74))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('TP53', 'Gene', '7157', (185, 189))	('EAC', 'Phenotype', 'HP:0011459', (80, 83))
107810	28376920	Several studies on P16 have reported clonal expansion of P16 alterations in all regions of BE segments, and it has been suggested that expansion of TP53 alterations occurs only in a background of P16 altered clones.	('alterations', 'Var', (153, 164))	('P16', 'Gene', (57, 60))	('P16', 'Gene', (196, 199))	('P16', 'Gene', '1029', (19, 22))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('P16', 'Gene', '1029', (57, 60))	('BE', 'Phenotype', 'HP:0100580', (91, 93))	('P16', 'Gene', '1029', (196, 199))	('alterations', 'Var', (61, 72))	('P16', 'Gene', (19, 22))
107811	28376920	However, others described progenitor clones containing TP53 alterations alone or in combination with P16 alterations present at many levels of BE segments.	('P16', 'Gene', '1029', (101, 104))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('BE', 'Phenotype', 'HP:0100580', (143, 145))	('alterations', 'Var', (60, 71))	('P16', 'Gene', (101, 104))
107812	28376920	concluded that BE was genetically heterogeneous, however they observed identical TP53 mutations in multiple BE crypts, indicating widespread and far-reaching clonal expansion as a consequence of the strong selective advantage that absence of TP53 function supposedly provide.	('BE', 'Phenotype', 'HP:0100580', (108, 110))	('mutations', 'Var', (86, 95))	('absence', 'NegReg', (231, 238))	('BE', 'Phenotype', 'HP:0100580', (15, 17))	('TP53', 'Gene', '7157', (242, 246))	('TP53', 'Gene', (242, 246))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
107813	28376920	Conceivably, intratumor heterogeneity can cause tumor sample bias using single biopsy approaches, since it may underestimate the mutation spectrum of a tumor.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (18, 23))	('heterogeneity', 'Var', (24, 37))	('tumor', 'Disease', (152, 157))	('cause', 'Reg', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mutation spectrum', 'MPA', (129, 146))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('underestimate', 'NegReg', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
107817	28376920	Even though the sample size is small, and targeted sequencing of only commonly mutated genes was performed, the current study provides evidence that although intratumor heterogeneity is present in EACs, known driver alterations in TP53 and P16 were homogeneously present in all five primary EACs, indicating clonal cellular expansion.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('EAC', 'Phenotype', 'HP:0011459', (291, 294))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TP53', 'Gene', '7157', (231, 235))	('P16', 'Gene', (240, 243))	('tumor', 'Disease', (163, 168))	('P16', 'Gene', '1029', (240, 243))	('TP53', 'Gene', (231, 235))	('alterations', 'Var', (216, 227))	('EAC', 'Phenotype', 'HP:0011459', (197, 200))
107990	25709477	Patients treated with multimodality therapy (including RT+CT [18%], S+CT [40%], or S+RT+CT [17%]) vs monotherapy (typically, S [18%]) had significantly improved OS (15.5 months vs 9.3 months) (P=0.02) and complete response rates.	('OS', 'Chemical', '-', (161, 163))	('S+RT+CT', 'Var', (83, 90))	('RT+CT', 'Chemical', '-', (85, 90))	('improved', 'PosReg', (152, 160))	('Patients', 'Species', '9606', (0, 8))	('RT+CT', 'Chemical', '-', (55, 60))
107992	25709477	Multimodality therapy (including RT+CT, S+CT, or S+RT+CT) improves OS for patients with LS-C-SCEC compared with monotherapy (typically, S).	('RT+CT', 'Chemical', '-', (33, 38))	('S+RT+CT', 'Var', (49, 56))	('LS', 'Chemical', '-', (88, 90))	('patients', 'Species', '9606', (74, 82))	('OS', 'Chemical', '-', (67, 69))	('improves', 'PosReg', (58, 66))	('LS-C-SCEC', 'Disease', (88, 97))	('RT+CT', 'Chemical', '-', (51, 56))
108001	25709477	Our previous study demonstrated that patients with pure LS-SCEC treated with RT+CT had an improved survival compared with those treated with S+CT.	('patients', 'Species', '9606', (37, 45))	('RT+CT', 'Chemical', '-', (77, 82))	('survival', 'CPA', (99, 107))	('improved', 'PosReg', (90, 98))	('RT+CT', 'Var', (77, 82))	('pure LS-SCEC', 'Disease', (51, 63))	('LS', 'Chemical', '-', (56, 58))
108031	25709477	Patients who received multimodality therapy (eg, RT+CT, S+CT, S+RT, or S+RT+CT) had significantly improved OS compared with those who received monotherapy with any technique (15.5 months vs 9.3 months) (P=0.02) (Figure 1C).	('RT+CT', 'Chemical', '-', (73, 78))	('RT+CT', 'Var', (49, 54))	('OS', 'Chemical', '-', (107, 109))	('S+CT', 'Var', (56, 60))	('Patients', 'Species', '9606', (0, 8))	('S+RT+CT', 'Var', (71, 78))	('S+RT', 'Var', (62, 66))	('improved', 'PosReg', (98, 106))	('RT+CT', 'Chemical', '-', (49, 54))
108034	25709477	Among the 19 patients with CR, the treatment modality was S alone (1/19 [5%]), CT+RT (1/19 [5%]), S+CT (12/19 [63%]), and S+CT+RT (5/19 [27%]).	('CR', 'Chemical', '-', (27, 29))	('patients', 'Species', '9606', (13, 21))	('S+CT', 'Var', (98, 102))	('S+CT+RT', 'Var', (122, 129))
108076	25709477	We recommend that S+CT+RT, S+CT, or CT+RT should be considered as possible treatment approaches for LS-C-SCEC patients.	('S+CT', 'Var', (27, 31))	('LS-C-SCEC', 'Disease', (100, 109))	('S+CT+RT', 'Var', (18, 25))	('LS', 'Chemical', '-', (100, 102))	('patients', 'Species', '9606', (110, 118))
108077	19047108	Association between CCND1 G/A870 polymorphism, allele-specific amplification, cyclin D1 expression and survival in esophageal and lung carcinoma Cyclin D1 (D1) is found on 11q13 which is a region frequently amplified in several tumor types.	('Cyclin D1', 'Gene', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('Association', 'Interaction', (0, 11))	('G/A870', 'Mutation', 'rs9344', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('D1', 'Gene', '27241', (152, 154))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('cyclin D1', 'Gene', (78, 87))	('cyclin D1', 'Gene', '595', (78, 87))	('G/A870 polymorphism', 'Var', (26, 45))	('D1', 'Gene', '27241', (23, 25))	('polymorphism', 'Var', (33, 45))	('D1', 'Gene', '27241', (85, 87))	('CCND1', 'Gene', '595', (20, 25))	('D1', 'Gene', '27241', (156, 158))	('CCND1', 'Gene', (20, 25))	('tumor', 'Disease', (228, 233))	('esophageal and lung carcinoma', 'Disease', 'MESH:D004938', (115, 144))	('Cyclin D1', 'Gene', '595', (145, 154))
108079	19047108	A common G/A polymorphism (G/A870) is thought to influence the expression levels of D1a and D1b.	('expression levels', 'MPA', (63, 80))	('G/A870', 'Var', (27, 33))	('G/A870', 'Mutation', 'rs9344', (27, 33))	('D1', 'Gene', '27241', (84, 86))	('D1', 'Gene', '27241', (92, 94))	('influence', 'Reg', (49, 58))
108083	19047108	We explored the relationship between gene amplification, G/A870 genotype, D1a and D1b expression and overall survival in esophageal adenocarcinoma (EAC) and non-small cell lung cancer (NSCLC).	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (121, 146))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (121, 146))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (157, 183))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (157, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('non-small cell lung cancer', 'Disease', (157, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('D1', 'Gene', '27241', (82, 84))	('D1', 'Gene', '27241', (74, 76))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (161, 183))	('G/A870', 'Var', (57, 63))	('G/A870', 'Mutation', 'rs9344', (57, 63))	('esophageal adenocarcinoma', 'Disease', (121, 146))	('NSCLC', 'Disease', (185, 190))
108085	19047108	D1 variant expression did not correlate with amplification, genotype or overall survival in either tumor type.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('variant', 'Var', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('D1', 'Gene', '27241', (0, 2))
108089	19047108	Genomic instability resulting in DNA amplification, rearrangements or deletions, is a common mechanism by which tumors modulate gene expression and acquire invasive and metastatic potential.	('acquire', 'PosReg', (148, 155))	('modulate', 'Reg', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('rearrangements', 'MPA', (52, 66))	('DNA amplification', 'MPA', (33, 50))	('gene expression', 'MPA', (128, 143))	('deletions', 'Var', (70, 79))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
108090	19047108	The chromosomal band 11q13 has been found to be amplified or rearranged in a wide variety of carcinomas including breast, head and neck, and bladder and this is often associated with poor prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('rearranged', 'Var', (61, 71))	('breast', 'Disease', (114, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('carcinomas', 'Disease', (93, 103))	('carcinomas', 'Disease', 'MESH:D002277', (93, 103))	('bladder', 'Disease', (141, 148))
108096	19047108	This G/A polymorphism (G/A870) occurs at the exon 4 splice donor site and although it does not alter the amino acid encoded, it is hypothesized to affect splicing at the exon 4/intron 4 boundary.	('G/A870', 'Mutation', 'rs9344', (23, 29))	('splicing', 'MPA', (154, 162))	('donor', 'Species', '9606', (59, 64))	('G/A870', 'Var', (23, 29))	('affect', 'Reg', (147, 153))
108105	19047108	Thus, while some differences in alternative splicing may be tissue specific, the association between the A/G870 SNP and cyclin D1, D1a, and D1b expression remains unclear.	('D1', 'Gene', '27241', (131, 133))	('A/G870', 'Mutation', 'rs9344', (105, 111))	('cyclin D1', 'Gene', '595', (120, 129))	('A/G870 SNP', 'Var', (105, 115))	('cyclin D1', 'Gene', (120, 129))	('D1', 'Gene', '27241', (140, 142))	('D1', 'Gene', '27241', (127, 129))
108106	19047108	Independent of cyclin D1 expression levels, several studies have identified a correlation between the A/A, A/G genotypes and an increased risk of developing cancer or decreased overall survival in various tumor types including breast, colon, head and neck, lung, and esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (278, 301))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (267, 301))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('overall', 'MPA', (177, 184))	('decreased', 'NegReg', (167, 176))	('breast', 'Disease', (227, 233))	('cyclin D1', 'Gene', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('A/A', 'Var', (102, 105))	('cyclin D1', 'Gene', '595', (15, 24))	('A/G', 'Var', (107, 110))	('cancer', 'Disease', (157, 163))	('esophageal squamous cell carcinoma', 'Disease', (267, 301))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('lung', 'Disease', (257, 261))	('tumor', 'Disease', (205, 210))	('colon', 'Disease', (235, 240))
108111	19047108	We report that amplification at 11q13 has no allele bias, the G/A870 SNP does not correlate with expression of cyclin D1a or D1b and that the G/A870 genotype does not correlate with patient survival.	('D1', 'Gene', '27241', (125, 127))	('cyclin D1', 'Gene', (111, 120))	('D1', 'Gene', '27241', (118, 120))	('G/A870', 'Mutation', 'rs9344', (62, 68))	('patient', 'Species', '9606', (182, 189))	('G/A870', 'Mutation', 'rs9344', (142, 148))	('cyclin D1', 'Gene', '595', (111, 120))	('G/A870 SNP', 'Var', (62, 72))
108123	19047108	PCR loci for the microsatellite reference pool included D4S1605, D5S478, D12S1699, D14S988, D21S1904, and D22S922 and used previously published primer sequences along with a FAM/BHQ dual labeled T(GT)10 probe.	('D1', 'Gene', '27241', (83, 85))	('D1', 'Gene', '27241', (73, 75))	('S988', 'CellLine', 'CVCL:V789', (86, 90))	('D22S922', 'Var', (106, 113))	('D21S1904', 'Var', (92, 100))	('D5S478', 'Var', (65, 71))	('D4S1605', 'Var', (56, 63))
108138	19047108	Analysis of variance (ANOVA) was used to assess the association between 11q13 amplification and cyclin D1, cyclin D1a, cyclin D1b, MYEOV, TAOS1 and TAOS2 expression as well as between genotype and D1, D1a, and D1b expression.	('D1', 'Gene', '27241', (210, 212))	('D1', 'Gene', '27241', (114, 116))	('D1', 'Gene', '27241', (201, 203))	('TAOS1', 'Gene', (138, 143))	('D1', 'Gene', '27241', (103, 105))	('cyclin D1', 'Gene', (96, 105))	('TAOS2', 'Gene', '55107', (148, 153))	('D1', 'Gene', '27241', (126, 128))	('cyclin D1', 'Gene', '595', (96, 105))	('cyclin D1', 'Gene', (119, 128))	('expression', 'MPA', (214, 224))	('TAOS1', 'Gene', '220064', (138, 143))	('association', 'Interaction', (52, 63))	('D1', 'Gene', '27241', (197, 199))	('TAOS2', 'Gene', (148, 153))	('11q13', 'Gene', (72, 77))	('cyclin D1', 'Gene', '595', (119, 128))	('cyclin D1', 'Gene', (107, 116))	('MYEOV', 'Gene', (131, 136))	('MYEOV', 'Gene', '26579', (131, 136))	('amplification', 'Var', (78, 91))	('cyclin D1', 'Gene', '595', (107, 116))	('expression', 'MPA', (154, 164))
108151	19047108	3-22 copies of the A allele were observed in 6 A/A (3 AC and 3 SCC) and 2 G/A (both AC) samples.	('SCC', 'Gene', (63, 66))	('2 G/A', 'Var', (72, 77))	('SCC', 'Gene', '6317', (63, 66))	('2 G/A', 'SUBSTITUTION', 'None', (72, 77))
108158	19047108	Previously published reports have demonstrated TAOS1, TAOS2, and MYEOV overexpression in breast, head and neck and esophageal squamous cell carcinoma samples with genomic amplification.	('TAOS2', 'Gene', (54, 59))	('TAOS1', 'Gene', '220064', (47, 52))	('TAOS1', 'Gene', (47, 52))	('overexpression', 'PosReg', (71, 85))	('MYEOV', 'Gene', '26579', (65, 70))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (115, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('genomic amplification', 'Var', (163, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('esophageal squamous cell carcinoma', 'Disease', (115, 149))	('TAOS2', 'Gene', '55107', (54, 59))	('MYEOV', 'Gene', (65, 70))	('breast', 'Disease', (89, 95))
108161	19047108	Interestingly, neither TAOS1 nor MYEOV expression correlated significantly with survival (Cox regression p=0.12 and p=0.56, respectively) but high expression of TAOS2 was associated with decreased survival (Cox regression p=0.030; log-rank p=0.045 based on a median split) (Fig 5B).	('TAOS2', 'Gene', (161, 166))	('survival', 'MPA', (197, 205))	('MYEOV', 'Gene', (33, 38))	('MYEOV', 'Gene', '26579', (33, 38))	('TAOS1', 'Gene', '220064', (23, 28))	('TAOS1', 'Gene', (23, 28))	('decreased', 'NegReg', (187, 196))	('high expression', 'Var', (142, 157))	('TAOS2', 'Gene', '55107', (161, 166))
108163	19047108	Although none of these SNPs result in amino acid substitutions the G/A transition at nucleotide 870 is thought to affect CCND1 expression because it occurs at the final intron/exon boundary and may alter recognition of the exon 4 splice donor site.	('alter', 'Reg', (198, 203))	('donor', 'Species', '9606', (237, 242))	('expression', 'MPA', (127, 137))	('substitutions', 'Var', (49, 62))	('affect', 'Reg', (114, 120))	('CCND1', 'Gene', '595', (121, 126))	('recognition of the exon 4 splice donor site', 'MPA', (204, 247))	('CCND1', 'Gene', (121, 126))
108164	19047108	It has been reported that the A allele at this SNP may be correlated with both increased risk of carcinoma and poor patient outcome, although these reports are somewhat inconsistent.	('carcinoma', 'Disease', 'MESH:D002277', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('patient', 'Species', '9606', (116, 123))	('A allele', 'Var', (30, 38))	('carcinoma', 'Disease', (97, 106))
108167	19047108	Theoretically, the AA genotype and/or amplification of an A allele in tumors would result in higher expression of cyclin D1b thus increasing cancer risk and resulting in a more aggressive disease.	('higher', 'PosReg', (93, 99))	('aggressive disease', 'Disease', 'MESH:D001523', (177, 195))	('resulting in', 'Reg', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cyclin D1', 'Gene', '595', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('increasing', 'PosReg', (130, 140))	('cyclin D1', 'Gene', (114, 123))	('aggressive disease', 'Disease', (177, 195))	('tumors', 'Disease', (70, 76))	('expression', 'MPA', (100, 110))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('more', 'PosReg', (172, 176))	('amplification', 'Var', (38, 51))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
108172	19047108	These contradictory results could suggest tissue specific or tumor type differences but in a 2007 review article, analysis of 48 NSCLC failed to demonstrate a correlation between the genotype and D1 isoform expression and the data supporting this was not shown leaving questions about the relationship between the G/A870 SNP and D1a or D1b expression.	('G/A870 SNP', 'Var', (314, 324))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('NSCLC', 'Disease', (129, 134))	('D1', 'Gene', '27241', (329, 331))	('G/A870', 'Mutation', 'rs9344', (314, 320))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('D1', 'Gene', '27241', (196, 198))	('D1', 'Gene', '27241', (336, 338))	('tumor', 'Disease', (61, 66))
108176	19047108	We observed that, for the most part, samples with amplified CCND1 exhibited increased total cyclin D1 mRNA expression, but neither D1a nor D1b levels individually were significantly elevated in amplified samples.	('D1', 'Gene', '27241', (63, 65))	('D1', 'Gene', '27241', (131, 133))	('cyclin D1', 'Gene', '595', (92, 101))	('increased', 'PosReg', (76, 85))	('D1', 'Gene', '27241', (139, 141))	('amplified', 'Var', (50, 59))	('CCND1', 'Gene', (60, 65))	('cyclin D1', 'Gene', (92, 101))	('D1', 'Gene', '27241', (99, 101))	('CCND1', 'Gene', '595', (60, 65))
108181	19047108	Currently, studies in multiple tumor types have examined the impact of the G/A870 polymorphism on cancer risk and survival.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('G/A870', 'Var', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('G/A870', 'Mutation', 'rs9344', (75, 81))
108182	19047108	While several studies in breast, head and neck, and colorectal cancers have implicated the A/A or A/G genotype with increased risk of carcinoma, other studies in the very same tumor types have implicated the G/G genotype with increased risk of carcinoma or have found no effect of the polymorphism.	('carcinoma', 'Disease', (134, 143))	('carcinoma', 'Disease', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('colorectal cancers', 'Disease', 'MESH:D015179', (52, 70))	('breast', 'Disease', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', (176, 181))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('carcinoma', 'Disease', 'MESH:D002277', (134, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('colorectal cancers', 'Disease', (52, 70))	('A/A', 'Var', (91, 94))	('G/G', 'Var', (208, 211))	('carcinoma', 'Disease', 'MESH:D002277', (244, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('A/G', 'Var', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
108183	19047108	In EAC, the A/A genotype was associated with increased risk of carcinoma in one study but not in another and increased D1 protein correlated with poor overall survival of patients.	('increased', 'PosReg', (109, 118))	('carcinoma', 'Disease', (63, 72))	('patients', 'Species', '9606', (171, 179))	('A/A', 'Var', (12, 15))	('D1', 'Gene', '27241', (119, 121))	('carcinoma', 'Disease', 'MESH:D002277', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('poor', 'NegReg', (146, 150))
108186	19047108	In addition, the G/A870 SNP may be in linkage disequilibrium with a C/G SNP at position 1722 in D1, since patients with A870 most likely carry C1722 as well.	('D1', 'Gene', '27241', (96, 98))	('G/A870', 'Var', (17, 23))	('G/A870', 'Mutation', 'rs9344', (17, 23))	('A870', 'Var', (120, 124))	('patients', 'Species', '9606', (106, 114))	('C1722', 'Var', (143, 148))
108200	19047108	Thus it is likely that cyclin D1 may have other, less understood roles in cell function and may exert its actions through CDK independent activities, as demonstrated by D1 mutants incapable of activating CDK 4/6.	('mutants', 'Var', (172, 179))	('cyclin D1', 'Gene', '595', (23, 32))	('D1', 'Gene', '27241', (169, 171))	('cyclin D1', 'Gene', (23, 32))	('D1', 'Gene', '27241', (30, 32))	('CDK 4/6', 'Gene', (204, 211))	('CDK 4/6', 'Gene', '1019;1021', (204, 211))
108207	19047108	Recently however TAOS1 expression was found to be more dependent on copy number than CCND1 in oral squamous cell carcinoma cell lines.	('CCND1', 'Gene', '595', (85, 90))	('copy number', 'Var', (68, 79))	('TAOS1', 'Gene', '220064', (17, 22))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('TAOS1', 'Gene', (17, 22))	('CCND1', 'Gene', (85, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('oral squamous cell carcinoma', 'Disease', (94, 122))	('expression', 'MPA', (23, 33))
108210	19047108	Thus TAOS1 and MYEOV appear to be regulated by gene copy number whereas TAOS2 expression is not.	('TAOS2', 'Gene', '55107', (72, 77))	('MYEOV', 'Gene', (15, 20))	('TAOS2', 'Gene', (72, 77))	('MYEOV', 'Gene', '26579', (15, 20))	('regulated', 'Reg', (34, 43))	('TAOS1', 'Gene', '220064', (5, 10))	('TAOS1', 'Gene', (5, 10))	('gene copy number', 'Var', (47, 63))
108235	33028804	For the EGFR targeted therapy in esophageal cancer, drug resistance due to mutations in EGFR-related genes must be considered.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('EGFR', 'Gene', '1956', (8, 12))	('drug resistance', 'Phenotype', 'HP:0020174', (52, 67))	('EGFR', 'Gene', '1956', (88, 92))	('mutations', 'Var', (75, 84))	('EGFR', 'Gene', (8, 12))	('EGFR', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
108237	33028804	Refer to this kind of strategy, we can combine targeted drugs with other treatment methods as much as possible to develop a combined plan; or we can use related methods, such as gene silencing, to inhibit pathways related to tumor resistance.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('inhibit', 'NegReg', (197, 204))	('gene silencing', 'Var', (178, 192))	('tumor', 'Disease', (225, 230))	('pathways', 'Pathway', (205, 213))
108243	33028804	According to Huang's report, for patients with ESCC with high EGFR expression, cetuximab could not only improve survival but also reduce the recurrence and metastatic potential of the tumor.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('survival', 'CPA', (112, 120))	('reduce', 'NegReg', (130, 136))	('EGFR', 'Gene', '1956', (62, 66))	('high', 'Var', (57, 61))	('patients', 'Species', '9606', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('EGFR', 'Gene', (62, 66))	('improve', 'PosReg', (104, 111))	('tumor', 'Disease', (184, 189))	('recurrence', 'CPA', (141, 151))	('cetuximab', 'Chemical', 'MESH:D000068818', (79, 88))
108262	33028804	In general, gefitinib is effective in treating ESCC and improves the survival of patients with advanced ESCC, but its efficacy with other anti-EGFR therapies needs to be further explored.	('EGFR', 'Gene', (143, 147))	('gefitinib', 'Var', (12, 21))	('ESCC', 'Disease', (47, 51))	('patients', 'Species', '9606', (81, 89))	('gefitinib', 'Chemical', 'MESH:D000077156', (12, 21))	('EGFR', 'Gene', '1956', (143, 147))	('improves', 'PosReg', (56, 64))	('survival', 'MPA', (69, 77))
108265	33028804	Icotinib is effective in the treatment of ESCC in patients with high EGFR expression.	('EGFR', 'Gene', '1956', (69, 73))	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))	('EGFR', 'Gene', (69, 73))	('Icotinib', 'Chemical', 'MESH:C531470', (0, 8))	('ESCC', 'Disease', (42, 46))
108266	33028804	observed EGFR overexpression or EGFR gene amplification in patients with advanced ESCC.	('ESCC', 'Disease', (82, 86))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('patients', 'Species', '9606', (59, 67))	('EGFR', 'Gene', (32, 36))	('gene amplification', 'Var', (37, 55))	('overexpression', 'PosReg', (14, 28))
108268	33028804	Therefore, this observation indicates that the activity of icotinib is favorable in patients with advanced treated ESCC with EGFR overexpression or gene amplification.	('ESCC', 'Disease', (115, 119))	('patients', 'Species', '9606', (84, 92))	('EGFR', 'Gene', '1956', (125, 129))	('overexpression', 'PosReg', (130, 144))	('icotinib', 'Chemical', 'MESH:C531470', (59, 67))	('gene amplification', 'Var', (148, 166))	('EGFR', 'Gene', (125, 129))	('activity', 'MPA', (47, 55))
108276	33028804	Doi explored the safety and tolerability of trastuzumab in patients with advanced gastric or gastro-esophageal cancer and found that trastuzumab could ameliorate and control the development of disease in most patients.	('trastuzumab', 'Chemical', 'MESH:D000068878', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('trastuzumab', 'Chemical', 'MESH:D000068878', (44, 55))	('cancer', 'Disease', (111, 117))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (59, 67))	('ameliorate', 'PosReg', (151, 161))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('trastuzumab', 'Var', (133, 144))	('gastric', 'Disease', (82, 89))
108310	33028804	studied the effect of Endostar in combination with chemotherapy on the ESCC cell line Eca-109 in mice and found that the combination of Endostar and chemotherapy reduced the tumor weight compared with that of either treatment alone.	('tumor', 'Disease', (174, 179))	('reduced', 'NegReg', (162, 169))	('combination', 'Var', (121, 132))	('mice', 'Species', '10090', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
108339	33028804	The results of phase II and phase III clinical trials of obinutuzumab combined with FOLFOX chemotherapy in gastric/GEJ adenocarcinoma have shown that obinutuzumab cannot improve PFS in MET-positive patients.	('MET', 'Gene', '79811', (185, 188))	('patients', 'Species', '9606', (198, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('obinutuzumab', 'Var', (150, 162))	('FOLFOX', 'Chemical', '-', (84, 90))	('MET', 'Gene', (185, 188))	('GEJ adenocarcinoma', 'Disease', 'MESH:D000230', (115, 133))	('obinutuzumab', 'Chemical', 'MESH:C543332', (57, 69))	('GEJ adenocarcinoma', 'Disease', (115, 133))	('PFS', 'Disease', (178, 181))	('obinutuzumab', 'Chemical', 'MESH:C543332', (150, 162))
108342	33028804	AMG337, a small-molecule inhibitor of MET, can effectively inhibit c-Met/HGF binding.	('AMG337', 'Var', (0, 6))	('MET', 'Gene', '79811', (38, 41))	('AMG337', 'Chemical', 'MESH:C000609912', (0, 6))	('binding', 'Interaction', (77, 84))	('MET', 'Gene', (38, 41))	('c-Met', 'Gene', (67, 72))	('HGF', 'Gene', (73, 76))	('inhibit', 'NegReg', (59, 66))	('c-Met', 'Gene', '4233', (67, 72))	('HGF', 'Gene', '3082', (73, 76))
108343	33028804	At present, completed phase I and II clinical trials have verified that AMG337 showed antitumor activity in patients with EAC with MET amplification.	('AMG337', 'Var', (72, 78))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MET', 'Gene', '79811', (131, 134))	('AMG337', 'Chemical', 'MESH:C000609912', (72, 78))	('patients', 'Species', '9606', (108, 116))	('MET', 'Gene', (131, 134))	('EAC', 'Disease', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
108346	33028804	Dysregulation of mTOR signaling plays a crucial role in tumorigenesis, angiogenesis, cell growth, and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', (56, 61))	('angiogenesis', 'CPA', (71, 83))	('cell growth', 'CPA', (85, 96))	('metastasis', 'CPA', (102, 112))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
108352	33028804	According to an analysis of ESCC patients from the TCGA database, PI3K has abnormal expression in ESCC and can affect survival in patients with ESCC.	('affect', 'Reg', (111, 117))	('abnormal', 'Reg', (75, 83))	('patients', 'Species', '9606', (33, 41))	('ESCC', 'Disease', (98, 102))	('PI3K', 'Var', (66, 70))	('ESCC', 'Disease', (144, 148))	('patients', 'Species', '9606', (130, 138))	('survival', 'CPA', (118, 126))	('expression', 'MPA', (84, 94))
108358	33028804	For example, mutations of the Ras and Raf genes may result in resistance to EGFR antibody, and mutations in genes associated with the PI3K/AKT pathway are related to resistance to HER2 antibody.	('HER2', 'Gene', (180, 184))	('AKT', 'Gene', '207', (139, 142))	('HER2', 'Gene', '2064', (180, 184))	('EGFR', 'Gene', '1956', (76, 80))	('Raf', 'Gene', '673', (38, 41))	('AKT', 'Gene', (139, 142))	('Raf', 'Gene', (38, 41))	('EGFR', 'Gene', (76, 80))	('mutations', 'Var', (95, 104))	('Ras', 'Gene', (30, 33))	('mutations', 'Var', (13, 22))	('result in', 'Reg', (52, 61))	('related', 'Reg', (155, 162))	('resistance', 'MPA', (62, 72))
108370	33028804	Antisense oligonucleotides (ASOs), miRNA sponges, and small interfering RNAs (siRNAs) can inhibit the expression of carcinogenic ncRNAs.	('inhibit', 'NegReg', (90, 97))	('expression', 'MPA', (102, 112))	('carcinogenic ncRNAs', 'Disease', (116, 135))	('carcinogenic ncRNAs', 'Disease', 'MESH:C565633', (116, 135))	('oligonucleotides', 'Chemical', 'MESH:D009841', (10, 26))	('Antisense', 'Var', (0, 9))
108389	33028804	A phase III clinical trial of camrelizumab in the treatment of ESCC was successfully completed and showed that camrelizumab monotherapy could significantly prolong the survival of patients with advanced or metastatic ESCC who failed to respond to first-line chemotherapy, which meant that camrelizumab is likely to be approved for the treatment of ESCC.	('metastatic', 'CPA', (206, 216))	('camrelizumab', 'Var', (111, 123))	('prolong', 'PosReg', (156, 163))	('ESCC', 'Disease', (217, 221))	('survival', 'CPA', (168, 176))	('patients', 'Species', '9606', (180, 188))
108403	33028804	Some studies have also found that tremelimumab could cause adverse effects such as pruritus, skin rash, eosinophilia, diarrhea and fatigue.	('pruritus', 'Phenotype', 'HP:0000989', (83, 91))	('eosinophilia', 'Disease', 'MESH:D004802', (104, 116))	('fatigue', 'Disease', 'MESH:D005221', (131, 138))	('eosinophilia', 'Disease', (104, 116))	('skin rash', 'Disease', (93, 102))	('tremelimumab', 'Chemical', 'MESH:C520704', (34, 46))	('rash', 'Phenotype', 'HP:0000988', (98, 102))	('fatigue', 'Disease', (131, 138))	('skin rash', 'Disease', 'MESH:D005076', (93, 102))	('pruritus', 'Disease', 'MESH:D011537', (83, 91))	('pruritus', 'Disease', (83, 91))	('diarrhea', 'Disease', 'MESH:D003967', (118, 126))	('diarrhea', 'Phenotype', 'HP:0002014', (118, 126))	('diarrhea', 'Disease', (118, 126))	('eosinophilia', 'Phenotype', 'HP:0001880', (104, 116))	('fatigue', 'Phenotype', 'HP:0012378', (131, 138))	('skin rash', 'Phenotype', 'HP:0000988', (93, 102))	('tremelimumab', 'Var', (34, 46))
108417	33028804	Its expression can inhibit the immune response of NK cells, which permits tumor cells to evade their effects and leads to immune escape.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('inhibit', 'NegReg', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('immune escape', 'CPA', (122, 135))	('tumor', 'Disease', (74, 79))	('expression', 'Var', (4, 14))	('immune response', 'CPA', (31, 46))	('leads to', 'Reg', (113, 121))
108425	33028804	Inhibitors of PD-L1 (pembrolizumab), VEGFR (ramucirumab), and HER-2 (trastuzumab) have been verified to improve survival and prognosis in advanced ESCC and EAC.	('HER-2', 'Gene', (62, 67))	('pembrolizumab', 'Chemical', 'MESH:C582435', (21, 34))	('VEGFR', 'Gene', (37, 42))	('EAC', 'Disease', (156, 159))	('Inhibitors', 'Var', (0, 10))	('improve', 'PosReg', (104, 111))	('ESCC', 'Disease', (147, 151))	('trastuzumab', 'Chemical', 'MESH:D000068878', (69, 80))	('VEGFR', 'Gene', '3791', (37, 42))	('PD-L1', 'Gene', (14, 19))	('EAC', 'Phenotype', 'HP:0011459', (156, 159))	('HER-2', 'Gene', '2064', (62, 67))	('ramucirumab', 'Chemical', 'MESH:C543333', (44, 55))
108453	33006693	A contrast-enhanced computed tomography scan (CE-CT) showed clearly enhanced rectal lesion in the upper rectum (Ra) with no lymphadenopathy or distant metastasis (cT3N0M0, cStage IIa, Japanese Society for Cancer of the Colon and Rectum (JSCCR), 3rd edition; cT3N0M0, cStage IIA, Union for International Cancer Control (UICC), 8th edition) (Fig.	('Cancer', 'Phenotype', 'HP:0002664', (205, 211))	('Cancer', 'Disease', (205, 211))	('enhanced', 'PosReg', (68, 76))	('cT3N0M0', 'Var', (258, 265))	('Cancer of the Colon', 'Disease', 'MESH:D015179', (205, 224))	('Cancer', 'Phenotype', 'HP:0002664', (303, 309))	('Cancer', 'Disease', 'MESH:D009369', (205, 211))	('CE-CT', 'Chemical', '-', (46, 51))	('lymphadenopathy', 'Disease', (124, 139))	('rectal lesion', 'CPA', (77, 90))	('Cancer of the Colon', 'Disease', (205, 224))	('lymphadenopathy', 'Disease', 'MESH:D008206', (124, 139))	('Cancer', 'Disease', 'MESH:D009369', (303, 309))	('Cancer', 'Disease', (303, 309))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (124, 139))
108458	33006693	No lymphadenopathy or distant metastasis was detected by CE-CT (cT3N0M0, cStage IIA, Japan Pancreas Society (JPS), 4th edition; cT3N0M0, cStage IIA, UICC 8th).	('cT3N0M0', 'Var', (128, 135))	('lymphadenopathy', 'Disease', 'MESH:D008206', (3, 18))	('distant metastasis', 'CPA', (22, 40))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (3, 18))	('JPS', 'Disease', 'MESH:C537702', (109, 112))	('CE-CT', 'Chemical', '-', (57, 62))	('lymphadenopathy', 'Disease', (3, 18))	('JPS', 'Disease', (109, 112))
108460	33006693	No lymphadenopathy or distant metastasis was detected by CE-CT (cT2N0M0, cStage II, Japan Esophageal Society (JES), 11th edition; cT2N0M0, cStage II, UICC 8th).	('lymphadenopathy', 'Disease', 'MESH:D008206', (3, 18))	('cT2N0M0', 'Var', (130, 137))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (3, 18))	('CE-CT', 'Chemical', '-', (57, 62))	('lymphadenopathy', 'Disease', (3, 18))
108467	33006693	The pathological result was moderately differentiated adenocarcinoma, Ra, pT3N0M0, pStage IIa (JSCCR 3rd); pT3N0M0, pStage IIA (UICC 8th), R0 resection (Fig.	('adenocarcinoma', 'Disease', (54, 68))	('pStage IIa', 'Disease', (83, 93))	('pT3N0M0', 'Var', (107, 114))	('pStage IIA', 'Var', (116, 126))	('adenocarcinoma', 'Disease', 'MESH:D000230', (54, 68))	('pT3N0M0', 'Var', (74, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
108477	33006693	Esophageal cancer showed regression in terms of its invasion into the muscularis mucosae (ycT1aN0M0, ycStage 0, JES 11th; ycT1aN0M0, ycStage I, UICC 8th) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ycT1aN0M0', 'Var', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('invasion', 'CPA', (52, 60))	('ycT1aN0M0', 'Var', (122, 131))
108479	33006693	As a result of the preoperative diagnosis of pancreatic cancer (ycT2N0M0, ycStage IB (JPS 4th) and ycT1cN0M0, ycStage IA (UICC 8th)), the pancreatoduodenectomy (PD) with portal vein resection and reconstruction was performed.	('pancreatic cancer', 'Disease', (45, 62))	('ycT2N0M0', 'Var', (64, 72))	('ycT1cN0M0', 'Var', (99, 108))	('JPS', 'Disease', (86, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('PD', 'Disease', 'MESH:D010300', (161, 163))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('JPS', 'Disease', 'MESH:C537702', (86, 89))	('ycStage IB', 'Disease', (74, 84))
108481	33006693	The pathological result indicated invasive ductal carcinoma of the pancreas (ypT1cN0M0, pStage IA (JPS 4th) and ypT1cN0M0, ycStage IA (UICC 8th)), R0 resection (Fig.	('JPS', 'Disease', (99, 102))	('invasive ductal carcinoma of the pancreas', 'Disease', (34, 75))	('ypT1cN0M0', 'Var', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('JPS', 'Disease', 'MESH:C537702', (99, 102))	('ypT1cN0M0', 'Var', (112, 121))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (43, 59))	('invasive ductal carcinoma of the pancreas', 'Disease', 'MESH:D021441', (34, 75))	('ycStage IA', 'Disease', (123, 133))	('pStage IA', 'Disease', (88, 97))
108537	32273764	Overall survival of patients with ESCC was shorter in the FGD5-AS1 high-expression group than in the FGD5-AS1 low-expression group.	('FGD5-AS1', 'Gene', (58, 66))	('high-expression', 'Var', (67, 82))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (58, 66))	('FGD5-AS1', 'Gene', (101, 109))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (101, 109))	('ESCC', 'Disease', (34, 38))	('patients', 'Species', '9606', (20, 28))	('Overall survival', 'MPA', (0, 16))	('shorter', 'NegReg', (43, 50))
108538	32273764	An FGD5-AS1 knockdown markedly attenuated ESCC cell proliferation, migration, and invasion and promoted apoptosis in vitro as well as slowed tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('promoted', 'PosReg', (95, 103))	('slowed', 'NegReg', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('invasion', 'CPA', (82, 90))	('knockdown', 'Var', (12, 21))	('attenuated', 'NegReg', (31, 41))	('ESCC', 'Disease', (42, 46))	('tumor', 'Disease', (141, 146))	('migration', 'CPA', (67, 76))	('apoptosis', 'CPA', (104, 113))	('FGD5-AS1', 'Gene', (3, 11))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (3, 11))
108540	32273764	An miR-383 knockdown and recovery of SP1 expression attenuated the inhibition of the malignant characteristics of ESCC cells by the FGD5-AS1 knockdown.	('knockdown', 'Var', (141, 150))	('inhibition', 'NegReg', (67, 77))	('miR-383', 'Gene', (3, 10))	('FGD5-AS1', 'Gene', (132, 140))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (132, 140))	('attenuated', 'NegReg', (52, 62))	('SP1', 'Gene', (37, 40))	('miR-383', 'Gene', '494332', (3, 10))
108578	32273764	TE-1 cells were transfected with a lentivirus containing either pLKO.1-sh-FGD5-AS1 or pLKO.1-sh-NC and were selected with 2 mug/mL puromycin.	('pLKO.1-sh-NC', 'Var', (86, 98))	('puromycin', 'Chemical', 'MESH:D011691', (131, 140))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (74, 82))	('FGD5-AS1', 'Gene', (74, 82))
108586	32273764	The fragment of the 3'-untranslated region (UTR) of SP1 containing either the wild-type (wt) miR-383-binding site or the mutant (mut) site was amplified by GenePharma and inserted into the pmirGLO Dual-Luciferase reporter vector (Promega, Madison, WI, USA), thereby resulting in reporter vectors SP1-wt and SP1-mut.	('miR-383', 'Gene', '494332', (93, 100))	('SP1', 'Gene', (52, 55))	('mutant', 'Var', (121, 127))	('miR-383', 'Gene', (93, 100))
108603	32273764	In addition, patients in the FGD5-AS1 high-expression group showed shorter overall survival compared to the patients in the FGD5-AS1 low-expression group (Figure 1C, P = 0.033).	('FGD5-AS1', 'Gene', (124, 132))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (124, 132))	('patients', 'Species', '9606', (13, 21))	('FGD5-AS1', 'Gene', (29, 37))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (29, 37))	('high-expression', 'Var', (38, 53))	('shorter', 'NegReg', (67, 74))	('overall survival', 'MPA', (75, 91))	('patients', 'Species', '9606', (108, 116))
108605	32273764	RT-qPCR analysis of TE-1 and Eca109 cells verified the success of the FGD5-AS1 knockdown by si-FGD5-AS1 transfection (Figure 2A, P < 0.05).	('si-FGD5-AS1', 'Gene', '100505641;5729', (92, 103))	('FGD5-AS1', 'Gene', (70, 78))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (70, 78))	('FGD5-AS1', 'Gene', (95, 103))	('si-FGD5-AS1', 'Gene', (92, 103))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (95, 103))	('knockdown', 'Var', (79, 88))
108607	32273764	As indicated in Figure 2B and C, the knockdown of FGD5-AS1 obviously decreased proliferation (P < 0.05) and enhanced the apoptosis (P < 0.05) of TE-1 and Eca109 cells.	('decreased', 'NegReg', (69, 78))	('knockdown', 'Var', (37, 46))	('FGD5-AS1', 'Gene', (50, 58))	('enhanced', 'PosReg', (108, 116))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (50, 58))	('apoptosis', 'CPA', (121, 130))
108619	32273764	RT-qPCR analysis was carried out to measure miR-383 expression in TE-1 and Eca109 cells after transfection with either si-FGD5-AS1 or si-NC; the results revealed that the knockdown of FGD5-AS1 substantially increased miR-383 expression (Figure 3E, P < 0.05).	('miR-383', 'Gene', (217, 224))	('si-FGD5-AS1', 'Gene', '100505641;5729', (119, 130))	('miR-383', 'Gene', '494332', (44, 51))	('FGD5-AS1', 'Gene', (184, 192))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (184, 192))	('increased', 'PosReg', (207, 216))	('si-FGD5-AS1', 'Gene', (119, 130))	('knockdown', 'Var', (171, 180))	('FGD5-AS1', 'Gene', (122, 130))	('miR-383', 'Gene', (44, 51))	('miR-383', 'Gene', '494332', (217, 224))	('expression', 'MPA', (225, 235))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (122, 130))
108625	32273764	The luciferase activity of reporter plasmid SP1-wt was dramatically lower in miR-383-overexpressing TE-1 and Eca109 cells (P < 0.05), whereas the mutation of the miR-383-binding site abrogated the negative impact of miR-383 upregulation on the luciferase activity (Figure 4B).	('miR-383', 'Gene', (216, 223))	('mutation', 'Var', (146, 154))	('lower', 'NegReg', (68, 73))	('miR-383', 'Gene', '494332', (162, 169))	('miR-383', 'Gene', '494332', (77, 84))	('activity', 'MPA', (15, 23))	('luciferase', 'Enzyme', (244, 254))	('miR-383', 'Gene', (162, 169))	('miR-383', 'Gene', '494332', (216, 223))	('miR-383', 'Gene', (77, 84))	('luciferase', 'Enzyme', (4, 14))	('activity', 'MPA', (255, 263))
108631	32273764	The FGD5-AS1 knockdown reduced the expression of SP1 in TE-1 and Eca109 cells at the mRNA (Figure 4G, P < 0.05) and protein levels (Figure 4H, P < 0.05).	('FGD5-AS1', 'Gene', '100505641;152273;5729', (4, 12))	('expression', 'MPA', (35, 45))	('protein levels', 'MPA', (116, 130))	('knockdown', 'Var', (13, 22))	('reduced', 'NegReg', (23, 30))	('FGD5-AS1', 'Gene', (4, 12))	('SP1', 'Gene', (49, 52))
108635	32273764	Antagomir-383 transfection markedly reduced the expression of miR-383 in TE-1 and Eca109 cells as evidenced by RT-qPCR (Figure 4J, P < 0.05).	('miR-383', 'Gene', (62, 69))	('expression', 'MPA', (48, 58))	('transfection', 'Var', (14, 26))	('reduced', 'NegReg', (36, 43))	('miR-383', 'Gene', '494332', (62, 69))	('Antagomir-383', 'Chemical', '-', (0, 13))
108637	32273764	The effects of the FGD5-AS1 knockdown on SP1 mRNA (Figure 4K, P < 0.05) and protein amounts (Figure 4L, P < 0.05) were reversed by antagomir-383.	('protein amounts', 'MPA', (76, 91))	('SP1 mRNA', 'MPA', (41, 49))	('FGD5-AS1', 'Gene', (19, 27))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (19, 27))	('knockdown', 'Var', (28, 37))
108644	32273764	In addition, the effects of the FGD5-AS1 knockdown on the migration (Figure 6D, P < 0.05) and invasiveness (Figure 6E, P < 0.05) of TE-1 and Eca109 cells were weakened by the reintroduction of SP1.	('FGD5-AS1', 'Gene', (32, 40))	('invasiveness', 'CPA', (94, 106))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (32, 40))	('weakened', 'NegReg', (159, 167))	('knockdown', 'Var', (41, 50))	('migration', 'CPA', (58, 67))
108651	32273764	In brief, the FGD5-AS1 knockdown targeted the miR-383-SP1 axis, thereby retarding the tumor growth of ESCC cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (14, 22))	('miR-383', 'Gene', '494332', (46, 53))	('tumor', 'Disease', (86, 91))	('ESCC', 'Disease', (102, 106))	('knockdown', 'Var', (23, 32))	('retarding', 'NegReg', (72, 81))	('miR-383', 'Gene', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('FGD5-AS1', 'Gene', (14, 22))
108658	32273764	High FGD5-AS1 expression showed a significant correlation with tumor size, TNM stage, lymph node metastasis, and shorter overall survival among patients with ESCC.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TNM', 'Gene', (75, 78))	('High', 'Var', (0, 4))	('lymph node metastasis', 'CPA', (86, 107))	('FGD5-AS1', 'Gene', (5, 13))	('overall', 'MPA', (121, 128))	('ESCC', 'Disease', (158, 162))	('expression', 'MPA', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (5, 13))	('TNM', 'Gene', '10178', (75, 78))	('patients', 'Species', '9606', (144, 152))	('shorter', 'NegReg', (113, 120))
108659	32273764	In terms of function, the FGD5-AS1 knockdown led to an obvious reduction in cell proliferation, migration, and invasion as well as induction of apoptosis.	('knockdown', 'Var', (35, 44))	('migration', 'CPA', (96, 105))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (26, 34))	('cell proliferation', 'CPA', (76, 94))	('induction', 'Reg', (131, 140))	('apoptosis', 'CPA', (144, 153))	('reduction', 'NegReg', (63, 72))	('FGD5-AS1', 'Gene', (26, 34))	('invasion', 'CPA', (111, 119))
108662	32273764	As for the mechanism, FGD5-AS1 can increase CDCA7 expression by sponging miR-302e and thereby raises the malignancy of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('raises', 'PosReg', (94, 100))	('increase', 'PosReg', (35, 43))	('malignancy of colorectal cancer', 'Disease', (105, 136))	('CDCA7', 'Gene', '83879', (44, 49))	('FGD5-AS1', 'Gene', (22, 30))	('malignancy of colorectal cancer', 'Disease', 'MESH:D015179', (105, 136))	('CDCA7', 'Gene', (44, 49))	('sponging', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (22, 30))	('miR-302e', 'Gene', (73, 81))	('expression', 'MPA', (50, 60))	('miR-302e', 'Gene', '100313774', (73, 81))
108666	32273764	Third, the knockdown of FGD5-AS1 increased the expression of miR-383 in ESCC cells.	('FGD5-AS1', 'Gene', (24, 32))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (24, 32))	('expression', 'MPA', (47, 57))	('miR-383', 'Gene', '494332', (61, 68))	('increased', 'PosReg', (33, 42))	('knockdown', 'Var', (11, 20))	('miR-383', 'Gene', (61, 68))
108668	32273764	Fifth, the knockdown of FGD5-AS1 decreased SP1 expression in ESCC cells at both the mRNA and protein levels and the positive influence of FGD5-AS1 on SP1 expression was demonstrated to be mediated by the sponging of miR-383.	('FGD5-AS1', 'Gene', (138, 146))	('FGD5-AS1', 'Gene', (24, 32))	('miR-383', 'Gene', (216, 223))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (138, 146))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (24, 32))	('SP1', 'Gene', (43, 46))	('miR-383', 'Gene', '494332', (216, 223))	('decreased', 'NegReg', (33, 42))	('knockdown', 'Var', (11, 20))
108669	32273764	Finally, the miR-383 knockdown and SP1 overexpression greatly attenuated the inhibitory influence of the FGD5-AS1 knockdown on the malignancy of ESCC cells.	('miR-383', 'Gene', (13, 20))	('attenuated', 'NegReg', (62, 72))	('knockdown', 'Var', (114, 123))	('malignancy', 'Disease', 'MESH:D009369', (131, 141))	('FGD5-AS1', 'Gene', (105, 113))	('malignancy', 'Disease', (131, 141))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (105, 113))	('inhibitory influence', 'MPA', (77, 97))	('miR-383', 'Gene', '494332', (13, 20))	('ESCC', 'Disease', (145, 149))
108676	32273764	The dysregulation of SP1 contributes to cancer initiation and progression by affecting a wide variety of biological behaviors.	('affecting', 'Reg', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('dysregulation', 'Var', (4, 17))	('contributes', 'Reg', (25, 36))	('cancer', 'Disease', (40, 46))	('SP1', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
108677	32273764	Our study indicates that the knockdown of FGD5-AS1 reduces miR-383 sponging, thus reducing SP1 expression in ESCC, thereby diminishing the malignancy of ESCC cells in vitro and in vivo.	('reducing', 'NegReg', (82, 90))	('knockdown', 'Var', (29, 38))	('miR-383', 'Gene', (59, 66))	('FGD5-AS1', 'Gene', '100505641;152273;5729', (42, 50))	('reduces', 'NegReg', (51, 58))	('SP1 expression', 'MPA', (91, 105))	('malignancy', 'Disease', 'MESH:D009369', (139, 149))	('malignancy', 'Disease', (139, 149))	('miR-383', 'Gene', '494332', (59, 66))	('diminishing', 'NegReg', (123, 134))	('FGD5-AS1', 'Gene', (42, 50))
108846	27838937	These technologies hold the promise to analyze a panel of indication-specific biomarkers in an individual's tumor which can guide oncologists to optimal patient management strategies based on what is expressed or mutated in a patient's tumor sample.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patient', 'Species', '9606', (226, 233))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('patient', 'Species', '9606', (153, 160))	('mutated', 'Var', (213, 220))	('tumor', 'Disease', (236, 241))
108886	27838937	Genomic alterations in cancer cells result in abnormalities of protein expression which can give insight on whether certain drugs will be effective.	('abnormalities', 'Var', (46, 59))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('protein expression', 'MPA', (63, 81))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('result', 'Reg', (36, 42))
108898	27838937	Indeed, earlier detection and an expanding arsenal of targeted therapy, small-molecule therapy and chemotherapies have contributed to heightened clinical care for cancer patients.	('patients', 'Species', '9606', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('small-molecule', 'Var', (72, 86))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
108929	27838937	The ToGA trial demonstrated that the cohorts of gastroesophageal patients with the most HER2 expression had longer survival rates on anti-HER2 therapy than other +3 IHC HER2 positive patients on the lower end of the HER2 expression, as quantified by mass spectrometry.	('expression', 'Var', (93, 103))	('HER2', 'Gene', '2064', (138, 142))	('HER2', 'Gene', (169, 173))	('survival rates', 'CPA', (115, 129))	('gastroesophageal', 'Disease', 'MESH:D005764', (48, 64))	('HER2', 'Gene', '2064', (169, 173))	('HER2', 'Gene', (88, 92))	('HER2', 'Gene', '2064', (88, 92))	('HER2', 'Gene', (216, 220))	('gastroesophageal', 'Disease', (48, 64))	('longer', 'PosReg', (108, 114))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (183, 191))	('HER2', 'Gene', '2064', (216, 220))	('HER2', 'Gene', (138, 142))
108937	27838937	Targeting the extracellular receptor tyrosine-protein kinase erbB-2 (HER2) transformed breast cancer therapy dramatically over the last 15 years when it was discovered that blocking the growth factor receptor with monoclonal antibodies demonstrated inhibition of tumor progression and metastases.	('blocking', 'Var', (173, 181))	('metastases', 'Disease', (285, 295))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('receptor tyrosine-protein kinase erbB-2', 'Gene', '2064', (28, 67))	('metastases', 'Disease', 'MESH:D009362', (285, 295))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('inhibition', 'NegReg', (249, 259))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('tumor', 'Disease', (263, 268))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('HER2', 'Gene', (69, 73))	('receptor tyrosine-protein kinase erbB-2', 'Gene', (28, 67))	('HER2', 'Gene', '2064', (69, 73))
108953	27838937	Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is expressed on the surface of helper T cells and binds to CD86 and CD80 on antigen-presenting cells transmitting an inhibitory signal to T-cells.	('inhibitory signal', 'MPA', (170, 187))	('CD86', 'Gene', '942', (112, 116))	('CD86', 'Gene', (112, 116))	('CD80', 'Var', (121, 125))	('binds', 'Interaction', (103, 108))	('Cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (0, 43))	('CTLA-4', 'Gene', '1493', (45, 51))	('Cytotoxic T-lymphocyte-associated protein 4', 'Gene', (0, 43))	('CTLA-4', 'Gene', (45, 51))
108955	27838937	CTLA-4 blockade has demonstrated an inhibitory effect on the immune system's tolerance to tumors and has opened another exciting avenue to a potentially useful immunotherapy strategy for cancer patients regardless of their PD-L1 status.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('inhibitory', 'NegReg', (36, 46))	('patients', 'Species', '9606', (194, 202))	('CTLA-4', 'Gene', (0, 6))	('cancer', 'Disease', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('CTLA-4', 'Gene', '1493', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('blockade', 'Var', (7, 15))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('inhibitory effect on the immune system', 'Phenotype', 'HP:0002721', (36, 74))
108963	27838937	MEDI4736 blocks the interaction between PD-L1 with the PD-1 (CD80) molecules, and enhancing T-cell activation and inhibiting immune defense avoidance.	('MEDI4736', 'Chemical', 'MESH:C000613593', (0, 8))	('interaction', 'Interaction', (20, 31))	('immune defense avoidance', 'Phenotype', 'HP:0002958', (125, 149))	('immune defense avoidance', 'CPA', (125, 149))	('T-cell activation', 'CPA', (92, 109))	('inhibiting', 'NegReg', (114, 124))	('blocks', 'NegReg', (9, 15))	('enhancing', 'PosReg', (82, 91))	('MEDI4736', 'Var', (0, 8))
108971	27838937	Adding an immunotherapy regimen would not be too cumbersome on esophageal cancer patients due to the following reasons: MEDI4736 - 1 hr infusions (10 mg/kg) every 14 days (Terminal half-life of MEDI4736 is 23 days, so infusion intervals may extend soon).	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('patients', 'Species', '9606', (81, 89))	('MEDI4736', 'Chemical', 'MESH:C000613593', (194, 202))	('MEDI4736', 'Chemical', 'MESH:C000613593', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('MEDI4736', 'Var', (120, 128))
108987	27838937	Out of all clinical trials, investigation NCT02340975 (shown in red in Table 2) has high potential to benefit esophageal adenocarcinoma patients directly as drugs MEDI4736 and tremelimumab would bring a double edged sword to the table, stimulating the immune system to attack cancer with or without the expression of PD-L1 in the tumor.	('esophageal adenocarcinoma', 'Disease', (110, 135))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (110, 135))	('MEDI4736', 'Chemical', 'MESH:C000613593', (163, 171))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (110, 135))	('tumor', 'Disease', (330, 335))	('patients', 'Species', '9606', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('stimulating', 'PosReg', (236, 247))	('NCT02340975', 'Var', (42, 53))	('tremelimumab', 'Chemical', 'MESH:C520704', (176, 188))	('benefit', 'PosReg', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
109000	27838937	PD-L1 positive patients also had progression-free survival (PFS) that was four months longer than those without PD-L1 in their tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('patients', 'Species', '9606', (15, 23))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('positive', 'Var', (6, 14))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('PD-L1', 'Gene', (0, 5))	('longer', 'PosReg', (86, 92))	('progression-free survival', 'CPA', (33, 58))
109011	27838937	It has been concluded that MEDI4736 + Tremelimumab should be 'fast-tracked' for treatment of esophageal cancer if the highlighted clinical trials are deemed safe and successful after peer review.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('Tremelimumab', 'Chemical', 'MESH:C520704', (38, 50))	('MEDI4736', 'Var', (27, 35))	('MEDI4736', 'Chemical', 'MESH:C000613593', (27, 35))
109048	27838937	PD-L1 is expressed in 40% of gastroesophageal cancers; therefore, anti-PD-L1 therapy in combination with anti-CTLA-4 immunotherapy would pack a large enough punch to potentially improve survival outcomes for esophageal cancer patients.	('anti-PD-L1', 'Var', (66, 76))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('improve', 'PosReg', (178, 185))	('CTLA-4', 'Gene', (110, 116))	('esophageal cancer', 'Disease', (208, 225))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (29, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('patients', 'Species', '9606', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('survival', 'CPA', (186, 194))	('CTLA-4', 'Gene', '1493', (110, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('gastroesophageal cancers', 'Disease', (29, 53))
109076	25810870	In vivo studies have also shown that fumonisins can cause intestinal villi atrophy and absorption disorder.	('fumonisins', 'Var', (37, 47))	('cause', 'Reg', (52, 57))	('intestinal villi atrophy', 'Phenotype', 'HP:0011473', (58, 82))	('intestinal villi atrophy and absorption disorder', 'Disease', 'MESH:C564600', (58, 106))	('fumonisin', 'Chemical', 'MESH:D037341', (37, 46))
109078	25810870	In addition, long-term consumption of fumonisin may also change intestinal cell morphology such as goblet cell reduction, cause atrophy and decrease mucin secretion.	('reduction', 'NegReg', (111, 120))	('cause', 'NegReg', (122, 127))	('fumonisin', 'Var', (38, 47))	('atrophy', 'Disease', (128, 135))	('fumonisin', 'Chemical', 'MESH:D037341', (38, 47))	('decrease', 'NegReg', (140, 148))	('intestinal cell morphology', 'CPA', (64, 90))	('change', 'Reg', (57, 63))	('atrophy', 'Disease', 'MESH:D001284', (128, 135))	('mucin secretion', 'MPA', (149, 164))	('goblet cell', 'CPA', (99, 110))
109080	25810870	Epidemiologic studies in some areas of South Africa, Japan, China and Iran have shown the high incidence of the esophageal cancer with the FB1 contaminated maize high consumption compared to low risk regions of esophageal cancer that had a lower intake of the FB1 contaminated maize (13, 17-20).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('maize', 'Species', '4577', (277, 282))	('maize', 'Species', '4577', (156, 161))	('FB1', 'Var', (139, 142))	('esophageal cancer', 'Disease', (211, 228))	('esophageal cancer', 'Disease', (112, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
109096	25810870	Briefly, the sections were treated with 3% (v/v) H2O2 at room temperature, blocked with 10% (v/v) goat or rabbit serum (Nichirei, Tokyo, Japan), and incubated with a rabbit monoclonal antibody against Ki-67 (Thermo Fisher Scientific Inc., San Jose, CA) diluted 1:200.	('H2O2', 'Var', (49, 53))	('rat', 'Species', '10116', (67, 70))	('goat', 'Species', '9925', (98, 102))	('rabbit', 'Species', '9986', (166, 172))	('Ki-67', 'Gene', '17345', (201, 206))	('Ki-67', 'Gene', (201, 206))	('rabbit', 'Species', '9986', (106, 112))	('H2O2', 'Chemical', 'MESH:D006861', (49, 53))
109130	25810870	On the other hand, FB1 has been identified as an inhibitor of ceramide enzyme, leading to significant alterations in sphingolipid metabolism, which is a key enzyme in sphingolipid metabolism, and various sphingolipids production involved in apoptosis.	('sphingolipids', 'Chemical', 'MESH:D013107', (204, 217))	('ceramide', 'Chemical', 'MESH:D002518', (62, 70))	('FB1', 'Var', (19, 22))	('sphingolipid', 'Chemical', 'MESH:D013107', (117, 129))	('sphingolipid metabolism', 'MPA', (117, 140))	('sphingolipids production', 'MPA', (204, 228))	('sphingolipid', 'Chemical', 'MESH:D013107', (204, 216))	('rat', 'Species', '10116', (106, 109))	('alterations', 'Reg', (102, 113))	('sphingolipid', 'Chemical', 'MESH:D013107', (167, 179))
109273	19930599	The CR rate for T1-3 M0 disease was significantly higher than for T4/M1 disease (84.2% versus 28.6%; p = 0.0031), while no statistical significance was observed for the response rate (CR + PR).	('CR', 'Chemical', '-', (184, 186))	('higher', 'PosReg', (50, 56))	('T1-3 M0', 'Var', (16, 23))	('CR', 'Chemical', '-', (4, 6))
109299	19930599	According to previous clinical trials of this type of chemoradiotherapy for esophageal squamous cell carcinoma, T1N0 M0 patients showed 3- and 5-year overall survival rates of 80% and 75.5%-77%, respectively, while the corresponding rates in T2-3/M0 patients were 49% and 46%, with a MST of 34 months.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (76, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('patients', 'Species', '9606', (250, 258))	('patients', 'Species', '9606', (120, 128))	('T1N0 M0', 'Var', (112, 119))	('esophageal squamous cell carcinoma', 'Disease', (76, 110))
109340	33728379	It is believed that dysregulation of Ca2+ cellular homeostasis could result in several pathological conditions such as cardiovascular diseases, neurodegenerative ailments, developmental abnormalities, diabetes, immunodeficiency disorders and cancer.	('cardiovascular diseases', 'Disease', (119, 142))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (119, 142))	('pathological', 'Disease', (87, 99))	('dysregulation', 'Var', (20, 33))	('immunodeficiency disorders', 'Disease', (211, 237))	('immunodeficiency disorders', 'Disease', 'MESH:D007153', (211, 237))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('immunodeficiency', 'Phenotype', 'HP:0002721', (211, 227))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (172, 199))	('diabetes', 'Disease', 'MESH:D003920', (201, 209))	('rat', 'Species', '10116', (155, 158))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (119, 142))	('neurodegenerative ailments', 'Phenotype', 'HP:0002180', (144, 170))	('developmental abnormalities', 'Disease', (172, 199))	('developmental abnormalities', 'Disease', 'MESH:D006130', (172, 199))	('cancer', 'Disease', (242, 248))	('neurodegenerative ailments', 'Disease', (144, 170))	('diabetes', 'Disease', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('result in', 'Reg', (69, 78))	('Ca2+', 'Chemical', 'MESH:D000069285', (37, 41))
109344	33728379	Ca2+ influx through CRAC channels causes the activation of various downstream signaling pathways which are involved in the regulation of gene expression, cell proliferation, apoptosis, cytokine generation and many other cellular activities.	('CRAC', 'Gene', (20, 24))	('rat', 'Species', '10116', (166, 169))	('Ca2+', 'Chemical', 'MESH:D000069285', (0, 4))	('downstream signaling pathways', 'Pathway', (67, 96))	('rat', 'Species', '10116', (198, 201))	('activation', 'PosReg', (45, 55))	('CRAC', 'Chemical', '-', (20, 24))	('Ca2+', 'Var', (0, 4))
109366	33728379	Also, STIM1 is reportedly a more efficient activator of CRAC channel activity, possibly due to its rapid aggregation kinetics and stronger ability to associate with Orai.	('activity', 'MPA', (69, 77))	('CRAC', 'Protein', (56, 60))	('associate', 'Interaction', (150, 159))	('CRAC', 'Chemical', '-', (56, 60))	('STIM1', 'Var', (6, 11))
109380	33728379	Calcineurin further causes the dephosphorylation of several phosphoserines located in the regulatory domain of NFAT (nuclear factor of activated T cells).	('causes', 'Reg', (20, 26))	('NFAT', 'Gene', (111, 115))	('phosphoserines', 'Chemical', 'MESH:D010768', (60, 74))	('dephosphorylation of several phosphoserines', 'MPA', (31, 74))	('Calcineurin', 'Var', (0, 11))
109382	33728379	Ca2+ entry through CRAC channels is also known to activate other transcription factors like NF-kB (nuclear factor-kB) and CREB (cAMP responsive element binding protein).	('CREB', 'Gene', (122, 126))	('Ca2+', 'Chemical', 'MESH:D000069285', (0, 4))	('cAMP responsive element binding protein', 'Gene', (128, 167))	('CREB', 'Gene', '1385', (122, 126))	('CRAC', 'Chemical', '-', (19, 23))	('NF-kB', 'Gene', (92, 97))	('CRAC', 'Gene', (19, 23))	('activate', 'PosReg', (50, 58))	('cAMP responsive element binding protein', 'Gene', '1385', (128, 167))	('Ca2+', 'Var', (0, 4))
109385	33728379	Ca2+ mediated activation of CREB has been reported to enhance the proliferation of vascular smooth muscle cells.	('activation', 'PosReg', (14, 24))	('proliferation of vascular smooth muscle cells', 'CPA', (66, 111))	('Ca2+', 'Chemical', 'MESH:D000069285', (0, 4))	('rat', 'Species', '10116', (73, 76))	('CREB', 'Gene', (28, 32))	('enhance', 'PosReg', (54, 61))	('CREB', 'Gene', '1385', (28, 32))	('Ca2+', 'Var', (0, 4))
109394	33728379	A microarray data analysis has shown that the breast cancer subtype with the poorest prognosis is linked to high STIM1 and low STIM2 tumor expression profile, indicating that alteration in CRAC channel pathway may be associated with poor prognosis in breast cancer patients.	('CRAC channel pathway', 'Pathway', (189, 209))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('STIM2', 'Gene', (127, 132))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Disease', (46, 59))	('STIM2', 'Gene', '57620', (127, 132))	('patients', 'Species', '9606', (265, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('CRAC', 'Chemical', '-', (189, 193))	('alteration', 'Var', (175, 185))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('breast cancer', 'Disease', (251, 264))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (133, 138))	('rat', 'Species', '10116', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('associated', 'Reg', (217, 227))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('low', 'NegReg', (123, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
109396	33728379	The essential role of Orai1 and STIM1 in breast cancer cell migration and metastasis has been delineated by Yang et al.. Silencing STIM1 or ORAI1 in highly metastatic human breast cancer cells or treatment with a pharmacological inhibitor of CRAC channel resulted in reduced tumor metastasis in mice.	('Silencing', 'Var', (121, 130))	('Orai1', 'Gene', '84876', (22, 27))	('tumor metastasis', 'Disease', (275, 291))	('human', 'Species', '9606', (167, 172))	('rat', 'Species', '10116', (63, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Disease', (173, 186))	('STIM1', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('ORAI1', 'Gene', (140, 145))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('mice', 'Species', '10090', (295, 299))	('Orai1', 'Gene', (22, 27))	('breast cancer', 'Disease', (41, 54))	('tumor metastasis', 'Disease', 'MESH:D009362', (275, 291))	('CRAC', 'Chemical', '-', (242, 246))	('reduced', 'NegReg', (267, 274))
109399	33728379	The same group later demonstrated that silencing Orai3 could cause reduction in the anchorage-independent growth and the invasion of MCF-7 breast cancer cells (estrogen receptor positive), while having no such effect on MDA-MB-231 cells (estrogen receptor negative).	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('anchorage-independent growth', 'CPA', (84, 112))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (220, 230))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (133, 152))	('Orai3', 'Gene', '93129', (49, 54))	('MCF-7 breast cancer', 'Disease', (133, 152))	('reduction', 'NegReg', (67, 76))	('silencing', 'Var', (39, 48))	('estrogen receptor', 'Gene', (238, 255))	('estrogen receptor', 'Gene', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('invasion', 'CPA', (121, 129))	('estrogen receptor', 'Gene', '2099', (238, 255))	('estrogen receptor', 'Gene', '2099', (160, 177))	('Orai3', 'Gene', (49, 54))	('rat', 'Species', '10116', (28, 31))
109402	33728379	Furthermore, Orai3 silencing led to inhibition of MCF-7 cell proliferation and cell cycle arrest at G1 phase.	('arrest', 'Disease', 'MESH:D006323', (90, 96))	('MCF-7', 'Gene', (50, 55))	('Orai3', 'Gene', '93129', (13, 18))	('inhibition', 'NegReg', (36, 46))	('silencing', 'Var', (19, 28))	('Orai3', 'Gene', (13, 18))	('arrest', 'Disease', (90, 96))	('rat', 'Species', '10116', (68, 71))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (79, 96))	('MCF-7', 'CellLine', 'CVCL:0031', (50, 55))
109403	33728379	Mechanistically, this was attributed to a decline in the expression of cyclins E/D1 as well as cyclin-dependent kinases (CDKs 4/2) and a concomitant accumulation of cyclin-dependent kinase inhibitor p21(Waf1/Cip1) and tumor suppressor protein p53.	('expression', 'MPA', (57, 67))	('decline', 'NegReg', (42, 49))	('CDKs 4/2', 'Gene', '1019;1017', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('cyclin-dependent', 'MPA', (95, 111))	('p21(Waf1/Cip1', 'Gene', '1026', (199, 212))	('E/D1', 'SUBSTITUTION', 'None', (79, 83))	('CDKs 4/2', 'Gene', (121, 129))	('E/D1', 'Var', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('accumulation', 'PosReg', (149, 161))	('p53', 'Gene', (243, 246))	('p53', 'Gene', '7157', (243, 246))	('tumor', 'Disease', (218, 223))	('cyclins', 'Protein', (71, 78))
109404	33728379	Silencing of Orai3, however, did not affect cell proliferation, cell cycle progression and the expression of cyclins D1/E, CDKs 4/2 and p21(Waf1/Cip1) in MCF-10A cells.	('Orai3', 'Gene', '93129', (13, 18))	('cell proliferation', 'CPA', (44, 62))	('rat', 'Species', '10116', (56, 59))	('cyclins D1/E, CDKs 4/2', 'Gene', '595;1019;1017', (109, 131))	('p21(Waf1/Cip1', 'Gene', '1026', (136, 149))	('Orai3', 'Gene', (13, 18))	('affect', 'Reg', (37, 43))	('cell cycle progression', 'CPA', (64, 86))	('Silencing', 'Var', (0, 9))	('MCF-10A', 'CellLine', 'CVCL:0598', (154, 161))
109409	33728379	The five-year survival rate was considerably lower in cervical cancer patients with high expression of STIM1.	('patients', 'Species', '9606', (70, 78))	('high expression', 'Var', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('rat', 'Species', '10116', (23, 26))	('lower', 'NegReg', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('STIM1', 'Gene', (103, 108))	('cancer', 'Disease', (63, 69))
109410	33728379	This comprehensive study further demonstrated that silencing of STIM1 could inhibit proliferation of cervical cancer cells by inducing cell cycle arrest at the S and G2/M phases.	('silencing', 'Var', (51, 60))	('cancer', 'Disease', (110, 116))	('inducing', 'Reg', (126, 134))	('inhibit', 'NegReg', (76, 83))	('rat', 'Species', '10116', (91, 94))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('rat', 'Species', '10116', (40, 43))	('arrest', 'Disease', 'MESH:D006323', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('STIM1', 'Gene', (64, 69))	('arrest', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
109411	33728379	In addition, the overexpression of STIM1 was found to promote migration of cervical cancer cells, while its knockdown reduced such invasive migration.	('migration', 'CPA', (62, 71))	('knockdown', 'Var', (108, 117))	('promote', 'PosReg', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('reduced', 'NegReg', (118, 125))	('rat', 'Species', '10116', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('overexpression', 'PosReg', (17, 31))	('invasive migration', 'CPA', (131, 149))	('STIM1', 'Gene', (35, 40))	('rat', 'Species', '10116', (65, 68))
109412	33728379	Also, high STIM1 expression correlated with tumor growth, local invasion and angiogenesis in animal models.	('expression', 'MPA', (17, 27))	('angiogenesis', 'CPA', (77, 89))	('local invasion', 'CPA', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('high', 'Var', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('STIM1', 'Gene', (11, 16))	('tumor', 'Disease', (44, 49))	('correlated', 'Reg', (28, 38))
109416	33728379	It was observed that ccRCC cell migration and proliferation declined considerably upon knocking down Orai1 or STIM1.	('Orai1', 'Gene', '84876', (101, 106))	('STIM1', 'Gene', (110, 115))	('knocking down', 'Var', (87, 100))	('declined', 'NegReg', (60, 68))	('rat', 'Species', '10116', (53, 56))	('ccRCC', 'Disease', (21, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('rat', 'Species', '10116', (35, 38))	('Orai1', 'Gene', (101, 106))
109419	33728379	The authors further reported that CRC cell motility gets enhanced by ectopic expression of STIM1, whereas STIM1 silencing via shRNA could prevent migration of CRC cells.	('rat', 'Species', '10116', (149, 152))	('migration of CRC cells', 'CPA', (146, 168))	('CRC', 'Phenotype', 'HP:0003003', (34, 37))	('STIM1', 'Gene', (91, 96))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('silencing', 'NegReg', (112, 121))	('CRC cell motility', 'CPA', (34, 51))	('prevent', 'NegReg', (138, 145))	('enhanced', 'PosReg', (57, 65))	('ectopic expression', 'Var', (69, 87))
109420	33728379	In addition, their results indicated that STIM1 mediated CRC cell migration involved enhanced COX-2 (cyclooxygenase-2) expression and production of PGE2 (prostaglandin E2).	('CRC', 'Phenotype', 'HP:0003003', (57, 60))	('expression', 'MPA', (119, 129))	('COX-2', 'Gene', (94, 99))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (154, 170))	('cyclooxygenase-2', 'Gene', (101, 117))	('enhanced', 'PosReg', (85, 93))	('CRC cell migration', 'CPA', (57, 75))	('cyclooxygenase-2', 'Gene', '5743', (101, 117))	('COX-2', 'Gene', '5743', (94, 99))	('PGE2', 'Chemical', 'MESH:D015232', (148, 152))	('production of PGE2', 'MPA', (134, 152))	('STIM1', 'Var', (42, 47))	('rat', 'Species', '10116', (69, 72))
109426	33728379	Moreover, this study showed that knockdown of Orai1 and STIM1 reduced the proliferation, migration and invasion of gastric cancer cells in vitro, as well as resulted in significant inhibition of tumor growth and metastasis in vivo.	('STIM1', 'Gene', (56, 61))	('Orai1', 'Gene', (46, 51))	('Orai1', 'Gene', '84876', (46, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('tumor', 'Disease', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('knockdown', 'Var', (33, 42))	('rat', 'Species', '10116', (81, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('rat', 'Species', '10116', (92, 95))	('inhibition', 'NegReg', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('migration', 'CPA', (89, 98))	('invasion', 'CPA', (103, 111))	('reduced', 'NegReg', (62, 69))	('gastric cancer', 'Disease', (115, 129))
109434	33728379	Therefore, Orai1 expression may be considered as a prognostic marker of 5-fluorouracil sensitivity for hepatocellular carcinoma therapy and blocking CRAC channel mediated SOCE may sensitize hepatocellular carcinoma cells to 5-fluorouracil chemotherapy.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('sensitize', 'Reg', (180, 189))	('blocking', 'Var', (140, 148))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('CRAC channel mediated', 'Gene', (149, 170))	('CRAC', 'Chemical', '-', (149, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('hepatocellular carcinoma', 'Disease', (103, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (190, 214))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (190, 214))	('Orai1', 'Gene', (11, 16))	('hepatocellular carcinoma', 'Disease', (190, 214))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (72, 86))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (224, 238))	('Orai1', 'Gene', '84876', (11, 16))
109436	33728379	It was observed that apoptosis induced by gemcitabine or 5-fluorouracil increased upon RNAi mediated silencing of ORAI1 and STIM1.	('STIM1', 'Gene', (124, 129))	('increased', 'PosReg', (72, 81))	('ORAI1', 'Gene', (114, 119))	('silencing', 'Var', (101, 110))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (57, 71))	('gemcitabine', 'Chemical', 'MESH:C056507', (42, 53))	('apoptosis', 'CPA', (21, 30))
109441	33728379	Cisplatin has been shown to induce apoptosis through modulating STIM1 in non-small cell lung cancer (NSCLC) cell lines A549 and H460.	('non-small cell lung cancer', 'Disease', (73, 99))	('modulating', 'Var', (53, 63))	('NSCLC', 'Disease', (101, 106))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('STIM1', 'Gene', (64, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (77, 99))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (73, 99))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (73, 99))	('apoptosis', 'CPA', (35, 44))	('A549', 'CellLine', 'CVCL:0023', (119, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
109446	33728379	Further, blocking CRAC channel pharmacologically or silencing Orai3 in NSCLC cell lines, namely NCI-H23 and NCI-H460, resulted in significant suppression of cell proliferation and arrest of cell cycle progression in G0/G1 phase.	('NCI-H23', 'CellLine', 'CVCL:1547', (96, 103))	('cell cycle progression in G0/G1 phase', 'CPA', (190, 227))	('arrest', 'Disease', 'MESH:D006323', (180, 186))	('rat', 'Species', '10116', (169, 172))	('silencing', 'Var', (52, 61))	('suppression', 'NegReg', (142, 153))	('CRAC', 'Chemical', '-', (18, 22))	('cell proliferation', 'CPA', (157, 175))	('Orai3', 'Gene', '93129', (62, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('CRAC channel', 'Protein', (18, 30))	('arrest', 'Disease', (180, 186))	('NCI-H460', 'CellLine', 'CVCL:0459', (108, 116))	('NSCLC', 'Disease', (71, 76))	('Orai3', 'Gene', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
109448	33728379	In addition, knockdown of Orai3 reduced the phosphorylation levels of Akt, indicating that Orai3 CRAC channel mediated SOCE in NSCLC regulated tumorigenesis through Akt signaling pathway.	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('CRAC', 'Chemical', '-', (97, 101))	('knockdown', 'Var', (13, 22))	('Orai3', 'Gene', '93129', (26, 31))	('Akt', 'Gene', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('NSCLC', 'Disease', (127, 132))	('Orai3', 'Gene', (91, 96))	('Akt', 'Gene', (70, 73))	('reduced', 'NegReg', (32, 39))	('phosphorylation levels', 'MPA', (44, 66))	('Akt', 'Gene', '207', (165, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('Akt', 'Gene', '207', (70, 73))	('regulated', 'Reg', (133, 142))	('Orai3', 'Gene', (26, 31))	('tumor', 'Disease', (143, 148))	('Orai3', 'Gene', '93129', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
109450	33728379	Use of CRAC channel blockers or siRNA knockdown of ORAI1 and STIM1 proteins, resulted in significant reduction in proliferation and a marked increase in apoptosis of C6 rat glioma cells.	('rat', 'Species', '10116', (169, 172))	('ORAI1', 'Gene', (51, 56))	('reduction', 'NegReg', (101, 110))	('CRAC', 'Chemical', '-', (7, 11))	('increase', 'PosReg', (141, 149))	('glioma', 'Disease', (173, 179))	('STIM1', 'Gene', (61, 66))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('proteins', 'Protein', (67, 75))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('knockdown', 'Var', (38, 47))	('apoptosis', 'CPA', (153, 162))	('rat', 'Species', '10116', (121, 124))
109451	33728379	Interestingly, a more significant antiproliferative effect was noticed in cells with siRNA knockdown of ORAI1 than those with STIM1 knockdown.	('rat', 'Species', '10116', (45, 48))	('ORAI1', 'Gene', (104, 109))	('knockdown', 'Var', (91, 100))	('antiproliferative effect', 'CPA', (34, 58))
109455	33728379	The authors further examined the functional significance of SOCE in glioblastoma by evaluating the effects of silencing STIM1 and Orai1 on cell proliferation and invasion.	('glioblastoma', 'Disease', (68, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('silencing', 'Var', (110, 119))	('Orai1', 'Gene', (130, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('Orai1', 'Gene', '84876', (130, 135))	('STIM1', 'Gene', (120, 125))	('rat', 'Species', '10116', (151, 154))
109456	33728379	It was demonstrated that silencing of STIM1 and Orai1 led to a significant reduction in cell invasion in glioblastoma cells, but not in human primary astrocytes.	('silencing', 'Var', (25, 34))	('human', 'Species', '9606', (136, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('Orai1', 'Gene', (48, 53))	('reduction', 'NegReg', (75, 84))	('Orai1', 'Gene', '84876', (48, 53))	('STIM1', 'Gene', (38, 43))	('glioblastoma', 'Disease', (105, 117))	('rat', 'Species', '10116', (14, 17))
109464	33728379	The study also demonstrated that silencing of Orai1 or STIM1 or inhibition of SOCE resulted in a reduction of cell viability and caused apoptosis and cell cycle arrest in multiple myeloma cell lines.	('reduction', 'NegReg', (97, 106))	('Orai1', 'Gene', '84876', (46, 51))	('multiple myeloma', 'Disease', (171, 187))	('STIM1', 'Gene', (55, 60))	('arrest', 'Disease', (161, 167))	('apoptosis', 'CPA', (136, 145))	('rat', 'Species', '10116', (22, 25))	('silencing', 'Var', (33, 42))	('cell viability', 'CPA', (110, 124))	('arrest', 'Disease', 'MESH:D006323', (161, 167))	('inhibition', 'NegReg', (64, 74))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (150, 167))	('multiple myeloma', 'Disease', 'MESH:D009101', (171, 187))	('SOCE', 'Gene', (78, 82))	('caused', 'Reg', (129, 135))	('multiple myeloma', 'Phenotype', 'HP:0006775', (171, 187))	('Orai1', 'Gene', (46, 51))
109465	33728379	Inhibition of CRAC channel activated SOCE in melanoma cells caused reduction in cell proliferation and migration.	('CRAC', 'Chemical', '-', (14, 18))	('CRAC', 'Gene', (14, 18))	('reduction', 'NegReg', (67, 76))	('rat', 'Species', '10116', (92, 95))	('cell proliferation', 'CPA', (80, 98))	('Inhibition', 'Var', (0, 10))	('rat', 'Species', '10116', (106, 109))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
109479	33728379	Inhibitors of CRAC channel may act by either directly blocking the Orai pore of the channel or by targeting STIM or by interfering with Orai-STIM interactions, thereby regulating the overall activity of the CRAC channel.	('CRAC', 'Chemical', '-', (14, 18))	('CRAC', 'Gene', (14, 18))	('Orai pore of the', 'MPA', (67, 83))	('CRAC', 'Chemical', '-', (207, 211))	('Inhibitors', 'Var', (0, 10))	('activity', 'MPA', (191, 199))	('regulating', 'Reg', (168, 178))	('blocking', 'NegReg', (54, 62))	('interactions', 'Interaction', (146, 158))	('interfering', 'NegReg', (119, 130))
109486	33728379	SKF-96365, an imidazole compound, was shown to block SOCE in Jurkat cells and rat basophilic leukemia cells.	('basophilic leukemia', 'Disease', 'MESH:D015471', (82, 101))	('SOCE', 'CPA', (53, 57))	('SKF-96365', 'Var', (0, 9))	('imidazole', 'Chemical', 'MESH:C029899', (14, 23))	('basophilic leukemia', 'Disease', (82, 101))	('leukemia', 'Phenotype', 'HP:0001909', (93, 101))	('rat', 'Species', '10116', (78, 81))	('SKF-96365', 'Chemical', 'MESH:C063159', (0, 9))	('block', 'NegReg', (47, 52))	('Jurkat', 'CellLine', 'CVCL:0065', (61, 67))
109487	33728379	SKF-96365 was found capable of reducing tumor metastasis in animal models of breast cancer.	('breast cancer', 'Disease', (77, 90))	('SKF-96365', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('reducing', 'NegReg', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('SKF-96365', 'Chemical', 'MESH:C063159', (0, 9))	('tumor metastasis', 'Disease', 'MESH:D009362', (40, 56))	('tumor metastasis', 'Disease', (40, 56))
109489	33728379	Inhibition of CRAC channel activity by SKF-96365 was shown to suppress the proliferation and migration of esophageal cancer cells in vitro and retard tumor growth in xenografted mice.	('suppress', 'NegReg', (62, 70))	('retard tumor', 'Disease', (143, 155))	('CRAC', 'Chemical', '-', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('Inhibition', 'NegReg', (0, 10))	('mice', 'Species', '10090', (178, 182))	('rat', 'Species', '10116', (96, 99))	('CRAC channel', 'Protein', (14, 26))	('SKF-96365', 'Chemical', 'MESH:C063159', (39, 48))	('rat', 'Species', '10116', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('retard tumor', 'Disease', 'MESH:D009369', (143, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('proliferation', 'CPA', (75, 88))	('SKF-96365', 'Var', (39, 48))
109490	33728379	Interestingly, SKF-96365 was reported to be non-selective for CRAC channels as it could block other calcium channels as well.	('calcium', 'Chemical', 'MESH:D002118', (100, 107))	('CRAC', 'Disease', (62, 66))	('CRAC', 'Chemical', '-', (62, 66))	('SKF-96365', 'Chemical', 'MESH:C063159', (15, 24))	('SKF-96365', 'Var', (15, 24))
109491	33728379	Nevertheless, it should be noted that silencing or overexpressing Orai1 and STIM1 in the above-mentioned studies gave similar results which corroborate the observation that the effects of SKF96365 in those models stem from its ability to block Orai1-STIM1 CRAC channel.	('SKF96365', 'Var', (188, 196))	('SKF96365', 'Chemical', 'MESH:C063159', (188, 196))	('block', 'NegReg', (238, 243))	('Orai1', 'Gene', (244, 249))	('Orai1', 'Gene', '84876', (66, 71))	('rat', 'Species', '10116', (147, 150))	('CRAC', 'Chemical', '-', (256, 260))	('Orai1', 'Gene', (66, 71))	('Orai1', 'Gene', '84876', (244, 249))	('silencing', 'Var', (38, 47))
109499	33728379	In an effort to overcome this problem, more selective 2-APB analogues, namely DPB-162AE and DPB-163AE, were developed, which proved to be 100 times more effective than 2-APB in blocking CRAC channel mediated SOCE.	('DPB', 'Chemical', 'MESH:C012939', (92, 95))	('DPB', 'Chemical', 'MESH:C012939', (78, 81))	('APB', 'Gene', (56, 59))	('DPB-163AE', 'Var', (92, 101))	('CRAC channel mediated SOCE', 'MPA', (186, 212))	('APB', 'Gene', (170, 173))	('CRAC', 'Chemical', '-', (186, 190))	('DPB-162AE', 'Var', (78, 87))	('APB', 'Gene', '6051', (56, 59))	('blocking', 'NegReg', (177, 185))	('APB', 'Gene', '6051', (170, 173))
109502	33728379	ML-9 was shown to potently induce a concentration and Ca2+ dependent autophagic cell death in prostate cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('autophagic cell death', 'CPA', (69, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (94, 109))	('rat', 'Species', '10116', (43, 46))	('ML-9', 'Chemical', 'MESH:C056218', (0, 4))	('induce', 'PosReg', (27, 33))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('ML-9', 'Var', (0, 4))	('Ca2+', 'Chemical', 'MESH:D000069285', (54, 58))	('prostate cancer', 'Disease', (94, 109))
109503	33728379	It was further observed that ML-9 significantly promoted antitumor effects of docetaxel, which underscored its potential to be used in combination with existing anticancer chemotherapy.	('ML-9', 'Var', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('docetaxel', 'Chemical', 'MESH:D000077143', (78, 87))	('promoted', 'PosReg', (48, 56))	('ML-9', 'Chemical', 'MESH:C056218', (29, 33))	('tumor', 'Disease', (61, 66))
109509	33728379	Further evidence for the anti-angiogenic properties were provided by a study where CAI was shown to inhibit the proliferation and tubulogenesis of endothelial progenitor cells from renal cellular carcinoma patients.	('renal cellular carcinoma', 'Disease', 'MESH:C538614', (181, 205))	('CAI', 'Chemical', 'MESH:C062058', (83, 86))	('rat', 'Species', '10116', (119, 122))	('patients', 'Species', '9606', (206, 214))	('tubulogenesis of endothelial progenitor cells', 'CPA', (130, 175))	('renal cellular carcinoma', 'Disease', (181, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('CAI', 'Var', (83, 86))	('inhibit', 'NegReg', (100, 107))
109511	33728379	In one such phase II trial, CAI was found to enhance disease stabilization in patients with relapsed epithelial ovarian carcinoma and was suggested to be useful as a maintenance therapy owing to its limited toxicity profile.	('epithelial ovarian carcinoma', 'Disease', (101, 129))	('CAI', 'Chemical', 'MESH:C062058', (28, 31))	('disease stabilization', 'CPA', (53, 74))	('enhance', 'PosReg', (45, 52))	('epithelial ovarian carcinoma', 'Disease', 'MESH:D010051', (101, 129))	('patients', 'Species', '9606', (78, 86))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (112, 129))	('toxicity', 'Disease', 'MESH:D064420', (207, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('CAI', 'Var', (28, 31))	('toxicity', 'Disease', (207, 215))
109515	33728379	have examined the anti-cancer effects of RP4010 in esophagus squamous cell carcinoma.	('esophagus squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 84))	('RP4010', 'Var', (41, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('esophagus squamous cell carcinoma', 'Disease', (51, 84))	('RP4010', 'Chemical', '-', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
109516	33728379	The authors demonstrated that RP4010 caused reduction in intracellular Ca2+ oscillations, concomitant with cell growth inhibition and cell cycle arrest at G0/G1 phase in cultured esophageal cancer cells as well as a decrease in tumor growth in vivo.	('RP4010', 'Var', (30, 36))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cell growth', 'CPA', (107, 118))	('arrest', 'Disease', 'MESH:D006323', (145, 151))	('intracellular Ca2+ oscillations', 'MPA', (57, 88))	('RP4010', 'Chemical', '-', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('arrest', 'Disease', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('rat', 'Species', '10116', (19, 22))	('decrease', 'NegReg', (216, 224))	('reduction', 'NegReg', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', (228, 233))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (134, 151))	('Ca2+', 'Chemical', 'MESH:D000069285', (71, 75))
109517	33728379	Recently our lab has also published a study on the effect of CRAC channel inhibition by RP4010 in pancreatic ductal adenocarcinoma models.	('RP4010', 'Chemical', '-', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('CRAC channel', 'Protein', (61, 73))	('pancreatic ductal adenocarcinoma', 'Disease', (98, 130))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (98, 130))	('inhibition', 'NegReg', (74, 84))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (98, 130))	('RP4010', 'Var', (88, 94))	('CRAC', 'Chemical', '-', (61, 65))
109518	33728379	RP4010 proved to be effective in suppressing the proliferation of various pancreatic cancer cell lines and was also able to reduce the growth of patient derived tumor xenograft in mice, more potently when combined with gemcitabine and nab-paclitaxel.	('suppressing', 'NegReg', (33, 44))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('rat', 'Species', '10116', (56, 59))	('RP4010', 'Var', (0, 6))	('gemcitabine', 'Chemical', 'MESH:C056507', (219, 230))	('proliferation', 'CPA', (49, 62))	('nab', 'Chemical', '-', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('patient', 'Species', '9606', (145, 152))	('pancreatic cancer', 'Disease', (74, 91))	('mice', 'Species', '10090', (180, 184))	('paclitaxel', 'Chemical', 'MESH:D017239', (239, 249))	('RP4010', 'Chemical', '-', (0, 6))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('reduce', 'NegReg', (124, 130))
109528	33728379	This anticancer therapeutic potential of targeting CRAC channel gets strengthened by the observation that pharmacological inhibition of CRAC channel or silencing of CRAC channel proteins can effectively suppress tumor growth and metastasis in several cancer models.	('CRAC', 'Chemical', '-', (136, 140))	('cancer', 'Disease', (9, 15))	('silencing', 'Var', (152, 161))	('inhibition', 'Var', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('CRAC', 'Chemical', '-', (165, 169))	('tumor', 'Disease', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('CRAC channel', 'Gene', (165, 177))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('CRAC', 'Chemical', '-', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('CRAC', 'Gene', (136, 140))	('proteins', 'Protein', (178, 186))	('suppress', 'NegReg', (203, 211))
109529	33728379	In addition, CRAC channel inhibition has been shown to enhance the effect of standard of care chemotherapy drugs.	('effect', 'MPA', (67, 73))	('CRAC channel', 'Protein', (13, 25))	('inhibition', 'Var', (26, 36))	('enhance', 'PosReg', (55, 62))	('CRAC', 'Chemical', '-', (13, 17))
109554	33728379	However, there is emerging evidence that certain mutations in Orai can result in its constitutive activation and consequent Ca2+ influx.	('Ca2+ influx', 'MPA', (124, 135))	('constitutive activation', 'MPA', (85, 108))	('mutations', 'Var', (49, 58))	('Ca2+', 'Chemical', 'MESH:D000069285', (124, 128))	('Orai', 'Gene', (62, 66))
109555	33728379	These mutations have been found in large-scale cancer genomics datasets for dysfunctional Orai1 mutants.	('Orai1', 'Gene', '84876', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('Orai1', 'Gene', (90, 95))	('dysfunctional', 'Disease', (76, 89))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('dysfunctional', 'Disease', 'MESH:D009461', (76, 89))	('mutants', 'Var', (96, 103))
109560	33728379	In fact, studies from our lab have recently demonstrated that CRAC channel inhibitor RP4010 was able to synergize with gemcitabine and nab-paclitaxel in pancreatic ductal adenocarcinoma preclinical models.	('gemcitabine', 'Chemical', 'MESH:C056507', (119, 130))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (153, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('CRAC', 'Chemical', '-', (62, 66))	('nab', 'Chemical', '-', (135, 138))	('RP4010', 'Chemical', '-', (85, 91))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (153, 185))	('paclitaxel', 'Chemical', 'MESH:D017239', (139, 149))	('rat', 'Species', '10116', (51, 54))	('CRAC', 'Protein', (62, 66))	('RP4010', 'Var', (85, 91))	('pancreatic ductal adenocarcinoma', 'Disease', (153, 185))
109561	33728379	Even though the Phase I/Ib clinical trial of RP4010 as a monotherapy in non-Hodgkin's lymphoma proved unyielding, the way forward would be to use RP4010 or any comparable CRAC channel blocker in combination with existing chemotherapy or even immunotherapy in the future clinical trials.	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (76, 94))	('RP4010', 'Var', (45, 51))	("non-Hodgkin's lymphoma", 'Disease', (72, 94))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (72, 94))	('RP4010', 'Var', (146, 152))	('CRAC', 'Chemical', '-', (171, 175))	('RP4010', 'Chemical', '-', (45, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (86, 94))	('RP4010', 'Chemical', '-', (146, 152))
109646	28758114	The immunoediting progresses through 3 main phases: (1) the elimination phase (or immunosurveillance), when the innate and adaptive immune cells remove the proliferating cells, thus protecting the host against cancer; (2) the equilibrium phase, when the tumour growth and the immunosurveillance enter into a dynamic balance; in this genetically instable phase, the increase of mutational load and the emergence of resistant clones among tumour cells lead to (3) the escape phase; at this point, tumour variants are able to avoid immune-mediated destruction and speed up tumour progression and clinical expression.	('tumour growth', 'Disease', (254, 267))	('avoid', 'NegReg', (523, 528))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumour', 'Phenotype', 'HP:0002664', (570, 576))	('tumour', 'Disease', 'MESH:D009369', (570, 576))	('tumour', 'Disease', (570, 576))	('mutational load', 'Var', (377, 392))	('tumour', 'Phenotype', 'HP:0002664', (495, 501))	('tumour', 'Disease', 'MESH:D009369', (495, 501))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('tumour', 'Disease', (495, 501))	('speed up', 'PosReg', (561, 569))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('tumour growth', 'Disease', 'MESH:D006130', (254, 267))	('tumour', 'Disease', (254, 260))	('tumour', 'Phenotype', 'HP:0002664', (437, 443))	('tumour', 'Disease', 'MESH:D009369', (437, 443))	('clinical expression', 'CPA', (593, 612))	('tumour', 'Disease', (437, 443))	('cancer', 'Disease', (210, 216))
109650	28758114	Examples include (1) the secretion of soluble immunosuppressive factors (TGF-beta, IL-10, VEGF, and indoleamine 2,3 dehydrogenase); (2) the activation of negative costimulatory signals in the tumour microenvironment such as PD-L1; (3) tumour-induced impairment of the antigen presentation machinery due to the accumulation of point mutations in the cell surface not recognised by cytotoxic T cells; and finally (4) the downregulation of the major histocompatibility complex (MHC) class I expression which plays a crucial role in tumour antigens presentation to T cells.	('downregulation', 'NegReg', (419, 433))	('secretion', 'MPA', (25, 34))	('tumour', 'Phenotype', 'HP:0002664', (529, 535))	('impairment', 'NegReg', (250, 260))	('tumour', 'Disease', 'MESH:D009369', (529, 535))	('tumour', 'Disease', (529, 535))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('PD-L1', 'Gene', (224, 229))	('TGF-beta', 'Gene', '7040', (73, 81))	('PD-L1', 'Gene', '29126', (224, 229))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('tumour', 'Disease', (235, 241))	('VEGF', 'Gene', '7422', (90, 94))	('VEGF', 'Gene', (90, 94))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('TGF-beta', 'Gene', (73, 81))	('IL-10', 'Gene', '3586', (83, 88))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('tumour', 'Disease', (192, 198))	('IL-10', 'Gene', (83, 88))	('point mutations', 'Var', (326, 341))	('expression', 'MPA', (488, 498))	('antigen', 'MPA', (268, 275))
109654	28758114	Interestingly, CAFs have a critical role in CRC immunosuppression: their activity in RAS mutant tumours overcome effector T cells signalling leading to tumour progression thanks to the activation of epithelial mesenchymal transition and TGF-beta/SMAD signalling.	('TGF-beta', 'Gene', (237, 245))	('CAFs', 'Gene', (15, 19))	('activation', 'PosReg', (185, 195))	('tumours', 'Disease', (96, 103))	('RAS', 'Gene', (85, 88))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))	('mutant', 'Var', (89, 95))	('effector T cells signalling', 'MPA', (113, 140))	('CAFs', 'Gene', '6899', (15, 19))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('TGF-beta', 'Gene', '7040', (237, 245))	('tumour', 'Disease', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('tumour', 'Disease', (152, 158))	('overcome', 'PosReg', (104, 112))	('epithelial mesenchymal transition', 'CPA', (199, 232))
109660	28758114	Data from many laboratories obtained during past few years indicate that defects in DCs are among the main factors responsible for tumour escape.	('tumour', 'Disease', (131, 137))	('defects', 'Var', (73, 80))	('man', 'Species', '9606', (10, 13))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('DCs', 'Protein', (84, 87))
109678	28758114	As an example, pembrolizumab received the breakthrough therapy designation in mCRC cancers with microsatellite instability in November 2015.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('microsatellite instability', 'Var', (96, 122))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('pembrolizumab', 'Chemical', 'MESH:C582435', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
109739	28758114	In this study, three cohorts of patients were recruited: (1) cohort A: patient with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) mCRC (n = 11); (2) cohort B: patients with microsatellite stability (MSS) or proficient (p)MMR mCRC (n = 21); and (3) cohort C: patients with MSI-H non-mCRC cancers (n = 9).	('patient', 'Species', '9606', (288, 295))	('deficient', 'Var', (127, 136))	('MSI-H', 'Disease', (117, 122))	('patients', 'Species', '9606', (189, 197))	('patient', 'Species', '9606', (32, 39))	('patient', 'Species', '9606', (71, 78))	('MSI-H', 'Disease', 'MESH:D000848', (302, 307))	('CRC', 'Phenotype', 'HP:0003003', (313, 316))	('CRC', 'Phenotype', 'HP:0003003', (256, 259))	('cancers', 'Phenotype', 'HP:0002664', (317, 324))	('MSI-H', 'Disease', 'MESH:D000848', (117, 122))	('CRC', 'Phenotype', 'HP:0003003', (161, 164))	('patients', 'Species', '9606', (288, 296))	('patient', 'Species', '9606', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('patients', 'Species', '9606', (32, 40))	('MSI-H non-mCRC cancers', 'Disease', (302, 324))	('MSI-H', 'Disease', (302, 307))	('MSI-H non-mCRC cancers', 'Disease', 'MESH:D009369', (302, 324))
109747	28758114	One year later, at the 2016 ASCO Annual Meeting, several encouraging preliminary data on immune-checkpoint inhibitors in the treatment of mCRC were presented, including the update of the KEYNOTE 016 trial, a new treatment strategy adopting a combination of anti-CTLA4 and anti PD1 (the CHECKMATE 142 trial), and a phase Ib study combining a MEK inhibitor and an anti-PD-L1 in patients with microsatellite stable (MSS) tumours.	('patients', 'Species', '9606', (376, 384))	('PD-L1', 'Gene', '29126', (367, 372))	('tumour', 'Phenotype', 'HP:0002664', (418, 424))	('CTLA4', 'Gene', '1493', (262, 267))	('tumours', 'Phenotype', 'HP:0002664', (418, 425))	('CTLA4', 'Gene', (262, 267))	('MSS) tumours', 'Disease', 'MESH:D013132', (413, 425))	('mCRC', 'Disease', (138, 142))	('microsatellite', 'Var', (390, 404))	('PD-L1', 'Gene', (367, 372))	('PD1', 'Gene', '5133', (277, 280))	('MEK', 'Gene', (341, 344))	('CRC', 'Phenotype', 'HP:0003003', (139, 142))	('MEK', 'Gene', '5609', (341, 344))	('PD1', 'Gene', (277, 280))
109751	28758114	Responses were observed regardless of tumour or immune cell PD-L1 expression, BRAF, KRAS mutation status, or clinical history of Lynch syndrome.	('BRAF', 'Gene', '673', (78, 82))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('BRAF', 'Gene', (78, 82))	('mutation', 'Var', (89, 97))	('PD-L1', 'Gene', (60, 65))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('KRAS', 'Gene', (84, 88))	('KRAS', 'Gene', '3845', (84, 88))	('Lynch syndrome', 'Disease', (129, 143))	('PD-L1', 'Gene', '29126', (60, 65))	('tumour', 'Disease', (38, 44))	('Lynch syndrome', 'Disease', 'MESH:D003123', (129, 143))
109758	28758114	In preclinical models, MEK inhibition alone increased the tumour-infiltrating CD8+ T cells and induced MHC-I upregulation, the combination of MEK inhibition with an anti-PD-L1 resulted in synergistic and durable tumour regression.	('tumour regression', 'Disease', 'MESH:D009365', (212, 229))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('MEK', 'Gene', (142, 145))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('inhibition', 'Var', (27, 37))	('tumour', 'Disease', (212, 218))	('MEK', 'Gene', (23, 26))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('upregulation', 'PosReg', (109, 121))	('CD8', 'Gene', '925', (78, 81))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('increased', 'PosReg', (44, 53))	('MHC-I', 'Gene', (103, 108))	('tumour regression', 'Disease', (212, 229))	('CD8', 'Gene', (78, 81))	('PD-L1', 'Gene', (170, 175))	('inhibition', 'NegReg', (146, 156))	('PD-L1', 'Gene', '29126', (170, 175))	('MEK', 'Gene', '5609', (142, 145))	('MEK', 'Gene', '5609', (23, 26))
109791	28758114	MSI status is assessed by means of immunohistochemistry evaluating altered expression of mismatch repair proteins (i.e., MLH1, PMS2, MSH2, and MSH6) or by means of PCR techniques detecting mutations on BAT25, BAT26, D2S123, D5S346, and D17D250, according to the Bethesda panel guidelines.	('MSH2', 'Gene', (133, 137))	('PMS2', 'Gene', (127, 131))	('MSI', 'Gene', '5928', (0, 3))	('MSH6', 'Gene', '2956', (143, 147))	('D5S346', 'Var', (224, 230))	('PMS2', 'Gene', '5395', (127, 131))	('BAT25', 'Gene', (202, 207))	('D17D250', 'Var', (236, 243))	('MSH2', 'Gene', '4436', (133, 137))	('BAT26', 'Gene', (209, 214))	('MSI', 'Gene', (0, 3))	('MLH1', 'Gene', '4292', (121, 125))	('MSH6', 'Gene', (143, 147))	('MLH1', 'Gene', (121, 125))	('mutations', 'Var', (189, 198))	('expression', 'MPA', (75, 85))	('D2S123', 'Var', (216, 222))
109792	28758114	Due to the association of MSI status with a higher mutational and neoantigen burden, also more sophisticated next-generation sequencing approaches have been successfully applied in the evaluation of mutational load in immunotherapy clinical trials, and these methods allow the identification of other hypermutated tumour classes such as those characterized by dysfunctions in DNA polymerases (POLE).	('tumour', 'Disease', (314, 320))	('MSI', 'Gene', (26, 29))	('dysfunctions', 'Var', (360, 372))	('tumour', 'Phenotype', 'HP:0002664', (314, 320))	('MSI', 'Gene', '5928', (26, 29))	('tumour', 'Disease', 'MESH:D009369', (314, 320))
109812	28758114	Although those two studies do not question the role of MSI status in CRC in terms of increased immune infiltrates, higher frequencies of frame shift mutations, and favorable outcome, still they demonstrate that the canonical MSI tests may be not sufficient to fish out all the patients that have a common "MSI phenotype" and could benefit from immunotherapy.	('MSI', 'Gene', '5928', (55, 58))	('MSI', 'Gene', (306, 309))	('mutations', 'Var', (149, 158))	('MSI', 'Gene', (225, 228))	('MSI', 'Gene', '5928', (306, 309))	('CRC', 'Phenotype', 'HP:0003003', (69, 72))	('MSI', 'Gene', '5928', (225, 228))	('patients', 'Species', '9606', (277, 285))	('MSI', 'Gene', (55, 58))
109813	28758114	also identified a MSI-H mutation signature by using whole genome and whole exome sequencing.	('MSI-H', 'Disease', (18, 23))	('MSI-H', 'Disease', 'MESH:D000848', (18, 23))	('mutation', 'Var', (24, 32))
109814	28758114	They confirmed this signature to be similar to germline DNA, thus meaning that a fraction of genetic variations arises through mutations escaping MSI.	('MSI', 'Gene', (146, 149))	('MSI', 'Gene', '5928', (146, 149))	('arises through', 'Reg', (112, 126))	('variations', 'Var', (101, 111))	('mutations', 'Var', (127, 136))
109815	28758114	Most importantly, they identified a large number of recurrent indels that can be used to detect MSI and that are currently under implementation for clinical application.	('MSI', 'Gene', (96, 99))	('indels', 'Var', (62, 68))	('MSI', 'Gene', '5928', (96, 99))
109817	28758114	Thus, further studies will be required to know if this applies to other tissues types that show microsatellite instability, such as gastric cancer, genitourinary tract malignancies, and esophageal cancer.	('microsatellite instability', 'Var', (96, 122))	('genitourinary tract malignancies', 'Disease', (148, 180))	('gastric cancer', 'Disease', (132, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('genitourinary tract malignancies', 'Disease', 'MESH:C564424', (148, 180))	('esophageal cancer', 'Disease', (186, 203))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
109829	28758114	Moreover, the oral administration of Bifidobacterium associates with tumour effect and when combined with anti-PDL1 therapy nearly abolishes tumour outgrowth.	('tumour', 'Disease', (69, 75))	('tumour outgrowth', 'Phenotype', 'HP:0001548', (141, 157))	('Bifidobacterium', 'Var', (37, 52))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('PDL1', 'Gene', '29126', (111, 115))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('tumour', 'Disease', (141, 147))	('abolishes', 'NegReg', (131, 140))	('PDL1', 'Gene', (111, 115))
109846	26925132	Methyl thiazolyl tetrazolium assay (MTT) and flow cytometry methods were used to determine the growth inhibitory rate and apoptosis rate of the U251 cells with FUBP1 silencing.	('U251', 'CellLine', 'CVCL:0021', (144, 148))	('FUBP1', 'Gene', (160, 165))	('apoptosis', 'CPA', (122, 131))	('growth inhibitory rate', 'CPA', (95, 117))	('silencing', 'Var', (166, 175))	('MTT', 'Chemical', '-', (36, 39))	('Methyl thiazolyl tetrazolium', 'Chemical', '-', (0, 28))	('FUBP1', 'Gene', '8880', (160, 165))
109853	26925132	FUBP1 silencing increases the growth inhibitory rate and apoptosis rate of the U251 cells, and enhances the chemotherapy sensitivity of U251 cells to DDP.	('chemotherapy sensitivity', 'CPA', (108, 132))	('DDP', 'Chemical', 'MESH:D002945', (150, 153))	('enhances', 'PosReg', (95, 103))	('U251', 'CellLine', 'CVCL:0021', (79, 83))	('growth inhibitory rate', 'CPA', (30, 52))	('apoptosis rate', 'CPA', (57, 71))	('FUBP1', 'Gene', (0, 5))	('increases', 'PosReg', (16, 25))	('silencing', 'Var', (6, 15))	('FUBP1', 'Gene', '8880', (0, 5))	('U251', 'CellLine', 'CVCL:0021', (136, 140))
109882	26925132	(Formula: (1) DeltaDeltaCt = DeltaCt, Experimental group - DeltaCt, Control group, (2) DeltaCt = Ct, Target gene - Ct, Reference gene).	('DeltaCt', 'Var', (87, 94))	('men', 'Species', '9606', (44, 47))	('DeltaDeltaCt', 'Var', (14, 26))
109905	26925132	The expression of FUBP1 protein in the C1, C2 and Fs groups was 0.473 +-0.023, 0.508 +-0.031 and 0.147 +-0.014 respectively.	('FUBP1', 'Gene', '8880', (18, 23))	('protein', 'Protein', (24, 31))	('0.473 +-0.023', 'Var', (64, 77))	('expression', 'MPA', (4, 14))	('0.508 +-0.031', 'Var', (79, 92))	('FUBP1', 'Gene', (18, 23))	('Fs', 'Chemical', '-', (50, 52))	('0.147 +-0.014', 'Var', (97, 110))
109912	26925132	The OD490 values of the DDP group with concentrations of 1, 3, 5 microg/ml were 0.647 +-0.036, 0.624 +-0.031 and 0.578 +-0.038, while OD490 values for the Fs + DDP group were 0.647 +-0.036, 0.624 +-0.031 and 0.578 +-0.038 respectively, and the value of the blank group was 0.756 +-0.037.	('DDP', 'Chemical', 'MESH:D002945', (160, 163))	('Fs', 'Chemical', '-', (155, 157))	('0.624', 'Var', (95, 100))	('OD490', 'MPA', (4, 9))	('DDP', 'Chemical', 'MESH:D002945', (24, 27))
109914	26925132	The inhibition rate at each DDP concentration was significantly higher in the Fs + DDP group than in the DDP group (all p < 0.05), indicating stronger inhibition of the U251 cell proliferation in the Fs + DDP group.	('DDP', 'Chemical', 'MESH:D002945', (105, 108))	('higher', 'PosReg', (64, 70))	('Fs + DDP', 'Var', (78, 86))	('Fs', 'Chemical', '-', (200, 202))	('U251', 'CellLine', 'CVCL:0021', (169, 173))	('DDP', 'Chemical', 'MESH:D002945', (28, 31))	('U251 cell proliferation', 'CPA', (169, 192))	('stronger', 'PosReg', (142, 150))	('DDP', 'Chemical', 'MESH:D002945', (83, 86))	('Fs', 'Chemical', '-', (78, 80))	('inhibition', 'NegReg', (151, 161))	('DDP', 'Chemical', 'MESH:D002945', (205, 208))
109917	26925132	The growth apoptosis rate at each DDP concentration was significantly higher in the Fs + DDP group than in the DDP group (all p < 0.05).	('DDP', 'Chemical', 'MESH:D002945', (89, 92))	('Fs + DDP', 'Var', (84, 92))	('DDP', 'Chemical', 'MESH:D002945', (34, 37))	('Fs', 'Chemical', '-', (84, 86))	('growth apoptosis rate', 'CPA', (4, 25))	('higher', 'PosReg', (70, 76))	('DDP', 'Chemical', 'MESH:D002945', (111, 114))
109919	26925132	The expression of NOXA at each DDP concentration was significantly higher in the Fs + DDP group than in the DDP group (all p < 0.05).	('higher', 'PosReg', (67, 73))	('NOXA', 'Gene', (18, 22))	('NOXA', 'Gene', '5366', (18, 22))	('expression', 'MPA', (4, 14))	('DDP', 'Chemical', 'MESH:D002945', (86, 89))	('Fs + DDP', 'Var', (81, 89))	('DDP', 'Chemical', 'MESH:D002945', (31, 34))	('DDP', 'Chemical', 'MESH:D002945', (108, 111))	('Fs', 'Chemical', '-', (81, 83))
109925	26925132	Moreover, FUBP1 gene mutation or abnormal expression has been reported in glioma and liver cancer in previous literature.	('FUBP1', 'Gene', '8880', (10, 15))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('liver cancer', 'Disease', 'MESH:D006528', (85, 97))	('liver cancer', 'Disease', (85, 97))	('expression', 'MPA', (42, 52))	('reported', 'Reg', (62, 70))	('mutation', 'Var', (21, 29))	('glioma', 'Disease', (74, 80))	('FUBP1', 'Gene', (10, 15))	('abnormal', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('liver cancer', 'Phenotype', 'HP:0002896', (85, 97))
109933	26925132	indicate that FUBP1 expression levels were increased in all glioma subtypes as compared to normal central nervous system (CNS) control tissue and were associated with increased proliferation, and FUBP1 mutation was associated with oligodendroglial differentiation.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('FUBP1', 'Gene', '8880', (14, 19))	('FUBP1', 'Gene', '8880', (196, 201))	('associated', 'Reg', (151, 161))	('oligodendroglial differentiation', 'CPA', (231, 263))	('mutation', 'Var', (202, 210))	('FUBP1', 'Gene', (196, 201))	('FUBP1', 'Gene', (14, 19))	('glioma', 'Disease', (60, 66))	('increased', 'PosReg', (167, 176))	('increased', 'PosReg', (43, 52))	('proliferation', 'CPA', (177, 190))	('associated with', 'Reg', (215, 230))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('expression levels', 'MPA', (20, 37))
109936	26925132	Our results showed that the gene silencing of FUBP1 induced remarkable apoptosis and reduced the proliferation ability of gliomas.	('apoptosis', 'CPA', (71, 80))	('FUBP1', 'Gene', '8880', (46, 51))	('gene silencing', 'Var', (28, 42))	('proliferation ability', 'CPA', (97, 118))	('gliomas', 'Disease', (122, 129))	('FUBP1', 'Gene', (46, 51))	('reduced', 'NegReg', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
109938	26925132	In addition, we checked the expression of stathmin protein in U251 cells with FUBP1 silenced, and the expression of stathmin showed no significant difference.	('FUBP1', 'Gene', (78, 83))	('stathmin', 'Gene', '3925', (42, 50))	('U251', 'CellLine', 'CVCL:0021', (62, 66))	('stathmin', 'Gene', (116, 124))	('FUBP1', 'Gene', '8880', (78, 83))	('silenced', 'Var', (84, 92))	('stathmin', 'Gene', '3925', (116, 124))	('checked', 'Reg', (16, 23))	('stathmin', 'Gene', (42, 50))
109939	26925132	reported that inhibition of FUBP1 reduced stathmin at the protein levels in liver cancer cells, which is not consistent with our data.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('stathmin', 'Gene', '3925', (42, 50))	('reduced', 'NegReg', (34, 41))	('FUBP1', 'Gene', '8880', (28, 33))	('FUBP1', 'Gene', (28, 33))	('liver cancer', 'Phenotype', 'HP:0002896', (76, 88))	('liver cancer', 'Disease', 'MESH:D006528', (76, 88))	('inhibition', 'Var', (14, 24))	('liver cancer', 'Disease', (76, 88))	('stathmin', 'Gene', (42, 50))
109946	26925132	FUBP1 is proven to be involved in regulating cell proliferation and apoptosis, and silencing of the FUBP1 gene induced remarkable apoptosis and reduced the proliferation ability of U251 cells.	('reduced', 'NegReg', (144, 151))	('apoptosis', 'CPA', (130, 139))	('FUBP1', 'Gene', '8880', (100, 105))	('FUBP1', 'Gene', (0, 5))	('FUBP1', 'Gene', (100, 105))	('proliferation ability', 'CPA', (156, 177))	('U251', 'CellLine', 'CVCL:0021', (181, 185))	('FUBP1', 'Gene', '8880', (0, 5))	('silencing', 'Var', (83, 92))
109954	26925132	The silencing of FUBP1 could enhance the chemotherapy sensitivity of DDP in U251 cells.	('FUBP1', 'Gene', '8880', (17, 22))	('FUBP1', 'Gene', (17, 22))	('U251', 'CellLine', 'CVCL:0021', (76, 80))	('DDP', 'Chemical', 'MESH:D002945', (69, 72))	('enhance', 'PosReg', (29, 36))	('chemotherapy sensitivity of DDP', 'CPA', (41, 72))	('silencing', 'Var', (4, 13))
109956	23333711	Hypomethylation of Noncoding DNA Regions and Overexpression of the Long Noncoding RNA, AFAP1-AS1, in Barrett's Esophagus and Esophageal Adenocarcinoma Alterations in methylation of protein-coding genes are associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC).	('Alterations', 'Var', (151, 162))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (125, 150))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (125, 150))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (251, 276))	('EAC', 'Phenotype', 'HP:0011459', (278, 281))	('BE', 'Phenotype', 'HP:0100580', (243, 245))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (251, 276))	('Esophageal Adenocarcinoma', 'Disease', (125, 150))	('AS1', 'Gene', (93, 96))	('associated', 'Reg', (206, 216))	('esophageal adenocarcinoma', 'Disease', (251, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	("Barrett's esophagus", 'Disease', (222, 241))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('AFAP1', 'Gene', '60312', (87, 92))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (222, 241))	('AS1', 'Gene', '5729', (93, 96))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (222, 241))	('methylation', 'MPA', (166, 177))	('AFAP1', 'Gene', (87, 92))
109969	23333711	Inhibition of its expression in EAC cells resulted in diminished cell growth, migration, and invasion, as well as in increased apoptosis, thereby establishing, to our knowledge for the first time, a functional cancer-related consequence of epigenetic alteration at a lncRNA genomic locus.	('cell growth', 'CPA', (65, 76))	('diminished', 'NegReg', (54, 64))	('EAC', 'Phenotype', 'HP:0011459', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('apoptosis', 'CPA', (127, 136))	('expression', 'MPA', (18, 28))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('epigenetic alteration', 'Var', (240, 261))	('invasion', 'CPA', (93, 101))	('cancer', 'Disease', (210, 216))
109977	23333711	Two different small interfering RNAs (siRNAs) that targeted AFAP1-AS1 RNA (siRNA n262319 and n262320; Life Technologies, Grand Island, NY) and a scrambled siRNA control were used.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (60, 69))	('AFAP1-AS1', 'Gene', (60, 69))	('n262320', 'Var', (93, 100))
109988	23333711	Unsupervised clustering based on methylation of all coding and noncoding regions, on the other hand, strikingly discriminated between NE and BE, even in matched patient sets (Figure 1C and D), establishing the importance of these novel changes.	('patient', 'Species', '9606', (161, 168))	('methylation', 'Var', (33, 44))	('BE', 'Phenotype', 'HP:0100580', (141, 143))	('discriminated', 'Reg', (112, 125))
109990	23333711	Because CpG island regions have previously been considered a principal target of epigenetic dysregulation in cancer, we next sought to determine whether noncoding regions affected by aberrant methylation were disproportionately associated with a higher density of CpGs.	('CpGs', 'Disease', (264, 268))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('aberrant', 'Var', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
110010	23333711	These data suggest that noncoding RNA AFAP1-AS1 is hypomethylated and up-regulated in BE and EAC but that this dysregulation appears to have no effect on the expression of its coding counterpart, AFAP1.	('BE', 'Phenotype', 'HP:0100580', (86, 88))	('hypomethylated', 'Var', (51, 65))	('up-regulated', 'PosReg', (70, 82))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (38, 47))	('AFAP1', 'Gene', (38, 43))	('AFAP1', 'Gene', '60312', (196, 201))	('AFAP1', 'Gene', '60312', (38, 43))	('EAC', 'Phenotype', 'HP:0011459', (93, 96))	('AFAP1', 'Gene', (196, 201))	('AFAP1-AS1', 'Gene', (38, 47))
110014	23333711	The level of AFAP1 expression was not significantly altered following AFAP1-AS1 knockdown relative to a scrambled siRNA control (Supplementary Figure 4A and B).	('knockdown', 'Var', (80, 89))	('AFAP1-AS1', 'Gene', (70, 79))	('AFAP1', 'Gene', '60312', (13, 18))	('AFAP1', 'Gene', (13, 18))	('AFAP1', 'Gene', (70, 75))	('AFAP1', 'Gene', '60312', (70, 75))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (70, 79))
110015	23333711	These results confirm that these siRNAs did not affect the expression level of AFAP1, suggesting that phenotypic effects observed following knockdown of AFAP1-AS1 were driven directly by AFAP1-AS1, rather than indirectly via AFAP1.	('AFAP1', 'Gene', (225, 230))	('AFAP1', 'Gene', (153, 158))	('AFAP1', 'Gene', (187, 192))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (187, 196))	('AFAP1', 'Gene', '60312', (153, 158))	('AFAP1', 'Gene', '60312', (187, 192))	('AFAP1-AS1', 'Gene', (153, 162))	('AFAP1-AS1', 'Gene', (187, 196))	('AFAP1', 'Gene', (79, 84))	('AFAP1', 'Gene', '60312', (79, 84))	('knockdown', 'Var', (140, 149))	('AFAP1', 'Gene', '60312', (225, 230))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (153, 162))
110016	23333711	To determine the functional consequences of deregulated AFAP1-AS1 expression, several in vitro assays were performed.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (56, 65))	('deregulated', 'Var', (44, 55))	('AFAP1-AS1', 'Gene', (56, 65))	('expression', 'MPA', (66, 76))
110017	23333711	In comparison with cells transfected with a scrambled control siRNA, transfection with specific siRNAs significantly decreased growth at day 5 in both SKGT4 and OE33 EAC cells (Figure 5A).	('growth at day 5', 'MPA', (127, 142))	('decreased growth', 'Phenotype', 'HP:0001510', (117, 133))	('decreased', 'NegReg', (117, 126))	('SKGT4', 'CellLine', 'CVCL:2195', (151, 156))	('transfection', 'Var', (69, 81))	('siRNAs', 'Gene', (96, 102))	('EAC', 'Phenotype', 'HP:0011459', (166, 169))
110023	23333711	Cleavage of caspase-3 into smaller bands (17 and 19 kilodaltons; Figure 5D) occurred only after AFAP1-AS1 siRNA treatment, suggesting that inhibition of AFAP1-AS1 induces apoptosis.	('inhibition', 'Var', (139, 149))	('AFAP1-AS1', 'Gene', (153, 162))	('caspase-3', 'Gene', (12, 21))	('apoptosis', 'CPA', (171, 180))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (153, 162))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (96, 105))	('caspase-3', 'Gene', '836', (12, 21))	('AFAP1-AS1', 'Gene', (96, 105))
110024	23333711	Knockdown of AFAP1-AS1 significantly induced G2/M-phase arrest (15.22%+- 0.79% vs 7.89% +- 0.43%; t test P< .05).	('G2/M-phase arrest', 'CPA', (45, 62))	('Knockdown', 'Var', (0, 9))	('induced', 'Reg', (37, 44))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (13, 22))	('AFAP1-AS1', 'Gene', (13, 22))
110028	23333711	AFAP1-AS1 knockdown resulted in attenuated motility of SKGT4 and OE33 cells.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (0, 9))	('SKGT4', 'CellLine', 'CVCL:2195', (55, 60))	('attenuated', 'NegReg', (32, 42))	('AFAP1-AS1', 'Gene', (0, 9))	('motility', 'CPA', (43, 51))	('knockdown', 'Var', (10, 19))
110030	23333711	As shown in Figure 6B, SKGT4 cell migration and invasion were reduced by 36.0% (P < .05) and 75.9% (P < .05), respectively, following AFAP1-AS1 inhibition.	('SKGT4 cell migration', 'CPA', (23, 43))	('SKGT4', 'CellLine', 'CVCL:2195', (23, 28))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (134, 143))	('inhibition', 'Var', (144, 154))	('AFAP1-AS1', 'Gene', (134, 143))	('invasion', 'CPA', (48, 56))	('reduced', 'NegReg', (62, 69))
110034	23333711	Although global hypomethylation has been reported in many epigenetic studies of cancer, the functional consequences of this change have not been completely elucidated.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))	('global hypomethylation', 'Var', (9, 31))
110035	23333711	It has been hypothesized that loss of methylation leads to carcinogenesis by encouraging genomic instability and aberrantly activating oncogenes.	('oncogenes', 'Gene', (135, 144))	('aberrantly', 'PosReg', (113, 123))	('methylation', 'Var', (38, 49))	('loss', 'Var', (30, 34))	('leads to', 'Reg', (50, 58))	('activating', 'PosReg', (124, 134))	('carcinogenesis', 'Disease', 'MESH:D063646', (59, 73))	('genomic instability', 'CPA', (89, 108))	('carcinogenesis', 'Disease', (59, 73))	('encouraging', 'PosReg', (77, 88))
110036	23333711	Our data establish that hypomethylation is associated with the overexpression of lncRNA transcripts, which exert functional pro-cancerous effects in esophageal cells.	('cancerous', 'Disease', (128, 137))	('hypomethylation', 'Var', (24, 39))	('lncRNA transcripts', 'Gene', (81, 99))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancerous', 'Disease', 'MESH:D009369', (128, 137))	('associated', 'Reg', (43, 53))	('overexpression', 'PosReg', (63, 77))
110041	23333711	Moreover, inhibition of AFAP1-AS1 increased apoptosis and G2/ M-phase arrest.	('G2/ M-phase arrest', 'CPA', (58, 76))	('increased', 'PosReg', (34, 43))	('apoptosis', 'CPA', (44, 53))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (24, 33))	('inhibition', 'Var', (10, 20))	('AFAP1-AS1', 'Gene', (24, 33))
110047	23333711	We hypothesized that the antisense RNA AFAP1-AS1 might regulate expression of its cognate sense gene, AFAP1.	('AFAP1', 'Gene', (39, 44))	('expression', 'MPA', (64, 74))	('AFAP1', 'Gene', '60312', (39, 44))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (39, 48))	('AFAP1', 'Gene', (102, 107))	('AFAP1', 'Gene', '60312', (102, 107))	('AFAP1-AS1', 'Gene', (39, 48))	('regulate', 'Reg', (55, 63))	('antisense', 'Var', (25, 34))
110055	23333711	This elevated expression of AFAP1-AS1, its role in cell proliferation and apoptosis, and its effect on cell migration and invasion suggest that dysregulated expression of AFAP1-AS1 is involved in development or progression of EAC and that AFAP1-AS1 represents a functional lncRNA in esophageal carcinogenesis.	('elevated', 'PosReg', (5, 13))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (171, 180))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (28, 37))	('EAC', 'Phenotype', 'HP:0011459', (226, 229))	('AFAP1-AS1', 'Gene', (239, 248))	('dysregulated', 'Var', (144, 156))	('expression', 'MPA', (14, 24))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (283, 308))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (239, 248))	('EAC', 'Disease', (226, 229))	('AFAP1-AS1', 'Gene', (171, 180))	('involved', 'Reg', (184, 192))	('AFAP1-AS1', 'Gene', (28, 37))	('esophageal carcinogenesis', 'Disease', (283, 308))
110142	19422085	This polycistron was upregulated progressively at successive stages of neoplasia, in association with genomic amplification and overexpression of MCM7.	('genomic amplification', 'Var', (102, 123))	('MCM7', 'Gene', '4176', (146, 150))	('polycistron', 'Chemical', '-', (5, 16))	('neoplasia', 'Disease', (71, 80))	('upregulated', 'PosReg', (21, 32))	('MCM7', 'Gene', (146, 150))	('neoplasia', 'Phenotype', 'HP:0002664', (71, 80))	('neoplasia', 'Disease', 'MESH:D009369', (71, 80))
110158	19422085	Herein, we describe novel findings showing that: (1) the miR 25-93-106b polycistron is activated in BE-associated neoplastic transformation; (2) DNA copy number variation is closely associated with activation of the miR 25-93-106b polycistron; and (3) the miR 25-93-106b polycistron exerts cell-proliferative and oncogenic effects via key downstream regulatory targets.	('miR 25', 'Gene', '407014', (216, 222))	('associated', 'Reg', (182, 192))	('miR 25', 'Gene', (256, 262))	('polycistron', 'Chemical', '-', (231, 242))	('miR 25', 'Gene', (57, 63))	('DNA', 'Gene', (145, 148))	('miR 25', 'Gene', '407014', (57, 63))	('miR 25', 'Gene', '407014', (256, 262))	('polycistron', 'Chemical', '-', (271, 282))	('cell-proliferative', 'CPA', (290, 308))	('miR 25', 'Gene', (216, 222))	('oncogenic effects', 'CPA', (313, 330))	('polycistron', 'Chemical', '-', (72, 83))	('copy number variation', 'Var', (149, 170))
110198	19422085	We also discovered significant de novo CNV of the MCM7 locus in paired NE and EAC tissue specimens from 11 patients (p=0.0037 by paired t test in Figure 2E).	('MCM7', 'Gene', (50, 54))	('CNV', 'Var', (39, 42))	('patients', 'Species', '9606', (107, 115))	('MCM7', 'Gene', '4176', (50, 54))
110204	19422085	Interestingly, miR mimic transfection induced significantly increased numbers of both BE and WI-38 cells, although the three miR mimics exerted this effect to differing degrees (Figures 4B and 3C).	('transfection', 'Var', (25, 37))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (125, 128))	('increased', 'PosReg', (60, 69))	('miR', 'Gene', (15, 18))
110211	19422085	Our discovery that the miR-106b-25 polycistron induced increased cell numbers in vitro prompted us to evaluate its effects in vivo.	('cell numbers', 'CPA', (65, 77))	('miR-106b', 'Gene', '406900', (23, 31))	('polycistron', 'Var', (35, 46))	('increased', 'PosReg', (55, 64))	('polycistron', 'Chemical', '-', (35, 46))	('miR-106b', 'Gene', (23, 31))
110221	19422085	Similarly, in our apoptosis experiments, miR inhibitors increased the population of apoptotic cells, thus, in combination with 3'UTR homology searches, we identified the pro-apoptotic tumor suppressor gene, BCL2L11 (BCL2-like 11 or Bim).	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('increased', 'PosReg', (56, 65))	('BCL2-like 11', 'Gene', (216, 228))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('population of apoptotic cells', 'CPA', (70, 99))	('miR', 'Gene', '220972', (41, 44))	('BCL2L11', 'Gene', '10018', (207, 214))	('miR', 'Gene', (41, 44))	('tumor', 'Disease', (184, 189))	('inhibitors', 'Var', (45, 55))	('BCL2L11', 'Gene', (207, 214))	('BCL2-like 11', 'Gene', '10018', (216, 228))	('Bim', 'Gene', (232, 235))	('Bim', 'Gene', '10018', (232, 235))
110230	19422085	Experimental evidence that has accumulated in recent years has led oncologists to speculate that unrevealed molecular actors, particularly non-coding RNAs previously been classified as "junk," play important roles in carcinogenesis.	('carcinogenesis', 'Disease', (217, 231))	('carcinogenesis', 'Disease', 'MESH:D063646', (217, 231))	('non-coding RNAs', 'Var', (139, 154))
110247	19422085	We also observed a close correlation between miR-106b-25 polycistron expression and CNV in matched RNA-DNA pairs from the same individuals (p=0.0014, 0.011 and 0.019, respectively; Figure 3).	('polycistron expression', 'Var', (57, 79))	('polycistron', 'Chemical', '-', (57, 68))	('miR-106b', 'Gene', (45, 53))	('miR-106b', 'Gene', '406900', (45, 53))	('CNV', 'Disease', (84, 87))
110248	19422085	These findings also support the conclusion that the miR-106b-25 polycistron is activated by genomic copy number variation at least in a proportion of cases.	('genomic copy number variation', 'Var', (92, 121))	('polycistron', 'Chemical', '-', (64, 75))	('miR-106b', 'Gene', (52, 60))	('activated', 'PosReg', (79, 88))	('miR-106b', 'Gene', '406900', (52, 60))
110250	19422085	There have been several articles describing concomitant de novo genomic amplification, a type of CNV, and miR overexpression.	('miR', 'Gene', (106, 109))	('genomic amplification', 'Var', (64, 85))	('miR', 'Gene', '220972', (106, 109))
110280	19422085	BE Barrett's esophagus CNV copy number variation EAC esophageal adenocarcinoma INH inhibitor MM mimic NE normal epithelium	('esophageal adenocarcinoma', 'Disease', (53, 78))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (53, 78))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (3, 22))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (53, 78))	('copy number variation', 'Var', (27, 48))
110287	32548687	About 6 months after the PBT, lower esophageal mucosal inflammation that progressed to an ulcer was noted.	('esophageal mucosal inflammation', 'Disease', 'MESH:D007249', (36, 67))	('ulcer', 'Disease', 'MESH:D014456', (90, 95))	('esophageal mucosal inflammation', 'Disease', (36, 67))	('ulcer', 'Disease', (90, 95))	('PBT', 'Var', (25, 28))
110299	32548687	However, in patients with an HCC adjacent to the gastrointestinal (GI) tract, a high dose of PBT may cause radiation-induced ischemic bowel complications or bowel perforation.	('ischemic bowel complications', 'Disease', 'MESH:D007511', (125, 153))	('patients', 'Species', '9606', (12, 20))	('PBT', 'Gene', (93, 96))	('bowel', 'Disease', (157, 162))	('HCC', 'Gene', '619501', (29, 32))	('ischemic bowel complications', 'Disease', (125, 153))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('cause', 'Reg', (101, 106))	('high dose', 'Var', (80, 89))	('bowel perforation', 'Phenotype', 'HP:0031368', (157, 174))	('HCC', 'Gene', (29, 32))
110413	26265176	Inhibition of autophagy has been reported to chemosensitize several otherwise resistant cancer cells including chronic myeloid leukemia, ovarian cancer, breast cancer, malignant glioma and esophageal cancer.	('esophageal cancer', 'Disease', (189, 206))	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', (88, 94))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('myeloid leukemia', 'Disease', 'MESH:D007951', (119, 135))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (119, 135))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (111, 135))	('malignant glioma', 'Disease', (168, 184))	('malignant glioma', 'Disease', 'MESH:D005910', (168, 184))	('autophagy', 'CPA', (14, 23))	('ovarian cancer', 'Disease', 'MESH:D010051', (137, 151))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('Inhibition', 'Var', (0, 10))	('ovarian cancer', 'Disease', (137, 151))	('cancer', 'Disease', (200, 206))	('myeloid leukemia', 'Disease', (119, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (189, 206))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', (153, 166))
110418	26265176	In particular, staining of LC3A stone-like structures (SLS) has been associated with tumor progression and a poor prognosis in epithelial tumors.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (138, 143))	('LC3A', 'Gene', (27, 31))	('LC3A', 'Gene', '84557', (27, 31))	('staining', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('associated with', 'Reg', (69, 84))	('epithelial tumors', 'Disease', (127, 144))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('SLS', 'Disease', 'MESH:D016111', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('epithelial tumors', 'Disease', 'MESH:D002277', (127, 144))	('SLS', 'Disease', (55, 58))
110433	26265176	OE21 and KYSE450 are of squamous origin and OE19 and OE33 are adenocarcinoma.	('OE21', 'Var', (0, 4))	('OE33', 'Var', (53, 57))	('KYSE450', 'Enzyme', (9, 16))	('adenocarcinoma', 'Disease', (62, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('OE19', 'Var', (44, 48))
110487	26265176	In Group 1 patients (neoadjuvant-naive), positive cytoplasmic reactivity to LC3B was predictive of favourable outcome, with > five-year survival, when compared with negative cytoplasmic staining [(p < 0.001) (Fig.	('patients', 'Species', '9606', (11, 19))	('LC3B', 'Gene', '81631', (76, 80))	('positive cytoplasmic', 'Var', (41, 61))	('LC3B', 'Gene', (76, 80))
110504	26265176	In group 1 (neoadjuvant-naive); the presence of LC3B positive globular structures (HR = 6.086; 95 % confidence interval (CI) = 3.179-11.653; p < 0.001) and vascular invasion (HR = 2.304; 95 % confidence interval (CI) = 1.211-4.384; p = 0.011) were independent predictors of poor prognosis in all the variables examined.	('presence', 'Var', (36, 44))	('LC3B', 'Gene', '81631', (48, 52))	('vascular invasion', 'CPA', (156, 173))	('LC3B', 'Gene', (48, 52))
110511	26265176	On the other hand, positivity for LC3B globular structures is associated with lymph node tumor metastasis (p = 0.013) and tumors with a late stage (III-IV) (p = 0.003).	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('positivity', 'Var', (19, 29))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor metastasis', 'Disease', 'MESH:D009362', (89, 105))	('LC3B', 'Gene', (34, 38))	('associated', 'Reg', (62, 72))	('lymph node tumor', 'Phenotype', 'HP:0002665', (78, 94))	('tumor metastasis', 'Disease', (89, 105))	('LC3B', 'Gene', '81631', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('lymph node tumor', 'Disease', (78, 94))	('lymph node tumor', 'Disease', 'MESH:D000072717', (78, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
110536	26265176	In glioblastoma, high positive cytoplasmic staining of LC3B was associated with an improved outcome in patients.	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('improved', 'PosReg', (83, 91))	('LC3B', 'Gene', (55, 59))	('high positive cytoplasmic staining', 'Var', (17, 51))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('LC3B', 'Gene', '81631', (55, 59))	('patients', 'Species', '9606', (103, 111))
110538	26265176	An analysis of LC3A (Abcam EP1528Y) and LC3B (Abcam polyclonal) expression in breast cancer found an association with triple negative and high grade tumors, but no overall association with prognosis.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('LC3B', 'Gene', '81631', (40, 44))	('Abcam EP1528Y', 'Var', (21, 34))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('triple negative', 'CPA', (118, 133))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('association', 'Interaction', (101, 112))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('LC3B', 'Gene', (40, 44))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('LC3A', 'Gene', (15, 19))	('LC3A', 'Gene', '84557', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
110581	25749038	Several lines of evidences have suggested that gene mutation or aberrant activation of critical signaling pathways within irradiated tumor cells contributed to radioresistance by enhancement of DNA damage repair response.	('activation', 'PosReg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('critical signaling pathways', 'Pathway', (87, 114))	('gene mutation', 'Var', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('DNA damage repair response', 'MPA', (194, 220))	('tumor', 'Disease', (133, 138))	('enhancement', 'PosReg', (179, 190))	('aberrant', 'Var', (64, 72))	('radioresistance', 'CPA', (160, 175))
110629	25749038	We found fractionated radiation alone (12 Gy in three fractions) significantly inhibited tumor volume and weight compared with PBS treatment (830.8727 mm3 vs 987.9588 mm3, P=0.04154; 0.6882 g vs 1.1038 g, P=0.0285) (Fig.	('0.6882 g', 'Var', (183, 191))	('PBS', 'Chemical', 'MESH:D007854', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('inhibited', 'NegReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
110630	25749038	Moreover, the tumor growth inhibitory effect of fractionated radiation was further significantly enhanced when combined with anti-WISP1 antibody (fractionated radiation was performed at day 4, 8 and 12 after injection of 4 mug/mL of anti-WISP1 antibody had began at day 1 for 12 consecutive days) (409.9544 mm3vs 830.8727 mm3, P=0.0102; 0.4348 g vs 0.6882 g, P=0.0325).	('tumor', 'Disease', (14, 19))	('enhanced', 'PosReg', (97, 105))	('409.9544 mm3vs 830.8727 mm3', 'Var', (298, 325))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('0.4348 g', 'Var', (337, 345))
110631	25749038	Treatment with anti-WISP1 antibody alone had no significant inhibitory effect on tumor growth (934.9269 mm3 vs 987.9588 mm3, P=0.1153; 1.0508 g vs 1.1038 g, P=0.3153) (Fig.	('inhibitory', 'NegReg', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('1.0508 g', 'Var', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
110635	25749038	We found WISP1-overexpressed tumors were more radioresistant with significantly increased tumor volume and weight than control tumors when treated with 12 Gy of radiation in three fractions (255.3928 mm3 vs 154.9216 mm3, P=0.029; 0.12705 g vs 0.0687 g, P=0.0134) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (127, 132))	('radioresistant', 'CPA', (46, 60))	('increased', 'PosReg', (80, 89))	('tumor', 'Disease', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumors', 'Disease', (29, 35))	('0.12705 g', 'Var', (230, 239))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
110636	25749038	Up-regulation of WISP1 expression alone had no significant promotion effect on the volume of KYSE-150 xenograft tumors (459.1966 mm3 vs 434.0424 mm3, P=0.0797; 0.4098 g vs 0.3862 g, P=0.1315) (Fig.	('KYSE-150 xenograft tumors', 'Disease', 'MESH:D009369', (93, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Up-regulation', 'PosReg', (0, 13))	('WISP1', 'Gene', (17, 22))	('0.4098 g', 'Var', (160, 168))	('KYSE-150 xenograft tumors', 'Disease', (93, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
110658	25749038	WISP1 was reported to induce its own expression in adult mouse cardiomyocytes by phosphorylation and inactivation of GSK3beta, a key enzyme that inhibits Wnt/beta-catenin pathway.	('GSK3beta', 'Protein', (117, 125))	('Wnt/beta-catenin pathway', 'Pathway', (154, 178))	('phosphorylation', 'Var', (81, 96))	('WISP1', 'Gene', (0, 5))	('inactivation', 'NegReg', (101, 113))	('expression', 'MPA', (37, 47))	('mouse', 'Species', '10090', (57, 62))
110663	25749038	Due to great difference of WISP1 expression in esophageal carcinoma tissues and in adjacent normal tissues, targeting WISP1 to reverse radioresistance would be more tumor-specific and thereby have minor adverse effect on normal tissues.	('radioresistance', 'MPA', (135, 150))	('esophageal carcinoma tissues', 'Disease', (47, 75))	('WISP1', 'Gene', (118, 123))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (47, 67))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('esophageal carcinoma tissues', 'Disease', 'MESH:D004938', (47, 75))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('WISP1', 'Gene', (27, 32))	('targeting', 'Var', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('tumor', 'Disease', (165, 170))
110670	25749038	It has been reported that PI3K kinase was associated with three known major radioresistance mechanisms including intrinsic radioresistance, tumor cell proliferation and hypoxia.	('intrinsic radioresistance', 'CPA', (113, 138))	('tumor', 'Disease', (140, 145))	('associated', 'Reg', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('PI3K kinase', 'Var', (26, 37))	('rat', 'Species', '10116', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('hypoxia', 'Disease', 'MESH:D000860', (169, 176))	('hypoxia', 'Disease', (169, 176))
110671	25749038	Inhibition of PI3K kinase activity could enhance tumor radiosensitivity.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('enhance', 'PosReg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('enhance tumor radiosensitivity', 'Phenotype', 'HP:0010997', (41, 71))	('tumor', 'Disease', (49, 54))	('Inhibition', 'Var', (0, 10))	('PI3K kinase', 'Pathway', (14, 25))
110673	25749038	In other human cancers such as endometrial endometrioid adenocarcinoma, breast cancer and colorectal cancer, the expression of WISP1 was also associated with poor prognosis of patients.	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('human', 'Species', '9606', (9, 14))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('endometrial endometrioid adenocarcinoma', 'Disease', (31, 70))	('breast cancer', 'Disease', (72, 85))	('colorectal cancer', 'Disease', (90, 107))	('endometrioid adenocarcinoma', 'Phenotype', 'HP:0012114', (43, 70))	('associated', 'Reg', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('expression', 'Var', (113, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('patients', 'Species', '9606', (176, 184))	('endometrial endometrioid adenocarcinoma', 'Disease', 'MESH:D016889', (31, 70))	('WISP1', 'Gene', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
110675	25749038	When deregulated, aberrant expression of WISP1 often led to accelerated cell growth and enhanced motility and invasion.	('cell growth', 'CPA', (72, 83))	('accelerated', 'PosReg', (60, 71))	('aberrant expression', 'Var', (18, 37))	('WISP1', 'Gene', (41, 46))	('rat', 'Species', '10116', (66, 69))	('enhanced', 'PosReg', (88, 96))
110691	25749038	Antibodies against gamma-H2AX, p-PI3K (Tyr199/458) and PI3K were purchased from Cell Signaling Technology (Beverly, MA, USA).	('p-PI3K (Tyr199/458', 'Var', (31, 49))	('Tyr199', 'Chemical', '-', (39, 45))	('gamma-H2AX', 'Chemical', '-', (19, 29))	('gamma-H2AX', 'Protein', (19, 29))
110934	22507220	In some areas in China, unhealthy diet, such as pickled vegetables and moldy or fermented foods, has been associated with increased risk of EAC.	('moldy', 'Var', (71, 76))	('EAC', 'Gene', (140, 143))	('men', 'Species', '9606', (83, 86))	('EAC', 'Gene', '1540', (140, 143))
110943	22507220	The first genome-wide association study of ESCC performed in Japanese individuals revealed two functional SNPs in alcohol dehydrogenase 1B (ADH1B) (rs1229984, OR = 1.79) and aldehyde dehydrogenase 2 family (ALDH2) (rs671, OR = 1.67), which encode metabolic enzymes for alcohol and carcinogens associated with altered ESCC risk.	('alcohol dehydrogenase 1B', 'Gene', '125', (114, 138))	('rs671', 'Mutation', 'rs671', (215, 220))	('rs1229984', 'Mutation', 'rs1229984', (148, 157))	('ALDH2', 'Gene', (207, 212))	('ADH1B', 'Gene', (140, 145))	('rs1229984', 'Var', (148, 157))	('ADH1B', 'Gene', '125', (140, 145))	('alcohol', 'Chemical', 'MESH:D000438', (269, 276))	('alcohol dehydrogenase 1B', 'Gene', (114, 138))	('alcohol', 'Chemical', 'MESH:D000438', (114, 121))	('rs671', 'Var', (215, 220))
110944	22507220	This study also reported gene-environmental interactions of rs671 with alcohol drinking and smoking, and found a similar link between SNP rs1229984 and alcohol drinking.	('alcohol', 'Chemical', 'MESH:D000438', (71, 78))	('alcohol drinking', 'Disease', (152, 168))	('alcohol drinking', 'Phenotype', 'HP:0030955', (71, 87))	('rs671', 'Mutation', 'rs671', (60, 65))	('alcohol drinking', 'MPA', (71, 87))	('rs1229984', 'Var', (138, 147))	('rs1229984', 'Mutation', 'rs1229984', (138, 147))	('alcohol drinking', 'Phenotype', 'HP:0030955', (152, 168))	('men', 'Species', '9606', (37, 40))	('interactions', 'Interaction', (44, 56))	('alcohol', 'Chemical', 'MESH:D000438', (152, 159))	('rs671', 'Var', (60, 65))
110945	22507220	In 2010, two genome-wide association studies in Chinese populations identified two additional susceptibility loci [rs2274223 in phospholipase C, epsilon 1 (PLCE1) and rs13042395 in chromosome 20 open reading frame (C20orf54)] for ESCC.	('rs13042395', 'Var', (167, 177))	('ESCC', 'Disease', (230, 234))	('PLCE1', 'Gene', (156, 161))	('C20orf54', 'Gene', (215, 223))	('Chinese', 'Species', '10029', (48, 55))	('rs13042395', 'Mutation', 'rs13042395', (167, 177))	('phospholipase C, epsilon 1', 'Gene', '100754217', (128, 154))	('PLCE1', 'Gene', '100754217', (156, 161))	('rs2274223', 'Mutation', 'rs2274223', (115, 124))
110946	22507220	More recently, a larger genome-wide association study (2043 cases and 2063 controls) on ESCC performed in Chinese Han individuals revealed three new SNPs, rs10052657 in phosphodiesterase 4D (PDE4D) (OR = 0.33), rs2014300 in runt-related transcription factor 1 (RUNX1) (OR = 0.62), and rs10484761 near to unc-5 homolog C (C. elegans)-like (UNC5CL) (OR = 1.77), to be associated with ESCC risk at significant level.	('RUNX1', 'Gene', (261, 266))	('rs10052657', 'Var', (155, 165))	('runt-related transcription factor 1', 'Gene', '100758283', (224, 259))	('rs10484761', 'Mutation', 'rs10484761', (285, 295))	('rs10052657', 'Mutation', 'rs10052657', (155, 165))	('unc-5 homolog C', 'Gene', (304, 319))	('phosphodiesterase 4D', 'Gene', '100754362', (169, 189))	('ESCC', 'Disease', (382, 386))	('phosphodiesterase 4D', 'Gene', (169, 189))	('PDE4D', 'Gene', (191, 196))	('RUNX1', 'Gene', '100758283', (261, 266))	('PDE4D', 'Gene', '100754362', (191, 196))	('unc-5 homolog C', 'Gene', '100762557', (304, 319))	('rs10484761 near', 'Var', (285, 300))	('C. elegans', 'Species', '6239', (321, 331))	('runt-related transcription factor 1', 'Gene', (224, 259))	('rs2014300', 'Mutation', 'rs2014300', (211, 220))	('Chinese', 'Species', '10029', (106, 113))	('rs2014300 in', 'Var', (211, 223))	('associated', 'Reg', (366, 376))
110947	22507220	This study reported that three variants (rs11066105, rs11066280, and rs2074356) in strong linkage disequilibrium on 12q24 conferred risk to ESCC in a gene-environmental interaction manner, with increased risk in tobacco and alcohol users.	('rs11066280', 'Var', (53, 63))	('tobacco', 'Species', '4097', (212, 219))	('men', 'Species', '9606', (162, 165))	('rs11066105', 'Var', (41, 51))	('ESCC', 'Disease', (140, 144))	('rs2074356', 'Mutation', 'rs2074356', (69, 78))	('rs11066105', 'Mutation', 'rs11066105', (41, 51))	('rs11066280', 'Mutation', 'rs11066280', (53, 63))	('conferred risk', 'Reg', (122, 136))	('alcohol', 'Chemical', 'MESH:D000438', (224, 231))	('rs2074356', 'Var', (69, 78))
110952	22507220	In these studies, variants of genes encoding phase I and II enzymes [e.g., glutathione S-transferase theta 1 (GSTT1), glutathione S-transferase pi 1 (GSTP1), and glutathione S-trans-ferase mu 3 (GSTM3)], DNA repair genes [e.g., XRCC1, excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), XPC, and XPD], and cell cycle control (e.g., TP53, TP73, and CCND1) were linked to EAC susceptibility.	('GSTM3', 'Gene', (195, 200))	('TP73', 'Gene', (381, 385))	('EAC', 'Gene', '1540', (413, 416))	('EAC', 'Gene', (413, 416))	('men', 'Species', '9606', (303, 306))	('glutathione S-trans-ferase mu 3', 'Gene', (162, 193))	('variants', 'Var', (18, 26))	('men', 'Species', '9606', (263, 266))	('linked', 'Reg', (403, 409))	('glutathione S-transferase pi 1', 'Gene', (118, 148))	('GSTP1', 'Gene', '2950', (150, 155))	('GSTM3', 'Gene', '2947', (195, 200))	('GSTT1', 'Gene', '2952', (110, 115))	('ERCC1', 'Gene', '2067', (322, 327))	('GSTP1', 'Gene', (150, 155))	('glutathione S-transferase theta 1', 'Gene', (75, 108))	('glutathione S-transferase pi 1', 'Gene', '2950', (118, 148))	('glutathione S-transferase theta 1', 'Gene', '2952', (75, 108))	('ERCC1', 'Gene', (322, 327))	('glutathione S-trans-ferase mu 3', 'Gene', '2947', (162, 193))	('GSTT1', 'Gene', (110, 115))	('TP73', 'Gene', '7161', (381, 385))
110953	22507220	SNPs in other genes, such as the vascular endothelial growth factor (VEGF) gene, were also reported to be associated with susceptibility for EAC in Western populations.	('VEGF', 'Gene', (69, 73))	('EAC', 'Gene', (141, 144))	('susceptibility', 'Reg', (122, 136))	('vascular endothelial growth factor', 'Gene', '7422', (33, 67))	('associated', 'Reg', (106, 116))	('VEGF', 'Gene', '7422', (69, 73))	('SNPs', 'Var', (0, 4))	('vascular endothelial growth factor', 'Gene', (33, 67))	('EAC', 'Gene', '1540', (141, 144))
110955	22507220	The only study conducted in an Indian population revealed that GSTM3 polymorphism might modulate the risk of EAC, but the sample size was very small.	('polymorphism', 'Var', (69, 81))	('modulate', 'Reg', (88, 96))	('EAC', 'Gene', '1540', (109, 112))	('EAC', 'Gene', (109, 112))	('GSTM3', 'Gene', (63, 68))	('GSTM3', 'Gene', '2947', (63, 68))
110966	22507220	However, patients with the same clinical features and treatments may have different clinical outcomes, indicating genetic variants may play an important role in esophageal cancer prognosis.	('patients', 'Species', '9606', (9, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('play', 'Reg', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('role', 'Reg', (153, 157))	('genetic variants', 'Var', (114, 130))	('esophageal cancer', 'Disease', (161, 178))	('men', 'Species', '9606', (59, 62))
110970	22507220	Researchers also found that genetic variants in MTHFR, TS, and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) might contribute to ESCC prognosis in German populations.	('genetic variants', 'Var', (28, 44))	('MTHFR', 'Gene', (48, 53))	('contribute', 'Reg', (131, 141))	('folate', 'Chemical', 'MESH:D005492', (81, 87))	('ESCC', 'Disease', (145, 149))
110972	22507220	The association between EAC outcomes and polymorphic variants on other pathways, including the inflammatory pathway [e.g., interleukin 1 beta (IL1B) and interleukin 6 (IL6)] and the folate pathway (e.g., TS and MTHFR), have also been evaluated in Western populations.	('IL6', 'Gene', '3569', (168, 171))	('EAC', 'Gene', (24, 27))	('folate pathway', 'Pathway', (182, 196))	('polymorphic variants', 'Var', (41, 61))	('folate', 'Chemical', 'MESH:D005492', (182, 188))	('interleukin 6', 'Gene', '3569', (153, 166))	('inflammatory pathway', 'Pathway', (95, 115))	('IL6', 'Gene', (168, 171))	('interleukin 1 beta', 'Gene', '3553', (123, 141))	('IL1B', 'Gene', (143, 147))	('interleukin 1 beta', 'Gene', (123, 141))	('interleukin 6', 'Gene', (153, 166))	('IL1B', 'Gene', '3553', (143, 147))	('EAC', 'Gene', '1540', (24, 27))
110982	22021675	Intraesophageal BEB55 and JP4-039 compared to formulation alone increased survival after single fraction (p=0.0209 and 0.0384, respectively) and four fraction thoracic irradiation (p=0.0241 and 0.0388, respectively).	('survival', 'CPA', (74, 82))	('BEB55', 'Chemical', '-', (16, 21))	('BEB55', 'Var', (16, 21))	('JP4', 'Gene', '319984', (26, 29))	('increased', 'PosReg', (64, 73))	('JP4', 'Gene', (26, 29))
110984	22021675	There was no significant radiation protection of lung tumors by BEB55 or JP4-039 compared to formulation only as assessed by survival (p=0.3021 and 0.3693, respectively).	('BEB55', 'Var', (64, 69))	('lung tumors', 'Disease', 'MESH:D008175', (49, 60))	('lung tumor', 'Phenotype', 'HP:0100526', (49, 59))	('JP4', 'Gene', '319984', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('BEB55', 'Chemical', '-', (64, 69))	('JP4', 'Gene', (73, 76))	('lung tumors', 'Phenotype', 'HP:0100526', (49, 60))	('lung tumors', 'Disease', (49, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
111001	22021675	In the present studies, we delivered BEB55 or JP4-039 to the esophagus of mice by orally administered cationically charged multilamellar liposome formulation (F15) and tested the relative effect of each on irradiation-induced esophagitis.	('esophagitis', 'Phenotype', 'HP:0100633', (226, 237))	('esophagitis', 'Disease', (226, 237))	('esophagitis', 'Disease', 'MESH:D004941', (226, 237))	('BEB55', 'Chemical', '-', (37, 42))	('tested', 'Reg', (168, 174))	('JP4', 'Gene', '319984', (46, 49))	('BEB55', 'Var', (37, 42))	('mice', 'Species', '10090', (74, 78))	('JP4', 'Gene', (46, 49))
111012	22021675	Cells were pelleted and resuspended in cold Hank's balanced salt solution (HBSS) (2% FBS, 10 mM HEPES) and incubated with anti-CD45-phycoerythrin (PE)-fluorescein isothiocyanate (FITC) and/or anti-Ter119-PE-Cy7 antibodies (BD Pharmingen, San Diego, CA, USA) at 1:200 dilutions to discriminate hematopoietic cells.	('anti-Ter119-PE-Cy7', 'Var', (192, 210))	('PE', 'Chemical', '-', (98, 100))	('PE', 'Chemical', '-', (147, 149))	('PE', 'Chemical', '-', (204, 206))	("Hank's balanced salt solution", 'Chemical', '-', (44, 73))	('CD45', 'Gene', '19264', (127, 131))	('fluorescein isothiocyanate', 'Chemical', 'MESH:D016650', (151, 177))	('HEPES', 'Chemical', 'MESH:D006531', (96, 101))	('CD45', 'Gene', (127, 131))	('FITC', 'Chemical', 'MESH:D016650', (179, 183))	('HBSS', 'Chemical', '-', (75, 79))
111027	22021675	Mice were given the following treatments: i) F15 plus 29 Gy; ii) MnSOD-PL 24 h prior to 29 Gy; iii) BEB55 immediately before 29 Gy; or iv) JP4-039 immediately before 29 Gy (15 mice per group).	('JP4', 'Gene', (139, 142))	('MnSOD', 'Gene', (65, 70))	('BEB55', 'Var', (100, 105))	('mice', 'Species', '10090', (176, 180))	('Mice', 'Species', '10090', (0, 4))	('BEB55', 'Chemical', '-', (100, 105))	('JP4', 'Gene', '319984', (139, 142))	('F15', 'Var', (45, 48))	('MnSOD', 'Gene', '20656', (65, 70))
111029	22021675	Subgroups of mice received i) F15 plus 11.5 Gy x 4; ii) MnSOD-PL 24 hours prior to the first and third fractions; iii) BEB55 before each fraction; or iv) JP4-039 prior to each fraction (15 mice per group).	('mice', 'Species', '10090', (13, 17))	('JP4', 'Gene', (154, 157))	('MnSOD', 'Gene', '20656', (56, 61))	('MnSOD', 'Gene', (56, 61))	('mice', 'Species', '10090', (189, 193))	('F15', 'Var', (30, 33))	('BEB55', 'Chemical', '-', (119, 124))	('JP4', 'Gene', '319984', (154, 157))
111030	22021675	To determine whether JP4-039 or BEB55 in tumor cells was radioprotective, mice with 3LL tumors were treated as follows: i) no additional treatment; ii) F15 plus 20 Gy x 1 thoracic irradiation (single fraction, 526 cGy/min); iii) BEB55 plus 20 Gy; iv) JP4-039 plus 20 Gy; or v) MnSOD-PL, 24 hours prior to 20 Gy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('BEB55', 'Chemical', '-', (229, 234))	('JP4', 'Gene', '319984', (21, 24))	('JP4', 'Gene', '319984', (251, 254))	('BEB55', 'Chemical', '-', (32, 37))	('3LL tumors', 'Disease', (84, 94))	('BEB55', 'Var', (229, 234))	('mice', 'Species', '10090', (74, 78))	('tumor', 'Disease', (88, 93))	('3LL tumors', 'Disease', 'MESH:D009369', (84, 94))	('MnSOD', 'Gene', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('F15', 'Var', (152, 155))	('JP4', 'Gene', (251, 254))	('JP4', 'Gene', (21, 24))	('MnSOD', 'Gene', '20656', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
111054	22021675	To determine whether intraesophageal administration of BEB55 or JP4-039 in F15 would ameliorate irradiation-induced esophagitis in mice, mice were treated with F15 only, JP4-039 or BEB55, immediately prior to a single fraction of 29 Gy thoracic irradiation.	('JP4', 'Gene', '319984', (64, 67))	('esophagitis', 'Disease', 'MESH:D004941', (116, 127))	('JP4', 'Gene', (64, 67))	('BEB55', 'Var', (55, 60))	('ameliorate', 'PosReg', (85, 95))	('JP4', 'Gene', '319984', (170, 173))	('F15', 'Gene', (75, 78))	('BEB55', 'Chemical', '-', (181, 186))	('mice', 'Species', '10090', (131, 135))	('JP4', 'Gene', (170, 173))	('mice', 'Species', '10090', (137, 141))	('esophagitis', 'Phenotype', 'HP:0100633', (116, 127))	('BEB55', 'Chemical', '-', (55, 60))	('esophagitis', 'Disease', (116, 127))
111056	22021675	Mice that were treated with JP4-039 or BEB55 prior to 29 Gy thoracic irradiation demonstrated increased survival compared to the F15 vehicle only group (p=0.0384 and 0.0209, respectively) (Figure 3A and 4A).	('BEB55', 'Chemical', '-', (39, 44))	('increased', 'PosReg', (94, 103))	('JP4', 'Gene', '319984', (28, 31))	('JP4', 'Gene', (28, 31))	('BEB55', 'Var', (39, 44))	('Mice', 'Species', '10090', (0, 4))
111058	22021675	To evaluate radioprotection by BEB55 and JP4-039 in multiple-fraction upper-body irradiation, mice were treated with intraesophageal BEB55 or JP4-039 prior to each of four fractions of 11.5 Gy thoracic irradiation.	('BEB55', 'Chemical', '-', (133, 138))	('JP4', 'Gene', '319984', (41, 44))	('JP4', 'Gene', (41, 44))	('JP4', 'Gene', '319984', (142, 145))	('BEB55', 'Var', (133, 138))	('JP4', 'Gene', (142, 145))	('mice', 'Species', '10090', (94, 98))	('BEB55', 'Chemical', '-', (31, 36))
111060	22021675	Mice treated with JP4-039 or BEB55 prior to irradiation had increased survival compared to the F15 only control group (p=0.0388 and 0.0241, respectively) (Figure 3B and 4B).	('BEB55', 'Chemical', '-', (29, 34))	('JP4', 'Gene', (18, 21))	('BEB55', 'Var', (29, 34))	('JP4', 'Gene', '319984', (18, 21))	('Mice', 'Species', '10090', (0, 4))	('survival', 'CPA', (70, 78))	('increased', 'PosReg', (60, 69))
111061	22021675	The data indicate that both BEB55 and JP4-039 are protectors against fractionated irradiation of the esophagus and are effective when given in multiple administrations.	('JP4', 'Gene', (38, 41))	('BEB55', 'Var', (28, 33))	('BEB55', 'Chemical', '-', (28, 33))	('JP4', 'Gene', '319984', (38, 41))
111086	22021675	While BEB55 and JP4-039 confer radioprotection by different mechanisms, previous work did not detect an additive effect when combining the two drugs in vitro compared to each alone.	('BEB55', 'Chemical', '-', (6, 11))	('radioprotection', 'CPA', (31, 46))	('JP4', 'Gene', (16, 19))	('JP4', 'Gene', '319984', (16, 19))	('BEB55', 'Var', (6, 11))
111087	22021675	Further investigation may reveal that BEB55 increases the uptake of JP4-039, or a synergistic radioprotective effect may be found when the two compounds are spaced appropriately.	('JP4', 'Gene', '319984', (68, 71))	('JP4', 'Gene', (68, 71))	('uptake', 'MPA', (58, 64))	('BEB55', 'Chemical', '-', (38, 43))	('increases', 'PosReg', (44, 53))	('BEB55', 'Var', (38, 43))
111095	22627741	Patients with superficial esophageal squamous cell carcinoma 1) thinner than 1200microm; 2) confined to the mucosa; 3) with submucosal invasion <250microm; 4) with submucosal invasion >=250microm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or 5) with submucosal invasion >=250microm but with weak VEGF expression and well differentiated histology had almost no risk of lymph node metastasis.	('>=250microm', 'Var', (319, 330))	('esophageal squamous cell carcinoma', 'Disease', (26, 60))	('VEGF', 'Gene', (345, 349))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('VEGF', 'Gene', (214, 218))	('Patients', 'Species', '9606', (0, 8))	('VEGF', 'Gene', '7422', (345, 349))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (26, 60))	('>=250microm', 'Var', (184, 195))	('VEGF', 'Gene', '7422', (214, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
111097	22627741	No additional treatment is needed for endoscopic resection cases with superficial esophageal squamous cell carcinoma 1) thinner than 1200microm; 2) confined to the mucosa; 3) with submucosal invasion <250microm; 4) with submucosal invasion >=250microm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or 5) with submucosal invasion >=250microm but with weak VEGF expression and well differentiated histology.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('VEGF', 'Gene', '7422', (401, 405))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('VEGF', 'Gene', (270, 274))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('<250microm', 'Var', (200, 210))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('VEGF', 'Gene', (401, 405))	('VEGF', 'Gene', '7422', (270, 274))
111146	22627741	The maximum depth of invasion was m2 in 22 patients (8%), m3 in 30 (11%), sm1 in 23 (9%), sm2 in 55 (20 %), and sm3 in 141 patients (52%).	('patients', 'Species', '9606', (43, 51))	('sm1', 'Gene', '7911', (74, 77))	('patients', 'Species', '9606', (123, 131))	('sm3', 'Var', (112, 115))	('sm1', 'Gene', (74, 77))	('sm2', 'Gene', (90, 93))	('sm2', 'Gene', '53366', (90, 93))
111162	22627741	The univariate areas under Receiver-Operating-Characteristic curves, in decreasing order, were 0.660, 0.618 and 0.617 for VEGF protein level, macroscopic tumor type and degree of differentiation, respectively (Table 4).	('VEGF', 'Gene', '7422', (122, 126))	('0.617', 'Var', (112, 117))	('0.618', 'Var', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('VEGF', 'Gene', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
111170	22627741	It has been reported that macroscopic shape correlates with invasion depth and lymph node metastasis, and patients with non-flat shapes have a higher frequency of metastasis.	('metastasis', 'CPA', (163, 173))	('patients', 'Species', '9606', (106, 114))	('invasion depth', 'CPA', (60, 74))	('macroscopic', 'Var', (26, 37))	('lymph node metastasis', 'CPA', (79, 100))
111180	22627741	So we think that additional surgical resection after endoscopic resection is probably not required for patients with total tumor thickness less than 1200microm, in tumors limited to the mucosa, or in cases with submucosal invasion less than 250microm, no matter what the other parameters show.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (123, 128))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('patients', 'Species', '9606', (103, 111))	('less', 'Var', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
111194	22627741	And in those who are endoscopic ultrasonography and CT negative, we recommend:   In patients with tumors invading the submucosa >=250microm, the most important criteria for deciding whether or not to recommend additional treatment are VEGF staining and tumor histology.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('VEGF', 'Gene', (235, 239))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('>=250microm', 'Var', (128, 139))	('tumor', 'Disease', (253, 258))	('tumor', 'Disease', (98, 103))	('VEGF', 'Gene', '7422', (235, 239))
111218	20395127	We classified tumors with site codes C00.1-C06.9 as oral cavity cancer.	('C00.1-C06.9', 'Var', (37, 48))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (64, 70))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
111219	20395127	Oro- and hypo- pharyngeal cancers included tumours of the tonsil (C09.0 - C09.9), oropharynx (C10.0 - C10.9), pyriform sinus (C12.9), hypopharynx (C13.0 - C13.9), and pharynx not otherwise specified (NOS) (C14.0).	('hypopharynx', 'Disease', (134, 145))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('hypo- pharyngeal cancers', 'Disease', 'MESH:D010610', (9, 33))	('oropharynx', 'Disease', (82, 92))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('C10.0 - C10.9', 'Var', (94, 107))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (15, 32))	('C12.9', 'Var', (126, 131))	('pharynx not otherwise specified', 'Disease', (167, 198))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('hypo- pharyngeal cancers', 'Disease', (9, 33))	('tumours', 'Disease', (43, 50))	('C13.0 - C13.9', 'Var', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('C09.0 - C09.9', 'Var', (66, 79))	('Oro- and', 'Disease', (0, 8))	('pyriform sinus', 'Disease', (110, 124))
111220	20395127	Tumors with site codes C32.0-C32.9 were classified as laryngeal cancer.	('laryngeal cancer', 'Disease', 'MESH:D007822', (54, 70))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('laryngeal cancer', 'Disease', (54, 70))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (54, 70))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('C32.0-C32.9', 'Var', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
111299	33937062	In the univariable regression, patients who received WBRT had improved OS compared to those who did not (HR = 0.249, p = 0.018), and patients with a DS-GPA score of 2.5-4 were associated with improved OS compared with patients with a DS-GPA score of 0-2 (HR = 0.050, p = 0.005).	('improved', 'PosReg', (192, 200))	('improved', 'PosReg', (62, 70))	('patients', 'Species', '9606', (218, 226))	('patients', 'Species', '9606', (133, 141))	('WBRT', 'Var', (53, 57))	('patients', 'Species', '9606', (31, 39))
111336	33937062	There were seven cases with CD56 positive, seven with Syn positive, four with ChrA positive, three with ChrA weak positive, seven with CK positive, four with NSE positive, two with NSE weak positive, and one with NSE negative.	('NSE', 'Gene', '2026', (181, 184))	('Syn', 'Gene', (54, 57))	('CD56 positive', 'Var', (28, 41))	('NSE', 'Gene', (158, 161))	('Syn', 'Gene', '23336', (54, 57))	('NSE', 'Gene', (213, 216))	('NSE', 'Gene', (181, 184))	('NSE', 'Gene', '2026', (213, 216))	('NSE', 'Gene', '2026', (158, 161))
111342	33937062	In the univariable Cox proportional hazard analysis (Table 3), patients with DS-GPA scores of 2.5-4 were associated with improved OS as compared to patients with DS-GPA scores of 0-2; patients who received WBRT had improved OS compared to those who did not.	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (184, 192))	('improved', 'PosReg', (121, 129))	('improved', 'PosReg', (215, 223))	('patients', 'Species', '9606', (63, 71))	('scores', 'Var', (84, 90))
111351	33937062	The prognosis of patients with the DS-GPA score of 2.5-4 was significantly better than that of patients with the DS-GPA score of 0-2 (HR = 0.050, 95% CI: 0.006 0.408, p = 0.005) (Table 3; Figure 3).	('better', 'PosReg', (75, 81))	('score', 'Var', (42, 47))	('DS-GPA score', 'Var', (35, 47))	('patients', 'Species', '9606', (95, 103))	('prognosis', 'CPA', (4, 13))	('patients', 'Species', '9606', (17, 25))
111372	33937062	The median OS in the group of patients who received brain radiotherapy was 11.9 months, which is significantly higher than that of the patients who did not receive brain radiotherapy (p = 0.018).	('higher', 'PosReg', (111, 117))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (135, 143))	('brain radiotherapy', 'Var', (52, 70))
111374	33937062	They found that the median OS of patients who received brain radiotherapy was significantly higher than that of patients who did not receive brain radiotherapy (7.13 vs. 3.4 months).	('patients', 'Species', '9606', (33, 41))	('higher', 'PosReg', (92, 98))	('brain radiotherapy', 'Var', (55, 73))	('patients', 'Species', '9606', (112, 120))
111397	33709689	The adverse bulk changes in the polymer structure were identified using differential scanning calorimetry (DSC), differential mechanical thermal analysis (DMTA), and attenuated total reflectance infrared spectroscopy (ATR-IR) and discussed in terms of melting point shift (9  C), glass-transition shift (4  C), differences in viscoelastic behavior, and systematic decrease of peaks intensities corresponding to C-H, C=O, and C-N polyurethane structural bonds.	('differences', 'Reg', (311, 322))	('C', 'Chemical', 'MESH:D002244', (307, 308))	('decrease', 'NegReg', (364, 372))	('C=O', 'Protein', (416, 419))	('polyurethane', 'Chemical', 'MESH:D011140', (429, 441))	('C', 'Chemical', 'MESH:D002244', (416, 417))	('DMTA', 'Chemical', '-', (155, 159))	('ATR', 'Gene', '545', (218, 221))	('peaks intensities', 'MPA', (376, 393))	('polymer', 'Chemical', 'MESH:D011108', (32, 39))	('C', 'Chemical', 'MESH:D002244', (411, 412))	('C-H', 'Disease', (411, 414))	('ATR', 'Gene', (218, 221))	('point shift', 'Phenotype', 'HP:0100810', (260, 271))	('viscoelastic behavior', 'MPA', (326, 347))	('C', 'Chemical', 'MESH:D002244', (276, 277))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('C-N', 'Var', (425, 428))	('C', 'Chemical', 'MESH:D002244', (425, 426))
111441	33709689	A Q800 DMA (TA Instruments, New Castle, DE) apparatus operating in a tensile mode was used to determine the storage modulus (E'), loss modulus (E''), and the tangent of the phase angle (tan delta).	('Q800', 'Var', (2, 6))	('storage modulus', 'MPA', (108, 123))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('men', 'Species', '9606', (21, 24))	('loss modulus', 'MPA', (130, 142))
111457	33709689	A modified Fusayama's artificial saliva (AS) was used at 37  C (pH 6), with the following chemical composition: NaCl (0.4 g/L), KCl (0.4 g/L), CaCl2 2H2O (0.795 g/L), Na2S 9H2O (0.005 g/L), NaH2PO4 2H2O (0.69 g/L), and urea (1 g/L).	('C', 'Chemical', 'MESH:D002244', (143, 144))	('C', 'Chemical', 'MESH:D002244', (145, 146))	('Na2S 9H2O', 'Chemical', '-', (167, 176))	('0.795 g/L', 'Var', (155, 164))	('NaCl', 'Chemical', 'MESH:D012965', (112, 116))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('KCl', 'Chemical', 'MESH:D011189', (128, 131))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('CaCl', 'Gene', (143, 147))	("Fusayama's artificial saliva", 'Chemical', '-', (11, 39))	('NaH2PO4 2H2O', 'Chemical', '-', (190, 202))	('urea', 'Chemical', 'MESH:D014508', (219, 223))	('CaCl', 'Gene', '123096', (143, 147))	('C', 'Chemical', 'MESH:D002244', (129, 130))
111464	33709689	In general, the observed trend for the proximal end is increase in Tmelt in the narrow range of 367-368  C, while for the distal end, the values are spread in the larger range of 356-369  C, as shown in Figure 2 (the error bars correspond to 0.2  C).	('increase', 'PosReg', (55, 63))	('C', 'Chemical', 'MESH:D002244', (247, 248))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('C', 'Chemical', 'MESH:D002244', (188, 189))	('367-368', 'Var', (96, 103))	('Tmelt', 'MPA', (67, 72))
111480	33709689	The characteristic maxima for polyurethane are observed at 2930 and 2858 cm-1 (asymmetric CH2 stretch vibration), 1738 and 1716 cm-1 (C=O stretch vibration), 1524 cm-1 (coupling N-H blending vibration with C-N stretching vibration), 1463 and 1403 cm-1 (CH2 bending vibration), 1244 cm-1 (amine III vibration, C-N), 1044 cm-1 (antisymmetric C-O-C), 955 cm-1 (C-H benzene ring out-of-plane bending), and 790 cm-1 (amine IV vibration).	('C', 'Chemical', 'MESH:D002244', (206, 207))	('polyurethane', 'Chemical', 'MESH:D011140', (30, 42))	('C', 'Chemical', 'MESH:D002244', (90, 91))	('C', 'Chemical', 'MESH:D002244', (344, 345))	('C', 'Chemical', 'MESH:D002244', (358, 359))	('C', 'Chemical', 'MESH:D002244', (340, 341))	('C', 'Chemical', 'MESH:D002244', (253, 254))	('1738', 'Var', (114, 118))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('C-N', 'Var', (309, 312))	('C', 'Chemical', 'MESH:D002244', (309, 310))
111481	33709689	Although the overall IR spectra are essentially similar, the detailed analysis of the three regions assigned to -CH2 (3000-2800 cm-1), C=O (1800-1600 cm-1), and C-N (1300-1150 cm-1) shows systematic changes in the characteristic bond absorption intensities, as presented in the bottom panels of Figures 3 and 4, respectively.	('characteristic bond absorption intensities', 'MPA', (214, 256))	('C-N (1300-1150 cm-1', 'Var', (161, 180))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('3000-2800 cm-1', 'Var', (118, 132))	('changes', 'Reg', (199, 206))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('C', 'Chemical', 'MESH:D002244', (161, 162))
111495	33709689	It can also be noted that on the polymeric surface, the crystalline precipitates are formed, which contain the typical ions presented in the simulated saliva (Na+, K+, Ca2+, PO43-, Cl-).	('polymer', 'Chemical', 'MESH:D011108', (33, 40))	('PO43-', 'Chemical', '-', (174, 179))	('C', 'Chemical', 'MESH:D002244', (168, 169))	('Na+', 'Var', (159, 162))	('Ca2+', 'Chemical', 'MESH:D000069285', (168, 172))	('Ca2+', 'MPA', (168, 172))	('C', 'Chemical', 'MESH:D002244', (181, 182))	('PO43-', 'Var', (174, 179))	('Cl-', 'MPA', (181, 184))
111551	33363398	Case-Control Study on TNFRSF6B Gene Polymorphism and Susceptibility to Gastric Cancer in a Chinese Han Population To explore the relationship between rs2297440 and rs2297441 polymorphisms of TNFRSF6B gene and susceptibility to gastric cancer.	('Susceptibility to Gastric Cancer', 'Phenotype', 'HP:0006753', (53, 85))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (71, 85))	('TNFRSF6B', 'Gene', '8771', (22, 30))	('TNFRSF6B', 'Gene', (22, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (227, 241))	('Gastric Cancer', 'Disease', (71, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (227, 241))	('susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (209, 241))	('rs2297440', 'Mutation', 'rs2297440', (150, 159))	('rs2297441', 'Mutation', 'rs2297441', (164, 173))	('rs2297440', 'Var', (150, 159))	('Gastric Cancer', 'Disease', 'MESH:D013274', (71, 85))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('rs2297441', 'Var', (164, 173))	('TNFRSF6B', 'Gene', '8771', (191, 199))	('TNFRSF6B', 'Gene', (191, 199))
111553	33363398	For TNFRSF6B rs2297440, among people <62 years old, the risk of gastric cancer in TC people was 1.84 times that in TT people.	('people', 'Species', '9606', (118, 124))	('TNFRSF6B', 'Gene', '8771', (4, 12))	('TC', 'Chemical', 'MESH:D013667', (82, 84))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gastric cancer', 'Disease', (64, 78))	('TNFRSF6B', 'Gene', (4, 12))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('rs2297440', 'Mutation', 'rs2297440', (13, 22))	('people', 'Species', '9606', (85, 91))	('rs2297440', 'Var', (13, 22))	('people', 'Species', '9606', (30, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))
111556	33363398	As for TNFRSF6B rs2297441, in males and non-drinkers, the risk of gastric cancer in the AG type was less than that in the GG type.	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('rs2297441', 'Mutation', 'rs2297441', (16, 25))	('TNFRSF6B', 'Gene', '8771', (7, 15))	('rs2297441', 'Var', (16, 25))	('less', 'NegReg', (100, 104))	('TNFRSF6B', 'Gene', (7, 15))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
111559	33363398	For TNFRSF6B rs2297440, the TC genotype may be a risk factor for gastric cancer in people <62 years old.	('people', 'Species', '9606', (83, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('TNFRSF6B', 'Gene', '8771', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TNFRSF6B', 'Gene', (4, 12))	('TC', 'Chemical', 'MESH:D013667', (28, 30))	('rs2297440', 'Mutation', 'rs2297440', (13, 22))	('risk', 'Reg', (49, 53))	('gastric cancer', 'Disease', (65, 79))	('rs2297440', 'Var', (13, 22))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))
111560	33363398	In the non-drinking population, the homozygous mutant of CC may be a protective factor for gastric cancer.	('gastric cancer', 'Disease', (91, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (91, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('homozygous mutant', 'Var', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
111562	33363398	For TNFRSF6B rs2297441, the AG genotype may be a risk factor for gastric cancer in males and non-drinkers.	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('TNFRSF6B', 'Gene', '8771', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TNFRSF6B', 'Gene', (4, 12))	('rs2297441', 'Mutation', 'rs2297441', (13, 22))	('risk', 'Reg', (49, 53))	('gastric cancer', 'Disease', (65, 79))	('rs2297441', 'Var', (13, 22))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))
111573	33363398	In these malignant tumors, amplification of the TNFRSF6B gene and high expression of mRNA or protein can be detected.	('expression', 'MPA', (71, 81))	('detected', 'Reg', (108, 116))	('mRNA or protein', 'MPA', (85, 100))	('malignant tumors', 'Disease', 'MESH:D009369', (9, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('TNFRSF6B', 'Gene', '8771', (48, 56))	('TNFRSF6B', 'Gene', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('amplification', 'Var', (27, 40))	('malignant tumors', 'Disease', (9, 25))
111574	33363398	The status of TNFRSF6B is closely related to the invasion and metastasis of malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('TNFRSF6B', 'Gene', '8771', (14, 22))	('TNFRSF6B', 'Gene', (14, 22))	('status', 'Var', (4, 10))	('related', 'Reg', (34, 41))	('malignant tumors', 'Disease', (76, 92))	('malignant tumors', 'Disease', 'MESH:D009369', (76, 92))
111577	33363398	The promoter of the TNFRSF6B gene contains two SNPs, rs2297441 (-539 G/A) and rs2257440 (147 C/T), which are common variants of Han Chinese.	('147 C/T', 'Mutation', 'rs2257440', (89, 96))	('C', 'Chemical', 'MESH:D002244', (93, 94))	('rs2297441', 'Mutation', 'rs2297441', (53, 62))	('rs2257440', 'Mutation', 'rs2257440', (78, 87))	('TNFRSF6B', 'Gene', '8771', (20, 28))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('TNFRSF6B', 'Gene', (20, 28))	('-539 G/A', 'Mutation', 'rs2297441', (64, 72))	('rs2257440 (147 C/T', 'Var', (78, 96))	('rs2297441 (-539 G/A', 'Var', (53, 72))
111578	33363398	Xiong et al found that the SNP rs2257440, present in exon 1 of DcR3, is significantly associated with the susceptibility of esophageal cancer.	('DcR3', 'Gene', '8771', (63, 67))	('cancer', 'Disease', (135, 141))	('age', 'Gene', (129, 132))	('susceptibility', 'Reg', (106, 120))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('associated', 'Reg', (86, 96))	('DcR3', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('age', 'Gene', '5973', (129, 132))	('rs2257440', 'Mutation', 'rs2257440', (31, 40))	('rs2257440', 'Var', (31, 40))
111579	33363398	Dai et al further found that rs2257440 is a functional SNP and that the T allele of rs2257440 can increase DcR3 expression because it promotes binding of the gene with the specific transcription factor MTF-1.	('binding', 'Interaction', (143, 150))	('rs2257440', 'Mutation', 'rs2257440', (84, 93))	('rs2257440', 'Var', (29, 38))	('rs2257440', 'Mutation', 'rs2257440', (29, 38))	('DcR3', 'Gene', '8771', (107, 111))	('promotes', 'PosReg', (134, 142))	('rs2257440', 'Var', (84, 93))	('MTF-1', 'Gene', (202, 207))	('MTF-1', 'Gene', '4520', (202, 207))	('increase', 'PosReg', (98, 106))	('DcR3', 'Gene', (107, 111))	('expression', 'MPA', (112, 122))
111580	33363398	Fu et al found that DcR3 gene polymorphisms are associated with sporadic breast infiltrating ductal carcinoma risk in northeast Chinese females.	('ductal carcinoma', 'Phenotype', 'HP:0030075', (93, 109))	('sporadic breast infiltrating ductal carcinoma', 'Disease', 'MESH:D001943', (64, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('associated', 'Reg', (48, 58))	('polymorphisms', 'Var', (30, 43))	('DcR3', 'Gene', (20, 24))	('C', 'Chemical', 'MESH:D002244', (128, 129))	('sporadic breast infiltrating ductal carcinoma', 'Disease', (64, 109))	('DcR3', 'Gene', '8771', (20, 24))
111582	33363398	Thus, we performed a case-control study to compare the genotypes and alleles of TNFRSF6B genes rs2297440 and rs2297441 in patients with GC and in healthy controls to analyze the relationship between TNFRSF6B polymorphism and GC susceptibility.	('TNFRSF6B', 'Gene', (80, 88))	('GC', 'Phenotype', 'HP:0012126', (136, 138))	('rs2297441', 'Mutation', 'rs2297441', (109, 118))	('TNFRSF6B', 'Gene', '8771', (199, 207))	('TNFRSF6B', 'Gene', (199, 207))	('rs2297440', 'Mutation', 'rs2297440', (95, 104))	('C', 'Chemical', 'MESH:D002244', (226, 227))	('patients', 'Species', '9606', (122, 130))	('rs2297440', 'Var', (95, 104))	('rs2297441', 'Var', (109, 118))	('C', 'Chemical', 'MESH:D002244', (137, 138))	('GC', 'Phenotype', 'HP:0012126', (225, 227))	('TNFRSF6B', 'Gene', '8771', (80, 88))
111600	33363398	The distributions of demographic characteristics, selected variables, and genotypes of the TNFRSF6B gene variant differences between the case and control groups were evaluated using the chi2 test.	('variant', 'Var', (105, 112))	('TNFRSF6B', 'Gene', '8771', (91, 99))	('TNFRSF6B', 'Gene', (91, 99))
111603	33363398	Table 1 lists the essential information on the TNFRSF6B gene rs2297440 and rs2297441 polymorphisms.	('TNFRSF6B', 'Gene', '8771', (47, 55))	('TNFRSF6B', 'Gene', (47, 55))	('rs2297440', 'Mutation', 'rs2297440', (61, 70))	('rs2297441', 'Mutation', 'rs2297441', (75, 84))	('rs2297440', 'Var', (61, 70))	('rs2297441', 'Var', (75, 84))
111606	33363398	As shown in Table 3, when wild type genotype TT served as the reference, the recurrence rate of TC heterozygous variations at the rs2269700 locus was higher in the case group than in the control group (48.60%>42.86%), but no evident disparity was observed between these two groups (P=0.097).	('higher', 'PosReg', (150, 156))	('rs2269700', 'Mutation', 'rs2269700', (130, 139))	('TC', 'Chemical', 'MESH:D013667', (96, 98))	('recurrence', 'MPA', (77, 87))	('rs2269700', 'Var', (130, 139))
111607	33363398	In the dominant model, the rate of recurrence distribution of TC+CC variations in the case group was higher than that in the control group (58.57%>55.37%).	('TC+CC', 'Chemical', '-', (62, 67))	('variations', 'Var', (68, 78))	('higher', 'PosReg', (101, 107))	('TC+CC', 'Gene', (62, 67))
111608	33363398	As demonstrated in Table 4, the analyses proved that the genotype frequencies of TNFRSF6B genes rs2297441 and rs2257440 did not significantly differ between the two groups (P>0.05).	('rs2297441', 'Var', (96, 105))	('TNFRSF6B', 'Gene', '8771', (81, 89))	('TNFRSF6B', 'Gene', (81, 89))	('rs2297441', 'Mutation', 'rs2297441', (96, 105))	('rs2257440', 'Var', (110, 119))	('rs2257440', 'Mutation', 'rs2257440', (110, 119))
111610	33363398	As shown in Table 5, haplotype analysis revealed no obvious difference in the frequencies of the rs2257440 and rs2297441 alleles between the groups (P=0.852, P=0.619).	('rs2257440', 'Var', (97, 106))	('rs2297441', 'Mutation', 'rs2297441', (111, 120))	('rs2297441', 'Var', (111, 120))	('rs2257440', 'Mutation', 'rs2257440', (97, 106))
111611	33363398	Furthermore, stratification analyses were performed to evaluate the effects of the TNFRSF6B gene rs2257440 on the risk of GC in consideration of age, gender, smoking, or alcohol drinking (Table 6).	('alcohol', 'Chemical', 'MESH:D000438', (170, 177))	('rs2257440', 'Var', (97, 106))	('GC', 'Phenotype', 'HP:0012126', (122, 124))	('alcohol drinking', 'Phenotype', 'HP:0030955', (170, 186))	('age', 'Gene', (145, 148))	('TNFRSF6B', 'Gene', '8771', (83, 91))	('TNFRSF6B', 'Gene', (83, 91))	('C', 'Chemical', 'MESH:D002244', (123, 124))	('rs2257440', 'Mutation', 'rs2257440', (97, 106))	('age', 'Gene', '5973', (145, 148))
111619	33363398	Stratification analyses were carried out to assess the effects of TNFRSF6B rs2297441 on GC risk in consideration of gender, smoking, age, and alcohol drinking (Table 7).	('C', 'Chemical', 'MESH:D002244', (89, 90))	('age', 'Gene', (133, 136))	('rs2297441', 'Mutation', 'rs2297441', (75, 84))	('age', 'Gene', '5973', (133, 136))	('alcohol', 'Chemical', 'MESH:D000438', (142, 149))	('alcohol drinking', 'Phenotype', 'HP:0030955', (142, 158))	('rs2297441', 'Var', (75, 84))	('TNFRSF6B', 'Gene', '8771', (66, 74))	('TNFRSF6B', 'Gene', (66, 74))	('GC', 'Phenotype', 'HP:0012126', (88, 90))
111636	33363398	SNPs rs2297441 (-539 G/A) and rs2257440 (147 C/T) are common mutations in Chinese Han when treating the promotor TNFRSF6B gene.	('TNFRSF6B', 'Gene', '8771', (113, 121))	('TNFRSF6B', 'Gene', (113, 121))	('rs2297441', 'Mutation', 'rs2297441', (5, 14))	('C', 'Chemical', 'MESH:D002244', (45, 46))	('147 C/T', 'Mutation', 'rs2257440', (41, 48))	('rs2257440', 'Mutation', 'rs2257440', (30, 39))	('C', 'Chemical', 'MESH:D002244', (74, 75))	('-539 G/A', 'Mutation', 'rs2297441', (16, 24))	('rs2257440 (147 C/T', 'Var', (30, 48))
111638	33363398	A previous study showed that the rs2257440 polymorphism of the TNFRSF6B gene is related to the danger of esophageal cancer and is strongly correlated with clinical TNM staging.	('age', 'Gene', '5973', (110, 113))	('rs2257440', 'Mutation', 'rs2257440', (33, 42))	('related', 'Reg', (80, 87))	('rs2257440', 'Var', (33, 42))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('TNM', 'Gene', (164, 167))	('TNFRSF6B', 'Gene', '8771', (63, 71))	('TNFRSF6B', 'Gene', (63, 71))	('age', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TNM', 'Gene', '10178', (164, 167))	('correlated with', 'Reg', (139, 154))
111640	33363398	When dealing with this research, 577 patients with GC and 678 healthy volunteers were selected to explore the correlation between TNFRSF6B gene rs2297441 (-539 G/A) and rs2257440 (147 C/T) loci and GC susceptibility in Chinese Han's population.	('rs2257440', 'Mutation', 'rs2257440', (169, 178))	('-539 G/A', 'Mutation', 'rs2297441', (155, 163))	('C', 'Chemical', 'MESH:D002244', (52, 53))	('rs2297441 (-539 G/A', 'Var', (144, 163))	('patients', 'Species', '9606', (37, 45))	('TNFRSF6B', 'Gene', '8771', (130, 138))	('TNFRSF6B', 'Gene', (130, 138))	('rs2257440 (147 C/T', 'Var', (169, 187))	('C', 'Chemical', 'MESH:D002244', (184, 185))	('GC', 'Phenotype', 'HP:0012126', (51, 53))	('rs2297441', 'Mutation', 'rs2297441', (144, 153))	('147 C/T', 'Mutation', 'rs2257440', (180, 187))	('GC', 'Phenotype', 'HP:0012126', (198, 200))	('C', 'Chemical', 'MESH:D002244', (199, 200))	('C', 'Chemical', 'MESH:D002244', (219, 220))
111643	33363398	The TNFRSF6B gene rs2257440 polymorphism was shown according to the stratified results.	('TNFRSF6B', 'Gene', '8771', (4, 12))	('rs2257440', 'Var', (18, 27))	('rs2257440', 'Mutation', 'rs2257440', (18, 27))	('TNFRSF6B', 'Gene', (4, 12))
111651	33363398	The rs2257440 polymorphism of the TNFRSF6B gene is associated with the danger of GC, and the C mutation may be a protective factor for GC.	('C', 'Chemical', 'MESH:D002244', (93, 94))	('TNFRSF6B', 'Gene', '8771', (34, 42))	('TNFRSF6B', 'Gene', (34, 42))	('associated', 'Reg', (51, 61))	('rs2257440', 'Mutation', 'rs2257440', (4, 13))	('rs2257440', 'Var', (4, 13))	('GC', 'Phenotype', 'HP:0012126', (135, 137))	('C', 'Chemical', 'MESH:D002244', (82, 83))	('C', 'Chemical', 'MESH:D002244', (136, 137))	('GC', 'Phenotype', 'HP:0012126', (81, 83))
111652	33363398	The rs2297441 polymorphism of the TNFRSF6B gene in the rate distribution and the logistic regression analysis of the case and control groups showed that the wild-type GG can be regarded as the reference type, the rate distribution of AG heterozygous mutants was higher in the case group than in the control group.	('rate', 'MPA', (213, 217))	('TNFRSF6B', 'Gene', '8771', (34, 42))	('TNFRSF6B', 'Gene', (34, 42))	('rs2297441', 'Mutation', 'rs2297441', (4, 13))	('rs2297441', 'Var', (4, 13))	('higher', 'PosReg', (262, 268))
111654	33363398	This result suggests that the rs2297441 polymorphism of the TNFRSF6B gene is also related to the danger of GC.	('TNFRSF6B', 'Gene', (60, 68))	('C', 'Chemical', 'MESH:D002244', (108, 109))	('rs2297441', 'Mutation', 'rs2297441', (30, 39))	('related', 'Reg', (82, 89))	('GC', 'Phenotype', 'HP:0012126', (107, 109))	('rs2297441 polymorphism', 'Var', (30, 52))	('TNFRSF6B', 'Gene', '8771', (60, 68))
111659	33363398	For TNFRSF6B rs2297440, the TC genotype may be a risk factor for GC in people <62 years old.	('C', 'Chemical', 'MESH:D002244', (66, 67))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('TNFRSF6B', 'Gene', '8771', (4, 12))	('GC', 'Phenotype', 'HP:0012126', (65, 67))	('people', 'Species', '9606', (71, 77))	('TNFRSF6B', 'Gene', (4, 12))	('TC', 'Chemical', 'MESH:D013667', (28, 30))	('rs2297440', 'Mutation', 'rs2297440', (13, 22))	('risk', 'Reg', (49, 53))	('rs2297440', 'Var', (13, 22))
111662	33363398	For TNFRSF6B rs2297441, the AG genotype may be a risk factor for GC in males and non-drinkers.	('C', 'Chemical', 'MESH:D002244', (66, 67))	('TNFRSF6B', 'Gene', '8771', (4, 12))	('GC', 'Phenotype', 'HP:0012126', (65, 67))	('TNFRSF6B', 'Gene', (4, 12))	('rs2297441', 'Mutation', 'rs2297441', (13, 22))	('risk', 'Reg', (49, 53))	('rs2297441', 'Var', (13, 22))
111675	31384397	We investigated a role of BAY1143572, a new highly specific CDK9 inhibitor, as a sensitizer to radiation in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (108, 133))	('esophageal adenocarcinoma', 'Disease', (108, 133))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (108, 133))	('BAY1143572', 'Var', (26, 36))	('BAY1143572', 'Chemical', 'MESH:C000625640', (26, 36))
111679	31384397	Western blot and qPCR demonstrated reduced Axl mRNA (p = 0.02) and protein levels after treatment with CDK9 inhibitor with or without radiation in FLO-1 and SKGT4 cells.	('reduced', 'NegReg', (35, 42))	('Axl', 'Gene', (43, 46))	('protein levels', 'MPA', (67, 81))	('inhibitor', 'Var', (108, 117))	('Axl', 'Gene', '558', (43, 46))	('CDK9', 'Gene', (103, 107))	('FLO-1', 'Chemical', '-', (147, 152))
111681	31384397	Clonogenic assay performed after overexpression of Axl in FLO-1 and SKGT4 cells enhanced radiosensitization by the CDK9 inhibitor, suggesting dependency of radiosensitization effects of the CDK9 inhibitor on Axl.	('inhibitor', 'Var', (120, 129))	('Axl', 'Gene', (208, 211))	('CDK9', 'Gene', (115, 119))	('Axl', 'Gene', '558', (51, 54))	('Axl', 'Gene', '558', (208, 211))	('radiosensitization', 'MPA', (89, 107))	('Axl', 'Gene', (51, 54))	('enhanced', 'PosReg', (80, 88))	('FLO-1', 'Chemical', '-', (58, 63))
111682	31384397	In conclusion, these findings indicate that targeting CDK9 by BAY1143572 significantly enhances the effects of radiation and Axl is a novel downstream target of CDK9 in esophageal adenocarcinoma.	('Axl', 'Gene', (125, 128))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (169, 194))	('esophageal adenocarcinoma', 'Disease', (169, 194))	('CDK9', 'Gene', (54, 58))	('effects of', 'MPA', (100, 110))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (169, 194))	('Axl', 'Gene', '558', (125, 128))	('BAY1143572', 'Var', (62, 72))	('BAY1143572', 'Chemical', 'MESH:C000625640', (62, 72))	('enhances', 'PosReg', (87, 95))
111691	31384397	Major limiting factor for successful implementation of molecular targeted therapy is low frequency and heterogeneity of alterations in targets like Her2-neu amplification/overexpression (15%), EGFR amplification (20%), EGFR activating mutations (0-12%) and c-MET amplification (2-10%).	('EGFR', 'Gene', '1956', (219, 223))	('c-MET', 'Gene', (257, 262))	('Her2-neu', 'Gene', (148, 156))	('Her2-neu', 'Gene', '2064', (148, 156))	('EGFR', 'Gene', (219, 223))	('amplification', 'Var', (198, 211))	('c-MET', 'Gene', '4233', (257, 262))	('activating', 'PosReg', (224, 234))	('EGFR', 'Gene', '1956', (193, 197))	('amplification/overexpression', 'PosReg', (157, 185))	('EGFR', 'Gene', (193, 197))
111696	31384397	BAY1143572 (Atuveciclib), a novel, first-in-class CDK9 specific inhibitor more potently inhibits CDK9 (PTEFb) activity because it's IC50 is 50 fold lower than the IC50 of other CDKs.	('CDKs', 'Gene', (177, 181))	('CDK9', 'Gene', (50, 54))	('IC50', 'MPA', (132, 136))	('activity', 'MPA', (110, 118))	('Atuveciclib', 'Chemical', 'MESH:C000625640', (12, 23))	('CDKs', 'Gene', '1025;107951', (177, 181))	('inhibits', 'NegReg', (88, 96))	('BAY1143572', 'Var', (0, 10))	('BAY1143572', 'Chemical', 'MESH:C000625640', (0, 10))
111697	31384397	BAY1143572 has high specificity for CDK9 at the nanomolar level without any off-target toxicity, unlike other CDK9 inhibitors.	('specificity', 'MPA', (20, 31))	('CDK9', 'Protein', (36, 40))	('toxicity', 'Disease', 'MESH:D064420', (87, 95))	('toxicity', 'Disease', (87, 95))	('BAY1143572', 'Var', (0, 10))	('BAY1143572', 'Chemical', 'MESH:C000625640', (0, 10))
111698	31384397	A recent study showed strong potential of BAY1143572 as a novel treatment for adult T-cell leukemia/lymphoma.	('adult T-cell leukemia/lymphoma', 'Disease', 'MESH:D015459', (78, 108))	('BAY1143572', 'Chemical', 'MESH:C000625640', (42, 52))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (100, 108))	('BAY1143572', 'Var', (42, 52))	('T-cell leukemia/lymphoma', 'Phenotype', 'HP:0005517', (84, 108))	('adult T-cell leukemia/lymphoma', 'Disease', (78, 108))
111699	31384397	BAY1143572 induces its anti-tumorigenic effects in adult T-cell leukemia/lymphoma by inhibiting pSer2 and pSer7 RNA Pol II, MYC, and MCL-1.	('adult T-cell leukemia/lymphoma', 'Disease', 'MESH:D015459', (51, 81))	('pSer7', 'Gene', (106, 111))	('tumor', 'Disease', (28, 33))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('T-cell leukemia/lymphoma', 'Phenotype', 'HP:0005517', (57, 81))	('inhibiting', 'NegReg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('MYC', 'Gene', (124, 127))	('MCL-1', 'Gene', '4170', (133, 138))	('adult T-cell leukemia/lymphoma', 'Disease', (51, 81))	('MCL-1', 'Gene', (133, 138))	('pSer2', 'Gene', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('MYC', 'Gene', '4609', (124, 127))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))	('BAY1143572', 'Var', (0, 10))	('BAY1143572', 'Chemical', 'MESH:C000625640', (0, 10))
111700	31384397	Our studies (unpublished data) indicate that CDK9/p-TEFb inhibition is the dominant mechanism of action for three CDK inhibitors: Flavopiridol, CAN 508 and BAY1143572, in esophageal adenocarcinoma.	('CDK', 'Gene', (114, 117))	('BAY1143572', 'Var', (156, 166))	('BAY1143572', 'Chemical', 'MESH:C000625640', (156, 166))	('inhibition', 'NegReg', (57, 67))	('esophageal adenocarcinoma', 'Disease', (171, 196))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (171, 196))	('CDK', 'Gene', '1025;107951', (45, 48))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (171, 196))	('Flavopiridol', 'Chemical', 'MESH:C077990', (130, 142))	('CDK', 'Gene', '1025;107951', (114, 117))	('CDK', 'Gene', (45, 48))
111701	31384397	In the present study, we show for the first time that inhibition of CDK9 potently enhances radiation sensitivity in various preclinical models of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (146, 171))	('inhibition', 'Var', (54, 64))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (146, 171))	('enhances', 'PosReg', (82, 90))	('CDK9', 'Gene', (68, 72))	('radiation sensitivity', 'CPA', (91, 112))	('esophageal adenocarcinoma', 'Disease', (146, 171))
111702	31384397	We further demonstrate that Axl, a tyrosine kinase critical in determining radiation sensitivity in solid tumors, is a novel target of CDK9 inhibitor with and without radiation in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (180, 205))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('inhibitor', 'Var', (140, 149))	('CDK9', 'Gene', (135, 139))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (180, 205))	('solid tumors', 'Disease', (100, 112))	('Axl', 'Gene', '558', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('Axl', 'Gene', (28, 31))	('solid tumors', 'Disease', 'MESH:D009369', (100, 112))	('esophageal adenocarcinoma', 'Disease', (180, 205))
111703	31384397	Previously, we showed that CDK9 inhibitors exert dose-dependent anti-proliferative effects against 6 esophageal adenocarcinoma cell lines.	('inhibitors', 'Var', (32, 42))	('esophageal adenocarcinoma', 'Disease', (101, 126))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (101, 126))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (101, 126))	('anti-proliferative effects', 'CPA', (64, 90))	('CDK9', 'Gene', (27, 31))
111705	31384397	In the present study, MTS assay confirmed dose-dependent anti-proliferative effects of BAY1143572 in radiosensitive OE33 and radioresistant OE33R cells (Supplementary Figures 1 and 2A, 2B).	('BAY1143572', 'Var', (87, 97))	('OE33R', 'Chemical', '-', (140, 145))	('BAY1143572', 'Chemical', 'MESH:C000625640', (87, 97))	('OE33', 'Chemical', '-', (116, 120))	('OE33', 'Chemical', '-', (140, 144))	('anti-proliferative', 'NegReg', (57, 75))
111706	31384397	The clonogenic survival assay demonstrated significantly higher survival fractions among the OE33R cells compared to OE33 at 4, 6 or 8 Gy (Figure 1A) confirming radiation resistance in OE33R cells.	('higher', 'PosReg', (57, 63))	('OE33R', 'Chemical', '-', (185, 190))	('OE33R', 'Chemical', '-', (93, 98))	('OE33', 'Chemical', '-', (185, 189))	('survival fractions', 'CPA', (64, 82))	('OE33R', 'Var', (93, 98))	('OE33', 'Chemical', '-', (117, 121))	('OE33', 'Chemical', '-', (93, 97))
111707	31384397	However, treatment with BAY1143572 had the highest degree of sensitization at a survival fraction of 10% (DERSF0.1) in FLO-1 cells (DERSF0.1, 1.37), followed by radioresistant OE33R cells (DERSF0.1, 1.35), SKGT4 cells (DERSF0.1, 1.33) and radiosensitive OE33 cells (DERSF0.1, 1.21) (Figure 1B).	('OE33', 'Chemical', '-', (254, 258))	('sensitization', 'MPA', (61, 74))	('OE33R', 'Chemical', '-', (176, 181))	('FLO-1', 'Chemical', '-', (119, 124))	('BAY1143572', 'Var', (24, 34))	('BAY1143572', 'Chemical', 'MESH:C000625640', (24, 34))	('OE33', 'Chemical', '-', (176, 180))
111708	31384397	At day 21, the mean volumes of FLO-1 xenografts treated with 12.5 mg/kg BAY1143572 only or 12.5 mg/kg plus radiation were 67% and 48% smaller than that of the control arm (Figure 2B).	('smaller', 'NegReg', (134, 141))	('BAY1143572', 'Var', (72, 82))	('FLO-1', 'Chemical', '-', (31, 36))	('FLO-1', 'Gene', (31, 36))	('BAY1143572', 'Chemical', 'MESH:C000625640', (72, 82))
111712	31384397	At day 21, the mean volumes of OE33 xenografts treated with 12.5 mg/kg CDK9 inhibitor or 12.5 mg/kg CDK9 inhibitor plus a total of 8 Gy of radiation were 94% (p = 0.005) and 100% (p = 0.005) smaller, respectively, than that of control xenografts (Figure 3B).	('inhibitor', 'Var', (76, 85))	('CDK9', 'Gene', (71, 75))	('smaller', 'NegReg', (191, 198))	('OE33', 'Chemical', '-', (31, 35))
111714	31384397	The mean volume of the CDK9 inhibitor-plus-radiation-treated xenografts was 85% smaller than that of xenografts treated with radiation only and 69% smaller than that of xenografts treated with the CDK9 inhibitor only (p = 0.01) in OE33R xenografts.	('CDK9', 'Gene', (23, 27))	('inhibitor-plus-radiation-treated', 'Var', (28, 60))	('smaller', 'NegReg', (148, 155))	('smaller', 'NegReg', (80, 87))	('OE33R', 'Chemical', '-', (231, 236))
111715	31384397	The mean volume of the CDK9 inhibitor-plus-radiation-treated xenografts was 100% smaller than that of xenografts treated with radiation only or CDK9 inhibitor only in OE33 cells.	('inhibitor-plus-radiation-treated', 'Var', (28, 60))	('OE33', 'Chemical', '-', (167, 171))	('CDK9', 'Gene', (23, 27))	('smaller', 'NegReg', (81, 88))
111731	31384397	Similarly, FLO-1, SKGT4 and OE33 cells treated with BAY1143572 (Figure 5C) had suppressed Axl protein levels compared to control cells, suggesting Axl may be regulated by CDK9 or CDK9 dependent pathways.	('BAY1143572', 'Var', (52, 62))	('FLO-1', 'Chemical', '-', (11, 16))	('BAY1143572', 'Chemical', 'MESH:C000625640', (52, 62))	('Axl', 'Gene', '558', (147, 150))	('suppressed', 'NegReg', (79, 89))	('Axl', 'Gene', '558', (90, 93))	('Axl', 'Gene', (147, 150))	('OE33', 'Chemical', '-', (28, 32))	('Axl', 'Gene', (90, 93))
111732	31384397	Akt was used as a control in addition to housekeeping controls beta-actin and GAPDH to confirm Axl downregulation by CDK9 inhibition.	('beta-actin', 'Gene', '728378', (63, 73))	('inhibition', 'Var', (122, 132))	('Axl', 'Gene', (95, 98))	('downregulation', 'NegReg', (99, 113))	('Akt', 'Gene', '207', (0, 3))	('GAPDH', 'Gene', '2597', (78, 83))	('Akt', 'Gene', (0, 3))	('GAPDH', 'Gene', (78, 83))	('Axl', 'Gene', '558', (95, 98))	('beta-actin', 'Gene', (63, 73))	('CDK9', 'Gene', (117, 121))
111733	31384397	Inhibition of CDK9 has shown downregulation of a large number of short-lived anti-apoptotic proteins such as MCL-1, thus time dependent Axl expression by CDK9 inhibition was determined at earlier time points (8 and 24 hours) at the protein and mRNA level (Supplementary Figure 4A and 4B).	('downregulation', 'NegReg', (29, 43))	('Axl', 'Gene', '558', (136, 139))	('Axl', 'Gene', (136, 139))	('Inhibition', 'Var', (0, 10))	('CDK9', 'Gene', (14, 18))	('MCL-1', 'Gene', '4170', (109, 114))	('MCL-1', 'Gene', (109, 114))	('inhibition', 'NegReg', (159, 169))
111734	31384397	There was no change in Axl protein and mRNA (p > 0.05), 8 hours after treatment with BAY1143572 (0.5 and 1muM), as compared to control in FLO-1 and SKGT4 cells.	('Axl', 'Gene', (23, 26))	('mRNA', 'MPA', (39, 43))	('BAY1143572', 'Var', (85, 95))	('BAY1143572', 'Chemical', 'MESH:C000625640', (85, 95))	('Axl', 'Gene', '558', (23, 26))	('FLO-1', 'Chemical', '-', (138, 143))
111735	31384397	However, at 24 hours, 1muM BAY1143572 treated FLO-1 and SKGT4 showed slight downregulation of Axl protein as compared to the control.	('BAY1143572', 'Var', (27, 37))	('FLO-1', 'Chemical', '-', (46, 51))	('Axl', 'Gene', '558', (94, 97))	('Axl', 'Gene', (94, 97))	('downregulation', 'NegReg', (76, 90))	('BAY1143572', 'Chemical', 'MESH:C000625640', (27, 37))
111736	31384397	BAY1143572 (0.5 and 1muM) decreased Axl RNA in FLO-1 and SKGT4 cells compared to control cells (p < 0.05) at 24 hours after treatment.	('Axl', 'Gene', (36, 39))	('BAY1143572', 'Chemical', 'MESH:C000625640', (0, 10))	('Axl', 'Gene', '558', (36, 39))	('FLO-1', 'Chemical', '-', (47, 52))	('decreased', 'NegReg', (26, 35))	('BAY1143572', 'Var', (0, 10))
111740	31384397	CDK9 inhibitor in combination with radiation further downregulated Axl and MCL-1 in FLO-1, and SKGT4 cells.	('Axl', 'Gene', (67, 70))	('FLO-1', 'Chemical', '-', (84, 89))	('MCL-1', 'Gene', '4170', (75, 80))	('Axl', 'Gene', '558', (67, 70))	('MCL-1', 'Gene', (75, 80))	('CDK9', 'Gene', (0, 4))	('inhibitor', 'Var', (5, 14))	('downregulated', 'NegReg', (53, 66))
111744	31384397	The mean H-scores of Axl staining on xenografts treated with combination of the CDK9 inhibitor with radiation were significantly lower than xenografts treated with radiation alone (p = 0.003 Figure 6C or Table 3).	('CDK9', 'Gene', (80, 84))	('Axl', 'Gene', '558', (21, 24))	('inhibitor', 'Var', (85, 94))	('combination', 'Interaction', (61, 72))	('H-scores', 'MPA', (9, 17))	('Axl', 'Gene', (21, 24))	('lower', 'NegReg', (129, 134))
111747	31384397	The clonogenic survival assay demonstrated enhanced sensitization to radiation by BAY1143572 in esophageal adenocarcinoma cells with stable overexpression of Axl (FLO-1 Axl and SKGT4 Axl) compared to negative control cells (FLO-1 RFP and SKGT4 RFP) OE33 at 4, 6 or 8 Gy (Figure 7B).	('enhanced', 'PosReg', (43, 51))	('Axl', 'Gene', (158, 161))	('overexpression', 'PosReg', (140, 154))	('FLO-1', 'Chemical', '-', (224, 229))	('RFP', 'Gene', (230, 233))	('OE33', 'Chemical', '-', (249, 253))	('RFP', 'Gene', (244, 247))	('RFP', 'Gene', '2358', (230, 233))	('Axl', 'Gene', '558', (169, 172))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (96, 121))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (96, 121))	('Axl', 'Gene', (169, 172))	('RFP', 'Gene', '2358', (244, 247))	('FLO-1', 'Chemical', '-', (163, 168))	('sensitization to radiation', 'MPA', (52, 78))	('Axl', 'Gene', '558', (183, 186))	('BAY1143572', 'Chemical', 'MESH:C000625640', (82, 92))	('enhanced sensitization to radiation', 'Phenotype', 'HP:0011133', (43, 78))	('esophageal adenocarcinoma', 'Disease', (96, 121))	('BAY1143572', 'Var', (82, 92))	('Axl', 'Gene', '558', (158, 161))	('Axl', 'Gene', (183, 186))
111748	31384397	These results indicate that cells with overexpressed Axl are relatively more sensitive to combination therapy compared to negative control cells.	('overexpressed', 'Var', (39, 52))	('sensitive', 'MPA', (77, 86))	('Axl', 'Gene', '558', (53, 56))	('Axl', 'Gene', (53, 56))
111749	31384397	Treatment with BAY1143572 had the higher degree of sensitization at a survival fraction of 10% (DERSF0.1) and 50% (DERSF0.5) in FLO-1 Axl cells (DERSF0.1, 1.76; DERSF0.5, 2.36) compared to its control FLO-1 RFP cells (DERSF0.1, 1.42; DERSF0.5, 1.82).	('Axl', 'Gene', '558', (134, 137))	('RFP', 'Gene', '2358', (207, 210))	('BAY1143572', 'Var', (15, 25))	('BAY1143572', 'Chemical', 'MESH:C000625640', (15, 25))	('sensitization', 'MPA', (51, 64))	('FLO-1', 'Chemical', '-', (128, 133))	('FLO-1', 'Chemical', '-', (201, 206))	('Axl', 'Gene', (134, 137))	('RFP', 'Gene', (207, 210))	('FLO-1', 'Var', (128, 133))
111750	31384397	Similarly, BAY1143572 exhibited higher degree of sensitization in SKGT4 Axl cells (DERSF0.1, 1.46; DERSF0.5, 2.27) compared to its control SKGT4 RFP (DERSF0.1, 1.29; DERSF0.5, 1.40) (Figure 7B).	('Axl', 'Gene', (72, 75))	('sensitization', 'MPA', (49, 62))	('RFP', 'Gene', (145, 148))	('Axl', 'Gene', '558', (72, 75))	('RFP', 'Gene', '2358', (145, 148))	('BAY1143572', 'Var', (11, 21))	('BAY1143572', 'Chemical', 'MESH:C000625640', (11, 21))
111752	31384397	Prior studies demonstrated a better pharmaceutical profile with high aqueous solubility of 479 mg/L of BAY1143572 as well as decreased efflux ratio and far better tolerability in vivo compared to other CDK9 inhibitors.	('tolerability', 'MPA', (163, 175))	('decreased', 'NegReg', (125, 134))	('BAY1143572', 'Chemical', 'MESH:C000625640', (103, 113))	('efflux ratio', 'MPA', (135, 147))	('BAY1143572', 'Var', (103, 113))	('high aqueous solubility', 'MPA', (64, 87))	('better', 'PosReg', (156, 162))
111753	31384397	These pharmacologic properties distinguish BAY1143572 from other CDK9 inhibitors in terms of potency, drug safety, and tolerability and enabled BAY1143572 to be the first highly selective PTEFb/CDK9 inhibitor to enter phase 1 clinical trials (NCT01938638 and NCT02345382).	('BAY1143572', 'Var', (43, 53))	('BAY1143572', 'Chemical', 'MESH:C000625640', (43, 53))	('BAY1143572', 'Chemical', 'MESH:C000625640', (144, 154))	('potency', 'MPA', (93, 100))	('BAY1143572', 'Var', (144, 154))
111763	31384397	We found that, unlike previous generations of CDK9 inhibitors, BAY1143572 had no noticeable systemic toxicities.	('BAY1143572', 'Chemical', 'MESH:C000625640', (63, 73))	('systemic toxicities', 'Disease', 'MESH:D010523', (92, 111))	('systemic toxicities', 'Disease', (92, 111))	('BAY1143572', 'Var', (63, 73))
111772	31384397	Thus downregulation of Axl by CDK9 inhibition may be one of the mechanisms by which CDK9 inhibition radiosensitizes esophageal adenocarcinoma cells.	('inhibition', 'Var', (89, 99))	('Axl', 'Gene', (23, 26))	('downregulation', 'NegReg', (5, 19))	('CDK9', 'Gene', (84, 88))	('esophageal adenocarcinoma', 'Disease', (116, 141))	('radiosensitizes', 'NegReg', (100, 115))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (116, 141))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (116, 141))	('Axl', 'Gene', '558', (23, 26))
111775	31384397	Several Axl inhibitors and monoclonal antibodies target the extracellular domains, kinase domains, or ligands of Axl; however, the inherent challenges these types of inhibitors pose; such as inability to recognize tumor cells with mutant ligands may be mitigated by CDK9's transcriptional regulation of Axl, thus improving the impact of targeting Axl-mediated resistance to therapy.	('Axl', 'Gene', (303, 306))	('Axl', 'Gene', (8, 11))	('inability', 'Disease', (191, 200))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('Axl', 'Gene', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('Axl', 'Gene', '558', (347, 350))	('Axl', 'Gene', '558', (8, 11))	('Axl', 'Gene', '558', (303, 306))	('mutant', 'Var', (231, 237))	('tumor', 'Disease', (214, 219))	('inability', 'Disease', 'MESH:D016388', (191, 200))	('Axl', 'Gene', '558', (113, 116))	('Axl', 'Gene', (347, 350))
111776	31384397	Additionally CDK9 inhibition has been shown to reactivate epigenetically silenced genes which may potentially be involved in modulating Axl protein levels.	('Axl', 'Gene', '558', (136, 139))	('modulating', 'Reg', (125, 135))	('epigenetically', 'Var', (58, 72))	('Axl', 'Gene', (136, 139))	('reactivate', 'NegReg', (47, 57))	('inhibition', 'Var', (18, 28))	('CDK9', 'Protein', (13, 17))
111778	31384397	However, due to multiple transcription initiation sites, GC rich promoter region, methylation within and around specific proteins (Sp) 1 and 3 binding sites, it is challenging to study transcription regulation of Axl.	('methylation', 'Var', (82, 93))	('Axl', 'Gene', (213, 216))	('Axl', 'Gene', '558', (213, 216))	('specific proteins (Sp) 1 and 3', 'Gene', '6667;6670', (112, 142))
111781	31384397	Our preclinical data suggest that CDK9 inhibition, particularly by BAY1143572, is a potential strategy for radio-sensitizing esophageal adenocarcinoma and support the investigation of BAY1143572 as an adjunct to radiation in clinical trials.	('esophageal adenocarcinoma', 'Disease', (125, 150))	('BAY1143572', 'Chemical', 'MESH:C000625640', (184, 194))	('CDK9', 'Protein', (34, 38))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (125, 150))	('BAY1143572', 'Var', (67, 77))	('BAY1143572', 'Chemical', 'MESH:C000625640', (67, 77))	('inhibition', 'NegReg', (39, 49))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (125, 150))
111798	31384397	To assess the radiosensitizing effects of CDK9 inhibitor, we subcutaneously injected 5 x 106 cells into the mice's contralateral hind legs (FLO-1 in right hind leg and SKGT4 in left hind leg or OE33 in right hind leg and OE33R in left hind leg).	('OE33', 'Var', (194, 198))	('OE33', 'Chemical', '-', (221, 225))	('OE33', 'Chemical', '-', (194, 198))	('mice', 'Species', '10090', (108, 112))	('FLO-1', 'Chemical', '-', (140, 145))	('OE33R', 'Chemical', '-', (221, 226))	('OE33R', 'Var', (221, 226))
111818	27588477	We hypothesized that eIF4E promoted ESCC tumorigenesis and facilitated the development of acquired resistance to the cisplatin-based chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('tumor', 'Disease', (41, 46))	('promoted', 'PosReg', (27, 35))	('eIF4E', 'Var', (21, 26))	('facilitated', 'PosReg', (59, 70))	('development', 'MPA', (75, 86))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('ESCC', 'Disease', (36, 40))
111820	27588477	We also showed here that knockdown of eIF4E in EC9706 would dramatically reduced cell proliferation, colony formation, migration and invasion, apoptosis in vitro as well as in vivo, and vice versa.	('cell proliferation', 'CPA', (81, 99))	('eIF4E', 'Gene', (38, 43))	('colony formation', 'CPA', (101, 117))	('EC9706', 'CellLine', 'CVCL:E307', (47, 53))	('invasion', 'CPA', (133, 141))	('reduced', 'NegReg', (73, 80))	('apoptosis', 'CPA', (143, 152))	('EC9706', 'Var', (47, 53))	('knockdown', 'Var', (25, 34))
111822	27588477	eIF4E knockdown by shRNA increased cisplatin-induced cytotoxicity in ESCC cell lines, and enhanced chemosensitivity to cisplatin in xenograft tumor models.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cytotoxicity', 'Disease', (53, 65))	('increased', 'PosReg', (25, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('xenograft tumor', 'Disease', 'MESH:D009369', (132, 147))	('eIF4E knockdown', 'Var', (0, 15))	('cytotoxicity', 'Disease', 'MESH:D064420', (53, 65))	('enhanced', 'PosReg', (90, 98))	('shRNA', 'Gene', (19, 24))	('chemosensitivity to cisplatin', 'MPA', (99, 128))	('knockdown', 'Var', (6, 15))	('xenograft tumor', 'Disease', (132, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
111823	27588477	Furthermore, we found that the PI3K/AKT pathway and Bcl-2/Bax ratio might be responsible for the eIF4E-induced cisplatin resistance in ESCC.	('ESCC', 'Disease', (135, 139))	('Bcl-2', 'Gene', (52, 57))	('Bax', 'Gene', '581', (58, 61))	('Bcl-2', 'Gene', '596', (52, 57))	('AKT', 'Gene', '207', (36, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('eIF4E-induced', 'Var', (97, 110))	('Bax', 'Gene', (58, 61))	('cisplatin resistance', 'MPA', (111, 131))	('AKT', 'Gene', (36, 39))
111845	27588477	Patients in the high eIF4E expression group were ~3.7 times likelier to die of ESCC than patients with low eIF4E levels (median survival time: 28 months versus > 60 months, P < 0.001; Figure 1E).	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (89, 97))	('ESCC', 'Disease', (79, 83))	('high eIF4E expression', 'Var', (16, 37))
111846	27588477	Similarly, the disease-free survival time in high eIF4E expression patients were ~2.9 times shorter than patients with low eIF4E expression (median survival time: 22 months versus 50 months, P < 0.001; Figure 1F).	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (67, 75))	('high eIF4E expression', 'Var', (45, 66))	('disease-free survival time', 'CPA', (15, 41))	('shorter', 'NegReg', (92, 99))
111847	27588477	Moreover, multiple COX analysis in Table 3 demonstrated that eIF4E along with N stage, TNM stage were independent indicator for ESCC prognosis.	('eIF4E', 'Var', (61, 66))	('TNM', 'Gene', '10178', (87, 90))	('COX', 'Gene', '1351', (19, 22))	('ESCC', 'Disease', (128, 132))	('TNM', 'Gene', (87, 90))	('COX', 'Gene', (19, 22))
111848	27588477	According to eIF4E expression in esophageal cell lines, qPCR showed that eIF4E was highly expressed in all three cancer cell lines (P < 0.05 for EC-1 & EC109 vs. HEEpic, and P < 0.01 for EC9706 vs. HEEpic) and EC9706 has the highest eIF4E expression (P < 0.05 for EC9706 vs. EC-1 or EC109) among these 3 ESCC cell lines, whereas it was weakly detected in Human Esophageal Epithelial Cells HEEpic (Figure 2A).	('EC-1', 'CellLine', 'CVCL:5V05', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('EC109', 'CellLine', 'CVCL:6898', (152, 157))	('eIF4E', 'Gene', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('EC109', 'CellLine', 'CVCL:6898', (283, 288))	('cancer', 'Disease', (113, 119))	('and', 'Var', (206, 209))	('for', 'Var', (183, 186))	('EC9706', 'CellLine', 'CVCL:E307', (210, 216))	('EC9706', 'CellLine', 'CVCL:E307', (264, 270))	('Human', 'Species', '9606', (355, 360))	('EC9706', 'CellLine', 'CVCL:E307', (187, 193))	('highest eIF4E', 'MPA', (225, 238))	('the', 'Reg', (221, 224))	('for', 'Var', (260, 263))	('EC-1', 'CellLine', 'CVCL:5V05', (275, 279))
111849	27588477	We then selected EC9706 cells to be transfected with eIF4E-PEGFP-N1 for eIF4E-overexpression (eIF4E-OE) and with eIF4E-shRNA for eIF4E-knowdown.	('EC9706', 'CellLine', 'CVCL:E307', (17, 23))	('eIF4E-overexpression', 'Var', (72, 92))	('eIF4E-overexpression', 'PosReg', (72, 92))	('eIF4E-shRNA', 'Var', (113, 124))	('eIF4E-PEGFP-N1', 'Var', (53, 67))
111852	27588477	Similarly, colony formation assays showed that the ability of proliferation in EC9706 cells were significantly repressed by down-regulation of eIF4E (Figure 2D).	('repressed', 'NegReg', (111, 120))	('down-regulation', 'NegReg', (124, 139))	('EC9706', 'Var', (79, 85))	('EC9706', 'CellLine', 'CVCL:E307', (79, 85))	('eIF4E', 'Gene', (143, 148))
111853	27588477	Furthermore, we found that overexpression of eIF4E promoted tumorigenicity in vivo when compared to blank control mice (P = 0.045, Supplementary Figure S2B), while knockdown of eIF4E significantly decreased the primary tumor size (P = 0.032, Supplementary Figure S2B).	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('eIF4E', 'Var', (177, 182))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('primary tumor', 'Disease', (211, 224))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('promoted', 'PosReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('eIF4E', 'Var', (45, 50))	('decreased', 'NegReg', (197, 206))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Disease', (60, 65))	('primary tumor', 'Disease', 'MESH:D009369', (211, 224))
111854	27588477	It indicated a oncogenic role of eIF4E in promoting the tumorgenesis of ESCC.	('eIF4E', 'Var', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('promoting', 'PosReg', (42, 51))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('ESCC', 'Disease', (72, 76))
111857	27588477	They were reported to promote the tumor cells resistance to apoptosis, proliferation, invasion and distant metastasis, even drug resistance induced by increased eIF4E.	('increased', 'PosReg', (151, 160))	('tumor', 'Disease', (34, 39))	('promote', 'PosReg', (22, 29))	('eIF4E', 'Var', (161, 166))	('drug resistance', 'CPA', (124, 139))	('distant metastasis', 'CPA', (99, 117))	('drug resistance', 'Phenotype', 'HP:0020174', (124, 139))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('invasion', 'CPA', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
111858	27588477	The present study have clarified the oncogenic role of eIF4E in ESCC, and confirmed that the weak mRNAs including C-myc, Cyclin D1, Bcl-2, Survivin, FGF-2, VEGF, and MMP-9 were regulated by eIF4E in ESCC cell line.	('FGF-2', 'Gene', (149, 154))	('FGF-2', 'Gene', '2247', (149, 154))	('Cyclin D1', 'Gene', (121, 130))	('ESCC', 'Disease', (64, 68))	('Cyclin D1', 'Gene', '595', (121, 130))	('VEGF', 'Gene', (156, 160))	('regulated', 'Reg', (177, 186))	('MMP-9', 'Gene', '4318', (166, 171))	('Bcl-2', 'Gene', (132, 137))	('MMP-9', 'Gene', (166, 171))	('Bcl-2', 'Gene', '596', (132, 137))	('VEGF', 'Gene', '7422', (156, 160))	('Survivin', 'MPA', (139, 147))	('C-myc', 'Gene', '4609', (114, 119))	('eIF4E', 'Var', (190, 195))	('C-myc', 'Gene', (114, 119))
111859	27588477	As is shown in Figure 3A, they were upregulated after eIF4E was increased in EC9706, while inhibited when the eIF4E was supressed.	('upregulated', 'PosReg', (36, 47))	('eIF4E', 'Var', (54, 59))	('EC9706', 'Var', (77, 83))	('increased', 'PosReg', (64, 73))	('EC9706', 'CellLine', 'CVCL:E307', (77, 83))
111864	27588477	The transfected cells with eIF4E overexpression or knockdown were treated with DDP as described above.	('overexpression', 'PosReg', (33, 47))	('eIF4E', 'Gene', (27, 32))	('DDP', 'Gene', (79, 82))	('DDP', 'Gene', '1678', (79, 82))	('knockdown', 'Var', (51, 60))
111866	27588477	In cells treated with DDP, eIF4E knockdown lead to a statistically significant decrease in growth compared to control shRNA treated cells (P < 0.01 for comparisons of eIF4E-shRNA to control eIF4E-shRNA-NC), while the cells with eIF4E overexpression have significant superior cell viability (P < 0.01 for all comparisons of eIF4E-OE to control eIF4E-OE-NC) (Figure 4A).	('superior', 'PosReg', (266, 274))	('knockdown', 'Var', (33, 42))	('growth', 'MPA', (91, 97))	('cell viability', 'CPA', (275, 289))	('DDP', 'Gene', '1678', (22, 25))	('eIF4E knockdown', 'Var', (27, 42))	('decrease', 'NegReg', (79, 87))	('DDP', 'Gene', (22, 25))
111867	27588477	To this end, EC9706 cells with eIF4E overexpression (transfected with eIF4E-OE) and knockdown (transfected with eIF4E-shRNA) were injected subcutaneously into flanks of nude mice to develop xenograft tumors.	('overexpression', 'PosReg', (37, 51))	('develop', 'PosReg', (182, 189))	('EC9706', 'CellLine', 'CVCL:E307', (13, 19))	('nude mice', 'Species', '10090', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('xenograft tumors', 'Disease', 'MESH:D009369', (190, 206))	('eIF4E', 'Var', (31, 36))	('xenograft tumors', 'Disease', (190, 206))
111870	27588477	Similar to the effects we observed in vitro, tumor growth decreased dramatically in eIF4E-shRNA group with DDP treated (Figure 4B, 4C).	('DDP', 'Gene', '1678', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('eIF4E-shRNA', 'Var', (84, 95))	('tumor', 'Disease', (45, 50))	('decreased', 'NegReg', (58, 67))	('DDP', 'Gene', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
111871	27588477	After treatment of 28 days, the average tumor volume of eIF4E-shRNA group (542.81 +- 98.13 mm3, 1399.71 +- 110.24 mm3 in DDP and NS, respectively) was significantly smaller than its corresponding blank control (1753.24 +- 115.27 mm3, 2163.41 +- 244.45 mm3 in DDP and NS, respectively) or elevated eIF4E group (2843.25 +- 216.55 mm3, 3398.52 +- 323.22 mm3 in DDP and NS, respectively).	('eIF4E-shRNA', 'Var', (56, 67))	('DDP', 'Gene', '1678', (121, 124))	('DDP', 'Gene', '1678', (358, 361))	('smaller', 'NegReg', (165, 172))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('DDP', 'Gene', '1678', (259, 262))	('DDP', 'Gene', (121, 124))	('DDP', 'Gene', (358, 361))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('DDP', 'Gene', (259, 262))
111872	27588477	Concurrently, repression of eIF4E contributed to boost the tumor growth inhibition of DDP, and tumors with eIF4E knockdown were much more sensitive to DDP than the blank control group (P = 0.0187, Figure 4D).	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('boost', 'PosReg', (49, 54))	('tumor', 'Disease', (59, 64))	('eIF4E', 'Gene', (107, 112))	('tumors', 'Disease', (95, 101))	('DDP', 'Gene', (151, 154))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('repression', 'NegReg', (14, 24))	('DDP', 'Gene', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('knockdown', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('DDP', 'Gene', '1678', (151, 154))	('eIF4E', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (95, 100))	('DDP', 'Gene', '1678', (86, 89))
111873	27588477	In contrast, there was no statistical difference between DDP treated and NS treated animals on the effect of tumor growth inhibition in eIF4E overexpressed group, which indicated that increased eIF4E might invalidate DDP anticancer effect (P = 0.3034, Figure 4D).	('eIF4E', 'Var', (194, 199))	('DDP', 'Gene', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (225, 231))	('increased', 'PosReg', (184, 193))	('DDP', 'Gene', (217, 220))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('invalidate', 'NegReg', (206, 216))	('DDP', 'Gene', '1678', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('DDP', 'Gene', '1678', (217, 220))
111881	27588477	These data indicate that eIF4E promotes PI3K/AKT signaling pathway and Bcl-2/Bax ratio in EC9706, which may imply the possible mechanism of eIF4E induced cisplatin resistance in ESCC.	('EC9706', 'Var', (90, 96))	('AKT', 'Gene', '207', (45, 48))	('AKT', 'Gene', (45, 48))	('Bax', 'Gene', (77, 80))	('eIF4E', 'Var', (140, 145))	('promotes', 'PosReg', (31, 39))	('EC9706', 'CellLine', 'CVCL:E307', (90, 96))	('Bcl-2', 'Gene', '596', (71, 76))	('cisplatin', 'MPA', (154, 163))	('Bcl-2', 'Gene', (71, 76))	('Bax', 'Gene', '581', (77, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('eIF4E', 'Var', (25, 30))
111886	27588477	In contrast, knockdown of eIF4E expression showed a significant delay for tumorigenicity, as well as decrease in tumor size and tumor weight compared to the mice with control or overexpressed eIF4E.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('decrease', 'NegReg', (101, 109))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('delay', 'NegReg', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (128, 133))	('eIF4E', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('knockdown', 'Var', (13, 22))
111887	27588477	We also found that eIF4E knockdown significantly potentiated cisplatin - induced cytotoxicity and long-term cell growth suppression, hence sensitizing esophageal cancer cells to cisplatin treatment in vitro and in vivo.	('esophageal cancer', 'Disease', (151, 168))	('cytotoxicity', 'Disease', (81, 93))	('sensitizing', 'Reg', (139, 150))	('long-term cell growth suppression', 'CPA', (98, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('eIF4E', 'Gene', (19, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cisplatin', 'CPA', (61, 70))	('potentiated', 'PosReg', (49, 60))	('knockdown', 'Var', (25, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))
111890	27588477	We found in this study that weak mRNAs including VEGF, FGF-2, MMP-9, Cyclin D1, Survivin and C-myc were positively regulated by eIF4E.	('VEGF', 'Gene', (49, 53))	('FGF-2', 'Gene', '2247', (55, 60))	('eIF4E', 'Var', (128, 133))	('MMP-9', 'Gene', (62, 67))	('MMP-9', 'Gene', '4318', (62, 67))	('FGF-2', 'Gene', (55, 60))	('VEGF', 'Gene', '7422', (49, 53))	('Survivin', 'MPA', (80, 88))	('C-myc', 'Gene', '4609', (93, 98))	('Cyclin D1', 'Gene', '595', (69, 78))	('C-myc', 'Gene', (93, 98))	('Cyclin D1', 'Gene', (69, 78))
111894	27588477	Our results demonstrated that inhibition of eIF4E expression resulted in an augmented cell viability inhibition in vitro and a significant tumor reduction and synergistic effects with cisplatin in a xenograft model.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('cell viability inhibition', 'CPA', (86, 111))	('inhibition', 'Var', (30, 40))	('reduction', 'NegReg', (145, 154))	('augmented', 'PosReg', (76, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('eIF4E', 'Gene', (44, 49))
111897	27588477	Moreover, abnormal eIF4E expression promoted rapamycin resistance by abberant activation of AKT.	('abnormal', 'Var', (10, 18))	('eIF4E', 'Gene', (19, 24))	('AKT', 'Gene', '207', (92, 95))	('rapamycin', 'Chemical', 'MESH:D020123', (45, 54))	('activation', 'PosReg', (78, 88))	('AKT', 'Gene', (92, 95))	('rapamycin resistance', 'MPA', (45, 65))	('promoted', 'PosReg', (36, 44))
111898	27588477	In the present study, we have demonstrated that eIF4E induced cisplatin-resistance in ESCC mainly by promoting PI3K/AKT pathway and increasing Bcl-2/Bax ratio, which is similar to eIF4E in triple-negative breast cancer cells.	('cisplatin-resistance', 'MPA', (62, 82))	('increasing', 'PosReg', (132, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('induced', 'Reg', (54, 61))	('Bax', 'Gene', '581', (149, 152))	('breast cancer', 'Disease', (205, 218))	('promoting', 'PosReg', (101, 110))	('AKT', 'Gene', '207', (116, 119))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('eIF4E', 'Var', (48, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('Bcl-2', 'Gene', (143, 148))	('Bax', 'Gene', (149, 152))	('Bcl-2', 'Gene', '596', (143, 148))	('AKT', 'Gene', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
111900	27588477	All these indicated that eIF4E involved in cisplatin resistance in ESCC mainly via disrupting the balance of apoptosis.	('balance of apoptosis', 'MPA', (98, 118))	('cisplatin resistance', 'MPA', (43, 63))	('involved', 'Reg', (31, 39))	('disrupting', 'NegReg', (83, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('eIF4E', 'Var', (25, 30))
111903	27588477	Overexpression or knockdown of eIF4E by RNA intervention modulated tumor cell growth and chemosensitivity to cisplatin both in vitro and in vivo, which suggested that eIF4E might have a great potency of synergistic effect of cisplatin to ameliorate drug resistance in ESCC and many other tumors.	('tumor', 'Disease', (288, 293))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('ameliorate', 'PosReg', (238, 248))	('eIF4E', 'Var', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('modulated', 'Reg', (57, 66))	('drug resistance', 'MPA', (249, 264))	('cisplatin', 'Chemical', 'MESH:D002945', (225, 234))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('ESCC', 'Disease', (268, 272))	('drug resistance', 'Phenotype', 'HP:0020174', (249, 264))	('tumors', 'Disease', (288, 294))
111904	27588477	The combination of targeting eIF4E and traditional anti-cancer agents will be a novel strategy in targeted cancer therapy and may become a promising substitute for the conventional chemotherapy in ESCC.	('targeting', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ESCC', 'Disease', (197, 201))	('eIF4E', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('combination', 'Interaction', (4, 15))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (107, 113))
111938	27588477	Nude mice were divided into 3 groups (n = 12 for each) and were subcutaneously (s.c.) inoculated into the right flanks with 3 x 106 of eIF4E-transfected or scramble control-transfected EC9706 cells (eIF4E-PEGFP-N1 for eIF4E overexpression, eIF4E-shRNA for eIF4E knockdown, and EC9706 cell only for blank control), respectively.	('Nude mice', 'Species', '10090', (0, 9))	('eIF4E', 'Var', (218, 223))	('EC9706', 'CellLine', 'CVCL:E307', (185, 191))	('overexpression', 'PosReg', (224, 238))	('eIF4E-shRNA', 'Var', (240, 251))	('EC9706', 'CellLine', 'CVCL:E307', (277, 283))
111969	27565381	Endoscopic screening as well as brush cytologic testing has been performed in China for patients with mild, moderate and severe dysplasia who have in increased risk of developing squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 202))	('squamous cell carcinoma', 'Disease', (179, 202))	('dysplasia', 'Disease', (128, 137))	('patients', 'Species', '9606', (88, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('mild', 'Disease', (102, 106))	('dysplasia', 'Disease', 'MESH:D004476', (128, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('moderate and', 'Var', (108, 120))
111973	27565381	Subjecting biopsy material to next-generation sequencing has been shown to identify patients with Barrett's esophagus who might have an increased risk for EAC, based on common mutations for example in tumor suppressors such as TP53, as well as APC and CDKN2A.	('EAC', 'Disease', (155, 158))	('mutations', 'Var', (176, 185))	('TP53', 'Gene', '7157', (227, 231))	('CDKN2A', 'Gene', (252, 258))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (98, 117))	('TP53', 'Gene', (227, 231))	('APC', 'Disease', 'MESH:D011125', (244, 247))	('CDKN2A', 'Gene', '1029', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('APC', 'Disease', (244, 247))	('tumor', 'Disease', (201, 206))
111981	27565381	A significant association of PPI treatment with a decreased risk of high-grade dysplasia and adenocarcinoma has been shown in clinic-based cohort studies for patients with Barrett's esophagus.	('men', 'Species', '9606', (38, 41))	('PPI', 'Var', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('decreased', 'NegReg', (50, 59))	("Barrett's esophagus", 'Disease', (172, 191))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (172, 191))	('patients', 'Species', '9606', (158, 166))	('dysplasia and adenocarcinoma', 'Disease', 'MESH:D000230', (79, 107))
112040	27565381	Administration of 5-FU reduces dTMP, thereby inducing cell death.	('inducing', 'PosReg', (45, 53))	('cell death', 'CPA', (54, 64))	('5-FU', 'Var', (18, 22))	('dTMP', 'Chemical', 'MESH:D013938', (31, 35))	('5-FU', 'Chemical', 'MESH:D005472', (18, 22))	('dTMP', 'MPA', (31, 35))	('reduces', 'NegReg', (23, 30))
112041	27565381	Biomedical modifications and pharmacomodulation resulted in increased therapeutic efficacy over a drug that has been reported first in 1957 as a new class of tumor inhibitors.	('tumor', 'Disease', (158, 163))	('modifications', 'Var', (11, 24))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('increased', 'PosReg', (60, 69))	('therapeutic efficacy', 'MPA', (70, 90))
112051	27565381	Paclitaxel-treated cells have mitotic spindle assembly and cell division defects, as paclitaxel stabilizes the microtubules and prevent them from disassembly.	('cell division defects', 'CPA', (59, 80))	('paclitaxel', 'Var', (85, 95))	('disassembly', 'MPA', (146, 157))	('stabilizes', 'MPA', (96, 106))	('microtubules', 'MPA', (111, 123))	('Paclitaxel', 'Chemical', 'MESH:D017239', (0, 10))	('paclitaxel', 'Chemical', 'MESH:D017239', (85, 95))	('prevent', 'NegReg', (128, 135))	('mitotic spindle assembly', 'CPA', (30, 54))
112066	27565381	The most well-known targeted approach to esophageal cancer has been the inhibition of epidermal growth factor receptor (EGFR).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('epidermal growth factor receptor', 'Gene', (86, 118))	('epidermal growth factor receptor', 'Gene', '1956', (86, 118))	('inhibition', 'Var', (72, 82))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'Gene', (120, 124))	('esophageal cancer', 'Disease', (41, 58))
112072	27565381	Resistance due to the accumulation of mutations in EGFR or pathway targets as well as overexpression of signaling targets.	('accumulation', 'PosReg', (22, 34))	('EGFR', 'Gene', (51, 55))	('mutations', 'Var', (38, 47))	('overexpression', 'PosReg', (86, 100))	('EGFR', 'Gene', '1956', (51, 55))
112083	27565381	While monoclonal antibodies used as drugs against specific target in the bodies can be considered immunotherapy as they cause an immune response to the cancer cell, there are other types of immunotherapy.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cause', 'Reg', (120, 125))	('immune response', 'MPA', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('monoclonal', 'Var', (6, 16))
112094	27565381	for anti-PD-L1 mAb BMS-936559) are small with only 7 gastric cancer patients of 207 enrolled patients overall.	('BMS-936559', 'Var', (19, 29))	('PD-L1', 'Gene', '29126', (9, 14))	('gastric cancer', 'Disease', (53, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('patients', 'Species', '9606', (93, 101))	('PD-L1', 'Gene', (9, 14))
112170	26380556	In this study, an EC cell line established from ED-L2-cyclin D1;p53 mice (as discussed in the GEMMs section) was transduced with or without the viral antigen human papilloma virus E7 protein antigen and was injected at the gastroesophageal junction of immunocompetent mice.	('mice', 'Species', '10090', (68, 72))	('p53', 'Gene', '22060', (64, 67))	('transduced', 'Var', (113, 123))	('mice', 'Species', '10090', (268, 272))	('human papilloma virus', 'Species', '10566', (158, 179))	('papilloma', 'Phenotype', 'HP:0012740', (164, 173))	('p53', 'Gene', (64, 67))
112171	26380556	The adenoviral-based immunotherapy reduced tumor growth and prolonged overall survival.	('prolonged', 'PosReg', (60, 69))	('reduced', 'NegReg', (35, 42))	('overall survival', 'CPA', (70, 86))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('adenoviral-based', 'Var', (4, 20))	('tumor', 'Disease', (43, 48))
112188	26380556	The presence of keratinization in mouse esophagus is thought to make it more resistant to injuries and to the development of EC.	('mouse', 'Species', '10090', (34, 39))	('keratinization', 'Protein', (16, 30))	('resistant', 'CPA', (77, 86))	('more', 'PosReg', (72, 76))	('presence', 'Var', (4, 12))
112196	26380556	ESCC is a multistep process that is caused by the accumulation of multiple genetic alterations, such as overexpression of EGFR and cyclin D1, inactivation of p16 and p53, and alterations in the Wnt and Notch pathways.	('cyclin D1', 'Gene', (131, 140))	('EGFR', 'Gene', (122, 126))	('p16', 'Gene', (158, 161))	('p53', 'Gene', (166, 169))	('caused by', 'Reg', (36, 45))	('ESCC', 'Disease', (0, 4))	('inactivation', 'Var', (142, 154))	('p53', 'Gene', '22060', (166, 169))	('alterations', 'Reg', (175, 186))	('p16', 'Gene', '12578', (158, 161))	('overexpression', 'PosReg', (104, 118))	('EGFR', 'Gene', '13649', (122, 126))
112198	26380556	Moreover, constitutively active nuclear cyclin D1 mutants have been identified in patients with ESCC.	('patients', 'Species', '9606', (82, 90))	('nuclear cyclin D1', 'Protein', (32, 49))	('ESCC', 'Disease', (96, 100))	('mutants', 'Var', (50, 57))
112200	26380556	Mutations in p53 are the most frequent genetic alterations found in EC and commonly occur during the early stages of the disease.	('Mutations', 'Var', (0, 9))	('p53', 'Gene', '22060', (13, 16))	('occur', 'Reg', (84, 89))	('p53', 'Gene', (13, 16))
112201	26380556	Several p53 mutations have loss-of-function properties.	('loss-of-function', 'NegReg', (27, 43))	('p53', 'Gene', '22060', (8, 11))	('mutations', 'Var', (12, 21))	('p53', 'Gene', (8, 11))
112207	26380556	Klf4 deletion in the esophageal epithelia of mice results in increased proliferation and squamous cell dysplasia.	('esophageal epithelia', 'Disease', (21, 41))	('deletion', 'Var', (5, 13))	('esophageal epithelia', 'Disease', 'MESH:D004941', (21, 41))	('Klf4', 'Gene', (0, 4))	('mice', 'Species', '10090', (45, 49))	('squamous cell dysplasia', 'Disease', 'MESH:D002294', (89, 112))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (89, 112))	('increased', 'PosReg', (61, 70))	('squamous cell dysplasia', 'Disease', (89, 112))	('proliferation', 'CPA', (71, 84))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (21, 41))	('Klf4', 'Gene', '16600', (0, 4))
112208	26380556	Interestingly, transgenic expression of Klf4 in esophageal epithelia induces inflammation and can lead to ESCC at an advanced age.	('transgenic', 'Species', '10090', (15, 25))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (48, 68))	('esophageal epithelia', 'Disease', 'MESH:D004941', (48, 68))	('Klf4', 'Gene', '16600', (40, 44))	('lead to', 'Reg', (98, 105))	('ESCC', 'Disease', (106, 110))	('induces', 'PosReg', (69, 76))	('esophageal epithelia', 'Disease', (48, 68))	('inflammation', 'Disease', 'MESH:D007249', (77, 89))	('transgenic expression', 'Var', (15, 36))	('Klf4', 'Gene', (40, 44))	('inflammation', 'Disease', (77, 89))
112214	26380556	The local inflammatory response associated with loss of p120-catenin includes increased expression of several proinflammatory cytokines and chemokines, massive recruitment of immature myeloid cells, and activation of signal transducer and activator of transcription 3 (STAT3) and Nuclear factor-kappaB (NFkappaB).	('loss', 'Var', (48, 52))	('Nuclear factor-kappaB', 'Gene', (280, 301))	('NFkappaB', 'Gene', '18033', (303, 311))	('signal transducer and activator of transcription 3', 'Gene', '20848', (217, 267))	('STAT3', 'Gene', '20848', (269, 274))	('STAT3', 'Gene', (269, 274))	('recruitment', 'MPA', (160, 171))	('Nuclear factor-kappaB', 'Gene', '18033', (280, 301))	('increased', 'PosReg', (78, 87))	('local inflammatory response', 'CPA', (4, 31))	('NFkappaB', 'Gene', (303, 311))	('activation', 'PosReg', (203, 213))	('expression', 'MPA', (88, 98))	('p120-catenin', 'Protein', (56, 68))
112215	26380556	This p120-catenin knockout model closely recapitulated human ESCC and clearly established the tumor-suppressing role of p120-catenin in this cancer.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ESCC', 'Disease', (61, 65))	('human', 'Species', '9606', (55, 60))	('tumor', 'Disease', (94, 99))	('p120-catenin', 'Var', (120, 132))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
112216	26380556	Gene amplification and overexpression of SOX-2 have been identified in patients with ESCC.	('overexpression', 'PosReg', (23, 37))	('patients', 'Species', '9606', (71, 79))	('ESCC', 'Disease', (85, 89))	('SOX-2', 'Gene', (41, 46))	('Gene amplification', 'Var', (0, 18))
112217	26380556	Ectopic expression of SOX-2 in basal progenitor cells using an inducible keratin 5 promoter leads to epithelial cell hyperplasia in the esophagus and squamous cell cancer in the forestomach.	('keratin 5', 'Gene', '110308', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Ectopic expression', 'Var', (0, 18))	('squamous cell cancer', 'Disease', (150, 170))	('squamous cell cancer', 'Disease', 'MESH:D002294', (150, 170))	('keratin 5', 'Gene', (73, 82))	('epithelial cell hyperplasia', 'Disease', 'MESH:D017573', (101, 128))	('epithelial cell hyperplasia', 'Disease', (101, 128))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (150, 170))	('leads to', 'Reg', (92, 100))
112236	26380556	4-NQO causes DNA damage, which includes DNA adducts, single-strand breaks, abasic sites, pyrimidine dimers, and oxidized bases.	('single-strand breaks', 'MPA', (53, 73))	('oxidized bases', 'MPA', (112, 126))	('DNA adducts', 'MPA', (40, 51))	('pyrimidine', 'Chemical', 'MESH:C030986', (89, 99))	('DNA', 'Disease', (13, 16))	('pyrimidine dimers', 'MPA', (89, 106))	('abasic sites', 'MPA', (75, 87))	('4-NQO', 'Var', (0, 5))	('4-NQO', 'Chemical', 'MESH:D015112', (0, 5))
112241	26380556	In this study by Tang et al, 100% of c57BL/6 or CBA mice developed esophageal tumors by 28 weeks after the start of the experiment (16 weeks of 4-NQO at a concentration of 100 mug/mL and then resume normal water for 12 weeks).	('4-NQO', 'Chemical', 'MESH:D015112', (144, 149))	('esophageal tumors', 'Disease', 'MESH:D004938', (67, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal tumors', 'Phenotype', 'HP:0100751', (67, 84))	('esophageal tumor', 'Phenotype', 'HP:0100751', (67, 83))	('c57BL/6', 'Var', (37, 44))	('esophageal tumors', 'Disease', (67, 84))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('developed', 'PosReg', (57, 66))	('water', 'Chemical', 'MESH:D014867', (206, 211))
112245	26380556	By contrast, knockouts for DNA methyltransferase 1 and Keap1 are protective against esophageal tumor formation induced by 4-NQO.	('esophageal tumor', 'Disease', 'MESH:D004938', (84, 100))	('esophageal tumor', 'Disease', (84, 100))	('Keap1', 'Gene', '50868', (55, 60))	('esophageal tumor', 'Phenotype', 'HP:0100751', (84, 100))	('Keap1', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('knockouts', 'Var', (13, 22))	('4-NQO', 'Chemical', 'MESH:D015112', (122, 127))
112256	26380556	Forty percent of the 15-month-old IL-1beta mutant mice treated with DCA developed tumors in their distant esophagus.	('DCA', 'Chemical', 'MESH:D003840', (68, 71))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('IL-1beta', 'Gene', '16176', (34, 42))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('developed', 'Reg', (72, 81))	('mutant', 'Var', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('IL-1beta', 'Gene', (34, 42))	('mice', 'Species', '10090', (50, 54))
112259	26380556	Moreover, IL-6 deficiency inhibited the development of BE and EAC.	('BE', 'Phenotype', 'HP:0100580', (55, 57))	('inhibited', 'NegReg', (26, 35))	('EAC', 'Phenotype', 'HP:0011459', (62, 65))	('deficiency', 'Var', (15, 25))	('IL-6', 'Gene', (10, 14))	('IL-6', 'Gene', '16193', (10, 14))	('IL-6 deficiency', 'Phenotype', 'HP:0030783', (10, 25))
112291	25648975	DNM in turn can be followed by severe complications, such as tracheal rupture, vascular compression), septic shock) and multiorgan failure, including pneumonia and cardiac or renal failure).	('septic shock', 'Disease', 'MESH:D012772', (102, 114))	('tracheal rupture', 'Disease', 'MESH:D014133', (61, 77))	('multiorgan failure', 'Disease', 'MESH:D017093', (120, 138))	('multiorgan failure', 'Disease', (120, 138))	('DNM', 'Chemical', '-', (0, 3))	('tracheal rupture', 'Disease', (61, 77))	('followed', 'Reg', (19, 27))	('pneumonia', 'Phenotype', 'HP:0002090', (150, 159))	('DNM', 'Var', (0, 3))	('shock', 'Phenotype', 'HP:0031273', (109, 114))	('cardiac or renal failure', 'Disease', 'MESH:D006333', (164, 188))	('septic shock', 'Disease', (102, 114))	('cardiac or renal failure', 'Disease', (164, 188))	('pneumonia', 'Disease', (150, 159))	('pneumonia', 'Disease', 'MESH:D011014', (150, 159))	('septic shock', 'Phenotype', 'HP:0100806', (102, 114))	('renal failure', 'Phenotype', 'HP:0000083', (175, 188))
112316	25648975	In addition, the mechanism by which DNM led to formation of the esophageal fistulas and gastric ulcers remains unknown.	('esophageal fistulas', 'Disease', (64, 83))	('DNM', 'Var', (36, 39))	('gastric ulcers', 'Disease', (88, 102))	('led to', 'Reg', (40, 46))	('esophageal fistulas', 'Disease', 'MESH:D004937', (64, 83))	('gastric ulcers', 'Phenotype', 'HP:0002592', (88, 102))	('gastric ulcers', 'Disease', 'MESH:D013276', (88, 102))	('DNM', 'Chemical', '-', (36, 39))
112323	33215762	Subgroup analysis showed that late-start nilotinib 150 mg significantly worsened using the sum of UPDRS Parts II + III and total UPDRS Parts I to III compared with late-start nilotinib 300 mg. Quality of life using the Parkinson's Disease Questionnaire in nilotinib 150 mg significantly declined between 15 and 27 months compared with nilotinib 300 mg, and there was no change in cognition using the Montreal Cognitive Assessment between groups.	('men', 'Species', '9606', (425, 428))	('nilotinib', 'Chemical', 'MESH:C498826', (175, 184))	('PD', 'Disease', 'MESH:D010300', (99, 101))	("Parkinson's Disease", 'Disease', (219, 238))	('PD', 'Disease', 'MESH:D010300', (130, 132))	('nilotinib', 'Chemical', 'MESH:C498826', (256, 265))	('nilotinib', 'Chemical', 'MESH:C498826', (335, 344))	('nilotinib', 'Chemical', 'MESH:C498826', (41, 50))	('declined', 'NegReg', (287, 295))	("Parkinson's Disease", 'Disease', 'MESH:D010300', (219, 238))	('Quality', 'MPA', (193, 200))	('nilotinib', 'Var', (256, 265))
112329	33215762	2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8 ,  9  Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with alpha-synuclein increases autophagy and reduces inflammation and neurotoxic proteins.	('inhibition', 'NegReg', (70, 80))	('neurotoxic proteins', 'Disease', 'MESH:D020258', (187, 206))	('inflammation', 'Disease', 'MESH:D007249', (170, 182))	('autophagy', 'CPA', (148, 157))	('increases', 'PosReg', (138, 147))	('DDR1', 'Gene', (84, 88))	('inflammation', 'Disease', (170, 182))	('reduces', 'NegReg', (162, 169))	('mouse', 'Species', '10090', (94, 99))	('neurotoxic proteins', 'Disease', (187, 206))	('deletion', 'Var', (58, 66))
112373	33215762	Falls were common AEs with nilotinib 150 mg (45.4%) and 300 mg (43%), but there was no significant difference (P = 0.86) between the groups.	('Falls', 'Disease', (0, 5))	('Falls', 'Phenotype', 'HP:0002527', (0, 5))	('nilotinib 150 mg', 'Var', (27, 43))	('nilotinib', 'Chemical', 'MESH:C498826', (27, 36))
112414	33215762	17 ,  18 ,  19 ,  20 ,  22  MAO-A activity between baseline and 12 months in the DB, placebo-controlled study was reduced (albeit nonsignificant) in nilotinib 150 mg (-240%, P = 0.31) and 300 mg (-379%, P = 0.21) versus placebo (Fig.	('activity', 'MPA', (34, 42))	('MAO-A', 'Gene', (28, 33))	('reduced', 'NegReg', (114, 121))	('MAO-A', 'Gene', '4128', (28, 33))	('nilotinib', 'Var', (149, 158))	('nilotinib', 'Chemical', 'MESH:C498826', (149, 158))
112423	33215762	In the DB period, there was a significant increase in the total number of SAEs in the nilotinib groups, but no significant difference was seen in cardiovascular SAEs, number of falls (albeit increased in the DB nilotinib groups), or the total number of AEs between all the groups.	('nilotinib', 'Var', (86, 95))	('cardiovascular SAEs', 'Phenotype', 'HP:0001626', (146, 165))	('cardiovascular SAEs', 'Disease', (146, 165))	('cardiovascular SAEs', 'Disease', 'MESH:D002318', (146, 165))	('SAEs', 'Disease', (74, 78))	('nilotinib', 'Chemical', 'MESH:C498826', (86, 95))	('nilotinib', 'Chemical', 'MESH:C498826', (211, 220))	('increase', 'PosReg', (42, 50))	('falls', 'Phenotype', 'HP:0002527', (177, 182))
112438	33215762	17 ,  18 ,  19 ,  20  Taken together, these findings suggest that nilotinib treatment in patients with early PD who are levodopa naive should be evaluated to determine whether nilotinib stabilizes PD symptoms and/or eliminates or delays resumption of levodopa treatment.	('PD', 'Disease', 'MESH:D010300', (197, 199))	('resumption', 'MPA', (237, 247))	('PD', 'Disease', 'MESH:D010300', (109, 111))	('levodopa', 'Chemical', 'MESH:D007980', (120, 128))	('levodopa', 'Chemical', 'MESH:D007980', (251, 259))	('men', 'Species', '9606', (265, 268))	('delays', 'NegReg', (230, 236))	('nilotinib', 'Var', (176, 185))	('nilotinib', 'Chemical', 'MESH:C498826', (66, 75))	('eliminates', 'NegReg', (216, 226))	('nilotinib', 'Chemical', 'MESH:C498826', (176, 185))	('patients', 'Species', '9606', (89, 97))	('men', 'Species', '9606', (81, 84))	('symptoms', 'MPA', (200, 208))	('stabilizes', 'PosReg', (186, 196))
112441	33215762	19  Accumulation of oligomeric alpha-synuclein results in age-dependent impairment of dopamine release, but reduction of oligomeric alpha-synuclein increases dopamine turnover.	('Accumulation', 'PosReg', (4, 16))	('dopamine', 'Chemical', 'MESH:D004298', (158, 166))	('impairment', 'NegReg', (72, 82))	('increases', 'PosReg', (148, 157))	('dopamine', 'Chemical', 'MESH:D004298', (86, 94))	('dopamine release', 'MPA', (86, 102))	('oligomeric', 'Var', (20, 30))	('men', 'Species', '9606', (78, 81))	('dopamine turnover', 'MPA', (158, 175))	('reduction', 'NegReg', (108, 117))
112452	33215762	17 ,  18 ,  19 ,  20 ,  22  These changes constitute an experimental biomarker system similar to the A/T/N system in AD 31  that should be investigated in correlation with potential clinical outcomes to evaluate the disease-modifying effects of nilotinib.	('men', 'Species', '9606', (62, 65))	('AD', 'Disease', 'MESH:D000544', (117, 119))	('AD', 'Disease', (117, 119))	('nilotinib', 'Chemical', 'MESH:C498826', (245, 254))	('changes', 'Var', (34, 41))	('AD', 'Phenotype', 'HP:0002511', (117, 119))
112488	33435562	Most of the patients with thyroid cancer received radioisotopes, while not the external beam radiation (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (12, 20))	('radioisotopes', 'Var', (50, 63))	('thyroid cancer', 'Phenotype', 'HP:0002890', (26, 40))	('radioisotope', 'Chemical', 'MESH:D011868', (50, 62))	('thyroid cancer', 'Disease', (26, 40))	('thyroid cancer', 'Disease', 'MESH:D013964', (26, 40))
112491	33435562	Owing to the limitations of Fine and Gray models, the proportional sub-distribution hazard assumption in the competing risk model is often impossible to hold over a long time of follow-up, thus in some multivariable models, Cox models were utilized to calculate the effect sizes of radiotherapy vs. no radiotherapy.	('Cox', 'Gene', '1351', (224, 227))	('radiotherapy', 'Var', (282, 294))	('Cox', 'Gene', (224, 227))
112510	33435562	In the PSM-adjusted population, according to the outcomes of the survival analysis (Kaplan-Meier) considering the competing-risks in event occurrence, the results could be divided into two groups: (I) Patients receiving radiotherapy were associated with more SPMs and (II) Patients who received radiotherapy showed similar SPM incidences.	('radiotherapy', 'Var', (220, 232))	('SPMs', 'Disease', (259, 263))	('Patients', 'Species', '9606', (273, 281))	('Patients', 'Species', '9606', (201, 209))
112617	32088725	In addition, patients with high expression of MTHFD2 had worse survival than those with low MTHFD2 expression (P<0.05).	('patients', 'Species', '9606', (13, 21))	('MTHFD2', 'Gene', (46, 52))	('high expression', 'Var', (27, 42))	('survival', 'MPA', (63, 71))	('worse', 'NegReg', (57, 62))
112620	32088725	Taken together, high expression of MTHFD2 was an independent unfavorable prognostic parameter for overall survival (OS) of ESCC patients, suggesting that MTHFD2 might be a potential therapeutic target for ESCC in the future.	('MTHFD2', 'Gene', (35, 41))	('overall', 'MPA', (98, 105))	('high', 'Var', (16, 20))	('ESCC', 'Disease', (123, 127))	('ESCC', 'Disease', 'MESH:C562729', (205, 209))	('OS', 'Chemical', '-', (116, 118))	('patients', 'Species', '9606', (128, 136))	('ESCC', 'Disease', 'MESH:C562729', (123, 127))	('ESCC', 'Disease', (205, 209))
112669	32088725	Patients with high MTHFD2 expression had shorter OS than patients with low MTHFD2 expression (95% CI 38.227-71.473 vs. 22.424-38.748, P=0.006; Figure 5A).	('OS', 'Chemical', '-', (49, 51))	('shorter', 'NegReg', (41, 48))	('patients', 'Species', '9606', (57, 65))	('Patients', 'Species', '9606', (0, 8))	('high MTHFD2 expression', 'Var', (14, 36))
112670	32088725	TNM stage was correlated with the prognosis of patients, and patients with TNM stage III/IV had worse OS than those with TNM stage I/II (95% CI 36.374-60.826 vs. 15.932-29.280, P=0.004; Figure 5B).	('OS', 'Chemical', '-', (102, 104))	('TNM', 'Gene', (75, 78))	('TNM', 'Gene', '10178', (0, 3))	('stage III/IV', 'Var', (79, 91))	('TNM', 'Gene', '10178', (121, 124))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (47, 55))	('TNM', 'Gene', (0, 3))	('TNM', 'Gene', '10178', (75, 78))	('TNM', 'Gene', (121, 124))
112672	32088725	Furthermore, Cox multivariate regression analysis showed that high expression of MTHFD2 was closely associated with the prognosis of patients, which could be used as an independent prognostic indicator for predicting ESCC (Table 3).	('ESCC', 'Disease', 'MESH:C562729', (217, 221))	('Cox', 'Gene', (13, 16))	('patients', 'Species', '9606', (133, 141))	('associated', 'Reg', (100, 110))	('MTHFD2', 'Gene', (81, 87))	('ESCC', 'Disease', (217, 221))	('high', 'Var', (62, 66))	('Cox', 'Gene', '1351', (13, 16))
112674	32088725	As shown in Figure 6, tumors with high expression of MTHFD2 had significantly higher expression of ki67 and p53.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('expression', 'MPA', (85, 95))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('high expression', 'Var', (34, 49))	('MTHFD2', 'Gene', (53, 59))	('higher', 'PosReg', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('ki67', 'Protein', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', (22, 28))	('ki67', 'Chemical', '-', (99, 103))
112675	32088725	Spearman's rank correlation analysis showed that the expression of MTHFD2 was significantly positively correlated between ki67 (r=0.441, P<0.001, Table 4) and p53 (r=0.249, P=0.028, Table 5) in ESCC tissues.	('ki67', 'Chemical', '-', (122, 126))	('ESCC', 'Disease', (194, 198))	('p53', 'Gene', (159, 162))	('correlated', 'Interaction', (103, 113))	('p53', 'Gene', '7157', (159, 162))	('MTHFD2', 'Gene', (67, 73))	('positively', 'PosReg', (92, 102))	('ESCC', 'Disease', 'MESH:C562729', (194, 198))	('expression', 'MPA', (53, 63))	('ki67', 'Var', (122, 126))
112690	32088725	found that knockout of the MTHFD2 gene leads to the death of breast cancer cells and reduces invasion and migration.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('death', 'Disease', 'MESH:D003643', (52, 57))	('death', 'Disease', (52, 57))	('MTHFD2', 'Gene', (27, 33))	('reduces', 'NegReg', (85, 92))	('knockout', 'Var', (11, 19))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
112691	32088725	Similarly, MTHFD2 was reported to promote the growth and metastasis of colorectal cancer cells, and MTHFD2 knockdown clearly inhibits tumor growth.	('knockdown', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MTHFD2', 'Gene', (100, 106))	('metastasis of colorectal cancer', 'Disease', 'MESH:D015179', (57, 88))	('metastasis of colorectal cancer', 'Disease', (57, 88))	('growth', 'CPA', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('inhibits', 'NegReg', (125, 133))	('promote', 'PosReg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('tumor', 'Disease', (134, 139))
112692	32088725	Furthermore, recent studies have demonstrated that many micro-RNAs in tumor cell pathways play an anti-tumor role by inhibiting the expression of MTHFD2, such as mir-940, mir-504-3p, and mirRNA-92a.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mir-940', 'Gene', '100126328', (162, 169))	('tumor', 'Disease', (103, 108))	('mir-940', 'Gene', (162, 169))	('tumor', 'Disease', (70, 75))	('MTHFD2', 'Gene', (146, 152))	('mir-504', 'Gene', (171, 178))	('inhibiting', 'NegReg', (117, 127))	('micro-RNAs', 'Var', (56, 66))	('mir-504', 'Gene', '574507', (171, 178))	('expression', 'MPA', (132, 142))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
112698	32088725	Furthermore, we observed that MTHFD2 overexpression was significantly correlated with the pathological grading and TNM stage of ESCC patients, suggesting that MTHFD2 is associated with the occurrence, development, and metastasis of ESCC.	('MTHFD2', 'Var', (159, 165))	('ESCC', 'Disease', (232, 236))	('patients', 'Species', '9606', (133, 141))	('ESCC', 'Disease', 'MESH:C562729', (128, 132))	('metastasis', 'CPA', (218, 228))	('associated', 'Reg', (169, 179))	('TNM', 'Gene', '10178', (115, 118))	('ESCC', 'Disease', (128, 132))	('ESCC', 'Disease', 'MESH:C562729', (232, 236))	('development', 'CPA', (201, 212))	('TNM', 'Gene', (115, 118))
112703	32088725	As a tumor suppressor gene, p53 regulates cell proliferation, but the mutant p53 is closely involved in the proliferation of various tumor cells and is related to poor prognosis of patients.	('p53', 'Gene', (28, 31))	('related', 'Reg', (152, 159))	('involved', 'Reg', (92, 100))	('p53', 'Gene', '7157', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('mutant', 'Var', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('patients', 'Species', '9606', (181, 189))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (5, 10))
112704	32088725	A previous study showed that ki67 and p53 were related to the occurrence and development of esophageal cancer.	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ki67', 'Var', (29, 33))	('related', 'Reg', (47, 54))	('esophageal cancer', 'Disease', (92, 109))	('ki67', 'Chemical', '-', (29, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
112786	30300980	On follow-up endoscopy performed 4 years after the RFA, a slightly elevated 6-mm nodular area (Paris classification: 0-IIa) covered by squamous mucosa was detected immediately above the gastroesophageal junction (Fig.	('RFA', 'Var', (51, 54))	('gastroesophageal junction', 'Disease', (186, 211))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (186, 211))	('elevated', 'PosReg', (67, 75))
112910	30944835	The expressions of cell surface molecules, including CD11c, CD40, CD80, CD83, and CD86, were measured by FCM using CD11c-PE-cy5, CD40-APC, CD80-PE-cy7, CD83-FITC, and CD86-PE FCM antibodies, respectively.	('CD11c', 'Gene', (53, 58))	('cy7', 'Chemical', '-', (147, 150))	('CD83', 'Gene', (72, 76))	('cy5', 'Chemical', 'MESH:C085321', (124, 127))	('CD86', 'Gene', (82, 86))	('CD40-APC', 'Var', (129, 137))	('CD80', 'Gene', (66, 70))	('FITC', 'Chemical', 'MESH:D016650', (157, 161))	('CD11c-PE-cy5', 'Var', (115, 127))	('CD40', 'Gene', (60, 64))	('CD80-PE-cy7', 'Var', (139, 150))
112917	30944835	Results showed that CIK cells cocultured with DCs loaded with lysate from PADI4-overexpressing ECA-109 cells, the ratio of CD3+CD4+ CIK cells was 14.3%, while that of CD3+CD8+ CIK cells was 82.8%, and that of CD3+CD16+CD56+ CIK cells was 39.4%.	('CD16', 'Gene', (213, 217))	('CD16', 'Gene', '2214', (213, 217))	('CD3+CD4+', 'Var', (123, 131))
112920	30944835	On encounter with MUC1, immature DCs increase cell surface expression of CD40, CD80, CD83, and CD86 molecules and the production of IL-6 and TNF-alpha cytokines.	('cell surface expression', 'MPA', (46, 69))	('CD80', 'Var', (79, 83))	('IL-6', 'Gene', '3569', (132, 136))	('CD40', 'Protein', (73, 77))	('CD83', 'Var', (85, 89))	('increase', 'PosReg', (37, 45))	('production', 'MPA', (118, 128))	('TNF-alpha cytokines', 'MPA', (141, 160))	('IL-6', 'Gene', (132, 136))	('CD86', 'Var', (95, 99))
112967	28583825	Using genetic in vivo lineage tracing, she found that the keratin 15 (Krt15) promoter marked a long-lived basal cell population capable of allocating all stages of differentiation, and that genetic depletion of Krt15 lineage-labeled cells resulted in decreased proliferation and epithelial atrophy.	('Krt15', 'Gene', (70, 75))	('epithelial atrophy', 'Disease', (279, 297))	('rat', 'Species', '10116', (268, 271))	('proliferation', 'CPA', (261, 274))	('decreased', 'NegReg', (251, 260))	('rat', 'Species', '10116', (60, 63))	('Krt15', 'Gene', (211, 216))	('keratin 15', 'Gene', (58, 68))	('Krt15', 'Gene', '16665', (70, 75))	('genetic depletion', 'Var', (190, 207))	('epithelial atrophy', 'Disease', 'MESH:D002277', (279, 297))	('keratin 15', 'Gene', '16665', (58, 68))	('Krt15', 'Gene', '16665', (211, 216))
112973	28583825	With the induction of mutant Kras, Mist1+ isthmus stem cells serve as the cell of origin for intestinal metaplasia, and give rise to both intestinal-type and diffuse-type gastric cancers when they lose Apc and E-cadherin, respectively.	('Kras', 'Gene', (29, 33))	('Kras', 'Gene', '16653', (29, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('give rise to', 'Reg', (120, 132))	('lose', 'NegReg', (197, 201))	('gastric cancers', 'Disease', (171, 186))	('intestinal metaplasia', 'Disease', (93, 114))	('Apc', 'Gene', '11789', (202, 205))	('gastric cancers', 'Disease', 'MESH:D013274', (171, 186))	('gastric cancers', 'Phenotype', 'HP:0012126', (171, 186))	('mutant', 'Var', (22, 28))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (93, 114))	('E-cadherin', 'Gene', (210, 220))	('E-cadherin', 'Gene', '12550', (210, 220))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('intestinal-type', 'Disease', (138, 153))	('Apc', 'Gene', (202, 205))
112983	28583825	This ADM becomes irreversible when it acquires an oncogenic KRas mutation, and neoplastic progression occurs in synergy with inflammation.	('KRas', 'Gene', (60, 64))	('mutation', 'Var', (65, 73))	('inflammation', 'Disease', 'MESH:D007249', (125, 137))	('inflammation', 'Disease', (125, 137))
112992	28583825	A p63 gene deletion prevents this epithelial change, and SOX2 down-regulation causes esophageal progenitor cells to differentiate abnormally into mucin-secreting cells.	('SOX2', 'Gene', '20674', (57, 61))	('p63', 'Gene', '22061', (2, 5))	('prevents', 'NegReg', (20, 28))	('SOX2', 'Gene', (57, 61))	('down-regulation', 'NegReg', (62, 77))	('deletion', 'Var', (11, 19))	('p63', 'Gene', (2, 5))	('esophageal progenitor cells', 'CPA', (85, 112))
113011	28583825	The gastric cardia normally is rich in stem/progenitor cells, including Lgr5+ and CCK2R+ cells, and transgenes marking either of those progenitor cell types can lineage-trace metaplasia in the L2-IL-1beta mouse.	('gastric cardia', 'Disease', 'MESH:D004938', (4, 18))	('IL-1beta', 'Gene', '16176', (196, 204))	('Lgr5', 'Gene', '14160', (72, 76))	('Lgr5', 'Gene', (72, 76))	('IL-1beta', 'Gene', (196, 204))	('mouse', 'Species', '10090', (205, 210))	('transgenes', 'Var', (100, 110))	('gastric cardia', 'Disease', (4, 18))	('metaplasia', 'CPA', (175, 185))
113017	28583825	Although classically neoplasia develops only in goblet cell-containing Barrett's epithelium, Dr Wright noted that esophageal nongoblet columnar epithelium can also undergo clonal expansion and harbor premalignant TP53 mutations.	('neoplasia', 'Phenotype', 'HP:0002664', (21, 30))	('harbor', 'Reg', (193, 199))	('TP53', 'Gene', (213, 217))	('neoplasia', 'Disease', 'MESH:D009369', (21, 30))	('mutations', 'Var', (218, 227))	('neoplasia', 'Disease', (21, 30))	('TP53', 'Gene', '22059', (213, 217))
113024	28583825	Dr Peek discussed the usefulness of H pylori eradication for inducing regression of intestinal metaplasia and, thereby, reducing gastric cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (84, 105))	('reducing', 'NegReg', (120, 128))	('reducing gastric cancer', 'Phenotype', 'HP:0006753', (120, 143))	('regression', 'CPA', (70, 80))	('eradication', 'Var', (45, 56))	('gastric cancer', 'Disease', (129, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('intestinal metaplasia', 'Disease', (84, 105))	('pylori', 'Species', '210', (38, 44))	('H pylori', 'Gene', (36, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))
113060	26177369	Based on multivariate analysis, patients with N1 LN involvement experienced longer survival than patients with N2 LN involvement (HR: 1.37; 95% CI: 1.12-1.68) or N3 LN involvement (HR: 1.96; 95% CI: 1.52-2.53).	('N1 LN involvement', 'Var', (46, 63))	('patients', 'Species', '9606', (32, 40))	('survival', 'MPA', (83, 91))	('longer', 'PosReg', (76, 82))	('patients', 'Species', '9606', (97, 105))
113112	26177369	Patients with N1 LN involvement experienced longer survival than patients with N2 (HR: 1.37; 95% CI: 1.12-1.68; P < 0.001) or N3 LN involvement (HR: 1.96; 95% CI: 1.52-2.53).	('longer', 'PosReg', (44, 50))	('Patients', 'Species', '9606', (0, 8))	('survival', 'CPA', (51, 59))	('patients', 'Species', '9606', (65, 73))	('N1 LN involvement', 'Var', (14, 31))
113186	25396043	Expression kits included alpha-smooth muscle actin (SMA), Hs00426835_g1; SM22alpha, Hs00162558_m1; lactase, Hs00158722_m1; maltase, Hs01090216_m1; cytokeratin (CK) 4, Hs00361611_m1; CK13, Hs00357961_g1; involucrin, Hs00846307_s1; GAPDH, Hs02758991_g1.	('lactase', 'Gene', '3938', (99, 106))	('S', 'Chemical', 'MESH:D013455', (52, 53))	('GAPDH', 'Gene', (230, 235))	('Hs02758991_g1', 'Var', (237, 250))	('Hs00846307_s1', 'Var', (215, 228))	('SM22alpha', 'Gene', '6876', (73, 82))	('SM22alpha', 'Gene', (73, 82))	('S', 'Chemical', 'MESH:D013455', (73, 74))	('GAPDH', 'Gene', '2597', (230, 235))	('CK13', 'Gene', '3860', (182, 186))	('CK13', 'Gene', (182, 186))	('lactase', 'Gene', (99, 106))	('Hs00158722_m1', 'Var', (108, 121))	('Hs00162558_m1', 'Var', (84, 97))
113233	23304539	Ascites and pleural effusion were exacerbated after BRTO in 26 (33.8%) and 31 (40.3%), respectively.	('Ascites', 'Disease', (0, 7))	('Ascites', 'Phenotype', 'HP:0001541', (0, 7))	('pleural effusion', 'Disease', 'MESH:D010996', (12, 28))	('pleural effusion', 'Disease', (12, 28))	('pleural effusion', 'Phenotype', 'HP:0002202', (12, 28))	('exacerbated', 'PosReg', (34, 45))	('BRTO', 'Var', (52, 56))
113240	23304539	In many reports, the liver function has been shown to be improved by an increase in portal hepatic blood flow, but BRTO may also exacerbate symptoms of portal hypertensive changes, including ascites, splenomegaly, and the development of portosystemic collaterals, and the influence on respiratory function and complication of venous thrombus are of concern.	('increase', 'PosReg', (72, 80))	('venous thrombus', 'Phenotype', 'HP:0004936', (326, 341))	('improved', 'PosReg', (57, 65))	('splenomegaly', 'Disease', 'MESH:D013163', (200, 212))	('splenomegaly', 'Phenotype', 'HP:0001744', (200, 212))	('liver function', 'MPA', (21, 35))	('hypertensive changes', 'Phenotype', 'HP:0000822', (159, 179))	('portosystemic collaterals', 'Phenotype', 'HP:0025154', (237, 262))	('BRTO', 'Var', (115, 119))	('hypertensive', 'Disease', (159, 171))	('exacerbate', 'PosReg', (129, 139))	('ascites', 'Disease', (191, 198))	('venous thrombus', 'Disease', 'MESH:D013927', (326, 341))	('portal hypertensive', 'Phenotype', 'HP:0001409', (152, 171))	('ascites', 'Disease', 'MESH:D001201', (191, 198))	('hypertensive', 'Disease', 'MESH:D006973', (159, 171))	('splenomegaly', 'Disease', (200, 212))	('venous thrombus', 'Disease', (326, 341))	('portal hepatic blood flow', 'MPA', (84, 109))	('ascites', 'Phenotype', 'HP:0001541', (191, 198))
113274	23304539	Among the factors exacerbating ascites, significant differences were noted in patients with hypoalbuminemia (P = 0.0067), hyperbilirubinemia (P = 0.0342), low PT% (P = 0.0076), and high Child-Pugh score (P = 0.0023) (Table 3).	('hypoalbuminemia', 'Disease', 'MESH:D034141', (92, 107))	('exacerbating', 'PosReg', (18, 30))	('hyperbilirubinemia', 'Phenotype', 'HP:0002904', (122, 140))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (92, 107))	('hypoalbuminemia', 'Disease', (92, 107))	('low PT%', 'Var', (155, 162))	('ascites', 'Disease', (31, 38))	('patients', 'Species', '9606', (78, 86))	('ascites', 'Phenotype', 'HP:0001541', (31, 38))	('hyperbilirubinemia', 'Disease', (122, 140))	('ascites', 'Disease', 'MESH:D001201', (31, 38))	('Child', 'Species', '9606', (186, 191))	('low PT', 'Phenotype', 'HP:0032198', (155, 161))	('hyperbilirubinemia', 'Disease', 'MESH:D006932', (122, 140))
113286	23304539	On the other hand, ascites improved after BRTO in one patient.	('BRTO', 'Var', (42, 46))	('patient', 'Species', '9606', (54, 61))	('ascites', 'Disease', 'MESH:D001201', (19, 26))	('improved', 'PosReg', (27, 35))	('ascites', 'Phenotype', 'HP:0001541', (19, 26))	('ascites', 'Disease', (19, 26))
113292	23304539	In our study, pleural effusion was exacerbated after BRTO in 40.3% (31/77), and it was significant in the patients with hypoalbuminemia.	('pleural effusion', 'Disease', 'MESH:D010996', (14, 30))	('exacerbated', 'PosReg', (35, 46))	('pleural effusion', 'Disease', (14, 30))	('hypoalbuminemia', 'Disease', (120, 135))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (120, 135))	('pleural effusion', 'Phenotype', 'HP:0002202', (14, 30))	('BRTO', 'Var', (53, 57))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (120, 135))	('patients', 'Species', '9606', (106, 114))
113374	33681289	Additionally, it is generally accepted that TMEM16A dysfunction is associated with a variety of disease states, including cystic fibrosis, asthma, gastroparesis, hypertension, rotavirus-induced diarrhea and polycystic kidney disease.	('gastroparesis', 'Disease', (147, 160))	('cystic fibrosis', 'Disease', (122, 137))	('TMEM16A', 'Gene', (44, 51))	('asthma', 'Disease', 'MESH:D001249', (139, 145))	('hypertension', 'Disease', 'MESH:D006973', (162, 174))	('asthma', 'Phenotype', 'HP:0002099', (139, 145))	('diarrhea', 'Phenotype', 'HP:0002014', (194, 202))	('polycystic kidney', 'Phenotype', 'HP:0000113', (207, 224))	('hypertension', 'Disease', (162, 174))	('cystic fibrosis', 'Disease', 'MESH:D003550', (122, 137))	('asthma', 'Disease', (139, 145))	('dysfunction', 'Var', (52, 63))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (207, 232))	('diarrhea', 'Disease', (194, 202))	('hypertension', 'Phenotype', 'HP:0000822', (162, 174))	('kidney disease', 'Phenotype', 'HP:0000112', (218, 232))	('associated', 'Reg', (67, 77))	('diarrhea', 'Disease', 'MESH:D003967', (194, 202))	('gastroparesis', 'Phenotype', 'HP:0002578', (147, 160))	('gastroparesis', 'Disease', 'MESH:D018589', (147, 160))	('polycystic kidney disease', 'Disease', (207, 232))
113389	33681289	These findings suggested that TMEM16A was used as a potential marker to predict clinical outcome of BC subtypes as defined by the ER, PR and HER2, and Ki67 status.	('HER2', 'Gene', '2064', (141, 145))	('Ki67', 'Var', (151, 155))	('TMEM16A', 'Gene', (30, 37))	('ER', 'Gene', '2099', (142, 144))	('PR', 'Gene', '5241', (134, 136))	('ER', 'Gene', '2099', (130, 132))	('HER2', 'Gene', (141, 145))
113391	33681289	Moreover, TMEM16A silencing effectively reduced BC cell proliferation, especially in combination with EGFR inhibitors.	('silencing', 'Var', (18, 27))	('BC cell proliferation', 'CPA', (48, 69))	('reduced', 'NegReg', (40, 47))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('TMEM16A', 'Gene', (10, 17))
113393	33681289	treated HER2-amplified SKBR3 cells with T16A-inhAO1 (a small molecule inhibitor of TMEM16A Cl-channel) and untreated cells served as the control group.	('HER2', 'Gene', (8, 12))	('T16A-inhAO1', 'Var', (40, 51))	('SKBR3', 'CellLine', 'CVCL:0033', (23, 28))	('HER2', 'Gene', '2064', (8, 12))	('T16A', 'Mutation', 'rs1211697061', (40, 44))
113398	33681289	Recently, copper reduction has emerged as a novel therapeutic strategy in the treatment of metastatic cancer.	('copper', 'Chemical', 'MESH:D003300', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('reduction', 'NegReg', (17, 26))	('copper', 'Var', (10, 16))
113405	33681289	TMEM16A overexpression and depletion in HNSCC cell lines caused parallel changes in the ATP7B expression level.	('overexpression', 'PosReg', (8, 22))	('expression level', 'MPA', (94, 110))	('ATP7B', 'Gene', (88, 93))	('depletion', 'Var', (27, 36))	('changes', 'Reg', (73, 80))	('TMEM16A', 'Gene', (0, 7))	('ATP7B', 'Gene', '540', (88, 93))
113409	33681289	Similarly, the pharmacological inhibition of MEK/ERK and the genetic inactivation of ERK1/2 eliminated the cancer promoting effect of TMEM16A.	('eliminated', 'NegReg', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('MEK', 'Gene', (45, 48))	('MEK', 'Gene', '5609', (45, 48))	('genetic inactivation', 'Var', (61, 81))	('TMEM16A', 'Gene', (134, 141))	('ERK', 'Gene', '5594', (85, 88))	('ERK', 'Gene', (85, 88))	('ERK1/2', 'Gene', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ERK1/2', 'Gene', '5595;5594', (85, 91))	('ERK', 'Gene', '5594', (49, 52))	('cancer', 'Disease', (107, 113))	('ERK', 'Gene', (49, 52))
113416	33681289	proved that the inhibition of TMEM16A and EGFR in a simultaneous manner could improve the reaction to cetuximab.	('reaction to cetuximab', 'MPA', (90, 111))	('improve', 'PosReg', (78, 85))	('EGFR', 'Gene', '1956', (42, 46))	('TMEM16A', 'Gene', (30, 37))	('EGFR', 'Gene', (42, 46))	('cetuximab', 'Chemical', 'MESH:D000068818', (102, 111))	('inhibition', 'Var', (16, 26))
113419	33681289	In contrast, targeting TMEM16A improved response to biologics designed for EGFR/HER family members.	('improved', 'PosReg', (31, 39))	('TMEM16A', 'Gene', (23, 30))	('targeting', 'Var', (13, 22))	('EGFR', 'Gene', '1956', (75, 79))	('ER', 'Gene', '2099', (81, 83))	('EGFR', 'Gene', (75, 79))	('response to biologics', 'MPA', (40, 61))
113427	33681289	implanted a specific cell of HNSCC cells expressing endogenous TMEM16A into the tongue of nude mice.	('endogenous', 'Var', (52, 62))	('TMEM16A', 'Gene', (63, 70))	('nude mice', 'Species', '10090', (90, 99))
113429	33681289	Significantly, TMEM16A knockdown led to a 60 percent increase in the viability of UM-SCC1 cell.	('viability of UM-SCC1 cell', 'CPA', (69, 94))	('knockdown', 'Var', (23, 32))	('TMEM16A', 'Gene', (15, 22))	('increase', 'PosReg', (53, 61))	('UM-SCC1', 'CellLine', 'CVCL:7707', (82, 89))
113430	33681289	In addition, when the UM-SCC1 cell proliferation was inhibited after transduced with TMEM16A lentivral shRNA.	('TMEM16A', 'Gene', (85, 92))	('transduced', 'Var', (69, 79))	('inhibited', 'NegReg', (53, 62))	('UM-SCC1', 'CellLine', 'CVCL:7707', (22, 29))
113434	33681289	The wound healing time of SCC-25 cells transfected with TMEM16A-shRNA lentivirus was significantly increased, which further enriched our understanding of the role of TMEM16A in OSCC and HNSCC cell migration.	('TMEM16A-shRNA', 'Var', (56, 69))	('SCC-25', 'CellLine', 'CVCL:1682', (26, 32))	('wound healing time', 'CPA', (4, 22))	('increased', 'PosReg', (99, 108))
113444	33681289	Vitro studies have shown that knockdown of TMEM16A inhibited the proliferation of KYSE30 and KYSE510 cells (ESCC cell lines).	('inhibited', 'NegReg', (51, 60))	('KYSE510', 'CellLine', 'CVCL:1354', (93, 100))	('TMEM16A', 'Gene', (43, 50))	('knockdown', 'Var', (30, 39))
113445	33681289	The results showed that high TMEM16A expression was significantly associated with lymph node metastasis, late tumor staging, and OS severity.	('associated', 'Reg', (66, 76))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('TMEM16A', 'Gene', (29, 36))	('lymph node metastasis', 'CPA', (82, 103))	('high', 'Var', (24, 28))	('expression', 'MPA', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
113451	33681289	In addition, the proliferation of PC-3 cells in TMEM16A silencing group was significantly reduced.	('proliferation', 'CPA', (17, 30))	('TMEM16A', 'Gene', (48, 55))	('silencing', 'Var', (56, 65))	('reduced', 'NegReg', (90, 97))	('PC-3', 'CellLine', 'CVCL:0035', (34, 38))
113455	33681289	TMEM16A silencing could up-regulate the expression of TNF-alpha, thus promoting the TNF-alpha signal and eventually leading to the induction of apoptosis and inhibiting the growth of tumor.	('expression', 'MPA', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('inhibiting', 'NegReg', (158, 168))	('up-regulate', 'PosReg', (24, 35))	('TNF-alpha', 'Gene', '7124', (54, 63))	('silencing', 'Var', (8, 17))	('promoting', 'PosReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('apoptosis', 'CPA', (144, 153))	('TNF-alpha', 'Gene', '7124', (84, 93))	('leading to', 'Reg', (116, 126))	('tumor', 'Disease', (183, 188))	('TNF-alpha', 'Gene', (84, 93))	('TNF-alpha', 'Gene', (54, 63))	('TMEM16A', 'Gene', (0, 7))
113462	33681289	These findings were confirmed by using Western blotting analysis in a subsequently manner, and the protein level of E-cadherin was elevated after the knockdown.	('elevated', 'PosReg', (131, 139))	('E-cadherin', 'Gene', (116, 126))	('E-cadherin', 'Gene', '999', (116, 126))	('knockdown', 'Var', (150, 159))	('protein level of', 'MPA', (99, 115))
113463	33681289	Furthermore, the results of clinical studies shown that the amplification and overexpression of TMEM16A showed a positive correlation with tumor node metastasis (TNM) staging and lymph node metastasis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('amplification', 'Var', (60, 73))	('overexpression', 'PosReg', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('lymph node metastasis', 'CPA', (179, 200))	('TMEM16A', 'Gene', (96, 103))
113464	33681289	Importantly, TMEM16A knockdown up-regulated E-cadherin by damaging TGF-beta secretion to prevent GC cell migration and invasion.	('TGF-beta', 'Gene', '7039', (67, 75))	('up-regulated', 'PosReg', (31, 43))	('prevent', 'NegReg', (89, 96))	('invasion', 'CPA', (119, 127))	('E-cadherin', 'Gene', (44, 54))	('GC cell migration', 'CPA', (97, 114))	('E-cadherin', 'Gene', '999', (44, 54))	('TGF-beta', 'Gene', (67, 75))	('damaging', 'NegReg', (58, 66))	('TMEM16A', 'Gene', (13, 20))	('secretion', 'MPA', (76, 85))	('knockdown', 'Var', (21, 30))
113466	33681289	CRC's genes are unstable, and its progress can best reflect the multi-stage transformation of tumorigenesis, including mutation activation of oncogenes and inactivation of tumor suppressor genes.	('activation', 'PosReg', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mutation', 'Var', (119, 127))	('CRC', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (94, 99))	('inactivation', 'Var', (156, 168))	('oncogenes', 'Gene', (142, 151))
113469	33681289	Hence, the study verified that TMEM16A knockdown blocked cell-cycle progression in SW620 cells, and thus inhibited the growth of TMEM16A shRNA cells.	('cell-cycle progression', 'CPA', (57, 79))	('inhibited', 'NegReg', (105, 114))	('knockdown', 'Var', (39, 48))	('SW620', 'CellLine', 'CVCL:0547', (83, 88))	('TMEM16A', 'Gene', (31, 38))	('blocked', 'NegReg', (49, 56))	('growth', 'CPA', (119, 125))
113470	33681289	GIST is a mesenchymal tumor based on the carcinogenic mutation of the stem cell factor receptor (KIT) or the platelet-derived growth factor receptor alpha (PDGFRA) gene, which can be treated with a tyrosine kinase inhibitor (TKI), such as imatinib.	('mutation', 'Var', (54, 62))	('KIT', 'Gene', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('carcinogenic', 'Disease', 'MESH:D063646', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('carcinogenic', 'Disease', (41, 53))	('PDGFRA', 'Gene', (156, 162))	('imatinib', 'Chemical', 'MESH:D000068877', (239, 247))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (109, 154))	('tumor', 'Disease', (22, 27))	('PDGFRA', 'Gene', '5156', (156, 162))	('platelet-derived growth factor receptor alpha', 'Gene', (109, 154))	('KIT', 'Gene', '3815', (97, 100))
113475	33681289	In the study, only 9% of PDGFRA mutations in GIST (3/32) were positive for KIT, whereas DOG1.1 was positive in most (23/29; 78%).	('DOG1', 'Gene', (88, 92))	('PDGFRA', 'Gene', (25, 31))	('KIT', 'Gene', '3815', (75, 78))	('PDGFRA', 'Gene', '5156', (25, 31))	('positive', 'Reg', (62, 70))	('KIT', 'Gene', (75, 78))	('mutations', 'Var', (32, 41))	('DOG1', 'Gene', '55107', (88, 92))
113478	33681289	It is noteworthy that TMEM16A knockdown resulted in 96% inhibition of chloride ion outflow in GIST-T1 and 90% inhibition in GIST882 by whole-cell patch-clamp experiments, indicating that TMEM16A is a key regulator for GIST cells to balance chloride balance.	('inhibition', 'NegReg', (56, 66))	('inhibition', 'NegReg', (110, 120))	('chloride', 'Chemical', 'MESH:D002712', (70, 78))	('TMEM16A', 'Gene', (22, 29))	('chloride ion outflow', 'MPA', (70, 90))	('knockdown', 'Var', (30, 39))	('chloride', 'Chemical', 'MESH:D002712', (240, 248))
113480	33681289	Furthermore, after TMEM16A blockade, the expression profiles of explants showed strong upregulation of IGFBP5 (a potent antiangiogenic factor associated with tumor suppression).	('tumor', 'Disease', (158, 163))	('TMEM16A', 'Gene', (19, 26))	('blockade', 'Var', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('IGFBP5', 'Gene', (103, 109))	('IGFBP5', 'Gene', '3488', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('upregulation', 'PosReg', (87, 99))
113486	33681289	Meanwhile, researchers injected SMMC-7721 cells transfected TMEM16A shRNA and NC-shRNA respectively into nude mice.	('TMEM16A', 'Gene', (60, 67))	('transfected', 'Var', (48, 59))	('nude mice', 'Species', '10090', (105, 114))	('SMMC-7721', 'CellLine', 'CVCL:0534', (32, 41))
113489	33681289	Therefore, researchers believed that high expression of TMEM16A in HCC induced cell cycle arrest, but does not affected apoptosis.	('arrest', 'Disease', 'MESH:D006323', (90, 96))	('high expression', 'Var', (37, 52))	('TMEM16A', 'Gene', (56, 63))	('arrest', 'Disease', (90, 96))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (79, 96))
113491	33681289	Moreover, MTT and invasion assays results showed that knockdown of TMEM16A could significantly inhibited the proliferation of SMMC-7721 cells and decreased SMMC-7721 cells migration and invasion.	('SMMC-7721', 'CellLine', 'CVCL:0534', (126, 135))	('knockdown', 'Var', (54, 63))	('inhibited', 'NegReg', (95, 104))	('TMEM16A', 'Gene', (67, 74))	('decreased', 'NegReg', (146, 155))	('MTT', 'Chemical', 'MESH:C070243', (10, 13))	('SMMC-7721', 'CellLine', 'CVCL:0534', (156, 165))	('proliferation of SMMC-7721 cells', 'CPA', (109, 141))
113526	33681289	On the one hand, researchers found that TMEM16A promoter hypermethylation promoted metastasis but inhibited proliferation of TMEM16A overexpressing cancer cells, with opposite effects when the promoter was hypomethylated.	('cancer', 'Disease', (148, 154))	('promoted', 'PosReg', (74, 82))	('promoter hypermethylation', 'Var', (48, 73))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('metastasis', 'CPA', (83, 93))	('TMEM16A', 'Gene', (125, 132))	('inhibited', 'NegReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('TMEM16A', 'Gene', (40, 47))	('proliferation', 'CPA', (108, 121))	('hypermethylation', 'Var', (57, 73))
113527	33681289	On the other hand, researchers found that TMEM16A was the direct target of miR-132 and TMEM16A overexpression was inversely associated with downregulation of miR-132 in human CRC.	('TMEM16A', 'Gene', (87, 94))	('miR-132', 'Gene', '406921', (158, 165))	('downregulation', 'NegReg', (140, 154))	('miR-132', 'Gene', '406921', (75, 82))	('miR-132', 'Gene', (75, 82))	('human', 'Species', '9606', (169, 174))	('overexpression', 'Var', (95, 109))	('miR-132', 'Gene', (158, 165))
113537	33681289	More importantly, the abnormal expression TMEM16A was significantly linked with poor overall survival of patients with GC, esophageal cancer, and CRC.	('TMEM16A', 'Gene', (42, 49))	('linked', 'Reg', (68, 74))	('esophageal cancer', 'Disease', (123, 140))	('CRC', 'Disease', (146, 149))	('patients', 'Species', '9606', (105, 113))	('poor', 'NegReg', (80, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('overall survival', 'MPA', (85, 101))	('abnormal', 'Var', (22, 30))
113539	33681289	In addition, studies showed that TMEM16A gene amplification and protein overexpression affect the clinical outcomes of HNSCC patients, especially HPV-negative HNSCC patients.	('clinical outcomes', 'CPA', (98, 115))	('affect', 'Reg', (87, 93))	('amplification', 'Var', (46, 59))	('TMEM16A', 'Gene', (33, 40))	('patients', 'Species', '9606', (165, 173))	('overexpression', 'PosReg', (72, 86))	('protein', 'Protein', (64, 71))	('HNSCC', 'Disease', (119, 124))	('patients', 'Species', '9606', (125, 133))
113542	33681289	Studies demonstrated that combined with clinically relevant markers such as ER, PR, HER2 and Ki67, the expression of TMEM16A may help predict the clinical prognosis of BC patients.	('PR', 'Gene', '5241', (80, 82))	('HER2', 'Gene', (84, 88))	('ER', 'Gene', '2099', (76, 78))	('HER2', 'Gene', '2064', (84, 88))	('patients', 'Species', '9606', (171, 179))	('predict', 'Reg', (134, 141))	('ER', 'Gene', '2099', (85, 87))	('expression', 'Var', (103, 113))	('TMEM16A', 'Gene', (117, 124))
113547	33681289	The expression of TMEM16A was confirmed to be related to the progression of precancerous lesions in 148 cases of intraepithelial lesions, and three-quarters of patients with high TMEM16A expression developed ESCC (34 cases) within 4-9 years after initial diagnosis.	('precancerous lesions', 'Disease', 'MESH:D011230', (76, 96))	('ESCC', 'Disease', (208, 212))	('patients', 'Species', '9606', (160, 168))	('precancerous lesions', 'Disease', (76, 96))	('related', 'Reg', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('high', 'Var', (174, 178))	('TMEM16A', 'Gene', (179, 186))
113552	33681289	Kaplan-Meier survival analysis showed that tumor patients with high expression of TMEM16A had lower overall survival rates (P<0.04, log-rank test).	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('TMEM16A', 'Gene', (82, 89))	('overall survival rates', 'CPA', (100, 122))	('high expression', 'Var', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('lower', 'NegReg', (94, 99))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Disease', (43, 48))
113569	33681289	Of note, epigenetics is related to the occurrence and development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('related', 'Reg', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('epigenetics', 'Var', (9, 20))	('cancer', 'Disease', (69, 75))
113571	33681289	Subsequently, the methylation of the TMEM16A promoter could regulate the protein level of TMEM16A in cancer cells.	('TMEM16A', 'Gene', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('protein level', 'MPA', (73, 86))	('regulate', 'Reg', (60, 68))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('TMEM16A', 'Gene', (37, 44))	('methylation', 'Var', (18, 29))
113579	33681289	Notably, gene editing, a hot topic in current research, may also provide an effective means for cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('gene editing', 'Var', (9, 21))
113580	33681289	shown that the lack of PTEN can mobilize a variety of cancer cell survival and host immunity.	('lack', 'Var', (15, 19))	('PTEN', 'Protein', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('host immunity', 'CPA', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mobilize', 'PosReg', (32, 40))
113586	33681289	At present, TMEM16A has been widely used in the prognostic study of BC and HNSCC, and its abnormal expression is closely linked with the prognosis of tumor.	('linked', 'Reg', (121, 127))	('TMEM16A', 'Gene', (12, 19))	('abnormal', 'Var', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
113590	33681289	Although the abnormal expression of TMEM16A in cancer for clinical detection and treatment of cancer to bring hope, but its role in different cancers is not the same, what is the cause of this difference is unknown; the future more research is needed to uncover its mysterious.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', (47, 53))	('TMEM16A', 'Gene', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('abnormal', 'Var', (13, 21))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', (142, 148))
113592	33681289	The aberrant expression of TMEM16A in malignant tumors suggested the opportunity for developing it as a clinical biomarker for prevention and early detection of cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('aberrant', 'Var', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('malignant tumors', 'Disease', (38, 54))	('malignant tumors', 'Disease', 'MESH:D009369', (38, 54))	('cancer', 'Disease', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('TMEM16A', 'Gene', (27, 34))
113598	33681289	In summary, it can regulate the life course of tumors, and the abnormal expression of TMEM16A in malignant tumors provides the possibility to prevent tumors and find clinical biomarkers for early diagnosis.	('tumors', 'Disease', (150, 156))	('regulate', 'Reg', (19, 27))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('abnormal', 'Var', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('prevent', 'NegReg', (142, 149))	('malignant tumors', 'Disease', (97, 113))	('malignant tumors', 'Disease', 'MESH:D009369', (97, 113))	('TMEM16A', 'Gene', (86, 93))
113608	32032585	The fourth subtype was characterized by DNA hypomethylation associated with structural rearrangements, copy number alterations, with preferential amplification for CCNE1 (cells with this gene amplification have been reported to be sensitive to CDK2 inhibitors).	('men', 'Species', '9606', (96, 99))	('CDK2', 'Gene', (244, 248))	('CCNE1', 'Gene', '898', (164, 169))	('CCNE1', 'Gene', (164, 169))	('alterations', 'Var', (115, 126))	('copy number alterations', 'Var', (103, 126))	('CDK2', 'Gene', '1017', (244, 248))	('preferential', 'PosReg', (133, 145))	('associated', 'Reg', (60, 70))
113628	32032585	Compared to its older version Illumina HumanMethylation450 BeadChip (450K, Illumina Inc.) over 90% of 450K probes are included in EPIC along with increased coverage over distal regulatory elements.	('probes', 'Var', (107, 113))	('450K', 'Gene', (102, 106))	('men', 'Species', '9606', (191, 194))
113641	32032585	TP53 and CDKN2A are the two most frequently altered genes across the cohort as expected, wherein TP53 is more preferentially mutated in Subtype 1 (78%) and Subtype 4 (78%) whereas in Subtype 2 and Subtype 3, 37% and 46% are altered.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('CDKN2A', 'Gene', '1029', (9, 15))	('TP53', 'Gene', '7157', (97, 101))	('mutated', 'Var', (125, 132))	('TP53', 'Gene', (97, 101))	('CDKN2A', 'Gene', (9, 15))
113652	32032585	This showed that for hypermethylation 77% of regions are marked by H3K27me3 and 23% by H3K27ac (Figure 2C) across all tissues.	('H3K27me3', 'Protein', (67, 75))	('hyper', 'Disease', (21, 26))	('H3K27ac', 'Chemical', '-', (87, 94))	('H3K27ac', 'Var', (87, 94))	('hyper', 'Disease', 'MESH:D053306', (21, 26))
113669	32032585	Widespread hypomethylation has been observed in both early and late stages of many cancer types including BE and EAC causing upregulation of certain coding and non-coding regions.	('upregulation', 'PosReg', (125, 137))	('hypomethylation', 'Var', (11, 26))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
113673	32032585	On a case by case basis, patients in Group 4 with low levels of methylation harbour a high level of SVs (figure 5D), in keeping with the idea that methylation levels may be important for maintaining genome stability.	('SVs', 'MPA', (100, 103))	('methylation', 'Var', (64, 75))	('patients', 'Species', '9606', (25, 33))
113675	32032585	Of the 237 genes with significantly lower expression in relation to increased methylation (Supplementary Table 3), few genes seem to be affected globally across all subtypes, with most silenced genes being more specific to Subtype 1 and 2 (Figure 6A).	('lower', 'NegReg', (36, 41))	('methylation', 'Var', (78, 89))	('men', 'Species', '9606', (97, 100))	('expression', 'MPA', (42, 52))	('increased', 'PosReg', (68, 77))
113677	32032585	We also observe that a few immune regulators (BLNK, CD40, VAV3, IRS2) are also affected by methylation.	('methylation', 'Var', (91, 102))	('CD40', 'Gene', (52, 56))	('BLNK', 'Gene', (46, 50))	('VAV3', 'Gene', (58, 62))	('IRS2', 'Gene', '8660', (64, 68))	('VAV3', 'Gene', '10451', (58, 62))	('affected', 'Reg', (79, 87))	('BLNK', 'Gene', '29760', (46, 50))	('IRS2', 'Gene', (64, 68))	('CD40', 'Gene', '958', (52, 56))
113678	32032585	Previous work has shown that the MGMT gene, a key regulator in DNA repair, is methylated in nearly 50% of glioblastoma cases and these patients benefited from temozolomide chemotherapy more than patients with an unmethylated MGMT promoter.	('patients', 'Species', '9606', (135, 143))	('methylated', 'Var', (78, 88))	('glioblastoma', 'Disease', (106, 118))	('MGMT', 'Gene', (33, 37))	('MGMT', 'Gene', (225, 229))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('temozolomide', 'Chemical', 'MESH:D000077204', (159, 171))	('MGMT', 'Gene', '4255', (33, 37))	('benefited', 'PosReg', (144, 153))	('MGMT', 'Gene', '4255', (225, 229))	('patients', 'Species', '9606', (195, 203))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('temozolomide chemotherapy', 'MPA', (159, 184))
113681	32032585	High sensitivity to Temozolomide was observed in organoids showing low expression of MGMT at both RNA and protein level such as CAM277, in contrast, organoids with stable MGMT expression showing resistance, for example in CAM408 (Figure 6D,E and S6E).	('Temozolomide', 'Chemical', 'MESH:D000077204', (20, 32))	('expression', 'MPA', (71, 81))	('CAM408', 'Var', (222, 228))	('CAM277', 'Var', (128, 134))	('MGMT', 'Gene', (85, 89))	('MGMT', 'Gene', '4255', (171, 175))	('MGMT', 'Gene', '4255', (85, 89))	('MGMT', 'Gene', (171, 175))	('low', 'NegReg', (67, 70))
113682	32032585	Similarly, CHFR, a cell cycle check point inhibitor, is methylated in many cancer types; in squamous cell carcinoma CHFR methylation sensitizes to taxane chemotherapy.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('CHFR', 'Gene', (11, 15))	('CHFR', 'Gene', '55743', (11, 15))	('squamous cell carcinoma CHFR', 'Disease', (92, 120))	('squamous cell carcinoma CHFR', 'Disease', 'MESH:D002294', (92, 120))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('sensitizes', 'Reg', (133, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('methylation', 'Var', (121, 132))	('CHFR', 'Gene', (116, 120))	('taxane', 'Chemical', 'MESH:C080625', (147, 153))	('CHFR', 'Gene', '55743', (116, 120))
113684	32032585	In our earlier driver gene analysis, we have shown that more than 50% of EAC (n=551) are predicted to benefit from CDK4/6 inhibitors along with EZH2 and BET inhibitors in a smaller proportion of cases.	('CDK4/6', 'Gene', (115, 121))	('EAC', 'Disease', (73, 76))	('EZH2', 'Gene', (144, 148))	('EZH2', 'Gene', '2146', (144, 148))	('BET', 'Gene', '92737', (153, 156))	('inhibitors', 'Var', (122, 132))	('CDK4/6', 'Gene', '1019;1021', (115, 121))	('BET', 'Gene', (153, 156))	('benefit', 'PosReg', (102, 109))
113696	32032585	It is also worth noting that Subtype 3 has a high prevalence of MDM2 amplification (8%), which is associated with resistance to and hyper-progression on immunotherapy.	('associated with', 'Reg', (98, 113))	('MDM2', 'Gene', '4193', (64, 68))	('MDM2', 'Gene', (64, 68))	('hyper', 'Disease', 'MESH:D053306', (132, 137))	('hyper', 'Disease', (132, 137))	('amplification', 'Var', (69, 82))
113705	32032585	In summary, this study elucidates diversity in the methylation landscape across BE and EAC and its influence on gene expression and genome integrity, suggesting a role for DNA methylation alteration in EAC carcinogenesis.	('methylation', 'Var', (176, 187))	('EAC carcinogenesis', 'Disease', 'MESH:C536611', (202, 220))	('alteration', 'Var', (188, 198))	('EAC carcinogenesis', 'Disease', (202, 220))
113744	30854040	To validate the microarray data, RT-qPCR was performed to detect the expression level of certain selected differentially-expressed miRNAs, including miR-664b-5p, miR-767-5p, miR-223-3p, miR-203a and miR-375.	('miR-664b', 'Gene', (149, 157))	('miR-767-5p', 'Var', (162, 172))	('miR-203a', 'Gene', (186, 194))	('miR-664b', 'Gene', '100847052', (149, 157))	('miR-375', 'Gene', '494324', (199, 206))	('miR-223-3p', 'Var', (174, 184))	('miR-203a', 'Gene', '406986', (186, 194))	('miR-375', 'Gene', (199, 206))
113757	30854040	Similar to the current study, Li et al demonstrated that miR-203a is downregulated in ESCC samples and the transfection of miR-203a in cells mimicking esophageal cancer inhibited their proliferation and invasive capacity, indicating that miR-203a serves a tumor suppressor role.	('miR-203a', 'Gene', (123, 131))	('miR-203a', 'Gene', '406986', (57, 65))	('miR-203a', 'Gene', '406986', (123, 131))	('esophageal cancer', 'Disease', (151, 168))	('proliferation', 'CPA', (185, 198))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('miR-203a', 'Gene', '406986', (238, 246))	('downregulated', 'NegReg', (69, 82))	('transfection', 'Var', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('miR-203a', 'Gene', (238, 246))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('miR-203a', 'Gene', (57, 65))	('inhibited', 'NegReg', (169, 178))	('tumor', 'Disease', (256, 261))	('ESCC', 'Disease', (86, 90))	('invasive capacity', 'CPA', (203, 220))
113764	30854040	Additionally, RT-qPCR was used to detect the expression levels of certain miRNAs, including miR-664b-5p, miR-767-5p, miR-223-3p, miR-203a and miR-375, which were identified to be differentially expressed using microarray analysis.	('miR-203a', 'Gene', (129, 137))	('miR-203a', 'Gene', '406986', (129, 137))	('miR-375', 'Gene', (142, 149))	('miR-767-5p', 'Var', (105, 115))	('miR-664b', 'Gene', (92, 100))	('expression', 'MPA', (45, 55))	('miR-223-3p', 'Var', (117, 127))	('miR-664b', 'Gene', '100847052', (92, 100))	('miR-375', 'Gene', '494324', (142, 149))
113769	30854040	According to a previous study, abnormal expression of glycolipids in tissues and organs may lead to carcinogenesis, and the abnormal metabolism of steroids is closely associated with the occurrence, metastasis and treatment of tumors.	('expression', 'MPA', (40, 50))	('abnormal', 'Var', (31, 39))	('steroids', 'Chemical', 'MESH:D013256', (147, 155))	('lead to', 'Reg', (92, 99))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('abnormal metabolism', 'Phenotype', 'HP:0032245', (124, 143))	('metabolism', 'MPA', (133, 143))	('associated', 'Reg', (167, 177))	('carcinogenesis', 'CPA', (100, 114))	('glycolipid', 'Chemical', 'MESH:D006017', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
113772	30854040	Therefore, the abnormal absorption of calcium ions in cells may be closely associated with tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('absorption of calcium ions', 'MPA', (24, 50))	('abnormal', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('associated', 'Reg', (75, 85))	('tumor', 'Disease', (91, 96))	('calcium', 'Chemical', 'MESH:D002118', (38, 45))
113787	30854040	In conclusion, the current study performed a preliminary analysis of the biological effects of differentially expressed miRNAs in ESCC in Kazakh patients, which may be associated with the occurrence of the disease.	('patients', 'Species', '9606', (145, 153))	('associated', 'Reg', (168, 178))	('miRNAs', 'Protein', (120, 126))	('ESCC', 'Disease', (130, 134))	('differentially expressed', 'Var', (95, 119))
113801	30800172	In addition, emerging evidences have implied as well that miRNAs can affect the occurrence and development of various tumors by regulating the signaling pathways in which their target genes are involved and play a role similar to oncogenes or tumor suppressor genes.	('occurrence', 'CPA', (80, 90))	('affect', 'Reg', (69, 75))	('development', 'CPA', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('signaling pathways', 'Pathway', (143, 161))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Disease', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('miRNAs', 'Var', (58, 64))	('tumors', 'Disease', (118, 124))	('regulating', 'Reg', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
113808	30800172	Finally, in order to evaluate the prediction performance of NBMDA, global leave-one-out cross validation (global LOOCV) and 5-fold cross validation (5-fold CV) were implemented simultaneously, and simulation results demonstrated that NBMDA could achieve reliable AUCs of 0.8983/0.8153 and 0.8975 under the global LOOCV and 5-fold CV, respectively, which were higher than several state-of-the-art computational models.	('0.8983/0.8153', 'Var', (271, 284))	('NBMDA', 'Chemical', '-', (234, 239))	('0.8975', 'Var', (289, 295))	('NBMDA', 'Chemical', '-', (60, 65))
113827	30800172	It is easy to see that NBMDA, RLSMDA, and WBSMDA can achieve reliable AUCs of 0.8983/0.8153, 0.8501/0.7702, and 0.7740/0.7142, respectively.	('0.8983/0.8153', 'Var', (78, 91))	('0.8501/0.7702', 'Var', (93, 106))	('0.7740/0.7142', 'Var', (112, 125))	('NBMDA', 'Chemical', '-', (23, 28))
113847	30800172	MiR-200c-141, miR-200b-200a-429, and miR-183-96-182 are downregulated in human breast cancer stem cells.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('miR-183', 'Gene', '406959', (37, 44))	('breast cancer', 'Disease', (79, 92))	('miR-183', 'Gene', (37, 44))	('MiR-200c-141', 'Var', (0, 12))	('human', 'Species', '9606', (73, 78))	('miR-200b', 'Gene', '406984', (14, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('downregulated', 'NegReg', (56, 69))	('miR-200b', 'Gene', (14, 22))
113868	30800172	And experimental results show that NBMDA can achieve reliable AUCs of 0.8983/0.8153 and 0.8975 in the frameworks of global LOOCV and 5-fold CV, respectively, which are much better than the AUCs achieved by state-of-the-art prediction models such as WBSMDA and RLSMDA.	('0.8975', 'Var', (88, 94))	('NBMDA', 'Chemical', '-', (35, 40))	('0.8983/0.8153', 'Var', (70, 83))
113880	29911659	Jacobian map measured the ratio of local tumor volume change where J < 1 indicated tumor shrinkage and J > 1 denoted expansion.	('expansion', 'PosReg', (117, 126))	('J > 1', 'Var', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('J < 1', 'Var', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
114009	28130162	A large proportion of these alterations in gene expression were associated with immune inflammatory responses, leading the authors to suggest that the pro-inflammatory expression can promote the development of additional polyps in the unaffected colon mucosa of patients with polyps.	('polyps', 'Disease', 'MESH:D011127', (221, 227))	('rat', 'Species', '10116', (32, 35))	('alterations', 'Var', (28, 39))	('patients', 'Species', '9606', (262, 270))	('colon mucosa', 'Disease', (246, 258))	('polyps', 'Disease', 'MESH:D011127', (276, 282))	('development', 'CPA', (195, 206))	('polyps', 'Disease', (221, 227))	('colon mucosa', 'Disease', 'MESH:D015179', (246, 258))	('polyps', 'Disease', (276, 282))	('promote', 'PosReg', (183, 190))	('pro-inflammatory expression', 'MPA', (151, 178))
114014	28130162	The requirement of T-cells for this progression was demonstrated through multiple means, including using T-cell-deficient crosses or T-cell receptor-deficient crosses of the TRAMP mice, and with T-cell reconstitution studies of these immune deficient mice.	('mice', 'Species', '10090', (251, 255))	('TRAMP', 'Gene', (174, 179))	('TRAMP', 'Gene', '85030', (174, 179))	('mice', 'Species', '10090', (180, 184))	('immune deficient', 'Phenotype', 'HP:0002721', (234, 250))	('crosses', 'Var', (159, 166))	('rat', 'Species', '10116', (59, 62))
114044	28130162	In contrast, a different study in which TGF-beta signaling was interrupted by deletion of Smad4 in T-cells showed increased levels of inflammatory and inhibitory cytokines, increased levels of Th17 cells and spontaneous development of premalignant lesions with the gastroduodenal regions of mice.	('mice', 'Species', '10090', (291, 295))	('Th17 cells', 'MPA', (193, 203))	('Smad4', 'Gene', (90, 95))	('levels', 'MPA', (183, 189))	('increased', 'PosReg', (114, 123))	('deletion', 'Var', (78, 86))	('premalignant lesions', 'CPA', (235, 255))	('increased', 'PosReg', (173, 182))	('Smad4', 'Gene', '17128', (90, 95))
114062	28130162	Consistent with these studies was demonstration that administration of selective inhibitors of cyclooxygenase-2 (COX-2) to rats diminishes the carcinogen-induced inflammatory NF-kB signaling pathways and retards development of colonic tumors.	('rats', 'Species', '10116', (123, 127))	('inhibitors', 'Var', (81, 91))	('cyclooxygenase-2', 'Gene', '29527', (95, 111))	('retards development', 'Phenotype', 'HP:0001263', (204, 223))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cyclooxygenase-2', 'Gene', (95, 111))	('rat', 'Species', '10116', (61, 64))	('retards development of colonic tumors', 'Disease', (204, 241))	('diminishes', 'NegReg', (128, 138))	('rat', 'Species', '10116', (123, 126))	('rat', 'Species', '10116', (41, 44))	('COX-2', 'Gene', (113, 118))	('COX-2', 'Gene', '29527', (113, 118))	('retards development of colonic tumors', 'Disease', 'MESH:D015179', (204, 241))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))
114102	28459652	It has long been known that unintentional weight loss is associated with more frequent side effects in patients with gastrointestinal (GI) cancer, whereas early nutrition intervention has been shown to improve clinical outcomes such as nutrition status, number of unplanned hospital admissions, and tolerance of the planned chemoradiation.	('weight loss', 'Disease', 'MESH:D015431', (42, 53))	('gastrointestinal (GI) cancer', 'Disease', 'MESH:D004067', (117, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('improve', 'PosReg', (202, 209))	('unintentional', 'Var', (28, 41))	('weight loss', 'Disease', (42, 53))	('nutrition status', 'MPA', (236, 252))	('weight loss', 'Phenotype', 'HP:0001824', (42, 53))	('patients', 'Species', '9606', (103, 111))
114270	28160546	Among patients with pT2-3 ESCC, the 5-year survival rate of patients with diffuse AE1 expression (40.2%) was significantly lower than that of patients with focal expression (74.0%).	('SCC', 'Gene', (27, 30))	('pT2-3', 'Var', (20, 25))	('lower', 'NegReg', (123, 128))	('patients', 'Species', '9606', (60, 68))	('SCC', 'Gene', '6317', (27, 30))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (142, 150))	('diffuse AE1', 'Var', (74, 85))	('survival', 'CPA', (43, 51))
114280	28160546	AE1 was unexpectedly found to be expressed and important for cell cycle progression in gastric and colonic cancers, and high AE1 levels have been associated with a poor prognosis.	('AE1 levels', 'MPA', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('high', 'Var', (120, 124))	('gastric and colonic cancers', 'Disease', 'MESH:D013274', (87, 114))	('associated', 'Reg', (146, 156))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
114286	28160546	In addition, microarray data revealed that the knocking down with AE1 siRNA affected a lot of genes related to mitogen-activated protein kinase (MAPK) and Hedgehog signaling.	('MAPK', 'Gene', '5594', (145, 149))	('MAPK', 'Gene', (145, 149))	('knocking down', 'Var', (47, 60))	('affected', 'Reg', (76, 84))	('AE1', 'Var', (66, 69))
114289	28160546	The median AE1 score was 1.8 (range=0-2.2; mean+-standard deviation (SD) = 1.54+-0.60), and patients were categorized into low (scores <1.8, n=28) and high expression groups (scores>=1.8, n=33) (Figure 1C-1D, Supplementary Figure 1A-1B).	('SD', 'Disease', 'MESH:D029461', (69, 71))	('scores', 'Var', (175, 181))	('patients', 'Species', '9606', (92, 100))	('AE1', 'Gene', (11, 14))
114293	28160546	Regarding pN category, frequency of lymph node metastasis tended to be higher in patents with diffuse AE1 expression (64.1%) than those with focal expression (40.9%) without significant difference (Table 1).	('higher', 'PosReg', (71, 77))	('lymph node metastasis', 'Disease', (36, 57))	('diffuse AE1 expression', 'Var', (94, 116))	('lymph node metastasis', 'Disease', 'MESH:D009362', (36, 57))
114296	28160546	Regarding the distribution pattern of AE1 in pT1 cases, the 5-year survival rate of the diffuse AE1 expression group (84.0%) was lower than that of the focal AE1 expression group (100%), but not significantly (p = 0.332) (Supplementary Table 1, Supplementary Figure 2).	('diffuse AE1 expression', 'Var', (88, 110))	('pT1', 'Gene', (45, 48))	('pT1', 'Gene', '58492', (45, 48))	('lower', 'NegReg', (129, 134))
114297	28160546	In patients with pT2-3 ESCC, the distribution pattern of AE1 was the strongest prognostic factor (p=0.039) (Table 2).	('SCC', 'Gene', (24, 27))	('SCC', 'Gene', '6317', (24, 27))	('patients', 'Species', '9606', (3, 11))	('pT2-3', 'Var', (17, 22))
114301	28160546	Further, the number of patients with lymphogenous recurrence was larger in the diffuse AE1 expression group (n=8, 42.1%) than in the focal AE1 expression group (n=2, 16.7%) without significant difference (p=0.14).	('patients', 'Species', '9606', (23, 31))	('diffuse AE1 expression', 'Var', (79, 101))	('lymphogenous recurrence', 'CPA', (37, 60))
114305	28160546	The knocking down of AE1 partially inhibited cell cycle process from the G1 to S phase in both KYSE150 and TE8 cells (Figure 4C).	('knocking down', 'Var', (4, 17))	('AE1', 'Gene', (21, 24))	('cell cycle process', 'CPA', (45, 63))	('inhibited', 'NegReg', (35, 44))	('KYSE150', 'CellLine', 'CVCL:1348', (95, 102))
114306	28160546	Cell number 72 h after transfection was lower in AE1 siRNA transfected KYSE150 cells than in control cells with significant differences (Figure 4D).	('AE1 siRNA transfected', 'Var', (49, 70))	('KYSE150', 'CellLine', 'CVCL:1348', (71, 78))	('lower', 'NegReg', (40, 45))	('Cell number', 'CPA', (0, 11))
114310	28160546	The AE1depletion increased early apoptosis (annexin V positive/PI negative) in KYSE150 and TE8 cell lines 48 h after siRNA transfection (Figure 5).	('AE1depletion', 'Var', (4, 16))	('KYSE150', 'CellLine', 'CVCL:1348', (79, 86))	('annexin V', 'Gene', (44, 53))	('annexin V', 'Gene', '308', (44, 53))
114312	28160546	In KYSE150 cells, AE1 siRNA significantly reduced cell migration and invasion (Figure 6).	('reduced', 'NegReg', (42, 49))	('AE1 siRNA', 'Var', (18, 27))	('KYSE150', 'CellLine', 'CVCL:1348', (3, 10))	('invasion', 'CPA', (69, 77))	('cell migration', 'CPA', (50, 64))
114315	28160546	The results revealed that the expressions of 3345 genes showed fold changes of > 2.0 in KYSE150 cell line upon the knockdown of AE1.	('expressions', 'MPA', (30, 41))	('KYSE150', 'CellLine', 'CVCL:1348', (88, 95))	('knockdown', 'Var', (115, 124))
114321	28160546	An analysis of the map of this pathway revealed that Hedgehog pathway-related genes were strongly down-regulated by the depletion of AE1 (Supplementary Figure 6A-6B), and also that MAPKs, such as "P38 MAPK", "JNK", and "ERK", were included in this map.	('MAPK', 'Gene', '5594', (181, 185))	('JNK"', 'Gene', '5599', (209, 213))	('MAPK', 'Gene', (181, 185))	('MAPK', 'Gene', '5594', (201, 205))	('depletion', 'Var', (120, 129))	('JNK"', 'Gene', (209, 213))	('ERK', 'Gene', (220, 223))	('P38', 'Gene', '5594', (197, 200))	('AE1', 'Var', (133, 136))	('MAPK', 'Gene', (201, 205))	('P38', 'Gene', (197, 200))	('Hedgehog pathway-related genes', 'Gene', (53, 83))	('ERK', 'Gene', '5594', (220, 223))	('down-regulated', 'NegReg', (98, 112))
114323	28160546	The gene expression profiles of AE1-depleted KYSE150 cells showed that several genes of MAPKs were down-regulated by the knockdown of AE1 (Table 3).	('down-regulated', 'NegReg', (99, 113))	('knockdown', 'Var', (121, 130))	('genes', 'MPA', (79, 84))	('KYSE150', 'CellLine', 'CVCL:1348', (45, 52))	('MAPK', 'Gene', '5594', (88, 92))	('MAPK', 'Gene', (88, 92))	('AE1', 'Var', (134, 137))
114327	28160546	The expression levels of DHH and GLI1 mRNA were decreased by the AE1 siRNA-transfection in KYSE150 cells (Figure 7B).	('expression levels', 'MPA', (4, 21))	('DHH', 'Protein', (25, 28))	('GLI1', 'Gene', '2735', (33, 37))	('decreased', 'NegReg', (48, 57))	('AE1 siRNA-transfection', 'Var', (65, 87))	('GLI1', 'Gene', (33, 37))	('KYSE150', 'CellLine', 'CVCL:1348', (91, 98))	('DHH', 'Species', '262775', (25, 28))
114337	28160546	A recent study showed that the transfection with miR-24 induced the return of p16 to the nucleus, confirming the miR-24-controlled AE1 down-regulation in gastric carcinoma.	('p16', 'Gene', (78, 81))	('down-regulation', 'NegReg', (135, 150))	('miR-24', 'Gene', (49, 55))	('gastric carcinoma', 'Disease', (154, 171))	('transfection', 'Var', (31, 43))	('miR-24', 'Chemical', '-', (113, 119))	('p16', 'Gene', '1029', (78, 81))	('miR-24', 'Chemical', '-', (49, 55))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (154, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('gastric carcinoma', 'Disease', 'MESH:D013274', (154, 171))
114338	28160546	Furthermore, AE1 expression in gastric carcinoma is associated with cellular alkalization, which plays a role in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('AE1 expression', 'Var', (13, 27))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (31, 48))	('associated', 'Reg', (52, 62))	('carcinogenesis', 'Disease', (113, 127))	('gastric carcinoma', 'Disease', 'MESH:D013274', (31, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('cellular alkalization', 'MPA', (68, 89))	('gastric carcinoma', 'Disease', (31, 48))
114339	28160546	The distribution pattern of AE1 also correlated with degree of the differentiation of SCC, and in non-cancerous esophageal epithelia, cells expressing AE1 were mainly observed in the lower and middle layer, and not detected in the basal and para-basal layers.	('SCC', 'Gene', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('non-cancerous esophageal epithelia', 'Disease', 'MESH:D004938', (98, 132))	('SCC', 'Gene', '6317', (86, 89))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (112, 132))	('non-cancerous esophageal epithelia', 'Disease', (98, 132))	('AE1', 'Var', (151, 154))
114344	28160546	In addition, based on the results of gene expression profiles in this report, we newly discovered that MAPK and Hedgehog signaling pathways are important networks regulated by AE1.	('AE1', 'Var', (176, 179))	('Hedgehog signaling pathways', 'Pathway', (112, 139))	('MAPK', 'Gene', '5594', (103, 107))	('MAPK', 'Gene', (103, 107))
114350	28160546	The results of the present study indicated the gene expression of these important factors in the Hedgehog signaling pathway, such as DHH, GLI1, and PTCH1, was changed by the knockdown of AE1, suggesting that AE1 regulates the tumor behavior of ESCC via this pathway.	('GLI1', 'Gene', '2735', (138, 142))	('SCC', 'Gene', '6317', (245, 248))	('changed', 'Reg', (159, 166))	('DHH', 'Species', '262775', (133, 136))	('regulates', 'Reg', (212, 221))	('GLI1', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('knockdown', 'Var', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('SCC', 'Gene', (245, 248))	('Hedgehog signaling pathway', 'Pathway', (97, 123))	('PTCH', 'Gene', '5727', (148, 152))	('PTCH', 'Gene', (148, 152))	('tumor', 'Disease', (226, 231))
114355	28160546	In ESCC, Hedgehog signaling-induced ERK activation was previously shown to be repressed by PD98059 and cyclopamine.	('SCC', 'Gene', (4, 7))	('ERK', 'Gene', '5594', (36, 39))	('PD98059', 'Chemical', 'MESH:C093973', (91, 98))	('SCC', 'Gene', '6317', (4, 7))	('ERK', 'Gene', (36, 39))	('activation', 'PosReg', (40, 50))	('PD98059', 'Var', (91, 98))	('cyclopamine', 'Chemical', 'MESH:C000541', (103, 114))
114356	28160546	An activation of Sonic Hedgehog enhanced proliferation, and this phenomenon was inhibited by a pre-incubation with cyclopamine and also by PD98059, suggesting that inactivation of ERK reduced the Hedgehog signaling-induced proliferation of ESCC cells.	('SCC', 'Gene', (241, 244))	('ERK', 'Gene', '5594', (180, 183))	('PD98059', 'Chemical', 'MESH:C093973', (139, 146))	('ERK', 'Gene', (180, 183))	('SCC', 'Gene', '6317', (241, 244))	('Hedgehog signaling-induced', 'Pathway', (196, 222))	('inactivation', 'Var', (164, 176))	('reduced', 'NegReg', (184, 191))	('enhanced', 'PosReg', (32, 40))	('Sonic', 'Gene', (17, 22))	('activation', 'PosReg', (3, 13))	('proliferation', 'CPA', (41, 54))	('cyclopamine', 'Chemical', 'MESH:C000541', (115, 126))
114361	28160546	Our previous reports revealed that the change of the [Cl-]i induced cell cycle arrest at the G0/G1 phase, and that the [Cl-]i controls the proliferation by affecting MAPKs in cancer cells.	('change', 'Var', (39, 45))	('cell cycle arrest at the G0/G1 phase', 'CPA', (68, 104))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('MAPK', 'Gene', '5594', (166, 170))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('MAPK', 'Gene', (166, 170))	('proliferation', 'CPA', (139, 152))	('affecting', 'Reg', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
114366	28160546	The results of an immunohistochemistry indicated that the diffuse AE1 expression was a valid poor prognostic indicator for advanced esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('esophageal cancer', 'Disease', (132, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('diffuse', 'Var', (58, 65))
114367	28160546	Our microarray analysis also suggests that AE1 markedly influences the gene expressions associated with the crosstalk between MAPK and Hedgehog signaling pathways.	('MAPK', 'Gene', (126, 130))	('influences', 'Reg', (56, 66))	('AE1', 'Var', (43, 46))	('Hedgehog signaling pathways', 'Pathway', (135, 162))	('gene expressions', 'MPA', (71, 87))	('MAPK', 'Gene', '5594', (126, 130))
114388	28160546	Regarding the pattern of distribution of AE1-expressing cells, we divided ESCC patients into 2 groups: focal AE1 expression (lesion with mosaic pattern staining >=50%) and diffuse AE1 expression (lesion with mosaic pattern staining<50%).	('SCC', 'Gene', '6317', (75, 78))	('mosaic pattern staining', 'Var', (137, 160))	('patients', 'Species', '9606', (79, 87))	('SCC', 'Gene', (75, 78))
114396	28160546	The expression levels of the following genes were measured: AE1 (Hs00978603_m1), DHH (Hs00368306_m1), and GLI1 (Hs00171790_m1) (Applied Biosystems).	('expression levels', 'MPA', (4, 21))	('Hs00978603_m1', 'Var', (65, 78))	('Hs00171790_m1', 'Var', (112, 125))	('GLI1', 'Gene', '2735', (106, 110))	('Hs00368306_m1', 'Var', (86, 99))	('DHH', 'Species', '262775', (81, 84))	('GLI1', 'Gene', (106, 110))
114441	27752108	We analyzed a cohort of 51 patients and found that hsa_circ_0067934 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues.	('overexpressed', 'PosReg', (86, 99))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('patients', 'Species', '9606', (27, 35))	('hsa_circ_0067934', 'Var', (51, 67))	('ESCC', 'Disease', (103, 107))	('hsa_circ_0067934', 'Chemical', '-', (51, 67))
114442	27752108	The high expression level of hsa_circ_0067934 was associated with poor differentiation (P = 0.025), I-II T stage (P = 0.04), and I-II TNM stage (P = 0.021).	('hsa_circ_0067934', 'Var', (29, 45))	('poor differentiation', 'CPA', (66, 86))	('I-II T', 'Disease', 'MESH:D056829', (129, 135))	('hsa_circ_0067934', 'Chemical', '-', (29, 45))	('I-II T', 'Disease', (100, 106))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('I-II TNM', 'Disease', 'MESH:D056829', (129, 137))	('high expression level', 'MPA', (4, 25))	('I-II T', 'Disease', 'MESH:D056829', (100, 106))	('I-II TNM', 'Disease', (129, 137))
114445	27752108	Our findings suggest that hsa_circ_0067934 is upregulated in ESCC tumor tissue.	('ESCC tumor', 'Disease', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('hsa_circ_0067934', 'Var', (26, 42))	('hsa_circ_0067934', 'Chemical', '-', (26, 42))	('ESCC tumor', 'Disease', 'MESH:D004938', (61, 71))	('upregulated', 'PosReg', (46, 57))
114461	27752108	According to the circBase database, has_circ_0067934 can be detected in many types of cancer cell lines, like K562 and A549.	('has_circ_0067934', 'Var', (36, 52))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('K562', 'CellLine', 'CVCL:0004', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('A549', 'CellLine', 'CVCL:0023', (119, 123))	('cancer', 'Disease', (86, 92))
114464	27752108	Therefore, in this study we characterized expression of hsa_circ_0067934 in ESCC and investigated its biological function in vitro.	('ESCC', 'Disease', (76, 80))	('hsa_circ_0067934', 'Var', (56, 72))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('hsa_circ_0067934', 'Chemical', '-', (56, 72))
114471	27752108	These results demonstrate hsa_circ_0067934 is consistently expressed in ESCC tumor tissues.	('hsa_circ_0067934', 'Var', (26, 42))	('hsa_circ_0067934', 'Chemical', '-', (26, 42))	('ESCC tumor', 'Disease', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ESCC tumor', 'Disease', 'MESH:D004938', (72, 82))	('si', 'Chemical', 'MESH:D012825', (49, 51))
114473	27752108	We found that hsa_circ_0067934 was significantly overexpressed in ESCC, and the average upregulation fold was 8.75 (p = 0.011) (Fig.	('upregulation', 'PosReg', (88, 100))	('overexpressed', 'PosReg', (49, 62))	('hsa_circ_0067934', 'Var', (14, 30))	('ESCC', 'Disease', (66, 70))	('hsa_circ_0067934', 'Chemical', '-', (14, 30))	('si', 'Chemical', 'MESH:D012825', (35, 37))
114476	27752108	As shown in Table 1, tumor differentiation, T stage, and TNM stage (P < 0.05) were significantly associated with the expression level of hsa_circ_0067934.	('TNM', 'Gene', '10178', (57, 60))	('T stage', 'CPA', (44, 51))	('tumor', 'Disease', (21, 26))	('hsa_circ_0067934', 'Var', (137, 153))	('expression', 'MPA', (117, 127))	('TNM', 'Gene', (57, 60))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('hsa_circ_0067934', 'Chemical', '-', (137, 153))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('associated', 'Reg', (97, 107))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
114485	27752108	We found hsa_circ_0067934 was most upregulated in TE-13 and ECA-109 cells.	('hsa_circ_0067934', 'Var', (9, 25))	('hsa_circ_0067934', 'Chemical', '-', (9, 25))	('ECA', 'Chemical', '-', (60, 63))	('upregulated', 'PosReg', (35, 46))	('TE-1', 'CellLine', 'CVCL:1759', (50, 54))
114492	27752108	qRT-PCR showed that si2-hsa_circ_0067934 had superior inhibition efficacy and si2-hsa_circ_0067934 was used in further functional experiments (Fig.	('si2-hsa_circ_0067934', 'Var', (20, 40))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('hsa_circ_0067934', 'Chemical', '-', (82, 98))	('inhibition', 'MPA', (54, 64))	('hsa_circ_0067934', 'Chemical', '-', (24, 40))
114496	27752108	Furthermore, the clone formation experiment also showed that si-hsa_circ_0067934 inhibited cell proliferation (Fig.	('si-hsa_circ_0067934', 'Chemical', '-', (61, 80))	('si-hsa_circ_0067934', 'Var', (61, 80))	('inhibited', 'NegReg', (81, 90))	('cell proliferation', 'CPA', (91, 109))
114497	27752108	We then performed flow cytometric analyses to further evaluate whether hsa_circ_0067934 affects proliferation of ESCC cells by altering apoptosis or cell cycle progression.	('altering', 'Reg', (127, 135))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('affects', 'Reg', (88, 95))	('apoptosis', 'CPA', (136, 145))	('hsa_circ_0067934', 'Var', (71, 87))	('si', 'Chemical', 'MESH:D012825', (167, 169))	('cell cycle progression', 'CPA', (149, 171))	('hsa_circ_0067934', 'Chemical', '-', (71, 87))
114498	27752108	TE-13 and ECA-109 cells transfected with si-hsa_circ_0067934 were arrested at the G2 phase (Fig.	('TE-1', 'CellLine', 'CVCL:1759', (0, 4))	('G2 phase', 'CPA', (82, 90))	('ECA', 'Chemical', '-', (10, 13))	('si-hsa_circ_0067934', 'Chemical', '-', (41, 60))	('si-hsa_circ_0067934', 'Var', (41, 60))
114500	27752108	In order to verify the cause of cell cycle change, the cyclin D protein levels were assessed in ESCC cells (Eca-109 cells and TE-13 cells) by western blot after si-hsa_circ_0067934 or si-NC transfection (Fig.	('si', 'Chemical', 'MESH:D012825', (184, 186))	('cyclin D protein levels', 'MPA', (55, 78))	('TE-1', 'CellLine', 'CVCL:1759', (126, 130))	('si-NC', 'Var', (184, 189))	('si-hsa_circ_0067934', 'Chemical', '-', (161, 180))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('cell cycle change', 'Phenotype', 'HP:0011018', (32, 49))	('si-hsa_circ_0067934', 'Var', (161, 180))
114503	27752108	Our results suggest that hsa_circ_0067934 promotes the motility and migration of ESCC cells and affects cell cycle status.	('motility', 'CPA', (55, 63))	('promotes', 'PosReg', (42, 50))	('affects', 'Reg', (96, 103))	('hsa_circ_0067934', 'Var', (25, 41))	('hsa_circ_0067934', 'Chemical', '-', (25, 41))	('migration', 'CPA', (68, 77))	('cell cycle status', 'CPA', (104, 121))
114510	27752108	Additionally, the lncRNAs HOTAIR and HNF1A-AS and microRNAs such as microRNA-98 and microRNA-214 are also associated with ESCC.	('associated', 'Reg', (106, 116))	('ESCC', 'Disease', (122, 126))	('HOTAIR', 'Gene', (26, 32))	('HNF1A', 'Gene', (37, 42))	('HOTAIR', 'Gene', '100124700', (26, 32))	('microRNA-214', 'Var', (84, 96))	('HNF1A', 'Gene', '6927', (37, 42))
114513	27752108	In this study, we demonstrated the expression of hsa_circ_0067934 in ESCC and assessed the correlation with clinical factors.	('hsa_circ_0067934', 'Var', (49, 65))	('hsa_circ_0067934', 'Chemical', '-', (49, 65))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('ESCC', 'Disease', (69, 73))
114514	27752108	We then explored the potential function of hsa_circ_0067934 by siRNA mediated silencing.	('hsa_circ_0067934', 'Chemical', '-', (43, 59))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('silencing', 'Var', (78, 87))	('siRNA', 'MPA', (63, 68))	('si', 'Chemical', 'MESH:D012825', (63, 65))
114515	27752108	Our data indicate hsa_circ_0067934 was significantly upregulated in ESCC tumor tissue.	('hsa_circ_0067934', 'Chemical', '-', (18, 34))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('ESCC tumor', 'Disease', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ESCC tumor', 'Disease', 'MESH:D004938', (68, 78))	('hsa_circ_0067934', 'Var', (18, 34))	('upregulated', 'PosReg', (53, 64))
114519	27752108	In summary, hsa_circ_0067934 may represent a potential biomarker for assessing the risk of esophageal cancer and could function as a marker of ESCC prognosis.	('hsa_circ_0067934', 'Chemical', '-', (12, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ESCC', 'Disease', (143, 147))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('function', 'Reg', (119, 127))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('esophageal cancer', 'Disease', (91, 108))	('hsa_circ_0067934', 'Var', (12, 28))
114520	27752108	We found that hsa_circ_0067934 promoted the proliferation and migration of ESCC cell lines in vitro.	('migration', 'CPA', (62, 71))	('ESCC', 'Disease', (75, 79))	('promoted', 'PosReg', (31, 39))	('hsa_circ_0067934', 'Var', (14, 30))	('hsa_circ_0067934', 'Chemical', '-', (14, 30))	('proliferation', 'CPA', (44, 57))
114522	27752108	Therefore, we hypothesize that hsa_circ_0067934 promotes the proliferation of ECSS cells by regulating the cell cycle.	('regulating', 'Reg', (92, 102))	('cell cycle', 'CPA', (107, 117))	('promotes', 'PosReg', (48, 56))	('hsa_circ_0067934', 'Var', (31, 47))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('proliferation', 'CPA', (61, 74))	('hsa_circ_0067934', 'Chemical', '-', (31, 47))
114523	27752108	In consistence with previous reports, the expression of has_circ_0067934 is not correlated with its host gene, PRKCI.	('PRKCI', 'Gene', (111, 116))	('has_circ_0067934', 'Var', (56, 72))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('PRKCI', 'Gene', '5584', (111, 116))
114528	27752108	In summary, hsa_circ_0067934 is upregulated in ESCC tumor tissues, and its expression is related to tumor differentiation, T stage, and TNM stage.	('ESCC tumor', 'Disease', (47, 57))	('hsa_circ_0067934', 'Chemical', '-', (12, 28))	('TNM', 'Gene', '10178', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (100, 105))	('related', 'Reg', (89, 96))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('ESCC tumor', 'Disease', 'MESH:D004938', (47, 57))	('TNM', 'Gene', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('hsa_circ_0067934', 'Var', (12, 28))	('expression', 'MPA', (75, 85))	('upregulated', 'PosReg', (32, 43))
114571	27752108	The primary antibodies used were anti-cyclin D (1:1000; CST) and anti-beta-actin (1:1000; Abcam).	('beta-actin', 'Gene', '728378', (70, 80))	('anti-cyclin', 'Var', (33, 44))	('beta-actin', 'Gene', (70, 80))
114604	22988408	Penetrating atherosclerotic ulcer can be difficult to differentiate from ulcerated atheromatous plaques, however, presence of contour abnormality is highly suggestive of penetrating atherosclerotic ulcer.	('presence', 'Var', (114, 122))	('atherosclerotic ulcer', 'Phenotype', 'HP:0031678', (182, 203))	('atherosclerotic ulcer', 'Disease', (12, 33))	('ulcerated atheromatous plaques', 'Disease', 'MESH:D058226', (73, 103))	('atherosclerotic ulcer', 'Disease', 'MESH:D050197', (12, 33))	('ulcerated atheromatous plaques', 'Disease', (73, 103))	('atheromatous plaques', 'Phenotype', 'HP:0002635', (83, 103))	('atherosclerotic ulcer', 'Phenotype', 'HP:0031678', (12, 33))	('penetrating atherosclerotic ulcer', 'Phenotype', 'HP:0031648', (170, 203))	('atherosclerotic ulcer', 'Disease', (182, 203))	('Penetrating atherosclerotic ulcer', 'Phenotype', 'HP:0031648', (0, 33))	('atherosclerotic ulcer', 'Disease', 'MESH:D050197', (182, 203))
114611	34046062	The abnormal expression of NOLC1 is involved in the tumorigenesis of various human tumors, whereas the function and mechanism of NOLC1 in ESCA remain unclear.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('ESCA', 'Phenotype', 'HP:0011459', (138, 142))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumorigenesis', 'CPA', (52, 65))	('NOLC1', 'Gene', (27, 32))	('involved', 'Reg', (36, 44))	('human', 'Species', '9606', (77, 82))
114613	34046062	A recombined lentiviral vector containing NOLC1 was applied for transfecting ESCA cells (Eca109 and TE-13) and established a stable cell line with low NOLC1 expression or high NOLC1 expression, in the absence or presence of PI3K inhibitor (LY294002) treatment.	('LY294002', 'Var', (240, 248))	('expression', 'MPA', (157, 167))	('expression', 'MPA', (182, 192))	('TE-1', 'CellLine', 'CVCL:1759', (100, 104))	('low', 'NegReg', (147, 150))	('NOLC1', 'Gene', (151, 156))	('LY294002', 'Chemical', 'MESH:C085911', (240, 248))	('NOLC1', 'Gene', (176, 181))	('ESCA', 'Phenotype', 'HP:0011459', (77, 81))
114617	34046062	NOLC1 knockdown inhibited proliferation, migration, invasion, and cyclin B1 expression and promoted the apoptosis and cleaved-caspase-3 expression of Eca109 and TE-13 cells.	('promoted', 'PosReg', (91, 99))	('expression', 'MPA', (136, 146))	('migration', 'CPA', (41, 50))	('inhibited', 'NegReg', (16, 25))	('caspase-3', 'Gene', '836', (126, 135))	('cyclin B1', 'Gene', '891', (66, 75))	('cyclin B1', 'Gene', (66, 75))	('NOLC1', 'Gene', (0, 5))	('expression', 'MPA', (76, 86))	('knockdown', 'Var', (6, 15))	('apoptosis', 'CPA', (104, 113))	('invasion', 'CPA', (52, 60))	('caspase-3', 'Gene', (126, 135))	('proliferation', 'CPA', (26, 39))
114636	34046062	After lentivirus infection, Eca109 and TE-13 cells with or without LY294002 were harvested and stained with Annexin V-FITC/PI (BD Biosciences, Bedford, USA) in the dark for 15 min.	('LY294002', 'Var', (67, 75))	('Annexin V', 'Gene', '308', (108, 117))	('Annexin V', 'Gene', (108, 117))
114640	34046062	showed that NOLC1 knockdown can enhance the drug sensitivity of NSCLC chemotherapy-resistant (A549/MDR) cells to multidrug response by inhibiting cell viability and accelerating cell apoptosis.	('knockdown', 'Var', (18, 27))	('NOLC1', 'Gene', (12, 17))	('drug sensitivity', 'Phenotype', 'HP:0020174', (44, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('accelerating', 'PosReg', (165, 177))	('cell apoptosis', 'CPA', (178, 192))	('A549', 'CellLine', 'CVCL:0023', (94, 98))	('drug sensitivity', 'MPA', (44, 60))	('cell viability', 'CPA', (146, 160))	('inhibiting', 'NegReg', (135, 145))	('enhance', 'PosReg', (32, 39))
114646	33078313	Pretreatment Primary Tumor Stage is a Risk Factor for Recurrence in Patients with Esophageal Squamous Cell Carcinoma Who Achieve Pathological Complete Response After Neoadjuvant Chemoradiotherapy Although pathological complete response (pCR) after multimodal treatment for esophageal cancer is associated to the best prognosis, recurrence may occur in 20-40% of cases.	('men', 'Species', '9606', (264, 267))	('Squamous Cell Carcinoma', 'Disease', (93, 116))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('Tumor', 'Phenotype', 'HP:0002664', (21, 26))	('men', 'Species', '9606', (8, 11))	('cancer', 'Disease', (284, 290))	('Patients', 'Species', '9606', (68, 76))	('Primary Tumor', 'Disease', (13, 26))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('Primary Tumor', 'Disease', 'MESH:D001932', (13, 26))	('Carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('pathological', 'Var', (205, 217))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (93, 116))
114656	33078313	According to our analysis, SCCs patients with cT4 stage have an increased risk to recur, so they should be managed differently by a personalized approach in terms of adjuvant treatment and follow-up.	('SCC', 'Gene', (27, 30))	('patients', 'Species', '9606', (32, 40))	('SCC', 'Phenotype', 'HP:0002860', (27, 30))	('SCC', 'Gene', '6317', (27, 30))	('men', 'Species', '9606', (180, 183))	('recur', 'CPA', (82, 87))	('cT4 stage', 'Var', (46, 55))
114663	33078313	The problem of locoregional and distant relapses of ypT0N0 esophageal and esophagogastric cancers is a highly debated topic.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ypT0N0', 'Var', (52, 58))	('esophageal', 'Disease', (59, 69))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
114771	32630408	The expression of Ki67, PTGS2, and SLC2A1 in tumors as compared to adjacent tissue was markedly more upregulated in EC than GC, by 2.8, 3.3, and 3.1-fold, respectively.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('SLC2A1', 'Gene', (35, 41))	('PTGS2', 'Gene', (24, 29))	('tumors', 'Disease', (45, 51))	('PTGS2', 'Gene', '5743', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('GC', 'Phenotype', 'HP:0012126', (124, 126))	('expression', 'MPA', (4, 14))	('more upregulated', 'PosReg', (96, 112))	('Ki67', 'Var', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('SLC2A1', 'Gene', '6513', (35, 41))
114781	32630408	The expression of Ki67 and NOS2 was independently associated with CLDN2 in non-cancerous adjacent tissue, explaining 83% in its variation, and BCLxL was independently associated with CLDN2 in gastric tumors, explaining 64% in its variability.	('gastric tumors', 'Disease', 'MESH:D013274', (192, 206))	('CLDN2', 'Gene', '9075', (66, 71))	('Ki67', 'Var', (18, 22))	('gastric tumor', 'Phenotype', 'HP:0006753', (192, 205))	('gastric tumors', 'Phenotype', 'HP:0006753', (192, 206))	('CLDN2', 'Gene', '9075', (183, 188))	('cancer', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CLDN2', 'Gene', (66, 71))	('gastric tumors', 'Disease', (192, 206))	('NOS2', 'Gene', '4843', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('BCLxL', 'Gene', (143, 148))	('NOS2', 'Gene', (27, 31))	('BCLxL', 'Gene', '598', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('associated', 'Reg', (50, 60))	('CLDN2', 'Gene', (183, 188))	('associated', 'Reg', (167, 177))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
114786	32630408	The expression of ODC1 was independently from other genes associated with SLC2A1 in adjacent tissue, explaining 72% in its variability, and Ki67 was independently associated with SLC2A1 in tumors, explaining 63% in gene variability.	('SLC2A1', 'Gene', (179, 185))	('ODC1', 'Gene', '4953', (18, 22))	('Ki67', 'Var', (140, 144))	('SLC2A1', 'Gene', '6513', (74, 80))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('associated', 'Reg', (163, 173))	('ODC1', 'Gene', (18, 22))	('SLC2A1', 'Gene', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('SLC2A1', 'Gene', '6513', (179, 185))
114829	32630408	Qualitative differences were accompanied by quantitative, as Ki67, PTGS2, and SLC2A upregulation was significantly more pronounced in EC.	('Ki67', 'Var', (61, 65))	('SLC2A', 'Gene', (78, 83))	('upregulation', 'PosReg', (84, 96))	('PTGS2', 'Gene', '5743', (67, 72))	('PTGS2', 'Gene', (67, 72))
114831	32630408	Actually, it has been argued that discerning molecular alterations happening in still non-transformed tissue is more informative on the processes leading to neoplastic transformation than the analysis based on already transformed cells and may pave the way to developing strategies for early cancer detection and/or primary chemoprevention.	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('informative', 'Reg', (117, 128))	('alterations', 'Var', (55, 66))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('cancer', 'Disease', (292, 298))
114844	32630408	Cancer-type related variance in GLUT1 abundance is of clinical relevance as it directly correlates with the uptake of 18F-fluoro-2-deoxyglucose, a glucose analog used for cancer detection.	('GLUT1', 'Gene', (32, 37))	('uptake of 18F-fluoro-2-deoxyglucose', 'MPA', (108, 143))	('variance', 'Var', (20, 28))	('GLUT1', 'Gene', '6513', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('Cancer', 'Disease', (0, 6))	('glucose', 'Chemical', 'MESH:D005947', (136, 143))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('glucose', 'Chemical', 'MESH:D005947', (147, 154))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('18F-fluoro-2-deoxyglucose', 'Chemical', 'MESH:D019788', (118, 143))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('correlates', 'Reg', (88, 98))
114852	32630408	Polyamines play a crucial role in maintaining and controlling its proliferative, survival, migration, and angiogenic potential.	('angiogenic potential', 'CPA', (106, 126))	('Polyamines', 'Var', (0, 10))	('survival', 'CPA', (81, 89))	('proliferative', 'CPA', (66, 79))	('Polyamines', 'Chemical', 'MESH:D011073', (0, 10))	('migration', 'CPA', (91, 100))
114857	32630408	It has been shown that in the stomach, ornithine decarboxylase and polyamines are necessary for epithelial restitution and that the polyamine-mediated repair of the epithelial barrier involves upregulation of ZO-1.	('polyamine-mediated', 'Var', (132, 150))	('upregulation', 'PosReg', (193, 205))	('ornithine decarboxylase', 'Gene', '4953', (39, 62))	('ZO-1', 'Gene', (209, 213))	('ornithine decarboxylase', 'Gene', (39, 62))	('polyamines', 'Chemical', 'MESH:D011073', (67, 77))	('polyamine', 'Chemical', 'MESH:D011073', (132, 141))	('ZO-1', 'Gene', '7082', (209, 213))	('polyamine', 'Chemical', 'MESH:D011073', (67, 76))
114860	32630408	Moreover, variability in CDKN1A expression independently predicted ODC1 variation in non-cancerous tissue and variability in Ki67:in gastric tumors.	('ODC1', 'Gene', (67, 71))	('gastric tumors', 'Disease', 'MESH:D013274', (133, 147))	('ODC1', 'Gene', '4953', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('gastric tumors', 'Disease', (133, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('gastric tumor', 'Phenotype', 'HP:0006753', (133, 146))	('variability', 'Var', (10, 21))	('variation', 'Var', (72, 81))	('CDKN1A', 'Gene', (25, 31))	('cancer', 'Disease', (89, 95))	('variability', 'Var', (110, 121))	('gastric tumors', 'Phenotype', 'HP:0006753', (133, 147))	('CDKN1A', 'Gene', '1026', (25, 31))	('predicted', 'Reg', (57, 66))	('expression', 'MPA', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
114867	32630408	The EMT is associated with rearrangement in tight junction proteins, including downregulation of the epithelial marker TJP1/ZO-1 and upregulation of the mesenchymal marker ACTA2/aSMA.	('ACTA2', 'Gene', (172, 177))	('ACTA2', 'Gene', '59', (172, 177))	('TJP1', 'Gene', '7082', (119, 123))	('ZO-1', 'Gene', '7082', (124, 128))	('aSMA', 'Gene', (178, 182))	('rearrangement', 'Var', (27, 40))	('upregulation', 'PosReg', (133, 145))	('aSMA', 'Gene', '58', (178, 182))	('TJP1', 'Gene', (119, 123))	('downregulation', 'NegReg', (79, 93))	('ZO-1', 'Gene', (124, 128))	('tight junction proteins', 'Protein', (44, 67))
114898	32630408	Long-term, IL-1beta oversecretion leads to the organ atrophy and adenocarcinoma.	('atrophy', 'Disease', 'MESH:D001284', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('leads to', 'Reg', (34, 42))	('atrophy', 'Disease', (53, 60))	('IL-1beta', 'Gene', '3552', (11, 19))	('adenocarcinoma', 'Disease', (65, 79))	('oversecretion', 'Var', (20, 33))	('IL-1beta', 'Gene', (11, 19))	('adenocarcinoma', 'Disease', 'MESH:D000230', (65, 79))
114899	32630408	Genetic studies have shown the risk for GC to depend on polymorphisms in the IL1B gene.	('GC', 'Phenotype', 'HP:0012126', (40, 42))	('polymorphisms', 'Var', (56, 69))	('IL1B', 'Gene', (77, 81))	('IL1B', 'Gene', '3553', (77, 81))
114900	32630408	Certain variants have been demonstrated to raise GC susceptibility by increasing IL-1beta and reducing IL-1ra production.	('IL-1beta', 'Gene', '3552', (81, 89))	('IL-1beta', 'Gene', (81, 89))	('GC', 'Phenotype', 'HP:0012126', (49, 51))	('variants', 'Var', (8, 16))	('increasing', 'PosReg', (70, 80))	('reducing', 'NegReg', (94, 102))	('IL-1ra', 'Gene', '3557', (103, 109))	('IL-1ra', 'Gene', (103, 109))
114948	32206103	In our previous whole-genome sequencing (WGS) study on 94 ESCC samples, we have identified 23 focal recurrent copy number gain regions containing 1,591 genes and the matched mRNA expression data showed 149 copy-number gain genes are overexpressed in tumor compared with adjacent normal samples.	('expression', 'Species', '29278', (179, 189))	('overexpressed', 'PosReg', (233, 246))	('copy-number', 'Var', (206, 217))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('copy', 'Var', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (250, 255))
114954	32206103	Overexpression of TIGAR has been associated with some types of human cancer.	('human', 'Species', '9606', (63, 68))	('expression', 'Species', '29278', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('associated', 'Reg', (33, 43))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
114963	32206103	Human ESCC cell lines KYSE30, KYSE150, KYSE450 and KYSE510 were kind gifts from Dr. Y. Shimada of Hyogo College of Medicine, Japan.	('Human', 'Species', '9606', (0, 5))	('KYSE450', 'Var', (39, 46))	('KYSE150', 'Var', (30, 37))	('KYSE510', 'Var', (51, 58))
114968	32206103	Of them, 149 genes were significantly overexpressed in tumor samples (differential expression analysis P < 0.05, fold change > 1.35) and the expression levels were significantly correlated with their copy-number gains (Spearman's correlation coefficient > 0.35, P < 0.05).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('overexpressed', 'PosReg', (38, 51))	('tumor', 'Disease', (55, 60))	('expression', 'Species', '29278', (141, 151))	('expression', 'Species', '29278', (83, 93))	('expression', 'MPA', (141, 151))	('copy-number gains', 'Var', (200, 217))
114997	32206103	When tumor size reached approximate 200 mm3, mice were randomly divided into groups (n = 6 per group) and treated with 5FU (i. p.), DDP (i. p.), CB-839 (p.	('mice', 'Species', '10090', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('DDP', 'Gene', '1678', (132, 135))	('CB-839', 'Var', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CB-839', 'Chemical', 'MESH:C000593334', (145, 151))	('5FU', 'Chemical', 'MESH:D005472', (119, 122))	('tumor', 'Disease', (5, 10))	('DDP', 'Gene', (132, 135))
115021	32206103	Briefly, the sections were incubated with primary antibody against TIGAR (1:200; Abcam, ab62533), p-AMPK (1:100; CST, 2535), GLS (1:100; Abcam, ab93434), Ki-67 (1:100; Abcam, ab16667) or cleaved CASPASE3 (1:200, CST, #9661) at 4  C overnight and then detected with the ABC Kit (Pierce).	('CST', 'Gene', '53897', (113, 116))	('1:200', 'Var', (205, 210))	('CST', 'Gene', '53897', (212, 215))	('GLS', 'Gene', (125, 128))	('CASPASE3', 'Gene', '12367', (195, 203))	('CST', 'Gene', (212, 215))	('AMPK', 'Gene', '5563', (100, 104))	('GLS', 'Gene', '14660', (125, 128))	('AMPK', 'Gene', (100, 104))	('CASPASE3', 'Gene', (195, 203))	('CST', 'Gene', (113, 116))
115022	32206103	The cBioPortal for cancer genomics (http://cbioportal.org) was used to analyze copy number variations of TIGAR in various types of cancer (date updated in May 2018).	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('copy number variations', 'Var', (79, 101))	('TIGAR', 'Gene', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
115024	32206103	We calculated Spearman's correlations between copy number and mRNA expression levels of specific genes and the correlation is deemed significant and positive when r > 0.35 and (nominal) P < 0.05.	('copy', 'Var', (46, 50))	('mRNA expression levels', 'MPA', (62, 84))	('expression', 'Species', '29278', (67, 77))
115025	32206103	Using RNA interfering-based high content screening in two ESCC cell lines KYSE450 and KYSE510 (Figure 1A), we found that knockdown of 18 of the 149 select candidate genes (see Methods for detail; Figure S1) had significant inhibitory effects on cancer cell proliferation (P < 0.05) (Figure 1B).	('knockdown', 'Var', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('inhibitory effects', 'NegReg', (223, 241))	('cancer', 'Disease', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
115026	32206103	Among the genes, knockdown of TIGAR expression most efficiently suppressed the malignant phenotypes of ESCC cells, with the rates of cell-proliferation inhibition being 44.2% (P = 0.002) in KYSE450 and 40.3% (P = 0.002) in KYSE510 compared with controls (Figure 1B).	('TIGAR expression', 'Gene', (30, 46))	('suppressed', 'NegReg', (64, 74))	('cell-proliferation', 'CPA', (133, 151))	('malignant phenotypes of ESCC cells', 'CPA', (79, 113))	('KYSE450', 'Var', (190, 197))	('knockdown', 'Var', (17, 26))	('expression', 'Species', '29278', (36, 46))
115028	32206103	We found that TIGAR knockout in KYSE150 and KYSE30 cells significantly repressed these cell growths, whereas the ectopic TIGAR overexpression significantly promoted their proliferation (Figure 1C-F; Figure S2A).	('KYSE30', 'Var', (44, 50))	('expression', 'Species', '29278', (131, 141))	('cell growths', 'CPA', (87, 99))	('repressed', 'NegReg', (71, 80))	('proliferation', 'CPA', (171, 184))	('promoted', 'PosReg', (156, 164))
115038	32206103	Patients with high TIGAR level in ESCC survived significantly shorter time than patients with low TIGAR level in ESCC (log-rank P = 5.25e-12; hazard ratio = 4.11; 95% confidence interval = 2.75-6.16) (Figure 2E).	('high', 'Var', (14, 18))	('shorter', 'NegReg', (62, 69))	('patients', 'Species', '9606', (80, 88))	('Patients', 'Species', '9606', (0, 8))
115049	32206103	AMPK expression knockdown by siRNA or inhibition of phosphorylated AMPK (p-AMPK) activity by specific inhibitor Dorsomorphin substantially reduced GLS expression (Figure 3G; Figure S4E), suggesting that GLS is a downstream target of p-AMPK.	('AMPK', 'Gene', (0, 4))	('Dorsomorphin', 'Chemical', 'MESH:C516138', (112, 124))	('AMPK', 'Gene', '5563', (0, 4))	('AMPK', 'Gene', '5563', (75, 79))	('AMPK', 'Gene', (235, 239))	('expression', 'Species', '29278', (151, 161))	('GLS', 'Gene', '14660', (147, 150))	('GLS', 'Gene', '14660', (203, 206))	('AMPK', 'Gene', (67, 71))	('knockdown', 'Var', (16, 25))	('AMPK', 'Gene', (75, 79))	('AMPK', 'Gene', '5563', (67, 71))	('reduced', 'NegReg', (139, 146))	('GLS', 'Gene', (147, 150))	('AMPK', 'Gene', '5563', (235, 239))	('expression', 'Species', '29278', (5, 15))	('GLS', 'Gene', (203, 206))
115050	32206103	In TIGAR-overexpressing ESCC cells, the ATP levels were significantly lower when AMPK was also knocked down, while in cells without TIGAR overexpression, the ATP production was not affected by AMPK knockdown (Figure 3H).	('ATP', 'Chemical', 'MESH:D000255', (40, 43))	('ATP', 'Chemical', 'MESH:D000255', (158, 161))	('ATP levels', 'MPA', (40, 50))	('AMPK', 'Gene', '5563', (81, 85))	('lower', 'NegReg', (70, 75))	('AMPK', 'Gene', (81, 85))	('AMPK', 'Gene', (193, 197))	('expression', 'Species', '29278', (142, 152))	('AMPK', 'Gene', '5563', (193, 197))	('knocked down', 'Var', (95, 107))
115052	32206103	We also looked at the effect of AMPK expression knockdown on ESCC cell apoptosis and the results were negative under our experimental conditions (Figure S4I).	('AMPK', 'Gene', (32, 36))	('ESCC', 'Disease', (61, 65))	('expression', 'Species', '29278', (37, 47))	('AMPK', 'Gene', '5563', (32, 36))	('knockdown', 'Var', (48, 57))
115062	32206103	We also evaluated the potential toxic effect of the drug combination on normal tissues and the results did not show any systemic toxicity as examined by the body weight gains, weight and histopathological changes of main organs including the liver, kidney, lung, heart and spleen in Tiger+/+ mice treated with 5FU/DDP and CB-839 or 5FU/DDP and CB-839 alone (Figure S6).	('toxicity', 'Disease', (129, 137))	('DDP', 'Gene', (336, 339))	('Tiger', 'Species', '9694', (283, 288))	('5FU', 'Chemical', 'MESH:D005472', (310, 313))	('5FU', 'Chemical', 'MESH:D005472', (332, 335))	('DDP', 'Gene', '1678', (314, 317))	('mice', 'Species', '10090', (292, 296))	('CB-839', 'Chemical', 'MESH:C000593334', (344, 350))	('weight gains', 'Phenotype', 'HP:0004324', (162, 174))	('CB-839', 'Var', (322, 328))	('DDP', 'Gene', '1678', (336, 339))	('CB-839', 'Chemical', 'MESH:C000593334', (322, 328))	('DDP', 'Gene', (314, 317))	('toxicity', 'Disease', 'MESH:D064420', (129, 137))
115063	32206103	In vitro assays showed that glutamine deprivation or GLS knockdown significantly inhibited ESCC cell proliferation and the inhibitory extent was much greater in TIGAR-overexpressing cells than control cells (Figures S7A-B).	('GLS', 'Gene', (53, 56))	('inhibited', 'NegReg', (81, 90))	('knockdown', 'Var', (57, 66))	('GLS', 'Gene', '14660', (53, 56))	('glutamine', 'Protein', (28, 37))	('glutamine', 'Chemical', 'MESH:D005973', (28, 37))	('ESCC cell proliferation', 'CPA', (91, 114))
115064	32206103	The ATP levels were remarkably declined in ESCC cells deprived of glutamine or with GLS knockdown and this result seemed to occur only in cells with but not without TIGAR overexpression (Figures S7C-D).	('ATP levels', 'MPA', (4, 14))	('GLS', 'Gene', (84, 87))	('knockdown', 'Var', (88, 97))	('ATP', 'Chemical', 'MESH:D000255', (4, 7))	('declined', 'NegReg', (31, 39))	('GLS', 'Gene', '14660', (84, 87))	('expression', 'Species', '29278', (175, 185))	('glutamine', 'Chemical', 'MESH:D005973', (66, 75))
115069	32206103	In mice, PDXs with high TIGAR expression grew faster than PDXs with low TIGAR expression (Figures 5E and 5G; Figures S8E-J), consistent with the aforementioned results showing that TIGAR plays an important part in ESCC progression.	('high', 'Var', (19, 23))	('ESCC', 'Disease', (214, 218))	('mice', 'Species', '10090', (3, 7))	('faster', 'PosReg', (46, 52))	('expression', 'Species', '29278', (30, 40))	('grew', 'CPA', (41, 45))	('expression', 'Species', '29278', (78, 88))
115071	32206103	We found that PDXs with high TIGAR expression were more resistant to 5FU/DPP treatment than PDX with low TIGAR expression.	('5FU', 'Chemical', 'MESH:D005472', (69, 72))	('resistant', 'MPA', (56, 65))	('expression', 'Species', '29278', (35, 45))	('expression', 'Species', '29278', (111, 121))	('high TIGAR expression', 'Var', (24, 45))	('DPP', 'Chemical', 'MESH:C038694', (73, 76))
115074	32206103	Additionally, we have found that high TIGAR expression levels are significantly correlated with advanced tumor stages, lymph node metastasis and poor patient survival.	('correlated', 'Reg', (80, 90))	('high', 'Var', (33, 37))	('patient', 'Species', '9606', (150, 157))	('lymph node metastasis', 'CPA', (119, 140))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('expression', 'Species', '29278', (44, 54))
115076	32206103	In an effort to explain the underlying mechanism, we have revealed that aberrant TIGAR expression inhibits glycolysis but activates the glutamine pathway, which may facilitate ESCC cell survival and progression.	('ESCC', 'Disease', (176, 180))	('glutamine pathway', 'Pathway', (136, 153))	('facilitate', 'PosReg', (165, 175))	('expression', 'Species', '29278', (87, 97))	('progression', 'CPA', (199, 210))	('activates', 'PosReg', (122, 131))	('aberrant', 'Var', (72, 80))	('glutamine', 'Chemical', 'MESH:D005973', (136, 145))	('glycolysis', 'MPA', (107, 117))	('inhibits', 'NegReg', (98, 106))	('TIGAR', 'Gene', (81, 86))
115077	32206103	More importantly, based on these results, we have performed treatment targeting the glutamine pathway in mouse primary ESCC and PDX models and found that inhibition of the pathway significantly represses ESCC progression and enhance the efficacy of cytotoxic chemotherapy (5FU/DDP).	('ESCC', 'Disease', (204, 208))	('DDP', 'Gene', (277, 280))	('inhibition', 'Var', (154, 164))	('5FU', 'Chemical', 'MESH:D005472', (273, 276))	('glutamine', 'Chemical', 'MESH:D005973', (84, 93))	('enhance', 'PosReg', (225, 232))	('represses', 'NegReg', (194, 203))	('DDP', 'Gene', '1678', (277, 280))	('mouse', 'Species', '10090', (105, 110))
115078	32206103	Together, these results demonstrate that TIGAR overexpression is essential for the development and progression of ESCC through an underlying mechanism of the glutamine pathway activation; thus, inhibition of aberrant TIGAR expression dependent glutamine pathway may be a therapeutic target for precision treatment of this malignancy (Figure 6).	('glutamine pathway', 'Pathway', (158, 175))	('ESCC', 'Disease', (114, 118))	('expression', 'Species', '29278', (223, 233))	('expression', 'Species', '29278', (51, 61))	('glutamine', 'Chemical', 'MESH:D005973', (158, 167))	('malignancy', 'Disease', 'MESH:D009369', (322, 332))	('glutamine', 'Chemical', 'MESH:D005973', (244, 253))	('aberrant', 'Var', (208, 216))	('malignancy', 'Disease', (322, 332))	('activation', 'PosReg', (176, 186))
115079	32206103	We detected a significantly reduced lactate level but a significantly increased NADPH level in ESCC overexpressing TIGAR consistent with the role of TIGAR in glucose metabolism and the proposed consequences of its overexpression.	('overexpressing', 'Var', (100, 114))	('lactate level', 'MPA', (36, 49))	('reduced', 'NegReg', (28, 35))	('increased', 'PosReg', (70, 79))	('lactate', 'Chemical', 'MESH:D019344', (36, 43))	('ESCC', 'Gene', (95, 99))	('NADPH level', 'MPA', (80, 91))	('expression', 'Species', '29278', (218, 228))	('glucose', 'Chemical', 'MESH:D005947', (158, 165))
115080	32206103	Since glycolysis is the major energy source for cancer cells, one would expect that inhibition of glycolysis may bring down the ATP levels in TIGAR-overexpressing ESCC cells; however, we observed a significantly elevated rather than decreased ATP level in these cells.	('ATP', 'Chemical', 'MESH:D000255', (243, 246))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('ATP', 'MPA', (243, 246))	('ATP', 'Chemical', 'MESH:D000255', (128, 131))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('ATP levels', 'MPA', (128, 138))	('inhibition', 'Var', (84, 94))
115086	32206103	Conversely, when AMPK activity is knocked down or inhibited, the GLS expression level is also concurrently decreased.	('expression', 'Species', '29278', (69, 79))	('AMPK', 'Gene', '5563', (17, 21))	('GLS', 'Gene', '14660', (65, 68))	('knocked down', 'Var', (34, 46))	('decreased', 'NegReg', (107, 116))	('AMPK', 'Gene', (17, 21))	('GLS', 'Gene', (65, 68))	('inhibited', 'NegReg', (50, 59))
115092	32206103	Genomic alteration caused metabolic remodeling could make cancer cells addicted to certain nutrients, which can then become a potential therapeutic target.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Genomic alteration', 'Var', (0, 18))	('make', 'Reg', (53, 57))	('addicted to', 'MPA', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
115096	32206103	Interestingly, we have found that inhibition of glutamine pathway enhances the sensitivity of TIGAR overexpressing ESCC cells towards cytotoxic anticancer agents, 5FU/DDP, suggesting that a combination of glutamine pathway inhibitors and conventional cytotoxic agents may be a promising novel treatment option for ESCC with TIGAR overexpression.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('enhances', 'PosReg', (66, 74))	('ESCC', 'Disease', (314, 318))	('5FU', 'Chemical', 'MESH:D005472', (163, 166))	('DDP', 'Gene', (167, 170))	('inhibition', 'Var', (34, 44))	('expression', 'Species', '29278', (334, 344))	('glutamine', 'Chemical', 'MESH:D005973', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('sensitivity', 'MPA', (79, 90))	('DDP', 'Gene', '1678', (167, 170))	('glutamine', 'Protein', (48, 57))	('glutamine', 'Chemical', 'MESH:D005973', (48, 57))
115102	32206103	In the present study, we found the TIGAR overexpression in ESCC is not correlated with P53 or c-MET expression (Figures S9A and S9B), but is associated with somatic copy number gain of the gene itself (Figure S9C).	('expression', 'Species', '29278', (100, 110))	('expression', 'Species', '29278', (45, 55))	('P53', 'Gene', '22060', (87, 90))	('copy number', 'Var', (165, 176))	('ESCC', 'Gene', (59, 63))	('gain', 'PosReg', (177, 181))	('P53', 'Gene', (87, 90))
115107	32206103	Based on these findings, we suggest that the aberrant TIGAR overexpression may sever as a biomarker for precision ESCC treatment and inhibition of the TIGAR-dependent glutamine pathway activation is a promising target therapy for ESCC.	('aberrant', 'Var', (45, 53))	('inhibition', 'Var', (133, 143))	('ESCC', 'Disease', (230, 234))	('TIGAR-dependent glutamine pathway', 'Pathway', (151, 184))	('glutamine', 'Chemical', 'MESH:D005973', (167, 176))	('expression', 'Species', '29278', (64, 74))
115153	31190988	The pooled results indicated that high SII was significantly related with shorter OS in EC patients following surgery (HR: 1.34, 95% CI: 1.15-1.53, P<0.001; Figure 3).	('shorter', 'Disease', (74, 81))	('patients', 'Species', '9606', (91, 99))	('high', 'Var', (34, 38))	('SII', 'Disease', 'None', (39, 42))	('OS', 'Chemical', '-', (82, 84))	('SII', 'Disease', (39, 42))
115164	31190988	As indicated in Figure 4D, high SII was correlated with the advanced clinical stage in patients with esophageal cancer (OR: 2.00, 95% CI: 1.51-2.65, P<0.001).	('SII', 'Disease', 'None', (32, 35))	('high', 'Var', (27, 31))	('esophageal cancer', 'Disease', (101, 118))	('SII', 'Disease', (32, 35))	('correlated', 'Reg', (40, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (87, 95))
115168	31190988	In addition, significant associations between high CAR level and poor OS were also found in the subgroup analyses of cut-off value (>=0.277 vs <0.277), treatments methods (With-surgery vs Mixed) and clinical staging (Non-metastatic vs Mixed).	('high', 'Var', (46, 50))	('OS', 'Chemical', '-', (70, 72))	('poor OS', 'Disease', (65, 72))	('CAR', 'Gene', '1525', (51, 54))	('CAR', 'Gene', (51, 54))
115200	29029421	The results showed that the presence of supraclavicular nodes (chi2 = 0.075, P = 0.785) and left gastric nodes (chi2 = 3.603, P = 0.058) metastasis had no significant influence on survival, while celiac nodes (chi2 = 33.775, P < 0.001) and common hepatic nodes (chi2 = 42.350, P < 0.001) metastasis were associated with significantly shorter survival, regardless of the sites of primary tumor.	('metastasis', 'Var', (288, 298))	('tumor', 'Disease', 'MESH:D009369', (387, 392))	('shorter', 'NegReg', (334, 341))	('survival', 'MPA', (342, 350))	('tumor', 'Phenotype', 'HP:0002664', (387, 392))	('tumor', 'Disease', (387, 392))
115221	29029421	As shown in Figures 2-4, the presence of celiac nodes and common hepatic nodes metastasis were associated with significantly shorter survival compared with no evidence of metastasis both in upper (for celiac nodes: chi2 = 15.429, P < 0.001, Figure 2C; for common hepatic nodes: chi2 = 10.712, P = 0.001, Figure 2D), middle (for celiac nodes: chi2 = 15.429, P < 0.001, Figure 3C; for common hepatic nodes: chi2 = 10.712, P = 0.001, Figure 3D) and lower ESCC (for celiac nodes: chi2 = 15.429, P < 0.001, Figure 4C; for common hepatic nodes: chi2 = 10.712, P = 0.001, Figure 4D).	('presence of celiac nodes', 'Phenotype', 'HP:0002608', (29, 53))	('presence', 'Var', (29, 37))	('shorter', 'NegReg', (125, 132))	('hepatic nodes metastasis', 'Disease', 'MESH:D009362', (65, 89))	('hepatic nodes metastasis', 'Disease', (65, 89))
115252	29029421	Our study also showed that the survival of patients received radiotherapy with >= 60Gy significantly longer than patients received < 60Gy.	('longer', 'PosReg', (101, 107))	('>= 60Gy', 'Var', (79, 86))	('patients', 'Species', '9606', (43, 51))	('survival', 'CPA', (31, 39))	('patients', 'Species', '9606', (113, 121))
115273	29029421	Features supporting a consideration for clinical metastasis included: 1) Nodes with a short axis >= 1 cm or these in periesophageal >= 0.5 cm on CT scan; 2) Nodes with necrotic center or inhomogeneous enhancement, regardless of the long of the axis.	('necrotic', 'Disease', (168, 176))	('necrotic', 'Disease', 'MESH:D009336', (168, 176))	('inhomogeneous', 'Var', (187, 200))
115281	28465481	Recently, tumor-specific aberrant DNA methylation of CpG islands around the promoter regions of tumor-related genes has been investigated as a possible biomarker for use in early diagnosis and prediction of prognosis.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('aberrant', 'Var', (25, 33))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
115284	28465481	We confirmed that HOXB2 and SEPT9 were highly methylated in LNM-positive tumors in 59 ESCC validation samples.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('SEPT9', 'Gene', '10801', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('LNM-positive', 'Disease', (60, 72))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('SEPT9', 'Gene', (28, 33))	('HOXB2', 'Gene', (18, 23))	('tumors', 'Disease', (73, 79))	('methylated', 'Var', (46, 56))
115293	28465481	Aberrant DNA methylation of CpG islands in the promotor region of tumor suppressor genes has been widely reported in several types of cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('Aberrant DNA methylation', 'Var', (0, 24))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('reported', 'Reg', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
115317	28465481	Finally, we confirmed that HOXB2 and SEPT9 were highly methylated in LNM-positive tumors in 59 ESCC validation samples.	('LNM-positive', 'Disease', (69, 81))	('tumors', 'Disease', (82, 88))	('SEPT9', 'Gene', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('HOXB2', 'Gene', (27, 32))	('methylated', 'Var', (55, 65))	('SEPT9', 'Gene', '10801', (37, 42))
115327	28465481	Overexpression of HOXB2 was shown to be associated with cancer progression in cervical cancer, pancreatic cancer, and lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('cancer', 'Disease', (106, 112))	('Overexpression', 'Var', (0, 14))	('pancreatic cancer', 'Disease', (95, 112))	('cancer', 'Disease', (56, 62))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cervical cancer', 'Disease', 'MESH:D002583', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cervical cancer', 'Disease', (78, 93))	('HOXB2', 'Gene', (18, 23))	('associated with', 'Reg', (40, 55))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('lung adenocarcinoma', 'Disease', (118, 137))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
115329	28465481	In addition, it was reported that expression of HOXB cluster genes was repressed by DNA methylation in oral cancer cell lines.	('expression', 'MPA', (34, 44))	('HOXB', 'Gene', '3210', (48, 52))	('HOXB', 'Gene', (48, 52))	('DNA methylation', 'Var', (84, 99))	('oral cancer', 'Disease', 'MESH:D009062', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('oral cancer', 'Disease', (103, 114))
115331	28465481	Our HM450 methylation array results (Supplementary Figure 1), demonstrated that the methylation status of some probes in tumor tissues were significantly hypermethylated compared with the paired normal tissue, and the intensity of methylation became higher with increasing LNM.	('LNM', 'Var', (273, 276))	('higher', 'PosReg', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('methylation status', 'MPA', (84, 102))	('hypermethylated', 'PosReg', (154, 169))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
115335	28465481	Detection of methylated SEPT9 in blood plasma has been used as an aid in the diagnostic evaluation of CRC.	('SEPT9', 'Gene', (24, 29))	('methylated', 'Var', (13, 23))	('SEPT9', 'Gene', '10801', (24, 29))	('CRC', 'Disease', (102, 105))
115338	28465481	Thus, in addition to HOXB2, methylation of SEPT9 may be a predictive biomarker in ESCC.	('ESCC', 'Disease', (82, 86))	('methylation', 'Var', (28, 39))	('SEPT9', 'Gene', '10801', (43, 48))	('SEPT9', 'Gene', (43, 48))
115347	28465481	In the present study, we investigated the association between methylation status and presence of LNM in ESCC, and observed that the methylation status of HOXB2 and SEPT9 may be useful as diagnostic or prognostic biomarkers in ESCC.	('SEPT9', 'Gene', '10801', (164, 169))	('HOXB2', 'Gene', (154, 159))	('ESCC', 'Disease', (226, 230))	('SEPT9', 'Gene', (164, 169))	('methylation', 'Var', (132, 143))
115364	27385211	Alisertib (MLN8237) is an investigational Aurora A selective inhibitor that has demonstrated activity against a wide variety of tumor types in vitro and in vivo, including CRC.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CRC', 'Phenotype', 'HP:0003003', (172, 175))	('Aurora A', 'Gene', '6790', (42, 50))	('activity', 'MPA', (93, 101))	('Alisertib', 'Chemical', 'MESH:C550258', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('MLN8237', 'Chemical', 'MESH:C550258', (11, 18))	('MLN8237', 'Var', (11, 18))	('Aurora A', 'Gene', (42, 50))	('tumor', 'Disease', (128, 133))	('CRC', 'Disease', (172, 175))
115367	27385211	We also observed an increase in p53 and p21 in a sensitive p53 wildtype cell line in contrast to the p53 mutant cell line or the resistant cell lines.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('mutant', 'Var', (105, 111))	('p53', 'Gene', (101, 104))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (101, 104))	('p53', 'Gene', '7157', (32, 35))	('p21', 'Gene', (40, 43))	('p21', 'Gene', '644914', (40, 43))	('increase', 'PosReg', (20, 28))
115371	27385211	Additionally, 5 KRAS wildtype and mutant PDX models were treated with alisertib as single agent or in combination with cetuximab or irinotecan, respectively.	('irinotecan', 'Chemical', 'MESH:D000077146', (132, 142))	('alisertib', 'Chemical', 'MESH:C550258', (70, 79))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (16, 20))	('cetuximab', 'Chemical', 'MESH:D000068818', (119, 128))	('mutant', 'Var', (34, 40))
115380	27385211	Aurora kinase A has been shown to directly phosphorylate p53 at Ser315 and inactivate it by enhancing its proteolytic degradation to cause a phenotype similar to loss of function of p53.	('enhancing', 'PosReg', (92, 101))	('Ser315', 'Chemical', '-', (64, 70))	('proteolytic degradation', 'MPA', (106, 129))	('inactivate', 'NegReg', (75, 85))	('Aurora kinase A', 'Gene', (0, 15))	('Ser315', 'Var', (64, 70))	('p53', 'Gene', '7157', (182, 185))	('Aurora kinase A', 'Gene', '6790', (0, 15))	('p53', 'Gene', (57, 60))	('p53', 'Gene', (182, 185))	('p53', 'Gene', '7157', (57, 60))	('cause', 'Reg', (133, 138))
115384	27385211	In some colorectal cancer cell lines, increased levels of phosphorylated histone H3 correlate with overexpression of Aurora kinase B. Alisertib (MLN8237) is a selective Aurora kinase A inhibitor that is currently undergoing Phase I-III clinical development (www.clinicaltrials.gov).	('Alisertib', 'Chemical', 'MESH:C550258', (134, 143))	('Aurora kinase A', 'Gene', (169, 184))	('Aurora kinase B', 'Gene', (117, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (8, 25))	('MLN8237', 'Chemical', 'MESH:C550258', (145, 152))	('Aurora kinase B', 'Gene', '9212', (117, 132))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (8, 25))	('Aurora kinase A', 'Gene', '6790', (169, 184))	('MLN8237', 'Var', (145, 152))	('colorectal cancer', 'Disease', (8, 25))
115427	27385211	Four additional models, CUCRC098, CUCRC040, CUCRC026, and CUCRC034 demonstrated a TGII of less than 20% TGII which was defined as a responder to alisertib.	('less', 'NegReg', (90, 94))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))	('CUCRC098', 'Chemical', '-', (24, 32))	('alisertib', 'Chemical', 'MESH:C550258', (145, 154))	('CUCRC026', 'Chemical', '-', (44, 52))	('CUCRC034', 'Chemical', '-', (58, 66))	('CRC', 'Phenotype', 'HP:0003003', (46, 49))	('CRC', 'Phenotype', 'HP:0003003', (36, 39))	('CUCRC034', 'Var', (58, 66))	('CRC', 'Phenotype', 'HP:0003003', (60, 63))	('CUCRC040', 'Chemical', '-', (34, 42))
115436	27385211	The addition of alisertib to irinotecan in KRAS mutant PDX models demonstrated near additive to synergistic effects in 4 out 5 tumor types tested (CUCRC042 average psi = 0.8, CUCRC098 average psi = 0.7, CUCRC102 average psi = 1.5 and CUCRC108 average psi = 0.7) and a less than additive effect in one model (CUCRC007 average psi = 0.5).	('alisertib', 'Chemical', 'MESH:C550258', (16, 25))	('CUCRC098', 'Var', (175, 183))	('KRAS', 'Gene', '3845', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('CUCRC108', 'Chemical', '-', (234, 242))	('mutant', 'Var', (48, 54))	('KRAS', 'Gene', (43, 47))	('CUCRC042', 'Var', (147, 155))	('CRC', 'Phenotype', 'HP:0003003', (177, 180))	('CUCRC108', 'Var', (234, 242))	('CUCRC102', 'Chemical', '-', (203, 211))	('CUCRC102', 'Var', (203, 211))	('CUCRC098', 'Chemical', '-', (175, 183))	('irinotecan', 'Chemical', 'MESH:D000077146', (29, 39))	('synergistic effects', 'MPA', (96, 115))	('tumor', 'Disease', (127, 132))	('CRC', 'Phenotype', 'HP:0003003', (149, 152))	('CRC', 'Phenotype', 'HP:0003003', (310, 313))	('CRC', 'Phenotype', 'HP:0003003', (205, 208))	('CRC', 'Phenotype', 'HP:0003003', (236, 239))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
115438	27385211	By contrast, the addition of alisertib to cetuximab therapy in KRAS wild-type PDTX models was far more variable with two models demonstrating synergy (CUCRC125 average psi = 1.3 and CUCRC026 average psi = 1.4), two models demonstrating a less than additive effect (CUCRC034 average psi = 0.2 and CUCRC047 average psi = 0.3) and one model exhibiting antagonism (CUCRC010 average psi = -0.8).	('CUCRC010', 'Chemical', '-', (361, 369))	('KRAS', 'Gene', '3845', (63, 67))	('cetuximab', 'Chemical', 'MESH:D000068818', (42, 51))	('CUCRC125', 'Var', (151, 159))	('CRC', 'Phenotype', 'HP:0003003', (267, 270))	('alisertib', 'Chemical', 'MESH:C550258', (29, 38))	('CUCRC047', 'Chemical', '-', (296, 304))	('CUCRC034', 'Chemical', '-', (265, 273))	('CRC', 'Phenotype', 'HP:0003003', (363, 366))	('CUCRC047', 'Var', (296, 304))	('CUCRC026', 'Var', (182, 190))	('CUCRC125', 'Chemical', '-', (151, 159))	('CRC', 'Phenotype', 'HP:0003003', (153, 156))	('CRC', 'Phenotype', 'HP:0003003', (184, 187))	('CUCRC026', 'Chemical', '-', (182, 190))	('CUCRC034', 'Var', (265, 273))	('CRC', 'Phenotype', 'HP:0003003', (298, 301))	('KRAS', 'Gene', (63, 67))
115447	27385211	For example, the pan-Aurora kinase inhibitors, PHA-739358 and PF-03814735 demonstrated inhibition of proliferation, induction of apoptosis and cell cycle arrest in multiple tumor types, including melanoma, HCC and SCLC.	('inhibition', 'NegReg', (87, 97))	('cell cycle arrest', 'CPA', (143, 160))	('apoptosis', 'CPA', (129, 138))	('SCLC', 'Disease', (214, 218))	('SCLC', 'Disease', 'MESH:D018288', (214, 218))	('PF-03814735', 'Var', (62, 73))	('proliferation', 'CPA', (101, 114))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (143, 160))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('HCC', 'Disease', (206, 209))	('melanoma', 'Disease', (196, 204))	('multiple tumor', 'Disease', (164, 178))	('multiple tumor', 'Disease', 'MESH:D009369', (164, 178))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('PHA-739358', 'Var', (47, 57))
115448	27385211	As with the other tumor types, colorectal cancer cells treated with the Aurora kinase inhibitor BPR1K0609S1, displayed an increase in G2/M arrested cells and induction of apoptosis as demonstrated by an increase in the number of cells in sub-G1 of the cell cycle.	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', (18, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('apoptosis', 'CPA', (171, 180))	('BPR1K0609S1', 'Var', (96, 107))	('colorectal cancer', 'Disease', (31, 48))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('G2/M arrested cells', 'CPA', (134, 153))	('increase', 'PosReg', (122, 130))	('increase', 'PosReg', (203, 211))
115454	27385211	Conversely, in our p53 mutant model, we observed only a slight increase in p53 at 24 hours and no increase at 48 hours.	('increase', 'PosReg', (63, 71))	('p53', 'Gene', (19, 22))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (19, 22))	('p53', 'Gene', '7157', (75, 78))	('mutant', 'Var', (23, 29))
115456	27385211	These data are somewhat consistent with what has been observed previously in that p53 mutant cells do not upregulate p53 at early time points after exposure to alisertib.	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('mutant', 'Var', (86, 92))	('alisertib', 'Chemical', 'MESH:C550258', (160, 169))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))
115458	27385211	p21, a known downstream target of p53 was also modestly increased following exposure to alisertib in the p53 wildtype cell lines whereas induction of p21 did not occur in the p53 mutant cell line which also exhibited only a minimal increase in p53.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('p21', 'Gene', '644914', (150, 153))	('p53', 'Gene', (244, 247))	('mutant', 'Var', (179, 185))	('p21', 'Gene', (0, 3))	('increased', 'PosReg', (56, 65))	('p21', 'Gene', '644914', (0, 3))	('p53', 'Gene', '7157', (244, 247))	('p53', 'Gene', (105, 108))	('alisertib', 'Chemical', 'MESH:C550258', (88, 97))	('p53', 'Gene', '7157', (105, 108))	('p21', 'Gene', (150, 153))	('p53', 'Gene', (175, 178))	('p53', 'Gene', '7157', (175, 178))
115459	27385211	This is similar to what was observed by our group in a related study, however in that work we observed more apoptotic activity in the p53 mutant cell line whereas in the current study the induction of apoptosis was similar among the sensitive cell lines.	('p53', 'Gene', (134, 137))	('mutant', 'Var', (138, 144))	('p53', 'Gene', '7157', (134, 137))	('apoptotic activity', 'CPA', (108, 126))
115463	27385211	However following 48 hours of alisertib exposure, an greater increase in aneuploidy was observed in the HCT116 cells compared to the LS123 and COLO678 cells and may be due to the differential effects of Aurora B, which is associated with effects on mitotic slippage and aneuploidy.	('HCT116', 'Var', (104, 110))	('alisertib', 'Chemical', 'MESH:C550258', (30, 39))	('aneuploidy', 'Disease', 'MESH:D000782', (270, 280))	('aneuploidy', 'Disease', (73, 83))	('aneuploidy', 'Disease', 'MESH:D000782', (73, 83))	('Aurora B', 'Gene', '9212', (203, 211))	('Aurora B', 'Gene', (203, 211))	('HCT116', 'CellLine', 'CVCL:0291', (104, 110))	('aneuploidy', 'Disease', (270, 280))	('increase', 'PosReg', (61, 69))	('LS123', 'Chemical', '-', (133, 138))
115474	27385211	Perhaps an explanation for these modest combinatorial effects is due to the fact that alisertib induces p21 and a G2/M cell cycle arrest and similarly it has been demonstrated that SN-38, the active metabolite of irinotecan, does not induce cell death in cells that are actively cell cycle-arrested.	('induces', 'PosReg', (96, 103))	('alisertib', 'Gene', (86, 95))	('alisertib', 'Chemical', 'MESH:C550258', (86, 95))	('SN-38', 'Var', (181, 186))	('G2/M cell cycle arrest', 'CPA', (114, 136))	('p21', 'Gene', (104, 107))	('irinotecan', 'Chemical', 'MESH:D000077146', (213, 223))	('p21', 'Gene', '644914', (104, 107))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (119, 136))	('SN-38', 'Chemical', 'MESH:D000077146', (181, 186))
115482	27385211	KM12L4, KM12C, and KM20, described previously, were all kindly provided by Scott Kopetz (MD Anderson Cancer Center, Houston, TX).	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (89, 107))	('MD Anderson Cancer', 'Disease', (89, 107))	('KM12L4', 'Var', (0, 6))
115521	27729745	Although PD-L1 positivity was not found to be associated with survival of ESCC patients, we show that it may play a critical role in distant failure and progression of ESCC.	('play', 'Reg', (109, 113))	('PD-L1', 'Gene', '29126', (9, 14))	('distant failure', 'CPA', (133, 148))	('positivity', 'Var', (15, 25))	('ESCC', 'Disease', (168, 172))	('patients', 'Species', '9606', (79, 87))	('PD-L1', 'Gene', (9, 14))
115527	27729745	The PD-L1/PD-1 interaction has been found to be associated with poor prognosis and clinical outcomes in various cancers such as non-small cell lung cancer, breast cancer, gastric cancer, soft tissue sarcomas and meningioma; however, its prognostic value is still controversial.	('sarcomas', 'Phenotype', 'HP:0100242', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))	('meningioma', 'Disease', 'MESH:D008577', (212, 222))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('PD-1', 'Gene', (10, 14))	('gastric cancer', 'Disease', (171, 185))	('PD-1', 'Gene', '5133', (10, 14))	('interaction', 'Var', (15, 26))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('cancers', 'Disease', (112, 119))	('breast cancer', 'Disease', (156, 169))	('non-small cell lung cancer', 'Disease', (128, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('soft tissue sarcomas', 'Disease', (187, 207))	('gastric cancer', 'Disease', 'MESH:D013274', (171, 185))	('PD-L1', 'Gene', (4, 9))	('PD-L1', 'Gene', '29126', (4, 9))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (187, 207))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (187, 207))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('meningioma', 'Disease', (212, 222))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('meningioma', 'Phenotype', 'HP:0002858', (212, 222))	('gastric cancer', 'Phenotype', 'HP:0012126', (171, 185))
115918	19965299	Sometimes a pleural effusion develops due to damage to the thoracic duct, with resultant spillage of chyle into pleural space.	('pleural', 'Disease', (112, 119))	('damage', 'Var', (45, 51))	('pleural effusion', 'Disease', 'MESH:D010996', (12, 28))	('pleural effusion', 'Disease', (12, 28))	('pleural', 'Disease', 'MESH:D010995', (12, 19))	('pleural effusion', 'Phenotype', 'HP:0002202', (12, 28))	('pleural', 'Disease', (12, 19))	('pleural', 'Disease', 'MESH:D010995', (112, 119))
115964	33563244	In addition, the risk of anastomotic leakage was decreased in MIE group (20.0% vs 3.3%, P < 0.001), while the occurrence of other complications did not have statistical significance between two groups.	('decreased', 'NegReg', (49, 58))	('anastomotic leakage', 'Disease', (25, 44))	('anastomotic leakage', 'Disease', 'MESH:D057868', (25, 44))	('MIE', 'Var', (62, 65))
115966	33563244	For the patients underwent neoadjuvant chemoradiotherapy, OS was significantly better in the MIE group (log rank = 6.197; P = 0.013).	('better', 'PosReg', (79, 85))	('MIE', 'Var', (93, 96))	('patients', 'Species', '9606', (8, 16))
116023	33563244	Nevertheless, MIE was significantly associated with better OS in patients underwent neoadjuvant chemoradiation.	('better OS', 'Disease', (52, 61))	('MIE', 'Var', (14, 17))	('patients', 'Species', '9606', (65, 73))
116030	33563244	In terms of operative outcomes, our study indicated that shorter operation time and less intraoperative blood loss were noted in the MIE group, which was consistent with the previous reports.	('intraoperative blood loss', 'Disease', (89, 114))	('MIE', 'Var', (133, 136))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (89, 114))
116071	31475462	WHO has estimated that 8.7% of global deaths in 2004 and 3.7% of disability-adjusted life years (DALYs) were attributable to cigarette smoking.1 Moreover, alcohol drinking caused 3.6% of deaths and 4.4% of DALYs.	('alcohol', 'Chemical', 'MESH:D000431', (155, 162))	('deaths', 'Disease', 'MESH:D003643', (187, 193))	('deaths', 'Disease', (187, 193))	('alcohol drinking', 'Phenotype', 'HP:0030955', (155, 171))	('deaths', 'Disease', 'MESH:D003643', (38, 44))	('deaths', 'Disease', (38, 44))	('alcohol drinking', 'Var', (155, 171))
116123	31475462	Recent study suggested that distributions of gene mutations in physiologically normal epithelia and esophageal squamous cell carcinoma were different.52 Thus, accumulation of non-specific gene alteration in normal esophageal mucosa and esophageal cancer-specific gene alteration might be necessary for esophageal carcinogenesis.	('esophageal cancer', 'Disease', 'MESH:D004938', (236, 253))	('alteration', 'Var', (193, 203))	('esophageal carcinogenesis', 'Disease', (302, 327))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (302, 327))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (100, 134))	('esophageal squamous cell carcinoma', 'Disease', (100, 134))	('esophageal cancer', 'Disease', (236, 253))
116159	28974922	Histology codes include adenocarcinoma (8140-8151, 8154-8231, 8243-8245, 8250-8576) and SCC (8000-8131, 8980-8981).	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('adenocarcinoma', 'Disease', (24, 38))	('8250-8576', 'Var', (73, 82))	('SCC', 'Gene', (88, 91))	('8154-8231', 'Var', (51, 60))	('adenocarcinoma', 'Disease', 'MESH:D000230', (24, 38))	('8140-8151', 'Var', (40, 49))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
116281	28868415	Levels of aminotransferases, alkaline phosphatase and/or gamma-glutamyl transpeptidase were normal in 87.5% of patients with UGIB, comparatively to 28.6% of patients without gastrointestinal haemorrhage (OR 17.50; 95% CI 1.59-191.89; p = 0.024).	('Levels', 'MPA', (0, 6))	('aminotransferases', 'MPA', (10, 27))	('UGIB', 'Var', (125, 129))	('normal', 'NegReg', (92, 98))	('gastrointestinal haemorrhage', 'Phenotype', 'HP:0002239', (174, 202))	('gastrointestinal haemorrhage', 'Disease', 'MESH:D006471', (174, 202))	('patients', 'Species', '9606', (157, 165))	('gamma-glutamyl transpeptidase', 'Gene', (57, 86))	('alkaline phosphatase', 'MPA', (29, 49))	('gamma-glutamyl transpeptidase', 'Gene', '102724197', (57, 86))	('gastrointestinal haemorrhage', 'Disease', (174, 202))	('patients', 'Species', '9606', (111, 119))
116335	26942464	Moreover, low LMR was significantly associated with some clinicopathological characteristics that are indicative of poor prognosis and disease aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (143, 157))	('aggressiveness', 'Disease', (143, 157))	('aggressiveness', 'Phenotype', 'HP:0000718', (143, 157))	('low LMR', 'Var', (10, 17))	('associated', 'Reg', (36, 46))
116346	26942464	A combined analysis showed that LMR lower than the cutoff was associated with poor OS in non-hematological malignancy (HR: 0.59, 95% CI: 0.53-0.66; P < 0.001) and hematological malignancy (HR: 0.44, 95% CI: 0.34-0.56; P < 0.001) with significant heterogeneity (I2 = 53.6% and 77.9%, respectively).	('non-hematological malignancy', 'Disease', 'MESH:D019337', (89, 117))	('non-hematological malignancy', 'Disease', (89, 117))	('hematological malignancy', 'Disease', 'MESH:D019337', (93, 117))	('hematological malignancy', 'Disease', 'MESH:D019337', (163, 187))	('LMR lower', 'Var', (32, 41))	('hematological malignancy', 'Phenotype', 'HP:0004377', (93, 117))	('hematological malignancy', 'Phenotype', 'HP:0004377', (163, 187))	('hematological malignancy', 'Disease', (163, 187))
116361	26942464	A combined analysis showed that LMR lower than the cutoff was associated with poor RFS in non-hematological malignancy (HR: 0.50, 95% CI: 0.36-0.70; P < 0.001).	('poor', 'NegReg', (78, 82))	('hematological malignancy', 'Phenotype', 'HP:0004377', (94, 118))	('RFS', 'Disease', (83, 86))	('non-hematological malignancy', 'Disease', (90, 118))	('non-hematological malignancy', 'Disease', 'MESH:D019337', (90, 118))	('LMR lower', 'Var', (32, 41))	('RFS', 'Disease', 'MESH:D005198', (83, 86))
116367	26942464	For each disease excluding urothelial carcinoma, low LMR was significantly associated with some clinicopathological characteristics that are indicative of poor prognosis and disease aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (182, 196))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (27, 47))	('aggressiveness', 'Disease', (182, 196))	('associated', 'Reg', (75, 85))	('aggressiveness', 'Phenotype', 'HP:0000718', (182, 196))	('low LMR', 'Var', (49, 56))	('urothelial carcinoma', 'Disease', (27, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))
116368	26942464	Regarding predictive factors for Hodgkin's lymphoma, low LMR was significantly associated with high white blood cell count (HR: 0.67, 95% CI: 0.46-0.99; P = 0.047), low albumin (HR: 0.47, 95% CI: 0.36-0.60; P < 0.001) and low Hemoglobin (HR: 0.41, 95% CI: 0.30-0.56; P < 0.001).	('low LMR', 'Var', (53, 60))	("Hodgkin's lymphoma", 'Disease', (33, 51))	('low', 'NegReg', (222, 225))	('lymphoma', 'Phenotype', 'HP:0002665', (43, 51))	('low albumin', 'Phenotype', 'HP:0003073', (165, 176))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (33, 51))	('high', 'PosReg', (95, 99))	('low', 'NegReg', (165, 168))	('high white blood cell count', 'Phenotype', 'HP:0001974', (95, 122))	('low Hemoglobin', 'Phenotype', 'HP:0001903', (222, 236))	('albumin', 'MPA', (169, 176))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (33, 51))
116379	26942464	LMR was associated with TNM stage in gastric cancer.	('LMR', 'Var', (0, 3))	('gastric cancer', 'Disease', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('TNM', 'Gene', '10178', (24, 27))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('associated', 'Reg', (8, 18))	('TNM', 'Gene', (24, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))
116395	26942464	showed poor clinical outcome associated with macrophage density in various tumor entities.	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('macrophage density', 'Var', (45, 63))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
116408	26942464	Our comprehensive meta-analysis strongly supports a low LMR is associated with adverse survival in various cancers.	('low LMR', 'Var', (52, 59))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('LMR', 'Var', (56, 59))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
116435	27602100	For example, it has been demonstrated that ATF3 expression levels are reduced in human colorectal cancer, and overexpression of ATF3 exhibits tumor suppressive roles, such that the protein reduces metastatic potential and promotes apoptosis in various cell lines to inhibit carcinogenesis.	('promotes', 'PosReg', (222, 230))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('expression levels', 'MPA', (48, 65))	('human', 'Species', '9606', (81, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carcinogenesis', 'Disease', (274, 288))	('ATF3', 'Gene', (43, 47))	('colorectal cancer', 'Disease', (87, 104))	('ATF3', 'Gene', (128, 132))	('reduced', 'NegReg', (70, 77))	('inhibit', 'NegReg', (266, 273))	('carcinogenesis', 'Disease', 'MESH:D063646', (274, 288))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('apoptosis', 'CPA', (231, 240))	('reduces', 'NegReg', (189, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('metastatic potential', 'CPA', (197, 217))	('overexpression', 'Var', (110, 124))
116436	27602100	In addition, ATF3 is able to suppress the oncogenic function of mutant p53 in lung cancer.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('suppress', 'NegReg', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('p53', 'Gene', (71, 74))	('oncogenic function', 'MPA', (42, 60))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('mutant', 'Var', (64, 70))
116444	27602100	Growing evidence suggests that ID1 is an oncogene and is critical in promoting tumor invasion and development, as it is overexpressed in human cancer of the pancreas, thyroid, breast, cervix, ovary, prostate, esophagus and lung, and high expression of ID1 is associated with a poor prognosis.	('esophagus', 'Disease', (209, 218))	('ID1', 'Gene', (31, 34))	('development', 'CPA', (98, 109))	('cancer of the pancreas', 'Disease', (143, 165))	('high expression', 'Var', (233, 248))	('ID1', 'Gene', (252, 255))	('cancer of the pancreas', 'Phenotype', 'HP:0002894', (143, 165))	('thyroid', 'Disease', (167, 174))	('human', 'Species', '9606', (137, 142))	('ovary', 'Disease', (192, 197))	('cervix', 'Disease', (184, 190))	('ovary', 'Disease', 'MESH:D010051', (192, 197))	('ID1', 'Gene', '3397', (31, 34))	('overexpressed', 'PosReg', (120, 133))	('ID1', 'Gene', '3397', (252, 255))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (79, 84))	('breast', 'Disease', (176, 182))	('cancer of the pancreas', 'Disease', 'MESH:D010190', (143, 165))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
116450	27602100	The present study aimed to determine the association between ATF3 and ID1 in ESCC tissues and in vitro by manipulating ATF3 expression.	('ID1', 'Gene', (70, 73))	('association', 'Interaction', (41, 52))	('manipulating', 'Var', (106, 118))	('ATF3', 'Gene', (119, 123))	('ATF3', 'Gene', (61, 65))	('expression', 'MPA', (124, 134))	('ID1', 'Gene', '3397', (70, 73))
116471	27602100	G8795, dilution 1:500) and beta-actin (cat no.	('beta-actin', 'Gene', '728378', (27, 37))	('beta-actin', 'Gene', (27, 37))	('G8795', 'Var', (0, 5))
116474	27602100	To determine the alterations of ID1 at mRNA levels, the EC109 and KYSE450 cells transfected with pFlag-ATF3 or pFlag-cDNA3 were collected after 48 h post transfection.	('ID1', 'Gene', (32, 35))	('pFlag-ATF3', 'Var', (97, 107))	('ID1', 'Gene', '3397', (32, 35))
116505	27602100	The current study observed that increased ATF3 expression was able to suppress the levels of p-STAT3 in the ESCC cell lines, and the downregulation of cyclin D1 and p-STAT3 partially led to inhibition of ESCC cell proliferation in vitro.	('cyclin D1', 'Gene', (151, 160))	('cyclin D1', 'Gene', '595', (151, 160))	('ATF3', 'Gene', (42, 46))	('inhibition', 'NegReg', (190, 200))	('suppress', 'NegReg', (70, 78))	('STAT3', 'Gene', '6774', (167, 172))	('expression', 'Var', (47, 57))	('downregulation', 'NegReg', (133, 147))	('STAT3', 'Gene', (167, 172))	('STAT3', 'Gene', '6774', (95, 100))	('increased', 'PosReg', (32, 41))	('STAT3', 'Gene', (95, 100))	('ESCC cell proliferation in vitro', 'CPA', (204, 236))
116507	27602100	A number of studies have reported that loss of E-cadherin expression increases cancer metastasis by separating cancer cells from another, thus activating specific downstream signal transduction pathways resulting in epithelial-mesenchymal transition.	('activating', 'PosReg', (143, 153))	('E-cadherin', 'Gene', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('epithelial-mesenchymal transition', 'CPA', (216, 249))	('increases cancer metastasis', 'Disease', 'MESH:D009362', (69, 96))	('downstream signal transduction pathways', 'Pathway', (163, 202))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('E-cadherin', 'Gene', '999', (47, 57))	('loss', 'Var', (39, 43))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('increases cancer metastasis', 'Disease', (69, 96))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
116508	27602100	Perturbation of E-cadherin-mediated cell adhesion is implicated in the progression of tumors, poor prognosis and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('implicated', 'Reg', (53, 63))	('E-cadherin', 'Gene', (16, 26))	('E-cadherin', 'Gene', '999', (16, 26))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('metastasis', 'CPA', (113, 123))	('Perturbation', 'Var', (0, 12))
116530	27100871	The three adverse events that occurred more often in the cetuximab arm were neutropenia (22% vs 13%), diarrhea (16% vs 0%), and nausea (13% vs 3%), while fatigue decreased (3% vs 10%).	('neutropenia', 'Disease', (76, 87))	('diarrhea', 'Disease', (102, 110))	('fatigue', 'Phenotype', 'HP:0012378', (154, 161))	('cetuximab', 'Var', (57, 66))	('diarrhea', 'Disease', 'MESH:D003967', (102, 110))	('neutropenia', 'Disease', 'MESH:D009503', (76, 87))	('nausea', 'Phenotype', 'HP:0002018', (128, 134))	('nausea', 'Disease', (128, 134))	('nausea', 'Disease', 'MESH:D009325', (128, 134))	('cetuximab', 'Chemical', 'MESH:D000068818', (57, 66))	('neutropenia', 'Phenotype', 'HP:0001875', (76, 87))	('diarrhea', 'Phenotype', 'HP:0002014', (102, 110))
116588	27100871	Tumor specific EGFR downstream signaling mutations in KRAS, BRAF, PTEN, and PIK3CA cause reduced benefit of cetuximab therapy in colon carcinoma patients.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (145, 153))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PIK3CA', 'Gene', '5290', (76, 82))	('PTEN', 'Gene', (66, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('cetuximab', 'Chemical', 'MESH:D000068818', (108, 117))	('PTEN', 'Gene', '5728', (66, 70))	('PIK3CA', 'Gene', (76, 82))	('KRAS', 'Gene', (54, 58))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('KRAS', 'Gene', '3845', (54, 58))	('reduced', 'NegReg', (89, 96))	('colon carcinoma', 'Disease', 'MESH:D015179', (129, 144))	('colon carcinoma', 'Disease', (129, 144))
116589	27100871	Germ line polymorphisms could also predict response to treatment, as has been studied in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('response', 'Disease', (43, 51))	('colorectal cancer', 'Disease', (89, 106))	('polymorphisms', 'Var', (10, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('predict', 'Reg', (35, 42))
116607	24742268	The myocardium sparing effect of IMRT may explain why esophageal cancer patients treated with IMRT had less cardiac complications and better survival compared to the ones treated with 3D-CRT.	('cardiac complications', 'Disease', (108, 129))	('better', 'PosReg', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('cardiac complications', 'Disease', 'MESH:D005117', (108, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('survival', 'CPA', (141, 149))	('IMRT', 'Var', (94, 98))	('patients', 'Species', '9606', (72, 80))
116626	24742268	Dose constraints for normal organs at risk (OAR) for complications were: spinal cord (Dmax <45 Gy), total lung (V5 < 50%, V10 < 40%, V15 < 30%, and V20 < 25%), cardiac ventricles (V10 < 50%), liver (V30 < 30%), kidneys (V15 < 30%), and bowels (V45 < 50%).	('V5 < 50%', 'Var', (112, 120))	('V15', 'Gene', '28814', (220, 223))	('V15', 'Gene', (133, 136))	('V10 < 50%', 'Var', (180, 189))	('V15', 'Gene', (220, 223))	('V20 < 25%', 'Var', (148, 157))	('V15', 'Gene', '28814', (133, 136))	('V10 < 40%', 'Var', (122, 131))	('V30 < 30%', 'Var', (199, 208))
116688	24742268	However, 3D-RT technique was associated with significant long-term toxicities because of excessive radiation dose to the lungs and hearts, resulting in pneumonitis and heart failures and/or cardiac arrythmia.	('cardiac arrythmia', 'Disease', (190, 207))	('heart failures', 'Disease', 'MESH:D006333', (168, 182))	('cardiac arrythmia', 'Disease', 'MESH:D001145', (190, 207))	('cardiac arrythmia', 'Phenotype', 'HP:0011675', (190, 207))	('heart failures', 'Disease', (168, 182))	('pneumonitis', 'Disease', (152, 163))	('toxicities', 'Disease', (67, 77))	('3D-RT', 'Var', (9, 14))	('pneumonitis', 'Disease', 'MESH:D011014', (152, 163))	('toxicities', 'Disease', 'MESH:D064420', (67, 77))	('heart failures', 'Phenotype', 'HP:0001635', (168, 182))
116846	23241138	Additionally, preferential use of branch chain amino acids, specifically leucine, is characteristic of stress states.	('leucine', 'Chemical', 'MESH:D007930', (73, 80))	('preferential', 'PosReg', (14, 26))	('leucine', 'Var', (73, 80))
116856	23241138	The metabolites most contributory to the overlapping region were related to energy metabolism and cellular proliferation (1-methylhistidine, o-acetylcarnitine) as well as those reflective of muscle wasting, including pi-methylhistidine, creatinine, and a number of amino acids and amino acid derivatives (leucine, tyrosine, isoleucine, valine, tryptophan and 4-hydroxyphenylacetate).	('creatinine', 'Chemical', 'MESH:D003404', (237, 247))	('1-methylhistidine', 'Chemical', 'MESH:C028120', (122, 139))	('valine', 'MPA', (336, 342))	('o-acetylcarnitine', 'Chemical', 'MESH:D000108', (141, 158))	('tryptophan', 'MPA', (344, 354))	('pi-methylhistidine', 'Chemical', 'MESH:C028120', (217, 235))	('4-hydroxyphenylacetate', 'Chemical', 'MESH:C026246', (359, 381))	('leucine', 'Chemical', 'MESH:D007930', (305, 312))	('tyrosine', 'MPA', (314, 322))	('isoleucine', 'MPA', (324, 334))	('cellular proliferation', 'CPA', (98, 120))	('tyrosine', 'Chemical', 'MESH:D014443', (314, 322))	('energy metabolism', 'MPA', (76, 93))	('muscle wasting', 'Phenotype', 'HP:0003202', (191, 205))	('isoleucine', 'Chemical', 'MESH:D007532', (324, 334))	('tryptophan', 'Chemical', 'MESH:D014364', (344, 354))	('leucine', 'Chemical', 'MESH:D007930', (327, 334))	('valine', 'Chemical', 'MESH:D014633', (336, 342))	('pi-methylhistidine', 'Var', (217, 235))
116921	18676871	Formation of O6-methylguanine adducts is considered to be an important early event in NMBA-induced esophageal carcinogenesis because these adducts produce GC AT transition mutations in the second base of codon 12 of the Hras1 oncogene, a gene that is activated early in esophageal tumorigenesis.	('mutations in', 'Var', (172, 184))	('esophageal carcinogenesis', 'Disease', (99, 124))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('AT', 'Disease', 'None', (158, 160))	('C', 'Chemical', 'MESH:D002244', (156, 157))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (13, 29))	('Hras1', 'Gene', '293621', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('NMBA', 'Chemical', 'MESH:C014707', (86, 90))	('Hras1', 'Gene', (220, 225))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (99, 124))
116939	18676871	As noted above, ~ 100% of rat esophageal tumors induced by NMBA have a GC   AT transition mutation in the second base of codon 12 of the Hras1 gene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('C', 'Chemical', 'MESH:D002244', (72, 73))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('esophageal tumors', 'Disease', 'MESH:D004938', (30, 47))	('esophageal tumors', 'Phenotype', 'HP:0100751', (30, 47))	('rat', 'Species', '10116', (26, 29))	('esophageal tumors', 'Disease', (30, 47))	('NMBA', 'Chemical', 'MESH:C014707', (59, 63))	('Hras1', 'Gene', '293621', (137, 142))	('Hras1', 'Gene', (137, 142))	('NMBA', 'Gene', (59, 63))	('mutation in', 'Var', (90, 101))	('AT', 'Disease', 'None', (76, 78))
116964	18676871	Overall, the data support the conclusion that an important mechanism of BRB chemoprevention is correcting expression of NMBA-dysregulated cell junction, adhesion, and motility genes.	('NMBA-dysregulated', 'Gene', (120, 137))	('NMBA', 'Chemical', 'MESH:C014707', (120, 124))	('adhesion', 'CPA', (153, 161))	('correcting', 'Var', (95, 105))	('BRB', 'Chemical', '-', (72, 75))	('motility', 'CPA', (167, 175))
116970	18676871	Therefore, correction of Mcl1 transcription by BRB should augment apoptotic activity in NMBA-initiated cells.	('augment', 'PosReg', (58, 65))	('BRB', 'Chemical', '-', (47, 50))	('NMBA', 'Chemical', 'MESH:C014707', (88, 92))	('Mcl1', 'Gene', '60430', (25, 29))	('BRB', 'Gene', (47, 50))	('correction', 'Var', (11, 21))	('apoptotic activity', 'CPA', (66, 84))	('Mcl1', 'Gene', (25, 29))
116981	18676871	Thus, its normalization by BRB should depress angiogenesis.	('BRB', 'Chemical', '-', (27, 30))	('BRB', 'Gene', (27, 30))	('normalization', 'Var', (10, 23))	('depress', 'NegReg', (38, 45))	('angiogenesis', 'CPA', (46, 58))
116992	18676871	Mutations in spindle checkpoint function kinase gene Bub1 have been associated with aneuploidy.	('Bub1', 'Gene', '296137', (53, 57))	('Bub1', 'Gene', (53, 57))	('associated', 'Reg', (68, 78))	('aneuploidy', 'Disease', (84, 94))	('Mutations', 'Var', (0, 9))	('aneuploidy', 'Disease', 'MESH:D000782', (84, 94))
117002	18676871	Thus, its dysregulation may cause inappropriate expression of genes with oncogenic or tumor suppressor activities.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('expression of genes', 'MPA', (48, 67))	('tumor', 'Disease', (86, 91))	('dysregulation', 'Var', (10, 23))	('cause', 'Reg', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
117043	33155374	Histopathology of the resected specimen confirmed squamous cell carcinoma with pT3N1M0, stage IIIB disease (Fig 3c-e).	('stage IIIB disease', 'Disease', (88, 106))	('pT3N1M0', 'Var', (79, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 73))	('stage IIIB disease', 'Disease', 'MESH:D009084', (88, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('squamous cell carcinoma', 'Disease', (50, 73))
117046	33155374	Most reported cases of esophageal cancer with SIT underwent hybrid MIE and the right decubitus position was adopted during the thoracic procedure.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('SIT', 'Disease', 'None', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('hybrid', 'Var', (60, 66))	('SIT', 'Disease', (46, 49))
117061	32403416	Here we presented the first set of methylation signatures with a higher predictive power for characterizing gastroesophageal tumors.	('gastroesophageal tumors', 'Disease', 'MESH:D005764', (108, 131))	('gastroesophageal tumor', 'Phenotype', 'HP:0100751', (108, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('methylation', 'Var', (35, 46))	('gastroesophageal tumors', 'Phenotype', 'HP:0100751', (108, 131))	('gastroesophageal tumors', 'Disease', (108, 131))	('esophageal tumors', 'Phenotype', 'HP:0100751', (114, 131))	('esophageal tumor', 'Phenotype', 'HP:0100751', (114, 130))
117082	32403416	found that, at the gene level of many cancer types, different methylation patterns can yield similar gene expressions.	('methylation patterns', 'Var', (62, 82))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('yield', 'Reg', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))
117105	32403416	Similarly, an independent validation dataset was formed using the methylation array data from the cohorts of GSE72872, GSE30601, GSE32925, and GSE81334 (nEC = 164, nGC = 383; referred to as V1).	('GSE72872', 'Var', (109, 117))	('GSE30601', 'Var', (119, 127))	('GSE81334', 'Var', (143, 151))	('EC', 'Disease', 'MESH:D005955', (154, 156))	('GSE32925', 'Var', (129, 137))
117243	30370344	An unfortunate commonality of these disease sites in Appalachian patients is the disparate access to optimal RT as a result of a number of socioeconomic factors, including but not limited to low income, lack of private insurance, limited access to diagnostic and treatment services (ie, colonoscopy for colorectal cancer screening), paucities in both number and quality of radiation centers, decreased access to up-to-date treatment recommendations, and the geographic region of the United States.	('colorectal cancer', 'Disease', 'MESH:D015179', (303, 320))	('colon', 'Disease', (287, 292))	('colorectal cancer', 'Phenotype', 'HP:0003003', (303, 320))	('decreased', 'NegReg', (392, 401))	('men', 'Species', '9606', (268, 271))	('colon', 'Disease', 'MESH:D015179', (287, 292))	('colorectal cancer', 'Disease', (303, 320))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('men', 'Species', '9606', (438, 441))	('patients', 'Species', '9606', (65, 73))	('men', 'Species', '9606', (428, 431))	('rectal cancer', 'Phenotype', 'HP:0100743', (307, 320))	('paucities', 'Var', (333, 342))
117258	23303440	In the 30 years since the discovery of H. pylori in the human stomach, there has been substantial evidence linking gastric colonization of H. pylori to increased risks of gastric adenocarcinoma, peptic ulcer disease, and lymphoma.	('peptic ulcer', 'Phenotype', 'HP:0004398', (195, 207))	('H. pylori', 'Species', '210', (39, 48))	('lymphoma', 'Phenotype', 'HP:0002665', (221, 229))	('peptic ulcer disease', 'Disease', (195, 215))	('gastric adenocarcinoma', 'Disease', (171, 193))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (171, 193))	('H. pylori', 'Var', (139, 148))	('human', 'Species', '9606', (56, 61))	('lymphoma', 'Disease', (221, 229))	('H. pylori', 'Species', '210', (139, 148))	('peptic ulcer disease', 'Disease', 'MESH:D010437', (195, 215))	('lymphoma', 'Disease', 'MESH:D008223', (221, 229))
117288	23303440	The final study population for association between cagA positivity and mortality included 7,354 subjects, over 105930 person-years of observation.	('positivity', 'Var', (56, 66))	('person', 'Species', '9606', (118, 124))	('association', 'Interaction', (31, 42))	('cagA', 'Gene', (51, 55))	('cagA', 'Gene', '6279', (51, 55))
117310	23303440	Subjects who were H. pylori-positive or H. pylori-positive/cagA-positive were more likely to be older, have lower educational attainment, have larger household size, and have higher body mass index, than H. pylori-negative or H. pylori-negative/cagA-negative subjects.	('higher body mass index', 'Phenotype', 'HP:0031418', (175, 197))	('cagA', 'Gene', (245, 249))	('H. pylori', 'Species', '210', (40, 49))	('H. pylori', 'Species', '210', (226, 235))	('higher', 'PosReg', (175, 181))	('cagA', 'Gene', '6279', (245, 249))	('lower educational attainment', 'Phenotype', 'HP:0001249', (108, 136))	('men', 'Species', '9606', (132, 135))	('cagA', 'Gene', (59, 63))	('H. pylori', 'Species', '210', (18, 27))	('body mass index', 'MPA', (182, 197))	('lower', 'NegReg', (108, 113))	('H. pylori', 'Species', '210', (204, 213))	('cagA', 'Gene', '6279', (59, 63))	('H. pylori-positive', 'Var', (18, 36))
117334	23303440	There was a strongly positive association between H. pylori-positivity and gastric cancer mortality, and positive associations of similar magnitude were observed for subjects who were H. pylori-positive/cagA-negative or H. pylori-positive/cagA-positive compared to those who were H. pylori-negative/cagA-negative.	('cagA', 'Gene', (239, 243))	('H. pylori', 'Species', '210', (220, 229))	('gastric cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cagA', 'Gene', '6279', (299, 303))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('cagA', 'Gene', (203, 207))	('positive', 'PosReg', (21, 29))	('H. pylori-positivity', 'Var', (50, 70))	('cagA', 'Gene', (299, 303))	('cagA', 'Gene', '6279', (239, 243))	('H. pylori', 'Species', '210', (184, 193))	('H. pylori', 'Species', '210', (280, 289))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('H. pylori', 'Species', '210', (50, 59))	('cagA', 'Gene', '6279', (203, 207))
117385	23303440	CI Confidence Interval ELISA enzyme-linked immunoassay FDR false discovery rate              H. pylori                           Helicobacter pylori              HR Hazard Ratio ICD-9 International Classification of Diseases, Ninth Revision ICD-10 International Statistical Classification of Diseases and Related Health Problems, 10th Revision NHANES III The National Health and Nutrition Examination Survey III NCHS National Center for Health Statistics NDI National Death Index H.pylori colonization has been associated with increased risk of gastric cancer, and reduced risks of asthma and allergy.	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (527, 559))	('allergy', 'Disease', (593, 600))	('gastric cancer', 'Disease', (545, 559))	('H.pylori', 'Var', (480, 488))	('reduced', 'NegReg', (565, 572))	('allergy', 'Phenotype', 'HP:0012393', (593, 600))	('gastric cancer', 'Disease', 'MESH:D013274', (545, 559))	('asthma', 'Disease', (582, 588))	('H.pylori', 'Species', '210', (480, 488))	('cancer', 'Phenotype', 'HP:0002664', (553, 559))	('asthma', 'Disease', 'MESH:D001249', (582, 588))	('H. pylori', 'Species', '210', (93, 102))	('allergy', 'Disease', 'MESH:D004342', (593, 600))	('asthma', 'Phenotype', 'HP:0002099', (582, 588))	('gastric cancer', 'Phenotype', 'HP:0012126', (545, 559))	('Helicobacter pylori', 'Species', '210', (129, 148))
117394	23054397	Here we extend the MSCE model to include clonal expansion of malignant cells, an advance that permits study of the effects of tumor growth and extinction on the incidence of colorectal, gastric, pancreatic and esophageal adenocarcinomas in the digestive tract.	('carcinomas', 'Phenotype', 'HP:0030731', (226, 236))	('esophageal adenocarcinomas', 'Disease', (210, 236))	('colorectal', 'Disease', 'MESH:D015179', (174, 184))	('pancreatic', 'Disease', 'MESH:D010195', (195, 205))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('clonal', 'Var', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('colorectal', 'Disease', (174, 184))	('pancreatic', 'Disease', (195, 205))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (210, 236))	('gastric', 'Disease', (186, 193))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (210, 235))	('tumor', 'Disease', (126, 131))
117398	23054397	However, long before symptoms signal cancer growth, several initiating mutations are generally required to overcome normal homeostatic regulation in a tissue allowing the gradual expansion of premalignant clones.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('homeostatic regulation', 'MPA', (123, 145))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
117400	23054397	In the context of the multistage-clonal-expansion (MSCE) carcinogenesis model described here, the first clonal expansion begins after normal tissue stem cells acquire two rate-limiting mutations or epigenomic changes that lead to abrogation of homeostatic tissue control, causing gradual outgrowth of occult premalignant clones over an extended time period that may range from years to decades.	('homeostatic tissue control', 'MPA', (244, 270))	('abrogation', 'NegReg', (230, 240))	('carcinogenesis', 'Disease', 'MESH:D063646', (57, 71))	('causing', 'Reg', (272, 279))	('changes', 'Var', (209, 216))	('carcinogenesis', 'Disease', (57, 71))	('gradual outgrowth', 'Phenotype', 'HP:0001548', (280, 297))	('outgrowth', 'PosReg', (288, 297))	('mutations', 'Var', (185, 194))	('epigenomic', 'Var', (198, 208))
117401	23054397	Clonal expansion of the premalignant cell population enhances the probability that one or more of these cells suffer additional mutations or epigenomic alterations that cause malignant transformation which enables tumors to accelerate their growth and invade neighboring tissue, a process captured by the second (malignant) clonal expansion in the model.	('growth', 'CPA', (241, 247))	('mutations', 'Var', (128, 137))	('enhances', 'PosReg', (53, 61))	('Clonal', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('accelerate', 'PosReg', (224, 234))	('tumors', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('invade', 'CPA', (252, 258))
117413	23054397	This is consistent with results from evolutionary models which find neoplastic progression to be driven mainly by mutations that confer only slight improvements in fitness, while the transition from a non-invasive to an invasive tumor, which expands with a significantly higher growth rate, constitutes a critical, rate-limiting event.	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('mutations', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('neoplastic', 'CPA', (68, 78))	('tumor', 'Disease', (229, 234))	('fitness', 'Disease', (164, 171))	('fitness', 'Disease', 'MESH:D012640', (164, 171))
117416	23054397	The two significant initial hits may represent biallelic inactivation of tumor suppressor genes, such as Tp53 or P16 that occur frequently in many cancers, or the Apc gene in colorectal cancer (CRC).	('P16', 'Gene', (113, 116))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('Tp53', 'Gene', '7157', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colorectal cancer', 'Disease', (175, 192))	('P16', 'Gene', '1029', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('Apc gene', 'Gene', (163, 171))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('Tp53', 'Gene', (105, 109))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('biallelic inactivation', 'Var', (47, 69))
117417	23054397	Inactivation of TP53 is seen during early development of many digestive tract cancers, including gastric (GaC), pancreatic (PaC), and esophageal adenocarcinomas (EAC).	('PaC', 'Phenotype', 'HP:0006699', (124, 127))	('tract cancers', 'Disease', (72, 85))	('pancreatic', 'Disease', 'MESH:D010195', (112, 122))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (134, 160))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('tract cancers', 'Disease', 'MESH:D014571', (72, 85))	('pancreatic', 'Disease', (112, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('esophageal adenocarcinomas', 'Disease', (134, 160))	('gastric', 'Disease', (97, 104))	('TP53', 'Gene', '7157', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (134, 159))	('TP53', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
117418	23054397	Inactivation of P16 often occurs early in the development of EAC and other cancers.	('occurs', 'Reg', (26, 32))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('EAC', 'Disease', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('P16', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))	('P16', 'Gene', '1029', (16, 19))
117419	23054397	However, the two hits may also represent activation of an oncogene such as Kras in combination with gain-of-function mutation in a tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Kras', 'Gene', (75, 79))	('tumor', 'Disease', (131, 136))	('gain-of-function', 'PosReg', (100, 116))	('activation', 'PosReg', (41, 51))	('mutation', 'Var', (117, 125))
117425	23054397	Clonal expansion of P cells is represented by a stochastic birth-death-mutation (bdm) process with cell division rate alphaP, death-or-differentiation rate betaP, and mutation rate mu2.	('mu2', 'Gene', (181, 184))	('mutation', 'Var', (167, 175))	('mu2', 'Gene', '10053', (181, 184))	('birth-death-mutation', 'Disease', (59, 79))
117427	23054397	Premalignant P cells may suffer further mutations with rate mu2 which transform them into malignant (M) cancer stem cells.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mu2', 'Gene', '10053', (60, 63))	('mu2', 'Gene', (60, 63))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (104, 110))	('transform', 'Reg', (70, 79))
117428	23054397	Although the premalignant cell population is likely to undergo a complex evolutionary process involving multiple mutations in critical regulatory pathways before acquiring a malignant phenotype, only two initial rate-limiting mutations prior to clonal expansion appear necessary to adequately describe the main shape of the incidence curve for the four digestive tract cancers studied here.	('cancers', 'Phenotype', 'HP:0002664', (369, 376))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('mutations', 'Var', (113, 122))	('tract cancers', 'Disease', (363, 376))	('tract cancers', 'Disease', 'MESH:D014571', (363, 376))
117444	23054397	Incident cancers were defined using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) as follows: colorectal cancer (C18-C20); esophageal (C150-C159, 8140/3 adenocarcinoma NOS); gastric cancer (C16); and pancreatic cancer (C25).	('adenocarcinoma NOS', 'Disease', (190, 208))	('pancreatic cancer', 'Disease', 'MESH:D010190', (237, 254))	('C150-C159', 'Var', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('pancreatic cancer', 'Disease', (237, 254))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('gastric cancer', 'Disease', (211, 225))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Oncology', 'Phenotype', 'HP:0002664', (85, 93))	('adenocarcinoma NOS', 'Disease', 'MESH:D000230', (190, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (237, 254))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('colorectal cancer', 'Disease', (131, 148))	('esophageal', 'Disease', (160, 170))
117559	23019389	Other recent studies have stated that PDT can be used as an effective treatment modality in combination with other techniques, such as stents and radiation therapy for palliation of obstructive esophageal cancer, alleviating dysphagia.	('palliation of obstructive esophageal cancer', 'Disease', 'MESH:D004938', (168, 211))	('palliation of obstructive esophageal cancer', 'Disease', (168, 211))	('PDT', 'Var', (38, 41))	('dysphagia', 'Disease', (225, 234))	('alleviating', 'NegReg', (213, 224))	('dysphagia', 'Phenotype', 'HP:0002015', (225, 234))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('dysphagia', 'Disease', 'MESH:D003680', (225, 234))
117561	23019389	In terms of treating difficult lesions, PDT has a significant advantage, compared with stents, in treating advanced esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('PDT', 'Var', (40, 43))	('esophageal cancer', 'Disease', (116, 133))
117683	33533655	The RTOG 94-05 (INT 0123) Phase III trial demonstrated that high-dose radiotherapy plus FP did not increase survival or local/regional control with a higher toxicity rate compared with standard-dose radiotherapy plus FP in patients with T1-T4N0/1M0 primary esophageal cancer.	('toxicity', 'Disease', 'MESH:D064420', (157, 165))	('T1-T4N0/1M0', 'Var', (237, 248))	('toxicity', 'Disease', (157, 165))	('esophageal cancer', 'Disease', (257, 274))	('esophageal cancer', 'Disease', 'MESH:D004938', (257, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('patients', 'Species', '9606', (223, 231))
117720	33533655	Randomization will be performed using an interactive response technology system and will be stratified according to PD-L1 status (CPS >=10 or CPS <10), radiation dose (50 or 60 Gy), and geographic region and histology (ESCC, East Asia; ESCC, all other regions; EAC, any region).	('CPS >=10', 'Var', (130, 138))	('CPS', 'Chemical', '-', (142, 145))	('ESCC', 'Disease', (236, 240))	('CPS <10', 'Var', (142, 149))	('CPS', 'Chemical', '-', (130, 133))
117740	33533655	Exploratory biomarker investigation may include genetic, microsatellite instability DNA, RNA and proteomic analyses of blood and tumor tissue samples.	('microsatellite instability', 'Var', (57, 83))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))
117753	33533655	In the esophageal cohort of the Phase Ib KEYNOTE-028 trial, pembrolizumab was associated with durable antitumor activity and a manageable safety profile in heavily pretreated, PD-L1+ advanced esophageal carcinoma.	('esophageal carcinoma', 'Disease', (192, 212))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (192, 212))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (192, 212))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('pembrolizumab', 'Chemical', 'MESH:C582435', (60, 73))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PD-L1+', 'Var', (176, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('tumor', 'Disease', (106, 111))
117789	32651652	Correspondingly, perioperative immunonutrition was found to reduce postoperative morbidity in gastrointestinal cancer surgery in a systematic review of randomized controlled trials (RCTs).	('reduce', 'NegReg', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('perioperative', 'Var', (17, 30))	('postoperative morbidity', 'MPA', (67, 90))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (94, 117))
117798	32651652	However, excessive fluid restriction may cause hypovolemia, hypotension, and need for catecholamines, thus increasing the risk for ischemia and AL.	('ischemia', 'Disease', (131, 139))	('hypotension', 'Disease', 'MESH:D007022', (60, 71))	('hypovolemia', 'Disease', 'MESH:D020896', (47, 58))	('excessive', 'Var', (9, 18))	('need for catecholamines', 'MPA', (77, 100))	('hypovolemia', 'Disease', (47, 58))	('ischemia', 'Disease', 'MESH:D007511', (131, 139))	('hypotension', 'Phenotype', 'HP:0002615', (60, 71))	('hypotension', 'Disease', (60, 71))	('cause', 'Reg', (41, 46))	('increasing', 'PosReg', (107, 117))	('excessive fluid restriction', 'Phenotype', 'HP:0011032', (9, 36))	('hypovolemia', 'Phenotype', 'HP:0011106', (47, 58))	('catecholamines', 'Chemical', 'MESH:D002395', (86, 100))
117805	32651652	Accordingly, removal of the lesser curvature during gastric tubulization may induce ischemia of the upper part of the stomach and increase the risk for AL.	('removal', 'Var', (13, 20))	('ischemia', 'Disease', (84, 92))	('ischemia', 'Disease', 'MESH:D007511', (84, 92))	('increase', 'PosReg', (130, 138))	('induce', 'Reg', (77, 83))
117813	32651652	In extreme cases, division of the branches of the right gastric artery, or even duodenal or pyloric diversion on a jejunal limb may generate extra mobility.	('gastric artery', 'Disease', (56, 70))	('division', 'Var', (18, 26))	('gastric artery', 'Disease', 'MESH:D013272', (56, 70))	('duodenal', 'Disease', (80, 88))
117820	32651652	In addition, gastric devascularization may lead to a demarcation of ischemic areas, facilitating the choice of the best location for anastomotic reconstruction.	('ischemic', 'Disease', (68, 76))	('gastric', 'Disease', (13, 20))	('lead to', 'Reg', (43, 50))	('ischemic', 'Disease', 'MESH:D007511', (68, 76))	('devascularization', 'Var', (21, 38))
117846	32923165	Significantly higher rate of natural killer (NK) cells (CD57+), intraepithelial CD8 + T lymphocytes and degranulating T- and NK-cells (CD107+) were observed in the healthy mucosa of patients with pCR.	('CD8', 'Gene', '925', (80, 83))	('degranulating', 'MPA', (104, 117))	('patients', 'Species', '9606', (182, 190))	('CD57', 'Gene', (56, 60))	('CD57', 'Gene', '27087', (56, 60))	('CD8', 'Gene', (80, 83))	('CD107+', 'Var', (135, 141))	('higher', 'PosReg', (14, 20))
117861	32923165	In addition, in these neoplasms, CD3+ and CD8+ tumor-infiltrating lymphocytes (TIL) show functional exhaustion and express high levels of PD-1.	('CD3+', 'Var', (33, 37))	('neoplasms', 'Phenotype', 'HP:0002664', (22, 31))	('CD8', 'Gene', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('PD-1', 'Gene', (138, 142))	('PD-1', 'Gene', '5133', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('neoplasms', 'Disease', 'MESH:D009369', (22, 31))	('CD8', 'Gene', '925', (42, 45))	('neoplasms', 'Disease', (22, 31))	('tumor', 'Disease', (47, 52))
117877	32923165	Based on preoperative staging, tumors staged T3N0 or any T N1 (locally advanced esophageal cancer) were considered suitable for neoadjuvant therapy.	('T N1', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('T3N0', 'Var', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
117897	32923165	Single-cell suspensions were subjected to flow cytometry to determine the proportion of activated CD8 + T cells (positive for CD28 and CD38) and epithelial cells acting as antigen-presenting cells (Cytokeratin+HLA-ABC+ and Cytokeratin+CD80+).	('CD80', 'Gene', '941', (235, 239))	('CD8', 'Gene', (98, 101))	('CD8', 'Gene', (235, 238))	('CD8', 'Gene', '925', (235, 238))	('Cytokeratin+HLA-ABC+', 'Var', (198, 218))	('CD8', 'Gene', '925', (98, 101))	('CD28', 'Gene', (126, 130))	('CD38', 'Gene', (135, 139))	('CD28', 'Gene', '940', (126, 130))	('CD80', 'Gene', (235, 239))	('CD38', 'Gene', '952', (135, 139))
117913	32923165	Finally, patients with complete response showed a globally higher number of CD107+ cells (p = .005) but not CD8+ cells (Figure 3(b)).	('patients', 'Species', '9606', (9, 17))	('CD107+ cells', 'Var', (76, 88))	('CD8', 'Gene', (108, 111))	('CD8', 'Gene', '925', (108, 111))	('higher', 'PosReg', (59, 65))
117943	32923165	However, patients with pCR showed a globally higher number of CD57+ and CD107+ cells but not CD8+ cells suggesting that NK activated cells play a direct role in the pCR and that their high infiltration in the healthy mucosa can be seen as an echo of the past battle.	('pCR', 'Disease', (165, 168))	('patients', 'Species', '9606', (9, 17))	('CD107+ cells', 'Var', (72, 84))	('CD57', 'Gene', (62, 66))	('CD57', 'Gene', '27087', (62, 66))	('CD8', 'Gene', (93, 96))	('CD8', 'Gene', '925', (93, 96))	('higher', 'PosReg', (45, 51))	('pCR', 'Disease', (23, 26))
117960	32923165	In healthy esophageal mucosa after pCR TLR4 might play in the innate immune activation binding to HMGB1 (High Mobility Group Box 1) released by cancer cell necrosis due to neoadjuvant therapy.	('cancer cell necrosis', 'Disease', (144, 164))	('HMGB1', 'Gene', (98, 103))	('HMGB1', 'Gene', '3146', (98, 103))	('play', 'Reg', (50, 54))	('cancer cell necrosis', 'Disease', 'MESH:D009369', (144, 164))	('High Mobility Group Box 1', 'Gene', '3146', (105, 130))	('binding', 'Interaction', (87, 94))	('TLR4', 'Gene', '7099', (39, 43))	('pCR', 'Var', (35, 38))	('TLR4', 'Gene', (39, 43))	('High Mobility Group Box 1', 'Gene', (105, 130))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
118014	29788901	reported a more enjoyable life and less interference with daily and social activities for the patients treated with self-dilation, with an improved long-term (32 months) overall health-related quality of life in 90% of cases.	('patients', 'Species', '9606', (94, 102))	('self-dilation', 'Var', (116, 129))	('improved', 'PosReg', (139, 147))	('more', 'PosReg', (11, 15))	('enjoyable life', 'CPA', (16, 30))
118074	29202716	Among 40 patients with high CRP levels, 16 developed SICs; anastomotic leakage in 12 patients, pneumonia in 2, abdominal abscess in 1, and pyothorax in 3.	('patients', 'Species', '9606', (9, 17))	('SICs', 'Disease', 'None', (53, 57))	('high', 'Var', (23, 27))	('pyothorax', 'Disease', (139, 148))	('CRP', 'Gene', (28, 31))	('SICs', 'Disease', (53, 57))	('anastomotic leakage', 'Disease', (59, 78))	('CRP', 'Gene', '1401', (28, 31))	('abscess', 'Phenotype', 'HP:0025615', (121, 128))	('abdominal abscess', 'Phenotype', 'HP:0025181', (111, 128))	('pneumonia', 'Phenotype', 'HP:0002090', (95, 104))	('patients', 'Species', '9606', (85, 93))	('pyothorax', 'Phenotype', 'HP:0011919', (139, 148))	('pneumonia', 'Disease', (95, 104))	('pneumonia', 'Disease', 'MESH:D011014', (95, 104))	('abdominal abscess', 'Disease', (111, 128))
118078	29202716	A high CRP level on POD 4 may encourage the performance of imaging studies to detect the focus and thereby lead to early medical and/or surgical intervention.	('lead to', 'Reg', (107, 114))	('imaging', 'CPA', (59, 66))	('high', 'Var', (2, 6))	('CRP', 'Gene', (7, 10))	('CRP', 'Gene', '1401', (7, 10))	('encourage', 'PosReg', (30, 39))
118116	26644118	Combining 5 studies (1 from each database), we found no increased risk, OR 1.11 (95% CI 0.97 to 1.27) of esophageal cancer in bisphosphonate users compared with non-users and no increased risk of gastric cancer in bisphosphonate users, OR 0.96 (95% CI 0.82 to 1.12).	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (178, 210))	('OR 1.11', 'Gene', (72, 79))	('bisphosphonate', 'Chemical', 'MESH:D004164', (126, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (196, 210))	('OR 1.11', 'Gene', '10823', (72, 79))	('bisphosphonate', 'Var', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('esophageal cancer', 'Disease', (105, 122))	('bisphosphonate', 'Chemical', 'MESH:D004164', (214, 228))	('gastric cancer', 'Disease', 'MESH:D013274', (196, 210))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('gastric cancer', 'Disease', (196, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))
118326	18990762	Associations between variants of the 8q24 chromosome and nine smoking-related cancer sites Recent genome-wide association (GWA) studies identified key single nucleotide polymorphisms (SNPs) in the 8q24 region to be associated with prostate cancer.	('variants', 'Var', (21, 29))	('Associations', 'Interaction', (0, 12))	('prostate cancer', 'Disease', (231, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('single nucleotide polymorphisms', 'Var', (151, 182))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (231, 246))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (240, 246))	('prostate cancer', 'Phenotype', 'HP:0012125', (231, 246))	('associated', 'Reg', (215, 225))
118327	18990762	8q24 SNPs have also been associated with colorectal cancer, suggesting this region may not be specifically associated to just prostate cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('associated', 'Reg', (25, 35))	('colorectal cancer', 'Disease', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('prostate cancer', 'Disease', (126, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('8q24 SNPs', 'Var', (0, 9))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))
118329	18990762	Using epidemiological data and biological samples previously collected in three case-control studies from U.S. and Chinese populations, we selected and genotyped one SNP from each of the three previously determined "regions" within the 8q24 loci: rs1447295 (region 1), rs16901979 (region 2), and rs6983267 (region 3), and examined their association with cancers of the lung, oropharynx, nasopharynx, larynx, esophagus, stomach, liver, bladder, and kidney.	('kidney', 'Disease', (448, 454))	('rs1447295', 'Mutation', 'rs1447295', (247, 256))	('stomach', 'Disease', (419, 426))	('esophagus', 'Disease', (408, 417))	('rs6983267', 'Var', (296, 305))	('nasopharynx', 'Disease', (387, 398))	('liver', 'Disease', (428, 433))	('rs16901979', 'Var', (269, 279))	('bladder', 'Disease', (435, 442))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('cancers of the lung', 'Disease', (354, 373))	('rs1447295', 'Var', (247, 256))	('larynx', 'Disease', (400, 406))	('rs6983267', 'Mutation', 'rs6983267', (296, 305))	('oropharynx', 'Disease', (375, 385))	('rs16901979', 'Mutation', 'rs16901979', (269, 279))	('cancers of the lung', 'Disease', 'MESH:D008175', (354, 373))	('cancers', 'Phenotype', 'HP:0002664', (354, 361))
118330	18990762	We observed noteworthy associations between rs6983267 and upper aero-digestive tract (UADT) cancers (ORadj=1.69, 95% CI=1.28, 2.24), particularly in oropharynx (ORadj=1.80, 95% CI=1.30, 2.49) and larynx (ORadj=2.04, 95% CI=1.12, 3.72).	('larynx', 'Disease', (196, 202))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('rs6983267', 'Mutation', 'rs6983267', (44, 53))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('oropharynx', 'Disease', (149, 159))	('cancers', 'Disease', (92, 99))	('associations', 'Interaction', (23, 35))	('upper aero-digestive tract', 'Disease', (58, 84))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('rs6983267', 'Var', (44, 53))	('UADT', 'Chemical', '-', (86, 90))
118331	18990762	We also observed a suggestive association between rs6983267 and liver cancer (ORadj=1.51, 95% CI=0.99, 2.31).	('liver cancer', 'Disease', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('rs6983267', 'Var', (50, 59))	('rs6983267', 'Mutation', 'rs6983267', (50, 59))	('liver cancer', 'Phenotype', 'HP:0002896', (64, 76))	('liver cancer', 'Disease', 'MESH:D006528', (64, 76))
118332	18990762	When we stratified our analysis by smoking status, rs6983267 was positively associated with lung cancer among ever-smokers (ORadj=1.45, 95% CI=1.05, 2.00) and inversely associated with bladder cancer among ever-smokers (ORadj=0.35, 95% CI=0.14, 0.83).	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('rs6983267', 'Var', (51, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (185, 199))	('rs6983267', 'Mutation', 'rs6983267', (51, 60))	('associated', 'Reg', (169, 179))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('bladder cancer', 'Disease', (185, 199))	('bladder cancer', 'Disease', 'MESH:D001749', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('inversely', 'NegReg', (159, 168))
118333	18990762	Associations were observed between rs16901979 and UADT cancer among never-smokers, and between rs1447295 and liver cancer among ever-smokers.	('UADT cancer', 'Disease', (50, 61))	('liver cancer', 'Disease', (109, 121))	('UADT cancer', 'Disease', 'MESH:D006258', (50, 61))	('Associations', 'Interaction', (0, 12))	('rs1447295', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rs16901979', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rs16901979', 'Mutation', 'rs16901979', (35, 45))	('liver cancer', 'Phenotype', 'HP:0002896', (109, 121))	('liver cancer', 'Disease', 'MESH:D006528', (109, 121))	('rs1447295', 'Mutation', 'rs1447295', (95, 104))
118334	18990762	Our results suggest variants of the 8q24 chromosome may play an important role in smoking-related cancer development.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('play', 'Reg', (56, 60))	('variants', 'Var', (20, 28))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('role', 'Reg', (74, 78))	('cancer', 'Disease', (98, 104))
118342	18990762	Amplification within the 8q24 loci has been observed within a diverse group of cancers.	('cancers', 'Disease', (79, 86))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('observed', 'Reg', (44, 52))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
118343	18990762	Recent genome-wide association (GWA) studies identified associations between genetic variants or single nucleotide polymorphisms (SNPs): DG8S737, rs1447295, rs16901979, and rs6983267, along the 8q24 region and prostate cancer among multiple study populations: Icelandic, Swedish, European-American, African American, and the Multiethnic Cohort.	('rs16901979', 'Var', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('rs1447295', 'Mutation', 'rs1447295', (146, 155))	('prostate cancer', 'Disease', 'MESH:D011471', (210, 225))	('associations', 'Interaction', (56, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (210, 225))	('rs16901979', 'Mutation', 'rs16901979', (157, 167))	('rs6983267', 'Var', (173, 182))	('rs1447295', 'Var', (146, 155))	('prostate cancer', 'Disease', (210, 225))	('rs6983267', 'Mutation', 'rs6983267', (173, 182))	('DG8S737', 'Var', (137, 144))
118345	18990762	DG8S737 and rs1447295 variants from "region 1" were previously observed to have strong associations with prostate cancer.	('rs1447295', 'Var', (12, 21))	('DG8S737', 'Var', (0, 7))	('prostate cancer', 'Disease', (105, 120))	('associations', 'Interaction', (87, 99))	('rs1447295', 'Mutation', 'rs1447295', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))
118346	18990762	Furthermore, studies have investigated the associations between variants of 8q24 region and cancers of the breast, colon, endometrium and testes.	('endometrium', 'Disease', (122, 133))	('testes', 'Disease', (138, 144))	('8q24 region', 'Gene', (76, 87))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('colon', 'Disease', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancers of the breast', 'Phenotype', 'HP:0100013', (92, 113))	('variants', 'Var', (64, 72))	('investigated', 'Reg', (26, 38))
118347	18990762	It is still unknown whether SNPs at 8q24 region are associated with tobacco smoking-related cancer sites.	('SNPs at', 'Var', (28, 35))	('cancer', 'Disease', (92, 98))	('tobacco', 'Species', '4097', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('associated', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
118349	18990762	Additionally, a number of studies observed associations between colorectal cancer and SNPs rs6983267; therefore, we hypothesize that 8q24 SNPs may be associated with smoking-related cancers.	('associated', 'Reg', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('colorectal cancer', 'Disease', (64, 81))	('rs6983267', 'Mutation', 'rs6983267', (91, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('8q24 SNPs', 'Var', (133, 142))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('associations', 'Interaction', (43, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))
118369	18990762	We selected from each "region" the strongest single association SNPs, "region 1": rs1447295, "region 2": rs16901979, and "region 3": rs6983267.	('rs1447295', 'Var', (82, 91))	('rs16901979', 'Mutation', 'rs16901979', (105, 115))	('rs6983267', 'Mutation', 'rs6983267', (133, 142))	('rs6983267', 'Var', (133, 142))	('rs1447295', 'Mutation', 'rs1447295', (82, 91))	('rs16901979', 'Var', (105, 115))
118379	18990762	Lastly, for the MSKCC study of bladder cancer, we adjusted for the following factors: gender, age (< 55, 55-<60, 60-<65, >=65), race (white vs nonwhite), and smoking (never vs. ever).	('< 55', 'Var', (99, 103))	('bladder cancer', 'Phenotype', 'HP:0009725', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('bladder cancer', 'Disease', 'MESH:D001749', (31, 45))	('bladder cancer', 'Disease', (31, 45))
118383	18990762	Due to the overwhelming evidence of associations between 8q24 variants with prostate and colon cancer, we assigned a prior probability range of 0.01-0.1 to detect an OR of 1.5 or 0.67.	('8q24', 'Gene', (57, 61))	('variants', 'Var', (62, 70))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('associations', 'Interaction', (36, 48))	('colon cancer', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('prostate', 'Disease', (76, 84))
118387	18990762	Table 2 presents ORs and 95% CIs for rs1447295, rs16901979, and rs6983267.	('rs1447295', 'Var', (37, 46))	('rs16901979', 'Var', (48, 58))	('rs6983267', 'Mutation', 'rs6983267', (64, 73))	('rs16901979', 'Mutation', 'rs16901979', (48, 58))	('rs1447295', 'Mutation', 'rs1447295', (37, 46))	('rs6983267', 'Var', (64, 73))
118388	18990762	After initial analyses by genotyping of each SNP, we determined the dominant model was appropriate for rs1447295 and rs16901979 in all cancer sites, whereas for rs6983267, the recessive model was appropriate for all sites except nasopharynx, stomach, and liver cancers, where the dominant model was employed.	('stomach', 'Disease', (242, 249))	('nasopharynx', 'Disease', (229, 240))	('rs1447295', 'Var', (103, 112))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('liver cancers', 'Disease', 'MESH:D006528', (255, 268))	('cancer', 'Disease', (261, 267))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('rs6983267', 'Var', (161, 170))	('liver cancer', 'Phenotype', 'HP:0002896', (255, 267))	('rs16901979', 'Var', (117, 127))	('liver cancers', 'Phenotype', 'HP:0002896', (255, 268))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('rs1447295', 'Mutation', 'rs1447295', (103, 112))	('rs6983267', 'Mutation', 'rs6983267', (161, 170))	('liver cancers', 'Disease', (255, 268))	('rs16901979', 'Mutation', 'rs16901979', (117, 127))	('cancer', 'Disease', 'MESH:D009369', (261, 267))
118389	18990762	Using a recessive model and adjusting for potential confounding factors, rs6983267 (region 3) was positively associated with UADT cancers (ORadj=1.69, 95% CI=1.28, 2.24).	('associated', 'Reg', (109, 119))	('rs6983267', 'Var', (73, 82))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('UADT cancers', 'Disease', (125, 137))	('rs6983267', 'Mutation', 'rs6983267', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('UADT cancers', 'Disease', 'MESH:D006258', (125, 137))
118390	18990762	When stratified by tumor site, rs6983267 was associated with cancers of the oropharynx (ORadj=1.80 95% CI=1.30, 2.49) and larynx (ORadj=2.04 95% CI=1.12, 3.72).	('rs6983267', 'Var', (31, 40))	('cancers of the oropharynx', 'Phenotype', 'HP:0100638', (61, 86))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('associated', 'Reg', (45, 55))	('rs6983267', 'Mutation', 'rs6983267', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancers', 'Disease', (61, 68))	('tumor', 'Disease', (19, 24))	('larynx', 'Disease', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
118391	18990762	Using the dominant model, there was a suggestive positive association between rs6983267 and liver cancer (ORadj=1.51, 95% CI=0.99, 2.31).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('liver cancer', 'Disease', (92, 104))	('rs6983267', 'Mutation', 'rs6983267', (78, 87))	('rs6983267', 'Var', (78, 87))	('liver cancer', 'Phenotype', 'HP:0002896', (92, 104))	('liver cancer', 'Disease', 'MESH:D006528', (92, 104))
118392	18990762	Lastly, in a pilot study, using the dominant model, we observed an inverse association of rs16901979 (region 2) with kidney cancer (OR=0.48, 95% CI=0.23, 1.00, data not shown).	('inverse', 'NegReg', (67, 74))	('kidney cancer', 'Phenotype', 'HP:0009726', (117, 130))	('kidney cancer', 'Disease', 'MESH:D007680', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rs16901979', 'Var', (90, 100))	('kidney cancer', 'Disease', (117, 130))	('rs16901979', 'Mutation', 'rs16901979', (90, 100))
118393	18990762	No obvious associations were observed between rs1447295 (region 1) and each smoking-related cancer.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('rs1447295', 'Mutation', 'rs1447295', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('rs1447295', 'Var', (46, 55))
118395	18990762	In assessing the relationship between rs6983267 (region3) and lung cancer stratified by smoking, we observed adjusted ORs of 1.45 (95% CI=1.05-2.00) for ever-smokers and 1.00 (95% CI=0.58-1.70) for never-smokers; suggesting possible interaction between smoking and the SNP rs6983267 on lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (286, 297))	('rs6983267', 'Mutation', 'rs6983267', (273, 282))	('lung cancer', 'Disease', (286, 297))	('lung cancer', 'Disease', 'MESH:D008175', (286, 297))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('rs6983267', 'Mutation', 'rs6983267', (38, 47))	('rs6983267', 'Var', (273, 282))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs6983267', 'Var', (38, 47))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('interaction', 'Interaction', (233, 244))
118396	18990762	Associations between rs6983267 and UADT cancers were observed in both never-smokers (ORadj=1.56, 95% CI=1.01, 2.39) and ever-smokers (ORadj=1.79, 95% CI=1.23, 2.61), suggesting the SNP rs6983267 may be independent of tobacco smoking for UADT cancers.	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('UADT cancers', 'Disease', (35, 47))	('Associations', 'Interaction', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('UADT cancers', 'Disease', (237, 249))	('tobacco', 'Species', '4097', (217, 224))	('rs6983267', 'Mutation', 'rs6983267', (185, 194))	('rs6983267', 'Mutation', 'rs6983267', (21, 30))	('UADT cancers', 'Disease', 'MESH:D006258', (35, 47))	('rs6983267', 'Var', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('UADT cancers', 'Disease', 'MESH:D006258', (237, 249))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('rs6983267', 'Var', (21, 30))
118397	18990762	Among smokers, the SNP rs6983267 was observed to be positively associated with oropharyngeal cancer (ORadj=2.01, 95% CI=1.29, 3.11) and laryngeal cancer (ORadj=2.05, 95% CI=1.09, 3.85) and inversely associated with bladder cancer (ORadj=0.35, 95% CI=0.14, 0.83).	('bladder cancer', 'Phenotype', 'HP:0009725', (215, 229))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (79, 99))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('bladder cancer', 'Disease', 'MESH:D001749', (215, 229))	('laryngeal cancer', 'Disease', 'MESH:D007822', (136, 152))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rs6983267', 'Var', (23, 32))	('oropharyngeal cancer', 'Disease', (79, 99))	('bladder cancer', 'Disease', (215, 229))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('laryngeal cancer', 'Disease', (136, 152))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (136, 152))	('rs6983267', 'Mutation', 'rs6983267', (23, 32))
118398	18990762	The SNP rs16901979 (region 2) was positively associated with UADT among never smokers (ORadj=1.86, 95% CI=1.06, 3.28).	('SNP', 'Var', (4, 7))	('UADT', 'Disease', (61, 65))	('UADT', 'Chemical', '-', (61, 65))	('associated with', 'Reg', (45, 60))	('rs16901979', 'Var', (8, 18))	('rs16901979', 'Mutation', 'rs16901979', (8, 18))
118399	18990762	When stratified by tumor site, rs16901979 was associated the cancer of the oropharynx (ORadj=2.28, 95% CI=1.19, 4.39).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('rs16901979', 'Var', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer of the oropharynx', 'Phenotype', 'HP:0100638', (61, 85))	('cancer', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (19, 24))	('associated', 'Reg', (46, 56))	('rs16901979', 'Mutation', 'rs16901979', (31, 41))
118400	18990762	Among ever-smokers, no obvious association was observed between rs16901979 and all tumor sites listed in Table 3.	('rs16901979', 'Var', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('rs16901979', 'Mutation', 'rs16901979', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
118401	18990762	For rs1447295 (region 1), when stratified by smoking, the only noteworthy change in odds ratio was found in liver cancer (p=0.025), ORadj=1.96 (95% CI=1.07-3.59) among smokers and 0.90 (95% CI=0.49-1.65) among never-smokers with an adjusted OR for interaction of 1.95 (95% CI: 1.09, 3.51).	('rs1447295', 'Mutation', 'rs1447295', (4, 13))	('liver cancer', 'Phenotype', 'HP:0002896', (108, 120))	('liver cancer', 'Disease', 'MESH:D006528', (108, 120))	('rs1447295', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('liver cancer', 'Disease', (108, 120))
118402	18990762	Assuming a prior probability of 0.01, we find two of our observed associations below FPRP threshold of 50%: rs6983267 and UADT cancers has an 11% probability of being a false positive and when stratified by tumor site, cancer of the oropharynx has a 22% probability of being a false positive.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('rs6983267', 'Var', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('UADT cancers', 'Disease', 'MESH:D006258', (122, 134))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('rs6983267', 'Mutation', 'rs6983267', (108, 117))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer of the oropharynx', 'Phenotype', 'HP:0100638', (219, 243))	('cancer', 'Disease', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('UADT cancers', 'Disease', (122, 134))
118404	18990762	Positive associations were observed between rs6983267 and UADT cancers in this study.	('UADT cancers', 'Disease', (58, 70))	('rs6983267', 'Mutation', 'rs6983267', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('UADT cancers', 'Disease', 'MESH:D006258', (58, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('rs6983267', 'Var', (44, 53))
118406	18990762	There was a clear dose-response relationship between rs6983267 and the UADT cancers (p for trend=0.0071).	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('rs6983267', 'Mutation', 'rs6983267', (53, 62))	('rs6983267', 'Var', (53, 62))	('UADT cancers', 'Disease', 'MESH:D006258', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('UADT cancers', 'Disease', (71, 83))
118408	18990762	There is no clear indication that the rs6983267 modifies the association between tobacco smoking and UADT cancers, although the point estimate of the adjusted OR was slightly higher among smokers.	('UADT cancers', 'Disease', 'MESH:D006258', (101, 113))	('tobacco', 'Species', '4097', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('rs6983267', 'Mutation', 'rs6983267', (38, 47))	('UADT cancers', 'Disease', (101, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('rs6983267', 'Var', (38, 47))	('modifies', 'Reg', (48, 56))	('association', 'Interaction', (61, 72))
118409	18990762	Among UADT cancers when stratified by tumor site, both cancers of oropharynx and larynx were positively associated with the rs6983267.	('UADT cancers', 'Disease', (6, 18))	('tumor', 'Disease', (38, 43))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('rs6983267', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('associated', 'Reg', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('UADT cancers', 'Disease', 'MESH:D006258', (6, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('rs6983267', 'Mutation', 'rs6983267', (124, 133))	('larynx', 'Disease', (81, 87))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('cancers', 'Disease', (55, 62))
118412	18990762	Although no overall association was observed between rs6983267 and lung cancer, a positive association was found for smokers (ORadj =1.45, 95% CI=1.05-2.00) and a null association for never-smokers, indicating possible effect modification of the rs6983267 on smoking and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (271, 282))	('rs6983267', 'Mutation', 'rs6983267', (53, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (271, 282))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('rs6983267', 'Var', (53, 62))	('lung cancer', 'Disease', (271, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('rs6983267', 'Mutation', 'rs6983267', (246, 255))
118413	18990762	The SNP rs6983267 was inversely associated with bladder cancer (ORadj=0.52, 95%CI=0.25, 1.07).	('bladder cancer', 'Disease', (48, 62))	('inversely', 'NegReg', (22, 31))	('rs6983267', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('associated', 'Reg', (32, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))	('rs6983267', 'Mutation', 'rs6983267', (8, 17))
118415	18990762	Our observations that rs6983267 was positively associated with UADT cancers, independent of tobacco smoking, positive associated with lung cancer only among smokers, and inversely associated with bladder cancer dependent of tobacco smoking status, implicates this SNP an important candidate marker for smoking related cancers with etiological heterogeneity.	('lung cancer', 'Disease', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('rs6983267', 'Var', (22, 31))	('UADT cancers', 'Disease', 'MESH:D006258', (63, 75))	('associated', 'Reg', (47, 57))	('tobacco', 'Species', '4097', (92, 99))	('cancers', 'Phenotype', 'HP:0002664', (318, 325))	('cancers', 'Disease', (318, 325))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('rs6983267', 'Mutation', 'rs6983267', (22, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('tobacco', 'Species', '4097', (224, 231))	('bladder cancer', 'Disease', 'MESH:D001749', (196, 210))	('bladder cancer', 'Disease', (196, 210))	('UADT cancers', 'Disease', (63, 75))	('bladder cancer', 'Phenotype', 'HP:0009725', (196, 210))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (318, 325))
118416	18990762	Our observations suggest that the SNP rs6983267 may play an important role in tobacco-related carcinogenesis involving target specific carcinogens, and perhaps metabolic, DNA repair and other related pathways.	('tobacco', 'Species', '4097', (78, 85))	('rs6983267', 'Mutation', 'rs6983267', (38, 47))	('rs6983267', 'Var', (38, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (94, 108))	('carcinogenesis', 'Disease', (94, 108))
118417	18990762	Among non-smokers, we observed positive associations between rs16901979 (region 2) and UADT as well as oropharyngeal cancers, and between rs6983267 and UADT cancer.	('UADT cancer', 'Disease', 'MESH:D006258', (152, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('rs16901979', 'Mutation', 'rs16901979', (61, 71))	('rs6983267', 'Var', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('oropharyngeal cancers', 'Disease', (103, 124))	('positive', 'PosReg', (31, 39))	('UADT', 'Disease', (87, 91))	('rs6983267', 'Mutation', 'rs6983267', (138, 147))	('UADT', 'Chemical', '-', (87, 91))	('oropharyngeal cancers', 'Disease', 'MESH:D009959', (103, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('rs16901979', 'Var', (61, 71))	('UADT', 'Chemical', '-', (152, 156))	('UADT cancer', 'Disease', (152, 163))
118419	18990762	Our results indicate that both rs16901979 and rs6983267 may play a role in non-smoking related pathways of UADT cancers.	('rs16901979', 'Var', (31, 41))	('UADT cancers', 'Disease', (107, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('play', 'Reg', (60, 64))	('rs6983267', 'Var', (46, 55))	('rs16901979', 'Mutation', 'rs16901979', (31, 41))	('rs6983267', 'Mutation', 'rs6983267', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('UADT cancers', 'Disease', 'MESH:D006258', (107, 119))
118420	18990762	SNPs of the 8q24 chromosome are notable for their associations in prostate cancer and increasing evidence with colorectal cancer; however, this region is one with few recognized genes and known functionality.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('SNPs', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('associations', 'Interaction', (50, 62))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))
118425	18990762	Our results and those of previous studies shows that SNPs of "region 3" are more often observed to be associated in cancer sites other than prostate, indicating that this specific "region" may be involved in other carcinogenic pathways, such as a tobacco-related carcinogenic pathway, or a combination of different pathways.	('involved', 'Reg', (196, 204))	('associated', 'Reg', (102, 112))	('tobacco', 'Species', '4097', (247, 254))	('cancer', 'Disease', (116, 122))	('SNPs', 'Var', (53, 57))	('carcinogenic pathway', 'Disease', (263, 283))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('carcinogenic pathway', 'Disease', 'MESH:D058606', (263, 283))	('carcinogenic pathway', 'Disease', (214, 234))	('carcinogenic pathway', 'Disease', 'MESH:D058606', (214, 234))	('prostate', 'Disease', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
118429	18990762	Studies of SNPs in LD with rs6983267, SNPs within "region 3," and those between 128.47 to 128.50 Mb in relation to smoking-related cancers may also be useful to detect new markers and reveal possible underlying biological mechanisms.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('rs6983267', 'Mutation', 'rs6983267', (27, 36))	('rs6983267', 'Var', (27, 36))
118430	18990762	Lastly, we cannot exclude the possibility that SNPs beyond "region 3" may also be associated with tobacco-related carcinogenesis and that our results for rs6982267 were due to its high MAF providing us with more precision to detect the observed associations.	('carcinogenesis', 'Disease', (114, 128))	('associated', 'Reg', (82, 92))	('tobacco', 'Species', '4097', (98, 105))	('rs6982267', 'Mutation', 'rs6982267', (154, 163))	('SNPs', 'Var', (47, 51))	('rs6982267', 'Var', (154, 163))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))
118432	18990762	Two minor deviations in HWE were observed (rs16901979 genotype distributions in African-Americans and rs6983267 genotype distribution in the Chinese population); however, the allelic proportions remained consistent with the previously published literature.	('rs16901979', 'Mutation', 'rs16901979', (43, 53))	('rs6983267', 'Var', (102, 111))	('rs6983267', 'Mutation', 'rs6983267', (102, 111))	('rs16901979', 'Var', (43, 53))
118433	18990762	After removing the African-American population in our analysis of rs16901979, we observed similar associations.	('rs16901979', 'Var', (66, 76))	('rs16901979', 'Mutation', 'rs16901979', (66, 76))	('associations', 'Interaction', (98, 110))
118434	18990762	The association between rs6983267 and liver cancer needs investigation by other studies.	('liver cancer', 'Phenotype', 'HP:0002896', (38, 50))	('liver cancer', 'Disease', 'MESH:D006528', (38, 50))	('rs6983267', 'Mutation', 'rs6983267', (24, 33))	('liver cancer', 'Disease', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('rs6983267', 'Var', (24, 33))
118436	18990762	Using our FPRP cutoff of 50% and a prior probability of 0.01, it is likely that the observed association between rs6983267 and UADT cancers (FPRP=11%), specifically cancer of the oropharynx (FPRP=22%), is not due to chance from multiple hypothesis testing.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancer', 'Disease', (132, 138))	('rs6983267', 'Mutation', 'rs6983267', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('UADT cancers', 'Disease', 'MESH:D006258', (127, 139))	('cancer of the oropharynx', 'Phenotype', 'HP:0100638', (165, 189))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('rs6983267', 'Var', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('UADT cancers', 'Disease', (127, 139))
118443	18990762	In conclusion, our results support the hypothesis that the 8q24 variants, particularly rs6983267, play a role in smoking-related cancer sites, particularly in upper aero-digestive tract cancers and lung cancer among smokers.	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Disease', (129, 135))	('tract cancers', 'Disease', 'MESH:D014571', (180, 193))	('rs6983267', 'Mutation', 'rs6983267', (87, 96))	('8q24', 'Gene', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('lung cancer', 'Disease', (198, 209))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tract cancers', 'Disease', (180, 193))	('smoking-related', 'Disease', (113, 128))	('role', 'Reg', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (203, 209))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('cancer', 'Disease', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('rs6983267', 'Var', (87, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))
118521	33912439	Collection and assembly of data: G-WM, YL, JW, L-LW, WH, XL, J-LW, J-BL, C-YC, JZ, Y-YH.	('J-BL', 'CellLine', 'CVCL:M891', (67, 71))	('J-LW', 'Var', (61, 65))	('J-BL', 'Var', (67, 71))	('C-YC', 'Var', (73, 77))	('L-LW', 'Var', (47, 51))
118522	33912439	Final approval of manuscript: G-WM, YL JW, L-LW, WH, XL, J-LW, J-BL, C-YC, JZ, Y-YH.	('L-LW', 'Var', (43, 47))	('J-BL', 'CellLine', 'CVCL:M891', (63, 67))	('J-BL', 'Var', (63, 67))	('J-LW', 'Var', (57, 61))
118570	28864851	After adjustment, BE risk was increased 79% and 71%, respectively, among those in the highest vs. lowest quartiles of sucrose (ORQ4vs.Q1=1.79, 95%CI=1.07-3.02, Ptrend=0.01) and added sugar intake (ORQ4vs.Q1=1.71, 95%CI=1.05-2.80, Ptrend=0.15) (Table 4).	('BE', 'Phenotype', 'HP:0100580', (18, 20))	('sucrose', 'Chemical', 'MESH:D013395', (118, 125))	('sugar', 'Chemical', 'MESH:D000073893', (183, 188))	('sucrose', 'MPA', (118, 125))	('ORQ4vs.Q1=1.71', 'Var', (197, 211))
118580	28864851	Our finding that added sugar was associated with increased risk of BE is consistent with a US-based cohort study that found that added sugar was associated with a 62% increase in EA risk.	('EA', 'Phenotype', 'HP:0011459', (179, 181))	('BE', 'Phenotype', 'HP:0100580', (67, 69))	('sugar', 'Chemical', 'MESH:D000073893', (135, 140))	('added sugar', 'Var', (129, 140))	('added sugar', 'Var', (17, 28))	('sugar', 'Chemical', 'MESH:D000073893', (23, 28))
118609	28864851	In summary, our pooled study examined multiple measures of sugar/starches intake in relation to the risk of developing BE, and we are the first to report that added sugar, sucrose, and sweetened desserts/beverages were associated with a 71%-79% increase in BE risk.	('sugar', 'Chemical', 'MESH:D000073893', (165, 170))	('sucrose', 'Chemical', 'MESH:D013395', (172, 179))	('sugar', 'Chemical', 'MESH:D000073893', (59, 64))	('starches', 'Chemical', 'MESH:D013213', (65, 73))	('BE', 'Phenotype', 'HP:0100580', (119, 121))	('BE', 'Phenotype', 'HP:0100580', (257, 259))	('developing BE', 'Disease', (108, 121))	('added sugar', 'Var', (159, 170))	('sucrose', 'Var', (172, 179))
118620	30355852	Epigenetic changes usually occurs early preceding the malignancy.	('occurs', 'Reg', (27, 33))	('malignancy', 'Disease', 'MESH:D009369', (54, 64))	('Epigenetic changes', 'Var', (0, 18))	('malignancy', 'Disease', (54, 64))
118624	30355852	Aberrant methylation cell-free DNA detected in the blood circulation appears to be a better biomarker for human cancers.	('methylation', 'Var', (9, 20))	('human', 'Species', '9606', (106, 111))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('Aberrant methylation', 'Var', (0, 20))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
118641	30355852	The presence of methylated DNA in the serum or plasma have been found in various types of malignancy, including bladder cancer, breast cancer, cervical cancer, colorectal cancer, lung cancer, and prostate cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('bladder cancer', 'Disease', (112, 126))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cervical cancer', 'Disease', (143, 158))	('cervical cancer', 'Disease', 'MESH:D002583', (143, 158))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('methylated', 'Var', (16, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('colorectal cancer', 'Disease', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', (179, 190))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('found', 'Reg', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('prostate cancer', 'Disease', 'MESH:D011471', (196, 211))	('prostate cancer', 'Phenotype', 'HP:0012125', (196, 211))	('prostate cancer', 'Disease', (196, 211))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))
118644	30478420	In non-neoplastic esophageal mucosae, FOXO1 expression was detectable in low and pSerine256-FOXO1 expression in high intensities.	('Serine256', 'Chemical', '-', (82, 91))	('expression', 'MPA', (44, 54))	('pSerine256-FOXO1', 'Var', (81, 97))	('non-neoplastic esophageal mucosae', 'Disease', (3, 36))	('FOXO1', 'Gene', (38, 43))	('neoplastic esophageal mucosa', 'Phenotype', 'HP:0100751', (7, 35))	('neoplastic esophageal mucosae', 'Phenotype', 'HP:0100751', (7, 36))	('non-neoplastic esophageal mucosae', 'Disease', 'MESH:D004938', (3, 36))
118646	30478420	Additionally, overexpression of FOXO1 and loss of pSerine256-FOXO1 expression predicted shortened survival of patients with EACs (p = 0.0003 and p = 0.0133) but were unrelated to outcome in patients with ESCCs (p = 0.7785 and p = 0.8426).	('pSerine256-FOXO1', 'Var', (50, 66))	('FOXO1', 'Gene', (32, 37))	('EACs', 'Disease', (124, 128))	('patients', 'Species', '9606', (190, 198))	('patients', 'Species', '9606', (110, 118))	('Serine256', 'Chemical', '-', (51, 60))	('survival', 'MPA', (98, 106))	('expression', 'MPA', (67, 77))	('overexpression', 'PosReg', (14, 28))	('shortened', 'NegReg', (88, 97))	('loss', 'NegReg', (42, 46))
118648	30478420	Thus, evaluation of FOXO1 and pSerine256-FOXO1 protein expression - either alone or in combination with other markers - might be useful for prediction of clinical outcome in patients with EAC.	('FOXO1', 'Gene', (20, 25))	('pSerine256-FOXO1', 'Var', (30, 46))	('patients', 'Species', '9606', (174, 182))	('EAC', 'Disease', (188, 191))	('Serine256', 'Chemical', '-', (31, 40))
118657	30478420	This study was performed to get more insights in the prognostic relevance of Forkhead box O 1 (FOXO1) and pSerine256-FOXO1 in esophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancers', 'Disease', (126, 144))	('pSerine256-FOXO1', 'Var', (106, 122))	('FOXO1', 'Gene', (95, 100))	('esophageal cancers', 'Disease', 'MESH:D004938', (126, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('Forkhead box O 1', 'Gene', '2308', (77, 93))	('Serine256', 'Chemical', '-', (107, 116))	('Forkhead box O 1', 'Gene', (77, 93))
118659	30478420	FOXO transcriptional activity is negatively regulated by phosphorylation at Serine256 in the PI3K/Akt signaling pathway.	('FOXO', 'Gene', (0, 4))	('Akt', 'Gene', '207', (98, 101))	('negatively', 'NegReg', (33, 43))	('Serine256', 'Chemical', '-', (76, 85))	('Akt', 'Gene', (98, 101))	('phosphorylation at Serine256', 'Var', (57, 85))	('transcriptional activity', 'MPA', (5, 29))
118661	30478420	Earlier IHC studies showed both overexpression and loss of FOXO1 and pSerine256-FOXO1 in malignant cells in comparison to the corresponding benign tissue.	('overexpression', 'PosReg', (32, 46))	('FOXO1', 'Gene', (59, 64))	('pSerine256-FOXO1', 'Var', (69, 85))	('Serine256', 'Chemical', '-', (70, 79))	('loss', 'NegReg', (51, 55))
118662	30478420	Additionally, FOXO1 and pSerine256-FOXO1 have been suggested as prognostic markers in malignancies, including breast cancer, bladder, renal cell, prostate cancer, and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (146, 161))	('pSerine256-FOXO1', 'Var', (24, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('prostate cancer', 'Disease', (146, 161))	('bladder', 'Disease', (125, 132))	('renal cell', 'Disease', (134, 144))	('FOXO1', 'Gene', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	('breast cancer', 'Disease', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('malignancies', 'Disease', 'MESH:D009369', (86, 98))	('malignancies', 'Disease', (86, 98))	('gastric cancer', 'Disease', (167, 181))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Serine256', 'Chemical', '-', (25, 34))	('bladder', 'Disease', 'MESH:D001745', (125, 132))
118663	30478420	However, the prevalence and clinical significance of FOXO1 and pSerine256-FOXO1 expression in esophageal cancer remains elusive.	('FOXO1', 'Gene', (53, 58))	('esophageal cancer', 'Disease', (94, 111))	('Serine256', 'Chemical', '-', (64, 73))	('pSerine256-FOXO1', 'Var', (63, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
118665	30478420	Our study shows that FOXO1 overexpression and loss of pSerine256-FOXO1 expression are associated with poor prognosis in esophageal adenocarcinomas.	('expression', 'MPA', (71, 81))	('loss', 'NegReg', (46, 50))	('pSerine256-FOXO1', 'Gene', (54, 70))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (120, 146))	('FOXO1', 'Gene', (21, 26))	('esophageal adenocarcinomas', 'Disease', (120, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('Serine256', 'Chemical', '-', (55, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('overexpression', 'PosReg', (27, 41))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (120, 145))	('pSerine256-FOXO1', 'Var', (54, 70))
118666	30478420	Thus, it can be speculated that the evaluation of FOXO1 and pSerine256-FOXO1 in tumor biopsies might be of clinical relevance in patients with EACs.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('pSerine256-FOXO1', 'Var', (60, 76))	('Serine256', 'Chemical', '-', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('FOXO1', 'Gene', (50, 55))	('EACs', 'Disease', (143, 147))	('patients', 'Species', '9606', (129, 137))	('tumor', 'Disease', (80, 85))
118670	30478420	Expression of pSerine256-FOXO1 was predominantly localized in the cytoplasm of the cells and was found in decreased intensities in malignant compared to benign esophageal epithelium.	('decreased', 'NegReg', (106, 115))	('Serine256', 'Chemical', '-', (15, 24))	('pSerine256-FOXO1', 'Var', (14, 30))
118671	30478420	Low pSerine256-FOXO1 immunostaining was found in 59.8% of EAC and 37.4% of ESCC samples.	('ESCC', 'Disease', (75, 79))	('pSerine256-FOXO1', 'Var', (4, 20))	('EAC', 'Disease', (58, 61))	('Low', 'NegReg', (0, 3))	('Serine256', 'Chemical', '-', (5, 14))
118673	30478420	The associations of FOXO1 and pSerine256-FOXO1 expression with tumor phenotype are shown in Tables 1 and 2.	('tumor', 'Disease', (63, 68))	('FOXO1', 'Gene', (20, 25))	('pSerine256-FOXO1', 'Var', (30, 46))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Serine256', 'Chemical', '-', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('associations', 'Interaction', (4, 16))
118675	30478420	Additionally, overexpression of FOXO1 and loss of pSerine256-FOXO1 expression were linked to presence of lymph node metastases in the subset of ESCCs (p = 0.0028 and p = 0.0119).	('pSerine256-FOXO1', 'Var', (50, 66))	('FOXO1', 'Gene', (32, 37))	('metastases', 'Disease', (116, 126))	('Serine256', 'Chemical', '-', (51, 60))	('expression', 'MPA', (67, 77))	('metastases', 'Disease', 'MESH:D009362', (116, 126))	('overexpression', 'PosReg', (14, 28))	('loss', 'NegReg', (42, 46))
118676	30478420	Kaplan Meyer curves demonstrated that high FOXO1 and low pSerine256-FOXO1 expressions were associated with shortened survival of patients with EACs (p = 0.0003 and p = 0.0133) but were unrelated to clinical outcome in patients with ESCCs (p = 0.7785 and p = 0.8426), as demonstrated in Fig.	('survival', 'MPA', (117, 125))	('low', 'NegReg', (53, 56))	('FOXO1', 'Gene', (43, 48))	('patients', 'Species', '9606', (129, 137))	('EACs', 'Disease', (143, 147))	('patients', 'Species', '9606', (218, 226))	('high', 'Var', (38, 42))	('shortened', 'NegReg', (107, 116))	('Serine256', 'Chemical', '-', (58, 67))	('pSerine256-FOXO1 expressions', 'MPA', (57, 85))
118678	30478420	The group of patients with high FOXO1 and low pSerine256-FOXO1 expressions was significantly linked to worse outcome in EACs as shown in Fig.	('FOXO1', 'Gene', (32, 37))	('Serine256', 'Chemical', '-', (47, 56))	('patients', 'Species', '9606', (13, 21))	('EACs', 'Disease', (120, 124))	('expressions', 'MPA', (63, 74))	('high', 'Var', (27, 31))	('low pSerine256-FOXO1', 'Var', (42, 62))
118684	30478420	Thus, analysis of FOXO1 and pSerine256-FOXO1 expression - either alone or in combination with other markers - might be useful for prediction of clinical outcome in these patients.	('patients', 'Species', '9606', (170, 178))	('FOXO1', 'Gene', (18, 23))	('Serine256', 'Chemical', '-', (29, 38))	('pSerine256-FOXO1', 'Var', (28, 44))
118685	30478420	Here, we evaluated FOXO1 and pSerine256-FOXO1 expressions in malignant and benign esophageal tissue samples on TMAs using immunohistochemistry.	('Serine256', 'Chemical', '-', (30, 39))	('FOXO1', 'Gene', (19, 24))	('pSerine256-FOXO1', 'Var', (29, 45))	('TMAs', 'Chemical', 'MESH:C071868', (111, 115))
118690	30478420	In detail, TMA and large section findings of p53, PR, and ER in breast cancer were compared and in summary the results showed that overinterpretation of focal p53 positivity in large sections obscured the established prognostic impact of p53, which was, however, significantly estimated in the TMA analysis.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('obscured', 'NegReg', (192, 200))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('p53', 'Gene', (238, 241))	('p53', 'Gene', '7157', (238, 241))	('TMA', 'Chemical', 'MESH:C071868', (294, 297))	('positivity', 'Var', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TMA', 'Chemical', 'MESH:C071868', (11, 14))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
118693	30478420	Here, we analyzed FOXO1 and pSerine256-FOXO1 expression in esophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancers', 'Disease', (59, 77))	('pSerine256-FOXO1', 'Var', (28, 44))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('esophageal cancers', 'Disease', 'MESH:D004938', (59, 77))	('Serine256', 'Chemical', '-', (29, 38))
118694	30478420	In our study, FOXO1 expression was found in increased intensities and pSerine256-FOXO1 expression in decreased intensities in malignant than in benign esophageal tissue.	('intensities', 'MPA', (54, 65))	('Serine256', 'Chemical', '-', (71, 80))	('decreased', 'NegReg', (101, 110))	('FOXO1', 'Gene', (14, 19))	('intensities', 'MPA', (111, 122))	('increased', 'PosReg', (44, 53))	('pSerine256-FOXO1', 'Var', (70, 86))
118696	30478420	Our observation of aberrant FOXO1 expression in cancerous relative to non-cancerous esophageal tissue is consistent with earlier studies on FOXO1 expression in diverse other cancer types, such as bladder, renal cell, breast, and prostate cancer.	('expression', 'MPA', (34, 44))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (48, 54))	('bladder', 'Disease', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancerous', 'Disease', 'MESH:D009369', (48, 57))	('cancerous', 'Disease', (74, 83))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('renal cell', 'Disease', (205, 215))	('breast', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('FOXO1', 'Gene', (28, 33))	('non-cancerous esophageal', 'Disease', 'MESH:D004938', (70, 94))	('prostate cancer', 'Disease', 'MESH:D011471', (229, 244))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('cancerous', 'Disease', (48, 57))	('non-cancerous esophageal', 'Disease', (70, 94))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('prostate cancer', 'Disease', (229, 244))	('bladder', 'Disease', 'MESH:D001745', (196, 203))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancerous', 'Disease', 'MESH:D009369', (74, 83))	('aberrant', 'Var', (19, 27))
118698	30478420	Our data demonstrate that FOXO1 overexpression and loss of pSerine256-FOXO1 expression are linked to a subset of esophageal cancers with aggressive tumor features.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('overexpression', 'PosReg', (32, 46))	('esophageal cancers', 'Disease', 'MESH:D004938', (113, 131))	('Serine256', 'Chemical', '-', (60, 69))	('aggressive tumor', 'Disease', (137, 153))	('FOXO1', 'Gene', (26, 31))	('pSerine256-FOXO1', 'Var', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('expression', 'MPA', (76, 86))	('linked', 'Reg', (91, 97))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('loss', 'NegReg', (51, 55))	('pSerine256-FOXO1', 'Gene', (59, 75))	('aggressive tumor', 'Disease', 'MESH:D001523', (137, 153))	('esophageal cancers', 'Disease', (113, 131))
118699	30478420	Of importance, the prognostic impact of FOXO1 and pSerine256-FOXO1 were limited to the histological subset of EACs, while the markers were unrelated to clinical outcome in ESCCs.	('pSerine256-FOXO1', 'Var', (50, 66))	('Serine256', 'Chemical', '-', (51, 60))	('FOXO1', 'Gene', (40, 45))
118700	30478420	Moreover, our data suggest that even the measurement of both IHC markers FOXO1 and pSerine256-FOXO1 might be in combination of clinical relevance.	('Serine256', 'Chemical', '-', (84, 93))	('pSerine256-FOXO1', 'Var', (83, 99))	('FOXO1', 'Gene', (73, 78))
118706	30478420	Dysregulation of PI3K-Akt signaling pathway has been associated with increase cancer cell growth, proliferation, migration and invasion in esophageal cancers in literature.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('Dysregulation', 'Var', (0, 13))	('invasion', 'CPA', (127, 135))	('Akt', 'Gene', (22, 25))	('increase cancer', 'Disease', (69, 84))	('esophageal cancers', 'Disease', (139, 157))	('migration', 'CPA', (113, 122))	('increase cancer', 'Disease', 'MESH:D009369', (69, 84))	('proliferation', 'CPA', (98, 111))	('esophageal cancers', 'Disease', 'MESH:D004938', (139, 157))	('Akt', 'Gene', '207', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
118707	30478420	For example, studies found that dysregulation of MAPK signaling, PI3K-Akt signaling, and wnt signaling were strongly involved in esophageal tumorigenesis.	('dysregulation', 'Var', (32, 45))	('Akt', 'Gene', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('involved', 'Reg', (117, 125))	('MAPK', 'Protein', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Akt', 'Gene', '207', (70, 73))	('tumor', 'Disease', (140, 145))
118708	30478420	It can be speculated that FOXO1 and pSerine256-FOXO1 as well as its regulating signaling pathways might be important roles during esophageal carcinogenesis.	('pSerine256-FOXO1', 'Var', (36, 52))	('Serine256', 'Chemical', '-', (37, 46))	('esophageal carcinogenesis', 'Disease', (130, 155))	('FOXO1', 'Gene', (26, 31))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (130, 155))	('roles', 'Reg', (117, 122))
118709	30478420	In earlier studies on FOXO1 expression in other cancer types, high FOXO1 expression was suggested to be a prognostic marker for improved clinical outcome in breast, lung and bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('FOXO1', 'Gene', (67, 72))	('bladder cancers', 'Phenotype', 'HP:0009725', (174, 189))	('lung', 'Disease', (165, 169))	('breast', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('bladder cancers', 'Disease', 'MESH:D001749', (174, 189))	('improved', 'PosReg', (128, 136))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('expression', 'MPA', (73, 83))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', (182, 188))	('bladder cancers', 'Disease', (174, 189))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('high', 'Var', (62, 66))
118717	30478420	Previously, studies analysing whole-genome and whole-exome sequences from tumor specimens identified mutations that are enriched in tumor samples compared to germline cells.	('mutations', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', (74, 79))
118718	30478420	It is widely accepted that these mutations are the main drivers of tumor progression.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', (67, 72))
118720	30478420	In detail, mutations in signaling proteins may over-enrich key signaling pathways or inhibit the function of tumor suppressor proteins, resulting in uncontrolled cell growth, tumor development and progression.	('mutations', 'Var', (11, 20))	('tumor', 'Disease', (175, 180))	('resulting in', 'Reg', (136, 148))	('inhibit', 'NegReg', (85, 92))	('function', 'MPA', (97, 105))	('uncontrolled', 'MPA', (149, 161))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('key signaling pathways', 'Pathway', (59, 81))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('over-enrich', 'PosReg', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (109, 114))	('progression', 'CPA', (197, 208))
118727	30478420	Primary antibody for FOXO1 (rabbit, Cell signaling) was applied at a dilution of 1:150 and for pSerine256-FOXO1 (rabbit, Abcam) at a dilution of 1:450 according to the manufacturer s directions.	('pSerine256-FOXO1', 'Var', (95, 111))	('Serine256', 'Chemical', '-', (96, 105))	('FOXO1', 'Gene', (21, 26))	('rabbit', 'Species', '9986', (113, 119))	('rabbit', 'Species', '9986', (28, 34))
118732	30478420	Contributed reagents/materials/analysis tools: K.G., N.M., AT.EG, R.G., A.H., E.B., M.R., G.WE., T.G., M.N., K.B., A.K., D.B.	('K.B.', 'Var', (109, 113))	('M.N.', 'Var', (103, 107))	('A.K.', 'Var', (115, 119))	('AT', 'Disease', 'None', (59, 61))
118743	29487968	reported that a different strain parameter, termed 'elastic ratio' (the strain distribution value, intrahepatic venous small vessels/value in the hepatic parenchyma), was highly correlated with biopsy proven fibrosis stage (Spearman correlation 0.82, p<0.001) with AUROC values to diagnose F>=2 (0.89), F>=3 (0.94) and F=4 (0.95).	('F=4', 'Var', (319, 322))	('intrahepatic venous', 'Disease', 'MESH:D002780', (99, 118))	('intrahepatic venous', 'Disease', (99, 118))	('F>=3', 'Var', (303, 307))	('correlated', 'Reg', (178, 188))	('fibrosis', 'Disease', 'MESH:D005355', (208, 216))	('fibrosis', 'Disease', (208, 216))
118751	29487968	reported AUROC values to distinguish liver fibrosis stages ranging from 0.649 to 0.934 for F>=2, 0.848 to 0.97 for F>=3 and 0.723 to 0.98 for F4.	('liver fibrosis', 'Disease', (37, 51))	('0.848', 'Var', (97, 102))	('liver fibrosis', 'Disease', 'MESH:D008103', (37, 51))	('liver fibrosis', 'Phenotype', 'HP:0001395', (37, 51))
118767	29487968	reported a significant difference in cortical stiffness values of DKD patients and healthy subjects(23.7kPa vs. 9.02, p<0.001).	('patients', 'Species', '9606', (70, 78))	('DKD', 'Var', (66, 69))	('cortical', 'MPA', (37, 45))
118828	28927043	Phosphorylated epidermal growth factor receptor (P-EGFR) activates a variety of intracellular signaling pathways, inducing cell proliferation and survival.	('Phosphorylated', 'Var', (0, 14))	('epidermal growth factor receptor', 'Gene', '1956', (15, 47))	('inducing', 'PosReg', (114, 122))	('EGFR', 'Gene', (51, 55))	('cell proliferation', 'CPA', (123, 141))	('EGFR', 'Gene', '1956', (51, 55))	('activates', 'PosReg', (57, 66))	('survival', 'CPA', (146, 154))	('epidermal growth factor receptor', 'Gene', (15, 47))	('intracellular signaling pathways', 'Pathway', (80, 112))
118857	28927043	The final results were as follows: (-) denoted negative expression (PE-GFR-, p-Akt-); and (+), (++) and (+++) represented positive expression (PE-GFR+, p-Akt+).	('++', 'Var', (96, 98))	('negative', 'NegReg', (47, 55))	('Akt', 'Gene', '207', (154, 157))	('Akt', 'Gene', (154, 157))	('positive', 'PosReg', (122, 130))	('Akt', 'Gene', '207', (79, 82))	('Akt', 'Gene', (79, 82))	('+++', 'Var', (105, 108))
118889	28927043	In vitro studies suggest that the phosphorylation of Akt residues threonine 308 and serine 473 was closely related to the activation of PI3K/Akt signaling.	('phosphorylation', 'MPA', (34, 49))	('Akt', 'Gene', '207', (53, 56))	('threonine', 'Chemical', 'MESH:D013912', (66, 75))	('serine 473', 'Var', (84, 94))	('threonine 308', 'Var', (66, 79))	('Akt', 'Gene', (53, 56))	('Akt', 'Gene', '207', (141, 144))	('serine', 'Chemical', 'MESH:D012694', (84, 90))	('Akt', 'Gene', (141, 144))
118975	26825906	Risk was also significantly underestimated in participant with current smoking, high BMI more than 25, and high level of triglyceride.	('high BMI more than 25', 'Var', (80, 101))	('triglyceride', 'Chemical', 'MESH:D014280', (121, 133))	('high level of triglyceride', 'Phenotype', 'HP:0002155', (107, 133))	('underestimated', 'NegReg', (28, 42))	('participant', 'Species', '9606', (46, 57))
118980	26825906	The score calculated for each person from the validation set estimated the likelihood of detecting erosive esophagitis as 3.9% for patients with a score of 0, and 23.8% for patients with a score of 6 in the complete dataset.	('patients', 'Species', '9606', (131, 139))	('score', 'Var', (147, 152))	('patients', 'Species', '9606', (173, 181))	('esophagitis', 'Phenotype', 'HP:0100633', (107, 118))	('esophagitis', 'Disease', (107, 118))	('esophagitis', 'Disease', 'MESH:D004941', (107, 118))	('person', 'Species', '9606', (30, 36))
119000	26825906	Clinical parameters such as current smoker, male sex, and BMI were also definite risk factors for developing erosive esophagitis.	('esophagitis', 'Disease', (117, 128))	('BMI', 'Var', (58, 61))	('esophagitis', 'Disease', 'MESH:D004941', (117, 128))	('esophagitis', 'Phenotype', 'HP:0100633', (117, 128))
119014	26825906	The current BMI cut-off points established by the WHO are >=25 kg/m2 for being overweight and >=30 kg/m2 for obesity.	('obesity', 'Disease', 'MESH:D009765', (109, 116))	('>=25 kg/m2', 'Var', (58, 68))	('obesity', 'Disease', (109, 116))	('overweight', 'Phenotype', 'HP:0025502', (79, 89))	('obesity', 'Phenotype', 'HP:0001513', (109, 116))	('>=30 kg/m2', 'Var', (94, 104))
119038	28035762	The Ct values were normalized based on the average of the normalizer assays in the panel and this included miR-191-5p, miR-423-5p, miR-425-5p, and miR-93-5p.	('miR-93', 'Gene', '407051', (147, 153))	('miR-425-5p', 'Gene', '100422898', (131, 141))	('miR-423-5p', 'Var', (119, 129))	('miR-93', 'Gene', (147, 153))	('miR-191', 'Gene', '406966', (107, 114))	('miR-191', 'Gene', (107, 114))	('miR-425-5p', 'Gene', (131, 141))
119062	28035762	The AUCs were 0.731, 0.656, 0.662, 0.736, and 0.689 for miR-20b-5p, miR-28-3p, miR-192-5p, miR-223-3p, and miR-296-5p, respectively (Fig.	('miR-20b', 'Gene', '574032', (56, 63))	('miR-296', 'Gene', '407022', (107, 114))	('miR-28', 'Gene', (68, 74))	('miR-20b', 'Gene', (56, 63))	('miR-296', 'Gene', (107, 114))	('miR-28', 'Gene', '407020', (68, 74))	('miR-223', 'Gene', '407008', (91, 98))	('-28-3p', 'Chemical', '-', (71, 77))	('miR-192', 'Gene', (79, 86))	('miR-192', 'Gene', '406967', (79, 86))	('miR-223', 'Gene', (91, 98))	('0.689', 'Var', (46, 51))
119110	28035762	It is reported that miR-296-5p overexpressed in both carcinoma in situ and ESCC tissues, and in vitro experiment showed that inhibition of miR-296-5p increased sensitivity to chemotherapeutic drugs in esophageal carcinoma cell lines 34.	('miR-296', 'Gene', (20, 27))	('sensitivity to chemotherapeutic drugs', 'MPA', (160, 197))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (201, 221))	('carcinoma in situ', 'Disease', 'MESH:D002278', (53, 70))	('miR-296', 'Gene', '407022', (139, 146))	('esophageal carcinoma', 'Disease', (201, 221))	('carcinoma in situ', 'Disease', (53, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('miR-296', 'Gene', (139, 146))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (201, 221))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (53, 70))	('increased', 'PosReg', (150, 159))	('inhibition', 'Var', (125, 135))	('miR-296', 'Gene', '407022', (20, 27))
119118	27095573	PIK3CA amplification is associated with poor prognosis among patients with curatively resected esophageal squamous cell carcinoma To investigate the clinicopathologic characteristics and the prognostic impact of PIK3CA gene amplification in curatively resected esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('esophageal squamous cell carcinoma', 'Disease', (95, 129))	('SCC', 'Gene', '6317', (298, 301))	('PIK3CA', 'Gene', (212, 218))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (261, 295))	('patients', 'Species', '9606', (61, 69))	('PIK3CA', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', '5290', (212, 218))	('esophageal squamous cell carcinoma', 'Disease', (261, 295))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (95, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (272, 295))	('amplification', 'Var', (7, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('SCC', 'Gene', (298, 301))	('SCC', 'Phenotype', 'HP:0002860', (298, 301))
119121	27095573	After adjusting for gender, tumor location, pathologic stage, histologic grade and adjuvant treatment, PIK3CA amplification was significantly associated with a shorter DFS (adjusted hazard ratio [AHR] 1.53; 95% CI, 1.10-2.17; P=0.02).	('tumor', 'Disease', (28, 33))	('amplification', 'Var', (110, 123))	('DFS', 'MPA', (168, 171))	('PIK3CA', 'Gene', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('shorter', 'NegReg', (160, 167))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
119122	27095573	PIK3CA mutations were detected in 6 (1.5%) of 388 cases; 5 cases with exon 9 mutations in E545K while one exon 20 mutation in H1047L.	('PIK3CA', 'Gene', (0, 6))	('E545K', 'Mutation', 'rs104886003', (90, 95))	('E545K', 'Var', (90, 95))	('H1047L', 'Mutation', 'rs121913279', (126, 132))	('H1047L', 'Var', (126, 132))
119123	27095573	PIK3CA amplification is a frequent oncogenic alteration and associated with shorter survival, suggesting its role as a prognostic biomarker in resected ESCC.	('SCC', 'Gene', '6317', (153, 156))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('survival', 'MPA', (84, 92))	('PIK3CA', 'Gene', (0, 6))	('SCC', 'Gene', (153, 156))	('shorter', 'NegReg', (76, 83))	('amplification', 'Var', (7, 20))
119136	27095573	Copy number gains of SOX2, PIK3CA, CCND1, and FGFR1 were more frequent in ESCC than in EAC, implicating these genes as therapeutic targets for ESCC.	('SCC', 'Gene', '6317', (75, 78))	('FGFR1', 'Gene', '2260', (46, 51))	('Copy number gains', 'Var', (0, 17))	('SCC', 'Gene', (144, 147))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('PIK3CA', 'Gene', (27, 33))	('CCND1', 'Gene', '595', (35, 40))	('SCC', 'Gene', '6317', (144, 147))	('EAC', 'Phenotype', 'HP:0011459', (87, 90))	('FGFR1', 'Gene', (46, 51))	('SCC', 'Gene', (75, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('SOX2', 'Gene', (21, 25))	('SOX2', 'Gene', '6657', (21, 25))	('CCND1', 'Gene', (35, 40))
119137	27095573	Very recently, we reported that FGFR1 amplification is frequently observed and an independent prognostic factor in resected ESCC.	('FGFR1', 'Gene', (32, 37))	('FGFR1', 'Gene', '2260', (32, 37))	('SCC', 'Gene', (125, 128))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('SCC', 'Gene', '6317', (125, 128))	('amplification', 'Var', (38, 51))
119140	27095573	Activation of the PI3K pathway occurs upon engagement with mutation or amplification of PIK3CA, the p110alpha catalytic subunit of PI3K.	('p110alpha', 'Gene', (100, 109))	('p110alpha', 'Gene', '5290', (100, 109))	('amplification', 'Var', (71, 84))	('Activation', 'PosReg', (0, 10))	('mutation', 'Var', (59, 67))	('engagement', 'Interaction', (43, 53))	('PIK3CA', 'Gene', (88, 94))	('PI3K pathway', 'Pathway', (18, 30))
119141	27095573	Amplification and mutation of PIK3CA is generally associated with increased PIK3CA expression, PI3K activation, and phosphorylation of downstream Akt, supporting the oncogenic role of PI3K aberration.	('PIK3CA', 'Gene', (30, 36))	('Amplification', 'Var', (0, 13))	('increased', 'PosReg', (66, 75))	('phosphorylation', 'MPA', (116, 131))	('Akt', 'Gene', (146, 149))	('PI3K', 'Pathway', (95, 99))	('PIK3CA', 'Gene', (76, 82))	('mutation', 'Var', (18, 26))	('expression', 'MPA', (83, 93))	('activation', 'PosReg', (100, 110))	('Akt', 'Gene', '207', (146, 149))
119142	27095573	PIK3CA gene amplification was found in 10-30% of non-small cell lung cancer, breast cancer, colon cancer and head/neck cancer.	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('head/neck cancer', 'Phenotype', 'HP:0012288', (109, 125))	('cell lung cancer', 'Disease', 'MESH:D008175', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('head/neck cancer', 'Disease', 'MESH:D006258', (109, 125))	('amplification', 'Var', (12, 25))	('cell lung cancer', 'Disease', (59, 75))	('colon cancer', 'Disease', (92, 104))	('head/neck cancer', 'Disease', (109, 125))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancer', 'Disease', (77, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('found', 'Reg', (30, 35))	('PIK3CA', 'Gene', (0, 6))
119143	27095573	Activating somatic mutations (codons 542 and 545 in exon 9 and codon 1047 in exon 20) were also identified in various solid tumors.	('Activating', 'PosReg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('solid tumors', 'Disease', 'MESH:D009369', (118, 130))	('codons 542', 'Var', (30, 40))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('solid tumors', 'Disease', (118, 130))	('codon 1047', 'Var', (63, 73))
119144	27095573	Despite accumulating evidence of biologic role, only a few studies have reported the frequency of PIK3CA aberration in ESCC and its prognostic role is still controversial.	('aberration', 'Var', (105, 115))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('PIK3CA', 'Gene', (98, 104))	('SCC', 'Gene', (120, 123))
119145	27095573	In this study, we evaluated the frequency of PIK3CA amplification and mutation in surgically resected ESCC.	('SCC', 'Gene', (103, 106))	('PIK3CA', 'Gene', (45, 51))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCC', 'Gene', '6317', (103, 106))	('mutation', 'Var', (70, 78))
119146	27095573	Furthermore, we also determined the prognostic impact of genetic aberration of PIK3CA in ESCC.	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('genetic aberration', 'Var', (57, 75))	('PIK3CA', 'Gene', (79, 85))	('SCC', 'Gene', '6317', (90, 93))
119156	27095573	The mean PIK3CA/CEN3 ratio was 2.3 (0.9-6.0) for the amplification group and 1.08 (0-1.9) for the no amplification group.	('CEN3', 'Gene', '1070', (16, 20))	('amplification', 'Var', (53, 66))	('CEN3', 'Gene', (16, 20))
119160	27095573	In the Cox proportional hazard model adjusted for gender, tumor location, pathologic stage, histologic grade and adjuvant treatment, PIK3CA amplification was significantly associated with a shorter DFS (adjusted hazard ration [AHR] 1.53; 95% CI, 1.10-2.17; P=0.02, Table 2).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('DFS', 'MPA', (198, 201))	('PIK3CA', 'Gene', (133, 139))	('amplification', 'Var', (140, 153))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('shorter', 'NegReg', (190, 197))
119164	27095573	The clinicopathologic characteristics of the 6 patients with PIK3CA mutations are listed in Table 3.	('mutations', 'Var', (68, 77))	('PIK3CA', 'Gene', (61, 67))	('patients', 'Species', '9606', (47, 55))
119165	27095573	PIK3CA exon 9 mutations were identified in 5 tumors of E545K (GAG to AAG), while exon 20 mutation was identified in H1047L (CAT to CTT) (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('GAG', 'Chemical', 'MESH:D006025', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('identified', 'Reg', (29, 39))	('PIK3CA', 'Gene', (0, 6))	('E545K', 'Mutation', 'rs104886003', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('E545K', 'Var', (55, 60))	('AAG', 'Gene', (69, 72))	('H1047L', 'Mutation', 'rs121913279', (116, 122))	('AAG', 'Gene', '4350', (69, 72))
119166	27095573	Of 6 PIK3CA mutants, the single case with exon 20 mutation satisfied the criteria of PIK3CA amplification with PIK3CA/CEN3 ratio of 2.5.	('PIK3CA', 'Gene', (5, 11))	('CEN3', 'Gene', (118, 122))	('CEN3', 'Gene', '1070', (118, 122))	('mutants', 'Var', (12, 19))	('PIK3CA', 'Gene', (85, 91))
119168	27095573	Furthermore, all tumors with PIK3CA mutations originated from the mid-to-lower esophageal region.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (36, 45))	('PIK3CA', 'Gene', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('originated', 'Reg', (46, 56))
119169	27095573	We conducted this study to examine the frequency and prognostic impact of PIK3CA amplification among curatively resected ESCCs.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('SCC', 'Gene', '6317', (122, 125))	('amplification', 'Var', (81, 94))	('PIK3CA', 'Gene', (74, 80))
119170	27095573	To our knowledge, this is the first study of PIK3CA amplification in a large cohort of East Asian ESCC patients.	('SCC', 'Gene', '6317', (99, 102))	('SCC', 'Gene', (99, 102))	('PIK3CA', 'Gene', (45, 51))	('patients', 'Species', '9606', (103, 111))	('amplification', 'Var', (52, 65))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))
119171	27095573	We found that PIK3CA amplification is a common genetic event and an independent poor prognostic factor in ESCC.	('SCC', 'Gene', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('PIK3CA', 'Gene', (14, 20))	('SCC', 'Gene', '6317', (107, 110))	('amplification', 'Var', (21, 34))
119174	27095573	A recent comparative genome study reported focal regions of DNA amplification or loss including SOX2, PIK3CA, CCND1, and FGFR1 are more frequent in ESCC than EAC.	('SOX2', 'Gene', (96, 100))	('CCND1', 'Gene', (110, 115))	('PIK3CA', 'Gene', (102, 108))	('SCC', 'Gene', (149, 152))	('EAC', 'Phenotype', 'HP:0011459', (158, 161))	('CCND1', 'Gene', '595', (110, 115))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('SCC', 'Gene', '6317', (149, 152))	('DNA amplification', 'Var', (60, 77))	('FGFR1', 'Gene', (121, 126))	('loss', 'NegReg', (81, 85))	('SOX2', 'Gene', '6657', (96, 100))	('FGFR1', 'Gene', '2260', (121, 126))
119177	27095573	Activation of the PI3K pathway, generally as a result of PIK3CA amplification, has been reported in upper aerodigestive tract cancers including 12% of lung squamous cell carcinoma (SCC), 18.2% of nasopharyngeal carcinoma, 20% of oropharyngeal SCC, and 32.2% of HNSCC.	('SCC', 'Gene', '6317', (243, 246))	('SCC', 'Gene', (181, 184))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (196, 220))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('SCC', 'Gene', (243, 246))	('SCC', 'Phenotype', 'HP:0002860', (263, 266))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (151, 179))	('PIK3CA', 'Gene', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SCC', 'Gene', '6317', (263, 266))	('nasopharyngeal carcinoma', 'Disease', (196, 220))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 179))	('amplification', 'Var', (64, 77))	('SCC', 'Phenotype', 'HP:0002860', (181, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('lung squamous cell carcinoma', 'Disease', (151, 179))	('Activation', 'PosReg', (0, 10))	('cancers', 'Disease', (126, 133))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (196, 220))	('SCC', 'Gene', (263, 266))	('PI3K pathway', 'Pathway', (18, 30))	('SCC', 'Phenotype', 'HP:0002860', (243, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('SCC', 'Gene', '6317', (181, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))
119178	27095573	For esophageal carcinoma, one study demonstrated 26.7% of PIK3CA gene amplification in ESCC.	('SCC', 'Gene', '6317', (88, 91))	('esophageal carcinoma', 'Disease', (4, 24))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (4, 24))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (4, 24))	('PIK3CA', 'Gene', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('SCC', 'Gene', (88, 91))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('amplification', 'Var', (70, 83))
119179	27095573	In nasopharyngeal carcinoma, PIK3CA amplification was strongly associated with distant metastasis, lymph node involvement, advanced tumor stage, and ultimately with reduced overall survival.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('nasopharyngeal carcinoma', 'Disease', (3, 27))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('associated', 'Reg', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('overall', 'MPA', (173, 180))	('amplification', 'Var', (36, 49))	('lymph node involvement', 'CPA', (99, 121))	('tumor', 'Disease', (132, 137))	('distant metastasis', 'CPA', (79, 97))	('PIK3CA', 'Gene', (29, 35))	('reduced', 'NegReg', (165, 172))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (3, 27))
119180	27095573	For non-lymph node metastatic HNSCC, patients with PIK3CA amplification showed earlier recurrence than those without (10% vs 31% disease free at 2 years).	('patients', 'Species', '9606', (37, 45))	('PIK3CA', 'Gene', (51, 57))	('SCC', 'Gene', (32, 35))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('amplification', 'Var', (58, 71))	('SCC', 'Gene', '6317', (32, 35))
119181	27095573	Angulo et al reported that PIK3CA amplification was significantly more frequent in lung SCC compared with adenocarcinoma (42% vs 3%, P<0.001), however, no association was found with other clinicopathologic characteristics.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adenocarcinoma', 'Disease', (106, 120))	('frequent', 'Reg', (71, 79))	('PIK3CA', 'Gene', (27, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (106, 120))	('SCC', 'Gene', (88, 91))	('amplification', 'Var', (34, 47))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
119183	27095573	In our study, by carefully assessing a large cohort of ESCC cases, we were able to clarify the prognostic value of PIK3CA amplification in a homogenous ESCC patients.	('SCC', 'Gene', '6317', (153, 156))	('SCC', 'Gene', (56, 59))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('amplification', 'Var', (122, 135))	('patients', 'Species', '9606', (157, 165))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('SCC', 'Gene', '6317', (56, 59))	('SCC', 'Gene', (153, 156))	('PIK3CA', 'Gene', (115, 121))
119184	27095573	Therefore, PIK3CA amplification was significantly associated with shorter DFS regardless of sex, histologic grade, and adjuvant therapy, implying a potential role as an independent negative prognostic factor in curatively resected ESCC.	('DFS', 'MPA', (74, 77))	('shorter', 'NegReg', (66, 73))	('PIK3CA', 'Gene', (11, 17))	('SCC', 'Gene', (232, 235))	('SCC', 'Phenotype', 'HP:0002860', (232, 235))	('amplification', 'Var', (18, 31))	('SCC', 'Gene', '6317', (232, 235))
119188	27095573	The frequency of PIK3CA mutation has been variously reported as 2.2 to 21% of ESCC cases, with controversial prognostic value.	('SCC', 'Gene', (79, 82))	('PIK3CA', 'Gene', (17, 23))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('mutation', 'Var', (24, 32))
119189	27095573	Here, we report PIK3CA mutations in 1.6% of ESCCs using standard, bidirectional Sanger sequencing.	('SCC', 'Gene', (45, 48))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('SCC', 'Gene', '6317', (45, 48))	('mutations', 'Var', (23, 32))	('PIK3CA', 'Gene', (16, 22))
119193	27095573	Cell lines with PIK3CA amplification was positively associated with BYL719 sensitivity (P=0.0037) and tumor-bearing mice with PIK3CA amplification responded to BYL719, leading to a response rate of -18% (lung cancer) and -80% (gastric cancer).	('mice', 'Species', '10090', (116, 120))	('PIK3CA', 'Gene', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('associated', 'Reg', (52, 62))	('amplification', 'Var', (23, 36))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('BYL719', 'MPA', (68, 74))	('PIK3CA', 'Gene', (16, 22))	('lung cancer', 'Disease', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('sensitivity', 'MPA', (75, 86))	('tumor', 'Disease', (102, 107))	('gastric cancer', 'Disease', (227, 241))	('gastric cancer', 'Disease', 'MESH:D013274', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
119194	27095573	Pan-PI3K (BKM120 and GDC-0941) and alpha-selective inhibitors (BYL719 and GDC-0032) demonstrated responses and prolonged stable disease in patients with PIK3CA mutation.	('mutation', 'Var', (160, 168))	('patients', 'Species', '9606', (139, 147))	('BKM120', 'Chemical', 'MESH:C571178', (10, 16))	('GDC-0941', 'Chemical', 'MESH:C532162', (21, 29))	('PIK3CA', 'Gene', (153, 159))	('stable', 'MPA', (121, 127))	('GDC-0032', 'Chemical', 'MESH:C582924', (74, 82))
119195	27095573	In a phase I trial of GDC-0941, a heavily treated ovarian cancer patient with PIK3CA amplification achieved disease stabilization for 4 months with significant pharmacodynamic changes.	('ovarian cancer', 'Disease', 'MESH:D010051', (50, 64))	('PIK3CA', 'Gene', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ovarian cancer', 'Disease', (50, 64))	('GDC-0941', 'Chemical', 'MESH:C532162', (22, 30))	('patient', 'Species', '9606', (65, 72))	('amplification', 'Var', (85, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (50, 64))
119196	27095573	To date, clinical trials with PI3K inhibitors have been reported in un-selected patients, and current trials with PI3K inhibitors are for patients with PIK3CA gene alterations are ongoing (ClinicalTrials.gov number NCT01928459 and NCT01608022).	('PIK3CA', 'Gene', (152, 158))	('alterations', 'Var', (164, 175))	('patients', 'Species', '9606', (138, 146))	('patients', 'Species', '9606', (80, 88))
119199	27095573	In conclusion, in our large cohort study, we demonstrated that PIK3CA amplification is an independent poor prognostic factor in resected ESCC.	('SCC', 'Gene', (138, 141))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('SCC', 'Gene', '6317', (138, 141))	('PIK3CA', 'Gene', (63, 69))	('amplification', 'Var', (70, 83))
119200	27095573	Our findings also provide strong implication that PIK3CA amplification and mutation is a promising therapeutic target in ESCC.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('mutation', 'Var', (75, 83))	('SCC', 'Gene', '6317', (122, 125))	('PIK3CA', 'Gene', (50, 56))
119210	27095573	The extracted DNA was used in a PCR amplification reaction with primers were designed to amplify the following regions at codon E542, E545 and H1047; exon 9; 5';- AGAGACAATGAATTAAGGGAAAATGAC-3';; 5';- TTTAGCACTTACCTGTGACTCCA-3';, exon 20; 5';-TATTCGACAGCATGCCAATC-3';; 5';- TGTGTGGAAGATCCAATCCA-3';,.	('H1047; exon', 'Var', (143, 154))	('AAG', 'Gene', '4350', (177, 180))	('exon', 'Var', (150, 154))	('GAG', 'Chemical', 'MESH:D006025', (164, 167))	('AAG', 'Gene', (281, 284))	('AAG', 'Gene', '4350', (281, 284))	('E542', 'Var', (128, 132))	('AAG', 'Gene', (177, 180))	('E545', 'Var', (134, 138))
119221	25934640	In addition, the CRP/Alb ratio could identify a group of patients with mGPS score of 0 who had comparable overall survival with those with mGPS score of 1.	('mGPS score of 0', 'Var', (71, 86))	('CRP/Alb', 'Gene', (17, 24))	('patients', 'Species', '9606', (57, 65))	('CRP/Alb', 'Gene', '1401;213', (17, 24))
119249	25934640	Patients with both CRP > 10 mg/L and albumin > 35 g/L were allocated a score of 1.	('> 10 mg/L', 'Var', (23, 32))	('CRP', 'Gene', (19, 22))	('CRP', 'Gene', '1401', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('albumin', 'Gene', (37, 44))	('albumin', 'Gene', '213', (37, 44))
119250	25934640	Patients with both CRP > 10 mg/L and albumin < 35 g/L were allocated a score of 2.	('> 10 mg/L', 'Var', (23, 32))	('CRP', 'Gene', (19, 22))	('CRP', 'Gene', '1401', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('albumin', 'Gene', (37, 44))	('albumin', 'Gene', '213', (37, 44))
119279	25934640	Other significant prognostic indexes identified by univariate analysis included age (<=54/> 54 yr), the TNM stage (I/II/III/IV), distant metastasis (No/Yes), surgery (No/Yes), treatment purpose (Curative treatment/Palliative treatment), BMI (<=20.43/> 20.43), mGPS (0/1/2), PNI (<=49.05/> 49.05), NLR (<=1.835/> 1.835), PLR (<=163.8/> 163.8), CRP (<=10/> 10), white blood cell (WBC) (<=10/> 10), albumin (<=35/> 35).	('CRP', 'Gene', (343, 346))	('<=10/> 10', 'Var', (348, 357))	('CRP', 'Gene', '1401', (343, 346))	('mGPS (0/1/2', 'Gene', '209318;56310', (260, 271))	('albumin', 'Gene', (396, 403))	('albumin', 'Gene', '213', (396, 403))	('<=10/', 'Var', (384, 389))
119319	25934640	Several studies proved that supplement of some trophic factors, for example, omega-3 polyunsaturated fatty acids, could improve plasma fatty acid profile, CRP/Alb status, and immune function and prevent weight loss during treatment in cancer patients.	('weight loss', 'Disease', 'MESH:D015431', (203, 214))	('fatty acid', 'Chemical', 'MESH:D005227', (135, 145))	('cancer', 'Disease', (235, 241))	('improve', 'PosReg', (120, 127))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('omega-3 polyunsaturated fatty acids', 'Chemical', '-', (77, 112))	('omega-3', 'Var', (77, 84))	('fatty acid', 'Chemical', 'MESH:D005227', (101, 111))	('prevent', 'NegReg', (195, 202))	('weight loss', 'Disease', (203, 214))	('CRP/Alb', 'Gene', '1401;213', (155, 162))	('CRP/Alb', 'Gene', (155, 162))	('plasma fatty acid profile', 'MPA', (128, 153))	('weight loss', 'Phenotype', 'HP:0001824', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('immune function', 'CPA', (175, 190))	('patients', 'Species', '9606', (242, 250))
119344	25934640	Although no statistical difference of discriminatory ability was found between the CRP/Alb ratio and the mGPS, the CRP/Alb ratio could identify a group of patients with mGPS score of 0, who had comparable overall survival with those with mGPS score of 1 (P < 0.001).	('patients', 'Species', '9606', (155, 163))	('CRP/Alb', 'Gene', (83, 90))	('mGPS score of 0', 'Var', (169, 184))	('CRP/Alb', 'Gene', (115, 122))	('CRP/Alb', 'Gene', '1401;213', (83, 90))	('CRP/Alb', 'Gene', '1401;213', (115, 122))
119409	25890715	For immunohistochemical (IHC) analyses, the contractile skeletal muscle marker, fast myosin skeletal heavy chain (MY32); the contractile smooth muscle maker, alpha-smooth muscle actin (alpha-SMA); epithelial-associated proteins, pan-cytokeratin (CK), CK5, involucrin (IVL); neuronal and endothelial markers, synaptophysin (SYP38) and CD31, respectively, and the proliferation marker, Ki67 were detected using the following primary antibodies: anti-MY32 [Abcam, Cambridge, MA, 1:200 dilution], anti-alpha-SMA [Sigma-Aldrich, St. Louis, MO, 1:200 dilution], anti-pan-CK [Dako, Carpinteria, CA, 1:150 dilution], anti-CK5 [Abcam, 1:200 dilution], anti-IVL [Sigma-Aldrich, 1:200 dilution], anti-SYP38 [Abcam, 1:50 dilution], anti-CD31 [Abcam, 1:100 dilution], and anti-Ki67 [Abcam, 1:200 dilution].	('alpha-SMA', 'Gene', (498, 507))	('CD31', 'Gene', '29583', (334, 338))	('CK5', 'Gene', (614, 617))	('synaptophysin', 'Gene', '24804', (308, 321))	('involucrin', 'Gene', (256, 266))	('CD31', 'Gene', '29583', (725, 729))	('rat', 'Species', '10116', (239, 242))	('CD31', 'Gene', (334, 338))	('CD31', 'Gene', (725, 729))	('synaptophysin', 'Gene', (308, 321))	('anti-Ki67', 'Var', (759, 768))	('alpha-SMA', 'Gene', (185, 194))	('IVL', 'Gene', '60583', (268, 271))	('IVL', 'Gene', (268, 271))	('anti-SYP38', 'Var', (685, 695))	('IVL', 'Gene', '60583', (648, 651))	('CK5', 'Gene', '369017', (251, 254))	('alpha-SMA', 'Gene', '25365', (498, 507))	('IVL', 'Gene', (648, 651))	('CK5', 'Gene', '369017', (614, 617))	('involucrin', 'Gene', '60583', (256, 266))	('alpha-smooth muscle actin', 'Gene', '25365', (158, 183))	('alpha-smooth muscle actin', 'Gene', (158, 183))	('CK5', 'Gene', (251, 254))	('rat', 'Species', '10116', (369, 372))	('alpha-SMA', 'Gene', '25365', (185, 194))
119411	25890715	The number and diameter of CD31+ vessels and SYP38+boutons were measured similarly in 4-8 independent microscopic fields (magnification 20X) and normalized to the total field area examined to ascertain the respective extent of de novo vascularization and innervation processes in all experimental groups.	('SYP38+boutons', 'Var', (45, 58))	('CD31', 'Gene', '29583', (27, 31))	('CD31', 'Gene', (27, 31))
119472	25890715	The percent of MY32+ area supported by SF implants significantly increased in the regenerating muscularis externa at 2 m post-op in comparison to the early timepoints and was found to be similar to the levels achieved in sham-operated controls.	('increased', 'PosReg', (65, 74))	('rat', 'Species', '10116', (229, 232))	('rat', 'Species', '10116', (88, 91))	('implants', 'Var', (42, 50))
119476	25890715	Regenerated tissues supported by both SF and SIS matrices displayed evidence of de novo innervation throughout the original implantation sites characterized by the appearance of SYP38+ boutons indicative of areas of synaptic transmission (Figure 9).	('SIS', 'Disease', (45, 48))	('SYP38+', 'Var', (178, 184))	('SIS', 'Disease', 'None', (45, 48))	('rat', 'Species', '10116', (6, 9))
119477	25890715	Following 1 m of SF matrix grafting, histomorphometric analysis demonstrated a significant 3.2-fold increase in the density of SYP38+ boutons present at the 1 wk timepoint.	('SYP38+', 'Var', (127, 133))	('increase', 'PosReg', (100, 108))	('rat', 'Species', '10116', (71, 74))
119479	25890715	In contrast, the density of SYP38+ boutons observed in the neotissues supported by the SIS cohort was significantly lower in comparison to the other experimental groups at similar timepoints and constituted only 29% of sham-operated control levels.	('lower', 'NegReg', (116, 121))	('SIS cohort', 'Disease', 'None', (87, 97))	('rat', 'Species', '10116', (227, 230))	('SIS cohort', 'Disease', (87, 97))	('SYP38+', 'Var', (28, 34))
119579	23192272	Accordingly, in the nude mouse xenograft model system, NDRG1 overexpression promoted the in vivo growth of KYSE30 derived xenografts, which could be attributed to the reduced apoptotic and enhanced angiogenic activities associated with this gene.	('NDRG1', 'Gene', (55, 60))	('apoptotic', 'CPA', (175, 184))	('enhanced', 'PosReg', (189, 197))	('growth', 'CPA', (97, 103))	('mouse', 'Species', '10090', (25, 30))	('angiogenic activities', 'CPA', (198, 219))	('promoted', 'PosReg', (76, 84))	('overexpression', 'Var', (61, 75))	('reduced', 'NegReg', (167, 174))
119587	23192272	However, observations regarding the functional roles of NDRG1 in tumor progression are highly contradictory, from both immunohistochemical analysis of clinical samples to functional studies using ectopic NDRG1 overexpression or knock-down.	('tumor', 'Disease', (65, 70))	('NDRG1', 'Gene', (204, 209))	('overexpression', 'PosReg', (210, 224))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('knock-down', 'Var', (228, 238))	('clinical samples', 'Species', '191496', (151, 167))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
119595	23192272	In functional studies, NDRG1 knock-down by RNA interference was shown to reduce cell proliferation and invasion, and induce apoptosis in hepatocellular carcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('induce', 'Reg', (117, 123))	('invasion', 'CPA', (103, 111))	('RNA interference', 'MPA', (43, 59))	('NDRG1', 'Gene', (23, 28))	('cell proliferation', 'CPA', (80, 98))	('rat', 'Species', '10116', (92, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (137, 161))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (137, 161))	('apoptosis', 'CPA', (124, 133))	('reduce', 'NegReg', (73, 79))	('hepatocellular carcinoma', 'Disease', (137, 161))	('knock-down', 'Var', (29, 39))
119609	23192272	Compared with wild type KYSE30 and vector control transfectants, markedly increased migration and invasion was observed in ectopic NDRG1-overexpressing transfectants (Fig.	('invasion', 'CPA', (98, 106))	('migration', 'CPA', (84, 93))	('ectopic', 'Var', (123, 130))	('increased', 'PosReg', (74, 83))	('NDRG1-overexpressing', 'Gene', (131, 151))	('rat', 'Species', '10116', (87, 90))
119616	23192272	Furthermore, an increase in VEGF-A protein secreted into the media, as determined by ELISA, was also observed with 300.7 +- 48.1, 311.6 +- 51.4, 293.3 +- 82.1 and 567.9 +- 49.1 pg VEGF-A/106 cells detected in wild type, NDRG1 RNAi (p = 0.660), vector control (p = 0.771) and NDRG1 overexpressing KYSE30 cells (p = 0.021), respectively.	('VEGF-A', 'Gene', '7422', (28, 34))	('293.3', 'Var', (145, 150))	('VEGF-A', 'Gene', (28, 34))	('VEGF-A', 'Gene', '7422', (180, 186))	('increase', 'PosReg', (16, 24))	('VEGF-A', 'Gene', (180, 186))
119619	23192272	Interestingly, the mRNA levels of several pro-inflammatory chemokines such as GRO-alpha/CXCL1, GRO-beta/CXCL-2 and IL-8/CXCL-8 were found significantly elevated in response to ectopic NDRG1 overexpression, suggesting the pleiotropic supportive role of NDRG1 on angiogenesis in KYSE30 cells (Fig.	('CXCL1', 'Gene', (88, 93))	('IL-8', 'Gene', (115, 119))	('elevated', 'PosReg', (152, 160))	('GRO-alpha', 'Gene', (78, 87))	('NDRG1', 'Gene', (184, 189))	('CXCL-2', 'Gene', (104, 110))	('GRO-beta', 'Gene', '2920', (95, 103))	('IL-8', 'Gene', '3576', (115, 119))	('GRO-beta', 'Gene', (95, 103))	('GRO-alpha', 'Gene', '2919', (78, 87))	('CXCL-8', 'Gene', '3576', (120, 126))	('CXCL-2', 'Gene', '2920', (104, 110))	('mRNA levels', 'MPA', (19, 30))	('CXCL-8', 'Gene', (120, 126))	('ectopic', 'Var', (176, 183))	('overexpression', 'PosReg', (190, 204))	('CXCL1', 'Gene', '2919', (88, 93))
119624	23192272	Compared with wild type KYSE30 cells, reduced apoptosis (measured by both PARP cleavage and caspase 3/7 activity) was observed in transfectants with ectopic NDRG1 overexpression, while similar levels of apoptosis were found in both NDRG1 knock-down and vector control transfectants.	('apoptosis', 'CPA', (46, 55))	('reduced', 'NegReg', (38, 45))	('caspase 3', 'Gene', (92, 101))	('caspase 3', 'Gene', '836', (92, 101))	('PARP', 'Gene', '1302', (74, 78))	('NDRG1', 'Gene', (157, 162))	('ectopic', 'Var', (149, 156))	('overexpression', 'PosReg', (163, 177))	('PARP', 'Gene', (74, 78))
119636	23192272	As shown in Figure 5A, significant bigger and more vascularized xenografts were generated from NDRG1 overexpressing cells.	('rat', 'Species', '10116', (84, 87))	('overexpressing', 'Var', (101, 115))	('NDRG1', 'Gene', (95, 100))	('more', 'PosReg', (46, 50))	('bigger', 'PosReg', (35, 41))
119637	23192272	Although the Ki-67 proliferation index was higher in NDRG1 overexpressing xenografts (36.2 +- 5.1%) compared with wild type xenografts (29.8 +- 7.5%) (p = 0.021), the small difference in absolute value lies within the same range and might not fully explain the large increase in xenograft tumor volume (Fig.	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('higher', 'PosReg', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('rat', 'Species', '10116', (26, 29))	('NDRG1', 'Gene', (53, 58))	('tumor', 'Disease', (289, 294))	('overexpressing', 'Var', (59, 73))	('Ki-67', 'Gene', (13, 18))
119651	23192272	Although functional studies have demonstrated that NDRG1 participates in trophoblast differentiation, a prerequisite event for the implantation of the embryo into the endometrium, NDRG1 deficient mice are fertile, suggesting NDRG1 may not be necessary for functional trophoblasts.	('NDRG1', 'Gene', (51, 56))	('NDRG1', 'Gene', (180, 185))	('mice', 'Species', '10090', (196, 200))	('trophoblast differentiation', 'CPA', (73, 100))	('rat', 'Species', '10116', (40, 43))	('participates', 'Reg', (57, 69))	('deficient', 'Var', (186, 195))
119672	23192272	Primers for VEGF-A, VEGF-C and PDGF-B were designed to detect all the transcript variants.	('PDGF-B', 'Gene', '5155', (31, 37))	('VEGF-C', 'Gene', '7424', (20, 26))	('VEGF-A', 'Gene', '7422', (12, 18))	('VEGF-A', 'Gene', (12, 18))	('VEGF-C', 'Gene', (20, 26))	('PDGF-B', 'Gene', (31, 37))	('variants', 'Var', (81, 89))
119765	33805318	In the study of Bedenne et al., pathological complete response was found in 25 (23%) of 110 patients with 6th AJCC T3N0-1M0 esophageal cancer receiving 30 Gy preoperative chemoradiotherapy.	('T3N0-1M0', 'Var', (115, 123))	('esophageal cancer', 'Disease', (124, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
119769	33805318	revealed that pathological complete response was found in 18 (49%) of 37 patients with 6th AJCC T1N1M0 or T2-3N0-1M0 ESCC receiving 41.4 Gy preoperative chemoradiotherapy.	('T1N1M0', 'Var', (96, 102))	('patients', 'Species', '9606', (73, 81))	('T2-3N0-1M0', 'Var', (106, 116))
119771	33805318	In the study of Tepper et al., 10 (40%) of 25 patients with 6th AJCC T1-3NxM0 esophageal cancer receiving 50.4 Gy preoperative chemoradiotherapy achieved a pathological complete response.	('patients', 'Species', '9606', (46, 54))	('T1-3NxM0', 'Var', (69, 77))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
119778	33805318	found a 20% major pulmonary complication rate in patients with 6th AJCC T1-3N0-1M0 esophageal cancer receiving 35 Gy preoperative chemoradiotherapy.	('T1-3N0-1M0', 'Var', (72, 82))	('esophageal cancer', 'Disease', (83, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (49, 57))	('major', 'Disease', (12, 17))
119779	33805318	However, in patients with 6th AJCC T1N1M0 or T2-3N0-1M0 esophageal cancer receiving 41.4Gy preoperative chemoradiotherapy, Hagen et al.	('patients', 'Species', '9606', (12, 20))	('esophageal cancer', 'Disease', (56, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('T1N1M0', 'Var', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('T2-3N0-1M0', 'Var', (45, 55))
119780	33805318	Moreover, in patients with 6th AJCC T1-3NxM0 esophageal cancer receiving 50.4 Gy preoperative chemoradiotherapy, Tepper et al.	('esophageal cancer', 'Disease', (45, 62))	('patients', 'Species', '9606', (13, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('T1-3NxM0', 'Var', (36, 44))
119799	33173311	Here, we explored the role and potential molecular mechanism of let-7c-5p in ESCC.	('ESCC', 'Disease', (77, 81))	('let-7c-5p', 'Var', (64, 73))	('let-7c-', 'Chemical', '-', (64, 71))
119802	33173311	The dual-luciferase reporter assay was used to verify the targeting relationship between let-7c-5p and CTHRC1.	('CTHRC1', 'Gene', (103, 109))	('let-7c-5p', 'Var', (89, 98))	('CTHRC1', 'Gene', '115908', (103, 109))	('let-7c-', 'Chemical', '-', (89, 96))
119803	33173311	The tumor xenograft model was constructed to further verify the effect of let-7c-5p on the growth of ESCC in vivo.	('tumor', 'Disease', (4, 9))	('let-7c-', 'Chemical', '-', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('let-7c-5p', 'Var', (74, 83))	('ESCC', 'Disease', (101, 105))
119805	33173311	Next, we found that let-7c-5p can be used to discriminate ESCC patients from normal control subjects by receiver operating characteristic (ROC) curve analysis.	('let-7c-5p', 'Var', (20, 29))	('rat', 'Species', '10116', (116, 119))	('let-7c-', 'Chemical', '-', (20, 27))	('patients', 'Species', '9606', (63, 71))	('ESCC', 'Disease', (58, 62))
119806	33173311	Subsequently, we observed that let-7c-5p overexpression inhibited proliferation and migration and promoted apoptosis, while let-7c-5p down-regulation promoted proliferation and migration and inhibited apoptosis of TE-1 and KYSE150 cells.	('KYSE150', 'CellLine', 'CVCL:1348', (223, 230))	('proliferation', 'CPA', (159, 172))	('down-regulation', 'NegReg', (134, 149))	('TE', 'Chemical', 'MESH:D013691', (214, 216))	('rat', 'Species', '10116', (87, 90))	('rat', 'Species', '10116', (166, 169))	('promoted', 'PosReg', (150, 158))	('let-7c-5p', 'Var', (31, 40))	('apoptosis', 'CPA', (201, 210))	('apoptosis', 'CPA', (107, 116))	('rat', 'Species', '10116', (180, 183))	('let-7c-5p', 'Var', (124, 133))	('let-7c-', 'Chemical', '-', (31, 38))	('inhibited', 'NegReg', (56, 65))	('inhibited', 'NegReg', (191, 200))	('proliferation', 'CPA', (66, 79))	('promoted', 'PosReg', (98, 106))	('migration', 'CPA', (177, 186))	('let-7c-', 'Chemical', '-', (124, 131))	('rat', 'Species', '10116', (73, 76))
119807	33173311	Furthermore, let-7c-5p overexpression inhibited tumor growth, while let-7c-5p inhibition promoted tumor growth in xenograft models.	('overexpression', 'PosReg', (23, 37))	('tumor', 'Disease', (48, 53))	('let-7c-5p', 'Var', (68, 77))	('let-7c-5p', 'Var', (13, 22))	('let-7c-', 'Chemical', '-', (68, 75))	('let-7c-', 'Chemical', '-', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('inhibited', 'NegReg', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('promoted', 'PosReg', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
119808	33173311	In addition, we confirmed that CTHRC1 was a direct target gene of let-7c-5p.	('let-7c-', 'Chemical', '-', (66, 73))	('CTHRC1', 'Gene', (31, 37))	('CTHRC1', 'Gene', '115908', (31, 37))	('let-7c-5p', 'Var', (66, 75))
119810	33173311	Moreover, we confirmed that let-7c-5p upregulation significantly reduced the phosphorylation of AKT and ERK by directly inhibiting CTHRC1, while let-7c-5p downregulation showed the opposite effect.	('phosphorylation', 'MPA', (77, 92))	('ERK', 'Gene', (104, 107))	('AKT', 'Gene', (96, 99))	('inhibiting', 'NegReg', (120, 130))	('reduced', 'NegReg', (65, 72))	('CTHRC1', 'Gene', '115908', (131, 137))	('CTHRC1', 'Gene', (131, 137))	('let-7c-5p', 'Var', (28, 37))	('let-7c-', 'Chemical', '-', (145, 152))	('let-7c-', 'Chemical', '-', (28, 35))	('AKT', 'Gene', '207', (96, 99))	('ERK', 'Gene', '5594', (104, 107))	('upregulation', 'PosReg', (38, 50))
119811	33173311	Our findings indicate that let-7c-5p is markedly downregulated in ESCC and suppresses proliferation and migration and promotes apoptosis of ESCC cells by inhibiting the AKT and ERK signaling pathways through negatively regulating CTHRC1.	('ERK', 'Gene', '5594', (177, 180))	('inhibiting', 'NegReg', (154, 164))	('negatively regulating', 'NegReg', (208, 229))	('ERK', 'Gene', (177, 180))	('AKT', 'Gene', (169, 172))	('suppresses', 'NegReg', (75, 85))	('let-7c-5p', 'Var', (27, 36))	('apoptosis', 'CPA', (127, 136))	('let-7c-', 'Chemical', '-', (27, 34))	('promotes', 'PosReg', (118, 126))	('rat', 'Species', '10116', (107, 110))	('rat', 'Species', '10116', (93, 96))	('downregulated', 'NegReg', (49, 62))	('ESCC', 'Disease', (66, 70))	('CTHRC1', 'Gene', '115908', (230, 236))	('AKT', 'Gene', '207', (169, 172))	('CTHRC1', 'Gene', (230, 236))
119812	33173311	Therefore, these results suggest that let-7c-5p may represent a novel biomarker and therapeutic target for ESCC.	('let-7c-', 'Chemical', '-', (38, 45))	('ESCC', 'Disease', (107, 111))	('let-7c-5p', 'Var', (38, 47))
119827	33173311	However, the biological function and molecular mechanism of let-7c-5p in ESCC remain unclear.	('let-7c-5p', 'Var', (60, 69))	('ESCC', 'Disease', (73, 77))	('let-7c-', 'Chemical', '-', (60, 67))
119828	33173311	We hypothesized that let-7c-5p might represent a promising biomarker of ESCC.	('let-7c-', 'Chemical', '-', (21, 28))	('let-7c-5p', 'Var', (21, 30))	('ESCC', 'Disease', (72, 76))
119834	33173311	The goal of this study was to explore the role and potential molecular mechanism of let-7c-5p in the occurrence and development of ESCC.	('let-7c-', 'Chemical', '-', (84, 91))	('let-7c-5p', 'Var', (84, 93))	('ESCC', 'Disease', (131, 135))
119839	33173311	Next, bioinformatics analysis predicted that CTHRC1 might be a potential target gene of let-7c-5p, which was further verified by a dual-luciferase report experiment.	('let-7c-', 'Chemical', '-', (88, 95))	('let-7c-5p', 'Var', (88, 97))	('CTHRC1', 'Gene', (45, 51))	('CTHRC1', 'Gene', '115908', (45, 51))
119840	33173311	Furthermore, we verified the effect of let-7c-5p on the progression of ESCC in vivo.	('ESCC', 'Disease', (71, 75))	('let-7c-5p', 'Var', (39, 48))	('let-7c-', 'Chemical', '-', (39, 46))
119844	33173311	ESCC tissues were collected and immediately placed in liquid nitrogen and stored at -80 C. The human ESCC cell lines, TE-1, TE-10, TE-11, KYSE140, and KYSE150, the normal esophageal epithelial cell line Het-1A and the human embryonic kidney cell line HEK-293T were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China).	('human', 'Species', '9606', (95, 100))	('embryonic kidney', 'Disease', (224, 240))	('KYSE150', 'CellLine', 'CVCL:1348', (151, 158))	('nitrogen', 'Chemical', 'MESH:D009584', (61, 69))	('TE', 'Chemical', 'MESH:D013691', (131, 133))	('HEK-293T', 'CellLine', 'CVCL:0063', (251, 259))	('TE', 'Chemical', 'MESH:D013691', (124, 126))	('embryonic kidney', 'Disease', 'MESH:D007674', (224, 240))	('TE', 'Chemical', 'MESH:D013691', (118, 120))	('human', 'Species', '9606', (218, 223))	('KYSE150', 'Var', (151, 158))
119854	33173311	U6 was used as an endogenous control for let-7c-5p, while GAPDH was an internal control for CTHRC1.	('GAPDH', 'Gene', '2597', (58, 63))	('GAPDH', 'Gene', (58, 63))	('let-7c-5p', 'Var', (41, 50))	('CTHRC1', 'Gene', (92, 98))	('CTHRC1', 'Gene', '115908', (92, 98))	('let-7c-', 'Chemical', '-', (41, 48))
119875	33173311	A dual-luciferase reporter assay was used to investigate whether let-7c-5p binds to the 3'-UTR of CTHRC1.	('let-7c-', 'Chemical', '-', (65, 72))	('let-7c-5p', 'Var', (65, 74))	('CTHRC1', 'Gene', (98, 104))	('CTHRC1', 'Gene', '115908', (98, 104))
119876	33173311	The wild type (WT) and mutant (MUT) 3'-UTRs of CTHRC1 were synthesized by ELK Biotechnology (Wuhan, China) and then inserted into the pGL6 basic vector with BamHI and HindIII restriction sites.	('CTHRC1', 'Gene', (47, 53))	('mutant', 'Var', (23, 29))	('CTHRC1', 'Gene', '115908', (47, 53))
119890	33173311	Pearson's correlation analysis was used to examine the correlation between let-7c-5p and CTHRC1.	('let-7c-5p', 'Var', (75, 84))	('CTHRC1', 'Gene', (89, 95))	('CTHRC1', 'Gene', '115908', (89, 95))	('let-7c-', 'Chemical', '-', (75, 82))
119891	33173311	To explore the potential clinicopathological significance of let-7c-5p in ESCC, we assessed expression of let-7c-5p in ESCC tissues and cell lines by qRT-PCR.	('let-7c-5p', 'Var', (106, 115))	('ESCC', 'Disease', (74, 78))	('ESCC', 'Disease', (119, 123))	('let-7c-', 'Chemical', '-', (61, 68))	('let-7c-', 'Chemical', '-', (106, 113))
119893	33173311	Similarly, we confirmed that let-7c-5p expression was markedly decreased in five ESCC cell lines (TE-1, TE-10, TE-11, KYSE140 and KYSE150) compared to normal esophageal epithelial cells, Het-1A (Figure 1B).	('TE', 'Chemical', 'MESH:D013691', (98, 100))	('let-7c-', 'Chemical', '-', (29, 36))	('decreased', 'NegReg', (63, 72))	('ESCC', 'Disease', (81, 85))	('KYSE150', 'Var', (130, 137))	('TE', 'Chemical', 'MESH:D013691', (104, 106))	('TE', 'Chemical', 'MESH:D013691', (111, 113))	('KYSE150', 'CellLine', 'CVCL:1348', (130, 137))	('expression', 'MPA', (39, 49))	('let-7c-5p', 'Gene', (29, 38))
119895	33173311	Importantly, we observed that lower expression of let-7c-5p was associated with advanced clinical stage (Figure 1C, Table 1, P<0.05) and lymph node metastasis (Figure 1D, Table 1, P<0.05); however, there was no significant correlation with gender, age, smoking status or tumor size (Table 1, P>0.05).	('lower', 'NegReg', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Disease', (271, 276))	('lymph node metastasis', 'CPA', (137, 158))	('let-7c-5p', 'Var', (50, 59))	('advanced clinical stage', 'CPA', (80, 103))	('expression', 'MPA', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('let-7c-', 'Chemical', '-', (50, 57))
119903	33173311	The AUC of let-7c-5p in advanced stage ESCC tissues was 0.88 (95% CI = 0.785-0.981, P<0.0001) and at a cutoff value of 0.68, the optimal sensitivity and specificity were 92% and 86%, respectively (Figure 1F).	('let-7c-5p', 'Var', (11, 20))	('let-7c-', 'Chemical', '-', (11, 18))	('ESCC', 'Disease', (39, 43))
119906	33173311	First, we detected the transfection efficiency of TE-1 and KYSE150 cells in response to transfection with let-7c-5p mimics or inhibitor by qRT-qPCR.	('KYSE150', 'CellLine', 'CVCL:1348', (59, 66))	('let-7c-', 'Chemical', '-', (106, 113))	('let-7c-5p mimics', 'Var', (106, 122))	('transfection', 'MPA', (23, 35))	('transfection', 'MPA', (88, 100))	('TE', 'Chemical', 'MESH:D013691', (50, 52))
119910	33173311	Results showed that overexpression of let-7c-5p using its mimics significantly inhibited cell proliferation (Figure 2B).	('rat', 'Species', '10116', (101, 104))	('cell proliferation', 'CPA', (89, 107))	('let-7c-5p', 'Var', (38, 47))	('overexpression', 'PosReg', (20, 34))	('inhibited', 'NegReg', (79, 88))	('let-7c-', 'Chemical', '-', (38, 45))
119912	33173311	Moreover, results of flow cytometry analysis indicated that overexpression of let-7c-5p increased apoptosis (Figure 3A and B), inversely, inhibition of let-7c-5p reduced apoptosis (Figure 3C and D).	('apoptosis', 'CPA', (98, 107))	('let-7c-', 'Chemical', '-', (78, 85))	('reduced', 'NegReg', (162, 169))	('overexpression', 'PosReg', (60, 74))	('let-7c-', 'Chemical', '-', (152, 159))	('let-7c-5p', 'Var', (78, 87))	('apoptosis', 'CPA', (170, 179))
119913	33173311	Therefore, these results suggest that let-7c-5p inhibits proliferation activity and promotes apoptosis in ESCC cells.	('let-7c-5p', 'Var', (38, 47))	('inhibits', 'NegReg', (48, 56))	('proliferation activity', 'CPA', (57, 79))	('rat', 'Species', '10116', (64, 67))	('let-7c-', 'Chemical', '-', (38, 45))	('apoptosis', 'CPA', (93, 102))	('promotes', 'PosReg', (84, 92))
119915	33173311	In the wound healing assay, we found that overexpression of let-7c-5p significantly inhibited the migration behavior of TE-1 and KYSE150 cells compared to the control group.	('let-7c-5p', 'Var', (60, 69))	('let-7c-', 'Chemical', '-', (60, 67))	('rat', 'Species', '10116', (101, 104))	('migration behavior of', 'CPA', (98, 119))	('overexpression', 'PosReg', (42, 56))	('TE', 'Chemical', 'MESH:D013691', (120, 122))	('KYSE150', 'CellLine', 'CVCL:1348', (129, 136))	('inhibited', 'NegReg', (84, 93))
119916	33173311	In contrast, inhibition of let-7c-5p significantly promoted cell migration (Figure 4A and B).	('cell migration', 'CPA', (60, 74))	('inhibition', 'Var', (13, 23))	('let-7c-', 'Chemical', '-', (27, 34))	('promoted', 'PosReg', (51, 59))	('rat', 'Species', '10116', (68, 71))	('let-7c-5p', 'Protein', (27, 36))
119917	33173311	Moreover, we confirmed by the Transwell assay that let-7c-5p overexpression significantly inhibited cell migration compared to the control group, while let-7c-5p inhibition significantly promoted cell migration (Figure 4C and D).	('inhibition', 'NegReg', (162, 172))	('rat', 'Species', '10116', (108, 111))	('cell migration', 'CPA', (196, 210))	('overexpression', 'PosReg', (61, 75))	('cell migration', 'CPA', (100, 114))	('rat', 'Species', '10116', (204, 207))	('let-7c-5p', 'Var', (152, 161))	('let-7c-5p', 'Var', (51, 60))	('let-7c-', 'Chemical', '-', (51, 58))	('promoted', 'PosReg', (187, 195))	('inhibited', 'NegReg', (90, 99))	('let-7c-', 'Chemical', '-', (152, 159))
119918	33173311	These results indicate that let-7c-5p inhibits the migration of ESCC cells.	('migration of ESCC cells', 'CPA', (51, 74))	('let-7c-5p', 'Var', (28, 37))	('inhibits', 'NegReg', (38, 46))	('rat', 'Species', '10116', (54, 57))	('let-7c-', 'Chemical', '-', (28, 35))
119919	33173311	To further explore the molecular mechanism of let-7c-5p effects, bioinformatics prediction analysis confirmed that CTHRC1 is a potential target of let-7c-5p, and its 3'-UTR contains a putative let-7c-5p binding site.	('let-7c-', 'Chemical', '-', (193, 200))	('let-7c-', 'Chemical', '-', (46, 53))	('CTHRC1', 'Gene', '115908', (115, 121))	('let-7c-5p', 'Var', (147, 156))	('let-7c-', 'Chemical', '-', (147, 154))	('CTHRC1', 'Gene', (115, 121))	('binding', 'Interaction', (203, 210))
119920	33173311	CTHRC1's wild type 3'-UTR (pGL6-miR-CTHRC1-WT) contained the predicted let-7c-5p target site, while CTHRC1's mutant 3'-UTR (pGL6-miR-CTHRC1-Mut) lacked the let-7c-5p binding site (Figure 5A).	('miR', 'Gene', (32, 35))	('let-7c-', 'Chemical', '-', (156, 163))	('CTHRC1', 'Gene', (0, 6))	('miR', 'Gene', '220972', (129, 132))	('let-7c-', 'Chemical', '-', (71, 78))	('miR', 'Gene', (129, 132))	('CTHRC1', 'Gene', '115908', (100, 106))	('CTHRC1', 'Gene', (100, 106))	('CTHRC1', 'Gene', '115908', (36, 42))	('CTHRC1', 'Gene', '115908', (133, 139))	('CTHRC1', 'Gene', (36, 42))	('lacked', 'NegReg', (145, 151))	('mutant', 'Var', (109, 115))	('let-7c-5p target site', 'MPA', (71, 92))	('CTHRC1', 'Gene', (133, 139))	('CTHRC1', 'Gene', '115908', (0, 6))	('miR', 'Gene', '220972', (32, 35))
119921	33173311	To verify bioinformatics predictions, we used the dual-luciferase reporter assay to investigate whether let-7c-5p directly targets CTHRC1.	('CTHRC1', 'Gene', '115908', (131, 137))	('CTHRC1', 'Gene', (131, 137))	('let-7c-5p', 'Var', (104, 113))	('targets', 'Reg', (123, 130))	('let-7c-', 'Chemical', '-', (104, 111))
119923	33173311	Results demonstrated that let-7c-5p overexpression significantly reduced luciferase activity in CTHRC1 wild-type (WT) 3'-UTRs, compared to the negative control group.	('luciferase', 'Enzyme', (73, 83))	('let-7c-', 'Chemical', '-', (26, 33))	('CTHRC1', 'Gene', (96, 102))	('reduced', 'NegReg', (65, 72))	('overexpression', 'PosReg', (36, 50))	('rat', 'Species', '10116', (15, 18))	('CTHRC1', 'Gene', '115908', (96, 102))	('activity', 'MPA', (84, 92))	('let-7c-5p', 'Var', (26, 35))
119925	33173311	Next, to further explore the regulation of let-7c-5p on CTHRC1 expression, we found that overexpression of let-7c-5p significantly inhibited mRNA expression of CTHRC1 (Figure 5C), while inhibition of let-7c-5p restored CTHRC1 expression by qRT-PCR (Figure 5D).	('CTHRC1', 'Gene', (219, 225))	('CTHRC1', 'Gene', (56, 62))	('let-7c-', 'Chemical', '-', (43, 50))	('let-7c-5p', 'Var', (107, 116))	('CTHRC1', 'Gene', '115908', (160, 166))	('overexpression', 'PosReg', (89, 103))	('CTHRC1', 'Gene', (160, 166))	('inhibited', 'NegReg', (131, 140))	('CTHRC1', 'Gene', '115908', (219, 225))	('mRNA expression', 'MPA', (141, 156))	('let-7c-', 'Chemical', '-', (107, 114))	('CTHRC1', 'Gene', '115908', (56, 62))	('let-7c-', 'Chemical', '-', (200, 207))
119926	33173311	Moreover, compared to the control group, overexpression of let-7c-5p significantly inhibited protein levels of CTHRC1, while let-7c-5p inhibition restored protein levels of CTHRC1 by Western blot (Figure 5E and F).	('CTHRC1', 'Gene', (111, 117))	('inhibition', 'NegReg', (135, 145))	('CTHRC1', 'Gene', '115908', (111, 117))	('let-7c-5p', 'Var', (59, 68))	('protein levels', 'MPA', (155, 169))	('protein levels', 'MPA', (93, 107))	('CTHRC1', 'Gene', '115908', (173, 179))	('let-7c-5p', 'Var', (125, 134))	('CTHRC1', 'Gene', (173, 179))	('inhibited', 'NegReg', (83, 92))	('restored', 'PosReg', (146, 154))	('let-7c-', 'Chemical', '-', (59, 66))	('let-7c-', 'Chemical', '-', (125, 132))
119927	33173311	These results indicate that CTHRC1 is a direct target of let-7c-5p and let-7c-5p regulates expression of CTHRC1 by binding to its 3'UTR.	('expression', 'MPA', (91, 101))	('CTHRC1', 'Gene', (28, 34))	('let-7c-', 'Chemical', '-', (71, 78))	('regulates', 'Reg', (81, 90))	('let-7c-', 'Chemical', '-', (57, 64))	('CTHRC1', 'Gene', '115908', (105, 111))	('CTHRC1', 'Gene', (105, 111))	('binding', 'Interaction', (115, 122))	('let-7c-5p', 'Var', (71, 80))	('CTHRC1', 'Gene', '115908', (28, 34))
119935	33173311	Since studies have reported that CTHRC1 plays an important role in the activation of the AKT/ERK pathway, to further elucidate molecular mechanism of let-7c-5p inhibiting the proliferation and migration of ESCC cells, we explored the possibility of let-7c-5p inhibiting AKT and EKR signaling pathways.	('inhibiting', 'NegReg', (160, 170))	('ERK', 'Gene', '5594', (93, 96))	('let-7c-5p', 'Var', (150, 159))	('ERK', 'Gene', (93, 96))	('let-7c-', 'Chemical', '-', (249, 256))	('let-7c-', 'Chemical', '-', (150, 157))	('AKT', 'Gene', '207', (270, 273))	('CTHRC1', 'Gene', '115908', (33, 39))	('CTHRC1', 'Gene', (33, 39))	('AKT', 'Gene', '207', (89, 92))	('rat', 'Species', '10116', (182, 185))	('AKT', 'Gene', (270, 273))	('rat', 'Species', '10116', (196, 199))	('AKT', 'Gene', (89, 92))	('inhibiting', 'NegReg', (259, 269))	('proliferation', 'CPA', (175, 188))
119936	33173311	Western blot analysis showed that transfection with let-7c-5p mimics in TE-1 and KYSE150 cells significantly reduced the expression of p-AKT and p-ERK, while expression of total AKT and ERK did not significantly change (Figure 7A and B), suggesting that AKT and ERK signaling pathways were inhibited.	('ERK', 'Gene', '5594', (186, 189))	('AKT', 'Gene', (254, 257))	('TE', 'Chemical', 'MESH:D013691', (72, 74))	('expression', 'MPA', (121, 131))	('AKT', 'Gene', '207', (137, 140))	('let-7c-', 'Chemical', '-', (52, 59))	('ERK', 'Gene', (147, 150))	('ERK', 'Gene', (186, 189))	('inhibited', 'NegReg', (290, 299))	('ERK', 'Gene', '5594', (262, 265))	('AKT', 'Gene', '207', (254, 257))	('AKT', 'Gene', (178, 181))	('let-7c-5p', 'Var', (52, 61))	('reduced', 'NegReg', (109, 116))	('KYSE150', 'CellLine', 'CVCL:1348', (81, 88))	('AKT', 'Gene', (137, 140))	('ERK', 'Gene', (262, 265))	('ERK', 'Gene', '5594', (147, 150))	('AKT', 'Gene', '207', (178, 181))
119938	33173311	Collectively, these data indicate that upregulation of let-7c-5p inhibited AKT/ERK signaling, while downregulation of let-7c-5p activated AKT/ERK signaling.	('ERK', 'Gene', (79, 82))	('activated', 'PosReg', (128, 137))	('ERK', 'Gene', (142, 145))	('AKT', 'Gene', '207', (75, 78))	('AKT', 'Gene', (138, 141))	('upregulation', 'PosReg', (39, 51))	('AKT', 'Gene', (75, 78))	('inhibited', 'NegReg', (65, 74))	('let-7c-5p', 'Var', (55, 64))	('downregulation', 'NegReg', (100, 114))	('let-7c-', 'Chemical', '-', (55, 62))	('ERK', 'Gene', '5594', (79, 82))	('let-7c-', 'Chemical', '-', (118, 125))	('ERK', 'Gene', '5594', (142, 145))	('AKT', 'Gene', '207', (138, 141))
119940	33173311	After transfection with siCTHRC1-2 in TE-1 and KYSE150 cells, we found that expression of CTHRC1 was most significantly downregulated by qRT-PCR (Figure 8A and B), which was consistent with protein expression levels by Western blot (Figure 8C and D).	('TE', 'Chemical', 'MESH:D013691', (38, 40))	('CTHRC1', 'Gene', (90, 96))	('downregulated', 'NegReg', (120, 133))	('CTHRC1', 'Gene', '115908', (26, 32))	('CTHRC1', 'Gene', (26, 32))	('expression', 'MPA', (76, 86))	('qRT-PCR', 'Var', (137, 144))	('KYSE150', 'CellLine', 'CVCL:1348', (47, 54))	('CTHRC1', 'Gene', '115908', (90, 96))
119943	33173311	These results revealed that knockdown of CTHRC1 suppresses AKT and ERK signaling pathways in ESCC.	('CTHRC1', 'Gene', (41, 47))	('ERK', 'Gene', '5594', (67, 70))	('ERK', 'Gene', (67, 70))	('AKT', 'Gene', (59, 62))	('suppresses', 'NegReg', (48, 58))	('AKT', 'Gene', '207', (59, 62))	('knockdown', 'Var', (28, 37))	('CTHRC1', 'Gene', '115908', (41, 47))	('ESCC', 'Disease', (93, 97))
119945	33173311	Results showed that inhibiting CTHRC1 inhibited expression of p-AKT and p-ERK activated by let-7c-5p inhibitor (Figure 8G and H).	('inhibiting', 'Var', (20, 30))	('CTHRC1', 'Gene', (31, 37))	('let-7c-', 'Chemical', '-', (91, 98))	('ERK', 'Gene', '5594', (74, 77))	('expression', 'MPA', (48, 58))	('AKT', 'Gene', '207', (64, 67))	('inhibited', 'NegReg', (38, 47))	('ERK', 'Gene', (74, 77))	('AKT', 'Gene', (64, 67))	('CTHRC1', 'Gene', '115908', (31, 37))
119946	33173311	In summary, these results indicate that let-7c-5p suppresses AKT and ERK signaling pathway with the inactivation of CTHRC1, consequently inhibiting cell proliferation and migration.	('inactivation', 'NegReg', (100, 112))	('let-7c-', 'Chemical', '-', (40, 47))	('rat', 'Species', '10116', (160, 163))	('suppresses', 'NegReg', (50, 60))	('inhibiting', 'NegReg', (137, 147))	('AKT', 'Gene', '207', (61, 64))	('CTHRC1', 'Gene', '115908', (116, 122))	('CTHRC1', 'Gene', (116, 122))	('rat', 'Species', '10116', (174, 177))	('AKT', 'Gene', (61, 64))	('ERK', 'Gene', '5594', (69, 72))	('ERK', 'Gene', (69, 72))	('let-7c-5p', 'Var', (40, 49))
119951	33173311	Compared to antagomir-NC, protein levels of CTHRC1 in antagomir group were significantly increased (Figure 9C and D).	('antagomir', 'Var', (54, 63))	('CTHRC1', 'Gene', '115908', (44, 50))	('protein levels', 'MPA', (26, 40))	('CTHRC1', 'Gene', (44, 50))	('increased', 'PosReg', (89, 98))
119952	33173311	These results indicate that let-7c-5p overexpression inhibits tumor growth, while let-7c-5p inhibition promotes tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibits', 'NegReg', (53, 61))	('let-7c-', 'Chemical', '-', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (62, 67))	('let-7c-5p', 'Gene', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('overexpression', 'PosReg', (38, 52))	('let-7c-', 'Chemical', '-', (28, 35))	('promotes', 'PosReg', (103, 111))	('tumor', 'Disease', (112, 117))	('let-7c-5p', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
119953	33173311	In this study, we observed that let-7c-5p is a tumor suppressor in ESCC and that overexpression of let-7c-5p inhibited proliferation and migration and promoted apoptosis by negatively regulating CTHRC1 and indirectly regulating the AKT and ERK signaling pathways.	('AKT', 'Gene', '207', (232, 235))	('let-7c-', 'Chemical', '-', (99, 106))	('promoted', 'PosReg', (151, 159))	('inhibited', 'NegReg', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ERK', 'Gene', '5594', (240, 243))	('proliferation', 'CPA', (119, 132))	('ESCC', 'Disease', (67, 71))	('negatively regulating', 'NegReg', (173, 194))	('rat', 'Species', '10116', (126, 129))	('let-7c-', 'Chemical', '-', (32, 39))	('ERK', 'Gene', (240, 243))	('regulating', 'Reg', (217, 227))	('AKT', 'Gene', (232, 235))	('CTHRC1', 'Gene', '115908', (195, 201))	('rat', 'Species', '10116', (140, 143))	('tumor', 'Disease', (47, 52))	('let-7c-5p', 'Var', (99, 108))	('apoptosis', 'CPA', (160, 169))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('CTHRC1', 'Gene', (195, 201))
119954	33173311	These findings indicated that let-7c-5p represents a possible therapeutic strategy for ESCC.	('let-7c-5p', 'Var', (30, 39))	('ESCC', 'Disease', (87, 91))	('let-7c-', 'Chemical', '-', (30, 37))	('rat', 'Species', '10116', (76, 79))
119955	33173311	It has been reported in a variety of solid tumors that let-7c-5p acts as a tumor suppressor, inhibiting cell proliferation, migration and invasion.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('solid tumors', 'Disease', 'MESH:D009369', (37, 49))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cell proliferation', 'CPA', (104, 122))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('rat', 'Species', '10116', (116, 119))	('let-7c-5p', 'Var', (55, 64))	('rat', 'Species', '10116', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('let-7c-', 'Chemical', '-', (55, 62))	('inhibiting', 'NegReg', (93, 103))	('tumor', 'Disease', (43, 48))	('solid tumors', 'Disease', (37, 49))	('tumor', 'Disease', (75, 80))
119959	33173311	Moreover, we found that let-7c-5p has high sensitivity and specificity in both early and late ESCC by ROC curve analysis, suggesting that let-7c-5p represents as a potential diagnostic biomarker in ESCC.	('let-7c-', 'Chemical', '-', (138, 145))	('let-7c-5p', 'Var', (138, 147))	('ESCC', 'Disease', (198, 202))	('let-7c-', 'Chemical', '-', (24, 31))
119961	33173311	Interestingly, we found that overexpression of let-7c-5p significantly inhibited proliferation, migration, and promoted apoptosis in vitro by functional experiments.	('migration', 'CPA', (96, 105))	('overexpression', 'PosReg', (29, 43))	('inhibited', 'NegReg', (71, 80))	('apoptosis', 'CPA', (120, 129))	('let-7c-', 'Chemical', '-', (47, 54))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (99, 102))	('proliferation', 'CPA', (81, 94))	('let-7c-5p', 'Var', (47, 56))	('promoted', 'PosReg', (111, 119))
119962	33173311	We further found that let-7c-5p overexpression inhibited tumor growth, while let-7c-5p inhibition promoted tumor growth in tumor xenograft models.	('overexpression', 'PosReg', (32, 46))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', (107, 112))	('inhibited', 'NegReg', (47, 56))	('let-7c-', 'Chemical', '-', (77, 84))	('let-7c-', 'Chemical', '-', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('promoted', 'PosReg', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('let-7c-5p', 'Var', (77, 86))	('let-7c-5p', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
119963	33173311	Our findings indicate that let-7c-5p might be a useful treatment strategy for ESCC.	('let-7c-', 'Chemical', '-', (27, 34))	('rat', 'Species', '10116', (67, 70))	('ESCC', 'Disease', (78, 82))	('let-7c-5p', 'Var', (27, 36))
119971	33173311	Overexpression of let-7c-5p significantly reduced the expression of CTHRC1, while inhibition of let-7c-5p restored the expression of CTHRC1.	('expression', 'MPA', (54, 64))	('expression', 'MPA', (119, 129))	('reduced', 'NegReg', (42, 49))	('let-7c-5p', 'Var', (18, 27))	('let-7c-', 'Chemical', '-', (96, 103))	('CTHRC1', 'Gene', '115908', (133, 139))	('let-7c-', 'Chemical', '-', (18, 25))	('CTHRC1', 'Gene', '115908', (68, 74))	('CTHRC1', 'Gene', (133, 139))	('CTHRC1', 'Gene', (68, 74))
119972	33173311	Bioinformatics prediction analysis found that the specific binding site of let-7c-5p existed in the 3'UTR of CTHRC1.	('CTHRC1', 'Gene', '115908', (109, 115))	('let-7c-5p', 'Var', (75, 84))	('CTHRC1', 'Gene', (109, 115))	('let-7c-', 'Chemical', '-', (75, 82))
119973	33173311	Next, we confirmed that CTHRC1 was a direct target gene of let-7c-5p by dual-luciferase report array.	('CTHRC1', 'Gene', (24, 30))	('CTHRC1', 'Gene', '115908', (24, 30))	('let-7c-5p', 'Var', (59, 68))	('let-7c-', 'Chemical', '-', (59, 66))
119977	33173311	We believe that targeted regulation of CTHRC1 and its downstream signaling pathways might represent a potential treatment for ESCC.	('targeted regulation', 'Var', (16, 35))	('CTHRC1', 'Gene', '115908', (39, 45))	('ESCC', 'Disease', (126, 130))	('CTHRC1', 'Gene', (39, 45))
119978	33173311	Wang CN et al found that PI3K-Akt and MAPK pathways were the two pathways most affected by CTHRC1 knockdown through KEGG pathway analysis.	('Akt', 'Gene', '207', (30, 33))	('MAPK pathways', 'Pathway', (38, 51))	('knockdown', 'Var', (98, 107))	('CTHRC1', 'Gene', '115908', (91, 97))	('CTHRC1', 'Gene', (91, 97))	('Akt', 'Gene', (30, 33))	('affected', 'Reg', (79, 87))
119979	33173311	In this study, we further confirmed by Western blot analysis that protein expression of p-AKT and p-ERK in TE-1 and KYSE150 cells were significantly reduced after knock down of CTHRC1, which was consistent with existing research reports.	('KYSE150', 'CellLine', 'CVCL:1348', (116, 123))	('CTHRC1', 'Gene', '115908', (177, 183))	('TE', 'Chemical', 'MESH:D013691', (107, 109))	('AKT', 'Gene', (90, 93))	('knock down', 'Var', (163, 173))	('protein expression', 'MPA', (66, 84))	('CTHRC1', 'Gene', (177, 183))	('reduced', 'NegReg', (149, 156))	('ERK', 'Gene', '5594', (100, 103))	('AKT', 'Gene', '207', (90, 93))	('ERK', 'Gene', (100, 103))
119980	33173311	To further explore the mechanism by which let-7c-5p inhibited cell proliferation and migration of ESCC, our study found that overexpression of let-7c-5p inhibited the protein expression of CTHRC1, thereby reducing phosphorylation levels of AKT and ERK, revealing that let -7c-5p inhibits AKT and ERK signaling pathways by directly downregulating CTHRC1.	('CTHRC1', 'Gene', (189, 195))	('AKT', 'Gene', '207', (288, 291))	('rat', 'Species', '10116', (88, 91))	('inhibited', 'NegReg', (52, 61))	('ERK', 'Gene', '5594', (248, 251))	('ERK', 'Gene', (296, 299))	('AKT', 'Gene', '207', (240, 243))	('let-7c-5p', 'Var', (143, 152))	('let-7c-', 'Chemical', '-', (42, 49))	('downregulating', 'NegReg', (331, 345))	('migration', 'CPA', (85, 94))	('protein expression', 'MPA', (167, 185))	('reducing', 'NegReg', (205, 213))	('inhibited', 'NegReg', (153, 162))	('ERK', 'Gene', (248, 251))	('cell proliferation', 'CPA', (62, 80))	('let-7c-', 'Chemical', '-', (143, 150))	('CTHRC1', 'Gene', '115908', (346, 352))	('AKT', 'Gene', (288, 291))	('let -7c-5p', 'Var', (268, 278))	('CTHRC1', 'Gene', '115908', (189, 195))	('inhibits', 'NegReg', (279, 287))	('phosphorylation levels', 'MPA', (214, 236))	('AKT', 'Gene', (240, 243))	('rat', 'Species', '10116', (74, 77))	('CTHRC1', 'Gene', (346, 352))	('ERK', 'Gene', '5594', (296, 299))
119981	33173311	In the current study, we showed for the first time the vital role and potential molecular mechanism of let-7c-5p in ESCC.	('ESCC', 'Disease', (116, 120))	('let-7c-5p', 'Var', (103, 112))	('let-7c-', 'Chemical', '-', (103, 110))
119983	33173311	In summary, our research demonstrates that expression of let-7c-5p is reduced in ESCC tissues and cells and that let-7c-5p inhibits cell proliferation and migration and promotes cell apoptosis by negatively regulating CTHRC1, indirectly regulating the AKT and ERK signaling pathways.	('let-7c-5p', 'Var', (113, 122))	('rat', 'Species', '10116', (32, 35))	('regulating', 'Reg', (237, 247))	('AKT', 'Gene', (252, 255))	('CTHRC1', 'Gene', (218, 224))	('cell apoptosis', 'CPA', (178, 192))	('negatively regulating', 'NegReg', (196, 217))	('rat', 'Species', '10116', (158, 161))	('rat', 'Species', '10116', (144, 147))	('let-7c-', 'Chemical', '-', (113, 120))	('inhibits', 'NegReg', (123, 131))	('reduced', 'NegReg', (70, 77))	('AKT', 'Gene', '207', (252, 255))	('ERK', 'Gene', '5594', (260, 263))	('let-7c-', 'Chemical', '-', (57, 64))	('promotes', 'PosReg', (169, 177))	('let-7c-5p', 'Gene', (57, 66))	('CTHRC1', 'Gene', '115908', (218, 224))	('ERK', 'Gene', (260, 263))	('cell proliferation', 'CPA', (132, 150))
119985	33173311	In conclusion, this study demonstrated that let-7c-5p is a tumor suppressor in ESCC, and let-7c-5p inhibited the proliferation, migration and promoted apoptosis by directly negatively regulating CTHRC1 and indirectly regulating AKT and ERK signaling pathways.	('let-7c-5p', 'Var', (89, 98))	('tumor', 'Disease', (59, 64))	('let-7c-', 'Chemical', '-', (44, 51))	('migration', 'CPA', (128, 137))	('rat', 'Species', '10116', (33, 36))	('AKT', 'Gene', (228, 231))	('rat', 'Species', '10116', (120, 123))	('promoted', 'PosReg', (142, 150))	('apoptosis', 'CPA', (151, 160))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('let-7c-', 'Chemical', '-', (89, 96))	('inhibited', 'NegReg', (99, 108))	('negatively regulating', 'NegReg', (173, 194))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('ERK', 'Gene', '5594', (236, 239))	('AKT', 'Gene', '207', (228, 231))	('regulating', 'Reg', (217, 227))	('CTHRC1', 'Gene', '115908', (195, 201))	('ESCC', 'Disease', (79, 83))	('rat', 'Species', '10116', (131, 134))	('ERK', 'Gene', (236, 239))	('CTHRC1', 'Gene', (195, 201))	('proliferation', 'CPA', (113, 126))
119986	33173311	Therefore, let-7c-5p may represent a new molecular marker for the treatment of ESCC.	('let-7c-5p', 'Var', (11, 20))	('let-7c-', 'Chemical', '-', (11, 18))	('ESCC', 'Disease', (79, 83))
119996	32313121	Therefore, we can believe that miRNA mutations, miRNA biogenic dysfunction, and miRNA's target disorders may be associated with a variety of diseases, such as lung cancer, lymphoma, breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('miRNA', 'Gene', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('mutations', 'Var', (37, 46))	('lung cancer', 'Disease', (159, 170))	('lymphoma, breast cancer', 'Disease', 'MESH:D001943', (172, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('lymphoma', 'Phenotype', 'HP:0002665', (172, 180))	('associated', 'Reg', (112, 122))
120038	32313121	This method identified two new tumor suppressor miRNA, including miR-182-5p and miR-455-5p, of which has-miR-182-5p was confirmed to be associated with esophageal cancer.	('associated', 'Reg', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('miR-182', 'Gene', (105, 112))	('miR-455-5p', 'Var', (80, 90))	('esophageal cancer', 'Disease', (152, 169))	('tumor', 'Disease', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('miR-182', 'Gene', '406958', (105, 112))	('miR-182', 'Gene', (65, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('miR-182', 'Gene', '406958', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
120058	29524114	On multivariate analysis, patients who underwent RFA had a threefold higher odds of having CE-IM than those who underwent cryotherapy (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.4-6.0, p = 0.004), but CE-D were similar between the two groups (OR 1.7, 95% CI 0.66-4.3, p = 0.28).	('CE-IM', 'Chemical', '-', (91, 96))	('RFA', 'Var', (49, 52))	('CE-IM', 'Disease', (91, 96))	('CE-D', 'Chemical', '-', (210, 214))	('patients', 'Species', '9606', (26, 34))
120122	29524114	After adjusting for age, length of BE, baseline biopsy, and time to last endoscopy, patients who received RFA were almost 3 times more likely to achieve CE-IM (OR2.9 (95% CI 1.4, 6) p = 0.004) compared to cryotherapy.	('patients', 'Species', '9606', (84, 92))	('CE-IM', 'Disease', (153, 158))	('BE', 'Disease', 'MESH:D001471', (35, 37))	('CE-IM', 'Chemical', '-', (153, 158))	('RFA', 'Var', (106, 109))	('BE', 'Phenotype', 'HP:0100580', (35, 37))
120130	29524114	Patients who underwent RFA were more likely to achieve CE-IM than patients who underwent cryotherapy.	('CE-IM', 'Disease', (55, 60))	('CE-IM', 'Chemical', '-', (55, 60))	('Patients', 'Species', '9606', (0, 8))	('RFA', 'Var', (23, 26))	('patients', 'Species', '9606', (66, 74))
120132	29524114	Although overall mortality was noted to be higher in the cryotherapy group (10.8 vs. 1.4%, p = 0.034), esophageal cancer-related mortality was similar among the two groups (5.4 vs. 1.4%, p = 0.37).	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cryotherapy', 'Var', (57, 68))	('esophageal cancer', 'Disease', (103, 120))
120135	29524114	However, the CE-IM rate of 66.7% for the RFA group and 41.3% for the cryotherapy group in our study was lower than the previously described rate of 78-88% and 53-65%, respectively.	('CE-IM', 'Chemical', '-', (13, 18))	('lower', 'NegReg', (104, 109))	('CE-IM', 'CPA', (13, 18))	('RFA', 'Var', (41, 44))
120141	29524114	It should be noted that among patients with flat BE, there were several patients with IMC (19%) in cryotherapy group as opposed to none in RFA group.	('BE', 'Disease', 'MESH:D001471', (49, 51))	('cryotherapy', 'Var', (99, 110))	('BE', 'Phenotype', 'HP:0100580', (49, 51))	('patients', 'Species', '9606', (30, 38))	('IMC', 'Disease', (86, 89))	('patients', 'Species', '9606', (72, 80))
120143	29524114	Secondly, we found that higher CE-IM rates were observed in patients undergoing RFA as compared to cryotherapy.	('patients', 'Species', '9606', (60, 68))	('RFA', 'Var', (80, 83))	('CE-IM', 'CPA', (31, 36))	('higher', 'PosReg', (24, 30))	('CE-IM', 'Chemical', '-', (31, 36))
120161	30061675	We have generated clinically annotated EAC organoid cultures that recapitulate the morphology, genomic, and transcriptomic landscape of the primary tumor including point mutations, copy number alterations, and mutational signatures.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('EAC', 'Phenotype', 'HP:0011459', (39, 42))	('point mutations', 'Var', (164, 179))	('tumor', 'Disease', (148, 153))	('copy number alterations', 'Var', (181, 204))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
120162	30061675	Karyotyping of organoid cultures has confirmed polyclonality reflecting the clonal architecture of the primary tumor.	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('polyclonality', 'Var', (47, 60))
120172	30061675	At present, inhibitors of HER2 and VEGFR2 are the only licensed drugs by the FDA for this disease, and they are used as second line therapy for metastatic disease.	('inhibitors', 'Var', (12, 22))	('VEGFR2', 'Gene', '3791', (35, 41))	('metastatic disease', 'Disease', (144, 162))	('HER2', 'Gene', (26, 30))	('VEGFR2', 'Gene', (35, 41))	('HER2', 'Gene', '2064', (26, 30))
120174	30061675	Recent sequencing studies (exome and whole genome) have shown that EAC is a cancer with a high mutation burden, a preponderance of copy number alterations and large-scale chromosomal rearrangements, and the lack of clear recurrent driver genes apart from TP53.	('TP53', 'Gene', (255, 259))	('EAC', 'Disease', (67, 70))	('copy number alterations', 'Var', (131, 154))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('EAC', 'Phenotype', 'HP:0011459', (67, 70))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('TP53', 'Gene', '7157', (255, 259))
120178	30061675	Genetically engineered mouse models of Barrett's have been developed by depleting p63 or overexpressing IL-1beta; however, the mice in the former model do not survive into maturity, and EAC tumors were found in less than 20% mice in the latter model.	('mice', 'Species', '10090', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('EAC tumors', 'Disease', (186, 196))	('depleting', 'Var', (72, 81))	('IL-1beta', 'Gene', '16176', (104, 112))	('mouse', 'Species', '10090', (23, 28))	('overexpressing', 'PosReg', (89, 103))	('IL-1beta', 'Gene', (104, 112))	('mice', 'Species', '10090', (225, 229))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('p63', 'Gene', '22061', (82, 85))	('EAC tumors', 'Disease', 'MESH:C536611', (186, 196))	('p63', 'Gene', (82, 85))	('EAC', 'Phenotype', 'HP:0011459', (186, 189))
120192	30061675	Regarding p53 status, 8/10 were mutated, in keeping with the prevalence observed in EAC  patients.	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('mutated', 'Var', (32, 39))	('EAC', 'Disease', (84, 87))	('patients', 'Species', '9606', (89, 97))	('p53', 'Gene', (10, 13))
120194	30061675	Disruption of cell polarity is one of the hallmarks of cancer which is important for tumor initiation and progression.	('tumor', 'Disease', (85, 90))	('cell polarity', 'CPA', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', (55, 61))	('Disruption', 'Var', (0, 10))
120197	30061675	The 10 organoids harbored a heterogeneous set of cancer drivers affected by nonsynonymous point mutations or insertions/deletions (InDels), some of which showed a variable pattern of alteration (Fig.	('affected', 'Reg', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('insertions/deletions', 'Var', (109, 129))	('cancer', 'Disease', (49, 55))
120200	30061675	In general, we observed a higher allele frequency of driver mutations in organoid cultures compared with patient-matched tumors, which is likely to be explained by the pure tumor cellularity in the organoids (Fig.	('patient', 'Species', '9606', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
120201	30061675	Beyond cancer drivers, most of the single nucleotide variants (SNV) and InDels, nonsynonymous or otherwise, were concordant between patient-matched tumor and organoid (Fig.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('single nucleotide variants', 'Var', (35, 61))	('tumor', 'Disease', (148, 153))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('patient', 'Species', '9606', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
120205	30061675	This consistency was observed for clinically relevant RTKs as well as for other focal or larger genomic segments; for example, amplifications on chromosome 12 in CAM277, CAM401, and CAM296, or on chromosome 17 in CAM408, and chromosome 20 in CAM338 (Fig.	('CAM277', 'Chemical', '-', (162, 168))	('CAM338', 'Chemical', '-', (242, 248))	('CAM296', 'Var', (182, 188))	('CAM408', 'Chemical', '-', (213, 219))	('amplifications', 'Var', (127, 141))	('CAM401', 'Chemical', '-', (170, 176))	('CAM296', 'Chemical', '-', (182, 188))	('CAM277', 'Var', (162, 168))	('CAM401', 'Var', (170, 176))
120209	30061675	Additional large segment amplifications were found in the organoid from CAM296, considerably fewer rearrangements in CAM292, as well as loss of ploidy in the CAM292 and CAM296 organoids compared to the tumors.	('CAM296', 'Chemical', '-', (72, 78))	('fewer', 'NegReg', (93, 98))	('rearrangements', 'MPA', (99, 113))	('CAM296', 'Chemical', '-', (169, 175))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('loss', 'NegReg', (136, 140))	('CAM296', 'Var', (72, 78))	('CAM292', 'Gene', (117, 123))	('CAM292', 'Chemical', '-', (158, 164))	('CAM292', 'Chemical', '-', (117, 123))	('ploidy', 'MPA', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
120210	30061675	For example, CAM296 had a reduced proportion of shared alterations with its matched tumor, but larger scale patterns such as structural variants or mutational signature composition, which are more likely to have an impact on tumor fitness and development, were generally well preserved.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor fitness', 'Disease', (225, 238))	('CAM296', 'Var', (13, 19))	('impact', 'Reg', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', (84, 89))	('CAM296', 'Chemical', '-', (13, 19))	('tumor fitness', 'Disease', 'MESH:D012640', (225, 238))
120217	30061675	CAM292 and CAM412 organoid samples failed to correlate highly with their counterpart tumor samples, in keeping with the reduced number of shared SNV's and InDels between these organoid cultures and matched tumors (Fig.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('InDels', 'Var', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Disease', (206, 211))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('CAM292', 'Chemical', '-', (0, 6))	('CAM412', 'Chemical', '-', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
120218	30061675	Consistent with DNA sequencing, there is a high concordance between the patient-matched tumor and the organoid with respect to driver gene mutations expressed at the mRNA level.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mutations', 'Var', (139, 148))	('patient', 'Species', '9606', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
120222	30061675	The organoid genomes were relatively stable with increasing passage with a small increase (<25%) in the number of total mutations and nonsynonymous variants over time, none of which affected cancer drivers (Supplementary Fig.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mutations', 'Var', (120, 129))
120225	30061675	In the 4  cultures tested, 2 models (CAM296 and CAM401) showed a rapid evolution then stasis, with minor subclones of the primary tumor becoming almost clonal in the first few passages and remaining dominant throughout propagation (Supplementary Fig.	('CAM401', 'Chemical', '-', (48, 54))	('CAM296', 'Chemical', '-', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('CAM401', 'Var', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CAM296', 'Var', (37, 43))	('tumor', 'Disease', (130, 135))
120227	30061675	We also observed that subclones containing somatic nonsynonymous or regulatory mutations in COSMIC cancer driver genes were more likely to expand in culture.	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('nonsynonymous', 'Var', (51, 64))
120228	30061675	For instance, in the trunk of CAM277 (clone 1), which contained 16715 somatic mutations including ALK and TP53, was fully clonal in the primary tumor and remained clonal in organoid cultures; branch clone (clone 2) and its subclone (clone 3) expanded during organoid propagation.	('tumor', 'Disease', (144, 149))	('ALK', 'Gene', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CAM277', 'Chemical', '-', (30, 36))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('ALK', 'Gene', '238', (98, 101))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
120231	30061675	Similarly, in CAM296, mutated KRAS and BCL6 were found in subclone 4 which became the dominate clone in culture (Supplementary Fig.	('CAM296', 'Chemical', '-', (14, 20))	('BCL6', 'Gene', '604', (39, 43))	('mutated', 'Var', (22, 29))	('BCL6', 'Gene', (39, 43))	('KRAS', 'Gene', (30, 34))
120236	30061675	The organoids with a DDR-impaired signature (CAM401 and CAM296) were sensitive to the greatest number of compounds.	('DDR-impaired', 'Disease', (21, 33))	('CAM401', 'Chemical', '-', (45, 51))	('CAM401', 'Var', (45, 51))	('CAM296', 'Var', (56, 62))	('CAM296', 'Chemical', '-', (56, 62))
120238	30061675	Whilst CAM296 and CAM247 were TP53 wild-type, only CAM296 demonstrated sensitivity to the MDM2 inhibitor Nutlin-3a (IC50 3.1 muM) while CAM247 failed to respond (IC50 16 muM).	('TP53', 'Gene', (30, 34))	('CAM247', 'Chemical', '-', (18, 24))	('CAM296', 'Chemical', '-', (51, 57))	('MDM2', 'Gene', '4193', (90, 94))	('CAM296', 'Var', (51, 57))	('muM', 'Gene', '56925', (125, 128))	('muM', 'Gene', '56925', (170, 173))	('CAM247', 'Chemical', '-', (136, 142))	('muM', 'Gene', (125, 128))	('sensitivity', 'MPA', (71, 82))	('CAM296', 'Chemical', '-', (7, 13))	('TP53', 'Gene', '7157', (30, 34))	('MDM2', 'Gene', (90, 94))	('muM', 'Gene', (170, 173))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (105, 114))
120241	30061675	Unsupervised clustering analysis of the cell viability following drug treatment revealed clustering of the ERK inhibitor SCH772984 and the MEK1/2 inhibitor Trametinib, as well clustering of the EGFR-family inhibitors Afatanib and Sapatinib.	('ERK', 'Gene', (107, 110))	('ERK', 'Gene', '2048', (107, 110))	('MEK1/2', 'Gene', '5604;5605', (139, 145))	('MEK1/2', 'Gene', (139, 145))	('SCH772984', 'Var', (121, 130))	('Trametinib', 'Chemical', 'MESH:C560077', (156, 166))	('EGFR', 'Gene', '1956', (194, 198))	('EGFR', 'Gene', (194, 198))	('Afatanib', 'Chemical', '-', (217, 225))	('SCH772984', 'Chemical', 'MESH:C587178', (121, 130))	('Sapatinib', 'Chemical', '-', (230, 239))
120245	30061675	Six of the organoid cultures (CAM388, CAM296, CAM338, CAM412, CAM277, CAM408) were insensitive to single and combination chemotherapy drugs.	('CAM412', 'Var', (54, 60))	('CAM296', 'Var', (38, 44))	('CAM412', 'Chemical', '-', (54, 60))	('CAM338', 'Chemical', '-', (46, 52))	('CAM277', 'Var', (62, 68))	('CAM408', 'Chemical', '-', (70, 76))	('CAM338', 'Var', (46, 52))	('CAM388', 'Chemical', '-', (30, 36))	('CAM277', 'Chemical', '-', (62, 68))	('CAM388', 'Var', (30, 36))	('CAM296', 'Chemical', '-', (38, 44))	('CAM408', 'Var', (70, 76))
120246	30061675	Three of these organoid cultures derived from chemo-treated patients (CAM388, CAM296, CAM338) who all had a poor response to therapy (TRG 4 or 5).	('CAM338', 'Var', (86, 92))	('TRG 4', 'Gene', (134, 139))	('CAM296', 'Var', (78, 84))	('CAM388', 'Chemical', '-', (70, 76))	('CAM388', 'Var', (70, 76))	('TRG 4', 'Gene', '64717', (134, 139))	('patients', 'Species', '9606', (60, 68))	('CAM296', 'Chemical', '-', (78, 84))	('CAM338', 'Chemical', '-', (86, 92))
120247	30061675	Two organoid cultures showed some limited sensitivity (CAM247 and CAM401).	('CAM247', 'Var', (55, 61))	('CAM247', 'Chemical', '-', (55, 61))	('CAM401', 'Var', (66, 72))	('CAM401', 'Chemical', '-', (66, 72))
120250	30061675	The comprehensive characterization of the organoid cultures confirmed that they recapitulated the features of the primary tumors from which they were derived in terms of histology, cancer driver alterations, mutational/copy-number/large-scale genomic rearrangement landscape, mutational signature subtypes, as well as expression profile.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('primary tumors', 'Disease', (114, 128))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutational/copy-number/large-scale', 'Var', (208, 242))	('cancer', 'Disease', (181, 187))	('primary tumors', 'Disease', 'MESH:D009369', (114, 128))
120254	30061675	Furthermore, mutations have a higher variant allele fraction in organoid cultures making SNV easier to detect compared to patient tissue (Fig.	('mutations', 'Var', (13, 22))	('variant', 'MPA', (37, 44))	('patient', 'Species', '9606', (122, 129))
120255	30061675	For example, in CAM277, a one-nucleotide deletion (Chr9:21972087) of CDKN2A was detected in 8  of 33 total reads in the primary tumor; in contrast, it was found in 23 of 23 total reads in the derived organoid culture (Supplementary Data 2).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CDKN2A', 'Gene', '1029', (69, 75))	('CAM277', 'Chemical', '-', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CDKN2A', 'Gene', (69, 75))	('tumor', 'Disease', (128, 133))	('CAM277', 'Var', (16, 22))
120256	30061675	Notably, additional variants identified in organoid cultures do not result in the acquisition of additional EAC specific cancer driver genes absent in the patient-matched tumor.	('variants', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('patient', 'Species', '9606', (155, 162))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('EAC', 'Phenotype', 'HP:0011459', (108, 111))	('tumor', 'Disease', (171, 176))	('cancer', 'Disease', (121, 127))
120261	30061675	Our observation of ongoing clonal evolution in organoid cultures indicates that these models could provide a facile in vitro experimental system to investigate factors such as the stromal cells, niche-factors and inter-clonal cooperation/competition, and ordering of driver mutations, which could impact on clonal evolution during tumor growth and response to therapy.	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('impact', 'Reg', (297, 303))	('stroma', 'Disease', 'None', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('tumor', 'Disease', (331, 336))	('stroma', 'Disease', (180, 186))	('mutations', 'Var', (274, 283))
120287	30061675	including DistanceToAlignmentEndMedia, DistanceToAlignmentEndMAD, LowMapQual, MapQualDiffMedian, VariantMapQualMedian, VariantBaseQualMedian, VariantAlleleCount, VariantAlleleCountControl, StrandBias, Repeat, SNVCluster50, SNVCluster 100).	('VariantAlleleCount', 'Var', (142, 160))	('VariantMapQualMedian', 'Var', (97, 117))	('VariantBaseQualMedian', 'Var', (119, 140))	('StrandBias', 'Disease', (189, 199))	('VariantAlleleCountControl', 'Var', (162, 187))	('StrandBias', 'Disease', 'None', (189, 199))
120288	30061675	In order to aid the detection of variants called in the organoids and missed in the tumor due to allele frequency below the imposed cut-offs (as a result of low purity/subclonal selection) in an automated manner, we combined the BAM files from the tumor and patient-matched organoid culture, and recalled the SNVs and InDels using Strelka on the combined resulting reads with the same filtering cut-offs.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patient', 'Species', '9606', (258, 265))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('variants', 'Var', (33, 41))
120289	30061675	This step had the effect of increasing the read count and confidence of calling real variants for the ones that differed between tumor and organoid.	('variants', 'Var', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('increasing', 'PosReg', (28, 38))	('tumor', 'Disease', (129, 134))	('read count', 'MPA', (43, 53))
120292	30061675	Such variants in key driver genes were manually inspected using the IGV tool, to confirm the concordance between the tumor and the organoid(s).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('variants', 'Var', (5, 13))
120297	30061675	The tumor sample for CAM412 showed much fewer expressed mutations than other samples and variant allele frequencies were low (Supplementary Fig.	('tumor', 'Disease', (4, 9))	('expressed mutations', 'MPA', (46, 65))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CAM412', 'Var', (21, 27))	('CAM412', 'Chemical', '-', (21, 27))	('fewer', 'NegReg', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
120298	30061675	The clustering indicated that for CAM412 the tumor sample showed an expression pattern more similar to normal samples than to other tumors, and the normal sample showed comparably little similarity to other normals.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('expression', 'MPA', (68, 78))	('CAM412', 'Var', (34, 40))	('tumor', 'Disease', (45, 50))	('CAM412', 'Chemical', '-', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
120307	30061675	Primary antibodies cytokeratin (AE1/AE3, 1:100, Dako), Vimentin (D21H3, 1:100, Cell Signaling Technology), and p53 (D07, 1:50, Leica) were optimized and applied with negative controls.	('Vimentin', 'Gene', '477991', (55, 63))	('Vimentin', 'Gene', (55, 63))	('D21H3', 'Var', (65, 70))
120315	30061675	Five human chromosome pools were labeled with ATTO 425-, ATTO 488-, CY3-, CY5-, and Texas Red-dUTPs (Jena Bioscience), respectively, using WGA 3 re-amplification kit (Sigma-Aldrich) and home-made dNTP mixtures optimized for the incorporation of the aforementioned labeled dUTPs by Taq polymerase.	('dUTPs', 'Chemical', 'MESH:C027078', (272, 277))	('CY3', 'Chemical', '-', (68, 71))	('dUTPs', 'Chemical', 'MESH:C027078', (94, 99))	('CY3-', 'Var', (68, 72))	('CY5', 'Chemical', 'MESH:C085321', (74, 77))	('dNTP', 'Chemical', 'MESH:D010278', (196, 200))	('human', 'Species', '9606', (5, 10))	('CY5-', 'Var', (74, 78))
120321	30061675	Images were visualized on a Zeiss AxioImager D1 fluorescent microscope equipped with narrow band-pass filters for DAPI, DEAC, FITC, CY3, TEXAS RED, and CY5 fluorescence and an ORCA-EA CCD camera (Hamamatsu).	('CY5', 'Var', (152, 155))	('RED', 'Disease', (143, 146))	('CY5', 'Chemical', 'MESH:C085321', (152, 155))	('DAPI', 'Chemical', 'MESH:C007293', (114, 118))	('EAC', 'Phenotype', 'HP:0011459', (121, 124))	('FITC', 'Chemical', 'MESH:D016650', (126, 130))	('RED', 'Disease', 'MESH:D000080822', (143, 146))	('DEAC', 'Chemical', '-', (120, 124))	('CY3', 'Chemical', '-', (132, 135))
120324	30061675	Analysis of clonal dynamics was carried out on four tumors (CAM277, CAM296, CAM338, and CAM401).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CAM277', 'Var', (60, 66))	('CAM401', 'Chemical', '-', (88, 94))	('CAM338', 'Var', (76, 82))	('CAM296', 'Var', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('CAM277', 'Chemical', '-', (60, 66))	('tumors', 'Disease', (52, 58))	('CAM296', 'Chemical', '-', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('CAM338', 'Chemical', '-', (76, 82))	('CAM401', 'Var', (88, 94))
120330	30061675	Quality control of subclonal clusters was performed to filter out clusters that may result from artefacts in mutation or copy number calling, using three metrics: (1) Clusters containing fewer than 1% of all mutations identified within a tumor; (2) Clusters for which the median CCF of the mutations assigned to that cluster differed by more than 0.2 from the CCF output from the Dirichlet process clustering, in one or more samples; (3) Clusters in which more than 50% mutations occurred on the same chromosome.	('tumor', 'Disease', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('mutations', 'Var', (290, 299))
120405	28464907	Nodal skip metastasis in thoracic esophageal squamous cell carcinoma: a cohort study Nodal skip metastasis is a prognostic factor in some sites of malignancies, but its role in esophageal cancer is still unclear.	('esophageal cancer', 'Disease', 'MESH:D004938', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('esophageal squamous cell carcinoma', 'Disease', (34, 68))	('malignancies', 'Disease', (147, 159))	('Nodal', 'Var', (85, 90))	('esophageal cancer', 'Disease', (177, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (34, 68))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))
120411	28464907	Adjusting for the number of lymph node metastases, patient with nodal skip metastasis had similar 5-year overall survival (14% vs. 13%, p = 0.93) and 5-year disease free survival (14% vs. 9%, p = 0.48) compared to patients with both peritumoral and distant lymph node metastases.	('lymph node metastases', 'Disease', (257, 278))	('patient', 'Species', '9606', (214, 221))	('tumor', 'Disease', (237, 242))	('patients', 'Species', '9606', (214, 222))	('nodal', 'Var', (64, 69))	('patient', 'Species', '9606', (51, 58))	('lymph node metastases', 'Disease', 'MESH:D009362', (28, 49))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('lymph node metastases', 'Disease', (28, 49))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('lymph node metastases', 'Disease', 'MESH:D009362', (257, 278))
120478	28464907	reported a favorable prognosis associated with the presence of NSM in a heterogeneous group of both ESCC and EAC patients.	('patients', 'Species', '9606', (113, 121))	('EAC', 'Gene', '1540', (109, 112))	('NSM', 'Gene', (63, 66))	('ESCC', 'Disease', (100, 104))	('EAC', 'Gene', (109, 112))	('presence', 'Var', (51, 59))
120564	22572013	Survival was better in patients with low TRG than in those with high TRG (chi2 = 6.405, P = 0.041, log-rank test) (Figure 1).	('TRG', 'Chemical', '-', (69, 72))	('low TRG', 'Var', (37, 44))	('better', 'PosReg', (13, 19))	('patients', 'Species', '9606', (23, 31))	('TRG', 'Var', (41, 44))	('Survival', 'MPA', (0, 8))	('TRG', 'Chemical', '-', (41, 44))
120651	33602210	The upregulated genes were significantly enriched in hsa04110: cell cycle, hsa03030:DNA replication, hsa05222: small-cell lung cancer, hsa03050: proteasome and hsa03410: base excision repair (Fig.	('DNA', 'CPA', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('hsa03050', 'Var', (135, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('cell cycle', 'CPA', (63, 73))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('upregulated', 'PosReg', (4, 15))	('cancer', 'Disease', (127, 133))	('hsa03410', 'Var', (160, 168))
120666	33602210	In addition, aberrant cell cycle progression has become one of the prominent features of various tumor cells.	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('aberrant', 'Var', (13, 21))
120675	33602210	demonstrated that inhibiting SPP1 expression inhibited proliferation and migration by activating ERK1/2 in ECA-109 cells, suggesting that SPP1 may play an important role in ESCC.	('ESCC', 'Disease', (173, 177))	('ERK1/2', 'Gene', (97, 103))	('inhibiting', 'Var', (18, 28))	('activating', 'PosReg', (86, 96))	('SPP1', 'Gene', '6696', (138, 142))	('ERK1/2', 'Gene', '5595;5594', (97, 103))	('SPP1', 'Gene', (138, 142))	('inhibited', 'NegReg', (45, 54))	('SPP1', 'Gene', '6696', (29, 33))	('SPP1', 'Gene', (29, 33))
120682	33602210	COL10A1 and COL5A2 are members of the collagen family, and the dysregulation of COL10A1 and COL5A2 may represent a basis for cancer invasion and migration.	('basis', 'Reg', (115, 120))	('COL10A1', 'Gene', '1300', (0, 7))	('COL10A1', 'Gene', (80, 87))	('COL10A1', 'Gene', '1300', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('migration', 'CPA', (145, 154))	('COL5A2', 'Gene', '1290', (12, 18))	('dysregulation', 'Var', (63, 76))	('COL10A1', 'Gene', (0, 7))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('COL5A2', 'Gene', '1290', (92, 98))	('COL5A2', 'Gene', (92, 98))	('COL5A2', 'Gene', (12, 18))
120683	33602210	The ectopic expression of COL10A1 and COL5A2 may affect the development of cancer, leading to genetic mutations and epigenetic alterations.	('genetic mutations', 'Var', (94, 111))	('affect', 'Reg', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('COL5A2', 'Gene', '1290', (38, 44))	('epigenetic alterations', 'Var', (116, 138))	('COL5A2', 'Gene', (38, 44))	('cancer', 'Disease', (75, 81))	('development of', 'CPA', (60, 74))	('COL10A1', 'Gene', (26, 33))	('ectopic expression', 'Var', (4, 22))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('COL10A1', 'Gene', '1300', (26, 33))	('leading to', 'Reg', (83, 93))
120684	33602210	Further analysis showed that these genes could activate ECM remodeling and the EMT, VEGFR3 and Wnt signaling pathways, which are oncogenic signaling pathways or processes.	('activate', 'PosReg', (47, 55))	('Wnt signaling pathways', 'Pathway', (95, 117))	('EMT', 'Gene', (79, 82))	('VEGFR3', 'Gene', '2324', (84, 90))	('EMT', 'Gene', '3702', (79, 82))	('VEGFR3', 'Gene', (84, 90))	('ECM remodeling', 'CPA', (56, 70))	('genes', 'Var', (35, 40))
120719	29277796	HER2 amplification is seen in several malignancies such as breast and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('amplification', 'Var', (5, 18))	('malignancies', 'Disease', 'MESH:D009369', (38, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('HER2', 'Gene', (0, 4))	('malignancies', 'Disease', (38, 50))	('seen', 'Reg', (22, 26))	('HER2', 'Gene', '2064', (0, 4))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (59, 84))
120749	29277796	HER2 overexpression or amplification was observed in 12.5% of all evaluable adenocarcinomas (21/168 cases) (Figure 1).	('adenocarcinomas', 'Disease', 'MESH:D000230', (76, 91))	('amplification', 'Var', (23, 36))	('overexpression', 'PosReg', (5, 19))	('adenocarcinomas', 'Disease', (76, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
120798	33093162	More recent studies of BE have revealed an unexpected number of pathogenic variants of a number of oncogenes and tumor suppressor genes in approximately 10-20% of BE cases.	('tumor', 'Disease', (113, 118))	('oncogenes', 'Gene', (99, 108))	('pathogenic', 'Reg', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('variants', 'Var', (75, 83))
120799	33093162	An analysis of 25 matched cases of BE and EAC using directed exome next generation sequencing revealed common tumor suppressor gene mutations, with few oncogene mutations and genomic alterations present.	('mutations', 'Var', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
120800	33093162	This study found that mutations in TP53 and SMAD4 were the most prevalent mutations in BE and that two pathways of BE progression appeared to be present.	('SMAD4', 'Gene', (44, 49))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('mutations', 'Var', (22, 31))	('prevalent', 'Reg', (64, 73))	('SMAD4', 'Gene', '4089', (44, 49))
120801	33093162	One pathway involves TP53 mutations and genomic doubling and may lead to the majority of EAC cases (>60%), while the other pathway involves the serial accumulation of mutations and is enriched for lesions with SMAD4 and CDKN2A alterations.	('TP53', 'Gene', (21, 25))	('SMAD4', 'Gene', '4089', (210, 215))	('EAC', 'Disease', (89, 92))	('mutations', 'Var', (26, 35))	('lead to', 'Reg', (65, 72))	('CDKN2A', 'Gene', (220, 226))	('SMAD4', 'Gene', (210, 215))	('CDKN2A', 'Gene', '1029', (220, 226))	('TP53', 'Gene', '7157', (21, 25))
120803	33093162	TP53 mutations have been found in less than 5% of nondysplastic BE; whereas, 70% of cases of HGD and EAC were TP53 mutant These results suggest that genetic alterations beyond TP53 and SMAD4 are not likely to yield clinically useful biomarkers for BE risk stratification.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (110, 114))	('SMAD4', 'Gene', '4089', (185, 190))	('TP53', 'Gene', (110, 114))	('genetic alterations', 'Var', (149, 168))	('TP53', 'Gene', '7157', (176, 180))	('mutant', 'Var', (115, 121))	('nondysplastic BE', 'Disease', (50, 66))	('SMAD4', 'Gene', (185, 190))	('TP53', 'Gene', (176, 180))
120804	33093162	EDRN funded studies by Grady and colleagues have shown that factors including aging smoking and obesity may play a role in the formation of these epigenetic alterations.	('obesity', 'Phenotype', 'HP:0001513', (96, 103))	('obesity', 'Disease', 'MESH:D009765', (96, 103))	('obesity', 'Disease', (96, 103))	('epigenetic', 'Var', (146, 156))
120806	33093162	Aberrant methylation of classic tumor suppressor genes such as CDKN2A and MGMT has been correlated with loss of mRNA and protein expression in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus.	('methylation', 'Var', (9, 20))	('loss', 'NegReg', (104, 108))	('CDKN2A', 'Gene', '1029', (63, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	("Barrett's esophagus", 'Disease', (190, 209))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (190, 209))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('MGMT', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Aberrant methylation', 'Var', (0, 20))	('MGMT', 'Gene', '4255', (74, 78))	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (147, 177))	('metaplasia-dysplasia-carcinoma', 'Disease', (147, 177))	('tumor', 'Disease', (32, 37))	('CDKN2A', 'Gene', (63, 69))
120808	33093162	In addition, this study uncovered a novel molecular mechanism by which EAC cells activate the oncogenic ERBB2/EGFR signaling pathway via epigenetically silencing the tyrosine phosphatase non-receptor 13 (PTPN13), specifically in the HM subtype.	('silencing', 'NegReg', (152, 161))	('activate', 'PosReg', (81, 89))	('EGFR', 'Gene', '1956', (110, 114))	('epigenetically', 'Var', (137, 151))	('EGFR', 'Gene', (110, 114))	('PTPN13', 'Gene', '5783', (204, 210))	('ERBB2', 'Gene', '2064', (104, 109))	('PTPN13', 'Gene', (204, 210))	('ERBB2', 'Gene', (104, 109))
120809	33093162	In summary, he published studies to date suggest aberrant DNA methylation is a common molecular mechanism that mediates the development of esophageal cancer and that aberrantly methylated genes and loci are very promising biomarkers for BE and EAC.	('aberrantly methylated', 'Var', (166, 187))	('mediates', 'Reg', (111, 119))	('aberrant', 'Var', (49, 57))	('esophageal cancer', 'Disease', (139, 156))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
120816	33093162	Genetic and epigenetic alterations occurring in Barrett esophagus (BE) and early stage esophageal cancer have the potential to be used as early detection biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('esophageal cancer', 'Disease', (87, 104))	('epigenetic alterations', 'Var', (12, 34))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (48, 65))	('Genetic', 'Var', (0, 7))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('Barrett esophagus', 'Disease', (48, 65))
120817	33093162	As noted above, candidate early detection markers include somatic mutations, aberrantly methylated genes, overexpressed miRNAs as well as deregulated proteins.	('miR', 'Gene', '220972', (120, 123))	('aberrantly methylated', 'Var', (77, 98))	('miR', 'Gene', (120, 123))	('proteins', 'Protein', (150, 158))
120818	33093162	As noted earlier, gene mutations arise in the BE EAC progression sequence and affect a substantially greater proportion of BE with dysplasia and EAC cases compared to non-dysplastic BE cases.	('EAC', 'Disease', (145, 148))	('dysplasia', 'Disease', (131, 140))	('gene mutations', 'Var', (18, 32))	('affect', 'Reg', (78, 84))	('dysplasia', 'Disease', 'MESH:C536170', (131, 140))
120821	33093162	These molecular alterations have been shown in early phase studies to serve as adjunctive markers to delineate the degree of dysplasia (e.g., use of FISH probes for C-MYC to confirm HGD or carcinoma) or to further risk stratify patients at greatest risk for progression to EAC (e.g., loss of ploidy associates with a 38.7% increased relative risk of developing EAC).	('loss of ploidy', 'Disease', 'MESH:D014786', (284, 298))	('dysplasia', 'Disease', (125, 134))	('carcinoma', 'Disease', (189, 198))	('alterations', 'Var', (16, 27))	('patients', 'Species', '9606', (228, 236))	('C-MYC', 'Gene', (165, 170))	('C-MYC', 'Gene', '4609', (165, 170))	('EAC', 'Disease', (273, 276))	('carcinoma', 'Disease', 'MESH:D009369', (189, 198))	('loss of ploidy', 'Disease', (284, 298))	('dysplasia', 'Disease', 'MESH:C536170', (125, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
120822	33093162	In contrast, TP53 mutations appear to have potential to be EAC screening biomarkers.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
120823	33093162	Aberrantly methylated genes and DNA loci have been shown to be robust biomarkers for use in cancer care and prevention for a variety of cancers.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Aberrantly methylated genes', 'Var', (0, 27))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
120824	33093162	Through the EDRN, Markowitz and colleagues recently demonstrated that methylated VIM has a high sensitivity for detecting esophageal adenocarcinomas (EAC) and Barrett's esophagus (BE), and that it even exceeded the robust sensitivity for detecting colon cancer that they had already shown.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('adenocarcinomas', 'Disease', 'MESH:D000230', (133, 148))	('VIM', 'Gene', '7431', (81, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('adenocarcinomas', 'Disease', (133, 148))	('detecting', 'Reg', (112, 121))	('VIM', 'Gene', (81, 84))	('methylated', 'Var', (70, 80))	('colon cancer', 'Phenotype', 'HP:0003003', (248, 260))	('colon cancer', 'Disease', 'MESH:D015179', (248, 260))	("Barrett's esophagus", 'Disease', (159, 178))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (159, 178))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (122, 147))	('colon cancer', 'Disease', (248, 260))
120825	33093162	The identification of methylated VIM DNA as a biomarker of BE suggested the potential for biomarker based early detection of BE and EAC.	('VIM', 'Gene', '7431', (33, 36))	('methylated', 'Var', (22, 32))	('VIM', 'Gene', (33, 36))
120826	33093162	This finding prompted Markowitz's team to develop a "molecular cytology" assay for methylated VIM in DNA samples from esophageal cytology brushings obtained during endoscopies of 322 individuals, divided into training and validation cohorts.	('methylated', 'Var', (83, 93))	('VIM', 'Gene', (94, 97))	('VIM', 'Gene', '7431', (94, 97))
120827	33093162	The assay showed 91% sensitivity for detecting BE, BE with dysplasia, and EAC at 93% specificity, with essentially identical results obtained in both the training and validation cohorts To further improve performance of a BE detection assay, they conducted a genome-wide analysis of DNA methylation in BE tissue samples using reduced representation bisulfite sequencing and found methylated CCNA1 DNA as a second BE biomarker with performance in both training and validation cohorts similar to methylated VIM.	('methylated', 'Var', (380, 390))	('CCNA1', 'Gene', '8900', (391, 396))	('VIM', 'Gene', '7431', (505, 508))	('dysplasia', 'Disease', 'MESH:C536170', (59, 68))	('dysplasia', 'Disease', (59, 68))	('VIM', 'Gene', (505, 508))	('CCNA1', 'Gene', (391, 396))
120828	33093162	When combined, the two-marker panel of methylated VIM and methylated CCNA1 DNAs detected 95% of BE, BE and dysplasia and EAC cases at 91% specificity, including detecting 96% of BE with dysplasia and 96% of EAC.	('dysplasia', 'Disease', (107, 116))	('VIM', 'Gene', '7431', (50, 53))	('dysplasia', 'Disease', 'MESH:C536170', (186, 195))	('EAC', 'Disease', (121, 124))	('CCNA1', 'Gene', (69, 74))	('dysplasia', 'Disease', (186, 195))	('EAC', 'Disease', (207, 210))	('detecting', 'Reg', (161, 170))	('VIM', 'Gene', (50, 53))	('methylated', 'Var', (58, 68))	('CCNA1', 'Gene', '8900', (69, 74))	('dysplasia', 'Disease', 'MESH:C536170', (107, 116))
120835	33093162	Using a Cytosponge based assay, Chettouh et al discovered and assessed hypermethylated TFPI2, TWIST1, ZNF345 and ZNF569 as potential BE screening markers.	('ZNF569', 'Gene', '148266', (113, 119))	('ZNF569', 'Gene', (113, 119))	('hypermethylated', 'Var', (71, 86))	('TWIST1', 'Gene', (94, 100))	('TFPI2', 'Gene', (87, 92))	('ZNF345', 'Gene', '25850', (102, 108))	('ZNF345', 'Gene', (102, 108))	('TFPI2', 'Gene', '7980', (87, 92))	('TWIST1', 'Gene', '7291', (94, 100))
120836	33093162	Methylated TFPI2 was shown to achieve the best sensitivity in both the pilot and validation Cytosponge cohorts (85% and 79%, respectively, AUC 0.88).	('TFPI2', 'Gene', (11, 16))	('TFPI2', 'Gene', '7980', (11, 16))	('Methylated', 'Var', (0, 10))
120837	33093162	In summary, these studies have established that methylated DNA has emerged as a promising new biomarker class that will enable practical non-endoscopic screening and early detection of BE, an approach with potential to reduce the steadily increasing mortality from EAC.	('mortality', 'Disease', 'MESH:D003643', (250, 259))	('methylated', 'Var', (48, 58))	('reduce', 'NegReg', (219, 225))	('mortality', 'Disease', (250, 259))	('EAC', 'Disease', (265, 268))
120852	33093162	In a retrospective study, EDRN investigator Steve Meltzer compared BE patients who progressed to HGD or EAC to those who did not, using hypermethylated CDKN2A (OR 1.74, 95% CI 1.33 - 2.20), RUNX3 (OR 1.80, 95% CI 1.08 - 2.81), and HPP1 (OR 1.77, 95% CI 1.06 - 2.81), which were associated with an increased risk of progression.	('CDKN2A', 'Gene', (152, 158))	('patients', 'Species', '9606', (70, 78))	('HPP1', 'Gene', '780897', (231, 235))	('CDKN2A', 'Gene', '1029', (152, 158))	('HPP1', 'Gene', (231, 235))	('hypermethylated', 'Var', (136, 151))	('RUNX3', 'Gene', (190, 195))	('RUNX3', 'Gene', '864', (190, 195))
120853	33093162	Age, BE segment length, and hypermethylation of other genes (TIMP3, APC, or CRBP1) were not found to be independent risk factors.	('hypermethylation', 'Var', (28, 44))	('CRBP1', 'Gene', '5947', (76, 81))	('APC', 'Disease', 'MESH:D011125', (68, 71))	('TIMP3', 'Gene', (61, 66))	('APC', 'Disease', (68, 71))	('TIMP3', 'Gene', '7078', (61, 66))	('CRBP1', 'Gene', (76, 81))
120866	33093162	One prospective study of 268 BE patients evaluated whether clonal expansions during the progression of BE leads to homogenous cell populations or results in clonal diversity.	('patients', 'Species', '9606', (32, 40))	('clonal', 'MPA', (157, 163))	('results in', 'Reg', (146, 156))	('clonal expansions', 'Var', (59, 76))	('homogenous', 'MPA', (115, 125))
120871	33093162	The presence of polysomy was associated with a significantly higher risk of developing EAC within 2 years (14.2%), compared with patients with a non-polysomic FISH result (1.4%, P < 0.001).	('patients', 'Species', '9606', (129, 137))	('polysomy', 'Var', (16, 24))	('EAC', 'Disease', (87, 90))
120872	33093162	Altered TP53 tissue expression is the most promising risk stratification biomarker to date and has near-term potential to be used in clinical care.	('TP53', 'Gene', (8, 12))	('TP53', 'Gene', '7157', (8, 12))	('Altered', 'Var', (0, 7))
120875	33093162	However, only 49% of patients who progressed had aberrant TP53 immunostaining, which significantly limits its potential clinical utility.	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('aberrant', 'Var', (49, 57))	('patients', 'Species', '9606', (21, 29))	('limits', 'NegReg', (99, 105))
120943	33066651	In subgroups, coffee intake decreased risk (up to 24-44%) in postmenopausal women, estrogen-receptor-negative breast cancer, and possibly in female carriers of the BRCA1 and BRCA2 mutations.	('estrogen-receptor', 'Gene', (83, 100))	('BRCA2', 'Gene', '675', (174, 179))	('estrogen-receptor', 'Gene', '2099', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (180, 189))	('decreased', 'NegReg', (28, 37))	('men', 'Species', '9606', (65, 68))	('BRCA1', 'Gene', (164, 169))	('men', 'Species', '9606', (78, 81))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('BRCA2', 'Gene', (174, 179))	('breast cancer', 'Disease', (110, 123))	('women', 'Species', '9606', (76, 81))	('BRCA1', 'Gene', '672', (164, 169))
120984	31981861	miR-135a Inhibits the Invasion and Migration of Esophageal Cancer Stem Cells through the Hedgehog Signaling Pathway by Targeting Smo Cancer stem cells (CSCs) have been reported to be involved in esophageal cancer (EC) development.	('esophageal cancer', 'Disease', (195, 212))	('Inhibits', 'NegReg', (9, 17))	('Targeting', 'NegReg', (119, 128))	('miR-135a', 'Var', (0, 8))	('Invasion', 'CPA', (22, 30))	('Hedgehog', 'Gene', (89, 97))	('Hedgehog', 'Gene', '42737', (89, 97))	('EC', 'Disease', 'MESH:D004938', (214, 216))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('involved', 'Reg', (183, 191))	('Smo', 'CPA', (129, 132))	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))
120991	31981861	In addition, overexpression of miR-135a or silencing of Smo decreased the expression of Gli1, Gli2, and Shh, thus inhibiting EC cell proliferation, migration, and invasion and promoting apoptosis.	('decreased', 'NegReg', (60, 69))	('EC', 'Disease', 'MESH:D004938', (125, 127))	('overexpression', 'PosReg', (13, 27))	('Smo', 'Gene', '6608', (56, 59))	('Gli1', 'Gene', '2735', (88, 92))	('invasion', 'CPA', (163, 171))	('expression', 'MPA', (74, 84))	('Smo', 'Gene', (56, 59))	('migration', 'CPA', (148, 157))	('Shh', 'Gene', '6469', (104, 107))	('inhibiting', 'NegReg', (114, 124))	('Gli2', 'Gene', (94, 98))	('apoptosis', 'CPA', (186, 195))	('miR-135a', 'Gene', (31, 39))	('promoting', 'PosReg', (176, 185))	('Gli1', 'Gene', (88, 92))	('silencing', 'Var', (43, 52))	('Gli2', 'Gene', '2736', (94, 98))	('Shh', 'Gene', (104, 107))
120992	31981861	Silencing of miR-135a was observed to reverse the inhibitory role of miR-135a in EC.	('miR-135a', 'Gene', (69, 77))	('inhibitory role', 'MPA', (50, 65))	('EC', 'Disease', 'MESH:D004938', (81, 83))	('Silencing', 'Var', (0, 9))	('miR-135a', 'Gene', (13, 21))
120993	31981861	These results suggest that miR-135a inhibited the migration and invasion of EC cells through inhibition of the Smo/Hh axis.	('inhibition', 'NegReg', (93, 103))	('Smo', 'Gene', (111, 114))	('miR-135a', 'Var', (27, 35))	('inhibited', 'NegReg', (36, 45))	('EC', 'Disease', 'MESH:D004938', (76, 78))	('invasion', 'CPA', (64, 72))	('migration', 'CPA', (50, 59))	('Smo', 'Gene', '6608', (111, 114))
120998	31981861	Studies have identified various risk factors associated with EC, including environmental and dietary causes, such as tobacco smoking, low vegetable intake, alcohol drinking, and low fruit intake, all of which have been found to play critical roles in esophageal carcinogenesis.	('alcohol drinking', 'Disease', (156, 172))	('low fruit', 'Var', (178, 187))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (251, 276))	('esophageal carcinogenesis', 'Disease', (251, 276))	('alcohol', 'Chemical', 'MESH:D000431', (156, 163))	('low vegetable', 'Var', (134, 147))	('EC', 'Disease', 'MESH:D004938', (61, 63))	('tobacco', 'Species', '4097', (117, 124))	('alcohol drinking', 'Phenotype', 'HP:0030955', (156, 172))
121031	31981861	The results collected suggested that miR-135a modulated Smo expression.	('Smo', 'Gene', (56, 59))	('miR-135a', 'Var', (37, 45))	('Smo', 'Gene', '6608', (56, 59))	('modulated', 'Reg', (46, 55))
121036	31981861	In order to demonstrate that the regulatory function of miR-135a on the Hh signaling pathway is Smo specific, a recovery experiment was performed.	('Hh signaling pathway', 'Pathway', (72, 92))	('Smo', 'Gene', (96, 99))	('miR-135a', 'Var', (56, 64))	('Smo', 'Gene', '6608', (96, 99))
121037	31981861	Overexpression of miR-135a in the Eca-109 cells inhibited the protein level of Gli1/Gli2, whereas the overexpression of Smo was observed to increase the protein level of Gli1/Gli2 (Figure 5E).	('Gli1', 'Gene', (79, 83))	('Gli2', 'Gene', '2736', (175, 179))	('Smo', 'Gene', '6608', (120, 123))	('Gli2', 'Gene', (175, 179))	('Gli1', 'Gene', '2735', (79, 83))	('Gli1', 'Gene', (170, 174))	('miR-135a', 'Var', (18, 26))	('inhibited', 'NegReg', (48, 57))	('Gli2', 'Gene', '2736', (84, 88))	('Smo', 'Gene', (120, 123))	('Gli1', 'Gene', '2735', (170, 174))	('Gli2', 'Gene', (84, 88))
121038	31981861	Similarly, interference with miR-135a levels in Eca-109 cells promoted the Gli1/Gli2 protein level, and simultaneous interference with the Smo and miR-135a levels was found to elevate the Gli1/Gli2 protein level as well (Figures 5C and 5D).	('Gli1', 'Gene', '2735', (75, 79))	('promoted', 'PosReg', (62, 70))	('Smo', 'Gene', (139, 142))	('Gli2', 'Gene', (193, 197))	('Gli2', 'Gene', '2736', (193, 197))	('interference', 'Var', (117, 129))	('Gli2', 'Gene', '2736', (80, 84))	('Gli1', 'Gene', (188, 192))	('elevate', 'PosReg', (176, 183))	('Smo', 'Gene', '6608', (139, 142))	('Gli1', 'Gene', (75, 79))	('interference', 'Var', (11, 23))	('Gli2', 'Gene', (80, 84))	('Gli1', 'Gene', '2735', (188, 192))
121039	31981861	In summary, these results provided evidence demonstrating that miR-135a restrained the Hh signaling pathway by targeting Smo.	('restrained', 'NegReg', (72, 82))	('miR-135a', 'Var', (63, 71))	('Hh signaling pathway', 'Pathway', (87, 107))	('Smo', 'Gene', '6608', (121, 124))	('targeting', 'Reg', (111, 120))	('Smo', 'Gene', (121, 124))
121045	31981861	Compared with that in the blank group, the apoptotic rate of the miR-135a and Smo-siRNA groups was significantly increased, whereas the apoptotic rate of the miR-135a-inhibitor group decreased (p < 0.05).	('miR-135a', 'Var', (65, 73))	('Smo', 'Gene', (78, 81))	('increased', 'PosReg', (113, 122))	('apoptotic rate', 'CPA', (43, 57))	('Smo', 'Gene', '6608', (78, 81))
121047	31981861	Thus, based on the results collected, we concluded that overexpression of miR-135a or silencing of Smo could facilitate cell apoptosis.	('silencing', 'Var', (86, 95))	('cell apoptosis', 'CPA', (120, 134))	('Smo', 'Gene', (99, 102))	('overexpression', 'PosReg', (56, 70))	('Smo', 'Gene', '6608', (99, 102))	('miR-135a', 'Gene', (74, 82))	('facilitate', 'PosReg', (109, 119))
121050	31981861	The migration ability was weaker in the miR-135a-inhibitor + Smo-siRNA than that in the miR-135a-inhibitor group (p < 0.05) (Figures 7A and 7B).	('weaker', 'NegReg', (26, 32))	('migration ability', 'CPA', (4, 21))	('miR-135a-inhibitor', 'Var', (40, 58))	('Smo', 'Gene', (61, 64))	('Smo', 'Gene', '6608', (61, 64))
121051	31981861	All of these results illustrated that miR-135a suppressed cell migration by regulating Smo.	('cell migration', 'CPA', (58, 72))	('suppressed', 'NegReg', (47, 57))	('miR-135a', 'Var', (38, 46))	('Smo', 'Gene', '6608', (87, 90))	('Smo', 'Gene', (87, 90))
121061	31981861	Our findings provided evidence that miR-135a could inhibit the carcinogenic potency of EC Eca-109 cells by inhibiting the Hh signaling pathway by targeting Smo.	('Smo', 'Gene', (156, 159))	('EC', 'Disease', 'MESH:D004938', (87, 89))	('carcinogenic', 'Disease', 'MESH:D063646', (63, 75))	('carcinogenic', 'Disease', (63, 75))	('Smo', 'Gene', '6608', (156, 159))	('targeting', 'Reg', (146, 155))	('inhibiting', 'NegReg', (107, 117))	('miR-135a', 'Var', (36, 44))	('inhibit', 'NegReg', (51, 58))	('Hh signaling pathway', 'Pathway', (122, 142))
121068	31981861	Second, our study demonstrated that following cell transfection, the mRNA and protein levels of Smo, Gli1, Gli2, and Shh in the miR-135a-mimic and Smo-siRNA groups exhibited a notable decrease when compared with those in the blank group, whereas the miR-135a-inhibitor group displayed a contrasting trend.	('decrease', 'NegReg', (184, 192))	('Smo', 'Gene', '6608', (147, 150))	('Gli1', 'Gene', (101, 105))	('Smo', 'Gene', '6608', (96, 99))	('Shh', 'Gene', '6469', (117, 120))	('Gli1', 'Gene', '2735', (101, 105))	('Gli2', 'Gene', '2736', (107, 111))	('Smo', 'Gene', (147, 150))	('Smo', 'Gene', (96, 99))	('Gli2', 'Gene', (107, 111))	('miR-135a-mimic', 'Var', (128, 142))	('Shh', 'Gene', (117, 120))
121071	31981861	It has been reported that Smo inhibition can inhibit the downstream activation of Gli transcription factors, which ultimately inhibits the Hh signaling pathway and represses genes associated with cancer growth.	('inhibits', 'NegReg', (126, 134))	('represses', 'NegReg', (164, 173))	('Gli', 'Gene', '2735', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('inhibition', 'Var', (30, 40))	('Smo', 'Gene', (26, 29))	('Hh signaling pathway', 'Pathway', (139, 159))	('activation', 'PosReg', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('genes associated', 'MPA', (174, 190))	('cancer', 'Disease', (196, 202))	('inhibit', 'NegReg', (45, 52))	('Smo', 'Gene', '6608', (26, 29))	('Gli', 'Gene', (82, 85))
121076	31981861	Finally, per the results of our experiments, in comparison to the blank group, the cell proliferation, migration, and invasion exhibited marked decreases, whereas the rate of cell apoptosis was elevated in the miR-135a-mimic and Smo-siRNA groups.	('decreases', 'NegReg', (144, 153))	('Smo', 'Gene', (229, 232))	('elevated', 'PosReg', (194, 202))	('cell apoptosis', 'CPA', (175, 189))	('cell proliferation', 'CPA', (83, 101))	('miR-135a-mimic', 'Var', (210, 224))	('Smo', 'Gene', '6608', (229, 232))	('invasion', 'CPA', (118, 126))	('migration', 'CPA', (103, 112))
121078	31981861	Moreover, miR-135a functions as a putative inhibitor through directly regulating the lipoprotein receptor in human gallbladder cancer.	('human', 'Species', '9606', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('gallbladder cancer', 'Disease', (115, 133))	('gallbladder cancer', 'Disease', 'MESH:D005706', (115, 133))	('miR-135a', 'Var', (10, 18))	('lipoprotein receptor', 'Protein', (85, 105))	('regulating', 'Reg', (70, 80))
121080	31981861	Taken together, the present study supported the notion that miR-135a blocks the Hh signaling pathway by downregulating Smo, thus repressing EC stem cell proliferation, migration, and invasion, which may facilitate the development of novel therapeutic methods for future EC treatments.	('migration', 'CPA', (168, 177))	('facilitate', 'PosReg', (203, 213))	('downregulating', 'NegReg', (104, 118))	('Smo', 'Gene', '6608', (119, 122))	('Smo', 'Gene', (119, 122))	('Hh signaling pathway', 'Pathway', (80, 100))	('EC', 'Disease', 'MESH:D004938', (270, 272))	('repressing', 'PosReg', (129, 139))	('blocks', 'NegReg', (69, 75))	('EC', 'Disease', 'MESH:D004938', (140, 142))	('invasion', 'CPA', (183, 191))	('miR-135a', 'Var', (60, 68))
121130	31981861	The mut-Smo expression plasmid was collected by mutating the 3' UTR sequence of Smo and the target gene of miR-135a and inserting it into the eukaryotic expression plasmid pcDNA3.1 vector.	('Smo', 'Gene', (8, 11))	('mutating', 'Var', (48, 56))	('Smo', 'Gene', (80, 83))	('Smo', 'Gene', '6608', (8, 11))	('Smo', 'Gene', '6608', (80, 83))
121154	30971268	In contrast, silencing PAK1 by lentiviral knockdown or a specific inhibitor IPA-3 resulted in a contrary effect.	('IPA-3', 'Chemical', '-', (76, 81))	('PAK1', 'Gene', (23, 27))	('silencing', 'Var', (13, 22))
121167	30971268	In addition, Ito et al reported that PAK1 mRNA expression is statistically associated with grade and the risk of recurrence in bladder cancers, and they also demonstrated that high PAK1 protein expression is an independent factor associated with recurrence.	('bladder cancers', 'Phenotype', 'HP:0009725', (127, 142))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('PAK1', 'Gene', (37, 41))	('bladder cancers', 'Disease', 'MESH:D001749', (127, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('PAK1', 'Gene', (181, 185))	('mRNA expression', 'MPA', (42, 57))	('protein', 'Protein', (186, 193))	('recurrence in bladder', 'Phenotype', 'HP:0012786', (113, 134))	('bladder cancers', 'Disease', (127, 142))	('associated', 'Reg', (75, 85))	('grade', 'Disease', (91, 96))	('high', 'Var', (176, 180))
121171	30971268	Indeed, ectopic expression of PAK1 facilitates the migration and invasion of gastric cancer cells.	('ectopic expression', 'Var', (8, 26))	('gastric cancer', 'Disease', (77, 91))	('migration', 'CPA', (51, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('facilitates', 'PosReg', (35, 46))	('PAK1', 'Gene', (30, 34))	('invasion of', 'CPA', (65, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
121173	30971268	Conversely, knockdown of PAK1 by pharmacological inhibition and using short-hairpin RNA (shRNA) can significantly in hibit human cancer cell proliferation, anchorage-independent growth, migration and invasion in vitro and reduce tumor growth and metastasis in animal models.	('invasion', 'CPA', (200, 208))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('reduce', 'NegReg', (222, 228))	('human', 'Species', '9606', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('knockdown', 'Var', (12, 21))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('PAK1', 'Gene', (25, 29))	('tumor', 'Disease', (229, 234))	('anchorage-independent growth', 'CPA', (156, 184))
121174	30971268	In addition, depletion of active PAK1 up-regulates the immune system of APC 14/+ mice and suppresses intestinal tumor development.	('suppresses', 'NegReg', (90, 100))	('intestinal tumor', 'Disease', (101, 117))	('PAK1', 'Gene', (33, 37))	('intestinal tumor', 'Disease', 'MESH:D007414', (101, 117))	('mice', 'Species', '10090', (81, 85))	('up-regulates', 'PosReg', (38, 50))	('active PAK1', 'Gene', (26, 37))	('depletion', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('APC', 'Disease', 'MESH:D011125', (72, 75))	('immune system', 'CPA', (55, 68))	('APC', 'Disease', (72, 75))
121178	30971268	Wong et al found that IPA-3 not only inhibits hepatocellular carcinoma (HCC) cell proliferation, colony formation and migration in vitro, but also suppresses tumorigenesis in a nude mouse xenograft model.	('tumor', 'Disease', (158, 163))	('colony formation', 'CPA', (97, 113))	('IPA-3', 'Chemical', '-', (22, 27))	('mouse', 'Species', '10090', (182, 187))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('IPA-3', 'Var', (22, 27))	('migration', 'CPA', (118, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('hepatocellular carcinoma', 'Disease', (46, 70))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (46, 70))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('suppresses', 'NegReg', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('inhibits', 'NegReg', (37, 45))
121182	30971268	We found that inhibition of PAK1 by using shRNA and a small-molecule inhibitor (IPA-3) remarkably suppressed ESCC cell proliferation, colony formation, migration and invasion in vitro, and tumor growth and lung metastasis in vivo, at least in part, via down-regulating the Raf1/MEK1/ERK signaling pathway.	('tumor', 'Disease', (189, 194))	('suppressed', 'NegReg', (98, 108))	('Raf1', 'Gene', '5894', (273, 277))	('ERK', 'Gene', '5594', (283, 286))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('ERK', 'Gene', (283, 286))	('down-regulating', 'NegReg', (253, 268))	('colony formation', 'CPA', (134, 150))	('MEK1', 'Gene', (278, 282))	('Raf1', 'Gene', (273, 277))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('MEK1', 'Gene', '5604', (278, 282))	('PAK1', 'Gene', (28, 32))	('IPA-3', 'Chemical', '-', (80, 85))	('lung metastasis', 'CPA', (206, 221))	('inhibition', 'Var', (14, 24))	('ESCC cell proliferation', 'CPA', (109, 132))
121184	30971268	Antibodies and their sources are as follows: antibodies against p-PAK1 (T423, #2601), PAK1 (#2602), PAK2 (#4825), PAK3 (#2609), Rac1/Cdc42 (#4651), Raf1 (#9422), p-Raf1 (S338, #9427), MEK1 (#2352), p-MEK1 (S298, #9128), ERK1/2 (#4695), p-ERK1/2 (T202/Y204, #4370), MMP-2 (#4022) and MMP-9 (#3852) were obtained from Cell Signaling Technology (Beverly, MA).	('#4825', 'Var', (106, 111))	('MEK1', 'Gene', (200, 204))	('MEK1', 'Gene', (184, 188))	('Cdc42', 'Gene', '998', (133, 138))	('T202/Y204', 'Var', (246, 255))	('MMP-9', 'Gene', '4318', (283, 288))	('Rac1', 'Gene', '5879', (128, 132))	('Raf1', 'Gene', '5894', (148, 152))	('MMP-9', 'Gene', (283, 288))	('p-Raf1', 'Gene', '64425', (162, 168))	('#2609', 'Var', (120, 125))	('#2352', 'Var', (190, 195))	('Raf1', 'Gene', (148, 152))	('Raf1', 'Gene', '5894', (164, 168))	('PAK2', 'Gene', (100, 104))	('MEK1', 'Gene', '5604', (184, 188))	('Raf1', 'Gene', (164, 168))	('MEK1', 'Gene', '5604', (200, 204))	('MMP-2', 'Gene', '4313', (265, 270))	('PAK2', 'Gene', '5062', (100, 104))	('#4022', 'Var', (272, 277))	('#2602', 'Var', (92, 97))	('p-Raf1', 'Gene', (162, 168))	('PAK3', 'Gene', (114, 118))	('#4695', 'Var', (228, 233))	('Cdc42', 'Gene', (133, 138))	('Rac1', 'Gene', (128, 132))	('#3852', 'Var', (290, 295))	('PAK3', 'Gene', '5063', (114, 118))	('#4651', 'Var', (140, 145))	('MMP-2', 'Gene', (265, 270))
121185	30971268	Primary antibodies against p-PAK2 (S141, #SAB4504634) and Actin (#4700) were purchased from Sigma-Aldrich (Shanghai, China).	('#4700', 'Var', (65, 70))	('S141', 'Var', (35, 39))	('PAK2', 'Gene', '5062', (29, 33))	('PAK2', 'Gene', (29, 33))	('#SAB4504634', 'Var', (41, 52))
121186	30971268	Human ESCC cell lines EC109, EC9706, KYSE30, KYSE70, KYSE150, KYSE450 and KYSE510 were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China), and cultured in RPMI 1640 medium (Invitrogen) containing 10% (v/v) heat-inactivated fetal bovine serum (FBS).	('Human', 'Species', '9606', (0, 5))	('EC9706', 'CellLine', 'CVCL:E307', (29, 35))	('KYSE510', 'Var', (74, 81))	('FBS', 'Disease', 'MESH:D005198', (273, 276))	('KYSE450', 'Var', (62, 69))	('EC9706', 'Var', (29, 35))	('KYSE510', 'CellLine', 'CVCL:1354', (74, 81))	('KYSE150', 'Var', (53, 60))	('RPMI 1640 medium', 'Chemical', '-', (185, 201))	('KYSE70', 'Var', (45, 51))	('bovine', 'Species', '9913', (259, 265))	('FBS', 'Disease', (273, 276))	('KYSE150', 'CellLine', 'CVCL:1348', (53, 60))	('KYSE30', 'Var', (37, 43))
121199	30971268	Briefly, a total of 500 cells each well were plated in six-well plates and cultured for 10-14 days (Ten days for EC109 and KYSE70; Two weeks for KYSE30 and KYSE150) until visible colonies formed.	('EC109', 'Var', (113, 118))	('KYSE70', 'Var', (123, 129))	('KYSE150', 'Var', (156, 163))	('KYSE30', 'Var', (145, 151))	('KYSE150', 'CellLine', 'CVCL:1348', (156, 163))
121241	30971268	1a, the mRNA expression of PAK1 were higher in six of seven ESCC cells (especially in KYSE30, KYSE150, KYSE450 and KYSE510 cells) compared with that of Het-1A cells.	('KYSE150', 'Var', (94, 101))	('KYSE510', 'CellLine', 'CVCL:1354', (115, 122))	('higher', 'PosReg', (37, 43))	('ESCC', 'Disease', (60, 64))	('KYSE150', 'CellLine', 'CVCL:1348', (94, 101))	('KYSE450', 'Var', (103, 110))	('KYSE30', 'Var', (86, 92))	('KYSE510', 'Var', (115, 122))	('PAK1', 'Gene', (27, 31))	('mRNA expression', 'MPA', (8, 23))
121249	30971268	The results showed that colony formation frequency in soft agar was significantly increased in PAK1-expressing cells compared with their control groups (Fig.	('PAK1-expressing', 'Var', (95, 110))	('colony formation frequency in soft agar', 'CPA', (24, 63))	('increased', 'PosReg', (82, 91))	('agar', 'Chemical', 'MESH:D000362', (59, 63))
121250	30971268	We next determined whether knockdown of PAK1 inhibits the tumorigenicity in ESCC cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('knockdown', 'Var', (27, 36))	('inhibits', 'NegReg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('ESCC', 'Disease', (76, 80))	('PAK1', 'Gene', (40, 44))
121252	30971268	Functional assays revealed that PAK1 silencing could effectively inhibit the tumorigenic phenotype by reducing cell growth, frequencies of focus formation and colony formation in soft agar compared with cells treated with shNC (Fig.	('PAK1', 'Gene', (32, 36))	('reducing', 'NegReg', (102, 110))	('cell growth', 'CPA', (111, 122))	('colony formation in soft agar', 'CPA', (159, 188))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('silencing', 'Var', (37, 46))	('agar', 'Chemical', 'MESH:D000362', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('inhibit', 'NegReg', (65, 72))	('tumor', 'Disease', (77, 82))
121253	30971268	We then investigated whether high expression of PAK1 confers ESCC cell abilities of migration and invasion, which are two of the most important processes in tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (157, 173))	('high expression', 'Var', (29, 44))	('invasion', 'CPA', (98, 106))	('tumor metastasis', 'Disease', (157, 173))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('PAK1', 'Gene', (48, 52))
121257	30971268	3f, both ESCC cell lines that transfected with shPAK1 displayed a smaller number of tumor cells that invaded through Matrigel in comparison with those of their corresponding control cells transfected with shNC.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('shPAK1', 'Var', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('smaller', 'NegReg', (66, 73))	('tumor', 'Disease', (84, 89))
121258	30971268	In addition, Western blotting results showed that knockdown of PAK1 significantly reduced the expression of MMP-2 and MMP-9 (Fig.	('MMP-2', 'Gene', '4313', (108, 113))	('knockdown', 'Var', (50, 59))	('MMP-9', 'Gene', '4318', (118, 123))	('PAK1', 'Gene', (63, 67))	('MMP-9', 'Gene', (118, 123))	('MMP-2', 'Gene', (108, 113))	('expression', 'MPA', (94, 104))	('reduced', 'NegReg', (82, 89))
121259	30971268	Taken together, these results demonstrated that targeting PAK1 by shRNA could suppress the migration, invasion, as well as the expression of MMP-2 and MMP-9 in ESCC cells.	('ESCC', 'Disease', (160, 164))	('MMP-9', 'Gene', (151, 156))	('expression', 'MPA', (127, 137))	('MMP-9', 'Gene', '4318', (151, 156))	('invasion', 'CPA', (102, 110))	('MMP-2', 'Gene', (141, 146))	('suppress', 'NegReg', (78, 86))	('PAK1', 'Gene', (58, 62))	('migration', 'CPA', (91, 100))	('targeting', 'Var', (48, 57))	('MMP-2', 'Gene', '4313', (141, 146))
121261	30971268	Intriguingly, Our results showed that ectopic expression of PAK1 in EC109 and KYSE70 cells increased the expression of p-Raf1 (S338), and its downstream targets: p-MEK1 (S298) and p-ERK1/2 (T202/Y204) (Fig.	('p-Raf1', 'Gene', '64425', (119, 125))	('PAK1', 'Gene', (60, 64))	('MEK1', 'Gene', '5604', (164, 168))	('MEK1', 'Gene', (164, 168))	('increased', 'PosReg', (91, 100))	('p-Raf1', 'Gene', (119, 125))	('expression', 'MPA', (105, 115))	('T202/Y204', 'Var', (190, 199))
121262	30971268	4a, Left); In contrast, PAK1 knockdown in KYSE30 and KYSE150 cells significantly decreased the protein levels of p-Raf1 (S338), as well as p-MEK1 (S298) and p-ERK1/2 (T202/Y204) (Fig.	('MEK1', 'Gene', (141, 145))	('decreased', 'NegReg', (81, 90))	('knockdown', 'Var', (29, 38))	('T202/Y204', 'Var', (167, 176))	('p-ERK1/2 (T202/Y204', 'Var', (157, 176))	('p-Raf1', 'Gene', (113, 119))	('protein levels', 'MPA', (95, 109))	('PAK1', 'Gene', (24, 28))	('MEK1', 'Gene', '5604', (141, 145))	('KYSE150', 'CellLine', 'CVCL:1348', (53, 60))	('p-Raf1', 'Gene', '64425', (113, 119))
121270	30971268	Consistently, wound healing and Transwell migration and invasion assays also showed that Raf1 knockdown resulted in a decrease in the migratory and invasive abilities in both PAK1-overexpressing ESCC cell lines (Fig.	('Raf1', 'Gene', '5894', (89, 93))	('knockdown', 'Var', (94, 103))	('decrease', 'NegReg', (118, 126))	('Raf1', 'Gene', (89, 93))
121271	30971268	Western blotting analysis demonstrated that silencing Raf1 remarkably attenuated the expression of MMP-2 and MMP-9 in PAK1-overexpressing EC109 and KYSE70 cells (Fig.	('MMP-9', 'Gene', (109, 114))	('expression', 'MPA', (85, 95))	('MMP-2', 'Gene', (99, 104))	('MMP-9', 'Gene', '4318', (109, 114))	('Raf1', 'Gene', '5894', (54, 58))	('attenuated', 'NegReg', (70, 80))	('Raf1', 'Gene', (54, 58))	('MMP-2', 'Gene', '4313', (99, 104))	('silencing', 'Var', (44, 53))
121273	30971268	Accordingly, results of Western blotting analysis showed that U0126 could effectively decrease expression levels of p-ERK1/2 (T202/Y204) (Fig.	('U0126', 'Chemical', 'MESH:C113580', (62, 67))	('T202/Y204', 'Var', (126, 135))	('p-ERK1/2', 'Gene', (116, 124))	('U0126', 'Var', (62, 67))	('decrease', 'NegReg', (86, 94))	('expression levels', 'MPA', (95, 112))
121274	30971268	Interestingly, U0126 treatment resulted in lower colony formation frequencies and reduced colony forming abilities in soft agar in EC109-PAK1 and KYSE70-PAK1 cells (Fig.	('agar', 'Chemical', 'MESH:D000362', (123, 127))	('U0126', 'Var', (15, 20))	('colony forming abilities in soft agar', 'CPA', (90, 127))	('U0126', 'Chemical', 'MESH:C113580', (15, 20))	('colony formation frequencies', 'CPA', (49, 77))	('reduced', 'NegReg', (82, 89))	('lower', 'NegReg', (43, 48))
121275	30971268	Moreover, wound healing assay showed that U0126 treatment attenuated the migratory abilities of PAK1-overexpressing ESCC cells (Fig.	('U0126', 'Chemical', 'MESH:C113580', (42, 47))	('attenuated', 'NegReg', (58, 68))	('U0126', 'Var', (42, 47))	('migratory abilities', 'CPA', (73, 92))
121276	30971268	Furthermore, the migratory and invasive abilities of PAK1-overexpressing cells were significantly inhibited by U0126, compared with their corresponding control cells (Fig.	('PAK1-overexpressing', 'Gene', (53, 72))	('U0126', 'Var', (111, 116))	('U0126', 'Chemical', 'MESH:C113580', (111, 116))	('inhibited', 'NegReg', (98, 107))
121277	30971268	Consistently, Western blotting analysis indicated that U0126 treatment dramatically inhibited the expression of MMP-2 and MMP-9 in a dose dependent manner in PAK1-overexpressing ESCC cells (Fig.	('MMP-2', 'Gene', (112, 117))	('expression', 'MPA', (98, 108))	('MMP-2', 'Gene', '4313', (112, 117))	('U0126', 'Chemical', 'MESH:C113580', (55, 60))	('MMP-9', 'Gene', '4318', (122, 127))	('U0126', 'Var', (55, 60))	('MMP-9', 'Gene', (122, 127))	('inhibited', 'NegReg', (84, 93))
121280	30971268	As expect, IPA-3 treatment resulted in a significant reduction in the levels of phosphorylated PAK1 at T423, but not the phospho-PAK2 (S141) and the total amount of PAK1 and PAK2 (Fig.	('PAK2', 'Gene', (129, 133))	('PAK2', 'Gene', (174, 178))	('T423', 'Var', (103, 107))	('reduction', 'NegReg', (53, 62))	('IPA-3', 'Chemical', '-', (11, 16))	('levels of phosphorylated', 'MPA', (70, 94))	('PAK2', 'Gene', '5062', (129, 133))	('PAK2', 'Gene', '5062', (174, 178))
121281	30971268	In addition, IPA-3 treatment also downregulated the expression of phospho-Raf1 (S338), phospho-MEK1 (S298) and phospho-ERK1/2 (T202/Y204) in a concentration dependent manner, while the total amount of Raf1, MEK1 and ERK1/2 proteins were not alternated (Fig.	('Raf1', 'Gene', '5894', (74, 78))	('downregulated', 'NegReg', (34, 47))	('Raf1', 'Gene', (201, 205))	('IPA-3', 'Chemical', '-', (13, 18))	('MEK1', 'Gene', '5604', (95, 99))	('expression', 'MPA', (52, 62))	('MEK1', 'Gene', (95, 99))	('Raf1', 'Gene', (74, 78))	('T202/Y204', 'Var', (127, 136))	('MEK1', 'Gene', '5604', (207, 211))	('Raf1', 'Gene', '5894', (201, 205))	('MEK1', 'Gene', (207, 211))
121284	30971268	Furthermore, soft agar assay also showed that the colony forming abilities in soft agar was significantly inhibited in KYSE30 and KYSE150 cells, with IC50 values of 5.81 muM and 6.35 muM, respectively (Fig.	('muM', 'Gene', '56925', (183, 186))	('colony forming abilities', 'CPA', (50, 74))	('KYSE30', 'Var', (119, 125))	('KYSE150', 'Var', (130, 137))	('inhibited', 'NegReg', (106, 115))	('agar', 'Chemical', 'MESH:D000362', (83, 87))	('agar', 'Chemical', 'MESH:D000362', (18, 22))	('muM', 'Gene', '56925', (170, 173))	('muM', 'Gene', (183, 186))	('KYSE150', 'CellLine', 'CVCL:1348', (130, 137))	('muM', 'Gene', (170, 173))
121293	30971268	Given that targeting PAK1 by shRNA or pharmacology inhibitor IPA-3 could significantly suppress cell growth, migration and invasion in vitro, therefore, we want to determine whether targeting PAK1 suppresses ESCC cell growth and metastasis in vivo.	('suppress', 'NegReg', (87, 95))	('ESCC', 'Disease', (208, 212))	('IPA-3', 'Chemical', '-', (61, 66))	('suppresses', 'NegReg', (197, 207))	('PAK1', 'Gene', (21, 25))	('PAK1', 'Gene', (192, 196))	('targeting', 'Var', (182, 191))	('cell growth', 'CPA', (96, 107))
121295	30971268	The growth curve (tumor volume versus time curve) of KYSE150 tumors was significantly inhibited by the treatment of IPA-3 (Fig.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (18, 23))	('IPA-3', 'Chemical', '-', (116, 121))	('KYSE150', 'Var', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('growth', 'MPA', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('inhibited', 'NegReg', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))	('KYSE150', 'CellLine', 'CVCL:1348', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
121296	30971268	In addition, the tumor weight in the IPA-3-treated mice was significantly lower than that of the vehicle-treated mice (Fig.	('IPA-3', 'Chemical', '-', (37, 42))	('tumor', 'Disease', (17, 22))	('mice', 'Species', '10090', (51, 55))	('IPA-3-treated', 'Var', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('lower', 'NegReg', (74, 79))	('mice', 'Species', '10090', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
121298	30971268	Similarly, the level of phospho-PAK1 (T423) and phospho-ERK1/2 (T202/Y204) was substantially diminished in the IPA-3-treated group compared with that from the vehicle-treated mice (Fig.	('mice', 'Species', '10090', (175, 179))	('phospho-PAK1', 'MPA', (24, 36))	('T202/Y204', 'Var', (64, 73))	('IPA-3', 'Chemical', '-', (111, 116))	('phospho-ERK1/2', 'MPA', (48, 62))	('diminished', 'NegReg', (93, 103))
121300	30971268	Consistent with these results, Western blotting analysis of cell lysates from xenografted tumors showed that IPA-3 dramatically inhibited the expression levels of phospho-PAK1 (T423), phospho-Raf1 (S338), phospho-MEK1 (S298) and phospho-ERK1/2 (T202/Y204), while the phospho-PAK2 (S141) and the total amount of PAK1, PAK2, Raf1, MEK1 and ERK1/2 proteins were not alternated (Fig.	('expression levels', 'MPA', (142, 159))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('PAK2', 'Gene', (317, 321))	('Raf1', 'Gene', '5894', (323, 327))	('PAK2', 'Gene', '5062', (317, 321))	('Raf1', 'Gene', (323, 327))	('PAK2', 'Gene', (275, 279))	('MEK1', 'Gene', '5604', (329, 333))	('MEK1', 'Gene', (213, 217))	('PAK2', 'Gene', '5062', (275, 279))	('Raf1', 'Gene', '5894', (192, 196))	('IPA-3', 'Var', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Raf1', 'Gene', (192, 196))	('inhibited', 'NegReg', (128, 137))	('IPA-3', 'Chemical', '-', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MEK1', 'Gene', '5604', (213, 217))	('MEK1', 'Gene', (329, 333))	('tumors', 'Disease', (90, 96))
121306	30971268	Collectively, these findings indicate that targeting PAK1 by pharmacological inhibitor IPA-3 could suppress tumor growth and metastatic behavior of ESCC cells and that it likely acts through blocking the Raf1/MEK1/ERK signaling pathway.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('Raf1', 'Gene', '5894', (204, 208))	('targeting', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ERK', 'Gene', '5594', (214, 217))	('PAK1', 'Gene', (53, 57))	('MEK1', 'Gene', '5604', (209, 213))	('Raf1', 'Gene', (204, 208))	('tumor', 'Disease', (108, 113))	('MEK1', 'Gene', (209, 213))	('ERK', 'Gene', (214, 217))	('blocking', 'NegReg', (191, 199))	('IPA-3', 'Chemical', '-', (87, 92))	('suppress', 'NegReg', (99, 107))	('metastatic behavior of', 'CPA', (125, 147))	('ESCC', 'Disease', (148, 152))	('IPA-3', 'Gene', (87, 92))
121307	30971268	In the present study, we found that PAK1 was frequently overexpressed in both ESCC cell lines and primary human ESCC tissues, suggesting that PAK1 may play an important oncogenic role in ESCC.	('ESCC', 'Disease', (187, 191))	('human', 'Species', '9606', (106, 111))	('overexpressed', 'PosReg', (56, 69))	('PAK1', 'Var', (142, 146))	('play', 'Reg', (151, 155))
121308	30971268	Indeed, silencing PAK1 by shRNA or a specific inhibitor IPA-3 significantly suppresses ESCC cell proliferation, focus formation, anchorage-independent growth, migration, invasion and the expression of MMP-2 and MMP-9 in vitro.	('anchorage-independent growth', 'CPA', (129, 157))	('expression', 'MPA', (187, 197))	('MMP-2', 'Gene', '4313', (201, 206))	('silencing', 'Var', (8, 17))	('migration', 'CPA', (159, 168))	('MMP-9', 'Gene', '4318', (211, 216))	('IPA-3', 'Chemical', '-', (56, 61))	('ESCC cell proliferation', 'CPA', (87, 110))	('focus formation', 'CPA', (112, 127))	('MMP-9', 'Gene', (211, 216))	('MMP-2', 'Gene', (201, 206))	('suppresses', 'NegReg', (76, 86))	('PAK1', 'Gene', (18, 22))	('invasion', 'CPA', (170, 178))
121319	30971268	In this study, we found that ectopic expression of PAK1 in ESCC results in aberrant activation of Raf1/MEK1/ERK signaling pathway as monitored by p-Raf1 (S338), p-MEK1 (S298), p-ERK1/2 (T202/Y204).	('T202/Y204', 'Var', (186, 195))	('ERK', 'Gene', (108, 111))	('MEK1', 'Gene', (163, 167))	('activation', 'PosReg', (84, 94))	('Raf1', 'Gene', (148, 152))	('p-Raf1', 'Gene', (146, 152))	('Raf1', 'Gene', '5894', (98, 102))	('MEK1', 'Gene', '5604', (103, 107))	('ERK', 'Gene', '5594', (178, 181))	('PAK1', 'Gene', (51, 55))	('Raf1', 'Gene', '5894', (148, 152))	('Raf1', 'Gene', (98, 102))	('p-Raf1', 'Gene', '64425', (146, 152))	('ERK', 'Gene', (178, 181))	('MEK1', 'Gene', '5604', (163, 167))	('ERK', 'Gene', '5594', (108, 111))	('MEK1', 'Gene', (103, 107))
121321	30971268	More importantly, we also found that enforced expression of Raf1 attenuates the inhibitory effect of IPA-3 on cell growth, colony formation, migration and invasion of ESCC cells.	('expression', 'Var', (46, 56))	('migration', 'CPA', (141, 150))	('Raf1', 'Gene', '5894', (60, 64))	('inhibitory effect', 'MPA', (80, 97))	('attenuates', 'NegReg', (65, 75))	('Raf1', 'Gene', (60, 64))	('invasion', 'CPA', (155, 163))	('colony formation', 'CPA', (123, 139))	('IPA-3', 'Chemical', '-', (101, 106))	('cell growth', 'CPA', (110, 121))
121322	30971268	Conversely, silencing Raf1 by shRNAs or using U0126, a MEK1 specific inhibitor, dramatically abrogates the promotive effect of PAK1 on ESCC cells.	('abrogates', 'NegReg', (93, 102))	('Raf1', 'Gene', '5894', (22, 26))	('U0126', 'Chemical', 'MESH:C113580', (46, 51))	('promotive effect', 'MPA', (107, 123))	('silencing', 'Var', (12, 21))	('Raf1', 'Gene', (22, 26))	('MEK1', 'Gene', '5604', (55, 59))	('MEK1', 'Gene', (55, 59))
121323	30971268	Therefore, our study demonstrates that targeting PAK1 suppresses ESCC cell growth, migration and invasion at least partly via blocking Raf1/MEK1/ERK signaling pathway.	('ERK', 'Gene', (145, 148))	('blocking', 'NegReg', (126, 134))	('targeting', 'Var', (39, 48))	('Raf1', 'Gene', (135, 139))	('MEK1', 'Gene', '5604', (140, 144))	('suppresses', 'NegReg', (54, 64))	('MEK1', 'Gene', (140, 144))	('ESCC', 'Disease', (65, 69))	('PAK1', 'Gene', (49, 53))	('ERK', 'Gene', '5594', (145, 148))	('invasion', 'CPA', (97, 105))	('Raf1', 'Gene', '5894', (135, 139))
121326	30971268	Similarly, overexpression of PAK1 also correlates with aberrant expression of EMT markers and poor prognosis in non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (112, 138))	('expression', 'MPA', (64, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('PAK1', 'Gene', (29, 33))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (116, 138))	('aberrant', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('non-small cell lung cancer', 'Disease', (112, 138))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (112, 138))	('overexpression', 'PosReg', (11, 25))	('EMT markers', 'Gene', (78, 89))
121328	30971268	These data indicate that PAK1 plays an important role in promoting tumor metastasis, therefore targeting PAK1 may significantly suppresses the metastasis of these cancer.	('PAK1', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('targeting', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('promoting', 'PosReg', (57, 66))	('tumor metastasis', 'Disease', 'MESH:D009362', (67, 83))	('tumor metastasis', 'Disease', (67, 83))	('cancer', 'Disease', (163, 169))	('suppresses', 'NegReg', (128, 138))
121329	30971268	Indeed, knocking down of PAK1 significantly reduces cell adhesion, migration, and invasion of gastric cancer cells in vitro and significantly prevents tumor metastasis in vivo.	('gastric cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cell adhesion', 'CPA', (52, 65))	('tumor metastasis', 'Disease', 'MESH:D009362', (151, 167))	('invasion', 'CPA', (82, 90))	('tumor metastasis', 'Disease', (151, 167))	('PAK1', 'Gene', (25, 29))	('knocking down', 'Var', (8, 21))	('migration', 'CPA', (67, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('prevents', 'NegReg', (142, 150))	('reduces', 'NegReg', (44, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))
121331	30971268	First, Conversely, knockdown of PAK1 by shRNAs or pharmacological inhibitor IPA-3 leads to opponent trends.	('PAK1', 'Gene', (32, 36))	('knockdown', 'Var', (19, 28))	('IPA-3', 'Chemical', '-', (76, 81))
121340	30971268	And vice versa, both MMP-2 and MMP-9 expression is concomitantly downregulated upon PAK1 knockdown by shRNAs or inhibition by a specific inhibitor IPA-3.	('PAK1', 'Gene', (84, 88))	('MMP-9', 'Gene', '4318', (31, 36))	('MMP-2', 'Gene', (21, 26))	('inhibition', 'NegReg', (112, 122))	('downregulated', 'NegReg', (65, 78))	('MMP-9', 'Gene', (31, 36))	('IPA-3', 'Chemical', '-', (147, 152))	('knockdown', 'Var', (89, 98))	('MMP-2', 'Gene', '4313', (21, 26))	('expression', 'MPA', (37, 47))
121342	30971268	Conversely, silencing Raf1 by shRNAs or using U0126, a MEK specific inhibitor, dramatically abrogates the promotive effect of PAK1 on the protein level of MMP-2 and MMP-9.	('MMP-9', 'Gene', (165, 170))	('Raf1', 'Gene', '5894', (22, 26))	('U0126', 'Chemical', 'MESH:C113580', (46, 51))	('MEK', 'Gene', (55, 58))	('abrogates', 'NegReg', (92, 101))	('MMP-2', 'Gene', (155, 160))	('silencing', 'Var', (12, 21))	('MEK', 'Gene', '5609', (55, 58))	('Raf1', 'Gene', (22, 26))	('MMP-9', 'Gene', '4318', (165, 170))	('promotive effect', 'MPA', (106, 122))	('MMP-2', 'Gene', '4313', (155, 160))
121344	30971268	Our data are in line with a previous study showing that inhibiting ERK1/2 activity by U0126 significantly suppresses the transcription activity of MMP-2 by inhibiting the phosphorylation of hnRNPK and its nuclear translocation in colorectal cancer (CRC) cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (230, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('U0126', 'Chemical', 'MESH:C113580', (86, 91))	('colorectal cancer', 'Disease', (230, 247))	('MMP-2', 'Gene', (147, 152))	('hnRNPK', 'Gene', (190, 196))	('phosphorylation', 'MPA', (171, 186))	('ERK1/2', 'Protein', (67, 73))	('hnRNPK', 'Gene', '3190', (190, 196))	('activity', 'MPA', (74, 82))	('nuclear translocation', 'MPA', (205, 226))	('inhibiting', 'NegReg', (56, 66))	('MMP-2', 'Gene', '4313', (147, 152))	('transcription activity', 'MPA', (121, 143))	('suppresses', 'NegReg', (106, 116))	('U0126', 'Var', (86, 91))	('inhibiting', 'NegReg', (156, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (230, 247))
121345	30971268	Similarly, U0126 completely abolished globular domain isoform of CTRP9 (gCTRP9)-induced upregulation of MMP-9 and phosphorylated ERK1/2 in adiposederived mesenchymal stem cells.	('CTRP9', 'Gene', '338872', (73, 78))	('CTRP9', 'Gene', '338872', (65, 70))	('abolished', 'NegReg', (28, 37))	('U0126', 'Chemical', 'MESH:C113580', (11, 16))	('MMP-9', 'Gene', '4318', (104, 109))	('CTRP9', 'Gene', (65, 70))	('phosphorylated', 'MPA', (114, 128))	('MMP-9', 'Gene', (104, 109))	('upregulation', 'PosReg', (88, 100))	('globular domain isoform', 'MPA', (38, 61))	('U0126', 'Var', (11, 16))	('CTRP9', 'Gene', (73, 78))
121346	30971268	However, Qin et al reported that treatment with MEK1/2 inhibitor U0126 in Peptidylargininedeiminase 1 (PAD1) knockdown cells significantly recovers MMP-2 expression, but has no effect on MMP-9 in human triple negative breast cancer (TNBC) cells.	('MMP-2', 'Gene', '4313', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('Qin', 'Gene', '2290', (9, 12))	('Qin', 'Gene', (9, 12))	('MMP-9', 'Gene', '4318', (187, 192))	('MMP-2', 'Gene', (148, 153))	('MMP-9', 'Gene', (187, 192))	('TNBC', 'Disease', 'None', (233, 237))	('U0126', 'Chemical', 'MESH:C113580', (65, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('U0126', 'Var', (65, 70))	('recovers', 'NegReg', (139, 147))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('MEK1/2', 'Gene', '5604;5605', (48, 54))	('breast cancer', 'Disease', (218, 231))	('MEK1/2', 'Gene', (48, 54))	('TNBC', 'Disease', (233, 237))	('human', 'Species', '9606', (196, 201))	('expression', 'MPA', (154, 164))
121348	30971268	Previous reports showed that cancer cells that carry mutations in RAS and Rac1 genes are more sensitive to PAK inhibitors.	('cancer', 'Disease', (29, 35))	('Rac1', 'Gene', '5879', (74, 78))	('RAS', 'Gene', (66, 69))	('Rac1', 'Gene', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mutations', 'Var', (53, 62))	('PAK', 'Gene', '5058;18479;5062;5063', (107, 110))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('PAK', 'Gene', (107, 110))
121350	30971268	Although the activating mutations in RAC1 gene in ESCC has not been published to date, we and others had found Rac1 protein is consistently higher in ESCC cell lines and tissues compared with the corresponding control group.	('Rac1', 'Gene', '5879', (111, 115))	('RAC1', 'Gene', '5879', (37, 41))	('higher', 'PosReg', (140, 146))	('RAC1', 'Gene', (37, 41))	('ESCC', 'Disease', (150, 154))	('Rac1', 'Gene', (111, 115))	('mutations', 'Var', (24, 33))	('protein', 'Protein', (116, 123))
121351	30971268	Moreover, the high expression of Rac-1 is significantly correlated with advanced tumor depth, lymph node metastasis, and shorter disease-free and survival time.	('expression', 'MPA', (19, 29))	('lymph node metastasis', 'CPA', (94, 115))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('high', 'Var', (14, 18))	('shorter', 'NegReg', (121, 128))	('Rac-1', 'Gene', '5879', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Rac-1', 'Gene', (33, 38))	('tumor', 'Disease', (81, 86))
121353	30971268	Therefore, targeting PAK1 may be a promising therapeutic strategy for ESCC patients, especially for those with RAS and Rac1 mutations.	('mutations', 'Var', (124, 133))	('Rac1', 'Gene', '5879', (119, 123))	('Rac1', 'Gene', (119, 123))	('patients', 'Species', '9606', (75, 83))	('PAK1', 'Gene', (21, 25))	('RAS', 'Gene', (111, 114))	('ESCC', 'Disease', (70, 74))
121354	30971268	Mechanistic analysis demonstrated that targeting PAK1 inhibits ESCC cell growth, colony formation, anchorage-independent growth, migration, invasion and metastasis, at least in part through blocking the Raf1/MEK1/ERK signaling pathway.	('Raf1', 'Gene', (203, 207))	('MEK1', 'Gene', '5604', (208, 212))	('targeting', 'Var', (39, 48))	('MEK1', 'Gene', (208, 212))	('anchorage-independent growth', 'CPA', (99, 127))	('ERK', 'Gene', '5594', (213, 216))	('migration', 'CPA', (129, 138))	('colony formation', 'CPA', (81, 97))	('blocking', 'NegReg', (190, 198))	('PAK1', 'Gene', (49, 53))	('inhibits', 'NegReg', (54, 62))	('ESCC', 'Disease', (63, 67))	('ERK', 'Gene', (213, 216))	('Raf1', 'Gene', '5894', (203, 207))
121355	30971268	These findings provide evidence for the first time that overexpressed PAK1 is an important molecule participating in the aberrant activation of Raf1/MEK1/ERK signaling pathway and thus may serve as a therapeutic target for ESCC.	('MEK1', 'Gene', (149, 153))	('overexpressed', 'Var', (56, 69))	('activation', 'PosReg', (130, 140))	('ERK', 'Gene', '5594', (154, 157))	('Raf1', 'Gene', '5894', (144, 148))	('ESCC', 'Disease', (223, 227))	('ERK', 'Gene', (154, 157))	('MEK1', 'Gene', '5604', (149, 153))	('PAK1', 'Gene', (70, 74))	('Raf1', 'Gene', (144, 148))
121461	26065368	To optimize the sensitivity of our case finding strategy, cases of EFI were identified by screening our electronic medical record and endoscopy records (The Clinical Outcomes Research Initiative database) using the International Classification of Diseases (ICD):9th Revision, Clinical Modification code (935.1) and current procedural terminology codes (CPT) (43215, 43247, 31511).	('EFI', 'Phenotype', 'HP:0031984', (67, 70))	('43215', 'Var', (359, 364))	('ICD', 'Disease', 'OMIM:252500', (257, 260))	('ICD', 'Disease', (257, 260))
121507	26065368	There is growing evidence that long-standing eosinophil-induced inflammation can lead to dysmotility and/or narrowing of the esophagus via edema and/or deposition of subepithelial fibrotic tissue, which eventually causes narrowing of the esophageal lumen.	('lead to', 'Reg', (81, 88))	('dysmotility', 'Disease', 'MESH:D015154', (89, 100))	('edema', 'Disease', 'MESH:D004487', (139, 144))	('edema', 'Phenotype', 'HP:0000969', (139, 144))	('inflammation', 'Disease', 'MESH:D007249', (64, 76))	('long-standing', 'Phenotype', 'HP:0003698', (31, 44))	('eosinophil-induced', 'Var', (45, 63))	('narrowing', 'Disease', (108, 117))	('inflammation', 'Disease', (64, 76))	('edema', 'Disease', (139, 144))	('dysmotility', 'Disease', (89, 100))	('narrowing of the esophagus', 'Phenotype', 'HP:0010450', (108, 134))	('causes', 'Reg', (214, 220))
121594	33388031	Multivariable binary logistic regression analysis showed SBP < 90mmHG for > 5 min was not significantly associated with composite outcomes of anastomotic leak, mortality, and prolonged hospital stay (AOR 1.06, 95% CI 0.98-1.14; p = 0.16).	('AOR', 'Chemical', '-', (200, 203))	('mortality', 'Disease', (160, 169))	('anastomotic leak', 'Disease', 'MESH:D057868', (142, 158))	('mortality', 'Disease', 'MESH:D003643', (160, 169))	('anastomotic leak', 'Disease', (142, 158))	('SBP', 'Var', (57, 60))
121606	33388031	This finding aligns with the retrospective cohort study on combined intraoperative blood pressure data by Monk et al which identified Systolic BP < 70 mmHg, not higher, for >= 5 min to be associated with increased 30-day operative mortality in non-cardiac surgery.	('non-cardiac surgery', 'Disease', (244, 263))	('Systolic BP < 70 mmHg', 'Var', (134, 155))	('mortality', 'Disease', (231, 240))	('mortality', 'Disease', 'MESH:D003643', (231, 240))
121629	31171663	Finally, we find that normal tissues harbor mutations in known cancer genes and hotspots.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
121631	31171663	Multiple macroscopic clonal expansions are detected across normal tissues, including clones with mutations in cancer genes.	('mutations', 'Var', (97, 106))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
121632	31171663	While most of these mutations are thought to be either neutral or slightly deleterious, a few may increase cellular fitness and contribute to clonal expansion.	('increase', 'PosReg', (98, 106))	('fitness', 'Disease', (116, 123))	('clonal expansion', 'CPA', (142, 158))	('fitness', 'Disease', 'MESH:D012640', (116, 123))	('mutations', 'Var', (20, 29))	('contribute', 'Reg', (128, 138))
121634	31171663	In cancer, the accumulation of several mutations (known as "cancer drivers") eventually may transform the cells and promote uncontrolled cellular growth.	('cells', 'CPA', (106, 111))	('transform', 'Reg', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('uncontrolled', 'MPA', (124, 136))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (39, 48))	('promote', 'PosReg', (116, 123))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
121637	31171663	Clonal expansions detected in normal blood are enriched with mutations in several genes implicated in hematologic cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('hematologic cancers', 'Disease', 'MESH:D009369', (102, 121))	('hematologic cancers', 'Disease', (102, 121))
121638	31171663	in normal skin and esophagus tissues focused on 74 cancer genes and detected a high burden of low-allele frequency mutations associated with skin and esophagus squamous cell carcinoma.	('mutations', 'Var', (115, 124))	('esophagus squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 183))	('esophagus squamous cell carcinoma', 'Disease', (150, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('associated', 'Reg', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
121642	31171663	Applying our standard somatic mutation calling pipeline (that was developed for DNA) to both DNA and RNA from the tumor samples, and using the matched-normal DNA as a germline control, we found 5-fold more mutations in RNA than in the corresponding DNA (Figs.	('mutations', 'Var', (206, 215))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('RNA', 'Gene', (219, 222))
121645	31171663	Overall, we conclude that high precision analysis of somatic mutations based on RNA is achievable despite the apparent limitations in calling mutations de novo from RNA-seq data, allowing for most cancer-associated genes as well as mutational processes to be revealed from RNA-seq data.	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
121647	31171663	After ensuring the samples were not contaminated with tumor cells, we detected 114 DNA-based mutations, with a median allele fraction of 0.06.	('mutations', 'Var', (93, 102))	('DNA-based', 'Gene', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
121651	31171663	Note that mutations detected in samples with 4 or fewer mutations are not necessarily false positives; for example, some of these samples harbored known cancer driver mutations that likely increased cell fitness.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('fitness', 'Disease', (204, 211))	('fitness', 'Disease', 'MESH:D012640', (204, 211))	('mutations', 'Var', (167, 176))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('increased', 'PosReg', (189, 198))
121652	31171663	Similar to what we observed from analyzing the tumor-adjacent normal samples from TCGA, the median allele fraction of the mutations in the GTEx normal tissue samples was 0.05 (Fig.	('mutations', 'Var', (122, 131))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
121653	31171663	Consistent with the majority of mutations being passengers, like we observe in cancer, ~59% were missense mutations (fig.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('missense mutations', 'Var', (97, 115))
121654	31171663	However, we also found that a few mutations in normal tissue types matched mutations observed in their corresponding cancer types (table S5).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (34, 43))
121661	31171663	As expected, when considering the top 10 tissues with the highest level of cell proliferation (as determined by MKI67 expression, a marker of proliferation, table S8), this relationship became more significant for the total number of mutations (one-sided Wilcoxon test P value = 2.3 x 10-5) and remained similar for the aging mutations (one-sided Wilcoxon test P value = 0.004).	('MKI67', 'Gene', (112, 117))	('mutations', 'Var', (234, 243))	('MKI67', 'Gene', '4288', (112, 117))
121664	31171663	We next directly examined whether cell proliferation associated with the number of accumulated mutations across tissues and indeed found a significantly higher expression level of MKI67 in tissues with a higher number of mutations (one-sided Wilcoxon test P value = 8.2 x 10-4 and P value = 1.2 x 10-4 for all primary and sub-region tissues, respectively, with an overall Spearman correlation of R = 0.44 and P value = 0.01, Figs.	('mutations', 'Var', (221, 230))	('higher', 'PosReg', (153, 159))	('cell proliferation', 'CPA', (34, 52))	('expression level', 'MPA', (160, 176))	('MKI67', 'Gene', (180, 185))	('MKI67', 'Gene', '4288', (180, 185))	('mutations', 'Var', (95, 104))
121669	31171663	This CGC set represents genes in which mutations have been causally implicated in cancer.	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('mutations', 'Var', (39, 48))
121672	31171663	Examining whether the number of mutations differed between samples carrying TP53 mutations and those that did not, we found that the TP53-associated samples had significantly more mutations (two-sided Wilcoxon P value = 9.2 x 10-9).	('mutations', 'Var', (180, 189))	('more', 'PosReg', (175, 179))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))
121673	31171663	To test if these TP53 mutations conferred a growth advantage to the cell, we analyzed their allele fraction level relative to all other detected mutations in the same sample.	('growth advantage', 'MPA', (44, 60))	('TP53', 'Gene', '7157', (17, 21))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (17, 21))
121674	31171663	Indeed, the allele fractions of TP53 mutations were significantly higher than other mutations in the corresponding sample (empirical P value < 0.02; fig.	('mutations', 'Var', (37, 46))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))	('higher', 'PosReg', (66, 72))
121676	31171663	Similarly, we also found that the NOTCH1-mutated cases had a significant increase in the overall number of mutations (two-sided Wilcoxon P value = 1 x 10-7) as well as a significantly higher allele fraction of the NOTCH1 mutation (empirical P value < 9.9 x 10-4, fig.	('mutation', 'Var', (221, 229))	('NOTCH1', 'Gene', '4851', (214, 220))	('NOTCH1', 'Gene', (214, 220))	('mutations', 'Var', (107, 116))	('increase', 'PosReg', (73, 81))	('NOTCH1', 'Gene', '4851', (34, 40))	('NOTCH1', 'Gene', (34, 40))	('higher', 'PosReg', (184, 190))
121680	31171663	This higher allele fraction of the TP53 and NOTCH1 mutations compared to other mutations in the same samples suggests that these mutations appear early in the history (i.e., the trunk) of these clones.	('mutations', 'Var', (51, 60))	('NOTCH1', 'Gene', '4851', (44, 50))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('NOTCH1', 'Gene', (44, 50))
121681	31171663	However, since early appearance in the trunk does not guarantee that these mutations conferred a growth advantage, we cannot rule out the possibility that these early events are the result of genetic drift; we do consider this possibility unlikely, however, since both TP53 and NOTCH1 are known cancer genes.	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Disease', (295, 301))	('TP53', 'Gene', '7157', (269, 273))	('mutations', 'Var', (75, 84))	('TP53', 'Gene', (269, 273))	('NOTCH1', 'Gene', (278, 284))	('NOTCH1', 'Gene', '4851', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))
121682	31171663	Overall, samples carrying TP53 or NOTCH1 mutations were found only in skin and esophagus tissues (with equal proportions in each tissue, table S3), but no samples harbored mutations in both of these genes.	('mutations', 'Var', (41, 50))	('TP53', 'Gene', (26, 30))	('NOTCH1', 'Gene', '4851', (34, 40))	('NOTCH1', 'Gene', (34, 40))	('TP53', 'Gene', '7157', (26, 30))
121685	31171663	The gene with the greatest number of detected hotspot mutations was TP53 with 16 known hotspot mutations in both skin and esophagus samples, 14 of which were observed once in our dataset (Fig.	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('mutations', 'Var', (54, 63))
121687	31171663	Reviewing IARC TP53 database, we found that all of these mutations were annotated as deleterious by SIFT.	('TP53', 'Gene', '7157', (15, 19))	('mutations', 'Var', (57, 66))	('TP53', 'Gene', (15, 19))
121688	31171663	Interestingly, although all of the mutations were annotated as loss-of-function in yeast, 3 (R248Q, R248W, R282W) were reported to have gain-of-function activities.	('R248W', 'Mutation', 'rs121912651', (100, 105))	('R282W', 'Mutation', 'rs28934574', (107, 112))	('R248W', 'Var', (100, 105))	('gain-of-function', 'PosReg', (136, 152))	('activities', 'MPA', (153, 163))	('R248Q', 'Var', (93, 98))	('loss-of-function', 'NegReg', (63, 79))	('yeast', 'Species', '4932', (83, 88))	('R248Q', 'Mutation', 'rs11540652', (93, 98))	('R282W', 'Var', (107, 112))
121689	31171663	R248Q knock-in mice showed an earlier onset of tumor formation and reduced lifespan, as well as an expansion of hematopoietic and mesenchymal stem cell progenitors.	('R248Q', 'Mutation', 'rs11540652', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('reduced', 'NegReg', (67, 74))	('expansion', 'PosReg', (99, 108))	('lifespan', 'CPA', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', (47, 52))	('R248Q', 'Var', (0, 5))
121690	31171663	The R248W variant was involved in multiple gain-of-function activities, including promotion of cell invasion and increased cell proliferation, among others.	('R248W', 'Var', (4, 9))	('cell proliferation', 'CPA', (123, 141))	('promotion', 'PosReg', (82, 91))	('increased', 'PosReg', (113, 122))	('R248W', 'Mutation', 'rs121912651', (4, 9))	('cell invasion', 'CPA', (95, 108))
121691	31171663	The R282W variant increased colony formation.	('R282W', 'Mutation', 'rs28934574', (4, 9))	('increased', 'PosReg', (18, 27))	('colon', 'Disease', (28, 33))	('R282W', 'Var', (4, 9))	('colon', 'Disease', 'MESH:D003110', (28, 33))
121693	31171663	Among the other 14 non-TP53 hotspot mutations, all but 2 were annotated as pathogenic by FATHMM, and 7 were also observed in their corresponding cancer type (Fig.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('observed', 'Reg', (113, 121))	('mutations', 'Var', (36, 45))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
121694	31171663	Three PIK3CA mutations in the p.H1047L and p.H1047R hotspots, which are common in multiple cancers (including esophageal cancer), were observed in normal esophagus mucosa samples.	('multiple cancers', 'Disease', 'MESH:D009369', (82, 98))	('p.H1047L', 'Mutation', 'rs121913279', (30, 38))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('p.H1047R', 'Mutation', 'rs121913279', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('PIK3CA', 'Gene', (6, 12))	('p.H1047L', 'Var', (30, 38))	('PIK3CA', 'Gene', '5290', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('multiple cancers', 'Disease', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('p.H1047R', 'Var', (43, 51))	('cancer', 'Disease', (121, 127))
121695	31171663	The p.Q61R KRAS hotspot mutation found in a normal testis sample of a 58-year-old male had been detected in a testicular germ cell cancer.	('cancer', 'Disease', (131, 137))	('KRAS', 'Gene', (11, 15))	('germ cell cancer', 'Phenotype', 'HP:0100728', (121, 137))	('KRAS', 'Gene', '3845', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('p.Q61R', 'Var', (4, 10))	('p.Q61R', 'Mutation', 'rs121913240', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
121696	31171663	The p.R183W hotspot mutation in the cell-growth regulator PPP2R1A detected in a normal colon sample here was also detected in colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('PPP2R1A', 'Gene', (58, 65))	('detected', 'Reg', (114, 122))	('colorectal cancer', 'Disease', (126, 143))	('colon', 'Disease', 'MESH:D003110', (87, 92))	('p.R183W', 'Var', (4, 11))	('colon', 'Disease', (87, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))	('PPP2R1A', 'Gene', '5518', (58, 65))	('p.R183W', 'Mutation', 'rs1057519946', (4, 11))
121698	31171663	The hotspot mutation p.S45F in CTNNB1 (beta-catenin) found in the normal adrenal gland sample of a 58-year-old female had previously been detected in adrenocortical adenomas; this hotspot was also found significantly mutated in adrenocortical tumors that resulting in Wnt/beta-catenin pathway deregulation.	('beta-catenin', 'Gene', (272, 284))	('CTNNB1', 'Gene', '1499', (31, 37))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (150, 173))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('p.S45F', 'Var', (21, 27))	('p.S45F', 'Mutation', 'rs121913409', (21, 27))	('resulting in', 'Reg', (255, 267))	('beta-catenin', 'Gene', '1499', (272, 284))	('CTNNB1', 'Gene', (31, 37))	('adrenocortical tumors', 'Disease', (228, 249))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (228, 249))	('deregulation', 'Reg', (293, 305))	('beta-catenin', 'Gene', (39, 51))	('adenomas', 'Disease', 'MESH:D000236', (165, 173))	('beta-catenin', 'Gene', '1499', (39, 51))	('adenomas', 'Disease', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
121699	31171663	The hotspot mutation p.R264C in the PPP6C gene that we detected in normal skin was also observed in melanoma, wherein this gene was found to be significantly mutated.	('p.R264C', 'Var', (21, 28))	('PPP6C', 'Gene', (36, 41))	('PPP6C', 'Gene', '5537', (36, 41))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('p.R264C', 'Mutation', 'rs763733111', (21, 28))
121709	31171663	Two out of the 8 samples also had a nonsense or missense mutation in NOTCH1 (hypergeometric P value = 0.02), a gene also located on 9q.	('NOTCH1', 'Gene', '4851', (69, 75))	('NOTCH1', 'Gene', (69, 75))	('nonsense', 'Var', (36, 44))
121710	31171663	Frequent amplifications of NOTCH1 were reported in esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (51, 85))	('NOTCH1', 'Gene', '4851', (27, 33))	('NOTCH1', 'Gene', (27, 33))	('reported', 'Reg', (39, 47))	('amplifications', 'Var', (9, 23))	('esophageal squamous cell carcinoma', 'Disease', (51, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
121711	31171663	Interestingly, 9q loss was more common in esophageal dysplasia than in esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('9q loss', 'Var', (15, 22))	('common', 'Reg', (32, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('esophageal dysplasia', 'Disease', (42, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('esophageal dysplasia', 'Disease', 'MESH:D004938', (42, 62))
121713	31171663	One additional sample with 9q imbalance was found to carry mutations in both TP53 and FAT1.	('imbalance', 'Phenotype', 'HP:0002172', (30, 39))	('FAT1', 'Gene', (86, 90))	('mutations', 'Var', (59, 68))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('FAT1', 'Gene', '2195', (86, 90))
121714	31171663	An allelic imbalance in 22p and a mutation in NOTCH1 were also identified in an additional esophagus sample (fig.	('imbalance', 'Phenotype', 'HP:0002172', (11, 20))	('mutation', 'Var', (34, 42))	('NOTCH1', 'Gene', '4851', (46, 52))	('NOTCH1', 'Gene', (46, 52))
121717	31171663	Taking advantage of our approach, thousands of somatic mutations were detected across all human tissues and in almost all tested individuals, including mutations at cancer hotspots and other cancer genes.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('mutations', 'Var', (152, 161))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (90, 95))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
121719	31171663	Indeed, these tissues are also among those carrying the greatest number of somatic mutations in cancer patients, consistent with the notion that a non-negligible proportion of the mutations observed in cancer accumulate well before disease.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (202, 208))	('patients', 'Species', '9606', (103, 111))	('cancer', 'Disease', (96, 102))
121721	31171663	In addition, it was previously argued that tissue compartmentalization can affect the rate at which cancer mutations accumulate.	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('affect', 'Reg', (75, 81))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
121722	31171663	Overall, the complex nature of transformation from a normal to a cancer cell within different tissues is a result of the interplay among genetic and epigenetic events, tissue structure, exposure, and the tissue microenvironment.	('epigenetic', 'Var', (149, 159))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
121728	31171663	Also, the detection of hotspots and other mutations in cancer genes across various normal human tissues emphasizes the need for identifying drivers of the disease while considering the non-pathogenic landscape of mutations.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (55, 61))
122042	29871674	NS1-BP also significantly enhanced IR-induced apoptosis, and abrogated IR-induced G2/M cell-cycle arrest and ATM/Chk1 phosphorylation.	('enhanced', 'PosReg', (26, 34))	('ATM', 'Gene', (109, 112))	('Chk1', 'Gene', '1111', (113, 117))	('NS1-BP', 'Var', (0, 6))	('ATM', 'Gene', '472', (109, 112))	('abrogated', 'NegReg', (61, 70))	('G2/M cell-cycle arrest', 'CPA', (82, 104))	('IR-induced apoptosis', 'CPA', (35, 55))	('Chk1', 'Gene', (113, 117))
122043	29871674	Immunoprecipitation assays indicated that NS1-BP could interact with c-Myc promoter regions to inhibit its transcription.	('interact', 'Interaction', (55, 63))	('c-Myc', 'Gene', (69, 74))	('inhibit', 'NegReg', (95, 102))	('transcription', 'MPA', (107, 120))	('NS1-BP', 'Var', (42, 48))	('c-Myc', 'Gene', '4609', (69, 74))
122060	29871674	reported that NS1-BP inhibited the proliferation of HeLa cells by suppressing c-Myc at the transcriptional level.	('c-Myc', 'Gene', (78, 83))	('proliferation', 'CPA', (35, 48))	('suppressing', 'NegReg', (66, 77))	('c-Myc', 'Gene', '4609', (78, 83))	('inhibited', 'NegReg', (21, 30))	('NS1-BP', 'Var', (14, 20))	('HeLa', 'CellLine', 'CVCL:0030', (52, 56))
122061	29871674	Moreover, ectopic overexpression of NS1-BP increased the repression of basal c-Myc transcription, and disrupted steady state levels of endogenous c-Myc mRNA and protein.	('c-Myc', 'Gene', '4609', (146, 151))	('NS1-BP', 'Var', (36, 42))	('disrupted', 'NegReg', (102, 111))	('c-Myc', 'Gene', (146, 151))	('c-Myc', 'Gene', '4609', (77, 82))	('repression', 'MPA', (57, 67))	('increased', 'PosReg', (43, 52))	('BP increased', 'Phenotype', 'HP:0032263', (40, 52))	('c-Myc', 'Gene', (77, 82))
122064	29871674	Aberrant c-Myc expression is widely implicated in tumorigenesis, sustained tumor growth and drug resistance in many tumor types.	('Aberrant', 'Var', (0, 8))	('c-Myc', 'Gene', '4609', (9, 14))	('tumor', 'Disease', (75, 80))	('implicated', 'Reg', (36, 46))	('c-Myc', 'Gene', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (50, 55))	('drug resistance', 'CPA', (92, 107))	('drug resistance', 'Phenotype', 'HP:0020174', (92, 107))
122066	29871674	Therefore, NS1-BP may affect tumorigenesis and determine cellular chemo- and radio-sensitivity via regulation of c-Myc.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('regulation', 'MPA', (99, 109))	('NS1-BP', 'Var', (11, 17))	('affect', 'Reg', (22, 28))	('tumor', 'Disease', (29, 34))	('c-Myc', 'Gene', '4609', (113, 118))	('c-Myc', 'Gene', (113, 118))	('determine', 'Reg', (47, 56))
122091	29871674	Antibodies against the following proteins were used for immunoblotting assays: NS1-BP, survivin and P27 (Abcam, Cambridge, MA, USA), c-Myc, cleaved-caspase3, cleaved-poly(ADP-ribose) polymerase (PARP), cyclin-dependent kinase (CDK) 4, phospho-ATM (Ser1981), phospho-Chk1 (Ser345) and phospho-Chk2 (Thr68) (Cell Signalling Technology, Danvers, MA, USA), and GAPDH (Santa Cruz Biotechnology, Santa Cruz, CA, USA).	('Chk1', 'Gene', '1111', (266, 270))	('GAPDH', 'Gene', (357, 362))	('PARP', 'Gene', (195, 199))	('ATM', 'Gene', (243, 246))	('P27', 'Gene', (100, 103))	('cyclin-dependent kinase (CDK) 4', 'Gene', '1019', (202, 233))	('c-Myc', 'Gene', '4609', (133, 138))	('Chk2', 'Gene', '11200', (292, 296))	('ATM', 'Gene', '472', (243, 246))	('PARP', 'Gene', '142', (195, 199))	('P27', 'Gene', '3429', (100, 103))	('c-Myc', 'Gene', (133, 138))	('Chk2', 'Gene', (292, 296))	('cleaved-poly(ADP-ribose) polymerase', 'Gene', '142', (158, 193))	('Ser1981', 'Var', (248, 255))	('GAPDH', 'Gene', '2597', (357, 362))	('Chk1', 'Gene', (266, 270))
122104	29871674	NS1-BP is one of the alpha-enolase/MBP-1 partners, and binds to the P2 promoter of c-Myc specifically.	('c-Myc', 'Gene', (83, 88))	('binds', 'Interaction', (55, 60))	('MBP-1', 'Gene', '2023', (35, 40))	('NS1-BP', 'Var', (0, 6))	('alpha-enolase', 'Gene', '2023', (21, 34))	('alpha-enolase', 'Gene', (21, 34))	('MBP-1', 'Gene', (35, 40))	('c-Myc', 'Gene', '4609', (83, 88))
122123	29871674	TE-1 and KYSE-30 cells with stable NS1-BP transfection had moderate NS1-BP expression levels (Fig.	('SE', 'Disease', 'None', (11, 13))	('NS1-BP expression levels', 'MPA', (68, 92))	('TE-1', 'Gene', (0, 4))	('NS1-BP transfection', 'Var', (35, 54))	('TE-1', 'Gene', '57816', (0, 4))
122125	29871674	Flow cytometry indicated that NS1-BP significantly promoted apoptosis of TE-1 and KYSE-30 cells (P < 0.05, Fig.	('TE-1', 'Gene', (73, 77))	('SE', 'Disease', 'None', (84, 86))	('NS1-BP', 'Var', (30, 36))	('apoptosis', 'CPA', (60, 69))	('promoted', 'PosReg', (51, 59))	('TE-1', 'Gene', '57816', (73, 77))
122128	29871674	Overexpression of NS1-BP inhibited c-Myc expression in both TE-1 and KYSE-30 cells (Fig.	('c-Myc', 'Gene', '4609', (35, 40))	('SE', 'Disease', 'None', (71, 73))	('c-Myc', 'Gene', (35, 40))	('TE-1', 'Gene', '57816', (60, 64))	('TE-1', 'Gene', (60, 64))	('inhibited', 'NegReg', (25, 34))	('NS1-BP', 'Var', (18, 24))
122129	29871674	In particular, survivin, a regulator of the mitotic spindle checkpoint, and CDK4 levels were decreased, whereas the inhibitory protein of cell cycle progression p27 increased in NS1-BP-overexpressing ESCC cells (Fig.	('CDK4', 'Gene', '1019', (76, 80))	('CDK4', 'Gene', (76, 80))	('p27', 'Gene', '3429', (161, 164))	('p27', 'Gene', (161, 164))	('survivin', 'MPA', (15, 23))	('decreased', 'NegReg', (93, 102))	('NS1-BP-overexpressing', 'Var', (178, 199))	('increased', 'PosReg', (165, 174))
122132	29871674	Overexpression of NS1-BP significantly inhibited IR-induced ATM/Chk1 phosphorylation, but did not affect Chk2 phosphorylation (Fig.	('Chk1', 'Gene', (64, 68))	('inhibited', 'NegReg', (39, 48))	('Chk2', 'Gene', '11200', (105, 109))	('ATM', 'Gene', (60, 63))	('Chk1', 'Gene', '1111', (64, 68))	('Chk2', 'Gene', (105, 109))	('ATM', 'Gene', '472', (60, 63))	('IR-induced', 'MPA', (49, 59))	('NS1-BP', 'Var', (18, 24))
122133	29871674	To further evaluate the mechanism whereby NS1-BP suppresses c-Myc expression, we tested the effect of NS1-BP overexpression using a reporter plasmid containing the c-Myc promoter upstream of the firefly luciferase gene.	('c-Myc', 'Gene', (164, 169))	('tested', 'Reg', (81, 87))	('NS1-BP', 'Var', (42, 48))	('c-Myc', 'Gene', '4609', (60, 65))	('c-Myc', 'Gene', '4609', (164, 169))	('suppresses', 'NegReg', (49, 59))	('c-Myc', 'Gene', (60, 65))
122134	29871674	ChIP assays indicated that NS1-BP binds to the promoter regions of c-Myc in both NS1-BP-overexpressing cells and the control cells (Fig.	('c-Myc', 'Gene', (67, 72))	('c-Myc', 'Gene', '4609', (67, 72))	('NS1-BP-overexpressing', 'Var', (81, 102))
122137	29871674	Consistent with the in vitro results, NS1-BP inhibited growth of TE-1 xenografts (Fig.	('NS1-BP', 'Var', (38, 44))	('inhibited', 'NegReg', (45, 54))	('TE-1', 'Gene', '57816', (65, 69))	('TE-1', 'Gene', (65, 69))
122138	29871674	NS1-BP also significantly delayed tumor xenograft growth treated with IR (Fig.	('tumor', 'Disease', (34, 39))	('NS1-BP', 'Var', (0, 6))	('delayed', 'NegReg', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
122139	29871674	Immunohistochemistry showed lower c-Myc expression in NS1-BP-overexpressing cells than the TE-1 vector control cells (Fig.	('NS1-BP-overexpressing', 'Var', (54, 75))	('c-Myc', 'Gene', (34, 39))	('lower', 'NegReg', (28, 33))	('TE-1', 'Gene', '57816', (91, 95))	('c-Myc', 'Gene', '4609', (34, 39))	('TE-1', 'Gene', (91, 95))
122142	29871674	NS1-BP reportedly inhibits pre-mRNA splicing, and regulates influenza A viral gene expression and replication.	('pre-mRNA splicing', 'MPA', (27, 44))	('influenza', 'Species', '11320', (60, 69))	('replication', 'MPA', (98, 109))	('inhibits', 'NegReg', (18, 26))	('influenza A viral gene', 'Gene', (60, 82))	('NS1-BP', 'Var', (0, 6))	('expression', 'MPA', (83, 93))	('regulates', 'Reg', (50, 59))
122154	29871674	NS1-BP also enhanced the sensitivity of ESCC cells to cisplatin (data not shown).	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('NS1-BP', 'Var', (0, 6))	('enhanced', 'PosReg', (12, 20))	('sensitivity', 'MPA', (25, 36))
122156	29871674	Perconti and colleagues reported that NS1-BP could inhibit the proliferation of HeLa cells and suppress c-Myc at the transcriptional level.	('HeLa', 'CellLine', 'CVCL:0030', (80, 84))	('c-Myc', 'Gene', '4609', (104, 109))	('suppress', 'NegReg', (95, 103))	('c-Myc', 'Gene', (104, 109))	('NS1-BP', 'Var', (38, 44))	('inhibit', 'NegReg', (51, 58))	('proliferation of HeLa cells', 'CPA', (63, 90))
122157	29871674	Consistently, we found that ectopic overexpression of NS1-BP significantly decreased c-Myc protein levels, likely via direct interaction between NS1-BP and c-Myc promoter sequence.	('c-Myc', 'Gene', (85, 90))	('NS1-BP', 'Var', (54, 60))	('c-Myc', 'Gene', '4609', (156, 161))	('c-Myc', 'Gene', '4609', (85, 90))	('c-Myc', 'Gene', (156, 161))	('decreased', 'NegReg', (75, 84))
122158	29871674	In our clinical ESCC tissues, we also found that c-Myc expression was inversely correlated with NS1-BP levels, and that high c-Myc expression predicted a poor DSS for ESCC patients.	('c-Myc', 'Gene', '4609', (49, 54))	('c-Myc', 'Gene', '4609', (125, 130))	('c-Myc', 'Gene', (49, 54))	('high', 'Var', (120, 124))	('c-Myc', 'Gene', (125, 130))	('ESCC', 'Disease', (167, 171))	('NS1-BP levels', 'MPA', (96, 109))	('patients', 'Species', '9606', (172, 180))	('DSS', 'Gene', (159, 162))	('DSS', 'Gene', '5376', (159, 162))
122161	29871674	As expected, we detected decreased levels of CDK4 and survivin, which are downstream factors of c-Myc that regulate cell cycle and cellular proliferation, following NS1-BP overexpression.	('c-Myc', 'Gene', '4609', (96, 101))	('cellular proliferation', 'CPA', (131, 153))	('c-Myc', 'Gene', (96, 101))	('decreased', 'NegReg', (25, 34))	('survivin', 'Protein', (54, 62))	('NS1-BP', 'Var', (165, 171))	('CDK4', 'Gene', (45, 49))	('CDK4', 'Gene', '1019', (45, 49))	('cell cycle', 'CPA', (116, 126))
122162	29871674	Similarly, a major cell cycle inhibitory protein, p27, was increased following c-Myc depletion.	('c-Myc', 'Gene', (79, 84))	('p27', 'Gene', (50, 53))	('depletion', 'Var', (85, 94))	('c-Myc', 'Gene', '4609', (79, 84))	('p27', 'Gene', '3429', (50, 53))	('increased', 'PosReg', (59, 68))
122167	29871674	The G1 checkpoint is defective in most cancer cells because of mutations/alterations of its key regulators, whereas activation of the G2 checkpoint is rarely impaired in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutations/alterations', 'Var', (63, 84))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('defective', 'NegReg', (21, 30))
122168	29871674	Therefore, abrogation of the G2 checkpoint often sensitizes cancer cells to IR.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('abrogation', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('sensitizes', 'Reg', (49, 59))
122169	29871674	Our findings showed that NS1-BP could decrease IR-induced G2/M cell-cycle arrest by suppressing the c-Myc/ATM-/Chk1 pathway and sensitizing ESCC cells to IR.	('G2/M cell-cycle arrest', 'CPA', (58, 80))	('Chk1', 'Gene', '1111', (111, 115))	('sensitizing', 'Reg', (128, 139))	('suppressing', 'NegReg', (84, 95))	('c-Myc', 'Gene', (100, 105))	('ESCC', 'Disease', (140, 144))	('decrease', 'NegReg', (38, 46))	('ATM', 'Gene', (106, 109))	('NS1-BP', 'Var', (25, 31))	('Chk1', 'Gene', (111, 115))	('c-Myc', 'Gene', '4609', (100, 105))	('ATM', 'Gene', '472', (106, 109))
122259	28620599	Dysphagia should be evoked in patients with EA who present with food aversion, food impaction, difficulty in swallowing, odynophagia, choking, cough, pneumonia, alteration in eating habits, vomiting, and malnutrition.	('cough', 'Disease', (143, 148))	('vomiting', 'Disease', 'MESH:D014839', (190, 198))	('malnutrition', 'Phenotype', 'HP:0004395', (204, 216))	('food aversion', 'Disease', (64, 77))	('vomiting', 'Phenotype', 'HP:0002013', (190, 198))	('malnutrition', 'Disease', (204, 216))	('odynophagia', 'Phenotype', 'HP:0032043', (121, 132))	('vomiting', 'Disease', (190, 198))	('cough', 'Phenotype', 'HP:0012735', (143, 148))	('patients', 'Species', '9606', (30, 38))	('rat', 'Species', '10116', (165, 168))	('EA', 'Phenotype', 'HP:0002032', (44, 46))	('choking', 'Disease', (134, 141))	('malnutrition', 'Disease', 'MESH:D044342', (204, 216))	('food impaction', 'Phenotype', 'HP:0031984', (79, 93))	('pneumonia', 'Phenotype', 'HP:0002090', (150, 159))	('odynophagia', 'Disease', 'None', (121, 132))	('alteration', 'Var', (161, 171))	('pneumonia', 'Disease', 'MESH:D011014', (150, 159))	('food impaction', 'Disease', (79, 93))	('Dysphagia', 'Disease', (0, 9))	('difficulty', 'Disease', (95, 105))	('odynophagia', 'Disease', (121, 132))	('difficulty in swallowing', 'Phenotype', 'HP:0200136', (95, 119))	('Dysphagia', 'Phenotype', 'HP:0002015', (0, 9))	('cough', 'Disease', 'MESH:D003371', (143, 148))	('pneumonia', 'Disease', (150, 159))	('Dysphagia', 'Disease', 'MESH:D003680', (0, 9))
122283	28620599	Analysis of esophageal innervation in dead EA newborn has reported abnormalities in the Auerbach plexus (plexus hypoplasia and abnormal interganglionic network).	('plexus hypoplasia', 'Disease', 'MESH:D020288', (105, 122))	('abnormalities', 'Var', (67, 80))	('plexus hypoplasia', 'Disease', (105, 122))	('EA', 'Phenotype', 'HP:0002032', (43, 45))	('Auerbach plexus', 'CPA', (88, 103))
122289	28620599	Therefore, the operative dissection may also likely worsen the dysmotility.	('dysmotility', 'Disease', 'MESH:D015154', (63, 74))	('operative dissection', 'Var', (15, 35))	('dysmotility', 'Disease', (63, 74))	('rat', 'Species', '10116', (18, 21))
122313	28344746	CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract.	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('tumors of the gastrointestinal tract', 'Disease', 'MESH:D004067', (254, 290))	('alterations', 'Var', (159, 170))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('adenocarcinomas', 'Disease', 'MESH:D000230', (35, 50))	('tumors of the gastrointestinal tract', 'Disease', (254, 290))	('adenocarcinomas', 'Disease', (35, 50))	('cancer', 'Disease', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('tumors of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (254, 290))	('transcription', 'MPA', (204, 217))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
122316	28344746	We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('epigenetic silencing', 'Var', (197, 217))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('CIMP', 'Chemical', '-', (93, 97))
122317	28344746	Besides known events in CIMP such as BRAF V600E mutation, CDKN2A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1.	('MLH1', 'Gene', '4292', (78, 82))	('MLH1', 'Gene', (78, 82))	('Wnt pathway', 'Pathway', (154, 165))	('BRAF', 'Gene', '673', (37, 41))	('RNF43', 'Gene', '54894', (211, 216))	('BRAF', 'Gene', (37, 41))	('RNF43', 'Gene', (211, 216))	('WIF1', 'Gene', (245, 249))	('epigenetic silencing', 'Var', (221, 241))	('V600E', 'Mutation', 'rs113488022', (42, 47))	('CDKN2A', 'Gene', (58, 64))	('CIMP', 'Chemical', '-', (24, 28))	('silencing', 'NegReg', (65, 74))	('deregulation', 'NegReg', (166, 178))	('truncating mutations', 'Var', (187, 207))	('WIF1', 'Gene', '11197', (245, 249))	('CDKN2A', 'Gene', '1029', (58, 64))
122321	28344746	We include new data implicating truncating mutations in RNF43 and silencing of WIF1I.	('WIF1', 'Gene', (79, 83))	('WIF1', 'Gene', '11197', (79, 83))	('silencing', 'NegReg', (66, 75))	('RNF43', 'Gene', (56, 61))	('truncating mutations', 'Var', (32, 52))	('RNF43', 'Gene', '54894', (56, 61))
122327	28344746	Hypermethylation of CpG dinucleotides within these regions results in the establishment or reinforcement of repressive chromatin and the steric occlusion of transcription factor binding, reducing gene expression.	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (20, 37))	('Hypermethylation', 'Var', (0, 16))	('gene expression', 'MPA', (196, 211))	('reducing', 'NegReg', (187, 195))	('binding', 'Interaction', (178, 185))
122329	28344746	For example, the heterozygous silencing of BRCA1 via DNA methylation plays a critical role in breast cancer oncogenesis and tumor proliferation.	('BRCA1', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('heterozygous silencing', 'Var', (17, 39))	('tumor', 'Disease', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA1', 'Gene', '672', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('oncogenesis', 'CPA', (108, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
122330	28344746	Other well-known examples of silencing involve MLH1 in CRCs and MGMT silencing in gliomas.	('MLH1', 'Gene', '4292', (47, 51))	('CRC', 'Phenotype', 'HP:0003003', (55, 58))	('silencing', 'Var', (29, 38))	('MLH1', 'Gene', (47, 51))	('CRCs', 'Disease', (55, 59))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('MGMT', 'Gene', (64, 68))	('gliomas', 'Disease', (82, 89))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('MGMT', 'Gene', '4255', (64, 68))
122331	28344746	In the case of MLH1, methylation-derived silencing inhibits DNA repair, which leads to microsatellite instability (MSI) and cascades into many other downstream functional consequences.	('microsatellite instability', 'MPA', (87, 113))	('DNA repair', 'MPA', (60, 70))	('leads to', 'Reg', (78, 86))	('silencing', 'Var', (41, 50))	('inhibits', 'NegReg', (51, 59))	('MLH1', 'Gene', '4292', (15, 19))	('cascades', 'Reg', (124, 132))	('methylation-derived', 'Var', (21, 40))	('MLH1', 'Gene', (15, 19))
122332	28344746	Researchers have identified reproducible, tissue-specific patterns of CpG island promoter hypermethylation in various types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('CpG island', 'Gene', (70, 80))	('hypermethylation', 'Var', (90, 106))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))
122334	28344746	To cite two examples, hypermethylation of the GSTP1 promoter in more than 90% of prostate adenocarcinomas has been used to improve diagnosis of this disease, whereas hypermethylation of SET pseudogene 9 allows researchers to differentiate among different stages of CRC.	('prostate adenocarcinomas', 'Disease', (81, 105))	('GSTP1', 'Gene', '2950', (46, 51))	('improve', 'PosReg', (123, 130))	('CRC', 'Phenotype', 'HP:0003003', (265, 268))	('hypermethylation', 'Var', (22, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('SET pseudogene 9', 'Gene', (186, 202))	('prostate adenocarcinomas', 'Disease', 'MESH:D011471', (81, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('GSTP1', 'Gene', (46, 51))	('SET pseudogene 9', 'Gene', '100129738', (186, 202))
122341	28344746	However, testing this hypothesis requires us to use consistent methods to assess DNA methylation across tumor types and to analyze large numbers of samples to provide statistical power.	('methylation', 'Var', (85, 96))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
122354	28344746	This signature represented an intermediate ranking between the fully methylated and unmethylated states, where the CIMP intermediate group corresponded to the serous subtype with TP53 mutations.	('mutations', 'Var', (184, 193))	('CIMP', 'Chemical', '-', (115, 119))	('TP53', 'Gene', '7157', (179, 183))	('TP53', 'Gene', (179, 183))
122358	28344746	The absence of a highly dichotomous methylation pattern suggests that a complex interplay of factors determines CIMP status, including tumor heterogeneity and clonality, multiple somatic/germline mutations, copy number variation, and mutation heterozygosity.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('CIMP', 'Chemical', '-', (112, 116))	('copy number variation', 'Var', (207, 228))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
122365	28344746	Colon and rectal tumor samples in the former class largely possess CIMP-low phenotypes and have almost indistinguishable molecular signatures in terms of copy number variation, mRNAs, and miRNAs.	('tumor', 'Disease', (17, 22))	('CIMP-', 'Chemical', '-', (67, 72))	('copy number variation', 'Var', (154, 175))	('rectal tumor', 'Phenotype', 'HP:0100743', (10, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
122367	28344746	Roughly three-quarters exhibit CIMP-high status, as well as ML H1 silencing and MSI, whereas the other quarter are characterized by mutations in other mismatch repair genes such as MLH3 and mutations in POLE.	('POLE', 'Gene', (203, 207))	('MLH3', 'Gene', '27030', (181, 185))	('mutations', 'Var', (190, 199))	('mutations', 'Var', (132, 141))	('MLH3', 'Gene', (181, 185))	('silencing', 'NegReg', (66, 75))	('MSI', 'Disease', (80, 83))	('CIMP-', 'Chemical', '-', (31, 36))
122371	28344746	This can be extrapolated to a pan-cancer dichotomization of tumors into a "mutator" class, characterized by a large number of somatic mutations, closer to CIMP+, and a "copy number" class, characterized by an abundance of copy-number alterations but lacking excessive mutations, closer to CIMP-.	('CIMP-', 'Chemical', '-', (289, 294))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('CIMP+', 'Chemical', '-', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (134, 143))	('copy-number alterations', 'Var', (222, 245))
122373	28344746	Even if it is conceptually helpful, the simple high-level dichotomy assessed by mutations or copy number alterations fails to adequately represent all of the mechanisms of diversity in gastric tumors.	('gastric tumors', 'Disease', 'MESH:D013274', (185, 199))	('gastric tumors', 'Disease', (185, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('gastric tumors', 'Phenotype', 'HP:0006753', (185, 199))	('copy number alterations', 'Var', (93, 116))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))
122378	28344746	For example, in patients infected with Helicobacter pylori, CIMP+ tumors exhibit higher rates of recurrence and metastasis than CIMP- tumors.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (134, 140))	('recurrence', 'CPA', (97, 107))	('CIMP+', 'Var', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('CIMP-', 'Chemical', '-', (128, 133))	('patients', 'Species', '9606', (16, 24))	('metastasis', 'CPA', (112, 122))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('CIMP+', 'Chemical', '-', (60, 65))	('Helicobacter pylori', 'Species', '210', (39, 58))
122381	28344746	In particular, subsets of tumors exhibiting high levels of methylation have been reported in both esophageal adenocarcinoma and Barrett's esophagus, a precursor lesion to esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (98, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('esophageal adenocarcinoma', 'Disease', (98, 123))	('esophageal adenocarcinoma', 'Disease', (171, 196))	('methylation', 'Var', (59, 70))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (171, 196))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (171, 196))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (98, 123))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (128, 147))	("Barrett's esophagus", 'Disease', (128, 147))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (128, 147))	('tumors', 'Disease', (26, 32))
122384	28344746	By contrast, MLH1 promoter methylation has been reported in esophageal squamous cell carcinomas, but not adenocarcinomas, confirming differences in methylation profiles between esophageal subtypes.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (71, 95))	('MLH1', 'Gene', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('MLH1', 'Gene', '4292', (13, 17))	('reported', 'Reg', (48, 56))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (60, 95))	('methylation', 'Var', (27, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('adenocarcinomas', 'Disease', 'MESH:D000230', (105, 120))	('esophageal squamous cell carcinomas', 'Disease', (60, 95))	('adenocarcinomas', 'Disease', (105, 120))
122402	28344746	This novel finding implies commonalities in the underlying generation of aberrant methylation across cancer types.	('aberrant', 'Var', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
122406	28344746	In this previous work, we investigated a cohort of 3299 samples that spanned 9 different cancer types and found that MLH1 promoter silencing was the single genomic functional event that displayed the strongest statistical association with CIMP.	('CIMP', 'Disease', (239, 243))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('CIMP', 'Chemical', '-', (239, 243))	('cancer', 'Disease', (89, 95))	('MLH1', 'Gene', (117, 121))	('promoter', 'Var', (122, 130))	('MLH1', 'Gene', '4292', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
122408	28344746	Indeed, MLH1 promoter silencing replicates the phenotype of MLH1 loss-of-function mutations in hereditary nonpolyposis colon cancer, which displays dinucleotide repeat instability.	('MLH1', 'Gene', (8, 12))	('MLH1', 'Gene', '4292', (60, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('MLH1', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('hereditary nonpolyposis colon cancer', 'Phenotype', 'HP:0006716', (95, 131))	('hereditary nonpolyposis colon cancer', 'Disease', 'MESH:D003123', (95, 131))	('loss-of-function', 'NegReg', (65, 81))	('silencing', 'NegReg', (22, 31))	('dinucleotide', 'Chemical', 'MESH:D015226', (148, 160))	('mutations', 'Var', (82, 91))	('hereditary nonpolyposis colon cancer', 'Disease', (95, 131))	('MLH1', 'Gene', '4292', (8, 12))
122409	28344746	Moreover, research in cell lines demonstrates that reversing MLH1 promoter hypermethylation increases transcription of the gene and restores mismatch repair capacity.	('restores', 'PosReg', (132, 140))	('transcription', 'MPA', (102, 115))	('MLH1', 'Gene', '4292', (61, 65))	('MLH1', 'Gene', (61, 65))	('increases', 'PosReg', (92, 101))	('hypermethylation', 'Var', (75, 91))	('mismatch repair capacity', 'MPA', (141, 165))
122410	28344746	It is therefore tempting to hypothesize that MLH1 promoter hypermethylation, which is strongly associated with CIMP and displays the functional hallmarks of a loss-of-function mutation, is a causal event in the onset of CIMP.	('CIMP', 'Chemical', '-', (111, 115))	('CIMP', 'Disease', (220, 224))	('MLH1', 'Gene', '4292', (45, 49))	('MLH1', 'Gene', (45, 49))	('loss-of-function', 'NegReg', (159, 175))	('CIMP', 'Disease', (111, 115))	('CIMP', 'Chemical', '-', (220, 224))	('mutation', 'Var', (176, 184))	('associated', 'Reg', (95, 105))
122411	28344746	However, previous studies, including our own, have shown that CIMP can be observed in the absence of MLH1 promoter hypermethylation or mutation, implying either a relationship that is correlational but not causal, or multiple mechanisms underlying CIMP development.	('CIMP', 'Disease', (62, 66))	('absence', 'NegReg', (90, 97))	('mutation', 'Var', (135, 143))	('MLH1', 'Gene', '4292', (101, 105))	('CIMP', 'Chemical', '-', (248, 252))	('CIMP', 'Chemical', '-', (62, 66))	('MLH1', 'Gene', (101, 105))
122413	28344746	In CRC, Fang et al have shown that the common BRAF V600E mutation leads to elevated levels of the protein MAFG.	('BRAF', 'Gene', (46, 50))	('MAFG', 'Gene', (106, 110))	('BRAF', 'Gene', '673', (46, 50))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('V600E', 'Var', (51, 56))	('elevated', 'PosReg', (75, 83))	('MAFG', 'Gene', '4097', (106, 110))	('V600E', 'Mutation', 'rs113488022', (51, 56))
122416	28344746	For instance, CDKN2A promoter hypermethylation is also linked to BRAF mutations, through increased expression of the DNA methyltransferase DMNT3B.	('expression', 'MPA', (99, 109))	('mutations', 'Var', (70, 79))	('CDKN2A', 'Gene', '1029', (14, 20))	('linked', 'Reg', (55, 61))	('BRAF', 'Gene', '673', (65, 69))	('increased', 'PosReg', (89, 98))	('BRAF', 'Gene', (65, 69))	('hypermethylation', 'Var', (30, 46))	('CDKN2A', 'Gene', (14, 20))
122421	28344746	A set of 24 probe sites were differentially methylated between the CIMP+ and CIMP- groups in COAD tumors, and an extended region of 38 probe sites were differentially methylated in STAD tumors (after Bonferroni correction for 41 positions).	('CIMP+', 'Var', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('STAD tumors', 'Disease', 'MESH:D009369', (181, 192))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('STAD tumors', 'Disease', (181, 192))	('COAD tumors', 'Disease', (93, 104))	('CIMP-', 'Chemical', '-', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('COAD tumors', 'Disease', 'MESH:D029424', (93, 104))	('CIMP+', 'Chemical', '-', (67, 72))	('differentially', 'Reg', (29, 43))
122422	28344746	The strongest association between MLH1 promoter hypermethylation and CIMP occurred in COAD tumors (Figure 2B): One-third (20/60) of CIMP+ samples in COAD exhibited MLH1 promoter hypermethylation, in contrast to less than 3% of CIMP- samples (2/71) (P = 2.1 x 10-6, Fisher's exact test).	('CIMP', 'Chemical', '-', (227, 231))	('COAD tumors', 'Disease', (86, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('COAD tumors', 'Disease', 'MESH:D029424', (86, 97))	('MLH1', 'Gene', '4292', (164, 168))	('MLH1', 'Gene', '4292', (34, 38))	('MLH1', 'Gene', (164, 168))	('CIMP+', 'Chemical', '-', (132, 137))	('MLH1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('promoter', 'MPA', (169, 177))	('CIMP-', 'Chemical', '-', (227, 232))	('CIMP', 'Chemical', '-', (69, 73))	('CIMP+', 'Var', (132, 137))	('CIMP', 'Chemical', '-', (132, 136))
122424	28344746	We also examined the association between mutations that disable MLH1 and the presence of CIMP.	('mutations', 'Var', (41, 50))	('MLH1', 'Gene', (64, 68))	('MLH1', 'Gene', '4292', (64, 68))	('CIMP', 'Disease', (89, 93))	('disable', 'NegReg', (56, 63))	('CIMP', 'Chemical', '-', (89, 93))
122426	28344746	The most detrimental somatic alterations in MLH1 are frameshift mutations, which render large fractions of the protein product nonfunctional.	('MLH1', 'Gene', (44, 48))	('nonfunctional', 'MPA', (127, 140))	('frameshift mutations', 'Var', (53, 73))	('MLH1', 'Gene', '4292', (44, 48))
122429	28344746	These data suggest that loss of function alterations at MLH1 might not be sufficient for the onset of CIMP.	('loss of function', 'NegReg', (24, 40))	('CIMP', 'Chemical', '-', (102, 106))	('MLH1', 'Gene', '4292', (56, 60))	('alterations', 'Var', (41, 52))	('MLH1', 'Gene', (56, 60))
122430	28344746	The evidence pointing to MLH1 inactivation as a corollary to the appearance of CIMP suggests that other tumor suppressor genes could potentially be silenced through promoter hypermethylation and result in comparable functional vulnerabilities as well; moreover, the silencing of these genes could represent actionable clinical targets.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('silenced', 'NegReg', (148, 156))	('inactivation', 'Var', (30, 42))	('tumor', 'Disease', (104, 109))	('MLH1', 'Gene', '4292', (25, 29))	('MLH1', 'Gene', (25, 29))	('functional vulnerabilities', 'MPA', (216, 242))	('promoter hypermethylation', 'Var', (165, 190))	('CIMP', 'Chemical', '-', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
122439	28344746	These data suggest that, in a subset of genes, selective pressure may favor loss-of-function events caused by DNA methylation, facilitating tumor growth.	('DNA methylation', 'Var', (110, 125))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('facilitating', 'PosReg', (127, 139))	('loss-of-function', 'NegReg', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
122442	28344746	Mutations associated with CIMP have been found in CDKN2A, IDH1/2, TET2 and RB1, among other genes.	('CDKN2A', 'Gene', (50, 56))	('TET2', 'Gene', (66, 70))	('CIMP', 'Disease', (26, 30))	('IDH1/2', 'Gene', '3417;3418', (58, 64))	('CDKN2A', 'Gene', '1029', (50, 56))	('associated', 'Reg', (10, 20))	('RB1', 'Gene', (75, 78))	('IDH1/2', 'Gene', (58, 64))	('Mutations', 'Var', (0, 9))	('CIMP', 'Chemical', '-', (26, 30))	('RB1', 'Gene', '5925', (75, 78))	('TET2', 'Gene', '54790', (66, 70))
122443	28344746	In addition, as discussed, mutations in BRAF directly lead to hypermethylation at specific loci, and their effects probably extend to myriad targets across the genome.	('mutations', 'Var', (27, 36))	('BRAF', 'Gene', '673', (40, 44))	('lead to', 'Reg', (54, 61))	('BRAF', 'Gene', (40, 44))	('hypermethylation', 'MPA', (62, 78))
122448	28344746	This mutation causes a frameshift in the last exon of RNF43, a tumor suppressor that encodes a RING-type E3 ubiquitin ligase (p.G659fs*41).	('tumor', 'Disease', (63, 68))	('p.G659fs*41', 'Var', (126, 137))	('p.G659fs*41', 'Mutation', 'p.G659fsX41', (126, 137))	('RNF43', 'Gene', (54, 59))	('RNF43', 'Gene', '54894', (54, 59))	('frameshift', 'Var', (23, 33))	('causes', 'Reg', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
122450	28344746	Two other top-scoring mutations affect APC, a tumor suppressor whose inactivation is associated with the onset of colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('APC', 'Disease', 'MESH:D011125', (39, 42))	('colon cancer', 'Disease', (114, 126))	('APC', 'Disease', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('affect', 'Reg', (32, 38))	('mutations', 'Var', (22, 31))	('colon cancer', 'Phenotype', 'HP:0003003', (114, 126))	('colon cancer', 'Disease', 'MESH:D015179', (114, 126))	('associated', 'Reg', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
122452	28344746	Not surprisingly, we also found a BRAF V600E mutation (A-to-T change at chr7:140,453,136) that was significantly associated with CIMP+ status (Figure 3A).	('CIMP+ status', 'Disease', (129, 141))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('V600E', 'Var', (39, 44))	('BRAF', 'Gene', '673', (34, 38))	('CIMP+', 'Chemical', '-', (129, 134))	('BRAF', 'Gene', (34, 38))	('associated', 'Reg', (113, 123))
122453	28344746	Together with a common KRAS mutation (C-to-T change at chr12:2,539,281; p.G13D), these represent the only two mutations significantly associated with CIMP+ in COAD samples; this is consistent with their already characterized presence in COAD.	('associated', 'Reg', (134, 144))	('mutations', 'Var', (110, 119))	('KRAS', 'Gene', (23, 27))	('CIMP+', 'Disease', (150, 155))	('p.G13D', 'Mutation', 'rs112445441', (72, 78))	('CIMP+', 'Chemical', '-', (150, 155))	('KRAS', 'Gene', '3845', (23, 27))
122457	28344746	These two MLL complexes are involved in H3K27 demethylation and H3K4 methylation, which regulate the transcription of many developmental genes, including the HOX gene family.	('regulate', 'Reg', (88, 96))	('MLL', 'Gene', (10, 13))	('MLL', 'Gene', '4297', (10, 13))	('H3K27', 'Protein', (40, 45))	('transcription', 'MPA', (101, 114))	('H3K4 methylation', 'Var', (64, 80))	('methylation', 'Var', (69, 80))	('demethylation', 'Var', (46, 59))
122458	28344746	The list of genes whose mutation levels were associated with CIMP status was also significantly enriched for genes from the RTK/RAS/PI(3)K signaling pathway (FDR < 4 x 10-8), including ERBB2, ERBB3, ERBB4, KRAS, PIK3CA, NRAS, and PTEN.	('PTEN', 'Gene', '5728', (230, 234))	('ERBB3', 'Gene', '2065', (192, 197))	('NRAS', 'Gene', '4893', (220, 224))	('ERBB4', 'Gene', '2066', (199, 204))	('KRAS', 'Gene', '3845', (206, 210))	('ERBB3', 'Gene', (192, 197))	('PIK3CA', 'Gene', (212, 218))	('ERBB2', 'Gene', '2064', (185, 190))	('associated', 'Reg', (45, 55))	('ERBB4', 'Gene', (199, 204))	('ERBB2', 'Gene', (185, 190))	('CIMP', 'Chemical', '-', (61, 65))	('PIK3CA', 'Gene', '5290', (212, 218))	('NRAS', 'Gene', (220, 224))	('mutation', 'Var', (24, 32))	('KRAS', 'Gene', (206, 210))	('PTEN', 'Gene', (230, 234))
122460	28344746	Finally, we applied binary decision trees to identify combinations of mutated genes that correlate with CIMP+ or CIMP- status (Figure 3C and D).	('CIMP+', 'Chemical', '-', (104, 109))	('CIMP+', 'Disease', (104, 109))	('CIMP-', 'Chemical', '-', (113, 118))	('mutated', 'Var', (70, 77))
122461	28344746	Using the pooled GIAD data set, our tree shows that KMT2D mutations recur in gastroesophageal (i.e., STAD and EAC) samples (Figure 3C).	('mutations', 'Var', (58, 67))	('gastroesophageal', 'Disease', (77, 93))	('GIAD', 'Disease', 'None', (17, 21))	('GIAD', 'Disease', (17, 21))	('EAC', 'Phenotype', 'HP:0011459', (110, 113))	('KMT2D', 'Gene', '8085', (52, 57))	('KMT2D', 'Gene', (52, 57))
122462	28344746	In fact, tumors with mutated KMT2D and wild-type TP53 consist exclusively of CIMP+ samples (n = 21).	('KMT2D', 'Gene', '8085', (29, 34))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('KMT2D', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('CIMP+', 'Chemical', '-', (77, 82))	('tumors', 'Disease', (9, 15))	('mutated', 'Var', (21, 28))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
122463	28344746	We observed a second set of samples (including representatives from all four histologies) that contained SOX7 mutations and lacked KMT2D mutations; all 11 of these tumors were CIMP+.	('KMT2D', 'Gene', (131, 136))	('KMT2D', 'Gene', '8085', (131, 136))	('mutations', 'Var', (110, 119))	('CIMP+', 'Chemical', '-', (176, 181))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('contained', 'Reg', (95, 104))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('SOX7', 'Gene', '83595', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('SOX7', 'Gene', (105, 109))
122464	28344746	Our trees from individual cancers (Figure 3D) show that KRAS and BRAF mutations in COAD, as well as RNF43, PIK3CA, and KRAS mutations in STAD, are associated with CIMP+ status.	('COAD', 'Gene', (83, 87))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', (26, 33))	('CIMP+', 'Chemical', '-', (163, 168))	('PIK3CA', 'Gene', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('STAD', 'Gene', (137, 141))	('KRAS', 'Gene', '3845', (119, 123))	('RNF43', 'Gene', '54894', (100, 105))	('BRAF', 'Gene', (65, 69))	('mutations', 'Var', (70, 79))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('KRAS', 'Gene', '3845', (56, 60))	('KRAS', 'Gene', (119, 123))	('PIK3CA', 'Gene', '5290', (107, 113))	('RNF43', 'Gene', (100, 105))	('mutations', 'Var', (124, 133))	('associated', 'Reg', (147, 157))	('KRAS', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (65, 69))	('CIMP+ status', 'Disease', (163, 175))
122470	28344746	As of today, there are no universally accepted methods to correct for tumor heterogeneity in DNA methylation studies; however, estimates of tumor heterogeneity can be computed from molecular data, such as copy number changes and mRNA expression, and these estimates can be used to discard problematic samples or to eliminate potential biases in downstream analyses.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mRNA expression', 'MPA', (229, 244))	('copy number changes', 'Var', (205, 224))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (140, 145))
122485	28344746	For example, we report recurrence of a frameshift mutation in RNF43 that is significantly associated with CIMP status in stomach and, to a lesser extent, colon tumors.	('colon tumors', 'Disease', 'MESH:D015179', (154, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('stomach', 'Disease', (121, 128))	('colon tumors', 'Disease', (154, 166))	('associated', 'Reg', (90, 100))	('CIMP', 'Chemical', '-', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('frameshift mutation', 'Var', (39, 58))	('colon tumors', 'Phenotype', 'HP:0100273', (154, 166))	('CIMP', 'MPA', (106, 110))	('RNF43', 'Gene', '54894', (62, 67))	('RNF43', 'Gene', (62, 67))
122486	28344746	A recent study linked RNF43 mutations to MSI in colorectal and endometrial tumors, which are Wnt-dependent.	('RNF43', 'Gene', (22, 27))	('endometrial tumors', 'Disease', (63, 81))	('RNF43', 'Gene', '54894', (22, 27))	('endometrial tumors', 'Disease', 'MESH:D016889', (63, 81))	('MSI', 'Disease', (41, 44))	('colorectal', 'Disease', 'MESH:D015179', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('colorectal', 'Disease', (48, 58))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (28, 37))
122487	28344746	The tumor suppressor function of this gene qualifies its mutations to be potential drivers of STAD, although mechanistic links to DNA methylation remain inconclusive.	('tumor', 'Disease', (4, 9))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('STAD', 'Disease', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
122488	28344746	In addition, RNF43 mutations had been identified in endometrioid and mucinous ovarian carcinomas; we have shown the former tumor subtype is largely CIMP+.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('identified', 'Reg', (38, 48))	('tumor', 'Disease', (123, 128))	('CIMP+', 'Chemical', '-', (148, 153))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (78, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('mucinous ovarian carcinomas', 'Phenotype', 'HP:0031494', (69, 96))	('mucinous ovarian carcinomas', 'Disease', 'MESH:D002288', (69, 96))	('mutations', 'Var', (19, 28))	('mucinous ovarian carcinomas', 'Disease', (69, 96))	('RNF43', 'Gene', (13, 18))	('RNF43', 'Gene', '54894', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('endometrioid', 'Disease', (52, 64))
122489	28344746	The RNF43 frameshift mutation that we highlighted in STAD samples in this paper is located within a 7-bp, CG-rich tract, and it may be created by the mismatch repair deficiency responsible for the MSI phenotype.	('RNF43', 'Gene', (4, 9))	('MSI', 'Disease', (197, 200))	('frameshift mutation', 'Var', (10, 29))	('RNF43', 'Gene', '54894', (4, 9))
122492	28344746	Furthermore, our results point to additional events that could target the Wnt signaling pathway, such as epigenetic silencing of WIF1, which is consistently observed across the four GIAD types, or several of the somatic mutations highlighted in Table 6.	('WIF1', 'Gene', (129, 133))	('WIF1', 'Gene', '11197', (129, 133))	('GIAD', 'Disease', (182, 186))	('epigenetic silencing', 'Var', (105, 125))	('Wnt signaling pathway', 'Pathway', (74, 95))	('GIAD', 'Disease', 'None', (182, 186))
122516	27310961	In contrast, TD ligation was reported to induce retroperitoneal fluid retention and lead to intravenous volume loss after surgery.	('fluid retention', 'Phenotype', 'HP:0000969', (64, 79))	('retention', 'Disease', (70, 79))	('intravenous volume loss', 'MPA', (92, 115))	('intravenous volume loss after surgery', 'Phenotype', 'HP:0004846', (92, 129))	('induce', 'PosReg', (41, 47))	('ligation', 'Var', (16, 24))	('retention', 'Disease', 'MESH:D016055', (70, 79))
122517	27310961	In terms of hepatic damage, Guler et al demonstrated that TD ligation had a negative effect on the liver in a canine model of peritonitis, which was induced by the amount of endotoxin to which the liver was exposed.	('peritonitis', 'Phenotype', 'HP:0002586', (126, 137))	('hepatic damage', 'Disease', 'MESH:D056486', (12, 26))	('canine', 'Species', '9615', (110, 116))	('peritonitis', 'Disease', 'MESH:D010534', (126, 137))	('ligation', 'Var', (61, 69))	('peritonitis', 'Disease', (126, 137))	('liver', 'MPA', (99, 104))	('negative', 'NegReg', (76, 84))	('hepatic damage', 'Disease', (12, 26))
122548	27310961	In patients with pT1 or pT2, incidence of TDLN metastasis was 4% and 26% in patients with pT3 or pT4.	('patients', 'Species', '9606', (76, 84))	('pT1', 'Gene', (17, 20))	('pT3', 'Gene', '7694', (90, 93))	('pT2', 'Var', (24, 27))	('TDLN metastasis', 'CPA', (42, 57))	('pT3', 'Gene', (90, 93))	('pT1', 'Gene', '58492', (17, 20))	('patients', 'Species', '9606', (3, 11))
122568	27310961	Furthermore, although more patients received NAC in TD-resected group, the incidence of postoperative complications, including chylothorax, did not increase in the TD-resected group.	('NAC', 'Var', (45, 48))	('chylothorax', 'Disease', (127, 138))	('NAC', 'Chemical', '-', (45, 48))	('chylothorax', 'Phenotype', 'HP:0010310', (127, 138))	('patients', 'Species', '9606', (27, 35))
122576	25883826	As reported by Ladd and Gross, duplication of the alimentary tract is a rare congenital malformation that develops potentially anywhere in the gastrointestinal tract, from the root of the tongue to the anus.	('congenital malformation', 'Disease', 'MESH:D000013', (77, 100))	('gastrointestinal tract', 'Disease', (143, 165))	('duplication', 'Var', (31, 42))	('congenital malformation', 'Disease', (77, 100))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (143, 165))
122587	25883826	Duplications of the alimentary tract are hollow structures that have a muscular coat, usually composed of two layers, and are lined with epithelium similar to that found in the colon or some other portions of the gastrointestinal tract.	('colon', 'Disease', (177, 182))	('Duplications', 'Var', (0, 12))	('colon', 'Disease', 'MESH:D015179', (177, 182))	('gastrointestinal tract', 'Disease', (213, 235))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (213, 235))
122588	25883826	However, due to their morphological and histological variation, even duplications located away from the gastrointestinal tract and those with no muscular layers are now classified as alimentary tract duplication.	('duplications', 'Var', (69, 81))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (104, 126))	('alimentary tract duplication', 'Disease', (183, 211))	('gastrointestinal tract', 'Disease', (104, 126))
122609	22832660	TA caused remarkable decrease in the expression of CYP2E1 in both liver lysates and sub-cellular fraction, while its response on other tested isozymes was marginal.	('decrease', 'NegReg', (21, 29))	('TA', 'Chemical', 'MESH:C009500', (0, 2))	('expression', 'MPA', (37, 47))	('CYP2E1', 'Var', (51, 57))
122611	22832660	These results demonstrate that TA modulates the expression of CYP2E1 which is associated with the bioactivation of carcinogens without causing apparent toxicity.	('TA', 'Chemical', 'MESH:C009500', (31, 33))	('modulates', 'Reg', (34, 43))	('rat', 'Species', '10116', (21, 24))	('toxicity', 'Disease', 'MESH:D064420', (152, 160))	('toxicity', 'Disease', (152, 160))	('CYP2E1', 'Var', (62, 68))
122612	22832660	These data suggest that TA-induced inhibition of CYP2E1 attenuates the bioactivation of carcinogens potentially leading to the chemoprevention of NMBA-induced esophageal tumorigenesis in rats.	('TA', 'Chemical', 'MESH:C009500', (24, 26))	('CYP2E1', 'Var', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('attenuates', 'NegReg', (56, 66))	('tumor', 'Disease', (170, 175))	('bioactivation of carcinogens', 'MPA', (71, 99))	('rats', 'Species', '10116', (187, 191))	('NMBA', 'Chemical', 'MESH:C014707', (146, 150))	('inhibition', 'NegReg', (35, 45))
122621	22832660	Other chemopreventive strategies under testing include cell proliferation inhibitors, inhibitors of metabolic activation of pro-carcinogens, and the inducers of protective mechanisms.	('cell proliferation', 'CPA', (55, 73))	('rat', 'Species', '10116', (24, 27))	('rat', 'Species', '10116', (67, 70))	('inhibitors', 'Var', (86, 96))
122637	22832660	CYP2E1 is a major catalyst in the bioactivation of several carcinogens and its participation in the metabolic activation of nitrosamines is well known.	('nitrosamines', 'Chemical', 'MESH:D009602', (124, 136))	('CYP2E1', 'Var', (0, 6))	('bioactivation', 'MPA', (34, 47))	('metabolic activation of nitrosamines', 'MPA', (100, 136))
122638	22832660	Due to the active role of CYP2E1 in the bioactivation of potentially carcinogenic compounds, it is linked to the development of carcinogen-induced human cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('human', 'Species', '9606', (147, 152))	('CYP2E1', 'Var', (26, 32))	('bioactivation of', 'MPA', (40, 56))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('carcinogenic', 'Disease', 'MESH:D063646', (69, 81))	('carcinogenic', 'Disease', (69, 81))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('linked', 'Reg', (99, 105))
122663	22832660	NSAIDs are expected to reduce chronic inflammation, which is a driving force behind the progression of a number of cancers and other diseases.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('reduce', 'NegReg', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('inflammation', 'Disease', 'MESH:D007249', (38, 50))	('chronic', 'Disease', (30, 37))	('NSAIDs', 'Var', (0, 6))	('inflammation', 'Disease', (38, 50))
122670	22832660	We have chosen a few candidates (CYP2E1, 1A2, 3A4 and 2C9) for screening in this investigation.	('3A4', 'Gene', (46, 49))	('CYP2E1', 'Var', (33, 39))	('3A4', 'Gene', '52978', (46, 49))
122683	22832660	CYP2E1 is a major catalyst in the bioactivation of several carcinogens and participates in the metabolic activation of nitrosamines including NMBA.	('nitrosamines', 'MPA', (119, 131))	('nitrosamines', 'Chemical', 'MESH:D009602', (119, 131))	('NMBA', 'Chemical', 'MESH:C014707', (142, 146))	('metabolic', 'MPA', (95, 104))	('CYP2E1', 'Var', (0, 6))	('bioactivation', 'MPA', (34, 47))
122685	22832660	It is known that CYP2E1 participates in carcinogen activation and promotes lipid peroxidation by the generation of activated oxygen species during turnover in the absence and presence of substrates.	('carcinogen activation', 'CPA', (40, 61))	('rat', 'Species', '10116', (105, 108))	('lipid peroxidation', 'MPA', (75, 93))	('rat', 'Species', '10116', (192, 195))	('oxygen species', 'Chemical', '-', (125, 139))	('promotes', 'PosReg', (66, 74))	('CYP2E1', 'Var', (17, 23))	('activated oxygen species', 'MPA', (115, 139))	('lipid', 'Chemical', 'MESH:D008055', (75, 80))
122686	22832660	Since CYP2E1 is critical in the bioactivation of pre-carcinogens to transform into ultimate carcinogens, the changes in the expression of this isozyme could affect the efficacy of carcinogens in causing cancer.	('changes', 'Var', (109, 116))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('expression', 'MPA', (124, 134))	('affect', 'Reg', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
122689	22832660	As presented in Figure 5A, tolfenamic acid inhibits the expression of CYP isozymes involved in the bioactivation of carcinogens and potentially impeding carcinogenesis.	('carcinogenesis', 'Disease', (153, 167))	('tolfenamic acid', 'Chemical', 'MESH:C009500', (27, 42))	('tolfenamic', 'Var', (27, 37))	('expression', 'MPA', (56, 66))	('CYP isozymes', 'Enzyme', (70, 82))	('carcinogenesis', 'Disease', 'MESH:D063646', (153, 167))	('impeding', 'NegReg', (144, 152))	('inhibits', 'NegReg', (43, 51))
122693	22832660	O6- methylguanine adducts are poorly repaired, become carcinogenic (Figure 5B) and ultimately leading to tumorigenesis.	('carcinogenic', 'Disease', (54, 66))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('O6- methylguanine', 'Chemical', 'MESH:C008449', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('O6- methylguanine adducts', 'Var', (0, 25))	('adducts', 'Var', (18, 25))	('tumor', 'Disease', (105, 110))	('carcinogenic', 'Disease', 'MESH:D063646', (54, 66))	('leading to', 'Reg', (94, 104))
122698	22832660	Studies also reported the association between CYP2E1 genetic polymorphism and the cancer incidence among human population in certain parts of the world.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('genetic polymorphism', 'Var', (53, 73))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CYP2E1', 'Gene', (46, 52))	('human', 'Species', '9606', (105, 110))	('association', 'Interaction', (26, 37))
122699	22832660	A recent meta-analysis involving 11 case controlled studies with 1088 cases and 2238 controls, demonstrated that CYP2E1 polymorphism was linked to the decreased risk of developing EC among Asian populations.	('rat', 'Species', '10116', (102, 105))	('CYP2E1', 'Gene', (113, 119))	('polymorphism', 'Var', (120, 132))	('decreased', 'NegReg', (151, 160))
122739	21935431	Accordingly, augurin would play a constitutive inhibitory function in normal CNS while down regulation of Ecrg4 gene expression in injury, like in cancer, dysinhibits proliferation.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('down regulation', 'NegReg', (87, 102))	('Ecrg4 gene', 'Gene', (106, 116))	('expression', 'MPA', (117, 127))	('dysinhibits', 'Var', (155, 166))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('rat', 'Species', '10116', (174, 177))	('cancer', 'Disease', (147, 153))	('proliferation', 'CPA', (167, 180))
122749	21935431	This hypothesis is supported by our observations that knockdown of Ecrg4 gene expression during zebrafish development induced cell over-proliferation in the developing CNS and generated a ventriculomegaly phenotype.	('knockdown', 'Var', (54, 63))	('rat', 'Species', '10116', (180, 183))	('zebrafish', 'Species', '7955', (96, 105))	('Ecrg4', 'Gene', (67, 72))	('cell over-proliferation in the developing CNS', 'CPA', (126, 171))	('ventriculomegaly', 'Phenotype', 'HP:0002119', (188, 204))	('rat', 'Species', '10116', (143, 146))	('generated', 'Reg', (176, 185))	('ventriculomegaly', 'Disease', 'MESH:D006849', (188, 204))	('ventriculomegaly', 'Disease', (188, 204))	('induced', 'Reg', (118, 125))
122831	20937111	The restoration of ECRG4 expression in ESCC cells inhibited cancer cells migration and invasion (P < 0.05), which did not affect cell adhesion capacity (P > 0.05).	('ECRG4', 'Gene', '84417', (19, 24))	('expression', 'MPA', (25, 35))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('invasion', 'CPA', (87, 95))	('ECRG4', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('inhibited', 'NegReg', (50, 59))	('restoration', 'Var', (4, 15))
122869	20937111	And the cell growth curve of EC9706/pcDNA3.1-ECRG4 and EC9706/pcDNA3.1 was plotted for further migration-invasion analysis (Figure 1C).	('ECRG4', 'Gene', '84417', (45, 50))	('ECRG4', 'Gene', (45, 50))	('EC9706/pcDNA3.1', 'Var', (55, 70))	('EC9706', 'CellLine', 'CVCL:E307', (55, 61))	('EC9706', 'CellLine', 'CVCL:E307', (29, 35))
122878	20937111	The percentages of cells in the G1, S and G2/M phase of cell cycle demonstrated that overexpression of ECRG4 in EC9706 cells resulted in an accumulation of cells in G1 phase and a decrease in S and G2/M phase compared with EC9706/pcDNA3.1 control cells (P < 0.05) (Table 2).	('accumulation', 'PosReg', (140, 152))	('EC9706', 'CellLine', 'CVCL:E307', (223, 229))	('overexpression', 'PosReg', (85, 99))	('ECRG4', 'Gene', (103, 108))	('G1 phase', 'CPA', (165, 173))	('EC9706', 'Var', (112, 118))	('ECRG4', 'Gene', '84417', (103, 108))	('cells', 'CPA', (156, 161))	('EC9706', 'CellLine', 'CVCL:E307', (112, 118))	('decrease', 'NegReg', (180, 188))
122888	20937111	Our previous study demonstrated that ECRG4 gene promoter hypermethylation accounted for decreased expression in ESCC, and the low expression of ECRG4 protein in patients with ESCC was associated with poor prognosis.	('ECRG4', 'Gene', (144, 149))	('ECRG4', 'Gene', '84417', (37, 42))	('ESCC', 'Disease', (112, 116))	('ECRG4', 'Gene', '84417', (144, 149))	('ESCC', 'Disease', (175, 179))	('low', 'NegReg', (126, 129))	('patients', 'Species', '9606', (161, 169))	('decreased', 'NegReg', (88, 97))	('hypermethylation', 'Var', (57, 73))	('ECRG4', 'Gene', (37, 42))	('expression', 'MPA', (98, 108))
122889	20937111	Furthermore, restoration of ECRG4 expression in ESCC cells inhibited tumor cells growth in vitro and in vivo .	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('expression', 'MPA', (34, 44))	('tumor', 'Disease', (69, 74))	('inhibited', 'NegReg', (59, 68))	('ECRG4', 'Gene', (28, 33))	('ECRG4', 'Gene', '84417', (28, 33))	('restoration', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
122910	33188661	MEX3A is upregulated in esophageal squamous cell carcinoma (ESCC) and promotes development and progression of ESCC through targeting CDK6 Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed malignant tumors worldwide and identified as a serious threat to human health.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 58))	('targeting', 'Var', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('promotes', 'PosReg', (70, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('esophageal squamous cell carcinoma', 'Disease', (24, 58))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('malignant tumors', 'Disease', (218, 234))	('CDK6', 'Gene', (133, 137))	('malignant tumors', 'Disease', 'MESH:D009369', (218, 234))	('MEX3A', 'Gene', (0, 5))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (149, 172))	('human', 'Species', '9606', (283, 288))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (24, 58))	('upregulated', 'PosReg', (9, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('squamous cell carcinoma', 'Disease', (149, 172))	('MEX3A', 'Gene', '92312', (0, 5))
122913	33188661	Further studies demonstrated that knockdown of CDK6 showed similar effects on the development of ESCC with MEX3A.	('CDK6', 'Gene', (47, 51))	('CDK6', 'Gene', '1021', (47, 51))	('effects', 'Reg', (67, 74))	('development of ESCC with MEX3A', 'CPA', (82, 112))	('knockdown', 'Var', (34, 43))
122914	33188661	More importantly, it was illustrated that CDK6 knockdown could alleviate the promotion effects of MEX3A overexpression on ESCC.	('ESCC', 'Disease', (122, 126))	('knockdown', 'Var', (47, 56))	('CDK6', 'Gene', (42, 46))	('alleviate', 'NegReg', (63, 72))	('CDK6', 'Gene', '1021', (42, 46))
122925	33188661	Human MEX3 protein may mediate ubiquitination of target protein through ring finger domain, thus regulating its stability and subcellular localization.	('stability', 'MPA', (112, 121))	('mediate', 'Reg', (23, 30))	('regulating', 'Reg', (97, 107))	('subcellular localization', 'MPA', (126, 150))	('Human', 'Species', '9606', (0, 5))	('ring finger domain', 'Var', (72, 90))	('ubiquitination', 'MPA', (31, 45))	('MEX3', 'Gene', (6, 10))
122929	33188661	High expression of MEX3A was found to be correlated with more advanced tumor stage, higher risk of lymphatic metastasis and poor prognosis.	('MEX3A', 'Gene', (19, 24))	('lymphatic metastasis', 'Disease', (99, 119))	('High', 'Var', (0, 4))	('lymphatic metastasis', 'Disease', 'MESH:D008207', (99, 119))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('correlated', 'Reg', (41, 51))
122935	33188661	The statistical analysis of the relationship between MEX3A expression with tumor characteristics showed that high MEX3A expression was associated with advanced tumor stage and higher risk of lymphatic metastasis (P < 0.01, Table 2), which was further verified by Spearman rank correlation analysis (P < 0.01, Supplementary Table 3).	('high', 'Var', (109, 113))	('expression', 'MPA', (120, 130))	('MEX3A', 'Gene', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('lymphatic metastasis', 'Disease', 'MESH:D008207', (191, 211))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', (75, 80))	('lymphatic metastasis', 'Disease', (191, 211))
122939	33188661	We also showed 80.1% and 51.7% knockdown of MEX3A in Eca-109 and TE-1 cells by qPCR (P < 0.01, Supplementary Figure 1B), respectively, which was further confirmed by western blotting (Figure 2A).	('TE-1', 'CellLine', 'CVCL:1759', (65, 69))	('knockdown', 'Var', (31, 40))	('Eca', 'Chemical', '-', (53, 56))	('MEX3A', 'Gene', (44, 49))
122940	33188661	The results of MTT assay showed that, after knockdown of MEX3A, cell proliferation was decreased in Eca-109 and TE-1 cells (P < 0.001, Figure 2B).	('TE-1', 'CellLine', 'CVCL:1759', (112, 116))	('MEX3A', 'Gene', (57, 62))	('cell proliferation', 'CPA', (64, 82))	('decreased', 'NegReg', (87, 96))	('Eca', 'Chemical', '-', (100, 103))	('knockdown', 'Var', (44, 53))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))
122942	33188661	The detection of cell apoptosis by flow cytometry showed apparently increased apoptotic cell percentage in shMEX3A group compared with shCtrl group of Eca-109 and TE-1 cells, respectively, indicating the ability of MEX3A knockdown to induce cell apoptosis (P < 0.001, Supplementary Figure 2A and 2D).	('increased apoptotic cell percentage', 'Phenotype', 'HP:0030887', (68, 103))	('Eca', 'Chemical', '-', (151, 154))	('knockdown', 'Var', (221, 230))	('induce', 'PosReg', (234, 240))	('cell apoptosis', 'CPA', (241, 255))	('apoptotic cell percentage', 'CPA', (78, 103))	('TE-1', 'CellLine', 'CVCL:1759', (163, 167))	('shMEX3A', 'Var', (107, 114))	('increased', 'PosReg', (68, 77))
122944	33188661	The results indicated that MEX3A knockdown caused the upregulation of Caspase3, Caspase8 and IGFBP-6, and downregulation of XIAP (P < 0.05, Figure 2E).	('IGFBP-6', 'Gene', (93, 100))	('XIAP', 'Gene', (124, 128))	('downregulation', 'NegReg', (106, 120))	('knockdown', 'Var', (33, 42))	('Caspase3', 'Gene', '836', (70, 78))	('XIAP', 'Gene', '331', (124, 128))	('upregulation', 'PosReg', (54, 66))	('Caspase3', 'Gene', (70, 78))	('IGFBP-6', 'Gene', '3489', (93, 100))	('MEX3A', 'Gene', (27, 32))	('Caspase8', 'Gene', '841', (80, 88))	('Caspase8', 'Gene', (80, 88))
122945	33188661	As shown in Figure 2F, upon MEX3A knockdown, cell migration rate was significantly decreased in TE-1 cells (P < 0.01).	('cell migration rate', 'CPA', (45, 64))	('TE-1', 'CellLine', 'CVCL:1759', (96, 100))	('decreased', 'NegReg', (83, 92))	('MEX3A', 'Gene', (28, 33))	('knockdown', 'Var', (34, 43))
122948	33188661	Before sacrificing the mice, in vivo imaging of tumors was facilitated by injection of D-Luciferin and showed obviously weaker luminescence intensity, as well as smaller tumor, in shMEX3A group (P < 0.001, Figure 3B).	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (48, 53))	('luminescence intensity', 'MPA', (127, 149))	('weaker', 'NegReg', (120, 126))	('D-Luciferin', 'Var', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('D-Luciferin', 'Chemical', 'MESH:C532924', (87, 98))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', (170, 175))	('facilitated', 'PosReg', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mice', 'Species', '10090', (23, 27))
122951	33188661	All the above results suggested that knockdown of MEX3A could suppress tumor growth of ESCC in vivo.	('suppress', 'NegReg', (62, 70))	('MEX3A', 'Gene', (50, 55))	('knockdown', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ESCC', 'Disease', (87, 91))	('tumor', 'Disease', (71, 76))
122955	33188661	Further combining the the analysis of MEX3A-related interaction network, we supposed that MEX3A knockdown may execute its function in ESCC through downregulating CDK6 (Figure 4D).	('downregulating', 'NegReg', (147, 161))	('knockdown', 'Var', (96, 105))	('ESCC', 'Disease', (134, 138))	('CDK6', 'Gene', (162, 166))	('MEX3A', 'Gene', (90, 95))	('CDK6', 'Gene', '1021', (162, 166))
122963	33188661	More importantly, we found that, with upregulated expression of MEX3A and downregulated expression of CDK6 in MEX3A+shCDK6 group (P < 0.01, Figure 6A and 6B), the effects of MEX3A overexpression on cell proliferation, colony formation, cell apoptosis and cell migration could be significantly alleviated even reversed by CDK6 knockdown (P < 0.05, Supplementary Figure 6 and Figure 6C-6G).	('CDK6', 'Gene', (118, 122))	('MEX3A', 'Gene', (64, 69))	('CDK6', 'Gene', (321, 325))	('cell migration', 'CPA', (255, 269))	('cell apoptosis', 'CPA', (236, 250))	('CDK6', 'Gene', (102, 106))	('CDK6', 'Gene', '1021', (321, 325))	('upregulated', 'PosReg', (38, 49))	('colony formation', 'CPA', (218, 234))	('CDK6', 'Gene', '1021', (102, 106))	('knockdown', 'Var', (326, 335))	('cell proliferation', 'CPA', (198, 216))	('downregulated', 'NegReg', (74, 87))	('expression', 'MPA', (50, 60))	('CDK6', 'Gene', '1021', (118, 122))
122969	33188661	found that knockdown of MEX3A in gastric cancer cells could effectively inhibit the proliferation of cancer cells and colony formation, indicating that MEX3A was involved in cell transformation.	('colony formation', 'CPA', (118, 134))	('gastric cancer', 'Disease', (33, 47))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (33, 47))	('cancer', 'Disease', (101, 107))	('MEX3A', 'Gene', (24, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('inhibit', 'NegReg', (72, 79))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('knockdown', 'Var', (11, 20))
122970	33188661	In addition, wound healing assay and Transwell assays showed that MEX3A knockdown significantly inhibited the migration of gastric cancer cells.	('migration of', 'CPA', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gastric cancer', 'Disease', (123, 137))	('MEX3A', 'Gene', (66, 71))	('inhibited', 'NegReg', (96, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('knockdown', 'Var', (72, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))
122976	33188661	Moreover, MEX3A high expression was positively associated with advanced tumor stage, higher risk of lymphatic metastasis and shorter survival period.	('high expression', 'Var', (16, 31))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('MEX3A', 'Gene', (10, 15))	('lymphatic metastasis', 'Disease', 'MESH:D008207', (100, 120))	('lymphatic metastasis', 'Disease', (100, 120))	('associated', 'Reg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
122978	33188661	More importantly, the ability of MEX3A knockdown to restrain tumor growth in vivo suggested that it may be used as novel therapeutic target in the treatment of ESCC.	('MEX3A', 'Gene', (33, 38))	('ESCC', 'Disease', (160, 164))	('knockdown', 'Var', (39, 48))	('restrain', 'NegReg', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
122984	33188661	reported that the CDK6 inhibitor PD0332991 could significantly inhibit cell proliferation of gastric cancer via the modulation of cell cycle.	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('PD0332991', 'Chemical', 'MESH:C500026', (33, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('PD0332991', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CDK6', 'Gene', (18, 22))	('CDK6', 'Gene', '1021', (18, 22))	('inhibit', 'NegReg', (63, 70))	('cell proliferation', 'CPA', (71, 89))	('cell cycle', 'CPA', (130, 140))	('gastric cancer', 'Disease', (93, 107))
122987	33188661	The results showed that there was abnormal amplification of CDK6 in ESCC samples, and the survival period of ESCC patients with high expression of CDK6 was significantly shorter than that of ESCC patients with low expression of CDK6, indicating that CDK6 played an oncogene role in ESCC.	('CDK6', 'Gene', '1021', (228, 232))	('CDK6', 'Gene', (60, 64))	('CDK6', 'Gene', (250, 254))	('ESCC', 'Disease', (109, 113))	('amplification', 'MPA', (43, 56))	('CDK6', 'Gene', '1021', (60, 64))	('CDK6', 'Gene', '1021', (250, 254))	('CDK6', 'Gene', (147, 151))	('CDK6', 'Gene', '1021', (147, 151))	('patients', 'Species', '9606', (196, 204))	('shorter', 'NegReg', (170, 177))	('patients', 'Species', '9606', (114, 122))	('high expression', 'Var', (128, 143))	('survival period', 'CPA', (90, 105))	('CDK6', 'Gene', (228, 232))
122990	33188661	The following in vitro experiments using CDK6 knockdown ESCC cell lines also proved the inhibition of ESCC development by CDK6 knockdown, represented by suppression of cell proliferation, colony formation, cell migration and promotion of cell apoptosis.	('cell apoptosis', 'CPA', (238, 252))	('suppression', 'NegReg', (153, 164))	('cell proliferation', 'CPA', (168, 186))	('inhibition', 'NegReg', (88, 98))	('cell migration', 'CPA', (206, 220))	('CDK6', 'Gene', (41, 45))	('CDK6', 'Gene', (122, 126))	('ESCC', 'Disease', (102, 106))	('colony formation', 'CPA', (188, 204))	('promotion', 'PosReg', (225, 234))	('CDK6', 'Gene', '1021', (41, 45))	('CDK6', 'Gene', '1021', (122, 126))	('knockdown', 'Var', (127, 136))
122991	33188661	More importantly, we further illustrated that knockdown of CDK6 could alleviate or reverse the promotion effects of MEX3A overexpression on ESCC, indicating its role as the downstream of CDK6 again.	('reverse', 'NegReg', (83, 90))	('knockdown', 'Var', (46, 55))	('ESCC', 'Disease', (140, 144))	('CDK6', 'Gene', (59, 63))	('CDK6', 'Gene', '1021', (59, 63))	('promotion', 'PosReg', (95, 104))	('CDK6', 'Gene', (187, 191))	('CDK6', 'Gene', '1021', (187, 191))
122994	33188661	Moreover, our results provided evidence that MEX3A may execute its effects on ESCC through upregulating CDK6.	('ESCC', 'Disease', (78, 82))	('CDK6', 'Gene', (104, 108))	('CDK6', 'Gene', '1021', (104, 108))	('MEX3A', 'Var', (45, 50))	('upregulating', 'PosReg', (91, 103))
123052	32118097	All procedures were performed using a high-resolution magnifying upper gastrointestinal endoscope (GIF-Q240Z, GIF-H260Z; Olympus Co., Tokyo, Japan) with an electronic endoscopy system (Evis Lucera Spectrum, Olympus Corporation, Tokyo, Japan).	('Q240Z', 'SUBSTITUTION', 'None', (103, 108))	('Q240Z', 'Var', (103, 108))	('gastrointestinal endoscope', 'Disease', 'MESH:D005767', (71, 97))	('H260Z', 'SUBSTITUTION', 'None', (114, 119))	('H260Z', 'Var', (114, 119))	('gastrointestinal endoscope', 'Disease', (71, 97))
123074	31949463	The average content of three ZHG batches (20151218, 20151221 and 20151224) of geniposide and atractylenolide III was 14.2 and 1.5 mg/g in ZHG, respectively.	('20151224', 'Var', (65, 73))	('20151221', 'Var', (52, 60))	('geniposide', 'Chemical', 'MESH:C007835', (78, 88))	('20151218', 'Var', (42, 50))
123091	31732666	HERES, a lncRNA that regulates canonical and noncanonical Wnt signaling pathways via interaction with EZH2 Aberrant lncRNA expression is responsible for cancer progression and metastasis, positioning lncRNAs not only as biomarkers but also as promising therapeutic targets for curing cancer.	('metastasis', 'CPA', (176, 186))	('EZH2', 'Gene', (102, 106))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('responsible', 'Reg', (137, 148))	('cancer', 'Disease', (284, 290))	('Aberrant', 'Var', (107, 115))	('regulates', 'Reg', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('interaction', 'Interaction', (85, 96))
123093	31732666	The most upregulated lncRNA, HERES, promotes cancer progression and epigenetically regulates canonical and noncanonical Wnt signaling pathways simultaneously through interaction with EZH2.	('upregulated', 'PosReg', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('epigenetically', 'Var', (68, 82))	('EZH2', 'Gene', (183, 187))	('lncRNA', 'Protein', (21, 27))	('regulates', 'Reg', (83, 92))	('interaction', 'Interaction', (166, 177))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('promotes', 'PosReg', (36, 44))
123095	31732666	Dysregulation of these pathways often causes cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Dysregulation', 'Var', (0, 13))	('causes', 'Reg', (38, 44))	('progression', 'CPA', (68, 79))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
123096	31732666	Here, we describe a long noncoding RNA (lncRNA), HERES, that epigenetically regulates both canonical and noncanonical Wnt signaling pathways in esophageal squamous cell carcinoma (ESCC).	('epigenetically', 'Var', (61, 75))	('noncanonical Wnt signaling pathways', 'Pathway', (105, 140))	('esophageal squamous cell carcinoma', 'Disease', (144, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('regulates', 'Reg', (76, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (144, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
123107	31732666	In particular, abnormal intracellular levels of the second messenger Ca2+ promote the Wnt signaling pathway, which in turn promotes the development and progression of many types of cancers.	('development', 'CPA', (136, 147))	('promotes', 'PosReg', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('promote', 'PosReg', (74, 81))	('Ca2+', 'Chemical', 'MESH:D000069285', (69, 73))	('abnormal', 'Var', (15, 23))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('Wnt signaling pathway', 'Pathway', (86, 107))	('cancers', 'Disease', (181, 188))	('progression', 'CPA', (152, 163))
123108	31732666	Controlling Wnt signaling may be a useful strategy for curing cancers caused by aberrations in such signaling.	('aberrations', 'Var', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Disease', (62, 69))
123109	31732666	The inhibition of either aberrant canonical or noncanonical Wnt signaling, however, has been shown to decrease progression in only a subset of cancers in a context-dependent manner.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('noncanonical', 'Protein', (47, 59))	('aberrant', 'Var', (25, 33))	('decrease', 'NegReg', (102, 110))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('progression', 'CPA', (111, 122))	('inhibition', 'NegReg', (4, 14))
123110	31732666	Because aberrations in Wnt signaling pathways result from various causes, such as mutations in different Wnt signaling-related genes, ligand overexpression, and dysregulation of regulators, targeting only the canonical Wnt signaling pathway might not be a universal therapeutic approach for cancers.	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('cancers', 'Disease', (291, 298))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('mutations', 'Var', (82, 91))	('Wnt signaling-related genes', 'Gene', (105, 132))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('Wnt signaling pathways', 'Pathway', (23, 45))
123111	31732666	Thus, the simultaneous inhibition of aberrant canonical and noncanonical Wnt signaling pathways could also benefit cancer therapy.	('cancer', 'Disease', (115, 121))	('inhibition', 'NegReg', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('benefit', 'PosReg', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('aberrant', 'Var', (37, 45))
123115	31732666	Moreover, mounting evidence indicates that aberrant lncRNA expression, by modulating cancer-related pathways, can be responsible for cancer progression.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('lncRNA expression', 'Protein', (52, 69))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('responsible', 'Reg', (117, 128))	('modulating', 'Reg', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('aberrant', 'Var', (43, 51))
123118	31732666	Recently, a Chinese group performed high-throughput RNA sequencing (RNA-seq) on tissue from 15 paired ESCC patients and normal individuals and identified lncRNAs dysregulated in ESCCs.	('dysregulated', 'Var', (162, 174))	('ESCC', 'Disease', (102, 106))	('ESCCs', 'Disease', (178, 183))	('lncRNAs', 'Gene', (154, 161))	('patients', 'Species', '9606', (107, 115))
123125	31732666	Six DE lncRNAs were significantly associated with survival rates, 2 (HERES and RP11-1L12.3) of which were associated with a high hazard ratio (HHR; P  0.05) and 4 (RP11-114H23.1, RP11-114H23.2, CTD-2319I12.1, and LINC00330) of which were associated with a low hazard ratio (LHR; P  0.05).	('RP11', 'Gene', '26121', (164, 168))	('associated', 'Reg', (34, 44))	('RP11', 'Gene', '26121', (179, 183))	('CTD-2319I12.1', 'CellLine', 'CVCL:9J62', (194, 207))	('RP11', 'Gene', '26121', (79, 83))	('LINC00330', 'Gene', '144817', (213, 222))	('survival rates', 'MPA', (50, 64))	('LINC00330', 'Gene', (213, 222))	('RP11', 'Gene', (179, 183))	('CTD-2319I12.1', 'Var', (194, 207))	('RP11', 'Gene', (164, 168))	('RP11', 'Gene', (79, 83))
123134	31732666	To investigate whether HERES is involved in cancer development and progression, the effects of HERES knockdown on cell proliferation, migration, invasion, and colony formation were explored with siControl- and siHERES-treated cells.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('HERES', 'Gene', (95, 100))	('siControl', 'Chemical', '-', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('knockdown', 'Var', (101, 110))
123135	31732666	Introduction of an siRNA targeting HERES (siHERES_1 or siHERES_2) to KYSE-30 and HCE-7 cells significantly reduced HERES expression (SI Appendix, Fig.	('siHERES_2', 'Var', (55, 64))	('reduced', 'NegReg', (107, 114))	('HERES expression', 'MPA', (115, 131))	('HCE-7', 'CellLine', 'CVCL:5138', (81, 86))
123136	31732666	values) were significantly reduced in both siHERES_1 and siHERES_2-treated cells compared to siControl-treated cells (Fig.	('reduced', 'NegReg', (27, 34))	('siHERES_2-treated', 'Var', (57, 74))	('siControl', 'Chemical', '-', (93, 102))	('siHERES_1', 'Var', (43, 52))
123137	31732666	Migration and invasion assays showed that both cell migration and invasion were greatly reduced in siHERES-treated cells compared to siControl-treated cells (Fig.	('reduced', 'NegReg', (88, 95))	('siHERES-treated', 'Var', (99, 114))	('cell migration', 'CPA', (47, 61))	('invasion', 'CPA', (66, 74))	('siControl', 'Chemical', '-', (133, 142))	('invasion assays', 'CPA', (14, 29))
123145	31732666	SFRP2 encodes a member of the SFRP family that modulates the Wnt signaling pathway; SFRP2 hypermethylation is known to enhance cell invasiveness in both cancers and noncancerous diseases.	('enhance', 'PosReg', (119, 126))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('hypermethylation', 'Var', (90, 106))	('cancers', 'Disease', (153, 160))	('Wnt signaling pathway', 'Pathway', (61, 82))	('noncancerous diseases', 'Disease', 'MESH:D003141', (165, 186))	('noncancerous diseases', 'Disease', (165, 186))	('cell invasiveness', 'CPA', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('SFRP2', 'Gene', (84, 89))	('modulates', 'Reg', (47, 56))
123147	31732666	S7E) were down-regulated and hypermethylated in the HERES-high group, whereas EPSTI1, SLC15A3, and BST2 were up-regulated and hypomethylated in the HERES-high subgroup.	('BST2', 'Gene', (99, 103))	('HERES-high', 'Disease', (52, 62))	('hypermethylated', 'Var', (29, 44))	('EPSTI1', 'Gene', (78, 84))	('BST2', 'Gene', '684', (99, 103))	('down-regulated', 'NegReg', (10, 24))	('hypomethylated', 'Var', (126, 140))	('SLC15A3', 'Gene', (86, 93))	('up-regulated', 'PosReg', (109, 121))	('SLC15A3', 'Gene', '51296', (86, 93))	('EPSTI1', 'Gene', '94240', (78, 84))
123153	31732666	Taken together, these results suggest that HERES down-regulation in cancers perturbs and promotes canonical and noncanonical Wnt signaling pathways via epigenetic regulation, resulting in the inhibition of cancer progression.	('inhibition', 'NegReg', (192, 202))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers perturbs', 'Disease', 'MESH:D009369', (68, 84))	('promotes', 'PosReg', (89, 97))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cancers perturbs', 'Disease', (68, 84))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('down-regulation', 'NegReg', (49, 64))	('epigenetic regulation', 'Var', (152, 173))
123166	31732666	A series of deletion mutants of human PRC2 revealed that the basic N-terminal helix of EZH2, particularly residues 32-42 in the helix, are the most critical for RNA binding through a G-rich motif.	('deletion', 'Var', (12, 20))	('PRC2', 'Gene', (38, 42))	('binding', 'Interaction', (165, 172))	('EZH2', 'Gene', (87, 91))	('human', 'Species', '9606', (32, 37))	('G-rich motif', 'Protein', (183, 195))	('RNA', 'MPA', (161, 164))
123224	28977953	Association of three promoter polymorphisms in interleukin-10 gene with cancer susceptibility in the Chinese population: a meta-analysis Numerous studies have examined the associations of three promoter polymorphisms (-1082A/G, -819T/C and -592A/C) in IL-10 gene with cancer susceptibility in the Chinese population, but the results remain inconclusive.	('-819T/C', 'Mutation', 'rs1800871', (228, 235))	('associations', 'Interaction', (172, 184))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', (72, 78))	('-592A/C', 'Mutation', 'rs1800872', (240, 247))	('the', 'Chemical', '-', (321, 324))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('interleukin-10', 'Gene', (47, 61))	('IL-10', 'Gene', '3586', (252, 257))	('interleukin-10', 'Gene', '3586', (47, 61))	('IL-10', 'Gene', (252, 257))	('the', 'Chemical', '-', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('the', 'Chemical', '-', (97, 100))	('cancer', 'Disease', (268, 274))	('-1082A/G', 'Mutation', 'rs1800896', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('-1082A/G', 'Var', (218, 226))	('the', 'Chemical', '-', (293, 296))
123227	28977953	Stratification analysis showed that the association was more pronounced for hepatocellular carcinoma and low quality studies for the -1082A/G polymorphism, lung cancer and oral cancer for the -819T/C polymorphism.	('the', 'Chemical', '-', (36, 39))	('the', 'Chemical', '-', (129, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('oral cancer', 'Disease', 'MESH:D009062', (172, 183))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (76, 100))	('-819T/C', 'Mutation', 'rs1800871', (192, 199))	('the', 'Chemical', '-', (188, 191))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('hepatocellular carcinoma', 'Disease', (76, 100))	('oral cancer', 'Disease', (172, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', (156, 167))	('the -1082A/G', 'Var', (129, 141))	('-1082A/G', 'Mutation', 'rs1800896', (133, 141))
123232	28977953	Although this association needs further confirmation by considering large studies, this meta-analysis suggested an association between IL-10 gene polymorphisms and cancer risk in the Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('IL-10', 'Gene', '3586', (135, 140))	('the', 'Chemical', '-', (179, 182))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('the', 'Chemical', '-', (35, 38))	('polymorphisms', 'Var', (146, 159))	('association', 'Interaction', (115, 126))	('IL-10', 'Gene', (135, 140))
123238	28977953	In view of these properties, we hypothesized that IL-10 gene polymorphisms could influence cancer susceptibility.	('the', 'Chemical', '-', (36, 39))	('polymorphisms', 'Var', (61, 74))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('influence', 'Reg', (81, 90))	('IL-10', 'Gene', (50, 55))	('the', 'Chemical', '-', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('IL-10', 'Gene', '3586', (50, 55))
123240	28977953	IL-10 gene promoter region is highly polymorphic, and three promoter single nucleotide polymorphisms (SNPs) such as -1082A/G (rs1800896), -819T/C (rs1800871) and -592A/C (rs1800872) have been reported to regulate IL-10 expression and alter the susceptibility to various types of cancers.	('rs1800871', 'Var', (147, 156))	('IL-10', 'Gene', (0, 5))	('-592A/C', 'Mutation', 'rs1800872', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('cancers', 'Disease', (279, 286))	('regulate', 'Reg', (204, 212))	('IL-10', 'Gene', '3586', (213, 218))	('rs1800896', 'Mutation', 'rs1800896', (126, 135))	('rs1800872', 'Var', (171, 180))	('rs1800872', 'Mutation', 'rs1800872', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('IL-10', 'Gene', (213, 218))	('-819T/C', 'Mutation', 'rs1800871', (138, 145))	('-1082A/G', 'Mutation', 'rs1800896', (116, 124))	('rs1800871', 'Mutation', 'rs1800871', (147, 156))	('the', 'Chemical', '-', (240, 243))	('cancers', 'Disease', 'MESH:D009369', (279, 286))	('rs1800896', 'Var', (126, 135))	('expression', 'MPA', (219, 229))	('alter', 'Reg', (234, 239))	('IL-10', 'Gene', '3586', (0, 5))
123250	28977953	For the studies assessing three polymorphisms (-1082A/G, -819T/C and -592A/C), two (-1082A/G and -592A/C), only one such as -1082A/G or -819T/C polymorphism and cancer risk but no other IL-10 gene polymorphisms, the genotypes distribution in the controls were deviated from HWE, thus, these studies were excluded in the final analysis.	('the', 'Chemical', '-', (181, 184))	('the', 'Chemical', '-', (212, 215))	('cancer', 'Disease', (161, 167))	('the', 'Chemical', '-', (242, 245))	('-1082A/G', 'Mutation', 'rs1800896', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('-592A/C', 'Mutation', 'rs1800872', (97, 104))	('-1082A/G', 'Mutation', 'rs1800896', (124, 132))	('-1082A/G', 'Var', (47, 55))	('the', 'Chemical', '-', (4, 7))	('-1082A/G', 'Mutation', 'rs1800896', (84, 92))	('-819T/C', 'Mutation', 'rs1800871', (136, 143))	('-1082A/G', 'Var', (84, 92))	('IL-10', 'Gene', '3586', (186, 191))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('IL-10', 'Gene', (186, 191))	('-592A/C', 'Mutation', 'rs1800872', (69, 76))	('-819T/C', 'Mutation', 'rs1800871', (57, 64))	('the', 'Chemical', '-', (285, 288))	('the', 'Chemical', '-', (316, 319))
123255	28977953	As regards the -1082A/G polymorphism, five studies focused on gastric cancer, three on hepatocellular carcinoma, two studies for each of the following cancer types, such as lung cancer, cervical cancer and esophageal cancer, and the other cancer types with one study per each cancer type.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('esophageal cancer', 'Disease', (206, 223))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (87, 111))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('-1082A/G', 'Mutation', 'rs1800896', (15, 23))	('gastric cancer', 'Disease', (62, 76))	('lung cancer', 'Disease', (173, 184))	('focused', 'Reg', (51, 58))	('-1082A/G', 'Var', (15, 23))	('hepatocellular carcinoma', 'Disease', (87, 111))	('the', 'Chemical', '-', (234, 237))	('the', 'Chemical', '-', (11, 14))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Disease', (70, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('cancer', 'Disease', (276, 282))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('the', 'Chemical', '-', (137, 140))	('cancer', 'Disease', (195, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cervical cancer', 'Disease', (186, 201))	('cervical cancer', 'Disease', 'MESH:D002583', (186, 201))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (87, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('esophageal cancer', 'Disease', 'MESH:D004938', (206, 223))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('the', 'Chemical', '-', (229, 232))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
123260	28977953	The main results regarding the association between IL-10 -1082A/G polymorphism and cancer risk are shown in Table 2 and Figure 2.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('association', 'Interaction', (31, 42))	('IL-10', 'Gene', '3586', (51, 56))	('polymorphism', 'Var', (66, 78))	('the', 'Chemical', '-', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('-1082A/G', 'Mutation', 'rs1800896', (57, 65))	('IL-10', 'Gene', (51, 56))	('cancer', 'Disease', (83, 89))
123261	28977953	A significant association was found between IL-10 -1082A/G polymorphism and overall cancer risk [dominant: odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.04-1.67, P < 0.001].	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('polymorphism', 'Var', (59, 71))	('cancer', 'Disease', (84, 90))	('IL-10', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('-1082A/G', 'Mutation', 'rs1800896', (50, 58))	('IL-10', 'Gene', '3586', (44, 49))
123266	28977953	The detailed results regarding the association between IL-10 -592A/C polymorphism and cancer risk are shown in Table 2.	('IL-10', 'Gene', (55, 60))	('polymorphism', 'Var', (69, 81))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('association', 'Interaction', (35, 46))	('IL-10', 'Gene', '3586', (55, 60))	('the', 'Chemical', '-', (31, 34))	('-592A/C', 'Mutation', 'rs1800872', (61, 68))	('cancer', 'Disease', (86, 92))
123270	28977953	Substantial heterogeneities were found among all studies regarding IL-10 -1082A/G polymorphism and overall cancer risk (homozygous: P = 0.025; heterozygous: P < 0.001; dominant: P < 0.001 and allele comparison: P < 0.001), but not under the recessive model (P = 0.242) (Table 2).	('IL-10', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('-1082A/G', 'Mutation', 'rs1800896', (73, 81))	('the', 'Chemical', '-', (237, 240))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('polymorphism', 'Var', (82, 94))	('IL-10', 'Gene', '3586', (67, 72))	('cancer', 'Disease', (107, 113))
123280	28977953	In this meta-analysis, we comprehensively investigated the associations between three promoter variants (-1082A/G, -819T/C and -592A/C) in IL-10 gene and cancer risk in the Chinese population through 53 articles.	('IL-10', 'Gene', (139, 144))	('-819T/C', 'Mutation', 'rs1800871', (115, 122))	('associations', 'Interaction', (59, 71))	('investigated', 'Reg', (42, 54))	('-1082A/G', 'Var', (105, 113))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('IL-10', 'Gene', '3586', (139, 144))	('the', 'Chemical', '-', (55, 58))	('-1082A/G', 'Mutation', 'rs1800896', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('the', 'Chemical', '-', (169, 172))	('-592A/C', 'Mutation', 'rs1800872', (127, 134))
123281	28977953	The results revealed that all the three IL-10 gene polymorphisms we considered were associated with an increased overall cancer risk.	('the', 'Chemical', '-', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('IL-10', 'Gene', (40, 45))	('associated', 'Reg', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('polymorphisms', 'Var', (51, 64))	('IL-10', 'Gene', '3586', (40, 45))	('cancer', 'Disease', (121, 127))
123282	28977953	Stratification analysis showed that the association between the -1082A/G polymorphism and cancer risk was more evident for hepatocellular carcinoma and low quality studies, the association between the -819T/C polymorphism and cancer risk was more obvious for lung cancer and oral cancer.	('the', 'Chemical', '-', (197, 200))	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('oral cancer', 'Disease', 'MESH:D009062', (275, 286))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (280, 286))	('oral cancer', 'Disease', (275, 286))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('the -819T/C', 'Var', (197, 208))	('the -1082A/G', 'Var', (60, 72))	('cancer', 'Disease', (264, 270))	('the', 'Chemical', '-', (36, 39))	('the', 'Chemical', '-', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))	('lung cancer', 'Disease', (259, 270))	('-819T/C', 'Mutation', 'rs1800871', (201, 208))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Disease', (90, 96))	('hepatocellular carcinoma', 'Disease', (123, 147))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('lung cancer', 'Disease', 'MESH:D008175', (259, 270))	('cancer', 'Disease', (226, 232))	('association', 'Interaction', (40, 51))	('the', 'Chemical', '-', (173, 176))	('-1082A/G', 'Mutation', 'rs1800896', (64, 72))
123287	28977953	Another meta-analysis including 15,942 cases and 22,336 controls investigated IL-10 -819C/T polymorphism and cancer risk, without finding any significant association between this polymorphism and overall cancer risk.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('IL-10', 'Gene', (78, 83))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('the', 'Chemical', '-', (3, 6))	('polymorphism', 'Var', (92, 104))	('IL-10', 'Gene', '3586', (78, 83))	('-819C/T', 'Mutation', 'rs1800871', (84, 91))
123289	28977953	Other meta-analyses with international studies have assessed the association between polymorphisms in IL-10 gene and susceptibility to some types of cancer.	('cancer', 'Disease', (149, 155))	('polymorphisms', 'Var', (85, 98))	('the', 'Chemical', '-', (61, 64))	('IL-10', 'Gene', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('IL-10', 'Gene', '3586', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('the', 'Chemical', '-', (1, 4))
123291	28977953	Some of the significant associations found in the previous studies were not validated in our meta-analysis, for example, IL-10 -1082A/G polymorphism was associated with an increased lung cancer risk.	('polymorphism', 'Var', (136, 148))	('-1082A/G', 'Mutation', 'rs1800896', (127, 135))	('lung cancer', 'Disease', (182, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('IL-10', 'Gene', '3586', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('the', 'Chemical', '-', (8, 11))	('IL-10', 'Gene', (121, 126))	('the', 'Chemical', '-', (46, 49))
123294	28977953	Interestingly, FPRP test results revealed that only the association between IL-10 -1082A/G polymorphism and overall cancer risk remained significant at the prior probability level of 0.1.	('-1082A/G', 'Mutation', 'rs1800896', (82, 90))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('IL-10', 'Gene', '3586', (76, 81))	('polymorphism', 'Var', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('the', 'Chemical', '-', (152, 155))	('the', 'Chemical', '-', (52, 55))	('IL-10', 'Gene', (76, 81))
123297	28977953	First, it identified the significant association between IL-10 -1082A/G, -819T/C and -592A/C polymorphisms and an increased overall cancer risk in the Chinese population.	('cancer', 'Disease', (132, 138))	('IL-10', 'Gene', '3586', (57, 62))	('-1082A/G', 'Mutation', 'rs1800896', (63, 71))	('IL-10', 'Gene', (57, 62))	('the', 'Chemical', '-', (21, 24))	('the', 'Chemical', '-', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('polymorphisms', 'Var', (93, 106))	('-592A/C', 'Mutation', 'rs1800872', (85, 92))	('-819T/C', 'Mutation', 'rs1800871', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
123304	28977953	In conclusion, this meta-analysis suggested an association between IL-10 gene polymorphisms and cancer risk in the Chinese population, especially for lung cancer, colorectal cancer and low quality studies.	('lung cancer', 'Disease', (150, 161))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (174, 180))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('polymorphisms', 'Var', (78, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('IL-10', 'Gene', '3586', (67, 72))	('cancer', 'Disease', (155, 161))	('IL-10', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancer', 'Disease', 'MESH:D015179', (163, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('the', 'Chemical', '-', (111, 114))	('colorectal cancer', 'Disease', (163, 180))
123336	24944666	Among the miRNAs, miR-133a is regarded as one of the major tumor suppressor miRNAs.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('miR-133a', 'Var', (18, 26))	('miR-133a', 'Chemical', '-', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
123337	24944666	Aberrant miR-133a expression was previously reported in human malignancies, including bladder cancer, head and neck cancer, rhabdomyosarcoma, esophageal cancer, colon cancer, tongue cancer and renal cell carcinoma, using high-throughput technology, including miRNA oligonucleotide arrays and quantitative polymerase chain reaction (qPCR).	('head and neck cancer', 'Phenotype', 'HP:0012288', (102, 122))	('tongue cancer', 'Disease', (175, 188))	('colon cancer', 'Phenotype', 'HP:0003003', (161, 173))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('miR-133a', 'Chemical', '-', (9, 17))	('renal cell carcinoma', 'Disease', (193, 213))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (193, 213))	('Aberrant', 'Var', (0, 8))	('tongue cancer', 'Disease', 'MESH:D014062', (175, 188))	('colon cancer', 'Disease', 'MESH:D015179', (161, 173))	('head and neck cancer', 'Disease', 'MESH:D006258', (102, 122))	('human', 'Species', '9606', (56, 61))	('expression', 'MPA', (18, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('bladder cancer', 'Disease', (86, 100))	('miR-133a', 'Gene', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('colon cancer', 'Disease', (161, 173))	('rhabdomyosarcoma', 'Disease', (124, 140))	('malignancies', 'Disease', (62, 74))	('esophageal cancer', 'Disease', (142, 159))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (193, 213))	('reported', 'Reg', (44, 52))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (124, 140))
123376	24944666	Additionally, cell apoptosis in OVCAR-3 cells increased following restoration of miR-133a expression (Fig.	('restoration', 'Var', (66, 77))	('increased', 'PosReg', (46, 55))	('miR-133a', 'Chemical', '-', (81, 89))	('miR-133a', 'Gene', (81, 89))	('expression', 'MPA', (90, 100))	('cell apoptosis', 'CPA', (14, 28))
123377	24944666	Collectively, these results indicate that miR-133a suppresses EOC growth in vitro.	('EOC', 'Phenotype', 'HP:0025318', (62, 65))	('EOC growth', 'CPA', (62, 72))	('miR-133a', 'Var', (42, 50))	('miR-133a', 'Chemical', '-', (42, 50))	('suppresses', 'NegReg', (51, 61))
123379	24944666	Following transfection with miR-133a mimics or NC in OVCAR-3, a significant downregulation of invasion into Matrigel was observed in miR-133a-transfected OVCAR-3 cells (Fig.	('invasion into Matrigel', 'CPA', (94, 116))	('miR-133a', 'Chemical', '-', (133, 141))	('miR-133a-transfected', 'Var', (133, 153))	('miR-133a', 'Chemical', '-', (28, 36))	('downregulation', 'NegReg', (76, 90))
123387	24944666	In addition, miR-133a was found to reduce OVCAR-3 cell viability, promote cell apoptosis and affect cell invasion and migration.	('affect', 'Reg', (93, 99))	('miR-133a', 'Var', (13, 21))	('cell apoptosis', 'CPA', (74, 88))	('promote', 'PosReg', (66, 73))	('cell invasion', 'CPA', (100, 113))	('miR-133a', 'Chemical', '-', (13, 21))	('reduce', 'NegReg', (35, 41))	('OVCAR-3 cell viability', 'CPA', (42, 64))
123391	24944666	For example, ectopic miR-133a has been reported to suppress cell growth in lung cancer, maxillary sinus squamous cell carcinoma, tongue cancer, esophageal cancer, prostate cancer, bladder cancer and renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('prostate cancer', 'Disease', (163, 178))	('suppress', 'NegReg', (51, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('tongue cancer', 'Disease', 'MESH:D014062', (129, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (199, 219))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', (75, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (180, 194))	('bladder cancer', 'Disease', (180, 194))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('ectopic', 'Var', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('miR-133a', 'Chemical', '-', (21, 29))	('bladder cancer', 'Phenotype', 'HP:0009725', (180, 194))	('renal cell carcinoma', 'Disease', (199, 219))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (199, 219))	('esophageal cancer', 'Disease', (144, 161))	('tongue cancer', 'Disease', (129, 142))	('maxillary sinus squamous cell carcinoma', 'Disease', (88, 127))	('maxillary sinus squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 127))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('prostate cancer', 'Disease', 'MESH:D011471', (163, 178))	('cell growth', 'CPA', (60, 71))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('miR-133a', 'Gene', (21, 29))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))
123392	24944666	Additionally, miR-133a was found to induce apoptosis in maxillary sinus squamous cell carcinoma, tongue cancer, bladder cancer and renal cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('bladder cancer', 'Disease', (112, 126))	('tongue cancer', 'Disease', 'MESH:D014062', (97, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('renal cell carcinoma', 'Disease', (131, 151))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('apoptosis', 'CPA', (43, 52))	('miR-133a', 'Chemical', '-', (14, 22))	('tongue cancer', 'Disease', (97, 110))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (131, 151))	('miR-133a', 'Var', (14, 22))	('maxillary sinus squamous cell carcinoma', 'Disease', (56, 95))	('maxillary sinus squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 95))	('induce', 'PosReg', (36, 42))
123393	24944666	miR-133a may also inhibit cell migration and invasion activities in esophageal cancer, prostate cancer, bladder cancer and renal cell carcinoma.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('inhibit', 'NegReg', (18, 25))	('renal cell carcinoma', 'Disease', (123, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (123, 143))	('esophageal cancer', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))	('bladder cancer', 'Disease', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('miR-133a', 'Chemical', '-', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('cell migration', 'CPA', (26, 40))	('invasion activities', 'CPA', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('miR-133a', 'Var', (0, 8))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (123, 143))	('prostate cancer', 'Disease', (87, 102))
123409	24575748	Genetic examination showed that the tumor had a mutation in exon 11.	('mutation in', 'Var', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (36, 41))
123461	22715394	We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA) and two intermediate endpoints, aneuploidy and tetraploidy.	('oxidative stress', 'Phenotype', 'HP:0025464', (78, 94))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (193, 218))	('esophageal adenocarcinoma', 'Disease', (193, 218))	('neoplastic progression', 'CPA', (167, 189))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (193, 218))	('selenium', 'Chemical', 'MESH:D012643', (30, 38))	('associated', 'Reg', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('genetic variation', 'Var', (99, 116))	('aneuploidy and tetraploidy', 'Disease', 'MESH:D057891', (256, 282))
123467	22715394	SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR) = 3.95, 95% confidence intervals (CI) = 1.42-10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31-32.58), but not selenoenzyme activity or oxidative stress markers.	('aneuploidy', 'Disease', 'MESH:D000782', (191, 201))	('aneuploidy', 'Disease', (191, 201))	('oxidative stress', 'Phenotype', 'HP:0025464', (269, 285))	('associated', 'Reg', (37, 47))	('concentrations', 'Var', (6, 20))	('SEPP1', 'Gene', (0, 5))	('SEPP1', 'Gene', '6414', (0, 5))
123471	22715394	Two trials in China found non-significant reduced risks of esophageal cancer (primarily squamous cell carcinoma) with supplementation of selenium in combination with other micronutrients for more than five years.	('esophageal cancer', 'Disease', (59, 76))	('reduced', 'NegReg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('selenium', 'Chemical', 'MESH:D012643', (137, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 111))	('squamous cell carcinoma', 'Disease', (88, 111))	('supplementation', 'Var', (118, 133))
123472	22715394	Case-cohort analysis within one of these trials found a statistically significant 44% lower risk of esophageal cancer among supplemented participants whose pre-trial serum selenium concentrations were in the highest (>82 microg/L) rather than the lowest (<60 microg/L) quartile.	('esophageal cancer', 'Disease', (100, 117))	('participants', 'Species', '9606', (137, 149))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lower', 'NegReg', (86, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('selenium', 'Chemical', 'MESH:D012643', (172, 180))	('>82 microg/L', 'Var', (217, 229))
123473	22715394	In the U.S., secondary analysis of the Nutritional Prevention of Cancer Trial showed a non-significant 70% lower risk of esophageal cancer in the group supplemented with selenium alone than in the placebo group after 6.4 years of follow-up, but included only eight esophageal cancer cases.	('selenium', 'Chemical', 'MESH:D012643', (170, 178))	('selenium', 'Var', (170, 178))	('esophageal cancer', 'Disease', (265, 282))	('esophageal cancer', 'Disease', (121, 138))	('lower', 'NegReg', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (265, 282))	('Cancer', 'Disease', (65, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('supplemented', 'Var', (152, 164))	('Cancer', 'Disease', 'MESH:D009369', (65, 71))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))
123475	22715394	The only previous study of genetic variants in selenoenzymes and risk of esophageal adenocarcinoma (EA) reported null finding.	('selenoenzymes', 'Protein', (47, 60))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (73, 98))	('genetic variants', 'Var', (27, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (73, 98))	('esophageal adenocarcinoma', 'Disease', (73, 98))
123481	22715394	Because selenium exerts its antioxidant property through selenoenzymes, we also examined whether the activity of, as well as genetic variations in, selenoenzymes were associated with the risk of progression.	('selenium', 'Chemical', 'MESH:D012643', (8, 16))	('activity', 'MPA', (101, 109))	('associated', 'Reg', (167, 177))	('genetic variations', 'Var', (125, 143))	('antioxidant property', 'MPA', (28, 48))
123513	22715394	Twelve SNPs were excluded for the following reasons: call rate <90% for three SNPs (rs75404373, rs2277501 and rs4807542); P-value for Hardy-Weinberg equilibrium <0.01 for four SNPs (rs2293627, rs6888691, rs3763011 and rs757229); concordance of the blinded QCs (10 pairs) <90% for two SNPs (rs2074452 and rs7579) and minor allele frequency <=5% for three SNPs (rs8179164, rs17883875 and rs4807543).	('rs6888691', 'Mutation', 'rs6888691', (193, 202))	('rs75404373', 'Var', (84, 94))	('rs2277501', 'Mutation', 'rs2277501', (96, 105))	('rs2293627', 'Mutation', 'rs2293627', (182, 191))	('rs8179164', 'Var', (360, 369))	('rs8179164', 'Mutation', 'rs8179164', (360, 369))	('rs75404373', 'Mutation', 'rs75404373', (84, 94))	('rs17883875', 'Mutation', 'rs17883875', (371, 381))	('rs2074452', 'Mutation', 'rs2074452', (290, 299))	('rs2293627', 'Var', (182, 191))	('rs4807542', 'Var', (110, 119))	('rs3763011', 'Var', (204, 213))	('rs6888691', 'Var', (193, 202))	('rs2277501', 'Var', (96, 105))	('rs4807542', 'Mutation', 'rs4807542', (110, 119))	('rs757229', 'Mutation', 'rs757229', (218, 226))	('rs2074452', 'Var', (290, 299))	('rs4807543', 'Var', (386, 395))	('rs17883875', 'Var', (371, 381))	('rs3763011', 'Mutation', 'rs3763011', (204, 213))	('rs757229)', 'Var', (218, 227))	('rs7579', 'Mutation', 'rs7579', (304, 310))	('rs4807543', 'Mutation', 'rs4807543', (386, 395))	('rs7579', 'Var', (304, 310))
123514	22715394	Cox proportional hazards regression models were used to assess the association of selenium, selenoenzyme activity, selenoprotein concentrations, oxidative stress and genetic variants in selenoenzymes with time to neoplastic progression to EA, aneuploidy and tetraploidy.	('variants', 'Var', (174, 182))	('selenium', 'Chemical', 'MESH:D012643', (82, 90))	('association', 'Interaction', (67, 78))	('oxidative stress', 'Phenotype', 'HP:0025464', (145, 161))	('aneuploidy and tetraploidy', 'Disease', 'MESH:D057891', (243, 269))
123535	22715394	Compared with the participants with serum selenium concentration <118 microg/L, the concentration >=118 microg/L was not associated with risk of neoplastic progression to EA (EA: HR = 1.23, 95% CI = 0.58-2.60; aneuploidy: HR = 2.15, 95% CI = 0.83-5.58; tetraploidy: HR = 1.38, 95% CI = 0.63-3.00, respectively).	('neoplastic progression', 'CPA', (145, 167))	('aneuploidy', 'Disease', (210, 220))	('>=118 microg/L', 'Var', (98, 112))	('aneuploidy', 'Disease', 'MESH:D000782', (210, 220))	('participants', 'Species', '9606', (18, 30))	('selenium', 'Chemical', 'MESH:D012643', (42, 50))
123536	22715394	Excluding participants with high-grade dysplasia or aneuploidy and/or tetraploidy at baseline did not materially change results (data not shown).	('tetraploidy', 'Var', (70, 81))	('aneuploidy', 'Disease', (52, 62))	('dysplasia', 'Disease', (39, 48))	('participants', 'Species', '9606', (10, 22))	('aneuploidy', 'Disease', 'MESH:D000782', (52, 62))	('dysplasia', 'Disease', 'MESH:D004476', (39, 48))
123537	22715394	SEPP1 concentrations were positively associated with the risk of EA and aneuploidy, but not tetraploidy ( Table 3 ).	('aneuploidy', 'Disease', (72, 82))	('aneuploidy', 'Disease', 'MESH:D000782', (72, 82))	('associated', 'Reg', (37, 47))	('concentrations', 'Var', (6, 20))	('SEPP1', 'Gene', (0, 5))	('SEPP1', 'Gene', '6414', (0, 5))
123539	22715394	Those in the highest tertile of SEPP1 concentrations had a 3.95-time higher risk of EA (HR = 3.95, 95% CI = 1.42-10.97, P for trend = 0.006) and a 6.53-time higher risk of aneuploidy (HR = 6.53, 95% CI = 1.31-32.58, P for trend = 0.02) compared with those at the lowest.	('aneuploidy', 'Disease', 'MESH:D000782', (172, 182))	('concentrations', 'Var', (38, 52))	('SEPP1', 'Gene', (32, 37))	('SEPP1', 'Gene', '6414', (32, 37))	('aneuploidy', 'Disease', (172, 182))
123543	22715394	Two SNPs in the GPX3 gene were statistically significantly associated with the risk of EA (P for trend = 0.03 for rs4958872 and P for trend = 0.04 for rs3792797); however, the overall genetic variation was not significant (global P = 0.33) ( Table 4 ).	('GPX3', 'Gene', (16, 20))	('rs4958872', 'Mutation', 'rs4958872', (114, 123))	('GPX3', 'Gene', '2878', (16, 20))	('rs3792797', 'Mutation', 'rs3792797', (151, 160))	('rs4958872', 'Var', (114, 123))	('associated', 'Reg', (59, 69))	('rs3792797', 'Var', (151, 160))
123546	22715394	None of the overall variation in GPX1-4 and SEPP1 genes was significantly associated with the risk of neoplastic progression to EA.	('neoplastic progression', 'CPA', (102, 124))	('variation', 'Var', (20, 29))	('GPX1', 'Gene', '2876', (33, 37))	('GPX1', 'Gene', (33, 37))	('SEPP1', 'Gene', (44, 49))	('SEPP1', 'Gene', '6414', (44, 49))	('associated', 'Reg', (74, 84))
123550	22715394	Hence, an inverse association observed in our previous cross-sectional analysis is most likely due to reverse causality or the fact that high serum selenium in our cohort might be associated with other factors that increase the risk of neoplastic progression to EA.	('selenium', 'Chemical', 'MESH:D012643', (148, 156))	('high', 'Var', (137, 141))	('neoplastic progression', 'CPA', (236, 258))
123551	22715394	Within the general population, clinical trials of selenium supplementation with or without other micronutrients in China and the U.S. reported non-significant 6% to 70% decreased risk of esophageal cancer with supplementation, although their 95% CI were large, likely due to their small sample sizes.	('selenium', 'Chemical', 'MESH:D012643', (50, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('decreased', 'NegReg', (169, 178))	('esophageal cancer', 'Disease', (187, 204))	('supplementation', 'Var', (210, 225))
123552	22715394	Two small case-control studies and a case-cohort of the trial in China, which reported a significant 44% lower risk of esophageal cancer with low selenium concentration (>82 microg/L vs. <60 microg/L), also support a protective effect of serum selenium on esophageal cancer.	('lower', 'NegReg', (105, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (256, 273))	('selenium', 'Chemical', 'MESH:D012643', (146, 154))	('>82 microg/L', 'Var', (170, 182))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('cancer with low selenium concentration', 'Phenotype', 'HP:0031903', (130, 168))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('low', 'NegReg', (142, 145))	('selenium concentration', 'MPA', (146, 168))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal cancer', 'Disease', (256, 273))	('selenium', 'Chemical', 'MESH:D012643', (244, 252))	('esophageal cancer', 'Disease', (119, 136))
123569	22715394	Only a single previous study has investigated the association between two potentially functional candidate variants in the GPX2 gene (rs4902346 and rs2737844, also known as gastrointestinal GPX) and the risk of EA in a case-control study; however, no association was found.	('rs2737844', 'Var', (148, 157))	('rs4902346', 'Mutation', 'rs4902346', (134, 143))	('GPX2', 'Gene', '2877', (123, 127))	('gastrointestinal GPX', 'Disease', 'MESH:D005767', (173, 193))	('rs4902346', 'Var', (134, 143))	('GPX2', 'Gene', (123, 127))	('rs2737844', 'Mutation', 'rs2737844', (148, 157))	('gastrointestinal GPX', 'Disease', (173, 193))
123571	22715394	Although two GPX3 variants were individually significantly associated with the risk of EA, the overall variation was not significant.	('GPX3', 'Gene', '2878', (13, 17))	('variants', 'Var', (18, 26))	('associated with', 'Reg', (59, 74))	('GPX3', 'Gene', (13, 17))
123581	33172906	Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant Fanconi anemia (FA) is a clinically heterogenous and genetically diverse disease with 22 known complementation groups (FA-A to FA-W), resulting from the inability to repair DNA interstrand cross-links.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('FANCA variant Fanconi anemia', 'Phenotype', 'HP:0001994', (91, 119))	('FA', 'Phenotype', 'HP:0001994', (121, 123))	('FANCA', 'Gene', (91, 96))	('FA', 'Phenotype', 'HP:0001994', (232, 234))	('variant', 'Var', (97, 104))	('FA', 'Phenotype', 'HP:0001994', (224, 226))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (105, 119))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('anemia', 'Phenotype', 'HP:0001903', (53, 59))	('Fanconi anemia', 'Disease', (45, 59))	('inability', 'Disease', 'MESH:D007319', (258, 267))	('Fanconi anemia', 'Disease', 'MESH:D005199', (45, 59))	('inability', 'Disease', (258, 267))	('FANCA', 'Gene', '2175', (91, 96))	('anemia', 'Phenotype', 'HP:0001903', (113, 119))	('Fanconi anemia', 'Disease', (105, 119))	('patients', 'Species', '9606', (63, 71))	('cancer', 'Disease', (11, 17))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (45, 59))	('FA', 'Phenotype', 'HP:0001994', (91, 93))	('Fanconi anemia', 'Disease', 'MESH:D005199', (105, 119))
123583	33172906	FANCA is the most commonly mutated gene in FA and a variety of mostly private mutations have been documented, including small and large indels and point and splicing variants.	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('point', 'Var', (147, 152))	('FANCA', 'Gene', '2175', (0, 5))	('FA', 'Phenotype', 'HP:0001994', (43, 45))	('FANCA', 'Gene', (0, 5))
123584	33172906	Genotype-phenotype associations in FA are complex, and a relationship between particular FANCA variants and the observed cellular phenotype or illness severity remains unclear.	('FA', 'Phenotype', 'HP:0001994', (89, 91))	('FA', 'Phenotype', 'HP:0001994', (35, 37))	('FANCA', 'Gene', '2175', (89, 94))	('variants', 'Var', (95, 103))	('FANCA', 'Gene', (89, 94))
123585	33172906	In this study, we describe two siblings with compound heterozygous FANCA variants (c.3788_3790delTCT and c.4199G > A) who both presented with esophageal squamous cell carcinoma at the age of 51.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (142, 176))	('c.3788_3790delTCT', 'Var', (83, 100))	('presented with', 'Reg', (127, 141))	('FANCA', 'Gene', '2175', (67, 72))	('c.4199G > A', 'Var', (105, 116))	('c.3788_3790delTCT', 'Mutation', 'rs397507553', (83, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('FANCA', 'Gene', (67, 72))	('esophageal squamous cell carcinoma', 'Disease', (142, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('c.4199G > A', 'Mutation', 'rs149851163', (105, 116))	('FA', 'Phenotype', 'HP:0001994', (67, 69))
123589	33172906	Based on our functional data demonstrating that the c.4199G > A/p.R1400H variant represents a hypomorphic FANCA allele, we conclude that the residual activity of the Fanconi anemia repair pathway accounts for lack of spontaneous bone marrow failure or infertility with the late presentation of malignancy as the initial disease manifestation.	('Fanconi anemia', 'Disease', (166, 180))	('c.4199G > A', 'Mutation', 'rs149851163', (52, 63))	('Fanconi anemia', 'Disease', 'MESH:D005199', (166, 180))	('FANCA', 'Gene', (106, 111))	('anemia', 'Phenotype', 'HP:0001903', (174, 180))	('malignancy', 'Disease', (294, 304))	('FA', 'Phenotype', 'HP:0001994', (106, 108))	('infertility', 'Disease', (252, 263))	('bone marrow failure', 'Disease', 'MESH:D000080983', (229, 248))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (166, 180))	('activity', 'MPA', (150, 158))	('infertility', 'Disease', 'MESH:D007247', (252, 263))	('bone marrow failure', 'Disease', (229, 248))	('bone marrow failure', 'Phenotype', 'HP:0005528', (229, 248))	('FANCA', 'Gene', '2175', (106, 111))	('infertility', 'Phenotype', 'HP:0000789', (252, 263))	('c.4199G > A/p.R1400H', 'Var', (52, 72))	('p.R1400H', 'Mutation', 'rs149851163', (64, 72))	('malignancy', 'Disease', 'MESH:D009369', (294, 304))
123592	33172906	FA is the most common genetic bone marrow failure syndrome affecting approximately one in 100,000 births and is caused by germline mutations in one of the 22 known FANC genes (FANCA-W).	('FANCA', 'Gene', (176, 181))	('mutations', 'Var', (131, 140))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('FA', 'Phenotype', 'HP:0001994', (176, 178))	('caused by', 'Reg', (112, 121))	('bone marrow failure', 'Phenotype', 'HP:0005528', (30, 49))	('bone marrow failure syndrome', 'Disease', (30, 58))	('bone marrow failure syndrome', 'Disease', 'MESH:D000080983', (30, 58))	('FANCA', 'Gene', '2175', (176, 181))	('FA', 'Phenotype', 'HP:0001994', (164, 166))
123603	33172906	Biallelic pathogenic variants in BRCA2/FANCD1 and PALB2/FANCN result in a severe subtype of FA with the majority of patients developing embryonal tumors (Wilms, neuroblastoma, medulloblastoma) and AML in early childhood.	('FA', 'Phenotype', 'HP:0001994', (92, 94))	('medulloblastoma', 'Disease', (176, 191))	('BRCA2', 'Gene', (33, 38))	('PALB2', 'Gene', '79728', (50, 55))	('Wilms', 'Disease', (154, 159))	('neuroblastoma', 'Disease', 'MESH:D009447', (161, 174))	('FA', 'Phenotype', 'HP:0001994', (56, 58))	('FANCD1', 'Gene', '675', (39, 45))	('patients', 'Species', '9606', (116, 124))	('developing', 'PosReg', (125, 135))	('BRCA2', 'Gene', '675', (33, 38))	('FA', 'Phenotype', 'HP:0001994', (39, 41))	('embryonal tumors', 'Phenotype', 'HP:0002898', (136, 152))	('embryonal tumors', 'Disease', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('AML', 'Disease', 'MESH:D015470', (197, 200))	('embryonal tumors', 'Disease', 'MESH:D009373', (136, 152))	('AML', 'Phenotype', 'HP:0004808', (197, 200))	('AML', 'Disease', (197, 200))	('Wilms', 'Disease', 'MESH:D009396', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('FANCD1', 'Gene', (39, 45))	('variants', 'Var', (21, 29))	('PALB2', 'Gene', (50, 55))	('FANCN', 'Gene', (56, 61))	('neuroblastoma', 'Disease', (161, 174))	('medulloblastoma', 'Phenotype', 'HP:0002885', (176, 191))	('medulloblastoma', 'Disease', 'MESH:D008527', (176, 191))	('FANCN', 'Gene', '79728', (56, 61))	('result in', 'Reg', (62, 71))	('neuroblastoma', 'Phenotype', 'HP:0003006', (161, 174))
123604	33172906	A study comparing FA-A and FA-G complementation groups found that FA patients with null variants in FANCA or pathogenic variants in FANCG will manifest with a more severe clinical course, earlier bone marrow failure onset, and hematologic malignancies.	('FANCA', 'Gene', '2175', (100, 105))	('FANCA', 'Gene', (100, 105))	('variants', 'Var', (120, 128))	('malignancies', 'Disease', (239, 251))	('bone marrow failure', 'Disease', (196, 215))	('FANCG', 'Gene', '2189', (132, 137))	('bone marrow failure', 'Disease', 'MESH:D000080983', (196, 215))	('FA', 'Phenotype', 'HP:0001994', (66, 68))	('FA', 'Phenotype', 'HP:0001994', (100, 102))	('FANCG', 'Gene', (132, 137))	('FA', 'Phenotype', 'HP:0001994', (27, 29))	('FA', 'Phenotype', 'HP:0001994', (132, 134))	('FA', 'Phenotype', 'HP:0001994', (18, 20))	('bone marrow failure', 'Phenotype', 'HP:0005528', (196, 215))	('patients', 'Species', '9606', (69, 77))	('malignancies', 'Disease', 'MESH:D009369', (239, 251))	('variants', 'Var', (88, 96))	('more', 'PosReg', (159, 163))
123605	33172906	Similarly, a recent study demonstrated in a cohort of patients with FANCB mutations that less severe disease correlated with increased residual FANCB function.	('FANCB', 'Gene', (68, 73))	('increased', 'PosReg', (125, 134))	('FANCB', 'Gene', (144, 149))	('FANCB', 'Gene', '2187', (68, 73))	('patients', 'Species', '9606', (54, 62))	('FANCB', 'Gene', '2187', (144, 149))	('mutations', 'Var', (74, 83))	('FA', 'Phenotype', 'HP:0001994', (68, 70))	('FA', 'Phenotype', 'HP:0001994', (144, 146))
123607	33172906	Hematopoietic mosaicism can result in partial or full rescue of chromosomal breakage levels in the peripheral blood and protect against aplastic anemia through restoration of a functional allele.	('aplastic anemia', 'Disease', 'MESH:D000741', (136, 151))	('mosaicism', 'Var', (14, 23))	('aplastic anemia', 'Disease', (136, 151))	('anemia', 'Phenotype', 'HP:0001903', (145, 151))	('aplastic anemia', 'Phenotype', 'HP:0001915', (136, 151))	('chromosomal breakage levels in', 'MPA', (64, 94))	('rescue', 'MPA', (54, 60))	('chromosomal breakage', 'Phenotype', 'HP:0040012', (64, 84))
123608	33172906	Pathogenic variants in FANCA, the most commonly mutated FA gene, are responsible for disease in two-thirds of FA patients.	('FA', 'Phenotype', 'HP:0001994', (23, 25))	('FANCA', 'Gene', '2175', (23, 28))	('FA', 'Phenotype', 'HP:0001994', (56, 58))	('variants', 'Var', (11, 19))	('patients', 'Species', '9606', (113, 121))	('FANCA', 'Gene', (23, 28))	('FA', 'Phenotype', 'HP:0001994', (110, 112))	('responsible', 'Reg', (69, 80))
123609	33172906	The high frequency and diverse spectrum of pathogenic variants in FANCA are owed in part to the large size of the gene (79 kb) with an open reading frame of 4.3 kb consisting of 43 exons.	('pathogenic', 'Reg', (43, 53))	('FA', 'Phenotype', 'HP:0001994', (66, 68))	('FANCA', 'Gene', '2175', (66, 71))	('variants', 'Var', (54, 62))	('FANCA', 'Gene', (66, 71))
123611	33172906	Many pathogenic FANCA variants are private mutations; however, common founder variants have been identified in the South African Afrikaners, Spanish Gypsies, and Tunisian populations.	('FANCA', 'Gene', '2175', (16, 21))	('Gypsies', 'Disease', (149, 156))	('FANCA', 'Gene', (16, 21))	('pathogenic', 'Reg', (5, 15))	('FA', 'Phenotype', 'HP:0001994', (16, 18))	('Gypsies', 'Disease', 'MESH:C535704', (149, 156))	('variants', 'Var', (22, 30))
123612	33172906	Previous reports have shown that there is not a clear correlation between specific FANCA mutations (i.e., homozygous null variants versus hypomorphic gene product) and the severity of the clinical phenotype with respect to congenital abnormalities and age at which hematologic abnormalities arise.	('FA', 'Phenotype', 'HP:0001994', (83, 85))	('congenital abnormalities', 'Disease', (223, 247))	('FANCA', 'Gene', '2175', (83, 88))	('hematologic abnormalities', 'Disease', 'MESH:D006402', (265, 290))	('congenital abnormalities', 'Disease', 'MESH:D000013', (223, 247))	('mutations', 'Var', (89, 98))	('hematologic abnormalities', 'Phenotype', 'HP:0001871', (265, 290))	('hematologic abnormalities', 'Disease', (265, 290))	('FANCA', 'Gene', (83, 88))
123614	33172906	We show that their atypical and delayed presentation, with lack of hematologic failure, is most likely secondary to the mitigating effects of a rare missense hypomorphic FANCA allele, c.4199G > A/p.R1400H.	('FANCA', 'Gene', '2175', (170, 175))	('FANCA', 'Gene', (170, 175))	('hematologic failure', 'Disease', (67, 86))	('FA', 'Phenotype', 'HP:0001994', (170, 172))	('c.4199G > A', 'Mutation', 'rs149851163', (184, 195))	('p.R1400H', 'Mutation', 'rs149851163', (196, 204))	('hematologic failure', 'Disease', 'MESH:D006402', (67, 86))	('c.4199G > A/p.R1400H', 'Var', (184, 204))
123623	33172906	The proband was found to be compound heterozygous for FANCA variants, c.3788_3790delTCT and c.4199G > A (Table 2).	('c.3788_3790delTCT', 'Var', (70, 87))	('FANCA', 'Gene', '2175', (54, 59))	('c.4199G > A', 'Var', (92, 103))	('c.3788_3790delTCT', 'Mutation', 'rs397507553', (70, 87))	('FANCA', 'Gene', (54, 59))	('c.4199G > A', 'Mutation', 'rs149851163', (92, 103))	('FA', 'Phenotype', 'HP:0001994', (54, 56))
123628	33172906	Targeted FANCA testing was performed and he was found to also carry the familial FANCA variants, c.3788_3790delTCT and c.4199G > A.	('c.4199G > A', 'Mutation', 'rs149851163', (119, 130))	('FANCA', 'Gene', (9, 14))	('FANCA', 'Gene', '2175', (81, 86))	('c.3788_3790delTCT', 'Var', (97, 114))	('c.4199G > A', 'Var', (119, 130))	('c.3788_3790delTCT', 'Mutation', 'rs397507553', (97, 114))	('FANCA', 'Gene', (81, 86))	('FA', 'Phenotype', 'HP:0001994', (81, 83))	('FA', 'Phenotype', 'HP:0001994', (9, 11))	('FANCA', 'Gene', '2175', (9, 14))
123632	33172906	Approximately 18 mo later the patient was diagnosed with synchronous primary laryngeal and anal SCC, which were both treated with radiation (5400 cGy to the pelvis and 6900cGy to the laryngeal and hypopharyngeal regions).	('patient', 'Species', '9606', (30, 37))	('5400 cGy', 'Var', (141, 149))	('6900cGy', 'Var', (168, 175))	('primary laryngeal', 'Disease', (69, 86))	('anal SCC', 'Disease', (91, 99))
123637	33172906	A next-generation sequencing panel for Fanconi anemia identified the heterozygous FANCA variants c.3788_3790delTCT and c.4199G > A (Table 2).	('c.4199G > A', 'Mutation', 'rs149851163', (119, 130))	('FANCA', 'Gene', '2175', (82, 87))	('Fanconi anemia', 'Disease', (39, 53))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (39, 53))	('c.3788_3790delTCT', 'Var', (97, 114))	('FANCA', 'Gene', (82, 87))	('c.4199G > A', 'Var', (119, 130))	('Fanconi anemia', 'Disease', 'MESH:D005199', (39, 53))	('c.3788_3790delTCT', 'Mutation', 'rs397507553', (97, 114))	('anemia', 'Phenotype', 'HP:0001903', (47, 53))	('FA', 'Phenotype', 'HP:0001994', (82, 84))
123640	33172906	CancerNext-Expanded panel (Ambry Genetics) identified no other pathogenic variants in 43 genes associated with hereditary cancer (Supplemental Table S1).	('hereditary cancer', 'Disease', 'MESH:D009369', (111, 128))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('hereditary cancer', 'Disease', (111, 128))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('variants', 'Var', (74, 82))
123642	33172906	The c.3788_3790delTCT variant is a known pathogenic variant that produces an in frame deletion in exon 38 (p.F1263del) and has an allele frequency of 0.0001 (ExAC database).	('c.3788_3790delTCT', 'Mutation', 'rs397507553', (4, 21))	('c.3788_3790delTCT', 'Var', (4, 21))	('p.F1263del', 'Mutation', 'p.1263delF', (107, 117))	('p.F1263del', 'Var', (107, 117))
123643	33172906	The second variant (c.4199G > A) is a point mutation in exon 42 and is a rare variant (allele frequency of 0.00004, ExAC database) that results in p.R1400H FANCA.	('FANCA', 'Gene', '2175', (156, 161))	('c.4199G > A', 'Mutation', 'rs149851163', (20, 31))	('FANCA', 'Gene', (156, 161))	('p.R1400H', 'Var', (147, 155))	('results in', 'Reg', (136, 146))	('c.4199G > A', 'Var', (20, 31))	('FA', 'Phenotype', 'HP:0001994', (156, 158))	('p.R1400H', 'Mutation', 'rs149851163', (147, 155))
123646	33172906	Consistent with a diagnosis of FA, fibroblasts derived from both brothers (proband RA3518, younger sibling RA3590) show increased chromosomal fragility when treated with DNA interstrand cross-linking agents including DEB and MMC (Fig.	('RA3590', 'Var', (107, 113))	('DEB', 'Chemical', 'MESH:C007366', (217, 220))	('MMC', 'Chemical', 'MESH:D016685', (225, 228))	('FA', 'Phenotype', 'HP:0001994', (31, 33))	('chromosomal fragility', 'CPA', (130, 151))	('increased', 'PosReg', (120, 129))
123648	33172906	RA3087 cells are deficient for FANCA because of homozygous deletion at the FANCA locus (g.88311999_88394999del83001(hg18), delEx9_43).	('FANCA', 'Gene', (31, 36))	('FANCA', 'Gene', '2175', (75, 80))	('FA', 'Phenotype', 'HP:0001994', (31, 33))	('g.88311999_88394999del83001', 'Var', (88, 115))	('FANCA', 'Gene', (75, 80))	('g.88311999_88394999del83001', 'Mutation', 'g.88311999_88394999del83001', (88, 115))	('FA', 'Phenotype', 'HP:0001994', (75, 77))	('deletion', 'Var', (59, 67))	('FANCA', 'Gene', '2175', (31, 36))
123650	33172906	Cellular sensitivity of RA3518 and RA3590 fibroblast to DEB-treated cells is similar to that seen in RA3087 FA-A patient fibroblast, whereas they are slightly less sensitive to MMC.	('patient', 'Species', '9606', (113, 120))	('RA3590', 'Var', (35, 41))	('DEB', 'Chemical', 'MESH:C007366', (56, 59))	('FA', 'Phenotype', 'HP:0001994', (108, 110))	('RA3518', 'Var', (24, 30))	('MMC', 'Chemical', 'MESH:D016685', (177, 180))
123651	33172906	Analysis of FANCA levels by western blot show that fibroblasts from the siblings (RA3518 and RA3590) have lower levels of endogenous FANCA in comparison to wild-type cells (Fig.	('lower', 'NegReg', (106, 111))	('FANCA', 'Gene', '2175', (12, 17))	('FANCA', 'Gene', '2175', (133, 138))	('FANCA', 'Gene', (12, 17))	('RA3590', 'Var', (93, 99))	('FANCA', 'Gene', (133, 138))	('FA', 'Phenotype', 'HP:0001994', (12, 14))	('RA3518', 'Var', (82, 88))	('FA', 'Phenotype', 'HP:0001994', (133, 135))
123653	33172906	Fibroblasts from the siblings (RA3518 and RA3590) were found to be deficient for FANCD2 monoubiquitination (Fig.	('RA3590', 'Var', (42, 48))	('monoubiquitination', 'MPA', (88, 106))	('FANCD2', 'Gene', '2177', (81, 87))	('FANCD2', 'Gene', (81, 87))	('RA3518', 'Var', (31, 37))	('deficient', 'NegReg', (67, 76))	('FA', 'Phenotype', 'HP:0001994', (81, 83))
123657	33172906	2A,B) Surprisingly, overexpression of FANCAc.4199G>A (p.R1400H) also rescued MMC hypersensitivity and FANCD2 monoubiquitination (Fig.	('hypersensitivity', 'Disease', 'MESH:D004342', (81, 97))	('MMC', 'Chemical', 'MESH:D016685', (77, 80))	('FA', 'Phenotype', 'HP:0001994', (38, 40))	('FA', 'Phenotype', 'HP:0001994', (102, 104))	('monoubiquitination', 'MPA', (109, 127))	('FANCD2', 'Gene', '2177', (102, 108))	('rescued', 'PosReg', (69, 76))	('p.R1400H', 'Mutation', 'rs149851163', (54, 62))	('c.4199G>A', 'SUBSTITUTION', 'None', (43, 52))	('FANCD2', 'Gene', (102, 108))	('c.4199G>A', 'Var', (43, 52))	('hypersensitivity', 'Disease', (81, 97))
123659	33172906	Overexpression of wild type and R1400H FANCA in RA3518 cells in immunofluorescence studies also rescued FANCD2 foci formation compared to RA3518 cells expressing an empty vector control (Fig.	('FANCA', 'Gene', '2175', (39, 44))	('FANCD2', 'Gene', (104, 110))	('R1400H', 'Mutation', 'rs149851163', (32, 38))	('FANCA', 'Gene', (39, 44))	('FA', 'Phenotype', 'HP:0001994', (104, 106))	('rescued', 'NegReg', (96, 103))	('FA', 'Phenotype', 'HP:0001994', (39, 41))	('R1400H', 'Var', (32, 38))	('FANCD2', 'Gene', '2177', (104, 110))
123660	33172906	However, the overexpressed R1400H FANCA protein was found to have cytoplasmic localization compared to the largely nuclear localization of the wild-type protein (Fig.	('FA', 'Phenotype', 'HP:0001994', (34, 36))	('R1400H', 'Var', (27, 33))	('FANCA', 'Gene', '2175', (34, 39))	('cytoplasmic localization', 'MPA', (66, 90))	('R1400H', 'Mutation', 'rs149851163', (27, 33))	('FANCA', 'Gene', (34, 39))
123661	33172906	Nuclear localization of FANCA is critical for proper function and impairment of this process by pathogenic missense variants has been recognized by multiple investigators.	('missense variants', 'Var', (107, 124))	('FANCA', 'Gene', '2175', (24, 29))	('FA', 'Phenotype', 'HP:0001994', (24, 26))	('FANCA', 'Gene', (24, 29))
123662	33172906	The proband and sibling carry the c.3788_3790delTCT variant that is predicted to express p.F1263del FANCA, a previously reported and well-studied pathogenic mutant.	('c.3788_3790delTCT', 'Var', (34, 51))	('died', 'Disease', (141, 145))	('died', 'Disease', 'MESH:D003643', (141, 145))	('FA', 'Phenotype', 'HP:0001994', (100, 102))	('p.F1263del', 'Var', (89, 99))	('p.F1263del', 'DELETION', 'None', (89, 99))	('c.3788_3790delTCT', 'Mutation', 'rs397507553', (34, 51))
123663	33172906	Overexpression of F1263del FANCA does not rescue cellular sensitivity of FA-deficient RA3087 patient fibroblasts or FANCD2 monoubiquitination after treatment with MMC (Fig.	('F1263del', 'DELETION', 'None', (18, 26))	('cellular sensitivity', 'MPA', (49, 69))	('FA-deficient', 'Disease', (73, 85))	('FA', 'Phenotype', 'HP:0001994', (27, 29))	('FA', 'Phenotype', 'HP:0001994', (116, 118))	('FANCD2', 'Gene', '2177', (116, 122))	('FA', 'Phenotype', 'HP:0001994', (73, 75))	('F1263del', 'Var', (18, 26))	('FANCD2', 'Gene', (116, 122))	('monoubiquitination', 'MPA', (123, 141))	('patient', 'Species', '9606', (93, 100))	('MMC', 'Chemical', 'MESH:D016685', (163, 166))	('FANCA', 'Gene', (27, 32))
123664	33172906	These data support a hypothesis that p.R1400H FANCA is a hypomorphic allele and p.F1263del is a loss of function allele.	('p.F1263del', 'Var', (80, 90))	('FANCA', 'Gene', (46, 51))	('p.R1400H', 'Var', (37, 45))	('p.F1263del', 'Mutation', 'p.1263delF', (80, 90))	('p.R1400H', 'Mutation', 'rs149851163', (37, 45))	('FA', 'Phenotype', 'HP:0001994', (46, 48))	('FANCA', 'Gene', '2175', (46, 51))
123665	33172906	Unexpectedly, FANCA R1400H, when overexpressed, provides enough function to restore resistance to cross-linking agents and rescue FANCD2 ubiquitination to wild-type levels.	('R1400H', 'Var', (20, 26))	('ubiquitination', 'MPA', (137, 151))	('FA', 'Phenotype', 'HP:0001994', (14, 16))	('FANCD2', 'Gene', '2177', (130, 136))	('R1400H', 'Mutation', 'rs149851163', (20, 26))	('FANCD2', 'Gene', (130, 136))	('FA', 'Phenotype', 'HP:0001994', (130, 132))	('FANCA', 'Gene', '2175', (14, 19))	('restore', 'PosReg', (76, 83))	('resistance to cross-linking agents', 'MPA', (84, 118))	('FANCA', 'Gene', (14, 19))	('rescue', 'PosReg', (123, 129))
123666	33172906	To further support our hypothesis that the R1400H FANCA is responsible for the milder FA phenotype observed in the siblings, the c.4199G > A missense variant was knocked-in at the endogenous FANCA locus of BJ cells to produce R1400H FANCA expressing cells (Fig.	('R1400H', 'Var', (226, 232))	('R1400H', 'Mutation', 'rs149851163', (43, 49))	('FANCA', 'Gene', '2175', (191, 196))	('FA', 'Phenotype', 'HP:0001994', (233, 235))	('FANCA', 'Gene', '2175', (50, 55))	('FA', 'Phenotype', 'HP:0001994', (86, 88))	('c.4199G > A', 'Var', (129, 140))	('R1400H', 'Mutation', 'rs149851163', (226, 232))	('FANCA', 'Gene', (191, 196))	('FANCA', 'Gene', '2175', (233, 238))	('FANCA', 'Gene', (50, 55))	('BJ', 'CellLine', 'CVCL:6573', (206, 208))	('FA', 'Phenotype', 'HP:0001994', (191, 193))	('FA', 'Phenotype', 'HP:0001994', (50, 52))	('c.4199G > A', 'Mutation', 'rs149851163', (129, 140))	('FANCA', 'Gene', (233, 238))
123668	33172906	A carboxy-terminal frameshift allele (p.E1394Gfs*31) was engineered in trans with c.4199G > A variant creating a compound heterozygous state.	('p.E1394Gfs*', 'Var', (38, 49))	('p.E1394Gfs*31', 'Mutation', 'p.E1394GfsX31', (38, 51))	('c.4199G > A', 'Mutation', 'rs149851163', (82, 93))	('c.4199G > A', 'Var', (82, 93))
123669	33172906	In addition, a cell line with biallelic p.L1256Hfs*11 frameshift (FS) was used as a null FANCA control.	('FA', 'Phenotype', 'HP:0001994', (89, 91))	('FANCA', 'Gene', '2175', (89, 94))	('p.L1256Hfs*', 'Var', (40, 51))	('p.L1256Hfs*11', 'Mutation', 'p.L1256HfsX11', (40, 53))	('FANCA', 'Gene', (89, 94))	('frameshift', 'Reg', (54, 64))
123671	33172906	Analysis of FANCA levels in BJ fibroblast expressing the FANCA variants by western blot show progressively decreased levels in FANCAR1400H/R1400H and FANCAR1400H/FS-expressing cells and absence of protein in FANCAFS/FS-expressing cells (Fig.	('FANCA', 'Gene', '2175', (57, 62))	('FANCA', 'Gene', '2175', (208, 213))	('FANCA', 'Gene', (12, 17))	('FA', 'Phenotype', 'HP:0001994', (208, 210))	('FA', 'Phenotype', 'HP:0001994', (57, 59))	('levels', 'MPA', (117, 123))	('FANCA', 'Gene', (208, 213))	('FANCA', 'Gene', '2175', (150, 155))	('FANCA', 'Gene', (57, 62))	('FANCA', 'Gene', '2175', (127, 132))	('BJ', 'CellLine', 'CVCL:6573', (28, 30))	('FA', 'Phenotype', 'HP:0001994', (150, 152))	('FA', 'Phenotype', 'HP:0001994', (127, 129))	('variants', 'Var', (63, 71))	('FANCA', 'Gene', (150, 155))	('FANCA', 'Gene', (127, 132))	('absence', 'NegReg', (186, 193))	('FANCA', 'Gene', '2175', (12, 17))	('decreased', 'NegReg', (107, 116))	('FA', 'Phenotype', 'HP:0001994', (12, 14))	('R1400H', 'Mutation', 'rs149851163', (155, 161))	('R1400H', 'Mutation', 'rs149851163', (139, 145))	('R1400H', 'Mutation', 'rs149851163', (132, 138))
123672	33172906	Consistent with the partially cytoplasmic localization of the overexpressed R1400H FANCA protein (Fig.	('R1400H', 'Var', (76, 82))	('FA', 'Phenotype', 'HP:0001994', (83, 85))	('FANCA', 'Gene', '2175', (83, 88))	('R1400H', 'Mutation', 'rs149851163', (76, 82))	('FANCA', 'Gene', (83, 88))
123673	33172906	2C), greater portion of the endogenously expressed R1400H FANCA is present in the cytoplasmic than in the nuclear fraction (Fig.	('FA', 'Phenotype', 'HP:0001994', (58, 60))	('R1400H', 'Var', (51, 57))	('FANCA', 'Gene', '2175', (58, 63))	('R1400H', 'Mutation', 'rs149851163', (51, 57))	('FANCA', 'Gene', (58, 63))
123677	33172906	In summary, CRISPR-Cas9 mediated genome engineering of the FANCA c.4199G > A (p.R1400H) variant into an alternate wild-type human fibroblast cell line demonstrates it is a pathogenic hypomorphic allele and that ICL repair is sensitive to the amount of hypomorphic allele available in the cell.	('FA', 'Phenotype', 'HP:0001994', (59, 61))	('c.4199G > A', 'Mutation', 'rs149851163', (65, 76))	('FANCA', 'Gene', '2175', (59, 64))	('human', 'Species', '9606', (124, 129))	('p.R1400H', 'Mutation', 'rs149851163', (78, 86))	('c.4199G > A', 'Var', (65, 76))	('FANCA', 'Gene', (59, 64))	('pathogenic', 'Reg', (172, 182))
123681	33172906	This atypical and mild clinical presentation of FA later in life is consistent with the hypothesis that although the p.F1263del allele likely provides no residual FANCA function, the second hypomorphic p.R1400H allele provides partial function.	('p.R1400H', 'Mutation', 'rs149851163', (202, 210))	('FA', 'Phenotype', 'HP:0001994', (48, 50))	('p.F1263del', 'Mutation', 'p.1263delF', (117, 127))	('FANCA', 'Gene', (163, 168))	('FA', 'Phenotype', 'HP:0001994', (163, 165))	('p.R1400H', 'Var', (202, 210))	('p.F1263del', 'Var', (117, 127))	('FANCA', 'Gene', '2175', (163, 168))
123682	33172906	p.R1400H FANCA likely supports enough FA pathway function to protect germ cell development and the bone marrow under non-stress conditions.	('germ cell development', 'CPA', (69, 90))	('FA', 'Phenotype', 'HP:0001994', (38, 40))	('FANCA', 'Gene', (9, 14))	('stress', 'Disease', (121, 127))	('stress', 'Disease', 'MESH:D000079225', (121, 127))	('p.R1400H', 'Var', (0, 8))	('FA', 'Phenotype', 'HP:0001994', (9, 11))	('FANCA', 'Gene', '2175', (9, 14))	('FA pathway', 'Pathway', (38, 48))	('p.R1400H', 'Mutation', 'rs149851163', (0, 8))
123685	33172906	The c.4199G > A/p.R1400H variant has been previously described in two other individuals with Fanconi anemia, but determining pathogenicity was difficult because, similar to our findings, it was reported that overexpression of the mutant allele resulted in complementation comparable to that obtained with the wild-type cDNA.	('Fanconi anemia', 'Disease', (93, 107))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (93, 107))	('overexpression', 'PosReg', (208, 222))	('c.4199G > A', 'Mutation', 'rs149851163', (4, 15))	('c.4199G > A/p.R1400H', 'Var', (4, 24))	('Fanconi anemia', 'Disease', 'MESH:D005199', (93, 107))	('anemia', 'Phenotype', 'HP:0001903', (101, 107))	('complementation', 'MPA', (256, 271))	('p.R1400H', 'Mutation', 'rs149851163', (16, 24))
123686	33172906	This suggests that overexpression of the mutant protein is able to compensate for protein instability and/or defects in FANCA protein function.	('function', 'MPA', (134, 142))	('mutant', 'Var', (41, 47))	('FANCA', 'Gene', '2175', (120, 125))	('defects', 'NegReg', (109, 116))	('FANCA', 'Gene', (120, 125))	('FA', 'Phenotype', 'HP:0001994', (120, 122))	('protein', 'Protein', (82, 89))
123687	33172906	Here the additional findings of the c.4199G > A/ p.R1400H variant in another FA family and our functional data support the variant as a most likely pathogenic allele.	('p.R1400H', 'Mutation', 'rs149851163', (49, 57))	('pathogenic', 'Reg', (148, 158))	('c.4199G > A', 'Mutation', 'rs149851163', (36, 47))	('FA', 'Phenotype', 'HP:0001994', (77, 79))	('c.4199G > A/ p.R1400H', 'Var', (36, 57))
123688	33172906	We observe increased mislocalization of mutant protein to the cytoplasm, decreased FANCD2 ubiquitination and foci formation, and cellular sensitivity to cross-linking agents.	('protein', 'Protein', (47, 54))	('FANCD2', 'Gene', '2177', (83, 89))	('increased', 'PosReg', (11, 20))	('FANCD2', 'Gene', (83, 89))	('decreased', 'NegReg', (73, 82))	('foci', 'MPA', (109, 113))	('mislocalization', 'MPA', (21, 36))	('FA', 'Phenotype', 'HP:0001994', (83, 85))	('ubiquitination', 'MPA', (90, 104))	('mutant', 'Var', (40, 46))
123689	33172906	Examining the variant by CRISPR-Cas9-mediated genome editing in an alternate cell line was key to demonstrating the defects of the R1400H mutant, which were further exacerbated when present in trans to a loss-of-function allele indicating a dose effect of a mutant protein.	('defects', 'MPA', (116, 123))	('R1400H', 'Mutation', 'rs149851163', (131, 137))	('R1400H', 'Var', (131, 137))
123698	33172906	Cell lines were immortalized with a catalytic subunit of human telomerase (hTERT) and were transformed by HPV E6 and E7 protein, unless otherwise stated in the text.	('human', 'Species', '9606', (57, 62))	('hTERT', 'Gene', '7015', (75, 80))	('HPV E6', 'Var', (106, 112))	('E7 protein', 'Var', (117, 127))	('hTERT', 'Gene', (75, 80))
123711	33172906	The microdeletion mutant (c.3788_3790delTCT) and the missense mutant (c.4199G > A) were generated with the QuikChange II XL-Site Directed Mutagenesis kit (Agilent Technologies) using a template of WT FANCA cDNA cloned in pENTR plasmid.	('FANCA', 'Gene', '2175', (200, 205))	('FANCA', 'Gene', (200, 205))	('c.4199G > A', 'Mutation', 'rs149851163', (70, 81))	('FA', 'Phenotype', 'HP:0001994', (200, 202))	('c.4199G > A', 'Var', (70, 81))	('c.3788_3790delTCT', 'Mutation', 'rs397507553', (26, 43))	('c.3788_3790delTCT', 'Var', (26, 43))
123713	33172906	Fibroblasts RA3518 and RA3590 are available from the International Fanconi Anemia Registry.	('Anemia', 'Phenotype', 'HP:0001903', (75, 81))	('RA3518', 'Var', (12, 18))	('Fanconi Anemia', 'Phenotype', 'HP:0001994', (67, 81))	('Fanconi Anemia', 'Disease', (67, 81))	('Fanconi Anemia', 'Disease', 'MESH:D005199', (67, 81))	('RA3590', 'Var', (23, 29))
123717	33172906	This work was supported by grants from the National Heart Lung and Blood Institute (R01 HL120922) (A.S.), National Cancer Institute (R01 CA204127) (A.S.), and National Center for Advancing Translational Sciences (UL1 TR001866).	('R01 HL120922', 'Var', (84, 96))	('HL120922', 'CellLine', 'CVCL:2492', (88, 96))	('Cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Cancer', 'Disease', (115, 121))	('Cancer', 'Disease', 'MESH:D009369', (115, 121))
123750	28596816	While studies had been performed previously testing for coffee consumption and its association with liver enzyme levels, one study evaluated effect of coffee in patients with risk factors for chronic liver disease: consumption of greater than two alcoholic beverages daily, positive serum HBV antigen, positive serum HCV antibody, transferrin saturation > 50%, elevated BMI, and uncontrolled diabetics.	('rat', 'Species', '10116', (347, 350))	('chronic liver disease', 'Disease', 'MESH:D058625', (192, 213))	('positive', 'Var', (274, 282))	('HCV', 'Species', '11103', (317, 320))	('elevated BMI', 'Phenotype', 'HP:0031418', (361, 373))	('liver disease', 'Phenotype', 'HP:0001392', (200, 213))	('diabetics', 'Disease', 'MESH:D003920', (392, 401))	('alcohol', 'Chemical', 'MESH:D000438', (247, 254))	('patients', 'Species', '9606', (161, 169))	('HBV', 'Species', '10407', (289, 292))	('positive', 'Reg', (302, 310))	('chronic liver disease', 'Disease', (192, 213))	('transferrin saturation', 'MPA', (331, 353))	('BMI', 'MPA', (370, 373))	('diabetics', 'Disease', (392, 401))	('serum HCV antibody', 'Protein', (311, 329))
123752	28596816	In a 2015 population-based prospective cohort study demonstrated coffee intake with reduced mortality from chronic liver disease.	('chronic liver disease', 'Disease', (107, 128))	('liver disease', 'Phenotype', 'HP:0001392', (115, 128))	('mortality', 'MPA', (92, 101))	('reduced', 'NegReg', (84, 91))	('chronic liver disease', 'Disease', 'MESH:D058625', (107, 128))	('coffee', 'Var', (65, 71))	('rat', 'Species', '10116', (59, 62))
123806	28596816	Yet another meta-analysis performed involving ten studies with 2260 HCC cases and six case-control studies from southern Europe and Japan with 1551 cases and four cohort studies from Japan accounting for 709 cases also confirmed an association with decreased risk of liver cancer and coffee consumption.	('coffee consumption', 'Var', (284, 302))	('liver cancer', 'Disease', (267, 279))	('decreased risk of liver', 'Phenotype', 'HP:0001410', (249, 272))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('decreased', 'NegReg', (249, 258))	('HCC', 'Phenotype', 'HP:0001402', (68, 71))	('liver cancer', 'Phenotype', 'HP:0002896', (267, 279))	('liver cancer', 'Disease', 'MESH:D006528', (267, 279))
123836	27845894	ATP1A1 was 12.3 times (adjusted odds ratio=12.3, 95% CI = 7.2-21.0) more likely to be overexpressed in cancer tissues than in normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('overexpressed', 'PosReg', (86, 99))	('rat', 'Species', '10116', (37, 40))	('ATP1A1', 'Var', (0, 6))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
123883	27845894	In the 319 patients with clinical TNM staging information, those with IHC scores >= 3 tended to have late stage of ESCC, compared to those with IHC scores < 1 (AOR = 3.6, 95% CI= 1.5-8.7) after adjusting for age and sex (Table 2).	('scores >= 3', 'Var', (74, 85))	('ESCC', 'Disease', (115, 119))	('TNM', 'Gene', '10178', (34, 37))	('TNM', 'Gene', (34, 37))	('patients', 'Species', '9606', (11, 19))
123890	27845894	The CE81T-4 cells were more invasive than the parenteral CE81T cells.	('CE81T-4', 'Var', (4, 11))	('invasive', 'CPA', (28, 36))	('CE81T-4', 'CellLine', 'CVCL:Y190', (4, 11))
123891	27845894	After ATP1A1 siRNA was transfected into CE81T and CE81T-4 cells, we found that ATP1A1 RNA levels decreased to a ratio of 0.3 +- 0.2 in CE81T cells and 0.11 +- 0.04 in CE81T-4 cells, compared to negative controls (NC) (Figure 4B).	('CE81T', 'Var', (135, 140))	('CE81T-4', 'CellLine', 'CVCL:Y190', (50, 57))	('rat', 'Species', '10116', (112, 115))	('decreased', 'NegReg', (97, 106))	('CE81T-4', 'CellLine', 'CVCL:Y190', (167, 174))	('ATP1A1', 'Var', (79, 85))
123894	27845894	Figure 4F and 4G, which depicts the results of our wound-healing and Matrigel-coated Transwell member assays, show that CE81T-4 was significantly more cable to migrate and invade than CE81T.	('rat', 'Species', '10116', (163, 166))	('invade', 'CPA', (172, 178))	('cable', 'CPA', (151, 156))	('more', 'PosReg', (146, 150))	('CE81T-4', 'CellLine', 'CVCL:Y190', (120, 127))	('CE81T-4', 'Var', (120, 127))
123895	27845894	Downregulation of ATP1A1 by ATP1A1 siRNA significantly inhibited cell migration and invasion ability in CE81T-4 cells, although its inhibiting effects were not as strong in CE81T.	('Downregulation', 'NegReg', (0, 14))	('CE81T-4', 'CellLine', 'CVCL:Y190', (104, 111))	('ATP1A1', 'Var', (28, 34))	('ATP1A1', 'Gene', (18, 24))	('inhibited', 'NegReg', (55, 64))	('rat', 'Species', '10116', (73, 76))
123910	27845894	They reported a 100-percent incidence rate for tumor in the tongue of mice mice exposed to both 4-NQO (200 mug/ml) and arecoline (500 mug/mL), 57% in mice exposed to 4-NQO only, and 0% in mice exposed to arecoline only.	('mice', 'Species', '10090', (188, 192))	('mice', 'Species', '10090', (150, 154))	('mice', 'Species', '10090', (75, 79))	('4-NQO', 'Chemical', 'MESH:D015112', (96, 101))	('200 mug/ml', 'Var', (103, 113))	('arecoline', 'Chemical', 'MESH:D001115', (119, 128))	('arecoline', 'Chemical', 'MESH:D001115', (204, 213))	('4-NQO', 'Chemical', 'MESH:D015112', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('rat', 'Species', '10116', (38, 41))	('tumor', 'Disease', (47, 52))	('tumor in the tongue', 'Phenotype', 'HP:0100648', (47, 66))
123914	27845894	Aberrant expressions of both ATP1A1 a1 and ATP1A1 b1 have been reported in various cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('ATP1A1', 'Var', (43, 49))	('reported', 'Reg', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ATP1A1 a1', 'Gene', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
123915	27845894	One recent study showed proliferation arrest and reduced cell migration of human HCC cells after knockdown of ATP1A1 expression.	('human HCC', 'CellLine', 'CVCL:3285', (75, 84))	('knockdown', 'Var', (97, 106))	('reduced', 'NegReg', (49, 56))	('rat', 'Species', '10116', (65, 68))	('proliferation arrest', 'Disease', (24, 44))	('proliferation arrest', 'Disease', 'MESH:D006323', (24, 44))	('cell migration', 'CPA', (57, 71))	('rat', 'Species', '10116', (31, 34))	('ATP1A1', 'Gene', (110, 116))
123916	27845894	The tumorigenicity of the HCC cells in nude mice was reported to be markedly decreased (100% vs. 10%) after being transfected with ATP1A1-shRNA.	('tumor', 'Disease', (4, 9))	('nude mice', 'Species', '10090', (39, 48))	('ATP1A1-shRNA', 'Var', (131, 143))	('transfected', 'Var', (114, 125))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('decreased', 'NegReg', (77, 86))
123917	27845894	Moreover, adding specific inhibitors of Na+/K+-ATPase (e.g., ouabain or digoxin) to certain cells can activate multiple signaling pathways, including the EGFR/Src-Ras-Erk pathway and the PI3K-PDK-Akt pathway.	('EGFR', 'Gene', (154, 158))	('Erk', 'Gene', '5594', (167, 170))	('activate', 'PosReg', (102, 110))	('ouabain', 'Chemical', 'MESH:D010042', (61, 68))	('Na+/K+-ATPase', 'Var', (40, 53))	('Akt', 'Gene', '207', (196, 199))	('Src', 'Gene', (159, 162))	('Src', 'Gene', '6714', (159, 162))	('digoxin', 'Chemical', 'MESH:D004077', (72, 79))	('EGFR', 'Gene', '1956', (154, 158))	('Erk', 'Gene', (167, 170))	('Akt', 'Gene', (196, 199))
123918	27845894	Thus, the known mechanisms through which ATP1A1 probably affects tumorigenicity and metastasis include (1) affecting K+ homeostasis resulting in cell apoptosis or necrosis, (2) affecting the translocation of fibroblast growth factor 2 (FGF2) from cytoplasm to extracellular and PI3K/Akt signaling pathway to influence cell proliferation, migration, and invasion, and (3) interacting with ATP1A1 alpha1-subunit and phosphoinositide 3-kinase (PI3K) regulatory unit to control focal adhesion kinase (FAK) phosphorylation in lamellipodia or invadopodia.	('invasion', 'CPA', (353, 361))	('K+ homeostasis', 'MPA', (117, 131))	('lamellipodia', 'Disease', (521, 533))	('cell apoptosis', 'CPA', (145, 159))	('phosphorylation', 'MPA', (502, 517))	('cell proliferation', 'CPA', (318, 336))	('fibroblast growth factor 2', 'Gene', '2247', (208, 234))	('tumor', 'Disease', (65, 70))	('influence', 'Reg', (308, 317))	('control', 'Reg', (466, 473))	('rat', 'Species', '10116', (341, 344))	('metastasis', 'CPA', (84, 94))	('Akt', 'Gene', (283, 286))	('affecting', 'Reg', (107, 116))	('ATP1A1', 'Var', (41, 47))	('FGF2', 'Gene', '2247', (236, 240))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('rat', 'Species', '10116', (330, 333))	('migration', 'CPA', (338, 347))	('Akt', 'Gene', '207', (283, 286))	('necrosis', 'Disease', 'MESH:D009336', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('translocation', 'MPA', (191, 204))	('affecting', 'Reg', (177, 186))	('FGF2', 'Gene', (236, 240))	('lamellipodia', 'Disease', 'None', (521, 533))	('fibroblast growth factor 2', 'Gene', (208, 234))	('affects', 'Reg', (57, 64))	('necrosis', 'Disease', (163, 171))	('focal', 'MPA', (474, 479))
123919	27845894	Consistent with previous studies of other cancer cell lines, our in-vitro experiments showed that ATP1A1 expression is highly correlated with the invasive ability of a subpopulation from the same ESCC cell line (CE81T vs. CE81T-4) established in our laboratory.	('invasive ability', 'CPA', (146, 162))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ATP1A1', 'Gene', (98, 104))	('correlated', 'Reg', (126, 136))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('CE81T-4', 'CellLine', 'CVCL:Y190', (222, 229))	('CE81T', 'Var', (212, 217))	('expression', 'MPA', (105, 115))	('rat', 'Species', '10116', (254, 257))
123920	27845894	By knocking down ATP1A1 with siRNA or ouabain, we were able to significantly reduce CE81T-4's ability to migrate and invade, compared to controls.	('rat', 'Species', '10116', (108, 111))	('reduce', 'NegReg', (77, 83))	('CE81T-4', 'CellLine', 'CVCL:Y190', (84, 91))	('ATP1A1', 'Gene', (17, 23))	('CE81T-4', 'Var', (84, 91))	('ouabain', 'Chemical', 'MESH:D010042', (38, 45))	('ability', 'CPA', (94, 101))	('knocking down', 'Var', (3, 16))
123921	27845894	The results of our cell proliferation assay showed that ATP1A1 siRNA, but not ouabain, effectively knocked down cell proliferation rate in CE81T-4.	('rat', 'Species', '10116', (124, 127))	('rat', 'Species', '10116', (131, 134))	('CE81T-4', 'CellLine', 'CVCL:Y190', (139, 146))	('ouabain', 'Chemical', 'MESH:D010042', (78, 85))	('knocked down', 'NegReg', (99, 111))	('ATP1A1 siRNA', 'Var', (56, 68))	('cell proliferation rate', 'CPA', (112, 135))	('rat', 'Species', '10116', (31, 34))
123979	27845894	From US Biomax, we obtained five different tissue array slides, including ES801 (80 cores of paired tumor and normal parts from 40 ESCC patients), ES802 (80 cores with duplicated tumor specimens without normal parts from 40 ESCC patients), ES1501 (150 cores with duplicated tumor specimens without normal parts from 75 ESCC patients), ES2001 (200 cores from 120 ESCC patients), and BC02022 (54 cores containing tumor specimen, adjacent normal, and distant normal parts from 18 ESCC patients) (Supplementary Table S1).	('tumor', 'Disease', (411, 416))	('patients', 'Species', '9606', (324, 332))	('patients', 'Species', '9606', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (411, 416))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('patients', 'Species', '9606', (482, 490))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (367, 375))	('tumor', 'Disease', 'MESH:D009369', (411, 416))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('ES801', 'Var', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (179, 184))
124035	28000729	PLR > 120 was only associated with advanced AJCC TNM stage (P = 0.015).	('PLR', 'Var', (0, 3))	('TNM', 'Gene', (49, 52))	('TNM', 'Gene', '10178', (49, 52))
124102	27027341	Interestingly, HMGA2 abrogation attenuated the malignant phenotype of two ESCC cell lines, suggesting that HMGA2 overexpression is involved in ESCC progression.	('malignant phenotype of', 'CPA', (47, 69))	('HMGA2', 'Gene', (15, 20))	('ESCC', 'Disease', (143, 147))	('HMGA2', 'Gene', '8091', (107, 112))	('attenuated', 'NegReg', (32, 42))	('abrogation', 'Var', (21, 31))	('HMGA2', 'Gene', (107, 112))	('involved', 'Reg', (131, 139))	('HMGA2', 'Gene', '8091', (15, 20))
124113	27027341	Here, we show that HMGA2, but not HMGA1, is overexpressed in ESCC samples and that the abrogation of its expression in ESCC cell lines attenuates the malignant phenotype.	('abrogation', 'Var', (87, 97))	('malignant phenotype', 'CPA', (150, 169))	('HMGA2', 'Gene', (19, 24))	('HMGA2', 'Gene', '8091', (19, 24))	('HMGA1', 'Gene', (34, 39))	('HMGA1', 'Gene', '3159', (34, 39))	('attenuates', 'NegReg', (135, 145))	('expression', 'MPA', (105, 115))
124145	27027341	Next, proliferation rates of TE-1 and TE-13 cells knocked-down for HMGA2 were analyzed during 8 consecutive days.	('TE-13', 'CellLine', 'CVCL:4463', (38, 43))	('HMGA2', 'Gene', '8091', (67, 72))	('HMGA2', 'Gene', (67, 72))	('knocked-down', 'Var', (50, 62))
124149	27027341	Finally, colony-forming efficiency of HMGA2 knocked-down TE-1 and TE-13 cells was assessed by colony-forming assay and it was found that TE-1 and TE-13 sh-HMGA2 cells gave rise to a lower number of colonies compared with control cells (Figure 4E).	('TE-13', 'Var', (146, 151))	('TE-13', 'CellLine', 'CVCL:4463', (146, 151))	('TE-13', 'CellLine', 'CVCL:4463', (66, 71))	('lower', 'NegReg', (182, 187))	('HMGA2', 'Gene', '8091', (38, 43))	('HMGA2', 'Gene', '8091', (155, 160))	('HMGA2', 'Gene', (38, 43))	('TE-1', 'Var', (137, 141))	('HMGA2', 'Gene', (155, 160))
124150	27027341	Together, these results indicate that HMGA2 expression enhances the malignant phenotype of ESCC cell lines.	('ESCC', 'Disease', (91, 95))	('expression', 'Var', (44, 54))	('HMGA2', 'Gene', '8091', (38, 43))	('malignant phenotype of', 'CPA', (68, 90))	('HMGA2', 'Gene', (38, 43))	('enhances', 'PosReg', (55, 63))
124155	27027341	Overexpression of HMGA family members, reported in a wide range of tumors, has been already demonstrated to play a critical role in malignant cell transformation and cancer progression and commonly correlates with a poor prognosis.	('play', 'Reg', (108, 112))	('role', 'Reg', (124, 128))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Overexpression', 'Var', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('malignant cell transformation', 'CPA', (132, 161))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Disease', (67, 73))	('HMGA', 'Gene', (18, 22))
124165	27027341	HMGA2 stable knockdown reduced important malignant hallmarks such as proliferation, and migration ability in both cell lines.	('migration ability', 'CPA', (88, 105))	('proliferation', 'CPA', (69, 82))	('HMGA2', 'Gene', '8091', (0, 5))	('HMGA2', 'Gene', (0, 5))	('malignant hallmarks', 'CPA', (41, 60))	('reduced', 'NegReg', (23, 30))	('knockdown', 'Var', (13, 22))
124169	27027341	In accordance with these reports, our results show that HMGA2 knockdown significantly reduced the growth of ESCC cell lines after eight consecutive days in culture, thus suggesting that HMGA2 abrogation could revert the deregulated expression of key genes involved with cell cycle progression and proliferation stimulus.	('HMGA2', 'Gene', (56, 61))	('reduced', 'NegReg', (86, 93))	('HMGA2', 'Gene', '8091', (186, 191))	('HMGA2', 'Gene', (186, 191))	('deregulated expression', 'MPA', (220, 242))	('revert', 'NegReg', (209, 215))	('HMGA2', 'Gene', '8091', (56, 61))	('abrogation', 'Var', (192, 202))	('growth', 'CPA', (98, 104))	('knockdown', 'Var', (62, 71))
124170	27027341	Moreover, we observed that stable silencing of HMGA2 also reduces the migration and colony formation by ESCC cells TE-1 and TE-13.	('reduces', 'NegReg', (58, 65))	('HMGA2', 'Gene', '8091', (47, 52))	('migration', 'CPA', (70, 79))	('HMGA2', 'Gene', (47, 52))	('colony formation', 'CPA', (84, 100))	('TE-13', 'CellLine', 'CVCL:4463', (124, 129))	('silencing', 'Var', (34, 43))
124174	27027341	In this way, the decrease in migratory activity mediated by HMGA2 abrogation in ESCC cell lines observed in our study could be related with a reversion in EMT phenotype in esophageal malignant cells, nonetheless, further studies are necessary to corroborate this hypothesis.	('migratory activity', 'CPA', (29, 47))	('HMGA2', 'Gene', '8091', (60, 65))	('EMT phenotype', 'CPA', (155, 168))	('decrease', 'NegReg', (17, 25))	('HMGA2', 'Gene', (60, 65))	('abrogation', 'Var', (66, 76))
124203	27027341	TE-1 and TE-13 cells were stably silenced for HMGA2 by transfecting 5 mug of DNA from either the shHMGA2 construct plasmid (#HSH019812-LvU6, GeneCopoeia) or the empty backbone vector (#CSHCTR001-LvU6, GeneCopoeia), used as an experimental control, both expressing the puromycin-resistance gene, using Lipofectamine 2000 (Invitrogen), following the manufacturer's protocol.	('HMGA2', 'Gene', (46, 51))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (301, 319))	('puromycin', 'Chemical', 'MESH:D011691', (268, 277))	('HMGA2', 'Gene', '8091', (99, 104))	('TE-13', 'CellLine', 'CVCL:4463', (9, 14))	('HMGA2', 'Gene', (99, 104))	('HMGA2', 'Gene', '8091', (46, 51))	('#HSH019812-LvU6', 'Var', (124, 139))
124329	24586291	 N-acetyltransferase 2 Polymorphisms and Risk of Esophageal Cancer in a Chinese Population Esophageal cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in China in 2009.	('death', 'Disease', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('N-acetyltransferase 2', 'Gene', '10', (1, 22))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (49, 66))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Polymorphisms', 'Var', (23, 36))	('death', 'Disease', 'MESH:D003643', (201, 206))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('N-acetyltransferase 2', 'Gene', (1, 22))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('Esophageal cancer', 'Disease', (91, 108))	('Esophageal Cancer', 'Disease', (49, 66))	('cancer', 'Disease', (147, 153))
124331	24586291	We conducted a hospital-based case-control study to evaluate ten NAT2 tagging single nucleotide polymorphisms (SNPs) on the risk of ESCC.	('single nucleotide polymorphisms', 'Var', (78, 109))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('NAT2', 'Gene', '10', (65, 69))	('NAT2', 'Gene', (65, 69))	('N', 'Chemical', 'MESH:D009584', (65, 66))
124332	24586291	In the single locus analyses, there was a borderline statistically significant difference in genotype frequencies of NAT2 rs1565684 T>C SNP between the cases and the controls (p = 0.057).	('NAT2', 'Gene', '10', (117, 121))	('rs1565684 T>C', 'Var', (122, 135))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('N', 'Chemical', 'MESH:D009584', (117, 118))	('NAT2', 'Gene', (117, 121))	('rs1565684', 'Mutation', 'rs1565684', (122, 131))
124333	24586291	The NAT2 rs1565684 CC genotype was associated with a borderline significantly increased risk for ESCC (CC vs. TT: adjusted OR = 1.77, 95% CI = 0.97-3.21, p = 0.063 and CC vs. TT/TC: adjusted OR = 1.68, 95% CI = 0.93-3.04, p = 0.085).	('NAT2', 'Gene', '10', (4, 8))	('NAT2', 'Gene', (4, 8))	('rs1565684', 'Mutation', 'rs1565684', (9, 18))	('rs1565684 CC', 'Var', (9, 21))	('ESCC', 'Disease', (97, 101))
124335	24586291	After the Bonferroni correction, in all comparison models, NAT2 rs1565684 T>C SNP was not associated with ESCC risk (p>0.05).	('NAT2', 'Gene', '10', (59, 63))	('rs1565684', 'Mutation', 'rs1565684', (64, 73))	('ESCC', 'Disease', (106, 110))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('NAT2', 'Gene', (59, 63))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('rs1565684 T>C SNP', 'Var', (64, 81))
124338	24586291	NAT2 rs1565684 T>C SNP might play a slight role in ESCC etiology.	('N', 'Chemical', 'MESH:D009584', (0, 1))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('rs1565684', 'Mutation', 'rs1565684', (5, 14))	('ESCC', 'Disease', (51, 55))	('NAT2', 'Gene', (0, 4))	('NAT2', 'Gene', '10', (0, 4))	('rs1565684 T>C', 'Var', (5, 18))
124344	24586291	NAT2 is polymorphic, and it was thought that NAT2 acetylation status alteration caused by NAT polymorphisms decreased enzymatic activity and result in absence of detoxification efficiency, which could lead to an increase in cancer susceptibility.	('NAT', 'Gene', '6046', (0, 3))	('enzymatic activity', 'MPA', (118, 136))	('detoxification efficiency', 'Disease', 'MESH:C565043', (162, 187))	('absence', 'NegReg', (151, 158))	('increase', 'PosReg', (212, 220))	('cancer', 'Disease', (224, 230))	('NAT', 'Gene', '6046', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('NAT', 'Gene', (0, 3))	('acetylation status alteration', 'MPA', (50, 79))	('NAT2', 'Gene', '10', (0, 4))	('NAT', 'Gene', (45, 48))	('NAT', 'Gene', '6046', (90, 93))	('NAT2', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('polymorphisms', 'Var', (94, 107))	('NAT2', 'Gene', '10', (45, 49))	('NAT', 'Gene', (90, 93))	('detoxification efficiency', 'Disease', (162, 187))	('decreased', 'NegReg', (108, 117))	('NAT2', 'Gene', (45, 49))
124345	24586291	It has been reported that NAT2 polymorphisms and/or their interaction with smoking is associated with various types of malignancies.	('interaction', 'Interaction', (58, 69))	('NAT2', 'Gene', (26, 30))	('malignancies', 'Disease', (119, 131))	('associated', 'Reg', (86, 96))	('polymorphisms', 'Var', (31, 44))	('NAT2', 'Gene', '10', (26, 30))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))
124346	24586291	Genetic variation of NAT2 may lead to differences in the rate of arylamine metabolism and consequently increase cancer risk.	('arylamine', 'Chemical', 'MESH:C023650', (65, 74))	('Genetic variation', 'Var', (0, 17))	('NAT2', 'Gene', '10', (21, 25))	('lead to differences', 'Reg', (30, 49))	('NAT2', 'Gene', (21, 25))	('increase cancer', 'Disease', (103, 118))	('arylamine metabolism', 'MPA', (65, 85))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('increase cancer', 'Disease', 'MESH:D009369', (103, 118))	('rate', 'MPA', (57, 61))
124348	24586291	NAT2 genetic variations may contribute to the development of ESCC.	('ESCC', 'Disease', (61, 65))	('genetic variations', 'Var', (5, 23))	('contribute', 'Reg', (28, 38))	('NAT2', 'Gene', (0, 4))	('NAT2', 'Gene', '10', (0, 4))
124363	24586291	Differences in the distributions of demographic characteristics, selected variables, and genotypes of the NAT2 variants between the cases and controls were evaluated using the chi 2 test.	('NAT2', 'Gene', '10', (106, 110))	('variants', 'Var', (111, 119))	('NAT2', 'Gene', (106, 110))
124368	24586291	The concordance rates of repeated analyses were 100% except NAT2 rs11996129 T>C (157/160, 98.13%), rs1565684 T>C (159/160, 99.38%) and rs1799930 G>A (159/160, 99.38%).	('rs1799930', 'Mutation', 'rs1799930', (135, 144))	('NAT2', 'Gene', (60, 64))	('rs11996129 T>C', 'Var', (65, 79))	('rs11996129', 'Mutation', 'rs11996129', (65, 75))	('rs1565684 T>C', 'Var', (99, 112))	('NAT2', 'Gene', '10', (60, 64))	('rs1799930 G>A', 'Var', (135, 148))	('rs1565684', 'Mutation', 'rs1565684', (99, 108))
124370	24586291	The observed genotype frequencies for these ten polymorphisms in the controls were all in HWE except NAT2 rs4540438 A>C (p = 0.015) (Table 2).	('rs4540438', 'Mutation', 'rs4540438', (106, 115))	('NAT2', 'Gene', (101, 105))	('NAT2', 'Gene', '10', (101, 105))	('rs4540438 A>C', 'Var', (106, 119))
124371	24586291	The genotype distributions of NAT2 rs1565684 T>C in the cases and the controls are shown in Table 3.	('NAT2', 'Gene', '10', (30, 34))	('rs1565684', 'Mutation', 'rs1565684', (35, 44))	('NAT2', 'Gene', (30, 34))	('rs1565684 T>C', 'Var', (35, 48))
124372	24586291	When the NAT2 rs1565684 TT homozygote genotype was used as the reference group, the TC genotype was not associated with the risk for ESCC (TC vs. TT: OR = 1.14, 95% CI = 0.90-1.44, p = 0.269); the CC genotype was associated with a significantly increased risk for ESCC (CC vs. TT: OR = 1.95, 95% CI = 1.08-3.51, p = 0.026).	('NAT2', 'Gene', (9, 13))	('rs1565684', 'Mutation', 'rs1565684', (14, 23))	('ESCC', 'Disease', (133, 137))	('NAT2', 'Gene', '10', (9, 13))	('ESCC', 'Disease', (264, 268))	('rs1565684', 'Var', (14, 23))
124373	24586291	In the dominant model, the NAT2 rs1565684 TC/CC variants were not associated with the risk of ESCC, compared with the NAT2 rs1565684 TT genotype (TC/CC vs. TT: OR = 1.20, 95% CI = 0.96-1.51, p = 0.107).	('rs1565684', 'Mutation', 'rs1565684', (123, 132))	('NAT2', 'Gene', (118, 122))	('NAT2', 'Gene', '10', (27, 31))	('TC/CC', 'Gene', (42, 47))	('rs1565684', 'Var', (32, 41))	('NAT2', 'Gene', (27, 31))	('NAT2', 'Gene', '10', (118, 122))	('rs1565684', 'Mutation', 'rs1565684', (32, 41))	('ESCC', 'Disease', (94, 98))
124374	24586291	In the recessive model, when the NAT2 rs1565684 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with an 86% increased risk of ESCC (CC vs. TT/TC: OR = 1.86, 95% CI = 1.04-3.33, p = 0.037) (Table 3).	('rs1565684', 'Mutation', 'rs1565684', (38, 47))	('NAT2', 'Gene', (33, 37))	('NAT2', 'Gene', '10', (33, 37))	('rs1565684', 'Var', (38, 47))	('ESCC', 'Disease', (170, 174))
124377	24586291	To evaluate the effects of NAT2 rs1565684 T>C genotypes on ESCC risk according to different age, sex, smoking and alcohol drinking status; we performed the stratification analyses (Table 4).	('rs1565684 T>C', 'Var', (32, 45))	('NAT2', 'Gene', '10', (27, 31))	('ESCC', 'Disease', (59, 63))	('NAT2', 'Gene', (27, 31))	('rs1565684', 'Mutation', 'rs1565684', (32, 41))	('alcohol', 'Chemical', 'MESH:D000438', (114, 121))	('alcohol drinking', 'Phenotype', 'HP:0030955', (114, 130))
124378	24586291	A significantly increased risk of ESCC associated with the NAT2 rs1565684 T>C polymorphism was evident among older patients and patients who never drunk (Table 4).	('NAT2', 'Gene', '10', (59, 63))	('rs1565684', 'Mutation', 'rs1565684', (64, 73))	('patients', 'Species', '9606', (115, 123))	('rs1565684 T>C', 'Var', (64, 77))	('NAT2', 'Gene', (59, 63))	('ESCC', 'Disease', (34, 38))	('patients', 'Species', '9606', (128, 136))
124379	24586291	In this hospital-based case-control study of ESCC, we found that ten selected NAT2 tagging SNPs were not associated with the risk of ESCC after the Bonferroni correction.	('N', 'Chemical', 'MESH:D009584', (92, 93))	('NAT2', 'Gene', (78, 82))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('ESCC', 'Disease', (133, 137))	('SNPs', 'Var', (91, 95))	('NAT2', 'Gene', '10', (78, 82))
124380	24586291	NAT2 rs1565684 CC genotype was associated with a borderline significantly increased risk for ESCC.	('rs1565684', 'Mutation', 'rs1565684', (5, 14))	('NAT2', 'Gene', (0, 4))	('rs1565684 CC', 'Var', (5, 17))	('ESCC', 'Disease', (93, 97))	('NAT2', 'Gene', '10', (0, 4))
124381	24586291	A significantly increased risk of ESCC associated with the NAT2 rs1565684 T>C polymorphism was evident among older patients and patients who never drunk.	('NAT2', 'Gene', '10', (59, 63))	('rs1565684', 'Mutation', 'rs1565684', (64, 73))	('patients', 'Species', '9606', (115, 123))	('rs1565684 T>C', 'Var', (64, 77))	('NAT2', 'Gene', (59, 63))	('ESCC', 'Disease', (34, 38))	('patients', 'Species', '9606', (128, 136))
124382	24586291	To the best of our knowledge, it's the first positive finding of NAT2 rs1565684 T>C polymorphism and ESCC risk.	('NAT2', 'Gene', '10', (65, 69))	('rs1565684', 'Mutation', 'rs1565684', (70, 79))	('NAT2', 'Gene', (65, 69))	('ESCC', 'Disease', (101, 105))	('rs1565684 T>C', 'Var', (70, 83))
124383	24586291	NAT2 is involved in the metabolism of a major class of tobacco smoke carcinogens (the aromatic amines) and NAT2 variant alleles result in slow clearance of aromatic amines.	('aromatic amines', 'Chemical', '-', (156, 171))	('clearance of aromatic amines', 'MPA', (143, 171))	('variant', 'Var', (112, 119))	('NAT2', 'Gene', '10', (107, 111))	('NAT2', 'Gene', (0, 4))	('tobacco', 'Species', '4097', (55, 62))	('slow', 'NegReg', (138, 142))	('aromatic amines', 'Chemical', '-', (86, 101))	('NAT2', 'Gene', (107, 111))	('NAT2', 'Gene', '10', (0, 4))
124388	24586291	However, in another study in Taiwan, NAT2 polymorphisms did not affect the risk of esophageal cancer, irrespective of environmental factors.	('esophageal cancer', 'Disease', (83, 100))	('NAT2', 'Gene', (37, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('polymorphisms', 'Var', (42, 55))	('NAT2', 'Gene', '10', (37, 41))
124390	24586291	NAT2 polymorphisms did not significantly modulate the cancer risk after interaction with environmental factors, such as tobacco, alcohol or occupational exposure.	('interaction', 'Interaction', (72, 83))	('alcohol', 'Chemical', 'MESH:D000438', (129, 136))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tobacco', 'Species', '4097', (120, 127))	('cancer', 'Disease', (54, 60))	('NAT2', 'Gene', (0, 4))	('modulate', 'Reg', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('polymorphisms', 'Var', (5, 18))	('NAT2', 'Gene', '10', (0, 4))
124391	24586291	In another study in the Kashmir Valley, none of the three NAT2 polymorphic alleles (rs1799929, rs1799930 and rs1799931) was found to be independently associated with risk of esophageal and gastric cancers, which was also in accordance with our results.	('associated', 'Reg', (150, 160))	('NAT2', 'Gene', '10', (58, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('rs1799929', 'Var', (84, 93))	('esophageal', 'Disease', (174, 184))	('gastric cancers', 'Disease', 'MESH:D013274', (189, 204))	('rs1799930', 'Mutation', 'rs1799930', (95, 104))	('rs1799931', 'Var', (109, 118))	('gastric cancers', 'Disease', (189, 204))	('rs1799929', 'Mutation', 'rs1799929', (84, 93))	('gastric cancers', 'Phenotype', 'HP:0012126', (189, 204))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('esophageal', 'Disease', 'MESH:D004941', (174, 184))	('rs1799931', 'Mutation', 'rs1799931', (109, 118))	('NAT2', 'Gene', (58, 62))	('rs1799930', 'Var', (95, 104))
124393	24586291	NAT2 rs1565684 T>C is in linkage disequilibrium with another important SNP NAT2 rs4345600 A>G (NS 12, -9306 A>G) (r2 = 0.845) in Chinese Han Beijing population.	('N', 'Chemical', 'MESH:D009584', (75, 76))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('rs4345600 A>G', 'Var', (80, 93))	('NAT2', 'Gene', (75, 79))	('NAT2', 'Gene', '10', (75, 79))	('rs1565684', 'Mutation', 'rs1565684', (5, 14))	('-9306 A>G', 'Mutation', 'rs4345600', (102, 111))	('NAT2', 'Gene', (0, 4))	('NAT2', 'Gene', '10', (0, 4))	('rs4345600', 'Mutation', 'rs4345600', (80, 89))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('rs1565684 T>C', 'Var', (5, 18))
124394	24586291	Although NAT2 rs1565684 T>C SNP is functional using SNP function prediction websites (http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm and http://www.regulomedb.org/).	('N', 'Chemical', 'MESH:D009584', (53, 54))	('NAT2', 'Gene', (9, 13))	('rs1565684', 'Mutation', 'rs1565684', (14, 23))	('rs1565684 T>C', 'Var', (14, 27))	('NAT2', 'Gene', '10', (9, 13))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('N', 'Chemical', 'MESH:D009584', (29, 30))
124395	24586291	The etiology of NAT2 rs1565684 T>C SNP is still not well known and need further investigation.	('rs1565684', 'Mutation', 'rs1565684', (21, 30))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('NAT2', 'Gene', (16, 20))	('rs1565684 T>C', 'Var', (21, 34))	('NAT2', 'Gene', '10', (16, 20))
124398	24586291	Finally, we did not obtain detailed information on cancer metastasis and survival, which restricted further analyses of the roles of the NAT2 polymorphisms in ESCC progression and prognosis.	('NAT2', 'Gene', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer metastasis', 'Disease', (51, 68))	('polymorphisms', 'Var', (142, 155))	('cancer metastasis', 'Disease', 'MESH:D009362', (51, 68))	('NAT2', 'Gene', '10', (137, 141))	('ESCC', 'Disease', (159, 163))
124400	33784583	The efficacy and safety of antibodies targeting PD-1 for treatment in advanced esophageal cancer: A systematic review and meta-analysis Programmed death 1 (PD-1) inhibitors have been proved to be effective in advanced esophageal cancer.	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('PD-1', 'Gene', (48, 52))	('PD-1', 'Gene', (156, 160))	('esophageal cancer', 'Disease', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('inhibitors', 'Var', (162, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))
124401	33784583	PD-1 inhibitors significantly prolonged the OS when compared with chemotherapy.	('prolonged', 'PosReg', (30, 39))	('inhibitors', 'Var', (5, 15))	('OS', 'Gene', '17451', (44, 46))	('PD-1', 'Gene', (0, 4))
124403	33784583	A novel therapy based on programmed death 1 (PD-1) inhibitors has been proved to be effective in advanced esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PD-1', 'Gene', (45, 49))	('esophageal cancer', 'Disease', (106, 123))	('inhibitors', 'Var', (51, 61))
124429	33784583	There are still many PD-1 inhibitors that made initial achievements in esophageal cancer, including SHR-1210, Sintilimab, etc.. Based on these study results, the anti-PD-1 therapy exerts a highly promising treatment paradigm in patients with advanced esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('esophageal cancer', 'Disease', (251, 268))	('esophageal cancer', 'Disease', 'MESH:D004938', (251, 268))	('patients', 'Species', '9606', (228, 236))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('anti-PD-1', 'Var', (162, 171))	('esophageal cancer', 'Disease', (71, 88))
124438	33784583	At final analysis, a significant improvement in OS was found among patients with advanced esophageal cancer treated with PD-1 inhibitors when compared with those treated with chemotherapy (HR: 0.79; 95% CI: 0.71-0.88; P<0.001; and heterogeneity: P = 0.34) (Fig.	('patients', 'Species', '9606', (67, 75))	('inhibitors', 'Var', (126, 136))	('improvement', 'PosReg', (33, 44))	('PD-1', 'Gene', (121, 125))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('OS', 'Gene', '17451', (48, 50))
124440	33784583	Same as before, patients with ESCC treated with PD-1 inhibitors received superior OS to chemotherapy (HR: 0.75; 95% CI: 0.66-0.84; P<0.001; and heterogeneity: P = 0.90)(Fig.	('inhibitors', 'Var', (53, 63))	('patients', 'Species', '9606', (16, 24))	('PD-1', 'Gene', (48, 52))	('ESCC', 'Disease', (30, 34))	('OS', 'Gene', '17451', (82, 84))
124455	33784583	We observed that PD-1 inhibitors significantly improved OS in advanced esophageal cancer when compared with chemotherapy.	('improved', 'PosReg', (47, 55))	('PD-1', 'Gene', (17, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('OS', 'Gene', '17451', (56, 58))	('inhibitors', 'Var', (22, 32))	('esophageal cancer', 'Disease', (71, 88))
124460	33784583	However, our results show that PD-1 inhibitors had a lower incidence of grade 3 - 5 treatment-related adverse effects than chemotherapy, which demonstrated patients receiving PD-1 inhibitors had a significant overall improvement in the quality of life.	('patients', 'Species', '9606', (156, 164))	('inhibitors', 'Var', (36, 46))	('PD-1', 'Gene', (175, 179))	('quality of life', 'CPA', (236, 251))	('PD-1', 'Gene', (31, 35))	('inhibitors', 'Var', (180, 190))	('improvement', 'PosReg', (217, 228))
124473	33784583	Some patients with esophageal cancer were reported to carry frequent amplification of chromosome 11q13 and those patients without 11q13 amplification, had significantly better ORR and PFS when compared with 11q13-amplified individuals.	('patients', 'Species', '9606', (5, 13))	('patients', 'Species', '9606', (113, 121))	('amplification', 'Var', (69, 82))	('esophageal cancer', 'Disease', (19, 36))	('better', 'PosReg', (169, 175))	('esophageal cancer', 'Disease', 'MESH:D004938', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
124477	33784583	This clinical study found that patients in the high TMB group obtained significant survival benefits.	('high', 'Var', (47, 51))	('TMB', 'Chemical', '-', (52, 55))	('patients', 'Species', '9606', (31, 39))	('survival benefits', 'CPA', (83, 100))
124480	33784583	This may explain why patients with advanced esophageal cancer might benefit from the OS when treated with PD-1 inhibitors and the difference of PFS and ORR in these studies.	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('PD-1', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patients', 'Species', '9606', (21, 29))	('inhibitors', 'Var', (111, 121))	('OS', 'Gene', '17451', (85, 87))	('benefit', 'PosReg', (68, 75))	('esophageal cancer', 'Disease', (44, 61))
124487	33784583	In conclusion, our analysis revealed that PD-1 inhibitors significantly prolonged the OS when compared with chemotherapy, while no significant difference in PFS and ORR for the population of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('OS', 'Gene', '17451', (86, 88))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('inhibitors', 'Var', (47, 57))	('PD-1', 'Gene', (42, 46))	('prolonged', 'PosReg', (72, 81))	('esophageal cancer', 'Disease', (191, 208))
124498	33123467	Lastly, the abnormal expression of miR-24 was involved in the chemo- and radio- therapies of cancer patients, indicating the role of miR-24 being as a predictive biomarker to cancer treatment.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('expression', 'MPA', (21, 31))	('miR-24', 'Gene', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('abnormal', 'Var', (12, 20))	('patients', 'Species', '9606', (100, 108))	('involved', 'Reg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
124505	33123467	For example, dysregulation of miRNAs has been widely involved in the activation of oncogenes in hepatocellular carcinoma (HCC), showing the potential diagnostic and therapeutic value of miRNAs in HCC.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', '220972', (186, 189))	('miR', 'Gene', (186, 189))	('involved', 'Reg', (53, 61))	('miR', 'Gene', (30, 33))	('hepatocellular carcinoma', 'Disease', (96, 120))	('HCC', 'Gene', (122, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('HCC', 'Gene', (196, 199))	('dysregulation', 'Var', (13, 26))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('HCC', 'Gene', '619501', (122, 125))	('HCC', 'Gene', '619501', (196, 199))	('oncogenes', 'Gene', (83, 92))	('HCC', 'Phenotype', 'HP:0001402', (196, 199))	('activation', 'PosReg', (69, 79))
124514	33123467	And ectopic miR-24 expression promoted NSCLC cell migration and invasion by targeting ZNF367.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('LC', 'Phenotype', 'HP:0100526', (42, 44))	('invasion', 'CPA', (64, 72))	('promoted', 'PosReg', (30, 38))	('NSCLC', 'Disease', (39, 44))	('ectopic', 'Var', (4, 11))	('targeting', 'Reg', (76, 85))	('miR-24', 'Gene', (12, 18))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('ZNF367', 'Gene', '195828', (86, 92))	('ZNF367', 'Gene', (86, 92))
124518	33123467	And patients whose primary tumors expressed high levels of miR-24-3p showed a significantly lower survival rate compared to patients with low miR-24-3p levels in the TCGA (The Cancer Genome Atlas Program) cohort.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('miR-24-3p', 'Chemical', '-', (59, 68))	('patients', 'Species', '9606', (124, 132))	('miR-24-3p', 'Var', (59, 68))	('miR-24-3p', 'Chemical', '-', (142, 151))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('Cancer', 'Disease', (176, 182))	('patients', 'Species', '9606', (4, 12))	('Cancer', 'Disease', 'MESH:D009369', (176, 182))	('lower', 'NegReg', (92, 97))	('survival rate', 'CPA', (98, 111))
124519	33123467	MiR-24 was found to reduce breast cancer cell apoptosis, cleaved caspase-3 and the expression of p27.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('MiR-24', 'Var', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('caspase-3', 'Gene', '836', (65, 74))	('reduce', 'NegReg', (20, 26))	('breast cancer', 'Disease', (27, 40))	('MiR-24', 'Chemical', '-', (0, 6))	('p27', 'Gene', '3429', (97, 100))	('p27', 'Gene', (97, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('expression', 'MPA', (83, 93))	('caspase-3', 'Gene', (65, 74))
124522	33123467	In colorectal cancer, miR-24-1-5p could decrease cell proliferation and migration by repressing beta-catenin expression, indicating its role as a tumor suppressor in CRC.	('decrease', 'NegReg', (40, 48))	('beta-catenin', 'Gene', '1499', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('miR-24-1-5p', 'Chemical', '-', (22, 33))	('miR-24-1-5p', 'Var', (22, 33))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cell proliferation', 'CPA', (49, 67))	('colorectal cancer', 'Disease', (3, 20))	('CRC', 'Phenotype', 'HP:0003003', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('repressing', 'NegReg', (85, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('beta-catenin', 'Gene', (96, 108))
124528	33123467	Several clinical evidences have supported the idea that dysregulation of miR-24 is correlated with the clinical features of human cancer.	('correlated', 'Reg', (83, 93))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('human', 'Species', '9606', (124, 129))	('dysregulation', 'Var', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miR-24', 'Gene', (73, 79))
124540	33123467	A variety of findings have confirmed that dysregulation of miR-24 is related to the clinical performance of human cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('clinical performance', 'CPA', (84, 104))	('dysregulation', 'Var', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('miR-24', 'Gene', (59, 65))	('human', 'Species', '9606', (108, 113))	('related', 'Reg', (69, 76))	('cancer', 'Disease', (114, 120))
124563	33123467	A study found that miR-24-3p had excellent diagnostic accuracy for oral squamous cell carcinoma [(AUC) = 0.738; P = 0.02], thus salivary exosomal miR-24-3p could be a potential novel diagnostic biomarker for OSCC.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('miR-24-3p', 'Chemical', '-', (146, 155))	('miR-24-3p', 'Chemical', '-', (19, 28))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 95))	('miR-24-3p', 'Var', (19, 28))	('oral squamous cell carcinoma', 'Disease', (67, 95))
124565	33123467	Regarding the differential expression of miR-24 in human cancer, miR-24 is associated with patient survival, indicating it could be a potential prognostic biomarker in cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('miR-24', 'Gene', (41, 47))	('human', 'Species', '9606', (51, 56))	('miR-24', 'Var', (65, 71))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('patient survival', 'CPA', (91, 107))	('associated', 'Reg', (75, 85))	('patient', 'Species', '9606', (91, 98))
124568	33123467	And in acute leukemia, Kaplan-Meier analysis showed that AL patients with high miR-24 expression tended to have shorter overall survival, and in the multivariate analysis stratified for known prognostic variables, miR-24 was identified as an independent prognostic marker.	('leukemia', 'Phenotype', 'HP:0001909', (13, 21))	('acute leukemia', 'Disease', 'MESH:D015470', (7, 21))	('high', 'Var', (74, 78))	('patients', 'Species', '9606', (60, 68))	('expression', 'MPA', (86, 96))	('acute leukemia', 'Phenotype', 'HP:0002488', (7, 21))	('miR-24', 'Gene', (79, 85))	('AL', 'Phenotype', 'HP:0002488', (57, 59))	('overall survival', 'MPA', (120, 136))	('shorter', 'NegReg', (112, 119))	('acute leukemia', 'Disease', (7, 21))	('AL', 'Disease', 'MESH:D009101', (57, 59))
124569	33123467	In contrast, CRC patients with low miR-24-3p level had a significantly poorer prognosis than those with high miR-24-3p level.	('CRC', 'Phenotype', 'HP:0003003', (13, 16))	('miR-24-3p', 'Chemical', '-', (35, 44))	('CRC', 'Disease', (13, 16))	('miR-24-3p level', 'Var', (35, 50))	('patients', 'Species', '9606', (17, 25))	('low', 'NegReg', (31, 34))	('miR-24-3p', 'Chemical', '-', (109, 118))
124570	33123467	And multivariate analysis revealed that miR-24-3p could be an independent prognostic indicator for OS of CRC patients.	('miR-24-3p', 'Chemical', '-', (40, 49))	('miR-24-3p', 'Var', (40, 49))	('patients', 'Species', '9606', (109, 117))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('OS of CRC', 'Disease', (99, 108))
124572	33123467	In nasopharyngeal carcinoma, a survey proved that exosomal miR-24-3p could serve as a prognostic biomarker, due to its involvement in tumor pathogenesis by mediating T-cell inhibition.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('T-cell inhibition', 'CPA', (166, 183))	('miR-24-3p', 'Chemical', '-', (59, 68))	('carcinoma', 'Disease', (18, 27))	('exosomal', 'Var', (50, 58))	('involvement', 'Reg', (119, 130))	('miR-24-3p', 'Protein', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('carcinoma', 'Disease', 'MESH:D009369', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
124580	33123467	In mesothelioma, miR-24-3p promoted tumorigenesis by inducing cancer cell growth and regulating Rho-GTP activity positively.	('miR-24-3p', 'Chemical', '-', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('GTP', 'Chemical', 'MESH:D006160', (100, 103))	('mesothelioma', 'Disease', (3, 15))	('regulating', 'Reg', (85, 95))	('promoted', 'PosReg', (27, 35))	('miR-24-3p', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('Rho-GTP activity', 'MPA', (96, 112))	('inducing', 'PosReg', (53, 61))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('tumor', 'Disease', (36, 41))
124581	33123467	In hepatocellular carcinoma, miR-24-3p increased cancer cell viability and reduced its cell apoptosis.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('reduced', 'NegReg', (75, 82))	('increased', 'PosReg', (39, 48))	('cell apoptosis', 'CPA', (87, 101))	('miR-24-3p', 'Chemical', '-', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('cancer', 'Disease', (49, 55))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('miR-24-3p', 'Var', (29, 38))
124585	33123467	Although a previous study showed that miR-24-3p functioned as a tumor suppressor in CRC.	('tumor', 'Disease', (64, 69))	('miR-24-3p', 'Chemical', '-', (38, 47))	('CRC', 'Disease', (84, 87))	('miR-24-3p', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
124588	33123467	MiR-24-3p mediated the tumorigenesis promotion and accelerated xenografted tumor growth of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('MiR-24-3p', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('MiR-24-3p', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (23, 28))	('accelerated', 'PosReg', (51, 62))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('tumor', 'Disease', (75, 80))
124589	33123467	As shown in Figure 1, overexpressing miR-24-3p promoted cell proliferation and inhibited cell apoptosis in breast cancer by targeting p27Kip1.	('p27Kip1', 'Gene', (134, 141))	('promoted', 'PosReg', (47, 55))	('cell apoptosis', 'CPA', (89, 103))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('inhibited', 'NegReg', (79, 88))	('breast cancer', 'Disease', (107, 120))	('cell proliferation', 'CPA', (56, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('miR-24-3p', 'Chemical', '-', (37, 46))	('targeting', 'Reg', (124, 133))	('p27Kip1', 'Gene', '1027', (134, 141))	('miR-24-3p', 'Var', (37, 46))
124592	33123467	In bladder cancer, miR-24-3p increased cell proliferation and migration ability by targeting DEDD (Asp-Glu-Asp-Asp domain).	('Asp', 'Chemical', 'MESH:D001224', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('DEDD', 'Gene', (93, 97))	('Glu', 'Chemical', 'MESH:D018698', (103, 106))	('increased', 'PosReg', (29, 38))	('migration ability', 'CPA', (62, 79))	('Asp', 'Chemical', 'MESH:D001224', (107, 110))	('DEDD', 'Gene', '9191', (93, 97))	('miR-24-3p', 'Chemical', '-', (19, 28))	('Asp', 'Chemical', 'MESH:D001224', (111, 114))	('bladder cancer', 'Disease', (3, 17))	('cell proliferation', 'CPA', (39, 57))	('miR-24-3p', 'Var', (19, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))
124593	33123467	On the other hand, however, miR-24 suppresses tumorigenesis in some human cancers.	('human', 'Species', '9606', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('tumor', 'Disease', (46, 51))	('miR-24', 'Var', (28, 34))	('cancers', 'Disease', (74, 81))	('suppresses', 'NegReg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
124595	33123467	In CRC, miR-24-3p suppressed cancer cell proliferation, cell migration and invasion, functioning as a tumor suppressor.	('cancer', 'Disease', (29, 35))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('invasion', 'CPA', (75, 83))	('cell migration', 'CPA', (56, 70))	('miR-24-3p', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('miR-24-3p', 'Chemical', '-', (8, 17))	('suppressed', 'NegReg', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
124596	33123467	And miR-24-1-5p decreased CRC cell proliferation, migration and survival significantly by repressing beta-catenin expression.	('survival', 'CPA', (64, 72))	('repressing', 'NegReg', (90, 100))	('beta-catenin', 'Gene', (101, 113))	('migration', 'CPA', (50, 59))	('beta-catenin', 'Gene', '1499', (101, 113))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))	('miR-24-1-5p', 'Chemical', '-', (4, 15))	('miR-24-1-5p', 'Var', (4, 15))	('CRC cell proliferation', 'CPA', (26, 48))	('decreased', 'NegReg', (16, 25))
124597	33123467	Ectopic expression of miR-24 inhibited cell cycle, proliferation, migration, and clonogenic potential of prostate cancer cells, as well as inducing cell apoptosis.	('inhibited', 'NegReg', (29, 38))	('migration', 'CPA', (66, 75))	('prostate cancer', 'Disease', (105, 120))	('clonogenic potential', 'CPA', (81, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('Ectopic expression', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('inducing', 'Reg', (139, 147))	('cell cycle', 'CPA', (39, 49))	('miR-24', 'Gene', (22, 28))	('cell apoptosis', 'CPA', (148, 162))
124598	33123467	In pancreatic ductal adenocarcinoma (PDA), miR-24-3p exerted its anti-cancer role by suppressing the expression of Laminin Subunit Beta 3 (LAMB3), an oncogene.	('LAMB3', 'Gene', '3914', (139, 144))	('LA', 'Phenotype', 'HP:0030078', (139, 141))	('Laminin Subunit Beta 3', 'Gene', (115, 137))	('suppressing', 'NegReg', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (3, 35))	('miR-24-3p', 'Chemical', '-', (43, 52))	('Laminin Subunit Beta 3', 'Gene', '3914', (115, 137))	('pancreatic ductal adenocarcinoma', 'Disease', (3, 35))	('LAMB3', 'Gene', (139, 144))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('expression', 'MPA', (101, 111))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('PDA', 'Phenotype', 'HP:0006725', (37, 40))	('miR-24-3p', 'Var', (43, 52))
124601	33123467	For example, in colorectal cancer, overexpression of miR-24-1-5p significantly repressed beta-catenin expression, and simultaneously decreased CRC cell migration.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('miR-24-1-5p', 'Chemical', '-', (53, 64))	('beta-catenin', 'Gene', '1499', (89, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('miR-24-1-5p', 'Var', (53, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('CRC cell migration', 'CPA', (143, 161))	('overexpression', 'PosReg', (35, 49))	('repressed', 'PosReg', (79, 88))	('beta-catenin', 'Gene', (89, 101))	('colorectal cancer', 'Disease', (16, 33))	('decreased', 'NegReg', (133, 142))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))
124602	33123467	also confirmed that miR-24 inhibited the cell growth of both lung and colon carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('miR-24', 'Var', (20, 26))	('colon carcinoma', 'Disease', (70, 85))	('inhibited', 'NegReg', (27, 36))	('cell growth', 'CPA', (41, 52))	('colon carcinoma', 'Disease', 'MESH:D003110', (70, 85))	('lung', 'Disease', (61, 65))
124604	33123467	And In lung adenocarcinoma, miR-24-3p could suppress cell proliferation, migration, and invasion by regulating FGFR3 directly.	('migration', 'CPA', (73, 82))	('miR-24-3p', 'Chemical', '-', (28, 37))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (7, 26))	('invasion', 'CPA', (88, 96))	('FGFR3', 'Gene', '2261', (111, 116))	('miR-24-3p', 'Var', (28, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (7, 26))	('suppress', 'NegReg', (44, 52))	('regulating', 'Reg', (100, 110))	('FGFR3', 'Gene', (111, 116))	('cell proliferation', 'CPA', (53, 71))	('lung adenocarcinoma', 'Disease', (7, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
124605	33123467	In acute lymphoblastic leukemia, miR-24-3p induced cell apoptosis by regulating XIAP (X-linked inhibitor of apoptosis protein).	('acute lymphoblastic leukemia', 'Disease', (3, 31))	('X-linked inhibitor of apoptosis protein', 'Gene', '331', (86, 125))	('leukemia', 'Phenotype', 'HP:0001909', (23, 31))	('induced', 'Reg', (43, 50))	('XIAP', 'Gene', (80, 84))	('XIAP', 'Gene', '331', (80, 84))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (3, 31))	('X-linked inhibitor of apoptosis protein', 'Gene', (86, 125))	('miR-24-3p', 'Chemical', '-', (33, 42))	('regulating', 'Reg', (69, 79))	('cell apoptosis', 'CPA', (51, 65))	('miR-24-3p', 'Var', (33, 42))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (3, 31))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (9, 31))
124613	33123467	What's more, ectopic expression of miR-24 could enhance the chemosensitivity of CRC cells to 5-fluorouracil (5-FU) by targeting RNA-binding protein DND1 (dead end protein 1).	('targeting', 'Reg', (118, 127))	('chemosensitivity of CRC cells', 'CPA', (60, 89))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (93, 107))	('RNA-binding protein', 'Protein', (128, 147))	('DND1', 'Gene', (148, 152))	('miR-24', 'Gene', (35, 41))	('enhance', 'PosReg', (48, 55))	('dead end protein 1', 'Gene', (154, 172))	('DND1', 'Gene', '373863', (148, 152))	('dead end protein 1', 'Gene', '373863', (154, 172))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('ectopic expression', 'Var', (13, 31))	('5-FU', 'Chemical', 'MESH:D005472', (109, 113))
124616	33123467	In prostate cancer, overexpression of miR-24-3p inhibited survival rate, half maximal inhibitory concentration (IC50) of paclitaxel (PTX) but increased apoptosis in prostate cancer cells after treatment of PTX, via regulating fascin1 (FSCN1).	('regulating', 'Reg', (215, 225))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('miR-24-3p', 'Chemical', '-', (38, 47))	('overexpression', 'PosReg', (20, 34))	('prostate cancer', 'Disease', (3, 18))	('FSCN1', 'Gene', (235, 240))	('paclitaxel', 'Chemical', 'MESH:D017239', (121, 131))	('miR-24-3p', 'Var', (38, 47))	('half', 'MPA', (73, 77))	('PTX', 'Chemical', 'MESH:D017239', (206, 209))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('fascin1', 'Gene', '6624', (226, 233))	('survival rate', 'CPA', (58, 71))	('PTX', 'Chemical', 'MESH:D017239', (133, 136))	('inhibited', 'NegReg', (48, 57))	('FSCN1', 'Gene', '6624', (235, 240))	('apoptosis', 'CPA', (152, 161))	('increased', 'PosReg', (142, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('fascin1', 'Gene', (226, 233))	('prostate cancer', 'Disease', (165, 180))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
124619	33123467	Interestingly, another study, published at the same year for the same cancer type, reported that miR-24-3p increased tamoxifen sensitivity by targeting Bim, leading to the induction of breast cancer cell apoptosis, acting as a tumor suppressor.	('tumor', 'Disease', (227, 232))	('cancer', 'Disease', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('increased', 'PosReg', (107, 116))	('tamoxifen', 'Chemical', 'MESH:D013629', (117, 126))	('cancer', 'Disease', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('miR-24-3p', 'Chemical', '-', (97, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('tamoxifen sensitivity', 'MPA', (117, 138))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('Bim', 'Gene', '10018', (152, 155))	('induction', 'Reg', (172, 181))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', (185, 198))	('miR-24-3p', 'Var', (97, 106))	('Bim', 'Gene', (152, 155))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
124700	31856412	The combination of multiple biomarkers could attain higher sensitivity compared with single biomarkers, which was consistent with the published data.27, 28, 29 Importantly, the further results indicated that the diagnostic value could be greatly improved via the combination of miRNAs and TAAbs, with AUC of 0.89 (0.85-0.93), sensitivity of 69%, specificity of 90%, and the accuracy of 81%, which was hopeful to surmount the tricky problem of low sensitivity of single type molecular marker.	('TAA', 'Chemical', 'MESH:C052697', (289, 292))	('combination', 'Interaction', (263, 274))	('miRNAs', 'Var', (278, 284))	('improved', 'PosReg', (246, 254))	('diagnostic', 'MPA', (212, 222))
124748	31284370	The esophageal hiatus is then expanded by a incision of the right pillar of the crus, followed by esophageal mobilization and an en-bloc lymphadenectomy in the lower mediastinum to about 5-7 cm above the level of the diaphragm (Figure 3c).	('esophageal hiatus', 'Disease', (4, 21))	('incision', 'Var', (44, 52))	('esophageal hiatus', 'Disease', 'MESH:D006551', (4, 21))
124824	30939533	HIV-infected individuals with low CD4 count are at highest risk for ESCC, but HIV infection was not independently associated with EAC or gastric cancer after adjusting for confounders.	('CD4', 'Gene', (34, 37))	('HIV infection', 'Disease', 'MESH:D015658', (78, 91))	('HIV-infected', 'Disease', (0, 12))	('ESCC', 'Disease', (68, 72))	('CD4', 'Gene', '920', (34, 37))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('HIV-infected', 'Disease', 'MESH:D015658', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('low', 'Var', (30, 33))	('gastric cancer', 'Disease', (137, 151))	('HIV infection', 'Disease', (78, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
124844	30939533	The HIV-infected cohort included patients aged 18 or above who fulfilled 2 out of the 3 following criteria: (1) laboratory criteria included patients with at least one positive HIV antibody test by Eliza or Western Blot; tested for HIV viral load (any +/-/indeterminate); or tested for CD4+ count; (2) treatment criteria included patients with at least one prescription in inpatient or outpatient pharmacy records for HIV ART; and (3) diagnosis criteria included any inpatient or outpatient encounter with an International Classification of Diseases, Ninth Revision (ICD-9) (042 or V08) or ICD-10 code (B20 & Z21) for HIV.	('outpatient', 'Species', '9606', (386, 396))	('outpatient', 'Species', '9606', (480, 490))	('HIV-infected', 'Disease', (4, 16))	('CD4', 'Gene', (286, 289))	('HIV-infected', 'Disease', 'MESH:D015658', (4, 16))	('patient', 'Species', '9606', (389, 396))	('patients', 'Species', '9606', (330, 338))	('patients', 'Species', '9606', (141, 149))	('patient', 'Species', '9606', (469, 476))	('patient', 'Species', '9606', (33, 40))	('patient', 'Species', '9606', (141, 148))	('Classification of Diseases', 'Disease', 'MESH:D008310', (523, 549))	('patient', 'Species', '9606', (483, 490))	('HIV ART', 'Disease', (418, 425))	('HIV ART', 'Disease', 'MESH:D015658', (418, 425))	('Classification of Diseases', 'Disease', (523, 549))	('patient', 'Species', '9606', (330, 337))	('B20 & Z21', 'Var', (603, 612))	('patients', 'Species', '9606', (33, 41))	('patient', 'Species', '9606', (375, 382))	('CD4', 'Gene', '920', (286, 289))
124856	30939533	First, we identified all esophageal and stomach cancer cases in the VA CCR based on primary site codes C15 and C16 with histology codes 817XX through 818XX as well as text searches.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('stomach cancer', 'Disease', 'MESH:D013274', (40, 54))	('esophageal', 'Disease', (25, 35))	('C15', 'Var', (103, 106))	('C16', 'Var', (111, 114))	('C16', 'CellLine', 'CVCL:2322', (111, 114))	('stomach cancer', 'Phenotype', 'HP:0012126', (40, 54))	('stomach cancer', 'Disease', (40, 54))
124857	30939533	We then identified patients with any ICD-9 (150.X and 151.X) or ICD-10 code (C15 and C16) for esophageal and stomach cancer from the inpatient and outpatient files of CDW.	('patient', 'Species', '9606', (135, 142))	('patient', 'Species', '9606', (19, 26))	('patient', 'Species', '9606', (150, 157))	('patients', 'Species', '9606', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('stomach cancer', 'Phenotype', 'HP:0012126', (109, 123))	('outpatient', 'Species', '9606', (147, 157))	('stomach cancer', 'Disease', 'MESH:D013274', (109, 123))	('esophageal', 'Disease', (94, 104))	('C15', 'Var', (77, 80))	('stomach cancer', 'Disease', (109, 123))	('C16', 'CellLine', 'CVCL:2322', (85, 88))	('150.X', 'Var', (44, 49))
124902	30939533	In addition to established risk factors for esophageal and stomach cancers (i.e., GERD for EAC, lower BMI and alcohol abuse for ESCC, and H. pylori infection for GNCC), we found that low CD4 count may be independently associated with increased risks for ESCC and GNCC in HIV-infected patients.	('patients', 'Species', '9606', (284, 292))	('CD4', 'Gene', '920', (187, 190))	('stomach cancers', 'Disease', (59, 74))	('GNCC', 'Chemical', '-', (162, 166))	('stomach cancers', 'Phenotype', 'HP:0012126', (59, 74))	('HIV-infected', 'Disease', (271, 283))	('lower BMI', 'Phenotype', 'HP:0045082', (96, 105))	('alcohol abuse', 'Disease', (110, 123))	('CD4', 'Gene', (187, 190))	('HIV-infected', 'Disease', 'MESH:D015658', (271, 283))	('H. pylori infection', 'Phenotype', 'HP:0005202', (138, 157))	('alcohol abuse', 'Disease', 'MESH:D000437', (110, 123))	('EAC', 'Phenotype', 'HP:0011459', (91, 94))	('alcohol abuse', 'Phenotype', 'HP:0030955', (110, 123))	('low', 'Var', (183, 186))	('esophageal', 'Disease', (44, 54))	('GNCC', 'Chemical', '-', (263, 267))	('H. pylori', 'Species', '210', (138, 147))	('infection', 'Disease', (148, 157))	('ESCC', 'Disease', (254, 258))	('infection', 'Disease', 'MESH:D007239', (148, 157))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('stomach cancer', 'Phenotype', 'HP:0012126', (59, 73))	('GNCC', 'Disease', (263, 267))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('stomach cancers', 'Disease', 'MESH:D013274', (59, 74))
124956	29149929	Numerous other mutations have been identified which predispose to RA, though none as strongly as the shared epitope, and none that are necessary or sufficient for development of disease.	('predispose', 'Reg', (52, 62))	('mutations', 'Var', (15, 24))	('RA', 'Phenotype', 'HP:0001370', (66, 68))	('men', 'Species', '9606', (170, 173))	('RA', 'Disease', 'MESH:D001172', (66, 68))
124960	29149929	Reactive arthritis is triggered by certain pathogens such as Campylobacter, Chlamydia and Salmonella.	('arthritis', 'Disease', (9, 18))	('arthritis', 'Disease', 'MESH:D001168', (9, 18))	('Chlamydia', 'Disease', (76, 85))	('arthritis', 'Phenotype', 'HP:0001369', (9, 18))	('triggered', 'Reg', (22, 31))	('Campylobacter', 'Var', (61, 74))	('Salmonella', 'Disease', (90, 100))
124974	29149929	Both of these studies suggested a pathogenic role of P. copri, with induction of disease and a TH-17 response following introduction of P. copri into a mouse model.	('TH', 'Chemical', 'MESH:D013910', (95, 97))	('P. copri', 'Var', (136, 144))	('P. copri', 'Species', '165179', (136, 144))	('TH-17 response', 'CPA', (95, 109))	('mouse', 'Species', '10090', (152, 157))	('disease', 'CPA', (81, 88))	('P. copri', 'Var', (53, 61))	('P. copri', 'Species', '165179', (53, 61))
124992	29149929	The typical patient has longstanding seropositive, erosive and nodular RA.	('nodular RA', 'Disease', (63, 73))	('seropositive', 'Var', (37, 49))	('nodular RA', 'Disease', 'MESH:D001172', (63, 73))	('patient', 'Species', '9606', (12, 19))	('RA', 'Phenotype', 'HP:0001370', (71, 73))	('erosive', 'Disease', (51, 58))
125053	29149929	About 35% of patients with Felty's syndrome with an abnormal liver enzyme have been found to have NRH on autopsy.	("Felty's syndrome", 'Disease', 'MESH:D005258', (27, 43))	('NRH', 'Disease', (98, 101))	('liver enzyme', 'Enzyme', (61, 73))	('patients', 'Species', '9606', (13, 21))	('abnormal', 'Var', (52, 60))	('abnormal liver enzyme', 'Phenotype', 'HP:0002910', (52, 73))	('abnormal liver', 'Phenotype', 'HP:0001392', (52, 66))	("Felty's syndrome", 'Disease', (27, 43))
125077	29149929	In another study, anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor were seen in 8-10% of patients with autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC)), while 5% of those patients actually had a clinical diagnosis of RA.	('PSC', 'Gene', (243, 246))	('rheumatoid', 'Disease', (73, 83))	('cholangitis', 'Disease', (192, 203))	('primary biliary cholangitis', 'Disease', 'MESH:D008105', (176, 203))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (219, 241))	('liver diseases', 'Phenotype', 'HP:0001392', (138, 152))	('cholangitis', 'Disease', 'MESH:D002761', (230, 241))	('RA', 'Phenotype', 'HP:0001370', (314, 316))	('patients', 'Species', '9606', (268, 276))	('primary biliary cholangitis', 'Disease', (176, 203))	('autoimmune liver diseases', 'Disease', 'MESH:D008107', (127, 152))	('autoimmune hepatitis', 'Disease', 'MESH:D019693', (154, 174))	('cholangitis', 'Disease', (230, 241))	('cholangitis', 'Phenotype', 'HP:0030151', (192, 203))	('primary biliary cholangitis', 'Phenotype', 'HP:0002613', (176, 203))	('hepatitis', 'Phenotype', 'HP:0012115', (165, 174))	('patients', 'Species', '9606', (113, 121))	('anti-cyclic', 'Var', (18, 29))	('cholangitis', 'Phenotype', 'HP:0030151', (230, 241))	('PSC', 'Gene', '100653366', (243, 246))	('rheumatoid', 'Disease', 'MESH:D001172', (73, 83))	('RA', 'Disease', 'MESH:D001172', (314, 316))	('autoimmune hepatitis', 'Disease', (154, 174))	('autoimmune liver diseases', 'Disease', (127, 152))	('cholangitis', 'Disease', 'MESH:D002761', (192, 203))
125078	29149929	There may be some shared genetic risk between RA and autoimmune hepatitis, as STAT4 polymorphisms have been associated with both conditions.	('STAT4', 'Gene', '6775', (78, 83))	('autoimmune hepatitis', 'Disease', (53, 73))	('STAT4', 'Gene', (78, 83))	('autoimmune hepatitis', 'Disease', 'MESH:D019693', (53, 73))	('RA', 'Disease', 'MESH:D001172', (46, 48))	('RA', 'Phenotype', 'HP:0001370', (46, 48))	('associated', 'Reg', (108, 118))	('hepatitis', 'Phenotype', 'HP:0012115', (64, 73))	('polymorphisms', 'Var', (84, 97))
125135	29149929	The risk of viral infections appears to be modestly increased in patients using biologic therapies, with about 1.9 times higher odds for viral infection in those treated with biologics compared to other RA treatments (95% CI 1.02-3.58).	('RA', 'Phenotype', 'HP:0001370', (203, 205))	('viral infections', 'Disease', 'MESH:D001102', (12, 28))	('viral infection', 'Disease', (137, 152))	('biologics', 'Var', (175, 184))	('men', 'Species', '9606', (211, 214))	('viral infection', 'Disease', 'MESH:D001102', (12, 27))	('patients', 'Species', '9606', (65, 73))	('RA', 'Disease', 'MESH:D001172', (203, 205))	('viral infection', 'Disease', 'MESH:D001102', (137, 152))	('viral infections', 'Disease', (12, 28))
125143	29149929	CMV has been described to cause myriad manifestations within the GI tract, including colitis, ulcerations, gastritis, esophagitis, ileitis, appendicitis, and hepatitis.	('cause', 'Reg', (26, 31))	('colitis', 'Phenotype', 'HP:0002583', (85, 92))	('ulcer', 'Disease', (94, 99))	('gastritis', 'Disease', 'MESH:D005756', (107, 116))	('ileitis', 'Disease', 'MESH:D007079', (131, 138))	('gastritis', 'Disease', (107, 116))	('esophagitis', 'Disease', (118, 129))	('appendicitis', 'Disease', (140, 152))	('esophagitis', 'Disease', 'MESH:D004941', (118, 129))	('colitis', 'Disease', (85, 92))	('hepatitis', 'Phenotype', 'HP:0012115', (158, 167))	('CMV', 'Var', (0, 3))	('appendicitis', 'Disease', 'MESH:D001064', (140, 152))	('hepatitis', 'Disease', 'MESH:D056486', (158, 167))	('esophagitis', 'Phenotype', 'HP:0100633', (118, 129))	('colitis', 'Disease', 'MESH:D003092', (85, 92))	('hepatitis', 'Disease', (158, 167))	('ulcer', 'Disease', 'MESH:D014456', (94, 99))	('gastritis', 'Phenotype', 'HP:0005263', (107, 116))	('ileitis', 'Phenotype', 'HP:0032564', (131, 138))	('ileitis', 'Disease', (131, 138))
125151	29149929	For example, azathioprine can be used in IBD and autoimmune hepatitis and may help improve RA.	('IBD', 'Disease', (41, 44))	('autoimmune hepatitis', 'Disease', (49, 69))	('RA', 'Disease', 'MESH:D001172', (91, 93))	('azathioprine', 'Chemical', 'MESH:D001379', (13, 25))	('improve', 'PosReg', (83, 90))	('autoimmune hepatitis', 'Disease', 'MESH:D019693', (49, 69))	('IBD', 'Phenotype', 'HP:0002037', (41, 44))	('azathioprine', 'Var', (13, 25))	('hepatitis', 'Phenotype', 'HP:0012115', (60, 69))	('RA', 'Phenotype', 'HP:0001370', (91, 93))
125269	25980316	Furthermore, knockdown of FAM84B delayed tumor growth in ectopic xenografts.	('delayed', 'NegReg', (33, 40))	('FAM84B', 'Gene', '157638', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('FAM84B', 'Gene', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('knockdown', 'Var', (13, 22))
125293	25980316	Patients with fold change <0.3 had a significantly higher chance to achieve pCR (p = 0.01).	('fold', 'Var', (14, 18))	('pCR', 'Disease', (76, 79))	('CR', 'Chemical', 'MESH:D002857', (77, 79))	('Patients', 'Species', '9606', (0, 8))	('<0.3', 'Var', (26, 30))
125294	25980316	In survival analysis, patients with fold change <0.3 had a trend toward longer progression-free survival (median not reached versus 18 months, p =0.15; Fig.	('progression-free survival', 'CPA', (79, 104))	('fold change <0.3', 'Var', (36, 52))	('patients', 'Species', '9606', (22, 30))	('longer', 'PosReg', (72, 78))	('<0.3', 'Var', (48, 52))
125303	25980316	Interestingly, patients with high intensity on pretreatment tumor biopsies had non-significant worse progression-free survival than those with low intensity (median 18 months versus not reached, p = 0.098; Fig.	('patients', 'Species', '9606', (15, 23))	('worse', 'NegReg', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('progression-free survival', 'CPA', (101, 126))	('tumor', 'Disease', (60, 65))	('high intensity', 'Var', (29, 43))
125306	25980316	Expression by the 9 esophageal SCC cell lines was strong in CE-81T/VGH, KYSE-30, KYSE-410, and OE-21, moderate in KYSE-150, and weak or absent in KYSE-70, KYSE-270, CE-48T/VGH (data not shown), and CE-146T/VGH (data not shown; Fig.	('strong', 'PosReg', (50, 56))	('SCC', 'Gene', (31, 34))	('Expression', 'MPA', (0, 10))	('SCC', 'Phenotype', 'HP:0002860', (31, 34))	('SCC', 'Gene', '6317', (31, 34))	('KYSE-410', 'Var', (81, 89))	('absent', 'NegReg', (136, 142))	('CE-81T/VGH', 'Var', (60, 70))	('KYSE-30', 'Var', (72, 79))
125329	25980316	We also analyzed whole blood for germline SNPs and identified two SNPs (rs16863886 and rs4954256) with a high accuracy for predicting CRT response.	('CRT response', 'MPA', (134, 146))	('rs4954256', 'Mutation', 'rs4954256', (87, 96))	('rs4954256', 'Var', (87, 96))	('CR', 'Chemical', 'MESH:D002857', (134, 136))	('rs16863886', 'Mutation', 'rs16863886', (72, 82))	('rs16863886', 'Var', (72, 82))
125345	25980316	Most interestingly, our in vivo ectopic xenografts showed knockout of FAM84B results in tumor growth delay.	('tumor growth delay', 'Disease', 'MESH:D006130', (88, 106))	('FAM84B', 'Gene', (70, 76))	('tumor growth delay', 'Disease', (88, 106))	('FAM84B', 'Gene', '157638', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('knockout', 'Var', (58, 66))	('growth delay', 'Phenotype', 'HP:0001510', (94, 106))
125351	25980316	Genetic variants of this locus have known associations with susceptibility to prostate, ovarian, and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('associations', 'Reg', (42, 54))	('prostate', 'Disease', (78, 86))	('variants', 'Var', (8, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('ovarian', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))
125352	25980316	found amplification of 8q24 in ESCC, but found c-MYC protein expression in part of the esophageal cancerous nest in only 4 of 46 cases by IHC analysis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('esophageal cancerous', 'Disease', (87, 107))	('c-MYC', 'Gene', '4609', (47, 52))	('SCC', 'Gene', (32, 35))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('amplification', 'Var', (6, 19))	('c-MYC', 'Gene', (47, 52))	('esophageal cancerous', 'Disease', 'MESH:D004938', (87, 107))	('expression', 'MPA', (61, 71))	('SCC', 'Gene', '6317', (32, 35))
125358	25980316	FAM84B gene expression is down-regulated in pancreatic cancer cells treated with the heat shock protein 90 inhibitor, IPI-504, and in BRAF mutant melanoma cells treated with the MEK inhibitor, PD-032590.	('FAM84B', 'Gene', (0, 6))	('shock', 'Phenotype', 'HP:0031273', (90, 95))	('FAM84B', 'Gene', '157638', (0, 6))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('MEK', 'Gene', '5609', (178, 181))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('BRAF', 'Gene', '673', (134, 138))	('IPI-504', 'Chemical', 'MESH:C112765', (118, 125))	('BRAF', 'Gene', (134, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('MEK', 'Gene', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Disease', (44, 61))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('PD-032590', 'Chemical', '-', (193, 202))	('mutant', 'Var', (139, 145))	('expression', 'MPA', (12, 22))	('down-regulated', 'NegReg', (26, 40))
125360	25980316	In present study, we showed that FAM84B knockdown resulted in tumor growth delay.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('growth delay', 'Phenotype', 'HP:0001510', (68, 80))	('knockdown', 'Var', (40, 49))	('FAM84B', 'Gene', (33, 39))	('tumor growth delay', 'Disease', 'MESH:D006130', (62, 80))	('FAM84B', 'Gene', '157638', (33, 39))	('tumor growth delay', 'Disease', (62, 80))
125379	25980316	The PCR conditions were as follows: 50 cycles of denaturation at 95  C for 15 sec and 1 min of annealing and elongation at 60  C. Beta-actin (Hs99999903_m1) was selected as an internal control.	('CR', 'Chemical', 'MESH:D002857', (5, 7))	('Beta-actin', 'Gene', '728378', (130, 140))	('Hs99999903_m1', 'Var', (142, 155))	('Beta-actin', 'Gene', (130, 140))
125389	25980316	The human esophageal squamous cell lines CE-48T/VGH, CE-81T/VGH, and CE-146/VGH (Bioresource Collection and Research Center [BCRC], Hsiuchu City, Taiwan) were maintained in DMEM (Gibco), while KYSE-30, KYSE-70, KYSE-150, KYSE-270, KYSE-410, OE-21 were gifts of Dr. Chih-Hung Hsu and cultured in RPMI 1640.	('human', 'Species', '9606', (4, 9))	('CR', 'Chemical', 'MESH:D002857', (126, 128))	('KYSE-410', 'Var', (231, 239))	('CE-146/VGH', 'Var', (69, 79))
125396	25980316	To establish a stable clonal cell population with knockout FAM84B, specific shRNA constructs cloned into plasmid pLKO.1-puro are obtained from The RNAi Consortium (TRC) via National RNAi Core Facility (Academia Sinica, Taiwan ROC).	('FAM84B', 'Gene', (59, 65))	('Academia Sinica', 'Disease', 'None', (202, 217))	('knockout', 'Var', (50, 58))	('FAM84B', 'Gene', '157638', (59, 65))	('Academia Sinica', 'Disease', (202, 217))
125574	33213103	However, one study identified a EUS-FNA-associated hemorrhage outside the gastrointestinal wall in 3 of 227 patients (1.3%), which was managed by inflating a balloon on the echoendoscope tip and compressing the puncture region for 15-20 min.	('patients', 'Species', '9606', (108, 116))	('hemorrhage', 'Disease', 'MESH:D006470', (51, 61))	('inflating', 'Var', (146, 155))	('hemorrhage', 'Disease', (51, 61))
125613	33213103	In addition, lesions in the pancreatic head or uncinate process require the endoscopist to navigate long distances through abundant pancreatic parenchyma to the puncture target site, which may increase the risk of developing acute pancreatitis.	('lesions', 'Var', (13, 20))	('pancreatitis', 'Phenotype', 'HP:0001733', (231, 243))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (225, 243))	('acute pancreatitis', 'Disease', (225, 243))	('acute pancreatitis', 'Disease', 'MESH:D010195', (225, 243))	('increase', 'Reg', (193, 201))	('pancreatic head', 'Disease', 'MESH:D010195', (28, 43))	('pancreatic head', 'Disease', (28, 43))
125621	33213103	It is possible that puncture during EUS-FNA can cause hemorrhage and adhesion development, which may influence the survival of tumor cells in the lymphatic vessels, and similar changes may occur within the gastric wall (Table 4).	('puncture', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('adhesion development', 'CPA', (69, 89))	('tumor', 'Disease', (127, 132))	('cause', 'Reg', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('survival', 'CPA', (115, 123))	('influence', 'Reg', (101, 110))	('hemorrhage', 'Disease', (54, 64))	('hemorrhage', 'Disease', 'MESH:D006470', (54, 64))
125654	33213103	Another study revealed only 1 case (1.0%) of mild abdominal pain that developed after EUS-FNA was performed in 104 patients with lymph node lesions, including 50 patients with mediastinal lymph node lesions and 48 patients with intraperitoneal lymph node lesions (1.0%).	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (115, 123))	('mediastinal lymph node lesions', 'Phenotype', 'HP:0100721', (176, 206))	('abdominal pain', 'Disease', 'MESH:D015746', (50, 64))	('patients', 'Species', '9606', (214, 222))	('lesions', 'Var', (140, 147))	('pain', 'Phenotype', 'HP:0012531', (60, 64))	('abdominal pain', 'Phenotype', 'HP:0002027', (50, 64))	('mild abdominal pain', 'Phenotype', 'HP:0002574', (45, 64))	('abdominal pain', 'Disease', (50, 64))
125666	33213103	Thus, it has been suggested that the Tru-Cut needles might cause major intra-tissue damage that might lead to intra-tissue hemorrhages and an environment that favors bacterial proliferation, with repeated punctures potentially being linked to the onset of severe infection.	('favors', 'PosReg', (159, 165))	('lead to', 'Reg', (102, 109))	('hemorrhages', 'Disease', 'MESH:D006470', (123, 134))	('severe infection', 'Phenotype', 'HP:0032169', (256, 272))	('hemorrhages', 'Disease', (123, 134))	('Tru-Cut needles', 'Var', (37, 52))	('bacterial proliferation', 'CPA', (166, 189))	('infection', 'Disease', (263, 272))	('infection', 'Disease', 'MESH:D007239', (263, 272))
125694	33213103	Moreover, although EUS-FNA is a fundamentally safe technique for adrenal lesions, adrenal hemorrhage has been reported, and computed tomography should be performed to investigate abdominal pain that develops after EUS-FNA.	('abdominal pain', 'Disease', (179, 193))	('adrenal hemorrhage', 'Disease', 'MESH:D006470', (82, 100))	('adrenal lesions', 'Disease', 'MESH:D000312', (65, 80))	('EUS-FNA', 'Var', (214, 221))	('abdominal pain', 'Disease', 'MESH:D015746', (179, 193))	('adrenal lesions', 'Disease', (65, 80))	('abdominal pain', 'Phenotype', 'HP:0002027', (179, 193))	('adrenal hemorrhage', 'Disease', (82, 100))	('pain', 'Phenotype', 'HP:0012531', (189, 193))
125703	33194605	Aberrant DNA Methylation in Esophageal Squamous Cell Carcinoma: Biological and Clinical Implications Almost all cancer cells possess multiple epigenetic abnormalities, which cooperate with genetic alterations to enable the acquisition of cancer hallmarks during tumorigenesis.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (39, 62))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('epigenetic abnormalities', 'Disease', (142, 166))	('tumor', 'Disease', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('Squamous Cell Carcinoma', 'Disease', (39, 62))	('epigenetic abnormalities', 'Disease', 'MESH:D018376', (142, 166))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('Carcinoma', 'Phenotype', 'HP:0030731', (53, 62))
125704	33194605	As the most frequently found epigenetic change in human cancers, aberrant DNA methylation manifests at two major forms: global genomic DNA hypomethylation and locus-specific promoter region hypermethylation.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('aberrant', 'Var', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('human', 'Species', '9606', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('hypomethylation', 'Var', (139, 154))
125706	33194605	In ESCC, DNA methylation alterations affect genes involved in cell cycle regulation, DNA damage repair, and cancer-related signaling pathways.	('alterations', 'Var', (25, 36))	('genes', 'Gene', (44, 49))	('affect', 'Reg', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('methylation alterations', 'Var', (13, 36))	('ESCC', 'Disease', (3, 7))	('cell', 'CPA', (62, 66))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
125711	33194605	Intensive molecular biological studies have revealed that epigenetic dysregulation is a fundamental characteristic of nearly all human cancers.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('epigenetic dysregulation', 'Var', (58, 82))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('human', 'Species', '9606', (129, 134))
125712	33194605	The most widely studied epigenetic modification is DNA methylation, which meanwhile is the most frequently found abnormal epigenetic change in human cancers.	('DNA methylation', 'Var', (51, 66))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('human', 'Species', '9606', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
125715	33194605	The two major DNA methylation changes that occur in human cancers, including ESCC, are global DNA hypomethylation and site-specific CpG island promoter hypermethylation.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ESCC', 'Disease', (77, 81))	('human', 'Species', '9606', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('hypomethylation', 'Var', (98, 113))
125716	33194605	Thus, global DNA hypomethylation increases chromosomal instability, leading to cancer development.	('chromosomal instability', 'Phenotype', 'HP:0040012', (43, 66))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('leading to', 'Reg', (68, 78))	('chromosomal instability', 'MPA', (43, 66))	('increases', 'PosReg', (33, 42))	('cancer', 'Disease', (79, 85))	('global DNA hypomethylation', 'Var', (6, 32))
125717	33194605	On the other hand, hypermethylation of the CpG islands located in gene promoter regions may involve in carcinogenesis as a result of three possible mechanisms: (1) cytosine methylation facilitates gene mutation, as 5-methylcytosine is deaminated to thymine; (2) aberrant DNA methylation may be associated with allelic loss; (3) tumor suppressor genes (TSGs) may be inactivated by promoter hypermethylation (Figure 1).	('thymine', 'Chemical', 'MESH:D013941', (249, 256))	('TSG', 'Gene', (352, 355))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('aberrant', 'Var', (262, 270))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (215, 231))	('promoter hypermethylation', 'Var', (380, 405))	('inactivated', 'NegReg', (365, 376))	('cytosine', 'Chemical', 'MESH:D003596', (164, 172))	('TSG', 'Gene', '57045', (352, 355))	('cytosine', 'Chemical', 'MESH:D003596', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('carcinogenesis', 'Disease', (103, 117))	('tumor', 'Disease', (328, 333))
125719	33194605	Mechanistically, changes in DNA methylation contribute to the cancer development process through regulation of the spatial chromatin organization and alteration of the transcriptome at the right timing and environment.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('contribute', 'Reg', (44, 54))	('transcriptome', 'MPA', (168, 181))	('changes', 'Var', (17, 24))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('alteration', 'Reg', (150, 160))	('spatial chromatin', 'MPA', (115, 132))
125724	33194605	Global DNA hypomethylation in cancer tissues was first observed more than 3 decades ago and has been recognized as a key mechanism involved in carcinogenesis.	('Global DNA', 'Var', (0, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('carcinogenesis', 'Disease', (143, 157))	('involved', 'Reg', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
125726	33194605	Importantly, genome-wide hypomethylation was consistently observed in ESCCs, and LINE-1 hypomethylation was strongly correlated with ESCC progression, leading to a poor prognosis among ESCC patients.	('hypomethylation', 'Var', (25, 40))	('patients', 'Species', '9606', (190, 198))	('ESCC', 'Disease', (133, 137))	('hypomethylation', 'Var', (88, 103))	('ESCCs', 'Disease', (70, 75))	('observed', 'Reg', (58, 66))	('correlated', 'Reg', (117, 127))
125727	33194605	In ESCC, as well as other malignancies, aberrant hypermethylation in promoter CpG islands is involved in the major components of cell cycle regulation, DNA damage repair, and cancer-related signaling pathways.	('malignancies', 'Disease', 'MESH:D009369', (26, 38))	('aberrant hypermethylation', 'Var', (40, 65))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('malignancies', 'Disease', (26, 38))	('involved', 'Reg', (93, 101))	('ESCC', 'Disease', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
125729	33194605	Inactivation of DNA repair genes MGMT, MLH1, and MSH2 in ESCC mainly attributes to the methylation change in their promoter regions.	('methylation change', 'MPA', (87, 105))	('MLH1', 'Gene', '4292', (39, 43))	('MLH1', 'Gene', (39, 43))	('MGMT', 'Gene', (33, 37))	('MSH2', 'Gene', (49, 53))	('MGMT', 'Gene', '4255', (33, 37))	('MSH2', 'Gene', '4436', (49, 53))	('Inactivation', 'Var', (0, 12))
125730	33194605	Promoter hypermethylation in the genes of APC, RUNX3, and ZNF382 respectively affects the Wnt/beta-catenin, TGF-beta, and NF-kappaB pathways in ESCC.	('TGF-beta', 'Gene', (108, 116))	('affects', 'Reg', (78, 85))	('RUNX3', 'Gene', '864', (47, 52))	('beta-catenin', 'Gene', (94, 106))	('NF-kappaB pathways', 'Pathway', (122, 140))	('ESCC', 'Disease', (144, 148))	('ZNF382', 'Gene', (58, 64))	('APC', 'Disease', 'MESH:D011125', (42, 45))	('beta-catenin', 'Gene', '1499', (94, 106))	('TGF-beta', 'Gene', '7039', (108, 116))	('ZNF382', 'Gene', '84911', (58, 64))	('APC', 'Disease', (42, 45))	('RUNX3', 'Gene', (47, 52))	('Promoter hypermethylation', 'Var', (0, 25))
125735	33194605	There is growing recognition that aberrant DNA methylation patterns occur in the earliest stage of ESCC and may parallel the histologic changes observed during ESCC carcinogenesis.	('ESCC', 'Disease', (160, 164))	('DNA methylation', 'MPA', (43, 58))	('aberrant', 'Var', (34, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (165, 179))	('ESCC', 'Disease', (99, 103))	('carcinogenesis', 'Disease', (165, 179))
125738	33194605	Methylation of this gene promoter occurs in the early stages of ESCC and accumulates with esophageal progression tendency during carcinogenesis, resulting in HIN-1 silencing in carcinomas-in-situ.	('esophageal progression', 'Disease', (90, 112))	('HIN-1 silencing in carcinomas-in-situ', 'Disease', (158, 195))	('ESCC', 'Disease', (64, 68))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('Methylation', 'Var', (0, 11))	('HIN-1 silencing in carcinomas-in-situ', 'Disease', 'MESH:D002278', (158, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinogenesis', 'Disease', (129, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))
125750	33194605	Their analysis also identified numerous DNA methylation alterations associated with ESCC carcinogenesis and lymph node metastasis.	('associated', 'Reg', (68, 78))	('lymph node metastasis', 'CPA', (108, 129))	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('carcinogenesis', 'Disease', (89, 103))	('methylation alterations', 'Var', (44, 67))
125755	33194605	In several cancer types, the methods of detecting aberrant DNA methylation changes have been applied to clinical fields related to early diagnosis, prognostic prediction, and personalized therapy.	('cancer', 'Disease', (11, 17))	('aberrant', 'Var', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))
125757	33194605	In fact, aberrantly methylated genes have been detected in the plasma or serum from ESCC patients, implying that they may serve as non-invasive diagnostic biomarkers.	('aberrantly methylated genes', 'Var', (9, 36))	('patients', 'Species', '9606', (89, 97))	('detected', 'Reg', (47, 55))	('ESCC', 'Disease', (84, 88))
125763	33194605	The aberrant methylation pattern has also been identified as a prognostic indicator for ESCC patients.	('aberrant methylation pattern', 'Var', (4, 32))	('patients', 'Species', '9606', (93, 101))	('ESCC patients', 'Disease', (88, 101))
125764	33194605	Recently, promoter hypermethylation of CHL1 and RHCG, two novel tumor suppressor candidates, has been reported to be associated with poor differentiation and increased invasion of ESCC, as well as advanced tumor stage and decreased overall survival.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('ESCC', 'Disease', (180, 184))	('tumor', 'Disease', (64, 69))	('associated', 'Reg', (117, 127))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('CHL1', 'Gene', (39, 43))	('poor differentiation', 'CPA', (133, 153))	('decreased', 'NegReg', (222, 231))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('RHCG', 'Gene', (48, 52))	('invasion', 'CPA', (168, 176))	('RHCG', 'Gene', '51458', (48, 52))	('overall survival', 'CPA', (232, 248))	('promoter hypermethylation', 'Var', (10, 35))	('CHL1', 'Gene', '10752', (39, 43))	('increased', 'PosReg', (158, 167))
125768	33194605	All in all, finding genes of prognostic impact aberrantly methylated allows one to customize therapy for ESCC patients: patients with a worse prognosis might benefit from a more aggressive treatment strategy, while patients with low risk can forego radical surgery.	('patients', 'Species', '9606', (215, 223))	('ESCC', 'Disease', (105, 109))	('aberrantly', 'Var', (47, 57))	('benefit', 'Reg', (158, 165))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (110, 118))
125771	33194605	PAX5 gene methylation was identified as an excellent marker for squamous cell carcinoma detection.	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('PAX5', 'Gene', (0, 4))	('PAX5', 'Gene', '5079', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('methylation', 'Var', (10, 21))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 87))	('squamous cell carcinoma', 'Disease', (64, 87))
125772	33194605	's study, hypermethylation of PAX5 was significantly correlated with increased ESCC cell proliferation and cisplatin resistance, leading to poor recurrence-free survival and overall survival.	('hypermethylation', 'Var', (10, 26))	('increased', 'PosReg', (69, 78))	('PAX5', 'Gene', '5079', (30, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('PAX5', 'Gene', (30, 34))	('cisplatin resistance', 'MPA', (107, 127))	('increased ESCC', 'Phenotype', 'HP:0003565', (69, 83))	('ESCC', 'Disease', (79, 83))	('poor', 'NegReg', (140, 144))	('overall survival', 'CPA', (174, 190))	('recurrence-free survival', 'CPA', (145, 169))
125774	33194605	Promoter region methylation of CHFR was found frequently in ESCC and shown to sensitize ESCC to taxane treatment.	('CHFR', 'Gene', (31, 35))	('ESCC', 'Disease', (60, 64))	('CHFR', 'Gene', '55743', (31, 35))	('sensitize', 'Reg', (78, 87))	('methylation', 'Var', (16, 27))	('taxane', 'Chemical', 'MESH:C080625', (96, 102))
125775	33194605	Epigenetic alterations have been recognized as key contributors to cancer initiation and progression.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
125776	33194605	Amongst these, DNA methylation is one of the most extensively studied epigenetic modifications that occurs in the earliest stage of cancers.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('DNA methylation', 'Var', (15, 30))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
125777	33194605	The aim of this review is to discuss the aberrant DNA methylation changes affecting ESCC carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('carcinogenesis', 'Disease', (89, 103))	('aberrant', 'Var', (41, 49))
125778	33194605	Accumulating evidence has shown that intergenic regions contain many regulatory elements, such as enhancers, silencers, and non-coding RNAs, and their functions may also be affected by DNA methylation.	('functions', 'MPA', (151, 160))	('methylation', 'Var', (189, 200))	('silencers', 'Disease', (109, 118))	('DNA methylation', 'Var', (185, 200))	('silencers', 'Disease', 'None', (109, 118))	('affected', 'Reg', (173, 181))
125779	33194605	However, the cancer type-specificity of many of these methylation changes remains to be determined in larger ESCC cohorts.	('methylation changes', 'Var', (54, 73))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('changes', 'Var', (66, 73))
125782	33194605	Indeed, several studies have demonstrated that TSG expression could be restored after treatment of cells with demethylating agents, and DNMT inhibitors, such as azacytidine and decitabine, are currently under preclinical and clinical investigations in various cancer types (e.g., ClinicalTrials.gov Identifier: NCT01193517, NCT03666559, and NCT04187703).	('TSG', 'Gene', '57045', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (260, 266))	('DNMT', 'Gene', '1786', (136, 140))	('decitabine', 'Chemical', 'MESH:D000077209', (177, 187))	('NCT03666559', 'Var', (324, 335))	('DNMT', 'Gene', (136, 140))	('TSG', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('NCT04187703', 'Var', (341, 352))	('azacytidine', 'Chemical', 'MESH:D001374', (161, 172))
125786	32017273	Lower VE intake or nutritional status has been shown to be associated with increased cancer risk, and supplementation of alpha-T to populations with VE insufficiency has shown beneficial effects in lowering the cancer risk in some intervention studies.	('lowering', 'NegReg', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('VE insufficiency', 'Disease', (149, 165))	('men', 'Species', '9606', (108, 111))	('cancer', 'Disease', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('VE', 'Chemical', 'MESH:D014810', (6, 8))	('cancer', 'Disease', (85, 91))	('VE', 'Chemical', 'MESH:D014810', (149, 151))	('supplementation', 'Var', (102, 117))	('VE insufficiency', 'Phenotype', 'HP:0005293', (149, 165))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('VE insufficiency', 'Disease', 'MESH:D000309', (149, 165))
125790	32017273	gamma-T3 and delta-T3 generally have even higher activities than gamma-T and delta-T.	('delta-T3', 'Var', (13, 21))	('delta-T', 'Chemical', 'MESH:C479072', (77, 84))	('activities', 'MPA', (49, 59))	('gamma-T', 'Chemical', 'MESH:D024504', (0, 7))	('delta-T', 'Chemical', 'MESH:C479072', (13, 20))	('higher', 'PosReg', (42, 48))	('delta-T3', 'Chemical', '-', (13, 21))	('gamma-T3', 'Chemical', '-', (0, 8))	('gamma-T', 'Chemical', 'MESH:D024504', (65, 72))
125796	32017273	For example, lower VE intake or nutritional status was found to be associated with higher risk of different types of cancers in many studies.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lower', 'NegReg', (13, 18))	('nutritional status', 'Var', (32, 50))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('VE', 'Chemical', 'MESH:D014810', (19, 21))
125809	32017273	Tocotrienols, however, are plentiful in palm oil (up to 800 mg/kg), mainly consisting of gamma-T3 and alpha-T3, and are consumed mostly in Southeast Asia.	('Tocotrienols', 'Chemical', 'MESH:D024508', (0, 12))	('gamma-T3', 'Var', (89, 97))	('alpha-T3', 'Gene', (102, 110))	('alpha-T3', 'Gene', '462', (102, 110))	('gamma-T3', 'Chemical', '-', (89, 97))	('palm oil', 'Chemical', 'MESH:D000073878', (40, 48))
125823	32017273	Nitrogen dioxide can also induce single-strand DNA breaks in V79 cells, and the reaction is optimally inhibited by gamma-T in comparison with other lipid soluble antioxidants.	('gamma-T', 'Chemical', 'MESH:D024504', (115, 122))	('Nitrogen', 'Chemical', 'MESH:D009584', (0, 8))	('lipid', 'Chemical', 'MESH:D008055', (148, 153))	('Nitrogen dioxide', 'Var', (0, 16))	('single-strand DNA breaks', 'MPA', (33, 57))	('induce', 'Reg', (26, 32))	('V79', 'CellLine', 'CVCL:2234', (61, 64))
125832	32017273	However, upon supplementation with gamma-T and delta-T3, their plasma concentration can be increased to higher than 20 muM and 5-10 muM, respectively, in healthy humans.	('humans', 'Species', '9606', (162, 168))	('rat', 'Species', '10116', (77, 80))	('delta-T3', 'Var', (47, 55))	('plasma concentration', 'MPA', (63, 83))	('delta-T3', 'Chemical', '-', (47, 55))	('gamma-T', 'Chemical', 'MESH:D024504', (35, 42))	('increased', 'PosReg', (91, 100))	('gamma-T', 'Var', (35, 42))	('men', 'Species', '9606', (20, 23))
125846	32017273	When alpha-T, gamma-T, delta-T, gamma-T3 and delta-T3, each at a dose of 75 mg/kg body weight, were administered as a mixture i.g.	('delta-T', 'Chemical', 'MESH:C479072', (23, 30))	('gamma-T3', 'Chemical', '-', (32, 40))	('delta-T', 'Var', (23, 30))	('gamma-T', 'Chemical', 'MESH:D024504', (14, 21))	('gamma-T3', 'Var', (32, 40))	('delta-T', 'Chemical', 'MESH:C479072', (45, 52))	('gamma-T', 'Chemical', 'MESH:D024504', (32, 39))	('delta-T3', 'Chemical', '-', (45, 53))
125856	32017273	There are many studies demonstrating that lower VE intake or nutritional status is associated with increased risk of different types of cancer.	('VE', 'Chemical', 'MESH:D014810', (48, 50))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('lower', 'Var', (42, 47))	('rat', 'Species', '10116', (30, 33))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
125875	32017273	Furthermore, results from a 10-year follow-up showed that the preventive effect of the combination of alpha-T/beta-carotene/selenium on gastric cardia cancer was sustained, and that this nutrient combination also protected against ESCC in younger subjects - when they were enrolled in the trial at ages 55 years old or younger (but not in those older than 55 years).	('gastric cardia cancer', 'Disease', 'MESH:D013274', (136, 157))	('alpha-T/beta-carotene/selenium', 'Var', (102, 132))	('ESCC', 'Disease', (231, 235))	('beta-carotene', 'Chemical', 'MESH:D019207', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('combination', 'Var', (87, 98))	('gastric cardia cancer', 'Disease', (136, 157))	('protected', 'Reg', (213, 222))	('selenium', 'Chemical', 'MESH:D012643', (124, 132))
125887	32017273	It was noted that the alpha-T supplementation caused a 50% decrease in the median plasma gamma-T levels.	('men', 'Species', '9606', (36, 39))	('decrease', 'NegReg', (59, 67))	('supplementation', 'Var', (30, 45))	('gamma-T', 'Chemical', 'MESH:D024504', (89, 96))
125895	32017273	Another possibility is that some of these subjects already had preneoplastic lesions when entering the trial, and the supplementation with high doses of alpha-T promoted prostate cancer development.	('prostate cancer', 'Disease', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('men', 'Species', '9606', (124, 127))	('men', 'Species', '9606', (193, 196))	('promoted', 'PosReg', (161, 169))	('prostate cancer', 'Disease', 'MESH:D011471', (170, 185))	('alpha-T', 'Chemical', 'MESH:C024566', (153, 160))	('prostate cancer', 'Phenotype', 'HP:0012125', (170, 185))	('supplementation', 'Var', (118, 133))
125904	32017273	The importance of nutritional levels of VE in influencing prostate cancer is also supported by a nested case-control study in the US, showing that three single nucleotide polymorphism (SNP) variations (involving BUD13, ZNF259 and APOA5), which resulted in higher circulating alpha-T levels, were correlated with a lowered risk of prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (58, 73))	('prostate cancer', 'Disease', (58, 73))	('lowered', 'NegReg', (314, 321))	('BUD13', 'Gene', (212, 217))	('lowered risk of prostate', 'Phenotype', 'HP:0008687', (314, 338))	('APOA5', 'Gene', '116519', (230, 235))	('variations', 'Var', (190, 200))	('APOA5', 'Gene', (230, 235))	('ZNF259', 'Gene', '8882', (219, 225))	('BUD13', 'Gene', '84811', (212, 217))	('VE', 'Chemical', 'MESH:D014810', (40, 42))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('higher', 'PosReg', (256, 262))	('prostate cancer', 'Disease', 'MESH:D011471', (330, 345))	('prostate cancer', 'Phenotype', 'HP:0012125', (330, 345))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('prostate cancer', 'Disease', (330, 345))	('ZNF259', 'Gene', (219, 225))	('prostate cancer', 'Disease', 'MESH:D011471', (58, 73))	('circulating alpha-T levels', 'MPA', (263, 289))
125906	32017273	The SNP variation for both SEC14L2 and SOD1 were associated with significantly lowered prostate cancer risk.	('prostate cancer', 'Disease', (87, 102))	('lowered prostate', 'Phenotype', 'HP:0008687', (79, 95))	('SEC14L2', 'Gene', '23541', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('SEC14L2', 'Gene', (27, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('SNP variation', 'Var', (4, 17))	('SOD1', 'Gene', (39, 43))	('SOD1', 'Gene', '6647', (39, 43))	('lowered', 'NegReg', (79, 86))
125908	32017273	In the Shanghai Women's Health Study (SWHS) with 72,829 female non-smokers and a follow-up period of 12 years, lung cancer risk was found to be lower in those who met dietary guidelines for Adequate Intake (AI) of tocopherols (14 mg/day or more), compared to those with lower intake than AI (Table 1).	('tocopherols', 'Chemical', 'MESH:D024505', (214, 225))	('lower', 'NegReg', (144, 149))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('tocopherols', 'Protein', (214, 225))	('14 mg/day', 'Var', (227, 236))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('Women', 'Species', '9606', (16, 21))
125938	32017273	In the British National Diet and Nutrition Survey, which involved 1,054 elderly men followed for 13-14 years, it was found that dietary VE had a significant inverse association with total cancer mortality in four different models.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('dietary', 'Var', (128, 135))	('inverse', 'NegReg', (157, 164))	('men', 'Species', '9606', (80, 83))	('cancer mortality', 'Disease', (188, 204))	('cancer mortality', 'Disease', 'MESH:D003643', (188, 204))	('VE', 'Chemical', 'MESH:D014810', (136, 138))
125943	32017273	In a Phase I window-of-opportunity trial of delta-T3 in 25 patients with pancreatic neoplasia, delta-T3 was given orally twice a day for 13 days before surgery, in a dose-escalation scheme with total daily doses from 200 mg to 3200 mg.	('pancreatic neoplasia', 'Disease', (73, 93))	('pancreatic neoplasia', 'Disease', 'MESH:D009369', (73, 93))	('delta-T3', 'Chemical', '-', (44, 52))	('pancreatic neoplasia', 'Phenotype', 'HP:0002894', (73, 93))	('delta-T3', 'Chemical', '-', (95, 103))	('neoplasia', 'Phenotype', 'HP:0002664', (84, 93))	('patients', 'Species', '9606', (59, 67))	('delta-T3', 'Var', (95, 103))
125945	32017273	delta-T3 at dose of 600 mg induced significant apoptosis in the neoplastic cells of patients.	('delta-T3', 'Var', (0, 8))	('apoptosis', 'CPA', (47, 56))	('delta-T3', 'Chemical', '-', (0, 8))	('patients', 'Species', '9606', (84, 92))
125964	32017273	As will be discussed in the next section, in animal models, gamma-T and delta-T are effective in inhibiting carcinogenesis, while alpha-T is not.	('gamma-T', 'Chemical', 'MESH:D024504', (60, 67))	('gamma-T', 'Var', (60, 67))	('delta-T', 'Chemical', 'MESH:C479072', (72, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('inhibiting', 'NegReg', (97, 107))	('delta-T', 'Var', (72, 79))	('carcinogenesis', 'Disease', (108, 122))
125975	32017273	In the transgenic rat for adenocarcinoma of prostate (TRAP) model, gamma-T at low concentrations of 50, 100 and 200 mg/kg diet dose-dependently reduced the number of adenocarcinomas in the ventral lobe, but alpha-T did not.	('rat', 'Species', '10116', (18, 21))	('reduced', 'NegReg', (144, 151))	('gamma-T', 'Chemical', 'MESH:D024504', (67, 74))	('adenocarcinoma of prostate', 'Disease', 'MESH:D011471', (26, 52))	('gamma-T', 'Var', (67, 74))	('rat', 'Species', '10116', (89, 92))	('adenocarcinoma of prostate', 'Disease', (26, 52))	('adenocarcinomas', 'Disease', 'MESH:D000230', (166, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('adenocarcinomas', 'Disease', (166, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
125981	32017273	Further studies with purified delta-T, gamma-T and alpha-T (2 g/kg diet) showed that delta-T was more effective than gamma-T or alpha-T in preventing mPIN formation and p-AKT elevation.	('mPIN formation', 'MPA', (150, 164))	('gamma-T', 'Chemical', 'MESH:D024504', (39, 46))	('delta-T', 'Chemical', 'MESH:C479072', (85, 92))	('delta-T', 'Chemical', 'MESH:C479072', (30, 37))	('p-AKT', 'CPA', (169, 174))	('preventing', 'NegReg', (139, 149))	('delta-T', 'Var', (85, 92))	('elevation', 'PosReg', (175, 184))	('mPIN', 'Chemical', '-', (150, 154))	('gamma-T', 'Chemical', 'MESH:D024504', (117, 124))
125982	32017273	In human prostate cancer cell lines LNCaP, VCaP and CWR22Rv1, delta-T showed a much stronger activity than alpha-T in inhibiting cell growth and inducing apoptosis.	('CWR22Rv1', 'CellLine', 'CVCL:1045', (52, 60))	('prostate cancer', 'Disease', (9, 24))	('human', 'Species', '9606', (3, 8))	('LNCaP', 'CellLine', 'CVCL:0395', (36, 41))	('VCa', 'CellLine', 'CVCL:2235', (43, 46))	('delta-T', 'Var', (62, 69))	('apoptosis', 'CPA', (154, 163))	('cell growth', 'CPA', (129, 140))	('inducing', 'Reg', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('delta-T', 'Chemical', 'MESH:C479072', (62, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (9, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (9, 24))	('inhibiting', 'NegReg', (118, 128))
125984	32017273	delta-T was also more potent than alpha-T in inhibiting the growth of LNCaP cell xenograft tumors in the immunodeficient SCID mice, and the inhibition was associated with lowered cell proliferation and enhanced cell apoptosis in tumors.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('mice', 'Species', '10090', (126, 130))	('rat', 'Species', '10116', (191, 194))	('lowered', 'NegReg', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('immunodeficient SCID', 'Disease', (105, 125))	('delta-T', 'Chemical', 'MESH:C479072', (0, 7))	('inhibiting', 'NegReg', (45, 55))	('LNCaP', 'CellLine', 'CVCL:0395', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('delta-T', 'Var', (0, 7))	('tumors', 'Disease', (229, 235))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('immunodeficient SCID', 'Disease', 'MESH:D053632', (105, 125))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('tumors', 'Disease', (91, 97))	('cell proliferation', 'CPA', (179, 197))	('enhanced', 'PosReg', (202, 210))	('cell apoptosis in', 'CPA', (211, 228))	('growth', 'CPA', (60, 66))
125985	32017273	In further studies with these and other prostate cancer cell lines, delta-T was also found to be more effective than gamma-T and alpha-T in inhibiting prostate cancer cell growth by inducing cell cycle arrest and apoptosis.	('inducing', 'PosReg', (182, 190))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('inhibiting', 'NegReg', (140, 150))	('prostate cancer', 'Disease', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('arrest', 'Disease', (202, 208))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (191, 208))	('delta-T', 'Chemical', 'MESH:C479072', (68, 75))	('prostate cancer', 'Disease', (151, 166))	('delta-T', 'Var', (68, 75))	('apoptosis', 'CPA', (213, 222))	('prostate cancer', 'Disease', 'MESH:D011471', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('gamma-T', 'Chemical', 'MESH:D024504', (117, 124))	('arrest', 'Disease', 'MESH:D006323', (202, 208))	('prostate cancer', 'Phenotype', 'HP:0012125', (40, 55))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))
125986	32017273	By profiling the effects of delta-T on cell signaling using a phospho-kinase array, we found that the most prominently inhibited target was the phosphorylation of AKT on T308.	('T308', 'Chemical', '-', (170, 174))	('phosphorylation', 'MPA', (144, 159))	('T308', 'Var', (170, 174))	('inhibited', 'NegReg', (119, 128))	('delta-T', 'Chemical', 'MESH:C479072', (28, 35))	('AKT', 'Pathway', (163, 166))
125988	32017273	Expression of dominant active PI3K and AKT in prostate cancer cell line DU145, in which PIK3, AKT, and PTEN are wild type, caused the cells to be refractory to the inhibition of delta-T, suggesting that delta-T inhibits the PIK3-mediated activation of AKT.	('prostate cancer', 'Disease', (46, 61))	('PI3K', 'Var', (30, 34))	('AKT', 'Pathway', (252, 255))	('PIK3', 'Gene', (224, 228))	('PIK3', 'Gene', '5294', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PIK3', 'Gene', '5294', (224, 228))	('delta-T', 'Chemical', 'MESH:C479072', (178, 185))	('inhibits', 'NegReg', (211, 219))	('prostate cancer', 'Disease', 'MESH:D011471', (46, 61))	('delta-T', 'Chemical', 'MESH:C479072', (203, 210))	('PIK3', 'Gene', (88, 92))	('AKT', 'Gene', (39, 42))	('prostate cancer', 'Phenotype', 'HP:0012125', (46, 61))	('DU145', 'CellLine', 'CVCL:0105', (72, 77))
125989	32017273	Our data also suggest that delta-T interferes with the EGF-induced EGFR internalization, leading to the inhibition of the receptor tyrosine kinase-dependent activation of AKT.	('inhibition', 'NegReg', (104, 114))	('receptor tyrosine kinase', 'Gene', '5979', (122, 146))	('EGF', 'Gene', '1950', (67, 70))	('interferes', 'NegReg', (35, 45))	('AKT', 'Pathway', (171, 174))	('internalization', 'MPA', (72, 87))	('delta-T', 'Chemical', 'MESH:C479072', (27, 34))	('EGFR', 'Gene', '1956', (67, 71))	('EGF', 'Gene', (55, 58))	('EGFR', 'Gene', (67, 71))	('delta-T', 'Var', (27, 34))	('EGF', 'Gene', '1950', (55, 58))	('receptor tyrosine kinase', 'Gene', (122, 146))	('EGF', 'Gene', (67, 70))
125990	32017273	The inhibition of AKT signaling and prostate carcinogenesis by delta-T was demonstrated in vivo in prostate-specific PTEN-/- (PTENp-/-) mice, in which the activation of AKT is the major driving force for tumorigenesis.	('delta-T', 'Chemical', 'MESH:C479072', (63, 70))	('delta-T', 'Var', (63, 70))	('prostate carcinogenesis', 'Disease', (36, 59))	('AKT signaling', 'Pathway', (18, 31))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('mice', 'Species', '10090', (136, 140))	('PTENp', 'Gene', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('prostate carcinogenesis', 'Disease', 'MESH:D011471', (36, 59))	('PTENp', 'Gene', '19211', (126, 131))	('tumor', 'Disease', (204, 209))	('rat', 'Species', '10116', (82, 85))	('inhibition', 'NegReg', (4, 14))
125992	32017273	Dietary delta-T also reduced the phosphorylation of AKT (T308), decreased proliferation and enhanced apoptosis in prostate lesions.	('reduced', 'NegReg', (21, 28))	('phosphorylation', 'MPA', (33, 48))	('AKT', 'Protein', (52, 55))	('prostate lesions', 'Disease', (114, 130))	('decreased', 'NegReg', (64, 73))	('delta-T', 'Var', (8, 15))	('prostate lesions', 'Disease', 'MESH:D011472', (114, 130))	('T308', 'Chemical', '-', (57, 61))	('rat', 'Species', '10116', (81, 84))	('proliferation', 'CPA', (74, 87))	('apoptosis', 'CPA', (101, 110))	('delta-T', 'Chemical', 'MESH:C479072', (8, 15))	('enhanced', 'PosReg', (92, 100))
125997	32017273	Our work also showed that delta-T, gamma-T and gamma-TmT inhibited tumorigenesis in estrogen receptor (ER) positive in vivo models of breast cancer by downregulation of ERalpha and Akt signaling, activation of PPARgamma, upregulation of Nrf2-mediated antioxidant response, inhibition of oxidative stress and inflammatory markers, and modulation of CYP1A1-mediated estrogen metabolism.	('gamma-T', 'Chemical', 'MESH:D024504', (35, 42))	('ER', 'Gene', '2099', (103, 105))	('oxidative stress', 'Phenotype', 'HP:0025464', (287, 303))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('delta-T', 'Var', (26, 33))	('estrogen receptor', 'Gene', (84, 101))	('downregulation', 'NegReg', (151, 165))	('tumor', 'Disease', (67, 72))	('ERalpha', 'Gene', '2099', (169, 176))	('PPARgamma', 'Gene', (210, 219))	('Akt', 'Gene', (181, 184))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('breast cancer', 'Disease', (134, 147))	('upregulation', 'PosReg', (221, 233))	('gamma-TmT', 'Chemical', '-', (47, 56))	('CYP1A1', 'Gene', (348, 354))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Akt', 'Gene', '207', (181, 184))	('inhibited', 'NegReg', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('inhibition', 'NegReg', (273, 283))	('gamma-T', 'Chemical', 'MESH:D024504', (47, 54))	('Nrf2', 'Gene', '4780', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('oxidative stress', 'MPA', (287, 303))	('CYP1A1', 'Gene', '1543', (348, 354))	('estrogen receptor', 'Gene', '2099', (84, 101))	('gamma-T', 'Var', (35, 42))	('PPARgamma', 'Gene', '5468', (210, 219))	('gamma-TmT', 'Var', (47, 56))	('delta-T', 'Chemical', 'MESH:C479072', (26, 33))	('ER', 'Gene', '2099', (169, 171))	('ERalpha', 'Gene', (169, 176))	('activation', 'PosReg', (196, 206))	('Nrf2', 'Gene', (237, 241))	('modulation', 'Reg', (334, 344))
125998	32017273	Dietary administration of delta-T and gamma-T, but not alpha-T, was shown to inhibit tumorigenesis in ER-positive breast cancer, while did not provide protective effects against ER-negative and HER-2 positive breast cancer, suggesting that the chemopreventive effects are due to estrogen-mediated and ER-dependent mechanisms.	('tumor', 'Disease', (85, 90))	('rat', 'Species', '10116', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('delta-T', 'Var', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('ER', 'Gene', '2099', (301, 303))	('inhibit', 'NegReg', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ER', 'Gene', '2099', (195, 197))	('gamma-T', 'Var', (38, 45))	('ER', 'Gene', '2099', (102, 104))	('HER-2', 'Gene', '2064', (194, 199))	('HER-2', 'Gene', (194, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('gamma-T', 'Chemical', 'MESH:D024504', (38, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('ER', 'Gene', '2099', (178, 180))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('delta-T', 'Chemical', 'MESH:C479072', (26, 33))	('breast cancer', 'Disease', (209, 222))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Disease', (114, 127))
125999	32017273	delta-T and gamma-T have been shown to inhibit estrogen-stimulated breast cancer tumor growth.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (67, 86))	('gamma-T', 'Var', (12, 19))	('estrogen-stimulated', 'CPA', (47, 66))	('inhibit', 'NegReg', (39, 46))	('breast cancer tumor', 'Disease', (67, 86))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('delta-T', 'Chemical', 'MESH:C479072', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('delta-T', 'Var', (0, 7))	('gamma-T', 'Chemical', 'MESH:D024504', (12, 19))	('breast cancer tumor', 'Disease', 'MESH:D001943', (67, 86))
126000	32017273	In a breast cancer model, mice with MCF-7 xenograft tumors implanted with estrogen, treatment with gamma-T, delta-T or gamma-TmT (2 g/kg diet) significantly reduced tumor volume and tumor weight, and inhibited cell proliferation-related genes such as cyclin D1 and c-Myc as well as estrogen-related genes TFF/pS2, cathepsin D, and progesterone receptor.	('tumor', 'Disease', (52, 57))	('c-Myc', 'Gene', (265, 270))	('cathepsin D', 'Gene', (314, 325))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('men', 'Species', '9606', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('c-Myc', 'Gene', '4609', (265, 270))	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('gamma-T', 'Chemical', 'MESH:D024504', (119, 126))	('rat', 'Species', '10116', (222, 225))	('gamma-TmT', 'Chemical', '-', (119, 128))	('breast cancer', 'Disease', 'MESH:D001943', (5, 18))	('cathepsin D', 'Gene', '13033', (314, 325))	('delta-T', 'Chemical', 'MESH:C479072', (108, 115))	('breast cancer', 'Disease', (5, 18))	('inhibited', 'NegReg', (200, 209))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('progesterone receptor', 'Gene', '18667', (331, 352))	('tumors', 'Disease', (52, 58))	('gamma-T', 'Var', (99, 106))	('pS2', 'Gene', '21784', (309, 312))	('reduced', 'NegReg', (157, 164))	('cyclin D1', 'Gene', (251, 260))	('tumor', 'Disease', (165, 170))	('MCF-7', 'CellLine', 'CVCL:0031', (36, 41))	('delta-T', 'Var', (108, 115))	('mice', 'Species', '10090', (26, 30))	('tumor', 'Disease', (182, 187))	('pS2', 'Gene', (309, 312))	('progesterone receptor', 'Gene', (331, 352))	('gamma-T', 'Chemical', 'MESH:D024504', (99, 106))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('gamma-TmT', 'Var', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('cell proliferation-related', 'CPA', (210, 236))
126003	32017273	delta-T, gamma-T and gamma-TmT all significantly reduced mammary tumor volume.	('gamma-T', 'Chemical', 'MESH:D024504', (9, 16))	('gamma-T', 'Var', (9, 16))	('reduced', 'NegReg', (49, 56))	('tumor', 'Disease', (65, 70))	('gamma-TmT', 'Var', (21, 30))	('delta-T', 'Chemical', 'MESH:C479072', (0, 7))	('gamma-T', 'Chemical', 'MESH:D024504', (21, 28))	('gamma-TmT', 'Chemical', '-', (21, 30))	('delta-T', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
126004	32017273	The biological activities of individual forms of tocopherols at the whole transcriptome level were evaluated using RNA sequencing analysis, and the results showed that delta-T and gamma-T had superior cancer preventive properties compared to alpha-T, based on their effects on transcriptome - in regulating the expression of genes involved in cell proliferation, metastasis, and tumor progression.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('expression', 'MPA', (311, 321))	('tumor', 'Disease', 'MESH:D009369', (379, 384))	('rat', 'Species', '10116', (355, 358))	('cancer', 'Disease', (201, 207))	('gamma-T', 'Var', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('tumor', 'Disease', (379, 384))	('delta-T', 'Chemical', 'MESH:C479072', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tocopherols', 'Chemical', 'MESH:D024505', (49, 60))	('delta-T', 'Var', (168, 175))	('gamma-T', 'Chemical', 'MESH:D024504', (180, 187))
126010	32017273	In a similar study in AOM-treated male BALB/c mice, however, gamma-T, but not gamma-TmT, (1 g/kg diet) suppressed moderate colitis-promoted colon tumorigenesis, but neither agent was effective in inhibiting severe colitis and related colon tumorigenesis.	('colon tumorigenesis', 'Disease', 'MESH:D063646', (140, 159))	('colitis', 'Phenotype', 'HP:0002583', (214, 221))	('suppressed', 'NegReg', (103, 113))	('gamma-TmT', 'Chemical', '-', (78, 87))	('rat', 'Species', '10116', (118, 121))	('colitis', 'Phenotype', 'HP:0002583', (123, 130))	('colon tumorigenesis', 'Disease', (234, 253))	('colon tumorigenesis', 'Disease', 'MESH:D063646', (234, 253))	('AOM', 'Chemical', 'MESH:D001397', (22, 25))	('colitis', 'Disease', (214, 221))	('colitis-promoted colon tumorigenesis', 'Disease', (123, 159))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('gamma-T', 'Chemical', 'MESH:D024504', (78, 85))	('gamma-T', 'Var', (61, 68))	('colitis', 'Disease', 'MESH:D003092', (214, 221))	('colitis-promoted colon tumorigenesis', 'Disease', 'MESH:D063646', (123, 159))	('colitis', 'Disease', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('gamma-T', 'Chemical', 'MESH:D024504', (61, 68))	('mice', 'Species', '10090', (46, 50))	('colitis', 'Disease', 'MESH:D003092', (123, 130))
126017	32017273	Supplementation with delta-T or gamma-T markedly increased the levels of delta-T or gamma-T (from very low to 6.69 or 21.20 mumol/L, respectively), and their side-chain degradation metabolites (with delta- or gamma-CEHCs at 23.32 or 6.07 mumol/L, respectively) in the serum.	('gamma-T', 'Chemical', 'MESH:D024504', (84, 91))	('gamma-T', 'Var', (32, 39))	('increased', 'PosReg', (49, 58))	('delta-T', 'Chemical', 'MESH:C479072', (21, 28))	('side-chain degradation metabolites', 'MPA', (158, 192))	('delta-T', 'Var', (21, 28))	('delta-T', 'MPA', (73, 80))	('delta-T', 'Chemical', 'MESH:C479072', (73, 80))	('CEHCs', 'Chemical', '-', (215, 220))	('gamma-T', 'MPA', (84, 91))	('gamma-T', 'Chemical', 'MESH:D024504', (32, 39))	('men', 'Species', '9606', (6, 9))
126021	32017273	During the DSS-treatment period, dietary delta-T decreased the levels of 8-oxo-dG and nitrotyrosine, as well as pro-inflammatory mediators (NF-kappaB p65 and p-STAT3), in tumors and adjacent tissues.	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('nitrotyrosine', 'MPA', (86, 99))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('nitrotyrosine', 'Chemical', 'MESH:C002744', (86, 99))	('STAT3', 'Gene', '6774', (160, 165))	('decreased', 'NegReg', (49, 58))	('dietary', 'Var', (33, 40))	('NF-kappaB p65', 'Gene', '5970', (140, 153))	('delta-T', 'Chemical', 'MESH:C479072', (41, 48))	('STAT3', 'Gene', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('levels of 8-oxo-dG', 'MPA', (63, 81))	('delta-T', 'Var', (41, 48))	('NF-kappaB p65', 'Gene', (140, 153))	('tumors', 'Disease', (171, 177))	('men', 'Species', '9606', (20, 23))
126026	32017273	These studies clearly demonstrate the higher activity of delta-T than gamma-T in inhibiting colon tumorigenesis, while alpha-T was ineffective.	('activity', 'MPA', (45, 53))	('colon tumorigenesis', 'Disease', 'MESH:D063646', (92, 111))	('colon tumorigenesis', 'Disease', (92, 111))	('inhibiting', 'NegReg', (81, 91))	('rat', 'Species', '10116', (29, 32))	('delta-T', 'Chemical', 'MESH:C479072', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('delta-T', 'Var', (57, 64))	('gamma-T', 'Chemical', 'MESH:D024504', (70, 77))
126030	32017273	In cell culture, the growth of H1299 cells was inhibited by tocopherols with their effectiveness following the order of delta-T > gamma-TmT > gamma-T, whereas alpha-T was not effective.	('H1299', 'CellLine', 'CVCL:0060', (31, 36))	('growth', 'CPA', (21, 27))	('inhibited', 'NegReg', (47, 56))	('gamma-T', 'Chemical', 'MESH:D024504', (130, 137))	('gamma-TmT', 'Chemical', '-', (130, 139))	('gamma-TmT', 'Var', (130, 139))	('tocopherols', 'Chemical', 'MESH:D024505', (60, 71))	('tocopherols', 'Protein', (60, 71))	('delta-T', 'Chemical', 'MESH:C479072', (120, 127))	('delta-T', 'Var', (120, 127))	('gamma-T', 'Chemical', 'MESH:D024504', (142, 149))
126033	32017273	In both the carcinogenesis and tumor growth models, the inhibitory action of gamma-TmT was associated with lowered levels of 8-oxo-dG, gamma-H2AX and nitrotyrosine, as well as enhanced apoptosis, in the tumors.	('tumor', 'Disease', (203, 208))	('gamma-TmT', 'Var', (77, 86))	('enhanced', 'PosReg', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('gamma-H2AX', 'MPA', (135, 145))	('lowered', 'NegReg', (107, 114))	('carcinogenesis', 'Disease', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('nitrotyrosine', 'MPA', (150, 163))	('levels of 8-oxo-dG', 'MPA', (115, 133))	('carcinogenesis', 'Disease', 'MESH:D063646', (12, 26))	('nitrotyrosine', 'Chemical', 'MESH:C002744', (150, 163))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('gamma-TmT', 'Chemical', '-', (77, 86))	('tumors', 'Disease', (203, 209))	('apoptosis', 'CPA', (185, 194))	('gamma-H2AX', 'Chemical', '-', (135, 145))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
126041	32017273	These results support the hypothesis that in humans, VE and selenium insufficiency makes the individual more susceptible to esophagitis, and supplementation with VE and selenium blocked the inflammatory mediators and inhibited carcinogenesis.	('esophagitis', 'Disease', 'MESH:D004938', (124, 135))	('esophagitis', 'Disease', (124, 135))	('selenium', 'Chemical', 'MESH:D012643', (169, 177))	('selenium', 'Chemical', 'MESH:D012643', (60, 68))	('humans', 'Species', '9606', (45, 51))	('insufficiency', 'Disease', 'MESH:D000309', (69, 82))	('blocked', 'NegReg', (178, 185))	('inhibited', 'NegReg', (217, 226))	('carcinogenesis', 'Disease', 'MESH:D063646', (227, 241))	('inflammatory', 'CPA', (190, 202))	('insufficiency', 'Disease', (69, 82))	('VE', 'Chemical', 'MESH:D014810', (162, 164))	('esophagitis', 'Phenotype', 'HP:0100633', (124, 135))	('carcinogenesis', 'Disease', (227, 241))	('supplementation', 'Var', (141, 156))	('VE', 'Chemical', 'MESH:D014810', (53, 55))	('men', 'Species', '9606', (147, 150))
126043	32017273	Most of the studies on tocotrienols (mostly gamma-T3 and delta-T3) have been carried out in cell lines, demonstrating the inhibition of cell growth and induction of apoptosis, and some of the studies have carried into xenograft tumor models.	('tocotrienols', 'Chemical', 'MESH:D024508', (23, 35))	('rat', 'Species', '10116', (111, 114))	('delta-T3', 'Var', (57, 65))	('gamma-T3', 'Chemical', '-', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('induction', 'Reg', (152, 161))	('apoptosis', 'CPA', (165, 174))	('cell growth', 'CPA', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('inhibition', 'NegReg', (122, 132))	('delta-T3', 'Chemical', '-', (57, 65))	('tumor', 'Disease', (228, 233))	('gamma-T3', 'Var', (44, 52))
126044	32017273	Some of the proposed molecular targets or pathways are highlighted in Figure 3. delta-T3 and gamma-T3 have been shown to inhibit growth and promote apoptosis in cell lines derived from gastric cancer, leukemia, breast cancer, oral cancer, lung cancer, glioblastoma, pancreatic cancer, prostate cancer, non-small cell lung cancer, bladder cancer and colorectal cancer (Table 4).	('inhibit', 'NegReg', (121, 128))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (306, 328))	('lung cancer', 'Disease', (239, 250))	('glioblastoma', 'Disease', 'MESH:D005909', (252, 264))	('delta-T3', 'Chemical', '-', (80, 88))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (266, 283))	('gamma-T3', 'Var', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (302, 328))	('apoptosis', 'CPA', (148, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('delta-T3', 'Var', (80, 88))	('growth', 'CPA', (129, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (185, 199))	('glioblastoma', 'Disease', (252, 264))	('oral cancer', 'Disease', (226, 237))	('glioblastoma', 'Phenotype', 'HP:0012174', (252, 264))	('lung cancer', 'Disease', 'MESH:D008175', (239, 250))	('colorectal cancer', 'Disease', 'MESH:D015179', (349, 366))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('non-small cell lung cancer', 'Disease', (302, 328))	('breast cancer', 'Disease', (211, 224))	('pancreatic cancer', 'Disease', 'MESH:D010190', (266, 283))	('lung cancer', 'Disease', 'MESH:D008175', (317, 328))	('prostate cancer', 'Disease', 'MESH:D011471', (285, 300))	('colorectal cancer', 'Disease', (349, 366))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('prostate cancer', 'Phenotype', 'HP:0012125', (285, 300))	('gastric cancer', 'Disease', (185, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (317, 328))	('leukemia', 'Phenotype', 'HP:0001909', (201, 209))	('prostate cancer', 'Disease', (285, 300))	('pancreatic cancer', 'Disease', (266, 283))	('gamma-T3', 'Chemical', '-', (93, 101))	('bladder cancer', 'Disease', 'MESH:D001749', (330, 344))	('bladder cancer', 'Disease', (330, 344))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('promote', 'PosReg', (140, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (330, 344))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (302, 328))	('leukemia', 'Disease', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('leukemia', 'Disease', 'MESH:D007938', (201, 209))	('gastric cancer', 'Disease', 'MESH:D013274', (185, 199))	('oral cancer', 'Disease', 'MESH:D009369', (226, 237))	('colorectal cancer', 'Phenotype', 'HP:0003003', (349, 366))
126047	32017273	The molecular mechanisms reported for the anti-proliferation, pro-apoptosis and other anti-cancer activities of delta-T3 and gamma-T3, as depicted in Fig.	('gamma-T3', 'Chemical', '-', (125, 133))	('delta-T3', 'Var', (112, 120))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('rat', 'Species', '10116', (54, 57))	('pro-apoptosis', 'CPA', (62, 75))	('gamma-T3', 'Var', (125, 133))	('delta-T3', 'Chemical', '-', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('anti-proliferation', 'CPA', (42, 60))
126052	32017273	In addition, pathway analysis of the tocotrienol-induced gene expression profile changes suggests that gamma-T3 and delta-T3 alter endoplasmic reticulum stress signaling and related autophagy and cell death.	('death', 'Disease', 'MESH:D003643', (201, 206))	('autophagy', 'CPA', (182, 191))	('death', 'Disease', (201, 206))	('tocotrienol', 'Chemical', 'MESH:D024508', (37, 48))	('delta-T3', 'Var', (116, 124))	('gamma-T3', 'Var', (103, 111))	('endoplasmic reticulum stress signaling', 'MPA', (131, 169))	('delta-T3', 'Chemical', '-', (116, 124))	('gamma-T3', 'Chemical', '-', (103, 111))	('alter', 'Reg', (125, 130))
126054	32017273	delta-T3 was shown to inhibit the formation of tumor spheres of human melanoma cells.	('melanoma', 'Disease', (70, 78))	('human', 'Species', '9606', (64, 69))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('inhibit', 'NegReg', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('delta-T3', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('tumor', 'Disease', (47, 52))	('delta-T3', 'Chemical', '-', (0, 8))
126055	32017273	delta-T3 was also reported to inhibit the expression of stem cell transcription factors, including NANOG, OCT4 and SOX2, in pancreatic cancer cells and surface stemness marker CD44 in xenograft tumors of pancreatic cancer cells.	('expression', 'MPA', (42, 52))	('SOX2', 'Gene', (115, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('SOX2', 'Gene', '6657', (115, 119))	('delta-T3', 'Var', (0, 8))	('tumors of pancreatic cancer', 'Disease', 'MESH:D010190', (194, 221))	('tumors of pancreatic cancer', 'Disease', (194, 221))	('pancreatic cancer', 'Disease', 'MESH:D010190', (204, 221))	('CD44', 'Gene', '960', (176, 180))	('CD44', 'Gene', (176, 180))	('pancreatic cancer', 'Disease', (124, 141))	('NANOG', 'Gene', '79923', (99, 104))	('inhibit', 'NegReg', (30, 37))	('NANOG', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('OCT4', 'Gene', '5460', (106, 110))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (204, 221))	('OCT4', 'Gene', (106, 110))	('delta-T3', 'Chemical', '-', (0, 8))
126056	32017273	gamma-T3 was reported to inhibit mevalonate pathway and activate de novo ceramide synthesis pathway, resulting in the reduced STAT-3 mediated signaling and leading to the inhibition on breast cancer stem-like cells.	('de novo ceramide synthesis pathway', 'Pathway', (65, 99))	('gamma-T3', 'Var', (0, 8))	('STAT-3', 'Gene', '6774', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('reduced', 'NegReg', (118, 125))	('STAT-3', 'Gene', (126, 132))	('breast cancer', 'Disease', (185, 198))	('inhibition', 'NegReg', (171, 181))	('ceramide', 'Chemical', 'MESH:D002518', (73, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('activate', 'PosReg', (56, 64))	('mevalonate pathway', 'Pathway', (33, 51))	('gamma-T3', 'Chemical', '-', (0, 8))	('inhibit', 'NegReg', (25, 32))	('mevalonate', 'Chemical', 'MESH:D008798', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
126057	32017273	delta-T3 and gamma-T3 have been demonstrated to inhibit tumor growth in xenograft models of pancreatic cancer cells, gastric cancer cells, mouse mammary cancer cells, liver cancer cells, and melanoma cells, as well as the transgenic pancreatic cancer mouse models (LSL-KrasG12D;LSL-Trp53R127H;Pdx-1-Cre [KPC mice]).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Disease', (153, 159))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('melanoma', 'Disease', (191, 199))	('delta-T3', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('gastric cancer', 'Disease', (117, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (233, 250))	('LSL', 'Gene', '7839', (278, 281))	('cancer', 'Disease', (103, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('LSL', 'Gene', (278, 281))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('inhibit', 'NegReg', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rat', 'Species', '10116', (39, 42))	('Trp53', 'Gene', '22059', (282, 287))	('pancreatic cancer', 'Disease', (92, 109))	('cancer', 'Disease', (125, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('liver cancer', 'Disease', 'MESH:D006528', (167, 179))	('pancreatic cancer', 'Disease', 'MESH:D010190', (233, 250))	('mouse', 'Species', '10090', (251, 256))	('cancer', 'Disease', (173, 179))	('Trp53', 'Gene', (282, 287))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('tumor', 'Disease', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gamma-T3', 'Chemical', '-', (13, 21))	('mouse', 'Species', '10090', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('LSL', 'Gene', (265, 268))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('liver cancer', 'Phenotype', 'HP:0002896', (167, 179))	('LSL', 'Gene', '7839', (265, 268))	('cancer', 'Disease', (244, 250))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('liver cancer', 'Disease', (167, 179))	('pancreatic cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('mice', 'Species', '10090', (308, 312))	('gamma-T3', 'Var', (13, 21))	('delta-T3', 'Chemical', '-', (0, 8))
126061	32017273	Using the same in vitro assays, delta-T3 was also found to suppress the migration and invasion of non-small lung cancer cells and colon cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('rat', 'Species', '10116', (75, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('delta-T3', 'Chemical', '-', (32, 40))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('colon cancer', 'Disease', (130, 142))	('small lung', 'Phenotype', 'HP:0002089', (102, 112))	('delta-T3', 'Var', (32, 40))	('suppress', 'NegReg', (59, 67))	('invasion', 'CPA', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
126062	32017273	Studies in xenograft models showed that delta-T3 inhibited pancreatic cancer tumor growth and liver and lung metastasis and that tocotrienols-rich mixture inhibited lung metastasis of breast cancer cells.	('tocotrienols', 'Chemical', 'MESH:D024508', (129, 141))	('pancreatic cancer tumor', 'Disease', 'MESH:D010190', (59, 82))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('delta-T3', 'Chemical', '-', (40, 48))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pancreatic cancer tumor', 'Disease', (59, 82))	('inhibited', 'NegReg', (155, 164))	('lung metastasis', 'CPA', (165, 180))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', (184, 197))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('inhibited', 'NegReg', (49, 58))	('delta-T3', 'Var', (40, 48))
126064	32017273	For examples, delta-T3 and gamma-T3 suppressed the tumor angiogenesis of xenograft tumors of pancreatic cancer cells, colorectal cells and liver cancer cells as well as pancreatic tumors developed in KPC transgenic mice.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Disease', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('liver cancer', 'Disease', 'MESH:D006528', (139, 151))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('gamma-T3', 'Var', (27, 35))	('delta-T3', 'Chemical', '-', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (51, 56))	('tumors of pancreatic cancer', 'Disease', 'MESH:D010190', (83, 110))	('delta-T3', 'Var', (14, 22))	('tumors of pancreatic cancer', 'Disease', (83, 110))	('pancreatic tumors', 'Disease', 'MESH:D010190', (169, 186))	('pancreatic tumors', 'Disease', (169, 186))	('liver cancer', 'Phenotype', 'HP:0002896', (139, 151))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('liver cancer', 'Disease', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('colorectal', 'Disease', (118, 128))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('mice', 'Species', '10090', (215, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))	('suppressed', 'NegReg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (180, 185))	('gamma-T3', 'Chemical', '-', (27, 35))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (169, 186))
126067	32017273	delta-T3 (10-100 muM) was found to inhibit colon cancer stem cell (CCSCs) survival and stemness (NANOG, OCT4 and SOX2) as well as markers for migration, invasion, inflammation (NF-kB), angiogenesis (VEGF) and metastasis (MMP9).	('colon cancer', 'Phenotype', 'HP:0003003', (43, 55))	('MMP9', 'Gene', (221, 225))	('MMP9', 'Gene', '4318', (221, 225))	('delta-T3', 'Var', (0, 8))	('SOX2', 'Gene', '6657', (113, 117))	('stemness', 'CPA', (87, 95))	('SOX2', 'Gene', (113, 117))	('angiogenesis', 'CPA', (185, 197))	('inflammation', 'Disease', (163, 175))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colon cancer', 'Disease', 'MESH:D015179', (43, 55))	('NF-kB', 'Gene', (177, 182))	('NANOG', 'Gene', '79923', (97, 102))	('NANOG', 'Gene', (97, 102))	('invasion', 'CPA', (153, 161))	('VEGF', 'Gene', '7422', (199, 203))	('colon cancer', 'Disease', (43, 55))	('NF-kB', 'Gene', '309165', (177, 182))	('metastasis', 'CPA', (209, 219))	('inhibit', 'NegReg', (35, 42))	('OCT4', 'Gene', '5460', (104, 108))	('rat', 'Species', '10116', (145, 148))	('VEGF', 'Gene', (199, 203))	('inflammation', 'Disease', 'MESH:D007249', (163, 175))	('delta-T3', 'Chemical', '-', (0, 8))	('OCT4', 'Gene', (104, 108))
126068	32017273	In an orthotopic (cecum-injected CCSCs) xenograft model of metastasis, delta-T3 (200 mg/kg administered orally twice a day for 4 weeks) significantly retarded the CCSCs-derived tumor growth (Ki-67), inflammation (NF-kB), angiogenesis (VEGF and CD31) and beta-catenin/CTNNB1, as well as induced apoptosis (cleaved-PARP) in tumor tissues.	('CTNNB1', 'Gene', (267, 273))	('NF-kB', 'Gene', '309165', (213, 218))	('Ki-67', 'Gene', '17345', (191, 196))	('VEGF', 'Gene', (235, 239))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('apoptosis', 'CPA', (294, 303))	('delta-T3', 'Chemical', '-', (71, 79))	('retarded', 'NegReg', (150, 158))	('PARP', 'Gene', '142', (313, 317))	('CD31', 'Gene', '5175', (244, 248))	('beta-catenin', 'Gene', (254, 266))	('delta-T3', 'Var', (71, 79))	('beta-catenin', 'Gene', '1499', (254, 266))	('PARP', 'Gene', (313, 317))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('Ki-67', 'Gene', (191, 196))	('induced', 'Reg', (286, 293))	('tumor', 'Disease', (177, 182))	('CTNNB1', 'Gene', '1499', (267, 273))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('CD31', 'Gene', (244, 248))	('inflammation', 'Disease', 'MESH:D007249', (199, 211))	('NF-kB', 'Gene', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('VEGF', 'Gene', '7422', (235, 239))	('tumor', 'Disease', (322, 327))	('inflammation', 'Disease', (199, 211))
126081	32017273	delta-T3-13`-COOH (0.22 g/kg diet) was found to significantly inhibit tumor formation, especially on tumors with size > 2mm2,.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('delta-T3-13`-COOH', 'Chemical', '-', (0, 17))	('delta-T3-13`-COOH', 'Var', (0, 17))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('inhibit', 'NegReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumors', 'Disease', (101, 107))
126082	32017273	This work demonstrates the cancer preventive activity of this delta-T3 metabolite, in agreement with its activities in inhibiting pro-inflammatory enzymes and DEGS to induce autophagy and apoptosis of human cancer cells.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (207, 213))	('inhibiting', 'NegReg', (119, 129))	('rat', 'Species', '10116', (17, 20))	('apoptosis', 'CPA', (188, 197))	('men', 'Species', '9606', (91, 94))	('DEGS', 'Gene', (159, 163))	('delta-T3', 'Var', (62, 70))	('DEGS', 'Gene', '8560', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('human', 'Species', '9606', (201, 206))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('induce', 'PosReg', (167, 173))	('autophagy', 'CPA', (174, 183))	('pro-inflammatory enzymes', 'MPA', (130, 154))	('delta-T3', 'Chemical', '-', (62, 70))
126083	32017273	The studies as reviewed above clearly demonstrated the cancer preventive activities of gamma-T and delta-T in different animal models, while alpha-T was not effective.	('gamma-T', 'Var', (87, 94))	('delta-T', 'Chemical', 'MESH:C479072', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('delta-T', 'Var', (99, 106))	('gamma-T', 'Chemical', 'MESH:D024504', (87, 94))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('rat', 'Species', '10116', (45, 48))
126085	32017273	For mechanistic studies, treatment of cancer cell lines in culture or xenograft tumors with gamma-T, delta-T, gamma-T3 and delta-T3 compounds affects multiple cellular signaling molecules and pathways, leading to enhanced apoptosis and inhibition of cell proliferation, migration, invasion and metastasis and angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('apoptosis', 'CPA', (222, 231))	('migration', 'CPA', (270, 279))	('tumors', 'Disease', (80, 86))	('cellular signaling molecules', 'Pathway', (159, 187))	('rat', 'Species', '10116', (262, 265))	('inhibition', 'NegReg', (236, 246))	('delta-T3', 'Chemical', '-', (123, 131))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('angiogenesis', 'CPA', (309, 321))	('cancer', 'Disease', (38, 44))	('gamma-T', 'Chemical', 'MESH:D024504', (110, 117))	('delta-T', 'Chemical', 'MESH:C479072', (101, 108))	('gamma-T3', 'Chemical', '-', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('delta-T3', 'Var', (123, 131))	('enhanced', 'PosReg', (213, 221))	('delta-T', 'Chemical', 'MESH:C479072', (123, 130))	('gamma-T', 'Var', (92, 99))	('men', 'Species', '9606', (30, 33))	('delta-T', 'Var', (101, 108))	('gamma-T', 'Chemical', 'MESH:D024504', (92, 99))	('gamma-T3', 'Var', (110, 118))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('rat', 'Species', '10116', (273, 276))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('affects', 'Reg', (142, 149))	('cell proliferation', 'CPA', (250, 268))
126092	32017273	In cell culture studies, gamma-T3 and delta-T3 are generally more active than gamma-T and delta-T.	('delta-T3', 'Chemical', '-', (38, 46))	('gamma-T', 'Chemical', 'MESH:D024504', (78, 85))	('active', 'MPA', (66, 72))	('delta-T3', 'Var', (38, 46))	('delta-T', 'Chemical', 'MESH:C479072', (38, 45))	('gamma-T3', 'Chemical', '-', (25, 33))	('gamma-T', 'Chemical', 'MESH:D024504', (25, 32))	('delta-T', 'Chemical', 'MESH:C479072', (90, 97))	('gamma-T3', 'Var', (25, 33))
126095	32017273	Our unpublished result in the PhIP/DSS-induced colon tumorigenesis in CYP1A-humanized mouse model showed that delta-T3 (0.5 g/kg diet) produced 58% inhibition in tumor multiplicity (Yang et al., unpublished results), and this is comparable to an inhibition produced by delta-T at a dose of 2 g/kg diet.	('colon tumorigenesis', 'Disease', (47, 66))	('PhIP', 'Chemical', 'MESH:C049584', (30, 34))	('delta-T3', 'Chemical', '-', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('inhibition', 'NegReg', (148, 158))	('colon tumorigenesis', 'Disease', 'MESH:D063646', (47, 66))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mouse', 'Species', '10090', (86, 91))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('human', 'Species', '9606', (76, 81))	('delta-T3', 'Var', (110, 118))	('tumor', 'Disease', (53, 58))	('delta-T', 'Chemical', 'MESH:C479072', (110, 117))	('delta-T', 'Chemical', 'MESH:C479072', (269, 276))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
126104	32017273	Beyond the nutritional level, in individuals that are sufficient in VE nutrition, supplementation with gamma-T, delta-T and tocotrienols, but not alpha-T, could reduce the cancer risk.	('VE', 'Chemical', 'MESH:D014810', (68, 70))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('delta-T', 'Chemical', 'MESH:C479072', (112, 119))	('reduce', 'NegReg', (161, 167))	('delta-T', 'Var', (112, 119))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('men', 'Species', '9606', (88, 91))	('tocotrienols', 'Chemical', 'MESH:D024508', (124, 136))	('cancer', 'Disease', (172, 178))	('gamma-T', 'Chemical', 'MESH:D024504', (103, 110))	('gamma-T', 'Var', (103, 110))
126111	32017273	Since ROS and RNS are involved in inflammation and carcinogenesis, quenching of these free radicals would have anti-inflammatory and anti-carcinogenic effects.	('anti-carcinogenic effects', 'CPA', (133, 158))	('inflammation', 'Disease', (34, 46))	('quenching', 'Var', (67, 76))	('ROS', 'Chemical', 'MESH:D017382', (6, 9))	('anti-inflammatory', 'CPA', (111, 128))	('ROS', 'Protein', (6, 9))	('RNS', 'Chemical', 'MESH:D026361', (14, 17))	('carcinogenesis', 'Disease', 'MESH:D063646', (51, 65))	('RNS', 'Protein', (14, 17))	('inflammation', 'Disease', 'MESH:D007249', (34, 46))	('carcinogenesis', 'Disease', (51, 65))
126119	32017273	In our studies, on the inhibition of prostate cancer cells, the possibility that delta-T binds to the membrane and influences tyrosine receptor kinase activity was proposed.	('delta-T', 'Chemical', 'MESH:C479072', (81, 88))	('prostate cancer', 'Disease', (37, 52))	('delta-T', 'Var', (81, 88))	('influences', 'Reg', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tyrosine receptor kinase activity', 'MPA', (126, 159))	('prostate cancer', 'Disease', 'MESH:D011471', (37, 52))	('binds', 'Interaction', (89, 94))	('prostate cancer', 'Phenotype', 'HP:0012125', (37, 52))
126128	32017273	These properties may contribute to the cancer preventive activities of gamma-T, delta-T, gamma-T3 and delta-T3.	('delta-T', 'Chemical', 'MESH:C479072', (80, 87))	('gamma-T', 'Chemical', 'MESH:D024504', (71, 78))	('gamma-T3', 'Var', (89, 97))	('cancer', 'Disease', (39, 45))	('gamma-T', 'Var', (71, 78))	('delta-T', 'Var', (80, 87))	('delta-T3', 'Var', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('gamma-T', 'Chemical', 'MESH:D024504', (89, 96))	('delta-T', 'Chemical', 'MESH:C479072', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('delta-T3', 'Chemical', '-', (102, 110))	('contribute', 'Reg', (21, 31))	('gamma-T3', 'Chemical', '-', (89, 97))
126135	32017273	As discussed previously, in two human studies, one with pancreatic cancer patients and one with healthy volunteers, delta-T3 at doses of 100 to 3200 mg per day for two weeks, did not show any side effects.	('delta-T3', 'Var', (116, 124))	('patients', 'Species', '9606', (74, 82))	('pancreatic cancer', 'Disease', (56, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('delta-T3', 'Chemical', '-', (116, 124))	('human', 'Species', '9606', (32, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))
126151	32017273	More human studies on the cancer preventive activities of gamma-T, delta-T, gamma-T3 and delta-T3.	('gamma-T', 'Chemical', 'MESH:D024504', (76, 83))	('delta-T', 'Chemical', 'MESH:C479072', (67, 74))	('gamma-T3', 'Chemical', '-', (76, 84))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('delta-T', 'Chemical', 'MESH:C479072', (89, 96))	('delta-T', 'Var', (67, 74))	('gamma-T', 'Chemical', 'MESH:D024504', (58, 65))	('gamma-T3', 'Var', (76, 84))	('delta-T3', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('gamma-T', 'Var', (58, 65))	('human', 'Species', '9606', (5, 10))	('delta-T3', 'Chemical', '-', (89, 97))
126155	32017273	alpha (beta, gamma or delta)-T alpha (beta, gamma or delta)-tocopherol alpha (beta, gamma or delta)-T3 alpha (beta, gamma or delta)-tocotrienols alpha-TTP alpha-T transfer protein ACF aberrant crypt foci COX2 cyclooxygenase-2 CRC colorectal cancer CYP1A1 cytochrome P450 1A1 DEGS dihydroceramide desturase ER estrogen receptor gamma-H2AX phosphorylated histone 2A variant X gamma-TmT gamma-T rich mixture of tocopherols IHC immunohistochemical KPC triple transgenic LSL-KrasG12D LSL Trp53R127H (mouse) Pdx-1-Cre LTB4 leukotriene B4 MBNA methylbenzylnitrosamine MMP matrix metalloproteinases MNU methylnitrosurea 8-oxo-dG 8-oxo-deoxyguanosine PDAC pancreatic ductal carcinoma PGE2 prostaglandin E2 PhIP 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine PIN prostatic intraepithelial neoplasia SNP single nucleotide polymorphism VE Vitamin E	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (764, 789))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (680, 696))	('CYP1A1', 'Gene', (248, 254))	('DEGS', 'Gene', '8560', (275, 279))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (754, 789))	('pancreatic ductal carcinoma', 'Disease', (647, 674))	('methylnitrosurea', 'Chemical', '-', (595, 611))	('Trp53', 'Gene', '22059', (483, 488))	('LTB4', 'Chemical', 'MESH:D007975', (512, 516))	('MBNA', 'Chemical', '-', (532, 536))	('-T3', 'Chemical', 'MESH:D014284', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('alpha-TTP', 'Gene', '7274', (145, 154))	('gamma-TmT', 'Chemical', '-', (374, 383))	('Trp53', 'Gene', (483, 488))	('colorectal cancer', 'Disease', 'MESH:D015179', (230, 247))	('Vitamin E', 'Chemical', 'MESH:D014810', (828, 837))	('prostatic intraepithelial neoplasia', 'Disease', (754, 789))	('COX2', 'Gene', (204, 208))	('leukotriene B4', 'Chemical', 'MESH:D007975', (517, 531))	('LSL', 'Gene', (466, 469))	('PIN', 'Gene', (750, 753))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (658, 674))	('colorectal cancer', 'Disease', (230, 247))	('LSL', 'Gene', '7839', (466, 469))	('estrogen receptor', 'Gene', '2099', (309, 326))	('neoplasia', 'Phenotype', 'HP:0002664', (780, 789))	('CYP1A1', 'Gene', '1543', (248, 254))	('single nucleotide polymorphism', 'Var', (794, 824))	('pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (647, 674))	('gamma-T', 'Chemical', 'MESH:D024504', (374, 381))	('PGE2', 'Chemical', 'MESH:D015232', (675, 679))	('methylbenzylnitrosamine', 'Chemical', 'MESH:C014707', (537, 560))	('ER', 'Gene', '2099', (306, 308))	('alpha (beta, gamma or delta)-tocopherol', 'Chemical', '-', (31, 70))	('PIN', 'Gene', '56455', (750, 753))	('PhIP', 'Chemical', 'MESH:C049584', (697, 701))	('carcinoma', 'Phenotype', 'HP:0030731', (665, 674))	('2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine', 'Chemical', 'MESH:C049584', (702, 749))	('VE', 'Chemical', 'MESH:D014810', (825, 827))	('gamma-H2AX', 'Chemical', '-', (327, 337))	('cyclooxygenase-2', 'Gene', '5743', (209, 225))	('colorectal cancer', 'Phenotype', 'HP:0003003', (230, 247))	('estrogen receptor', 'Gene', (309, 326))	('COX2', 'Gene', '5743', (204, 208))	('DEGS', 'Gene', (275, 279))	('LSL', 'Gene', (479, 482))	('alpha-TTP', 'Gene', (145, 154))	('alpha (beta, gamma or delta)-tocotrienols', 'Chemical', '-', (103, 144))	('gamma-T', 'Chemical', 'MESH:D024504', (384, 391))	('LSL', 'Gene', '7839', (479, 482))	('mouse', 'Species', '10090', (495, 500))	('MNU', 'Chemical', 'MESH:D008770', (591, 594))	('tocopherols', 'Chemical', 'MESH:D024505', (408, 419))	('dihydroceramide', 'Chemical', 'MESH:C109343', (280, 295))	('cyclooxygenase-2', 'Gene', (209, 225))
126178	31844033	Here, we analyzed the expression of miR-203 in two human EC cell lines with different metastatic potential, KYSE30 (less metastatic potential) and KYSE510 (greater metastatic potential).	('KYSE510', 'Var', (147, 154))	('miR-203', 'Gene', '406986', (36, 43))	('miR-203', 'Gene', (36, 43))	('EC', 'Disease', 'MESH:D004938', (57, 59))	('less', 'NegReg', (116, 120))	('human', 'Species', '9606', (51, 56))	('KYSE510', 'CellLine', 'CVCL:1354', (147, 154))	('greater', 'PosReg', (156, 163))	('KYSE30', 'Var', (108, 114))
126179	31844033	The level of miR-203 was significantly decreased in both KYSE30 and KYSE510 compared to the normal esophageal cell line, HEEC (Figure 3A).	('KYSE510', 'Var', (68, 75))	('KYSE510', 'CellLine', 'CVCL:1354', (68, 75))	('miR-203', 'Gene', (13, 20))	('miR-203', 'Gene', '406986', (13, 20))	('decreased', 'NegReg', (39, 48))	('HEEC', 'CellLine', 'None', (121, 125))	('KYSE30', 'Var', (57, 63))
126180	31844033	Furthermore, KYSE510 cells had a much lower level of miR-203 than KYSE30 cells (Figure 3A).	('KYSE510', 'Var', (13, 20))	('lower', 'NegReg', (38, 43))	('miR-203', 'Gene', (53, 60))	('miR-203', 'Gene', '406986', (53, 60))	('KYSE510', 'CellLine', 'CVCL:1354', (13, 20))
126183	31844033	in vitro transwell and wound healing assays as well as in vivo experimental pulmonary metastasis assays showed that miR-203 inhibitor vigorously enhanced migration, invasion and pulmonary metastasis of KYSE30 cells, while miR-203 mimic produced the opposite results in KYSE 510 cells (Figure 3D-3H).	('pulmonary metastasis', 'CPA', (178, 198))	('inhibitor', 'Var', (124, 133))	('invasion', 'CPA', (165, 173))	('miR-203', 'Gene', (116, 123))	('miR-203', 'Gene', (222, 229))	('miR-203', 'Gene', '406986', (116, 123))	('miR-203', 'Gene', '406986', (222, 229))	('enhanced', 'PosReg', (145, 153))	('migration', 'CPA', (154, 163))
126209	31844033	However, the effect of KIF5C on these proteins was markedly reversed in the presence of miR-203 or IWR-1-endo, which induces the level of Axin2 and beta-catenin degradation.	('Axin2', 'Gene', '8313', (138, 143))	('beta-catenin', 'Gene', (148, 160))	('beta-catenin', 'Gene', '1499', (148, 160))	('miR-203', 'Gene', '406986', (88, 95))	('induces', 'Reg', (117, 124))	('KIF5C', 'Gene', (23, 28))	('miR-203', 'Gene', (88, 95))	('IWR-1-endo', 'Var', (99, 109))	('level', 'MPA', (129, 134))	('Axin2', 'Gene', (138, 143))	('KIF5C', 'Gene', '3800', (23, 28))
126210	31844033	And, more importantly, miR-203 and IWR-1-endo showed synergistic effects on expression of E-cadherin, N-cadherin, MMP2 and MMP9 (Figure 6G).	('IWR-1-endo', 'Var', (35, 45))	('MMP2', 'Gene', '4313', (114, 118))	('E-cadherin', 'Gene', (90, 100))	('N-cadherin', 'Gene', (102, 112))	('miR-203', 'Gene', '406986', (23, 30))	('miR-203', 'Gene', (23, 30))	('N-cadherin', 'Gene', '1000', (102, 112))	('expression', 'MPA', (76, 86))	('MMP2', 'Gene', (114, 118))	('MMP9', 'Gene', '4318', (123, 127))	('MMP9', 'Gene', (123, 127))	('E-cadherin', 'Gene', '999', (90, 100))
126307	31151416	We found that in highly T-cell infiltrated tumors (CD3 high) high XIAP expression is detrimental for overall survival.	('XIAP', 'Gene', '331', (66, 70))	('XIAP', 'Gene', (66, 70))	('high', 'Var', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
126318	31151416	We could furthermore show that elevated XIAP expression compromises overall survival in patients with highly T-cell infiltrated tumors that normally have a promising prognosis and that patients that respond to chemotherapy and have high XIAP protein levels are at high risk.	('compromises', 'NegReg', (56, 67))	('XIAP', 'Gene', (237, 241))	('patients', 'Species', '9606', (88, 96))	('XIAP', 'Gene', '331', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('XIAP', 'Gene', (40, 44))	('XIAP', 'Gene', '331', (40, 44))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('patients', 'Species', '9606', (185, 193))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('overall', 'MPA', (68, 75))	('elevated', 'Var', (31, 39))
126403	27012988	For OS, pN+ stage and irradicality remained independently and significantly associated with worse OS in multivariable analysis.	('pN+', 'Chemical', 'MESH:C070006', (8, 11))	('OS', 'Chemical', '-', (4, 6))	('OS', 'Chemical', '-', (98, 100))	('worse OS', 'Disease', (92, 100))	('irradicality', 'Var', (22, 34))
126451	27196482	Furthermore, CRT can also induce fistula formation by damaging the walls of the esophagus and adjacent organs.	('damaging', 'NegReg', (54, 62))	('fistula', 'Disease', 'MESH:D005402', (33, 40))	('CRT', 'Var', (13, 16))	('walls of the esophagus', 'CPA', (67, 89))	('fistula', 'Disease', (33, 40))	('induce', 'Reg', (26, 32))
126524	24223481	In addition, there has been information suggesting that specific defects in known cell cycle checkpoint genes such as p16 can result in resistance to photodynamic therapy on a clinical basis.	('p16', 'Gene', '1029', (118, 121))	('resistance', 'MPA', (136, 146))	('result in', 'Reg', (126, 135))	('p16', 'Gene', (118, 121))	('defects', 'Var', (65, 72))
126747	32408627	Evidence for Cytoprotective Effect of Carbon Monoxide Donor in the Development of Acute Esophagitis Leading to Acute Esophageal Epithelium Lesions Exposure to acidic gastric content due to malfunction of lower esophageal sphincter leads to acute reflux esophagitis (RE) leading to disruption of esophageal epithelial cells.	('malfunction', 'Var', (189, 200))	('Acute Esophagitis', 'Disease', (82, 99))	('gas', 'Gene', (166, 169))	('acute reflux esophagitis', 'Disease', (240, 264))	('esophagitis', 'Phenotype', 'HP:0100633', (253, 264))	('gas', 'Gene', '25320', (166, 169))	('Acute Esophagitis', 'Disease', 'MESH:D004938', (82, 99))	('Carbon Monoxide', 'Chemical', 'MESH:D002248', (38, 53))	('Esophagitis', 'Phenotype', 'HP:0100633', (88, 99))	('acute reflux esophagitis', 'Disease', 'MESH:D005764', (240, 264))
126857	32408627	did not significantly affect lesion score but L-NNA significantly reduced EBF as compared with CORM-2 administered alone (p < 0.05, Figure 3).	('reduced', 'NegReg', (66, 73))	('CO', 'Chemical', 'MESH:D002248', (95, 97))	('L-NNA', 'Chemical', 'MESH:D019335', (46, 51))	('L-NNA', 'Var', (46, 51))	('EBF', 'Disease', (74, 77))
126893	32408627	Interestingly, L-NNA but not indomethacin reduced hyperemic effect of CORM-2 showing that the impairment of esophageal microcirculation by the NO-synthase inhibition per se is not detrimental for the esophagoprotective activity exhibited by this CO-donor.	('hyperemic', 'Disease', (50, 59))	('inhibition', 'NegReg', (155, 165))	('hyperemic', 'Disease', 'MESH:D006940', (50, 59))	('L-NNA', 'Chemical', 'MESH:D019335', (15, 20))	('esophageal microcirculation', 'MPA', (108, 135))	('L-NNA', 'Var', (15, 20))	('CO', 'Chemical', 'MESH:D002248', (70, 72))	('CO', 'Chemical', 'MESH:D002248', (246, 248))	('indomethacin', 'Chemical', 'MESH:D007213', (29, 41))
126897	32408627	In agreement with this notion, we have reported that CORM-2 attenuated the aspirin-induced gastric damage and the inhibition of NO synthase by L-NNA only partially reduced CORM-2-induced protection, but did not reverse completely this effect.	('aspirin', 'Chemical', 'MESH:D001241', (75, 82))	('CO', 'Chemical', 'MESH:D002248', (53, 55))	('gastric damage', 'Disease', (91, 105))	('CO', 'Chemical', 'MESH:D002248', (172, 174))	('gastric damage', 'Disease', 'MESH:D013272', (91, 105))	('inhibition', 'Var', (114, 124))	('attenuated', 'NegReg', (60, 70))	('reduced', 'NegReg', (164, 171))	('L-NNA', 'Chemical', 'MESH:D019335', (143, 148))
126902	32408627	In our study, the esophagoprotective and hyperemic effects of CORM-2 were reduced by the ablation of sensory nerves by a high dose of capsaicin or blockade of TRPV1 by capsazepine.	('blockade', 'NegReg', (147, 155))	('capsaicin', 'Chemical', 'MESH:D002211', (134, 143))	('capsazepine', 'Chemical', 'MESH:C071423', (168, 179))	('CO', 'Chemical', 'MESH:D002248', (62, 64))	('CORM-2', 'Gene', (62, 68))	('ablation', 'Var', (89, 97))	('hyperemic', 'Disease', (41, 50))	('TRPV1', 'Gene', '83810', (159, 164))	('reduced', 'NegReg', (74, 81))	('TRPV1', 'Gene', (159, 164))	('hyperemic', 'Disease', 'MESH:D006940', (41, 50))
126909	32408627	reported that inhibition of p38 MAPK pathway in an animal model of reflux-induced esophagitis reduced mRNA levels of IL-1beta, IL-6 and TNF-alpha in esophageal mucosa and protein levels of TNF-alpha, IL-6, and IL-1beta in serum.	('esophagitis', 'Disease', (82, 93))	('IL-6', 'Gene', (200, 204))	('reduced', 'NegReg', (94, 101))	('IL-6', 'Gene', '24498', (200, 204))	('TNF-alpha', 'MPA', (136, 145))	('p38 MAPK pathway', 'Pathway', (28, 44))	('protein levels', 'MPA', (171, 185))	('IL-6', 'Gene', (127, 131))	('IL-6', 'Gene', '24498', (127, 131))	('esophagitis', 'Disease', 'MESH:D004938', (82, 93))	('inhibition', 'Var', (14, 24))	('esophagitis', 'Phenotype', 'HP:0100633', (82, 93))	('mRNA levels of IL-1beta', 'MPA', (102, 125))
126913	32408627	In contrast to IL-1alpha and IL-1beta which promotes inflammation, IL-1RA has been demonstrated to suppress angiogenesis accompanying gastric and esophageal cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gas', 'Gene', '25320', (134, 137))	('inflammation', 'Disease', 'MESH:D007249', (53, 65))	('IL-1alpha', 'Gene', (15, 24))	('IL-1RA', 'Var', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('IL-1alpha', 'Gene', '24493', (15, 24))	('gas', 'Gene', (134, 137))	('inflammation', 'Disease', (53, 65))	('cancer', 'Disease', (157, 163))	('suppress', 'NegReg', (99, 107))	('angiogenesis', 'CPA', (108, 120))	('rat', 'Species', '10116', (90, 93))
126938	31720102	Overall treatment-related adverse effects were compatible in groups S and T (p = 0.878), but the total cost of terlipressin and somatostatin differed i.e., USD 621.32 and USD 496.43 respectively.	('USD', 'Var', (171, 174))	('somatostatin', 'Gene', '6750', (128, 140))	('USD 621.32', 'Var', (156, 166))	('somatostatin', 'Gene', (128, 140))
126955	31720102	The former consisted of chest tightness/pain, hypertension (defined as SBP > 140 mmHg), abdominal pain, arrhythmia, hyponatremia (Na < 125 mmol/L), lymphangitis, renal failure (Cr > 2 mg/dL), hyperglycemia (Glu > 300 mg/dL) and flush.	('hypertension', 'Phenotype', 'HP:0000822', (46, 58))	('hyponatremia', 'Phenotype', 'HP:0002902', (116, 128))	('pain', 'Phenotype', 'HP:0012531', (98, 102))	('hyponatremia', 'Disease', (116, 128))	('hyperglycemia', 'Phenotype', 'HP:0003074', (192, 205))	('flush', 'Phenotype', 'HP:0031284', (228, 233))	('pain', 'Phenotype', 'HP:0012531', (40, 44))	('abdominal pain', 'Phenotype', 'HP:0002027', (88, 102))	('Cr > 2', 'Species', '2498238', (177, 183))	('hyponatremia', 'Disease', 'MESH:D007010', (116, 128))	('lymphangitis', 'Disease', 'MESH:D008205', (148, 160))	('lymphangitis', 'Disease', (148, 160))	('chest tightness/pain', 'Disease', 'MESH:D002637', (24, 44))	('Glu', 'Chemical', 'MESH:C094686', (207, 210))	('SBP', 'Gene', '8991', (71, 74))	('renal failure', 'Phenotype', 'HP:0000083', (162, 175))	('chest tightness/pain', 'Disease', (24, 44))	('hypertension', 'Disease', 'MESH:D006973', (46, 58))	('hyperglycemia', 'Disease', (192, 205))	('renal failure', 'Disease', 'MESH:D051437', (162, 175))	('hypertension', 'Disease', (46, 58))	('Cr', 'Var', (177, 179))	('abdominal pain', 'Disease', (88, 102))	('Glu', 'Var', (207, 210))	('renal failure', 'Disease', (162, 175))	('arrhythmia', 'Phenotype', 'HP:0011675', (104, 114))	('abdominal pain', 'Disease', 'MESH:D015746', (88, 102))	('hyperglycemia', 'Disease', 'MESH:D006943', (192, 205))	('flush', 'Disease', (228, 233))	('SBP', 'Gene', (71, 74))	('chest tightness', 'Phenotype', 'HP:0031352', (24, 39))	('arrhythmia', 'Disease', 'MESH:D001145', (104, 114))	('arrhythmia', 'Disease', (104, 114))
127071	30079369	More patients treated with IMRT had grade 4 lymphopenia as compared with those treated with PBT (Table 3).	('patients', 'Species', '9606', (5, 13))	('lymphopenia', 'Disease', 'MESH:D008231', (44, 55))	('lymphopenia', 'Disease', (44, 55))	('IMRT', 'Var', (27, 31))	('lymphopenia', 'Phenotype', 'HP:0001888', (44, 55))
127079	30079369	In patients with stage III or IVA disease, IMRT (HR, 1.50; 95% CI, 0.98-2.31; P = .06) trended toward significant association with DFS on univariable analysis (Supplemental Figure 2) but was not significantly associated with DFS (HR for IMRT, 1.42; 95% CI, 0.92-2.19; P = .11) in a multivariable model adjusting for log (PTV) and lymphocyte count reduction.	('stage III', 'Disease', (17, 26))	('DFS', 'Var', (131, 134))	('IVA disease', 'Disease', (30, 41))	('IVA disease', 'Disease', 'MESH:C538167', (30, 41))	('lymphocyte count reduction', 'Phenotype', 'HP:0001888', (330, 356))	('patients', 'Species', '9606', (3, 11))	('PTV', 'Chemical', '-', (321, 324))
127081	30079369	In this study with 200 patients matched by propensity score and treated definitively with PBT or IMRT and chemotherapy for esophageal cancer, we found that treatment with IMRT compared with PBT, greater PTV, and increased age were predictive of grade 4 lymphopenia.	('esophageal cancer', 'Disease', (123, 140))	('patients', 'Species', '9606', (23, 31))	('PTV', 'Chemical', '-', (203, 206))	('lymphopenia', 'Disease', (253, 264))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('IMRT', 'Var', (171, 175))	('atm', 'Gene', '472', (159, 162))	('lymphopenia', 'Phenotype', 'HP:0001888', (253, 264))	('atm', 'Gene', (159, 162))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('lymphopenia', 'Disease', 'MESH:D008231', (253, 264))
127086	30079369	We also found greater PTV to be associated with a greater risk of grade 4 lymphopenia, which supports the hypothesis that a larger volume of low-integral dose to surrounding lymphocyte-harboring organs enhances the risk of lymphopenia.	('lymphopenia', 'Disease', 'MESH:D008231', (223, 234))	('lymphopenia', 'Phenotype', 'HP:0001888', (223, 234))	('lymphopenia', 'Disease', (74, 85))	('PTV', 'Var', (22, 25))	('lymphopenia', 'Disease', (223, 234))	('enhances', 'PosReg', (202, 210))	('PTV', 'Chemical', '-', (22, 25))	('lymphopenia', 'Phenotype', 'HP:0001888', (74, 85))	('lymphopenia', 'Disease', 'MESH:D008231', (74, 85))
127091	30079369	In patients with poorer-risk esophageal cancer treated nonsurgically with definitive CRT, IMRT, as compared with PBT, and greater PTV were strongly associated with grade 4 lymphopenia.	('lymphopenia', 'Phenotype', 'HP:0001888', (172, 183))	('PTV', 'Chemical', '-', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('lymphopenia', 'Disease', 'MESH:D008231', (172, 183))	('grade', 'Disease', (164, 169))	('esophageal cancer', 'Disease', (29, 46))	('patients', 'Species', '9606', (3, 11))	('lymphopenia', 'Disease', (172, 183))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('IMRT', 'Var', (90, 94))
127226	28874958	EUS-LB produced significantly longer total specimen length than transjugular liver biopsy (40 mm vs 34 mm, P = 0.01) and similar complete portal triads (17 vs 15.5, P = 0.22).	('EUS-LB', 'Chemical', '-', (0, 6))	('longer', 'PosReg', (30, 36))	('EUS-LB', 'Var', (0, 6))
127383	25202347	Mutation of the p53 gene results in the loss of its ability to induce cell death, which leads to uncontrolled cell growth, thus, promoting tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('uncontrolled cell growth', 'MPA', (97, 121))	('p53', 'Gene', (16, 19))	('Mutation', 'Var', (0, 8))	('loss', 'NegReg', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('p53', 'Gene', '7157', (16, 19))	('cell death', 'CPA', (70, 80))	('promoting', 'PosReg', (129, 138))	('ability', 'MPA', (52, 59))
127402	25202347	The IHC staining of mutant (MT)p53 was assessed according to the immune-reactive score (IRS) as described previously with slight adjustments, which evaluated the percentage of positive cells and the staining intensity.	('p53', 'Gene', (31, 34))	('mutant', 'Var', (20, 26))	('p53', 'Gene', '7157', (31, 34))
127426	25202347	The wild-type (WT)p53 protein contains 393 amino acids and p53 is a tumor suppressor that has a close association with numerous types of human cancer; the mutation or loss of the p53 gene can be identified in >50% of all human cancers.	('p53', 'Gene', (59, 62))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('tumor', 'Disease', (68, 73))	('human', 'Species', '9606', (137, 142))	('p53', 'Gene', (18, 21))	('human', 'Species', '9606', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', (143, 149))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('loss', 'NegReg', (167, 171))	('cancer', 'Disease', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('p53', 'Gene', '7157', (59, 62))	('p53', 'Gene', '7157', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('mutation', 'Var', (155, 163))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancers', 'Disease', (227, 234))
127435	25202347	Previous studies have detected the p53 mutation using IHC and were able to define the tissue via the strong staining of the p53 protein as MTp53.	('p53', 'Gene', (124, 127))	('p53', 'Gene', (141, 144))	('p53', 'Gene', (35, 38))	('mutation', 'Var', (39, 47))	('p53', 'Gene', '7157', (141, 144))	('p53', 'Gene', '7157', (35, 38))	('p53', 'Gene', '7157', (124, 127))
127436	25202347	Based on this finding, the point mutation in the p53 gene was associated with p53 protein stabilization.	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('associated', 'Reg', (62, 72))	('point mutation', 'Var', (27, 41))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (78, 81))
127438	25202347	Recently, Zhu et al demonstrated that the knock-down of MTp53 using small interfering RNA induced cell cylce arrest and triggered apoptosis in bladder cancer cells.	('triggered', 'Reg', (120, 129))	('knock-down', 'Var', (42, 52))	('apoptosis', 'CPA', (130, 139))	('cell', 'CPA', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (143, 157))	('bladder cancer', 'Disease', (143, 157))	('bladder cancer', 'Disease', 'MESH:D001749', (143, 157))	('arrest', 'Disease', 'MESH:D006323', (109, 115))	('induced', 'Reg', (90, 97))	('arrest', 'Disease', (109, 115))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
127488	23599766	Overall, 147 of 285 (51.58%) cases were positive for high-risk HPV, of which 137 (48.07%) were associated with HPV16, 6 (2.11%) with HPV18, 2 (0.70%) with HPV53 and 2 (0.70%) with HPV58.	('HPV18', 'Var', (133, 138))	('HPV', 'Species', '10566', (63, 66))	('HPV', 'Species', '10566', (155, 158))	('HPV', 'Species', '10566', (180, 183))	('HPV', 'Disease', (63, 66))	('HPV', 'Species', '10566', (111, 114))	('HPV16', 'Species', '333760', (111, 116))	('HPV53', 'Var', (155, 160))	('associated', 'Reg', (95, 105))	('HPV', 'Species', '10566', (133, 136))	('HPV16', 'Var', (111, 116))
127489	23599766	The number of cases with low-risk HPV positivity (138/285, 48.42%) was higher compared with other HPV types and the majority of cases had esophageal cancer.	('esophageal cancer', 'Disease', (138, 155))	('positivity', 'Var', (38, 48))	('HPV', 'Gene', (34, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HPV', 'Species', '10566', (98, 101))	('HPV', 'Species', '10566', (34, 37))
127530	23599766	Persistent infection of the uterine cervix with high-risk HPV genotypes, particularly HPV16 and HPV18, is essential for the development of SCC.	('HPV', 'Species', '10566', (96, 99))	('SCC', 'Gene', '6317', (139, 142))	('Persistent infection', 'Phenotype', 'HP:0031035', (0, 20))	('HPV', 'Species', '10566', (86, 89))	('HPV18', 'Var', (96, 101))	('HPV16', 'Species', '333760', (86, 91))	('SCC', 'Gene', (139, 142))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('uterine cervix', 'Phenotype', 'HP:0030160', (28, 42))	('HPV', 'Species', '10566', (58, 61))
127561	23115442	It has been reported that one particular allele of p53 with an arginine rather than a proline at a certain position is much more susceptible to degradation by E6.	('p53', 'Gene', (51, 54))	('arginine', 'Var', (63, 71))	('proline', 'Chemical', 'MESH:D011392', (86, 93))	('arginine', 'Chemical', 'MESH:D001120', (63, 71))	('degradation', 'MPA', (144, 155))
127563	23115442	In order to demonstrate the effect of viruses and tumor promoters on the tumorigenicity, human embryonic esophageal cells were infected with HPV-18 E6 E7-AAV in synergy with exposure to 12-o-tetradecanoyl phorbol 13-acetate (TPA).	('HPV-18', 'Gene', (141, 147))	('embryonic esophageal', 'Disease', 'MESH:D004941', (95, 115))	('12-o-tetradecanoyl phorbol 13-acetate', 'Chemical', 'MESH:D013755', (186, 223))	('embryonic esophageal', 'Disease', (95, 115))	('E6 E7-AAV', 'Var', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('TPA', 'Chemical', 'MESH:D013755', (225, 228))	('E7-AAV', 'Var', (151, 157))
127612	33674602	Two aldehyde groups are significantly enriched in EAC biopsies and adjacent tissue: (i) short-chain alkanals, and (ii) medium-chain alkanals, including decanal.	('EAC', 'Phenotype', 'HP:0011459', (50, 53))	('short-chain', 'Var', (88, 99))	('alkanals', 'Chemical', '-', (132, 140))	('EAC', 'Disease', (50, 53))	('medium-chain alkanals', 'Var', (119, 140))	('aldehyde', 'Chemical', 'MESH:D000447', (4, 12))	('alkanals', 'Chemical', '-', (100, 108))
127615	33674602	Tissue and breath concentrations of the medium-chain alkanal decanal are correlated, and increased decanal is linked to reduced ALDH3A2 expression, TP53 deletion, and adverse clinical features.	('expression', 'MPA', (136, 146))	('deletion', 'Var', (153, 161))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('ALDH3A2', 'Gene', (128, 135))	('decanal', 'MPA', (99, 106))	('rat', 'Species', '10116', (25, 28))	('increased', 'PosReg', (89, 98))	('reduced', 'NegReg', (120, 127))
127626	33674602	For esophageal squamous cancers, inactivating variants in ALDH2 convey predisposing risk.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('ALDH2', 'Gene', '217', (58, 63))	('esophageal squamous cancers', 'Disease', (4, 31))	('ALDH2', 'Gene', (58, 63))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('inactivating variants', 'Var', (33, 54))	('esophageal squamous cancers', 'Disease', 'MESH:D002294', (4, 31))
127630	33674602	We show that short-chain genotoxic alkanals and also medium-chain alkanals are specifically enriched in EAC and associated tissues, on a genetic background of reduced aldehyde detoxification.	('alkanals', 'Chemical', '-', (35, 43))	('alkanals', 'Chemical', '-', (66, 74))	('aldehyde detoxification', 'MPA', (167, 190))	('aldehyde', 'Chemical', 'MESH:D000447', (167, 175))	('EAC', 'Phenotype', 'HP:0011459', (104, 107))	('short-chain genotoxic', 'Var', (13, 34))
127638	33674602	These data complement those from epidemiological and genomic studies which link deactivating ALDH variants to esophageal malignancies.	('esophageal malignancies', 'Phenotype', 'HP:0100751', (110, 133))	('malignancies', 'Disease', 'MESH:D009369', (121, 133))	('deactivating', 'NegReg', (80, 92))	('malignancies', 'Disease', (121, 133))	('variants', 'Var', (98, 106))	('ALDH', 'Gene', (93, 97))
127643	33674602	Thus, low expression of ALDH3A1 was common to all esophageal glandular epithelia, whereas loss of ALDH3A2 was linked to malignant transformation and progression.	('loss', 'Var', (90, 94))	('linked', 'Reg', (110, 116))	('expression', 'MPA', (10, 20))	('ALDH3A1', 'Gene', '218', (24, 31))	('low', 'NegReg', (6, 9))	('ALDH3A2', 'Gene', (98, 105))	('progression', 'CPA', (149, 160))	('ALDH3A1', 'Gene', (24, 31))	('malignant transformation', 'CPA', (120, 144))	('esophageal glandular epithelia', 'Phenotype', 'HP:0012859', (50, 80))
127658	33674602	Silencing individual ALDH isoenzymes in OE33 cells under normal conditions led to enrichment of acetaldehyde, nonanal, decanal, and some enals (see Supplementary Fig.	('enrichment', 'MPA', (82, 92))	('decanal', 'MPA', (119, 126))	('acetaldehyde', 'Chemical', 'MESH:D000079', (96, 108))	('nonanal', 'MPA', (110, 117))	('acetaldehyde', 'MPA', (96, 108))	('ALDH', 'Enzyme', (21, 25))	('Silencing', 'Var', (0, 9))
127700	33674602	Congenital ALDH3A2 mutations cause Sjogren-Larsson syndrome (SLS), a neuro-cutaneous syndrome in which keratinocyte hyperplasia and fatty alkanal accumulation are features.	('hyperplasia', 'Disease', 'MESH:D006965', (116, 127))	('Sjogren-Larsson syndrome', 'Disease', 'MESH:D016111', (35, 59))	('rat', 'Species', '10116', (105, 108))	('neuro-cutaneous syndrome', 'Disease', (69, 93))	('neuro-cutaneous syndrome', 'Disease', 'MESH:C536203', (69, 93))	('mutations', 'Var', (19, 28))	('Sjogren-Larsson syndrome', 'Disease', (35, 59))	('SLS', 'Disease', 'MESH:D016111', (61, 64))	('hyperplasia', 'Disease', (116, 127))	('SLS', 'Disease', (61, 64))	('cause', 'Reg', (29, 34))	('ALDH3A2', 'Gene', (11, 18))
127701	33674602	Given that loss of ALDH3A2 (and enriched decanal) was associated with EAC progression, whereas ALDH3A1 is generally suppressed in all glandular esophageal cell types, we then focused on the regulation of ALDH3A2 as the key mediator of decanal metabolism in EAC development.	('EAC', 'Disease', (70, 73))	('loss', 'Var', (11, 15))	('EAC', 'Phenotype', 'HP:0011459', (257, 260))	('ALDH3A1', 'Gene', (95, 102))	('ALDH3A2', 'Gene', (19, 26))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))	('associated', 'Reg', (54, 64))	('ALDH3A1', 'Gene', '218', (95, 102))
127702	33674602	6d), and an analysis of ALDH3A2 expression in The Cancer Cell Line Encyclopedia dataset showed a positive correlation with copy number (Supplementary Fig.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('ALDH3A2', 'Gene', (24, 31))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('copy number', 'Var', (123, 134))
127708	33674602	5k), in keeping with TCGA and ICGC genomic data, which supports the hypothesis that ALDH3A2 copy loss and reduced expression is related TP53 copy loss.	('copy', 'Var', (92, 96))	('ALDH3A2', 'Gene', (84, 91))	('expression', 'MPA', (114, 124))	('TP53', 'Gene', '7157', (136, 140))	('copy', 'Var', (141, 145))	('TP53', 'Gene', (136, 140))	('reduced', 'NegReg', (106, 113))
127711	33674602	In summary, reduced ALDH3A2 expression is associated with 17p copy loss involving TP53, and inversely related to tissue and exhaled decanal.	('ALDH3A2', 'Gene', (20, 27))	('TP53', 'Gene', (82, 86))	('17p copy loss', 'Var', (58, 71))	('reduced', 'NegReg', (12, 19))	('expression', 'MPA', (28, 38))	('TP53', 'Gene', '7157', (82, 86))
127713	33674602	We found suppressed aldehyde oxidation to be an EAC hallmark, consistent with observations of impaired glutathione-mediated redox defense in Barrett's and EAC, and epidemiological series which linked inactivating ALDH variants to esophageal malignancies.	('inactivating', 'Var', (200, 212))	('esophageal malignancies', 'Phenotype', 'HP:0100751', (230, 253))	('EAC', 'Phenotype', 'HP:0011459', (155, 158))	('malignancies', 'Disease', 'MESH:D009369', (241, 253))	('ALDH', 'Gene', (213, 217))	('glutathione', 'Chemical', 'MESH:D005978', (103, 114))	('aldehyde', 'Chemical', 'MESH:D000447', (20, 28))	('aldehyde oxidation', 'MPA', (20, 38))	('EAC', 'Phenotype', 'HP:0011459', (48, 51))	('suppressed', 'NegReg', (9, 19))	('impaired glutathione', 'Phenotype', 'HP:0003343', (94, 114))	('glutathione-mediated redox defense', 'MPA', (103, 137))	('malignancies', 'Disease', (241, 253))	('variants', 'Var', (218, 226))
127721	33674602	Gastro-esophageal acid reflux is a risk factor for EAC, and low pH enhances carbonyl-based nucleophilic addition reactions such as aldehyde-nucleotide adduction.	('aldehyde', 'Chemical', 'MESH:D000447', (131, 139))	('enhances', 'PosReg', (67, 75))	('low', 'Var', (60, 63))	('aldehyde-nucleotide', 'MPA', (131, 150))	('carbonyl-based nucleophilic addition reactions', 'MPA', (76, 122))	('acid reflux', 'Phenotype', 'HP:0002020', (18, 29))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('Gastro-esophageal acid reflux', 'Disease', (0, 29))	('EAC', 'Disease', (51, 54))
127724	33674602	We found decanal accumulation to be an affiliated metabolic phenotype of chromosome 17p deletion in EAC, which involves TP53 deletion.	('deletion', 'Var', (88, 96))	('decanal accumulation', 'MPA', (9, 29))	('EAC', 'Phenotype', 'HP:0011459', (100, 103))	('TP53', 'Gene', '7157', (120, 124))	('EAC', 'Gene', (100, 103))	('TP53', 'Gene', (120, 124))
127726	33674602	Enhanced tumorigenecity from co-deleted TP53 neighbors has brought 17p arm deletions into focus, and our results suggest that ALDH3A2 could provide TP53-independent metabolic surrogates of this event.	('deletions', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('TP53', 'Gene', '7157', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('TP53', 'Gene', (148, 152))	('TP53', 'Gene', '7157', (40, 44))	('tumor', 'Disease', (9, 14))	('TP53', 'Gene', (40, 44))	('ALDH3A2', 'Gene', (126, 133))	('Enhanced', 'PosReg', (0, 8))
127728	33674602	Given that up to a quarter of a typical cancer genome involves arm-level copy number aberration, druggable genetic driver events may also provide reliable metabolic surrogates amenable to non-invasive testing, via collateral effects on non-redundant metabolic genes.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('rat', 'Species', '10116', (89, 92))	('copy number aberration', 'Var', (73, 95))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
127730	33674602	A number of context-specific factors may mediate the net phenotype from deregulation of an individual ALDH gene, including (i) the activity of the other ALDH genes, particularly those with overlapping specificities, (ii) the redox state, (iii) microenvironmental factors, including hypoxia and co-factor availability, (iv) mechanisms of endogenous aldehyde production, and (v) the activity of collateral detoxification and repair mechanisms, for example, the DNA damage response.	('aldehyde', 'Chemical', 'MESH:D000447', (348, 356))	('deregulation', 'Var', (72, 84))	('activity', 'MPA', (131, 139))	('ALDH gene', 'Gene', (102, 111))	('DNA damage response', 'CPA', (459, 478))	('hypoxia', 'Disease', 'MESH:D000860', (282, 289))	('hypoxia', 'Disease', (282, 289))
127735	33674602	TP53 copy loss), rather than the cause.	('TP53', 'Gene', '7157', (0, 4))	('copy', 'Var', (5, 9))	('TP53', 'Gene', (0, 4))	('rat', 'Species', '10116', (17, 20))
127751	33674602	Fresh human material and associated clinical metadata was collected and accessed under UK National Research Ethics Service Ref: 14/LO/0742, Imperial College Healthcare Tissuebank Review Board Approvals R14067, R14087, and R16018.	('human', 'Species', '9606', (6, 11))	('R14087', 'Var', (210, 216))	('R14067', 'Var', (202, 208))	('R16018', 'Var', (222, 228))
127780	33674602	Analytical variation was controlled with six isotope-labeled standards (ISTDs):C2:0-d4 (Sigma, for short-chain alkanals), C6:0-d12 (Sigma, for medium-chain alkanals), C16:0-d5 (Santa Cruz, for fatty alkanals), HNE-d3 (Cambridge Bioscience, for dienals), ONE-d3 (Cambridge Bioscience, for dialdehydes), and MDA-d2 (prepared by diluting 10 muL 1,1,3,3-tetraethoxypropane-1,3-d2 (Santa Cruz) in 10 mL of 0.1 M HCl and hydrolyzing at 100  C for 10 min)).	('C16', 'CellLine', 'CVCL:2322', (167, 170))	('C6:0-d12', 'Var', (122, 130))	('alkanals', 'Chemical', '-', (199, 207))	('HNE', 'Chemical', 'MESH:C027576', (210, 213))	('muL', 'Gene', '4591', (338, 341))	('alkanals', 'Chemical', '-', (111, 119))	('alkanals', 'Chemical', '-', (156, 164))	('muL', 'Gene', (338, 341))	('dialdehydes', 'Chemical', '-', (288, 299))
127811	33674602	Two datasets, GSE26886 and GSE13898 were found on ArraryExpress and Gene Expression Omnibus reporting esophageal squamous mucosa and EAC transcriptomes and were included in geneset enrichment analysis (Broad Institute, MIT, Cambridge, MA, USA).	('esophageal squamous mucosa', 'Disease', 'MESH:D000077277', (102, 128))	('esophageal squamous mucosa', 'Disease', (102, 128))	('EAC', 'Phenotype', 'HP:0011459', (133, 136))	('GSE13898', 'Var', (27, 35))
127816	33674602	Copy number alterations along with ploidy and purity estimates were then derived from these read counts using ASCAT (2.3), and compared to matched RNA-seq expression data.	('rat', 'Species', '10116', (16, 19))	('ploidy', 'Disease', 'None', (35, 41))	('Copy', 'Var', (0, 4))	('ploidy', 'Disease', (35, 41))
127882	33574243	In addition, exosomes overexpressing of mir-23b and miR-320b in epithelial cells in breast cancer upregulate the expression of PLAU.	('expression', 'MPA', (113, 123))	('PLAU', 'Gene', (127, 131))	('miR-320b', 'Var', (52, 60))	('PLAU', 'Gene', '5328', (127, 131))	('mir-23b', 'Gene', '407011', (40, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('upregulate', 'PosReg', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('mir-23b', 'Gene', (40, 47))	('breast cancer', 'Disease', (84, 97))
127892	33574243	As previously described, the ESCC cell lines KYSE-30, KYSE-70, KYSE-140, KYSE-150, KYSE-180, KYSE-450, and KYSE-510 were cultured in RPMI 1640 medium (HyClone), and Het-1a esophageal epithelial cells were cultured in BEGM BulletKit medium (Lonza/Clonetics).	('KYSE-510', 'Var', (107, 115))	('KYSE-70', 'Var', (54, 61))	('KYSE-140', 'Var', (63, 71))	('RPMI 1640 medium', 'Chemical', '-', (133, 149))	('KYSE-180', 'Var', (83, 91))	('KYSE-450', 'CellLine', 'CVCL:1353', (93, 101))	('KYSE-450', 'Var', (93, 101))	('KYSE-150', 'Var', (73, 81))	('KYSE-30', 'Var', (45, 52))
127896	33574243	As previously described, we constructed ESCC cells with knockdown or overexpression of PLAU and controls.	('overexpression', 'PosReg', (69, 83))	('PLAU', 'Gene', (87, 91))	('PLAU', 'Gene', '5328', (87, 91))	('knockdown', 'Var', (56, 65))
127907	33574243	HY-111192, Selleck) was added 1 h prior to inhibiting PLAU-uPAR and before any other treatments.	('inhibiting', 'NegReg', (43, 53))	('uPAR', 'Gene', (59, 63))	('PLAU', 'Gene', (54, 58))	('uPAR', 'Gene', '5329', (59, 63))	('PLAU', 'Gene', '5328', (54, 58))	('HY-111192', 'Var', (0, 9))
127912	33574243	In another experiment, CAFs treated with IPR-803 or PBS were seeded in a 24-well plate, and KYSE-450 cells overexpressing PLAU were seeded in the upper chamber.	('PLAU', 'Gene', (122, 126))	('PLAU', 'Gene', '5328', (122, 126))	('CAF', 'Gene', (23, 26))	('KYSE-450', 'CellLine', 'CVCL:1353', (92, 100))	('IPR-803', 'Var', (41, 48))	('CAF', 'Gene', '8850', (23, 26))	('PBS', 'Chemical', 'MESH:D007854', (52, 55))	('IPR-803', 'Chemical', '-', (41, 48))
127924	33574243	Transfected cells (KYSE30,1 x 104 or KYSE450, 5 x 104) were plated into the upper chamber and cultured in serum-free RPMI 1640 medium with or without treatment (cells overexpressing PLAU with U0126 added in the upper chamber).	('U0126', 'Chemical', 'MESH:C113580', (192, 197))	('KYSE450', 'Var', (37, 44))	('KYSE450', 'CellLine', 'CVCL:1353', (37, 44))	('PLAU', 'Gene', (182, 186))	('PLAU', 'Gene', '5328', (182, 186))	('RPMI 1640 medium', 'Chemical', '-', (117, 133))
127941	33574243	In addition, high PLAU expression predicted poor prognosis at both the RNA and protein expression levels (Fig.	('high PLAU', 'Phenotype', 'HP:0007906', (13, 22))	('high', 'Var', (13, 17))	('PLAU', 'Gene', (18, 22))	('PLAU', 'Gene', '5328', (18, 22))	('expression', 'MPA', (23, 33))
127946	33574243	Given that PLAU is a secreted protein, we simultaneously assessed the supernatant of PLAU knockdown and overexpressing cells, and the results were consistent with that noted for total protein expression (Fig.	('knockdown', 'Var', (90, 99))	('PLAU', 'Gene', (85, 89))	('PLAU', 'Gene', '5328', (85, 89))	('PLAU', 'Gene', (11, 15))	('PLAU', 'Gene', '5328', (11, 15))
127948	33574243	Using CCK8 experiments, we found that the proliferation of knockdown PLAU cells was reduced compared with the control, whereas the proliferation of cells overexpressing PLAU was enhanced (Fig.	('enhanced', 'PosReg', (178, 186))	('proliferation', 'CPA', (42, 55))	('proliferation', 'CPA', (131, 144))	('PLAU', 'Gene', (69, 73))	('reduced', 'NegReg', (84, 91))	('PLAU', 'Gene', '5328', (69, 73))	('knockdown', 'Var', (59, 68))	('PLAU', 'Gene', (169, 173))	('PLAU', 'Gene', '5328', (169, 173))
127950	33574243	In vivo, the knockdown PLAU group exhibited reduced tumor growth and weight than the control group (Fig.	('PLAU', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('PLAU', 'Gene', '5328', (23, 27))	('tumor', 'Disease', (52, 57))	('reduced', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('knockdown', 'Var', (13, 22))
127954	33574243	Using Boyden chamber transwell assays, we found that the migration ability of cells with PLAU knockdown was decreased compared with the control (Fig.	('migration ability', 'CPA', (57, 74))	('knockdown', 'Var', (94, 103))	('PLAU', 'Gene', (89, 93))	('PLAU', 'Gene', '5328', (89, 93))	('decreased', 'NegReg', (108, 117))
127956	33574243	In addition, in vivo experiments showed that the number of pulmonary nodules in the knockdown PLAU group was less than that in the control group, whereas the number of pulmonary nodules in the PLAU overexpression group increased (Fig.	('less', 'NegReg', (109, 113))	('knockdown', 'Var', (84, 93))	('PLAU', 'Gene', (193, 197))	('PLAU', 'Gene', '5328', (193, 197))	('pulmonary nodules', 'CPA', (59, 76))	('PLAU', 'Gene', (94, 98))	('PLAU', 'Gene', '5328', (94, 98))
127960	33574243	The results revealed reduced phosphorylated c-raf, MEK, and Erk1/2 levels in knockdown PLAU cells compared with control, whereas the expression of these phosphorylated proteins was increased in cells overexpressing PLAU (Fig.	('reduced', 'NegReg', (21, 28))	('Erk1/2', 'Gene', (60, 66))	('expression', 'MPA', (133, 143))	('c-raf', 'Gene', (44, 49))	('MEK', 'Gene', (51, 54))	('PLAU', 'Gene', (87, 91))	('MEK', 'Gene', '5609', (51, 54))	('knockdown', 'Var', (77, 86))	('PLAU', 'Gene', '5328', (87, 91))	('PLAU', 'Gene', (215, 219))	('Erk1/2', 'Gene', '5595;5594', (60, 66))	('increased', 'PosReg', (181, 190))	('PLAU', 'Gene', '5328', (215, 219))	('c-raf', 'Gene', '5894', (44, 49))
127965	33574243	We found that MMP9 expression in PLAU knockdown cells was reduced compared with sh-vec cells, whereas MMP9 expression in cells overexpressing PLAU was increased (Fig.	('MMP9', 'Gene', (14, 18))	('expression', 'MPA', (19, 29))	('MMP9', 'Gene', '4318', (14, 18))	('reduced', 'NegReg', (58, 65))	('PLAU', 'Gene', (142, 146))	('PLAU', 'Gene', '5328', (142, 146))	('MMP9', 'Gene', (102, 106))	('knockdown', 'Var', (38, 47))	('PLAU', 'Gene', (33, 37))	('MMP9', 'Gene', '4318', (102, 106))	('PLAU', 'Gene', '5328', (33, 37))
127966	33574243	In addition, the highly selective MEK1/2 inhibitor U0126 reduce the high levels of MEK1/2 and Erk1/2 phosphorylation and Slug and MMP9 expression in cells overexpressing PLAU (Fig.	('reduce', 'NegReg', (57, 63))	('U0126', 'Chemical', 'MESH:C113580', (51, 56))	('MEK1/2', 'Gene', '5604;5605', (83, 89))	('Slug', 'Gene', '6591', (121, 125))	('MEK1/2', 'Gene', (83, 89))	('MEK1/2', 'Gene', '5604;5605', (34, 40))	('Erk1/2', 'Gene', '5595;5594', (94, 100))	('expression', 'MPA', (135, 145))	('Slug', 'Gene', (121, 125))	('Erk1/2', 'Gene', (94, 100))	('PLAU', 'Gene', (170, 174))	('MMP9', 'Gene', (130, 134))	('phosphorylation', 'MPA', (101, 116))	('PLAU', 'Gene', '5328', (170, 174))	('MEK1/2', 'Gene', (34, 40))	('U0126', 'Var', (51, 56))	('MMP9', 'Gene', '4318', (130, 134))	('high levels', 'MPA', (68, 79))
127967	33574243	In addition, U0126 also reversed PLAU-mediated promotion of ESCC cell proliferation, colony formation and migration (Fig.	('ESCC cell proliferation', 'CPA', (60, 83))	('U0126', 'Var', (13, 18))	('colony formation', 'CPA', (85, 101))	('promotion', 'PosReg', (47, 56))	('migration', 'CPA', (106, 115))	('PLAU', 'Gene', (33, 37))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))	('PLAU', 'Gene', '5328', (33, 37))
128001	33574243	Increased PLAU expression mediated by IL8 is reversed upon treatment with SB225005, a CXCR2 inhibitor (Fig.	('PLAU', 'Gene', (10, 14))	('Increased PLAU', 'Phenotype', 'HP:0007906', (0, 14))	('CXCR2', 'Gene', '3579', (86, 91))	('PLAU', 'Gene', '5328', (10, 14))	('SB225005', 'Var', (74, 82))	('CXCR2', 'Gene', (86, 91))	('SB225005', 'Chemical', '-', (74, 82))	('IL8', 'Gene', (38, 41))	('IL8', 'Gene', '3576', (38, 41))
128008	33574243	Consistent with previous studies, high PLAU expression promotes the progression of ESCC, and other various tumors, including breast, bladder, and lung cancer.	('PLAU', 'Gene', '5328', (39, 43))	('expression', 'MPA', (44, 54))	('high PLAU', 'Phenotype', 'HP:0007906', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast', 'Disease', (125, 131))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('progression', 'CPA', (68, 79))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('promotes', 'PosReg', (55, 63))	('high', 'Var', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('bladder', 'Disease', (133, 140))	('lung cancer', 'Disease', (146, 157))	('ESCC', 'Disease', (83, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('PLAU', 'Gene', (39, 43))
128100	33363724	Furthermore, anastomotic dilatation for the relief of post-surgical and/or recurrent dysphagia due to stenosis of the cervical esophagogastrostomy may be required in 38.5-50% of patients and dumping symptoms have been reported in 4-19% of patients.	('dilatation', 'Phenotype', 'HP:0002617', (25, 35))	('dysphagia', 'Disease', 'MESH:D003680', (85, 94))	('gas', 'Gene', (135, 138))	('gas', 'Gene', '2520', (135, 138))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (239, 247))	('dysphagia', 'Disease', (85, 94))	('stenosis', 'Var', (102, 110))	('dysphagia', 'Phenotype', 'HP:0002015', (85, 94))
128111	33363724	], reported the pull-down technique or the verticalization of the esophageal axis to improve the clinical outcomes of LHM + Dor for sigmoid achalasia (diameter >6 cm) particularly when kinked to the left and outside of the esophageal axis.	('achalasia', 'Phenotype', 'HP:0002571', (140, 149))	('improve', 'PosReg', (85, 92))	('Dor', 'Gene', '58476', (124, 127))	('achalasia', 'Disease', (140, 149))	('Dor', 'Gene', (124, 127))	('LHM', 'Var', (118, 121))	('achalasia', 'Disease', 'MESH:D004931', (140, 149))
128124	33363724	Other surgical options that have been used in the management of massively dilated esophagus include laparoscopic esophagogastrostomy with posterior hemi-fundoplication, distal esophagectomy with antrectomy and Roux-en-Y diversion, esophagectomy with gastric, colon or jejunal interposition, esophagocardioplasty, vagotomy-antrectomy, and Roux-en-Y gastrojejunostomy (Serra Doria operation), Y-cardioplasty truncal vagotomy for selected cases, partial distal gastrectomy, subtotal esophagectomy, Vagal-sparing esophagectomy and Vertical esophagectomy + myotomy.	('gas', 'Gene', '2520', (121, 124))	('gas', 'Gene', (121, 124))	('Dor', 'Gene', (373, 376))	('Dor', 'Gene', '58476', (373, 376))	('gas', 'Gene', '2520', (348, 351))	('gas', 'Gene', (348, 351))	('gas', 'Gene', '2520', (458, 461))	('gas', 'Gene', (458, 461))	('gas', 'Gene', (250, 253))	('Vagal-sparing esophagectomy', 'Disease', (495, 522))	('subtotal', 'Var', (471, 479))	('gas', 'Gene', '2520', (250, 253))	('jejunal interposition', 'Phenotype', 'HP:0004786', (268, 289))	('partial distal', 'Var', (443, 457))
128167	32068233	In the development of esophageal cancer, the rs11473 polymorphism of the miR-483-5p binding site plays a vital role in the 3'-UTR of the basigin gene.	('basigin', 'Gene', (137, 144))	('miR-483-5p', 'Gene', (73, 83))	('miR-483-5p', 'Chemical', '-', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('rs11473', 'Var', (45, 52))	('esophageal cancer', 'Disease', (22, 39))	('basigin', 'Gene', '682', (137, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))	('rs11473', 'Mutation', 'rs11473', (45, 52))
128168	32068233	Single nucleotide polymorphisms (SNPs) in TERT may be associated with susceptibility to esophageal cancer and contribute to the development of esophageal cancer.	('contribute to', 'Reg', (110, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('TERT', 'Gene', '7015', (42, 46))	('TERT', 'Gene', (42, 46))	('associated', 'Reg', (54, 64))	('esophageal cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('esophageal cancer', 'Disease', (143, 160))
128172	32068233	MicroRNA-506 inhibits proliferation of esophageal cancer cells by targeting CREB1.	('CREB1', 'Gene', '1385', (76, 81))	('MicroRNA-506', 'Var', (0, 12))	('CREB1', 'Gene', (76, 81))	('esophageal cancer', 'Disease', (39, 56))	('targeting', 'Reg', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('proliferation', 'CPA', (22, 35))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))	('inhibits', 'NegReg', (13, 21))
128193	32068233	We believe that the presence of these DEGs is closely related to the development of various stages of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('related', 'Reg', (54, 61))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('presence', 'Var', (20, 28))
128220	32068233	Importantly, positive CPLX2 expression is associated with lymphatic invasion, pathological staging, and adverse disease-specific survival in LNET patients.	('positive', 'Var', (13, 21))	('associated', 'Reg', (42, 52))	('expression', 'MPA', (28, 38))	('pathological staging', 'CPA', (78, 98))	('CPLX2', 'Gene', (22, 27))	('CPLX2', 'Gene', '10814', (22, 27))	('patients', 'Species', '9606', (146, 154))	('lymphatic invasion', 'CPA', (58, 76))
128226	32068233	After knocking out the DPEP1 gene, cells (SW480 and HCT116) essentially increased apoptosis and attenuated cell proliferation and cell invasion.	('increased', 'PosReg', (72, 81))	('apoptosis', 'CPA', (82, 91))	('attenuated', 'NegReg', (96, 106))	('SW480', 'CellLine', 'CVCL:0546', (42, 47))	('HCT116', 'CellLine', 'CVCL:0291', (52, 58))	('cell proliferation', 'CPA', (107, 125))	('DPEP1', 'Gene', (23, 28))	('DPEP1', 'Gene', '1800', (23, 28))	('cell invasion', 'CPA', (130, 143))	('knocking out', 'Var', (6, 18))
128233	32068233	found that knockdown of ThBS4 inhibited migration and invasion of hepatocellular carcinoma cells, as well as hemangiocarcinoma-induced angiogenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ThBS4', 'Gene', (24, 29))	('invasion', 'CPA', (54, 62))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('inhibited', 'NegReg', (30, 39))	('hepatocellular carcinoma', 'Disease', (66, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('hemangiocarcinoma', 'Disease', (109, 126))	('ThBS4', 'Gene', '7060', (24, 29))	('hemangiocarcinoma', 'Disease', 'None', (109, 126))	('knockdown', 'Var', (11, 20))
128241	32068233	In the study of isoleucine anti-esophageal squamous cell carcinoma, it was found that iso-valine can inhibit tumor growth by activating the p53 pathway.	('esophageal squamous cell carcinoma', 'Disease', (32, 66))	('iso-valine', 'Chemical', 'MESH:C032737', (86, 96))	('inhibit', 'NegReg', (101, 108))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (32, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('activating', 'PosReg', (125, 135))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('iso-valine', 'Var', (86, 96))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('tumor', 'Disease', (109, 114))
128249	32068233	Any level of distortion in these organ size regulation processes can lead to a variety of pathological conditions, of which cancer is the most terrifying.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('pathological', 'Disease', (90, 102))	('lead to', 'Reg', (69, 76))	('distortion', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
128256	32068233	Recently, some studies have shown that EGFR inhibitors may exhibit anti-tumor effects, which are associated with the continued promotion of reactive oxygen species production and induction of apoptosis.	('promotion', 'PosReg', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('induction', 'Reg', (179, 188))	('inhibitors', 'Var', (44, 54))	('reactive oxygen species production', 'MPA', (140, 174))	('tumor', 'Disease', (72, 77))	('apoptosis', 'CPA', (192, 201))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (140, 163))	('EGFR', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
128265	32068233	found that hypermethylation of the SST promoter is common and is associated with early tumor progression in Barrett's esophagus.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('hypermethylation', 'Var', (11, 27))	('tumor', 'Disease', (87, 92))	('associated with', 'Reg', (65, 80))	('SST promoter', 'Gene', (35, 47))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (108, 127))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	("Barrett's esophagus", 'Disease', (108, 127))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (108, 127))
128268	32068233	It is also possible to play an important role in the regulation of esophageal cancer by methylation modification.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal cancer', 'Disease', (67, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('methylation modification', 'Var', (88, 112))
128269	32068233	studied the effect of SH3GL2 methylation on the pathogenesis of head and neck squamous cell carcinoma, and the disorder of sh3gl2 is an independent pathway for early developmental abnormalities of the head and neck.	('SH3GL2', 'Gene', (22, 28))	('developmental abnormalities of the head', 'Disease', 'MESH:D006130', (166, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('sh3gl2', 'Gene', '6456', (123, 129))	('sh3gl2', 'Gene', (123, 129))	('SH3GL2', 'Gene', '6456', (22, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('abnormalities of the head', 'Phenotype', 'HP:0000234', (180, 205))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (64, 101))	('disorder', 'Var', (111, 119))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (166, 193))	('developmental abnormalities of the head', 'Disease', (166, 205))
128285	31859915	Hence, the anastomotic dehiscences in this organ appear with a higher incidence, prolonging the permanence of patients in hospitals as well as increasing hospital costs, causing greater suffering for the patients and showing a relationship with stenosis, which is another obstacle that follows the esophageal surgery  .	('patients', 'Species', '9606', (204, 212))	('stenosis', 'Disease', (245, 253))	('stenosis', 'Disease', 'MESH:D003251', (245, 253))	('increasing', 'PosReg', (143, 153))	('causing', 'Reg', (170, 177))	('anastomotic dehiscences', 'Var', (11, 34))	('prolonging', 'PosReg', (81, 91))	('patients', 'Species', '9606', (110, 118))
128288	31859915	In advanced megaesophagus of chagasic origin the disease damages the contractility of the organ due to plexular denervation impairing deglutition, with the consequent malnutrition.	('malnutrition', 'Disease', (167, 179))	('plexular denervation', 'CPA', (103, 123))	('disease', 'Var', (49, 56))	('impairing deglutition', 'Disease', (124, 145))	('malnutrition', 'Disease', 'MESH:D044342', (167, 179))	('impairing deglutition', 'Disease', 'MESH:D003680', (124, 145))	('impairing deglutition', 'Phenotype', 'HP:0002015', (124, 145))	('damages', 'NegReg', (57, 64))	('malnutrition', 'Phenotype', 'HP:0004395', (167, 179))	('contractility', 'MPA', (69, 82))
128358	31236125	JDTYS could downregulate the expression of proliferation related proteins Ki67 and c-Jun.	('c-Jun', 'Protein', (83, 88))	('rat', 'Species', '10116', (50, 53))	('Ki67', 'Protein', (74, 78))	('JDTYS', 'Var', (0, 5))	('expression', 'MPA', (29, 39))	('JDTYS', 'Chemical', '-', (0, 5))	('downregulate', 'NegReg', (12, 24))
128359	31236125	Moreover, inflammation related proteins NF-kappaB, COX-2, and CD11B were inhibited and PTX3 was increased by JDTYS.	('COX-2', 'Gene', (51, 56))	('increased', 'PosReg', (96, 105))	('NF-kappaB', 'Gene', '4790', (40, 49))	('NF-kappaB', 'Gene', (40, 49))	('PTX3', 'Gene', '689388', (87, 91))	('CD11B', 'Gene', (62, 67))	('inhibited', 'NegReg', (73, 82))	('PTX3', 'Gene', (87, 91))	('JDTYS', 'Var', (109, 114))	('JDTYS', 'Chemical', '-', (109, 114))	('inflammation', 'Disease', 'MESH:D007249', (10, 22))	('inflammation', 'Disease', (10, 22))	('COX-2', 'Gene', '29527', (51, 56))
128360	31236125	In all, JDTYS is a promising chemopreventive formula against esophageal carcinogenesis by regulating inflammation and inhibiting cell proliferation.	('esophageal carcinogenesis', 'Disease', (61, 86))	('cell proliferation', 'CPA', (129, 147))	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('inflammation', 'Disease', (101, 113))	('JDTYS', 'Var', (8, 13))	('regulating', 'PosReg', (90, 100))	('JDTYS', 'Chemical', '-', (8, 13))	('inhibiting', 'NegReg', (118, 128))	('rat', 'Species', '10116', (141, 144))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (61, 86))
128385	31236125	In the present study, we found that JDTYS can inhibit the formation of preneoplastic lesions induced by NMBA.	('inhibit', 'NegReg', (46, 53))	('formation of preneoplastic lesions', 'CPA', (58, 92))	('NMBA', 'Chemical', 'MESH:C014707', (104, 108))	('JDTYS', 'Var', (36, 41))	('JDTYS', 'Chemical', '-', (36, 41))
128387	31236125	JDTYS also inhibited COX-2 expression and increased PTX3 expression in rat serum.	('increased', 'PosReg', (42, 51))	('expression', 'MPA', (57, 67))	('rat', 'Species', '10116', (71, 74))	('JDTYS', 'Chemical', '-', (0, 5))	('expression', 'MPA', (27, 37))	('PTX3', 'Gene', '689388', (52, 56))	('JDTYS', 'Var', (0, 5))	('PTX3', 'Gene', (52, 56))	('inhibited', 'NegReg', (11, 20))	('COX-2', 'Gene', '29527', (21, 26))	('COX-2', 'Gene', (21, 26))
128425	31236125	Our results indicated that both ZSP and JDTYS can inhibit precancerous lesions induced by NMBA; furthermore, the inhibition effect of JDTYS 25 g/kg on moderate and severe dysplasia is stronger than that of the ZSP group.	('NMBA', 'Chemical', 'MESH:C014707', (90, 94))	('precancerous lesions', 'Disease', (58, 78))	('moderate', 'Disease', (151, 159))	('JDTYS', 'Chemical', '-', (40, 45))	('NMBA', 'Gene', (90, 94))	('inhibit', 'NegReg', (50, 57))	('JDTYS', 'Chemical', '-', (134, 139))	('ZSP', 'Chemical', '-', (32, 35))	('precancerous lesions', 'Disease', 'MESH:D011230', (58, 78))	('severe dysplasia', 'Disease', (164, 180))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('JDTYS 25 g/kg', 'Var', (134, 147))	('rat', 'Species', '10116', (155, 158))	('stronger', 'PosReg', (184, 192))	('ZSP', 'Chemical', '-', (210, 213))	('severe dysplasia', 'Disease', 'MESH:D001523', (164, 180))
128428	31236125	The JDTYS 10 g/kg, JDTYS 25 g/kg, and ZSP groups all significantly reduced the expression of Ki67 protein compared with the NMBA group (Figure 3(a)).	('ZSP', 'Chemical', '-', (38, 41))	('expression', 'MPA', (79, 89))	('JDTYS 10 g/kg', 'Var', (4, 17))	('reduced', 'NegReg', (67, 74))	('JDTYS 25 g/kg', 'Var', (19, 32))	('JDTYS', 'Chemical', '-', (19, 24))	('Ki67 protein', 'Protein', (93, 105))	('NMBA', 'Chemical', 'MESH:C014707', (124, 128))	('JDTYS', 'Chemical', '-', (4, 9))
128429	31236125	The expression of c-Jun was reduced in the JDTYS 10 g/kg, JDTYS 25 g/kg, and ZSP groups compared with the NMBA group (Figure 3(b)).	('JDTYS', 'Chemical', '-', (58, 63))	('reduced', 'NegReg', (28, 35))	('c-Jun', 'Protein', (18, 23))	('NMBA', 'Chemical', 'MESH:C014707', (106, 110))	('expression', 'MPA', (4, 14))	('ZSP', 'Chemical', '-', (77, 80))	('JDTYS', 'Chemical', '-', (43, 48))	('JDTYS', 'Var', (58, 63))	('JDTYS 10 g/kg', 'Var', (43, 56))
128433	31236125	NF-kappaB p65 was significantly inhibited in the JDTYS 10 g/kg, JDTYS 25 g/kg, and ZSP groups compared with the NMBA group (Figure 4(a)).	('p65', 'Gene', '25716', (10, 13))	('ZSP', 'Chemical', '-', (83, 86))	('NF-kappaB', 'Gene', '4790', (0, 9))	('inhibited', 'NegReg', (32, 41))	('NF-kappaB', 'Gene', (0, 9))	('JDTYS', 'Chemical', '-', (49, 54))	('NMBA', 'Chemical', 'MESH:C014707', (112, 116))	('p65', 'Gene', (10, 13))	('JDTYS', 'Var', (64, 69))	('JDTYS 10 g/kg', 'Var', (49, 62))	('JDTYS', 'Chemical', '-', (64, 69))
128435	31236125	The JDTYS 10 g/kg, JDTYS 25 g/kg, and ZSP groups all significantly inhibited the expression of COX-2 (Figure 4(b)).	('ZSP', 'Chemical', '-', (38, 41))	('inhibited', 'NegReg', (67, 76))	('JDTYS 10 g/kg', 'Var', (4, 17))	('JDTYS 25 g/kg', 'Var', (19, 32))	('COX-2', 'Gene', (95, 100))	('COX-2', 'Gene', '29527', (95, 100))	('JDTYS', 'Chemical', '-', (19, 24))	('JDTYS', 'Chemical', '-', (4, 9))	('expression', 'MPA', (81, 91))
128436	31236125	In the JDTYS 10 g/kg group and the JDTYS 25 g/kg group, CD11B staining cells were also reduced compared with the NMBA group (Figure 5(a)).	('JDTYS', 'Chemical', '-', (7, 12))	('JDTYS', 'Var', (35, 40))	('NMBA', 'Chemical', 'MESH:C014707', (113, 117))	('reduced', 'NegReg', (87, 94))	('JDTYS', 'Chemical', '-', (35, 40))	('JDTYS 10 g/kg', 'Var', (7, 20))	('CD11B', 'Protein', (56, 61))
128437	31236125	At 35w, COX-2 level was inhibited in rat serum of the ZSP, JDTYS 10 g/kg, and JDTYS 25 g/kg groups compared with the NMBA group.	('JDTYS', 'Chemical', '-', (59, 64))	('COX-2', 'Gene', '29527', (8, 13))	('COX-2', 'Gene', (8, 13))	('rat', 'Species', '10116', (37, 40))	('ZSP', 'Chemical', '-', (54, 57))	('inhibited', 'NegReg', (24, 33))	('JDTYS', 'Var', (78, 83))	('JDTYS 10 g/kg', 'Var', (59, 72))	('JDTYS', 'Chemical', '-', (78, 83))	('NMBA', 'Chemical', 'MESH:C014707', (117, 121))
128438	31236125	So, JDTYS significantly reduced COX-2 production in rat serum treated with JDTYS (Figure 5(b)).	('rat', 'Species', '10116', (52, 55))	('reduced', 'NegReg', (24, 31))	('COX-2', 'Gene', '29527', (32, 37))	('COX-2', 'Gene', (32, 37))	('JDTYS', 'Var', (75, 80))	('JDTYS', 'Var', (4, 9))	('JDTYS', 'Chemical', '-', (75, 80))	('JDTYS', 'Chemical', '-', (4, 9))
128439	31236125	PTX3 deficiency triggers complement-dependent tumor-promoting inflammation.	('inflammation', 'Disease', 'MESH:D007249', (62, 74))	('inflammation', 'Disease', (62, 74))	('deficiency', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PTX3', 'Gene', '689388', (0, 4))	('triggers', 'Reg', (16, 24))	('PTX3', 'Gene', (0, 4))	('tumor', 'Disease', (46, 51))	('complement-dependent', 'CPA', (25, 45))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
128440	31236125	We found, at week 35, the JDTYS 25 g/kg group had higher serum PTX3 level when compared with the NMBA group (Figure 5(c)).	('higher', 'PosReg', (50, 56))	('PTX3', 'Gene', '689388', (63, 67))	('PTX3', 'Gene', (63, 67))	('JDTYS', 'Chemical', '-', (26, 31))	('JDTYS 25 g/kg', 'Var', (26, 39))	('NMBA', 'Chemical', 'MESH:C014707', (97, 101))
128447	31236125	In this study, we confirmed that JDTYS significantly inhibited esophageal preneoplastic lesions formation in rat treated with NMBA.	('inhibited', 'NegReg', (53, 62))	('esophageal preneoplastic lesions', 'Disease', (63, 95))	('JDTYS', 'Var', (33, 38))	('rat', 'Species', '10116', (109, 112))	('NMBA', 'Chemical', 'MESH:C014707', (126, 130))	('JDTYS', 'Chemical', '-', (33, 38))	('esophageal preneoplastic lesions', 'Disease', 'MESH:D011230', (63, 95))
128448	31236125	Importantly, the inhibitory function of JDTYS high dose on moderate dysplasia and severe dysplasia of rat esophageal epithelium had significant difference compared with ZSP, which is traditional Chinese medicine for esophageal preneoplastic lesions treatment.	('rat', 'Species', '10116', (63, 66))	('JDTYS', 'Chemical', '-', (40, 45))	('ZSP', 'Chemical', '-', (169, 172))	('inhibitory function', 'MPA', (17, 36))	('esophageal preneoplastic lesions', 'Disease', (216, 248))	('esophageal preneoplastic lesions', 'Disease', 'MESH:D011230', (216, 248))	('dysplasia', 'Disease', 'MESH:D004476', (89, 98))	('rat', 'Species', '10116', (102, 105))	('severe dysplasia', 'Disease', (82, 98))	('dysplasia', 'Disease', (89, 98))	('dysplasia', 'Disease', (68, 77))	('JDTYS high', 'Var', (40, 50))	('severe dysplasia', 'Disease', 'MESH:D001523', (82, 98))	('dysplasia', 'Disease', 'MESH:D004476', (68, 77))
128450	31236125	JDTYS significantly inhibited the expression of c-Jun.	('expression', 'MPA', (34, 44))	('inhibited', 'NegReg', (20, 29))	('JDTYS', 'Var', (0, 5))	('c-Jun', 'MPA', (48, 53))	('JDTYS', 'Chemical', '-', (0, 5))
128451	31236125	Ki67, a nuclear antigen that indicates the status of cell proliferation, was strongly inhibited after JDTYS treatment.	('JDTYS treatment', 'Var', (102, 117))	('Ki67', 'Gene', (0, 4))	('inhibited', 'NegReg', (86, 95))	('JDTYS', 'Chemical', '-', (102, 107))	('rat', 'Species', '10116', (65, 68))
128458	31236125	JDTYS also significantly decreased the expression of COX-2 in rat esophageal epithelium and serum.	('COX-2', 'Gene', '29527', (53, 58))	('COX-2', 'Gene', (53, 58))	('decreased', 'NegReg', (25, 34))	('JDTYS', 'Var', (0, 5))	('expression', 'MPA', (39, 49))	('rat', 'Species', '10116', (62, 65))	('JDTYS', 'Chemical', '-', (0, 5))
128462	31236125	In summary, we provided evidence that JDTYS significantly inhibits the formation of esophageal precancerous lesions induced by NMBA.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('esophageal precancerous lesions', 'Disease', (84, 115))	('formation of', 'CPA', (71, 83))	('inhibits', 'NegReg', (58, 66))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (84, 115))	('NMBA', 'Chemical', 'MESH:C014707', (127, 131))	('JDTYS', 'Var', (38, 43))	('JDTYS', 'Chemical', '-', (38, 43))
128464	31236125	Collectively, our data suggest that JDTYS can prevent esophageal carcinogenesis by inhibiting cell proliferation and downregulating inflammation.	('downregulating', 'NegReg', (117, 131))	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('inflammation', 'Disease', (132, 144))	('inhibiting', 'NegReg', (83, 93))	('JDTYS', 'Var', (36, 41))	('rat', 'Species', '10116', (106, 109))	('cell proliferation', 'CPA', (94, 112))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (54, 79))	('JDTYS', 'Chemical', '-', (36, 41))	('esophageal carcinogenesis', 'Disease', (54, 79))
128473	26879020	Most cell and animal experiments showed inhibition of autophagy by either pharmacological approaches or via genetic silencing of autophagy regulatory gene, resulting in a promotion of 5-FU-induced cancer cells death.	('autophagy regulatory gene', 'Gene', (129, 154))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('5-FU-induced', 'MPA', (184, 196))	('inhibition', 'NegReg', (40, 50))	('autophagy', 'CPA', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('silencing', 'Var', (116, 125))	('promotion', 'PosReg', (171, 180))	('5-FU', 'Chemical', 'MESH:D005472', (184, 188))
128479	26879020	The resistance to anticancer drugs can be attributed to a wide variety of mechanisms including tumor cell heterogeneity, drug efflux, and other periods of tumor microenvironment stress-induced genetic or epigenetic alterations as a cellular response to drug exposure.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('epigenetic alterations', 'Var', (204, 226))	('drug efflux', 'MPA', (121, 132))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', (22, 28))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('resistance', 'MPA', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('rat', 'Species', '10116', (219, 222))	('genetic', 'Var', (193, 200))	('tumor', 'Disease', (95, 100))
128505	26879020	Previous studies have demonstrated that inhibition of autophagy augments anticancer effects of 5-FU in colorectal cancer, and autophagy responds to 5-FU through the regulation of Bcl-2 and Bcl-xL.	('Bcl-xL', 'Gene', '598', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('autophagy', 'CPA', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Bcl-2', 'Gene', (179, 184))	('autophagy', 'CPA', (126, 135))	('augments', 'NegReg', (64, 72))	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('colorectal cancer', 'Disease', (103, 120))	('Bcl-2', 'Gene', '596', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('inhibition', 'Var', (40, 50))	('cancer', 'Disease', (77, 83))	('rat', 'Species', '10116', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('5-FU', 'Chemical', 'MESH:D005472', (95, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('5-FU', 'Chemical', 'MESH:D005472', (148, 152))	('Bcl-xL', 'Gene', (189, 195))	('cancer', 'Disease', (114, 120))
128518	26879020	Moreover, the combination of CQ with sorafenib (a potent multikinase inhibitor that has been recognized as the standard systemic treatment for patients with advanced HCC-based on the results of Study of Heart and Renal Protection trial) can generate more ER stress-induced cell death in HCC both in vivo and in vitro.	('ER stress-induced cell death', 'CPA', (255, 283))	('combination', 'Var', (14, 25))	('rat', 'Species', '10116', (245, 248))	('HCC', 'Phenotype', 'HP:0001402', (166, 169))	('HCC', 'Disease', (287, 290))	('patients', 'Species', '9606', (143, 151))	('CQ', 'Chemical', 'MESH:D002738', (29, 31))	('HCC', 'Phenotype', 'HP:0001402', (287, 290))	('sorafenib', 'Chemical', 'MESH:D000077157', (37, 46))	('generate', 'Reg', (241, 249))
128520	26879020	Blocking p53 leads to impaired activation of autophagy, increased nutrient starvation, and 5-FU-induced cell death in nutrient-deprived HCC accompanied by a remarkable increase in the reactive oxygen species (ROS) generation and mitochondrial damage.	('increase', 'PosReg', (168, 176))	('ROS', 'Chemical', 'MESH:D017382', (209, 212))	('5-FU', 'Chemical', 'MESH:D005472', (91, 95))	('autophagy', 'CPA', (45, 54))	('mitochondrial damage', 'CPA', (229, 249))	('Blocking', 'Var', (0, 8))	('increased', 'PosReg', (56, 65))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('rat', 'Species', '10116', (218, 221))	('HCC', 'Phenotype', 'HP:0001402', (136, 139))	('nutrient starvation', 'CPA', (66, 85))	('cell death', 'CPA', (104, 114))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (184, 207))
128529	26879020	Inhibition of autophagy with CQ promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma both in vitro and in vivo.	('autophagy', 'CPA', (14, 23))	('PI3K-mTOR pathway', 'Pathway', (95, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (116, 141))	('apoptotic cell death', 'CPA', (41, 61))	('inhibition', 'NegReg', (77, 87))	('CQ', 'Chemical', 'MESH:D002738', (29, 31))	('Inhibition', 'Var', (0, 10))	('promotes', 'PosReg', (32, 40))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (116, 141))	('pancreatic adenocarcinoma', 'Disease', (116, 141))
128530	26879020	In this sense, Type I PI3K inhibitors (lithium and carbamazepine), type III PI3K inhibitors (3-MA, LY294002 and wortmannin), AKT inhibitors (perifosine and API-2), and mTORinhibitors (rapamycin, RAD001 and CCI-779) currently undergoing clinical evaluation are all promising anticancer agents to improve treatment outcomes in pancreatic adenocarcinoma.	('wortmannin', 'Chemical', 'MESH:D000077191', (112, 122))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (325, 350))	('cancer', 'Disease', (278, 284))	('LY294002', 'Var', (99, 107))	('perifosine', 'Chemical', 'MESH:C105905', (141, 151))	('rapamycin', 'Chemical', 'MESH:D020123', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (341, 350))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('API-2', 'Gene', (156, 161))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (325, 350))	('pancreatic adenocarcinoma', 'Disease', (325, 350))	('lithium', 'Chemical', 'MESH:D008094', (39, 46))	('API-2', 'Gene', '330', (156, 161))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('LY294002', 'Chemical', 'MESH:C085911', (99, 107))	('RAD001', 'Chemical', 'MESH:D000068338', (195, 201))	('3-MA', 'Chemical', '-', (93, 97))	('CCI-779', 'Chemical', 'MESH:C401859', (206, 213))	('carbamazepine', 'Chemical', 'MESH:D002220', (51, 64))
128559	26879020	First, although 5-FU induces autophagy in many gastrointestinal cancer cells, it is still difficult to explain whether the autophagy accompanies or induces cell death, or only functions as a protective mechanism activated in response to stress-induced by the treatment of 5-FU or is a cell death pathway activated when apoptosis is disabled, or whether all the effects arise in different contexts.	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (47, 70))	('5-FU', 'Chemical', 'MESH:D005472', (16, 20))	('induces', 'Reg', (21, 28))	('gastrointestinal cancer', 'Disease', (47, 70))	('5-FU', 'Chemical', 'MESH:D005472', (272, 276))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (47, 70))	('5-FU', 'Var', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
128643	26625258	Recently, we reported that proinflammatory proteins S100A8/A9 via interaction with RAGE enhanced the activation of NK cells, which produce interferon-gamma (IFN-gamma), and significantly suppressed tumor growth.	('interferon-gamma', 'Gene', '3458', (139, 155))	('interaction', 'Interaction', (66, 77))	('interferon-gamma', 'Gene', (139, 155))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('RAGE', 'Gene', '5891', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('IFN-gamma', 'Gene', (157, 166))	('RAGE', 'Gene', (83, 87))	('IFN-gamma', 'Gene', '3458', (157, 166))	('tumor', 'Disease', (198, 203))	('S100A8/A9', 'Var', (52, 61))	('enhanced', 'PosReg', (88, 96))	('suppressed', 'NegReg', (187, 197))	('activation', 'MPA', (101, 111))
128645	26625258	Interestingly, in epithelial I-type ESCCs without relapse compared with mesenchymal I-type with early relapse, S100A8 and S100A9 were found to be overexpressed 3.3- and 5.2-fold, respectively (S7 Table).	('S100A8', 'Var', (111, 117))	('S100A9', 'Gene', '6280', (122, 128))	('S100A9', 'Gene', (122, 128))	('overexpressed', 'PosReg', (146, 159))
128657	26625258	Recently, remarkable advances have been recognized in the cancer immunotherapy field, such as clinical success in anti-CTLA-4 antibody or anti-PD1 antibody, and the upcoming T cell therapy including chimeric antigen receptor-T cells.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (58, 64))	('clinical', 'Species', '191496', (94, 102))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('anti-PD1', 'Var', (138, 146))	('anti-CTLA-4', 'Var', (114, 125))	('anti-CTLA-4', 'Gene', (114, 125))
128660	26625258	Overexpression of S100A8 and S100A9 in epithelial I-type ESCCs without relapse may activate a cellular immunity including NK cells and CTLs, which produce IFN-gamma (S7 Table).	('cellular immunity', 'CPA', (94, 111))	('IFN-gamma', 'Gene', '3458', (155, 164))	('IFN-gamma', 'Gene', (155, 164))	('activate', 'PosReg', (83, 91))	('S100A8', 'Var', (18, 24))	('S100A9', 'Gene', '6280', (29, 35))	('S100A9', 'Gene', (29, 35))
128665	26625258	Therefore, S100A8/A9 may be provided by myeloid cells including neutrophils but not by tumor cells in ESCC tissues.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('S100A8/A9', 'Var', (11, 20))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
128826	22701199	Immunohistochemistry for p53 and Ki67 has also been reported to correlate with the severity of dysplasia in assessing Barrett's biopsies.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('dysplasia', 'Disease', (95, 104))	('dysplasia', 'Disease', 'MESH:D004476', (95, 104))	('Ki67', 'Var', (33, 37))
128880	22701199	In a trial of RFA in dysplastic BE, among the patients with LGD, complete eradication of dysplasia was seen in 90.5% patients who received RFA compared with 22.7% in controls (sham procedure) (P < 0.001).	('patients', 'Species', '9606', (46, 54))	('dysplastic', 'Disease', (21, 31))	('dysplastic', 'Disease', 'MESH:D004416', (21, 31))	('BE', 'Phenotype', 'HP:0100580', (32, 34))	('RFA', 'Var', (139, 142))	('dysplasia', 'Disease', (89, 98))	('patients', 'Species', '9606', (117, 125))	('dysplasia', 'Disease', 'MESH:D004476', (89, 98))	('eradication', 'NegReg', (74, 85))
128906	22701199	Among patients with HGD, complete eradication of dysplasia was achieved in 81% in the ablation group compared with 19% in the control group (P < 0.001).	('dysplasia', 'Disease', (49, 58))	('ablation', 'Var', (86, 94))	('patients', 'Species', '9606', (6, 14))	('dysplasia', 'Disease', 'MESH:D004476', (49, 58))
128937	22701199	Inhibition of COX-2 attenuates cell growth and proliferation, inhibits angiogenesis, and restores apoptosis.	('attenuates', 'NegReg', (20, 30))	('apoptosis', 'CPA', (98, 107))	('inhibits', 'NegReg', (62, 70))	('angiogenesis', 'CPA', (71, 83))	('restores', 'PosReg', (89, 97))	('Inhibition', 'Var', (0, 10))	('COX-2', 'Gene', '4513', (14, 19))	('COX-2', 'Gene', (14, 19))
128958	32072277	The possibility of endoscopic treatment of cN0 submucosal esophageal cancer: results from a surgical cohort We analyzed the pathological characteristics and recurrence pattern of cN0 submucosal esophageal cancer after esophagectomy and conducted risk stratification to determine the feasibility of performing endoscopic resection for cN0pT1b esophageal squamous cell malignancies.	('submucosal esophageal cancer', 'Disease', 'MESH:D004938', (183, 211))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cN0', 'Var', (179, 182))	('cancer', 'Disease', (205, 211))	('submucosal esophageal cancer', 'Disease', (183, 211))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal squamous cell malignancies', 'Disease', (342, 379))	('squamous cell malignancies', 'Phenotype', 'HP:0002860', (353, 379))	('cN0pT1b', 'Var', (334, 341))	('submucosal esophageal cancer', 'Disease', 'MESH:D004938', (47, 75))	('esophageal squamous cell malignancies', 'Disease', 'MESH:D000077277', (342, 379))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('submucosal esophageal cancer', 'Disease', (47, 75))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', (69, 75))
128971	32072277	In contrast, T1b esophageal carcinomas with submucosal invasion have a much higher lymph node metastasis rate of approximately 12-54%.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('T1b', 'Var', (13, 16))	('esophageal carcinomas', 'Disease', (17, 38))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (17, 37))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (17, 38))	('lymph node metastasis rate', 'CPA', (83, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (17, 38))
128975	32072277	A recent study by the Japan Clinical Oncology Group (JCOG0508 study) of patients with T1b (sm1-2) N0M0 thoracic esophageal SCC confirmed the efficacy of endoscopic resection combined with selective chemoradiotherapy, with results comparable to those following surgery.	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('N0M0', 'Var', (98, 102))	('Oncology', 'Phenotype', 'HP:0002664', (37, 45))	('sm1', 'Gene', '7911', (91, 94))	('SCC', 'Gene', '6317', (123, 126))	('patients', 'Species', '9606', (72, 80))	('sm1', 'Gene', (91, 94))	('SCC', 'Gene', (123, 126))
128978	32072277	This retrospective study analyzed data for patients with pathologically confirmed T1b esophageal SCC with clinical N0 submucosal lesions treated with esophagectomy in our center over a 3-year period.	('T1b', 'Var', (82, 85))	('patients', 'Species', '9606', (43, 51))	('SCC', 'Gene', (97, 100))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('SCC', 'Gene', '6317', (97, 100))
128983	32072277	After excluding 62 patients preoperatively diagnosed with lymph node metastasis (cN1), we analyzed data for 167 patients diagnosed with cN0pT1b esophageal SCC (Fig.	('patients', 'Species', '9606', (19, 27))	('cN0pT1b', 'Var', (136, 143))	('SCC', 'Gene', (155, 158))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('patients', 'Species', '9606', (112, 120))	('cN1', 'Gene', '84618', (81, 84))	('SCC', 'Gene', '6317', (155, 158))	('cN1', 'Gene', (81, 84))
128985	32072277	Our focus in this study was patients with stage cN0pT1b esophageal SCC, therefore, we excluded data for stage cN0cT1b patients.	('stage cN0pT1b', 'Var', (42, 55))	('SCC', 'Gene', (67, 70))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('patients', 'Species', '9606', (28, 36))	('SCC', 'Gene', '6317', (67, 70))	('patients', 'Species', '9606', (118, 126))
129039	32072277	However, less is known about the biological features of cN0pT1b esophageal SCC.	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('SCC', 'Gene', '6317', (75, 78))	('cN0pT1b', 'Var', (56, 63))	('SCC', 'Gene', (75, 78))
129040	32072277	Some studies evaluated small numbers of patients with esophageal adenocarcinoma, while others included larger numbers and evaluated patients undergoing endoscopic submucosal resection for either T1a or T1b superficial esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (218, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('esophageal adenocarcinoma', 'Disease', (218, 243))	('esophageal adenocarcinoma', 'Disease', (54, 79))	('T1b', 'Var', (202, 205))	('patients', 'Species', '9606', (40, 48))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (54, 79))	('T1a', 'Gene', (195, 198))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (218, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('T1a', 'Gene', '10630', (195, 198))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (54, 79))	('patients', 'Species', '9606', (132, 140))
129048	32072277	To our knowledge, our study is the largest single-center study of patients with cN0pT1b esophageal SCC (n = 167).	('SCC', 'Gene', '6317', (99, 102))	('SCC', 'Gene', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('patients', 'Species', '9606', (66, 74))	('cN0pT1b', 'Var', (80, 87))
129049	32072277	Because the overall lymph node metastasis rate in our patients (cN0pT1b) was 3% (5/167), R0 resection in patients with cN0pT1b lesions based only on clinical N0 findings is insufficient.	('patients', 'Species', '9606', (54, 62))	('lymph node metastasis', 'CPA', (20, 41))	('patients', 'Species', '9606', (105, 113))	('cN0pT1b', 'Var', (119, 126))
129071	32072277	However, the results of the JCOG0508 study showed excellent long-term outcomes for T1b esophageal cancer treated by endoscopic resection followed by chemoradiotherapy.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('T1b', 'Var', (83, 86))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
129074	32072277	Our study involved 167 patients with clinical N0 pathologic T1b esophageal SCC confirmed surgically and 23 (23/167, 13.8%) sm3 patients.	('SCC', 'Gene', '6317', (75, 78))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (127, 135))	('SCC', 'Gene', (75, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('T1b', 'Var', (60, 63))
129085	32072277	This study has several limitations, namely, its single-center, retrospective design, and the lack of accurate clinical staging, which meant we were unable to compare outcomes of surgical vs non-surgical treatments in our patients with cN0pT1b esophageal SCC.	('patients', 'Species', '9606', (221, 229))	('cN0pT1b', 'Var', (235, 242))	('SCC', 'Gene', (254, 257))	('SCC', 'Phenotype', 'HP:0002860', (254, 257))	('SCC', 'Gene', '6317', (254, 257))	('men', 'Species', '9606', (208, 211))
129089	32072277	In conclusion, careful clinical stratification of diagnosis and treatment is required in the treatment of patients with cN0 submucosal esophageal SCC.	('men', 'Species', '9606', (69, 72))	('cN0', 'Var', (120, 123))	('SCC', 'Gene', (146, 149))	('patients', 'Species', '9606', (106, 114))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('SCC', 'Gene', '6317', (146, 149))	('men', 'Species', '9606', (98, 101))
129133	33403046	The results showed that all samples (GSE17351, GSE20347, GSE23400, GSE100942, GSE38129 and GSE77861) were clearly divided into normal and tumor groups, except for dataset GSE23400, where four normal samples (GSM573926, GSM573867, GSM573888 and GSM573889) and three tumor samples (GSM573926, GSM573935 and GSM573944) showed no difference between normal tissue and tumors; therefore, these were removed from further analyses (Fig.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumors', 'Disease', (363, 369))	('GSM573888', 'Var', (230, 239))	('tumors', 'Disease', 'MESH:D009369', (363, 369))	('tumor', 'Disease', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (363, 369))	('GSM573935', 'Var', (291, 300))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('GSM573889', 'Var', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('tumor', 'Disease', (363, 368))	('GSM573944', 'Var', (305, 314))	('GSM573926', 'Var', (280, 289))	('GSM573926', 'Var', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
129156	33403046	Ohashi et al found that PBK overexpressed is associated with worse outcomes in ESCC.	('overexpressed', 'Var', (28, 41))	('PBK', 'Gene', (24, 27))	('ESCC', 'Disease', (79, 83))	('PBK', 'Gene', '55872', (24, 27))
129157	33403046	However, our results revealed that high PBK expression significantly correlated with better outcomes (HR=0.25, logrank P= 0.00062).	('expression', 'MPA', (44, 54))	('PBK', 'Gene', '55872', (40, 43))	('PBK', 'Gene', (40, 43))	('high', 'Var', (35, 39))
129160	33403046	Previous studies have demonstrated that high KIF2C expression can serve as an independent marker of poor prognosis in several tumors, including glioma, colorectal cancer, and gastric cancer.	('high', 'Var', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('expression', 'MPA', (51, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (175, 189))	('colorectal cancer', 'Disease', (152, 169))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('glioma', 'Disease', (144, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('KIF2C', 'Gene', '11004', (45, 50))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('KIF2C', 'Gene', (45, 50))	('gastric cancer', 'Disease', (175, 189))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
129165	33403046	Previous studies have shown that NUF2 is an effective prognostic molecule for hepatocellular carcinoma, and silencing NUF2 can suppress human hepatocellular carcinoma tumor growth and induce apoptosis.	('apoptosis', 'CPA', (191, 200))	('NUF2', 'Gene', '83540', (118, 122))	('induce', 'Reg', (184, 190))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (142, 166))	('hepatocellular carcinoma tumor', 'Disease', (142, 172))	('NUF2', 'Gene', (33, 37))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (78, 102))	('human', 'Species', '9606', (136, 141))	('hepatocellular carcinoma tumor', 'Disease', 'MESH:D006528', (142, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('suppress', 'NegReg', (127, 135))	('hepatocellular carcinoma', 'Disease', (78, 102))	('NUF2', 'Gene', '83540', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('silencing', 'Var', (108, 117))	('NUF2', 'Gene', (118, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (142, 166))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (78, 102))
129177	33403046	Moreover, silencing of RAD51AP1 can inhibit epithelial-mesenchymal transition and metastasis in non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('RAD51AP1', 'Gene', (23, 31))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (96, 122))	('inhibit', 'NegReg', (36, 43))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('silencing', 'Var', (10, 19))	('RAD51AP1', 'Gene', '10635', (23, 31))
129203	32228632	In recent years, neoadjuvant chemotherapy has become increasingly important in the treatment of ESCC; in particular, neoadjuvant chemotherapy decreases the tumor stage in patients with advanced preoperative tumor staging, regaining surgical opportunities and significantly prolonging progression-free survival and overall survival.	('tumor', 'Disease', (207, 212))	('decreases', 'NegReg', (142, 151))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('prolonging', 'NegReg', (273, 283))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('patients', 'Species', '9606', (171, 179))	('regaining', 'PosReg', (222, 231))	('overall survival', 'CPA', (314, 330))	('surgical opportunities', 'CPA', (232, 254))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('neoadjuvant chemotherapy', 'Var', (117, 141))	('ESCC', 'Disease', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('progression-free survival', 'CPA', (284, 309))
129312	31118982	The postoperative esophagogastric varices rebleeding rate was low in the LSEGDS group (6.2%, 2/32) compared with the LEGDS group (10%, 4/40) but the difference was not significant.	('esophagogastric varices', 'Disease', (18, 41))	('bleeding', 'Disease', 'MESH:D006470', (44, 52))	('low', 'NegReg', (62, 65))	('bleeding', 'Disease', (44, 52))	('gastric varices', 'Phenotype', 'HP:0030169', (26, 41))	('LSEGDS', 'Var', (73, 79))	('esophagogastric varices', 'Phenotype', 'HP:0002040', (18, 41))
129323	31118691	Survival analyses showed that high cystatin SN expression benefited ESCC patients but did harm to other types of cancer patients.	('ESCC', 'Disease', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cystatin SN', 'Gene', '1469', (35, 46))	('high', 'Var', (30, 34))	('cystatin SN', 'Gene', (35, 46))	('cancer', 'Disease', (113, 119))	('patients', 'Species', '9606', (120, 128))	('benefited', 'PosReg', (58, 67))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
129350	31118691	In MDA-MB-231 and SW480 cancer cells, CST1 knockdown lead to IL-6 accumulation, which affected the growth of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('CST1', 'Gene', '1469', (38, 42))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (3, 13))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('knockdown', 'Var', (43, 52))	('cancer', 'Disease', (109, 115))	('CST1', 'Gene', (38, 42))	('cancer', 'Disease', (24, 30))	('SW480', 'CellLine', 'CVCL:0546', (18, 23))	('IL-6', 'Gene', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('IL-6', 'Gene', '3569', (61, 65))	('affected', 'Reg', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
129352	31118691	In SW480 colon cancer cells and MDA-MB-231 breast cancer cells, CST1 knockdown exhibited G1-phase cell cycle arrest, which was caused by the expression of cell cycle inhibitors p21 and p16 and the downregulation of cyclin D1 and p-Rb.	('p-Rb', 'Gene', (229, 233))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('arrest', 'Disease', (109, 115))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('downregulation', 'NegReg', (197, 211))	('p16', 'Gene', (185, 188))	('cyclin D1', 'Gene', (215, 224))	('p-Rb', 'Gene', '5925', (229, 233))	('p16', 'Gene', '1029', (185, 188))	('CST1', 'Gene', (64, 68))	('colon cancer', 'Disease', 'MESH:D015179', (9, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('SW480', 'CellLine', 'CVCL:0546', (3, 8))	('cyclin D1', 'Gene', '595', (215, 224))	('arrest', 'Disease', 'MESH:D006323', (109, 115))	('CST1', 'Gene', '1469', (64, 68))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (32, 42))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (43, 56))	('colon cancer', 'Disease', (9, 21))	('p21', 'Gene', (177, 180))	('p21', 'Gene', '644914', (177, 180))	('knockdown', 'Var', (69, 78))
129356	31118691	However, another study showed CST1 knockdown also contributed to cellular senescence and inhibited cancer cell proliferation and tumor growth.	('CST1', 'Gene', '1469', (30, 34))	('knockdown', 'Var', (35, 44))	('CST1', 'Gene', (30, 34))	('inhibited', 'NegReg', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cellular senescence', 'CPA', (65, 84))	('contributed', 'Reg', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
129363	31118691	In ESCC, high expression of cystatin SN was a profitable survival factor; however, other cancer types showed completely opposite results.	('high expression', 'Var', (9, 24))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cystatin SN', 'Gene', '1469', (28, 39))	('ESCC', 'Disease', (3, 7))	('cancer', 'Disease', (89, 95))	('cystatin SN', 'Gene', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
129366	31118691	Patients with high level of cystatin SN expression had more favorable survival time after surgical treatment than those with low expression, (Figure 2A and B).	('high level', 'Var', (14, 24))	('cystatin SN', 'Gene', '1469', (28, 39))	('Patients', 'Species', '9606', (0, 8))	('cystatin SN', 'Gene', (28, 39))	('survival time', 'CPA', (70, 83))
129370	31118691	High expression level of cystatin SN was observed in non-small-cell lung cancer (NSCLC) patients (Figure 1), and patients with high level of cystatin SN showed more serious recurrence and poorer survival times compared to those with lower expression (Figure 2C and D).	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (57, 79))	('expression', 'MPA', (5, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('poorer', 'NegReg', (188, 194))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('cystatin SN', 'Gene', (141, 152))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (53, 79))	('high level', 'Var', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lung cancer', 'Disease', (68, 79))	('cystatin SN', 'Gene', '1469', (25, 36))	('patients', 'Species', '9606', (113, 121))	('survival times', 'CPA', (195, 209))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('patients', 'Species', '9606', (88, 96))	('cystatin SN', 'Gene', (25, 36))	('cystatin SN', 'Gene', '1469', (141, 152))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('NSCLC', 'Disease', (81, 86))	('recurrence', 'CPA', (173, 183))
129371	31118691	Through univariate and multivariate analyses, we could infer that high expression of cystatin SN was a significant prognostic indicator for a higher rate of recurrence, metastatic risk, and poor survival in patients with surgically resected NSCLCs, as summarized in Table 2.	('patients', 'Species', '9606', (207, 215))	('metastatic risk', 'CPA', (169, 184))	('NSCLC', 'Disease', (241, 246))	('NSCLC', 'Disease', 'MESH:D002289', (241, 246))	('NSCLC', 'Phenotype', 'HP:0030358', (241, 246))	('recurrence', 'CPA', (157, 167))	('high', 'Var', (66, 70))	('cystatin SN', 'Gene', '1469', (85, 96))	('cystatin SN', 'Gene', (85, 96))
129376	31118691	CST1 knockdown in BT-474 and MDA-MB-468 cells significantly inhibited cell migration capability.	('CST1', 'Gene', '1469', (0, 4))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (29, 39))	('knockdown', 'Var', (5, 14))	('CST1', 'Gene', (0, 4))	('inhibited', 'NegReg', (60, 69))	('BT-474', 'CellLine', 'CVCL:0179', (18, 24))	('cell migration capability', 'CPA', (70, 95))
129377	31118691	In MDA-MB-231 cells, CST1 knockdown increased phosphorylation of glycogen synthase kinase 3beta at serine 9, leading to induction of glycogen accumulation associated with cellular senescence and inhibition of tumor proliferation, which indicated cystatin SN might affect the growth of cancer cells by affecting the GSK3 signaling pathway (Figure 3A).	('affecting', 'Reg', (301, 310))	('glycogen', 'Chemical', 'MESH:D006003', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('serine', 'Chemical', 'MESH:D012694', (99, 105))	('tumor', 'Disease', (209, 214))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (3, 13))	('cellular senescence', 'CPA', (171, 190))	('inhibition', 'NegReg', (195, 205))	('increased', 'PosReg', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('phosphorylation', 'MPA', (46, 61))	('cancer', 'Disease', (285, 291))	('glycogen', 'Chemical', 'MESH:D006003', (133, 141))	('GSK3 signaling pathway', 'Pathway', (315, 337))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('knockdown', 'Var', (26, 35))	('glycogen accumulation', 'MPA', (133, 154))	('increased phosphorylation of glycogen synthase kinase 3beta', 'Phenotype', 'HP:0003240', (36, 95))	('cystatin SN', 'Gene', '1469', (246, 257))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('affect', 'Reg', (264, 270))	('growth', 'CPA', (275, 281))	('CST1', 'Gene', (21, 25))	('cystatin SN', 'Gene', (246, 257))	('CST1', 'Gene', '1469', (21, 25))
129378	31118691	Furthermore, CST1 knockdown suppressed cancer cell proliferation and tumor growth in a xenograft model and led to IL-6 accumulation, which indicated that cystatin SN might also affect the IL-6 signaling pathway (Figure 3A).	('knockdown', 'Var', (18, 27))	('CST1', 'Gene', (13, 17))	('cystatin SN', 'Gene', (154, 165))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('IL-6', 'Gene', (114, 118))	('led to', 'Reg', (107, 113))	('cancer', 'Disease', (39, 45))	('IL-6', 'Gene', (188, 192))	('tumor', 'Disease', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('IL-6', 'Gene', '3569', (114, 118))	('affect', 'Reg', (177, 183))	('suppressed', 'NegReg', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('IL-6', 'Gene', '3569', (188, 192))	('CST1', 'Gene', '1469', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cystatin SN', 'Gene', '1469', (154, 165))
129389	31118691	In several pancreatic cancer cell lines (BXPC-3, PANC-1, SW1990), CST1 was upregulated at both protein and mRNA levels, and was correlated closely with malignancy-associated proteins such as PCNA, cyclin D1, cyclin A2, and cyclin E. Consistent with this finding, CST1 knockdown reduced the expression of the proliferation-related proteins p-AKT and PCNA significantly, as well as colony formation and xenograft development in vitro.	('AKT', 'Gene', (341, 344))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (11, 28))	('PCNA', 'Gene', (191, 195))	('malignancy', 'Disease', (152, 162))	('BXPC-3', 'CellLine', 'CVCL:0186', (41, 47))	('PCNA', 'Gene', (349, 353))	('proliferation-related', 'CPA', (308, 329))	('CST1', 'Gene', (66, 70))	('CST1', 'Gene', (263, 267))	('PANC-1', 'CellLine', 'CVCL:0480', (49, 55))	('AKT', 'Gene', '207', (341, 344))	('PCNA', 'Gene', '5111', (191, 195))	('CST1', 'Gene', '1469', (66, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (11, 28))	('reduced', 'NegReg', (278, 285))	('cyclin A2', 'Gene', (208, 217))	('cyclin D1', 'Gene', (197, 206))	('PCNA', 'Gene', '5111', (349, 353))	('CST1', 'Gene', '1469', (263, 267))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('SW1990', 'CellLine', 'CVCL:1723', (57, 63))	('pancreatic cancer', 'Disease', (11, 28))	('cyclin D1', 'Gene', '595', (197, 206))	('colony formation', 'CPA', (380, 396))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))	('xenograft development', 'CPA', (401, 422))	('cyclin A2', 'Gene', '890', (208, 217))	('expression', 'MPA', (290, 300))	('knockdown', 'Var', (268, 277))
129392	31118691	Survival analysis has demonstrated that high cystatin SN expression was closely associated with poor clinical status in colon cancer patients (Figure 2).	('high', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cystatin SN', 'Gene', '1469', (45, 56))	('patients', 'Species', '9606', (133, 141))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('cystatin SN', 'Gene', (45, 56))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('associated', 'Reg', (80, 90))	('colon cancer', 'Disease', (120, 132))
129395	31118691	Furthermore, CST1 knockdown suppressed tumor growth in vivo and led to IL-6 accumulation, which indicated cystatin SN might affect the IL-6 signaling pathway (Figure 3A).	('knockdown', 'Var', (18, 27))	('IL-6', 'Gene', (135, 139))	('CST1', 'Gene', (13, 17))	('cystatin SN', 'Gene', '1469', (106, 117))	('cystatin SN', 'Gene', (106, 117))	('IL-6', 'Gene', (71, 75))	('affect', 'Reg', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('IL-6', 'Gene', '3569', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('suppressed', 'NegReg', (28, 38))	('IL-6', 'Gene', '3569', (71, 75))	('accumulation', 'PosReg', (76, 88))	('tumor', 'Disease', (39, 44))	('CST1', 'Gene', '1469', (13, 17))
129401	31118691	High expression of cystatin SN was closely related to poor prognosis such as recurrence and metastasis in several cancer types like gastric cancer, CRC, pancreatic cancer, and lung cancer; however, in ESCC, high cystatin SN expression patients showed more favorable survival times after surgical treatment.	('high', 'Var', (207, 211))	('cystatin SN', 'Gene', '1469', (212, 223))	('CRC', 'Disease', (148, 151))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('ESCC', 'Disease', (201, 205))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('cystatin SN', 'Gene', (212, 223))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('patients', 'Species', '9606', (235, 243))	('cystatin SN', 'Gene', '1469', (19, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('gastric cancer', 'Disease', (132, 146))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', (164, 170))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))	('cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cystatin SN', 'Gene', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('pancreatic cancer', 'Disease', (153, 170))	('survival times', 'CPA', (266, 280))	('lung cancer', 'Disease', (176, 187))	('cancer', 'Disease', (114, 120))
129424	30931257	The TM-V30 was most strongly associated with HT3+ and on multivariate analysis, patients with TM-V30 >= 14% had a 5.7-fold (95% CI 2.42-14.54, p < 0.001) increased odds of HT3+ in the entire cohort and a 4-fold (95% CI 1.54-11.11, p = 0.006) increased odds of HT3+ in the carboplatin/paclitaxel cohort compared to patients with TM-V30 < 14%.	('patients', 'Species', '9606', (314, 322))	('patients', 'Species', '9606', (80, 88))	('HT3+', 'Disease', (260, 264))	('HT3+', 'MPA', (172, 176))	('carboplatin', 'Chemical', 'MESH:D016190', (272, 283))	('paclitaxel', 'Chemical', 'MESH:D017239', (284, 294))	('TM-V30 >= 14%', 'Var', (94, 107))
129458	30931257	Patients treated with IMRT (N = 50) had significantly higher TM V5 (60.5% vs. 52.4%, p = 0.001) and TM V10 (46.0% vs. 39.7%, p = 0.001) compared to patients treated with 3DRT.	('patients', 'Species', '9606', (148, 156))	('TM V10', 'MPA', (100, 106))	('TM V5', 'MPA', (61, 66))	('higher', 'PosReg', (54, 60))	('IMRT', 'Var', (22, 26))	('Patients', 'Species', '9606', (0, 8))
129475	30931257	For example, patients with TM-V50 >= 1.5% had a 2.66-fold increase (95% CI 1.26-5.80, p = 0.012) in the odds of HT3+ for the entire cohort and a 2.68-fold increase (95% CI 1.07-6.97, p = 0.038) in the carboplatin/paclitaxel cohort after adjusting for confounders.	('increase', 'PosReg', (155, 163))	('increase', 'PosReg', (58, 66))	('HT3+', 'MPA', (112, 116))	('patients', 'Species', '9606', (13, 21))	('carboplatin', 'Chemical', 'MESH:D016190', (201, 212))	('TM-V50 >= 1.5%', 'Var', (27, 41))	('paclitaxel', 'Chemical', 'MESH:D017239', (213, 223))
129478	30931257	On multivariate analysis, the VB-mean dose (OR = 1.06, p = 0.032), VB-V30 (OR = 1.15, p = 0.010), VB-V40 (OR = 1.19, p = 0.002) and VB-V50 (OR = 1.32, p = 0.013) were associated with higher rates of HT3+ in the entire cohort (Table 8) while only VB-V40 (OR = 1.16, p = 0.044) remained significant in the carboplatin/paclitaxel cohort (Table 9).	('paclitaxel', 'Chemical', 'MESH:D017239', (316, 326))	('higher', 'PosReg', (183, 189))	('VB-V40', 'Var', (98, 104))	('carboplatin', 'Chemical', 'MESH:D016190', (304, 315))	('OR', 'Var', (75, 77))	('HT3+', 'MPA', (199, 203))
129479	30931257	The optimal cut-point for VB-V40 was 29% resulting in odds-ratios of 3.58 (95% CI 1.60-8.04, p = 0.002) and 3.55 (95% CI 1.36-9.26, p = 0.010) for patients with VB-V40 >= 29% vs. VB-V40 < 29% in the entire cohort and carboplatin/paclitaxel cohorts, respectively.	('carboplatin', 'Chemical', 'MESH:D016190', (217, 228))	('patients', 'Species', '9606', (147, 155))	('paclitaxel', 'Chemical', 'MESH:D017239', (229, 239))	('VB-V40 >= 29%', 'Var', (161, 174))	('VB-V40', 'Gene', (26, 32))
129480	30931257	Those 3 variables (rib-mean, rib-V20, and rib-V30) remained significantly associated with HT3+ in the carboplatin/taxol cohort (Table 9).	('carboplatin', 'Chemical', 'MESH:D016190', (102, 113))	('taxol', 'Chemical', 'MESH:D017239', (114, 119))	('rib-V30', 'Var', (42, 49))	('HT3+', 'MPA', (90, 94))	('associated', 'Reg', (74, 84))
129481	30931257	In the carboplatin/paclitaxel cohort, rib-mean (OR = 1.24, p = 0.046), rib-V20 (OR = 1.43, p = 0.038), and rib-V30 (OR = 2.03, p = 0.015) were significantly associated with HT3+.	('HT3+', 'Disease', (173, 177))	('rib-mean', 'Var', (38, 46))	('associated with', 'Reg', (157, 172))	('rib-V20', 'Var', (71, 78))	('carboplatin', 'Chemical', 'MESH:D016190', (7, 18))	('rib-V30', 'Var', (107, 114))	('paclitaxel', 'Chemical', 'MESH:D017239', (19, 29))
129482	30931257	Table 10 demonstrates the multivariate analyses incorporating the optimal cutpoints for VB-V40 and rib-mean, rib-V20, or rib-V30 for the entire cohort and the carboplatin/paclitaxel cohort.	('rib-V20', 'Var', (109, 116))	('paclitaxel', 'Chemical', 'MESH:D017239', (171, 181))	('rib-V30', 'Var', (121, 128))	('carboplatin', 'Chemical', 'MESH:D016190', (159, 170))	('VB-V40', 'Var', (88, 94))
129498	30931257	On multivariate analysis, treatment with carboplatin/paclitaxel, the most common regimen at our institution, was the variable most strongly associated with development of HT3+.	('paclitaxel', 'Chemical', 'MESH:D017239', (53, 63))	('associated', 'Reg', (140, 150))	('carboplatin', 'Chemical', 'MESH:D016190', (41, 52))	('HT3+', 'Var', (171, 175))
129502	30931257	The authors found that higher radiation dose to the VB (mean dose and V5-V30) and rib (mean dose and V5-V30) were associated with higher rates of grade 3 WBC toxicity, and that the VB dose had the strongest association with hematologic toxicity.	('V5-V30', 'Var', (70, 76))	('WBC toxicity', 'Disease', 'MESH:D064420', (154, 166))	('WBC toxicity', 'Disease', (154, 166))	('V5-V30', 'Var', (101, 107))	('hematologic toxicity', 'Disease', (224, 244))	('hematologic toxicity', 'Disease', 'MESH:D006402', (224, 244))
129505	30931257	suggested constraining the VB to mean dose <=23Gy, V5 <= 65%, V10 <= 60%, and V20 <= 50% may decrease acute HT in patients receiving CRT for NSCLC.	('V20 <= 50%', 'Var', (78, 88))	('V5 <= 65%', 'Var', (51, 60))	('V10 <= 60%', 'Var', (62, 72))	('NSCLC', 'Disease', (141, 146))	('acute HT', 'MPA', (102, 110))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('decrease', 'NegReg', (93, 101))	('patients', 'Species', '9606', (114, 122))
129506	30931257	also noted the relationship between VB radiation and leukopenia, recommending a mean VB doses of <= 23.9 Gy, V20 <= 56.0%, and V30 <= 52.1%.	('leukopenia', 'Phenotype', 'HP:0001882', (53, 63))	('leukopenia', 'Disease', (53, 63))	('leukopenia', 'Disease', 'MESH:D007970', (53, 63))	('V30', 'Var', (127, 130))	('V20 <=', 'Var', (109, 115))
129633	28487611	The pathological evaluation of the 28 resected lesions showed that the depth of invasion was pTis in 12 lesions, pT1a in 13 lesions, and pT1b in 3 lesions.	('T1a', 'Gene', (114, 117))	('pT1b', 'Var', (137, 141))	('T1a', 'Gene', '10630', (114, 117))
129685	22683420	This suggests that tumors with high DEK protein expression may be correlated with poor clinical response to clastogenic therapies.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('DEK', 'Gene', '7913', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('DEK', 'Gene', (36, 39))	('high', 'Var', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
129709	22683420	DEK is an inhibitor of cell death and proliferation, and the knockdown of DEK results in apoptosis and senescence in cancer cells in culture and in preclinical animal models.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('DEK', 'Gene', '7913', (74, 77))	('apoptosis', 'CPA', (89, 98))	('results in', 'Reg', (78, 88))	('knockdown', 'Var', (61, 70))	('DEK', 'Gene', '7913', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('DEK', 'Gene', (74, 77))	('senescence', 'CPA', (103, 113))	('cancer', 'Disease', (117, 123))	('DEK', 'Gene', (0, 3))
129758	22683420	Mutations in genes such as p53 and Notch1 were identified which highlight a distinct set of proteins with broad functions in the suppression of HNSCC.	('p53', 'Gene', '7157', (27, 30))	('Notch1', 'Gene', (35, 41))	('Mutations', 'Var', (0, 9))	('Notch1', 'Gene', '4851', (35, 41))	('HNSCC', 'Disease', (144, 149))	('p53', 'Gene', (27, 30))
129760	22683420	This genome-wide DNA sequencing effort also revealed non-overlapping activating mutations in PIK3CA and Ras, and inactivating mutations in PTEN.	('PIK3CA', 'Gene', '5290', (93, 99))	('Ras', 'Gene', (104, 107))	('PTEN', 'Gene', (139, 143))	('activating', 'PosReg', (69, 79))	('PTEN', 'Gene', '5728', (139, 143))	('PIK3CA', 'Gene', (93, 99))	('inactivating mutations', 'Var', (113, 135))
129761	22683420	These genetic alterations are all expected to converge on the activation of the Akt-mTOR pathway.	('Akt', 'Gene', '207', (80, 83))	('Akt', 'Gene', (80, 83))	('genetic alterations', 'Var', (6, 25))
129763	22683420	The mTOR-regulated molecular network coordinates mitogenic signaling with nutrient-sensing pathways thereby controlling cell proliferation, and emerging information suggests that activation of mTOR represents one of the most frequent events in cancer.	('activation', 'Var', (179, 189))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('mTOR', 'Gene', (193, 197))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
129764	22683420	Extensive studies using HNSCC tumor xenografts in mice, as well as genetically-defined and chemically-induced HNSCC experimental cancer models support the pre-clinical efficacy of mTOR inhibitors for HNSCC.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mTOR', 'Gene', (180, 184))	('HNSCC', 'Disease', (200, 205))	('HNSCC experimental cancer', 'Disease', 'MESH:D000077195', (110, 135))	('inhibitors', 'Var', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mice', 'Species', '10090', (50, 54))	('HNSCC tumor', 'Disease', (24, 35))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (24, 35))	('HNSCC experimental cancer', 'Disease', (110, 135))
129772	22683420	Modifications conferring tumor-selective replication include deletion of the p300/CBP-binding or the pRB-binding region of E1A (resulting in selective killing of tumor cells with defects in the Rb pathway), or deletion of partial or the entire E1B 55K gene resulting in the loss of p53 degradation and late viral RNA export.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('p53', 'Gene', (282, 285))	('degradation', 'MPA', (286, 297))	('tumor', 'Disease', (162, 167))	('loss', 'NegReg', (274, 278))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('CBP', 'Gene', '1387', (82, 85))	('E1B 55K', 'Gene', (244, 251))	('CBP', 'Gene', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (25, 30))	('deletion', 'Var', (61, 69))	('deletion', 'Var', (210, 218))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('p300', 'Gene', (77, 81))	('p53', 'Gene', '7157', (282, 285))	('E1A', 'Gene', (123, 126))	('p300', 'Gene', '2033', (77, 81))	('Rb pathway', 'Pathway', (194, 204))
129773	22683420	Capsid-modified oncolytic adenovirus, Ad5/3-delta24, was effective in inhibiting growth of laryngeal squamous cell carcinoma cells in vitro and in a xenograft model in vivo.	('adenovirus, Ad5', 'Species', '28285', (26, 41))	('growth', 'MPA', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('inhibiting', 'NegReg', (70, 80))	('Ad5/3-delta24', 'Var', (38, 51))	('laryngeal squamous cell carcinoma', 'Disease', (91, 124))
129790	22683420	In addition to ICP34.5 gene deletion, viruses with a deletion of ICP47 are being tested for tumor-selective viral replication and cell death.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('deletion', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('ICP47', 'Gene', (65, 70))	('tumor', 'Disease', (92, 97))
129791	22683420	ICP47 expression blocks antigen presentation of MHC class I and II molecules via inhibition of the TAP1 and TAP2 transporters.	('TAP1', 'Gene', (99, 103))	('TAP1', 'Gene', '6890', (99, 103))	('inhibition', 'NegReg', (81, 91))	('blocks', 'NegReg', (17, 23))	('antigen presentation', 'MPA', (24, 44))	('ICP47', 'Gene', (0, 5))	('TAP2', 'Gene', '6891', (108, 112))	('TAP2', 'Gene', (108, 112))	('expression', 'Var', (6, 16))
129812	22683420	Accordingly, DEK depletion resulted in increased DNA damage marked by increased gammaH2AX expression.	('DNA damage', 'MPA', (49, 59))	('DEK', 'Gene', (13, 16))	('increased', 'PosReg', (70, 79))	('DEK', 'Gene', '7913', (13, 16))	('depletion', 'Var', (17, 26))	('expression', 'MPA', (90, 100))	('increased', 'PosReg', (39, 48))	('gammaH2AX', 'Protein', (80, 89))
129814	22683420	DEK knockdown in human keratinocytes and HPV positive cancer cells resulted in p53 dependent apoptosis.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('HPV', 'Species', '10566', (41, 44))	('knockdown', 'Var', (4, 13))	('human', 'Species', '9606', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('DEK', 'Gene', '7913', (0, 3))	('apoptosis', 'CPA', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('DEK', 'Gene', (0, 3))
129914	29701625	Deaths for all cancers were identified through ICD-9 codes 140 to 239; for malignant neoplasm of the pleura through code 163 and for lung cancer through code 162.	('malignant neoplasm of the pleura', 'Disease', (75, 107))	('Deaths', 'Disease', (0, 6))	('neoplasm', 'Phenotype', 'HP:0002664', (85, 93))	('lung cancer', 'Disease', (133, 144))	('Deaths', 'Disease', 'MESH:D003643', (0, 6))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('codes 140', 'Var', (53, 62))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('code 163', 'Var', (116, 124))	('neoplasm of the pleura', 'Phenotype', 'HP:0100527', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('malignant neoplasm of the pleura', 'Disease', 'MESH:D009369', (75, 107))
130030	31620495	Focal dermal hypoplasia, also known as Goltz syndrome, is a rare X-linked dominant disorder caused by a mutation in the PORCN gene located on the X chromosome (p11.23).	('PORCN', 'Gene', (120, 125))	('Goltz syndrome', 'Disease', (39, 53))	('Goltz syndrome', 'Disease', 'MESH:D005489', (39, 53))	('X-linked dominant disorder', 'Disease', (65, 91))	('Focal dermal hypoplasia', 'Phenotype', 'HP:0007510', (0, 23))	('PORCN', 'Gene', '64840', (120, 125))	('caused by', 'Reg', (92, 101))	('dermal hypoplasia', 'Disease', 'MESH:D005489', (6, 23))	('X-linked dominant disorder', 'Disease', 'MESH:D040181', (65, 91))	('mutation', 'Var', (104, 112))	('dermal hypoplasia', 'Disease', (6, 23))
130033	31620495	Hence, the dysregulation of this pathway results in a wide array of multisystemic manifestations involving the skin (reticular hyperpigmentation or hypopigmentation, atrophy, telangiectasias, and papillomas), skeleton (syndactyly, ectrodactyly, hypoplasia or aplasia of truncal skeleton), eyes (coloboma, microphthalmia), mucous membranes (raspberry papillomas), and teeth (small, malformed, or absent teeth).	('raspberry papillomas', 'Disease', (340, 360))	('telangiectasias', 'Disease', (175, 190))	('hypoplasia or aplasia', 'Disease', 'MESH:C535568', (245, 266))	('telangiectasias', 'Disease', 'MESH:D013684', (175, 190))	('papillomas', 'Disease', 'MESH:D010212', (350, 360))	('syndactyly', 'Phenotype', 'HP:0001159', (219, 229))	('microphthalmia', 'Disease', 'MESH:D008850', (305, 319))	('reticular hyperpigmentation', 'Disease', (117, 144))	('syndactyly', 'Disease', (219, 229))	('coloboma', 'Phenotype', 'HP:0000589', (295, 303))	('atrophy', 'Disease', 'MESH:D001284', (166, 173))	('skin', 'Disease', (111, 115))	('papillomas', 'Phenotype', 'HP:0012740', (350, 360))	('atrophy', 'Disease', (166, 173))	('dysregulation', 'Var', (11, 24))	('papillomas', 'Disease', (350, 360))	('results in', 'Reg', (41, 51))	('reticular hyperpigmentation', 'Disease', 'MESH:D017495', (117, 144))	('microphthalmia', 'Disease', (305, 319))	('ectrodactyly', 'Phenotype', 'HP:0100257', (231, 243))	('hypopigmentation', 'Phenotype', 'HP:0001010', (148, 164))	('reticular hyperpigmentation', 'Phenotype', 'HP:0007588', (117, 144))	('hypopigmentation', 'Disease', (148, 164))	('microphthalmia', 'Phenotype', 'HP:0000568', (305, 319))	('raspberry papillomas', 'Disease', 'MESH:D010212', (340, 360))	('papillomas', 'Disease', 'MESH:D010212', (196, 206))	('hypopigmentation', 'Disease', 'MESH:D017496', (148, 164))	('hypoplasia or aplasia', 'Disease', (245, 266))	('papillomas', 'Phenotype', 'HP:0012740', (196, 206))	('ectrodactyly', 'Disease', (231, 243))	('syndactyly', 'Disease', 'MESH:D013576', (219, 229))	('papillomas', 'Disease', (196, 206))
130116	29972731	People with high body mass index, especially those with high waist circumference, have increased intraabdominal pressure and decreased lower esophageal sphincter tonus.	('high waist circumference', 'Var', (56, 80))	('esophageal sphincter tonus', 'Disease', (141, 167))	('increased', 'PosReg', (87, 96))	('esophageal sphincter tonus', 'Disease', 'MESH:D009122', (141, 167))	('sphincter tonus', 'Phenotype', 'HP:0002839', (152, 167))	('decreased', 'NegReg', (125, 134))	('intraabdominal pressure', 'MPA', (97, 120))	('high waist circumference', 'Phenotype', 'HP:0031819', (56, 80))	('People', 'Species', '9606', (0, 6))	('high body mass index', 'Phenotype', 'HP:0031418', (12, 32))
130219	26886618	Other factors associated with higher risk of multimorbidity included non-Turkmen ethnicity, low education, unemployment, low socioeconomic status, physical inactivity, overweight, obesity, former smoking, opium and alcohol use, and poor oral health.	('low socioeconomic status', 'Var', (121, 145))	('low education', 'Var', (92, 105))	('obesity', 'Disease', (180, 187))	('alcohol', 'Chemical', 'MESH:D000438', (215, 222))	('physical', 'Disease', (147, 155))	('opium', 'Disease', (205, 210))	('poor oral', 'Phenotype', 'HP:0000160', (232, 241))	('alcohol use', 'Phenotype', 'HP:0030955', (215, 226))	('men', 'Species', '9606', (115, 118))	('men', 'Species', '9606', (77, 80))	('overweight', 'Phenotype', 'HP:0025502', (168, 178))	('former', 'Disease', (189, 195))	('obesity', 'Phenotype', 'HP:0001513', (180, 187))	('overweight', 'Disease', (168, 178))	('low education', 'Phenotype', 'HP:0001249', (92, 105))	('obesity', 'Disease', 'MESH:D009765', (180, 187))
130242	26886618	In multivariate models, older people, women, non-Turkmens, unemployed people, opium users, alcohol users, and those with low education, low physical activity, low SES, high BMI, and high DMFT (an indicator of poorer oral hygiene) were at a higher risk of multimorbidity (all P < 0.05) (Table 2).	('alcohol', 'Chemical', 'MESH:D000438', (91, 98))	('high DMFT', 'Var', (182, 191))	('people', 'Species', '9606', (70, 76))	('low education', 'Phenotype', 'HP:0001249', (121, 134))	('low', 'NegReg', (136, 139))	('women', 'Species', '9606', (38, 43))	('men', 'Species', '9606', (40, 43))	('poorer oral', 'Phenotype', 'HP:0000160', (209, 220))	('alcohol use', 'Phenotype', 'HP:0030955', (91, 102))	('men', 'Species', '9606', (53, 56))	('people', 'Species', '9606', (30, 36))	('multimorbidity', 'Disease', (255, 269))	('low SES', 'Var', (159, 166))	('high BMI', 'Var', (168, 176))
130309	24658651	In addition, patients with Siewert type III AEG showed more advanced disease, larger tumor diameters and depth, and a more advanced pathological stage than those with Siewert type II AEG, although the incidence of lymph node metastasis was high in both groups (64.1 % in type II AEG and 75.0 % in type III AEG).	('tumor', 'Disease', (85, 90))	('AEG', 'Chemical', '-', (279, 282))	('AEG', 'Chemical', '-', (183, 186))	('AEG', 'Chemical', '-', (306, 309))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('larger', 'PosReg', (78, 84))	('AEG', 'Chemical', '-', (44, 47))	('Siewert type III', 'Var', (27, 43))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
130311	24658651	In addition, tumor diameter was larger in Siewert type II AEG patients with lymph node involvement compared to those without (55.0 vs. 38.0 mm, P = 0.019), whereas there was no such association between tumor diameter and nodal status among Siewert type III AEG patients (69.0 vs. 63.5 mm, P = 0.827).	('tumor', 'Disease', (13, 18))	('AEG', 'Chemical', '-', (257, 260))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', (202, 207))	('larger', 'PosReg', (32, 38))	('Siewert type II AEG', 'Var', (42, 61))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('patients', 'Species', '9606', (261, 269))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('patients', 'Species', '9606', (62, 70))	('AEG', 'Chemical', '-', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
130317	24658651	The index was higher than 5 in stations 1 (right paracardia), 3 (lesser curvature), and 7 (along the left gastric artery) in patients with Siewert type II AEG compared to stations 1, 2 (left paracardia), 3, 7, and 9 (along the celiac artery) in those with Siewert type III AEG.	('right paracardia', 'Disease', 'MESH:C535682', (43, 59))	('right paracardia', 'Disease', (43, 59))	('AEG', 'Chemical', '-', (155, 158))	('AEG', 'Chemical', '-', (273, 276))	('left paracardia', 'Disease', 'MESH:D018487', (186, 201))	('Siewert', 'Var', (139, 146))	('left paracardia', 'Disease', (186, 201))	('higher', 'PosReg', (14, 20))	('patients', 'Species', '9606', (125, 133))
130325	24658651	Theoretically, the epicenter of Siewert type III AEG is far from the EGJ compared to that of Siewert type II AEG; thus, Siewert type III AEG must be larger in diameter to infiltrate the junction, as was the case in the present study, resulting in the deeper tumor infiltration and advanced stage observed.	('Siewert', 'Var', (120, 127))	('AEG', 'Chemical', '-', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('AEG', 'Chemical', '-', (49, 52))	('deeper tumor', 'Disease', 'MESH:D009369', (251, 263))	('advanced stage', 'CPA', (281, 295))	('AEG', 'Chemical', '-', (109, 112))	('deeper tumor', 'Disease', (251, 263))
130352	25680115	Association between Glu504Lys Polymorphism of ALDH2 Gene and Cancer Risk: A Meta-Analysis The association of the aldehyde dehydrogenases-2 (ALDH2) Glu504Lys polymorphism (also named Glu487Lys, or rs671) and cancers has been investigated.	('ALDH2', 'Gene', '217', (140, 145))	('Glu487Lys', 'SUBSTITUTION', 'None', (182, 191))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancers', 'Disease', (207, 214))	('ALDH2', 'Gene', (140, 145))	('ALDH2', 'Gene', '217', (46, 51))	('Glu504Lys', 'Var', (20, 29))	('Glu504Lys', 'SUBSTITUTION', 'None', (20, 29))	('rs671', 'Mutation', 'rs671', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('Glu504Lys', 'Var', (147, 156))	('Glu504Lys', 'SUBSTITUTION', 'None', (147, 156))	('Glu487Lys', 'Var', (182, 191))	('ALDH2', 'Gene', (46, 51))
130354	25680115	A meta-analysis based on 51 case-control studies consisting of 16774 cases and 32060 controls was performed to evaluate the association between the ALDH2 Glu504Lys polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Glu504Lys', 'Var', (154, 163))	('ALDH2', 'Gene', '217', (148, 153))	('association', 'Interaction', (124, 135))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('Glu504Lys', 'SUBSTITUTION', 'None', (154, 163))	('cancer', 'Disease', (181, 187))	('ALDH2', 'Gene', (148, 153))
130355	25680115	The comparison of genotypes Lys+ (Lys/Lys and Lys/Glu) with Glu/Glu yielded a significant 20% increased cancer risk (OR = 1.20, 95%CI: 1.03-1.39, P = 0.02, I2 = 92%).	('Lys', 'Chemical', 'MESH:D008239', (34, 37))	('Lys', 'Chemical', 'MESH:D008239', (38, 41))	('Lys', 'Chemical', 'MESH:D008239', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('increased', 'PosReg', (94, 103))	('Lys/Glu', 'Var', (46, 53))	('Lys', 'Chemical', 'MESH:D008239', (46, 49))	('Glu', 'Chemical', 'MESH:D018698', (60, 63))	('Glu', 'Chemical', 'MESH:D018698', (50, 53))	('Lys+', 'Chemical', 'MESH:D008239', (28, 32))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('Glu', 'Chemical', 'MESH:D018698', (64, 67))
130356	25680115	Subgroup analysis by cancer type indicated a significantly increased UADT cancer risk (OR = 1.39, 95%CI: 1.11-1.73, P = 0.004, I2 = 94%) in individuals with the Lys+ genotypes.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('Lys+', 'Chemical', 'MESH:D008239', (161, 165))	('UADT cancer', 'Disease', 'MESH:D006258', (69, 80))	('cancer', 'Disease', (21, 27))	('Lys+', 'Var', (161, 165))	('UADT cancer', 'Disease', (69, 80))	('increased', 'PosReg', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
130357	25680115	Subgroup analysis by country indicated that individuals from Japan with the Lys+ genotypes had a significant 38% increased cancer risk (OR = 1.38, 95%CI: 1.12-1.71, P = 0.003, I2 = 93%).	('Lys+', 'Chemical', 'MESH:D008239', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Lys+', 'Var', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
130358	25680115	Our results indicated that the ALDH2 Glu504Lys polymorphism is a susceptible loci associated with overall cancers, especially esophageal cancer and among Japanese population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('associated', 'Reg', (82, 92))	('Glu504Lys', 'Var', (37, 46))	('Glu504Lys', 'SUBSTITUTION', 'None', (37, 46))	('ALDH2', 'Gene', '217', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('ALDH2', 'Gene', (31, 36))	('especially esophageal cancer', 'Disease', (115, 143))	('especially esophageal cancer', 'Disease', 'MESH:D004938', (115, 143))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
130364	25680115	Human ALDH2 gene is located on chromosome 12q24 and the polymorphisms of ALDH2 gene would affect the blood acetaldehyde concentrations after alcohol consumption.	('ALDH2', 'Gene', '217', (6, 11))	('affect', 'Reg', (90, 96))	('ALDH2', 'Gene', (73, 78))	('Human', 'Species', '9606', (0, 5))	('blood acetaldehyde', 'Phenotype', 'HP:0003533', (101, 119))	('blood acetaldehyde concentrations', 'MPA', (101, 134))	('ALDH2', 'Gene', (6, 11))	('ALDH2', 'Gene', '217', (73, 78))	('alcohol', 'Chemical', 'MESH:D000438', (141, 148))	('acetaldehyde', 'Chemical', 'MESH:D000079', (107, 119))	('polymorphisms', 'Var', (56, 69))	('blood acetaldehyde concentrations', 'Phenotype', 'HP:0003533', (101, 134))
130365	25680115	The Glu504Lys polymorphism (also named Glu487Lys, or rs671 has been the most commonly studied.	('Glu504Lys', 'Var', (4, 13))	('Glu487Lys', 'Var', (39, 48))	('rs671', 'Var', (53, 58))	('Glu504Lys', 'SUBSTITUTION', 'None', (4, 13))	('Glu487Lys', 'SUBSTITUTION', 'None', (39, 48))	('rs671', 'Mutation', 'rs671', (53, 58))
130367	25680115	Such a polymorphism (Glu to Lys, or G to A, or *1 to *2) was reported to have decreased activity of ALDH2 enzyme and cause much higher blood levels of acetaldehyde, which is highly prevalent among East Asians.	('Glu', 'Chemical', 'MESH:D018698', (21, 24))	('Lys', 'Chemical', 'MESH:D008239', (28, 31))	('Glu to Lys', 'Var', (21, 31))	('ALDH2', 'Gene', '217', (100, 105))	('activity', 'MPA', (88, 96))	('G to A', 'Var', (36, 42))	('acetaldehyde', 'Chemical', 'MESH:D000079', (151, 163))	('higher blood levels of acetaldehyde', 'Phenotype', 'HP:0003533', (128, 163))	('cause', 'Reg', (117, 122))	('ALDH2', 'Gene', (100, 105))	('decreased', 'NegReg', (78, 87))	('blood levels of acetaldehyde', 'MPA', (135, 163))	('higher', 'PosReg', (128, 134))
130368	25680115	Therefore, it is hypothesized that the genetic polymorphism in ALDH2 gene may be strongly correlated with the susceptibility to cancer, and a number of studies have investigated the association between ALDH2 Glu504Lys polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('Glu504Lys', 'Var', (208, 217))	('ALDH2', 'Gene', '217', (63, 68))	('Glu504Lys', 'SUBSTITUTION', 'None', (208, 217))	('correlated', 'Reg', (90, 100))	('association', 'Interaction', (182, 193))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('ALDH2', 'Gene', '217', (202, 207))	('ALDH2', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ALDH2', 'Gene', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Disease', (128, 134))
130370	25680115	In a meta-analysis by Yang et al, ALDH2 504Lys allele was found to increase the risk of esophageal cancer at all levels of exposure to ethanol and acetaldehyde after drinking.	('504Lys', 'Var', (40, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('ALDH2', 'Gene', '217', (34, 39))	('acetaldehyde', 'Chemical', 'MESH:D000079', (147, 159))	('ethanol', 'Chemical', 'MESH:D000431', (135, 142))	('increase', 'PosReg', (67, 75))	('ALDH2', 'Gene', (34, 39))	('Lys', 'Chemical', 'MESH:D008239', (43, 46))	('esophageal cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
130371	25680115	On contrary, another meta-analysis by Zhao et al showed reduced risk for colorectal cancer associated with ALDH2 504lys allele carriers.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('reduced', 'NegReg', (56, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('ALDH2', 'Gene', '217', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('504lys', 'Var', (113, 119))	('colorectal cancer', 'Disease', (73, 90))	('ALDH2', 'Gene', (107, 112))
130372	25680115	Considering the contradictory results of the previous studies on ALDH2 Glu504Lys polymorphism with different cancers, we conducted the present meta-analysis to evaluate the relation of ALDH2 Glu504Lys polymorphism with the overall cancer risk.	('Glu504Lys', 'Var', (191, 200))	('ALDH2', 'Gene', '217', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Glu504Lys', 'Var', (71, 80))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('Glu504Lys', 'SUBSTITUTION', 'None', (71, 80))	('Glu504Lys', 'SUBSTITUTION', 'None', (191, 200))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (231, 237))	('cancers', 'Disease', (109, 116))	('cancer', 'Disease', (109, 115))	('ALDH2', 'Gene', (185, 190))	('ALDH2', 'Gene', '217', (65, 70))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('ALDH2', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
130376	25680115	Studies that we identified were required to meet the following criteria: (1) study on the evaluation of the ALDH2 Glu504Lys polymorphism and cancer risk; (2) case-control study that used either population- or hospital-based designs; (3) study that contained complete information about all genotype frequency.	('Glu504Lys', 'SUBSTITUTION', 'None', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('ALDH2', 'Gene', '217', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('Glu504Lys', 'Var', (114, 123))	('ALDH2', 'Gene', (108, 113))
130379	25680115	Before estimating the relationship between the ALDH2 Glu504Lys polymorphism and cancer risk, we tested whether the genotype frequencies of the controls were in Hardy-Weinberg equilibrium (HWE) using a chi 2 test (P>0.05).	('Glu504Lys', 'Var', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Glu504Lys', 'SUBSTITUTION', 'None', (53, 62))	('ALDH2', 'Gene', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))	('ALDH2', 'Gene', '217', (47, 52))
130380	25680115	The strength of the association between the ALDH2 Glu504Lys polymorphism and cancer risk was measured by odds ratios (ORs) with their 95% confidence intervals (95%CI).	('Glu504Lys', 'SUBSTITUTION', 'None', (50, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('ALDH2', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Glu504Lys', 'Var', (50, 59))	('ALDH2', 'Gene', '217', (44, 49))
130383	25680115	In the genotypic model, the comparison of Lys+ with Glu/Glu genotype generated a significant 20% increased cancer risk (OR = 1.20, 95%CI: 1.03-1.39, P = 0.02, I2 = 92%; Table 2, Fig.	('increased', 'PosReg', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Glu', 'Chemical', 'MESH:D018698', (56, 59))	('Glu', 'Chemical', 'MESH:D018698', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Lys+', 'Chemical', 'MESH:D008239', (42, 46))	('cancer', 'Disease', (107, 113))	('Lys+', 'Var', (42, 46))
130384	25680115	However, in the allelic model, comparison of Lys with Glu allele generated a non-significant 3% increased cancer risk (OR = 1.03, 95%CI: 0.94-1.13, P = 0.52, I2 = 86%; Table 2).	('Lys', 'Chemical', 'MESH:D008239', (45, 48))	('increased', 'PosReg', (96, 105))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('Lys', 'Var', (45, 48))	('Glu', 'Chemical', 'MESH:D018698', (54, 57))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
130386	25680115	A significantly increased risk of UADT cancer (OR = 1.39, 95%CI: 1.11-1.73, P = 0.004, I2 = 94%; Table 2) was observed in individuals with the Lys+ genotypes.	('UADT cancer', 'Disease', 'MESH:D006258', (34, 45))	('Lys+', 'Chemical', 'MESH:D008239', (143, 147))	('UADT cancer', 'Disease', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Lys+', 'Var', (143, 147))
130388	25680115	The results indicated that individuals with the variant allele (504Lys) significantly increased 52% risk of esophageal cancer (OR = 1.52, 95%CI: 1.12-2.08, P = 0.008, I2 = 96%; Fig.	('504Lys', 'Var', (64, 70))	('Lys', 'Chemical', 'MESH:D008239', (67, 70))	('esophageal cancer', 'Disease', (108, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
130392	25680115	We found individuals from Japan with the Lys+ genotypes had a significant 38% increased cancer risk (OR = 1.38, 95%CI: 1.12-1.71, P = 0.003, I2 = 93%; Table 2).	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Lys+', 'Chemical', 'MESH:D008239', (41, 45))	('Lys+', 'Var', (41, 45))
130396	25680115	Then we performed subgroup analysis based on cancer type, country, study design and sample size and assessed the source of heterogeneity for genetic model comparison (Lys+ vs Glu/Glu).	('Glu', 'Chemical', 'MESH:D018698', (179, 182))	('Glu/Glu', 'Var', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Lys+', 'Chemical', 'MESH:D008239', (167, 171))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('Lys+', 'Var', (167, 171))	('cancer', 'Disease', (45, 51))	('Glu', 'Chemical', 'MESH:D018698', (175, 178))
130400	25680115	To our knowledge, this is the first meta-analysis to evaluate the association between the Glu504Lys polymorphism of ALDH2 gene and the overall cancer risk.	('Glu504Lys', 'SUBSTITUTION', 'None', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('ALDH2', 'Gene', (116, 121))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('Glu504Lys', 'Var', (90, 99))	('ALDH2', 'Gene', '217', (116, 121))
130401	25680115	Our study suggests that individuals with the variant allele (504Lys) appear to be associated with an increased risk of cancer.	('504Lys', 'Var', (61, 67))	('associated', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('Lys', 'Chemical', 'MESH:D008239', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
130402	25680115	Due to the prevalent of ALDH2 polymorphism in approximately half of East Asians but absent in Europeans and Africans and possibility of population admixture that may potentially elevate type I error rate of association studies and lead to inconsistent results, we further excluded mixed populations and restricted analyses to Asians.	('ALDH2', 'Gene', (24, 29))	('elevate', 'PosReg', (178, 185))	('polymorphism', 'Var', (30, 42))	('ALDH2', 'Gene', '217', (24, 29))
130404	25680115	McKay et al reported the increased UADT cancer risk with the minor allele of rs4767364 in Europeans, which is similar to the UADT cancer risk effect observed for heterozygote rs671 carriers in Asians.	('UADT cancer', 'Disease', (125, 136))	('rs4767364', 'Var', (77, 86))	('rs671', 'Mutation', 'rs671', (175, 180))	('rs4767364', 'Mutation', 'rs4767364', (77, 86))	('UADT cancer', 'Disease', 'MESH:D006258', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('UADT cancer', 'Disease', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('UADT cancer', 'Disease', 'MESH:D006258', (125, 136))
130405	25680115	Their results implicated the variant at 12q24 in UADT cancer susceptibility.	('UADT cancer', 'Disease', (49, 60))	('variant at', 'Var', (29, 39))	('UADT cancer', 'Disease', 'MESH:D006258', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
130406	25680115	With an elaborative genome-wide gene-environment interaction analysis, Wu et al found that the most significant interaction region was for variants at 12q24 harboring ALDH2 and a joint analysis showed that alcohol drinkers carrying both risk alleles of ALDH2 and ADH1B had the highest risk of ESCC.	('alcohol drinkers', 'Phenotype', 'HP:0030955', (206, 222))	('ADH1B', 'Gene', (263, 268))	('ALDH2', 'Gene', (253, 258))	('ALDH2', 'Gene', (167, 172))	('ADH1B', 'Gene', '125', (263, 268))	('alcohol', 'Chemical', 'MESH:D000438', (206, 213))	('variants', 'Var', (139, 147))	('ALDH2', 'Gene', '217', (253, 258))	('ESCC', 'Disease', (293, 297))	('ALDH2', 'Gene', '217', (167, 172))
130407	25680115	Furthermore, Ioannidis et al provided an overview of GWA-identified genetic associations with solid tumors since 2007 and showed the association between esophageal cancer and genetic variant rs671 with a median odds ratio (OR) of 1.67 (interquartile range = 1.58-1.76).	('rs671', 'Mutation', 'rs671', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('association', 'Interaction', (133, 144))	('solid tumors', 'Disease', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('solid tumors', 'Disease', 'MESH:D009369', (94, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('esophageal cancer', 'Disease', (153, 170))	('rs671', 'Var', (191, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
130408	25680115	The results from these GWA studies and our meta-analysis collectively suggest the importance of ALDH2 polymorphism carrying the susceptibility of cancer risks.	('polymorphism', 'Var', (102, 114))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('ALDH2', 'Gene', '217', (96, 101))	('ALDH2', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
130409	25680115	In the subgroup analysis by cancer type, significantly increased risk of UADT cancer with ALDH2 polymorphism was observed but no significant association was found among studies of other cancers (i.e., colorectal cancer, hepatocellular cancer, breast cancer, lung cancer and pancreatic cancer).	('lung cancer', 'Disease', 'MESH:D008175', (258, 269))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Disease', (263, 269))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (274, 291))	('lung cancer', 'Phenotype', 'HP:0100526', (258, 269))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('ALDH2', 'Gene', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('colorectal cancer', 'Phenotype', 'HP:0003003', (201, 218))	('other cancers', 'Disease', 'MESH:D009369', (180, 193))	('hepatocellular cancer', 'Disease', (220, 241))	('UADT cancer', 'Disease', 'MESH:D006258', (73, 84))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('other cancers', 'Disease', (180, 193))	('cancer', 'Disease', (285, 291))	('pancreatic cancer', 'Disease', 'MESH:D010190', (274, 291))	('breast cancer', 'Disease', (243, 256))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (220, 241))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('polymorphism', 'Var', (96, 108))	('cancer', 'Disease', (78, 84))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (220, 241))	('ALDH2', 'Gene', '217', (90, 95))	('lung cancer', 'Disease', (258, 269))	('cancer', 'Disease', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('pancreatic cancer', 'Disease', (274, 291))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('colorectal cancer', 'Disease', 'MESH:D015179', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (250, 256))	('colorectal cancer', 'Disease', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('UADT cancer', 'Disease', (73, 84))
130410	25680115	In the UADT cancer subgroup, we further performed position-specific analyses and the results showed that individuals with the variant allele (504Lys) significantly increased 52% risk of esophageal cancer, 22% risk of head and neck cancer and 18% risk of gastric cancer.	('Lys', 'Chemical', 'MESH:D008239', (145, 148))	('gastric cancer', 'Phenotype', 'HP:0012126', (254, 268))	('head and neck cancer', 'Phenotype', 'HP:0012288', (217, 237))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('UADT cancer', 'Disease', 'MESH:D006258', (7, 18))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('gastric cancer', 'Disease', (254, 268))	('UADT cancer', 'Disease', (7, 18))	('esophageal cancer', 'Disease', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('head and neck cancer', 'Disease', 'MESH:D006258', (217, 237))	('504Lys', 'Var', (142, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (254, 268))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('increased', 'PosReg', (164, 173))
130411	25680115	Furthermore, when we excluded the studies that were not in HWE or the P HWE values were not available, interestingly, we found the effect of variant allele (504Lys) on colorectal cancer was contrary to that on UADT cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('504Lys', 'Var', (157, 163))	('colorectal cancer', 'Disease', (168, 185))	('Lys', 'Chemical', 'MESH:D008239', (160, 163))	('UADT cancer', 'Disease', 'MESH:D006258', (210, 221))	('UADT cancer', 'Disease', (210, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))
130412	25680115	Recently, Zhao et al had reported a similar result and put forward a possible explanation that the unpleasant symptoms resulting from high blood acetaldehyde levels after alcohol consumption may prevent the individuals with the variant allele (504Lys) from consuming alcohol and may keep them from developing alcoholism thus they have much lower chance to expose to the carcinogen acetaldehyde.	('variant', 'Var', (228, 235))	('alcoholism', 'Disease', (309, 319))	('developing', 'MPA', (298, 308))	('alcohol', 'Chemical', 'MESH:D000438', (309, 316))	('alcoholism', 'Disease', 'MESH:D000437', (309, 319))	('alcoholism', 'Phenotype', 'HP:0030955', (309, 319))	('alcohol', 'Chemical', 'MESH:D000438', (267, 274))	('acetaldehyde', 'Chemical', 'MESH:D000079', (381, 393))	('alcohol', 'Chemical', 'MESH:D000438', (171, 178))	('prevent', 'NegReg', (195, 202))	('keep', 'Reg', (283, 287))	('504Lys', 'Var', (244, 250))	('blood acetaldehyde levels', 'MPA', (139, 164))	('acetaldehyde', 'Chemical', 'MESH:D000079', (145, 157))	('Lys', 'Chemical', 'MESH:D008239', (247, 250))	('blood acetaldehyde', 'Phenotype', 'HP:0003533', (139, 157))
130417	25680115	Oze et al had collected four studies and showed that the Glu504Lys polymorphism had strong effect modification with alcohol drinking and alcohol drinking would increase the risk of esophageal cancer in the Japanese population.	('esophageal cancer', 'Disease', (181, 198))	('Glu504Lys', 'Var', (57, 66))	('Glu504Lys', 'SUBSTITUTION', 'None', (57, 66))	('alcohol drinking', 'Phenotype', 'HP:0030955', (137, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('alcohol', 'Chemical', 'MESH:D000438', (116, 123))	('alcohol drinking', 'Phenotype', 'HP:0030955', (116, 132))	('increase', 'PosReg', (160, 168))	('alcohol', 'Chemical', 'MESH:D000438', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
130424	25680115	In conclusion, this meta-analysis indicated that the Glu504Lys polymorphism of ALDH2 gene is a candidate for susceptibility to overall cancers, especially in esophageal cancer and among Japanese population.	('susceptibility', 'Reg', (109, 123))	('Glu504Lys', 'Var', (53, 62))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('cancers', 'Disease', (135, 142))	('ALDH2', 'Gene', '217', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('Glu504Lys', 'SUBSTITUTION', 'None', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ALDH2', 'Gene', (79, 84))	('esophageal cancer', 'Disease', (158, 175))
130448	20506380	Eligibility was determined using ICD-O codes: C00, C01, C02, C03, C04, C05, C06, C09, C10, C12, C13, C14.0, C14.8, C15.0, C15.3, C15.4, C15.5, C15.8, C15.9, and C32.	('C32', 'Gene', (161, 164))	('C05', 'Var', (71, 74))	('C13', 'Gene', (96, 99))	('C01', 'CellLine', 'CVCL:E303', (51, 54))	('C15', 'Gene', '51316', (115, 118))	('C01', 'Var', (51, 54))	('C10', 'Gene', '113246', (86, 89))	('C10', 'Gene', (86, 89))	('C15', 'Gene', '51316', (129, 132))	('C15', 'Gene', '51316', (122, 125))	('C15', 'Gene', (115, 118))	('C32', 'Gene', '51192', (161, 164))	('C15', 'Gene', (129, 132))	('C13', 'Gene', '3229', (96, 99))	('C14.8', 'Var', (108, 113))	('C15', 'Gene', (122, 125))	('C09', 'Var', (81, 84))	('C02', 'Var', (56, 59))	('C15', 'Gene', '51316', (150, 153))	('C04', 'Var', (66, 69))	('C15', 'Gene', '51316', (136, 139))	('C15', 'Gene', '51316', (143, 146))	('C15.9', 'CellLine', 'CVCL:0H97', (150, 155))	('C06', 'Var', (76, 79))	('C15', 'Gene', (150, 153))	('C15', 'Gene', (143, 146))	('C15', 'Gene', (136, 139))	('C14.0', 'Var', (101, 106))	('C12', 'Var', (91, 94))	('C03', 'Var', (61, 64))
130461	20506380	The models were adjusted for the following variables: center, sex, age (in 5 year intervals), smoking status including pack-years (7 categories: never smoker, former smoker: 0<pack-years<=20, 20<pack-years<=40, or pack-years >=40, current smoker:0<pack-years<=20, 20< pack-years<=40, or pack-years>=40), fruit and vegetable intake (low, medium, and high), education (finished primary school, finished further school, university degree), and alcohol consumption frequency (never, <1drink per day, 1 to 2 drinks/day, 3 to 4 drinks/day, and 5+drinks/day).	('<1drink', 'Var', (479, 486))	('alcohol', 'Chemical', 'MESH:D000438', (441, 448))	('low', 'Var', (332, 335))
130469	20506380	Leanness (13 to 18.4kg/m2) at time of interview and 2 years prior were associated with UADT cancers (OR=1.90; 95% CI=1.28, 2.82 and OR=2.10; 95% CI=1.16, 3.81, respectively).	('Leanness', 'Disease', (0, 8))	('UADT cancers', 'Disease', (87, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('Leanness', 'Disease', 'MESH:D013851', (0, 8))	('13 to 18.4kg/m2', 'Var', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('UADT cancers', 'Disease', 'MESH:D006258', (87, 99))	('associated', 'Reg', (71, 81))
130470	20506380	Whereas, heavier BMIs (25.0 to 29.9 kg/m2 or 30 to 53.0 kg/m2) at 2 years prior to interview was inversely associated with UADT cancers (OR=0.74; 95% CI=0.62, 0.88 and OR=0.74; 95% CI=0.59, 0.93, respectively).	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('UADT cancers', 'Disease', 'MESH:D006258', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('25.0 to 29.9 kg/m2', 'Var', (23, 41))	('UADT cancers', 'Disease', (123, 135))	('inversely', 'NegReg', (97, 106))
130552	24883234	For example, mutations in the RAS-MAPK-ERK and PI3K-Akt-mTOR pathways and SRC can induce higher glucose uptake through modulating glucose transporter expression and translocation.	('modulating', 'Reg', (119, 129))	('mTOR', 'Gene', (56, 60))	('Akt', 'Gene', (52, 55))	('mTOR', 'Gene', '2475', (56, 60))	('RAS-MAPK-ERK', 'Gene', (30, 42))	('glucose transporter expression', 'MPA', (130, 160))	('SRC', 'Gene', '6714', (74, 77))	('SRC', 'Gene', (74, 77))	('translocation', 'MPA', (165, 178))	('glucose', 'Chemical', 'MESH:D005947', (130, 137))	('higher', 'PosReg', (89, 95))	('glucose', 'Chemical', 'MESH:D005947', (96, 103))	('glucose uptake', 'MPA', (96, 110))	('mutations', 'Var', (13, 22))	('Akt', 'Gene', '207', (52, 55))
130608	24883234	Subsequent studies confirmed a high staging accuracy of 18F-FDG PET/CT in non-small-cell lung cancer, breast cancer, esophageal cancer, colorectal cancer, lymphoma, melanoma, cervical cancer, head and neck cancers, bone and soft tissue sarcomas, and myeloma.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('soft tissue sarcomas', 'Disease', (224, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('esophageal cancer', 'Disease', (117, 134))	('head and neck cancers', 'Phenotype', 'HP:0012288', (192, 213))	('lymphoma', 'Disease', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cervical cancer', 'Disease', (175, 190))	('cervical cancer', 'Disease', 'MESH:D002583', (175, 190))	('lymphoma', 'Disease', 'MESH:D008223', (155, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (224, 244))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (224, 243))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (224, 244))	('breast cancer', 'Disease', (102, 115))	('myeloma', 'Disease', (250, 257))	('head and neck cancers', 'Disease', 'MESH:D006258', (192, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('colorectal cancer', 'Disease', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('sarcomas', 'Phenotype', 'HP:0100242', (236, 244))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('lymphoma', 'Phenotype', 'HP:0002665', (155, 163))	('18F-FDG PET/CT', 'Var', (56, 70))	('18F-FDG', 'Chemical', 'MESH:D019788', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('myeloma', 'Disease', 'MESH:D009101', (250, 257))	('non-small-cell lung cancer', 'Disease', (74, 100))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (74, 100))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
130616	24883234	For instance, in 260 patients with Hodgkin's lymphoma, positive PET findings after two cycles of chemotherapy were associated with a 2-year progression-free survival of 13 %, whereas 95 % of patients with negative PET findings were progression free after 2 years.	('patients', 'Species', '9606', (191, 199))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (35, 53))	('patients', 'Species', '9606', (21, 29))	('positive', 'Var', (55, 63))	('lymphoma', 'Phenotype', 'HP:0002665', (45, 53))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (35, 53))	("Hodgkin's lymphoma", 'Disease', (35, 53))
130627	24883234	Moreover, erlotinib increases tumor tissue oxygenation and reduces the tumor uptake of PET hypoxia probes, which may also account for reductions in tumor 18F-FDG uptake in response to treatment.	('18F-FDG', 'Chemical', 'MESH:D019788', (154, 161))	('reduces', 'NegReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('erlotinib', 'Chemical', 'MESH:D000069347', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('erlotinib', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('increases tumor', 'Disease', (20, 35))	('oxygen', 'Chemical', 'MESH:D010100', (43, 49))	('tumor', 'Disease', (71, 76))	('hypoxia', 'Disease', (91, 98))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('reductions', 'NegReg', (134, 144))	('increases tumor', 'Disease', 'MESH:D009369', (20, 35))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))
130649	24883234	As another example, lung cancer patients who were randomized to presurgical workup with PET/CT had a significantly lower number of futile surgical procedures than those who underwent conventional staging.	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('lung cancer', 'Disease', (20, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('lower', 'NegReg', (115, 120))	('PET/CT', 'Var', (88, 94))
130700	17436135	The majority of patients in all groups had pT3 tumors, 48% in the pN0 group compared with 71, 64, and 82% in the N = 1, N = 2-3, and N > 3 groups, respectively (p < 0.05).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('pN0', 'Var', (66, 69))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
130743	33670587	Using an in vivo mouse model, we recently demonstrated that conjugated bile at a strongly acidic pH of 3.0 caused invasive squamous cell carcinoma in exposed hypopharyngeal mucosa (HM).	('invasive squamous cell carcinoma', 'Disease', (114, 146))	('caused', 'Reg', (107, 113))	('mouse', 'Species', '10090', (17, 22))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 146))	('HM', 'Chemical', '-', (181, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('pH', 'Gene', '5053', (97, 99))	('conjugated', 'Var', (60, 70))
130763	33670587	Using AQUA, scoring for Ki67 and CK14 revealed significantly higher expression levels of these epithelial cell proliferation markers in bile treated-HM compared to controls (Figure 2B(a,b)) (p < 0.05, t-test; means+-SD; multiple comparisons by Holm-Sidak).	('Ki67', 'Gene', '17345', (24, 28))	('higher', 'PosReg', (61, 67))	('CK14', 'Gene', (33, 37))	('HM', 'Chemical', '-', (149, 151))	('CK14', 'Gene', '16664', (33, 37))	('Ki67', 'Gene', (24, 28))	('expression levels', 'MPA', (68, 85))	('bile treated-HM', 'Var', (136, 151))
130764	33670587	To explore if chronic weakly acidic bile exposure can cause DNA oxidative damage and double-strand breaks (DSBs) in murine HM, we performed IHC analysis using DNA/RNA oxidative damage markers (oxo8dG, 8-hydroxy-20 -deoxyguanosine; oxo8Gua, 8-oxo-7,8-dihydroguanine; and oxo8G, 8-oxo-7,8-dihydroguanosine), and gammaH2Ax, a specific marker for DSBs.	('oxo8G', 'Chemical', 'MESH:C046215', (231, 236))	('8-oxo-7,8-dihydroguanine', 'Chemical', 'MESH:C024829', (240, 264))	('HM', 'Chemical', '-', (123, 125))	('murine', 'Species', '10090', (116, 122))	('oxo8G', 'Chemical', 'MESH:C046215', (270, 275))	('oxo8Gua', 'Chemical', 'MESH:C024829', (231, 238))	('8-hydroxy-20 -deoxyguanosine', 'MPA', (201, 229))	('oxo8dG', 'Chemical', '-', (193, 199))	('DSBs', 'Chemical', '-', (343, 347))	('8-hydroxy-20 -deoxyguanosine', 'Chemical', '-', (201, 229))	('gammaH2Ax', 'Gene', '15270', (310, 319))	('8-oxo-7,8-dihydroguanosine', 'Chemical', 'MESH:C046215', (277, 303))	('oxo8G', 'Var', (270, 275))	('gammaH2Ax', 'Gene', (310, 319))	('oxo8Gua', 'MPA', (231, 238))	('DSBs', 'Chemical', '-', (107, 111))
130775	33670587	To detect if chronic weakly acidic bile exposure can enhance p53 expression in murine HM, we performed IHC analysis for p53 (detecting either mutant or wild form) and analyzed its expression levels relative to controls.	('HM', 'Chemical', '-', (86, 88))	('mutant', 'Var', (142, 148))	('p53', 'Gene', '22059', (61, 64))	('expression', 'MPA', (65, 75))	('enhance', 'PosReg', (53, 60))	('p53', 'Gene', (61, 64))	('p53', 'Gene', (120, 123))	('murine', 'Species', '10090', (79, 85))	('p53', 'Gene', '22059', (120, 123))
130796	33670587	We have previously showed that DCA alone can produce a significant activation of NF-kappaB and promote preneoplastic lesions in murine laryngopharyngeal mucosa.	('preneoplastic lesions', 'CPA', (103, 124))	('murine', 'Species', '10090', (128, 134))	('promote', 'PosReg', (95, 102))	('activation', 'PosReg', (67, 77))	('DCA', 'Var', (31, 34))	('DCA', 'Chemical', 'MESH:D003840', (31, 34))	('NF-kappaB', 'Protein', (81, 90))
130808	33670587	We further provide evidence that the presence of DCA in bile refluxate accelerates the upregulation of NF-kappaB related oncogenic factors (Figure 4A) and induce premalignant squamous epithelial lesions and microinvasion in murine hypopharynx.	('premalignant squamous epithelial lesions', 'Disease', (162, 202))	('NF-kappaB', 'Protein', (103, 112))	('DCA', 'Chemical', 'MESH:D003840', (49, 52))	('bile refluxate', 'Phenotype', 'HP:0000076', (56, 70))	('DCA', 'Var', (49, 52))	('presence', 'Var', (37, 45))	('induce', 'PosReg', (155, 161))	('murine', 'Species', '10090', (224, 230))	('microinvasion', 'CPA', (207, 220))	('premalignant squamous epithelial lesions', 'Disease', 'MESH:D000081483', (162, 202))	('accelerates', 'PosReg', (71, 82))	('upregulation', 'PosReg', (87, 99))
130813	33670587	So, although in normal tissue p53 is expressed at low levels, its abundant expression (of mutant or wild p53 form) may have a role in the neoplastic process.	('neoplastic process', 'CPA', (138, 156))	('mutant', 'Var', (90, 96))	('neoplastic process', 'Phenotype', 'HP:0002664', (138, 156))	('p53', 'Gene', (105, 108))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '22059', (105, 108))	('p53', 'Gene', '22059', (30, 33))	('role', 'Reg', (126, 130))	('expression', 'MPA', (75, 85))
130815	33670587	Identifying and characterizing weakly acidic bile fluid as an independent risk factor in head and neck malignancies would be considered novel.	('neck malignancies', 'Disease', 'MESH:D006258', (98, 115))	('neck malignancies', 'Disease', (98, 115))	('head and neck malignancies', 'Phenotype', 'HP:0012288', (89, 115))	('weakly acidic', 'Var', (31, 44))
130833	33670587	For fluorescence staining we used anti-rabbit or anti-mouse secondary DyLight 488 (green), DyLight 549 (red) for target proteins and DAPI (blue) to distinguish positive nuclei (DyLight 488 and DyLight 549; Vector Labs, USA).	('mouse', 'Species', '10090', (54, 59))	('DyLight 488', 'Var', (177, 188))	('DyLight 549', 'Var', (193, 204))
130839	33670587	We provide in vivo evidence that bile at a weakly acidic pH, similar to bile at a strongly acidic pH, is capable of inducing DNA damage, NF-kappaB-mediated antiapoptotic function, and histologic changes consistent with a premalignant phenotype.	('DNA damage', 'MPA', (125, 135))	('bile', 'Var', (33, 37))	('pH', 'Gene', '5053', (98, 100))	('NF-kappaB-mediated', 'Protein', (137, 155))	('inducing', 'PosReg', (116, 124))	('pH', 'Gene', '5053', (57, 59))
130881	32957725	Nevertheless, several such mutations have been generated in laboratory conditions and the number of mutations identified in Erks has dramatically increased following the development of Erk-specific pharmacological inhibitors and the identification of mutations that cause resistance to these compounds.	('mutations', 'Var', (100, 109))	('mutations', 'Var', (251, 260))	('cause', 'Reg', (266, 271))	('Erk', 'Gene', (124, 127))	('increased', 'PosReg', (146, 155))	('Erk', 'Gene', '5594', (185, 188))	('Erk', 'Gene', '5594', (124, 127))	('resistance', 'MPA', (272, 282))	('Erk', 'Gene', (185, 188))
130882	32957725	Several Erk mutations have also been recently found in cancer patients.	('Erk', 'Gene', (8, 11))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Erk', 'Gene', '5594', (8, 11))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('patients', 'Species', '9606', (62, 70))	('cancer', 'Disease', (55, 61))	('found', 'Reg', (46, 51))
130883	32957725	summarize the impressive number of mutations identified in Erks so far, describe their properties, and discuss their possible mechanism of action.	('Erk', 'Gene', '5594', (59, 62))	('Erk', 'Gene', (59, 62))	('mutations', 'Var', (35, 44))
130885	32957725	In future precision medicine, Erk1 mutations that cause drug resistance could already be taken into consideration when a therapeutic strategy is planned, and then specific drugs could be applied according to the mutation that appears in the tumor.	('tumor', 'Disease', (241, 246))	('drug resistance', 'Phenotype', 'HP:0020174', (56, 71))	('Erk1', 'Gene', '5595', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('Erk1', 'Gene', (30, 34))	('mutations', 'Var', (35, 44))
130894	32957725	has identified ATP6V0a3 (one of the six V0 transmembrane subunits) as a negative regulator of migration and invasion of pancreatic ductal adenocarcinoma cells, where a3 is mainly found in lysosomal membranes and consistent with its mainly lysosomal role, a3 knockdown does not decrease net acid extrusion.	('ATP6V0a3', 'Gene', '10312', (15, 23))	('net acid extrusion', 'MPA', (286, 304))	('migration', 'CPA', (94, 103))	('ATP6V0a3', 'Gene', (15, 23))	('pancreatic ductal adenocarcinoma', 'Disease', (120, 152))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (120, 152))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (120, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('knockdown', 'Var', (258, 267))
130902	32957725	It is also a kinase that can activate MZF1 by phosphorylating it in response to ErbB2 activation.	('ErbB2', 'Gene', '2064', (80, 85))	('MZF1', 'Gene', (38, 42))	('ErbB2', 'Gene', (80, 85))	('MZF1', 'Gene', '7593', (38, 42))	('activation', 'PosReg', (86, 96))	('phosphorylating', 'Var', (46, 61))
130921	32957725	Its expression is increased in cancer progression and it is connected to the increased expression of WNT and STAT3 targets cluster of differentiation 44 (CD44) and tyrosine 705 phosphorylated STAT3 (pYSTAT3) in esophageal cancer.	('STAT3', 'Gene', '6774', (201, 206))	('expression', 'MPA', (4, 14))	('STAT3', 'Gene', '6774', (192, 197))	('increased', 'PosReg', (77, 86))	('CD44', 'Gene', (154, 158))	('cancer', 'Disease', (222, 228))	('tyrosine 705', 'Var', (164, 176))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (31, 37))	('STAT3', 'Gene', (109, 114))	('tyrosine', 'Chemical', 'MESH:D014443', (164, 172))	('increased', 'PosReg', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('expression', 'MPA', (87, 97))	('STAT3', 'Gene', '6774', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('STAT3', 'Gene', (201, 206))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('STAT3', 'Gene', (192, 197))
130923	32957725	The Danish Cancer Society Scientific Committee (KBVU) (R124-A7854-15-S2 and R56-A3108-12-S2), Novo Nordisk Foundation (NNF15OC0017324) and the Danish National Research Foundation (DNRF125).	('R56-A3108-12-S2', 'Var', (76, 91))	('Cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Cancer', 'Disease', (11, 17))	('R124-A7854-15-S2', 'Var', (55, 71))	('Cancer', 'Disease', 'MESH:D009369', (11, 17))	('R56-A3108-12-S2', 'CellLine', 'CVCL:9N76', (76, 91))
131069	31031862	All cases of esophageal carcinomas had tumor site codes (C15.0-C15.9) and ICD-9 codes and were diagnosed between 2004 and 2014.	('esophageal carcinomas', 'Disease', (13, 34))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (13, 34))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (13, 33))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (13, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('C15.0-C15.9', 'Var', (57, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
131071	31031862	These codes corresponded to the following clinical/histological diagnoses: NEC (8013, 8041 and 8246); SCC (8051, 8070, 8074, 8077, 8083, and 8560); and AC (8140, 8148, 8200, 8244, and 8430).	('8244', 'Var', (174, 178))	('8013', 'Var', (80, 84))	('8430', 'Var', (184, 188))	('SCC', 'Gene', '6317', (102, 105))	('NEC', 'Disease', (75, 78))	('SCC', 'Gene', (102, 105))	('8074', 'Var', (119, 123))	('8560', 'Var', (141, 145))	('8083', 'Var', (131, 135))	('8051', 'Var', (107, 111))	('8200', 'Var', (168, 172))	('8077', 'Var', (125, 129))	('8140', 'Var', (156, 160))
131099	31031862	With the exception of metastasis to the brain, SCC metastasis to the liver, lung and bone increased the risk of death.	('death', 'Disease', 'MESH:D003643', (112, 117))	('death', 'Disease', (112, 117))	('SCC', 'Gene', '6317', (47, 50))	('metastasis', 'Var', (51, 61))	('bone increased', 'Phenotype', 'HP:0100774', (85, 99))	('SCC', 'Gene', (47, 50))
131177	24982207	Kaplan-Meier survival curves were plotted for each of the four treatment groups (namely, unirradiated control group; 19 Gy upper body irradiation only; F15 intraesophageal administration prior to irradiation; and intraesophageal JP4-039/F15 prior to irradiation).	('JP4', 'Gene', (229, 232))	('F15', 'Var', (152, 155))	('JP4', 'Gene', '319984', (229, 232))	('intraesophageal', 'Var', (213, 228))
131204	24982207	There were no differences in lung morphology detected in the JP4-039/F15-or F15-treated groups when compared to the irradiated control group.	('F15-treated', 'Var', (76, 87))	('JP4', 'Gene', (61, 64))	('JP4', 'Gene', '319984', (61, 64))
131213	24982207	The results suggest caution in using this CRE-recombinase-induced transgenic lung cancer model for studies of the therapy of aggressive rather than limitedstage lung cancers and suggest the need for use of another model, which includes a mutant p53 allele.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('lung cancers', 'Disease', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('transgenic lung cancer', 'Disease', 'MESH:D008175', (66, 88))	('lung cancers', 'Disease', 'MESH:D008175', (161, 173))	('p53', 'Gene', (245, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('mutant', 'Var', (238, 244))	('lung cancers', 'Phenotype', 'HP:0100526', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('transgenic lung cancer', 'Disease', (66, 88))	('p53', 'Gene', '22060', (245, 248))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
131245	30407355	1) identified a stricture in the middle of the esophagus.	('middle', 'Disease', 'MESH:D020244', (33, 39))	('middle', 'Disease', (33, 39))	('stricture', 'Var', (16, 25))
131249	30407355	Immunohistochemical results were as follows: AE1/AE3 (+), CD138 (-), Ki-67 (index 40%), S-100 (-), SMA (-), P53 (-), ER (80%).	('S-100', 'Var', (88, 93))	('CD138', 'Gene', (58, 63))	('AE1', 'Gene', '6521', (45, 48))	('AE3', 'Gene', (49, 52))	('Ki-67', 'Var', (69, 74))	('AE1', 'Gene', (45, 48))	('P53', 'Gene', '7157', (108, 111))	('AE3', 'Gene', '6508', (49, 52))	('P53', 'Gene', (108, 111))	('CD138', 'Gene', '6382', (58, 63))	('SMA', 'Gene', '6606', (99, 102))	('SMA', 'Gene', (99, 102))
131289	30407355	In conclusion, to our knowledge, we report the first case of metastatic breast cancer to the esophagus initially presented with dysphagia.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('dysphagia', 'Disease', (128, 137))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('dysphagia', 'Phenotype', 'HP:0002015', (128, 137))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('dysphagia', 'Disease', 'MESH:D003680', (128, 137))	('metastatic', 'Var', (61, 71))
131300	29348864	Of the tumor cell pool, beneficial mutations conferring a selective advantage on the cell may arise, followed by a successive wave of clonal expansion.	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('mutations', 'Var', (35, 44))	('tumor', 'Disease', (7, 12))
131306	29348864	WGD event was inferred to occur both before and after other copy-number alterations (CNAs) across various cancer types.	('copy-number alterations', 'Var', (60, 83))	('GD', 'Chemical', '-', (1, 3))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
131308	29348864	Copy number losses that occur on the background of a diploid genome before GD will result in loss of heterozygosity (LOH) whereby one of the parental alleles is lost.	('loss', 'NegReg', (93, 97))	('lost', 'NegReg', (161, 165))	('losses', 'NegReg', (12, 18))	('GD', 'Chemical', '-', (75, 77))	('heterozygosity', 'MPA', (101, 115))	('Copy number', 'Var', (0, 11))
131312	29348864	Previously, we have reported the role of APOBEC family of cytidinedeamiases in mutagenesis and identified its connection with hotspot mutations of PIK3CA in ESCC.	('connection', 'Reg', (110, 120))	('hotspot', 'PosReg', (126, 133))	('mutagenesis', 'MPA', (79, 90))	('PIK3CA', 'Gene', (147, 153))	('ESCC', 'Disease', (157, 161))	('PIK3CA', 'Gene', '5290', (147, 153))	('mutations', 'Var', (134, 143))
131313	29348864	In addition, a Japanese ESCC study displays an association of APOBEC signature with ZNF750 mutations.	('ZNF750', 'Gene', '79755', (84, 90))	('mutations', 'Var', (91, 100))	('APOBEC signature', 'Gene', (62, 78))	('ZNF750', 'Gene', (84, 90))	('association', 'Interaction', (47, 58))
131314	29348864	Assuredly, the signatures of genomic instability could be extended to genomic aberrations, for example, allelic imbalance at telomere is a marker for deficient homologous recombination repair, and it is also predictive of benefit from DNA damaging in breast and ovarian cancers.	('deficient', 'NegReg', (150, 159))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (251, 277))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('homologous recombination repair', 'MPA', (160, 191))	('ovarian cancers', 'Phenotype', 'HP:0100615', (262, 277))	('imbalance', 'Phenotype', 'HP:0002172', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('allelic imbalance at', 'Var', (104, 124))	('benefit', 'PosReg', (222, 229))
131315	29348864	In ESCC, through whole-genome analyses, we observed diverse models of genomic signatures including breakage-fusion-bridge (BFB), chromothripsis and kategsis, which frequently lead to oncogene amplifications such as CCND1 and FGFR1.	('FGFR1', 'Gene', '2260', (225, 230))	('chromothripsis', 'Disease', 'MESH:D000072837', (129, 143))	('amplifications', 'Var', (192, 206))	('kategsis', 'Disease', (148, 156))	('BFB', 'Chemical', '-', (123, 126))	('oncogene', 'MPA', (183, 191))	('CCND1', 'Gene', (215, 220))	('lead to', 'Reg', (175, 182))	('chromothripsis', 'Disease', (129, 143))	('FGFR1', 'Gene', (225, 230))	('CCND1', 'Gene', '595', (215, 220))	('breakage-fusion-bridge', 'Disease', (99, 121))
131317	29348864	Given the complexity of cancer genome that consists of genomic changes from point mutation to larger-scale copy number alteration or WGD, characterization of the potential genomic signatures and their mutational ordering may provide useful insights into the ESCC genome evolution.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('copy number alteration', 'Var', (107, 129))	('GD', 'Chemical', '-', (134, 136))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('point mutation', 'Var', (76, 90))
131322	29348864	Conversely, largely copy number alterations (CNAs) were observed in almost all of esophageal carcinoma (ESCA) and frequent copy-number changes were not clustered in specific chromosome (Figure 1A).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('observed', 'Reg', (56, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (82, 102))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (82, 102))	('ESCA', 'Phenotype', 'HP:0011459', (104, 108))	('copy number alterations', 'Var', (20, 43))	('esophageal carcinoma', 'Disease', (82, 102))
131339	29348864	Region 9p21.3 contained three genes (CDKN2A, CDKN2B, MTAP) known to be inactivated by homozygous deletion (Figure 2C).	('CDKN2A', 'Gene', (37, 43))	('CDKN2A', 'Gene', '1029', (37, 43))	('MTAP', 'Gene', (53, 57))	('MTAP', 'Gene', '4507', (53, 57))	('CDKN2B', 'Gene', (45, 51))	('deletion', 'Var', (97, 105))	('CDKN2B', 'Gene', '1030', (45, 51))
131340	29348864	Importantly, copy-number analyses verified the deletion of CDKN2A and immunohischemistry (IHC) staining in tissue-microarray containing 36 atypical hyperplasia tissues and 72 of ESCC tumors confirmed the loss of expression of p16INK4A (Figure 2D-2F), indicating that CDKN2A depletion may be a potential biomarker for early detection of ESCC.	('CDKN2A', 'Gene', (267, 273))	('ESCC tumors', 'Disease', (178, 189))	('hyperplasia', 'Disease', (148, 159))	('ESCC', 'Disease', (336, 340))	('CDKN2A', 'Gene', '1029', (267, 273))	('expression', 'MPA', (212, 222))	('loss', 'NegReg', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('p16INK4A', 'Gene', (226, 234))	('ESCC tumors', 'Disease', 'MESH:D004938', (178, 189))	('hyperplasia', 'Disease', 'MESH:D006965', (148, 159))	('deletion', 'Var', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('CDKN2A', 'Gene', (59, 65))	('p16INK4A', 'Gene', '1029', (226, 234))	('CDKN2A', 'Gene', '1029', (59, 65))
131342	29348864	In parallel, we verified the amplifications of these candidate genes and the over-expression of these proteins in 36 of atypical hyperplasia tissues and 72 of ESCC tumors (Figure 2D-2F).	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('over-expression', 'PosReg', (77, 92))	('ESCC tumors', 'Disease', (159, 170))	('hyperplasia', 'Disease', (129, 140))	('ESCC tumors', 'Disease', 'MESH:D004938', (159, 170))	('amplifications', 'Var', (29, 43))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('hyperplasia', 'Disease', 'MESH:D006965', (129, 140))
131351	29348864	It is particularly strong that heterozygosity of chromosome 9p and 17p was loss in 16 out of 17 GD tumors (94%) and in 11 out of 17 GD tumors (65%), as well as chromosome 5q (47%), 9q (88%), 13q (76%), 3p (82%), respectively, suggesting that deletion on chromosomes 3p, 5q, 9p, 9q, 13q and 17p occurred before GD events during the development of ESCC.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('GD tumors', 'Disease', 'MESH:D005776', (96, 105))	('deletion', 'Var', (242, 250))	('GD tumors', 'Disease', (96, 105))	('GD', 'Chemical', '-', (132, 134))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('GD tumors', 'Disease', (132, 141))	('GD tumors', 'Disease', 'MESH:D005776', (132, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('loss', 'NegReg', (75, 79))	('GD', 'Chemical', '-', (96, 98))	('GD', 'Chemical', '-', (310, 312))
131353	29348864	These results suggest that an abundance of combinations of deletions involving suppressor genes may play an important role in the tumorigenesis of ESCC.	('deletions', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('ESCC', 'Disease', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('play', 'Reg', (100, 104))	('tumor', 'Disease', (130, 135))
131361	29348864	Of note, telomere-bounded deletion of 11q not only leads to the BFB cycles that cause high-level amplification of CCND1 but also deletion of TSGs (e.g.	('CCND1', 'Gene', (114, 119))	('deletion', 'Var', (26, 34))	('deletion', 'Var', (129, 137))	('CCND1', 'Gene', '595', (114, 119))	('leads', 'Reg', (51, 56))	('high-level amplification', 'MPA', (86, 110))	('TSGs', 'Gene', (141, 145))	('BFB', 'Chemical', '-', (64, 67))
131362	29348864	FAT3) (Supplementary Figure 4B), suggesting the dual role of telomere-bounded deletion in tumorigenesis of ESCC.	('FAT3', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('deletion', 'Var', (78, 86))	('tumor', 'Disease', (90, 95))	('FAT3', 'Gene', '120114', (0, 4))	('ESCC', 'Disease', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
131364	29348864	In our data, nearly all of SOX2 amplifications were TCNA, which could be further validated in a Japanese ESCC cohort.	('amplifications', 'Var', (32, 46))	('SOX2', 'Gene', (27, 31))	('SOX2', 'Gene', '6657', (27, 31))	('TCNA', 'Disease', (52, 56))
131369	29348864	First, the homozygous deletion of CDKN2A and TP53 mutations were the most common alterations in ESCC cohort regardless of GD events.	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('GD', 'Chemical', '-', (122, 124))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('ESCC', 'Disease', (96, 100))	('common', 'Reg', (74, 80))	('TP53', 'Gene', '7157', (45, 49))
131370	29348864	There were 15 ESCCs having homozygous CDKN2A (9p21.3) deletion and 5 tumors harboring NLOH or deletion of chr9p (Supplementary Figure 6A, left panel).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('chr9p', 'Gene', (106, 111))	('deletion', 'Var', (94, 102))	('deletion', 'Var', (54, 62))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('CDKN2A', 'Gene', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('CDKN2A', 'Gene', '1029', (38, 44))	('NLOH', 'Chemical', '-', (86, 90))
131371	29348864	In the 15 tumors with TP53 mutations, 11 tumors have mutations at least two alleles, which suggest that TP53 mutation precedes its amplification (Supplementary Figure 6A, right panel).	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('15 tumors', 'Disease', 'MESH:C567447', (7, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('15 tumors', 'Disease', (7, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
131372	29348864	High proportion of homozygous CDKN2A loss and TP53 mutation also support that both of them tend to occur before the amplification.	('CDKN2A', 'Gene', (30, 36))	('TP53', 'Gene', '7157', (46, 50))	('CDKN2A', 'Gene', '1029', (30, 36))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('loss', 'NegReg', (37, 41))
131375	29348864	The most frequent arm of NLOH is chr17p, which account for more than half of samples (Supplementary Figure 6B), further supporting TP53 mutations is an early event in most of ESCCs.	('TP53', 'Gene', (131, 135))	('NLOH', 'Chemical', '-', (25, 29))	('mutations', 'Var', (136, 145))	('TP53', 'Gene', '7157', (131, 135))
131378	29348864	Altogether, these results implied a consensus path of ESCC evolution, beginning with the CDKN2A/TP53 mutations, followed by NLOH, and ultimately, some of them suffer GD (Figure 5B and Supplementary Figure 6D).	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (96, 100))	('ESCC', 'Disease', (54, 58))	('GD', 'Chemical', '-', (166, 168))	('CDKN2A', 'Gene', (89, 95))	('CDKN2A', 'Gene', '1029', (89, 95))	('suffer', 'Reg', (159, 165))	('NLOH', 'Chemical', '-', (124, 128))	('TP53', 'Gene', '7157', (96, 100))
131379	29348864	Specially, we found the coexistence of clonal and subclonal mutations for TP53 gene in case ESCC-315T and ESCC-260T.	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('ESCC-260T', 'Var', (106, 115))	('ESCC-315T', 'Var', (92, 101))
131383	29348864	Moreover, the high rate of NLOH suggests that epigenetic abnormalities of many particular genes might be involved in the development and progression of ESCC.	('NLOH', 'Chemical', '-', (27, 31))	('involved', 'Reg', (105, 113))	('epigenetic abnormalities', 'Var', (46, 70))	('ESCC', 'Disease', (152, 156))
131387	29348864	Unlike colorectal cancers in that GD is an early event, we found, in the majority of ESCC tumors, GD likely occurred as a relatively late event, after CDKN2A/TP53 mutations and NLOH, suggesting that CIN occurs before GD in ESCC evolution.	('TP53', 'Gene', (158, 162))	('colorectal cancers', 'Disease', (7, 25))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('CIN', 'Phenotype', 'HP:0040012', (199, 202))	('ESCC tumors', 'Disease', 'MESH:D004938', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('CIN', 'Disease', 'MESH:D007674', (199, 202))	('TP53', 'Gene', '7157', (158, 162))	('NLOH', 'Chemical', '-', (177, 181))	('colorectal cancers', 'Disease', 'MESH:D015179', (7, 25))	('GD', 'Chemical', '-', (34, 36))	('CDKN2A', 'Gene', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('GD', 'Chemical', '-', (217, 219))	('ESCC tumors', 'Disease', (85, 96))	('mutations', 'Var', (163, 172))	('CIN', 'Disease', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('GD', 'Chemical', '-', (98, 100))	('CDKN2A', 'Gene', '1029', (151, 157))
131390	29348864	It is well known that high-level amplification is a marked feature of CIN and always accompanies with over-expression of oncogenes leading to tumor progression.	('high-level amplification', 'Var', (22, 46))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('CIN', 'Phenotype', 'HP:0040012', (70, 73))	('accompanies', 'Reg', (85, 96))	('CIN', 'Disease', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('CIN', 'Disease', 'MESH:D007674', (70, 73))
131396	29348864	We also observed copy number gain in FEN1, MTA2 and ZBTB3, suggesting that copy number gain is responsible for overexpression of these genes in at least a subset of patients with ESCC.	('FEN1', 'Gene', (37, 41))	('ZBTB3', 'Gene', (52, 57))	('MTA2', 'Gene', (43, 47))	('ZBTB3', 'Gene', '79842', (52, 57))	('ESCC', 'Disease', (179, 183))	('copy number gain', 'Var', (75, 91))	('copy number gain', 'Var', (17, 33))	('patients', 'Species', '9606', (165, 173))	('overexpression', 'PosReg', (111, 125))	('FEN1', 'Gene', '2237', (37, 41))	('MTA2', 'Gene', '9219', (43, 47))
131397	29348864	The involvement of FEN1, ZBTB3, and MTA2 in controlling genomic stability suggests that functional dysregulation of these genes through mutations would facilitate further tumor mutagenesis, raising the possibility of these oncogenes as potential therapeutic targets for ESCC patients.	('FEN1', 'Gene', (19, 23))	('MTA2', 'Gene', (36, 40))	('ESCC', 'Disease', (270, 274))	('ZBTB3', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('ZBTB3', 'Gene', '79842', (25, 30))	('FEN1', 'Gene', '2237', (19, 23))	('mutations', 'Var', (136, 145))	('facilitate', 'PosReg', (152, 162))	('MTA2', 'Gene', '9219', (36, 40))	('patients', 'Species', '9606', (275, 283))	('tumor', 'Disease', (171, 176))
131399	29348864	In their study, half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and mTOR whereas the majority of truncal and clonal driver mutations occurred in tumor-suppressor genes, including TP53, KMT2D and ZNF750.	('NFE2L2', 'Gene', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('mTOR', 'Gene', (146, 150))	('KMT2D', 'Gene', (263, 268))	('mTOR', 'Gene', '2475', (146, 150))	('TP53', 'Gene', (257, 261))	('ZNF750', 'Gene', '79755', (273, 279))	('targeted', 'Reg', (97, 105))	('PIK3CA', 'Gene', '5290', (127, 133))	('ZNF750', 'Gene', (273, 279))	('KMT2D', 'Gene', '8085', (263, 268))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('NFE2L2', 'Gene', '4780', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('TP53', 'Gene', '7157', (257, 261))	('mutations', 'Var', (201, 210))	('occurred', 'Reg', (211, 219))	('PIK3CA', 'Gene', (127, 133))	('mutations', 'Var', (35, 44))
131401	29348864	Moreover, several driver mutations that were found in all tumor cells among these 21 ESCC genomes can be placed on the shared trunk of the phylogenetic tree, including mutations of TP53, CDKN2A, AJUBA, PIK3CA, NOTCH1, FBXW7, RB1, FAT1, and ZNF750.	('TP53', 'Gene', (181, 185))	('CDKN2A', 'Gene', (187, 193))	('FAT1', 'Gene', '2195', (230, 234))	('FBXW7', 'Gene', '55294', (218, 223))	('mutations', 'Var', (168, 177))	('tumor', 'Disease', (58, 63))	('CDKN2A', 'Gene', '1029', (187, 193))	('PIK3CA', 'Gene', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('TP53', 'Gene', '7157', (181, 185))	('RB1', 'Gene', (225, 228))	('NOTCH1', 'Gene', (210, 216))	('FAT1', 'Gene', (230, 234))	('ZNF750', 'Gene', '79755', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('FBXW7', 'Gene', (218, 223))	('AJUBA', 'Gene', '84962', (195, 200))	('ZNF750', 'Gene', (240, 246))	('PIK3CA', 'Gene', '5290', (202, 208))	('RB1', 'Gene', '5925', (225, 228))	('NOTCH1', 'Gene', '4851', (210, 216))	('AJUBA', 'Gene', (195, 200))
131403	29348864	For example, PIK3CA showed recurrent activating mutations suggesting that this gene may be potential therapeutic target for ESCC patients harboring PIK3CA mutation.	('PIK3CA', 'Gene', '5290', (148, 154))	('PIK3CA', 'Gene', (13, 19))	('patients', 'Species', '9606', (129, 137))	('PIK3CA', 'Gene', '5290', (13, 19))	('mutation', 'Var', (155, 163))	('PIK3CA', 'Gene', (148, 154))	('activating', 'MPA', (37, 47))	('ESCC', 'Disease', (124, 128))
131415	29348864	A modified version of a published method was used to classify the focal SCNAs with absolute copy number less than 6, via their timing relative to GD event.	('less than 6', 'Var', (104, 115))	('focal SCNAs', 'Disease', (66, 77))	('GD', 'Chemical', '-', (146, 148))
131421	29348864	Reasoning mutations that arise early in tumorigenesis or that foster rapid outgrowth would tend to be clonal whereas late-arising alterations would more often be subclonal.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('rapid outgrowth', 'CPA', (69, 84))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
131429	29348864	BFB breakage-fusion-bridge CIN Chromosomal instability CNAs copy-number alterations COAD colorectal carcinoma ESCA esophageal carcinoma ESCC esophageal squamous cell carcinoma FEN1 Flap structure-specific Endonuclease 1 GD genome doubling HNSCC head and neck squamous cell carcinoma IHC immunohischemistry LOH loss of heterozygosity LIHC liver hepatocellular carcinoma NGD non-genomedoubling NLOH neutral loss of heterozygosity NMF nonnegative matrix factorization NSCLC non-small cell lung cancer PAAD pancreatic adenocarcinoma STAD stomach adenocarcinoma SCNA somatic copy number alteration SNV single-nucleotide variations TSGs tumor suppressor genes TCNAs telomere-bounded copy number alterations WGD whole genome doubling WGS whole-genome sequencing wGII genome instability index	('single-nucleotide variations', 'Var', (597, 625))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (89, 109))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (534, 556))	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (141, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('tumor', 'Disease', 'MESH:D009369', (631, 636))	('Flap structure-specific Endonuclease 1', 'Gene', (181, 219))	('liver hepatocellular carcinoma', 'Disease', (338, 368))	('NSCLC', 'Disease', 'MESH:D002289', (465, 470))	('NLOH', 'Chemical', '-', (392, 396))	('lung cancer', 'Phenotype', 'HP:0100526', (486, 497))	('cell lung cancer', 'Disease', 'MESH:D008175', (481, 497))	('LIHC', 'Disease', 'None', (333, 337))	('BFB', 'Chemical', '-', (0, 3))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (344, 368))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (259, 282))	('COAD', 'Disease', 'MESH:D029424', (84, 88))	('TCNAs', 'Gene', (654, 659))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('neck squamous cell carcinoma', 'Disease', (254, 282))	('CIN', 'Disease', (27, 30))	('NSCLC', 'Disease', (465, 470))	('GD', 'Chemical', '-', (370, 372))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (254, 282))	('tumor', 'Phenotype', 'HP:0002664', (631, 636))	('HNSCC', 'Phenotype', 'HP:0012288', (239, 244))	('cell lung cancer', 'Disease', (481, 497))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (115, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (31, 54))	('GD', 'Chemical', '-', (220, 222))	('NSCLC', 'Phenotype', 'HP:0030358', (465, 470))	('GD', 'Chemical', '-', (702, 704))	('cancer', 'Phenotype', 'HP:0002664', (491, 497))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (503, 528))	('stomach adenocarcinoma', 'Disease', (534, 556))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (471, 497))	('FEN1', 'Gene', '2237', (176, 180))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (338, 368))	('esophageal carcinoma', 'Disease', (115, 135))	('COAD', 'Disease', (84, 88))	('PAAD', 'Phenotype', 'HP:0006725', (498, 502))	('LIHC', 'Disease', (333, 337))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (475, 497))	('CIN', 'Phenotype', 'HP:0040012', (27, 30))	('SNV', 'Gene', (593, 596))	('Flap structure-specific Endonuclease 1', 'Gene', '2237', (181, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (245, 282))	('ESCA', 'Phenotype', 'HP:0011459', (110, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('CIN', 'Disease', 'MESH:D007674', (27, 30))	('FEN1', 'Gene', (176, 180))	('colorectal carcinoma', 'Disease', (89, 109))	('tumor', 'Disease', (631, 636))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (503, 528))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (115, 135))	('pancreatic adenocarcinoma', 'Disease', (503, 528))
131451	27642498	For example, the inhibition of ROS could be beneficial in skeletal muscle to reduce the magnitude of atrophy but deleterious within tumor as this may accelerate proliferation and growth.	('rat', 'Species', '10116', (156, 159))	('accelerate', 'PosReg', (150, 160))	('atrophy', 'Disease', 'MESH:D001284', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('growth', 'CPA', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('atrophy', 'Disease', (101, 108))	('OS', 'Phenotype', 'HP:0025464', (32, 34))	('inhibition', 'Var', (17, 27))	('ROS', 'Chemical', 'MESH:D017382', (31, 34))	('ROS', 'Protein', (31, 34))	('rat', 'Species', '10116', (168, 171))	('tumor', 'Disease', (132, 137))	('proliferation', 'CPA', (161, 174))
131483	27642498	Basically, ROS promote muscle wasting and cachexia progression through the activation of three main catabolic pathways: ubiquitin proteasome system (UPS), autophagy lysosome pathway, and calcium-dependent calpain pathway.	('cachexia', 'Disease', (42, 50))	('ROS', 'Var', (11, 14))	('promote', 'PosReg', (15, 22))	('muscle wasting', 'Phenotype', 'HP:0003202', (23, 37))	('ROS', 'Chemical', 'MESH:D017382', (11, 14))	('calcium', 'Chemical', 'MESH:D002118', (187, 194))	('pain', 'Phenotype', 'HP:0012531', (208, 212))	('autophagy', 'CPA', (155, 164))	('activation', 'PosReg', (75, 85))	('cachexia', 'Phenotype', 'HP:0004326', (42, 50))	('muscle wasting', 'CPA', (23, 37))	('pain', 'Disease', 'MESH:D010146', (208, 212))	('pain', 'Disease', (208, 212))	('cachexia', 'Disease', 'MESH:D002100', (42, 50))	('ubiquitin', 'CPA', (120, 129))	('OS', 'Phenotype', 'HP:0025464', (12, 14))
131496	27642498	A previous study demonstrated that nuclear factor-kappaB (NF-kappaB) was rapidly activated by H2O2, following treatment of C2C12 muscle cells with TNF-alpha.	('H2O2', 'Chemical', 'MESH:D006861', (94, 98))	('H2O2', 'Var', (94, 98))	('nuclear factor-kappaB', 'Gene', '18033', (35, 56))	('activated', 'PosReg', (81, 90))	('men', 'Species', '9606', (115, 118))	('nuclear factor-kappaB', 'Gene', (35, 56))	('C2C12', 'CellLine', 'CVCL:0188', (123, 128))	('rat', 'Species', '10116', (24, 27))
131542	27642498	Clinically, the expression of NOX-1 and NOX-4 in tumor was associated with poor survival and cancer relapse.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('NOX-4', 'Gene', '50507', (40, 45))	('expression', 'Var', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('poor', 'NegReg', (75, 79))	('tumor', 'Disease', (49, 54))	('associated', 'Reg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('NOX-1', 'Gene', '27035', (30, 35))	('NOX-1', 'Gene', (30, 35))	('NOX-4', 'Gene', (40, 45))
131553	27642498	Since NOX controls the activation of various downstream kinases that play an essential role in proliferation, differentiation, and inflammation, the silencing of NOX isoforms, especially NOX-4, could provide a particular therapeutic interest to limit cancer cells proliferation and reduce the magnitude of muscle degradation.	('NOX', 'Chemical', '-', (6, 9))	('inflammation', 'Disease', 'MESH:D007249', (131, 143))	('inflammation', 'Disease', (131, 143))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('silencing', 'Var', (149, 158))	('NOX', 'Chemical', '-', (162, 165))	('NOX', 'Chemical', '-', (187, 190))	('NOX-4', 'Gene', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('reduce', 'NegReg', (282, 288))	('muscle degradation', 'CPA', (306, 324))	('rat', 'Species', '10116', (102, 105))	('rat', 'Species', '10116', (271, 274))	('cancer', 'Disease', (251, 257))	('NOX-4', 'Gene', '50507', (187, 192))	('limit', 'NegReg', (245, 250))
131589	27642498	The perturbations in glucose metabolism and reduced nutrients supply, due to symptoms such as anorexia and vomiting, can lead to an inadequate synthesis of reducing compounds and, therefore, may explain the GSH deficiency observed in cachectic individuals.	('vomiting', 'Disease', (107, 115))	('inadequate', 'NegReg', (132, 142))	('glucose metabolism', 'Disease', 'MESH:D044882', (21, 39))	('GSH', 'Chemical', '-', (207, 210))	('anorexia', 'Disease', 'MESH:D000855', (94, 102))	('nutrients supply', 'MPA', (52, 68))	('anorexia', 'Phenotype', 'HP:0002039', (94, 102))	('deficiency', 'Disease', (211, 221))	('perturbations', 'Var', (4, 17))	('synthesis of reducing compounds', 'MPA', (143, 174))	('anorexia', 'Disease', (94, 102))	('reduced', 'NegReg', (44, 51))	('glucose metabolism', 'Disease', (21, 39))	('vomiting', 'Phenotype', 'HP:0002013', (107, 115))	('GSH', 'MPA', (207, 210))	('vomiting', 'Disease', 'MESH:D014839', (107, 115))	('deficiency', 'Disease', 'MESH:D007153', (211, 221))
131604	27642498	It is though that ROS accumulation could promote cancer progression via the activation of several transcriptional factors, including FOXO6, regulating the expression of cell cycle genes (i.e., p27 and cyclin-D1).	('cyclin-D1', 'Gene', '595', (201, 210))	('FOXO6', 'Gene', (133, 138))	('OS', 'Phenotype', 'HP:0025464', (19, 21))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ROS accumulation', 'Var', (18, 34))	('expression', 'MPA', (155, 165))	('promote', 'PosReg', (41, 48))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('p27', 'Gene', '3429', (193, 196))	('p27', 'Gene', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('FOXO6', 'Gene', '100132074', (133, 138))	('cyclin-D1', 'Gene', (201, 210))	('activation', 'PosReg', (76, 86))	('cancer', 'Disease', (49, 55))
131614	27642498	Contrariwise, in rats bearing AT-1 prostate cancer, the inhibition of OS decreased tumor oxidative damage and proliferation, indicating that the reduction of OS could either enhance or slow tumor proliferation and progression depending on tumor type and localization.	('bearing AT-1 prostate cancer', 'Disease', (22, 50))	('inhibition', 'NegReg', (56, 66))	('decreased', 'NegReg', (73, 82))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('rats', 'Species', '10116', (17, 21))	('OS', 'Phenotype', 'HP:0025464', (158, 160))	('bearing AT-1 prostate cancer', 'Disease', 'MESH:D011471', (22, 50))	('slow', 'NegReg', (185, 189))	('tumor', 'Disease', (239, 244))	('OS', 'Phenotype', 'HP:0025464', (70, 72))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('rat', 'Species', '10116', (117, 120))	('progression', 'CPA', (214, 225))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor oxidative damage', 'Disease', (83, 105))	('tumor', 'Disease', (190, 195))	('rat', 'Species', '10116', (203, 206))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor oxidative damage', 'Disease', 'MESH:D004194', (83, 105))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('rat', 'Species', '10116', (17, 20))	('reduction', 'Var', (145, 154))	('enhance', 'PosReg', (174, 181))
131636	27642498	Accordingly, supplementation with vitamin E and beta-carotene increased cancer recurrence and overall mortality in head and neck cancer patients undergoing radiotherapy.	('men', 'Species', '9606', (19, 22))	('increased', 'PosReg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('head and neck cancer', 'Disease', 'MESH:D006258', (115, 135))	('vitamin E', 'Chemical', 'MESH:D014810', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('supplementation', 'Var', (13, 28))	('patients', 'Species', '9606', (136, 144))	('head and neck cancer', 'Phenotype', 'HP:0012288', (115, 135))	('beta-carotene', 'Chemical', 'MESH:D019207', (48, 61))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('beta-carotene', 'Protein', (48, 61))	('cancer', 'Disease', (72, 78))
131660	27642498	Although most of these studies found that polyphenols positively affected muscle mass and function, there is a lack of evidence concerning their effects on tumor growth.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('muscle mass', 'CPA', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('function', 'CPA', (90, 98))	('polyphenols', 'Chemical', 'MESH:D059808', (42, 53))	('affected', 'Reg', (65, 73))	('tumor', 'Disease', (156, 161))	('polyphenols', 'Var', (42, 53))
131673	27642498	Furthermore, short-term supplementation was likely to reduce chemotherapy-related toxicity and side-effects in cachectic patients, without affecting its anticancer potential.	('toxicity', 'Disease', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('reduce', 'NegReg', (54, 60))	('side-effects', 'CPA', (95, 107))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('men', 'Species', '9606', (30, 33))	('supplementation', 'Var', (24, 39))	('patients', 'Species', '9606', (121, 129))	('toxicity', 'Disease', 'MESH:D064420', (82, 90))
131697	27642498	Additionally, recent evidence from animal studies suggest that moderate endurance exercise improves muscle mass, reduces fatigue, and extends survival, while resistance exercise worsens cachexia symptoms.	('rat', 'Species', '10116', (67, 70))	('fatigue', 'Disease', 'MESH:D005221', (121, 128))	('improves', 'PosReg', (91, 99))	('moderate endurance', 'Var', (63, 81))	('fatigue', 'Disease', (121, 128))	('fatigue', 'Phenotype', 'HP:0012378', (121, 128))	('improves muscle mass', 'Phenotype', 'HP:0003199', (91, 111))	('cachexia symptoms', 'Disease', (186, 203))	('muscle', 'MPA', (100, 106))	('survival', 'CPA', (142, 150))	('extends', 'PosReg', (134, 141))	('exercise worsens', 'Phenotype', 'HP:0003546', (169, 185))	('reduces', 'NegReg', (113, 120))	('cachexia symptoms', 'Disease', 'MESH:D002100', (186, 203))	('cachexia', 'Phenotype', 'HP:0004326', (186, 194))
131719	26799587	LncRNA TP73-AS1 knockdown inhibited BDH2 expression in EC9706 and KYSE30 cells, whereas BDH2 knockdown repressed esophageal cancer cell proliferation and induced apoptosis via the caspase-3 dependent apoptotic pathway.	('knockdown', 'Var', (93, 102))	('caspase-3', 'Gene', (180, 189))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('inhibited', 'NegReg', (26, 35))	('expression', 'MPA', (41, 51))	('induced', 'Reg', (154, 161))	('BDH2', 'Gene', (36, 40))	('BDH2', 'Gene', '56898', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BDH2', 'Gene', (88, 92))	('BDH2', 'Gene', '56898', (88, 92))	('EC9706', 'CellLine', 'CVCL:E307', (55, 61))	('caspase-3', 'Gene', '836', (180, 189))	('apoptosis', 'CPA', (162, 171))	('repressed', 'NegReg', (103, 112))	('esophageal cancer', 'Disease', (113, 130))
131721	26799587	In mouse xenografts, tumor size was reduced in lncRNA TP73-ASI siRNA-transfected tumors, suggesting that downregulation of lncRNA TP73-AS1 attenuated EC proliferation in vitro and in vivo.	('lncRNA', 'Gene', (123, 129))	('EC proliferation', 'CPA', (150, 166))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Disease', (21, 26))	('downregulation', 'NegReg', (105, 119))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('attenuated', 'NegReg', (139, 149))	('lncRNA', 'Var', (47, 53))	('reduced', 'NegReg', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
131722	26799587	In addition, BDH2 or lncRNA TP73-AS1 knockdown enhanced the chemosensitivity of esophageal cancer cells to 5-FU and cisplatin.	('enhanced', 'PosReg', (47, 55))	('esophageal cancer', 'Disease', (80, 97))	('knockdown', 'Var', (37, 46))	('5-FU', 'Chemical', 'MESH:D005472', (107, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('BDH2', 'Gene', (13, 17))	('chemosensitivity', 'CPA', (60, 76))	('BDH2', 'Gene', '56898', (13, 17))
131739	26799587	LncRNA TP73-AS1 expression was generally upregulated in EC cell lines (Eca109, EC-1, EC9706, KYSE30, and KYSE150) (Figure 1F).	('EC-1', 'CellLine', 'CVCL:5V05', (79, 83))	('LncRNA TP73-AS1', 'Gene', (0, 15))	('upregulated', 'PosReg', (41, 52))	('EC9706', 'Var', (85, 91))	('KYSE150', 'Var', (105, 112))	('expression', 'MPA', (16, 26))	('EC9706', 'CellLine', 'CVCL:E307', (85, 91))
131740	26799587	Higher lncRNA TP73-AS1 levels in both EC tissues and cell lines as compared to non-cancer controls suggested that lncRNA TP73-AS1 might play an important role in EC tumorigenesis.	('lncRNA TP73-AS1 levels', 'MPA', (7, 29))	('lncRNA TP73-AS1', 'Var', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('play', 'Reg', (136, 140))	('Higher', 'PosReg', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('tumor', 'Disease', (165, 170))
131745	26799587	The results showed that the number of early and late apoptotic cells at 48-96 hours post-siRNA-transfection was significantly higher in EC9706 and KYSE30 cells (Figure 2E) compared to controls.	('EC9706', 'CellLine', 'CVCL:E307', (136, 142))	('KYSE30', 'Var', (147, 153))	('EC9706', 'Var', (136, 142))	('higher', 'PosReg', (126, 132))
131746	26799587	LncRNA TP73-AS1 knockdown also clearly induced apoptosis in EC9706 and KYSE30 cells as indicated by the Hoechst 33342 staining assay (Figure 2F).	('induced', 'Reg', (39, 46))	('apoptosis', 'CPA', (47, 56))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (104, 117))	('knockdown', 'Var', (16, 25))	('EC9706', 'CellLine', 'CVCL:E307', (60, 66))
131747	26799587	To confirm the growth inhibitory effect of lncRNATP73-AS1 siRNA on EC in vivo, a xenograft tumor growth assay was performed.	('xenograft tumor', 'Disease', (81, 96))	('growth inhibitory effect', 'MPA', (15, 39))	('xenograft tumor', 'Disease', 'MESH:D009369', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('lncRNATP73-AS1', 'Var', (43, 57))
131748	26799587	Tumor size and luciferase signal were significantly reduced in the lncRNATP73-AS1 siRNA mice group (EC9706 and KYSE30 cells transfected with lncRNATP73-AS1 siRNA1) as compared to control mice (NC and Blank groups) at the fourth week (P<0.05, Figure 2G & 2H).	('lncRNATP73-AS1 siRNA1', 'Gene', '5729', (141, 162))	('luciferase', 'Enzyme', (15, 25))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('signal', 'MPA', (26, 32))	('reduced', 'NegReg', (52, 59))	('EC9706', 'CellLine', 'CVCL:E307', (100, 106))	('mice', 'Species', '10090', (187, 191))	('Tumor size', 'CPA', (0, 10))	('lncRNATP73-AS1 siRNA1', 'Gene', (141, 162))	('mice', 'Species', '10090', (88, 92))	('lncRNATP73-AS1 siRNA', 'Var', (67, 87))
131749	26799587	To explore the molecular mechanisms of lncRNA TP73-AS1 in tumorigenesis, mRNA microarray analysis was performed using EC9706 and KYSE30 cells transfected with lncRNATP73-AS1 siRNA or nonsense siRNA.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('lncRNATP73-AS1', 'Var', (159, 173))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EC9706', 'CellLine', 'CVCL:E307', (118, 124))
131750	26799587	BDH2 expression was significantly decreased in EC9706 and KYSE30 cells transfected with lncRNATP73-AS1 siRNA compared to the control (P<0.05; Figure 3A).	('EC9706', 'CellLine', 'CVCL:E307', (47, 53))	('expression', 'MPA', (5, 15))	('decreased', 'NegReg', (34, 43))	('EC9706', 'Var', (47, 53))	('BDH2', 'Gene', '56898', (0, 4))	('BDH2', 'Gene', (0, 4))
131762	26799587	The number of apoptotic cells post-BDH2 siRNA transfection significantly increased in EC9706 and KYSE30 cells as compared to controls (Figure 4D).	('increased', 'PosReg', (73, 82))	('apoptotic cells', 'CPA', (14, 29))	('BDH2', 'Gene', (35, 39))	('BDH2', 'Gene', '56898', (35, 39))	('EC9706', 'CellLine', 'CVCL:E307', (86, 92))	('transfection', 'Var', (46, 58))
131763	26799587	These results suggest that BDH2 knockdown inhibits EC cell proliferation and induces apoptosis, which is similar to the effects of lncRNA TP73-AS1 siRNA on EC cells.	('BDH2', 'Gene', '56898', (27, 31))	('inhibits', 'NegReg', (42, 50))	('knockdown', 'Var', (32, 41))	('apoptosis', 'CPA', (85, 94))	('EC cell proliferation', 'CPA', (51, 72))	('induces', 'Reg', (77, 84))	('BDH2', 'Gene', (27, 31))
131765	26799587	We have shown that both BDH2 siRNA and lncRNATP73-AS1 siRNA induce apoptosis.	('apoptosis', 'CPA', (67, 76))	('BDH2', 'Gene', (24, 28))	('lncRNATP73-AS1', 'Var', (39, 53))	('induce', 'Reg', (60, 66))	('BDH2', 'Gene', '56898', (24, 28))
131767	26799587	BDH2 expression significantly decreased in EC9706 and KYSE30 cells after BDH2 siRNA1 or lncRNATP73-AS1 siRNA1 transfection (Figure 5A & 5B).	('BDH2', 'Gene', (73, 77))	('expression', 'MPA', (5, 15))	('lncRNATP73-AS1 siRNA1', 'Gene', (88, 109))	('BDH2', 'Gene', '56898', (73, 77))	('lncRNATP73-AS1 siRNA1', 'Gene', '5729', (88, 109))	('EC9706', 'CellLine', 'CVCL:E307', (43, 49))	('transfection', 'Var', (110, 122))	('BDH2', 'Gene', '56898', (0, 4))	('BDH2', 'Gene', (0, 4))	('decreased', 'NegReg', (30, 39))
131778	26799587	Therefore, knockdown of BDH2 or lncRNATP73-AS1 enhanced the chemosensitivity of EC cells to 5-FU and cisplatin.	('chemosensitivity', 'MPA', (60, 76))	('enhanced', 'PosReg', (47, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))	('lncRNATP73-AS1', 'Var', (32, 46))	('BDH2', 'Gene', '56898', (24, 28))	('knockdown', 'Var', (11, 20))	('BDH2', 'Gene', (24, 28))
131780	26799587	Western blot analysis showed that transfection increased BDH2 expression (Figure 6A).	('expression', 'MPA', (62, 72))	('BDH2', 'Gene', '56898', (57, 61))	('transfection', 'Var', (34, 46))	('increased', 'PosReg', (47, 56))	('BDH2', 'Gene', (57, 61))
131783	26799587	Apoptosis assays indicated that lncRNA TP73-AS1 knockdown increased apoptosis induced by serum starvation in EC9706 and KYSE30 cells.	('EC9706', 'CellLine', 'CVCL:E307', (109, 115))	('apoptosis', 'CPA', (68, 77))	('increased', 'PosReg', (58, 67))	('knockdown', 'Var', (48, 57))
131806	26799587	We inferred that knockdown of lncRNA TP73-AS1 or BDH2 induced cell apoptosis via a caspase-3 dependent apoptosis pathway.	('BDH2', 'Gene', (49, 53))	('caspase-3', 'Gene', '836', (83, 92))	('lncRNA TP73-AS1', 'Var', (30, 45))	('cell apoptosis', 'CPA', (62, 76))	('caspase-3', 'Gene', (83, 92))	('BDH2', 'Gene', '56898', (49, 53))
131810	26799587	We found that BDH2 or lncRNA TP73-AS1 knockdown enhanced chemosensitivity to 5-FU or cisplatin in EC cells.	('BDH2', 'Gene', (14, 18))	('BDH2', 'Gene', '56898', (14, 18))	('5-FU', 'Chemical', 'MESH:D005472', (77, 81))	('lncRNA TP73-AS1', 'Gene', (22, 37))	('chemosensitivity to 5-FU or cisplatin', 'MPA', (57, 94))	('enhanced', 'PosReg', (48, 56))	('knockdown', 'Var', (38, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
131821	26799587	The cell lines were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS, Gibco, Australia), 100 U/mL penicillin, and 50 mug/mL streptomycin, and were kept in incubators with humidified atmospheres of 5% CO2 and 95% air at 37 C. Recombinant lentiviral vectors carrying lncRNA TP73-AS1 siRNA1, TP73-AS1 siRNA2, BDH2 siRNA1 or BDH2 siRNA2 were constructed with standard molecular techniques.	('bovine', 'Species', '9913', (77, 83))	('BDH2', 'Gene', (347, 351))	('BDH2', 'Gene', '56898', (347, 351))	('RPMI-1640 medium', 'Chemical', '-', (32, 48))	('TP73-AS1', 'Var', (315, 323))	('FBS', 'Disease', (91, 94))	('BDH2', 'Gene', (332, 336))	('BDH2', 'Gene', '56898', (332, 336))	('streptomycin', 'Chemical', 'MESH:D013307', (150, 162))	('CO2', 'Chemical', '-', (226, 229))	('penicillin', 'Chemical', 'MESH:D010406', (124, 134))	('FBS', 'Disease', 'MESH:D005198', (91, 94))
131832	26799587	The PVDF membranes were blocked with 5% BSA in 0.05% Tween 20-TBS for 1 hour and incubated with the corresponding primary antibody diluted in blocking buffer overnight at 4 C. Dilutions for primary antibodies were as follows: anti-BDH2 (1:1,000, Santa Cruz Biotech, Dallas, TX, USA), anti-BCL-2 (1:400, Santa Cruz Biotech), anti-BAX (1:1,000, Santa Cruz Biotech), anti-cleaved-caspase-9 (1:1,000, Santa Cruz Biotech), anti-pro-caspase-9 (1:1000, Santa Cruz Biotech), and anti-cleaved caspase-3 (1:1,000, Santa Cruz Biotech).	('BAX', 'Gene', (329, 332))	('caspase-3', 'Gene', '836', (484, 493))	('BAX', 'Gene', '581', (329, 332))	('PVDF', 'Chemical', 'MESH:C024865', (4, 8))	('caspase-9', 'Gene', (427, 436))	('BDH2', 'Gene', (231, 235))	('BDH2', 'Gene', '56898', (231, 235))	('BCL-2', 'Gene', '596', (289, 294))	('caspase-9', 'Gene', '842', (377, 386))	('caspase-3', 'Gene', (484, 493))	('BCL-2', 'Gene', (289, 294))	('caspase-9', 'Gene', (377, 386))	('caspase-9', 'Gene', '842', (427, 436))	('1:400', 'Var', (296, 301))
131862	27036107	Staging was remarkable for yT2N1M0, stage IIB, lower thoracic esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (62, 87))	('thoracic esophageal adenocarcinoma', 'Disease', (53, 87))	('thoracic esophageal adenocarcinoma', 'Disease', 'MESH:D013899', (53, 87))	('yT2N1M0', 'Var', (27, 34))
131971	33537830	It was found that silencing LINC00491 expression in KYSE30 and KYSE410 cells significantly inhibited cell invasion and migration compared with the NC group (Figs.	('silencing', 'Var', (18, 27))	('inhibited', 'NegReg', (91, 100))	('KYSE410', 'CellLine', 'CVCL:1352', (63, 70))	('LINC00491', 'Gene', '285708', (28, 37))	('LINC00491', 'Gene', (28, 37))
131979	33537830	Moreover, abnormal expression of lncRNA promotes tumor development by affecting the expression of cancer-related genes at the pre-transcriptional, transcriptional and post-transcriptional levels.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('expression', 'MPA', (19, 29))	('expression', 'MPA', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('abnormal', 'Var', (10, 18))	('ncRNA', 'Gene', (34, 39))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('affecting', 'Reg', (70, 79))	('ncRNA', 'Gene', '220202', (34, 39))	('promotes', 'PosReg', (40, 48))
131989	33537830	A normal cell cycle is a key process to ensure the orderly proliferation of cells, and cell cycle disorders may cause normal cells to transform into infinitely increasing tumor cells.	('cause', 'Reg', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cell cycle disorders', 'Phenotype', 'HP:0011018', (87, 107))	('disorders', 'Var', (98, 107))	('cell', 'CPA', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
131991	33537830	In the present study, the sample size was expanded to detect the expression of LINC00491 in ESCC and to study the effect of knocking down the expression of LINC00491 on the biological features of ESCC cell lines, such as proliferation, migration, invasion and apoptosis.	('LINC00491', 'Gene', (79, 88))	('knocking', 'Var', (124, 132))	('LINC00491', 'Gene', (156, 165))	('invasion', 'CPA', (247, 255))	('apoptosis', 'CPA', (260, 269))	('proliferation', 'CPA', (221, 234))	('migration', 'CPA', (236, 245))	('LINC00491', 'Gene', '285708', (79, 88))	('LINC00491', 'Gene', '285708', (156, 165))
131995	33537830	Thus, it was indicated that knockdown of LINC00491 may have an inhibitory effect on ESCC disease progression.	('LINC00491', 'Gene', (41, 50))	('inhibitory', 'NegReg', (63, 73))	('LINC00491', 'Gene', '285708', (41, 50))	('knockdown', 'Var', (28, 37))	('ESCC disease', 'Disease', (84, 96))
131998	33537830	Furthermore, in ESCC cells, knockdown of LINC00491 inhibited proliferation and migration, and promoted apoptosis.	('LINC00491', 'Gene', (41, 50))	('knockdown', 'Var', (28, 37))	('LINC00491', 'Gene', '285708', (41, 50))	('apoptosis', 'CPA', (103, 112))	('inhibited', 'NegReg', (51, 60))	('promoted', 'PosReg', (94, 102))
132005	28244855	Furthermore, we observed that knockdown of DDX5 inhibited the expression of beta-catenin, c-Myc, and cyclin D1 in EC cells.	('cyclin D1', 'Gene', '595', (101, 110))	('cyclin D1', 'Gene', (101, 110))	('c-Myc', 'Gene', '4609', (90, 95))	('beta-catenin', 'Gene', (76, 88))	('expression', 'MPA', (62, 72))	('c-Myc', 'Gene', (90, 95))	('DDX5', 'Gene', (43, 47))	('inhibited', 'NegReg', (48, 57))	('knockdown', 'Var', (30, 39))	('beta-catenin', 'Gene', '1499', (76, 88))
132006	28244855	In conclusion, our findings provide the first evidence that siRNA-DDX5 inhibited the proliferation and invasion of EC cells through suppressing the Wnt/beta-catenin signaling pathway.	('siRNA-DDX5', 'Var', (60, 70))	('inhibited', 'NegReg', (71, 80))	('Wnt', 'Gene', '7472;7474', (148, 151))	('beta-catenin', 'Gene', (152, 164))	('beta-catenin', 'Gene', '1499', (152, 164))	('suppressing', 'NegReg', (132, 143))	('invasion', 'CPA', (103, 111))	('proliferation', 'CPA', (85, 98))	('Wnt', 'Gene', (148, 151))
132032	28244855	To investigate the critical role of DDX5 in regulating EC, we transfected shRNA-DDX5 or scramble into EC9706 and ECA109 cells, respectively, finding that the shRNA-DDX5 significantly reduced the expression of DDX5 in EC9706 and ECA109 cells (Fig.	('shRNA-DDX5', 'Var', (158, 168))	('expression', 'MPA', (195, 205))	('EC9706', 'CellLine', 'CVCL:E307', (102, 108))	('EC9706', 'CellLine', 'CVCL:E307', (217, 223))	('reduced', 'NegReg', (183, 190))	('DDX5', 'Gene', (209, 213))
132033	28244855	In addition, the results of the CCK-8 assay showed that knockdown of DDX5 dramatically inhibited proliferation in EC9706 and ECA109 cells (Fig.	('proliferation', 'CPA', (97, 110))	('inhibited', 'NegReg', (87, 96))	('EC9706', 'CellLine', 'CVCL:E307', (114, 120))	('knockdown', 'Var', (56, 65))	('DDX5', 'Gene', (69, 73))
132034	28244855	The Transwell migration assay indicated that, compared to control parental cells, knockdown of DDX5 markedly decreased the cell migration rate in both EC9706 and ECA109 cells (Fig.	('decreased', 'NegReg', (109, 118))	('EC9706', 'CellLine', 'CVCL:E307', (151, 157))	('knockdown', 'Var', (82, 91))	('DDX5', 'Gene', (95, 99))	('cell migration rate', 'CPA', (123, 142))
132035	28244855	Moreover, the invasion assay showed that the invasiveness of cells was significantly lower in EC9706 and ECA109 cells (Fig.	('EC9706', 'Var', (94, 100))	('lower', 'NegReg', (85, 90))	('EC9706', 'CellLine', 'CVCL:E307', (94, 100))	('invasiveness of cells', 'CPA', (45, 66))	('invasion assay', 'CPA', (14, 28))	('ECA109', 'Var', (105, 111))
132036	28244855	Knockdown of DDX5 in EC9706 cells led to an increase in epithelial cell markers, such as E-cadherin, and a decrease in mesenchymal cell markers, such as N-cadherin and vimentin (Fig.	('vimentin', 'Gene', (168, 176))	('DDX5', 'Gene', (13, 17))	('N-cadherin', 'Gene', '1000', (153, 163))	('EC9706', 'CellLine', 'CVCL:E307', (21, 27))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('increase', 'PosReg', (44, 52))	('decrease', 'NegReg', (107, 115))	('mesenchymal cell markers', 'CPA', (119, 143))	('N-cadherin', 'Gene', (153, 163))	('vimentin', 'Gene', '7431', (168, 176))	('EC9706', 'Var', (21, 27))	('epithelial cell markers', 'CPA', (56, 79))
132037	28244855	To further confirm the effects of DDX5 on tumor growth in vivo, EC9706 cells infected with shRNA-DDX5 or scramble were implanted subcutaneously into the flank of nude mice.	('EC9706', 'CellLine', 'CVCL:E307', (64, 70))	('infected', 'Disease', 'MESH:D007239', (77, 85))	('tumor', 'Disease', (42, 47))	('infected', 'Disease', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('shRNA-DDX5', 'Var', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('nude mice', 'Species', '10090', (162, 171))
132038	28244855	We found that knockdown of DDX5 significantly inhibited the weight of the EC tumor (Fig.	('weight of the EC tumor', 'Disease', 'MESH:D015431', (60, 82))	('weight of the EC tumor', 'Disease', (60, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('knockdown', 'Var', (14, 23))	('DDX5', 'Gene', (27, 31))	('inhibited', 'NegReg', (46, 55))
132041	28244855	Western blot analysis revealed that knockdown of DDX5 dramatically decreased the expression of beta-catenin, cyclin D1, and c-Myc in EC9706 cells, compared with the scramble group (Fig.	('DDX5', 'Gene', (49, 53))	('EC9706', 'CellLine', 'CVCL:E307', (133, 139))	('c-Myc', 'Gene', '4609', (124, 129))	('cyclin D1', 'Gene', '595', (109, 118))	('c-Myc', 'Gene', (124, 129))	('knockdown', 'Var', (36, 45))	('beta-catenin', 'Gene', (95, 107))	('cyclin D1', 'Gene', (109, 118))	('decreased', 'NegReg', (67, 76))	('beta-catenin', 'Gene', '1499', (95, 107))	('expression', 'MPA', (81, 91))
132045	28244855	Another study showed that the expression of DDX5 was significantly increased in colon cancer, and knockdown of DDX5 in colon cancer cells inhibits their proliferation and diminishes their ability to form tumors in vivo.	('colon cancer', 'Disease', (80, 92))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('diminishes', 'NegReg', (171, 181))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('knockdown', 'Var', (98, 107))	('increased', 'PosReg', (67, 76))	('tumors', 'Disease', (204, 210))	('colon cancer', 'Phenotype', 'HP:0003003', (80, 92))	('DDX5', 'Gene', (111, 115))	('inhibits', 'NegReg', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colon cancer', 'Disease', 'MESH:D015179', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('colon cancer', 'Disease', 'MESH:D015179', (80, 92))	('expression', 'MPA', (30, 40))	('colon cancer', 'Disease', (119, 131))	('proliferation', 'CPA', (153, 166))	('DDX5', 'Gene', (44, 48))
132046	28244855	In accordance with these reports, in the present study we demonstrate that DDX5 was overexpressed in human EC cell lines, and knockdown of DDX5 significantly inhibited the proliferation of EC cells in vitro and EC tumor growth in vivo.	('knockdown', 'Var', (126, 135))	('proliferation', 'CPA', (172, 185))	('EC tumor', 'Disease', 'MESH:D009369', (211, 219))	('DDX5', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('inhibited', 'NegReg', (158, 167))	('human', 'Species', '9606', (101, 106))	('EC tumor', 'Disease', (211, 219))	('EC cells', 'CPA', (189, 197))
132049	28244855	In addition, we observed that knockdown of DDX5 led to an increase in E-cadherin and a decrease in N-cadherin and vimentin.	('vimentin', 'Gene', '7431', (114, 122))	('N-cadherin', 'Gene', (99, 109))	('increase', 'PosReg', (58, 66))	('vimentin', 'Gene', (114, 122))	('N-cadherin', 'Gene', '1000', (99, 109))	('DDX5', 'Gene', (43, 47))	('decrease', 'NegReg', (87, 95))	('knockdown', 'Var', (30, 39))	('E-cadherin', 'Gene', (70, 80))	('E-cadherin', 'Gene', '999', (70, 80))
132058	28244855	In the present study, we found that knockdown of DDX5 significantly inhibited the expression of the Wnt/beta-catenin pathway components (beta-catenin, c-Myc, and cyclin D1) in EC cells.	('c-Myc', 'Gene', '4609', (151, 156))	('beta-catenin', 'Gene', (137, 149))	('beta-catenin', 'Gene', '1499', (137, 149))	('beta-catenin', 'Gene', (104, 116))	('cyclin D1', 'Gene', (162, 171))	('expression', 'MPA', (82, 92))	('c-Myc', 'Gene', (151, 156))	('Wnt', 'Gene', '7472;7474', (100, 103))	('beta-catenin', 'Gene', '1499', (104, 116))	('inhibited', 'NegReg', (68, 77))	('knockdown', 'Var', (36, 45))	('Wnt', 'Gene', (100, 103))	('cyclin D1', 'Gene', '595', (162, 171))	('DDX5', 'Gene', (49, 53))
132074	33329840	In addition, a perforation that is unrecognized, particularly by the endoscopist, can cause pneumoperitoneum and/or pneumomediastinum and can further aggravate respiratory problems.	('respiratory problems', 'Disease', (160, 180))	('respiratory problems', 'Phenotype', 'HP:0002795', (160, 180))	('pneumomediastinum', 'Phenotype', 'HP:0025421', (116, 133))	('perforation', 'Var', (15, 26))	('pneumoperitoneum', 'Disease', 'MESH:D011027', (92, 108))	('pneumomediastinum', 'Disease', (116, 133))	('cause', 'Reg', (86, 91))	('aggravate', 'Reg', (150, 159))	('pneumoperitoneum', 'Disease', (92, 108))
132111	33329840	Undetected microperforation or unrecognized perforation by an endoscopist in esophageal EPs may cause severe pneumoperitoneum and/or pneumomediastinum by continuous leakage of insufflation air used during the procedure.	('pneumomediastinum', 'Phenotype', 'HP:0025421', (133, 150))	('pneumomediastinum', 'Disease', (133, 150))	('pneumoperitoneum', 'Disease', 'MESH:D011027', (109, 125))	('cause', 'Reg', (96, 101))	('EP', 'Gene', '2069', (88, 90))	('microperforation', 'Var', (11, 27))	('pneumoperitoneum', 'Disease', (109, 125))
132133	32323828	In summary, the results demonstrate that in ESCC cells, 125I seed radiation induces cell death through both apoptosis and paraptosis; and at the same time initiates protective autophagy.	('paraptosis', 'CPA', (122, 132))	('death', 'Disease', 'MESH:D003643', (89, 94))	('protective autophagy', 'CPA', (165, 185))	('initiates', 'PosReg', (155, 164))	('death', 'Disease', (89, 94))	('125I seed', 'Var', (56, 65))	('apoptosis', 'CPA', (108, 117))	('125I', 'Chemical', 'MESH:C000614960', (56, 60))
132140	32323828	Compared with external beam radiotherapy (EBRT) using single/fractionated high-dose-rate irradiation, 125I seed brachytherapy has the advantages of easy preparation, direct contact with tumor tissue, less radiation to adjacent normal tissues and a higher relative biological effect (RBE) on tumor cells.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('125I', 'Var', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('125I', 'Chemical', 'MESH:C000614960', (102, 106))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumor', 'Disease', (291, 296))	('higher', 'PosReg', (248, 254))
132213	32323828	Furthermore, the degree of G2/M cell cycle arrest following irradiation was higher in KYSE-150 cells compared with the Eca-109 cells.	('KYSE-150', 'CellLine', 'CVCL:1348', (86, 94))	('KYSE-150', 'Var', (86, 94))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (32, 49))	('arrest', 'Disease', 'MESH:D006323', (43, 49))	('arrest', 'Disease', (43, 49))	('higher', 'PosReg', (76, 82))
132250	32323828	Studies have shown that de novo protein synthesis is required for cytoplasmic vacuolation in paraptosis, and CHX, a protein synthesis inhibitor, inhibits paraptosis.	('CHX', 'Var', (109, 112))	('CHX', 'Chemical', 'MESH:D003513', (109, 112))	('inhibits', 'NegReg', (145, 153))	('paraptosis', 'MPA', (154, 164))
132270	32323828	7A), and the weights and volumes of harvested tumors were significantly lower in the 125I seed group compared with the control group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('125I seed', 'Var', (85, 94))	('lower', 'NegReg', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('125I', 'Chemical', 'MESH:C000614960', (85, 89))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
132272	32323828	Increased levels of ROS were observed in the 125I seed group (Fig.	('ROS', 'MPA', (20, 23))	('ROS', 'Chemical', 'MESH:D017382', (20, 23))	('125I', 'Chemical', 'MESH:C000614960', (45, 49))	('125I seed', 'Var', (45, 54))
132274	32323828	Furthermore, 125I seed radiation resulted in apoptosis (TUNEL assay, Fig.	('apoptosis', 'CPA', (45, 54))	('125I seed radiation', 'Var', (13, 32))	('125I', 'Chemical', 'MESH:C000614960', (13, 17))
132286	32323828	125I seed radiation induced significant DNA damage and cell cycle arrest at the G2/M phase in both cell lines; however, the mode of cell death and the prominence of each mode differed in each cell line.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (55, 72))	('DNA damage', 'CPA', (40, 50))	('arrest', 'Disease', 'MESH:D006323', (66, 72))	('arrest', 'Disease', (66, 72))	('125I', 'Var', (0, 4))	('death', 'Disease', 'MESH:D003643', (137, 142))	('death', 'Disease', (137, 142))	('125I', 'Chemical', 'MESH:C000614960', (0, 4))
132302	32323828	The results of the present study showed that, in Eca-109 cells, paraptosis was at least partially responsible for cell death induced by 125I seed radiation, and may be important for cell death following mitotic catastrophe.	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('125I', 'Chemical', 'MESH:C000614960', (136, 140))	('125I seed radiation', 'Var', (136, 155))	('responsible', 'Reg', (98, 109))	('paraptosis', 'MPA', (64, 74))	('death', 'Disease', 'MESH:D003643', (187, 192))	('death', 'Disease', (187, 192))
132308	32323828	The majority of studies on 125I seed radiation have only focused on the ROS-mediated DNA damage and consequent apoptosis, whereas over-accumulation of ROS also interferes with various organelles, including the mitochondria and ER, resulting in mitochondrial dysfunction and ER stress response.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (244, 269))	('ROS-mediated', 'MPA', (72, 84))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (244, 269))	('ROS', 'Chemical', 'MESH:D017382', (151, 154))	('mitochondrial dysfunction', 'Disease', (244, 269))	('over-accumulation', 'Var', (130, 147))	('ROS', 'Gene', (151, 154))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('125I', 'Chemical', 'MESH:C000614960', (27, 31))	('mitochondria', 'MPA', (210, 222))	('DNA damage', 'MPA', (85, 95))	('interferes', 'NegReg', (160, 170))	('organelles', 'MPA', (184, 194))
132311	32323828	Furthermore, NAC attenuated 125I seed radiation-induced ER stress, autophagy and reduced cell viability in both cell lines.	('attenuated', 'NegReg', (17, 27))	('ER stress', 'CPA', (56, 65))	('NAC', 'Chemical', 'MESH:D000111', (13, 16))	('autophagy', 'CPA', (67, 76))	('125I', 'Chemical', 'MESH:C000614960', (28, 32))	('reduced', 'NegReg', (81, 88))	('NAC', 'Var', (13, 16))	('cell viability', 'CPA', (89, 103))
132315	32323828	The results of the present study demonstrated that, in the human ESCC cell lines Eca-109 and KYSE-150, in addition to DNA damage, G2/M cell cycle arrest and apoptosis, 125I seed radiation initiated paraptosis, a relatively novel type of PCD.	('human', 'Species', '9606', (59, 64))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('initiated', 'Reg', (188, 197))	('paraptosis', 'Disease', (198, 208))	('arrest', 'Disease', 'MESH:D006323', (146, 152))	('125I seed radiation', 'Var', (168, 187))	('PCD', 'Disease', (237, 240))	('arrest', 'Disease', (146, 152))	('125I', 'Chemical', 'MESH:C000614960', (168, 172))	('PCD', 'Disease', 'MESH:D007619', (237, 240))	('KYSE-150', 'CellLine', 'CVCL:1348', (93, 101))
132316	32323828	Additionally, 125I seed radiation also resulted in the initiation of protective autophagy to attenuate cell death, and 125I seed radiation-induced apoptosis, paraptosis and autophagy were predominantly mediated by ROS production in these two ESCC cell lines.	('ROS', 'Protein', (214, 217))	('125I', 'Var', (119, 123))	('paraptosis', 'CPA', (158, 168))	('protective autophagy', 'CPA', (69, 89))	('125I', 'Chemical', 'MESH:C000614960', (119, 123))	('attenuate', 'NegReg', (93, 102))	('autophagy', 'CPA', (173, 182))	('apoptosis', 'CPA', (147, 156))	('125I', 'Chemical', 'MESH:C000614960', (14, 18))	('death', 'Disease', 'MESH:D003643', (108, 113))	('death', 'Disease', (108, 113))	('ROS', 'Chemical', 'MESH:D017382', (214, 217))
132320	31884247	However, the detailed mechanisms of Hippo signaling dys-regulation in ESCC remain not clear.	('ESCC', 'Disease', (70, 74))	('dys-regulation', 'Var', (52, 66))	('ESCC', 'Disease', 'MESH:C562729', (70, 74))
132322	31884247	SHARPIN depletion significantly decreases cell migration and invasion capacity in ESCC, which effects could be rescued by further YAP depletion.	('YAP', 'Gene', (130, 133))	('depletion', 'Var', (8, 17))	('cell migration', 'CPA', (42, 56))	('ESCC', 'Disease', (82, 86))	('YAP', 'Gene', '10413', (130, 133))	('decreases', 'NegReg', (32, 41))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))	('invasion capacity', 'CPA', (61, 78))
132331	31884247	Recent genomic-based sequencing and molecular biology studies reveal that the dysregulation of Hippo signaling is common in ESCC, while inhibition of Hippo signaling core factor YAP leads to decreased cell proliferation and invasion of ESCC.	('inhibition', 'Var', (136, 146))	('ESCC', 'Disease', 'MESH:C562729', (124, 128))	('dysregulation', 'MPA', (78, 91))	('ESCC', 'Disease', (236, 240))	('YAP', 'Gene', (178, 181))	('invasion', 'CPA', (224, 232))	('YAP', 'Gene', '10413', (178, 181))	('decreased', 'NegReg', (191, 200))	('Hippo signaling', 'MPA', (95, 110))	('cell proliferation', 'CPA', (201, 219))	('ESCC', 'Disease', (124, 128))	('ESCC', 'Disease', 'MESH:C562729', (236, 240))
132337	31884247	The abnormality of Hippo signaling components was found in several cancers, including esophageal cancer.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('abnormality', 'Var', (4, 15))	('esophageal cancer', 'Disease', (86, 103))	('found', 'Reg', (50, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Hippo signaling components', 'Gene', (19, 45))
132338	31884247	For example, Hippo signaling is dys-regulated by mutations, such as FATs and AJUBA, and gene amplifications, such as YAP in esophageal cancer.	('AJUBA', 'Gene', '84962', (77, 82))	('FATs', 'Gene', (68, 72))	('YAP', 'Gene', '10413', (117, 120))	('Hippo signaling', 'MPA', (13, 28))	('esophageal cancer', 'Disease', (124, 141))	('mutations', 'Var', (49, 58))	('YAP', 'Gene', (117, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('FATs', 'Gene', '118611', (68, 72))	('AJUBA', 'Gene', (77, 82))
132343	31884247	Quite a few studies showed that SHAPRIN might function as an oncogenic role in cancer, through modulating NFKB signaling and PTEN signaling.	('NFKB signaling', 'MPA', (106, 120))	('PTEN', 'Gene', (125, 129))	('SHAPRIN', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PTEN', 'Gene', '5728', (125, 129))	('modulating', 'Reg', (95, 105))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
132359	31884247	The antibodies used in this study were listed here: Anti-SHARPIN alpha (Ab125188, Abcam); Anti-YAP (SC-101199, Santa Cruz); Anti-HA (MMS-101R, COVANCE); Anti-myc (9E10, ab32, Abcam); Anti-myc (Ab9106, Abcam); Anti-GAPDH (GB12002, Servicebio).	('YAP', 'Gene', '10413', (95, 98))	('Ab9106', 'Var', (193, 199))	('GAPDH', 'Gene', '2597', (214, 219))	('YAP', 'Gene', (95, 98))	('GAPDH', 'Gene', (214, 219))	('Ab125188', 'Chemical', 'MESH:C551307', (72, 80))	('MMS', 'Chemical', 'MESH:C035596', (133, 136))	('Anti-HA', 'Var', (124, 131))
132370	31884247	Western blot with HA antibody was performed to detect K48 or K63 poly-ubiquitinated YAP.	('YAP', 'Gene', '10413', (84, 87))	('K48', 'Var', (54, 57))	('K63 poly-ubiquitinated', 'Var', (61, 83))	('YAP', 'Gene', (84, 87))
132377	31884247	The trans-well assay indicated that SHARPIN depletion via two independent siRNAs significantly increased cell invasion capacity in EC109 and KYSE150 cells (Figure 1C-F).	('KYSE150', 'CellLine', 'CVCL:1348', (141, 148))	('depletion', 'Var', (44, 53))	('EC109', 'CellLine', 'CVCL:6898', (131, 136))	('increased', 'PosReg', (95, 104))	('cell invasion capacity', 'CPA', (105, 127))
132378	31884247	Besides, wound-healing assay showed that SHARPIN depletion promoted cell migration in both EC109 and KYSE150 cells (Figure 1G-J).	('KYSE150 cells', 'CPA', (101, 114))	('promoted', 'PosReg', (59, 67))	('KYSE150', 'CellLine', 'CVCL:1348', (101, 108))	('EC109', 'CellLine', 'CVCL:6898', (91, 96))	('cell migration in', 'CPA', (68, 85))	('depletion', 'Var', (49, 58))
132379	31884247	The WST-1 assay indicated that depletion SHARPIN does not statistically affect cell proliferation and proliferation related gene expression in both EC109 and KYSE150 cells (Supplementary Figure 1A-D).	('depletion', 'Var', (31, 40))	('cell proliferation', 'CPA', (79, 97))	('KYSE150', 'CellLine', 'CVCL:1348', (158, 165))	('EC109', 'CellLine', 'CVCL:6898', (148, 153))
132380	31884247	SHARPIN depletion significantly increased YAP protein level in both EC109 and KYSE150 cells (Figure 2A and B).	('depletion', 'Var', (8, 17))	('EC109', 'CellLine', 'CVCL:6898', (68, 73))	('YAP', 'Gene', (42, 45))	('increased', 'PosReg', (32, 41))	('YAP', 'Gene', '10413', (42, 45))	('KYSE150', 'CellLine', 'CVCL:1348', (78, 85))
132382	31884247	By examining of YAP/TEAD target genes, we found that SHARPIN depletion significantly increased YAP/TEAD target gene expression (CTGF and CYR61) in both EC109 and KYSE150 cells (Figure 2D and E).	('depletion', 'Var', (61, 70))	('SHARPIN', 'Gene', (53, 60))	('YAP', 'Gene', '10413', (16, 19))	('CTGF', 'Gene', '1490', (128, 132))	('YAP', 'Gene', '10413', (95, 98))	('EC109', 'CellLine', 'CVCL:6898', (152, 157))	('CTGF', 'Gene', (128, 132))	('KYSE150', 'CellLine', 'CVCL:1348', (162, 169))	('YAP', 'Gene', (16, 19))	('CYR61', 'Gene', (137, 142))	('YAP', 'Gene', (95, 98))	('increased', 'PosReg', (85, 94))	('CYR61', 'Gene', '3491', (137, 142))
132384	31884247	Our previous data showed that SHARPIN depletion could increase YAP signaling activity and dramatically increase cancer cell migration capacity, our further experiments aimed to provide the inner logic link between YAP signaling and cell phenotype in SHARPIN depletion condition.	('increase', 'PosReg', (103, 111))	('cancer', 'Disease', (112, 118))	('YAP', 'Gene', (63, 66))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('SHARPIN', 'Gene', (30, 37))	('increase', 'PosReg', (54, 62))	('depletion', 'Var', (38, 47))	('YAP', 'Gene', '10413', (214, 217))	('YAP', 'Gene', '10413', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('YAP', 'Gene', (214, 217))
132385	31884247	Our data indicated that SHARPIN depletion increased YAP protein level and YAP/TEAD target gene expression, while further depletion of YAP in the cells could bring back the YAP protein level and YAP/TEAD target gene expression in both EC109 and KYSE150 cells (Figure 3A and B; Supplementary Figure 2A).	('increased', 'PosReg', (42, 51))	('YAP', 'Gene', (172, 175))	('depletion', 'Var', (32, 41))	('KYSE150', 'CellLine', 'CVCL:1348', (244, 251))	('YAP', 'Gene', '10413', (172, 175))	('YAP', 'Gene', '10413', (74, 77))	('YAP', 'Gene', '10413', (194, 197))	('YAP', 'Gene', (74, 77))	('YAP', 'Gene', (52, 55))	('EC109', 'CellLine', 'CVCL:6898', (234, 239))	('YAP', 'Gene', '10413', (52, 55))	('YAP', 'Gene', (194, 197))	('YAP', 'Gene', '10413', (134, 137))	('bring back', 'PosReg', (157, 167))	('depletion', 'Var', (121, 130))	('YAP', 'Gene', (134, 137))	('expression', 'MPA', (95, 105))	('expression', 'MPA', (215, 225))
132386	31884247	Interestingly, the trans-well assay showed that the increased invaded cell number by SHARPIN knocking-down could be at least partially rescued by further YAP depletion in EC109 and KYSE150 cells (Figure 3C and D; Supplementary Figure 2B and C).	('knocking-down', 'Var', (93, 106))	('increased', 'PosReg', (52, 61))	('KYSE150', 'CellLine', 'CVCL:1348', (181, 188))	('invaded cell number', 'CPA', (62, 81))	('depletion', 'NegReg', (158, 167))	('SHARPIN', 'Gene', (85, 92))	('YAP', 'Gene', '10413', (154, 157))	('YAP', 'Gene', (154, 157))	('EC109', 'CellLine', 'CVCL:6898', (171, 176))
132387	31884247	Besides, the wound-healing assay also indicated that the increased wound healing speed by SHARPIN knocking-down could be partially rescued by further YAP depletion in EC109 cells (Figure 3E and F; Supplementary Figure 2D and E).	('increased wound healing', 'Phenotype', 'HP:0001058', (57, 80))	('depletion', 'NegReg', (154, 163))	('wound healing speed', 'CPA', (67, 86))	('YAP', 'Gene', '10413', (150, 153))	('knocking-down', 'Var', (98, 111))	('YAP', 'Gene', (150, 153))	('increased', 'PosReg', (57, 66))	('EC109', 'CellLine', 'CVCL:6898', (167, 172))	('SHARPIN', 'Gene', (90, 97))
132393	31884247	Up on inhibition of protein synthesis of cycloheximide, the presence of SHARPIN significantly decreased the half-life of YAP in HEK293 cells (Figure 4C and D).	('half-life', 'MPA', (108, 117))	('presence', 'Var', (60, 68))	('YAP', 'Gene', (121, 124))	('decreased', 'NegReg', (94, 103))	('SHARPIN', 'Gene', (72, 79))	('HEK293', 'CellLine', 'CVCL:0045', (128, 134))	('cycloheximide', 'Chemical', 'MESH:D003513', (41, 54))	('YAP', 'Gene', '10413', (121, 124))
132395	31884247	Interestingly SHARPIN depletion also prolongs YAP half-life in MDAMB231 cells (Breast cancer cell line) (Supplementary Figure 4A and B).	('YAP', 'Gene', '10413', (46, 49))	('Breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('depletion', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('prolongs', 'PosReg', (37, 45))	('Breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('YAP', 'Gene', (46, 49))	('Breast cancer', 'Disease', (79, 92))	('MDAMB231', 'CellLine', 'CVCL:0062', (63, 71))
132400	31884247	Further co-IP showed that SHARPIN associated with YAP through its UBL domain, while YAP interacted with SHARPIN by its WW domain (171AA-292 AA) (Supplementary Figure 5).	('associated', 'Reg', (34, 44))	('YAP', 'Gene', '10413', (50, 53))	('YAP', 'Gene', '10413', (84, 87))	('YAP', 'Gene', (50, 53))	('YAP', 'Gene', (84, 87))	('171AA-292 AA', 'Var', (130, 142))
132403	31884247	It showed that SHARPIN depletion decreased the endogenous YAP poly-ubiquitination (Figure 5C).	('decreased', 'NegReg', (33, 42))	('YAP', 'Gene', (58, 61))	('YAP', 'Gene', '10413', (58, 61))	('depletion', 'Var', (23, 32))
132405	31884247	Previous studies showed that K48-linked ubiquitination of YAP leaded to protein degradation, while K63-linked ubiquitination of YAP linked to non-proteolytic modification and promoted YAP co-activator function in the nuclear.	('YAP', 'Gene', '10413', (128, 131))	('YAP', 'Gene', (58, 61))	('K48-linked', 'Var', (29, 39))	('co-activator function', 'MPA', (188, 209))	('protein degradation', 'MPA', (72, 91))	('YAP', 'Gene', '10413', (184, 187))	('YAP', 'Gene', (128, 131))	('K63-linked ubiquitination', 'Var', (99, 124))	('promoted', 'PosReg', (175, 183))	('YAP', 'Gene', (184, 187))	('YAP', 'Gene', '10413', (58, 61))	('leaded to', 'Reg', (62, 71))
132407	31884247	Interestingly, SHARPIN could shift the ubiquitination manner of YAP from non-proteolytic to proteolytic dominant way and inhibits YAP nuclear function (Figure 6).	('YAP', 'Gene', (130, 133))	('shift', 'Reg', (29, 34))	('SHARPIN', 'Var', (15, 22))	('YAP', 'Gene', '10413', (64, 67))	('inhibits', 'NegReg', (121, 129))	('YAP', 'Gene', '10413', (130, 133))	('ubiquitination', 'MPA', (39, 53))	('YAP', 'Gene', (64, 67))
132408	31884247	On this basis, modulation SHARPIN expression level or activity could be a strategy to modulate YAP/TEAD signaling and subsequently inhibit cancer cell progression in ESCC.	('modulate', 'Reg', (86, 94))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('inhibit', 'NegReg', (131, 138))	('YAP', 'Gene', '10413', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('modulation', 'Var', (15, 25))	('ESCC', 'Disease', 'MESH:C562729', (166, 170))	('activity', 'MPA', (54, 62))	('YAP', 'Gene', (95, 98))	('ESCC', 'Disease', (166, 170))	('cancer', 'Disease', (139, 145))
132420	31884247	For example, LATS1/2 could promote YAP phosphorylation in multiple sites (S61, S109, S127 and S381), which subsequently promote YAP1 association with 14-3-3 proteins.	('YAP', 'Gene', '10413', (128, 131))	('LATS1/2', 'Gene', '9113;26524', (13, 20))	('S61', 'Chemical', 'MESH:C117212', (74, 77))	('association', 'Interaction', (133, 144))	('YAP', 'Gene', (35, 38))	('S127', 'Var', (85, 89))	('YAP', 'Gene', (128, 131))	('S109', 'Var', (79, 83))	('promote', 'PosReg', (120, 127))	('YAP1', 'Gene', (128, 132))	('LATS1/2', 'Gene', (13, 20))	('promote', 'PosReg', (27, 34))	('S127', 'Chemical', 'MESH:C000670', (85, 89))	('YAP1', 'Gene', '10413', (128, 132))	('YAP', 'Gene', '10413', (35, 38))	('S381', 'Var', (94, 98))	('S61', 'Var', (74, 77))
132431	31884247	We, and others have shown that SHARPIN could inhibit several tumor-suppressive proteins, such as PTEN and P53.	('PTEN', 'Gene', (97, 101))	('PTEN', 'Gene', '5728', (97, 101))	('P53', 'Gene', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('P53', 'Gene', '7157', (106, 109))	('inhibit', 'NegReg', (45, 52))	('SHARPIN', 'Var', (31, 38))	('tumor', 'Disease', (61, 66))
132432	31884247	Besides, SHARPIN could facilitate quite a few oncogenic pathways, including ER alpha signaling and NFKB signaling.	('ER alpha', 'Gene', (76, 84))	('oncogenic pathways', 'Pathway', (46, 64))	('SHARPIN', 'Var', (9, 16))	('NFKB signaling', 'Pathway', (99, 113))	('ER alpha', 'Gene', '2099', (76, 84))	('facilitate', 'PosReg', (23, 33))
132433	31884247	However, ER alpha signaling does not exist (https://www.proteinatlas.org/), while the majority of P53 is mutated in ESCC (about 75% mutation), which indicates both of the pathways are not largely compromised in ESCC.	('ER alpha', 'Gene', (9, 17))	('ESCC', 'Disease', (211, 215))	('P53', 'Gene', (98, 101))	('ESCC', 'Disease', (116, 120))	('P53', 'Gene', '7157', (98, 101))	('ESCC', 'Disease', 'MESH:C562729', (211, 215))	('mutated', 'Var', (105, 112))	('ER alpha', 'Gene', '2099', (9, 17))	('ESCC', 'Disease', 'MESH:C562729', (116, 120))
132439	31884247	SHARPIN depletion promotes cancer cell progression and activates YAP/TEAD signaling in multiple esophageal cancer cell lines.	('depletion', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('YAP', 'Gene', (65, 68))	('activates', 'PosReg', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('SHARPIN', 'Gene', (0, 7))	('promotes', 'PosReg', (18, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', (107, 113))	('YAP', 'Gene', '10413', (65, 68))
132440	31884247	As a novel discovered modulator for Hippo signaling, modulation of SHARPIN activity or expression level could be a promising approach to treat esophageal cancer.	('SHARPIN', 'Gene', (67, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('modulation', 'Var', (53, 63))	('expression', 'MPA', (87, 97))	('activity', 'MPA', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('esophageal cancer', 'Disease', (143, 160))
132447	31110076	Experimental innovation shows that QGS can significantly slow down the mobility of EC cells by regulating the Gas6/Axl complex and downstream signaling pathways, and provides a theoretical basis for the pharmacological effects of QGS in the therapy of EC.	('Gas6', 'Gene', (110, 114))	('regulating', 'Reg', (95, 105))	('downstream signaling pathways', 'Pathway', (131, 160))	('mobility of EC cells', 'CPA', (71, 91))	('ling', 'Species', '163112', (147, 151))	('QGS', 'Var', (35, 38))	('Gas6', 'Gene', '2621', (110, 114))	('slow down', 'NegReg', (57, 66))
132457	31110076	Studies have reported that QGS can better inhibit the metastasis of patients with esophageal cancer compared with other traditional Chinese compounds.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('inhibit', 'NegReg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (68, 76))	('QGS', 'Var', (27, 30))	('metastasis', 'CPA', (54, 64))	('esophageal cancer', 'Disease', (82, 99))
132459	31110076	Studies have shown that QGS can improve the symptoms of esophageal cancer and postoperative patients, showing the trend of QGS can delay the recurrence and metastasis of esophageal cancer,.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('esophageal cancer', 'Disease', (56, 73))	('patients', 'Species', '9606', (92, 100))	('QGS', 'Var', (123, 126))	('metastasis of esophageal cancer', 'Disease', (156, 187))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('delay', 'NegReg', (131, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))	('recurrence', 'CPA', (141, 151))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (156, 187))
132464	31110076	Our previous protein chip results showed that QGS can reduce the expression of Gas6 of esophageal cancer cells (unpublished data).	('Gas6', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('QGS', 'Var', (46, 49))	('esophageal cancer', 'Disease', (87, 104))	('reduce', 'NegReg', (54, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('expression', 'MPA', (65, 75))	('Gas6', 'Gene', '2621', (79, 83))
132467	31110076	Our previous studies have shown that QGS can increase the expression of adhesion proteins and enhance cell adhesion, thereby inhibiting the invasion and migration of esophageal cancer cells..	('QGS', 'Var', (37, 40))	('expression', 'MPA', (58, 68))	('increase', 'PosReg', (45, 53))	('esophageal cancer', 'Disease', (166, 183))	('enhance', 'PosReg', (94, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('inhibiting', 'NegReg', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cell adhesion', 'CPA', (102, 115))	('adhesion proteins', 'Protein', (72, 89))
132468	31110076	Therefore, we explore the effects of other mechanisms on cell invasion and migration, we hypothesize that QGS can inhibits the cell mobility of ESCC by inhibiting the Gas6 to regulating the Gas6/AXL signaling pathway, which leads to the decrease of PI3K, AKT, NF-kappaB, matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) signals.	('PI3', 'Gene', '5266', (249, 252))	('Gas6', 'Gene', '2621', (167, 171))	('matrix metalloproteinase-9', 'Gene', (309, 335))	('cell mobility', 'CPA', (127, 140))	('QGS', 'Var', (106, 109))	('AKT', 'Gene', '207', (255, 258))	('decrease', 'NegReg', (237, 245))	('MMP2', 'Gene', '4313', (299, 303))	('Gas6', 'Gene', (167, 171))	('matrix metalloproteinase-2', 'Gene', (271, 297))	('Gas6', 'Gene', '2621', (190, 194))	('Gas6', 'Gene', (190, 194))	('PI3', 'Gene', (249, 252))	('matrix metalloproteinase-9', 'Gene', '4318', (309, 335))	('MMP9', 'Gene', (337, 341))	('inhibits', 'NegReg', (114, 122))	('MMP9', 'Gene', '4318', (337, 341))	('NF-kappaB', 'Gene', (260, 269))	('inhibiting', 'NegReg', (152, 162))	('matrix metalloproteinase-2', 'Gene', '4313', (271, 297))	('NF-kappaB', 'Gene', '4790', (260, 269))	('AKT', 'Gene', (255, 258))	('ling', 'Species', '163112', (204, 208))	('MMP2', 'Gene', (299, 303))
132469	31110076	Study is in order to confirm that QGS can regulate Gas6/Axl and its downstream signaling pathway, thereby inhibiting cell invasion and migration, so as to provide theoretical basis for QGS as a treatment for esophageal cancer.	('Gas6', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('inhibiting', 'NegReg', (106, 116))	('ling', 'Species', '163112', (84, 88))	('Gas6', 'Gene', '2621', (51, 55))	('esophageal cancer', 'Disease', (208, 225))	('downstream signaling pathway', 'Pathway', (68, 96))	('QGS', 'Var', (34, 37))	('regulate', 'Reg', (42, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))
132500	31110076	Western blotting result analysis is further presented that QGS stimulation significantly reduced the expressions of Gas6, Axl, and shows a concentration-dependent trend.	('Gas6', 'Gene', '2621', (116, 120))	('QGS', 'Var', (59, 62))	('Gas6', 'Gene', (116, 120))	('reduced', 'NegReg', (89, 96))	('expressions', 'MPA', (101, 112))	('Axl', 'Protein', (122, 125))
132501	31110076	This is proof that QGS effectively affects the Gas6/Axl signaling pathway.	('QGS', 'Var', (19, 22))	('Gas6', 'Gene', '2621', (47, 51))	('ling', 'Species', '163112', (61, 65))	('affects', 'Reg', (35, 42))	('Gas6', 'Gene', (47, 51))
132502	31110076	In order to demonstrate the mechanism of QGS inhibiting mobility of ESCC cells, we studied that PI3K/AKT and NF-kappaB signaling pathways.	('NF-kappaB', 'Gene', '4790', (109, 118))	('ling', 'Species', '163112', (124, 128))	('AKT', 'Gene', '207', (101, 104))	('mobility', 'CPA', (56, 64))	('NF-kappaB', 'Gene', (109, 118))	('AKT', 'Gene', (101, 104))	('PI3', 'Gene', '5266', (96, 99))	('QGS', 'Var', (41, 44))	('inhibiting', 'NegReg', (45, 55))	('PI3', 'Gene', (96, 99))
132505	31110076	This indicates that QGS has a significant inhibitory effect on PI3K/AKT and NF-kappaB protein expression.	('PI3', 'Gene', (63, 66))	('NF-kappaB', 'Gene', (76, 85))	('inhibitory', 'NegReg', (42, 52))	('PI3', 'Gene', '5266', (63, 66))	('AKT', 'Gene', '207', (68, 71))	('QGS', 'Var', (20, 23))	('NF-kappaB', 'Gene', '4790', (76, 85))	('AKT', 'Gene', (68, 71))
132508	31110076	This suggests that QGS effectively inhibits PI3K/AKT and NF-kappaB signaling pathways.	('ling', 'Species', '163112', (72, 76))	('AKT', 'Gene', (49, 52))	('QGS', 'Var', (19, 22))	('NF-kappaB', 'Gene', (57, 66))	('inhibits', 'NegReg', (35, 43))	('PI3', 'Gene', (44, 47))	('AKT', 'Gene', '207', (49, 52))	('NF-kappaB', 'Gene', '4790', (57, 66))	('PI3', 'Gene', '5266', (44, 47))
132509	31110076	In order to demonstrate the mechanism of QGS inhibiting cell mobility of ESCC cells, We also studied two protein pathways in which MMP2 and MMP9, these are closely related to esophageal cancer infiltration and metastasis.	('esophageal cancer', 'Disease', (175, 192))	('MMP2', 'Gene', '4313', (131, 135))	('MMP9', 'Gene', '4318', (140, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('related', 'Reg', (164, 171))	('inhibiting', 'NegReg', (45, 55))	('QGS', 'Var', (41, 44))	('MMP2', 'Gene', (131, 135))	('cell mobility', 'CPA', (56, 69))	('MMP9', 'Gene', (140, 144))
132515	31110076	Experiments shows that QGS not only shortens the effective distance of esophageal cancer cell movement, but also reduces the average speed of movement, thereby significantly inhibiting the invasion and migration of tumor cells in a dose trend.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('effective', 'MPA', (49, 58))	('inhibiting', 'NegReg', (174, 184))	('QGS', 'Var', (23, 26))	('average speed of movement', 'MPA', (125, 150))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('shortens', 'NegReg', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('esophageal cancer', 'Disease', (71, 88))	('tumor', 'Disease', (215, 220))	('reduces', 'NegReg', (113, 120))
132521	31110076	Experiment results also demonstrate that QGS can effectively inhibit the expression of Gas6 and AXL, and can affect the cell localization of Gas6/AXL complex.	('AXL', 'Protein', (96, 99))	('Gas6', 'Gene', (141, 145))	('inhibit', 'NegReg', (61, 68))	('QGS', 'Var', (41, 44))	('expression', 'MPA', (73, 83))	('affect', 'Reg', (109, 115))	('cell localization', 'MPA', (120, 137))	('Gas6', 'Gene', '2621', (87, 91))	('Gas6', 'Gene', '2621', (141, 145))	('Gas6', 'Gene', (87, 91))
132527	31110076	Therefore, inhibition of PI3K/AKT and NF-kappaB pathways is likely to be an effective method for the treatment of ESCC.	('ESCC', 'Disease', (114, 118))	('NF-kappaB', 'Gene', '4790', (38, 47))	('PI3', 'Gene', '5266', (25, 28))	('AKT', 'Gene', '207', (30, 33))	('inhibition', 'Var', (11, 21))	('NF-kappaB', 'Gene', (38, 47))	('AKT', 'Gene', (30, 33))	('PI3', 'Gene', (25, 28))
132536	31110076	Experiments have shown that NF-kB binding sites: NF-kappaB I (-1418/-1409), NF-kappaB II (-626/-617), and NF-kappaB III (-353/-345), of which NF-kappaB II (-626/-617) binding to MMP9 promoter.	('NF-kappaB', 'Gene', '4790', (106, 115))	('MMP9', 'Gene', (178, 182))	('NF-kappaB', 'Gene', (76, 85))	('-353/-345', 'Var', (121, 130))	('MMP9', 'Gene', '4318', (178, 182))	('NF-kappaB', 'Gene', (106, 115))	('NF-kappaB', 'Gene', '4790', (142, 151))	('NF-kappaB', 'Gene', '4790', (76, 85))	('binding', 'Interaction', (167, 174))	('-1418/-1409', 'Var', (62, 73))	('NF-kappaB', 'Gene', (142, 151))	('NF-kappaB', 'Gene', '4790', (49, 58))	('-626/-617', 'Var', (90, 99))	('NF-kappaB', 'Gene', (49, 58))	('-626/-617', 'Var', (156, 165))
132537	31110076	This experiment also showed that QGS inhibits the migration of esophageal cancer cells by affecting p65 phosphorylation and inhibiting the expression of MMP9.	('p65', 'Gene', '5970', (100, 103))	('QGS', 'Var', (33, 36))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('migration', 'CPA', (50, 59))	('MMP9', 'Gene', (153, 157))	('inhibiting', 'NegReg', (124, 134))	('p65', 'Gene', (100, 103))	('MMP9', 'Gene', '4318', (153, 157))	('expression', 'MPA', (139, 149))	('affecting', 'Reg', (90, 99))	('inhibits', 'NegReg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
132542	31110076	QGS can significantly inhibit the migration of ESCC cells by regulating the GAS6/AXL pathway by QGS, inhibiting the binding of the complex, thereby affecting the downstream PI3K/AKT and NF-kappaB pathways.	('NF-kappaB', 'Gene', (186, 195))	('AKT', 'Gene', (178, 181))	('PI3', 'Gene', (173, 176))	('binding', 'Interaction', (116, 123))	('regulating', 'Reg', (61, 71))	('inhibit', 'NegReg', (22, 29))	('AKT', 'Gene', '207', (178, 181))	('the complex', 'Protein', (127, 138))	('QGS', 'Var', (96, 99))	('NF-kappaB', 'Gene', '4790', (186, 195))	('affecting', 'Reg', (148, 157))	('complex', 'Protein', (131, 138))	('migration', 'CPA', (34, 43))	('GAS6', 'Gene', '2621', (76, 80))	('PI3', 'Gene', '5266', (173, 176))	('GAS6', 'Gene', (76, 80))	('inhibiting', 'NegReg', (101, 111))
132546	31110076	Adjuctive therapy with TCM can significantly improve the clinical symptoms of liver cancer, gastric cancer patients on the basis of conventional treatment, and the proportion of distant metastasis in the TCM use was significantly lower than in non-TCM use.	('liver cancer', 'Disease', (78, 90))	('lower', 'NegReg', (230, 235))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('liver cancer', 'Disease', 'MESH:D006528', (78, 90))	('improve', 'PosReg', (45, 52))	('clinical symptoms', 'CPA', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('distant metastasis', 'CPA', (178, 196))	('liver cancer', 'Phenotype', 'HP:0002896', (78, 90))	('patients', 'Species', '9606', (107, 115))	('TCM use', 'Var', (204, 211))
132550	31110076	In our hospital, we observed that QGS has a positive effect on controlling metastasis and improving symptoms in patients after esophageal cancer surgery.	('improving', 'PosReg', (90, 99))	('esophageal cancer', 'Disease', (127, 144))	('controlling metastasis', 'CPA', (63, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('symptoms', 'MPA', (100, 108))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('QGS', 'Var', (34, 37))	('ling', 'Species', '163112', (70, 74))
132551	31110076	Clinical observations show that QGS can significantly improve the clinical symptoms of patients with esophageal cancer, and no adverse drug reactions have been found.	('clinical symptoms', 'CPA', (66, 83))	('QGS', 'Var', (32, 35))	('adverse drug reactions', 'Phenotype', 'HP:0020172', (127, 149))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (87, 95))	('improve', 'PosReg', (54, 61))
132585	31098683	The pathological diagnosis was ypT1bN0M0 Stage IA (UICC-TNM 7th edition).	('TNM', 'Gene', '10178', (56, 59))	('ypT1bN0M0 Stage', 'Var', (31, 46))	('TNM', 'Gene', (56, 59))
132672	28536623	Our analysis suggested that lncRNAs like NEAT1 and TCONS_00287673 may upregulate PTEN though competitive sponging of miR-26a-5p and miR-182-5p.	('TCONS_00287673', 'Var', (51, 65))	('PTEN', 'Disease', (81, 85))	('NEAT1', 'Gene', (41, 46))	('NEAT1', 'Gene', '283131', (41, 46))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', (117, 120))	('upregulate', 'PosReg', (70, 80))	('miR-182-5p', 'Gene', (132, 142))	('miR', 'Gene', (132, 135))	('miR-182-5p', 'Gene', '100302183', (132, 142))
132758	23937253	Trends in surgery and radiation for patients with T1-T3N1M0 squamous cell or adenocarcinoma of the mid or distal esophagus in the SEER database from 1998-2008 were analyzed using generalized linear models including year as predictor; SEER doesn't record chemotherapy data.	('adenocarcinoma of the mid', 'Disease', 'MESH:D000230', (77, 102))	('patients', 'Species', '9606', (36, 44))	('squamous cell', 'Disease', (60, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('T1-T3N1M0', 'Var', (50, 59))	('adenocarcinoma of the mid', 'Disease', (77, 102))
132770	23937253	The purpose of this study was to use the Surveillance, Epidemiology, and End Results (SEER) database, which is the largest population-based cancer registry in the United States and contains 17 registries that cover 28% of the US population, to examine local treatment trends in the use of surgery and external beam radiotherapy (EBRT) among patients with locally advanced but potentially resectable T1-3N1M0 esophageal cancer of the mid and distal esophagus to test the hypothesis that combined local therapy was superior to either surgery or EBRT alone in the treatment of these patients.	('patients', 'Species', '9606', (341, 349))	('esophageal cancer', 'Disease', (408, 425))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('EBRT', 'Chemical', '-', (329, 333))	('esophageal cancer', 'Disease', 'MESH:D004938', (408, 425))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (580, 588))	('cancer', 'Disease', 'MESH:D009369', (419, 425))	('EBRT', 'Chemical', '-', (543, 547))	('T1-3N1M0', 'Var', (399, 407))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (419, 425))
132859	22272378	Reflux of duodenal contents can induce mucosal injury, stimulate cell proliferation, and promote tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mucosal injury', 'Disease', (39, 53))	('promote', 'PosReg', (89, 96))	('rat', 'Species', '10116', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mucosal injury', 'Disease', 'MESH:D052016', (39, 53))	('tumor', 'Disease', (97, 102))	('cell proliferation', 'CPA', (65, 83))	('Reflux', 'Var', (0, 6))	('stimulate', 'PosReg', (55, 64))
132869	22272378	Alteration in the p53 tumor suppressor gene seems to be one of the most important events in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Alteration', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('p53 tumor suppressor gene', 'Gene', (18, 43))	('human', 'Species', '9606', (92, 97))
132871	22272378	There is overwhelming evidence that p53 gene alterations are early and frequent events in esophageal cancer and that this gene is associated with the malignant transformation of Barrett's esophagus.	('alterations', 'Var', (45, 56))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (178, 197))	('p53', 'Gene', (36, 39))	("Barrett's esophagus", 'Disease', (178, 197))	('esophageal cancer', 'Disease', (90, 107))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (178, 197))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associated with', 'Reg', (130, 145))
132936	32887395	In this review, we critically evaluate the evidence that altered TRP channel expression in HNSCC may be used as a diagnostic aid to recognize malignant transformation and/or progression to invasive disease.	('invasive disease', 'Disease', (189, 205))	('TRP', 'Gene', '43542', (65, 68))	('altered', 'Var', (57, 64))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('TRP', 'Gene', (65, 68))	('invasive disease', 'Disease', 'MESH:D009361', (189, 205))
132937	32887395	We also examine the literature data if altered TRP channel expression may help to identify a group of HNSCC patients with poor prognosis who could benefit from more aggressive therapy.	('TRP', 'Gene', '43542', (47, 50))	('patients', 'Species', '9606', (108, 116))	('expression', 'MPA', (59, 69))	('TRP', 'Gene', (47, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (102, 107))	('HNSCC', 'Disease', (102, 107))	('altered', 'Var', (39, 46))	('rat', 'Species', '10116', (24, 27))
132973	32887395	Indeed, the Trpv3 knockout mouse has a characteristic wavy hair coat, whereas the constitutively active gain-of-function mutation Trpv3Gly573Ser results in a hairless phenotype.	('hairless phenotype', 'CPA', (158, 176))	('Trpv3Gly573Ser', 'Var', (130, 144))	('mouse', 'Species', '10090', (27, 32))	('wavy hair coat', 'CPA', (54, 68))	('Trpv3Gly573Ser', 'Chemical', '-', (130, 144))	('Trpv3Gly573Ser', 'Gene', (130, 144))	('gain-of-function', 'PosReg', (104, 120))	('Trpv3', 'Gene', (12, 17))
132974	32887395	Moreover, the skin-targeted Trpv3Gly573Ser transgenic animals spontaneously develop an inflammatory condition associated with scratching behavior similarly to human atopic dermatitis.	('atopic dermatitis', 'Phenotype', 'HP:0001047', (165, 182))	('dermatitis', 'Phenotype', 'HP:0011123', (172, 182))	('Trpv3Gly573Ser', 'Chemical', '-', (28, 42))	('atopic dermatitis', 'Disease', 'MESH:D003876', (165, 182))	('human', 'Species', '9606', (159, 164))	('atopic dermatitis', 'Disease', (165, 182))	('develop', 'PosReg', (76, 83))	('scratching behavior', 'Disease', (126, 145))	('Trpv3Gly573Ser transgenic', 'Var', (28, 53))	('rat', 'Species', '10116', (128, 131))	('inflammatory condition', 'Disease', (87, 109))	('Trpv3Gly573Ser', 'Gene', (28, 42))
132978	32887395	Recently, a gain-of-function mutation in TRPM4 has been linked to erythrokeratoderma.	('erythrokeratoderma', 'Disease', 'MESH:C563781', (66, 84))	('mutation', 'Var', (29, 37))	('TRPM4', 'Gene', '54795', (41, 46))	('TRPM4', 'Gene', (41, 46))	('gain-of-function', 'PosReg', (12, 28))	('erythrokeratoderma', 'Disease', (66, 84))
133016	32887395	Certain regions of the TRP receptor coding sequences are targets for epigenetic modification.	('epigenetic modification', 'Var', (69, 92))	('TRP', 'Gene', (23, 26))	('TRP', 'Gene', '43542', (23, 26))
133020	32887395	The methylation of human TRPA1 promoter region results in elevated TRPA1 expression and altered pain perception.	('pain', 'Disease', 'MESH:D010146', (96, 100))	('pain', 'Disease', (96, 100))	('methylation', 'Var', (4, 15))	('TRPA1', 'Gene', (25, 30))	('expression', 'MPA', (73, 83))	('TRPA1', 'Gene', '8989', (25, 30))	('pain', 'Phenotype', 'HP:0012531', (96, 100))	('altered', 'Reg', (88, 95))	('elevated', 'PosReg', (58, 66))	('human', 'Species', '9606', (19, 24))	('TRPA1', 'Gene', (67, 72))	('TRPA1', 'Gene', '8989', (67, 72))
133021	32887395	In erytroleukemic cells, transactivation of the TRPA1 promoter via Notch1 receptor intracellular domain induces TRPA1 expression and suppresses erythroid differentiation.	('TRPA1', 'Gene', '8989', (112, 117))	('induces', 'PosReg', (104, 111))	('transactivation', 'Var', (25, 40))	('TRPA1', 'Gene', (48, 53))	('TRPA1', 'Gene', '8989', (48, 53))	('suppresses', 'NegReg', (133, 143))	('erythroid differentiation', 'CPA', (144, 169))	('expression', 'MPA', (118, 128))	('TRPA1', 'Gene', (112, 117))
133033	32887395	VEGF inhibitors are, however, plagued by side-effects like hypotension, blood clots, and impaired surgical wound healing.	('blood clots', 'CPA', (72, 83))	('hypotension', 'Phenotype', 'HP:0002615', (59, 70))	('impaired surgical wound healing', 'Phenotype', 'HP:0001058', (89, 120))	('VEGF', 'Gene', '7422', (0, 4))	('inhibitors', 'Var', (5, 15))	('surgical wound healing', 'CPA', (98, 120))	('hypotension', 'Disease', 'MESH:D007022', (59, 70))	('blood clots', 'Phenotype', 'HP:0001907', (72, 83))	('hypotension', 'Disease', (59, 70))	('VEGF', 'Gene', (0, 4))
133034	32887395	It remains to be seen if TRP channel modulators can block neoangiogenesis without the adverse effects of existing VEGF inhibitors.	('modulators', 'Var', (37, 47))	('block', 'NegReg', (52, 57))	('VEGF', 'Gene', (114, 118))	('TRP', 'Gene', '43542', (25, 28))	('neoangiogenesis', 'CPA', (58, 73))	('TRP', 'Gene', (25, 28))	('VEGF', 'Gene', '7422', (114, 118))
133069	32887395	The activation of the TRPM2 channel by H2O2 increases apoptosis of SCC cells through the p53 and p21 pathways.	('apoptosis', 'CPA', (54, 63))	('p53', 'Gene', '7157', (89, 92))	('TRPM2', 'Gene', '101928607', (22, 27))	('p21', 'Gene', (97, 100))	('p53', 'Gene', (89, 92))	('p21', 'Gene', '644914', (97, 100))	('H2O2', 'Chemical', 'MESH:D006861', (39, 43))	('H2O2', 'Var', (39, 43))	('increases', 'PosReg', (44, 53))	('TRPM2', 'Gene', (22, 27))	('activation', 'PosReg', (4, 14))
133085	32887395	Knocking down TRPP2 in the human laryngeal carcinoma cell line, Hep2, suppressed ATP-induced Ca2+ release, migration, invasion, and the epithelial-mesenchymal transition process (Table 1).	('rat', 'Species', '10116', (110, 113))	('migration', 'CPA', (107, 116))	('Knocking down', 'Var', (0, 13))	('TRPP2', 'Gene', '5311', (14, 19))	('ATP-induced Ca2+ release', 'MPA', (81, 105))	('epithelial-mesenchymal transition process', 'CPA', (136, 177))	('carcinoma', 'Disease', 'MESH:D009369', (43, 52))	('TRPP2', 'Gene', (14, 19))	('human', 'Species', '9606', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (33, 52))	('suppressed', 'NegReg', (70, 80))	('Ca2+', 'Chemical', 'MESH:D000069285', (93, 97))	('Hep2', 'CellLine', 'CVCL:1906', (64, 68))	('invasion', 'CPA', (118, 126))	('carcinoma', 'Disease', (43, 52))	('ATP', 'Chemical', 'MESH:D000255', (81, 84))
133094	32887395	In other words, the absence of TRPV1 will lead to increased total EGFR protein with enhanced activation of downstream signaling components of the EGFR pathway.	('EGFR', 'Gene', '1956', (146, 150))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('increased', 'PosReg', (50, 59))	('EGFR', 'Gene', (146, 150))	('downstream signaling components', 'MPA', (107, 138))	('absence', 'Var', (20, 27))	('enhanced activation', 'PosReg', (84, 103))	('TRPV1', 'Gene', (31, 36))
133198	30668599	Despite prospective data in colorectal cancer showing that transfusion is associated with increased risk of recurrence, the low transfusion rates of 9%-12% seen in this study reduced statistical power to detect an association with recurrence.	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('recurrence', 'Disease', (108, 118))	('colorectal cancer', 'Disease', (28, 45))	('transfusion', 'Var', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))
133277	26956728	Bit1 knockdown contributes to growth suppression as well as the decreases of migration and invasion abilities in esophageal squamous cell carcinoma via suppressing FAK-paxillin pathway There is growing evidence that Bit1 exerts different roles in the development and progression of human cancers.	('growth suppression', 'CPA', (30, 48))	('knockdown', 'Var', (5, 14))	('FAK', 'Gene', '5747', (164, 167))	('cancers', 'Phenotype', 'HP:0002664', (288, 295))	('cancers', 'Disease', (288, 295))	('Bit1', 'Gene', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('paxillin', 'Gene', '5829', (168, 176))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('Bit1', 'Gene', '51651', (216, 220))	('migration', 'CPA', (77, 86))	('Bit1', 'Gene', (0, 4))	('paxillin', 'Gene', (168, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('cancers', 'Disease', 'MESH:D009369', (288, 295))	('Bit1', 'Gene', '51651', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('suppressing', 'NegReg', (152, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('human', 'Species', '9606', (282, 287))	('FAK', 'Gene', (164, 167))	('invasion abilities', 'CPA', (91, 109))	('decreases', 'NegReg', (64, 73))
133278	26956728	MTT, migration assay, invasion experiment, ELISA and Flow cytometry were utilized to determine the effects of Bit1 knockdown on cell proliferation, migration, invasion and apoptosis, respectively.	('Bit1', 'Gene', (110, 114))	('migration', 'CPA', (148, 157))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('apoptosis', 'CPA', (172, 181))	('invasion', 'CPA', (159, 167))	('knockdown', 'Var', (115, 124))
133280	26956728	We found Bit1 expression in all human ESCC cell lines tested was significantly higher than that in normal esophageal epithelial cell Het-1A (P < 0.05), in which EC9706 presented the highest Bit1 level.	('EC9706', 'Var', (161, 167))	('EC9706', 'CellLine', 'CVCL:E307', (161, 167))	('Bit1', 'Gene', (9, 13))	('Bit1 level', 'MPA', (190, 200))	('expression', 'MPA', (14, 24))	('human', 'Species', '9606', (32, 37))	('higher', 'PosReg', (79, 85))
133281	26956728	Moreover, Bit1 depletion contributed to growth inhibition in vitro and in vivo, reduced cell migration and invasion abilities, and induced cell apoptosis in EC9706 and TE1 cells.	('Bit1', 'Gene', (10, 14))	('depletion', 'Var', (15, 24))	('induced', 'Reg', (131, 138))	('EC9706', 'CellLine', 'CVCL:E307', (157, 163))	('reduced', 'NegReg', (80, 87))	('growth inhibition', 'CPA', (40, 57))	('cell apoptosis', 'CPA', (139, 153))
133284	26956728	Moreover, paxillin was downregulated at mRNA and protein levels in Bit1 shRNA group, coupled with the decreases of FAK mRNA and protein expressions.	('FAK', 'Gene', (115, 118))	('downregulated', 'NegReg', (23, 36))	('FAK', 'Gene', '5747', (115, 118))	('paxillin', 'Gene', '5829', (10, 18))	('decreases', 'NegReg', (102, 111))	('paxillin', 'Gene', (10, 18))	('Bit1 shRNA', 'Var', (67, 77))
133299	26956728	To further verify the underlying functions of Bit1 in ESCC, therefore, in the present study, we examined Bit1 expression in a panel of ESCC cell lines, and investigated the effects of Bit1 knockdown on tumor growth, migration and invasion as well as cell apoptosis in ESCC, and further preliminarily elucidated the possible molecular mechanisms.	('tumor', 'Disease', (202, 207))	('Bit1', 'Gene', (184, 188))	('Bit1', 'Gene', (105, 109))	('examined', 'Reg', (96, 104))	('invasion', 'CPA', (230, 238))	('migration', 'CPA', (216, 225))	('investigated', 'Reg', (156, 168))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('knockdown', 'Var', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
133300	26956728	All data presented herein suggest Bit1 may be a promising molecular target for the therapy of ESCC, and thus intervention of Bit1 may lead to better therapeutic outcomes for the patients with ESCC.	('lead to', 'Reg', (134, 141))	('Bit1', 'Gene', (125, 129))	('ESCC', 'Disease', (192, 196))	('patients', 'Species', '9606', (178, 186))	('intervention', 'Var', (109, 121))	('ESCC', 'Disease', (94, 98))
133301	26956728	However, Bit1 level was differentially expressed in these ESCC cell lines, and relative high level was displayed in EC9706, Eca109, TE13 and KYSE-70 cells, the other ESCC cell lines harbored lower Bit1 level, the difference was statistical significance (P < 0.05) (Fig.	('lower', 'NegReg', (191, 196))	('EC9706', 'Var', (116, 122))	('EC9706', 'CellLine', 'CVCL:E307', (116, 122))	('Bit1 level', 'MPA', (197, 207))
133306	26956728	To test whether Bit1 depletion affected cell proliferation, migration and invasion abilities, MTT, Wound healing migration assay and Transwell invasion experiment were utilized to determine the effects of Bit1 knockdown on cell proliferation, migration and invasion abilities, respectively.	('knockdown', 'Var', (210, 219))	('Bit1', 'Gene', (205, 209))	('affected', 'Reg', (31, 39))	('MTT', 'Chemical', 'MESH:C070243', (94, 97))	('Bit1', 'Gene', (16, 20))	('migration', 'CPA', (60, 69))	('cell proliferation', 'CPA', (40, 58))	('invasion abilities', 'CPA', (74, 92))
133307	26956728	We found that cell proliferation was significantly suppressed on days 2, 3, 4 and 5 after transfection with Bit1-shRNA in EC9706 cells, compared with untreated group and negative group (P < 0.05) (Fig.	('EC9706', 'CellLine', 'CVCL:E307', (122, 128))	('suppressed', 'NegReg', (51, 61))	('cell proliferation', 'CPA', (14, 32))	('Bit1-shRNA', 'Var', (108, 118))
133308	26956728	Stepwise investigation from Wound healing migration assay revealed that migration distance of EC9706 and TE1 cells in Bit1 shRNA group at different time points (12 h, 24 h and 36 h) was all significantly lower than those in untreated group and negative group (P < 0.05) (Fig.	('EC9706', 'Var', (94, 100))	('EC9706', 'CellLine', 'CVCL:E307', (94, 100))	('lower', 'NegReg', (204, 209))	('Bit1 shRNA', 'Var', (118, 128))	('migration distance', 'CPA', (72, 90))
133309	26956728	3c, d, e and f), suggesting Bit1 shRNA can inhibit cell migration in both EC9706 and TE1 cells.	('inhibit', 'NegReg', (43, 50))	('Bit1 shRNA', 'Var', (28, 38))	('cell migration in', 'CPA', (51, 68))	('EC9706', 'CellLine', 'CVCL:E307', (74, 80))
133310	26956728	Furthermore, the results from Transwell invasion experiment demonstrated that invasive cell numbers of EC9706 and TE1 cells in Bit1 shRNA group were markedly lower than those in untreated group and negative group (P < 0.05) (Fig.	('EC9706', 'Var', (103, 109))	('lower', 'NegReg', (158, 163))	('EC9706', 'CellLine', 'CVCL:E307', (103, 109))	('TE1 cells', 'CPA', (114, 123))	('invasive cell numbers', 'CPA', (78, 99))
133312	26956728	We reasoned that EC9706  and TE1 cells underwent apoptosis if ablation of the Bit1 anti-apoptotic pathway may trigger cell apoptosis.	('ablation', 'Var', (62, 70))	('cell apoptosis', 'CPA', (118, 132))	('Bit1 anti-apoptotic pathway', 'Pathway', (78, 105))	('EC9706', 'CellLine', 'CVCL:E307', (17, 23))
133315	26956728	Furthermore, the results of Flow cytometry demonstrated that the early apoptotic cell numbers and total apoptotic cell numbers of EC9706 and TE1 cells in Bit1 shRNA group were both markedly increased compared with untreated group and negative group (P < 0.05) (Fig.	('EC9706', 'Var', (130, 136))	('EC9706', 'CellLine', 'CVCL:E307', (130, 136))	('increased', 'PosReg', (190, 199))	('Bit1 shRNA', 'Var', (154, 164))
133320	26956728	5a and b), suggesting Bit1-shRNA mediated inhibitory effect on tumor growth displays in a dose-dependent manner.	('tumor', 'Disease', (63, 68))	('inhibitory effect', 'NegReg', (42, 59))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Bit1-shRNA', 'Var', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
133330	26956728	We found that Bit1 shRNA significantly donwregulated paxillin mRNA and protein expressions, compared with untreated group and negative group (P < 0.05) (Fig.	('donwregulated', 'NegReg', (39, 52))	('Bit1 shRNA', 'Var', (14, 24))	('paxillin', 'Gene', (53, 61))	('paxillin', 'Gene', '5829', (53, 61))
133337	26956728	found that reintroduction of Bit1 was sufficient to suppress the anchorage-independent growth; conversely, Bit1 downregulation significantly enhances anchorage-independent growth in A549 cells and further investigation revealed that the Bit1-depletion cells displayed significantly enhanced tumorigenecity in vivo, implying Bit1 functions as tumor suppressor in lung carcinoma.	('enhances', 'PosReg', (141, 149))	('anchorage-independent growth', 'CPA', (150, 178))	('Bit1', 'Gene', (107, 111))	('lung carcinoma', 'Disease', (362, 376))	('downregulation', 'NegReg', (112, 126))	('lung carcinoma', 'Disease', 'MESH:D008175', (362, 376))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('A549', 'CellLine', 'CVCL:0023', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (367, 376))	('Bit1-depletion', 'Var', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('enhanced', 'PosReg', (282, 290))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('tumor', 'Disease', (291, 296))	('tumor', 'Disease', (342, 347))
133338	26956728	Conversely, Bit1 depletion contributed to cell growth suppression in cervical cancer cell line HeLa, compared with control cells.	('cell growth', 'CPA', (42, 53))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('depletion', 'Var', (17, 26))	('Bit1', 'Gene', (12, 16))	('HeLa', 'CellLine', 'CVCL:0030', (95, 99))	('suppression', 'NegReg', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
133341	26956728	The investigation from Karmali PP and colleagues demonstrated that metastatic numbers and foci in Bit1-depletion B16F1 cells were significantly increased compared with control B16F1 cells, whereas Bit1 overexpression by exogenous introduction reduced the formation of lung metastatic colonies, implying Bit1 functions as the suppressor of metastasis in melanoma.	('B16F1', 'Var', (113, 118))	('formation of lung metastatic colonies', 'CPA', (255, 292))	('Bit1-depletion B16F1', 'Var', (98, 118))	('melanoma', 'Phenotype', 'HP:0002861', (353, 361))	('melanoma', 'Disease', (353, 361))	('B16F1', 'CellLine', 'CVCL:0158', (113, 118))	('melanoma', 'Disease', 'MESH:D008545', (353, 361))	('metastatic numbers', 'CPA', (67, 85))	('reduced', 'NegReg', (243, 250))	('B16F1', 'CellLine', 'CVCL:0158', (176, 181))	('foci', 'CPA', (90, 94))	('increased', 'PosReg', (144, 153))
133346	26956728	Therefore, to further confirm the role of Bit1 in EC9706 cells xenografted nude mice, we found that Bit1 downregulation mediated by shRNA significantly decreased the levels of Bcl-2 and MMP-2 mRNA and proteins in EC9706 cells xenografted nude mice, compared to negative groups, coupled with the increases of apoptotic index.	('apoptotic index', 'CPA', (308, 323))	('Bit1', 'Gene', (100, 104))	('EC9706', 'CellLine', 'CVCL:E307', (213, 219))	('nude mice', 'Species', '10090', (238, 247))	('downregulation', 'NegReg', (105, 119))	('nude mice', 'Species', '10090', (75, 84))	('decreased', 'NegReg', (152, 161))	('shRNA', 'Gene', (132, 137))	('EC9706', 'Var', (213, 219))	('levels of Bcl-2', 'MPA', (166, 181))	('EC9706', 'CellLine', 'CVCL:E307', (50, 56))
133362	26956728	Total protein (0.4 mg) was added to 5x protein sample buffer, heated at 100  C for 2 min and separated by SDS-PAGE with 3 mul of pre-stained protein molecular weight marker (Fermentas Life Sciences, Burlington, ON, Canada) as a standard, which was transferred to a polyvinylidene fluoride (PVDF) membrane and incubated with the following respective primary antibodies including anti-Bit1 (1:10000), anti-FAK (1: 1000), anti-paxillin (1:200), and control anti-beta-actin (1:500) overnight at 4  C, followed by secondary antibodies (goat anti mouse, 1:5000, goat anti rabbit, 1:2000) conjugated with horseradish peroxidase.	('mouse', 'Species', '10090', (541, 546))	('goat', 'Species', '9925', (531, 535))	('FAK', 'Gene', (404, 407))	('FAK', 'Gene', '5747', (404, 407))	('horseradish', 'Species', '3704', (598, 609))	('rabbit', 'Species', '9986', (566, 572))	('paxillin', 'Gene', '5829', (424, 432))	('goat', 'Species', '9925', (556, 560))	('beta-actin', 'Gene', '728378', (459, 469))	('paxillin', 'Gene', (424, 432))	('beta-actin', 'Gene', (459, 469))	('1: 1000', 'Var', (409, 416))
133375	26956728	Briefly, after transfection with pSilencer3.1-H1-neo-Bit1-shRNA or pSilencer3.1-H1-neo-negative-shRNA for 24 h, cells (3-5 x 104 per well) were seeded into ECM gel pre-coated, porous upper chamber inserts and allowed to invade overnight at 37  C in a CO2 incubator.	('ECM', 'Gene', '22915', (156, 159))	('pSilencer3.1-H1-neo-negative-shRNA', 'Var', (67, 101))	('ECM', 'Gene', (156, 159))	('CO2', 'Chemical', '-', (251, 254))
133378	26956728	Exponentially growing EC9706 and TE1 cells were plated in sterile petri dishes and transfected with pSilencer3.1-H1-neo-Bit1-shRNA or pSilencer3.1-H1-neo-negative -shRNA.	('pSilencer3.1-H1-neo-negative -shRNA', 'Var', (134, 169))	('EC9706', 'CellLine', 'CVCL:E307', (22, 28))	('pSilencer3.1-H1-neo-Bit1-shRNA', 'Var', (100, 130))
133384	26956728	The different complexes, which consisted of pSilencer3.1-H1-neo-Bit1-shRNA (5 mug and 10 mug) or pSilencer3.1-H1-neo-negative-shRNA (5 mug and 10 mug) and corresponding volume of Lipofectamine 2000, were injected to nude mice via intratumor route every 4 days (injection on days 5, 9, 13, 17, respectively).	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('pSilencer3.1-H1-neo-negative-shRNA', 'Var', (97, 131))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (179, 197))	('nude mice', 'Species', '10090', (216, 225))	('tumor', 'Disease', (235, 240))
133407	26765432	In 1998, gain-of-function mutations in the c-kit proto-oncogene protein (KIT) protooncogene in GISTs were demonstrated by Hirota et al.	('c-kit proto-oncogene protein', 'Gene', '3815', (43, 71))	('gain-of-function', 'PosReg', (9, 25))	('KIT', 'Gene', (73, 76))	('mutations', 'Var', (26, 35))	('c-kit proto-oncogene protein', 'Gene', (43, 71))	('GISTs', 'Phenotype', 'HP:0100723', (95, 100))
133432	26765432	CD117 positivity was detected in 119 patients (119/123, 96.75%), CD34 positivity was detected in 110 patients (110/117, 94.02%), and discovered on GIST 1 positivity was detected in 11 patients (11/13, 84.62%).	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (37, 45))	('positivity', 'Var', (6, 16))	('CD34', 'Gene', '947', (65, 69))	('CD34', 'Gene', (65, 69))	('CD117', 'Gene', '3815', (0, 5))	('CD117', 'Gene', (0, 5))
133434	26765432	Fifteen patients carried a mutation in exon 11 of KIT (15/25, 60%).	('mutation in exon', 'Var', (27, 43))	('KIT', 'Gene', (50, 53))	('patients', 'Species', '9606', (8, 16))
133459	26765432	Only 20% to 25% of gastric GISTs were associated with platelet-derived growth factor receptor alpha mutations, including exon 18 and exon 12 mutations.	('associated', 'Reg', (38, 48))	('exon 12 mutations', 'Var', (133, 150))	('GISTs', 'Phenotype', 'HP:0100723', (27, 32))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (54, 99))	('gastric GISTs', 'Disease', (19, 32))	('exon 18', 'Var', (121, 128))	('platelet-derived growth factor receptor alpha', 'Gene', (54, 99))
133497	25870698	Whereas an aneuploid/ intermediate digital image cytometry (DICM) warrants an early re-endoscopy, a diploid DICM underscores the low-risk status especially of patients with low-grade dysplasia .	('IC', 'Chemical', 'MESH:D007203', (109, 111))	('low-grade dysplasia', 'Disease', (173, 192))	('aneuploid/', 'Var', (11, 21))	('IC', 'Chemical', 'MESH:D007203', (61, 63))
133511	23755374	As a result, we show efficient uptake of nano-curcumin by the EAC cell lines, OE33, and OE19.	('nano-curcumin', 'Chemical', '-', (41, 54))	('OE33', 'Chemical', '-', (78, 82))	('EAC', 'Phenotype', 'HP:0011459', (62, 65))	('nano-curcumin', 'Var', (41, 54))	('uptake', 'MPA', (31, 37))
133512	23755374	Moreover, nano-curcumin significantly decreased the proliferation of the EAC cells, while did not affect the normal esophageal cell line HET-1A.	('decreased', 'NegReg', (38, 47))	('proliferation', 'CPA', (52, 65))	('EAC', 'Phenotype', 'HP:0011459', (73, 76))	('nano-curcumin', 'Var', (10, 23))	('EAC cells', 'CPA', (73, 82))	('nano-curcumin', 'Chemical', '-', (10, 23))
133513	23755374	We also found that nano-curcumin significantly up-regulated the expression of the co-stimulatory molecule CD86 in DCs and significantly decreased the secretion of pro-inflammatory cytokines from in vitro activated T cells.	('CD86', 'Gene', '942', (106, 110))	('expression', 'MPA', (64, 74))	('nano-curcumin', 'Var', (19, 32))	('CD86', 'Gene', (106, 110))	('secretion of pro-inflammatory cytokines', 'MPA', (150, 189))	('nano-curcumin', 'Chemical', '-', (19, 32))	('up-regulated', 'PosReg', (47, 59))	('decreased', 'NegReg', (136, 145))
133514	23755374	When we combined T cells with nano-curcumin treatment in OE19 and OE33, we found that the basic levels of T cell induced cytotoxicity of 6.4 and 4.1%, increased to 15 and 13%, respectively.	('increased', 'PosReg', (151, 160))	('nano-curcumin', 'Chemical', '-', (30, 43))	('cytotoxicity', 'Disease', 'MESH:D064420', (121, 133))	('OE33', 'Var', (66, 70))	('OE33', 'Chemical', '-', (66, 70))	('cytotoxicity', 'Disease', (121, 133))
133515	23755374	In conclusion, we found that nano-curcumin is effective against EAC, sensitizes EAC cells to T cell induced cytotoxicity and decreases the pro-inflammatory signals from T cells.	('nano-curcumin', 'Var', (29, 42))	('cytotoxicity', 'Disease', 'MESH:D064420', (108, 120))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('decreases', 'NegReg', (125, 134))	('pro-inflammatory signals from T cells', 'MPA', (139, 176))	('nano-curcumin', 'Chemical', '-', (29, 42))	('EAC', 'Disease', (64, 67))	('cytotoxicity', 'Disease', (108, 120))	('sensitizes', 'Reg', (69, 79))	('EAC', 'Phenotype', 'HP:0011459', (80, 83))
133541	23755374	Finally, we tested whether nano-curcumin would sensitize the tumor cells to DC-mediated cytotoxic T cell response and would more effectively induce lysis of esophageal cancer cells.	('tumor', 'Disease', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tested', 'Reg', (12, 18))	('nano-curcumin', 'Chemical', '-', (27, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('induce', 'Reg', (141, 147))	('esophageal cancer', 'Disease', (157, 174))	('lysis', 'MPA', (148, 153))	('sensitize', 'Reg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('nano-curcumin', 'Var', (27, 40))
133585	23755374	In Figure 1 it is shown that after 1 h of incubation with 50 muM nano-curcumin, all the cell lines show a green signal, which increased after 2 and 4 h, as compared to the negative untreated cells.	('nano-curcumin', 'Chemical', '-', (65, 78))	('muM', 'Gene', (61, 64))	('green signal', 'MPA', (106, 118))	('nano-curcumin', 'Var', (65, 78))	('increased', 'PosReg', (126, 135))	('muM', 'Gene', '56925', (61, 64))
133590	23755374	Figure 2A shows that treatment of the cells with 50 muM nano-curcumin for 48 h, significantly decreased cell proliferation in the EAC cell lines OE19 and OE33, but not in the normal esophageal squamous cell line HET-1A, indicating that nano-curcumin selectively affects the proliferation of cancer cells leaving the normal squamous epithelial cells unaffected.	('nano-curcumin', 'Var', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (291, 297))	('nano-curcumin', 'Chemical', '-', (56, 69))	('muM', 'Gene', '56925', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('cell proliferation', 'CPA', (104, 122))	('decreased', 'NegReg', (94, 103))	('OE33', 'Chemical', '-', (154, 158))	('muM', 'Gene', (52, 55))	('nano-curcumin', 'Chemical', '-', (236, 249))	('proliferation', 'CPA', (274, 287))	('affects', 'Reg', (262, 269))
133596	23755374	Thus unlike previous reports on free curcumin, nano-curcumin leaves the functional phenotype of DCs intact (Figure 3A).	('curcumin', 'Chemical', 'MESH:D003474', (37, 45))	('nano-curcumin', 'Var', (47, 60))	('DCs', 'Disease', (96, 99))	('curcumin', 'Chemical', 'MESH:D003474', (52, 60))	('nano-curcumin', 'Chemical', '-', (47, 60))
133597	23755374	Also, we observed that nano-curcumin significantly increased the expression level of the co-stimulatory molecule CD86 in DCs, indicating that it drives DCs to mature toward a functional phenotype.	('CD86', 'Gene', (113, 117))	('nano-curcumin', 'Var', (23, 36))	('increased', 'PosReg', (51, 60))	('drives', 'PosReg', (145, 151))	('nano-curcumin', 'Chemical', '-', (23, 36))	('CD86', 'Gene', '942', (113, 117))	('expression level', 'MPA', (65, 81))
133598	23755374	We also observed that nano-curcumin has no effects on the cytokine profile of these DCs (Figure 3B) and that it did not induce apoptosis of DCs (Figure 3C).	('induce', 'Reg', (120, 126))	('cytokine profile', 'MPA', (58, 74))	('nano-curcumin', 'Var', (22, 35))	('nano-curcumin', 'Chemical', '-', (22, 35))
133601	23755374	In activated T cells, nano-curcumin significantly decreased the amount of early apoptotic cells (Figure 4F) but had no effect on resting T cells (Figure 4C).	('decreased', 'NegReg', (50, 59))	('nano-curcumin', 'Var', (22, 35))	('early apoptotic cells', 'CPA', (74, 95))	('nano-curcumin', 'Chemical', '-', (22, 35))
133602	23755374	Accordingly, nano-curcumin did not affect the production of cytokines of resting T cells (Figure 4B), but it did significantly reduce the secretion of TNF-alpha, IL-8, IL-6, IL-10, and IL-1beta in activated T cells.	('IL-10', 'Gene', '3586', (174, 179))	('TNF-alpha', 'Gene', '7124', (151, 160))	('TNF-alpha', 'Gene', (151, 160))	('IL-10', 'Gene', (174, 179))	('reduce', 'NegReg', (127, 133))	('nano-curcumin', 'Chemical', '-', (13, 26))	('IL-1beta', 'Gene', (185, 193))	('nano-curcumin', 'Var', (13, 26))	('IL-8', 'Gene', '3576', (162, 166))	('IL-1beta', 'Gene', '3553', (185, 193))	('IL-6', 'Gene', (168, 172))	('IL-8', 'Gene', (162, 166))	('IL-6', 'Gene', '3569', (168, 172))
133603	23755374	This indicates that nano-curcumin modulates the cytokine profile of activated T cells toward a profile that negatively affects tumor cell growth and migration (Figure 4E).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('nano-curcumin', 'Chemical', '-', (20, 33))	('modulates', 'Reg', (34, 43))	('tumor', 'Disease', (127, 132))	('cytokine profile', 'MPA', (48, 64))	('nano-curcumin', 'Var', (20, 33))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
133604	23755374	From our results we can conclude that nano-curcumin has no negative effects on the immune-profile of both DCs and T cells and does not negatively affect their function.	('nano-curcumin', 'Chemical', '-', (38, 51))	('nano-curcumin', 'Var', (38, 51))	('immune-profile', 'MPA', (83, 97))
133605	23755374	Instead, these results for the first time show that nano-curcumin supports the function of DCs and T cells in inducing anti-tumor immune responses.	('inducing', 'PosReg', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('nano-curcumin', 'Chemical', '-', (52, 65))	('tumor', 'Disease', (124, 129))	('nano-curcumin', 'Var', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
133606	23755374	To determine whether nano-curcumin enhances DC-mediated T cell induced cytotoxicity, we tested the effects of nano-curcumin pre-treatment of EAC cell lines in CTL cytotoxicity assays.	('cytotoxicity', 'Disease', 'MESH:D064420', (163, 175))	('tested', 'Reg', (88, 94))	('nano-curcumin', 'Chemical', '-', (21, 34))	('cytotoxicity', 'Disease', (71, 83))	('EAC', 'Phenotype', 'HP:0011459', (141, 144))	('nano-curcumin', 'Chemical', '-', (110, 123))	('cytotoxicity', 'Disease', (163, 175))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))	('enhances', 'PosReg', (35, 43))	('nano-curcumin', 'Var', (21, 34))
133609	23755374	Using an effector (CTLs) to target (EAC cells) ratio of 10:1, in OE19 and OE33 cells, the CTLs induced a mean cell lysis of 6.4 and 4.06%, respectively (Figure 5A).	('OE33', 'Var', (74, 78))	('OE33', 'Chemical', '-', (74, 78))	('CTLs', 'Var', (90, 94))	('cell lysis', 'CPA', (110, 120))	('EAC', 'Phenotype', 'HP:0011459', (36, 39))
133610	23755374	Pre-treatment of the tumor cells with 50 muM nano-curcumin significantly increased the mean cell lysis to 15 and 13%, respectively.	('increased', 'PosReg', (73, 82))	('muM', 'Gene', '56925', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('muM', 'Gene', (41, 44))	('nano-curcumin', 'Chemical', '-', (45, 58))	('nano-curcumin', 'Var', (45, 58))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
133611	23755374	This indicates that pre-treatment with nano-curcumin sensitizes EAC cells to specific CTL-induced cytotoxicity.	('sensitizes', 'Reg', (53, 63))	('cytotoxicity', 'Disease', (98, 110))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('nano-curcumin', 'Var', (39, 52))	('cytotoxicity', 'Disease', 'MESH:D064420', (98, 110))	('nano-curcumin', 'Chemical', '-', (39, 52))
133614	23755374	When CTLs where incubated with OE33, however, nano-curcumin pre-treatment significantly increased the production of IFN-gamma, while the production of IL-8 significantly decreased.	('IL-8', 'Gene', '3576', (151, 155))	('production', 'MPA', (137, 147))	('increased', 'PosReg', (88, 97))	('IL-8', 'Gene', (151, 155))	('nano-curcumin', 'Chemical', '-', (46, 59))	('decreased', 'NegReg', (170, 179))	('OE33', 'Var', (31, 35))	('OE33', 'Chemical', '-', (31, 35))	('IFN-gamma', 'Gene', '3458', (116, 125))	('IFN-gamma', 'Gene', (116, 125))
133616	23755374	This is interesting considering that IL-8 was found to be highly expressed in OE33 and OE19 (data not shown) and was previously reported to be highly expressed in EAC (Milano et al.,).	('OE33', 'Var', (78, 82))	('OE33', 'Chemical', '-', (78, 82))	('IL-8', 'Gene', '3576', (37, 41))	('IL-8', 'Gene', (37, 41))	('OE19', 'Var', (87, 91))	('EAC', 'Phenotype', 'HP:0011459', (163, 166))
133617	23755374	Reduced levels of IL-8 may reduce the migratory functions of esophageal cancer cells, while higher levels of IFN-gamma support the function of DCs and T cells, again indicating that nano-curcumin seems to enhance the function of the immune system against tumor cells.	('migratory functions', 'CPA', (38, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('nano-curcumin', 'Chemical', '-', (182, 195))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('reduce', 'NegReg', (27, 33))	('enhance', 'PosReg', (205, 212))	('IL-8', 'Gene', '3576', (18, 22))	('nano-curcumin', 'Var', (182, 195))	('IFN-gamma', 'Gene', '3458', (109, 118))	('IFN-gamma', 'Gene', (109, 118))	('IL-8', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('esophageal cancer', 'Disease', (61, 78))
133627	23755374	We show that nano-curcumin has a direct anti-proliferative effect on EAC cell lines, in line with previous results showing that free curcumin decreases the proliferation and survival of esophageal cancer cells (Subramaniam et al.,).	('anti-proliferative effect', 'MPA', (40, 65))	('survival', 'CPA', (174, 182))	('curcumin', 'Chemical', 'MESH:D003474', (133, 141))	('decreases', 'NegReg', (142, 151))	('proliferation', 'CPA', (156, 169))	('EAC', 'Phenotype', 'HP:0011459', (69, 72))	('esophageal cancer', 'Disease', (186, 203))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('nano-curcumin', 'Var', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('curcumin', 'Chemical', 'MESH:D003474', (18, 26))	('nano-curcumin', 'Chemical', '-', (13, 26))
133628	23755374	It is worth mentioning the specific anti-proliferative effect of nano-curcumin toward cancer but not normal cell lines.	('anti-proliferative effect', 'MPA', (36, 61))	('nano-curcumin', 'Chemical', '-', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('nano-curcumin', 'Var', (65, 78))	('cancer', 'Disease', (86, 92))
133630	23755374	Instead, it could be speculated that divergences in signaling pathways between cancer and normal cells account for the selective proliferative effects of the nano-curcumin.	('nano-curcumin', 'Chemical', '-', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('nano-curcumin', 'Var', (158, 171))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
133631	23755374	For example, the signaling pathways affected by nano-curcumin, might be more activated in esophageal cancer cells as compared to normal cells, rendering the cancer cells more susceptible to the effects of nano-curcumin.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('susceptible', 'MPA', (175, 186))	('signaling pathways', 'Pathway', (17, 35))	('cancer', 'Disease', (101, 107))	('activated', 'PosReg', (77, 86))	('nano-curcumin', 'Chemical', '-', (48, 61))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('esophageal cancer', 'Disease', (90, 107))	('nano-curcumin', 'Chemical', '-', (205, 218))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (157, 163))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('nano-curcumin', 'Var', (48, 61))	('more', 'PosReg', (170, 174))
133633	23755374	Therefore, it is tempting to speculate that by inhibiting this pathway, nano-curcumin might selectively suppress proliferation of the EAC cell lines.	('suppress', 'NegReg', (104, 112))	('inhibiting', 'NegReg', (47, 57))	('EAC', 'Phenotype', 'HP:0011459', (134, 137))	('nano-curcumin', 'Chemical', '-', (72, 85))	('proliferation', 'CPA', (113, 126))	('nano-curcumin', 'Var', (72, 85))
133634	23755374	Although nano-curcumin has been demonstrated to also induce apoptosis in a variety of cells including pancreatic cancer cells (Sahu et al.,; Jutooru et al.,), we did not observe an effect on apoptosis of esophageal cell lines.	('nano-curcumin', 'Var', (9, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('apoptosis', 'CPA', (60, 69))	('nano-curcumin', 'Chemical', '-', (9, 22))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('induce', 'PosReg', (53, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
133642	23755374	We found that nano-curcumin has a sensitizing effect on DC-mediated T cell cytotoxicity by increasing cell lysis on EAC cells.	('increasing', 'PosReg', (91, 101))	('cytotoxicity', 'Disease', (75, 87))	('nano-curcumin', 'Chemical', '-', (14, 27))	('EAC', 'Phenotype', 'HP:0011459', (116, 119))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('nano-curcumin', 'Var', (14, 27))	('cell lysis', 'CPA', (102, 112))
133643	23755374	We also observed that nano-curcumin increased the IFN-gamma secretion and decreased the TNF-alpha secretion in the co-culture of OE33 with CTLs and nano-curcumin.	('OE33', 'Chemical', '-', (129, 133))	('nano-curcumin', 'Chemical', '-', (148, 161))	('nano-curcumin', 'Var', (22, 35))	('IFN-gamma', 'Gene', '3458', (50, 59))	('IFN-gamma', 'Gene', (50, 59))	('increased', 'PosReg', (36, 45))	('TNF-alpha', 'Gene', '7124', (88, 97))	('decreased', 'NegReg', (74, 83))	('TNF-alpha', 'Gene', (88, 97))	('nano-curcumin', 'Chemical', '-', (22, 35))
133646	23755374	Instead, we found that nano-curcumin up-regulated the expression of the co-stimulatory molecule CD86 and reduced the levels of anti-inflammatory cytokines in activated T cells, asserting the role of nano-curcumin in anti-inflammatory processes.	('expression', 'MPA', (54, 64))	('nano-curcumin', 'Chemical', '-', (199, 212))	('nano-curcumin', 'Var', (23, 36))	('CD86', 'Gene', '942', (96, 100))	('CD86', 'Gene', (96, 100))	('up-regulated', 'PosReg', (37, 49))	('levels of anti-inflammatory cytokines', 'MPA', (117, 154))	('reduced', 'NegReg', (105, 112))	('nano-curcumin', 'Chemical', '-', (23, 36))
133647	23755374	This is as well in line with previous findings were it was shown that nano-curcumin reduces the levels of multiple pro-inflammatory cytokines (Bisht et al.,; Anand et al.,).	('nano-curcumin', 'Var', (70, 83))	('nano-curcumin', 'Chemical', '-', (70, 83))	('levels of multiple pro-inflammatory cytokines', 'MPA', (96, 141))	('reduces', 'NegReg', (84, 91))
133650	23755374	Our results confirm that nano-curcumin not only directly affects EAC cancer cell proliferation but also potentiates the immune response to the tumor cells, making this compound extremely attractive to be used in immune combinatorial therapies for EAC.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('EAC', 'Disease', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('nano-curcumin', 'Chemical', '-', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('EAC', 'Phenotype', 'HP:0011459', (247, 250))	('affects', 'Reg', (57, 64))	('immune response', 'CPA', (120, 135))	('EAC', 'Phenotype', 'HP:0011459', (65, 68))	('nano-curcumin', 'Var', (25, 38))	('potentiates', 'PosReg', (104, 115))	('cancer', 'Disease', (69, 75))
133748	33264481	The idea that tumor-derived cfDNA, known as circulating tumor DNA (ctDNA), is present in the circulation came from the observation that cfDNA derived from cancer patients harbored tumor-specific genetic alterations [11, 12].	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('patients', 'Species', '9606', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('genetic alterations', 'Var', (195, 214))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
133751	33264481	Crucially, the fraction of cfDNA which is released from primary tumors or metastases, referred to as ctDNA, harbors genetic alterations that can be potentially used as diagnostic, prognostic, and predictive biomarkers [11, 12].	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('metastases', 'Disease', (74, 84))	('genetic alterations', 'Var', (116, 135))	('metastases', 'Disease', 'MESH:D009362', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
133756	33264481	Quantitative PCR (qPCR) [31], BEAMing [32], and droplet digital PCR (ddPCR) [33] can detect individual point mutations in cfDNA and identify and quantify alterations at VAFs of 0.01% or less [32, 33].	('detect', 'Reg', (85, 91))	('BE', 'Chemical', 'MESH:D001608', (30, 32))	('point mutations', 'Var', (103, 118))	('cfDNA', 'Gene', (122, 127))
133759	33264481	ddPCR detects mutations in cfDNA with high sensitivity, but it is only suitable when the mutations are already known from previous tumor tissue-based analyses [42].	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cfDNA', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('mutations', 'Var', (14, 23))
133760	33264481	The overwhelming majority of cancers harbor genetic and epigenetic alterations in both coding and non-coding regions.	('genetic', 'Var', (44, 51))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))	('epigenetic alterations', 'Var', (56, 78))
133761	33264481	These alterations can influence normal gene expression and contribute to cancer occurrence and development [44].	('cancer', 'Disease', (73, 79))	('alterations', 'Var', (6, 17))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('development', 'CPA', (95, 106))	('normal gene expression', 'MPA', (32, 54))	('influence', 'Reg', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('contribute to', 'Reg', (59, 72))
133762	33264481	Genetic changes in cfDNA can potentially be used to detect cancers or track their dynamics during treatment in real time [45, 46].	('Genetic changes', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cfDNA', 'Gene', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))
133763	33264481	In particular, deep whole-genome sequencing (WGS) can identify signature mutations and detect chromatin openness state, an important epigenetic marker, whereas targeted gene panel sequencing (TGPS) can detect known cancer-specific mutations.	('TGPS', 'Disease', (192, 196))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('openness', 'Disease', 'MESH:D005597', (104, 112))	('detect', 'Reg', (87, 93))	('TGPS', 'Disease', 'None', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('openness', 'Disease', (104, 112))	('mutations', 'Var', (73, 82))
133764	33264481	Also, cfDNA bisulfite sequencing can characterize methylation status, another important cancer epigenetic marker, in specific regions of DNA [47].	('cancer', 'Disease', (88, 94))	('methylation status', 'Var', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))
133767	33264481	This requires simultaneous sequencing of DNA extracted from WBCs [50] to correctly attribute the cfDNA mutations to tumors.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (103, 112))	('cfDNA', 'Gene', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
133776	33264481	The cfDNA genetic profiles matched the status of the cancer and showed the diagnostic utility of mutations in 4 genes (TP53, fat atypical cadherin 3 [FAT3], mixed lineage leukemia 3 [MLL3], and ajuba LIM protein [AJUBA]).	('mutations', 'Var', (97, 106))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('MLL3', 'Gene', '58508', (183, 187))	('FAT3', 'Gene', (150, 154))	('mixed lineage leukemia 3', 'Gene', (157, 181))	('AJUBA', 'Gene', '84962', (213, 218))	('FAT3', 'Gene', '120114', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('fat atypical cadherin 3', 'Gene', '120114', (125, 148))	('fat atypical cadherin 3', 'Gene', (125, 148))	('mixed lineage leukemia 3', 'Gene', '58508', (157, 181))	('AJUBA', 'Gene', (213, 218))	('MLL3', 'Gene', (183, 187))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
133777	33264481	In both cfDNA and tumor tissues, the use of these mutations achieved 78.9% sensitivity, 100% specificity, and 92.3% diagnostic accuracy [56].	('tumor', 'Disease', (18, 23))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cfDNA', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
133780	33264481	NGS without MB produced background errors of 3.22% as the maximum frequency, which was reduced to 0.08% after inclusion of MB [58], suggesting that this combined approach can be used to detect cfDNA mutations in ESCC patients.	('ESCC', 'Disease', (212, 216))	('MB', 'Chemical', '-', (12, 14))	('cfDNA', 'Gene', (193, 198))	('mutations', 'Var', (199, 208))	('patients', 'Species', '9606', (217, 225))	('MB', 'Chemical', '-', (123, 125))
133781	33264481	Mutations in ctDNA of 38 EAC patients were detected using ddPCR and SiMSen-seq (simple, multiplexed, PCR-based barcoding of DNA for sensitive mutation detection) [59].	('patients', 'Species', '9606', (29, 37))	('Mutations', 'Var', (0, 9))	('EAC', 'Phenotype', 'HP:0011459', (25, 28))	('ctDNA', 'Gene', (13, 18))
133783	33264481	A deep sequencing comparison of pre- and postoperative plasma ctDNA in 11 ESCC patients showed that some ctDNA mutations were reduced in frequency or even disappeared postoperatively [61].	('mutations', 'Var', (111, 120))	('ESCC', 'Disease', (74, 78))	('ctDNA', 'Gene', (105, 110))	('patients', 'Species', '9606', (79, 87))	('disappeared', 'NegReg', (155, 166))	('reduced', 'NegReg', (126, 133))
133786	33264481	A subset of cancer-specific mutations could be detected in preoperative cfDNA from most patients at stages II and III.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (28, 37))
133788	33264481	In 21 EC patients with identified mutations (7 ESCC, 19 EAC, and 1 Barret's esophagus), cfDNA mutations were observed with a higher rate in ddPCR (8/21, 38%) than in NGS (3/21, 14%).	('patients', 'Species', '9606', (9, 17))	('ddPCR', 'Disease', (140, 145))	('mutations', 'Var', (94, 103))	('EAC', 'Phenotype', 'HP:0011459', (56, 59))	('cfDNA', 'Disease', (88, 93))
133789	33264481	During the follow-up period, 67% of patients with somatic cfDNA alterations during primary staging suffered from an early recurrence and had a shorter progression-free survival as compared with the patients who had cfDNA without somatic alterations.	('progression-free survival', 'CPA', (151, 176))	('cfDNA', 'Gene', (58, 63))	('shorter', 'NegReg', (143, 150))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (198, 206))	('alterations', 'Var', (64, 75))	('suffered', 'Reg', (99, 107))
133790	33264481	In contrast, tumor recurrence was only observed in 10% of patients with no detected mutations, suggesting that these cfDNA alterations in patients with locally advanced EC can predict recurrence postoperatively.	('tumor', 'Disease', (13, 18))	('cfDNA', 'Gene', (117, 122))	('predict', 'Reg', (176, 183))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('patients', 'Species', '9606', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('alterations', 'Var', (123, 134))	('patients', 'Species', '9606', (138, 146))
133803	33264481	VAFs of concordant mutations in serial plasma samples were useful not only for assessing tumor status but also for predicting ESCC recurrence.	('mutations', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('ESCC', 'Disease', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
133804	33264481	In particular, concordant mutations in cfDNA with high frequency appeared 6 months prior to the detection of recurrences by imaging tests in 2 ESCC patients.	('mutations', 'Var', (26, 35))	('cfDNA', 'Gene', (39, 44))	('patients', 'Species', '9606', (148, 156))
133823	33264481	Epigenetic alterations are early events during carcinogenesis [73], and in cancer patients these are reflected in cfDNA [74].	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Disease', (75, 81))	('carcinogenesis', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('carcinogenesis', 'Disease', 'MESH:D063646', (47, 61))
133826	33264481	Cancer cells exhibit two types of DNA methylation alteration: site-specific hypermethylation at the promoter of oncosuppressor genes and global DNA hypomethylation [76, 77].	('oncosuppressor genes', 'Gene', (112, 132))	('hypermethylation', 'Var', (76, 92))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('hypomethylation', 'Var', (148, 163))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
133830	33264481	Recently, an analysis of methylation patterns of long interspersed nuclear element (LINE-1) sequences, a good surrogate indicator of global DNA methylation, showed that hypomethylation of these sequences was present in cfDNA in 19 EAC patients [84].	('cfDNA', 'Disease', (219, 224))	('patients', 'Species', '9606', (235, 243))	('hypomethylation', 'Var', (169, 184))	('EAC', 'Phenotype', 'HP:0011459', (231, 234))
133831	33264481	Also, longitudinal studies on 2 BE patients suggested an association between methylation status of LINE-1 sequences in cfDNA and progression to EAC [77].	('cfDNA', 'Disease', (119, 124))	('LINE-1', 'Gene', (99, 105))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('EAC [77]', 'Disease', (144, 152))	('methylation status', 'Var', (77, 95))	('patients', 'Species', '9606', (35, 43))	('BE', 'Chemical', 'MESH:D001608', (32, 34))
133838	33264481	Recently, data from one study with longitudinal EAC samples indicated that ctDNA has the potential to be a dynamic biomarker to monitor treatment response in patients with EAC, and VAFs of some mutations were lowered or eliminated in ESCC patients' postoperative plasma [60].	('lowered', 'NegReg', (209, 216))	('patients', 'Species', '9606', (239, 247))	('mutations', 'Var', (194, 203))	('EAC', 'Phenotype', 'HP:0011459', (172, 175))	('eliminated', 'NegReg', (220, 230))	('EAC', 'Phenotype', 'HP:0011459', (48, 51))	('patients', 'Species', '9606', (158, 166))
133842	33264481	Thus, studies suggest that cfDNA analysis may enable detection of genetic alterations specific to molecular subtypes of cancer which are associated with mechanism of resistance and may be therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('genetic alterations', 'Var', (66, 85))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
133848	33264481	Similarly, multiple studies have shown that detection of tumor-specific mutations in cfDNA after surgery can predict prognosis in EC.	('mutations', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('predict', 'Reg', (109, 116))	('tumor', 'Disease', (57, 62))	('cfDNA', 'Gene', (85, 90))
133849	33264481	For example, in ESCC patients, an increased frequency of concordant somatic mutations in cfDNA occurred 6 months earlier than recurrences identified by imaging studies [56], and detection of somatic mutations in the cfDNA of EC patients at the time of primary staging may be indicative of a increased risk of postoperative tumor recurrence [42].	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('mutations', 'Var', (76, 85))	('postoperative tumor', 'Disease', (309, 328))	('ESCC', 'Disease', (16, 20))	('patients', 'Species', '9606', (228, 236))	('patients', 'Species', '9606', (21, 29))	('postoperative tumor', 'Disease', 'MESH:D010149', (309, 328))	('cfDNA', 'Gene', (216, 221))	('cfDNA', 'Gene', (89, 94))
133860	28643144	Survival was not longer in ypT0N0 patients than in ypStage I patients (HR 1.29; p = 0.377).	('ypT0N0', 'Var', (27, 33))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (34, 42))	('age', 'Gene', (55, 58))	('age', 'Gene', '5973', (55, 58))
133862	28643144	ypT0N0 patients, although not defined in the 8th edition, may be considered for inclusion in the ypStage I group.	('patients', 'Species', '9606', (7, 15))	('ypT0N0', 'Var', (0, 6))	('age', 'Gene', '5973', (101, 104))	('age', 'Gene', (101, 104))
133902	28643144	Survival for patients with ypT0N0 did not differ from that of ypStage I patients (HR, 1.29, 95% CI, 0.73-2.28; p = 0.377), whereas survival for patients with y pT0N1 was significantly shorter than that of ypStage I patients (HR, 4.34, 95% CI, 1.63-11.6; p = 0.003).	('patients', 'Species', '9606', (215, 223))	('age', 'Gene', (209, 212))	('y pT0N1', 'Var', (158, 165))	('patients', 'Species', '9606', (13, 21))	('age', 'Gene', (66, 69))	('age', 'Gene', '5973', (209, 212))	('patients', 'Species', '9606', (144, 152))	('shorter', 'NegReg', (184, 191))	('age', 'Gene', '5973', (66, 69))	('patients', 'Species', '9606', (72, 80))
133903	28643144	Because ypT0N1 patients had diminished survival as compared to ypStage I patients by multivariable Cox regression analysis, additional assessments were conducted to compare tumor characteristics among ypT0N0, ypT0N1, and ypStage I groups (Table 5).	('patients', 'Species', '9606', (15, 23))	('age', 'Gene', '5973', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('age', 'Gene', '5973', (225, 228))	('diminished', 'NegReg', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('survival', 'MPA', (39, 47))	('age', 'Gene', (225, 228))	('patients', 'Species', '9606', (73, 81))	('age', 'Gene', (67, 70))	('ypT0N1', 'Var', (8, 14))
133904	28643144	ypT0N1 patients had higher rates of concomitant organ resection (57%; p = 0.008), cN-positive disease (86%; p = 0.035), and use of preoperative chemoradiation therapy (100%; p = 0.019) than other groups; these results indicated that ypT0N1 patients had more advanced tumors at presentation.	('ypT0N1', 'Var', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('patients', 'Species', '9606', (240, 248))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('tumors', 'Disease', (267, 273))	('patients', 'Species', '9606', (7, 15))	('tumors', 'Disease', 'MESH:D009369', (267, 273))
133905	28643144	Of note, ypT1N1 patients (n = 8) in ypStage I group had excellent survival.	('patients', 'Species', '9606', (16, 24))	('age', 'Gene', '5973', (40, 43))	('age', 'Gene', (40, 43))	('ypT1N1', 'Var', (9, 15))
133907	28643144	Our findings suggest that ypT0N0 should be considered for inclusion in the ypStage I group, but the shorter survival observed in ypT0N1 patients needs further study to define the best category for staging.	('ypT0N1', 'Var', (129, 135))	('age', 'Gene', (79, 82))	('patients', 'Species', '9606', (136, 144))	('age', 'Gene', '5973', (79, 82))
133914	28643144	For example, ypT3N0 patients likely have better survival than do ypT3N1 patients (median survival in this study, 7.8 vs. 3.1 years, respectively; 3-year OS, 82% vs. 61%), although both ypT3N0 and ypT3N1 are included in ypStage II (Table 3).	('ypT3N0', 'Var', (13, 19))	('better', 'PosReg', (41, 47))	('patients', 'Species', '9606', (20, 28))	('age', 'Gene', (223, 226))	('age', 'Gene', '5973', (223, 226))	('patients', 'Species', '9606', (72, 80))
133917	28643144	In the current study, ypT0N0 patients did not have better survival than ypStage I patients.	('patients', 'Species', '9606', (29, 37))	('age', 'Gene', '5973', (76, 79))	('patients', 'Species', '9606', (82, 90))	('ypT0N0', 'Var', (22, 28))	('age', 'Gene', (76, 79))
133919	28643144	Theoretically, ypT0N1 cannot be categorized higher than ypStage I, because ypT1N1 is defined as the ypStage I group and showed excellent survival in the current study despite the small number of patients (n = 8).	('age', 'Gene', '5973', (104, 107))	('age', 'Gene', '5973', (60, 63))	('age', 'Gene', (104, 107))	('patients', 'Species', '9606', (195, 203))	('ypT1N1', 'Var', (75, 81))	('age', 'Gene', (60, 63))
133920	28643144	Based on comparisons of tumor characteristics (Table 5), the poor survival in the ypT0N1 group was thought to be mainly derived from advanced tumor status at presentation, which frequently required concomitant organ resections.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (24, 29))	('ypT0N1', 'Var', (82, 88))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
133921	28643144	A higher rate of chemoradiation therapy use may have contributed to the enhanced treatment effect in the primary tumor in the ypT0N1 group.	('tumor', 'Disease', (113, 118))	('ypT0N1', 'Var', (126, 132))	('enhanced', 'PosReg', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('treatment effect', 'CPA', (81, 97))
133923	28643144	reported that survival of ypT0N1 patients was similar to that of stage II patients rather than that of stage I patients.	('age', 'Gene', (105, 108))	('ypT0N1', 'Var', (26, 32))	('age', 'Gene', '5973', (67, 70))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (74, 82))	('age', 'Gene', '5973', (105, 108))	('age', 'Gene', (67, 70))	('patients', 'Species', '9606', (111, 119))
133924	28643144	reported that cN-positive status was associated with diminished survival among patients with ypN0 status, indicating that downstaged ypStage does not guarantee survival similar to that of ypStage without downstaging.	('diminished', 'NegReg', (53, 63))	('age', 'Gene', '5973', (128, 131))	('age', 'Gene', (192, 195))	('age', 'Gene', (137, 140))	('survival', 'MPA', (64, 72))	('ypN0 status', 'Var', (93, 104))	('age', 'Gene', '5973', (137, 140))	('age', 'Gene', (128, 131))	('patients', 'Species', '9606', (79, 87))	('cN-positive status', 'Var', (14, 32))	('age', 'Gene', '5973', (192, 195))
133925	28643144	also reported that persistent ypN-positive status was associated with poor survival, regardless of pathological response in the primary tumor (tumor regression grade).	('poor', 'NegReg', (70, 74))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('ypN-positive status', 'Var', (30, 49))	('survival', 'MPA', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
133928	28643144	When comparing 3-year OS of ypT2N0 versus ypT2N1 (86% vs. 78%) and ypT3N0 vs. ypT3N1 (82% vs. 61%), the impact of ypN1 status was modest, and ypT stage seemed equally or more important in survival prediction in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('age', 'Gene', '5973', (148, 151))	('gastric cancer', 'Disease', (211, 225))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('age', 'Gene', (148, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('ypT3N0', 'Var', (67, 73))
133952	28643144	Particularly in ypT0N1 patients who had poor survival and ypT1N1 patients who had excellent survival, careful interpretation of those results is necessary.	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (23, 31))	('ypT0N1', 'Var', (16, 22))	('ypT1N1', 'Var', (58, 64))
134027	29937461	Using a cell culture system, we found that (1) acrolein caused necrosis in Ramos Burkitt's lymphoma cells, (2) the necrosis was inhibited by preincubation of acrolein with milk, and (3) acrolein formed adducts with milk proteins.	('milk', 'Gene', (172, 176))	('acrolein', 'Chemical', 'MESH:D000171', (186, 194))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (81, 99))	('necrosis', 'Disease', (63, 71))	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	("Burkitt's lymphoma", 'Disease', (81, 99))	('milk', 'Gene', (215, 219))	('adducts', 'Interaction', (202, 209))	('milk', 'Gene', '100532204', (172, 176))	('necrosis', 'Disease', 'MESH:D009336', (63, 71))	('necrosis', 'Disease', (115, 123))	('acrolein', 'Chemical', 'MESH:D000171', (47, 55))	('acrolein', 'Var', (47, 55))	('milk', 'Gene', '100532204', (215, 219))	('acrolein', 'Chemical', 'MESH:D000171', (158, 166))	('necrosis', 'Disease', 'MESH:D009336', (115, 123))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (81, 99))
134036	29937461	Acrolein is also a strong inhibitor of aldehyde dehydrogenase, which is an acetaldehyde detoxification enzyme, suggesting that acrolein may augment the toxicity of acetaldehyde.	('acetaldehyde', 'Chemical', 'MESH:D000079', (75, 87))	('augment', 'PosReg', (140, 147))	('Acrolein', 'Chemical', 'MESH:D000171', (0, 8))	('acetaldehyde', 'Chemical', 'MESH:D000079', (164, 176))	('aldehyde', 'Chemical', 'MESH:D000447', (39, 47))	('acrolein', 'Chemical', 'MESH:D000171', (127, 135))	('toxicity', 'Disease', 'MESH:D064420', (152, 160))	('aldehyde', 'Chemical', 'MESH:D000447', (79, 87))	('toxicity', 'Disease', (152, 160))	('acrolein', 'Var', (127, 135))	('aldehyde', 'Chemical', 'MESH:D000447', (168, 176))
134038	29937461	Furthermore, it is well known that acrolein is metabolized from cyclophosphamide, a chemotherapeutic drug, and causes bladder inflammation and cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('bladder inflammation', 'Disease', (118, 138))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (64, 80))	('causes', 'Reg', (111, 117))	('acrolein', 'Chemical', 'MESH:D000171', (35, 43))	('bladder inflammation', 'Disease', 'MESH:D001745', (118, 138))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('acrolein', 'Var', (35, 43))
134089	29937461	Given that acetaldehyde is a known carcinogen of esophageal cancer, acrolein may cause esophageal cancer in a direct or indirect manner.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cause', 'Reg', (81, 86))	('esophageal cancer', 'Disease', (49, 66))	('esophageal cancer', 'Disease', (87, 104))	('acrolein', 'Chemical', 'MESH:D000171', (68, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('acrolein', 'Var', (68, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('acetaldehyde', 'Chemical', 'MESH:D000079', (11, 23))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
134109	30069061	These results suggest that Twist1-Prrx1-TNC PFL may be a core component of bistable (ON/OFF) switch determining fibroblast activation in wound healing and various fibrotic diseases.	('Twist1-Prrx1-TNC', 'Var', (27, 43))	('fibrotic diseases', 'Disease', 'MESH:D004194', (163, 180))	('fibroblast', 'CPA', (112, 122))	('fibrotic diseases', 'Disease', (163, 180))
134131	30069061	WT mice), exogenous TNC generated multifocal fibroblastic nodules that were histologically similar to the fibrotic foci of IPF whereas in the wound sites of the control group (mice injected with PBS), the fibroblasts exhibited a nonproliferative and mature fibroblast phenotype, which is highly compatible with the normal remodeling phase (Fig.	('exhibited', 'Reg', (217, 226))	('mice', 'Species', '10090', (3, 7))	('nonproliferative', 'CPA', (229, 245))	('TNC', 'Var', (20, 23))	('PBS', 'Disease', 'MESH:D011535', (195, 198))	('mice', 'Species', '10090', (176, 180))	('exogenous', 'Var', (10, 19))	('PBS', 'Disease', (195, 198))
134134	30069061	In addition, mIHC revealed that fibroblasts expressing all three genes, Twist1, Prrx1, and TNC, were exclusively concentrated within fibrotic nodules generated by exogenous TNC (Fig.	('mIHC', 'Gene', '11797', (13, 17))	('Twist1', 'Gene', (72, 78))	('mIHC', 'Gene', (13, 17))	('TNC', 'Var', (173, 176))	('TNC', 'Gene', (91, 94))	('Prrx1', 'Gene', (80, 85))
134141	30069061	Based on our in vitro, in vivo and computational studies strongly suggesting that Twist-Prrx1-TNC PFL may induce perpetual fibroblast activation under pathologic conditions, we further investigated clinical implications of this PFL in CAFs and fibrotic diseases.	('induce', 'Reg', (106, 112))	('fibrotic diseases', 'Disease', 'MESH:D004194', (244, 261))	('CAFs', 'Disease', (235, 239))	('clinical', 'Species', '191496', (198, 206))	('fibrotic diseases', 'Disease', (244, 261))	('Twist-Prrx1-TNC', 'Var', (82, 97))	('perpetual fibroblast activation', 'CPA', (113, 144))
134145	30069061	These data strongly indicate that the coexpression of these three genes in CAFs is common in various types of cancers.	('cancers', 'Disease', (110, 117))	('common', 'Reg', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('coexpression', 'Var', (38, 50))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
134147	30069061	The results show that gene signatures related to ECM remodeling, angiogenesis, apoptosis, epithelial-mesenchymal transition, and p53 suppression were significantly enriched in the Twist1/Prrx1/TNC (+/+/+) group in all 11 cancer types (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('p53', 'Gene', '22060', (129, 132))	('Twist1/Prrx1/TNC (+/+/+', 'Var', (180, 203))	('cancer', 'Disease', (221, 227))	('apoptosis', 'CPA', (79, 88))	('epithelial-mesenchymal transition', 'CPA', (90, 123))	('p53', 'Gene', (129, 132))	('suppression', 'NegReg', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('angiogenesis', 'CPA', (65, 77))
134150	30069061	There was also a very strong association between the Twist1-Prrx1-TNC PFL expression in CAFs and the patients' poor prognosis in esophageal cancer (P < 0.001; Fig.	('patients', 'Species', '9606', (101, 109))	('Twist1-Prrx1-TNC', 'Var', (53, 69))	('esophageal cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
134158	30069061	Recently, TNC has emerged as an essential determinant of fibroblast activation; for instance, it was revealed to induce persistent fibroblast activation by functioning as a damage-associated molecular pattern; TNC was also shown to generate the fibrogenic niche in kidney fibrosis.	('kidney fibrosis', 'Phenotype', 'HP:0030760', (265, 280))	('kidney fibrosis', 'Disease', 'MESH:D005355', (265, 280))	('TNC', 'Var', (210, 213))	('kidney fibrosis', 'Disease', (265, 280))	('fibrogenic niche', 'CPA', (245, 261))
134166	30069061	Indeed, exogenous TNC-mediated persistent PFL activation not only led to hyperactivation of fibroblasts but also generated fibrotic foci very similar to IPF.	('fibrotic foci very', 'Disease', (123, 141))	('fibroblasts', 'CPA', (92, 103))	('activation', 'PosReg', (46, 56))	('TNC-mediated', 'Gene', (18, 30))	('exogenous', 'Var', (8, 17))	('hyperactivation', 'Disease', 'MESH:D011504', (73, 88))	('hyperactivation', 'Disease', (73, 88))	('fibrotic foci very', 'Disease', 'MESH:C565785', (123, 141))	('PFL', 'Gene', (42, 45))
134170	30069061	6 and 7); In this experiment, FSP1-promoter Cre mice were employed to generate fibroblast-specific Twist1 deletion.	('FSP1', 'Gene', (30, 34))	('mice', 'Species', '10090', (48, 52))	('deletion', 'Var', (106, 114))	('FSP1', 'Gene', '20198', (30, 34))	('Twist1', 'Gene', (99, 105))
134173	30069061	For instance, tamoxifen-mediated Twist1 deletion in adult tissue using the Cre-ER/loxP system did not reveal any fatal effects.	('deletion', 'Var', (40, 48))	('tamoxifen', 'Chemical', 'MESH:D013629', (14, 23))	('Twist1', 'Gene', (33, 39))
134175	30069061	In conclusion, we confirmed that Twist1, Prrx1, and TNC create a PFL in activated fibroblasts, and we inferred that this Twist1-Prrx1-TNC PFL operated as a bistable (ON/OFF) switch through mathematical modeling; this concept has been thoroughly demonstrated by in vitro, in vivo, and clinical studies.	('Twist1', 'Var', (33, 39))	('Prrx1', 'Var', (41, 46))	('clinical', 'Species', '191496', (284, 292))	('TNC', 'Var', (52, 55))
134184	30069061	Sections were then incubated with primary antibodies: anti-Twist1 (ab50887, 1:200), anti-Prrx1 (HPA051084, 1:200), and anti-Tenascin-C (ab108930, 1:500) in TBST containing 4% skim milk for 60 min at room temperature.	('TBST', 'Chemical', '-', (156, 160))	('Tenascin-C', 'Gene', (124, 134))	('anti-Prrx1', 'Var', (84, 94))	('Tenascin-C', 'Gene', '21923', (124, 134))	('anti-Twist1', 'Var', (54, 65))
134189	30069061	We selected 40 Twist1-high expressing group and 39 Twist1-low expressing group from 185 esophageal cancer patients included in TCGA dataset.	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('Twist1-high expressing', 'Var', (15, 37))	('patients', 'Species', '9606', (106, 114))	('esophageal cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
134192	30069061	Protein detection for Western blotting was performed using ECL reagent (#1705061, Bio-Rad).	('Rad', 'Gene', (86, 89))	('Rad', 'Gene', '56437', (86, 89))	('#1705061', 'Var', (72, 80))
134201	30069061	Fibroblasts were centrifuged at 800 rpm for 8 min; they were washed twice with PBS and cultured in D/F12 media supplemented with 10% FBS and 1% antibiotics.	('FBS', 'Disease', 'MESH:D005198', (133, 136))	('D/F12', 'Var', (99, 104))	('FBS', 'Disease', (133, 136))	('D/F12', 'SUBSTITUTION', 'None', (99, 104))	('PBS', 'Disease', 'MESH:D011535', (79, 82))	('PBS', 'Disease', (79, 82))
134215	30069061	Twist1-DNA complexes were immunoprecipitated using Protein G Dynabeads (Invitrogen) conjugated with anti-Twist1 IgG (Abcam, ab50887) or control normal mouse IgG (sc2025, Santa Cruz).	('anti-Twist1', 'Var', (100, 111))	('mouse', 'Species', '10090', (151, 156))	('IgG', 'Protein', (112, 115))
134228	30069061	Mice with conditional deletion of Twist1 were generated by crossing FSP1-Cre-expressing mice (FSP1-Cre from Jackson Laboratory, Bar Harbor, ME, stock no.	('FSP1', 'Gene', (68, 72))	('FSP1', 'Gene', '20198', (94, 98))	('deletion', 'Var', (22, 30))	('FSP1', 'Gene', '20198', (68, 72))	('Mice', 'Species', '10090', (0, 4))	('FSP1', 'Gene', (94, 98))	('mice', 'Species', '10090', (88, 92))	('Twist1', 'Gene', (34, 40))
134238	30069061	Slides were blocked with 4% skim milk in TBST for 30 min and incubated in primary antibodies: anti-Twist1 (ab50887, 1:200), anti-Prrx1 (HPA051084, 1:200), and anti-TNC (ab108930, 1:500) for 60 min at room temperature.	('anti-Prrx1', 'Var', (124, 134))	('TBST', 'Chemical', '-', (41, 45))	('ab50887', 'Var', (107, 114))	('anti-Twist1', 'Var', (94, 105))
134240	30069061	In ImageJ Fiji, coregistered and exported images were processed with Plugin, color deconvolution for separating of DAB/AEC and hematoxylin staining signal (Twist1-green, Prrx1-red, TNC-yellow and hematoxylin-blue).	('hematoxylin', 'Chemical', 'MESH:D006416', (196, 207))	('hematoxylin', 'Chemical', 'MESH:D006416', (127, 138))	('Twist1-green', 'Var', (156, 168))	('AEC', 'Chemical', 'MESH:C020702', (119, 122))	('Prrx1-red', 'Var', (170, 179))	('DAB', 'Chemical', 'MESH:C000469', (115, 118))
134254	28973012	Furthermore, among the Asian populations, the prevalence of the variant allele of aldehyde dehydrogenase-2, which breaks down acetaldehyde to acetate in the metabolism of alcohol, is much higher (28-45%) in comparison with other ethnic groups.	('breaks down', 'NegReg', (114, 125))	('breaks down acetaldehyde', 'Phenotype', 'HP:0003533', (114, 138))	('aldehyde dehydrogenase-2', 'Gene', '217', (82, 106))	('acetaldehyde', 'Chemical', 'MESH:D000079', (126, 138))	('higher', 'PosReg', (188, 194))	('variant', 'Var', (64, 71))	('alcohol', 'Chemical', 'MESH:D000438', (171, 178))	('aldehyde dehydrogenase-2', 'Gene', (82, 106))	('breaks down', 'Phenotype', 'HP:0001061', (114, 125))	('acetate', 'Chemical', 'MESH:D000085', (142, 149))
134263	28973012	The primary endpoint of this study was newly diagnosed esophageal, gastric, and colorectal cancers, which were defined with the International Classification of Diseases, 10th revision (ICD-10) codes (C150-155, C158, C159, C160 except for C1699 and C180-200) and the National Cancer Registry database.	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('C158', 'Var', (210, 214))	('C150-155', 'Var', (200, 208))	('C160', 'Var', (222, 226))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('colorectal cancers', 'Disease', 'MESH:D015179', (80, 98))	('esophageal', 'Disease', (55, 65))	('gastric', 'Disease', 'MESH:D013274', (67, 74))	('gastric', 'Disease', (67, 74))	('Cancer', 'Disease', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('C159', 'Var', (216, 220))	('Cancer', 'Phenotype', 'HP:0002664', (275, 281))	('colorectal cancers', 'Disease', (80, 98))	('Cancer', 'Disease', 'MESH:D009369', (275, 281))
134272	28973012	The presence of hypertension was defined if when the presence of at least one claim per year for the prescription of antihypertensive agent under ICD-10 codes I10-I15 was confirmed.	('hypertension', 'Phenotype', 'HP:0000822', (16, 28))	('I10-I15', 'Var', (159, 166))	('hypertension', 'Disease', 'MESH:D006973', (16, 28))	('hypertension', 'Disease', (16, 28))
134286	28973012	Regular exercise was associated with the elevated risk of the three gastrointestinal cancers.	('Regular exercise', 'Var', (0, 16))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('gastrointestinal cancers', 'Disease', (68, 92))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (68, 91))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (68, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
134288	28973012	The adjusted hazard ratios of all of the three cancers in those who consumed < 10 g per day (light drinking) were an adverse relationship (S1 Table).	('< 10 g', 'Var', (77, 83))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
134291	28973012	Among the three gastrointestinal cancers, esophageal cancer was the most associated with alcohol consumption as well as with the amount of alcohol consumption.	('esophageal cancer', 'Disease', (42, 59))	('gastrointestinal cancers', 'Disease', (16, 40))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (16, 40))	('alcohol', 'Chemical', 'MESH:D000438', (89, 96))	('alcohol', 'Chemical', 'MESH:D000438', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (16, 39))	('alcohol consumption', 'Var', (89, 108))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('associated', 'Interaction', (73, 83))
134309	28973012	We showed that prediagnosis alcohol consumption of even less than 10g per day was associated with a significantly higher risk of esophageal (squamous cell-type), stomach, and colorectal cancer in a large cohort of South Korean adults.	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colorectal cancer', 'Disease', (175, 192))	('stomach', 'Disease', (162, 169))	('less than 10g', 'Var', (56, 69))	('alcohol', 'Chemical', 'MESH:D000438', (28, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))
134320	28973012	While, there is a report that moderate amount of alcohol consumption compared with little or no alcohol consumption was associated with a reduced risk of colorectal cancer, a recent meta-analysis showed no association between light alcohol consumption and colorectal cancer risk.	('alcohol', 'Chemical', 'MESH:D000438', (232, 239))	('colorectal cancer', 'Disease', (256, 273))	('reduced', 'NegReg', (138, 145))	('colorectal cancer', 'Disease', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))	('moderate amount', 'Var', (30, 45))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('colorectal cancer', 'Disease', 'MESH:D015179', (256, 273))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (256, 273))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))
134327	28973012	The difference in frequency of polymorphism on the aldehyde dehydrogenase-2 is often addressed as a possible mechanism for the conflicting results in the association between alcohol and the three gastrointestinal cancers.	('association', 'Interaction', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('polymorphism', 'Var', (31, 43))	('alcohol', 'Chemical', 'MESH:D000438', (174, 181))	('aldehyde dehydrogenase-2', 'Gene', '217', (51, 75))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('gastrointestinal cancers', 'Disease', (196, 220))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (196, 220))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (196, 219))	('aldehyde dehydrogenase-2', 'Gene', (51, 75))
134328	28973012	The relatively high prevalence of the variant genotype (poor metabolizer) in Asian populations may account for the stronger association between alcohol and gastric and colorectal neoplasia observed in Asian studies.	('neoplasia', 'Phenotype', 'HP:0002664', (179, 188))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (168, 188))	('alcohol', 'Chemical', 'MESH:D000438', (144, 151))	('gastric', 'Disease', 'MESH:D013274', (156, 163))	('gastric', 'Disease', (156, 163))	('variant', 'Var', (38, 45))	('colorectal neoplasia', 'Disease', (168, 188))
134334	28973012	This study showed an unexpected adverse effect of exercise for prevention of the three cancers and this might come from recall bias or other compounding factors.	('cancers', 'Disease', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('exercise', 'Var', (50, 58))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
134346	28973012	Some studies have evaluated the association between molecularly distinct colorectal cancer subtypes defined by microsatellite instability, CpG island methylator phenotype and/or BRAF mutation status and alcohol consumption.	('BRAF', 'Gene', (178, 182))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('mutation', 'Var', (183, 191))	('BRAF', 'Gene', '673', (178, 182))	('alcohol', 'Chemical', 'MESH:D000438', (203, 210))
134360	28405153	Females are heterozygous or mosaic for mutation in the PORCN gene; affected males are typically mosaic.	('PORCN', 'Gene', (55, 60))	('PORCN', 'Gene', '64840', (55, 60))	('mutation', 'Var', (39, 47))
134467	21162752	In a previously analyzed retrospective cohort, we showed a reduction in postoperative nosocomial infections in patients with SDD compared to patients without SDD (data not published at the time).	('SDD', 'Var', (125, 128))	('postoperative nosocomial infections', 'Disease', (72, 107))	('SDD', 'Chemical', 'MESH:C003361', (158, 161))	('reduction', 'NegReg', (59, 68))	('postoperative nosocomial infections', 'Disease', 'MESH:D010149', (72, 107))	('patients', 'Species', '9606', (141, 149))	('SDD', 'Chemical', 'MESH:C003361', (125, 128))	('patients', 'Species', '9606', (111, 119))
134507	21162752	Patients without SDD were compared to the patients of the prospective cohort with SDD (Table 2); the postoperative 30-day mortality rate was significantly lower in patients with SDD (1.2% vs. 17.6%; p = 0.001).	('SDD', 'Chemical', 'MESH:C003361', (82, 85))	('SDD', 'Chemical', 'MESH:C003361', (178, 181))	('SDD', 'Chemical', 'MESH:C003361', (17, 20))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (155, 160))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (42, 50))	('SDD', 'Var', (178, 181))
134513	21162752	This observational study corroborates the hypothesis that SDD reduces perioperative morbidity and mortality in patients who undergo a distal esophageal anastomosis.	('perioperative morbidity', 'CPA', (70, 93))	('reduces', 'NegReg', (62, 69))	('esophageal anastomosis', 'Disease', (141, 163))	('mortality', 'CPA', (98, 107))	('SDD', 'Chemical', 'MESH:C003361', (58, 61))	('esophageal anastomosis', 'Disease', 'MESH:D004941', (141, 163))	('esophageal anastomosis', 'Phenotype', 'HP:0100628', (141, 163))	('SDD', 'Var', (58, 61))	('patients', 'Species', '9606', (111, 119))
134516	21162752	The perioperative mortality rate of patients who postoperatively developed an anastomotic leakage was clearly lower in the SDD group, although this difference was not significant.	('SDD', 'Chemical', 'MESH:C003361', (123, 126))	('patients', 'Species', '9606', (36, 44))	('lower', 'NegReg', (110, 115))	('SDD', 'Var', (123, 126))	('anastomotic leakage', 'MPA', (78, 97))
134529	21162752	However, in that study, SDD was not applied in a standardized fashion, and pulmonary infections were not significantly reduced in the SDD group.	('pulmonary infection', 'Phenotype', 'HP:0006532', (75, 94))	('pulmonary infections', 'Disease', (75, 95))	('SDD', 'Chemical', 'MESH:C003361', (134, 137))	('pulmonary infections', 'Disease', 'MESH:D008171', (75, 95))	('pulmonary infections', 'Phenotype', 'HP:0006532', (75, 95))	('SDD', 'Chemical', 'MESH:C003361', (24, 27))	('reduced', 'NegReg', (119, 126))	('SDD', 'Var', (134, 137))
134539	34031527	Our data suggest that the inhibitors of TTK and possibly other genes identified in this study have potential to inhibit/reduce growth and spontaneous as well as chemotherapy-induced genomic instability in EAC and possibly other cancers.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('growth', 'CPA', (127, 133))	('cancers', 'Disease', (228, 235))	('EAC', 'Disease', (205, 208))	('inhibit/reduce', 'NegReg', (112, 126))	('inhibitors', 'Var', (26, 36))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('TTK', 'Gene', (40, 43))	('reduce growth', 'Phenotype', 'HP:0001510', (120, 133))	('EAC', 'Phenotype', 'HP:0011459', (205, 208))
134546	34031527	Evaluation of single-nucleotide polymorphisms (SNPs) in patient genomes has shown that in addition to EAC, genomic changes can also be seen in a majority of Barrett's esophagus cases.	('single-nucleotide polymorphisms', 'Var', (14, 45))	('EAC', 'Phenotype', 'HP:0011459', (102, 105))	("Barrett's esophagus", 'Disease', (157, 176))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (157, 176))	('patient', 'Species', '9606', (56, 63))
134550	34031527	Moreover, it has been shown that although mutational load in precancerous Barrett's esophagus cases is lower than in EAC, it is higher than that observed in certain other cancer types.	('higher', 'Reg', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (74, 93))	('cancer', 'Disease', (171, 177))	('lower', 'NegReg', (103, 108))	('EAC', 'Phenotype', 'HP:0011459', (117, 120))	('mutational', 'Var', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
134563	34031527	Although BUB1B did not show any impact in siRNA screen, its knockdown by CRISPR/Cas9 resulted in a significant inhibition of HR activity by all three guides.	('HR activity', 'CPA', (125, 136))	('BUB1B', 'Gene', '701', (9, 14))	('BUB1B', 'Gene', (9, 14))	('knockdown', 'Var', (60, 69))	('inhibition', 'NegReg', (111, 121))
134575	34031527	Normal primary human esophageal epithelial cells transduced with control plasmid or those overexpressing TTK, TPX2, or RAD54B (shown in Fig.	('RAD54B', 'Var', (119, 125))	('TPX2', 'Gene', (110, 114))	('TTK', 'Gene', (105, 108))	('human', 'Species', '9606', (15, 20))
134576	34031527	The somatic mutations in a cancer genome bear specific signatures or scar marks of distinct mutational processes, or the mechanisms that give rise to these mutations.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('scar', 'Phenotype', 'HP:0100699', (69, 73))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
134583	34031527	To evaluate the impact of TTK inhibitor on efficacy of chemotherapeutic agents, EAC cell lines (FLO-1 and OE19) were treated with inhibitor, alone as well as in the presence of 5-fluorouracil or cisplatin, and cell viability measured after 72 h. TTK inhibitor increased cytotoxicity of both the fluorouracil (Fig.	('inhibitor', 'Var', (250, 259))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (177, 191))	('TTK', 'Gene', (246, 249))	('cytotoxicity', 'Disease', 'MESH:D064420', (270, 282))	('fluorouracil', 'Chemical', 'MESH:D005472', (295, 307))	('fluorouracil', 'Chemical', 'MESH:D005472', (179, 191))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))	('increased', 'PosReg', (260, 269))	('EAC', 'Phenotype', 'HP:0011459', (80, 83))	('cytotoxicity', 'Disease', (270, 282))
134585	34031527	6e) show that TTK inhibitor synergistically increased the cytotoxicity of both chemotherapeutic agents in both cell lines tested.	('TTK', 'Gene', (14, 17))	('inhibitor', 'Var', (18, 27))	('cytotoxicity', 'Disease', (58, 70))	('increased', 'PosReg', (44, 53))	('cytotoxicity', 'Disease', 'MESH:D064420', (58, 70))
134596	34031527	Using EAC and MM as model systems, we previously showed that dysregulated HR significantly contributes to genomic instability, development of drug resistance, and tumor growth.	('genomic instability', 'CPA', (106, 125))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('EAC', 'Phenotype', 'HP:0011459', (6, 9))	('development', 'CPA', (127, 138))	('drug resistance', 'Phenotype', 'HP:0020174', (142, 157))	('tumor', 'Disease', (163, 168))	('dysregulated', 'Var', (61, 73))	('contributes', 'Reg', (91, 102))
134604	34031527	Cancer cells with increased genetic instability also show increased sensitivity to suppression of TPX2.	('increased', 'PosReg', (58, 67))	('suppression', 'NegReg', (83, 94))	('TPX2', 'Gene', (98, 102))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('genetic instability', 'Var', (28, 47))	('sensitivity', 'MPA', (68, 79))
134611	34031527	Similarly, Signature 9 indicates activity of AID, a gene that creates mutations in DNA by deamination of cytosine to uracil and contributes to somatic hypermutation and class-switch recombination.	('cytosine', 'Chemical', 'MESH:D003596', (105, 113))	('mutations', 'Var', (70, 79))	('uracil', 'Chemical', 'MESH:D014498', (117, 123))	('DNA', 'Gene', (83, 86))	('deamination of cytosine to uracil', 'MPA', (90, 123))	('contributes', 'Reg', (128, 139))
134612	34031527	Our functional screens, subsequent loss- and gain-of-function studies, and previous investigations in EAC suggest that dysregulated HR is probably a common or predominant mechanism that drives genomic instability in EAC and possibly in other cancers.	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancers', 'Disease', (242, 249))	('EAC', 'Phenotype', 'HP:0011459', (102, 105))	('EAC', 'Phenotype', 'HP:0011459', (216, 219))	('dysregulated', 'Var', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('EAC', 'Disease', (216, 219))	('genomic instability', 'MPA', (193, 212))
134615	34031527	Evidence from pancreatic and breast cancers suggests that the mechanism of cell death following treatment with TTK inhibitors is induction of genomic instability.	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('TTK', 'Gene', (111, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (29, 43))	('pancreatic and breast cancers', 'Disease', 'MESH:D001943', (14, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('death', 'Disease', 'MESH:D003643', (80, 85))	('death', 'Disease', (80, 85))	('inhibitors', 'Var', (115, 125))	('genomic instability', 'MPA', (142, 161))
134630	34031527	Consistently, we have demonstrated that inhibition of HR in EAC cells inhibits genomic instability and tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inhibition', 'Var', (40, 50))	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('genomic instability', 'CPA', (79, 98))	('tumor', 'Disease', (103, 108))	('inhibits', 'NegReg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
134631	34031527	Our recent data in MM have also demonstrated that inhibition of APEX1 nuclease, a gene that drives genomic evolution in myeloma, increases cytotoxicity while inhibiting genomic instability caused by a chemotherapeutic agent.	('inhibition', 'Var', (50, 60))	('inhibiting', 'NegReg', (158, 168))	('APEX1', 'Gene', '328', (64, 69))	('increases cytotoxicity', 'Disease', 'MESH:D064420', (129, 151))	('increases cytotoxicity', 'Disease', (129, 151))	('myeloma', 'Disease', (120, 127))	('genomic instability', 'MPA', (169, 188))	('APEX1', 'Gene', (64, 69))	('myeloma', 'Disease', 'MESH:D009101', (120, 127))
134632	34031527	Small-molecule inhibitors of TTK and other genes identified in this study have the potential to inhibit/delay genomic evolution and tumor growth.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('Small-molecule', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('inhibit/delay', 'NegReg', (96, 109))	('tumor', 'Disease', (132, 137))	('TTK', 'Gene', (29, 32))	('genomic evolution', 'CPA', (110, 127))
134649	34031527	The mice were exposed to 150 rads x-irradiation and injected subcutaneously with 5 x 106 EAC (FLO-1) cells, either untransduced (for evaluation of TTK inhibitor) or transduced with shRNAs (control or those targeting TTK, TPX2, and RAD54B).	('transduced', 'Var', (165, 175))	('EAC', 'Phenotype', 'HP:0011459', (89, 92))	('mice', 'Species', '10090', (4, 8))	('shRNAs', 'Gene', (181, 187))
134751	32554852	Previous studies have indicated that complex epigenetic and genetic changes may result in the progression of esophageal squamous cell carcinoma (ESCC).	('result in', 'Reg', (80, 89))	('esophageal squamous cell carcinoma', 'Disease', (109, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (109, 143))	('epigenetic', 'Var', (45, 55))
134759	32554852	Crk knock-down (KD) caused a marked inhibition of GC cell invasion.	('inhibition', 'NegReg', (36, 46))	('GC cell invasion', 'CPA', (50, 66))	('knock-down', 'Var', (4, 14))	('Crk', 'Gene', '1398', (0, 3))	('Crk', 'Gene', (0, 3))
134766	32554852	To assess the role of miR-126 in xenograft ESCC generation, we subcutaneously injected nude BALB/c mice with TE13-miR-126i or TE13-NC cells and observed the animals every day for tumor formation.	('mice', 'Species', '10090', (99, 103))	('TE13-miR-126i', 'Var', (109, 122))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('TE13-miR-126i', 'Chemical', '-', (109, 122))	('tumor', 'Disease', (179, 184))
134767	32554852	First, miR-126 expression was measured in esophageal tissues to confirm miR-126 knock-down in the miR-126-silenced mice (Figure 2A).	('mice', 'Species', '10090', (115, 119))	('knock-down', 'Var', (80, 90))	('miR-126', 'Gene', (72, 79))
134770	32554852	Likewise, the results of a soft agar CFA showed that aberrant miR-126 expression caused an obvious reduction in the colony numbers formed by TE13 and Eca109 cells, whereas the NC-inhibitor had no effect (Figure 3C, 3D).	('miR-126', 'Gene', (62, 69))	('reduction', 'NegReg', (99, 108))	('expression', 'MPA', (70, 80))	('agar', 'Chemical', 'MESH:D000362', (32, 36))	('colony numbers formed', 'CPA', (116, 137))	('aberrant', 'Var', (53, 61))
134774	32554852	Autophagy was enhanced in the two ESCC cell lines following miR-126 inhibition, as indicated by the augmented LC3B biosynthesis and processing and p62 degradation (two main indicators of autophagy) (Figure 5C, 5D).	('p62', 'Gene', '23636', (147, 150))	('LC3B', 'Gene', '81631', (110, 114))	('LC3B', 'Gene', (110, 114))	('inhibition', 'Var', (68, 78))	('enhanced', 'PosReg', (14, 22))	('p62', 'Gene', (147, 150))	('augmented', 'PosReg', (100, 109))	('Autophagy', 'CPA', (0, 9))	('processing', 'CPA', (132, 142))	('miR-126', 'Gene', (60, 67))
134782	32554852	Tumorigenesis is a synergistic process involving the activation of multiple oncogenes, tumor inhibitor genes, and epigenetic alterations, all of which lead to tumor formation.	('oncogenes', 'Gene', (76, 85))	('epigenetic alterations', 'Var', (114, 136))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('activation', 'PosReg', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Tumorigenesis', 'CPA', (0, 13))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (159, 164))	('lead to', 'Reg', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
134783	32554852	In vivo experiments showed that miR-126 knock-down inhibited ESCC tumor growth in mice and inhibited the expression of STAT3, an essential oncogene and therapeutic target.	('mice', 'Species', '10090', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('knock-down', 'Var', (40, 50))	('tumor', 'Disease', (66, 71))	('inhibited', 'NegReg', (91, 100))	('ESCC', 'Disease', (61, 65))	('STAT3', 'Gene', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inhibited', 'NegReg', (51, 60))	('expression', 'MPA', (105, 115))	('miR-126', 'Gene', (32, 39))
134787	32554852	Previous DLRA results showed that STAT3 acts directly on miR-126 in ESCC and plays a role in many diverse biological processes, whereas phosphorylated STAT3 regulates a number of different genes, including Bcl-xL, Bcl-2, VEGF, and MMPs.	('VEGF', 'Gene', (221, 225))	('MMPs', 'Gene', (231, 235))	('miR-126', 'Var', (57, 64))	('ESCC', 'Disease', (68, 72))	('regulates', 'Reg', (157, 166))	('Bcl-xL', 'Gene', '598', (206, 212))	('VEGF', 'Gene', '7422', (221, 225))	('Bcl-2', 'Gene', (214, 219))	('Bcl-xL', 'Gene', (206, 212))	('Bcl-2', 'Gene', '596', (214, 219))	('plays', 'Reg', (77, 82))	('role', 'Reg', (85, 89))
134790	32554852	In summary, this research provides strong evidence that miR-126 may have a multi-functional effect on oncogenes, as suggested by the major changes observed in the ESCC cell lines and ESCC tumorigenesis in the mouse model.	('tumor', 'Disease', (188, 193))	('ESCC', 'Disease', (163, 167))	('changes', 'Reg', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('ESCC', 'Disease', (183, 187))	('miR-126', 'Var', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('mouse', 'Species', '10090', (209, 214))
134797	32554852	To examine the impact of miR-126 exhaustion on malignancy generation, we transplanted TE13-miR-126i or TE13-NC cells subcutaneously into the dorsal flank of recipient mice (1 x 107 cells/ml).	('TE13-miR-126i', 'Var', (86, 99))	('TE13-miR-126i', 'Chemical', '-', (86, 99))	('malignancy', 'Disease', (47, 57))	('malignancy', 'Disease', 'MESH:D009369', (47, 57))	('mice', 'Species', '10090', (167, 171))
134819	32272797	Recent studies suggest that radiotherapy enhances the anti-cancer immune response and also improves the efficacy of immunotherapy.	('improves', 'PosReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('efficacy of immunotherapy', 'CPA', (104, 129))	('enhances', 'PosReg', (41, 49))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('radiotherapy', 'Var', (28, 40))
134831	32272797	The recent enthusiasm on the synergy of radiotherapy and immunotherapy has renewed interest in the mechanisms by which sublethal radiation enhances cancer immunogenicity.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('enthusiasm', 'Disease', 'None', (11, 21))	('enhances', 'PosReg', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('sublethal radiation', 'Var', (119, 138))	('enthusiasm', 'Disease', (11, 21))
134848	32272797	The effect on cell viability was larger for the HNSCC compared to the NSCLC cell lines and had no association with cell doubling time or SF2 values of the cell lines.	('HNSCC', 'Phenotype', 'HP:0012288', (48, 53))	('SF2', 'Gene', '6426', (137, 140))	('NSCLC', 'Disease', (70, 75))	('cell viability', 'CPA', (14, 28))	('HNSCC', 'Var', (48, 53))	('SF2', 'Gene', (137, 140))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
134903	32272797	Additionally, in contrast to the former gene categories, genes of the negatively affected categories were those that participate in other constitutive cellular functions besides antigen processing and presentation, and their dysregulation has a more modest association with tumor immunogenicity.	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('dysregulation', 'Var', (225, 238))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (274, 279))
135275	29950898	The positive rates of serum biomarkers such as CEA, CA19-9 and CA72-4 have been strongly related to TNM staging and prognosis of resected GC patients, as indicated in a meta-analysis by Xiao et al.	('TNM', 'Gene', '10178', (100, 103))	('related', 'Reg', (89, 96))	('CA72-4', 'Var', (63, 69))	('GC', 'Phenotype', 'HP:0012126', (138, 140))	('CA19-9', 'Var', (52, 58))	('CEA', 'Gene', (47, 50))	('TNM', 'Gene', (100, 103))	('CEA', 'Gene', '1084', (47, 50))	('resected', 'Disease', (129, 137))	('patients', 'Species', '9606', (141, 149))
135276	29950898	A recent Asian study performed among 573 resected GC patients showed that elevated preoperative CEA, CA19-9, CA24-2 and CA72-4 were significantly associated with pathological types (p<0.05) and TNM staging (p<0.05).	('TNM', 'Gene', (194, 197))	('CA72-4', 'Var', (120, 126))	('CEA', 'Gene', '1084', (96, 99))	('CA19-9', 'Var', (101, 107))	('patients', 'Species', '9606', (53, 61))	('elevated', 'PosReg', (74, 82))	('pathological types', 'CPA', (162, 180))	('TNM', 'Gene', '10178', (194, 197))	('GC', 'Phenotype', 'HP:0012126', (50, 52))	('CA24-2', 'Var', (109, 115))	('CEA', 'Gene', (96, 99))
135277	29950898	In a multivariate analysis, high preoperative CA72-4 and CA24-2 served as prognostic factors for GC and were useful to find early tumor recurrence and metastasis.	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('CA72-4', 'Var', (46, 52))	('tumor', 'Disease', (130, 135))	('CA24-2', 'Var', (57, 63))
135296	29950898	Hsu et al evaluated HER2 expression in 1036 GC patients who underwent curative surgery; 6.1% of patients showed HER2 positivity that was more often related to differentiated histology.	('positivity', 'Var', (117, 127))	('patients', 'Species', '9606', (47, 55))	('HER2', 'Gene', (112, 116))	('HER2', 'Gene', '2064', (112, 116))	('HER2', 'Gene', (20, 24))	('patients', 'Species', '9606', (96, 104))	('HER2', 'Gene', '2064', (20, 24))	('GC', 'Phenotype', 'HP:0012126', (44, 46))	('related', 'Reg', (148, 155))
135304	29950898	Lack of E-cadherin activity can be caused by several molecular mechanisms, such as somatic and germline mutations of CDH1 gene or epigenetic factors, such as DNA methylation, loss of hetero-zygosity (LOH), promoter hypermethylation or activation of E-cadherin transcriptional repressors (Snail and Slug).	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('mutations', 'Var', (104, 113))	('Lack', 'NegReg', (0, 4))	('Slug', 'Gene', (298, 302))	('Snail', 'Gene', (288, 293))	('E-cadherin', 'Gene', (249, 259))	('loss of hetero-zygosity', 'Var', (175, 198))	('CDH1', 'Gene', (117, 121))	('Snail', 'Gene', '6615', (288, 293))	('CDH1', 'Gene', '999', (117, 121))	('activation', 'PosReg', (235, 245))	('activity', 'MPA', (19, 27))	('E-cadherin', 'Gene', '999', (249, 259))	('promoter hypermethylation', 'Var', (206, 231))	('N', 'Chemical', 'MESH:D009584', (159, 160))	('Slug', 'Gene', '6591', (298, 302))
135308	29950898	Moreover, patients with CDH1 epigenetic alterations had more often diffuse histotype tumors and more frequently displayed lymph node metastases.	('CDH1', 'Gene', (24, 28))	('epigenetic alterations', 'Var', (29, 51))	('CDH1', 'Gene', '999', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('metastases', 'Disease', 'MESH:D009362', (133, 143))	('metastases', 'Disease', (133, 143))	('diffuse histotype', 'Disease', (67, 84))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('displayed', 'Reg', (112, 121))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
135309	29950898	A recent translational study assessed the correlation of several biomarkers, including E-cadherin, with the outcome of resected GC patients, finding a correlation between abnormal E-cadherin expression and more advanced disease stage and poor outcome.	('E-cadherin', 'Gene', '999', (180, 190))	('patients', 'Species', '9606', (131, 139))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', (180, 190))	('E-cadherin', 'Gene', '999', (87, 97))	('GC', 'Phenotype', 'HP:0012126', (128, 130))	('expression', 'MPA', (191, 201))	('abnormal', 'Var', (171, 179))
135314	29950898	Recently, a meta-analysis by Chen et al found a significant link between high VEGF expression and poor survival of resected GC Asian patients, confirming its prognostic significance.	('poor survival', 'CPA', (98, 111))	('patients', 'Species', '9606', (133, 141))	('GC', 'Phenotype', 'HP:0012126', (124, 126))	('VEGF', 'Gene', (78, 82))	('expression', 'MPA', (83, 93))	('high', 'Var', (73, 77))	('VEGF', 'Gene', '7422', (78, 82))
135316	29950898	MSI results from alterations in genes responsible for DNA repair, such as MLH1 and MSH2.	('MLH1', 'Gene', '4292', (74, 78))	('MLH1', 'Gene', (74, 78))	('MSH2', 'Gene', (83, 87))	('MSH2', 'Gene', '4436', (83, 87))	('MSI', 'Gene', (0, 3))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('alterations', 'Var', (17, 28))	('MSI', 'Gene', '5928', (0, 3))
135347	29950898	Significant survival benefits were found with adjuvant CT in stage III patients (HR: 0.67, 95% CI: 0.47-0.97, p=0.033) but not in stage I or II patients (HR: 0.52, 95% CI: 0.21-1.30, p=0.161).	('patients', 'Species', '9606', (71, 79))	('patients', 'Species', '9606', (144, 152))	('adjuvant', 'Var', (46, 54))	('benefits', 'PosReg', (21, 29))	('survival', 'CPA', (12, 20))
135382	29950898	Severe (grade 3 or 4) toxicities observed more frequently in the FLOT arm compared to the ECF/ECX arm were diarrhea (10%), neutropenia (51%), infections (18%) and sensory changes (7%).	('neutropenia', 'Phenotype', 'HP:0001875', (123, 134))	('sensory', 'Disease', (163, 170))	('neutropenia', 'Disease', 'MESH:D009503', (123, 134))	('FLOT', 'Var', (65, 69))	('infections', 'Disease', (142, 152))	('toxicities', 'Disease', (22, 32))	('diarrhea', 'Phenotype', 'HP:0002014', (107, 115))	('diarrhea', 'Disease', 'MESH:D003967', (107, 115))	('neutropenia', 'Disease', (123, 134))	('diarrhea', 'Disease', (107, 115))	('infections', 'Disease', 'MESH:D007239', (142, 152))	('toxicities', 'Disease', 'MESH:D064420', (22, 32))
135412	29950898	However, when considering the population of patients with node positive involvement (396/458, 86%), a statistically significant improvement in DFS was noted for patients randomized to XP+RT vs XP (p=0.0365), maintained in multivariate analysis adjusted for other risk factors (HR: 0.68, 95% CI: 0.4735-0.9952, p=0.0471).	('patients', 'Species', '9606', (44, 52))	('improvement', 'PosReg', (128, 139))	('DFS', 'MPA', (143, 146))	('patients', 'Species', '9606', (161, 169))	('XP+RT', 'Var', (184, 189))
135418	29950898	In patients having N ratio >25%, the 5-year DFS was greater (HR: 0.527, 95% CI: 0.307-0.904, p=0.020) in the XP+RT arm (55%) than in the XP arm (HR: 0.52, 95% CI: 0.307-0.904, p=0.020).	('DFS', 'MPA', (44, 47))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('XP+RT', 'Var', (109, 114))	('greater', 'PosReg', (52, 59))	('patients', 'Species', '9606', (3, 11))
135495	26933914	Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer.	('Fibroblast growth factor receptor 2', 'Gene', (0, 35))	('tumor', 'Disease', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Fibroblast growth factor receptor 2', 'Gene', '2263', (0, 35))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('associated', 'Reg', (86, 96))	('cancer', 'Disease', (294, 300))	('lead to', 'Reg', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('junction adenocarcinoma', 'Disease', (153, 176))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('genetic alterations', 'Var', (221, 240))	('junction adenocarcinoma', 'Disease', 'MESH:D000230', (153, 176))	('FGFR2', 'Gene', (214, 219))	('tumor', 'Disease', (102, 107))	('Fibroblast growth factor receptor 2', 'Gene', (177, 212))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('FGFR2', 'Gene', '2263', (214, 219))	('Fibroblast growth factor receptor 2', 'Gene', '2263', (177, 212))
135496	26933914	We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma.	('associated', 'Reg', (44, 54))	('FGFR2', 'Gene', (21, 26))	('FGFR2', 'Gene', '2263', (21, 26))	('tumor', 'Disease', (91, 96))	('adenocarcinoma', 'Disease', (157, 171))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('poorer', 'NegReg', (108, 114))	('esophagogastric junction', 'Disease', (126, 150))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('adenocarcinoma', 'Disease', 'MESH:D000230', (157, 171))	('FGFR2', 'Gene', (60, 65))	('FGFR2', 'Gene', '2263', (60, 65))	('amplification', 'Var', (27, 40))
135506	26933914	FGFR2 amplification was significantly associated with FGFR2 expression.	('expression', 'MPA', (60, 70))	('associated', 'Reg', (38, 48))	('FGFR2', 'Gene', (54, 59))	('FGFR2', 'Gene', '2263', (54, 59))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
135516	26933914	We previously identified FGFR2 amplification in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (48, 73))	('FGFR2', 'Gene', (25, 30))	('FGFR2', 'Gene', '2263', (25, 30))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (48, 73))	('esophageal adenocarcinoma', 'Disease', (48, 73))	('amplification', 'Var', (31, 44))
135517	26933914	FGFR2 exerts an oncogenic effect when stimulated by fibroblast growth factors (FGFs) or FGFR2 alterations.	('alterations', 'Var', (94, 105))	('oncogenic effect', 'MPA', (16, 32))	('FGFR2', 'Gene', (88, 93))	('stimulated', 'PosReg', (38, 48))	('FGFR2', 'Gene', '2263', (88, 93))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
135519	26933914	Based on this evidence, we hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in aggressive tumors and poorer patient outcomes.	('aggressive tumors', 'Disease', 'MESH:D001523', (115, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('poorer', 'NegReg', (137, 143))	('FGFR2', 'Gene', (45, 50))	('FGFR2', 'Gene', '2263', (45, 50))	('aggressive tumors', 'Disease', (115, 132))	('FGFR2', 'Gene', (84, 89))	('FGFR2', 'Gene', '2263', (84, 89))	('patient', 'Species', '9606', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('amplification', 'Var', (51, 64))
135528	26933914	Although the FGFR2 copy number was relatively high in the OE19 cell line, it was not associated with FGFR2 mRNA or FGFR2 expression (Figure 1A-1C).	('copy number', 'Var', (19, 30))	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', (115, 120))	('FGFR2', 'Gene', '2263', (115, 120))	('FGFR2', 'Gene', '2263', (101, 106))	('FGFR2', 'Gene', '2263', (13, 18))	('FGFR2', 'Gene', (13, 18))
135534	26933914	FGFR2 amplification was not associated with any clinicopathological factors (Table 1).	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
135539	26933914	In 21 cases with FGFR2 amplification, 16 cases (16/21 = 76.2%) were positive for FGFR2 IHC.	('FGFR2', 'Gene', (17, 22))	('FGFR2', 'Gene', '2263', (17, 22))	('amplification', 'Var', (23, 36))	('FGFR2', 'Gene', (81, 86))	('FGFR2', 'Gene', '2263', (81, 86))
135540	26933914	FGFR2 IHC positivity was also significantly associated with tumor depth and lymph node metastasis (all P < 0.001, Table 1) [Bonferroni-corrected P < 0.003 (= 0.05/16)].	('associated', 'Reg', (44, 54))	('lymph node metastasis', 'CPA', (76, 97))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('positivity', 'Var', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('FGFR2', 'Gene', (0, 5))	('tumor', 'Disease', (60, 65))	('FGFR2', 'Gene', '2263', (0, 5))
135541	26933914	Notably, tumor depth was significantly related to FGFR2 IHC positivity in the multivariate logistic analysis (multivariate odds ratio = 4.57; 95% confidence interval 1.99-11.02; P < 0.001, Table 2) [Bonferroni-corrected P < 0.004 (= 0.05/14)].	('positivity', 'Var', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('related', 'Reg', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('FGFR2', 'Gene', '2263', (50, 55))	('tumor', 'Disease', (9, 14))	('FGFR2', 'Gene', (50, 55))
135542	26933914	There was no association between FGFR2 amplification status and clinicopathological factors (Supplementary Table 2).	('FGFR2', 'Gene', '2263', (33, 38))	('FGFR2', 'Gene', (33, 38))	('amplification status', 'Var', (39, 59))	('men', 'Species', '9606', (99, 102))
135545	26933914	FGFR2 amplification status was not associated with patient outcome (Supplementary Figure 3).	('patient', 'Species', '9606', (51, 58))	('men', 'Species', '9606', (74, 77))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
135548	26933914	The OS, however, was considerably worse in patients with positive FGFR2 IHC tumors than in their negative-testing counterparts (P = 0.007; significant at the P = 0.0125 (0.05/4) level; Figure 1I).	('positive', 'Var', (57, 65))	('worse', 'NegReg', (34, 39))	('FGFR2', 'Gene', (66, 71))	('FGFR2', 'Gene', '2263', (66, 71))	('OS', 'Chemical', '-', (4, 6))	('patients', 'Species', '9606', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('IHC tumors', 'Disease', (72, 82))	('IHC tumors', 'Disease', 'MESH:D009369', (72, 82))
135549	26933914	In the survival analysis according to combinations of FGFR2 amplification and FGFR2 expression, the patients with FGFR2-amplified/FGFR2-IHC-positive tumor seemed to experience worse outcomes compared to the other groups, but there was no significant difference (Supplementary Figure 4).	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('combinations', 'Var', (38, 50))	('FGFR2', 'Gene', (114, 119))	('FGFR2', 'Gene', '2263', (114, 119))	('men', 'Species', '9606', (268, 271))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('patients', 'Species', '9606', (100, 108))	('FGFR2', 'Gene', (78, 83))	('tumor', 'Disease', (149, 154))	('FGFR2', 'Gene', (54, 59))	('FGFR2', 'Gene', '2263', (78, 83))	('FGFR2', 'Gene', (130, 135))	('FGFR2', 'Gene', '2263', (54, 59))	('FGFR2', 'Gene', '2263', (130, 135))
135552	26933914	In this cell line, which overexpresses FGFR2, the siRNA-mediated knockdown of FGFR2 significantly suppressed the cell proliferation in a time-dependent manner (Figure 3B).	('cell proliferation', 'CPA', (113, 131))	('suppressed', 'NegReg', (98, 108))	('FGFR2', 'Gene', (78, 83))	('FGFR2', 'Gene', (39, 44))	('FGFR2', 'Gene', '2263', (39, 44))	('FGFR2', 'Gene', '2263', (78, 83))	('knockdown', 'Var', (65, 74))
135554	26933914	Compared with the control siRNA, phosphorylated-AKT and phosphorylated-ERK were suppressed by FGFR2 knockdown in OACM5.1C (Figure 3A).	('knockdown', 'Var', (100, 109))	('ERK', 'Gene', '5594', (71, 74))	('AKT', 'Gene', (48, 51))	('FGFR2', 'Gene', (94, 99))	('FGFR2', 'Gene', '2263', (94, 99))	('ERK', 'Gene', (71, 74))	('suppressed', 'NegReg', (80, 90))	('AKT', 'Gene', '207', (48, 51))
135555	26933914	These results suggest that de-phosphorylation of ERK and AKT governs the strong association between FGFR2 expression and tumor cell proliferation.	('FGFR2', 'Gene', (100, 105))	('FGFR2', 'Gene', '2263', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('expression', 'MPA', (106, 116))	('tumor', 'Disease', (121, 126))	('AKT', 'Gene', '207', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('de-phosphorylation', 'Var', (27, 45))	('ERK', 'Gene', '5594', (49, 52))	('AKT', 'Gene', (57, 60))	('ERK', 'Gene', (49, 52))
135557	26933914	According to the cell cycle analysis at 72 h after FGFR2 knockdown by siRNAs, the FGFR2-overexpressing OACM5.1C tumor cells were significantly accumulated in the G0/G1 phase population (P < 0.05), and concomitantly decreased in the G2/M phase population (P < 0.05) (Figure 3C, 3D).	('decreased', 'NegReg', (215, 224))	('FGFR2', 'Gene', (51, 56))	('FGFR2', 'Gene', '2263', (51, 56))	('G0/G1 phase', 'CPA', (162, 173))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('G2/M phase population', 'CPA', (232, 253))	('knockdown', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('FGFR2', 'Gene', (82, 87))	('FGFR2', 'Gene', '2263', (82, 87))	('tumor', 'Disease', (112, 117))	('accumulated', 'PosReg', (143, 154))
135564	26933914	We next investigated whether pan-FGFR inhibitor AZD4547 can therapeutically target the EGJ adenocarcinoma cell line OACM5.1C, which overexpresses FGFR2.	('AZD4547', 'Var', (48, 55))	('FGFR2', 'Gene', (146, 151))	('FGFR2', 'Gene', '2263', (146, 151))	('AZD4547', 'Chemical', 'MESH:C572463', (48, 55))	('EGJ adenocarcinoma', 'Disease', (87, 105))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (87, 105))
135567	26933914	In the proliferation assay, AZD4547 significantly suppressed the tumor cell growth (P < 0.05, Figure 5A).	('AZD4547', 'Var', (28, 35))	('suppressed', 'NegReg', (50, 60))	('tumor', 'Disease', (65, 70))	('AZD4547', 'Chemical', 'MESH:C572463', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
135569	26933914	AZD4547 treatment clearly de-phosphorylated the ERK, regardless of FGF7 stimulation.	('ERK', 'Gene', (48, 51))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGF7', 'Gene', '2252', (67, 71))	('de-phosphorylated', 'NegReg', (26, 43))	('FGF7', 'Gene', (67, 71))	('ERK', 'Gene', '5594', (48, 51))	('AZD4547', 'Var', (0, 7))	('men', 'Species', '9606', (13, 16))
135570	26933914	However, the change in the de-phosphorylated AKT was more evident under FGF7 stimulation than under no stimulation (Figure 5B).	('FGF7', 'Gene', (72, 76))	('de-phosphorylated', 'MPA', (27, 44))	('AKT', 'Gene', (45, 48))	('stimulation', 'Var', (77, 88))	('FGF7', 'Gene', '2252', (72, 76))	('AKT', 'Gene', '207', (45, 48))
135573	26933914	FGFR2 copy number was amplified in 21 (15%) of the 140 assayed EGJ adenocarcinoma cases, and FGFR2 expression was elevated in 108 cases (61%) of the 176 cases assayed by IHC.	('expression', 'MPA', (99, 109))	('FGFR2', 'Gene', (93, 98))	('FGFR2', 'Gene', '2263', (93, 98))	('EGJ adenocarcinoma', 'Disease', (63, 81))	('copy number', 'Var', (6, 17))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (63, 81))	('FGFR2', 'Gene', (0, 5))	('elevated', 'PosReg', (114, 122))	('FGFR2', 'Gene', '2263', (0, 5))
135576	26933914	In addition, the pan-FGFR inhibitor AZD4547 suppressed EGJ adenocarcinoma growth through de-phosphorylation of AKT and ERK.	('AKT', 'Gene', '207', (111, 114))	('suppressed', 'NegReg', (44, 54))	('ERK', 'Gene', '5594', (119, 122))	('ERK', 'Gene', (119, 122))	('EGJ adenocarcinoma', 'Disease', (55, 73))	('AKT', 'Gene', (111, 114))	('AZD4547', 'Var', (36, 43))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (55, 73))	('de-phosphorylation', 'MPA', (89, 107))	('AZD4547', 'Chemical', 'MESH:C572463', (36, 43))
135581	26933914	FGFR2 amplification may play different roles in distal gastric cancer and EGJ adenocarcinoma, as the two cancers exhibit different biology.	('gastric cancer', 'Disease', (55, 69))	('EGJ adenocarcinoma', 'Disease', (74, 92))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (74, 92))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('roles', 'Reg', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('amplification', 'Var', (6, 19))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('play', 'Reg', (24, 28))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
135587	26933914	Our study found no association between FGFR2 amplification and histological tumor type or patient outcome in EGJ adenocarcinoma.	('EGJ adenocarcinoma', 'Disease', (109, 127))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('FGFR2', 'Gene', (39, 44))	('patient', 'Species', '9606', (90, 97))	('FGFR2', 'Gene', '2263', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('amplification', 'Var', (45, 58))
135589	26933914	FGFR2 amplification has been reported in 4.1-7.2% of gastric cancer cases, and in 4.0% of triple-negative breast cancer cases.	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('gastric cancer', 'Disease', (53, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('reported', 'Reg', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
135590	26933914	In the present study, FGFR2 was amplified in 15% (21/140) of the investigated EGJ adenocarcinoma cases, higher than in previous reports.	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (78, 96))	('FGFR2', 'Gene', '2263', (22, 27))	('FGFR2', 'Gene', (22, 27))	('amplified', 'Var', (32, 41))	('EGJ adenocarcinoma', 'Disease', (78, 96))
135591	26933914	Nonetheless, in our copy number assay, FGFR2 amplification status and FGFR2 expression status in the five tested cell lines correlated well with the clinical features of EGJ adenocarcinoma.	('correlated', 'Reg', (124, 134))	('FGFR2', 'Gene', (70, 75))	('FGFR2', 'Gene', '2263', (70, 75))	('clinical', 'Species', '191496', (149, 157))	('amplification status', 'Var', (45, 65))	('FGFR2', 'Gene', (39, 44))	('EGJ adenocarcinoma', 'Disease', (170, 188))	('expression', 'MPA', (76, 86))	('FGFR2', 'Gene', '2263', (39, 44))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (170, 188))
135593	26933914	Although FGFR2 amplification was associated with FGFR2 IHC positivity, FGFR2 IHC positivity, but not FGFR2 amplification, strongly correlated with tumor aggressiveness, and patient outcome in this study.	('aggressiveness', 'Phenotype', 'HP:0000718', (153, 167))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor aggressiveness', 'Disease', (147, 167))	('amplification', 'Var', (15, 28))	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', '2263', (101, 106))	('FGFR2', 'Gene', (49, 54))	('FGFR2', 'Gene', '2263', (49, 54))	('FGFR2', 'Gene', (9, 14))	('FGFR2', 'Gene', '2263', (9, 14))	('correlated with', 'Reg', (131, 146))	('associated', 'Reg', (33, 43))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (147, 167))	('FGFR2', 'Gene', (71, 76))	('FGFR2', 'Gene', '2263', (71, 76))	('patient', 'Species', '9606', (173, 180))
135594	26933914	This discrepancy may be explained by the epigenetic or transcriptional regulation of FGFR2 expression.	('FGFR2', 'Gene', '2263', (85, 90))	('epigenetic', 'Var', (41, 51))	('FGFR2', 'Gene', (85, 90))
135595	26933914	In thyroid cancer, FGFR2 expression is controlled by methylation of the DNA promoter.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('thyroid cancer', 'Disease', 'MESH:D013964', (3, 17))	('expression', 'MPA', (25, 35))	('controlled by', 'Reg', (39, 52))	('FGFR2', 'Gene', (19, 24))	('FGFR2', 'Gene', '2263', (19, 24))	('thyroid cancer', 'Disease', (3, 17))	('thyroid cancer', 'Phenotype', 'HP:0002890', (3, 17))	('methylation', 'Var', (53, 64))
135597	26933914	Specifically, miR125b controls FGFR2 expression in dermatological disease.	('FGFR2', 'Gene', '2263', (31, 36))	('FGFR2', 'Gene', (31, 36))	('miR125b', 'Var', (14, 21))	('dermatological disease', 'Phenotype', 'HP:0000951', (51, 73))	('dermatological disease', 'Disease', (51, 73))	('expression', 'MPA', (37, 47))
135598	26933914	Considering that miR125b regulates HER2 in gastric cancer, we would expect further comprehensive miRNA assays may reveal the underlying mechanism of transcriptional regulation of FGFR2 in EGJ adenocarcinoma.	('EGJ adenocarcinoma', 'Disease', (188, 206))	('miR125b', 'Var', (17, 24))	('HER2', 'Gene', (35, 39))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (188, 206))	('HER2', 'Gene', '2064', (35, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (43, 57))	('gastric cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('regulates', 'Reg', (25, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (43, 57))	('FGFR2', 'Gene', '2263', (179, 184))	('FGFR2', 'Gene', (179, 184))
135612	26933914	A recent phase II clinical trial of SHINE study compared AZD 4547 with paclitaxel in previously treated cases of advanced gastric or EGJ cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('clinical', 'Species', '191496', (18, 26))	('AZD 4547', 'Var', (57, 65))	('AZD 4547', 'Chemical', '-', (57, 65))	('gastric or EGJ cancer', 'Disease', (122, 143))	('paclitaxel', 'Chemical', 'MESH:D017239', (71, 81))	('gastric or EGJ cancer', 'Disease', 'MESH:D013274', (122, 143))
135615	26933914	FGFR2 amplification status was 9%, which was confirmed by FISH testing.	('FGFR2', 'Gene', (0, 5))	('amplification status', 'Var', (6, 26))	('FGFR2', 'Gene', '2263', (0, 5))
135616	26933914	In those FGFR2 amplified case, FGFR2 expression was observed in only 21%, which was much lower than 76.2% (16/21 cases) that we observed in our study.	('FGFR2', 'Gene', '2263', (31, 36))	('FGFR2', 'Gene', (31, 36))	('amplified', 'Var', (15, 24))	('FGFR2', 'Gene', '2263', (9, 14))	('FGFR2', 'Gene', (9, 14))
135620	26933914	This study focused on the mechanistic role of FGFR2 amplification in EGJ adenocarcinoma.	('FGFR2', 'Gene', '2263', (46, 51))	('FGFR2', 'Gene', (46, 51))	('EGJ adenocarcinoma', 'Disease', (69, 87))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (69, 87))	('amplification', 'Var', (52, 65))
135621	26933914	In conclusion, we found that (i) FGFR2 amplification is associated with FGFR2 expression, and (ii) FGFR2 expression, but not FGFR2 amplification, is associated with depth of tumor invasion and poorer outcomes in EGJ adenocarcinoma.	('tumor', 'Disease', (174, 179))	('expression', 'MPA', (78, 88))	('FGFR2', 'Gene', (72, 77))	('FGFR2', 'Gene', (125, 130))	('EGJ adenocarcinoma', 'Disease', (212, 230))	('FGFR2', 'Gene', '2263', (72, 77))	('amplification', 'Var', (39, 52))	('FGFR2', 'Gene', '2263', (125, 130))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (212, 230))	('associated', 'Reg', (56, 66))	('associated with', 'Reg', (149, 164))	('FGFR2', 'Gene', '2263', (99, 104))	('FGFR2', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('FGFR2', 'Gene', '2263', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('FGFR2', 'Gene', (99, 104))
135638	26933914	Tumor DNA was analyzed with TaqMan Copy Number Assays (Life Technologies) using Hs05182482_cn (intron 14 of FGFR2, amplicon length 80 bp; Life Technologies) as primers.	('FGFR2', 'Gene', '2263', (108, 113))	('Hs05182482_cn', 'Var', (80, 93))	('FGFR2', 'Gene', (108, 113))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))
135642	26933914	FISH FGFR2 probe was labeled with bacterial artificial chromosomes (BACs), RP11-7P17, RP11-984I17, RP11-78A18, RP11-615K11 and RP11-62L18, which were labeled with Cy3 (Chromosomescience laboratory, Sapporo, Japan).	('Cy3', 'Chemical', '-', (163, 166))	('RP11-984I17', 'Var', (86, 97))	('RP11-615K11', 'Var', (111, 122))	('FGFR2', 'Gene', (5, 10))	('FGFR2', 'Gene', '2263', (5, 10))	('RP11-7P17', 'Var', (75, 84))	('RP11-62L18', 'Var', (127, 137))	('RP11-78A18', 'Var', (99, 109))
135643	26933914	FISH chromosome 10 centromere (CEN10) was labeled with BACs RP11-300L24, RP11-178A10, RP11-110L24, and RP11-379D20, which were labeled with FITC (Chromosomescience laboratory, Sapporo, Japan).	('RP11-110L24', 'Var', (86, 97))	('RP11-178A10', 'Var', (73, 84))	('RP11-379D20', 'Var', (103, 114))	('FITC', 'Chemical', 'MESH:D016650', (140, 144))	('BACs', 'Var', (55, 59))
135653	26933914	The primary antibodies, FGFR2 (#11835s), AKT (#9272), phospho-AKT Ser473 (#9271), ERK1/2 (#9102), phospho-ERK1/2 Thr202/Tyr204 (#4376) and Beta-actin (#4967s), were purchased from Cell Signaling Technology (Danvers, MA, USA).	('#9272', 'Var', (46, 51))	('Ser473', 'Chemical', '-', (66, 72))	('AKT', 'Gene', (62, 65))	('Thr202', 'Chemical', '-', (113, 119))	('FGFR2', 'Gene', '2263', (24, 29))	('#9271', 'Var', (74, 79))	('Tyr204', 'Chemical', '-', (120, 126))	('#11835s', 'Var', (31, 38))	('AKT', 'Gene', '207', (41, 44))	('#9102', 'Var', (90, 95))	('AKT', 'Gene', '207', (62, 65))	('FGFR2', 'Gene', (24, 29))	('AKT', 'Gene', (41, 44))
135664	26933914	Two individual FGFR2-specific small-interfering RNAs (siRNAs) were chemically synthesized to target different regions of FGFR2 (s5174 and s5175, Life Technologies).	('s5174', 'Var', (128, 133))	('FGFR2', 'Gene', (121, 126))	('FGFR2', 'Gene', '2263', (121, 126))	('FGFR2', 'Gene', '2263', (15, 20))	('FGFR2', 'Gene', (15, 20))	('s5175', 'Var', (138, 143))
135676	26933914	The associations between clinicopathological factors and FGFR2 amplification status (negative vs. positive) or FGFR2 IHC (negative vs. positive) were identified in univariate analyses.	('FGFR2', 'Gene', '2263', (111, 116))	('FGFR2', 'Gene', (111, 116))	('amplification status', 'Var', (63, 83))	('FGFR2', 'Gene', '2263', (57, 62))	('FGFR2', 'Gene', (57, 62))
135739	27011205	Positive biomarkers for GBM are seen with Cr, Gly, Gln, and hypo-taurine (h-Tau), while none of them were present as significant factors in the metabolomic profiles of metastasis.	('Cr', 'Chemical', 'MESH:D003401', (42, 44))	('GBM', 'Disease', (24, 27))	('Tau', 'Chemical', 'MESH:D013654', (76, 79))	('Gly', 'Var', (46, 49))	('hypo-taurine', 'Chemical', 'MESH:C003949', (60, 72))	('hypo-taurine', 'Phenotype', 'HP:0500182', (60, 72))	('h-Tau', 'Phenotype', 'HP:0500182', (74, 79))	('Gln', 'Var', (51, 54))	('hypo-taurine', 'MPA', (60, 72))	('Gly', 'Chemical', 'MESH:D005998', (46, 49))	('Gln', 'Chemical', 'MESH:D005973', (51, 54))
135769	27011205	In intact tissue experiments, only tumors treated with 40 microM of thioglycoside showed a significant reduction in size, which also showed a two-fold increase in Cho and a 1.4-times increase in PChol with a higher PChol/GPC ratio (1.69 +- 0.68 vs. 1.34 +- 0.5) in treated tumors compared with those of the control.	('Cho', 'MPA', (163, 166))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('PChol/GPC ratio', 'MPA', (215, 230))	('Cho', 'Chemical', 'MESH:D002794', (216, 219))	('GPC', 'Chemical', 'MESH:D005997', (221, 224))	('thioglycoside', 'Var', (68, 81))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('PChol', 'Chemical', 'MESH:D010767', (215, 220))	('PChol', 'MPA', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('men', 'Species', '9606', (23, 26))	('size', 'MPA', (116, 120))	('Cho', 'Chemical', 'MESH:D002794', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('reduction', 'NegReg', (103, 112))	('Cho', 'Chemical', 'MESH:D002794', (163, 166))	('tumors', 'Disease', (273, 279))	('thioglycoside', 'Chemical', 'MESH:D013865', (68, 81))	('higher', 'PosReg', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('increase', 'PosReg', (183, 191))	('PChol', 'Chemical', 'MESH:D010767', (195, 200))	('tumors', 'Disease', (35, 41))	('increase', 'PosReg', (151, 159))	('tumors', 'Disease', 'MESH:D009369', (273, 279))
135777	27011205	Patients of oligodendrogliomas with high HDAC1 expression formed a metabolically distinct group, with significantly reduced GPC/PChol ratios, from patients with unchanged HDAC1 expression.	('HDAC1', 'Gene', '3065', (41, 46))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('HDAC1', 'Gene', (171, 176))	('oligodendrogliomas', 'Disease', (12, 30))	('GPC/PChol ratios', 'MPA', (124, 140))	('expression', 'Var', (47, 57))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (147, 155))	('HDAC1', 'Gene', '3065', (171, 176))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('HDAC1', 'Gene', (41, 46))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (12, 30))	('reduced', 'NegReg', (116, 123))	('GPC', 'Chemical', 'MESH:D005997', (124, 127))	('high', 'Var', (36, 40))	('PChol', 'Chemical', 'MESH:D010767', (128, 133))
135779	27011205	These results suggest that the GPC/PChol ratio is associated with high-grade tumors and that the expression of HDAC1 might influence tumor aggressiveness, as reflected in the metabolomic profiles.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('HDAC1', 'Gene', '3065', (111, 116))	('aggressiveness', 'Phenotype', 'HP:0000718', (139, 153))	('expression', 'Var', (97, 107))	('GPC/PChol', 'MPA', (31, 40))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (133, 153))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('influence', 'Reg', (123, 132))	('GPC', 'Chemical', 'MESH:D005997', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('HDAC1', 'Gene', (111, 116))	('associated', 'Reg', (50, 60))	('PChol', 'Chemical', 'MESH:D010767', (35, 40))	('tumor aggressiveness', 'Disease', (133, 153))
135809	27011205	One drug target of interest has been the phosphatidylinositol 3-kinase (PI3K) pathway, since it is frequently activated in cancer cells through mutations.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (41, 70))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('phosphatidylinositol 3-kinase', 'Gene', (41, 70))	('mutations', 'Var', (144, 153))	('activated', 'PosReg', (110, 119))
135811	27011205	Experimental tissues from xenograft models representing both basal-like and luminal-like breast cancer have been used to quantify the PI3K pathway associated metabolite changes before and after treatment with PI3K inhibitors (MK-2206 and BEZ235), and to determine metabolic biomarkers that reflect treatment response.	('MK-2206', 'Var', (226, 233))	('men', 'Species', '9606', (199, 202))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('men', 'Species', '9606', (303, 306))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('PI3K pathway', 'Pathway', (134, 146))	('BEZ235', 'Chemical', 'MESH:C531198', (238, 244))	('MK-2206', 'Chemical', 'MESH:C548887', (226, 233))	('men', 'Species', '9606', (6, 9))
135813	27011205	BEZ235 increased glucose and GPC in basal-like tumors as well.	('tumors', 'Disease', (47, 53))	('increased', 'PosReg', (7, 16))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('basal-like tumors', 'Phenotype', 'HP:0002671', (36, 53))	('BEZ235', 'Var', (0, 6))	('GPC', 'Chemical', 'MESH:D005997', (29, 32))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('glucose', 'Chemical', 'MESH:D005947', (17, 24))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('increased glucose', 'Phenotype', 'HP:0003074', (7, 24))
135898	27011205	Results from a study were able to differentiate between sporadic (n = 48) and succinate dehydrogenase gene (SDHx) mutation-related (n = 23) pheochromocytomas/ paragangliomas by analyzing the 24 identified metabolites present in all 71 spectra with PCA and OPLS-DA.	('pheochromocytomas', 'Disease', (140, 157))	('pheochromocytomas', 'Disease', 'MESH:D010673', (140, 157))	('gliomas', 'Phenotype', 'HP:0009733', (166, 173))	('PCA', 'Disease', (248, 251))	('OPLS-DA', 'Chemical', '-', (256, 263))	('succinate', 'Chemical', 'MESH:D019802', (78, 87))	('paragangliomas', 'Disease', (159, 173))	('paragangliomas', 'Disease', 'MESH:D010235', (159, 173))	('paragangliomas', 'Phenotype', 'HP:0002668', (159, 173))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (140, 157))	('SDHx', 'Chemical', '-', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('SDHx', 'Gene', (108, 112))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (140, 156))	('mutation-related', 'Var', (114, 130))
135900	27011205	PCA and OPLS-DA have also been applied to differentiate HRMAS MRS metabolomic profiles of cells with six pathogenic missense Menin variants from those with functional and over-expression of WT Menin.	('missense', 'Var', (116, 124))	('Menin', 'Gene', '4221', (125, 130))	('OPLS-DA', 'Chemical', '-', (8, 15))	('Menin', 'Gene', (193, 198))	('Menin', 'Gene', '4221', (193, 198))	('variants', 'Var', (131, 139))	('Menin', 'Gene', (125, 130))
135901	27011205	Mutations to the MEN1 gene, which encodes the Menin protein, are responsible for multiple endocrine neoplasia syndrome, type 1 (MEN1), an example of a hereditary cancer.	('multiple endocrine neoplasia syndrome', 'Disease', (81, 118))	('hereditary cancer', 'Disease', (151, 168))	('Menin', 'Gene', '4221', (46, 51))	('MEN1', 'Gene', '4221', (128, 132))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (90, 109))	('neoplasia', 'Phenotype', 'HP:0002664', (100, 109))	('MEN1', 'Gene', (128, 132))	('multiple endocrine neoplasia syndrome', 'Disease', 'MESH:D009377', (81, 118))	('MEN1', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('hereditary cancer', 'Disease', 'MESH:D009369', (151, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('responsible', 'Reg', (65, 76))	('Menin', 'Gene', (46, 51))	('MEN1', 'Gene', '4221', (17, 21))
135936	24806664	This was followed by our studies which showed that NNN was an esophageal carcinogen in rats and that NNK induced lung tumors in mice and adenocarcinoma of the lung in addition to nasal cavity and liver tumors in rats.	('induced', 'Reg', (105, 112))	('lung tumors', 'Phenotype', 'HP:0100526', (113, 124))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (137, 163))	('esophageal', 'Disease', (62, 72))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('liver tumors', 'Disease', 'MESH:D008113', (196, 208))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (142, 163))	('lung tumors', 'Disease', (113, 124))	('liver tumors', 'Phenotype', 'HP:0002896', (196, 208))	('esophageal', 'Disease', 'MESH:D004941', (62, 72))	('NNN', 'Chemical', 'MESH:C008655', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('liver tumors', 'Disease', (196, 208))	('rats', 'Species', '10116', (87, 91))	('mice', 'Species', '10090', (128, 132))	('adenocarcinoma of the lung', 'Disease', (137, 163))	('NNK', 'Chemical', 'MESH:C016583', (101, 104))	('rats', 'Species', '10116', (212, 216))	('NNK', 'Var', (101, 104))	('lung tumors', 'Disease', 'MESH:D008175', (113, 124))
135951	24806664	The results demonstrated that (S)-NNN is a powerful oral cavity carcinogen, inducing a total of 89 benign and malignant oral cavity tumors in a group of 20 rats, as well as a 100% incidence of esophageal tumors while (R)-NNN was somewhat less active.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('rat', 'Species', '10116', (156, 159))	('esophageal tumors', 'Disease', 'MESH:D004938', (193, 210))	('esophageal tumors', 'Phenotype', 'HP:0100751', (193, 210))	('oral cavity tumors', 'Phenotype', 'HP:0100649', (120, 138))	('esophageal tumors', 'Disease', (193, 210))	('rat', 'Species', '10116', (19, 22))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('inducing', 'Reg', (76, 84))	('(S)-NNN', 'Chemical', 'MESH:C008655', (30, 37))	('(R)-NNN', 'Chemical', '-', (217, 224))	('tumors', 'Disease', (204, 210))	('tumors', 'Disease', (132, 138))	('rats', 'Species', '10116', (156, 160))	('S)-NNN', 'Var', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))
135972	24806664	One study found that NNN concentrations were 380 times lower and those of NNK 40 times lower in the vapor of e-cigarettes than in the smoke of conventional cigarettes.	('NNN', 'Chemical', 'MESH:C008655', (21, 24))	('e-cigarettes', 'Var', (109, 121))	('rat', 'Species', '10116', (32, 35))	('NNK', 'Chemical', 'MESH:C016583', (74, 77))	('lower', 'NegReg', (87, 92))	('NNN concentrations', 'MPA', (21, 39))	('lower', 'NegReg', (55, 60))
136024	24806664	The second explanation revolves around NNK, which robustly induces adenocarcinoma of the lung in animal models, as noted above.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma of the lung', 'Disease', (67, 93))	('NNK', 'Chemical', 'MESH:C016583', (39, 42))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (72, 93))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (67, 93))	('induces', 'Reg', (59, 66))	('NNK', 'Var', (39, 42))
136036	24806664	It is plausible that the increased levels of adenocarcinoma are attributable to both higher levels of NNK in cigarette tobacco and to cigarette design changes which lead smokers to smoke more intensely, thereby increasing the areas of the lung exposed to carcinogens.	('tobacco', 'Species', '4097', (119, 126))	('increasing', 'PosReg', (211, 221))	('adenocarcinoma', 'Disease', 'MESH:D000230', (45, 59))	('NNK', 'Chemical', 'MESH:C016583', (102, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('lead', 'Reg', (165, 169))	('adenocarcinoma', 'Disease', (45, 59))	('changes', 'Var', (151, 158))	('NNK', 'MPA', (102, 105))
136053	24806664	These results show a noteworthy association of NNN with esophageal cancer and demonstrate coherence with carcinogenicity studies of NNN and NNK in rats, in which NNN induces predominantly esophageal and oral cavity cancer, but not lung cancer while NNK induced predominantly lung cancer but not esophageal cancer.	('lung cancer', 'Disease', (231, 242))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('rats', 'Species', '10116', (147, 151))	('NNK', 'Chemical', 'MESH:C016583', (249, 252))	('cancer', 'Disease', (280, 286))	('esophageal', 'Disease', 'MESH:D004941', (295, 305))	('induces', 'Reg', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('esophageal', 'Disease', 'MESH:D004941', (56, 66))	('NNN', 'Chemical', 'MESH:C008655', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('carcinogenic', 'Disease', (105, 117))	('esophageal', 'Disease', (188, 198))	('cancer', 'Disease', (215, 221))	('lung cancer', 'Disease', (275, 286))	('NNN', 'Var', (162, 165))	('NNN', 'Chemical', 'MESH:C008655', (132, 135))	('rat', 'Species', '10116', (85, 88))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('carcinogenic', 'Disease', 'MESH:D063646', (105, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('esophageal cancer', 'Disease', 'MESH:D004938', (295, 312))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('NNN', 'Chemical', 'MESH:C008655', (162, 165))	('cancer', 'Disease', (236, 242))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('rat', 'Species', '10116', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('esophageal', 'Disease', 'MESH:D004941', (188, 198))	('esophageal cancer', 'Disease', (295, 312))	('lung cancer', 'Disease', 'MESH:D008175', (275, 286))	('cancer', 'Disease', (306, 312))	('esophageal', 'Disease', (295, 305))	('cancer', 'Disease', (67, 73))	('esophageal cancer', 'Disease', (56, 73))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('NNK', 'Chemical', 'MESH:C016583', (140, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('esophageal', 'Disease', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('association', 'Interaction', (32, 43))
136081	24806664	All data summarized here strongly indicate that a decrease in lung, oral cavity, and esophageal cancer incidence among long-term smokers of these modified cigarettes will occur, but predicting the extent or the timing of that decrease would be speculative because there are too many other variables.	('modified', 'Var', (146, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung', 'Disease', (62, 66))	('oral cavity', 'Disease', (68, 79))	('esophageal cancer', 'Disease', (85, 102))	('decrease', 'NegReg', (50, 58))
136090	23372429	An Association Study on Genetic Polymorphisms of Rab37 Gene with the Risk of Esophageal Squamous Cell Carcinoma in a Chinese Han Population Background: Rab37 encodes a Rab GTPase which regulates the vesicular transport of exocytosis.	('Polymorphisms', 'Var', (32, 45))	('Carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('Rab', 'Gene', (152, 155))	('Rab37', 'Gene', (49, 54))	('Rab37', 'Gene', (152, 157))	('Esophageal Squamous Cell Carcinoma', 'Disease', (77, 111))	('Rab', 'Gene', '5873;326624;5864', (168, 171))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('Rab', 'Gene', '5873;326624;5864', (49, 52))	('regulates', 'MPA', (185, 194))	('Rab37', 'Gene', '326624', (152, 157))	('Rab37', 'Gene', '326624', (49, 54))	('Rab', 'Gene', (168, 171))	('Rab', 'Gene', '5873;326624;5864', (152, 155))	('Rab', 'Gene', (49, 52))	('vesicular transport of exocytosis', 'MPA', (199, 232))
136094	23372429	Results: Rab37 mRNA could be specifically detected in two ESCC cell lines, EC109 and EC9706, but not in KYS150 and KYS450.	('Rab37', 'Gene', (9, 14))	('KYS150', 'Chemical', '-', (104, 110))	('EC9706', 'Var', (85, 91))	('Rab37', 'Gene', '326624', (9, 14))	('EC109', 'CellLine', 'CVCL:6898', (75, 80))	('KYS450', 'Chemical', '-', (115, 121))	('EC9706', 'CellLine', 'CVCL:E307', (85, 91))	('detected', 'Reg', (42, 50))
136095	23372429	The allele, genotype and haplotype frequencies of rs9904078G>A, rs2034310T>C and rs5018106T>C, located in Rab37, did not significantly differ between the patients and the controls.	('rs9904078G>A', 'DBSNP_MENTION', 'None', (50, 62))	('rs2034310T>C', 'Var', (64, 76))	('rs9904078G>A', 'Var', (50, 62))	('patients', 'Species', '9606', (154, 162))	('rs5018106T>C', 'DBSNP_MENTION', 'None', (81, 93))	('Rab37', 'Gene', (106, 111))	('rs2034310T>C', 'DBSNP_MENTION', 'None', (64, 76))	('rs5018106T>C', 'Var', (81, 93))	('Rab37', 'Gene', '326624', (106, 111))
136104	23372429	Knockdown of its expression caused significant reduction of cancer cell growth, suggesting that Rab37 was important for the survival of RCC cells.	('Knockdown', 'Var', (0, 9))	('Rab37', 'Gene', '326624', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('reduction of cancer', 'Disease', (47, 66))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('reduction of cancer', 'Disease', 'MESH:D009369', (47, 66))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))	('Rab37', 'Gene', (96, 101))
136105	23372429	But the lower Rab37 mRNA expression was found in the most non-small cell lung cancer (NSCLC) patients and its knockdown led to a significant increase in cell migration.	('knockdown', 'Var', (110, 119))	('cell lung cancer', 'Disease', (68, 84))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (58, 84))	('patients', 'Species', '9606', (93, 101))	('increase', 'PosReg', (141, 149))	('NSCLC', 'Disease', (86, 91))	('cell lung cancer', 'Disease', 'MESH:D008175', (68, 84))	('Rab37', 'Gene', '326624', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('cell migration', 'CPA', (153, 167))	('mRNA expression', 'MPA', (20, 35))	('rat', 'Species', '10116', (161, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('lower', 'NegReg', (8, 13))	('Rab37', 'Gene', (14, 19))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (62, 84))
136113	23372429	As previous work shown, we had demonstrated that survivin, decoy receptor 3, microRNA-196a and microRNA-146a were associated with the risk of ESCC in Chinese Han population.	('survivin', 'Protein', (49, 57))	('associated', 'Reg', (114, 124))	('ESCC', 'Disease', (142, 146))	('rat', 'Species', '10116', (38, 41))	('microRNA-146a', 'Var', (95, 108))	('microRNA-196a', 'Var', (77, 90))
136115	23372429	KYS150, KYS450, EC109, EC9706 and Huh7 were from Tumor Center of Chinese Academy of Medical Science.	('Huh7', 'Gene', (34, 38))	('EC9706', 'CellLine', 'CVCL:E307', (23, 29))	('EC109', 'Var', (16, 21))	('KYS450', 'Var', (8, 14))	('Huh7', 'Gene', '284424', (34, 38))	('KYS150', 'Chemical', '-', (0, 6))	('Tumor', 'Phenotype', 'HP:0002664', (49, 54))	('EC109', 'CellLine', 'CVCL:6898', (16, 21))	('KYS450', 'Chemical', '-', (8, 14))	('EC9706', 'Var', (23, 29))	('KYS150', 'Var', (0, 6))
136125	23372429	Cycling conditions included 95 C for 5 min, followed by 35 cycles at 94  C for 15 s, 61  C for 15 s and 72  C for 30 s. The 3 Tag SNPs in Rab37 gene were enrolled in this study, which were rs9904078G>A, rs2034310T>C, rs5018106T>C, respectively.	('rs5018106T>C', 'DBSNP_MENTION', 'None', (217, 229))	('Rab37', 'Gene', '326624', (138, 143))	('rs5018106T>C', 'Var', (217, 229))	('rs2034310T>C', 'DBSNP_MENTION', 'None', (203, 215))	('rs9904078G>A', 'Var', (189, 201))	('rs9904078G>A', 'DBSNP_MENTION', 'None', (189, 201))	('rs2034310T>C', 'Var', (203, 215))	('Rab37', 'Gene', (138, 143))
136126	23372429	Rs9904078 was located in the promoter region, rs2034310 was located in the exton and caused the amino acid at 218 changed form glutamine to arginine, and rs5018106 was located in the intron region of the gene downstream.	('rs5018106', 'Var', (154, 163))	('changed', 'Reg', (114, 121))	('arginine', 'Chemical', 'MESH:D001120', (140, 148))	('rs2034310', 'Mutation', 'rs2034310', (46, 55))	('glutamine', 'Chemical', 'MESH:D005973', (127, 136))	('Rs9904078', 'Mutation', 'Rs9904078', (0, 9))	('Rs9904078', 'Var', (0, 9))	('glutamine to arginine', 'MPA', (127, 148))	('rs2034310', 'Var', (46, 55))	('rs5018106', 'Mutation', 'rs5018106', (154, 163))
136135	23372429	The expression of Rab37 mRNA was positive in MCF7, SW1990 and Huh7, but negative in EA.hy926 and HepG2 cells lines (Figure 1).	('HepG2', 'CellLine', 'CVCL:0027', (97, 102))	('MCF7', 'Var', (45, 49))	('positive', 'PosReg', (33, 41))	('EA', 'Phenotype', 'HP:0011459', (84, 86))	('Huh7', 'Gene', (62, 66))	('Rab37', 'Gene', '326624', (18, 23))	('SW1990', 'Var', (51, 57))	('expression', 'MPA', (4, 14))	('Huh7', 'Gene', '284424', (62, 66))	('SW1990', 'CellLine', 'CVCL:1723', (51, 57))	('EA.hy926', 'CellLine', 'CVCL:3901', (84, 92))	('MCF7', 'CellLine', 'CVCL:0031', (45, 49))	('Rab37', 'Gene', (18, 23))
136141	23372429	To discriminate Rab37 genotypes at 3 Tag SNP sites, rs9904078, rs2034310, rs5018106, three restriction endonucleases, MboII, AccII and HaeIII, were used respectively.	('rs9904078', 'Mutation', 'rs9904078', (52, 61))	('rs2034310', 'Mutation', 'rs2034310', (63, 72))	('rs2034310', 'Var', (63, 72))	('Rab37', 'Gene', (16, 21))	('rs5018106', 'Mutation', 'rs5018106', (74, 83))	('Rab37', 'Gene', '326624', (16, 21))	('rs9904078', 'Var', (52, 61))	('rs5018106', 'Var', (74, 83))
136144	23372429	Furthermore, as for our data on the MAF of rs9904078, A allele was 0.154 in patients and 0.124 in control respectively and the MAF of rs9904078 in the Beijing Han Chinese (CHB) population in the database of SNP (dbSNP) is about 0.122-0.167.	('patients', 'Species', '9606', (76, 84))	('rs9904078', 'Var', (134, 143))	('rs9904078', 'Var', (43, 52))	('rs9904078', 'Mutation', 'rs9904078', (43, 52))	('rs9904078', 'Mutation', 'rs9904078', (134, 143))
136145	23372429	As for the MAF of rs2034310, T allele was 0.290 in patients and 0.343 in control respectively, which are included in the range of that in CHB (0.221-0.378) in dbSNP.	('rs2034310', 'Mutation', 'rs2034310', (18, 27))	('rs2034310', 'Var', (18, 27))	('patients', 'Species', '9606', (51, 59))	('dbSNP', 'Disease', (159, 164))
136146	23372429	Also, as for the MAF of rs5018106, C allele was 0.113 in patients and 0.124 in control respectively, which are included in the range of that in CHB (0.089-0.195) in dbSNP.	('rs5018106', 'Mutation', 'rs5018106', (24, 33))	('dbSNP', 'Disease', (165, 170))	('patients', 'Species', '9606', (57, 65))	('rs5018106', 'Var', (24, 33))
136151	23372429	Those data demonstrated that there was no significant association between the polymorphisms of Rab37 and the risk of ESCC cancer.	('ESCC cancer', 'Disease', 'MESH:D004938', (117, 128))	('rat', 'Species', '10116', (18, 21))	('ESCC cancer', 'Disease', (117, 128))	('Rab37', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('polymorphisms', 'Var', (78, 91))	('Rab37', 'Gene', '326624', (95, 100))
136152	23372429	In addition, we analyzed the association between the polymorphisms of Rab37 and the clinic TNM stage of ESCC patients in Table 4.	('TNM', 'Gene', (91, 94))	('Rab37', 'Gene', (70, 75))	('patients', 'Species', '9606', (109, 117))	('Rab37', 'Gene', '326624', (70, 75))	('ESCC', 'Disease', (104, 108))	('TNM', 'Gene', '10178', (91, 94))	('polymorphisms', 'Var', (53, 66))
136153	23372429	The allele and genotype distributions were not significantly different between the stage I-IIa and stage IIb-IV patients (P>0.05), indicating no association between the polymorphisms and the lymphonodus transfer or metastasis of ESCC.	('ESCC', 'Disease', (229, 233))	('metastasis', 'CPA', (215, 225))	('patients', 'Species', '9606', (112, 120))	('polymorphisms', 'Var', (169, 182))	('lymphonodus transfer', 'CPA', (191, 211))
136161	23372429	Even in their following focused testing, the variation of C20orf54 would be a risk factor for esophageal cancer patients form Shanxi Province (the North of China) but not from Jiangsu Province (the East of China).	('C20orf54', 'Gene', (58, 66))	('C20orf54', 'Gene', '113278', (58, 66))	('esophageal cancer', 'Disease', (94, 111))	('patients', 'Species', '9606', (112, 120))	('variation', 'Var', (45, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('risk factor', 'Reg', (78, 89))
136162	23372429	In this report, we failed to find the association of the 3 Tag SNPs, rs9904078, rs2034310 and rs5018106, located in Rab37 gene region with the risk of ESCC.	('rs9904078', 'Mutation', 'rs9904078', (69, 78))	('Rab37', 'Gene', '326624', (116, 121))	('rs2034310', 'Mutation', 'rs2034310', (80, 89))	('ESCC', 'Disease', (151, 155))	('rs5018106', 'Var', (94, 103))	('rs5018106', 'Mutation', 'rs5018106', (94, 103))	('rs9904078', 'Var', (69, 78))	('rs2034310', 'Var', (80, 89))	('Rab37', 'Gene', (116, 121))
136165	23372429	Our data on the MAF of rs9904078 were consistent with that in CHB and obviously lower than that of CEU.	('rs9904078', 'Var', (23, 32))	('rs9904078', 'Mutation', 'rs9904078', (23, 32))	('lower', 'NegReg', (80, 85))
136166	23372429	Furthermore, our data on the MAF of rs2034310 were included in the range of that in CHB and obviously higher than that in CEU (0.173-0.183).	('rs2034310', 'Var', (36, 45))	('higher', 'PosReg', (102, 108))	('rs2034310', 'Mutation', 'rs2034310', (36, 45))
136167	23372429	If the two SNPs, rs9904078 and rs2034310, could be analyzed in non-Chinese populations, the more information on the relationship between Rab37 gene and the risk of ESCC would be further discovered.	('rs2034310', 'Mutation', 'rs2034310', (31, 40))	('Rab37', 'Gene', '326624', (137, 142))	('rs2034310', 'Var', (31, 40))	('ESCC', 'Disease', (164, 168))	('rs9904078', 'Var', (17, 26))	('Rab37', 'Gene', (137, 142))	('rs9904078', 'Mutation', 'rs9904078', (17, 26))
136293	33681225	observed that Clostridia was significant increase in the esophagus of men with PPI therapy after 8 weeks.	('men', 'Species', '9606', (70, 73))	('Clostridia', 'Disease', (14, 24))	('esophagus', 'Disease', (57, 66))	('increase', 'PosReg', (41, 49))	('PPI therapy', 'Var', (79, 90))
136462	31130076	The mean values of V60 and corresponding normal tissue complication probability, incorporating interfractional esophageal motion, correlated positively with esophageal toxicity grade.	('esophageal toxicity', 'Disease', (157, 176))	('V60', 'Var', (19, 22))	('esophageal toxicity', 'Disease', 'MESH:D004935', (157, 176))
136501	31130076	The statistical plots here display (1) regional shift mean and deviation between CT2 and CT1 (star-marked statistical plots of Figures 2B, D, and F), and (2) regional shift mean and deviation between CT3 and CT1 (circle-marked statistical plots of Figures 2B, D, and F).	('CT1', 'Gene', (208, 211))	('CT3', 'Gene', '285782', (200, 203))	('CT1', 'Gene', '1489', (89, 92))	('CT2', 'Gene', '30848', (81, 84))	('CT1', 'Gene', (89, 92))	('deviation', 'MPA', (63, 72))	('CT1', 'Gene', '1489', (208, 211))	('CT2', 'Gene', (81, 84))	('deviation', 'Var', (182, 191))	('CT3', 'Gene', (200, 203))
136504	31130076	Taking into account esophageal motion, 3 additional cases with equally weighted V60 from both CT2 and CT3 violated the planning constraint, that is, V60 increased from 14% to 29% in patient 16, from 11% to 44% in patient 22 (see Figure.	('CT2', 'Gene', '30848', (94, 97))	('CT3', 'Gene', (102, 105))	('patient', 'Species', '9606', (213, 220))	('increased', 'PosReg', (153, 162))	('patient', 'Species', '9606', (182, 189))	('CT3', 'Gene', '285782', (102, 105))	('CT2', 'Gene', (94, 97))	('V60', 'Var', (149, 152))
136512	31130076	It was found that high-interfractional mean values of V60 (Figure 3) and NTCP (Figure 4) from all CTs that took into account of esophageal motion correlated positively with high-grade toxicity.	('V60', 'Var', (54, 57))	('toxicity', 'Disease', 'MESH:D064420', (184, 192))	('NTCP', 'Gene', (73, 77))	('toxicity', 'Disease', (184, 192))	('CT', 'Gene', '1489', (98, 100))
136545	31130076	Indeed, high V60 and NTCP (the averaged values based on all CTs that take esophageal motion into account) correlated well with high-grade esophageal toxicity.	('V60', 'Var', (13, 16))	('high V60', 'Var', (8, 16))	('esophageal toxicity', 'Disease', (138, 157))	('NTCP', 'Gene', (21, 25))	('esophageal toxicity', 'Disease', 'MESH:D004935', (138, 157))	('CT', 'Gene', '1489', (60, 62))
136730	26372339	Based on the data in Table 3, the sensitivity of the diagnosis of RLN lymph node metastases by preoperative EBUS showed a significant difference from the sensitivity and accuracy of diagnosis by EUS and CT.	('EBUS', 'Var', (108, 112))	('RLN lymph node metastases', 'Disease', (66, 91))	('EBUS', 'Chemical', '-', (108, 112))	('RLN lymph node metastases', 'Disease', 'MESH:D009362', (66, 91))
136732	26372339	According to the data shown in Table 4, the sensitivity of the diagnosis of right RLN lymph node metastases by EBUS was significantly different from that by EUS or CT (P <0.05).	('EBUS', 'Var', (111, 115))	('EBUS', 'Chemical', '-', (111, 115))	('RLN lymph node metastases', 'Disease', (82, 107))	('RLN lymph node metastases', 'Disease', 'MESH:D009362', (82, 107))
136746	26372339	Furthermore, the three-field dissection significantly increased the incidence of RLN injury and pulmonary complications.	('RLN injury and pulmonary complications', 'Disease', 'MESH:D055370', (81, 119))	('increased', 'PosReg', (54, 63))	('pulmonary complications', 'Phenotype', 'HP:0006532', (96, 119))	('three-field', 'Var', (17, 28))
136773	26372339	However, as for thoracic surgeons, EBUS-TBNA for recurrent laryngeal lymph nodes may cause post-procedural hematomas around the lymph node that can interfere with lymph node dissection in a clean plane, which will increase the risk of RLN paralysis.	('EBUS', 'Chemical', '-', (35, 39))	('hematomas', 'Disease', (107, 116))	('paralysis', 'Phenotype', 'HP:0003470', (239, 248))	('EBUS-TBNA', 'Var', (35, 44))	('cause', 'Reg', (85, 90))	('hematomas', 'Disease', 'MESH:D006406', (107, 116))	('RLN paralysis', 'Disease', (235, 248))	('RLN paralysis', 'Disease', 'MESH:D010243', (235, 248))
136815	19461512	Recent studies have reported that frequent loss of heterozygosity (LOH) as well as allelic imbalances in chromosomes in esophageal adenocarcinoma.	('imbalances', 'Phenotype', 'HP:0002172', (91, 101))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (120, 145))	('allelic', 'Var', (83, 90))	('loss', 'NegReg', (43, 47))	('esophageal adenocarcinoma', 'Disease', (120, 145))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (120, 145))
136869	19461512	Early follow-up study of cohort of 23 patients whose biopsy-specimens were stained for p53 protein on both baseline and follow-up visit reported that p53 abnormalities were associated with a neoplastic progression in BE.	('men', 'Species', '9606', (65, 68))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('neoplastic progression', 'CPA', (191, 213))	('p53', 'Gene', (150, 153))	('p53', 'Gene', '7157', (150, 153))	('associated with', 'Reg', (173, 188))	('abnormalities', 'Var', (154, 167))	('patients', 'Species', '9606', (38, 46))	('BE', 'Phenotype', 'HP:0100580', (217, 219))
136875	19461512	When p16 is intact, cyclin D1 alteration is a key cell cycle checkpoint for tumor progression.	('p16', 'Gene', (5, 8))	('alteration', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('p16', 'Gene', '1029', (5, 8))	('cyclin D1', 'Gene', '595', (20, 29))	('cyclin D1', 'Gene', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
136876	19461512	A polymorphism of the gene which codes cyclin D1 was reported to be associated with increased risk for EAC in a prospective case-control study.	('EAC', 'Disease', (103, 106))	('associated', 'Reg', (68, 78))	('cyclin D1', 'Gene', '595', (39, 48))	('cyclin D1', 'Gene', (39, 48))	('EAC', 'Phenotype', 'HP:0011459', (103, 106))	('polymorphism', 'Var', (2, 14))
136883	19461512	The study reported that bi-allelic inactivation of p53 was associated with elevated 4N fractions, which had been associated with the future development of EAC.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('bi-allelic inactivation', 'Var', (24, 47))	('elevated', 'PosReg', (75, 83))	('EAC', 'Phenotype', 'HP:0011459', (155, 158))	('4N fractions', 'MPA', (84, 96))	('men', 'Species', '9606', (147, 150))	('associated', 'Reg', (113, 123))
136886	19461512	Recently different sets of probes were assessed for the detection of dysplasia and EAC in patients with BE and the study showed a probe set consisting of probes to 8q24 (c-myc), 9p21 (p16), 17q11.2 (HER-2/neu), and 20q13.2 had a sensitivity and specificity, respectively, of 70% and 89% for LGD, 84% and 93% for HGD, and 94% and 93% for EAC.	('EAC', 'Disease', (83, 86))	('EAC', 'Disease', (337, 340))	('BE', 'Phenotype', 'HP:0100580', (104, 106))	('HER-2/neu', 'Gene', (199, 208))	('20q13.2', 'Var', (215, 222))	('dysplasia', 'Disease', 'MESH:D004476', (69, 78))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))	('HGD', 'Disease', (312, 315))	('p16', 'Gene', '1029', (184, 187))	('c-myc', 'Gene', '4609', (170, 175))	('HER-2/neu', 'Gene', '2064', (199, 208))	('17q11.2', 'Var', (190, 197))	('LGD', 'Disease', (291, 294))	('EAC', 'Phenotype', 'HP:0011459', (337, 340))	('patients', 'Species', '9606', (90, 98))	('dysplasia', 'Disease', (69, 78))	('p16', 'Gene', (184, 187))	('c-myc', 'Gene', (170, 175))
136936	23155356	VEGF -634C/G Genotype is Predictive of Long-term Survival after Treatment with a Definitive 5-Fluorouracil/cisplatin-based Chemoradiotherapy in Japanese Patients with Esophageal Squamous Cell Carcinoma Background: Reports have been accumulating that genetic properties are predictive of clinical response after and/or toxicity during cancer chemotherapy, but little information is available concerning effects on long-term survival.	('-634C/G', 'SUBSTITUTION', 'None', (5, 12))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('VEGF', 'Gene', '7422', (0, 4))	('Esophageal Squamous Cell Carcinoma', 'Disease', (167, 201))	('Patients', 'Species', '9606', (153, 161))	('toxicity', 'Disease', (318, 326))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (167, 201))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('-634C/G', 'Var', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('Carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (92, 106))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('VEGF', 'Gene', (0, 4))	('toxicity', 'Disease', 'MESH:D064420', (318, 326))	('cancer', 'Disease', (334, 340))
136939	23155356	The VEGF genotypes -1498T/C, -1154G/A, -634C/G, -7C/T, 936C/T, and 1612G/A were evaluated.	('936C/T', 'Var', (55, 61))	('-1154G/A', 'Mutation', 'rs1570360', (29, 37))	('1612G/A', 'Mutation', 'rs10434', (67, 74))	('-7C/T', 'Mutation', 'rs25648', (48, 53))	('-634C/G', 'Mutation', 'rs2010963', (39, 46))	('VEGF', 'Gene', '7422', (4, 8))	('936C/T', 'Mutation', 'rs3025039', (55, 61))	('-1498T/C', 'Mutation', 'rs833061', (19, 27))	('1612G/A', 'Var', (67, 74))	('VEGF', 'Gene', (4, 8))
136946	23155356	A clinical report published in 1999, the RTOG (Radiation Therapy Oncology Group) 85-01 trial involving 134 patients with T1-3, N0-1, and M0 esophageal cancer, was of great interest in terms of clinical outcome because it demonstrated a 5-year survival rate of 26 %.	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('esophageal cancer', 'Disease', (140, 157))	('M0 esophageal cancer', 'Phenotype', 'HP:0011459', (137, 157))	('Oncology', 'Phenotype', 'HP:0002664', (65, 73))	('T1-3', 'Var', (121, 125))	('patients', 'Species', '9606', (107, 115))
136954	23155356	The genotypes of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, were evaluated, since clinical reports suggested that their genetic variations have the potential to influence the expression of VEGF, and thereby the growth of tumors, metastatic spread, and response to treatment; however, they failed to predict the response.	('expression', 'MPA', (213, 223))	('vascular endothelial growth factor', 'Gene', (17, 51))	('metastatic spread', 'CPA', (267, 284))	('VEGF', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('influence', 'Reg', (199, 208))	('genetic variations', 'Var', (158, 176))	('tumors', 'Disease', (259, 265))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('vascular endothelial growth factor', 'Gene', '7422', (17, 51))	('VEGF', 'Gene', '7422', (227, 231))	('variations', 'Var', (166, 176))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('VEGF', 'Gene', '7422', (53, 57))	('VEGF', 'Gene', (227, 231))
136959	23155356	The VEGF genotypes -1498T/C (known as -460T/C, rs833061) and -1154G/A (rs1570360) in the promoter region, -634C/G (known as 405C/G, rs2010963) and -7C/T (rs25648) in the 5' untranslated region (UTR), and 936C/T (rs3025039) and 1612G/A (rs10434) in the 3'UTR, were evaluated using peripheral blood and the TaqManR MGB probe-based polymerase chain reaction and confirmed by direct sequencing.	('rs3025039', 'Mutation', 'rs3025039', (212, 221))	('405C/G', 'Mutation', 'rs2010963', (124, 130))	('VEGF', 'Gene', '7422', (4, 8))	('rs2010963', 'Mutation', 'rs2010963', (132, 141))	('VEGF', 'Gene', (4, 8))	('-460T/C', 'Mutation', 'rs833061', (38, 45))	('rs25648', 'Mutation', 'rs25648', (154, 161))	('rs10434', 'Mutation', 'rs10434', (236, 243))	('-7C/T', 'Mutation', 'rs25648', (147, 152))	('1612G/A', 'Mutation', 'rs10434', (227, 234))	('rs3025039', 'Var', (212, 221))	('rs833061', 'Var', (47, 55))	('936C/T', 'Mutation', 'rs3025039', (204, 210))	('rs1570360', 'Var', (71, 80))	('rs10434', 'Var', (236, 243))	('rs833061', 'Mutation', 'rs833061', (47, 55))	('rs1570360', 'Mutation', 'rs1570360', (71, 80))	('-1498T/C', 'Mutation', 'rs833061', (19, 27))	('-634C/G', 'Mutation', 'rs2010963', (106, 113))	('-1154G/A', 'Mutation', 'rs1570360', (61, 69))	('rs2010963', 'Var', (132, 141))
136972	23155356	The median overall survival time (+-SE) was 29.5+-22.3 months for all patients, and more than 60 months, more than 60 months, and 13.0+-9.0 months for the patients with CC-634, CG-634, and GG-634, respectively, but the genotype did not have enough power to predict survival (P=0.079, Log-rank).	('patients', 'Species', '9606', (70, 78))	('GG-634', 'Var', (189, 195))	('CC-634', 'Var', (169, 175))	('patients', 'Species', '9606', (155, 163))	('CG', 'Chemical', 'MESH:C028505', (177, 179))	('CG-634', 'Var', (177, 183))
136978	23155356	Genetic polymorphisms in the promoter region, 5'UTR, and 3'UTR of the VEGF gene are associated with VEGF levels in plasma or tumors, and therefore can be diagnostic, prognostic, and predictive biomarkers for patients with tumors.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('VEGF', 'Gene', (70, 74))	('patients', 'Species', '9606', (208, 216))	('VEGF', 'Gene', '7422', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('VEGF', 'Gene', '7422', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('associated', 'Reg', (84, 94))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('VEGF', 'Gene', (100, 104))	('polymorphisms', 'Var', (8, 21))
136987	23155356	We do not have enough data to clarify the role of VEGF in cardiopulmonary diseases, but VEGF genetic variations might be biomarkers for patients with cardiopulmonary diseases.	('VEGF', 'Gene', (50, 54))	('VEGF', 'Gene', (88, 92))	('cardiopulmonary diseases', 'Disease', 'MESH:D006323', (150, 174))	('patients', 'Species', '9606', (136, 144))	('VEGF', 'Gene', '7422', (50, 54))	('cardiopulmonary diseases', 'Disease', (150, 174))	('cardiopulmonary diseases', 'Disease', 'MESH:D006323', (58, 82))	('VEGF', 'Gene', '7422', (88, 92))	('cardiopulmonary diseases', 'Disease', (58, 82))	('genetic variations', 'Var', (93, 111))
137050	33483558	Adverse events tended to develop more frequently in the high radial force (39%, 22/56) than in the low radial force stent group (24%, 12/51); however, the difference was not significant (P = 0.098).	('ste', 'Gene', '6783', (116, 119))	('Adverse', 'Disease', (0, 7))	('ste', 'Gene', (116, 119))	('high radial force', 'Var', (56, 73))
137052	33483558	The incidence of SAEs tended to be higher in patients who had undergone RT/CRT (17%, 4/24 procedures) than in those who had not RT/CRT (6%, 5/83 procedures); however, this difference was not statistically significant (P = 0.11).	('higher', 'PosReg', (35, 41))	('patients', 'Species', '9606', (45, 53))	('SAEs', 'Disease', (17, 21))	('RT/CRT', 'Var', (72, 78))
137053	33483558	When we compared the incidence of SAEs by stent type (Table 2), we found that SAEs developed more frequently in the high radial force (14%, 8/56 procedures) than in the low radial force stent group (2%, 1/51 procedures) (P = 0.03).	('ste', 'Gene', (186, 189))	('ste', 'Gene', '6783', (186, 189))	('high radial force', 'Var', (116, 133))	('ste', 'Gene', (42, 45))	('SAEs', 'Disease', (78, 82))	('ste', 'Gene', '6783', (42, 45))
137054	33483558	In the subgroup of patients who had undergone prior RT/CRT, SAEs also developed more frequently in the high radial force (36%: 4/11 procedures) than in the low radial force stent group (0%, 0/13 procedures) (P = 0.03).	('ste', 'Gene', '6783', (173, 176))	('patients', 'Species', '9606', (19, 27))	('SAEs', 'Disease', (60, 64))	('high', 'Var', (103, 107))	('ste', 'Gene', (173, 176))
137055	33483558	Multivariate analysis showed an association between high radial force stents and SAEs (Table 3).	('high', 'Var', (52, 56))	('ste', 'Gene', '6783', (70, 73))	('ste', 'Gene', (70, 73))	('SAEs', 'Disease', (81, 85))
137062	33483558	SAEs developed more frequently in patients in the high radial force (16%, 7/44 procedures) than low radial force stent group (3%, 1/35 procedures); this difference was not significant (P = 0.07).	('SAEs', 'Disease', (0, 4))	('high radial force', 'Var', (50, 67))	('ste', 'Gene', (113, 116))	('ste', 'Gene', '6783', (113, 116))	('patients', 'Species', '9606', (34, 42))
137063	33483558	In the subgroup of patients who had undergone prior RT/CRT, SAEs developed more frequently in the high radial force (40%, 4/10 procedures) than low radial force stent group (0%: 0/12 procedures) (P = 0.03).	('patients', 'Species', '9606', (19, 27))	('high', 'Var', (98, 102))	('ste', 'Gene', (161, 164))	('ste', 'Gene', '6783', (161, 164))	('SAEs', 'Disease', (60, 64))
137077	33483558	Esophageal RT/CRT can cause vasculitis, hypoxemia, and fragility of the esophageal wall that can manifest as esophagitis, ulcer, fibrosis, and stricture.	('cause', 'Reg', (22, 27))	('Esophageal RT/CRT', 'Var', (0, 17))	('vasculitis', 'Disease', 'MESH:D014657', (28, 38))	('hypoxemia', 'Phenotype', 'HP:0012418', (40, 49))	('fibrosis', 'Disease', 'MESH:D005355', (129, 137))	('vasculitis', 'Phenotype', 'HP:0002633', (28, 38))	('hypoxemia', 'Disease', (40, 49))	('esophagitis', 'Phenotype', 'HP:0100633', (109, 120))	('vasculitis', 'Disease', (28, 38))	('esophagitis', 'Disease', 'MESH:D004938', (109, 120))	('hypoxemia', 'Disease', 'MESH:D000860', (40, 49))	('stricture', 'Disease', (143, 152))	('fragility', 'Disease', (55, 64))	('ulcer', 'Disease', 'MESH:D014456', (122, 127))	('ulcer', 'Disease', (122, 127))	('esophagitis', 'Disease', (109, 120))	('fibrosis', 'Disease', (129, 137))
137081	33483558	In support of this contention, the incidence of SAEs was significantly higher in the high radial force (36.4%, 4/11 patients) than the low radial force stent group (0%, 0/13 patients).	('ste', 'Gene', (152, 155))	('ste', 'Gene', '6783', (152, 155))	('SAEs', 'Disease', (48, 52))	('patients', 'Species', '9606', (116, 124))	('high radial force', 'Var', (85, 102))	('patients', 'Species', '9606', (174, 182))
137161	30863768	As there was no serous layer of the esophagus, resection of the muscularis propria of the esophagus would be more prone to concurrent subcutaneous emphysema, pneumothorax, and secondary infection than the gastric muscularis propria.	('muscularis propria', 'Phenotype', 'HP:0030936', (64, 82))	('subcutaneous emphysema', 'Disease', 'MESH:D013352', (134, 156))	('subcutaneous emphysema', 'Disease', (134, 156))	('muscularis propria', 'Phenotype', 'HP:0030936', (213, 231))	('secondary infection', 'Disease', (176, 195))	('infection than the gastric muscularis propria', 'Disease', (186, 231))	('infection than the gastric muscularis propria', 'Disease', 'MESH:D013274', (186, 231))	('prone', 'Reg', (114, 119))	('emphysema', 'Phenotype', 'HP:0002097', (147, 156))	('pneumothorax', 'Disease', (158, 170))	('resection', 'Var', (47, 56))	('pneumothorax', 'Phenotype', 'HP:0002107', (158, 170))	('secondary infection', 'Disease', 'MESH:D060085', (176, 195))
137171	28052566	Kaplan-Meier analysis demonstrated a trend that patients who underwent MIME had longer overall (79.5% vs. 64.1%; P = 0.063) and disease-free three-year survival (65.3% vs. 82.8%; P = 0.058) compared with patients who underwent DIE.	('patients', 'Species', '9606', (204, 212))	('DIE', 'Chemical', '-', (227, 230))	('disease-free three-year survival', 'CPA', (128, 160))	('longer', 'PosReg', (80, 86))	('patients', 'Species', '9606', (48, 56))	('MIME', 'Var', (71, 75))	('MIME', 'Chemical', '-', (71, 75))
137173	28052566	However, MIME was associated with better overall and disease-free three-year survival compared with DIE.	('better', 'PosReg', (34, 40))	('MIME', 'Chemical', '-', (9, 13))	('MIME', 'Var', (9, 13))	('DIE', 'Chemical', '-', (100, 103))	('disease-free three-year survival', 'CPA', (53, 85))
137211	28052566	However, after matching, there was a trend of longer three-year OS (64.1% vs. 79.5%; P = 0.063) and DFS (65.3% vs. 82.8%; P = 0.058) in the patients who underwent MIME compared with the patients who underwent DIE (Fig 2).	('longer', 'PosReg', (46, 52))	('DIE', 'Chemical', '-', (209, 212))	('DFS', 'MPA', (100, 103))	('patients', 'Species', '9606', (140, 148))	('MIME', 'Var', (163, 167))	('MIME', 'Chemical', '-', (163, 167))	('patients', 'Species', '9606', (186, 194))
137215	28052566	Most importantly, a trend indicated that MIME was associated with better three-year OS and DFS compared with DIE.	('MIME', 'Var', (41, 45))	('MIME', 'Chemical', '-', (41, 45))	('DIE', 'Chemical', '-', (109, 112))	('better', 'PosReg', (66, 72))	('DFS', 'CPA', (91, 94))
137230	28052566	However, MIME was associated with better three-year OS and DFS compared with DIE.	('DFS', 'CPA', (59, 62))	('better', 'PosReg', (34, 40))	('DIE', 'Chemical', '-', (77, 80))	('MIME', 'Var', (9, 13))	('MIME', 'Chemical', '-', (9, 13))
137245	27391431	However, HMGB1 acts as both a tumor suppressor and an oncogenic factor in tumorigenesis and cancer therapy depending on the context and HMGB1 location and modification.	('cancer', 'Disease', (92, 98))	('HMGB1', 'Gene', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('modification', 'Var', (155, 167))	('tumor', 'Disease', (74, 79))	('HMGB1', 'Gene', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (30, 35))
137256	27391431	The OS was significantly shorter in patients with high HMGB1 expression compared those with low HMGB1 expression in both Asia (HR: 1.94; 95% CI, 1.67-2.26) and Europe (HR: 2.93; 95% CI, 1.58-5.43) (Figure 4).	('patients', 'Species', '9606', (36, 44))	('HR', 'Phenotype', 'HP:0001402', (168, 170))	('shorter', 'NegReg', (25, 32))	('HR', 'Phenotype', 'HP:0001402', (127, 129))	('expression', 'Var', (61, 71))	('HMGB1', 'Gene', (55, 60))	('high', 'Var', (50, 54))
137267	27391431	These cancer hallmarks include: sustainment of proliferative signaling; evasion of growth suppressors; avoidance of immune destruction; enablement of replicative immortality; tumor-promoting inflammation; activation of invasion and metastasis; induction of angiogenesis; genome instability and mutation; resistance to cell death; and deregulation of cellular energetics.	('invasion', 'CPA', (219, 227))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('evasion', 'MPA', (72, 79))	('enablement', 'PosReg', (136, 146))	('genome instability', 'CPA', (271, 289))	('mutation', 'Var', (294, 302))	('tumor', 'Disease', (175, 180))	('inflammation', 'Disease', 'MESH:D007249', (191, 203))	('sustainment', 'MPA', (32, 43))	('replicative immortality', 'CPA', (150, 173))	('cellular energetics', 'CPA', (350, 369))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('cancer', 'Disease', (6, 12))	('proliferative signaling', 'MPA', (47, 70))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('activation', 'PosReg', (205, 215))	('inflammation', 'Disease', (191, 203))	('angiogenesis', 'CPA', (257, 269))	('resistance to cell death', 'CPA', (304, 328))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('avoidance of immune destruction', 'Phenotype', 'HP:0002721', (103, 134))
137279	27391431	Inhibition of RAGE-HMGB1 interaction has been proved to be effective in inhibiting tumor angiogenesis and growth, metastasis, migration and invasion of cancer cells.	('growth', 'CPA', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('RAGE', 'Gene', '177', (14, 18))	('interaction', 'Interaction', (25, 36))	('tumor', 'Disease', (83, 88))	('inhibiting', 'NegReg', (72, 82))	('RAGE', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
137280	27391431	Therefore, serum HMGB1 can be a potential powerful diagnostic and prognostic biomarker for patients with cancer.	('serum', 'Var', (11, 16))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('HMGB1', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
137281	27391431	Among included studies, 4 researches showed that overexpressed serum HMGB1 was closely correlated with the advanced stage of cancer in pancreatic cancer, cervical carcinoma, and malignant pleural mesothelioma.	('cancer', 'Disease', (146, 152))	('HMGB1', 'Gene', (69, 74))	('pancreatic cancer', 'Disease', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (188, 208))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (178, 208))	('cervical carcinoma', 'Disease', (154, 172))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('cervical carcinoma', 'Disease', 'MESH:D002575', (154, 172))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('overexpressed', 'PosReg', (49, 62))	('serum', 'Var', (63, 68))	('correlated', 'Reg', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('malignant pleural mesothelioma', 'Disease', (178, 208))	('pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
137283	27391431	Meanwhile, Chung et al and Sheng et al respectively exhibited serum HMGB1 was a remarkable biomarker to predict pancreatic ductal adenocarcinoma and recurrent cervical squamous cell carcinomas with superior sensitivity or specificity compared to existing biomarkers.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (168, 192))	('squamous cell carcinomas', 'Disease', (168, 192))	('serum', 'Var', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('HMGB1', 'Gene', (68, 73))	('pancreatic ductal adenocarcinoma', 'Disease', (112, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (168, 192))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (112, 144))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (112, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))
137291	27391431	Jube et al showed that treatment with HMGB1 inhibitors could prolong the survival of malignant mesothelioma xenograft mice, offering a preclinical proof-of-principle that antibody-mediated ablation of HMBG1 was sufficient to elicit antitumor therapeutic activity.	('elicit', 'Reg', (225, 231))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (85, 107))	('inhibitors', 'Var', (44, 54))	('prolong', 'PosReg', (61, 68))	('HMGB1', 'Gene', (38, 43))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (85, 107))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('survival', 'CPA', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('ablation', 'Var', (189, 197))	('malignant mesothelioma', 'Disease', (85, 107))	('mice', 'Species', '10090', (118, 122))	('HMBG1', 'Gene', (201, 206))	('tumor', 'Disease', (236, 241))
137304	25129146	In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10-20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10-13).	('rs1642764', 'Var', (233, 242))	('rs7447927', 'Var', (141, 150))	('rs7447927', 'Mutation', 'rs7447927', (141, 150))	('rs1642764', 'Mutation', 'rs1642764', (233, 242))
137305	25129146	rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53.	('TMEM173', 'Gene', (66, 73))	('ATP1B2', 'Gene', (110, 116))	('rs1642764', 'Mutation', 'rs1642764', (78, 87))	('TMEM173', 'Gene', '340061', (66, 73))	('ATP1B2', 'Gene', '482', (110, 116))	('TP53', 'Gene', '7157', (123, 127))	('rs7447927', 'Var', (0, 9))	('TP53', 'Gene', (123, 127))	('rs7447927', 'Mutation', 'rs7447927', (0, 9))	('rs1642764', 'Var', (78, 87))
137306	25129146	Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10-10).	('rs35597309', 'Var', (60, 70))	('ESSC', 'Disease', (149, 153))	('HLA', 'Gene', '3117', (28, 31))	('HLA', 'Gene', (28, 31))	('rs35597309', 'Mutation', 'rs35597309', (60, 70))
137323	25129146	The joint analysis identified two new genome-wide significant loci at 5q31.2 (Figure 1a) and 17p13.1 (Figure 1b) associated with risk of ESCC in the pooled data of individual genotypes of all three GWAS and two replication studies (Table 1 and Supplementary Table 3).	('men', 'Species', '9606', (250, 253))	('17p13.1', 'Var', (93, 100))	('ESCC', 'Disease', (137, 141))	('associated', 'Reg', (113, 123))
137324	25129146	At 5q31.2, rs7447927, a synonymous SNP located in transmembrane protein 173 (TMEM173), had a combined per allele odds ratio (OR) and 95% confidence interval (95% CI) of 0.85 (0.82-0.88), P=7.72x10-20.	('TMEM173', 'Gene', '340061', (77, 84))	('rs7447927', 'Var', (11, 20))	('transmembrane protein 173', 'Gene', (50, 75))	('rs7447927', 'Mutation', 'rs7447927', (11, 20))	('transmembrane protein 173', 'Gene', '340061', (50, 75))	('TMEM173', 'Gene', (77, 84))
137325	25129146	At 17p13.1, rs1642764, an intronic SNP located in ATPase, Na+/K+ transporting, beta 2 polypeptide (ATP1B2), which is just telomeric to the tumor suppressor gene, TP53, had a combined per allele OR (95%CI) of 0.88 (0.85-0.91), P=3.10x10-13.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('ATP1B2', 'Gene', '482', (99, 105))	('rs1642764', 'Mutation', 'rs1642764', (12, 21))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('rs1642764', 'Var', (12, 21))	('ATP1B2', 'Gene', (99, 105))
137326	25129146	Table 1 also shows that when the analyses were restricted to subjects from the high incidence regions, rs35597309, located in the HLA Class II gene region between HLA-DRB1 and HLA-DQA1, had a per allele OR (95% CI) of 1.33 (1.22-1.46), P=1.99 x 10-10 (Supplementary Figure 6).	('HLA', 'Gene', '3117', (176, 179))	('men', 'Species', '9606', (258, 261))	('HLA', 'Gene', (176, 179))	('rs35597309', 'Mutation', 'rs35597309', (103, 113))	('HLA-DQA1', 'Gene', '3117', (176, 184))	('HLA-DRB1', 'Gene', '3123', (163, 171))	('HLA', 'Gene', '3117', (130, 133))	('HLA-DQA1', 'Gene', (176, 184))	('HLA', 'Gene', (130, 133))	('HLA', 'Gene', '3117', (163, 166))	('rs35597309', 'Var', (103, 113))	('HLA-DRB1', 'Gene', (163, 171))	('HLA', 'Gene', (163, 166))
137329	25129146	Finally, our joint analysis observed a promising association with rs61271866 (P=5.18 x 10-8), an intergenic SNP at 9p21.3 that includes the cyclin-dependent kinase inhibitor 2B (CDKN2B)-CDKN2A gene cluster (Supplementary Table 3).	('CDKN2A', 'Gene', '1029', (186, 192))	('cyclin-dependent kinase inhibitor 2B', 'Gene', (140, 176))	('CDKN2B', 'Gene', (178, 184))	('rs61271866', 'Var', (66, 76))	('cyclin-dependent kinase inhibitor 2B', 'Gene', '1030', (140, 176))	('men', 'Species', '9606', (213, 216))	('CDKN2A', 'Gene', (186, 192))	('CDKN2B', 'Gene', '1030', (178, 184))	('rs61271866', 'Mutation', 'rs61271866', (66, 76))
137330	25129146	Variants in this region have been associated with risk of melanoma, childhood acute lymphoblastic leukemia, chronic lymphocytic leukemia, and glioma, as well as ESCC in a prior study using a subset of the samples examined here.	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('associated', 'Reg', (34, 44))	('Variants', 'Var', (0, 8))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (84, 106))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (108, 136))	('glioma', 'Disease', (142, 148))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (78, 106))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (108, 136))	('leukemia', 'Phenotype', 'HP:0001909', (128, 136))	('chronic lymphocytic leukemia', 'Disease', (108, 136))	('ESCC', 'Disease', (161, 165))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (78, 106))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('acute lymphoblastic leukemia', 'Disease', (78, 106))	('melanoma', 'Disease', (58, 66))
137333	25129146	For these four SNPs (rs7447927, rs1642764, rs35597309, and rs61271866), we tested for interactions by use of alcohol (Supplementary Table 5) or tobacco (Supplementary Table 6).	('rs61271866', 'Mutation', 'rs61271866', (59, 69))	('rs35597309', 'Var', (43, 53))	('rs7447927', 'Var', (21, 30))	('men', 'Species', '9606', (159, 162))	('tested', 'Reg', (75, 81))	('alcohol', 'Chemical', 'MESH:D000438', (109, 116))	('rs7447927', 'Mutation', 'rs7447927', (21, 30))	('men', 'Species', '9606', (124, 127))	('rs1642764', 'Mutation', 'rs1642764', (32, 41))	('tobacco', 'Species', '4097', (144, 151))	('rs35597309', 'Mutation', 'rs35597309', (43, 53))	('rs61271866', 'Var', (59, 69))	('rs1642764', 'Var', (32, 41))
137336	25129146	Here we report a new finding of an association between rs7447927, a synonymous SNP in TMEM173, and ESCC risk.	('rs7447927', 'Var', (55, 64))	('TMEM173', 'Gene', (86, 93))	('ESCC', 'Disease', (99, 103))	('rs7447927', 'Mutation', 'rs7447927', (55, 64))	('TMEM173', 'Gene', '340061', (86, 93))
137338	25129146	The only previous GWAS hit at this locus (rs13181561) was demonstrated to be associated with the modulation of interferon-alpha responses to the smallpox vaccine and is highly correlated (r2=0.956 in 1000 Genomes data for CHB population) with rs7447927.	('rs13181561', 'Var', (42, 52))	('interferon-alpha responses', 'MPA', (111, 137))	('rs13181561', 'Mutation', 'rs13181561', (42, 52))	('smallpox', 'Species', '10255', (145, 153))	('rs7447927', 'Var', (243, 252))	('modulation', 'MPA', (97, 107))	('rs7447927', 'Mutation', 'rs7447927', (243, 252))	('associated', 'Reg', (77, 87))
137339	25129146	rs13181561 is also tagged as an expression quantitative trait locus in lymphoblastoid cells (Supplementary Table 7) that alters expression of genes in segment AC135457.2.	('rs13181561', 'Var', (0, 10))	('alters', 'Reg', (121, 127))	('men', 'Species', '9606', (154, 157))	('rs13181561', 'Mutation', 'rs13181561', (0, 10))	('men', 'Species', '9606', (99, 102))	('expression', 'MPA', (128, 138))
137341	25129146	Interestingly, low vitamin C has been implicated in risk of ESCC.	('low', 'Var', (15, 18))	('ESCC', 'Disease', (60, 64))	('vitamin C', 'Chemical', 'MESH:D001205', (19, 28))	('low vitamin C', 'Phenotype', 'HP:0100510', (15, 28))	('vitamin', 'Gene', (19, 26))
137342	25129146	The new susceptibility locus at 17p13.1 is marked by rs1642764, an intronic SNP located within the ATP1B2 gene; this variant resides in an LD block that includes the 3' region of TP53 (Figure 1b).	('ATP1B2', 'Gene', '482', (99, 105))	('rs1642764', 'Mutation', 'rs1642764', (53, 62))	('ATP1B2', 'Gene', (99, 105))	('rs1642764', 'Var', (53, 62))	('TP53', 'Gene', '7157', (179, 183))	('TP53', 'Gene', (179, 183))
137343	25129146	Alteration of TP53 regulation or function could be a plausible explanation for the observed association between rs1642764 and risk of ESCC.	('rs1642764', 'Var', (112, 121))	('TP53', 'Gene', '7157', (14, 18))	('Alteration', 'Reg', (0, 10))	('TP53', 'Gene', (14, 18))	('ESCC', 'Disease', (134, 138))	('rs1642764', 'Mutation', 'rs1642764', (112, 121))	('regulation', 'MPA', (19, 29))	('function', 'MPA', (33, 41))
137344	25129146	It is noteworthy that no prior cancer GWAS has reported a conclusive association with a variant in or around TP53.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('variant', 'Var', (88, 95))	('TP53', 'Gene', '7157', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('TP53', 'Gene', (109, 113))	('cancer', 'Disease', (31, 37))
137345	25129146	Recently, a candidate gene study of genotyped and imputed SNPs across TP53 reported a strong association of a SNP with a low minor allele frequency, rs78378222, with glioma risk (P=6.86 x 10-24 with a MAF=0.013 in a population of European ancestry).	('TP53', 'Gene', '7157', (70, 74))	('glioma', 'Disease', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('MAF', 'Gene', '4094', (201, 204))	('TP53', 'Gene', (70, 74))	('rs78378222', 'Var', (149, 159))	('association', 'Interaction', (93, 104))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('rs78378222', 'Mutation', 'rs78378222', (149, 159))	('MAF', 'Gene', (201, 204))	('minor', 'Species', '53258', (125, 130))
137347	25129146	Our target SNP in this region is in LD with several other SNPs, notably rs1050541 (r2=0.575), which alters a binding site for RAD21 (Supplementary Table 7).	('rs1050541', 'Var', (72, 81))	('rs1050541', 'Mutation', 'rs1050541', (72, 81))	('RAD21', 'Gene', (126, 131))	('men', 'Species', '9606', (139, 142))	('alters', 'Reg', (100, 106))	('RAD21', 'Gene', '5885', (126, 131))	('binding', 'Interaction', (109, 116))
137349	25129146	Alternatively, this SNP falls between recombination hotspots that includes the SHBG gene, and variants bracketing this SNP are known to be associated with sex hormone binding globulin regulation and serum testosterone concentration.	('testosterone', 'Chemical', 'MESH:D013739', (205, 217))	('falls', 'Phenotype', 'HP:0002527', (24, 29))	('serum testosterone concentration', 'MPA', (199, 231))	('associated', 'Reg', (139, 149))	('variants', 'Var', (94, 102))	('sex hormone binding globulin regulation', 'MPA', (155, 194))	('SHBG', 'Gene', '6462', (79, 83))	('SHBG', 'Gene', (79, 83))
137352	25129146	In published GWAS, HLA Class II genetic variants in close proximity (<20 kb) of rs35597309 on 6p21.32 have been associated with multiple cancers including nasopharyngeal carcinoma, hepatocellular carcinoma, lung cancer in never smokers, and familial chronic lymphocytic leukemia as well as autoimmune diseases, including Crohn's disease and lupus .	('rs35597309', 'Mutation', 'rs35597309', (80, 90))	('multiple cancers', 'Disease', 'MESH:D009369', (128, 144))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (155, 179))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('HLA', 'Gene', '3117', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (181, 205))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('variants', 'Var', (40, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (181, 205))	('hepatocellular carcinoma', 'Disease', (181, 205))	('associated with', 'Reg', (112, 127))	('multiple cancers', 'Disease', (128, 144))	('nasopharyngeal carcinoma', 'Disease', (155, 179))	('lupus', 'Disease', (341, 346))	("Crohn's disease", 'Phenotype', 'HP:0100280', (321, 336))	('autoimmune diseases', 'Disease', 'MESH:D001327', (290, 309))	("Crohn's disease", 'Disease', 'MESH:D003424', (321, 336))	("Crohn's disease", 'Disease', (321, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('familial chronic lymphocytic leukemia', 'Disease', (241, 278))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('autoimmune diseases', 'Disease', (290, 309))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (155, 179))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (290, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('HLA', 'Gene', (19, 22))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (250, 278))	('familial chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (241, 278))	('leukemia', 'Phenotype', 'HP:0001909', (270, 278))	('lung cancer', 'Disease', (207, 218))	('rs35597309', 'Var', (80, 90))
137355	25129146	rs35597309 is in perfect LD (r2=1.0) with 34 other SNPs within 2 MB (Supplementary Table 7) including two missense mutations in HLADQA1 and a host of putative protein binding sites, enhancers, and regulatory motifs.	('HLADQA1', 'Gene', (128, 135))	('missense', 'Var', (106, 114))	('rs35597309', 'Mutation', 'rs35597309', (0, 10))	('men', 'Species', '9606', (75, 78))	('rs35597309', 'Var', (0, 10))	('HLADQA1', 'Gene', '3117', (128, 135))	('binding', 'Interaction', (167, 174))
137356	25129146	But the LD with top hits in this region from previously reported studies of cancer was low; r2<0.1 for rs2860580 (nasopharyngeal carcinoma), rs9272105 (hepatocellular carcinoma), rs2395185 (lung cancer), and rs674313 (chronic lymphocytic leukemia) in 1000 Genomes data for CHB+JPT populations.	('chronic lymphocytic leukemia', 'Disease', (218, 246))	('rs9272105', 'Mutation', 'rs9272105', (141, 150))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (114, 138))	('rs2860580', 'Mutation', 'rs2860580', (103, 112))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('hepatocellular carcinoma', 'Disease', (152, 176))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (218, 246))	('lung cancer', 'Disease', (190, 201))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (114, 138))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (152, 176))	('cancer', 'Disease', (195, 201))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('rs2395185', 'Mutation', 'rs2395185', (179, 188))	('rs2395185', 'Var', (179, 188))	('cancer', 'Disease', (76, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('rs674313', 'Var', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('nasopharyngeal carcinoma', 'Disease', (114, 138))	('rs674313', 'Mutation', 'rs674313', (208, 216))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (152, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('leukemia', 'Phenotype', 'HP:0001909', (238, 246))	('rs2860580', 'Var', (103, 112))	('rs9272105', 'Var', (141, 150))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (218, 246))
137375	25129146	To technically validate our imputation findings, we optimized TaqMan assays for rs7447927, rs1642764, and rs35597309.	('rs1642764', 'Var', (91, 100))	('rs35597309', 'Mutation', 'rs35597309', (106, 116))	('rs7447927', 'Var', (80, 89))	('rs7447927', 'Mutation', 'rs7447927', (80, 89))	('rs1642764', 'Mutation', 'rs1642764', (91, 100))	('rs35597309', 'Var', (106, 116))
137378	25129146	In this second approach, we generated the set of eigenvectors based on each GWAS and identified significant eigenvectors to control for population stratification in each individual GWAS (EV1 for NCI; EV1, EV5 and EV7 for Beijing; no EV was needed for Henan).	('EV7', 'Var', (213, 216))	('EV1', 'Gene', '11322', (187, 190))	('EV1', 'Gene', '11322', (200, 203))	('EV1', 'Gene', (187, 190))	('EV1', 'Gene', (200, 203))	('EV5', 'Var', (205, 208))
137418	23673354	Site and histology definitions used the International Classification of Disease for Oncology, 2nd edition, codes for esophageal carcinoma (C15.0-C15.9) and the gastroesophageal junction (C16.0); both locations were included to permit identification of all pertinent cancers.	('Oncology', 'Phenotype', 'HP:0002664', (84, 92))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('C16.0', 'Var', (187, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal carcinoma', 'Disease', (117, 137))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (117, 137))	('gastroesophageal junction', 'Disease', (160, 185))	('pertinent cancers', 'Disease', 'MESH:D009369', (256, 273))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (117, 137))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('pertinent cancers', 'Disease', (256, 273))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (160, 185))	('C15.0-C15.9', 'Var', (139, 150))
137533	33178590	A total of 10,967 tumor samples comprising 32 cancer types from The Cancer Genome Atlas (TCGA) datasets were analyzed for MET abnormal expression, mutations, and copy number variants (CNVs).	('MET', 'Gene', '79811', (122, 125))	('mutations', 'Var', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', (18, 23))	('cancer', 'Disease', (46, 52))	('MET', 'Gene', (122, 125))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('Cancer', 'Disease', (68, 74))	('copy number variants', 'Var', (162, 182))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
137535	33178590	Lung adenocarcinoma (LUAD) has most targetable mutations located in the juxtamembrane domain, and both high expression and amplification of MET are significantly associated with poor prognosis.	('MET', 'Gene', '79811', (140, 143))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('MET', 'Gene', (140, 143))	('mutations', 'Var', (47, 56))	('associated', 'Reg', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('amplification', 'Var', (123, 136))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))
137540	33178590	This study provided significant and comprehensive information regarding MET abnormal expression, alterations (mutations and CNVs), and their clinical associations among 32 cancer types and offered insights into the full MET alteration spectrum and its implications for prognosis and treatment.	('MET', 'Gene', '79811', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('abnormal', 'Var', (76, 84))	('MET', 'Gene', (220, 223))	('alterations', 'Var', (97, 108))	('cancer', 'Disease', (172, 178))	('MET', 'Gene', '79811', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('MET', 'Gene', (72, 75))	('associations', 'Interaction', (150, 162))
137543	33178590	It is frequently activated in human tumors by various mechanisms, such as mutations, amplification, and overexpression, thus leading to malignant transformation and metastasis.	('malignant transformation', 'CPA', (136, 160))	('leading to', 'Reg', (125, 135))	('metastasis', 'CPA', (165, 175))	('human', 'Species', '9606', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('overexpression', 'Var', (104, 118))	('mutations', 'Var', (74, 83))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
137546	33178590	Moreover, in esophageal carcinoma (ESCA) and kidney renal papillary cell carcinoma (KIRP), gene amplification with consequent protein overexpression and constitutive kinase activation of MET has been reported.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (13, 33))	('protein', 'Protein', (126, 133))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (13, 33))	('overexpression', 'PosReg', (134, 148))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (52, 82))	('MET', 'Gene', '79811', (187, 190))	('ESCA', 'Phenotype', 'HP:0011459', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('MET', 'Gene', (187, 190))	('kidney renal papillary cell carcinoma', 'Disease', (45, 82))	('gene amplification', 'Var', (91, 109))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (45, 82))	('esophageal carcinoma', 'Disease', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
137549	33178590	Especially in lung cancer, inhibition of MET receptor activity has shown promising results and has become a standard therapy for patients.	('patients', 'Species', '9606', (129, 137))	('MET', 'Gene', (41, 44))	('lung cancer', 'Disease', (14, 25))	('MET', 'Gene', '79811', (41, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('inhibition', 'Var', (27, 37))	('activity', 'MPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
137563	33178590	Especially, in single- and cross-cancer queries, OQL algorithm can be utilized to accurately identify copy number alterations, mutations, mRNA, and protein expression profiles.	('copy number alterations', 'Var', (102, 125))	('mRNA', 'MPA', (138, 142))	('cross-cancer', 'Disease', (27, 39))	('cross-cancer', 'Disease', 'MESH:D009369', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (127, 136))
137581	33178590	MET mutations were observed most commonly in UCEC (12.3%), SKCM (10.5%), KIRP (8.8%), bladder urothelial carcinoma (BLCA, 4.4%), COADREAD (4.4%), and LUAD (4.2%).	('KIRP', 'Disease', (73, 77))	('MET', 'Gene', '79811', (0, 3))	('bladder urothelial carcinoma', 'Disease', (86, 114))	('observed', 'Reg', (19, 27))	('COADREAD', 'Disease', (129, 137))	('MET', 'Gene', (0, 3))	('UCEC', 'Disease', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('mutations', 'Var', (4, 13))	('SKCM', 'Disease', (59, 63))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (86, 114))
137587	33178590	The most common domains were the other domain (91 samples), Sema domain (83 samples), Pkinase-Tyr domain (69 samples), TIG domain (563-654 aa, 18 samples), TIG domain (742-815 aa, 17 samples), TIG domain (657-728 aa, 12 samples), and PSI domain (7 samples).	('Sema', 'Gene', '7869', (60, 64))	('Tyr', 'Chemical', 'MESH:D014443', (94, 97))	('657-728 aa', 'Var', (205, 215))	('Sema', 'Gene', (60, 64))
137589	33178590	Mutations in KIRP were primarily located in the Pkinase-Tyr domain, approximately three times more than the mutations located in the other domain.	('Tyr', 'Chemical', 'MESH:D014443', (56, 59))	('Mutations', 'Var', (0, 9))	('KIRP', 'Gene', (13, 17))
137590	33178590	Mutations in COADREAD and GBM were mainly located in the Sema domain (Figure 2B and Supplementary Table S3).	('located', 'Reg', (42, 49))	('GBM', 'Gene', (26, 29))	('Sema', 'Gene', (57, 61))	('Sema', 'Gene', '7869', (57, 61))	('Mutations', 'Var', (0, 9))	('COADREAD', 'Gene', (13, 21))
137593	33178590	For example, the 1,010-aa mutation was found in seven samples (six samples with X1010 splice, one with D1010fs) and occurred almost exclusively in LUAD (6/7) (Supplementary Figure S2B).	('D1010fs', 'Var', (103, 110))	('D1010fs', 'Mutation', 'p.D1010fsX', (103, 110))	('X1010 splice', 'Var', (80, 92))	('LUAD', 'Phenotype', 'HP:0030078', (147, 151))
137596	33178590	The only other tumor with mutations at this position was LGG (one sample with X1010_splice), but its role was almost unknown to this cancer.	('LGG', 'Disease', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', (15, 20))	('X1010_splice', 'Var', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
137597	33178590	The 1,148-aa mutation in the Pkinase-Tyr domain was also observed in seven samples [six samples with R1148Q (three SKCMs, one BLCA, one BRCA, one COADREAD), one sample with R1148* (one UCEC)].	('R1148*', 'Var', (173, 179))	('observed', 'Reg', (57, 65))	('Pkinase-Tyr', 'Enzyme', (29, 40))	('R1148Q', 'Var', (101, 107))	('R1148Q', 'Mutation', 'p.R1148Q', (101, 107))	('Tyr', 'Chemical', 'MESH:D014443', (37, 40))	('R1148*', 'SUBSTITUTION', 'None', (173, 179))
137599	33178590	The most mutated positions in KIRP (17 of 25 mutations) were located at the Pkinase Tyr domain, especially at the 1,250-aa position (four samples with M1250T) and the 1,092- to 1,094-aa position (three with V1092I, three with H1094Y).	('H1094Y', 'Var', (226, 232))	('V1092I', 'Var', (207, 213))	('M1250T', 'Var', (151, 157))	('Tyr', 'Chemical', 'MESH:D014443', (84, 87))	('H1094Y', 'Mutation', 'p.H1094Y', (226, 232))	('V1092I', 'Mutation', 'p.V1092I', (207, 213))	('M1250T', 'Mutation', 'p.M1250T', (151, 157))	('mutated', 'Reg', (9, 16))
137601	33178590	The most mutated positions in UCEC (3 of 78 mutations) were located at the Pkinase-Tyr domain at the 1,186-aa position (one with L1186F, one with L1186I, one with L1186R), but its oncogenic role was considered unknown.	('L1186F', 'Mutation', 'p.L1186F', (129, 135))	('L1186F', 'Var', (129, 135))	('Tyr', 'Chemical', 'MESH:D014443', (83, 86))	('L1186I', 'Mutation', 'p.L1186I', (146, 152))	('L1186R', 'Mutation', 'p.L1186R', (163, 169))	('L1186I', 'Var', (146, 152))	('L1186R', 'Var', (163, 169))	('mutated', 'Reg', (9, 16))
137602	33178590	D1228Y/A and T222K alterations were found in UCEC (one with D1228Y, one with D1228A, one with T222K) and known to be likely oncogenic and predicted oncogenic, respectively (Supplementary Figure S2D).	('D1228Y', 'SUBSTITUTION', 'None', (60, 66))	('D1228Y', 'Var', (60, 66))	('D1228A', 'Var', (77, 83))	('T222K', 'Var', (13, 18))	('T222K', 'Mutation', 'p.T222K', (94, 99))	('D1228Y', 'Mutation', 'p.D1228Y', (0, 6))	('D1228A', 'Mutation', 'p.D1228A', (77, 83))	('D1228Y', 'SUBSTITUTION', 'None', (0, 6))	('D1228Y', 'Var', (0, 6))	('UCEC', 'Disease', (45, 49))	('D1228Y', 'Mutation', 'p.D1228Y', (60, 66))	('T222K', 'Mutation', 'p.T222K', (13, 18))
137604	33178590	Next, we analyzed the clinical targeted therapy implications of MET mutation using cBioPortal, which could provide the annotation of variants from different databases, including COSMIC, Cancer Hotspots method, CIViC, My Cancer Genome, and OncoKB.	('MET', 'Gene', (64, 67))	('CIViC', 'Disease', 'None', (210, 215))	('MET', 'Gene', '79811', (64, 67))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('CIViC', 'Disease', (210, 215))	('Cancer', 'Disease', (220, 226))	('Cancer', 'Disease', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (220, 226))	('Cancer', 'Phenotype', 'HP:0002664', (220, 226))	('variants', 'Var', (133, 141))
137605	33178590	Thus, for the clinical targeted therapy implications, each MET somatic mutation could be classified into four levels as defined by OncoKB: level 2 (seven mutations), level 3B (one mutation), level 4 (13 mutations), and level NA (290 mutations) (Figure 4A and Supplementary Table S2).	('MET', 'Gene', '79811', (59, 62))	('MET', 'Gene', (59, 62))	('mutations', 'Var', (154, 163))
137612	33178590	Among the 311 samples with MET mutations mentioned above, 129 also harbored MET CNVs (108 with gain, nine with amplification, and 12 with shallow deletion).	('mutations', 'Var', (31, 40))	('MET', 'Gene', (27, 30))	('MET', 'Gene', '79811', (76, 79))	('MET', 'Gene', '79811', (27, 30))	('MET', 'Gene', (76, 79))	('gain', 'PosReg', (95, 99))
137614	33178590	As shown in Figure 5A and Figures 1A,B, KIRP harbored a very high proportion of gain and was also the cancer type with higher MET expression.	('MET', 'Gene', '79811', (126, 129))	('KIRP', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MET', 'Gene', (126, 129))	('gain', 'PosReg', (80, 84))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
137619	33178590	MET alterations were observed most commonly in UCEC (10.21%), SKCM (10.14%), and KIRP (9.89%), in which mutations were more common.	('SKCM', 'Disease', (62, 66))	('MET', 'Gene', '79811', (0, 3))	('alterations', 'Var', (4, 15))	('MET', 'Gene', (0, 3))	('UCEC', 'Disease', (47, 51))	('KIRP', 'Disease', (81, 85))	('observed', 'Reg', (21, 29))
137620	33178590	Other cancer types with dominant MET mutations but at much lower mutation rates included LUAD (3.53%), BLCA (3.89%), COADREAD (3.2%), UCS (3.51%), and PAAD (0.54%).	('COADREAD', 'Disease', (117, 125))	('LUAD', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('UCS', 'Disease', (134, 137))	('PAAD', 'Phenotype', 'HP:0006725', (151, 155))	('PAAD', 'Disease', (151, 155))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('BLCA', 'Disease', (103, 107))	('MET', 'Gene', '79811', (33, 36))	('cancer', 'Disease', (6, 12))	('MET', 'Gene', (33, 36))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
137623	33178590	Approximately half of the mutations (29 of 67 mutations) in the Pkinase-Tyr domain also had MET copy gain, while nearly half of the mutations (44 of 90 mutations) in the other function-unknown domain were accompanied by amplification, gain, and shallow deletion.	('Pkinase-Tyr', 'Gene', (64, 75))	('copy', 'MPA', (96, 100))	('mutations', 'Var', (46, 55))	('MET', 'Gene', (92, 95))	('mutations', 'Var', (132, 141))	('gain', 'PosReg', (101, 105))	('amplification', 'MPA', (220, 233))	('Tyr', 'Chemical', 'MESH:D014443', (72, 75))	('mutations', 'Var', (26, 35))	('gain', 'PosReg', (235, 239))	('MET', 'Gene', '79811', (92, 95))
137630	33178590	Moreover, when the survival association analysis was performed only for MET mutation status, MET mutations were associated with poor prognosis in LUAD (Figure 7D).	('mutations', 'Var', (97, 106))	('LUAD', 'Phenotype', 'HP:0030078', (146, 150))	('MET', 'Gene', '79811', (93, 96))	('LUAD', 'Disease', (146, 150))	('MET', 'Gene', '79811', (72, 75))	('MET', 'Gene', (93, 96))	('MET', 'Gene', (72, 75))
137632	33178590	UCEC, SKCM, and KIRP had the highest MET alteration, and mutations accounted for the major proportion.	('MET', 'Gene', (37, 40))	('mutations', 'Var', (57, 66))	('MET', 'Gene', '79811', (37, 40))
137633	33178590	While mutations in UCEC and SKCM were most commonly located in the Sema domain and the other function-unknown domain, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is more important for treatment selection.	('KIRP', 'Gene', (131, 135))	('located', 'Reg', (52, 59))	('Sema', 'Gene', (67, 71))	('mutations', 'Var', (118, 127))	('Sema', 'Gene', '7869', (67, 71))	('Tyr', 'Chemical', 'MESH:D014443', (174, 177))	('mutations', 'Var', (6, 15))	('UCEC', 'Gene', (19, 23))
137635	33178590	Other cancer types, including LUAD, BLCA, COADREAD, and UCS harbored similar characteristics; all their alteration frequency was between 4 and 6%, and mutation was the primary alteration.	('LUAD', 'Disease', (30, 34))	('BLCA', 'Disease', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('COADREAD', 'Disease', (42, 50))	('UCS', 'Disease', (56, 59))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))
137636	33178590	Mutations in LUAD are mainly X1010_splices, which are in exon 14, and mutations in this region are known for targeted therapy in clinical practice in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('LUAD', 'Gene', (13, 17))	('X1010_splices', 'Var', (29, 42))	('NSCLC', 'Disease', (150, 155))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))
137644	33178590	In addition, the prognostic role of MET in LUAD was quite clear, and both high expression and amplification of MET were significantly associated with poor prognosis.	('associated', 'Reg', (134, 144))	('amplification', 'Var', (94, 107))	('high', 'Var', (74, 78))	('MET', 'Gene', '79811', (111, 114))	('MET', 'Gene', (111, 114))	('MET', 'Gene', '79811', (36, 39))	('MET', 'Gene', (36, 39))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))
137647	33178590	Compared with other cancer types, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is known for targeted therapy with TKIs.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Tyr', 'Chemical', 'MESH:D014443', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('mutations', 'Var', (34, 43))
137650	33178590	In addition, high expression of MET was discovered in KIRP, and most mutations in KIRP were oncogenic and likely oncogenic; however, there was no association observed between MET expression and patient prognosis in this dataset, although some reports indicated otherwise.	('MET', 'Gene', '79811', (175, 178))	('mutations', 'Var', (69, 78))	('patient', 'Species', '9606', (194, 201))	('MET', 'Gene', (175, 178))	('KIRP', 'Gene', (82, 86))	('MET', 'Gene', '79811', (32, 35))	('MET', 'Gene', (32, 35))
137651	33178590	This paradox could be due to the absence of well-known responsive mutations and the presence of alternative compensatory pathways interacting with MET pathways, such as the MAPK/ERK and PI3K/AKT pathways, which inspired further research on combinatorial therapy strategies in KIRP.	('mutations', 'Var', (66, 75))	('MET', 'Gene', '79811', (147, 150))	('AKT', 'Gene', '207', (191, 194))	('MET', 'Gene', (147, 150))	('AKT', 'Gene', (191, 194))	('ERK', 'Gene', '2048', (178, 181))	('ERK', 'Gene', (178, 181))
137653	33178590	It is well known that genomic instability and high mutation rates cause cancer to acquire numerous mutations during evolution.	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('genomic instability', 'Var', (22, 41))	('cancer', 'Disease', (72, 78))
137656	33178590	However, several recent reports have showed that passenger mutations may also have critical functional roles in driving cancer, with some authors describing them as mini drivers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (120, 126))	('mutations', 'Var', (59, 68))
137657	33178590	They found that the aggregated impact of putative passenger mutations could provide significant predictive power to distinguish cancer from non-cancer phenotypes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('non-cancer', 'Disease', 'MESH:D009369', (140, 150))	('cancer', 'Disease', (144, 150))	('non-cancer', 'Disease', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (128, 134))
137658	33178590	The above content implied to us that in some types of cancers, such as UCEC, even most of these mutations belonged to the unknown class; more efforts are needed to determine the meanings of these mutations, which might be found to also have important functional roles in driving tumorigenesis.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('cancers', 'Disease', (54, 61))	('UCEC', 'Disease', (71, 75))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Disease', (279, 284))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (196, 205))
137659	33178590	In addition, several reports have showed that some gene mutations, like BRAF mutation and ERBB2 mutation, were associated with MSI status in several cancer types.	('cancer', 'Disease', (149, 155))	('BRAF', 'Gene', (72, 76))	('MSI status', 'Disease', (127, 137))	('mutation', 'Var', (77, 85))	('associated', 'Reg', (111, 121))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('BRAF', 'Gene', '673', (72, 76))	('ERBB2', 'Gene', '2064', (90, 95))	('ERBB2', 'Gene', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
137679	33178590	Some alterations are more involved in the development of tumors, while others participate more in targeted therapy.	('involved', 'Reg', (26, 34))	('participate', 'Reg', (78, 89))	('alterations', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
137703	30635729	Based on these preoperative analyses, the patient was diagnosed with cT2N0M0, cStageII esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('cStageII', 'Disease', (78, 86))	('patient', 'Species', '9606', (42, 49))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('cT2N0M0', 'Var', (69, 76))
137736	30635729	Other authors have noted that immune check-point inhibitors, such as anti-CTLA-4 and anti-PD-1 antibodies, benefit patients with advanced PMME.	('patients', 'Species', '9606', (115, 123))	('anti-PD-1', 'Var', (85, 94))	('CTLA-4', 'Gene', '1493', (74, 80))	('benefit', 'PosReg', (107, 114))	('PMME', 'Disease', (138, 142))	('CTLA-4', 'Gene', (74, 80))	('PMME', 'Chemical', '-', (138, 142))
137775	29961130	The equivalent values for SM cancer staging were 0.86 for sensitivity (95%CI 0.82-0.89), 0.86 for specificity (95%CI 0.83-0.89), 5.13 for positive likelihood ratio (95%CI 3.36-7.82), and 0.17 for negative likelihood ratio (95%CI 0.09-0.30).	('cancer', 'Disease', (29, 35))	('0.86', 'Var', (89, 93))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))
137818	29984200	proposed a tumor progression pathway in which Barrett's epithelium, after losing heterozygosity at chromosome arm 9p, exhibits further loss of heterozygosity at several other chromosomal loci and a missense mutation in the p53 gene.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('p53', 'Gene', '7157', (223, 226))	('p53', 'Gene', (223, 226))	('tumor', 'Disease', (11, 16))	('missense mutation', 'Var', (198, 215))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
138015	28423738	The results showed that the miR-338 mimic transfection sharply reduced the luciferase activity of the WT vector but could not changed that of the MUT vector (Figure 1E).	('reduced', 'NegReg', (63, 70))	('luciferase', 'Enzyme', (75, 85))	('activity', 'MPA', (86, 94))	('transfection', 'Var', (42, 54))	('miR-338', 'Gene', '442906', (28, 35))	('miR-338', 'Gene', (28, 35))
138018	28423738	The results showed that the miR-338 antagomir transfection decreased the miR-338 level by ~80% (Figure 2A) and caused a ~2-fold increase in the level of CystC (Figure 2B).	('miR-338', 'Gene', (73, 80))	('increase', 'PosReg', (128, 136))	('level of CystC', 'MPA', (144, 158))	('miR-338', 'Gene', '442906', (73, 80))	('decreased', 'NegReg', (59, 68))	('transfection', 'Var', (46, 58))	('miR-338', 'Gene', '442906', (28, 35))	('miR-338', 'Gene', (28, 35))
138021	28423738	Additionally, CCK-8 cell proliferation assay and Annexin V-FITC/PI apoptosis detection showed that silencing miR-338 significantly increased proliferation and decreased apoptosis of the primary esophageal cancer cells (Figure 2C and 2D).	('apoptosis', 'CPA', (169, 178))	('increased', 'PosReg', (131, 140))	('Annexin V', 'Gene', '308', (49, 58))	('miR-338', 'Gene', '442906', (109, 116))	('esophageal cancer', 'Disease', (194, 211))	('miR-338', 'Gene', (109, 116))	('decreased', 'NegReg', (159, 168))	('Annexin V', 'Gene', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('silencing', 'Var', (99, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))
138022	28423738	In contrast to the results from the miR-338 antagomir transfection, the miR-338 mimic transfection robustly elevated the level of miR-338 and sharply reduced CystC expression (Figure 3A and 3B).	('CystC expression', 'MPA', (158, 174))	('miR-338', 'Gene', (36, 43))	('miR-338', 'Gene', '442906', (130, 137))	('miR-338', 'Gene', (130, 137))	('miR-338', 'Gene', '442906', (36, 43))	('reduced', 'NegReg', (150, 157))	('transfection', 'Var', (86, 98))	('elevated', 'PosReg', (108, 116))	('miR-338', 'Gene', '442906', (72, 79))	('miR-338', 'Gene', (72, 79))
138028	28423738	Cell proliferation and apoptosis assayes showed that Snhg1 overexpression significantly increased proliferation and decreased apoptosis of the cells, while silencing Snhg1 reduced proliferation and markedly exacerbated apoptosis of the cells (Figure 4C and 4D).	('reduced', 'NegReg', (172, 179))	('Snhg1', 'Gene', (166, 171))	('silencing', 'Var', (156, 165))	('exacerbated', 'PosReg', (207, 218))	('Snhg1', 'Gene', (53, 58))	('increased', 'PosReg', (88, 97))	('apoptosis', 'CPA', (219, 228))	('Snhg1', 'Gene', '23642', (166, 171))	('apoptosis of the cells', 'CPA', (126, 148))	('decreased', 'NegReg', (116, 125))	('Snhg1', 'Gene', '23642', (53, 58))
138029	28423738	In consistent with the results of cell proliferation and apoptosis assayes, Snhg1 overexpression increased the levels of CystC and diminished the levels of caspase-8/3, while silencing Snhg1 decreased the levels of CystC and elevated the levels of caspase-8/3 (Figure 4E).	('elevated', 'PosReg', (225, 233))	('Snhg1', 'Gene', '23642', (185, 190))	('Snhg1', 'Gene', (76, 81))	('caspase-8/3', 'Gene', '841;836', (248, 259))	('levels of CystC', 'MPA', (111, 126))	('caspase-8/3 (Figure 4E', 'Gene', '841;836', (248, 270))	('levels of CystC', 'MPA', (205, 220))	('Snhg1', 'Gene', '23642', (76, 81))	('caspase-8/3', 'Gene', (248, 259))	('decreased', 'NegReg', (191, 200))	('diminished', 'NegReg', (131, 141))	('silencing', 'Var', (175, 184))	('caspase-8/3', 'Gene', (156, 167))	('caspase-8/3', 'Gene', '841;836', (156, 167))	('Snhg1', 'Gene', (185, 190))	('overexpression increased', 'PosReg', (82, 106))
138055	28423738	However, some other studies indicated that high serum CysC level was related with poor prognosis and it could promote the progression of several cancers.	('cancers', 'Disease', (145, 152))	('high serum CysC level', 'Phenotype', 'HP:0500151', (43, 64))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('high', 'Var', (43, 47))	('progression', 'CPA', (122, 133))	('CysC', 'Chemical', '-', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('promote', 'PosReg', (110, 117))	('serum CysC level', 'MPA', (48, 64))	('cancers', 'Disease', 'MESH:D009369', (145, 152))
138110	25435940	Furthermore, knockdown of Nfia increased Hes1 expression and inhibited cell growth in TE-1 cells.	('inhibited', 'NegReg', (61, 70))	('cell growth in TE-1 cells', 'CPA', (71, 96))	('increased', 'PosReg', (31, 40))	('Nfia', 'Gene', (26, 30))	('Hes1', 'Gene', (41, 45))	('TE-1', 'CellLine', 'CVCL:1759', (86, 90))	('Nfia', 'Gene', '4774', (26, 30))	('Hes1', 'Gene', '3280', (41, 45))	('expression', 'MPA', (46, 56))	('knockdown', 'Var', (13, 22))
138114	25435940	Notch signaling is important for esophageal epithelial homeostasis, for example Notch signaling regulates cell proliferation within the squamous epithelia.	('cell proliferation', 'CPA', (106, 124))	('esophageal epithelial homeostasis', 'Disease', 'MESH:D002277', (33, 66))	('esophageal epithelial homeostasis', 'Disease', (33, 66))	('squamous epithelia', 'Phenotype', 'HP:0002860', (136, 154))	('Notch', 'Var', (80, 85))	('squamous epithelia', 'Disease', 'MESH:D002294', (136, 154))	('regulates', 'Reg', (96, 105))	('squamous epithelia', 'Disease', (136, 154))
138172	25435940	The knockdown of Nfia significantly increased the gene (Fig 4A) and protein (Fig 4B) expression levels of Hes1 in TE-1 cells.	('Hes1', 'Gene', (106, 110))	('Nfia', 'Gene', (17, 21))	('increased', 'PosReg', (36, 45))	('TE-1', 'CellLine', 'CVCL:1759', (114, 118))	('Hes1', 'Gene', '3280', (106, 110))	('Nfia', 'Gene', '4774', (17, 21))	('knockdown', 'Var', (4, 13))
138173	25435940	Furthermore, the knockdown of Nfia reduced cell proliferation and resulted in an accumulation of cells in the G0/G1 phase (Fig.	('reduced', 'NegReg', (35, 42))	('Nfia', 'Gene', (30, 34))	('knockdown', 'Var', (17, 26))	('cells in the G0/G1 phase', 'CPA', (97, 121))	('cell proliferation', 'CPA', (43, 61))	('Nfia', 'Gene', '4774', (30, 34))	('accumulation', 'PosReg', (81, 93))
138176	25435940	The downregulation of miR-29 family members has been correlated with various types of cancer, including leukemia, melanoma, and liver, colon, cervical and lung cancer; thus, miR-29s may serve as tumor suppressors.	('liver', 'Disease', (128, 133))	('tumor', 'Disease', (195, 200))	('miR-29s', 'Var', (174, 181))	('leukemia', 'Disease', (104, 112))	('leukemia', 'Disease', 'MESH:D007938', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('cancer', 'Disease', (160, 166))	('lung cancer', 'Disease', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('miR-29', 'Gene', (22, 28))	('cancer', 'Disease', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cervical', 'Disease', (142, 150))	('downregulation', 'NegReg', (4, 18))	('colon', 'Disease', (135, 140))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Disease', 'MESH:D009369', (86, 92))
138178	25435940	It has been reported that the dysfunction of miR-29a results in abnormal cell growth.	('miR-29a', 'Gene', (45, 52))	('cell growth', 'CPA', (73, 84))	('dysfunction', 'Var', (30, 41))	('miR-29a', 'Gene', '407021', (45, 52))
138188	25435940	Unlike the majority of signaling pathways, Notch signaling can be oncogenic or tumor-suppressive, depending on the cellular context.	('oncogenic', 'CPA', (66, 75))	('tumor', 'Disease', (79, 84))	('Notch signaling', 'Var', (43, 58))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
138215	22719875	PDT with mono-l-aspartyl chlorin e6 (NPe6, talaporfin sodium, Laserphyrin ), a second-generation photosensitizer, has advantages such as: 1) a shorter period of light shielding of about 2 weeks, 2) 10% incidence of skin toxicity because of reduced photosensitivity, and 3) expected treatment effect in the deep-lying tissue areas with a laser at 664 nm instead of at 630 nm as used with Photofrin PDT.	('NPe6', 'Chemical', 'MESH:C053434', (37, 41))	('mono-l-aspartyl', 'Var', (9, 24))	('photosensitivity', 'Phenotype', 'HP:0000992', (248, 264))	('mono-l-aspartyl chlorin e6', 'Chemical', 'MESH:C053434', (9, 35))	('talaporfin sodium', 'Chemical', 'MESH:C053434', (43, 60))	('Laserphyrin', 'Chemical', 'MESH:C053434', (62, 73))	('skin toxicity', 'Disease', (215, 228))	('skin toxicity', 'Disease', 'MESH:D012871', (215, 228))
138245	22719875	No infiltration of inflammatory cells, fibrosis, hemorrhage, or necrosis was observed in the extra-adventitial tissue in the 25 J/cm2 group.	('fibrosis', 'Disease', 'MESH:D005355', (39, 47))	('fibrosis', 'Disease', (39, 47))	('necrosis', 'Disease', 'MESH:D009336', (64, 72))	('adventitia', 'Disease', (99, 109))	('hemorrhage', 'Disease', (49, 59))	('hemorrhage', 'Disease', 'MESH:D006470', (49, 59))	('necrosis', 'Disease', (64, 72))	('25 J/cm2', 'Var', (125, 133))	('adventitia', 'Disease', 'None', (99, 109))
138260	22719875	Laserphyrin PDT is expected to have a greater effect on the deep-tissue layers compared with Photofrin PDT.	('Laserphyrin', 'Chemical', 'MESH:C053434', (0, 11))	('deep-tissue layers', 'CPA', (60, 78))	('Laserphyrin', 'Var', (0, 11))
138503	33603272	Furthermore, three-field lymph node dissection has also been associated with an increased risk of RLN nerve damage.	('RLN nerve damage', 'Disease', (98, 114))	('RLN nerve damage', 'Disease', 'MESH:D010523', (98, 114))	('three-field lymph node dissection', 'Var', (13, 46))
138513	33603272	Recently, Zhang H et al showed that the 5-year survival rates for pN0, pN1, pN2, and pN3 were 47.7%, 31.4%, 19.7%, and 7.0%, respectively.	('pN1', 'Gene', '5270', (71, 74))	('pN0', 'Var', (66, 69))	('pN1', 'Gene', (71, 74))	('pN2', 'Gene', (76, 79))	('pN3', 'Gene', '6336', (85, 88))	('pN2', 'Gene', '351', (76, 79))	('pN3', 'Gene', (85, 88))
138610	32054499	During 3 months of follow-up after ERI, the patient had no recurrence of dysphagia.	('patient', 'Species', '9606', (44, 51))	('dysphagia', 'Disease', (73, 82))	('dysphagia', 'Phenotype', 'HP:0002015', (73, 82))	('dysphagia', 'Disease', 'MESH:D003680', (73, 82))	('ERI', 'Var', (35, 38))	('ERI', 'Chemical', '-', (35, 38))
138681	30081903	Phosphorylated ANXA2 (Tyr23) interacted with MYC and inhibited ubiquitin-dependent proteasomal degradation of MYC protein.	('Tyr23', 'Var', (22, 27))	('inhibited', 'NegReg', (53, 62))	('Tyr23', 'Chemical', '-', (22, 27))	('MYC', 'Protein', (45, 48))	('ubiquitin-dependent proteasomal degradation', 'MPA', (63, 106))	('interacted', 'Interaction', (29, 39))	('MYC', 'Protein', (110, 113))	('ANXA2', 'Gene', (15, 20))
138684	30081903	This study provides evidence that highly expressed p-ANXA2 (Tyr23) contributes to ESCC progression by promoting migration, invasion and metastasis, and suggests that targeting the SRC-ANXA2-MYC-HIF1A-MYC axis may be an efficient strategy for ESCC treatment.	('SRC', 'Gene', '6714', (180, 183))	('ESCC', 'Disease', (82, 86))	('p-ANXA2 (Tyr23', 'Var', (51, 65))	('Tyr23', 'Chemical', '-', (60, 65))	('migration', 'CPA', (112, 121))	('HIF1A', 'Gene', '3091', (194, 199))	('promoting', 'PosReg', (102, 111))	('contributes', 'Reg', (67, 78))	('HIF1A', 'Gene', (194, 199))	('SRC', 'Gene', (180, 183))
138688	30081903	Aberrantly expressed ANXA2 is observed in a wide range of malignancies, including ESCC, and plays pivotal roles in tumor formation and progression by modulating cell proliferation, apoptosis, adhesion, invasion, metastasis, and tumor neovascularization.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Disease', (115, 120))	('malignancies', 'Disease', 'MESH:D009369', (58, 70))	('roles', 'Reg', (106, 111))	('apoptosis', 'CPA', (181, 190))	('invasion', 'CPA', (202, 210))	('malignancies', 'Disease', (58, 70))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('Aberrantly expressed', 'Var', (0, 20))	('ESCC', 'Disease', (82, 86))	('cell proliferation', 'CPA', (161, 179))	('ANXA2', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('modulating', 'Reg', (150, 160))	('metastasis', 'CPA', (212, 222))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('observed', 'Reg', (30, 38))	('adhesion', 'CPA', (192, 200))	('tumor', 'Disease', (228, 233))
138689	30081903	Moreover, inhibition of ANXA2 can suppress tumor cell proliferation, survival and metastasis.	('ANXA2', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('suppress', 'NegReg', (34, 42))	('inhibition', 'Var', (10, 20))	('tumor', 'Disease', (43, 48))
138695	30081903	The human ESCC cell lines KYSE30, KYSE70, KYSE150, KYSE180, KYSE410, KYSE450 and KYSE510 were provided by Dr. Y. Shimada (Kyoto University, Kyoto, Japan).	('KYSE510', 'Var', (81, 88))	('KYSE150', 'Var', (42, 49))	('KYSE30', 'Var', (26, 32))	('human', 'Species', '9606', (4, 9))	('KYSE410', 'Var', (60, 67))	('KYSE450', 'CellLine', 'CVCL:1353', (69, 76))	('KYSE150', 'CellLine', 'CVCL:1348', (42, 49))	('KYSE450', 'Var', (69, 76))	('KYSE70', 'Var', (34, 40))	('KYSE180', 'Var', (51, 58))
138701	30081903	Immunoblotting was performed with primary antibodies against ANXA2 (1:200), p-ANXA2 (Tyr23, 1:200), VEGF (1:200) (Santa Cruz Biotechnology, Dallas, Texas, USA), MYC (1:1000), p-SRC (Tyr418, 1:1000) (Abcam, Cambridge, UK), Ubiquitin (1:500), Histone H3 (1:1000) (CST, Danvers, MA, USA), HIF1A (1:500), SRC (1:500), HA-tag (1:3000), His-tag (1:3000) (Proteintech, Wuhan, China).	('SRC', 'Gene', '6714', (177, 180))	('SRC', 'Gene', '6714', (301, 304))	('SRC', 'Gene', (301, 304))	('VEGF', 'Gene', '7422', (100, 104))	('Tyr23', 'Chemical', '-', (85, 90))	('HIF1A', 'Gene', (286, 291))	('HIF1A', 'Gene', '3091', (286, 291))	('1:500', 'Var', (306, 311))	('Tyr418', 'Chemical', '-', (182, 188))	('1:3000', 'Var', (322, 328))	('VEGF', 'Gene', (100, 104))	('SRC', 'Gene', (177, 180))
138723	30081903	In this study, we detected the expression levels of ANXA2 in seven ESCC cell lines and found that it is highly expressed in KYSE30, KYSE150 and KYSE450 cells but exhibites lower expression levels in KYSE180 and KYSE70 cells (Fig.	('KYSE150', 'CellLine', 'CVCL:1348', (132, 139))	('KYSE450', 'CellLine', 'CVCL:1353', (144, 151))	('ANXA2', 'Gene', (52, 57))	('KYSE30', 'Var', (124, 130))
138725	30081903	Additionally, the reduced migration and invasion abilities of KYSE30 and KYSE150 cells mediated by ANXA2 depletion were recovered after overexpression of a ANXA2 rescue construct, namely ANXA2-R (Fig.	('depletion', 'Var', (105, 114))	('ANXA2-R', 'Gene', '389289', (187, 194))	('reduced', 'NegReg', (18, 25))	('KYSE150', 'CellLine', 'CVCL:1348', (73, 80))	('ANXA2-R', 'Gene', (187, 194))	('migration', 'CPA', (26, 35))	('invasion abilities', 'CPA', (40, 58))
138727	30081903	Six weeks after inoculation, the lungs of both groups had macroscopic metastases, but the number of lung metastases in the sh-scramble group was much higher than that in the shANXA2 group.	('lung metastases', 'Disease', (100, 115))	('lung metastases', 'Disease', 'MESH:D009362', (100, 115))	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('metastases', 'Disease', 'MESH:D009362', (70, 80))	('higher', 'PosReg', (150, 156))	('metastases', 'Disease', (105, 115))	('sh-scramble', 'Var', (123, 134))	('metastases', 'Disease', (70, 80))
138728	30081903	H&E staining of paraffin-embedded lung tissues further confirmed that the number of metastastic lung nodules in the shANXA2 group were less than that in the sh-scramble group (Fig.	('the', 'Var', (112, 115))	('H&E', 'Chemical', '-', (0, 3))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('were', 'NegReg', (130, 134))
138729	30081903	Our recent work revealed that high vascular endothelial growth factor (VEGF) expression promotes ESCC cell migration and invasion.	('promotes', 'PosReg', (88, 96))	('high', 'Var', (30, 34))	('VEGF', 'Gene', (71, 75))	('vascular endothelial growth factor', 'Gene', (35, 69))	('invasion', 'CPA', (121, 129))	('vascular endothelial growth factor', 'Gene', '7422', (35, 69))	('ESCC', 'Disease', (97, 101))	('VEGF', 'Gene', '7422', (71, 75))
138730	30081903	Herein, we found that knockdown of ANXA2 with siRNA reduced both VEGF mRNA and protein levels (Fig.	('reduced', 'NegReg', (52, 59))	('VEGF', 'Gene', '7422', (65, 69))	('ANXA2', 'Gene', (35, 40))	('knockdown', 'Var', (22, 31))	('VEGF', 'Gene', (65, 69))
138735	30081903	Meanwhile, silencing of HIF1A indeed reduced the mRNA and protein expression of VEGF in ESCC cells, but ANXA2 expression was not altered in HIF1A-depleted cells (Additional file 4: Figure S3).	('silencing', 'Var', (11, 20))	('HIF1A', 'Gene', (140, 145))	('VEGF', 'Gene', (80, 84))	('HIF1A', 'Gene', (24, 29))	('HIF1A', 'Gene', '3091', (140, 145))	('HIF1A', 'Gene', '3091', (24, 29))	('VEGF', 'Gene', '7422', (80, 84))	('reduced', 'NegReg', (37, 44))
138738	30081903	Furthermore, cell migration and invasion abilities were significantly suppressed by HIF1A knockdown in KYSE30 and KYSE150 cells (Fig.	('cell migration', 'CPA', (13, 27))	('HIF1A', 'Gene', '3091', (84, 89))	('knockdown', 'Var', (90, 99))	('suppressed', 'NegReg', (70, 80))	('KYSE150', 'CellLine', 'CVCL:1348', (114, 121))	('invasion abilities', 'CPA', (32, 50))	('HIF1A', 'Gene', (84, 89))
138744	30081903	3a) and that the ANXA2 knockdown-induced HIF1A decrease was markedly reversed by MYC overexpression (Fig.	('ANXA2', 'Gene', (17, 22))	('decrease', 'NegReg', (47, 55))	('HIF1A', 'Gene', '3091', (41, 46))	('HIF1A', 'Gene', (41, 46))	('knockdown-induced', 'Var', (23, 40))
138745	30081903	In addition, the expression of HIF1A mRNA was reduced upon MYC knockdown (Fig.	('expression', 'MPA', (17, 27))	('mRNA', 'MPA', (37, 41))	('HIF1A', 'Gene', (31, 36))	('reduced', 'NegReg', (46, 53))	('HIF1A', 'Gene', '3091', (31, 36))	('MYC knockdown', 'Var', (59, 72))	('knockdown', 'Var', (63, 72))
138750	30081903	Reporter assays further confirmed that both ANXA2 and MYC knockdown inhibited HIF1A transcription in KYSE30 and KYSE150 cells (Fig.	('KYSE150', 'CellLine', 'CVCL:1348', (112, 119))	('inhibited', 'NegReg', (68, 77))	('HIF1A', 'Gene', '3091', (78, 83))	('transcription', 'MPA', (84, 97))	('knockdown', 'Var', (58, 67))	('HIF1A', 'Gene', (78, 83))
138751	30081903	Moreover, deletion of the MYC binding element in the HIF1A reporter construct greatly diminished the promoter activity of HIF1A compared with the wild-type HIF1A reporter construct (Fig.	('HIF1A', 'Gene', (122, 127))	('promoter activity', 'MPA', (101, 118))	('HIF1A', 'Gene', '3091', (122, 127))	('HIF1A', 'Gene', (156, 161))	('diminished', 'NegReg', (86, 96))	('deletion', 'Var', (10, 18))	('HIF1A', 'Gene', '3091', (156, 161))	('HIF1A', 'Gene', '3091', (53, 58))	('HIF1A', 'Gene', (53, 58))
138753	30081903	Taken together, our data suggest that aberrant ANXA2 expression promotes ESCC cell invasion and metastasis through activation of the MYC-HIF1A-VEGF axis.	('metastasis', 'CPA', (96, 106))	('promotes', 'PosReg', (64, 72))	('activation', 'PosReg', (115, 125))	('aberrant', 'Var', (38, 46))	('MYC-HIF1A-VEGF', 'Gene', (133, 147))	('ESCC', 'Disease', (73, 77))	('MYC-HIF1A-VEGF', 'Gene', '7422', (133, 147))	('ANXA2', 'Gene', (47, 52))
138754	30081903	Considering that phosphorylation modification of certain amino acids, such as Tyr23 or Ser25 (counting Ser1 as the first amino acid), affects the cellular localization and function of ANXA2, we investigated the influence of the phosphorylation status on ANXA2 localization through exogenous expression of different ANXA2 mutants in ESCC cells.	('Tyr23', 'Var', (78, 83))	('affects', 'Reg', (134, 141))	('ANXA2', 'Gene', (315, 320))	('Ser25', 'Chemical', '-', (87, 92))	('Tyr23', 'Chemical', '-', (78, 83))	('Ser1', 'Chemical', '-', (103, 107))	('cellular localization', 'MPA', (146, 167))	('mutants', 'Var', (321, 328))	('function', 'MPA', (172, 180))	('investigated', 'Reg', (194, 206))
138755	30081903	Immunofluorescence staining results demonstrated that forced ANXA2Y23D (phospho-mimicking mutant) expression was predominantly located in nuclei, while ANXA2Y23A (phosphorylation refractory mutant) was expressed on the plasma membrane and in the cytoplasm of the ESCC cell lines KYSE30 and KYSE150 (Fig.	('ANXA2Y23A', 'Var', (152, 161))	('ANXA2Y23D', 'Gene', (61, 70))	('KYSE150', 'CellLine', 'CVCL:1348', (290, 297))
138757	30081903	Altogether, these results suggest that phosphorylation at Tyr23 triggers ANXA2 translocation from the plasma membrane/cytoplasm into the nucleus where it activates MYC-HIF1A signaling.	('triggers', 'Reg', (64, 72))	('translocation', 'MPA', (79, 92))	('HIF1A', 'Gene', (168, 173))	('phosphorylation at Tyr23', 'Var', (39, 63))	('HIF1A', 'Gene', '3091', (168, 173))	('Tyr23', 'Chemical', '-', (58, 63))	('activates', 'PosReg', (154, 163))	('ANXA2', 'Gene', (73, 78))
138758	30081903	In parallel, KYSE30 and KYSE150 cells had higher levels of p-ANXA2Tyr23 than KYSE180 cells, which coincided with their migration and invasion capacity (Fig.	('levels of p-ANXA2Tyr23', 'MPA', (49, 71))	('migration', 'CPA', (119, 128))	('KYSE150', 'CellLine', 'CVCL:1348', (24, 31))	('KYSE30', 'Var', (13, 19))	('higher', 'PosReg', (42, 48))	('Tyr23', 'Chemical', '-', (66, 71))	('invasion capacity', 'CPA', (133, 150))	('KYSE150', 'Var', (24, 31))
138760	30081903	4e), which confirmed the prometastatic function of p-ANXA2 (Tyr23).	('prometastatic function', 'MPA', (25, 47))	('Tyr23', 'Chemical', '-', (60, 65))	('p-ANXA2', 'Var', (51, 58))
138761	30081903	As expected, we observed that p-ANXA2 (Tyr23) co-localized with MYC in the nucleus of ESCC cells (Fig.	('co-localized', 'Reg', (46, 58))	('p-ANXA2 (Tyr23', 'Var', (30, 44))	('MYC', 'Protein', (64, 67))	('Tyr23', 'Chemical', '-', (39, 44))
138764	30081903	Taken together, our data suggest that aberrantly expressed p-ANXA2 (Tyr23) potentiates the metastatic potential of ESCC cells by elevating the MYC protein level.	('Tyr23', 'Chemical', '-', (68, 73))	('aberrantly expressed p-ANXA2 (Tyr23', 'Var', (38, 73))	('potentiates', 'PosReg', (75, 86))	('elevating', 'PosReg', (129, 138))	('metastatic potential', 'CPA', (91, 111))	('MYC protein level', 'MPA', (143, 160))
138765	30081903	To decipher the mechanism underlying the p-ANXA2 (Tyr23)-mediated increase in the MYC protein level, we transfected ESCC cells with the ANXA2Y23D or ANXA2Y23A mutant.	('increase', 'PosReg', (66, 74))	('ANXA2Y23A', 'Var', (149, 158))	('Tyr23', 'Chemical', '-', (50, 55))	('MYC protein level', 'MPA', (82, 99))	('ANXA2Y23D', 'Var', (136, 145))
138766	30081903	Notably, a cycloheximide chase assay showed that overexpression of ANXA2Y23D led to more stable ANXA2 protein compared with ANXA2Y23A overexpression (Fig.	('ANXA2 protein', 'Protein', (96, 109))	('cycloheximide', 'Chemical', 'MESH:D003513', (11, 24))	('ANXA2Y23D', 'Var', (67, 76))	('more', 'PosReg', (84, 88))
138767	30081903	Moreover, treatment of cells with the proteasome inhibitor MG132 led to accumulation of ubiquitinated MYC protein in ANXA2Y23A- but not ANXA2Y23D-overexpressing ESCC cells (Fig.	('ubiquitinated MYC protein', 'MPA', (88, 113))	('accumulation', 'PosReg', (72, 84))	('ANXA2Y23A-', 'Var', (117, 127))	('MG132', 'Chemical', 'MESH:C072553', (59, 64))
138768	30081903	Taken together, these results suggest that highly expressed p-ANXA2 (Tyr23) stabilizes MYC protein mainly by inhibiting its degradation via the ubiquitin-dependent proteasome pathway.	('ubiquitin-dependent proteasome pathway', 'Pathway', (144, 182))	('p-ANXA2 (Tyr23', 'Var', (60, 74))	('MYC protein', 'Protein', (87, 98))	('degradation', 'MPA', (124, 135))	('inhibiting', 'NegReg', (109, 119))	('stabilizes', 'MPA', (76, 86))	('Tyr23', 'Chemical', '-', (69, 74))
138780	30081903	Moreover, this study revealed that phosphorylation of ANXA2 at Tyr23 by SRC increases MYC protein abundance through inhibiting its proteasomal degradation in ESCC cells.	('SRC', 'Gene', (72, 75))	('inhibiting', 'NegReg', (116, 126))	('increases', 'PosReg', (76, 85))	('proteasomal degradation', 'MPA', (131, 154))	('Tyr23', 'Var', (63, 68))	('MYC protein abundance', 'MPA', (86, 107))	('Tyr23', 'Chemical', '-', (63, 68))	('phosphorylation', 'MPA', (35, 50))	('SRC', 'Gene', '6714', (72, 75))	('ANXA2', 'Gene', (54, 59))
138783	30081903	In line with our findings, overexpression of ANXA2 has been demonstrated to facilitate cancer cell migraton, invasion and metastasis in the majority of cancer types.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('overexpression', 'Var', (27, 41))	('facilitate', 'PosReg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ANXA2', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
138786	30081903	Our earlier and current study demonstrate that both VEGF and HIF1A overexpression potentiates the migratory and invasive ability of ESCC cells, which coincides with observations in other malignancies.	('VEGF', 'Gene', (52, 56))	('HIF1A', 'Gene', (61, 66))	('VEGF', 'Gene', '7422', (52, 56))	('malignancies', 'Disease', 'MESH:D009369', (187, 199))	('overexpression', 'Var', (67, 81))	('potentiates', 'PosReg', (82, 93))	('malignancies', 'Disease', (187, 199))	('HIF1A', 'Gene', '3091', (61, 66))
138790	30081903	Of note, we observed that Tyr23-phosphorylated ANXA2 accumulated in the nucleus, where it promoted cell motility and invasion.	('cell motility', 'CPA', (99, 112))	('Tyr23-phosphorylated', 'Var', (26, 46))	('Tyr23', 'Chemical', '-', (26, 31))	('ANXA2', 'Gene', (47, 52))	('promoted', 'PosReg', (90, 98))	('invasion', 'CPA', (117, 125))
138791	30081903	Likewise, previous studies indicate that Tyr23 phosphorylation of ANXA2 accelerates cancer cell migration, invasion and metastasis.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('ANXA2', 'Gene', (66, 71))	('accelerates', 'PosReg', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Tyr23', 'Chemical', '-', (41, 46))	('Tyr23 phosphorylation', 'Var', (41, 62))
138798	30081903	Considering that abnormally expressed p-ANXA2 (Tyr23) confers metastatic potential to ESCC cells, specific blocking of ANXA2 phosphorlation of Tyr23 using dasatinib or another inhibitor might be a feasible therapeutic strategy for patients with unresectable advanced ESCC.	('metastatic potential', 'CPA', (62, 82))	('ESCC', 'Disease', (267, 271))	('patients', 'Species', '9606', (231, 239))	('Tyr23', 'Chemical', '-', (47, 52))	('dasatinib', 'Chemical', 'MESH:D000069439', (155, 164))	('Tyr23', 'Chemical', '-', (143, 148))	('ESCC', 'Disease', (86, 90))	('abnormally', 'Var', (17, 27))
138802	30081903	Moreover, these data suggest that inhibition of SRC-ANXA2-MYC-HIF1A-VEGF signaling may offer a potential therapeutic strategy for patients with ESCC.	('MYC-HIF1A-VEGF', 'Gene', '7422', (58, 72))	('inhibition', 'Var', (34, 44))	('ESCC', 'Disease', (144, 148))	('patients', 'Species', '9606', (130, 138))	('SRC', 'Gene', '6714', (48, 51))	('SRC', 'Gene', (48, 51))	('MYC-HIF1A-VEGF', 'Gene', (58, 72))
138806	30022999	Tylosis with esophageal cancer syndrome (TOC) is a rare autosomal dominant proliferative skin disease caused by missense mutations in the rhomboid 5 homolog 2 (RHBDF2) gene.	('Tylosis', 'Disease', 'MESH:D053546', (0, 7))	('skin disease', 'Phenotype', 'HP:0000951', (89, 101))	('RHBDF2', 'Gene', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('missense mutations', 'Var', (112, 130))	('Tylosis', 'Disease', (0, 7))	('autosomal dominant proliferative skin disease', 'Disease', 'MESH:D012871', (56, 101))	('caused by', 'Reg', (102, 111))	('esophageal cancer syndrome', 'Disease', (13, 39))	('autosomal dominant proliferative skin disease', 'Disease', (56, 101))	('esophageal cancer syndrome', 'Disease', 'MESH:D004938', (13, 39))
138809	30022999	Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models exhibit several key aspects of the disease, including a proliferative skin phenotype, a rapid wound healing phenotype, susceptibility to epithelial cancer, and aberrant epidermal growth factor receptor (EGFR) signaling.	('epidermal growth factor receptor', 'Gene', (342, 374))	('rapid wound healing', 'Phenotype', 'HP:0001058', (261, 280))	('epithelial cancer', 'Phenotype', 'HP:0031492', (310, 327))	('aberrant', 'Var', (333, 341))	('mouse', 'Species', '10090', (17, 22))	('epithelial cancer', 'Disease', (310, 327))	('epidermal growth factor receptor', 'Gene', '13649', (342, 374))	('epithelial cancer', 'Disease', 'MESH:D000077216', (310, 327))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('mouse', 'Species', '10090', (160, 165))	('rapid wound healing', 'CPA', (261, 280))	('human', 'Species', '9606', (71, 76))
138812	30022999	Gain-of-function (GOF) mutations in the human rhomboid 5 homolog 2 (RHBDF2) gene constitutively activate epidermal growth factor receptor (EGFR) signaling to cause tylosis with esophageal cancer syndrome (TOC; OMIM: 148500).	('tylosis', 'Disease', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('human', 'Species', '9606', (40, 45))	('activate', 'PosReg', (96, 104))	('tylosis', 'Disease', 'MESH:D053546', (164, 171))	('cause', 'Reg', (158, 163))	('esophageal cancer syndrome', 'Disease', (177, 203))	('RHBDF2', 'Gene', (68, 74))	('mutations', 'Var', (23, 32))	('Gain-of-function', 'PosReg', (0, 16))	('esophageal cancer syndrome', 'Disease', 'MESH:D004938', (177, 203))	('epidermal growth factor receptor', 'Gene', '13649', (105, 137))	('epidermal growth factor receptor', 'Gene', (105, 137))
138818	30022999	In recent years, we have generated and validated mice carrying the human TOC disease mutation p.P189L (; Figure 1A, top panel, Figure 1B), characterized a spontaneous mutation that results in a TOC phenotype, and used these mouse models of TOC in studies in which we identified AREG as a functional driver of the disease; established an essential role for ADAM17 in mediating the disease; and, most recently, demonstrated that RHBDF2-AREG-EGFR signaling, and not the immune system or surrounding microenvironment, plays a role in mediating the disease.	('p.P189L', 'Mutation', 'rs387907130', (94, 101))	('mice', 'Species', '10090', (49, 53))	('p.P189L', 'Var', (94, 101))	('mouse', 'Species', '10090', (224, 229))	('mutation p.P189L', 'Var', (85, 101))	('human', 'Species', '9606', (67, 72))
138826	30022999	Next, to test the influence of mouse strain background on the Rhbdf2cub/cub phenotype, we backcrossed the Rhbdf2cub/cub mutation from the C57BL/6J background onto the MRL/MpJ background for more than 20 generations, creating a true congenic strain, MRL/MpJ-Rhbdf2cub/cub mice.	('cub', 'Gene', '217344', (267, 270))	('cub', 'Gene', '217344', (112, 115))	('cub', 'Gene', '217344', (68, 71))	('cub', 'Gene', '217344', (116, 119))	('mice', 'Species', '10090', (271, 275))	('cub', 'Gene', (72, 75))	('mutation', 'Var', (120, 128))	('mouse', 'Species', '10090', (31, 36))	('cub', 'Gene', (267, 270))	('cub', 'Gene', (68, 71))	('cub', 'Gene', (263, 266))	('cub', 'Gene', '217344', (72, 75))	('cub', 'Gene', (112, 115))	('cub', 'Gene', (116, 119))	('cub', 'Gene', '217344', (263, 266))
138827	30022999	We observed not only the rapid cutaneous wound-healing phenotype but also the hyperproliferative-skin phenotype in these mice, suggesting that the Rhbdf2cub/cub mutation results in a similar phenotype regardless of the mouse inbred strain background.	('cub', 'Gene', '217344', (157, 160))	('results in', 'Reg', (170, 180))	('mutation', 'Var', (161, 169))	('mouse', 'Species', '10090', (219, 224))	('cub', 'Gene', (153, 156))	('mice', 'Species', '10090', (121, 125))	('cub', 'Gene', (157, 160))	('cub', 'Gene', '217344', (153, 156))
138829	30022999	Because cigarette smoking and alcohol consumption are known risk factors for esophageal squamous cell carcinoma, we reasoned that the Rhbdf2cub mutation could increase the susceptibility to epithelial cancers and tested the role of RHBDF2 in adenoma formation in ApcMin/+ mice, a mouse model of human colon cancer.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('tested', 'Reg', (213, 219))	('colon cancer', 'Disease', (301, 313))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('human', 'Species', '9606', (295, 300))	('epithelial cancers', 'Disease', (190, 208))	('Rhbdf2cub', 'Gene', (134, 143))	('alcohol', 'Chemical', 'MESH:D000438', (30, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('epithelial cancers', 'Disease', 'MESH:D000077216', (190, 208))	('colon cancer', 'Phenotype', 'HP:0003003', (301, 313))	('mice', 'Species', '10090', (272, 276))	('mutation', 'Var', (144, 152))	('increase', 'PosReg', (159, 167))	('adenoma', 'Disease', (242, 249))	('epithelial cancer', 'Phenotype', 'HP:0031492', (190, 207))	('colon cancer', 'Disease', 'MESH:D015179', (301, 313))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('adenoma', 'Disease', 'MESH:D000236', (242, 249))	('mouse', 'Species', '10090', (280, 285))
138833	30022999	Together, these data suggest that GOF mutations in RHBDF2 accelerate tumor growth with an associated increase in AREG secretion, suggesting a critical role for RHBDF2 in controlling tumor growth through enhanced secretion of AREG.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (69, 74))	('enhanced', 'PosReg', (203, 211))	('accelerate', 'PosReg', (58, 68))	('increase', 'PosReg', (101, 109))	('AREG secretion', 'MPA', (113, 127))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('mutations', 'Var', (38, 47))	('RHBDF2', 'Gene', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
138835	30022999	Using CRISPR/Cas9-mediated targeting and homology-directed repair in C57BL/6J zygotes, we recently generated mice carrying the human TOC mutation p.P189L (p.P159L in mice) in RHBDF2 (Figure 1A, top and middle panels, Figure 1B) and showed that the Rhbdf2P159L GOF mutation enhances AREG secretion to cause alopecia, rapid cutaneous wound healing, hyperplasia, and hyperkeratosis.	('enhances', 'PosReg', (273, 281))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (364, 378))	('alopecia', 'Disease', (306, 314))	('rapid cutaneous wound healing', 'CPA', (316, 345))	('p.P159L', 'Mutation', 'p.P159L', (155, 162))	('mice', 'Species', '10090', (109, 113))	('hyperplasia', 'Disease', (347, 358))	('hyperplasia', 'Disease', 'MESH:D006965', (347, 358))	('p.P189L', 'Var', (146, 153))	('cause', 'Reg', (300, 305))	('human', 'Species', '9606', (127, 132))	('p.P189L', 'Mutation', 'rs387907130', (146, 153))	('GOF', 'PosReg', (260, 263))	('hyperkeratosis', 'Disease', (364, 378))	('alopecia', 'Phenotype', 'HP:0001596', (306, 314))	('Rhbdf2P159L', 'Var', (248, 259))	('hyperkeratosis', 'Disease', 'MESH:D017488', (364, 378))	('RHBDF2', 'Gene', (175, 181))	('mice', 'Species', '10090', (166, 170))	('AREG secretion', 'MPA', (282, 296))
138837	30022999	Together, these data suggest that, analogous to the phenomena in human TOC mutations, Rhbdf2P159L/P159L is a GOF mutation in the mouse Rhbdf2 gene, and that these GOF mutations enhance secretion of AREG and lead to constitutive activation of EGFR signaling to cause TOC.	('human', 'Species', '9606', (65, 70))	('activation', 'PosReg', (228, 238))	('Rhbdf2', 'Gene', '217344', (86, 92))	('secretion', 'MPA', (185, 194))	('mutations', 'Var', (167, 176))	('Rhbdf2', 'Gene', (86, 92))	('P159L', 'Mutation', 'p.P159L', (92, 97))	('P159L', 'Mutation', 'p.P159L', (98, 103))	('Rhbdf2', 'Gene', (135, 141))	('AREG', 'Protein', (198, 202))	('TOC', 'Disease', (266, 269))	('Rhbdf2', 'Gene', '217344', (135, 141))	('mouse', 'Species', '10090', (129, 134))	('EGFR signaling', 'Pathway', (242, 256))	('constitutive', 'MPA', (215, 227))	('enhance', 'PosReg', (177, 184))
138838	30022999	Since GOF mutations in RHBDF2 cause skin hyperkeratosis and hyperplasia examined whether loss of RHBDF2 has any effect on skin thickness.	('cause', 'Reg', (30, 35))	('RHBDF2', 'Gene', (23, 29))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (41, 55))	('mutations', 'Var', (10, 19))	('skin hyperkeratosis and hyperplasia', 'Disease', 'MESH:D006965', (36, 71))
138841	30022999	Because of the reduced K16 expression associated with loss of RHBDF2 and a thinner epidermis, the authors examined K16 expression in the skin of human TOC patients using immunohistochemistry and observed a considerable increase in K16 expression.	('expression', 'MPA', (235, 245))	('K16', 'MPA', (231, 234))	('K16', 'Gene', (23, 26))	('human', 'Species', '9606', (145, 150))	('expression', 'MPA', (27, 37))	('reduced', 'NegReg', (15, 22))	('loss', 'Var', (54, 58))	('RHBDF2', 'Gene', (62, 68))	('patients', 'Species', '9606', (155, 163))	('increase', 'PosReg', (219, 227))
138849	30022999	We found that ADAM17 deficiency in the skin of Rhbdf2cub/cub mice restored a full hair coat and impaired the rapid wound-healing phenotype observed in Rhbdf2cub/cub mice, demonstrating that ADAM17 is the major ectodomain sheddase of AREG and that RHBDF2 does not directly participate in the shedding of AREG.	('cub', 'Gene', '217344', (53, 56))	('ADAM17', 'Gene', (14, 20))	('cub', 'Gene', '217344', (157, 160))	('cub', 'Gene', '217344', (57, 60))	('mice', 'Species', '10090', (61, 65))	('cub', 'Gene', '217344', (161, 164))	('mice', 'Species', '10090', (165, 169))	('rapid wound-healing', 'Phenotype', 'HP:0001058', (109, 128))	('full hair', 'Phenotype', 'HP:0100874', (77, 86))	('full hair coat', 'MPA', (77, 91))	('deficiency', 'Var', (21, 31))	('cub', 'Gene', (53, 56))	('cub', 'Gene', (57, 60))	('restored', 'PosReg', (66, 74))	('rapid wound-healing phenotype', 'CPA', (109, 138))	('cub', 'Gene', (157, 160))	('impaired', 'NegReg', (96, 104))	('cub', 'Gene', (161, 164))
138854	30022999	In further support of this model, it has been shown that lack of RHBDF2 significantly decreases ADAM17-dependent AREG secretion after stimulation with the protein kinase C stimulant PMA, whereas GOF RHBDF2 mutations such as those observed in human TOC enhance ADAM17 sheddase activity to significantly increase AREG secretion.	('mutations', 'Var', (206, 215))	('lack', 'Var', (57, 61))	('increase', 'PosReg', (302, 310))	('activity', 'MPA', (276, 284))	('ADAM17-dependent AREG secretion', 'MPA', (96, 127))	('AREG secretion', 'MPA', (311, 325))	('RHBDF2', 'Gene', (199, 205))	('decreases', 'NegReg', (86, 95))	('RHBDF2', 'Gene', (65, 71))	('ADAM17 sheddase', 'Enzyme', (260, 275))	('enhance', 'PosReg', (252, 259))	('human', 'Species', '9606', (242, 247))
138855	30022999	Furthermore, it has been suggested that RHBDF1, a paralog of RHBDF2, can compensate for the loss of RHBDF2 in regulating ADAM17 maturation, trafficking, and activity.	('ADAM17', 'Protein', (121, 127))	('trafficking', 'MPA', (140, 151))	('RHBDF1', 'Gene', '13650', (40, 46))	('loss', 'Var', (92, 96))	('RHBDF1', 'Gene', (40, 46))	('RHBDF2', 'Gene', (100, 106))	('activity', 'MPA', (157, 165))
138863	30022999	While current murine models of human TOC, both spontaneous mutant and genetically engineered mice, do not recapitulate all characteristics of the human disease, these models have yielded valuable insights into disease mechanisms, including the identification of AREG as a functional driver of the disease, verification of the essential role of metalloprotease ADAM17 in shedding of AREG, demonstration of the susceptibility of mice carrying Rhbdf2 GOF mutations to epithelial cancer, and determination of the tissue-specific role of the RHBDF2-AREG-ADAM17-EGFR pathway.	('murine', 'Species', '10090', (14, 20))	('epithelial cancer', 'Phenotype', 'HP:0031492', (465, 482))	('human', 'Species', '9606', (31, 36))	('mutations', 'Var', (452, 461))	('epithelial cancer', 'Disease', (465, 482))	('human', 'Species', '9606', (146, 151))	('epithelial cancer', 'Disease', 'MESH:D000077216', (465, 482))	('GOF', 'PosReg', (448, 451))	('mice', 'Species', '10090', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (476, 482))	('Rhbdf2', 'Gene', '217344', (441, 447))	('Rhbdf2', 'Gene', (441, 447))	('mice', 'Species', '10090', (427, 431))
138885	29687051	This is a type IV para-oesophageal hernia, and we suggest that anomalous attachment of the diaphragm to the sternum and adjacent ribs during gestation is the etiologic factor.	('type IV para-oesophageal hernia', 'Disease', (10, 41))	('hernia', 'Phenotype', 'HP:0100790', (35, 41))	('oesophageal hernia', 'Phenotype', 'HP:0002036', (23, 41))	('anomalous', 'Var', (63, 72))	('type IV para-oesophageal hernia', 'Disease', 'MESH:D005764', (10, 41))	('esophageal hernia', 'Phenotype', 'HP:0002036', (24, 41))
138947	29343267	Human esophageal carcinoma cell lines (EC9076, KYSE410, KYSE150, TE-1 and EC109) and human normal esophageal epithelial cells HEEC were purchased from Cell Bank of Chinese Academy of Science (Shanghai, China).	('Human', 'Species', '9606', (0, 5))	('EC9076', 'CellLine', 'CVCL:5V07', (39, 45))	('esophageal carcinoma', 'Disease', (6, 26))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (6, 26))	('EC109', 'CellLine', 'CVCL:6898', (74, 79))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (6, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('EC9076', 'Var', (39, 45))	('human', 'Species', '9606', (85, 90))
138949	29343267	After transfection for 8-10 days, pAd-V and pAd-TIPE recombination plasmids were transfected into HEK 293 cells using Lipofectamine 2000 (Invitrogen) to generate Ad-V and Ad-TIPE2 adenovirus, respectively.	('Ad-V', 'Var', (162, 166))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (118, 136))	('Ad-TIPE2', 'Var', (171, 179))	('HEK 293', 'CellLine', 'CVCL:0045', (98, 105))
138955	29343267	Next, the membranes were blocked in 5% skim milk for 1 h at room temperature and probed with primary antibodies against TIPE2 (ab110389, 1:1000, Abcam, Cambridge, MA, USA), beta-actin (ab8227, 1:5000, Abcam), beta-catenin (ab32572, 1:5000, Abcam), c-Myc (ab32072, 1:1000, Abcam), and cyclinD1 (ab134175, 1:1000, Abcam) overnight at 4  C, followed by the incubation with horseradish peroxidase (HRP)-conjugated goat-anti rabbit second antibodies (ab6721, 1:1000, Abcam) for 1 h at room temperature.	('beta-actin', 'Gene', '728378', (173, 183))	('goat', 'Species', '9925', (410, 414))	('beta-actin', 'Gene', (173, 183))	('c-Myc', 'Gene', (248, 253))	('rabbit', 'Species', '9986', (420, 426))	('beta-catenin', 'Gene', '1499', (209, 221))	('ab32572', 'Var', (223, 230))	('ab134175', 'Var', (294, 302))	('cyclinD1', 'Gene', (284, 292))	('horseradish', 'Species', '3704', (370, 381))	('ab32072', 'Var', (255, 262))	('cyclinD1', 'Gene', '595', (284, 292))	('beta-catenin', 'Gene', (209, 221))	('c-Myc', 'Gene', '4609', (248, 253))
138965	29343267	Briefly, EC9076 and EC109 cells (105/well) infected with Ad-V or Ad-TIPE2 were resuspended in serum-free RPMI-1640 medium (100 mul) and seeded into the upper chamber pre-coated with 40 microl Matrigel (BD Biosciences), while the lower chamber was filled with 700 mul RPMI-1640 medium containing 10% FBS.	('FBS', 'Disease', (299, 302))	('RPMI-1640 medium', 'Chemical', '-', (105, 121))	('Ad-TIPE2', 'Var', (65, 73))	('RPMI-1640 medium', 'Chemical', '-', (267, 283))	('FBS', 'Disease', 'MESH:D005198', (299, 302))	('Ad-V', 'Gene', (57, 61))	('EC109', 'CellLine', 'CVCL:6898', (20, 25))	('EC9076', 'CellLine', 'CVCL:5V07', (9, 15))
138971	29343267	To explore the effect of TIPE2 overexpression on tumor growth in vivo, EC9706 cells infected with Ad-V or Ad-TIPE2 at a concentration of 1 x 107 cells/ml were injected subcutaneously into the flank region of nude mice.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('nude mice', 'Species', '10090', (208, 217))	('Ad-TIPE2', 'Var', (106, 114))	('tumor', 'Disease', (49, 54))	('EC9706', 'CellLine', 'CVCL:E307', (71, 77))
138981	29343267	Furthermore, western blot assay manifested that TIPE2 was also distinctly downregulated in esophageal carcinoma cell lines (KYSE410, EC9706, KYSE150, TE-1, and EC109) than that in normal human esophageal epithelial cells (HEEC) (Fig.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (91, 111))	('EC109', 'Var', (160, 165))	('EC9706', 'CellLine', 'CVCL:E307', (133, 139))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (91, 111))	('EC9706', 'Var', (133, 139))	('human', 'Species', '9606', (187, 192))	('EC109', 'CellLine', 'CVCL:6898', (160, 165))	('esophageal carcinoma', 'Disease', (91, 111))	('KYSE410', 'Var', (124, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('TIPE2', 'Gene', (48, 53))	('downregulated', 'NegReg', (74, 87))	('KYSE150', 'Var', (141, 148))
138983	29343267	To determine the effect of TIPE2 overexpression on the progression of esophageal carcinoma, the coding sequence of TIPE2 was cloned into the recombinant adenovirus vectors to generate Ad-TIPE2 adenovirus, followed by adenovirus infection into EC9706 and EC109 cells.	('EC109', 'CellLine', 'CVCL:6898', (254, 259))	('adenovirus infection', 'Disease', (217, 237))	('EC9706', 'CellLine', 'CVCL:E307', (243, 249))	('adenovirus infection', 'Disease', 'MESH:D000257', (217, 237))	('TIPE2', 'Gene', (115, 120))	('esophageal carcinoma', 'Disease', (70, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('Ad-TIPE2', 'Var', (184, 192))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (70, 90))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (70, 90))
138991	29343267	EdU quantification results further revealed that the proliferation rates of cells were remarkably reduced in Ad-TIPE2-infected EC9706 (Fig.	('proliferation rates of cells', 'CPA', (53, 81))	('EC9706', 'CellLine', 'CVCL:E307', (127, 133))	('reduced', 'NegReg', (98, 105))	('Ad-TIPE2-infected', 'Gene', (109, 126))	('EC9706', 'Var', (127, 133))
138999	29343267	Subsequently, to further explore the effect of TIPE2 on tumor growth in vivo, xenograft tumor models were established by injecting with EC9706 cells infected with Ad-V or Ad-TIPE2 cells into nude mice.	('EC9706', 'CellLine', 'CVCL:E307', (136, 142))	('Ad-TIPE2', 'Var', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('nude mice', 'Species', '10090', (191, 200))	('tumor', 'Disease', (56, 61))	('xenograft tumor', 'Disease', (78, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('xenograft tumor', 'Disease', 'MESH:D009369', (78, 93))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
139000	29343267	4a, c, adenovirus-mediated TIPE2 overexpression strikingly hindered tumor growth, as evidenced by the reduced tumor volume (Fig.	('tumor', 'Disease', (68, 73))	('TIPE2', 'Gene', (27, 32))	('hindered', 'NegReg', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('c, adenovirus', 'Species', '10537', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('overexpression', 'Var', (33, 47))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('reduced', 'NegReg', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
139008	29343267	Hence, the effect of TIPE2 on the Wnt/beta-catenin pathway was further assessed in EC9706 cells and xenograft tumors infected with blank Ad-V adenovirus or Ad-TIPE2 adenovirus.	('beta-catenin', 'Gene', (38, 50))	('xenograft tumors infected', 'Disease', 'MESH:D009369', (100, 125))	('xenograft tumors infected', 'Disease', (100, 125))	('beta-catenin', 'Gene', '1499', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('EC9706', 'CellLine', 'CVCL:E307', (83, 89))	('Ad-TIPE2', 'Var', (156, 164))
139016	29343267	Additionally, enforced expression of TIPE2 was revealed to suppress cell proliferation, colony formation and invasion in lung carcinoma cells, and suppressed lung carcinoma tumor growth in vivo.	('lung carcinoma', 'Disease', (121, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('cell proliferation', 'CPA', (68, 86))	('lung carcinoma tumor', 'Disease', 'MESH:D009369', (158, 178))	('TIPE2', 'Gene', (37, 42))	('suppressed', 'NegReg', (147, 157))	('expression', 'Var', (23, 33))	('colony formation', 'CPA', (88, 104))	('lung carcinoma', 'Disease', 'MESH:D008175', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('suppress', 'NegReg', (59, 67))	('lung carcinoma', 'Disease', 'MESH:D008175', (121, 135))	('lung carcinoma tumor', 'Disease', (158, 178))
139017	29343267	Notably, it was also manifested that TIPE2 suppressed activation of oncogenic gene Ras, indicating that TIPE2 played a critical role in the development of carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinoma', 'Disease', (155, 164))	('TIPE2', 'Var', (37, 42))	('activation', 'MPA', (54, 64))	('suppressed', 'NegReg', (43, 53))
139020	29343267	Previous studies manifested that abnormal expression of TIPE2 was closely correlated with pathological processes of cancer including proliferation, migration, invasion and apoptosis.	('TIPE2', 'Gene', (56, 61))	('migration', 'CPA', (148, 157))	('cancer', 'Disease', (116, 122))	('expression', 'MPA', (42, 52))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('correlated', 'Reg', (74, 84))	('abnormal', 'Var', (33, 41))	('invasion', 'CPA', (159, 167))	('apoptosis', 'CPA', (172, 181))	('proliferation', 'CPA', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
139028	29343267	For instance, TIPE2 suppressed hypoxia-triggered the Wnt/beta-catenin pathway activation in glioma.	('suppressed', 'NegReg', (20, 30))	('glioma', 'Disease', (92, 98))	('activation', 'PosReg', (78, 88))	('hypoxia', 'Disease', (31, 38))	('hypoxia', 'Disease', 'MESH:D000860', (31, 38))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('beta-catenin', 'Gene', (57, 69))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('beta-catenin', 'Gene', '1499', (57, 69))	('TIPE2', 'Var', (14, 19))
139029	29343267	Moreover, TIPE2 overexpression hampered metastasis by promoting beta-catenin degradation and inhibiting beta-catenin signaling pathway in gastric cancer.	('gastric cancer', 'Disease', (138, 152))	('hampered', 'NegReg', (31, 39))	('TIPE2', 'Gene', (10, 15))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('beta-catenin', 'Gene', (104, 116))	('beta-catenin', 'Gene', '1499', (104, 116))	('promoting', 'PosReg', (54, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('overexpression', 'Var', (16, 30))	('metastasis', 'CPA', (40, 50))	('beta-catenin', 'Gene', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('inhibiting', 'NegReg', (93, 103))	('beta-catenin', 'Gene', '1499', (64, 76))
139030	29343267	In the present study, we demonstrated that adenovirus-mediated TIPE2 overexpression suppressed the expression of beta-catenin in EC9706 cells and xenograft tumors of esophageal carcinoma, indicating that TIPE2 acted as a tumor suppressor by inactivating the Wnt/beta-catenin pathway in esophageal carcinoma.	('expression', 'MPA', (99, 109))	('EC9706', 'CellLine', 'CVCL:E307', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('overexpression', 'Var', (69, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('esophageal carcinoma', 'Disease', (286, 306))	('xenograft tumors of esophageal carcinoma', 'Disease', 'MESH:D009369', (146, 186))	('tumor', 'Disease', (156, 161))	('beta-catenin', 'Gene', (262, 274))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('beta-catenin', 'Gene', '1499', (262, 274))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (166, 186))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (286, 306))	('suppressed', 'NegReg', (84, 94))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('xenograft tumors of esophageal carcinoma', 'Disease', (146, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('beta-catenin', 'Gene', (113, 125))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (166, 186))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (286, 306))	('inactivating', 'NegReg', (241, 253))	('TIPE2', 'Gene', (63, 68))	('beta-catenin', 'Gene', '1499', (113, 125))
139035	29343267	reported that beta-catenin knockdown suppressed the expression of downstream effectors such as c-myc and cyclinD1 in esophageal carcinoma.	('knockdown', 'Var', (27, 36))	('beta-catenin', 'Gene', (14, 26))	('c-myc', 'Gene', (95, 100))	('beta-catenin', 'Gene', '1499', (14, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal carcinoma', 'Disease', (117, 137))	('expression', 'MPA', (52, 62))	('cyclinD1', 'Gene', (105, 113))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (117, 137))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (117, 137))	('cyclinD1', 'Gene', '595', (105, 113))	('c-myc', 'Gene', '4609', (95, 100))	('suppressed', 'NegReg', (37, 47))
139051	26317790	Modulation of IGFBP2 expression in EAC cell lines promoted cell proliferation, migration and invasion, implicating a role in the metastatic potential of these cells.	('Modulation', 'Var', (0, 10))	('migration', 'CPA', (79, 88))	('promoted', 'PosReg', (50, 58))	('IGFBP2', 'Gene', (14, 20))	('cell proliferation', 'CPA', (59, 77))	('EAC', 'Phenotype', 'HP:0011459', (35, 38))	('invasion', 'CPA', (93, 101))	('IGFBP2', 'Gene', '3485', (14, 20))
139052	26317790	Additionally, knockdown of IGFBP2 sensitized EAC cells to cisplatin in a serum-dependent manner.	('IGFBP2', 'Gene', (27, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('knockdown', 'Var', (14, 23))	('IGFBP2', 'Gene', '3485', (27, 33))	('sensitized', 'Reg', (34, 44))
139054	26317790	Silencing of IGFBP2 enhanced IGF1-induced immediate activation of AKT and reduced cisplatin-induced ERK activation.	('IGF1', 'Gene', (29, 33))	('enhanced IGF1', 'Phenotype', 'HP:0030269', (20, 33))	('AKT', 'Gene', (66, 69))	('enhanced', 'PosReg', (20, 28))	('activation', 'PosReg', (52, 62))	('Silencing', 'Var', (0, 9))	('IGF1', 'Gene', '3479', (29, 33))	('IGFBP2', 'Gene', '3485', (13, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('ERK', 'Gene', '5594', (100, 103))	('AKT', 'Gene', '207', (66, 69))	('reduced', 'NegReg', (74, 81))	('IGFBP2', 'Gene', (13, 19))	('ERK', 'Gene', (100, 103))
139060	26317790	Only complete responders (those patients who are restaged as T0N0 or T1N0) have improved survival as compared to incomplete or non-responders.	('patients', 'Species', '9606', (32, 40))	('T1N0', 'Var', (69, 73))	('improved', 'PosReg', (80, 88))	('T0N0', 'Var', (61, 65))	('survival', 'MPA', (89, 97))
139062	26317790	Overexpression of IGF1R is prevalent in esophageal adenocarcinoma (EAC), as high as 75%, and has been associated with the progression of Barrett's to EAC.	('associated with', 'Reg', (102, 117))	('EAC', 'Phenotype', 'HP:0011459', (150, 153))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (40, 65))	('esophageal adenocarcinoma', 'Disease', (40, 65))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (40, 65))	('IGF1R', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('EAC', 'Phenotype', 'HP:0011459', (67, 70))	('IGF1R', 'Gene', '3480', (18, 23))	('prevalent', 'Reg', (27, 36))	('Barrett', 'Disease', (137, 144))
139063	26317790	Overexpression of IGF1R also appears to be an independent predictor of survival.	('IGF1R', 'Gene', '3480', (18, 23))	('IGF1R', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))
139066	26317790	Function-altering polymorphisms in IGF1R as well as IGF1 microsatellite repeats and single strand nucleotide polymorphisms have been shown to affect risk for developing Barrett's esophagus and/or EAC.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (169, 188))	('IGF1', 'Gene', '3479', (52, 56))	('affect', 'Reg', (142, 148))	('IGF1R', 'Gene', '3480', (35, 40))	('microsatellite repeats', 'Var', (57, 79))	('IGF1', 'Gene', '3479', (35, 39))	('EAC', 'Phenotype', 'HP:0011459', (196, 199))	('single strand nucleotide polymorphisms', 'Var', (84, 122))	('polymorphisms', 'Var', (18, 31))	('IGF1', 'Gene', (52, 56))	('Function-altering', 'Reg', (0, 17))	('EAC', 'Disease', (196, 199))	('IGF1R', 'Gene', (35, 40))	("Barrett's esophagus", 'Disease', (169, 188))	('IGF1', 'Gene', (35, 39))
139071	26317790	Inhibition of its expression has been reported to increase apoptosis and decrease migration of human leukemia cells, while its overexpression significantly increased the invasive capability of glioblastoma and ovarian cancer cells.	('invasive capability', 'CPA', (170, 189))	('increased', 'PosReg', (156, 165))	('ovarian cancer', 'Disease', 'MESH:D010051', (210, 224))	('glioblastoma', 'Disease', 'MESH:D005909', (193, 205))	('expression', 'Protein', (18, 28))	('apoptosis', 'CPA', (59, 68))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('glioblastoma', 'Disease', (193, 205))	('ovarian cancer', 'Disease', (210, 224))	('human', 'Species', '9606', (95, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('ovarian cancer', 'Phenotype', 'HP:0100615', (210, 224))	('increase', 'PosReg', (50, 58))	('decrease', 'NegReg', (73, 81))	('Inhibition', 'Var', (0, 10))	('leukemia', 'Disease', (101, 109))	('leukemia', 'Disease', 'MESH:D007938', (101, 109))	('overexpression', 'PosReg', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
139073	26317790	We show that modulation of IGFBP2 expression affects proliferation, motility, and chemosensitization of EAC cells in a serum-dependent manner.	('IGFBP2', 'Gene', (27, 33))	('chemosensitization', 'CPA', (82, 100))	('proliferation', 'CPA', (53, 66))	('EAC', 'Phenotype', 'HP:0011459', (104, 107))	('affects', 'Reg', (45, 52))	('modulation', 'Var', (13, 23))	('IGFBP2', 'Gene', '3485', (27, 33))	('motility', 'CPA', (68, 76))
139074	26317790	Silencing of IGFBP2 affects both AKT and ERK activity and addition of targeted pharmacologic inhibitors of these pathways enhances siIGFBP2-induced cisplatin (CDDP) chemosensitization.	('activity', 'MPA', (45, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('AKT', 'Gene', '207', (33, 36))	('CDDP', 'Chemical', '-', (159, 163))	('enhances', 'PosReg', (122, 130))	('IGFBP2', 'Gene', '3485', (13, 19))	('IGFBP2', 'Gene', '3485', (133, 139))	('IGFBP2', 'Gene', (133, 139))	('ERK', 'Gene', '5594', (41, 44))	('AKT', 'Gene', (33, 36))	('Silencing', 'Var', (0, 9))	('IGFBP2', 'Gene', (13, 19))	('ERK', 'Gene', (41, 44))
139075	26317790	IGFBP2 is a potential mediator of chemoresistance in a subset of EACs and its modulation in overexpressing EAC tumors may be an effective approach to sensitizing resistant tumors to standard of care chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('EAC tumors', 'Disease', (107, 117))	('mediator', 'Reg', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('IGFBP2', 'Gene', '3485', (0, 6))	('EAC tumors', 'Disease', 'MESH:C536611', (107, 117))	('EAC', 'Phenotype', 'HP:0011459', (107, 110))	('EAC', 'Phenotype', 'HP:0011459', (65, 68))	('modulation', 'Var', (78, 88))	('IGFBP2', 'Gene', (0, 6))
139101	26317790	This inhibitory effect of IGFBP2 knockdown was not consistently observed in serum-replete conditions, suggesting that IGFBP2 may have differential roles or significance based on the availability of additional growth factors.	('IGFBP2', 'Gene', '3485', (118, 124))	('IGFBP2', 'Gene', (118, 124))	('knockdown', 'Var', (33, 42))	('IGFBP2', 'Gene', '3485', (26, 32))	('IGFBP2', 'Gene', (26, 32))
139105	26317790	SiRNA knockdown of IGFBP2 in Flo-1 was associated with increased expression of several epithelial-mesenchymal transition-related genes, including SNAI1, ZEB1, VIM, MMP9, and MMP1 (Supplementary Figure S5A).	('MMP9', 'Gene', (164, 168))	('VIM', 'Gene', (159, 162))	('ZEB1', 'Gene', '6935', (153, 157))	('Flo-1', 'Gene', (29, 34))	('MMP1', 'Gene', '4312', (174, 178))	('ZEB1', 'Gene', (153, 157))	('MMP9', 'Gene', '4318', (164, 168))	('increased', 'PosReg', (55, 64))	('IGFBP2', 'Gene', '3485', (19, 25))	('IGFBP2', 'Gene', (19, 25))	('epithelial-mesenchymal transition-related genes', 'Gene', (87, 134))	('expression', 'MPA', (65, 75))	('MMP1', 'Gene', (174, 178))	('VIM', 'Gene', '7431', (159, 162))	('knockdown', 'Var', (6, 15))	('SNAI1', 'Gene', '6615', (146, 151))	('SNAI1', 'Gene', (146, 151))
139112	26317790	Boyden chamber assays using IGFBP2-expressing Flo-1 cells showed only marginal Matrigel invasion differences upon knockdown of IGFBP2 (Supplementary Figure S6C).	('Matrigel invasion', 'CPA', (79, 96))	('knockdown', 'Var', (114, 123))	('IGFBP2', 'Gene', '3485', (127, 133))	('IGFBP2', 'Gene', '3485', (28, 34))	('IGFBP2', 'Gene', (127, 133))	('IGFBP2', 'Gene', (28, 34))
139115	26317790	Inhibition of IGFBP2 expression sensitized Flo-1 cells to CDDP but not 5-FU in serum-replete conditions (Figure 3A).	('5-FU', 'Chemical', 'MESH:D005472', (71, 75))	('IGFBP2', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))	('sensitized', 'Reg', (32, 42))	('IGFBP2', 'Gene', '3485', (14, 20))	('CDDP', 'Chemical', '-', (58, 62))
139117	26317790	In serum-free cell cultures, IGFBP2 knockdown did not enhance the response to chemotherapy.	('knockdown', 'Var', (36, 45))	('IGFBP2', 'Gene', '3485', (29, 35))	('response', 'MPA', (66, 74))	('IGFBP2', 'Gene', (29, 35))
139118	26317790	Acute 24 hr treatments with high doses of CDDP following IGFBP2 knockdown were also performed.	('CDDP', 'Chemical', '-', (42, 46))	('IGFBP2', 'Gene', '3485', (57, 63))	('IGFBP2', 'Gene', (57, 63))	('knockdown', 'Var', (64, 73))
139119	26317790	In contrast to 3-day low-dose CDDP treatments, siIGFBP2-treated Flo-1 cells were only slightly sensitized to CDDP (Supplementary Figure S7A), suggesting that the chemosensitization effect of IGFBP2 knockdown may be dependent on its modulation of proliferation and would require longer incubation periods to detect differences.	('IGFBP2', 'Gene', '3485', (49, 55))	('IGFBP2', 'Gene', (49, 55))	('IGFBP2', 'Gene', '3485', (191, 197))	('knockdown', 'Var', (198, 207))	('CDDP', 'Chemical', '-', (109, 113))	('IGFBP2', 'Gene', (191, 197))	('CDDP', 'Chemical', '-', (30, 34))	('chemosensitization', 'MPA', (162, 180))
139121	26317790	The chemosensitization effect of knocking down IGFBP2 was also examined in endogenously-expressing OE19 cells.	('IGFBP2', 'Gene', '3485', (47, 53))	('IGFBP2', 'Gene', (47, 53))	('knocking down', 'Var', (33, 46))
139124	26317790	To further explore the mechanism of IGFBP2-induced chemoresistance, we assessed whether inhibition of IGFBP2 could modulate IGF1-induced ERK and/or AKT activation (Figure 4A).	('AKT', 'Gene', '207', (148, 151))	('modulate', 'Reg', (115, 123))	('activation', 'PosReg', (152, 162))	('IGFBP2', 'Gene', '3485', (36, 42))	('IGF1', 'Gene', '3479', (124, 128))	('AKT', 'Gene', (148, 151))	('IGFBP2', 'Gene', (36, 42))	('ERK', 'Gene', '5594', (137, 140))	('IGF1', 'Gene', (124, 128))	('ERK', 'Gene', (137, 140))	('IGFBP2', 'Gene', '3485', (102, 108))	('IGFBP2', 'Gene', (102, 108))	('inhibition', 'Var', (88, 98))
139127	26317790	In contrast, AKT was significantly activated by exogenous IGF1 or IGFBP2 knockdown at each measured time point as compared to the non-targeting siRNA control.	('IGFBP2', 'Gene', (66, 72))	('IGF1', 'Gene', '3479', (58, 62))	('AKT', 'Gene', '207', (13, 16))	('IGF1', 'Gene', (58, 62))	('IGFBP2', 'Gene', '3485', (66, 72))	('activated', 'PosReg', (35, 44))	('AKT', 'Gene', (13, 16))	('knockdown', 'Var', (73, 82))
139133	26317790	Interestingly, in both Flo-1 and OE33 cell cultures, cells surviving repeated acute IC90 CDDP treatments had decreased expression of IGFBP2 (data not shown).	('decreased', 'NegReg', (109, 118))	('expression', 'MPA', (119, 129))	('IC90', 'Var', (84, 88))	('IGFBP2', 'Gene', '3485', (133, 139))	('IGFBP2', 'Gene', (133, 139))	('CDDP', 'Chemical', '-', (89, 93))
139144	26317790	In serum-free conditions, ERK activation decreased following IGFBP2 knockdown.	('ERK', 'Gene', '5594', (26, 29))	('decreased', 'NegReg', (41, 50))	('ERK', 'Gene', (26, 29))	('IGFBP2', 'Gene', '3485', (61, 67))	('IGFBP2', 'Gene', (61, 67))	('knockdown', 'Var', (68, 77))	('activation', 'MPA', (30, 40))
139147	26317790	Further examination of these signaling pathways using the individual siRNAs to IGFBP2 in the SMARTpool confirmed that IGFBP2 knockdown reduced CDDP-induced ERK activation (Figure 4D).	('knockdown', 'Var', (125, 134))	('ERK', 'Gene', '5594', (156, 159))	('ERK', 'Gene', (156, 159))	('IGFBP2', 'Gene', (118, 124))	('IGFBP2', 'Gene', (79, 85))	('IGFBP2', 'Gene', '3485', (118, 124))	('reduced', 'NegReg', (135, 142))	('CDDP', 'Chemical', '-', (143, 147))	('IGFBP2', 'Gene', '3485', (79, 85))
139152	26317790	When combined with knockdown of IGFBP2, both selumetinib and trametinib increased sensitivity to CDDP in serum-replete (Figure 5C and 5D) but not in serum-free culture conditions (Supplementary Figure S9A and S9B).	('trametinib', 'Chemical', 'MESH:C560077', (61, 71))	('increased', 'PosReg', (72, 81))	('CDDP', 'Chemical', '-', (97, 101))	('IGFBP2', 'Gene', '3485', (32, 38))	('knockdown', 'Var', (19, 28))	('IGFBP2', 'Gene', (32, 38))	('sensitivity to CDDP', 'MPA', (82, 101))	('selumetinib', 'Chemical', 'MESH:C517975', (45, 56))
139153	26317790	Since knockdown of IGFBP2 induced AKT activation in Flo-1 cells, we hypothesized that inhibition of this pathway would further sensitize cells to CDDP.	('AKT', 'Gene', (34, 37))	('CDDP', 'Chemical', '-', (146, 150))	('IGFBP2', 'Gene', '3485', (19, 25))	('IGFBP2', 'Gene', (19, 25))	('AKT', 'Gene', '207', (34, 37))	('knockdown', 'Var', (6, 15))	('activation', 'PosReg', (38, 48))
139177	26317790	Silencing IGFBP2 in Flo-1 EAC cells resulted in significant sensitization to CDDP in serum-supplemented conditions, independent of the addition of IGF1 or IGF2, but was not as effective in serum-free conditions.	('IGFBP2', 'Gene', (10, 16))	('EAC', 'Phenotype', 'HP:0011459', (26, 29))	('IGF2', 'Gene', (155, 159))	('IGF1', 'Gene', (147, 151))	('IGFBP2', 'Gene', '3485', (10, 16))	('CDDP', 'Chemical', '-', (77, 81))	('sensitization', 'MPA', (60, 73))	('Silencing', 'Var', (0, 9))	('IGF2', 'Gene', '3481', (155, 159))	('IGF1', 'Gene', '3479', (147, 151))
139180	26317790	We also observed, however, that IGFBP2 knockdown alone and CDDP treatment itself induced the expression of several EMT-promoting genes in Flo-1 cells.	('EMT-promoting genes', 'Gene', (115, 134))	('IGFBP2', 'Gene', '3485', (32, 38))	('knockdown', 'Var', (39, 48))	('induced', 'Reg', (81, 88))	('IGFBP2', 'Gene', (32, 38))	('expression', 'MPA', (93, 103))	('CDDP', 'Chemical', '-', (59, 63))
139182	26317790	It plays a key role in AKT pathway activation during glioma development and progression and its knockdown has been shown to decrease IGF1-stimulated AKT activation in vascular smooth muscle cells and acute leukemia cells.	('knockdown', 'Var', (96, 105))	('IGF1', 'Gene', (133, 137))	('leukemia', 'Phenotype', 'HP:0001909', (206, 214))	('glioma', 'Disease', (53, 59))	('AKT', 'Gene', '207', (23, 26))	('AKT', 'Gene', (149, 152))	('leukemia', 'Disease', 'MESH:D007938', (206, 214))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('leukemia', 'Disease', (206, 214))	('acute leukemia', 'Phenotype', 'HP:0002488', (200, 214))	('AKT', 'Gene', '207', (149, 152))	('activation', 'MPA', (153, 163))	('AKT', 'Gene', (23, 26))	('decrease', 'NegReg', (124, 132))	('IGF1', 'Gene', '3479', (133, 137))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('activation', 'PosReg', (35, 45))
139183	26317790	In contrast to what has been previously reported, IGFBP2 knockdown activated AKT in Flo-1 EAC cells, and the effect was further enhanced by the addition of IGF1.	('AKT', 'Gene', '207', (77, 80))	('activated', 'PosReg', (67, 76))	('IGFBP2', 'Gene', '3485', (50, 56))	('knockdown', 'Var', (57, 66))	('IGF1', 'Gene', '3479', (156, 160))	('IGFBP2', 'Gene', (50, 56))	('enhanced', 'PosReg', (128, 136))	('EAC', 'Phenotype', 'HP:0011459', (90, 93))	('AKT', 'Gene', (77, 80))	('IGF1', 'Gene', (156, 160))
139186	26317790	In the absence of serum but in the presence of IGF1, AKT inhibitor VIII further enhanced the effects of a 3-day treatment with CDDP and was even more effective following IGFBP2 knockdown, suggesting that the acute AKT activation following IGFBP2 knockdown may have been a compensatory survival mechanism.	('VIII', 'Gene', (67, 71))	('VIII', 'Gene', '1351', (67, 71))	('IGF1', 'Gene', (47, 51))	('IGF1', 'Gene', '3479', (47, 51))	('activation', 'PosReg', (218, 228))	('IGFBP2', 'Gene', '3485', (170, 176))	('IGFBP2', 'Gene', (170, 176))	('knockdown', 'Var', (246, 255))	('enhanced', 'PosReg', (80, 88))	('AKT', 'Gene', '207', (214, 217))	('AKT', 'Gene', '207', (53, 56))	('IGFBP2', 'Gene', '3485', (239, 245))	('CDDP', 'Chemical', '-', (127, 131))	('effects', 'MPA', (93, 100))	('IGFBP2', 'Gene', (239, 245))	('AKT', 'Gene', (214, 217))	('AKT', 'Gene', (53, 56))
139188	26317790	In the presence of serum, however, inhibition of AKT phosphorylation did not improve response to chemotherapy over IGFBP2 knockdown alone, indicating that these mediators may be acting through the same signaling pathway or that other signaling pathways predominate in serum-replete conditions.	('AKT', 'Gene', (49, 52))	('IGFBP2', 'Gene', (115, 121))	('inhibition', 'Var', (35, 45))	('AKT', 'Gene', '207', (49, 52))	('IGFBP2', 'Gene', '3485', (115, 121))
139189	26317790	Modulation of IGFBP2 levels has been shown to affect ERK activation as well.	('Modulation', 'Var', (0, 10))	('IGFBP2', 'Gene', (14, 20))	('ERK', 'Gene', '5594', (53, 56))	('affect', 'Reg', (46, 52))	('ERK', 'Gene', (53, 56))	('IGFBP2', 'Gene', '3485', (14, 20))
139191	26317790	Inhibition of the ERK pathway with PD98059 and U1026 abrogated IGFBP2-induced activation.	('IGFBP2', 'Gene', '3485', (63, 69))	('IGFBP2', 'Gene', (63, 69))	('ERK', 'Gene', (18, 21))	('U1026', 'Var', (47, 52))	('U1026', 'Chemical', '-', (47, 52))	('PD98059', 'Var', (35, 42))	('abrogated', 'NegReg', (53, 62))	('activation', 'PosReg', (78, 88))	('PD98059', 'Chemical', 'MESH:C093973', (35, 42))	('ERK', 'Gene', '5594', (18, 21))
139192	26317790	While lentivirus-based shRNA silencing of IGFBP2 decreased activation of ERK and AKT in human leukemia cells, it resulted in the inability of p53 to inhibit IGF1-induced ERK phosphorylation in PC-3 cells.	('ERK', 'Gene', '5594', (170, 173))	('PC-3', 'CellLine', 'CVCL:0035', (193, 197))	('AKT', 'Gene', '207', (81, 84))	('human', 'Species', '9606', (88, 93))	('IGF1', 'Gene', '3479', (157, 161))	('ERK', 'Gene', '5594', (73, 76))	('inhibit', 'NegReg', (149, 156))	('p53', 'Gene', '7157', (142, 145))	('silencing', 'Var', (29, 38))	('ERK', 'Gene', (170, 173))	('decreased', 'NegReg', (49, 58))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('p53', 'Gene', (142, 145))	('ERK', 'Gene', (73, 76))	('IGF1', 'Gene', (157, 161))	('activation', 'MPA', (59, 69))	('AKT', 'Gene', (81, 84))	('IGFBP2', 'Gene', '3485', (42, 48))	('leukemia', 'Disease', (94, 102))	('leukemia', 'Disease', 'MESH:D007938', (94, 102))	('IGFBP2', 'Gene', (42, 48))
139193	26317790	We show that IGFBP2 knockdown also led to decreased ERK activation in Flo-1 and OE19 EAC cells, suggesting that ERK may be a downstream target of IGFBP2 in this tissue type as well.	('ERK', 'Gene', '5594', (52, 55))	('EAC', 'Phenotype', 'HP:0011459', (85, 88))	('ERK', 'Gene', (52, 55))	('decreased', 'NegReg', (42, 51))	('IGFBP2', 'Gene', '3485', (146, 152))	('decreased ERK', 'Phenotype', 'HP:0000654', (42, 55))	('ERK', 'Gene', '5594', (112, 115))	('IGFBP2', 'Gene', (146, 152))	('activation', 'MPA', (56, 66))	('ERK', 'Gene', (112, 115))	('IGFBP2', 'Gene', '3485', (13, 19))	('knockdown', 'Var', (20, 29))	('IGFBP2', 'Gene', (13, 19))
139201	26317790	IGFBP2 modulation is a promising alternative to IGF-1R inhibition due to its multi-faceted nature as a modulator of the IGF pathway, integrin signaling, cell-matrix interactions and transcription.	('IGF pathway', 'Pathway', (120, 131))	('modulation', 'Var', (7, 17))	('integrin', 'MPA', (133, 141))	('modulator', 'Reg', (103, 112))	('IGFBP2', 'Gene', (0, 6))	('IGFBP2', 'Gene', '3485', (0, 6))	('IGF-1R', 'Gene', '3480', (48, 54))	('IGF-1R', 'Gene', (48, 54))	('cell-matrix', 'CPA', (153, 164))
139207	26317790	Further in vitro analyses of its role in EAC progression and chemoresistance showed that modulation of IGFBP2 expression affected proliferation, motility, and chemosensitization of EAC cells in a serum-dependent manner.	('IGFBP2', 'Gene', (103, 109))	('IGFBP2', 'Gene', '3485', (103, 109))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('motility', 'CPA', (145, 153))	('EAC', 'Phenotype', 'HP:0011459', (181, 184))	('affected', 'Reg', (121, 129))	('proliferation', 'CPA', (130, 143))	('chemosensitization', 'CPA', (159, 177))	('modulation', 'Var', (89, 99))
139208	26317790	Silencing of IGFBP2 affected both AKT and ERK activity and addition of targeted pharmacologic inhibitors of these pathways enhanced siIGFBP2-induced CDDP chemosensitization.	('ERK', 'Gene', (42, 45))	('enhanced', 'PosReg', (123, 131))	('AKT', 'Gene', (34, 37))	('CDDP', 'Chemical', '-', (149, 153))	('CDDP chemosensitization', 'CPA', (149, 172))	('activity', 'MPA', (46, 54))	('IGFBP2', 'Gene', '3485', (134, 140))	('IGFBP2', 'Gene', '3485', (13, 19))	('AKT', 'Gene', '207', (34, 37))	('ERK', 'Gene', '5594', (42, 45))	('IGFBP2', 'Gene', (134, 140))	('Silencing', 'Var', (0, 9))	('IGFBP2', 'Gene', (13, 19))
139209	26317790	Modulation of IGFBP2 in overexpressing EACs may be an effective approach to sensitizing resistant tumors to standard of care chemotherapy.	('Modulation', 'Var', (0, 10))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('IGFBP2', 'Gene', (14, 20))	('EAC', 'Phenotype', 'HP:0011459', (39, 42))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IGFBP2', 'Gene', '3485', (14, 20))
139225	26317790	ON-TARGETplus Human IGFBP2 (Cat#: L-010-896-00-0005) and Non-targeting Control (Cat#s: D-001810-01 and D-001210-05) siRNAs were purchased from Dharmacon, Inc (Lafayette CO).	('Human', 'Species', '9606', (14, 19))	('IGFBP2', 'Gene', (20, 26))	('D-001210-05', 'Var', (103, 114))	('IGFBP2', 'Gene', '3485', (20, 26))
139269	25366905	We and others have used this approach to characterize aberrant kinase signaling in various cancers and demonstrated its utility in identifying potential therapeutic targets 16, 17, 18.	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('kinase signaling', 'MPA', (63, 79))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('aberrant', 'Var', (54, 62))
139276	25366905	For preparation of super-SILAC mix, two ESCC cell lines (TE2, TE8) were cultured in DMEM high-glucose media containing 13C6 arginine and 13C6 lysine supplemented with 10% FBS.	('high-glucose', 'Phenotype', 'HP:0003074', (89, 101))	('FBS', 'Gene', (171, 174))	('TE2', 'Gene', '8260', (57, 60))	('13C6 arginine', 'Var', (119, 132))	('FBS', 'Gene', '26269', (171, 174))	('13C6 lysine', 'Chemical', '-', (137, 148))	('TE2', 'Gene', (57, 60))	('13C6 lysine', 'Var', (137, 148))	('13C6 arginine', 'Chemical', '-', (119, 132))	('DMEM high-glucose', 'Chemical', '-', (84, 101))
139288	25366905	The search parameters included carbamidomethylation of cysteine residues as fixed modification, oxidation of methionine, phosphorylation on tyrosine, serine and threonine and heavy lysine (13C6) and arginine (13C6) as variable modifications.	('cysteine', 'Chemical', 'MESH:D003545', (55, 63))	('tyrosine', 'Chemical', 'MESH:D014443', (140, 148))	('13C6', 'Chemical', '-', (209, 213))	('methionine', 'Chemical', 'MESH:D008715', (109, 119))	('carbamidomethylation', 'MPA', (31, 51))	('oxidation of methionine', 'MPA', (96, 119))	('13C6', 'Chemical', '-', (189, 193))	('arginine', 'Chemical', 'MESH:D001120', (199, 207))	('13C6', 'Var', (209, 213))	('13C6', 'Var', (189, 193))	('phosphorylation on tyrosine', 'MPA', (121, 148))	('threonine', 'Chemical', 'MESH:D013912', (161, 170))	('lysine', 'Chemical', 'MESH:D008239', (181, 187))	('serine', 'Chemical', 'MESH:D012694', (150, 156))
139316	25366905	We and others have demonstrated the utility of phosphoproteomics approaches in identifying aberrantly activated kinase signaling pathways in various malignancies.	('aberrantly', 'Var', (91, 101))	('malignancies', 'Disease', (149, 161))	('malignancies', 'Disease', 'MESH:D009369', (149, 161))
139321	25366905	In prostate cancers, progressively higher levels of EPHA2 was observed in high-grade prostatic intraepithelial neoplasia and prostatic carcinoma cells suggesting increased expression of EPHA2 is associated with a more aggressive phenotype 49.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('prostate cancers', 'Phenotype', 'HP:0012125', (3, 19))	('prostate cancers', 'Disease', (3, 19))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (85, 120))	('increased', 'PosReg', (162, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('prostatic carcinoma', 'Disease', 'MESH:D011472', (125, 144))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (95, 120))	('prostatic carcinoma', 'Phenotype', 'HP:0012125', (125, 144))	('prostatic intraepithelial neoplasia', 'Disease', (85, 120))	('EPHA2', 'Var', (186, 191))	('associated', 'Reg', (195, 205))	('neoplasia', 'Phenotype', 'HP:0002664', (111, 120))	('higher', 'PosReg', (35, 41))	('prostate cancers', 'Disease', 'MESH:D011471', (3, 19))	('levels', 'MPA', (42, 48))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('prostatic carcinoma', 'Disease', (125, 144))	('expression', 'MPA', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
139375	23021251	From a histopathologic perspective, Fanburg Smith and colleagues proposed the following six criteria to determine whether a tumor is malignant or not: (1) the presence of necrosis, (2) the emergence of spindle cells, (3) a vacuolar nucleus with an enlarged nuclear body, (4) increase in nuclear division (2 mitoses/10HPF), (5) increase in the nucleoplasmic ratio, and (6) polymorphism.	('necrosis', 'Disease', 'MESH:D009336', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('increase', 'PosReg', (327, 335))	('polymorphism', 'Var', (372, 384))	('tumor', 'Disease', (124, 129))	('nucleoplasmic ratio', 'MPA', (343, 362))	('necrosis', 'Disease', (171, 179))	('increase', 'PosReg', (275, 283))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
139399	23021251	On MMG, the tumor is seen as a substantial round-shaped lesion with distinct edges of the hyperplasia invading into the surrounding tissues, and irregularity, speculation, isodensity sometimes associated with hypodense rims, and heterogenicity are commonly observed (Figure 1).	('isodensity', 'Var', (172, 182))	('hyperplasia', 'Disease', (90, 101))	('hypodense rims', 'Disease', (209, 223))	('hyperplasia', 'Disease', 'MESH:D006965', (90, 101))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('hypodense rims', 'Disease', 'MESH:C536816', (209, 223))	('tumor', 'Disease', (12, 17))	('associated', 'Reg', (193, 203))
139420	22563286	However, the incidence of bleeding is highest with IGV type 1 followed by GOV type 2.	('bleeding', 'Disease', (26, 34))	('IGV type 1', 'Var', (51, 61))	('bleeding', 'Disease', 'MESH:D006470', (26, 34))
139422	22563286	Thus, small increments in portal pressure can lead to an exponential increase in the wall stress (sigma), precipitating rupture.	('rupture', 'Disease', 'MESH:D012421', (120, 127))	('increments', 'Var', (12, 22))	('increase', 'PosReg', (69, 77))	('precipitating', 'Reg', (106, 119))	('rupture', 'Disease', (120, 127))
139451	22563286	Cyanoacrylate injection may cause some serious complications, including embolization into the renal vein, IVC, pulmonary or systemic vessels, fever, paravariceal injection with mucosal necrosis and bleeding, intraperitoneal injection inducing severe pain, needle sticking in the varix, and adherence of the glue to the endoscope.	('mucosal necrosis', 'Disease', (177, 193))	('embolization', 'CPA', (72, 84))	('fever', 'Phenotype', 'HP:0001945', (142, 147))	('inducing', 'Reg', (234, 242))	('bleeding', 'Disease', 'MESH:D006470', (198, 206))	('Cyanoacrylate', 'Var', (0, 13))	('bleeding', 'Disease', (198, 206))	('adherence', 'CPA', (290, 299))	('paravariceal', 'Disease', (149, 161))	('needle sticking', 'CPA', (256, 271))	('mucosal necrosis', 'Disease', 'MESH:D052016', (177, 193))	('cause', 'Reg', (28, 33))	('pain', 'Phenotype', 'HP:0012531', (250, 254))	('pain', 'Disease', 'MESH:D010146', (250, 254))	('pain', 'Disease', (250, 254))	('fever', 'Disease', 'MESH:D005334', (142, 147))	('Cyanoacrylate', 'Chemical', 'MESH:D003487', (0, 13))	('fever', 'Disease', (142, 147))
139475	30271164	Previous molecular pathology studies have revealed that VEGF overexpression could be detected in about 44.43% of esophageal cancer and the estimated mortality risk was 1.82-fold greater in patients with high VEGF expression, which indicated that antiangiogenic agents may have a therapeutic effect on esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('greater', 'PosReg', (178, 185))	('VEGF', 'Gene', (56, 60))	('overexpression', 'PosReg', (61, 75))	('VEGF', 'Gene', (208, 212))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('high', 'Var', (203, 207))	('VEGF', 'Gene', '7422', (56, 60))	('esophageal cancer', 'Disease', (113, 130))	('patients', 'Species', '9606', (189, 197))	('VEGF', 'Gene', '7422', (208, 212))	('esophageal cancer', 'Disease', (301, 318))	('esophageal cancer', 'Disease', 'MESH:D004938', (301, 318))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
139520	30271164	Furthermore, apatinib can markedly increase the intracellular accumulation of conventional chemotherapy agents in side population cells sorted from K562 cells, and cisplatin-resistant non-small-cell lung carcinoma A549 cell could be resensitized through suppressing extracellular signal-regulated kinase signaling pathway.	('increase', 'PosReg', (35, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (188, 213))	('apatinib', 'Var', (13, 21))	('suppressing', 'NegReg', (254, 265))	('K562', 'CellLine', 'CVCL:0004', (148, 152))	('apatinib', 'Chemical', 'MESH:C553458', (13, 21))	('lung carcinoma A549', 'Disease', 'MESH:D008175', (199, 218))	('lung carcinoma A549', 'Disease', (199, 218))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (184, 213))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
139533	29620226	In addition we found that knockdown of NONO could reduce protein levels of phosphorylated Akt and Erk1/2.	('Akt', 'Gene', (90, 93))	('reduce', 'NegReg', (50, 56))	('Erk1/2', 'Gene', (98, 104))	('NONO', 'Gene', (39, 43))	('protein levels', 'MPA', (57, 71))	('NONO', 'Gene', '4841', (39, 43))	('knockdown', 'Var', (26, 35))	('Akt', 'Gene', '207', (90, 93))	('Erk1/2', 'Gene', '5595;5594', (98, 104))
139548	29620226	Chromosomal translocation of NONO and TFE3 genes are frequently detected in papillary rental cell carcinoma.	('TFE3', 'Gene', '7030', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('papillary rental cell carcinoma', 'Disease', (76, 107))	('NONO', 'Gene', (29, 33))	('Chromosomal translocation', 'Var', (0, 25))	('NONO', 'Gene', '4841', (29, 33))	('detected', 'Reg', (64, 72))	('TFE3', 'Gene', (38, 42))	('papillary rental cell carcinoma', 'Disease', 'MESH:C538614', (76, 107))
139560	29620226	Human ESCC cell lines (TE-1, TE-2, TE-10, KYSE30, KYSE70, KYSE140, KYSE450, EC109, EC9706) were generously provided by Cancer Institute and Hospital, Chinese Academy of Medical Sciences and cell authentication were reported.	('Human', 'Species', '9606', (0, 5))	('KYSE140', 'Var', (58, 65))	('KYSE70', 'Var', (50, 56))	('Cancer', 'Disease', (119, 125))	('TE-2', 'Gene', '8260', (29, 33))	('KYSE30', 'Var', (42, 48))	('Cancer', 'Disease', 'MESH:D009369', (119, 125))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('TE-10', 'CellLine', 'CVCL:1760', (35, 40))	('EC9706', 'CellLine', 'CVCL:E307', (83, 89))	('TE-2', 'Gene', (29, 33))	('KYSE450', 'Var', (67, 74))
139573	29620226	Antibodies against Akt, phosphorylated Akt (p-Akt) (Ser473), Erk, p-Erk1/2 (Thr202/Tyr204), caspase-3 and cleaved PARP-1 were purchased from Cell Signaling Technology (Beverly, MA, USA).	('Ser473', 'Chemical', '-', (52, 58))	('Erk', 'Gene', '5594', (61, 64))	('Erk', 'Gene', '5594', (68, 71))	('Akt', 'Gene', (46, 49))	('Akt', 'Gene', (39, 42))	('Erk1/2', 'Gene', '5595;5594', (68, 74))	('Akt', 'Gene', '207', (46, 49))	('Akt', 'Gene', '207', (39, 42))	('Thr202', 'Chemical', '-', (76, 82))	('PARP-1', 'Gene', '142', (114, 120))	('caspase-3', 'Gene', '836', (92, 101))	('caspase-3', 'Gene', (92, 101))	('Tyr204', 'Chemical', '-', (83, 89))	('Akt', 'Gene', (19, 22))	('Akt', 'Gene', '207', (19, 22))	('Erk1/2', 'Gene', (68, 74))	('PARP-1', 'Gene', (114, 120))	('Erk', 'Gene', (61, 64))	('Ser473', 'Var', (52, 58))	('Erk', 'Gene', (68, 71))
139599	29620226	However, NONO mRNA levels varies among these cell lines with relatively higher levels in KYSE30 and KYSE70 cell lines and lower levels in TE-1, TE-2 and TE-10 cell lines.	('lower', 'NegReg', (122, 127))	('TE-2', 'Gene', (144, 148))	('TE-10', 'CellLine', 'CVCL:1760', (153, 158))	('NONO', 'Gene', (9, 13))	('NONO', 'Gene', '4841', (9, 13))	('higher', 'PosReg', (72, 78))	('TE-2', 'Gene', '8260', (144, 148))	('KYSE70', 'Var', (100, 106))
139604	29620226	3A and B, NONO knockdown by specific siRNA significantly inhibited growth of TE-1 and KYSE70 cells.	('inhibited', 'NegReg', (57, 66))	('NONO', 'Gene', (10, 14))	('NONO', 'Gene', '4841', (10, 14))	('knockdown', 'Var', (15, 24))
139613	29620226	As in vitro assays showed that NONO is overexpressed in ESCC tissues and cells, and that knockdown NONO inhibits proliferation, induces apoptosis and reduces mobility of TE-1 and KYSE70 cells, we then explored the molecular mechanism underlying the effects.	('NONO', 'Gene', (31, 35))	('NONO', 'Gene', '4841', (31, 35))	('inhibits', 'NegReg', (104, 112))	('mobility', 'CPA', (158, 166))	('apoptosis', 'CPA', (136, 145))	('NONO', 'Gene', '4841', (99, 103))	('knockdown', 'Var', (89, 98))	('induces', 'Reg', (128, 135))	('NONO', 'Gene', (99, 103))	('reduces', 'NegReg', (150, 157))	('proliferation', 'CPA', (113, 126))
139615	29620226	Since Erk1/2 and AKT are activated through phosphorylation, we detected the expression of the Thr202/Tyr204 phosphorylated form of Erk1/2 and Ser473 phosphorylated form of AKT by western blotting.	('Ser473', 'Var', (142, 148))	('AKT', 'Gene', (17, 20))	('Erk1/2', 'Gene', '5595;5594', (6, 12))	('AKT', 'Gene', (172, 175))	('Thr202/Tyr204', 'Var', (94, 107))	('Ser473', 'Chemical', '-', (142, 148))	('Erk1/2', 'Gene', '5595;5594', (131, 137))	('Thr202', 'Chemical', '-', (94, 100))	('Erk1/2', 'Gene', (6, 12))	('AKT', 'Gene', '207', (172, 175))	('AKT', 'Gene', '207', (17, 20))	('Erk1/2', 'Gene', (131, 137))	('Tyr204', 'Chemical', '-', (101, 107))
139617	29620226	We found that the expression levels of phosphorylated Erk1/2 and AKT were dramatically decreased in both TE-1 and KYSE70 NONO-knockdown cells (Fig.	('KYSE70', 'Var', (114, 120))	('Erk1/2', 'Gene', (54, 60))	('NONO', 'Gene', (121, 125))	('expression levels', 'MPA', (18, 35))	('decreased', 'NegReg', (87, 96))	('AKT', 'Gene', (65, 68))	('NONO', 'Gene', '4841', (121, 125))	('AKT', 'Gene', '207', (65, 68))	('Erk1/2', 'Gene', '5595;5594', (54, 60))
139633	29620226	We showed that knockdown of NONO could inhibit caspase-3 and PARP-1 cleavage, which was according to its role of apoptosis inhibitor.	('cleavage', 'MPA', (68, 76))	('NONO', 'Gene', (28, 32))	('knockdown', 'Var', (15, 24))	('inhibit', 'NegReg', (39, 46))	('caspase-3', 'Gene', (47, 56))	('PARP-1', 'Gene', (61, 67))	('PARP-1', 'Gene', '142', (61, 67))	('caspase-3', 'Gene', '836', (47, 56))	('NONO', 'Gene', '4841', (28, 32))
139635	29620226	The effects of PI3K on tumor growth and progression are thought to be mediated mainly by Akt.	('progression', 'CPA', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('Akt', 'Gene', '207', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Akt', 'Gene', (89, 92))	('PI3K', 'Var', (15, 19))
139640	29620226	This study is the first to report that NONO silencing downregulated the expression level of p-Akt and p-Erk1/2 protein without affecting the total Akt and Erk1/2 expression level in ESCC cell lines, which suggested that NONO might play an important role in growth, apoptosis and metastasis of ESCC by activating both the PI3K/Akt and MAPK/Erk signaling pathways.	('Erk1/2', 'Gene', '5595;5594', (155, 161))	('Akt', 'Gene', (94, 97))	('Akt', 'Gene', '207', (326, 329))	('NONO', 'Gene', '4841', (39, 43))	('Erk1/2', 'Gene', (104, 110))	('Akt', 'Gene', '207', (94, 97))	('NONO', 'Gene', '4841', (220, 224))	('activating', 'PosReg', (301, 311))	('Erk', 'Gene', (104, 107))	('expression level', 'MPA', (72, 88))	('Erk', 'Gene', '5594', (104, 107))	('Akt', 'Gene', (147, 150))	('downregulated', 'NegReg', (54, 67))	('Erk1/2', 'Gene', '5595;5594', (104, 110))	('NONO', 'Gene', (39, 43))	('Akt', 'Gene', '207', (147, 150))	('Erk', 'Gene', (339, 342))	('Erk1/2', 'Gene', (155, 161))	('silencing', 'Var', (44, 53))	('ESCC', 'Disease', (293, 297))	('NONO', 'Gene', (220, 224))	('Erk', 'Gene', '5594', (339, 342))	('Erk', 'Gene', (155, 158))	('Erk', 'Gene', '5594', (155, 158))	('Akt', 'Gene', (326, 329))
139643	29620226	Taken together, our results demonstrated that knockdown of NONO could inhibit proliferation and invasion, and promote apoptosis through the PI3K/Akt and MAPK/Erk signaling pathways in ESCC cancer cells.	('apoptosis', 'CPA', (118, 127))	('Akt', 'Gene', (145, 148))	('NONO', 'Gene', '4841', (59, 63))	('knockdown', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('invasion', 'CPA', (96, 104))	('proliferation', 'CPA', (78, 91))	('promote', 'PosReg', (110, 117))	('Erk', 'Gene', '5594', (158, 161))	('Akt', 'Gene', '207', (145, 148))	('inhibit', 'NegReg', (70, 77))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('Erk', 'Gene', (158, 161))	('NONO', 'Gene', (59, 63))	('cancer', 'Disease', (189, 195))
139652	28832500	Importantly, inhibition of the NF-kappaB signaling pathway or knockdown of NF-kappaB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells.	('miR-145', 'Gene', (118, 125))	('p65', 'Gene', '5970', (86, 89))	('miR-145', 'Gene', '406937', (118, 125))	('NF-kappaB', 'Gene', (75, 84))	('ESCC', 'Disease', (167, 171))	('NF-kappaB', 'Gene', '4790', (31, 40))	('invasion', 'CPA', (147, 155))	('NF-kappaB', 'Gene', '4790', (75, 84))	('EMT', 'CPA', (160, 163))	('p65', 'Gene', (86, 89))	('inhibition', 'NegReg', (13, 23))	('migration', 'CPA', (136, 145))	('NF-kappaB', 'Gene', (31, 40))	('knockdown', 'Var', (62, 71))
139659	28832500	In ESCC, down-regulation of miR-145 was commonly epigenetically regulated by promoter hypermethylation.	('miR-145', 'Gene', '406937', (28, 35))	('promoter hypermethylation', 'Var', (77, 102))	('miR-145', 'Gene', (28, 35))	('down-regulation', 'NegReg', (9, 24))
139663	28832500	Importantly, knockdown of Sp1 or NF-kappaB (p65) and inhibition of the NF-kappaB signaling pathway using CAPE phenocopied the effects of miR-145-5p overexpression on the respective tumor cell phenotypes.	('NF-kappaB', 'Gene', (33, 42))	('tumor', 'Disease', (181, 186))	('inhibition', 'NegReg', (53, 63))	('p65', 'Gene', (44, 47))	('NF-kappaB', 'Gene', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('miR-145', 'Gene', (137, 144))	('p65', 'Gene', '5970', (44, 47))	('CAPE', 'Chemical', 'MESH:C055494', (105, 109))	('miR-145', 'Gene', '406937', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('Sp1', 'Gene', (26, 29))	('NF-kappaB', 'Gene', '4790', (33, 42))	('knockdown', 'Var', (13, 22))	('NF-kappaB', 'Gene', '4790', (71, 80))
139665	28832500	To study the tumorigenic roles of miR-145-5p in ESCC, we first evaluated the expression levels in four ESCC cell lines including KYSE30, KYSE180, KYSE150 and KYSE510 by real-time polymerase chain reaction (RT-PCR).	('tumor', 'Disease', (13, 18))	('KYSE150', 'Var', (146, 153))	('KYSE510', 'Var', (158, 165))	('KYSE30', 'Var', (129, 135))	('KYSE180', 'Var', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('KYSE510', 'CellLine', 'CVCL:1354', (158, 165))	('miR-145', 'Gene', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('miR-145', 'Gene', '406937', (34, 41))
139666	28832500	KYSE150 and KYSE510 exhibited lower expression levels than other two cell lines (Figure 1E).	('lower', 'NegReg', (30, 35))	('KYSE510', 'CellLine', 'CVCL:1354', (12, 19))	('KYSE510', 'Var', (12, 19))	('KYSE150', 'Var', (0, 7))	('expression levels', 'MPA', (36, 53))
139670	28832500	The results showed that miR-145-5p decreased the mRNA levels of cell cycle regulatory genes (CCNA2, CCND1 and CCNE1) in KYSE150 and KYSE510 (Figure 2D).	('CCND1', 'Gene', (100, 105))	('mRNA levels', 'MPA', (49, 60))	('KYSE510', 'CellLine', 'CVCL:1354', (132, 139))	('CCNA2', 'Gene', (93, 98))	('CCND1', 'Gene', '595', (100, 105))	('decreased', 'NegReg', (35, 44))	('CCNA2', 'Gene', '890', (93, 98))	('KYSE150', 'Var', (120, 127))	('KYSE510', 'Var', (132, 139))	('CCNE1', 'Gene', '898', (110, 115))	('miR-145', 'Gene', (24, 31))	('CCNE1', 'Gene', (110, 115))	('miR-145', 'Gene', '406937', (24, 31))
139687	28832500	Silencing of Sp1 also significantly inhibited the EMT, and down-regulated the expressions of Slug, MMP2, MMP7 and MMP13 (Figure 4G-I).	('MMP13', 'Gene', (114, 119))	('MMP2', 'Gene', (99, 103))	('expressions', 'MPA', (78, 89))	('inhibited', 'NegReg', (36, 45))	('MMP7', 'Gene', '4316', (105, 109))	('MMP13', 'Gene', '4322', (114, 119))	('Slug', 'Gene', '6591', (93, 97))	('MMP2', 'Gene', '4313', (99, 103))	('down-regulated', 'NegReg', (59, 73))	('EMT', 'CPA', (50, 53))	('Slug', 'Gene', (93, 97))	('Silencing', 'Var', (0, 9))	('MMP7', 'Gene', (105, 109))	('Sp1', 'Gene', (13, 16))
139693	28832500	Silencing of NF-kappaB (p65) also significantly reduced the mRNA levels of MMP2, MMP7 and MMP13 (Figure 6E).	('MMP2', 'Gene', (75, 79))	('MMP7', 'Gene', (81, 85))	('MMP13', 'Gene', '4322', (90, 95))	('NF-kappaB', 'Gene', '4790', (13, 22))	('reduced', 'NegReg', (48, 55))	('MMP2', 'Gene', '4313', (75, 79))	('MMP7', 'Gene', '4316', (81, 85))	('NF-kappaB', 'Gene', (13, 22))	('p65', 'Gene', (24, 27))	('Silencing', 'Var', (0, 9))	('p65', 'Gene', '5970', (24, 27))	('MMP13', 'Gene', (90, 95))
139694	28832500	All of the above suggested that inhibition of the NF-kappaB signaling pathway or knockdown of NF-kappaB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells.	('invasion', 'CPA', (166, 174))	('migration', 'CPA', (155, 164))	('ESCC', 'Disease', (186, 190))	('p65', 'Gene', (105, 108))	('inhibition', 'NegReg', (32, 42))	('p65', 'Gene', '5970', (105, 108))	('knockdown', 'Var', (81, 90))	('miR-145', 'Gene', (137, 144))	('NF-kappaB', 'Gene', '4790', (94, 103))	('miR-145', 'Gene', '406937', (137, 144))	('EMT of', 'CPA', (179, 185))	('NF-kappaB', 'Gene', '4790', (50, 59))	('NF-kappaB', 'Gene', (94, 103))	('NF-kappaB', 'Gene', (50, 59))
139713	28832500	Inhibition of NF-kappaB signaling pathway or knockdown of NF-kappaB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells.	('miR-145', 'Gene', (101, 108))	('Inhibition', 'NegReg', (0, 10))	('migration', 'CPA', (119, 128))	('miR-145', 'Gene', '406937', (101, 108))	('NF-kappaB', 'Gene', '4790', (58, 67))	('invasion', 'CPA', (130, 138))	('NF-kappaB', 'Gene', '4790', (14, 23))	('ESCC', 'Disease', (150, 154))	('NF-kappaB', 'Gene', (14, 23))	('p65', 'Gene', (69, 72))	('NF-kappaB', 'Gene', (58, 67))	('EMT', 'CPA', (143, 146))	('knockdown', 'Var', (45, 54))	('p65', 'Gene', '5970', (69, 72))
139719	28832500	Low expression of miR-145 is associated with poor prognosis in NSCLC, and silencing lincRNA ROR posttranscriptionally regulates the expression of p53, while silencing ROR or p53 could upregulate miR-145 levels.	('NSCLC', 'Disease', (63, 68))	('miR-145', 'Gene', (18, 25))	('ROR', 'Gene', '100885779', (167, 170))	('lincRNA ROR', 'Gene', (84, 95))	('p53', 'Gene', (146, 149))	('expression', 'MPA', (4, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('silencing', 'Var', (157, 166))	('Low', 'NegReg', (0, 3))	('p53', 'Gene', '7157', (174, 177))	('ROR', 'Gene', (92, 95))	('p53', 'Gene', (174, 177))	('miR-145', 'Gene', '406937', (195, 202))	('ROR', 'Gene', '100885779', (92, 95))	('silencing', 'Var', (74, 83))	('miR-145', 'Gene', (195, 202))	('upregulate', 'PosReg', (184, 194))	('miR-145', 'Gene', '406937', (18, 25))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('p53', 'Gene', '7157', (146, 149))	('lincRNA ROR', 'Gene', '100885779', (84, 95))	('ROR', 'Gene', (167, 170))	('expression', 'MPA', (132, 142))	('regulates', 'Reg', (118, 127))
139733	28832500	The human esophageal squamous cell carcinoma (ESCC) cell lines, including KYSE30, KYSE150, KYSE180 and KYSE510, were provided by Yutaka.	('KYSE510', 'CellLine', 'CVCL:1354', (103, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (10, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('human', 'Species', '9606', (4, 9))	('KYSE180', 'Var', (91, 98))	('esophageal squamous cell carcinoma', 'Disease', (10, 44))	('KYSE150', 'Var', (82, 89))	('KYSE510', 'Var', (103, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))
139758	27785326	However, aberrant melanocyte migration during embryogenesis or reflux esophagitis chronic inflammatory reasons differentiation of stem cells in the basal layer of melanocytes occur are thought to result.	('esophagitis', 'Phenotype', 'HP:0100633', (70, 81))	('aberrant', 'Var', (9, 17))	('reflux esophagitis', 'Disease', 'MESH:D005764', (63, 81))	('aberrant melanocyte', 'Phenotype', 'HP:0002861', (9, 28))	('reflux esophagitis', 'Disease', (63, 81))
139819	27785326	Gastric acid, bile and trypsin reflux depending on the NF-kB, AP-1, IL-8, etc.	('IL-8', 'Gene', '3576', (68, 72))	('IL-8', 'Gene', (68, 72))	('AP-1', 'Gene', '3726', (62, 66))	('AP-1', 'Gene', (62, 66))	('NF-kB', 'Var', (55, 60))	('Gastric acid', 'MPA', (0, 12))
139830	27785326	In several studies, particularly Cag A (+) HP infection esophageal epithelial cells, to cause DNA strand breaks, has been reported to contribute to the formation of esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (176, 199))	('DNA strand breaks', 'MPA', (94, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('esophageal epithelial', 'Disease', 'MESH:D002277', (56, 77))	('HP infection esophageal', 'Disease', 'MESH:C537262', (43, 66))	('esophageal squamous cell carcinoma', 'Disease', (165, 199))	('contribute', 'Reg', (134, 144))	('Cag', 'Var', (33, 36))	('esophageal epithelial', 'Disease', (56, 77))	('HP infection esophageal', 'Disease', (43, 66))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (165, 199))
139933	27148877	Hypoperfusion also might induce occult remnant cancer, if any, to turn to an aggressive tumor, leading to a low overall survival rate during the follow-up period.	('aggressive tumor', 'Disease', 'MESH:D001523', (77, 93))	('induce', 'Reg', (25, 31))	('aggressive tumor', 'Disease', (77, 93))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('Hypoperfusion', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('low', 'NegReg', (108, 111))	('occult', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('overall survival', 'MPA', (112, 128))
139946	27148877	Dihydropyridine, a type of CCB that exclusively acts on the vasculature, results in vasodilation.	('Dihydropyridine', 'Var', (0, 15))	('vasodilation', 'MPA', (84, 96))	('Dihydropyridine', 'Chemical', 'MESH:C038806', (0, 15))
139948	27148877	Patients who receive preoperative dihydropyridine-type CCBs might be at a greater risk of developing hypotensive events.	('hypotensive', 'Disease', 'MESH:D007022', (101, 112))	('dihydropyridine-type', 'Var', (34, 54))	('hypotensive events', 'Phenotype', 'HP:0002615', (101, 119))	('hypotensive', 'Disease', (101, 112))	('dihydropyridine-type', 'Chemical', '-', (34, 54))	('Patients', 'Species', '9606', (0, 8))
139952	27148877	Blockage of the renin-angiotensin system using ACEIs or ARBs has beneficial effects on the atrial remodeling in animal and human models.	('Blockage', 'Var', (0, 8))	('renin', 'Gene', '5972', (16, 21))	('beneficial', 'PosReg', (65, 75))	('atrial remodeling', 'CPA', (91, 108))	('human', 'Species', '9606', (123, 128))	('renin', 'Gene', (16, 21))
139992	26600954	In FAP-associated fundic gland polyps, inactivating mutations in the APC tumor suppressor gene on chromosome 5q have been found.	('APC tumor', 'Disease', 'MESH:D011125', (69, 78))	('FAP', 'Disease', 'MESH:C567782', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('fundic gland polyps', 'Disease', 'MESH:D011127', (18, 37))	('APC tumor', 'Disease', (69, 78))	('inactivating mutations', 'Var', (39, 61))	('found', 'Reg', (122, 127))	('fundic gland polyps', 'Disease', (18, 37))	('FAP', 'Disease', (3, 6))
140009	26600954	Long-term administration of PPIs has been shown to cause parietal cell hyperplasia secondary to PPI-induced hypergastrinemia.	('hypergastrinemia', 'Disease', 'None', (108, 124))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (108, 124))	('PPI-induced', 'Var', (96, 107))	('parietal cell hyperplasia', 'Disease', 'MESH:D006965', (57, 82))	('cause', 'Reg', (51, 56))	('hypergastrinemia', 'Disease', (108, 124))	('parietal cell hyperplasia', 'Disease', (57, 82))	('PPIs', 'Gene', (28, 32))
140010	26600954	Protrusion of hyperplastic parietal cells into the glandular lumina of gastric fundic glands causes narrowing and obstruction of the glandular lumina and cystic dilatation of fundic glands, characteristic of fundic gland polyps.	('obstruction of the glandular lumina', 'Disease', 'MESH:D002277', (114, 149))	('fundic gland polyps', 'Disease', (208, 227))	('dilatation', 'Phenotype', 'HP:0002617', (161, 171))	('gastric fundic', 'Disease', 'MESH:C566775', (71, 85))	('obstruction of the glandular lumina', 'Disease', (114, 149))	('Protrusion', 'Var', (0, 10))	('fundic gland polyps', 'Disease', 'MESH:D011127', (208, 227))	('gastric fundic', 'Disease', (71, 85))	('cystic dilatation', 'CPA', (154, 171))
140013	26600954	The rate of fundic gland polyps was the same in the two groups, 5.2% in PPI group and 5.0% in control group.	('fundic gland polyps', 'Disease', 'MESH:D011127', (12, 31))	('PPI group', 'Var', (72, 81))	('fundic gland polyps', 'Disease', (12, 31))
140033	26600954	In this patient, implantation of MSA allowed for cessation of her PPI therapy.	('implantation', 'Var', (17, 29))	('cessation', 'NegReg', (49, 58))	('patient', 'Species', '9606', (8, 15))
140138	23509872	Several studies in fact demonstrated that the risks of respiratory complication, wound dehiscence, chylous leakage, and infection are higher after trans-thoracic esophagectomy  than trans-hiatal approach.	('infection', 'Disease', 'MESH:D007239', (120, 129))	('respiratory complication', 'Phenotype', 'HP:0011947', (55, 79))	('wound dehiscence', 'CPA', (81, 97))	('trans-thoracic', 'Var', (147, 161))	('wound dehiscence', 'Phenotype', 'HP:0032156', (81, 97))	('chylous', 'Disease', (99, 106))	('respiratory complication', 'CPA', (55, 79))	('infection', 'Disease', (120, 129))
140160	22750256	Disruption of regulatory networks inevitably leads to defective separation and malformation of the trachea and esophagus and results in the formation of a relatively common birth defect, esophageal atresia with or without tracheoesophageal fistula (EA/TEF).	('malformation of the trachea', 'Disease', (79, 106))	('defective', 'NegReg', (54, 63))	('esophageal atresia', 'Phenotype', 'HP:0002032', (187, 205))	('leads to', 'Reg', (45, 53))	('Disruption', 'Var', (0, 10))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (222, 247))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (222, 247))	('malformation of the trachea', 'Disease', 'MESH:D000014', (79, 106))	('malformation of the trachea', 'Phenotype', 'HP:0002778', (79, 106))	('tracheoesophageal fistula', 'Disease', (222, 247))	('separation', 'CPA', (64, 74))	('birth defect', 'Disease', (173, 185))	('birth defect', 'Disease', 'MESH:D000014', (173, 185))	('results in', 'Reg', (125, 135))	('esophageal atresia', 'Disease', 'MESH:D004933', (187, 205))	('esophageal atresia', 'Disease', (187, 205))
140163	22750256	Abnormalities in these regulatory networks lead to defective separation processes resulting in birth defects such as esophageal atresia with or without tracheoesophageal fistula (EA/TEF), a condition commonly seen in clinics.	('birth defects', 'Disease', 'MESH:D000014', (95, 108))	('separation processes', 'CPA', (61, 81))	('birth defects', 'Disease', (95, 108))	('Abnormalities', 'Var', (0, 13))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (152, 177))	('esophageal atresia', 'Phenotype', 'HP:0002032', (117, 135))	('esophageal atresia', 'Disease', 'MESH:D004933', (117, 135))	('tracheoesophageal fistula', 'Disease', (152, 177))	('esophageal atresia', 'Disease', (117, 135))	('defective', 'NegReg', (51, 60))	('resulting in', 'Reg', (82, 94))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (152, 177))
140164	22750256	We have previously summarized the mutations in genes encoding components of multiple signaling pathways that lead to the formation of EA/TEF in both human patients and mouse models.	('lead to', 'Reg', (109, 116))	('mouse', 'Species', '10090', (168, 173))	('EA/TEF', 'Disease', (134, 140))	('human', 'Species', '9606', (149, 154))	('patients', 'Species', '9606', (155, 163))	('mutations', 'Var', (34, 43))
140167	22750256	By contrast, deletion of Nkx2.1 also results in defects in foregut separation and the formation of EA/TEF with high Sox2 expression in the epithelium of the TEF.	('Nkx2.1', 'Gene', '21869', (25, 31))	('expression', 'MPA', (121, 131))	('deletion', 'Var', (13, 21))	('Nkx2.1', 'Gene', (25, 31))	('Sox2', 'Gene', (116, 120))	('high', 'PosReg', (111, 115))	('foregut separation', 'CPA', (59, 77))	('defects', 'NegReg', (48, 55))
140168	22750256	Conversely, the epithelial cells in the fistula of Sox2GFP/COND hypomorphic mutants express high levels of Nkx2.1 suggesting that in the absence of a sufficiently high level of Sox2, Nkx2.1 expression expands dorsally and reprograms the dorsal epithelium to a respiratory fate.	('expands', 'PosReg', (201, 208))	('epithelia', 'Disease', 'None', (16, 25))	('reprograms', 'CPA', (222, 232))	('Nkx2.1', 'Gene', '21869', (107, 113))	('epithelia', 'Disease', (16, 25))	('Nkx2.1', 'Gene', '21869', (183, 189))	('mutants', 'Var', (76, 83))	('Nkx2.1', 'Gene', (107, 113))	('fistula', 'Disease', 'MESH:D005402', (40, 47))	('fistula', 'Disease', (40, 47))	('Nkx2.1', 'Gene', (183, 189))	('Sox2GFP/COND', 'Gene', (51, 63))
140173	22750256	However, foregut separation proceeds normally in Fgf10 null mutants despite a lack of lung morphogenesis, suggesting that there are other signaling molecules involved in the regulation of Sox2/Nkx2.1 patterning in the early foregut.	('Nkx2.1', 'Gene', (193, 199))	('Fgf10', 'Gene', (49, 54))	('foregut separation', 'CPA', (9, 27))	('mutants', 'Var', (60, 67))	('Nkx2.1', 'Gene', '21869', (193, 199))	('lack of lung', 'Phenotype', 'HP:0005944', (78, 90))	('Fgf10', 'Gene', '14165', (49, 54))
140182	22750256	At E9.5, Wnt signaling is active in the ventral side of the unseparated foregut tube, where Wnt ligands Wnt2 and Wnt2b proteins are enriched (Figure 1A).	('Wnt2', 'Gene', (113, 117))	('E9.5', 'Var', (3, 7))	('Wnt2b', 'Gene', (113, 118))	('Wnt2', 'Gene', '22413', (104, 108))	('Wnt2b', 'Gene', '22414', (113, 118))	('Wnt2', 'Gene', (104, 108))	('Wnt2', 'Gene', '22413', (113, 117))
140184	22750256	In line with this notion, deletion of beta-catenin in the epithelium using Shh-Cre results in abnormal separation of the foregut tube and complete lung agenesis.	('beta-catenin', 'Gene', (38, 50))	('results in', 'Reg', (83, 93))	('lung agenesis', 'CPA', (147, 160))	('deletion', 'Var', (26, 34))	('beta-catenin', 'Gene', '12387', (38, 50))	('lung agenesis', 'Phenotype', 'HP:0005944', (147, 160))
140185	22750256	It has further been shown that at the cellular level, Wnt/beta-catenin abrogation reduces cell proliferation by diminishing Cyclin D1 protein levels.	('beta-catenin', 'Gene', (58, 70))	('Cyclin D1', 'Gene', (124, 133))	('cell proliferation', 'CPA', (90, 108))	('abrogation', 'Var', (71, 81))	('beta-catenin', 'Gene', '12387', (58, 70))	('Cyclin D1', 'Gene', '12443', (124, 133))	('diminishing', 'NegReg', (112, 123))	('reduces', 'NegReg', (82, 89))
140186	22750256	Moreover, dorsal-ventral patterning of Sox2/Nkx2.1 is disrupted in Shh-Cre;beta-cateninloxp/loxp mutants in which high levels of Sox2 protein are expressed in the ventral region at the expense of the Nkx2.1+ve domain.	('disrupted', 'NegReg', (54, 63))	('Sox2', 'Protein', (129, 133))	('Nkx2.1', 'Gene', (44, 50))	('beta-catenin', 'Gene', '12387', (75, 87))	('dorsal-ventral patterning', 'CPA', (10, 35))	('Shh-Cre', 'Gene', (67, 74))	('Nkx2.1', 'Gene', '21869', (200, 206))	('mutants', 'Var', (97, 104))	('beta-catenin', 'Gene', (75, 87))	('Nkx2.1', 'Gene', (200, 206))	('Nkx2.1', 'Gene', '21869', (44, 50))
140188	22750256	Consistent with the importance of mesenchymal Wnt expression in foregut separation, the combined deletion of Wnt2/2b results in similar phenotypic changes.	('Wnt2', 'Gene', (109, 113))	('Wnt2', 'Gene', '22413', (109, 113))	('deletion', 'Var', (97, 105))
140189	22750256	Notably, Wnt7b is expressed in the endoderm of the early foregut and its deletion results in irregular lung branching morphogenesis and vasculature development but does not disrupt foregut separation.	('irregular lung branching morphogenesis', 'CPA', (93, 131))	('vasculature development', 'CPA', (136, 159))	('Wnt7b', 'Gene', (9, 14))	('Wnt7b', 'Gene', '22422', (9, 14))	('results in', 'Reg', (82, 92))	('deletion', 'Var', (73, 81))
140192	22750256	Deletion of Barx1 leads to a dorsal shift of the domain of Wnt activity accompanied by dorsal expansion of Nkx2.1, resulting in separation defects.	('Nkx2.1', 'Gene', '21869', (107, 113))	('Barx1', 'Gene', (12, 17))	('leads to', 'Reg', (18, 26))	('Barx1', 'Gene', '12022', (12, 17))	('separation defects', 'CPA', (128, 146))	('Nkx2.1', 'Gene', (107, 113))	('resulting in', 'Reg', (115, 127))	('dorsal shift', 'MPA', (29, 41))	('Deletion', 'Var', (0, 8))
140193	22750256	However, single deletion of Wnt5a or Wnt11 has no reported foregut separation defects, possibly due to functional redundancy between these genes.	('single deletion', 'Var', (9, 24))	('Wnt5a', 'Gene', (28, 33))	('Wnt11', 'Gene', (37, 42))	('foregut separation defects', 'CPA', (59, 85))	('Wnt5a', 'Gene', '22418', (28, 33))	('Wnt11', 'Gene', '22411', (37, 42))
140194	22750256	It will be interesting to determine if a combined deletion of Wnt5a and Wnt11 induces defects in the separation process.	('separation process', 'CPA', (101, 119))	('Wnt5a', 'Gene', '22418', (62, 67))	('deletion', 'Var', (50, 58))	('Wnt11', 'Gene', (72, 77))	('Wnt11', 'Gene', '22411', (72, 77))	('Wnt5a', 'Gene', (62, 67))	('defects', 'NegReg', (86, 93))
140197	22750256	In vitro knockdown of Rhou disrupts the differentiation and morphogenesis of foregut derivatives in cultured embryos.	('Rhou', 'Gene', '69581', (22, 26))	('knockdown', 'Var', (9, 18))	('morphogenesis of foregut derivatives', 'CPA', (60, 96))	('Rhou', 'Gene', (22, 26))	('disrupts', 'NegReg', (27, 35))	('differentiation', 'CPA', (40, 55))
140200	22750256	The effect of Rhou deletion on the separation process in vivo remains to be determined.	('Rhou', 'Gene', '69581', (14, 18))	('deletion', 'Var', (19, 27))	('Rhou', 'Gene', (14, 18))
140202	22750256	Disruption of dorsal-ventral patterning by Noggin deletion leads to the formation of EA/TEF in ~70% of the mutants.	('Disruption', 'NegReg', (0, 10))	('deletion', 'Var', (50, 58))	('dorsal-ventral patterning', 'CPA', (14, 39))	('Noggin', 'Gene', '18121', (43, 49))	('Noggin', 'Gene', (43, 49))
140203	22750256	Similar to the developing skeleton and heart, Noggin deletion leads to increased Bmp signaling in the foregut.	('Bmp signaling in the foregut', 'MPA', (81, 109))	('deletion', 'Var', (53, 61))	('Noggin', 'Gene', '18121', (46, 52))	('Noggin', 'Gene', (46, 52))	('increased', 'PosReg', (71, 80))
140204	22750256	Removal of one copy of Bmp4 or Bmp7 in the Noggin null background rescues separation defects.	('Bmp4', 'Gene', '12159', (23, 27))	('Bmp7', 'Gene', '12162', (31, 35))	('Bmp4', 'Gene', (23, 27))	('Removal', 'Var', (0, 7))	('rescues', 'PosReg', (66, 73))	('Bmp7', 'Gene', (31, 35))	('Noggin', 'Gene', (43, 49))	('Noggin', 'Gene', '18121', (43, 49))	('separation', 'MPA', (74, 84))
140205	22750256	In addition, Noggin deletion also induces abnormal delamination of the notochord from the early definite endoderm epithelial sheet, resulting in epithelial cells of endodermal origin being present in the kinky notochord.	('epithelia', 'Disease', 'None', (114, 123))	('epithelia', 'Disease', (114, 123))	('epithelia', 'Disease', (145, 154))	('induces', 'Reg', (34, 41))	('deletion', 'Var', (20, 28))	('Noggin', 'Gene', (13, 19))	('Noggin', 'Gene', '18121', (13, 19))	('epithelia', 'Disease', 'None', (145, 154))	('delamination', 'CPA', (51, 63))
140206	22750256	Further support for the importance of dorsal-ventral Bmp signaling comes from findings from the tissue specific ablation of Bmp4.	('Bmp4', 'Gene', '12159', (124, 128))	('ablation', 'Var', (112, 120))	('Bmp4', 'Gene', (124, 128))
140207	22750256	Deletion of Bmp4 using Foxg1-Cre results in tracheal agenesis accompanied by reduced cellular proliferation in both the epithelial and mesenchymal compartments.	('cellular proliferation in', 'CPA', (85, 110))	('Foxg1', 'Gene', (23, 28))	('Bmp4', 'Gene', (12, 16))	('epithelia', 'Disease', 'None', (120, 129))	('epithelia', 'Disease', (120, 129))	('reduced', 'NegReg', (77, 84))	('Foxg1', 'Gene', '15228', (23, 28))	('tracheal agenesis', 'CPA', (44, 61))	('Bmp4', 'Gene', '12159', (12, 16))	('Deletion', 'Var', (0, 8))
140209	22750256	In line with these findings, deletion of Bmp receptors 1a and 1b in Shhcre/+; Bmpr1afl/-; Bmpr1b-/- compound mutants also leads to tracheal agenesis, reduction of Nkx2.1 and ventral expansion of Sox2, which is associated with the abrogation of Bmp signaling.	('Sox2', 'Gene', (195, 199))	('deletion', 'Var', (29, 37))	('ventral expansion', 'CPA', (174, 191))	('leads to', 'Reg', (122, 130))	('Nkx2.1', 'Gene', '21869', (163, 169))	('tracheal agenesis', 'CPA', (131, 148))	('Bmpr1b', 'Gene', (90, 96))	('reduction', 'NegReg', (150, 159))	('Nkx2.1', 'Gene', (163, 169))	('mutants', 'Var', (109, 116))	('Bmp receptors', 'Gene', (41, 54))	('Bmpr1b', 'Gene', '12167', (90, 96))
140210	22750256	A genetic complementation study showed that removal of the Sox2 gene in a Shhcre/+; Bmpr1afl/-; Bmpr1b-/- background rescues the separation defect, further emphasizing that a dorsal-ventral distribution of signaling and transcription factors is required for foregut separation.	('Sox2 gene', 'Gene', (59, 68))	('Bmpr1b', 'Gene', (96, 102))	('removal', 'Var', (44, 51))	('separation defect', 'MPA', (129, 146))	('Bmpr1b', 'Gene', '12167', (96, 102))
140213	22750256	Significantly, no foregut separation defects result from the deletion of Smad4 using Nkx2.5-Cre, which is active at ~ E9.5 in both the mesenchyme and epithelium in the ventral foregut [ and Que J unpublished observation].	('deletion', 'Var', (61, 69))	('foregut separation defects', 'CPA', (18, 44))	('Smad4', 'Gene', '17128', (73, 78))	('Smad4', 'Gene', (73, 78))
140214	22750256	This could be due to the fact that Smad4 mediates both Bmp and Tgfbeta signaling, suggesting that simultaneous loss of these two signals rescues foregut separation defects.	('Tgfbeta', 'Gene', (63, 70))	('Tgfbeta', 'Gene', '21803', (63, 70))	('loss', 'Var', (111, 115))	('Smad4', 'Gene', (35, 40))	('Smad4', 'Gene', '17128', (35, 40))	('rescues', 'NegReg', (137, 144))	('foregut separation defects', 'CPA', (145, 171))
140225	22750256	Reduced Sox2 protein levels in Sox2GFP/COND hypomorphic mutants blocks the formation of a stratified squamous epithelium, resulting in simple columnar epithelial cells that secrete a large amount of mucin.	('blocks', 'NegReg', (64, 70))	('secrete', 'MPA', (173, 180))	('mutants', 'Var', (56, 63))	('Reduced', 'NegReg', (0, 7))	('epithelia', 'Disease', 'None', (151, 160))	('epithelia', 'Disease', (151, 160))	('Sox2GFP/COND', 'Gene', (31, 43))	('Sox2', 'Protein', (8, 12))
140229	22750256	Moreover, recent studies have shown that SOX2 gene amplification and increased SOX2 protein levels are associated with esophageal squamous cancer.	('increased', 'PosReg', (69, 78))	('associated', 'Reg', (103, 113))	('squamous cancer', 'Phenotype', 'HP:0002860', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (119, 145))	('esophageal squamous cancer', 'Disease', (119, 145))	('SOX2 protein levels', 'MPA', (79, 98))	('gene amplification', 'Var', (46, 64))	('SOX2', 'Gene', (41, 45))
140233	22750256	Deletion of the p63 gene affects all stratified epithelia, including the skin and esophagus.	('p63', 'Gene', '22061', (16, 19))	('p63', 'Gene', (16, 19))	('epithelia', 'Disease', 'None', (48, 57))	('epithelia', 'Disease', (48, 57))	('affects', 'Reg', (25, 32))	('Deletion', 'Var', (0, 8))
140234	22750256	Interestingly, epithelial cells in the forestomach switch on genes normally expressed by mucous-producing cells, suggesting that p63 deletion not only abrogates stratification but also affects epithelial differentiation.	('epithelia', 'Disease', 'None', (193, 202))	('epithelia', 'Disease', 'None', (15, 24))	('epithelia', 'Disease', (15, 24))	('deletion', 'Var', (133, 141))	('epithelia', 'Disease', (193, 202))	('p63', 'Gene', (129, 132))	('affects', 'Reg', (185, 192))	('p63', 'Gene', '22061', (129, 132))	('abrogates', 'NegReg', (151, 160))	('stratification', 'CPA', (161, 175))
140238	22750256	The cytoprotective function of Nrf2 protein in the developing esophagus is revealed by the study of mutants lacking Keap1, which die at weaning from occlusion of the upper digestive tract by keratin overproduction.	('mutants', 'Var', (100, 107))	('Nrf2', 'Gene', '18024', (31, 35))	('lacking', 'NegReg', (108, 115))	('Keap1', 'Gene', '50868', (116, 121))	('Nrf2', 'Gene', (31, 35))	('Keap1', 'Gene', (116, 121))
140239	22750256	The mutants have increased expression of the differentiation markers Involucrin and Loricrin despite no changes in epithelial proliferation.	('increased', 'PosReg', (17, 26))	('mutants', 'Var', (4, 11))	('Loricrin', 'Gene', '16939', (84, 92))	('Loricrin', 'Gene', (84, 92))	('expression', 'MPA', (27, 37))	('epithelia', 'Disease', 'None', (115, 124))	('epithelia', 'Disease', (115, 124))
140240	22750256	In addition, high levels of Nrf2 protein accumulate in the nuclei of Keap1 mutants and initiate the transcription of Nqo1 and GSTs.	('accumulate', 'PosReg', (41, 51))	('Keap1', 'Gene', '50868', (69, 74))	('GSTs', 'Gene', '111484', (126, 130))	('Nqo1', 'Gene', (117, 121))	('Keap1', 'Gene', (69, 74))	('Nrf2', 'Gene', '18024', (28, 32))	('mutants', 'Var', (75, 82))	('transcription', 'MPA', (100, 113))	('Nqo1', 'Gene', '18104', (117, 121))	('Nrf2', 'Gene', (28, 32))	('GSTs', 'Gene', (126, 130))	('protein', 'Protein', (33, 40))
140241	22750256	Deletion of Nrf2 in a Keap1 null background rescues the hyperkeratosis phenotype.	('Nrf2', 'Gene', '18024', (12, 16))	('Nrf2', 'Gene', (12, 16))	('hyperkeratosis', 'Disease', 'MESH:D017488', (56, 70))	('Keap1', 'Gene', '50868', (22, 27))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (56, 70))	('Keap1', 'Gene', (22, 27))	('rescues', 'PosReg', (44, 51))	('hyperkeratosis', 'Disease', (56, 70))	('Deletion', 'Var', (0, 8))
140244	22750256	In Noggin null mutants, Bmp signaling is ectopically activated during the first stage and results in a simple columnar epithelium that contains a decreased number of p63 positive cells and forms convoluted glandular mucin-secreting pits.	('Noggin', 'Gene', (3, 9))	('activated', 'PosReg', (53, 62))	('pits', 'Disease', (232, 236))	('pits', 'Disease', 'MESH:C536528', (232, 236))	('p63', 'Gene', '22061', (166, 169))	('decreased', 'NegReg', (146, 155))	('p63', 'Gene', (166, 169))	('mutants', 'Var', (15, 22))	('decreased number of p63 positive cells', 'Phenotype', 'HP:0045080', (146, 184))	('Noggin', 'Gene', '18121', (3, 9))	('Bmp signaling', 'MPA', (24, 37))	('results in', 'Reg', (90, 100))
140246	22750256	Deletion of Bmp receptor IA with Shh-Cre perturbs lineage differentiation, resulting in Sox2 and p63 expression in the top layers of the epithelium.	('resulting in', 'Reg', (75, 87))	('perturbs', 'NegReg', (41, 49))	('p63', 'Gene', '22061', (97, 100))	('lineage differentiation', 'CPA', (50, 73))	('p63', 'Gene', (97, 100))	('Bmp receptor', 'Gene', (12, 24))	('Deletion', 'Var', (0, 8))
140251	22750256	These findings were further confirmed by a selective gene deletion strategy in which SmMHC-Cre was used to delete loxP-flanked myogenin, a gene essential for striated myogenesis.	('myogenin', 'Gene', '17928', (127, 135))	('delete', 'Var', (107, 113))	('SmMHC', 'Gene', '17880', (85, 90))	('SmMHC', 'Gene', (85, 90))	('myogenin', 'Gene', (127, 135))
140255	22750256	Loss of Myf5 but not MyoD in the E17.5 esophagus results in the loss of skeletal muscle and outer muscle layers that remain positive for smooth muscle actin.	('Myf5', 'Gene', (8, 12))	('MyoD', 'Gene', (21, 25))	('smooth muscle actin', 'Protein', (137, 156))	('loss of skeletal muscle', 'Disease', (64, 87))	('positive', 'Reg', (124, 132))	('loss of skeletal muscle', 'Disease', 'MESH:D005207', (64, 87))	('Myf5', 'Gene', '17877', (8, 12))	('MyoD', 'Gene', '17927', (21, 25))	('Loss', 'Var', (0, 4))
140257	22750256	Consistently, severe defects of myotomal components within the somite have been reported in Shh-/- mutants along with decreased expression of Myf5 and MyoD.	('defects of myotomal components', 'Disease', 'MESH:C562869', (21, 51))	('Shh-/-', 'Gene', (92, 98))	('defects of myotomal components', 'Disease', (21, 51))	('Myf5', 'Gene', '17877', (142, 146))	('MyoD', 'Gene', (151, 155))	('MyoD', 'Gene', '17927', (151, 155))	('decreased', 'NegReg', (118, 127))	('expression', 'MPA', (128, 138))	('Myf5', 'Gene', (142, 146))	('mutants', 'Var', (99, 106))
140265	22750256	Animals homozygous for this mutation (Dom/Dom) die during embryogenesis (60% die at E12-E13) and lack enteric neurons and their precursors from the entire length of the esophagus and gastrointestinal tract.	('gastrointestinal tract', 'Disease', (183, 205))	('enteric neurons', 'CPA', (102, 117))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (183, 205))	('lack', 'NegReg', (97, 101))	('mutation', 'Var', (28, 36))	('E12-E13', 'Var', (84, 91))
140269	22750256	Disruption of Gdnf/Ret signaling in Ret null mutants reduces the number of enteric neurons in the esophagus and forestomach and leads to aganglionosis in other parts of gastrointestinal tract.	('gastrointestinal tract', 'Disease', (169, 191))	('Ret', 'Gene', '19713', (36, 39))	('mutants', 'Var', (45, 52))	('Ret', 'Gene', '19713', (19, 22))	('Disruption', 'Var', (0, 10))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (169, 191))	('Gdnf', 'Gene', (14, 18))	('leads to', 'Reg', (128, 136))	('reduces', 'NegReg', (53, 60))	('Gdnf', 'Gene', '14573', (14, 18))	('Ret', 'Gene', (36, 39))	('Ret', 'Gene', (19, 22))
140270	22750256	Consistently, combined deletion of Sulf1 and Sulf2, sulfotransferases that modify the binding of Gdnf to extracellular matrix and c-Ret, also leads to reduced esophageal innervation.	('reduced', 'NegReg', (151, 158))	('c-Ret', 'Gene', '19713', (130, 135))	('Sulf2', 'Gene', (45, 50))	('deletion', 'Var', (23, 31))	('c-Ret', 'Gene', (130, 135))	('Sulf1', 'Gene', '240725', (35, 40))	('esophageal innervation', 'CPA', (159, 181))	('binding', 'Interaction', (86, 93))	('Sulf2', 'Gene', '72043', (45, 50))	('Gdnf', 'Gene', (97, 101))	('Gdnf', 'Gene', '14573', (97, 101))	('Sulf1', 'Gene', (35, 40))
140273	22750256	Deletion of Mash1 leads to the loss of serotonin- and nitric oxide synthase (NOS)-containing neurons.	('Mash1', 'Gene', '17172', (12, 17))	('loss', 'NegReg', (31, 35))	('Mash1', 'Gene', (12, 17))	('nitric oxide synthase', 'Gene', '18125', (54, 75))	('nitric oxide synthase', 'Gene', (54, 75))	('Deletion', 'Var', (0, 8))
140274	22750256	Interestingly, while Sox10 is not required for the expression of Mash1 in neural crest progenitor cells in vitro, it regulates Mash1 induction in vivo and Mash1 expression is lost in Dom/Dom mutants.	('Sox10', 'Gene', '20665', (21, 26))	('Sox10', 'Gene', (21, 26))	('lost', 'NegReg', (175, 179))	('induction', 'MPA', (133, 142))	('expression', 'MPA', (161, 171))	('mutants', 'Var', (191, 198))	('Mash1', 'Gene', '17172', (127, 132))	('regulates', 'Reg', (117, 126))	('Mash1', 'Gene', (65, 70))	('Mash1', 'Gene', '17172', (155, 160))	('Mash1', 'Gene', (127, 132))	('Mash1', 'Gene', '17172', (65, 70))	('Mash1', 'Gene', (155, 160))
140279	22750256	Defects in the generation of distal esophageal inhibitory neurons (NOS+ve) can also lead to achalasia, a motility disorder in which the lower esophageal sphincter (LES) fails to relax.	('lead to', 'Reg', (84, 91))	('esophageal sphincter', 'Disease', (142, 162))	('achalasia', 'Disease', (92, 101))	('Defects', 'Var', (0, 7))	('achalasia', 'Disease', 'MESH:D004931', (92, 101))	('esophageal sphincter', 'Disease', 'MESH:D009122', (142, 162))	('motility disorder', 'Disease', (105, 122))	('motility disorder', 'Disease', 'MESH:D015835', (105, 122))	('achalasia', 'Phenotype', 'HP:0002571', (92, 101))
140462	32813194	This was a real-life, multicenter, open-label, proof-of-concept trial to determine the safety and efficacy of 12 months of treatment with PR-PFD in combination with standard of care treatment in adult patients with chronic liver disease whose fibrosis continued to progress despite abstaining from alcohol (ALD), achieving 1 year sustained virologic response (VHC), or otherwise maintaining stable disease (NAFLD, AIH) including healthy life style recommendations.	('patients', 'Species', '9606', (201, 209))	('PR-PFD', 'Gene', (138, 144))	('fibrosis', 'Disease', 'MESH:D005355', (243, 251))	('NAFLD', 'Disease', 'MESH:D065626', (407, 412))	('PR-PFD', 'Gene', '5199', (138, 144))	('alcohol', 'Chemical', 'MESH:D000438', (298, 305))	('chronic liver disease', 'Disease', (215, 236))	('chronic liver disease', 'Disease', 'MESH:D058625', (215, 236))	('stable disease', 'Disease', (391, 405))	('ALD', 'Disease', 'MESH:D000326', (307, 310))	('ALD', 'Disease', (307, 310))	('liver disease', 'Phenotype', 'HP:0001392', (223, 236))	('abstaining', 'Var', (282, 292))	('fibrosis', 'Disease', (243, 251))	('NAFLD', 'Disease', (407, 412))
140465	32813194	Patients were excluded if they used hepatotoxic drug, decompensation in the previous 6 months, prior history of malignancy, active infectious processes not of a self-limited nature, hemolysis, alpha-fetoprotein > 100 ng/L, pregnancy, and alcohol or intravenous drug abuse within the previous year, were on active treatment with PR-PFD less than 12 months (n = 88) or lacked baseline and final fibrosis measurements (n = 71) (Fig.	('hemolysis', 'Disease', (182, 191))	('alpha-fetoprotein', 'Gene', (193, 210))	('hemolysis', 'Disease', 'MESH:D006461', (182, 191))	('hepatotoxic', 'Disease', 'MESH:D056486', (36, 47))	('> 100 ng/L', 'Var', (211, 221))	('PR-PFD', 'Gene', (328, 334))	('Patients', 'Species', '9606', (0, 8))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('alpha-fetoprotein', 'Gene', '174', (193, 210))	('hepatotoxic', 'Disease', (36, 47))	('alcohol', 'Chemical', 'MESH:D000438', (238, 245))	('PR-PFD', 'Gene', '5199', (328, 334))	('fibrosis', 'Disease', 'MESH:D005355', (393, 401))	('fibrosis', 'Disease', (393, 401))	('malignancy', 'Disease', (112, 122))
140473	32813194	Patients were negative for hepatocellular carcinoma (HCC) as determined by hepatic ultrasound and had the following lab values: hematocrit > 30%, hemoglobin > 10 g/dL, platelet count > 30 x 109/L, white blood cell count > 3 x 109/L, and serum creatinine level < 1.5 mg/dL.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (27, 51))	('creatinine', 'Chemical', 'MESH:D003404', (243, 253))	('serum creatinine level', 'MPA', (237, 259))	('hemoglobin', 'MPA', (146, 156))	('hematocrit', 'MPA', (128, 138))	('platelet', 'MPA', (168, 176))	('Patients', 'Species', '9606', (0, 8))	('HCC', 'Phenotype', 'HP:0001402', (53, 56))	('> 30', 'Var', (139, 143))	('> 30 x 109/L', 'Var', (183, 195))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (27, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('hepatocellular carcinoma', 'Disease', (27, 51))
140673	32736599	showed that the rate of anastomotic leakage was significantly higher in patients undergoing hand-sewn anastomosis than in patients treated via linear stapled anastomosis.	('hand-sewn anastomosis', 'Var', (92, 113))	('anastomotic leakage', 'Disease', (24, 43))	('higher', 'PosReg', (62, 68))	('patients', 'Species', '9606', (122, 130))	('anastomotic leakage', 'Disease', 'MESH:D057868', (24, 43))	('patients', 'Species', '9606', (72, 80))
140677	32736599	The authors showed that anastomotic leakage was less frequent in the modified Collard group than in the hand-sewn group but that the difference was not significant.	('less', 'NegReg', (48, 52))	('anastomotic leakage', 'Disease', 'MESH:D057868', (24, 43))	('anastomotic leakage', 'Disease', (24, 43))	('modified Collard', 'Var', (69, 85))
140678	32736599	Anastomotic stenosis occurred to a significantly lower extent in the modified Collard group, and the period between esophagectomy and initial dilatation was significantly shorter in the hand-sewn anastomosis group.	('shorter', 'NegReg', (171, 178))	('dilatation', 'Phenotype', 'HP:0002617', (142, 152))	('lower', 'NegReg', (49, 54))	('modified', 'Var', (69, 77))	('Anastomotic stenosis', 'Disease', (0, 20))	('Anastomotic stenosis', 'Disease', 'MESH:D057868', (0, 20))
140697	31908624	The areas under the ROC curves for the ability to predict significantly tumor response were 0.768 for Roundness (P = .001, 95% CI = 0.603-0.889).	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Roundness', 'Var', (102, 111))
140733	31908624	The areas under the ROC curves for the ability to predict significantly tumor response were 0.768 for Roundness (P = .001, 95% confidence interval = 0.603-0.889).	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Roundness', 'Var', (102, 111))
140751	31908624	In the recovery radiotherapy, roundness has some predicted effects on the partial result to the late period of esophageal cancer, but it has no predicted effect on the total lifetime.	('effects', 'Reg', (59, 66))	('roundness', 'Var', (30, 39))	('esophageal cancer', 'Disease', (111, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
140754	31041783	Mutations in foregut SOX2+ cells induce efficient proliferation via CXCR2 pathway Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion.	('CXCR2', 'Gene', (68, 73))	('CXCR2', 'Gene', '12765', (68, 73))	('SOX2', 'Gene', '20674', (21, 25))	('tumor initiation', 'Disease', 'MESH:D009369', (218, 234))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('Mutations', 'Var', (0, 9))	('tumor initiation', 'Disease', (218, 234))	('SOX2', 'Gene', (21, 25))
140756	31041783	Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion.	('KRAS', 'Gene', (55, 59))	('KRAS', 'Gene', '16653', (55, 59))	('mutation', 'Var', (60, 68))	('P53', 'Gene', '22060', (73, 76))	('deletion', 'Var', (77, 85))	('P53', 'Gene', (73, 76))
140760	31041783	Cancer arises from a progressive accumulation of genetic mutations in proto-oncogenes and tumor suppressor genes (Visvader and Lindeman,; Blanpain and Simons,).	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('proto-oncogenes', 'Gene', (70, 85))	('genetic mutations', 'Var', (49, 66))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
140761	31041783	For example, the oncogene Kras and the tumor suppressor gene p53 are frequently mutated in a wide range of human cancers (Serrano et al.	('Kras', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('human', 'Species', '9606', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('mutated', 'Var', (80, 87))	('cancers', 'Disease', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('p53', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
140767	31041783	Not only is the specific genetic mutation a determining factor for tumor initiation but the cell type from which the tumor originates is also important.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutation', 'Var', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (117, 122))	('tumor initiation', 'Disease', 'MESH:D009369', (67, 83))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('tumor initiation', 'Disease', (67, 83))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
140771	31041783	By initially focusing on oncogenic Kras, together with the loss of p53, we found that foregut basal cells that express SOX2 efficiently proliferated to hyperplasia in response to oncogenic mutations.	('hyperplasia', 'Disease', (152, 163))	('SOX2', 'Gene', (119, 123))	('proliferated', 'CPA', (136, 148))	('hyperplasia', 'Disease', 'MESH:D006965', (152, 163))	('mutations', 'Var', (189, 198))
140772	31041783	We also revealed distinct roles of oncogenic KRAS and P53 deletion in driving hyperplasia.	('P53', 'Gene', (54, 57))	('P53', 'Gene', '22060', (54, 57))	('hyperplasia', 'Disease', (78, 89))	('hyperplasia', 'Disease', 'MESH:D006965', (78, 89))	('deletion', 'Var', (58, 66))	('KRAS', 'Gene', '16653', (45, 49))	('KRAS', 'Gene', (45, 49))
140774	31041783	To determine which stem cell populations are the most vulnerable to oncogenic transformation, we expressed oncogenic Kras (G12D) and deleted one copy of the p53 gene in dividing cells of the adult mouse.	('deleted', 'Var', (133, 140))	('p53', 'Gene', (157, 160))	('G12D', 'Mutation', 'rs121913529', (123, 127))	('mouse', 'Species', '10090', (197, 202))
140775	31041783	Oncogenic Kras and p53 mutations were chosen because they are frequently observed in a wide range of human cancers (Serrano et al.,; Kuilman et al.,).	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Kras', 'Gene', (10, 14))	('human', 'Species', '9606', (101, 106))	('mutations', 'Var', (23, 32))	('p53', 'Gene', (19, 22))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('observed', 'Reg', (73, 81))
140779	31041783	Mcm2CreER/WT mice were bred with mice carrying a loxP-STOP-loxP (LSL)-oncogenic Kras (G12D) (KrasLSL-G12D/WT) and loxP-p53-loxP mice (p53Flox/Flox) (Marino et al.,; Jackson et al.,).	('Mcm2', 'Gene', (0, 4))	('mice', 'Species', '10090', (13, 17))	('G12D', 'Mutation', 'rs121913529', (86, 90))	('Mcm2', 'Gene', '17216', (0, 4))	('Flox', 'Chemical', '-', (137, 141))	('G12D', 'Mutation', 'rs121913529', (101, 105))	('p53Flox/Flox', 'Var', (134, 146))	('mice', 'Species', '10090', (128, 132))	('mice', 'Species', '10090', (33, 37))	('Flox', 'Chemical', '-', (142, 146))
140780	31041783	Upon genotyping, we verified and selected mice carrying the appropriate genetic modifications, namely Mcm2CreER/WT; KrasG12D/WT; p53Flox/WT (hereafter referred to as MKPFlox/WT mice).	('Mcm2', 'Gene', '17216', (102, 106))	('Flox', 'Chemical', '-', (169, 173))	('mice', 'Species', '10090', (42, 46))	('p53Flox/WT', 'Var', (129, 139))	('Mcm2', 'Gene', (102, 106))	('mice', 'Species', '10090', (177, 181))	('Flox', 'Chemical', '-', (132, 136))	('KrasG12D/WT', 'Var', (116, 127))
140781	31041783	MKPFlox/WT mice allow for the selective induction of KrasG12D expression and the heterozygous deletion of p53 in all dividing cells upon tamoxifen (TAM) administration.	('deletion', 'Var', (94, 102))	('TAM', 'Chemical', 'MESH:D013629', (148, 151))	('KrasG12D', 'Gene', (53, 61))	('tamoxifen', 'Chemical', 'MESH:D013629', (137, 146))	('expression', 'MPA', (62, 72))	('mice', 'Species', '10090', (11, 15))	('Flox', 'Chemical', '-', (3, 7))	('p53', 'Gene', (106, 109))
140786	31041783	BLI revealed that Luc signals were specifically observed in the esophagus and stomach of SKPFlox/WT mice, whereas LKPFlox/WT mice exhibited strong Luc signals in the duodenum, small intestine, and colon (Fig.	('SKPFlox/WT', 'Var', (89, 99))	('Flox', 'Chemical', '-', (92, 96))	('mice', 'Species', '10090', (100, 104))	('mice', 'Species', '10090', (125, 129))	('Luc', 'MPA', (147, 150))	('Luc', 'MPA', (18, 21))	('SKPFlox', 'Chemical', '-', (89, 96))	('Flox', 'Chemical', '-', (117, 121))	('observed', 'Reg', (48, 56))
140799	31041783	Previous reports showed that KrasG12D does not seem to be commonly mutated in human esophageal squamous cell carcinoma (ESCC) (Shigaki et al.,), although related pathways are often activated (Lin et al.,) and this mutation is also observed in the Chinese population (Liu et al.,).	('G12D', 'Mutation', 'rs121913529', (33, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (84, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('activated', 'PosReg', (181, 190))	('KrasG12D', 'Var', (29, 37))	('human', 'Species', '9606', (78, 83))	('esophageal squamous cell carcinoma', 'Disease', (84, 118))
140800	31041783	Therefore, we next examined the effect of PIK3CA (H0147R), which is a mutation associated with ESCC (Lin et al.,; Song et al.,).	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('PIK3CA', 'Gene', (42, 48))	('ESCC', 'Disease', (95, 99))	('H0147R', 'Var', (50, 56))	('H0147R', 'Mutation', 'p.H0147R', (50, 56))	('PIK3CA', 'Gene', '18706', (42, 48))
140802	31041783	Together, these results indicate that SOX2+ cells can be the cells-of-origin of forestomach and esophagus hyperplasia and suggest that SOX2+ basal cells in the esophagus and forestomach seem more susceptible to oncogenic stimuli than SOX2+ cells from other tissues in the body, implying tissue-specific vulnerabilities upon oncogenic insults.	('susceptible', 'MPA', (196, 207))	('forestomach and esophagus hyperplasia', 'Disease', 'MESH:D004938', (80, 117))	('SOX2+', 'Var', (135, 140))
140804	31041783	Upon TAM administration, stomach hyperplasia was only observed in animals that expressed mutant Kras, indicating that KrasG12D expression, but not p53 heterozygous deletion, was sufficient to induce the hyperplastic phenotype.	('induce', 'Reg', (192, 198))	('stomach hyperplasia', 'Disease', (25, 44))	('KrasG12D', 'Var', (118, 126))	('TAM', 'Chemical', 'MESH:D013629', (5, 8))	('stomach hyperplasia', 'Disease', 'MESH:D006965', (25, 44))	('mutant', 'Var', (89, 95))	('stomach hyperplasia', 'Phenotype', 'HP:0005207', (25, 44))
140805	31041783	Notably, hyperplasia was observed in almost all SKPFlox/WT mice whereas lower rates were observed in mice carrying only mutant Kras (Fig.	('mice', 'Species', '10090', (59, 63))	('SKPFlox/WT', 'Var', (48, 58))	('SKPFlox', 'Chemical', '-', (48, 55))	('hyperplasia', 'Disease', (9, 20))	('mice', 'Species', '10090', (101, 105))	('hyperplasia', 'Disease', 'MESH:D006965', (9, 20))
140806	31041783	3A), suggesting that deletion of one copy of p53 accelerates tumorigenic proliferation by expanding SOX2+ cells, as supported by our BLI measurements (Fig.	('p53', 'Gene', (45, 48))	('deletion', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('expanding', 'PosReg', (90, 99))	('accelerates', 'PosReg', (49, 60))	('SOX2+ cells', 'MPA', (100, 111))	('tumor', 'Disease', (61, 66))
140807	31041783	To characterize the molecular events that contribute to abnormal proliferation in the presence of oncogenic Kras, we next performed RNA-Sequencing (RNA-Seq) analysis using samples from the forestomach, esophagus, and lungs of Sox2-CreER mice with/without KrasG12D and with/without one copy of the p53 gene (see Fig.	('KrasG12D', 'Var', (255, 263))	('p53', 'Gene', (297, 300))	('Sox2', 'Gene', '20674', (226, 230))	('mice', 'Species', '10090', (237, 241))	('Sox2', 'Gene', (226, 230))
140808	31041783	Gene ontology enrichment analysis further indicated a distinct impact of oncogenic KRAS versus P53 deletion (Fig.	('KRAS', 'Gene', (83, 87))	('KRAS', 'Gene', '16653', (83, 87))	('P53', 'Gene', '22060', (95, 98))	('deletion', 'Var', (99, 107))	('P53', 'Gene', (95, 98))
140809	31041783	Because Kras mutation was sufficient to initiate hyperplasia in SOX2+ cells, we sought to identify specific KRAS target genes.	('KRAS', 'Gene', (108, 112))	('KRAS', 'Gene', '16653', (108, 112))	('Kras', 'Gene', (8, 12))	('mutation', 'Var', (13, 21))	('hyperplasia', 'Disease', 'MESH:D006965', (49, 60))	('hyperplasia', 'Disease', (49, 60))
140814	31041783	3E), recapitulating the different impacts of oncogenic KRAS and P53 deletion.	('KRAS', 'Gene', (55, 59))	('KRAS', 'Gene', '16653', (55, 59))	('P53', 'Gene', (64, 67))	('deletion', 'Var', (68, 76))	('P53', 'Gene', '22060', (64, 67))
140818	31041783	More importantly, chemical inhibition of the CXCR2 signaling pathway with the compound SB225002 (White et al.,) in SKPFlox/WT mice (1-week following TAM exposure) resulted in a marked decrease in proliferating cells (BrdU+ cells) and in a thinner hyperplastic layer, to levels comparable to the control mice (Figs.	('decrease', 'NegReg', (184, 192))	('TAM', 'Chemical', 'MESH:D013629', (149, 152))	('mice', 'Species', '10090', (126, 130))	('thinner', 'NegReg', (239, 246))	('CXCR2 signaling pathway', 'Pathway', (45, 68))	('SB225002', 'Var', (87, 95))	('SB225002', 'Chemical', 'MESH:C112019', (87, 95))	('mice', 'Species', '10090', (303, 307))	('SKPFlox', 'Chemical', '-', (115, 122))	('inhibition', 'NegReg', (27, 37))
140823	31041783	The observation that a p53 heterozygous background potentiated KrasG12D-induced hyperplastic proliferation led us to further explore the impact of homozygous p53 deletion on tumor progression.	('potentiated', 'PosReg', (51, 62))	('tumor', 'Disease', (174, 179))	('KrasG12D-induced', 'Var', (63, 79))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('G12D', 'Mutation', 'rs121913529', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
140824	31041783	We therefore generated Sox2CreER/WT; KrasLSL-G12D/WT; p53Flox/Flox (SKPFlox/Flox) mice and treated them with TAM for 1 week.	('mice', 'Species', '10090', (82, 86))	('p53Flox/Flox', 'Var', (54, 66))	('Flox', 'Chemical', '-', (57, 61))	('Sox2', 'Gene', '20674', (23, 27))	('Flox', 'Chemical', '-', (71, 75))	('TAM', 'Chemical', 'MESH:D013629', (109, 112))	('Flox', 'Chemical', '-', (62, 66))	('Sox2', 'Gene', (23, 27))	('SKPFlox', 'Chemical', '-', (68, 75))	('G12D', 'Mutation', 'rs121913529', (45, 49))	('Flox', 'Chemical', '-', (76, 80))
140830	31041783	Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion in tumor formation.	('KRAS', 'Gene', (55, 59))	('mutation', 'Var', (60, 68))	('KRAS', 'Gene', '16653', (55, 59))	('P53', 'Gene', '22060', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('deletion', 'Var', (77, 85))	('P53', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
140833	31041783	For example, amplification of the SOX2 gene has been reported in human squamous cell carcinomas (SCC) of the lung and esophagus, small-cell lung cancer (SCLC) and glioblastoma (Bass et al.,; Annovazzi et al.,; Rudin et al.,).	('human', 'Species', '9606', (65, 70))	('SCLC', 'Disease', 'MESH:D018288', (153, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('glioblastoma', 'Disease', (163, 175))	('amplification', 'Var', (13, 26))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('SOX2', 'Gene', (34, 38))	('squamous cell carcinomas', 'Disease', (71, 95))	('SCLC', 'Disease', (153, 157))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (129, 151))	('small-cell lung cancer', 'Disease', (129, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (71, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (71, 95))	('reported', 'Reg', (53, 61))	('glioblastoma', 'Disease', 'MESH:D005909', (163, 175))
140834	31041783	Overexpression of Sox2 leads to hyperplasia and tumor formation in several tissues (Lu et al.,; Liu et al.,; Mukhopadhyay et al.,).	('tumor', 'Disease', (48, 53))	('hyperplasia', 'Disease', (32, 43))	('Sox2', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Sox2', 'Gene', '20674', (18, 22))	('hyperplasia', 'Disease', 'MESH:D006965', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
140836	31041783	SOX2+ cells are also responsible for propagating medulloblastoma and targeting them prevented tumor growth (Vanner et al.,).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('medulloblastoma', 'Disease', 'MESH:D008527', (49, 64))	('targeting', 'Var', (69, 78))	('medulloblastoma', 'Phenotype', 'HP:0002885', (49, 64))	('prevented', 'NegReg', (84, 93))	('medulloblastoma', 'Disease', (49, 64))
140842	31041783	Oncogenic Kras expression, but not p53 deletion, was sufficient to induce a hyperplasic phenotype; and p53 deletion accelerated tumorigenic proliferation in KrasG12D-induced hyperplasia.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('p53', 'Gene', (103, 106))	('hyperplasic', 'Disease', 'None', (76, 87))	('accelerated', 'PosReg', (116, 127))	('hyperplasic', 'Disease', (76, 87))	('hyperplasia', 'Disease', (174, 185))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('deletion', 'Var', (107, 115))	('hyperplasia', 'Disease', 'MESH:D006965', (174, 185))
140843	31041783	Similarly, others have found that the loss of p53 in stem cells of the colon results in tumor formation only when combined with DNA damage and chronic inflammation (Schwitalla et al.,; Davidson et al.,).	('loss', 'Var', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('p53', 'Gene', (46, 49))	('results in', 'Reg', (77, 87))	('chronic inflammation', 'Disease', 'MESH:D007249', (143, 163))	('chronic inflammation', 'Disease', (143, 163))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
140844	31041783	Importantly, p53 homozygous deletion along with the Kras mutation led to an invasive phenotype and highly malignant tumors, highlighting the role of P53 in tumor invasion.	('led to', 'Reg', (66, 72))	('invasive phenotype', 'CPA', (76, 94))	('P53', 'Gene', '22060', (149, 152))	('malignant tumors', 'Disease', (106, 122))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('homozygous deletion', 'Var', (17, 36))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('P53', 'Gene', (149, 152))	('malignant tumors', 'Disease', 'MESH:D018198', (106, 122))	('p53', 'Gene', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))
140870	31041783	Briefly, the esophagi were isolated, opened longitudinally, washed in PBS followed by Dispase (1 U/mL) for 15-20 min at 37  C. The opened esophagi were minced with forceps and incubated with TrypLE for 10 min at 37  C. After inactivation of TrypLE with FBS, the cell suspension was filtered through 100-mum and 40-mum cell strainers.	('PBS', 'Disease', 'MESH:D011535', (70, 73))	('PBS', 'Disease', (70, 73))	('FBS', 'Disease', 'MESH:D005198', (253, 256))	('FBS', 'Disease', (253, 256))	('inactivation', 'Var', (225, 237))
140890	29348395	For instance, siRNA mediated disruption of NF-kappaB significantly suppressed migration and invasion of ESCC cells though attenuation of the epithelial mesenchymal transition (EMT), the initial step for tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('NF-kappaB', 'Gene', (43, 52))	('invasion', 'CPA', (92, 100))	('epithelial mesenchymal transition', 'CPA', (141, 174))	('tumor metastasis', 'Disease', 'MESH:D009362', (203, 219))	('attenuation', 'NegReg', (122, 133))	('tumor metastasis', 'Disease', (203, 219))	('NF-kappaB', 'Gene', '4790', (43, 52))	('suppressed', 'NegReg', (67, 77))	('disruption', 'Var', (29, 39))
140896	29348395	Expression level was characterized in a panel of ESCC cancer cell lines including Eca109, Eca9706, KYSE30, KYSE510, KYSE520, KYSE140 and KYSE150 and one immortalized esophageal squamous cell (NE1).	('KYSE30', 'Var', (99, 105))	('KYSE520', 'Var', (116, 123))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('Eca9706', 'CellLine', 'CVCL:E307', (90, 97))	('cancer', 'Disease', (54, 60))	('KYSE510', 'Var', (107, 114))	('KYSE150', 'Var', (137, 144))	('KYSE140', 'Var', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('KYSE520', 'CellLine', 'CVCL:1355', (116, 123))
140906	29348395	qPCR assays clearly confirmed effective knockdown of NKILA in Eca109 and Eca9706 cells (Fig.	('NKILA', 'Gene', (53, 58))	('NKILA', 'Gene', '105416157', (53, 58))	('Eca9706', 'CellLine', 'CVCL:E307', (73, 80))	('knockdown', 'Var', (40, 49))
140907	29348395	CCK8 assays showed that knockdown of NKILA significantly promoted cell proliferation in Eca109 and Eca9706 cells (Fig.	('NKILA', 'Gene', (37, 42))	('promoted', 'PosReg', (57, 65))	('cell proliferation', 'CPA', (66, 84))	('NKILA', 'Gene', '105416157', (37, 42))	('Eca9706', 'CellLine', 'CVCL:E307', (99, 106))	('knockdown', 'Var', (24, 33))
140908	29348395	Silencing of NKILA promoted colony formation capability of Eca109 and Eca9706 cells (Fig.	('NKILA', 'Gene', '105416157', (13, 18))	('promoted', 'PosReg', (19, 27))	('colony formation capability', 'CPA', (28, 55))	('NKILA', 'Gene', (13, 18))	('Eca9706', 'CellLine', 'CVCL:E307', (70, 77))	('Silencing', 'Var', (0, 9))
140916	29348395	4A, knockdown of NKILA induced remarkable increase of migration capacity of Eca109 and Eca9706 cells.	('migration capacity', 'CPA', (54, 72))	('NKILA', 'Gene', '105416157', (17, 22))	('Eca9706', 'CellLine', 'CVCL:E307', (87, 94))	('NKILA', 'Gene', (17, 22))	('knockdown', 'Var', (4, 13))	('increase', 'PosReg', (42, 50))
140926	29348395	After tail vein injection of KYSE30/EV and KYSE30/NKILA cells, the lung metastasis was examined by H&E staining and showed significant decrease in the overexpression group (Fig.	('H&E', 'Chemical', '-', (99, 102))	('NKILA', 'Gene', (50, 55))	('lung metastasis', 'CPA', (67, 82))	('significant', 'NegReg', (123, 134))	('NKILA', 'Gene', '105416157', (50, 55))	('KYSE30/EV', 'Var', (29, 38))
140939	29348395	BAY 11-7082 reversed pro-metastasis effects of NKILA knockdown in Eca109 and Eca9706 cells (Supplementary Figure S4A), while TNFalpha blocked the anti-metastasis roles of NKILA reintroduction in KYSE30 and KYSE520 cells (Supplementary Figure S4B), further indicating that NKILA regulated migration of ESCC cells via NF-kappaB pathway.	('NKILA', 'Gene', '105416157', (272, 277))	('anti-metastasis', 'MPA', (146, 161))	('NKILA', 'Gene', (47, 52))	('NKILA', 'Gene', (171, 176))	('knockdown', 'Var', (53, 62))	('NKILA', 'Gene', (272, 277))	('pro-metastasis', 'MPA', (21, 35))	('TNFalpha', 'Gene', (125, 133))	('NF-kappaB', 'Gene', '4790', (316, 325))	('NKILA', 'Gene', '105416157', (47, 52))	('BAY 11-7082', 'Chemical', 'MESH:C434003', (0, 11))	('NKILA', 'Gene', '105416157', (171, 176))	('NF-kappaB', 'Gene', (316, 325))	('Eca9706', 'CellLine', 'CVCL:E307', (77, 84))	('KYSE520', 'CellLine', 'CVCL:1355', (206, 213))	('TNFalpha', 'Gene', '7124', (125, 133))
140951	29348395	Previous reports have thoroughly studied molecular mechanisms underlying dysregulated NKILA expression in breast cancer.	('breast cancer', 'Disease', (106, 119))	('dysregulated', 'Var', (73, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('NKILA', 'Gene', '105416157', (86, 91))	('NKILA', 'Gene', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
140957	29348395	In the present study, both qPCR and western blot analysis showed that the NF-kappaB target genes including CCND1, TWIST1, MMP9 and XIAP was upregulated following silence of NKILA and downregulated following NKILA overexpression.	('MMP9', 'Gene', (122, 126))	('NKILA', 'Gene', (207, 212))	('CCND1', 'Gene', '595', (107, 112))	('NF-kappaB', 'Gene', (74, 83))	('upregulated', 'PosReg', (140, 151))	('silence', 'Var', (162, 169))	('XIAP', 'Gene', (131, 135))	('XIAP', 'Gene', '331', (131, 135))	('NKILA', 'Gene', '105416157', (173, 178))	('TWIST1', 'Gene', (114, 120))	('NKILA', 'Gene', '105416157', (207, 212))	('TWIST1', 'Gene', '7291', (114, 120))	('NF-kappaB', 'Gene', '4790', (74, 83))	('downregulated', 'NegReg', (183, 196))	('NKILA', 'Gene', (173, 178))	('CCND1', 'Gene', (107, 112))	('MMP9', 'Gene', '4318', (122, 126))
141103	29216866	Selenium is an essential element that is necessary in small amounts for human health, but at a high dose selenium becomes toxic and may even promote carcinogenesis.	('Selenium', 'Chemical', 'MESH:D012643', (0, 8))	('carcinogenesis', 'Disease', (149, 163))	('men', 'Species', '9606', (28, 31))	('selenium', 'Chemical', 'MESH:D012643', (105, 113))	('selenium', 'Var', (105, 113))	('human', 'Species', '9606', (72, 77))	('promote', 'PosReg', (141, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))
141198	27533456	For example, the miRNA deregulation is closely related to the development of various cancers.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('miRNA', 'MPA', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('related', 'Reg', (47, 54))	('cancers', 'Disease', (85, 92))	('deregulation', 'Var', (23, 35))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
141235	27533456	Recently, accumulating studies have shown that many miRNAs are associated with Kidney Neoplasms.	('Kidney Neoplasms', 'Phenotype', 'HP:0009726', (79, 95))	('associated', 'Reg', (63, 73))	('Neoplasms', 'Phenotype', 'HP:0002664', (86, 95))	('miRNAs', 'Var', (52, 58))	('Kidney Neoplasms', 'Disease', 'MESH:D007680', (79, 95))	('Kidney Neoplasms', 'Disease', (79, 95))	('Neoplasm', 'Phenotype', 'HP:0002664', (86, 94))	('Kidney Neoplasm', 'Phenotype', 'HP:0009726', (79, 94))
141236	27533456	For example, miR-215, miR-200c, miR-192, miR-194 and miR-141 were downregulated in Kidney Neoplasms.	('miR-141', 'Gene', (53, 60))	('miR-194', 'Var', (41, 48))	('miR-215', 'Gene', (13, 20))	('miR-200c', 'Gene', (22, 30))	('Kidney Neoplasms', 'Phenotype', 'HP:0009726', (83, 99))	('downregulated', 'NegReg', (66, 79))	('miR-141', 'Gene', '406933', (53, 60))	('miR-200c', 'Gene', '406985', (22, 30))	('Kidney Neoplasms', 'Disease', 'MESH:D007680', (83, 99))	('Kidney Neoplasms', 'Disease', (83, 99))	('miR-215', 'Gene', '406997', (13, 20))	('Neoplasm', 'Phenotype', 'HP:0002664', (90, 98))	('Neoplasms', 'Phenotype', 'HP:0002664', (90, 99))	('miR-192', 'Gene', '406967', (32, 39))	('Kidney Neoplasm', 'Phenotype', 'HP:0009726', (83, 98))	('miR-192', 'Gene', (32, 39))
141329	19272389	Support for this study was provided by the National Cancer Institute (R01 CA106773) and National Institute of Diabetes and Digestive and Kidney Diseases (K24 DK080941), National Institutes of Health and an unrestricted research grant from BARRX, the company that developed, manufactures and distributes the radiofrequency ablation device modeled in one arm of this study.	('Diabetes', 'Disease', (110, 118))	('Kidney Diseases', 'Disease', 'MESH:D007674', (137, 152))	('Cancer', 'Disease', (52, 58))	('Kidney Diseases', 'Phenotype', 'HP:0000112', (137, 152))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Kidney Diseases', 'Disease', (137, 152))	('K24', 'Var', (154, 157))	('Diabetes', 'Disease', 'MESH:D003920', (110, 118))
141340	19272389	Ablation with PDT, RFA or APC followed by surveillance in all patients is predicted to increase life by 1 dQALY compared to no surveillance, with concomitant increases in resource utilization of approximately $13,000 using APC or RFA, or $27,000 with PDT.	('APC', 'Disease', 'MESH:D011125', (26, 29))	('life', 'MPA', (96, 100))	('increase', 'PosReg', (87, 95))	('APC', 'Disease', (26, 29))	('resource utilization', 'MPA', (171, 191))	('APC', 'Disease', 'MESH:D011125', (223, 226))	('APC', 'Disease', (223, 226))	('patients', 'Species', '9606', (62, 70))	('increases', 'PosReg', (158, 167))	('RFA', 'Var', (230, 233))	('PDT', 'Gene', (14, 17))
141348	19272389	However, if discontinuation of surveillance after successful ablation is not a clinically viable option, a strategy of surveillance using ablation for incident dysplasia is equally cost-effective compared to strategies of ablation with APC, MPEC or RFA with surveillance continued in all patients (Figure 2C).	('dysplasia', 'Disease', (160, 169))	('patients', 'Species', '9606', (288, 296))	('dysplasia', 'Disease', 'MESH:D004476', (160, 169))	('MPEC', 'Chemical', '-', (241, 245))	('ablation', 'Var', (138, 146))	('APC', 'Disease', 'MESH:D011125', (236, 239))	('APC', 'Disease', (236, 239))
141392	19272389	Although absolute results have varied across studies, these have shown ablation to be superior to comparator arms in the treatment of HGD.	('men', 'Species', '9606', (126, 129))	('HGD', 'Disease', (134, 137))	('ablation', 'Var', (71, 79))
141455	31354907	p53 in most cancers, including ESC cell, is mutated, and the mutated p53 losses its original function and acquires "gain of function" that allows for promoting the hallmarks of cancer, such as antiapoptosis, metastasis, invasion, angiogenesis, and resistance to chemotherapy.	('cancer', 'Disease', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('p53', 'Gene', '7157', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('original function', 'MPA', (84, 101))	('angiogenesis', 'CPA', (230, 242))	('mutated', 'Var', (61, 68))	('p53', 'Gene', (0, 3))	('losses', 'NegReg', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('p53', 'Gene', '7157', (69, 72))	('antiapoptosis', 'CPA', (193, 206))	('resistance to chemotherapy', 'CPA', (248, 274))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('p53', 'Gene', (69, 72))	('cancers', 'Disease', (12, 19))	('cancer', 'Disease', (12, 18))	('metastasis', 'CPA', (208, 218))	('invasion', 'CPA', (220, 228))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('promoting', 'PosReg', (150, 159))
141458	31354907	The results showed that DpdtbA exhibited an excellent antiproliferative effect for ESC cell lines (IC50 <= 4.5 +- 0.4 muM for Kyse 450, 3.2 +- 0.6 muM for Kyse 510 cell, and 10.0 +- 0.6 muM for Kyse 150) and led to cell cycle arrest at the S phase which correlated to CDK2 downregulation.	('DpdtbA', 'Var', (24, 30))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (215, 232))	('downregulation', 'NegReg', (273, 287))	('muM', 'Gene', (147, 150))	('CDK2', 'Gene', (268, 272))	('CDK2', 'Gene', '1017', (268, 272))	('cell cycle arrest at the S phase', 'CPA', (215, 247))	('antiproliferative effect', 'CPA', (54, 78))	('DpdtbA', 'Chemical', '-', (24, 30))	('muM', 'Gene', '56925', (118, 121))	('muM', 'Gene', '56925', (186, 189))	('muM', 'Gene', (118, 121))	('muM', 'Gene', (186, 189))	('muM', 'Gene', '56925', (147, 150))
141460	31354907	In addition, DpdtbA also induced a downregulation of EGFR, p53, and AKT, which hinted that mutant p53 still played a role in the regulation of its downstream targets.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('DpdtbA', 'Var', (13, 19))	('DpdtbA', 'Chemical', '-', (13, 19))	('AKT', 'Gene', '207', (68, 71))	('p53', 'Gene', (98, 101))	('downregulation', 'NegReg', (35, 49))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('mutant', 'Var', (91, 97))	('p53', 'Gene', '7157', (98, 101))	('AKT', 'Gene', (68, 71))
141462	31354907	Taken together, the DpdtbA-induced growth inhibition in a mechanism was through inactivating the p53/EGFR/AKT signal pathway.	('AKT', 'Gene', (106, 109))	('inactivating', 'NegReg', (80, 92))	('p53', 'Gene', (97, 100))	('EGFR', 'Gene', '1956', (101, 105))	('p53', 'Gene', '7157', (97, 100))	('EGFR', 'Gene', (101, 105))	('DpdtbA', 'Chemical', '-', (20, 26))	('AKT', 'Gene', '207', (106, 109))	('DpdtbA-induced', 'Var', (20, 34))	('growth', 'MPA', (35, 41))
141468	31354907	And mutant p53 (mutp53) cancers are dependent on their hyper stable mutp53 protein for survival.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutant', 'Var', (4, 10))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))
141470	31354907	p53 mutants are categorized into structural (R175, G245, R249, and R282) and contact (R248 and R273) mutations with effects of gross conformational alterations and loss of anchorage to DNA, respectively.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('R273', 'Var', (95, 99))	('R282', 'Var', (67, 71))	('R175', 'Var', (45, 49))	('R249', 'Var', (57, 61))	('anchorage', 'MPA', (172, 181))	('R248', 'Var', (86, 90))	('G245', 'Var', (51, 55))	('loss', 'NegReg', (164, 168))
141472	31354907	As mentioned above, since different mutant p53 alleles may exhibit certain unique characteristics in cancer development and progression, therefore, targeting mutant p53 for protein degradation, rather than its reactivation, might be another strategy for drug development.	('p53', 'Gene', (165, 168))	('p53', 'Gene', '7157', (165, 168))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('protein degradation', 'MPA', (173, 192))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutant', 'Var', (36, 42))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('mutant', 'Var', (158, 164))
141473	31354907	reported that a Zn(II)-curcumin complex displayed growth inhibition involved in the induction of mutant p53 degradation, implying that mutant p53 degradation was one of the options in cancer treatment.	('cancer', 'Disease', (184, 190))	('p53', 'Gene', (104, 107))	('degradation', 'MPA', (108, 119))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('p53', 'Gene', '7157', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutant', 'Var', (97, 103))	('Zn(II)-curcumin', 'Chemical', '-', (16, 31))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('growth inhibition', 'MPA', (50, 67))
141477	31354907	Overexpression of EGFR is seen in many solid tumors, including esophageal cancer, and is associated with poor prognosis.	('solid tumors', 'Disease', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('esophageal cancer', 'Disease', (63, 80))	('EGFR', 'Gene', '1956', (18, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('EGFR', 'Gene', (18, 22))	('solid tumors', 'Disease', 'MESH:D009369', (39, 51))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
141478	31354907	In addition, the frequent gene amplification of EGFR, HER2, and FGFR2 and the presence of active EGFR mutations were observed in ESC specimens.	('ESC', 'Disease', (129, 132))	('FGFR2', 'Gene', '2263', (64, 69))	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'Gene', '1956', (97, 101))	('HER2', 'Gene', (54, 58))	('EGFR', 'Gene', (48, 52))	('HER2', 'Gene', '2064', (54, 58))	('EGFR', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('FGFR2', 'Gene', (64, 69))	('observed', 'Reg', (117, 125))
141482	31354907	As mentioned above, different mutant p53 alleles play an important role in cancer development and progression; therefore, targeting mutant p53 through protein degradation, rather than its reactivation, might be another strategy for drug development.	('protein degradation', 'MPA', (151, 170))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutant', 'Var', (132, 138))	('cancer', 'Disease', (75, 81))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
141486	31354907	Interestingly, the DpdtbA-induced growth inhibition involved p53 depletion, which was not consistent with that reported previously in gastric cancer cell lines.	('DpdtbA-induced', 'Var', (19, 33))	('DpdtbA', 'Chemical', '-', (19, 25))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('depletion', 'NegReg', (65, 74))	('growth inhibition', 'CPA', (34, 51))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))
141488	31354907	Furthermore, concomitant to the degradation of mutated p53, a downregulation of EGFR and AKT was observed, indicating that inactivation of the p53/EGFR/AKT axis could achieve the growth inhibition in p53 mutation-overexpressed ESC cell lines.	('EGFR', 'Gene', (147, 151))	('AKT', 'Gene', '207', (89, 92))	('EGFR', 'Gene', '1956', (80, 84))	('p53', 'Gene', '7157', (200, 203))	('downregulation', 'NegReg', (62, 76))	('mutated', 'Var', (47, 54))	('mutation-overexpressed', 'Var', (204, 226))	('p53', 'Gene', '7157', (143, 146))	('inactivation', 'Var', (123, 135))	('AKT', 'Gene', '207', (152, 155))	('p53', 'Gene', '7157', (55, 58))	('p53', 'Gene', (200, 203))	('growth inhibition', 'CPA', (179, 196))	('EGFR', 'Gene', '1956', (147, 151))	('p53', 'Gene', (143, 146))	('p53', 'Gene', (55, 58))	('EGFR', 'Gene', (80, 84))	('AKT', 'Gene', (89, 92))	('AKT', 'Gene', (152, 155))
141489	31354907	Those results definitely enriched our knowledge that targeting mutant p53 may be one of the options in successful anticancer therapy.	('cancer', 'Disease', (118, 124))	('mutant', 'Var', (63, 69))	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
141492	31354907	The dose-response curves are depicted in Figure 1, and significant growth inhibition for the ESC cell lines (IC50 <= 4.5 +- 0.4 muM for Kyse 450, 3.2 +- 0.6 muM for Kyse 510, and 10.0 +- 0.7 muM for Kyse 150) was observed compared to control (p < 0.05), but the cell line dependence was not evident.	('muM', 'Gene', (157, 160))	('muM', 'Gene', '56925', (128, 131))	('Kyse 510', 'Var', (165, 173))	('muM', 'Gene', '56925', (191, 194))	('growth', 'CPA', (67, 73))	('muM', 'Gene', (128, 131))	('muM', 'Gene', (191, 194))	('Kyse 450', 'Var', (136, 144))	('muM', 'Gene', '56925', (157, 160))
141494	31354907	As shown in Figure 1(c), DpdtbA induced a significant reduction in colony numbers and populations for Kyse 450 (p < 0.05); the quantitative analysis is shown in Figure 1(d).	('populations for', 'MPA', (86, 101))	('colony numbers', 'CPA', (67, 81))	('reduction', 'NegReg', (54, 63))	('DpdtbA', 'Var', (25, 31))	('DpdtbA', 'Chemical', '-', (25, 31))
141496	31354907	As shown in Figure 2, DpdtbA caused an accumulation of the ESC cells in the S phase for both cell lines, and the percentages at the S phase significantly increased by 10 to 17% during 24 h insult of the agent, thereby decreasing the proportion of cells in the G1 phase.	('decreasing', 'NegReg', (218, 228))	('DpdtbA', 'Chemical', '-', (22, 28))	('ESC', 'MPA', (59, 62))	('accumulation', 'PosReg', (39, 51))	('increased', 'PosReg', (154, 163))	('DpdtbA', 'Var', (22, 28))
141497	31354907	Those indicated that DpdtbA could disturb cell cycle and arrest the cells at the S phase, which was not consistent with that in gastric cell lines, indicating that DpdtbA-induced cell cycle delay was cell line dependent.	('arrest', 'Reg', (57, 63))	('cell cycle', 'CPA', (42, 52))	('DpdtbA', 'Var', (21, 27))	('DpdtbA', 'Chemical', '-', (21, 27))	('DpdtbA', 'Chemical', '-', (164, 170))	('cells at the S phase', 'CPA', (68, 88))	('disturb', 'Reg', (34, 41))
141499	31354907	As shown in Figure S2, DpdtbA led to a downregulation of CDK2, which contributed to S phase arrest, in accordance with that reported previously.	('DpdtbA', 'Var', (23, 29))	('CDK2', 'Gene', '1017', (57, 61))	('DpdtbA', 'Chemical', '-', (23, 29))	('S phase arrest', 'MPA', (84, 98))	('downregulation', 'NegReg', (39, 53))	('CDK2', 'Gene', (57, 61))
141500	31354907	Previous study revealed that DpdtbA-induced apoptosis contributed to the growth inhibition in gastric cancer lines; similar action may occur in ESC cells.	('gastric cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('DpdtbA-induced', 'Var', (29, 43))	('apoptosis', 'CPA', (44, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('growth inhibition', 'CPA', (73, 90))	('DpdtbA', 'Chemical', '-', (29, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))
141504	31354907	Moreover, the apoptotic portions in both cell lines were obviously different, which may be relative to IC50 value; as a whole, DpdtbA induced a limited apoptosis.	('DpdtbA', 'Var', (127, 133))	('apoptosis', 'CPA', (152, 161))	('DpdtbA', 'Chemical', '-', (127, 133))
141508	31354907	The portions of apoptosis cells in Kyse 450 were higher than that of Kyse 150, consistent with the results from annexin V/PI stains (Figure 3).	('Kyse', 'Var', (35, 39))	('annexin V', 'Gene', '308', (112, 121))	('apoptosis cells', 'CPA', (16, 31))	('annexin V', 'Gene', (112, 121))	('higher', 'PosReg', (49, 55))
141510	31354907	To understand how DpdtbA induced apoptosis, we further examined the alteration in the expression of apoptosis-related genes in ESC cells.	('examined', 'Reg', (55, 63))	('DpdtbA', 'Chemical', '-', (18, 24))	('DpdtbA', 'Var', (18, 24))
141511	31354907	As shown in Figure 4, the DpdtbA treatment led to slight downregulation of the bcl-2 level, but the expression of bax was not increased, and similar situation occurred for cytochrome c. It was well documented that translocation of bax on mitochondria could lead to alteration in mitochondrial membrane permeability (MMP).	('bax', 'Gene', '581', (231, 234))	('DpdtbA', 'Chemical', '-', (26, 32))	('cytochrome c', 'Gene', (172, 184))	('bax', 'Gene', (114, 117))	('bcl-2', 'Gene', (79, 84))	('cytochrome c', 'Gene', '54205', (172, 184))	('bcl-2', 'Gene', '596', (79, 84))	('translocation', 'Var', (214, 227))	('lead to alteration', 'Reg', (257, 275))	('bax', 'Gene', (231, 234))	('mitochondrial membrane permeability', 'MPA', (279, 314))	('bax', 'Gene', '581', (114, 117))
141516	31354907	Compared to control (Figure 5(a)), the ROS production induced by DpdtbA (Figures 5(b) and 5(c)) was significantly increased (p < 0.05, Figure 5(d)) in Kyse 450, indicating that ROS indeed involved the action of DpdtbA.	('DpdtbA', 'Chemical', '-', (211, 217))	('increased', 'PosReg', (114, 123))	('ROS', 'Chemical', '-', (177, 180))	('DpdtbA', 'Var', (65, 71))	('DpdtbA', 'Chemical', '-', (65, 71))	('ROS', 'Chemical', '-', (39, 42))	('ROS production', 'MPA', (39, 53))
141519	31354907	Unexpectedly, DpdtbA did not induce ferritinophagy that led to ferritin degradation; contrarily, an upregulated ferritin was observed with downregulated NCOA4 (Figure 5(e)).	('upregulated ferritin', 'Phenotype', 'HP:0003281', (100, 120))	('ferritin', 'MPA', (63, 71))	('DpdtbA', 'Var', (14, 20))	('upregulated', 'PosReg', (100, 111))	('NCOA4', 'Gene', (153, 158))	('downregulated', 'NegReg', (139, 152))	('NCOA4', 'Gene', '8031', (153, 158))	('DpdtbA', 'Chemical', '-', (14, 20))	('ferritin', 'MPA', (112, 120))
141524	31354907	To this end, the level of SOD was investigated, as shown in Figure 5(g); DpdtbA led to downregulation of SOD with a significant difference compared to control (p < 0.01 at 10 muM, Figure 5(h)).	('SOD', 'Gene', '6647', (26, 29))	('muM', 'Gene', (175, 178))	('SOD', 'Gene', (26, 29))	('DpdtbA', 'Var', (73, 79))	('SOD', 'Gene', (105, 108))	('downregulation', 'NegReg', (87, 101))	('DpdtbA', 'Chemical', '-', (73, 79))	('muM', 'Gene', '56925', (175, 178))	('SOD', 'Gene', '6647', (105, 108))
141526	31354907	Taken together, the ROS production during DpdtbA insult mainly stemmed from inactivation and downregulation of SOD.	('SOD', 'Gene', '6647', (111, 114))	('ROS', 'Chemical', '-', (20, 23))	('ROS production', 'MPA', (20, 34))	('SOD', 'Gene', (111, 114))	('inactivation', 'Var', (76, 88))	('DpdtbA', 'Chemical', '-', (42, 48))	('downregulation', 'NegReg', (93, 107))
141527	31354907	It has shown that EGFR mediates cell proliferation, and generally, EGFR (wild-type or mutated) is overexpressed in ESC cells.	('mutated', 'Var', (86, 93))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('overexpressed', 'PosReg', (98, 111))	('cell proliferation', 'CPA', (32, 50))
141528	31354907	Whether the growth inhibition induced by DpdtbA was associated with alteration of EGFR, with this purpose, we determined the expression of EGFR in the presence or absence of DpdtbA.	('growth', 'MPA', (12, 18))	('EGFR', 'Gene', (82, 86))	('DpdtbA', 'Var', (41, 47))	('DpdtbA', 'Chemical', '-', (174, 180))	('EGFR', 'Gene', '1956', (139, 143))	('DpdtbA', 'Chemical', '-', (41, 47))	('EGFR', 'Gene', (139, 143))	('EGFR', 'Gene', '1956', (82, 86))
141530	31354907	The quantitative analysis of EGFR revealed that DpdtbA induced downregulation of EGFR had a statistical significance (p < 0.01), hinting that depletion of EGFR might involve in the growth inhibition.	('depletion', 'MPA', (142, 151))	('EGFR', 'Gene', '1956', (155, 159))	('DpdtbA', 'Var', (48, 54))	('EGFR', 'Gene', (155, 159))	('growth inhibition', 'CPA', (181, 198))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('DpdtbA', 'Chemical', '-', (48, 54))	('downregulation', 'NegReg', (63, 77))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
141533	31354907	The fact that DpdtbA induced a downregulation of EGFR prompted us to explore the underlying mechanism.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('DpdtbA', 'Var', (14, 20))	('downregulation', 'NegReg', (31, 45))	('DpdtbA', 'Chemical', '-', (14, 20))
141535	31354907	Generally, AKT was regulated by EGFR (or phosphorylated EGFR); the alteration of EGFR might also affect its downstream target, AKT; thus, the level of AKT in the presence or absence of DpdtbA was determined.	('AKT', 'Gene', (11, 14))	('alteration', 'Var', (67, 77))	('AKT', 'Gene', (151, 154))	('EGFR', 'Gene', '1956', (56, 60))	('affect', 'Reg', (97, 103))	('EGFR', 'Gene', '1956', (32, 36))	('AKT', 'Gene', '207', (127, 130))	('EGFR', 'Gene', (56, 60))	('AKT', 'Gene', '207', (11, 14))	('EGFR', 'Gene', (32, 36))	('AKT', 'Gene', '207', (151, 154))	('DpdtbA', 'Chemical', '-', (185, 191))	('EGFR', 'Gene', '1956', (81, 85))	('AKT', 'Gene', (127, 130))	('EGFR', 'Gene', (81, 85))
141537	31354907	The quantitative analysis indicated that DpdtbA induced the decrease of AKT which had a statistical significance (p < 0.01) in both cell lines, indicating that EGFR was involved in the regulation of AKT.	('AKT', 'Gene', '207', (72, 75))	('decrease', 'NegReg', (60, 68))	('AKT', 'Gene', (199, 202))	('DpdtbA', 'Var', (41, 47))	('AKT', 'Gene', (72, 75))	('EGFR', 'Gene', '1956', (160, 164))	('DpdtbA', 'Chemical', '-', (41, 47))	('EGFR', 'Gene', (160, 164))	('AKT', 'Gene', '207', (199, 202))
141539	31354907	Interestingly, DpdtbA also led to p53 downregulation (Figure 7(a)).	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('DpdtbA', 'Chemical', '-', (15, 21))	('downregulation', 'NegReg', (38, 52))	('DpdtbA', 'Var', (15, 21))
141540	31354907	Statistical analysis revealed that the levels of p53, EGFR, and p-EGFR were significantly decreased after DpdtbA treatment (p < 0.05, Figure 7(b)), which hinted that downregulation of EGFR and AKT might stem from the downregulation of p53 (or mutant p53 might still play a role in the modulation of its downstream targets).	('AKT', 'Gene', '207', (193, 196))	('p53', 'Gene', '7157', (49, 52))	('levels', 'MPA', (39, 45))	('decreased', 'NegReg', (90, 99))	('EGFR', 'Gene', '1956', (54, 58))	('p53', 'Gene', (49, 52))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', (184, 188))	('AKT', 'Gene', (193, 196))	('DpdtbA', 'Chemical', '-', (106, 112))	('downregulation', 'NegReg', (217, 231))	('p53', 'Gene', '7157', (250, 253))	('p53', 'Gene', '7157', (235, 238))	('EGFR', 'Gene', (54, 58))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', '1956', (184, 188))	('p53', 'Gene', (250, 253))	('p53', 'Gene', (235, 238))	('downregulation', 'NegReg', (166, 180))	('mutant', 'Var', (243, 249))
141541	31354907	As mentioned above, DpdtbA treatment led to downregulation of p53 at the protein level in both Kyse 450 and Kyse 150 cell lines, which could be achieved through modulation in transcription and in translation.	('DpdtbA', 'Var', (20, 26))	('downregulation', 'NegReg', (44, 58))	('DpdtbA', 'Chemical', '-', (20, 26))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
141546	31354907	There is convincing evidence from reporter assays that mutant p53 has the ability to transactivate specific target genes, such as c-Myc and EGFR promoter in a manner distinct from wild-type.	('EGFR', 'Gene', (140, 144))	('mutant', 'Var', (55, 61))	('transactivate', 'MPA', (85, 98))	('Myc', 'Gene', '4609', (132, 135))	('Myc', 'Gene', (132, 135))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('EGFR', 'Gene', '1956', (140, 144))
141547	31354907	To determine whether the mutant p53 (H179R in Kyse 450, R248Q and R155Q in Kyse 150) could regulate its downstream target genes, the p53 inhibitor, PFT-alpha was used to confirm the action of p53.	('regulate', 'Reg', (91, 99))	('R155Q', 'Var', (66, 71))	('R248Q', 'Mutation', 'rs11540652', (56, 61))	('p53', 'Gene', '7157', (133, 136))	('R248Q', 'Var', (56, 61))	('H179R', 'Mutation', 'rs1057519991', (37, 42))	('p53', 'Gene', '7157', (192, 195))	('H179R', 'Var', (37, 42))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('R155Q', 'Mutation', 'rs1281325154', (66, 71))	('p53', 'Gene', (133, 136))	('p53', 'Gene', (192, 195))
141549	31354907	And interestingly, similar situation occurred for both EGFR and AKT, supporting that the mutated p53 played a role in downstream gene regulation in the ESC cell lines.	('role', 'Reg', (110, 114))	('EGFR', 'Gene', '1956', (55, 59))	('p53', 'Gene', (97, 100))	('EGFR', 'Gene', (55, 59))	('p53', 'Gene', '7157', (97, 100))	('AKT', 'Gene', '207', (64, 67))	('mutated', 'Var', (89, 96))	('AKT', 'Gene', (64, 67))
141550	31354907	Furthermore, quantitative analysis was given in Figure 8(b); clearly, the alteration in the p53/EGFR/AKT axis had a significant difference before and after DpdtbA treatment (p < 0.05), but the additional effect was not observed in the combination treatment, which might be due to the difference in interaction between PFT-alpha and mutant and wild-type p53.	('interaction', 'Interaction', (298, 309))	('AKT', 'Gene', '207', (101, 104))	('DpdtbA', 'Chemical', '-', (156, 162))	('p53', 'Gene', '7157', (353, 356))	('EGFR', 'Gene', (96, 100))	('AKT', 'Gene', (101, 104))	('p53', 'Gene', (92, 95))	('alteration', 'Reg', (74, 84))	('p53', 'Gene', (353, 356))	('p53', 'Gene', '7157', (92, 95))	('mutant', 'Var', (332, 338))	('EGFR', 'Gene', '1956', (96, 100))
141553	31354907	As mentioned above, DpdtbA induced p53 degradation; accordingly, its downstream target, EGFR and AKT, was also downregulated; it was suggested that the degradation of p53 was mainly a molecular event.	('AKT', 'Gene', '207', (97, 100))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('DpdtbA', 'Var', (20, 26))	('AKT', 'Gene', (97, 100))	('DpdtbA', 'Chemical', '-', (20, 26))	('downregulated', 'NegReg', (111, 124))	('p53', 'Gene', '7157', (167, 170))	('degradation', 'MPA', (39, 50))	('EGFR', 'Gene', '1956', (88, 92))	('p53', 'Gene', (167, 170))	('EGFR', 'Gene', (88, 92))
141558	31354907	Moreover, such effect in downregulation of p53 could also be achieved by MDM2 knockdown via siRNA (Figure S8), indicating that the function of MDM2s E3 ligase was not involved in the ubiquitination of p53, which was further supported by the fact that addition of proteasome inhibitor, MG-132, did not attenuate the p53 degradation (Figure S9).	('MG-132', 'Chemical', 'MESH:C072553', (285, 291))	('p53', 'Gene', (201, 204))	('MDM2', 'Gene', '4193', (143, 147))	('MDM2', 'Gene', (143, 147))	('knockdown', 'Var', (78, 87))	('p53', 'Gene', '7157', (201, 204))	('MDM2', 'Gene', '4193', (73, 77))	('p53', 'Gene', (315, 318))	('p53', 'Gene', '7157', (315, 318))	('MDM2', 'Gene', (73, 77))	('degradation', 'MPA', (319, 330))	('downregulation', 'NegReg', (25, 39))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))
141560	31354907	It was reported that chip (stub1) promoted autophagy-mediated degradation of aggregating mutant p53; DpdtbA-induced p53 degradation might involve this pathway.	('p53', 'Gene', (96, 99))	('DpdtbA', 'Chemical', '-', (101, 107))	('stub1', 'Gene', '10273', (27, 32))	('p53', 'Gene', '7157', (96, 99))	('stub1', 'Gene', (27, 32))	('autophagy-mediated', 'CPA', (43, 61))	('p53', 'Gene', '7157', (116, 119))	('promoted', 'PosReg', (34, 42))	('aggregating', 'Disease', (77, 88))	('mutant', 'Var', (89, 95))	('p53', 'Gene', (116, 119))
141568	31354907	This conclusion was further supported by the experiment of RNA interference, because the knockdown of stub1 by siRNA could attenuate p53 depletion induced by DpdtbA (Figure S10).	('attenuate', 'NegReg', (123, 132))	('stub1', 'Gene', '10273', (102, 107))	('p53', 'Gene', '7157', (133, 136))	('DpdtbA', 'Chemical', '-', (158, 164))	('knockdown', 'Var', (89, 98))	('p53', 'Gene', (133, 136))	('stub1', 'Gene', (102, 107))
141570	31354907	Similar result was observed in Kyse 150 cells (Figures 10(c) and 10(d)), supporting that stub1 chaperon-mediated autophagy involved the p53 degradation, and the mutant p53 still played a role in the gene regulation.	('mutant', 'Var', (161, 167))	('p53', 'Gene', '7157', (136, 139))	('played', 'Reg', (178, 184))	('p53', 'Gene', '7157', (168, 171))	('degradation', 'MPA', (140, 151))	('p53', 'Gene', (168, 171))	('stub1', 'Gene', '10273', (89, 94))	('stub1', 'Gene', (89, 94))	('p53', 'Gene', (136, 139))
141571	31354907	As mentioned above, DpdtbA induced growth inhibition, cell cycle arrest, and apoptosis, which involved ROS production due to SOD inhibition.	('SOD', 'Gene', '6647', (125, 128))	('DpdtbA', 'Var', (20, 26))	('apoptosis', 'CPA', (77, 86))	('ROS', 'Chemical', '-', (103, 106))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('SOD', 'Gene', (125, 128))	('ROS production', 'MPA', (103, 117))	('DpdtbA', 'Chemical', '-', (20, 26))	('cell cycle arrest', 'CPA', (54, 71))	('growth inhibition', 'CPA', (35, 52))
141572	31354907	Further mechanistic study revealed that DpdtbA led to stub1-mediated autophagic degradation of p53 that dominated the level of its downstream targets EGFR and AKT; thus, DpdtbA-induced growth inhibition could be through inactivating the p53/EGFR/AKT signal pathway.	('DpdtbA', 'Var', (40, 46))	('p53', 'Gene', '7157', (95, 98))	('EGFR', 'Gene', '1956', (150, 154))	('AKT', 'Gene', '207', (159, 162))	('p53', 'Gene', '7157', (237, 240))	('DpdtbA-induced', 'Var', (170, 184))	('AKT', 'Gene', '207', (246, 249))	('EGFR', 'Gene', (241, 245))	('inactivating', 'NegReg', (220, 232))	('p53', 'Gene', (95, 98))	('p53', 'Gene', (237, 240))	('DpdtbA', 'Chemical', '-', (170, 176))	('growth inhibition', 'CPA', (185, 202))	('stub1', 'Gene', '10273', (54, 59))	('stub1', 'Gene', (54, 59))	('autophagic degradation', 'CPA', (69, 91))	('EGFR', 'Gene', (150, 154))	('EGFR', 'Gene', '1956', (241, 245))	('AKT', 'Gene', (159, 162))	('DpdtbA', 'Chemical', '-', (40, 46))	('AKT', 'Gene', (246, 249))
141581	31354907	Similarly, the DpdtbA also induced ESC cell accumulation at the S phase (Figure 2) and a decrease of CDK2 (Figure S1).	('ESC cell accumulation at the S phase', 'CPA', (35, 71))	('DpdtbA', 'Chemical', '-', (15, 21))	('decrease', 'NegReg', (89, 97))	('CDK2', 'Gene', (101, 105))	('CDK2', 'Gene', '1017', (101, 105))	('DpdtbA', 'Var', (15, 21))
141582	31354907	In addition, ROS production normally is involved in the action of mechanism for most chemotherapeutic drugs, and the ROS can be generated through Fenton reaction, dysfunction of mitochondria, or imbalance of the redox system, which result in apoptosis and autophagy.	('apoptosis', 'CPA', (242, 251))	('ROS', 'Chemical', '-', (117, 120))	('result in', 'Reg', (232, 241))	('dysfunction', 'Var', (163, 174))	('imbalance', 'Var', (195, 204))	('autophagy', 'CPA', (256, 265))	('imbalance', 'Phenotype', 'HP:0002172', (195, 204))	('ROS', 'Chemical', '-', (13, 16))
141589	31354907	DpdtbA as metal chelator may influence SOD activity.	('SOD', 'Gene', '6647', (39, 42))	('metal', 'Chemical', 'MESH:D008670', (10, 15))	('DpdtbA', 'Var', (0, 6))	('DpdtbA', 'Chemical', '-', (0, 6))	('SOD', 'Gene', (39, 42))	('influence', 'Reg', (29, 38))
141590	31354907	Our data revealed that DpdtbA both inactivated SOD activity and also led to downregulation of SOD (Figures 5(f) and 5(g)), resulting in the imbalance of the redox system.	('DpdtbA', 'Var', (23, 29))	('SOD', 'Gene', (94, 97))	('DpdtbA', 'Chemical', '-', (23, 29))	('inactivated', 'NegReg', (35, 46))	('SOD', 'Gene', '6647', (47, 50))	('SOD', 'Gene', '6647', (94, 97))	('downregulation', 'NegReg', (76, 90))	('imbalance', 'Phenotype', 'HP:0002172', (140, 149))	('SOD', 'Gene', (47, 50))	('imbalance of the redox system', 'MPA', (140, 169))
141591	31354907	Furthermore, excessive ROS production led to occurrence of apoptosis; the results both from flow cytometric analysis and from AO/EB staining (Figure 3 and Figure S4) demonstrated that DpdtbA could induce the occurrence of apoptosis, but the susceptibility of apoptosis induction for the investigated cell lines was a slight difference; Kyse 450 cells seem to be more prone to induce apoptosis than Kyse 150 cells.	('apoptosis', 'CPA', (383, 392))	('excessive ROS production', 'Phenotype', 'HP:0025464', (13, 37))	('EB', 'Chemical', 'MESH:C004912', (129, 131))	('apoptosis', 'CPA', (222, 231))	('DpdtbA', 'Var', (184, 190))	('ROS', 'Chemical', '-', (23, 26))	('DpdtbA', 'Chemical', '-', (184, 190))
141592	31354907	We speculated that the difference in apoptosis induction may relate to the status and abundance of mutation of p53, while the prosurvival effect of bcl-2 might retreat to the back of the p53, playing a secondary role in response to chemotherapeutic agent because mutant p53 (mutp53) cancers are dependent on their hyper stable mutp53 protein for survival (Figures 4 and 7); this might endow Kyse 150 cell less sensitive than Kyse 450 cell.	('bcl-2', 'Gene', '596', (148, 153))	('p53', 'Gene', (330, 333))	('p53', 'Gene', '7157', (330, 333))	('p53', 'Gene', (278, 281))	('p53', 'Gene', '7157', (278, 281))	('protein', 'Protein', (334, 341))	('p53', 'Gene', (187, 190))	('cancers', 'Disease', 'MESH:D009369', (283, 290))	('cancers', 'Disease', (283, 290))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('p53', 'Gene', '7157', (187, 190))	('bcl-2', 'Gene', (148, 153))	('mutant', 'Var', (263, 269))	('p53', 'Gene', (270, 273))	('p53', 'Gene', '7157', (270, 273))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))
141597	31354907	In the present study, we illustrated that DpdtbA could downregulate EGFR in ESC cell lines (Figure 6), which forced us to consider whether the alteration of EGFR stemmed from the alteration of its upstream molecule, p53.	('EGFR', 'Gene', (157, 161))	('DpdtbA', 'Var', (42, 48))	('p53', 'Gene', '7157', (216, 219))	('EGFR', 'Gene', '1956', (68, 72))	('downregulate', 'NegReg', (55, 67))	('DpdtbA', 'Chemical', '-', (42, 48))	('EGFR', 'Gene', '1956', (157, 161))	('EGFR', 'Gene', (68, 72))	('p53', 'Gene', (216, 219))
141599	31354907	Furthermore, DpdtbA also caused downregulation of AKT, a downstream molecule of EGFR, indicating that DpdtbA could inactivate the p53/EGFR/AKT pathway, in accordance with the observation from literature.	('downregulation', 'NegReg', (32, 46))	('DpdtbA', 'Var', (102, 108))	('DpdtbA', 'Var', (13, 19))	('EGFR', 'Gene', (134, 138))	('AKT', 'Gene', '207', (50, 53))	('AKT', 'Gene', '207', (139, 142))	('DpdtbA', 'Chemical', '-', (13, 19))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('AKT', 'Gene', (139, 142))	('AKT', 'Gene', (50, 53))	('DpdtbA', 'Chemical', '-', (102, 108))	('p53', 'Gene', (130, 133))	('inactivate', 'NegReg', (115, 125))	('EGFR', 'Gene', '1956', (134, 138))	('p53', 'Gene', '7157', (130, 133))
141600	31354907	It is well documented that p53 is often mutated and overexpressed in cancer cells, restoring p53 function; reintroducing or rescuing wild-type p53 into cancer cells could achieve inhibition of cancer.	('restoring', 'PosReg', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('p53', 'Gene', '7157', (143, 146))	('p53', 'Gene', '7157', (27, 30))	('cancer', 'Disease', (193, 199))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('reintroducing', 'Var', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('function', 'MPA', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('p53', 'Gene', (143, 146))	('p53', 'Gene', (27, 30))
141601	31354907	On the other hand, the accumulating evidences reveal that stabilization of mutant p53 in tumors is important for its oncogenic activities; thus, depletion of mutant p53 may attenuate the malignant properties of cancer cells.	('p53', 'Gene', (165, 168))	('tumors', 'Disease', (89, 95))	('p53', 'Gene', '7157', (165, 168))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('depletion', 'MPA', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (211, 217))	('mutant', 'Var', (75, 81))	('attenuate', 'NegReg', (173, 182))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('mutant', 'Var', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
141604	31354907	Autophagy is an important proteolytic system to devote to clearing cellular misfolded proteins or protein aggregates, and moreover, it was also reported that chip promotes autophagy-mediated degradation of aggregating mutant p53; we speculated that the mutant p53 degradation might involve autophagy.	('p53', 'Gene', (225, 228))	('autophagy-mediated degradation', 'CPA', (172, 202))	('p53', 'Gene', '7157', (225, 228))	('p53', 'Gene', (260, 263))	('p53', 'Gene', '7157', (260, 263))	('mutant', 'Var', (218, 224))	('promotes', 'PosReg', (163, 171))	('mutant', 'Var', (253, 259))
141605	31354907	stub1 (chip) has been shown to be important for mutant p53 degradation both in normoxia and in hypoxia; the stub1 (chip) might also involve the p53 degradation induced by DpdtbA.	('degradation', 'MPA', (59, 70))	('mutant', 'Var', (48, 54))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (144, 147))	('p53', 'Gene', '7157', (55, 58))	('hypoxia', 'Disease', (95, 102))	('hypoxia', 'Disease', 'MESH:D000860', (95, 102))	('DpdtbA', 'Chemical', '-', (171, 177))	('stub1', 'Gene', '10273', (108, 113))	('stub1', 'Gene', (108, 113))	('stub1', 'Gene', '10273', (0, 5))	('stub1', 'Gene', (0, 5))	('p53', 'Gene', (144, 147))
141606	31354907	As expected, the stub1 was downregulated with the decrease of p53 when DpdtbA was exposed to the cells (Figure 9), and knocking down of stub1 by siRNA intervention led to downregulation of p53, which supported that stub1 mediated the degradation of p53 (Figure S10).	('stub1', 'Gene', '10273', (17, 22))	('stub1', 'Gene', (17, 22))	('DpdtbA', 'Chemical', '-', (71, 77))	('p53', 'Gene', '7157', (189, 192))	('downregulation', 'NegReg', (171, 185))	('stub1', 'Gene', (136, 141))	('p53', 'Gene', (189, 192))	('p53', 'Gene', '7157', (62, 65))	('downregulated', 'NegReg', (27, 40))	('stub1', 'Gene', '10273', (215, 220))	('p53', 'Gene', (249, 252))	('stub1', 'Gene', (215, 220))	('p53', 'Gene', '7157', (249, 252))	('stub1', 'Gene', '10273', (136, 141))	('p53', 'Gene', (62, 65))	('knocking down', 'Var', (119, 132))	('decrease', 'NegReg', (50, 58))
141608	31354907	Those indicated that mutant p53 (H179R) (or R248Q and R155Q in kyse150) in Kyse 450 cells still played a role in gene regulation, in accordance with the findings from other laboratories, such as Dong et al., who demonstrated that the expression of p53 gain-of-function mutation R175H in endometrial cancer cells increased the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway.	('p53', 'Gene', (28, 31))	('gain-of-function', 'PosReg', (252, 268))	('p53', 'Gene', '7157', (248, 251))	('R248Q', 'Mutation', 'rs11540652', (44, 49))	('H179R', 'Mutation', 'rs1057519991', (33, 38))	('R155Q', 'Var', (54, 59))	('R248Q', 'Var', (44, 49))	('EGFR', 'Gene', (367, 371))	('p53', 'Gene', (248, 251))	('AKT', 'Gene', (377, 380))	('activation', 'PosReg', (349, 359))	('EGFR', 'Gene', '1956', (367, 371))	('endometrial cancer', 'Phenotype', 'HP:0012114', (287, 305))	('R175H', 'Mutation', 'rs28934578', (278, 283))	('R155Q', 'Mutation', 'rs1281325154', (54, 59))	('p53', 'Gene', '7157', (28, 31))	('R175H', 'Var', (278, 283))	('endometrial cancer', 'Disease', (287, 305))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('AKT', 'Gene', '207', (377, 380))	('endometrial cancer', 'Disease', 'MESH:D016889', (287, 305))
141609	31354907	In addition, some mutants of p53 (G245C and R273H) in esophageal squamous cells confer a stronger proliferative capacity.	('G245C', 'Mutation', 'rs28934573', (34, 39))	('esophageal', 'Disease', (54, 64))	('G245C', 'Var', (34, 39))	('proliferative capacity', 'CPA', (98, 120))	('p53', 'Gene', (29, 32))	('stronger', 'PosReg', (89, 97))	('esophageal', 'Disease', 'MESH:D004941', (54, 64))	('R273H', 'Var', (44, 49))	('R273H', 'Mutation', 'rs28934576', (44, 49))	('p53', 'Gene', '7157', (29, 32))
141610	31354907	Those demonstrated that depletion of mutant p53 is one of the important strategies in cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutant', 'Var', (37, 43))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('depletion', 'MPA', (24, 33))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
141614	31354907	Furthermore, DpdtbA could induce downregulation of EGFR, p53, and AKT, hinting that the mutant p53 still played a role in the proliferation of ESC cells.	('played', 'Reg', (105, 111))	('p53', 'Gene', '7157', (57, 60))	('DpdtbA', 'Var', (13, 19))	('AKT', 'Gene', (66, 69))	('EGFR', 'Gene', (51, 55))	('ESC', 'Disease', (143, 146))	('role', 'Reg', (114, 118))	('DpdtbA', 'Chemical', '-', (13, 19))	('mutant', 'Var', (88, 94))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('p53', 'Gene', (57, 60))	('AKT', 'Gene', '207', (66, 69))	('downregulation', 'NegReg', (33, 47))	('EGFR', 'Gene', '1956', (51, 55))
141616	31354907	Taken together, DpdtbA-induced growth inhibition was through inactivating the p53/EGFR/AKT signal pathway.	('growth inhibition', 'CPA', (31, 48))	('EGFR', 'Gene', (82, 86))	('DpdtbA-induced', 'Var', (16, 30))	('DpdtbA', 'Chemical', '-', (16, 22))	('AKT', 'Gene', (87, 90))	('inactivating', 'NegReg', (61, 73))	('p53', 'Gene', (78, 81))	('EGFR', 'Gene', '1956', (82, 86))	('p53', 'Gene', '7157', (78, 81))	('AKT', 'Gene', '207', (87, 90))
141619	31354907	Antibodies p53, p-p53, and ferritin were purchased from Cell Signaling Technology (Massachusetts, USA); siRNA for MDM2 (stB0001232) and stub1 (stB0001238) were obtained from RiboBio (Guangzhou, China).	('p53', 'Gene', (11, 14))	('MDM2', 'Gene', (114, 118))	('p53', 'Gene', '7157', (11, 14))	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('stB0001232', 'Var', (120, 130))	('stB0001238', 'Var', (143, 153))	('stub1', 'Gene', '10273', (136, 141))	('stub1', 'Gene', (136, 141))	('MDM2', 'Gene', '4193', (114, 118))
141622	31354907	According to the Catalogue of Somatic Mutations in Cancer (COSMIC) database (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/), the status of TP53 is H179R in Kyse 450, R248Q and R155Q in Kyse 150, and nonmutation in Kyse 510.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('TP53', 'Gene', (150, 154))	('R155Q', 'Mutation', 'rs1281325154', (187, 192))	('cancer', 'Disease', (84, 90))	('R248Q', 'Mutation', 'rs11540652', (177, 182))	('Cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('R155Q', 'Var', (187, 192))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('H179R', 'Var', (158, 163))	('TP53', 'Gene', '7157', (150, 154))	('cancer', 'Disease', (104, 110))	('R248Q', 'Var', (177, 182))	('H179R', 'Mutation', 'rs1057519991', (158, 163))
141651	30258911	At early stages of tumorigenesis, the inactivation and/or loss of growth-retarding tumor suppressor genes (such as PTEN and p53) promote uncontrolled cell division and transformation into cancer cells.	('transformation', 'CPA', (168, 182))	('promote', 'PosReg', (129, 136))	('tumor', 'Disease', (83, 88))	('inactivation', 'Var', (38, 50))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('PTEN', 'Gene', (115, 119))	('growth-retarding tumor', 'Disease', 'MESH:D006130', (66, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('loss', 'NegReg', (58, 62))	('p53', 'Gene', '7157', (124, 127))	('PTEN', 'Gene', '5728', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancer', 'Disease', (188, 194))	('uncontrolled cell division', 'CPA', (137, 163))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('p53', 'Gene', (124, 127))	('growth-retarding tumor', 'Disease', (66, 88))	('growth-retarding', 'Phenotype', 'HP:0001510', (66, 82))
141652	30258911	During metastasis, malignant tumors invade other organs and spread to distant sites, usually accompanied by the inactivation and/or loss of metastasis suppressor genes (such as E-cadherin), which specifically suppress metastasis without affecting primary tumor growth.	('malignant tumors', 'Disease', (19, 35))	('inactivation', 'Var', (112, 124))	('E-cadherin', 'Gene', (177, 187))	('primary tumor', 'Disease', (247, 260))	('malignant tumors', 'Disease', 'MESH:D018198', (19, 35))	('loss', 'NegReg', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('E-cadherin', 'Gene', '999', (177, 187))	('metastasis', 'CPA', (218, 228))	('primary tumor', 'Disease', 'MESH:D009369', (247, 260))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('suppress', 'NegReg', (209, 217))
141666	30258911	Two serine residues (serine 362 and serine 604) were identified as putative ERK1/2 phosphorylation sites in human EPLIN proteins, and point mutations at these residues (serine to alanine) rendered resistance to EGF-induced protein turnover.	('alanine', 'Chemical', 'MESH:D000409', (179, 186))	('point mutations', 'Var', (134, 149))	('serine', 'Var', (21, 27))	('ERK1/2', 'Gene', (76, 82))	('rendered', 'Reg', (188, 196))	('EGF', 'Gene', '1950', (211, 214))	('serine', 'Chemical', 'MESH:D012694', (4, 10))	('ERK1/2', 'Gene', '5595;5594', (76, 82))	('resistance', 'MPA', (197, 207))	('serine', 'Chemical', 'MESH:D012694', (21, 27))	('serine', 'Var', (169, 175))	('human', 'Species', '9606', (108, 113))	('serine', 'Chemical', 'MESH:D012694', (169, 175))	('serine', 'Chemical', 'MESH:D012694', (36, 42))	('EGF', 'Gene', (211, 214))
141685	30258911	Consistent with our findings, an inverse association between EPLIN transcripts and the metastatic potential or tumor grade of prostate, colon, and head and neck cancer was observed.	('metastatic potential', 'CPA', (87, 107))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('head and neck cancer', 'Phenotype', 'HP:0012288', (147, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('inverse', 'NegReg', (33, 40))	('EPLIN', 'Protein', (61, 66))	('colon', 'Disease', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('neck cancer', 'Disease', 'MESH:D006258', (156, 167))	('neck cancer', 'Disease', (156, 167))	('tumor', 'Disease', (111, 116))	('prostate', 'Disease', (126, 134))	('transcripts', 'Var', (67, 78))
141688	30258911	Further, EPLIN depletion disrupts the apical organization of F-actin and the association between the cortical actin bundles and the cadherin-catenin complex, suggesting that EPLIN is indispensable for the stabilization of the circumferential actin belt at adherens junctions (AJs).	('depletion', 'Var', (15, 24))	('EPLIN', 'Gene', (9, 14))	('F-actin', 'Protein', (61, 68))	('cadherin', 'Gene', (132, 140))	('disrupts', 'NegReg', (25, 33))	('cadherin', 'Gene', '999;1003', (132, 140))	('apical organization', 'CPA', (38, 57))	('association', 'Interaction', (77, 88))
141693	30258911	Small-interfering RNA (siRNA) depletion of EPLIN from Hela and MCF-7 cells induces cytokinesis failure, suggesting that the loss of EPLIN may induce aneuploidy and contribute to genomic instability.	('EPLIN', 'Gene', (132, 137))	('loss', 'Var', (124, 128))	('aneuploidy', 'Disease', (149, 159))	('MCF-7', 'CellLine', 'CVCL:0031', (63, 68))	('cytokinesis failure', 'MPA', (83, 102))	('contribute', 'Reg', (164, 174))	('induce', 'Reg', (142, 148))	('Hela', 'CellLine', 'CVCL:0030', (54, 58))	('aneuploidy', 'Disease', 'MESH:D000782', (149, 159))	('genomic instability', 'CPA', (178, 197))
141700	30258911	Conversely, EPLIN-alpha depletion in ovarian cancer cells increased growth, invasion, adhesion and migration in vitro.	('ovarian cancer', 'Disease', 'MESH:D010051', (37, 51))	('increased', 'PosReg', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('adhesion', 'CPA', (86, 94))	('ovarian cancer', 'Disease', (37, 51))	('depletion', 'Var', (24, 33))	('EPLIN-alpha', 'Protein', (12, 23))	('migration', 'CPA', (99, 108))	('ovarian cancer', 'Phenotype', 'HP:0100615', (37, 51))	('growth', 'CPA', (68, 74))	('invasion', 'CPA', (76, 84))
141710	30258911	On the contrary, however, we observed that EPLIN knockdown in ARCaPE cells induced cell cycle arrest and inhibited the in vitro proliferation and in vivo growth in athymic nude mice ( and unpublished results).	('knockdown', 'Var', (49, 58))	('EPLIN', 'Protein', (43, 48))	('in vitro proliferation', 'CPA', (119, 141))	('inhibited', 'NegReg', (105, 114))	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('arrest', 'Disease', (94, 100))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('nude mice', 'Species', '10090', (172, 181))
141711	30258911	EPLIN depletion also significantly enhanced cell resistance to treatment with docetaxel and doxorubicin (by ~8-fold and ~4.4-fold, respectively).	('cell resistance', 'CPA', (44, 59))	('doxorubicin', 'Chemical', 'MESH:D004317', (92, 103))	('EPLIN', 'Protein', (0, 5))	('enhanced', 'PosReg', (35, 43))	('depletion', 'Var', (6, 15))	('docetaxel', 'Chemical', 'MESH:D000077143', (78, 87))
141713	30258911	The acquired invasiveness upon EPLIN depletion was accompanied by the changes of EMT markers at molecular levels, including reduced E-cadherin and increased vimentin.	('E-cadherin', 'Gene', (132, 142))	('increased', 'PosReg', (147, 156))	('reduced', 'NegReg', (124, 131))	('depletion', 'Var', (37, 46))	('E-cadherin', 'Gene', '999', (132, 142))	('changes', 'Reg', (70, 77))	('EPLIN', 'Protein', (31, 36))	('vimentin', 'Gene', '7431', (157, 165))	('invasiveness', 'CPA', (13, 25))	('vimentin', 'Gene', (157, 165))
141716	30258911	EPLIN depletion also resulted in a remarkable reduction of several microRNAs (miRNAs), including miR-205, miR-200b and miR-429, whose downregulation is thought to be the essential feature of EMT and acquisition of cancer stem cell properties.	('miR-205', 'Gene', (97, 104))	('reduction', 'NegReg', (46, 55))	('cancer', 'Disease', (214, 220))	('miR-200b', 'Gene', '406984', (106, 114))	('miR-429', 'Gene', (119, 126))	('miR-205', 'Gene', '406988', (97, 104))	('EPLIN', 'Protein', (0, 5))	('miR-429', 'Gene', '554210', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('depletion', 'Var', (6, 15))	('miR-200b', 'Gene', (106, 114))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
141723	30258911	In prostate cancer and melanoma cells, it has become clear that EPLIN depletion promotes EMT and activates oncogenic pathways, which is associated with dramatic changes in morphology and cellular behaviors (such as chemoresistance).	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('activates', 'PosReg', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('EPLIN', 'Protein', (64, 69))	('melanoma', 'Disease', (23, 31))	('changes', 'Reg', (161, 168))	('prostate cancer', 'Disease', (3, 18))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('oncogenic pathways', 'Pathway', (107, 125))	('depletion', 'Var', (70, 79))	('EMT', 'CPA', (89, 92))	('promotes', 'PosReg', (80, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
141730	29221213	This meta-analysis indicated that positive/high expression of cyclin B1 may have a close association with worse survival in patients with esophageal cancer, but better prognosis in patients with colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (195, 212))	('esophageal cancer', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cyclin B1', 'Gene', '891', (62, 71))	('cyclin B1', 'Gene', (62, 71))	('better', 'PosReg', (161, 167))	('colorectal cancer', 'Disease', (195, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('patients', 'Species', '9606', (181, 189))	('colorectal cancer', 'Disease', 'MESH:D015179', (195, 212))	('positive/high', 'Var', (34, 47))	('patients', 'Species', '9606', (124, 132))
141744	29221213	A total of 9 studies were included to analyze the relationship of positive/high cyclin B1 expression with 3-year overall survival in patients with digestive cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('positive/high', 'Var', (66, 79))	('cyclin B1', 'Gene', '891', (80, 89))	('cyclin B1', 'Gene', (80, 89))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('expression', 'MPA', (90, 100))	('cancer', 'Disease', (157, 163))
141746	29221213	Ten studies reported the association between positive/high expression of cyclin B1 and 5-year OS, of which four were about patients with esophageal cancer, four about gastric cancer and two about colorectal cancer.	('positive/high', 'Var', (45, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('colorectal cancer', 'Disease', (196, 213))	('gastric cancer', 'Disease', (167, 181))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('patients', 'Species', '9606', (123, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (196, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	('colorectal cancer', 'Disease', 'MESH:D015179', (196, 213))	('esophageal cancer', 'Disease', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cyclin B1 and 5', 'Gene', '891', (73, 88))
141757	29221213	The results indicated significant association between positive/high cyclin B1 expression and Size of tumor (OR 0.60, 95% CI 0.38, 0.93; P = 0.02) and Distant metastasis (OR 0.30, 95% CI 0.13, 0.71; P = 0.006), using fixed-effect models.	('cyclin B1', 'Gene', (68, 77))	('expression', 'MPA', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('positive/high', 'Var', (54, 67))	('Distant metastasis', 'CPA', (150, 168))	('cyclin B1', 'Gene', '891', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
141758	29221213	Subgroup analysis was conducted to find the prognostic effects of positive/high cyclin B1 expression on 3 and 5-year OS.	('cyclin B1', 'Gene', '891', (80, 89))	('cyclin B1', 'Gene', (80, 89))	('expression', 'MPA', (90, 100))	('positive/high', 'Var', (66, 79))
141765	29221213	It has been implicated that high expression of cyclin B1, to a certain extent, may impede the autogenous controlling of cell growth and lead to a malignant phenotype.	('impede', 'NegReg', (83, 89))	('lead to', 'Reg', (136, 143))	('high expression', 'Var', (28, 43))	('cyclin B1', 'Gene', '891', (47, 56))	('cyclin B1', 'Gene', (47, 56))	('autogenous controlling of cell growth', 'CPA', (94, 131))	('malignant phenotype', 'CPA', (146, 165))
141778	29221213	However, surprisingly, we found the prominent pertinence between the high/over-expression of cyclin B1 and esophageal cancer or colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('cyclin B1', 'Gene', '891', (93, 102))	('cyclin B1', 'Gene', (93, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('high/over-expression', 'Var', (69, 89))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colorectal cancer', 'Disease', (128, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))
141779	29221213	In esophageal cancer, cyclin B1 positive/high expression had an evident association with both 3-year OS (OR 0.21, 95% CI 0.12-0.37; P < 0.00001) (Figure 4) and 5-year OS (OR 0.20, 95% CI 0.12-0.34; P < 0.00001) (Figure 5).	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('positive/high', 'Var', (32, 45))	('cyclin B1', 'Gene', '891', (22, 31))	('cyclin B1', 'Gene', (22, 31))
141782	29221213	According to the results, patients with cyclin B1 positive/high expression experienced a poor prognosis and low 3 or 5-year OS in esophageal cancer, but high 5-year OS in patients with colorectal cancer, which was consistent with the study of Korenaga D et al.	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('colorectal cancer', 'Phenotype', 'HP:0003003', (185, 202))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('positive/high', 'Var', (50, 63))	('colorectal cancer', 'Disease', (185, 202))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (171, 179))	('low', 'NegReg', (108, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (185, 202))	('cyclin B1', 'Gene', '891', (40, 49))	('cyclin B1', 'Gene', (40, 49))	('esophageal cancer', 'Disease', (130, 147))
141789	29221213	In subgroup analysis of 3 and 5-year OS, the results indicated that positive/high cyclin B1 expression was prominently correlated with 3-year OS of patients with stage I-III (OR 0.25; 95% CI 0.11, 0.58; P = 0.001) and 5-year OS of patients with stage I-III (OR 0.23; 95% CI 0.11, 0.48; P < 0.0001) and TNM stage P < 0.05 (OR 0.32; 95% CI 0.13, 0.76; P=0.010), but not in other subgroups.	('TNM', 'Gene', (302, 305))	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (231, 239))	('TNM', 'Gene', '10178', (302, 305))	('positive/high', 'Var', (68, 81))	('cyclin B1', 'Gene', '891', (82, 91))	('cyclin B1', 'Gene', (82, 91))	('expression', 'MPA', (92, 102))
141793	29221213	Indeed, cut-off values of > 30%, > 40%, and > 50% also were correlated significantly with patient outcome, with values of P < 0.0001.	('> 50%', 'Var', (44, 49))	('patient', 'Species', '9606', (90, 97))	('> 40%', 'Var', (33, 38))
141795	29221213	Indeed, according to our results, patients with stage I-III who had high/positive cyclin B1 expression had poor 3 or 5-year OS.	('high/positive', 'Var', (68, 81))	('patients', 'Species', '9606', (34, 42))	('cyclin B1', 'Gene', (82, 91))	('cyclin B1', 'Gene', '891', (82, 91))	('poor', 'NegReg', (107, 111))	('expression', 'MPA', (92, 102))
141806	29221213	The primary objective was the association between cyclin B1 high/positive expression and 3-year OS or 5-year OS.	('high/positive expression', 'Var', (60, 84))	('cyclin B1', 'Gene', (50, 59))	('cyclin B1', 'Gene', '891', (50, 59))	('association', 'Interaction', (30, 41))
141807	29221213	The secondary objective was the association between cyclin B1 high/positive expression and clinical features including Age, Gender, Size of tumor, Histologic type, Pathologic T, Pathologic N, distant metastasis, Blood vessel invasion, Lymphatic vessel invasion and clinical TNM stage.	('Blood vessel invasion', 'CPA', (212, 233))	('TNM', 'Gene', (274, 277))	('TNM', 'Gene', '10178', (274, 277))	('cyclin B1', 'Gene', '891', (52, 61))	('high/positive expression', 'Var', (62, 86))	('cyclin B1', 'Gene', (52, 61))	('Lymphatic vessel invasion', 'CPA', (235, 260))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('distant metastasis', 'CPA', (192, 210))	('association', 'Interaction', (32, 43))	('tumor', 'Disease', (140, 145))
141817	27486968	In contrast, dietary nitrite intake was positively associated with adult glioma and thyroid cancer risk with pooled RR of 1.21 (95%CI = 1.03-1.42) and 1.52 (95%CI = 1.12-2.05), respectively.	('nitrite', 'Chemical', 'MESH:D009573', (21, 28))	('thyroid cancer', 'Disease', (84, 98))	('adult glioma', 'Disease', (67, 79))	('thyroid cancer', 'Phenotype', 'HP:0002890', (84, 98))	('adult glioma', 'Disease', 'MESH:D005910', (67, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('thyroid cancer', 'Disease', 'MESH:D013964', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('associated', 'Interaction', (51, 61))	('dietary', 'Var', (13, 20))
141907	27678357	Seventh tumor-node-metastasis staging of gastric cancer: Five-year follow-up Seventh tumor-node-metastasis (TNM) classification for gastric cancer, published in 2010, introduced changes in all of its three parameters with the aim to increase its accuracy in prognostication.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))	('tumor-node-metastasis', 'Disease', (8, 29))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (8, 29))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('changes', 'Var', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('gastric cancer', 'Disease', (132, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('tumor-node-metastasis', 'Disease', (85, 106))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (85, 106))	('tumor', 'Disease', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('increase', 'PosReg', (233, 241))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('gastric cancer', 'Disease', (41, 55))
141937	27678357	Most studies concluded that LNR is superior to the traditional N stage in TNM system in stratifying the prognosis of gastric cancer patients.	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastric cancer', 'Disease', (117, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('LNR', 'Var', (28, 31))	('patients', 'Species', '9606', (132, 140))
141947	27678357	However, patients with N3b tumors do have a very scarce prognosis, although they are considered same as N3a in stage grouping.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('patients', 'Species', '9606', (9, 17))	('N3b', 'Var', (23, 26))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))
141985	26412785	In addition, there was a trend toward improved survival in mice administered both rh-Endo and IR, although statistical significance was not attained (Fig.	('mice', 'Species', '10090', (59, 63))	('improved', 'PosReg', (38, 46))	('survival', 'CPA', (47, 55))	('rh-Endo', 'Var', (82, 89))	('rh-Endo', 'Chemical', '-', (82, 89))
141989	26412785	In further analysis, it was observed that treatment with rh-Endo caused a greater reduction of new vessels than functional vessels, as well as an increase in pericyte coverage (Fig.	('increase', 'PosReg', (146, 154))	('new vessels', 'CPA', (95, 106))	('reduction', 'NegReg', (82, 91))	('rh-Endo', 'Var', (57, 64))	('rh-Endo', 'Chemical', '-', (57, 64))	('pericyte coverage', 'CPA', (158, 175))
141990	26412785	Interestingly, treatment with rh-Endo significantly improved tumor hypoxia on D22 (i.e.	('improved', 'PosReg', (52, 60))	('D22', 'Var', (78, 81))	('rh-Endo', 'Chemical', '-', (30, 37))	('rh-Endo', 'Gene', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor hypoxia', 'Disease', 'MESH:D000860', (61, 74))	('tumor hypoxia', 'Disease', (61, 74))
141996	26412785	Flow cytometry experiments revealed that rh-Endo (at concentrations that did not affect growth of ESCC cell lines) induced apoptosis of HUVECs in vitro in a dose-dependent manner (Fig.	('rh-Endo', 'Var', (41, 48))	('apoptosis', 'CPA', (123, 132))	('rh-Endo', 'Chemical', '-', (41, 48))	('HUVEC', 'CellLine', 'CVCL:2959', (136, 141))
141998	26412785	These data suggest that the target of rh-Endo is endothelial cells rather than tumor cells, and that the alleviation of hypoxia was not due to tumor cell killing.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('rh-Endo', 'Chemical', '-', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (143, 148))	('hypoxia', 'Disease', (120, 127))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('rh-Endo', 'Var', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
142009	26412785	Translational experiments indicated that the improved radioresponse with rh-Endo might be attributable to tumor vasculature remodeling and hypoxia reduction, possibly through regulation of the HIF/VEGF pathway.	('hypoxia reduction', 'Disease', (139, 156))	('VEGF', 'Gene', '7422', (197, 201))	('hypoxia reduction', 'Disease', 'MESH:D000860', (139, 156))	('rh-Endo', 'Chemical', '-', (73, 80))	('improved', 'PosReg', (45, 53))	('tumor vasculature remodeling', 'Disease', (106, 134))	('VEGF', 'Gene', (197, 201))	('radioresponse', 'MPA', (54, 67))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor vasculature remodeling', 'Disease', 'MESH:C565633', (106, 134))	('rh-Endo', 'Var', (73, 80))
142013	26412785	Aberrant tumor vasculature is hyperpermeable and tortuous, and confers compromised blood supply to tumor tissues leading to a hypoxic and acidic tumor microenvironment.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('hypoxic', 'Disease', (126, 133))	('Aberrant', 'Var', (0, 8))	('hypoxic', 'Disease', 'MESH:D000860', (126, 133))	('acidic tumor', 'Disease', 'MESH:D009369', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (9, 14))	('acidic tumor', 'Disease', (138, 150))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
142017	26412785	In contrast to the reduced MVD, we observed an increase in the amount of pericytes and their endothelial coverage 5 days after rh-Endo treatment (IHC of alpha-SMA).	('endothelial coverage', 'CPA', (93, 113))	('alpha-SMA', 'Gene', (153, 162))	('alpha-SMA', 'Gene', '11475', (153, 162))	('rh-Endo', 'Var', (127, 134))	('increase', 'PosReg', (47, 55))	('rh-Endo', 'Chemical', '-', (127, 134))
142019	26412785	In our study, pimonidazole was employed to validate the hypoxic change, and rh-Endo was found to reduce overall tumor hypoxia from day 5.	('tumor hypoxia', 'Disease', (112, 125))	('rh-Endo', 'Var', (76, 83))	('pimonidazole', 'Chemical', 'MESH:C033815', (14, 26))	('hypoxic change', 'Disease', 'MESH:D009402', (56, 70))	('hypoxic change', 'Disease', (56, 70))	('rh-Endo', 'Chemical', '-', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor hypoxia', 'Disease', 'MESH:D000860', (112, 125))	('reduce', 'NegReg', (97, 103))
142022	26412785	In vitro studies were conducted to determine whether rh-Endo radiosensitizes ESCC cells directly, and these showed no radiosensitization effect in ESCC cell lines.	('ESCC', 'Disease', (77, 81))	('rh-Endo', 'Chemical', '-', (53, 60))	('rh-Endo', 'Var', (53, 60))
142024	26412785	In the molecular analysis, we detected HIF/VEGF expression changes in the tissues after treatment with rh-Endo, and this was enhanced by irradiation.	('rh-Endo', 'Chemical', '-', (103, 110))	('expression', 'MPA', (48, 58))	('changes', 'Reg', (59, 66))	('VEGF', 'Gene', (43, 47))	('enhanced', 'PosReg', (125, 133))	('rh-Endo', 'Var', (103, 110))	('VEGF', 'Gene', '7422', (43, 47))
142032	26412785	Fifth, although there appeared to be a trend for improved survival in mice treated with both rh-Endo and IR, statistical significance was not attained.	('improved', 'PosReg', (49, 57))	('rh-Endo', 'Chemical', '-', (93, 100))	('survival', 'CPA', (58, 66))	('mice', 'Species', '10090', (70, 74))	('rh-Endo', 'Var', (93, 100))
142138	25777421	Recently, a retrospective study showed that metformin use is associated with an increased CRT response in esophageal adenocarcinoma, but no benefit of metformin was observed for OS.	('metformin', 'Var', (44, 53))	('increased', 'PosReg', (80, 89))	('metformin', 'Chemical', 'MESH:D008687', (44, 53))	('esophageal adenocarcinoma', 'Disease', (106, 131))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (106, 131))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (106, 131))	('metformin', 'Chemical', 'MESH:D008687', (151, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('CRT response', 'MPA', (90, 102))	('OS', 'Chemical', '-', (178, 180))
142203	24179544	The Eca109, Eca109/PCDNA3.1 and Eca109/ABCG2 cells (4x105) were incubated with 0.02 mug/ml ADM at 37 C for 2 h and washed twice with ice-cold PBS.	('ADM', 'Chemical', 'MESH:D004317', (91, 94))	('ABCG2', 'Gene', (39, 44))	('0.02', 'Var', (79, 83))	('ABCG2', 'Gene', '9429', (39, 44))	('PBS', 'Chemical', '-', (142, 145))
142233	24179544	The increased accumulation of ADM in the Eca109/ABCG2 cells caused by Art was due to the inhibition of the ADM efflux (Fig.	('ADM', 'Chemical', 'MESH:D004317', (107, 110))	('ABCG2', 'Gene', '9429', (48, 53))	('accumulation', 'PosReg', (14, 26))	('ADM', 'Chemical', 'MESH:D004317', (30, 33))	('Art', 'Chemical', 'MESH:D000077332', (70, 73))	('inhibition', 'NegReg', (89, 99))	('ADM efflux', 'MPA', (107, 117))	('Art', 'Var', (70, 73))	('ABCG2', 'Gene', (48, 53))
142241	24179544	Overexpression of these transporters results in drug resistance in a number of tumors.	('results in', 'Reg', (37, 47))	('drug resistance', 'Phenotype', 'HP:0020174', (48, 63))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Overexpression', 'Var', (0, 14))	('drug resistance', 'MPA', (48, 63))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
142349	31943824	Adjuvant radiotherapy and chemotherapy may have a synergistic effect in eliminating cancer cells of local residual and distant micrometastasis.9 Those reports, as well as our analysis, suggested that patients with both older age and less than 15 resected lymph nodes were at higher risk of disease progression, and of diminished survival.	('less than', 'Var', (233, 242))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('diminished', 'NegReg', (318, 328))	('patients', 'Species', '9606', (200, 208))	('cancer', 'Disease', (84, 90))	('survival', 'CPA', (329, 337))	('disease progression', 'CPA', (290, 309))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
142356	28376832	HOX transcript antisense RNA (HOTAIR), a long noncoding RNA (lncRNA) expressed from the HOXC locus, has been recently revealed as an oncogenic regulator in ESCC.	('SCC', 'Gene', (157, 160))	('antisense', 'Var', (15, 24))	('SCC', 'Gene', '6317', (157, 160))	('HOXC', 'Gene', '3220', (88, 92))	('HOTAIR', 'Gene', (30, 36))	('HOXC', 'Gene', (88, 92))	('HOTAIR', 'Gene', '100124700', (30, 36))
142493	28000881	As summarized in Table I, the high expression of C14orf166 was significantly associated with T staging (P<0.001), lymph node metastasis (P=0.000) and TNM stage (P=0.000) respectively.	('TNM', 'Gene', '10178', (150, 153))	('C14orf166', 'Gene', '51637', (49, 58))	('lymph node metastasis', 'CPA', (114, 135))	('high expression', 'Var', (30, 45))	('T staging', 'CPA', (93, 102))	('TNM', 'Gene', (150, 153))	('C14orf166', 'Gene', (49, 58))	('associated', 'Reg', (77, 87))
142521	28000881	Dysfunction of GSK-3beta is prevalent in tumor formation, promoting progression and contributing to drug resistance by interfering with signaling pathways, including phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR), Wnt/beta-catenin and JAK2/STAT3 signaling pathways.	('mTOR', 'Gene', (257, 261))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('drug resistance', 'Phenotype', 'HP:0020174', (100, 115))	('JAK2', 'Gene', '3717', (285, 289))	('AKT', 'Gene', (221, 224))	('mTOR', 'Gene', '2475', (257, 261))	('mammalian target of rapamycin', 'Gene', '2475', (226, 255))	('JAK2', 'Gene', (285, 289))	('AKT', 'Gene', '207', (221, 224))	('beta-catenin', 'Gene', (268, 280))	('Dysfunction', 'Var', (0, 11))	('promoting', 'PosReg', (58, 67))	('tumor', 'Disease', (41, 46))	('mammalian target of rapamycin', 'Gene', (226, 255))	('GSK-3beta', 'Gene', '2932', (15, 24))	('beta-catenin', 'Gene', '1499', (268, 280))	('STAT3', 'Gene', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('prevalent', 'Reg', (28, 37))	('progression', 'CPA', (68, 79))	('STAT3', 'Gene', '6774', (290, 295))	('GSK-3beta', 'Gene', (15, 24))	('contributing', 'Reg', (84, 96))	('interfering', 'NegReg', (119, 130))	('signaling pathways', 'Pathway', (136, 154))
142525	28000881	The dysregulated intracellular JAK2/STAT3 signaling pathway is common in numerous types of carcinoma and is associated with malignancy and poor prognosis, an antagonist of the pathway attenuates tumor bearing and improves drug efficacy.	('tumor', 'Disease', (195, 200))	('STAT3', 'Gene', '6774', (36, 41))	('drug efficacy', 'CPA', (222, 235))	('improves drug efficacy', 'Phenotype', 'HP:0020173', (213, 235))	('malignancy', 'Disease', 'MESH:D009369', (124, 134))	('improves', 'PosReg', (213, 221))	('STAT3', 'Gene', (36, 41))	('attenuates', 'NegReg', (184, 194))	('malignancy', 'Disease', (124, 134))	('associated', 'Reg', (108, 118))	('antagonist', 'Var', (158, 168))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('JAK2', 'Gene', '3717', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('JAK2', 'Gene', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('carcinoma', 'Disease', (91, 100))
142544	27168458	Knowledge of a precursor's dwell time may therefore be advantageous in determining the cancer risk due to the stepwise accumulation of critical mutations in the precursor.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (144, 153))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
142555	27168458	found a significant increase of the annual progression risk with patient age (2-fold from age <50 to age 60-69) suggesting that the BE-to-EAC progression risk is not constant but rather increases with the age of the BE tissue due to the stepwise accumulation of genetic and epigenetic alterations that drive premalignant and malignant progressions in BE.	('si', 'Chemical', 'MESH:D012825', (149, 151))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('si', 'Chemical', 'MESH:D012825', (342, 344))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('increases', 'PosReg', (186, 195))	('epigenetic alterations', 'Var', (274, 296))	('patient', 'Species', '9606', (65, 72))	('genetic', 'Var', (262, 269))	('premalignant', 'Disease', (308, 320))	('malignant progressions', 'CPA', (325, 347))
142571	27168458	The quantitative predictions of both BE onset times and inferred EAC risks for BE patients without neoplasia (D2) and familial BE (D3) suggest that BE onset is a useful event-marker of cancer risk.	('neoplasia', 'Disease', 'MESH:D009369', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (82, 90))	('neoplasia', 'Disease', (99, 108))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('familial', 'Var', (118, 126))	('neoplasia', 'Phenotype', 'HP:0002664', (99, 108))	('cancer', 'Disease', (185, 191))
142576	27168458	Next we filtered out unreliable, gender bias, and noisy probes from downstream analysis, including probes having the average detection p-values across samples greater than 0.05, chromosome X-associated probes, and those containing at least one SNP with low minor allele frequency (MAF = 0) in the probe body.	('probes', 'Var', (202, 208))	('MAF', 'Gene', (281, 284))	('MAF', 'Gene', '4094', (281, 284))	('si', 'Chemical', 'MESH:D012825', (84, 86))
142612	27168458	As we will show, this categorization distinguishes positive and negative methylomic drift in BE tissue, respectively for hypo- and hypermethylated CpGs in the reference SQ tissue.	('si', 'Chemical', 'MESH:D012825', (53, 55))	('methylomic drift', 'MPA', (73, 89))	('hypo-', 'Var', (121, 126))	('CpGs', 'Chemical', 'MESH:C015772', (147, 151))	('hypermethylated', 'Var', (131, 146))	('negative', 'NegReg', (64, 72))
142615	27168458	As expected, the majority (67) of the 75 differential, upward drifting CpGs have estimated BE drift rates that are in fact larger than the corresponding SQ drift rates, while only 3 out of 14 differential, downward drifting CpGs have estimated BE drift rates that are lower than the corresponding SQ drift rates.	('differential', 'Var', (41, 53))	('CpGs', 'Chemical', 'MESH:C015772', (71, 75))	('upward', 'PosReg', (55, 61))	('drift', 'MPA', (94, 99))	('CpGs', 'Chemical', 'MESH:C015772', (224, 228))
142810	32541467	Environmental factors and genetic carcinogenic factors may lead to gene mutation in cells, changing both apoptosis-regulating genes and DNA repair genes.	('gene mutation', 'Var', (67, 80))	('changing', 'Reg', (91, 99))	('DNA repair genes', 'Gene', (136, 152))	('apoptosis-regulating genes', 'Gene', (105, 131))	('lead', 'Reg', (59, 63))	('genetic carcinogenic', 'Disease', (26, 46))	('genetic carcinogenic', 'Disease', 'MESH:D030342', (26, 46))
142811	32541467	These mutations may result in the inactivation of tumor suppressor genes and the activation of proto-oncogenes, which may change the growth pattern of cells.	('change', 'Reg', (122, 128))	('proto-oncogenes', 'Gene', (95, 110))	('inactivation', 'NegReg', (34, 46))	('result', 'Reg', (20, 26))	('growth pattern of cells', 'CPA', (133, 156))	('activation', 'PosReg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('mutations', 'Var', (6, 15))
142813	32541467	The mutated cells may first show polyclonal hyperplasia and in the course of its evolution, there may be relatively unlimited monoclonal hyperplasia.	('mutated', 'Var', (4, 11))	('hyperplasia', 'Disease', 'MESH:D006965', (137, 148))	('hyperplasia', 'Disease', (44, 55))	('hyperplasia', 'Disease', (137, 148))	('hyperplasia', 'Disease', 'MESH:D006965', (44, 55))
142814	32541467	Through additional mutation, subclonal proliferation of monoclonal hyperplasia occurs, leading to infinite proliferation of cells with different characteristics.	('leading to', 'Reg', (87, 97))	('mutation', 'Var', (19, 27))	('hyperplasia', 'Disease', (67, 78))	('infinite proliferation', 'CPA', (98, 120))	('subclonal proliferation', 'CPA', (29, 52))	('hyperplasia', 'Disease', 'MESH:D006965', (67, 78))
142827	32541467	When a gene mutation occurs in PTPN12 that makes the activity of PTPN12 decrease, the mutant PTPN12 cannot dephosphorylate and activate SHC, which weakens the inhibitory regulation of the Ras-Raf-MEK-ERK pathway, leading to the occurrence of tumors.	('Raf', 'Gene', (192, 195))	('MEK', 'Gene', '5609', (196, 199))	('PTPN12', 'Gene', (93, 99))	('inhibitory regulation', 'MPA', (159, 180))	('occurrence', 'Reg', (228, 238))	('SHC', 'Gene', (136, 139))	('MEK', 'Gene', (196, 199))	('leading to', 'Reg', (213, 223))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('Raf', 'Gene', '22882', (192, 195))	('weakens', 'NegReg', (147, 154))	('PTPN12', 'Gene', (65, 71))	('mutant', 'Var', (86, 92))	('ERK', 'Gene', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('activity', 'MPA', (53, 61))	('SHC', 'Gene', '6464', (136, 139))	('tumors', 'Disease', (242, 248))	('PTPN12', 'Gene', (31, 37))	('ERK', 'Gene', '2048', (200, 203))	('decrease', 'NegReg', (72, 80))	('mutation', 'Var', (12, 20))	('tumors', 'Disease', 'MESH:D009369', (242, 248))
142833	32541467	The phosphorylated ERK enters the nucleus and initiates transcription of multiple transcription factors.	('phosphorylated', 'Var', (4, 18))	('ERK', 'Gene', '2048', (19, 22))	('ERK', 'Gene', (19, 22))	('initiates', 'Reg', (46, 55))
142836	32541467	The abnormal expression of any of these proteins would activate the pathway, causing abnormal proliferation of cells and leading to malignant transformation of cells and further formation of tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('abnormal proliferation of cells', 'Phenotype', 'HP:0031377', (85, 116))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('causing', 'Reg', (77, 84))	('malignant transformation of cells', 'CPA', (132, 165))	('tumors', 'Disease', (191, 197))	('leading to', 'Reg', (121, 131))
142840	32541467	On the contrary, the inactivation of the tumor suppressor gene will lead to a weakened negative regulation of the Ras-Raf-MEK-ERK signaling pathway, which causes the occurrence of tumors.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('inactivation', 'Var', (21, 33))	('negative regulation', 'MPA', (87, 106))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('ERK', 'Gene', '2048', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('weakened', 'NegReg', (78, 86))	('tumors', 'Disease', (180, 186))	('Raf', 'Gene', (118, 121))	('tumor', 'Disease', (41, 46))	('MEK', 'Gene', '5609', (122, 125))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('causes', 'Reg', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('MEK', 'Gene', (122, 125))	('tumor', 'Disease', (180, 185))	('Raf', 'Gene', '22882', (118, 121))	('ERK', 'Gene', (126, 129))
142844	32541467	Abnormal expression of PTPN12 has been reported in the literature to be associated with a variety of malignancies, such as breast cancer, ovarian cancer, hepatocellular carcinoma (HCC), and prostate cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('associated', 'Reg', (72, 82))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (154, 178))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian cancer', 'Disease', 'MESH:D010051', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Abnormal', 'Var', (0, 8))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (154, 178))	('ovarian cancer', 'Disease', (138, 152))	('HCC', 'Gene', '619501', (180, 183))	('HCC', 'Phenotype', 'HP:0001402', (180, 183))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('prostate cancer', 'Disease', 'MESH:D011471', (190, 205))	('hepatocellular carcinoma', 'Disease', (154, 178))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))	('HCC', 'Gene', (180, 183))	('prostate cancer', 'Phenotype', 'HP:0012125', (190, 205))	('malignancies', 'Disease', (101, 113))	('prostate cancer', 'Disease', (190, 205))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast cancer', 'Disease', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('PTPN12', 'Gene', (23, 29))
142846	32541467	It has also been found that PTPN12 can inhibit the malignant transformation of various tyrosine kinases, such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-beta.	('malignant transformation', 'CPA', (51, 75))	('EGFR', 'Gene', (147, 151))	('tyrosine', 'Chemical', 'MESH:D014443', (87, 95))	('inhibit', 'NegReg', (39, 46))	('epidermal growth factor receptor', 'Gene', '1956', (113, 145))	('platelet-derived growth factor receptor-beta', 'Gene', (157, 201))	('PTPN12', 'Var', (28, 34))	('platelet-derived growth factor receptor-beta', 'Gene', '5159', (157, 201))	('tyrosine kinases', 'Enzyme', (87, 103))	('EGFR', 'Gene', '1956', (147, 151))	('epidermal growth factor receptor', 'Gene', (113, 145))
142847	32541467	The H230Y mutation of the PTPN12 protein could enhance the phosphorylation of platelet-derived growth factor receptor, leading to tumor development.	('enhance', 'PosReg', (47, 54))	('H230Y', 'Var', (4, 9))	('H230Y', 'Mutation', 'rs1218679746', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('phosphorylation', 'MPA', (59, 74))	('leading to', 'Reg', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('PTPN12', 'Gene', (26, 32))	('protein', 'Protein', (33, 40))	('tumor', 'Disease', (130, 135))
142858	32541467	Subsequently, Li et al found experimentally that the expression rate of PTPN12 protein deletion in triple negative breast cancer was significantly higher than that in normal breast tissue.	('PTPN12', 'Gene', (72, 78))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('protein', 'Protein', (79, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('higher', 'PosReg', (147, 153))	('expression', 'MPA', (53, 63))	('deletion', 'Var', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))
142859	32541467	This result also further proved that in its inactive state, PTPN12 leads to the occurrence of tumors.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PTPN12', 'Var', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))
142860	32541467	Through animal experiments, Li et al found that the deletion of PTPN12 gene activity promoted the development of breast cancer cells in mouse models, which supports the view that PTPN12 serves as a human tumor suppressor.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mouse', 'Species', '10090', (136, 141))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('breast cancer', 'Disease', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('development of', 'CPA', (98, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('promoted', 'PosReg', (85, 93))	('tumor', 'Disease', (204, 209))	('human', 'Species', '9606', (198, 203))	('PTPN12', 'Gene', (64, 70))	('deletion', 'Var', (52, 60))
142861	32541467	At the same time, this experiment also showed that the inhibition of tumor cell survival made by the PTPN12 gene is related to the inhibition of Cas, Pyk2 tyrosine phosphorylation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tyrosine', 'Chemical', 'MESH:D014443', (155, 163))	('tyrosine', 'Protein', (155, 163))	('Cas', 'Gene', '9564', (145, 148))	('tumor', 'Disease', (69, 74))	('Pyk2', 'Gene', '2185', (150, 154))	('Pyk2', 'Gene', (150, 154))	('gene', 'Var', (108, 112))	('PTPN12', 'Gene', (101, 107))	('inhibition', 'NegReg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('Cas', 'Gene', (145, 148))	('inhibition', 'NegReg', (131, 141))
142867	32541467	Shen et al found that PTPN12 can increase the risk of CRC by modifying Ras-MEK-ERK signal transduction, which will provide new insights into the role of CRC pathogenesis.	('ERK', 'Gene', (79, 82))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('PTPN12', 'Var', (22, 28))	('CRC', 'Disease', (54, 57))	('modifying', 'Reg', (61, 70))	('CRC', 'Phenotype', 'HP:0003003', (153, 156))	('CRC', 'Phenotype', 'HP:0003003', (54, 57))	('MEK', 'Gene', (75, 78))	('MEK', 'Gene', '5609', (75, 78))	('ERK', 'Gene', '2048', (79, 82))
142872	32541467	High expression of PTPN12 is associated with disease-free survival and overall survival in patients with esophageal cancer.	('patients', 'Species', '9606', (91, 99))	('High', 'Var', (0, 4))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('overall survival', 'CPA', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('PTPN12', 'Gene', (19, 25))	('associated', 'Reg', (29, 39))
142878	32541467	At the same time, it was concluded that high PTPN12 expression level is beneficial to the 5-year survival rate of lung cancer, especially in non-NSCLC patients.	('high', 'Var', (40, 44))	('beneficial', 'PosReg', (72, 82))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('NSCLC', 'Disease', (145, 150))	('patients', 'Species', '9606', (151, 159))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('PTPN12', 'Gene', (45, 51))
142883	32541467	More importantly, the multivariate analysis identified the expression of PTPN12 as an independent prognostic factor in nasopharyngeal carcinoma.	('carcinoma', 'Disease', (134, 143))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (119, 143))	('carcinoma', 'Disease', 'MESH:D009369', (134, 143))	('PTPN12', 'Gene', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('expression', 'Var', (59, 69))
142894	32541467	PTPN12 is associated with STAT3 and induces STAT3 dephosphorylation.	('associated', 'Reg', (10, 20))	('STAT3', 'Gene', '6774', (26, 31))	('STAT3', 'Gene', '6774', (44, 49))	('STAT3', 'Gene', (26, 31))	('STAT3', 'Gene', (44, 49))	('PTPN12', 'Var', (0, 6))	('induces', 'Reg', (36, 43))
142897	32541467	Villa-Moruzzi et al found that PTPN12 directly acts on focal adhesion kinase in a her2-dependent manner, causing a negative regulation of the migration of ovarian cancer cells.	('migration of ovarian cancer', 'Disease', 'MESH:D014085', (142, 169))	('her2', 'Gene', '2064', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('migration of ovarian cancer', 'Disease', (142, 169))	('her2', 'Gene', (82, 86))	('causing', 'Reg', (105, 112))	('negative regulation', 'NegReg', (115, 134))	('PTPN12', 'Var', (31, 37))
142900	32541467	Therefore, it was concluded that miR-194 directly acts on the PTPN12 gene and inhibits its activity, which leads to the occurrence of ovarian cancer.	('PTPN12', 'Gene', (62, 68))	('ovarian cancer', 'Disease', 'MESH:D010051', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('miR-194', 'Chemical', '-', (33, 40))	('ovarian cancer', 'Disease', (134, 148))	('activity', 'MPA', (91, 99))	('leads to', 'Reg', (107, 115))	('acts', 'Reg', (50, 54))	('inhibits', 'NegReg', (78, 86))	('miR-194', 'Var', (33, 40))	('ovarian cancer', 'Phenotype', 'HP:0100615', (134, 148))
142905	32541467	In glioblastoma cells with low expression of PTPN12, the association between the receptor tyrosine kinase and beta 8 integrin might be changed, resulting in reduced growth but increased invasiveness.	('growth', 'CPA', (165, 171))	('reduced', 'NegReg', (157, 164))	('increased', 'PosReg', (176, 185))	('changed', 'Reg', (135, 142))	('invasiveness', 'CPA', (186, 198))	('glioblastoma', 'Disease', (3, 15))	('low expression', 'Var', (27, 41))	('receptor tyrosine kinase', 'Gene', (81, 105))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('association', 'Interaction', (57, 68))	('receptor tyrosine kinase', 'Gene', '5979', (81, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('PTPN12', 'Gene', (45, 51))
142907	32541467	Many predictions of copy number variants of somatic cells in glioblastoma involved PTPN12, suggesting that PTPN12 was very common in glioblastoma through various rearrangements and regulation.	('glioblastoma', 'Disease', (133, 145))	('PTPN12', 'Gene', (83, 89))	('copy number variants', 'Var', (20, 40))	('glioblastoma', 'Disease', (61, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('involved', 'Reg', (74, 82))
142908	32541467	PTPN12 was known to dephosphorylate the oncogenes c-abl and Src, and PTPN12 may contribute to tumor survival.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('c-abl', 'Gene', (50, 55))	('Src', 'Gene', '6714', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('contribute', 'Reg', (80, 90))	('PTPN12', 'Var', (69, 75))	('Src', 'Gene', (60, 63))	('c-abl', 'Gene', '25', (50, 55))
142909	32541467	Given the number of rearrangement candidates for PTPN12, the most important factor for glioblastoma might be the regulation of PTPN12, not necessarily any single rearrangement.	('rearrangement', 'Var', (20, 33))	('PTPN12', 'Gene', (49, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('glioblastoma', 'Disease', (87, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))
142910	32541467	The main driver of melanoma progression is cytogenetic heterogeneity due to chromosomal instability.	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('chromosomal instability', 'Var', (76, 99))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('chromosomal instability', 'Phenotype', 'HP:0040012', (76, 99))
142911	32541467	One study examined chromosomal changes in a group of melanoma cell lines based on the aCGH atlas, showing that chromosome loss in the 7q region seems to be associated with aggressive behavior.	('chromosome loss', 'Var', (111, 126))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('aggressive behavior', 'CPA', (172, 191))	('associated', 'Reg', (156, 166))	('aggressive behavior', 'Phenotype', 'HP:0000718', (172, 191))
142912	32541467	MRNA expression analysis provided the first evidence that structural and functional changes in PTPN12 genes play an important role in melanoma invasion.	('changes', 'Var', (84, 91))	('melanoma invasion', 'Disease', (134, 151))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('PTPN12', 'Gene', (95, 101))	('melanoma invasion', 'Disease', 'MESH:D008545', (134, 151))
142935	32541467	The difference is that the high expression of PTPN12 in the treatment of malignant tumors can regulate the occurrence and development of tumors and enhance the sensitivity of malignant tumors to targeted drugs.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', (185, 191))	('development', 'CPA', (122, 133))	('high expression', 'Var', (27, 42))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('regulate', 'Reg', (94, 102))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('enhance', 'PosReg', (148, 155))	('sensitivity', 'MPA', (160, 171))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('malignant tumors', 'Disease', (73, 89))	('malignant tumors', 'Disease', 'MESH:D009369', (73, 89))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', (83, 89))	('malignant tumors', 'Disease', (175, 191))	('PTPN12', 'Gene', (46, 52))	('malignant tumors', 'Disease', 'MESH:D009369', (175, 191))	('occurrence', 'MPA', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
142944	31757094	Insights into the Regulation of Tumor Angiogenesis by Micro-RNAs One of the hallmarks of cancer is angiogenesis, a series of events leading to the formation of the abnormal vascular network required for tumor growth, development, progression, and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('leading to', 'Reg', (132, 142))	('tumor', 'Disease', (203, 208))	('nt', 'Chemical', 'MESH:D009711', (226, 228))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('nt', 'Chemical', 'MESH:D009711', (10, 12))	('cancer', 'Disease', (89, 95))	('nt', 'Chemical', 'MESH:D009711', (128, 130))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('Tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Micro-RNAs', 'Var', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
142963	31757094	In particular, miRNAs are so involved in the regulation of angiogenesis that global miRNA depletion suppresses the angiogenic process.	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (84, 87))	('angiogenic process', 'CPA', (115, 133))	('suppresses', 'NegReg', (100, 110))	('depletion', 'Var', (90, 99))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
142979	31757094	Mechanical and metabolic stress, and genetic mutations (for instance, expression of oncogenes or deletion of tumor-suppressor genes that regulate the production of angiogenesis regulators) can also influence the balance.	('tumor-suppressor', 'Gene', '7248', (109, 125))	('influence', 'Reg', (198, 207))	('tumor-suppressor', 'Gene', (109, 125))	('balance', 'MPA', (212, 219))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('deletion', 'Var', (97, 105))
143034	31757094	miR-21 targets phosphatase and tensin homolog deleted on chromosome ten (PTEN) and induces angiogenesis through the upregulation of HIF-1alpha and VEGF expression via the activation of AKT (RAC-Alpha Serine/Threonine-Protein Kinase) and extracellular regulated kinase (ERK) pathways, as demonstrated in prostate cancer cell lines, glioma, pancreatic cancer cell lines, breast cancer, and HCC.	('VEGF', 'Gene', '7422', (147, 151))	('RAC-Alpha Serine/Threonine-Protein Kinase', 'Gene', (190, 231))	('miR-21', 'Gene', (0, 6))	('glioma', 'Disease', (331, 337))	('HCC', 'Disease', (388, 391))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('HCC', 'Phenotype', 'HP:0001402', (388, 391))	('glioma', 'Disease', 'MESH:D005910', (331, 337))	('AKT', 'Gene', '207', (185, 188))	('VEGF', 'Gene', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('pancreatic cancer', 'Disease', 'MESH:D010190', (339, 356))	('prostate cancer', 'Disease', 'MESH:D011471', (303, 318))	('prostate cancer', 'Phenotype', 'HP:0012125', (303, 318))	('HIF-1alpha', 'Gene', (132, 142))	('glioma', 'Phenotype', 'HP:0009733', (331, 337))	('expression', 'MPA', (152, 162))	('prostate cancer', 'Disease', (303, 318))	('breast cancer', 'Phenotype', 'HP:0003002', (369, 382))	('pancreatic cancer', 'Disease', (339, 356))	('PTEN', 'Gene', (73, 77))	('HCC', 'Disease', 'MESH:D006528', (388, 391))	('deleted', 'Var', (46, 53))	('upregulation', 'PosReg', (116, 128))	('breast cancer', 'Disease', 'MESH:D001943', (369, 382))	('miR-21', 'Gene', '406991', (0, 6))	('breast cancer', 'Disease', (369, 382))	('AKT', 'Gene', (185, 188))	('PTEN', 'Gene', '5728', (73, 77))	('angiogenesis', 'CPA', (91, 103))	('induces', 'PosReg', (83, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (339, 356))	('RAC-Alpha Serine/Threonine-Protein Kinase', 'Gene', '207', (190, 231))	('HIF-1alpha', 'Gene', '3091', (132, 142))
143039	31757094	miR-296 contributes significantly to angiogenesis by directly targeting hepatocyte-growth-factor-regulated tyrosine kinase substrate (HGS) mRNA, causing a decrease in HGS levels and thereby a reduction in the HGS-mediated degradation of VEGFR-2 and PDGF receptor beta.	('HGS', 'Gene', (167, 170))	('HGS', 'Gene', (209, 212))	('HGS', 'Gene', (134, 137))	('VEGFR-2', 'Gene', (237, 244))	('HGS', 'Gene', '9146', (209, 212))	('PDGF', 'Protein', (249, 253))	('decrease', 'NegReg', (155, 163))	('HGS', 'Gene', '9146', (167, 170))	('HGS', 'Gene', '9146', (134, 137))	('nt', 'Chemical', 'MESH:D009711', (10, 12))	('miR-296', 'Var', (0, 7))	('hepatocyte-growth-factor-regulated tyrosine kinase substrate', 'Gene', '9146', (72, 132))	('nt', 'Chemical', 'MESH:D009711', (29, 31))	('reduction', 'NegReg', (192, 201))	('VEGFR-2', 'Gene', '3791', (237, 244))
143053	31757094	In glioblastoma cells, miR-221/222 are expressed at high levels and their downregulation results in a reduction of tumor invasion, migration, proliferation, and angiogenesis in association with decreased levels of MMP-2, MMP-9 and VEGF, and inactivation of the Janus kinase (JAK)/signal transducer of activation (STAT) pathway by the upregulation of SOCS3 (suppressor of cytokine signaling-3).	('proliferation', 'CPA', (142, 155))	('SOCS3', 'Gene', (350, 355))	('angiogenesis', 'CPA', (161, 173))	('MMP-2', 'Gene', (214, 219))	('SOCS3', 'Gene', '9021', (350, 355))	('reduction of tumor invasion', 'Disease', (102, 129))	('inactivation', 'NegReg', (241, 253))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('VEGF', 'Gene', '7422', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('reduction of tumor invasion', 'Disease', 'MESH:D009361', (102, 129))	('migration', 'CPA', (131, 140))	('VEGF', 'Gene', (231, 235))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('miR-221/222', 'Var', (23, 34))	('MMP-9', 'Gene', '4318', (221, 226))	('downregulation', 'NegReg', (74, 88))	('MMP-2', 'Gene', '4313', (214, 219))	('suppressor of cytokine signaling-3', 'Gene', '9021', (357, 391))	('MMP-9', 'Gene', (221, 226))	('suppressor of cytokine signaling-3', 'Gene', (357, 391))	('decreased', 'NegReg', (194, 203))	('upregulation', 'PosReg', (334, 346))
143054	31757094	demonstrated that miR-221/222 are significantly upregulated in glioma cells and promote angiogenesis by targeting TIMP2, an anti-angiogenic factor that inhibits tube formation by halting the activity of MMPs.	('MMPs', 'Gene', '4313;4318', (203, 207))	('TIMP2', 'Gene', '7077', (114, 119))	('angiogenesis', 'CPA', (88, 100))	('nt', 'Chemical', 'MESH:D009711', (125, 127))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('activity', 'MPA', (191, 199))	('MMPs', 'Gene', (203, 207))	('TIMP2', 'Gene', (114, 119))	('miR-221/222', 'Var', (18, 29))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('upregulated', 'PosReg', (48, 59))	('targeting', 'Var', (104, 113))	('promote', 'PosReg', (80, 87))	('nt', 'Chemical', 'MESH:D009711', (43, 45))	('glioma', 'Disease', (63, 69))
143056	31757094	Both c-Kit and VEGFR2 are targets of miR-221/-222 and of the small-molecule anti-tumor agent sunitinib.	('c-Kit', 'Gene', (5, 10))	('miR-221/-222', 'Var', (37, 49))	('VEGFR2', 'Gene', (15, 21))	('c-Kit', 'Gene', '3815', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('nt', 'Chemical', 'MESH:D009711', (90, 92))	('VEGFR2', 'Gene', '3791', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('sunitinib', 'Chemical', 'MESH:C473478', (93, 102))	('tumor', 'Disease', (81, 86))	('nt', 'Chemical', 'MESH:D009711', (77, 79))
143057	31757094	showed that the upregulation of miR-221/-222 is associated with a decrease in VEGFR-2 expression and the poor survival of patients with metastatic renal cell carcinoma treated with sunitinib.	('VEGFR-2', 'Gene', (78, 85))	('poor', 'NegReg', (105, 109))	('upregulation', 'PosReg', (16, 28))	('sunitinib', 'Chemical', 'MESH:C473478', (181, 190))	('expression', 'MPA', (86, 96))	('patients', 'Species', '9606', (122, 130))	('metastatic renal cell carcinoma', 'Disease', (136, 167))	('miR-221/-222', 'Var', (32, 44))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (136, 167))	('decrease', 'NegReg', (66, 74))	('VEGFR-2', 'Gene', '3791', (78, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (147, 167))
143058	31757094	miR-221/-222 also target the transcription factor E26 transformation-specific sequence-1, thus decreasing angiotensin II-induced HUVEC migration.	('miR-221/-222', 'Var', (0, 12))	('angiotensin II', 'Gene', '183', (106, 120))	('decreasing', 'NegReg', (95, 105))	('decreasing angiotensin', 'Phenotype', 'HP:0004319', (95, 117))	('angiotensin II', 'Gene', (106, 120))
143079	31757094	In gastric cancer, its expression inhibits tumor growth, migration, invasion, and angiogenesis by targeting the focal adhesion kinase pathway, which regulates VEGF signaling.	('targeting', 'Reg', (98, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('inhibits', 'NegReg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('VEGF', 'Gene', (159, 163))	('invasion', 'CPA', (68, 76))	('angiogenesis', 'CPA', (82, 94))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('expression', 'Var', (23, 33))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('VEGF', 'Gene', '7422', (159, 163))	('gastric cancer', 'Disease', (3, 17))	('tumor', 'Disease', (43, 48))	('focal adhesion kinase pathway', 'Pathway', (112, 141))
143152	31615499	Moreover, particularly in elderly patients, dysfunction of vital organs such as the heart, lungs or kidneys is associated frequently with esophageal cancer.	('kidneys', 'Disease', (100, 107))	('kidneys', 'Disease', 'MESH:D007674', (100, 107))	('esophageal cancer', 'Disease', (138, 155))	('associated', 'Reg', (111, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('patients', 'Species', '9606', (34, 42))	('dysfunction', 'Var', (44, 55))
143158	31615499	We retrieved data for 432 patients in accordance with the criteria as follows: subtotal esophagectomy with systematic 2- or 3-field lymphadenectomy; clinical T1-3 esophageal cancer according to the Union for International Cancer Control (UICC) Classification (8th Edition); and R0 resection.	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('patients', 'Species', '9606', (26, 34))	('T1-3', 'Var', (158, 162))	('esophageal cancer', 'Disease', (163, 180))	('subtotal', 'Disease', (79, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
143210	29245356	We present a case of a man diagnosed in the Gastroenterology Department of Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, which presented a deep and big esophageal ulcer with irregular borders caused by type 16 HPV infection.	('esophageal ulcer', 'Disease', 'MESH:D014456', (179, 195))	('HPV infection', 'Disease', 'MESH:D030361', (237, 250))	('esophageal ulcer', 'Disease', (179, 195))	('esophageal ulcer', 'Phenotype', 'HP:0004791', (179, 195))	('man', 'Species', '9606', (23, 26))	('HPV infection', 'Disease', (237, 250))	('type 16', 'Var', (229, 236))	('caused by', 'Reg', (219, 228))
143339	27470056	Therefore, we started salvage surgery with RAMIE in patients with cT4b esophageal tumors after long-course chemoradiotherapy.	('esophageal tumors', 'Disease', 'MESH:D004938', (71, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('esophageal tumors', 'Phenotype', 'HP:0100751', (71, 88))	('esophageal tumors', 'Disease', (71, 88))	('RAMIE', 'Species', '83906', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cT4b', 'Var', (66, 70))	('patients', 'Species', '9606', (52, 60))
143527	25255777	We constructed vectors expressing the green fluorescent protein gene with Ad5 or modified Ad5 bearing the type 35 fiber region (AdF35), and examined the infectivity to MSCs with flow cytometry.	('Ad5', 'Gene', (74, 77))	('modified', 'Var', (81, 89))	('Ad5', 'Gene', '8081', (90, 93))	('Ad5', 'Gene', '8081', (74, 77))	('Ad5', 'Gene', (90, 93))
143531	25255777	MSCs expressed CD46 but scarcely CAR molecules, and subsequently were transduced with AdF35 but not with Ad5.	('CAR', 'Gene', (33, 36))	('Ad5', 'Gene', (105, 108))	('AdF35', 'Var', (86, 91))	('CD46', 'Gene', (15, 19))	('CD46', 'Gene', '4179', (15, 19))	('CAR', 'Gene', '1525', (33, 36))	('Ad5', 'Gene', '8081', (105, 108))
143550	25255777	In this study, we examined infectivity of Ad5 and AdF35 to human MSCs and investigated a possible use of MSCs as a vehicle to deliver gene products to tumors.	('human', 'Species', '9606', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('Ad5', 'Gene', '8081', (42, 45))	('tumors', 'Disease', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('Ad5', 'Gene', (42, 45))	('AdF35', 'Var', (50, 55))
143558	25255777	The fiber modified Ad expressing the above genes, AdF35-GFP, AdF35-LacZ, and AdF35-IL-28A, and type 5 Ad bearing the GFP gene (Ad5-GFP) were produced by transfecting the respective DNA into HEK293 cells and purified with an Adeno-X virus purification kit (BD Biosciences).	('Ad5', 'Gene', '8081', (127, 130))	('AdF35-LacZ', 'Var', (61, 71))	('AdF35-GFP', 'Var', (50, 59))	('IL-28A', 'Gene', (83, 89))	('IL-28A', 'Gene', '282616', (83, 89))	('Ad5', 'Gene', (127, 130))	('HEK293', 'CellLine', 'CVCL:0045', (190, 196))
143559	25255777	Cells were infected with Ad5-GFP or AdF35-GFP at multiplicity of infection (MOI) of 3 or 30 for 30 min and were washed to remove Ad.	('Ad5', 'Gene', '8081', (25, 28))	('infection', 'Disease', (65, 74))	('AdF35-GFP', 'Var', (36, 45))	('infection', 'Disease', 'MESH:D007239', (65, 74))	('Ad5', 'Gene', (25, 28))
143561	25255777	OBA-LK1 cells were cultured in 96-well plates with MSCs uninfected or infected with AdF35-IL-28A or AdF35-LacZ (MOI = 100), at a ratio of 10: 1 or 10: 3.	('AdF35-LacZ', 'Var', (100, 110))	('IL-28A', 'Gene', '282616', (90, 96))	('IL-28A', 'Gene', (90, 96))
143563	25255777	OBA-LK1 cells were also labeled with PKH 26 dye according to the manufacturer's protocol (Sigma-Aldrich, St Louis, MO, USA) and cultured with MSCs, uninfected or infected with AdF35-IL-28A or AdF35-LacZ (MOI = 100), at a ratio of 10: 1 or 10: 3 for 4 days.	('IL-28A', 'Gene', (182, 188))	('AdF35-LacZ', 'Var', (192, 202))	('IL-28A', 'Gene', '282616', (182, 188))
143574	25255777	HEK293 cells became GFP positive after transduction with either Ad5-GFP or AdF35-GFP, but MSCs expressed GFP only when transduced with AdF35-GFP (Figure  3B).	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('Ad5', 'Gene', (64, 67))	('Ad5', 'Gene', '8081', (64, 67))	('AdF35-GFP', 'Var', (75, 84))
143575	25255777	Percentages of GFP positive HEK293 cells were not different when they were transduced either with Ad5-GFP or AdF35-GFP (Figure  4).	('AdF35-GFP', 'Var', (109, 118))	('HEK293', 'CellLine', 'CVCL:0045', (28, 34))	('Ad5', 'Gene', (98, 101))	('Ad5', 'Gene', '8081', (98, 101))
143577	25255777	The differential GFP positive rates were attributable to viral infectivity to the cells since both Ad5-GFP and AdF35-GFP used the same CMV promoter.	('Ad5', 'Gene', (99, 102))	('AdF35-GFP', 'Var', (111, 120))	('Ad5', 'Gene', '8081', (99, 102))
143602	25255777	Comparison of receptor expressions between HEK293 cells and MSCs further showed that CD46 expression levels on MSCs were not as great as those on HEK293 cells, which resulted in lower transduction efficacy of AdF35 to MSCs than to HEK293 cells.	('HEK293', 'CellLine', 'CVCL:0045', (43, 49))	('AdF35', 'Var', (209, 214))	('HEK293', 'CellLine', 'CVCL:0045', (231, 237))	('lower', 'NegReg', (178, 183))	('transduction efficacy', 'MPA', (184, 205))	('HEK293', 'CellLine', 'CVCL:0045', (146, 152))	('CD46', 'Gene', '4179', (85, 89))	('CD46', 'Gene', (85, 89))
143608	25255777	Usage of gene modified MSCs has several advantages over direct Ad administrations in the anti-tumor activity.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('gene modified', 'Var', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))
143629	25054828	PIK3CA Gene Mutations and Overexpression: Implications for Prognostic Biomarker and Therapeutic Target in Chinese Esophageal Squamous Cell Carcinoma To evaluate PIK3CA gene mutations and PIK3CA expression status in Chinese esophageal squamous cell carcinoma (ESCC) patients, and their correlation with clinicopathological characteristics and clinical outcomes.	('PIK3CA', 'Gene', '5290', (187, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (114, 148))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (223, 257))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('PIK3CA', 'Gene', (161, 167))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (173, 182))	('esophageal squamous cell carcinoma', 'Disease', (223, 257))	('PIK3CA', 'Gene', '5290', (161, 167))	('PIK3CA', 'Gene', '5290', (0, 6))	('patients', 'Species', '9606', (265, 273))	('PIK3CA', 'Gene', (187, 193))	('Carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('Esophageal Squamous Cell Carcinoma', 'Disease', (114, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
143630	25054828	Direct sequencing was applied to investigate mutations in exons 9 and 20 of PIK3CA in 406 Chinese ESCC patients.	('mutations', 'Var', (45, 54))	('ESCC', 'Disease', (98, 102))	('PIK3CA', 'Gene', (76, 82))	('patients', 'Species', '9606', (103, 111))	('PIK3CA', 'Gene', '5290', (76, 82))
143634	25054828	However in the ESCC patients with family cancer history, PIK3CA mutations were independently correlated with worse overall survival (multivariate hazard ratio (HR) = 10.493, 95% CI: 2.432-45.267, P = 0.002).	('worse', 'NegReg', (109, 114))	('PIK3CA', 'Gene', '5290', (57, 63))	('overall survival', 'MPA', (115, 131))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('patients', 'Species', '9606', (20, 28))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('PIK3CA', 'Gene', (57, 63))
143638	25054828	Our results suggest PIK3CA gene mutation and overexpression could act as biomarkers for individualized molecular targeted therapy for Chinese ESCC patients.	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))	('patients', 'Species', '9606', (147, 155))	('mutation', 'Var', (32, 40))	('overexpression', 'PosReg', (45, 59))
143646	25054828	In the studies specifically examining PIK3CA mutations, the frequency of PIK3CA mutation were detected in a range from 2.2% to 21% in ESCC patients.	('PIK3CA', 'Gene', '5290', (73, 79))	('patients', 'Species', '9606', (139, 147))	('detected', 'Reg', (94, 102))	('ESCC', 'Disease', (134, 138))	('PIK3CA', 'Gene', (38, 44))	('PIK3CA', 'Gene', '5290', (38, 44))	('PIK3CA', 'Gene', (73, 79))	('mutation', 'Var', (80, 88))
143647	25054828	Given the frequency of the mutation, PIK3CA is at the forefront of investigations in ESCC to serve as a potential therapeutic target.	('mutation', 'Var', (27, 35))	('PIK3CA', 'Gene', '5290', (37, 43))	('PIK3CA', 'Gene', (37, 43))	('ESCC', 'Disease', (85, 89))
143650	25054828	More than 80% of the PIK3CA mutations detected were localized in exons 9 and 20 (helical and kinase domain), with three 'hot-spot' mutations, E542K, E545K and H1047R.	('H1047R', 'Var', (159, 165))	('E542K', 'Var', (142, 147))	('PIK3CA', 'Gene', (21, 27))	('H1047R', 'Mutation', 'rs121913279', (159, 165))	('E542K', 'Mutation', 'rs121913273', (142, 147))	('E545K', 'Mutation', 'rs104886003', (149, 154))	('PIK3CA', 'Gene', '5290', (21, 27))	('E545K', 'Var', (149, 154))
143651	25054828	Cancer cells with PIK3CA mutations have been demonstrated to acquire enhanced sensitivity to PI3K pathway inhibitors.	('sensitivity', 'MPA', (78, 89))	('mutations', 'Var', (25, 34))	('PI3K pathway', 'Pathway', (93, 105))	('enhanced', 'PosReg', (69, 77))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('PIK3CA', 'Gene', (18, 24))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('PIK3CA', 'Gene', '5290', (18, 24))
143652	25054828	Moreover clinical phase I trials revealed that the PIK3CA mutation is associated with response to PI3K pathway inhibitors.	('associated', 'Reg', (70, 80))	('mutation', 'Var', (58, 66))	('PIK3CA', 'Gene', (51, 57))	('PI3K pathway', 'Pathway', (98, 110))	('PIK3CA', 'Gene', '5290', (51, 57))
143653	25054828	In this study, we sought to determine the frequency of PIK3CA mutation and PIK3CA expression status in 406 Chinese ESCC patients.	('ESCC', 'Disease', (115, 119))	('PIK3CA', 'Gene', (75, 81))	('PIK3CA', 'Gene', '5290', (75, 81))	('mutation', 'Var', (62, 70))	('PIK3CA', 'Gene', (55, 61))	('patients', 'Species', '9606', (120, 128))	('PIK3CA', 'Gene', '5290', (55, 61))
143655	25054828	To the best of our knowledge, this is, by far, the largest study on the prognostic role of PIK3CA mutations and PIK3CA expressions in ESCC to date.	('PIK3CA', 'Gene', (91, 97))	('PIK3CA', 'Gene', '5290', (112, 118))	('PIK3CA', 'Gene', '5290', (91, 97))	('ESCC', 'Disease', (134, 138))	('mutations', 'Var', (98, 107))	('PIK3CA', 'Gene', (112, 118))
143662	25054828	For those samples with PIK3CA mutations, DNA from the paired normal tissue samples was extracted.	('mutations', 'Var', (30, 39))	('PIK3CA', 'Gene', (23, 29))	('PIK3CA', 'Gene', '5290', (23, 29))
143679	25054828	For statistical analysis, we classified PIK3CA expression of score 0 or 1+ as negative and score 2+ or 3+ as positive.	('PIK3CA', 'Gene', '5290', (40, 46))	('PIK3CA', 'Gene', (40, 46))	('score 0', 'Var', (61, 68))
143680	25054828	The association between PIK3CA mutations or PIK3CA expression and the clinicopathological variables were performed using the chi2-test or Fisher's exact probability test.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('PIK3CA', 'Gene', '5290', (44, 50))	('PIK3CA', 'Gene', '5290', (24, 30))	('expression', 'MPA', (51, 61))
143691	25054828	PIK3CA mutations were detected in 30 (7.4%) ESCC samples and no mutations were identified in correspondent normal tissues ( Table 1  ,   Figure 1 ).	('ESCC', 'Disease', (44, 48))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('detected', 'Reg', (22, 30))	('mutations', 'Var', (7, 16))
143693	25054828	Other mutations including c.1625A>G (p.E542G) mutation, c.1633G>C (p.E545K) and c.1633G>A (p.E545Q) were detected in 3, 2 and 1 samples, respectively (Table S1).	('c.1633G>A', 'Var', (80, 89))	('c.1633G>C', 'Mutation', 'rs104886003', (56, 65))	('p.E545Q', 'Mutation', 'rs104886003', (91, 98))	('p.E542G', 'Mutation', 'rs1057519927', (37, 44))	('c.1633G>A', 'Mutation', 'rs104886003', (80, 89))	('c.1625A>G', 'Var', (26, 35))	('c.1625A>G', 'Mutation', 'rs1057519927', (26, 35))	('c.1633G>C', 'Var', (56, 65))	('p.E545K', 'Mutation', 'rs104886003', (67, 74))
143695	25054828	PIK3CA mutations were not correlated with clinicopathological characteristics, including age, gender, tobacco use, alcohol use, family cancer history, tumor location, pathologic stage, differentiation, lymph node metastasis, tumor embolus, local recurrence, and prognosis.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('cancer', 'Disease', (135, 141))	('tumor embolus', 'Disease', 'MESH:D004617', (225, 238))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tobacco', 'Species', '4097', (102, 109))	('tumor', 'Disease', (151, 156))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Disease', (225, 230))	('local recurrence', 'CPA', (240, 256))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('PIK3CA', 'Gene', '5290', (0, 6))	('alcohol use', 'Phenotype', 'HP:0030955', (115, 126))	('tumor embolus', 'Disease', (225, 238))	('alcohol', 'Chemical', 'MESH:D000438', (115, 122))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('mutations', 'Var', (7, 16))
143696	25054828	However for the patients with the age <59 years or with family cancer history, PIK3CA mutations were correlated with worse overall survival (log rank P = 0.039, 0.026 respectively) (Figure S1).	('mutations', 'Var', (86, 95))	('worse', 'NegReg', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (16, 24))	('PIK3CA', 'Gene', (79, 85))	('overall survival', 'MPA', (123, 139))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('PIK3CA', 'Gene', '5290', (79, 85))	('cancer', 'Disease', (63, 69))
143697	25054828	In the multivariate Cox regression analysis, PIK3CA mutations were found to be independently associated with worse overall survival in the patients with family cancer history (multivariate HR = 10.493, 95% CI: 2.432-45.267, P = 0.002) ( Table 2 ).	('mutations', 'Var', (52, 61))	('worse', 'NegReg', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('overall survival', 'MPA', (115, 131))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Disease', (160, 166))	('Cox', 'Gene', (20, 23))	('Cox', 'Gene', '1351', (20, 23))	('PIK3CA', 'Gene', (45, 51))	('PIK3CA', 'Gene', '5290', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
143710	25054828	No significant correlation between PIK3CA mutation and PIK3CA expression was identified (r = 0.049, P = 0.326) (Table S3).	('expression', 'MPA', (62, 72))	('mutation', 'Var', (42, 50))	('PIK3CA', 'Gene', (35, 41))	('PIK3CA', 'Gene', (55, 61))	('PIK3CA', 'Gene', '5290', (35, 41))	('PIK3CA', 'Gene', '5290', (55, 61))
143712	25054828	Also, PIK3CA mutation could constitutively active PI3K/Akt signaling cascade, leading to cell survival, proliferation, anti-apoptosis, tumorigenesis, angiogenesis, invasion and metastasis.	('Akt', 'Gene', (55, 58))	('cell survival', 'CPA', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('proliferation', 'CPA', (104, 117))	('mutation', 'Var', (13, 21))	('tumor', 'Disease', (135, 140))	('angiogenesis', 'CPA', (150, 162))	('leading', 'PosReg', (78, 85))	('PIK3CA', 'Gene', (6, 12))	('metastasis', 'CPA', (177, 187))	('active', 'PosReg', (43, 49))	('PIK3CA', 'Gene', '5290', (6, 12))	('invasion', 'CPA', (164, 172))	('Akt', 'Gene', '207', (55, 58))	('anti-apoptosis', 'CPA', (119, 133))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
143715	25054828	The mutation of PIK3CA has been reported in 2.2% to 21% of ESCC patients.	('PIK3CA', 'Gene', '5290', (16, 22))	('patients', 'Species', '9606', (64, 72))	('mutation', 'Var', (4, 12))	('ESCC', 'Disease', (59, 63))	('PIK3CA', 'Gene', (16, 22))
143716	25054828	In our study, 7.4% of ESCC cases were identified with PIK3CA mutation.	('mutation', 'Var', (61, 69))	('PIK3CA', 'Gene', '5290', (54, 60))	('ESCC', 'Disease', (22, 26))	('PIK3CA', 'Gene', (54, 60))
143721	25054828	Using high-sensitive detection methods, even very low percentage of the cancer cells carrying PIK3CA mutation could be identified.	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PIK3CA', 'Gene', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mutation', 'Var', (101, 109))	('PIK3CA', 'Gene', '5290', (94, 100))
143725	25054828	PIK3CA mutations were only found in exon 9 in this study, which is consistent with three other studies.	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
143726	25054828	However, researchers also found PIK3CA mutations in exon 20 (H1047R and H1047L) except in exon 9.	('PIK3CA', 'Gene', '5290', (32, 38))	('H1047L', 'Mutation', 'rs121913279', (72, 78))	('H1047R', 'Var', (61, 67))	('H1047L', 'Var', (72, 78))	('H1047R', 'Mutation', 'rs121913279', (61, 67))	('PIK3CA', 'Gene', (32, 38))
143727	25054828	A study reported PIK3CA mutations in exon 4 (L339F), which was rare in other reports.	('L339F', 'Mutation', 'p.L339F', (45, 50))	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))
143729	25054828	However a few studies have reported to consider c.1634A>C as a result of the amplification of the pseudogene CES located on chromosome 22q11.2, herein not a mutation.	('c.1634A>C', 'Mutation', 'rs121913274', (48, 57))	('c.1634A>C', 'Var', (48, 57))	('CES', 'Gene', '1055', (109, 112))	('CES', 'Gene', (109, 112))
143730	25054828	This assumption was raised based on the identification of the c.1634A>C in both cancer and normal cells.	('c.1634A>C', 'Mutation', 'rs121913274', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('c.1634A>C', 'Var', (62, 71))	('cancer', 'Disease', (80, 86))
143731	25054828	In our study, we did observe the c.1634A>C in almost half of the ESCC cases using the first pair of the PCR primer.	('c.1634A>C', 'Mutation', 'rs121913274', (33, 42))	('c.1634A>C', 'Var', (33, 42))	('ESCC', 'Disease', (65, 69))
143734	25054828	Therefore the identification of c.1634A>C in both cancer and normal cells hindered the authors to consider the fact that the c.1634A>C mutation did exist.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('c.1634A>C', 'Mutation', 'rs121913274', (125, 134))	('c.1634A>C', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('hindered', 'NegReg', (74, 82))	('c.1634A>C', 'Mutation', 'rs121913274', (32, 41))	('c.1634A>C', 'Var', (125, 134))
143736	25054828	The mutations in codon 542 or 545 could relieve the inhibitory effect of p85 on p110alpha leading to increased PI3K activity and enhanced downstream signaling elements, including AKT.	('enhanced', 'PosReg', (129, 137))	('AKT', 'Gene', (179, 182))	('downstream', 'MPA', (138, 148))	('p110alpha', 'Gene', '5290', (80, 89))	('increased PI3K activity', 'Phenotype', 'HP:0003240', (101, 124))	('p110alpha', 'Gene', (80, 89))	('PI3K', 'Pathway', (111, 115))	('increased', 'PosReg', (101, 110))	('p85', 'Gene', '5296', (73, 76))	('men', 'Species', '9606', (162, 165))	('p85', 'Gene', (73, 76))	('activity', 'MPA', (116, 124))	('relieve', 'PosReg', (40, 47))	('mutations', 'Var', (4, 13))	('AKT', 'Gene', '207', (179, 182))	('inhibitory effect', 'MPA', (52, 69))
143739	25054828	Cells with PIK3CA mutation have been demonstrated to be more susceptible to the inhibitors than those without.	('susceptible', 'MPA', (61, 72))	('PIK3CA', 'Gene', '5290', (11, 17))	('mutation', 'Var', (18, 26))	('PIK3CA', 'Gene', (11, 17))
143740	25054828	The PI3K inhibitor LY294002 has been shown to reduce proliferation more effectively in an ESCC cell line with E545K mutation compared to the cell lines with wild type PIK3CA.	('reduce', 'NegReg', (46, 52))	('PIK3CA', 'Gene', '5290', (167, 173))	('LY294002', 'Chemical', 'MESH:C085911', (19, 27))	('proliferation', 'CPA', (53, 66))	('E545K', 'Mutation', 'rs104886003', (110, 115))	('E545K mutation', 'Var', (110, 124))	('LY294002', 'Var', (19, 27))	('PIK3CA', 'Gene', (167, 173))
143741	25054828	Currently early-phase and phase I clinical trials have proved higher response rate for the cancer patients with PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors than for those without the mutations.	('PIK3CA', 'Gene', '5290', (112, 118))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('patients', 'Species', '9606', (98, 106))	('higher', 'PosReg', (62, 68))	('AKT', 'Gene', '207', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('response', 'MPA', (69, 77))	('mTOR', 'Gene', (151, 155))	('mutations', 'Var', (119, 128))	('mTOR', 'Gene', '2475', (151, 155))	('PIK3CA', 'Gene', (112, 118))	('AKT', 'Gene', (147, 150))
143742	25054828	Since the mutation c.1634A>C (p.E545A) is uncommon in other cancer types, the susceptibility of the ESCC patients with c.1634A>C to the inhibitors need to be studied.	('patients', 'Species', '9606', (105, 113))	('c.1634A>C', 'Mutation', 'rs121913274', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('c.1634A>C', 'Var', (19, 28))	('p.E545A', 'Mutation', 'rs121913274', (30, 37))	('cancer', 'Disease', (60, 66))	('c.1634A>C', 'Mutation', 'rs121913274', (19, 28))	('c.1634A>C', 'Var', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
143743	25054828	PIK3CA mutation has been reported to indicate a favorable prognosis in Japanese ESCC patients.	('PIK3CA', 'Gene', (0, 6))	('patients', 'Species', '9606', (85, 93))	('Japanese ESCC', 'Disease', (71, 84))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))
143746	25054828	Although PIK3CA mutation was not correlated with patient outcome in this cohort, it was independently associated with worse overall survival in the ESCC patients with family cancer history.	('overall survival', 'MPA', (124, 140))	('mutation', 'Var', (16, 24))	('associated', 'Reg', (102, 112))	('patients', 'Species', '9606', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('patient', 'Species', '9606', (49, 56))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('patient', 'Species', '9606', (153, 160))	('PIK3CA', 'Gene', (9, 15))	('worse', 'NegReg', (118, 123))	('ESCC', 'Disease', (148, 152))	('PIK3CA', 'Gene', '5290', (9, 15))
143749	25054828	However according to our study, the dysregulation of PI3K pathway caused by PIK3CA mutation could possibly cooperate with the altered signal pathway(s) to make the patients with family cancer history to have worse survival.	('dysregulation', 'Var', (36, 49))	('PIK3CA', 'Gene', '5290', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('PI3K pathway', 'Pathway', (53, 65))	('mutation', 'Var', (83, 91))	('PIK3CA', 'Gene', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Disease', (185, 191))
143753	25054828	The PIK3CA mutation rate was dramatically less than the protein expression rate and no correlation between the mutation and the expression was identified.	('mutation', 'Var', (11, 19))	('less', 'NegReg', (42, 46))	('PIK3CA', 'Gene', (4, 10))	('PIK3CA', 'Gene', '5290', (4, 10))
143762	25054828	It has been demonstrated that the PI3K utilizes AKT-dependent and AKT-independent pathway in activating estrogen receptor alpha (ERalpha) in breast cancer cells and it could help the cancer cells to escape from tamoxifen-induced apoptosis.	('escape', 'CPA', (199, 205))	('AKT', 'Gene', (48, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('ERalpha', 'Gene', '2099', (129, 136))	('cancer', 'Disease', (183, 189))	('PI3K', 'Var', (34, 38))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', (141, 154))	('AKT', 'Gene', '207', (48, 51))	('AKT', 'Gene', '207', (66, 69))	('estrogen receptor alpha', 'Gene', '2099', (104, 127))	('AKT', 'Gene', (66, 69))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Disease', (148, 154))	('tamoxifen', 'Chemical', 'MESH:D013629', (211, 220))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('activating', 'MPA', (93, 103))	('help', 'PosReg', (174, 178))	('estrogen receptor alpha', 'Gene', (104, 127))	('ERalpha', 'Gene', (129, 136))
143763	25054828	In conclusion, PIK3CA was mutated in 7.4% of Chinese ESCC patients and c.1634A>C (p.E545A) was the dominant mutation type.	('ESCC', 'Disease', (53, 57))	('PIK3CA', 'Gene', '5290', (15, 21))	('c.1634A>C', 'Var', (71, 80))	('p.E545A', 'Mutation', 'rs121913274', (82, 89))	('c.1634A>C', 'Mutation', 'rs121913274', (71, 80))	('patients', 'Species', '9606', (58, 66))	('PIK3CA', 'Gene', (15, 21))
143764	25054828	The family cancer history is a risk factor for shorter overall survival for the patients with PIK3CA mutations.	('overall survival', 'MPA', (55, 71))	('shorter', 'NegReg', (47, 54))	('mutations', 'Var', (101, 110))	('patients', 'Species', '9606', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('PIK3CA', 'Gene', (94, 100))	('cancer', 'Disease', (11, 17))	('PIK3CA', 'Gene', '5290', (94, 100))
143772	24737952	Though incomplete, we have identified several key molecular events involved in carcinogenesis and targeting them offers survival benefit in several cancers such as breast cancer, colon cancer and leukemia.	('targeting', 'Var', (98, 107))	('colon cancer', 'Disease', 'MESH:D015179', (179, 191))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('leukemia', 'Phenotype', 'HP:0001909', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('colon cancer', 'Disease', (179, 191))	('leukemia', 'Disease', (196, 204))	('leukemia', 'Disease', 'MESH:D007938', (196, 204))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('breast cancer', 'Disease', (164, 177))	('carcinogenesis', 'Disease', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colon cancer', 'Phenotype', 'HP:0003003', (179, 191))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('survival benefit', 'CPA', (120, 136))
143791	24737952	At 4 mo, PFS rate was 61% (95% CI: 36-83) in cetuximab group compared to 44% (95% CI: 20-70) in the other group.	('cetuximab', 'Var', (45, 54))	('PFS', 'Disease', (9, 12))	('cetuximab', 'Chemical', 'MESH:D000068818', (45, 54))
143840	24737952	Median OS and PFS were significantly longer in Ziv-aflibercept group compared with the placebo group (13.5 mo.	('OS', 'Chemical', '-', (7, 9))	('longer', 'PosReg', (37, 43))	('Ziv-aflibercept', 'Var', (47, 62))	('Ziv', 'Chemical', '-', (47, 50))	('PFS', 'CPA', (14, 17))
143860	24737952	Patients with mutant KRAS metastatic colorectal cancer refractory to fluoropyrimidine-and oxaliplatin-based chemotherapy were randomized to FOLFIRI plus conatumumab, ganitumab, or placebo.	('colorectal cancer', 'Disease', (37, 54))	('fluoropyrimidine', 'Chemical', '-', (69, 85))	('KRAS', 'Gene', '3845', (21, 25))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutant', 'Var', (14, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('ganitumab', 'Chemical', 'MESH:C545764', (166, 175))	('Patients', 'Species', '9606', (0, 8))	('FOLFIRI', 'Chemical', '-', (140, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('KRAS', 'Gene', (21, 25))	('conatumumab', 'Chemical', 'MESH:C554537', (153, 164))
143871	24737952	One year survival (23% vs. 17%; P = 0.023) and PFS (3.75 mo vs. 3.55 mo, HR: 0.77, 95% CI: 0.64-0.92, P = 0.004) were also greater in erlotinib arm.	('erlotinib', 'Chemical', 'MESH:D000069347', (134, 143))	('PFS', 'CPA', (47, 50))	('greater', 'PosReg', (123, 130))	('erlotinib', 'Var', (134, 143))
143894	24737952	When different c-KIT (stem cell factor receptor) mutations and treatment response were analyzed in these patients, exon-9 c-KIT mutation was the strongest adverse prognostic factor for response to imatinib and higher dose regimen resulted in significant superior median PFS (P = 0.0013).	('patients', 'Species', '9606', (105, 113))	('c-KIT', 'Gene', '3815', (122, 127))	('imatinib', 'Chemical', 'MESH:D000068877', (197, 205))	('response to imatinib', 'MPA', (185, 205))	('c-KIT', 'Gene', (15, 20))	('mutation', 'Var', (128, 136))	('superior', 'PosReg', (254, 262))	('c-KIT', 'Gene', '3815', (15, 20))	('exon-9', 'Var', (115, 121))	('c-KIT', 'Gene', (122, 127))
143919	24737952	In human and murine HCC cells, gefitinib induced cell cycle arrest, apoptosis and cell growth inhibition.	('cell cycle arrest', 'CPA', (49, 66))	('human', 'Species', '9606', (3, 8))	('gefitinib', 'Chemical', 'MESH:D000077156', (31, 40))	('cell growth inhibition', 'CPA', (82, 104))	('HCC', 'Phenotype', 'HP:0001402', (20, 23))	('apoptosis', 'CPA', (68, 77))	('murine', 'Species', '10090', (13, 19))	('gefitinib', 'Var', (31, 40))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))
143920	24737952	In phase II trials, FOLFOX4 + gefitinib showed median OS of 12 mo and median event free survival of 5.4 mo in previously treated metastatic colorectal cancer, as well as median OS of 20.5 mo and median TTP of 9.3 mo in previously untreated metastatic cases.	('gefitinib', 'Chemical', 'MESH:D000077156', (30, 39))	('FOLFOX4', 'Chemical', '-', (20, 27))	('FOLFOX4', 'Var', (20, 27))	('colorectal cancer', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('metastatic', 'Disease', (129, 139))	('OS', 'Chemical', '-', (177, 179))	('OS', 'Chemical', '-', (54, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))
143923	24737952	EGFR phosphorylation status in colon cancer is predictive of response to gefitinib, even synergistic when used with platinum based chemotherapy.	('colon cancer', 'Disease', (31, 43))	('predictive', 'Reg', (47, 57))	('EGFR', 'Gene', (0, 4))	('gefitinib', 'Chemical', 'MESH:D000077156', (73, 82))	('phosphorylation', 'Var', (5, 20))	('response', 'MPA', (61, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (31, 43))	('colon cancer', 'Disease', 'MESH:D015179', (31, 43))	('platinum', 'Chemical', 'MESH:D010984', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('EGFR', 'Gene', '1956', (0, 4))
143942	24737952	In a phase III, randomized, placebo controlled trial of previously untreated metastatic colorectal cancer, patients were randomly assigned to FOLFOX4 + vatalanib (evaluable n = 581) or FOLFOX4 + placebo (evaluable n = 575) arm.	('colorectal cancer', 'Disease', (88, 105))	('FOLFOX4', 'Chemical', '-', (142, 149))	('FOLFOX4', 'Chemical', '-', (185, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('vatalanib', 'Chemical', 'MESH:C404768', (152, 161))	('FOLFOX4', 'Var', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('patients', 'Species', '9606', (107, 115))
143984	24737952	Combination of selumetinib and vorinostat synergistically inhibits cell proliferation in two colorectal cancer cell lines with KRAS mutation.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('vorinostat', 'Chemical', 'MESH:D000077337', (31, 41))	('inhibits', 'NegReg', (58, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('KRAS', 'Gene', (127, 131))	('selumetinib', 'Chemical', 'MESH:C517975', (15, 26))	('colorectal cancer', 'Disease', (93, 110))	('KRAS', 'Gene', '3845', (127, 131))	('cell proliferation', 'CPA', (67, 85))	('mutation', 'Var', (132, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))
143993	24737952	Imatinib is used for GIST expressing c-KIT and further studies of KIT mutation and platelet derived growth factor mutations have also been shown to correlate with response/resistance to imatinib.	('KIT', 'Gene', (66, 69))	('GI', 'Disease', 'MESH:D005767', (21, 23))	('c-KIT', 'Gene', '3815', (37, 42))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('response/resistance', 'MPA', (163, 182))	('mutations', 'Var', (114, 123))	('GIST', 'Phenotype', 'HP:0100723', (21, 25))	('imatinib', 'Chemical', 'MESH:D000068877', (186, 194))	('c-KIT', 'Gene', (37, 42))	('correlate', 'Reg', (148, 157))	('mutation', 'Var', (70, 78))
143994	24737952	Although initially approved for all metastatic colon cancers, the label was changed to indicate cetuximab should only be used for the treatment of KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer (in combination with FOLFIRI as first-line treatment, in combination with irinotecan [in patients refractory to irinotecan-based chemotherapy], or as a single agent in patients who have failed oxaliplatin and irinotecan based chemotherapy or who are intolerant to irinotecan).	('patients', 'Species', '9606', (396, 404))	('colorectal cancer', 'Disease', 'MESH:D015179', (210, 227))	('cetuximab', 'Chemical', 'MESH:D000068818', (96, 105))	('colorectal cancer', 'Disease', (210, 227))	('KRAS', 'Gene', (147, 151))	('EGFR', 'Gene', (183, 187))	('mutation-negative', 'Var', (152, 169))	('irinotecan', 'Chemical', 'MESH:D000077146', (302, 312))	('irinotecan', 'Chemical', 'MESH:D000077146', (492, 502))	('colon cancers', 'Phenotype', 'HP:0003003', (47, 60))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('irinotecan', 'Chemical', 'MESH:D000077146', (437, 447))	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (210, 227))	('FOLFIRI', 'Chemical', '-', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('colon cancers', 'Disease', 'MESH:D015179', (47, 60))	('EGFR', 'Gene', '1956', (183, 187))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (421, 432))	('colon cancers', 'Disease', (47, 60))	('irinotecan', 'Chemical', 'MESH:D000077146', (340, 350))	('patients', 'Species', '9606', (317, 325))	('KRAS', 'Gene', '3845', (147, 151))
144020	24658763	Bowel obstruction (0.0% vs. 7.2% p = 0.003), abdominal distension (9.1% vs. 19% p = 0.022), and the occurrence of pneumonia (11.6% vs. 26.1% p = 0.003) were significantly lower in the RGF group.	('pneumonia', 'Phenotype', 'HP:0002090', (114, 123))	('Bowel obstruction', 'Disease', (0, 17))	('pneumonia', 'Disease', (114, 123))	('Bowel obstruction', 'Phenotype', 'HP:0005214', (0, 17))	('RGF', 'Var', (184, 187))	('pneumonia', 'Disease', 'MESH:D011014', (114, 123))	('abdominal', 'CPA', (45, 54))	('Bowel obstruction', 'Disease', 'MESH:D015212', (0, 17))	('abdominal distension', 'Phenotype', 'HP:0003270', (45, 65))	('lower', 'NegReg', (171, 176))
144049	24658763	There were significantly lower incidences of digestive system complications in the RGF group compared to the JF group (bowel obstruction: 0 of 121 [0.0%] vs. 11 of 153 [7.2%], p = 0.003; abdominal distension: 11 of 121 [9.1%] vs. 29 of 153 [19%], p = 0.022).	('RGF', 'Var', (83, 86))	('digestive system', 'Disease', (45, 61))	('bowel obstruction', 'Disease', 'MESH:D015212', (119, 136))	('bowel obstruction', 'Phenotype', 'HP:0005214', (119, 136))	('bowel obstruction', 'Disease', (119, 136))	('lower', 'NegReg', (25, 30))	('abdominal distension', 'Disease', (187, 207))	('abdominal distension', 'Phenotype', 'HP:0003270', (187, 207))
144050	24658763	There were lower incidences of complications related to the feeding tube in the RGF group compared to the JF group (wound infection 2 vs. 10; peritonitis 0 vs. 11; catheter displacement 2 vs. 7; catheter blockade 4 vs. 9); the difference was significant for peritonitis (p = 0.003).	('infection', 'Disease', (122, 131))	('peritonitis', 'Phenotype', 'HP:0002586', (258, 269))	('infection', 'Disease', 'MESH:D007239', (122, 131))	('peritonitis', 'Phenotype', 'HP:0002586', (142, 153))	('RGF', 'Var', (80, 83))	('lower', 'NegReg', (11, 16))	('peritonitis', 'Disease', 'MESH:D010534', (258, 269))	('peritonitis', 'Disease', 'MESH:D010534', (142, 153))	('peritonitis', 'Disease', (258, 269))	('peritonitis', 'Disease', (142, 153))
144082	22094011	Grossly, BE is classified on the basis of its length: long segment (afflicted part of the esophagus is longer than 3 cm), short segment (shorter than 3 cm), and ultra-short segment (which is not actually observed by the endoscopic examination).	('men', 'Species', '9606', (62, 65))	('ultra-short segment', 'Var', (161, 180))	('men', 'Species', '9606', (131, 134))	('men', 'Species', '9606', (176, 179))	('BE', 'Phenotype', 'HP:0100580', (9, 11))	('shorter', 'Var', (137, 144))
144177	30811100	EAL could lead to mediastinitis and pyothorax during postoperative period and therefore significantly increases the postoperative morbidity and mortality.	('EAL', 'Var', (0, 3))	('EAL', 'Phenotype', 'HP:0100628', (0, 3))	('pyothorax', 'Disease', (36, 45))	('lead to', 'Reg', (10, 17))	('EAL', 'Chemical', '-', (0, 3))	('mediastinitis', 'Disease', 'MESH:D008480', (18, 31))	('pyothorax', 'Phenotype', 'HP:0011919', (36, 45))	('mediastinitis', 'Disease', (18, 31))	('increases', 'PosReg', (102, 111))
144178	30811100	Recent research reported that EAL could also adversely impact the long-term survival and induce the recurrence of locoregional cancer 3.	('induce', 'Reg', (89, 95))	('EAL', 'Var', (30, 33))	('EAL', 'Phenotype', 'HP:0100628', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('long-term survival', 'CPA', (66, 84))	('cancer', 'Disease', (127, 133))	('EAL', 'Chemical', '-', (30, 33))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('recurrence', 'CPA', (100, 110))	('impact', 'Reg', (55, 61))
144187	30811100	Briefly, the cells were incubated with Mouse Mesenchymal Stromal Cell Marker antibodies (1:100, Abcam, Cambridge, U.K., http://www.abcam.com/) for CD29, CD44, CD90, and CD45 for 1 hour at room temperature.	('CD90', 'Gene', '21838', (159, 163))	('Mouse', 'Species', '10090', (39, 44))	('CD45', 'Gene', (169, 173))	('CD45', 'Gene', '19264', (169, 173))	('CD29', 'Gene', '16412', (147, 151))	('CD90', 'Gene', (159, 163))	('CD29', 'Gene', (147, 151))	('CD44', 'Var', (153, 157))
144228	30811100	In addition, the infection rate was 33.3% (4/12) for AAMSC/FS group compared with 88.9% (8/9) for control with a significant difference (p = .02; Fig.	('infection', 'CPA', (17, 26))	('AAMSC/FS', 'Var', (53, 61))	('FS', 'Chemical', '-', (59, 61))
144250	30811100	We inferred 2 mechanisms that contribute to the EALs healing process: one of possible mechanism may be related to differentiation potential of the AAMSCs; the other was that AAMSCs may stimulate the transdifferentiation of other cells around EALs to myofibroblasts.	('EAL', 'Chemical', '-', (242, 245))	('AAMSCs', 'Var', (174, 180))	('transdifferentiation', 'CPA', (199, 219))	('stimulate', 'PosReg', (185, 194))	('EAL', 'Phenotype', 'HP:0100628', (48, 51))	('EAL', 'Phenotype', 'HP:0100628', (242, 245))	('EAL', 'Chemical', '-', (48, 51))
144259	30811100	In addition, a clearly higher closure rate of EAL was achieved in AAMSC/FS group than control group (83.3% vs. 11.1%).	('AAMSC/FS', 'Var', (66, 74))	('EAL', 'Chemical', '-', (46, 49))	('higher', 'PosReg', (23, 29))	('EAL', 'Disease', (46, 49))	('AAMSC/FS', 'Disease', (66, 74))	('EAL', 'Phenotype', 'HP:0100628', (46, 49))	('FS', 'Chemical', '-', (72, 74))
144264	30811100	Furthermore, the survival rate of AAMSC/FS group was more than twice higher than control group (55.9% vs. 25%), although no statistic difference in mortality was detected between the 2 groups.	('survival', 'CPA', (17, 25))	('higher', 'PosReg', (69, 75))	('FS', 'Chemical', '-', (40, 42))	('AAMSC/FS', 'Var', (34, 42))
144284	28279462	About 40% of HDGC is due to mutations in E-cadherin (CDH1).	('HDGC', 'Disease', (13, 17))	('CDH1', 'Gene', '999', (53, 57))	('due to', 'Reg', (21, 27))	('CDH1', 'Gene', (53, 57))	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))	('mutations', 'Var', (28, 37))
144285	28279462	Mutations in CTNNA1 have also recently been found in a subset of patients with the condition.	('CTNNA1', 'Gene', '1495', (13, 19))	('found', 'Reg', (44, 49))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (65, 73))	('CTNNA1', 'Gene', (13, 19))
144302	28279462	A case control study also demonstrated a reduction in odds ratio (OR) of death from gastric cancer at 1 and 2 years in subjects screened with pepsinogen levels.	('gastric cancer', 'Disease', (84, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('pepsinogen', 'Var', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('death', 'Disease', 'MESH:D003643', (73, 78))	('death', 'Disease', (73, 78))	('reduction', 'NegReg', (41, 50))
144345	28279462	Reid and colleagues have promoted the use of aneuploidy and tetraploidy, evidence of genetic instability, as a marker of potential tumor progression.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('aneuploidy', 'Disease', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('aneuploidy', 'Disease', 'MESH:D000782', (45, 55))	('tumor', 'Disease', (131, 136))	('tetraploidy', 'Var', (60, 71))
144387	28279462	In a multicenter, sham-controlled, randomized trial, complete eradication of dysplasia was achieved in 91% of cases with low-grade dysplasia and in 81% of cases with high-grade dysplasia.	('dysplasia', 'Disease', (131, 140))	('dysplasia', 'Disease', 'MESH:D004476', (131, 140))	('low-grade', 'Var', (121, 130))	('dysplasia', 'Disease', (77, 86))	('dysplasia', 'Disease', (177, 186))	('dysplasia', 'Disease', 'MESH:D004476', (177, 186))	('dysplasia', 'Disease', 'MESH:D004476', (77, 86))
144399	28279462	Genome-wide association studies have shown SNPs for alcohol dehydrogenase 1B (rs1229984), aldehyde dehydrogenase 2 family (rs671), and a region of chromosome 20 (C20orf54).	('rs671', 'Var', (123, 128))	('alcohol dehydrogenase 1B', 'Gene', '125', (52, 76))	('rs671', 'Mutation', 'rs671', (123, 128))	('C20orf54', 'Gene', (162, 170))	('C20orf54', 'Gene', '113278', (162, 170))	('rs1229984', 'Mutation', 'rs1229984', (78, 87))	('rs1229984', 'Var', (78, 87))	('alcohol dehydrogenase 1B', 'Gene', (52, 76))
144500	28282392	At the end of the selection strategy, the best prognostic performances were obtained with n2 = 3 complementary features: NRI (group 2), WHO performance status, and MTV (group 6), which led to an AUC of 0.822+-0.059 (RFerr = 28+-5%, SVMerr = 34+-5%, Se = 79+-9%, Sp = 95+-6%; see Table 7).	('RF', 'Chemical', '-', (216, 218))	('NRI', 'Var', (121, 124))	('MTV', 'Var', (164, 167))	('n2 =', 'Var', (90, 94))	('MTV', 'Chemical', '-', (164, 167))
144710	27219458	Exposure to nitrosamines, polyaromatic hydrocarbons, smoked food, hot beverages and opium are considered as risk factors for SCC, while AC is mostly related to chronic gastroesophageal reflux disease.	('nitrosamines', 'Chemical', 'MESH:D009602', (12, 24))	('chronic gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (160, 199))	('SCC', 'Gene', (125, 128))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('polyaromatic', 'Var', (26, 38))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (168, 191))	('polyaromatic hydrocarbons', 'Chemical', '-', (26, 51))	('SCC', 'Gene', '6317', (125, 128))	('chronic gastroesophageal reflux disease', 'Disease', (160, 199))
144736	26646323	High expression of ERK in esophageal cancer leads to a more aggressive phenotype in clinicopathology, resulting in tumor malignance.	('High expression', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('resulting in', 'Reg', (102, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (26, 43))	('ERK', 'Gene', '5594', (19, 22))	('tumor', 'Disease', (115, 120))	('ERK', 'Gene', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('more', 'PosReg', (55, 59))	('leads to', 'Reg', (44, 52))	('esophageal cancer', 'Disease', (26, 43))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
144757	26646323	As shown in Figure 2A, TE1 and KYSE150 cells treated with 10 muM GPX for 48 h could not form colonies, indicating that GPX inhibits the proliferation of these cell lines.	('KYSE150', 'CellLine', 'CVCL:1348', (31, 38))	('muM', 'Gene', (61, 64))	('GPX', 'Chemical', 'MESH:C000600533', (119, 122))	('proliferation', 'CPA', (136, 149))	('GPX', 'Chemical', 'MESH:C000600533', (65, 68))	('GPX', 'Var', (119, 122))	('inhibits', 'NegReg', (123, 131))	('muM', 'Gene', '56925', (61, 64))
144760	26646323	Dose-dependent G2/M arrest was observed (Figure 2B), and the statistical analysis showed that GPX caused G2/M cell cycle arrest in TE1 and KYSE150 cells (Figure 2C).	('GPX', 'Var', (94, 97))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (110, 127))	('G2/M', 'MPA', (105, 109))	('KYSE150', 'CellLine', 'CVCL:1348', (139, 146))	('GPX', 'Chemical', 'MESH:C000600533', (94, 97))
144769	26646323	Additionally, the weight of the lungs in the GPX and 5-FU treated groups decreased significantly compared to that in the control group (Figure 3C).	('decreased', 'NegReg', (73, 82))	('GPX', 'Chemical', 'MESH:C000600533', (45, 48))	('5-FU', 'Var', (53, 57))	('weight of the lungs', 'CPA', (18, 37))	('5-FU', 'Chemical', 'MESH:D005472', (53, 57))
144779	26646323	In TE1 and KYSE150, 5 muM and 10 muM of GPX, respectively, decreased the protein levels.	('muM', 'Gene', (33, 36))	('KYSE150', 'CellLine', 'CVCL:1348', (11, 18))	('decreased', 'NegReg', (59, 68))	('protein levels', 'MPA', (73, 87))	('GPX', 'Chemical', 'MESH:C000600533', (40, 43))	('muM', 'Gene', '56925', (22, 25))	('muM', 'Gene', '56925', (33, 36))	('KYSE150', 'Var', (11, 18))	('muM', 'Gene', (22, 25))
144843	26646323	The primary antibodies C-RAF (Cat.9422), MEK1/2 (Cat.9122), p-MEK (Ser217/221, Cat.9154), ERK (Cat.4695), p-ERK (Tyr202/Tyr204, Cat.4370), GAPDH (Cat.5174), p-AKT (Ser473, Cat.9171), cyclinB1 (Cat.12231), E-cadherin (Cat.3195), vimentin (Cat.5741), and snail (Cat.3879) were purchased from Cell Signaling Technologies (Danvers, MA, USA).	('MEK', 'Gene', (62, 65))	('ERK', 'Gene', (108, 111))	('E-cadherin', 'Gene', (205, 215))	('Ser217/221', 'Var', (67, 77))	('E-cadherin', 'Gene', '999', (205, 215))	('cyclinB1', 'Gene', (183, 191))	('Cat.9422', 'CellLine', 'CVCL:6F73', (30, 38))	('Tyr202/Tyr204', 'Var', (113, 126))	('snail', 'Gene', (253, 258))	('GAPDH', 'Gene', (139, 144))	('C-RAF', 'Gene', '5894', (23, 28))	('AKT', 'Gene', '207', (159, 162))	('Cat.9171', 'CellLine', 'CVCL:6F73', (172, 180))	('Cat.3195', 'Var', (217, 225))	('ERK', 'Gene', (90, 93))	('cyclinB1', 'Gene', '891', (183, 191))	('Cat.9154', 'CellLine', 'CVCL:T300', (79, 87))	('C-RAF', 'Gene', (23, 28))	('MEK', 'Gene', '5609', (41, 44))	('Cat.12231', 'Var', (193, 202))	('ERK', 'Gene', '5594', (90, 93))	('Cat.9122', 'CellLine', 'CVCL:6F73', (49, 57))	('snail', 'Gene', '6615', (253, 258))	('ERK', 'Gene', '5594', (108, 111))	('MEK1/2', 'Gene', '5604;5605', (41, 47))	('MEK', 'Gene', '5609', (62, 65))	('MEK', 'Gene', (41, 44))	('MEK1/2', 'Gene', (41, 47))	('AKT', 'Gene', (159, 162))	('p-ERK', 'Gene', '9451', (106, 111))	('vimentin', 'Gene', '7431', (228, 236))	('GAPDH', 'Gene', '2597', (139, 144))	('Cat.9422', 'Var', (30, 38))	('Cat.5174', 'Var', (146, 154))	('vimentin', 'Gene', (228, 236))	('p-ERK', 'Gene', (106, 111))
144941	21192846	Patients in group three, with a strong expression of laminin-5 gamma2 chain and SPARC, had a 5-year survival rate of 7.7%, while patients in group one, without strong expression of laminin-5 gamma2 chain or SPARC, had a 5-year survival rate of 51.0% and patients in group two, with strong expression of either laminin-5 gamma2 chain or SPARC, had a 5-year survival rate of 41.9%.	('SPARC', 'Gene', (207, 212))	('SPARC', 'Gene', '6678', (336, 341))	('SPARC', 'Gene', (80, 85))	('patients', 'Species', '9606', (129, 137))	('SPARC', 'Gene', (336, 341))	('SPARC', 'Gene', '6678', (80, 85))	('Patients', 'Species', '9606', (0, 8))	('SPARC', 'Gene', '6678', (207, 212))	('patients', 'Species', '9606', (254, 262))	('laminin-5 gamma2 chain', 'Var', (53, 75))
144961	21192846	In addition, the expression of SPARC increases MMP expression in fibroblasts and monocytes.	('SPARC', 'Gene', '6678', (31, 36))	('increases', 'PosReg', (37, 46))	('expression', 'Var', (17, 27))	('MMP expression', 'MPA', (47, 61))	('SPARC', 'Gene', (31, 36))
144962	21192846	MMP facilitates the degradation of extracellular matrix components, leading to the increased ability of cancer cell movement related to cancer invasion, metastasis, and prognosis.	('increased', 'PosReg', (83, 92))	('MMP', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('degradation of extracellular matrix components', 'MPA', (20, 66))	('metastasis', 'CPA', (153, 163))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
144988	32831056	Several factors, such as smoking, obesity, low vegetable consumption, have been proven to adversely predict esophageal carcinoma.	('obesity', 'Phenotype', 'HP:0001513', (34, 41))	('low vegetable consumption', 'Var', (43, 68))	('esophageal carcinoma', 'Disease', (108, 128))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (108, 128))	('obesity', 'Disease', 'MESH:D009765', (34, 41))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (108, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('obesity', 'Disease', (34, 41))
145009	32831056	The risk score calculating formula was (0.6295 x TBK1 expression) + (1.0691 x ATG5 expression) + (0.3706 x HSP90AB1 expression) + (0.9976 x VAMP7 expression) + (0.5236 x DNAJB1 expression) + (1.0485 x GABARAPL2 expression) - (0.6739 x MAP2K7 expression).	('DNAJB1', 'Gene', '3337', (170, 176))	('GABARAPL2', 'Gene', (201, 210))	('TBK1', 'Gene', '29110', (49, 53))	('VAMP7', 'Gene', '6845', (140, 145))	('ATG5', 'Gene', '9474', (78, 82))	('TBK1', 'Gene', (49, 53))	('VAMP7', 'Gene', (140, 145))	('DNAJB1', 'Gene', (170, 176))	('MAP2K7', 'Gene', (235, 241))	('HSP90AB1', 'Gene', (107, 115))	('MAP2K7', 'Gene', '5609', (235, 241))	('GABARAPL2', 'Gene', '11345', (201, 210))	('0.6295', 'Var', (40, 46))	('ATG5', 'Gene', (78, 82))	('HSP90AB1', 'Gene', '3326', (107, 115))
145038	32831056	Furthermore, autophagy abolition through the ATG5/7 re-sensitized EC109/CDDP knockdown or the use of pharmacological inhibitors is greatly significant not only in the esophageal, but also in gastric, colorectal, bladder, ovarian, and prostate cancers.	('esophageal', 'Disease', (167, 177))	('EC109/CDDP', 'Gene', (66, 76))	('prostate cancers', 'Disease', 'MESH:D011471', (234, 250))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('CDDP', 'Chemical', 'MESH:D002945', (72, 76))	('knockdown', 'Var', (77, 86))	('colorectal, bladder, ovarian', 'Disease', 'MESH:D001749', (200, 228))	('ATG5/7', 'Gene', (45, 51))	('prostate cancers', 'Phenotype', 'HP:0012125', (234, 250))	('ATG5/7', 'Gene', '9474;10533', (45, 51))	('prostate cancers', 'Disease', (234, 250))	('gastric', 'Disease', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('autophagy', 'CPA', (13, 22))
145048	30739906	MYH9 was first discovered due to thrombocytopenia caused by MYH9 mutation-related abnormalities.	('thrombocytopenia', 'Disease', (33, 49))	('caused by', 'Reg', (50, 59))	('MYH9', 'Gene', (60, 64))	('thrombocytopenia', 'Disease', 'MESH:D013921', (33, 49))	('mutation-related abnormalities', 'Var', (65, 95))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (33, 49))
145059	30739906	MYH9 was first discovered due to thrombocytopenia caused by MYH9 mutation-related abnormalities, such as May-Hegglin anomaly (MHA), Epstein syndrome (EPS), Fechtner syndrome (FTNS), and Sebastian syndrome (SBS), which are autosomal dominant genetic diseases.	('thrombocytopenia', 'Disease', (33, 49))	('genetic diseases', 'Disease', (241, 257))	('MHA', 'Disease', (126, 129))	('caused', 'Reg', (50, 56))	('Fechtner syndrome', 'Disease', 'MESH:C535507', (156, 173))	('anomaly', 'Disease', (117, 124))	('MYH9', 'Gene', (60, 64))	('SBS', 'Disease', (206, 209))	('EPS', 'Disease', 'MESH:D001480', (150, 153))	('thrombocytopenia', 'Disease', 'MESH:D013921', (33, 49))	('SBS', 'Disease', 'MESH:C536611', (206, 209))	('mutation-related abnormalities', 'Var', (65, 95))	('abnormalities', 'Var', (82, 95))	('FTNS', 'Disease', 'MESH:C535507', (175, 179))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (33, 49))	('Epstein syndrome', 'Disease', (132, 148))	('FTNS', 'Disease', (175, 179))	('genetic diseases', 'Disease', 'MESH:D030342', (241, 257))	('MHA', 'Disease', 'MESH:C535507', (126, 129))	('Sebastian syndrome', 'Disease', 'MESH:C535507', (186, 204))	('Epstein syndrome', 'Disease', 'MESH:C535507', (132, 148))	('anomaly', 'Disease', 'MESH:D000014', (117, 124))	('Fechtner syndrome', 'Disease', (156, 173))	('EPS', 'Disease', (150, 153))	('Sebastian syndrome', 'Disease', (186, 204))
145067	30739906	found a relationship between more than 80 genetic mutations, specific mutations, and features of clinical diseases; mutations affecting residue R702 (exon 17) are correlated with severe thrombocytopenia, end-stage renal disease, and early episodes of deafness.	('renal disease', 'Phenotype', 'HP:0000112', (214, 227))	('end-stage renal disease', 'Phenotype', 'HP:0003774', (204, 227))	('deafness', 'Disease', (251, 259))	('thrombocytopenia', 'Disease', 'MESH:D013921', (186, 202))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (186, 202))	('mutations', 'Var', (116, 125))	('correlated with', 'Reg', (163, 178))	('deafness', 'Disease', 'MESH:D003638', (251, 259))	('end-stage renal disease', 'Disease', (204, 227))	('thrombocytopenia', 'Disease', (186, 202))	('end-stage renal disease', 'Disease', 'MESH:D007676', (204, 227))	('deafness', 'Phenotype', 'HP:0000365', (251, 259))
145068	30739906	Mutations in exon 2, mutations affecting residues R1165 (exon 26), and a p.D1424H substitution (exon 31) are associated with moderate risk of thrombocytopenia and additional hematologic manifestations.	('thrombocytopenia', 'Disease', 'MESH:D013921', (142, 158))	('p.D1424H', 'Var', (73, 81))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (142, 158))	('rat', 'Species', '10116', (129, 132))	('p.D1424H', 'Mutation', 'rs80338831', (73, 81))	('thrombocytopenia', 'Disease', (142, 158))
145069	30739906	Finally, mutations affecting the C-terminal non-helical tail, p.D1424N (exon 31), p.E1841K (exon 39,) or nonsense/frameshift mutations are associated with moderate thrombocytopenia and extravasation manifestations.	('p.E1841K', 'Mutation', 'rs80338834', (82, 90))	('p.D1424N', 'Var', (62, 70))	('nonsense/frameshift mutations', 'Var', (105, 134))	('thrombocytopenia', 'Disease', (164, 180))	('p.D1424N', 'Mutation', 'rs80338831', (62, 70))	('p.E1841K', 'Var', (82, 90))	('associated', 'Reg', (139, 149))	('extravasation manifestations', 'Disease', (185, 213))	('rat', 'Species', '10116', (159, 162))	('thrombocytopenia', 'Disease', 'MESH:D013921', (164, 180))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (164, 180))
145074	30739906	Previous studies have found that down-regulation of 18 miRNAs and up-regulation of 3 miRNAs resulted in increased MYH9 expression, and an association was found between low MIR-188-5p and overall survival (OS) and event-free survival (EFS) of cytogenetically normal acute myeloid leukemia CN-AML.	('expression', 'MPA', (119, 129))	('MYH9', 'Gene', (114, 118))	('event-free survival', 'CPA', (213, 232))	('leukemia', 'Phenotype', 'HP:0001909', (279, 287))	('up-regulation', 'PosReg', (66, 79))	('increased', 'PosReg', (104, 113))	('down-regulation', 'NegReg', (33, 48))	('overall survival', 'CPA', (187, 203))	('low', 'NegReg', (168, 171))	('myeloid leukemia CN-AML', 'Disease', 'MESH:D015470', (271, 294))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (271, 287))	('myeloid leukemia CN-AML', 'Disease', (271, 294))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (265, 287))	('MIR-188-5p', 'Var', (172, 182))
145077	30739906	Patients with M4 and high expression of MYH9 are prone to invasion of skin, bone marrow, and other tissues, and are resistant to chemotherapy.	('MYH9', 'Gene', (40, 44))	('prone', 'Reg', (49, 54))	('invasion of skin', 'CPA', (58, 74))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (21, 36))
145089	30739906	Survival analysis using Kaplan-Meier method showed that the high expression of MYH9 in primary tumors was significantly associated with shortened survival.	('shortened', 'NegReg', (136, 145))	('high', 'Var', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('MYH9', 'Gene', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (95, 100))
145090	30739906	Five-year cumulative survival rates were 49% (31/63) and 86% (51/59) in patients with high and low expression of MYH9, respectively.	('low', 'NegReg', (95, 98))	('MYH9', 'Gene', (113, 117))	('rat', 'Species', '10116', (30, 33))	('high', 'Var', (86, 90))	('patients', 'Species', '9606', (72, 80))
145096	30739906	Therefore, MYH9 is an independent prognostic factor for lung cancer (in patients with stage 1-3 resectable non-small cell lung cancer); furthermore, it has been found that patients with resectable non-small cell lung cancer and patients with high expression of MYH9 had poor prognoses.	('high expression', 'Var', (242, 257))	('non-small cell lung cancer', 'Disease', (107, 133))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (197, 223))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('MYH9', 'Gene', (261, 265))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (201, 223))	('patients', 'Species', '9606', (228, 236))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (107, 133))	('patients', 'Species', '9606', (172, 180))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (197, 223))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (107, 133))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', 'MESH:D008175', (212, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('non-small cell lung cancer', 'Disease', (197, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('patients', 'Species', '9606', (72, 80))
145102	30739906	Additionally, it was also found that low expression of NMIIA was related to poor prognosis of patients with squamous cell carcinoma of the head and neck, which may be related to mutations in MYH9.	('MYH9', 'Gene', (191, 195))	('low', 'NegReg', (37, 40))	('patients', 'Species', '9606', (94, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('expression', 'MPA', (41, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('NMIIA', 'Gene', (55, 60))	('squamous cell carcinoma', 'Disease', (108, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('mutations', 'Var', (178, 187))
145103	30739906	Mutations in MYH9 were found in about 5% of patients, with these mutations mainly occurring in the NMIIA MgATP domain or the entire NMIIA molecule, and these mutations may be MYH9-related diseases or may eventually develop into skin cancer.	('skin cancer', 'Disease', 'MESH:D012878', (228, 239))	('MYH9-related diseases', 'Disease', (175, 196))	('develop', 'Reg', (215, 222))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('occurring', 'Reg', (82, 91))	('patients', 'Species', '9606', (44, 52))	('MgATP', 'Chemical', 'MESH:D000255', (105, 110))	('MYH9', 'Gene', (13, 17))	('skin cancer', 'Phenotype', 'HP:0008069', (228, 239))	('Mutations', 'Var', (0, 9))	('skin cancer', 'Disease', (228, 239))	('mutations', 'Var', (158, 167))	('mutations', 'Var', (65, 74))
145105	30739906	MYH9 plays a role in the P53 pathway through FOXE1; MYH9 affects PAX5 expression through its interaction with Thy28 (thymocyte protein) and activates AKT (protein kinase B) through RAC1 and PAK1, suggesting its role in gene regulation.	('PAX5', 'Gene', (65, 69))	('FOXE1', 'Gene', '2304', (45, 50))	('P53', 'Gene', '7157', (25, 28))	('AKT', 'Gene', '207', (150, 153))	('PAX5', 'Gene', '5079', (65, 69))	('interaction', 'Interaction', (93, 104))	('activates', 'PosReg', (140, 149))	('PAK1', 'Gene', (190, 194))	('MYH9', 'Var', (52, 56))	('expression', 'MPA', (70, 80))	('RAC1', 'Gene', (181, 185))	('PAK1', 'Gene', '5058', (190, 194))	('Thy28', 'Gene', (110, 115))	('P53', 'Gene', (25, 28))	('affects', 'Reg', (57, 64))	('RAC1', 'Gene', '5879', (181, 185))	('FOXE1', 'Gene', (45, 50))	('AKT', 'Gene', (150, 153))	('Thy28', 'Gene', '29087', (110, 115))
145115	30739906	Meanwhile, in a comparison between MCF7 cells (high expression of MYH9) and MCF6/7 cells (low expression of MYH9), we observed that the former had stronger invasive ability, and its invasion ability was clearly weakened after knockout of MYH9.	('weakened', 'NegReg', (211, 219))	('MYH9', 'Gene', (238, 242))	('invasive ability', 'CPA', (156, 172))	('invasion ability', 'CPA', (182, 198))	('MCF7', 'CellLine', 'CVCL:0031', (35, 39))	('stronger', 'PosReg', (147, 155))	('knockout', 'Var', (226, 234))	('MCF6/7', 'CellLine', 'CVCL:W972', (76, 82))
145125	30739906	Dlc1 also inhibits stress fiber formation via Rho and phosphorylation of MYH9-activated ROCK kinase via MLC20.	('MLC20', 'Gene', '103910', (104, 109))	('inhibits', 'NegReg', (10, 18))	('Rho', 'CPA', (46, 49))	('stress fiber formation', 'CPA', (19, 41))	('Dlc1', 'Var', (0, 4))	('MLC20', 'Gene', (104, 109))	('phosphorylation', 'MPA', (54, 69))
145204	28673358	PBT is expected to be associated with reduced treatment-related toxicities, because of the unique physical characteristic of the proton beam, wherein the peak energy, represented by the so-called Bragg peak, is delivered just before the particles come to rest, with the energy declining rapidly thereafter.	('PBT', 'Var', (0, 3))	('toxicities', 'Disease', 'MESH:D064420', (64, 74))	('toxicities', 'Disease', (64, 74))
145239	28673358	However, inconsistent results have been reported from previous studies for the case of high-energy proton beams (200-230-MeV), which are widely used for the clinical treatment of solid tumors.	('solid tumors', 'Disease', (179, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('solid tumors', 'Disease', 'MESH:D009369', (179, 191))	('200-230-MeV', 'Var', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
145250	28673358	In contrast, the residual number of gammaH2AX foci at 24 h after the irradiation was significantly higher for position #4 (distal end) of the SOBP in both cell lines.	('position #4', 'Var', (110, 121))	('gammaH2AX', 'Chemical', '-', (36, 45))	('higher', 'PosReg', (99, 105))
145257	28673358	also revealed that the higher the LET, the longer the gammaH2AX foci persist, as compared to that following irradiation with gamma-rays.	('rays', 'Species', '255564', (131, 135))	('gammaH2AX', 'Chemical', '-', (54, 63))	('gammaH2AX', 'Var', (54, 63))	('LET', 'MPA', (34, 37))
145329	23866060	In our study, the MLNR was categorized by deciles into 0 (MLNR0), >0 to <0.1 (MLNR1), 0.1 to <0.3 (MLNR2) and >=0.3 (MLNR3), based on the AJCC Seventh Edition classification system.	('MLNR', 'Gene', (58, 62))	('MLNR', 'Gene', (117, 121))	('MLNR', 'Gene', '2862', (78, 82))	('MLNR', 'Gene', '2862', (99, 103))	('AJCC Seventh Edition', 'Disease', (138, 158))	('MLNR', 'Gene', (78, 82))	('AJCC Seventh Edition', 'Disease', 'MESH:D005155', (138, 158))	('MLNR', 'Gene', '2862', (58, 62))	('MLNR', 'Gene', (99, 103))	('0.1 to <0.3', 'Var', (86, 97))	('MLNR', 'Gene', '2862', (18, 22))	('MLNR', 'Gene', '2862', (117, 121))	('MLNR', 'Gene', (18, 22))
145332	23866060	classified 144 patients into 4 groups according to MLNR: 0, <=25%, >25 to <=50% and > 50%.	('patients', 'Species', '9606', (15, 23))	('MLNR', 'Gene', '2862', (51, 55))	('MLNR', 'Gene', (51, 55))	('<=25%', 'Var', (60, 65))
145394	23363448	Dilution of methylene blue with crystal violet seems to improve visualization of the lesion and may also decrease the potential risk of DNA damage due to a higher concentration of methylene blue.	('Dilution', 'Var', (0, 8))	('methylene blue', 'Chemical', 'MESH:D008751', (180, 194))	('methylene blue', 'Chemical', 'MESH:D008751', (12, 26))	('higher', 'PosReg', (156, 162))	('crystal violet', 'Chemical', 'MESH:D005840', (32, 46))	('DNA damage', 'MPA', (136, 146))	('improve', 'PosReg', (56, 63))	('visualization', 'MPA', (64, 77))	('decrease', 'NegReg', (105, 113))
145397	23363448	Antigen retrieval was performed by boiling for 15 minutes in 10 mM monocitric acid buffer (pH 6.0) for anti-Ki-67 staining and in 10 mM Tris/ethylenediaminetetraacetic acid buffer (pH 9.0) for anti-p53 staining.	('boiling', 'Phenotype', 'HP:0020083', (35, 42))	('anti-Ki-67', 'Var', (103, 113))	('Tris/ethylenediaminetetraacetic acid', 'Chemical', '-', (136, 172))	('p53', 'Gene', '7157', (198, 201))	('p53', 'Gene', (198, 201))	('Ki-67', 'Chemical', '-', (108, 113))	('monocitric acid', 'Chemical', '-', (67, 82))
145401	23363448	To detect Ki-67 and p53, 3-amino-9-ethylcarbazole was used as the substrate.	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('Ki-67', 'Var', (10, 15))	('Ki-67', 'Chemical', '-', (10, 15))	('3-amino-9-ethylcarbazole', 'Chemical', 'MESH:C020702', (25, 49))
145464	21845042	Antisense oligonucleotide (ASON) to inhibit mRNA expression has been studied as a potentially important gene therapy in recent years.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('ASON', 'Chemical', 'MESH:D016376', (27, 31))	('oligonucleotide', 'Chemical', 'MESH:D009841', (10, 25))	('mRNA expression', 'MPA', (44, 59))	('inhibit', 'NegReg', (36, 43))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('Antisense', 'Var', (0, 9))
145502	21845042	For the esophageal carcinoma model, EC9706 cells were trypsinized, washed twice with phosphate-buffered saline, and injected into the mice subcutaneously as 2 x 106 cells into the axillae bilaterally.	('phosphate-buffered saline', 'Chemical', '-', (85, 110))	('mice', 'Species', '10090', (134, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('esophageal carcinoma', 'Disease', (8, 28))	('EC9706', 'Var', (36, 42))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (8, 28))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (8, 28))	('EC9706', 'CellLine', 'CVCL:E307', (36, 42))
145544	21845042	As expected, incorporation of ASON into the complexes inhibited the activity of DNase I.	('incorporation', 'Var', (13, 26))	('inhibited', 'NegReg', (54, 63))	('ASON', 'Chemical', 'MESH:D016376', (30, 34))	('ASON', 'Protein', (30, 34))	('activity', 'MPA', (68, 76))	('DNase I', 'Gene', '13419', (80, 87))	('DNase I', 'Gene', (80, 87))
145547	21845042	The samples of ASON (1), PEI/ASON (N/P 4.0) (3) and PEI/ASON (N/P 10.0) (5) complexes were not degraded by DNase I.	('N/P 10', 'SUBSTITUTION', 'None', (62, 68))	('N/P 4', 'Var', (35, 40))	('PEI', 'Chemical', 'MESH:D011094', (25, 28))	('N/P 4', 'SUBSTITUTION', 'None', (35, 40))	('ASON', 'Chemical', 'MESH:D016376', (56, 60))	('DNase I', 'Gene', '13419', (107, 114))	('PEI', 'Chemical', 'MESH:D011094', (52, 55))	('ASON', 'Chemical', 'MESH:D016376', (15, 19))	('ASON', 'Chemical', 'MESH:D016376', (29, 33))	('DNase I', 'Gene', (107, 114))	('N/P 10', 'Var', (62, 68))
145548	21845042	The samples of ASON (2), PEI/ASON (N/P 4.0) (4) and PEI/ASON (N/P 10.0) (6) complexes were degraded by DNase I (Figure 4).	('N/P 10', 'SUBSTITUTION', 'None', (62, 68))	('N/P 4', 'Var', (35, 40))	('DNase I', 'Gene', '13419', (103, 110))	('PEI', 'Chemical', 'MESH:D011094', (25, 28))	('N/P 4', 'SUBSTITUTION', 'None', (35, 40))	('ASON', 'Chemical', 'MESH:D016376', (56, 60))	('DNase I', 'Gene', (103, 110))	('PEI', 'Chemical', 'MESH:D011094', (52, 55))	('ASON', 'Chemical', 'MESH:D016376', (15, 19))	('ASON', 'Chemical', 'MESH:D016376', (29, 33))	('degraded', 'NegReg', (91, 99))	('N/P 10', 'Var', (62, 68))
145549	21845042	The samples of ASON (1), NGR/PEI/ASON (N/P 4.0) (3) and NGR/PEI/ASON (N/P 10.0) (5) complexes were not degraded by DNase I.	('PEI', 'Chemical', 'MESH:D011094', (29, 32))	('PEI', 'Chemical', 'MESH:D011094', (60, 63))	('N/P 10', 'Var', (70, 76))	('N/P 10', 'SUBSTITUTION', 'None', (70, 76))	('N/P 4', 'Var', (39, 44))	('DNase I', 'Gene', '13419', (115, 122))	('ASON', 'Chemical', 'MESH:D016376', (15, 19))	('DNase I', 'Gene', (115, 122))	('ASON', 'Chemical', 'MESH:D016376', (33, 37))	('ASON', 'Chemical', 'MESH:D016376', (64, 68))	('N/P 4', 'SUBSTITUTION', 'None', (39, 44))
145550	21845042	The samples of ASON (2), NGR/PEI/ASON (N/P 4.0) (4) and NGR/PEI/ASON (N/P 10.0) (6) complexes were not degraded by DNase I (Figure 5).	('PEI', 'Chemical', 'MESH:D011094', (29, 32))	('PEI', 'Chemical', 'MESH:D011094', (60, 63))	('N/P 10', 'Var', (70, 76))	('N/P 10', 'SUBSTITUTION', 'None', (70, 76))	('N/P 4', 'Var', (39, 44))	('NGR/PEI/ASON', 'Var', (56, 68))	('DNase I', 'Gene', '13419', (115, 122))	('ASON', 'Chemical', 'MESH:D016376', (15, 19))	('DNase I', 'Gene', (115, 122))	('ASON', 'Chemical', 'MESH:D016376', (33, 37))	('ASON', 'Chemical', 'MESH:D016376', (64, 68))	('N/P 4', 'SUBSTITUTION', 'None', (39, 44))
145556	21845042	Liver, kidney, lung, heart, brain, and tumor tissues were removed from the mice to prepare frozen sections at hours 1, 3, and 6 after injection of the NGR/PEI/ASON or PEI/ASON complexes.	('ASON', 'Chemical', 'MESH:D016376', (171, 175))	('mice', 'Species', '10090', (75, 79))	('NGR/PEI/ASON', 'Var', (151, 163))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PEI', 'Chemical', 'MESH:D011094', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ASON', 'Chemical', 'MESH:D016376', (159, 163))	('PEI', 'Chemical', 'MESH:D011094', (155, 158))	('tumor', 'Disease', (39, 44))
145561	21845042	Tumor uptake increased gradually from 1-6 hours after injection of the NGR/PEI/ASON complexes, but this trend was not evident after injection of the PEI/ASON complexes.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NGR/PEI/ASON complexes', 'Var', (71, 93))	('ASON', 'Chemical', 'MESH:D016376', (79, 83))	('increased', 'PosReg', (13, 22))	('ASON', 'Chemical', 'MESH:D016376', (153, 157))	('PEI', 'Chemical', 'MESH:D011094', (149, 152))	('Tumor uptake', 'CPA', (0, 12))	('PEI', 'Chemical', 'MESH:D011094', (75, 78))
145562	21845042	In comparison with the fluorescent tumor intensity in the mice injected with the NGR/PEI/ASON complexes, the fluorescent intensity in the tumors of mice injected with PEI/ASON was significantly lower, suggesting that the NGR peptide may enhance the ability of an ASON delivery system to home to tumor tissues.	('enhance', 'PosReg', (237, 244))	('fluorescent intensity', 'MPA', (109, 130))	('tumor', 'Disease', (138, 143))	('ASON', 'Chemical', 'MESH:D016376', (89, 93))	('mice', 'Species', '10090', (148, 152))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('lower', 'NegReg', (194, 199))	('ASON delivery system', 'MPA', (263, 283))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('ASON', 'Chemical', 'MESH:D016376', (171, 175))	('home', 'MPA', (287, 291))	('PEI', 'Chemical', 'MESH:D011094', (167, 170))	('mice', 'Species', '10090', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('PEI', 'Chemical', 'MESH:D011094', (85, 88))	('tumors', 'Disease', (138, 144))	('NGR peptide', 'Var', (221, 232))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('ASON', 'Chemical', 'MESH:D016376', (263, 267))
145571	32130756	The EQ-5D utility scores for EC and precancer patients were estimated as 0.748 +- 0.009 and 0.852 +- 0.022, and the scores of EC at stage I, stage II, stage III, and stage IV were 0.693 +- 0.031, 0.747 +- 0.014, 0.762 +- 0.015, and 0.750 +- 0.023, respectively.	('patients', 'Species', '9606', (46, 54))	('0.747 +- 0.014', 'Var', (196, 210))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('EQ', 'Chemical', '-', (4, 6))
145627	32130756	The corresponding mean EQ-5D utility scores were 0.693 +- 0.031 at stage I, 0.747 +- 0.014 at stage II, 0.762 +- 0.015 at stage III, and 0.750 +- 0.023 at stage IV.	('0.762 +- 0.015', 'Var', (104, 118))	('EQ', 'Chemical', '-', (23, 25))	('0.747 +- 0.014', 'Var', (76, 90))	('0.750 +- 0.023', 'Var', (137, 151))	('0.693 +- 0.031', 'Var', (49, 63))
145761	30109578	We included patients who had T1-3, N0, M0 tumors to focus on early-stage cancer who are most likely to receive treatment, including surgery.	('T1-3', 'Var', (29, 33))	('cancer', 'Disease', (73, 79))	('patients', 'Species', '9606', (12, 20))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
145785	30109578	Chemotherapy receipt also was associated with a lower hazard for mortality in the overall (HR 0.82, 95% CI 0.72-0.93, p = 0.002) and cancer-specific models (HR 0.79, 95% CI 0.68-0.91, p = 0.002).	('lower', 'NegReg', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('Chemotherapy receipt', 'Var', (0, 20))	('mortality', 'MPA', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
145829	29796185	Microarray analyses showed that the depletion of CLIC1 with small interfering RNA (siRNA) changed the expression levels of many genes involved in apoptosis and epithelial-mesenchymal transition (EMT).	('small interfering', 'Var', (60, 77))	('changed', 'Reg', (90, 97))	('CLIC1', 'Gene', '1192', (49, 54))	('depletion', 'MPA', (36, 45))	('epithelial-mesenchymal transition', 'CPA', (160, 193))	('expression levels', 'MPA', (102, 119))	('CLIC1', 'Gene', (49, 54))
145837	29796185	In KYSE70 cells, the number of CLIC1-depleted cells was significantly lower than that of control cells 48 and 72 h after transfection (Figure 1C).	('lower', 'NegReg', (70, 75))	('CLIC1', 'Gene', (31, 36))	('CLIC1', 'Gene', '1192', (31, 36))	('KYSE70', 'Var', (3, 9))
145838	29796185	In the cell cycle analysis, the knockdown of CLIC1 increased the number of cells in the sub-G1 phase in the TE5 and KYSE70 cell lines (Figure 2A).	('increased', 'PosReg', (51, 60))	('CLIC1', 'Gene', (45, 50))	('knockdown', 'Var', (32, 41))	('CLIC1', 'Gene', '1192', (45, 50))
145849	29796185	The results obtained revealed that the expression of 3099 genes showed fold changes of > 3.0 in the KYSE70 cell line following the knockdown of CLIC1.	('CLIC1', 'Gene', (144, 149))	('CLIC1', 'Gene', '1192', (144, 149))	('knockdown', 'Var', (131, 140))	('expression', 'MPA', (39, 49))
145873	29796185	These results support the depletion of CLIC1 promoting cellular movement in in vitro experiments.	('CLIC1', 'Gene', (39, 44))	('promoting', 'PosReg', (45, 54))	('depletion', 'Var', (26, 35))	('CLIC1', 'Gene', '1192', (39, 44))	('cellular movement', 'CPA', (55, 72))
145893	29796185	demonstrated that activating the MAPK/JNK pathway induced autophagy and apoptotic cell death in colonic cancer cells.	('apoptotic cell death', 'CPA', (72, 92))	('colonic cancer', 'Phenotype', 'HP:0003003', (96, 110))	('autophagy', 'CPA', (58, 67))	('JNK', 'Gene', '5599', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('activating', 'Var', (18, 28))	('MAPK', 'Gene', '5594', (33, 37))	('colonic cancer', 'Disease', 'MESH:D015179', (96, 110))	('MAPK', 'Gene', (33, 37))	('JNK', 'Gene', (38, 41))	('colonic cancer', 'Disease', (96, 110))
145895	29796185	This is the first study to show that the expression of CLIC1 may influence the activation of the TLR2/JNK pathway in ESCC cells.	('TLR2', 'Gene', '7097', (97, 101))	('CLIC1', 'Gene', '1192', (55, 60))	('JNK', 'Gene', (102, 105))	('influence', 'Reg', (65, 74))	('expression', 'Var', (41, 51))	('JNK', 'Gene', '5599', (102, 105))	('CLIC1', 'Gene', (55, 60))	('TLR2', 'Gene', (97, 101))
145909	29796185	In in vitro experiments with ESCC cells, the expression of CLIC1 regulated tumor behaviors, including cell proliferation, apoptosis, and cellular movement, and our immunohistochemical results supported those obtained in in vitro experiments; that is, the group of very strong CLIC1 expression was poorer prognosis due to inhibiting apoptosis of ESCC cells, and the group of very weak CLIC1 expression was poorer prognosis due to promoting cell movement of ESCC cells.	('CLIC1', 'Gene', '1192', (384, 389))	('CLIC1', 'Gene', '1192', (59, 64))	('tumor behaviors', 'Disease', 'MESH:D001523', (75, 90))	('apoptosis', 'CPA', (332, 341))	('CLIC1', 'Gene', '1192', (276, 281))	('CLIC1', 'Gene', (384, 389))	('CLIC1', 'Gene', (59, 64))	('tumor behaviors', 'Disease', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cell movement', 'CPA', (439, 452))	('expression', 'Var', (282, 292))	('CLIC1', 'Gene', (276, 281))	('inhibiting', 'NegReg', (321, 331))	('promoting', 'PosReg', (429, 438))
145923	29796185	Expression levels were measured for the following genes: CLIC1 (Hs00559461_m1), MYD88 (Hs01573837_g1), TLR2 (Hs02621280_s1), JUN (Hs01103582_s1), Bcl2 (Hs00608023_m1), CDH1 (Hs00170423_m1), VIM (Hs00185584_m1), SNAI1 (Hs00195591_m1), CTNNB1 (Hs00355049_m1), and CLDN1 (Hs00221623_m1) (Applied Biosystems).	('CTNNB1', 'Gene', '1499', (234, 240))	('Hs00185584_m1', 'Var', (195, 208))	('CDH1', 'Gene', (168, 172))	('MYD88', 'Gene', '4615', (80, 85))	('SNAI1', 'Gene', '6615', (211, 216))	('Expression levels', 'MPA', (0, 17))	('SNAI1', 'Gene', (211, 216))	('Hs00195591_m1', 'Var', (218, 231))	('Hs01103582_s1', 'Var', (130, 143))	('Hs00170423_m1', 'Var', (174, 187))	('CLIC1', 'Gene', (57, 62))	('Bcl2', 'Gene', (146, 150))	('CTNNB1', 'Gene', (234, 240))	('MYD88', 'Gene', (80, 85))	('CLDN1', 'Gene', (262, 267))	('Bcl2', 'Gene', '596', (146, 150))	('Hs02621280_s1', 'Var', (109, 122))	('Hs00355049_m1', 'Var', (242, 255))	('Hs00559461_m1', 'Var', (64, 77))	('Hs01573837_g1', 'Var', (87, 100))	('TLR2', 'Gene', '7097', (103, 107))	('VIM', 'Gene', '7431', (190, 193))	('TLR2', 'Gene', (103, 107))	('Hs00221623_m1', 'Var', (269, 282))	('CLDN1', 'Gene', '9076', (262, 267))	('CDH1', 'Gene', '999', (168, 172))	('VIM', 'Gene', (190, 193))	('Hs00608023_m1', 'Var', (152, 165))	('CLIC1', 'Gene', '1192', (57, 62))
145999	29713180	Twelve of the 14 patients with anastomotic insufficiency showed a stenosis of TC (n=11) or SMA (n=1) in the preoperative CT scan.	('TC', 'Chemical', '-', (78, 80))	('stenosis', 'Var', (66, 74))	('anastomotic insufficiency', 'Disease', 'MESH:D000309', (31, 56))	('patients', 'Species', '9606', (17, 25))	('anastomotic insufficiency', 'Disease', (31, 56))	('SMA', 'Phenotype', 'HP:0100859', (91, 94))
146000	29713180	Among the patients without anastomotic leakage, 58 showed stenosis in TC (n=56) and/or SMA (n=9).	('stenosis', 'Var', (58, 66))	('anastomotic leak', 'Disease', 'MESH:D057868', (27, 43))	('SMA', 'Phenotype', 'HP:0100859', (87, 90))	('TC', 'Chemical', '-', (70, 72))	('anastomotic leak', 'Disease', (27, 43))	('patients', 'Species', '9606', (10, 18))
146008	29713180	The presence of TC stenosis had a significant impact on anastomotic healing (p=0.004), whereas no correlation between stenosis of the SMA and anastomotic leakage could be shown (p=0.601).	('TC', 'Chemical', '-', (16, 18))	('impact', 'Reg', (46, 52))	('SMA', 'Phenotype', 'HP:0100859', (134, 137))	('anastomotic healing', 'CPA', (56, 75))	('anastomotic leak', 'Disease', 'MESH:D057868', (142, 158))	('stenosis', 'Var', (19, 27))	('anastomotic leak', 'Disease', (142, 158))
146025	29713180	Arterial calcification of the blood vessels supplying the gastric tube has been identified as an independent risk factor for leakage after esophagectomy with cervical anastomosis.	('leakage', 'Disease', (125, 132))	('calcification', 'Disease', 'MESH:D002114', (9, 22))	('Arterial calcification', 'Phenotype', 'HP:0003207', (0, 22))	('Arterial', 'Var', (0, 8))	('calcification', 'Disease', (9, 22))	('cervical anastomosis', 'Phenotype', 'HP:0002949', (158, 178))
146026	29713180	Calcifications of the aorta and the right postceliac arteries were found to be independent risk factors for anastomotic insufficiency.	('Calcifications of the aorta', 'Phenotype', 'HP:0004963', (0, 27))	('Calcifications', 'Var', (0, 14))	('anastomotic insufficiency', 'Disease', (108, 133))	('anastomotic insufficiency', 'Disease', 'MESH:D000309', (108, 133))
146042	29713180	On the other hand, the lumina of TC and SMA are relatively small; hence, measurement deviations in the submillimeter range, which are unavoidable, have a relatively high impact on interobserver agreement.	('impact', 'Reg', (170, 176))	('men', 'Species', '9606', (199, 202))	('interobserver', 'MPA', (180, 193))	('deviations', 'Var', (85, 95))	('men', 'Species', '9606', (80, 83))	('SMA', 'Phenotype', 'HP:0100859', (40, 43))	('TC', 'Chemical', '-', (33, 35))
146056	29713180	Within the limitations of this study, we are able to show that TC stenosis is positively correlated with anastomotic leakage, the likelihood of anastomotic insufficiency increases with the degree of stenosis, and that high-grade stenoses are reliably detectable with CE-CT analysis.	('anastomotic leak', 'Disease', (105, 121))	('stenosis', 'Var', (66, 74))	('anastomotic insufficiency', 'Disease', 'MESH:D000309', (144, 169))	('increases', 'PosReg', (170, 179))	('anastomotic insufficiency', 'Disease', (144, 169))	('TC', 'Chemical', '-', (63, 65))	('correlated', 'Reg', (89, 99))	('anastomotic leak', 'Disease', 'MESH:D057868', (105, 121))
146066	29108314	However, malignant EUS-FNA of PTN/SCN was independently prognostic, conferred a shorter OS, and altered the management of 35% of patients.	('altered', 'Reg', (96, 103))	('patients', 'Species', '9606', (129, 137))	('men', 'Species', '9606', (114, 117))	('malignant', 'Var', (9, 18))	('shorter OS', 'MPA', (80, 90))	('PTN', 'Species', '9606', (30, 33))	('OS', 'Chemical', '-', (88, 90))
146097	29108314	In the multivariate analysis, malignant PTN/SCN was associated with higher hazard ratio (HR) for death (2.4 with 95% CI: 1.3 to 4.4; p = 0.005) in the reduced model.	('death', 'Disease', 'MESH:D003643', (97, 102))	('malignant PTN/SCN', 'Var', (30, 47))	('PTN', 'Species', '9606', (40, 43))	('death', 'Disease', (97, 102))
146155	28073841	Interestingly, the aberrant overexpression of AURKA in cancer cells is associated with gain of novel oncogenic functions that extend beyond its normal physiological functions in forming and stabilizing mitotic spindles during cell division.	('gain', 'PosReg', (87, 91))	('oncogenic functions', 'CPA', (101, 120))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('AURKA', 'Gene', (46, 51))	('overexpression', 'PosReg', (28, 42))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('aberrant', 'Var', (19, 27))	('cancer', 'Disease', (55, 61))
146159	28073841	Alisertib, also known as MLN8237, is an investigational small molecule inhibitor of AURKA that has shown promising efficacy in pre-clinical studies leading to its entry into multiple clinical trials for patients with hematologic malignancies and solid tumors.	('hematologic malignancies', 'Disease', (217, 241))	('solid tumors', 'Disease', 'MESH:D009369', (246, 258))	('Alisertib', 'Chemical', 'MESH:C550258', (0, 9))	('MLN8237', 'Chemical', 'MESH:C550258', (25, 32))	('MLN8237', 'Var', (25, 32))	('patients', 'Species', '9606', (203, 211))	('AURKA', 'Gene', (84, 89))	('solid tumors', 'Disease', (246, 258))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('hematologic malignancies', 'Disease', 'MESH:D019337', (217, 241))
146179	28073841	MYC, p-PP2Ac (Y307), P-ERK 1/2 (T202/Y204), ERK antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz Biotechnology Inc. Santa Cruz, CA), and beta-Actin antibody from Sigma-Aldrich (GmbH).	('MYC', 'Gene', (0, 3))	('T202/Y204', 'Var', (32, 41))	('beta-Actin', 'Gene', (155, 165))	('beta-Actin', 'Gene', '728378', (155, 165))	('ERK', 'Gene', '5594', (44, 47))	('Y307', 'Chemical', '-', (14, 18))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'Gene', (23, 26))	('ERK', 'Gene', (44, 47))	('PP2Ac', 'Gene', '5515', (7, 12))	('MYC', 'Gene', '4609', (0, 3))	('ERK 1', 'Gene', (23, 28))	('ERK 1', 'Gene', '5595', (23, 28))	('PP2Ac', 'Gene', (7, 12))	('Y307', 'Var', (14, 18))
146202	28073841	Cells were seeded at 1000 cells per well in 96-well plates and treated with 0.075, 0.150, 0.315, 0.625, 1.25, 2.5 and 10 micromol/L of RAD001, alisertib or combination for five days.	('RAD', 'Gene', '6236', (135, 138))	('0.315', 'Var', (90, 95))	('0.625', 'Var', (97, 102))	('RAD', 'Gene', (135, 138))	('0.150', 'Var', (83, 88))	('0.075', 'Var', (76, 81))	('alisertib', 'Chemical', 'MESH:C550258', (143, 152))
146235	28073841	Notably, we did not detect substantial differences in p-mTOR (S2448) or p-4EBP1 (S65) protein levels between parental and resistant cells.	('mTOR', 'Gene', (56, 60))	('4EBP1', 'Gene', '1978', (74, 79))	('mTOR', 'Gene', '2475', (56, 60))	('S2448', 'Var', (62, 67))	('4EBP1', 'Gene', (74, 79))
146243	28073841	AURKA knockdown markedly decreasedEIF4E phosphorylation and c-MYC protein levels in FLO-1 and SK-GT-4 resistant cells, whereas RAD001 treatment had no effect (Figure 2C and Supplementary Figure S3).	('AURKA', 'Gene', (0, 5))	('RAD', 'Gene', (127, 130))	('c-MYC', 'Gene', '4609', (60, 65))	('EIF4E', 'Gene', (34, 39))	('RAD', 'Gene', '6236', (127, 130))	('c-MYC', 'Gene', (60, 65))	('knockdown', 'Var', (6, 15))	('EIF4E', 'Gene', '1977', (34, 39))
146246	28073841	Using AURKA knockdown or inhibition with alisertib, we did not detect changes in the protein levels of phospho-MNK(T197/202), albeit the remarkable decrease in phospho-EIF4E (Supplementary Figure S4).	('MNK', 'Gene', '538', (111, 114))	('alisertib', 'Chemical', 'MESH:C550258', (41, 50))	('knockdown', 'Var', (12, 21))	('EIF4E', 'Gene', (168, 173))	('MNK', 'Gene', (111, 114))	('decrease', 'NegReg', (148, 156))	('EIF4E', 'Gene', '1977', (168, 173))
146251	28073841	In addition, the data indicated that inhibition or knockdown of AURKA with alisertib or siRNA, respectively, significantly decreased cap-dependent protein translation activity (p<0.01, Figure 3A & 3B).	('knockdown', 'Var', (51, 60))	('cap-dependent protein translation activity', 'MPA', (133, 175))	('alisertib', 'Chemical', 'MESH:C550258', (75, 84))	('decreased', 'NegReg', (123, 132))
146254	28073841	Conversely, inhibition or knockdown of AURKA significantly decreased c-MYC transcriptional activity in RAD001 resistant cells (p<0.05, Figure 3C & 3D).	('c-MYC', 'Gene', (69, 74))	('decreased', 'NegReg', (59, 68))	('c-MYC', 'Gene', '4609', (69, 74))	('AURKA', 'Gene', (39, 44))	('knockdown', 'Var', (26, 35))	('RAD', 'Gene', (103, 106))	('RAD', 'Gene', '6236', (103, 106))
146256	28073841	Indeed, we detected a significant decrease in the levels of translated polysomal mRNA ofc-MYC and CCND1, as compared to their total RNA levels, in response to knockdown of AURKA in FLO-1 cells (p<0.01) (Figure 3E).	('c-MYC', 'Gene', '4609', (88, 93))	('knockdown', 'Var', (159, 168))	('AURKA', 'Gene', (172, 177))	('decrease', 'NegReg', (34, 42))	('CCND1', 'Gene', (98, 103))	('c-MYC', 'Gene', (88, 93))	('CCND1', 'Gene', '595', (98, 103))	('levels of', 'MPA', (50, 59))
146265	28073841	Consistent with the increased phosphorylation of p-PP2Ac (Y307), we detected a significant reduction in the PP2A activity (Figure 4B & 4F).	('Y307', 'Var', (58, 62))	('increased', 'PosReg', (20, 29))	('phosphorylation', 'MPA', (30, 45))	('PP2A', 'Gene', '5524', (51, 55))	('Y307', 'Chemical', '-', (58, 62))	('PP2A', 'Gene', '5524', (108, 112))	('reduction', 'NegReg', (91, 100))	('activity', 'MPA', (113, 121))	('PP2A', 'Gene', (51, 55))	('PP2A', 'Gene', (108, 112))	('PP2Ac', 'Gene', '5515', (51, 56))	('PP2Ac', 'Gene', (51, 56))
146268	28073841	AURKA inhibition or knockdown significantly restored PP2A activity in the resistant cells (Figure 4C, 4D, 4G & 4H).	('knockdown', 'Var', (20, 29))	('restored', 'PosReg', (44, 52))	('PP2A', 'Gene', '5524', (53, 57))	('PP2A', 'Gene', (53, 57))
146270	28073841	Western blot data demonstrated that knocking down PP2Ac alone resulted in increased phosphorylation of EIF4E in resistant cells (Figure 4I & 4J), confirming PP2A as a negative regulator of EIF4E.	('PP2A', 'Gene', (50, 54))	('EIF4E', 'Gene', '1977', (189, 194))	('PP2Ac', 'Gene', '5515', (50, 55))	('EIF4E', 'Gene', '1977', (103, 108))	('EIF4E', 'Gene', (189, 194))	('PP2Ac', 'Gene', (50, 55))	('PP2A', 'Gene', (157, 161))	('increased', 'PosReg', (74, 83))	('EIF4E', 'Gene', (103, 108))	('PP2A', 'Gene', '5524', (50, 54))	('knocking down', 'Var', (36, 49))	('phosphorylation', 'MPA', (84, 99))	('PP2A', 'Gene', '5524', (157, 161))
146271	28073841	Although knocking down AURKA downregulated p-EIF4E (S209), combined knockdown of AURKA and PP2Ac prevented this effect, suggesting that PP2A is required for EIF4E activation by AURKA (Figure 4I & 4J).	('PP2A', 'Gene', '5524', (91, 95))	('PP2A', 'Gene', '5524', (136, 140))	('PP2Ac', 'Gene', '5515', (91, 96))	('EIF4E', 'Gene', (157, 162))	('PP2A', 'Gene', (91, 95))	('PP2A', 'Gene', (136, 140))	('PP2Ac', 'Gene', (91, 96))	('EIF4E', 'Gene', '1977', (45, 50))	('EIF4E', 'Gene', (45, 50))	('knocking', 'Var', (9, 17))	('AURKA', 'Gene', (23, 28))	('EIF4E', 'Gene', '1977', (157, 162))	('downregulated', 'NegReg', (29, 42))
146285	28073841	Additionally, AURKA knockdown or inhibition decreased cap-dependent translation and c-MYC transcriptional activity in MKN45 cells as measured by reporter assays (Figure 5H & 5I).	('c-MYC', 'Gene', '4609', (84, 89))	('inhibition decreased', 'NegReg', (33, 53))	('AURKA', 'Gene', (14, 19))	('c-MYC', 'Gene', (84, 89))	('cap-dependent translation', 'MPA', (54, 79))	('knockdown', 'Var', (20, 29))
146293	28073841	Amplifications and overexpression of AURKA at the 20q region are frequently detected in gastric and esophageal adenocarcinomas.	('overexpression', 'PosReg', (19, 33))	('esophageal adenocarcinomas', 'Disease', (100, 126))	('detected', 'Reg', (76, 84))	('Amplifications', 'Var', (0, 14))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (100, 126))	('AURKA', 'Gene', (37, 42))	('gastric', 'Disease', (88, 95))
146295	28073841	Of note, the aberrant overexpression of AURKA in cancer is associated with the gain of oncogenic functions that extend beyond its normal physiological functions in forming and stabilizing mitotic spindles during cell division.	('oncogenic functions', 'CPA', (87, 106))	('overexpression', 'PosReg', (22, 36))	('gain', 'PosReg', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('AURKA', 'Gene', (40, 45))	('cancer', 'Disease', (49, 55))	('aberrant', 'Var', (13, 21))
146310	28073841	Although knocking down AURKA decreased p-EIF4Eprotein levels, our data indicated lack of direct interaction between EIF4E and AURKA, suggesting that AURKA-induced activation of EIF4E could be mediated by an effector molecule downstream of AURKA.	('EIF4E', 'Gene', (116, 121))	('activation', 'PosReg', (163, 173))	('EIF4E', 'Gene', (177, 182))	('EIF4E', 'Gene', '1977', (41, 46))	('knocking down', 'Var', (9, 22))	('EIF4E', 'Gene', '1977', (177, 182))	('decreased', 'NegReg', (29, 38))	('AURKA', 'Gene', (23, 28))	('EIF4E', 'Gene', (41, 46))	('EIF4E', 'Gene', '1977', (116, 121))
146314	28073841	Phosphorylation of EIF4E at Ser209 has been shown to be essential for EIF4E oncogenic activity.	('EIF4E', 'Gene', '1977', (70, 75))	('Ser209', 'Var', (28, 34))	('Phosphorylation', 'MPA', (0, 15))	('EIF4E', 'Gene', (70, 75))	('EIF4E', 'Gene', '1977', (19, 24))	('Ser209', 'Chemical', '-', (28, 34))	('EIF4E', 'Gene', (19, 24))
146318	28073841	We show that AURKA can modulate the PP2A activity and the PP2A-EIF4E axis, whereby AURKA inhibition or knockdown restores PP2A activity and suppresses EIF4E phosphorylation.	('PP2A', 'Gene', '5524', (122, 126))	('EIF4E', 'Gene', '1977', (63, 68))	('knockdown', 'Var', (103, 112))	('AURKA', 'Gene', (83, 88))	('EIF4E', 'Gene', '1977', (151, 156))	('PP2A', 'Gene', (36, 40))	('PP2A', 'Gene', '5524', (58, 62))	('restores', 'PosReg', (113, 121))	('PP2A', 'Gene', (122, 126))	('suppresses', 'NegReg', (140, 150))	('modulate', 'Reg', (23, 31))	('EIF4E', 'Gene', (63, 68))	('EIF4E', 'Gene', (151, 156))	('PP2A', 'Gene', '5524', (36, 40))	('PP2A', 'Gene', (58, 62))	('activity', 'MPA', (127, 135))
146319	28073841	Furthermore, knockdown of both AURKA and PP2Ac restored theEIF4E activity, indicating that AURKA activation of EIF4E requires inhibition of PP2A in resistant cells.	('PP2A', 'Gene', '5524', (41, 45))	('PP2Ac', 'Gene', (41, 46))	('activity', 'MPA', (65, 73))	('PP2A', 'Gene', '5524', (140, 144))	('EIF4E', 'Gene', '1977', (111, 116))	('EIF4E', 'Gene', (59, 64))	('PP2A', 'Gene', (41, 45))	('PP2A', 'Gene', (140, 144))	('EIF4E', 'Gene', (111, 116))	('PP2Ac', 'Gene', '5515', (41, 46))	('knockdown', 'Var', (13, 22))	('EIF4E', 'Gene', '1977', (59, 64))
146327	28073841	We also can not ignore the possible effects of targeting AURKA on cell cycle and signaling pathways where inhibition of AURKA has been shown to lead to mitotic catastrophe, inhibition of NF-kB, beta-catenin, and STAT3.	('AURKA', 'Gene', (120, 125))	('NF-kB', 'Protein', (187, 192))	('inhibition', 'NegReg', (173, 183))	('beta-catenin', 'Gene', (194, 206))	('inhibition', 'Var', (106, 116))	('STAT3', 'Gene', '6774', (212, 217))	('lead to', 'Reg', (144, 151))	('beta-catenin', 'Gene', '1499', (194, 206))	('STAT3', 'Gene', (212, 217))	('mitotic catastrophe', 'CPA', (152, 171))
146344	28178659	In summary, our meta-analysis provides strong evidence that detection of CTCs in the peripheral blood is an independent prognostic indicator of poor outcome for esophageal squamous cell carcinoma patients.	('esophageal squamous cell carcinoma', 'Disease', (161, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('patients', 'Species', '9606', (196, 204))	('CTCs', 'Var', (73, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (161, 195))
146361	28178659	The result indicated that except OS for post-therapy (95% CI =0.94-3.01) and OS for sample size (<50: 95% CI =0.89-8.27), patients with positive CTCs had a higher risk for poor disease progression than patients with negative CTCs.	('positive', 'Var', (136, 144))	('CTCs', 'Gene', (145, 149))	('poor disease progression', 'CPA', (172, 196))	('patients', 'Species', '9606', (202, 210))	('patients', 'Species', '9606', (122, 130))
146364	28178659	Recent meta-analyses demonstrate that detection of CTCs in the peripheral blood is an independent prognosticator of poor survival in triple negative breast cancer, ovarian and gastric cancer patients.	('patients', 'Species', '9606', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ovarian and gastric cancer', 'Disease', 'MESH:D013274', (164, 190))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CTCs', 'Var', (51, 55))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('breast cancer', 'Disease', (149, 162))
146371	28178659	However, our meta-analysis confirms that detection of CTCs independently correlates with poor prognosis in esophageal cancer patients, irrespective of experimental approaches by different groups.	('CTCs', 'Var', (54, 58))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('detection', 'Var', (41, 50))	('patients', 'Species', '9606', (125, 133))
146372	28178659	It is therefore safe to conclude that detection of CTCs independently correlates with poor prognosis in esophageal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('patients', 'Species', '9606', (122, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('CTCs', 'Var', (51, 55))
146451	28008387	showed that RFS (cut-off >=7) had a lower yield in the diagnosis of LPR as compared with RSI .	('lower', 'NegReg', (36, 41))	('RFS', 'Var', (12, 15))	('RSI', 'Disease', (89, 92))	('LPR', 'Disease', (68, 71))	('RSI', 'Disease', 'None', (89, 92))	('RFS', 'Chemical', '-', (12, 15))
146512	25896470	It has been demonstrated that the alteration of coagulation pathways was associated with tumor progression and poor prognosis in various malignancies.	('malignancies', 'Disease', 'MESH:D009369', (137, 149))	('coagulation pathways', 'Pathway', (48, 68))	('alteration', 'Var', (34, 44))	('malignancies', 'Disease', (137, 149))	('associated', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
146529	25896470	Plasma fibrinogen levels and platelet counts greater than 4.0 g/L and 300 x 109/L were defined as hyperfibrinogenemia and thrombocytosis, respectively, according to the normal reference range in our hospital.	('fibrinogen', 'Gene', (7, 17))	('hyperfibrinogenemia', 'Phenotype', 'HP:0011899', (98, 117))	('thrombocytosis', 'Phenotype', 'HP:0001894', (122, 136))	('platelet', 'MPA', (29, 37))	('300 x 109/L', 'Var', (70, 81))	('hyperfibrinogenemia and thrombocytosis', 'Disease', 'MESH:D013922', (98, 136))	('fibrinogen', 'Gene', '2244', (7, 17))	('fibrinogen', 'Gene', '2244', (103, 113))	('fibrinogen', 'Gene', (103, 113))
146569	25896470	found that a high platelet count is associated with tumor progression and poor survival in patients with esophageal cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('patients', 'Species', '9606', (91, 99))	('tumor', 'Disease', (52, 57))	('high', 'Var', (13, 17))	('poor', 'NegReg', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('esophageal cancer', 'Disease', (105, 122))	('high platelet count', 'Phenotype', 'HP:0001894', (13, 32))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('associated', 'Reg', (36, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('platelet count', 'MPA', (18, 32))
146611	25266029	Five-year overall and relapse-free survival was slightly higher in the group that underwent the transthoracic approach than in the group that underwent the transhiatal approach, parallel to more frequent nonradical resections of the esophagus and recurrent mediastinal metastases following transhiatal resection.	('higher', 'PosReg', (57, 63))	('metastases', 'Disease', 'MESH:D009362', (269, 279))	('relapse-free survival', 'CPA', (22, 43))	('overall', 'CPA', (10, 17))	('transthoracic', 'Var', (96, 109))	('metastases', 'Disease', (269, 279))
146752	25266029	The transthoracic approach in R0 operations of functionally safe patients with cancer types Siewert II and Siewert III, regardless of the level of transition to the esophagus, achieved reliably better outcomes.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Siewert', 'Var', (107, 114))	('patients', 'Species', '9606', (65, 73))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
146788	25266029	Prophylactic irradiation covering the area treated by radical esophagectomy in all patients with T1N0M0 tumors may be controversial, because of the incidence of severe toxicities associated with CRT.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('toxicities', 'Disease', 'MESH:D064420', (168, 178))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('T1N0M0', 'Var', (97, 103))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('patients', 'Species', '9606', (83, 91))	('toxicities', 'Disease', (168, 178))
146818	25266029	The determination of Her2 status is mandatory for prediction of therapy response to treatment with trastuzumab, which has been approved for the treatment of metastatic gastric and gastroesophageal adenocarcinomas in case of Her2 positivity.	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('metastatic gastric', 'Disease', (157, 175))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (186, 211))	('gastroesophageal adenocarcinomas', 'Disease', (180, 212))	('gastroesophageal adenocarcinomas', 'Disease', 'MESH:D005764', (180, 212))	('Her2', 'Gene', (224, 228))	('Her2', 'Gene', (21, 25))	('Her2', 'Gene', '2064', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('trastuzumab', 'Chemical', 'MESH:D000068878', (99, 110))	('Her2', 'Gene', '2064', (224, 228))	('positivity', 'Var', (229, 239))
146830	25266029	Table 2 summarizes results from two high-volume U.S. centers and one each from the Netherlands and Ireland specifically comparing outcomes of positive cut margins (CAP) with close resection margins (RCP) in locally advanced T3 tumors.	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('T3 tumors', 'Disease', 'MESH:C537047', (224, 233))	('T3 tumors', 'Disease', (224, 233))	('positive', 'Var', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
146858	25266029	An interesting randomized trial of a narrow gastric tube versus whole-stomach conduit in 104 patients revealed, perhaps not surprisingly, better QOL in the narrow gastric tube group at 6 and 12 months compared to the whole-stomach group, with impaired pulmonary function and worse reflux in the whole-stomach group.	('narrow', 'Var', (156, 162))	('gastric tube', 'Disease', 'MESH:D013274', (163, 175))	('impaired pulmonary function', 'Phenotype', 'HP:0005952', (243, 270))	('impaired pulmonary function', 'Disease', (243, 270))	('gastric tube', 'Disease', 'MESH:D013274', (44, 56))	('gastric tube', 'Disease', (163, 175))	('better', 'PosReg', (138, 144))	('reflux', 'MPA', (281, 287))	('QOL', 'MPA', (145, 148))	('gastric tube', 'Disease', (44, 56))	('impaired pulmonary function', 'Disease', 'MESH:D003072', (243, 270))	('patients', 'Species', '9606', (93, 101))
147077	20878160	In a report from the V325 study group, advanced gastric or gastroesophageal junction cancer patients receiving DCF not only had statistically improved overall survival and time to tumor progression, but they also had better preservation of quality of life compared with patients receiving FP therapy.	('overall survival', 'CPA', (151, 167))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('patients', 'Species', '9606', (270, 278))	('DCF', 'Var', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('gastric or gastroesophageal junction cancer', 'Disease', (48, 91))	('tumor', 'Disease', (180, 185))	('improved', 'PosReg', (142, 150))	('patients', 'Species', '9606', (92, 100))	('DCF', 'Chemical', '-', (111, 114))	('time', 'CPA', (172, 176))	('quality of life', 'CPA', (240, 255))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gastric or gastroesophageal junction cancer', 'Disease', 'MESH:D013274', (48, 91))
147085	20878160	They also had to have an EOCG performance status of 0, 1, or 2, a life expectancy of >12 weeks, and adequate liver, bone marrow, renal and cardiovascular function (serum bilirubin <= 1.5 mg/dl; neutrophil count  1,500/mm3; serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= twice the upper limit of normal range; platelet count >=10 x 104/mm3; hemoglobin >=8.0 g/dl; and creatinine <=1.2 mg/dl (or creatinine clearance >60 ml/min).	('AST', 'Gene', (257, 260))	('alanine aminotransferase', 'Gene', '2875', (266, 290))	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (223, 255))	('aspartate aminotransferase', 'Gene', '26503', (229, 255))	('AST', 'Gene', '26503', (257, 260))	('creatinine', 'MPA', (397, 407))	('aspartate aminotransferase', 'Gene', (229, 255))	('>=10', 'Var', (354, 358))	('bilirubin', 'Chemical', 'MESH:D001663', (170, 179))	('creatinine clearance', 'MPA', (424, 444))	('creatinine', 'Chemical', 'MESH:D003404', (424, 434))	('hemoglobin', 'MPA', (370, 380))	('creatinine', 'Chemical', 'MESH:D003404', (397, 407))	('alanine aminotransferase', 'Gene', (266, 290))
147170	20878160	TXT 75-100 mg/m2 every 3-4 weeks is associated with a quite pronounced neutropenia, with an up to 44% rate of febrile neutropenia in patients with recurrent ovarian cancer.	('TXT 75-100 mg/m2', 'Var', (0, 16))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (147, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('neutropenia', 'Disease', (71, 82))	('neutropenia', 'Disease', (118, 129))	('patients', 'Species', '9606', (133, 141))	('TXT', 'Chemical', 'MESH:D000077143', (0, 3))	('febrile neutropenia', 'Disease', (110, 129))	('febrile neutropenia', 'Disease', 'MESH:D009503', (110, 129))	('neutropenia', 'Phenotype', 'HP:0001875', (71, 82))	('neutropenia', 'Disease', 'MESH:D009503', (118, 129))	('ovarian cancer', 'Disease', (157, 171))	('neutropenia', 'Phenotype', 'HP:0001875', (118, 129))	('neutropenia', 'Disease', 'MESH:D009503', (71, 82))
147171	20878160	reported that the major toxicity of DCF, repeated every 3 weeks at doses of TXT 50 mg/m2, CDDP 70 mg/m2, and 5-FU 700 mg/m2, was myelosuppression and that the frequencies of grade 3/4 leucopenia and neutropenia in a phase II study were 53.8 and 43.6%, respectively.	('CDDP 70 mg/m2', 'Var', (90, 103))	('myelosuppression', 'Disease', 'MESH:D001855', (129, 145))	('myelosuppression', 'Disease', (129, 145))	('toxicity', 'Disease', 'MESH:D064420', (24, 32))	('toxicity', 'Disease', (24, 32))	('neutropenia', 'Disease', 'MESH:D009503', (199, 210))	('leucopenia', 'Disease', 'MESH:C536227', (184, 194))	('DCF', 'Chemical', '-', (36, 39))	('CDDP', 'Chemical', 'MESH:D002945', (90, 94))	('neutropenia', 'Phenotype', 'HP:0001875', (199, 210))	('TXT', 'Chemical', 'MESH:D000077143', (76, 79))	('5-FU', 'Chemical', 'MESH:D005472', (109, 113))	('neutropenia', 'Disease', (199, 210))	('leucopenia', 'Disease', (184, 194))
147199	20177920	EUS-FNA had a positive impact on clinical management in 84% of cases by either influencing the decision to perform surgery (49%) or excluding malignant lymphadenopathy (35%), and a negative impact in 7% of cases because of inadequate (3%) or false-negative (4%) cytology.	('excluding', 'NegReg', (132, 141))	('men', 'Species', '9606', (48, 51))	('influencing', 'Reg', (79, 90))	('malignant lymphadenopathy', 'Disease', (142, 167))	('malignant lymphadenopathy', 'Disease', 'MESH:D009369', (142, 167))	('EUS-FNA', 'Var', (0, 7))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (152, 167))
147233	20177920	EUS-FNA had a positive impact on clinical management in 178 of 213 (84%) procedures (Table 5), particularly by excluding malignant lymphadenopathy (35%) or influencing the decision to perform surgery (49%).	('men', 'Species', '9606', (48, 51))	('malignant lymphadenopathy', 'Disease', (121, 146))	('malignant lymphadenopathy', 'Disease', 'MESH:D009369', (121, 146))	('influencing', 'Reg', (156, 167))	('excluding', 'NegReg', (111, 120))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (131, 146))	('EUS-FNA', 'Var', (0, 7))
147291	33293583	Esophageal cancer is also among the tumor types with the highest median mutation burden, and is ranked higher than kidney, head and neck, and colorectal cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', (153, 159))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('colorectal cancer', 'Disease', (142, 159))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutation', 'Var', (72, 80))	('cancer', 'Disease', (11, 17))	('tumor', 'Disease', (36, 41))
147311	33293583	We then analyzed "other" cluster form tumors, and found that most cells had copy number variations (CNVs), including both amplifications and deletions, suggesting that this cluster included tumor cells (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('deletions', 'Var', (141, 150))	('copy number variations', 'Var', (76, 98))
147316	33293583	There were only minor differences between the matched adjacent and tumor tissues in three tumor-adjacent tissue pairs (S133, S134, and S150).	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('S150', 'Var', (135, 139))	('S133', 'Var', (119, 123))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('S134', 'Var', (125, 129))
147318	33293583	In contrast, the immune profiles of four other tumor-adjacent pairs (S135, S149, S158, S159) presented a significant shift in a PCA, in which 6-12% of total cells were T cells in tumors (Fig.	('S135', 'Var', (69, 73))	('S158, S159', 'Var', (81, 91))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('PCA', 'Disease', (128, 131))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('shift', 'Reg', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (179, 184))
147389	33293583	While some patients showed minimal clonal expansion (S134, S135, and S158), others were strongly dominated by a small number of T cell clones (S149 and S150).	('S135', 'Var', (59, 63))	('S134', 'Var', (53, 57))	('S150', 'Var', (152, 156))	('S149', 'Var', (143, 147))	('patients', 'Species', '9606', (11, 19))	('S158', 'Var', (69, 73))
147390	33293583	Indeed, S149 and S150 tumors showed 65% and 68% of T cells with TCRs shared by more than two cells, indicating the high clonal expansion of T cells in these tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('S150', 'Var', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('expansion of T cells', 'Phenotype', 'HP:0100828', (127, 147))	('TCR', 'Gene', '6962', (64, 67))	('S149', 'Var', (8, 12))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('TCR', 'Gene', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', (22, 28))
147420	33293583	BHLHE40 has recently been reported to mediate tissue-specific control of macrophage self-renewal, and proliferation and we found that BHELHE40 was associated with poor prognosis of ESCC (Supplementary Fig.	('HE', 'Chemical', '-', (138, 140))	('HE', 'Chemical', '-', (135, 137))	('BHLHE40', 'Gene', (0, 7))	('BHLHE40', 'Gene', '8553', (0, 7))	('ESCC', 'Disease', (181, 185))	('HE', 'Chemical', '-', (3, 5))	('BHELHE40', 'Var', (134, 142))
147472	33293583	Pre-exhausted clusters CD8-C5-CCL5 and CD8-C6-STMN1 may serve as better targets for immunotherapies compared to the exhausted cluster (CD8-C7-TIGIT), as the latter are in a permanent and less reversible exhausted stage, making them more resistant to checkpoint inhibition due to their epigenetic changes.	('epigenetic', 'Var', (285, 295))	('TIGIT', 'Gene', (142, 147))	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', (23, 26))	('CD8', 'Gene', '925', (135, 138))	('CD8', 'Gene', '925', (39, 42))	('CD8', 'Gene', '925', (23, 26))	('CCL5', 'Gene', '6352', (30, 34))	('STMN1', 'Gene', '3925', (46, 51))	('STMN1', 'Gene', (46, 51))	('CD8', 'Gene', (135, 138))	('TIGIT', 'Gene', '201633', (142, 147))	('CCL5', 'Gene', (30, 34))
147475	33293583	Our results suggested alternative pathways to re-activate anti-tumor immunity in ESCC, such as the blockade of NKG2A and CD49d alone or in combination with anti-PD1/PD-L1, which may improve the immunotherapeutic response.	('tumor', 'Disease', (63, 68))	('NKG2A', 'Gene', '3821', (111, 116))	('re-activate', 'PosReg', (46, 57))	('improve', 'PosReg', (182, 189))	('ESCC', 'Disease', (81, 85))	('CD49d', 'Gene', '3676', (121, 126))	('blockade', 'Var', (99, 107))	('NKG2A', 'Gene', (111, 116))	('PD-L1', 'Gene', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CD49d', 'Gene', (121, 126))	('PD-L1', 'Gene', '29126', (165, 170))	('immunotherapeutic response', 'CPA', (194, 220))
147505	33293583	LILRB1 expression was upregulated on TAMs, disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo.	('upregulated', 'PosReg', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('disruption', 'Var', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('LILRB1', 'Gene', '10859', (0, 6))	('MHC class I', 'Gene', (64, 75))	('expression', 'MPA', (7, 17))	('tumor', 'Disease', (114, 119))	('LILRB1', 'Gene', (0, 6))	('TAMs', 'Chemical', '-', (37, 41))	('potentiated', 'PosReg', (86, 97))	('LILRB1', 'Gene', (79, 85))	('LILRB1', 'Gene', '10859', (79, 85))
147506	33293583	Investigating the mechanisms underlying this immunosuppressive MHC class I-LILRB1 signaling axis in TAMs will be useful in developing therapies to restore macrophage function, and blocking this pathway may promote antitumor immunity in ESCC.	('LILRB1', 'Gene', (75, 81))	('LILRB1', 'Gene', '10859', (75, 81))	('ESCC', 'Disease', (236, 240))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('macrophage function', 'MPA', (155, 174))	('TAMs', 'Chemical', '-', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('promote', 'PosReg', (206, 213))	('blocking', 'Var', (180, 188))	('tumor', 'Disease', (218, 223))
147513	33293583	Tumor and adjacent tissues were isolated by mincing the freshly obtained surgical specimens into 1-mm cubic pieces, followed by enzymatic digestion using 0.1% collagenase IV, 0.002% DNAse I, and 0.01% hyaluronidase, and were incubated on a rocker for 20-40 min at 37  C. The digested tissues were then passed through a 40 microm cell strainer and washed twice with PBS prior to surface staining.	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PBS', 'Chemical', '-', (365, 368))	('Tumor', 'Disease', (0, 5))	('0.002', 'Var', (175, 180))
147551	33293583	The primary antibodies used were anti-human CD3 (LEICA, 1:200), anti-human CD20 (LEICA, 1:300), anti-human MPO (Long island, 1:100), anti-human CD56 (Long island, 1:400), and anti-human CD68 (Long island, 1:100).	('CD56', 'Gene', '4684', (144, 148))	('anti-human', 'Var', (175, 185))	('CD20', 'Gene', '54474', (75, 79))	('human', 'Species', '9606', (38, 43))	('CD20', 'Gene', (75, 79))	('CD68', 'Gene', (186, 190))	('anti-human', 'Var', (133, 143))	('MPO', 'Gene', (107, 110))	('human', 'Species', '9606', (180, 185))	('human', 'Species', '9606', (138, 143))	('human', 'Species', '9606', (69, 74))	('CD56', 'Gene', (144, 148))	('CD68', 'Gene', '968', (186, 190))	('human', 'Species', '9606', (101, 106))	('anti-human', 'Var', (96, 106))	('MPO', 'Gene', '4353', (107, 110))
147702	31792298	Recently, new discovered members of the B7 family of costimulatory molecules, such as B7-H1, B7-H3, B7-H4 and B7-H6, are widely expressed in many human tumour tissue types and can participate in the negative regulation of the T/natural killer (NK) cell-mediated antitumour immune response, thus attracting wide attention.	('B7-H6', 'Gene', '374383', (110, 115))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('participate', 'Reg', (180, 191))	('tumour', 'Disease', (152, 158))	('B7-H6', 'Gene', (110, 115))	('tumour', 'Disease', (266, 272))	('negative', 'NegReg', (199, 207))	('human', 'Species', '9606', (146, 151))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('B7-H4', 'Gene', (100, 105))	('B7-H3', 'Gene', '102657', (93, 98))	('B7-H3', 'Gene', (93, 98))	('B7-H4', 'Gene', '79679', (100, 105))	('B7-H1', 'Var', (86, 91))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('tumour', 'Disease', 'MESH:D009369', (266, 272))
147707	31792298	Patients with both high levels of B7-H3 and B7-H4 had the poorest prognosis.	('high', 'Var', (19, 23))	('B7-H4', 'Gene', (44, 49))	('B7-H4', 'Gene', '79679', (44, 49))	('B7-H3', 'Gene', '102657', (34, 39))	('B7-H3', 'Gene', (34, 39))	('Patients', 'Species', '9606', (0, 8))
147708	31792298	demonstrated that B7-H4 expression was associated with ESCC progression and survival by reducing tumor immunosurveillance.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ESCC', 'Disease', 'MESH:C562729', (55, 59))	('tumor', 'Disease', (97, 102))	('associated', 'Reg', (39, 49))	('B7-H4', 'Gene', (18, 23))	('B7-H4', 'Gene', '79679', (18, 23))	('ESCC', 'Disease', (55, 59))	('expression', 'Var', (24, 34))	('reducing', 'NegReg', (88, 96))
147737	31792298	The HLA-B-associated transcript 3 (BAT3) and the pp65 proteins have been revealed to bind NKp30, but they don't bind to ligands on the surface of tumour cell because pp65 was a cytomegalovirus tegument protein and BAT3 was a nuclear protein released after heat-shock treatment.	('cytomegalovirus tegument', 'Disease', (177, 201))	('shock', 'Phenotype', 'HP:0031273', (261, 266))	('tumour', 'Disease', (146, 152))	('NKp30', 'Gene', '259197', (90, 95))	('pp65', 'Var', (166, 170))	('BAT3', 'Gene', '7917', (214, 218))	('BAT3', 'Gene', '7917', (35, 39))	('cytomegalovirus tegument', 'Disease', 'MESH:D003586', (177, 201))	('NKp30', 'Gene', (90, 95))	('BAT3', 'Gene', (35, 39))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('HLA-B-associated transcript 3', 'Gene', (4, 33))	('bind', 'Interaction', (85, 89))	('BAT3', 'Gene', (214, 218))	('HLA-B-associated transcript 3', 'Gene', '7917', (4, 33))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
147756	31792298	In the past three years, some studies about the knockdown of B7-H6 expression in tumours have been carried out and implied that B7-H6 might be a meaningful target for cancer therapy.	('B7-H6', 'Gene', '374383', (128, 133))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('B7-H6', 'Gene', '374383', (61, 66))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (167, 173))	('B7-H6', 'Gene', (128, 133))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('tumours', 'Disease', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('B7-H6', 'Gene', (61, 66))	('knockdown', 'Var', (48, 57))
147809	30288105	The dysregulation of claudin-7 plays a tumor suppressor role or conversely has carcinogenic effects in different target tissues or cells, but the exact underlying mechanism is still unclear.	('claudin-7', 'Gene', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('dysregulation', 'Var', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('carcinogenic', 'Disease', 'MESH:D063646', (79, 91))	('carcinogenic', 'Disease', (79, 91))	('tumor', 'Disease', (39, 44))
147823	30288105	The abnormal expression of claudin-7 results in the destruction of TJs, loss of the contact inhibition of cells, and abnormal proliferation and migration, and is closely related to the occurrence and development of various malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('contact inhibition of cells', 'CPA', (84, 111))	('loss', 'NegReg', (72, 76))	('related', 'Reg', (170, 177))	('abnormal', 'Var', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('expression', 'MPA', (13, 23))	('claudin-7', 'Gene', (27, 36))	('malignant tumors', 'Disease', (223, 239))	('abnormal proliferation and migration', 'Phenotype', 'HP:0002269', (117, 153))	('destruction', 'NegReg', (52, 63))	('malignant tumors', 'Disease', 'MESH:D018198', (223, 239))	('TJs', 'CPA', (67, 70))
147833	30288105	The dysregulation of claudin proteins and disruption of epithelial barrier function have been observed in intestinal inflammation and tumors.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('dysregulation', 'Var', (4, 17))	('intestinal inflammation', 'Disease', 'MESH:D007249', (106, 129))	('inflammation and tumors', 'Disease', 'MESH:D007249', (117, 140))	('intestinal inflammation', 'Disease', (106, 129))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('claudin proteins', 'Protein', (21, 37))
147840	30288105	Deletion of claudin-2 and -15 in mouse intestinal epithelial cells resulted in intestinal destruction because the transepithelial resistance and paracellular Na+ permeability were decreased.	('mouse', 'Species', '10090', (33, 38))	('paracellular Na+ permeability', 'MPA', (145, 174))	('intestinal destruction', 'Phenotype', 'HP:0005214', (79, 101))	('decreased', 'NegReg', (180, 189))	('intestinal destruction', 'CPA', (79, 101))	('claudin-2 and -15', 'Gene', '12738;60363', (12, 29))	('Deletion', 'Var', (0, 8))
147844	30288105	Overexpression of claudin-7 reduces the paracellular Cl- permeability and increases the paracellular Na+ conductance in renal LLC-PK1 cells, whereas claudin-7 knockdown increases Na+ permeability in MDCK cells.	('PK1', 'Gene', '5313', (130, 133))	('knockdown', 'Var', (159, 168))	('PK1', 'Gene', (130, 133))	('renal LLC', 'Phenotype', 'HP:0030409', (120, 129))	('reduces', 'NegReg', (28, 35))	('paracellular Cl- permeability', 'MPA', (40, 69))	('MDCK', 'CellLine', 'CVCL:0422', (199, 203))	('paracellular Na+ conductance', 'MPA', (88, 116))	('increases', 'PosReg', (74, 83))
147846	30288105	The paracellular flux (pFlux) of small organic solutes was enhanced by claudin-7 deficiency, but not for the larger organic solutes, resulting in increased infiltration of N-formyl-L-methionyl-L-leucyl-Lphenylalanine (438 Da), a major bacterial product, and aggravated intestinal inflammation.	('deficiency', 'Var', (81, 91))	('N-formyl-L-methionyl-L-leucyl-Lphenylalanine', 'Chemical', '-', (172, 216))	('increased', 'PosReg', (146, 155))	('enhanced', 'PosReg', (59, 67))	('intestinal inflammation', 'Disease', 'MESH:D007249', (269, 292))	('claudin-7', 'Gene', (71, 80))	('aggravated', 'PosReg', (258, 268))	('intestinal inflammation', 'Disease', (269, 292))	('infiltration', 'MPA', (156, 168))
147851	30288105	Claudin-7 colocalizes with integrin alpha2 in normal intestinal epithelium, and deletion of claudin-7 altered integrin alpha2 expression and localization and decreased the claudin-7/integrin alpha2/claudin-1 protein complex formation.	('integrin alpha2', 'Gene', '3673', (110, 125))	('integrin alpha2', 'Gene', (110, 125))	('deletion', 'Var', (80, 88))	('decreased', 'NegReg', (158, 167))	('expression', 'MPA', (126, 136))	('localization', 'MPA', (141, 153))	('claudin-7', 'Gene', (92, 101))	('integrin alpha2', 'Gene', (182, 197))	('integrin alpha2', 'Gene', (27, 42))	('integrin alpha2', 'Gene', '3673', (182, 197))	('integrin alpha2', 'Gene', '3673', (27, 42))	('altered', 'Reg', (102, 109))
147854	30288105	With the inhibition of claudin-7, cell growth was significantly accelerated, the expression of integrin beta1 and phosphorylated focal adhesion kinase (FAK) was significantly decreased, and extracellular matrix adhesion was weakened, which led to a weakened adhesion capacity of cancer cells, thereby accelerating invasion and metastasis.	('accelerated', 'PosReg', (64, 75))	('integrin beta1', 'Gene', '3688', (95, 109))	('cancer', 'Disease', (279, 285))	('claudin-7', 'Gene', (23, 32))	('inhibition', 'Var', (9, 19))	('decreased', 'NegReg', (175, 184))	('expression', 'MPA', (81, 91))	('focal adhesion kinase', 'Gene', (129, 150))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('extracellular matrix adhesion', 'CPA', (190, 219))	('FAK', 'Gene', (152, 155))	('integrin beta1', 'Gene', (95, 109))	('FAK', 'Gene', '5747', (152, 155))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('weakened', 'NegReg', (249, 257))	('accelerating', 'PosReg', (301, 313))	('adhesion capacity', 'CPA', (258, 275))	('focal adhesion kinase', 'Gene', '5747', (129, 150))	('weakened', 'NegReg', (224, 232))	('cell growth', 'CPA', (34, 45))
147858	30288105	Deletion of claudin-7 reduces the abnormal expression and position of integrin alpha2, which destroys the claudin-7/integrin alpha2/claudin-1 complex formation in the intestinal epithelium.	('integrin alpha2', 'Gene', '3673', (70, 85))	('integrin alpha2', 'Gene', (70, 85))	('destroys', 'NegReg', (93, 101))	('claudin-7', 'Gene', (12, 21))	('reduces', 'NegReg', (22, 29))	('integrin alpha2', 'Gene', (116, 131))	('integrin alpha2', 'Gene', '3673', (116, 131))	('abnormal expression', 'MPA', (34, 53))	('position', 'MPA', (58, 66))	('Deletion', 'Var', (0, 8))
147862	30288105	This model shows that loss of claudin-7 can increase the absorption of intestinal bacterial products and initiate colonic inflammation.	('colonic inflammation', 'Disease', 'MESH:D007249', (114, 134))	('initiate', 'Reg', (105, 113))	('increase', 'PosReg', (44, 52))	('claudin-7', 'Gene', (30, 39))	('absorption of intestinal bacterial products', 'MPA', (57, 100))	('loss', 'Var', (22, 26))	('colonic inflammation', 'Disease', (114, 134))
147869	30288105	The three mouse models were tested for the effects of claudin-7 knockdown on intestinal inflammation and tumors.	('intestinal inflammation', 'Disease', 'MESH:D007249', (77, 100))	('intestinal inflammation', 'Disease', (77, 100))	('mouse', 'Species', '10090', (10, 15))	('inflammation and tumors', 'Disease', 'MESH:D007249', (88, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('knockdown', 'Var', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
147872	30288105	Claudin-7 knockout mice exhibit severe intestinal inflammation, increased paracellular permeability, a dysfunctional intestinal barrier, and successful induction of intestinal tumors, indicating that claudin-7 has protective effects on intestinal epithelial cells, maintains intestinal homeostasis, and may play a role in tumor inhibition.	('claudin-7', 'Var', (200, 209))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('intestinal tumors', 'Disease', (165, 182))	('protective effects', 'CPA', (214, 232))	('intestinal inflammation', 'Disease', (39, 62))	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('mice', 'Species', '10090', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('intestinal inflammation', 'Disease', 'MESH:D007249', (39, 62))	('play', 'Reg', (307, 311))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('intestinal tumors', 'Disease', 'MESH:D007414', (165, 182))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('maintains', 'PosReg', (265, 274))	('paracellular permeability', 'MPA', (74, 99))	('intestinal homeostasis', 'MPA', (275, 297))	('increased', 'PosReg', (64, 73))	('tumor', 'Disease', (322, 327))
147873	30288105	As a critical protein in epithelial cells, abnormal expression and distribution of claudin-7 have been reported in a variety of human malignancies, including lung, colon, ovarian, breast, gastric, esophageal, and prostate cancers and has been associated with cancer progression and metastasis.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('colon', 'Disease', (164, 169))	('breast', 'Disease', (180, 186))	('distribution', 'MPA', (67, 79))	('ovarian', 'Disease', (171, 178))	('esophageal', 'Disease', (197, 207))	('cancer', 'Disease', (222, 228))	('human', 'Species', '9606', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('prostate cancer', 'Phenotype', 'HP:0012125', (213, 228))	('cancer', 'Disease', (259, 265))	('lung', 'Disease', (158, 162))	('malignancies', 'Disease', 'MESH:D009369', (134, 146))	('claudin-7', 'Gene', (83, 92))	('prostate cancers', 'Disease', 'MESH:D011471', (213, 229))	('reported', 'Reg', (103, 111))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('malignancies', 'Disease', (134, 146))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('abnormal', 'Var', (43, 51))	('gastric', 'Disease', (188, 195))	('associated', 'Reg', (243, 253))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('expression', 'MPA', (52, 62))	('prostate cancers', 'Phenotype', 'HP:0012125', (213, 229))	('prostate cancers', 'Disease', (213, 229))
147876	30288105	Accordingly, loss of claudin-7 is associated with loss of cell adhesion and tumor progression.	('claudin-7', 'Gene', (21, 30))	('cell adhesion', 'CPA', (58, 71))	('loss', 'NegReg', (50, 54))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('loss', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
147881	30288105	Claudin-7 knockdown cells have high phosphorylation of ERK1/2; however, cell proliferation, invasive ability, and ERK1/2 phosphorylation were significantly reduced with the restoration of claudin-7.	('claudin-7', 'Gene', (188, 197))	('ERK1/2', 'Gene', (55, 61))	('ERK1/2', 'Gene', (114, 120))	('invasive ability', 'CPA', (92, 108))	('phosphorylation', 'MPA', (121, 136))	('ERK1/2', 'Gene', '5595;5594', (55, 61))	('reduced', 'NegReg', (156, 163))	('restoration', 'Var', (173, 184))	('cell proliferation', 'CPA', (72, 90))	('ERK1/2', 'Gene', '5595;5594', (114, 120))	('phosphorylation', 'MPA', (36, 51))
147883	30288105	The deletion of claudin-7 eliminated the ability to inhibit the interaction between PDK1 and Akt and caused sustained phosphorylation of Akt, resulting in cell proliferation disorders of lung squamous cell carcinoma.	('claudin-7', 'Gene', (16, 25))	('PDK1', 'Gene', '5170', (84, 88))	('PDK1', 'Gene', (84, 88))	('Akt', 'Gene', (93, 96))	('ability', 'MPA', (41, 48))	('resulting in', 'Reg', (142, 154))	('phosphorylation', 'MPA', (118, 133))	('cell proliferation disorders', 'CPA', (155, 183))	('Akt', 'Gene', '207', (93, 96))	('eliminated', 'NegReg', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (187, 215))	('deletion', 'Var', (4, 12))	('Akt', 'Gene', (137, 140))	('inhibit', 'NegReg', (52, 59))	('Akt', 'Gene', '207', (137, 140))	('caused', 'Reg', (101, 107))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (187, 215))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('interaction', 'Interaction', (64, 75))	('lung squamous cell carcinoma', 'Disease', (187, 215))
147884	30288105	A new digital image classification, fragmentation index, morphological analysis method for quantitative analysis of the expression pattern of claudin-7 in lung cancer also showed that claudin-7 can be used as a biomarker for identifying lung cancer.	('claudin-7', 'Var', (184, 193))	('claudin-7', 'Gene', (142, 151))	('lung cancer', 'Disease', (237, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (237, 248))	('lung cancer', 'Disease', (155, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('lung cancer', 'Disease', 'MESH:D008175', (237, 248))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
147886	30288105	Claudin-7 hypermethylation occurred at the invasive front of esophageal squamous cell carcinoma and may lead to heterogeneous and reduced expression of claudin-7.	('hypermethylation', 'Var', (10, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('heterogeneous', 'MPA', (112, 125))	('Claudin-7', 'Gene', (0, 9))	('esophageal squamous cell carcinoma', 'Disease', (61, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('claudin-7', 'Protein', (152, 161))	('reduced', 'NegReg', (130, 137))	('expression', 'MPA', (138, 148))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (61, 95))	('occurred', 'Reg', (27, 35))
147888	30288105	The abnormal localization of claudin-7 promotes cell transformation and regulates E-cadherin expression during tumor progression.	('cell transformation', 'CPA', (48, 67))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('promotes', 'PosReg', (39, 47))	('abnormal', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('E-cadherin', 'Gene', (82, 92))	('E-cadherin', 'Gene', '999', (82, 92))	('expression', 'MPA', (93, 103))	('regulates', 'Reg', (72, 81))	('claudin-7', 'Gene', (29, 38))
147892	30288105	Claudin-7 deletion leads to tumors with decreased tubular arrangement.	('Claudin-7', 'Gene', (0, 9))	('decreased tubular arrangement', 'Disease', (40, 69))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('deletion', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('decreased tubular arrangement', 'Disease', 'MESH:D005198', (40, 69))
147896	30288105	Loss of TJ proteins is an event well known to reduce cell adhesion, and the deletion of intercellular adhesion molecules has been associated with decreased cell cohesion, and cytoskeleton remodeling, which is conducive to tumor cell detachment and distant metastasis.	('deletion', 'Var', (76, 84))	('reduce', 'NegReg', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('reduce cell adhesion', 'Phenotype', 'HP:0008352', (46, 66))	('cytoskeleton remodeling', 'CPA', (175, 198))	('decreased', 'NegReg', (146, 155))	('Loss', 'NegReg', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('cell cohesion', 'CPA', (156, 169))	('cell adhesion', 'CPA', (53, 66))	('tumor', 'Disease', (222, 227))
147905	30288105	Palmitoylated claudin-7 may support tumor cell metastasis by interacting with MMPs and CD147.	('MMPs', 'Gene', '17395;4323', (78, 82))	('MMPs', 'Gene', (78, 82))	('interacting', 'Interaction', (61, 72))	('CD147', 'Gene', '682', (87, 92))	('Palmitoylated', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CD147', 'Gene', (87, 92))	('support', 'PosReg', (28, 35))	('tumor', 'Disease', (36, 41))
147906	30288105	However, knockdown of claudin-7 inhibits tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('knockdown', 'Var', (9, 18))	('tumor', 'Disease', (41, 46))	('inhibits', 'NegReg', (32, 40))	('claudin-7', 'Gene', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
147909	30288105	The overall survival time of patients with high claudin-7 expression was decreased.	('expression', 'MPA', (58, 68))	('patients', 'Species', '9606', (29, 37))	('decreased', 'NegReg', (73, 82))	('high', 'Var', (43, 47))
147913	30288105	The complexes of claudin-7, EpCAM, and CD44 variants may be involved in the invasive phenotype of undifferentiated thyroid carcinoma, but some experiments have shown that claudin-7 expression is not significantly different between benign and malignant thyroid cancers and thus is not a sub- typing marker.	('malignant thyroid cancers', 'Disease', (242, 267))	('CD44', 'Gene', '960', (39, 43))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (115, 132))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('undifferentiated thyroid carcinoma', 'Disease', 'MESH:D002277', (98, 132))	('CD44', 'Gene', (39, 43))	('thyroid cancer', 'Phenotype', 'HP:0002890', (252, 266))	('malignant thyroid cancers', 'Disease', 'MESH:D013964', (242, 267))	('undifferentiated thyroid carcinoma', 'Disease', (98, 132))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('variants', 'Var', (44, 52))
147915	30288105	Non-palmitoylated claudin-7, as a TJ protein, is involved in the formation of intercellular TJs and inhibits tumor progression and metastasis through TJ function.	('Non-palmitoylated', 'Var', (0, 17))	('inhibits', 'NegReg', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
147916	30288105	However, palmitoylated claudin-7 inhibits the formation of TJs and promotes the degradation of the extracellular matrix through its non-TJ function or interaction with MMPs, thereby accelerating the movement of tumor cells and promoting tumor progression.	('promotes', 'PosReg', (67, 75))	('tumor', 'Disease', (237, 242))	('interaction', 'Interaction', (151, 162))	('palmitoylated', 'Var', (9, 22))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('promoting', 'PosReg', (227, 236))	('accelerating', 'PosReg', (182, 194))	('degradation of the extracellular matrix', 'MPA', (80, 119))	('MMPs', 'Gene', '17395;4323', (168, 172))	('MMPs', 'Gene', (168, 172))	('TJs', 'MPA', (59, 62))	('formation', 'MPA', (46, 55))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('inhibits', 'NegReg', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('non-TJ', 'MPA', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
147940	30288105	Increased claudin-7 expression in low-claudin-7 SW620 colon cancer cells induced epithelial differentiation and reduced the ability of tumor formation, whereas knockdown of claudin-7 in the HT-29 or DLD-1 cell lines induced EMT and increased tumorigenicity, tumor growth, and invasiveness in nude mice.	('induced', 'PosReg', (216, 223))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (258, 263))	('colon cancer', 'Disease', (54, 66))	('tumor', 'Disease', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('induced', 'Reg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('SW620', 'CellLine', 'CVCL:0547', (48, 53))	('low-claudin-7', 'Var', (34, 47))	('reduced', 'NegReg', (112, 119))	('nude mice', 'Species', '10090', (292, 301))	('HT-29', 'CellLine', 'CVCL:0320', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('epithelial differentiation', 'CPA', (81, 107))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('invasiveness', 'CPA', (276, 288))	('increased', 'PosReg', (232, 241))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('EMT', 'CPA', (224, 227))	('claudin-7', 'Gene', (10, 19))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
147943	30288105	Palmitoylation of cld7 enhances the efficacy of EpIC and increases the expression of EMT- related transcription factors and mesenchymal proteins, such as FGF, TGFbeta, and N-cadherin.	('expression', 'MPA', (71, 81))	('FGF', 'Gene', (154, 157))	('N-cadherin', 'Gene', (172, 182))	('enhances', 'PosReg', (23, 31))	('cld7', 'Gene', (18, 22))	('increases', 'PosReg', (57, 66))	('efficacy', 'CPA', (36, 44))	('N-cadherin', 'Gene', '1000', (172, 182))	('TGFbeta', 'Gene', (159, 166))	('Palmitoylation', 'Var', (0, 14))	('EMT- related transcription factors', 'Gene', (85, 119))
147944	30288105	HT29-cld7kd and SW948-cld7kd cells affect the recruitment of EpCAM and display decreased intercellular connections, growth, and holoclone and sphere formation, resulting in the delayed tumor growth and decreased migration.	('tumor', 'Disease', (185, 190))	('SW948-cld7kd', 'Var', (16, 28))	('decreased', 'NegReg', (79, 88))	('decreased', 'NegReg', (202, 211))	('recruitment', 'MPA', (46, 57))	('SW948', 'CellLine', 'CVCL:0632', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('growth', 'CPA', (116, 122))	('intercellular connections', 'CPA', (89, 114))	('migration', 'CPA', (212, 221))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('EpCAM', 'Protein', (61, 66))
147945	30288105	Flow analysis and WB showed that N-cadherin, vimentin, and the transcription factor Snail were downregulated after claudin-7 knockdown, and E-cadherin was significantly upregulated.	('Snail', 'Gene', '6615', (84, 89))	('vimentin', 'Gene', (45, 53))	('knockdown', 'Var', (125, 134))	('downregulated', 'NegReg', (95, 108))	('claudin-7', 'Gene', (115, 124))	('E-cadherin', 'Gene', (140, 150))	('E-cadherin', 'Gene', '999', (140, 150))	('N-cadherin', 'Gene', (33, 43))	('upregulated', 'PosReg', (169, 180))	('vimentin', 'Gene', '7431', (45, 53))	('N-cadherin', 'Gene', '1000', (33, 43))	('Snail', 'Gene', (84, 89))
147946	30288105	Claudin-7 knockdown reduced drug resistance, promoted caspase activation, and decreased the activation of the anti-apoptotic PI3K/Akt pathway, indicating that claudin-7 may play a carcinogenic role.	('Claudin-7', 'Gene', (0, 9))	('reduced', 'NegReg', (20, 27))	('carcinogenic', 'Disease', (180, 192))	('drug resistance', 'Phenotype', 'HP:0020174', (28, 43))	('caspase', 'CPA', (54, 61))	('Akt', 'Gene', '207', (130, 133))	('promoted', 'PosReg', (45, 53))	('Akt', 'Gene', (130, 133))	('activation', 'PosReg', (62, 72))	('carcinogenic', 'Disease', 'MESH:D063646', (180, 192))	('decreased', 'NegReg', (78, 87))	('activation', 'MPA', (92, 102))	('knockdown', 'Var', (10, 19))	('drug resistance', 'MPA', (28, 43))
147947	30288105	The precise molecular mechanisms involved in the progression of cancer are still largely unknown, and recent studies have shown that transcription factors, cytokines, growth factors, post-translational modifications, and epigenetic mechanisms affect claudin-7 expression.	('expression', 'MPA', (260, 270))	('epigenetic mechanisms', 'Var', (221, 242))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('affect', 'Reg', (243, 249))	('claudin-7', 'Gene', (250, 259))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
147952	30288105	Epigenetic mechanisms include DNA methylation, histone modifications, or microRNAs, which are the major regulatory mechanisms regulating claudin protein and tumors.	('microRNAs', 'CPA', (73, 82))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('DNA methylation', 'Var', (30, 45))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('histone modifications', 'Var', (47, 68))
147954	30288105	Hahn-Stromberg et al used bisulfite pyrosequencing to analyze DNA methylation of claudin-1, -4, and -7 in tumors and the adjacent non-neoplastic mucosa and found that claudin-1 was significantly hypomethylated in the tumor tissues, while claudin-7 methylation levels showed no significant difference between tumors and paracancerous tissues.	('tumors', 'Disease', (106, 112))	('claudin-1', 'Gene', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('paracancerous tissues', 'Disease', (319, 340))	('tumor', 'Disease', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('tumor', 'Disease', (217, 222))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('claudin-1, -4, and -7', 'Gene', '9076;1364;1366', (81, 102))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('hypomethylated', 'Var', (195, 209))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumors', 'Disease', (308, 314))	('bisulfite', 'Chemical', 'MESH:C042345', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (308, 313))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('paracancerous tissues', 'Disease', 'MESH:D009380', (319, 340))
147955	30288105	The aforementioned studies showed that abnormal methylation of the claudin-7 gene reduced the expression of claudin-7 and plays an important role in the occurrence and development of tumors.	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('claudin-7', 'Gene', (108, 117))	('development', 'CPA', (168, 179))	('methylation', 'Var', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('abnormal methylation', 'Var', (39, 59))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('expression', 'MPA', (94, 104))	('plays', 'Reg', (122, 127))	('reduced', 'NegReg', (82, 89))	('claudin-7', 'Gene', (67, 76))	('tumors', 'Disease', (183, 189))
147956	30288105	In CRC, claudin-7 phosphorylation enhances paracellular permeability of epithelial cells, increases the entry of growth factors and nutrients into tumor cells, and results in abnormal localization of claudin-7.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('increases', 'PosReg', (90, 99))	('localization', 'MPA', (184, 196))	('enhances', 'PosReg', (34, 42))	('claudin-7', 'Gene', (8, 17))	('paracellular permeability of epithelial cells', 'MPA', (43, 88))	('results in', 'Reg', (164, 174))	('claudin-7', 'Protein', (200, 209))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('phosphorylation', 'Var', (18, 33))
147957	30288105	Palmitoylation of claudin-7 can affect the localization of claudin-7; interfere with the formation of cell-cell adhesion in TJs; promote the recruitment of integrins and EpCAM to the GEM; interact with cytoskeletal connexin, MMP14, CD147, and TACE; participate in drug resistance; and activate the PI3K/Akt anti-apoptotic pathway, further promoting tumor invasion and metastasis.	('promote', 'PosReg', (129, 136))	('drug resistance', 'CPA', (264, 279))	('participate', 'Reg', (249, 260))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('interact', 'Interaction', (188, 196))	('interfere', 'NegReg', (70, 79))	('promoting', 'PosReg', (339, 348))	('CD147', 'Gene', '682', (232, 237))	('TACE', 'Gene', (243, 247))	('formation', 'MPA', (89, 98))	('EpCAM', 'Protein', (170, 175))	('Palmitoylation', 'Var', (0, 14))	('MMP14', 'Gene', '4323', (225, 230))	('MMP14', 'Gene', (225, 230))	('CD147', 'Gene', (232, 237))	('drug resistance', 'Phenotype', 'HP:0020174', (264, 279))	('TACE', 'Gene', '6868', (243, 247))	('tumor', 'Disease', (349, 354))	('localization', 'MPA', (43, 55))	('metastasis', 'CPA', (368, 378))	('Akt', 'Gene', (303, 306))	('activate', 'PosReg', (285, 293))	('affect', 'Reg', (32, 38))	('integrins', 'Protein', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('Akt', 'Gene', '207', (303, 306))	('recruitment', 'MPA', (141, 152))
147958	30288105	APC mutation induces claudin-1 expression in colonic epithelial cells, while claudin-1 inhibits the expression of claudin-7.	('induces', 'Reg', (13, 20))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('inhibits', 'NegReg', (87, 95))	('mutation', 'Var', (4, 12))	('expression', 'MPA', (100, 110))	('expression', 'MPA', (31, 41))	('APC', 'Disease', (0, 3))	('claudin-1', 'Gene', (21, 30))
147999	28336725	Variable peptide modifications included TMT-modified N termini and lysines (additional 229.1629 Da) and oxidized methionines, with carbamidomethylation of cysteines set as a fixed modification.	('cysteines', 'Chemical', 'MESH:D003545', (155, 164))	('TMT-modified', 'Var', (40, 52))	('lysines', 'Chemical', 'MESH:D008239', (67, 74))	('oxidized methionines', 'MPA', (104, 124))	('methionines', 'Chemical', 'MESH:D008715', (113, 124))
148030	26357671	We used a single-channel upper gastrointestinal endoscope with a water jet system (GIF-H260Z, GIF-Q260J; Olympus, Tokyo, Japan) and a high-frequency generator with an automatically controlled system (ICC 200; ERBE Elektromedizin GmbH, Tubingen, Germany) set at Endocut mode, 120 W, effect 2 for circumferential incision/forced coagulation or at 50 W for dissection.	('water jet', 'Phenotype', 'HP:0000969', (65, 74))	('Q260J', 'Var', (98, 103))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (25, 57))	('H260Z', 'Var', (87, 92))	('H260Z', 'SUBSTITUTION', 'None', (87, 92))	('water', 'Chemical', 'MESH:D014867', (65, 70))	('Q260J', 'SUBSTITUTION', 'None', (98, 103))	('upper gastrointestinal endoscope', 'Disease', (25, 57))
148101	26322197	Paired in sex, age, tobacco, and alcohol consumption; the fewer number of remaining teeth were associated with increased risk of head, neck, esophageal, and lung cancers.	('head', 'Disease', (129, 133))	('alcohol', 'Chemical', 'MESH:D000438', (33, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('lung cancers', 'Disease', 'MESH:D008175', (157, 169))	('lung cancers', 'Phenotype', 'HP:0100526', (157, 169))	('esophageal', 'Disease', (141, 151))	('fewer number', 'Var', (58, 70))	('tobacco', 'Species', '4097', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('lung cancers', 'Disease', (157, 169))
148104	26322197	Loss of 11 or more teeth showed 2.7-fold increased risk of oral cancer after adjustment for alcohol and smoking.	('alcohol', 'Chemical', 'MESH:D000438', (92, 99))	('more teeth', 'Phenotype', 'HP:0011069', (14, 24))	('men', 'Species', '9606', (83, 86))	('oral cancer', 'Disease', 'MESH:D009062', (59, 70))	('oral cancer', 'Disease', (59, 70))	('Loss', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
148106	26322197	After adjusting of age, gender, fruit and vegetable intake, smoking, and drinking habit; no significant increase in risk of oral cancer were found but poor condition of mouth and missing 16 or more teeth were associated with oral cancer after smoking and alcohol control.	('associated', 'Reg', (209, 219))	('mouth', 'Disease', 'MESH:D009059', (169, 174))	('oral cancer', 'Disease', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('poor condition', 'Var', (151, 165))	('missing', 'Var', (179, 186))	('alcohol', 'Chemical', 'MESH:D000438', (255, 262))	('more teeth', 'Phenotype', 'HP:0011069', (193, 203))	('oral cancer', 'Disease', 'MESH:D009062', (124, 135))	('oral cancer', 'Disease', (124, 135))	('condition of mouth', 'Phenotype', 'HP:0000153', (156, 174))	('oral cancer', 'Disease', 'MESH:D009062', (225, 236))	('mouth', 'Disease', (169, 174))
148128	26322197	According to this study, the loss of 10 teeth and more resulted in a 2-fold increased risk for gastric cancer.	('loss of 10 teeth', 'Phenotype', 'HP:0000677', (29, 45))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('gastric cancer', 'Disease', (95, 109))	('loss', 'Var', (29, 33))	('10 teeth', 'Phenotype', 'HP:0011069', (37, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))
148142	26322197	This means that the evidence did not yet support a specific association between esophageal cancer, periodontal disease with overall poor oral condition (Silnss and Loe plaque index more than 40%), and increased number of missing teeth.	('periodontal disease', 'Disease', (99, 118))	('periodontal disease', 'Disease', 'MESH:D010510', (99, 118))	('missing teeth', 'Phenotype', 'HP:0006349', (221, 234))	('poor oral', 'Phenotype', 'HP:0000160', (132, 141))	('esophageal cancer', 'Disease', (80, 97))	('Silnss', 'Var', (153, 159))	('periodontal disease', 'Phenotype', 'HP:0000704', (99, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
148166	25149537	Finally, incubation of SCCHN cells with antibody to CD271 results in decreased Erk phosphorylation and decreased tumor formation in vivo.	('tumor', 'Disease', (113, 118))	('Erk phosphorylation', 'MPA', (79, 98))	('SCC', 'Gene', '6317', (23, 26))	('CD271', 'Gene', '4804', (52, 57))	('decreased', 'NegReg', (69, 78))	('decreased', 'NegReg', (103, 112))	('antibody', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('decreased Erk', 'Phenotype', 'HP:0000654', (69, 82))	('SCC', 'Gene', (23, 26))	('CD271', 'Gene', (52, 57))
148172	25149537	Specifically, the CD44+ population has been shown to contain the TIC subpopulation, since purified CD44+ cells from heterogenous primary tumors are able to give rise to tumors much more readily in xenograft model systems compared to CD44- cells, and these xenograft tumors subsequently reproduce the original tumor heterogeneity observed in the primary tumor.	('CD44+', 'Var', (99, 104))	('primary tumor', 'Disease', (345, 358))	('give rise to tumors', 'Disease', 'MESH:D009369', (156, 175))	('primary tumors', 'Disease', (129, 143))	('tumor', 'Disease', (266, 271))	('tumor', 'Disease', (353, 358))	('xenograft tumors', 'Disease', (256, 272))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('tumor', 'Disease', (169, 174))	('xenograft tumors', 'Disease', 'MESH:D009369', (256, 272))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('primary tumors', 'Disease', 'MESH:D009369', (129, 143))	('tumor', 'Disease', (309, 314))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('give rise to tumors', 'Disease', (156, 175))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('TIC', 'Phenotype', 'HP:0100033', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('primary tumor', 'Disease', 'MESH:D009369', (345, 358))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('primary tumor', 'Disease', 'MESH:D009369', (129, 142))
148173	25149537	This population has also been shown to have a significantly greater ability to metastasize to regional lymph nodes in animal models, and patients whose tumors have greater percentages of CD44+ cells have a significantly poorer clinical outcome.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('metastasize to regional lymph nodes', 'CPA', (79, 114))	('patients', 'Species', '9606', (137, 145))	('CD44+ cells', 'Var', (187, 198))	('greater', 'PosReg', (60, 67))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
148181	25149537	Further, our data demonstrate that this receptor is functional in SCCHN and that inhibition of CD271 has profound negative effects on SCCHN tumor-initiating capacity, providing evidence for the first functional and targetable molecule specific to TICs in this malignancy.	('CD271', 'Gene', '4804', (95, 100))	('SCC', 'Gene', (66, 69))	('TICs', 'Phenotype', 'HP:0100033', (247, 251))	('TIC', 'Phenotype', 'HP:0100033', (247, 250))	('tumor', 'Disease', (140, 145))	('inhibition', 'Var', (81, 91))	('CD271', 'Gene', (95, 100))	('SCC', 'Gene', '6317', (134, 137))	('SCC', 'Gene', '6317', (66, 69))	('negative', 'NegReg', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('malignancy', 'Disease', 'MESH:D009369', (260, 270))	('SCC', 'Gene', (134, 137))	('malignancy', 'Disease', (260, 270))
148204	25149537	The knockdown of CD271 significantly affected cell growth in vitro (Figure 2C).	('affected', 'Reg', (37, 45))	('CD271', 'Gene', '4804', (17, 22))	('CD271', 'Gene', (17, 22))	('knockdown', 'Var', (4, 13))	('cell growth in vitro', 'CPA', (46, 66))
148205	25149537	In an MTT assay, the CD271hi cell lines (UPCI:SCC-103 and PCI-13), that were transduced with the CD271 shRNA, grew significantly more slowly compared to controls.	('grew', 'CPA', (110, 114))	('CD271', 'Gene', '4804', (21, 26))	('slowly', 'NegReg', (134, 140))	('MTT', 'Chemical', 'MESH:C070243', (6, 9))	('CD271', 'Gene', (21, 26))	('CD271', 'Gene', '4804', (97, 102))	('SCC', 'Gene', (46, 49))	('SCC', 'Gene', '6317', (46, 49))	('CD271', 'Gene', (97, 102))	('transduced', 'Var', (77, 87))
148214	25149537	Thus, knockdown of CD271 resulted in cells that were significantly less tumorigenic compared to control cells in the same microenvironment, indicating that CD271 is a functional receptor expressed on the tumor-initiating population in SCCHN.	('CD271', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('SCC', 'Gene', '6317', (235, 238))	('CD271', 'Gene', (156, 161))	('tumor', 'Disease', (72, 77))	('CD271', 'Gene', '4804', (19, 24))	('less', 'NegReg', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('knockdown', 'Var', (6, 15))	('CD271', 'Gene', '4804', (156, 161))	('SCC', 'Gene', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
148217	25149537	Incubation of PCI-13 SCCHN cells with the antibody resulted in a significant reduction in cell proliferation in vitro compared to cells treated with isotype control IgG (Figure 4A).	('SCC', 'Gene', (21, 24))	('cell proliferation in vitro', 'CPA', (90, 117))	('SCC', 'Gene', '6317', (21, 24))	('reduction', 'NegReg', (77, 86))	('antibody', 'Var', (42, 50))
148227	25149537	CD271 loss-of-function in these tumor cells results in a significant decrease in their capacity for tumor initiation, and targeting CD271 with a monoclonal antibody results in the inhibition of tumor growth in vivo.	('targeting', 'Var', (122, 131))	('tumor', 'Disease', (100, 105))	('tumor initiation', 'Disease', (100, 116))	('CD271', 'Gene', (0, 5))	('decrease', 'NegReg', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('inhibition', 'NegReg', (180, 190))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('CD271', 'Gene', '4804', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (32, 37))	('CD271', 'Gene', (132, 137))	('CD271', 'Gene', '4804', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('loss-of-function', 'NegReg', (6, 22))	('tumor initiation', 'Disease', 'MESH:D009369', (100, 116))
148245	25149537	In SCCHN, the percent of CD44+ cells has been correlated with regional metastatic recurrence.	('SCC', 'Gene', '6317', (3, 6))	('CD44+ cells', 'Var', (25, 36))	('correlated', 'Reg', (46, 56))	('SCC', 'Gene', (3, 6))	('regional metastatic recurrence', 'CPA', (62, 92))
148248	25149537	Since Schwann cells around neurons and epithelium rich in neurons express NGF, it is possible that expression of CD271 may predispose tumor cells to PNI.	('NGF', 'Gene', '4803', (74, 77))	('CD271', 'Gene', '4804', (113, 118))	('NGF', 'Gene', (74, 77))	('CD271', 'Gene', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('expression', 'Var', (99, 109))	('PNI', 'Disease', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('predispose', 'Reg', (123, 133))	('tumor', 'Disease', (134, 139))
148249	25149537	Indeed, in malignant melanoma, expression of CD271 has been associated with PNI, and in oral cancer and pancreatic cancer, the expression of NGF has also been associated with PNI.	('malignant melanoma', 'Phenotype', 'HP:0002861', (11, 29))	('PNI', 'Disease', (175, 178))	('pancreatic cancer', 'Disease', (104, 121))	('associated', 'Reg', (159, 169))	('malignant melanoma', 'Disease', 'MESH:D008545', (11, 29))	('NGF', 'Gene', (141, 144))	('CD271', 'Gene', '4804', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('malignant melanoma', 'Disease', (11, 29))	('NGF', 'Gene', '4803', (141, 144))	('CD271', 'Gene', (45, 50))	('oral cancer', 'Disease', 'MESH:D009062', (88, 99))	('PNI', 'Disease', (76, 79))	('associated', 'Reg', (60, 70))	('oral cancer', 'Disease', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('expression', 'Var', (31, 41))
148288	25149537	For the lentiviral transduction of the cell lines, cells were harvested, washed, resuspended in fresh medium and plated at the appropriate concentration (1x106 cells per 10 cm plates).	('pen', 'Gene', '27344', (86, 89))	('lentiviral', 'Var', (8, 18))	('pen', 'Gene', (86, 89))
148311	25149537	To determine the percentage of cells within the PCI-13 cell line that were actively undergoing apoptosis after p75NTR knock down, the FITC Annexin V Kit from BD Pharmingen was used following the manufacturer's instructions.	('p75NTR', 'Gene', (111, 117))	('p75NTR', 'Gene', '4804', (111, 117))	('knock down', 'Var', (118, 128))	('Annexin V', 'Gene', '308', (139, 148))	('FITC', 'Chemical', 'MESH:D016650', (134, 138))	('Annexin V', 'Gene', (139, 148))
148329	19661933	Epigenetic modifications of DNA in cancer and precancerous lesions offer the promise of novel biomarkers for early cancer detection, prediction, prognosis, and response to treatment.	('precancerous lesions', 'Disease', 'MESH:D011230', (46, 66))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', (115, 121))	('precancerous lesions', 'Disease', (46, 66))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('DNA', 'Gene', (28, 31))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('Epigenetic modifications', 'Var', (0, 24))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (35, 41))
148331	19661933	It is theorized that hypomethylation contributes to carcinogenesis by favoring mitotic recombination, leading to deletions, translocations, and chromosomal rearrangements.	('chromosomal rearrangements', 'CPA', (144, 170))	('mitotic recombination', 'CPA', (79, 100))	('deletions', 'Var', (113, 122))	('favoring', 'PosReg', (70, 78))	('hypomethylation', 'Var', (21, 36))	('leading to', 'Reg', (102, 112))	('carcinogenesis', 'Disease', 'MESH:D063646', (52, 66))	('translocations', 'CPA', (124, 138))	('carcinogenesis', 'Disease', (52, 66))
148333	19661933	Thus, hypermethylation of tumor suppressor genes is now recognized as a means of silencing alternative to mutation or allelic loss in the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('hypermethylation', 'Var', (6, 22))	('cancer', 'Disease', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('silencing', 'NegReg', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
148334	19661933	Hypermethylation of genes involved in the cell cycle, DNA repair, angiogenesis, metabolism of carcinogens, apoptosis, and cell-cell interaction has been implicated in carcinogenesis.	('Hypermethylation', 'Var', (0, 16))	('carcinogenesis', 'Disease', (167, 181))	('implicated', 'Reg', (153, 163))	('carcinogenesis', 'Disease', 'MESH:D063646', (167, 181))
148335	19661933	Methylation can also inhibit the transcription of microRNA, resulting in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('inhibit', 'NegReg', (21, 28))	('microRNA', 'Protein', (50, 58))	('transcription', 'MPA', (33, 46))
148340	19661933	Thus, deacetylation is implicated in the silencing of tumor suppressor genes in carcinogenesis.	('silencing', 'NegReg', (41, 50))	('deacetylation', 'Var', (6, 19))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('tumor', 'Disease', (54, 59))	('carcinogenesis', 'Disease', (80, 94))
148342	19661933	Epigenetic modifications are important in the pathogenesis of both esophageal squamous-cell carcinoma and esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal squamous-cell carcinoma', 'Disease', (67, 101))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('esophageal adenocarcinoma', 'Disease', (106, 131))	('important', 'Reg', (29, 38))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (106, 131))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (106, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('Epigenetic modifications', 'Var', (0, 24))	('esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (67, 101))
148344	19661933	Promoter hypermethylation is also of critical importance in the development of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('esophageal adenocarcinoma', 'Disease', (79, 104))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))	('Promoter hypermethylation', 'Var', (0, 25))
148345	19661933	The most relevant genes targeted by hypermethylation in esophageal adenocarcinoma are CDKN2A and RPRM (cell cycle arrest); DAPK (apoptosis); CDH1 (adhesion); TIMP3 (extracellular matrix degradation); MGMT (purine metabolism); and APC, SFRP1, SFRP2, WIF1, AKAP12, RUNX3, SOCS1, and SOCS3 (signaling and transcriptional regulators).	('SOCS3', 'Gene', '9021', (281, 286))	('DAPK', 'Gene', (123, 127))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (56, 81))	('MGMT', 'Gene', '4255', (200, 204))	('APC', 'Disease', 'MESH:D011125', (230, 233))	('APC', 'Disease', (230, 233))	('CDH1', 'Gene', '999', (141, 145))	('SFRP2', 'Gene', '6423', (242, 247))	('RPRM', 'Gene', '56475', (97, 101))	('AKAP12', 'Gene', '9590', (255, 261))	('esophageal adenocarcinoma', 'Disease', (56, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('DAPK', 'Gene', '1612', (123, 127))	('CDH1', 'Gene', (141, 145))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (56, 81))	('SOCS1', 'Gene', '8651', (270, 275))	('RUNX3', 'Gene', '864', (263, 268))	('WIF1', 'Gene', '11197', (249, 253))	('SFRP1', 'Gene', (235, 240))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (103, 120))	('RPRM', 'Gene', (97, 101))	('SFRP2', 'Gene', (242, 247))	('MGMT', 'Gene', (200, 204))	('hypermethylation', 'Var', (36, 52))	('WIF1', 'Gene', (249, 253))	('TIMP3', 'Gene', '7078', (158, 163))	('TIMP3', 'Gene', (158, 163))	('CDKN2A', 'Gene', (86, 92))	('SOCS3', 'Gene', (281, 286))	('SFRP1', 'Gene', '6422', (235, 240))	('RUNX3', 'Gene', (263, 268))	('SOCS1', 'Gene', (270, 275))	('AKAP12', 'Gene', (255, 261))	('CDKN2A', 'Gene', '1029', (86, 92))	('purine', 'Chemical', 'MESH:C030985', (206, 212))
148346	19661933	Detection of panels of hypermethylated genes has also been shown to predict response to chemotherapy and radiation in both types of esophageal cancer, as well as to predict neoplastic progression in Barrett's esophagus.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('neoplastic progression', 'CPA', (173, 195))	('hypermethylated genes', 'Var', (23, 44))	('esophageal cancer', 'Disease', (132, 149))	("Barrett's esophagus", 'Disease', (199, 218))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (199, 218))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('predict', 'Reg', (68, 75))	('predict', 'Reg', (165, 172))
148347	19661933	Amplification of the gene encoding histone demethylase is another epigenetic phenomenon reported in esophageal cancer.	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('esophageal cancer', 'Disease', (100, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))
148350	19661933	For example, CDH1 is hypermethylated more frequently in diffuse-type than in intestinal-type GC.	('CDH1', 'Gene', '999', (13, 17))	('GC', 'Phenotype', 'HP:0012126', (93, 95))	('hypermethylated', 'Var', (21, 36))	('diffuse-type', 'Disease', (56, 68))	('CDH1', 'Gene', (13, 17))
148354	19661933	Multiple epigenetic events contribute to colorectal carcinogenesis.	('epigenetic events', 'Var', (9, 26))	('colorectal carcinogenesis', 'Disease', (41, 66))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (41, 66))	('contribute', 'Reg', (27, 37))
148356	19661933	Gene-specific CpG island hypermethylation is also prevalent in colorectal cancer (CRC), of which examples include hMLH1, p16, p14, RARB, SFRP, and WRN.	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('p16', 'Gene', '1029', (121, 124))	('hypermethylation', 'Var', (25, 41))	('p14', 'Gene', (126, 129))	('prevalent', 'Reg', (50, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('RARB', 'Gene', (131, 135))	('p14', 'Gene', '1029', (126, 129))	('colorectal cancer', 'Disease', (63, 80))	('RARB', 'Gene', '5915', (131, 135))	('p16', 'Gene', (121, 124))	('hMLH1', 'Gene', (114, 119))	('WRN', 'Gene', '7486', (147, 150))	('hMLH1', 'Gene', '4292', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('WRN', 'Gene', (147, 150))
148357	19661933	Similarly, hypermethylation has been detected in colorectal adenomas and aberrant crypt foci, suggesting that methylation is an early event in the pathogenesis of CRC.	('CRC', 'Disease', (163, 166))	('colorectal adenomas', 'Disease', (49, 68))	('hypermethylation', 'Var', (11, 27))	('colorectal adenomas', 'Disease', 'MESH:D015179', (49, 68))	('CRC', 'Phenotype', 'HP:0003003', (163, 166))
148358	19661933	In addition, methylation-induced transcriptional inactivation appears to be the driving molecular mechanism underlying the hyperplastic polyp-serrated adenoma-adenocarcinoma sequence.	('methylation-induced', 'Var', (13, 32))	('transcriptional', 'MPA', (33, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('adenoma-adenocarcinoma', 'Disease', 'MESH:D000236', (151, 173))	('hyperplastic polyp-serrated', 'Phenotype', 'HP:0032222', (123, 150))	('adenoma-adenocarcinoma', 'Disease', (151, 173))
148360	19661933	CIMP+ cancers exhibit hypermethylation of multiple genes, as well as microsatellite instability.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('microsatellite instability', 'MPA', (69, 95))	('hypermethylation', 'Var', (22, 38))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('CIMP+', 'Chemical', '-', (0, 5))
148363	19661933	Some examples of genes silenced by hypermethylation in HCC are SOCS1, RASSF1A, GSTP1, and p16.	('hypermethylation', 'Var', (35, 51))	('p16', 'Gene', '1029', (90, 93))	('SOCS1', 'Gene', (63, 68))	('GSTP1', 'Gene', (79, 84))	('RASSF1A', 'Gene', (70, 77))	('HCC', 'Gene', (55, 58))	('RASSF1A', 'Gene', '11186', (70, 77))	('p16', 'Gene', (90, 93))	('GSTP1', 'Gene', '2950', (79, 84))	('SOCS1', 'Gene', '8651', (63, 68))	('HCC', 'Phenotype', 'HP:0001402', (55, 58))
148364	19661933	Hypermethylation of these and other genes has also been seen in preneoplastic cirrhosis and dysplastic nodules.	('dysplastic nodules', 'Disease', (92, 110))	('cirrhosis', 'Phenotype', 'HP:0001394', (78, 87))	('Hypermethylation', 'Var', (0, 16))	('seen', 'Reg', (56, 60))	('preneoplastic cirrhosis', 'Disease', (64, 87))	('dysplastic nodules', 'Disease', 'MESH:D004416', (92, 110))	('preneoplastic cirrhosis', 'Disease', 'MESH:D005355', (64, 87))
148366	19661933	In addition, relative to HCCs in patients with nonviral hepatitis, HCCs in patients with viral hepatitis manifest a unique set of genes inactivated by hypermethylation.	('patients', 'Species', '9606', (33, 41))	('HCCs', 'Gene', '3052', (67, 71))	('viral hepatitis', 'Disease', 'MESH:D006525', (89, 104))	('hepatitis', 'Phenotype', 'HP:0012115', (56, 65))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('viral hepatitis', 'Phenotype', 'HP:0006562', (50, 65))	('HCCs', 'Gene', (25, 29))	('patients', 'Species', '9606', (75, 83))	('viral hepatitis', 'Phenotype', 'HP:0006562', (89, 104))	('viral hepatitis', 'Disease', (50, 65))	('HCCs', 'Gene', '3052', (25, 29))	('hepatitis', 'Phenotype', 'HP:0012115', (95, 104))	('viral hepatitis', 'Disease', (89, 104))	('HCC', 'Phenotype', 'HP:0001402', (25, 28))	('inactivated', 'NegReg', (136, 147))	('viral hepatitis', 'Disease', 'MESH:D006525', (50, 65))	('hypermethylation', 'Var', (151, 167))	('HCCs', 'Gene', (67, 71))
148367	19661933	The hypermethylation and subsequent inactivation of several genes is associated with cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (85, 103))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (85, 103))	('associated', 'Reg', (69, 79))	('inactivation', 'NegReg', (36, 48))	('cholangiocarcinoma', 'Disease', (85, 103))	('hypermethylation', 'Var', (4, 20))
148368	19661933	Genes found to be hypermethylated include inhibitors of the cell cycle as well as other tumor suppressor genes (p16, p14, 14-3-3 sigma, RASSF1A), genes involved in adhesion and metastasis (CDH1), and DNA repair genes (MLH1, GSTP1).	('MLH1', 'Gene', '4292', (218, 222))	('cell', 'CPA', (60, 64))	('CDH1', 'Gene', (189, 193))	('p16', 'Gene', (112, 115))	('MLH1', 'Gene', (218, 222))	('RASSF1A', 'Gene', '11186', (136, 143))	('CDH1', 'Gene', '999', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('p14', 'Gene', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('p16', 'Gene', '1029', (112, 115))	('GSTP1', 'Gene', (224, 229))	('tumor', 'Disease', (88, 93))	('p14', 'Gene', '1029', (117, 120))	('RASSF1A', 'Gene', (136, 143))	('GSTP1', 'Gene', '2950', (224, 229))	('hypermethylated', 'Var', (18, 33))
148369	19661933	Whether or not these epigenetic events can be used to aid in the diagnosis of cholangiocarcinoma remains to be elucidated.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('aid', 'Reg', (54, 57))	('epigenetic', 'Var', (21, 31))	('cholangiocarcinoma', 'Disease', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
148370	19661933	The pathogenesis of pancreatic ductal adenocarcinoma involves hypermethylation of multiple genes: CDKN1A, CDKN1C, CCND2, RARB, RPRM, and SPARC (cell cycle regulation); BNIP3 and WWOX (apoptosis); MLH1 (DNA mismatch repair); and TFPI2, SOCS1, DUSP6, HHIP, RUNX3, MDFI, FOXE1, SFRP4, and SFRP5 (cell signaling and transcriptional regulation).	('RUNX3', 'Gene', (255, 260))	('MLH1', 'Gene', (196, 200))	('DUSP6', 'Gene', '1848', (242, 247))	('HHIP', 'Gene', (249, 253))	('SOCS1', 'Gene', (235, 240))	('pancreatic ductal adenocarcinoma', 'Disease', (20, 52))	('SFRP5', 'Gene', '6425', (286, 291))	('CCND2', 'Gene', (114, 119))	('SFRP4', 'Gene', '6424', (275, 280))	('SFRP5', 'Gene', (286, 291))	('HHIP', 'Gene', '64399', (249, 253))	('MLH1', 'Gene', '4292', (196, 200))	('CDKN1A', 'Gene', (98, 104))	('DUSP6', 'Gene', (242, 247))	('SPARC', 'Gene', (137, 142))	('CCND2', 'Gene', '894', (114, 119))	('RPRM', 'Gene', '56475', (127, 131))	('CDKN1A', 'Gene', '1026', (98, 104))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (20, 52))	('WWOX', 'Gene', '51741', (178, 182))	('MDFI', 'Gene', (262, 266))	('CDKN1C', 'Gene', (106, 112))	('TFPI2', 'Gene', '7980', (228, 233))	('hypermethylation', 'Var', (62, 78))	('SPARC', 'Gene', '6678', (137, 142))	('RARB', 'Gene', (121, 125))	('SFRP4', 'Gene', (275, 280))	('RUNX3', 'Gene', '864', (255, 260))	('SOCS1', 'Gene', '8651', (235, 240))	('MDFI', 'Gene', '4188', (262, 266))	('BNIP3', 'Gene', (168, 173))	('RARB', 'Gene', '5915', (121, 125))	('RPRM', 'Gene', (127, 131))	('FOXE1', 'Gene', (268, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('FOXE1', 'Gene', '2304', (268, 273))	('BNIP3', 'Gene', '664', (168, 173))	('WWOX', 'Gene', (178, 182))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (20, 52))	('TFPI2', 'Gene', (228, 233))	('CDKN1C', 'Gene', '1028', (106, 112))
148371	19661933	Aberrant hypermethylation of SFRP1, RPRM, and LHX1 has been described in pancreatic cancer precursor lesions, known as PanINs (pancreatic intraepithelial neoplasias), of varying degrees, suggesting that aberrant CpG island methylation is an early event in this disease.	('intraepithelial neoplasias', 'Phenotype', 'HP:0032187', (138, 164))	('described', 'Reg', (60, 69))	('pancreatic cancer', 'Disease', (73, 90))	('RPRM', 'Gene', (36, 40))	('LHX1', 'Gene', (46, 50))	('pancreatic intraepithelial neoplasias', 'Disease', 'MESH:D018290', (127, 164))	('LHX1', 'Gene', '3975', (46, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('RPRM', 'Gene', '56475', (36, 40))	('pancreatic intraepithelial neoplasias', 'Disease', (127, 164))	('SFRP1', 'Gene', '6422', (29, 34))	('hypermethylation', 'Var', (9, 25))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('PanINs', 'Disease', (119, 125))	('SFRP1', 'Gene', (29, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('neoplasias', 'Phenotype', 'HP:0002664', (154, 164))
148372	19661933	Hypermethylation of several cancer-related genes in pancreatic juice obtained from cancer patients offers the potential for a new diagnostic modality.	('pancreatic', 'Disease', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('pancreatic', 'Disease', 'MESH:D010195', (52, 62))	('cancer', 'Disease', (28, 34))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Disease', (83, 89))
148387	33034026	Common genomic alterations included single nucleotide variants, copy number alterations and alterations in multiple signaling pathways.	('rat', 'Species', '10116', (80, 83))	('multiple signaling pathways', 'Pathway', (107, 134))	('rat', 'Species', '10116', (19, 22))	('alterations', 'Reg', (92, 103))	('single nucleotide variants', 'Var', (36, 62))	('rat', 'Species', '10116', (96, 99))	('copy number alterations', 'Var', (64, 87))
148394	33034026	In the normal esophagus of rodents and humans, NOTCH1, NOTCH2, and NOTCH3 are highly expressed whereas NOTCH4 is expressed at a minimal level.	('NOTCH3', 'Var', (67, 73))	('NOTCH4', 'Gene', '4855', (103, 109))	('humans', 'Species', '9606', (39, 45))	('NOTCH2', 'Gene', (55, 61))	('NOTCH1', 'Var', (47, 53))	('NOTCH2', 'Gene', '4853', (55, 61))	('NOTCH4', 'Gene', (103, 109))
148396	33034026	Although NOTCH1 is the major regulator of squamous differentiation among four NOTCH receptors, even in triple knockout mice (Notch1, Notch2, Notch3) the epidermis still formed almost normally except for the phenotypes of squamous hyperplasia and deficient barrier function.	('Notch1', 'Var', (125, 131))	('mice', 'Species', '10090', (119, 123))	('Notch2', 'Gene', (133, 139))	('squamous hyperplasia', 'Disease', 'MESH:D006965', (221, 241))	('barrier function', 'CPA', (256, 272))	('Notch3', 'Gene', '18131', (141, 147))	('squamous hyperplasia', 'Disease', (221, 241))	('Notch2', 'Gene', '18129', (133, 139))	('squamous hyperplasia', 'Phenotype', 'HP:0002860', (221, 241))	('Notch3', 'Gene', (141, 147))
148402	33034026	It is surprising that NOTCH1, NOTCH2, and NOTCH3 mutations occurred much more often in physiologically normal human esophageal epithelia (66.2% samples) than in ESCC (15% samples), and distribution pattern of the mutation sites was similar in normal and ESCC samples.	('SCC', 'Gene', (255, 258))	('mutations', 'Var', (49, 58))	('NOTCH2', 'Gene', '4853', (30, 36))	('NOTCH1', 'Gene', (22, 28))	('SCC', 'Gene', '6317', (255, 258))	('NOTCH3', 'Gene', (42, 48))	('SCC', 'Phenotype', 'HP:0002860', (255, 258))	('human', 'Species', '9606', (110, 115))	('SCC', 'Gene', (162, 165))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (116, 136))	('NOTCH2', 'Gene', (30, 36))	('age', 'Gene', (121, 124))	('SCC', 'Gene', '6317', (162, 165))	('age', 'Gene', '5973', (121, 124))
148403	33034026	Human subjects with ESCC risk factors (alcohol drinking, tobacco smoking, aging) were more likely to carry NOTCH mutations than those without these risk factors.	('SCC', 'Gene', (21, 24))	('Human', 'Species', '9606', (0, 5))	('NOTCH mutations', 'Var', (107, 122))	('alcohol', 'Chemical', 'MESH:D000438', (39, 46))	('tobacco', 'Species', '4097', (57, 64))	('alcohol drinking', 'Phenotype', 'HP:0030955', (39, 55))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('SCC', 'Gene', '6317', (21, 24))
148404	33034026	These data suggest that NOTCH mutations are not sufficient to drive carcinogenesis, and some other mutations are needed.	('carcinogenesis', 'Disease', (68, 82))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('mutations', 'Var', (30, 39))
148405	33034026	NOTCH mutations can be either driver or passenger mutations in human ESCC.	('human', 'Species', '9606', (63, 68))	('SCC', 'Gene', (70, 73))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))	('NOTCH mutations', 'Var', (0, 15))	('SCC', 'Gene', '6317', (70, 73))
148406	33034026	Why normal esophageal epithelial cells are susceptible to NOTCH mutations?	('age', 'Gene', '5973', (16, 19))	('age', 'Gene', (16, 19))	('NOTCH mutations', 'Var', (58, 73))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (11, 31))
148415	33034026	Moreover, inhibition of the NOTCH pathway favored goblet cell differentiation, which is diagnostic of human BE.	('BE', 'Phenotype', 'HP:0100580', (108, 110))	('favored', 'PosReg', (42, 49))	('NOTCH pathway', 'Pathway', (28, 41))	('goblet cell differentiation', 'CPA', (50, 77))	('inhibition', 'Var', (10, 20))	('human', 'Species', '9606', (102, 107))
148426	33034026	Based on the original data from two studies of 227 cases of human ESCC, NOTCH1, NOTCH2, and NOTCH3 mutations took place in 8%, 3% and 1.9% of human ESCC, respectively.	('SCC', 'Gene', (149, 152))	('NOTCH2', 'Gene', (80, 86))	('human', 'Species', '9606', (142, 147))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('SCC', 'Gene', (67, 70))	('mutations', 'Var', (99, 108))	('SCC', 'Gene', '6317', (149, 152))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('NOTCH2', 'Gene', '4853', (80, 86))	('SCC', 'Gene', '6317', (67, 70))	('NOTCH1', 'Gene', (72, 78))	('human', 'Species', '9606', (60, 65))	('NOTCH3', 'Gene', (92, 98))
148427	33034026	RBPJ (a key repressor of canonical NOTCH pathway) and FBXW7 (the substrate-recognition subunit of an SCF-type ubiquitin ligase complex targeting NOTCH1) were also frequently mutated.	('RBPJ', 'Gene', '3516', (0, 4))	('rat', 'Species', '10116', (70, 73))	('FBXW7', 'Gene', (54, 59))	('mutated', 'Var', (174, 181))	('FBXW7', 'Gene', '55294', (54, 59))	('RBPJ', 'Gene', (0, 4))
148428	33034026	It was interesting that NOTCH1 mutation was mutually exclusive with PIK3CA mutation.	('PIK3CA', 'Gene', '5290', (68, 74))	('mutation', 'Var', (31, 39))	('PIK3CA', 'Gene', (68, 74))	('NOTCH1', 'Gene', (24, 30))
148429	33034026	NOTCH1 mutation was associated with well-differentiated, early-stage malignancy, and less metastasis to regional lymph nodes.	('malignancy', 'Disease', 'MESH:D009369', (69, 79))	('malignancy', 'Disease', (69, 79))	('well-differentiated', 'CPA', (36, 55))	('less metastasis to regional lymph nodes', 'CPA', (85, 124))	('age', 'Gene', (65, 68))	('mutation', 'Var', (7, 15))	('NOTCH1', 'Gene', (0, 6))	('age', 'Gene', '5973', (65, 68))
148431	33034026	In contrast, patients with PIK3CA mutations had better response to chemotherapy and longer survival time than those without.	('survival', 'CPA', (91, 99))	('PIK3CA', 'Gene', '5290', (27, 33))	('patients', 'Species', '9606', (13, 21))	('better', 'PosReg', (48, 54))	('PIK3CA', 'Gene', (27, 33))	('response', 'MPA', (55, 63))	('mutations', 'Var', (34, 43))
148434	33034026	Exposure to an oro-esophageal carcinogen, 4-nitroquinoline 1-oxide (4NQO), caused loss of NOTCH1 expression in the basal cells of normal esophageal squamous epithelium, as well as Notch1 mutations.	('age', 'Gene', '5973', (142, 145))	('4NQO', 'Chemical', 'MESH:D015112', (68, 72))	('Notch1', 'Gene', (180, 186))	('mutations', 'Var', (187, 196))	('age', 'Gene', (24, 27))	('age', 'Gene', (142, 145))	('loss', 'NegReg', (82, 86))	('4-nitroquinoline 1-oxide', 'Chemical', 'MESH:D015112', (42, 66))	('NOTCH1', 'Gene', (90, 96))	('age', 'Gene', '5973', (24, 27))	('expression', 'MPA', (97, 107))
148435	33034026	Loss of Notch1 in the squamous epithelial cells caused spontaneous SCC in the skin, but not the esophagus.	('caused', 'Reg', (48, 54))	('Notch1', 'Gene', (8, 14))	('SCC', 'Gene', '6317', (67, 70))	('SCC', 'Gene', (67, 70))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('Loss', 'Var', (0, 4))
148436	33034026	However, loss of Notch1 promoted 4NQO-induced oro-esophageal SCC.	('Notch1', 'Gene', (17, 23))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('SCC', 'Gene', '6317', (61, 64))	('loss', 'Var', (9, 13))	('age', 'Gene', (55, 58))	('promoted', 'PosReg', (24, 32))	('4NQO', 'Chemical', 'MESH:D015112', (33, 37))	('age', 'Gene', '5973', (55, 58))	('SCC', 'Gene', (61, 64))
148437	33034026	Similarly, NOTCH inhibition in mouse esophagus increased the number and size of tumors following exposure to an esophageal carcinogen, diethylnitrosamine.	('NOTCH inhibition', 'Var', (11, 27))	('age', 'Gene', '5973', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mouse', 'Species', '10090', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('increased', 'PosReg', (47, 56))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (135, 153))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('age', 'Gene', (117, 120))
148438	33034026	Using the lineage tracing technique in mice carrying a conditional dominant-negative mutant of Maml1 (a transcriptional coactivator for NOTCH), Alcolea et al found that NOTCH inhibition prevented differentiation of mutant progenitor cells and promoted differentiation of neighboring wild-type progenitor cells in mouse esophagus.	('promoted', 'PosReg', (243, 251))	('mouse', 'Species', '10090', (313, 318))	('mice', 'Species', '10090', (39, 43))	('age', 'Gene', (14, 17))	('inhibition prevented', 'NegReg', (175, 195))	('differentiation', 'CPA', (252, 267))	('age', 'Gene', '5973', (14, 17))	('mutant', 'Var', (215, 221))	('Maml1', 'Gene', (95, 100))	('mutant', 'Var', (85, 91))	('differentiation', 'CPA', (196, 211))	('NOTCH', 'Var', (169, 174))
148439	33034026	Such combined effects led to clonal expansion with mutant cells eventually replacing the entire epithelium, supporting the idea that NOTCH mutation promotes field change in the human esophageal epithelium.	('mutation', 'Var', (139, 147))	('age', 'Gene', (188, 191))	('field', 'MPA', (157, 162))	('mutant', 'Var', (51, 57))	('age', 'Gene', '5973', (188, 191))	('promotes', 'PosReg', (148, 156))	('human', 'Species', '9606', (177, 182))
148447	33034026	Both deficiency and activation of Notch1 promoted oral squamous cell carcinogenesis in a genetic model driven by HPV E6/E7 and KrasG12D.	('E6/E7', 'Var', (117, 122))	('promoted', 'PosReg', (41, 49))	('oral squamous cell carcinogenesis', 'Disease', 'MESH:D002294', (50, 83))	('oral squamous cell carcinogenesis', 'Disease', (50, 83))	('activation', 'PosReg', (20, 30))	('deficiency', 'Disease', (5, 15))	('Notch1', 'Gene', (34, 40))	('deficiency', 'Disease', 'MESH:D007153', (5, 15))
148448	33034026	Inactivation of the NOTCH pathway by a dominant-negative form of Maml1 promoted HNSCC induced by 4NQO, especially in the presence of p53 mutation or HPV16 E6/E7 oncoproteins.	('Maml1', 'Gene', (65, 70))	('NOTCH pathway', 'Pathway', (20, 33))	('HPV16', 'Gene', (149, 154))	('HPV16', 'Species', '333760', (149, 154))	('SCC', 'Gene', '6317', (82, 85))	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('mutation', 'Var', (137, 145))	('promoted', 'PosReg', (71, 79))	('p53', 'Gene', '7157', (133, 136))	('E6/E7', 'Var', (155, 160))	('4NQO', 'Chemical', 'MESH:D015112', (97, 101))	('p53', 'Gene', (133, 136))	('SCC', 'Gene', (82, 85))	('Inactivation', 'Var', (0, 12))
148532	32694610	Despite this variability, overall sensitivity and specificity remained high regardless of clinical covariate status; the PanSeer assay was able to utilize methylation signals to detect cancer up to four years before conventional diagnosis regardless of clinical covariates.	('detect', 'Reg', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('methylation', 'Var', (155, 166))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
148535	32694610	These genomic regions either showed hypermethylation in cancer tissue and hypomethylation in cancer plasma, or vise versa.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('hypermethylation', 'Var', (36, 52))	('hypomethylation', 'Var', (74, 89))	('showed', 'Reg', (29, 35))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
148590	32694610	Extracted DNA from 160 cancer and 40 healthy tissue samples was purchased from Biochain (D8235086-1, D8235090-1, D8235152-1, D8235248-1).	('D8235090-1', 'Var', (101, 111))	('D8235086-1', 'Var', (89, 99))	('cancer', 'Disease', (23, 29))	('D8235248-1', 'Var', (125, 135))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('D8235152-1', 'Var', (113, 123))
148611	32694610	A cutoff of 0.583 was chosen based on the final training set scores to achieve a specificity as close to 95% as possible; samples with scores above this value were considered cancerous, while samples with scores below this value were considered healthy.	('cancerous', 'Disease', 'MESH:D009369', (175, 184))	('scores', 'Var', (135, 141))	('cancerous', 'Disease', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
148631	31819487	PDHA1 Gene Knockout In Human Esophageal Squamous Cancer Cells Resulted In Greater Warburg Effect And Aggressive Features In Vitro And In Vivo One of the remarkable metabolic characteristics of cancer cells is that they prefer glycolysis rather than oxidative phosphorylation (OXPHOS).	('Aggressive Features', 'Disease', (101, 120))	('Knockout', 'Var', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('prefer', 'PosReg', (219, 225))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PDHA1', 'Gene', '5160', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('glycolysis', 'MPA', (226, 236))	('PDHA1', 'Gene', (0, 5))	('oxidative', 'MPA', (249, 258))	('Squamous Cancer', 'Phenotype', 'HP:0002860', (40, 55))	('Warburg Effect', 'CPA', (82, 96))	('Aggressive Features', 'Disease', 'MESH:D001523', (101, 120))	('Greater', 'PosReg', (74, 81))	('Human', 'Species', '9606', (23, 28))
148636	31819487	In the PDHA1 KO cells, the glycolysis and the consumption of glucose and glutamine were significantly enhanced, while the OXPHOS was significantly suppressed, implying Warburg effect in the PDHA1 KO cells.	('enhanced', 'PosReg', (102, 110))	('PDHA1 KO', 'Var', (7, 15))	('suppressed', 'NegReg', (147, 157))	('OXPHOS', 'MPA', (122, 128))	('glutamine', 'Chemical', 'MESH:C578860', (73, 82))	('glucose', 'Chemical', 'MESH:D005947', (61, 68))	('glycolysis', 'MPA', (27, 37))
148638	31819487	Inhibition of PDHA1 gene expression in human ESCC leads to metabolic reprogramming of Warburg effect and increased malignancies.	('human', 'Species', '9606', (39, 44))	('metabolic reprogramming', 'CPA', (59, 82))	('Inhibition', 'Var', (0, 10))	('increased', 'PosReg', (105, 114))	('Warburg effect', 'Disease', (86, 100))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('malignancies', 'Disease', (115, 127))	('PDHA1', 'Gene', (14, 19))
148643	31819487	Pyruvate dehydrogenase complex (PDHc) plays an important role in oxidative phosphorylation (OXPHOS) by converting pyruvate into acetyl coenzyme A. Inhibition of PDHc activity promotes malignant phenotype and growth of tumor cells, and its low expression level is related to poor prognosis.	('PDHc', 'Gene', (161, 165))	('Pyruvate', 'Chemical', 'MESH:D011773', (0, 8))	('expression', 'MPA', (243, 253))	('promotes', 'PosReg', (175, 183))	('activity', 'MPA', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('acetyl', 'Chemical', 'MESH:C011632', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('Inhibition', 'Var', (147, 157))	('pyruvate', 'Chemical', 'MESH:D011773', (114, 122))	('tumor', 'Disease', (218, 223))	('malignant phenotype', 'CPA', (184, 203))
148646	31819487	Another study of us suggested that the PDHA1 knockout (KO) in human prostate cancer LnCap cells leads to "Warburg effect", resistance to chemotherapy, enhanced migration ability and increased expression of stem cell makers.	('increased', 'PosReg', (182, 191))	('resistance', 'CPA', (123, 133))	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('enhanced', 'PosReg', (151, 159))	('PDHA1', 'Gene', (39, 44))	('human', 'Species', '9606', (62, 67))	('expression', 'MPA', (192, 202))	('prostate cancer', 'Disease', (68, 83))	('knockout', 'Var', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('migration ability', 'CPA', (160, 177))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))
148649	31819487	Cells were cultured in RPMI 1640 (21875-034, Gibco, UK) supplemented with 10% FBS (16000-044, Gibco, USA), 100 U/mL of penicillin and 100 microg/mL streptomycin (15140-122, Gibco, USA) at 37 C and 5% CO2.	('16000-044', 'Var', (83, 92))	('FBS', 'Gene', (78, 81))	('streptomycin', 'Chemical', 'MESH:D013307', (148, 160))	('FBS', 'Gene', '26269', (78, 81))	('penicillin', 'Chemical', 'MESH:D010406', (119, 129))	('21875-034', 'Var', (34, 43))	('15140-122', 'Var', (162, 171))	('CO2', 'Chemical', 'MESH:D002245', (200, 203))
148701	31819487	Compared with the parental cells, the PDHA1 KO cells held increased percentage of S phase (p<0.001) and decreased percentage of G1 and G2/M phase (p<0.001) (Figure 3C and D).	('S phase', 'CPA', (82, 89))	('increased', 'PosReg', (58, 67))	('G1 and G2', 'Gene', '5544', (128, 137))	('decreased', 'NegReg', (104, 113))	('PDHA1', 'Var', (38, 43))
148711	31819487	Compared with the control group, the average tumor weight was heavier (Figure 6C), and the average tumor volume was significantly bigger in the PDHA1 KO group (P<0.01, both in day 23 and day 25) (Figure 6D), indicating PDHA1 KO cells had growth advantage in nude mice.	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('heavier', 'PosReg', (62, 69))	('growth advantage', 'CPA', (238, 254))	('PDHA1 KO', 'Var', (219, 227))	('tumor', 'Disease', (45, 50))	('bigger', 'PosReg', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('nude mice', 'Species', '10090', (258, 267))	('PDHA1', 'Var', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
148712	31819487	However, despite the heavier tumor weight, the body weight of the PDHA1 KO mice was lighter, which meant that these mice were in worse physical condition (Figure 6E).	('heavier', 'PosReg', (21, 28))	('mice', 'Species', '10090', (116, 120))	('mice', 'Species', '10090', (75, 79))	('body weight', 'CPA', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('PDHA1 KO', 'Var', (66, 74))	('tumor', 'Disease', (29, 34))	('lighter', 'NegReg', (84, 91))
148718	31819487	Compared with the control cells, the protein expression of P53 and phosphorylated P53 (S15), angiopoietin-2 (ANG2) and vascular endothelial growth factor A (VEGFA) were significantly increased in the PDHA1 KO cells (Figure 7A and B).	('ANG2', 'Gene', (109, 113))	('P53', 'Gene', (82, 85))	('VEGFA', 'Gene', '7422', (157, 162))	('increased', 'PosReg', (183, 192))	('ANG2', 'Gene', '285', (109, 113))	('P53', 'Gene', '7157', (82, 85))	('vascular endothelial growth factor A', 'Gene', '7422', (119, 155))	('angiopoietin-2', 'Gene', '285', (93, 107))	('P53', 'Gene', (59, 62))	('angiopoietin-2', 'Gene', (93, 107))	('P53', 'Gene', '7157', (59, 62))	('PDHA1 KO', 'Var', (200, 208))	('VEGFA', 'Gene', (157, 162))	('protein expression', 'MPA', (37, 55))	('vascular endothelial growth factor A', 'Gene', (119, 155))
148723	31819487	Inhibition of activated metabolic activity can inhibit the proliferation of tumors.	('activated metabolic activity', 'CPA', (14, 42))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('inhibit', 'NegReg', (47, 54))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('Inhibition', 'Var', (0, 10))
148730	31819487	Our previous studies have found that inhibition of PDHA1 expression promoted the stemness of prostate cancer cells and low level of PDHA1 protein expression was associated with poor prognosis in esophageal cancer clinical samples.	('esophageal cancer', 'Disease', (195, 212))	('inhibition', 'Var', (37, 47))	('PDHA1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('associated', 'Reg', (161, 171))	('promoted', 'PosReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('PDHA1', 'Gene', (132, 137))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))	('stemness of prostate cancer', 'Disease', (81, 108))	('clinical samples', 'Species', '191496', (213, 229))	('stemness of prostate cancer', 'Disease', 'MESH:D011471', (81, 108))
148736	31819487	In our experiments, we found that the KYSE450 PDHA1 KO cells showed resistance to both docetaxel and paclitaxel, at the same time the expression of ABCG2 was significantly increased, implying the potential role of increased ABCG2 expression in the chemoresistance of the PDHA1 KO cells.	('chemoresistance', 'CPA', (248, 263))	('PDHA1', 'Gene', (46, 51))	('ABCG2', 'Gene', (148, 153))	('resistance', 'CPA', (68, 78))	('ABCG2', 'Gene', (224, 229))	('expression', 'MPA', (134, 144))	('increased', 'PosReg', (172, 181))	('KYSE450', 'Var', (38, 45))	('ABCG2', 'Gene', '9429', (148, 153))	('increased', 'PosReg', (214, 223))	('ABCG2', 'Gene', '9429', (224, 229))	('paclitaxel', 'Chemical', 'MESH:D017239', (101, 111))	('docetaxel', 'Chemical', 'MESH:C067311', (87, 96))
148746	31819487	Studies have shown that phosphorylation of Ser15 can increase the stability of p53 and enhance its transcriptional activity.	('transcriptional activity', 'MPA', (99, 123))	('stability', 'MPA', (66, 75))	('Ser15', 'Gene', (43, 48))	('Ser15', 'Chemical', 'MESH:C530429', (43, 48))	('enhance', 'PosReg', (87, 94))	('increase', 'PosReg', (53, 61))	('p53', 'Protein', (79, 82))	('phosphorylation', 'Var', (24, 39))
148754	31819487	CRISPR/cas9 technology was applied in our study to successfully knock out the PDHA1 gene in human esophageal squamous cancer cell line KYSE450, and a KYSE450 PDHA1 KO cell line was established.	('squamous cancer', 'Phenotype', 'HP:0002860', (109, 124))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (98, 124))	('knock', 'Var', (64, 69))	('PDHA1', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal squamous cancer', 'Disease', (98, 124))	('human', 'Species', '9606', (92, 97))
148758	29137437	DNA hypermethyation and silencing of PITX1 correlated with advanced stage and poor postoperative prognosis of esophageal squamous cell carcinoma Esophageal squamous cell carcinoma (ESCC) is associated with the accumulation of genetic and epigenetic changes in the background mucosa.	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (145, 179))	('PITX1', 'Gene', '5307', (37, 42))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (110, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('Esophageal squamous cell carcinoma', 'Disease', (145, 179))	('PITX1', 'Gene', (37, 42))	('esophageal squamous cell carcinoma', 'Disease', (110, 144))	('epigenetic changes', 'Var', (238, 256))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('silencing', 'Var', (24, 33))
148759	29137437	Dysregulated DNA methylation is known to lead to the inactivation of tumor suppressor genes and the activation of oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('oncogenes', 'Gene', (114, 123))	('tumor', 'Disease', (69, 74))	('methylation', 'Var', (17, 28))	('lead', 'Reg', (41, 45))	('inactivation', 'MPA', (53, 65))	('Dysregulated', 'Var', (0, 12))	('DNA', 'Protein', (13, 16))	('activation', 'PosReg', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
148761	29137437	Using surgically resected tissues of 40 cases, we confirmed that the paired-like homeodomain 1 (PITX1) gene was hypermethylated in ESCC compared to that in normal tissues (P < 0.0001) by pyrosequencing.	('PITX1', 'Gene', (96, 101))	('paired-like homeodomain 1', 'Gene', (69, 94))	('hypermethylated', 'Var', (112, 127))	('paired-like homeodomain 1', 'Gene', '5307', (69, 94))	('ESCC', 'Disease', (131, 135))
148763	29137437	Hypermethylation of PITX1 was associated with tumor depth (P = 0.0011) and advanced tumor stage (P = 0.0052) and predicted poor survival in ESCC (hazard ratio, 0.1538; 95% confidence interval, 0.03159-0.7488; P = 0.0169).	('associated', 'Reg', (30, 40))	('PITX1', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Hypermethylation', 'Var', (0, 16))	('ESCC', 'Disease', (140, 144))	('poor', 'NegReg', (123, 127))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
148765	29137437	Hypermethylation of the PITX1 in ESCC correlated with tumor progression and advanced stage cancer, and may predict a poor prognosis.	('advanced', 'Disease', (76, 84))	('PITX1', 'Gene', (24, 29))	('correlated with', 'Reg', (38, 53))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (54, 59))
148768	29137437	As with many other types of cancers, exposure of the esophageal epithelial mucosa to such conditions induces genetic mutations and epigenetic changes.	('cancers', 'Disease', (28, 35))	('genetic mutations', 'Var', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('epigenetic', 'MPA', (131, 141))	('man', 'Species', '9606', (8, 11))	('induces', 'Reg', (101, 108))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
148770	29137437	CpG island hypermethylation occurs frequently in cancer cells and is associated with transcriptional repression and subsequent reduction or loss of gene function.	('hypermethylation', 'Var', (11, 27))	('CpG island', 'Protein', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('transcriptional', 'MPA', (85, 100))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('reduction', 'NegReg', (127, 136))	('loss', 'NegReg', (140, 144))	('cancer', 'Disease', (49, 55))
148771	29137437	A previous global study using bead arrays to detect promoter-DNA methylation in ESCC demonstrated that a total of 37 CpG sites were differentially methylated between esophageal squamous cell tumors and normal mucosa.	('esophageal squamous cell tumors', 'Disease', (166, 197))	('methylated', 'Var', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('esophageal squamous cell tumors', 'Disease', 'MESH:D000077277', (166, 197))	('squamous cell tumors', 'Phenotype', 'HP:0002860', (177, 197))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('differentially', 'Reg', (132, 146))
148772	29137437	The hypermethylation of some genes, such as APC, FHIT, PGP9.5, and TFLC1, is related to certain clinicopathological features of ESCC, including poor prognosis and treatment responses.	('FHIT', 'Gene', '2272', (49, 53))	('APC', 'Disease', 'MESH:D011125', (44, 47))	('APC', 'Disease', (44, 47))	('related', 'Reg', (77, 84))	('PGP9.5', 'Gene', '7345', (55, 61))	('TFLC1', 'Gene', (67, 72))	('PGP9.5', 'Gene', (55, 61))	('FHIT', 'Gene', (49, 53))	('ESCC', 'Disease', (128, 132))	('hypermethylation', 'Var', (4, 20))
148775	29137437	Herein, we found that paired-like homeodomain 1 (PITX1) was markedly suppressed by hypermethylation on the promoter in ESCC samples.	('paired-like homeodomain 1', 'Gene', (22, 47))	('hypermethylation', 'Var', (83, 99))	('PITX1', 'Gene', (49, 54))	('suppressed', 'NegReg', (69, 79))	('paired-like homeodomain 1', 'Gene', '5307', (22, 47))
148777	29137437	Finally, we demonstrated for the first time that hypermethylation of PITX1 was a poor prognostic factor for patients with ESCC.	('patients', 'Species', '9606', (108, 116))	('ESCC', 'Disease', (122, 126))	('PITX1', 'Gene', (69, 74))	('hypermethylation', 'Var', (49, 65))
148783	29137437	Endogenous mRNA expression levels were determined in four ESCC cell lines (KYSE30, KYSE140, KYSE150 and KYSE270) and compared with the levels in cells treated with 5-aza-2'-deoxycytidine (5-aza-dC), an inhibitor of DNA methyltransferase.	('5-aza-dC', 'Chemical', 'MESH:D000077209', (188, 196))	('KYSE270', 'Var', (104, 111))	('mRNA expression levels', 'MPA', (11, 33))	('KYSE150', 'Var', (92, 99))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (164, 186))	('KYSE150', 'CellLine', 'CVCL:1348', (92, 99))
148784	29137437	In all cell lines, treatment with 5-aza-dC significantly increased selected gene expression (Figure 1B).	('5-aza-dC', 'Var', (34, 42))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (34, 42))	('increased', 'PosReg', (57, 66))	('selected gene expression', 'MPA', (67, 91))
148785	29137437	These results indicate that PITX1, PRSS27, CST6, and HOPX selected from our integrative analysis are likely the targets of aberrant DNA hypermethylation, and DNA hypermethylation likely downregulated expression in ESCC.	('ESCC', 'Gene', (214, 218))	('HOPX', 'Gene', (53, 57))	('DNA hypermethylation', 'Var', (158, 178))	('CST6', 'Gene', '1474', (43, 47))	('CST6', 'Gene', (43, 47))	('PRSS27', 'Gene', (35, 41))	('HOPX', 'Gene', '84525', (53, 57))	('expression', 'MPA', (200, 210))	('downregulated', 'NegReg', (186, 199))	('PRSS27', 'Gene', '83886', (35, 41))	('hypermethylation', 'Var', (136, 152))
148787	29137437	In other words, the loss of PITX1 may be associated with cancer cell proliferation.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('loss', 'Var', (20, 24))	('associated', 'Reg', (41, 51))	('PITX1', 'Gene', (28, 33))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
148794	29137437	In agreement with the results on TERT expression, the ectopic expression of PITX1 inhibited telomerase activity in both PITX1-transfected clones (Figure 3D).	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('inhibited', 'NegReg', (82, 91))	('PITX1', 'Gene', (76, 81))	('ectopic expression', 'Var', (54, 72))	('telomerase activity', 'MPA', (92, 111))
148795	29137437	In addition, treatment of KYSE30 cells with 5-aza-dC resulted in a 0.6-fold decrease in telomerase activity (Figure 3E), concomitant with the induction of PITX1 expression (Figure 1B).	('expression', 'MPA', (161, 171))	('PITX1', 'Gene', (155, 160))	('induction', 'PosReg', (142, 151))	('telomerase activity', 'MPA', (88, 107))	('5-aza-dC', 'Var', (44, 52))	('decrease', 'NegReg', (76, 84))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (44, 52))
148798	29137437	PITX1 transfectants formed smaller tumors than mock transfectants (Figure 3H).	('PITX1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('smaller', 'NegReg', (27, 34))	('transfectants', 'Var', (6, 19))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
148806	29137437	Univariate analysis revealed no difference between the hypermethylated and methylated groups with respect to gender, tumor location, lymph node metastasis, or distant metastasis.	('distant metastasis', 'CPA', (159, 177))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('lymph node metastasis', 'CPA', (133, 154))	('hypermethylated', 'Var', (55, 70))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
148807	29137437	However, there were significant differences between patients in the hypermethylated and methylated groups with respect to age (P = 0.0388), tumor depth (P = 0.0017), and tumor stage (P = 0.0053).	('differences', 'Reg', (32, 43))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('hypermethylated', 'Var', (68, 83))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (52, 60))	('tumor', 'Disease', (140, 145))
148810	29137437	These results suggest that the DNA hypermethylation of PITX1 is associated with cancer progression and predicts poor postoperative survival in ESCC.	('associated', 'Reg', (64, 74))	('DNA', 'Var', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PITX1', 'Gene', (55, 60))	('poor', 'NegReg', (112, 116))	('ESCC', 'Disease', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
148812	29137437	Hypermethylation of PITX1 clearly correlated with advanced tumor size, advanced tumor stage, and a poor prognosis, suggesting the possibility of the methylation status of PITX1 as prognostic markers of ESCC.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('PITX1', 'Gene', (20, 25))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', (80, 85))	('ESCC', 'Disease', (202, 206))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('correlated', 'Reg', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
148818	29137437	In fact, the presence of aberrant DNA hypermethylation in noncancerous esophageal mucosa of ESCC cases was reported in association with smoking history.	('ESCC', 'Disease', (92, 96))	('noncancerous esophageal mucosa', 'Disease', (58, 88))	('aberrant', 'Var', (25, 33))	('DNA', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('noncancerous esophageal mucosa', 'Disease', 'MESH:D004941', (58, 88))
148819	29137437	Combined with our previous publications, we have now reported two new target genes of increased promoter-DNA methylation in ESCC: PITX1 and PPL.	('PPL', 'Gene', (140, 143))	('increased', 'PosReg', (86, 95))	('promoter-DNA methylation', 'Var', (96, 120))	('PPL', 'Gene', '5493', (140, 143))	('ESCC', 'Gene', (124, 128))	('PITX1', 'Gene', (130, 135))
148820	29137437	Another noteworthy observation is that DNA hypermethylation of PITX1 correlated with advanced tumor size, advanced tumor stage, and a poor postoperative prognosis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('correlated', 'Reg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('PITX1', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (94, 99))	('DNA', 'Var', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
148822	29137437	Although PITX1 methylation may correlate with total epigenetic alteration of many genes, which is associated with the phenotypes of clinically advanced tumor cells, our studies clearly demonstrate that PITX1 methylation status of the tumor could be used as a clinical marker to predict prognoses.	('epigenetic alteration', 'MPA', (52, 73))	('methylation', 'Var', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('man', 'Species', '9606', (77, 80))	('tumor', 'Disease', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('PITX1', 'Gene', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
148829	29137437	Because activation of the RAS/mitogen-activated protein kinase (MAPK) pathway contributes to the tumorigenesis and progression of ESCC and PITX1 has been identified as a negative regulator of the RAS pathway via the downregulation of RASAL1, the epigenetic silencing of PITX1 may result in the activation of the RAS/MAPK pathway, leading to the hyperproliferation of the esophageal epithelium.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('RASAL1', 'Gene', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('activation', 'PosReg', (294, 304))	('hyperproliferation', 'Disease', (345, 363))	('epigenetic silencing', 'Var', (246, 266))	('RAS/MAPK pathway', 'Pathway', (312, 328))	('downregulation', 'NegReg', (216, 230))	('PITX1', 'Gene', (270, 275))	('leading to', 'Reg', (330, 340))	('RASAL1', 'Gene', '8437', (234, 240))
148831	29137437	Thus, our results are the first to indicate that PITX1 functions as a tumor suppressor gene in ESCC, and that hypermethylation of its promoter serves as a novel biomarker for predicting prognosis in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('hypermethylation', 'Var', (110, 126))	('tumor', 'Disease', (70, 75))	('PITX1', 'Gene', (49, 54))	('ESCC', 'Disease', (95, 99))	('ESCC', 'Disease', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
148849	29137437	The TaqMan Gene expression assay IDs used in this study for the genes as follows: PITX1, Hs00267528_m1; PRSS27, Hs01029754_m1; CST6, Hs01029754_m1; HOPX, Hs04188695_m1; TERT, Hs00972656_m1; GAPDH, Hs00266705_g1.	('TERT', 'Gene', '7015', (169, 173))	('Hs00266705_g1', 'Var', (197, 210))	('HOPX', 'Gene', '84525', (148, 152))	('GAPDH', 'Gene', '2597', (190, 195))	('CST6', 'Gene', '1474', (127, 131))	('Hs01029754_m1', 'Var', (133, 146))	('PRSS27', 'Gene', (104, 110))	('Hs01029754_m1', 'Var', (112, 125))	('Hs04188695_m1', 'Var', (154, 167))	('GAPDH', 'Gene', (190, 195))	('PRSS27', 'Gene', '83886', (104, 110))	('Hs00267528_m1', 'Var', (89, 102))	('TERT', 'Gene', (169, 173))	('HOPX', 'Gene', (148, 152))	('CST6', 'Gene', (127, 131))
148866	29137437	KYSE30 and KYSE150 transfectants were seeded in 96-well plates at 1000 cells per well and cell proliferation was measured by using a MTT assay kit (Nacalai tesque, Kyoto, Japan).	('KYSE150', 'CellLine', 'CVCL:1348', (11, 18))	('KYSE150', 'Var', (11, 18))	('MTT', 'Chemical', 'MESH:C070243', (133, 136))	('cell proliferation', 'CPA', (90, 108))
148877	26910465	Overall survival (OS) was higher in patients with a HNSCC SPM compared to non-HNSCC SPM (p<0.001), with no difference in disease-specific survival(DSS).	('HNSCC SPM', 'Var', (52, 61))	('DSS', 'Chemical', '-', (147, 150))	('higher', 'PosReg', (26, 32))	('patients', 'Species', '9606', (36, 44))	('HNSCC', 'Phenotype', 'HP:0012288', (52, 57))	('OS', 'Chemical', '-', (18, 20))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('Overall survival', 'MPA', (0, 16))
148893	26910465	The study cohort was defined using International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) histology codes for squamous cell carcinoma and histologically similar cancers (8010, 8011, 8020, 8051, 8070-8076, 8078, and 8081-8084) from major and minor subsites of the upper aerodigestive tract (nasal cavity, nasopharynx, sinuses and middle/inner ear, oral cavity, oropharynx, hypopharynx, larynx, and trachea).	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('Oncology', 'Phenotype', 'HP:0002664', (80, 88))	('cancers', 'Disease', (183, 190))	('hypopharynx', 'Disease', (394, 405))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('squamous cell carcinoma', 'Disease', (132, 155))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 155))	('8010', 'Var', (192, 196))	('oral cavity', 'Disease', (369, 380))	('larynx', 'Disease', (407, 413))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('oropharynx', 'Disease', (382, 392))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
148944	26910465	Moreover, identification of these non-head and neck SPMs is of particular importance as they may portend a worse prognosis (particularly lung and esophageal tumors).	('esophageal tumors', 'Disease', (146, 163))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('non-head', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('esophageal tumors', 'Disease', 'MESH:D004938', (146, 163))	('esophageal tumors', 'Phenotype', 'HP:0100751', (146, 163))	('lung', 'Disease', (137, 141))
148969	26357670	According to the Japanese classification of esophageal cancer published by the Japan Esophageal Society, macroscopic types were as follows: 0-I, 2 lesions; 0-IIa, 50 lesions; 0-IIb, 56 lesions; 0-IIc, 7 lesions.	('0-I', 'Var', (140, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('0-IIb', 'Var', (175, 180))	('esophageal cancer', 'Disease', (44, 61))
148982	26202837	Drug resistance may be mediated by genetic changes in the tumor; therefore, the identification of gene mutations may lead to better therapeutic outcomes.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (103, 112))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('lead to', 'Reg', (117, 124))
148999	26202837	The approach uses a modified piggyBac (PB) and Sleeping Beauty (SB) transposon to generate libraries of mutagenized cells, each containing transposon insertions that randomly activate nearby gene expression.	('PB', 'Chemical', '-', (39, 41))	('transposon', 'Gene', (139, 149))	('activate', 'PosReg', (175, 183))	('insertions', 'Var', (150, 160))
149050	26202837	CDDP induces tumor death by means of platinum complexes binding to and causing cross-linking of DNA, ultimately triggering apoptosis.	('triggering', 'Reg', (112, 122))	('DNA', 'Protein', (96, 99))	('cross-linking', 'MPA', (79, 92))	('platinum', 'Chemical', 'MESH:D010984', (37, 45))	('tumor death', 'Disease', (13, 24))	('CDDP', 'Var', (0, 4))	('binding', 'Interaction', (56, 63))	('tumor death', 'Disease', 'MESH:D003643', (13, 24))	('CDDP', 'Chemical', '-', (0, 4))	('induces', 'Reg', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
149061	26202837	Recent studies have implicated the de-regulation of JAK2 kinase activity in a number of myeloproliferative diseases which is due to chromosomal translocations in hematopoietic tumors and mutations within the pseudokinase domain.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('myeloproliferative diseases', 'Disease', (88, 115))	('mutations', 'Var', (187, 196))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (162, 182))	('activity', 'MPA', (64, 72))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('JAK2 kinase', 'Enzyme', (52, 63))	('de-regulation', 'NegReg', (35, 48))	('hematopoietic tumors', 'Disease', (162, 182))
149062	26202837	In particular, a somatic mutation in the JAK2 protein, V617F, was identified in myeloproliferative neoplasms, including 95% of patients with polycythemia vera and ~50% of patients with essential thrombocythemia and primary myelofibrosis.	('polycythemia', 'Phenotype', 'HP:0001901', (141, 153))	('V617F', 'SUBSTITUTION', 'None', (55, 60))	('identified', 'Reg', (66, 76))	('essential thrombocythemia', 'Disease', (185, 210))	('myeloproliferative neoplasms', 'Disease', (80, 108))	('thrombocythemia', 'Phenotype', 'HP:0001894', (195, 210))	('polycythemia vera', 'Disease', 'MESH:D011087', (141, 158))	('neoplasms', 'Phenotype', 'HP:0002664', (99, 108))	('patients', 'Species', '9606', (171, 179))	('V617F', 'Var', (55, 60))	('patients', 'Species', '9606', (127, 135))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (80, 108))	('myelofibrosis', 'Phenotype', 'HP:0011974', (223, 236))	('polycythemia vera', 'Disease', (141, 158))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (80, 108))	('myelofibrosis', 'Disease', 'MESH:D055728', (223, 236))	('essential thrombocythemia', 'Disease', 'MESH:D013920', (185, 210))	('myelofibrosis', 'Disease', (223, 236))
149063	26202837	Moreover, it has been reported that mutant JAK2 enhanced the resistance to CDDP-induced DNA damage and also suppressed apoptosis.	('JAK2', 'Gene', (43, 47))	('enhanced', 'PosReg', (48, 56))	('apoptosis', 'CPA', (119, 128))	('suppressed', 'NegReg', (108, 118))	('mutant', 'Var', (36, 42))	('CDDP', 'Chemical', '-', (75, 79))	('resistance to CDDP-induced DNA damage', 'MPA', (61, 98))
149277	23031450	Moreover, the survival of patients with distant metastasis was significantly worse than that of patients with locoregional recurrence.	('distant', 'Var', (40, 47))	('patients', 'Species', '9606', (26, 34))	('survival', 'CPA', (14, 22))	('patients', 'Species', '9606', (96, 104))	('worse', 'NegReg', (77, 82))
149298	22185224	The most cancer-protective effect was observed for the combination of high folate and vitamin E intakes (OR: 0.02, 95%CI: 0.00-0.87; p < 0.001).	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('high folate and vitamin E intakes', 'Phenotype', 'HP:0032164', (70, 103))	('vitamin E', 'Chemical', 'MESH:D014810', (86, 95))	('high', 'Var', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('folate', 'Chemical', 'MESH:D005492', (75, 81))
149332	22185224	The fully-adjusted model, on the other hand, included the following covariates: age (years), sex (male/female), GERD symptoms (yes/no), BMI (<=24.9, >24.9 kg/m2kg/m2), smoking status (never/former/current), smoking intensity and duration (<20, >=20 pack-years), physical activity (MET) (light/heavy), and education level (illiterate, literate).	('>24.9', 'Var', (149, 154))	('GERD', 'Disease', (112, 116))	('GERD', 'Disease', 'MESH:D005764', (112, 116))	('<=24.9', 'Var', (141, 147))
149371	22185224	Folate is an important cofactor in DNA metabolism and its deficiency has been linked to higher risk of epithelial tumors.	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('deficiency', 'Var', (58, 68))	('epithelial tumors', 'Disease', (103, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('linked', 'Reg', (78, 84))	('epithelial tumors', 'Disease', 'MESH:D002277', (103, 120))
149419	22185224	Additionally, availability of B-vitamins is influenced by diet, supplement use, alcohol consumption and generic polymorphism and B-vitamins are all involved in one-carbon metabolism which requires vitamin B2, B6, B9 and B12.	('B6', 'Chemical', '-', (209, 211))	('carbon', 'Chemical', 'MESH:D002244', (164, 170))	('vitamin B2', 'Chemical', 'MESH:D012256', (197, 207))	('men', 'Species', '9606', (70, 73))	('influenced', 'Reg', (44, 54))	('B12', 'Gene', (220, 223))	('involved', 'Reg', (148, 156))	('polymorphism', 'Var', (112, 124))	('B12', 'Gene', '4709', (220, 223))	('alcohol', 'Chemical', 'MESH:D000438', (80, 87))
149491	20078887	In contrast, HPV positivity was associated with alcohol use (OR = 1.69, 95% CI = 1.01-2.83).	('alcohol', 'Chemical', 'MESH:D000438', (48, 55))	('positivity', 'Var', (17, 27))	('alcohol use', 'Phenotype', 'HP:0030955', (48, 59))	('associated', 'Reg', (32, 42))	('alcohol use', 'Disease', (48, 59))	('HPV', 'Gene', (13, 16))	('HPV', 'Species', '10566', (13, 16))
149509	20078887	It is of interest to note that HPV57 presented as the second most common genotype and accounted for 22.9% of L1 positive esophageal cancer tissues from all four areas under investigation.	('HPV57', 'Var', (31, 36))	('HPV', 'Species', '10566', (31, 34))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))
149512	20078887	NIH 3T3 cells expressing HPV57 exhibited morphological transformation indicating that the activity of HPV57 in vitro is comparable to other high-risk HPV types.	('HPV57', 'Var', (25, 30))	('exhibited', 'Reg', (31, 40))	('HPV', 'Species', '10566', (25, 28))	('morphological transformation', 'CPA', (41, 69))	('HPV', 'Species', '10566', (150, 153))	('NIH 3T3', 'CellLine', 'CVCL:0594', (0, 7))	('HPV', 'Species', '10566', (102, 105))
149693	29467939	In the multivariate analysis, we adjusted for age (continuous), sex (men/women), place of residence (urban/rural), marital status (unmarried/married/divorced or widowed), family history of esophageal cancer among first-degree relatives (yes/no), smoking (never/<=30.0 pack-years/>30.0 pack-years), alcohol drinking (never/<=82.5 g/d/>82.5 g/d), tea drinking (never/ever), body mass index of 10 years ago (<18.5/18.5-23.9/>=24), sum of missing and filled teeth (none/<6/>=6), and daily frequency of brushing teeth (<2/>=2).	('esophageal cancer', 'Disease', (189, 206))	('never/<=82.5', 'Var', (316, 328))	('brushing teeth', 'Disease', (498, 512))	('men', 'Species', '9606', (69, 72))	('adjusted', 'Reg', (33, 41))	('women', 'Species', '9606', (73, 78))	('sum of missing and filled teeth', 'Phenotype', 'HP:0000674', (428, 459))	('alcohol drinking', 'Phenotype', 'HP:0030955', (298, 314))	('brushing teeth', 'Disease', 'MESH:D018677', (498, 512))	('esophageal cancer', 'Disease', 'MESH:D004938', (189, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('alcohol', 'Chemical', 'MESH:D000438', (298, 305))	('brushing teeth', 'Phenotype', 'HP:0000670', (498, 512))	('men', 'Species', '9606', (75, 78))
149786	28841839	High TF expression was significantly associated with tumor location in the tongue (p = 0.018) and relapse of disease (p = 0.001).	('High', 'Var', (0, 4))	('TF', 'Gene', '2152', (5, 7))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('associated', 'Reg', (37, 47))	('tumor', 'Disease', (53, 58))	('relapse', 'Disease', (98, 105))
149821	28841839	In the correlation analysis, high TF expression was associated with relapse of disease.	('high', 'Var', (29, 33))	('relapse of disease', 'Disease', (68, 86))	('TF', 'Gene', '2152', (34, 36))	('associated with', 'Reg', (52, 67))	('expression', 'MPA', (37, 47))
149828	28841839	Our study confirms the findings in the latter study, as high uPAR expression only for the sub-group of well differentiated tumors was associated negatively with OS in the univariate analysis and reached borderline significance in the multivariate analysis.	('OS', 'Chemical', '-', (161, 163))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('uPAR', 'Gene', (61, 65))	('negatively', 'NegReg', (145, 155))	('uPAR', 'Gene', '5329', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('high', 'Var', (56, 60))
149928	28190657	While it is important to consider the possibility that perinatal transmission, a major route of hepatitis B virus transmission, resulted in the high odds ratio observed in chronic hepatitis B, several genome-wide association studies (GWAS), which identified some single nucleotide polymorphism loci significantly associated with these diseases in Japan, support the finding that genetic factors are associated with these diseases.	('hepatitis B', 'Disease', (180, 191))	('hepatitis B virus', 'Species', '10407', (96, 113))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (172, 189))	('single nucleotide polymorphism loci', 'Var', (263, 298))	('hepatitis', 'Phenotype', 'HP:0012115', (96, 105))	('hepatitis', 'Phenotype', 'HP:0012115', (180, 189))	('associated', 'Reg', (313, 323))	('hepatitis B', 'Disease', 'MESH:D006509', (96, 107))	('hepatitis B', 'Disease', (96, 107))	('hepatitis B', 'Disease', 'MESH:D006509', (180, 191))
149941	28219406	On univariate analysis for OS, combined chemotherapy (p = 0.000055), disease-free interval (DFI) >=12 months (p = 0.0013), LN max diameter <=22 mm (p = 0.0052), and Karnofsky performance status >=80% (p = 0.030) were associated with a significantly better prognosis.	('>=12', 'Var', (97, 101))	('OS', 'Chemical', '-', (27, 29))	('<=22', 'Var', (139, 143))
149994	28219406	In the present study, univariate analyses showed that the significant prognostic factors for OS were CRT, DFI >=12 months, MLD <=22 mm, and KPS >=80%.	('CRT', 'Disease', (101, 104))	('KPS >=80%', 'Var', (140, 149))	('OS', 'Chemical', '-', (93, 95))	('MLD', 'Disease', (123, 126))	('MLD', 'Disease', 'MESH:D007966', (123, 126))
150091	27895406	Kumagai et al already indicated that the microvessel density in SESCC gradually increased in proportion to the depth by using immunohistochemical staining with CD34 and CD105.	('SCC', 'Gene', (66, 69))	('CD34', 'Gene', (160, 164))	('microvessel density', 'CPA', (41, 60))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('increased', 'PosReg', (80, 89))	('SCC', 'Gene', '6317', (66, 69))	('CD105', 'Var', (169, 174))	('CD34', 'Gene', '947', (160, 164))
150134	26445852	A search was performed in May 2014 of the PubMed and EMBASE databases, using the MOOSE and PRISMA guidelines and the following term: [((((esophageal OR esophagus OR gastro esophageal)) AND (Barrett's OR metaplasia OR columnar)) AND (genomic OR genetic OR genome OR pharmacogenetic OR pharmacogenomic OR amplification OR copy OR mutation OR polymorphism OR polymorphic OR variant OR deletion OR insertion OR locus OR loci OR allele OR ploidy OR instability OR biomarker))].	('deletion', 'Var', (382, 390))	('copy OR mutation OR polymorphism', 'Var', (320, 352))	('esophageal OR esophagus OR gastro esophageal', 'Disease', 'MESH:D004941', (138, 182))	("Barrett's OR metaplasia", 'Disease', (190, 213))	('esophageal OR esophagus OR gastro esophageal', 'Disease', (138, 182))	("Barrett's OR metaplasia", 'Disease', 'MESH:D001471', (190, 213))	('variant', 'Var', (371, 378))	('MOOSE', 'Species', '999462', (81, 86))	('insertion OR locus OR loci', 'Var', (394, 420))
150138	26445852	However, for 2 of these (rs6785049 and rs9344) precise p values were not provided to allow for Bonferroni correction.	('rs6785049', 'Mutation', 'rs6785049', (25, 34))	('rs6785049', 'Var', (25, 34))	('rs9344', 'Var', (39, 45))	('rs9344', 'Mutation', 'rs9344', (39, 45))
150141	26445852	Of the 12 significant candidate associations reported, only rs1695 (GSTP1) and rs25487 (XRCC1) were assessed by more than one study.	('XRCC1', 'Gene', (88, 93))	('rs1695', 'Var', (60, 66))	('GSTP1', 'Gene', (68, 73))	('rs25487', 'Mutation', 'rs25487', (79, 86))	('rs1695', 'Mutation', 'rs1695', (60, 66))	('rs25487', 'Var', (79, 86))	('GSTP1', 'Gene', '2950', (68, 73))	('XRCC1', 'Gene', '7515', (88, 93))
150142	26445852	These include 3 growth factor variants: rs444903 (EGFR; notably associated with reflux esophagitis and EAC), rs6214 (IGF1), and rs2229765 (IGF1R).	('IGF1R', 'Gene', (139, 144))	('rs444903', 'Mutation', 'rs444903', (40, 48))	('rs6214', 'Var', (109, 115))	('rs444903', 'Var', (40, 48))	('rs2229765', 'Var', (128, 137))	('EGFR', 'Gene', (50, 54))	('IGF1', 'Gene', (139, 143))	('EAC', 'Phenotype', 'HP:0011459', (103, 106))	('associated', 'Reg', (64, 74))	('rs2229765', 'Mutation', 'rs2229765', (128, 137))	('IGF1', 'Gene', '3479', (117, 121))	('EAC', 'Gene', '1540', (103, 106))	('reflux esophagitis', 'Disease', (80, 98))	('EAC', 'Gene', (103, 106))	('esophagitis', 'Phenotype', 'HP:0100633', (87, 98))	('EGFR', 'Gene', '1956', (50, 54))	('IGF1', 'Gene', '3479', (139, 143))	('IGF1', 'Gene', (117, 121))	('reflux esophagitis', 'Disease', 'MESH:D005764', (80, 98))	('IGF1R', 'Gene', '3480', (139, 144))	('rs6214', 'Mutation', 'rs6214', (109, 115))
150143	26445852	Two interleukin variants also appear plausible: rs3212227 (IL12B) and rs917997 (IL18RAP), with the former demonstrated to be independent of all other tested genotypes.	('rs3212227', 'Var', (48, 57))	('rs3212227', 'Mutation', 'rs3212227', (48, 57))	('IL12B', 'Gene', '3593', (59, 64))	('IL18RAP', 'Gene', (80, 87))	('IL18RAP', 'Gene', '8807', (80, 87))	('IL12B', 'Gene', (59, 64))	('rs917997', 'Mutation', 'rs917997', (70, 78))
150145	26445852	Of these, however, only wild-type rs917997 (IL18RAP) persisted following correction for multiple comparisons.	('rs917997', 'Var', (34, 42))	('IL18RAP', 'Gene', (44, 51))	('rs917997', 'Mutation', 'rs917997', (34, 42))	('IL18RAP', 'Gene', '8807', (44, 51))
150146	26445852	The remaining 5 candidate variants included associations with 3 caudal homeobox 1 (CDX1) variants: rs3776082, rs2237091, and rs717767.	('caudal homeobox 1', 'Gene', '1044', (64, 81))	('CDX1', 'Gene', (83, 87))	('rs717767', 'Var', (125, 133))	('rs3776082', 'Mutation', 'rs3776082', (99, 108))	('rs2237091', 'Mutation', 'rs2237091', (110, 119))	('associations', 'Interaction', (44, 56))	('CDX1', 'Gene', '1044', (83, 87))	('rs717767', 'Mutation', 'rs717767', (125, 133))	('caudal homeobox 1', 'Gene', (64, 81))	('rs2237091', 'Var', (110, 119))	('rs3776082', 'Var', (99, 108))
150147	26445852	The authors demonstrated these variants to be significantly associated with established risk factors for BE: age, gender, and the presence of hiatus hernia.	('hiatus hernia', 'Phenotype', 'HP:0002036', (142, 155))	('variants', 'Var', (31, 39))	('hiatus hernia', 'Disease', (142, 155))	('hiatus hernia', 'Disease', 'MESH:D006551', (142, 155))	('BE', 'Phenotype', 'HP:0100580', (105, 107))	('hernia', 'Phenotype', 'HP:0100790', (149, 155))	('associated', 'Reg', (60, 70))
150148	26445852	Of the remaining 2, an association was demonstrated for the rs6785049 (NR1I2) variant; however, similarly this was not adjusted for risk factors.	('NR1I2', 'Gene', (71, 76))	('rs6785049', 'Var', (60, 69))	('association', 'Reg', (23, 34))	('NR1I2', 'Gene', '8856', (71, 76))	('rs6785049', 'Mutation', 'rs6785049', (60, 69))
150150	26445852	Two were identified by the initial report: rs9257809 within the major histocompatibility complex (MHC; OR 1.21 [1.13-1.28]; p = 4.09 x 10-9) and rs9936833 (related to FOXF1; OR 1.14 [1.10-1.19]; p = 2.74 x 10-10).	('rs9257809', 'Mutation', 'rs9257809', (43, 52))	('FOXF1', 'Gene', '2294', (167, 172))	('FOXF1', 'Gene', (167, 172))	('rs9257809', 'Var', (43, 52))	('rs9936833', 'Var', (145, 154))	('MHC', 'Gene', (98, 101))	('rs9936833', 'Mutation', 'rs9936833', (145, 154))	('MHC', 'Gene', '3107', (98, 101))
150151	26445852	Subsequent replication identified rs3072 (related to GDF7: OR 1.14 [1.09-1.18]; p = 1.80 x 10-11) and rs2701108 (related to TBX5: OR 0.90 [0.86-0.93]; p = 7.50 x 10-9).	('rs2701108', 'Mutation', 'rs2701108', (102, 111))	('rs3072', 'Var', (34, 40))	('GDF7', 'Gene', (53, 57))	('rs3072', 'Mutation', 'rs3072', (34, 40))	('rs2701108', 'Var', (102, 111))	('GDF7', 'Gene', '151449', (53, 57))	('TBX5', 'Gene', (124, 128))	('TBX5', 'Gene', '6910', (124, 128))
150156	26445852	However, on subsequent meta-analysis of both GWAS, rs2687201 (FOXP1, similarly involved in developmental regulation) was significantly associated with BE alone, in addition to a further variant associated with either BE/EAC.	('rs2687201', 'Var', (51, 60))	('BE alone', 'Disease', (151, 159))	('rs2687201', 'Mutation', 'rs2687201', (51, 60))	('FOXP1', 'Gene', '27086', (62, 67))	('EAC', 'Phenotype', 'HP:0011459', (220, 223))	('associated', 'Reg', (135, 145))	('FOXP1', 'Gene', (62, 67))	('EAC', 'Gene', '1540', (220, 223))	('BE', 'Phenotype', 'HP:0100580', (217, 219))	('BE', 'Phenotype', 'HP:0100580', (151, 153))	('EAC', 'Gene', (220, 223))
150159	26445852	Of 7 variants assessed, 5 associations were identified: CIN, CNV (>70 Mbp), TP53 LOH, p16 LOH, and mutant TP53 (Table 4).	('LOH', 'NegReg', (81, 84))	('Mbp', 'Gene', (70, 73))	('TP53', 'Gene', '7157', (76, 80))	('Mbp', 'Gene', '4155', (70, 73))	('CIN', 'Phenotype', 'HP:0040012', (56, 59))	('p16', 'Gene', (86, 89))	('TP53', 'Gene', (76, 80))	('CIN', 'Disease', (56, 59))	('mutant', 'Var', (99, 105))	('CNV', 'Disease', (61, 64))	('TP53', 'Gene', '7157', (106, 110))	('CIN', 'Disease', 'MESH:D007674', (56, 59))	('TP53', 'Gene', (106, 110))	('p16', 'Gene', '1029', (86, 89))
150169	26445852	While more than one study assessed mutant TP53 (n = 3) and LOH TP53 (n = 2), meta-analysis was not possible for either.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', (42, 46))	('mutant', 'Var', (35, 41))	('LOH', 'Var', (59, 62))
150172	26445852	Five (rs9257809, rs9936833, and subsequently rs3072, rs2701108, and rs2687201) were derived from GWAS and are therefore most likely to be reproducible.	('rs9936833', 'Var', (17, 26))	('rs2701108', 'Mutation', 'rs2701108', (53, 62))	('rs9936833', 'Mutation', 'rs9936833', (17, 26))	('rs9257809', 'Mutation', 'rs9257809', (6, 15))	('rs2701108', 'Var', (53, 62))	('rs3072', 'Var', (45, 51))	('rs9257809', 'Var', (6, 15))	('rs3072', 'Mutation', 'rs3072', (45, 51))	('rs2687201', 'Var', (68, 77))	('rs2687201', 'Mutation', 'rs2687201', (68, 77))
150173	26445852	Of the 6 candidate markers assessed by more than one study, meta-analysis was supportive for one (rs1695, GSTP1).	('rs1695', 'Mutation', 'rs1695', (98, 104))	('GSTP1', 'Gene', '2950', (106, 111))	('GSTP1', 'Gene', (106, 111))	('rs1695', 'Var', (98, 104))
150174	26445852	Five non-meta-analyzed variants affecting either growth factors or inflammatory cytokines appear plausible and therefore represent priorities for validation: rs444903 (EGFR), rs6214 (IGF1), rs2229765 (IGF1R), rs3212227 (IL12B), and rs917997 (IL18RAP).	('EGFR', 'Gene', '1956', (168, 172))	('IGF1R', 'Gene', '3480', (201, 206))	('rs3212227', 'Var', (209, 218))	('rs2229765', 'Var', (190, 199))	('IGF1', 'Gene', (183, 187))	('rs2229765', 'Mutation', 'rs2229765', (190, 199))	('IL12B', 'Gene', (220, 225))	('IGF1R', 'Gene', (201, 206))	('rs444903', 'Mutation', 'rs444903', (158, 166))	('rs444903', 'Var', (158, 166))	('rs6214', 'Mutation', 'rs6214', (175, 181))	('rs917997', 'Var', (232, 240))	('rs3212227', 'Mutation', 'rs3212227', (209, 218))	('EGFR', 'Gene', (168, 172))	('rs6214', 'Var', (175, 181))	('IGF1', 'Gene', '3479', (201, 205))	('IGF1', 'Gene', '3479', (183, 187))	('rs917997', 'Mutation', 'rs917997', (232, 240))	('IL18RAP', 'Gene', '8807', (242, 249))	('IL18RAP', 'Gene', (242, 249))	('IL12B', 'Gene', '3593', (220, 225))	('IGF1', 'Gene', (201, 205))
150179	26445852	Inaccurate DNA replication, repair, and chromosomal segregation, results in accumulation of genomic errors and is a major factor driving tumorigenesis.	('tumor', 'Disease', (137, 142))	('DNA replication', 'CPA', (11, 26))	('repair', 'CPA', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('accumulation', 'PosReg', (76, 88))	('chromosomal segregation', 'CPA', (40, 63))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('genomic errors', 'MPA', (92, 106))	('Inaccurate', 'Var', (0, 10))
150185	26445852	This identified somatic nonsense mutations in genes including AT-rich interactive domain 1A (ARID1A), a member of the SWI/SNF family involved in gene expression via chromatin remodeling, which has been independently identified as a driver gene of EAC by of other NGS studies.	('nonsense mutations', 'Var', (24, 42))	('AT-rich interactive domain 1A', 'Gene', (62, 91))	('EAC', 'Phenotype', 'HP:0011459', (247, 250))	('mutations', 'Var', (33, 42))	('EAC', 'Gene', '1540', (247, 250))	('ARID1A', 'Gene', '8289', (93, 99))	('ARID1A', 'Gene', (93, 99))	('EAC', 'Gene', (247, 250))	('AT-rich interactive domain 1A', 'Gene', '8289', (62, 91))
150188	26445852	One hundred and seven BE samples were then genotyped, with the notable finding that most such mutations were already present in non-dysplastic epithelium; just TP53 and SMAD4 mutations occurred later, in HGD and EAC.	('SMAD4', 'Gene', (169, 174))	('HGD', 'Disease', (204, 207))	('TP53', 'Gene', '7157', (160, 164))	('EAC', 'Phenotype', 'HP:0011459', (212, 215))	('BE', 'Phenotype', 'HP:0100580', (22, 24))	('EAC', 'Gene', '1540', (212, 215))	('TP53', 'Gene', (160, 164))	('mutations', 'Var', (175, 184))	('dysplastic', 'Disease', 'MESH:D004416', (132, 142))	('dysplastic', 'Disease', (132, 142))	('SMAD4', 'Gene', '4089', (169, 174))	('EAC', 'Gene', (212, 215))
150189	26445852	Additionally, germline rather than somatic mutations in EAC driver genes have been shown to predispose to EAC, although this has yet to be demonstrated in BE.	('EAC', 'Gene', '1540', (56, 59))	('EAC', 'Gene', (56, 59))	('EAC', 'Phenotype', 'HP:0011459', (106, 109))	('predispose', 'Reg', (92, 102))	('germline', 'Var', (14, 22))	('EAC', 'Gene', '1540', (106, 109))	('EAC', 'Gene', (106, 109))	('EAC', 'Phenotype', 'HP:0011459', (56, 59))	('BE', 'Phenotype', 'HP:0100580', (155, 157))
150242	25777422	This meta-analysis highlights an over sixfold increased risk of esophageal cancer in the presence of HPV 16 infection, providing a strong evidence to date of a potential role for HPV 16 in the etiology of esophageal cancer in Chinese population.	('HPV 16', 'Gene', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('esophageal cancer', 'Disease', (205, 222))	('HPV 16', 'Species', '333760', (101, 107))	('infection', 'Disease', (108, 117))	('infection', 'Disease', 'MESH:D007239', (108, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (205, 222))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('presence', 'Var', (89, 97))	('HPV 16', 'Species', '333760', (179, 185))
150280	25777422	Thirdly, we mainly focused on the association between HPV 16 and esophageal cancer in this study and did not investigate the overall HPV risk on esophageal cancer which is essential for esophageal cancer prevention in China.	('association', 'Interaction', (34, 45))	('esophageal cancer', 'Disease', (65, 82))	('HPV 16', 'Var', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('HPV 16', 'Species', '333760', (54, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('esophageal cancer', 'Disease', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('esophageal cancer', 'Disease', (186, 203))	('HPV', 'Species', '10566', (54, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('HPV', 'Species', '10566', (133, 136))
150283	32653028	LncRNA HOTAIR-mediated MTHFR methylation inhibits 5-fluorouracil sensitivity in esophageal cancer cells Esophageal cancer (EC) represents one of the most aggressive digestive neoplasms globally, with marked geographical variations in morbidity and mortality.	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('neoplasms', 'Disease', (175, 184))	('MTHFR', 'Gene', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (50, 64))	('digestive neoplasms', 'Phenotype', 'HP:0007378', (165, 184))	('HOTAIR', 'Gene', '100124700', (7, 13))	('mortality', 'Disease', (248, 257))	('methylation', 'Var', (29, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (175, 184))	('HOTAIR', 'Gene', (7, 13))	('cancer', 'Disease', (115, 121))	('inhibits', 'NegReg', (41, 49))	('cancer', 'Disease', (91, 97))	('5-fluorouracil sensitivity', 'MPA', (50, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mortality', 'Disease', 'MESH:D003643', (248, 257))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('MTHFR', 'Gene', '4524', (23, 28))	('neoplasms', 'Disease', 'MESH:D009369', (175, 184))
150305	32653028	Previous studies have revealed that alterations in DNA methylation are innate to various human cancers, including EC.	('human', 'Species', '9606', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('alterations', 'Var', (36, 47))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
150306	32653028	HOTAIR is known to regulate gene expression through epigenetic modifications, including DNA methylation.	('expression', 'Species', '29278', (33, 43))	('DNA', 'Var', (88, 91))	('regulate', 'Reg', (19, 27))	('epigenetic', 'Var', (52, 62))
150330	32653028	The MTHFR dual luciferase reporter gene vector and mutants with lncRNA HOTAIR binding site mutation (MTHFR-WT and MTHFR-MUT) were each constructed.	('mutation', 'Var', (91, 99))	('MTHFR', 'Gene', (114, 119))	('MTHFR', 'Gene', (4, 9))	('MTHFR', 'Gene', '4524', (114, 119))	('MTHFR', 'Gene', '4524', (101, 106))	('MTHFR', 'Gene', '4524', (4, 9))	('MTHFR', 'Gene', (101, 106))
150335	32653028	Cell lysates were incubated with protein-G agarose beads pre-coated with anti-DNMT1 (ab13537, Abcam, Cambridge, UK), anti-DNMT3a (, ab2850, Abcam, Cambridge, UK), anti-DNMT3b (ab2851, Abcam, Cambridge, UK) or normal rabbit IgG.	('DNMT3a', 'Gene', (122, 128))	('DNMT3b', 'Gene', '1789', (168, 174))	('DNMT3a', 'Gene', '1788', (122, 128))	('agarose', 'Chemical', 'MESH:D012685', (43, 50))	('DNMT1', 'Gene', (78, 83))	('DNMT3b', 'Gene', (168, 174))	('DNMT1', 'Gene', '1786', (78, 83))	('ab13537', 'Var', (85, 92))	('ab2851', 'Var', (176, 182))
150342	32653028	Cell lysates were sonicated to generate chromatin fragments of 200-300 bp and immunoprecipitated with DNMT1 (ab13537, Abcam, Cambridge, UK), DNMT3a (ab2850, Abcam, Cambridge, UK), DNMT3b (ab2851, Abcam, Cambridge, UK), IgG as a negative control, or RNA polymerase ii antibody as a positive control.	('DNMT3b', 'Gene', '1789', (180, 186))	('DNMT3a', 'Gene', (141, 147))	('ab2850', 'Var', (149, 155))	('DNMT1', 'Gene', (102, 107))	('ab2851', 'Var', (188, 194))	('DNMT1', 'Gene', '1786', (102, 107))	('DNMT3a', 'Gene', '1788', (141, 147))	('DNMT3b', 'Gene', (180, 186))
150372	32653028	EC-related data in the TCGA database was analyzed using 'Ualcan' database, and the resultant survival curve showed that HOTAIR expression was significantly correlated with survival in EC (p < 0.05) (Fig.	('correlated with', 'Reg', (156, 171))	('HOTAIR expression', 'Var', (120, 137))	('expression', 'Species', '29278', (127, 137))
150376	32653028	Furthermore, RT-qPCR displayed increased HOTAIR expression in EC cell lines EC109, KYSE150, and TE-1 in comparison to HEEC cells (p < 0.05) (Fig.	('TE-1', 'Gene', (96, 100))	('HEEC', 'CellLine', 'None', (118, 122))	('HOTAIR expression', 'MPA', (41, 58))	('expression', 'Species', '29278', (48, 58))	('increased', 'PosReg', (31, 40))	('EC109', 'CellLine', 'CVCL:6898', (76, 81))	('RT-qPCR', 'Var', (13, 20))	('TE-1', 'Gene', '57816', (96, 100))
150386	32653028	3e), HOTAIR expression was decreased in TE-1/5-FU cells treated with sh1-lncRNA HOTAIR and sh2-lncRNA HOTAIR plasmids, with a more pronounced decline upon treatment with sh1-lncRNA HOTAIR (p < 0.05).	('TE-1', 'Gene', '57816', (40, 44))	('decreased', 'NegReg', (27, 36))	('HOTAIR', 'Gene', (5, 11))	('5-FU', 'Chemical', 'MESH:D005472', (45, 49))	('expression', 'Species', '29278', (12, 22))	('TE-1', 'Gene', (40, 44))	('sh1-lncRNA HOTAIR', 'Var', (69, 86))	('sh2-lncRNA', 'Var', (91, 101))
150391	32653028	EdU assay and flow cytometry showed that silencing of lncRNA HOTAIR suppressed TE-1/5-FU cell proliferation and enhanced apoptosis (p < 0.05) (Fig.	('enhanced', 'PosReg', (112, 120))	('silencing', 'Var', (41, 50))	('TE-1', 'Gene', (79, 83))	('suppressed', 'NegReg', (68, 78))	('EdU', 'Chemical', 'MESH:C031086', (0, 3))	('apoptosis', 'CPA', (121, 130))	('TE-1', 'Gene', '57816', (79, 83))	('lncRNA HOTAIR', 'Gene', (54, 67))	('5-FU', 'Chemical', 'MESH:D005472', (84, 88))
150392	32653028	Next, we adopted PI staining using flow cytometry to verify the cell cycle of EC cells, which identified more cells at the G0/G1 phase but fewer cells in the S phase upon silencing lncRNA HOTAIR, whereas an opposite trend was observed in response to lncRNA HOTAIR overexpression (p < 0.05) (Fig.	('lncRNA HOTAIR', 'Gene', (181, 194))	('fewer', 'NegReg', (139, 144))	('silencing', 'Var', (171, 180))	('expression', 'Species', '29278', (268, 278))
150428	32653028	These results confirmed that restoration of MTHFR facilitated chemosensitivity to 5-FU and apoptosis while suppressing the proliferation of EC cells.	('proliferation', 'CPA', (123, 136))	('5-FU', 'Chemical', 'MESH:D005472', (82, 86))	('facilitated', 'PosReg', (50, 61))	('MTHFR', 'Gene', (44, 49))	('apoptosis', 'CPA', (91, 100))	('restoration', 'Var', (29, 40))	('chemosensitivity to 5-FU', 'MPA', (62, 86))	('suppressing', 'NegReg', (107, 118))	('MTHFR', 'Gene', '4524', (44, 49))
150430	32653028	Twenty-eight days after TE-1 implantation, we examined whether silencing of lncRNA HOTAIR increased the sensitivity of EC cells to 5-FU.	('TE-1', 'Gene', (24, 28))	('increased', 'PosReg', (90, 99))	('TE-1', 'Gene', '57816', (24, 28))	('sensitivity', 'MPA', (104, 115))	('lncRNA HOTAIR', 'Gene', (76, 89))	('5-FU', 'Chemical', 'MESH:D005472', (131, 135))	('silencing', 'Var', (63, 72))
150434	32653028	Immunohistochemistry showed that the positive rate of MTHFR in tumors was significantly increased by silencing of lncRNA HOTAIR (p < 0.05), and an opposite trend was observed upon overexpression of lncRNA HOTAIR (Fig.	('silencing', 'Var', (101, 110))	('MTHFR', 'Gene', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('increased', 'PosReg', (88, 97))	('positive', 'MPA', (37, 45))	('expression', 'Species', '29278', (184, 194))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('lncRNA HOTAIR', 'Gene', (114, 127))	('MTHFR', 'Gene', '4524', (54, 59))
150435	32653028	MSP results revealed that silencing of lncRNA HOTAIR inhibited MTHFR methylation in tumor tissues, and an opposite trend was observed upon overexpression of lncRNA HOTAIR (Fig.	('expression', 'Species', '29278', (143, 153))	('lncRNA HOTAIR', 'Gene', (39, 52))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('inhibited', 'NegReg', (53, 62))	('methylation', 'MPA', (69, 80))	('MTHFR', 'Gene', '4524', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('MTHFR', 'Gene', (63, 68))	('silencing', 'Var', (26, 35))
150436	32653028	These findings illustrated that HOTAIR knockdown could upregulate MTHFR to promote chemosensitivity of EC cells to 5-FU in vivo.	('promote', 'PosReg', (75, 82))	('MTHFR', 'Gene', '4524', (66, 71))	('chemosensitivity', 'CPA', (83, 99))	('knockdown', 'Var', (39, 48))	('5-FU', 'Chemical', 'MESH:D005472', (115, 119))	('upregulate', 'PosReg', (55, 65))	('MTHFR', 'Gene', (66, 71))
150441	32653028	The results of the current study displayed that silencing of HOTAIR promoted chemosensitivity to 5-FU and apoptosis while repressing cell proliferation and tumor growth in EC.	('silencing', 'Var', (48, 57))	('cell proliferation', 'CPA', (133, 151))	('chemosensitivity to 5-FU', 'MPA', (77, 101))	('promoted', 'PosReg', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('HOTAIR', 'Gene', (61, 67))	('apoptosis', 'CPA', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('5-FU', 'Chemical', 'MESH:D005472', (97, 101))	('repressing', 'NegReg', (122, 132))	('tumor', 'Disease', (156, 161))
150443	32653028	have similarly shown that 5-FU could repress proliferation and induce the apoptosis of EC cells.	('5-FU', 'Chemical', 'MESH:D005472', (26, 30))	('apoptosis', 'CPA', (74, 83))	('induce', 'PosReg', (63, 69))	('5-FU', 'Var', (26, 30))	('repress', 'NegReg', (37, 44))
150445	32653028	Overexpression of HOTAIR is associated with the elevation of cell proliferation, migration, and invasion in EC, facilitating its progression and development.	('HOTAIR', 'Gene', (18, 24))	('expression', 'Species', '29278', (4, 14))	('progression', 'CPA', (129, 140))	('invasion', 'CPA', (96, 104))	('Overexpression', 'Var', (0, 14))	('development', 'CPA', (145, 156))	('elevation', 'PosReg', (48, 57))	('migration', 'CPA', (81, 90))	('cell proliferation', 'CPA', (61, 79))
150447	32653028	Taken together, there exists significant evidence indicating that HOTAIR is able to promote the chemosensitivity of EC cells to 5-FU by inhibiting proliferation and increasing the apoptosis of EC cells.	('inhibiting', 'NegReg', (136, 146))	('promote', 'PosReg', (84, 91))	('chemosensitivity', 'MPA', (96, 112))	('HOTAIR', 'Var', (66, 72))	('5-FU', 'Chemical', 'MESH:D005472', (128, 132))	('increasing', 'PosReg', (165, 175))	('apoptosis', 'CPA', (180, 189))	('proliferation', 'CPA', (147, 160))
150452	32653028	Our results imply that silencing of HOTAIR elevated MTHFR expression by decreasing MTHFR methylation.	('expression', 'Species', '29278', (58, 68))	('MTHFR', 'Gene', '4524', (83, 88))	('expression', 'MPA', (58, 68))	('elevated', 'PosReg', (43, 51))	('HOTAIR', 'Gene', (36, 42))	('MTHFR', 'Gene', '4524', (52, 57))	('silencing', 'Var', (23, 32))	('MTHFR', 'Gene', (83, 88))	('decreasing', 'NegReg', (72, 82))	('MTHFR', 'Gene', (52, 57))	('methylation', 'MPA', (89, 100))
150454	32653028	The MTHFR is reported to play anti-tumor roles in human cancers through hypomethylation of DNA.	('cancers', 'Disease', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('hypomethylation', 'Var', (72, 87))	('MTHFR', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Disease', (35, 40))	('DNA', 'Protein', (91, 94))	('human', 'Species', '9606', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('MTHFR', 'Gene', '4524', (4, 9))
150458	32653028	In conclusion, silencing of lncRNA HOTAIR promotes the chemosensitivity of EC cells to 5-FU and leads to abnormal cell proliferation and apoptosis of EC cells via the regulation of MTHFR methylation (Fig.	('cell proliferation', 'CPA', (114, 132))	('MTHFR', 'Gene', '4524', (181, 186))	('apoptosis', 'CPA', (137, 146))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (105, 132))	('leads to', 'Reg', (96, 104))	('5-FU', 'Chemical', 'MESH:D005472', (87, 91))	('lncRNA HOTAIR', 'Gene', (28, 41))	('MTHFR', 'Gene', (181, 186))	('silencing', 'Var', (15, 24))	('methylation', 'MPA', (187, 198))	('promotes', 'PosReg', (42, 50))	('regulation', 'Reg', (167, 177))	('chemosensitivity', 'MPA', (55, 71))
150459	32653028	This identification of HOTAIR knockdown via MTHFR in mediating the chemosensitivity of EC cells to 5-FU may advance an understanding of the molecular mechanisms underpinning EC, with the potential of serving as a prognostic marker during chemotherapeutic treatment of EC.	('5-FU', 'Chemical', 'MESH:D005472', (99, 103))	('MTHFR', 'Gene', (44, 49))	('advance', 'PosReg', (108, 115))	('knockdown', 'Var', (30, 39))	('MTHFR', 'Gene', '4524', (44, 49))
150461	32653028	Further studies are required, however, to fully understand the specific mechanisms of HOTAIR combined with MTHFR methylation on chemosensitivity to 5-FU treatment in EC.	('MTHFR', 'Gene', (107, 112))	('methylation', 'Var', (113, 124))	('5-FU', 'Chemical', 'MESH:D005472', (148, 152))	('MTHFR', 'Gene', '4524', (107, 112))
150470	30474922	Moreover, inhibition of CD44v9 expression decreased the migration and invasiveness of esophageal squamous cell carcinoma cells.	('migration', 'CPA', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('decreased', 'NegReg', (42, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('CD44', 'Gene', '960', (24, 28))	('expression', 'MPA', (31, 41))	('invasiveness of esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (70, 120))	('rat', 'Species', '10116', (59, 62))	('invasiveness of esophageal squamous cell carcinoma', 'Disease', (70, 120))	('inhibition', 'Var', (10, 20))	('CD44', 'Gene', (24, 28))
150507	30474922	The primary antibodies used were as follows: anti-CD44v9 (LKG-M001, 1:1000 dilution; COSMO BIO LTD), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (GTX100118, 1:1000 dilution; GeneTex Inc, Irvine, CA, USA), anti-E-cadherin (24E10, 1:1000 dilution; Cell Signaling Technology Japan, Tokyo, Japan), and anti-vimentin (D21H3, 1:1000 dilution; Cell Signaling Technology Japan).	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '403755', (101, 141))	('CD44', 'Gene', (50, 54))	('GAPDH', 'Gene', (143, 148))	('D21H3', 'Var', (318, 323))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (101, 141))	('GAPDH', 'Gene', '403755', (143, 148))	('CD44', 'Gene', '960', (50, 54))
150508	30474922	At 48 hour after siCD44v9 transfection, TGF-beta treatment, or combined siCD44v9 transfection and TGF-beta treatment, TE6 cells were seeded at 5000 cells/well in 96-well plates and incubated at 37 C in an atmosphere containing 5% CO2.	('CD44', 'Gene', '960', (74, 78))	('transfection', 'Var', (26, 38))	('CD44', 'Gene', (19, 23))	('transfection', 'Var', (81, 93))	('TGF-beta', 'Gene', '7040', (40, 48))	('CD44', 'Gene', (74, 78))	('TGF-beta', 'Gene', '7040', (98, 106))	('TGF-beta', 'Gene', (40, 48))	('TE6', 'CellLine', 'CVCL:1765', (118, 121))	('CO2', 'Chemical', '-', (230, 233))	('TGF-beta', 'Gene', (98, 106))	('CD44', 'Gene', '960', (19, 23))
150525	30474922	CD44v9 expression at the TIF was significantly higher in the EMT group compared with the non-EMT group (P < 0.001) (Table S2).	('higher', 'PosReg', (47, 53))	('CD44', 'Gene', '960', (0, 4))	('expression', 'MPA', (7, 17))	('EMT', 'Var', (61, 64))	('CD44', 'Gene', (0, 4))
150573	30474922	We found that the intracellular ROS level was increased 96 hours after siCD44v9 transfection and after combined siCD44v9 transfection and TGF-beta treatment (P = 0.0051 and 0.0051, respectively).	('intracellular ROS level', 'MPA', (18, 41))	('CD44', 'Gene', (114, 118))	('increased', 'PosReg', (46, 55))	('TGF-beta', 'Gene', (138, 146))	('CD44', 'Gene', '960', (73, 77))	('ROS', 'Chemical', '-', (32, 35))	('transfection', 'Var', (80, 92))	('CD44', 'Gene', (73, 77))	('TGF-beta', 'Gene', '7040', (138, 146))	('CD44', 'Gene', '960', (114, 118))
150647	26989388	The majority of studies show that MIE is associated with a significant reduction of pulmonary complications, blood loss, and shorter length of stay on the intensive care unit.	('reduction of pulmonary complications', 'Disease', (71, 107))	('blood loss', 'Disease', (109, 119))	('pulmonary complications', 'Phenotype', 'HP:0006532', (84, 107))	('blood loss', 'Disease', 'MESH:D006473', (109, 119))	('MIE', 'Chemical', '-', (34, 37))	('reduction of pulmonary complications', 'Disease', 'MESH:D008171', (71, 107))	('MIE', 'Var', (34, 37))
150672	26989388	in 2003, cMIE is supposed to be capable of substantially reducing the morbidity of esophagectomy.	('esophagectomy', 'Disease', (83, 96))	('reducing', 'NegReg', (57, 65))	('MIE', 'Chemical', '-', (10, 13))	('cMIE', 'Var', (9, 13))
150683	26989388	A reduction of stay on the intensive care unit (ICU) and of the length of hospital stay was seen only in cMIE patients but not in HMIE patients.	('stay', 'MPA', (15, 19))	('patients', 'Species', '9606', (135, 143))	('reduction', 'NegReg', (2, 11))	('MIE', 'Chemical', '-', (131, 134))	('cMIE', 'Var', (105, 109))	('MIE', 'Chemical', '-', (106, 109))	('patients', 'Species', '9606', (110, 118))
150688	26989388	showed a significantly reduced rate of pulmonary infections following cMIE compared to OE (9 vs. 29%, p = 0.005), a reduced blood loss (200 vs. 475 ml, p < 0.001), and reduced pain during the first 10 days postoperatively (p = 0.001).	('blood loss', 'Disease', 'MESH:D006473', (124, 134))	('pain', 'Phenotype', 'HP:0012531', (176, 180))	('pain', 'Disease', 'MESH:D010146', (176, 180))	('pain', 'Disease', (176, 180))	('blood loss', 'Disease', (124, 134))	('pulmonary infections', 'Disease', (39, 59))	('cMIE', 'Var', (70, 74))	('MIE', 'Chemical', '-', (71, 74))	('reduced pain', 'Phenotype', 'HP:0007328', (168, 180))	('pulmonary infections', 'Phenotype', 'HP:0006532', (39, 59))	('pulmonary infections', 'Disease', 'MESH:D008171', (39, 59))	('reduced', 'NegReg', (23, 30))	('reduced', 'NegReg', (116, 123))	('reduced', 'NegReg', (168, 175))
150690	26989388	Vocal cord paralysis was less frequent in the cMIE group (2 vs. 14%, p = 0.012).	('cord paralysis', 'Disease', (6, 20))	('Vocal cord paralysis', 'Phenotype', 'HP:0001605', (0, 20))	('cMIE', 'Var', (46, 50))	('MIE', 'Chemical', '-', (47, 50))	('paralysis', 'Phenotype', 'HP:0003470', (11, 20))	('cord paralysis', 'Disease', 'MESH:D014826', (6, 20))
150694	26989388	MIE led to a reduction of 14% of postoperative respiratory complications (p = 0.049).	('respiratory complications', 'Phenotype', 'HP:0011947', (47, 72))	('MIE', 'Chemical', '-', (0, 3))	('postoperative respiratory complications', 'Disease', 'MESH:D011183', (33, 72))	('postoperative respiratory complications', 'Disease', (33, 72))	('reduction', 'NegReg', (13, 22))	('MIE', 'Var', (0, 3))
150695	26989388	Reinterventions (17.6 vs. 21%, p = 0.006) and reoperations (5.6 vs. 8.8%, p < 0.001) were more frequent following MIE.	('Reinterventions', 'CPA', (0, 15))	('reoperations', 'CPA', (46, 58))	('MIE', 'Var', (114, 117))	('MIE', 'Chemical', '-', (114, 117))
150706	26989388	found a statistical trend towards increased 1-year survival following MIE when compared to OE (odds ratio = 0.68, 95% confidence interval = 0.46-1.01, p = 0.058).	('MIE', 'Chemical', '-', (70, 73))	('1-year survival', 'CPA', (44, 59))	('increased', 'PosReg', (34, 43))	('MIE', 'Var', (70, 73))
150715	26989388	revealed a higher endoscopic reintervention rate following cMIE than HMIE (16.2 vs. 6.4%, p < 0.001).	('endoscopic reintervention', 'MPA', (18, 43))	('cMIE', 'Var', (59, 63))	('MIE', 'Chemical', '-', (70, 73))	('MIE', 'Chemical', '-', (60, 63))	('higher', 'PosReg', (11, 17))
150717	26989388	This group found a significant reduction of major morbidity in cMIE (19.2 vs. 44.1%, p < 0.01), especially due to a reduction in pneumonia (6.7 vs. 20.5%, p = 0.01) and respiratory failure (15.4 vs. 30.8%, p = 0.03).	('reduction', 'NegReg', (31, 40))	('pneumonia', 'Phenotype', 'HP:0002090', (129, 138))	('cMIE', 'Var', (63, 67))	('MIE', 'Chemical', '-', (64, 67))	('reduction in pneumonia', 'Disease', (116, 138))	('respiratory failure', 'Disease', (169, 188))	('respiratory failure', 'Disease', 'MESH:D012131', (169, 188))	('reduction in pneumonia', 'Disease', 'MESH:D011014', (116, 138))	('respiratory failure', 'Phenotype', 'HP:0002878', (169, 188))	('major morbidity', 'MPA', (44, 59))
150719	26989388	The same analysis showed an improved 5-year survival rate after cMIE compared to OE + HMIE (71.9 vs. 64.3%, p < 0.001).	('MIE', 'Chemical', '-', (87, 90))	('MIE', 'Chemical', '-', (65, 68))	('cMIE', 'Var', (64, 68))	('improved', 'PosReg', (28, 36))
150720	26989388	The analysis was adjusted for age, sex, total lymph nodes harvested, lymph node ratio, neoadjuvant therapy, and stage and hereupon showed a twofold greater risk of death after OE + HMIE than after cMIE (hazard ratio (HR) 2.00, 95% CI 1.12-3.57, p = 0.019).	('death', 'Disease', 'MESH:D003643', (164, 169))	('death', 'Disease', (164, 169))	('OE + HMIE', 'Var', (176, 185))	('MIE', 'Chemical', '-', (198, 201))	('MIE', 'Chemical', '-', (182, 185))
150721	26989388	have shown in a multivariate analysis that cMIE leads to improved long-term survival when compared to OE (HR 0.5186, p = 0.0406).	('MIE', 'Chemical', '-', (44, 47))	('long-term survival', 'CPA', (66, 84))	('improved', 'PosReg', (57, 65))	('cMIE', 'Var', (43, 47))
150732	26989388	To date, a number of single-center studies have demonstrated that MIE is associated with several advantages in short-term outcome known from other minimally invasive procedures.	('MIE', 'Var', (66, 69))	('short-term outcome', 'MPA', (111, 129))	('advantages', 'PosReg', (97, 107))	('MIE', 'Chemical', '-', (66, 69))
150734	26989388	While one single-center study did not find any reduction in pulmonary complications due to MIE, all other studies and the existing meta-analysis demonstrated that MIE leads to a significant reduction in pulmonary complications.	('MIE', 'Var', (163, 166))	('pulmonary complications', 'Phenotype', 'HP:0006532', (60, 83))	('MIE', 'Chemical', '-', (163, 166))	('reduction in pulmonary complications', 'Disease', 'MESH:D008171', (190, 226))	('reduction in pulmonary complications', 'Disease', (190, 226))	('reduction in pulmonary complications', 'Disease', 'MESH:D008171', (47, 83))	('reduction in pulmonary complications', 'Disease', (47, 83))	('MIE', 'Chemical', '-', (91, 94))	('pulmonary complications', 'Phenotype', 'HP:0006532', (203, 226))
150737	26989388	This group found a significant reduction in the pulmonary complication rate after cMIE but not for HMIE, which included laparoscopy and thoracotomy.	('MIE', 'Chemical', '-', (100, 103))	('reduction', 'NegReg', (31, 40))	('pulmonary complication', 'CPA', (48, 70))	('MIE', 'Chemical', '-', (83, 86))	('cMIE', 'Var', (82, 86))
150750	26989388	even found a lower R1 rate following cMIE.	('R1 rate', 'MPA', (19, 26))	('MIE', 'Chemical', '-', (38, 41))	('cMIE', 'Var', (37, 41))	('lower', 'NegReg', (13, 18))
150752	26989388	have stated an increased lymph node yield following cMIE and HMIE when compared to OE.	('cMIE', 'Var', (52, 56))	('increased', 'PosReg', (15, 24))	('lymph node yield', 'CPA', (25, 41))	('MIE', 'Chemical', '-', (53, 56))	('MIE', 'Chemical', '-', (62, 65))
150791	22450896	Commercially available RFA devices include the HALO90 and HALO360 (BARRX Medical Inc, Sunnyvale, CA), designed for focal and circumferential ablation respectively.	('HALO90', 'Var', (47, 53))	('HALO360', 'Var', (58, 65))	('HALO360', 'Chemical', '-', (58, 65))
150807	22450896	The PDT group also experienced a statistically significant decrease in the rate of progression to EA (13%) compared to the control group receiving only surveillance endoscopy and omeprazole (27%).	('PDT', 'Var', (4, 7))	('decrease', 'NegReg', (59, 67))	('omeprazole', 'Chemical', 'MESH:D009853', (179, 189))	('EA', 'Phenotype', 'HP:0011459', (98, 100))
150808	22450896	Progression to cancer was also significantly lower in the PDT group (15%) compared to the control group (29%).	('PDT', 'Var', (58, 61))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('lower', 'NegReg', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
150818	22450896	PDT is associated with a higher rate of buried metaplasia compared to RFA (14.2% compared to 0.9% respectively).	('PDT', 'Var', (0, 3))	('metaplasia', 'Disease', 'MESH:D008679', (47, 57))	('metaplasia', 'Disease', (47, 57))
150828	22450896	Patients who have not responded to RFA may benefit from cryoablation (Figure 4) If ablative therapy is performed following EMR it should be done 4-6 weeks following resection in order to allow mucosal healing.	('Patients', 'Species', '9606', (0, 8))	('benefit', 'PosReg', (43, 50))	('cryoablation', 'Var', (56, 68))
150863	22232390	The goal of the learning algorithm in this model is to modify the weights associated with the connections between the nodes (represented by lines in figure 2a) such that an input vector will produce the specified desired output vector, essentially mapping the input space onto the output classes of a normal or disordered swallow.	('disordered swallow', 'Phenotype', 'HP:0002015', (311, 329))	('modify', 'Var', (55, 61))	('disordered', 'Disease', 'MESH:D030342', (311, 321))	('disordered', 'Disease', (311, 321))
150903	21916995	Proposed markers have included tumor suppressor genes (CDKN2A and TP53) along with the presence of epithelial aneuploidy or tetraploidy .	('CDKN2A', 'Gene', '1029', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('tetraploidy', 'Var', (124, 135))	('tumor', 'Disease', (31, 36))	('epithelial aneuploidy', 'Disease', (99, 120))	('epithelial aneuploidy', 'Disease', 'MESH:D000782', (99, 120))	('CDKN2A', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
150904	21916995	The cumulative 5-year incidence of EAC was 43% and 56% in BE patients with aneuploidy and tetraploidy respectively, compared to 5% without either finding .	('EAC', 'Disease', (35, 38))	('tetraploidy', 'Var', (90, 101))	('aneuploidy', 'Disease', 'MESH:D000782', (75, 85))	('patients', 'Species', '9606', (61, 69))	('EAC', 'Phenotype', 'HP:0011459', (35, 38))	('aneuploidy', 'Disease', (75, 85))	('BE', 'Phenotype', 'HP:0100580', (58, 60))
150966	21916995	These have included markers for tumor suppressor genes, aneuploidy, or tetraploidy.	('aneuploidy', 'Disease', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tetraploidy', 'Var', (71, 82))	('aneuploidy', 'Disease', 'MESH:D000782', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
150976	21916995	In nude mice, knockdown of DCAMKL-1 results in cessation of HCT-116-mediated tumor xenograft growth.	('tumor', 'Disease', (77, 82))	('HCT-116', 'CellLine', 'CVCL:0291', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('HCT-116-mediated', 'Gene', (60, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('nude mice', 'Species', '10090', (3, 12))	('knockdown', 'Var', (14, 23))	('DCAMKL-1', 'Gene', (27, 35))	('cessation', 'NegReg', (47, 56))
150991	21352519	We found that GPR39 was frequently overexpressed in primary ESCCs in both mRNA level (27/50, 54%) and protein level (121/207, 58.5%), which was significantly associated with the lymph node metastasis and advanced TNM stage (P < 0.01).	('TNM', 'Gene', '10178', (213, 216))	('associated', 'Reg', (158, 168))	('GPR39', 'Var', (14, 19))	('TNM', 'Gene', (213, 216))	('overexpressed', 'PosReg', (35, 48))	('si', 'Chemical', 'MESH:D012825', (144, 146))	('si', 'Chemical', 'MESH:D012825', (196, 198))	('lymph node metastasis', 'CPA', (178, 199))
150994	21352519	The mechanism by which amplified GPR39 induces tumorigenesis was associated with its role in promoting G1/S transition via up-regulation of cyclin D1 and CDK6.	('G1/S transition', 'CPA', (103, 118))	('promoting', 'PosReg', (93, 102))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('CDK6', 'Gene', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('amplified', 'Var', (23, 32))	('CDK6', 'Gene', '1021', (154, 158))	('induces', 'PosReg', (39, 46))	('cyclin D1', 'Gene', '595', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('GPR39', 'Gene', (33, 38))	('cyclin D1', 'Gene', (140, 149))	('tumor', 'Disease', (47, 52))	('up-regulation', 'PosReg', (123, 136))
150995	21352519	Further study found GPR39 could enhance cell motility and invasiveness by inducing EMT and remodeling cytoskeleton.	('invasiveness', 'CPA', (58, 70))	('remodeling cytoskeleton', 'CPA', (91, 114))	('GPR39', 'Var', (20, 25))	('EMT', 'CPA', (83, 86))	('cell motility', 'CPA', (40, 53))	('inducing', 'PosReg', (74, 82))	('enhance', 'PosReg', (32, 39))	('si', 'Chemical', 'MESH:D012825', (62, 64))
150996	21352519	Moreover, depletion of endogenous GPR39 by siRNA could effectively decrease the oncogenicity of ESCC cells.	('decrease', 'NegReg', (67, 75))	('oncogenicity of ESCC cells', 'CPA', (80, 106))	('endogenous', 'Var', (23, 33))	('GPR39', 'Var', (34, 39))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('depletion', 'MPA', (10, 19))
150999	21352519	Like other types of solid tumors, the development of ESCC is also the accumulation of the abnormal expression of oncogenes and tumor suppressor genes (TSGs).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('expression', 'MPA', (99, 109))	('ESCC', 'Disease', (53, 57))	('TSG', 'Gene', '57045', (151, 154))	('solid tumors', 'Disease', (20, 32))	('tumor', 'Disease', (127, 132))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('abnormal', 'Var', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('oncogenes', 'Gene', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('solid tumors', 'Disease', 'MESH:D009369', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('TSG', 'Gene', (151, 154))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
151000	21352519	Several genetic alterations have been associated with the development of ESCC including mutations of p53 and p16, amplification of cyclin D, c-myc, and EGFR, as well as allelic loss on chromosomes 3p, 5q, 8p, 9p, 9q, 13q, 17p, 18q, and 21q.	('cyclin D', 'Protein', (131, 139))	('amplification', 'Var', (114, 127))	('p16', 'Gene', (109, 112))	('associated', 'Reg', (38, 48))	('c-myc', 'Gene', '4609', (141, 146))	('mutations', 'Var', (88, 97))	('EGFR', 'Gene', '1956', (152, 156))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('p16', 'Gene', '1029', (109, 112))	('c-myc', 'Gene', (141, 146))	('EGFR', 'Gene', (152, 156))	('rat', 'Species', '10116', (20, 23))	('ESCC', 'Disease', (73, 77))	('allelic loss', 'Var', (169, 181))
151001	21352519	Our previous studies have characterized the common deletion regions at 3p and candidate TSGs within frequently deleted regions including PLCD1 and PCAF .	('PLCD1', 'Gene', (137, 142))	('PCAF', 'Gene', (147, 151))	('TSG', 'Gene', (88, 91))	('TSG', 'Gene', '57045', (88, 91))	('PCAF', 'Gene', '8850', (147, 151))	('PLCD1', 'Gene', '5333', (137, 142))	('deletion', 'Var', (51, 59))
151008	21352519	A recent study suggests that overexpression of GPR39 may inhibit cell death induced by oxidative stress, endoplasmic reticulum (ER) stress, and activation of the caspase by Bax overexpression.	('Bax', 'Gene', (173, 176))	('oxidative stress', 'MPA', (87, 103))	('GPR39', 'Var', (47, 52))	('caspase', 'CPA', (162, 169))	('si', 'Chemical', 'MESH:D012825', (187, 189))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('inhibit', 'NegReg', (57, 64))	('oxidative stress', 'Phenotype', 'HP:0025464', (87, 103))	('activation', 'PosReg', (144, 154))	('Bax', 'Gene', '581', (173, 176))	('cell death', 'CPA', (65, 75))
151015	21352519	Six Japanese ESCC cell lines (KYSE30, KYSE140, KYSE180, KYSE410, KYSE510 and KYSE520) were obtained from DSMZ (Braunschweig, Germany), the German Resource Centre for Biological Material.	('KYSE520', 'Var', (77, 84))	('KYSE30', 'Var', (30, 36))	('KYSE180', 'CellLine', 'CVCL:1349', (47, 54))	('KYSE140', 'Var', (38, 45))	('KYSE510', 'Var', (65, 72))	('KYSE180', 'Var', (47, 54))	('KYSE410', 'Var', (56, 63))
151019	21352519	Reverse transcripation of total RNA (2 mug) was done using SuperScript II reverse transcriptase (Invitrogen, Carlsbad, CA), and cDNA was subjected to PCR for a 30-cycle amplification with primers for GPR39Fw: 5'-GCCACCGGGGTCTCACTTGC-3' and GPR39Rv: 5'-GGCCGCAGCCATGATCCTCC-3'.	('si', 'Chemical', 'MESH:D012825', (54, 56))	('GPR39Fw', 'Var', (200, 207))	("GPR39Rv: 5'-GGCCGCAGCCATGATCCTCC-3", 'Var', (240, 274))
151051	21352519	Small interfering RNA (siRNA) (20 muM) against GPR39 (s6073; Ambion) was transfected into KYSE180 cells in 6-well plates using Lipofectamine 2000 Reagent (Invitrogen) according to the manufacturer's instructions.	('GPR39', 'Gene', (47, 52))	('s6073;', 'Var', (54, 60))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (127, 145))	('KYSE180', 'CellLine', 'CVCL:1349', (90, 97))
151060	21352519	Overexpression of GPR39 was also frequently detected in ESCC cell lines (HKESC1, KYSE140, KYSE180, KYSE410, KYSE510 and KYSE520; Figure 1B).	('KYSE180', 'Var', (90, 97))	('HKESC1', 'CellLine', 'CVCL:D568', (73, 79))	('KYSE520', 'Var', (120, 127))	('GPR39', 'Gene', (18, 23))	('KYSE410', 'Var', (99, 106))	('detected', 'Reg', (44, 52))	('KYSE510', 'Var', (108, 115))	('KYSE180', 'CellLine', 'CVCL:1349', (90, 97))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('KYSE140', 'Var', (81, 88))
151067	21352519	To investigate the tumorigenic potential of GPR39, GPR39-expression vector was stably transfected into KYSE30 cells with silenced GPR39.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('silenced', 'Var', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('GPR39', 'Gene', (130, 135))
151072	21352519	Cell growth assay also revealed that the cell growth rates in GPR39-c1 and GPR39-c4 cells were significantly enhanced by GPR39 compared with Vec-30 cells (P < 0.01, Figure 2D).	('cell growth rates', 'CPA', (41, 58))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('rat', 'Species', '10116', (53, 56))	('GPR39', 'Var', (121, 126))	('enhanced', 'PosReg', (109, 117))
151073	21352519	To further explore the in vivo tumorigenic ability of GPR39, tumor formation in nude mice was tested by injection of GPR39-c1 cells (n = 5) or GPR39-c4 cells (n = 5), whereas Vec-30 cells were used as controls.	('tested', 'Reg', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('nude mice', 'Species', '10090', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('GPR39-c4', 'Var', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('GPR39-c1', 'Var', (117, 125))	('tumor', 'Disease', (61, 66))
151074	21352519	The results showed that the tumor growth curve of GPR39-overexpressing cells was significantly increased compared to Vec-30 cells (P < 0.01, Figure 2E).	('tumor', 'Disease', (28, 33))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('GPR39-overexpressing', 'Var', (50, 70))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('increased', 'PosReg', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
151075	21352519	After 3 days' serum starvation followed by addition of 10% serum for 8 hrs, the percentage of cells in S phase was significantly increased in GPR39-c4 cells compared to Vec-30 cells (26.43 +- 0.71% versus 8.97 +- 0.31%, P < 0.05; Figure 3A), suggesting that GPR39 was able to promote G1/S transition.	('si', 'Chemical', 'MESH:D012825', (293, 295))	('GPR39-c4', 'Var', (142, 150))	('cells in S phase', 'CPA', (94, 110))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('G1/S transition', 'CPA', (284, 299))	('GPR39', 'Var', (258, 263))	('increased', 'PosReg', (129, 138))	('promote', 'PosReg', (276, 283))
151076	21352519	To reveal the potential molecular mechanism of GPR39 in cell cycle promotion, expressions of several key cell cycle regulators including p21, cyclin D1, CDK4 and CDK6 were compared between GPR39-c4 and Vec-30 cells.	('p21', 'Gene', '644914', (137, 140))	('cyclin D1', 'Gene', (142, 151))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('CDK4', 'Gene', (153, 157))	('CDK4', 'Gene', '1019', (153, 157))	('CDK6', 'Gene', (162, 166))	('cyclin D1', 'Gene', '595', (142, 151))	('CDK6', 'Gene', '1021', (162, 166))	('GPR39-c4', 'Var', (189, 197))	('p21', 'Gene', (137, 140))
151077	21352519	Increased expression of cyclin D1 and CDK6, but not p21 and CDK4, were detected in GPR39-c4 (Figure 3B).	('si', 'Chemical', 'MESH:D012825', (16, 18))	('CDK4', 'Gene', (60, 64))	('expression', 'MPA', (10, 20))	('p21', 'Gene', (52, 55))	('CDK6', 'Gene', (38, 42))	('Increased', 'PosReg', (0, 9))	('p21', 'Gene', '644914', (52, 55))	('CDK6', 'Gene', '1021', (38, 42))	('CDK4', 'Gene', '1019', (60, 64))	('cyclin D1', 'Gene', '595', (24, 33))	('cyclin D1', 'Gene', (24, 33))	('GPR39-c4', 'Var', (83, 91))
151079	21352519	Wound-healing assay showed that that the ectopic expression of GPR39 could significantly increase cell migration ability in GPR39-transfected cells compared with empty-vector control (P < 0.05, Figure 3C).	('GPR39', 'Gene', (63, 68))	('cell migration ability', 'CPA', (98, 120))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('rat', 'Species', '10116', (106, 109))	('ectopic expression', 'Var', (41, 59))	('increase', 'PosReg', (89, 97))
151080	21352519	Matrigel invasion assay also found that the ectopic expression of GPR39 could significantly enhanced the invasiveness of ESCC cells, as demonstrated by a significant increase in the number of invaded cells (P < 0.01, Figure 3D), in GPR39-transfected cells compared with empty-vector control.	('increase', 'PosReg', (166, 174))	('GPR39', 'Gene', (66, 71))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('rat', 'Species', '10116', (143, 146))	('ectopic expression', 'Var', (44, 62))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('invasiveness of ESCC cells', 'CPA', (105, 131))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('enhanced', 'PosReg', (92, 100))
151081	21352519	To determine whether the effect of GPR39 on cell motility was associated with EMT, expressions of several epithelial markers (E-cadherin, N-cadherin) and mesenchymal markers (vimentin, and fibronectin) were compared between GPR39-c4 and Vec-30 cells by RT-PCR and Western blot analysis.	('fibronectin', 'Gene', (189, 200))	('epithelia', 'Disease', 'None', (106, 115))	('E-cadherin', 'Gene', (126, 136))	('epithelia', 'Disease', (106, 115))	('E-cadherin', 'Gene', '999', (126, 136))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('N-cadherin', 'Gene', (138, 148))	('fibronectin', 'Gene', '2335', (189, 200))	('vimentin', 'Gene', '7431', (175, 183))	('si', 'Chemical', 'MESH:D012825', (282, 284))	('GPR39-c4', 'Var', (224, 232))	('N-cadherin', 'Gene', '1000', (138, 148))	('vimentin', 'Gene', (175, 183))
151084	21352519	The results showed that GPR39-expressing cells exhibited enhanced lamellipodia formation compared with control cells (Figure 4C), indicating that GPR39 could induce cytoskeleton remodeling to facilitate esophageal cancer cell migration and invasion.	('facilitate', 'PosReg', (192, 202))	('esophageal cancer', 'Disease', (203, 220))	('cytoskeleton remodeling', 'CPA', (165, 188))	('rat', 'Species', '10116', (229, 232))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('invasion', 'CPA', (240, 248))	('GPR39', 'Var', (146, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (203, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('si', 'Chemical', 'MESH:D012825', (244, 246))	('induce', 'Reg', (158, 164))
151087	21352519	The result showed that the GPR39-si1 had a better silencing effect (Figure 5A).	('si', 'Chemical', 'MESH:D012825', (50, 52))	('GPR39-si1', 'Var', (27, 36))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('silencing', 'MPA', (50, 59))
151088	21352519	Silencing of GPR39 resulted in a significant inhibition of the cell growth rate (P < 0.01, Figure 5B) and migration (Figure 5C).	('inhibition', 'NegReg', (45, 55))	('cell growth rate', 'CPA', (63, 79))	('GPR39', 'Gene', (13, 18))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('rat', 'Species', '10116', (75, 78))	('rat', 'Species', '10116', (109, 112))	('migration', 'CPA', (106, 115))	('Silencing', 'Var', (0, 9))
151089	21352519	DNA content analysis by flow cytometry showed that GPR39-si1 was able to inhibit the cell cycle at the G1/S checkpoint (Figure 5D).	('GPR39-si1', 'Var', (51, 60))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('cell cycle at the G1/S checkpoint', 'CPA', (85, 118))	('inhibit', 'NegReg', (73, 80))
151090	21352519	The percentage of cells in the S phase was significantly reduced in GPR39-si1-treated cells (27.23 +- 1.26%) compared with that in control-si-treated cells (35.13 +- 1.12%; P < 0.05).	('GPR39-si1-treated', 'Var', (68, 85))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('cells in the S phase', 'CPA', (18, 38))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('reduced', 'NegReg', (57, 64))
151094	21352519	To our knowledge, this is the first illustration that GPR39 contributes to the development and progression of ESCC.	('contributes', 'Reg', (60, 71))	('GPR39', 'Var', (54, 59))	('ESCC', 'Disease', (110, 114))	('si', 'Chemical', 'MESH:D012825', (102, 104))	('rat', 'Species', '10116', (42, 45))
151096	21352519	Functional studies showed that GPR39 could effectively promote ESCC cancer cell growth, increase foci formation and colony formation and enhance tumor formation in nude mice.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('enhance', 'PosReg', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('increase foci', 'Disease', (88, 101))	('GPR39', 'Var', (31, 36))	('colony formation', 'CPA', (116, 132))	('tumor', 'Disease', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('nude mice', 'Species', '10090', (164, 173))	('cancer', 'Disease', (68, 74))	('promote', 'PosReg', (55, 62))	('increase foci', 'Disease', 'MESH:C565785', (88, 101))
151098	21352519	Our study also provided evidence that ectopic expression of GPR39 increased ESCC cancer cell growth, indicating involvement of the GPR39 receptor in the tumorigenesis of esophageal cancer.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('increased', 'PosReg', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('increased ESCC', 'Phenotype', 'HP:0003565', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('esophageal cancer', 'Disease', (170, 187))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('ectopic expression', 'Var', (38, 56))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('involvement', 'Reg', (112, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))	('cancer', 'Disease', (181, 187))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('GPR39', 'Gene', (60, 65))
151101	21352519	We showed for the first time that GPR39 controls cell cycle progression through the activation of CDK6 and its activating protein, cyclin D1.	('cyclin D1', 'Gene', (131, 140))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('CDK6', 'Gene', (98, 102))	('GPR39', 'Var', (34, 39))	('cell cycle progression', 'CPA', (49, 71))	('activation', 'PosReg', (84, 94))	('CDK6', 'Gene', '1021', (98, 102))	('controls', 'Reg', (40, 48))	('cyclin D1', 'Gene', '595', (131, 140))
151103	21352519	On the other hand, we found that silencing of GPR39 expression could inhibit tumorigenicity in KYSE180 cells through the cell cycle arrest at G1/S checkpoint.	('si', 'Chemical', 'MESH:D012825', (33, 35))	('KYSE180', 'CellLine', 'CVCL:1349', (95, 102))	('silencing', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('GPR39', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cell cycle arrest at G1/S checkpoint', 'CPA', (121, 157))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('tumor', 'Disease', (77, 82))	('inhibit', 'NegReg', (69, 76))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))
151104	21352519	Another interesting finding of this study is the promoting effect of GPR39 on tumor metastasis in ESCC.	('promoting', 'PosReg', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('ESCC', 'Disease', (98, 102))	('GPR39', 'Var', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
151108	21352519	Moreover, the observation of overexpression of GPR39 resulting in cell morphological alteration promoted us to further investigate its effect on EMT.	('GPR39', 'Var', (47, 52))	('cell morphological alteration', 'CPA', (66, 95))	('overexpression', 'PosReg', (29, 43))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('rat', 'Species', '10116', (89, 92))
151109	21352519	We found that GPR39 has some impact on the EMT as shown by decreasing the epithelial molecule E-cadherin, an event critical in tumour invasion and a 'master' regulator of EMT.	('E-cadherin', 'Gene', (94, 104))	('E-cadherin', 'Gene', '999', (94, 104))	('si', 'Chemical', 'MESH:D012825', (138, 140))	('epithelia', 'Disease', 'None', (74, 83))	('epithelia', 'Disease', (74, 83))	('GPR39', 'Var', (14, 19))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour invasion', 'Disease', 'MESH:D009361', (127, 142))	('decreasing', 'NegReg', (59, 69))	('EMT', 'CPA', (43, 46))	('tumour invasion', 'Disease', (127, 142))	('si', 'Chemical', 'MESH:D012825', (65, 67))
151112	21352519	As expected, our result showed that GPR39 led to significant alterations on cytoskeleton by inducing the lamellipodia formation in GPR39-transfected ESCC cells.	('GPR39', 'Var', (36, 41))	('rat', 'Species', '10116', (65, 68))	('alterations', 'Reg', (61, 72))	('inducing', 'PosReg', (92, 100))	('lamellipodia formation', 'CPA', (105, 127))	('GPR39-transfected', 'Var', (131, 148))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('cytoskeleton', 'MPA', (76, 88))
151113	21352519	This finding was consistent to previous studies that some G protein-coupled receptors (GPCRs) were able to promote actin reorganization and result in cell shape changes and enhanced cell migration, indicating that GPR39 might directly alter the cytoskeleton to favor the tumor cell invasion and metastasis in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('cell shape changes', 'CPA', (150, 168))	('actin reorganization', 'CPA', (115, 135))	('si', 'Chemical', 'MESH:D012825', (302, 304))	('si', 'Chemical', 'MESH:D012825', (286, 288))	('favor', 'PosReg', (261, 266))	('rat', 'Species', '10116', (190, 193))	('GPCR', 'Gene', '442206', (87, 91))	('tumor', 'Disease', (271, 276))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('ESCC', 'Disease', (309, 313))	('enhanced', 'PosReg', (173, 181))	('GPR39', 'Var', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('alter', 'Reg', (235, 240))	('cell migration', 'CPA', (182, 196))	('G protein-coupled receptors', 'Protein', (58, 85))	('metastasis', 'CPA', (295, 305))	('GPCR', 'Gene', (87, 91))	('promote', 'PosReg', (107, 114))
151114	21352519	In this study, we have also provided evidence that targeting of GPR39 with specific RNAi will reduce the oncogenic characteristics of ESCC tumor cells.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('GPR39', 'Var', (64, 69))	('ESCC', 'Disease', (134, 138))	('targeting', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('oncogenic characteristics of', 'CPA', (105, 133))	('reduce', 'NegReg', (94, 100))
151117	21352519	In summary, our findings demonstrate that GPR39 plays an important role in ESCC development and progression via promoting cell proliferation, enhancing cell motility and invasiveness, regulating cytoskeleton and inducing EMT.	('rat', 'Species', '10116', (32, 35))	('GPR39', 'Var', (42, 47))	('cytoskeleton', 'MPA', (195, 207))	('ESCC', 'Disease', (75, 79))	('EMT', 'CPA', (221, 224))	('invasiveness', 'CPA', (170, 182))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('enhancing', 'PosReg', (142, 151))	('cell motility', 'CPA', (152, 165))	('rat', 'Species', '10116', (134, 137))	('inducing', 'PosReg', (212, 220))	('promoting', 'PosReg', (112, 121))	('regulating', 'Reg', (184, 194))	('cell proliferation', 'CPA', (122, 140))
151122	21352519	The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/11/86/prepub This work was supported by Grants from National Natural Science Foundation of China (30772475, 30700820 and 30971606), Sun Yat-Sen University "Hundred Talents Program" (85000-3171311), Grant from the Major State Basic Research Program of China (2006CB910104), Research Fund for the Doctoral Program of Higher Education of China (20070558272) and Research Grant Council Central Allocation (HKUST 2/06C).	('si', 'Chemical', 'MESH:D012825', (331, 333))	('30772475', 'Var', (202, 210))	('20070558272', 'Var', (446, 457))	('30700820', 'Var', (212, 220))	('30971606', 'Var', (225, 233))	('si', 'Chemical', 'MESH:D012825', (254, 256))
151218	30368777	A variant form of CD44 (CD44v) interacts with cysteine-glutamate transporter and maintain high levels of intracellular reduced glutathione (GSH), leading to protect cells from oxidative stress .	('protect', 'PosReg', (157, 164))	('oxidative stress', 'MPA', (176, 192))	('glutathione', 'Chemical', 'MESH:D005978', (127, 138))	('cysteine-glutamate transporter', 'MPA', (46, 76))	('maintain', 'PosReg', (81, 89))	('variant', 'Var', (2, 9))	('cysteine', 'Chemical', 'MESH:D003545', (46, 54))	('CD44', 'Gene', '960', (24, 28))	('glutamate', 'Chemical', 'None', (55, 64))	('CD44', 'Gene', '960', (18, 22))	('oxidative stress', 'Phenotype', 'HP:0025464', (176, 192))	('CD44v', 'Gene', (24, 29))	('interacts', 'Interaction', (31, 40))	('CD44v', 'Gene', '960', (24, 29))	('CD44', 'Gene', (24, 28))	('GSH', 'Chemical', 'MESH:D005978', (140, 143))	('CD44', 'Gene', (18, 22))
151233	29483964	Conclusions: This meta-analysis based on the largest-scale of published literature confirms that post-CCRT yields significant survival benefit and improves local-regional control with tolerable toxicity for patients with esophageal carcinoma.	('patients', 'Species', '9606', (207, 215))	('toxicity', 'Disease', (194, 202))	('post-CCRT', 'Var', (97, 106))	('local-regional control', 'CPA', (156, 178))	('improves', 'PosReg', (147, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('esophageal carcinoma', 'Disease', (221, 241))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (221, 241))	('toxicity', 'Disease', 'MESH:D064420', (194, 202))	('survival benefit', 'CPA', (126, 142))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (221, 241))
151247	29483964	The survival benefits were also observed in the comparisons of post-CCRT with surgery alone (SA) or with post-RT.	('SA', 'Chemical', '-', (93, 95))	('benefits', 'PosReg', (13, 21))	('post-CCRT', 'Var', (63, 72))
151256	29483964	The pooled analysis results revealed that post-CCRT didn't increase the risk of grade 3-4 anemia (OR=1.26, 95% CI=0.34-4.73, P=0.73) and thrombocytopenia (OR=0.84, 95% CI=0.25-2.82, P=0.77) compared with post-CT or post-RT.	('anemia', 'Disease', 'MESH:D000740', (90, 96))	('thrombocytopenia', 'Disease', (137, 153))	('anemia', 'Phenotype', 'HP:0001903', (90, 96))	('thrombocytopenia', 'Disease', 'MESH:D013921', (137, 153))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (137, 153))	('anemia', 'Disease', (90, 96))	('post-CCRT', 'Var', (42, 51))
151257	29483964	Compared with post-RT, post-CCRT increased the risk of esophagitis (OR=1.71, 95% CI=1.09-2.66, P=0.02) but not pneumonitis (OR=0.89, 95% CI=0.55-1.44, P=0.63) or anastomotic stenosis (OR=0.54, 95% CI=0.18-1.59, P=0.26)(Supplementary Table S3).	('pneumonitis', 'Disease', (111, 122))	('anastomotic stenosis', 'Disease', 'MESH:D057868', (162, 182))	('esophagitis', 'Phenotype', 'HP:0100633', (55, 66))	('esophagitis', 'Disease', (55, 66))	('esophagitis', 'Disease', 'MESH:D004941', (55, 66))	('post-CCRT', 'Var', (23, 32))	('pneumonitis', 'Disease', 'MESH:D011014', (111, 122))	('anastomotic stenosis', 'Disease', (162, 182))
151261	29483964	The only one previously published meta-analysis conducted by Zheng indicated that patients with esophageal cancer after surgery could gain survival benefit from post-CCRT.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (82, 90))	('esophageal cancer', 'Disease', (96, 113))	('survival benefit', 'CPA', (139, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('post-CCRT', 'Var', (161, 170))	('gain', 'PosReg', (134, 138))
151263	29483964	Our meta-analysis based on the 2165 esophageal cancer patients confirmed that post-CCRT can significantly improve the overall survival as well as the local-regional control as compared with non-CCRT strategies after surgery.	('esophageal cancer', 'Disease', 'MESH:D004938', (36, 53))	('overall survival', 'CPA', (118, 134))	('improve', 'PosReg', (106, 113))	('patients', 'Species', '9606', (54, 62))	('post-CCRT', 'Var', (78, 87))	('local-regional control', 'CPA', (150, 172))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancer', 'Disease', (36, 53))
151264	29483964	What's more, subgroup analyses showed that patients receiving post-CCRT had greater survival benefits than those treated with post-RT or SA.	('patients', 'Species', '9606', (43, 51))	('SA', 'Chemical', '-', (137, 139))	('survival benefits', 'CPA', (84, 101))	('post-CCRT', 'Var', (62, 71))
151268	29483964	What's more, meta-analysis of head and neck cancer also confirmed that post-CCRT significantly improved survival and local-regional control but not the distant control.	('head', 'Disease', (30, 34))	('survival', 'CPA', (104, 112))	('post-CCRT', 'Var', (71, 80))	('neck cancer', 'Disease', (39, 50))	('improved', 'PosReg', (95, 103))	('neck cancer', 'Disease', 'MESH:D006258', (39, 50))	('head and neck cancer', 'Phenotype', 'HP:0012288', (30, 50))	('local-regional control', 'CPA', (117, 139))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
151269	29483964	This meta-analysis is highly representative for including all the studies concerning about post-CCRT in the treatment of esophageal carcinoma all over the world.	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('esophageal carcinoma', 'Disease', (121, 141))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (121, 141))	('post-CCRT', 'Var', (91, 100))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (121, 141))
151273	29483964	In our study, with SCC accounting for approximately 95% of all cases, subgroup analysis was performed with trials only including patients with SCC and the pooled result confirmed that post-CCRT could significantly improve the prognosis for these patients.	('SCC', 'Gene', (143, 146))	('improve', 'PosReg', (214, 221))	('SCC', 'Gene', '6317', (19, 22))	('prognosis', 'MPA', (226, 235))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (246, 254))	('post-CCRT', 'Var', (184, 193))	('SCC', 'Gene', '6317', (143, 146))	('SCC', 'Gene', (19, 22))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))
151278	29483964	Actually, studies included in our meta-analysis showed that common toxicities related to post-CCRT were hypohemoglobinemia, leucocytopenia, thrombocytopenia, nausea/vomiting, esophagitis and stomatitis.	('thrombocytopenia', 'Phenotype', 'HP:0001873', (140, 156))	('nausea/vomiting', 'Phenotype', 'HP:0002017', (158, 173))	('toxicities', 'Disease', (67, 77))	('nausea/vomiting', 'Disease', (158, 173))	('stomatitis', 'Phenotype', 'HP:0010280', (191, 201))	('esophagitis', 'Disease', (175, 186))	('stomatitis', 'Disease', (191, 201))	('nausea', 'Phenotype', 'HP:0002018', (158, 164))	('nausea/vomiting', 'Disease', 'MESH:D020250', (158, 173))	('esophagitis', 'Disease', 'MESH:D004941', (175, 186))	('vomiting', 'Phenotype', 'HP:0002013', (165, 173))	('leucocytopenia', 'Disease', (124, 138))	('hypohemoglobinemia', 'Disease', 'None', (104, 122))	('esophagitis', 'Phenotype', 'HP:0100633', (175, 186))	('thrombocytopenia', 'Disease', (140, 156))	('hypohemoglobinemia', 'Disease', (104, 122))	('stomatitis', 'Disease', 'MESH:D013280', (191, 201))	('leucocytopenia', 'Disease', 'None', (124, 138))	('post-CCRT', 'Var', (89, 98))	('toxicities', 'Disease', 'MESH:D064420', (67, 77))	('thrombocytopenia', 'Disease', 'MESH:D013921', (140, 156))
151279	29483964	Post-CCRT didn't significantly increase the risk of pneumonitis, anastomotic stenosis and severe hematologic toxicity compared with post-CT or post-RT.	('Post-CCRT', 'Var', (0, 9))	('pneumonitis', 'Disease', (52, 63))	('anastomotic stenosis', 'Disease', (65, 85))	('pneumonitis', 'Disease', 'MESH:D011014', (52, 63))	('anastomotic stenosis', 'Disease', 'MESH:D057868', (65, 85))	('toxicity', 'Disease', 'MESH:D064420', (109, 117))	('toxicity', 'Disease', (109, 117))
151280	29483964	Though esophagitis was significantly increased in the CCRT group, it all graded no more than 2 and could be well tolerated after symptomatic and supportive treatment.	('esophagitis', 'Phenotype', 'HP:0100633', (7, 18))	('esophagitis', 'Disease', (7, 18))	('esophagitis', 'Disease', 'MESH:D004941', (7, 18))	('increased', 'PosReg', (37, 46))	('CCRT', 'Var', (54, 58))
151281	29483964	What's more, meta-analyses studying about preoperative CCRT in the treatment of resectable esophageal carcinoma confirmed that CCRT was associated with no increased risk of postoperative morbidity or perioperative mortality.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (91, 111))	('CCRT', 'Var', (127, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('esophageal carcinoma', 'Disease', (91, 111))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (91, 111))
151283	29483964	Although our meta-analysis confirmed significant improvement in both loco-regional control and overall survival with post-CCRT in the treatment of esophageal carcinoma, there are still some issues need further clarification.	('improvement', 'PosReg', (49, 60))	('post-CCRT', 'Var', (117, 126))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (147, 167))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (147, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('loco-regional control', 'CPA', (69, 90))	('esophageal carcinoma', 'Disease', (147, 167))
151284	29483964	What's more, though post-CCRT could provide survival benefit for esophageal cancer patients, the studies conducted with SEER database indicated that preoperative CCRT (or RT) provides superior survival compared with post-CCRT (or RT).	('esophageal cancer', 'Disease', (65, 82))	('superior', 'PosReg', (184, 192))	('survival', 'MPA', (193, 201))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CCRT', 'Var', (162, 166))	('patients', 'Species', '9606', (83, 91))
151287	29483964	In conclusion, this meta-analysis including the largest-scale of relatively high quality trials confirms the value of post-CCRT in the treatment of esophageal carcinoma, especially in SCC.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('post-CCRT', 'Var', (118, 127))	('esophageal carcinoma', 'Disease', (148, 168))	('SCC', 'Gene', (184, 187))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (148, 168))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (148, 168))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('SCC', 'Gene', '6317', (184, 187))
151288	29483964	Post-CCRT brings about significant survival benefit and improves local-regional control without increased risk of severe toxicities compared with non-CCRT treatment.	('toxicities', 'Disease', (121, 131))	('Post-CCRT', 'Var', (0, 9))	('local-regional control', 'CPA', (65, 87))	('toxicities', 'Disease', 'MESH:D064420', (121, 131))	('improves', 'PosReg', (56, 64))	('survival benefit', 'CPA', (35, 51))
151297	29435162	OS was significantly lower in PD-L1-positive patients than in PD-L1-negative patients at 1 year (P = 0.039), 3 years (P < 0.001) and 5 years (P < 0.001).	('PD-L1-positive', 'Var', (30, 44))	('patients', 'Species', '9606', (45, 53))	('lower', 'NegReg', (21, 26))	('patients', 'Species', '9606', (77, 85))
151316	29435162	PD-L1 expression was associated with worse 1-year OS for the following types of solid tumor (Table 2): gastric cancer, 2.48 (1.80-3.41); renal cell carcinoma, 3.38 (2.13-5.39); and hepatocellular carcinoma, 1.87 (1.01-3.46).	('hepatocellular carcinoma', 'Disease', (181, 205))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (181, 205))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('renal cell carcinoma', 'Disease', (137, 157))	('PD-L1', 'Gene', (0, 5))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('solid tumor', 'Disease', (80, 91))	('gastric cancer', 'Disease', (103, 117))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (137, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('expression', 'Var', (6, 16))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (181, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('solid tumor', 'Disease', 'MESH:D009369', (80, 91))
151317	29435162	PD-L1 expression was associated with worse 3-year OS for the following cancers: esophageal cancer, 2.77 (1.78-4.30); gastric cancer, 1.63 (1.43-1.87); pancreatic cancer, 1.48 (1.06-2.06); and renal cell carcinoma, 4.14 (2.07-8.26).	('PD-L1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('gastric cancer', 'Disease', (117, 131))	('expression', 'Var', (6, 16))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('renal cell carcinoma', 'Disease', (192, 212))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('esophageal cancer', 'Disease', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 212))	('pancreatic cancer', 'Disease', (151, 168))
151318	29435162	PD-L1 expression was associated with worse 5-year OS for esophageal cancer, 3.55 (2.63-5.65); gastric cancer, 1.45 (1.18-1.79); hepatocellular carcinoma, 1.58 (1.11-2.25); and renal cell carcinoma, 2.57 (1.46-4.52).	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('renal cell carcinoma', 'Disease', (176, 196))	('gastric cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (128, 152))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (176, 196))	('hepatocellular carcinoma', 'Disease', (128, 152))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (128, 152))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (176, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('PD-L1', 'Gene', (0, 5))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('esophageal cancer', 'Disease', (57, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('expression', 'Var', (6, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))
151323	29435162	While studies published more than a decade ago established that PD-L1 promotes cancer immune escape and that blocking PD-L1 can improve the anti-tumor efficacy of anti-tumor responses, whether PD-L1 expression by solid tumors negatively affects patient prognosis remains unclear.	('tumor', 'Disease', (219, 224))	('solid tumors', 'Disease', (213, 225))	('promotes', 'PosReg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('blocking', 'Var', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', (145, 150))	('solid tumors', 'Disease', 'MESH:D009369', (213, 225))	('cancer', 'Disease', (79, 85))	('patient', 'Species', '9606', (245, 252))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('PD-L1', 'Gene', (118, 123))	('tumor', 'Disease', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('improve', 'PosReg', (128, 135))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
151324	29435162	Here we reviewed 59 studies involving 20,004 patients with 11 types of solid tumors and found strong evidence that PD-L1 expression is associated with significantly lower OS at 1, 3 and 5 years.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('solid tumors', 'Disease', (71, 83))	('lower', 'NegReg', (165, 170))	('solid tumors', 'Disease', 'MESH:D009369', (71, 83))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('expression', 'Var', (121, 131))	('PD-L1', 'Gene', (115, 120))
151329	29435162	Our results are consistent with previous reports that PD-L1 expression is associated with worse 5-year outcome in patients with gastrointestinal carcinomas such as esophageal cancer and gastric cancer as well as colorectal cancer.	('gastrointestinal carcinomas', 'Disease', (128, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (128, 155))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('esophageal cancer', 'Disease', (164, 181))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('expression', 'Var', (60, 70))	('colorectal cancer', 'Disease', 'MESH:D015179', (212, 229))	('patients', 'Species', '9606', (114, 122))	('gastric cancer', 'Disease', (186, 200))	('colorectal cancer', 'Disease', (212, 229))	('PD-L1', 'Gene', (54, 59))	('worse', 'NegReg', (90, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('gastrointestinal carcinomas', 'Disease', 'MESH:D004067', (128, 155))	('colorectal cancer', 'Phenotype', 'HP:0003003', (212, 229))
151340	29435162	This outcome was compared between patients showing high or positive PD-L1 expression and patients showing low or no expression, as defined within the individual studies.	('patients', 'Species', '9606', (89, 97))	('expression', 'Var', (74, 84))	('PD-L1', 'Gene', (68, 73))	('patients', 'Species', '9606', (34, 42))
151344	29026004	Western blot results showed that CoCl2 and H2O2 treatment of TE-1 cells led to significant reduction in mitochondrial respiratory chain complex subunits expression and increasing intracellular reactive oxygen species (ROS) production.	('TE-1', 'CellLine', 'CVCL:1759', (61, 65))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (193, 216))	('increasing', 'PosReg', (168, 178))	('H2O2', 'Chemical', 'MESH:D006861', (43, 47))	('H2O2', 'Var', (43, 47))	('reduction', 'NegReg', (91, 100))	('expression', 'MPA', (153, 163))	('ROS', 'Chemical', 'MESH:D017382', (218, 221))	('CoCl2', 'Chemical', 'MESH:C018021', (33, 38))
151346	29026004	However, H2O2 treatment decreased both the mitochondrial respiration and aerobic glycolysis significantly.	('aerobic glycolysis', 'MPA', (73, 91))	('decreased', 'NegReg', (24, 33))	('H2O2', 'Chemical', 'MESH:D006861', (9, 13))	('H2O2', 'Var', (9, 13))	('mitochondrial respiration', 'MPA', (43, 68))
151347	29026004	Moreover, we found that H2O2 induces apoptosis in TE-1 cells through the activation of PARP, Caspase 3, and Caspase 9.	('H2O2', 'Var', (24, 28))	('activation', 'PosReg', (73, 83))	('Caspase 3', 'Gene', '836', (93, 102))	('apoptosis', 'CPA', (37, 46))	('Caspase 9', 'Gene', (108, 117))	('PARP', 'Gene', (87, 91))	('Caspase 9', 'Gene', '842', (108, 117))	('Caspase 3', 'Gene', (93, 102))	('TE-1', 'CellLine', 'CVCL:1759', (50, 54))	('PARP', 'Gene', '142', (87, 91))	('H2O2', 'Chemical', 'MESH:D006861', (24, 28))
151348	29026004	Therefore, our findings indicate that CoCl2 and H2O2 could cause mitochondrial dysfunction by up-regulation of ROS and regulating the cellular bioenergy metabolism, thus affecting the survival of tumor cells.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (65, 90))	('H2O2', 'Chemical', 'MESH:D006861', (48, 52))	('H2O2', 'Var', (48, 52))	('tumor', 'Disease', (196, 201))	('up-regulation', 'PosReg', (94, 107))	('mitochondrial dysfunction', 'Disease', (65, 90))	('regulating', 'Reg', (119, 129))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (65, 90))	('CoCl2', 'Chemical', 'MESH:C018021', (38, 43))	('cause', 'Reg', (59, 64))	('ROS', 'Chemical', 'MESH:D017382', (111, 114))	('ROS', 'Protein', (111, 114))	('affecting', 'Reg', (170, 179))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('cellular bioenergy metabolism', 'MPA', (134, 163))	('CoCl2', 'Var', (38, 43))
151359	29026004	H2O2 is also an important signaling molecule in tumor cells, which can regulate cell signaling pathways and transcription factors at different levels.	('tumor', 'Disease', (48, 53))	('transcription', 'Protein', (108, 121))	('regulate', 'Reg', (71, 79))	('cell signaling pathways', 'Pathway', (80, 103))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
151360	29026004	For example, H2O2 can induce the activation of EGFR, which leads to the amplification of Ras signaling cascade and activation of mitogen-activated protein kinases (MAPKs).	('activation', 'PosReg', (115, 125))	('activation', 'PosReg', (33, 43))	('Ras signaling cascade', 'Pathway', (89, 110))	('amplification', 'PosReg', (72, 85))	('mitogen-activated protein kinases', 'Pathway', (129, 162))	('EGFR', 'Gene', '1956', (47, 51))	('H2O2', 'Chemical', 'MESH:D006861', (13, 17))	('H2O2', 'Var', (13, 17))	('EGFR', 'Gene', (47, 51))
151361	29026004	Moreover, H2O2 can indirectly regulate PTK-EGFR-Ras signaling in cancer cells, and finally the activation of MAPK, so that ERK, JNK, p38, three subfamilies signaling pathways are regulated.	('PTK', 'Gene', (39, 42))	('JNK', 'Gene', '5599', (128, 131))	('ERK', 'Gene', (123, 126))	('cancer', 'Disease', (65, 71))	('EGFR', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('regulate', 'Reg', (30, 38))	('H2O2', 'Chemical', 'MESH:D006861', (10, 14))	('PTK', 'Gene', '2185', (39, 42))	('three subfamilies signaling pathways', 'Pathway', (138, 174))	('EGFR', 'Gene', '1956', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('MAPK', 'Gene', (109, 113))	('H2O2', 'Var', (10, 14))	('p38', 'Gene', '7965', (133, 136))	('ERK', 'Gene', '5594', (123, 126))	('p38', 'Gene', (133, 136))	('regulated', 'Reg', (179, 188))	('JNK', 'Gene', (128, 131))
151362	29026004	Low concentration of H2O2 plays an essential role in regulating cell division and growth as a signaling molecule; however, when the amount of H2O2 exceeds a certain critical value, the cell cycle will be blocked and even lead to apoptosis.	('H2O2', 'Chemical', 'MESH:D006861', (142, 146))	('H2O2', 'Var', (142, 146))	('cell cycle', 'CPA', (185, 195))	('blocked', 'NegReg', (204, 211))	('H2O2', 'Chemical', 'MESH:D006861', (21, 25))	('apoptosis', 'CPA', (229, 238))	('lead to', 'Reg', (221, 228))
151396	29026004	In addition, we detected the ability of glycolysis in TE-1 cells when treated with CoCl2, as result showed that when compared with the negative control, the glycolysis ability of TE-1 cells significantly increased under the treatment of CoCl2 and the difference was statistically significant (Figure 2C,D).	('CoCl2', 'Var', (237, 242))	('TE-1', 'CellLine', 'CVCL:1759', (179, 183))	('increased', 'PosReg', (204, 213))	('CoCl2', 'Chemical', 'MESH:C018021', (83, 88))	('CoCl2', 'Chemical', 'MESH:C018021', (237, 242))	('glycolysis', 'MPA', (157, 167))	('TE-1', 'CellLine', 'CVCL:1759', (54, 58))
151400	29026004	On the one hand, TE-1 cells inhibited the expression of mitochondrial complex subunits by increasing ROS level; on the other hand, TE-1 cell enhanced glycolysis ability by increasing the expression of glucose metabolism related enzymes.	('TE-1', 'CellLine', 'CVCL:1759', (17, 21))	('glycolysis ability', 'MPA', (150, 168))	('glucose metabolism related enzymes', 'MPA', (201, 235))	('expression', 'MPA', (42, 52))	('glucose', 'Chemical', 'MESH:D005947', (201, 208))	('increasing', 'PosReg', (172, 182))	('inhibited', 'NegReg', (28, 37))	('TE-1', 'Var', (131, 135))	('mitochondrial complex subunits', 'MPA', (56, 86))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('enhanced', 'PosReg', (141, 149))	('ROS level', 'MPA', (101, 110))	('expression', 'MPA', (187, 197))	('TE-1', 'CellLine', 'CVCL:1759', (131, 135))	('increasing', 'PosReg', (90, 100))
151411	29026004	The result showed that compared with the negative control group, intracellular ROS level increased in a dose-dependent manner in H2O2-treated TE-1 cells (Figure 4B).	('intracellular ROS level', 'MPA', (65, 88))	('ROS', 'Chemical', 'MESH:D017382', (79, 82))	('TE-1', 'CellLine', 'CVCL:1759', (142, 146))	('H2O2', 'Chemical', 'MESH:D006861', (129, 133))	('H2O2-treated', 'Var', (129, 141))	('ROS level increased', 'Phenotype', 'HP:0025464', (79, 98))	('increased', 'PosReg', (89, 98))
151414	29026004	We also analyzed the effects of H2O2 and CoCl2 on cell growth, and found that both H2O2 and CoCl2 could suppress cell growth in TE-1 cells.	('H2O2', 'Chemical', 'MESH:D006861', (83, 87))	('H2O2', 'Var', (83, 87))	('suppress', 'NegReg', (104, 112))	('cell growth in TE-1', 'CPA', (113, 132))	('H2O2', 'Chemical', 'MESH:D006861', (32, 36))	('TE-1', 'CellLine', 'CVCL:1759', (128, 132))	('CoCl2', 'Chemical', 'MESH:C018021', (41, 46))	('CoCl2', 'Chemical', 'MESH:C018021', (92, 97))	('CoCl2', 'Gene', (92, 97))
151415	29026004	However, H2O2 had a stronger suppressive activity than CoCl2 on TE-1 cells (Supplementary Figure S1).	('suppressive activity', 'MPA', (29, 49))	('TE-1', 'CellLine', 'CVCL:1759', (64, 68))	('H2O2', 'Chemical', 'MESH:D006861', (9, 13))	('H2O2', 'Var', (9, 13))	('CoCl2', 'Chemical', 'MESH:C018021', (55, 60))
151419	29026004	B and complex IV subunits (COXI and COXIV) were decreased in TE-1 cells treated with H2O2.	('TE-1', 'CellLine', 'CVCL:1759', (61, 65))	('COXIV', 'Gene', '1327', (36, 41))	('decreased', 'NegReg', (48, 57))	('COXIV', 'Gene', (36, 41))	('H2O2', 'Chemical', 'MESH:D006861', (85, 89))	('H2O2', 'Var', (85, 89))
151421	29026004	To further investigate the effects of H2O2 on TE-1 cellular bioenergetics, we analyzed mitochondrial respiration by determining the OCR (Figure 5B), and found that cells under the treatment of H2O2 displayed a lower basal respiration and a significantly lower maximum respiratory capacity and accompanied by less ATP production compared with the negative control group (Figure 5C).	('ATP production', 'MPA', (313, 327))	('OCR', 'Chemical', '-', (132, 135))	('less', 'NegReg', (308, 312))	('lower', 'NegReg', (254, 259))	('H2O2', 'Var', (193, 197))	('H2O2', 'Chemical', 'MESH:D006861', (193, 197))	('maximum respiratory capacity', 'MPA', (260, 288))	('lower', 'NegReg', (210, 215))	('ATP', 'Chemical', 'MESH:D000255', (313, 316))	('TE-1', 'CellLine', 'CVCL:1759', (46, 50))	('basal respiration', 'MPA', (216, 233))	('H2O2', 'Chemical', 'MESH:D006861', (38, 42))
151422	29026004	In addition, we found that the glycolysis rates of TE-1 cells were significantly decreased after H2O2 treatment (Figure 5D,E).	('decreased', 'NegReg', (81, 90))	('H2O2', 'Chemical', 'MESH:D006861', (97, 101))	('H2O2', 'Var', (97, 101))	('TE-1', 'CellLine', 'CVCL:1759', (51, 55))	('glycolysis rates', 'MPA', (31, 47))
151423	29026004	To further confirm the reduction in respiration and aerobic glycolysis were caused by H2O2 treatment, we used ROS scavenger NAC to investigate whether NAC could rescue these effects.	('NAC', 'Gene', '6622', (151, 154))	('H2O2', 'Chemical', 'MESH:D006861', (86, 90))	('H2O2', 'Var', (86, 90))	('NAC', 'Gene', (151, 154))	('NAC', 'Gene', '6622', (124, 127))	('respiration', 'MPA', (36, 47))	('reduction', 'NegReg', (23, 32))	('ROS', 'Chemical', 'MESH:D017382', (110, 113))	('NAC', 'Gene', (124, 127))	('aerobic glycolysis', 'MPA', (52, 70))
151427	29026004	These results indicated that H2O2 could cause the reduction in cellular bioenergetics of TE-1 cells via decreasing the expression of mitochondrial respiratory chain complex subunits.	('expression', 'MPA', (119, 129))	('mitochondrial respiratory chain complex subunits', 'MPA', (133, 181))	('reduction', 'NegReg', (50, 59))	('TE-1', 'CellLine', 'CVCL:1759', (89, 93))	('H2O2', 'Chemical', 'MESH:D006861', (29, 33))	('H2O2', 'Var', (29, 33))	('cellular', 'MPA', (63, 71))	('decreasing', 'NegReg', (104, 114))
151428	29026004	Based on the above data, we speculated that H2O2 induced apoptosis in TE-1 cells may be due to cellular energy metabolism disorders that were caused by the increase in ROS.	('ROS', 'Chemical', 'MESH:D017382', (168, 171))	('ROS', 'Protein', (168, 171))	('apoptosis', 'CPA', (57, 66))	('energy metabolism disorders', 'Disease', 'MESH:D008659', (104, 131))	('increase', 'PosReg', (156, 164))	('energy metabolism disorders', 'Disease', (104, 131))	('H2O2', 'Var', (44, 48))	('H2O2', 'Chemical', 'MESH:D006861', (44, 48))	('TE-1', 'CellLine', 'CVCL:1759', (70, 74))
151430	29026004	Moreover, we examined the apoptosis by flow cytometry, with the increased concentration of H2O2, the apoptosis rate gradually increased, but when TE-1 cells were treated with NAC simultaneously, we found that apoptosis induced by H2O2 was significantly reduced (Figure 7B,C).	('H2O2', 'Var', (230, 234))	('NAC', 'Gene', '6622', (175, 178))	('NAC', 'Gene', (175, 178))	('apoptosis', 'CPA', (209, 218))	('TE-1', 'CellLine', 'CVCL:1759', (146, 150))	('reduced', 'NegReg', (253, 260))	('H2O2', 'Chemical', 'MESH:D006861', (91, 95))	('H2O2', 'Chemical', 'MESH:D006861', (230, 234))
151431	29026004	Thus, we believed that H2O2 may induce the production of ROS and cause progressive oxidative damaged, mitochondrial dysfunction, cell bioenergetics metabolism disorders, and ultimately cell death.	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('ROS', 'Protein', (57, 60))	('oxidative damaged', 'MPA', (83, 100))	('cause', 'Reg', (65, 70))	('H2O2', 'Var', (23, 27))	('H2O2', 'Chemical', 'MESH:D006861', (23, 27))	('metabolism disorders', 'Disease', 'MESH:D008659', (148, 168))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (102, 127))	('metabolism disorders', 'Disease', (148, 168))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (102, 127))	('induce', 'PosReg', (32, 38))	('production', 'MPA', (43, 53))	('mitochondrial dysfunction', 'Disease', (102, 127))
151433	29026004	Mitochondria as key actors in cancer metabolic reprogramming, not just because these organelles play a significant role in energy production and biosynthetic intermediates formation, as well as occurrence of mutations in both nuclear and mtDNA encoding metabolic enzymes is associated with different types of cancer.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('mutations', 'Var', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('mtDNA', 'Gene', (238, 243))	('nuclear', 'Gene', (226, 233))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('associated', 'Reg', (274, 284))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (309, 315))
151438	29026004	Previous studies have shown that mutations in mtDNA, mitochondrial fusion and fission dysfunction and mitochondria-related active enzyme mutation can cause normal cells transformed into cancer cells.	('cause', 'Reg', (150, 155))	('mtDNA', 'Gene', (46, 51))	('fission dysfunction', 'Disease', 'OMIM:614388', (78, 97))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mutations', 'Var', (33, 42))	('fission dysfunction', 'Disease', (78, 97))	('mitochondrial fusion', 'CPA', (53, 73))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
151451	29026004	Second, H2O2 as a widely used inducer of cell damage and apoptosis, is capable of producing large amounts of oxygen free radicals that cause cellular oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (150, 166))	('oxygen free radicals', 'Chemical', '-', (109, 129))	('H2O2', 'Chemical', 'MESH:D006861', (8, 12))	('H2O2', 'Var', (8, 12))	('cause', 'Reg', (135, 140))	('oxygen free radicals', 'MPA', (109, 129))	('cellular oxidative stress', 'MPA', (141, 166))
151452	29026004	Our data proved that H2O2 indeed could induce apoptosis and inhibit the expression of mitochondria respiratory chain complex subunits.	('apoptosis', 'CPA', (46, 55))	('inhibit', 'NegReg', (60, 67))	('mitochondria respiratory chain complex subunits', 'MPA', (86, 133))	('expression', 'MPA', (72, 82))	('H2O2', 'Chemical', 'MESH:D006861', (21, 25))	('H2O2', 'Var', (21, 25))	('induce', 'PosReg', (39, 45))
151453	29026004	Moreover, we found that H2O2 could dramatically suppress the OCR and ATP production and simultaneously inhibited the cellular glycolytic rate.	('H2O2', 'Var', (24, 28))	('suppress', 'NegReg', (48, 56))	('OCR', 'Chemical', '-', (61, 64))	('ATP', 'Chemical', 'MESH:D000255', (69, 72))	('inhibited', 'NegReg', (103, 112))	('cellular glycolytic rate', 'MPA', (117, 141))	('H2O2', 'Chemical', 'MESH:D006861', (24, 28))
151454	29026004	Hence, we proposed that the apoptosis induced by H2O2 may be due to the energy metabolism dysfunction that is caused by the increase in ROS levels.	('H2O2', 'Var', (49, 53))	('increase', 'PosReg', (124, 132))	('ROS', 'Chemical', 'MESH:D017382', (136, 139))	('increase in ROS levels', 'Phenotype', 'HP:0025464', (124, 146))	('energy metabolism dysfunction', 'Disease', (72, 101))	('apoptosis', 'CPA', (28, 37))	('energy metabolism dysfunction', 'Disease', 'MESH:D008659', (72, 101))	('ROS levels', 'MPA', (136, 146))	('H2O2', 'Chemical', 'MESH:D006861', (49, 53))
151456	29026004	These results demonstrate that oxidative stress caused by H2O2 leads to severe impairment in TE-1 cell energy metabolism.	('H2O2', 'Chemical', 'MESH:D006861', (58, 62))	('H2O2', 'Var', (58, 62))	('TE-1 cell', 'CPA', (93, 102))	('TE-1', 'CellLine', 'CVCL:1759', (93, 97))	('oxidative stress', 'Phenotype', 'HP:0025464', (31, 47))	('oxidative stress', 'MPA', (31, 47))	('impairment', 'NegReg', (79, 89))
151457	29026004	Moreover, our findings show that H2O2 mediates apoptosis of TE-1 cells through activating caspase 3 and caspase 9.	('activating', 'PosReg', (79, 89))	('apoptosis', 'CPA', (47, 56))	('caspase 3', 'Gene', (90, 99))	('caspase 3', 'Gene', '836', (90, 99))	('H2O2', 'Chemical', 'MESH:D006861', (33, 37))	('H2O2', 'Var', (33, 37))	('caspase 9', 'Gene', (104, 113))	('caspase 9', 'Gene', '842', (104, 113))	('TE-1', 'CellLine', 'CVCL:1759', (60, 64))
151458	29026004	Therefore, H2O2 induced the increase in ROS levels, causing cell oxidative damage, mitochondrial dysfunction, and resulting in cell biological energy metabolism disorder, and ultimately induced apoptosis.	('induced', 'Reg', (186, 193))	('H2O2', 'Var', (11, 15))	('energy metabolism disorder', 'Disease', (143, 169))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (83, 108))	('H2O2', 'Chemical', 'MESH:D006861', (11, 15))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (83, 108))	('increase in ROS levels', 'Phenotype', 'HP:0025464', (28, 50))	('mitochondrial dysfunction', 'Disease', (83, 108))	('resulting in', 'Reg', (114, 126))	('causing', 'Reg', (52, 59))	('energy metabolism disorder', 'Disease', 'MESH:D008659', (143, 169))	('ROS levels', 'MPA', (40, 50))	('ROS', 'Chemical', 'MESH:D017382', (40, 43))	('increase', 'PosReg', (28, 36))	('cell oxidative damage', 'MPA', (60, 81))
151468	27667995	Using quantitative reverse-transcription PCR (qRT-PCR), expression levels of six candidate miRNAs (miR-143, miR-145, miR-192, miR-194, miR-203, and miR-205) were examined across a discovery cohort of patients with GERD (n = 24) versus Ctrls (n = 24).	('miR-205', 'Gene', '406988', (148, 155))	('miR-194', 'Var', (126, 133))	('miR-143', 'Gene', '406935', (99, 106))	('miR-143', 'Gene', (99, 106))	('miR-203', 'Var', (135, 142))	('miR-192', 'Gene', (117, 124))	('miR-192', 'Gene', '406967', (117, 124))	('miR-145', 'Gene', (108, 115))	('miR-205', 'Gene', (148, 155))	('miR-145', 'Gene', '406937', (108, 115))
151474	27667995	have shown that miR-203 and miR-205 are high in normal squamous epithelium and low in columnar epithelia, while miR-21, miR-143, miR-145, miR-194, and miR-215 are significantly upregulated in columnar tissues compared with normal squamous epithelium.	('upregulated', 'PosReg', (177, 188))	('miR-203', 'Var', (16, 23))	('miR-21', 'Gene', (151, 157))	('miR-21', 'Gene', '406991', (112, 118))	('miR-194', 'Var', (138, 145))	('miR-145', 'Var', (129, 136))	('miR-215', 'Gene', (151, 158))	('miR-205', 'Var', (28, 35))	('miR-143', 'Var', (120, 127))	('columnar epithelia', 'Disease', (86, 104))	('miR-215', 'Gene', '406997', (151, 158))	('miR-21', 'Gene', (112, 118))	('miR-21', 'Gene', '406991', (151, 157))	('columnar epithelia', 'Disease', 'None', (86, 104))
151476	27667995	reported that miR-143, miR-145, miR-192, and miR-194 were upregulated in esophageal epithelial cells upon acidic bile salt stimulation.	('miR-194', 'Gene', (45, 52))	('miR-145', 'Var', (23, 30))	('upregulated', 'PosReg', (58, 69))	('bile salt', 'Chemical', 'MESH:D001647', (113, 122))	('miR-192', 'Var', (32, 39))	('miR-143', 'Var', (14, 21))
151493	23263780	Black and hispanic patients were more likely than whites to have SCC (86% vs. 41% vs. 26%, respectively; p<0.001) and lesions in the mid-esophagus (58% vs. 38% vs. 26%, respectively; p<0.001).	('lesions', 'Var', (118, 125))	('SCC', 'Gene', '6317', (65, 68))	('patients', 'Species', '9606', (19, 27))	('SCC', 'Gene', (65, 68))
151580	25008389	The loci (CHK2 rs738722, C12orf51 rs2074356, and PLCE1 rs2274223) were genotyped, and the presence or absence of HPV16 in serum was measured by ELISA.	('C12orf51', 'Gene', (25, 33))	('rs2274223', 'Mutation', 'rs2274223', (55, 64))	('PLCE1', 'Gene', '51196', (49, 54))	('rs738722', 'Var', (15, 23))	('rs2274223', 'Var', (55, 64))	('rs2074356', 'Mutation', 'rs2074356', (34, 43))	('HPV16', 'Species', '333760', (113, 118))	('CHK2', 'Gene', (10, 14))	('C12orf51', 'Gene', '283450', (25, 33))	('CHK2', 'Gene', '11200', (10, 14))	('rs2074356', 'Var', (34, 43))	('rs738722', 'Mutation', 'rs738722', (15, 23))	('PLCE1', 'Gene', (49, 54))
151582	25008389	A significant interaction was found between HPV16 serology and rs2074356 (P = 0.005, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.11-1.77) or rs2274223 (P < 0.001, OR 1.53, 95% CI 1.23-1.91), but not for rs738722.	('HPV16', 'Species', '333760', (44, 49))	('rs738722', 'Mutation', 'rs738722', (212, 220))	('rs2074356', 'Mutation', 'rs2074356', (63, 72))	('HPV16', 'Gene', (44, 49))	('rs2274223', 'Mutation', 'rs2274223', (150, 159))	('rs2274223', 'Var', (150, 159))	('rs2074356', 'Var', (63, 72))
151583	25008389	For rs2074356, risk of ESCC was increased substantially in smokers (P < 0.001, OR 8.25, 95% CI 3.84-17.71) and drinkers (OR4.04, P = 0.001, 95% CI 1.79-9.10) who carried risk alleles (TT or TC genotype) and were HPV16-seropositive.	('SCC', 'Gene', (24, 27))	('SCC', 'Phenotype', 'HP:0002860', (24, 27))	('HPV16', 'Species', '333760', (212, 217))	('rs2074356', 'Mutation', 'rs2074356', (4, 13))	('SCC', 'Gene', '6317', (24, 27))	('rs2074356', 'Var', (4, 13))
151585	25008389	Consistent with the previous study, loci at rs2074356 and rs2274223 could increase the risk of ESCC, furthermore, there were significant interactions between HPV sero-status and the susceptibility loci on the risk of ESCC.	('interactions', 'Interaction', (137, 149))	('SCC', 'Phenotype', 'HP:0002860', (218, 221))	('SCC', 'Gene', '6317', (218, 221))	('SCC', 'Gene', (96, 99))	('HPV', 'Species', '10566', (158, 161))	('rs2074356', 'Mutation', 'rs2074356', (44, 53))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('SCC', 'Gene', '6317', (96, 99))	('SCC', 'Gene', (218, 221))	('rs2074356', 'Var', (44, 53))	('rs2274223', 'Mutation', 'rs2274223', (58, 67))	('rs2274223', 'Var', (58, 67))
151596	25008389	As five susceptibility loci located in PLCE1 at 10q23 had strong pair-wise linkage disequilibrium, we chose the most significant locus rs2274223.	('PLCE1', 'Gene', (39, 44))	('rs2274223', 'Var', (135, 144))	('PLCE1', 'Gene', '51196', (39, 44))	('rs2274223', 'Mutation', 'rs2274223', (135, 144))
151599	25008389	As for 22q12, only one susceptibility locus rs738722 located in CHK2 appeared significantly.	('CHK2', 'Gene', '11200', (64, 68))	('rs738722', 'Mutation', 'rs738722', (44, 52))	('CHK2', 'Gene', (64, 68))	('rs738722', 'Var', (44, 52))
151600	25008389	C12orf51 transcript on 12q24 and has been reported to be in high linkage disequilibrium with SNPs in ALDH2 and ALDH2 was reported to be associated with cardiomyocyte apoptosis post myocardial infarction induced by microRNA-34A, and H2O2-induced apoptosis in peripheral blood mononuclear cells.	('SNPs', 'Var', (93, 97))	('C12orf51', 'Gene', (0, 8))	('cardiomyocyte apoptosis post myocardial infarction', 'Disease', (152, 202))	('cardiomyocyte apoptosis post myocardial infarction', 'Disease', 'MESH:D009203', (152, 202))	('ALDH2', 'Gene', '217', (101, 106))	('associated with', 'Reg', (136, 151))	('H2O2', 'Chemical', 'MESH:D006861', (232, 236))	('ALDH2', 'Gene', '217', (111, 116))	('myocardial infarction', 'Phenotype', 'HP:0001658', (181, 202))	('C12orf51', 'Gene', '283450', (0, 8))	('microRNA-34A', 'Var', (214, 226))	('ALDH2', 'Gene', (101, 106))	('ALDH2', 'Gene', (111, 116))
151601	25008389	As for 12q24, three variants in high linkage disequilibrium conferred their risks to ESCC in a gene-life style interaction manner, with more pronounced risk enhancement seen in tobacco and alcohol users.	('risks', 'Reg', (76, 81))	('SCC', 'Gene', (86, 89))	('variants', 'Var', (20, 28))	('alcohol use', 'Phenotype', 'HP:0030955', (189, 200))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('SCC', 'Gene', '6317', (86, 89))	('alcohol', 'Chemical', 'MESH:D000438', (189, 196))	('tobacco', 'Species', '4097', (177, 184))
151602	25008389	Among these three variants located in 12q24, only association with rs2074356 remained genome-wide significant after adjusting for the effects of the other two variants, indicating rs2074356 could be an independent susceptibility marker.	('rs2074356', 'Mutation', 'rs2074356', (67, 76))	('rs2074356', 'Var', (180, 189))	('rs2074356', 'Var', (67, 76))	('rs2074356', 'Mutation', 'rs2074356', (180, 189))
151604	25008389	To our knowledge, no studies have been performed to investigate the interactions of the three SNPs CHK2 rs738722, C12orf51 rs2074356, and PLCE1 rs2274223 at apoptosis associated genes and HPV16 serostatus on the risk of ESCC.	('SCC', 'Gene', '6317', (221, 224))	('rs2274223', 'Var', (144, 153))	('PLCE1', 'Gene', '51196', (138, 143))	('C12orf51', 'Gene', '283450', (114, 122))	('HPV16', 'Species', '333760', (188, 193))	('CHK2', 'Gene', (99, 103))	('C12orf51', 'Gene', (114, 122))	('rs2074356', 'Mutation', 'rs2074356', (123, 132))	('rs738722', 'Mutation', 'rs738722', (104, 112))	('SCC', 'Gene', (221, 224))	('CHK2', 'Gene', '11200', (99, 103))	('rs2274223', 'Mutation', 'rs2274223', (144, 153))	('SCC', 'Phenotype', 'HP:0002860', (221, 224))	('rs738722', 'Var', (104, 112))	('PLCE1', 'Gene', (138, 143))	('rs2074356', 'Var', (123, 132))	('apoptosis associated genes', 'Gene', (157, 183))
151617	25008389	The three SNPs (rs738722, rs2074356, and rs2274223) were genotyped by a Taqman real-time polymerase chain reaction method using a 7900 HT sequence detector system (Applied Biosystems, Foster City, CA, USA).	('rs2274223', 'Var', (41, 50))	('rs738722', 'Var', (16, 24))	('rs2074356', 'Mutation', 'rs2074356', (26, 35))	('rs2074356', 'Var', (26, 35))	('rs2274223', 'Mutation', 'rs2274223', (41, 50))	('rs738722', 'Mutation', 'rs738722', (16, 24))
151621	25008389	Distributions of demographic characteristics (age, sex), exposure factors (smoking, drinking, and HPV16 serostatus) and genotypes of the PLCE1 rs2274223, C12orf51 rs2074356 and CHK2 rs738722 variants between cases and controls were examined with chi-square tests.	('C12orf51', 'Gene', (154, 162))	('HPV16', 'Species', '333760', (98, 103))	('PLCE1', 'Gene', '51196', (137, 142))	('CHK2', 'Gene', (177, 181))	('rs2074356', 'Var', (163, 172))	('CHK2', 'Gene', '11200', (177, 181))	('rs738722', 'Mutation', 'rs738722', (182, 190))	('C12orf51', 'Gene', '283450', (154, 162))	('PLCE1', 'Gene', (137, 142))	('rs2274223', 'Mutation', 'rs2274223', (143, 152))	('rs2074356', 'Mutation', 'rs2074356', (163, 172))	('rs2274223', 'Var', (143, 152))
151628	25008389	A much higher proportion of cases smoked tobacco than controls (70.6% vs. 40.7%, P < 0.001), and more cases drank alcohol than controls (63.3% vs. 50.3%, P = 0.001); moreover, more cases were HPV16 seropositivity (54.3%) than controls (43.3%, P = 0.006).	('seropositivity', 'Var', (198, 212))	('tobacco', 'Species', '4097', (41, 48))	('HPV16', 'Species', '333760', (192, 197))	('HPV16', 'Gene', (192, 197))	('alcohol', 'Chemical', 'MESH:D000438', (114, 121))
151632	25008389	Among participants who did not smoke or drink, those who were HPV16-seropositive did not have significantly higher risk of ESCC than those who were HPV16-seronegative (P = 0.355, OR 1.35, 95% CI 0.72-2.52).	('SCC', 'Gene', '6317', (124, 127))	('participants', 'Species', '9606', (6, 18))	('SCC', 'Gene', (124, 127))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('HPV16', 'Species', '333760', (148, 153))	('HPV16', 'Species', '333760', (62, 67))	('HPV16-seropositive', 'Var', (62, 80))
151636	25008389	The observed genotype frequencies among controls were in agreement with the Hardy-Weinberg equilibrium (P = 0.689 for rs738722, P = 0.433 for rs2074356, and P = 0.609 for rs2274223).	('rs2074356', 'Var', (142, 151))	('rs2074356', 'Mutation', 'rs2074356', (142, 151))	('rs2274223', 'Mutation', 'rs2274223', (171, 180))	('rs738722', 'Var', (118, 126))	('rs2274223', 'Var', (171, 180))	('rs738722', 'Mutation', 'rs738722', (118, 126))
151639	25008389	For rs2074356, compared with the GG genotype, significantly increased risk of ESCC was associated with the AG genotype (OR 1.61, 95% CI 1.12-2.30) and the combined AA/AG genotypes (OR 1.52, 95% CI 1.07-2.16).	('SCC', 'Gene', (79, 82))	('rs2074356', 'Mutation', 'rs2074356', (4, 13))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('rs2074356', 'Var', (4, 13))
151640	25008389	For rs2274223, compared with the AA genotype, significantly increased risk of ESCC was associated with the GG genotype (OR 2.86, 95% CI 1.22-6.71), the AG genotype (OR 1.70, 95% CI 1.20-2.41) and the combined GG/AG genotypes (OR 1.75, 95% CI 1.25-2.46).	('SCC', 'Gene', (79, 82))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('rs2274223', 'Mutation', 'rs2274223', (4, 13))	('rs2274223', 'Var', (4, 13))
151641	25008389	For rs2074356 and rs2274223, the risk of ESCC may have increased with increasing numbers of variant alleles (Ptrend = 0.019 for rs2074356 and Ptrend = 0.001 for rs2274223) (Table 2).	('rs2274223', 'Var', (18, 27))	('SCC', 'Gene', (42, 45))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('rs2074356', 'Var', (128, 137))	('rs2074356', 'Mutation', 'rs2074356', (4, 13))	('SCC', 'Gene', '6317', (42, 45))	('rs2274223', 'Mutation', 'rs2274223', (161, 170))	('rs2274223', 'Mutation', 'rs2274223', (18, 27))	('rs2274223', 'Var', (161, 170))	('rs2074356', 'Mutation', 'rs2074356', (128, 137))	('rs2074356', 'Var', (4, 13))
151642	25008389	As indicated in Table 3, patients with rs2074356 CT/TT genotypes and rs2274223 GG/AG genotypes simultaneously had increased risk of ESCC, compared to patients with rs2074356 CC and rs2274223 AA genotypes (OR 3.31, 95% CI 1.87-5.83).	('rs2074356', 'Mutation', 'rs2074356', (39, 48))	('SCC', 'Gene', '6317', (133, 136))	('rs2274223', 'Mutation', 'rs2274223', (69, 78))	('rs2074356', 'Mutation', 'rs2074356', (164, 173))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (25, 33))	('rs2074356', 'Var', (39, 48))	('CT', 'Chemical', 'MESH:D002251', (49, 51))	('rs2274223', 'Mutation', 'rs2274223', (181, 190))	('rs2274223 GG/AG', 'Var', (69, 84))	('SCC', 'Gene', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))
151643	25008389	There was an interaction between rs2074356 and rs2274223 on the risk of ESCC (OR 1.26, 95% CI 1.09-1.45).	('SCC', 'Gene', (73, 76))	('rs2074356', 'Var', (33, 42))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('rs2274223', 'Mutation', 'rs2274223', (47, 56))	('rs2274223', 'Var', (47, 56))	('SCC', 'Gene', '6317', (73, 76))	('rs2074356', 'Mutation', 'rs2074356', (33, 42))
151644	25008389	As shown in Table 4, compared to HPV16-seronegative subjects with the rs738722 CC genotype, the risk of ESCC increased among HPV16-seropositive participants with the CC genotype (P = 0.002, OR 2.00, 95% CI 1.29-3.10) and among HPV16-seropositive subjects with TT or CT genotype (P = 0.003, OR 2.09, 95% CI 1.29-3.38).	('HPV16-seropositive', 'Gene', (125, 143))	('HPV16', 'Species', '333760', (33, 38))	('CT', 'Chemical', 'MESH:D002251', (266, 268))	('HPV16', 'Species', '333760', (125, 130))	('participants', 'Species', '9606', (144, 156))	('HPV16', 'Species', '333760', (227, 232))	('SCC', 'Gene', (105, 108))	('rs738722', 'Mutation', 'rs738722', (70, 78))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('rs738722', 'Var', (70, 78))	('SCC', 'Gene', '6317', (105, 108))
151645	25008389	However, the interaction between rs738722 genotypes and HPV16 serology for ESCC risk was not significant (P = 0.068).	('rs738722', 'Mutation', 'rs738722', (33, 41))	('rs738722', 'Var', (33, 41))	('SCC', 'Gene', (76, 79))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('SCC', 'Gene', '6317', (76, 79))	('HPV16', 'Species', '333760', (56, 61))
151647	25008389	Here the interaction between rs2074356 genotypes and HPV16 serology for ESCC risk was significant (P = 0.005, OR 1.40, 95% CI 1.11-1.77).	('rs2074356', 'Mutation', 'rs2074356', (29, 38))	('HPV16', 'Gene', (53, 58))	('HPV16', 'Species', '333760', (53, 58))	('rs2074356', 'Var', (29, 38))	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('SCC', 'Gene', '6317', (73, 76))
151648	25008389	Compared with HPV16-seronegative participants with the rs2274223 AA genotype, the risk of ESCC was elevated among HPV16-seropositive subjects with the AA genotype (P = 0.042, OR 1.55, 95% CI 1.02-2.37) and HPV16-seropositive participants with the GG or AG genotype (P < 0.001, OR 3.17, 95% CI 1.94-5.17).	('rs2274223', 'Mutation', 'rs2274223', (55, 64))	('rs2274223', 'Var', (55, 64))	('SCC', 'Gene', '6317', (91, 94))	('HPV16-seropositive', 'Gene', (114, 132))	('HPV16', 'Species', '333760', (14, 19))	('elevated', 'PosReg', (99, 107))	('participants', 'Species', '9606', (33, 45))	('SCC', 'Gene', (91, 94))	('HPV16', 'Species', '333760', (206, 211))	('HPV16', 'Species', '333760', (114, 119))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('participants', 'Species', '9606', (225, 237))
151649	25008389	The interaction between rs2274223 genotypes and HPV16 serology for ESCC risk was also significant (P < 0.001, OR 1.53, 95% CI, 1.23-1.91).	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (68, 71))	('HPV16', 'Species', '333760', (48, 53))	('HPV16', 'Gene', (48, 53))	('SCC', 'Gene', (68, 71))	('rs2274223', 'Mutation', 'rs2274223', (24, 33))	('rs2274223', 'Var', (24, 33))
151650	25008389	As shown above, HPV16 seropositivity synergized with different rs2074356 or rs2274223 genotypes to increase the risk of ESCC, but this synergy was not observed for rs738722.	('HPV16', 'Species', '333760', (16, 21))	('seropositivity', 'Var', (22, 36))	('rs2274223', 'Var', (76, 85))	('HPV16', 'Gene', (16, 21))	('SCC', 'Gene', (121, 124))	('rs738722', 'Mutation', 'rs738722', (164, 172))	('rs2074356', 'Mutation', 'rs2074356', (63, 72))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('SCC', 'Gene', '6317', (121, 124))	('increase', 'PosReg', (99, 107))	('rs2074356', 'Var', (63, 72))	('rs2274223', 'Mutation', 'rs2274223', (76, 85))
151652	25008389	For rs2074356, the OR in HPV16-seropositive smokers carrying risk alleles (TT or TC genotype) was more than six times higher than that in HPV16-seronegative smokers carrying the non-risk alleles (CC genotype), and was approximately seven times higher than for HPV16-seropositive nonsmokers carrying risk alleles (TT or TC genotype) (Figure 1A).	('higher', 'PosReg', (118, 124))	('HPV16-seropositive', 'Gene', (25, 43))	('HPV16', 'Species', '333760', (260, 265))	('rs2074356', 'Mutation', 'rs2074356', (4, 13))	('HPV16', 'Species', '333760', (138, 143))	('HPV16', 'Species', '333760', (25, 30))	('rs2074356', 'Var', (4, 13))
151653	25008389	Similar results were observed for the analysis of the joint effects of drinking, rs2074356, and HPV16 serology (Figure 1B).	('HPV16', 'Species', '333760', (96, 101))	('HPV16', 'Gene', (96, 101))	('rs2074356', 'Mutation', 'rs2074356', (81, 90))	('rs2074356', 'Var', (81, 90))
151654	25008389	The effect sizes of rs2074356 and HPV16 serology in nonsmokers or nondrinkers were not large (Figures 1A and B).	('HPV16', 'Gene', (34, 39))	('rs2074356', 'Var', (20, 29))	('rs2074356', 'Mutation', 'rs2074356', (20, 29))	('HPV16', 'Species', '333760', (34, 39))
151655	25008389	For rs2274223, the OR in HPV16-seropositive smokers carrying risk alleles (GG or AG genotype) was nearly four times higher than for HPV16-seronegative smokers carrying non-risk alleles (AA genotype), and was approximately three times higher than for HPV16-seropositive nonsmokers carrying risk alleles (GG or AG genotype) (Figure 1C).	('HPV16-seropositive', 'Gene', (25, 43))	('higher', 'PosReg', (116, 122))	('HPV16', 'Species', '333760', (250, 255))	('HPV16', 'Species', '333760', (25, 30))	('higher', 'PosReg', (234, 240))	('rs2274223', 'Mutation', 'rs2274223', (4, 13))	('rs2274223', 'Var', (4, 13))	('HPV16', 'Species', '333760', (132, 137))
151656	25008389	Similar results were seen for the analysis of the joint effects of drinking, rs2274223, and HPV16 serology (Figure 1D).	('rs2274223', 'Var', (77, 86))	('HPV16', 'Gene', (92, 97))	('HPV16', 'Species', '333760', (92, 97))	('rs2274223', 'Mutation', 'rs2274223', (77, 86))
151657	25008389	For rs738722, risk of ESCC was not increased among HPV16-seropositive smokers or drinkers with GG/AG alleles compared with HPV16-seropositive nonsmokers or nondrinkers with GG/AG alleles (data not shown).	('SCC', 'Gene', '6317', (23, 26))	('HPV16-seropositive', 'Gene', (51, 69))	('GG/AG alleles', 'Var', (95, 108))	('rs738722', 'Mutation', 'rs738722', (4, 12))	('rs738722', 'Var', (4, 12))	('alleles', 'Var', (101, 108))	('HPV16', 'Species', '333760', (123, 128))	('HPV16', 'Species', '333760', (51, 56))	('SCC', 'Gene', (23, 26))	('SCC', 'Phenotype', 'HP:0002860', (23, 26))
151658	25008389	We found that genotypes at rs2274223 and rs2074356 contributed to the risk of ESCC independently of HPV16 seropositivity, as had been found in previous genome-wide association studies; however, we found that rs738722 did not contribute to the risk of ESCC.	('rs2274223', 'Var', (27, 36))	('rs2074356', 'Var', (41, 50))	('SCC', 'Gene', (79, 82))	('rs738722', 'Mutation', 'rs738722', (208, 216))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('SCC', 'Gene', (252, 255))	('HPV16', 'Species', '333760', (100, 105))	('rs2074356', 'Mutation', 'rs2074356', (41, 50))	('SCC', 'Phenotype', 'HP:0002860', (252, 255))	('rs2274223', 'Mutation', 'rs2274223', (27, 36))	('SCC', 'Gene', '6317', (252, 255))	('rs738722', 'Var', (208, 216))
151659	25008389	Although HPV16 serostatus was not an independent risk factor for ESCC in nonsmokers and nondrinkers, the interaction of HPV16 serostatus and rs2074356 or rs2274223 significantly increased the risk of ESCC in these subjects.	('SCC', 'Gene', (66, 69))	('rs2074356', 'Var', (141, 150))	('HPV16', 'Gene', (120, 125))	('SCC', 'Gene', (201, 204))	('SCC', 'Gene', '6317', (66, 69))	('HPV16', 'Species', '333760', (120, 125))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('rs2274223', 'Mutation', 'rs2274223', (154, 163))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('rs2074356', 'Mutation', 'rs2074356', (141, 150))	('SCC', 'Gene', '6317', (201, 204))	('interaction', 'Interaction', (105, 116))	('rs2274223', 'Var', (154, 163))	('HPV16', 'Species', '333760', (9, 14))	('increased', 'PosReg', (178, 187))
151660	25008389	In addition, smoking and drinking synergized with the joint effect of HPV16 serostatus and rs2074356 or rs2274223 to substantially increase ESCC risk.	('rs2274223', 'Var', (104, 113))	('SCC', 'Gene', (141, 144))	('rs2074356', 'Mutation', 'rs2074356', (91, 100))	('increase', 'PosReg', (131, 139))	('increase ESCC', 'Phenotype', 'HP:0003565', (131, 144))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('SCC', 'Gene', '6317', (141, 144))	('HPV16', 'Gene', (70, 75))	('rs2074356', 'Var', (91, 100))	('HPV16', 'Species', '333760', (70, 75))	('rs2274223', 'Mutation', 'rs2274223', (104, 113))
151662	25008389	Our multivariable logistic regression models showed no association between rs738722 and the risk of ESCC after adjusting for age, sex, smoking, drinking, and HPV16 status.	('rs738722', 'Mutation', 'rs738722', (75, 83))	('rs738722', 'Var', (75, 83))	('HPV16', 'Species', '333760', (158, 163))	('SCC', 'Gene', (101, 104))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('SCC', 'Gene', '6317', (101, 104))
151663	25008389	This is consistent with findings from a previous genome-wide association study that the apparent association between rs738722 and ESCC risk was not statistically significant in the second phase (Ptrend = 0.14, OR 1.20, 95% CI 0.94-1.53).	('SCC', 'Gene', (131, 134))	('rs738722', 'Mutation', 'rs738722', (117, 125))	('SCC', 'Gene', '6317', (131, 134))	('SCC', 'Phenotype', 'HP:0002860', (131, 134))	('rs738722', 'Var', (117, 125))
151664	25008389	Another study also reported that variant alleles of CHEK2 rs738722 were not associated with risk of ESCC.	('CHEK2', 'Gene', '11200', (52, 57))	('CHEK2', 'Gene', (52, 57))	('SCC', 'Gene', (101, 104))	('rs738722', 'Mutation', 'rs738722', (58, 66))	('rs738722', 'Var', (58, 66))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('SCC', 'Gene', '6317', (101, 104))
151665	25008389	Further study is needed to investigate the association between rs738722 and ESCC risk.	('rs738722', 'Var', (63, 71))	('rs738722', 'Mutation', 'rs738722', (63, 71))	('SCC', 'Gene', (77, 80))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))	('SCC', 'Gene', '6317', (77, 80))
151669	25008389	The effect of HPV16 seropositivity on ESCC risk in our current study is consistent with our previous study.	('SCC', 'Gene', '6317', (39, 42))	('seropositivity', 'Var', (20, 34))	('HPV16', 'Species', '333760', (14, 19))	('SCC', 'Gene', (39, 42))	('HPV16', 'Gene', (14, 19))	('SCC', 'Phenotype', 'HP:0002860', (39, 42))
151670	25008389	The current study included a larger number of cases (313 vs. 225) and a better method of identifying HPV seropositivity via identification of antibodies against HPV16 L1 rather than merely high-risk HPV.	('HPV', 'Species', '10566', (199, 202))	('HPV16', 'Species', '333760', (161, 166))	('HPV', 'Species', '10566', (101, 104))	('HPV', 'Species', '10566', (161, 164))	('antibodies', 'Var', (142, 152))	('HPV16 L1', 'Gene', (161, 169))
151672	25008389	HLA-DRB1*1501 and HLA-DQB1*0301 was reported to influence HPV-encoded epitopes and affect the risk of ESCC among Kazakhs in XinJiang, China.	('HPV-encoded epitopes', 'Disease', (58, 78))	('affect', 'Reg', (83, 89))	('HLA-DRB1*1501', 'Var', (0, 13))	('SCC', 'Gene', (103, 106))	('HPV-encoded epitopes', 'Disease', 'MESH:D030361', (58, 78))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCC', 'Gene', '6317', (103, 106))	('influence', 'Reg', (48, 57))
151673	25008389	Our another previous study demonstrated that HPV16 seropositivity synergized with p53 Arg/Arg or Arg/Pro and increased ESCC risk, especially in smokers or drinkers.	('Arg', 'Chemical', 'MESH:D001120', (86, 89))	('Arg', 'Chemical', 'MESH:D001120', (90, 93))	('Pro', 'Chemical', 'MESH:D011392', (101, 104))	('Arg', 'Chemical', 'MESH:D001120', (97, 100))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('Arg/Pro', 'MPA', (97, 104))	('HPV16', 'Gene', (45, 50))	('seropositivity', 'Var', (51, 65))	('HPV16', 'Species', '333760', (45, 50))	('p53 Arg/Arg', 'Var', (82, 93))	('increased', 'PosReg', (109, 118))	('increased ESCC', 'Phenotype', 'HP:0003565', (109, 123))	('SCC', 'Gene', (120, 123))
151675	25008389	After HPV infection, the E6 protein can bind to p53 through E6AP and prevent p53 from inducing apoptosis through targeting it for degradation via the ubiquitin-proteasome pathway.	('E6AP', 'Var', (60, 64))	('targeting', 'Reg', (113, 122))	('bind', 'Interaction', (40, 44))	('HPV infection', 'Disease', (6, 19))	('apoptosis', 'CPA', (95, 104))	('inducing', 'Reg', (86, 94))	('p53', 'Gene', (77, 80))	('prevent', 'NegReg', (69, 76))	('HPV infection', 'Disease', 'MESH:D030361', (6, 19))
151681	25008389	In summary, we found that SNPs at two susceptibility loci identified in previous genome-wide association studies (rs2274223 and rs2074356) increased the risk of ESCC independent of HPV16 seropositivity, but a third SNP (rs738722) did not.	('rs2274223', 'Mutation', 'rs2274223', (114, 123))	('rs2274223', 'Var', (114, 123))	('increased', 'PosReg', (139, 148))	('rs2074356', 'Var', (128, 137))	('rs738722', 'Mutation', 'rs738722', (220, 228))	('HPV16', 'Species', '333760', (181, 186))	('SCC', 'Gene', (162, 165))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))	('SCC', 'Gene', '6317', (162, 165))	('rs2074356', 'Mutation', 'rs2074356', (128, 137))
151683	25008389	However, interactions between HPV16 seropositivity and risk alleles of rs2074356 or rs2274223 increased the risk of ESCC substantially, especially in smokers or drinkers.	('rs2074356', 'Mutation', 'rs2074356', (71, 80))	('HPV16', 'Species', '333760', (30, 35))	('SCC', 'Gene', (117, 120))	('increased', 'PosReg', (94, 103))	('rs2274223', 'Mutation', 'rs2274223', (84, 93))	('rs2274223', 'Var', (84, 93))	('HPV16', 'Gene', (30, 35))	('rs2074356', 'Var', (71, 80))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('interactions', 'Interaction', (9, 21))	('SCC', 'Gene', '6317', (117, 120))
151771	22888304	The results showed that CXCL12, CYP2C9, TGM3, MAL, S100A9, EMP-1 and SPRR3 were highly associated with ESCC development.	('MAL', 'Gene', (46, 49))	('SPRR3', 'Gene', (69, 74))	('TGM3', 'Gene', '7053', (40, 44))	('CYP2C9', 'Gene', (32, 38))	('S100A9', 'Gene', '6280', (51, 57))	('CXCL12', 'Var', (24, 30))	('EMP-1', 'Gene', (59, 64))	('MAL', 'Gene', '4118', (46, 49))	('EMP-1', 'Gene', '2012', (59, 64))	('CYP2C9', 'Gene', '1559', (32, 38))	('SPRR3', 'Gene', '6707', (69, 74))	('S100A9', 'Gene', (51, 57))	('associated with', 'Reg', (87, 102))	('ESCC development', 'CPA', (103, 119))	('TGM3', 'Gene', (40, 44))
151782	22888304	Two ESCC related expression profiles, GSE23400 and GSE20347, were obtained separately from a public functional genomics data repository GEO, based on the Affymetrix Human Genome U133A Array and Affymetrix Human Genome U133A 2.0 Array, respectively.	('Human', 'Species', '9606', (165, 170))	('GSE20347', 'Var', (51, 59))	('ESCC', 'Disease', (4, 8))	('GSE23400', 'Var', (38, 46))	('Human', 'Species', '9606', (205, 210))
151790	22888304	The overall and disease-free survival rate is significantly lower in patients with positive CXCL12 expression than in those with negative.	('patients', 'Species', '9606', (69, 77))	('positive', 'Var', (83, 91))	('CXCL12 expression', 'MPA', (92, 109))	('lower', 'NegReg', (60, 65))
151800	22888304	Its ectopic expression in carcinoma TE3 cells could lead to the repressed formation of tumors in nude mice, the inhibition of cell motility, and the production of apoptosis by the Fas pathway, whereby the proposal that Mal may be a tumor suppressor gene in ESCC development.	('nude mice', 'Species', '10090', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cell motility', 'CPA', (126, 139))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('ESCC', 'Disease', (257, 261))	('ectopic expression', 'Var', (4, 22))	('carcinoma', 'Disease', (26, 35))	('Mal', 'Gene', (219, 222))	('tumors', 'Disease', (87, 93))	('tumor', 'Disease', (232, 237))	('lead to', 'Reg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Disease', (87, 92))	('carcinoma', 'Disease', 'MESH:D002277', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('inhibition', 'NegReg', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('Mal', 'Gene', '17153', (219, 222))
151802	22888304	Moreover, S100A9 staining is decreased in poorly and moderately differentiated ESCCs, when compared with those well-differentiated, hence the inferrence that loss of S100A9 expression in ESCC generally occurs along with worsening esophageal epithelial differentiation in histological grades.	('loss', 'Var', (158, 162))	('esophageal epithelia', 'Disease', (230, 250))	('esophageal epithelia', 'Disease', 'MESH:D004941', (230, 250))	('worsening', 'PosReg', (220, 229))	('S100A9', 'Gene', '6280', (10, 16))	('S100A9', 'Gene', (10, 16))	('S100A9', 'Gene', '6280', (166, 172))	('decreased', 'NegReg', (29, 38))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (230, 250))	('expression', 'MPA', (173, 183))	('S100A9', 'Gene', (166, 172))
151808	22888304	In addition, EMP-1 transfection could induce different forms of gene expression, such as integrin beta 7 (ITGB7), integrin beta 8 (ITGB8) and cadherin 5 (CDH5), involved in cell signaling, cell adhesion and cell-cell communication.	('ITGB8', 'Gene', '3696', (131, 136))	('transfection', 'Var', (19, 31))	('cadherin 5', 'Gene', (142, 152))	('induce', 'Reg', (38, 44))	('integrin beta 7', 'Gene', '3695', (89, 104))	('ITGB8', 'Gene', (131, 136))	('integrin beta 8', 'Gene', '3696', (114, 129))	('EMP-1', 'Gene', '2012', (13, 18))	('ITGB7', 'Gene', '3695', (106, 111))	('CDH5', 'Gene', (154, 158))	('EMP-1', 'Gene', (13, 18))	('integrin beta 8', 'Gene', (114, 129))	('integrin beta 7', 'Gene', (89, 104))	('ITGB7', 'Gene', (106, 111))	('CDH5', 'Gene', '1003', (154, 158))	('cadherin 5', 'Gene', '1003', (142, 152))
151830	33977239	Nine years earlier, he had undergone left open partial nephrectomy with intraoperative temporary left renal artery ischemia; clinical stage and pathological findings were cT1aN0M0 and pT1a with clear cell RCC, Fuhrman grade 2 and resection margin negative, respectively.	('pT1a', 'Var', (184, 188))	('RCC', 'Disease', (205, 208))	('cT1aN0M0', 'Var', (171, 179))	('renal artery ischemia', 'Phenotype', 'HP:0002637', (102, 123))	('left renal artery ischemia', 'Disease', (97, 123))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('left renal artery ischemia', 'Disease', 'MESH:D014715', (97, 123))
151950	30361067	In contrast, peaks 7-9 tended to be down-regulated in healthy controls, individuals with colorectal polyps and pre-operative CRC patients, then up-regulated in post-operative patients.	('up-regulated', 'PosReg', (144, 156))	('colorectal polyps', 'Disease', (89, 106))	('colorectal polyps', 'Disease', 'MESH:D003111', (89, 106))	('colorectal polyp', 'Phenotype', 'HP:0200063', (89, 105))	('patients', 'Species', '9606', (129, 137))	('peaks', 'Var', (13, 18))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('patients', 'Species', '9606', (175, 183))	('colorectal polyps', 'Phenotype', 'HP:0200063', (89, 106))	('down-regulated', 'NegReg', (36, 50))
151951	30361067	Five of these nine peptide peaks (Peak 1, m/z: 2676.04; Peak 5, m/z: 5343.69; Peak 6, m/z: 4793.31; Peak 7, m/z: 3446.91; Peak 9, m/z: 2663.37) with the most significant difference (>1.9 times) between healthy controls and CRC patients were selected for peak identification, and consideration as potential biomarkers for CRC (Table 1).	('Peak 1', 'Gene', (34, 40))	('CRC', 'Phenotype', 'HP:0003003', (223, 226))	('si', 'Chemical', 'MESH:D012825', (158, 160))	('CRC', 'Phenotype', 'HP:0003003', (321, 324))	('m/z: 3446.91', 'Var', (108, 120))	('Peak 1', 'Gene', '79834', (34, 40))	('si', 'Chemical', 'MESH:D012825', (282, 284))	('patients', 'Species', '9606', (227, 235))	('CRC', 'Disease', (223, 226))
151952	30361067	Moreover, these five peaks (Peak 1, m/z: 2676.04; Peak 5, m/z: 5343.69; Peak 6, m/z: 4793.31; Peak 7, m/z: 3446.91; Peak 9, m/z: 2663.37) have significant differences between paired pre- and post-operative CRC patients (P < .05, based on the paired t-test).	('m/z: 5343.69', 'Var', (58, 70))	('CRC', 'Phenotype', 'HP:0003003', (206, 209))	('m/z: 3446.91', 'Var', (102, 114))	('Peak 1', 'Gene', (28, 34))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('differences', 'Reg', (155, 166))	('patients', 'Species', '9606', (210, 218))	('CRC', 'Disease', (206, 209))	('m/z: 4793.31', 'Var', (80, 92))	('Peak 1', 'Gene', '79834', (28, 34))
151967	30361067	High SETD7 expression was significantly associated with T stage (P = .0139) and microsatellite instability (MSI, P = .0372).	('High', 'Var', (0, 4))	('SETD7', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('microsatellite instability', 'MPA', (80, 106))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('T stage', 'CPA', (56, 63))	('SETD7', 'Gene', '80854', (5, 10))	('associated', 'Reg', (40, 50))
151969	30361067	High SETD7 expression was significantly associated with T stage (Fig.	('High', 'Var', (0, 4))	('SETD7', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('associated', 'Reg', (40, 50))	('SETD7', 'Gene', '80854', (5, 10))	('T stage', 'Disease', (56, 63))
151972	30361067	Compared with the control group, SETD7 knockdown inhibited cell proliferation (Fig.	('SETD7', 'Gene', (33, 38))	('knockdown', 'Var', (39, 48))	('cell proliferation', 'CPA', (59, 77))	('SETD7', 'Gene', '80854', (33, 38))	('inhibited', 'NegReg', (49, 58))
151977	30361067	Three up-regulated peptides were identified as peptide regions of FGA (Peak 1, m/z: 2676.04), MUC5AC (Peak 5, m/z: 5343.69), SETD7 (Peak 6, m/z: 4793.31), and two down-regulated peptides were identified as peptide regions of FGA (Peak 7, m/z: 3446.91, Peak 9, m/z: 2663.37).	('m/z: 3446.91', 'Var', (238, 250))	('SETD7', 'Gene', (125, 130))	('Peak 1', 'Gene', (71, 77))	('FGA', 'Gene', '2243', (66, 69))	('MUC5AC', 'Gene', (94, 100))	('SETD7', 'Gene', '80854', (125, 130))	('Peak 1', 'Gene', '79834', (71, 77))	('FGA', 'Gene', (66, 69))	('FGA', 'Gene', '2243', (225, 228))	('MUC5AC', 'Gene', '4586', (94, 100))	('up-regulated', 'PosReg', (6, 18))	('FGA', 'Gene', (225, 228))
152031	29899837	The average weight of AE2 plasmid transfected tumors was reduced in comparison with control tumors (Supplementary Figure 4C).	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('weight', 'MPA', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (46, 52))	('reduced', 'NegReg', (57, 64))	('AE2 plasmid transfected', 'Var', (22, 45))	('tumors', 'Disease', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
152034	29899837	In KYSE170 and TE13 cells, AE2 siRNA significantly increased cell migration (Figure 2B).	('increased', 'PosReg', (51, 60))	('KYSE170', 'CellLine', 'CVCL:1358', (3, 10))	('AE2 siRNA', 'Var', (27, 36))	('cell migration', 'CPA', (61, 75))
152057	29899837	Regarding the expression of AE2 at the IF, the 5-year overall survival rate of patients with the low-grade expression of AE2 (53.9%) was significantly lower than that of patients with the high-grade expression of AE2 in IF (79.4%) (p = 0.0388) (Figure 5B, Table 3).	('patients', 'Species', '9606', (170, 178))	('overall survival', 'CPA', (54, 70))	('lower', 'NegReg', (151, 156))	('low-grade expression', 'Var', (97, 117))	('patients', 'Species', '9606', (79, 87))	('AE2', 'Var', (121, 124))
152061	29899837	In the gastrointestinal tract, AE2 is distributed in the basolateral membrane of parietal cells and serves tissue-specific functions, such as acid secretion.	('acid secretion', 'MPA', (142, 156))	('AE2', 'Var', (31, 34))	('gastrointestinal tract', 'Disease', (7, 29))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (7, 29))	('serves', 'Reg', (100, 106))
152062	29899837	A previous in vivo study showed that AE2-/- mice were emaciated, toothless, and exhibited severe growth retardation, and most died around the time of weaning, suggesting its critical significance in life support.	('growth retardation', 'Disease', (97, 115))	('severe growth retardation', 'Phenotype', 'HP:0008850', (90, 115))	('AE2-/-', 'Var', (37, 43))	('growth retardation', 'Phenotype', 'HP:0001510', (97, 115))	('growth retardation', 'Disease', 'MESH:D006130', (97, 115))	('mice', 'Species', '10090', (44, 48))
152073	29899837	Several reports including our previous study demonstrated that the expression of hypoxia-inducible factors was elevated with the change of pH regulators, such as carbonic anhydrase (CA), suggesting that they become effective prognostic factors in microenvironment where the expression of hypoxia-inducible factors is increased.	('elevated', 'PosReg', (111, 119))	('hypoxia', 'Disease', 'MESH:D000860', (288, 295))	('hypoxia', 'Disease', (81, 88))	('change', 'Var', (129, 135))	('hypoxia', 'Disease', (288, 295))	('pH', 'Gene', '2821', (139, 141))	('hypoxia', 'Disease', 'MESH:D000860', (81, 88))	('expression', 'MPA', (67, 77))
152076	29899837	The results obtained suggest a role for AE2 in cellular movement as well as the importance of its distribution in tumors as a prognostic predictor.	('AE2', 'Var', (40, 43))	('cellular movement', 'CPA', (47, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))
152084	29899837	The results of the microarrays performed in the present study also revealed that the gene expression of important factors in cellular movement, such as MMP1, MMP12, and TIMP4, metalloproteinase inhibitor, was changed by the knockdown of AE2, suggesting that AE2 regulates the tumor behavior of ESCC via this pathway.	('TIMP4', 'Gene', (169, 174))	('cellular movement', 'CPA', (125, 142))	('MMP1', 'Gene', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('TIMP4', 'Gene', '7079', (169, 174))	('AE2', 'Gene', (237, 240))	('MMP1', 'Gene', '4312', (158, 162))	('ESCC', 'Disease', (294, 298))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('changed', 'Reg', (209, 216))	('tumor', 'Disease', (276, 281))	('MMP12', 'Gene', '4321', (158, 163))	('MMP1', 'Gene', '4312', (152, 156))	('regulates', 'Reg', (262, 271))	('MMP1', 'Gene', (158, 162))	('gene', 'MPA', (85, 89))	('knockdown', 'Var', (224, 233))	('MMP12', 'Gene', (158, 163))
152110	29899837	The expression levels of the following genes were measured: AE2 (Hs01586776_m1), MMP1 (Hs00899658_m1), MMP12 (Hs00159178_m1), and TIMP4 (Hs00162784_m1) (Applied Biosystems).	('expression levels', 'MPA', (4, 21))	('Hs00899658_m1', 'Var', (87, 100))	('MMP1', 'Gene', '4312', (81, 85))	('MMP12', 'Gene', (103, 108))	('TIMP4', 'Gene', (130, 135))	('TIMP4', 'Gene', '7079', (130, 135))	('MMP1', 'Gene', '4312', (103, 107))	('MMP1', 'Gene', (81, 85))	('MMP12', 'Gene', '4321', (103, 108))	('Hs00159178_m1', 'Var', (110, 123))	('Hs00162784_m1', 'Var', (137, 150))	('MMP1', 'Gene', (103, 107))	('Hs01586776_m1', 'Var', (65, 78))
152126	28900478	Ashkenazi Jews were diagnosed at an older age than Sephardic Jews (median: 73 vs. 65 years, p=0.001), had a higher rate of family history of GI cancer (34% vs. 17%, p=0.026) and a higher rate of cardiovascular co-morbidity (41% vs. 24%, p=0.041).	('Ashkenazi', 'Var', (0, 9))	('GI cancer', 'Phenotype', 'HP:0007378', (141, 150))	('GI cancer', 'Disease', (141, 150))	('cardiovascular co-morbidity', 'Phenotype', 'HP:0001626', (195, 222))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('GI cancer', 'Disease', 'MESH:D009369', (141, 150))
152158	28900478	A comparison between the two main Jewish ethnic groups is summarized in Table 3 and reveals several differences: Ashkenazi Jews were diagnosed at an older age (median: 73 vs. 65 years, p=0.001), had a higher rate of family history of GI-cancer (34% vs. 17%, p=0.026) and had a higher rate of cardiovascular co-morbidity (41% vs. 24%, p=0.041).	('cardiovascular co-morbidity', 'Phenotype', 'HP:0001626', (292, 319))	('GI-cancer', 'Disease', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('GI-cancer', 'Disease', 'MESH:D009369', (234, 243))	('Ashkenazi', 'Var', (113, 122))	('GI-cancer', 'Phenotype', 'HP:0007378', (234, 243))	('higher', 'PosReg', (201, 207))
152171	28900478	Interestingly, our findings are in line with our group's previous report on gastric cancer, whose biology overlaps significantly with that of EC, both showing that Ashkenazi Jews were diagnosed at an older age and had a higher rate of cardiovascular disease.	('Ashkenazi', 'Var', (164, 173))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (235, 257))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('cardiovascular disease', 'Disease', 'MESH:D002318', (235, 257))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('higher', 'PosReg', (220, 226))	('cardiovascular disease', 'Disease', (235, 257))	('gastric cancer', 'Disease', (76, 90))
152172	28900478	The predominance of Ashkenazi Jews and their high rate of family history of cancer may suggest genetic predisposition, as is known in other malignancies, including colorectal, breast, ovarian and gastric cancers.	('cancer', 'Disease', (204, 210))	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('Ashkenazi', 'Var', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('gastric cancer', 'Phenotype', 'HP:0012126', (196, 210))	('gastric cancers', 'Phenotype', 'HP:0012126', (196, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('malignancies', 'Disease', (140, 152))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('colorectal, breast, ovarian and gastric cancers', 'Disease', 'MESH:D013274', (164, 211))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
152183	28900478	Nevertheless, we identified several unique characteristics, including predominance of Ashkenazi Jews, high prevalence of other cancers, abundance of SCC histology in the distal esophagus and delayed reversal of the SCC:ADC ratio.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SCC', 'Gene', (149, 152))	('Ashkenazi', 'Var', (86, 95))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('SCC', 'Gene', '6317', (149, 152))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('SCC', 'Gene', (215, 218))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('SCC', 'Phenotype', 'HP:0002860', (215, 218))	('SCC', 'Gene', '6317', (215, 218))
152239	28250898	When insurance status was evaluated, patients with Medicare were significantly more likely to have gastric IM [OR 1.94 (1.20, 3.17), P = 0.007], whereas patients with private insurance were less likely to have gastric IM [OR 0.66 (0.44, 0.99), P = 0.047].	('Medicare', 'Var', (51, 59))	('gastric IM', 'Disease', (210, 220))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (37, 45))	('OR 1.94', 'Gene', (111, 118))	('gastric IM', 'Disease', (99, 109))	('OR 1.94', 'Gene', '284383', (111, 118))
152317	26557504	The effects on smooth muscle cells and leukocyte infiltration were determined by immunohistochemistry using anti-alphaSMA and anti-CD45, respectively.	('anti-alphaSMA', 'Var', (108, 121))	('CD45', 'Gene', (131, 135))	('CD45', 'Gene', '19264', (131, 135))
152446	25436453	PAK7 was upregulated by Aurora-A overexpression at both mRNA and protein levels.	('upregulated', 'PosReg', (9, 20))	('Aurora-A', 'Gene', (24, 32))	('overexpression', 'Var', (33, 47))	('PAK7', 'Gene', (0, 4))	('Aurora-A', 'Gene', '6790', (24, 32))
152449	25436453	Furthermore, we demonstrated that PAK7 knockdown led to increased apoptosis, and Aurora-A-induced resistance to CDDP was reversed by downregulation of PAK7, suggesting PAK7 was a downstream player of Aurora-A that mediated chemoresistance of ESCC cells to CDDP.	('Aurora-A', 'Gene', (81, 89))	('increased', 'PosReg', (56, 65))	('knockdown', 'Var', (39, 48))	('Aurora-A', 'Gene', '6790', (81, 89))	('PAK7', 'Gene', (151, 155))	('downregulation', 'NegReg', (133, 147))	('apoptosis', 'CPA', (66, 75))	('PAK7', 'Gene', (34, 38))	('chemoresistance', 'CPA', (223, 238))	('CDDP', 'Chemical', 'MESH:D002945', (256, 260))	('Aurora-A', 'Gene', '6790', (200, 208))	('CDDP', 'Chemical', 'MESH:D002945', (112, 116))	('Aurora-A', 'Gene', (200, 208))
152454	25436453	In the latter two cancer types, the aberrant expression of Aurora-A was also often found to be associated with metastasis.	('aberrant expression', 'Var', (36, 55))	('metastasis', 'CPA', (111, 121))	('Aurora-A', 'Gene', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('Aurora-A', 'Gene', '6790', (59, 67))	('associated', 'Reg', (95, 105))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
152456	25436453	Inhibitors of Aurora-A are developed as potential anticancer drugs and some are in phase I and II clinical trials.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Disease', (54, 60))	('Aurora-A', 'Gene', '6790', (14, 22))	('Aurora-A', 'Gene', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
152466	25436453	Knockdown of PAK7 significantly increased sensitivity of tumor cells to CDDP treatment, unveiling a novel role of PAK7 in the treatment of esophageal cancers with Aurora-A overexpression.	('Knockdown', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('CDDP', 'Chemical', 'MESH:D002945', (72, 76))	('sensitivity', 'MPA', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('PAK7', 'Gene', (13, 17))	('esophageal cancers', 'Disease', (139, 157))	('increased', 'PosReg', (32, 41))	('Aurora-A', 'Gene', '6790', (163, 171))	('tumor', 'Disease', (57, 62))	('esophageal cancers', 'Disease', 'MESH:D004938', (139, 157))	('Aurora-A', 'Gene', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
152469	25436453	AURKA kinase- dead (KD) mutant was created through K162M site-directed mutagenesis using QuikChange  Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA, USA).	('AURKA', 'Gene', (0, 5))	('K162M', 'Mutation', 'p.K162M', (51, 56))	('K162M', 'Var', (51, 56))	('AURKA', 'Gene', '6790', (0, 5))
152472	25436453	EC9706-Aur, EC9706-Aur-KD, and EC9706-P4 were selected with Zeocin (100 microg/ml) for 2 weeks.	('Zeocin', 'Chemical', 'MESH:C105427', (60, 66))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('EC9706-P4', 'Var', (31, 40))	('EC9706', 'CellLine', 'CVCL:E307', (31, 37))	('EC9706-Aur-KD', 'Var', (12, 25))	('EC9706-Aur', 'Var', (0, 10))	('EC9706', 'CellLine', 'CVCL:E307', (12, 18))
152478	25436453	The antibodies for immunoprecipitation include an anti-E2F1 (sc-193x, Santa Cruz) antibody or mouse IgG (Active Motif).	('mouse', 'Species', '10090', (94, 99))	('E2F1', 'Gene', '1869', (55, 59))	('E2F1', 'Gene', (55, 59))	('sc-193x', 'Var', (61, 68))
152484	25436453	Esophageal cancer tissue array(cat#: ES481, ES482, ES807)were purcased from Yingchao Biotech, Xi'an, China.	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ES482', 'Var', (44, 49))	('Esophageal cancer', 'Disease', (0, 17))	('ES807', 'Var', (51, 56))
152488	25436453	EC9706-P4 and EC9706-Aur cells were plated at a density of 5000 cells/well into 96-well plates and then subjected to CDDP treatment at 10 microM for 55 hours.	('EC9706-P4', 'Var', (0, 9))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('CDDP', 'Chemical', 'MESH:D002945', (117, 121))	('EC9706', 'CellLine', 'CVCL:E307', (14, 20))	('EC9706-Aur', 'Var', (14, 24))
152504	25436453	PI staining showed that EC9706-Aur had less percentage of apoptotic cells, while the cancer cells expressing kinase-dead Aurora-A showed comparable apoptosis rate to the parental cells (Fig 1C), indicating that kinase activity is important for chemoresistance induced by Aurora-A.	('apoptotic cells', 'CPA', (58, 73))	('EC9706', 'CellLine', 'CVCL:E307', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('Aurora-A', 'Gene', '6790', (271, 279))	('less', 'NegReg', (39, 43))	('Aurora-A', 'Gene', (271, 279))	('EC9706-Aur', 'Var', (24, 34))	('cancer', 'Disease', (85, 91))	('Aurora-A', 'Gene', '6790', (121, 129))	('Aurora-A', 'Gene', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
152505	25436453	We also compared the cell viability by MTT assay between EC9706-Aur and EC9706-Aur-KD cells upon different doses of CDDP treatment, and discovered that the kinase-dead cells (EC9706-Aur-KD) were more sensitive to CDDP treatment than their WT counterparts EC9706-Aur cells (Fig 1D), further implicating the involvement of kinase activity.	('EC9706', 'CellLine', 'CVCL:E307', (175, 181))	('CDDP', 'Chemical', 'MESH:D002945', (213, 217))	('MTT', 'Chemical', 'MESH:C070243', (39, 42))	('EC9706', 'CellLine', 'CVCL:E307', (255, 261))	('EC9706', 'CellLine', 'CVCL:E307', (72, 78))	('sensitive', 'MPA', (200, 209))	('EC9706-Aur-KD', 'Var', (175, 188))	('EC9706', 'CellLine', 'CVCL:E307', (57, 63))	('CDDP', 'Chemical', 'MESH:D002945', (116, 120))
152510	25436453	Interestingly, expression level of PAK7 was decreased when the cells were treated with MLN8237, a small molecule inhibitor of Aurora-A, indicating that the regulation of PAK7 by Aurora-A requires the kinase activity (Fig 2E).	('PAK7', 'Gene', (170, 174))	('Aurora-A', 'Gene', (178, 186))	('Aurora-A', 'Gene', '6790', (178, 186))	('Aurora-A', 'Gene', '6790', (126, 134))	('expression level', 'MPA', (15, 31))	('Aurora-A', 'Gene', (126, 134))	('MLN8237', 'Chemical', 'MESH:C550258', (87, 94))	('MLN8237', 'Var', (87, 94))	('decreased', 'NegReg', (44, 53))
152523	25436453	In consistent with this, another apoptosis detection experiment, TUNEL, also showed that PAK7 knockdown was able to significantly reverse the apoptosis resistance rendered by Aurora-A, further demonstrating that Aurora-A induced drug resistance is at least partly mediated by PAK7 (Fig.	('knockdown', 'Var', (94, 103))	('apoptosis resistance', 'MPA', (142, 162))	('drug resistance', 'MPA', (229, 244))	('Aurora-A', 'Gene', (212, 220))	('Aurora-A', 'Gene', '6790', (175, 183))	('Aurora-A', 'Gene', '6790', (212, 220))	('Aurora-A', 'Gene', (175, 183))	('PAK7', 'Gene', (89, 93))	('reverse', 'NegReg', (130, 137))	('drug resistance', 'Phenotype', 'HP:0020174', (229, 244))
152530	25436453	Knockdown of PAK7 led to increase of sensitivity of Aurora-A overexpressing ESCC cells to CDDP, implicating that additional strategies, i.e., PAK7 targeting, are required along with CDDP-based chemotherapy to achieve desirable therapeutic effects in the subsets of ESCC patients with Aurora-A overexpression.	('Aurora-A', 'Gene', (284, 292))	('ESCC', 'Disease', (265, 269))	('CDDP', 'Chemical', 'MESH:D002945', (182, 186))	('Knockdown', 'Var', (0, 9))	('patients', 'Species', '9606', (270, 278))	('CDDP', 'Chemical', 'MESH:D002945', (90, 94))	('PAK7', 'Gene', (13, 17))	('Aurora-A', 'Gene', '6790', (52, 60))	('increase', 'PosReg', (25, 33))	('Aurora-A', 'Gene', (52, 60))	('sensitivity', 'MPA', (37, 48))	('Aurora-A', 'Gene', '6790', (284, 292))
152538	25436453	Indeed, Wang et al reported that overexpression of PAK7 inhibited camptothecin-induced apoptosis by inhibiting the activity of caspase-8 in colorectal carcinoma cells.	('overexpression', 'PosReg', (33, 47))	('caspase-8', 'Gene', (127, 136))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (140, 160))	('camptothecin-induced', 'MPA', (66, 86))	('PAK7', 'Var', (51, 55))	('camptothecin', 'Chemical', 'MESH:D002166', (66, 78))	('caspase-8', 'Gene', '841', (127, 136))	('activity', 'MPA', (115, 123))	('inhibiting', 'NegReg', (100, 110))	('colorectal carcinoma', 'Disease', (140, 160))	('inhibited', 'NegReg', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
152539	25436453	In this study we discovered that in the context of esophageal cancers where abnormal expression of Aurora-A induced cell resistance to CDDP treatment, PAK7 upregulation and thereby inhibition of apoptosis, is of vital importance, suggesting that PAK7 may be a promising therapeutic target candidate in cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('Aurora-A', 'Gene', (99, 107))	('abnormal', 'Var', (76, 84))	('upregulation', 'PosReg', (156, 168))	('apoptosis', 'CPA', (195, 204))	('Aurora-A', 'Gene', '6790', (99, 107))	('esophageal cancers', 'Disease', (51, 69))	('inhibition', 'NegReg', (181, 191))	('CDDP', 'Chemical', 'MESH:D002945', (135, 139))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('esophageal cancers', 'Disease', 'MESH:D004938', (51, 69))	('cancer', 'Disease', (302, 308))
152561	24427776	A lot of researches, conducted by methods of enzyme-linked immunosorbent assay (ELISA), western blot (WB), immunohistochemistry (IHC), and proteomic or flight-mass spectrometry approaches, detect dysregulation of protein level in serum and/or tumor tissues in ESCC patients.	('protein level', 'MPA', (213, 226))	('ESCC', 'Disease', (260, 264))	('dysregulation', 'Var', (196, 209))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('patients', 'Species', '9606', (265, 273))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
152586	24427776	Molecular studies have revealed that genetic alterations, along with alcohol consumption and cigarette smoking, are responsible for the sequence of pathological changes in squamous epithelium of esophagus.	('alcohol', 'Chemical', 'MESH:D000438', (69, 76))	('genetic alterations', 'Var', (37, 56))	('responsible', 'Reg', (116, 127))
152615	24427776	In clinical studies, high expression of VEGF-A was found to be associated with tumor progression, and especially, with local metastases to lymph nodes.	('VEGF-A', 'Gene', (40, 46))	('metastases', 'Disease', (125, 135))	('tumor', 'Disease', (79, 84))	('associated', 'Reg', (63, 73))	('metastases', 'Disease', 'MESH:D009362', (125, 135))	('high', 'Var', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('VEGF-A', 'Gene', '7422', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
152624	24427776	have shown by IHC study that bFGF expression is significantly associated with microvessel formation and also with primary tumor progression and lymph node metastasis.	('bFGF', 'Gene', (29, 33))	('microvessel formation', 'CPA', (78, 99))	('associated', 'Reg', (62, 72))	('expression', 'Var', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('bFGF', 'Gene', '2247', (29, 33))	('lymph node metastasis', 'CPA', (144, 165))	('tumor', 'Disease', (122, 127))
152667	33376627	Meanwhile, SMAD4 was enriched in the CK2 promoter region and thus inhibited its expression.	('CK2', 'Gene', (37, 40))	('SMAD4', 'Var', (11, 16))	('inhibited', 'NegReg', (66, 75))	('expression', 'MPA', (80, 90))	('CK2', 'Gene', '13000', (37, 40))
152677	33376627	Moreover, SOX2 can regulate the expression of microRNA-30e-5p (miR-30e-5p) to promote breast cancer cell migration.	('promote', 'PosReg', (78, 85))	('microRNA-30e-5p', 'Var', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))
152685	33376627	Of note, USP4 has been documented to decrease Drosophila protein, mothers against decapentaplegic homolog 4 (SMAD4) monoubiquitination to sustain SMAD4 activity.	('Drosophila', 'Species', '7227', (46, 56))	('decrease', 'NegReg', (37, 45))	('activity', 'MPA', (152, 160))	('monoubiquitination', 'MPA', (116, 134))	('SMAD4', 'Gene', (109, 114))	('USP4', 'Var', (9, 13))	('Drosophila protein', 'MPA', (46, 64))
152690	33376627	Besides, patients with high SOX2 expression had shorter osteoporosis (OS) and disease free survival (DFS) than those with low expression of SOX2 (Figure 1C).	('patients', 'Species', '9606', (9, 17))	('SOX2', 'Gene', (28, 32))	('high', 'Var', (23, 27))	('expression', 'Var', (33, 43))	('osteoporosis', 'Disease', 'MESH:D010024', (56, 68))	('shorter', 'NegReg', (48, 55))	('osteoporosis', 'Disease', (56, 68))	('disease free survival', 'CPA', (78, 99))	('OS', 'Phenotype', 'HP:0000939', (70, 72))	('osteoporosis', 'Phenotype', 'HP:0000939', (56, 68))
152702	33376627	We performed immunofluorescence co-localization detection of USP4 and SMAD4 in TE-1 cells and found that both USP4 and SMAD4 existed in the cytoplasm, with an obvious co-localization phenomenon (Figure 4D).	('TE-1', 'CellLine', 'CVCL:1759', (79, 83))	('USP4', 'Var', (110, 114))	('SMAD4', 'Gene', (119, 124))	('co-localization', 'Interaction', (167, 182))
152704	33376627	In the presence of hemagglutinin-ubiquitin (HA-Ub), the ubiquitination of SMAD4 was examined using mutated USP4 (CS; K48- and K63-site mutations that only form lys48 and lys63 polyubiquitin, respectively) and USP4-WT after interaction with SMAD4.	('interaction', 'Interaction', (223, 234))	('K63-site', 'Var', (126, 134))	('USP4', 'Gene', (107, 111))	('CS', 'Gene', '1431', (113, 115))	('form', 'Reg', (155, 159))	('lys63', 'Var', (170, 175))	('mutated', 'Var', (99, 106))	('lys48', 'Var', (160, 165))
152705	33376627	After immunoprecipitation of SMAD4, we found that USP4-WT was able to remove the monomeric ubiquitination of SMAD4, but mutant (CS) USP4 did not remove the ubiquitination of SMAD4 (Figure 4F).	('CS', 'Gene', '1431', (128, 130))	('SMAD4', 'Gene', (109, 114))	('remove', 'NegReg', (70, 76))	('monomeric ubiquitination', 'MPA', (81, 105))	('mutant', 'Var', (120, 126))
152707	33376627	The conversion of lysine 519 to arginine specifically abolished the ubiquitination of SMAD4 (Figure 4J).	('lysine 519', 'Var', (18, 28))	('SMAD4', 'Protein', (86, 91))	('ubiquitination', 'MPA', (68, 82))	('conversion', 'Var', (4, 14))	('abolished', 'NegReg', (54, 63))	('lysine 519 to arginine', 'Mutation', 'rs1015480027', (18, 40))
152710	33376627	As reported in Figure 4L, the monomer and multi-chain ubiquitination of SMAD4 appeared, and ectopic expression of USP4-WT inhibited the ubiquitination of SMAD4, while ectopic expression of the catalytically inactive mutant USP4 (CS) failed to inhibit the ubiquitination of SMAD4.	('multi-chain ubiquitination', 'MPA', (42, 68))	('CS', 'Gene', '1431', (229, 231))	('inhibited', 'NegReg', (122, 131))	('monomer', 'MPA', (30, 37))	('USP4-WT', 'Var', (114, 121))	('ubiquitination', 'MPA', (136, 150))
152711	33376627	Additionally, ectopically expressed USP4-WT not mutant USP4-CS eliminated endogenous SMAD4 mononucleotide (Figure 4M).	('mutant', 'Var', (48, 54))	('CS', 'Gene', '1431', (60, 62))	('eliminated', 'NegReg', (63, 73))	('endogenous SMAD4 mononucleotide', 'MPA', (74, 105))	('mononucleotide', 'Chemical', '-', (91, 105))
152714	33376627	The above experiments demonstrated that SMAD4 deubiquitination promoted its translocation into nuclei, and previous evidence has suggested that SMAD4 inhibited the expression of CK2 as a transcription factor in the nucleus.	('translocation into nuclei', 'MPA', (76, 101))	('SMAD4', 'Gene', (40, 45))	('inhibited', 'NegReg', (150, 159))	('expression', 'MPA', (164, 174))	('deubiquitination', 'MPA', (46, 62))	('SMAD4', 'Var', (144, 149))	('promoted', 'PosReg', (63, 71))	('CK2', 'Gene', (178, 181))	('CK2', 'Gene', '13000', (178, 181))
152717	33376627	In addition, silencing SMAD4 elevated the expression of CK2 in Eca109 cells, among which sh-SMAD4-2 had a better effect, and thus was chosen for subsequent experiments (Figures 5D and 5E).	('elevated', 'PosReg', (29, 37))	('CK2', 'Gene', (56, 59))	('SMAD4', 'Gene', (23, 28))	('expression', 'MPA', (42, 52))	('CK2', 'Gene', '13000', (56, 59))	('silencing', 'Var', (13, 22))
152719	33376627	Eca109 cells were treated with sh-SMAD4 or in combination with sh-CK2.	('CK2', 'Gene', (66, 69))	('sh-SMAD4', 'Var', (31, 39))	('CK2', 'Gene', '13000', (66, 69))
152720	33376627	qRT-PCR results exhibited that the expression of CK2 was enhanced in sh-SMAD4-treated Eca109 cells, but simultaneous silencing of CK2 and SMAD4 reduced the expression of CK2 in Eca109 cells (Figure 5G).	('CK2', 'Gene', '13000', (130, 133))	('CK2', 'Gene', (49, 52))	('reduced', 'NegReg', (144, 151))	('CK2', 'Gene', '13000', (49, 52))	('silencing', 'Var', (117, 126))	('CK2', 'Gene', (170, 173))	('expression', 'MPA', (35, 45))	('CK2', 'Gene', (130, 133))	('CK2', 'Gene', '13000', (170, 173))	('expression', 'MPA', (156, 166))	('enhanced', 'PosReg', (57, 65))
152722	33376627	As documented in Figure 5K, expression of N-cadherin and Vimentin was significantly enhanced, while that of E-cadherin was significantly reduced in sh-SMAD4-treated Eca109 cells, which was negated following simultaneous silencing of SMAD4 and CK2.	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('Vimentin', 'Gene', '7431', (57, 65))	('expression', 'MPA', (28, 38))	('N-cadherin', 'Gene', (42, 52))	('CK2', 'Gene', (243, 246))	('sh-SMAD4-treated', 'Var', (148, 164))	('N-cadherin', 'Gene', '1000', (42, 52))	('Vimentin', 'Gene', (57, 65))	('CK2', 'Gene', '13000', (243, 246))	('enhanced', 'PosReg', (84, 92))	('reduced', 'NegReg', (137, 144))
152728	33376627	Moreover, after simultaneous silencing of CK2 and overexpression of SOX2, the expression of SOX2, miR-30e, USP4, and SMAD4 did not change prominently, while that of CK2 was decreased severely (Figures 6C and 6D).	('CK2', 'Gene', '13000', (165, 168))	('overexpression', 'PosReg', (50, 64))	('silencing', 'Var', (29, 38))	('CK2', 'Gene', '13000', (42, 45))	('SOX2', 'Gene', (68, 72))	('CK2', 'Gene', (165, 168))	('decreased', 'NegReg', (173, 182))	('CK2', 'Gene', (42, 45))
152733	33376627	The present study intended to dissect out the roles of SOX2-mediated miR-30e in biology and tumor growth of EC cells.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('miR-30e', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
152745	33376627	Meanwhile, in a mouse model of lung cancer, USP4 knockdown enhances tumorigenesis and tumor growth.	('tumor', 'Disease', (68, 73))	('knockdown', 'Var', (49, 58))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('USP4', 'Gene', (44, 48))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('enhances', 'PosReg', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
152755	33376627	Taken together, the findings of our study suggested that SOX2 increased miR-30e expression, promoted the miR-30e-mediated USP4 inhibition, suppressed the deubiquitination of SMAD4, and upregulated CK2 expression, ultimately inducing EC cell migration, migration, and invasion (Figure 7).	('miR-30e-mediated', 'Var', (105, 121))	('EC cell migration', 'CPA', (233, 250))	('miR-30e', 'Gene', (72, 79))	('increased', 'PosReg', (62, 71))	('expression', 'MPA', (201, 211))	('invasion', 'CPA', (267, 275))	('CK2', 'Gene', (197, 200))	('promoted', 'PosReg', (92, 100))	('deubiquitination', 'MPA', (154, 170))	('upregulated', 'PosReg', (185, 196))	('USP4', 'Gene', (122, 126))	('CK2', 'Gene', '13000', (197, 200))	('inhibition', 'NegReg', (127, 137))	('migration', 'CPA', (252, 261))	('expression', 'MPA', (80, 90))	('SMAD4', 'Protein', (174, 179))	('inducing', 'PosReg', (224, 232))	('suppressed', 'NegReg', (139, 149))
152765	33376627	EC9706 and TE-1 or Eca109 and KYSE150 were subjected to culture in DMEM or RPMI 1640 medium (GIBCO by Life Technologies, Grand Island, NY, USA) encompassing 10% FBS and 10% penicillin-streptomycin at the controlled temperature of 37 C with 5% CO2.	('penicillin', 'Chemical', 'MESH:D010406', (173, 183))	('CO2', 'Chemical', 'MESH:D002245', (243, 246))	('EC9706', 'Var', (0, 6))	('streptomycin', 'Chemical', 'MESH:D013307', (184, 196))	('KYSE150', 'Var', (30, 37))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('TE-1', 'CellLine', 'CVCL:1759', (11, 15))	('RPMI 1640 medium', 'Chemical', '-', (75, 91))	('DMEM', 'Chemical', '-', (67, 71))
152779	33376627	Following 1-h sealing in 5% BSA at the ambient temperature, the membrane was left to be probed overnight at the controlled temperature of 4 C with primary rabbit anti-human antibodies to SOX2 (ab97959, 1:100), USP4 (ab236987, 1:5,000), SMAD4 (ab244370, 1:5,000), CK2 (MAB7957, 1:25, R&D Systems, Minneapolis, MN, USA), E-cadherin (ab15148, 1:500), beta-catenin (ab2365, 1:500), N-cadherin (ab207608, 1:1,000), Vimentin (ab137321, 1:2,000), H3 (ab1791, 1:1,000), and GAPDH (ab9785, 1:2,500).	('and', 'Protein', (462, 465))	('MN', 'CellLine', 'CVCL:U508', (309, 311))	('beta-catenin', 'Gene', (348, 360))	('N-cadherin', 'Gene', (378, 388))	('ab244370', 'Var', (243, 251))	('Vimentin', 'Gene', (410, 418))	('CK2', 'Gene', (263, 266))	('N-cadherin', 'Gene', '1000', (378, 388))	('E-cadherin', 'Gene', (319, 329))	('Vimentin', 'Gene', '7431', (410, 418))	('E-cadherin', 'Gene', '999', (319, 329))	('beta-catenin', 'Gene', '1499', (348, 360))	('CK2', 'Gene', '13000', (263, 266))	('human', 'Species', '9606', (167, 172))	('GAPDH', 'Gene', (466, 471))	('GAPDH', 'Gene', '2597', (466, 471))
152806	33376627	GST-USP4-WT and mutant expression were cloned into pGEX-4T1 vector.	('GST', 'Gene', (0, 3))	('GST', 'Gene', '373156', (0, 3))	('mutant', 'Var', (16, 22))
152843	33362377	Supranormal spleen diameter (SD) is regarded as an independent risk marker in diagnosing large esophageal varices for cirrhotic patients.	('patients', 'Species', '9606', (128, 136))	('esophageal varices', 'Phenotype', 'HP:0002040', (95, 113))	('large esophageal varices', 'Disease', (89, 113))	('Supranormal', 'Var', (0, 11))
152879	33362377	In the training cohort, the C-index values to predict EV severity were 0.846, 0.738, 0.714, 0.726, 0.609, and 0.700 for EV severity prediction nomogram, LFI, SPI, PSR, King's score, and Lok index, respectively.	('L', 'Gene', '21832', (186, 187))	('PSR', 'Gene', (163, 166))	('PSR', 'Gene', '23210', (163, 166))	('Lok', 'Gene', (186, 189))	('L', 'Gene', '21832', (153, 154))	('Lok', 'Gene', '6793', (186, 189))	('0.700', 'Var', (110, 115))
152983	31216681	The result showed that the expression of RNF128 had no significant difference among the nine cell lines including EC109 and KYSE270 with a low metastatic grade, and KYSE30, KYSE520, and EC9706 with a higher metastatic grade.	('RNF128', 'Gene', (41, 47))	('EC9706', 'Var', (186, 192))	('EC109', 'CellLine', 'CVCL:6898', (114, 119))	('KYSE270', 'Var', (124, 131))	('EC9706', 'CellLine', 'CVCL:E307', (186, 192))	('KYSE520', 'Var', (173, 180))
152987	31216681	Then, we observed the suppression of the EMT progress via RNF128 knockdown with the decreased levels of N-cadherin, vimentin, and fibronectin (Figure 2C).	('RNF128', 'Gene', (58, 64))	('fibronectin', 'Gene', (130, 141))	('fibronectin', 'Gene', '2335', (130, 141))	('vimentin', 'Gene', '7431', (116, 124))	('suppression', 'NegReg', (22, 33))	('levels of', 'MPA', (94, 103))	('N-cadherin', 'Gene', (104, 114))	('vimentin', 'Gene', (116, 124))	('knockdown', 'Var', (65, 74))	('decreased', 'NegReg', (84, 93))	('N-cadherin', 'Gene', '1000', (104, 114))	('EMT progress', 'CPA', (41, 53))
152988	31216681	To better understand the molecular events, we used transcriptome sequencing (ANORAD, Jiangsu, China) to screen for differentially regulated genes in KYSE150-Luc and KYSE150-RNF128 cells (Figure 3A).	('KYSE150-RNF128', 'Gene', (165, 179))	('KYSE150-RNF128', 'Gene', '79589', (165, 179))	('KYSE150-Luc', 'Var', (149, 160))
152993	31216681	Conversely, these phosphoproteins were downregulated in ESCC cells with stably repressed RNF128 (Figure 3C), suggesting that RNF128 mediated the EGFR/MAPK/MMP-2 pathway in ESCC cells.	('RNF128', 'Var', (125, 131))	('EGFR', 'Gene', '1956', (145, 149))	('MMP-2', 'Gene', (155, 160))	('EGFR', 'Gene', (145, 149))	('mediated', 'Reg', (132, 140))	('MMP-2', 'Gene', '4313', (155, 160))
152995	31216681	To further validate the role of the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK)/matrix matalloproteinases 2 (MMP-2) activation in RNF128-induced metastasis, we analyzed the impact of introducing gefitinib (an inhibitor of EGFR), PD98059 (an inhibitor of MEK/ERK), and MMP-2 inhibitor into ESCC cells with stably overexpressed RNF128.	('EGFR', 'Gene', '1956', (258, 262))	('MMP-2', 'Gene', '4313', (145, 150))	('epidermal growth factor receptor', 'Gene', '1956', (36, 68))	('EGFR', 'Gene', (258, 262))	('MMP-2', 'Gene', '4313', (304, 309))	('PD98059', 'Var', (265, 272))	('EGFR', 'Gene', '1956', (70, 74))	('ERK', 'Gene', '5594', (294, 297))	('RNF128', 'Gene', (362, 368))	('MMP-2', 'Gene', (145, 150))	('EGFR', 'Gene', (70, 74))	('gefitinib', 'Chemical', 'MESH:D000077156', (231, 240))	('PD98059', 'Chemical', 'MESH:C093973', (265, 272))	('ERK', 'Gene', (294, 297))	('epidermal growth factor receptor', 'Gene', (36, 68))	('MEK', 'Gene', (290, 293))	('MEK', 'Gene', '5609', (290, 293))	('MMP-2', 'Gene', (304, 309))
152997	31216681	Inhibition with PD98059 attenuated the expression of p-MEK, p-ERK, and MMP-2 (Figure 4B).	('attenuated', 'NegReg', (24, 34))	('MMP-2', 'Gene', '4313', (71, 76))	('MEK', 'Gene', (55, 58))	('MEK', 'Gene', '5609', (55, 58))	('PD98059', 'Var', (16, 23))	('p-ERK', 'Gene', '9451', (60, 65))	('expression', 'MPA', (39, 49))	('MMP-2', 'Gene', (71, 76))	('p-ERK', 'Gene', (60, 65))	('PD98059', 'Chemical', 'MESH:C093973', (16, 23))
152999	31216681	Subsequently, we also found that the migration and invasion abilities of KYSE150-RNF128 and KYSE410-RNF128 cells were suppressed by the treatment with gefitinib, PD98058, and MMP-2 inhibitor (Figure 4D,E).	('MMP-2', 'Gene', (175, 180))	('gefitinib', 'Chemical', 'MESH:D000077156', (151, 160))	('PD98058', 'Var', (162, 169))	('invasion abilities', 'CPA', (51, 69))	('KYSE150-RNF128', 'Gene', '79589', (73, 87))	('MMP-2', 'Gene', '4313', (175, 180))	('KYSE410-RNF128', 'Var', (92, 106))	('PD98058', 'Chemical', 'MESH:C466090', (162, 169))	('KYSE150-RNF128', 'Gene', (73, 87))	('suppressed', 'NegReg', (118, 128))
153010	31216681	As shown in Figure 5C, the interaction between EGFR and p53 was reduced with RNF128 overexpression, but increased in RNF128 knockdown cells.	('interaction', 'Interaction', (27, 38))	('p53', 'Gene', (56, 59))	('increased', 'PosReg', (104, 113))	('p53', 'Gene', '7157', (56, 59))	('overexpression', 'Var', (84, 98))	('RNF128', 'Gene', (77, 83))	('EGFR', 'Gene', '1956', (47, 51))	('reduced', 'NegReg', (64, 71))	('EGFR', 'Gene', (47, 51))
153015	31216681	CoIP demonstrated that RNF128 interacted with p53, and p53 interacted with EGFR and then promoted the activation of the EGFR/MAPK/MMP-2 pathway (Figure 7).	('interacted', 'Interaction', (59, 69))	('MMP-2', 'Gene', (130, 135))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('p53', 'Gene', (46, 49))	('p53', 'Gene', '7157', (46, 49))	('activation', 'PosReg', (102, 112))	('promoted', 'PosReg', (89, 97))	('interacted', 'Interaction', (30, 40))	('MMP-2', 'Gene', '4313', (130, 135))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', '1956', (120, 124))	('RNF128', 'Var', (23, 29))	('EGFR', 'Gene', (75, 79))	('EGFR', 'Gene', (120, 124))
153023	31216681	With this in mind, we here verified that the increased expression of RNF128 in ESCC cells promotes MMP-2 expression levels, indicating that RNF128 has the potential to induce ESCC invasion and metastasis.	('invasion', 'CPA', (180, 188))	('MMP-2', 'Gene', (99, 104))	('RNF128', 'Var', (140, 146))	('RNF128', 'Gene', (69, 75))	('increased', 'PosReg', (45, 54))	('induce', 'PosReg', (168, 174))	('metastasis', 'CPA', (193, 203))	('expression', 'MPA', (55, 65))	('ESCC', 'Disease', (175, 179))	('MMP-2', 'Gene', '4313', (99, 104))	('promotes', 'PosReg', (90, 98))
153024	31216681	We further found that RNF128 promotes phosphorylation of EGFR, and that inhibition of EGFR phosphorylation suppresses RNF128-induced MMP-2 expression, confirming that the EGFR/MAPK/MMP-2 pathway is involved.	('EGFR', 'Gene', (171, 175))	('MMP-2', 'Gene', (181, 186))	('phosphorylation', 'MPA', (38, 53))	('EGFR', 'Gene', '1956', (86, 90))	('MMP-2', 'Gene', '4313', (133, 138))	('RNF128', 'Gene', (22, 28))	('EGFR', 'Gene', (86, 90))	('EGFR', 'Gene', '1956', (57, 61))	('inhibition', 'Var', (72, 82))	('RNF128-induced', 'Gene', (118, 132))	('MMP-2', 'Gene', '4313', (181, 186))	('expression', 'MPA', (139, 149))	('EGFR', 'Gene', '1956', (171, 175))	('suppresses', 'NegReg', (107, 117))	('EGFR', 'Gene', (57, 61))	('MMP-2', 'Gene', (133, 138))	('promotes', 'PosReg', (29, 37))
153028	31216681	All cells including KYSE150, KYSE510, KYSE410, KYSE520, KYSE270, KYSE30, EC9706, EC109 and T.TN were grown in 1640 (RPMI-1640) medium containing 10% fetal bovine serum (Gibco, Grand Island, NY, USA) and cultured in an incubator containing 5% carbon dioxide at 37  C. The RNF128 shRNA expression vector and the shRNA non-target control were purchased from TransheepBio (Shanghai, China).	('carbon dioxide', 'Chemical', 'MESH:D002245', (242, 256))	('EC109', 'Var', (81, 86))	('KYSE520', 'Var', (47, 54))	('EC9706', 'Var', (73, 79))	('bovine', 'Species', '9913', (155, 161))	('KYSE510', 'Var', (29, 36))	('KYSE270', 'Var', (56, 63))	('KYSE30', 'Var', (65, 71))	('EC9706', 'CellLine', 'CVCL:E307', (73, 79))	('EC109', 'CellLine', 'CVCL:6898', (81, 86))	('KYSE410', 'Var', (38, 45))	('KYSE150', 'Var', (20, 27))	('RNF128', 'Gene', (271, 277))
153031	31216681	The plasmids expressing p53 and RNF128-flag were gifts from Dr. Bin Li (College of Life Science and Technology, Jinan University).	('RNF128-flag', 'Var', (32, 43))	('p53', 'Gene', '7157', (24, 27))	('p53', 'Gene', (24, 27))
153049	30930933	Association of mir-196a-2 rs11614913 and mir-149 rs2292832 Polymorphisms With Risk of Cancer: An Updated Meta-Analysis Background: Accumulating evidence suggests that functional dysregulations of miRNAs, especially miR-196a-2 and miR-149, in cancers could be attributed to polymorphisms in miRNA sequences.	('mir-149', 'Gene', '406941', (41, 48))	('rs2292832', 'Mutation', 'rs2292832', (49, 58))	('miR', 'Gene', '220972', (290, 293))	('miR', 'Gene', (196, 199))	('rs2292832', 'Var', (49, 58))	('rs11614913', 'Var', (26, 36))	('Association', 'Interaction', (0, 11))	('miR-196a-2', 'Gene', (215, 225))	('miR-196a-2', 'Gene', '406973', (215, 225))	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('miR', 'Gene', (290, 293))	('miR-149', 'Gene', (230, 237))	('rs11614913', 'Mutation', 'rs11614913', (26, 36))	('miR', 'Gene', '220972', (215, 218))	('miR', 'Gene', '220972', (230, 233))	('miR-149', 'Gene', '406941', (230, 237))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mir-196a-2', 'Gene', '406973', (15, 25))	('miR', 'Gene', (215, 218))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancers', 'Disease', (242, 249))	('miR', 'Gene', '220972', (196, 199))	('miR', 'Gene', (230, 233))	('mir-149', 'Gene', (41, 48))	('mir-196a-2', 'Gene', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
153050	30930933	This study was aimed at clarifying the association of mir-196a-2 rs11614913 and mir-149 rs2292832 with cancer risk by performing an updated meta-analysis of genetic association studies.	('mir-196a-2', 'Gene', '406973', (54, 64))	('mir-149', 'Gene', (80, 87))	('mir-196a-2', 'Gene', (54, 64))	('rs11614913', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rs2292832', 'Mutation', 'rs2292832', (88, 97))	('mir-149', 'Gene', '406941', (80, 87))	('rs11614913', 'Mutation', 'rs11614913', (65, 75))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('rs2292832', 'Var', (88, 97))	('association', 'Interaction', (39, 50))
153051	30930933	Studies should meet the following criteria to be included in the meta-analysis: evaluation of genetic association between rs11614913 and/or rs2292832 and susceptibility to cancer; A case-control design; Written in English; Availability of sufficient data for estimating odds ratio (OR) and its 95% confidence interval (95%CI).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('rs2292832', 'Var', (140, 149))	('rs11614913', 'Mutation', 'rs11614913', (122, 132))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('rs2292832', 'Mutation', 'rs2292832', (140, 149))	('cancer', 'Disease', (172, 178))	('rs11614913', 'Var', (122, 132))
153052	30930933	Pooled ORs and 95% CIs were estimated using a total of 111 studies (41,673 cases and 49,570 controls) for mir-196a rs11614913 and 44 studies (15,954 cases and 19,594 controls) for mir-149 rs2292832.	('mir', 'Gene', (180, 183))	('mir-149', 'Gene', (180, 187))	('mir', 'Gene', '220972', (106, 109))	('rs2292832', 'Var', (188, 197))	('rs11614913', 'Var', (115, 125))	('mir-149', 'Gene', '406941', (180, 187))	('rs2292832', 'Mutation', 'rs2292832', (188, 197))	('mir', 'Gene', '220972', (180, 183))	('mir', 'Gene', (106, 109))	('rs11614913', 'Mutation', 'rs11614913', (115, 125))
153054	30930933	Results: Mir-196a-2 rs11614913 T allele was associated with decreased cancer risk in overall population.	('rs11614913 T', 'Var', (20, 32))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('decreased cancer', 'Disease', (60, 76))	('rs11614913', 'Mutation', 'rs11614913', (20, 30))	('Mir-196a-2', 'Gene', '406973', (9, 19))	('decreased cancer', 'Disease', 'MESH:D009369', (60, 76))	('Mir-196a-2', 'Gene', (9, 19))
153056	30930933	Mir-149 rs2292832 was not associated with cancer risk in overall population and there were no differences between Asians and Caucasians.	('rs2292832', 'Var', (8, 17))	('rs2292832', 'Mutation', 'rs2292832', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Mir-149', 'Gene', (0, 7))	('Mir-149', 'Gene', '406941', (0, 7))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
153057	30930933	However, the T allele was associated with a decrease risk of gastrointestinal tract cancers under the heterozygote model and an increased risk of colorectal cancer under the recessive model.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('decrease', 'NegReg', (44, 52))	('gastrointestinal tract cancers', 'Disease', 'MESH:D004067', (61, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('T allele', 'Var', (13, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('gastrointestinal tract cancers', 'Disease', (61, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (146, 163))
153058	30930933	Conclusions: The present meta-analysis suggests that mir-196a-2 rs11614913 may contribute to the risk of cancer especially in Asians.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('rs11614913', 'Mutation', 'rs11614913', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mir-196a-2', 'Gene', (53, 63))	('rs11614913', 'Var', (64, 74))	('mir-196a-2', 'Gene', '406973', (53, 63))
153059	30930933	Mir-149 rs2292832 may modulate the risk of gastrointestinal tract cancers especially colorectal cancer.	('rs2292832', 'Var', (8, 17))	('rs2292832', 'Mutation', 'rs2292832', (8, 17))	('Mir-149', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('modulate', 'Reg', (22, 30))	('Mir-149', 'Gene', '406941', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('gastrointestinal tract cancers especially colorectal cancer', 'Disease', 'MESH:D015179', (43, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
153064	30930933	Until recent years, much effort has been devoted to link the alteration of protein coding genes to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('alteration', 'Var', (61, 71))
153068	30930933	It has been shown that single nucleotide polymorphism (SNP) in miRNA genes, such as hsa-mir-196a-2 rs11614913 and hsa-mir-149 rs2292832, may influence their functions through altering miRNA expression, maturation and/or efficiency of targeting and, thereby, contribute to the risk of cancer (Hu et al.,; Hoffman et al.,; Tu et al.,; Nariman-Saleh-Fam et al.,).	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('rs11614913', 'Mutation', 'rs11614913', (99, 109))	('contribute', 'Reg', (258, 268))	('rs2292832', 'Mutation', 'rs2292832', (126, 135))	('mir-149', 'Gene', (118, 125))	('rs2292832', 'Var', (126, 135))	('mir-149', 'Gene', '406941', (118, 125))	('influence', 'Reg', (141, 150))	('miR', 'Gene', '220972', (184, 187))	('single nucleotide polymorphism', 'Var', (23, 53))	('targeting', 'MPA', (234, 243))	('cancer', 'Disease', (284, 290))	('miR', 'Gene', '220972', (63, 66))	('functions', 'MPA', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('maturation', 'MPA', (202, 212))	('miR', 'Gene', (184, 187))	('altering', 'Reg', (175, 183))	('hsa-mir-196a-2', 'Gene', '406973', (84, 98))	('miR', 'Gene', (63, 66))	('rs11614913', 'Var', (99, 109))	('hsa-mir-196a-2', 'Gene', (84, 98))
153069	30930933	Several association studies in a range of populations evaluated the contribution of mir-196a-2 rs11614913 and mir-149 rs2292832 to cancer risk; but results are inconclusive.	('cancer', 'Disease', (131, 137))	('mir-149', 'Gene', '406941', (110, 117))	('rs2292832', 'Mutation', 'rs2292832', (118, 127))	('rs11614913', 'Mutation', 'rs11614913', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mir-196a-2', 'Gene', (84, 94))	('rs11614913', 'Var', (95, 105))	('mir-196a-2', 'Gene', '406973', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('mir-149', 'Gene', (110, 117))	('rs2292832', 'Var', (118, 127))
153070	30930933	Therefore, this study was aimed at clarifying the association of mir-196a-2 rs11614913 and mir-149 rs2292832 with cancer risk by performing an updated meta-analysis of genetic association studies.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('rs2292832', 'Var', (99, 108))	('rs11614913', 'Var', (76, 86))	('mir-149', 'Gene', (91, 98))	('rs2292832', 'Mutation', 'rs2292832', (99, 108))	('mir-196a-2', 'Gene', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mir-196a-2', 'Gene', '406973', (65, 75))	('mir-149', 'Gene', '406941', (91, 98))	('rs11614913', 'Mutation', 'rs11614913', (76, 86))	('association', 'Interaction', (50, 61))	('cancer', 'Disease', (114, 120))
153071	30930933	("microRNA 196a2" OR "miRNA-196a2" OR "mir-196a2" OR "mir196a" OR "mir-196a-2" OR "pre-mir-196a" OR "pre-mir196a" OR "196a" OR "rs11614913") OR ("microRNA 149" OR "miRNA-149" OR "mir-149" OR "mir149" OR "pre-mir-149" OR "pre-mir149" OR "rs2292832") AND ("single nucleotide polymorphism" OR "SNP" OR "variant" OR "variation" OR "polymorphism" OR "mutation" OR "locus") AND ("neoplasm" OR "cancer" OR "tumor" OR "carcinoma" OR "sarcoma" OR "lymphoma" OR "adenoma" OR "leukemia" OR "leucemia" OR "malignancy" OR "malignance" OR "malignant" OR "glioma").	('"glioma', 'Disease', (540, 547))	('mir', 'Gene', (67, 70))	('malignancy', 'Disease', (494, 504))	('mir', 'Gene', '220972', (192, 195))	('"glioma', 'Disease', 'MESH:D005910', (540, 547))	('miR', 'Gene', (164, 167))	('mir-149', 'Gene', (208, 215))	('tumor', 'Disease', (400, 405))	('mir149', 'Gene', (225, 231))	('"neoplasm" OR "cancer', 'Disease', 'MESH:D009369', (373, 394))	('mir-149', 'Gene', '406941', (208, 215))	('lymphoma', 'Phenotype', 'HP:0002665', (439, 447))	('rs2292832', 'Mutation', 'rs2292832', (237, 246))	('mir', 'Gene', (179, 182))	('"single nucleotide polymorphism" OR "SNP" OR "variant" OR "variation', 'Var', (254, 322))	('mir149', 'Gene', (192, 198))	('mir', 'Gene', '220972', (208, 211))	('mir-196a-2', 'Gene', '406973', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (400, 405))	('mir', 'Gene', (105, 108))	('mir', 'Gene', (225, 228))	('rs2292832', 'Var', (237, 246))	('mir', 'Gene', (192, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (411, 420))	('mir', 'Gene', '220972', (87, 90))	('mir-196a-2', 'Gene', (67, 77))	('rs11614913', 'Mutation', 'rs11614913', (128, 138))	('mir', 'Gene', '220972', (54, 57))	('leukemia', 'Phenotype', 'HP:0001909', (466, 474))	('sarcoma', 'Phenotype', 'HP:0100242', (426, 433))	('mir', 'Gene', '220972', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('mir', 'Gene', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (400, 405))	('carcinoma" OR "sarcoma" OR "lymphoma" OR "adenoma" OR "leukemia" OR "leucemia"', 'Disease', 'MESH:D000236', (411, 489))	('mir-149', 'Gene', (179, 186))	('mir', 'Gene', '220972', (67, 70))	('malignancy', 'Disease', 'MESH:D009369', (494, 504))	('glioma', 'Phenotype', 'HP:0009733', (541, 547))	('"neoplasm" OR "cancer', 'Disease', (373, 394))	('mir-149', 'Gene', '406941', (179, 186))	('mir', 'Gene', (87, 90))	('miR', 'Gene', '220972', (22, 25))	('neoplasm', 'Phenotype', 'HP:0002664', (374, 382))	('miR', 'Gene', '220972', (164, 167))	('mir', 'Gene', '220972', (179, 182))	('mir', 'Gene', (54, 57))	('mir149', 'Gene', '406941', (192, 198))	('mir149', 'Gene', '406941', (225, 231))	('mir', 'Gene', (39, 42))	('mir', 'Gene', '220972', (225, 228))	('miR', 'Gene', (22, 25))	('mir', 'Gene', '220972', (105, 108))
153072	30930933	Studies should meet the following criteria to be included in the meta-analysis: (1) evaluation of genetic association between rs11614913 and/or rs2292832 and susceptibility to cancer; (2) a case-control design; (3) Written in English; (4) Availability of sufficient data for estimating odds ratio (OR) and its 95% confidence interval (95%CI).	('rs11614913', 'Mutation', 'rs11614913', (126, 136))	('rs2292832', 'Var', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('rs2292832', 'Mutation', 'rs2292832', (144, 153))	('rs11614913', 'Var', (126, 136))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
153076	30930933	Association of rs11614913 and rs2292832 with cancer was estimated by calculating pooled ORs and their 95% CIs assuming homozygote, heterozygote, dominant, recessive, and allelic models.	('rs2292832', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('rs11614913', 'Var', (15, 25))	('rs2292832', 'Mutation', 'rs2292832', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('Association', 'Interaction', (0, 11))	('cancer', 'Disease', (45, 51))	('rs11614913', 'Mutation', 'rs11614913', (15, 25))
153080	30930933	A total of 110 articles which included 111 studies (41,673 cases and 49,570 controls) evaluated the association of miR-196a-2 rs11614913 and cancer risk (Table 1).	('rs11614913', 'Mutation', 'rs11614913', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('association', 'Interaction', (100, 111))	('miR-196a-2', 'Gene', (115, 125))	('miR-196a-2', 'Gene', '406973', (115, 125))	('rs11614913', 'Var', (126, 136))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
153082	30930933	The final meta-analysis of mir-196a-2 rs11614913 and cancer risk included 111 studies (including 41,673 patients and 49,570 controls), among which 93 were scored greater than eight in the quality assessment and regarded as high quality studies.	('rs11614913', 'Var', (38, 48))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('mir-196a-2', 'Gene', (27, 37))	('mir-196a-2', 'Gene', '406973', (27, 37))	('rs11614913', 'Mutation', 'rs11614913', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('patients', 'Species', '9606', (104, 112))
153083	30930933	In 93 out of 111 studies, the genotype distribution of rs11614913 in the control group was concordant with HWE.	('HWE', 'Disease', (107, 110))	('rs11614913', 'Mutation', 'rs11614913', (55, 65))	('rs11614913', 'Var', (55, 65))
153084	30930933	Mir-196a-2 rs11614913 were genotype using a range of techniques with the most common being PCR-RFLP (n = 53).	('rs11614913', 'Var', (11, 21))	('Mir-196a-2', 'Gene', '406973', (0, 10))	('rs11614913', 'Mutation', 'rs11614913', (11, 21))	('Mir-196a-2', 'Gene', (0, 10))	('PC', 'Phenotype', 'HP:0012125', (91, 93))
153091	30930933	Moreover, 43 articles comprising 44 studies (15,954 cases and 19,594 controls) evaluated the association of mir-149 rs2292832 and cancer risk (Table 2), among which 39 studies were evaluated as being high quality (quality score > 8).	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('rs2292832', 'Var', (116, 125))	('mir-149', 'Gene', '406941', (108, 115))	('cancer', 'Disease', (130, 136))	('rs2292832', 'Mutation', 'rs2292832', (116, 125))	('association', 'Interaction', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mir-149', 'Gene', (108, 115))
153095	30930933	Statistically significant associations between mir-196a2 rs11614913 and cancer risk were observed assuming the homozygote (TT vs. CC, ORRE [95% CI]: 0.88 [0.79-0.98], P: 0.027) and the recessive (TT vs. CC+CT, ORRE [95% CI]: 0.89 [0.83-0.95], P: 0.001) models (Table 3).	('rs11614913', 'Mutation', 'rs11614913', (57, 67))	('mir', 'Gene', '220972', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mir', 'Gene', (47, 50))	('rs11614913', 'Var', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
153096	30930933	Mir-196a-2 rs11614913 was not associated with cancer risk in the heterozygote and dominant models and there was a non-significant borderline association in the allele contrast (Table 3).	('rs11614913', 'Var', (11, 21))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('Mir-196a-2', 'Gene', '406973', (0, 10))	('cancer', 'Disease', (46, 52))	('rs11614913', 'Mutation', 'rs11614913', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('Mir-196a-2', 'Gene', (0, 10))
153097	30930933	Supplementary Figure S1 shows the forest plots of association of mir-196a-2 rs11614913 and cancer risk in five models.	('rs11614913', 'Var', (76, 86))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mir-196a-2', 'Gene', (65, 75))	('mir-196a-2', 'Gene', '406973', (65, 75))	('rs11614913', 'Mutation', 'rs11614913', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('association', 'Interaction', (50, 61))
153098	30930933	The results of subgroup analysis for mir-196a-2 rs11614913 are shown in Table 4.	('mir-196a-2', 'Gene', (37, 47))	('mir-196a-2', 'Gene', '406973', (37, 47))	('rs11614913', 'Var', (48, 58))	('rs11614913', 'Mutation', 'rs11614913', (48, 58))
153099	30930933	Decreased risk of cancer was found in high quality studies under the homozygote (TT vs. CC, ORRE [95% CI]: 0.87 [0.77-0.97], P: 0.017), the recessive (TT vs. CC+CT, ORRE [95% CI]: 0.88 [0.81-0.95], P: 0.001) and the allele contrasts (T vs. C, ORRE [95% CI]: 0.93 [0.88-0.99], P: 0.020).	('TT vs.', 'Var', (151, 157))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
153101	30930933	Subgrouping by broad cancer categories indicated that mir-196a-2 rs11614913 was associated by a decreased risk of gynecologic cancer (GyC) assuming the recessive model (TT vs. CC+CT, ORFE [95% CI]: 0.80 [0.68-0.95], P: 0.010) and the allelic contrast (T vs. C, ORFE [95% CI]: 0.88 [0.79-0.98], P: 0.021) (Figure 3).	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('mir-196a-2', 'Gene', '406973', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mir-196a-2', 'Gene', (54, 64))	('rs11614913', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('decreased', 'NegReg', (96, 105))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('ORFE', 'Species', '69811', (261, 265))	('cancer', 'Disease', (21, 27))	('rs11614913', 'Mutation', 'rs11614913', (65, 75))	('ORFE', 'Species', '69811', (183, 187))
153104	30930933	Further subgrouping by cancer type revealed significant association of mir-196a-2 rs11614913 with hepatocellular carcinoma (Figure 4) under the homozygote model (TT vs. CC, ORRE [95% CI]: 0.73[0.57-0.94], P: 0.017), the recessive model (TT vs. CC+CT, ORRE [95% CI]: 0.79 [0.66-0.95], P: 0.017) and the allele contrast (T vs. C, ORFE [95% CI]: 0.88 [0.78-0.98], P: 0.030), and with ovarian cancer (Figure 5) under the recessive model (TT vs. CC+CT, ORFE [95% CI]: 0.73[0.60-0.90], P: 0.003).	('ovarian cancer', 'Phenotype', 'HP:0100615', (381, 395))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('association', 'Interaction', (56, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('rs11614913', 'Var', (82, 92))	('cancer', 'Disease', (389, 395))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('rs11614913', 'Mutation', 'rs11614913', (82, 92))	('ORFE', 'Species', '69811', (328, 332))	('ORFE', 'Species', '69811', (448, 452))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('cancer', 'Disease', (23, 29))	('ovarian cancer', 'Disease', 'MESH:D010051', (381, 395))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (98, 122))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('mir-196a-2', 'Gene', '406973', (71, 81))	('ovarian cancer', 'Disease', (381, 395))	('hepatocellular carcinoma', 'Disease', (98, 122))	('mir-196a-2', 'Gene', (71, 81))
153109	30930933	When corrected for HWD, mir-196a-2 rs11614913 was found to be significantly associated with breast cancer under the homozygote (TT vs. CC, HWD-adjusted ORRE [95% CI]: 0.75 [0.61-0.93], P: 0.011) and recessive (TT vs. CC+CT, HWD-adjusted ORRE [95% CI]: 0.84 [0.71-0.98], P: 0.030) models (Figure 6).	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('rs11614913', 'Var', (35, 45))	('mir-196a-2', 'Gene', (24, 34))	('associated', 'Reg', (76, 86))	('mir-196a-2', 'Gene', '406973', (24, 34))	('rs11614913', 'Mutation', 'rs11614913', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
153111	30930933	Furthermore, adjustment for HWD confirmed that mir-196a-2 rs11614913 is not associated with colorectal or lung cancer assuming any genetic model (Supplementary Table S2).	('mir-196a-2', 'Gene', (47, 57))	('rs11614913', 'Var', (58, 68))	('mir-196a-2', 'Gene', '406973', (47, 57))	('colorectal or lung cancer', 'Disease', 'MESH:D015179', (92, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (76, 86))	('rs11614913', 'Mutation', 'rs11614913', (58, 68))	('colorectal or lung cancer', 'Disease', (92, 117))
153113	30930933	Supplementary Figure S4 shows the forest plots for the association of mir-149 rs2292832 and cancer risk under different genetic models.	('rs2292832', 'Var', (78, 87))	('mir-149', 'Gene', '406941', (70, 77))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('rs2292832', 'Mutation', 'rs2292832', (78, 87))	('association', 'Interaction', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mir-149', 'Gene', (70, 77))
153114	30930933	However, in subgroup analyses (Table 5) significant association of rs2292832 with cancer risk was observed in studies which used a genotyping method other than PCR-RFLP (CT vs. CC, ORFE [95% CI]: 0.88 [0.79-0.98], P: 0.025).	('rs2292832', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('rs2292832', 'Mutation', 'rs2292832', (67, 76))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ORFE', 'Species', '69811', (181, 185))	('PC', 'Phenotype', 'HP:0012125', (160, 162))
153118	30930933	Sensitivity analysis revealed that HWD studies had no significant effect on point estimates in the overall meta-analysis of mir-149 rs2292832 and cancer risk, and still no significant association was observed in overall analysis (Table 5).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('mir-149', 'Gene', '406941', (124, 131))	('rs2292832', 'Mutation', 'rs2292832', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mir-149', 'Gene', (124, 131))	('rs2292832', 'Var', (132, 141))
153120	30930933	Adjusting for HWD in these subgroups confirmed the results of original analyses and showed that rs2292832 is associated with cancer risk in non-RFLP subgroup under the heterozygote model (Figure 8, CT vs. CC, HWD-adjusted ORRE [95% CI]: 0.68 [0.48-0.98], P: 0.040) and with colorectal cancer risk under the recessive model (TT vs. CT+CC, HWD-adjusted ORFE [95% CI]: 1.29 [1.11-1.50], P: 0.0007).	('colorectal cancer', 'Phenotype', 'HP:0003003', (274, 291))	('associated', 'Reg', (109, 119))	('colorectal cancer', 'Disease', (274, 291))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('rs2292832', 'Var', (96, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (274, 291))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rs2292832', 'Mutation', 'rs2292832', (96, 105))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('ORFE', 'Species', '69811', (351, 355))
153122	30930933	Significant between study heterogeneity was observed in the overall estimation under all genetic models for mir-196a-2 rs11614913 and consequently random effect model was used.	('mir-196a-2', 'Gene', (108, 118))	('rs11614913', 'Var', (119, 129))	('rs11614913', 'Mutation', 'rs11614913', (119, 129))	('mir-196a-2', 'Gene', '406973', (108, 118))
153125	30930933	Statistically significant heterogeneity was also observed in the overall analysis of miR-149 rs2292832 and cancer risk and, consequently, RE model was used to estimate pooled OR (Table 3).	('rs2292832', 'Mutation', 'rs2292832', (93, 102))	('miR-149', 'Gene', (85, 92))	('miR-149', 'Gene', '406941', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('rs2292832', 'Var', (93, 102))	('cancer', 'Disease', (107, 113))
153126	30930933	Rank correlation test of the mir-196a-2 rs11614913 Begger's funnel plot asymmetry revealed no statistically significant evidence of publication bias in any contrast (Table 3 and Supplementary Figure S10).	('S10', 'Gene', '9861', (199, 202))	('S10', 'Gene', (199, 202))	('rs11614913', 'Mutation', 'rs11614913', (40, 50))	('mir-196a-2', 'Gene', (29, 39))	('rs11614913', 'Var', (40, 50))	('mir-196a-2', 'Gene', '406973', (29, 39))
153127	30930933	However, rank correlation test for asymmetry of mir-149 rs2292832 funnel plots showed statistically significant results in the homozygote, recessive and the allelic contrasts (Table 3 and Supplementary Figure S11).	('mir-149', 'Gene', (48, 55))	('mir-149', 'Gene', '406941', (48, 55))	('S11', 'Gene', '6267', (209, 212))	('rs2292832', 'Var', (56, 65))	('results', 'Reg', (112, 119))	('S11', 'Gene', (209, 212))	('rs2292832', 'Mutation', 'rs2292832', (56, 65))
153131	30930933	Accumulating evidence suggests that, at least a part of functional dysregulations of miRNAs in cancers could be attributed to polymorphisms in miRNA sequences (Hu et al.,; Hoffman et al.,; Tu et al.,; Ghaedi et al.,; Nariman-Saleh-Fam et al.,).	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', (143, 146))	('polymorphisms', 'Var', (126, 139))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
153132	30930933	Two mature miRNAs, miR-196a-5p and miR-196a-3p, are generated from the stem-loop structure of hsa-mir-196a-2 (Kozomara and Griffiths-Jones,) with the studied polymorphism, rs11614913, residing in the 3' arm (Figure 9A).	('miR', 'Gene', '220972', (19, 22))	('rs11614913', 'Var', (172, 182))	('miR', 'Gene', (19, 22))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('miR', 'Gene', '220972', (35, 38))	('rs11614913', 'Mutation', 'rs11614913', (172, 182))	('miR', 'Gene', (35, 38))	('hsa-mir-196a-2', 'Gene', (94, 108))	('hsa-mir-196a-2', 'Gene', '406973', (94, 108))
153133	30930933	This polymorphism, therefore, may potentially alter miRNA processing and also binding to related target mRNAs (Hoffman et al.,) (Figure 9B).	('binding', 'Interaction', (78, 85))	('miR', 'Gene', '220972', (52, 55))	('polymorphism', 'Var', (5, 17))	('alter', 'Reg', (46, 51))	('miR', 'Gene', (52, 55))
153136	30930933	The potential of rs11614913 in influencing targeting function of mir-196a-2 has also been documented by whole-genome expression microarrays which found different numbers of dysregulated mRNAs after transfecting cells with pre-mir-196a-C or pre-mir-196a-T vector (Hoffman et al.,).	('rs11614913', 'Var', (17, 27))	('influencing', 'Reg', (31, 42))	('mir', 'Gene', '220972', (226, 229))	('targeting function', 'MPA', (43, 61))	('rs11614913', 'Mutation', 'rs11614913', (17, 27))	('mir-196a-2', 'Gene', (65, 75))	('mir', 'Gene', '220972', (65, 68))	('mir', 'Gene', '220972', (244, 247))	('mir-196a-2', 'Gene', '406973', (65, 75))	('mir', 'Gene', (226, 229))	('mir', 'Gene', (65, 68))	('mir', 'Gene', (244, 247))	('dysregulated', 'MPA', (173, 185))
153137	30930933	Hsa-mir-149 also generates two mature miRNAs (miR-149-5p and miR-149-3p) and the studied polymorphism, rs2292832, does not reside in the mature sequence of neither miR-149-5p or miR-149-3p (Figure 10A).	('miR', 'Gene', (46, 49))	('miR', 'Gene', '220972', (61, 64))	('miR-149', 'Gene', '406941', (61, 68))	('miR', 'Gene', (164, 167))	('miR', 'Gene', '220972', (178, 181))	('rs2292832', 'Var', (103, 112))	('miR-149', 'Gene', '406941', (178, 185))	('miR', 'Gene', (38, 41))	('miR', 'Gene', (61, 64))	('miR', 'Gene', (178, 181))	('miR-149', 'Gene', (46, 53))	('Hsa-mir-149', 'Gene', '406941', (0, 11))	('miR-149', 'Gene', (164, 171))	('Hsa-mir-149', 'Gene', (0, 11))	('miR', 'Gene', '220972', (46, 49))	('miR-149', 'Gene', (61, 68))	('miR-149', 'Gene', (178, 185))	('miR', 'Gene', '220972', (164, 167))	('miR-149', 'Gene', '406941', (46, 53))	('miR-149', 'Gene', '406941', (164, 171))	('miR', 'Gene', '220972', (38, 41))	('rs2292832', 'Mutation', 'rs2292832', (103, 112))
153138	30930933	Therefore, it has been hypothesized that rs2292832 is not a structure-shifting polymorphism for pri-mir-149 or pre-mir-149 (Wei et al.,).	('mir-149', 'Gene', (115, 122))	('mir-149', 'Gene', '406941', (100, 107))	('mir-149', 'Gene', '406941', (115, 122))	('rs2292832', 'Var', (41, 50))	('mir-149', 'Gene', (100, 107))	('rs2292832', 'Mutation', 'rs2292832', (41, 50))
153139	30930933	reported that the T allele may disrupt the maturation process compared with the C allele and, consequently, decrease miR-149 expression (Tu et al.,) (Figure 10B) in head and neck squamous cell carcinoma patients.	('neck squamous cell carcinoma', 'Disease', (174, 202))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (174, 202))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('disrupt', 'NegReg', (31, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('expression', 'MPA', (125, 135))	('patients', 'Species', '9606', (203, 211))	('miR-149', 'Gene', (117, 124))	('maturation process', 'CPA', (43, 61))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (165, 202))	('T allele', 'Var', (18, 26))	('decrease', 'NegReg', (108, 116))	('miR-149', 'Gene', '406941', (117, 124))
153141	30930933	Several meta-analyses have evaluated the risk of cancer associated with mir-196a-2 rs11614913 or mir-149 rs2292832 (Chu et al.,; Zhang H. et al.,; Feng et al.,; Yan et al.,; Liu et al.,).	('mir-149', 'Gene', (97, 104))	('rs2292832', 'Var', (105, 114))	('rs11614913', 'Var', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('rs2292832', 'Mutation', 'rs2292832', (105, 114))	('mir-149', 'Gene', '406941', (97, 104))	('mir-196a-2', 'Gene', '406973', (72, 82))	('mir-196a-2', 'Gene', (72, 82))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('rs11614913', 'Mutation', 'rs11614913', (83, 93))	('cancer', 'Disease', (49, 55))
153142	30930933	Therefore, it was necessary to perform an updated meta-analysis with larger number of studies to clarify the association of mir-196a-2 rs11614913 or mir-149 rs2292832 with cancer risk.	('mir-149', 'Gene', (149, 156))	('rs2292832', 'Var', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('rs11614913', 'Mutation', 'rs11614913', (135, 145))	('rs11614913', 'Var', (135, 145))	('rs2292832', 'Mutation', 'rs2292832', (157, 166))	('mir-149', 'Gene', '406941', (149, 156))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('mir-196a-2', 'Gene', '406973', (124, 134))	('mir-196a-2', 'Gene', (124, 134))	('cancer', 'Disease', (172, 178))
153143	30930933	For mir-196a-2 rs11614913, the previous largest meta-analysis, conducted by Liu et al., included 84 studies compared to 111 studies in the present meta-analysis.	('mir-196a-2', 'Gene', (4, 14))	('rs11614913', 'Var', (15, 25))	('rs11614913', 'Mutation', 'rs11614913', (15, 25))	('mir-196a-2', 'Gene', '406973', (4, 14))
153145	30930933	The results also suggest that mir-196a-2 rs11614913 may pose an ethnic dependent effect on cancer risk as associations with cancer were only observed in Asians.	('rs11614913', 'Var', (41, 51))	('cancer', 'Disease', (124, 130))	('mir-196a-2', 'Gene', '406973', (30, 40))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rs11614913', 'Mutation', 'rs11614913', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('mir-196a-2', 'Gene', (30, 40))
153147	30930933	In-line with previous studies, the current meta-analysis also confirmed that rs11614913 is associated with decreased risks of hepatocellular cancer under three genetic models (Liu et al.,) and that it may not modulate risk of urogenital cancers (Wang et al.,).	('rs11614913', 'Mutation', 'rs11614913', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (126, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('hepatocellular cancer', 'Disease', (126, 147))	('urogenital cancers', 'Disease', 'MESH:D014565', (226, 244))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('decreased', 'NegReg', (107, 116))	('urogenital cancers', 'Disease', (226, 244))	('rs11614913', 'Var', (77, 87))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (126, 147))
153152	30930933	(ii) Additionally, the present meta-analysis found significant associations between mir-196a-2 rs11614913 and decreased risks of gynecologic cancers (especially ovarian cancer), which have not been reported in any previous meta-analysis.	('rs11614913', 'Mutation', 'rs11614913', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('decreased', 'NegReg', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('especially ovarian cancer', 'Disease', (150, 175))	('especially ovarian cancer', 'Disease', 'MESH:D010051', (150, 175))	('rs11614913', 'Var', (95, 105))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('mir-196a-2', 'Gene', '406973', (84, 94))	('mir-196a-2', 'Gene', (84, 94))	('cancers', 'Disease', (141, 148))
153154	30930933	(iii) Although previous meta-analyses (Yan et al.,; Zhang H. et al.,; Liu et al.,) failed to find a significant association between mir-196a-2 rs11614913 and breast cancer, the current study showed, by incorporating more association studies and performing HWD sensitivity analysis, that adjusting for departure from HWE may reveal significant associations under the homozygote and recessive contrasts (Figure 6 and Supplementary Table S2).	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('rs11614913', 'Mutation', 'rs11614913', (143, 153))	('mir-196a-2', 'Gene', (132, 142))	('mir-196a-2', 'Gene', '406973', (132, 142))	('rs11614913', 'Var', (143, 153))
153157	30930933	The current meta-analysis also showed that mir-149 rs2292832 is not associated with risk of cancer in any genetic model and the results were statistically reliable, as summary effects were not influenced by excluding any single study, HWE-deviated or low quality studies.	('rs2292832', 'Mutation', 'rs2292832', (51, 60))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mir-149', 'Gene', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('rs2292832', 'Var', (51, 60))	('mir-149', 'Gene', '406941', (43, 50))
153170	30930933	First, significant heterogeneity was present in most analyses especially for mir-196a-2 polymorphism.	('polymorphism', 'Var', (88, 100))	('mir-196a-2', 'Gene', '406973', (77, 87))	('mir-196a-2', 'Gene', (77, 87))
153172	30930933	This, in turn, may limit the efficacy of the overall analysis especially in the case of miR-196a-2 rs11614913.	('efficacy', 'MPA', (29, 37))	('rs11614913', 'Mutation', 'rs11614913', (99, 109))	('miR-196a-2', 'Gene', (88, 98))	('miR-196a-2', 'Gene', '406973', (88, 98))	('rs11614913', 'Var', (99, 109))	('limit', 'NegReg', (19, 24))
153174	30930933	Fourth, some limitations such as language restriction or lack of access to the genotype counts of mir-196a-2 rs11614913 in four studies with insufficiently reported data may bring in publication bias.	('mir-196a-2', 'Gene', '406973', (98, 108))	('rs11614913', 'Mutation', 'rs11614913', (109, 119))	('insufficiently', 'Disease', (141, 155))	('bring', 'Reg', (174, 179))	('rs11614913', 'Var', (109, 119))	('insufficiently', 'Disease', 'MESH:D000309', (141, 155))	('mir-196a-2', 'Gene', (98, 108))
153175	30930933	Although rank correlation test of funnel plots of mir-149 rs2292832 was significant in three genetic models raising the possibility of publication bias, adjusting for such a bias using trim-and-fill method did not afford any change in analysis of overall studies in these models (Supplementary Figure S4).	('rs2292832', 'Var', (58, 67))	('mir-149', 'Gene', (50, 57))	('rs2292832', 'Mutation', 'rs2292832', (58, 67))	('mir-149', 'Gene', '406941', (50, 57))
153178	30930933	In conclusion, this meta-analysis showed that mir-196a-2 rs11614913 T allele is associated with decreased cancer risk in overall population, high quality studies and studies on Asian populations.	('mir-196a-2', 'Gene', '406973', (46, 56))	('rs11614913', 'Mutation', 'rs11614913', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('rs11614913 T', 'Var', (57, 69))	('decreased cancer', 'Disease', (96, 112))	('mir-196a-2', 'Gene', (46, 56))	('decreased cancer', 'Disease', 'MESH:D009369', (96, 112))
153180	30930933	Mir-149 rs2292832 was not associated with cancer risk in overall population, high quality studies, Asians or Caucasians.	('rs2292832', 'Var', (8, 17))	('rs2292832', 'Mutation', 'rs2292832', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Mir-149', 'Gene', (0, 7))	('Mir-149', 'Gene', '406941', (0, 7))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
153238	26225858	In women, all of individuals with grade B-D esophagitis had hiatus hernia, although the difference was not reached to the significance as compared with those with grade A esophagitis (p = 0.16).	('esophagitis', 'Phenotype', 'HP:0100633', (171, 182))	('esophagitis', 'Disease', (171, 182))	('A esophagitis', 'Disease', (169, 182))	('esophagitis', 'Disease', 'MESH:D004941', (171, 182))	('grade B-D', 'Var', (34, 43))	('hiatus hernia', 'Phenotype', 'HP:0002036', (60, 73))	('hiatus hernia', 'Disease', (60, 73))	('women', 'Species', '9606', (3, 8))	('A esophagitis', 'Disease', 'MESH:D004941', (169, 182))	('esophagitis', 'Phenotype', 'HP:0100633', (44, 55))	('hernia', 'Phenotype', 'HP:0100790', (67, 73))	('esophagitis', 'Disease', (44, 55))	('hiatus hernia', 'Disease', 'MESH:D006551', (60, 73))	('esophagitis', 'Disease', 'MESH:D004941', (44, 55))
153264	26225858	The present study showed that visceral fat accumulation was associated with the presence of RE in both men and women.	('R', 'Chemical', '-', (92, 93))	('women', 'Species', '9606', (111, 116))	('men', 'Species', '9606', (103, 106))	('presence', 'Var', (80, 88))	('visceral fat accumulation', 'MPA', (30, 55))	('men', 'Species', '9606', (113, 116))
153382	23237990	Three human esophageal epithelial cell lines, EPC2-hTERT, EPC394, and EPC425, were grown at 37  C in a humidified 5% CO2 incubator, and maintained keratinocyte serum free medium (KSFM, Invitrogen, Grand Island, NY) containing human epidermal growth factor (1ng/mL), bovine pituitary extract (50ug/mL), and penicillin (100 units/mL) and streptomycin (100mug/ml).	('CO2', 'Chemical', '-', (117, 120))	('human', 'Species', '9606', (226, 231))	('human', 'Species', '9606', (6, 11))	('KSFM', 'Chemical', '-', (179, 183))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (46, 56))	('bovine', 'Species', '9913', (266, 272))	('epidermal growth factor', 'Gene', (232, 255))	('streptomycin', 'Chemical', 'MESH:D013307', (336, 348))	('penicillin', 'Chemical', 'MESH:D010406', (306, 316))	('epidermal growth factor', 'Gene', '1950', (232, 255))	('50ug/mL', 'Var', (292, 299))
153404	23237990	For organotypic culture and patient biopsy slides, sections were re-hydrated and boiled in sodium citrate buffer, then incubated with the primary antibodies [chicken anti-human vimentin (Novus Biologicals, Littleton, CO) 1:5000, E-cadherin 1:200, alphaSMA 1:1000] at 4 C, followed by secondary anti-chicken antibody (Jackson Immunolaboratories) (1:600)or anti-mouse Dylight antibody (1:600) for 1 hour at room temperature prior to mounting in DAPI mounting media.	('sodium citrate', 'Chemical', 'MESH:D000077559', (91, 105))	('mouse', 'Species', '10090', (360, 365))	('chicken', 'Species', '9031', (158, 165))	('DAPI', 'Chemical', 'MESH:C007293', (443, 447))	('E-cadherin', 'Gene', (229, 239))	('vimentin', 'Gene', '7431', (177, 185))	('boiled', 'Phenotype', 'HP:0020083', (81, 87))	('E-cadherin', 'Gene', '999', (229, 239))	('patient', 'Species', '9606', (28, 35))	('chicken', 'Species', '9031', (299, 306))	('1:600', 'Var', (384, 389))	('vimentin', 'Gene', (177, 185))	('human', 'Species', '9606', (171, 176))
153426	23237990	Although fibroblast expression and secretion of TGF-beta was not detected in our model system, we hypothesized that exogenous TGF-beta might further enhance the pro-fibrogenic effects of IL-1beta and TNFalpha upon EPC2-hTERT cells.	('TGF-beta', 'Gene', (126, 134))	('pro-fibrogenic effects', 'CPA', (161, 183))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (214, 224))	('enhance', 'PosReg', (149, 156))	('TNFalpha', 'Gene', (200, 208))	('exogenous', 'Var', (116, 125))	('TNFalpha', 'Gene', '7124', (200, 208))
153464	23237990	Unexpectedly, FCM was a more potent inducer of EMT (Figure 3) compared to the combined effect of recombinant cytokines (Figure 2).	('FCM', 'Var', (14, 17))	('EMT', 'CPA', (47, 50))	('FCM', 'Chemical', '-', (14, 17))	('inducer', 'PosReg', (36, 43))
153474	23237990	In addition, variations in fibroblast phenotype and activation state are known to influence the invasive behavior of the adjacent epithelium in cell culture models of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('influence', 'Reg', (82, 91))	('variations', 'Var', (13, 23))	('invasive behavior of the adjacent epithelium', 'CPA', (96, 140))	('esophageal cancer', 'Disease', (167, 184))
153545	22073098	Puncture or dilation tracheostoma may lead to granulation and thus to obstruction of the trachea so that the situation has to change to classic tracheostoma.	('granulation', 'CPA', (46, 57))	('obstruction of the trachea', 'Disease', 'MESH:C557675', (70, 96))	('dilation tracheostoma', 'Disease', (12, 33))	('tracheostoma', 'Disease', (21, 33))	('obstruction of the trachea', 'Disease', (70, 96))	('Puncture', 'Var', (0, 8))	('tracheostoma', 'Disease', (144, 156))	('lead to', 'Reg', (38, 45))	('dilation tracheostoma', 'Disease', 'MESH:D002311', (12, 33))	('tracheostoma', 'Disease', 'None', (21, 33))	('tracheostoma', 'Disease', 'None', (144, 156))
153632	22073098	In particular patients suffering form perceptual disorder, the insertion of the cannula may cause severe reactions and even vomiting because of the vagal irritation.	('cause', 'Reg', (92, 97))	('perceptual disorder', 'Disease', (38, 57))	('severe reactions', 'Disease', (98, 114))	('insertion', 'Var', (63, 72))	('vomiting', 'Phenotype', 'HP:0002013', (124, 132))	('vomiting', 'Disease', (124, 132))	('vagal irritation', 'Phenotype', 'HP:0002886', (148, 164))	('reactions', 'Disease', (105, 114))	('perceptual disorder', 'Disease', 'MESH:D010468', (38, 57))	('patients', 'Species', '9606', (14, 22))	('vagal irritation', 'Disease', (148, 164))	('vomiting', 'Disease', 'MESH:D014839', (124, 132))	('vagal irritation', 'Disease', 'MESH:C536827', (148, 164))
153791	22073098	Filtering or modulation of the noises in the vocal tract leads to an adaptation (formant creation) so that the esophageal voice has a natural sound in comparison to electronic speaking aids.	('esophageal voice', 'MPA', (111, 127))	('aid', 'Gene', (185, 188))	('modulation', 'Var', (13, 23))	('natural sound', 'MPA', (134, 147))	('aid', 'Gene', '57379', (185, 188))	('man', 'Species', '9606', (84, 87))
153852	22073098	The exit of fluids into the trachea during the drinking process, generally associated with coughing, can occur when the closure is defect, for example caused by a defective valve or perifistular leakiness.	('coughing', 'Phenotype', 'HP:0012735', (91, 99))	('cough', 'Phenotype', 'HP:0012735', (91, 96))	('perifistular leakiness', 'Disease', (182, 204))	('coughing', 'Disease', (91, 99))	('defective valve', 'Var', (163, 178))	('perifistular leakiness', 'Disease', 'MESH:C535298', (182, 204))
153859	22073098	Additionally gastro-intestinal reflux or stenoses in the pharyngo-esophageal transition segment may have a negative impact.	('gastro-intestinal reflux', 'Disease', (13, 37))	('-intestinal reflux', 'Phenotype', 'HP:0002020', (19, 37))	('stenoses', 'Var', (41, 49))	('men', 'Species', '9606', (91, 94))
153921	20536417	That is, given that the efficacy of target-specific anti-cancer drugs may decrease or even be lost over time due to the high epigenetic variation within cancer cells, blocking a protein that affects numerous cancer-related pathways, such as Hsp90, can be an effective and efficient means of treating drug-resistant cancers.	('numerous cancer', 'Disease', (199, 214))	('cancer', 'Disease', (208, 214))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('cancer', 'Disease', (57, 63))	('cancers', 'Disease', 'MESH:D009369', (315, 322))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('epigenetic variation', 'Var', (125, 145))	('blocking', 'NegReg', (167, 175))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (315, 322))	('cancer', 'Disease', (315, 321))	('cancers', 'Disease', (315, 322))	('numerous cancer', 'Disease', 'MESH:D009369', (199, 214))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('protein', 'Protein', (178, 185))	('Hsp90', 'Protein', (241, 246))
153933	20536417	3) To assess this natural product's capacity as an anticancer agent, GA was tested against the National Cancer Institute (NCI) 60 tumor cell lines and it demonstrated a mean GI50 of 180nM across the panel; notably, GI50 = 0.1nM for prostate cancer cell lines PC3 and DU-145.	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('prostate cancer', 'Disease', 'MESH:D011471', (232, 247))	('GA', 'Chemical', 'MESH:C001277', (69, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (232, 247))	('tumor', 'Disease', (130, 135))	('C', 'Gene', '67088', (123, 124))	('prostate cancer', 'Disease', (232, 247))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('GI50', 'Var', (215, 219))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (55, 61))	('PC3', 'CellLine', 'CVCL:0035', (259, 262))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('C', 'Gene', '67088', (104, 105))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('C', 'Gene', '67088', (260, 261))	('DU-145', 'CellLine', 'CVCL:0105', (267, 273))
153944	20536417	When bound to Hsp90, the C-7 carbamate of GA is stabilized in the pocket by hydrogen bonding directly to amino acid residue Asp79, and indirectly to Leu 34, Gly83, and Thr171 via water molecules.	('hydrogen bonding', 'MPA', (76, 92))	('Leu', 'Chemical', 'MESH:D007930', (149, 152))	('Gly83', 'Var', (157, 162))	('water', 'Chemical', 'MESH:D014867', (179, 184))	('GA', 'Chemical', 'MESH:C001277', (42, 44))	('C-7', 'Gene', '730', (25, 28))	('Thr171', 'Chemical', '-', (168, 174))	('Leu 34', 'Var', (149, 155))	('C-7', 'Gene', (25, 28))	('bound', 'Interaction', (5, 10))	('Asp79', 'Chemical', '-', (124, 129))	('hydrogen', 'Chemical', 'MESH:D006859', (76, 84))	('carbamate', 'Chemical', 'MESH:D002219', (29, 38))	('Gly83', 'Chemical', '-', (157, 162))
153954	20536417	Equally important is the carbamate moiety at position 7, where alterations at this position resulted in a 1000-fold decrease in the compound's activity and deletion of this group generated a compound that had no activity (IC50 > 3900nM).	('alterations', 'Var', (63, 74))	('C', 'Gene', '67088', (223, 224))	('decrease', 'NegReg', (116, 124))	('carbamate', 'Chemical', 'MESH:D002219', (25, 34))	('activity', 'MPA', (143, 151))	('deletion', 'Var', (156, 164))
153957	20536417	In summary, some of these derivatives showed depletion of p185 to the same level as GA, however, these derivatives were not nearly as active as GA in in vivo studies, which Schnur et al.	('depletion', 'MPA', (45, 54))	('GA', 'Chemical', 'MESH:C001277', (144, 146))	('p185', 'Var', (58, 62))	('GA', 'Chemical', 'MESH:C001277', (84, 86))
153969	20536417	All ether group substitutions at C-11, with the exception of O-methyl, gave compounds that had a 2-3 fold decrease in binding affinity for Hsp90.	('C-11', 'Gene', (33, 37))	('ether', 'Chemical', 'MESH:D004986', (4, 9))	('Hsp90', 'Protein', (139, 144))	('decrease', 'NegReg', (106, 114))	('O-methyl', 'Chemical', '-', (61, 69))	('substitutions', 'Var', (16, 29))	('binding', 'Interaction', (118, 125))	('C-11', 'Gene', '51728', (33, 37))
153975	20536417	It was also anticipated that conversion of the C-17 methoxy group to amino groups, would increase the molecule's solubility in aqueous media, improving pharmacological properties of GA, while not compromising its potency.	('increase', 'PosReg', (89, 97))	('C-17', 'Gene', (47, 51))	('potency', 'MPA', (213, 220))	('GA', 'Chemical', 'MESH:C001277', (182, 184))	('C-17', 'Gene', '54360', (47, 51))	('pharmacological properties', 'MPA', (152, 178))	('conversion', 'Var', (29, 39))	('solubility in aqueous media', 'MPA', (113, 140))	('improving', 'PosReg', (142, 151))
153979	20536417	Within the amide derivatives, aromatic functional groups had better potencies than their aliphatic counterparts (IC50 = 200-1000nM and 1700microM for aromatic versus aliphatic respectively).	('better', 'PosReg', (61, 67))	('C', 'Gene', '67088', (114, 115))	('potencies', 'MPA', (68, 77))	('aromatic', 'Var', (30, 38))	('amide', 'Chemical', 'MESH:D000577', (11, 16))
153980	20536417	Compounds that contained benzylalkylamino groups were three times more active than dialkylamino groups.	('C', 'Gene', '67088', (0, 1))	('benzylalkylamino groups', 'Var', (25, 48))	('active', 'MPA', (71, 77))
153989	20536417	9), and it was hoped that this C-17 modification would show decreased liver toxicity and improved aqueous solubility and metabolic stability over its parent compound, GA. Like GA, 17-AAG binds to the N-terminal domain of Hsp90, blocking the binding of numerous client proteins, which results in the degradation of these proteins, thereby impairing their ability to induce cell growth.	('modification', 'Var', (36, 48))	('C-17', 'Gene', (31, 35))	('improved', 'PosReg', (89, 97))	('degradation', 'MPA', (299, 310))	('binding', 'Interaction', (241, 248))	('GA', 'Chemical', 'MESH:C001277', (176, 178))	('decreased liver toxicity', 'Disease', 'MESH:D056486', (60, 84))	('metabolic stability', 'MPA', (121, 140))	('N', 'Chemical', 'MESH:D009584', (200, 201))	('decreased liver', 'Phenotype', 'HP:0001410', (60, 75))	('cell growth', 'CPA', (372, 383))	('GA', 'Chemical', 'MESH:C001277', (167, 169))	('proteins', 'Protein', (320, 328))	('C-17', 'Gene', '54360', (31, 35))	('decreased liver toxicity', 'Disease', (60, 84))	('17-AAG', 'Chemical', 'MESH:C112765', (180, 186))	('aqueous solubility', 'MPA', (98, 116))	('impairing', 'NegReg', (338, 347))	('client proteins', 'Protein', (261, 276))	('ability', 'MPA', (354, 361))	('blocking', 'NegReg', (228, 236))
153990	20536417	In a binding assay using lysed v-src transformed NIH/3T3 fibroblasts cells and GA-affinity beads, 17-AAG competed effectively with GA for Hsp90, inhibiting src from binding to Hsp90 in this assay.	('17-AAG', 'Chemical', 'MESH:C112765', (98, 104))	('Hsp90', 'Protein', (138, 143))	('Hsp90', 'Protein', (176, 181))	('binding', 'Interaction', (165, 172))	('GA', 'Chemical', 'MESH:C001277', (131, 133))	('17-AAG', 'Var', (98, 104))	('GA', 'Chemical', 'MESH:C001277', (79, 81))	('NIH/3T3', 'CellLine', 'CVCL:0594', (49, 56))	('inhibiting', 'NegReg', (145, 155))	('src', 'MPA', (156, 159))
153994	20536417	Grbovic and coworkers determined that the mutated form of B-Raf, a protein kinase that is a member of the Raf gene family, relies on Hsp90 (Fig.	('mutated', 'Var', (42, 49))	('Raf', 'Gene', '22882', (106, 109))	('Raf', 'Gene', (60, 63))	('Hsp90', 'Protein', (133, 138))	('Raf', 'Gene', (106, 109))	('B-Raf', 'Gene', (58, 63))	('B-Raf', 'Gene', '673', (58, 63))	('Raf', 'Gene', '22882', (60, 63))
153997	20536417	Mutated forms of B-Raf activate the Ras/Raf /MAKT signaling pathways, which are typically activated in most melanomas.	('activate', 'PosReg', (23, 31))	('melanomas', 'Disease', 'MESH:D008545', (108, 117))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('Raf', 'Gene', (40, 43))	('Raf', 'Gene', (19, 22))	('B-Raf', 'Gene', '673', (17, 22))	('B-Raf', 'Gene', (17, 22))	('Raf', 'Gene', '22882', (19, 22))	('melanomas', 'Disease', (108, 117))	('Raf', 'Gene', '22882', (40, 43))	('Mutated', 'Var', (0, 7))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
153998	20536417	The most common mutated form of B-Raf is named V600EBraf for the glutamic acid replacement of valine at amino acid 600.	('B-Raf', 'Gene', '673', (32, 37))	('B-Raf', 'Gene', (32, 37))	('glutamic acid replacement of valine at amino acid 600', 'Mutation', 'rs113488022', (65, 118))	('V600EBraf', 'Var', (47, 56))	('Br', 'Chemical', 'MESH:D001966', (52, 54))
153999	20536417	Over 90% of all B-Raf mutants found in melanoma cancers have this glutamic acid substitution.	('glutamic acid', 'Chemical', 'MESH:D018698', (66, 79))	('glutamic acid substitution', 'Var', (66, 92))	('B-Raf', 'Gene', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('B-Raf', 'Gene', '673', (16, 21))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma cancers', 'Disease', (39, 55))	('melanoma cancers', 'Disease', 'MESH:C563985', (39, 55))	('mutants', 'Var', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
154000	20536417	In nearly 70% of melanomas, V600EBraf is up-regulated.	('up-regulated', 'PosReg', (41, 53))	('V600EBraf', 'Var', (28, 37))	('Br', 'Chemical', 'MESH:D001966', (33, 35))	('melanomas', 'Disease', (17, 26))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('melanomas', 'Disease', 'MESH:D008545', (17, 26))
154002	20536417	However, in the V600EBraf mutated cell line SK-Mel-28, treatment of 17-AAG caused depletion of V600EBraf in as little as 12 hours.	('Br', 'Chemical', 'MESH:D001966', (100, 102))	('17-AAG', 'Chemical', 'MESH:C112765', (68, 74))	('depletion', 'MPA', (82, 91))	('Br', 'Chemical', 'MESH:D001966', (21, 23))	('V600EBraf', 'Var', (95, 104))
154004	20536417	These data establish that B-Raf plays an important role in melanoma, and that once mutated to V600EBraf, it relies heavily on Hsp90 for stabilization.	('B-Raf', 'Gene', (26, 31))	('melanoma', 'Disease', (59, 67))	('B-Raf', 'Gene', '673', (26, 31))	('V600EBraf', 'Var', (94, 103))	('Br', 'Chemical', 'MESH:D001966', (99, 101))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('Hsp90', 'Protein', (126, 131))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
154030	20536417	Studies show that 17-AAG increases apoptosis, down-regulates NPM-ALK, and causes G0/G1 cell cycle arrest in ALCL cells.	('down-regulates', 'NegReg', (46, 60))	('17-AAG', 'Var', (18, 24))	('causes', 'Reg', (74, 80))	('NPM-ALK', 'Gene', (61, 68))	('17-AAG', 'Chemical', 'MESH:C112765', (18, 24))	('increases', 'PosReg', (25, 34))	('G0/G1 cell cycle arrest', 'CPA', (81, 104))	('C', 'Gene', '67088', (110, 111))	('apoptosis', 'CPA', (35, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))
154033	20536417	In SKBr3, Hsp90 client proteins include p185, Raf-1 and mutant p53.	('p53', 'Gene', (63, 66))	('mutant', 'Var', (56, 62))	('p185', 'Var', (40, 44))	('SKBr3', 'CellLine', 'CVCL:0033', (3, 8))	('Raf-1', 'Gene', (46, 51))	('Hsp90', 'Protein', (10, 15))
154034	20536417	It was observed that 17-AAG had lower EC50 values for blocking these three client proteins from binding than GA: the EC50 values for 17-AAG were 45nM, 80nM, and 62nM and for GA were 90nM, 170nM, and 210nM for p185, Raf-1, and mutant p53, respectively.	('17-AAG', 'Chemical', 'MESH:C112765', (21, 27))	('mutant', 'Var', (226, 232))	('GA', 'Chemical', 'MESH:C001277', (109, 111))	('GA', 'Chemical', 'MESH:C001277', (174, 176))	('binding', 'Interaction', (96, 103))	('C', 'Gene', '67088', (118, 119))	('C', 'Gene', '67088', (39, 40))	('p185', 'Var', (209, 213))	('17-AAG', 'Chemical', 'MESH:C112765', (133, 139))	('p53', 'Gene', (233, 236))
154042	20536417	As observed in other cell lines, 17-AAG increased apoptosis in the chronic lymphatic leukemia (CLL) cell line, by inhibiting the Akt pathway.	('chronic lymphatic leukemia', 'Phenotype', 'HP:0005550', (67, 93))	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('17-AAG', 'Var', (33, 39))	('Akt pathway', 'Pathway', (129, 140))	('chronic lymphatic leukemia', 'Disease', 'MESH:D015451', (67, 93))	('17-AAG', 'Chemical', 'MESH:C112765', (33, 39))	('CLL', 'Phenotype', 'HP:0005550', (95, 98))	('inhibiting', 'NegReg', (114, 124))	('chronic lymphatic leukemia', 'Disease', (67, 93))	('C', 'Gene', '67088', (95, 96))	('apoptosis', 'CPA', (50, 59))	('lymphatic leukemia', 'Phenotype', 'HP:0005526', (75, 93))
154045	20536417	As is observed in most cancer cells, Hsp90 expression is up-regulated in non-small cell lung cancer (NSCLC) cells, specifically: A549, H226B and ChaGo-K1.	('H226B', 'Var', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('H226B', 'SUBSTITUTION', 'None', (135, 140))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (73, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('NSCLC', 'Disease', (101, 106))	('Hsp90', 'Protein', (37, 42))	('C', 'Gene', '67088', (145, 146))	('C', 'Gene', '67088', (105, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('non-small cell lung cancer', 'Disease', (73, 99))	('C', 'Gene', '67088', (103, 104))	('cancer', 'Disease', (23, 29))	('expression', 'MPA', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (77, 99))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (73, 99))	('up-regulated', 'PosReg', (57, 69))	('A549', 'CellLine', 'CVCL:0023', (129, 133))
154047	20536417	These up-regulated and activated client proteins include a mutated EGF receptor, a receptor kinase that activates and promotes cell proliferation and survival, Akt, and a mutated p53, whose normal function is to regulate the cell cycle and suppress tumor growth.	('p53', 'Gene', (179, 182))	('activates', 'PosReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('EGF receptor', 'Protein', (67, 79))	('suppress', 'NegReg', (240, 248))	('cell proliferation', 'CPA', (127, 145))	('regulate', 'Reg', (212, 220))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('promotes', 'PosReg', (118, 126))	('tumor', 'Disease', (249, 254))	('cell cycle', 'CPA', (225, 235))	('mutated', 'Var', (171, 178))	('Akt', 'CPA', (160, 163))	('up-regulated', 'PosReg', (6, 18))	('mutated', 'Var', (59, 66))
154050	20536417	The activation of Akt is seen in 51% of NSCLC cell lines, and p53 is mutated in 50% of NSCLC tissues.	('NSCLC', 'Disease', (87, 92))	('Akt', 'Pathway', (18, 21))	('mutated', 'Var', (69, 76))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('NSCLC', 'Disease', (40, 45))	('activation', 'PosReg', (4, 14))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
154051	20536417	17-AAG inhibited cell growth with IC50 values 124nM, 61nM, and 110nM for A549, H226B, and ChaGo-K1 cell lines, respectively.	('17-AAG', 'Chemical', 'MESH:C112765', (0, 6))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('C', 'Gene', '67088', (90, 91))	('C', 'Gene', '67088', (35, 36))	('H226B', 'SUBSTITUTION', 'None', (79, 84))	('cell growth', 'CPA', (17, 28))	('inhibited', 'NegReg', (7, 16))	('H226B', 'Var', (79, 84))
154084	20536417	Despite these issues, 17-AAG was recommended for clinical trials due to its improved metabolic stability over GA. To date, 17-AAG has passed through Phase I clinical trials and is now in Phase II/III clinical trials and is still being tested against a variety of cancer cell lines including melanoma, breast, prostate and thyroid cancer.	('17-AAG', 'Chemical', 'MESH:C112765', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('thyroid cancer', 'Disease', 'MESH:D013964', (322, 336))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('cancer', 'Disease', (263, 269))	('thyroid cancer', 'Phenotype', 'HP:0002890', (322, 336))	('thyroid cancer', 'Disease', (322, 336))	('17-AAG', 'Chemical', 'MESH:C112765', (22, 28))	('17-AAG', 'Var', (123, 129))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('GA', 'Chemical', 'MESH:C001277', (110, 112))	('melanoma', 'Disease', (291, 299))	('prostate', 'Disease', (309, 317))	('breast', 'Disease', (301, 307))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Disease', (330, 336))
154093	20536417	One trial used fifteen metastatic melanoma patients, the majority of whom had the V600EBraf mutation.	('Br', 'Chemical', 'MESH:D001966', (87, 89))	('patients', 'Species', '9606', (43, 51))	('melanoma', 'Disease', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('V600EBraf', 'Var', (82, 91))
154094	20536417	These patients were monitored for the effects on the Hsp90 client protein Raf-1, however this client protein was not depleted, suggesting that 17-AAG has either a short-lived effect in patients, or its ability to modulate client protein depletion, specifically Raf, in vitro does not translate to in vivo conditions.	('17-AAG', 'Chemical', 'MESH:C112765', (143, 149))	('Raf', 'Gene', (74, 77))	('Raf', 'Gene', '22882', (261, 264))	('client protein depletion', 'MPA', (222, 246))	('patients', 'Species', '9606', (6, 14))	('Raf', 'Gene', (261, 264))	('patients', 'Species', '9606', (185, 193))	('modulate', 'Reg', (213, 221))	('Raf', 'Gene', '22882', (74, 77))	('17-AAG', 'Var', (143, 149))
154099	20536417	Thus, unlike the clinical trials where 17-AAG is used alone and the client proteins appear to recover function after a short period of time, using 17-AAG in conjunction with drugs that inhibit the same pathways may prevent client protein recovery, leading to an effect that would be similar to that observed in vitro.	('client protein recovery', 'MPA', (223, 246))	('function', 'MPA', (102, 110))	('17-AAG', 'Chemical', 'MESH:C112765', (147, 153))	('prevent', 'NegReg', (215, 222))	('17-AAG', 'Chemical', 'MESH:C112765', (39, 45))	('17-AAG', 'Var', (147, 153))
154111	20536417	A siRNA knockdown of the expression of cdc37 in cells leads to a decrease in client proteins ERK, Akt, and mTOR.	('ERK', 'Gene', '5594', (93, 96))	('client proteins', 'MPA', (77, 92))	('ERK', 'Gene', (93, 96))	('cdc37', 'Gene', '11140', (39, 44))	('N', 'Chemical', 'MESH:D009584', (5, 6))	('mTOR', 'Gene', (107, 111))	('cdc37', 'Gene', (39, 44))	('knockdown', 'Var', (8, 17))	('mTOR', 'Gene', '2475', (107, 111))	('decrease', 'NegReg', (65, 73))	('Akt', 'Pathway', (98, 101))
154112	20536417	Gray and coworkers determined that cdc37 is up-regulated in pancreatic cancer cell lines and they showed that using a knockdown, followed by 17-AAG treatment, resulted in greater tumor growth inhibition than cells that were treated with 17-AAG alone.	('cdc37', 'Gene', (35, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('knockdown', 'Var', (118, 127))	('17-AAG', 'Chemical', 'MESH:C112765', (237, 243))	('17-AAG', 'Chemical', 'MESH:C112765', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('up-regulated', 'PosReg', (44, 56))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('cdc37', 'Gene', '11140', (35, 40))	('tumor', 'Disease', (179, 184))
154120	20536417	Further, this hydrophilic analog also showed an increased bioavailability over that of 17-AAG, where in pancreatic carcinoma mouse xenographs, 17-DMAG decreased metastases at doses of 6.7-10mg/kg twice daily for 5 days when administered orally, while 17-AAG had no effect.	('17-DMAG', 'Var', (143, 150))	('17-AAG', 'Chemical', 'MESH:C112765', (251, 257))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (104, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('mouse', 'Species', '10090', (125, 130))	('17-AAG', 'Chemical', 'MESH:C112765', (87, 93))	('decreased', 'NegReg', (151, 160))	('17-DMAG', 'Chemical', 'MESH:C448659', (143, 150))	('bioavailability', 'MPA', (58, 73))	('metastases', 'Disease', (161, 171))	('pancreatic carcinoma', 'Disease', (104, 124))	('metastases', 'Disease', 'MESH:D009362', (161, 171))
154122	20536417	It was observed in mechanistic assays that treatment of several melanoma cell lines with 17-DMAG led to the depletion of Akt, cdk4, and Raf-1 client proteins.	('depletion of', 'MPA', (108, 120))	('17-DMAG', 'Var', (89, 96))	('cdk4', 'Gene', (126, 130))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('Raf-1', 'Gene', (136, 141))	('melanoma', 'Disease', (64, 72))	('17-DMAG', 'Chemical', 'MESH:C448659', (89, 96))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('cdk4', 'Gene', '1019', (126, 130))	('Akt', 'Protein', (121, 124))
154123	20536417	However, 17-DMAG has a dose limiting toxicity problem, with high liver and cardiac toxicity.	('toxicity', 'Disease', (37, 45))	('17-DMAG', 'Chemical', 'MESH:C448659', (9, 16))	('cardiac toxicity', 'Disease', (75, 91))	('cardiac toxicity', 'Disease', 'MESH:D066126', (75, 91))	('toxicity', 'Disease', 'MESH:D064420', (83, 91))	('toxicity', 'Disease', (83, 91))	('17-DMAG', 'Var', (9, 16))	('high liver', 'Phenotype', 'HP:0002240', (60, 70))	('liver and', 'MPA', (65, 74))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))
154133	20536417	It was shown in competitive binding assays that IPI-504 had a nearly 2-fold higher binding affinity for Hsp90 than 17-AAG.	('Hsp90', 'Protein', (104, 109))	('IPI-504', 'Chemical', 'MESH:C112765', (48, 55))	('binding', 'Interaction', (28, 35))	('17-AAG', 'Chemical', 'MESH:C112765', (115, 121))	('higher', 'PosReg', (76, 82))	('binding affinity', 'Interaction', (83, 99))	('IPI-504', 'Var', (48, 55))
154135	20536417	IPI-504 also demonstrated comparable IC50 values in cell lines to 17-AAG, and had similar effects on Hsp90 client proteins to those shown by 17-AAG.	('IPI-504', 'Chemical', 'MESH:C112765', (0, 7))	('C', 'Gene', '67088', (38, 39))	('Hsp90', 'Protein', (101, 106))	('17-AAG', 'Chemical', 'MESH:C112765', (141, 147))	('17-AAG', 'Chemical', 'MESH:C112765', (66, 72))	('IPI-504', 'Var', (0, 7))
154138	20536417	EGFR is a tyrosine kinase receptor, it is also an Hsp90 client protein, and is frequently mutated in non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (101, 127))	('non-small cell lung cancer', 'Disease', (101, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('EGFR', 'Gene', (0, 4))	('mutated', 'Var', (90, 97))	('tyrosine', 'Chemical', 'MESH:D014443', (10, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (105, 127))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (101, 127))	('NSCLC', 'Disease', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('EGFR', 'Gene', '1956', (0, 4))
154139	20536417	Phase I clinical trials of IPI-504 treatment of NSCLC involved 9 patients with known EGFR mutations.	('EGFR', 'Gene', (85, 89))	('IPI-504', 'Chemical', 'MESH:C112765', (27, 34))	('mutations', 'Var', (90, 99))	('NSCLC', 'Disease', (48, 53))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('patients', 'Species', '9606', (65, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('EGFR', 'Gene', '1956', (85, 89))
154141	20536417	IPI-504 was then advanced to Phase II clinical trials for 10 patients with stage IIIB or IV NSCLC and known EGFR mutations.	('IPI-504', 'Chemical', 'MESH:C112765', (0, 7))	('EGFR', 'Gene', '1956', (108, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('EGFR', 'Gene', (108, 112))	('patients', 'Species', '9606', (61, 69))	('mutations', 'Var', (113, 122))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('stage IIIB', 'Disease', (75, 85))
154143	20536417	This positive result led to an expansion of the clinical trials with a patient population of 57 patients with either EGFR mutant, wild-type, or unknown expression.	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('patient', 'Species', '9606', (96, 103))	('patients', 'Species', '9606', (96, 104))	('patient', 'Species', '9606', (71, 78))	('mutant', 'Var', (122, 128))
154148	20536417	Against multiple myeloma (MM) cells, IPI-504 proved to be an effective Hsp90 inhibitor, disrupting many of the chaperone's functions.	('functions', 'MPA', (123, 132))	('chaperone', 'MPA', (111, 120))	('multiple myeloma', 'Disease', 'MESH:D009101', (8, 24))	('IPI-504', 'Var', (37, 44))	('multiple myeloma', 'Phenotype', 'HP:0006775', (8, 24))	('multiple myeloma', 'Disease', (8, 24))	('Hsp90', 'Protein', (71, 76))	('IPI-504', 'Chemical', 'MESH:C112765', (37, 44))	('disrupting', 'NegReg', (88, 98))
154153	20536417	Thus, it appears that IPI-504 is a promising treatment for myeloma, where the UPR pathway is active.	('IPI-504', 'Var', (22, 29))	('myeloma', 'Disease', (59, 66))	('myeloma', 'Disease', 'MESH:D009101', (59, 66))	('IPI-504', 'Chemical', 'MESH:C112765', (22, 29))
154160	20536417	Preclinical data shows that IPI-504 degrades Her2 both in vitro and in vivo.	('degrades', 'NegReg', (36, 44))	('IPI-504', 'Chemical', 'MESH:C112765', (28, 35))	('Her2', 'Gene', (45, 49))	('IPI-504', 'Var', (28, 35))	('Her2', 'Gene', '2064', (45, 49))
154169	20536417	It was noted earlier that modifications to GA at the C-17 position generated potent compounds 17-AAG and 17-DMAG.	('GA', 'Chemical', 'MESH:C001277', (43, 45))	('C-17', 'Gene', '54360', (53, 57))	('17-AAG', 'Chemical', 'MESH:C112765', (94, 100))	('17-DMAG', 'Chemical', 'MESH:C448659', (105, 112))	('modifications', 'Var', (26, 39))	('C-17', 'Gene', (53, 57))
154170	20536417	synthesized HA derivatives with modifications at the 17 and/or 19-amino position incorporating dimethylamines, allylamines, cyclopropylamines, or methylpiperazines.	('cyclopropylamines', 'Chemical', 'MESH:C067351', (124, 141))	('methylpiperazines', 'Chemical', '-', (146, 163))	('dimethylamines', 'Chemical', 'MESH:D004123', (95, 109))	('cyclopropylamines', 'MPA', (124, 141))	('modifications', 'Var', (32, 45))	('dimethylamines', 'MPA', (95, 109))	('allylamines', 'Chemical', 'MESH:D000499', (111, 122))	('allylamines', 'MPA', (111, 122))
154174	20536417	This derivative showed significant antitumor activity with 141 T/C and 2/3 mice surviving treatment, compared to HA with 109 T/C and 0/4 mice surviving treatment.	('mice', 'Species', '10090', (75, 79))	('141 T/C', 'SUBSTITUTION', 'None', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('109 T/C', 'Var', (121, 128))	('109 T/C', 'SUBSTITUTION', 'None', (121, 128))	('141 T/C', 'Var', (59, 66))	('tumor', 'Disease', (39, 44))	('mice', 'Species', '10090', (137, 141))
154187	20536417	Specifically, binding of RD to the N-terminal binding site of Hsp90 has led to the decrease of these client proteins: v-src, Raf-1, EGFR, p185, Cdk4, and mutated p53 (Table 1).	('Hsp90', 'Protein', (62, 67))	('p185', 'Var', (138, 142))	('EGFR', 'Gene', '1956', (132, 136))	('p53', 'Gene', (162, 165))	('v-src', 'Protein', (118, 123))	('binding', 'Interaction', (14, 21))	('Cdk4', 'Gene', (144, 148))	('EGFR', 'Gene', (132, 136))	('decrease', 'NegReg', (83, 91))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('mutated', 'Var', (154, 161))	('Cdk4', 'Gene', '1019', (144, 148))	('Raf-1', 'Gene', (125, 130))
154200	20536417	The cytotoxicity values of KF25706 in K-ras transformed cell line KNRK and v-src-transformed cell line SR-3Y1 were 39 nM and 26 nM, respectively, which is comparable to the activity of RD.	('KNRK', 'CellLine', 'CVCL:3731', (66, 70))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))	('KF25706', 'Var', (27, 34))	('cytotoxicity', 'Disease', (4, 16))
154201	20536417	Further, KF25706 competes with GA for binding to Hsp90 in vitro, suggesting that it has a similar mode of action to that of GA. For in vivo studies, an effective dose of KF2706 (100mg/kg twice daily for 5 days), has led to decreased levels of Raf-1 and Cdk4 oncogenic client proteins in MX1 human breast cancer cell xenographs in mice.	('KF2706', 'Var', (170, 176))	('Cdk4', 'Gene', (253, 257))	('breast cancer', 'Disease', (297, 310))	('breast cancer', 'Phenotype', 'HP:0003002', (297, 310))	('decreased', 'NegReg', (223, 232))	('MX1', 'Gene', (287, 290))	('mice', 'Species', '10090', (330, 334))	('MX1', 'Gene', '4599', (287, 290))	('GA', 'Chemical', 'MESH:C001277', (31, 33))	('GA', 'Chemical', 'MESH:C001277', (124, 126))	('Raf-1', 'Protein', (243, 248))	('Cdk4', 'Gene', '1019', (253, 257))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('breast cancer', 'Disease', 'MESH:D001943', (297, 310))	('levels', 'MPA', (233, 239))	('human', 'Species', '9606', (291, 296))
154217	20536417	Inversion of the stereocenter at C10 gave a compound that also had poor activity, with an ED50 = 5 microM against Hsp90 and IC50 = 2 microM in MCF-7 cells.	('Inversion', 'Var', (0, 9))	('MCF-7', 'CellLine', 'CVCL:0031', (143, 148))	('Hsp90', 'Protein', (114, 119))	('C', 'Gene', '67088', (125, 126))	('C', 'Gene', '67088', (33, 34))	('C', 'Gene', '67088', (144, 145))
154219	20536417	Despite these results, the fact that the cyclopropyl analogue 12 still binds in the namomolar range suggests that the interaction between the Lys44 (Fig.	('interaction', 'Interaction', (118, 129))	('cyclopropyl analogue 12', 'Chemical', '-', (41, 64))	('Lys44', 'Var', (142, 147))	('Lys44', 'Chemical', '-', (142, 147))
154226	20536417	When evaluated for Hsp90 affinity in a binding assay, Pochonin D had an IC50 = 80 nM, suggesting that both the epoxide and the conjugated diene moieties are unimportant for binding to Hsp90.	('epoxide', 'Chemical', 'MESH:D004852', (111, 118))	('Pochonin', 'Var', (54, 62))	('Pochonin D', 'Chemical', 'MESH:C502130', (54, 64))	('C', 'Gene', '67088', (73, 74))	('binding', 'Interaction', (173, 180))	('diene', 'Chemical', '-', (138, 143))
154238	20536417	Biological activity studies have revealed that RDM has a significant effect on Hsp90 client protein Her-2, where the addition of RDM to cytosol led to the degradation of Her2.	('Her-2', 'Gene', '2064', (100, 105))	('RDM', 'Var', (129, 132))	('Her2', 'Gene', (170, 174))	('Her2', 'Gene', '2064', (170, 174))	('Her-2', 'Gene', (100, 105))	('degradation', 'MPA', (155, 166))
154266	33725708	Further analysis revealed genetic variants associated with cell cycle, chromatin modification, Notch, and Janus kinase-signal transducer and activator of transcription signaling pathways, which may be key pathways in the development and progression of ESCC.	('variants', 'Var', (34, 42))	('Janus kinase-signal transducer and', 'Pathway', (106, 140))	('Notch', 'Gene', (95, 100))	('ESCC', 'Disease', (252, 256))	('cell cycle', 'CPA', (59, 69))	('associated', 'Reg', (43, 53))	('Notch', 'Gene', '4851;4854', (95, 100))
154278	33725708	Patients without CCND1/FGF3/FGF4/FGF19 amplification had significantly better objective response rates and progression-free survival than individuals with CCND1/FGF3/FGF4/FGF19 amplification.	('objective response rates', 'CPA', (78, 102))	('FGF3', 'Gene', (161, 165))	('FGF19', 'Gene', '9965', (171, 176))	('FGF3', 'Gene', '2248', (161, 165))	('FGF19', 'Gene', (171, 176))	('CCND1', 'Gene', '595', (17, 22))	('FGF4', 'Gene', '2249', (166, 170))	('progression-free survival', 'CPA', (107, 132))	('Patients', 'Species', '9606', (0, 8))	('FGF4', 'Gene', (28, 32))	('CCND1', 'Gene', (17, 22))	('FGF3', 'Gene', (23, 27))	('FGF19', 'Gene', '9965', (33, 38))	('FGF3', 'Gene', '2248', (23, 27))	('better', 'PosReg', (71, 77))	('FGF19', 'Gene', (33, 38))	('FGF4', 'Gene', '2249', (28, 32))	('amplification', 'Var', (39, 52))	('CCND1', 'Gene', '595', (155, 160))	('FGF4', 'Gene', (166, 170))	('CCND1', 'Gene', (155, 160))
154279	33725708	The genomic amplification of CCND1/FGF3/FGF4/FGF19 may be related to the poor prognosis of immunotherapy.	('FGF3', 'Gene', (35, 39))	('genomic amplification', 'Var', (4, 25))	('FGF4', 'Gene', '2249', (40, 44))	('CCND1', 'Gene', (29, 34))	('FGF3', 'Gene', '2248', (35, 39))	('related', 'Reg', (58, 65))	('FGF19', 'Gene', (45, 50))	('FGF19', 'Gene', '9965', (45, 50))	('CCND1', 'Gene', '595', (29, 34))	('FGF4', 'Gene', (40, 44))
154289	33725708	A panel of 520 genes which are closely related to cancer mechanisms and targeted therapies were analyzed using probe hybridization to detect the entire exon region of 312 genes and hot spot mutations (exons, introns, and promoter regions) of 208 genes.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (190, 199))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))
154290	33725708	Aberrations, such as gene mutations, amplifications, and fusions, which had a clear clinical correlation with cancer, were detected in a comprehensive and accurate manner [Supplementary Table 2].	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('fusions', 'Var', (57, 64))	('gene mutations', 'Var', (21, 35))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('amplifications', 'Var', (37, 51))
154297	33725708	Among 520 genes closely related to cancer mechanism and targeted therapy, 421 genomic alterations were identified, of which there were 230 SNVs, 35 insertions and deletions (INDELs), 147 copy number amplifications, and nine copy number deletions [Figure 1, Supplementary Table 3].	('copy number amplifications', 'Var', (187, 213))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('SNVs', 'Gene', (139, 143))	('copy number deletions', 'Var', (224, 245))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('insertions', 'Var', (148, 158))	('deletions', 'Var', (163, 172))	('cancer', 'Disease', (35, 41))
154298	33725708	Comparing the detected mutation sites with those in the COSMIC database, 192 novel mutation sites were discovered, with the TP53 hotspot mutations, p.R273H, p.R248Q, and p.R175H, in four samples and the PIK3CA hotspot mutation, p.H1047L, in one sample.	('p.R248Q', 'Mutation', 'rs11540652', (157, 164))	('TP53', 'Gene', '7157', (124, 128))	('p.R175H', 'Var', (170, 177))	('p.R273H', 'Mutation', 'rs28934576', (148, 155))	('PIK3CA', 'Gene', (203, 209))	('p.R273H', 'Var', (148, 155))	('p.H1047L', 'Var', (228, 236))	('TP53', 'Gene', (124, 128))	('p.R248Q', 'Var', (157, 164))	('PIK3CA', 'Gene', '5290', (203, 209))	('p.R175H', 'Mutation', 'rs28934578', (170, 177))	('p.H1047L', 'Mutation', 'rs121913279', (228, 236))
154299	33725708	Copy number variation occurred in 69.0% (20/29) of patients with ESCC.	('Copy number variation', 'Var', (0, 21))	('occurred', 'Reg', (22, 30))	('ESCC', 'Disease', (65, 69))	('patients', 'Species', '9606', (51, 59))
154302	33725708	The copy number deleted genes were CDKN2A/2B (10.3%, 3/29) and MET (6.9%, 2/29).	('copy number deleted', 'Var', (4, 23))	('MET', 'Gene', '79811', (63, 66))	('MET', 'Gene', (63, 66))	('CDKN2A/2B', 'Gene', '1029', (35, 44))	('CDKN2A/2B', 'Gene', (35, 44))
154306	33725708	Cell cycle regulators constituted the most frequently disrupted category, including mutations in TP53 (96.6%, 28/29), EP300 (17.2%, 5/29), CREBBP (10.3%, 3/29), STAG2 (10.3%, 3/29), RB1 (6.9%, 2/29), PRKDC (6.9%, 2/29), ATM (6.9%, 2/29), ATR (6.9%, 2/29), MYC (3.4%, 1/29) and amplifications or deletions of CCND1 (41.4%, 12/29), CDKN2A/B (10.3%, 3/29), CDK6 (6.9%, 2/29), and CCNE1 (6.9%, 2/29).	('PRKDC', 'Gene', '5591', (200, 205))	('TP53', 'Gene', '7157', (97, 101))	('PRKDC', 'Gene', (200, 205))	('MYC', 'Gene', (256, 259))	('EP300', 'Gene', (118, 123))	('ATM', 'Gene', '472', (220, 223))	('amplifications', 'Var', (277, 291))	('RB1', 'Gene', '5925', (182, 185))	('CREBBP', 'Gene', '1387', (139, 145))	('CCND1', 'Gene', '595', (308, 313))	('CDK6', 'Gene', '1021', (354, 358))	('ATR', 'Gene', '545', (238, 241))	('deletions', 'Var', (295, 304))	('CDKN2A/B', 'Gene', (330, 338))	('MYC', 'Gene', '4609', (256, 259))	('CCND1', 'Gene', (308, 313))	('CCNE1', 'Gene', (377, 382))	('mutations', 'Var', (84, 93))	('ATM', 'Gene', (220, 223))	('TP53', 'Gene', (97, 101))	('CDK6', 'Gene', (354, 358))	('STAG2', 'Gene', '10735', (161, 166))	('CCNE1', 'Gene', '898', (377, 382))	('STAG2', 'Gene', (161, 166))	('EP300', 'Gene', '2033', (118, 123))	('CDKN2A/B', 'Gene', '1029;1030', (330, 338))	('RB1', 'Gene', (182, 185))	('CREBBP', 'Gene', (139, 145))	('ATR', 'Gene', (238, 241))
154307	33725708	Components of the SWI/SNF (SWItch/Sucrose Non-Fermentable) complex, including AT-rich interaction domain 1A (ARID1A) (4/29, 13.8%), ATRX (3/29, 10.3%), ARID2 (1/29, 3.4%), and SMARCA4 (1/29, 3.4%), were mutated in ESCC.	('ARID2', 'Gene', '196528', (152, 157))	('mutated', 'Var', (203, 210))	('ESCC', 'Disease', (214, 218))	('AT-rich interaction domain 1A', 'Gene', '8289', (78, 107))	('AT-rich interaction domain 1A', 'Gene', (78, 107))	('ARID2', 'Gene', (152, 157))	('ATRX', 'Gene', (132, 136))	('SMARCA4', 'Gene', (176, 183))	('Sucrose', 'Chemical', 'MESH:D013395', (34, 41))	('SMARCA4', 'Gene', '6597', (176, 183))	('ARID1A', 'Gene', '8289', (109, 115))	('ATRX', 'Gene', '546', (132, 136))	('ARID1A', 'Gene', (109, 115))
154309	33725708	TP63 was amplified in 10.3% (3/29) of ESCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('amplified', 'Var', (9, 18))	('ESCC', 'Disease', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('TP63', 'Gene', '8626', (0, 4))	('tumors', 'Disease', (43, 49))	('TP63', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
154310	33725708	Genes involved in the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway were altered in 75.9% (22/29) of tumors, and included mutations in JAK1, JAK2, JAK3, STAT3, and PIK3CA.	('JAK1', 'Gene', '3716', (180, 184))	('JAK2', 'Gene', (186, 190))	('mutations', 'Var', (167, 176))	('STAT3', 'Gene', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('JAK3', 'Gene', '3718', (192, 196))	('STAT3', 'Gene', '6774', (198, 203))	('PIK3CA', 'Gene', (209, 215))	('altered', 'Reg', (118, 125))	('STAT', 'Gene', '6774', (89, 93))	('STAT', 'Gene', (89, 93))	('JAK1', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('STAT', 'Gene', '6774', (198, 202))	('STAT', 'Gene', (198, 202))	('JAK2', 'Gene', '3717', (186, 190))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('PIK3CA', 'Gene', '5290', (209, 215))	('JAK3', 'Gene', (192, 196))	('tumors', 'Disease', (146, 152))
154311	33725708	The amplification of IL7R was found in 10.3% (3/29) of cases.	('IL7R', 'Gene', (21, 25))	('amplification', 'Var', (4, 17))	('IL7R', 'Gene', '3575', (21, 25))
154312	33725708	Altered genes in the Notch signaling pathway, playing an important role in regulating normal cell differentiation, were mutated in 48.3% (14/29) of cases.	('Notch', 'Gene', '4851;4854', (21, 26))	('mutated', 'Var', (120, 127))	('Notch', 'Gene', (21, 26))
154313	33725708	NOTCH1 showed mutations in eight cases.	('mutations', 'Var', (14, 23))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))
154314	33725708	In addition, the mutations in CREBBP and EP300 were detected in three and five samples, respectively.	('detected', 'Reg', (52, 60))	('CREBBP', 'Gene', (30, 36))	('EP300', 'Gene', (41, 46))	('EP300', 'Gene', '2033', (41, 46))	('CREBBP', 'Gene', '1387', (30, 36))	('mutations', 'Var', (17, 26))
154318	33725708	KMT2D mutations were associated with lymph node metastasis (r = 0.407, P = 0.028).	('associated', 'Reg', (21, 31))	('lymph node metastasis', 'CPA', (37, 58))	('KMT2D', 'Gene', '8085', (0, 5))	('KMT2D', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
154319	33725708	CCND1/FGF3/FGF4/FGF19 amplification (r = -0.473, P = 0.009) and CDKN2A deletion (r = -0.654, P < 0.001) were associated with the depth of infiltration.	('amplification', 'MPA', (22, 35))	('associated', 'Reg', (109, 119))	('FGF3', 'Gene', '2248', (6, 10))	('CDKN2A', 'Gene', (64, 70))	('deletion', 'Var', (71, 79))	('FGF4', 'Gene', (11, 15))	('CCND1', 'Gene', (0, 5))	('FGF3', 'Gene', (6, 10))	('FGF19', 'Gene', (16, 21))	('FGF19', 'Gene', '9965', (16, 21))	('CCND1', 'Gene', '595', (0, 5))	('FGF4', 'Gene', '2249', (11, 15))
154326	33725708	Lin et al found that patients with APOBEC-mediated mutational signature had more targeted driver genes including ZNF750, PIK3CA, MLL2, MLL3, and RB1.	('RB1', 'Gene', (145, 148))	('mutational', 'Var', (51, 61))	('ZNF750', 'Gene', (113, 119))	('RB1', 'Gene', '5925', (145, 148))	('MLL2', 'Gene', (129, 133))	('MLL3', 'Gene', '58508', (135, 139))	('patients', 'Species', '9606', (21, 29))	('PIK3CA', 'Gene', (121, 127))	('MLL2', 'Gene', '8085', (129, 133))	('ZNF750', 'Gene', '79755', (113, 119))	('PIK3CA', 'Gene', '5290', (121, 127))	('APOBEC-mediated', 'Gene', (35, 50))	('MLL3', 'Gene', (135, 139))
154327	33725708	Signature 10, which was previously associated with altered activity of the error-prone POLE, generates a massive number of mutations in uterine cancer and colorectal subsets.	('colorectal subsets', 'Disease', (155, 173))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('uterine cancer', 'Phenotype', 'HP:0010784', (136, 150))	('mutations', 'Var', (123, 132))
154330	33725708	The signature 6, present in microsatellite unstable tumors, is closely related to the inactivation of the DNA MMR gene.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('microsatellite unstable tumors', 'Disease', 'MESH:D053842', (28, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('related', 'Reg', (71, 78))	('inactivation', 'Var', (86, 98))	('DNA MMR gene', 'Gene', (106, 118))	('microsatellite unstable tumors', 'Disease', (28, 58))
154331	33725708	Li et al found that signature 16 was significantly associated with alcohol consumption.	('associated', 'Reg', (51, 61))	('signature 16', 'Var', (20, 32))	('alcohol', 'Chemical', 'MESH:D000438', (67, 74))	('alcohol consumption', 'Disease', (67, 86))
154333	33725708	Further analysis revealed genetic variants were associated with cell cycle, chromatin modification, Notch and JAK-STAT signaling pathways, which may be key pathways in the development and progression of ESCC.	('variants', 'Var', (34, 42))	('Notch', 'Gene', '4851;4854', (100, 105))	('STAT', 'Gene', '6774', (114, 118))	('associated', 'Reg', (48, 58))	('STAT', 'Gene', (114, 118))	('Notch', 'Gene', (100, 105))	('ESCC', 'Disease', (203, 207))	('chromatin modification', 'MPA', (76, 98))	('cell cycle', 'CPA', (64, 74))
154335	33725708	EP300 encoding the E1A-binding protein p300 was mutated in 5 samples (5/29, 17.2%), and the incidence was higher than a Japanese study (8.3%).	('mutated', 'Var', (48, 55))	('EP300', 'Gene', (0, 5))	('EP300', 'Gene', '2033', (0, 5))	('p300', 'Gene', '2033', (39, 43))	('p300', 'Gene', (39, 43))
154336	33725708	Cancer-associated histone acetyl transferases (HAT) domain-altering mutations and deletions impair the HAT activity of p300, leading to the hypothesis that p300 and CREBBP acetyltransferase activities might be tumor-suppressive.	('p300', 'Gene', (119, 123))	('deletions', 'Var', (82, 91))	('CREBBP', 'Gene', '1387', (165, 171))	('p300', 'Gene', '2033', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('p300', 'Gene', '2033', (119, 123))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('CREBBP', 'Gene', (165, 171))	('p300', 'Gene', (156, 160))	('HAT activity', 'MPA', (103, 115))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (68, 77))	('HAT', 'Gene', (47, 50))	('domain-altering', 'Reg', (52, 67))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('impair', 'NegReg', (92, 98))
154351	33725708	In this study, the clinical significance of KMT2D mutation, CCND1/FGF3/FGF4/FGF19 amplification, and CDKN2A deletion in ESCC progression and metastasis was identified by analyzing the relationship between gene mutation and clinicopathological characteristics.	('FGF4', 'Gene', (71, 75))	('FGF3', 'Gene', '2248', (66, 70))	('CDKN2A', 'Gene', (101, 107))	('deletion', 'Var', (108, 116))	('KMT2D', 'Gene', (44, 49))	('ESCC', 'Disease', (120, 124))	('KMT2D', 'Gene', '8085', (44, 49))	('FGF4', 'Gene', '2249', (71, 75))	('CCND1', 'Gene', (60, 65))	('FGF19', 'Gene', '9965', (76, 81))	('FGF19', 'Gene', (76, 81))	('FGF3', 'Gene', (66, 70))	('CCND1', 'Gene', '595', (60, 65))	('mutation', 'Var', (50, 58))
154352	33725708	KMT2D mutation, CCND1/FGF3/FGF4/FGF19 amplification, and CDKN2A deletion may be new prognostic factors and therapeutic targets for ESCC.	('CDKN2A', 'Gene', (57, 63))	('FGF4', 'Gene', (27, 31))	('mutation', 'Var', (6, 14))	('deletion', 'Var', (64, 72))	('CCND1', 'Gene', (16, 21))	('FGF3', 'Gene', (22, 26))	('ESCC', 'Disease', (131, 135))	('KMT2D', 'Gene', (0, 5))	('KMT2D', 'Gene', '8085', (0, 5))	('CCND1', 'Gene', '595', (16, 21))	('FGF19', 'Gene', '9965', (32, 37))	('FGF3', 'Gene', '2248', (22, 26))	('FGF4', 'Gene', '2249', (27, 31))	('FGF19', 'Gene', (32, 37))
154395	30555700	OPCML is hypermethylated in a subset of patients with metaplastic changes in their esophagus OPCML hypermethylation is considered a promising cancer biomarker.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('OPCML', 'Gene', '4978', (93, 98))	('patients', 'Species', '9606', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('OPCML', 'Gene', (0, 5))	('hypermethylation', 'Var', (99, 115))	('OPCML', 'Gene', '4978', (0, 5))	('OPCML', 'Gene', (93, 98))	('cancer', 'Disease', (142, 148))
154407	30555700	This inactivation was later associated with hepatocellular carcinoma, lung adenocarcinoma and gastric and brain cancers, followed by a variety of other cancers from both primary and metastatic tumors as well as tumor cell lines, including those derived from esophageal adenocarcinoma (EAC).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (44, 68))	('tumor', 'Disease', (211, 216))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('inactivation', 'Var', (5, 17))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('cancers', 'Disease', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', (112, 119))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (44, 68))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', (193, 198))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (258, 283))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (258, 283))	('lung adenocarcinoma and gastric and brain cancers', 'Disease', 'MESH:D013274', (70, 119))	('associated', 'Reg', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('hepatocellular carcinoma', 'Disease', (44, 68))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('esophageal adenocarcinoma', 'Disease', (258, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('tumors', 'Disease', (193, 199))
154408	30555700	The hypermethylation of OPCML and its consequential transcriptional silencing in a wide variety of cancers is indicative of its role as a tumor suppressor gene (TSG) as well as its role as a potential biomarker for cancer.	('tumor suppressor', 'Gene', '7248', (138, 154))	('OPCML', 'Gene', (24, 29))	('TSG', 'Gene', '57045', (161, 164))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('silencing', 'NegReg', (68, 77))	('TSG', 'Gene', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('OPCML', 'Gene', '4978', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('hypermethylation', 'Var', (4, 20))	('tumor suppressor', 'Gene', (138, 154))	('transcriptional', 'MPA', (52, 67))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
154409	30555700	Further, induced expression in vitro has been found to inhibit the growth of cancer cell lines.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('expression', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('inhibit', 'NegReg', (55, 62))
154438	30555700	Methylation levels of three CpG sites within exon 1 of OPCML (position 1: hg19_chr11:133402185; CpG site: cg19151121) were measured in esophageal samples from patients within the EAC cascade.	('cg19151121', 'Var', (106, 116))	('Methylation levels', 'MPA', (0, 18))	('OPCML', 'Gene', '4978', (55, 60))	('patients', 'Species', '9606', (159, 167))	('OPCML', 'Gene', (55, 60))
154458	30555700	OPCML promoter epigenetic silencing in the form of hypermethylation has been proposed as a potential biomarker of a range of cancers.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('OPCML', 'Gene', (0, 5))	('hypermethylation', 'MPA', (51, 67))	('epigenetic silencing', 'Var', (15, 35))	('OPCML', 'Gene', '4978', (0, 5))
154464	30555700	We suggest that OPCML hypermethylation in these patients could suggest early signs of dysplastic events not detected histologically.	('OPCML', 'Gene', (16, 21))	('dysplastic', 'Disease', 'MESH:D004416', (86, 96))	('dysplastic', 'Disease', (86, 96))	('hypermethylation', 'Var', (22, 38))	('OPCML', 'Gene', '4978', (16, 21))	('patients', 'Species', '9606', (48, 56))
154474	30555700	Given that hypermethylation of the OPCML promoter has been linked to downregulation of expression, further validation of the effects of hypermethylation of OPCML exon 1 should come in the form of OPCML expression profiling in local tissues.	('OPCML', 'Gene', '4978', (196, 201))	('hypermethylation', 'Var', (11, 27))	('OPCML', 'Gene', (156, 161))	('OPCML', 'Gene', '4978', (35, 40))	('expression', 'MPA', (87, 97))	('OPCML', 'Gene', '4978', (156, 161))	('OPCML', 'Gene', (196, 201))	('OPCML', 'Gene', (35, 40))	('downregulation', 'NegReg', (69, 83))
154476	30555700	In conclusion, OPCML hypermethylation appears to be a signature that should be investigated further in carcinogenesis.	('hypermethylation', 'Var', (21, 37))	('OPCML', 'Gene', (15, 20))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('OPCML', 'Gene', '4978', (15, 20))	('carcinogenesis', 'Disease', (103, 117))
154534	28723752	The postoperative anastomotic leak is a dreaded complication, with a 3-fold higher mortality rate seen in patients with leaks than in patients without leaks.	('postoperative anastomotic leak', 'Disease', 'MESH:D057868', (4, 34))	('patients', 'Species', '9606', (134, 142))	('leaks', 'Var', (120, 125))	('postoperative anastomotic leak', 'Disease', (4, 34))	('patients', 'Species', '9606', (106, 114))	('rat', 'Species', '10116', (11, 14))	('rat', 'Species', '10116', (93, 96))
154628	24529193	Four human ESCC cell lines, TE-1, Eca109, KYSE150 and KYSE510, are revealed increased levels of Mcl-1 mRNA and protein compare with HaCaT, an immortal non-tumorigenic cell line.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('HaCaT', 'CellLine', 'CVCL:0038', (132, 137))	('Mcl-1', 'Gene', '4170', (96, 101))	('levels', 'MPA', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('increased', 'PosReg', (76, 85))	('KYSE150', 'CellLine', 'CVCL:1348', (42, 49))	('tumor', 'Disease', (155, 160))	('Mcl-1', 'Gene', (96, 101))	('human', 'Species', '9606', (5, 10))	('KYSE510', 'Var', (54, 61))
154629	24529193	Results of reporter gene assays demonstrate that human Mcl-1 promoter activity is decreased by mutation of kappaB binding site, specific NF-kappaB inhibitor Bay11-7082 or dominant inhibitory molecule DNMIkappaBalpha in TE-1 and KYSE150 cell lines.	('NF-kappaB', 'Gene', '4790', (137, 146))	('DNMIkappaBalpha', 'Chemical', '-', (200, 215))	('human', 'Species', '9606', (49, 54))	('Mcl-1', 'Gene', '4170', (55, 60))	('NF-kappaB', 'Gene', (137, 146))	('KYSE150', 'CellLine', 'CVCL:1348', (228, 235))	('Bay11-7082', 'Chemical', 'MESH:C434003', (157, 167))	('Mcl-1', 'Gene', (55, 60))	('decreased', 'NegReg', (82, 91))	('mutation', 'Var', (95, 103))
154630	24529193	Mcl-1 protein level is also attenuated by Bay11-7082 treatment or co-transfection of DNMIkappaBalpha in TE-1 and KYSE150 cells.	('attenuated', 'NegReg', (28, 38))	('Mcl-1', 'Gene', (0, 5))	('co-transfection', 'Var', (66, 81))	('DNMIkappaBalpha', 'Gene', (85, 100))	('KYSE150', 'CellLine', 'CVCL:1348', (113, 120))	('DNMIkappaBalpha', 'Chemical', '-', (85, 100))	('Mcl-1', 'Gene', '4170', (0, 5))	('Bay11-7082', 'Chemical', 'MESH:C434003', (42, 52))	('Bay11-7082', 'Var', (42, 52))
154640	24529193	In addition, frequent Mcl-1 gene amplification was identified in lung, breast, neural and gastrointestinal cancers, through which cancer cells depend on the expression of this gene for survival.	('Mcl-1', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('lung', 'Disease', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('amplification', 'Var', (33, 46))	('cancer', 'Disease', (130, 136))	('breast', 'Disease', (71, 77))	('Mcl-1', 'Gene', '4170', (22, 27))	('neural', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('expression', 'Species', '120121', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastrointestinal cancers', 'Disease', (90, 114))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (90, 114))	('cancer', 'Disease', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
154647	24529193	Previous studies demonstrated that inhibition of NF-kappaB activation by a novel NF-kappaB inhibitor V1810 or Thiocolchicoside accompanied by the downregulation of Mcl-1 expression.	('NF-kappaB', 'Gene', '4790', (81, 90))	('downregulation', 'NegReg', (146, 160))	('Mcl-1', 'Gene', '4170', (164, 169))	('Thiocolchicoside', 'Chemical', 'MESH:C004280', (110, 126))	('NF-kappaB', 'Gene', (81, 90))	('Mcl-1', 'Gene', (164, 169))	('V1810', 'Var', (101, 106))	('expression', 'Species', '120121', (170, 180))	('NF-kappaB', 'Gene', '4790', (49, 58))	('activation', 'PosReg', (59, 69))	('NF-kappaB', 'Gene', (49, 58))	('V1810', 'Chemical', 'MESH:C553325', (101, 106))
154662	24529193	Using human ESCC cell lines as models, reporter gene assays demonstrate that human Mcl-1 promoter activity is decreased by mutation of kappaB site, specific NF-kappaB inhibitor Bay11-7082 or dominant inhibitory molecule DNMIkappaBalpha in TE-1 and KYSE150 cells.	('DNMIkappaBalpha', 'Chemical', '-', (220, 235))	('NF-kappaB', 'Gene', '4790', (157, 166))	('human', 'Species', '9606', (6, 11))	('Mcl-1', 'Gene', '4170', (83, 88))	('mutation', 'Var', (123, 131))	('KYSE150', 'CellLine', 'CVCL:1348', (248, 255))	('Bay11-7082', 'Chemical', 'MESH:C434003', (177, 187))	('NF-kappaB', 'Gene', (157, 166))	('decreased', 'NegReg', (110, 119))	('Mcl-1', 'Gene', (83, 88))	('human', 'Species', '9606', (77, 82))
154663	24529193	Mcl-1 level is attenuated by Bay11-7082 treatment or co-transfection of DNMIkappaBalpha in TE-1 and KYSE150 cells.	('DNMIkappaBalpha', 'Chemical', '-', (72, 87))	('Mcl-1', 'Gene', (0, 5))	('KYSE150', 'CellLine', 'CVCL:1348', (100, 107))	('Bay11-7082', 'Var', (29, 39))	('attenuated', 'NegReg', (15, 25))	('Bay11-7082', 'Chemical', 'MESH:C434003', (29, 39))	('Mcl-1', 'Gene', '4170', (0, 5))	('DNMIkappaBalpha', 'Gene', (72, 87))	('co-transfection', 'Var', (53, 68))
154674	24529193	The specific NF-kappaB inhibitor Bay11-7082 (Calbiochem, Darmstadt, Germany) was prepared as a stock solution of 20 mM in DMSO (Sigma, St. Louis, MO).	('Bay11-7082', 'Chemical', 'MESH:C434003', (33, 43))	('Bay11-7082', 'Var', (33, 43))	('NF-kappaB', 'Gene', '4790', (13, 22))	('DMSO', 'Chemical', 'MESH:D004121', (122, 126))	('NF-kappaB', 'Gene', (13, 22))
154687	24529193	Cells were harvested for protein extraction and immunoblotting to confirm p50 or p65 knockdown.	('p65', 'Gene', (81, 84))	('p50', 'Gene', (74, 77))	('p50', 'Gene', '4790', (74, 77))	('p65', 'Gene', '5970', (81, 84))	('knockdown', 'Var', (85, 94))
154694	24529193	At 24 h post-transfection, cells were trypsinized, an aliquot of cells was maintained in six-well plate, harvested at 120 h after NF-kappaB subunit siRNA transfection and analyzed the Mcl-1 levels by Western blotting.	('NF-kappaB', 'Gene', '4790', (130, 139))	('NF-kappaB', 'Gene', (130, 139))	('transfection', 'Var', (154, 166))	('Mcl-1', 'Gene', '4170', (184, 189))	('Mcl-1', 'Gene', (184, 189))
154705	24529193	For antibody supershift experiments, the reaction mixtures were preincubated with 2 mug of p50 (sc-8414X), p52 (sc-298X), p65 (sc-8008X), c-Rel (sc-272X), RelB (sc-226X) or rabbit IgG (sc-2027) antibody (all from Santa Cruz, CA) for 30 min at room temperature.	('c-Rel', 'Gene', '5966', (138, 143))	('p50', 'Gene', (91, 94))	('rabbit', 'Species', '9986', (173, 179))	('p50', 'Gene', '4790', (91, 94))	('p65', 'Gene', (122, 125))	('RelB', 'Gene', (155, 159))	('sc-226X', 'Var', (161, 168))	('c-Rel', 'Gene', (138, 143))	('p52', 'Gene', (107, 110))	('p52', 'Gene', '4791', (107, 110))	('RelB', 'Gene', '5971', (155, 159))	('p65', 'Gene', '5970', (122, 125))	('sc-272X', 'Var', (145, 152))
154709	24529193	Antibodies used for immunoprecipitation were: p50 (sc-8414X), p52 (sc-298X), p65 (sc-8008X), c-Rel (sc-272X), RelB (sc-226X) and rabbit IgG (sc-2027) (all from Santa Cruz, CA).	('p50', 'Gene', (46, 49))	('p52', 'Gene', (62, 65))	('p65', 'Gene', (77, 80))	('p50', 'Gene', '4790', (46, 49))	('sc-226X', 'Var', (116, 123))	('RelB', 'Gene', (110, 114))	('RelB', 'Gene', '5971', (110, 114))	('p52', 'Gene', '4791', (62, 65))	('c-Rel', 'Gene', (93, 98))	('sc-298X', 'Var', (67, 74))	('p65', 'Gene', '5970', (77, 80))	('rabbit', 'Species', '9986', (129, 135))	('sc-272X', 'Var', (100, 107))	('c-Rel', 'Gene', '5966', (93, 98))
154712	24529193	As shown in Figure 1A, four human esophageal carcinoma cell lines, including TE-1, Eca109, KYSE150 and KYSE510 revealed increased levels of Mcl-1 protein compare with an immortal non-tumorigenic keratinocyte HaCaT cell line, which was used as a normal control for Mcl-1 expression.	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (34, 54))	('KYSE510', 'Var', (103, 110))	('Mcl-1', 'Gene', '4170', (140, 145))	('HaCaT', 'CellLine', 'CVCL:0038', (208, 213))	('KYSE150', 'CellLine', 'CVCL:1348', (91, 98))	('Mcl-1', 'Gene', '4170', (264, 269))	('Mcl-1', 'Gene', (140, 145))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (34, 54))	('levels', 'MPA', (130, 136))	('tumor', 'Disease', (183, 188))	('increased', 'PosReg', (120, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('esophageal carcinoma', 'Disease', (34, 54))	('human', 'Species', '9606', (28, 33))	('KYSE150', 'Var', (91, 98))	('expression', 'Species', '120121', (270, 280))	('Mcl-1', 'Gene', (264, 269))
154717	24529193	As shown in Figure 1C, higher mRNA levels of Mcl-1 in TE-1, Eca109, KYSE150 and KYSE510 cells, about a 5-fold increase of Mcl-1 for each cell line compared with HaCaT cells.	('increase', 'PosReg', (110, 118))	('Mcl-1', 'Gene', (122, 127))	('Mcl-1', 'Gene', '4170', (45, 50))	('HaCaT', 'CellLine', 'CVCL:0038', (161, 166))	('higher', 'PosReg', (23, 29))	('KYSE150', 'Var', (68, 75))	('Mcl-1', 'Gene', (45, 50))	('KYSE510', 'Var', (80, 87))	('Mcl-1', 'Gene', '4170', (122, 127))	('KYSE150', 'CellLine', 'CVCL:1348', (68, 75))
154731	24529193	However, with a promoter construct mutated at the kappaB site, the loss of Mcl-1 promoter activity was observed in TE-1 and KYSE150 cells (Figure 3A).	('mutated', 'Var', (35, 42))	('Mcl-1', 'Gene', (75, 80))	('KYSE150', 'CellLine', 'CVCL:1348', (124, 131))	('loss', 'NegReg', (67, 71))	('Mcl-1', 'Gene', '4170', (75, 80))
154732	24529193	Dominant negative mutants of IkappaBalpha (DNMIkappaBalpha), a truncant mutant with a deletion of 71 amino acids at the N terminus of IkappaBalpha, can competitively inhibit the activation of NF-kappaB was used to block NF-kappaB activation as described previously.	('inhibit', 'NegReg', (166, 173))	('IkappaBalpha', 'Gene', '4792', (46, 58))	('activation', 'MPA', (178, 188))	('NF-kappaB', 'Gene', '4790', (220, 229))	('deletion of', 'Var', (86, 97))	('IkappaBalpha', 'Gene', '4792', (29, 41))	('NF-kappaB', 'Gene', '4790', (192, 201))	('mutants', 'Var', (18, 25))	('IkappaBalpha', 'Gene', (46, 58))	('NF-kappaB', 'Gene', (220, 229))	('IkappaBalpha', 'Gene', '4792', (134, 146))	('IkappaBalpha', 'Gene', (29, 41))	('negative', 'NegReg', (9, 17))	('NF-kappaB', 'Gene', (192, 201))	('DNMIkappaBalpha', 'Chemical', '-', (43, 58))	('IkappaBalpha', 'Gene', (134, 146))
154734	24529193	Furthermore, compared with their respective DMSO control, treatment with 20 muM Bay11-7082, a specific NF-kappaB inhibitor, resulted in the Mcl-1 promoter activity drastically curtailed in both TE-1 and KYSE150 cells.	('curtailed', 'NegReg', (176, 185))	('Bay11-7082', 'Chemical', 'MESH:C434003', (80, 90))	('Bay11-7082', 'Var', (80, 90))	('Mcl-1', 'Gene', (140, 145))	('DMSO', 'Chemical', 'MESH:D004121', (44, 48))	('KYSE150', 'CellLine', 'CVCL:1348', (203, 210))	('NF-kappaB', 'Gene', '4790', (103, 112))	('NF-kappaB', 'Gene', (103, 112))	('Mcl-1', 'Gene', '4170', (140, 145))
154735	24529193	The activity of the Mcl-1 promoter with mutated NF-kappaB site was essentially unaffected by inhibitor treatment (Figure 3A).	('Mcl-1', 'Gene', (20, 25))	('activity', 'MPA', (4, 12))	('NF-kappaB', 'Gene', '4790', (48, 57))	('mutated', 'Var', (40, 47))	('NF-kappaB', 'Gene', (48, 57))	('Mcl-1', 'Gene', '4170', (20, 25))
154738	24529193	Bay11-7082 (20 muM) significantly attenuated the increased transcriptional activity of NF-kappaB-driven luciferase reporter in these two cell lines, thus confirmed the efficiency of Bay11-7082 as an NF-kappaB inhibitor (Figure 3B).	('NF-kappaB', 'Gene', '4790', (199, 208))	('increased', 'PosReg', (49, 58))	('transcriptional activity', 'MPA', (59, 83))	('NF-kappaB', 'Gene', '4790', (87, 96))	('NF-kappaB', 'Gene', (199, 208))	('Bay11-7082', 'Chemical', 'MESH:C434003', (182, 192))	('Bay11-7082', 'Var', (182, 192))	('NF-kappaB', 'Gene', (87, 96))	('Bay11-7082', 'Chemical', 'MESH:C434003', (0, 10))	('Bay11-7082', 'Var', (0, 10))	('attenuated', 'NegReg', (34, 44))
154746	24529193	As verified by Western blotting analysis, expression of DNMIkappaBalpha in TE-1 (Figure 4C) or KYSE150 (Figure 4D) cells led to a significant decrease of Mcl-1 induction compared with the vector control.	('DNMIkappaBalpha', 'Chemical', '-', (56, 71))	('Mcl-1', 'Gene', (154, 159))	('Mcl-1', 'Gene', '4170', (154, 159))	('KYSE150', 'Var', (95, 102))	('DNMIkappaBalpha', 'Protein', (56, 71))	('decrease', 'NegReg', (142, 150))	('KYSE150', 'CellLine', 'CVCL:1348', (95, 102))	('expression', 'Species', '120121', (42, 52))
154769	24529193	Compared with the control siRNA, silencing of p50 or p65 each simultaneously led to a significant decrease of Mcl-1 protein levels (Figure 6C).	('p50', 'Gene', (46, 49))	('decrease', 'NegReg', (98, 106))	('p65', 'Gene', (53, 56))	('p50', 'Gene', '4790', (46, 49))	('Mcl-1', 'Gene', '4170', (110, 115))	('silencing', 'Var', (33, 42))	('p65', 'Gene', '5970', (53, 56))	('Mcl-1', 'Gene', (110, 115))
154770	24529193	With these data confirming the knockdown of NF-kappaB subunits and the downregulation of Mcl-1 expression, we next tested the effect of the NF-kappaB subunit siRNAs on TE-1 cell viability.	('downregulation', 'NegReg', (71, 85))	('NF-kappaB', 'Gene', '4790', (44, 53))	('Mcl-1', 'Gene', (89, 94))	('NF-kappaB', 'Gene', '4790', (140, 149))	('NF-kappaB', 'Gene', (140, 149))	('expression', 'Species', '120121', (95, 105))	('NF-kappaB', 'Gene', (44, 53))	('knockdown', 'Var', (31, 40))	('Mcl-1', 'Gene', '4170', (89, 94))	('tested', 'Reg', (115, 121))	('expression', 'MPA', (95, 105))
154771	24529193	Silencing of p50 or p65 resulted in decrease of Mcl-1 level (Figure 6D), which significantly inhibited the viability of TE-1 cells (Figure 6E).	('Mcl-1', 'Gene', '4170', (48, 53))	('viability of TE-1 cells', 'CPA', (107, 130))	('p50', 'Gene', (13, 16))	('p65', 'Gene', (20, 23))	('Mcl-1', 'Gene', (48, 53))	('p50', 'Gene', '4790', (13, 16))	('p65', 'Gene', '5970', (20, 23))	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (93, 102))	('decrease', 'NegReg', (36, 44))
154780	24529193	Mutational inactivation of E3 ligase FBW7 was found to occur in several neoplastic diseases, which can decrease Mcl-1 degradation, resulting in increased Mcl-1 protein levels and resistance to chemotherapeutic agents.	('Mcl-1', 'Gene', (112, 117))	('FBW7', 'Gene', '55294', (37, 41))	('neoplastic diseases', 'Disease', 'MESH:D009386', (72, 91))	('resistance', 'CPA', (179, 189))	('Mcl-1', 'Gene', (154, 159))	('decrease Mcl', 'Phenotype', 'HP:0025066', (103, 115))	('neoplastic diseases', 'Disease', (72, 91))	('Mutational inactivation', 'Var', (0, 23))	('FBW7', 'Gene', (37, 41))	('increased Mcl', 'Phenotype', 'HP:0005518', (144, 157))	('Mcl-1', 'Gene', '4170', (112, 117))	('decrease', 'NegReg', (103, 111))	('E3 ligase', 'Protein', (27, 36))	('Mcl-1', 'Gene', '4170', (154, 159))	('increased', 'PosReg', (144, 153))
154783	24529193	Moreover, phosphorylation of Mcl-1 at Thr 163 by ERK prolongs the Mcl-1 half-life while phosphorylation at Thr 163 by GSK-3beta or Thr 92 by CDK1 enhances Mcl-1 degradation.	('enhances', 'PosReg', (146, 154))	('phosphorylation', 'MPA', (10, 25))	('GSK-3beta', 'Gene', (118, 127))	('Mcl-1', 'Gene', '4170', (29, 34))	('Thr', 'Chemical', 'MESH:D013912', (38, 41))	('ERK', 'Gene', '5594', (49, 52))	('Mcl-1', 'Gene', '4170', (155, 160))	('Thr', 'Chemical', 'MESH:D013912', (107, 110))	('Mcl-1', 'Gene', (29, 34))	('ERK', 'Gene', (49, 52))	('Thr', 'Chemical', 'MESH:D013912', (131, 134))	('Mcl-1', 'Gene', '4170', (66, 71))	('phosphorylation', 'Var', (88, 103))	('Mcl-1', 'Gene', (155, 160))	('prolongs', 'PosReg', (53, 61))	('GSK-3beta', 'Gene', '2932', (118, 127))	('Mcl-1', 'Gene', (66, 71))	('CDK1', 'Gene', (141, 145))	('CDK1', 'Gene', '983', (141, 145))
154784	24529193	In addition, Mcl-1 transcripts can be influenced by microRNAs (miRs).	('Mcl-1', 'Gene', (13, 18))	('influenced', 'Reg', (38, 48))	('microRNAs', 'Var', (52, 61))	('Mcl-1', 'Gene', '4170', (13, 18))
154789	24529193	For instance, in large granular lymphocyte leukemia, targeting Stat3 with its upstream kinase JAK-selective inhibitor AG490 transcriptionally suppresses Mcl-1 and promotes apoptosis.	('leukemia', 'Disease', (43, 51))	('suppresses', 'NegReg', (142, 152))	('targeting', 'Var', (53, 62))	('Mcl-1', 'Gene', '4170', (153, 158))	('Stat3', 'Gene', (63, 68))	('Stat3', 'Gene', '6774', (63, 68))	('apoptosis', 'CPA', (172, 181))	('lymphocyte leukemia', 'Phenotype', 'HP:0005526', (32, 51))	('promotes', 'PosReg', (163, 171))	('Mcl-1', 'Gene', (153, 158))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))	('leukemia', 'Disease', 'MESH:D007938', (43, 51))
154790	24529193	PI3K/Akt signaling is involved in Mcl-1 induction, targeting this pathway by newly developed PI3K inhibitor PI103 is showed to suppress Mcl-1 and induced apoptosis and restore sensitivity to TRAIL-induced apoptosis in neuroblastoma.	('Mcl-1', 'Gene', '4170', (34, 39))	('Akt', 'Gene', '207', (5, 8))	('neuroblastoma', 'Disease', 'MESH:D009447', (218, 231))	('Mcl-1', 'Gene', (136, 141))	('restore', 'PosReg', (168, 175))	('PI103', 'Var', (108, 113))	('apoptosis', 'CPA', (154, 163))	('neuroblastoma', 'Disease', (218, 231))	('Mcl-1', 'Gene', (34, 39))	('induced', 'PosReg', (146, 153))	('Akt', 'Gene', (5, 8))	('TRAIL', 'Gene', '8743', (191, 196))	('neuroblastoma', 'Phenotype', 'HP:0003006', (218, 231))	('suppress', 'NegReg', (127, 135))	('Mcl-1', 'Gene', '4170', (136, 141))	('TRAIL', 'Gene', (191, 196))
154793	24529193	Our data indicated that inhibition of NF-kappaB pathway by Bay11-7082 (Figure 4A, B), DNMIkappaBalpha (Figure 4C, D) or NF-kappaB subunit siRNA (Figure 6) attenuates Mcl-1 expression in human ESCC cells.	('NF-kappaB', 'Gene', '4790', (120, 129))	('expression', 'Species', '120121', (172, 182))	('DNMIkappaBalpha', 'Chemical', '-', (86, 101))	('Bay11-7082', 'Var', (59, 69))	('attenuates', 'NegReg', (155, 165))	('NF-kappaB', 'Gene', '4790', (38, 47))	('Mcl-1', 'Gene', '4170', (166, 171))	('NF-kappaB', 'Gene', (120, 129))	('human', 'Species', '9606', (186, 191))	('NF-kappaB', 'Gene', (38, 47))	('inhibition', 'NegReg', (24, 34))	('Mcl-1', 'Gene', (166, 171))	('Bay11-7082', 'Chemical', 'MESH:C434003', (59, 69))
154827	24265177	Previous studies have confirmed ~3.5 fold inter-donor variations in intraepithelial Phase II enzymes.	('intraepithelial Phase II enzymes', 'Enzyme', (68, 100))	('variations', 'Var', (54, 64))	('donor', 'Species', '9606', (48, 53))
154839	24265177	Notably, smokeless tobacco use results in exposure to 100 to 1000 fold higher nitrosamine levels relative to those obtained via food e.g.	('higher', 'PosReg', (71, 77))	('nitrosamine', 'Chemical', 'MESH:D009602', (78, 89))	('tobacco', 'Species', '4097', (19, 26))	('nitrosamine levels', 'MPA', (78, 96))	('smokeless tobacco use', 'Var', (9, 30))
154847	24265177	Optimally P450-mediated oxidations would reduce nitrosamines' carcinogenicity as their purpose is detoxification.	('P450', 'Gene', '1555', (10, 14))	('oxidations', 'Var', (24, 34))	('reduce', 'NegReg', (41, 47))	('P450', 'Gene', (10, 14))	('carcinogenic', 'Disease', 'MESH:D063646', (62, 74))	('nitrosamines', 'MPA', (48, 60))	('carcinogenic', 'Disease', (62, 74))	('nitrosamines', 'Chemical', 'MESH:D009602', (48, 60))
154850	24265177	Analogous to other tissues with high metabolic enzyme activities, the distribution of Phase I relative to Phase II enzymes in addition to actual levels of xenobiotic metabolizing enzyme in the mouth will impact the relative risk of developing OSCC during smokeless tobacco use.	('distribution', 'Var', (70, 82))	('impact', 'Reg', (204, 210))	('tobacco', 'Species', '4097', (265, 272))	('OSCC', 'Disease', (243, 247))
154855	24265177	Additionally, nitrosamine metabolism is further complicated by genetic polymorphisms which render some isoforms totally or partially inactive.	('isoforms', 'MPA', (103, 111))	('complicated', 'Reg', (48, 59))	('nitrosamine', 'Chemical', 'MESH:D009602', (14, 25))	('inactive', 'MPA', (133, 141))	('genetic polymorphisms', 'Var', (63, 84))	('nitrosamine metabolism', 'MPA', (14, 36))
154856	24265177	Relevant polymorphisms are present in the P450 2A6 which has the potential to bioactivate nitrosamine procarcinogens.	('bioactivate nitrosamine procarcinogens', 'MPA', (78, 116))	('P450', 'Gene', '1555', (42, 46))	('nitrosamine', 'Chemical', 'MESH:D009602', (90, 101))	('P450', 'Gene', (42, 46))	('polymorphisms', 'Var', (9, 22))
154863	24265177	The involved primary antibodies and their working dilutions are: P450 1A2 (1:200, mouse monoclonal, Santa Cruz Biotechnology, Santa Cruz, CA), P450 2A6 (1:200, mouse monoclonal, Santa Cruz Biotechnology, Santa Cruz, CA), P450 2A13 (1:100, rabbit polyclonal, AbCam, Cambridge, MA), P450 2E1 (1:200, Santa Cruz Biotechnology, Santa Cruz, CA), P450 3A4 (1:200, mouse monoclonal, Santa Cruz Biotechnology, Santa Cruz, CA).	('mouse', 'Species', '10090', (82, 87))	('mouse', 'Species', '10090', (160, 165))	('P450', 'Gene', '1555', (65, 69))	('P450', 'Gene', (281, 285))	('1:200', 'Var', (291, 296))	('P450', 'Gene', (143, 147))	('P450', 'Gene', '1555', (221, 225))	('P450', 'Gene', '1555', (341, 345))	('P450', 'Gene', (65, 69))	('rabbit', 'Species', '9986', (239, 245))	('mouse', 'Species', '10090', (358, 363))	('P450', 'Gene', (221, 225))	('P450', 'Gene', (341, 345))	('1:200', 'Var', (351, 356))	('P450', 'Gene', '1555', (281, 285))	('P450', 'Gene', '1555', (143, 147))
154929	24265177	This generation of P450-activated nitrosamine electrophiles in proximity to replicating basal layer keratinocytes and associated transient amplifying cells' DNA could greatly contribute to the probability of mutations in oral epithelia.	('P450', 'Gene', (19, 23))	('nitrosamine', 'Chemical', 'MESH:D009602', (34, 45))	('rat', 'Species', '10116', (9, 12))	('oral epithelia', 'Disease', (221, 235))	('oral epithelia', 'Disease', 'MESH:D020820', (221, 235))	('contribute', 'Reg', (175, 185))	('mutations', 'Var', (208, 217))	('P450', 'Gene', '1555', (19, 23))	('rat', 'Species', '10116', (102, 105))
154952	24265177	Due to the shorter life span of rats and the need to induce tumors in an expeditious fashion, the rats were treated with a high dose (14 +- 2 ppm) at the onset of the experiment whereas the patient had a ten year history of smokeless tobacco use.	('rats', 'Species', '10116', (98, 102))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tobacco', 'Species', '4097', (234, 241))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('14 +- 2 ppm', 'Var', (134, 145))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('rats', 'Species', '10116', (32, 36))	('patient', 'Species', '9606', (190, 197))
154955	24265177	the dibenzo[a,l]pyrene metabolite dibenz[a,l]pyrene diol epoxide, induced oral squamous cell carcinomas with similar mutation profiles as noted in human OSCCs such as p53.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('human', 'Species', '9606', (147, 152))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (74, 103))	('oral squamous cell carcinomas', 'Disease', (74, 103))	('dibenzo[a,l]pyrene', 'Chemical', 'MESH:C041517', (4, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('p53', 'Gene', '7157', (167, 170))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (79, 103))	('induced', 'Reg', (66, 73))	('dibenz[a,l]pyrene diol epoxide', 'Chemical', '-', (34, 64))	('dibenz[a', 'Var', (34, 42))	('p53', 'Gene', (167, 170))
155019	23370813	Obstruction of the esophagus leads to progressive dysphagia, malnutrition, and aspiration pneumonia.	('aspiration pneumonia', 'Disease', (79, 99))	('malnutrition', 'Disease', (61, 73))	('malnutrition', 'Disease', 'MESH:D044342', (61, 73))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (79, 99))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (79, 99))	('dysphagia', 'Disease', (50, 59))	('Obstruction', 'Var', (0, 11))	('malnutrition', 'Phenotype', 'HP:0004395', (61, 73))	('dysphagia', 'Phenotype', 'HP:0002015', (50, 59))	('aspiration', 'Phenotype', 'HP:0002835', (79, 89))	('pneumonia', 'Phenotype', 'HP:0002090', (90, 99))	('dysphagia', 'Disease', 'MESH:D003680', (50, 59))
155032	23370813	Misplacement of the stents has occurred frequently and might diminish their therapeutic efficacy.	('men', 'Species', '9606', (8, 11))	('diminish', 'NegReg', (61, 69))	('Misplacement', 'Var', (0, 12))	('therapeutic', 'MPA', (76, 87))
155034	23370813	However, it is very important to precisely place a stent in the cervical esophagus because stent misplacement may reduce its effectiveness and cause unexpected complications.	('misplacement', 'Var', (97, 109))	('men', 'Species', '9606', (105, 108))	('cause', 'Reg', (143, 148))	('reduce', 'NegReg', (114, 120))	('effectiveness', 'MPA', (125, 138))
155114	33638948	This study identified a high consistency between DNA copy number variations and abnormal methylations in EC by analyzing genomics, epigenetics and transcriptomics data and investigating mutual correlations of DNA copy number variation, methylation and gene expressions, and stratified copy number variation genes (CNV-Gs) and methylation genes (MET-Gs).	('MET', 'Gene', (345, 348))	('variations', 'Var', (65, 75))	('MET', 'Gene', '79811', (345, 348))	('EC', 'Phenotype', 'HP:0011459', (105, 107))
155123	33638948	Genomic variation as a result of DNA copy number variation (CNV) and single nucleotide mutations (SNPs) could easily lead to tumor development.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('DNA copy number variation', 'Var', (33, 58))	('lead to', 'Reg', (117, 124))	('single nucleotide mutations', 'Var', (69, 96))
155124	33638948	DNA copy number variation played a key regulatory role in the progression of ESCC, and transcriptional disorders caused by copy number changes were potential driving events in EC progression.	('transcriptional disorders', 'Disease', 'MESH:D030342', (87, 112))	('ESCC', 'Disease', (77, 81))	('transcriptional disorders', 'Disease', (87, 112))	('copy number changes', 'Var', (123, 142))	('EC', 'Phenotype', 'HP:0011459', (176, 178))	('caused', 'Reg', (113, 119))
155125	33638948	On the other hand, analysis of DNA methylation profiles has demonstrated the vast heterogeneity of epigenome disorders in EC and other cancer types, and further studies also proved that DNA methylation contributes to heterogeneous biological behaviors and is actively involved in the progression of ESCC.	('methylation', 'Var', (190, 201))	('heterogeneous biological behaviors', 'MPA', (217, 251))	('cancer', 'Disease', (135, 141))	('EC', 'Phenotype', 'HP:0011459', (122, 124))	('contributes', 'Reg', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('involved', 'Reg', (268, 276))	('ESCC', 'Disease', (299, 303))	('DNA', 'Gene', (186, 189))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
155126	33638948	The number of CNV Gain, CNV Loss, MetHyper and MetHypo for each sample were counted to analyze the relationship between the frequency of CNV Gain and CNV Loss in each sample, and we detected a significant positive correlation (R=0.52, p=2.1e-12) (Figure 2A), which suggested that high frequency of copy number amplification events in the EC patients' genome were accompanied by high frequency of deletions.	('deletions', 'MPA', (396, 405))	('patients', 'Species', '9606', (341, 349))	('copy number amplification events', 'Var', (298, 330))	('EC', 'Phenotype', 'HP:0011459', (338, 340))
155134	33638948	The distribution of CNV-Gs and MET-Gs on the genome were analyzed, and we observed that CNV-Gs were mainly distributed on chromosome 12 (Figure 3B), but the MET-Gs were mainly distributed on chromosomes 6 and 7 (Figure 3C).	('CNV-Gs', 'Var', (88, 94))	('MET', 'Gene', (157, 160))	('MET', 'Gene', '79811', (31, 34))	('MET', 'Gene', (31, 34))	('MET', 'Gene', '79811', (157, 160))
155136	33638948	Univariate survival analysis determined that 268 CNV-Gs and 125 MET-Gs were significantly related to prognosis of EC (log rank p < 0.05), with an intersection of 43 genes (Figure 3F).	('MET', 'Gene', (64, 67))	('CNV-Gs', 'Var', (49, 55))	('related', 'Reg', (90, 97))	('MET', 'Gene', '79811', (64, 67))	('EC', 'Phenotype', 'HP:0011459', (114, 116))
155165	33638948	Specifically, GABRB3 is an inhibitory gene of head and neck cancer; SYNE1 gene hypermethylation can be used as biomarkers in colorectal; SYNE1 polymorphisms are associated with the risk of developing invasive epithelial ovarian cancer; intratumoral heterogeneity of HMCN1 mutant alleles is associated with poor prognosis of breast cancer patients; the combination of SLITRK5 and TP53 is associated with the clinical outcome of gastric cancer patients.	('mutant', 'Var', (272, 278))	('SYNE1', 'Gene', (137, 142))	('associated', 'Reg', (161, 171))	('SLITRK5', 'Gene', '26050', (367, 374))	('TP53', 'Gene', (379, 383))	('patients', 'Species', '9606', (338, 346))	('breast cancer', 'Phenotype', 'HP:0003002', (324, 337))	('SYNE1', 'Gene', '23345', (137, 142))	('head and neck cancer', 'Disease', 'MESH:D006258', (46, 66))	('HMCN1', 'Gene', (266, 271))	('gastric cancer', 'Disease', (427, 441))	('tumor', 'Disease', (241, 246))	('GABRB3', 'Gene', (14, 20))	('patients', 'Species', '9606', (442, 450))	('ovarian cancer', 'Phenotype', 'HP:0100615', (220, 234))	('invasive epithelial ovarian cancer', 'Disease', (200, 234))	('breast cancer', 'Disease', 'MESH:D001943', (324, 337))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('breast cancer', 'Disease', (324, 337))	('associated', 'Reg', (387, 397))	('gastric cancer', 'Disease', 'MESH:D013274', (427, 441))	('TP53', 'Gene', '7157', (379, 383))	('SLITRK5', 'Gene', (367, 374))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (209, 234))	('cancer', 'Phenotype', 'HP:0002664', (435, 441))	('HMCN1', 'Gene', '83872', (266, 271))	('GABRB3', 'Gene', '2562', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('SYNE1', 'Gene', (68, 73))	('invasive epithelial ovarian cancer', 'Disease', 'MESH:D009362', (200, 234))	('gastric cancer', 'Phenotype', 'HP:0012126', (427, 441))	('head and neck cancer', 'Phenotype', 'HP:0012288', (46, 66))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('SYNE1', 'Gene', '23345', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
155169	33638948	As a hallmark of malignancy, genomic instability leads to DNA copy number variations in multiple cancer types, and these CNVs were important factors affecting changes in gene expressions.	('cancer', 'Disease', (97, 103))	('DNA', 'Gene', (58, 61))	('malignancy', 'Disease', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('leads to', 'Reg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('malignancy', 'Disease', 'MESH:D009369', (17, 27))	('variations', 'Var', (74, 84))
155170	33638948	In addition to copy number abnormalities, DNA methylation is a critical regulator of gene transcription and one of the most studied epigenetic modifications.	('DNA', 'Var', (42, 45))	('number abnormalities', 'Disease', (20, 40))	('number abnormalities', 'Disease', 'MESH:D007674', (20, 40))
155171	33638948	Abnormal hypomethylation could induce genomic instability and overexpression of oncogenes, while hypermethylation of the tumor suppressor promoter region disrupts cell cycle regulation, apoptosis and DNA repair, and leads to malignant cell transformation.	('leads to', 'Reg', (216, 224))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('induce', 'Reg', (31, 37))	('disrupts', 'NegReg', (154, 162))	('genomic', 'MPA', (38, 45))	('Abnormal hypomethylation', 'Disease', 'MESH:D018376', (0, 24))	('tumor', 'Disease', (121, 126))	('Abnormal hypomethylation', 'Disease', (0, 24))	('hypermethylation', 'Var', (97, 113))	('cell cycle regulation', 'CPA', (163, 184))	('DNA repair', 'CPA', (200, 210))	('overexpression', 'PosReg', (62, 76))	('malignant cell transformation', 'CPA', (225, 254))	('apoptosis', 'CPA', (186, 195))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
155174	33638948	Therefore, we were interested in analyzing the relationship between epigenetic and CNVs using 159 samples from TCGA, and found that DNA copy number abnormalities were consistent with methylation abnormalities.	('number abnormalities', 'Disease', (141, 161))	('methylation', 'Var', (183, 194))	('number abnormalities', 'Disease', 'MESH:D007674', (141, 161))
155188	33638948	Abnormal methylation of CLDN3 has been reported to be associated with the occurrence of ESCC.	('ESCC', 'Disease', (88, 92))	('CLDN3', 'Gene', (24, 29))	('Abnormal', 'Var', (0, 8))	('methylation', 'MPA', (9, 20))	('CLDN3', 'Gene', '1365', (24, 29))	('associated', 'Reg', (54, 64))
155200	33638948	For SNP data, the file in MAF format was parsed, the mutations in the intron interval and the mutations annotated as silence were removed.	('MAF', 'Gene', '4094', (26, 29))	('MAF', 'Gene', (26, 29))	('mutations', 'Var', (53, 62))
155264	29432922	However, long segment BE and a higher Charlson Comorbidity Index was associated with an increased risk of over-utilization (Table 2).	('over-utilization', 'MPA', (106, 122))	('long', 'Var', (9, 13))	('men', 'Species', '9606', (17, 20))
155265	29432922	Long segment BE was associated with an almost 4 times higher risk of over-utilization as compared to short segment BE (adjusted odds ratio [aOR] = 3.78, 95% confidence interval [CI] = 1.51 - 9.46) (Table 2).	('men', 'Species', '9606', (110, 113))	('Long segment BE', 'Var', (0, 15))	('men', 'Species', '9606', (8, 11))	('over-utilization', 'MPA', (69, 85))
155266	29432922	Furthermore, a PCP at the University of Michigan as the referring physician for the third endoscopy was associated with a reduced risk of over-surveillance as compared to a University of Michigan GI provider (aOR = 0.51, 95% CI = 0.27 - 0.95) (Table 2).	('PCP', 'Var', (15, 18))	('over-surveillance', 'MPA', (138, 155))	('reduced', 'NegReg', (122, 129))	('PCP', 'Chemical', '-', (15, 18))
155273	29432922	In the multivariable analysis, male patients (aOR 1.90, 95% CI 1.01-3.57), long segment BE (aOR 3.02, 95% CI 1.10-8.25), and a higher Charlson Comorbidity Index (aOR 3.01, 95% CI 1.19-7.58) were associated with an increased risk of never being surveilled (Table 4).	('long segment', 'Var', (75, 87))	('men', 'Species', '9606', (83, 86))	('never being surveilled', 'Disease', (232, 254))	('patients', 'Species', '9606', (36, 44))
155295	29432922	Third, long-segment Barrett's disease was associated with an increased risk of over-surveillance, under-surveillance and never surveilled in our multivariable analyses, as compared to appropriate surveillance.	("Barrett's disease", 'Disease', 'MESH:D001471', (20, 37))	('long-segment', 'Var', (7, 19))	('men', 'Species', '9606', (15, 18))	('over-surveillance', 'MPA', (79, 96))	('under-surveillance', 'MPA', (98, 116))	("Barrett's disease", 'Disease', (20, 37))
155366	33672929	In some studies, a statistically significant survival adverse effect of microscopic residual tumor on the trachea or shaving off of the thyroid tumor from the trachea was demonstrated when compared to a clear margin on final pathology.	('tumor', 'Disease', (144, 149))	('thyroid tumor', 'Disease', 'MESH:D013964', (136, 149))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor from the trachea', 'Phenotype', 'HP:0100551', (144, 166))	('thyroid tumor', 'Phenotype', 'HP:0100031', (136, 149))	('tumor', 'Disease', (93, 98))	('adverse', 'NegReg', (54, 61))	('microscopic', 'Var', (72, 83))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('thyroid tumor', 'Disease', (136, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor on the trachea', 'Phenotype', 'HP:0100551', (93, 113))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
155374	33672929	It appears that, although the presence of microscopic residual disease did not affect recurrence-free survival, microscopic tumor remnants had a detrimental impact on survival, which was associated with a significant difference in DSS between patients with R0 and R2 statuses.	('detrimental', 'NegReg', (145, 156))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('patients', 'Species', '9606', (243, 251))	('residual disease', 'Disease', (54, 70))	('tumor', 'Disease', (124, 129))	('microscopic', 'Var', (112, 123))	('DSS', 'Chemical', '-', (231, 234))	('survival', 'MPA', (167, 175))	('DSS', 'MPA', (231, 234))	('residual disease', 'Disease', 'MESH:D018365', (54, 70))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
155403	33672929	When the resection range is wide, as in cases of defects larger than half of the tracheal circumference or with tracheal defects equivalent in diameter to up to 10 rings of the trachea, grafting of hard tissues or use of graft materials are required to avoid a collapse of the soft-tissue roof, to achieve an intact luminal lining, and to restore tracheal function for clearing secretions.	('restore', 'PosReg', (339, 346))	('luminal', 'Chemical', 'MESH:D010634', (316, 323))	('clearing secretions', 'MPA', (369, 388))	('tracheal defects', 'Disease', (112, 128))	('tracheal defects', 'Disease', 'MESH:D014133', (112, 128))	('tracheal defects', 'Phenotype', 'HP:0002778', (112, 128))	('tracheal defect', 'Phenotype', 'HP:0002778', (112, 127))	('tracheal function', 'MPA', (347, 364))	('defects', 'Var', (49, 56))
155537	32887889	Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('variants', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('carcinogenic', 'Disease', 'MESH:D063646', (181, 193))	('carcinogenic', 'Disease', (181, 193))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', (142, 148))
155539	32887889	Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('variants', 'Var', (168, 176))	('influence', 'Reg', (223, 232))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
155546	32887889	Genome-wide association studies (GWAS) of individual cancers have identified loci associated with multiple cancer types, including 1q32 (MDM4); 2q33 (CASP8-ALS2CR12); 3q28 (TP63); 4q24 (TET2); 5p15 (TERT-CLPTM1L); 6p21 (HLA complex); 7p15; 8q24; 11q13; 17q12 (HNF1B); and 19q13 (MERIT40).	('p15', 'Gene', '1030', (235, 238))	('MDM4', 'Gene', (137, 141))	('associated', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('MERIT40', 'Gene', '29086', (279, 286))	('4q24', 'Var', (180, 184))	('p15', 'Gene', '1030', (194, 197))	('CASP8', 'Gene', '841', (150, 155))	('TET2', 'Gene', (186, 190))	('ALS2CR12', 'Gene', '130540', (156, 164))	('3q28', 'Var', (167, 171))	('ALS2CR12', 'Gene', (156, 164))	('CLPTM1L', 'Gene', '81037', (204, 211))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('CASP8', 'Gene', (150, 155))	('cancers', 'Disease', (53, 60))	('cancer', 'Disease', (53, 59))	('19q13', 'Var', (272, 277))	('TP63', 'Gene', (173, 177))	('HNF1B', 'Gene', '6928', (260, 265))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('HNF1B', 'Gene', (260, 265))	('cancer', 'Disease', (107, 113))	('p15', 'Gene', (235, 238))	('CLPTM1L', 'Gene', (204, 211))	('TET2', 'Gene', '54790', (186, 190))	('TP63', 'Gene', '8626', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TERT', 'Gene', (199, 203))	('MERIT40', 'Gene', (279, 286))	('TERT', 'Gene', '7015', (199, 203))	('p15', 'Gene', (194, 197))	('MDM4', 'Gene', '4194', (137, 141))
155547	32887889	In addition, recent studies have tested single-nucleotide polymorphisms (SNPs) previously associated with one cancer to discover pleiotropic associations with other cancer types.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('single-nucleotide polymorphisms', 'Var', (40, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('P', 'Chemical', 'MESH:D010758', (75, 76))
155556	32887889	We seek to detect risk SNPs and pleiotropic loci and variants and to estimate the heritability of and genetic correlations between cancer types.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('P', 'Chemical', 'MESH:D010758', (25, 26))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('variants', 'Var', (53, 61))
155557	32887889	We then conduct in silico functional analyses of pleiotropic variants to catalog biological mechanisms potentially shared across cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Disease', (129, 136))	('variants', 'Var', (61, 69))
155560	32887889	We found 21 previously unreported genome-wide significant associations between variants and cancers at P < 5 x 10-8 upon meta-analysis of the UKB and GERA results (Table 1).	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('variants', 'Var', (79, 87))	('P', 'Chemical', 'MESH:D010758', (103, 104))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
155561	32887889	These included 20 unique variants, with 1 variant that was associated with two cancers (rs78378222).	('cancers', 'Disease', (79, 86))	('variants', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('associated', 'Reg', (59, 69))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('rs78378222', 'Mutation', 'rs78378222', (88, 98))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
155564	32887889	Fourteen of these 21 associations indicated pleiotropy in that the relevant variants were in regions previously associated with at least one of the other cancer types evaluated in this study (Table 1).	('variants', 'Var', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))
155566	32887889	In addition, there were nine previously unreported variants associated with cancers at P < 5 x 10-8 that were only genotyped or imputed in one cohort (Supplementary Data 1; yellow rows).	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('variants', 'Var', (51, 59))	('P', 'Chemical', 'MESH:D010758', (87, 88))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('associated', 'Reg', (60, 70))
155568	32887889	Finally, we replicated 308 independent cancer risk variants identified as GWAS significant by previous studies (Supplementary Data 2; P < 1 x 10-6).	('cancer', 'Disease', (39, 45))	('P', 'Chemical', 'MESH:D010758', (134, 135))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('variants', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
155584	32887889	The remaining pleiotropic region, indexed by rs6507874, was in SMAD7, which has been previously linked to colorectal cancer, and we confirmed its association with colon and rectal cancers separately.	('rs6507874', 'Var', (45, 54))	('rectal cancer', 'Phenotype', 'HP:0100743', (110, 123))	('colon and rectal cancers', 'Disease', 'MESH:D015179', (163, 187))	('rectal cancer', 'Phenotype', 'HP:0100743', (173, 186))	('colorectal cancer', 'Disease', (106, 123))	('linked', 'Reg', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('SMAD7', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('SMAD7', 'Gene', '4092', (63, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('rs6507874', 'Mutation', 'rs6507874', (45, 54))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))
155585	32887889	We assessed variant-specific pleiotropy by testing all variants genome-wide using the summary statistics for each cancer using ASSET.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('variants', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('testing', 'Reg', (43, 50))	('cancer', 'Disease', (114, 120))
155586	32887889	We found 85 independent (LD r2 < 0.1) one-directional pleiotropic variants with at least two associated cancers, the same direction of effect for all associated cancers, and an overall pleiotropic P < 5 x 10-8 (Supplementary Data 4).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('variants', 'Var', (66, 74))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (161, 168))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('P', 'Chemical', 'MESH:D010758', (197, 198))
155587	32887889	Of these one-directional pleiotropic variants, there were 17 for which the overall pleiotropic P was smaller than the P for each of the associated cancers (Fig.	('P', 'Chemical', 'MESH:D010758', (95, 96))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('P', 'Chemical', 'MESH:D010758', (118, 119))	('variants', 'Var', (37, 45))	('cancers', 'Disease', (147, 154))
155588	32887889	While 84 of the 85 one-directional pleiotropic variants were in regions that have previously been associated with any cancer, 68 were associated with at least one cancer not previously reported.	('associated', 'Reg', (134, 144))	('cancer', 'Disease', (118, 124))	('variants', 'Var', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('associated', 'Reg', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
155589	32887889	The variant in a region not previously associated with any cancer is rs150260898, intronic of RABIF5, which was associated with melanoma and oral cavity/pharyngeal cancer.	('associated with', 'Reg', (112, 127))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('RABIF5', 'Gene', (94, 100))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('rs150260898', 'Var', (69, 80))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('rs150260898', 'Mutation', 'rs150260898', (69, 80))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
155590	32887889	We also considered bidirectional pleiotropic associations, wherein the same allele for a given variant was associated with an increased risk for some cancers but a decreased risk for others.	('decreased', 'NegReg', (164, 173))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('variant', 'Var', (95, 102))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
155593	32887889	While all of the bidirectional pleiotropic variants were in regions that have previously been associated with cancer, six were independent of known risk variants, and all 15 were associated with at least one cancer not previously reported.	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', (208, 214))	('associated with', 'Reg', (179, 194))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('associated', 'Reg', (94, 104))	('variants', 'Var', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
155594	32887889	For any pair of cancers associated with the same variant, the type of association falls in one of three categories: (1) SNPs identified in the one-directional analysis, where all associations are in the same direction; (2) SNPs identified in the bidirectional analysis, where both cancers in the pair are associated in the same direction (both risk increasing or both risk decreasing), even though at least one other cancer is associated in the opposite direction; and (3) SNPs identified in the bidirectional analysis, where the pair of cancers are associated in opposite directions (one risk increasing and one risk decreasing).	('cancer', 'Disease', 'MESH:D009369', (538, 544))	('cancers', 'Disease', 'MESH:D009369', (538, 545))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('P', 'Chemical', 'MESH:D010758', (225, 226))	('variant', 'Var', (49, 56))	('cancers', 'Disease', (281, 288))	('cancer', 'Disease', 'MESH:D009369', (417, 423))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('P', 'Chemical', 'MESH:D010758', (122, 123))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (538, 545))	('cancers', 'Disease', (538, 545))	('cancer', 'Disease', (538, 544))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('cancer', 'Phenotype', 'HP:0002664', (538, 544))	('cancer', 'Disease', (417, 423))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('fall', 'Phenotype', 'HP:0002527', (82, 86))	('cancer', 'Disease', (281, 287))	('P', 'Chemical', 'MESH:D010758', (475, 476))	('cancer', 'Phenotype', 'HP:0002664', (417, 423))	('decreasing', 'NegReg', (373, 383))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('falls', 'Phenotype', 'HP:0002527', (82, 87))
155598	32887889	For three cancer pairs, at least 50% of the shared variants were associated in opposite directions.	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('variants', 'Var', (51, 59))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))
155601	32887889	rs111362352-C was significantly positively associated with the risk of low grade prostate cancer in GERA, while it was not associated with high-grade disease.	('rs111362352-C', 'Var', (0, 13))	('prostate cancer', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('low grade prostate', 'Phenotype', 'HP:0008687', (71, 89))	('associated', 'Reg', (43, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('rs111362352', 'Mutation', 'rs111362352', (0, 11))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))
155606	32887889	Regulatory effects mediated by chromatin looping were observed for 28 variants, including 3 enhancer-promoter links in 6p21.23 (rs535777, rs73728618) and 22q13.2 (rs5759167, PACSIN2 promoter; Supplementary Fig.	('rs73728618', 'Mutation', 'rs73728618', (138, 148))	('rs535777', 'Mutation', 'rs535777', (128, 136))	('rs535777', 'Var', (128, 136))	('enhancer-promoter', 'PosReg', (92, 109))	('PACSIN2', 'Gene', '11252', (174, 181))	('rs5759167', 'Mutation', 'rs5759167', (163, 172))	('PACSIN2', 'Gene', (174, 181))	('rs73728618', 'Var', (138, 148))	('rs5759167', 'Var', (163, 172))
155607	32887889	Notably, rs5759167 is an eQTL for PACSIN2 in whole blood (BIOS QTL: P = 9.89 x 10-14; GTEx v8: P = 3.39 x 10-7).	('P', 'Chemical', 'MESH:D010758', (95, 96))	('P', 'Chemical', 'MESH:D010758', (34, 35))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('rs5759167', 'Mutation', 'rs5759167', (9, 18))	('rs5759167', 'Var', (9, 18))	('PACSIN2', 'Gene', '11252', (34, 41))	('PACSIN2', 'Gene', (34, 41))
155608	32887889	Pleiotropic variants had a significantly higher proportion of enhancers (P = 3.38 x 10-4), eQTLs (P = 3.38 x 10-4; >1 tissue: P = 2.33 x 10-3; >1 gene: P = 1.34 x 10-4), and chromatin interactions (P = 3.48 x 10-4).	('P', 'Chemical', 'MESH:D010758', (98, 99))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('P', 'Chemical', 'MESH:D010758', (126, 127))	('enhancers', 'PosReg', (62, 71))	('variants', 'Var', (12, 20))	('eQTLs', 'MPA', (91, 96))	('chromatin interactions', 'CPA', (174, 196))	('P', 'Chemical', 'MESH:D010758', (198, 199))	('P', 'Chemical', 'MESH:D010758', (73, 74))	('P', 'Chemical', 'MESH:D010758', (152, 153))
155610	32887889	Genes represented by pleiotropic variants were significantly enriched for 36 KEGG pathways that formed two clusters broadly characterized by immune-related functions and cancer-specific genes (Supplementary Table 2 and Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('KEGG pathways', 'Pathway', (77, 90))	('variants', 'Var', (33, 41))
155614	32887889	By characterizing pleiotropy at the genome-wide, locus-specific, and variant-specific levels for a large number of cancer sites, we generated several insights into cancer susceptibility.	('cancer', 'Disease', (115, 121))	('variant-specific', 'Var', (69, 85))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
155615	32887889	Specifically, we detected 21 previously unreported genome-wide significant variant associations across 11 of the 18 individual cancers examined.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('variant', 'Var', (75, 82))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
155616	32887889	We also detected 100 independent variants displaying one- or bidirectional pleiotropy that were enriched for a number of regulatory functions that reflect hallmarks of carcinogenesis.	('variants', 'Var', (33, 41))	('carcinogenesis', 'Disease', (168, 182))	('carcinogenesis', 'Disease', 'MESH:D063646', (168, 182))
155617	32887889	One notable finding from our cervical cancer GWAS was rs10175462 in PAX8 on 2q13, which, to our knowledge, is the first genome-wide significant cervical cancer risk SNP identified outside of the HLA region in a European ancestry population.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('rs10175462', 'Var', (54, 64))	('PAX8', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (153, 159))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('rs10175462', 'Mutation', 'rs10175462', (54, 64))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('PAX8', 'Gene', '7849', (68, 72))	('cancer', 'Disease', (38, 44))	('P', 'Chemical', 'MESH:D010758', (167, 168))
155618	32887889	In a candidate SNP study of PAX8 eQTLs in a Han Chinese population, two variants in LD with rs10175462 in Europeans (rs1110839, r2 = 0.33; rs4848320, r2 = 0.34) were suggestively associated with cervical cancer risk in the same direction.	('cancer', 'Disease', (204, 210))	('rs1110839', 'Var', (117, 126))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('rs10175462', 'Mutation', 'rs10175462', (92, 102))	('PAX8', 'Gene', '7849', (28, 32))	('associated with', 'Reg', (179, 194))	('P', 'Chemical', 'MESH:D010758', (17, 18))	('P', 'Chemical', 'MESH:D010758', (28, 29))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('PAX8', 'Gene', (28, 32))	('rs1110839', 'Mutation', 'rs1110839', (117, 126))	('rs4848320', 'Mutation', 'rs4848320', (139, 148))	('rs4848320', 'Var', (139, 148))	('rs10175462', 'Var', (92, 102))
155619	32887889	Several GWAS findings also provided evidence of pleiotropy, in that previously unreported risk variants for one cancer had known associations with one or more other cancers.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('variants', 'Var', (95, 103))	('associations', 'Interaction', (129, 141))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Disease', (165, 172))
155620	32887889	For instance, rs9818780 was associated with melanoma and has been implicated in sunburn risk.	('rs9818780', 'Mutation', 'rs9818780', (14, 23))	('associated', 'Reg', (28, 38))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('rs9818780', 'Var', (14, 23))	('sunburn', 'Disease', (80, 87))
155634	32887889	The assessment of pleiotropy at the locus level confirmed previously reported associations at 5p15.33, HLA, and 8q24 (refs.	('associations', 'Interaction', (78, 90))	('p15', 'Gene', (95, 98))	('p15', 'Gene', '1030', (95, 98))	('8q24', 'Var', (112, 116))
155638	32887889	Variant-specific analyses provided further evidence in support of locus-specific cancer pleiotropy, including validation of previously reported signals at 1q32 (refs. )	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('Variant-specific', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
155640	32887889	Interestingly, our lead 1q32 variant (rs1398148) maps to PIK3C2B and is in LD (r2 > 0.60) with known MDM4 cancer risk variants, suggesting that the 1q32 locus may be involved in modulating both p53-and PI3K-mediated oncogenic pathways.	('modulating', 'Reg', (178, 188))	('MDM4', 'Gene', '4194', (101, 105))	('rs1398148', 'Mutation', 'rs1398148', (38, 47))	('variant', 'Var', (29, 36))	('PIK3C2B', 'Gene', (57, 64))	('variants', 'Var', (118, 126))	('PIK3C2B', 'Gene', '5287', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('MDM4', 'Gene', (101, 105))	('p53', 'Gene', (194, 197))	('P', 'Chemical', 'MESH:D010758', (202, 203))	('cancer', 'Disease', (106, 112))	('p53', 'Gene', '7157', (194, 197))	('involved', 'Reg', (166, 174))	('P', 'Chemical', 'MESH:D010758', (57, 58))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
155642	32887889	Although 99 of the 100 variants showing one- or bidirectional pleiotropic associations are in regions previously associated with cancer, 83 of the 99 were associated with at least one cancer not previously reported.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('associated', 'Reg', (155, 165))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('variants', 'Var', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
155645	32887889	Specifically, mutations that create neoantigens more likely to be recognized by specific HLA alleles are less likely to be present in tumors from patients carrying such alleles.	('mutations', 'Var', (14, 23))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('patients', 'Species', '9606', (146, 154))
155647	32887889	In contrast to the HLA region, the majority of the 8q24 pleiotropic variants had the same direction of effect for all associated cancers, implying the existence of shared genetic mechanisms driving tumorigenesis across sites.	('variants', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))
155649	32887889	Consistent with this hypothesis, we observed heritability enrichment for variants with the H3K27ac annotation for breast (P = 3.09 x 10-4), colon (P = 4.44 x 10-4), prostate (P = 2.74 x 10-5), and rectal (P = 0.036) cancers:all of which share susceptibility variants in 8q24, according to our analyses and previous studies.	('colon', 'Disease', (140, 145))	('P', 'Chemical', 'MESH:D010758', (122, 123))	('P', 'Chemical', 'MESH:D010758', (175, 176))	('variants', 'Var', (258, 266))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('variants', 'Var', (73, 81))	('P', 'Chemical', 'MESH:D010758', (147, 148))	('breast', 'Disease', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('prostate', 'Disease', (165, 173))	('cancers', 'Disease', (216, 223))	('rectal', 'Disease', (197, 203))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('P', 'Chemical', 'MESH:D010758', (205, 206))	('H3K27ac', 'Gene', (91, 98))
155650	32887889	In silico analyses found the 100 pleiotropic variants to be enriched across multiple regulatory domains compared to non-pleiotropic randomly selected variants and highlighted cross-cancer susceptibility loci.	('cross-cancer', 'Disease', 'MESH:D009369', (175, 187))	('variants', 'Var', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cross-cancer', 'Disease', (175, 187))
155651	32887889	The 11q13.3 region includes rs12275055, which maps to active enhancers and is also an eQTL for TPCN2, a gene involved in controlling the angiogenic response to VEGF and extracellular vesicle trafficking in cancer cells.	('VEGF', 'Gene', '7422', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('rs12275055', 'Var', (28, 38))	('rs12275055', 'Mutation', 'rs12275055', (28, 38))	('VEGF', 'Gene', (160, 164))	('TPCN2', 'Gene', (95, 100))	('TPCN2', 'Gene', '219931', (95, 100))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
155652	32887889	An additional interesting region, 22q13.2, is indexed by rs5759167, an intergenic variant linked to prostate and lung cancers risk.	('rs5759167', 'Mutation', 'rs5759167', (57, 66))	('rs5759167', 'Var', (57, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('lung cancers', 'Disease', 'MESH:D008175', (113, 125))	('lung cancers', 'Phenotype', 'HP:0100526', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('prostate', 'Disease', (100, 108))	('lung cancers', 'Disease', (113, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
155654	32887889	This is consistent with our observation that that the risk-increasing G-allele is associated with increased PACSIN2 expression in whole blood.	('PACSIN2', 'Gene', '11252', (108, 115))	('PACSIN2', 'Gene', (108, 115))	('expression', 'MPA', (116, 126))	('increased', 'PosReg', (98, 107))	('G-allele', 'Var', (70, 78))
155655	32887889	Lastly, our pathway analysis indicated that pleiotropic variants as a group are enriched for genes involved in immune regulation and infection, as well as cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('pleiotropic variants', 'Var', (44, 64))	('infection', 'Disease', (133, 142))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('infection', 'Disease', 'MESH:D007239', (133, 142))
155664	32887889	Broad analyses of genetic susceptibility and targeted analyses of specific loci and variants may both contribute insights into different dimensions of cancer pleiotropy.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('variants', 'Var', (84, 92))
155696	32887889	In addition, the correlation was very high between imputed and sequenced genotypes for 44 EUR samples from the 1000 Genomes Project genotyped with the Axiom UK Biobank array and imputed using the 1KGP WGS Phase 3 reference panel: the average r2 was 0.97 for SNPs and 0.90 for indels (MAF > 0.01; Jeremy Gollub, Personal Communication).	('P', 'Chemical', 'MESH:D010758', (260, 261))	('P', 'Chemical', 'MESH:D010758', (311, 312))	('indels', 'Var', (276, 282))	('P', 'Chemical', 'MESH:D010758', (199, 200))	('P', 'Chemical', 'MESH:D010758', (124, 125))	('SNPs', 'Var', (258, 262))	('P', 'Chemical', 'MESH:D010758', (205, 206))
155701	32887889	For variants that were only examined in one cohort (22% of the total 10,003,934 SNPs analyzed), original summary statistics were merged with the meta-analyzed SNPs to create a union set of SNP statistics for each cancer for use in downstream analyses (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('P', 'Chemical', 'MESH:D010758', (82, 83))	('P', 'Chemical', 'MESH:D010758', (161, 162))	('variants', 'Var', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('P', 'Chemical', 'MESH:D010758', (191, 192))
155744	32887889	The distribution of functional features among pleiotropic cancer risk variants was compared to a random sample of the same number of SNPs.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('variants', 'Var', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('P', 'Chemical', 'MESH:D010758', (135, 136))	('cancer', 'Disease', (58, 64))
155860	29356784	The symptoms of GERD were assessed with validated questionnaires that separately assessed the symptoms of acid reflux and heartburn, allowing us to show that the presence of either symptom was strongly associated with risk of Barrett's esophagus.	('GERD', 'Disease', 'MESH:D005764', (16, 20))	('heartburn', 'Phenotype', 'HP:0002020', (122, 131))	('associated', 'Reg', (202, 212))	('presence', 'Var', (162, 170))	("Barrett's esophagus", 'Disease', (226, 245))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (226, 245))	('acid reflux', 'Phenotype', 'HP:0002020', (106, 117))	('GERD', 'Disease', (16, 20))
155866	29356784	This is further supported by our finding that at least weekly PPI use increases risk of Barrett's esophagus 10 fold, likely serving as a marker for severe GERD.	("Barrett's esophagus", 'Disease', (88, 107))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (88, 107))	('PPI', 'Var', (62, 65))	('GERD', 'Disease', (155, 159))	('GERD', 'Disease', 'MESH:D005764', (155, 159))
155904	28445275	For cases 1 and 2, lesions were completely resected by ESD; invasive depth for both was T1a-LPM (lamina propria mucosae, according to Japanese Classification of Esophageal Cancer, 11th edition).	('Esophageal Cancer', 'Disease', (161, 178))	('T1a-LPM', 'Var', (88, 95))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (161, 178))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))
155916	28445275	Meanwhile, the rate of lymph node metastasis for T1a-MM (muscularis mucosae) cases was only 6.7%, without metastatic cases for T1a-EP (carcinoma in situ) and T1a-LPM.	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('lymph node metastasis', 'CPA', (23, 44))	('carcinoma in situ', 'Disease', (135, 152))	('T1a-MM', 'Var', (49, 55))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (135, 152))	('carcinoma in situ', 'Disease', 'MESH:D002278', (135, 152))
155940	27777949	Incorporation of taxanes into cisplatin-based CCRT may be associated with prolonged survival.	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('taxanes', 'Chemical', 'MESH:D043823', (17, 24))	('Incorporation', 'Var', (0, 13))	('prolonged', 'PosReg', (74, 83))
156045	27777949	In conclusion, incorporation of taxane into cisplatin-based CCRT is potentially associated with better survival outcome in patients with pMR to neoadjuvant CCRT after esophagectomy.	('better', 'PosReg', (96, 102))	('taxane', 'Chemical', 'MESH:C080625', (32, 38))	('patients', 'Species', '9606', (123, 131))	('incorporation', 'Var', (15, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))
156063	26370982	Clinical findings suggesting an association between alterations in SOX2 gene and developmental maladies have been evidenced.	('developmental maladies', 'Disease', (81, 103))	('SOX2', 'Gene', '6657', (67, 71))	('alterations', 'Var', (52, 63))	('SOX2', 'Gene', (67, 71))
156064	26370982	For instance, anophthalmia-esophageal-genital (AEG) syndrome characterized by an abnormal development of ectodermal and endodermal tissues, has been found to occur as a result of a heterozygous mutation in SOX2 gene.	('SOX2', 'Gene', '6657', (206, 210))	('heterozygous mutation', 'Var', (181, 202))	('anophthalmia', 'Phenotype', 'HP:0000528', (14, 26))	('anophthalmia-esophageal-genital (AEG) syndrome', 'Disease', 'MESH:C565948', (14, 60))	('SOX2', 'Gene', (206, 210))
156084	26370982	In order to further confirm the involvement of Slug in SOX2-mediated EMT, we incubated the SOX2-overexpressing Eca-109 cells with siRNA to knock down the Slug.	('SOX2', 'Gene', (55, 59))	('Eca-1', 'Gene', (111, 116))	('Slug', 'Gene', (47, 51))	('Slug', 'Gene', '6591', (154, 158))	('Slug', 'Gene', (154, 158))	('SOX2', 'Gene', '6657', (55, 59))	('knock down', 'Var', (139, 149))	('Eca-1', 'Gene', '50966', (111, 116))	('SOX2', 'Gene', '6657', (91, 95))	('SOX2', 'Gene', (91, 95))	('Slug', 'Gene', '6591', (47, 51))
156095	26370982	Our results showed that blockade of both STAT3 and HIF-1alpha caused a significant suppression of Slug expression (Figure 4B).	('STAT3', 'Gene', (41, 46))	('suppression', 'NegReg', (83, 94))	('HIF-1alpha', 'Gene', (51, 61))	('Slug', 'Gene', (98, 102))	('blockade', 'Var', (24, 32))	('HIF-1alpha', 'Gene', '3091', (51, 61))	('STAT3', 'Gene', '6774', (41, 46))	('Slug', 'Gene', '6591', (98, 102))
156100	26370982	Aberrant expression of SOX2 has been identified in several human tumors including lung, pancreatic, breast, ovarian, hepatocellular and head/neck.	('lung', 'Disease', (82, 86))	('human', 'Species', '9606', (59, 64))	('pancreatic', 'Disease', 'MESH:D010195', (88, 98))	('Aberrant', 'Var', (0, 8))	('head/neck', 'Disease', (136, 145))	('breast', 'Disease', (100, 106))	('hepatocellular', 'Disease', (117, 131))	('ovarian', 'Disease', (108, 115))	('pancreatic', 'Disease', (88, 98))	('tumors', 'Disease', (65, 71))	('SOX2', 'Gene', (23, 27))	('expression', 'MPA', (9, 19))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('identified', 'Reg', (37, 47))	('SOX2', 'Gene', '6657', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
156103	26370982	A few studies have revealed an association of SOX2 expression with a favorable prognosis in non-small cell lung cancer, gastric cancer and renal cell carcinoma.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (92, 118))	('renal cell carcinoma', 'Disease', (139, 159))	('SOX2', 'Gene', '6657', (46, 50))	('gastric cancer', 'Disease', (120, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (139, 159))	('association', 'Interaction', (31, 42))	('non-small cell lung cancer', 'Disease', (92, 118))	('SOX2', 'Gene', (46, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (139, 159))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('expression', 'Var', (51, 61))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))
156108	26370982	Previous studies have shown that over expressing SOX2 in ESCC cells promote proliferation and in vivo tumor growth.	('SOX2', 'Gene', (49, 53))	('SOX2', 'Gene', '6657', (49, 53))	('promote', 'PosReg', (68, 75))	('over', 'Var', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('proliferation', 'CPA', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
156114	26370982	The association of EMT with SOX2 was first reported by Lin et al., who showed that silencing of SOX2 in colorectal cancer cells induced the mesenchymal-to-epithelial transition (MET), a process reciprocal to EMT.	('SOX2', 'Gene', (96, 100))	('SOX2', 'Gene', '6657', (28, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('SOX2', 'Gene', (28, 32))	('SOX2', 'Gene', '6657', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('mesenchymal-to-epithelial transition', 'CPA', (140, 176))	('colorectal cancer', 'Disease', (104, 121))	('induced', 'Reg', (128, 135))	('silencing', 'Var', (83, 92))
156119	26370982	In addition, in SOX2-over expressing cells, the knockdown of Slug led to a significant suppression of cell invasion and EMT, indicating the role of Slug in promoting SOX2-induced metastasis, at least in part.	('Slug', 'Gene', (61, 65))	('suppression', 'NegReg', (87, 98))	('SOX2', 'Gene', '6657', (166, 170))	('SOX2', 'Gene', (166, 170))	('Slug', 'Gene', '6591', (61, 65))	('Slug', 'Gene', '6591', (148, 152))	('SOX2', 'Gene', '6657', (16, 20))	('Slug', 'Gene', (148, 152))	('SOX2', 'Gene', (16, 20))	('cell invasion', 'CPA', (102, 115))	('knockdown', 'Var', (48, 57))
156131	26370982	The resulting cells stably expressing SOX2 or control vectors were selected as Eca109/pCMV-SOX2 and Eca109pCMV, respectively.	('SOX2', 'Gene', (38, 42))	('Eca109pCMV', 'Var', (100, 110))	('SOX2', 'Gene', '6657', (91, 95))	('SOX2', 'Gene', (91, 95))	('SOX2', 'Gene', '6657', (38, 42))
156138	26370982	Equal numbers (1 x 105) of untransfected cells and cells stably transfected with pCMV-N-His-SOX2 or pCMV-N-His were plated in separate wells.	('pCMV-N-His', 'Chemical', '-', (81, 91))	('SOX2', 'Gene', (92, 96))	('pCMV-N-His', 'Var', (100, 110))	('SOX2', 'Gene', '6657', (92, 96))	('pCMV-N-His', 'Chemical', '-', (100, 110))
156233	26339635	AGS cells that were infected with DHA pretreated H. pylori showed a 3-fold reduction in IL-8 production and a decrease in COX-2 and inducible nitric oxide synthase (iNOS).	('H. pylori', 'Var', (49, 58))	('nitric oxide', 'Chemical', 'MESH:D009569', (142, 154))	('DHA', 'Chemical', 'MESH:D004281', (34, 37))	('inducible nitric oxide synthase', 'MPA', (132, 163))	('reduction', 'NegReg', (75, 84))	('decrease', 'NegReg', (110, 118))	('COX-2', 'Gene', (122, 127))	('H. pylori', 'Species', '210', (49, 58))	('COX-2', 'Gene', '29527', (122, 127))	('IL-8 production', 'MPA', (88, 103))
156239	26339635	In another study, DHA-fed Smad3 knockout mice had significantly higher levels of plasma IL-5, IL-13, and IL-9 (Th2-biasing cytokines) and cecal IgA compared with control, leading to the emerging concept that fish oil might enhance B cell function in vivo to aggravate an existing inflammatory response.	('IL-9', 'Gene', '16198', (105, 109))	('knockout', 'Var', (32, 40))	('IL-5', 'Gene', '16191', (88, 92))	('mice', 'Species', '10090', (41, 45))	('Smad3', 'Gene', (26, 31))	('higher', 'PosReg', (64, 70))	('cecal IgA', 'MPA', (138, 147))	('aggravate', 'PosReg', (258, 267))	('IL-13', 'Gene', (94, 99))	('inflammatory response', 'CPA', (280, 301))	('enhance', 'PosReg', (223, 230))	('levels', 'MPA', (71, 77))	('IL-9', 'Gene', (105, 109))	('Smad3', 'Gene', '17127', (26, 31))	('IL-13', 'Gene', '16163', (94, 99))	('DHA', 'Chemical', 'MESH:D004281', (18, 21))	('B cell function', 'CPA', (231, 246))	('IL-5', 'Gene', (88, 92))
156257	26339635	Anti-H. pylori effects of DHA are associated with changes in bacterial morphology, metabolism, and alteration of the composition of outer membrane proteins, which ultimately reduces the adhesion of bacteria and the burden of H. pylori-related inflammation.	('changes', 'Reg', (50, 57))	('rat', 'Species', '10116', (103, 106))	('metabolism', 'MPA', (83, 93))	('H. pylori', 'Species', '210', (225, 234))	('inflammation', 'Disease', 'MESH:D007249', (243, 255))	('adhesion', 'MPA', (186, 194))	('Anti-H.', 'Disease', (0, 7))	('composition of', 'MPA', (117, 131))	('bacterial morphology', 'CPA', (61, 81))	('alteration', 'Reg', (99, 109))	('inflammation', 'Disease', (243, 255))	('DHA', 'Var', (26, 29))	('H. pylori', 'Species', '210', (5, 14))	('DHA', 'Chemical', 'MESH:D004281', (26, 29))	('reduces', 'NegReg', (174, 181))
156285	26339635	showing that a diet of 1 : 1 ratio of EPA/DHA improves many oxidative stress parameters like superoxide dismutase (SOD) and glutathione peroxidase (GPx) in erythrocytes, plasma antioxidant capacity, and cardiovascular risk factors (glycated hemoglobin) relative to the other diets.	('oxidative stress parameters', 'MPA', (60, 87))	('superoxide', 'Chemical', 'MESH:D013481', (93, 103))	('oxidative stress', 'Phenotype', 'HP:0025464', (60, 76))	('rat', 'Species', '10116', (29, 32))	('DHA', 'Chemical', 'MESH:D004281', (42, 45))	('EPA', 'Chemical', 'MESH:D015118', (38, 41))	('glutathione', 'Chemical', 'MESH:D005978', (124, 135))	('plasma antioxidant capacity', 'MPA', (170, 197))	('glycated hemoglobin', 'Phenotype', 'HP:0040217', (232, 251))	('superoxide dismutase', 'MPA', (93, 113))	('improves', 'PosReg', (46, 54))	('EPA/DHA', 'Var', (38, 45))
156305	26339635	In addition, incorporation of n-3 PUFAs into the cell membrane alters the fluidity, structure, and/or function of lipid rafts or caveolae.	('incorporation', 'Var', (13, 26))	('function', 'MPA', (102, 110))	('lipid', 'Protein', (114, 119))	('fluidity', 'MPA', (74, 82))	('n-3', 'Gene', (30, 33))	('n-3', 'Gene', '18131', (30, 33))	('lipid', 'Chemical', 'MESH:D008055', (114, 119))	('rat', 'Species', '10116', (20, 23))	('alters', 'Reg', (63, 69))	('structure', 'MPA', (84, 93))	('3 PUFAs', 'Chemical', '-', (32, 39))
156319	26339635	H. pylori, a Gram-negative bacterial pathogen that infects approximately 50% of the world's population, provokes chronic gastric inflammation, which is considered to be a major risk factor for development of gastric and duodenal ulcers, mucosa-associated lymphoid tissue lymphoma (MALToma), and gastric cancer.	('gastric inflammation', 'Disease', 'MESH:D007249', (121, 141))	('H. pylori', 'Species', '210', (0, 9))	('provokes', 'PosReg', (104, 112))	('lymphoid tissue lymphoma', 'Disease', 'MESH:D008223', (255, 279))	('gastric cancer', 'Disease', 'MESH:D013274', (295, 309))	('lymphoma', 'Phenotype', 'HP:0002665', (271, 279))	('H. pylori', 'Var', (0, 9))	('chronic gastric inflammation', 'Phenotype', 'HP:0005231', (113, 141))	('ulcers', 'Disease', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('lymphoid tissue lymphoma', 'Disease', (255, 279))	('gastric cancer', 'Phenotype', 'HP:0012126', (295, 309))	('ulcers', 'Disease', 'MESH:D014456', (229, 235))	('gastric inflammation', 'Phenotype', 'HP:0005263', (121, 141))	('duodenal ulcers', 'Phenotype', 'HP:0002588', (220, 235))	('MALToma', 'Disease', 'None', (281, 288))	('duodenal ulcer', 'Phenotype', 'HP:0002588', (220, 234))	('MALToma', 'Disease', (281, 288))	('gastric cancer', 'Disease', (295, 309))	('gastric inflammation', 'Disease', (121, 141))
156325	26339635	However, this treatment can fail for several reasons, which include insufficient antibiotic concentration due to mutation-acquired resistance, limited antibiotic efficacy in a low gastric pH, and insufficient antibiotic concentration due to a high bacterial load.	('rat', 'Species', '10116', (227, 230))	('insufficient', 'Disease', (68, 80))	('antibiotic concentration', 'MPA', (209, 233))	('insufficient', 'Disease', 'MESH:D000309', (68, 80))	('insufficient', 'Disease', (196, 208))	('insufficient', 'Disease', 'MESH:D000309', (196, 208))	('resistance', 'Var', (131, 141))	('mutation-acquired', 'Reg', (113, 130))	('rat', 'Species', '10116', (99, 102))	('antibiotic efficacy', 'MPA', (151, 170))	('antibiotic concentration', 'MPA', (81, 105))
156336	26339635	They are an ample source of dietary fiber, B vitamin, and essential mineral such as magnesium, copper, manganese, calcium, and potassium as well as monounsaturated and polyunsaturated fats, which can potentially lower the LDL cholesterol.	('lower', 'NegReg', (212, 217))	('lower the LDL cholesterol', 'Phenotype', 'HP:0003563', (212, 237))	('copper', 'Chemical', 'MESH:D003300', (95, 101))	('fats', 'Gene', (184, 188))	('calcium', 'Chemical', 'MESH:D002118', (114, 121))	('monounsaturated', 'Var', (148, 163))	('magnesium', 'Chemical', 'MESH:D008274', (84, 93))	('fats', 'Gene', '118611', (184, 188))	('cholesterol', 'Chemical', 'MESH:D002784', (226, 237))	('potassium', 'Chemical', 'MESH:D011188', (127, 136))	('rat', 'Species', '10116', (158, 161))	('rat', 'Species', '10116', (178, 181))	('manganese', 'Chemical', 'MESH:D008345', (103, 112))	('essential', 'Chemical', '-', (58, 67))	('LDL cholesterol', 'Disease', (222, 237))
156363	26339635	Recent studies suggest that endogenous n-3 PUFAs delay the progression of stomach cancer and elevating n-3 PUFAs could be an important strategy to delay/prevent gastrointestinal cancer in high-risk patients.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (198, 206))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (161, 184))	('n-3', 'Gene', (39, 42))	('3 PUFAs', 'Chemical', '-', (41, 48))	('gastrointestinal cancer', 'Disease', (161, 184))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (161, 184))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('n-3', 'Gene', '18131', (103, 106))	('n-3', 'Gene', '18131', (39, 42))	('stomach cancer', 'Disease', (74, 88))	('delay', 'NegReg', (49, 54))	('endogenous', 'Var', (28, 38))	('progression', 'CPA', (59, 70))	('rat', 'Species', '10116', (137, 140))	('elevating', 'Var', (93, 102))	('stomach cancer', 'Disease', 'MESH:D013274', (74, 88))	('stomach cancer', 'Phenotype', 'HP:0012126', (74, 88))	('n-3', 'Gene', (103, 106))	('3 PUFAs', 'Chemical', '-', (105, 112))
156374	33375169	The differences in prognoses or progression patterns between T4b non-N4 and non-T4b N4 esophageal squamous cell carcinoma post chemoradiotherapy (CRT) is unclear.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('non-T4b N4', 'Var', (76, 86))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('T4b non-N4', 'Var', (61, 71))	('N', 'Chemical', 'MESH:D009584', (69, 70))
156382	33375169	We found no significant differences in prognoses or progression patterns among patients with T4b non-N4, non-T4b N4, and T4b N4 esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (128, 162))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('T4b N4', 'Var', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('T4b non-N4', 'Var', (93, 103))	('patients', 'Species', '9606', (79, 87))	('N', 'Chemical', 'MESH:D009584', (125, 126))	('non-T4b N4', 'Var', (105, 115))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('esophageal squamous cell carcinoma', 'Disease', (128, 162))
156396	33375169	The T/N factor groups were T4bN0-3 (28 patients, 42.4%), T1-4aN4 (24 patients, 36.4%), and T4bN4 (14 patients, 21.2%).	('patients', 'Species', '9606', (101, 109))	('T4bN4', 'Var', (91, 96))	('patients', 'Species', '9606', (39, 47))	('T1-4aN4', 'Var', (57, 64))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('T4bN0-3', 'Var', (27, 34))	('patients', 'Species', '9606', (69, 77))	('N', 'Chemical', 'MESH:D009584', (94, 95))
156407	33375169	In the T1-4aN4 group, progression or recurrence occurred inside the irradiated area with/without out-of-field recurrence (eight patients, 33%), outside the irradiated area with/without in-field recurrence (14 patients, 58%), and in both areas (four patients, 17%).	('recurrence', 'CPA', (37, 47))	('progression', 'CPA', (22, 33))	('N', 'Chemical', 'MESH:D009584', (12, 13))	('patients', 'Species', '9606', (249, 257))	('T1-4aN4', 'Var', (7, 14))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (128, 136))
156408	33375169	In the T4bN4 group, progression or recurrence occurred inside the irradiated area with/without out-of-field recurrence (six patients, 43%) and outside the irradiated area with/without in-field recurrence (six patients, 43%).	('T4bN4', 'Var', (7, 12))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('patients', 'Species', '9606', (209, 217))	('progression', 'CPA', (20, 31))	('recurrence', 'CPA', (35, 45))	('patients', 'Species', '9606', (124, 132))
156420	33375169	However, we did not manage to detect differences among the T4bN0-3, T1-4aN4, and T4bN4 groups in terms of their progression pattern, PFS, and OS.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('T4bN4', 'Var', (81, 86))	('T4bN0-3', 'Var', (59, 66))	('N', 'Chemical', 'MESH:D009584', (62, 63))
156424	33375169	While stage IVa esophageal cancer includes locally advanced T4b; lymph node spread tendency N4; and T4bnon-N4, non-T4b N4, and T4b N4 disease, to our knowledge, no previous studies have examined their differences in outcomes or progression patterns.	('T4bnon-N4', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('stage IVa esophageal cancer', 'Disease', (6, 33))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('lymph', 'Disease', (65, 70))	('stage IVa esophageal cancer', 'Disease', 'MESH:D004938', (6, 33))
156425	33375169	Our results indicated that the T4bN0-3, T1-4aN4, and T4bN4 groups had similar outcomes in terms of progression pattern, PFS, and OS.	('T1-4aN4', 'Var', (40, 47))	('PFS', 'CPA', (120, 123))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('T4bN0-3', 'Var', (31, 38))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('T4bN4', 'Var', (53, 58))
156428	33375169	Thus, stage IVa esophageal cancer with either T4b or N4 requires both sufficient radiotherapy as local treatment and chemotherapy as a systemic treatment because progression can occur in and out of the irradiated field, regardless of T/N factors.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('N', 'Chemical', 'MESH:D009584', (236, 237))	('men', 'Species', '9606', (149, 152))	('men', 'Species', '9606', (108, 111))	('stage IVa esophageal cancer', 'Disease', (6, 33))	('T4b', 'Var', (46, 49))	('stage IVa esophageal cancer', 'Disease', 'MESH:D004938', (6, 33))
156445	33375169	Although ENI may reduce regional nodal failure, these recent studies suggest that prophylactically expanding the irradiation field may not be prudent to reduce toxicities, especially hematological, and complete planned definitive CRT.	('toxicities', 'Disease', 'MESH:D064420', (160, 170))	('reduce', 'NegReg', (17, 23))	('regional nodal failure', 'Disease', 'MESH:D006333', (24, 46))	('regional nodal failure', 'Disease', (24, 46))	('ENI', 'Chemical', '-', (9, 12))	('toxicities', 'Disease', (160, 170))	('ENI', 'Var', (9, 12))
156446	33375169	However, this study did not manage to detect differences among the T4bN0-3, T1-4aN4, and T4bN4 groups in terms of their progression pattern, PFS, and OS.	('T4bN0-3', 'Var', (67, 74))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('T4bN4', 'Var', (89, 94))	('N', 'Chemical', 'MESH:D009584', (70, 71))
156562	33194702	Because inherited predisposition, such as a mutation in one allele of a tumor-suppressor gene, theoretically exists in every cell, against such a genetic background, familial cancers are likely to develop at multiple sites, whereas most sporadic cancers develop as a solitary lesion.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('familial cancers', 'Disease', (166, 182))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('cancers', 'Disease', (246, 253))	('tumor', 'Disease', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('mutation in', 'Var', (44, 55))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancers', 'Disease', (175, 182))	('familial cancers', 'Disease', 'MESH:D009369', (166, 182))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
156574	33194702	A single-nucleotide polymorphism in PLCE-1, for instance, has been consistently found to be associated with the risk of ESCC, GCA, and head and neck cancer in the Chinese population.	('head and neck cancer', 'Disease', 'MESH:D006258', (135, 155))	('ESCC', 'Disease', (120, 124))	('PLCE-1', 'Gene', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('head and neck cancer', 'Phenotype', 'HP:0012288', (135, 155))	('single-nucleotide polymorphism', 'Var', (2, 32))	('PLCE-1', 'Gene', '51196', (36, 42))	('GCA', 'Disease', (126, 129))	('associated', 'Reg', (92, 102))
156575	33194702	With head and neck cancer, effects of risk alleles of PLCE-1 were associated with cancers of the oral cavity, hypopharynx, or larynx but not with cancers of the oropharynx.	('alleles', 'Var', (43, 50))	('PLCE-1', 'Gene', '51196', (54, 60))	('cancers', 'Disease', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('head and neck cancer', 'Disease', 'MESH:D006258', (5, 25))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('hypopharynx', 'Disease', (110, 121))	('PLCE-1', 'Gene', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancers of the oropharynx', 'Phenotype', 'HP:0100638', (146, 171))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('head and neck cancer', 'Phenotype', 'HP:0012288', (5, 25))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('associated', 'Interaction', (66, 76))	('larynx', 'Disease', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
156626	32049826	The data to be collected will include the following: author, year of publication, number needed to treat, race, model, algorithm, image source, diagnostic gold standard, sensitivity (SEN), specificity (SPE), true positive (TP) rate, false positive (FP) rate, false negative (FN) rate, true negative (TN) rate, nodule segmentation, feature extraction and selection, nodule classification, and AI for diagnosing thoracic disease.	('thoracic disease', 'Disease', (410, 426))	('thoracic disease', 'Disease', 'MESH:D013896', (410, 426))	('false', 'Var', (259, 264))	('true', 'MPA', (285, 289))
156682	31486278	The median OS time was 22.2 months (95% CI, 18.5-25.8 months) in the tumor length <= 6 cm group and 13.4 months (95% CI, 12.1-14.6 months) in the tumor length > 6 cm group (chi 2 = 50.654, P < .001, HR = 1.85, 95% CI, 1.558-2.198, Figure 1A).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (146, 151))	('<= 6', 'Var', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
156691	31486278	The 1-, 3-, and 5-year PFS rates were 59.2%, 33.9% and 25.4%, respectively, in the tumor diameter <= 3.5 cm group and 38.3%, 14.7%, and 11.4%, respectively, in the tumor diameter > 3.5 cm group.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('PFS', 'CPA', (23, 26))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('<= 3.5', 'Var', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
156731	31308693	Secondly, inhibition of LSD1 by tranylcypromine (TCP) or shRNA could decrease the expressions of related proteins in Notch and PI3K/Akt/mTOR signaling pathways in ESCC cells.	('tranylcypromine', 'Chemical', 'MESH:D014191', (32, 47))	('LSD1', 'Gene', '23028', (24, 28))	('TCP', 'Chemical', 'MESH:D014191', (49, 52))	('Akt', 'Gene', (132, 135))	('mTOR', 'Gene', '2475', (136, 140))	('expressions of related proteins', 'MPA', (82, 113))	('decrease', 'NegReg', (69, 77))	('Akt', 'Gene', '207', (132, 135))	('mTOR', 'Gene', (136, 140))	('inhibition', 'Var', (10, 20))	('shRNA', 'Gene', (57, 62))	('LSD1', 'Gene', (24, 28))
156739	31308693	Epigenetic changes, such as abnormal DNA methylation and modification of histone, were reported to be associated with the development of various cancers.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('modification', 'Var', (57, 69))	('associated', 'Reg', (102, 112))	('DNA methylation', 'MPA', (37, 52))	('abnormal', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('histone', 'Protein', (73, 80))
156740	31308693	Lysine-specific demethylase 1 (LSD1, KDM1A), the first identified histone demethylase, could specifically catalyze the demethylation of monomethyl and dimethyl H3K4 (H3K4me1/2) and H3K9 (H3K9me1/2).	('monomethyl', 'Var', (136, 146))	('KDM1A', 'Gene', '23028', (37, 42))	('LSD1', 'Gene', '23028', (31, 35))	('LSD1', 'Gene', (31, 35))	('H3K9', 'Protein', (181, 185))	('KDM1A', 'Gene', (37, 42))	('Lysine-specific demethylase 1', 'Gene', '23028', (0, 29))	('demethylation', 'MPA', (119, 132))	('Lysine-specific demethylase 1', 'Gene', (0, 29))
156745	31308693	It is reported that Notch pathway interacts with other signaling pathways such as PI3K/Akt/mTOR, Wnt and Ras/MAPK to regulate tumorigenesis in many types of cancers, and activated PI3K (phosphoinositide 3-kinase) regulates cell survival and proliferation by stimulating its downstream factors such as Akt and mTOR.	('Akt', 'Gene', (87, 90))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('mTOR', 'Gene', (91, 95))	('regulate', 'Reg', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Akt', 'Gene', '207', (87, 90))	('phosphoinositide 3-kinase', 'Gene', '5293', (186, 211))	('activated PI3K', 'Var', (170, 184))	('mTOR', 'Gene', '2475', (91, 95))	('phosphoinositide 3-kinase', 'Gene', (186, 211))	('mTOR', 'Gene', (309, 313))	('cell survival', 'CPA', (223, 236))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('stimulating', 'PosReg', (258, 269))	('mTOR', 'Gene', '2475', (309, 313))	('tumor', 'Disease', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Akt', 'Gene', (301, 304))	('regulates', 'Reg', (213, 222))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Akt', 'Gene', '207', (301, 304))
156750	31308693	Primary antibodies recognizing LSD1 (ab17721) and Hes1 (ab71559) were obtained from Abcam (UK), DTX1 (GTX112367) were obtained from GeneTex (USA), and H3 (9728S), Notch 1 (3608S), Notch 3 (3889S), H3K4me2 (3889S), PI3K (4228S), Rictor (9476S), p-Akt (Ser473) (4060S), Akt (2920S), p-mTOR (Ser2448) (5536S), p-mTOR (Ser2481) (2974S), mTOR (2983S), Raptor (2280S), p-p70S6K (Thr389) (9206S) and GAPDH (5174S) as well as the secondary antibodies were obtained from Cell Signaling Technology (USA).	('Akt', 'Gene', '207', (246, 249))	('mTOR', 'Gene', '2475', (283, 287))	('GAPDH', 'Gene', (393, 398))	('p70S6K', 'Gene', (365, 371))	('DTX1', 'Gene', '1840', (96, 100))	('Rictor', 'Gene', (228, 234))	('9206S', 'Var', (382, 387))	('Hes1', 'Gene', '3280', (50, 54))	('LSD1', 'Gene', '23028', (31, 35))	('LSD1', 'Gene', (31, 35))	('Akt', 'Gene', (268, 271))	('Notch 1', 'Gene', '4851', (163, 170))	('Akt', 'Gene', '207', (268, 271))	('Hes1', 'Gene', (50, 54))	('DTX1', 'Gene', (96, 100))	('mTOR', 'Gene', (309, 313))	('5536S', 'Var', (299, 304))	('mTOR', 'Gene', (333, 337))	('p70S6K', 'Gene', '6198', (365, 371))	('mTOR', 'Gene', '2475', (309, 313))	('Rictor', 'Gene', '253260', (228, 234))	('Notch 1', 'Gene', (163, 170))	('Akt', 'Gene', (246, 249))	('GAPDH', 'Gene', '2597', (393, 398))	('mTOR', 'Gene', (283, 287))	('Ser473', 'Chemical', '-', (251, 257))	('mTOR', 'Gene', '2475', (333, 337))
156781	31308693	After the expression of LSD1 in ESCC cells was knocked down, the expressions of Notch3, Notch1, DTX1 and Hes1 also decreased at ratios of 68.2%, 38.2%, 54.9% and 39.6%, respectively in ECa109 cells, and 53.7%, 41.8%, 53.3% and 30.2%, respectively in EC9706 cells (P<0.05).	('DTX1', 'Gene', (96, 100))	('LSD1', 'Gene', '23028', (24, 28))	('Hes1', 'Gene', (105, 109))	('Hes1', 'Gene', '3280', (105, 109))	('decreased', 'NegReg', (115, 124))	('knocked', 'Var', (47, 54))	('Notch1', 'Gene', (88, 94))	('expressions', 'MPA', (65, 76))	('Notch3', 'Gene', '4854', (80, 86))	('Notch3', 'Gene', (80, 86))	('EC9706', 'CellLine', 'CVCL:E307', (250, 256))	('Notch1', 'Gene', '4851', (88, 94))	('DTX1', 'Gene', '1840', (96, 100))	('LSD1', 'Gene', (24, 28))
156782	31308693	These findings demonstrate that inhibition of LSD1 by either TCP or shRNA decreased the expressions of related proteins in the Notch signaling pathway, suggesting that LSD1 might promote activation of the Notch signaling pathway in ESCC cells.	('TCP', 'Chemical', 'MESH:D014191', (61, 64))	('inhibition', 'Var', (32, 42))	('LSD1', 'Gene', (168, 172))	('LSD1', 'Gene', '23028', (168, 172))	('LSD1', 'Gene', (46, 50))	('Notch signaling pathway', 'Pathway', (127, 150))	('expressions of related proteins', 'MPA', (88, 119))	('LSD1', 'Gene', '23028', (46, 50))	('promote activation', 'PosReg', (179, 197))	('decreased', 'NegReg', (74, 83))	('Notch signaling pathway', 'Pathway', (205, 228))
156784	31308693	Moreover, downregulation of LSD1 by shRNA had a similar effect with TCP: the expressions of PI3K, p-Akt (Ser473), p-mTOR (Ser2448), p-mTOR (Ser2481) and Rictor decreased in the LSD1 shRNA group (P<0.05) compared with the control shRNA group, atratios of 80.5%, 41.4%, 30.4%, 28.9% and 44.7% in ECa109 cells and 55.9%, 54.1%, 24.1%, 33.7% and 41.3% in EC9706 cells, respectively (Figure 4B; P<0.05).	('decreased', 'NegReg', (160, 169))	('mTOR', 'Gene', '2475', (116, 120))	('Akt', 'Gene', (100, 103))	('expressions', 'MPA', (77, 88))	('Rictor', 'Gene', '253260', (153, 159))	('Ser473', 'Var', (105, 111))	('Akt', 'Gene', '207', (100, 103))	('Ser473', 'Chemical', '-', (105, 111))	('LSD1', 'Gene', (28, 32))	('LSD1', 'Gene', '23028', (28, 32))	('mTOR', 'Gene', (134, 138))	('TCP', 'Chemical', 'MESH:D014191', (68, 71))	('PI3K', 'Gene', (92, 96))	('Rictor', 'Gene', (153, 159))	('EC9706', 'CellLine', 'CVCL:E307', (351, 357))	('LSD1', 'Gene', (177, 181))	('downregulation', 'NegReg', (10, 24))	('mTOR', 'Gene', (116, 120))	('LSD1', 'Gene', '23028', (177, 181))	('mTOR', 'Gene', '2475', (134, 138))
156790	31308693	The unbalance of histone methylation and demethylation has been shown to be associated with the tumorigenesis of many cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('unbalance', 'Var', (4, 13))	('tumor', 'Disease', (96, 101))	('demethylation', 'Var', (41, 54))	('histone', 'Protein', (17, 24))	('associated', 'Reg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
156792	31308693	The TCP-based LSD1 inhibitors have shown significant therapeutic effects in cancers and some of these have been tested in clinical trials, such as ORY1001 and GSK2879552, which indicated the potential of LSD1 as a therapeutic target for cancers.	('LSD1', 'Gene', (14, 18))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('TCP', 'Chemical', 'MESH:D014191', (4, 7))	('LSD1', 'Gene', '23028', (14, 18))	('cancers', 'Disease', (76, 83))	('ORY1001', 'Chemical', '-', (147, 154))	('GSK2879552', 'Chemical', 'MESH:C000602008', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('inhibitors', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('LSD1', 'Gene', (204, 208))	('cancers', 'Disease', (237, 244))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('LSD1', 'Gene', '23028', (204, 208))	('therapeutic effects', 'CPA', (53, 72))
156797	31308693	In this study, we showed that inhibition of LSD1 decreased the expressions of related protein, not only in the Notch pathway (such as Notch3, Notch1, DTX1 and Hes1), but also in the PI3K/Akt/mTOR pathway such as PI3K, p-Akt (Ser473), p-mTOR (Ser2448), p-mTOR (Ser2481) and Rictor in ESCC cells, which indicated that LSD1 might have positively regulating effects on the Notch and PI3K/Akt/mTOR signaling pathways in ESCC.	('Hes1', 'Gene', (159, 163))	('Notch3', 'Gene', '4854', (134, 140))	('Notch3', 'Gene', (134, 140))	('Rictor', 'Gene', '253260', (273, 279))	('expressions', 'MPA', (63, 74))	('mTOR', 'Gene', '2475', (236, 240))	('Akt', 'Gene', (220, 223))	('mTOR', 'Gene', (191, 195))	('Akt', 'Gene', (187, 190))	('LSD1', 'Gene', '23028', (316, 320))	('LSD1', 'Gene', (316, 320))	('Ser473', 'Chemical', '-', (225, 231))	('decreased', 'NegReg', (49, 58))	('Akt', 'Gene', '207', (220, 223))	('Akt', 'Gene', (384, 387))	('LSD1', 'Gene', (44, 48))	('Akt', 'Gene', '207', (187, 190))	('LSD1', 'Gene', '23028', (44, 48))	('Notch pathway', 'Pathway', (111, 124))	('mTOR', 'Gene', (254, 258))	('Akt', 'Gene', '207', (384, 387))	('mTOR', 'Gene', '2475', (191, 195))	('Rictor', 'Gene', (273, 279))	('Notch1', 'Gene', (142, 148))	('Notch1', 'Gene', '4851', (142, 148))	('DTX1', 'Gene', '1840', (150, 154))	('mTOR', 'Gene', (388, 392))	('mTOR', 'Gene', '2475', (254, 258))	('PI3K', 'Var', (212, 216))	('inhibition', 'Var', (30, 40))	('Hes1', 'Gene', '3280', (159, 163))	('mTOR', 'Gene', (236, 240))	('mTOR', 'Gene', '2475', (388, 392))	('DTX1', 'Gene', (150, 154))
156865	31099496	Patients with high CEs concentration had significantly worse OS (P = 0.01) (Figure 4A) and PFS (P = 0.03) (Figure 4B) compared with patients with low CEs concentration.	('CEs', 'Chemical', '-', (150, 153))	('CEs concentration', 'MPA', (19, 36))	('worse', 'NegReg', (55, 60))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (61, 63))	('CEs', 'Chemical', '-', (19, 22))	('PFS', 'MPA', (91, 94))	('patients', 'Species', '9606', (132, 140))
156870	31099496	In the wound scratching assay, it was observed that CEs increased cellular motility of ESCC cells.	('CEs', 'Chemical', '-', (52, 55))	('CEs', 'Var', (52, 55))	('cellular motility of', 'CPA', (66, 86))	('increased', 'PosReg', (56, 65))
156872	31099496	When studied in a transwell migration assay, cells treated with CEs also demonstrated increased invasion compared with control cells (Figure 5A).	('invasion', 'CPA', (96, 104))	('CEs', 'Var', (64, 67))	('increased', 'PosReg', (86, 95))	('CEs', 'Chemical', '-', (64, 67))
156882	31099496	The OS and PFS were significantly shorter in the presence of high CEs.	('high CEs', 'Var', (61, 69))	('shorter', 'NegReg', (34, 41))	('CEs', 'Chemical', '-', (66, 69))	('OS', 'Chemical', '-', (4, 6))
156903	30602219	The cumulative EVB incidence was significantly higher in patients with ASPS >=2.60 than in those with ASPS <2.60 (p<0.001).	('patients', 'Species', '9606', (57, 65))	('higher', 'PosReg', (47, 53))	('EVB', 'Disease', (15, 18))	('EVB', 'Phenotype', 'HP:0002040', (15, 18))	('ASPS', 'Chemical', '-', (71, 75))	('ASPS', 'Chemical', '-', (102, 106))	('EVB', 'Chemical', '-', (15, 18))	('ASPS >=2.60', 'Var', (71, 82))
156906	30602219	At an ASPS of 4.50 (sensitivity, 66.7%; specificity, 70.6%; AUROC, 0.691), the cumulative EVB incidence was significantly higher in patients with a high ASPS than in those with a low ASPS (p=0.045).	('ASPS', 'Chemical', '-', (6, 10))	('ASPS', 'Chemical', '-', (183, 187))	('EVB', 'Phenotype', 'HP:0002040', (90, 93))	('higher', 'PosReg', (122, 128))	('ASPS', 'Chemical', '-', (153, 157))	('EVB', 'Chemical', '-', (90, 93))	('high', 'Var', (148, 152))	('patients', 'Species', '9606', (132, 140))	('EVB', 'Disease', (90, 93))
156909	30602219	Prophylactic management should be considered for patients with HEVs and ASPS >=4.50.	('EVs', 'Phenotype', 'HP:0002040', (64, 67))	('ASPS', 'Chemical', '-', (72, 76))	('patients', 'Species', '9606', (49, 57))	('men', 'Species', '9606', (19, 22))	('ASPS >=4.50', 'Var', (72, 83))	('HEV', 'Chemical', '-', (63, 66))	('HEVs', 'Disease', (63, 67))
156917	30602219	Thus, based on the current European (Baveno VI) and American (American Association for the Study of Liver Diseases) recommendations, patients with liver stiffness (LS) <20 kPa and platelet count >150,000/ mm3 were suggested to avoid endoscopy by undergoing annual surveillance of platelet count and EVs via transient elastography (TE).	('liver stiffness', 'Disease', (147, 162))	('liver stiffness', 'Disease', 'MESH:D017093', (147, 162))	('men', 'Species', '9606', (121, 124))	('EVs', 'Phenotype', 'HP:0002040', (299, 302))	('LS', 'Chemical', '-', (164, 166))	('patients', 'Species', '9606', (133, 141))	('TE', 'Chemical', '-', (331, 333))	('Liver Diseases', 'Phenotype', 'HP:0001392', (100, 114))	('Liver Diseases', 'Disease', 'MESH:D008107', (100, 114))	('Liver Diseases', 'Disease', (100, 114))	('<20', 'Var', (168, 171))
156971	30602219	The cumulative EVB incidence in patients with an ASPS >=2.60 was significantly higher than that in those with an ASPS <2.60 (p<0.001) (Fig.	('patients', 'Species', '9606', (32, 40))	('ASPS', 'Chemical', '-', (49, 53))	('EVB', 'Disease', (15, 18))	('ASPS >=2.60', 'Var', (49, 60))	('ASPS', 'Chemical', '-', (113, 117))	('EVB', 'Phenotype', 'HP:0002040', (15, 18))	('higher', 'PosReg', (79, 85))	('EVB', 'Chemical', '-', (15, 18))
156994	30602219	Most studies have shown that patients with an LS of 20 to 21kPa are at high risk of developing EVB.	('LS', 'Chemical', '-', (46, 48))	('patients', 'Species', '9606', (29, 37))	('EVB', 'Disease', (95, 98))	('EVB', 'Phenotype', 'HP:0002040', (95, 98))	('EVB', 'Chemical', '-', (95, 98))	('LS of 20 to 21kPa', 'Var', (46, 63))
157003	30602219	Another problem is that patients in our study population with an ASPS <4.50 still had many HEVs compared with patients with ASPS >=4.50 (50.9% vs 78.6%).	('ASPS', 'Chemical', '-', (65, 69))	('ASPS', 'Chemical', '-', (124, 128))	('HEV', 'Chemical', '-', (91, 94))	('HEVs', 'Disease', (91, 95))	('ASPS <4.50', 'Var', (65, 75))	('patients', 'Species', '9606', (24, 32))	('EVs', 'Phenotype', 'HP:0002040', (92, 95))	('patients', 'Species', '9606', (110, 118))
157019	30115035	PIK3CA mutations were significantly associated with APC alterations (p = 0.0007) and BRAF mutations (p = 0.0090).	('mutations', 'Var', (90, 99))	('BRAF', 'Gene', (85, 89))	('PIK3CA', 'Gene', (0, 6))	('BRAF', 'Gene', '673', (85, 89))	('APC', 'Disease', 'MESH:D011125', (52, 55))	('associated', 'Reg', (36, 46))	('APC', 'Disease', (52, 55))	('mutations', 'Var', (7, 16))
157020	30115035	Our study provided profiles of cancer-related genes in Japanese patients with esophageal cancer by next-generation sequencing using surgically resected formalin-fixed, paraffin-embedded tissue, and identified the PIK3CA mutation as a favorable prognosis biomarker.	('formalin', 'Chemical', 'MESH:D005557', (152, 160))	('PIK3CA', 'Gene', (213, 219))	('patients', 'Species', '9606', (64, 72))	('paraffin', 'Chemical', 'MESH:D010232', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('mutation', 'Var', (220, 228))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
157031	30115035	The goal of this study was to evaluate the profiles of genetic alterations in esophageal cancer and to assess the effect of molecular characteristics on clinical outcome.	('genetic alterations', 'Var', (55, 74))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
157032	30115035	To this end, we extensively analyzed gene expression and mutations obtained by automated quantitative fluorescent immunohistochemistry (AQUA) and MPS using archived FFPE samples from 135 esophageal cancer patients who underwent surgical resection, and correlated these results with the clinicopathological features, such as smoking status and survival outcomes.	('patients', 'Species', '9606', (205, 213))	('MPS', 'Disease', (146, 149))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('esophageal cancer', 'Disease', (187, 204))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('MPS', 'Disease', 'MESH:D009084', (146, 149))
157045	30115035	On the other hand, 188 nonsynonymous mutations were detected in 38 UDG pretreated samples with DeltaCt of 1.55 or greater (Fig.	('nonsynonymous mutations', 'Var', (23, 46))	('UDG', 'Gene', (67, 70))	('UDG', 'Gene', '7374', (67, 70))
157046	30115035	Amplicon-based MPS was performed on MiSeq sequencer (Illumina) using the TruSeq  Amplicon Cancer Panel (Illumina), which was designed to detect somatic mutations in 48 cancer-related genes, according to the manufacturer's instructions.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('MPS', 'Disease', 'MESH:D009084', (15, 18))	('mutations', 'Var', (152, 161))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('MPS', 'Disease', (15, 18))	('Cancer', 'Disease', (90, 96))	('cancer', 'Disease', (168, 174))	('Cancer', 'Disease', 'MESH:D009369', (90, 96))
157062	30115035	Somatic mutational analysis by TSACP identified 290 gene alterations, including single nucleotide variants, deletions, and insertions.	('deletions', 'Var', (108, 117))	('TSACP', 'Chemical', '-', (31, 36))	('insertions', 'Var', (123, 133))	('single nucleotide variants', 'Var', (80, 106))
157064	30115035	Most of these genes exhibited missense mutations, followed by nonsense mutations and frameshift mutations, suggesting their tumor suppressor roles.	('nonsense mutations', 'Var', (62, 80))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('missense mutations', 'Var', (30, 48))	('tumor', 'Disease', (124, 129))	('exhibited', 'Reg', (20, 29))	('frameshift mutations', 'Var', (85, 105))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
157065	30115035	Of all gene alterations in PIK3CA (n = 17), gene amplification was detected in three patients (2.4%), and PIK3CA mutations occurred in 14 patients (11.1%).	('PIK3CA', 'Gene', (27, 33))	('gene alterations', 'Var', (7, 23))	('patients', 'Species', '9606', (85, 93))	('detected', 'Reg', (67, 75))	('gene amplification', 'MPA', (44, 62))	('patients', 'Species', '9606', (138, 146))
157066	30115035	Of all PIK3CA alterations, 58.8% were identified in three known hotspots, E542K/E542V (17.6%) and E545K (23.5%) in exon 9, and H1047R/H1047L (23.5%) in exon 20.	('E545K', 'Mutation', 'rs104886003', (98, 103))	('E545K', 'Var', (98, 103))	('H1047R', 'SUBSTITUTION', 'None', (127, 133))	('E542K', 'Var', (74, 79))	('PIK3CA', 'Gene', (7, 13))	('E542K', 'SUBSTITUTION', 'None', (74, 79))	('E542V', 'Mutation', 'rs1057519927', (80, 85))	('H1047L', 'SUBSTITUTION', 'None', (134, 140))	('H1047R', 'Var', (127, 133))	('H1047L', 'Var', (134, 140))
157067	30115035	Both E542V missense mutations and the frameshift deletion in H554 were detected in one case.	('H554', 'Gene', (61, 65))	('detected', 'Reg', (71, 79))	('frameshift deletion', 'Var', (38, 57))	('E542V missense mutations', 'Var', (5, 29))	('E542V', 'Mutation', 'rs1057519927', (5, 10))
157068	30115035	There were 17 APC mutations in 13 patients (10.3%), including the nonsense mutation alone (n = 8), missense mutation alone (n = 1), both frameshift deletion and missense mutation (n = 1), and both frameshift deletion and nonsense mutation (n = 1) (Fig.	('frameshift deletion', 'Var', (197, 216))	('APC', 'Disease', 'MESH:D011125', (14, 17))	('frameshift deletion', 'Var', (137, 156))	('patients', 'Species', '9606', (34, 42))	('APC', 'Disease', (14, 17))	('missense mutation', 'Var', (99, 116))	('nonsense mutation', 'Var', (221, 238))	('missense mutation', 'Var', (161, 178))
157076	30115035	Male gender and the p53 mutation were marginally statistically associated with poor OS in all patients (hazard ratio (HR) 2.36; p = 0.096, HR 1.72; p = 0.059, respectively).	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('patients', 'Species', '9606', (94, 102))	('associated', 'Reg', (63, 73))	('poor OS', 'Disease', (79, 86))	('OS', 'Chemical', '-', (84, 86))	('mutation', 'Var', (24, 32))
157077	30115035	However, patients with PIK3CA mutations had better OS (median OS 2902 days, 95% CI 1264 days-not reached) than patients with wild-type PIK3CA (median OS 1129 days, 95% CI 938-1622 days; p = 0.077 (Table 2, Fig.	('patients', 'Species', '9606', (9, 17))	('better', 'PosReg', (44, 50))	('PIK3CA', 'Gene', (23, 29))	('OS', 'Chemical', '-', (62, 64))	('OS', 'Chemical', '-', (51, 53))	('mutations', 'Var', (30, 39))	('OS', 'Chemical', '-', (150, 152))	('patients', 'Species', '9606', (111, 119))
157080	30115035	Furthermore, the HR for patients with the PIK3CA mutation was 0.34 (95% CI: 0.12-0.96) compared with patients with the wild-type PIK3CA (p = 0.042) (Table 2).	('PIK3CA', 'Gene', (42, 48))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (101, 109))	('mutation', 'Var', (49, 57))
157081	30115035	However, the prognostic value of PIK3CA amplification was not statistically significant (HR 2.66; 95% CI 0.64-11.05; p = 0.177), and this probably occurred because of the limited number of patients with the PIK3CA amplification (n = 3).	('patients', 'Species', '9606', (189, 197))	('PIK3CA', 'Gene', (33, 39))	('amplification', 'Var', (40, 53))	('PIK3CA', 'Gene', (207, 213))
157082	30115035	We then evaluated the clinicopathological and molecular characteristics of PIK3CA mutations in esophageal cancer.	('PIK3CA', 'Gene', (75, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('mutations', 'Var', (82, 91))	('esophageal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
157083	30115035	APC gene alterations occurred more frequently in the PIK3CA mutation than in the wild-type (p = 0.0007).	('mutation', 'Var', (60, 68))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('alterations', 'Var', (9, 20))	('APC', 'Disease', (0, 3))	('PIK3CA', 'Gene', (53, 59))
157084	30115035	BRAF mutations also statistically significantly occurred with the PIK3CA mutations (p = 0.0090).	('occurred', 'Reg', (48, 56))	('PIK3CA', 'Gene', (66, 72))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (73, 82))
157086	30115035	Amplicon-based MPS identified mutations in TP53, PIK3CA, APC, ERBB4, and FBXW7 as the most frequent gene alterations.	('MPS', 'Disease', 'MESH:D009084', (15, 18))	('APC', 'Disease', 'MESH:D011125', (57, 60))	('APC', 'Disease', (57, 60))	('ERBB4', 'Gene', '2066', (62, 67))	('MPS', 'Disease', (15, 18))	('FBXW7', 'Gene', '55294', (73, 78))	('PIK3CA', 'Gene', (49, 55))	('mutations', 'Var', (30, 39))	('ERBB4', 'Gene', (62, 67))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('FBXW7', 'Gene', (73, 78))
157087	30115035	Importantly, patients with the PIK3CA mutations had significantly better survival than those with the wild-type PIK3CA.	('patients', 'Species', '9606', (13, 21))	('better', 'PosReg', (66, 72))	('PIK3CA', 'Gene', (31, 37))	('survival', 'CPA', (73, 81))	('mutations', 'Var', (38, 47))
157088	30115035	To the best of our knowledge, the present report is the first to investigate the prognostic significance of PIK3CA mutations based on NGS data in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutations', 'Var', (115, 124))	('esophageal cancer', 'Disease', (146, 163))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('PIK3CA', 'Gene', (108, 114))
157092	30115035	PIK3CA, which encodes the p110a catalytic subunit of the phosphoinositide 3-kinase (PI3K), is an oncogene in various cancers, and its mutation or amplification and subsequent activation of the PI3K/AKT signaling pathway regulates cell proliferation, growth, survival, apoptosis, and glucose metabolism.	('apoptosis', 'CPA', (268, 277))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('AKT', 'Gene', (198, 201))	('amplification', 'Var', (146, 159))	('cell proliferation', 'CPA', (230, 248))	('activation', 'PosReg', (175, 185))	('phosphoinositide 3-kinase', 'Gene', '5290', (57, 82))	('glucose metabolism', 'Disease', (283, 301))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('survival', 'CPA', (258, 266))	('AKT', 'Gene', '207', (198, 201))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('phosphoinositide 3-kinase', 'Gene', (57, 82))	('cancers', 'Disease', (117, 124))	('mutation', 'Var', (134, 142))	('regulates', 'Reg', (220, 229))	('PIK3CA', 'Gene', (0, 6))	('growth', 'CPA', (250, 256))	('glucose metabolism', 'Disease', 'MESH:D044882', (283, 301))
157093	30115035	In our study, 13.5% of cases were identified as having a PIK3CA mutation or amplification, all of which presented squamous cell carcinoma histology.	('mutation', 'Var', (64, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 137))	('squamous cell carcinoma', 'Disease', (114, 137))	('PIK3CA', 'Gene', (57, 63))	('amplification', 'Var', (76, 89))
157094	30115035	Hotspot mutations of PIK3CA in exon 9 and exon 20 are known to be oncogenic in various tumor types, including esophageal, colorectal, brain, and gastric cancers.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('esophageal', 'Disease', 'MESH:D004941', (110, 120))	('colorectal', 'Disease', 'MESH:D015179', (122, 132))	('PIK3CA', 'Gene', (21, 27))	('tumor', 'Disease', (87, 92))	('mutations', 'Var', (8, 17))	('colorectal', 'Disease', (122, 132))	('brain', 'Disease', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('gastric cancers', 'Disease', (145, 160))	('gastric cancers', 'Disease', 'MESH:D013274', (145, 160))	('gastric cancers', 'Phenotype', 'HP:0012126', (145, 160))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('esophageal', 'Disease', (110, 120))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
157095	30115035	PIK3CA mutations were not significantly associated with any clinicopathological characteristics, except for the APC and BRAF genotype as discussed below, which was consistent with the results of other studies in Korea, China, and Japan.	('APC', 'Disease', 'MESH:D011125', (112, 115))	('APC', 'Disease', (112, 115))	('BRAF', 'Gene', '673', (120, 124))	('PIK3CA', 'Gene', (0, 6))	('BRAF', 'Gene', (120, 124))	('mutations', 'Var', (7, 16))
157096	30115035	The prognostic relevance of PIK3CA mutations has been investigated in various solid tumors, and PIK3CA mutations are generally associated with an unfavorable prognosis in patients with colorectal or lung cancer.	('solid tumors', 'Disease', (78, 90))	('mutations', 'Var', (103, 112))	('associated with', 'Reg', (127, 142))	('colorectal or lung cancer', 'Disease', (185, 210))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('colorectal or lung cancer', 'Disease', 'MESH:D015179', (185, 210))	('patients', 'Species', '9606', (171, 179))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('PIK3CA', 'Gene', (96, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (199, 210))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
157097	30115035	On the other hand, studies on breast and ovarian cancer demonstrated that the patients with the PIK3CA mutation showed a trend towards a favorable prognosis.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('patients', 'Species', '9606', (78, 86))	('PIK3CA', 'Gene', (96, 102))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (30, 55))	('mutation', 'Var', (103, 111))
157099	30115035	Our multivariate analysis revealed that PIK3CA gene mutations were associated with a favorable prognosis among Japanese patients with curatively resected esophageal cancer, mainly ESCC, suggesting that the PIK3CA gene mutational status may be a prognostic biomarker for Japanese esophageal cancer patients.	('mutations', 'Var', (52, 61))	('esophageal cancer', 'Disease', (279, 296))	('PIK3CA', 'Gene', (40, 46))	('esophageal cancer', 'Disease', (154, 171))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('patients', 'Species', '9606', (297, 305))	('esophageal cancer', 'Disease', 'MESH:D004938', (279, 296))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('ESCC', 'Disease', (180, 184))
157101	30115035	We further separately analyzed the survival in patients with PIK3CA mutations in coding exon 9 and 20.	('mutations', 'Var', (68, 77))	('PIK3CA', 'Gene', (61, 67))	('patients', 'Species', '9606', (47, 55))
157103	30115035	That is, both patients with exon 9 and 20 mutation had better OS than patients with wild-type PIK3CA.	('patients', 'Species', '9606', (70, 78))	('OS', 'Chemical', '-', (62, 64))	('exon 9', 'Var', (28, 34))	('better', 'PosReg', (55, 61))	('patients', 'Species', '9606', (14, 22))
157105	30115035	The possible reasons for the different results might be different patient cohorts, sample sizes, methods used to assess PIK3CA mutations, or ethnicity.	('mutations', 'Var', (127, 136))	('PIK3CA', 'Gene', (120, 126))	('patient', 'Species', '9606', (66, 73))
157108	30115035	Furthermore, although FFPE samples are the most practically available material when performing mutation testing, one of the pitfalls of using FFPE samples is DNA fragmentation and artificial C: G > T: A single nucleotide variants because of deamination of cytosine to uracil.	('cytosine', 'Chemical', 'MESH:D003596', (256, 264))	('uracil', 'Chemical', 'MESH:D014498', (268, 274))	('deamination', 'MPA', (241, 252))	('C: G > T: A single nucleotide variants', 'Var', (191, 229))
157109	30115035	We previously demonstrated that UDG pretreatment is efficacious for excluding nonspecific single nucleotide variants in amplicon-based MPS that occur if poor-quality DNA from FFPE samples was used.	('single nucleotide variants', 'Var', (90, 116))	('MPS', 'Disease', 'MESH:D009084', (135, 138))	('UDG', 'Gene', (32, 35))	('UDG', 'Gene', '7374', (32, 35))	('MPS', 'Disease', (135, 138))
157110	30115035	It is expected that PIK3CA mutations would imply poor clinical outcome, because the presence of oncogene activation leads to aggressive tumor behavior.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (20, 26))	('activation', 'PosReg', (105, 115))	('aggressive tumor', 'Disease', 'MESH:D001523', (125, 141))	('presence', 'Var', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('oncogene', 'Protein', (96, 104))	('aggressive tumor', 'Disease', (125, 141))	('leads to', 'Reg', (116, 124))
157111	30115035	One possible hypothesis to explain the paradoxical result may be a negative feedback mechanism through which the PI3K/AKT pathway is inactivated in PIK3CA mutant tumors.	('inactivated', 'NegReg', (133, 144))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('AKT', 'Gene', '207', (118, 121))	('mutant', 'Var', (155, 161))	('AKT', 'Gene', (118, 121))	('tumors', 'Disease', (162, 168))	('PIK3CA', 'Gene', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
157116	30115035	To further characterize the PIK3CA mutation and wild-type, we also investigated the clinicopathological characteristics of esophageal cancer patients with respect to PIK3CA status.	('esophageal cancer', 'Disease', (123, 140))	('PIK3CA', 'Gene', (28, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('mutation', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('patients', 'Species', '9606', (141, 149))
157117	30115035	PIK3CA mutations were significantly associated with the APC mutation.	('PIK3CA', 'Gene', (0, 6))	('APC', 'Disease', 'MESH:D011125', (56, 59))	('associated', 'Reg', (36, 46))	('APC', 'Disease', (56, 59))	('mutations', 'Var', (7, 16))
157118	30115035	The type of APC gene alteration detected in this study was different from that reported to occur frequently in upper gastrointestinal cancers, such as at codons 1450, 1462-1465, and 1554-1556.	('APC', 'Disease', (12, 15))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (111, 141))	('1554-1556', 'Var', (182, 191))	('1462-1465', 'Var', (167, 176))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('upper gastrointestinal cancers', 'Disease', (111, 141))	('APC', 'Disease', 'MESH:D011125', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
157119	30115035	The most frequently noted mutations in our cohort were nonsense mutations (11/17; 64.7%), which resulted in truncated APC proteins.	('nonsense mutations', 'Var', (55, 73))	('truncated', 'MPA', (108, 117))	('resulted', 'Reg', (96, 104))	('APC', 'Disease', 'MESH:D011125', (118, 121))	('APC', 'Disease', (118, 121))
157120	30115035	APC frameshift deletions in the codon 1556 hot spot, 1301, and 1384 detected in this study also lead to loss of APC function.	('loss of APC function', 'Disease', (104, 124))	('APC', 'Disease', 'MESH:D011125', (112, 115))	('APC', 'Disease', (112, 115))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('APC', 'Disease', (0, 3))	('frameshift deletions', 'Var', (4, 24))	('loss of APC function', 'Disease', 'MESH:D011125', (104, 124))
157121	30115035	The coexistence of APC alterations with PIK3CA mutation may be partially explained by a previous study using a mouse model with PIK3CA mutation, which demonstrated that the PIK3CA mutation alone was insufficient to initiate intestinal tumorigenesis in intestinal cancers.	('APC', 'Disease', 'MESH:D011125', (19, 22))	('PIK3CA', 'Gene', (40, 46))	('APC', 'Disease', (19, 22))	('intestinal cancers', 'Disease', 'MESH:D007414', (252, 270))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('insufficient', 'Disease', 'MESH:D000309', (199, 211))	('mouse', 'Species', '10090', (111, 116))	('mutation', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('intestinal cancers', 'Disease', (252, 270))	('insufficient', 'Disease', (199, 211))	('tumor', 'Disease', (235, 240))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutation', 'Var', (135, 143))	('mutation', 'Var', (180, 188))	('PIK3CA', 'Gene', (173, 179))
157122	30115035	Thus, loss of APC activity may synergistically act with active PI3K, resulting in tumorigenesis.	('loss', 'Var', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('APC', 'Disease', 'MESH:D011125', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('APC', 'Disease', (14, 17))	('tumor', 'Disease', (82, 87))
157123	30115035	As compared to PIK3CA alterations, the mutations involved in the RAS-RAF pathway were rare.	('RAF', 'Gene', (69, 72))	('RAF', 'Gene', '22882', (69, 72))	('mutations', 'Var', (39, 48))
157126	30115035	Instead, there were nine cases with BRAF mutations at codons 598 (n = 3), 469 (n = 2), and 444 (n = 2).	('mutations', 'Var', (41, 50))	('BRAF', 'Gene', (36, 40))	('BRAF', 'Gene', '673', (36, 40))
157127	30115035	We also found statistically significant coexistence of BRAF mutations and PIK3CA mutations.	('BRAF', 'Gene', '673', (55, 59))	('mutations', 'Var', (60, 69))	('significant', 'Reg', (28, 39))	('BRAF', 'Gene', (55, 59))	('PIK3CA', 'Gene', (74, 80))
157128	30115035	successfully established and characterized patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models, and found that PDECX models with PIK3CA mutation had no significant response to cytotoxic agents.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('esophageal squamous cell carcinoma xenograft', 'Disease', 'MESH:D000077277', (59, 103))	('patient', 'Species', '9606', (43, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('esophageal squamous cell carcinoma xenograft', 'Disease', (59, 103))	('PIK3CA', 'Gene', (159, 165))	('mouse', 'Species', '10090', (112, 117))	('mutation', 'Var', (166, 174))
157129	30115035	This result suggests that PIK3CA mutation is also involved in sensitivity to chemotherapy, and may provide an information for the treatment of ESCC patients in the future.	('patients', 'Species', '9606', (148, 156))	('mutation', 'Var', (33, 41))	('ESCC', 'Disease', (143, 147))	('involved', 'Reg', (50, 58))	('PIK3CA', 'Gene', (26, 32))
157132	30115035	Our study provides comprehensive genomic profiling of resected esophageal cancer by NGS using surgically resected FFPE tissue and identified PIK3CA mutations as a favorable prognosis biomarker.	('mutations', 'Var', (148, 157))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('PIK3CA', 'Gene', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
157133	30115035	In the future, PIK3CA mutations may be potential targets in therapeutic development of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('esophageal cancer', 'Disease', (87, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('mutations', 'Var', (22, 31))	('PIK3CA', 'Gene', (15, 21))
157189	29100443	Alcohol drinking was also associated with the risk of esophageal cancer.	('Alcohol drinking', 'Var', (0, 16))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('Alcohol drinking', 'Phenotype', 'HP:0030955', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('associated', 'Reg', (26, 36))
157214	29100443	In our study, smoking, male gender and BMI > 25 were risk factors for reflux esophagitis and Barrett's esophagus.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (93, 112))	("Barrett's esophagus", 'Disease', (93, 112))	('BMI > 25', 'Var', (39, 47))	('esophagitis', 'Phenotype', 'HP:0100633', (77, 88))	('reflux esophagitis', 'Disease', (70, 88))	('reflux esophagitis', 'Disease', 'MESH:D005764', (70, 88))
157224	29100443	Different alkaloids including guvacine, arecoline, arecaidine and guvacoline are the components of areca nut that can induce systemic effects and arecoline can cause carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (166, 175))	('arecoline', 'Chemical', 'MESH:D001115', (40, 49))	('alkaloids', 'Chemical', 'MESH:D000470', (10, 19))	('systemic effects', 'MPA', (125, 141))	('cause', 'Reg', (160, 165))	('arecoline', 'Var', (146, 155))	('guvacine', 'Chemical', 'MESH:C015910', (30, 38))	('areca nut', 'Species', '184783', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('guvacoline', 'Chemical', 'MESH:C000588631', (66, 76))	('arecoline', 'Chemical', 'MESH:D001115', (146, 155))	('induce', 'Reg', (118, 124))	('carcinoma', 'Disease', (166, 175))	('arecaidine', 'Chemical', 'MESH:C015688', (51, 61))
157302	28148891	Comparing the results of non-cardiac surgery after myocardial revascularization using either PCI or CABG operation, it was demonstrated that the incidence of myocardial infarction and mortality were higher among those patients who received PCI.	('myocardial infarction', 'Disease', (158, 179))	('mortality', 'CPA', (184, 193))	('myocardial infarction', 'Disease', 'MESH:D009203', (158, 179))	('patients', 'Species', '9606', (218, 226))	('higher', 'PosReg', (199, 205))	('PCI', 'Var', (240, 243))	('myocardial infarction', 'Phenotype', 'HP:0001658', (158, 179))
157383	28361224	An increase in the burden of nonsynonymous mutations in tumors has been associated with improvements in objective response and long-lasting clinical benefit as well as progression-free survival (PFS).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('nonsynonymous mutations', 'Var', (29, 52))	('improvements', 'PosReg', (88, 100))	('objective response', 'CPA', (104, 122))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('progression-free', 'CPA', (168, 184))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('clinical benefit', 'CPA', (140, 156))
157428	28361224	Progressively growing tumors contain mutant tumor antigen-specific T cells.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutant', 'Var', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', (44, 49))	('tumors', 'Disease', (22, 28))
157429	28361224	These are reactivated after treatment with anti-PD-1 and/or anti-CTLA-4, and although they show some overlap, their transcriptional profiles are mostly treatment-specific, giving them the ability to mediate tumor rejection.	('anti-CTLA-4', 'Var', (60, 71))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('mediate', 'Reg', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('anti-PD-1', 'Var', (43, 52))
157430	28361224	Tumor-specific mutant antigens are thus not only major targets in checkpoint blockade therapy but can be further used in the development of personalized and cancer-specific vaccines as well as in the investigation of the mechanisms underlying the various checkpoint blockade treatments.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('mutant', 'Var', (15, 21))
157448	28361224	Nevertheless, most of these clinical responses were associated with both on- and off-target toxicity, and death from complications has occurred in some patients receiving gene-modified T cells.	('toxicity', 'Disease', 'MESH:D064420', (92, 100))	('patients', 'Species', '9606', (152, 160))	('toxicity', 'Disease', (92, 100))	('gene-modified', 'Var', (171, 184))
157453	28361224	A phase I study of T cells engineered to recognize the NY-ESO-1 marker (TBI-1301) in patients with solid tumors, including ESCC (NCT02366546).	('NY-ESO-1', 'Gene', '246100', (55, 63))	('NCT02366546', 'Var', (129, 140))	('NY-ESO-1', 'Gene', (55, 63))	('TBI-1301', 'Gene', (72, 80))	('SCC', 'Gene', (124, 127))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('patients', 'Species', '9606', (85, 93))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('SCC', 'Gene', '6317', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('solid tumors', 'Disease', (99, 111))
157477	28361224	These promising results have led to a number of phase I trials currently testing combination treatment with an anti-CTLA-4 and an anti-PD-1/PD-L1 antibody.	('testing', 'Reg', (73, 80))	('anti-CTLA-4', 'Gene', (111, 122))	('combination', 'Interaction', (81, 92))	('PD-L1', 'Gene', (140, 145))	('PD-L1', 'Gene', '29126', (140, 145))	('anti-CTLA-4', 'Var', (111, 122))
157581	27602398	A significant relation has been established between over-expression of COX-2 and survival of patients with various cancers in retrospective studies.	('over-expression', 'Var', (52, 67))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('COX-2', 'Gene', (71, 76))	('patients', 'Species', '9606', (93, 101))
157582	27602398	reported that mefenamic acid had an inhibitory effect on proliferation of human liver cancer cells, and induced apoptosis in them.	('human', 'Species', '9606', (74, 79))	('apoptosis', 'CPA', (112, 121))	('inhibitory effect', 'NegReg', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mefenamic', 'Var', (14, 23))	('liver cancer', 'Phenotype', 'HP:0002896', (80, 92))	('liver cancer', 'Disease', 'MESH:D006528', (80, 92))	('proliferation', 'CPA', (57, 70))	('induced', 'Reg', (104, 111))	('liver cancer', 'Disease', (80, 92))
157596	27602398	These authors believe that inhibitors of COX-1 and COX-2 can bring about a 50-93% reduction in the incidence of colorectal, prostate, lung, liver, and breast cancers.	('COX-2', 'Gene', (51, 56))	('lung', 'Disease', (134, 138))	('breast cancers', 'Phenotype', 'HP:0003002', (151, 165))	('liver', 'Disease', (140, 145))	('reduction', 'NegReg', (82, 91))	('colorectal', 'Disease', (112, 122))	('breast cancers', 'Disease', 'MESH:D001943', (151, 165))	('breast cancers', 'Disease', (151, 165))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('inhibitors', 'Var', (27, 37))	('prostate', 'Disease', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('COX-1', 'Enzyme', (41, 46))
157597	27602398	Studies have also shown that these inhibitors can increase life span of people with breast, digestive system and lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('lung cancers', 'Disease', 'MESH:D008175', (113, 125))	('lung cancers', 'Phenotype', 'HP:0100526', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast', 'Disease', (84, 90))	('increase', 'PosReg', (50, 58))	('life span', 'CPA', (59, 68))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('inhibitors', 'Var', (35, 45))	('lung cancers', 'Disease', (113, 125))	('digestive system', 'Disease', (92, 108))
157615	27602398	studied COX-2 inhibitors (indometacin and NS398) in HNSCC and found inhibition of growth of tumor cells in vitro, cell cycle analysis, and quantification of apoptosis.	('growth of tumor cells', 'CPA', (82, 103))	('NS398', 'Var', (42, 47))	('apoptosis', 'CPA', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cell cycle analysis', 'CPA', (114, 133))	('inhibition', 'NegReg', (68, 78))	('NS398', 'Chemical', 'MESH:C080955', (42, 47))
157646	27336869	LT patients with NOD were likely to be older and of male sex than LT patients without NOD, and with a higher risk of preoperative chronic hepatitis (97.88% vs 92.03, P = 0.0034), including alcoholic hepatitis (25.40% vs 16.61%, P = 0.0023) and hepatitis C (26.98% vs 18.99%, P = 0.0081), ascites (56.08% vs 45.02%, P = 0.0035), hepatic coma (43.39% vs 31.03%, P = 0.0005), and esophageal varices (60.32% vs 47.94%, P = 0.0011).	('alcoholic hepatitis', 'Disease', 'MESH:D006519', (189, 208))	('chronic hepatitis', 'Disease', (130, 147))	('hepatitis', 'Disease', (138, 147))	('NOD', 'Var', (17, 20))	('hepatic coma', 'Disease', 'MESH:D056486', (328, 340))	('patients', 'Species', '9606', (69, 77))	('hepatitis', 'Phenotype', 'HP:0012115', (199, 208))	('ascites', 'Disease', (288, 295))	('coma', 'Phenotype', 'HP:0001259', (336, 340))	('hepatitis', 'Disease', 'MESH:D056486', (199, 208))	('hepatitis', 'Disease', (199, 208))	('chronic hepatitis', 'Disease', 'MESH:D056487', (130, 147))	('hepatitis', 'Phenotype', 'HP:0012115', (244, 253))	('ascites', 'Disease', 'MESH:D001201', (288, 295))	('hepatitis', 'Disease', 'MESH:D056486', (244, 253))	('patients', 'Species', '9606', (3, 11))	('NOD', 'Phenotype', 'HP:0100651', (17, 20))	('esophageal varices', 'Phenotype', 'HP:0002040', (377, 395))	('hepatic coma', 'Disease', (328, 340))	('alcoholic hepatitis', 'Disease', (189, 208))	('hepatitis', 'Disease', (244, 253))	('esophageal varices', 'Disease', (377, 395))	('ascites', 'Phenotype', 'HP:0001541', (288, 295))	('hepatitis', 'Phenotype', 'HP:0012115', (138, 147))	('hepatitis', 'Disease', 'MESH:D056486', (138, 147))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (130, 147))	('NOD', 'Phenotype', 'HP:0100651', (86, 89))
157652	27336869	The length of ICU stay was shorter in LT patients with NOD, compared to those without NOD (P < 0.015).	('NOD', 'Phenotype', 'HP:0100651', (55, 58))	('NOD', 'Phenotype', 'HP:0100651', (86, 89))	('shorter', 'NegReg', (27, 34))	('patients', 'Species', '9606', (41, 49))	('NOD', 'Var', (55, 58))
157658	27336869	There were a higher 5-year survival rate in patients with NOD than patients without NOD (P = 0.0190) and with diabetes before transplantation (P = 0.0041).	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (67, 75))	('diabetes', 'Disease', (110, 118))	('higher', 'PosReg', (13, 19))	('diabetes', 'Disease', 'MESH:D003920', (110, 118))	('NOD', 'Phenotype', 'HP:0100651', (84, 87))	('NOD', 'Var', (58, 61))	('5-year survival', 'CPA', (20, 35))	('NOD', 'Phenotype', 'HP:0100651', (58, 61))
157661	27336869	The Kaplan-Meier survival analysis also showed a higher 5-year survival rate in patients with NOD than without NOD (P = 0.0063) (Fig.	('NOD', 'Phenotype', 'HP:0100651', (94, 97))	('patients', 'Species', '9606', (80, 88))	('NOD', 'Phenotype', 'HP:0100651', (111, 114))	('NOD', 'Var', (94, 97))	('higher', 'PosReg', (49, 55))
157673	27336869	Our report also showed that older patients and males were more likely to have NOD, which is consistent with the results of the meta-analysis by Li et al.. LT patients with NOD were likely to have a higher risk of preoperative hepatitis C, alcoholic hepatitis, ascites, hepatic coma, and esophageal varices.	('ascites', 'Disease', 'MESH:D001201', (260, 267))	('hepatic coma', 'Disease', (269, 281))	('hepatitis', 'Disease', (249, 258))	('NOD', 'Phenotype', 'HP:0100651', (78, 81))	('patients', 'Species', '9606', (158, 166))	('NOD', 'Phenotype', 'HP:0100651', (172, 175))	('ascites', 'Phenotype', 'HP:0001541', (260, 267))	('alcoholic hepatitis', 'Disease', (239, 258))	('hepatitis', 'Disease', (226, 235))	('hepatic coma', 'Disease', 'MESH:D056486', (269, 281))	('NOD', 'Var', (172, 175))	('alcoholic hepatitis', 'Disease', 'MESH:D006519', (239, 258))	('patients', 'Species', '9606', (34, 42))	('hepatitis', 'Phenotype', 'HP:0012115', (226, 235))	('ascites', 'Disease', (260, 267))	('hepatitis', 'Disease', 'MESH:D056486', (226, 235))	('esophageal varices', 'Phenotype', 'HP:0002040', (287, 305))	('coma', 'Phenotype', 'HP:0001259', (277, 281))	('hepatitis', 'Phenotype', 'HP:0012115', (249, 258))	('esophageal varices', 'Disease', (287, 305))	('hepatitis', 'Disease', 'MESH:D056486', (249, 258))
157686	27336869	However, the length of ICU stay was shorter in LT patients with NOD, compared with those without NOD.	('patients', 'Species', '9606', (50, 58))	('NOD', 'Phenotype', 'HP:0100651', (97, 100))	('NOD', 'Var', (64, 67))	('NOD', 'Phenotype', 'HP:0100651', (64, 67))	('shorter', 'NegReg', (36, 43))
157688	27336869	The length of ICU stay was shorter in LT patients with NOD, compared with those without NOD.	('NOD', 'Phenotype', 'HP:0100651', (55, 58))	('shorter', 'NegReg', (27, 34))	('NOD', 'Phenotype', 'HP:0100651', (88, 91))	('patients', 'Species', '9606', (41, 49))	('NOD', 'Var', (55, 58))
157690	27336869	In this study, the 5-year mortality rate post-LT was lower in patients with NOD than in those without NOD.	('NOD', 'Phenotype', 'HP:0100651', (76, 79))	('NOD', 'Phenotype', 'HP:0100651', (102, 105))	('patients', 'Species', '9606', (62, 70))	('lower', 'NegReg', (53, 58))	('NOD', 'Var', (76, 79))
157777	23818775	These parameters were chosen because a large body of work implicates mitochondrial impairment as being an important cause of cell death, particularly given that the mitochondria serve as gatekeepers for the "life-or-death" decision.	('gatekeepers', 'Species', '111938', (187, 198))	('impairment', 'Var', (83, 93))	('mitochondrial impairment', 'Phenotype', 'HP:0003287', (69, 93))	('mitochondrial impairment', 'Var', (69, 93))
157890	19707773	In contrast, patients who underwent colon interposition were noted to have more frequent gastroesophageal reflux disease and poorer weight gain at long-term follow-up.	('weight gain', 'Phenotype', 'HP:0004324', (132, 143))	('colon interposition', 'Var', (36, 55))	('weight gain', 'Disease', (132, 143))	('patients', 'Species', '9606', (13, 21))	('gastroesophageal reflux disease', 'Disease', (89, 120))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (89, 112))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (89, 120))	('weight gain', 'Disease', 'MESH:D015430', (132, 143))	('poorer weight gain', 'Phenotype', 'HP:0001508', (125, 143))
157924	19703839	However, the patients with T1b are at risk of lymph node metastasis and therefore EMR alone cannot be considered as curative.	('lymph node metastasis', 'Disease', 'MESH:D009362', (46, 67))	('patients', 'Species', '9606', (13, 21))	('T1b', 'Var', (27, 30))	('lymph node metastasis', 'Disease', (46, 67))
157945	19703839	This trial determines the efficacy and the safety of combined treatment of EMR and chemoradiotherapy for cT1b esophageal cancer in terms of 3-year OS.	('OS', 'Chemical', '-', (147, 149))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal cancer', 'Disease', (110, 127))	('cT1b', 'Var', (105, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))
157959	19829958	Despite ED are usually asymptomatic, especially when they are small, the enlargement of their size can produce symptoms such as dysphagia, regurgitation of undigested food, retrosternal discomfort, halitosis, and weight loss.	('halitosis', 'Disease', 'MESH:D006209', (198, 207))	('produce', 'Reg', (103, 110))	('weight loss', 'Disease', (213, 224))	('halitosis', 'Phenotype', 'HP:0100812', (198, 207))	('retrosternal discomfort', 'Disease', (173, 196))	('weight loss', 'Phenotype', 'HP:0001824', (213, 224))	('halitosis', 'Disease', (198, 207))	('dysphagia', 'Disease', (128, 137))	('ED', 'Chemical', '-', (8, 10))	('regurgitation of undigested food', 'Phenotype', 'HP:0002024', (139, 171))	('dysphagia', 'Phenotype', 'HP:0002015', (128, 137))	('enlargement', 'Var', (73, 84))	('regurgitation', 'Disease', (139, 152))	('weight loss', 'Disease', 'MESH:D015431', (213, 224))	('dysphagia', 'Disease', 'MESH:D003680', (128, 137))
158012	27108080	The laboratory examination results showed a neutrophil count >=2.0 x 109, a hemoglobin level >=100 g/L, a platelet count >=100 x 109, and the values of serum creatinine, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were lower than the upper limit of the normal values.	('hemoglobin level', 'MPA', (76, 92))	('alanine aminotransferase', 'Gene', '2875', (170, 194))	('aspartate aminotransferase', 'MPA', (196, 222))	('total bilirubin', 'MPA', (228, 243))	('creatinine', 'Chemical', 'MESH:D003404', (158, 168))	('bilirubin', 'Chemical', 'MESH:D001663', (234, 243))	('>=2.0', 'Var', (61, 66))	('serum creatinine', 'MPA', (152, 168))	('neutrophil', 'MPA', (44, 54))	('platelet count', 'CPA', (106, 120))	('lower', 'NegReg', (249, 254))	('>=100', 'Var', (121, 126))	('alanine aminotransferase', 'Gene', (170, 194))
158108	27108080	Our study also observed this condition: the percentage of severe esophagitis in patients who received one single dose per fraction of >=2.7-Gy radiation on the esophagus was markedly higher than in those who received a dose lower than 2.7 Gy (80 % vs 0, respectively).	('higher', 'PosReg', (183, 189))	('patients', 'Species', '9606', (80, 88))	('esophagitis', 'Phenotype', 'HP:0100633', (65, 76))	('esophagitis', 'Disease', (65, 76))	('esophagitis', 'Disease', 'MESH:D004941', (65, 76))	('>=2.7-Gy', 'Var', (134, 142))
158120	27108080	In our study, among the five cases of grade III acute esophagitis, only one case was finally transformed into late grade III esophageal injury, indicating that 69 Gy might not cause a severe late esophageal toxicity.	('late esophageal toxicity', 'Disease', 'MESH:D004941', (191, 215))	('esophagitis', 'Disease', 'MESH:D004941', (54, 65))	('esophageal injury', 'Disease', (125, 142))	('late esophageal toxicity', 'Disease', (191, 215))	('esophageal injury', 'Disease', 'MESH:D004941', (125, 142))	('69 Gy', 'Var', (160, 165))	('esophagitis', 'Disease', (54, 65))	('esophagitis', 'Phenotype', 'HP:0100633', (54, 65))
158205	26989392	In a clinical trial comparing SEMS with brachytherapy as single treatment modalities, SEMS showed a more rapid improvement within 30 days; however, brachytherapy was associated with a significantly reduced dysphagia at later time points and significantly more overall days with almost no dysphagia (115 vs. 82).	('dysphagia', 'Disease', (206, 215))	('dysphagia', 'Disease', 'MESH:D003680', (288, 297))	('brachytherapy', 'Var', (148, 161))	('more', 'PosReg', (255, 259))	('dysphagia', 'Phenotype', 'HP:0002015', (206, 215))	('reduced', 'NegReg', (198, 205))	('dysphagia', 'Disease', 'MESH:D003680', (206, 215))	('dysphagia', 'Disease', (288, 297))	('dysphagia', 'Phenotype', 'HP:0002015', (288, 297))
158206	26989392	Additionally, brachytherapy had a lower complication rate, better quality of life scores, and a less frequent need of repeated treatment due to recurrent or persistent dysphagia.	('brachytherapy', 'Var', (14, 27))	('dysphagia', 'Phenotype', 'HP:0002015', (168, 177))	('lower', 'NegReg', (34, 39))	('quality of life scores', 'CPA', (66, 88))	('better', 'PosReg', (59, 65))	('dysphagia', 'Disease', 'MESH:D003680', (168, 177))	('complication', 'CPA', (40, 52))	('dysphagia', 'Disease', (168, 177))
158278	26243571	Prominent esophageal tissue Raman peaks with tentative assignments can be observed in the FP region, i.e., 853 (v(C-C) proteins), 1004 (nus(C-C) ring breathing of phenylalanine), 1078 (nu(C-C) of lipids), 1265 (amide III v(C-N) and delta(N-H) of proteins), 1302 (CH2 twisting and wagging of lipids), 1335 (CH3CH2 twisting of proteins and nucleic acids), 1445 (delta(CH2) deformation of proteins and lipids), 1618 (v(C = C) of porphyrins), 1655 (amide I v(C = O) of proteins) and 1745 cm-1 (v(C = O) of phospholipids).	('lipids', 'Chemical', 'MESH:D008055', (196, 202))	('lipids', 'Chemical', 'MESH:D008055', (509, 515))	('1655', 'Var', (439, 443))	('amide', 'Chemical', 'MESH:D000577', (211, 216))	('men', 'Species', '9606', (61, 64))	('1445', 'Var', (354, 358))	('1335', 'Var', (300, 304))	('lipids', 'Chemical', 'MESH:D008055', (399, 405))	('amide', 'Chemical', 'MESH:D000577', (445, 450))	('1004', 'Var', (130, 134))	('1618', 'Var', (408, 412))	('lipids', 'Chemical', 'MESH:D008055', (291, 297))
158283	26243571	In particular, seven spectral sub-regions with statically significant difference (p < 1E-10) between ESCC and normal esophagus were found: i.e., 840-940 cm-1, 1025-1100 cm-1, 1310-1355 cm-1, 1585-1690 cm-1, and 2830-2975 cm-1 related to proteins, lipids and nucleic acids.	('2830-2975 cm-1', 'Var', (211, 225))	('840-940 cm-1', 'Var', (145, 157))	('1310-1355 cm-1', 'Var', (175, 189))	('1025-1100 cm-1', 'Var', (159, 173))	('ESCC', 'Disease', (101, 105))	('1585-1690 cm-1', 'Var', (191, 205))	('lipids', 'Chemical', 'MESH:D008055', (247, 253))
158295	26243571	On the other hand, unpaired two-sided Student's t-test identified three statistically different sub-regions of HW Raman bands (2830-2975, 3160-3260 and 3370-3420 cm-1) related to lipids, proteins and water changes associated with ESCC transformation.	('lipids', 'Chemical', 'MESH:D008055', (179, 185))	('ESCC', 'Disease', (230, 234))	('lipids', 'MPA', (179, 185))	('water', 'Chemical', 'MESH:D014867', (200, 205))	('related', 'Reg', (168, 175))	('3370-3420 cm-1', 'Var', (152, 166))	('2830-2975', 'Var', (127, 136))
158296	26243571	ESCC was characterised by a relatively decreased lipid and increased protein content as indicated by the higher Raman peak intensity ratio of I2940/I2850in ESCC.	('I2940/I2850in', 'Var', (142, 155))	('higher', 'PosReg', (105, 111))	('lipid', 'Chemical', 'MESH:D008055', (49, 54))	('lipid', 'MPA', (49, 54))	('protein content', 'MPA', (69, 84))	('decreased', 'NegReg', (39, 48))	('increased', 'PosReg', (59, 68))	('Raman peak intensity ratio', 'MPA', (112, 138))
158306	26243571	Furthermore, misclassified spectra by the FP Raman (that were correctly classified by the integrated FP/HW Raman) are comprised of weaker tissue Raman signals and relatively high AF background; while the addition of the HW Raman containing stronger tissue Raman peaks (e.g., 2885, 2940, 3250 and 3400 cm-1) but much reduced AF could improve the overall signal-to-noise ratio (SNR) of integrated FP/HW Raman spectra, therefore, enhancing the performance of classification.	('improve', 'PosReg', (333, 340))	('AF', 'Disease', 'MESH:D001281', (179, 181))	('signal-to-noise ratio', 'MPA', (353, 374))	('AF', 'Disease', 'MESH:D001281', (324, 326))	('classification', 'MPA', (456, 470))	('enhancing', 'PosReg', (427, 436))	('2940', 'Var', (281, 285))
158355	21538848	(-)-Epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), and (-)-epicatechin (EC) are the major catechins in green tea.	('(-)-epicatechin', 'Chemical', 'MESH:D002392', (67, 82))	('EGCG', 'Chemical', 'MESH:C045651', (32, 36))	('EC', 'Chemical', 'MESH:D002392', (94, 96))	('(-)-epigallocatechin', 'Chemical', 'MESH:C057580', (39, 59))	('EGC', 'Chemical', 'MESH:C057580', (61, 64))	('(-)-epicatechin-3-gallate', 'Chemical', 'MESH:C062669', (67, 92))	('-)-epicatechin-3-gallate', 'Var', (68, 92))	('tea', 'Gene', (158, 161))	('tea', 'Gene', '11988', (158, 161))	('catechins', 'Chemical', 'MESH:D002392', (139, 148))	('-)-epigallocatechin', 'Var', (40, 59))	('ECG', 'Chemical', 'MESH:C062669', (94, 97))	('(-)-Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (0, 30))	('EGC', 'Chemical', 'MESH:C057580', (32, 35))	('(-)-epicatechin', 'Chemical', 'MESH:D002392', (104, 119))	('EC', 'Chemical', 'MESH:D002392', (121, 123))
158380	21538848	Alcohol consumption, tobacco use, and deficiencies in certain nutrients present in fresh fruits or vegetables have been identified as the main risk factors for esophageal squamous cell carcinoma, especially in high-risk populations.	('deficiencies', 'Var', (38, 50))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (160, 194))	('tobacco', 'Species', '4097', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('esophageal squamous cell carcinoma', 'Disease', (160, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))
158396	21538848	In the groups of rats receiving 0.6% decaffeinated green tea or decaffeinated black tea (6 mg tea solids per mL) as the sole source of drinking fluid during the NMBA-treatment period, esophageal tumor incidence, and multiplicity were reduced by approximately 70%.	('rats', 'Species', '10116', (17, 21))	('black tea', 'Species', '4442', (78, 87))	('tea', 'Gene', '11988', (94, 97))	('reduced', 'NegReg', (234, 241))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('esophageal tumor', 'Phenotype', 'HP:0100751', (184, 200))	('tea', 'Gene', (84, 87))	('tea', 'Gene', (57, 60))	('NMBA', 'Chemical', 'MESH:C014707', (161, 165))	('tea', 'Gene', '11988', (84, 87))	('tea', 'Gene', (94, 97))	('decaffeinated', 'Var', (64, 77))	('tea', 'Gene', '11988', (57, 60))	('multiplicity', 'CPA', (216, 228))	('men', 'Species', '9606', (171, 174))	('esophageal tumor', 'Disease', 'MESH:D004938', (184, 200))	('decaffeinated green', 'Chemical', '-', (37, 56))	('esophageal tumor', 'Disease', (184, 200))
158399	21538848	In the groups of rats receiving 0.9% regular green tea or decaffeinated green tea after the NMBA treatment period, tumor multiplicity was decreased by more than 55%.	('rats', 'Species', '10116', (17, 21))	('decaffeinated', 'Var', (58, 71))	('NMBA', 'Chemical', 'MESH:C014707', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('decaffeinated green', 'Chemical', '-', (58, 77))	('decreased', 'NegReg', (138, 147))	('tumor', 'Disease', (115, 120))	('regular green', 'Chemical', '-', (37, 50))	('tea', 'Gene', (78, 81))	('tea', 'Gene', '11988', (78, 81))	('tea', 'Gene', (51, 54))	('men', 'Species', '9606', (102, 105))	('tea', 'Gene', '11988', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
158444	21538848	A population-based case-control study involved 107 patients with esophageal squamous cell carcinoma and an equal number of sex- and age-matched control subjects in Jiangsu Province, China, reported that regular green intake was associated with a statistically significantly reduced risk of esophageal carcinoma (multivariate-adjusted OR =0.13, 95% CI =0.03-0.62, p =0.01) compared with no consumption of green tea.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (290, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('regular green', 'Var', (203, 216))	('esophageal squamous cell carcinoma', 'Disease', (65, 99))	('tea', 'Gene', (410, 413))	('tea', 'Gene', '11988', (410, 413))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('patients', 'Species', '9606', (51, 59))	('regular green', 'Chemical', '-', (203, 216))	('reduced', 'NegReg', (274, 281))	('esophageal carcinoma', 'Disease', (290, 310))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (290, 310))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (65, 99))
158452	21538848	Using validated urinary biomarkers for tea polyphenol uptake and metabolism, the investigators demonstrated a decreased risk for both esophageal and gastric cancers for the presence of EGC in urine.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tea', 'Gene', (39, 42))	('EGC', 'Chemical', 'MESH:C057580', (185, 188))	('tea', 'Gene', '11988', (39, 42))	('decreased', 'NegReg', (110, 119))	('polyphenol', 'Chemical', 'MESH:D059808', (43, 53))	('presence', 'Var', (173, 181))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (134, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('rat', 'Species', '10116', (102, 105))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('gastric cancers', 'Phenotype', 'HP:0012126', (149, 164))	('EGC', 'Gene', (185, 188))
158475	21538848	PPE decreased tumor load by approximately 59%.	('decreased', 'NegReg', (4, 13))	('tumor', 'Disease', (14, 19))	('PPE', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('PPE', 'Chemical', 'MESH:C472086', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
158483	21538848	Either PPE alone or atorvastatin alone did not show inhibitory effect on lung tumorigenesis, whereas the combination of PPE and atorvastatin significantly reduced both the tumor multiplicity and tumor burden by 56 and 55%, respectively (p<0.05).	('PPE', 'Chemical', 'MESH:C472086', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (195, 200))	('reduced', 'NegReg', (155, 162))	('tumor', 'Disease', (172, 177))	('PPE', 'Var', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('atorvastatin', 'Chemical', 'MESH:D000069059', (20, 32))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', (78, 83))	('atorvastatin', 'Chemical', 'MESH:D000069059', (128, 140))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('PPE', 'Chemical', 'MESH:C472086', (7, 10))
158519	21538848	Individuals with chronic hepatitis B and exposure to dietary aflatoxin given 500-1000 mg tea polyphenols per day for 3 months had 50% reduced urinary 8-OH-dG than those in the placebo arm.	('chronic hepatitis B', 'Disease', 'MESH:D019694', (17, 36))	('chronic hepatitis B', 'Disease', (17, 36))	('hepatitis', 'Phenotype', 'HP:0012115', (25, 34))	('8-OH-dG', 'Chemical', 'MESH:C067134', (150, 157))	('urinary 8-OH-dG', 'MPA', (142, 157))	('tea', 'Gene', (89, 92))	('500-1000 mg', 'Var', (77, 88))	('tea', 'Gene', '11988', (89, 92))	('reduced', 'NegReg', (134, 141))	('polyphenols', 'Chemical', 'MESH:D059808', (93, 104))	('aflatoxin', 'Chemical', 'MESH:D000348', (61, 70))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (17, 34))
158526	21538848	These results suggest that in cell culture conditions, the auto-oxidation of EGCG exists and may lead to the inactivation of epidermal growth factor receptor-related signaling pathway.	('EGCG', 'Chemical', 'MESH:C045651', (77, 81))	('auto-oxidation', 'Var', (59, 73))	('EGCG', 'Gene', (77, 81))	('inactivation', 'NegReg', (109, 121))	('epidermal growth factor receptor', 'Gene', (125, 157))	('epidermal growth factor receptor', 'Gene', '1956', (125, 157))
158530	21538848	In humans, PPE treatment (800 mg/day for 4 wk) significantly enhanced the total GST activity and GST-pi level in blood lymphocytes.	('enhanced', 'PosReg', (61, 69))	('PPE', 'Var', (11, 14))	('GST-pi level', 'CPA', (97, 109))	('humans', 'Species', '9606', (3, 9))	('PPE', 'Chemical', 'MESH:C472086', (11, 14))	('GST activity', 'CPA', (80, 92))	('men', 'Species', '9606', (20, 23))
158531	21538848	The enzyme induction effects of PPE were much stronger in individuals with low baseline enzyme activity.	('PPE', 'Chemical', 'MESH:C472086', (32, 35))	('stronger', 'PosReg', (46, 54))	('activity', 'MPA', (95, 103))	('enzyme induction', 'MPA', (4, 20))	('PPE', 'Var', (32, 35))
158538	21538848	demonstrated that even after lung adenoma had formed, administration of PPE inhibited the progression of adenoma to adenocarcinoma.	('adenoma to adenocarcinoma', 'Disease', (105, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('adenoma', 'Disease', (105, 112))	('PPE', 'Chemical', 'MESH:C472086', (72, 75))	('adenoma', 'Disease', 'MESH:D000236', (34, 41))	('adenoma to adenocarcinoma', 'Disease', 'MESH:D000236', (105, 130))	('rat', 'Species', '10116', (7, 10))	('adenoma', 'Disease', (34, 41))	('PPE', 'Var', (72, 75))	('rat', 'Species', '10116', (62, 65))	('inhibited', 'NegReg', (76, 85))	('adenoma', 'Disease', 'MESH:D000236', (105, 112))
158623	30156760	Injection site reactions (ISRs) were very common (21.4% ixekizumab [4.5% placebo]), with ISR discontinuation rates of 1.1% (ixekizumab) and 0.4% (placebo).	('discontinuation', 'NegReg', (93, 108))	('ixekizumab', 'Chemical', 'MESH:C549079', (56, 66))	('ixekizumab', 'Var', (56, 66))	('ixekizumab', 'Chemical', 'MESH:C549079', (124, 134))	('Injection site reactions', 'Disease', (0, 24))
158632	30156760	Overall, treatment-emergent adverse events, injection site reactions, serious infections, mucocutaneous (but not systemic) Candida infection, and hypersensitivities (non-anaphylactic) were observed more frequently in the ixekizumab group than in the placebo group.	('injection site reactions', 'CPA', (44, 68))	('infections', 'Disease', 'MESH:D007239', (78, 88))	('Candida infection', 'Disease', (123, 140))	('hypersensitivities', 'Disease', (146, 164))	('hypersensitivities', 'Disease', 'MESH:D004342', (146, 164))	('ixekizumab', 'Chemical', 'MESH:C549079', (221, 231))	('Candida infection', 'Disease', 'MESH:C536777', (123, 140))	('serious', 'Disease', (70, 77))	('infections', 'Disease', (78, 88))	('mucocutaneous', 'Disease', (90, 103))	('ixekizumab', 'Var', (221, 231))
158639	30156760	Given the role of IL-17A in host immunity, safety considerations for IL-17A inhibitors include an increased risk of certain types of infections, including mucocutaneous Candida and upper respiratory tract infections 10, 11, 12, 13.	('IL-17A', 'Gene', (69, 75))	('upper respiratory tract infections', 'Disease', 'MESH:D012141', (181, 215))	('infections', 'Disease', 'MESH:D007239', (205, 215))	('IL-17A', 'Gene', (18, 24))	('respiratory tract infections', 'Phenotype', 'HP:0011947', (187, 215))	('Candida', 'Species', '5476', (169, 176))	('infections', 'Disease', 'MESH:D007239', (133, 143))	('respiratory tract infection', 'Phenotype', 'HP:0011947', (187, 214))	('infections', 'Disease', (205, 215))	('upper respiratory tract infections', 'Disease', (181, 215))	('mucocutaneous Candida', 'Phenotype', 'HP:0002728', (155, 176))	('IL-17A', 'Gene', '3605', (18, 24))	('upper respiratory tract infection', 'Phenotype', 'HP:0002788', (181, 214))	('inhibitors', 'Var', (76, 86))	('IL-17A', 'Gene', '3605', (69, 75))	('infections', 'Disease', (133, 143))	('upper respiratory tract infections', 'Phenotype', 'HP:0002788', (181, 215))	('mucocutaneous Candida', 'Disease', (155, 176))
158642	30156760	Monoclonal antibody treatment may cause hypersensitivity, including anaphylaxis 16.	('anaphylaxis', 'Phenotype', 'HP:0100845', (68, 79))	('cause', 'Reg', (34, 39))	('hypersensitivity,', 'Disease', 'MESH:D004342', (40, 57))	('Monoclonal antibody treatment', 'Var', (0, 29))	('anaphylaxis 16', 'Disease', (68, 82))
158710	30156760	The frequencies of grade 1 or worse and grade 2 or worse neutropenia were higher in ixekizumab-treated patients than those in placebo-treated patients.	('neutropenia', 'Disease', (57, 68))	('ixekizumab', 'Chemical', 'MESH:C549079', (84, 94))	('patients', 'Species', '9606', (103, 111))	('grade', 'Disease', (19, 24))	('ixekizumab-treated', 'Var', (84, 102))	('neutropenia', 'Phenotype', 'HP:0001875', (57, 68))	('patients', 'Species', '9606', (142, 150))	('neutropenia', 'Disease', 'MESH:D009503', (57, 68))
158719	30156760	The frequency of infection-related TEAEs was comparable in patients with neutrophil counts <2.0 x 109/liter (54.4%) versus patients whose counts were above this cutoff (49.0%) and in patients with neutrophil counts <1.5 x 109/liter (42.0%) versus patients whose counts were above the latter (<1.5 x 109/liter) cutoff (50.1%).	('infection', 'Disease', (17, 26))	('patients', 'Species', '9606', (123, 131))	('infection', 'Disease', 'MESH:D007239', (17, 26))	('patients', 'Species', '9606', (247, 255))	('<2.0', 'Var', (91, 95))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (183, 191))
158781	30156760	The higher frequency of TEAEs in the ixekizumab group compared with the placebo group was mainly attributable to a higher frequency of patients with >=1 ISR.	('patients', 'Species', '9606', (135, 143))	('ixekizumab', 'Var', (37, 47))	('ixekizumab', 'Chemical', 'MESH:C549079', (37, 47))	('TEAEs', 'Disease', (24, 29))
158844	27625097	In KYSE-450-PTX3, KYSE-450-vector, and KYSE-450-wild-type cells, the rates of apoptosis were 10.10%, 2.73%, and 3.01%, respectively.	('KYSE-450-PTX3', 'Var', (3, 16))	('apoptosis', 'CPA', (78, 87))	('KYSE-450', 'CellLine', 'CVCL:1353', (39, 47))	('KYSE-450', 'CellLine', 'CVCL:1353', (3, 11))	('KYSE-450', 'CellLine', 'CVCL:1353', (18, 26))	('KYSE-450-vector', 'Var', (18, 33))
158849	27625097	In mice bearing EC109-vector or KYSE-450-vector tumors, the average tumor volume was 1485.00 and 1433.66 mm3, respectively; this was similar to that observed with wild-type EC109 and KYSE-450 cells, which produced average tumor volumes of 1452.07 and 1425.19 mm3, respectively [Figure 6b].	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('EC109-vector', 'Var', (16, 28))	('tumors', 'Disease', (48, 54))	('mice', 'Species', '10090', (3, 7))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('KYSE-450', 'CellLine', 'CVCL:1353', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('KYSE-450', 'CellLine', 'CVCL:1353', (32, 40))
158854	27625097	Studies on human ESCC have shown that the PTX3 promoter is hypermethylated in ESCC, and that this results in PTX3 gene silencing.	('PTX3', 'Gene', (109, 113))	('ESCC', 'Disease', (78, 82))	('human', 'Species', '9606', (11, 16))	('gene', 'MPA', (114, 118))	('hypermethylated', 'Var', (59, 74))
158860	27625097	stably transfected two breast cancer cell lines with PTX3 and found that it reduced tumor growth in vivo; and a long PTX3-derived pentapeptide has been shown to inhibit the proliferation and angiogenic potential of FGF8b-dependent tumor cells.	('breast cancer', 'Disease', (23, 36))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('PTX3', 'Var', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('angiogenic potential', 'CPA', (191, 211))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', (84, 89))	('reduced', 'NegReg', (76, 83))	('proliferation', 'CPA', (173, 186))	('inhibit', 'NegReg', (161, 168))	('FGF8b-dependent', 'Gene', (215, 230))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
158869	24963355	Glutathione peroxidase 7 (GPX7) is frequently silenced through DNA hypermethylation during Barrett's tumorigenesis.	('GPX7', 'Gene', (26, 30))	('silenced', 'NegReg', (46, 54))	('Glutathione peroxidase 7', 'Gene', '2882', (0, 24))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('hypermethylation', 'Var', (67, 83))	('Glutathione peroxidase 7', 'Gene', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
158875	24963355	Taken together, the loss of GPX7 expression promotes bile salt-induced activation of pro-inflammatory cytokines and chemokines; important contributors to GERD-associated Barrett's carcinogenesis.	("Barrett's carcinogenesis", 'Disease', (170, 194))	('promotes', 'PosReg', (44, 52))	('loss', 'Var', (20, 24))	('pro-inflammatory cytokines and chemokines', 'MPA', (85, 126))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (170, 194))	('GERD', 'Phenotype', 'HP:0002020', (154, 158))	('activation', 'PosReg', (71, 81))	('bile salt', 'Chemical', 'MESH:D001647', (53, 62))	('bile salt-induced', 'MPA', (53, 70))	('GPX7', 'Gene', (28, 32))
158884	24963355	Nuclear factor-kappa B (NF-kappaB) is one of the few key regulatory signaling molecules; the aberrant activation of NF-kappaB is associated with inflammation and cancer in mouse models and human disease.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('associated', 'Reg', (129, 139))	('inflammation', 'Disease', 'MESH:D007249', (145, 157))	('cancer', 'Disease', (162, 168))	('inflammation', 'Disease', (145, 157))	('NF-kappaB', 'Gene', (116, 125))	('mouse', 'Species', '10090', (172, 177))	('Nuclear factor-kappa B', 'Gene', (0, 22))	('human', 'Species', '9606', (189, 194))	('Nuclear factor-kappa B', 'Gene', '18033', (0, 22))	('activation', 'PosReg', (102, 112))	('aberrant', 'Var', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
158886	24963355	Bile acids, in particular, deoxycholic acid has been shown to activate NF-kappaB pathway.	('activate', 'PosReg', (62, 70))	('NF-kappaB pathway', 'Pathway', (71, 88))	('Bile acids', 'Chemical', 'MESH:D001647', (0, 10))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (27, 43))	('deoxycholic acid', 'Var', (27, 43))
158887	24963355	Upon activation of NF-kappaB by phosphorylation, it translocates to the nucleus where it regulates the transcription of several pro-inflammatory cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-8 and chemokines such as CXCL-1 and CXCL-2.	('IL-8', 'Gene', '3576', (194, 198))	('CXCL-2', 'Gene', '2920', (233, 239))	('NF-kappaB', 'Gene', (19, 28))	('IL-8', 'Gene', (194, 198))	('regulates', 'Reg', (89, 98))	('IL-1beta', 'Gene', (174, 182))	('phosphorylation', 'Var', (32, 47))	('TNF-alpha', 'Gene', '7124', (163, 172))	('activation', 'PosReg', (5, 15))	('IL-6', 'Gene', '3569', (184, 188))	('CXCL-1', 'Gene', '2919', (222, 228))	('IL-1beta', 'Gene', '3553', (174, 182))	('transcription', 'MPA', (103, 116))	('TNF-alpha', 'Gene', (163, 172))	('CXCL-2', 'Gene', (233, 239))	('CXCL-1', 'Gene', (222, 228))	('IL-6', 'Gene', (184, 188))
158889	24963355	We have previously shown that GPX7 has very limited or none of the glutathione peroxidase enzyme activity but can neutralize H2O2 in vitro independent of glutathione and protect normal esophageal epithelia from acidic bile salts-induced oxidative stress, oxidative DNA damage and double strand breaks.	('glutathione', 'Chemical', 'MESH:D005978', (154, 165))	('esophageal epithelia', 'Disease', 'MESH:D004941', (185, 205))	('H2O2', 'Chemical', 'MESH:D006861', (125, 129))	('esophageal epithelia', 'Disease', (185, 205))	('oxidative stress', 'Phenotype', 'HP:0025464', (237, 253))	('GPX7', 'Var', (30, 34))	('protect', 'Reg', (170, 177))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (185, 205))	('bile salts', 'Chemical', 'MESH:D001647', (218, 228))	('glutathione peroxidase enzyme', 'Enzyme', (67, 96))	('glutathione', 'Chemical', 'MESH:D005978', (67, 78))	('neutralize H2O2', 'MPA', (114, 129))
158892	24963355	Loss of expression and dysfunction of GPX7 are frequent in EAC and its precancerous lesions.	('GPX7', 'Gene', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('Loss of expression', 'NegReg', (0, 18))	('EAC', 'Phenotype', 'HP:0011459', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('EAC', 'Disease', (59, 62))	('dysfunction', 'Var', (23, 34))
158928	24963355	Aberrant activation of NF-kappaB has been associated with inflammation and tumor development and progression.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('NF-kappaB', 'Protein', (23, 32))	('men', 'Species', '9606', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('inflammation', 'Disease', 'MESH:D007249', (58, 70))	('tumor', 'Disease', (75, 80))	('inflammation', 'Disease', (58, 70))
158933	24963355	The qRT-PCR data demonstrated that expression of NF-kappaB target genes, cytokines (TNF-alpha, IL-1beta, IL-6, and IL-8) and chemokines (CXCL-1and CXCL-2), were significantly suppressed in FLO-1 cells stably expressing GPX7 as compared to control cells (Figure 4 C).	('IL-8', 'Gene', (115, 119))	('CXCL-2', 'Gene', '2920', (147, 153))	('CXCL-2', 'Gene', (147, 153))	('IL-1beta', 'Gene', (95, 103))	('suppressed', 'NegReg', (175, 185))	('CXCL-1', 'Gene', (137, 143))	('IL-6', 'Gene', (105, 109))	('IL-1beta', 'Gene', '3553', (95, 103))	('expression', 'MPA', (35, 45))	('TNF-alpha', 'Gene', '7124', (84, 93))	('IL-6', 'Gene', '3569', (105, 109))	('GPX7', 'Var', (219, 223))	('TNF-alpha', 'Gene', (84, 93))	('CXCL-1', 'Gene', '2919', (137, 143))	('NF-kappaB', 'Gene', (49, 58))	('IL-8', 'Gene', '3576', (115, 119))
158934	24963355	We have previously reported that GPX7 is frequently silenced in Barrett's carcinogenesis through location-specific promoter DNA hypermethylation.	('silenced', 'NegReg', (52, 60))	("Barrett's carcinogenesis", 'Disease', (64, 88))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (64, 88))	('promoter DNA hypermethylation', 'Var', (115, 144))	('GPX7', 'Gene', (33, 37))
158938	24963355	We also show that GPX7 can suppress the up-regulation of these cytokines through inhibiting the bile salts-induced phosphorylation and activation of NF-kappaB-p65.	('p65', 'Gene', '5970', (159, 162))	('bile salts', 'Chemical', 'MESH:D001647', (96, 106))	('inhibiting', 'NegReg', (81, 91))	('activation', 'PosReg', (135, 145))	('p65', 'Gene', (159, 162))	('suppress', 'NegReg', (27, 35))	('GPX7', 'Var', (18, 22))	('up-regulation', 'MPA', (40, 53))	('bile salts-induced phosphorylation', 'MPA', (96, 130))
158940	24963355	For the first time, our data demonstrated that GPX7 can suppress bile salts-induced inflammatory responses and expression of cytokines and chemokines associated with Barrett's carcinogenesis.	('expression of cytokines', 'MPA', (111, 134))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (166, 190))	('GPX7', 'Var', (47, 51))	('suppress', 'NegReg', (56, 64))	('bile salts', 'Chemical', 'MESH:D001647', (65, 75))	('bile salts-induced inflammatory responses', 'MPA', (65, 106))	("Barrett's carcinogenesis", 'Disease', (166, 190))
158955	24963355	Bile salts have been shown to induce intracellular ROS, and ROS could induce activation of NF-kappaB.	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('activation', 'PosReg', (77, 87))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))	('NF-kappaB', 'Protein', (91, 100))	('ROS', 'Var', (60, 63))	('ROS', 'MPA', (51, 54))	('Bile salts', 'Chemical', 'MESH:D001647', (0, 10))	('induce', 'Reg', (30, 36))
158957	24963355	Our data showed that Tiron (a ROS scavenger) alone reduced p-p65 protein level in esophageal cells, indicating that ROS is capable of inducing activation of NF-kappaB.	('ROS', 'Var', (116, 119))	('ROS', 'Chemical', 'MESH:D017382', (116, 119))	('reduced', 'NegReg', (51, 58))	('p65', 'Gene', (61, 64))	('NF-kappaB', 'Protein', (157, 166))	('activation', 'PosReg', (143, 153))	('p65', 'Gene', '5970', (61, 64))	('Tiron', 'Chemical', 'MESH:D014013', (21, 26))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
158967	24963355	Interestingly, a recent study has shown GPX3 hypermethylation and underexpression in human colon cancer.	('hypermethylation', 'Var', (45, 61))	('colon cancer', 'Disease', 'MESH:D015179', (91, 103))	('underexpression', 'NegReg', (66, 81))	('colon cancer', 'Disease', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('GPX3', 'Enzyme', (40, 44))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))	('human', 'Species', '9606', (85, 90))
158968	24963355	This study demonstrated that GPX3-deficient mouse model exhibited increased inflammation and tumor number, suggesting that loss of GPX3 is involved in inflammatory colonic tumorigenesis.	('inflammation', 'Disease', 'MESH:D007249', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('increased', 'PosReg', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('inflammation', 'Disease', (76, 88))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (93, 98))	('GPX3', 'Gene', (131, 135))	('loss', 'Var', (123, 127))	('involved', 'Reg', (139, 147))	('mouse', 'Species', '10090', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
158977	15070421	Aberrant methylation was examined as a cause for lack of annexin I expression by treating cells 5-Aza-2-deoxycytidine.	('Aberrant', 'Var', (0, 8))	('lack', 'NegReg', (49, 53))	('annexin I', 'Gene', '327662', (57, 66))	('methylation', 'MPA', (9, 20))	('expression', 'MPA', (67, 77))	('annexin I', 'Gene', (57, 66))	('5-Aza-2-deoxycytidine', 'Chemical', 'MESH:D000077209', (96, 117))
158978	15070421	Reexpression of annexin I was observed after prolonged treatment with the demethylating agent indicating methylation may be one of the mechanisms of annexin I silencing.	('silencing', 'NegReg', (159, 168))	('methylation', 'Var', (105, 116))	('annexin I', 'Gene', '327662', (149, 158))	('annexin I', 'Gene', '327662', (16, 25))	('annexin I', 'Gene', (149, 158))	('annexin I', 'Gene', (16, 25))
158982	15070421	Our results suggest that, similar to prostate and esophageal cancers, annexin I may be an endogenous suppressor of cancer development, and loss of annexin I may contribute to B-cell lymphoma development.	('cancer', 'Disease', (115, 121))	('esophageal cancers', 'Disease', 'MESH:D004938', (50, 68))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (175, 190))	('annexin I', 'Gene', '327662', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('annexin I', 'Gene', (147, 156))	('cancer', 'Disease', (61, 67))	('annexin I', 'Gene', (70, 79))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('loss', 'Var', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('contribute', 'Reg', (161, 171))	('lymphoma', 'Phenotype', 'HP:0002665', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('B-cell lymphoma development', 'CPA', (175, 202))	('esophageal cancers', 'Disease', (50, 68))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('annexin I', 'Gene', '327662', (147, 156))
159041	15070421	Methylation of the CpG dinucleotide has been shown to directly inhibit transcription or stabilize structural changes in chromatin that prevent transcription.	('prevent', 'NegReg', (135, 142))	('transcription', 'MPA', (143, 156))	('Methylation', 'Var', (0, 11))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (19, 35))	('transcription', 'MPA', (71, 84))	('inhibit', 'NegReg', (63, 70))	('stabilize structural changes', 'MPA', (88, 116))
159049	15070421	The data in Figure 5 (panel B) show that exposure of Raji cells to H2O2 did not cause annexin I expression.	('annexin I', 'Gene', '327662', (86, 95))	('expression', 'MPA', (96, 106))	('H2O2', 'Chemical', 'MESH:D006861', (67, 71))	('H2O2', 'Var', (67, 71))	('annexin I', 'Gene', (86, 95))	('Raji', 'CellLine', 'CVCL:0511', (53, 57))
159079	15070421	Thus, methylation of annexin I promoter could be one of the mechanisms for annexin I silencing in these cells.	('annexin I', 'Gene', (21, 30))	('annexin I', 'Gene', '327662', (75, 84))	('silencing', 'NegReg', (85, 94))	('methylation', 'Var', (6, 17))	('annexin I', 'Gene', '327662', (21, 30))	('annexin I', 'Gene', (75, 84))
159080	15070421	These results are similar to the reexpression of annexin II observed in a prostate cancer cell line after treatment with deoxyC, indicating methylation as a general mechanism for silencing annexins I and II in cancer tissues.	('methylation', 'Var', (140, 151))	('prostate cancer', 'Disease', (74, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('annexin II', 'Gene', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('silencing', 'NegReg', (179, 188))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('deoxyC', 'Chemical', 'MESH:D000077209', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('annexins I and II', 'Gene', '302', (189, 206))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('annexin II', 'Gene', '302', (49, 59))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (83, 89))
159083	15070421	Thus, annexin I may be an endogenous suppressor of cancer development, and loss of annexin I may contribute to B-cell lymphoma development.	('contribute', 'Reg', (97, 107))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('annexin I', 'Gene', (6, 15))	('annexin I', 'Gene', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (111, 126))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('B-cell', 'CPA', (111, 117))	('annexin I', 'Gene', '327662', (6, 15))	('cancer', 'Disease', (51, 57))	('loss', 'Var', (75, 79))	('annexin I', 'Gene', '327662', (83, 92))
159138	23964331	The patients with reintervention had a significantly longer life expectancy (222+-26 days vs. 86+-14 days, p<0.001) than those without it.	('patients', 'Species', '9606', (4, 12))	('life expectancy', 'CPA', (60, 75))	('reintervention', 'Var', (18, 32))	('longer', 'PosReg', (53, 59))
159154	23964331	Three of 25 patients (12%) with the antireflux Z stents had significant reflux, compared to 24 of 25 patients (96%) with a standard open Flamingo Wallstent (p<0.001).	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (101, 109))	('Flamingo', 'Species', '435638', (137, 145))	('reflux', 'MPA', (72, 78))	('antireflux', 'Var', (36, 46))
159439	33499345	From previous reports, we predicted that patients with a good prognosis might contain a stronger clonal expansion of TIL, which might play an important role in improving the prognosis after definitive CRT.	('improving', 'PosReg', (160, 169))	('patients', 'Species', '9606', (41, 49))	('clonal expansion', 'Var', (97, 113))	('TIL', 'Gene', (117, 120))	('stronger', 'PosReg', (88, 96))
159470	33499345	We predicted that not only the clonal expansion of TIL but, also, PD-L1 suppression, which is likely upregulated during chemotherapy and chemoradiation therapy, should play an important role in improving the prognosis.	('PD-L1 suppression', 'Disease', 'MESH:D010300', (66, 83))	('clonal', 'Var', (31, 37))	('PD-L1 suppression', 'Disease', (66, 83))	('upregulated', 'PosReg', (101, 112))
159502	31707149	PGE2 and PGES are associated with BE and EAC and acetylsalicylic acid (ASA), a COX1/2 inhibitor, can decrease the level of PGE2 in BE patients.	('PGE2', 'Chemical', 'MESH:D015232', (123, 127))	('PGE2', 'MPA', (123, 127))	('PGE2', 'Chemical', 'MESH:D015232', (0, 4))	('patients', 'Species', '9606', (134, 142))	('acetylsalicylic', 'Var', (49, 64))	('PGES', 'Gene', '9536', (9, 13))	('level', 'MPA', (114, 119))	('acetylsalicylic acid', 'Chemical', 'MESH:D001241', (49, 69))	('decrease', 'NegReg', (101, 109))	('ASA', 'Chemical', 'MESH:D001241', (71, 74))	('PGES', 'Gene', (9, 13))
159513	31707149	Antibodies to detect COX2 (#D5H5), NFkappaB (p65) (#D14E12), p-ERKs (#9101), ERKs (#9102), and PCNA (#D3H8P) were from Cell Signaling Technology (Danvers, MA).	('#D14E12', 'Var', (51, 58))	('ERKs', 'Gene', '5595;5594;5595', (63, 67))	('PCNA', 'Gene', (95, 99))	('#9101', 'Var', (69, 74))	('ERKs', 'Gene', (77, 81))	('COX2', 'Gene', (21, 25))	('NFkappaB (p65', 'Gene', (35, 48))	('#9102', 'Var', (83, 88))	('COX2', 'Gene', '4513', (21, 25))	('PCNA', 'Gene', '5111', (95, 99))	('ERKs', 'Gene', '5595;5594;5595', (77, 81))	('#D5H5', 'Var', (27, 32))	('NFkappaB (p65)', 'Gene', '5970', (35, 49))	('ERKs', 'Gene', (63, 67))
159514	31707149	The thromboxane synthase polyclonal antibody (#160715) and COX1 monoclonal antibody (#160110) were obtained from Cayman Chemical Company (Ann Arbor, MI).	('COX1', 'Gene', '4512', (59, 63))	('COX1', 'Gene', (59, 63))	('#160715', 'Var', (46, 53))	('#160110', 'Var', (85, 92))
159572	31707149	Uncontrolled cell growth and abnormalities in differentiation and survival are hallmarks of cancer.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('abnormalities', 'Var', (29, 42))	('differentiation', 'CPA', (46, 61))	('survival', 'CPA', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
159574	31707149	We first used two different small hairpin (sh)RNA sequences to generate COX1 or COX2 knockdown BE and EAC cells, respectively (Fig.	('COX2', 'Gene', '4513', (80, 84))	('COX1', 'Gene', (72, 76))	('knockdown', 'Var', (85, 94))	('COX1', 'Gene', '4512', (72, 76))	('COX2', 'Gene', (80, 84))
159575	31707149	Crystal violet and anchorage-independent cell growth assays were performed to evaluate the effect of knocking down COX1 or COX2 expression on cell growth.	('COX2', 'Gene', (123, 127))	('knocking', 'Var', (101, 109))	('COX2', 'Gene', '4513', (123, 127))	('COX1', 'Gene', (115, 119))	('Crystal violet', 'Chemical', 'MESH:D005840', (0, 14))	('COX1', 'Gene', '4512', (115, 119))
159576	31707149	The results showed that knockdown of COX1 or COX2 expression in human BE and EAC cells resulted in decreased growth compared with mock control (shCon) cells.	('human', 'Species', '9606', (64, 69))	('decreased', 'NegReg', (99, 108))	('COX1', 'Gene', '4512', (37, 41))	('growth', 'MPA', (109, 115))	('decreased growth', 'Phenotype', 'HP:0001510', (99, 115))	('COX2', 'Gene', (45, 49))	('COX2', 'Gene', '4513', (45, 49))	('knockdown', 'Var', (24, 33))	('COX1', 'Gene', (37, 41))
159577	31707149	Interestingly, knocking down expression of COX1 or COX2 decreased the expression level of TBXAS in BE and EAC cells.	('TBXAS', 'Gene', (90, 95))	('COX1', 'Gene', '4512', (43, 47))	('TBXAS', 'Chemical', '-', (90, 95))	('expression level', 'MPA', (70, 86))	('decreased', 'NegReg', (56, 65))	('COX2', 'Gene', (51, 55))	('knocking', 'Var', (15, 23))	('COX2', 'Gene', '4513', (51, 55))	('COX1', 'Gene', (43, 47))
159579	31707149	We generated TBXAS knockdown in BE and EAC cells and the results showed that deficient TBXAS expression also results in reduction of BE and EAC cell growth (Fig.	('TBXAS', 'Chemical', '-', (87, 92))	('TBXAS', 'Gene', (87, 92))	('deficient', 'Var', (77, 86))	('reduction', 'NegReg', (120, 129))	('expression', 'MPA', (93, 103))	('TBXAS', 'Chemical', '-', (13, 18))
159581	31707149	The results showed that knocking down TBXAS expression significantly decreased tumor size and weight (Fig.	('knocking down', 'Var', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('decreased', 'NegReg', (69, 78))	('TBXAS', 'Gene', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('TBXAS', 'Chemical', '-', (38, 43))
159582	31707149	In addition, compared with control (shCon) cells, knocking down TBXAS levels decreased the expression of proliferating cell nuclear antigen (PCNA), which is a cell cycle-related antigen and has been used for the evaluation of the proliferation ability of tumors.	('expression', 'MPA', (91, 101))	('PCNA', 'Gene', '5111', (141, 145))	('proliferating cell nuclear antigen', 'Gene', '5111', (105, 139))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('TBXAS', 'Chemical', '-', (64, 69))	('tumors', 'Disease', (255, 261))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('knocking down', 'Var', (50, 63))	('PCNA', 'Gene', (141, 145))	('TBXAS', 'Gene', (64, 69))	('proliferating cell nuclear antigen', 'Gene', (105, 139))	('decreased', 'NegReg', (77, 86))
159583	31707149	Collectively, these results suggested that blocking TBXAS significantly reduced the malignant potential of EAC.	('reduced', 'NegReg', (72, 79))	('blocking', 'Var', (43, 51))	('EAC', 'Disease', (107, 110))	('TBXAS', 'Chemical', '-', (52, 57))	('malignant potential', 'CPA', (84, 103))	('TBXAS', 'Gene', (52, 57))
159584	31707149	Kinase phosphorylation profiling results showed that knocking down expression of TBXAS suppressed ERKs, MSK1/2, CREB, c-Jun and STAT3 activation (Supplementary Fig.	('c-Jun', 'Gene', '3725', (118, 123))	('CREB', 'Gene', (112, 116))	('STAT3', 'Gene', '6774', (128, 133))	('STAT3', 'Gene', (128, 133))	('CREB', 'Gene', '1385', (112, 116))	('c-Jun', 'Gene', (118, 123))	('MSK1/2', 'Gene', '3688;9252;8986', (104, 110))	('ERKs', 'Gene', (98, 102))	('TBXAS', 'Chemical', '-', (81, 86))	('TBXAS', 'Gene', (81, 86))	('suppressed', 'NegReg', (87, 97))	('knocking down', 'Var', (53, 66))	('MSK1/2', 'Gene', (104, 110))	('ERKs', 'Gene', '5595;5594;5595', (98, 102))
159589	31707149	Importantly, knocking down the expression of TBXAS decreased ERKs activation (Supplementary Fig.	('ERKs', 'Gene', '5595;5594;5595', (61, 65))	('TBXAS', 'Gene', (45, 50))	('knocking down', 'Var', (13, 26))	('TBXAS', 'Chemical', '-', (45, 50))	('decreased ERKs', 'Phenotype', 'HP:0000654', (51, 65))	('decreased', 'NegReg', (51, 60))	('ERKs', 'Gene', (61, 65))
159610	31707149	In addition, both lower- and higher-dose ASA + PPI significantly decreased the absolute change between post-treatment and pre-treatment TXA2 by 4692.7 +- 5400.5 pg/mL (p = 0.001, vs placebo + PPI group) and 7536.2 +- 6722.2 pg/mL (p < 0.001, vs placebo + PPI group, Wilcoxon rank sum test), respectively.	('ASA', 'Chemical', 'MESH:D001241', (41, 44))	('7536.2 +- 6722.2', 'Var', (207, 223))	('decreased', 'NegReg', (65, 74))	('TXA2', 'Chemical', 'MESH:D013928', (136, 140))	('ASA + PPI', 'Var', (41, 50))	('TXA2', 'MPA', (136, 140))
159616	31707149	Overall, our findings indicated that inhibition of COX1/2-TBXAS signaling limited inflammation and suppressed BE and EAC development.	('inhibition', 'Var', (37, 47))	('suppressed', 'NegReg', (99, 109))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('inflammation', 'Disease', (82, 94))	('limited', 'NegReg', (74, 81))	('TBXAS', 'Chemical', '-', (58, 63))
159622	31707149	Previous study showed that COX1/2 inhibitors and PGE2 receptor antagonist AH-23848B suppressed tumor growth in a xenograft derived from OE33 cells.	('COX1/2', 'Enzyme', (27, 33))	('PGE2', 'Chemical', 'MESH:D015232', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('AH-23848B', 'Chemical', 'MESH:C046926', (74, 83))	('suppressed', 'NegReg', (84, 94))	('tumor', 'Disease', (95, 100))	('AH-23848B', 'Var', (74, 83))
159634	31707149	Our results suggest that either or both COX1 and COX2 mediate BE and EAC cell growth through the TXA2 pathway, and COX inhibition results in decreased BE and EAC cell growth and reduced EAC xenograft tumor growth (Fig.	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('inhibition', 'Var', (119, 129))	('decreased', 'NegReg', (141, 150))	('TXA2 pathway', 'Pathway', (97, 109))	('reduced EAC xenograft tumor', 'Disease', (178, 205))	('COX1', 'Gene', (40, 44))	('COX2', 'Gene', (49, 53))	('TXA2', 'Chemical', 'MESH:D013928', (97, 101))	('COX2', 'Gene', '4513', (49, 53))	('reduced EAC xenograft tumor', 'Disease', 'MESH:C536611', (178, 205))	('COX1', 'Gene', '4512', (40, 44))	('COX', 'Enzyme', (115, 118))
159635	31707149	Our kinase phosphorylation profiling results showed that knockdown expression of TBXAS markedly decreased the activation of ERKs, MSK1/2, CREB, c-Jun and STAT3.	('ERKs', 'Gene', (124, 128))	('MSK1/2', 'Gene', (130, 136))	('decreased', 'NegReg', (96, 105))	('ERKs', 'Gene', '5595;5594;5595', (124, 128))	('STAT3', 'Gene', '6774', (154, 159))	('activation', 'MPA', (110, 120))	('c-Jun', 'Gene', '3725', (144, 149))	('CREB', 'Gene', (138, 142))	('TBXAS', 'Chemical', '-', (81, 86))	('TBXAS', 'Gene', (81, 86))	('knockdown expression', 'Var', (57, 77))	('MSK1/2', 'Gene', '3688;9252;8986', (130, 136))	('STAT3', 'Gene', (154, 159))	('CREB', 'Gene', '1385', (138, 142))	('c-Jun', 'Gene', (144, 149))
159660	31707149	Inhibition of COX1/2-driven TXA2 pathway in the GERD or BE stage should be a promising approach to preventing EAC.	('TXA2', 'Chemical', 'MESH:D013928', (28, 32))	('COX1/2-driven TXA2 pathway', 'Pathway', (14, 40))	('Inhibition', 'Var', (0, 10))	('EAC', 'Disease', (110, 113))
159672	31707149	This work was also supported by the , Division of Cancer Prevention (contracts HHSN261200421 and N01CN35000 to P.J.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('N01CN', 'CellLine', 'CVCL:B396', (97, 102))	('N01CN35000', 'Var', (97, 107))
159690	31874608	DAG(DD) = (d, T(DD), E(DD)) is used to describe disease DD, where T(DD) is the node set and E(DD) is the corresponding links set.	('E(DD)', 'Gene', '51366', (21, 26))	('disease DD', 'Disease', (48, 58))	('T(DD', 'Var', (66, 70))	('DAG', 'Chemical', '-', (0, 3))	('E(DD', 'Gene', (92, 96))	('E(DD', 'Gene', (21, 25))	('E(DD)', 'Gene', '51366', (92, 97))
159733	30737573	Inhibition of NQO1 in ESCC cells by shRNA or NQO1 inhibitor resulted in an increased sensitivity of cells to THC, whereas overexpression of NQO1 antagonized it.	('Inhibition', 'NegReg', (0, 10))	('NQO1', 'Gene', '1728', (140, 144))	('NQO1', 'Gene', (14, 18))	('inhibitor', 'Var', (50, 59))	('NQO1', 'Gene', (45, 49))	('NQO1', 'Gene', (140, 144))	('NQO1', 'Gene', '1728', (45, 49))	('THC', 'Chemical', '-', (109, 112))	('increased', 'PosReg', (75, 84))	('NQO1', 'Gene', '1728', (14, 18))	('sensitivity', 'MPA', (85, 96))
159773	30737573	Moreover, THC significantly increased SABG-positive senescent cells in ESCC cells (Supplementary Fig.	('increased', 'PosReg', (28, 37))	('THC', 'Var', (10, 13))	('SABG-positive senescent cells', 'CPA', (38, 67))	('SABG', 'Chemical', '-', (38, 42))	('THC', 'Chemical', '-', (10, 13))
159792	30737573	Knockdown of KEAP1 resulted in an increased expression of NMRAL2P, while knockdown of NRF2 caused a reduction of NMRAL2P levels in both TE-5 and TE-8 cells with and without THC treatment (Supplementary Fig.	('reduction', 'NegReg', (100, 109))	('KEAP1', 'Gene', '9817', (13, 18))	('expression', 'MPA', (44, 54))	('NRF2', 'Gene', '4780', (86, 90))	('NMRAL2P', 'Gene', (113, 120))	('THC', 'Chemical', '-', (173, 176))	('KEAP1', 'Gene', (13, 18))	('TE', 'Chemical', 'MESH:D013691', (145, 147))	('NRF2', 'Gene', (86, 90))	('NMRAL2P', 'Gene', (58, 65))	('NMRAL2P', 'Gene', '344887', (113, 120))	('increased', 'PosReg', (34, 43))	('NMRAL2P', 'Gene', '344887', (58, 65))	('TE', 'Chemical', 'MESH:D013691', (136, 138))	('knockdown', 'Var', (73, 82))
159793	30737573	4f, g, knockdown of NMRAL2P or NRF2 attenuated NQO1 mRNA and protein induction by THC.	('NRF2', 'Gene', (31, 35))	('NRF2', 'Gene', '4780', (31, 35))	('NQO1', 'Gene', (47, 51))	('THC', 'Chemical', '-', (82, 85))	('NQO1', 'Gene', '1728', (47, 51))	('attenuated', 'NegReg', (36, 46))	('NMRAL2P', 'Gene', (20, 27))	('knockdown', 'Var', (7, 16))	('NMRAL2P', 'Gene', '344887', (20, 27))
159799	30737573	In addition, 8-OHdG, a marker of oxidative DNA damage, was increased by THC treatment (Fig.	('THC treatment', 'Var', (72, 85))	('THC', 'Chemical', '-', (72, 75))	('8-OHdG', 'Chemical', 'MESH:C067134', (13, 19))	('8-OHdG', 'MPA', (13, 19))	('increased', 'PosReg', (59, 68))
159805	30737573	NQO1 knockdown resulted in an increase of 8-OHdG-indicated oxidative damage in THC-treated cells (Fig.	('THC', 'Chemical', '-', (79, 82))	('knockdown', 'Var', (5, 14))	('8-OHdG-indicated oxidative damage', 'MPA', (42, 75))	('NQO1', 'Gene', (0, 4))	('8-OHdG', 'Chemical', 'MESH:C067134', (42, 48))	('increase', 'PosReg', (30, 38))	('NQO1', 'Gene', '1728', (0, 4))
159806	30737573	Although NQO1 knockdown alone did not affect cell growth (data not shown), susceptibility to THC in NQO1 knockdown cells was significantly higher than that in control cells (Fig.	('NQO1', 'Gene', (9, 13))	('THC', 'Disease', (93, 96))	('THC', 'Chemical', '-', (93, 96))	('NQO1', 'Gene', '1728', (9, 13))	('knockdown', 'Var', (105, 114))	('susceptibility', 'MPA', (75, 89))	('NQO1', 'Gene', (100, 104))	('NQO1', 'Gene', '1728', (100, 104))	('higher', 'PosReg', (139, 145))
159810	30737573	Because of the additive effects of THC and NQO1 inhibition, we next examined whether NQO1 inhibitor enhanced the cytotoxic effects of THC.	('THC', 'Chemical', '-', (35, 38))	('NQO1', 'Gene', (43, 47))	('enhanced', 'PosReg', (100, 108))	('inhibitor', 'Var', (90, 99))	('NQO1', 'Gene', (85, 89))	('NQO1', 'Gene', '1728', (85, 89))	('NQO1', 'Gene', '1728', (43, 47))	('cytotoxic effects', 'CPA', (113, 130))	('THC', 'Chemical', '-', (134, 137))
159811	30737573	ESCC cells were treated with THC and ES936, which is a mechanism-based inhibitor of NQO1.	('NQO1', 'Gene', '1728', (84, 88))	('ES936', 'Var', (37, 42))	('THC', 'Chemical', '-', (29, 32))	('NQO1', 'Gene', (84, 88))
159812	30737573	ES936 has been shown not to decrease NQO1 protein expression.	('NQO1', 'Gene', (37, 41))	('NQO1', 'Gene', '1728', (37, 41))	('ES936', 'Var', (0, 5))
159824	30737573	As a note, THC treatment did not cause any histological damages in normal esophageal tissues, and it did not increase ROS levels (8-OHdG levels) in normal esophageal tissues (data not shown).	('THC', 'Chemical', '-', (11, 14))	('8-OHdG', 'Chemical', 'MESH:C067134', (130, 136))	('THC', 'Var', (11, 14))	('ROS levels', 'MPA', (118, 128))	('ROS', 'Chemical', 'MESH:D017382', (118, 121))	('increase ROS levels', 'Phenotype', 'HP:0025464', (109, 128))
159840	30737573	Our results showed that KEAP1 knockdown increased expression of NMRAL2P, while NRF2 knockdown reduced it.	('KEAP1', 'Gene', '9817', (24, 29))	('NRF2', 'Gene', (79, 83))	('reduced', 'NegReg', (94, 101))	('NMRAL2P', 'Gene', (64, 71))	('knockdown', 'Var', (84, 93))	('KEAP1', 'Gene', (24, 29))	('increased', 'PosReg', (40, 49))	('NMRAL2P', 'Gene', '344887', (64, 71))	('NRF2', 'Gene', '4780', (79, 83))	('expression', 'MPA', (50, 60))
159841	30737573	Moreover, NMRAL2P knockdown inhibited NQO1 induction by THC.	('knockdown', 'Var', (18, 27))	('NMRAL2P', 'Gene', '344887', (10, 17))	('induction', 'MPA', (43, 52))	('THC', 'Chemical', '-', (56, 59))	('inhibited', 'NegReg', (28, 37))	('NQO1', 'Gene', (38, 42))	('NQO1', 'Gene', '1728', (38, 42))	('NMRAL2P', 'Gene', (10, 17))
159847	30737573	In addition, 2-oxoglutaric acid-dependent dioxygenases mediate the demethylation of DNA and histones, which is involved in regulation of the expression of many genes, and depletion of 2-oxoglutaric acid was able to cause epigenetic changes.	('demethylation', 'MPA', (67, 80))	('2-oxoglutaric acid', 'Chemical', 'MESH:D007656', (13, 31))	('2-oxoglutaric acid', 'Chemical', 'MESH:D007656', (184, 202))	('depletion', 'Var', (171, 180))
159851	30737573	To examine the role of NQO1 in THC-mediated cytotoxicity in ESCC cells, we performed the experiments using cells with NQO1 gene modification and/or NQO1 inhibitors.	('NQO1', 'Gene', (118, 122))	('THC', 'Chemical', '-', (31, 34))	('NQO1', 'Gene', '1728', (148, 152))	('cytotoxicity', 'Disease', (44, 56))	('NQO1', 'Gene', (23, 27))	('NQO1', 'Gene', '1728', (118, 122))	('NQO1', 'Gene', '1728', (23, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (44, 56))	('NQO1', 'Gene', (148, 152))	('gene modification', 'Var', (123, 140))
159855	30737573	Accordingly, we thought that inhibition of NQO1 could enhance the antitumor effects of THC and we revealed that the strategy is effective.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('NQO1', 'Gene', (43, 47))	('THC', 'Chemical', '-', (87, 90))	('tumor', 'Disease', (70, 75))	('NQO1', 'Gene', '1728', (43, 47))	('enhance', 'PosReg', (54, 61))	('inhibition', 'Var', (29, 39))
159864	30737573	Importantly, NQO1 inhibitor enhanced the THC-induced antitumor effects (Supplementary Fig.	('inhibitor', 'Var', (18, 27))	('enhanced', 'PosReg', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('NQO1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('NQO1', 'Gene', '1728', (13, 17))	('tumor', 'Disease', (57, 62))	('THC', 'Chemical', '-', (41, 44))
159918	28385379	Overexpression of CCL28 has been shown to be associated with tumor progression in other studies of SCC, but to our knowledge, this gene has not been studied exclusively in EAC tumors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('CCL28', 'Chemical', '-', (18, 23))	('SCC', 'Disease', (99, 102))	('tumor', 'Disease', (176, 181))	('CCL28', 'Gene', (18, 23))	('associated', 'Reg', (45, 55))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('EAC', 'Phenotype', 'HP:0011459', (172, 175))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
159959	29780579	While in any patient with suspected liver cirrhosis a standard examination used to include endoscopy, new guidelines recommend abstaining from early endoscopy in patients with liver stiffness <20 kPa and platelet count >150 G/L , .	('patient', 'Species', '9606', (162, 169))	('patients', 'Species', '9606', (162, 170))	('liver cirrhosis', 'Disease', (36, 51))	('patient', 'Species', '9606', (13, 20))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (36, 51))	('cirrhosis', 'Phenotype', 'HP:0001394', (42, 51))	('liver stiffness', 'Disease', (176, 191))	('<20 kPa', 'Var', (192, 199))	('liver stiffness', 'Disease', 'MESH:D017093', (176, 191))	('liver cirrhosis', 'Disease', 'MESH:D008103', (36, 51))	('>150', 'Var', (219, 223))
159981	29780579	Patients with compensated cirrhosis and HVPG <10 mmHg have a rather low risk of developing varices or decompensation of liver function .	('cirrhosis', 'Phenotype', 'HP:0001394', (26, 35))	('decompensation of liver function', 'Phenotype', 'HP:0001410', (102, 134))	('varices', 'Disease', (91, 98))	('cirrhosis', 'Disease', 'MESH:D005355', (26, 35))	('<10', 'Var', (45, 48))	('Patients', 'Species', '9606', (0, 8))	('cirrhosis', 'Disease', (26, 35))
160020	29780579	In most patients, TIPS implantation reduces portal pressure by more than 50%, as assessed by the portal pressure gradient.	('reduces', 'NegReg', (36, 43))	('implantation', 'Var', (23, 35))	('portal pressure', 'MPA', (44, 59))	('patients', 'Species', '9606', (8, 16))
160056	29780579	It is worth noting that it has been argued in this context that NSBB, besides their effect on splanchnic hemodynamics, modulate systemic inflammation in liver cirrhosis .	('liver cirrhosis', 'Disease', (153, 168))	('systemic inflammation', 'Disease', (128, 149))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (153, 168))	('NSBB', 'Var', (64, 68))	('modulate', 'Reg', (119, 127))	('systemic inflammation', 'Disease', 'MESH:D007249', (128, 149))	('liver cirrhosis', 'Disease', 'MESH:D008103', (153, 168))	('inflammation in liver', 'Phenotype', 'HP:0012115', (137, 158))	('cirrhosis', 'Phenotype', 'HP:0001394', (159, 168))
160059	29780579	The type of NSBB for patients with liver cirrhosis has become an issue since it has been shown that, in patients with cirrhosis, carvedilol, a NSBB with additional alpha-1 adrenoceptor-blocking properties, induces a better hemodynamic response , , as determined by HVPG drop, than propranolol or nadolol and prevents the progression of small esophageal varices , an effect not found with propranolol.	('hemodynamic response', 'MPA', (223, 243))	('prevents', 'NegReg', (308, 316))	('liver cirrhosis', 'Disease', 'MESH:D008103', (35, 50))	('patients', 'Species', '9606', (21, 29))	('cirrhosis', 'Phenotype', 'HP:0001394', (41, 50))	('carvedilol', 'Chemical', 'MESH:D000077261', (129, 139))	('propranolol', 'Chemical', 'MESH:D011433', (281, 292))	('induces', 'PosReg', (206, 213))	('cirrhosis', 'Disease', 'MESH:D005355', (118, 127))	('cirrhosis', 'Disease', (41, 50))	('propranolol', 'Chemical', 'MESH:D011433', (388, 399))	('nadolol', 'Chemical', 'MESH:D009248', (296, 303))	('liver cirrhosis', 'Disease', (35, 50))	('cirrhosis', 'Phenotype', 'HP:0001394', (118, 127))	('better', 'PosReg', (216, 222))	('cirrhosis', 'Disease', (118, 127))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (35, 50))	('patients', 'Species', '9606', (104, 112))	('carvedilol', 'Var', (129, 139))	('esophageal varices', 'Phenotype', 'HP:0002040', (342, 360))	('small esophageal varices', 'Disease', (336, 360))	('cirrhosis', 'Disease', 'MESH:D005355', (41, 50))
160060	29780579	Retrospective data even asserted the prolongation of survival in patients with cirrhosis and ascites receiving carvedilol , while a recent letter analyzing several clinical studies drew the conclusion that carvedilol may even increase mortality compared to propranolol and nadolol .	('cirrhosis', 'Disease', (79, 88))	('carvedilol', 'Chemical', 'MESH:D000077261', (206, 216))	('carvedilol', 'Var', (206, 216))	('carvedilol', 'Chemical', 'MESH:D000077261', (111, 121))	('nadolol', 'Chemical', 'MESH:D009248', (273, 280))	('prolongation', 'PosReg', (37, 49))	('mortality', 'MPA', (235, 244))	('cirrhosis', 'Phenotype', 'HP:0001394', (79, 88))	('cirrhosis', 'Disease', 'MESH:D005355', (79, 88))	('ascites', 'Disease', (93, 100))	('patients', 'Species', '9606', (65, 73))	('ascites', 'Phenotype', 'HP:0001541', (93, 100))	('increase', 'PosReg', (226, 234))	('ascites', 'Disease', 'MESH:D001201', (93, 100))	('propranolol', 'Chemical', 'MESH:D011433', (257, 268))
160068	29780579	Important among these are increased intrahepatic formation of the vasodilator nitric oxide , downregulation of signaling molecules that activate hepatic stellate cells -  by reduced prenylation of small GTPases, modulation of the crosstalk between hepatic stellate cells and endothelial cells, upregulation of transcription factors that restore intrahepatic endothelial function , and downregulation of intrahepatic inflammatory cytokines , .	('intrahepatic inflammatory cytokines', 'MPA', (403, 438))	('prenylation', 'MPA', (182, 193))	('modulation', 'Var', (212, 222))	('intrahepatic endothelial function', 'MPA', (345, 378))	('upregulation', 'PosReg', (294, 306))	('nitric oxide', 'Chemical', 'MESH:D009569', (78, 90))	('downregulation', 'NegReg', (385, 399))	('transcription factors', 'Gene', (310, 331))	('increased', 'PosReg', (26, 35))	('restore', 'PosReg', (337, 344))	('reduced', 'NegReg', (174, 181))	('downregulation', 'NegReg', (93, 107))	('crosstalk', 'Interaction', (230, 239))
160081	29780579	Alcohol is the most common cause of progressive liver dysfunction and portal hypertension in the Western world , although only a minority of heavy drinkers develop liver cirrhosis , .	('hypertension', 'Disease', 'MESH:D006973', (77, 89))	('cirrhosis', 'Phenotype', 'HP:0001394', (170, 179))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('hypertension', 'Disease', (77, 89))	('liver dysfunction', 'Phenotype', 'HP:0001410', (48, 65))	('liver dysfunction', 'Disease', (48, 65))	('hypertension', 'Phenotype', 'HP:0000822', (77, 89))	('cause', 'Reg', (27, 32))	('liver cirrhosis', 'Disease', (164, 179))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (164, 179))	('portal hypertension', 'Phenotype', 'HP:0001409', (70, 89))	('Alcohol', 'Var', (0, 7))	('liver dysfunction', 'Disease', 'MESH:D017093', (48, 65))	('liver cirrhosis', 'Disease', 'MESH:D008103', (164, 179))
160122	29780579	One small randomized study found not only a significantly reduced occurrence of portal vein thrombosis but also fewer events of decompensation and even improved survival in patients with advanced cirrhosis receiving low-molecular-weight heparin over a period of nearly one year .	('cirrhosis', 'Disease', (196, 205))	('vein thrombosis', 'Disease', 'MESH:D020246', (87, 102))	('vein thrombosis', 'Disease', (87, 102))	('patients', 'Species', '9606', (173, 181))	('portal vein thrombosis', 'Phenotype', 'HP:0030242', (80, 102))	('vein thrombosis', 'Phenotype', 'HP:0004936', (87, 102))	('portal', 'Disease', (80, 86))	('improved', 'PosReg', (152, 160))	('heparin', 'Chemical', 'MESH:D006493', (237, 244))	('cirrhosis', 'Phenotype', 'HP:0001394', (196, 205))	('cirrhosis', 'Disease', 'MESH:D005355', (196, 205))	('survival', 'MPA', (161, 169))	('reduced', 'NegReg', (58, 65))	('low-molecular-weight', 'Var', (216, 236))
160136	29780579	At this stage, reduction of portal hypertension by modulation of the intestine as a source of inflammatory stimuli or retarding inflammatory pathways may be promising strategies.	('modulation', 'Var', (51, 61))	('inflammatory pathways', 'Pathway', (128, 149))	('hypertension', 'Disease', 'MESH:D006973', (35, 47))	('reduction', 'NegReg', (15, 24))	('hypertension', 'Disease', (35, 47))	('hypertension', 'Phenotype', 'HP:0000822', (35, 47))	('portal hypertension', 'Phenotype', 'HP:0001409', (28, 47))
160142	29780579	Interruption or modulation of inflammatory stimuli leading to liver damage and dysfunction of other organs is key in order to prevent death or liver transplantation as ultimate rescue.	('liver damage and dysfunction', 'Disease', 'MESH:D008107', (62, 90))	('death', 'Disease', (134, 139))	('modulation', 'Var', (16, 26))	('death', 'Disease', 'MESH:D003643', (134, 139))
160209	28983230	However, in case of low-grade dysplasia, or reactive atypia by Western criteria, it may take a longer time in Poland than in Japan to confirm that the lesion is actually invasive carcinoma, and then, the risk of the lesion to develop up to advanced carcinoma becomes high.	('carcinoma', 'Disease', (179, 188))	('invasive carcinoma', 'Disease', 'MESH:D009361', (170, 188))	('low-grade', 'Var', (20, 29))	('carcinoma', 'Disease', 'MESH:D002277', (249, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('invasive carcinoma', 'Disease', (170, 188))	('carcinoma', 'Disease', 'MESH:D002277', (179, 188))	('carcinoma', 'Disease', (249, 258))	('dysplasia', 'Disease', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('dysplasia', 'Disease', 'MESH:D004476', (30, 39))
160295	25607998	Folate may prevent tumor development before the existence of preneoplastic lesions, but increase tumorigenesis once preneoplastic lesions are established.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('increase', 'PosReg', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (97, 102))	('prevent', 'NegReg', (11, 18))	('Folate', 'Var', (0, 6))	('tumor', 'Disease', (19, 24))
160318	25607998	Similarly, in the Danish cohort study, the risk of liver cancer associated with elevated B12 remained robust after the stratification on prior liver diseases, indicating that underlying liver diseases did not confound this association.	('liver cancer', 'Phenotype', 'HP:0002896', (51, 63))	('liver diseases', 'Phenotype', 'HP:0001392', (143, 157))	('liver diseases', 'Disease', (143, 157))	('B12', 'Gene', (89, 92))	('B12', 'Gene', '4709', (89, 92))	('liver diseases', 'Disease', 'MESH:D008107', (143, 157))	('liver cancer', 'Disease', 'MESH:D006528', (51, 63))	('elevated', 'Var', (80, 88))	('liver cancer', 'Disease', (51, 63))	('liver diseases', 'Disease', 'MESH:D008107', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('liver diseases', 'Phenotype', 'HP:0001392', (186, 200))	('liver diseases', 'Disease', (186, 200))
160323	25607998	Such finding seems to be consistent with the before-mentioned observation in rodent models that the additional removal of vitamin B12 from folate-/methyl-deficient diet may not effectively induce hepatocarcinogenesis.	('hepatocarcinogenesis', 'Disease', (196, 216))	('induce', 'Reg', (189, 195))	('removal', 'Var', (111, 118))	('B12', 'Gene', (130, 133))	('folate', 'Chemical', 'MESH:D005492', (139, 145))	('B12', 'Gene', '4709', (130, 133))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (196, 216))
160380	26098635	Hemodynamically instable patients with insufficient response to volume-therapy, catecholamine dependence, reduced vigilance or repetitive blood regurgitation were transferred to a intensive care unit (ICU) where protective intubation was performed before endoscopy.	('insufficient', 'Disease', 'MESH:D000309', (39, 51))	('vigilance', 'MPA', (114, 123))	('catecholamine', 'Chemical', 'MESH:D002395', (80, 93))	('reduced vigilance', 'Phenotype', 'HP:0032044', (106, 123))	('patients', 'Species', '9606', (25, 33))	('repetitive blood regurgitation', 'Disease', 'MESH:D006402', (127, 157))	('catecholamine', 'Var', (80, 93))	('reduced', 'NegReg', (106, 113))	('repetitive blood regurgitation', 'Disease', (127, 157))	('insufficient', 'Disease', (39, 51))
160454	26098635	Moreover blind delivery might lead to via falsa pulmonary damage and should therefore be limited to ultima ratio situations with absence of an endoscopic facility.	('blind', 'Var', (9, 14))	('lead to', 'Reg', (30, 37))	('falsa pulmonary damage', 'Disease', (42, 64))	('falsa pulmonary damage', 'Disease', 'MESH:D008171', (42, 64))
160469	26076456	Deregulated HOXB7 Expression Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma and Regulates Cancer Cell Proliferation In Vitro and In Vivo We observed abnormal HOXB7 expression in esophageal squamous cell carcinoma (ESCC) previously.	('Patients', 'Species', '9606', (56, 64))	('Deregulated', 'Var', (0, 11))	('Carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('Cancer', 'Disease', (119, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (218, 241))	('HOXB7', 'Gene', '3217', (187, 192))	('HOXB7', 'Gene', '3217', (12, 17))	('Cancer', 'Disease', 'MESH:D009369', (119, 125))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('HOXB7', 'Gene', (187, 192))	('HOXB7', 'Gene', (12, 17))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (207, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('Esophageal Squamous Cell Carcinoma', 'Disease', (70, 104))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('esophageal squamous cell carcinoma', 'Disease', (207, 241))
160473	26076456	The median survival of patients with high HOXB7 expression was significantly shorter than that with low expression (45 months vs. 137 months, p = 0.007 for cohort 1; 19 months vs. 34 months, p = 0.001 for cohort 2).	('patients', 'Species', '9606', (23, 31))	('shorter', 'NegReg', (77, 84))	('HOXB7', 'Gene', (42, 47))	('high', 'Var', (37, 41))
160474	26076456	Experiments in vitro and in vivo showed that after knockdown of HOXB7, the proliferation rate dropped, growth rate descended, colony-formation ability reduced, G1-phase arrest occurred and the tumorigenicity reduced remarkably.	('descended', 'NegReg', (115, 124))	('reduced', 'NegReg', (151, 158))	('occurred', 'Reg', (176, 184))	('arrest', 'Disease', 'MESH:D006323', (169, 175))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('reduced', 'NegReg', (208, 215))	('growth rate', 'CPA', (103, 114))	('colony-formation ability', 'CPA', (126, 150))	('arrest', 'Disease', (169, 175))	('dropped', 'NegReg', (94, 101))	('HOXB7', 'Gene', (64, 69))	('knockdown', 'Var', (51, 60))
160532	26076456	The median survival time was 45 months for patients with high expression, which was significantly shorter than the 137 months for patients with low expression (Table 2).	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (130, 138))	('shorter', 'NegReg', (98, 105))	('high expression', 'Var', (57, 72))
160540	26076456	Cell strains with EC109/Scramble, EC109/shHOXB7 and KYSE150/Scramble, KYSE150/shHOXB7 cells were injected into nude mice.	('nude mice', 'Species', '10090', (111, 120))	('EC109/Scramble', 'Var', (18, 32))	('KYSE150/Scramble', 'Var', (52, 68))	('EC109/shHOXB7', 'Var', (34, 47))
160542	26076456	As shown in Fig 3A and 3B, the tumors formed by the EC109/shHOXB7 and KYSE150/shHOXB7 cells were significantly smaller than those of control cells-formed tumors.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (154, 160))	('KYSE150/shHOXB7', 'Var', (70, 85))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('EC109/shHOXB7', 'Var', (52, 65))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('smaller', 'NegReg', (111, 118))
160543	26076456	The average weight and volume of tumors in EC109/shHOXB7 group were 869+-295 mg and 870+-370 mm3, respectively, compared with 1292+-453 mg and 1416+-472 mm3 in the EC109/Scramble group (P <0.05).	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('EC109/shHOXB7', 'Var', (43, 56))	('tumors', 'Disease', (33, 39))
160544	26076456	The average weight and volume of tumors in KYSE150/shHOXB7 group were 415+-254 mg and 603+-362 mm3, respectively, compared with 697+-253 mg and 1069+-377 mm3 in the KYSE150/Scramble group (P <0.05).	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('KYSE150/shHOXB7', 'Var', (43, 58))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))
160545	26076456	As shown in Fig 3C, knockdown of HOXB7 protein resulted in G1 arrest, with an increase in G1 proportion and a decrease in S and G2 proportion.	('G1 proportion', 'MPA', (90, 103))	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('arrest', 'Disease', (62, 68))	('increase', 'PosReg', (78, 86))	('S and', 'MPA', (122, 127))	('decrease', 'NegReg', (110, 118))	('HOXB7', 'Gene', (33, 38))	('knockdown', 'Var', (20, 29))	('protein', 'Protein', (39, 46))
160554	26076456	The median survival time of patients with high HOXB7 expression was significantly shorter than that of patients with low HOXB7 expression (45 months vs. 137 months, p = 0.007).	('high HOXB7', 'Var', (42, 52))	('survival time', 'CPA', (11, 24))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (28, 36))	('shorter', 'NegReg', (82, 89))
160557	26076456	The median survival time of patients with high HOXB7 expression was significantly shorter than that of patients with low HOXB7 expression (19 months vs. 34 months, p = 0.001).	('high HOXB7', 'Var', (42, 52))	('survival time', 'CPA', (11, 24))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (28, 36))	('shorter', 'NegReg', (82, 89))
160558	26076456	Moreover, multivariate analysis with variables including age, sex, tumor location, TNM stage, T stage, N stage, and HOXB7 expression showed that HOXB7 expression and TNM stage were independent prognostic factors in 177 patients recruited in the prospective database (HR[95%CI] = 0.573, [0.341-0.963], p = 0.036) and 103 patients recruited in another cohort without prospective data (HR[95%CI] = 0.543, [0.350-0.844], p = 0.024), indicating that HOXB7 had prognostic value for patients with ESCC.	('TNM', 'Gene', (166, 169))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ESCC', 'Disease', (490, 494))	('patients', 'Species', '9606', (476, 484))	('TNM', 'Gene', '10178', (166, 169))	('TNM', 'Gene', '10178', (83, 86))	('HOXB7', 'Var', (445, 450))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('TNM', 'Gene', (83, 86))	('patients', 'Species', '9606', (320, 328))
160559	26076456	Our results showed that the rate of cell proliferation was slower in HOXB7-knockdown cell strains, colony formation rate was reduced, G1-phase arrest occurred in the malignant cells, and the proportion of cells in G1 phases increased significantly.	('HOXB7-knockdown', 'Var', (69, 84))	('arrest', 'Disease', (143, 149))	('reduced', 'NegReg', (125, 132))	('colony formation rate', 'CPA', (99, 120))	('slower', 'NegReg', (59, 65))	('arrest', 'Disease', 'MESH:D006323', (143, 149))	('increased', 'PosReg', (224, 233))	('cell proliferation', 'CPA', (36, 54))
160561	26076456	In fact, the dysregulation of HOXB7 expression has been reported in a variety of tumors, including breast cancer, ovarian cancer, oral cancer, colorectal cancer, lung cancer, melanoma and pancreatic cancer.	('tumors', 'Disease', (81, 87))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('dysregulation', 'Var', (13, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('melanoma', 'Disease', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))	('oral cancer', 'Disease', 'MESH:D009062', (130, 141))	('pancreatic cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('oral cancer', 'Disease', (130, 141))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('colorectal cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ovarian cancer', 'Disease', (114, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('reported', 'Reg', (56, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('lung cancer', 'Disease', (162, 173))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('HOXB7', 'Gene', (30, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))
160564	26076456	Based on the above-discussed preliminary findings, we believe that HOXB7 is likely to be identified as a prognostic biomarker for ESCC patients, and abnormal HOXB7 expression could affect the proliferative capacity of cells.	('HOXB7', 'Gene', (158, 163))	('patients', 'Species', '9606', (135, 143))	('ESCC', 'Disease', (130, 134))	('expression', 'MPA', (164, 174))	('abnormal', 'Var', (149, 157))	('proliferative capacity of cells', 'CPA', (192, 223))	('affect', 'Reg', (181, 187))
160569	26076456	The expression of bFGF could activate Ras-RAF-MAPK pathway through autocrine signaling cascades in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('bFGF', 'Gene', '2247', (18, 22))	('autocrine signaling', 'MPA', (67, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('Ras-RAF-MAPK pathway', 'Pathway', (38, 58))	('bFGF', 'Gene', (18, 22))	('expression', 'Var', (4, 14))	('activate', 'PosReg', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
160669	23823625	Among the participants are Dr. Franklin Salisbury [President of National Foundation for Cancer Research (NFCR)], Dr. Sujuan Ba [President for Asian Fund for Cancer Research (AFCR) and Chief Operating Officer of NFCR], and Dr. Frederic Biemar (Senior Program Administrator, Stand Up To Cancer, Scientific Review and Grants Administration Department at AACR), who represented AACR.	('Cancer', 'Disease', 'MESH:D009369', (88, 94))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Dr.', 'Var', (113, 116))	('Cancer', 'Phenotype', 'HP:0002664', (285, 291))	('Cancer', 'Disease', (157, 163))	('participants', 'Species', '9606', (10, 22))	('Cancer', 'Disease', 'MESH:D009369', (157, 163))	('Cancer', 'Disease', (285, 291))	('Cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Cancer', 'Disease', 'MESH:D009369', (285, 291))	('Cancer', 'Disease', (88, 94))
160678	23823625	Dr. Zhang ended his speech by introducing the newly elected President of USCACA, Dr. Shiyuan Cheng, Professor in the Ken & Ruth Davee Department of Neurology, the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine.	('Dr. Shiyuan', 'Var', (81, 92))	('Cancer', 'Disease', 'MESH:D009369', (193, 199))	('Ken', 'Gene', (117, 120))	('Ken', 'Gene', '5116', (117, 120))	('Cancer', 'Phenotype', 'HP:0002664', (193, 199))	('Cancer', 'Disease', (193, 199))
160729	21939555	One potential candidate is nuclear factor-kappaB (NF-kappaB), a sequence-specific transcription factor that responds to cellular signaling pathways involved in cell survival and resistance to chemotherapy; notably, aberrant NF-kappaB activation has been associated with some malignancies.	('malignancies', 'Disease', 'MESH:D009369', (275, 287))	('associated', 'Reg', (254, 264))	('NF-kappaB', 'Gene', '4790', (224, 233))	('malignancies', 'Disease', (275, 287))	('NF-kappaB', 'Gene', (224, 233))	('aberrant', 'Var', (215, 223))	('NF-kappaB', 'Gene', '4790', (50, 59))	('activation', 'PosReg', (234, 244))	('NF-kappaB', 'Gene', (50, 59))
160730	21939555	Although abnormities of NF-kappaB signaling have been reported to play an important role in carcinogenesis by promoting tumor-induced angiogenesis and neoplastic proliferation, the association of NF-kappaB with lymphangiogenesis in ESCC is less clear.	('neoplastic proliferation', 'CPA', (151, 175))	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('ESCC', 'Disease', (232, 236))	('carcinogenesis', 'Disease', (92, 106))	('NF-kappaB', 'Gene', '4790', (196, 205))	('NF-kappaB', 'Gene', '4790', (24, 33))	('abnormities', 'Var', (9, 20))	('promoting', 'PosReg', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('neoplastic proliferation', 'Phenotype', 'HP:0002664', (151, 175))	('NF-kappaB', 'Gene', (196, 205))	('NF-kappaB', 'Gene', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
160790	21939555	The mechanistic aspect of the linkage between NF-kappaB and LVD was supported by the report that activation of NF-kappaB followed by sequential up-regulation of VEGFR-3 expression in cultured lymphatic endothelial cells and increasing of proliferation and migration, it suggested that induction of NF-kappaB enhanced the responsiveness of preexisting lymphatic endothelium to VEGFR-3 binding factors and resulted in lymphangiogenesis.	('NF-kappaB', 'Gene', (46, 55))	('enhanced', 'PosReg', (308, 316))	('lymphangiogenesis', 'CPA', (416, 433))	('NF-kappaB', 'Gene', '4790', (298, 307))	('resulted in', 'Reg', (404, 415))	('induction', 'Var', (285, 294))	('NF-kappaB', 'Gene', (298, 307))	('NF-kappaB', 'Gene', '4790', (111, 120))	('NF-kappaB', 'Gene', '4790', (46, 55))	('responsiveness', 'MPA', (321, 335))	('NF-kappaB', 'Gene', (111, 120))
160795	21939555	In a malignant environment, such as invasive breast carcinoma, cleaved (activated) Notch1 has been observed in a subset of lymphatic endothelial nuclei, indicating that Notch1 is not only expressed but is activated in tumor lymphatic vessels.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('cleaved', 'Var', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('Notch1', 'Gene', (83, 89))	('Notch1', 'Gene', '4851', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('Notch1', 'Gene', (169, 175))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (36, 61))	('tumor', 'Disease', (218, 223))	('Notch1', 'Gene', '4851', (169, 175))	('breast carcinoma', 'Phenotype', 'HP:0003002', (45, 61))	('invasive breast carcinoma', 'Disease', (36, 61))
160865	33713583	Western blot analyses showed that the protein expression level of MMP-10 in ESCC cells (especially EC109 and EC9706) were significantly higher than that of the normal human esophageal epithelial cell line (Figure S1a,b).	('EC9706', 'CellLine', 'CVCL:E307', (109, 115))	('protein expression level', 'MPA', (38, 62))	('higher', 'PosReg', (136, 142))	('EC9706', 'Var', (109, 115))	('MMP-10', 'Gene', (66, 72))	('MMP-10', 'Gene', '4319', (66, 72))	('human', 'Species', '9606', (167, 172))
160875	33713583	siRNA interference of MMP10 was shown to enhance the enrichment of E-cadherin and the decrease of N-cadherin and MMP10 (Figure 3a-c).	('N-cadherin', 'Gene', (98, 108))	('MMP10', 'Gene', (22, 27))	('enhance', 'PosReg', (41, 48))	('N-cadherin', 'Gene', '1000', (98, 108))	('E-cadherin', 'Gene', (67, 77))	('E-cadherin', 'Gene', '999', (67, 77))	('decrease', 'NegReg', (86, 94))	('siRNA interference', 'MPA', (0, 18))	('enrichment', 'MPA', (53, 63))	('MMP10', 'Var', (113, 118))
160896	33713583	Activation of MMP10 has been previously reported to stimulate cancer cell proliferation, migration and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('MMP10', 'Gene', (14, 19))	('cancer', 'Disease', (62, 68))	('Activation', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('stimulate', 'PosReg', (52, 61))	('migration', 'CPA', (89, 98))
160956	33244736	We identified statistically significant differences in baseline characteristics between patients with adv/met GC/GEJC and patients with adv/met EAC that reflect underlying differences in disease epidemiology.	('significant differences', 'Reg', (28, 51))	('adv/met', 'Var', (102, 109))	('patients', 'Species', '9606', (88, 96))	('GC', 'Phenotype', 'HP:0012126', (110, 112))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('patients', 'Species', '9606', (122, 130))
160965	33244736	However, we did observe that first-line taxane plus platinum-based therapy appeared to be lower in patients with adv/met GC/GEJC than with adv/met EAC.	('platinum', 'Chemical', 'MESH:D010984', (52, 60))	('EAC', 'Phenotype', 'HP:0011459', (147, 150))	('GC', 'Phenotype', 'HP:0012126', (121, 123))	('patients', 'Species', '9606', (99, 107))	('lower', 'NegReg', (90, 95))	('taxane', 'Chemical', 'MESH:C080625', (40, 46))	('adv/met GC/GEJC', 'Var', (113, 128))
160970	33244736	Expression of other biomarkers, including microsatellite instability-high or deficient mismatch repair, programmed death 1/programmed death ligand 1, and Epstein-Barr virus, may differ between EAC, GC, and GEJC, but as these biomarkers were not routinely tested for in clinical practice during the study observation period (2011-2018), we were unable to consider their impact in the current study.	('deficient', 'NegReg', (77, 86))	('death', 'Disease', 'MESH:D003643', (134, 139))	('microsatellite instability-high', 'Var', (42, 73))	('death', 'Disease', (134, 139))	('death', 'Disease', 'MESH:D003643', (115, 120))	('death', 'Disease', (115, 120))	('differ', 'Reg', (178, 184))	('EAC', 'Phenotype', 'HP:0011459', (193, 196))	('GC', 'Phenotype', 'HP:0012126', (198, 200))
160976	33244736	Additionally, Flatiron holds no information on tumor mutational burden and microsatellite instability, which are known prognostic indicators in multiple solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('microsatellite instability', 'Var', (75, 101))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (47, 52))
161147	31186263	In this study, we tested whether higher levels of circulating 25(OH)D are associated with better overall survival among patients with esophageal adenocarcinoma.	('25(OH)D', 'Var', (62, 69))	('25(OH)D', 'Chemical', 'MESH:C101470', (62, 69))	('overall', 'MPA', (97, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('better', 'PosReg', (90, 96))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (134, 159))	('esophageal adenocarcinoma', 'Disease', (134, 159))	('patients', 'Species', '9606', (120, 128))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (134, 159))
161210	31186263	Nor did we find evidence that the association of 25(OH)D on overall survival in esophageal adenocarcinoma patients differs by stage at diagnosis or BMI at diagnosis.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('25(OH)D', 'Var', (49, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('25(OH)D', 'Chemical', 'MESH:C101470', (49, 56))	('patients', 'Species', '9606', (106, 114))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (80, 105))	('esophageal adenocarcinoma', 'Disease', (80, 105))
161215	31186263	At least one study in esophageal squamous cell carcinoma reported patients with >10ng/mL 25(OH)D at time of diagnosis had longer overall survival than those with <10ng/mL, but they did not clearly report if or how they adjusted for the effects of seasonal variability of blood draw.	('esophageal squamous cell carcinoma', 'Disease', (22, 56))	('longer', 'PosReg', (122, 128))	('25(OH)D', 'Chemical', 'MESH:C101470', (89, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (22, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('overall survival', 'MPA', (129, 145))	('>10ng/mL 25', 'Var', (80, 91))	('patients', 'Species', '9606', (66, 74))
161218	31186263	Human observational studies, Mendelian randomization studies, and RCTs have reported that low levels of vitamin D are associated with increased risk of total cancer mortality.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('vitamin D', 'Chemical', 'MESH:D014807', (104, 113))	('low levels of vitamin D', 'Phenotype', 'HP:0100512', (90, 113))	('cancer', 'Disease', (158, 164))	('low levels', 'Var', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
161237	31186263	In contrast, another recent longitudinal study of melanoma patients found that baseline levels of 25(OH)D were not associated with risk of relapse but change in 25(OH)D during follow-up (both increased and decreased) was associated with worse prognosis, although they did not report change in vitamin D status per specific treatment modality.	('25(OH)D', 'Chemical', 'MESH:C101470', (98, 105))	('25(OH)D', 'Chemical', 'MESH:C101470', (161, 168))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('decreased', 'NegReg', (206, 215))	('change', 'Var', (151, 157))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('vitamin D', 'Chemical', 'MESH:D014807', (293, 302))	('patients', 'Species', '9606', (59, 67))	('men', 'Species', '9606', (328, 331))
161247	31186263	A recent trial of vitamin D supplementation found those taking supplementation had reduced risk of cancer mortality, and the association was strongest after excluding the first 2 years of follow-up after cancer diagnosis.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('men', 'Species', '9606', (69, 72))	('vitamin D', 'Chemical', 'MESH:D014807', (18, 27))	('reduced', 'NegReg', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', (99, 105))	('supplementation', 'Var', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('men', 'Species', '9606', (34, 37))
161281	27781415	Eight human ESCC cell lines, including CaES-17, EC18 (gift from Professor Guan), Eca109, EC9706, KYSE-140, KYSE-450,KYSE-510, and TE-1, one immortalized human normal esophageal epithelial cell (HEEC), and one human embryonic kidney 293 (HEK293) cell lines purchased commercially were maintained in Dulbecco's modified Eagle's medium (Invitrogen, San Diego, CA) supplemented with 10% fetal bovine serum (HyClone, Logan, UT) and 1% penicillin/streptomycin in a humidified atmosphere with 5% CO2.	('human', 'Species', '9606', (209, 214))	('293 (HEK293)', 'CellLine', 'CVCL:0045', (232, 244))	('EC9706', 'CellLine', 'CVCL:E307', (89, 95))	('KYSE-510', 'Var', (116, 124))	('human', 'Species', '9606', (153, 158))	('p', 'Gene', '8202', (178, 179))	('EC18', 'CellLine', 'CVCL:5V07', (48, 52))	('P', 'Gene', '8202', (64, 65))	('p', 'Gene', '8202', (169, 170))	('p', 'Gene', '8202', (256, 257))	('EC9706', 'Var', (89, 95))	('bovine', 'Species', '9913', (389, 395))	('embryonic kidney', 'Disease', (215, 231))	('p', 'Gene', '8202', (430, 431))	('human', 'Species', '9606', (6, 11))	('p', 'Gene', '8202', (445, 446))	('p', 'Gene', '8202', (364, 365))	('KYSE-450', 'Var', (107, 115))	('embryonic kidney', 'Disease', 'MESH:D007674', (215, 231))	('p', 'Gene', '8202', (475, 476))	('p', 'Gene', '8202', (363, 364))	('KYSE-140', 'Var', (97, 105))
161303	27781415	As shown in Figure 1D, patients whose tumors have high SRC-3 levels by immunohistochemistry have significantly shorter overall (P = 0.0076, log-rank test) and progression-free (P = 0.0069, log-rank test) survival time than patients with low SRC-3 levels.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('p', 'Gene', '8202', (159, 160))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (23, 31))	('p', 'Gene', '8202', (23, 24))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('SRC-3', 'Gene', (55, 60))	('shorter', 'NegReg', (111, 118))	('P', 'Gene', '8202', (128, 129))	('patients', 'Species', '9606', (223, 231))	('p', 'Gene', '8202', (223, 224))	('P', 'Gene', '8202', (177, 178))	('high', 'Var', (50, 54))
161308	27781415	Western blot experiment confirmed significant reduction in SRC-3 expression in SRC-3 knockdown cells relative to a scrambled control shRNA (Fig.	('reduction', 'NegReg', (46, 55))	('p', 'Gene', '8202', (15, 16))	('SRC-3', 'Gene', (59, 64))	('SRC-3', 'Gene', (79, 84))	('p', 'Gene', '8202', (67, 68))	('knockdown', 'Var', (85, 94))
161309	27781415	2B, the proliferation rate of endogenous SRC-3 knockdown Eca109 cells, as assessed by the BrdU assay, was significantly reduced to 44% compared to the scrambled control cells.	('p', 'Gene', '8202', (8, 9))	('SRC-3', 'Gene', (41, 46))	('knockdown', 'Var', (47, 56))	('BrdU', 'Chemical', 'MESH:D001973', (90, 94))	('p', 'Gene', '8202', (138, 139))	('reduced', 'NegReg', (120, 127))
161311	27781415	In the MTT assay, relative cell viability of SRC-3 knockdown Eca109 and EC18 cells was significantly reduced to 55% and 52% by the seventh day, respectively (Fig.	('MTT', 'Chemical', '-', (7, 10))	('cell viability', 'CPA', (27, 41))	('SRC-3', 'Gene', (45, 50))	('EC18', 'CellLine', 'CVCL:5V07', (72, 76))	('reduced', 'NegReg', (101, 108))	('p', 'Gene', '8202', (147, 148))	('knockdown', 'Var', (51, 60))
161313	27781415	As shown in Figure 2D and E, silencing SRC-3 significantly decreased the colony formation in both assays, demonstrating that SRC-3 enhances anchorage-independent growth and colony formation.	('colony formation', 'CPA', (73, 89))	('enhances', 'PosReg', (131, 139))	('colony formation', 'CPA', (173, 189))	('decreased', 'NegReg', (59, 68))	('silencing', 'Var', (29, 38))	('p', 'Gene', '8202', (154, 155))	('SRC-3', 'Var', (125, 130))	('SRC-3', 'Gene', (39, 44))
161314	27781415	To elucidate the mechanism underlying growth inhibition by downregulation of SRC-3, flow cytometric analysis was performed to compare cell distributions in cell cycle between SRC-3 knockdown cells and control cells.	('SRC-3', 'Gene', (175, 180))	('p', 'Gene', '8202', (129, 130))	('downregulation', 'NegReg', (59, 73))	('p', 'Gene', '8202', (113, 114))	('knockdown', 'Var', (181, 190))	('SRC-3', 'Gene', (77, 82))
161315	27781415	The percentage of SRC-3 knockdown cells in G0/G1 phases was increased by 11% and 20% in Eca109 and EC18 cells, respectively; and this was associated with a concomitant decrease in cell in S phase compared with that in control cells, suggesting that SRC-3 knockdown was able to inhibit DNA synthesis and arrest cell cycle at G1/S transition (Fig.	('p', 'Gene', '8202', (49, 50))	('DNA synthesis', 'MPA', (285, 298))	('knockdown', 'Var', (255, 264))	('p', 'Gene', '8202', (114, 115))	('p', 'Gene', '8202', (190, 191))	('SRC-3', 'Gene', (18, 23))	('cell cycle at G1/S transition', 'CPA', (310, 339))	('arrest', 'Disease', 'MESH:D006323', (303, 309))	('inhibit', 'NegReg', (277, 284))	('arrest', 'Disease', (303, 309))	('p', 'Gene', '8202', (4, 5))	('p', 'Gene', '8202', (199, 200))	('decrease', 'NegReg', (168, 176))	('EC18', 'CellLine', 'CVCL:5V07', (99, 103))	('SRC-3', 'Gene', (249, 254))	('increased', 'PosReg', (60, 69))	('knockdown', 'Var', (24, 33))
161318	27781415	Matrigel invasion assay also found that knockdown of SRC-3 could inhibit the invasiveness of ESCC cells, as showed by a significant decrease in the number of invaded cells in Eca109 and EC18 cells compared to scramble control (P < 0.001, Fig.	('p', 'Gene', '8202', (200, 201))	('knockdown', 'Var', (40, 49))	('EC18', 'CellLine', 'CVCL:5V07', (186, 190))	('P', 'Gene', '8202', (227, 228))	('invasiveness of ESCC cells', 'CPA', (77, 103))	('SRC-3', 'Gene', (53, 58))	('inhibit', 'NegReg', (65, 72))	('decrease', 'NegReg', (132, 140))
161321	27781415	SRC-3 knockdown Eca109 and EC18 tumors grew much slower than control tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('EC18', 'CellLine', 'CVCL:5V07', (27, 31))	('SRC-3', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('grew', 'CPA', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (69, 75))	('knockdown', 'Var', (6, 15))	('slower', 'NegReg', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
161322	27781415	At the end of the study (day 32), tumor size of SRC-3 knockdown group (309 +- 34 mm3, 293 +- 27 mm3) was only 43% and 48% of the control group (715 +- 51 mm3, 616 +- 27 mm3), respectively, and tumor weight of SRC-3-silenced group (229 +- 22 mg, 201 +- 14 mg) was also significantly lower than the scramble control group (537 +- 82 mg, 466 +- 61 mg), respectively (Fig.	('p', 'Gene', '8202', (141, 142))	('tumor', 'Disease', (34, 39))	('knockdown', 'Var', (54, 63))	('p', 'Gene', '8202', (228, 229))	('p', 'Gene', '8202', (318, 319))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('SRC-3', 'Gene', (48, 53))	('lower', 'NegReg', (282, 287))	('p', 'Gene', '8202', (68, 69))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('p', 'Gene', '8202', (353, 354))	('p', 'Gene', '8202', (178, 179))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
161343	27781415	This notion was supported by our findings that shRNA-mediated SRC-3 knockdown causes inhibition of cell growth and colony formation in vitro and the in vivo growth inhibition of tumors in nude mice of two different ESCC cell lines.	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('SRC-3', 'Gene', (62, 67))	('growth inhibition', 'CPA', (157, 174))	('inhibition', 'NegReg', (85, 95))	('cell growth', 'CPA', (99, 110))	('nude mice', 'Species', '10090', (188, 197))	('knockdown', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
161351	27781415	Consistent with these findings, we showed that shRNA-mediated SRC-3 knockdown in the Eca109 and EC18 cells inhibited the ability of either cell migration or invasion.	('EC18', 'CellLine', 'CVCL:5V07', (96, 100))	('invasion', 'CPA', (157, 165))	('SRC-3', 'Gene', (62, 67))	('knockdown', 'Var', (68, 77))	('inhibited', 'NegReg', (107, 116))
161360	27781415	Deregulation of multiple IGF/AKT signaling components have been detected in a wide variety of human carcinomas and considered to play a central role in cancer progression 16, 17, 18, 40, 41.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('p', 'Gene', '8202', (159, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('Deregulation', 'Var', (0, 12))	('carcinomas', 'Disease', (100, 110))	('carcinomas', 'Disease', 'MESH:D002277', (100, 110))	('AKT', 'Gene', '207', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('p', 'Gene', '8202', (46, 47))	('p', 'Gene', '8202', (129, 130))	('detected', 'Reg', (64, 72))	('human', 'Species', '9606', (94, 99))	('AKT', 'Gene', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('p', 'Gene', '8202', (21, 22))
161362	27781415	reported that inhibition of IGF-IR suppressed proliferation, colony formation, and motility through blocking ligand-induced AKT activation 43.	('blocking', 'NegReg', (100, 108))	('motility', 'CPA', (83, 91))	('AKT', 'Gene', (124, 127))	('p', 'Gene', '8202', (37, 38))	('p', 'Gene', '8202', (46, 47))	('p', 'Gene', '8202', (2, 3))	('IGF-IR', 'Gene', (28, 34))	('colony formation', 'CPA', (61, 77))	('IGF-IR', 'Gene', '3480', (28, 34))	('p', 'Gene', '8202', (38, 39))	('inhibition', 'Var', (14, 24))	('AKT', 'Gene', '207', (124, 127))
161413	27821908	Antigen retrieval was performed in an autoclave for 10 min at 121 C in 10 mM citrate buffer (pH 6.0) for Ki-67, p21, and p53 or in a microwave for 10 min at 90 C in Target Retrieval Solution, pH 9 (Dako, Tokyo, Japan), for cleaved caspase-3.	('Ki-67', 'Var', (105, 110))	('citrate', 'Chemical', 'MESH:D019343', (77, 84))	('p53', 'Var', (121, 124))	('cleaved', 'Var', (223, 230))
161421	27821908	MTBITC has been reported to induce apoptosis in HeLa (human cervical epithelial carcinoma), A549 (human alveolar basal epithelial carcinoma), MCF-7 (human mammary epithelial carcinoma), and PC-3 (human prostate epithelial carcinoma) cell lines.	('MCF-7', 'CellLine', 'CVCL:0031', (142, 147))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (163, 183))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (69, 89))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (69, 89))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (163, 183))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (211, 231))	('PC-3', 'Gene', (190, 194))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (211, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('HeLa', 'CellLine', 'CVCL:0030', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('alveolar basal epithelial carcinoma', 'Disease', 'MESH:D002282', (104, 139))	('PC-3', 'Gene', '3853', (190, 194))	('human', 'Species', '9606', (149, 154))	('prostate epithelial carcinoma', 'Disease', (202, 231))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('apoptosis', 'CPA', (35, 44))	('human', 'Species', '9606', (54, 59))	('MTBITC', 'Var', (0, 6))	('prostate epithelial carcinoma', 'Disease', 'MESH:D011472', (202, 231))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (119, 139))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (119, 139))	('human', 'Species', '9606', (196, 201))	('alveolar basal epithelial carcinoma', 'Disease', (104, 139))	('epithelial carcinoma', 'Disease', (69, 89))	('epithelial carcinoma', 'Disease', (163, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('human', 'Species', '9606', (98, 103))
161422	27821908	Specifically, MTBITC was shown to upregulate the expression of Bax and caspase-3, two pro-apoptotic genes, and downregulate the expression of Bcl-2 and Bcl-xl, two anti-apoptotic genes.	('Bcl-2', 'Gene', (142, 147))	('Bcl-xl', 'Gene', (152, 158))	('MTBITC', 'Var', (14, 20))	('caspase-3', 'Gene', (71, 80))	('expression', 'MPA', (49, 59))	('Bcl-2', 'Gene', '24224', (142, 147))	('upregulate', 'PosReg', (34, 44))	('Bcl-xl', 'Gene', '24888', (152, 158))	('Bax', 'Gene', (63, 66))	('expression', 'MPA', (128, 138))	('Bax', 'Gene', '24887', (63, 66))	('downregulate', 'NegReg', (111, 123))
161424	27821908	SNF has been known to induce apoptosis derived from reactive oxygen species and to elevate the transcription of p21 through the inhibition of histone deacetylase (HDAC) activity in human prostate adenocarcinoma cells.	('apoptosis', 'CPA', (29, 38))	('inhibition', 'NegReg', (128, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('elevate', 'PosReg', (83, 90))	('activity', 'MPA', (169, 177))	('SNF', 'Var', (0, 3))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (52, 75))	('induce', 'PosReg', (22, 28))	('transcription', 'MPA', (95, 108))	('p21', 'Gene', (112, 115))
161426	27821908	Mutations in the p53 gene have been observed in NMBA-induced esophageal tumors in rats and in esophageal tumors in humans.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('esophageal tumors', 'Disease', (94, 111))	('observed', 'Reg', (36, 44))	('esophageal tumors', 'Disease', 'MESH:D004938', (94, 111))	('humans', 'Species', '9606', (115, 121))	('esophageal tumors', 'Disease', 'MESH:D004938', (61, 78))	('esophageal tumors', 'Phenotype', 'HP:0100751', (61, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('esophageal tumors', 'Disease', (61, 78))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('p53', 'Gene', (17, 20))	('esophageal tumors', 'Phenotype', 'HP:0100751', (94, 111))
161428	27821908	MTBITC has been shown to inhibit genotoxicity in vitro and in vivo,  and to induce several types of antioxidative enzymes, including quinone reductase, NAD(P)H:quinone oxidoreductase, heme oxygenase-1, thioredoxin reductase, and glutathione S-transferase in HepG2 (human hepatocellular carcinoma) cells or hepatocytes of rats and mice, .	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('MTBITC', 'Var', (0, 6))	('genotoxicity', 'MPA', (33, 45))	('hepatocellular carcinoma', 'Disease', (271, 295))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (271, 295))	('antioxidative', 'MPA', (100, 113))	('glutathione S-transferase', 'Gene', '373156', (229, 254))	('heme oxygenase-1', 'Enzyme', (184, 200))	('mice', 'Species', '10090', (330, 334))	('NAD(P)H', 'Disease', 'MESH:C000656865', (152, 159))	('thioredoxin reductase', 'Gene', (202, 223))	('induce', 'PosReg', (76, 82))	('quinone reductase', 'Enzyme', (133, 150))	('thioredoxin reductase', 'Gene', '25824', (202, 223))	('inhibit', 'NegReg', (25, 32))	('HepG2', 'CellLine', 'CVCL:0027', (258, 263))	('glutathione S-transferase', 'Gene', (229, 254))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (271, 295))
161432	27821908	In addition, MTBITC inhibits CYP3A2 in primary cultures of rat hepatocytes.	('CYP3A2', 'Gene', '266682', (29, 35))	('MTBITC', 'Var', (13, 19))	('CYP3A2', 'Gene', (29, 35))	('inhibits', 'NegReg', (20, 28))
161439	26147856	Flow cytometry revealed that RPS induced apoptosis and cell cycle G2/M arrest in the esophageal cancer cells.	('M arrest', 'Disease', (69, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('RPS', 'Var', (29, 32))	('apoptosis', 'CPA', (41, 50))	('M arrest', 'Disease', 'MESH:D006323', (69, 77))	('esophageal cancer', 'Disease', (85, 102))
161440	26147856	The expression of cyclooxygenases-2 (COX-2) and Cyclin D1 in rat esophageal tissues and the esophageal cancer cells were also significantly reduced by RPS (all P < 0.01).	('Cyclin D1', 'Gene', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cyclooxygenases-2', 'Gene', (18, 35))	('expression', 'MPA', (4, 14))	('COX-2', 'Gene', (37, 42))	('rat', 'Species', '10116', (61, 64))	('Cyclin D1', 'Gene', '58919', (48, 57))	('COX-2', 'Gene', '5743', (37, 42))	('esophageal cancer', 'Disease', (92, 109))	('RPS', 'Var', (151, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))	('reduced', 'NegReg', (140, 147))
161441	26147856	Consistently, RPS also significantly decreased the release of prostaglandin E2, a downstream molecule of COX-2, in a dose-dependent manner (P < 0.01).	('release of prostaglandin E2', 'MPA', (51, 78))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (62, 78))	('COX-2', 'Gene', (105, 110))	('decreased the release of prostaglandin E2', 'Phenotype', 'HP:0003566', (37, 78))	('COX-2', 'Gene', '5743', (105, 110))	('decreased', 'NegReg', (37, 46))	('RPS', 'Var', (14, 17))
161442	26147856	Our study suggests that RPS inhibit esophageal cancer development by promoting apoptosis and cell cycle arrest and inhibiting the COX-2 pathway.	('RPS', 'Var', (24, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (36, 53))	('promoting', 'PosReg', (69, 78))	('cell cycle arrest', 'CPA', (93, 110))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))	('inhibiting', 'NegReg', (115, 125))	('apoptosis', 'CPA', (79, 88))	('COX-2', 'Gene', (130, 135))	('men', 'Species', '9606', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancer', 'Disease', (36, 53))	('COX-2', 'Gene', '5743', (130, 135))	('inhibit', 'NegReg', (28, 35))
161453	26147856	In addition to inhibiting cancer growth, RPS also significantly reduces the migration and invasion of lung cancer cells and B16 melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('migration', 'CPA', (76, 85))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('lung cancer', 'Disease', (102, 113))	('B16', 'CellLine', 'CVCL:N540', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('rat', 'Species', '10116', (79, 82))	('reduces', 'NegReg', (64, 71))	('RPS', 'Var', (41, 44))	('cancer', 'Disease', (107, 113))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('invasion', 'CPA', (90, 98))	('melanoma', 'Disease', (128, 136))
161458	26147856	Results from studies on different types of human cancer cells consistently show that RPS induces apoptosis in cancer cells by activating both caspase-dependent and caspase-independent apoptotic pathways and inhibits the migration and invasion by suppressing the enzymatic activity and protein expression of matrix metalloproteinases (MMP) such as MMP-2 and MMP-9.	('MMP-9', 'Gene', '4318', (357, 362))	('MMP-9', 'Gene', (357, 362))	('invasion', 'CPA', (234, 242))	('MMP', 'Gene', (347, 350))	('MMP', 'Gene', '4313;4318', (347, 350))	('cancer', 'Disease', (49, 55))	('rat', 'Species', '10116', (223, 226))	('activating', 'PosReg', (126, 136))	('migration', 'CPA', (220, 229))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('MMP-2', 'Gene', (347, 352))	('caspase-independent apoptotic pathways', 'Pathway', (164, 202))	('caspase-dependent', 'Pathway', (142, 159))	('cancer', 'Disease', (110, 116))	('MMP', 'Gene', (334, 337))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MMP', 'Gene', '4313;4318', (334, 337))	('RPS', 'Var', (85, 88))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('suppressing', 'NegReg', (246, 257))	('enzymatic activity', 'MPA', (262, 280))	('MMP', 'Gene', (357, 360))	('MMP', 'Gene', '4313;4318', (357, 360))	('inhibits', 'NegReg', (207, 215))	('protein expression', 'MPA', (285, 303))	('MMP-2', 'Gene', '4313', (347, 352))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('human', 'Species', '9606', (43, 48))
161520	26147856	RPS at 350mg/kg significantly reduced the number (3.5 +- 1.58 vs 1.4 +- 1.11, P < 0.01, Fig 2A and 2B) and average size of tumors (17.71 +- 9.16 mm3 vs 6.47 +- 5.86 mm3, P < 0.01, Fig 2A and 2C) on the esophagus.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('reduced', 'NegReg', (30, 37))	('RPS', 'Var', (0, 3))
161526	26147856	Indeed, our flow cytometry results demonstrated that RPS at the concentration of 10 mug/mL or higher significantly increased the proportion of apoptotic cells in both EC9706 and KYSE150 cells (Fig 4, P < 0.01).	('apoptotic cells', 'CPA', (143, 158))	('rat', 'Species', '10116', (71, 74))	('increased', 'PosReg', (115, 124))	('RPS', 'Var', (53, 56))	('EC9706', 'CellLine', 'CVCL:E307', (167, 173))	('rat', 'Species', '10116', (42, 45))	('KYSE150', 'CellLine', 'CVCL:1348', (178, 185))
161527	26147856	Consistently, RPS at the same concentration markedly increased the proportion of cells in G2 phase (Fig 5, P < 0.01), suggesting that RPS treatment induce G2/M cell cycle arrest in the esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('esophageal cancer', 'Disease', (185, 202))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (160, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (185, 202))	('G2/M cell cycle arrest', 'CPA', (155, 177))	('rat', 'Species', '10116', (37, 40))	('RPS', 'Var', (134, 137))	('men', 'Species', '9606', (143, 146))
161533	26147856	COX-2 pathway disorder has been associated with cancer in digestive system.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('digestive system', 'Disease', (58, 74))	('disorder', 'Var', (14, 22))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer in digestive system', 'Phenotype', 'HP:0007378', (48, 74))	('associated', 'Reg', (32, 42))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))
161538	26147856	In this study, we found RPS significantly suppressed tumor development in a rat model of NMBA-induced esophageal cancer and inhibited the viability, migration, and invasion of human esophageal cancer cells EC9706 and KYSE150.	('esophageal cancer', 'Disease', (182, 199))	('men', 'Species', '9606', (66, 69))	('rat', 'Species', '10116', (152, 155))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('human', 'Species', '9606', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('invasion', 'CPA', (164, 172))	('inhibited', 'NegReg', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('migration', 'CPA', (149, 158))	('EC9706', 'CellLine', 'CVCL:E307', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('RPS', 'Var', (24, 27))	('KYSE150', 'CellLine', 'CVCL:1348', (217, 224))	('viability', 'CPA', (138, 147))	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('rat', 'Species', '10116', (76, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('suppressed', 'NegReg', (42, 52))	('NMBA', 'Chemical', 'MESH:C014707', (89, 93))	('tumor', 'Disease', (53, 58))	('esophageal cancer', 'Disease', (102, 119))
161539	26147856	These results are consistent with the findings on other types of cancers, further supporting the anti-cancer effects of RPS.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('RPS', 'Var', (120, 123))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
161540	26147856	Our study also showed that RPS induced apoptosis in the esophageal cancer cells.	('apoptosis', 'CPA', (39, 48))	('esophageal cancer', 'Disease', (56, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('RPS', 'Var', (27, 30))
161542	26147856	In addition to inducing apoptosis, we also found RPS caused cell cycle G2/M arrest in esophageal cancer cells.	('RPS', 'Var', (49, 52))	('M arrest', 'Disease', 'MESH:D006323', (74, 82))	('M arrest', 'Disease', (74, 82))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('inducing', 'Reg', (15, 23))
161543	26147856	reported that RPS promoted dramatic G2/M phase arrest in human ovarian cancer cells SKOV3, and Jiang et al.	('SKOV3', 'CellLine', 'CVCL:0532', (84, 89))	('G2/M phase arrest', 'CPA', (36, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (63, 77))	('RPS', 'Var', (14, 17))	('human', 'Species', '9606', (57, 62))	('ovarian cancer', 'Disease', (63, 77))
161544	26147856	demonstrated that RPS induced G2/M arrest in nonsmall cell lung cancer cells.	('RPS', 'Var', (18, 21))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (45, 70))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (45, 70))	('M arrest', 'Disease', 'MESH:D006323', (33, 41))	('M arrest', 'Disease', (33, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('rat', 'Species', '10116', (7, 10))	('nonsmall cell lung cancer', 'Disease', (45, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
161546	26147856	These results further confirm that RPS inhibits tumor development by inducing apoptosis and promoting cell cycle G2/M arrest in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('RPS', 'Var', (35, 38))	('apoptosis', 'CPA', (78, 87))	('tumor', 'Disease', (48, 53))	('inducing', 'PosReg', (69, 77))	('M arrest', 'Disease', 'MESH:D006323', (116, 124))	('promoting', 'PosReg', (92, 101))	('M arrest', 'Disease', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('men', 'Species', '9606', (61, 64))	('inhibits', 'NegReg', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cancer', 'Disease', (128, 134))
161550	26147856	The role of COX-2 pathway in esophageal cancer is also supported by epidemiologic and preclinical studies demonstrating that COX-2 inhibitors reduce the risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('esophageal cancer', 'Disease', (161, 178))	('COX-2', 'Gene', (125, 130))	('COX-2', 'Gene', '5743', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('COX-2', 'Gene', (12, 17))	('COX-2', 'Gene', '5743', (12, 17))	('rat', 'Species', '10116', (113, 116))	('esophageal cancer', 'Disease', (29, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('reduce', 'NegReg', (142, 148))	('inhibitors', 'Var', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
161552	26147856	RPS also markedly reduced COX-2 expression and PGE2 release from esophageal cancer cells EC9706 and KYSE150.	('esophageal cancer', 'Disease', (65, 82))	('EC9706', 'CellLine', 'CVCL:E307', (89, 95))	('KYSE150', 'CellLine', 'CVCL:1348', (100, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('reduced', 'NegReg', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PGE2 release', 'MPA', (47, 59))	('COX-2', 'Gene', (26, 31))	('COX-2', 'Gene', '5743', (26, 31))	('RPS', 'Var', (0, 3))	('PGE2', 'Chemical', 'MESH:D015232', (47, 51))
161570	33243967	After treatment, the therapy response rate (the sum of the complete and partial remission rates) was significantly higher in the Apatinib group than in the CCRT group (P=0.045); the complete remission rate was particularly higher in the Apatinib group.	('CCRT', 'Chemical', '-', (156, 160))	('therapy response', 'CPA', (21, 37))	('Apatinib', 'Chemical', 'MESH:C553458', (129, 137))	('Apatinib', 'Var', (129, 137))	('Apatinib', 'Chemical', 'MESH:C553458', (237, 245))	('higher', 'PosReg', (223, 229))	('higher', 'PosReg', (115, 121))
161580	33243967	Previously, through in vitro assays, we found that Apatinib can induce apoptosis and cell cycle arrest in esophageal cancer cells Kyse-150; moreover, Apatinib increased the radiosensitivity of these cells and showed a synergistic effect when combined with X-ray radiation.	('arrest', 'Disease', 'MESH:D006323', (96, 102))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('apoptosis', 'CPA', (71, 80))	('arrest', 'Disease', (96, 102))	('Apatinib', 'Chemical', 'MESH:C553458', (150, 158))	('radiosensitivity', 'CPA', (173, 189))	('increased', 'PosReg', (159, 168))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))	('Apatinib', 'Chemical', 'MESH:C553458', (51, 59))	('Apatinib', 'Var', (150, 158))	('esophageal cancer', 'Disease', (106, 123))
161617	33243967	The RTOG85-01 trial showed that in patients with T1-3N0-1M0 esophageal cancer, the 5-year survival rate of cisplatin/5-fluorouracil chemotherapy plus 50.4 Gy radiotherapy was significantly higher than 64 Gy radiotherapy alone.	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('higher', 'PosReg', (189, 195))	('patients', 'Species', '9606', (35, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (117, 131))	('T1-3N0-1M0', 'Var', (49, 59))
161623	33243967	Studies have shown that patients with esophageal cancer with a high expression of VEGF had 1.82 times higher risk of death, indicating that anti-VEGF therapy may improve the efficacy and prognosis of esophageal cancer.	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('VEGF', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('patients', 'Species', '9606', (24, 32))	('VEGF', 'Gene', (82, 86))	('esophageal cancer', 'Disease', (200, 217))	('high expression', 'Var', (63, 78))	('death', 'Disease', (117, 122))	('improve', 'PosReg', (162, 169))	('death', 'Disease', 'MESH:D003643', (117, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (200, 217))	('VEGF', 'Gene', '7422', (145, 149))	('VEGF', 'Gene', '7422', (82, 86))
161646	33080692	Patients with critically COVID-19 usually require invasive respiratory support, and the airway management is particularly important and the prognosis is poor.	('COVID-19', 'Disease', 'MESH:C000657245', (25, 33))	('men', 'Species', '9606', (101, 104))	('Patients', 'Species', '9606', (0, 8))	('COVID-19', 'Disease', (25, 33))	('critically', 'Var', (14, 24))
161690	33080692	At the beginning of the mechanical ventilation treatment, the ventilator alarmed of airway hypertension (up to 47 cmH2O) repeatedly and the blood gas report was reviewed again: pH: 7.240, pCO2: 110.3 mm Hg.	('hypertension', 'Disease', (91, 103))	('hypertension', 'Phenotype', 'HP:0000822', (91, 103))	('O2', 'Chemical', 'MESH:D010100', (190, 192))	('pH: 7.240', 'Var', (177, 186))	('men', 'Species', '9606', (52, 55))	('hypertension', 'Disease', 'MESH:D006973', (91, 103))
161733	33080692	Studies have shown that for ARDS, the efficacy was significantly better in the small tidal volume ventilation mild hypercarbonation group than in the high tidal volume ventilation group.	('ARDS', 'Disease', 'MESH:D012128', (28, 32))	('better', 'PosReg', (65, 71))	('ARDS', 'Disease', (28, 32))	('efficacy', 'MPA', (38, 46))	('mild hypercarbonation', 'Var', (110, 131))
161753	32927604	These results will improve our understanding on how dysfunction of NDRG4 contributes to esophageal adenocarcinoma.	('NDRG4', 'Gene', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('dysfunction', 'Var', (52, 63))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('contributes', 'Reg', (73, 84))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (88, 113))
161754	32927604	DNA hypermethylation of NDRG4 may be a useful biomarker in clinical monitoring of esophageal adenocarcinoma patients.	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (82, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('NDRG4', 'Gene', (24, 29))	('esophageal adenocarcinoma', 'Disease', (82, 107))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (82, 107))	('patients', 'Species', '9606', (108, 116))	('hypermethylation', 'Var', (4, 20))
161761	32927604	Functionally, we found that the reconstitution of NDRG4 resulted in a significant reduction in tumor cell growth in two-dimensional (2D) and three-dimensional (3D) organotypic culture models and inhibited tumor cell proliferation as indicated by the EdU (5-ethynyl-2'-deoxyuridine) proliferation assay.	('NDRG4', 'Gene', (50, 55))	('EdU', 'Chemical', 'MESH:C031086', (250, 253))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('reduction', 'NegReg', (82, 91))	('inhibited', 'NegReg', (195, 204))	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (255, 280))	('reconstitution', 'Var', (32, 46))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
161765	32927604	Hypermethylation of gene promoter regions is associated with gene silencing of many tumor suppressor genes, such as p16, CDH1 and many others.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('CDH1', 'Gene', (121, 125))	('p16', 'Gene', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Hypermethylation', 'Var', (0, 16))	('associated', 'Reg', (45, 55))	('tumor', 'Disease', (84, 89))	('CDH1', 'Gene', '999', (121, 125))	('gene', 'MPA', (61, 65))	('p16', 'Gene', '1029', (116, 119))
161766	32927604	We and others have reported frequent silencing of several genes, such as GSTM2, GSTM3, GPX3, GPX7 and MT3, through aberrant DNA methylation in esophageal adenocarcinoma.	('GSTM3', 'Gene', (80, 85))	('GSTM2', 'Gene', '2946', (73, 78))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (143, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('GSTM3', 'Gene', '2947', (80, 85))	('MT3', 'Gene', (102, 105))	('aberrant DNA methylation', 'Var', (115, 139))	('silencing', 'NegReg', (37, 46))	('GPX3', 'Gene', '2878', (87, 91))	('esophageal adenocarcinoma', 'Disease', (143, 168))	('GPX3', 'Gene', (87, 91))	('GSTM2', 'Gene', (73, 78))	('GPX7', 'Gene', '2882', (93, 97))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (143, 168))	('GPX7', 'Gene', (93, 97))	('MT3', 'Gene', '4504', (102, 105))
161767	32927604	These epigenetic changes may wipe out protective mechanisms in Barrett's esophagus, contributing to Barrett's tumorigenesis.	('wipe out', 'NegReg', (29, 37))	('tumor', 'Disease', (110, 115))	('epigenetic changes', 'Var', (6, 24))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (63, 82))	('contributing', 'Reg', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
161780	32927604	The genes with significant upregulation after 5-Aza treatment (provided in Table S1) and genes with significant downregulation in EAC as compared to normal samples (provided in Table S2) were considered as most likely candidate genes methylated in EAC (the experimental flow chart is shown in Figure 1).	('EAC', 'Disease', (248, 251))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('methylated', 'Var', (234, 244))	('EAC', 'Phenotype', 'HP:0011459', (248, 251))	('upregulation', 'PosReg', (27, 39))	('5-Aza', 'Chemical', '-', (46, 51))
161784	32927604	Because NDRG4 methylation has been reported in colorectal cancers and our screening data showed downregulation of NDRG4 expression that was reversed following 5-Aza treatment, we hypothesized that NDRG4 promoter DNA hypermethylation may be the major mechanism to silence NDRG4 in EAC.	('hypermethylation', 'Var', (216, 232))	('colorectal cancers', 'Disease', (47, 65))	('silence', 'NegReg', (263, 270))	('EAC', 'Phenotype', 'HP:0011459', (280, 283))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('expression', 'MPA', (120, 130))	('EAC', 'Disease', (280, 283))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NDRG4', 'Gene', (271, 276))	('downregulation', 'NegReg', (96, 110))	('NDRG4', 'Gene', (114, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('colorectal cancers', 'Disease', 'MESH:D015179', (47, 65))	('NDRG4', 'Gene', (8, 13))	('5-Aza', 'Chemical', '-', (159, 164))
161789	32927604	The reconstitution of NDRG4 significantly suppressed tumor cell growth as shown in Figure 5A,D, the cell growth curves (A for FLO1 and D for JH-eso-ad1).	('reconstitution', 'Var', (4, 18))	('NDRG4', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('suppressed', 'NegReg', (42, 52))	('cell growth curves', 'CPA', (100, 118))	('tumor', 'Disease', (53, 58))
161790	32927604	The colony formation assay confirmed that NDRG4 inhibited tumor cell colony formation capacity in FLO1 cells (Figure 5B,C, p < 0.05) and JH-eso-ad1 cells (Figure 5E,F, p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('NDRG4', 'Var', (42, 47))	('inhibited', 'NegReg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
161803	32927604	To further confirm this note, we treated two EAC cell lines with high DNA methylation levels and silence of NDRG4 with 5-Aza, a DNA methyltransferase inhibitor.	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('silence', 'Var', (97, 104))	('NDRG4', 'Gene', (108, 113))	('5-Aza', 'Chemical', '-', (119, 124))
161807	32927604	It has been reported that TSA could induce global and gene specific demethylation in human cancer cell lines.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('TSA', 'Var', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('human', 'Species', '9606', (85, 90))	('TSA', 'Chemical', 'MESH:C012589', (26, 29))
161813	32927604	Of note, the reconstitution of NDRG4 in EAC cells significantly inhibited tumor cell growth and cell proliferation, suggesting a tumor suppressor role in EAC.	('EAC', 'Phenotype', 'HP:0011459', (154, 157))	('EAC', 'Phenotype', 'HP:0011459', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('inhibited', 'NegReg', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NDRG4', 'Gene', (31, 36))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (129, 134))	('reconstitution', 'Var', (13, 27))
161815	32927604	Along these lines, NDRG4 methylation has emerged as a useful DNA methylation marker, in combination with other markers, for colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('methylation', 'Var', (25, 36))	('colorectal cancers', 'Disease', 'MESH:D015179', (124, 142))	('colorectal cancers', 'Disease', (124, 142))	('NDRG4', 'Gene', (19, 24))
161826	32927604	Genes that were picked up in both data sets, upregulated by 5-Aza and silenced in EAC, were the candidate genes most likely silenced through DNA hypermethylation.	('upregulated', 'PosReg', (45, 56))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('5-Aza', 'Var', (60, 65))	('5-Aza', 'Chemical', '-', (60, 65))
161858	32927604	The GEO cohorts include GSE13898 (EAC: 75, NE: 28), GSE92396 (EAC: 12, NE: 10), GSE74553 (EAC: 52, NE: 8), GSE26886 (EAC: 20, NE: 17), and GSE1420 (EAC: 8, NE: 8).	('GSE1420', 'Chemical', '-', (139, 146))	('GSE92396', 'Var', (52, 60))	('GSE1420', 'Var', (139, 146))	('GSE26886', 'Var', (107, 115))	('EAC', 'Phenotype', 'HP:0011459', (34, 37))	('EAC', 'Phenotype', 'HP:0011459', (62, 65))	('GSE74553', 'Var', (80, 88))	('EAC', 'Phenotype', 'HP:0011459', (90, 93))	('GSE13898', 'Var', (24, 32))	('EAC', 'Phenotype', 'HP:0011459', (117, 120))	('EAC', 'Phenotype', 'HP:0011459', (148, 151))
161861	32927604	In summary, we have demonstrated that the NDRG4 gene is frequently downregulated in esophageal adenocarcinoma through promoter DNA hypermethylation and may play a tumor suppressor role by inhibiting tumor cell proliferation.	('tumor', 'Disease', (199, 204))	('play', 'Reg', (156, 160))	('promoter DNA hypermethylation', 'Var', (118, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('inhibiting', 'NegReg', (188, 198))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('esophageal adenocarcinoma', 'Disease', (84, 109))	('NDRG4', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (84, 109))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (84, 109))	('downregulated', 'NegReg', (67, 80))
161933	32889988	Patients who received modified doses of CRT tended to have better OS rates than other groups (p = 0.05).	('OS rates', 'MPA', (66, 74))	('better', 'PosReg', (59, 65))	('modified doses', 'Var', (22, 36))	('Patients', 'Species', '9606', (0, 8))
161934	32889988	From the outcomes of the elderly ESCC patients in this study, we demonstrate that patients receiving a modified dose of chemotherapy experienced acceptable toxicities, better treatment compliance and trend for better OS than patients in the other two groups.	('toxicities', 'Disease', 'MESH:D064420', (156, 166))	('patients', 'Species', '9606', (225, 233))	('patients', 'Species', '9606', (82, 90))	('better', 'PosReg', (210, 216))	('better', 'PosReg', (168, 174))	('toxicities', 'Disease', (156, 166))	('patients', 'Species', '9606', (38, 46))	('modified', 'Var', (103, 111))
161958	32889988	In our subgroup analysis, we found a higher 3-year OS rate of 53.8% in patients treated with modified dose chemotherapy than those who were administered standard dose and lower dose chemotherapy.	('patients', 'Species', '9606', (71, 79))	('modified dose chemotherapy', 'Var', (93, 119))	('higher', 'PosReg', (37, 43))
161959	32889988	This result also corresponds to our findings that patients in the modified group showed both better treatment compliance and a higher response rate than patients in other two groups (Table 3).	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (50, 58))	('response', 'CPA', (134, 142))	('higher', 'PosReg', (127, 133))	('better', 'PosReg', (93, 99))	('modified', 'Var', (66, 74))
161993	26774417	At the 8 month follow-up %EBWL was 52%, also presented with mild dysphagia to solids; an esophagogastroduodenoscopy (EGD) was performed that reported inflammation of the gastric and esophageal mucosa with no strictures.	('esophageal mucosa', 'Disease', (182, 199))	('esophageal mucosa', 'Disease', 'MESH:D004941', (182, 199))	('dysphagia', 'Phenotype', 'HP:0002015', (65, 74))	('inflammation', 'Disease', 'MESH:D007249', (150, 162))	('EBWL', 'Var', (26, 30))	('dysphagia', 'Disease', 'MESH:D003680', (65, 74))	('inflammation', 'Disease', (150, 162))	('dysphagia', 'Disease', (65, 74))
162084	24711267	Failures in the group of patients with lower esophageal tumors occurred in the following lymph node stations: right or left SCV (3 patients), 2R/L (2 patients), 3 (1 patient), 5 (2 patients), 7 (1 patient), and celiac (1 patient).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('patient', 'Species', '9606', (25, 32))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (181, 189))	('esophageal tumors', 'Phenotype', 'HP:0100751', (45, 62))	('2R/L', 'SUBSTITUTION', 'None', (142, 146))	('patient', 'Species', '9606', (150, 157))	('2R/L', 'Var', (142, 146))	('esophageal tumor', 'Phenotype', 'HP:0100751', (45, 61))	('patient', 'Species', '9606', (221, 228))	('patient', 'Species', '9606', (166, 173))	('patient', 'Species', '9606', (197, 204))	('patients', 'Species', '9606', (131, 139))	('patient', 'Species', '9606', (181, 188))	('patients', 'Species', '9606', (25, 33))	('esophageal tumors', 'Disease', (45, 62))	('esophageal tumors', 'Disease', 'MESH:D004938', (45, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('patient', 'Species', '9606', (131, 138))
162150	23620117	Under low pH conditions, chemical reduction of nitrate can lead to the generation of carcinogenic N-nitroso compounds and nitric oxide.	('generation of carcinogenic N-nitroso compounds', 'MPA', (71, 117))	('nitrate', 'Chemical', 'MESH:D009566', (47, 54))	('N-nitroso compounds', 'Chemical', '-', (98, 117))	('chemical reduction', 'Var', (25, 43))	('nitric oxide', 'MPA', (122, 134))	('lead to', 'Reg', (59, 66))	('nitric oxide', 'Chemical', 'MESH:D009569', (122, 134))	('nitrate', 'MPA', (47, 54))
162168	23620117	Within 3 days of initial colonization of the gastric mucosa, H. pylori induces profound hypochlorhydria and activates pro-inflammatory pathways that are involved in further development of mucosal pathology.	('H. pylori', 'Species', '210', (61, 70))	('activates', 'PosReg', (108, 117))	('pro-inflammatory pathways', 'Pathway', (118, 143))	('hypochlorhydria', 'Disease', 'MESH:D000126', (88, 103))	('H. pylori', 'Var', (61, 70))	('induces', 'Reg', (71, 78))	('hypochlorhydria', 'Disease', (88, 103))
162179	23620117	Thirteen of the 20 patients (65%) who received NAC cleared their infection while only four of the 20 patients (20%) who received placebo did so (P < 0.01).	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (19, 27))	('infection', 'Disease', (65, 74))	('NAC', 'Chemical', 'MESH:D000111', (47, 50))	('infection', 'Disease', 'MESH:D007239', (65, 74))	('NAC', 'Var', (47, 50))
162295	23620117	Specific biofilm formation indices were significantly higher among AIEC strains compared to other colonic E. coli isolates.	('AIEC', 'Var', (67, 71))	('E. coli', 'Species', '562', (106, 113))	('higher', 'PosReg', (54, 60))
162319	25551563	MiR-145 Expression Accelerates Esophageal Adenocarcinoma Progression by Enhancing Cell Invasion and Anoikis Resistance Carcinoma of the esophagus has a high case fatality ratio and is now the 6th most common cause of cancer deaths in the world.	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (31, 56))	('Accelerates', 'PosReg', (19, 30))	('Carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (119, 145))	('Carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('Enhancing', 'PosReg', (72, 81))	('MiR-145', 'Gene', (0, 7))	('cancer deaths', 'Disease', (217, 230))	('Anoikis Resistance', 'CPA', (100, 118))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (31, 56))	('Cell Invasion', 'CPA', (82, 95))	('Carcinoma of the esophagus', 'Disease', (119, 145))	('Carcinoma of the esophagus', 'Disease', 'MESH:D004938', (119, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('Expression', 'Var', (8, 18))	('MiR-145', 'Gene', '406937', (0, 7))	('cancer deaths', 'Disease', 'MESH:D003643', (217, 230))	('Esophageal Adenocarcinoma', 'Disease', (31, 56))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
162329	25551563	Although more work is required to understand how miR-145 conveys these effects, expression of miR-145 appears to promote EAC progression by enhancing invasion and protection against anoikis, which could in turn facilitate distant metastasis.	('protection', 'CPA', (163, 173))	('EAC', 'Disease', (121, 124))	('enhancing', 'PosReg', (140, 149))	('promote', 'PosReg', (113, 120))	('distant metastasis', 'CPA', (222, 240))	('invasion', 'CPA', (150, 158))	('miR-145', 'Gene', '406937', (94, 101))	('facilitate', 'PosReg', (211, 221))	('miR-145', 'Gene', (49, 56))	('miR-145', 'Gene', (94, 101))	('miR-145', 'Gene', '406937', (49, 56))	('expression', 'Var', (80, 90))
162336	25551563	As deregulation of these processes are features of cancer, it is likely that miRNAs play a role in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('deregulation', 'Var', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('carcinogenesis', 'Disease', (99, 113))	('mi', 'Chemical', 'MESH:C011506', (77, 79))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
162391	25551563	After 8 h of incubation, both OE33 and SK-GT-4 miR-145 cells closed the wound faster than their respective controls (Fig.	('closed the wound', 'CPA', (61, 77))	('OE33', 'Var', (30, 34))	('miR-145', 'Gene', (47, 54))	('miR-145', 'Gene', '406937', (47, 54))	('SK-GT-4', 'Chemical', '-', (39, 46))
162395	25551563	The effect on cell invasion was more moderate for OE33 when compared to FLO-1 and SK-GT-4 but was still significant.	('OE33', 'Var', (50, 54))	('cell invasion', 'CPA', (14, 27))	('SK-GT-4', 'Chemical', '-', (82, 89))	('FLO-1', 'Chemical', '-', (72, 77))
162436	25551563	In our results, we showed that miR-145 expression leads to stronger cell adhesion to fibronectin, but not to vitronectin, which has been previously described in prostate cancer cells.	('vitronectin', 'Gene', (109, 120))	('cell adhesion', 'CPA', (68, 81))	('expression', 'Var', (39, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('fibronectin', 'Gene', '2335', (85, 96))	('stronger', 'PosReg', (59, 67))	('prostate cancer', 'Disease', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('fibronectin', 'Gene', (85, 96))	('miR-145', 'Gene', (31, 38))	('miR-145', 'Gene', '406937', (31, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (161, 176))	('vitronectin', 'Gene', '7448', (109, 120))
162445	25551563	In conclusion, expression of miR-145 in EAC cell lines generally results in increased cell adhesion to fibronectin, increased cell invasion and resistance to anoikis, but did not affect cell proliferation or response to chemotherapy drugs.	('cell invasion', 'CPA', (126, 139))	('cell adhesion to', 'CPA', (86, 102))	('resistance to anoikis', 'CPA', (144, 165))	('expression', 'Var', (15, 25))	('increased', 'PosReg', (76, 85))	('fibronectin', 'Gene', (103, 114))	('miR-145', 'Gene', (29, 36))	('miR-145', 'Gene', '406937', (29, 36))	('increased', 'PosReg', (116, 125))	('fibronectin', 'Gene', '2335', (103, 114))
162534	20875123	Strictures were most frequently reported with porfimer sodium PDT (18.5%), followed by laser ablation (4.4%) and APC (2.9%) (Table 6).	('Strictures', 'Disease', (0, 10))	('APC', 'Disease', 'MESH:D011125', (113, 116))	('APC', 'Disease', (113, 116))	('porfimer sodium PDT', 'Var', (46, 65))
162537	20875123	Photosensitivity following PDT was more common with porfimer sodium (26.4%) than with ALA (ranging from 0% to 13.6%).	('ALA', 'Chemical', 'MESH:D000622', (86, 89))	('porfimer', 'Var', (52, 60))	('PDT', 'Disease', (27, 30))	('Photosensitivity', 'Phenotype', 'HP:0000992', (0, 16))	('Photosensitivity', 'Disease', (0, 16))
162556	19584152	We report on the prognostic significance of vascular endothelial growth factor (VEGF) single nucleotide polymorphisms in esophageal cancer.	('vascular endothelial growth factor', 'Gene', (44, 78))	('single nucleotide polymorphisms', 'Var', (86, 117))	('VEGF', 'Gene', (80, 84))	('esophageal cancer', 'Disease', (121, 138))	('vascular endothelial growth factor', 'Gene', '7422', (44, 78))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('VEGF', 'Gene', '7422', (80, 84))
162557	19584152	We demonstrate a statistically significant association between the variant allele of a putatively functional VEGF polymorphism and overall survival in multivariate analysis.	('polymorphism', 'Var', (114, 126))	('variant', 'Var', (67, 74))	('overall survival', 'CPA', (131, 147))	('VEGF', 'Gene', (109, 113))	('significant association', 'Reg', (31, 54))	('VEGF', 'Gene', '7422', (109, 113))
162558	19584152	This demonstrates VEGF polymorphisms have potential prognostic capabilities in esophageal cancer, which may ultimately enhance the selection of patients with esophageal cancer that require additional treatment.	('polymorphisms', 'Var', (23, 36))	('enhance', 'PosReg', (119, 126))	('esophageal cancer', 'Disease', (79, 96))	('esophageal cancer', 'Disease', (158, 175))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('VEGF', 'Gene', '7422', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('patients', 'Species', '9606', (144, 152))	('VEGF', 'Gene', (18, 22))
162561	19584152	We investigated the prognostic significance of three VEGF single nucleotide polymorphisms (SNPs) in esophageal cancer.	('single nucleotide polymorphisms', 'Var', (58, 89))	('esophageal cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('VEGF', 'Gene', (53, 57))	('VEGF', 'Gene', '7422', (53, 57))
162562	19584152	361 patients were genotyped for three VEGF SNPs (-460T/C, +405G/C and +936C/T), using DNA extracted from prospectively collected blood samples.	('-460T/C', 'Mutation', 'rs833061', (49, 56))	('VEGF', 'Gene', '7422', (38, 42))	('+936C/T', 'Mutation', 'rs3025039', (70, 77))	('+936C/T', 'Var', (70, 77))	('-460T/C', 'Var', (49, 56))	('+405G/C', 'Mutation', 'rs2010963', (58, 65))	('patients', 'Species', '9606', (4, 12))	('VEGF', 'Gene', (38, 42))
162582	19584152	The prognostic significance of VEGF polymorphisms has not been evaluated in esophageal cancer.	('VEGF', 'Gene', (31, 35))	('polymorphisms', 'Var', (36, 49))	('esophageal cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('VEGF', 'Gene', '7422', (31, 35))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))
162584	19584152	This was investigated, prospectively, in a large cohort of patients with esophageal cancer by evaluating the association of each SNP independently, and in addition exploring the prognostic significance of haplotypes of the three SNPs (VEGF-460T/C, +405G/C and +936C/T) combined.	('VEGF-46', 'Gene', '7424', (235, 242))	('esophageal cancer', 'Disease', (73, 90))	('VEGF-46', 'Gene', (235, 242))	('+405G/C', 'Var', (248, 255))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (59, 67))	('+936C/T', 'Mutation', 'rs3025039', (260, 267))	('+405G/C', 'Mutation', 'rs2010963', (248, 255))
162591	19584152	All patients were genotyped for three VEGF SNPs: VEGF -460T/C (rs833061), VEGF +405G/C (rs2010963), and VEGF 936C/T (rs3025039).	('VEGF', 'Gene', (49, 53))	('VEGF', 'Gene', '7422', (74, 78))	('936C/T', 'Mutation', 'rs3025039', (109, 115))	('VEGF', 'Gene', '7422', (38, 42))	('VEGF', 'Gene', '7422', (104, 108))	('VEGF', 'Gene', (74, 78))	('VEGF', 'Gene', '7422', (49, 53))	('rs3025039', 'Mutation', 'rs3025039', (117, 126))	('rs833061', 'Var', (63, 71))	('-460T/C', 'Mutation', 'rs833061', (54, 61))	('rs3025039', 'Var', (117, 126))	('rs2010963', 'Mutation', 'rs2010963', (88, 97))	('rs833061', 'Mutation', 'rs833061', (63, 71))	('patients', 'Species', '9606', (4, 12))	('VEGF', 'Gene', (38, 42))	('rs2010963', 'Var', (88, 97))	('+405G/C', 'Mutation', 'rs2010963', (79, 86))	('VEGF', 'Gene', (104, 108))
162597	19584152	VEGF-460T/C, +405G/C and +936C/T are in linkage disequilibrium.	('+936C/T', 'Mutation', 'rs3025039', (25, 32))	('+936C/T', 'Var', (25, 32))	('+405G/C', 'Mutation', 'rs2010963', (13, 20))	('VEGF-46', 'Gene', '7424', (0, 7))	('VEGF-46', 'Gene', (0, 7))
162606	19584152	The three SNPs were in linkage disequilibrium (Lewontin D' s were 0.88 and 0.81 for VEGF -460T/C: 405G/C and 405G/C: 936C/T respectively).	('405G/C', 'SUBSTITUTION', 'None', (109, 115))	('405G/C', 'SUBSTITUTION', 'None', (98, 104))	('936C/T', 'SUBSTITUTION', 'None', (117, 123))	('-460T/C', 'SUBSTITUTION', 'None', (89, 96))	('VEGF', 'Gene', (84, 88))	('936C/T', 'Var', (117, 123))	('405G/C', 'Var', (109, 115))	('VEGF', 'Gene', '7422', (84, 88))	('-460T/C', 'Var', (89, 96))	('405G/C', 'Var', (98, 104))
162609	19584152	We also evaluated the association between VEGF 936C/T and OS using a dominant model of inheritance, whereby the presence of at least one variant allele is sufficient to affect OS compared to the wildtype genotype.	('OS', 'Chemical', '-', (58, 60))	('OS', 'Chemical', '-', (176, 178))	('affect', 'Reg', (169, 175))	('VEGF', 'Gene', '7422', (42, 46))	('presence', 'Var', (112, 120))	('936C/T', 'Mutation', 'rs3025039', (47, 53))	('VEGF', 'Gene', (42, 46))
162621	19584152	Of these haplotypes, CGC was found to confer a poorer prognosis compared with the other haplotypes: CGC/CGC (AHR 1.51, 95%CI 1.00-2.30, p=0.05) and CGC/---- OS AHR 1.37, 95%CI 1.00-1.88), p=0.05.	('AHR', 'Gene', '196', (160, 163))	('AHR', 'Gene', (160, 163))	('AHR', 'Gene', '196', (109, 112))	('CGC', 'Var', (21, 24))	('AHR', 'Gene', (109, 112))	('poorer', 'NegReg', (47, 53))	('OS', 'Chemical', '-', (157, 159))
162636	19584152	In our study, we also found patients carrying the heterozygous genotype (frequency 22%, n=79), had an improved prognosis in both additive and dominant models, in keeping with that of a non-small cell lung cancer study (n=462) which demonstrated a trend for significance favoring the variant allele of VEGF 936C/T.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (185, 211))	('cell lung cancer', 'Disease', (195, 211))	('variant', 'Var', (283, 290))	('936C/T', 'Mutation', 'rs3025039', (306, 312))	('prognosis', 'MPA', (111, 120))	('VEGF', 'Gene', (301, 305))	('cell lung cancer', 'Disease', 'MESH:D008175', (195, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('patients', 'Species', '9606', (28, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (189, 211))	('VEGF', 'Gene', '7422', (301, 305))	('improved', 'PosReg', (102, 110))
162646	19584152	The mechanism by which altered VEGF expression from germline variation impacts on outcome, may arise early in the disease process, through the promotion of early vascularisation of metastases, or reflect an interaction between the tumor and the cellular environment which also bears the same germline variation.	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('VEGF', 'Gene', (31, 35))	('impacts', 'Reg', (71, 78))	('germline variation', 'Var', (52, 70))	('outcome', 'CPA', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (231, 236))	('VEGF', 'Gene', '7422', (31, 35))	('altered', 'Reg', (23, 30))	('metastases', 'Disease', (181, 191))	('expression', 'MPA', (36, 46))	('promotion', 'PosReg', (143, 152))
162650	19584152	In conclusion, this is the first study to evaluate the prognostic significance of VEGF polymorphisms in a large cohort of esophageal cancer patients.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('VEGF', 'Gene', (82, 86))	('polymorphisms', 'Var', (87, 100))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('VEGF', 'Gene', '7422', (82, 86))
162672	18778701	Preliminary work in ESCC has shown that cetuximab can induce antibody-dependent cell cytotoxicity in ESCC cell lines.	('SCC', 'Gene', (21, 24))	('SCC', 'Gene', '6317', (102, 105))	('SCC', 'Gene', '6317', (21, 24))	('cetuximab', 'Var', (40, 49))	('cytotoxicity', 'Disease', (85, 97))	('cetuximab', 'Chemical', 'MESH:D000068818', (40, 49))	('SCC', 'Gene', (102, 105))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('induce', 'PosReg', (54, 60))
162684	18778701	Knockout of each of the ErbB family members in mouse models leads to early stage lethality, limiting the study of ErbBs in the development of the aerodigestive tract.	('mouse', 'Species', '10090', (47, 52))	('early stage lethality', 'CPA', (69, 90))	('Knockout', 'Var', (0, 8))	('ErbB', 'Gene', (24, 28))
162705	18778701	Additionally, EGFR mRNA overexpression may result from dysregulated p53, which directly increases EGFR gene transcription in SCCHN.	('dysregulated', 'Var', (55, 67))	('SCC', 'Gene', (125, 128))	('overexpression', 'PosReg', (24, 38))	('increases', 'PosReg', (88, 97))	('transcription', 'MPA', (108, 121))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('SCC', 'Gene', '6317', (125, 128))	('EGFR gene', 'Gene', (98, 107))
162706	18778701	Abnormalities in dinucleotide repeats in the first intron of the EGFR gene have also been implicated in altering the efficiency of EGFR gene transcription.	('dinucleotide repeats', 'Var', (17, 37))	('implicated', 'Reg', (90, 100))	('dinucleotide', 'Chemical', 'MESH:D015226', (17, 29))	('Abnormalities', 'Var', (0, 13))	('EGFR', 'Gene', (65, 69))	('efficiency', 'MPA', (117, 127))	('altering', 'Reg', (104, 112))	('transcription', 'MPA', (141, 154))	('EGFR gene', 'Gene', (131, 140))
162707	18778701	In 12 SCCHN cell lines, those with lower numbers of dinucleotide repeats had increased levels of EGFR mRNA and protein.	('SCC', 'Gene', (6, 9))	('levels', 'MPA', (87, 93))	('dinucleotide repeats', 'Var', (52, 72))	('dinucleotide', 'Chemical', 'MESH:D015226', (52, 64))	('SCC', 'Gene', '6317', (6, 9))	('increased', 'PosReg', (77, 86))
162714	18778701	ErbB2 gene amplification is found in few cases of ESCC (~5%) but is more common in EA (~15%).	('ErbB2', 'Gene', (0, 5))	('SCC', 'Gene', (51, 54))	('common', 'Reg', (73, 79))	('SCC', 'Gene', '6317', (51, 54))	('EA', 'Phenotype', 'HP:0011459', (83, 85))	('amplification', 'Var', (11, 24))
162721	18778701	A correlation between patient survival and ErbB2 overexpression or gene amplification has not been clearly elucidated in esophageal carcinomas.	('esophageal carcinomas', 'Disease', 'MESH:D004938', (121, 142))	('ErbB2', 'Gene', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('esophageal carcinomas', 'Disease', (121, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (121, 141))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (121, 142))	('gene amplification', 'Var', (67, 85))	('overexpression', 'PosReg', (49, 63))	('patient', 'Species', '9606', (22, 29))
162733	18778701	Expression of ErbB4 did not correlate with invasion, angiogenesis, metastasis or SCCHN tumor progression, although expression of all four ErbB receptors in oral SCC was significantly associated with decreased patient survival.	('patient survival', 'CPA', (209, 225))	('SCC', 'Gene', '6317', (81, 84))	('SCC', 'Gene', (161, 164))	('patient', 'Species', '9606', (209, 216))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('decreased', 'NegReg', (199, 208))	('SCCHN tumor', 'Disease', 'MESH:D009369', (81, 92))	('SCC', 'Gene', '6317', (161, 164))	('SCC', 'Gene', (81, 84))	('ErbB', 'Gene', (138, 142))	('expression', 'Var', (115, 125))	('SCCHN tumor', 'Disease', (81, 92))
162736	18778701	Cytoplasmic and nuclear staining of ErbB4 expressing cells may result from ErbB4 cleavage by tumor necrosis factor alpha converting enzyme (TACE) and gamma-secretase producing an intracellular domain fragment that can be translocated to the nucleus where it functions as a transcription factor.	('TACE', 'Gene', '6868', (140, 144))	('ErbB4', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TACE', 'Gene', (140, 144))	('tumor necrosis factor alpha converting enzyme', 'Gene', '6868', (93, 138))	('tumor necrosis factor alpha converting enzyme', 'Gene', (93, 138))	('result from', 'Reg', (63, 74))	('ErbB4', 'Gene', (75, 80))	('cleavage', 'Var', (81, 89))
162738	18778701	Unlike non-small cell lung carcinoma, SCCHN is not characterized by mutations of the EGFR kinase domain.	('EGFR', 'Gene', (85, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (7, 36))	('SCC', 'Gene', (38, 41))	('cell lung carcinoma', 'Disease', (17, 36))	('SCC', 'Gene', '6317', (38, 41))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (11, 36))	('mutations', 'Var', (68, 77))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (17, 36))
162740	18778701	Expression of the EGFR variant III has been identified in up to 40% of SCCHN tumors but has not been studied, to date, in esophageal carcinomas.	('SCCHN tumors', 'Disease', 'MESH:D009369', (71, 83))	('esophageal carcinomas', 'Disease', (122, 143))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (122, 143))	('SCCHN tumors', 'Disease', (71, 83))	('variant', 'Var', (23, 30))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (122, 142))	('EGFR', 'Gene', (18, 22))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (122, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('identified', 'Reg', (44, 54))
162745	18778701	We have shown that EGFRvIII expression in SCCHN cell lines leads to increased cell proliferation in vitro and increased tumorigenicity in vivo as compared to vector-transfected control cells.	('increased', 'PosReg', (110, 119))	('EGFRvIII', 'Gene', (19, 27))	('SCC', 'Gene', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('expression', 'Var', (28, 38))	('SCC', 'Gene', '6317', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('increased', 'PosReg', (68, 77))	('tumor', 'Disease', (120, 125))	('cell proliferation', 'CPA', (78, 96))
162747	18778701	ErbB2-ErbB3 heterodimers have been shown to induce the PI3K pathway, most likely because ErbB3 can directly bind the PI3K p85 subunit.	('PI3K pathway', 'Pathway', (55, 67))	('induce', 'PosReg', (44, 50))	('p85', 'Gene', (122, 125))	('bind', 'Interaction', (108, 112))	('ErbB3', 'Gene', (89, 94))	('ErbB3', 'Gene', (6, 11))	('heterodimers', 'Var', (12, 24))	('ErbB3', 'Gene', '2065', (89, 94))	('ErbB3', 'Gene', '2065', (6, 11))	('p85', 'Gene', '5296', (122, 125))
162752	18778701	Following EGFR activation, Grb2 and Sos (adaptor proteins) bind EGFR directly at Y1092 and Y1110 or through Shc (which binds at EGFR Y1172 and Y1197).	('Grb2', 'Gene', (27, 31))	('Shc', 'Gene', '6464', (108, 111))	('Y1197', 'Var', (143, 148))	('Y1110', 'Var', (91, 96))	('Sos', 'Gene', (36, 39))	('Y1172', 'Var', (133, 138))	('Y1092', 'Var', (81, 86))	('Grb2', 'Gene', '2885', (27, 31))	('EGFR', 'Gene', (64, 68))	('Shc', 'Gene', (108, 111))	('Sos', 'Gene', '64132', (36, 39))
162760	18778701	A separate study combined radiation treatment with the MEK inhibitor PD98059 and found synergistic effects on cell killing in esophageal cancer cell lines indicating that MAPK signaling may be a contributing factor in cell survival in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (235, 252))	('MEK', 'Gene', (55, 58))	('PD98059', 'Var', (69, 76))	('MEK', 'Gene', '5609', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('esophageal cancer', 'Disease', (235, 252))	('PD98059', 'Chemical', 'MESH:C093973', (69, 76))	('esophageal cancer', 'Disease', (126, 143))
162771	18778701	STAT5 is also overexpressed and activated in SCCHN and an antisense blockade of STAT5b inhibited tumor growth.	('STAT5', 'Gene', (0, 5))	('antisense blockade', 'Var', (58, 76))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('STAT5', 'Gene', '6776', (80, 85))	('SCC', 'Gene', (45, 48))	('STAT5b', 'Gene', '6777', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('activated', 'PosReg', (32, 41))	('SCC', 'Gene', '6317', (45, 48))	('tumor', 'Disease', (97, 102))	('STAT5', 'Gene', (80, 85))	('inhibited', 'NegReg', (87, 96))	('STAT5', 'Gene', '6776', (0, 5))	('STAT5b', 'Gene', (80, 86))
162777	18778701	In SCCHN cell lines Src family kinases are activated by TGF- alpha stimulation via direct binding to EGFR at Y915 and Y944.	('TGF- alpha', 'Gene', (56, 66))	('SCC', 'Gene', '6317', (3, 6))	('activated', 'PosReg', (43, 52))	('EGFR', 'Gene', (101, 105))	('Y915', 'Var', (109, 113))	('binding', 'Interaction', (90, 97))	('Y944', 'Var', (118, 122))	('Src', 'Gene', (20, 23))	('Src', 'Gene', '6714', (20, 23))	('TGF- alpha', 'Gene', '7039', (56, 66))	('SCC', 'Gene', (3, 6))
162782	18778701	In SCCHN Src can be activated independently of EGFR and transphosphorylate EGFR at Y845, leading to EGFR receptor activation.	('activation', 'PosReg', (114, 124))	('Y845', 'Var', (83, 87))	('Src', 'Gene', '6714', (9, 12))	('SCC', 'Gene', '6317', (3, 6))	('EGFR receptor', 'Protein', (100, 113))	('Src', 'Gene', (9, 12))	('SCC', 'Gene', (3, 6))
162790	18778701	Other in vitro experiments on SCCHN cells demonstrated that chemotaxis and invasion of metastatic SCCHN cells were dependent on PI3K and its substrate PLCgamma-1 although this pathway can be activated through EGFR or chemokine receptor 7.	('SCC', 'Gene', '6317', (30, 33))	('PLCgamma-1', 'Gene', '5335', (151, 161))	('SCC', 'Gene', '6317', (98, 101))	('PI3K', 'Var', (128, 132))	('PLCgamma-1', 'Gene', (151, 161))	('SCC', 'Gene', (30, 33))	('chemotaxis', 'CPA', (60, 70))	('dependent', 'Reg', (115, 124))	('SCC', 'Gene', (98, 101))
162794	18778701	Cell migration may also be mediated by the Rho family of GTP-binding proteins and PI3K through activation of Ras and Rac.	('PI3K', 'Var', (82, 86))	('GTP', 'Chemical', 'MESH:D006160', (57, 60))	('Rac', 'Protein', (117, 120))	('Cell migration', 'CPA', (0, 14))	('activation', 'PosReg', (95, 105))	('Ras', 'Protein', (109, 112))	('Rho family of GTP-binding proteins', 'Protein', (43, 77))
162797	18778701	PI3K catalyzes the conversion of PIP2 to a lipid second messenger PIP3, which results in recruiting and activating of PKB and AKT through PDK.	('AKT', 'Gene', (126, 129))	('PI3K', 'Var', (0, 4))	('recruiting', 'PosReg', (89, 99))	('PIP2', 'Chemical', 'MESH:D019269', (33, 37))	('PKB', 'Gene', '207', (118, 121))	('activating', 'PosReg', (104, 114))	('PKB', 'Gene', (118, 121))	('PIP3', 'Chemical', '-', (66, 70))	('AKT', 'Gene', '207', (126, 129))	('lipid', 'Chemical', 'MESH:D008055', (43, 48))
162799	18778701	PI3K then induces downstream amplification of PDK1, which in turn phosphorylates AKT.	('phosphorylates', 'Reg', (66, 80))	('PI3K', 'Var', (0, 4))	('AKT', 'Gene', '207', (81, 84))	('induces', 'Reg', (10, 17))	('downstream amplification', 'MPA', (18, 42))	('AKT', 'Gene', (81, 84))	('PDK1', 'Gene', '5163', (46, 50))	('PDK1', 'Gene', (46, 50))
162801	18778701	Studies in SCCHN have shown that PTEN mutations are extremely rare indicating that PI3K activation through loss of PTEN function is not a major factor in dysregulated PI3K signaling in SCCHN.	('activation', 'PosReg', (88, 98))	('function', 'MPA', (120, 128))	('SCC', 'Gene', (11, 14))	('SCC', 'Gene', (185, 188))	('loss', 'NegReg', (107, 111))	('PTEN', 'Gene', (115, 119))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (115, 119))	('SCC', 'Gene', '6317', (11, 14))	('PTEN', 'Gene', '5728', (33, 37))	('SCC', 'Gene', '6317', (185, 188))	('mutations', 'Var', (38, 47))	('PI3K', 'Enzyme', (83, 87))
162806	18778701	Irradiation combined with the inhibitor of PI3K LY294002 resulted in a synergistic increase in radiation-induced cell killing as compared to radiation alone in esophageal cancer cell lines.	('PI3K', 'Var', (43, 47))	('increase', 'PosReg', (83, 91))	('LY294002', 'Var', (48, 56))	('esophageal cancer', 'Disease', (160, 177))	('radiation-induced cell killing', 'CPA', (95, 125))	('LY294002', 'Chemical', 'MESH:C085911', (48, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
162811	18778701	GPCR-EGFR crosstalk has been shown to contribute to lung and head and neck cancer progression.	('neck cancer', 'Disease', 'MESH:D006258', (70, 81))	('neck cancer', 'Disease', (70, 81))	('lung', 'Disease', (52, 56))	('contribute', 'Reg', (38, 48))	('GPCR', 'Gene', (0, 4))	('GPCR', 'Gene', '441931', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('head and neck cancer', 'Phenotype', 'HP:0012288', (61, 81))	('crosstalk', 'Var', (10, 19))
162816	18778701	GPCRs can also activate EGFR via Src-mediated phosphorylation of EGFR at Y845 in SCCHN.	('Src', 'Gene', (33, 36))	('Src', 'Gene', '6714', (33, 36))	('SCC', 'Gene', '6317', (81, 84))	('EGFR', 'Protein', (24, 28))	('EGFR', 'Gene', (65, 69))	('GPCR', 'Gene', (0, 4))	('GPCR', 'Gene', '441931', (0, 4))	('SCC', 'Gene', (81, 84))	('at Y845', 'Var', (70, 77))	('activate', 'PosReg', (15, 23))
162817	18778701	Transactivation of EGFR by cell adhesion molecules such as E-cadherin from neighboring tumor cells has been proposed to prevent apoptosis in the early stages of metastasis as the tumor cell detaches from the extracellular matrix.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('prevent', 'NegReg', (120, 127))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Transactivation', 'Var', (0, 15))	('EGFR', 'Gene', (19, 23))	('E-cadherin', 'Gene', '999', (59, 69))	('E-cadherin', 'Gene', (59, 69))	('apoptosis', 'CPA', (128, 137))	('tumor', 'Disease', (179, 184))
162818	18778701	Cell adhesion molecules such as E-cadherin and integrins in SCCHN can form a complex with EGFR and transactivate EGFR (figure 1).	('transactivate', 'Var', (99, 112))	('complex', 'Interaction', (77, 84))	('E-cadherin', 'Gene', (32, 42))	('SCC', 'Gene', '6317', (60, 63))	('E-cadherin', 'Gene', '999', (32, 42))	('EGFR', 'Gene', (90, 94))	('EGFR', 'Gene', (113, 117))	('SCC', 'Gene', (60, 63))
162824	18778701	These cumulative results suggest that there are several potential pathways to transactivate EGFR in this cancer.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('transactivate', 'Var', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('EGFR', 'Gene', (92, 96))
162825	18778701	Overexpression of EGFR is relatively common in both SCCHN and esophageal carcinomas where expression levels have been correlated with decreased survival.	('decreased', 'NegReg', (134, 143))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (62, 83))	('esophageal carcinomas', 'Disease', (62, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('SCC', 'Gene', (52, 55))	('common', 'Reg', (37, 43))	('EGFR', 'Gene', (18, 22))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (62, 82))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (62, 83))	('Overexpression', 'Var', (0, 14))	('SCC', 'Gene', '6317', (52, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
162894	31308987	Throughout the course of treatment, there was no significant difference when comparing placebo to either BoNT/A (p = .84) or BoNT/A and B (p = .56) for scintigraphic uptake or salivary excretion fraction (p = .44 for both formulations).	('salivary excretion', 'Disease', (176, 194))	('salivary excretion', 'Disease', 'MESH:D012466', (176, 194))	('scintigraphic uptake', 'MPA', (152, 172))	('BoNT/A', 'Var', (125, 131))	('men', 'Species', '9606', (30, 33))
162923	31308987	The authors also reported on measures not addressed previously in the literature, including reflux symptoms and use of promotility agents, which were higher in the botulinum intervention arm.	('reflux symptoms', 'Phenotype', 'HP:0002020', (92, 107))	('higher', 'PosReg', (150, 156))	('botulinum', 'Chemical', '-', (164, 173))	('use', 'MPA', (112, 115))	('botulinum', 'Var', (164, 173))	('reflux symptoms', 'MPA', (92, 107))
162979	31117892	The dysphagia scores were significantly reduced after PDT.	('dysphagia', 'Disease', (4, 13))	('dysphagia', 'Phenotype', 'HP:0002015', (4, 13))	('dysphagia', 'Disease', 'MESH:D003680', (4, 13))	('reduced', 'NegReg', (40, 47))	('PDT', 'Var', (54, 57))
163012	30571768	Using culture techniques, Campylobacter was identified in about 50% of both reflux esophagitis and BE patients and was associated with increased interleukin-18 (IL-18).	('interleukin-18', 'Gene', '3606', (145, 159))	('interleukin-18', 'Gene', (145, 159))	('patients', 'Species', '9606', (102, 110))	('esophagitis', 'Phenotype', 'HP:0100633', (83, 94))	('increased', 'PosReg', (135, 144))	('IL-18', 'Gene', '3606', (161, 166))	('increased interleukin-', 'Phenotype', 'HP:0030783', (135, 157))	('Campylobacter', 'Var', (26, 39))	('IL-18', 'Gene', (161, 166))	('reflux esophagitis', 'Disease', 'MESH:D005764', (76, 94))	('reflux esophagitis', 'Disease', (76, 94))
163030	30571768	Alterations in oral microbiota may also be associated with esophageal cancer risk.	('esophageal cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Alterations', 'Var', (0, 11))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('associated', 'Reg', (43, 53))	('rat', 'Species', '10116', (4, 7))
163033	30571768	Actinomyces cardiffensis, Selenomonas oral taxon 134, and Veillonella oral taxon 917 were also associated with increased risk of EAC, while other organisms from the oral microbiota such as Prevotella nanceiensis and Streptococcus pneumoniae were associated with protective effects.	('Veillonella oral', 'Disease', 'MESH:D020820', (58, 74))	('Prevotella nanceiensis', 'Species', '425941', (189, 211))	('Actinomyces cardiffensis', 'Species', '181487', (0, 24))	('Veillonella oral', 'Disease', (58, 74))	('Streptococcus pneumoniae', 'Species', '1313', (216, 240))	('Selenomonas oral taxon 134', 'Species', '712530', (26, 52))	('EAC', 'Disease', (129, 132))	('Selenomonas', 'Var', (26, 37))
163060	30571768	Over the past few years, studies have strongly suggested that variation in the esophageal microbiota is associated with esophageal disease.	('associated', 'Reg', (104, 114))	('esophageal disease', 'Disease', (120, 138))	('esophageal disease', 'Disease', 'MESH:D004935', (120, 138))	('variation', 'Var', (62, 71))
163069	30571768	The potential role of PPIs in the pathologic alteration of the esophageal microbiome represents a particularly interesting area of research because while PPIs reduce acid levels (and acid-related esophageal damage), the higher pH leads to a less bactericidal milieu.	('esophageal damage', 'Disease', 'MESH:D004935', (196, 213))	('less bactericidal milieu', 'MPA', (241, 265))	('rat', 'Species', '10116', (49, 52))	('acid levels', 'MPA', (166, 177))	('esophageal damage', 'Disease', (196, 213))	('reduce', 'NegReg', (159, 165))	('PPIs', 'Var', (154, 158))
163144	25644553	A 37-year-old Japanese man was diagnosed with T4b (descending aorta) N2M0, Stage IIIC middle thoracic esophageal squamous cell carcinoma.	('man', 'Species', '9606', (23, 26))	('thoracic esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('descending aorta', 'Phenotype', 'HP:0025495', (51, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('T4b', 'Var', (46, 49))	('thoracic esophageal squamous cell carcinoma', 'Disease', (93, 136))
163165	25644553	Based on these results, this patient was diagnosed with T4b (descending aorta) N2M0, Stage IIIC middle thoracic esophageal squamous cell carcinoma.	('patient', 'Species', '9606', (29, 36))	('descending aorta', 'Phenotype', 'HP:0025495', (61, 77))	('thoracic esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (103, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('T4b', 'Var', (56, 59))	('thoracic esophageal squamous cell carcinoma', 'Disease', (103, 146))
163217	18215315	Diagnosis can be typically established by the triad: antimitochondrial antibodies (AMA) in serum, cholestatic indices and liver histology diagnostic or compatible with PBC.	('PBC', 'Gene', (168, 171))	('cholestatic', 'Disease', 'MESH:D002779', (98, 109))	('PBC', 'Gene', '1737', (168, 171))	('cholestatic', 'Disease', (98, 109))	('antimitochondrial antibodies', 'Phenotype', 'HP:0030167', (53, 81))	('antimitochondrial', 'Var', (53, 70))	('AMA', 'Phenotype', 'HP:0030167', (83, 86))	('PBC', 'Phenotype', 'HP:0002613', (168, 171))
163309	18215315	Although the disease is virtually identical in women and men, recent data suggest that X-chromosome monosomy in lymphoid cells is common in women with PBC.	('X-chromosome monosomy', 'Var', (87, 108))	('men', 'Species', '9606', (49, 52))	('PBC', 'Gene', '1737', (151, 154))	('men', 'Species', '9606', (142, 145))	('PBC', 'Gene', (151, 154))	('women', 'Species', '9606', (47, 52))	('women', 'Species', '9606', (140, 145))	('men', 'Species', '9606', (57, 60))	('PBC', 'Phenotype', 'HP:0002613', (151, 154))
163346	18215315	However, granulomas and eosinophilic infiltration are seen only in NOD.c3c4 mice.	('granulomas', 'Disease', 'MESH:D006099', (9, 19))	('granulomas', 'Phenotype', 'HP:0032252', (9, 19))	('eosinophilic infiltration', 'Disease', 'MESH:D004802', (24, 49))	('mice', 'Species', '10090', (76, 80))	('granulomas', 'Disease', (9, 19))	('eosinophilic infiltration', 'Disease', (24, 49))	('NOD.c3c4', 'Var', (67, 75))
163407	18215315	A recent meta-analysis indicates that treatment with rifampin leads to complete or partial resolution of pruritus in 77% of patients as compared with 20% treated with placebo or alternative.	('rifampin', 'Var', (53, 61))	('partial', 'NegReg', (83, 90))	('pruritus', 'Phenotype', 'HP:0000989', (105, 113))	('men', 'Species', '9606', (43, 46))	('rifampin', 'Chemical', 'MESH:D012293', (53, 61))	('patients', 'Species', '9606', (124, 132))	('pruritus', 'Disease', 'MESH:D011537', (105, 113))	('pruritus', 'Disease', (105, 113))
163410	18215315	Rifampin may cause hepatitis, hemolytic anemia and renal dysfunction, usually within the initial few weeks of therapy.	('hemolytic anemia', 'Disease', (30, 46))	('Rifampin', 'Var', (0, 8))	('hepatitis', 'Disease', 'MESH:D056486', (19, 28))	('renal dysfunction', 'Phenotype', 'HP:0000083', (51, 68))	('renal dysfunction', 'Disease', (51, 68))	('cause', 'Reg', (13, 18))	('hepatitis', 'Disease', (19, 28))	('renal dysfunction', 'Disease', 'MESH:D007674', (51, 68))	('hepatitis', 'Phenotype', 'HP:0012115', (19, 28))	('Rifampin', 'Chemical', 'MESH:D012293', (0, 8))	('hemolytic anemia', 'Disease', 'MESH:D000743', (30, 46))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (30, 46))	('anemia', 'Phenotype', 'HP:0001903', (40, 46))
163431	18215315	In the development of osteoporosis in PBC, there are two mechanisms that are commonly used to classify primary osteoporosis: "low-turnover" with normal resorption but reduced synthesis and slow mineralization of matrix and "high-turnover" with increased resorption due to reduced osteoblast function or increased activity of osteoclast.	('osteoporosis', 'Phenotype', 'HP:0000939', (111, 123))	('synthesis', 'MPA', (175, 184))	('resorption', 'CPA', (254, 264))	('osteoporosis', 'Disease', 'MESH:D010024', (111, 123))	('PBC', 'Gene', '1737', (38, 41))	('osteoporosis', 'Disease', (22, 34))	('reduced', 'NegReg', (272, 279))	('osteoporosis', 'Phenotype', 'HP:0000939', (22, 34))	('reduced', 'NegReg', (167, 174))	('osteoporosis', 'Disease', 'MESH:D010024', (22, 34))	('reduced osteoblast function', 'Phenotype', 'HP:0030328', (272, 299))	('increased', 'PosReg', (303, 312))	('PBC', 'Gene', (38, 41))	('high-turnover', 'Var', (224, 237))	('osteoblast function', 'CPA', (280, 299))	('men', 'Species', '9606', (14, 17))	('PBC', 'Phenotype', 'HP:0002613', (38, 41))	('activity', 'MPA', (313, 321))	('osteoporosis', 'Disease', (111, 123))	('slow', 'NegReg', (189, 193))	('increased', 'PosReg', (244, 253))
163479	18215315	Another recent study including patients with early-stage disease has demonstrated that the independent predictive factors of cirrhosis development were serum bilirubin (>17 mumol/L), serum albumin (<38 g/L) and moderate to severe lymphocytic piecemeal necrosis.	('bilirubin', 'Chemical', 'MESH:D001663', (158, 167))	('men', 'Species', '9606', (142, 145))	('cirrhosis', 'Disease', (125, 134))	('serum albumin', 'MPA', (183, 196))	('serum bilirubin', 'MPA', (152, 167))	('<38', 'Var', (198, 201))	('lymphocytic piecemeal necrosis', 'Disease', 'MESH:D009336', (230, 260))	('lymphocytic piecemeal necrosis', 'Disease', (230, 260))	('cirrhosis', 'Phenotype', 'HP:0001394', (125, 134))	('patients', 'Species', '9606', (31, 39))	('moderate', 'Disease', (211, 219))	('cirrhosis', 'Disease', 'MESH:D005355', (125, 134))
163512	33435549	We only focused on the RPs and the diseases related to the deregulation of RPs, and the miRNAs targeting RPs.	('miR', 'Gene', (88, 91))	('RPs', 'Disease', (23, 26))	('deregulation', 'Var', (59, 71))	('RPs', 'Protein', (75, 78))	('miR', 'Gene', '220972', (88, 91))
163519	33435549	For example, Ribosomal protein L33 (RPL33) is required for ribosome biogenesis, subunit joining, and a mutation in RPL33 causes the repression of GCN4 translation in yeast, which is a transcription factor and master regulator of the genes, and is highly conserved in mammalian species named as activating transcription factor-4 (ATF4).	('activating transcription factor-4', 'Gene', '468', (294, 327))	('activating transcription factor-4', 'Gene', (294, 327))	('RPL3', 'Gene', '6122', (115, 119))	('GCN4', 'Gene', (146, 150))	('RPL3', 'Gene', '6122', (36, 40))	('causes', 'Reg', (121, 127))	('ATF4', 'Gene', (329, 333))	('mammalian', 'Species', '9606', (267, 276))	('repression', 'MPA', (132, 142))	('Ribosomal protein L3', 'Gene', '6122', (13, 33))	('translation', 'MPA', (151, 162))	('Ribosomal protein L3', 'Gene', (13, 33))	('yeast', 'Species', '4932', (166, 171))	('RPL3', 'Gene', (115, 119))	('mutation', 'Var', (103, 111))	('ATF4', 'Gene', '468', (329, 333))	('RPL3', 'Gene', (36, 40))	('GCN4', 'Gene', '856709', (146, 150))
163520	33435549	The mutation in RPL33 also reduces the processing efficiency of the 35S and 27S pre-rRNAs following the reduction of the accumulation of all four mature rRNAs; thus, RPL33 could have a mass influence on the global gene expression through the deregulation of master transcription factor GCN4 or ATF4.	('RPL3', 'Gene', (16, 20))	('GCN4', 'Gene', '856709', (286, 290))	('ATF4', 'Gene', (294, 298))	('reduces', 'NegReg', (27, 34))	('global gene expression', 'MPA', (207, 229))	('RPL3', 'Gene', '6122', (166, 170))	('GCN4', 'Gene', (286, 290))	('mutation', 'Var', (4, 12))	('RPL3', 'Gene', '6122', (16, 20))	('processing efficiency', 'MPA', (39, 60))	('ATF4', 'Gene', '468', (294, 298))	('RPL3', 'Gene', (166, 170))	('deregulation', 'Reg', (242, 254))	('influence', 'Reg', (190, 199))
163521	33435549	Similarly, Ribosomal protein S20 (RPS20) is responsible for the mRNA binding and subunits association, and lacking RPS20 causes drastic reduction in the formation of the 70S complex as well as mRNA binding through an initiation that defects to the 30S subunit.	('Ribosomal protein S20', 'Gene', (11, 32))	('RPS20', 'Gene', (34, 39))	('formation of', 'MPA', (153, 165))	('mRNA binding', 'MPA', (193, 205))	('lacking', 'Var', (107, 114))	('RPS20', 'Gene', '6224', (34, 39))	('Ribosomal protein S20', 'Gene', '6224', (11, 32))	('reduction', 'NegReg', (136, 145))	('RPS20', 'Gene', (115, 120))	('initiation', 'MPA', (217, 227))	('RPS20', 'Gene', '6224', (115, 120))
163531	33435549	Hence, deregulation of RPs impairs the synthesis, processing and assembly of rRNA, translation and modification of proteins, and eventually lead to the progression of diseases (Table 3) including developmental, systemic and metabolic complications, and cancers.	('modification of', 'MPA', (99, 114))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('deregulation', 'Var', (7, 19))	('processing', 'MPA', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancers', 'Disease', (253, 260))	('lead to', 'Reg', (140, 147))	('proteins', 'Protein', (115, 123))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('diseases', 'Disease', (167, 175))	('RPs', 'Protein', (23, 26))	('impairs', 'NegReg', (27, 34))	('developmental', 'CPA', (196, 209))	('synthesis', 'MPA', (39, 48))	('rRNA', 'Protein', (77, 81))	('assembly of', 'MPA', (65, 76))	('translation', 'MPA', (83, 94))
163535	33435549	5q-syndrome is a type of anemia that is caused by the haplo-insufficiency of RPS14, a critical component for 40S assembly, and depletion of RPS14 in human CD34+ cells is sufficient to recapitulate the 5q-defect of erythropoiesis with sparing of megakaryocytes.	('CD34', 'Gene', (155, 159))	('RPS14', 'Gene', (77, 82))	('anemia', 'Phenotype', 'HP:0001903', (25, 31))	('RPS14', 'Gene', '6208', (77, 82))	('RPS14', 'Gene', (140, 145))	('-defect of erythropoiesis', 'Phenotype', 'HP:0010972', (203, 228))	('RPS14', 'Gene', '6208', (140, 145))	('depletion', 'Var', (127, 136))	('human', 'Species', '9606', (149, 154))	('CD34', 'Gene', '947', (155, 159))	('anemia', 'Disease', (25, 31))	('anemia', 'Disease', 'MESH:D000740', (25, 31))	('5q-syndrome', 'Disease', (0, 11))
163536	33435549	The clinical sign of SDS disease includes exocrine pancreatic insufficiency, hematologic abnormalities such as neutropenia, neurocognitive dysfunction, and results from the bi-allelic mutations in the ribosome maturation protein SBDS, which compromises its ability to couple GTP hydrolysis by the GTPase EFL1 to the release of eIF6 from the 60S subunit.	('SBDS', 'Gene', '51119', (229, 233))	('hematologic abnormalities', 'Disease', 'MESH:D006402', (77, 102))	('exocrine pancreatic insufficiency', 'Disease', 'MESH:D010188', (42, 75))	('hematologic abnormalities', 'Disease', (77, 102))	('ability', 'MPA', (257, 264))	('neutropenia', 'Phenotype', 'HP:0001875', (111, 122))	('neutropenia', 'Disease', 'MESH:D009503', (111, 122))	('hematologic abnormalities', 'Phenotype', 'HP:0001871', (77, 102))	('EFL1', 'Gene', (304, 308))	('SBDS', 'Gene', (229, 233))	('couple GTP hydrolysis', 'MPA', (268, 289))	('exocrine pancreatic insufficiency', 'Disease', (42, 75))	('results from', 'Reg', (156, 168))	('SDS disease', 'Disease', (21, 32))	('neurocognitive dysfunction', 'Disease', 'MESH:D019965', (124, 150))	('neutropenia', 'Disease', (111, 122))	('bi-allelic mutations', 'Var', (173, 193))	('GTP', 'Chemical', 'MESH:D006160', (275, 278))	('GTP', 'Chemical', 'MESH:D006160', (297, 300))	('eIF6', 'Gene', '3692', (327, 331))	('neurocognitive dysfunction', 'Disease', (124, 150))	('compromises', 'NegReg', (241, 252))	('eIF6', 'Gene', (327, 331))	('EFL1', 'Gene', '79631', (304, 308))	('exocrine pancreatic insufficiency', 'Phenotype', 'HP:0001738', (42, 75))
163538	33435549	CHH is characterized by the short stature deformities of bone and abnormalities in the growth of hair and potentially results from mutation of the RMRP gene.	('CHH', 'Disease', (0, 3))	('RMRP', 'Gene', (147, 151))	('growth of hair', 'CPA', (87, 101))	('CHH', 'Disease', 'MESH:C535916', (0, 3))	('RMRP', 'Gene', '6023', (147, 151))	('short stature', 'Phenotype', 'HP:0004322', (28, 41))	('results from', 'Reg', (118, 130))	('short stature deformities of bone and abnormalities', 'Disease', 'MESH:D006130', (28, 79))	('mutation', 'Var', (131, 139))
163539	33435549	TCS is identified by the craniofacial abnormalities and caused by the mutation in the TCOF1 gene, which is involved in rRNA transcription.	('TCS', 'Disease', (0, 3))	('TCS', 'Phenotype', 'HP:0005321', (0, 3))	('TCOF1', 'Gene', (86, 91))	('craniofacial abnormalities', 'Disease', 'MESH:D019465', (25, 51))	('craniofacial abnormalities', 'Disease', (25, 51))	('TCOF1', 'Gene', '6949', (86, 91))	('mutation', 'Var', (70, 78))	('caused by', 'Reg', (56, 65))
163541	33435549	NAIC is an autosomal recessive abnormality of the CIRH1A gene, which codes for cirhin, and clinical symptoms include biliary, cirrhosis, portal and hypertension.	('cirhin', 'Gene', (79, 85))	('autosomal recessive abnormality', 'Disease', 'MESH:D030342', (11, 42))	('cirhin', 'Gene', '84916', (79, 85))	('autosomal recessive abnormality', 'Disease', (11, 42))	('NAIC', 'Var', (0, 4))	('cirrhosis', 'Phenotype', 'HP:0001394', (126, 135))	('cirrhosis', 'Disease', 'MESH:D005355', (126, 135))	('hypertension', 'Disease', 'MESH:D006973', (148, 160))	('biliary', 'Disease', (117, 124))	('CIRH1A', 'Gene', '84916', (50, 56))	('CIRH1A', 'Gene', (50, 56))	('hypertension', 'Disease', (148, 160))	('cirrhosis', 'Disease', (126, 135))	('hypertension', 'Phenotype', 'HP:0000822', (148, 160))
163542	33435549	The clinical patient data obtained from the cBioportal database  of the TCGA research network showed the frequent copy number alteration of the RPs coding genes (Figure 1a).	('patient', 'Species', '9606', (13, 20))	('copy number alteration', 'Var', (114, 136))	('RPs coding', 'Gene', (144, 154))
163543	33435549	It also showed that the patients with an alteration status of RPs had lower median month survival compared to the patients without alterations in the RPs (Figure 1b).	('median month survival', 'MPA', (76, 97))	('alteration status', 'Var', (41, 58))	('lower', 'NegReg', (70, 75))	('RPs', 'Gene', (62, 65))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (114, 122))
163544	33435549	Moreover, deregulated expression of the RPs is also recorded at the mRNA level, for example, the RNA-seq data of 300 ovarian cancer patients obtained from the same database (Supplementary Figure S1).	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (117, 131))	('deregulated', 'Var', (10, 21))	('ovarian cancer', 'Disease', (117, 131))	('patients', 'Species', '9606', (132, 140))	('expression', 'MPA', (22, 32))
163547	33435549	Ribosomal Protein L34 (RPL34) functions as an oncogene and modulates esophageal cancer cells by the inactivation of the PI3K/Akt signaling pathway, and silencing of RPL34 inhibits the proliferation and metastasis of esophageal cancer cells.	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('Ribosomal Protein L34', 'Gene', '6164', (0, 21))	('cancer', 'Disease', (80, 86))	('age', 'Gene', '5973', (221, 224))	('Akt', 'Gene', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Akt', 'Gene', '207', (125, 128))	('age', 'Gene', (74, 77))	('inhibits', 'NegReg', (171, 179))	('modulates', 'Reg', (59, 68))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('inactivation', 'NegReg', (100, 112))	('silencing', 'Var', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('RPL34', 'Gene', (23, 28))	('age', 'Gene', '5973', (74, 77))	('Ribosomal Protein L34', 'Gene', (0, 21))	('RPL34', 'Gene', '6164', (23, 28))	('RPL34', 'Gene', (165, 170))	('RPL34', 'Gene', '6164', (165, 170))	('age', 'Gene', (221, 224))
163548	33435549	Ribosomal Protein L22 (RPL22) controls the dissemination of T-cell lymphoma: single copy loss of RPL22 promoted lymphomagenesis and dissemination, while loss of both copies results in mediastinal retention.	('loss', 'Var', (89, 93))	('lymphoma', 'Phenotype', 'HP:0002665', (67, 75))	('cell lymphoma', 'Phenotype', 'HP:0012191', (62, 75))	('lymphomagenesis', 'Disease', (112, 127))	('RPL22', 'Gene', '6146', (23, 28))	('promoted', 'PosReg', (103, 111))	('Ribosomal Protein L22', 'Gene', (0, 21))	('Ribosomal Protein L22', 'Gene', '6146', (0, 21))	('RPL22', 'Gene', (23, 28))	('lymphomagenesis', 'Disease', 'None', (112, 127))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (60, 75))	('mediastinal retention', 'Disease', (184, 205))	('dissemination', 'CPA', (132, 145))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (60, 75))	('RPL22', 'Gene', '6146', (97, 102))	('T-cell lymphoma', 'Disease', (60, 75))	('loss', 'Var', (153, 157))	('RPL22', 'Gene', (97, 102))
163549	33435549	Mutation of Ribosomal Protein S20 (RPS20) in the germline cells might cause hereditary nonpolyposis colorectal carcinoma.	('Ribosomal Protein S20', 'Gene', (12, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('Ribosomal Protein S20', 'Gene', '6224', (12, 33))	('hereditary nonpolyposis colorectal carcinoma', 'Disease', 'MESH:D003123', (76, 120))	('hereditary nonpolyposis colorectal carcinoma', 'Disease', (76, 120))	('Mutation', 'Var', (0, 8))	('RPS20', 'Gene', (35, 40))	('cause', 'Reg', (70, 75))	('hereditary nonpolyposis colorectal carcinoma', 'Phenotype', 'HP:0006716', (76, 120))	('RPS20', 'Gene', '6224', (35, 40))
163550	33435549	Based on the above discussion, the RPs are not only the building block of the translation machinery, but also have important roles in other physiological processes, and deregulation of the RPs might cause severe diseases including different types of ribosomopathy and cancers.	('RPs', 'Protein', (189, 192))	('cause', 'Reg', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('deregulation', 'Var', (169, 181))	('ribosomopathy and cancers', 'Disease', 'MESH:D009369', (250, 275))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))
163556	33435549	However, there is a prominent trend of global suppression of miRNAs expression in different types of cancers, and this process of global suppression of miRNAs expression could be a result of multiple conditions such as genomic defects in the miRNA coding region (mutations, amplifications or deletions), transcription factor mediated repression (such as Myc), epigenetic alterations in the promoter region (CpG islands hypermethylation), and the deregulation of Dicer and Drosha, the machineries for the processing of miRNAs.	('Drosha', 'Gene', (472, 478))	('defects', 'Var', (227, 234))	('miR', 'Gene', '220972', (61, 64))	('Drosha', 'Gene', '29102', (472, 478))	('miR', 'Gene', (242, 245))	('miR', 'Gene', '220972', (518, 521))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('miR', 'Gene', (61, 64))	('epigenetic alterations', 'Var', (360, 382))	('suppression', 'NegReg', (46, 57))	('Myc', 'Gene', (354, 357))	('miR', 'Gene', '220972', (152, 155))	('miR', 'Gene', (518, 521))	('result', 'Reg', (181, 187))	('miR', 'Gene', (152, 155))	('repression', 'NegReg', (334, 344))	('deregulation', 'Var', (446, 458))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('Dicer', 'Gene', '23405', (462, 467))	('Dicer', 'Gene', (462, 467))	('Myc', 'Gene', '4609', (354, 357))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miR', 'Gene', '220972', (242, 245))	('suppression', 'NegReg', (137, 148))
163557	33435549	Deregulated expression of miRNAs is detected with many other types of diseases such as neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis, eye diseases including glaucoma, and myopia, traumatic brain injury, diabetes, rheumatoid arthritis, autoimmune and chronic inflammatory diseases, lung diseases, skeletal diseases, age-related diseases, myocardial infarction and cardiovascular diseases.	('amyotrophic lateral sclerosis', 'Disease', (175, 204))	('lung diseases', 'Disease', (353, 366))	('myocardial infarction', 'Disease', 'MESH:D009203', (409, 430))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (285, 305))	('age', 'Gene', (387, 390))	('Parkinson', 'Disease', (137, 146))	('diabetes', 'Disease', 'MESH:D003920', (275, 283))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (87, 113))	('eye diseases', 'Phenotype', 'HP:0000478', (206, 218))	('Parkinson', 'Disease', 'MESH:D010302', (137, 146))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (87, 113))	('inflammatory diseases', 'Disease', 'MESH:D007249', (330, 351))	('cardiovascular diseases', 'Disease', (435, 458))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (435, 458))	('eye diseases', 'Disease', (206, 218))	('eye diseases', 'Disease', 'MESH:D000853', (206, 218))	('miR', 'Gene', '220972', (26, 29))	('Deregulated', 'Var', (0, 11))	('traumatic brain injury', 'Disease', (251, 273))	("Huntington's disease", 'Disease', (150, 170))	('skeletal diseases', 'Disease', 'MESH:C535850', (368, 385))	("Huntington's disease", 'Disease', 'MESH:D006816', (150, 170))	('myopia', 'Phenotype', 'HP:0000545', (243, 249))	('age', 'Gene', '5973', (387, 390))	('skeletal diseases', 'Disease', (368, 385))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (285, 305))	('glaucoma', 'Disease', 'MESH:D005901', (229, 237))	('neurodegenerative diseases', 'Disease', (87, 113))	('diabetes', 'Disease', (275, 283))	('miR', 'Gene', (26, 29))	('arthritis', 'Phenotype', 'HP:0001369', (296, 305))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (175, 204))	('Alzheimer', 'Disease', (124, 133))	('inflammatory diseases', 'Disease', (330, 351))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (435, 458))	('myocardial infarction', 'Disease', (409, 430))	('lung diseases', 'Phenotype', 'HP:0002088', (353, 366))	('rheumatoid arthritis', 'Disease', (285, 305))	('Alzheimer', 'Disease', 'MESH:D000544', (124, 133))	('lung diseases', 'Disease', 'MESH:D008171', (353, 366))	('traumatic brain injury', 'Disease', 'MESH:D000070642', (251, 273))	('glaucoma', 'Phenotype', 'HP:0000501', (229, 237))	('glaucoma', 'Disease', (229, 237))	('myocardial infarction', 'Phenotype', 'HP:0001658', (409, 430))	('myopia', 'Disease', (243, 249))	('myopia', 'Disease', 'MESH:D009216', (243, 249))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (175, 204))
163569	33435549	To illustrate, firstly, the deregulation in the expression of miRNAs, which are involved in the regulation of RPs coding mRNAs, could result in an imbalanced synthesis of RPs.	('deregulation', 'Var', (28, 40))	('imbalanced synthesis of RPs', 'MPA', (147, 174))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('result in', 'Reg', (134, 143))	('imbalance', 'Phenotype', 'HP:0002172', (147, 156))
163581	33435549	Furthermore, miR-16-5p might have a role in osteoclastogenesis and could be an important biomarker of rheumatoid arthritis.	('arthritis', 'Phenotype', 'HP:0001369', (113, 122))	('role', 'Reg', (36, 40))	('miR-16-5p', 'Chemical', '-', (13, 22))	('miR-16-5p', 'Var', (13, 22))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (102, 122))	('rheumatoid arthritis', 'Disease', (102, 122))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (102, 122))	('osteoclastogenesis', 'CPA', (44, 62))
163584	33435549	Similarly, blocking of miR-92a-3p induces apoptosis in leukemia and colorectal cancer cells.	('colorectal cancer', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miR-92a-3p', 'Chemical', '-', (23, 33))	('induces', 'Reg', (34, 41))	('leukemia', 'Disease', 'MESH:D007938', (55, 63))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('apoptosis', 'CPA', (42, 51))	('leukemia', 'Disease', (55, 63))	('miR-92a-3p', 'Gene', (23, 33))	('blocking', 'Var', (11, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))
163586	33435549	It also has diagnostic value, miR-92a-3p is a biomarker for several diseases such as Kawasaki disease, schizophrenia, systemic lupus erythematosus, and white matter impairment and post-stroke depression.	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (118, 146))	('systemic lupus erythematosus', 'Disease', (118, 146))	('depression', 'Phenotype', 'HP:0000716', (192, 202))	('white matter impairment and post-stroke depression', 'Disease', 'MESH:D000275', (152, 202))	('schizophrenia', 'Phenotype', 'HP:0100753', (103, 116))	('stroke', 'Phenotype', 'HP:0001297', (185, 191))	('Kawasaki disease', 'Disease', 'MESH:D009080', (85, 101))	('miR-92a-3p', 'Chemical', '-', (30, 40))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (118, 146))	('miR-92a-3p', 'Var', (30, 40))	('white matter impairment', 'Phenotype', 'HP:0002500', (152, 175))	('schizophrenia', 'Disease', 'MESH:D012559', (103, 116))	('schizophrenia', 'Disease', (103, 116))	('Kawasaki disease', 'Disease', (85, 101))
163588	33435549	The third, fourth and fifth miRNAs in the list are miR-100-5p, miR-615-3p and miR-484, respectively: oncogenic miR-100-5p is a potent regulator of viability, metastasis and apoptosis of different cancer types, blocking of miR-100-5p induces apoptosis and prevents the re-emergence of prostate cancer, renal cell carcinoma (RCC), oral cancer and NSCLC.	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('RCC', 'Disease', (323, 326))	('RCC', 'Phenotype', 'HP:0005584', (323, 326))	('miR', 'Gene', (222, 225))	('miR', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('miR', 'Gene', '220972', (51, 54))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (301, 321))	('miR', 'Gene', '220972', (28, 31))	('cancer', 'Disease', (334, 340))	('RCC', 'Disease', 'MESH:C538614', (323, 326))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('miR-615-3p', 'Chemical', '-', (63, 73))	('NSCLC', 'Disease', 'MESH:D002289', (345, 350))	('miR', 'Gene', (51, 54))	('miR', 'Gene', (28, 31))	('miR-100-5p', 'Chemical', '-', (51, 61))	('cancer', 'Disease', (293, 299))	('renal cell carcinoma', 'Disease', (301, 321))	('NSCLC', 'Disease', (345, 350))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (301, 321))	('prevents', 'NegReg', (255, 263))	('blocking', 'Var', (210, 218))	('miR', 'Gene', '220972', (63, 66))	('apoptosis', 'CPA', (241, 250))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('miR-100-5p', 'Chemical', '-', (111, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (284, 299))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('miR', 'Gene', '220972', (111, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (284, 299))	('NSCLC', 'Phenotype', 'HP:0030358', (345, 350))	('induces', 'PosReg', (233, 240))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('miR-100-5p', 'Chemical', '-', (222, 232))	('miR', 'Gene', '220972', (222, 225))	('miR', 'Gene', '220972', (78, 81))	('prostate cancer', 'Disease', (284, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('miR', 'Gene', (63, 66))	('miR', 'Gene', (111, 114))
163590	33435549	While, miR-615-3p plays important role in the differentiation of cells, it suppresses GDF5 and FOXO1 and inhibits osteogenesis in the lumbar ligamentum flavum cells, it is also known to have a feed-forward loop with HOXC5, and repress hTERT during the differentiation of cells.	('miR-615-3p', 'Var', (7, 17))	('miR-615-3p', 'Chemical', '-', (7, 17))	('osteogenesis', 'Disease', 'MESH:D010013', (114, 126))	('repress', 'NegReg', (227, 234))	('FOXO1', 'Gene', (95, 100))	('suppresses', 'NegReg', (75, 85))	('FOXO1', 'Gene', '2308', (95, 100))	('HOXC5', 'Gene', '3222', (216, 221))	('GDF5', 'Gene', (86, 90))	('hTERT', 'Gene', '7015', (235, 240))	('GDF5', 'Gene', '8200', (86, 90))	('HOXC5', 'Gene', (216, 221))	('inhibits', 'NegReg', (105, 113))	('osteogenesis', 'Disease', (114, 126))	('hTERT', 'Gene', (235, 240))
163591	33435549	In cancer, miR-615-3p plays a dual role depending on the type, for example, it promotes gastric cancer potentially by targeting CELF2 and prostate cancer, but reported to be a suppressor of NSCLC potentially targeting IGF2 and esophageal cancer.	('targeting', 'Reg', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('prostate cancer', 'Disease', 'MESH:D011471', (138, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('NSCLC', 'Disease', (190, 195))	('prostate cancer', 'Disease', (138, 153))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (238, 244))	('NSCLC', 'Phenotype', 'HP:0030358', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('IGF2', 'Gene', (218, 222))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('age', 'Gene', (232, 235))	('miR-615-3p', 'Var', (11, 21))	('CELF2', 'Gene', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('CELF2', 'Gene', '10659', (128, 133))	('age', 'Gene', '5973', (232, 235))	('gastric cancer', 'Disease', (88, 102))	('miR-615-3p', 'Chemical', '-', (11, 21))	('IGF2', 'Gene', '3481', (218, 222))	('promotes', 'PosReg', (79, 87))	('cancer', 'Disease', (3, 9))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
163595	33435549	miR-484 also promotes NSCLC by targeting APAF-1 and adrenocortical cancer by targeting Fis1, which are regulators of apoptosis.	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('targeting', 'Reg', (77, 86))	('Fis1', 'Gene', '51024', (87, 91))	('promotes', 'PosReg', (13, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (52, 73))	('APAF-1', 'Gene', '317', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('NSCLC', 'Disease', (22, 27))	('targeting', 'Reg', (31, 40))	('miR-484', 'Var', (0, 7))	('Fis1', 'Gene', (87, 91))	('APAF-1', 'Gene', (41, 47))	('adrenocortical cancer', 'Disease', (52, 73))
163596	33435549	In addition, the presence of miR-484 in the blood serum could be considered as a biomarker for both NSCLC and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('NSCLC', 'Disease', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('miR-484', 'Var', (29, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('presence', 'Var', (17, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('colorectal cancer', 'Disease', (110, 127))
163597	33435549	As well, miR-484 promotes neurogenesis by targeting PCDH19, prevents ischemia-reperfusion injury by inhibiting CAS3 and CAS9 mediated apoptosis of myocardial cells in rats, creates resistance to sunitinib mediated therapy in metastatic renal carcinoma and reverses cytidine deaminase axis (CDA)-mediated chemoresistance in breast cancer.	('renal carcinoma', 'Disease', (236, 251))	('ischemia-reperfusion injury', 'Disease', 'MESH:D015427', (69, 96))	('renal carcinoma', 'Phenotype', 'HP:0005584', (236, 251))	('inhibiting', 'NegReg', (100, 110))	('CDA', 'Gene', '362638', (290, 293))	('breast cancer', 'Phenotype', 'HP:0003002', (323, 336))	('ischemia-reperfusion injury', 'Disease', (69, 96))	('targeting', 'Var', (42, 51))	('reverses', 'NegReg', (256, 264))	('CDH1', 'Gene', '999', (53, 57))	('prevents', 'NegReg', (60, 68))	('breast cancer', 'Disease', 'MESH:D001943', (323, 336))	('neurogenesis', 'CPA', (26, 38))	('breast cancer', 'Disease', (323, 336))	('cytidine deaminase', 'Gene', (265, 283))	('CDH1', 'Gene', (53, 57))	('rats', 'Species', '10116', (167, 171))	('sunitinib', 'Chemical', 'MESH:D000077210', (195, 204))	('promotes', 'PosReg', (17, 25))	('miR-484', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('resistance', 'MPA', (181, 191))	('CDA', 'Gene', (290, 293))	('creates', 'Reg', (173, 180))	('renal carcinoma', 'Disease', 'MESH:C538614', (236, 251))	('cytidine deaminase', 'Gene', '362638', (265, 283))
163606	33435549	The eighth, ninth and tenth of the candidate miRNAs are miR-193b-3p, let-7a-5p and miR-331-3p, respectively.	('miR-331-3p', 'Chemical', '-', (83, 93))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('let-7a-5p', 'Var', (69, 78))
163609	33435549	While, let-7a-5p inhibits osteogenesis and several cancers, the osteogenesis is inhibited by targeting TGFBR1, and the lung cancer is inhibited by mediating G1/S phase arrest most probably by regulating BCL2L1-mediated PI3Kgamma signaling, it also inhibits HCC.	('HCC', 'CPA', (257, 260))	('TGFBR1', 'Gene', '7046', (103, 109))	('lung cancer', 'Disease', (119, 130))	('osteogenesis', 'Disease', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('osteogenesis', 'Disease', (26, 38))	('PI3Kgamma', 'Gene', '5294', (219, 228))	('let-7a-5p', 'Var', (7, 16))	('BCL2L1', 'Gene', '598', (203, 209))	('arrest', 'Disease', 'MESH:D006323', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('BCL2L1', 'Gene', (203, 209))	('osteogenesis', 'Disease', 'MESH:D010013', (64, 76))	('osteogenesis', 'Disease', 'MESH:D010013', (26, 38))	('PI3Kgamma', 'Gene', (219, 228))	('targeting', 'Var', (93, 102))	('HCC', 'Phenotype', 'HP:0001402', (257, 260))	('inhibited', 'NegReg', (80, 89))	('inhibits', 'NegReg', (17, 25))	('arrest', 'Disease', (168, 174))	('inhibited', 'NegReg', (134, 143))	('inhibits', 'NegReg', (248, 256))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('TGFBR1', 'Gene', (103, 109))
163611	33435549	Among non-cancer diseases, let-7a-5p is involved in the pathogenesis of diabetic nephropathy by targeting HMGA2, and could be a marker for hepatic fibrosis.	('hepatic fibrosis', 'Disease', (139, 155))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('HMGA2', 'Gene', '8091', (106, 111))	('targeting', 'NegReg', (96, 105))	('cancer diseases', 'Disease', (10, 25))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (139, 155))	('HMGA2', 'Gene', (106, 111))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (72, 92))	('diabetic nephropathy', 'Disease', (72, 92))	('cancer diseases', 'Disease', 'MESH:D009369', (10, 25))	('let-7a-5p', 'Var', (27, 36))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (139, 155))	('involved', 'Reg', (40, 48))	('nephropathy', 'Phenotype', 'HP:0000112', (81, 92))
163612	33435549	Similarly, miR-331-3p is also involved in different disease conditions, and known for both anti- and pro-oncogenic characteristics in different types of cancers: it promotes pancreatic cancer by targeting ST7L, HCC by downregulating E2F1 and ING5, while its' presence in the serum indicates the invasive status of the HCC as well as recurrence in the case of esophageal adenocarcinoma.	('pancreatic cancer', 'Disease', 'MESH:D010190', (174, 191))	('cancers', 'Disease', (153, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (375, 384))	('promotes', 'PosReg', (165, 173))	('age', 'Gene', (364, 367))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('HCC', 'Phenotype', 'HP:0001402', (318, 321))	('ST7L', 'Gene', (205, 209))	('E2F1', 'Gene', '1869', (233, 237))	('pancreatic cancer', 'Disease', (174, 191))	('miR-331-3p', 'Chemical', '-', (11, 21))	('adenocarcinoma', 'Disease', (370, 384))	('ING5', 'Gene', '84289', (242, 246))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('downregulating', 'NegReg', (218, 232))	('ING5', 'Gene', (242, 246))	('age', 'Gene', '5973', (364, 367))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('HCC', 'Phenotype', 'HP:0001402', (211, 214))	('adenocarcinoma', 'Disease', 'MESH:D000230', (370, 384))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (174, 191))	('HCC', 'Gene', (211, 214))	('E2F1', 'Gene', (233, 237))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (359, 384))	('targeting', 'Var', (195, 204))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('ST7L', 'Gene', '54879', (205, 209))
163614	33435549	miR-331-3p also plays a role in inhibiting intracranial aneurysm by regulating TNF-alpha and CD14, as well as by maintaining contractile vascular smooth muscle.	('miR-331-3p', 'Chemical', '-', (0, 10))	('intracranial aneurysm', 'Phenotype', 'HP:0004944', (43, 64))	('miR-331-3p', 'Var', (0, 10))	('regulating', 'Reg', (68, 78))	('TNF-alpha', 'Gene', (79, 88))	('aneurysm', 'Phenotype', 'HP:0002617', (56, 64))	('maintaining', 'PosReg', (113, 124))	('CD14', 'Gene', (93, 97))	('intracranial aneurysm', 'Disease', 'MESH:D002532', (43, 64))	('intracranial aneurysm', 'Disease', (43, 64))	('CD14', 'Gene', '929', (93, 97))	('contractile vascular smooth muscle', 'CPA', (125, 159))	('TNF-alpha', 'Gene', '7124', (79, 88))
163616	33435549	Interestingly, miR-92b-3p acts as a preventive molecule against several neural and cardiac diseases; for example, it facilitates the growth of neurite, and healing of acute spinal cord injury by mediating the PTEN/AKT pathway.	('PTEN', 'Gene', (209, 213))	('cardiac diseases', 'Disease', 'MESH:D006331', (83, 99))	('miR-92b-3p', 'Chemical', '-', (15, 25))	('acute spinal cord injury', 'Phenotype', 'HP:0100561', (167, 191))	('healing', 'CPA', (156, 163))	('spinal cord injury', 'Disease', 'MESH:D013119', (173, 191))	('facilitates', 'PosReg', (117, 128))	('cardiac diseases', 'Disease', (83, 99))	('AKT', 'Gene', '207', (214, 217))	('spinal cord injury', 'Disease', (173, 191))	('mediating', 'Reg', (195, 204))	('AKT', 'Gene', (214, 217))	('miR-92b-3p', 'Var', (15, 25))	('growth of neurite', 'CPA', (133, 150))	('PTEN', 'Gene', '5728', (209, 213))
163617	33435549	Another example is cardiac hypertrophy, which is suppressed in mice by miR-92b-3p, potentially by targeting MEF2D and HAND2.	('targeting', 'Reg', (98, 107))	('miR-92b-3p', 'Var', (71, 81))	('cardiac hypertrophy', 'Disease', (19, 38))	('miR-92b-3p', 'Chemical', '-', (71, 81))	('mice', 'Species', '10090', (63, 67))	('MEF2D', 'Gene', '17261', (108, 113))	('MEF2D', 'Gene', (108, 113))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (19, 38))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (19, 38))	('HAND2', 'Gene', (118, 123))	('HAND2', 'Gene', '15111', (118, 123))
163619	33435549	In cancer, miR-92b-3p have both anti- and pro-cancer roles in different types of cancers: it suppresses pancreatic cancer by targeting GABRA3, but promotes several others such as colorectal cancer by inhibiting FBXW7, esophageal squamous cell carcinoma by target KLF4 and DCS2, gastric cancer by downregulating MMP2, MMP9 and HOXD10, and also could be a biomarker for synovial sarcoma.	('suppresses', 'NegReg', (93, 103))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('KLF4', 'Gene', (263, 267))	('synovial sarcoma', 'Disease', 'MESH:D013584', (368, 384))	('MMP9', 'Gene', (317, 321))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('GABRA3', 'Gene', '2556', (135, 141))	('pancreatic cancer', 'Disease', (104, 121))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', (81, 88))	('target', 'NegReg', (256, 262))	('MMP9', 'Gene', '4318', (317, 321))	('gastric cancer', 'Disease', 'MESH:D013274', (278, 292))	('FBXW7', 'Gene', '55294', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', (190, 196))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (368, 384))	('colorectal cancer', 'Phenotype', 'HP:0003003', (179, 196))	('GABRA3', 'Gene', (135, 141))	('promotes', 'PosReg', (147, 155))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (229, 252))	('HOXD10', 'Gene', (326, 332))	('miR-92b-3p', 'Var', (11, 21))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (218, 252))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('inhibiting', 'NegReg', (200, 210))	('miR-92b-3p', 'Chemical', '-', (11, 21))	('KLF4', 'Gene', '9314', (263, 267))	('MMP2', 'Gene', (311, 315))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('downregulating', 'NegReg', (296, 310))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (46, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (278, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (179, 196))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('HOXD10', 'Gene', '3236', (326, 332))	('DCS2', 'MPA', (272, 276))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (377, 384))	('FBXW7', 'Gene', (211, 216))	('colorectal cancer', 'Disease', (179, 196))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('MMP2', 'Gene', '4313', (311, 315))	('cancer', 'Disease', (3, 9))	('synovial sarcoma', 'Disease', (368, 384))	('gastric cancer', 'Disease', (278, 292))	('esophageal squamous cell carcinoma', 'Disease', (218, 252))
163620	33435549	Similarly, miR-652-3p is also reported to have both anti- and pro-cancer characteristics, it sensitizes lymphoblastic leukemia cells to chemotherapy but promotes bladder cancer by targeting KCNN3, NSCLC by targeting Lgl1 as well as prostate cancer.	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (104, 126))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('prostate cancer', 'Disease', 'MESH:D011471', (232, 247))	('Lgl1', 'Gene', (216, 220))	('prostate cancer', 'Phenotype', 'HP:0012125', (232, 247))	('miR-652-3p', 'Chemical', '-', (11, 21))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('miR-652-3p', 'Var', (11, 21))	('KCNN3', 'Gene', '3782', (190, 195))	('prostate cancer', 'Disease', (232, 247))	('NSCLC', 'Disease', (197, 202))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (104, 126))	('Lgl1', 'Gene', '3996', (216, 220))	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('lymphoblastic leukemia', 'Disease', (104, 126))	('promotes', 'PosReg', (153, 161))	('bladder cancer', 'Disease', 'MESH:D001749', (162, 176))	('bladder cancer', 'Disease', (162, 176))	('bladder cancer', 'Phenotype', 'HP:0009725', (162, 176))	('KCNN3', 'Gene', (190, 195))	('cancer', 'Disease', (241, 247))	('targeting', 'Reg', (180, 189))	('cancer', 'Disease', (66, 72))
163621	33435549	In addition, miR-652-3p inhibits healing of endothelial damage and atherosclerosis by downregulating Cyclin D2 but promotes trophoblast cells proliferation potentially by targeting HOXA9 and regulating EphB4.	('atherosclerosis', 'Disease', 'MESH:D050197', (67, 82))	('targeting', 'Reg', (171, 180))	('downregulating', 'NegReg', (86, 100))	('inhibits', 'NegReg', (24, 32))	('atherosclerosis', 'Disease', (67, 82))	('EphB4', 'Gene', (202, 207))	('EphB4', 'Gene', '2050', (202, 207))	('Cyclin D2', 'Gene', (101, 110))	('atherosclerosis', 'Phenotype', 'HP:0002621', (67, 82))	('HOXA9', 'Gene', (181, 186))	('age', 'Gene', (59, 62))	('promotes', 'PosReg', (115, 123))	('HOXA9', 'Gene', '3205', (181, 186))	('Cyclin D2', 'Gene', '894', (101, 110))	('trophoblast cells proliferation', 'CPA', (124, 155))	('age', 'Gene', '5973', (59, 62))	('miR-652-3p', 'Chemical', '-', (13, 23))	('miR-652-3p', 'Var', (13, 23))	('regulating', 'Reg', (191, 201))
163622	33435549	miR-766-3p is also known as a dual player in cancer, it showed an anti-cancer effect on HCC by targeting WNT3A, but it is also known to inhibit cell-cycle progression and metastasis of RCC by targeting SF2 and HCC by targeting MTA3, respectively.	('HCC', 'CPA', (210, 213))	('SF2', 'Gene', '6426', (202, 205))	('HCC', 'Phenotype', 'HP:0001402', (88, 91))	('WNT3A', 'Gene', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('miR-766-3p', 'Var', (0, 10))	('cancer', 'Disease', (71, 77))	('metastasis', 'CPA', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-766-3p', 'Chemical', '-', (0, 10))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Disease', (185, 188))	('MTA3', 'Gene', (227, 231))	('cell-cycle progression', 'CPA', (144, 166))	('targeting', 'Reg', (192, 201))	('MTA3', 'Gene', '57504', (227, 231))	('cancer', 'Disease', (45, 51))	('HCC', 'Phenotype', 'HP:0001402', (210, 213))	('RCC', 'Disease', 'MESH:C538614', (185, 188))	('WNT3A', 'Gene', '89780', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('inhibit', 'NegReg', (136, 143))	('SF2', 'Gene', (202, 205))
163630	33435549	Therefore, the ultimate results of the miRNA mediated regulation of the RPs are improper functioning of the translation machinery and deregulated synthesis proteins.	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('improper', 'Var', (80, 88))	('functioning', 'MPA', (89, 100))	('deregulated synthesis proteins', 'MPA', (134, 164))
163632	33435549	Deregulation of both RPs and miRNAs is very common in diseases including almost all types of cancers.	('cancers', 'Disease', (93, 100))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('Deregulation', 'Var', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('common', 'Reg', (44, 50))	('RPs', 'Protein', (21, 24))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
163666	33213383	The following endoscopies were used: RQ260Z, GIF-Q240Z, H260Z, H290Z, and H290EC with the EVIS LUCERA ELITE endoscopic system (Olympus Medical Systems Co., Tokyo, Japan).	('Q240Z', 'SUBSTITUTION', 'None', (49, 54))	('H260Z', 'CellLine', 'CVCL:L934', (56, 61))	('H290Z', 'CellLine', 'CVCL:A555', (63, 68))	('H290EC', 'CellLine', 'CVCL:A555', (74, 80))	('Q240Z', 'Var', (49, 54))	('GIF', 'Gene', '2694', (45, 48))	('H260Z', 'Var', (56, 61))	('RQ260Z', 'Var', (37, 43))	('H290Z', 'Var', (63, 68))	('GIF', 'Gene', (45, 48))	('H290EC', 'Var', (74, 80))
163668	33213383	The recorded video during the study period that met the following criteria were retrieved: histologically confirmed esophageal SCC, lesion size < 20 mm by endoscopic observation, and 0-II type morphology by the Paris classification.	('SCC', 'Gene', (127, 130))	('SCC', 'Phenotype', 'HP:0002860', (127, 130))	('SCC', 'Gene', '6317', (127, 130))	('0-II type morphology', 'Var', (183, 203))
163694	33213383	With thickening of the esophageal wall, the normal esophagus appears brighter (more whitish) because of the thickening of the keratinous layer, while the brownish color change in the cancerous area remains unchanged since the keratinous layer is usually absent in the cancerous area.	('cancerous', 'Disease', (183, 192))	('cancerous', 'Disease', 'MESH:D009369', (268, 277))	('brighter', 'PosReg', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('thickening', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancerous', 'Disease', 'MESH:D009369', (183, 192))	('cancerous', 'Disease', (268, 277))
163747	32275699	The inclusion criteria were pathologically confirmed esophageal cancer cases that were extracted based on the relevant ICD-10 diagnostic codes (C150-C159).	('esophageal cancer', 'Disease', (53, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('C150-C159', 'Var', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
163752	32275699	Based on the modified criteria of Asian-Pacific guidelines of the World Health Organization, the participants were categorized according to the body mass index (BMI) as follows: normal (< 23 kg/m2), overweight (23-24.9 kg/m2) and obese (>= 25 kg/m2).	('obese', 'Disease', 'MESH:D009765', (230, 235))	('overweight', 'Phenotype', 'HP:0025502', (199, 209))	('>= 25 kg/m2', 'Var', (237, 248))	('obese', 'Disease', (230, 235))	('23-24.9 kg/m2', 'Var', (211, 224))	('participants', 'Species', '9606', (97, 109))
163799	32275699	Among patients with stage II-III disease, significantly longer OS was associated with neo-adjuvant therapy (3.5 years, 95% CI: 2.77-4.23 years) and adjuvant therapy (3.8 years, 95% CI: 3.01-4.59 years), relative to definitive CCRT (1.6 years, 95% CI: 1.40-1.80; p<0.001), although no significant difference in survival was detected when we compared the neo-adjuvant and adjuvant treatment groups (Fig 3).	('II-III disease', 'Disease', (26, 40))	('adjuvant', 'Var', (148, 156))	('longer', 'PosReg', (56, 62))	('patients', 'Species', '9606', (6, 14))	('II-III disease', 'Disease', 'MESH:D005776', (26, 40))
163801	32275699	Among patients with stage II-III disease, definitive CCRT was independently associated with poorer survival relative to multi-modality therapy with surgery (HR: 1.75, 95% CI: 1.56-1.97, p<0.001) after adjusting for all prognostic factors except metachronous lesions because of the small number of cases with metachronous lesions (S3 Table).	('metachronous lesions', 'Disease', 'MESH:D016609', (308, 328))	('metachronous lesions', 'Disease', (245, 265))	('metachronous lesions', 'Disease', 'MESH:D016609', (245, 265))	('II-III disease', 'Disease', (26, 40))	('metachronous lesions', 'Disease', (308, 328))	('definitive CCRT', 'Var', (42, 57))	('patients', 'Species', '9606', (6, 14))	('survival', 'MPA', (99, 107))	('II-III disease', 'Disease', 'MESH:D005776', (26, 40))	('poorer', 'NegReg', (92, 98))
163858	30817620	T1bN0M0, stage IA for gastric cancer and T1bN0M0, stage IB for esophageal cancer were observed.	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('T1bN0M0', 'Var', (0, 7))	('gastric cancer', 'Disease', (22, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (22, 36))	('T1bN0M0', 'Var', (41, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (22, 36))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
163865	30817620	T3N0M0, stage IIA for esophageal cancer and T1bN0M0, stage IA for gastric cancer were observed.	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('T1bN0M0', 'Var', (44, 51))	('esophageal cancer', 'Disease', (22, 39))	('gastric cancer', 'Disease', (66, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
163899	31579724	In cT2NxM0 carcinomas, primary surgery is indicated.	('carcinomas', 'Disease', 'MESH:D002277', (11, 21))	('carcinomas', 'Disease', (11, 21))	('cT2NxM0', 'Var', (3, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
163901	31579724	However, current studies show no prognostic benefit for neoadjuvant treatment in cT1 or cT2N0M0 esophageal cancer,.	('cT1', 'Gene', '1489', (81, 84))	('cT2N0M0', 'Var', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('cT1', 'Gene', (81, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))
163920	31579724	Novel genetic risk variants for the development of Barrett's esophagus and esophageal AC have been found by genomic analysis of more than 6000 patients with Barrett's esophagus and more than 4000 esophageal AC.	('esophageal AC', 'Disease', (196, 209))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (157, 176))	('patients', 'Species', '9606', (143, 151))	('esophageal AC', 'Disease', 'MESH:D004941', (75, 88))	("Barrett's esophagus", 'Disease', (157, 176))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (157, 176))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (51, 70))	("Barrett's esophagus", 'Disease', (51, 70))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (51, 70))	('esophageal AC', 'Disease', 'MESH:D004941', (196, 209))	('variants', 'Var', (19, 27))	('esophageal AC', 'Disease', (75, 88))
163958	30881503	p53 overexpression is a prognosticator of poor outcome in esophageal cancer Immunohistochemistry studies on p53 inactivation in esophageal cancer are available with inconclusive results.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('inactivation', 'Var', (112, 124))	('p53', 'Gene', (108, 111))	('esophageal cancer', 'Disease', (58, 75))	('esophageal cancer', 'Disease', (128, 145))	('p53', 'Gene', '7157', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))
163962	30881503	Heterozygous TP53 deletions occurred in 40.9% in AC and in 19.4% in SCC.	('occurred', 'Reg', (28, 36))	('TP53', 'Gene', (13, 17))	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (68, 71))	('deletions', 'Var', (18, 27))	('SCC', 'Gene', (68, 71))
163963	30881503	High-level p53 immunostaining was associated with shortened overall survival in AC and SCC while TP53 deletions alone showed no correlation with survival.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('High-level', 'Var', (0, 10))	('SCC', 'Gene', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('overall survival', 'MPA', (60, 76))	('SCC', 'Gene', '6317', (87, 90))	('shortened', 'NegReg', (50, 59))
163964	30881503	High-level p53 immunostaining in patients with AC was associated with advanced tumor (P=0.019) and Union for International Cancer Control stages (P=0.004), grading (P=0.027) and the resection margin status (P=0.006).	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('patients', 'Species', '9606', (33, 41))	('tumor', 'Disease', (79, 84))	('High-level', 'Var', (0, 10))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancer', 'Disease', (123, 129))	('Cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
163966	30881503	TP53 deletions were found to be associated with advanced tumor stages (P=0.028) and the presence of lymph node metastasis (P=0.009) in SCC.	('TP53', 'Gene', (0, 4))	('lymph node metastasis', 'CPA', (100, 121))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('SCC', 'Gene', (135, 138))	('SCC', 'Phenotype', 'HP:0002860', (135, 138))	('associated', 'Reg', (32, 42))	('tumor', 'Disease', (57, 62))	('deletions', 'Var', (5, 14))	('SCC', 'Gene', '6317', (135, 138))
163977	30881503	Mutations in TP53 were found in >50% of human cancers, which makes it one of the most mutated genes in tumors.	('TP53', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Disease', (46, 53))	('found', 'Reg', (23, 28))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('human', 'Species', '9606', (40, 45))
163978	30881503	In esophageal cancer, mutations have been described in frequencies between 40-70%, depending on the underlying cell type.	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (22, 31))
163979	30881503	As shown for several tumor entities, inactivation of the TP53 tumor suppressor gene leads to the development of malignant cell clones and accelerates the carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (21, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (154, 168))	('development of malignant cell clones', 'CPA', (97, 133))	('tumor', 'Disease', (62, 67))	('carcinogenesis', 'Disease', (154, 168))	('accelerates', 'PosReg', (138, 149))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('TP53', 'Gene', (57, 61))	('leads to', 'Reg', (84, 92))	('inactivation', 'Var', (37, 49))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
163980	30881503	Different mechanisms of functional p53 inactivation have been described including functionally relevant point mutations and gross chromosomal alterations, mostly driven by chromosome 17p deletions.	('point mutations', 'Var', (104, 119))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('inactivation', 'NegReg', (39, 51))
163983	30881503	Data on TP53 deletion status is available from only one report including 40 patients suffering from esophageal squamous cell carcinoma.	('patients', 'Species', '9606', (76, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (100, 134))	('deletion', 'Var', (13, 21))	('esophageal squamous cell carcinoma', 'Disease', (100, 134))	('TP53', 'Gene', (8, 12))
163984	30881503	To further elucidate the clinical relevance of TP53 mutations and p53 expression as prognostic biomarkers in esophageal cancer we took advantage of our preexisting tissue microarray (TMA) containing nearly 700 esophageal cancer specimens with attached clinical follow-up and clinico-pathological data.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('p53', 'Gene', '7157', (66, 69))	('esophageal cancer', 'Disease', (210, 227))	('TMA', 'Chemical', '-', (183, 186))	('esophageal cancer', 'Disease', 'MESH:D004938', (210, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))	('TP53', 'Gene', (47, 51))	('p53', 'Gene', (66, 69))
163985	30881503	Our findings demonstrate that strong p53 immunostaining is correlated with unfavorable prognosis in esophageal cancer, while homozygous TP53 deletions represent a catastrophic event leading to cell death.	('death', 'Disease', 'MESH:D003643', (198, 203))	('death', 'Disease', (198, 203))	('esophageal cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('deletions', 'Var', (141, 150))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('TP53', 'Gene', (136, 140))
164001	30881503	Colon cancers with known p53 alterations served as positive controls and normal prostate tissue as negative controls on each TMA section.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('Colon cancers', 'Disease', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('alterations', 'Var', (29, 40))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('Colon cancers', 'Phenotype', 'HP:0003003', (0, 13))	('Colon cancers', 'Disease', 'MESH:D015179', (0, 13))	('TMA', 'Chemical', '-', (125, 128))
164004	30881503	Negative: No staining at all or 1+/2+ staining in <10% of tumor cells, low: 1+ staining in >=10% or 2+ staining in >=10% but <=70% of tumor cells or 3+ staining in <=10% of tumor cells, high: 2+ staining in >70% of tumor cells or 3+ staining in >10% of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('low', 'Var', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('high: 2+', 'Var', (186, 194))	('tumor', 'Disease', (253, 258))	('tumor', 'Disease', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
164011	30881503	Deletion of TP53 was defined as presence of fewer TP53 signals than centromere 17 probe signals (heterozygous deletion) or complete absence of TP53 signals but presence of at least one centromere 17 probe signal (homozygous deletion) in >=60% of tumor nuclei.	('TP53', 'Gene', (12, 16))	('TP53 signals', 'MPA', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('fewer', 'NegReg', (44, 49))	('tumor', 'Disease', (246, 251))	('Deletion', 'Var', (0, 8))
164017	30881503	1. p53 positivity was associated with tumor stage (P=0.019), UICC stage (P=0.004), grading (P=0.027) and surgical resection margin status (P=0.006) in esophageal AC (Table I), while no associations between clinico-pathological data and p53 immunostaining in squamous cell carcinoma were revealed (Table II).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('p53', 'Gene', '7157', (3, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('positivity', 'Var', (7, 17))	('squamous cell carcinoma', 'Disease', (258, 281))	('p53', 'Gene', (236, 239))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (258, 281))	('esophageal AC', 'Disease', (151, 164))	('p53', 'Gene', (3, 6))	('p53', 'Gene', '7157', (236, 239))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('associated', 'Reg', (22, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))
164018	30881503	FISH was interpretable for TP53 deletions in 269 (67.6%) samples in esophageal adenocarcinoma and 237 (80.9%) samples in squamous cell carcinoma.	('deletions', 'Var', (32, 41))	('TP53', 'Gene', (27, 31))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (68, 93))	('esophageal adenocarcinoma', 'Disease', (68, 93))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (68, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
164020	30881503	Heterozygous TP53 deletions were detectable in 110 samples (40.9%) in EC and 46 samples (19.4%) in SCC.	('TP53', 'Gene', (13, 17))	('SCC', 'Gene', '6317', (99, 102))	('detectable', 'Reg', (33, 43))	('deletions', 'Var', (18, 27))	('SCC', 'Gene', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))
164021	30881503	TP53 deletions were associated with age (P=0.031) and surgical resection margin (P=0.029) in adenocarcinoma (Table I).	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('associated', 'Reg', (20, 30))	('TP53', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('adenocarcinoma', 'Disease', (93, 107))	('deletions', 'Var', (5, 14))
164022	30881503	For squamous cell carcinoma, associations were detected between heterozygous TP53 deletions and tumor stage (P=0.028) and presence of lymph node metastasis (P=0.009) (Table II).	('deletions', 'Var', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (4, 27))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('squamous cell carcinoma', 'Disease', (4, 27))	('tumor', 'Disease', (96, 101))	('associations', 'Interaction', (29, 41))	('lymph node metastasis', 'CPA', (134, 155))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('TP53', 'Gene', (77, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (4, 27))
164023	30881503	Not one single TMA spot revealed cells with homozygous TP53 deletions.	('deletions', 'Var', (60, 69))	('TP53', 'Gene', (55, 59))	('TMA', 'Chemical', '-', (15, 18))
164025	30881503	A correlation between high p53 immunostaining and TP53 deletion could not be revealed for AC (P=0.643) while in SCC an association (P=0.044) was seen.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('TP53', 'Gene', (50, 54))	('p53', 'Gene', '7157', (27, 30))	('SCC', 'Gene', '6317', (112, 115))	('deletion', 'Var', (55, 63))	('p53', 'Gene', (27, 30))	('SCC', 'Gene', (112, 115))
164026	30881503	In adenocarcinoma, 54 (21.8%) tumors showed heterozygous TP53 deletion accompanied by high p53 expression which was also displayed by 25 SCC (11.2%).	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('SCC', 'Gene', '6317', (137, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('adenocarcinoma', 'Disease', (3, 17))	('p53', 'Gene', (91, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (3, 17))	('p53', 'Gene', '7157', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('TP53', 'Gene', (57, 61))	('deletion', 'Var', (62, 70))	('SCC', 'Gene', (137, 140))
164028	30881503	High-level p53 immunostaining was linked to shortened overall-survival (OS) in both esophageal AC and SCC as analyzed by Kaplan-Meier (P=0.021 and P=0.013, respectively; Fig.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('overall-survival', 'CPA', (54, 70))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('shortened', 'NegReg', (44, 53))	('SCC', 'Gene', '6317', (102, 105))	('immunostaining', 'Var', (15, 29))	('esophageal AC', 'Disease', (84, 97))	('SCC', 'Gene', (102, 105))
164029	30881503	TP53 deletions were not associated with OS irrespective of the histological type (P=0.973 (AC) and P=0.099 (SCC); Fig.	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (24, 34))	('SCC', 'Gene', (108, 111))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('SCC', 'Gene', '6317', (108, 111))	('deletions', 'Var', (5, 14))
164030	30881503	Combination of p53 expression and TP53 deletion status did not improve the prognostic power compared to p53 IHC alone (Fig.	('p53', 'Gene', (104, 107))	('TP53', 'Gene', (34, 38))	('p53', 'Gene', '7157', (104, 107))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('deletion status', 'Var', (39, 54))
164036	30881503	In our analysis p53 alterations are present in 40-45% of esophageal cancer, irrespective of the underlying histological type.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('alterations', 'Var', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('p53', 'Gene', (16, 19))	('p53', 'Gene', '7157', (16, 19))	('esophageal cancer', 'Disease', (57, 74))
164044	30881503	p53 mutations have been found in multiple cancers with large variances in the mutation frequency, depending on the observed tumor entity.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('multiple cancers', 'Disease', (33, 49))	('tumor', 'Disease', (124, 129))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('multiple cancers', 'Disease', 'MESH:D009369', (33, 49))	('mutations', 'Var', (4, 13))	('found', 'Reg', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
164045	30881503	In our study heterozygous TP53 deletions were found in 41% of AC and 19% of SCC.	('TP53', 'Gene', (26, 30))	('SCC', 'Gene', (76, 79))	('deletions', 'Var', (31, 40))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('SCC', 'Gene', '6317', (76, 79))	('found', 'Reg', (46, 51))
164047	30881503	As already shown in prostate cancer on a TMA with >11,000 patient samples, 100% concordance between array-CGH detected deletions and FISH could be achieved for PTEN and TP53 deletions using these criteria.	('prostate cancer', 'Disease', 'MESH:D011471', (20, 35))	('deletions', 'Var', (119, 128))	('PTEN', 'Gene', (160, 164))	('patient', 'Species', '9606', (58, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('PTEN', 'Gene', '5728', (160, 164))	('deletions', 'Var', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TMA', 'Chemical', '-', (41, 44))	('prostate cancer', 'Disease', (20, 35))	('TP53', 'Gene', (169, 173))
164049	30881503	The deletion rate of 19% supports the assumption that TP53 deletions have only minor significance as a pathway for p53 inactivation in esophageal SCC.	('deletions', 'Var', (59, 68))	('esophageal SCC', 'Disease', (135, 149))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('esophageal SCC', 'Disease', 'MESH:D004941', (135, 149))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('TP53', 'Gene', (54, 58))	('inactivation', 'NegReg', (119, 131))
164050	30881503	In line with the results revealed by our study, the impact of p53 mutations is of higher importance with respect to tumor progression than the heterozygous gene deletion of chromosome 17p13.	('mutations', 'Var', (66, 75))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
164055	30881503	By analyzing p53 immunostaining and TP53 deletions, we were able to correlate p53 IHC and TP53 deletion status with corresponding clinical data of our patient cohort.	('p53', 'Gene', (13, 16))	('patient', 'Species', '9606', (151, 158))	('TP53', 'Gene', (90, 94))	('p53', 'Gene', (78, 81))	('deletions', 'Var', (41, 50))	('TP53', 'Gene', (36, 40))	('p53', 'Gene', '7157', (78, 81))	('p53', 'Gene', '7157', (13, 16))
164059	30881503	In contrast, in our analysis, heterozygous TP53 deletions do not affect the OS, neither in AC nor in SCC.	('SCC', 'Gene', (101, 104))	('deletions', 'Var', (48, 57))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('TP53', 'Gene', (43, 47))	('SCC', 'Gene', '6317', (101, 104))
164060	30881503	These results confirm the findings of former studies in EC and other tumor entities that mono-allelic protein expression is sufficient for regular cell cycle control mediated by p53.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cell cycle', 'CPA', (147, 157))	('mono-allelic', 'Var', (89, 101))	('tumor', 'Disease', (69, 74))	('p53', 'Gene', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('p53', 'Gene', '7157', (178, 181))
164061	30881503	Our data show, that mono-allelic TP53 deletion cannot be considered a major driver for tumor progression in esophageal cancer while there is no mutation in the remaining TP53 allele.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('esophageal cancer', 'Disease', (108, 125))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('deletion', 'Var', (38, 46))	('TP53', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
164062	30881503	Since the poor outcome of patients with strong p53 immunostaining was independent of the TP53 deletion status, it is tempting to speculate that these cancers may at least carry dominant negative mutations with complete inactivation of wild-type p53 protein through complex formation with mutant p53 protein.	('p53', 'Gene', '7157', (295, 298))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('complex formation', 'Interaction', (265, 282))	('p53', 'Gene', (47, 50))	('inactivation', 'NegReg', (219, 231))	('protein', 'Protein', (299, 306))	('cancers', 'Disease', (150, 157))	('p53', 'Gene', (245, 248))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('patients', 'Species', '9606', (26, 34))	('p53', 'Gene', '7157', (245, 248))	('negative', 'NegReg', (186, 194))	('mutations', 'Var', (195, 204))	('protein', 'Protein', (249, 256))	('mutant', 'Var', (288, 294))	('p53', 'Gene', (295, 298))	('p53', 'Gene', '7157', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
164063	30881503	This mechanism is known to lead to massive nuclear accumulation of inactive p53 complexes composed of mutated and non-mutated p53 protein.	('p53', 'Gene', '7157', (126, 129))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('p53', 'Gene', (126, 129))	('nuclear accumulation', 'MPA', (43, 63))	('protein', 'Protein', (130, 137))	('mutated', 'Var', (102, 109))
164064	30881503	While IHC reveals both mutated and non-mutated p53, cells with accumulation of inactive p53 complexes are the ones that will predominantly show strong staining.	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('mutated', 'Var', (23, 30))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
164066	30881503	Alterations of p53 have been found in virtually every region of the protein but only a handful of the most frequently occurring mutations haven been studied in depth for their contribution to cancer progression.	('Alterations', 'Var', (0, 11))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', (15, 18))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
164068	30881503	Numerous in vitro and in vivo studies confirmed the ability of mutant p53 to drive enhanced cancer invasion and motility, with evidence that mutant p53 can enhance signaling through receptors such as transforming growth factor beta (TGFbeta) or epidermal growth factor receptor (EGFR).	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('epidermal growth factor receptor', 'Gene', (245, 277))	('motility', 'CPA', (112, 120))	('EGFR', 'Gene', (279, 283))	('epidermal growth factor receptor', 'Gene', '1956', (245, 277))	('enhance', 'PosReg', (156, 163))	('transforming growth factor beta', 'Gene', (200, 231))	('mutant', 'Var', (63, 69))	('cancer', 'Disease', (92, 98))	('mutant', 'Var', (141, 147))	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', '7157', (148, 151))	('TGFbeta', 'Gene', (233, 240))	('TGFbeta', 'Gene', '7040', (233, 240))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('EGFR', 'Gene', '1956', (279, 283))	('p53', 'Gene', (148, 151))	('p53', 'Gene', (70, 73))	('signaling', 'MPA', (164, 173))	('enhanced', 'PosReg', (83, 91))	('transforming growth factor beta', 'Gene', '7040', (200, 231))
164069	30881503	Additionally, although mutated p53 has generally lost the ability to bind p53 DNA binding regions in target gene promoters, various p53 mutants can bind directly to DNA with some degree of selectivity and may thereby control the transcription of certain genes.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('bind', 'Interaction', (148, 152))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('p53', 'Gene', (74, 77))	('control', 'Reg', (217, 224))	('genes', 'Gene', (254, 259))	('mutants', 'Var', (136, 143))	('p53', 'Gene', '7157', (74, 77))	('transcription', 'MPA', (229, 242))
164070	30881503	Furthermore, there is increasing evidence that mutated p53 has an inhibitory effect on transcription factors, such as TAp63, which is of regulative importance for numerous miRNA with important roles in cancer invasion and progression.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('transcription factors', 'MPA', (87, 108))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('inhibitory effect', 'NegReg', (66, 83))	('cancer', 'Disease', (202, 208))	('mutated', 'Var', (47, 54))
164071	30881503	In contrast to other cancers, such as prostate cancer, the combination of gene deletion and mutation status does not increase the malignant potential in esophageal cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('prostate cancer', 'Disease', (38, 53))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('esophageal cancer', 'Disease', (153, 170))	('cancers', 'Disease', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('gene deletion', 'Var', (74, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
164072	30881503	In esophageal adenocarcinoma only 53 (21%) patients showed TP53 deletion combined with strong p53 immunostaining, the rate being even lower in SCC with only 11%.	('SCC', 'Gene', (143, 146))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (3, 28))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('p53', 'Gene', (94, 97))	('TP53', 'Gene', (59, 63))	('p53', 'Gene', '7157', (94, 97))	('patients', 'Species', '9606', (43, 51))	('SCC', 'Gene', '6317', (143, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('deletion', 'Var', (64, 72))	('esophageal adenocarcinoma', 'Disease', (3, 28))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (3, 28))
164073	30881503	These low frequencies suggest that biallelic inactivation, which is associated with a total loss of functional p53, is a catastrophic cellular event related with a high level of apoptosis.	('loss of functional', 'NegReg', (92, 110))	('biallelic inactivation', 'Var', (35, 57))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))
164074	30881503	Studies using transgenic mouse models carrying heterozygous TP53 deletions show larger and more mammalian tumors than animals with two wild type TP53 alleles.	('mammalian', 'Species', '9606', (96, 105))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mouse', 'Species', '10090', (25, 30))	('deletions', 'Var', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TP53', 'Gene', (60, 64))
164082	30881503	In summary, the results of our large-scale TMA analysis in esophageal adeno- and squamous cell carcinoma show that different types of p53 alterations characterize subgroups of patients with different outcomes.	('esophageal adeno-', 'Disease', (59, 76))	('patients', 'Species', '9606', (176, 184))	('p53', 'Gene', '7157', (134, 137))	('TMA', 'Chemical', '-', (43, 46))	('alterations', 'Var', (138, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('squamous cell carcinoma', 'Disease', (81, 104))	('p53', 'Gene', (134, 137))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 104))
164165	30285872	It was reported that ipilimumab could increase the risk of mortality by 130% in cancer patients, with an overall FAE incidence of 1.13%.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ipilimumab', 'Var', (21, 31))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Disease', (80, 86))	('ipilimumab', 'Chemical', 'MESH:D000074324', (21, 31))
164215	27806322	The CCK-8 assay results showed that HOTTIP downregulation significantly impeded the proliferation of EC109 and KYSE30 cell lines, and overexpression of HOTTIP increased the ability of cell proliferation of EC9706 (Figure 3A-3C).	('EC9706', 'Var', (206, 212))	('EC109', 'CellLine', 'CVCL:6898', (101, 106))	('downregulation', 'NegReg', (43, 57))	('overexpression', 'PosReg', (134, 148))	('increased', 'PosReg', (159, 168))	('EC9706', 'CellLine', 'CVCL:E307', (206, 212))	('cell proliferation', 'CPA', (184, 202))	('proliferation', 'CPA', (84, 97))	('HOTTIP', 'Gene', (152, 158))	('impeded', 'NegReg', (72, 79))	('HOTTIP', 'Gene', (36, 42))
164216	27806322	Suppression of HOTTIP decreased the S-phase pencentage and increased G0/G1 phase percentage of EC109 and KYSE30 cells (Figure 4A and 4B).	('G0/G1 phase percentage', 'CPA', (69, 91))	('Suppression', 'Var', (0, 11))	('S-phase pencentage', 'MPA', (36, 54))	('HOTTIP', 'Gene', (15, 21))	('increased', 'PosReg', (59, 68))	('EC109', 'CellLine', 'CVCL:6898', (95, 100))	('decreased', 'NegReg', (22, 31))
164218	27806322	Conversely, the migration activity of HOTTIP-overexpressing EC9706 cells was significantly increased (Figure 5C).	('migration activity', 'CPA', (16, 34))	('EC9706', 'Var', (60, 66))	('EC9706', 'CellLine', 'CVCL:E307', (60, 66))	('increased', 'PosReg', (91, 100))
164219	27806322	Because EMT is the remarkable presentation for cell invasion, whether silencing HOTTIP expression inhibited mesenchymal features need to be identified.	('inhibited', 'NegReg', (98, 107))	('silencing', 'Var', (70, 79))	('EMT', 'Gene', (8, 11))	('EMT', 'Gene', '3702', (8, 11))	('HOTTIP expression', 'Gene', (80, 97))
164220	27806322	As showed in Figure 6, Vimentin and N-cadherin were downregulated after HOTTIP knockdown while E-cadherin was overexpressed in EC109 and KYSE30 cells (Figure 6A and 6B).	('EC109', 'CellLine', 'CVCL:6898', (127, 132))	('N-cadherin', 'Gene', '1000', (36, 46))	('E-cadherin', 'Gene', (95, 105))	('downregulated', 'NegReg', (52, 65))	('E-cadherin', 'Gene', '999', (95, 105))	('Vimentin', 'Gene', (23, 31))	('knockdown', 'Var', (79, 88))	('N-cadherin', 'Gene', (36, 46))	('Vimentin', 'Gene', '7431', (23, 31))
164226	27806322	Previous study reported that silencing HOTTIP attenuated hepatocellular carcinoma cell proliferation in vitro as well as tumorigenicity in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('silencing', 'Var', (29, 38))	('tumor', 'Disease', (121, 126))	('attenuated hepatocellular carcinoma', 'Disease', (46, 81))	('attenuated hepatocellular carcinoma', 'Disease', 'MESH:C538265', (46, 81))	('HOTTIP', 'Gene', (39, 45))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (57, 81))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
164228	27806322	Previous studies showed that in colorectal cancer cells, HOTTIP knockdown also inhibited migratory capability and significantly decreased lung metastatic lesions in mouse xenograft mode, similar to the results in our study.	('mouse', 'Species', '10090', (165, 170))	('colorectal cancer', 'Disease', (32, 49))	('lung metastatic lesions in', 'CPA', (138, 164))	('colorectal cancer', 'Disease', 'MESH:D015179', (32, 49))	('decreased', 'NegReg', (128, 137))	('inhibited', 'NegReg', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('knockdown', 'Var', (64, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (32, 49))	('decreased lung', 'Phenotype', 'HP:0002089', (128, 142))	('HOTTIP', 'Gene', (57, 63))	('migratory capability', 'CPA', (89, 109))
164231	27806322	In our study, HOTTIP knockdown downregulated Vimentin and N-cadherin and upregulated E-cadherin.	('Vimentin', 'Gene', (45, 53))	('N-cadherin', 'Gene', (58, 68))	('Vimentin', 'Gene', '7431', (45, 53))	('HOTTIP', 'Gene', (14, 20))	('E-cadherin', 'Gene', (85, 95))	('downregulated', 'NegReg', (31, 44))	('N-cadherin', 'Gene', '1000', (58, 68))	('E-cadherin', 'Gene', '999', (85, 95))	('upregulated', 'PosReg', (73, 84))	('knockdown', 'Var', (21, 30))
164246	27806322	The primary antibodies included rabbit anti E-cadherin, anti-N-cadherin, anti-Vimentin (Santa Cruz Bio-technology, Santa Cruz, CA, USA) and anti-human GAPDH (CST).	('GAPDH', 'Gene', '2597', (151, 156))	('anti-human', 'Var', (140, 150))	('N-cadherin', 'Gene', '1000', (61, 71))	('CST', 'Gene', (158, 161))	('rabbit', 'Species', '9986', (32, 38))	('E-cadherin', 'Gene', (44, 54))	('GAPDH', 'Gene', (151, 156))	('human', 'Species', '9606', (145, 150))	('E-cadherin', 'Gene', '999', (44, 54))	('Vimentin', 'Gene', (78, 86))	('CST', 'Gene', '106478911', (158, 161))	('Vimentin', 'Gene', '7431', (78, 86))	('N-cadherin', 'Gene', (61, 71))
164271	24236193	Encouraging evidence that many tumors respond to PAK1 inhibitors expands opportunities for the development of novel anti-cancer drugs.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('inhibitors', 'Var', (54, 64))	('respond', 'Reg', (38, 45))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('PAK1', 'Gene', '5058', (49, 53))	('PAK1', 'Gene', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
164332	24236193	In addition, high expression was associated with large tumor size (>6 cm vs. <=6 cm, P = 0.006) and positive residual surgical margin (P = 0.033), while PAK1 levels were not remarkably altered between tumors of different histological grades (Table1; Figure S2).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('PAK1', 'Gene', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('high', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('PAK1', 'Gene', '5058', (153, 157))
164335	24236193	Together, these data demonstrate that PAK1 overexpression is associated with malignant properties mainly relevant to invasion and LN metastasis and thus support the hypothesis that the altered PAK1 may contribute to tumor progression of GEJ adenocarcinoma.	('tumor', 'Disease', (216, 221))	('altered', 'Var', (185, 192))	('GEJ adenocarcinoma', 'Disease', 'MESH:D000230', (237, 255))	('overexpression', 'PosReg', (43, 57))	('PAK1', 'Gene', '5058', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('GEJ adenocarcinoma', 'Disease', (237, 255))	('malignant properties', 'CPA', (77, 97))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('PAK1', 'Gene', (38, 42))	('contribute', 'Reg', (202, 212))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('associated', 'Reg', (61, 71))	('PAK1', 'Gene', '5058', (193, 197))	('PAK1', 'Gene', (193, 197))
164367	24236193	Similarly to our study, PAK1 protein overexpression and copy number gain were found in more than 40% of gastric cancer tissues, and advanced gastric cancer tissues express higher PAK1 levels than do matched noncancerous adjacent mucosa.	('overexpression', 'PosReg', (37, 51))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PAK1', 'Gene', '5058', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gastric cancer', 'Disease', (141, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('higher', 'PosReg', (172, 178))	('PAK1', 'Gene', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))	('copy number', 'Var', (56, 67))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('PAK1', 'Gene', '5058', (24, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('PAK1', 'Gene', (179, 183))	('gain', 'PosReg', (68, 72))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('gastric cancer', 'Disease', (104, 118))
164390	24236193	Overexpressed PAK1 is a molecular signature of GEJ tumorigenic progression.	('Overexpressed', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('GEJ', 'Disease', (47, 50))	('PAK1', 'Gene', '5058', (14, 18))	('PAK1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
164393	23407878	Non-Invasive Detection of Esophageal Cancer using Genetic Changes in Circulating Cell-Free DNA Cell free DNA (cfDNA) is a genetic biomarker that is present in serum or plasma in high concentration in many types of cancer.	('Esophageal Cancer', 'Disease', 'MESH:D004938', (26, 43))	('cancer', 'Disease', (214, 220))	('Esophageal Cancer', 'Disease', (26, 43))	('Genetic Changes', 'Var', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
164395	23407878	Detection of point mutations, microsatellite alterations, DNA hypermethylations and losses of heterozygosity in circulating cell free DNA have been characterized in esophagus cancer.	('hypermethylations', 'Var', (62, 79))	('esophagus cancer', 'Disease', 'MESH:D004938', (165, 181))	('point mutations', 'Var', (13, 28))	('losses', 'Var', (84, 90))	('esophagus cancer', 'Disease', (165, 181))	('microsatellite alterations', 'Var', (30, 56))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
164426	23407878	The most common genetic alterations in esophageal cancer involve genetic alterations in several oncogenes, tumor suppressor genes, and DNA repair genes.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('esophageal cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('oncogenes', 'Gene', (96, 105))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))	('genetic alterations', 'Var', (65, 84))
164427	23407878	Furthermore, the most common alterations found in esophageal cancers such as deletions, amplifications and Loss Of Heterozygosity (LOH) has been reported to occur on several chromosomes listed in Table 2.	('esophageal cancers', 'Disease', 'MESH:D004938', (50, 68))	('deletions', 'Var', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Loss', 'NegReg', (107, 111))	('amplifications', 'Var', (88, 102))	('esophageal cancers', 'Disease', (50, 68))
164429	23407878	Alteration of these genes such as LOH and mutation can lead to the loss of regulation of cell growth, which is important in carcinogenesis.	('regulation of cell growth', 'MPA', (75, 100))	('mutation', 'Var', (42, 50))	('LOH', 'Disease', (34, 37))	('loss of', 'NegReg', (67, 74))	('carcinogenesis', 'Disease', 'MESH:D063646', (124, 138))	('carcinogenesis', 'Disease', (124, 138))
164430	23407878	Mutation of p53 has been extensively investigated in both SCC and ADC.	('SCC', 'Gene', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('ADC', 'Disease', (66, 69))	('Mutation', 'Var', (0, 8))	('SCC', 'Gene', '6317', (58, 61))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('investigated', 'Reg', (37, 49))
164431	23407878	Previous studies have reported the incidence of p53 mutations (53 percent in ADC and more than 93 percent in SCC) especially, in the exons 5-8 (encoding the DNA-binding domain of the protein) in SCC.	('mutations', 'Var', (52, 61))	('p53', 'Gene', (48, 51))	('SCC', 'Gene', '6317', (109, 112))	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('SCC', 'Gene', (195, 198))	('SCC', 'Phenotype', 'HP:0002860', (195, 198))	('p53', 'Gene', '7157', (48, 51))	('SCC', 'Gene', '6317', (195, 198))	('SCC', 'Gene', (109, 112))	('ADC', 'Disease', (77, 80))
164432	23407878	In addition to mutations in p53, LOH at chromosome 17q13 is a significant event in both SCC and ADC.	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (28, 31))	('LOH at chromosome', 'Var', (33, 50))	('ADC', 'Disease', (96, 99))	('SCC', 'Gene', (88, 91))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
164433	23407878	In principle, the hypotheses were that p53 alteration occurs frequently as an early event in the tumor progression of esophagus carcinoma.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('esophagus carcinoma', 'Phenotype', 'HP:0011459', (118, 137))	('alteration', 'Var', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('tumor', 'Disease', (97, 102))	('esophagus carcinoma', 'Disease', 'MESH:D004938', (118, 137))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('esophagus carcinoma', 'Disease', (118, 137))
164434	23407878	However, inactivation of the p16 gene, LOH, genetic mutation and aberrant DNA methylation in the coding and non-coding (promoter) regions also frequently occur in both SSC and ADC.	('p16', 'Gene', (29, 32))	('occur', 'Reg', (154, 159))	('LOH', 'Gene', (39, 42))	('p16', 'Gene', '1029', (29, 32))	('ADC', 'Disease', (176, 179))	('genetic mutation', 'Var', (44, 60))	('inactivation', 'Var', (9, 21))	('aberrant DNA methylation', 'Var', (65, 89))	('SSC', 'Disease', (168, 171))
164436	23407878	However, aberrant p16 hypermethylation in the promoter region is a common mechanism for the inactivation of this gene in SCC.	('p16', 'Gene', '1029', (18, 21))	('SCC', 'Gene', (121, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('hypermethylation', 'Var', (22, 38))	('p16', 'Gene', (18, 21))	('aberrant', 'Var', (9, 17))	('inactivation', 'NegReg', (92, 104))	('SCC', 'Gene', '6317', (121, 124))
164437	23407878	Taghavi et al, showed the aberrant hypermethylation of this gene in 62 percent of SCC patients in Iran.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('SCC', 'Gene', '6317', (82, 85))	('aberrant hypermethylation', 'Var', (26, 51))	('SCC', 'Gene', (82, 85))	('patients', 'Species', '9606', (86, 94))
164439	23407878	Furthermore, inactivation of p14 and p15 genes has been observed in esophagus cancer.	('p14', 'Gene', '1029', (29, 32))	('p15', 'Gene', '1030', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('observed', 'Reg', (56, 64))	('inactivation', 'Var', (13, 25))	('esophagus cancer', 'Disease', (68, 84))	('p14', 'Gene', (29, 32))	('esophagus cancer', 'Disease', 'MESH:D004938', (68, 84))	('p15', 'Gene', (37, 40))
164440	23407878	Xing et al, reported alteration of methylation patterns in the promoter of p14 and p15 genes and incidence of LOH in p14 and p15 genes in SCC tumor samples.	('SCC tumor', 'Disease', 'MESH:D009369', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('p15', 'Gene', '1030', (83, 86))	('p14', 'Gene', (117, 120))	('p15', 'Gene', '1030', (125, 128))	('LOH', 'Var', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('p15', 'Gene', (125, 128))	('p14', 'Gene', (75, 78))	('p15', 'Gene', (83, 86))	('methylation patterns', 'MPA', (35, 55))	('SCC tumor', 'Disease', (138, 147))	('alteration', 'Reg', (21, 31))	('p14', 'Gene', '1029', (75, 78))	('p14', 'Gene', '1029', (117, 120))
164442	23407878	One of the alterations in this gene is LOH at 5q, occurring in about 55-80 percent of SCC and 20-55 percent of ADC cases, but mutation of APC is under 10 percent in this cancer type.	('alterations', 'Var', (11, 22))	('LOH', 'Var', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('SCC', 'Gene', (86, 89))	('cancer', 'Disease', (170, 176))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('SCC', 'Gene', '6317', (86, 89))	('APC', 'Phenotype', 'HP:0005227', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('APC', 'Disease', 'MESH:D011125', (138, 141))	('ADC', 'Disease', (111, 114))	('APC', 'Disease', (138, 141))
164443	23407878	The most common type of gene inactivation occurs via hypermethylation in the promoter region of the APC gene with an incidence of 92 percent in ADC and 50 percent in patients with SCC.	('ADC', 'Disease', (144, 147))	('APC', 'Phenotype', 'HP:0005227', (100, 103))	('SCC', 'Gene', (180, 183))	('APC', 'Disease', 'MESH:D011125', (100, 103))	('APC', 'Disease', (100, 103))	('hypermethylation', 'Var', (53, 69))	('SCC', 'Phenotype', 'HP:0002860', (180, 183))	('SCC', 'Gene', '6317', (180, 183))	('patients', 'Species', '9606', (166, 174))
164444	23407878	Therefore, the hypermethylation of this gene has noticeable roles in both SCC and ADC.	('roles', 'Reg', (60, 65))	('hypermethylation', 'Var', (15, 31))	('SCC', 'Gene', (74, 77))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('SCC', 'Gene', '6317', (74, 77))	('ADC', 'Disease', (82, 85))
164450	23407878	The overexpression and gene amplifications of erbB-2 has been demonstrated in patients with SCC and ADC with 20 to 60 percent frequency.	('ADC', 'Disease', (100, 103))	('SCC', 'Gene', '6317', (92, 95))	('gene amplifications', 'Var', (23, 42))	('patients', 'Species', '9606', (78, 86))	('erbB-2', 'Gene', (46, 52))	('erbB-2', 'Gene', '2064', (46, 52))	('overexpression', 'PosReg', (4, 18))	('SCC', 'Gene', (92, 95))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))
164458	23407878	For example Prostate Specific Antigen (PSA), CA19-9, CA125, squamous cell carcinoma antigen (SCC) and cytokeratin 19 fragment (CYFRA) are clinically applied as biomarkers.	('Prostate Specific Antigen', 'Gene', '354', (12, 37))	('Prostate Specific Antigen', 'Gene', (12, 37))	('men', 'Species', '9606', (121, 124))	('cytokeratin 19', 'Gene', '3880', (102, 116))	('CA125', 'Gene', (53, 58))	('SCC', 'Gene', (93, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('cytokeratin 19', 'Gene', (102, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('SCC', 'Gene', '6317', (93, 96))	('CA19-9', 'Var', (45, 51))	('CA125', 'Gene', '94025', (53, 58))	('squamous cell carcinoma', 'Disease', (60, 83))
164462	23407878	Over the past decade, tremendous amount of information has been accumulated which are related to cancer-specific changes such as gene mutation, Single Nucleotide Polymorphism (SNP), gene deletion, LOH, epigenetic alterations, genome instability and aberrant at the expression level at RNAs and protein levels.	('Single Nucleotide Polymorphism', 'Var', (144, 174))	('gene', 'Disease', (129, 133))	('gene deletion', 'Var', (182, 195))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('men', 'Species', '9606', (25, 28))	('genome instability', 'CPA', (226, 244))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('LOH', 'Var', (197, 200))	('aberrant', 'Var', (249, 257))	('epigenetic alterations', 'Var', (202, 224))
164463	23407878	In recent years, efforts in many laboratories throughout the world have been focused on the utilization of genetic and expression abnormalities in circulating biomarkers for early detection, prognosis and assessment of cancer patients after therapy.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('men', 'Species', '9606', (211, 214))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('abnormalities', 'Var', (130, 143))	('patients', 'Species', '9606', (226, 234))	('cancer', 'Disease', (219, 225))
164472	23407878	Diehl et al, developed a technique called BEAMing (beads, emulsion, amplification and magnetics) for quantification of circulating mutant cfDNA in serum or plasma of tumor patients.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('cfDNA', 'Gene', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutant', 'Var', (131, 137))	('tumor', 'Disease', (166, 171))	('patients', 'Species', '9606', (172, 180))
164483	23407878	Detection of differences in cfDNA levels may be a good approach and potentially a valuable tool for early detection and for the evaluation of the prognosis of patients with esophagus carcinoma.	('differences', 'Var', (13, 24))	('esophagus carcinoma', 'Phenotype', 'HP:0011459', (173, 192))	('cfDNA levels', 'MPA', (28, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('esophagus carcinoma', 'Disease', 'MESH:D004938', (173, 192))	('esophagus carcinoma', 'Disease', (173, 192))	('patients', 'Species', '9606', (159, 167))
164484	23407878	Aberrant DNA methylation patterns as a measurement of epigenetic changes are frequently found in several types of cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Aberrant', 'Var', (0, 8))	('found', 'Reg', (88, 93))	('men', 'Species', '9606', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('DNA methylation', 'MPA', (9, 24))	('cancer', 'Disease', (114, 120))
164485	23407878	For example, tumor suppressor genes have been demonstrated to be hypermethylated at an early stage of tumorigenesis and hypermethylation process is known to silence regulatory genes involved in the cellular pathways related to cancer.	('tumor', 'Disease', (13, 18))	('cellular pathways', 'Pathway', (198, 215))	('silence', 'NegReg', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('regulatory genes', 'Gene', (165, 181))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('hypermethylation', 'Var', (120, 136))
164486	23407878	Esteller et al, proposed detection of aberrant methylation changes of cfDNA in the serum or plasma in tumor patients and suggested it can be used as a tool for early detection and monitoring of the efficacy of therapy in tumor patients.	('cfDNA', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('aberrant', 'Var', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('methylation', 'MPA', (47, 58))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('patients', 'Species', '9606', (227, 235))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
164490	23407878	Therefore, detection of aberrant promoter hypermethylation of cancer related genes in serum may be useful for esophageal cancer early diagnosis and detection of recurrence.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('aberrant', 'Var', (24, 32))	('esophageal cancer', 'Disease', (110, 127))	('cancer', 'Disease', (62, 68))	('promoter', 'MPA', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('cancer', 'Disease', (121, 127))
164491	23407878	Microsatellite analysis of circulating cfDNA represents an appearing group of biomolecular tumor markers, where as control subjects show no serum alterations.	('Microsatellite', 'Var', (0, 14))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
164494	23407878	Identification and analysis of microsatellite alterations in the serum DNA from SCC patients may be a valuable tool for evaluation at early stage and follow-up studies.	('SCC', 'Gene', '6317', (80, 83))	('patients', 'Species', '9606', (84, 92))	('microsatellite alterations', 'Var', (31, 57))	('SCC', 'Gene', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))
164502	23407878	The combined observations that a correlation exists between molecular alterations such as mutations, microsatellite instability and aberrant methylations in cfDNA and clinical data in esophageal cancer patients, is a strong indicator that cfDNA would likely play a role in early diagnosis and prognosis of esophageal cancer patients in the future.	('patients', 'Species', '9606', (324, 332))	('mutations', 'Var', (90, 99))	('microsatellite instability', 'Var', (101, 127))	('esophageal cancer', 'Disease', (306, 323))	('esophageal cancer', 'Disease', (184, 201))	('patients', 'Species', '9606', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('esophageal cancer', 'Disease', 'MESH:D004938', (306, 323))	('aberrant methylations', 'Var', (132, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('cfDNA', 'Gene', (157, 162))	('methylations', 'Var', (141, 153))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
164597	21103956	The overall 1-year age-standardized relative survivals for gastric cancer were 48% and 21% in BC and Ardabil, respectively (p < 0.01).	('Ardabil', 'Chemical', '-', (101, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gastric cancer', 'Disease', (59, 73))	('Ardabil', 'Var', (101, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))
164598	21103956	The overall 1-year age-standardized relative survival for esophageal cancer was 33% and 17% in BC and Ardabil, respectively (p < 0.05).	('esophageal cancer', 'Disease', (58, 75))	('Ardabil', 'Var', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('Ardabil', 'Chemical', '-', (102, 109))
164617	21103956	Gastric cancers were grouped into three anatomic subsites: proximal third (i.e., cardia) in the gastroesophageal junction or upper third of the stomach (C16.0 and C16.1), distal stomach or lower two thirds of the stomach (C16.2-C16.7), and unknown or unspecified/overlapping lesion (C16.8 and C16.9).	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('Gastric cancers', 'Disease', (0, 15))	('gastroesophageal junction', 'Disease', (96, 121))	('Gastric cancers', 'Phenotype', 'HP:0012126', (0, 15))	('C16.0', 'Var', (153, 158))	('C16.1', 'CellLine', 'CVCL:2322', (163, 168))	('unspecified', 'Species', '32644', (251, 262))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (96, 121))	('C16.2-C16.7', 'CellLine', 'CVCL:2322', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('cardia', 'Disease', (81, 87))	('C16.9', 'CellLine', 'CVCL:2322', (293, 298))	('cardia', 'Disease', 'MESH:D004938', (81, 87))	('Gastric cancers', 'Disease', 'MESH:D013274', (0, 15))
164618	21103956	Histological categories for esophageal cancers were squamous cell carcinoma (ICD-O codes 8050-8082), adenocarcinoma (8140-8573), and others (mainly 8000-8020).	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('squamous cell carcinoma', 'Disease', (52, 75))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 75))	('adenocarcinoma', 'Disease', 'MESH:D000230', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('esophageal cancers', 'Disease', (28, 46))	('esophageal cancers', 'Disease', 'MESH:D004938', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('8140-8573', 'Var', (117, 126))	('adenocarcinoma', 'Disease', (101, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))
164620	21103956	Diffuse gastric tumors are defined by ICD-O histology codes 8142, 8145, and 8490; other gastric tumors are defined as intestinal.	('8145', 'Var', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('gastric tumors', 'Phenotype', 'HP:0006753', (8, 22))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('gastric tumor', 'Phenotype', 'HP:0006753', (88, 101))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('gastric tumor', 'Phenotype', 'HP:0006753', (8, 21))	('gastric tumors', 'Phenotype', 'HP:0006753', (88, 102))	('gastric tumors', 'Disease', (8, 22))	('gastric tumors', 'Disease', 'MESH:D013274', (8, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('gastric tumors', 'Disease', (88, 102))	('gastric tumors', 'Disease', 'MESH:D013274', (88, 102))
164668	21103956	Also, the high incidence of diffuse gastric cancer in the ethnically homogeneous Ardabil population is consistent with some cases having inherited mutations in the E-cadherin gene that underlie hereditary diffuse gastric cancer.	('mutations', 'Var', (147, 156))	('gastric cancer', 'Phenotype', 'HP:0012126', (213, 227))	('gastric cancer', 'Disease', (36, 50))	('Ardabil', 'Chemical', '-', (81, 88))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('gastric cancer', 'Disease', (213, 227))	('E-cadherin', 'Gene', (164, 174))	('E-cadherin', 'Gene', '999', (164, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (213, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
164696	21194430	In addition, laparoscopic gastric mobilization leads to less trauma than an open gastroplasty.	('trauma', 'Disease', 'MESH:D014947', (61, 67))	('open gastroplasty', 'Disease', (76, 93))	('open gastroplasty', 'Disease', 'MESH:D005597', (76, 93))	('trauma', 'Disease', (61, 67))	('laparoscopic', 'Var', (13, 25))
164778	18330569	In pigs, hepatic arterial embolization with 166HoMS in amounts corresponding with liver-absorbed doses of over 100 Gy, if correctly administered, is not associated with clinically relevant side effects.	('hepatic arterial embolization', 'MPA', (9, 38))	('hepatic arterial embolization', 'Phenotype', 'HP:0030243', (9, 38))	('166HoMS', 'Var', (44, 51))	('arterial embolization', 'Phenotype', 'HP:0004420', (17, 38))	('pigs', 'Species', '9823', (3, 7))
164790	18330569	In all animals treated with 166HoMS, tumour growth was arrested and necrosis set in.	('necrosis', 'Disease', 'MESH:D009336', (68, 76))	('166HoMS', 'Var', (28, 35))	('tumour', 'Disease', (37, 43))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('necrosis', 'Disease', (68, 76))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
164822	18330569	Complications that occurred were either due to erroneous microsphere delivery, i.e., extrahepatic deposition, or due to comorbidity, with the exception of pig 3.	('extrahepatic deposition', 'MPA', (85, 108))	('erroneous', 'Var', (47, 56))	('pig', 'Species', '9823', (155, 158))
164836	18330569	In the ALP serum levels, a trivial difference was observed between the 165HoMS group and the 166HoMS group, which was already present in the baseline values.	('ALP', 'Gene', '100860026', (7, 10))	('ALP', 'Gene', (7, 10))	('165HoMS', 'Var', (71, 78))
164872	18330569	Catheter manipulation can also lead to vasospasm, for which pigs are predisposed, further increasing the risk of backflow.	('backflow', 'MPA', (113, 121))	('pigs', 'Species', '9823', (60, 64))	('Catheter', 'Var', (0, 8))	('vasospasm', 'Disease', 'MESH:D020301', (39, 48))	('lead to', 'Reg', (31, 38))	('vasospasm', 'Disease', (39, 48))	('vasospasm', 'Phenotype', 'HP:0025637', (39, 48))
164903	33248456	Cell proliferation and migration were decreased when CE81FN+ cells overexpressed transgenic miR-146a compared to the parental cells, indicating an inverse correlation between low miR-146a expression and high proliferation as well as motility of FN assembly ESCC cells.	('high proliferation', 'CPA', (203, 221))	('miR-146a', 'Gene', (92, 100))	('decreased', 'NegReg', (38, 47))	('motility', 'CPA', (233, 241))	('FN', 'Gene', '2335', (245, 247))	('expression', 'MPA', (188, 198))	('miR-146a', 'Gene', (179, 187))	('low', 'NegReg', (175, 178))	('transgenic', 'Var', (81, 91))	('miR-146a', 'Gene', '406938', (92, 100))	('overexpressed', 'PosReg', (67, 80))	('miR-146a', 'Gene', '406938', (179, 187))	('Cell proliferation', 'CPA', (0, 18))	('FN', 'Gene', '2335', (57, 59))
164919	33248456	Overexpression of FN together with vimentin is associated with advanced stage and poor prognosis of ESCC patients.	('patients', 'Species', '9606', (105, 113))	('vimentin', 'Gene', (35, 43))	('ESCC', 'Disease', (100, 104))	('Overexpression', 'Var', (0, 14))	('FN', 'Gene', '2335', (18, 20))	('vimentin', 'Gene', '7431', (35, 43))
164924	33248456	Dysfunction of miRNA regulation affects cellular homeostasis and triggers various diseases including cancers.	('affects', 'Reg', (32, 39))	('cellular homeostasis', 'MPA', (40, 60))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('Dysfunction', 'Var', (0, 11))	('cancers', 'Disease', (101, 108))	('diseases', 'Disease', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('triggers', 'Reg', (65, 73))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
164939	33248456	The above cell lines and human embryonic kidney 293T cells were maintained in Dulbecco's modified Eagle's medium (DMEM; Gibco, Maryland, USA) containing 10% fetal bovine serum (FBS; Biological Industries, Kibbutz Beit haemek, Israel), penicillin (200 U/ml; Sigma, Missouri, USA) and streptomycin (100 mug/ml; Sigma) at 37  C in a 5% CO2 incubator.	('embryonic kidney', 'Disease', (31, 47))	('CO2', 'Chemical', 'MESH:D002245', (333, 336))	('200 U/ml', 'Var', (247, 255))	('penicillin', 'Chemical', 'MESH:D010406', (235, 245))	('293T', 'CellLine', 'CVCL:0063', (48, 52))	('human', 'Species', '9606', (25, 30))	('streptomycin', 'Chemical', 'MESH:D013307', (283, 295))	('embryonic kidney', 'Disease', 'MESH:D007674', (31, 47))	('DMEM', 'Chemical', '-', (114, 118))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (78, 112))
164942	33248456	The target sequences of 3'-UTR region of wild- and mutant-type vimentin are provided in the Additional file 1: Table S1.	('vimentin', 'Gene', '7431', (63, 71))	('vimentin', 'Gene', (63, 71))	('mutant-type', 'Var', (51, 62))
164945	33248456	The negative small interfering RNA controls used were pre-miRNA (Applied Biosystems), anti-miRNA (Applied Biosystems), and si-RNA (Invitrogen).	('miR', 'Gene', (91, 94))	('si-RNA', 'Var', (123, 129))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('miR', 'Gene', '220972', (91, 94))
164949	33248456	The following antibodies were used: vimentin (1:1000, MILLIPORE) and beta-actin (1:5000, Sigma).	('vimentin', 'Gene', '7431', (36, 44))	('1:5000', 'Var', (81, 87))	('vimentin', 'Gene', (36, 44))	('1:1000', 'Var', (46, 52))	('beta-actin', 'Protein', (69, 79))
164992	33248456	We constructed the pMIR-luciferase reporter plasmid harboring either the wild-type or mutant vimentin 3'UTR.	('mutant', 'Var', (86, 92))	('vimentin', 'Gene', (93, 101))	('vimentin', 'Gene', '7431', (93, 101))
164994	33248456	HEK293T cells were co-transfected with either wild-type or mutant-type vimentin 3'UTR plasmid and pre-miR-146a or control microRNA (N.C.) for 48 h (Additional file 1: Figure S2).	('miR-146a', 'Gene', (102, 110))	('vimentin', 'Gene', '7431', (71, 79))	('miR-146a', 'Gene', '406938', (102, 110))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('vimentin', 'Gene', (71, 79))	('mutant-type', 'Var', (59, 70))
164996	33248456	However, miR-146a showed no significant suppression of the mutant vimentin luciferase reporter activity (Additional file 1: Figure S2).	('vimentin', 'Gene', '7431', (66, 74))	('miR-146a', 'Gene', '406938', (9, 17))	('mutant', 'Var', (59, 65))	('vimentin', 'Gene', (66, 74))	('suppression', 'NegReg', (40, 51))	('activity', 'MPA', (95, 103))	('miR-146a', 'Gene', (9, 17))
165042	33248456	MiR-146 is further classified as miR-146a and miR-146b, which are located on chromosome 5 and 10, respectively.	('miR-146a', 'Gene', (33, 41))	('miR-146a', 'Gene', '406938', (33, 41))	('MiR-146', 'Var', (0, 7))	('miR-146b', 'Gene', (46, 54))	('miR-146b', 'Gene', '574447', (46, 54))
165068	33248456	Notably, we demonstrated that either low miR-146a or high vimentin expression was significantly correlated with tumor formation, tumor stages and poor overall survival rate of ESCC patients (Fig.	('correlated', 'Reg', (96, 106))	('ESCC', 'Disease', (176, 180))	('vimentin', 'Gene', (58, 66))	('low', 'Var', (37, 40))	('miR-146a', 'Gene', '406938', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('miR-146a', 'Gene', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('patients', 'Species', '9606', (181, 189))	('expression', 'MPA', (67, 77))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (129, 134))	('vimentin', 'Gene', '7431', (58, 66))
165078	33248456	More importantly, the underlying mechanism for downregulation of miR-146a through epigenetic alteration during ESCC progression might be elucidated in the future.	('downregulation', 'NegReg', (47, 61))	('epigenetic alteration', 'Var', (82, 103))	('miR-146a', 'Gene', (65, 73))	('miR-146a', 'Gene', '406938', (65, 73))	('ESCC', 'Disease', (111, 115))
165081	33248456	MiR-200c suppresses proliferation by down-regulating mutant K-ras expression in breast and lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('proliferation', 'CPA', (20, 33))	('MiR-200c', 'Gene', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('expression', 'MPA', (66, 76))	('breast and lung cancer', 'Disease', 'MESH:D001943', (80, 102))	('down-regulating', 'NegReg', (37, 52))	('K-ras', 'Gene', (60, 65))	('mutant', 'Var', (53, 59))	('K-ras', 'Gene', '3845', (60, 65))	('MiR-200c', 'Gene', '406985', (0, 8))	('suppresses', 'NegReg', (9, 19))
165190	32813914	After correcting for other confounders including sex, the clinical stage, smoking/drinking status, BMI, handgrip strength and treatment received, complication with diabetes was found to be associated with a slightly increased risk of both cancer-specific (hazard ratio (HR) = 1.282, 95% confidence interval (CI) 1.070-1.536, P = .007) and overall mortality (HR = 1.206, 95% CI 1.040-1.399, P = .013).	('diabetes', 'Disease', (164, 172))	('diabetes', 'Disease', 'MESH:D003920', (164, 172))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('men', 'Species', '9606', (131, 134))	('cancer', 'Disease', (239, 245))	('complication', 'Var', (146, 158))	('mortality', 'Disease', 'MESH:D003643', (347, 356))	('mortality', 'Disease', (347, 356))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
165195	32813914	However, nutritional risk detected by NRS2002 seemed to have little bearing on the survival of patients with cancers of the digestive tract.	('patients', 'Species', '9606', (95, 103))	('NRS2002', 'Var', (38, 45))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers of the digestive tract', 'Phenotype', 'HP:0007378', (109, 139))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
165236	32046777	Methylation silencing of TGF-beta receptor type II is involved in malignant transformation of esophageal squamous cell carcinoma Although massive studies have been conducted to investigate the mechanisms of esophageal squamous cell carcinoma (ESCC) carcinogenesis, the understanding of molecular alterations during the malignant transformation of epithelial dysplasia is still lacking, especially regarding epigenetic changes.	('esophageal squamous cell carcinoma', 'Disease', (207, 241))	('epithelial dysplasia', 'Disease', (347, 367))	('carcinogenesis', 'Disease', (249, 263))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (207, 241))	('ESCC', 'Disease', (243, 247))	('Methylation silencing', 'Var', (0, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (218, 241))	('malignant transformation of epithelial dysplasia', 'Phenotype', 'HP:0031492', (319, 367))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('epithelial dysplasia', 'Disease', 'MESH:C567703', (347, 367))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (94, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (249, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('ESCC', 'Disease', 'MESH:C562729', (243, 247))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))	('involved', 'Reg', (54, 62))	('TGF-beta', 'Gene', (25, 33))
165242	32046777	The characterization of methylation silencing of TGFBR2 in ESCC will enable us to further explore whether this epigenetic change could be considered as a predictor of malignant transformation in esophageal epithelial dysplasia and whether use of a TGFBR2 agonist may lead to a new therapeutic strategy in patients with ESCC.	('ESCC', 'Disease', 'MESH:C562729', (59, 63))	('ESCC', 'Disease', 'MESH:C562729', (319, 323))	('esophageal epithelial dysplasia', 'Disease', 'MESH:D004941', (195, 226))	('lead to', 'Reg', (267, 274))	('esophageal epithelial dysplasia', 'Disease', (195, 226))	('TGFBR2', 'Gene', (49, 55))	('ESCC', 'Disease', (319, 323))	('methylation silencing', 'Var', (24, 45))	('patients', 'Species', '9606', (305, 313))	('esophageal epithelial dysplasia', 'Phenotype', 'HP:0012859', (195, 226))	('ESCC', 'Disease', (59, 63))
165250	32046777	Methylation of CpG islands in promoter regions frequently contributing to gene transcriptional silencing may serve as an important mechanism to inactivate tumor suppressor genes in cancer.	('gene transcriptional', 'MPA', (74, 94))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (155, 160))	('inactivate', 'NegReg', (144, 154))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))
165252	32046777	Thus, the identification of methylation changes in tumor suppressor genes is of tremendous importance since it could contribute to early detection and new drug development for ESCC patients.	('ESCC', 'Disease', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('contribute', 'Reg', (117, 127))	('tumor', 'Disease', (51, 56))	('ESCC', 'Disease', 'MESH:C562729', (176, 180))	('patients', 'Species', '9606', (181, 189))	('methylation', 'Var', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
165260	32046777	This study provides significant insight into the epigenetic regulation in ESCC associated with TGFBR2 which could be a potential molecular target in the ESCC diagnosis and treatment.	('associated', 'Reg', (79, 89))	('ESCC', 'Disease', (74, 78))	('ESCC', 'Disease', 'MESH:C562729', (153, 157))	('ESCC', 'Disease', 'MESH:C562729', (74, 78))	('epigenetic regulation', 'Var', (49, 70))	('TGFBR2', 'Gene', (95, 101))	('ESCC', 'Disease', (153, 157))
165269	32046777	To investigate whether DNA methylation variations are associated with alterations in gene expression in the development of ESCC, we identified differentially methylated regions (DMRs) between the different stages.	('ESCC', 'Disease', 'MESH:C562729', (123, 127))	('variations', 'Var', (39, 49))	('ESCC', 'Disease', (123, 127))
165272	32046777	This result suggested that in these genes, promoter hypomethylation likely occurred very early in ESCC development and might therefore serve as potential biomarkers for the diagnosis of esophageal dysplasia.	('promoter hypomethylation', 'Var', (43, 67))	('ESCC', 'Disease', (98, 102))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (186, 206))	('esophageal dysplasia', 'Disease', (186, 206))	('ESCC', 'Disease', 'MESH:C562729', (98, 102))
165276	32046777	Notably, previous studies have reported mutations in TGFBR2 in ESCC, but at a comparatively low mutation rate.	('mutations', 'Var', (40, 49))	('ESCC', 'Disease', 'MESH:C562729', (63, 67))	('TGFBR2', 'Gene', (53, 59))	('ESCC', 'Disease', (63, 67))
165281	32046777	Although not statistically significant, patients with high TGFBR2 expression had a relatively favor prognosis compared to those with low expression levels (expression threshold 63.5; Fig.	('TGFBR2', 'Gene', (59, 65))	('patients', 'Species', '9606', (40, 48))	('high', 'Var', (54, 58))
165283	32046777	Using RT-qPCR, we obtained that TGFBR2 mRNA levels were also downregulated in several ESCC cell lines (HET-1A, TE-1, ECA-109, KYSE-150, KYSE-180, KYSE-510, KYSE-410, KYSE-30) dramatically compared to an immortalized esophageal epithelial cell line, Het-1A (Fig.	('downregulated', 'NegReg', (61, 74))	('KYSE-510', 'Var', (146, 154))	('KYSE-180', 'Chemical', 'MESH:C092722', (136, 144))	('ESCC', 'Disease', 'MESH:C562729', (86, 90))	('KYSE-180', 'Var', (136, 144))	('mRNA levels', 'MPA', (39, 50))	('KYSE-150', 'Var', (126, 134))	('TGFBR2', 'Gene', (32, 38))	('EC', 'Disease', 'MESH:D004938', (117, 119))	('ESCC', 'Disease', (86, 90))
165287	32046777	In summary, these data demonstrated that the methylation of promoter mediated transcriptional silencing of TGFBR2 in ESCC cell lines.	('silencing', 'NegReg', (94, 103))	('TGFBR2', 'Gene', (107, 113))	('ESCC', 'Disease', 'MESH:C562729', (117, 121))	('methylation', 'Var', (45, 56))	('transcriptional', 'MPA', (78, 93))	('ESCC', 'Disease', (117, 121))
165289	32046777	The expression of phospho-SMAD2 was dramatically reactivated in the TGFBR2 overexpression cells which suggested the TGFbeta signaling is restored (Fig.	('reactivated', 'PosReg', (49, 60))	('expression', 'MPA', (4, 14))	('overexpression', 'Var', (75, 89))	('TGFbeta', 'Disease', (116, 123))	('phospho', 'Chemical', 'MESH:C033601', (18, 25))	('TGFbeta', 'Disease', 'None', (116, 123))	('TGFBR2', 'Gene', (68, 74))
165291	32046777	Consistently, the TGFBR2 overexpression cells induced cell cycle G2/M arrest relative to the wild-type cells as determined through flow cytometry analysis of propidium staining (Fig.	('propidium', 'Chemical', 'MESH:D011419', (158, 167))	('induced', 'Reg', (46, 53))	('overexpression', 'Var', (25, 39))	('TGFBR2', 'Gene', (18, 24))	('cell cycle G2/M arrest', 'CPA', (54, 76))
165293	32046777	To determine whether TGFBR2 suppressed ESCC proliferation in vivo, we established a subcutaneous ESCC xenograft model in nude mice using KYSE-150-TGFBR2 and control KYSE-150-vector cells.	('KYSE-150-TGFBR2', 'Var', (137, 152))	('ESCC', 'Disease', (39, 43))	('ESCC', 'Disease', 'MESH:C562729', (97, 101))	('ESCC', 'Disease', 'MESH:C562729', (39, 43))	('ESCC', 'Disease', (97, 101))	('nude mice', 'Species', '10090', (121, 130))
165294	32046777	IHC confirmed that the level of TGFBR2 protein was upregulated and Pan-Keratin (CK) was downregulated in KYSE-150-TGFBR2 tumors when compared to the controls.	('KYSE-150-TGFBR2', 'Var', (105, 120))	('Pan-Keratin', 'Chemical', 'MESH:D001585', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('TGFBR2', 'Gene', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('upregulated', 'PosReg', (51, 62))	('level', 'MPA', (23, 28))	('protein', 'Protein', (39, 46))	('downregulated', 'NegReg', (88, 101))
165296	32046777	Taken together, these results indicated that TGFBR2 expression significantly inhibited ESCC growth in vivo.	('ESCC', 'Disease', 'MESH:C562729', (87, 91))	('inhibited', 'NegReg', (77, 86))	('TGFBR2', 'Gene', (45, 51))	('ESCC', 'Disease', (87, 91))	('expression', 'Var', (52, 62))
165302	32046777	We observed a similar genome-wide trend toward hypomethylation in the development of normal esophageal tissue into cancer.	('cancer', 'Disease', (115, 121))	('hypomethylation', 'Var', (47, 62))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
165306	32046777	TGFBR2 methylation was inversely correlated to its expression in tumor samples.	('tumor', 'Disease', (65, 70))	('TGFBR2', 'Gene', (0, 6))	('methylation', 'Var', (7, 18))	('expression', 'MPA', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
165307	32046777	In addition, TGFBR2 promoter methylation was increased in tumors with copy number loss compared to those remaining intact at the gene site.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('copy number loss', 'Var', (70, 86))	('increased', 'PosReg', (45, 54))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('promoter methylation', 'MPA', (20, 40))	('TGFBR2', 'Gene', (13, 19))
165309	32046777	Downregulation or missense mutation of TGFBR2 has been found in several cancers.	('found', 'Reg', (55, 60))	('missense mutation', 'Var', (18, 35))	('Downregulation', 'NegReg', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('TGFBR2', 'Gene', (39, 45))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
165312	32046777	TCGA consortium and others have reported the mutations of TGFBR2 in ESCC.	('TGFBR2', 'Gene', (58, 64))	('mutations', 'Var', (45, 54))	('ESCC', 'Disease', 'MESH:C562729', (68, 72))	('ESCC', 'Disease', (68, 72))
165315	32046777	Hypermethylation of the CpG islands in promoter region is highly associated with silenced tumor-related genes through the reduction of mRNA transcription.	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('associated', 'Reg', (65, 75))	('reduction', 'NegReg', (122, 131))	('mRNA transcription', 'MPA', (135, 153))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
165317	32046777	In addition, epigenetic silencing genes are often involved in several circuit of carcinogenesis, such as apoptosis, cell cycle, and DNA repair.	('epigenetic silencing genes', 'Var', (13, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('apoptosis', 'Disease', (105, 114))	('carcinogenesis', 'Disease', (81, 95))	('DNA repair', 'Disease', (132, 142))	('involved', 'Reg', (50, 58))	('cell cycle', 'CPA', (116, 126))
165322	32046777	DNA methylation changes in tumor-related genes are frequent and early events during carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('carcinogenesis', 'Disease', (84, 98))	('tumor', 'Disease', (27, 32))	('methylation changes', 'Var', (4, 23))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
165324	32046777	Methylation of specific sites may therefore be of biological and further clinical value in the early detection of ESCC, which is urgent for more favorable outcomes in the treatment of patients.	('Methylation', 'Var', (0, 11))	('ESCC', 'Disease', 'MESH:C562729', (114, 118))	('ESCC', 'Disease', (114, 118))	('patients', 'Species', '9606', (184, 192))
165325	32046777	Hotspots for DNA methylation are also valuable as biomarkers in the so-called liquid biopsy for cancer diagnosis and therapy since they are not only detected in resected tissues, but also in various body fluids, including peripheral blood, saliva, and urine.	('methylation', 'Var', (17, 28))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))
165326	32046777	In fact, methylated APC and CDKN2A have already been detected in the plasma of a subset of ESCC patients.	('ESCC', 'Disease', (91, 95))	('APC', 'Disease', 'MESH:D011125', (20, 23))	('CDKN2A', 'Gene', (28, 34))	('detected', 'Reg', (53, 61))	('APC', 'Disease', (20, 23))	('methylated', 'Var', (9, 19))	('patients', 'Species', '9606', (96, 104))	('CDKN2A', 'Gene', '1029', (28, 34))	('ESCC', 'Disease', 'MESH:C562729', (91, 95))
165327	32046777	The feasibility of the detection of TGFBR2 methylation in serum of ESCC patients is therefore warranted.	('ESCC', 'Disease', (67, 71))	('methylation', 'Var', (43, 54))	('TGFBR2', 'Gene', (36, 42))	('ESCC', 'Disease', 'MESH:C562729', (67, 71))	('patients', 'Species', '9606', (72, 80))
165329	32046777	The high level of methylated CpGs in TGFBR2 in ESCC suggests that DNA methylation in TGFBR2 promoter region would contribute to absent or reduced TGFBR2 mRNA expression, and hence promote ESCC carcinogenesis.	('reduced', 'NegReg', (138, 145))	('ESCC', 'Disease', (188, 192))	('carcinogenesis', 'Disease', (193, 207))	('ESCC', 'Disease', (47, 51))	('absent', 'NegReg', (128, 134))	('CpGs', 'Chemical', 'MESH:C024660', (29, 33))	('TGFBR2', 'Gene', (146, 152))	('ESCC', 'Disease', 'MESH:C562729', (47, 51))	('methylation', 'Var', (70, 81))	('TGFBR2', 'Gene', (37, 43))	('TGFBR2', 'Gene', (85, 91))	('ESCC', 'Disease', 'MESH:C562729', (188, 192))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('promote', 'PosReg', (180, 187))	('mRNA expression', 'MPA', (153, 168))
165392	31859928	The number of positive lymph nodes retrieved (PLNr) was associated with gender (p=0.044), adenocarcinoma histology (p<0.001), and pCR on the primary tumor site (p<0.001) on univariate analysis (Table 3).	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('pCR', 'Var', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('tumor', 'Disease', (149, 154))	('adenocarcinoma', 'Disease', (90, 104))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))
165404	30847299	Association Between ERCC1 rs3212986 and ERCC2/XPD rs1799793 and OS in Patients With Advanced Esophageal Cancer Esophageal cancer (EC) is a very aggressive tumor, and no reliable prognostic markers exist especially for resectable advanced neoplasia.	('ERCC1', 'Gene', (20, 25))	('XPD', 'Gene', (46, 49))	('neoplasia', 'Disease', 'MESH:D009369', (238, 247))	('rs1799793', 'Mutation', 'rs1799793', (50, 59))	('Association', 'Interaction', (0, 11))	('Esophageal cancer', 'Disease', (111, 128))	('rs1799793', 'Var', (50, 59))	('neoplasia', 'Disease', (238, 247))	('rs3212986', 'Var', (26, 35))	('very aggressive tumor', 'Disease', (139, 160))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ERCC2', 'Gene', (40, 45))	('rs3212986', 'Mutation', 'rs3212986', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('ERCC2', 'Gene', '2068', (40, 45))	('neoplasia', 'Phenotype', 'HP:0002664', (238, 247))	('Advanced Esophageal Cancer', 'Disease', 'MESH:D004938', (84, 110))	('very aggressive tumor', 'Disease', 'MESH:D000326', (139, 160))	('XPD', 'Gene', '2068', (46, 49))	('Patients', 'Species', '9606', (70, 78))	('ERCC1', 'Gene', '2067', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Advanced Esophageal Cancer', 'Disease', (84, 110))
165405	30847299	The principal aim of this study was to investigate the association of germline polymorphisms in nucleotide excision repair (NER) pathway genes with the overall survival (OS) of patients with advanced EC.	('patients', 'Species', '9606', (177, 185))	('overall', 'MPA', (152, 159))	('NER) pathway', 'Gene', (124, 136))	('OS', 'Chemical', '-', (170, 172))	('association', 'Interaction', (55, 66))	('germline polymorphisms', 'Var', (70, 92))
165406	30847299	As a second aim, we also studied the association of NER gene variants with response to cisplatin-based chemotherapy.	('NER gene', 'Gene', (52, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('variants', 'Var', (61, 69))
165408	30847299	Patients were genotyped for four NER variants, two in the ERCC1 (rs11615 and rs3212986) and two in the ERCC2/XPD (rs1799793 and rs13181) genes.	('rs11615', 'Mutation', 'rs11615', (65, 72))	('rs3212986', 'Mutation', 'rs3212986', (77, 86))	('rs1799793', 'Var', (114, 123))	('ERCC2', 'Gene', '2068', (103, 108))	('ERCC1', 'Gene', '2067', (58, 63))	('ERCC1', 'Gene', (58, 63))	('XPD', 'Gene', '2068', (109, 112))	('ERCC2', 'Gene', (103, 108))	('rs11615', 'Var', (65, 72))	('rs3212986', 'Var', (77, 86))	('rs13181', 'Mutation', 'rs13181', (128, 135))	('Patients', 'Species', '9606', (0, 8))	('rs1799793', 'Mutation', 'rs1799793', (114, 123))	('XPD', 'Gene', (109, 112))
165409	30847299	Kaplan-Meier analyses and Cox proportional hazards model were used to evaluate the associations of the selected variants with OS; association with response to neoadjuvant therapy was investigated using logistic regression.	('OS', 'Chemical', '-', (126, 128))	('OS', 'Disease', (126, 128))	('variants', 'Var', (112, 120))	('associations', 'Interaction', (83, 95))
165410	30847299	Results showed that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 were significantly associated with shorter OS.	('XPD', 'Gene', '2068', (54, 57))	('ERCC1', 'Gene', (24, 29))	('ERCC2', 'Gene', (48, 53))	('rs3212986', 'Mutation', 'rs3212986', (30, 39))	('ERCC1', 'Gene', '2067', (24, 29))	('rs3212986', 'Var', (30, 39))	('associated', 'Reg', (87, 97))	('OS', 'Chemical', '-', (111, 113))	('rs1799793', 'Mutation', 'rs1799793', (58, 67))	('rs1799793', 'Var', (58, 67))	('XPD', 'Gene', (54, 57))	('ERCC2', 'Gene', '2068', (48, 53))	('shorter OS', 'Disease', (103, 113))
165411	30847299	On the contrary, response association analysis displayed that, while rs11615 and rs3212986 in ERCC1 were associated with response, both ERCC2/XPD variants were not.	('rs11615', 'Mutation', 'rs11615', (69, 76))	('rs3212986', 'Mutation', 'rs3212986', (81, 90))	('XPD', 'Gene', (142, 145))	('rs11615', 'Var', (69, 76))	('rs3212986', 'Var', (81, 90))	('ERCC1', 'Gene', (94, 99))	('ERCC1', 'Gene', '2067', (94, 99))	('ERCC2', 'Gene', '2068', (136, 141))	('XPD', 'Gene', '2068', (142, 145))	('associated', 'Reg', (105, 115))	('ERCC2', 'Gene', (136, 141))	('response', 'Disease', (121, 129))
165412	30847299	By creating survival prediction models, we showed that the rs3212986 and the rs1799793 have a better predictability of the tumor stage alone.	('rs1799793', 'Mutation', 'rs1799793', (77, 86))	('tumor', 'Disease', (123, 128))	('rs1799793', 'Var', (77, 86))	('rs3212986', 'Mutation', 'rs3212986', (59, 68))	('rs3212986', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
165413	30847299	In conclusion, our results indicate that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 could be used as surrogate markers for a better stratification of EC patients with advanced resectable tumor.	('tumor', 'Disease', (192, 197))	('ERCC2', 'Gene', (69, 74))	('ERCC1', 'Gene', '2067', (45, 50))	('ERCC1', 'Gene', (45, 50))	('rs1799793', 'Mutation', 'rs1799793', (79, 88))	('ERCC2', 'Gene', '2068', (69, 74))	('rs3212986', 'Mutation', 'rs3212986', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('rs1799793', 'Var', (79, 88))	('patients', 'Species', '9606', (158, 166))	('XPD', 'Gene', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('XPD', 'Gene', '2068', (75, 78))	('rs3212986', 'Var', (51, 60))
165420	30847299	One of the mechanism involved in cancer-related inflammation is the induction of genetic instability resulting in random DNA alterations.	('inflammation', 'Disease', 'MESH:D007249', (48, 60))	('inflammation', 'Disease', (48, 60))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('genetic instability', 'Var', (81, 100))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('random DNA alterations', 'MPA', (114, 136))
165421	30847299	Thus, DNA repair genes and their constitutive variants have been indicated as a possible cause of the inter-individual variability to chemotherapy and patient outcome or as a factor that could modify the risk of tumor development.	('cause', 'Reg', (89, 94))	('modify', 'Reg', (193, 199))	('DNA repair genes', 'Gene', (6, 22))	('patient', 'Species', '9606', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('variants', 'Var', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (212, 217))
165424	30847299	Both ERCC1 and ERCC2/XPD have single nucleotide polymorphisms (SNPs) that modulate their DNA repair capability.	('XPD', 'Gene', (21, 24))	('ERCC2', 'Gene', '2068', (15, 20))	('modulate', 'Reg', (74, 82))	('DNA repair', 'MPA', (89, 99))	('XPD', 'Gene', '2068', (21, 24))	('ERCC1', 'Gene', (5, 10))	('ERCC2', 'Gene', (15, 20))	('single nucleotide polymorphisms', 'Var', (30, 61))	('ERCC1', 'Gene', '2067', (5, 10))
165425	30847299	So far, numerous studies have investigated the potential predictive/prognostic power of constitutive genetic variants of these repair genes in a wide range of neoplasia, including EC, with contradictory results.	('neoplasia', 'Disease', (159, 168))	('investigated', 'Reg', (30, 42))	('neoplasia', 'Phenotype', 'HP:0002664', (159, 168))	('neoplasia', 'Disease', 'MESH:D009369', (159, 168))	('variants', 'Var', (109, 117))
165426	30847299	The first aim of this study was to define a possible association between variants in ERCC1 (rs11615 and rs3212986), and ERCC2/XPD (rs13181 and rs1799793) genes and OS of patients with advanced resectable EC; as a second aim, we also evaluated the association of the same genetic variants with response to cisplatin-based neoadjuvant chemotherapy.	('ERCC2', 'Gene', (120, 125))	('patients', 'Species', '9606', (170, 178))	('XPD', 'Gene', (126, 129))	('rs13181', 'Var', (131, 138))	('ERCC1', 'Gene', '2067', (85, 90))	('rs11615', 'Var', (92, 99))	('XPD', 'Gene', '2068', (126, 129))	('rs1799793', 'Mutation', 'rs1799793', (143, 152))	('rs1799793', 'Var', (143, 152))	('rs3212986', 'Mutation', 'rs3212986', (104, 113))	('rs11615', 'Mutation', 'rs11615', (92, 99))	('ERCC2', 'Gene', '2068', (120, 125))	('rs13181', 'Mutation', 'rs13181', (131, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (305, 314))	('association', 'Interaction', (53, 64))	('OS', 'Chemical', '-', (164, 166))	('ERCC1', 'Gene', (85, 90))	('rs3212986', 'Var', (104, 113))
165428	30847299	The rs11615 (Asn118Asn) and rs3212986 (C8092A) in ERCC1, and the rs13181 (Lys751Gln) and rs1799793 (Asp312Asn) in ERCC2/XPD were selected based on their putative association with altered DNA repair capability, and their high frequency in the Caucasian population (minor allele frequency ranging from 28 to 42%).	('XPD', 'Gene', (120, 123))	('rs3212986', 'Mutation', 'rs3212986', (28, 37))	('ERCC2', 'Gene', (114, 119))	('C8092A', 'Mutation', 'rs3212986', (39, 45))	('Asp312Asn', 'SUBSTITUTION', 'None', (100, 109))	('ERCC1', 'Gene', '2067', (50, 55))	('ERCC2', 'Gene', '2068', (114, 119))	('rs13181', 'Mutation', 'rs13181', (65, 72))	('Asp312Asn', 'Var', (100, 109))	('rs11615', 'Var', (4, 11))	('ERCC1', 'Gene', (50, 55))	('Lys751Gln', 'Var', (74, 83))	('rs1799793', 'Mutation', 'rs1799793', (89, 98))	('XPD', 'Gene', '2068', (120, 123))	('Asn118Asn', 'Chemical', '-', (13, 22))	('rs11615', 'Mutation', 'rs11615', (4, 11))	('altered', 'Reg', (179, 186))	('DNA repair', 'MPA', (187, 197))	('Lys751Gln', 'SUBSTITUTION', 'None', (74, 83))
165448	30847299	All patients were successfully genotyped for rs11615 (Asn118Asn) and rs3212986 (C8092) in the ERCC1, and rs13181 (Lys751Gln) and rs1799793 (Asp312Asn) in the ERCC2/XPD.	('XPD', 'Gene', (164, 167))	('Asp312Asn', 'Var', (140, 149))	('rs11615', 'Mutation', 'rs11615', (45, 52))	('Asn118Asn', 'Chemical', '-', (54, 63))	('ERCC2', 'Gene', (158, 163))	('Asp312Asn', 'SUBSTITUTION', 'None', (140, 149))	('XPD', 'Gene', '2068', (164, 167))	('rs11615', 'Var', (45, 52))	('rs3212986', 'Mutation', 'rs3212986', (69, 78))	('ERCC1', 'Gene', '2067', (94, 99))	('ERCC1', 'Gene', (94, 99))	('Lys751Gln', 'SUBSTITUTION', 'None', (114, 123))	('patients', 'Species', '9606', (4, 12))	('rs3212986 (C8092', 'Var', (69, 85))	('ERCC2', 'Gene', '2068', (158, 163))	('rs13181', 'Mutation', 'rs13181', (105, 112))	('rs1799793', 'Mutation', 'rs1799793', (129, 138))	('Lys751Gln', 'Var', (114, 123))
165449	30847299	Genotype distribution respected the Hardy-Weinberg equilibrium (HWE) for rs11615, rs13181, and rs3212986 with p-values ranging from 0.76 to 0.12.	('rs3212986', 'Mutation', 'rs3212986', (95, 104))	('rs3212986', 'Var', (95, 104))	('rs11615', 'Var', (73, 80))	('rs13181', 'Var', (82, 89))	('rs13181', 'Mutation', 'rs13181', (82, 89))	('rs11615', 'Mutation', 'rs11615', (73, 80))
165450	30847299	On the contrary, rs1799793 in the ERCC2/XPD exhibited a p = 0.04, suggesting a possible role in EC onset for this genetic variant.	('XPD', 'Gene', '2068', (40, 43))	('ERCC2', 'Gene', (34, 39))	('rs1799793', 'Mutation', 'rs1799793', (17, 26))	('role', 'Reg', (88, 92))	('rs1799793', 'Var', (17, 26))	('XPD', 'Gene', (40, 43))	('ERCC2', 'Gene', '2068', (34, 39))
165452	30847299	As reported in Figure 2, among the analyzed variables, only the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 resulted associated with OS (log-rank: p = 0.03 and p = 0.004, respectively).	('rs1799793', 'Mutation', 'rs1799793', (98, 107))	('ERCC1', 'Gene', (64, 69))	('ERCC1', 'Gene', '2067', (64, 69))	('rs1799793', 'Var', (98, 107))	('ERCC2', 'Gene', '2068', (88, 93))	('XPD', 'Gene', (94, 97))	('associated with', 'Reg', (117, 132))	('rs3212986', 'Mutation', 'rs3212986', (70, 79))	('ERCC2', 'Gene', (88, 93))	('XPD', 'Gene', '2068', (94, 97))	('OS', 'Chemical', '-', (133, 135))	('rs3212986', 'Var', (70, 79))
165453	30847299	The median survival of patients carrying the A allele of ERCC1 rs3212986 in homozygosity was 16 months vs. > 32 months of patients with CC or CA genotypes.	('patients', 'Species', '9606', (23, 31))	('rs3212986', 'Mutation', 'rs3212986', (63, 72))	('patients', 'Species', '9606', (122, 130))	('rs3212986', 'Var', (63, 72))	('ERCC1', 'Gene', (57, 62))	('ERCC1', 'Gene', '2067', (57, 62))
165454	30847299	Concerning ERCC2/XPD rs1799793, the GA and AA genotypes exhibited a median survival of 26 and 19 months, respectively, vs. 47 months of the patients carrying the GG genotype.	('XPD', 'Gene', (17, 20))	('ERCC2', 'Gene', (11, 16))	('XPD', 'Gene', '2068', (17, 20))	('rs1799793', 'Mutation', 'rs1799793', (21, 30))	('rs1799793', 'Var', (21, 30))	('patients', 'Species', '9606', (140, 148))	('ERCC2', 'Gene', '2068', (11, 16))
165455	30847299	Comparable results were obtained when survival functions of the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 were analyzed with the univariate Cox proportional method using the codominant model and, based on the Kaplan-Meier plots, the recessive (rs3212986) or the dominant (rs1799793) genetic model (Table 2).	('rs1799793', 'Mutation', 'rs1799793', (98, 107))	('ERCC1', 'Gene', (64, 69))	('ERCC1', 'Gene', '2067', (64, 69))	('rs1799793', 'Mutation', 'rs1799793', (274, 283))	('ERCC2', 'Gene', '2068', (88, 93))	('rs1799793', 'Var', (274, 283))	('rs3212986', 'Var', (246, 255))	('XPD', 'Gene', (94, 97))	('rs3212986', 'Mutation', 'rs3212986', (70, 79))	('ERCC2', 'Gene', (88, 93))	('XPD', 'Gene', '2068', (94, 97))	('rs3212986', 'Var', (70, 79))	('rs3212986', 'Mutation', 'rs3212986', (246, 255))
165456	30847299	After adjustment for clinical variables, such as age at diagnosis, histotype, clinical stage, and therapeutic strategy, the association of the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 with OS remained statistically significant (Table 2).	('rs3212986', 'Var', (149, 158))	('ERCC1', 'Gene', (143, 148))	('rs1799793', 'Var', (177, 186))	('ERCC1', 'Gene', '2067', (143, 148))	('XPD', 'Gene', (173, 176))	('association', 'Interaction', (124, 135))	('ERCC2', 'Gene', '2068', (167, 172))	('XPD', 'Gene', '2068', (173, 176))	('OS', 'Chemical', '-', (192, 194))	('rs3212986', 'Mutation', 'rs3212986', (149, 158))	('rs1799793', 'Mutation', 'rs1799793', (177, 186))	('ERCC2', 'Gene', (167, 172))
165457	30847299	We constructed survival prediction models to explore whether the survival-associated rs3212986 and rs1799793 could increase the predictability of the clinical features.	('rs1799793', 'Mutation', 'rs1799793', (99, 108))	('rs1799793', 'Var', (99, 108))	('rs3212986', 'Var', (85, 94))	('rs3212986', 'Mutation', 'rs3212986', (85, 94))
165462	30847299	By analyzing the 134 EC patients treated with neoadjuvant cisplatin-based chemotherapy, no association with response was found for the ERCC2/XPD rs13181 and the ERCC2/XPD rs1799793.	('XPD', 'Gene', (167, 170))	('ERCC2', 'Gene', '2068', (135, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('rs13181', 'Var', (145, 152))	('rs1799793', 'Mutation', 'rs1799793', (171, 180))	('XPD', 'Gene', '2068', (167, 170))	('rs1799793', 'Var', (171, 180))	('XPD', 'Gene', (141, 144))	('ERCC2', 'Gene', (135, 140))	('rs13181', 'Mutation', 'rs13181', (145, 152))	('ERCC2', 'Gene', '2068', (161, 166))	('XPD', 'Gene', '2068', (141, 144))	('patients', 'Species', '9606', (24, 32))	('ERCC2', 'Gene', (161, 166))
165463	30847299	On the contrary, the minor A allele of ERCC1 rs3212986 both in homozygosity and heterozygosity exhibited a weak association (p = 0.02) as well as the CC genotype of the ERCC1 rs11615 (p = 0.04) (Table 4).	('rs11615', 'Var', (175, 182))	('rs3212986', 'Mutation', 'rs3212986', (45, 54))	('ERCC1', 'Gene', (169, 174))	('ERCC1', 'Gene', (39, 44))	('rs11615', 'Mutation', 'rs11615', (175, 182))	('ERCC1', 'Gene', '2067', (169, 174))	('ERCC1', 'Gene', '2067', (39, 44))	('rs3212986', 'Var', (45, 54))
165464	30847299	Interestingly, the ERCC2/XPD rs1799793 though not associated with response (see Table 4), was still associated with OS (p = 0.009, under the dominant genetic model) (Figure 4).	('rs1799793', 'Var', (29, 38))	('XPD', 'Gene', (25, 28))	('XPD', 'Gene', '2068', (25, 28))	('ERCC2', 'Gene', '2068', (19, 24))	('associated with', 'Reg', (100, 115))	('OS', 'Chemical', '-', (116, 118))	('ERCC2', 'Gene', (19, 24))	('rs1799793', 'Mutation', 'rs1799793', (29, 38))
165467	30847299	In this study, we investigated the association between four germline variants in DNA repair genes, two in the ERCC1 (rs11615 and rs3212986), and two in the ERCC2/XPD (rs13181 and rs1799793) and the outcome of patients with advanced EC.	('rs13181', 'Mutation', 'rs13181', (167, 174))	('rs11615', 'Mutation', 'rs11615', (117, 124))	('rs3212986', 'Var', (129, 138))	('investigated', 'Reg', (18, 30))	('rs1799793', 'Mutation', 'rs1799793', (179, 188))	('DNA repair genes', 'Gene', (81, 97))	('ERCC2', 'Gene', '2068', (156, 161))	('XPD', 'Gene', (162, 165))	('association', 'Interaction', (35, 46))	('rs1799793', 'Var', (179, 188))	('rs11615', 'Var', (117, 124))	('ERCC1', 'Gene', (110, 115))	('ERCC1', 'Gene', '2067', (110, 115))	('patients', 'Species', '9606', (209, 217))	('rs13181', 'Var', (167, 174))	('XPD', 'Gene', '2068', (162, 165))	('ERCC2', 'Gene', (156, 161))	('rs3212986', 'Mutation', 'rs3212986', (129, 138))
165470	30847299	We observed that, among the analyzed variants, the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 remained statistically associated with a poor OS after correction for multiple tests.	('rs3212986', 'Mutation', 'rs3212986', (57, 66))	('OS', 'Chemical', '-', (141, 143))	('rs1799793', 'Mutation', 'rs1799793', (85, 94))	('rs1799793', 'Var', (85, 94))	('rs3212986', 'Var', (57, 66))	('ERCC2', 'Gene', '2068', (75, 80))	('ERCC1', 'Gene', '2067', (51, 56))	('ERCC1', 'Gene', (51, 56))	('ERCC2', 'Gene', (75, 80))	('XPD', 'Gene', (81, 84))	('XPD', 'Gene', '2068', (81, 84))
165472	30847299	Concerning the rs1799793, patients carrying the variant A allele both in homozygosity or heterozygosity exhibited a significant shorter survival compared to patients with the GG genotype (median survival 23 months vs. 47 months).	('rs1799793', 'Var', (15, 24))	('patients', 'Species', '9606', (157, 165))	('shorter', 'NegReg', (128, 135))	('patients', 'Species', '9606', (26, 34))	('survival', 'MPA', (136, 144))	('rs1799793', 'Mutation', 'rs1799793', (15, 24))	('variant', 'Var', (48, 55))
165473	30847299	When, as a second aim, we analyzed the association of the same NER variants with the response to neoadjuvant therapy, only the rs3212986 and rs11615 in ERCC1 exhibited an association.	('rs3212986', 'Mutation', 'rs3212986', (127, 136))	('ERCC1', 'Gene', (152, 157))	('rs11615', 'Var', (141, 148))	('ERCC1', 'Gene', '2067', (152, 157))	('rs3212986', 'Var', (127, 136))	('rs11615', 'Mutation', 'rs11615', (141, 148))
165475	30847299	This last finding strengthens the hypothesis that ERCC2/XPD rs1799793 may only have a prognostic value.	('rs1799793', 'Mutation', 'rs1799793', (60, 69))	('rs1799793', 'Var', (60, 69))	('ERCC2', 'Gene', '2068', (50, 55))	('XPD', 'Gene', (56, 59))	('XPD', 'Gene', '2068', (56, 59))	('ERCC2', 'Gene', (50, 55))
165476	30847299	Association of ERCC1 rs3212986 and ERCC2/XPD rs1799793 with survival has been previously investigated in a few EC Caucasian patient cohorts and results are in contrast with those reported in this study.	('ERCC2', 'Gene', '2068', (35, 40))	('XPD', 'Gene', (41, 44))	('XPD', 'Gene', '2068', (41, 44))	('rs3212986', 'Mutation', 'rs3212986', (21, 30))	('ERCC2', 'Gene', (35, 40))	('rs3212986', 'Var', (21, 30))	('rs1799793', 'Mutation', 'rs1799793', (45, 54))	('patient', 'Species', '9606', (124, 131))	('rs1799793', 'Var', (45, 54))	('ERCC1', 'Gene', (15, 20))	('ERCC1', 'Gene', '2067', (15, 20))	('Association', 'Interaction', (0, 11))
165477	30847299	In particular, Bradbury and co-workers reported that the presence of the CA and AA genotypes of the rs3212986, and the GA and AA genotypes of the rs1799793 correlated with a better outcome.	('rs1799793', 'Var', (146, 155))	('rs3212986', 'Var', (100, 109))	('rs1799793', 'Mutation', 'rs1799793', (146, 155))	('rs3212986', 'Mutation', 'rs3212986', (100, 109))
165478	30847299	Similarly, in a previous study conducted in a small cohort of Caucasian EADC and ESCC patients, we also found a positive association between OS and the minor allele of ERCC1 rs3212986.	('EADC', 'Chemical', '-', (72, 76))	('ERCC1', 'Gene', (168, 173))	('positive', 'PosReg', (112, 120))	('rs3212986', 'Mutation', 'rs3212986', (174, 183))	('OS', 'Chemical', '-', (141, 143))	('ERCC1', 'Gene', '2067', (168, 173))	('ESCC', 'Disease', (81, 85))	('rs3212986', 'Var', (174, 183))	('patients', 'Species', '9606', (86, 94))
165481	30847299	The observed deviation from HWE of the ERCC2/XPD rs1799793 in our cohort might reflect its involvement in development of the EC.	('rs1799793', 'Var', (49, 58))	('XPD', 'Gene', (45, 48))	('involvement', 'Reg', (91, 102))	('ERCC2', 'Gene', '2068', (39, 44))	('XPD', 'Gene', '2068', (45, 48))	('rs1799793', 'Mutation', 'rs1799793', (49, 58))	('ERCC2', 'Gene', (39, 44))
165482	30847299	The contribution of rs1799793 to EC onset might also explain its impact in patient survival by promoting tumor progression and aggressiveness, rather than by influencing the response to therapeutic treatment.	('aggressiveness', 'Disease', 'MESH:D001523', (127, 141))	('aggressiveness', 'Disease', (127, 141))	('rs1799793', 'Mutation', 'rs1799793', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('rs1799793', 'Var', (20, 29))	('aggressiveness', 'Phenotype', 'HP:0000718', (127, 141))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('promoting', 'PosReg', (95, 104))	('tumor', 'Disease', (105, 110))	('patient', 'Species', '9606', (75, 82))	('influencing', 'Reg', (158, 169))
165483	30847299	So far, the altered DNA repair activity of the ERCC1 and ERCC2/XPD variants has been considered central for its association with tumor risk and cancer patient outcome.	('association', 'Interaction', (112, 123))	('ERCC1', 'Gene', '2067', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('XPD', 'Gene', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('XPD', 'Gene', '2068', (63, 66))	('altered', 'Reg', (12, 19))	('ERCC2', 'Gene', '2068', (57, 62))	('cancer', 'Disease', (144, 150))	('patient', 'Species', '9606', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('DNA repair activity', 'MPA', (20, 39))	('tumor', 'Disease', (129, 134))	('ERCC1', 'Gene', (47, 52))	('ERCC2', 'Gene', (57, 62))	('variants', 'Var', (67, 75))
165484	30847299	However, ERCC2/XPD is a helicase also endowed with transcriptional activity, and the codon Asp312Asn is located in the Arch transcriptional domain (that encompasses codons S246-D439) of the protein.	('XPD', 'Gene', '2068', (15, 18))	('ERCC2', 'Gene', '2068', (9, 14))	('helicase', 'Protein', (24, 32))	('ERCC2', 'Gene', (9, 14))	('XPD', 'Gene', (15, 18))	('Asp312Asn', 'SUBSTITUTION', 'None', (91, 100))	('Asp312Asn', 'Var', (91, 100))
165485	30847299	Furthermore, this possibility might also explain why the rs1799793 influences patient survival but not the efficacy of chemotherapy, which is considered more related to the removal of DNA adducts.	('rs1799793', 'Mutation', 'rs1799793', (57, 66))	('patient', 'Species', '9606', (78, 85))	('rs1799793', 'Var', (57, 66))	('influences', 'Reg', (67, 77))	('patient survival', 'CPA', (78, 94))
165486	30847299	Although our data clearly indicate that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 affect OS in advanced EC, the study presents some limitations.	('ERCC1', 'Gene', (44, 49))	('XPD', 'Gene', '2068', (74, 77))	('ERCC2', 'Gene', (68, 73))	('rs3212986', 'Var', (50, 59))	('affect', 'Reg', (88, 94))	('rs1799793', 'Var', (78, 87))	('ERCC1', 'Gene', '2067', (44, 49))	('OS', 'Chemical', '-', (95, 97))	('rs3212986', 'Mutation', 'rs3212986', (50, 59))	('XPD', 'Gene', (74, 77))	('ERCC2', 'Gene', '2068', (68, 73))	('advanced EC', 'Disease', (101, 112))	('rs1799793', 'Mutation', 'rs1799793', (78, 87))
165487	30847299	This can explain the poor clinical impact of the rs3212986 and the rs1799793 (AUC 0.669) as prognostic biomarkers, despite their statistical significant association with OS.	('rs3212986', 'Var', (49, 58))	('association', 'Reg', (153, 164))	('rs1799793', 'Var', (67, 76))	('OS', 'Chemical', '-', (170, 172))	('rs3212986', 'Mutation', 'rs3212986', (49, 58))	('rs1799793', 'Mutation', 'rs1799793', (67, 76))
165488	30847299	Indeed, although there is no doubt about the relevance of constitutive variants on cancer onset and outcome, their limited power is still the greatest obstacle to their clinical use.	('variants', 'Var', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))
165489	30847299	Thus, further studies are needed to find other germline variants that, together with the rs3212986 and the rs1799793, could generate a prognostic panel with increased clinical impact.	('rs3212986', 'Var', (89, 98))	('rs1799793', 'Var', (107, 116))	('rs3212986', 'Mutation', 'rs3212986', (89, 98))	('rs1799793', 'Mutation', 'rs1799793', (107, 116))
165490	30847299	Nevertheless, until the discovery of a more powerful prognostic signature, we believe that both the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 could contribute to the better stratification of patients with advanced resectable EC.	('patients', 'Species', '9606', (193, 201))	('ERCC2', 'Gene', '2068', (124, 129))	('rs3212986', 'Mutation', 'rs3212986', (106, 115))	('rs1799793', 'Mutation', 'rs1799793', (134, 143))	('XPD', 'Gene', '2068', (130, 133))	('rs1799793', 'Var', (134, 143))	('contribute', 'Reg', (150, 160))	('ERCC1', 'Gene', '2067', (100, 105))	('ERCC1', 'Gene', (100, 105))	('ERCC2', 'Gene', (124, 129))	('rs3212986', 'Var', (106, 115))	('XPD', 'Gene', (130, 133))
165493	28231690	Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18 The purpose of this study was to investigate the effect of human antigen R (HuR) downregulation and the potential target genes of HuR on the progression of esophageal squamous cell carcinoma (ESCC).	('HuR', 'Gene', '1994', (167, 170))	('human antigen R', 'Gene', (150, 165))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (247, 281))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('HuR', 'Gene', (18, 21))	('HuR', 'Gene', (167, 170))	('HuR', 'Gene', '1994', (18, 21))	('human antigen R', 'Gene', '1994', (150, 165))	('Inhibits', 'NegReg', (22, 30))	('Downregulation', 'Var', (0, 14))	('esophageal squamous cell carcinoma', 'Disease', (247, 281))	('HuR', 'Gene', '1994', (221, 224))	('downregulation', 'NegReg', (172, 186))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (50, 67))	('HuR', 'Gene', (221, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('Esophageal Cancer', 'Disease', (50, 67))
165498	28231690	In addition, the metastasis of esophageal cancer cells was inhibited, while the expression of E-cadherin was increased and the expression of matrix metalloproteinase (MMP) 2, MMP9, and vimentin was decreased after HuR knockdown.	('E-cadherin', 'Gene', (94, 104))	('MMP9', 'Gene', (175, 179))	('E-cadherin', 'Gene', '999', (94, 104))	('expression', 'Species', '29278', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (17, 48))	('inhibited', 'NegReg', (59, 68))	('increased', 'PosReg', (109, 118))	('vimentin', 'Gene', '7431', (185, 193))	('matrix metalloproteinase (MMP) 2', 'Gene', '4313', (141, 173))	('vimentin', 'Gene', (185, 193))	('knockdown', 'Var', (218, 227))	('expression', 'MPA', (80, 90))	('decreased', 'NegReg', (198, 207))	('expression', 'MPA', (127, 137))	('HuR', 'Gene', (214, 217))	('expression', 'Species', '29278', (80, 90))	('HuR', 'Gene', '1994', (214, 217))	('metastasis of esophageal cancer', 'Disease', (17, 48))	('MMP9', 'Gene', '4318', (175, 179))
165499	28231690	Moreover, silencing of HuR disturbed the cell cycle of ESCC cells mainly by inducing G1 arrest.	('disturbed', 'Reg', (27, 36))	('cell cycle', 'CPA', (41, 51))	('G1 arrest', 'CPA', (85, 94))	('inducing', 'Reg', (76, 84))	('HuR', 'Gene', '1994', (23, 26))	('HuR', 'Gene', (23, 26))	('silencing', 'Var', (10, 19))
165502	28231690	IL-18 expression was decreased in ESCC tissues, and exogenous IL-18 significantly inhibited the proliferation and metastasis of ESCC cells.	('exogenous', 'Var', (52, 61))	('expression', 'Species', '29278', (6, 16))	('IL-18', 'Gene', (62, 67))	('inhibited', 'NegReg', (82, 91))	('decreased', 'NegReg', (21, 30))	('expression', 'MPA', (6, 16))	('ESCC', 'Disease', (128, 132))	('IL-18', 'Gene', '3606', (0, 5))	('IL-18', 'Gene', (0, 5))	('IL-18', 'Gene', '3606', (62, 67))
165512	28231690	In recent years, there have been reports of abnormally high HuR expression in gastric cancer, colorectal cancer and breast cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('colorectal cancer', 'Disease', (94, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('gastric cancer', 'Disease', (78, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('HuR', 'Gene', (60, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))	('abnormally', 'Var', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('HuR', 'Gene', '1994', (60, 63))	('expression', 'Species', '29278', (64, 74))
165515	28231690	Downregulation of HuR can increase the sensitivity of breast cancer line MCF-7 to doxorubicin and increase its rate of apoptosis.	('sensitivity', 'MPA', (39, 50))	('breast cancer', 'Disease', (54, 67))	('HuR', 'Gene', (18, 21))	('HuR', 'Gene', '1994', (18, 21))	('doxorubicin', 'Chemical', 'MESH:D004317', (82, 93))	('Downregulation', 'Var', (0, 14))	('increase', 'PosReg', (98, 106))	('MCF-7', 'CellLine', 'CVCL:0031', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('increase', 'PosReg', (26, 34))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
165520	28231690	In addition, inhibition of HuR can significantly inhibit the proliferation and metastasis of ESCC cells through interleukin 18 (IL-18).	('HuR', 'Gene', (27, 30))	('IL-18', 'Gene', '3606', (128, 133))	('metastasis of', 'CPA', (79, 92))	('inhibition', 'Var', (13, 23))	('interleukin 18', 'Gene', '3606', (112, 126))	('IL-18', 'Gene', (128, 133))	('interleukin 18', 'Gene', (112, 126))	('proliferation', 'CPA', (61, 74))	('ESCC', 'Disease', (93, 97))	('HuR', 'Gene', '1994', (27, 30))	('inhibit', 'NegReg', (49, 56))
165567	28231690	Carbamidomethyl on Cys were specified as fixed modifications and oxidation on Met were specified as variable modifications.	('Carbamidomethyl', 'Var', (0, 15))	('oxidation', 'MPA', (65, 74))	('Cys', 'MPA', (19, 22))	('Cys', 'Chemical', 'MESH:D003545', (19, 22))
165598	28231690	Studies have reported that endogenous IL-18 can affect hepatic metastasis by upregulating melanoma cell adhesion to HSE cells and tumor growth, implicating a possible antimetastatic benefit of neutralizing IL-18.	('melanoma', 'Disease', (90, 98))	('affect', 'Reg', (48, 54))	('upregulating', 'PosReg', (77, 89))	('IL-18', 'Gene', (38, 43))	('IL-18', 'Gene', (206, 211))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('endogenous', 'Var', (27, 37))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('IL-18', 'Gene', '3606', (38, 43))	('hepatic metastasis', 'MPA', (55, 73))	('tumor', 'Disease', (130, 135))	('IL-18', 'Gene', '3606', (206, 211))
165603	28231690	Western blot analysis showed that HuR knockdown could significantly upregulate the expression of IL-18 (Fig.	('HuR', 'Gene', '1994', (34, 37))	('IL-18', 'Gene', '3606', (97, 102))	('IL-18', 'Gene', (97, 102))	('expression', 'Species', '29278', (83, 93))	('upregulate', 'PosReg', (68, 78))	('expression', 'MPA', (83, 93))	('knockdown', 'Var', (38, 47))	('HuR', 'Gene', (34, 37))
165627	28231690	In a study by Muralidharan et al., it was shown that HuR-specific siRNA contained in a folate-targeted lipid nanoparticle (HuR-FNP) was capable of delivering HuR targeting siRNA to folate receptor alpha-expressing tumor cells to produce cell-specific knockdown of HuR and HuR-regulated target proteins.	('HuR', 'Gene', '1994', (272, 275))	('HuR', 'Gene', '1994', (264, 267))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('HuR', 'Gene', (272, 275))	('HuR', 'Gene', (264, 267))	('lipid', 'Chemical', 'MESH:D008055', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (214, 219))	('HuR', 'Gene', (53, 56))	('HuR', 'Gene', (123, 126))	('HuR', 'Gene', '1994', (53, 56))	('HuR', 'Gene', '1994', (123, 126))	('HuR', 'Gene', (158, 161))	('knockdown', 'Var', (251, 260))	('HuR', 'Gene', '1994', (158, 161))
165642	28231690	They showed that HuR acted as a translation repressor of IGF-IR mRNA by binding at the 5'-UTR and that ectopic HuR expression increased IGF-IR mRNA stability and protein expression.	('HuR', 'Gene', '1994', (17, 20))	('increased IGF-', 'Phenotype', 'HP:0030269', (126, 140))	('mRNA stability', 'MPA', (143, 157))	('binding', 'Interaction', (72, 79))	('protein expression', 'MPA', (162, 180))	('expression', 'Species', '29278', (115, 125))	('HuR', 'Gene', '1994', (111, 114))	('HuR', 'Gene', (111, 114))	('expression', 'Species', '29278', (170, 180))	('ectopic', 'Var', (103, 110))	('increased', 'PosReg', (126, 135))	('HuR', 'Gene', (17, 20))
165702	25997064	Radiotherapy also increases the production of free radicals and oxidative stress, processes that upregulate numerous pathways pertinent to vascular disease, including matrix metalloproteinases (MMP), adhesion molecules, pro-inflammatory cytokines, and smooth muscle cell proliferation and apoptosis, while inactivating vasculoprotective nitric oxide (NO).	('free radicals', 'Chemical', 'MESH:D005609', (46, 59))	('inactivating', 'NegReg', (306, 318))	('nitric oxide', 'Chemical', 'MESH:D009569', (337, 349))	('oxidative stress', 'Phenotype', 'HP:0025464', (64, 80))	('upregulate', 'PosReg', (97, 107))	('vasculoprotective nitric oxide', 'MPA', (319, 349))	('increases', 'PosReg', (18, 27))	('Radiotherapy', 'Var', (0, 12))	('production of free radicals', 'MPA', (32, 59))	('smooth muscle cell proliferation', 'CPA', (252, 284))	('vascular disease', 'Disease', 'MESH:D000783', (139, 155))	('oxidative stress', 'MPA', (64, 80))	('MMP', 'Gene', '4313;4317;4318', (194, 197))	('vascular disease', 'Disease', (139, 155))	('apoptosis', 'CPA', (289, 298))	('MMP', 'Gene', (194, 197))
165709	25997064	Although CCRT is more effective at tumor eradication than radiotherapy alone, the combined use of CDDP, 5-FU, and radiotherapy can cause unpredictable localized and systemic vascular inflammation with a higher incidence of atherosclerotic disease, coronary artery disease, and myocardial infarction.	('radiotherapy', 'Var', (114, 126))	('atherosclerotic disease', 'Phenotype', 'HP:0002621', (223, 246))	('atherosclerotic disease', 'Disease', (223, 246))	('vascular inflammation', 'Phenotype', 'HP:0002633', (174, 195))	('coronary artery disease', 'Disease', 'MESH:D003324', (248, 271))	('coronary artery disease', 'Disease', (248, 271))	('CDDP', 'Var', (98, 102))	('5-FU', 'Chemical', 'MESH:D005472', (104, 108))	('tumor', 'Disease', (35, 40))	('myocardial infarction', 'Disease', (277, 298))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('systemic vascular inflammation', 'Disease', (165, 195))	('myocardial infarction', 'Phenotype', 'HP:0001658', (277, 298))	('cause', 'Reg', (131, 136))	('myocardial infarction', 'Disease', 'MESH:D009203', (277, 298))	('CDDP', 'Chemical', 'MESH:D002945', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('systemic vascular inflammation', 'Disease', 'MESH:D007249', (165, 195))	('atherosclerotic disease', 'Disease', 'MESH:D050197', (223, 246))
165710	25997064	A previous study showed that CDDP results in a decrease in NO production and the upregulation of ICAM-1 expression in endothelial cells that accelerate vascular inflammation.	('decrease', 'NegReg', (47, 55))	('ICAM-1', 'Gene', '3383', (97, 103))	('CDDP', 'Chemical', 'MESH:D002945', (29, 33))	('accelerate', 'PosReg', (141, 151))	('upregulation', 'PosReg', (81, 93))	('expression', 'MPA', (104, 114))	('ICAM-1', 'Gene', (97, 103))	('vascular inflammation', 'Disease', 'MESH:D007249', (152, 173))	('NO production', 'MPA', (59, 72))	('vascular inflammation', 'Phenotype', 'HP:0002633', (152, 173))	('CDDP', 'Var', (29, 33))	('vascular inflammation', 'Disease', (152, 173))
165711	25997064	Furthermore, an experimental study in rabbits showed that damage to the intima caused by 5-FU occasionally results in thrombus formation.	('5-FU', 'Var', (89, 93))	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('thrombus', 'Disease', 'MESH:D013927', (118, 126))	('rabbits', 'Species', '9986', (38, 45))	('results in', 'Reg', (107, 117))	('thrombus', 'Disease', (118, 126))
165753	19626700	Among white males, odds ratios (ORs) were elevated in relation to carrying at least one c.901C>G allele for EGA (OR= 1.9; 95%CI=1.0-3.6) and non-cardia gastric cancer (OR=2.5; 95%CI=1.2-5.5), but not ES.	('non-cardia gastric cancer', 'Disease', (141, 166))	('EGA', 'Gene', (108, 111))	('c.901C>G', 'Mutation', 'c.901C>G', (88, 96))	('c.901C>G', 'Var', (88, 96))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (141, 166))	('gastric cancer', 'Phenotype', 'HP:0012126', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('elevated', 'PosReg', (42, 50))
165754	19626700	An association between carrying the c.5002G>A genotype and EGA was not evident.	('EGA', 'Disease', (59, 62))	('c.5002G>A', 'Var', (36, 45))	('c.5002G>A', 'Mutation', 'c.5002G>A', (36, 45))
165755	19626700	These findings suggest that non-synonymous polymorphisms in M6P/IGF2R may contribute to the risks of EGA and non-cardia adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('non-cardia adenocarcinomas', 'Disease', (109, 135))	('contribute', 'Reg', (74, 84))	('non-cardia adenocarcinomas', 'Disease', 'MESH:D004938', (109, 135))	('risks', 'Reg', (92, 97))	('M6P/IGF2R', 'Gene', (60, 69))	('non-synonymous polymorphisms', 'Var', (28, 56))	('EGA', 'Disease', (101, 104))	('M6P/IGF2R', 'Gene', '3482', (60, 69))
165770	19626700	IGF2R inactivation has been associated with risk of poorly differentiated breast and lung tumors.	('inactivation', 'Var', (6, 18))	('associated', 'Reg', (28, 38))	('lung tumors', 'Phenotype', 'HP:0100526', (85, 96))	('IGF2R', 'Gene', '3482', (0, 5))	('breast and lung tumors', 'Disease', 'MESH:D001943', (74, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('IGF2R', 'Gene', (0, 5))
165771	19626700	Recurrent loss of heterozygosity at the IGF2R locus, and mutations in the remaining allele appear to be early events in breast cancer, squamous cell lung cancer, hepatocellular carcinoma, non-Hodgkin lymphoma, ovarian cancer and renal cell carcinoma.	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (192, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('mutations', 'Var', (57, 66))	('ovarian cancer', 'Disease', 'MESH:D010051', (210, 224))	('non-Hodgkin lymphoma', 'Disease', (188, 208))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (188, 208))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (135, 160))	('lymphoma', 'Phenotype', 'HP:0002665', (200, 208))	('IGF2R', 'Gene', '3482', (40, 45))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (162, 186))	('squamous cell lung cancer', 'Disease', (135, 160))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (229, 249))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (188, 208))	('loss', 'NegReg', (10, 14))	('ovarian cancer', 'Disease', (210, 224))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (210, 224))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (162, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (135, 160))	('renal cell carcinoma', 'Disease', (229, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (229, 249))	('hepatocellular carcinoma', 'Disease', (162, 186))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('IGF2R', 'Gene', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
165772	19626700	Chromosomal loss in a region that includes the IGF2R gene has also been linked with androgen insensitive prostate cancer.	('Chromosomal loss', 'Var', (0, 16))	('IGF2R', 'Gene', '3482', (47, 52))	('prostate cancer', 'Disease', (105, 120))	('linked', 'Reg', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('IGF2R', 'Gene', (47, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))
165773	19626700	These findings point to the involvement of IGF2R as a tumor suppressor in the development of cancer, but the relation of genetic variants in IGF2R to EGA risk has not been evaluated.	('involvement', 'Reg', (28, 39))	('cancer', 'Disease', (93, 99))	('men', 'Species', '9606', (35, 38))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('IGF2R', 'Gene', (141, 146))	('IGF2R', 'Gene', '3482', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('IGF2R', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('men', 'Species', '9606', (85, 88))	('IGF2R', 'Gene', '3482', (141, 146))	('tumor', 'Disease', (54, 59))	('variants', 'Var', (129, 137))
165774	19626700	More than 1,200 single nucleotide polymorphisms (SNPs) have been identified in IGF2R to date.	('single nucleotide polymorphisms', 'Var', (16, 47))	('IGF2R', 'Gene', (79, 84))	('IGF2R', 'Gene', '3482', (79, 84))
165775	19626700	Six are in the coding region and three of these (c.6206 A>G, Asn2020Ser; c.901C>G, Leu252Val and c.5002G>A Gly1619Arg) are non-synonymous.	('Asn2020Ser', 'SUBSTITUTION', 'None', (61, 71))	('c.901C>G', 'Mutation', 'c.901C>G', (73, 81))	('Gly1619Arg', 'SUBSTITUTION', 'None', (107, 117))	('c.6206 A>G', 'Mutation', 'c.6206A>G', (49, 59))	('c.5002G>A', 'Var', (97, 106))	('Leu252Val', 'Var', (83, 92))	('c.5002G>A', 'SUBSTITUTION', 'None', (97, 106))	('c.6206 A>G', 'Var', (49, 59))	('Gly1619Arg', 'Var', (107, 117))	('Asn2020Ser', 'Var', (61, 71))	('c.901C>G', 'Var', (73, 81))	('Leu252Val', 'Chemical', '-', (83, 92))
165776	19626700	Two of these, c.901C>G, Leu252Val and c.5002G>A Gly1619Arg, have a minor allele frequency that is more than 5% among Caucasians.	('c.5002G>A', 'Var', (38, 47))	('c.5002G>A', 'SUBSTITUTION', 'None', (38, 47))	('Gly1619Arg', 'SUBSTITUTION', 'None', (48, 58))	('Leu252Val', 'Var', (24, 33))	('c.901C>G', 'Mutation', 'c.901C>G', (14, 22))	('Gly1619Arg', 'Var', (48, 58))	('c.901C>G', 'Var', (14, 22))	('Leu252Val', 'Chemical', '-', (24, 33))
165791	19626700	Primers for the c.5002 (rs629849) in exon 34 and c.901 (rs8191754) in exon 6 were designed by Applied Biosystem.	('rs629849', 'Var', (24, 32))	('rs8191754', 'Mutation', 'rs8191754', (56, 65))	('rs629849', 'Mutation', 'rs629849', (24, 32))	('rs8191754', 'Var', (56, 65))
165792	19626700	For c.901 C>G, the forward primer was 5'-CTA AGG GTA CTG TGA TTA TCA CTC-3' and the reverse primer was 5'-GAA AGT CAG GTC CTT GCT GGA G-3'.	('c.901 C>G', 'Var', (4, 13))	('GAA', 'Gene', (106, 109))	('GAA', 'Gene', '2548', (106, 109))	('c.901 C>G', 'Mutation', 'c.901C>G', (4, 13))
165793	19626700	For the c.5002G>A, the forward primer was 5'-GAA ATT GAT GGT CCT GAC TTG CG-3' and the reverse primer was 5'-GCA CTG GAG ATG CAC TTC TCC-3'.	('c.5002G>A', 'Mutation', 'c.5002G>A', (8, 17))	('CCT', 'Gene', (61, 64))	('GAA', 'Gene', '2548', (45, 48))	('c.5002G>A', 'Var', (8, 17))	('CCT', 'Gene', '907', (61, 64))	('GAT', 'Gene', '10249', (53, 56))	('GAA', 'Gene', (45, 48))	('GAT', 'Gene', (53, 56))
165795	19626700	Undetermined genotypes were excluded from analyses and constituted 4.2% and 5% of the total population for the c.901 C>G and c.5002 G>A variants, respectively.	('c.5002 G>A', 'Mutation', 'c.5002G>A', (125, 135))	('c.901 C>G', 'Var', (111, 120))	('c.5002 G>A', 'Var', (125, 135))	('c.901 C>G', 'Mutation', 'c.901C>G', (111, 120))
165796	19626700	We tested deviation from Hardy-Weinberg equilibrium (HWE) of IGF2R c.5002 and IGF2R c.901 genotypes among the controls for the overall and site-specific analyses using chi-square tests.	('IGF2R', 'Gene', '3482', (61, 66))	('IGF2R', 'Gene', '3482', (78, 83))	('tested', 'Reg', (3, 9))	('c.5002', 'Var', (67, 73))	('IGF2R', 'Gene', (61, 66))	('IGF2R', 'Gene', (78, 83))
165797	19626700	Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between carrying the IGF2R c.5002 or the c.901 allele, and risk of esophageal or gastric cancer by histologic subtype.	('gastric cancer', 'Phenotype', 'HP:0012126', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('c.901', 'Var', (177, 182))	('IGF2R', 'Gene', '3482', (157, 162))	('c.5002', 'Var', (163, 169))	('esophageal', 'Disease', (203, 213))	('gastric cancer', 'Disease', (217, 231))	('IGF2R', 'Gene', (157, 162))	('gastric cancer', 'Disease', 'MESH:D013274', (217, 231))	('esophageal', 'Disease', 'MESH:D004941', (203, 213))
165802	19626700	There was no evidence that genotype frequencies from the IGF2R c.901 deviated from Hardy-Weinberg equilibrium (p-values= 0.14), although the evidence for the c.5002 was less clear (p=0.05).	('IGF2R', 'Gene', (57, 62))	('IGF2R', 'Gene', '3482', (57, 62))	('c.901', 'Var', (63, 68))
165804	19626700	There was little evidence for an association between carrying the minor IGF2R c.5002 A-allele and risks for GCA (OR=1.21, 95%CI=0.58-2.54), non-cardia gastric cancer (OR=0.98, 95%CI=0.46-2.08), or EA (OR=0.60, 95%CI=0.25-1.44) or ES (OR=1.80, 95%CI=0.64-5.06).	('GCA', 'Disease', (108, 111))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (140, 165))	('IGF2R', 'Gene', (72, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('c.5002 A-allele', 'Var', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-cardia gastric cancer', 'Disease', (140, 165))	('IGF2R', 'Gene', '3482', (72, 77))
165805	19626700	We conducted additional stratified analyses in the combined category of EGA, to explore the association with IGF2R c.5002, since the origin of these junctional tumors is difficult to pinpoint, and also share risk factor profiles, as well as incidence trajectories.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('IGF2R', 'Gene', '3482', (109, 114))	('c.5002', 'Var', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('IGF2R', 'Gene', (109, 114))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
165806	19626700	There was no evidence of an association between IGF2R c.901 A>G and ES (OR=1.06, 95%CI=0.33-3.36), but a suggestive association was seen with non-cardia gastric adenocarcinomas (OR=1.80, 95%CI=0.92-3.57).	('IGF2R', 'Gene', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('c.901 A>G', 'Var', (54, 63))	('IGF2R', 'Gene', '3482', (48, 53))	('c.901 A>G', 'Mutation', 'c.901A>G', (54, 63))	('non-cardia gastric adenocarcinomas', 'Disease', 'MESH:D004938', (142, 176))	('non-cardia gastric adenocarcinomas', 'Disease', (142, 176))
165808	19626700	Interestingly, the associations between this variant and risks of ES, GCA, EA and non-cardia gastric cancer were weaker for esophageal tumors and stronger and statistically significant for gastric cardia and gastric ones.	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (82, 107))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('GCA', 'Disease', (70, 73))	('weaker', 'NegReg', (113, 119))	('non-cardia gastric cancer', 'Disease', (82, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('esophageal tumors', 'Disease', 'MESH:D004938', (124, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('esophageal tumors', 'Phenotype', 'HP:0100751', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('variant', 'Var', (45, 52))	('gastric', 'Disease', (208, 215))	('esophageal tumors', 'Disease', (124, 141))	('gastric cardia', 'Disease', (189, 203))	('gastric cardia', 'Disease', 'MESH:D004938', (189, 203))
165809	19626700	Exploratory stratified analyses also suggest that the associations between carrying the IGF2R c.901 G-allele and EGA varied with past exposures to NSAID use and cigarette smoking.	('EGA', 'Disease', (113, 116))	('IGF2R', 'Gene', '3482', (88, 93))	('c.901 G-allele', 'Var', (94, 108))	('associations', 'Interaction', (54, 66))	('IGF2R', 'Gene', (88, 93))
165810	19626700	This is the first epidemiologic study to evaluate associations between non-synonymous variants of the IGF2R tumor suppressor gene and esophageal and gastric cancer.	('gastric cancer', 'Disease', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('esophageal', 'Disease', (134, 144))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('IGF2R', 'Gene', '3482', (102, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('tumor', 'Disease', (108, 113))	('variants', 'Var', (86, 94))	('esophageal', 'Disease', 'MESH:D004941', (134, 144))	('associations', 'Interaction', (50, 62))	('IGF2R', 'Gene', (102, 107))	('non-synonymous variants', 'Var', (71, 94))
165812	19626700	We analyzed the two polymorphic variants with minor allele frequencies more than 5%, with the working hypothesis that these variants altered this tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('variants', 'Var', (124, 132))	('tumor', 'Disease', (146, 151))	('altered', 'Reg', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
165813	19626700	We found no evidence of an association between carrying the IGF2R c.5002 G>A minor allele and any subtype of esophageal or gastric cancer regardless of the subpopulation evaluated.	('esophageal', 'Disease', (109, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))	('IGF2R', 'Gene', '3482', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('esophageal', 'Disease', 'MESH:D004941', (109, 119))	('gastric cancer', 'Disease', (123, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('IGF2R', 'Gene', (60, 65))	('c.5002 G>A', 'Var', (66, 76))	('c.5002 G>A', 'Mutation', 'c.5002G>A', (66, 76))
165814	19626700	However, an association was seen between carrying at least one IGF2R c.901C>G allele and EGA and with non-cardia gastric adenocarcinoma among white males with a history of cigarette smoking but infrequent use of NSAIDS.	('EGA', 'Disease', (89, 92))	('non-cardia gastric adenocarcinoma', 'Disease', (102, 135))	('IGF2R', 'Gene', '3482', (63, 68))	('c.901C>G', 'Mutation', 'c.901C>G', (69, 77))	('c.901C>G', 'Var', (69, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('non-cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (102, 135))	('IGF2R', 'Gene', (63, 68))
165815	19626700	The finding of no association between the IGF2R c.5002 A-allele and risk of esophageal or gastric cancers was unexpected since this polymorphism is located within extracellular domain 11 of the M6P/IGF2R where IGF2 binding occurs.	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('M6P/IGF2R', 'Gene', '3482', (194, 203))	('gastric cancers', 'Disease', 'MESH:D013274', (90, 105))	('gastric cancers', 'Disease', (90, 105))	('gastric cancers', 'Phenotype', 'HP:0012126', (90, 105))	('IGF2', 'Gene', (210, 214))	('IGF2R', 'Gene', '3482', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('IGF2', 'Gene', '3481', (198, 202))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('esophageal', 'Disease', (76, 86))	('IGF2', 'Gene', (42, 46))	('IGF2R', 'Gene', (42, 47))	('M6P/IGF2R', 'Gene', (194, 203))	('IGF2', 'Gene', '3481', (210, 214))	('esophageal', 'Disease', 'MESH:D004941', (76, 86))	('IGF2R', 'Gene', '3482', (42, 47))	('IGF2', 'Gene', (198, 202))	('IGF2R', 'Gene', (198, 203))	('IGF2', 'Gene', '3481', (42, 46))	('c.5002 A-allele', 'Var', (48, 63))
165816	19626700	Based on this location, carrying this variant was expected to alter IGF2 binding affinity, thereby increasing the bioavailability of IGF2.	('increasing', 'PosReg', (99, 109))	('IGF2', 'Gene', '3481', (68, 72))	('IGF2', 'Gene', '3481', (133, 137))	('binding', 'Interaction', (73, 80))	('IGF2', 'Gene', (68, 72))	('IGF2', 'Gene', (133, 137))	('bioavailability', 'MPA', (114, 129))	('alter', 'Reg', (62, 67))	('variant', 'Var', (38, 45))
165817	19626700	Individuals carrying the c.5002 A-variant have been reported to be at higher risk for lung cancer while no association was found in a recent study of osteosarcoma.	('osteosarcoma', 'Disease', (150, 162))	('osteosarcoma', 'Phenotype', 'HP:0002669', (150, 162))	('osteosarcoma', 'Disease', 'MESH:D012516', (150, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('c.5002 A-variant', 'Var', (25, 41))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
165819	19626700	However, a recent study suggests that the c.5002 A-allele does not significantly alter binding of IGF2 relative to the c.5002 G-allele nor does it alter protein trafficking or stability, although effects on IGF2R dimerization or the stability and binding of IGF2 to the soluble form of the IGF2R were not evaluted.	('IGF2R', 'Gene', '3482', (207, 212))	('IGF2', 'Gene', '3481', (258, 262))	('c.5002', 'Var', (42, 48))	('IGF2', 'Gene', (258, 262))	('IGF2R', 'Gene', '3482', (290, 295))	('IGF2', 'Gene', '3481', (290, 294))	('IGF2', 'Gene', (207, 211))	('protein trafficking', 'MPA', (153, 172))	('stability', 'MPA', (176, 185))	('IGF2', 'Gene', '3481', (207, 211))	('IGF2', 'Gene', '3481', (98, 102))	('IGF2R', 'Gene', (207, 212))	('alter', 'Reg', (147, 152))	('IGF2', 'Gene', (290, 294))	('IGF2R', 'Gene', (290, 295))	('IGF2', 'Gene', (98, 102))	('c.5002', 'Var', (119, 125))	('dimerization', 'MPA', (213, 225))
165820	19626700	The etiologic significance of finding an association between c.901 and esophageal and gastric cancer is presently unclear.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('c.901', 'Var', (61, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('esophageal', 'Disease', 'MESH:D004941', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (86, 100))	('esophageal', 'Disease', (71, 81))
165821	19626700	The amino acid variant c.901Leu252Val is a conservative substitution with respect to hydrophobicity, but may lead to protein destabilization due to replacement of the isobutyl group with an isopropyl side chain.	('men', 'Species', '9606', (155, 158))	('lead to', 'Reg', (109, 116))	('c.901Leu252Val', 'Var', (23, 37))	('destabilization', 'NegReg', (125, 140))	('protein', 'MPA', (117, 124))	('Leu252Val', 'Chemical', '-', (28, 37))
165825	19626700	It is possible that this role may be impeded by the c.901 variant allele presumably enhancing cancer risk.	('c.901 variant', 'Var', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('enhancing', 'PosReg', (84, 93))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
165827	19626700	Indeed recent data from a cohort study suggest that esophageal and non-cardia adenocarcinoma risk may be determined, in part, in utero and birth weight has been positively associated with carrying the c.901 variant in at least one allele.	('esophageal', 'Disease', 'MESH:D004941', (52, 62))	('non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (67, 92))	('c.901', 'Var', (201, 206))	('esophageal', 'Disease', (52, 62))	('non-cardia adenocarcinoma', 'Disease', (67, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
165829	19626700	A limitation of this study was the small sample sizes and low p-value for the HWE test that may have contributed to our inability to detect associations between the c.5002 variant and the subtypes of esophageal and gastric cancers.	('gastric cancers', 'Phenotype', 'HP:0012126', (215, 230))	('c.5002', 'Var', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('gastric cancer', 'Phenotype', 'HP:0012126', (215, 229))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (200, 230))	('associations', 'Interaction', (140, 152))
165833	19626700	In summary, we found evidence of an association between esophageal, gastric cardia and non-cardia gastric adenocarcinomas and carrying the IGF2R c.901 G allele, particularly among white men reporting cigarette smoking and none or irregular use of NSAIDS.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('esophageal', 'Disease', 'MESH:D004941', (56, 66))	('IGF2R', 'Gene', (139, 144))	('esophageal', 'Disease', (56, 66))	('men', 'Species', '9606', (186, 189))	('gastric cardia', 'Disease', (68, 82))	('c.901 G', 'Var', (145, 152))	('non-cardia gastric adenocarcinomas', 'Disease', 'MESH:D004938', (87, 121))	('gastric cardia', 'Disease', 'MESH:D004938', (68, 82))	('non-cardia gastric adenocarcinomas', 'Disease', (87, 121))	('IGF2R', 'Gene', '3482', (139, 144))
165834	19626700	No association was found between these tumors and the IGF2R c.5002 genotype.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('IGF2R', 'Gene', '3482', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('IGF2R', 'Gene', (54, 59))	('c.5002', 'Var', (60, 66))	('tumors', 'Disease', (39, 45))
165839	33472175	TPE-IQ-2O PDT can not only reduce tumor recurrence in surgical treatment but also effectively improve the response to ICIs in immunotherapy without obvious toxicity.	('tumor', 'Disease', (34, 39))	('reduce', 'NegReg', (27, 33))	('improve', 'PosReg', (94, 101))	('response', 'MPA', (106, 114))	('toxicity', 'Disease', 'MESH:D064420', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('toxicity', 'Disease', (156, 164))	('TPE-IQ-2O', 'Chemical', '-', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('TPE-IQ-2O PDT', 'Var', (0, 13))
165841	33472175	Thus, TPE-IQ-2O PDT is a safe and effective antitumor therapy that can be combined with surgery or immunotherapy.	('TPE-IQ-2O PDT', 'Var', (6, 19))	('TPE-IQ-2O', 'Chemical', '-', (6, 15))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
165845	33472175	ROS can induce cancer cell death directly or indirectly by causing damage to the tumor vasculature.	('ROS', 'Var', (0, 3))	('causing', 'Reg', (59, 66))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('induce', 'Reg', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', (81, 86))
165862	33472175	Gui C and Tang BZ et al reported that TPE-IQ-2O served as an ideal PS and could specifically target the mitochondria of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('TPE-IQ-2O', 'Var', (38, 47))	('mitochondria', 'MPA', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('target', 'Reg', (93, 99))	('TPE-IQ-2O', 'Chemical', '-', (38, 47))	('tumor', 'Disease', (120, 125))
165864	33472175	This investigation utilized various tumor cell lines and a tumor-bearing animal model to assess the biological safety and efficacy of TPE-IQ-2O PDT as well as the value of TPE-IQ-2O-related combination therapy.	('tumor', 'Disease', (59, 64))	('TPE-IQ-2O', 'Chemical', '-', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('TPE-IQ-2O', 'Var', (134, 143))	('TPE-IQ-2O', 'Chemical', '-', (134, 143))	('tumor', 'Disease', (36, 41))
165869	33472175	Next, to determine whether TPE-IQ-2O specifically targets tumor cells, multiple tumor and normal cell lines were treated with gradient concentrations of TPE-IQ-2O (100/200/400/800 nM).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TPE-IQ-2O', 'Chemical', '-', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('TPE-IQ-2O', 'Chemical', '-', (153, 162))	('tumor', 'Disease', (80, 85))	('100/200/400/800 nM', 'Var', (164, 182))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
165883	33472175	CCK-8 data demonstrated that TPE-IQ-2O with light exposure (5 W, 85 mW/cm2) could inhibit LLC and A549 cell proliferation in vitro in a dose-dependent manner.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('inhibit', 'NegReg', (82, 89))	('TPE-IQ-2O', 'Var', (29, 38))	('TPE-IQ-2O', 'Chemical', '-', (29, 38))	('CCK-8', 'Chemical', '-', (0, 5))
165886	33472175	As expected, cleaved caspase-3 and Bax/Bcl-2 expression was significantly higher in the TPE-IQ-2O PDT group than in the control group for the LLC and A549 cell lines.	('A549', 'CellLine', 'CVCL:0023', (150, 154))	('higher', 'PosReg', (74, 80))	('caspase-3', 'Gene', '12367', (21, 30))	('Bax', 'Gene', '12028', (35, 38))	('TPE-IQ-2O', 'Var', (88, 97))	('TPE-IQ-2O', 'Chemical', '-', (88, 97))	('Bcl-2', 'Gene', '12043', (39, 44))	('expression', 'MPA', (45, 55))	('cleaved', 'MPA', (13, 20))	('Bcl-2', 'Gene', (39, 44))	('Bax', 'Gene', (35, 38))	('caspase-3', 'Gene', (21, 30))
165888	33472175	The results show that TPE-IQ-2O PDT can inhibit the viability of tumor cells and induce tumor cell apoptosis.	('induce', 'PosReg', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('inhibit', 'NegReg', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('TPE-IQ-2O PDT', 'Var', (22, 35))	('TPE-IQ-2O', 'Chemical', '-', (22, 31))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
165890	33472175	TPE-IQ-2O PDT exhibited a stronger antitumor effect at six hours after treatment than light or TPE-IQ-2O monotherapy (Figure 3A, Supplementary Figure 5A).	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('stronger', 'PosReg', (26, 34))	('PDT', 'Var', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('TPE-IQ-2O', 'Chemical', '-', (0, 9))	('TPE-IQ-2O', 'Chemical', '-', (95, 104))	('TPE-IQ-2O PDT', 'Var', (0, 13))
165896	33472175	In addition, the tumor activity in the TPE-IQ-2O PDT group was lower than that in the 5-ALA PDT group (Figure 3B, Supplementary Figure 5B).	('tumor', 'Disease', (17, 22))	('lower', 'NegReg', (63, 68))	('5-ALA', 'Chemical', 'MESH:C000614854', (86, 91))	('TPE-IQ-2O', 'Var', (39, 48))	('TPE-IQ-2O', 'Chemical', '-', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
165898	33472175	There were two cases of pulmonary metastasis in the 5-ALA PDT group, but no distant metastases were found in the control group or TPE-IQ-2O PDT group (Figure 3C).	('pulmonary metastasis', 'Disease', (24, 44))	('metastases', 'Disease', (84, 94))	('5-ALA PDT', 'Var', (52, 61))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('5-ALA', 'Chemical', 'MESH:C000614854', (52, 57))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (24, 44))	('TPE-IQ-2O', 'Chemical', '-', (130, 139))
165901	33472175	This result nicely corroborates the conclusion that the TPE-IQ-2O PDT was capable of targeting tumor cells without obvious damage on normal cells.	('TPE-IQ-2O', 'Var', (56, 65))	('TPE-IQ-2O', 'Chemical', '-', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
165919	33472175	As expected, blood vessels in the tumor mass were destroyed after TPE-IQ-2O PDT.	('TPE-IQ-2O', 'Chemical', '-', (66, 75))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('TPE-IQ-2O PDT', 'Var', (66, 79))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('destroyed', 'NegReg', (50, 59))
165921	33472175	In addition, an orthotopic implantation tumor model and subcutaneous xenograft model were established with KYSE-30 cells to evaluate whether local TPE-IQ-2O PDT had any effect (abscopal effect) on distant tumors (Figure 5A).	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('TPE-IQ-2O', 'Var', (147, 156))	('TPE-IQ-2O', 'Chemical', '-', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumors', 'Disease', (205, 211))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
165925	33472175	However, the rate of tumorigenesis in EV/SN + surgery + PDT group (4/10) was significantly lower than that in the EV/SN + surgery group (10/10) (P<0.01) (Figure 5C, 5D).	('lower', 'NegReg', (91, 96))	('tumor', 'Disease', (21, 26))	('SN', 'Chemical', 'MESH:D014001', (117, 119))	('SN', 'Chemical', 'MESH:D014001', (41, 43))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('EV/SN + surgery +', 'Var', (38, 55))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
165932	33472175	In addition, TPE-IQ-2O PDT + BMS202 had a significantly stronger effect than PDT treatment alone (P<0.001).	('BMS202', 'Chemical', '-', (29, 35))	('stronger', 'PosReg', (56, 64))	('TPE-IQ-2O', 'Chemical', '-', (13, 22))	('PDT + BMS202', 'Var', (23, 35))
165934	33472175	In the MC38 tumor-bearing C57/B6 mouse model, we found that the TPE-IQ-2O PDT group and the TPE-IQ-2O PDT + BMS202 group exhibited obvious antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('TPE-IQ-2O', 'Chemical', '-', (64, 73))	('tumor', 'Disease', (143, 148))	('BMS202', 'Chemical', '-', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('TPE-IQ-2O', 'Chemical', '-', (92, 101))	('mouse', 'Species', '10090', (33, 38))	('TPE-IQ-2O', 'Var', (64, 73))	('tumor', 'Disease', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
165936	33472175	However, the BMS202 group quickly recovered and showed a rapid rate of increase on the 10th day and the difference was significant compared with the two remaining groups (Figure 6C, 6E, P<0.001).	('BMS202', 'Chemical', '-', (13, 19))	('increase', 'PosReg', (71, 79))	('BMS202', 'Var', (13, 19))
165937	33472175	Tumor-infiltrating lymphocytes (TILs), especially CD8+ subpopulations, are known to be significantly associated with the outcome of immunotherapy in cancers.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('CD8+', 'Var', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('associated with', 'Reg', (101, 116))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
165940	33472175	In the LLC subcutaneous tumor model, the proportions of CD8+ TILs in the control group, the PDT group, the BMS202 group and the combined treatment group were 0.960+-0.221%, 8.523+-1.963%, 3.044+-0.701% and 9.146+-2.106%, respectively, and the proportions of CD4+ infiltrating lymphocytes in four groups were 2.063+-0.631%, 4.631+-1.216%, 2.589+-0.75%, and 6.100+-1.554%, respectively.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('CD8+', 'Var', (56, 60))	('tumor', 'Disease', (24, 29))	('CD4', 'Gene', (258, 261))	('CD4', 'Gene', '12504', (258, 261))	('BMS202', 'Chemical', '-', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (11, 29))
165942	33472175	In the MC38 subcutaneous tumor model, the proportions of CD8+ TILs in the control group, the PDT group, the BMS202 group and the combined treatment group were 12.207+-2.812%, 10.287+-2.369%, 10.535+-2.426% and 15.712+-3.619%, respectively, and the proportions of CD4+ TILs were 13.275+-3.209%, 14.929+-3.591%, 12.066+-2.930% and 12.971+-3.139%, respectively.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (12, 30))	('tumor', 'Disease', (25, 30))	('10.287+-2.369%', 'Var', (175, 189))	('CD8+', 'Var', (57, 61))	('CD4', 'Gene', (263, 266))	('BMS202', 'Chemical', '-', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('CD4', 'Gene', '12504', (263, 266))
165944	33472175	The proportions of CD8+ TILs in the control group, the PDT group, the BMS202 group and the combined treatment group were 3.315+-0.718%, 8.489+-1.955%, 4.904+-1.129% and 15.240+-3.51%, respectively, and the proportions of CD4+ infiltrating lymphocytes were 2.729+-0.782%, 6.333+-1.608%, 12.799+-3.099% and 13.516+-3.265%, respectively.	('CD4', 'Gene', '12504', (221, 224))	('CD4', 'Gene', (221, 224))	('BMS202', 'Chemical', '-', (70, 76))	('CD8+', 'Var', (19, 23))
165948	33472175	In the LLC subcutaneous tumor model, the percentage of CD45+, CD8+CD45+ lymphocytes in the TPE-IQ-2O PDT group and the ratio of CD8+/CD45+ lymphocytes in the combined group were significantly increased (Figure 8A, P<0.001).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('CD4', 'Gene', '12504', (133, 136))	('TPE-IQ-2O', 'Chemical', '-', (91, 100))	('CD4', 'Gene', (66, 69))	('CD4', 'Gene', (55, 58))	('tumor', 'Disease', (24, 29))	('CD4', 'Gene', '12504', (66, 69))	('CD4', 'Gene', '12504', (55, 58))	('TPE-IQ-2O', 'Var', (91, 100))	('CD4', 'Gene', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (11, 29))	('increased', 'PosReg', (192, 201))
165953	33472175	TPE-IQ-2O PDT not only inhibits tumor growth directly via local therapeutic effects but also stimulates systemic antitumor immunity, which further decreases postoperative recurrence and improves the response of PD-L1 ICIs.	('improves', 'PosReg', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PD-L1 ICIs', 'Disease', 'MESH:D010300', (211, 221))	('postoperative recurrence', 'CPA', (157, 181))	('decreases', 'NegReg', (147, 156))	('tumor', 'Disease', (117, 122))	('PD-L1 ICIs', 'Disease', (211, 221))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('response', 'MPA', (199, 207))	('TPE-IQ-2O', 'Chemical', '-', (0, 9))	('tumor', 'Disease', (32, 37))	('inhibits', 'NegReg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('stimulates', 'PosReg', (93, 103))	('TPE-IQ-2O PDT', 'Var', (0, 13))
165955	33472175	In addition to its function as a PS, TPE-IQ-2O can also serve as a tumor-targeting fluorescent probe.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TPE-IQ-2O', 'Var', (37, 46))	('TPE-IQ-2O', 'Chemical', '-', (37, 46))	('tumor', 'Disease', (67, 72))
165964	33472175	However, the antitumor effect of TPE-IQ-2O PDT on mouse models, especially immunodeficient nude mice, was weaker than that found in vitro and in a highly transparent zebrafish model.	('immunodeficient', 'Disease', 'MESH:D007153', (75, 90))	('immunodeficient', 'Disease', (75, 90))	('tumor', 'Disease', (17, 22))	('weaker', 'NegReg', (106, 112))	('nude mice', 'Species', '10090', (91, 100))	('zebrafish', 'Species', '7955', (166, 175))	('TPE-IQ-2O PDT', 'Var', (33, 46))	('TPE-IQ-2O', 'Chemical', '-', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('mouse', 'Species', '10090', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
165972	33472175	TUNEL assays suggested that TPE-IQ-2O PDT could inhibit superficial tumor strongly but not so effective in central tumor cells (Supplementary Figure 8).	('tumor', 'Disease', (68, 73))	('TPE-IQ-2O', 'Chemical', '-', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TPE-IQ-2O PDT', 'Var', (28, 41))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('inhibit', 'NegReg', (48, 55))
165977	33472175	This finding prompted us to conclude that the therapeutic effect of TPE-IQ-2O PDT was related to the tumor burden.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('TPE-IQ-2O', 'Var', (68, 77))	('TPE-IQ-2O', 'Chemical', '-', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
165978	33472175	However, a particularly encouraging finding was that no tumor recurrence was observed in the TPE-IQ-2O PDT combined with surgery group in the KYSE-30 and LLC-Luc cell nude mouse models.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TPE-IQ-2O', 'Var', (93, 102))	('TPE-IQ-2O', 'Chemical', '-', (93, 102))	('mouse', 'Species', '10090', (172, 177))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
165979	33472175	These results indicate that adjuvant TPE-IQ-2O PDT after surgery can effectively reduce tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('reduce', 'NegReg', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('TPE-IQ-2O', 'Var', (37, 46))	('TPE-IQ-2O', 'Chemical', '-', (37, 46))	('tumor', 'Disease', (88, 93))
165985	33472175	We speculate that even in the absence of T cells, TPE-IQ-2O PDT may still inhibit tumors through innate immunity.	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('TPE-IQ-2O PDT', 'Var', (50, 63))	('TPE-IQ-2O', 'Chemical', '-', (50, 59))	('inhibit', 'NegReg', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
165989	33472175	We observed significantly elevated CD8+ T cell accumulation after TPE-IQ-2O PDT treatment alone, suggesting that this treatment can stimulate adaptive immunity.	('CD8+ T cell accumulation', 'MPA', (35, 59))	('TPE-IQ-2O', 'Var', (66, 75))	('TPE-IQ-2O', 'Chemical', '-', (66, 75))	('adaptive immunity', 'CPA', (142, 159))	('elevated', 'PosReg', (26, 34))	('stimulate', 'PosReg', (132, 141))
165990	33472175	Additionally, we found that TPE-IQ-2O PDT was more effective in a xenograft model established with normal mice than one established with severely immunodeficient mice.	('TPE-IQ-2O', 'Chemical', '-', (28, 37))	('xenograft model', 'CPA', (66, 81))	('mice', 'Species', '10090', (106, 110))	('TPE-IQ-2O PDT', 'Var', (28, 41))	('mice', 'Species', '10090', (162, 166))	('immunodeficient', 'Disease', (146, 161))	('immunodeficient', 'Disease', 'MESH:D007153', (146, 161))
166001	33472175	In the above two models, our tumor volume data indicate that TPE-IQ-2O PDT combined with BMS202 could be more effective than BMS202 alone.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BMS202', 'Chemical', '-', (89, 95))	('TPE-IQ-2O', 'Var', (61, 70))	('BMS202', 'Chemical', '-', (125, 131))	('tumor', 'Disease', (29, 34))	('TPE-IQ-2O', 'Chemical', '-', (61, 70))
166004	33472175	These results suggest that TPE-IQ-2O PDT could further activate CD8+ T lymphocytes, enhance cellular immunity, and inhibit tumor cell proliferation via synergistic effects produced in combination with BMS202.	('BMS202', 'Chemical', '-', (201, 207))	('TPE-IQ-2O PDT', 'Var', (27, 40))	('TPE-IQ-2O', 'Chemical', '-', (27, 36))	('tumor', 'Disease', (123, 128))	('inhibit', 'NegReg', (115, 122))	('CD8+ T lymphocytes', 'CPA', (64, 82))	('enhance cellular immunity', 'Phenotype', 'HP:0002843', (84, 109))	('cellular immunity', 'CPA', (92, 109))	('activate', 'PosReg', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('enhance', 'PosReg', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
166008	33472175	We have clarified the general principle that TPE-IQ-2O PDT can enhance the efficacy of PD-L1 ICI therapy.	('enhance', 'PosReg', (63, 70))	('TPE-IQ-2O PDT', 'Var', (45, 58))	('TPE-IQ-2O', 'Chemical', '-', (45, 54))
166009	33472175	Another main common denominator of the two models was that the ratio of CD8+/CD4+ T cells was inverted after TPE-IQ-2O PDT compared with BMS202 alone.	('TPE-IQ-2O', 'Chemical', '-', (109, 118))	('BMS202', 'Chemical', '-', (137, 143))	('CD4', 'Gene', (77, 80))	('TPE-IQ-2O PDT', 'Var', (109, 122))	('CD4', 'Gene', '12504', (77, 80))
166011	33472175	In the MC38 C57 subcutaneous tumor model, although TPE-IQ-2O PDT could increase the infiltration of CD8+ T lymphocytes, the change was not as obvious as that in the LLC C57 subcutaneous tumor model.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('infiltration of', 'CPA', (84, 99))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('TPE-IQ-2O PDT', 'Var', (51, 64))	('TPE-IQ-2O', 'Chemical', '-', (51, 60))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (16, 34))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (173, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (29, 34))	('increase', 'PosReg', (71, 79))
166013	33472175	This suggests that the mechanisms by which TPE-IQ-2O PDT enhances the response rate in the two models may be different in some points.	('response', 'MPA', (70, 78))	('TPE-IQ-2O PDT', 'Var', (43, 56))	('TPE-IQ-2O', 'Chemical', '-', (43, 52))	('enhances', 'PosReg', (57, 65))
166018	33472175	More importantly, TPE-IQ-2O PDT combined with ICIs can overcome the low response rate of ICIs, promote tumor CD8+ T cell infiltration and improve prognosis.	('prognosis', 'CPA', (146, 155))	('TPE-IQ-2O PDT', 'Var', (18, 31))	('TPE-IQ-2O', 'Chemical', '-', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('promote', 'PosReg', (95, 102))	('tumor', 'Disease', (103, 108))	('improve', 'PosReg', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
166019	33472175	Therefore, the combination of TPE-IQ-2O PDT with ICI therapy or surgery described in our research provides a promising strategy for cancer therapy.	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('TPE-IQ-2O PDT', 'Var', (30, 43))	('TPE-IQ-2O', 'Chemical', '-', (30, 39))
166108	31891614	Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16x10-7 and rs1540, Pcombined = 4.16x10-6) which represent eQTLs for CFDP1 and SLC22A3, respectively.	('CFDP1', 'Gene', (169, 174))	('SLC22A3', 'Gene', (179, 186))	('SLC22A3', 'Gene', '6581', (179, 186))	('rs1540', 'Var', (112, 118))	('rs1540', 'DBSNP_MENTION', 'None', (112, 118))	('rs7754014', 'Var', (75, 84))	('rs7754014', 'DBSNP_MENTION', 'None', (75, 84))	('CFDP1', 'Gene', '10428', (169, 174))
166119	31891614	Since many non-coding GWAS risk variants exert their effects via gene regulatory mechanisms, expression quantitative trait loci (eQTL) analyses make an important contribution to the elucidation of multifactorial disease etiology.	('GWAS', 'Gene', (22, 26))	('multifactorial disease', 'Disease', (197, 219))	('multifactorial disease', 'Disease', 'MESH:D004194', (197, 219))	('effects', 'Reg', (53, 60))	('variants', 'Var', (32, 40))
166123	31891614	The esophageal mucosa sample comprised tissues of 241 individuals with 6,169 cis-eQTLs (eQTL-gene located < 1 Mb distance from genetic variant) and the gastroesophageal junction sample comprised tissues of 127 individuals with 2,237 cis-eQTLs.	('gastroesophageal junction', 'Disease', (152, 177))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (152, 177))	('cis-eQTLs', 'Var', (77, 86))
166132	31891614	Of the 16 index SNPs representing the novel candidate loci, three variants (rs59341339, rs11145842, rs12985299) were excluded from the plex for technical reasons.	('rs59341339', 'DBSNP_MENTION', 'None', (76, 86))	('rs11145842', 'Var', (88, 98))	('rs11145842', 'DBSNP_MENTION', 'None', (88, 98))	('rs12985299', 'Var', (100, 110))	('rs59341339', 'Var', (76, 86))	('rs12985299', 'DBSNP_MENTION', 'None', (100, 110))
166133	31891614	The index SNPs of three further loci, which were excluded due to the same technical reasons, were replaced by variants in high LD [r2 > 0.95; rs2442722 (P = 1.22x10-6) was replaced by rs36057735 (P = 5.13x10-6), rs76510925 (P = 7.86x10-6) by rs12112778 (P = 1.57x10-5), and rs11169302 (P = 1.05x10-5) by rs9364 (P = 2.23x10-5)].	('rs9364', 'Var', (304, 310))	('rs36057735', 'Var', (184, 194))	('rs76510925', 'Var', (212, 222))	('rs12112778', 'DBSNP_MENTION', 'None', (242, 252))	('rs9364', 'DBSNP_MENTION', 'None', (304, 310))	('rs2442722', 'DBSNP_MENTION', 'None', (142, 151))	('rs11169302', 'DBSNP_MENTION', 'None', (274, 284))	('rs76510925', 'DBSNP_MENTION', 'None', (212, 222))	('rs11169302', 'Var', (274, 284))	('rs36057735', 'DBSNP_MENTION', 'None', (184, 194))	('rs12112778', 'Var', (242, 252))	('rs2442722', 'Var', (142, 151))
166139	31891614	Upon statistical analysis, the variant rs1540 on 16q23 showed a nominally significant association to BE/EA in the independent replication study (Preplication = 0.019).	('significant association', 'Reg', (74, 97))	('BE', 'Phenotype', 'HP:0100580', (101, 103))	('EA', 'Phenotype', 'HP:0011459', (104, 106))	('rs1540', 'Var', (39, 45))	('rs1540', 'DBSNP_MENTION', 'None', (39, 45))	('BE', 'Disease', 'MESH:D001471', (101, 103))	('16q23', 'Gene', (49, 54))
166142	31891614	Similarly, rs7754014 on 6q25 showed a nominally significant association to BE/EA in the replication study (Preplication = 0.028) and a lower P-value in the combined analysis (Pmeta-analysis = 2.07x10-6, Pcombined = 3.16x10-7).	('rs7754014', 'Var', (11, 20))	('rs7754014', 'DBSNP_MENTION', 'None', (11, 20))	('BE', 'Phenotype', 'HP:0100580', (75, 77))	('significant association', 'Reg', (48, 71))	('BE', 'Disease', 'MESH:D001471', (75, 77))	('EA', 'Phenotype', 'HP:0011459', (78, 80))
166146	31891614	The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk variants among the suggestively associated variants through the integration of eQTL- and genetic association data.	('variants', 'Var', (188, 196))	('variants', 'Var', (145, 153))	('BE', 'Phenotype', 'HP:0100580', (92, 94))	('BE', 'Disease', 'MESH:D001471', (92, 94))	('EA', 'Phenotype', 'HP:0011459', (95, 97))
166148	31891614	The replication study yielded two nominally significant BE/EA-associated variants: rs1540 and rs7754014.	('rs1540', 'DBSNP_MENTION', 'None', (83, 89))	('rs7754014', 'DBSNP_MENTION', 'None', (94, 103))	('rs1540', 'Var', (83, 89))	('rs7754014', 'Var', (94, 103))	('BE', 'Disease', 'MESH:D001471', (56, 58))	('EA', 'Phenotype', 'HP:0011459', (59, 61))	('BE', 'Phenotype', 'HP:0100580', (56, 58))
166149	31891614	Variant rs1540 on 16q23 regulates the expression of the gene CFDP1 (craniofacial development protein 1) in the gastroesophageal junction.	('craniofacial development protein 1', 'Gene', (68, 102))	('CFDP1', 'Gene', '10428', (61, 66))	('expression', 'MPA', (38, 48))	('rs1540', 'DBSNP_MENTION', 'None', (8, 14))	('CFDP1', 'Gene', (61, 66))	('gastroesophageal junction', 'Disease', (111, 136))	('rs1540', 'Var', (8, 14))	('craniofacial development protein 1', 'Gene', '10428', (68, 102))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (111, 136))	('regulates', 'Reg', (24, 33))
166151	31891614	Variant rs7754014 on 6q25 represents an eQTL for the gene SLC22A3 (solute carrier family 22 member 3) in the esophageal mucosa.	('solute carrier family 22 member 3', 'Gene', (67, 100))	('SLC22A3', 'Gene', (58, 65))	('rs7754014', 'DBSNP_MENTION', 'None', (8, 17))	('rs7754014', 'Var', (8, 17))	('SLC22A3', 'Gene', '6581', (58, 65))	('solute carrier family 22 member 3', 'Gene', '6581', (67, 100))
166159	31891614	The most significantly associated risk variant from the BE/EA GWAS meta-analysis was rs7255 on 2p24.	('rs7255', 'Var', (85, 91))	('2p24', 'Gene', (95, 99))	('rs7255', 'DBSNP_MENTION', 'None', (85, 91))	('BE', 'Disease', 'MESH:D001471', (56, 58))	('EA', 'Phenotype', 'HP:0011459', (59, 61))	('BE', 'Phenotype', 'HP:0100580', (56, 58))
166162	31891614	The BE/EA risk variant rs92578209 on 6p22 regulates the expression of the gene ZFP57 (zinc finger protein 57) in both the esophageal mucosa and the gastroesophageal junction.	('zinc finger protein 57', 'Gene', (86, 108))	('EA', 'Phenotype', 'HP:0011459', (7, 9))	('BE', 'Disease', 'MESH:D001471', (4, 6))	('ZFP57', 'Gene', (79, 84))	('gastroesophageal junction', 'Disease', (148, 173))	('rs92578209', 'DBSNP_MENTION', 'None', (23, 33))	('expression', 'MPA', (56, 66))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (148, 173))	('zinc finger protein 57', 'Gene', '126295', (86, 108))	('rs92578209', 'Var', (23, 33))	('regulates', 'Reg', (42, 51))	('BE', 'Phenotype', 'HP:0100580', (4, 6))
166164	31891614	The third BE/EA risk variant from the GWAS meta-analysis was rs147462972 on 5p15, which represents an eQTL for the expression of SLC9A3 (solute carrier family 9 member A3) in the esophageal mucosa.	('EA', 'Phenotype', 'HP:0011459', (13, 15))	('BE', 'Disease', 'MESH:D001471', (10, 12))	('rs147462972', 'DBSNP_MENTION', 'None', (61, 72))	('SLC9A3', 'Gene', '6550', (129, 135))	('solute carrier family 9 member A3', 'Gene', (137, 170))	('SLC9A3', 'Gene', (129, 135))	('rs147462972', 'Var', (61, 72))	('solute carrier family 9 member A3', 'Gene', '6550', (137, 170))	('BE', 'Phenotype', 'HP:0100580', (10, 12))
166165	31891614	The BE/EA risk allele of this variant results in a structural change in the binding sites of the transcription factors CTCF and RAD21.	('CTCF', 'Gene', '10664', (119, 123))	('RAD21', 'Gene', (128, 133))	('RAD21', 'Gene', '5885', (128, 133))	('structural', 'MPA', (51, 61))	('change', 'Reg', (62, 68))	('EA', 'Phenotype', 'HP:0011459', (7, 9))	('BE', 'Disease', 'MESH:D001471', (4, 6))	('variant', 'Var', (30, 37))	('binding', 'Interaction', (76, 83))	('CTCF', 'Gene', (119, 123))	('BE', 'Phenotype', 'HP:0100580', (4, 6))
166180	31891614	Follow-up analyses are warranted to refine the regulatory annotation and to elucidate the mechanisms through which the implicated variants and genes influence BE/EA development.	('influence', 'Reg', (149, 158))	('variants', 'Var', (130, 138))	('BE', 'Phenotype', 'HP:0100580', (159, 161))	('BE', 'Disease', 'MESH:D001471', (159, 161))	('EA', 'Phenotype', 'HP:0011459', (162, 164))
166194	30767773	Depending on a variety of factors, the obstruction to the passage of food, through the expanding and stricturing tumor area, results in clinically overt symptoms first at a relatively advanced local stage of the disease.	('tumor', 'Disease', (113, 118))	('obstruction', 'Var', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('results in', 'Reg', (125, 135))
166286	24676302	have shown that patients with NERD presented endoscopic signs of esophagitis with minimal abnormalities proven by histological alterations significantly more frequently in comparison with the control group (sensitivity 62% and specificity 74%).	('esophagitis', 'Phenotype', 'HP:0100633', (65, 76))	('NERD', 'Var', (30, 34))	('esophagitis', 'Disease', (65, 76))	('patients', 'Species', '9606', (16, 24))	('esophagitis', 'Disease', 'MESH:D004941', (65, 76))
166291	24676302	The sensitivity and specificity of the abnormalities of the intrapapillary capillary loops, such as increase in number, dilatation, tortuosity and microerosions to identify patients with GERD was 94% and 63%, respectively.	('patients', 'Species', '9606', (173, 181))	('GERD', 'Disease', 'MESH:D005764', (187, 191))	('dilatation', 'Phenotype', 'HP:0002617', (120, 130))	('abnormalities', 'Var', (39, 52))	('GERD', 'Disease', (187, 191))	('number', 'MPA', (112, 118))	('dilatation', 'MPA', (120, 130))	('tortuosity', 'CPA', (132, 142))	('increase', 'PosReg', (100, 108))	('microerosions', 'Disease', (147, 160))
166316	24676302	The sensitivity, specificity and positive predictive value of the irregular/distorted pattern for high grade dysplasia were 100%, 98.7, and 95.3, respectively.	('dysplasia', 'Disease', (109, 118))	('irregular/distorted', 'Var', (66, 85))	('dysplasia', 'Disease', 'MESH:D004476', (109, 118))
166402	33742771	To further validate these results, we analyzed the expression profile of GPR12 in the TCGA data sets of EC (Figure 2(a)), head and neck cancer (HNC) (Figure 2(b)), laryngeal cancer (LC) (Figure 2(c)), oral cancer (OC) (Figure 2(d)), and tongue cancer (TC) (Figure 2(e)), and in the GEO data sets of GSE 30784 (Figure 2(f)) and GSE84957 (Figure 2(g)).	('GPR12', 'Gene', (73, 78))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (164, 180))	('GSE', 'Chemical', '-', (327, 330))	('cancer', 'Disease', (174, 180))	('GSE84957', 'Var', (327, 335))	('cancer', 'Disease', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('head and neck cancer', 'Phenotype', 'HP:0012288', (122, 142))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('neck cancer', 'Disease', 'MESH:D006258', (131, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('neck cancer', 'Disease', (131, 142))	('cancer', 'Disease', (244, 250))	('GSE', 'Chemical', '-', (299, 302))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('GPR12', 'Gene', '2835', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
166476	32373377	There was a somatic mutation in PIK3CA, E542K, making her eligible for Taselisib on the MATCH trial.	('PIK3CA', 'Gene', '5290', (32, 38))	('E542K', 'Var', (40, 45))	('Taselisib', 'Chemical', 'MESH:C582924', (71, 80))	('E542K', 'Mutation', 'rs121913273', (40, 45))	('PIK3CA', 'Gene', (32, 38))
166507	31783812	In addition, high CAR was also related to worse CSS in EC (pooled HR = 2.61; 95% CI = 1.67-4.06; P < 0.001).	('EC', 'Disease', 'MESH:D004938', (55, 57))	('CSS', 'MPA', (48, 51))	('high CAR', 'Var', (13, 21))
166542	31783812	Sensitivity analysis showed that deletion of any study did not change the negative association between CAR and OS in EC (Fig.	('deletion', 'Var', (33, 41))	('CAR', 'Disease', (103, 106))	('EC', 'Disease', 'MESH:D004938', (117, 119))
166545	31783812	The pooled analysis showed that high CAR was related to worse CSS in EC (pooled HR = 2.61; 95% CI = 1.67-4.06; P < 0.001) (Table 2; Fig.	('high CAR', 'Var', (32, 40))	('EC', 'Disease', 'MESH:D004938', (69, 71))	('CSS', 'Disease', (62, 65))
166553	31783812	Because patients with high CAR usually have severe tumor-related inflammatory reaction or poor nutritional status, these patients may benefit from anti-inflammatory therapy or nutritional support.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('high CAR', 'Var', (22, 30))	('patients', 'Species', '9606', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('patients', 'Species', '9606', (8, 16))
166560	31783812	In addition, this meta-analysis showed that high CAR was also related to worse CSS for EC patients.	('high CAR', 'Var', (44, 52))	('patients', 'Species', '9606', (90, 98))	('EC', 'Disease', 'MESH:D004938', (87, 89))	('CSS', 'Disease', (79, 82))
166624	29956810	The patients were principally divided into 3 groups on the basis of BMI: Underweight (<18.5 kg/m2), normal (>=18.5 to <25.0 kg/m2) and high (>=25.0 kg/m2).	('>=18.5 to <25.0', 'Var', (108, 123))	('<18.5 kg/m2', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
166625	29956810	The high group included two sub-groups: Overweight (>=25 to <30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (75, 80))	('Overweight', 'Phenotype', 'HP:0025502', (40, 50))	('>=30 kg/m2', 'Var', (82, 92))	('obese', 'Disease', (75, 80))	('>=25', 'Var', (52, 56))
166663	29956810	The result suggested that high BMI (>=25) was a high risk factor for cancer in the gallbladder, rectum, kidney and uterus.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high', 'Var', (26, 30))
166702	29956810	We identified a positive correlation between a high BMI and the corresponding two/five-year survival rate in cancer samples (r=0.53, Spearman correlation coefficient, Figs.	('BMI', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('high', 'Var', (47, 51))	('cancer', 'Disease', (109, 115))	('two/five-year survival rate', 'CPA', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
166716	29956810	For example, high levels of testosterone, and estrogen and progesterone are risk factors for prostate cancer and breast cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('risk factors', 'Reg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('testosterone', 'Chemical', 'MESH:D013739', (28, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))
166726	29956810	Patients with a low BMI (<18.5) had a reduced incidence for all 38 types of cancer.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Patients', 'Species', '9606', (0, 8))	('<18.5', 'Var', (25, 30))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
166779	28462378	One prominent example was the concept that cancer develops by gradual linear accumulation of genetic alterations, which was derived from earlier disease models that have been deeply embedded in medical thought for decades.	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('genetic alterations', 'Var', (93, 112))
166804	28462378	Inherited mutations that predispose to gastric cancer or to EA offer the greatest window of opportunity for cancer interception and prevention.	('EA', 'Phenotype', 'HP:0011459', (60, 62))	('gastric cancer', 'Disease', (39, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (39, 53))	('predispose to gastric cancer', 'Phenotype', 'HP:0006753', (25, 53))	('cancer', 'Disease', (47, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
166808	28462378	TCGA and other data indicate that EA is genomically similar to the chromosome instability (CIN) subtype of gastric adenocarcinoma with high rates of TP53 mutations and copy number alterations.	('CIN', 'Disease', (91, 94))	('EA', 'Phenotype', 'HP:0011459', (34, 36))	('copy number alterations', 'Var', (168, 191))	('CIN', 'Disease', 'MESH:D007674', (91, 94))	('TP53', 'Gene', '7157', (149, 153))	('CIN', 'Phenotype', 'HP:0040012', (91, 94))	('gastric adenocarcinoma', 'Disease', (107, 129))	('TP53', 'Gene', (149, 153))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (107, 129))	('mutations', 'Var', (154, 163))	('chromosome instability', 'Disease', (67, 89))	('chromosome instability', 'Phenotype', 'HP:0040012', (67, 89))
166809	28462378	However, the 3 other gastric adenocarcinoma subtypes, Epstein-Barr, microsatellite unstable, and genomically stable, appear different and might require different strategies.	('gastric adenocarcinoma subtypes', 'Disease', (21, 52))	('gastric adenocarcinoma subtypes', 'Disease', 'MESH:D013274', (21, 52))	('microsatellite', 'Var', (68, 82))	('Epstein-Barr', 'Disease', (54, 66))	('Epstein-Barr', 'Disease', 'MESH:D020031', (54, 66))
166811	28462378	Some cancers may contain large numbers of well-characterized oncogenic mutations, whereas the role played by other mutations may be poorly understood.	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
166826	28462378	In 2011, Wang et al reported that p63 null mouse embryos develop intestine-like metaplasia with gene expression profiles very similar to human BE.	('human', 'Species', '9606', (137, 142))	('metaplasia', 'Disease', (80, 90))	('intestine-like', 'Disease', (65, 79))	('develop', 'PosReg', (57, 64))	('BE', 'Phenotype', 'HP:0100580', (143, 145))	('p63', 'Var', (34, 37))	('mouse', 'Species', '10090', (43, 48))	('metaplasia', 'Disease', 'MESH:D008679', (80, 90))
166830	28462378	It might be argued that the solution to the challenges of cancer interception would be to undertake ultra-deep sequencing to detect small "dangerous" clones of mutant cells in different tissues.	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutant', 'Var', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (58, 64))
166831	28462378	However, sequencing of physiologically normal human eyelids has revealed an unexpected high mutation rate in aged, sun-exposed skin, revealing "a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations while maintaining the physiologic functions of epidermis."	('mutations', 'Var', (241, 250))	('human', 'Species', '9606', (46, 51))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
166844	28462378	EA develops as a result of somatic genome instability that generates mutations and chromosome abnormalities that lead to expansion of clones with genetic variants, genetic heterogeneity, and progression of these variants to EA.	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (83, 107))	('mutations', 'Var', (69, 78))	('expansion', 'PosReg', (121, 130))	('chromosome abnormalities', 'Disease', (83, 107))	('EA', 'Phenotype', 'HP:0011459', (0, 2))	('EA', 'Phenotype', 'HP:0011459', (224, 226))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (83, 107))	('variants', 'Var', (212, 220))
166849	28462378	The current iteration of Cytosponge would only detect TP53 mutations, and there are no other obvious mutations beyond those affecting the TP53 pathway that would add significant value to the test.	('TP53', 'Gene', '7157', (138, 142))	('TP53', 'Gene', (138, 142))	('TP53', 'Gene', '7157', (54, 58))	('mutations', 'Var', (59, 68))	('TP53', 'Gene', (54, 58))
166863	28454432	Therefore, positive RASSF1 expression is associated with ESCC RT sensitivity, and may be a useful independent prognostic factor for ESCC.	('ESCC RT sensitivity', 'Disease', (57, 76))	('associated', 'Reg', (41, 51))	('RASSF1', 'Gene', '11186', (20, 26))	('expression', 'MPA', (27, 37))	('positive', 'Var', (11, 19))	('RASSF1', 'Gene', (20, 26))	('ESCC', 'Disease', (132, 136))
166867	28454432	However, radiosensitization in ESCC patients may affect therapeutic efficacy and, therefore, patient prognosis.	('affect', 'Reg', (49, 55))	('patient', 'Species', '9606', (36, 43))	('patients', 'Species', '9606', (36, 44))	('patient', 'Species', '9606', (93, 100))	('ESCC', 'Disease', (31, 35))	('radiosensitization', 'Var', (9, 27))	('therapeutic efficacy', 'CPA', (56, 76))
166870	28454432	High XRCC1 expression levels are associated with resistance to RT in patients with gastric, ovarian, lung, head and neck cancer.	('XRCC1', 'Gene', (5, 10))	('ovarian', 'Disease', 'MESH:D010051', (92, 99))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('expression levels', 'MPA', (11, 28))	('gastric', 'Disease', 'MESH:D013274', (83, 90))	('head and neck cancer', 'Phenotype', 'HP:0012288', (107, 127))	('gastric', 'Disease', (83, 90))	('patients', 'Species', '9606', (69, 77))	('lung', 'Disease', (101, 105))	('associated', 'Reg', (33, 43))	('XRCC1', 'Gene', '7515', (5, 10))	('neck cancer', 'Disease', 'MESH:D006258', (116, 127))	('neck cancer', 'Disease', (116, 127))	('ovarian', 'Disease', (92, 99))	('resistance', 'Disease', (49, 59))
166911	28454432	Finally, the CR in the RASSF1 positive expression group was 36/45 (80.0%), which was significantly higher compared with the RASSF1 negative expression group (38.7%, 12/31; P<0.001).	('RASSF1', 'Gene', (124, 130))	('higher', 'PosReg', (99, 105))	('RASSF1', 'Gene', '11186', (23, 29))	('positive expression', 'Var', (30, 49))	('RASSF1', 'Gene', (23, 29))	('RASSF1', 'Gene', '11186', (124, 130))	('CR', 'Chemical', '-', (13, 15))
166915	28454432	Conversely, patients with positive RASSF1 expression had an increased median OS (31.0 months; 95% CI: 19.17-42.83 months) compared with patients with negative RASSF1 expression (15.0 months; 95% CI: 12.27-17.73 months; chi2=19.90; P<0.001; Fig.	('RASSF1', 'Gene', (35, 41))	('patients', 'Species', '9606', (12, 20))	('RASSF1', 'Gene', (159, 165))	('positive', 'Var', (26, 34))	('patients', 'Species', '9606', (136, 144))	('expression', 'Var', (42, 52))	('RASSF1', 'Gene', '11186', (159, 165))	('RASSF1', 'Gene', '11186', (35, 41))
166916	28454432	Patients with negative RASSF1 expression had a poorer median PFS compared with patients with positive expression (11.0 months; 95% CI: 7.98-14.02 months vs. 21.0 months; 95% CI: 15.70-26.30; chi2=16.42; P<0.001; Fig.	('PFS', 'MPA', (61, 64))	('RASSF1', 'Gene', '11186', (23, 29))	('expression', 'Var', (30, 40))	('negative', 'NegReg', (14, 22))	('Patients', 'Species', '9606', (0, 8))	('RASSF1', 'Gene', (23, 29))	('patients', 'Species', '9606', (79, 87))
166926	28454432	Conversely, positive RASSF1 expression exhibited a significant correlation with lower clinical stage, an improved response to RT and increased rates of PFS and OS (P<0.05).	('improved', 'PosReg', (105, 113))	('PFS', 'Disease', (152, 155))	('clinical stage', 'CPA', (86, 100))	('response to RT', 'MPA', (114, 128))	('expression', 'MPA', (28, 38))	('RASSF1', 'Gene', '11186', (21, 27))	('lower', 'NegReg', (80, 85))	('increased', 'PosReg', (133, 142))	('RASSF1', 'Gene', (21, 27))	('positive', 'Var', (12, 20))
166941	28454432	This is mitigated to a certain extent by non-specific DNA repair systems; therefore, high XRCC1 expression levels may increase the DNA repair capacity of tumor cells, leading to an increased tolerance to DNA damage induced by chemoradiation.	('increase', 'PosReg', (118, 126))	('XRCC1', 'Gene', '7515', (90, 95))	('expression', 'MPA', (96, 106))	('high', 'Var', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('XRCC1', 'Gene', (90, 95))	('increased', 'PosReg', (181, 190))	('DNA repair', 'MPA', (131, 141))	('tolerance to DNA damage', 'MPA', (191, 214))	('tumor', 'Disease', (154, 159))
166943	28454432	XRCC1 gene polymorphisms may predict the response to cisplatin based neoadjuvant chemoradiotherapy in patients with EC.	('XRCC1', 'Gene', (0, 5))	('patients', 'Species', '9606', (102, 110))	('predict', 'Reg', (29, 36))	('polymorphisms', 'Var', (11, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('XRCC1', 'Gene', '7515', (0, 5))
166944	28454432	Polymorphisms of the XRCC1 gene care able to alter the phenotype of the XRCC1 protein and cause a deficiency in its DNA repair mechanism, which is significantly associated with patient survival rate.	('phenotype', 'MPA', (55, 64))	('DNA repair mechanism', 'MPA', (116, 136))	('XRCC1', 'Gene', '7515', (21, 26))	('XRCC1', 'Gene', '7515', (72, 77))	('associated', 'Reg', (161, 171))	('Polymorphisms', 'Var', (0, 13))	('patient', 'Species', '9606', (177, 184))	('XRCC1', 'Gene', (21, 26))	('deficiency', 'Disease', (98, 108))	('XRCC1', 'Gene', (72, 77))	('alter', 'Reg', (45, 50))	('deficiency', 'Disease', 'MESH:D007153', (98, 108))	('protein', 'Protein', (78, 85))
166947	28454432	Patients with HNSCC and high XRCC1 expression levels had a poorer OS and PFS; among those receiving chemoradiation, high XRCC1 protein expression levels were independently associated with a poorer survival rate.	('high', 'Var', (116, 120))	('XRCC1', 'Gene', '7515', (121, 126))	('poorer', 'NegReg', (59, 65))	('XRCC1', 'Gene', '7515', (29, 34))	('Patients', 'Species', '9606', (0, 8))	('poorer', 'NegReg', (190, 196))	('high', 'Var', (24, 28))	('XRCC1', 'Gene', (121, 126))	('PFS', 'CPA', (73, 76))	('XRCC1', 'Gene', (29, 34))
166958	28454432	Positive expression of RASSF1 was significantly associated with an improved response to RT, PFS and OS, which may be used to predict the survival rate of patients with ESCC prior to the administration of RT.	('Positive expression', 'Var', (0, 19))	('response to RT', 'MPA', (76, 90))	('RASSF1', 'Gene', '11186', (23, 29))	('patients', 'Species', '9606', (154, 162))	('RASSF1', 'Gene', (23, 29))	('ESCC', 'Disease', (168, 172))	('improved', 'PosReg', (67, 75))
166961	28454432	In conclusion, the positive expression of COX-2 is significantly associated with a poor response to RT, but is not associated with the survival rate in ESCC.	('associated', 'Reg', (65, 75))	('COX-2', 'Gene', '5743', (42, 47))	('COX-2', 'Gene', (42, 47))	('positive expression', 'Var', (19, 38))
166970	26908460	P2Y receptors are consist of eight subtypes: five Gq/G11-coupled subtypes (P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11), usually activating phospholipase C-IP3 pathway that modulates endoplasmic reticulum calcium release, and three Gi/o-coupled subtypes (P2Y12, P2Y13 and P2Y14), mainly inhibiting adenylyl cyclase to regulate cyclic AMP/protein kinase A (PKA).	('P2Y11', 'Gene', '5032', (102, 107))	('P2Y12', 'Gene', '64805', (244, 249))	('P2Y14', 'Gene', (261, 266))	('phospholipase C-IP3 pathway', 'Pathway', (129, 156))	('P2Y11', 'Gene', (102, 107))	('P2Y4', 'Var', (87, 91))	('calcium', 'Chemical', 'MESH:D002118', (194, 201))	('activating', 'PosReg', (118, 128))	('endoplasmic reticulum calcium release', 'MPA', (172, 209))	('cyclic AMP/protein kinase A', 'MPA', (316, 343))	('P2Y14', 'Gene', '9934', (261, 266))	('IP3', 'Chemical', 'MESH:D015544', (145, 148))	('modulates', 'Reg', (162, 171))	('P2Y13', 'Var', (251, 256))	('P2Y2', 'Var', (81, 85))	('P2Y1', 'Var', (75, 79))	('adenylyl cyclase', 'Enzyme', (287, 303))	('cyclic AMP', 'Chemical', 'MESH:D000242', (316, 326))	('P2Y12', 'Gene', (244, 249))	('inhibiting', 'NegReg', (276, 286))
166972	26908460	ADP has been claimed to be selective agonist of P2Y1, P2Y12 and P2Y13 receptors; however, UTP predominantly binds to P2Y2 and P2Y4 receptors, and to a lesser extent to P2Y6 receptors which preferential agonist is UDP.	('P2Y4', 'Var', (126, 130))	('P2Y12', 'Gene', '64805', (54, 59))	('binds', 'Interaction', (108, 113))	('P2Y6 receptor', 'Gene', '5031', (168, 181))	('P2Y6 receptor', 'Gene', (168, 181))	('UDP', 'Chemical', 'MESH:D014530', (213, 216))	('P2Y12', 'Gene', (54, 59))	('ADP', 'Chemical', 'MESH:D000244', (0, 3))	('P2Y2', 'Var', (117, 121))	('UTP', 'Chemical', 'MESH:D014544', (90, 93))
166973	26908460	P2Y14 receptors are mainly activated by UDP-glucose and other UDP-sugars, or by UDP.	('UDP-glucose', 'Var', (40, 51))	('UDP', 'Chemical', 'MESH:D014530', (80, 83))	('UDP-glucose', 'Chemical', 'MESH:D014532', (40, 51))	('UDP', 'Chemical', 'MESH:D014530', (40, 43))	('activated', 'PosReg', (27, 36))	('P2Y14', 'Gene', (0, 5))	('UDP', 'Chemical', 'MESH:D014530', (62, 65))	('P2Y14', 'Gene', '9934', (0, 5))	('UDP-sugars', 'Chemical', 'MESH:D014539', (62, 72))
166981	26908460	Although gastric acid secretion is mainly regulated by P1 adenosine receptors, P2Y receptors may also regulate gastric acid secretion, gastric contraction, relaxation and neurotransmission.	('gastric contraction', 'Disease', (135, 154))	('adenosine', 'Chemical', 'MESH:D000241', (58, 67))	('P1 adenosine receptors', 'Protein', (55, 77))	('regulate', 'Reg', (102, 110))	('neurotransmission', 'CPA', (171, 188))	('gastric contraction', 'Disease', 'MESH:D013274', (135, 154))	('gastric acid secretion', 'MPA', (111, 133))	('gastric acid secretion', 'MPA', (9, 31))	('P2Y', 'Var', (79, 82))	('relaxation', 'CPA', (156, 166))
166988	26908460	P2Y1 receptors induce glycogen phosphorylase of rat hepatocyte by raising intracellular calcium concentrations but inhibiting cyclic AMP accumulations.	('glycogen', 'Chemical', 'MESH:D006003', (22, 30))	('rat', 'Species', '10116', (103, 106))	('raising intracellular calcium concentrations', 'Phenotype', 'HP:0003575', (66, 110))	('cyclic AMP accumulations', 'MPA', (126, 150))	('raising', 'PosReg', (66, 73))	('P2Y1 receptors', 'Var', (0, 14))	('calcium', 'Chemical', 'MESH:D002118', (88, 95))	('inhibiting', 'NegReg', (115, 125))	('glycogen phosphorylase', 'MPA', (22, 44))	('intracellular calcium concentrations', 'MPA', (74, 110))	('cyclic AMP', 'Chemical', 'MESH:D000242', (126, 136))	('rat', 'Species', '10116', (48, 51))	('induce', 'PosReg', (15, 21))
166989	26908460	P2Y2 receptors in human hepatocytes regulate both glycogen metabolism and proliferation-associated responses through Ca2+ and MAPK pathways, and induce ERK phosphorylation, Egr-1 expression, and cyclins and cell cycle progression, which are essential for efficient hepatocyte proliferation.	('ERK', 'Gene', '5594', (152, 155))	('P2Y2 receptors', 'Var', (0, 14))	('expression', 'MPA', (179, 189))	('MAPK pathways', 'Pathway', (126, 139))	('ERK', 'Gene', (152, 155))	('rat', 'Species', '10116', (81, 84))	('Egr-1', 'Gene', (173, 178))	('Ca2+', 'Chemical', 'MESH:D000069285', (117, 121))	('rat', 'Species', '10116', (283, 286))	('human', 'Species', '9606', (18, 23))	('induce', 'PosReg', (145, 151))	('glycogen metabolism', 'MPA', (50, 69))	('Egr-1', 'Gene', '1958', (173, 178))	('cell cycle progression', 'CPA', (207, 229))	('Ca2+', 'Pathway', (117, 121))	('glycogen', 'Chemical', 'MESH:D006003', (50, 58))	('proliferation-associated responses', 'CPA', (74, 108))
166991	26908460	P2Y13 receptors modulate reverse cholesterol transport by increasing hepatic HDL cholesterol uptake, overall hepatocyte cholesterol content, and biliary output.	('hepatic HDL cholesterol uptake', 'MPA', (69, 99))	('hepatocyte cholesterol content', 'MPA', (109, 139))	('cholesterol', 'Chemical', 'MESH:D002784', (33, 44))	('cholesterol', 'Chemical', 'MESH:D002784', (81, 92))	('biliary output', 'MPA', (145, 159))	('modulate', 'Reg', (16, 24))	('P2Y13 receptors', 'Var', (0, 15))	('cholesterol', 'Chemical', 'MESH:D002784', (120, 131))	('increasing', 'PosReg', (58, 68))	('reverse cholesterol transport', 'MPA', (25, 54))
166992	26908460	P2Y1, 2, 4, 6, 11, 12 and 13 receptor subtypes have been identified in INS-1betacells, mouse, rat and human pancreaticbetacells.	('rat', 'Species', '10116', (94, 97))	('mouse', 'Species', '10090', (87, 92))	('pancreatic', 'Disease', (108, 118))	('pancreatic', 'Disease', 'MESH:D010195', (108, 118))	('P2Y1', 'Var', (0, 4))	('INS-1betacells', 'Disease', (71, 85))	('human', 'Species', '9606', (102, 107))
166995	26908460	P2Y1 and P2Y6 receptors in MIN6 cells induce intracellular calcium release and insulin secretion, and prevent TNF-alpha induced betacells apoptosis.	('intracellular calcium release', 'MPA', (45, 74))	('insulin', 'Gene', '3630', (79, 86))	('induce', 'PosReg', (38, 44))	('prevent', 'NegReg', (102, 109))	('P2Y6 receptor', 'Gene', '5031', (9, 22))	('insulin', 'Gene', (79, 86))	('P2Y1', 'Var', (0, 4))	('calcium', 'Chemical', 'MESH:D002118', (59, 66))	('P2Y6 receptor', 'Gene', (9, 22))	('TNF-alpha', 'Protein', (110, 119))
166999	26908460	Activation of P2Y1 receptors can induce nerve-mediated relaxation via inhibitory neuromuscular transmission in human intestines, guinea pig small intestine and rat colon.	('guinea pig', 'Species', '10141', (129, 139))	('rat', 'Species', '10116', (160, 163))	('human', 'Species', '9606', (111, 116))	('inhibitory neuromuscular transmission', 'MPA', (70, 107))	('Activation', 'Var', (0, 10))	('P2Y1 receptors', 'Protein', (14, 28))	('nerve-mediated relaxation', 'MPA', (40, 65))
167001	26908460	Basolateral UTP-induced Cl- secretion in jejunum was partially reduced in P2Y2 knockout (40%) and P2Y4 knockout (60%) null mice.	('P2Y4', 'Var', (98, 102))	('Basolateral UTP-induced Cl- secretion in jejunum', 'MPA', (0, 48))	('UTP', 'Chemical', 'MESH:D014544', (12, 15))	('reduced', 'NegReg', (63, 70))	('P2Y2', 'Gene', (74, 78))	('knockout', 'Var', (79, 87))	('mice', 'Species', '10090', (123, 127))
167004	26908460	Over the past decades, many studies have highlighted fundamental roles of P2Y receptors in inflammatory diseases, particularly P2Y2, 6, 12 receptors have been well studied, such as P2Y2 receptor agonists can treat cystic fiborosis, and promote wound healing and leukocyte functions.	('cystic fiborosis', 'Disease', 'MESH:D052177', (214, 230))	('promote', 'PosReg', (236, 243))	('treat', 'PosReg', (208, 213))	('wound healing', 'CPA', (244, 257))	('P2Y2', 'Var', (181, 185))	('P2Y2, 6', 'Gene', '5029;5031', (127, 134))	('cystic fiborosis', 'Disease', (214, 230))	('leukocyte functions', 'CPA', (262, 281))
167009	26908460	Liver damage and necrosis are largely decreased in C57BL/6 wild-type mice injected with suramin, an inhibitor of P2Y receptors, or in P2Y2 receptors knockout mice, in which acetaminophen-induced liver damage is also alleviated.	('necrosis', 'Disease', (17, 25))	('decreased', 'NegReg', (38, 47))	('P2Y receptors', 'Protein', (113, 126))	('C57BL/6', 'Var', (51, 58))	('mice', 'Species', '10090', (158, 162))	('necrosis', 'Disease', 'MESH:D009336', (17, 25))	('liver damage', 'Disease', (195, 207))	('mice', 'Species', '10090', (69, 73))	('Liver damage', 'Disease', (0, 12))	('liver damage', 'Disease', 'MESH:D056486', (195, 207))	('Liver damage', 'Disease', 'MESH:D056486', (0, 12))	('acetaminophen', 'Chemical', 'MESH:D000082', (173, 186))	('suramin', 'Chemical', 'MESH:D013498', (88, 95))
167010	26908460	P2Y2 receptors can promote neutrophil infiltration, regulate cell survival, and promote tumor necrosis factor-mediated cell death, supporting the view that activation of P2Y2 receptors stimulates the recruitment of neutrophils into the liver to cause hepatocyte death.	('recruitment', 'MPA', (200, 211))	('promote', 'PosReg', (19, 26))	('neutrophil infiltration', 'CPA', (27, 50))	('stimulates', 'PosReg', (185, 195))	('P2Y2', 'Gene', (170, 174))	('cell survival', 'CPA', (61, 74))	('tumor necrosis', 'Disease', 'MESH:D009336', (88, 102))	('rat', 'Species', '10116', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('hepatocyte death', 'Disease', 'MESH:D003643', (251, 267))	('P2Y2', 'Var', (0, 4))	('hepatocyte death', 'Disease', (251, 267))	('cause', 'Reg', (245, 250))	('tumor necrosis', 'Disease', (88, 102))	('promote', 'PosReg', (80, 87))
167013	26908460	Interestingly, P2Y2 and P2Y4 receptors are expressed in quiescent hepatic stellate cells, whereas P2Y6 receptors are expressed in activated hepatic stellate cells.	('P2Y6 receptor', 'Gene', (98, 111))	('P2Y4', 'Var', (24, 28))	('P2Y6 receptor', 'Gene', '5031', (98, 111))	('P2Y2', 'Var', (15, 19))
167020	26908460	Intestinal inflammation can upregulate mRNA expression of P2Y2 and P2Y6 receptors in the colonic mucosa of colitic mice.	('inflammation', 'Disease', (11, 23))	('P2Y6 receptor', 'Gene', (67, 80))	('colonic mucosa of colitic', 'Disease', (89, 114))	('mRNA expression', 'MPA', (39, 54))	('colonic mucosa of colitic', 'Disease', 'MESH:D015179', (89, 114))	('upregulate', 'PosReg', (28, 38))	('mice', 'Species', '10090', (115, 119))	('P2Y2', 'Var', (58, 62))	('P2Y6 receptor', 'Gene', '5031', (67, 80))	('inflammation', 'Disease', 'MESH:D007249', (11, 23))
167024	26908460	In addition, ATP or UTP facilitates the migration of neutrophil-like PLB-985 cells and macrophage across the Caco-2 monolayer and promotes macrophage-like U-937 cells adhere to IEC monolayers.	('ATP', 'Gene', (13, 16))	('ATP', 'Gene', '51761', (13, 16))	('facilitates', 'PosReg', (24, 35))	('promotes', 'PosReg', (130, 138))	('UTP', 'Var', (20, 23))	('rat', 'Species', '10116', (43, 46))	('U-937', 'CellLine', 'CVCL:0007', (155, 160))	('Caco-2', 'CellLine', 'CVCL:0025', (109, 115))	('migration', 'CPA', (40, 49))	('UTP', 'Chemical', 'MESH:D014544', (20, 23))	('macrophage-like U-937 cells adhere', 'CPA', (139, 173))	('PLB-985', 'CellLine', 'CVCL:2162', (69, 76))
167034	26908460	UDP also increases ERK1/2 phosphorylation of IEC-6 cells, suggesting the involvement of P2Y6 receptors.	('P2Y6 receptor', 'Gene', '5031', (88, 101))	('UDP', 'Var', (0, 3))	('P2Y6 receptor', 'Gene', (88, 101))	('IEC-6', 'CellLine', 'CVCL:0343', (45, 50))	('ERK1/2', 'Protein', (19, 25))	('increases', 'PosReg', (9, 18))	('UDP', 'Chemical', 'MESH:D014530', (0, 3))	('phosphorylation', 'MPA', (26, 41))
167037	26908460	P2Y6 regulation of CXCL8 expression requires PKCdeltaactivation upstream of the signaling pathway composed of MEK1/2-ERK1/2 and c-fos.	('PKCdeltaactivation', 'Enzyme', (45, 63))	('MEK1/2', 'Gene', '5604;5605', (110, 116))	('MEK1/2', 'Gene', (110, 116))	('c-fos', 'Gene', '2353', (128, 133))	('P2Y6', 'Var', (0, 4))	('CXCL8', 'Gene', '3576', (19, 24))	('CXCL8', 'Gene', (19, 24))	('c-fos', 'Gene', (128, 133))
167039	26908460	Interestingly, UDP, P2Y6 receptors selective agonist, activates peripheral T cells and increases mRNA levels of P2Y6 receptors, and raises intracellular calcium concentration.	('calcium', 'Chemical', 'MESH:D002118', (153, 160))	('intracellular calcium concentration', 'MPA', (139, 174))	('UDP', 'Chemical', 'MESH:D014530', (15, 18))	('increases', 'PosReg', (87, 96))	('P2Y6 receptor', 'Gene', '5031', (112, 125))	('P2Y6 receptor', 'Gene', (112, 125))	('activates', 'PosReg', (54, 63))	('P2Y6 receptor', 'Gene', '5031', (20, 33))	('P2Y6 receptor', 'Gene', (20, 33))	('peripheral T cells', 'CPA', (64, 82))	('rat', 'Species', '10116', (168, 171))	('raises intracellular calcium concentration', 'Phenotype', 'HP:0003575', (132, 174))	('UDP', 'Var', (15, 18))	('raises', 'PosReg', (132, 138))
167041	26908460	Different subtypes of P2Y receptors are expressed in many cancer cells and tissues to be likely involved in cancer development, such as P2Y receptors in melanoma, skin squamous cell carcinoma, lung cancer, prostate cancer, glioma, breast cancer, ovarian cancer, and haematological malignancies, etc.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('involved', 'Reg', (96, 104))	('melanoma', 'Disease', (153, 161))	('skin squamous cell carcinoma', 'Disease', (163, 191))	('cancer', 'Disease', (254, 260))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', (198, 204))	('cancer', 'Disease', (215, 221))	('haematological malignancies', 'Disease', 'MESH:D019337', (266, 293))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('skin squamous cell carcinoma', 'Phenotype', 'HP:0006739', (163, 191))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('P2Y', 'Var', (136, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('glioma', 'Disease', (223, 229))	('ovarian cancer', 'Disease', 'MESH:D010051', (246, 260))	('prostate cancer', 'Disease', 'MESH:D011471', (206, 221))	('prostate cancer', 'Phenotype', 'HP:0012125', (206, 221))	('glioma', 'Disease', 'MESH:D005910', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('prostate cancer', 'Disease', (206, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('lung cancer', 'Disease', (193, 204))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ovarian cancer', 'Disease', (246, 260))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('skin squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 191))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('haematological malignancies', 'Disease', (266, 293))	('cancer', 'Disease', (58, 64))	('ovarian cancer', 'Phenotype', 'HP:0100615', (246, 260))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))	('breast cancer', 'Disease', (231, 244))
167046	26908460	The squamous esophageal cancer cell line, Kyse-140 cells express mRNA of P2X4, P2X5, and P2Y2 receptors, but not P2X1 and P2X7 receptors that are mainly associated with apoptosis.	('P2Y2 receptors', 'Var', (89, 103))	('P2X5', 'Gene', '5026', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('P2X4', 'Gene', '5025', (73, 77))	('P2X1', 'Gene', '5023', (113, 117))	('squamous esophageal cancer', 'Disease', 'MESH:D004938', (4, 30))	('P2X7', 'Gene', '5027', (122, 126))	('P2X5', 'Gene', (79, 83))	('squamous esophageal cancer', 'Disease', (4, 30))	('P2X1', 'Gene', (113, 117))	('P2X4', 'Gene', (73, 77))	('P2X7', 'Gene', (122, 126))
167050	26908460	Incubation of Kyse-140 cells with the phospholipase C inhibitor U73122 dose-dependently inhibits ATP-induced intracellular Ca2+ level, suggesting that P2Y2 receptors mediate intracellular Ca2+ via phospholipase C (PLC) activation in Kyse-140 cells.	('U73122', 'Chemical', 'MESH:C060229', (64, 70))	('activation', 'PosReg', (219, 229))	('P2Y2', 'Var', (151, 155))	('mediate', 'Reg', (166, 173))	('inhibits', 'NegReg', (88, 96))	('ATP', 'Gene', (97, 100))	('ATP', 'Gene', '51761', (97, 100))	('Ca2+', 'Chemical', 'MESH:D000069285', (123, 127))	('Ca2+', 'Chemical', 'MESH:D000069285', (188, 192))
167060	26908460	Insulin and ATP induce a dose-dependent increase in p44/42 MAPK phosphorylation in rat HCC cells and chelation of extracellular Ca2+ with EGTA diminishes ATP- and insulin-induced p44/42 MAPK phosphorylation.	('diminishes', 'NegReg', (143, 153))	('Insulin', 'Gene', '3630', (0, 7))	('p44', 'Gene', (179, 182))	('ATP', 'Gene', '51761', (12, 15))	('insulin', 'Gene', (163, 170))	('ATP', 'Gene', '51761', (154, 157))	('p44', 'Gene', (52, 55))	('HCC', 'Phenotype', 'HP:0001402', (87, 90))	('Ca2+', 'Chemical', 'MESH:D000069285', (128, 132))	('rat HCC', 'CellLine', 'CVCL:0492', (83, 90))	('p44', 'Gene', '50689', (179, 182))	('p44', 'Gene', '50689', (52, 55))	('Insulin', 'Gene', (0, 7))	('ATP', 'Gene', (12, 15))	('ATP', 'Gene', (154, 157))	('EGTA', 'Chemical', 'MESH:D004533', (138, 142))	('insulin', 'Gene', '3630', (163, 170))	('chelation', 'Var', (101, 110))	('increase', 'PosReg', (40, 48))
167066	26908460	Although the mRNAs for P2Y1, P2Y2, P2Y4 and P2Y6 purinergic receptors subtypes are found in biliary epithelial cancer cells (Mz-Cha-1), but only P2Y2 receptors are present at the protein level.	('P2Y2', 'Var', (29, 33))	('biliary epithelial cancer', 'Disease', 'MESH:D001661', (92, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('P2Y6', 'Var', (44, 48))	('P2Y1', 'Var', (23, 27))	('P2Y4', 'Var', (35, 39))	('biliary epithelial cancer', 'Disease', (92, 117))	('purinergic', 'Chemical', '-', (49, 59))	('epithelial cancer', 'Phenotype', 'HP:0031492', (100, 117))
167070	26908460	P2Y receptors, especially P2Y1, P2Y2 and P2Y6 receptors are highly expressed in PANC-1, a duct epithelial cell derived from human primary pancreatic cancer cells.	('P2Y2', 'Var', (32, 36))	('PANC-1', 'CellLine', 'CVCL:0480', (80, 86))	('pancreatic cancer', 'Disease', (138, 155))	('P2Y6 receptor', 'Gene', '5031', (41, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('P2Y6 receptor', 'Gene', (41, 54))	('P2Y1', 'Var', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('human', 'Species', '9606', (124, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))
167071	26908460	P2Y1 and P2Y6 proteins were also found in PANC-1 cells.	('P2Y1', 'Var', (0, 4))	('P2Y6', 'Var', (9, 13))	('proteins', 'Protein', (14, 22))	('PANC-1', 'CellLine', 'CVCL:0480', (42, 48))
167074	26908460	UTP or P2Y2 receptor selective agonist MRS2768 can increase proliferation of PANC-1, which is significantly decreased by P2Y receptor antagonist suramin and siRNA against P2Y2 receptors.	('increase', 'PosReg', (51, 59))	('rat', 'Species', '10116', (67, 70))	('suramin', 'Chemical', 'MESH:D013498', (145, 152))	('PANC-1', 'CellLine', 'CVCL:0480', (77, 83))	('decreased', 'NegReg', (108, 117))	('MRS2768', 'Chemical', '-', (39, 46))	('UTP', 'Chemical', 'MESH:D014544', (0, 3))	('PANC-1', 'Gene', (77, 83))	('proliferation', 'CPA', (60, 73))	('MRS2768', 'Var', (39, 46))
167078	26908460	P2Y2 and P2Y4 receptors are overexpressed in human colon cancer compared with normal colon tissues although their functional significance need further studies.	('colon cancer', 'Disease', (51, 63))	('overexpressed', 'PosReg', (28, 41))	('human', 'Species', '9606', (45, 50))	('P2Y4', 'Var', (9, 13))	('colon cancer', 'Phenotype', 'HP:0003003', (51, 63))	('colon cancer', 'Disease', 'MESH:D015179', (51, 63))	('P2Y2', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
167081	26908460	The mRNA of P2Y2 receptors is expressed in two colorectal carcinoma cell lines (HT29, Colo320DM) and short-term stimulation of P2Y2 receptors cause both intracellular Ca2+ release and transmembrane Ca2+ influx, and a subsequent increase in cyclic AMP.	('Ca2+', 'Chemical', 'MESH:D000069285', (167, 171))	('HT29', 'CellLine', 'CVCL:0320', (80, 84))	('DM', 'Disease', 'MESH:D009223', (93, 95))	('intracellular Ca2+ release', 'MPA', (153, 179))	('cyclic AMP', 'Chemical', 'MESH:D000242', (240, 250))	('P2Y2', 'Var', (127, 131))	('increase', 'PosReg', (228, 236))	('cyclic AMP', 'MPA', (240, 250))	('colorectal carcinoma', 'Disease', (47, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('Ca2+', 'Chemical', 'MESH:D000069285', (198, 202))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (47, 67))	('transmembrane Ca2+ influx', 'MPA', (184, 209))
167087	26908460	The primary cell cultures of human colorectal carcinomas and HT29 cell line express functional P2U-receptors (P2Y2 and P2Y4).	('P2U-receptors', 'Protein', (95, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('HT29', 'CellLine', 'CVCL:0320', (61, 65))	('human', 'Species', '9606', (29, 34))	('colorectal carcinomas', 'Disease', (35, 56))	('P2Y2', 'Var', (110, 114))	('P2Y4', 'Var', (119, 123))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (35, 56))
167090	26908460	Two human colorectal carcinoma cell lines (HCT8 and Caco-2) express mRNA of P2Y1, 2, 4, 6, 11, 12 receptors and proteins of P2Y1 and P2Y2 receptors.	('P2Y1', 'Var', (76, 80))	('human', 'Species', '9606', (4, 9))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (10, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('HCT8', 'CellLine', 'CVCL:2478', (43, 47))	('colorectal carcinoma', 'Disease', (10, 30))	('Caco-2', 'CellLine', 'CVCL:0025', (52, 58))
167092	26908460	UTP can trigger calcium influxes through either P2Y2 or P2Y4 receptors, which is inhibited by suramin.	('calcium influxes', 'MPA', (16, 32))	('calcium', 'Chemical', 'MESH:D002118', (16, 23))	('suramin', 'Chemical', 'MESH:D013498', (94, 101))	('P2Y4', 'Var', (56, 60))	('P2Y2', 'Protein', (48, 52))	('UTP', 'Chemical', 'MESH:D014544', (0, 3))
167095	26908460	The mRNA of P2Y2 and P2Y4 receptors is found in Caco-2 cells.	('Caco-2', 'CellLine', 'CVCL:0025', (48, 54))	('P2Y4', 'Var', (21, 25))	('P2Y2', 'Var', (12, 16))
167096	26908460	ATP, UTP and UDP increase phosphorylation of MAPK by stimulating P2Y receptors, probably through subtypes of P2Y2, P2Y4, P2Y6 and P2Y11 receptors.	('stimulating', 'PosReg', (53, 64))	('P2Y11', 'Gene', '5032', (130, 135))	('P2Y2', 'Var', (109, 113))	('P2Y11', 'Gene', (130, 135))	('UTP', 'Chemical', 'MESH:D014544', (5, 8))	('P2Y receptors', 'Protein', (65, 78))	('ATP', 'Gene', (0, 3))	('MAPK', 'Gene', (45, 49))	('UDP', 'Chemical', 'MESH:D014530', (13, 16))	('ATP', 'Gene', '51761', (0, 3))	('P2Y4', 'Var', (115, 119))	('increase', 'PosReg', (17, 25))	('P2Y6', 'Var', (121, 125))	('phosphorylation', 'MPA', (26, 41))
167103	26908460	Such as HCT8 and Caco-2 cells express P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, and P2Y12 receptors.	('P2Y6', 'Var', (56, 60))	('P2Y12', 'Gene', (73, 78))	('P2Y2', 'Var', (44, 48))	('P2Y11', 'Gene', '5032', (62, 67))	('P2Y11', 'Gene', (62, 67))	('HCT8', 'CellLine', 'CVCL:2478', (8, 12))	('P2Y4', 'Var', (50, 54))	('P2Y1', 'Var', (38, 42))	('Caco-2', 'CellLine', 'CVCL:0025', (17, 23))	('P2Y12', 'Gene', '64805', (73, 78))
167104	26908460	Lower concentrations of ATP and UTP stimulate proliferation of these cells via P2Y2 receptors activation, but high concentrations of ATP induce apoptosis and anti-proliferation through P2Y1 and P2X7 receptors.	('ATP', 'Gene', (133, 136))	('ATP', 'Gene', '51761', (133, 136))	('UTP', 'Chemical', 'MESH:D014544', (32, 35))	('P2X7', 'Gene', '5027', (194, 198))	('P2Y2 receptors', 'Protein', (79, 93))	('rat', 'Species', '10116', (170, 173))	('ATP', 'Gene', (24, 27))	('apoptosis', 'CPA', (144, 153))	('P2X7', 'Gene', (194, 198))	('proliferation', 'CPA', (46, 59))	('rat', 'Species', '10116', (53, 56))	('ATP', 'Gene', '51761', (24, 27))	('rat', 'Species', '10116', (13, 16))	('rat', 'Species', '10116', (122, 125))	('anti-proliferation', 'CPA', (158, 176))	('P2Y1', 'Var', (185, 189))	('activation', 'PosReg', (94, 104))
167133	27447608	In addition, the effects of DIM on cancer cells were strong enough to attenuate the proliferation of cancer cells.	('DIM', 'Chemical', 'MESH:C016392', (28, 31))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('rat', 'Species', '10116', (91, 94))	('cancer', 'Disease', (101, 107))	('DIM', 'Var', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('attenuate', 'NegReg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
167141	27447608	Studies on DIM and cancer cells have proven that DIM triggers cellular endoplasmic reticulum (ER) stress and apoptosis within cancer cells.	('DIM', 'Chemical', 'MESH:C016392', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('DIM', 'Var', (49, 52))	('DIM', 'Chemical', 'MESH:C016392', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('apoptosis within cancer', 'Disease', (109, 132))	('apoptosis within cancer', 'Disease', 'MESH:D001929', (109, 132))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
167172	27447608	The overexpression of aryl hydrocarbon is evident during gastric carcinogenesis; thus, modulation of the AhR may contribute to restraining gastric cancer growth.	('gastric cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('modulation', 'Var', (87, 97))	('aryl hydrocarbon', 'Chemical', '-', (22, 38))	('AhR', 'Gene', '196', (105, 108))	('gastric carcinogenesis', 'Disease', (57, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('AhR', 'Gene', (105, 108))	('restraining', 'NegReg', (127, 138))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (57, 79))
167176	27447608	reported that DIM potentiates paclitaxel-induced antitumor effects and also that DIM potentiates the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of gastric cancer cells.	('potentiates', 'PosReg', (18, 29))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('DIM', 'Chemical', 'MESH:C016392', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('potentiates', 'PosReg', (85, 96))	('tumor necrosis factor-related apoptosis-inducing ligand', 'Gene', '8743', (101, 156))	('TRAIL', 'Gene', '8743', (158, 163))	('gastric cancer', 'Disease', (186, 200))	('DIM', 'Chemical', 'MESH:C016392', (81, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('tumor', 'Disease', (101, 106))	('TRAIL', 'Gene', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('DIM', 'Var', (81, 84))	('paclitaxel', 'Chemical', 'MESH:D017239', (30, 40))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
167194	27447608	I3C, independent of p53, induces the expression of activating transcription factor 3, which sequentially triggers NAG-1 to suppress cell proliferation in human colorectal cancer (HCT-116) cells.	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('NAG-1', 'Gene', (114, 119))	('human', 'Species', '9606', (154, 159))	('colorectal cancer', 'Disease', (160, 177))	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('NAG-1', 'Gene', '9518', (114, 119))	('I3C', 'Chemical', 'MESH:C016517', (0, 3))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('suppress', 'NegReg', (123, 131))	('cell proliferation', 'CPA', (132, 150))	('expression', 'MPA', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('rat', 'Species', '10116', (144, 147))	('I3C', 'Var', (0, 3))	('HCT-116', 'CellLine', 'CVCL:0291', (179, 186))
167209	27447608	C-DIM and DIM-C-pPhOH were found to bind and inactivate nuclear receptor (NR4A1) and also act as a NR4A1 antagonist in lung and pancreatic cancer cells.	('DIM-C-pPhOH', 'Var', (10, 21))	('NR4A1', 'Gene', '3164', (99, 104))	('C', 'Chemical', 'MESH:D002244', (14, 15))	('DIM-C-pPhOH', 'Chemical', '-', (10, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('bind', 'Interaction', (36, 40))	('pancreatic cancer', 'Disease', (128, 145))	('DIM', 'Chemical', 'MESH:C016392', (2, 5))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('C-DIM', 'Var', (0, 5))	('NR4A1', 'Gene', (74, 79))	('NR4A1', 'Gene', '3164', (74, 79))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('inactivate', 'NegReg', (45, 55))	('DIM', 'Chemical', 'MESH:C016392', (10, 13))	('NR4A1', 'Gene', (99, 104))
167220	27447608	In another study, we found that DIM enhances the toxicity of LY294002, a PI3K inhibitor, in colon cancer cells, as demonstrated by the results of a cell-viability assay, clonogenic assay, and immunoblotting analysis of apoptotic markers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('enhances', 'PosReg', (36, 44))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('toxicity', 'Disease', 'MESH:D064420', (49, 57))	('LY294002', 'Chemical', 'MESH:C085911', (61, 69))	('toxicity', 'Disease', (49, 57))	('DIM', 'Chemical', 'MESH:C016392', (32, 35))	('colon cancer', 'Disease', (92, 104))	('rat', 'Species', '10116', (122, 125))	('LY294002', 'Var', (61, 69))
167225	27447608	investigated the combined effect of DIM and butyrate in colon cancer cells containing a mutation in the adenomatous polyposis coli (APC) gene.	('mutation', 'Var', (88, 96))	('colon cancer', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (104, 130))	('DIM', 'Chemical', 'MESH:C016392', (36, 39))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (104, 130))	('butyrate', 'Chemical', 'MESH:D002087', (44, 52))	('adenomatous polyposis coli', 'Disease', (104, 130))	('APC', 'Phenotype', 'HP:0005227', (132, 135))	('APC', 'Gene', (132, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (56, 68))	('colon cancer', 'Disease', 'MESH:D015179', (56, 68))	('APC', 'Gene', '324', (132, 135))
167226	27447608	Butyrate alone does not induce apoptosis in colon cancer cells with the APC gene mutation, but combined treatment with DIM accentuates the ability of butyrate to induce apoptosis in these butyrate-resilient cells by downregulating Survivin, both in vitro and in vivo.	('accentuates', 'PosReg', (123, 134))	('apoptosis', 'CPA', (169, 178))	('Survivin', 'Protein', (231, 239))	('downregulating', 'NegReg', (216, 230))	('colon cancer', 'Disease', 'MESH:D015179', (44, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (44, 56))	('mutation', 'Var', (81, 89))	('Butyrate', 'Chemical', 'MESH:D002087', (0, 8))	('colon cancer', 'Disease', (44, 56))	('APC', 'Phenotype', 'HP:0005227', (72, 75))	('APC', 'Gene', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('butyrate', 'Chemical', 'MESH:D002087', (188, 196))	('DIM', 'Chemical', 'MESH:C016392', (119, 122))	('butyrate', 'Chemical', 'MESH:D002087', (150, 158))	('APC', 'Gene', '324', (72, 75))
167235	27447608	For example, DIM was found to induce apoptosis in SMMC-7721 hepatoma cells.	('hepatoma', 'Disease', (60, 68))	('hepatoma', 'Disease', 'MESH:D006528', (60, 68))	('C', 'Chemical', 'MESH:D002244', (53, 54))	('DIM', 'Chemical', 'MESH:C016392', (13, 16))	('DIM', 'Var', (13, 16))	('induce', 'Reg', (30, 36))
167245	27447608	Moreover, I3C has been shown to have unsolicited tumor-enhancing activities in the rat liver.	('I3C', 'Var', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('rat', 'Species', '10116', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('I3C', 'Chemical', 'MESH:C016517', (10, 13))
167246	27447608	In this study, Parkin and Malejka-Giganti found that I3C promotes tumor activities, whereas DIM appeared to suppress tumor growth in mammary tumor-bearing rats.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('I3C', 'Chemical', 'MESH:C016517', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (141, 146))	('I3C', 'Var', (53, 56))	('rats', 'Species', '10116', (155, 159))	('DIM', 'Chemical', 'MESH:C016392', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('suppress', 'NegReg', (108, 116))	('promotes', 'PosReg', (57, 65))
167254	27447608	Using fluorescence-activated cell sorting analysis, they found that DIM-CpPhCF3 is more effective at inhibiting G0/G1-S phase progression.	('C', 'Chemical', 'MESH:D002244', (72, 73))	('C', 'Chemical', 'MESH:D002244', (76, 77))	('G0/G1-S phase progression', 'CPA', (112, 137))	('DIM-CpPhCF3', 'Var', (68, 79))	('DIM', 'Chemical', 'MESH:C016392', (68, 71))	('inhibiting', 'NegReg', (101, 111))
167256	27447608	DIM-C-pPhCF3 was found to induce p21 expression through a new pathway that includes interactions between peroxisome proliferator-activated receptor gamma (PPARgamma) and both specificity protein (Sp)1 and Sp4 proteins bound to the proximal GC-rich motifs of the p21 promoter.	('p21', 'Gene', (33, 36))	('DIM-C-pPhCF3', 'Chemical', '-', (0, 12))	('induce', 'PosReg', (26, 32))	('C', 'Chemical', 'MESH:D002244', (241, 242))	('C', 'Chemical', 'MESH:D002244', (9, 10))	('p21', 'Gene', (262, 265))	('Sp4', 'Gene', '6671', (205, 208))	('PPARgamma', 'Gene', '5468', (155, 164))	('PPARgamma', 'Gene', (155, 164))	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (105, 153))	('p21', 'Gene', '1026', (33, 36))	('expression', 'MPA', (37, 47))	('bound', 'Interaction', (218, 223))	('specificity protein (Sp)1', 'Gene', (175, 200))	('Sp4', 'Gene', (205, 208))	('p21', 'Gene', '1026', (262, 265))	('peroxisome proliferator-activated receptor gamma', 'Gene', (105, 153))	('interactions', 'Interaction', (84, 96))	('specificity protein (Sp)1', 'Gene', '6667', (175, 200))	('DIM-C-pPhCF3', 'Var', (0, 12))	('C', 'Chemical', 'MESH:D002244', (4, 5))
167269	27447608	found that treatment with DIM downregulates miR-221 expression and upregulates phosphatase and tensin homolog (PTEN), p27, p57, and p53 upregulated modulator of apoptosis (PUMA) expression, thus inhibiting the proliferation and migration of MiaPaCa-2 and Panc-1 cells.	('rat', 'Species', '10116', (231, 234))	('expression', 'MPA', (178, 188))	('inhibiting', 'NegReg', (195, 205))	('downregulates', 'NegReg', (30, 43))	('p27', 'Gene', '3429', (118, 121))	('p27', 'Gene', (118, 121))	('migration', 'CPA', (228, 237))	('upregulated', 'PosReg', (136, 147))	('p53', 'Gene', '7157', (132, 135))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (241, 250))	('miR-221', 'Gene', (44, 51))	('p57', 'Var', (123, 126))	('DIM', 'Chemical', 'MESH:C016392', (26, 29))	('miR-221', 'Gene', '407006', (44, 51))	('upregulates', 'PosReg', (67, 78))	('PTEN', 'Gene', (111, 115))	('p53', 'Gene', (132, 135))	('proliferation', 'CPA', (210, 223))	('Panc-1', 'CellLine', 'CVCL:0480', (255, 261))	('expression', 'MPA', (52, 62))	('rat', 'Species', '10116', (217, 220))
167272	27447608	Their results prove that B-DIM increases miR-146a and hinders invasion through decreases in EGFR and NF-kappaB.	('B-DIM', 'Chemical', '-', (25, 30))	('decreases', 'NegReg', (79, 88))	('hinders', 'NegReg', (54, 61))	('increases', 'PosReg', (31, 40))	('miR-146a', 'Gene', (41, 49))	('NF-kappaB', 'Gene', '4790', (101, 110))	('EGFR', 'Gene', '1956', (92, 96))	('invasion', 'CPA', (62, 70))	('EGFR', 'Gene', (92, 96))	('miR-146a', 'Gene', '406938', (41, 49))	('NF-kappaB', 'Gene', (101, 110))	('B-DIM', 'Var', (25, 30))
167279	27447608	Altogether, this review article offers a comprehensive outline of biological mechanisms, targets, and modes of action of DIM in gastrointestinal cancer (Table 1), signifying that DIM could prospectively be beneficial for chemoprevention and as a cancer therapeutic.	('cancer', 'Disease', (145, 151))	('DIM', 'Var', (179, 182))	('DIM', 'Chemical', 'MESH:C016392', (179, 182))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (246, 252))	('DIM', 'Var', (121, 124))	('DIM', 'Chemical', 'MESH:C016392', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (128, 151))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('gastrointestinal cancer', 'Disease', (128, 151))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (128, 151))
167355	26926447	For membranous p120ctn expression, ND-BE samples had an average score of 3.7 using the quartile scoring method and an IRS score of 8.0.	('BE', 'Phenotype', 'HP:0100580', (38, 40))	('membranous', 'Var', (4, 14))	('p120ctn', 'Gene', '1500', (15, 22))	('p120ctn', 'Gene', (15, 22))
167364	26926447	These data demonstrate that through the progression from ND-BE to EAC, p120ctn membranous expression is significantly decreased (p <= 0.001 for both scoring methods) (Additional file 1: Figure S1c and d).	('EAC', 'Phenotype', 'HP:0011459', (66, 69))	('BE', 'Phenotype', 'HP:0100580', (60, 62))	('decreased', 'NegReg', (118, 127))	('EAC', 'Var', (66, 69))	('p120ctn', 'Gene', (71, 78))	('p120ctn', 'Gene', '1500', (71, 78))
167381	26926447	For these reasons, we focused on IRS scoring to test if our IHC panel can aid in the accurate diagnosis of partial/non-consensus samples.	('aid', 'Gene', '57379', (74, 77))	('aid', 'Gene', (74, 77))	('partial/non-consensus', 'Var', (107, 128))
167402	26926447	Also, c-myc copy number gain has been found to play a key role in the process of disease progression in cervical dysplasia.	('copy number', 'Var', (12, 23))	('gain', 'PosReg', (24, 28))	('c-myc', 'Gene', '4609', (6, 11))	('c-myc', 'Gene', (6, 11))	('cervical dysplasia', 'Disease', 'MESH:D002575', (104, 122))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (104, 122))	('cervical dysplasia', 'Disease', (104, 122))
167434	26630178	With this model system, we found that Pax9 knockdown resulted in loss or disorganization of the squamous epithelium, as well as down-regulation of the differentiation markers Krt4 and Krt5.	('loss', 'NegReg', (65, 69))	('Krt5', 'Gene', '797351', (184, 188))	('Pax9', 'Gene', (38, 42))	('knockdown', 'Var', (43, 52))	('disorganization', 'CPA', (73, 88))	('Krt5', 'Gene', (184, 188))	('Krt4', 'Gene', (175, 179))	('Krt4', 'Gene', '794486', (175, 179))	('down-regulation', 'NegReg', (128, 143))
167439	26630178	For example, P63 regulates growth, invasion and metastasis of esophageal squamous cell carcinoma (ESCC) cells, and Sox2 functions as an amplified lineage-survival oncogene in ESCC.	('P63', 'Var', (13, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('growth', 'CPA', (27, 33))	('metastasis of esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (48, 96))	('regulates', 'Reg', (17, 26))	('Sox2', 'Gene', (115, 119))	('Sox2', 'Gene', '378723', (115, 119))	('invasion', 'CPA', (35, 43))	('metastasis of esophageal squamous cell carcinoma', 'Disease', (48, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
167472	26630178	To confirm the effect on splicing induced by P63 and Pax9 MOs, 50 zebrafish embryos injected with P63 MO-2, Pax9 MO-1 and control MO were collected at 3, 5 and 7 dpf.	('P63 MO-2', 'Var', (98, 106))	('zebrafish', 'Species', '7955', (66, 75))	('splicing', 'MPA', (25, 33))	('dpf', 'Chemical', '-', (162, 165))
167488	26630178	In order to examine the suitability of this squamous epithelium for molecular studies of esophageal epithelial development, we knocked down P63, a transcription factor known to be critical for mammalian esophageal development, using an antisense MO to interfere with mRNA splicing of P63 transcripts.	('mRNA', 'MPA', (267, 271))	('knocked', 'Var', (127, 134))	('mammalian', 'Species', '9606', (193, 202))	('P63', 'Gene', (140, 143))
167491	26630178	On the contrary, in zebrafish injected with the antisense MO, the un-spliced transcript was abundant at 3dpf, and still detectable at 5dpf and 7dpf, suggesting that the MO knockdown effect lasted up to 7 days after injection (Fig 2G).	('zebrafish', 'Species', '7955', (20, 29))	('dpf', 'Chemical', '-', (144, 147))	('knockdown', 'NegReg', (172, 181))	('to 7', 'Species', '1214577', (199, 203))	('dpf', 'Chemical', '-', (135, 138))	('dpf', 'Chemical', '-', (105, 108))	('antisense', 'Var', (48, 57))
167492	26630178	Consistent with the RT-PCR data, IHC showed that P63 protein was also reduced in the esophageal squamous epithelium (ESQE) at 7dpf as compared with that in control samples (Fig 2A and 2B).	('reduced', 'NegReg', (70, 77))	('P63', 'Var', (49, 52))	('esophageal squamous', 'Disease', 'MESH:D000077277', (85, 104))	('esophageal squamous', 'Disease', (85, 104))	('dpf', 'Chemical', '-', (127, 130))
167493	26630178	Furthermore, antisense MO caused loss of the pectoral fins (Fig 2C and 2D) in 67% of the injected zebrafish (S2B Fig), which was similar to the armless phenotype in P63 knockout mice.	('zebrafish', 'Species', '7955', (98, 107))	('mice', 'Species', '10090', (178, 182))	('loss', 'NegReg', (33, 37))	('antisense MO', 'Var', (13, 25))	('pectoral fins', 'CPA', (45, 58))
167494	26630178	Using serial sectioning and H&E staining, we found that P63 knockdown resulted in loss of the whole epithelium in 45% zebrafish (S3B Fig) and disappearance of the dead cell layer (Fig 2E and 2F) in 55% zebrafish (S2C Fig).	('zebrafish', 'Species', '7955', (202, 211))	('and', 'NegReg', (138, 141))	('H&E', 'Chemical', '-', (28, 31))	('zebrafish', 'Species', '7955', (118, 127))	('that', 'Gene', (51, 55))	('P63', 'Var', (56, 59))
167496	26630178	In addition, the number of squamous epithelial cells was also significantly reduced in P63 knockdown zebrafish as compared to controls (Fig 2H).	('zebrafish', 'Species', '7955', (101, 110))	('reduced', 'NegReg', (76, 83))	('knockdown', 'Var', (91, 100))	('P63', 'Gene', (87, 90))
167502	26630178	As expected, Pax9 knockdown resulted in defects of the jaw, hypomandibular cartilage and palatal skeleton (Fig 3A, 3B, 3C and 3D), which was similar to the phenotype in Pax9 knockout mice.	('knockdown', 'Var', (18, 27))	('hypomandibular cartilage and palatal skeleton', 'Disease', 'MESH:D002972', (60, 105))	('Pax9', 'Gene', (13, 17))	('defects of the jaw', 'Disease', (40, 58))	('mice', 'Species', '10090', (183, 187))	('defects of the jaw', 'Disease', 'MESH:D007569', (40, 58))
167503	26630178	Moreover, Pax9 knockdown resulted in a loss of the epithelium in 52% of zebrafish (S2C Fig), and a disorganized epithelium (elongation of epithelial cells and loss of the dead cell layer) in 48% of zebrafish (Fig 3E and 3F) (S2C Fig).	('knockdown', 'Var', (15, 24))	('Pax9', 'Gene', (10, 14))	('zebrafish', 'Species', '7955', (72, 81))	('loss', 'NegReg', (39, 43))	('zebrafish', 'Species', '7955', (198, 207))
167504	26630178	In those zebrafish with ESQE, the number of squamous epithelial cells also significantly decreased in Pax9 knockdown zebrafish as compared with controls (Fig 3L).	('knockdown', 'Var', (107, 116))	('Pax9', 'Gene', (102, 106))	('zebrafish', 'Species', '7955', (117, 126))	('zebrafish', 'Species', '7955', (9, 18))	('number of squamous epithelial cells', 'CPA', (34, 69))	('decreased', 'NegReg', (89, 98))
167505	26630178	This epithelium was found on 3-4 sections per zebrafish in Pax9 knockdown zebrafish as compared with 8-10 sections in control zebrafish (S2D Fig).	('zebrafish', 'Species', '7955', (126, 135))	('Pax9', 'Gene', (59, 63))	('zebrafish', 'Species', '7955', (46, 55))	('zebrafish', 'Species', '7955', (74, 83))	('knockdown', 'Var', (64, 73))
167506	26630178	In addition, Pax9 knockdown impaired the differentiation of ESQE as evidenced by down-regulation of differentiation markers, Krt5 and Krt4 (Fig 3G, 3H, 3I and 3J).	('Krt4', 'Gene', '794486', (134, 138))	('knockdown', 'Var', (18, 27))	('Krt5', 'Gene', '797351', (125, 129))	('Pax9', 'Gene', (13, 17))	('impaired', 'NegReg', (28, 36))	('down-regulation', 'NegReg', (81, 96))	('ESQE', 'Disease', (60, 64))	('Krt5', 'Gene', (125, 129))	('Krt4', 'Gene', (134, 138))	('differentiation', 'CPA', (41, 56))
167507	26630178	A schematic cartoon is drawn to show the phenotype of ESQE in Pax9 knockdown zebrafish at 7dpf (Fig 3M and 3N).	('dpf', 'Chemical', '-', (91, 94))	('knockdown', 'Var', (67, 76))	('zebrafish', 'Species', '7955', (77, 86))	('Pax9', 'Gene', (62, 66))
167518	26630178	Similarly, knocking down P63 in zebrafish resulted in a thinner and less squamous epithelium, suggesting the feasibility of this zebrafish model for developmental study.	('knocking down', 'Var', (11, 24))	('less', 'NegReg', (68, 72))	('P63', 'Gene', (25, 28))	('zebrafish', 'Species', '7955', (129, 138))	('zebrafish', 'Species', '7955', (32, 41))
167519	26630178	Our data showed that Pax9 knockdown in zebrafish impaired differentiation of ESQE, supporting an important role of Pax9 in the pathogenesis of Barrett's esophagus and ESCC.	('differentiation', 'MPA', (58, 73))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (143, 162))	('Pax9', 'Gene', (21, 25))	('ESCC', 'Disease', (167, 171))	("Barrett's esophagus", 'Disease', (143, 162))	('knockdown', 'Var', (26, 35))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (143, 162))	('zebrafish', 'Species', '7955', (39, 48))	('impaired', 'NegReg', (49, 57))
167520	26630178	Given the fact that genomic knockout of Pax9 in mouse resulted in postnatal death with no visible phenotype, we generated a Krt5Cre;Pax9fl/fl mouse line for conditional knockout of Pax9 in esophageal epithelium.	('Krt5', 'Gene', '797351', (124, 128))	('Pax9', 'Gene', (181, 185))	('mouse', 'Species', '10090', (48, 53))	('mouse', 'Species', '10090', (142, 147))	('postnatal death', 'Disease', (66, 81))	('postnatal death', 'Disease', 'MESH:D003643', (66, 81))	('knockout', 'Var', (28, 36))	('Krt5', 'Gene', (124, 128))	('Pax9', 'Gene', (40, 44))
167557	26322395	For all stages, there were more patients with male gender, white race, married, diagnosed in 2000-2011, non-GE junction site, grade II-III, and adenocarcinoma histology.	('grade II-III', 'Var', (126, 138))	('patients', 'Species', '9606', (32, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('adenocarcinoma', 'Disease', (144, 158))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('non-GE junction site', 'Disease', (104, 124))
167651	25841575	There were no significant difference in the rates of GI bleeding, perforation, or hospitalization among different racial groups, but Asians had a significantly higher stricture rate compared to Caucasians (10.0% vs. 4.1%; p = 0.02) (Table 4).	('higher', 'PosReg', (160, 166))	('stricture', 'MPA', (167, 176))	('GI bleeding', 'Disease', 'MESH:D006470', (53, 64))	('Asians', 'Var', (133, 139))	('GI bleeding', 'Phenotype', 'HP:0002239', (53, 64))	('GI bleeding', 'Disease', (53, 64))
167676	25841575	found that among 115 patients with histologically confirmed BE, although non-statistically significant, non-Hispanic whites had increased dysplasia (7% non-Hispanic whites vs. 0% African Americans and Others; p = 0.763).	('dysplasia', 'Disease', (138, 147))	('dysplasia', 'Disease', 'MESH:D004476', (138, 147))	('non-Hispanic whites', 'Var', (104, 123))	('increased', 'PosReg', (128, 137))	('patients', 'Species', '9606', (21, 29))	('BE', 'Phenotype', 'HP:0100580', (60, 62))
167698	19174788	Understanding gastrointestinal disease has indicated that germline adenomatous polyposis coli mutations predispose with a 99% certainty to colorectal cancer, whereas squamous esophageal cancer is caused by a combination of environmental exposures (including alcohol consumption, cigarette smoke, ingestion of contaminated preserved food) and/or infection (specifically with human papilloma virus), in most cases.	('gastrointestinal disease', 'Disease', (14, 38))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('mutations', 'Var', (94, 103))	('colorectal cancer', 'Disease', 'MESH:D015179', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colorectal cancer', 'Disease', (139, 156))	('human papilloma virus', 'Species', '10566', (374, 395))	('gastrointestinal disease', 'Disease', 'MESH:D005767', (14, 38))	('papilloma', 'Phenotype', 'HP:0012740', (380, 389))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (67, 93))	('squamous esophageal cancer', 'Disease', 'MESH:D004938', (166, 192))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (67, 88))	('alcohol', 'Chemical', 'MESH:D000438', (258, 265))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (67, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (139, 156))	('gastrointestinal disease', 'Phenotype', 'HP:0011024', (14, 38))	('squamous esophageal cancer', 'Disease', (166, 192))	('adenomatous polyposis coli', 'Disease', (67, 93))
167700	19174788	In this edition of the Journal, there is intriguing evidence that a common, single base-pair change in the secondary messenger gene GNbeta3 (i.e., a single-nucleotide polymorphism) may be important, perhaps through promoting abnormal perception of visceral pain in the esophagus.	('visceral pain', 'Disease', (248, 261))	('abnormal perception of visceral pain', 'Phenotype', 'HP:0010832', (225, 261))	('single-nucleotide polymorphism', 'Var', (149, 179))	('visceral pain', 'Disease', 'MESH:D059265', (248, 261))	('beta3', 'Gene', '1934', (134, 139))	('pain in the esophagus', 'Phenotype', 'HP:0100633', (257, 278))	('pain', 'Phenotype', 'HP:0012531', (257, 261))	('promoting', 'PosReg', (215, 224))	('beta3', 'Gene', (134, 139))
167703	19174788	The classical paradigm of inherited predisposition to gastrointestinal (GI) disease is familial adenomatous polyposis, in which adenomatous polyposis coli germline mutations are associated with a 99% rate of colorectal cancer by 40 years of age.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('colorectal cancer', 'Disease', 'MESH:D015179', (208, 225))	('associated with', 'Reg', (178, 193))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (128, 149))	('gastrointestinal (GI) disease', 'Disease', 'MESH:D005767', (54, 83))	('familial adenomatous polyposis', 'Disease', (87, 117))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (128, 154))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (128, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (208, 225))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (87, 117))	('adenomatous polyposis coli', 'Disease', (128, 154))	('germline mutations', 'Var', (155, 173))	('colorectal cancer', 'Disease', (208, 225))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (96, 117))
167708	19174788	Polymorphisms in the 825T allele of the GNbeta3 gene may thus mediate an increased response to acid neurotransmitters.	('increased', 'PosReg', (73, 82))	('beta3', 'Gene', (42, 47))	('response to acid neurotransmitters', 'MPA', (83, 117))	('Polymorphisms in', 'Var', (0, 16))	('beta3', 'Gene', '1934', (42, 47))
167716	19174788	The only genetic association reported in functional dyspepsia is the link to GNbeta3; this has been found in the United States, Europe, and Asia, although the sample sizes remain relatively small in all of these studies, which may account for some of the variability in the associations detected (Table 1).	('functional dyspepsia', 'Disease', (41, 61))	('dyspepsia', 'Phenotype', 'HP:0410281', (52, 61))	('functional dyspepsia', 'Disease', 'MESH:D004415', (41, 61))	('beta3', 'Gene', '1934', (79, 84))	('link', 'Var', (69, 73))	('beta3', 'Gene', (79, 84))
167740	33937139	The other risk factors implicated in the causation of ECs include consumption of very hot liquids, lack of fruits and vegetables, consumption of mate tea, poor oral hygiene, opioid use, polycyclic aromatic hydrocarbon exposure, chewing betel nuts, and association with Helicobacter pylori infection among others.	('poor oral', 'Phenotype', 'HP:0000160', (155, 164))	('polycyclic', 'Var', (186, 196))	('Helicobacter pylori', 'Species', '210', (269, 288))	('infection', 'Disease', (289, 298))	('polycyclic aromatic hydrocarbon', 'Chemical', 'MESH:D011084', (186, 217))	('infection', 'Disease', 'MESH:D007239', (289, 298))	('association', 'Interaction', (252, 263))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (269, 298))
167764	33659048	Therefore, alteration in CYPs function within alimentary canal could contribute to GI carcinogenesis and affect the response of tumors to chemotherapy.	('GI carcinogenesis', 'Disease', (83, 100))	('GI carcinogenesis', 'Disease', 'MESH:D063646', (83, 100))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('affect', 'Reg', (105, 111))	('response', 'MPA', (116, 124))	('CYP', 'Gene', (25, 28))	('alteration', 'Var', (11, 21))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('contribute', 'Reg', (69, 79))	('CYP', 'Gene', '4051', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
167780	33659048	Tissue specific CYPs produce different ratios of EET regioisomers, thereby alterations in CYPs activity could reduce the availability of AA for other metabolic pathways.	('CYP', 'Gene', '4051', (90, 93))	('availability of AA', 'MPA', (121, 139))	('EET regioisomers', 'MPA', (49, 65))	('CYP', 'Gene', (16, 19))	('CYP', 'Gene', '4051', (16, 19))	('rat', 'Species', '10116', (39, 42))	('alterations', 'Var', (75, 86))	('activity', 'MPA', (95, 103))	('rat', 'Species', '10116', (79, 82))	('CYP', 'Gene', (90, 93))	('reduce', 'NegReg', (110, 116))
167801	33659048	In fact, Jiang and co-authors characterized CYP2J2 expression in tissue samples obtained from 130 patients with different types of cancer.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('patients', 'Species', '9606', (98, 106))	('CYP2J2', 'Var', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
167803	33659048	The CYP2J2 expression was observed in most samples from all tumor types, including ESSC (20 of 31) and EAC (4 of 4).	('CYP2J2', 'Var', (4, 10))	('EAC', 'Disease', (103, 106))	('ESSC', 'Disease', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('observed', 'Reg', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('EAC', 'Phenotype', 'HP:0011459', (103, 106))	('tumor', 'Disease', (60, 65))
167804	33659048	The data demonstrated that CYP2J2 plays an important role in the pathogenesis and progression of several types of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rat', 'Species', '10116', (16, 19))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('CYP2J2', 'Var', (27, 33))
167805	33659048	Notably, CYP2J2 has been associated with inflammation and the pathogenesis of Crohn's disease.	('CYP2J2', 'Var', (9, 15))	('associated', 'Reg', (25, 35))	("Crohn's disease", 'Phenotype', 'HP:0100280', (78, 93))	('inflammation', 'Disease', 'MESH:D007249', (41, 53))	("Crohn's disease", 'Disease', 'MESH:D003424', (78, 93))	("Crohn's disease", 'Disease', (78, 93))	('inflammation', 'Disease', (41, 53))
167806	33659048	Interestingly, inhibition of CYP2J2 with terfenadine-related compounds decreased EET production and suppressed growth and proliferation in human tongue carcinoma cells and in murine xenograft models.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('EET production', 'MPA', (81, 95))	('tongue carcinoma', 'Disease', (145, 161))	('rat', 'Species', '10116', (129, 132))	('murine', 'Species', '10090', (175, 181))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (145, 161))	('human', 'Species', '9606', (139, 144))	('CYP2J2', 'Gene', (29, 35))	('suppressed', 'NegReg', (100, 110))	('terfenadine', 'Chemical', 'MESH:D016593', (41, 52))	('tongue carcinoma', 'Disease', 'MESH:D014062', (145, 161))	('decreased', 'NegReg', (71, 80))	('inhibition', 'Var', (15, 25))
167807	33659048	Together, these findings suggest that CYP2J2 might contribute to neoplastic pathogenesis of GI epithelium.	('contribute', 'Reg', (51, 61))	('GI', 'Gene', '2770', (92, 94))	('CYP2J2', 'Var', (38, 44))
167808	33659048	Alterations of CYP expression in patients with ESCC support a potential role of these enzymes in the pathogenesis of esophageal malignancies.	('CYP', 'Gene', (15, 18))	('patients', 'Species', '9606', (33, 41))	('CYP', 'Gene', '4051', (15, 18))	('Alterations', 'Var', (0, 11))	('ESCC', 'Disease', (47, 51))	('esophageal malignancies', 'Phenotype', 'HP:0100751', (117, 140))	('malignancies', 'Disease', 'MESH:D009369', (128, 140))	('age', 'Gene', (122, 125))	('rat', 'Species', '10116', (4, 7))	('age', 'Gene', '5973', (122, 125))	('malignancies', 'Disease', (128, 140))
167813	33659048	Additionally, the increased expression of CYP2J2 relative to adjacent normal tissue was shown in 5 out of 5 studied human gastric cancer samples.	('CYP2J2', 'Var', (42, 48))	('increased', 'PosReg', (18, 27))	('expression', 'MPA', (28, 38))	('gastric cancer', 'Disease', (122, 136))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('human', 'Species', '9606', (116, 121))
167825	33659048	Tumor-specific expression of CYP2W1 was detected in approximately 30% of higher-grade colon cancers, while the expression of this enzyme was insignificant in normal colon tissues.	('colon cancers', 'Disease', (86, 99))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CYP2W1', 'Var', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('colon cancers', 'Phenotype', 'HP:0003003', (86, 99))	('detected', 'Reg', (40, 48))	('colon cancers', 'Disease', 'MESH:D015179', (86, 99))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
167826	33659048	Interestingly, mouse and human developmental studies showed that CYP2W1 is expressed in the small intestine and colon tissues in the early stages of embryonic development and silenced shortly after birth.	('age', 'Gene', '5973', (141, 144))	('CYP2W1', 'Var', (65, 71))	('human', 'Species', '9606', (25, 30))	('age', 'Gene', (141, 144))	('mouse', 'Species', '10090', (15, 20))
167829	33659048	Although activation of CYP2W1 by demethylation in colorectal cancer (CRC) has been confirmed, the precise mechanisms of epigenetic modifications of CYP2W1 gene remain unclear.	('CRC', 'Phenotype', 'HP:0030731', (69, 72))	('activation', 'PosReg', (9, 19))	('CYP2W1', 'Gene', (23, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('demethylation', 'Var', (33, 46))	('CRC', 'Phenotype', 'HP:0003003', (69, 72))	('CYP2W1', 'Gene', (148, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colorectal cancer', 'Disease', (50, 67))
167831	33659048	Larger scale clinical studies will be required to validate the potential application of CYP2W1 as a prognostic cancer biomarker.	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CYP2W1', 'Var', (88, 94))
167855	33659048	AQ4N does not bind to DNA, while its derivative AQ4 has a high DNA affinity and is a potent topoisomerase II inhibitor, preventing tumor cells from proliferating.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('AQ4', 'Var', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('DNA affinity', 'Interaction', (63, 75))	('preventing', 'NegReg', (120, 130))	('AQ4', 'Chemical', '-', (0, 3))	('AQ4', 'Chemical', '-', (48, 51))	('rat', 'Species', '10116', (155, 158))
167857	33659048	AQ4N, as a potential hypoxia-activated cancer chemotherapy drug, underwent clinical trials (NCT00394628).	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('hypoxia', 'Disease', 'MESH:D000860', (21, 28))	('AQ4N', 'Var', (0, 4))	('hypoxia', 'Disease', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('AQ4', 'Chemical', '-', (0, 3))
167858	33659048	It has been shown that intra-tumoral injection of CYP3A4, CYP2B6 and CYP1A1 gene constructs in combination with AQ4N and radiation suppresses the growth of tumors in RIF-1 sarcoma mouse model.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('CYP3A4', 'Gene', '1576', (50, 56))	('tumor', 'Disease', (156, 161))	('CYP3A4', 'Gene', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('RIF-1 sarcoma', 'Disease', 'MESH:D012509', (166, 179))	('RIF-1 sarcoma', 'Disease', (166, 179))	('mouse', 'Species', '10090', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('AQ4', 'Chemical', '-', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', (156, 162))	('CYP2B6', 'Gene', '1555', (58, 64))	('CYP2B6', 'Gene', (58, 64))	('CYP1A1 gene', 'Var', (69, 80))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('suppresses', 'NegReg', (131, 141))
167862	33659048	An approach was proposed to use CYP2W1 as a new tumor-associated antigen for cancer immunotherapy.	('tumor', 'Disease', (48, 53))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('CYP2W1', 'Var', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
167863	33659048	Notably, the imatinib-induced expression of tumor CYP2W1 followed by activation of duocarmycin prodrugs was suggested as an adjuvant therapy of CRC.	('CRC', 'Phenotype', 'HP:0030731', (144, 147))	('CRC', 'Phenotype', 'HP:0003003', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('CYP2W1', 'Var', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('imatinib', 'Chemical', 'MESH:D000068877', (13, 21))	('duocarmycin', 'MPA', (83, 94))	('tumor', 'Disease', (44, 49))	('CRC', 'Disease', (144, 147))
167864	33659048	Additionally, CYP2W1 was reported to metabolize high affinity exogenous indolines, especially chloromethylindolines, into cytotoxic metabolites that inhibit growth of human colon tumors in a mouse xenograft model.	('chloromethylindolines', 'Chemical', '-', (94, 115))	('inhibit', 'NegReg', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('CYP2W1', 'Var', (14, 20))	('colon tumors', 'Disease', 'MESH:D003110', (173, 185))	('colon tumors', 'Phenotype', 'HP:0100273', (173, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('indolines', 'Chemical', 'MESH:C057812', (106, 115))	('growth', 'MPA', (157, 163))	('mouse', 'Species', '10090', (191, 196))	('indolines', 'Chemical', 'MESH:C057812', (72, 81))	('human', 'Species', '9606', (167, 172))	('colon tumors', 'Disease', (173, 185))
167865	33659048	The CRC specific expression of CYP2W1 and its effective activation of prodrugs makes it a valuable target for novel cancer therapeutics.	('CRC', 'Phenotype', 'HP:0003003', (4, 7))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('CRC', 'Phenotype', 'HP:0030731', (4, 7))	('activation', 'MPA', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CYP2W1', 'Var', (31, 37))
167867	33659048	An increasing body of evidence indicates that many medications, including those used in cancer treatment, are substrates for CYP2J2.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('rat', 'Species', '10116', (115, 118))	('CYP2J2', 'Var', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
167868	33659048	CYP2J2 and CYP3A4 play a key role in the metabolism of cancer drugs known to cause cardiotoxicity.	('cardiotoxicity', 'Disease', 'MESH:D066126', (83, 97))	('CYP3A4', 'Gene', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cardiotoxicity', 'Disease', (83, 97))	('CYP3A4', 'Gene', '1576', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('metabolism', 'MPA', (41, 51))	('CYP2J2', 'Var', (0, 6))
167876	33659048	The drug-metabolizing function of CYPs can be affected by genetic polymorphism of these enzymes.	('genetic polymorphism', 'Var', (58, 78))	('drug-metabolizing function', 'MPA', (4, 30))	('CYP', 'Gene', (34, 37))	('CYP', 'Gene', '4051', (34, 37))	('affected', 'Reg', (46, 54))
167881	33659048	While multiple studies have shown that CYP1A1 genetic polymorphisms (CYP1A1 Msp I and CYP1A1 Ile/Val) could be risk factors for esophageal, gastric, and colorectal cancers, the current data remain controversial.	('risk factors', 'Reg', (111, 123))	('gastric', 'Disease', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('age', 'Gene', (133, 136))	('CYP1A1', 'Gene', (39, 45))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('age', 'Gene', '5973', (133, 136))	('colorectal cancers', 'Disease', 'MESH:D015179', (153, 171))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('CYP1A1', 'Var', (86, 92))	('colorectal cancers', 'Disease', (153, 171))
167882	33659048	Notably, a meta-analysis of the published data of CYP1A1 and CYP1A2 polymorphisms in different ethnicities revealed possible associations between CYP1A1 MspI and CYP1A2*1F polymorphisms and gastric cancer, and no significant associations between CYP1A1 Ile462Val polymorphism and gastric cancer.	('Ile462Val', 'Chemical', '-', (253, 262))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('CYP1A2', 'Gene', '1544', (162, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (280, 294))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('gastric cancer', 'Disease', (280, 294))	('CYP1A1', 'Gene', (146, 152))	('CYP1A2', 'Gene', '1544', (61, 67))	('polymorphisms', 'Var', (172, 185))	('CYP1A2', 'Gene', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('CYP1A2', 'Gene', (61, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (280, 294))	('gastric cancer', 'Disease', (190, 204))
167884	33659048	Particularly, the study of single nucleotide polymorphisms (SNPs) of CYP1A1 (rs4646421, rs4646422, and rs1048943), GSTM1, and GSTT1, the key enzymes in the carcinogen metabolizing pathway, revealed that CYP1A1 (rs4646422) polymorphism could be implicated in gastric carcinogenesis in the Japanese population.	('implicated', 'Reg', (244, 254))	('GSTM1', 'Gene', (115, 120))	('CYP1A1', 'Gene', (69, 75))	('rs4646422', 'Mutation', 'rs4646422', (88, 97))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (258, 280))	('rs4646422', 'Mutation', 'rs4646422', (211, 220))	('GSTT1', 'Gene', (126, 131))	('rs4646422', 'Var', (211, 220))	('GSTT1', 'Gene', '2952', (126, 131))	('rs4646421', 'Mutation', 'rs4646421', (77, 86))	('rs4646421', 'Var', (77, 86))	('GSTM1', 'Gene', '2944', (115, 120))	('rs1048943', 'Var', (103, 112))	('rs1048943', 'Mutation', 'rs1048943', (103, 112))	('CYP1A1', 'Gene', (203, 209))	('gastric carcinogenesis', 'Disease', (258, 280))
167885	33659048	The key SNP, rs890293, is in the proximal promoter at (-76 G>T) and disrupts one of the SP1 binding sites, which results in 50% decrease of promoter activity as compared to the wild-type promoter.	('disrupts', 'NegReg', (68, 76))	('rs890293', 'Mutation', 'rs890293', (13, 21))	('-76 G>T', 'Mutation', 'rs890293', (55, 62))	('promoter activity', 'MPA', (140, 157))	('SP1', 'Protein', (88, 91))	('decrease', 'NegReg', (128, 136))	('rs890293', 'Var', (13, 21))
167886	33659048	Pharmacogenetic studies in patients with gastric ulcers under H. pylori eradication therapy demonstrated the effect of CYP2C19 polymorphism on pharmacokinetics of proton pump inhibitors (PPI), omeprazole, lansoprazole, pantoprazole, and to a lesser extent, rabeprazole.	('polymorphism', 'Var', (127, 139))	('CYP2C19', 'Gene', (119, 126))	('rabeprazole', 'Chemical', 'MESH:D064750', (257, 268))	('proton pump', 'Gene', '495', (163, 174))	('gastric ulcers', 'Phenotype', 'HP:0002592', (41, 55))	('rat', 'Species', '10116', (99, 102))	('H. pylori', 'Species', '210', (62, 71))	('proton pump', 'Gene', (163, 174))	('patients', 'Species', '9606', (27, 35))	('gastric ulcers', 'Disease', 'MESH:D013276', (41, 55))	('CYP2C19', 'Gene', '1557', (119, 126))	('effect', 'Reg', (109, 115))	('omeprazole', 'Chemical', 'MESH:D009853', (193, 203))	('pantoprazole', 'Chemical', 'MESH:D000077402', (219, 231))	('gastric ulcers', 'Disease', (41, 55))	('pharmacokinetics', 'MPA', (143, 159))	('lansoprazole', 'Chemical', 'MESH:D064747', (205, 217))
167892	33659048	Surprisingly, esomeprazole-induced healing of GERD was not associated with the CYP2C19 polymorphism and was explained by the CYP3A4 metabolic activity.	('CYP2C19', 'Gene', '1557', (79, 86))	('CYP3A4', 'Gene', (125, 131))	('polymorphism', 'Var', (87, 99))	('esomeprazole', 'Chemical', 'MESH:D064098', (14, 26))	('CYP2C19', 'Gene', (79, 86))	('GERD', 'Disease', (46, 50))	('CYP3A4', 'Gene', '1576', (125, 131))	('GERD', 'Disease', 'MESH:D005764', (46, 50))
167895	33659048	While monogenic polymorphisms explain the variability for only few enzymes, most enzymes are controlled by several factors that include additional polymorphisms in regulatory genes and factors such as sex, age, disease, and hormones.	('controlled by', 'Reg', (93, 106))	('polymorphisms', 'Var', (147, 160))	('age', 'Gene', '5973', (206, 209))	('age', 'Gene', (206, 209))
167913	27697099	High TRAF6 Expression Is Associated With Esophageal Carcinoma Recurrence and Prompts Cancer Cell Invasion Esophageal cancer is one of the most common types of cancer, and it has a poor prognosis.	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('High', 'Var', (0, 4))	('Cancer', 'Disease', (85, 91))	('Carcinoma', 'Disease', (52, 61))	('Expression', 'MPA', (11, 21))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (41, 61))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Carcinoma', 'Disease', 'MESH:D009369', (52, 61))	('Cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('Carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('TRAF6', 'Gene', (5, 10))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('TRAF6', 'Gene', '7189', (5, 10))	('cancer', 'Disease', (117, 123))	('Associated With', 'Reg', (25, 40))
167918	27697099	Expression of TRAF6 was highly elevated in esophageal cancer tissues, and patients with high TRAF6 expression have a significantly shorter survival time than those with low TRAF6 expression.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('TRAF6', 'Gene', (93, 98))	('high', 'Var', (88, 92))	('TRAF6', 'Gene', '7189', (14, 19))	('TRAF6', 'Gene', '7189', (93, 98))	('Expression', 'MPA', (0, 10))	('patients', 'Species', '9606', (74, 82))	('TRAF6', 'Gene', (173, 178))	('TRAF6', 'Gene', '7189', (173, 178))	('elevated', 'PosReg', (31, 39))	('shorter', 'NegReg', (131, 138))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('survival time', 'CPA', (139, 152))	('TRAF6', 'Gene', (14, 19))
167919	27697099	Furthermore, loss-of-function experiments showed that knockdown of TRAF6 significantly reduced the migration and invasion abilities of esophageal cancer cells.	('loss-of-function', 'NegReg', (13, 29))	('knockdown', 'Var', (54, 63))	('reduced', 'NegReg', (87, 94))	('esophageal cancer', 'Disease', (135, 152))	('TRAF6', 'Gene', (67, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('TRAF6', 'Gene', '7189', (67, 72))	('invasion abilities of', 'CPA', (113, 134))
167921	27697099	Altogether, our data suggest that high expression of TRAF6 is significant for esophageal cancer progression, and TRAF6 indicates poor prognosis in esophageal cancer patients, which might be a novel prognostic biomarker or potential therapeutic target in esophageal cancer.	('esophageal cancer', 'Disease', (147, 164))	('esophageal cancer', 'Disease', (254, 271))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('poor', 'NegReg', (129, 133))	('esophageal cancer', 'Disease', 'MESH:D004938', (254, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('TRAF6', 'Gene', (53, 58))	('high', 'Var', (34, 38))	('TRAF6', 'Gene', '7189', (53, 58))	('TRAF6', 'Gene', (113, 118))	('patients', 'Species', '9606', (165, 173))	('expression', 'MPA', (39, 49))	('esophageal cancer', 'Disease', (78, 95))	('TRAF6', 'Gene', '7189', (113, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
167925	27697099	Therefore, alteration of Ub ligases is a frequent event in cancer.	('Ub ligases', 'Protein', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('alteration', 'Var', (11, 21))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
167927	27697099	Amplified TRAF6 locus was found to be a somatic and frequent event in several human cancer types.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('TRAF6', 'Gene', '7189', (10, 15))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('human', 'Species', '9606', (78, 83))	('TRAF6', 'Gene', (10, 15))	('Amplified', 'Var', (0, 9))
167937	27697099	Altogether, our results suggest that high expression of TRAF6 increased EC cell migration and invasion.	('invasion', 'CPA', (94, 102))	('increased', 'PosReg', (62, 71))	('high expression', 'Var', (37, 52))	('TRAF6', 'Gene', (56, 61))	('TRAF6', 'Gene', '7189', (56, 61))
167938	27697099	In addition, high TRAF6 expression was significantly related to a short time to relapse in patients suffering from EC, suggesting that TRAF6 might be a novel biomarker or potential therapeutic target in EC treatment.	('TRAF6', 'Gene', (18, 23))	('TRAF6', 'Gene', '7189', (18, 23))	('patients', 'Species', '9606', (91, 99))	('TRAF6', 'Gene', (135, 140))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('TRAF6', 'Gene', '7189', (135, 140))
167983	27697099	Moreover, the silencing of TRAF6 significantly decreased their invading capacity into Matrigel with the Transwell assay (Figs.	('silencing', 'Var', (14, 23))	('TRAF6', 'Gene', '7189', (27, 32))	('TRAF6', 'Gene', (27, 32))	('decreased', 'NegReg', (47, 56))	('invading capacity into Matrigel', 'CPA', (63, 94))
167984	27697099	Altogether, the tumor cell migration and invasion assay indicated that TRAF6 depletion significantly reduced the invasion and migration capabilities of EC cells.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('depletion', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('reduced', 'NegReg', (101, 108))	('tumor', 'Disease', (16, 21))	('TRAF6', 'Gene', (71, 76))	('TRAF6', 'Gene', '7189', (71, 76))
167986	27697099	Interestingly, our Western blot analysis found that depletion of TRAF6 dramatically reduced AEP and MMP2 (Fig.	('TRAF6', 'Gene', (65, 70))	('TRAF6', 'Gene', '7189', (65, 70))	('AEP', 'Gene', '5641', (92, 95))	('MMP2', 'Gene', (100, 104))	('AEP', 'Gene', (92, 95))	('reduced', 'NegReg', (84, 91))	('MMP2', 'Gene', '4313', (100, 104))	('depletion', 'Var', (52, 61))
167997	27697099	showed that TRAF6 knockdown reduced EC109 cell proliferation and elevated apoptosis.	('apoptosis', 'CPA', (74, 83))	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (28, 35))	('TRAF6', 'Gene', (12, 17))	('TRAF6', 'Gene', '7189', (12, 17))	('elevated', 'PosReg', (65, 73))	('EC109', 'CellLine', 'CVCL:6898', (36, 41))	('EC109 cell proliferation', 'CPA', (36, 60))
167998	27697099	In our studies, we constructed two EC cells with stably knocked-down TRAF6 and found that TRAF6 silencing significantly reduced the migration and invasion abilities of both EC cells.	('silencing', 'Var', (96, 105))	('TRAF6', 'Gene', (69, 74))	('TRAF6', 'Gene', (90, 95))	('TRAF6', 'Gene', '7189', (69, 74))	('TRAF6', 'Gene', '7189', (90, 95))	('invasion abilities', 'CPA', (146, 164))	('knocked-down', 'Var', (56, 68))	('reduced', 'NegReg', (120, 127))
168003	27697099	Our data demonstrate that TRAF6 knockdown reduced the protein levels of MMP2 and AEP.	('AEP', 'Gene', '5641', (81, 84))	('reduced', 'NegReg', (42, 49))	('AEP', 'Gene', (81, 84))	('knockdown', 'Var', (32, 41))	('MMP2', 'Gene', (72, 76))	('protein levels', 'MPA', (54, 68))	('TRAF6', 'Gene', (26, 31))	('TRAF6', 'Gene', '7189', (26, 31))	('MMP2', 'Gene', '4313', (72, 76))
168112	29719481	Only patients with tumors of clinical stage T1N1 or T2-3N0-1 with no clinical evidence of metastatic spread, according to the International Union against Cancer Tumor-Node-Metastasis classification, were enrolled.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('patients', 'Species', '9606', (5, 13))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('T2-3N0-1', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
168157	29719481	in their study in locally advanced adenocarcinoma of the esophagus found a > 67% change in baseline maximal SUV optimally predicted histopathological response(Sensitivity 79% and Specificity 75%) and they concluded that [18F]-FDG-PET CT can distinguish a group of patients with worse prognosis after NACT.	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (35, 66))	('NACT', 'Chemical', '-', (300, 304))	('patients', 'Species', '9606', (264, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('adenocarcinoma of the esophagus', 'Disease', (35, 66))	('FDG', 'Chemical', 'MESH:D019788', (226, 229))	('[18F', 'Var', (220, 224))
168164	29719481	Despite that, we could conclude by this study that [18F]-FDG-PET-CT is a good diagnostic modality for response assessment after NAT in locally advanced carcinoma esophagus patients and helps in differentiating between responders and nonresponders significantly.	('carcinoma esophagus', 'Disease', (152, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('carcinoma esophagus', 'Disease', 'MESH:D004938', (152, 171))	('carcinoma esophagus', 'Phenotype', 'HP:0011459', (152, 171))	('[18F]-FDG-PET-CT', 'Var', (51, 67))	('FDG', 'Chemical', 'MESH:D019788', (57, 60))	('patients', 'Species', '9606', (172, 180))
168169	27422292	Although the two phase I metabolites contain a catecholic structure, which is expected to be involved in redox cycling, only 4-OH-AOH increased reactive oxygen species (ROS) in human esophageal cells (KYSE510), 4 times more pronounced than AOH.	('KYSE510', 'CellLine', 'CVCL:1354', (201, 208))	('reactive oxygen species', 'MPA', (144, 167))	('4-OH-AOH', 'Chemical', '-', (125, 133))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (134, 167))	('4-OH-AOH', 'Var', (125, 133))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (144, 167))	('ROS', 'Chemical', 'MESH:D017382', (169, 172))	('AOH', 'Chemical', 'MESH:C005197', (130, 133))	('human', 'Species', '9606', (177, 182))	('AOH', 'Chemical', 'MESH:C005197', (240, 243))	('catechol', 'Chemical', 'MESH:C034221', (47, 55))	('increased', 'PosReg', (134, 143))	('catecholic structure', 'MPA', (47, 67))
168172	27422292	Although the level of ROS was significantly increased by 4-OH-AOH, neither DNA strand breaks nor enhanced levels of formamidopyrimidine-DNA-glycosylase (FPG)-sensitive sites were observed.	('DNA', 'MPA', (75, 78))	('level', 'MPA', (13, 18))	('4-OH-AOH', 'Chemical', '-', (57, 65))	('ROS', 'MPA', (22, 25))	('increased', 'PosReg', (44, 53))	('ROS', 'Chemical', 'MESH:D017382', (22, 25))	('4-OH-AOH', 'Var', (57, 65))	('formamidopyrimidine', 'Chemical', '-', (116, 135))
168272	27422292	Cell viability of KYSE510 cells was affected by AOH and 4-OH-AOH after 24 h of incubation (Fig.	('4-OH-AOH', 'Chemical', '-', (56, 64))	('KYSE510', 'CellLine', 'CVCL:1354', (18, 25))	('Cell viability', 'CPA', (0, 14))	('AOH', 'Var', (48, 51))	('AOH', 'Chemical', 'MESH:C005197', (61, 64))	('4-OH-AOH', 'Var', (56, 64))	('AOH', 'Chemical', 'MESH:C005197', (48, 51))	('affected', 'Reg', (36, 44))
168273	27422292	The mitochondrial activity was significantly reduced by 25 microM AOH by about 20 +- 10 %, whereas 25 microM 4-OH-AOH caused only a minor reduction in about 10 to 90 +- 7 % yet without statistical significance.	('reduced', 'NegReg', (45, 52))	('4-OH-AOH', 'Chemical', '-', (109, 117))	('mitochondrial activity', 'MPA', (4, 26))	('AOH', 'Var', (66, 69))	('AOH', 'Chemical', 'MESH:C005197', (66, 69))	('AOH', 'Chemical', 'MESH:C005197', (114, 117))
168277	27422292	Hydroxylation in 4-position of AOH or AME generates a catecholic structure which might undergo redox cycling.	('rat', 'Species', '10116', (46, 49))	('AME', 'Chemical', 'MESH:C018206', (38, 41))	('catecholic structure', 'MPA', (54, 74))	('catechol', 'Chemical', 'MESH:C034221', (54, 62))	('AOH', 'Chemical', 'MESH:C005197', (31, 34))	('Hydroxylation', 'Var', (0, 13))
168279	27422292	AOH, 4-OH-AOH and AME increased fluorescence intensity in a concentration-dependent manner (Fig.	('rat', 'Species', '10116', (67, 70))	('4-OH-AOH', 'Chemical', '-', (5, 13))	('increased', 'PosReg', (22, 31))	('AME', 'Chemical', 'MESH:C018206', (18, 21))	('AOH', 'Chemical', 'MESH:C005197', (10, 13))	('AOH', 'Chemical', 'MESH:C005197', (0, 3))	('4-OH-AOH', 'Var', (5, 13))	('fluorescence intensity', 'MPA', (32, 54))
168283	27422292	The ROS level generated by 50 microM 4-OH-AOH was significantly higher than that of the parent compound, whereas the fluorescence signal caused by 4-OH-AME did not exceed the signal of its parent substance.	('rat', 'Species', '10116', (18, 21))	('ROS', 'Chemical', 'MESH:D017382', (4, 7))	('ROS level', 'MPA', (4, 13))	('higher', 'PosReg', (64, 70))	('4-OH-AOH', 'Chemical', '-', (37, 45))	('4-OH-AOH', 'Var', (37, 45))	('4-OH-AME', 'Chemical', '-', (147, 155))
168287	27422292	After 20-h incubation, the bioluminescence signal was significantly raised concentration-dependently by 4-OH-AOH to 1.3 +- 0.08-fold at 50 microM (Fig.	('bioluminescence signal', 'MPA', (27, 49))	('4-OH-AOH', 'Var', (104, 112))	('rat', 'Species', '10116', (82, 85))	('raised', 'PosReg', (68, 74))	('4-OH-AOH', 'Chemical', '-', (104, 112))
168294	27422292	Inhibition of topoisomerase II activity was already apparent at a concentration of 10 microM 4-OH-AOH, and the enzyme activity was completely suppressed with 25 microM 4-OH-AOH (Fig.	('activity', 'MPA', (31, 39))	('4-OH-AOH', 'Chemical', '-', (93, 101))	('Inhibition', 'NegReg', (0, 10))	('activity', 'MPA', (118, 126))	('4-OH-AOH', 'Var', (93, 101))	('4-OH-AOH', 'Var', (168, 176))	('topoisomerase II', 'Enzyme', (14, 30))	('suppressed', 'NegReg', (142, 152))	('4-OH-AOH', 'Chemical', '-', (168, 176))	('rat', 'Species', '10116', (73, 76))
168302	27422292	To verify topoisomerase inhibition on the cellular level, the ICE assay was used, determining the amount of cleavable complexes formed with DNA and topoisomerase IIalpha or IIbeta in KYSE510 after 1-h incubation with 10 microM and 50 microM AOH, AME, 4-OH-AOH and 4-OH-AME.	('AME', 'Chemical', 'MESH:C018206', (246, 249))	('ICE', 'Gene', '834', (62, 65))	('AOH', 'Chemical', 'MESH:C005197', (256, 259))	('4-OH-AME', 'Chemical', '-', (264, 272))	('AME', 'Chemical', 'MESH:C018206', (269, 272))	('AOH', 'Chemical', 'MESH:C005197', (241, 244))	('4-OH-AOH', 'Chemical', '-', (251, 259))	('KYSE510', 'Var', (183, 190))	('ICE', 'Gene', (62, 65))	('KYSE510', 'CellLine', 'CVCL:1354', (183, 190))
168303	27422292	Topoisomerase IIbeta-DNA complexes were significantly raised to 277 +- 107 % by AOH, 208 +- 61 % by 4-OH-AOH, 203 +- 38 % by AME and 143 +- 36 % by 4-OH-AME with the highest concentration tested (Fig.	('Topoisomerase IIbeta', 'Gene', '7155', (0, 20))	('AOH', 'Chemical', 'MESH:C005197', (105, 108))	('AOH', 'Chemical', 'MESH:C005197', (80, 83))	('4-OH-AOH', 'Var', (100, 108))	('4-OH-AME', 'Chemical', '-', (148, 156))	('raised', 'PosReg', (54, 60))	('Topoisomerase IIbeta', 'Gene', (0, 20))	('AME', 'Chemical', 'MESH:C018206', (125, 128))	('rat', 'Species', '10116', (181, 184))	('AOH', 'Var', (80, 83))	('4-OH-AOH', 'Chemical', '-', (100, 108))	('AME', 'Chemical', 'MESH:C018206', (153, 156))
168306	27422292	A significant raise in tail intensities (5 +- 3.5 %, FPG-treated 6.6 +- 1.4 %) mediated by 50 microM AOH was detected, whereas 4-OH-AOH (50 microM; 3.1 +- 0.4 %, FPG-treated 3.7 +- 2.9 %) did not significantly affect DNA integrity.	('AOH', 'Chemical', 'MESH:C005197', (101, 104))	('tail intensities', 'MPA', (23, 39))	('4-OH-AOH', 'Chemical', '-', (127, 135))	('AOH', 'Var', (101, 104))	('raise', 'PosReg', (14, 19))	('AOH', 'Chemical', 'MESH:C005197', (132, 135))
168333	27422292	Of note, the amount of ROS was increased fourfold by 50 microM 4-OH-AOH as compared to AOH.	('increased', 'PosReg', (31, 40))	('4-OH-AOH', 'Var', (63, 71))	('AOH', 'Chemical', 'MESH:C005197', (68, 71))	('ROS', 'MPA', (23, 26))	('4-OH-AOH', 'Chemical', '-', (63, 71))	('ROS', 'Chemical', 'MESH:D017382', (23, 26))	('AOH', 'Chemical', 'MESH:C005197', (87, 90))
168339	27422292	Luciferase activity was indeed significantly increased by AOH, AME and 4-OH-AOH, whereas 4-OH-AME turned out to be ineffective.	('4-OH-AOH', 'Var', (71, 79))	('AME', 'Var', (63, 66))	('activity', 'MPA', (11, 19))	('AOH', 'Var', (58, 61))	('increased', 'PosReg', (45, 54))	('AME', 'Chemical', 'MESH:C018206', (63, 66))	('4-OH-AOH', 'Chemical', '-', (71, 79))	('AOH', 'Chemical', 'MESH:C005197', (58, 61))	('AME', 'Chemical', 'MESH:C018206', (94, 97))	('4-OH-AME', 'Chemical', '-', (89, 97))	('Luciferase', 'Enzyme', (0, 10))	('AOH', 'Chemical', 'MESH:C005197', (76, 79))
168349	27422292	After 24-h incubation of KYSE510 cells with 50 microM AOH or 4-OH-AOH, a significant decrease in about 40 and 50 %, respectively, in mitochondrial activity was detected in the WST-1 assay (Fig.	('AOH', 'Chemical', 'MESH:C005197', (54, 57))	('mitochondrial activity', 'MPA', (133, 155))	('decrease', 'NegReg', (85, 93))	('AOH', 'Chemical', 'MESH:C005197', (66, 69))	('4-OH-AOH', 'Chemical', '-', (61, 69))	('KYSE510', 'CellLine', 'CVCL:1354', (25, 32))	('4-OH-AOH', 'Var', (61, 69))
168350	27422292	Although 4-OH-AOH induced a higher ROS production than its parent compound, no significant difference was obvious between both regarding the impact on cell viability of KYSE510 cells exposed to the highest concentration tested.	('4-OH-AOH', 'Chemical', '-', (9, 17))	('ROS', 'Chemical', 'MESH:D017382', (35, 38))	('higher', 'PosReg', (28, 34))	('4-OH-AOH', 'Var', (9, 17))	('rat', 'Species', '10116', (213, 216))	('ROS production', 'MPA', (35, 49))	('KYSE510', 'CellLine', 'CVCL:1354', (169, 176))
168352	27422292	Under cell-free conditions 4-OH-AOH had a greater impact on topoisomerase II activity than AOH (Fig.	('4-OH-AOH', 'Var', (27, 35))	('AOH', 'Chemical', 'MESH:C005197', (32, 35))	('AOH', 'Chemical', 'MESH:C005197', (91, 94))	('topoisomerase II', 'Enzyme', (60, 76))	('activity', 'MPA', (77, 85))	('4-OH-AOH', 'Chemical', '-', (27, 35))
168354	27422292	However, in the ICE assay, detecting the impact of the test compounds on topoisomerase II within cells, it became apparent that the stronger topoisomerase inhibitory effects of 4-OH-AOH and 4-OH-AME are limited to cell-free conditions.	('4-OH-AOH', 'Chemical', '-', (177, 185))	('ICE', 'Gene', (16, 19))	('4-OH-AME', 'Chemical', '-', (190, 198))	('ICE', 'Gene', '834', (16, 19))	('topoisomerase inhibitory effects', 'MPA', (141, 173))	('stronger', 'PosReg', (132, 140))	('4-OH-AOH', 'Var', (177, 185))
168365	27422292	The question arises which mechanisms prevent the formation of DNA strand breaks in KYSE510 after AME, 4-OH-AOH and 4-OH-AME incubation, although inducing the stabilization of topoisomerase IIbeta-DNA complexes.	('DNA strand breaks', 'MPA', (62, 79))	('topoisomerase IIbeta', 'Gene', '7155', (175, 195))	('AME', 'Chemical', 'MESH:C018206', (120, 123))	('4-OH-AME', 'Chemical', '-', (115, 123))	('stabilization', 'MPA', (158, 171))	('inducing', 'Reg', (145, 153))	('KYSE510', 'Var', (83, 90))	('4-OH-AOH', 'Chemical', '-', (102, 110))	('AME', 'Chemical', 'MESH:C018206', (97, 100))	('topoisomerase IIbeta', 'Gene', (175, 195))	('KYSE510', 'CellLine', 'CVCL:1354', (83, 90))
168385	27422292	The low concentration of 4-OH-AOH and 4-OH-AME in the cell lysate after incubation might be indicative for a poor cellular uptake resulting in the minor effects observed in the ICE- and comet assay.	('4-OH-AME', 'Chemical', '-', (38, 46))	('4-OH-AOH', 'Var', (25, 33))	('rat', 'Species', '10116', (15, 18))	('poor', 'NegReg', (109, 113))	('ICE', 'Gene', (177, 180))	('cellular uptake', 'CPA', (114, 129))	('comet', 'Species', '302767', (186, 191))	('ICE', 'Gene', '834', (177, 180))	('4-OH-AOH', 'Chemical', '-', (25, 33))	('4-OH-AME', 'Var', (38, 46))
168387	27422292	Following this consideration, incubations with 4-OH-AOH exhibited increased amounts of sulfation conjugates in the incubation medium (Fig.	('increased', 'PosReg', (66, 75))	('rat', 'Species', '10116', (22, 25))	('4-OH-AOH', 'Chemical', '-', (47, 55))	('sulfation conjugates', 'MPA', (87, 107))	('amounts', 'MPA', (76, 83))	('4-OH-AOH', 'Var', (47, 55))
168390	27422292	Therefore, it seems likely that methylation of 4-OH-AOH is a way of detoxification in KYSE510 cells, which might explain the minor effects in the other assays as compared to AOH.	('AOH', 'Chemical', 'MESH:C005197', (52, 55))	('methylation', 'Var', (32, 43))	('AOH', 'Chemical', 'MESH:C005197', (174, 177))	('4-OH-AOH', 'Chemical', '-', (47, 55))	('KYSE510', 'CellLine', 'CVCL:1354', (86, 93))	('4-OH-AOH', 'Var', (47, 55))	('detoxification', 'MPA', (68, 82))
168394	27422292	Despite the huge induction of ROS by 4-OH-AOH, the transcriptional activity of Nrf2 was not affected accordingly.	('ROS', 'Protein', (30, 33))	('Nrf2', 'Gene', '4780', (79, 83))	('induction', 'PosReg', (17, 26))	('4-OH-AOH', 'Chemical', '-', (37, 45))	('Nrf2', 'Gene', (79, 83))	('4-OH-AOH', 'Var', (37, 45))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
168405	28058385	In patients with esophageal varices, P/S was found to be correlated with large varices with 82% sensitivity.	('esophageal varices', 'Disease', (17, 35))	('P/S', 'Var', (37, 40))	('large varices', 'Disease', (73, 86))	('correlated', 'Reg', (57, 67))	('S', 'Chemical', 'MESH:D013455', (39, 40))	('esophageal varices', 'Phenotype', 'HP:0002040', (17, 35))	('patients', 'Species', '9606', (3, 11))	('P', 'Chemical', 'MESH:D010758', (37, 38))
168457	28058385	Similarly, studies conducted in cirrhotic patients have demonstrated that decrease in platelet count and supranormal diameter of spleen are independent risk factors in determination of large esophageal varices.	('decrease in platelet count', 'Phenotype', 'HP:0001873', (74, 100))	('decrease', 'NegReg', (74, 82))	('esophageal varices', 'Phenotype', 'HP:0002040', (191, 209))	('large esophageal varices', 'Disease', (185, 209))	('supranormal', 'Var', (105, 116))	('platelet count', 'MPA', (86, 100))	('patients', 'Species', '9606', (42, 50))	('S', 'Chemical', 'MESH:D013455', (0, 1))
168460	28058385	demonstrated that P/S could predict presence of varices with 84% sensitivity and 70% specificity.	('S', 'Chemical', 'MESH:D013455', (20, 21))	('P/S', 'Var', (18, 21))	('P', 'Chemical', 'MESH:D010758', (18, 19))	('varices', 'Disease', (48, 55))
168475	26950245	Common Polymorphisms in IL-27 Genes May Contribute to Risk of Various Human Diseases in Asian Populations: A Meta-Analysis Genetic variations in the IL-27 gene have been proven to be associated with various types of human cancers and diseases.	('human', 'Species', '9606', (216, 221))	('Contribute', 'Reg', (40, 50))	('IL-27', 'Gene', (149, 154))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('variations', 'Var', (131, 141))	('Human', 'Species', '9606', (70, 75))	('cancers', 'Disease', (222, 229))	('associated', 'Reg', (183, 193))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('IL-27', 'Gene', '246778', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('IL-27', 'Gene', (24, 29))	('IL-27', 'Gene', '246778', (24, 29))
168476	26950245	The purpose of the current study was to clarify the associations of the IL-27 rs153109 A>G and rs181206 T>C variants with human diseases using a meta-analysis study.	('human', 'Species', '9606', (122, 127))	('rs181206 T>C', 'Var', (95, 107))	('rs153109', 'Mutation', 'rs153109', (78, 86))	('IL-27', 'Gene', '246778', (72, 77))	('associations', 'Interaction', (52, 64))	('rs153109 A>G', 'Var', (78, 90))	('rs181206', 'Mutation', 'rs181206', (95, 103))	('IL-27', 'Gene', (72, 77))
168477	26950245	Our study showed that the carriers of the rs181206 T>C and rs153109 A>G polymorphism in the IL-27 gene have elevated risks of diseases in the allele model (rs181206 T>C: OR=0.76, 95%CI=0.69~0.84, P<0.001; rs153109 A>G: OR=0.85, 95%CI=0.76~0.94, P=0.002) and dominant model (rs181206 T>C: OR=0.77, 95%CI=0.69~0.87, P<0.001; rs153109 A>G: OR=0.84, 95%CI=0.71~0.99, P=0.033).	('rs181206 T>C:', 'Var', (274, 287))	('rs181206', 'Mutation', 'rs181206', (42, 50))	('IL-27', 'Gene', (92, 97))	('rs181206', 'Mutation', 'rs181206', (156, 164))	('diseases', 'Disease', (126, 134))	('rs153109', 'Mutation', 'rs153109', (59, 67))	('rs181206 T>C', 'Var', (42, 54))	('rs153109 A>G', 'Var', (59, 71))	('rs181206 T>C:', 'Var', (156, 169))	('rs153109', 'Mutation', 'rs153109', (323, 331))	('IL-27', 'Gene', '246778', (92, 97))	('rs181206', 'Mutation', 'rs181206', (274, 282))	('rs153109', 'Mutation', 'rs153109', (205, 213))	('rs153109 A>G: OR=0.84', 'Var', (323, 344))
168478	26950245	Disease type-stratified subgroup analysis yielded increased risk of related diseases in IL-27 rs181206 T>C carriers in the allele model in immune thrombocytopenia (ITP), asthma, and esophageal cancer (EC) subgroups (ITP: OR=0.69, 95%CI=0.53~0.88, P=0.004; asthma: OR=0.60, 95%CI=0.41~0.89, P=0.010; EC: OR=0.79, 95%CI=0.64~0.97, P=0.026); and IL-27 rs153109 A>G polymorphism was remarkably associated with the increased risk of related diseases in the allele model in ovarian cancer (OC), systemic lupus erythematosus (SLE), tuberculosis (TB), ulcerative colitis (UC), and chronic obstructive pulmonary disease (COPD) subgroups (all P<0.05).	('ulcerative colitis', 'Disease', (544, 562))	('thrombocytopenia', 'Disease', 'MESH:D013921', (146, 162))	('esophageal cancer', 'Disease', (182, 199))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (489, 517))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (573, 610))	('SLE', 'Disease', 'MESH:D008180', (519, 522))	('SLE', 'Disease', (519, 522))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (146, 162))	('IL-27', 'Gene', (88, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (468, 482))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (573, 610))	('SLE', 'Phenotype', 'HP:0002725', (519, 522))	('IL-27', 'Gene', '246778', (88, 93))	('IL-27', 'Gene', (343, 348))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('associated', 'Reg', (390, 400))	('IL-27', 'Gene', '246778', (343, 348))	('ITP', 'Phenotype', 'HP:0001973', (164, 167))	('chronic obstructive pulmonary disease', 'Disease', (573, 610))	('ulcerative colitis', 'Disease', 'MESH:D003093', (544, 562))	('asthma', 'Disease', 'MESH:D001249', (256, 262))	('asthma', 'Disease', 'MESH:D001249', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (476, 482))	('asthma', 'Phenotype', 'HP:0002099', (170, 176))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (581, 610))	('rs181206', 'Var', (94, 102))	('asthma', 'Phenotype', 'HP:0002099', (256, 262))	('rs153109', 'Mutation', 'rs153109', (349, 357))	('systemic lupus erythematosus', 'Disease', (489, 517))	('COPD', 'Phenotype', 'HP:0006510', (612, 616))	('asthma', 'Disease', (170, 176))	('ovarian cancer', 'Disease', 'MESH:D010051', (468, 482))	('rs181206', 'Mutation', 'rs181206', (94, 102))	('thrombocytopenia', 'Disease', (146, 162))	('COPD', 'Disease', 'MESH:D029424', (612, 616))	('asthma', 'Disease', (256, 262))	('tuberculosis', 'Disease', 'MESH:D014376', (525, 537))	('COPD', 'Disease', (612, 616))	('colitis', 'Phenotype', 'HP:0002583', (555, 562))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (544, 562))	('ITP', 'Phenotype', 'HP:0001973', (216, 219))	('rs153109 A>G', 'Var', (349, 361))	('UC', 'Phenotype', 'HP:0100279', (564, 566))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('tuberculosis', 'Disease', (525, 537))	('OC', 'Phenotype', 'HP:0100615', (484, 486))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (489, 517))	('immune thrombocytopenia', 'Phenotype', 'HP:0001973', (139, 162))	('ovarian cancer', 'Disease', (468, 482))
168479	26950245	Our results indicate that the genetic polymorphisms of IL-27 rs153109 and rs181206 may be involved in the progression of human cancers and diseases, especially of TB, UC, COPD, OC, and ITP.	('ITP', 'Disease', (185, 188))	('rs153109', 'Mutation', 'rs153109', (61, 69))	('human', 'Species', '9606', (121, 126))	('involved', 'Reg', (90, 98))	('COPD', 'Phenotype', 'HP:0006510', (171, 175))	('COPD', 'Disease', 'MESH:D029424', (171, 175))	('COPD', 'Disease', (171, 175))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('rs153109', 'Var', (61, 69))	('OC', 'Phenotype', 'HP:0100615', (177, 179))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('IL-27', 'Gene', (55, 60))	('IL-27', 'Gene', '246778', (55, 60))	('UC', 'Phenotype', 'HP:0100279', (167, 169))	('rs181206', 'Var', (74, 82))	('ITP', 'Phenotype', 'HP:0001973', (185, 188))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('rs181206', 'Mutation', 'rs181206', (74, 82))
168484	26950245	Mutations of IL-27 were recently reported to be susceptible to a variety of diseases, such as colorectal cancer, asthma, rheumatoid arthritis, ovarian cancer, Crohn's disease, nasopharyngeal carcinoma, and esophageal cancer.	("Crohn's disease", 'Phenotype', 'HP:0100280', (159, 174))	('esophageal cancer', 'Disease', (206, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	("Crohn's disease", 'Disease', 'MESH:D003424', (159, 174))	("Crohn's disease", 'Disease', (159, 174))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('nasopharyngeal carcinoma', 'Disease', (176, 200))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (121, 141))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (176, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('Mutations', 'Var', (0, 9))	('arthritis', 'Phenotype', 'HP:0001369', (132, 141))	('asthma', 'Disease', 'MESH:D001249', (113, 119))	('asthma', 'Phenotype', 'HP:0002099', (113, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('rheumatoid arthritis', 'Disease', (121, 141))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (176, 200))	('ovarian cancer', 'Disease', 'MESH:D010051', (143, 157))	('IL-27', 'Gene', (13, 18))	('colorectal cancer', 'Disease', (94, 111))	('susceptible', 'Reg', (48, 59))	('asthma', 'Disease', (113, 119))	('IL-27', 'Gene', '246778', (13, 18))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (121, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (206, 223))	('ovarian cancer', 'Disease', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
168485	26950245	Specifically, according to previous studies, 2 single-nucleotide polymorphisms (SNPs) of IL-27, 964A/G (rs153109) and 4730 T/C (rs181206), are commonly found to be associated with various diseases.	('rs153109', 'Var', (104, 112))	('associated', 'Reg', (164, 174))	('rs181206', 'Mutation', 'rs181206', (128, 136))	('964A/G', 'Mutation', 'rs153109', (96, 102))	('4730 T/C (rs181206', 'Var', (118, 136))	('4730 T/C', 'Mutation', 'rs181206', (118, 126))	('rs153109', 'Mutation', 'rs153109', (104, 112))	('IL-27', 'Gene', (89, 94))	('IL-27', 'Gene', '246778', (89, 94))
168486	26950245	For instance, a previous study investigated the association of IL-27 gene polymorphism with Crohn's disease (CD) risk in a Chinese Han population found remarkable association between IL-27 rs153109 and rs181206 polymorphisms and CD risks.	('rs181206', 'Mutation', 'rs181206', (202, 210))	('CD', 'Phenotype', 'HP:0100280', (109, 111))	('IL-27', 'Gene', '246778', (63, 68))	('CD', 'Phenotype', 'HP:0100280', (229, 231))	('IL-27', 'Gene', (183, 188))	('association', 'Interaction', (48, 59))	('association', 'Interaction', (163, 174))	('rs153109', 'Mutation', 'rs153109', (189, 197))	('rs181206', 'Var', (202, 210))	('IL-27', 'Gene', '246778', (183, 188))	("Crohn's disease", 'Phenotype', 'HP:0100280', (92, 107))	('IL-27', 'Gene', (63, 68))	("Crohn's disease", 'Disease', 'MESH:D003424', (92, 107))	('rs153109', 'Var', (189, 197))	("Crohn's disease", 'Disease', (92, 107))
168487	26950245	Moreover, previous studies also found that rs153109 polymorphism may be a protective factor for breast cancer in premenopausal women and is associated with decreased risk of lymph node metastasis in papillary thyroid cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rs153109', 'Mutation', 'rs153109', (43, 51))	('papillary thyroid cancer', 'Disease', (199, 223))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (199, 223))	('decreased', 'NegReg', (156, 165))	('rs153109', 'Var', (43, 51))	('breast cancer', 'Disease', (96, 109))	('lymph node metastasis', 'CPA', (174, 195))	('women', 'Species', '9606', (127, 132))	('decreased risk of lymph node', 'Phenotype', 'HP:0002732', (156, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('thyroid cancer', 'Phenotype', 'HP:0002890', (209, 223))	('cancer in premenopausal women', 'Phenotype', 'HP:0008209', (103, 132))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (199, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
168488	26950245	Through the promotion of pro-inflammatory immune response, polymorphisms rs153109 and rs181206 of IL-27 reduce or delay common antitumor activities responded to by Th1 cytotoxic, increasing the susceptibility to diseases.	('rs181206', 'Var', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('IL-27', 'Gene', (98, 103))	('rs181206', 'Mutation', 'rs181206', (86, 94))	('diseases', 'Disease', (212, 220))	('tumor', 'Disease', (131, 136))	('promotion', 'PosReg', (12, 21))	('Th1', 'Gene', '51497', (164, 167))	('delay', 'NegReg', (114, 119))	('reduce', 'NegReg', (104, 110))	('IL-27', 'Gene', '246778', (98, 103))	('rs153109', 'Mutation', 'rs153109', (73, 81))	('pro-inflammatory immune', 'MPA', (25, 48))	('Th1', 'Gene', (164, 167))
168490	26950245	Previous studies have also shown that variants of IL-27 are closely correlated with diseases, including numerous common cancers, such as colorectal cancer, nasopharyngeal carcinoma, and ovarian cancer, while some other studies have presented different results.	('colorectal cancer', 'Disease', (137, 154))	('IL-27', 'Gene', (50, 55))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (156, 180))	('correlated', 'Reg', (68, 78))	('IL-27', 'Gene', '246778', (50, 55))	('ovarian cancer', 'Disease', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (186, 200))	('cancers', 'Disease', (120, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('nasopharyngeal carcinoma', 'Disease', (156, 180))	('variants', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (156, 180))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (186, 200))
168491	26950245	Therefore, the current study was performed to investigate the potential relationships between the polymorphisms of IL-27, rs153109, and rs181206, and their susceptibility to diseases, and to evaluate the role of IL-27 as a biomarker for the diagnosis and prognosis of diseases.	('IL-27', 'Gene', (115, 120))	('rs181206', 'Mutation', 'rs181206', (136, 144))	('polymorphisms', 'Var', (98, 111))	('rs153109', 'Mutation', 'rs153109', (122, 130))	('IL-27', 'Gene', '246778', (115, 120))	('rs181206', 'Var', (136, 144))	('IL-27', 'Gene', (212, 217))	('rs153109', 'Var', (122, 130))	('IL-27', 'Gene', '246778', (212, 217))
168493	26950245	Retrieved studies were assessed based on the following criteria: (1) studies published in peer-reviewed journal and conducted in human populations; (2) case-control studies investigating the association between SNPs in IL-27 (rs153109 A>G or rs181206 T>C) and susceptibility and human diseases; (3) patients were confirmed by the diagnostic criteria for each disease type; (4) provided sufficient original data on the genotype frequencies of polymorphisms within the IL-27 genes; (5) genotype frequencies of IL-27 met Hardy-Weinberg equilibrium (HWE); (6) studies with overlapping data were only enrolled once.	('IL-27', 'Gene', '246778', (508, 513))	('IL-27', 'Gene', '246778', (467, 472))	('IL-27', 'Gene', '246778', (219, 224))	('rs153109', 'Mutation', 'rs153109', (226, 234))	('human', 'Species', '9606', (279, 284))	('rs181206', 'Mutation', 'rs181206', (242, 250))	('rs153109 A>G', 'Var', (226, 238))	('Hardy-Weinberg equilibrium', 'Disease', (518, 544))	('patients', 'Species', '9606', (299, 307))	('human', 'Species', '9606', (129, 134))	('rs181206 T>C', 'Var', (242, 254))	('IL-27', 'Gene', (508, 513))	('IL-27', 'Gene', (219, 224))	('IL-27', 'Gene', (467, 472))
168494	26950245	The effect size, as represented by the unadjusted odds ratios (ORs) for the presence of the SNP in IL-27 in patients and controls, was calculated.	('presence', 'Var', (76, 84))	('IL-27', 'Gene', (99, 104))	('patients', 'Species', '9606', (108, 116))	('SNP', 'Var', (92, 95))	('IL-27', 'Gene', '246778', (99, 104))
168497	26950245	When focused on the SNPs information, 9 studies analyzed rs153109 A>G and rs181206 T>C SNPs, (Lin XY, Chen S, 2014, Chen S, 2012, Tao YP, Huang ZQ, Zhao B, Li CS, Pan GG and Huang N) and 8 studies only investigated rs153109 A>G SNPs (Zhang Z, Zhao HF, Peng QL, Guo JY, Lan Y, Zhu CL, Zhan YZ and Qiu RF).	('rs181206 T>C', 'Var', (74, 86))	('rs153109', 'Mutation', 'rs153109', (57, 65))	('rs153109 A>G', 'Var', (57, 69))	('rs181206', 'Mutation', 'rs181206', (74, 82))	('rs153109', 'Mutation', 'rs153109', (215, 223))
168499	26950245	In the current study, 2 SNPs (rs153109 A>G, and rs181206 T>C) within the IL-27 gene were identified.	('IL-27', 'Gene', (73, 78))	('rs153109', 'Mutation', 'rs153109', (30, 38))	('rs181206', 'Mutation', 'rs181206', (48, 56))	('IL-27', 'Gene', '246778', (73, 78))	('rs153109 A>G', 'Var', (30, 42))	('rs181206 T>C', 'Var', (48, 60))
168500	26950245	Our results suggested that the carriers of the rs181206 T>C polymorphism in the IL-27 gene have an elevated risk of diseases in the allele model (OR=0.76, 95%CI=0.69~0.84, P<0.001) and dominant model (OR=0.77, 95%CI=0.69~0.87, P<0.001).	('IL-27', 'Gene', (80, 85))	('rs181206 T>C', 'Var', (47, 59))	('IL-27', 'Gene', '246778', (80, 85))	('diseases', 'Disease', (116, 124))	('rs181206', 'Mutation', 'rs181206', (47, 55))
168501	26950245	With respect to the rs153109 A>G polymorphism, findings in the present study suggested that the population containing rs153109 A>G polymorphism was more likely to develop related diseases in comparison to the control group in both the allele model (OR=0.85, 95%CI=0.76~0.94, P=0.002) and the dominant model (OR=0.84, 95%CI=0.71~0.99, P=0.033) (Figure 2A-2D).	('related diseases', 'Disease', (171, 187))	('rs153109', 'Mutation', 'rs153109', (20, 28))	('develop', 'PosReg', (163, 170))	('rs153109', 'Mutation', 'rs153109', (118, 126))	('rs153109 A>G', 'Var', (118, 130))
168502	26950245	In the disease type-stratified subgroup analysis, our results yielded elevated risk of related diseases in IL-27 rs181206 T>C carriers in allele model in the ITP, Asthma, and EC subgroup (ITP: OR=0.69, 95%CI=0.53~0.88, P=0.004; Asthma: OR=0.60, 95%CI=0.41~0.89, P=0.010; EC: OR=0.79, 95%CI=0.64~0.97, P=0.026), but not in RA, CD, NPC, CRC, Glioma, UC, and COPD (all P > 0.05).	('ITP', 'Phenotype', 'HP:0001973', (158, 161))	('COPD', 'Phenotype', 'HP:0006510', (356, 360))	('NPC', 'Disease', (330, 333))	('COPD', 'Disease', 'MESH:D029424', (356, 360))	('COPD', 'Disease', (356, 360))	('Glioma', 'Phenotype', 'HP:0009733', (340, 346))	('UC', 'Phenotype', 'HP:0100279', (348, 350))	('ITP', 'Phenotype', 'HP:0001973', (188, 191))	('Asthma', 'Phenotype', 'HP:0002099', (228, 234))	('rs181206 T>C', 'Var', (113, 125))	('RA', 'Phenotype', 'HP:0001370', (322, 324))	('CRC', 'Disease', (335, 338))	('Glioma', 'Disease', (340, 346))	('Asthma', 'Phenotype', 'HP:0002099', (163, 169))	('CRC', 'Phenotype', 'HP:0003003', (335, 338))	('CD', 'Phenotype', 'HP:0100280', (326, 328))	('Asthma', 'Disease', (163, 169))	('IL-27', 'Gene', (107, 112))	('IL-27', 'Gene', '246778', (107, 112))	('Glioma', 'Disease', 'MESH:D005910', (340, 346))	('rs181206', 'Mutation', 'rs181206', (113, 121))	('NPC', 'Phenotype', 'HP:0100630', (330, 333))
168503	26950245	It has been suggested that subjects with the IL-27 rs153109 A>G polymorphism had elevated risk of related diseases in the allele model in the OC, SLE, TB, UC and the COPD subgroups (all P<0.05); but not in the CD, CHB, LC, HCC, NPC, CRC, Asthma, EC, or Glioma subgroups (all P>0.05) (Figure 3A, 3B and Table 2).	('Asthma', 'Phenotype', 'HP:0002099', (238, 244))	('Glioma', 'Phenotype', 'HP:0009733', (253, 259))	('SLE', 'Disease', 'MESH:D008180', (146, 149))	('SLE', 'Disease', (146, 149))	('SLE', 'Phenotype', 'HP:0002725', (146, 149))	('CD', 'Phenotype', 'HP:0100280', (210, 212))	('rs153109', 'Mutation', 'rs153109', (51, 59))	('CHB', 'Disease', (214, 217))	('HCC', 'Phenotype', 'HP:0001402', (223, 226))	('CRC', 'Phenotype', 'HP:0003003', (233, 236))	('Glioma subgroups', 'Disease', 'MESH:D005910', (253, 269))	('UC', 'Phenotype', 'HP:0100279', (155, 157))	('rs153109 A>G', 'Var', (51, 63))	('IL-27', 'Gene', (45, 50))	('NPC', 'Phenotype', 'HP:0100630', (228, 231))	('CHB', 'Disease', 'None', (214, 217))	('IL-27', 'Gene', '246778', (45, 50))	('Glioma subgroups', 'Disease', (253, 269))	('LC', 'Phenotype', 'HP:0001394', (219, 221))	('COPD', 'Phenotype', 'HP:0006510', (166, 170))	('COPD', 'Disease', 'MESH:D029424', (166, 170))	('OC', 'Phenotype', 'HP:0100615', (142, 144))	('COPD', 'Disease', (166, 170))
168504	26950245	Finally, Egger's regression test implied no asymmetrical distribution in the funnel plot in the rs181206 T>C (allele model: t=0.08, P=0.934; dominant model: t=0.15, P=0.883, respectively), and the rs153109 A>G (allele model: t=0.05, P=0.961; dominant model: t=-0.44, P=0.667, respectively) (Figure 5A-5D).	('rs181206 T>C', 'Var', (96, 108))	('rs153109', 'Mutation', 'rs153109', (197, 205))	('rs153109 A>G', 'Var', (197, 209))	('rs181206', 'Mutation', 'rs181206', (96, 104))
168505	26950245	A meta-analysis was performed to explore the relationship between polymorphisms of rs153109 (-964 A/G), rs181206 (4730 T/C) in the IL-27 gene and the development of some inflammatory, autoimmune diseases and cancer.	('autoimmune diseases', 'Phenotype', 'HP:0002960', (184, 203))	('cancer', 'Disease', (208, 214))	('rs181206 (4730 T/C', 'Var', (104, 122))	('-964 A/G', 'Mutation', 'rs153109', (93, 101))	('IL-27', 'Gene', (131, 136))	('rs181206', 'Mutation', 'rs181206', (104, 112))	('4730 T/C', 'Mutation', 'rs181206', (114, 122))	('IL-27', 'Gene', '246778', (131, 136))	('rs153109', 'Mutation', 'rs153109', (83, 91))	('inflammatory', 'Disease', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('rs153109 (-964 A/G', 'Var', (83, 101))	('autoimmune diseases', 'Disease', 'MESH:D001327', (184, 203))	('autoimmune diseases', 'Disease', (184, 203))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
168506	26950245	The results of our meta-analysis demonstrated the relationship of the polymorphisms of rs153109 with the pathogenesis of TB, SLE, UC, COPD, and OC and the connection between polymorphisms of rs181206 with the development of ITP, asthma, and EC.	('asthma', 'Phenotype', 'HP:0002099', (229, 235))	('rs181206', 'Var', (191, 199))	('COPD', 'Disease', 'MESH:D029424', (134, 138))	('ITP', 'Disease', (224, 227))	('SLE', 'Disease', 'MESH:D008180', (125, 128))	('SLE', 'Disease', (125, 128))	('UC', 'Phenotype', 'HP:0100279', (130, 132))	('OC', 'Phenotype', 'HP:0100615', (144, 146))	('ITP', 'Phenotype', 'HP:0001973', (224, 227))	('COPD', 'Disease', (134, 138))	('SLE', 'Phenotype', 'HP:0002725', (125, 128))	('asthma', 'Disease', (229, 235))	('rs181206', 'Mutation', 'rs181206', (191, 199))	('asthma', 'Disease', 'MESH:D001249', (229, 235))	('rs153109', 'Mutation', 'rs153109', (87, 95))	('connection', 'Reg', (155, 165))	('rs153109', 'Gene', (87, 95))	('COPD', 'Phenotype', 'HP:0006510', (134, 138))
168507	26950245	Increasing data demonstrate that many human diseases may be associated with the gene polymorphisms of IL-8, IL-6, IL-1beta, and IL-10.	('IL-1beta', 'Gene', '3553', (114, 122))	('IL-10', 'Gene', (128, 133))	('IL-6', 'Gene', '3569', (108, 112))	('human', 'Species', '9606', (38, 43))	('IL-8', 'Gene', '3576', (102, 106))	('IL-8', 'Gene', (102, 106))	('IL-10', 'Gene', '3586', (128, 133))	('gene polymorphisms', 'Var', (80, 98))	('IL-1beta', 'Gene', (114, 122))	('human diseases', 'Disease', (38, 52))	('associated', 'Reg', (60, 70))	('IL-6', 'Gene', (108, 112))
168513	26950245	Human IL-27 gene consists of 5 exons, with rs153109 (-964 A/G), rs181206 (4730 T/C) in the promoter of the IL-27 gene, which could modulate the expression of IL-27.	('Human', 'Species', '9606', (0, 5))	('IL-27', 'Gene', '246778', (107, 112))	('rs153109', 'Mutation', 'rs153109', (43, 51))	('modulate', 'Reg', (131, 139))	('expression', 'MPA', (144, 154))	('-964 A/G', 'Mutation', 'rs153109', (53, 61))	('IL-27', 'Gene', (6, 11))	('rs181206 (4730 T/C', 'Var', (64, 82))	('rs181206', 'Mutation', 'rs181206', (64, 72))	('IL-27', 'Gene', (158, 163))	('IL-27', 'Gene', '246778', (6, 11))	('IL-27', 'Gene', (107, 112))	('4730 T/C', 'Mutation', 'rs181206', (74, 82))	('IL-27', 'Gene', '246778', (158, 163))
168514	26950245	Recently, increasing data found that the rs153109 and rs181206 in IL-27 gene was associated with risk of asthma.	('rs181206', 'Var', (54, 62))	('IL-27', 'Gene', '246778', (66, 71))	('rs153109', 'Mutation', 'rs153109', (41, 49))	('asthma', 'Disease', (105, 111))	('rs181206', 'Mutation', 'rs181206', (54, 62))	('asthma', 'Disease', 'MESH:D001249', (105, 111))	('associated', 'Reg', (81, 91))	('rs153109', 'Var', (41, 49))	('IL-27', 'Gene', (66, 71))	('asthma', 'Phenotype', 'HP:0002099', (105, 111))
168515	26950245	One mechanism could be the polymorphism of rs153109 of the IL-27 gene just located in the disease-related locus such as UC and CD, suggesting the association with susceptibility to UC and CD.	('association', 'Reg', (146, 157))	('IL-27', 'Gene', '246778', (59, 64))	('UC', 'Phenotype', 'HP:0100279', (181, 183))	('rs153109', 'Mutation', 'rs153109', (43, 51))	('CD', 'Phenotype', 'HP:0100280', (188, 190))	('CD', 'Phenotype', 'HP:0100280', (127, 129))	('rs153109', 'Var', (43, 51))	('susceptibility', 'Reg', (163, 177))	('UC', 'Phenotype', 'HP:0100279', (120, 122))	('IL-27', 'Gene', (59, 64))
168518	26950245	rs153109 is located in the promoter of IL-27, which could play a crucial role in initiating the transcription and protein expression regulation, which was associated with epithelial ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('rs153109', 'Mutation', 'rs153109', (0, 8))	('associated', 'Reg', (155, 165))	('IL-27', 'Gene', (39, 44))	('transcription', 'MPA', (96, 109))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (171, 196))	('epithelial ovarian cancer', 'Disease', (171, 196))	('IL-27', 'Gene', '246778', (39, 44))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (171, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('rs153109', 'Var', (0, 8))
168520	26950245	We conclude from the above analysis that the polymorphisms of IL-27 participate in many diseases because of the location in the disease-related area and the promoter, and different genotypes and haplotypes of IL-27.	('IL-27', 'Gene', (62, 67))	('diseases', 'Disease', (88, 96))	('IL-27', 'Gene', '246778', (62, 67))	('IL-27', 'Gene', '246778', (209, 214))	('participate', 'Reg', (68, 79))	('polymorphisms', 'Var', (45, 58))	('IL-27', 'Gene', (209, 214))
168521	26950245	found that rs153109 variant was susceptible with tuberculosis due to the decreased IFN-gamma and IL-12 secretion to improve the survival of tubercle bacilli in the macrophages to abate the immune reaction to tubercle bacilli (http://www.cabdirect.org/abstracts/20103084194.html;jsessionid=43F95B13D04B3CF47861675891E2BCC6).	('IFN-gamma', 'Gene', '3458', (83, 92))	('IFN-gamma', 'Gene', (83, 92))	('tuberculosis', 'Disease', 'MESH:D014376', (49, 61))	('rs153109', 'Var', (11, 19))	('improve', 'PosReg', (116, 123))	('decreased', 'NegReg', (73, 82))	('tuberculosis', 'Disease', (49, 61))	('rs153109', 'Mutation', 'rs153109', (11, 19))
168522	26950245	Considering that possible related influential factors may influence the link of rs153109 and rs181206 in IL-27 gene polymorphisms and the development of diseases, we conducted a stratified analysis based on different diseases and detection methods.	('link', 'Interaction', (72, 76))	('rs153109', 'Var', (80, 88))	('rs181206', 'Mutation', 'rs181206', (93, 101))	('IL-27', 'Gene', (105, 110))	('influence', 'Reg', (58, 67))	('IL-27', 'Gene', '246778', (105, 110))	('rs153109', 'Mutation', 'rs153109', (80, 88))	('rs181206', 'Var', (93, 101))
168523	26950245	Subgroup analysis of different diseases show that the IL-27 gene polymorphisms are related with specific diseases, such as ITP, OC, TB, CD, UC, asthma, EC, and COPD, which may due to different pathogenesis of different diseases.	('ITP', 'Phenotype', 'HP:0001973', (123, 126))	('UC', 'Phenotype', 'HP:0100279', (140, 142))	('asthma', 'Phenotype', 'HP:0002099', (144, 150))	('CD', 'Phenotype', 'HP:0100280', (136, 138))	('polymorphisms', 'Var', (65, 78))	('IL-27', 'Gene', (54, 59))	('COPD', 'Phenotype', 'HP:0006510', (160, 164))	('IL-27', 'Gene', '246778', (54, 59))	('COPD', 'Disease', 'MESH:D029424', (160, 164))	('ITP', 'Disease', (123, 126))	('asthma', 'Disease', 'MESH:D001249', (144, 150))	('OC', 'Phenotype', 'HP:0100615', (128, 130))	('related', 'Reg', (83, 90))	('asthma', 'Disease', (144, 150))	('COPD', 'Disease', (160, 164))
168524	26950245	In conclusion, our results are consistent with other studies reporting that the polymorphisms of rs153109 and rs181206 in the IL-27 gene have a close relationship with many diseases, suggesting the IL-27 gene polymorphisms may be important in disease diagnosis and prognosis.	('rs153109', 'Var', (97, 105))	('diseases', 'Disease', (173, 181))	('rs181206', 'Mutation', 'rs181206', (110, 118))	('IL-27', 'Gene', (198, 203))	('relationship', 'Reg', (150, 162))	('IL-27', 'Gene', (126, 131))	('IL-27', 'Gene', '246778', (198, 203))	('rs153109', 'Mutation', 'rs153109', (97, 105))	('rs181206', 'Var', (110, 118))	('IL-27', 'Gene', '246778', (126, 131))
168525	26950245	Firstly, only 2 SNPs (rs153109 and rs181206), widely discussed in various research, were investigated in our study.	('rs153109', 'Var', (22, 30))	('rs181206', 'Var', (35, 43))	('rs153109', 'Mutation', 'rs153109', (22, 30))	('rs181206', 'Mutation', 'rs181206', (35, 43))
168528	26950245	Finally, further investigations to identify IL-27 rs153109 and rs181206 polymorphisms with human diseases are needed to validate and confirm our results.	('IL-27', 'Gene', '246778', (44, 49))	('rs153109', 'Mutation', 'rs153109', (50, 58))	('rs181206', 'Mutation', 'rs181206', (63, 71))	('rs153109', 'Var', (50, 58))	('IL-27', 'Gene', (44, 49))	('rs181206', 'Var', (63, 71))	('human', 'Species', '9606', (91, 96))
168529	26950245	Taken together, our findings suggest that the genetic polymorphism of IL-27 rs153109 and rs181206 may be involved in the progression of human cancers and diseases, especially of TB, UC, COPD, OC, and ITP.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('UC', 'Phenotype', 'HP:0100279', (182, 184))	('ITP', 'Disease', (200, 203))	('rs181206', 'Var', (89, 97))	('rs153109', 'Mutation', 'rs153109', (76, 84))	('human', 'Species', '9606', (136, 141))	('rs181206', 'Mutation', 'rs181206', (89, 97))	('COPD', 'Phenotype', 'HP:0006510', (186, 190))	('COPD', 'Disease', 'MESH:D029424', (186, 190))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('COPD', 'Disease', (186, 190))	('IL-27', 'Gene', (70, 75))	('cancers', 'Disease', (142, 149))	('rs153109', 'Var', (76, 84))	('IL-27', 'Gene', '246778', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('OC', 'Phenotype', 'HP:0100615', (192, 194))	('ITP', 'Phenotype', 'HP:0001973', (200, 203))	('involved', 'Reg', (105, 113))
168699	26043031	The author gave the following explanation: "A possible explanation for this was that the patients in Group E received damage by preoperative chemotherapy, which was more frequently observed in Group E compared with Group L. The damage to cell recycling, vascularization, and tissue regeneration may affect the anastomotic failure, which was more frequent in Group E." The patients in this study did not receive preoperative systemic chemotherapy and radiotherapy, so there was no difference in this aspect among the groups.	('tissue regeneration', 'CPA', (275, 294))	('affect', 'Reg', (299, 305))	('anastomotic failure', 'Disease', (310, 329))	('damage', 'Var', (228, 234))	('patients', 'Species', '9606', (89, 97))	('anastomotic failure', 'Disease', 'MESH:D057868', (310, 329))	('patients', 'Species', '9606', (372, 380))
168715	25891159	The present study aimed to investigate whether inhibition of autophagy may decrease overall tumor resistance to radiation.	('decrease', 'NegReg', (75, 83))	('inhibition', 'Var', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('autophagy', 'CPA', (61, 70))
168719	25891159	Inhibition of autophagy was shown to significantly increase the radiosensitivity of the tumors in vitro and in vivo.	('increase', 'PosReg', (51, 59))	('autophagy', 'CPA', (14, 23))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Inhibition', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
168720	25891159	The enhancement ratio of sensitization in EC9706 cells was 1.76 when the cells were treated with 10 mM 3-MA, alongside ionizing radiation.	('enhancement', 'PosReg', (4, 15))	('sensitization', 'MPA', (25, 38))	('EC9706', 'CellLine', 'CVCL:E307', (42, 48))	('3-MA', 'Chemical', 'MESH:C025946', (103, 107))	('EC9706', 'Var', (42, 48))
168723	25891159	The present study demonstrated in vitro and in vivo that radiation-induced autophagy has a protective effect against cell death, and inhibition of autophagy is able to enhance the radiosensitivity of esophageal squamous cell carcinoma.	('enhance', 'PosReg', (168, 175))	('autophagy', 'CPA', (147, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('inhibition', 'Var', (133, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('radiosensitivity', 'CPA', (180, 196))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (200, 234))	('cell death', 'CPA', (117, 127))	('protective effect', 'CPA', (91, 108))	('esophageal squamous cell carcinoma', 'Disease', (200, 234))
168734	25891159	Previous studies have demonstrated that autophagy inhibits angiogenesis, whereas other studies have suggested that autophagy promotes cancer, and inhibition of autophagy prevents angiogenesis.	('autophagy', 'CPA', (115, 124))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('angiogenesis', 'CPA', (179, 191))	('autophagy', 'CPA', (40, 49))	('angiogenesis', 'CPA', (59, 71))	('inhibits', 'NegReg', (50, 58))	('promotes', 'PosReg', (125, 133))	('inhibition', 'Var', (146, 156))	('prevents', 'NegReg', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
168736	25891159	A preliminary study demonstrated that inhibition of autophagy enhanced the cytotoxicity of radiotherapy in the TE-1 esophageal cancer cell line.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('autophagy', 'CPA', (52, 61))	('cytotoxicity', 'Disease', (75, 87))	('enhanced', 'PosReg', (62, 70))	('inhibition', 'Var', (38, 48))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('esophageal cancer', 'Disease', (116, 133))
168738	25891159	The present study provided proof that the inhibition of autophagy may improve the outcomes of radiation therapy of human esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (121, 155))	('autophagy', 'CPA', (56, 65))	('outcomes', 'MPA', (82, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('inhibition', 'Var', (42, 52))	('improve', 'PosReg', (70, 77))	('human', 'Species', '9606', (115, 120))	('esophageal squamous cell carcinoma', 'Disease', (121, 155))
168746	25891159	sc-1836), anti-cleaved caspase-3 (cat.	('caspase-3', 'Gene', (23, 32))	('caspase-3', 'Gene', '836', (23, 32))	('anti-cleaved', 'Var', (10, 22))
168747	25891159	sc-22171-R), anti-cleaved caspase-9 (cat.	('anti-cleaved', 'Var', (13, 25))	('caspase-9', 'Gene', '842', (26, 35))	('caspase-9', 'Gene', (26, 35))
168748	25891159	sc-56073), anti-cleaved poly(ADP ribose) polymerase (PARP; cat.	('PARP', 'Gene', (53, 57))	('poly(ADP ribose) polymerase', 'Gene', (24, 51))	('poly(ADP ribose) polymerase', 'Gene', '142', (24, 51))	('PARP', 'Gene', '142', (53, 57))	('anti-cleaved', 'Var', (11, 23))
168766	25891159	The membranes were then blocked with 5% skimmed milk (Cusabio Biotech Co., Ltd.) for 1 h and incubated overnight at 4 C with the following primary antibodies: anti-LC3-I/II (diluted 1:2,000), anti-beclin-1 (diluted 1:800), anti-VEGF (diluted 1:400), anti-caspase-3 (diluted 1:400), anti-caspase-9 (diluted 1:500), anti-PARP (diluted 1:400), anti-PCNA (diluted 1:1,000), anti-Ki-67 (diluted 1:800), anti-Bax (diluted 1:1,000) and anti-Bcl-2 (diluted 1:1,000).	('Bcl-2', 'Gene', (434, 439))	('caspase-3', 'Gene', '836', (255, 264))	('VEGF', 'Gene', (228, 232))	('PCNA', 'Gene', '5111', (346, 350))	('caspase-3', 'Gene', (255, 264))	('LC3-I', 'Gene', '84557', (164, 169))	('Bcl-2', 'Gene', '596', (434, 439))	('LC3-I', 'Gene', (164, 169))	('beclin-1', 'Gene', '8678', (197, 205))	('Bax', 'Gene', (403, 406))	('caspase-9', 'Gene', '842', (287, 296))	('diluted', 'Var', (382, 389))	('Bax', 'Gene', '581', (403, 406))	('beclin-1', 'Gene', (197, 205))	('PARP', 'Gene', '142', (319, 323))	('PCNA', 'Gene', (346, 350))	('caspase-9', 'Gene', (287, 296))	('PARP', 'Gene', (319, 323))	('VEGF', 'Gene', '7422', (228, 232))
168801	25891159	In the presence of 3-MA, there was an increase in the number of EC9706 cells in G2/M phase by 65.7% and 218.0% following treatment with 5.0 and 10 mM of 3-MA, respectively.	('EC9706', 'CellLine', 'CVCL:E307', (64, 70))	('increase', 'PosReg', (38, 46))	('3-MA', 'Chemical', 'MESH:C025946', (153, 157))	('EC9706', 'Var', (64, 70))	('3-MA', 'Chemical', 'MESH:C025946', (19, 23))
168808	25891159	These results indicated that radiation-induced autophagy has a protective role in tumor cells against apoptosis, and inhibition of autophagy subsequently enhances the rate of apoptosis in the cells.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('autophagy', 'CPA', (131, 140))	('enhances', 'PosReg', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibition', 'Var', (117, 127))	('tumor', 'Disease', (82, 87))
168811	25891159	The protein expression levels of VEGF were reduced in EC9706 cells treated with 3-MA, as compared with those in the untreated cells.	('VEGF', 'Gene', (33, 37))	('3-MA', 'Chemical', 'MESH:C025946', (80, 84))	('EC9706', 'Var', (54, 60))	('protein expression levels', 'MPA', (4, 29))	('reduced', 'NegReg', (43, 50))	('VEGF', 'Gene', '7422', (33, 37))	('EC9706', 'CellLine', 'CVCL:E307', (54, 60))
168814	25891159	The response of the EC9706 xenografts to radiation plus 3-MA was significantly enhanced, as compared with the that of the untreated, 3-MA alone and radiation alone groups (P<0.01, Fig.	('EC9706', 'CellLine', 'CVCL:E307', (20, 26))	('3-MA', 'Chemical', 'MESH:C025946', (56, 60))	('enhanced', 'PosReg', (79, 87))	('EC9706', 'Var', (20, 26))	('response', 'MPA', (4, 12))	('3-MA', 'Chemical', 'MESH:C025946', (133, 137))
168835	25891159	Autophagy is frequently observed in cancer cells following exposure to ionizing radiation, and inhibition of autophagy has been shown to precipitate radiation-induced cell death.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('inhibition', 'Var', (95, 105))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Autophagy', 'CPA', (0, 9))	('autophagy', 'CPA', (109, 118))
168852	25891159	Furthermore, cellular proliferation was evaluated by measuring the expression levels of PCNA and Ki-67; decreased protein expression levels of PCNA and Ki-67 were most significant in the radiation plus 3-MA-treated tumor samples.	('PCNA', 'Gene', (88, 92))	('3-MA', 'Chemical', 'MESH:C025946', (202, 206))	('protein expression levels', 'MPA', (114, 139))	('PCNA', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('PCNA', 'Gene', '5111', (88, 92))	('Ki-67', 'Var', (152, 157))	('decreased', 'NegReg', (104, 113))	('PCNA', 'Gene', '5111', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))
168858	25891159	Autophagy inhibition has garnered attention as a novel anti-cancer therapeutic strategy, and inhibitors of autophagy have been reported to act as potent anti-cancer drugs and to sensitize cancer cells to anti-cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('inhibition', 'NegReg', (10, 20))	('autophagy', 'CPA', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', (188, 194))	('Autophagy', 'CPA', (0, 9))	('inhibitors', 'Var', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
168859	25891159	The present study demonstrated that inhibition of autophagy was able to markedly enhance the anti-cancer effects of radiotherapy by promoting apoptotic cell death and downregulating angiogenesis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inhibition', 'Var', (36, 46))	('autophagy', 'CPA', (50, 59))	('promoting', 'PosReg', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('angiogenesis', 'CPA', (182, 194))	('downregulating', 'NegReg', (167, 181))	('cancer', 'Disease', (98, 104))	('apoptotic cell death', 'CPA', (142, 162))	('enhance', 'PosReg', (81, 88))
168863	25322694	A2780cp cisplatin-resistant ovarian carcinoma cells and the A2780 parental cell line, were used as a model throughout the present study.	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (8, 17))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (28, 45))	('A2780cp', 'Var', (0, 7))	('A2780', 'CellLine', 'CVCL:0134', (60, 65))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (28, 45))	('ovarian carcinoma', 'Disease', (28, 45))	('A2780', 'CellLine', 'CVCL:0134', (0, 5))
168866	25322694	In both A2780cp and A2780 cells, cisplatin induced the formation of autophagosomes and upregulated the expression levels of autophagy protein markers, LC3 II and Beclin 1.	('A2780', 'Var', (20, 25))	('LC3', 'Gene', '84557', (151, 154))	('A2780cp', 'Var', (8, 15))	('formation of autophagosomes', 'CPA', (55, 82))	('LC3', 'Gene', (151, 154))	('Beclin 1', 'Gene', (162, 170))	('expression levels', 'MPA', (103, 120))	('A2780', 'CellLine', 'CVCL:0134', (8, 13))	('Beclin 1', 'Gene', '8678', (162, 170))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('upregulated', 'PosReg', (87, 98))	('A2780', 'CellLine', 'CVCL:0134', (20, 25))
168867	25322694	However, the levels of autophagy were significantly higher in A2780cp cells, as compared with the A2780 cells.	('A2780', 'CellLine', 'CVCL:0134', (62, 67))	('autophagy', 'CPA', (23, 32))	('higher', 'PosReg', (52, 58))	('A2780', 'CellLine', 'CVCL:0134', (98, 103))	('A2780cp', 'Var', (62, 69))
168869	25322694	However, inhibition of autophagy by siRNA knockdown of Beclin 1 expression enhanced cisplatin-induced cell death and apoptosis.	('inhibition', 'NegReg', (9, 19))	('enhanced', 'PosReg', (75, 83))	('cisplatin-induced', 'MPA', (84, 101))	('Beclin 1', 'Gene', '8678', (55, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('autophagy', 'CPA', (23, 32))	('apoptosis', 'CPA', (117, 126))	('knockdown', 'Var', (42, 51))	('Beclin 1', 'Gene', (55, 63))
168870	25322694	The findings of the present study suggest that autophagy has a protective role in human ovarian cancer cells, and that targeting autophagy may promote chemotherapeutic sensitivity.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('chemotherapeutic sensitivity', 'CPA', (151, 179))	('ovarian cancer', 'Disease', (88, 102))	('targeting', 'Var', (119, 128))	('promote', 'PosReg', (143, 150))	('ovarian cancer', 'Disease', 'MESH:D010051', (88, 102))	('autophagy', 'CPA', (129, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))	('autophagy', 'CPA', (47, 56))	('human', 'Species', '9606', (82, 87))
168877	25322694	Dysregulation of autophagy has been associated with numerous diseases, including cancer; however, the role of autophagy in cancer chemoresistance remains unknown.	('autophagy', 'CPA', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('Dysregulation', 'Var', (0, 13))	('numerous diseases', 'Disease', (52, 69))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('numerous diseases', 'Disease', 'MESH:D004194', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('associated', 'Reg', (36, 46))
168878	25322694	Inhibition of autophagy by 3-methyladenine (3-MA), or Beclin 1 small interfering (si)RNA, was previously shown to increase chemotherapy-induced apoptosis in human hepatocellular carcinoma cells, and inhibit tumor growth in a mouse xenograft model.	('autophagy', 'CPA', (14, 23))	('3-methyladenine', 'Chemical', 'MESH:C025946', (27, 42))	('increase', 'PosReg', (114, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (163, 187))	('hepatocellular carcinoma', 'Disease', (163, 187))	('Beclin 1', 'Gene', '8678', (54, 62))	('small interfering', 'Var', (63, 80))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (163, 187))	('Beclin 1', 'Gene', (54, 62))	('mouse', 'Species', '10090', (225, 230))	('chemotherapy-induced apoptosis', 'CPA', (123, 153))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('3-MA', 'Chemical', 'MESH:C025946', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('tumor', 'Disease', (207, 212))	('inhibit', 'NegReg', (199, 206))	('human', 'Species', '9606', (157, 162))
168879	25322694	Furthermore, knockdown of Beclin 1 and autophagy-related protein 7 (ATG7) expression levels, in OE19 and KYSE450 esophageal cancer cells, enhanced the effects of 5-fluorouracil (5-FU), a chemotherapeutic agent used to treat esophageal cancer.	('autophagy-related protein 7', 'Gene', (39, 66))	('ATG7', 'Gene', '10533', (68, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('esophageal cancer', 'Disease', (224, 241))	('Beclin 1', 'Gene', '8678', (26, 34))	('5-FU', 'Chemical', 'MESH:D005472', (178, 182))	('effects', 'MPA', (151, 158))	('autophagy-related protein 7', 'Gene', '10533', (39, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (224, 241))	('ATG7', 'Gene', (68, 72))	('enhanced', 'PosReg', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Beclin 1', 'Gene', (26, 34))	('esophageal cancer', 'Disease', (113, 130))	('knockdown', 'Var', (13, 22))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (162, 176))
168880	25322694	Conversely, in MCF-7 breast cancer cells, knockdown of migration inhibitory factor expression, was shown to enhance the cytotoxicity of doxorubicin and etoposide, by inducing autophagy.	('etoposide', 'Chemical', 'MESH:D005047', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (15, 34))	('inducing', 'PosReg', (166, 174))	('MCF-7 breast cancer', 'Disease', (15, 34))	('doxorubicin', 'Chemical', 'MESH:D004317', (136, 147))	('cytotoxicity', 'Disease', (120, 132))	('enhance', 'PosReg', (108, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('migration inhibitory factor expression', 'Gene', (55, 93))	('cytotoxicity', 'Disease', 'MESH:D064420', (120, 132))	('knockdown', 'Var', (42, 51))	('autophagy', 'CPA', (175, 184))
168884	25322694	The A2780 cisplatin-sensitive human ovarian cancer cell line, and the A2780cp cisplatin-resistant clone, were obtained from the Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases (Shanghai, China).	('ovarian cancer', 'Disease', 'MESH:D010051', (36, 50))	('human', 'Species', '9606', (30, 35))	('A2780', 'CellLine', 'CVCL:0134', (70, 75))	('ovarian cancer', 'Disease', (36, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (36, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('A2780cp', 'Var', (70, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('A2780', 'CellLine', 'CVCL:0134', (4, 9))
168885	25322694	The A2780 cisplatin-sensitive cells were cultured in Dulbecco's modified Eagle's medium (DMEM; Gibco Life Technologies, Carlsbad, CA, USA), supplemented with 10% fetal bovine serum (FBS South American origin; Bio-west, Logan, UT, USA), 100 U/ml penicillin and 100 mug/ml streptomycin (Sigma-Aldrich, St.Louis, MO, USA), in a humidified 5% CO2 atmosphere, at 37 C. A2780cp cells were grown in DMEM, supplemented with 10% FBS and 1 mug/ml cisplatin, to maintain resistance.	('DMEM', 'Chemical', '-', (89, 93))	('A2780', 'CellLine', 'CVCL:0134', (364, 369))	('bovine', 'Species', '9913', (168, 174))	('FBS', 'Disease', 'MESH:D005198', (420, 423))	('FBS', 'Disease', 'MESH:D005198', (182, 185))	('DMEM', 'Chemical', '-', (392, 396))	('FBS', 'Disease', (420, 423))	('cisplatin', 'Chemical', 'MESH:D002945', (437, 446))	('CO2', 'Chemical', '-', (339, 342))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (53, 87))	('penicillin', 'Chemical', 'MESH:D010406', (245, 255))	('FBS', 'Disease', (182, 185))	('streptomycin', 'Chemical', 'MESH:D013307', (271, 283))	('A2780cp', 'Var', (364, 371))	('cisplatin', 'Chemical', 'MESH:D002945', (10, 19))	('A2780', 'CellLine', 'CVCL:0134', (4, 9))
168886	25322694	The cisplatin was purchased from Hansoh Pharmaceutical Co., Ltd. (Lianyungang, Jiangsu, China), and the 3-MA (M9281; Sigma-Aldrich) was dissolved in sterile double distilled water at 65 C. The A2780 and A2780cp cells were seeded at 1x104 cells/well, in 96-well plates.	('A2780', 'CellLine', 'CVCL:0134', (203, 208))	('3-MA', 'Chemical', 'MESH:C025946', (104, 108))	('A2780', 'CellLine', 'CVCL:0134', (193, 198))	('water', 'Chemical', 'MESH:D014867', (174, 179))	('A2780', 'Var', (193, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('A2780cp', 'Var', (203, 210))
168896	25322694	The A2780 and A2780cp cells were grown on round glass coverslips (Fisher Scientific, Waltham, MA, USA) in 35 mm cell culture dishes.	('A2780', 'Var', (4, 9))	('A2780', 'CellLine', 'CVCL:0134', (14, 19))	('A2780cp', 'Var', (14, 21))	('A2780', 'CellLine', 'CVCL:0134', (4, 9))
168907	25322694	The percentage of surviving cells decreased in a dose-dependent manner in both the A2780 and A2780cp cells (Fig.	('A2780cp', 'Var', (93, 100))	('A2780', 'CellLine', 'CVCL:0134', (83, 88))	('A2780', 'CellLine', 'CVCL:0134', (93, 98))	('decreased', 'NegReg', (34, 43))	('A2780', 'Var', (83, 88))
168908	25322694	However, as expected, the A2780cp cells were 6.5x more resistant to cisplatin, as compared with the A2780 parental cells (P<0.01).	('A2780', 'CellLine', 'CVCL:0134', (100, 105))	('A2780cp', 'Var', (26, 33))	('resistant to cisplatin', 'MPA', (55, 77))	('A2780', 'CellLine', 'CVCL:0134', (26, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
168910	25322694	Using phase-contrast microscopy, the A2780cp cells were observed as having a regular, round shape, and were markedly larger as compared with the A2780 cells (Fig.	('A2780', 'CellLine', 'CVCL:0134', (145, 150))	('A2780cp', 'Var', (37, 44))	('larger', 'PosReg', (117, 123))	('A2780', 'CellLine', 'CVCL:0134', (37, 42))
168911	25322694	The endogenous levels of autophagy were compared in the A2780cp cisplatin-resistant and A2780 sensitive cell lines, by measuring the protein expression levels of LC3 II and Beclin 1.	('A2780cp', 'Var', (56, 63))	('A2780', 'CellLine', 'CVCL:0134', (56, 61))	('protein expression levels', 'MPA', (133, 158))	('Beclin 1', 'Gene', (173, 181))	('LC3', 'Gene', '84557', (162, 165))	('LC3', 'Gene', (162, 165))	('A2780', 'CellLine', 'CVCL:0134', (88, 93))	('A2780', 'Var', (88, 93))	('Beclin 1', 'Gene', '8678', (173, 181))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))
168912	25322694	A2780cp cells exhibited higher expression levels of LC3 II and Beclin 1 proteins, as compared with the A2780 cells (Fig.	('A2780', 'CellLine', 'CVCL:0134', (103, 108))	('Beclin 1', 'Gene', '8678', (63, 71))	('expression levels', 'MPA', (31, 48))	('LC3', 'Gene', '84557', (52, 55))	('higher', 'PosReg', (24, 30))	('LC3', 'Gene', (52, 55))	('A2780cp', 'Var', (0, 7))	('A2780', 'CellLine', 'CVCL:0134', (0, 5))	('Beclin 1', 'Gene', (63, 71))
168913	25322694	Immunofluorescence staining for LC3 and p62, another autophagy-related protein, also showed that the cisplatin-resistant cells exhibited higher levels of autophagy (Fig.	('cisplatin-resistant', 'Var', (101, 120))	('p62', 'Gene', (40, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('higher', 'PosReg', (137, 143))	('LC3', 'Gene', '84557', (32, 35))	('LC3', 'Gene', (32, 35))	('autophagy', 'CPA', (154, 163))	('p62', 'Gene', '8878', (40, 43))
168919	25322694	Electron microscopic analyses also revealed that treatment with cisplatin increased the amount of autophagosomes in both cell lines; however, the number of autophagosomes increased to a greater extent in the A2780cp cells, as compared with the A2780 cells (Fig.	('A2780', 'CellLine', 'CVCL:0134', (244, 249))	('A2780cp', 'Var', (208, 215))	('A2780', 'CellLine', 'CVCL:0134', (208, 213))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('increased', 'PosReg', (171, 180))
168920	25322694	These findings suggest that cisplatin may induce autophagy in ovarian cancer cell lines, and the induced level of autophagy was higher in A2780cp cells, as compared with that in A2780 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('A2780cp', 'Var', (138, 145))	('higher', 'PosReg', (128, 134))	('A2780', 'CellLine', 'CVCL:0134', (178, 183))	('A2780', 'CellLine', 'CVCL:0134', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('induce', 'PosReg', (42, 48))	('autophagy', 'CPA', (49, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (62, 76))	('ovarian cancer', 'Disease', (62, 76))
168921	25322694	A2780cp cells were shown to have elevated levels of autophagy.	('autophagy', 'CPA', (52, 61))	('A2780', 'CellLine', 'CVCL:0134', (0, 5))	('elevated', 'PosReg', (33, 41))	('A2780cp', 'Var', (0, 7))
168926	25322694	Furthermore, knockdown of Beclin 1 expression sensitized A2780cp cells to cisplatin, by enhancing cisplatin-induced cell death (Fig.	('Beclin 1', 'Gene', '8678', (26, 34))	('A2780', 'CellLine', 'CVCL:0134', (57, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('cisplatin-induced', 'MPA', (98, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('Beclin 1', 'Gene', (26, 34))	('sensitized', 'Reg', (46, 56))	('knockdown', 'Var', (13, 22))	('enhancing', 'PosReg', (88, 97))
168939	25322694	A cell viability assay confirmed that A2780 and A2780cp cells provide an ideal pair of cell lines to use for these studies, since A2780cp cells were 6.5x more resistant to cisplatin, as compared with the parental cell line.	('A2780', 'CellLine', 'CVCL:0134', (38, 43))	('A2780', 'CellLine', 'CVCL:0134', (48, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (172, 181))	('A2780cp', 'Var', (130, 137))	('resistant', 'MPA', (159, 168))	('A2780', 'CellLine', 'CVCL:0134', (130, 135))
168945	25322694	In the present study, following the treatment of the cells with different concentrations of cisplatin for 24 h, both autophagy markers, LC3 and Beclin 1 were upregulated in A2780cp cells, as compared with the A2780 cells, as determined by western blot analysis.	('A2780cp', 'Var', (173, 180))	('autophagy', 'CPA', (117, 126))	('upregulated', 'PosReg', (158, 169))	('LC3', 'Gene', (136, 139))	('Beclin 1', 'Gene', '8678', (144, 152))	('A2780', 'CellLine', 'CVCL:0134', (173, 178))	('cisplatin', 'Chemical', 'MESH:D002945', (92, 101))	('Beclin 1', 'Gene', (144, 152))	('A2780', 'CellLine', 'CVCL:0134', (209, 214))	('LC3', 'Gene', '84557', (136, 139))
168946	25322694	Furthermore, untreated A2780cp cells expressed greater amounts of LC3 and a lower amount of p62, as determined by immunofluorescence, as compared with the A2780 cells.	('p62', 'Gene', '8878', (92, 95))	('greater', 'PosReg', (47, 54))	('LC3', 'Gene', '84557', (66, 69))	('A2780', 'CellLine', 'CVCL:0134', (155, 160))	('LC3', 'Gene', (66, 69))	('A2780cp', 'Var', (23, 30))	('lower', 'NegReg', (76, 81))	('A2780', 'CellLine', 'CVCL:0134', (23, 28))	('p62', 'Gene', (92, 95))
168950	25322694	The levels of autophagy increased in response to cisplatin, in a dose dependent manner, in the A2780cp resistant cells.	('autophagy', 'CPA', (14, 23))	('levels', 'MPA', (4, 10))	('A2780', 'CellLine', 'CVCL:0134', (95, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('A2780cp', 'Var', (95, 102))	('increased', 'PosReg', (24, 33))
168957	25322694	In the present study, knockdown of Beclin 1 expression, using siRNA, significantly inhibited autophagy and sensitized A2780cp cells to cisplatin treatment.	('autophagy', 'CPA', (93, 102))	('sensitized', 'Reg', (107, 117))	('Beclin 1', 'Gene', '8678', (35, 43))	('inhibited', 'NegReg', (83, 92))	('knockdown', 'Var', (22, 31))	('A2780', 'CellLine', 'CVCL:0134', (118, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('Beclin 1', 'Gene', (35, 43))
168963	25322694	However, knockdown of Beclin 1 expression, with siRNA, significantly inhibited autophagy and increased cisplatin-induced apoptosis.	('autophagy', 'CPA', (79, 88))	('cisplatin-induced', 'MPA', (103, 120))	('knockdown', 'Var', (9, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('increased', 'PosReg', (93, 102))	('Beclin 1', 'Gene', (22, 30))	('inhibited', 'NegReg', (69, 78))	('Beclin 1', 'Gene', '8678', (22, 30))
168964	25322694	This finding is consistent with a previous study, which indicated that the cleavage of Beclin 1 reduced autophagy and promoted apoptosis in HeLa cells.	('Beclin 1', 'Gene', (87, 95))	('autophagy', 'CPA', (104, 113))	('apoptosis', 'CPA', (127, 136))	('Beclin 1', 'Gene', '8678', (87, 95))	('HeLa', 'CellLine', 'CVCL:0030', (140, 144))	('promoted', 'PosReg', (118, 126))	('cleavage', 'Var', (75, 83))	('reduced', 'NegReg', (96, 103))
168966	25322694	In conclusion, higher levels of autophagy were observed in cisplatin-resistant ovarian cancer cells, whereas knockdown of Beclin 1 expression restored cisplatin-sensitivity to these cells, which is attributed to autophagy inhibition.	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('Beclin 1', 'Gene', '8678', (122, 130))	('higher', 'PosReg', (15, 21))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('knockdown', 'Var', (109, 118))	('cisplatin-sensitivity', 'MPA', (151, 172))	('autophagy', 'CPA', (32, 41))	('ovarian cancer', 'Disease', (79, 93))	('Beclin 1', 'Gene', (122, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))
168971	22179833	We have previously shown that short-term ZD (6 weeks) in rats induces overexpression of the proinflammatory mediators S100a8 and S100a9 in the esophageal mucosa with accompanying esophageal epithelial hyperplasia.	('ZD', 'Chemical', '-', (41, 43))	('rats', 'Species', '10116', (57, 61))	('esophageal epithelial hyperplasia', 'Phenotype', 'HP:0012859', (179, 212))	('S100a8', 'Var', (118, 124))	('esophageal epithelial hyperplasia', 'Disease', 'MESH:D017573', (179, 212))	('esophageal epithelial hyperplasia', 'Disease', (179, 212))	('S100a9', 'Var', (129, 135))	('overexpression', 'PosReg', (70, 84))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (179, 199))
168997	22179833	The tumorigenicity of NMBA in rodents is the results of the bioactivation of the carcinogen by esophageal cytochrome P450 isozymes to produce a DNA-methylating agent, leading to the formation of the mutagenic DNA adduct O6-methylguanine, and a high prevalence of mutations in Ha-Ras and p53 genes in papillomas.	('tumor', 'Disease', (4, 9))	('mutagenic DNA adduct O6-methylguanine', 'MPA', (199, 236))	('papillomas', 'Disease', (300, 310))	('Ha-Ras', 'Gene', (276, 282))	('NMBA', 'Chemical', 'MESH:C014707', (22, 26))	('mutations', 'Var', (263, 272))	('p53', 'Gene', '301300', (287, 290))	('papillomas', 'Phenotype', 'HP:0012740', (300, 310))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('p53', 'Gene', (287, 290))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (220, 236))	('papillomas', 'Disease', 'MESH:D010212', (300, 310))
169028	22179833	Additionally, enzyme-linked immunosorbent assay (ELISA) and immunoblot (Figure 2b) analyses showed that the Zn-modulating effects observed at the transcript levels for Il1b, Cxcl5, NF-kB p65, Cox-2, S100a8, S100a9, Cxcl2, and Hif1a were also reflected at the protein level.	('Zn-modulating', 'MPA', (108, 121))	('S100a8', 'Gene', (199, 205))	('S100a9', 'Var', (207, 213))	('Zn', 'Chemical', 'MESH:D015032', (108, 110))	('p65', 'Gene', '25716', (187, 190))	('NF-kB', 'Gene', '81736', (181, 186))	('Il1b', 'Gene', (168, 172))	('p65', 'Gene', (187, 190))	('NF-kB', 'Gene', (181, 186))
169035	22179833	In particular, the involved biological processes included "chemotaxis" at the tumor endpoint with 8 inflammation genes (Cxcl3, Ccr1, Cxcl2, Cxcl1, S100a8, Cxcl5, S100a9, and Il1b, P=8.34E-08) and also at the early dysplastic stage with 4 inflammation genes (Cxcl2, S100a8, Cxcl5, S100a9).	('inflammation', 'Disease', (100, 112))	('inflammation', 'Disease', 'MESH:D007249', (238, 250))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('inflammation', 'Disease', (238, 250))	('Cxcl2', 'Var', (258, 263))	('dysplastic', 'Disease', 'MESH:D004416', (214, 224))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('inflammation', 'Disease', 'MESH:D007249', (100, 112))	('dysplastic', 'Disease', (214, 224))
169037	22179833	Thus, the DAVID data support the conclusion that these inflammatory chemokines (Cxcl5, Cxcl3, Cxcl2, Cxcl1), cytokine (Il1b), and S100a8/a9 are relevant to the ZD-driven development of ESCC.	('ZD', 'Chemical', '-', (160, 162))	('ESCC', 'Disease', (185, 189))	('S100a8/a9', 'Var', (130, 139))
169050	22179833	At 23 weeks, serum Zn levels were significantly lower in ZD (42 mug/100 ml, 95% CI = 39 to 45 mg/100 ml) than ZS rats (88 mug/100 ml, 95% CI = 85 to 91 mg/100 ml) (P < 0.0001).	('lower', 'NegReg', (48, 53))	('serum Zn levels', 'MPA', (13, 28))	('ZD', 'Chemical', '-', (57, 59))	('Zn', 'Chemical', 'MESH:D015032', (19, 21))	('ZS', 'Chemical', '-', (110, 112))	('42 mug/100', 'Var', (61, 71))	('rats', 'Species', '10116', (113, 117))
169051	22179833	We found that long-term ZD resulted in an amplified inflammatory gene repertoire with upregulation of 12 inflammation genes (Cxcl5, Cxcl3, Cxcl2, Cxcr4, Il1b, Ptgs2, Ccr2, and Ccl2, S100a8, S100a9, Hif1a, and Tlr4) (Figure 2d), as compared with only 4 genes (S100a8, S100a9, Hif1a, and Tlr4) in short-term ZD esophagus.	('ZD', 'Chemical', '-', (24, 26))	('ZD esophagus', 'Phenotype', 'HP:0100580', (306, 318))	('ZD', 'Chemical', '-', (306, 308))	('upregulation', 'PosReg', (86, 98))	('inflammation', 'Disease', 'MESH:D007249', (105, 117))	('inflammatory gene', 'Gene', (52, 69))	('S100a9', 'Var', (190, 196))	('Tlr4', 'Gene', (286, 290))	('inflammation', 'Disease', (105, 117))	('Tlr4', 'Gene', '29260', (209, 213))	('S100a8', 'Var', (182, 188))	('Tlr4', 'Gene', '29260', (286, 290))	('Tlr4', 'Gene', (209, 213))
169053	22179833	Immunoblot (Figure 2f) and IHC (Figure 3b) analyses showed that long-term ZD induced overexpression of COX-2, NF-kB p65, S100A8, S100A9, NF-kB p65, and HIF1A protein in the highly proliferative esophageal epithelium that showed intense and abundant immunostaining of PCNA and KRT14 protein.	('PCNA', 'Gene', '25737', (267, 271))	('p65', 'Gene', '25716', (116, 119))	('overexpression', 'PosReg', (85, 99))	('p65', 'Gene', (116, 119))	('S100A8', 'Var', (121, 127))	('protein', 'Protein', (158, 165))	('immunostaining', 'MPA', (249, 263))	('NF-kB', 'Gene', (137, 142))	('p65', 'Gene', '25716', (143, 146))	('rat', 'Species', '10116', (187, 190))	('NF-kB', 'Gene', '81736', (137, 142))	('KRT14', 'Gene', '287701', (276, 281))	('p65', 'Gene', (143, 146))	('S100A9', 'Var', (129, 135))	('PCNA', 'Gene', (267, 271))	('NF-kB', 'Gene', '81736', (110, 115))	('KRT14', 'Gene', (276, 281))	('NF-kB', 'Gene', (110, 115))	('ZD', 'Chemical', '-', (74, 76))	('HIF1A', 'Gene', (152, 157))	('HIF1A', 'Gene', '29560', (152, 157))	('COX-2', 'Gene', (103, 108))
169066	22179833	Importantly, these same inflammatory mediators CXCL5, CXCL2, CXCR4, IL1B, COX-2, S100A8, and S100A9 are all overexpressed in human ESCC.	('CXCR4', 'Gene', '7852', (61, 66))	('human', 'Species', '9606', (125, 130))	('S100A9', 'Var', (93, 99))	('CXCR4', 'Gene', (61, 66))	('CXCL2', 'Gene', '2920', (54, 59))	('CXCL2', 'Gene', (54, 59))
169072	22179833	Perhaps most significantly, the present study shows that replenishing Zn after carcinogenic exposure reverses the inflammatory gene signature and prevents ESCC development.	('inflammatory gene signature', 'MPA', (114, 141))	('prevents', 'NegReg', (146, 154))	('Zn', 'Chemical', 'MESH:D015032', (70, 72))	('reverses', 'NegReg', (101, 109))	('ESCC', 'Disease', (155, 159))	('replenishing', 'Var', (57, 69))
169073	22179833	Recently, we reported that Zn supplementation in nutritionally complete rodents also inhibits forestomach and tongue carcinogenesis through attenuation of inflammation.	('Zn', 'Chemical', 'MESH:D015032', (27, 29))	('inhibits', 'NegReg', (85, 93))	('tongue carcinogenesis', 'Disease', 'MESH:D063646', (110, 131))	('supplementation', 'Var', (30, 45))	('attenuation', 'NegReg', (140, 151))	('tongue carcinogenesis', 'Disease', (110, 131))	('forestomach', 'Disease', (94, 105))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))	('inflammation', 'Disease', (155, 167))
169077	22179833	Our study suggests that deficiency of Zn in the diet is a likely etiologic agent of chronic inflammation in the esophagus that contributes to ESCC development in humans.	('chronic inflammation', 'Disease', (84, 104))	('contributes', 'Reg', (127, 138))	('humans', 'Species', '9606', (162, 168))	('chronic inflammation', 'Disease', 'MESH:D007249', (84, 104))	('deficiency', 'Var', (24, 34))	('ESCC development', 'Disease', (142, 158))	('Zn', 'Chemical', 'MESH:D015032', (38, 40))	('inflammation in the esophagus', 'Phenotype', 'HP:0100633', (92, 121))
169092	22179833	Expression profiling of esophageal epithelia from NMBA-treated ZD, ZR, and control ZS rats (n=4/group) was performed at 5 weeks after the first NMBA dose and at tumor endpoint, using Affymetrix Rat Genome 230 2.0 GeneChip (Affymetrix, Santa Clara, CA) that contains more than 31,000 probe sets that represent >30,000 transcripts and variants from ~28,000 genes.	('esophageal epithelia', 'Disease', (24, 44))	('NMBA', 'Chemical', 'MESH:C014707', (50, 54))	('esophageal epithelia', 'Disease', 'MESH:D004941', (24, 44))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (24, 44))	('variants', 'Var', (333, 341))	('ZD', 'Chemical', '-', (63, 65))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('NMBA', 'Chemical', 'MESH:C014707', (144, 148))	('rats', 'Species', '10116', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('ZR', 'Chemical', '-', (67, 69))	('ZS', 'Chemical', '-', (83, 85))	('tumor', 'Disease', (161, 166))	('Rat', 'Species', '10116', (194, 197))
169108	22179833	IHC was carried out as previously described, using primary antibodies for proliferating cell nuclear antigen (PCNA) (clone PC-10, Ab-1, Neomarker (Thermo Scientific), KRT14 (NCL-LL002, Novocastra, Buffalo Grove, IL), COX-2 (160106, Cayman Chemical), S100A8 (T-1032, BMA, Augst, Switzerland), S100A9 (AF2065, R&D), and NF-kB p65 (Ab-7970, Abcam).	('NF-kB', 'Gene', '81736', (318, 323))	('proliferating cell nuclear antigen', 'Gene', '25737', (74, 108))	('NCL', 'Gene', (174, 177))	('p65', 'Gene', '25716', (324, 327))	('NCL', 'Gene', '25135', (174, 177))	('160106', 'Var', (224, 230))	('NF-kB', 'Gene', (318, 323))	('PCNA', 'Gene', '25737', (110, 114))	('PCNA', 'Gene', (110, 114))	('proliferating cell nuclear antigen', 'Gene', (74, 108))	('KRT14', 'Gene', (167, 172))	('p65', 'Gene', (324, 327))	('KRT14', 'Gene', '287701', (167, 172))	('S100A9', 'Var', (292, 298))
169128	30778778	The estimated overall survival rate was also higher with MIE than OE.	('higher', 'PosReg', (45, 51))	('MIE', 'Var', (57, 60))	('overall survival', 'CPA', (14, 30))	('MIE', 'Chemical', '-', (57, 60))
169202	28339468	In the cases studies of three important human diseases, 88% (Esophageal Neoplasms), 88% (Kidney Neoplasms) and 90% (Colon Neoplasms) of top-50 predicted miRNAs have been manually confirmed by previous experimental reports from literatures.	('Esophageal Neoplasms', 'Disease', 'MESH:D004938', (61, 81))	('miRNAs', 'Var', (153, 159))	('Colon Neoplasms', 'Disease', 'MESH:D003110', (116, 131))	('Neoplasms', 'Phenotype', 'HP:0002664', (72, 81))	('Kidney Neoplasms', 'Phenotype', 'HP:0009726', (89, 105))	('Neoplasms', 'Phenotype', 'HP:0002664', (96, 105))	('Kidney Neoplasms', 'Disease', 'MESH:D007680', (89, 105))	('Esophageal Neoplasms', 'Disease', (61, 81))	('Kidney Neoplasms', 'Disease', (89, 105))	('Colon Neoplasms', 'Disease', (116, 131))	('Colon Neoplasms', 'Phenotype', 'HP:0100273', (116, 131))	('Neoplasms', 'Phenotype', 'HP:0002664', (122, 131))	('human', 'Species', '9606', (40, 45))	('Esophageal Neoplasms', 'Phenotype', 'HP:0100751', (61, 81))
169209	28339468	With the advances in molecular biology and biotechnology, miRNAs have been proven to influence many important physiological processes such as cell growth, immune reaction, cell differentiation, cell development, cell cycle regulation, inflammation, cell apoptosis, stress response, and tumor invasion.	('cell growth', 'CPA', (142, 153))	('cell apoptosis', 'CPA', (249, 263))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('cell differentiation', 'CPA', (172, 192))	('cell development', 'CPA', (194, 210))	('inflammation', 'Disease', 'MESH:D007249', (235, 247))	('influence', 'Reg', (85, 94))	('cell cycle regulation', 'CPA', (212, 233))	('inflammation', 'Disease', (235, 247))	('immune reaction', 'CPA', (155, 170))	('stress response', 'CPA', (265, 280))	('miRNAs', 'Var', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (286, 291))
169238	28339468	As a result, the reliable AUCs of 0.9169 and 0.8341 in the frameworks of global and local LOOCV were obtained by PBMDA.	('0.9169', 'Var', (34, 40))	('0.8341', 'Var', (45, 51))	('PBMDA', 'Chemical', '-', (113, 118))
169242	28339468	As a result, PBMDA, WBSMDA, RLSMDA and HDMP achieved AUCs of 0.9169, 0.8030, 0.8426 and 0.8366 in the framework of global LOOCV, respectively.	('0.8030', 'Var', (69, 75))	('0.9169', 'Var', (61, 67))	('PBMDA', 'Chemical', '-', (13, 18))	('0.8426', 'Var', (77, 83))	('0.8366', 'Var', (88, 94))	('WBSMDA', 'Chemical', '-', (20, 26))
169244	28339468	The other methods (WBSMDA, RWRMDA, HDMP, and RLSMDA) obtained AUCs of 0.8031, 0.7891, 0.7702 and 0.6953, respectively.	('WBSMDA', 'Chemical', '-', (19, 25))	('0.7702', 'Var', (86, 92))	('0.7891', 'Var', (78, 84))	('0.6953', 'Var', (97, 103))
169245	28339468	In addition, 5-fold CV was implemented on PBMDA, WBSMDA, RLSMDA and HDMP with average AUC value of 0.9172+/-0.0007, 0.8185+/-0.0009, 0.8569+/-0.0020 and 0.8342+/-0.0010, respectively, which was observed that PBMDA obtained the best performance based on 5-fold CV.	('0.8185+/-0.0009', 'Var', (116, 131))	('0.8342+/-0.0010', 'Var', (153, 168))	('WBSMDA', 'Chemical', '-', (49, 55))	('PBMDA', 'Chemical', '-', (42, 47))	('0.8569+/-0.0020', 'Var', (133, 148))	('0.9172+/-0.0007', 'Var', (99, 114))	('PBMDA', 'Chemical', '-', (208, 213))
169267	28339468	Previous research showed that hsa-miR-125b (2nd in the prediction list) can promote cell proliferation in Esophageal Neoplasms by influencing the target transcripts: CYP24, ERBB2 and ERBB3.	('ERBB2', 'Gene', (173, 178))	('promote', 'PosReg', (76, 83))	('Esophageal Neoplasms', 'Disease', 'MESH:D004938', (106, 126))	('Esophageal Neoplasms', 'Phenotype', 'HP:0100751', (106, 126))	('Neoplasms', 'Phenotype', 'HP:0002664', (117, 126))	('Esophageal Neoplasms', 'Disease', (106, 126))	('CYP24', 'Gene', '1591', (166, 171))	('CYP24', 'Gene', (166, 171))	('ERBB3', 'Gene', '2065', (183, 188))	('influencing', 'Reg', (130, 141))	('cell proliferation', 'CPA', (84, 102))	('ERBB3', 'Gene', (183, 188))	('hsa-miR-125b', 'Var', (30, 42))	('ERBB2', 'Gene', '2064', (173, 178))
169272	28339468	Besides, MiRs-141/200c were considered as the most down-regulated miRNAs in RCC by targeting ZEB2, which is a type of transcriptional repressor.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('MiRs-141/200c', 'Var', (9, 22))	('RCC', 'Disease', (76, 79))	('targeting', 'Reg', (83, 92))	('down-regulated', 'NegReg', (51, 65))	('ZEB2', 'Gene', '9839', (93, 97))	('ZEB2', 'Gene', (93, 97))
169283	28339468	In the prediction list, 9 of top-10 and 45 of top-50 predicted miRNAs obtained confirmation of their associations with Colon Neoplasms based on recent experimental literatures (see Table 6).	('Colon Neoplasms', 'Disease', 'MESH:D003110', (119, 134))	('Colon Neoplasms', 'Disease', (119, 134))	('Neoplasms', 'Phenotype', 'HP:0002664', (125, 134))	('associations', 'Interaction', (101, 113))	('Colon Neoplasms', 'Phenotype', 'HP:0100273', (119, 134))	('miRNAs', 'Var', (63, 69))
169301	28339468	Fifteen out of top-20 and 37 out of top-50 predicted miRNAs have been verified to be associated with Glioblastoma by HMDD, dbDEMC and miR2Disease.	('miRNAs', 'Var', (53, 59))	('HMDD', 'Chemical', '-', (117, 121))	('Glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('dbDEMC', 'Chemical', '-', (123, 129))	('Glioblastoma', 'Disease', (101, 113))	('Glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('associated', 'Reg', (85, 95))
169307	28339468	Compared with four state-of-the-art computational models, PBMDA achieved the highest AUCs of 0.9169, 0.8341 and 0.9172+/-0.0007 in the evaluation frameworks of global LOOCV, local LOOCV and 5-fold CV, respectively, demonstrating the most reliable prediction performance.	('0.9172+/-0.0007', 'Var', (112, 127))	('PBMDA', 'Chemical', '-', (58, 63))	('0.8341', 'Var', (101, 107))
169319	25349680	Systematic Review of Zinc Biomarkers and Esophageal Cancer Risk BACKGROUND  It is hypothesized that poor zinc nutritional status is associated with an increased risk of esophageal cancer (EC), but current evidence is contradictory.	('Esophageal Cancer', 'Disease', 'MESH:D004938', (41, 58))	('Esophageal Cancer', 'Disease', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('poor', 'Var', (100, 104))	('esophageal cancer', 'Disease', (169, 186))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('associated', 'Reg', (132, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (169, 186))	('poor zinc', 'Phenotype', 'HP:0031831', (100, 109))
169327	25349680	In animal models, a Zn deficient diet results in a precancerous condition in the upper digestive tract, including the esophagus  and enhances the effects of esophageal carcinogens (e.g., N-nitrosomethyl benzylamine)  by different mechanism including increased cell proliferation, cyclin D1 over expression  and p53 deficiency.	('deficient', 'Var', (23, 32))	('cyclin D1', 'Gene', '595', (280, 289))	('N-nitrosomethyl benzylamine', 'Chemical', 'MESH:C014707', (187, 214))	('p53', 'Gene', (311, 314))	('Zn', 'Chemical', 'MESH:D015032', (20, 22))	('deficiency', 'Var', (315, 325))	('condition in the upper digestive tract', 'Phenotype', 'HP:0002087', (64, 102))	('increased', 'PosReg', (250, 259))	('effects', 'MPA', (146, 153))	('over expression', 'PosReg', (290, 305))	('esophageal carcinogens', 'Disease', (157, 179))	('enhances', 'PosReg', (133, 141))	('results in', 'Reg', (38, 48))	('precancerous condition', 'Disease', 'MESH:D011230', (51, 73))	('esophageal carcinogens', 'Disease', 'MESH:D004941', (157, 179))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('precancerous condition', 'Disease', (51, 73))	('cell proliferation', 'CPA', (260, 278))	('cyclin D1', 'Gene', (280, 289))	('p53', 'Gene', '7157', (311, 314))	('rat', 'Species', '10116', (272, 275))
169328	25349680	Other mechanisms may include cyclooxygenase-2 (COX-2) over expression, activating S100A inflammation, P450-dependent metabolism of nitrosamines, and reduced alkyl guanine DNA methyltransferase activity.	('S100A', 'Var', (82, 87))	('nitrosamines', 'Chemical', 'MESH:D009602', (131, 143))	('alkyl guanine DNA methyltransferase', 'Enzyme', (157, 192))	('P450-dependent metabolism', 'Enzyme', (102, 127))	('over expression', 'PosReg', (54, 69))	('inflammation', 'Disease', 'MESH:D007249', (88, 100))	('cyclooxygenase-2', 'Gene', '5743', (29, 45))	('reduced', 'NegReg', (149, 156))	('activity', 'MPA', (193, 201))	('cyclooxygenase-2', 'Gene', (29, 45))	('inflammation', 'Disease', (88, 100))	('COX-2', 'Gene', (47, 52))	('COX-2', 'Gene', '5743', (47, 52))	('activating', 'PosReg', (71, 81))	('S100A', 'SUBSTITUTION', 'None', (82, 87))
169370	25349680	Two other trials in Huxian, China, assessed the effect of Zn in combination with retinol and riboflavin versus placebo; this combination was effective in reducing the prevalence of micronuclei in esophageal cells  and precancerous lesions.	('Zn', 'Chemical', 'MESH:D015032', (58, 60))	('retinol', 'Chemical', 'MESH:D014801', (81, 88))	('precancerous lesions', 'Disease', 'MESH:D011230', (218, 238))	('reducing', 'NegReg', (154, 162))	('riboflavin', 'Chemical', 'MESH:D012256', (93, 103))	('precancerous lesions', 'Disease', (218, 238))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('micronuclei', 'Var', (181, 192))
169373	25349680	Currently, observational studies of Zn biomarkers suggest that higher Zn status is associated with reduced risk of EC, but the evidence base is limited by the small number of studies and that many had weak study designs and small sample sizes.	('Zn', 'Chemical', 'MESH:D015032', (70, 72))	('Zn status', 'MPA', (70, 79))	('Zn', 'Chemical', 'MESH:D015032', (36, 38))	('higher', 'Var', (63, 69))	('reduced', 'NegReg', (99, 106))
169379	20138038	Aberrant Epithelial-Mesenchymal Hedgehog Signaling Characterizes Barrett's Metaplasia The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (146, 165))	('Aberrant', 'Var', (0, 8))	('epithelial metaplasia', 'Disease', (121, 142))	('Epithelial-Mesenchymal', 'Protein', (9, 31))	("Barrett's Metaplasia", 'Disease', (65, 85))	("Barrett's Metaplasia", 'Disease', 'MESH:D001471', (65, 85))	('epithelial metaplasia', 'Disease', 'MESH:D008679', (121, 142))
169380	20138038	Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium.	('genes', 'Var', (175, 180))	('columnar differentiation of esophageal epithelium', 'CPA', (221, 270))	('men', 'Species', '9606', (76, 79))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (147, 166))	('promote', 'PosReg', (213, 220))
169397	20138038	Multiple genetic and epigenetic changes occur in BE, BE with dysplasia, and adenocarcinoma including silencing, loss or mutation of P16, P53 and APC and overexpression of cyclin D1.	('overexpression', 'PosReg', (153, 167))	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('BE', 'Phenotype', 'HP:0100580', (53, 55))	('mutation', 'Var', (120, 128))	('P53', 'Gene', (137, 140))	('cyclin D1', 'Gene', '595', (171, 180))	('dysplasia', 'Disease', (61, 70))	('P53', 'Gene', '7157', (137, 140))	('silencing', 'MPA', (101, 110))	('loss', 'NegReg', (112, 116))	('cyclin D1', 'Gene', (171, 180))	('adenocarcinoma', 'Disease', (76, 90))	('P16', 'Gene', (132, 135))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('dysplasia', 'Disease', 'MESH:D004476', (61, 70))	('APC', 'Disease', (145, 148))	('P16', 'Gene', '1029', (132, 135))	('BE', 'Phenotype', 'HP:0100580', (49, 51))
169398	20138038	Other reported genetic changes include aneuploidy; C-ERB2, EGFR, and P21 overexpression; SRC and telomerase activation; K-RAS mutations; and P27 and E-cadherin underexpression.	('K-RAS', 'Gene', (120, 125))	('P21', 'Gene', (69, 72))	('P27', 'Gene', '3429', (141, 144))	('EGFR', 'Gene', (59, 63))	('E-cadherin', 'Gene', '999', (149, 159))	('aneuploidy', 'Disease', (39, 49))	('SRC', 'Gene', '6714', (89, 92))	('P27', 'Gene', (141, 144))	('SRC', 'Gene', (89, 92))	('C-ERB2', 'Gene', (51, 57))	('P21', 'Gene', '644914', (69, 72))	('mutations', 'Var', (126, 135))	('K-RAS', 'Gene', '3845', (120, 125))	('underexpression', 'NegReg', (160, 175))	('overexpression', 'PosReg', (73, 87))	('EGFR', 'Gene', '1956', (59, 63))	('E-cadherin', 'Gene', (149, 159))	('activation', 'PosReg', (108, 118))
169428	20138038	Sixty percent confluent OE33 cells were transfected with 25nM non-targeting or SOX9-specific siRNAs (Dharmacon) using Lipofectamine LTX and Plus reagent.	('SOX9', 'Gene', '6662', (79, 83))	('SOX9', 'Gene', (79, 83))	('non-targeting', 'Var', (62, 75))	('Lipofectamine LTX', 'Chemical', '-', (118, 135))
169453	20138038	Interestingly, upregulation of Hh ligand expression occurred at pH<=4, the cutoff used to diagnose patients with GERD on ambulatory esophageal pH measurements.	('pH<=4', 'Var', (64, 69))	('expression', 'MPA', (41, 51))	('Hh ligand', 'Protein', (31, 40))	('upregulation', 'PosReg', (15, 27))	('patients', 'Species', '9606', (99, 107))	('men', 'Species', '9606', (153, 156))	('GERD', 'Disease', 'MESH:D005764', (113, 117))	('GERD', 'Disease', (113, 117))
169469	20138038	To determine how SOX9 and Hh signaling interact in esophageal epithelium, we treated HET-1A cells with conditioned media containing Shh, transfected them with a Gli1 expression vector, and infected them with adenovirus containing a constitutively active mutant form of Smo.	('Gli1', 'Gene', '2735', (161, 165))	('SOX9', 'Gene', (17, 21))	('Smo', 'Gene', '6608', (269, 272))	('SOX9', 'Gene', '6662', (17, 21))	('HET-1A', 'CellLine', 'CVCL:3702', (85, 91))	('Smo', 'Gene', (269, 272))	('mutant', 'Var', (254, 260))	('Gli1', 'Gene', (161, 165))
169474	20138038	By qRT-PCR, BMP4 induced a 2.5 fold upregulation of SOX9 expression compared to vehicle while BMPRIA* induced a 3.9 fold upregulation compared to empty vector (Figure 5B).	('BMPRIA', 'Chemical', '-', (94, 100))	('expression', 'MPA', (57, 67))	('upregulation', 'PosReg', (121, 133))	('upregulation', 'PosReg', (36, 48))	('SOX9', 'Gene', (52, 56))	('BMP4', 'Gene', '652', (12, 16))	('SOX9', 'Gene', '6662', (52, 56))	('qRT-PCR', 'Var', (3, 10))	('BMP4', 'Gene', (12, 16))
169505	20138038	Our data present a compelling argument for a connection between aberrant Hh signaling and the initiation of columnar metaplasia in BE.	('BE', 'Phenotype', 'HP:0100580', (131, 133))	('initiation of columnar metaplasia', 'Disease', 'MESH:D008679', (94, 127))	('aberrant', 'Var', (64, 72))	('initiation of columnar metaplasia', 'Disease', (94, 127))	('men', 'Species', '9606', (34, 37))
169519	20138038	In the first, loss of Paneth cells as well as increased crypt size in the mutant mice were seen.	('Paneth cells', 'CPA', (22, 34))	('mice', 'Species', '10090', (81, 85))	('increased', 'PosReg', (46, 55))	('crypt size', 'CPA', (56, 66))	('mutant', 'Var', (74, 80))	('loss', 'NegReg', (14, 18))
169520	20138038	The second study found a 40% loss of goblet cells and almost complete loss of Paneth cells in the mutant mice with extension of the proliferative compartment into the area where Paneth cells reside.	('loss', 'NegReg', (70, 74))	('rat', 'Species', '10116', (139, 142))	('loss', 'NegReg', (29, 33))	('men', 'Species', '9606', (153, 156))	('Paneth cells', 'CPA', (78, 90))	('mice', 'Species', '10090', (105, 109))	('goblet cells', 'CPA', (37, 49))	('mutant', 'Var', (98, 104))
169548	33926524	HDAC2 and CXCL10 were up-regulated while miR-503-5p was down-regulated in ESCC.	('miR-503-5p', 'Var', (41, 51))	('ESCC', 'Disease', (74, 78))	('down-regulated', 'NegReg', (56, 70))	('miR-503-5p', 'Chemical', '-', (41, 51))	('CXCL10', 'Gene', '3627', (10, 16))	('CXCL10', 'Gene', (10, 16))	('up-regulated', 'PosReg', (22, 34))
169549	33926524	HDAC2 bound to miR-503-5p and miR-503-5p targeted CXCL10.	('CXCL10', 'Gene', '3627', (50, 56))	('targeted', 'Reg', (41, 49))	('bound', 'Reg', (6, 11))	('miR-503-5p', 'Chemical', '-', (30, 40))	('CXCL10', 'Gene', (50, 56))	('HDAC2', 'Gene', (0, 5))	('miR-503-5p', 'Var', (30, 40))	('miR-503-5p', 'Chemical', '-', (15, 25))
169550	33926524	Silencing HDAC2 or restoring miR-503-5p depressed viability, colony-forming, invasion and migration abilities and enhanced apoptosis of ESCC cells in vitro, as well as suppressed ESCC tumorigenesis in vivo.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('suppressed', 'NegReg', (168, 178))	('invasion', 'CPA', (77, 85))	('ESCC', 'Disease', (179, 183))	('HDAC2', 'Gene', (10, 15))	('enhanced', 'PosReg', (114, 122))	('apoptosis', 'CPA', (123, 132))	('depressed', 'NegReg', (40, 49))	('tumor', 'Disease', (184, 189))	('viability', 'CPA', (50, 59))	('Silencing', 'Var', (0, 9))	('miR-503-5p', 'Chemical', '-', (29, 39))	('migration abilities', 'CPA', (90, 109))	('colony-forming', 'CPA', (61, 75))
169552	33926524	This work elucidates that HDAC2 knockdown retards the process of ESCC by elevating miR-503-5p and inhibiting CXCL10 expression, which may provide a guidance for ESCC management.	('elevating', 'PosReg', (73, 82))	('retards', 'Disease', 'MESH:D008607', (42, 49))	('HDAC2', 'Gene', (26, 31))	('CXCL10', 'Gene', '3627', (109, 115))	('CXCL10', 'Gene', (109, 115))	('knockdown', 'Var', (32, 41))	('retards', 'Disease', (42, 49))	('miR-503-5p', 'MPA', (83, 93))	('ESCC', 'Disease', (65, 69))	('miR-503-5p', 'Chemical', '-', (83, 93))	('inhibiting', 'NegReg', (98, 108))
169556	33926524	Histone deacetylases (HDACs) inhibitors are anti-tumorigenic, as evidenced by their potentials in arresting cell cycle progression, inhibiting differentiation/angiogenesis and inducing apoptosis by modification of cellular proteins.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('arrest', 'Disease', (98, 104))	('inhibitors', 'Var', (29, 39))	('modification', 'Reg', (198, 210))	('Histone', 'Protein', (0, 7))	('cellular proteins', 'Protein', (214, 231))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cell cycle progression', 'CPA', (108, 130))	('apoptosis', 'CPA', (185, 194))	('tumor', 'Disease', (49, 54))	('inducing', 'Reg', (176, 184))	('HDAC', 'Gene', (22, 26))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('HDAC', 'Gene', '9734', (22, 26))	('inhibiting', 'NegReg', (132, 142))	('differentiation/angiogenesis', 'CPA', (143, 171))
169565	33926524	Jointly, how the combination of HDAC2, miR-503-5p and CXCL10 functions in the progression of ESCC is indefinable.	('miR-503-5p', 'Chemical', '-', (39, 49))	('CXCL10', 'Gene', '3627', (54, 60))	('CXCL10', 'Gene', (54, 60))	('miR-503-5p', 'Var', (39, 49))	('ESCC', 'Disease', (93, 97))
169596	33926524	Luciferase plasmids (GenePharma) containing wild-type (pmirGLO-CXCL10-WT) or mutant (pmirGLO-CXCL10-MUT) CXCL10 binding sites targeting miR-503-5p were prepared.	('CXCL10', 'Gene', (93, 99))	('CXCL10', 'Gene', '3627', (105, 111))	('miR-503-5p', 'Chemical', '-', (136, 146))	('CXCL10', 'Gene', (105, 111))	('CXCL10', 'Gene', '3627', (63, 69))	('mutant', 'Var', (77, 83))	('CXCL10', 'Gene', (63, 69))	('CXCL10', 'Gene', '3627', (93, 99))
169617	33926524	Also, we examined HDAC2 and miR-503-5p expression in mice tumors and found that silencing HDAC2 reduced HDAC2 and elevated miR-503-5p expression levels (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('silencing', 'Var', (80, 89))	('tumors', 'Disease', (58, 64))	('HDAC2', 'MPA', (104, 109))	('miR-503-5p', 'Chemical', '-', (123, 133))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('miR-503-5p', 'Chemical', '-', (28, 38))	('miR-503-5p expression levels', 'MPA', (123, 151))	('elevated', 'PosReg', (114, 122))	('HDAC2', 'Gene', (90, 95))	('mice', 'Species', '10090', (53, 57))	('reduced', 'NegReg', (96, 103))
169619	33926524	In short, HDAC2 knockdown inhibited tumor growth.	('inhibited', 'NegReg', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('knockdown', 'Var', (16, 25))	('HDAC2', 'Gene', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
169623	33926524	The anti-tumorigenic effect of miR-503-5p has been documented in human cancers including ESCC.	('human', 'Species', '9606', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('miR-503-5p', 'Var', (31, 41))	('cancers', 'Disease', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('ESCC', 'Disease', (89, 93))	('tumor', 'Disease', (9, 14))	('miR-503-5p', 'Chemical', '-', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
169624	33926524	Based on that, we measured miR-503-5p expression in Ec109 and KYSE30 cells after knocking down HDAC2 and discovered that inhibiting HDAC2 elevated miR-503-5p expression (Fig.	('HDAC2', 'Gene', (95, 100))	('inhibiting', 'Var', (121, 131))	('miR-503-5p expression', 'MPA', (147, 168))	('miR-503-5p', 'Chemical', '-', (27, 37))	('miR-503-5p', 'Chemical', '-', (147, 157))	('knocking down', 'Var', (81, 94))	('HDAC2', 'Gene', (132, 137))	('elevated', 'PosReg', (138, 146))
169625	33926524	Also, ESCC cell lines which expressed low HDAC2 were featured by up-regulated miR-503-5p (Fig.	('up-regulated', 'PosReg', (65, 77))	('HDAC2', 'Gene', (42, 47))	('miR-503-5p', 'Chemical', '-', (78, 88))	('miR-503-5p', 'Gene', (78, 88))	('low', 'Var', (38, 41))
169626	33926524	Moreover, we uncovered that miR-503-5p was lowly expressed in ESCC cancer tissues (Fig.	('miR-503-5p', 'Var', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('miR-503-5p', 'Chemical', '-', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
169630	33926524	After various assays, we discovered that miR-503-5p overexpression diminished viability, colony-forming, invasion and migration abilities, enhanced apoptosis of KYSE30 and Ec109 cells (Fig.	('invasion', 'CPA', (105, 113))	('diminished', 'NegReg', (67, 77))	('miR-503-5p', 'Var', (41, 51))	('migration abilities', 'CPA', (118, 137))	('colony-forming', 'CPA', (89, 103))	('miR-503-5p', 'Chemical', '-', (41, 51))	('apoptosis', 'CPA', (148, 157))	('overexpression', 'PosReg', (52, 66))	('enhanced', 'PosReg', (139, 147))	('viability', 'CPA', (78, 87))
169633	33926524	Bioinformatics analysis revealed that miR-503-5p could bind to the 3'-untranslated region of CXCL10 (Fig.	('CXCL10', 'Gene', (93, 99))	('bind', 'Interaction', (55, 59))	('miR-503-5p', 'Var', (38, 48))	('miR-503-5p', 'Chemical', '-', (38, 48))	('CXCL10', 'Gene', '3627', (93, 99))
169634	33926524	6a) and dual-luciferase experiments detected that miR-503-5p mimic and CXCL10-WT co-transfected resulted in reduction of cell luciferase activity (Fig.	('cell luciferase', 'Enzyme', (121, 136))	('CXCL10', 'Gene', (71, 77))	('miR-503-5p', 'Chemical', '-', (50, 60))	('miR-503-5p mimic', 'Var', (50, 66))	('activity', 'MPA', (137, 145))	('CXCL10', 'Gene', '3627', (71, 77))	('reduction', 'NegReg', (108, 117))
169635	33926524	Furthermore, CXCL10 expression in KYSE30 and Ec109 cells were tested after regulation of HDAC2 or miR-503-5p via RT-qPCR and Western blot assay, and the results pictured that knocking down HDAC2 or up-regulating miR-503-5p suppressed CXCL10 expression while down-regulating miR-503-5p increased CXCL10 expression (Fig.	('down-regulating', 'NegReg', (258, 273))	('miR-503-5p', 'Chemical', '-', (98, 108))	('miR-503-5p', 'Chemical', '-', (274, 284))	('increased', 'PosReg', (285, 294))	('up-regulating', 'PosReg', (198, 211))	('CXCL10', 'Gene', (295, 301))	('CXCL10', 'Gene', '3627', (295, 301))	('HDAC2', 'Gene', (189, 194))	('CXCL10', 'Gene', '3627', (13, 19))	('miR-503-5p', 'Chemical', '-', (212, 222))	('suppressed', 'NegReg', (223, 233))	('CXCL10', 'Gene', (13, 19))	('CXCL10', 'Gene', '3627', (234, 240))	('CXCL10', 'Gene', (234, 240))	('knocking down', 'Var', (175, 188))	('miR-503-5p', 'Gene', (212, 222))
169640	33926524	7a) and miR-503-5p inhibitor or pcDNA-CXCL10 functionally reversed the effects of HDAC2 knockout on ESCC cells (Fig.	('HDAC2', 'Gene', (82, 87))	('knockout', 'Var', (88, 96))	('ESCC', 'Disease', (100, 104))	('CXCL10', 'Gene', '3627', (38, 44))	('CXCL10', 'Gene', (38, 44))	('miR-503-5p', 'Chemical', '-', (8, 18))
169646	33926524	The experimental data highlighted that HDAC2 knockdown retarded ESCC progression through restoring miR-503-5p and silencing CXCL10.	('HDAC2', 'Gene', (39, 44))	('CXCL10', 'Gene', (124, 130))	('ESCC', 'Disease', (64, 68))	('miR-503-5p', 'MPA', (99, 109))	('silencing', 'NegReg', (114, 123))	('miR-503-5p', 'Chemical', '-', (99, 109))	('CXCL10', 'Gene', '3627', (124, 130))	('restoring', 'PosReg', (89, 98))	('knockdown', 'Var', (45, 54))	('retarded', 'NegReg', (55, 63))
169648	33926524	For further elucidation of the performance of HDAC2 in ESCC, HDAC2 down-regulation assay was implemented on ESCC cells with the findings revealing that silencing HDAC2 depressed ESCC cell viability, invasion, migration and colony-forming properties, arrested cell cycle and reinforced apoptosis.	('depressed', 'NegReg', (168, 177))	('silencing', 'Var', (152, 161))	('migration', 'CPA', (209, 218))	('arrest', 'Disease', 'MESH:D006323', (250, 256))	('invasion', 'CPA', (199, 207))	('cell cycle', 'CPA', (259, 269))	('HDAC2', 'Gene', (162, 167))	('colony-forming properties', 'CPA', (223, 248))	('reinforced', 'PosReg', (274, 284))	('ESCC', 'Disease', (178, 182))	('apoptosis', 'CPA', (285, 294))	('arrest', 'Disease', (250, 256))
169649	33926524	Further validated by tumor xenografts in mice, depressed HDAC2 was anti-tumorigenic in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('HDAC2', 'Gene', (57, 62))	('tumor', 'Disease', (21, 26))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Disease', (72, 77))	('ESCC', 'Disease', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('depressed', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
169651	33926524	Conducted by a prior study, it is stressed out that HDAC2 expression is elevated in ESCC tissues, connecting with lymph node metastasis, invasion depth, histological grade, TNM stage and knocking down HDAC2 obstructs ESCC cells to proliferate, arrests G0/G1 phase cell cycle and accelerates apoptosis.	('elevated', 'PosReg', (72, 80))	('HDAC2', 'Gene', (201, 206))	('arrest', 'Disease', 'MESH:D006323', (244, 250))	('apoptosis', 'CPA', (291, 300))	('expression', 'MPA', (58, 68))	('arrest', 'Disease', (244, 250))	('knocking down', 'Var', (187, 200))	('proliferate', 'CPA', (231, 242))	('accelerates', 'PosReg', (279, 290))	('HDAC2', 'Gene', (52, 57))	('G0/G1 phase cell cycle', 'CPA', (252, 274))
169652	33926524	Then, the link between HDAC2 and miR-503-5p was discovered, and the results displayed that HDAC2 was bound to miR-503-5p promoter and inhibited miR-503-5p expression.	('miR-503-5p', 'Chemical', '-', (33, 43))	('miR-503-5p expression', 'MPA', (144, 165))	('inhibited', 'NegReg', (134, 143))	('miR-503-5p', 'Chemical', '-', (144, 154))	('bound', 'Interaction', (101, 106))	('miR-503-5p', 'Chemical', '-', (110, 120))	('HDAC2', 'Var', (91, 96))
169654	33926524	As to the performance of miR-503-5p in the process of ESCC, it was depicted that restoring miR-503-5p repressed ESCC cell progression.	('miR-503-5p', 'Chemical', '-', (91, 101))	('miR-503-5p', 'Chemical', '-', (25, 35))	('ESCC', 'Disease', (112, 116))	('miR-503-5p', 'Var', (91, 101))
169657	33926524	Experimentally explored, it is recorded that miR-503-5p expression tends to decrease in the early stage of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (107, 131))	('hepatocellular carcinoma', 'Disease', (107, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (107, 131))	('miR-503-5p expression', 'Var', (45, 66))	('miR-503-5p', 'Chemical', '-', (45, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('decrease', 'NegReg', (76, 84))
169658	33926524	Mechanistically, the decreased miR-503-5p has also been presented in cervical cancer, whereas miR-503-5p restoration blocks the way for cervical cancer cells to behave aggressively.	('cancer', 'Disease', (145, 151))	('decreased', 'NegReg', (21, 30))	('miR-503-5p', 'Var', (94, 104))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('miR-503-5p', 'MPA', (31, 41))	('blocks', 'NegReg', (117, 123))	('miR-503-5p', 'Chemical', '-', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('miR-503-5p', 'Chemical', '-', (94, 104))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
169659	33926524	Moreover, miR-503-5p expression trends toward a decrease in ovarian cancer and its down-regulation is auxiliary for ovarian cancer cell viability while suppressive for apoptosis.	('decrease in ovarian cancer', 'Disease', (48, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (116, 130))	('miR-503-5p expression', 'Var', (10, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('ovarian cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('decrease in ovarian cancer', 'Disease', 'MESH:D002303', (48, 74))	('miR-503-5p', 'Chemical', '-', (10, 20))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))	('down-regulation', 'NegReg', (83, 98))
169662	33926524	Moreover, another result concluded in this work was that miR-503-5p inhibition or CXCL10 elevation negated HDAC2 knockout-induced effects on ESCC tumorigenesis.	('miR-503-5p', 'Chemical', '-', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('CXCL10', 'Gene', '3627', (82, 88))	('tumor', 'Disease', (146, 151))	('CXCL10', 'Gene', (82, 88))	('negated', 'NegReg', (99, 106))	('HDAC2', 'Gene', (107, 112))	('miR-503-5p', 'Var', (57, 67))	('ESCC', 'Disease', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
169801	33097096	Notably, micro-fragmented fat has improved paracrine anti-inflammatory, anti-fibrotic, and pro-angiogenic proprieties instrumental for supporting tissue regeneration compared to cultured MSC.	('improved', 'PosReg', (34, 42))	('paracrine anti-inflammatory', 'MPA', (43, 70))	('micro-fragmented', 'Var', (9, 25))	('fat', 'Gene', (26, 29))	('pro-angiogenic', 'CPA', (91, 105))	('fat', 'Gene', '2195', (26, 29))	('anti-fibrotic', 'CPA', (72, 85))	('rat', 'Species', '10116', (159, 162))
169815	32303675	A tumor-specific modulation of heterogeneous ribonucleoprotein A0 promotes excessive mitosis and growth in colorectal cancer cells RNA regulation mediating RNA-binding proteins (RBPs) have been shown to be related to the maintenance of homeostasis as well as cancer progression.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Disease', (118, 124))	('modulation', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('mitosis', 'CPA', (85, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('related', 'Reg', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('colorectal cancer', 'Disease', (107, 124))	('tumor', 'Disease', (2, 7))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))	('cancer', 'Disease', (259, 265))
169823	32303675	Therefore, the tumor-specific biological functions characterized by the abnormal phosphorylation of RBPs are considered to be an attractive target for tumor treatment.	('phosphorylation', 'MPA', (81, 96))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (151, 156))	('abnormal', 'Var', (72, 80))	('tumor', 'Disease', (15, 20))	('RBPs', 'Gene', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
169826	32303675	Therefore, cancer-specific alterations that strongly promote the growth of tumors have been explored as targets of cancer therapy.	('cancer', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (11, 17))	('growth', 'MPA', (65, 71))	('tumors', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('alterations', 'Var', (27, 38))	('promote', 'PosReg', (53, 60))
169827	32303675	RNA regulation, including stabilization, splicing, and degradation, plays an indispensable role in the biological activity, such as the development, differentiation and formation of organs, and their alterations are associated with the development and progression of many types of tumors.	('tumors', 'Disease', (281, 287))	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('alterations', 'Var', (200, 211))	('associated', 'Reg', (216, 226))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))
169830	32303675	To resolve this issue, the cancer-specific modifications of RBPs that possess strong enhancement for tumor progression and the detailed mechanisms underlying their tumor-associated functions must be identified in each organ.	('tumor', 'Disease', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('RBPs', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('enhancement', 'PosReg', (85, 96))	('modifications', 'Var', (43, 56))	('cancer', 'Disease', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
169838	32303675	Among 20 hnRNPs, the knockdown of hnRNP A0 was associated with the strongest inhibition of HCT116 cells (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (91, 97))	('HCT116 cells', 'CPA', (91, 103))	('hnRNP', 'Gene', '3183', (34, 39))	('hnRNP', 'Gene', '3183', (9, 14))	('hnRNP', 'Gene', (9, 14))	('inhibition', 'NegReg', (77, 87))	('knockdown', 'Var', (21, 30))	('hnRNP', 'Gene', (34, 39))
169839	32303675	The knockdown of hnRNPA0 also exerted anti-tumor effects in other cancer cell lines, including gastric cancer MKN45 cells, pancreatic cancer SUIT-2 cells and PANC-1 cells, and esophageal cancer OE33 cells.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('gastric cancer', 'Disease', (95, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('cancer', 'Disease', (103, 109))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Disease', (134, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (176, 193))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('hnRNPA0', 'Gene', (17, 24))	('esophageal cancer', 'Disease', (176, 193))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PANC-1', 'CellLine', 'CVCL:0480', (158, 164))	('hnRNPA0', 'Gene', '10949', (17, 24))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))	('pancreatic cancer', 'Disease', (123, 140))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (66, 72))
169860	32303675	However, functional modifications of hnRNPs alter the phenotypes of cells through changes in their mRNA expression.	('mRNA expression', 'MPA', (99, 114))	('alter', 'Reg', (44, 49))	('hnRNP', 'Gene', (37, 42))	('changes', 'Reg', (82, 89))	('phenotypes', 'MPA', (54, 64))	('hnRNP', 'Gene', '3183', (37, 42))	('modifications', 'Var', (20, 33))
169869	32303675	Either RAB3GAP1 or OPN3 siRNA caused G2/M arrest similarly to that observed with HNRNP A0 knockdown (Fig.	('M arrest', 'Disease', 'MESH:D006323', (40, 48))	('OPN3', 'Gene', (19, 23))	('M arrest', 'Disease', (40, 48))	('OPN3', 'Gene', '23596', (19, 23))	('RAB3GAP1', 'Var', (7, 15))
169880	32303675	Inhibitor of MK-2 (PF-3644022), which is an upstream enzyme involved in the phosphorylation of hnRNP A0 (Supplementary Fig.	('MK-2', 'Gene', '9261', (13, 17))	('MK-2', 'Gene', (13, 17))	('PF-3644022', 'Chemical', 'MESH:C549914', (19, 29))	('hnRNP A0', 'Gene', (95, 103))	('PF-3644022', 'Var', (19, 29))
169881	32303675	11), dramatically reduced the mRNA expression of NUDT12 (HCT116, Panc-1, MKN45), OPN3 (HCT116), and RAB3GAP1 (HCT116, SUIT-2, Panc-1, MKN45).	('HCT116', 'CellLine', 'CVCL:0291', (57, 63))	('Panc-1', 'CellLine', 'CVCL:0480', (126, 132))	('OPN3', 'Gene', '23596', (81, 85))	('NUDT12', 'Gene', (49, 55))	('HCT116', 'Var', (87, 93))	('HCT116', 'CellLine', 'CVCL:0291', (87, 93))	('HCT116', 'Var', (110, 116))	('mRNA expression', 'MPA', (30, 45))	('reduced', 'NegReg', (18, 25))	('HCT116', 'Var', (57, 63))	('Panc-1', 'CellLine', 'CVCL:0480', (65, 71))	('NUDT12', 'Gene', '83594', (49, 55))	('OPN3', 'Gene', (81, 85))	('HCT116', 'CellLine', 'CVCL:0291', (110, 116))	('RAB3GAP1', 'Gene', (100, 108))
169891	32303675	The growth of the transplanted tumor was significantly inhibited by PF-3644022 treatment (Fig.	('PF-3644022', 'Var', (68, 78))	('inhibited', 'NegReg', (55, 64))	('PF-3644022', 'Chemical', 'MESH:C549914', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
169892	32303675	4i), indicating that the tumor-specific phosphorylation of Ser84 of hnRNP A0 was a key step in cancer progression.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Ser84', 'Chemical', '-', (59, 64))	('hnRNP A0', 'Gene', (68, 76))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', (25, 30))	('cancer', 'Disease', (95, 101))	('Ser84', 'Var', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('phosphorylation', 'MPA', (40, 55))
169894	32303675	Because chromosomal misalignment causes G2/M arrest, the importance of hnRNP A0-RAB3GAP1 or OPN3 mRNA interaction in mitotic cells was assessed.	('chromosomal', 'Var', (8, 19))	('M arrest', 'Disease', 'MESH:D006323', (43, 51))	('OPN3', 'Gene', (92, 96))	('M arrest', 'Disease', (43, 51))	('OPN3', 'Gene', '23596', (92, 96))	('causes', 'Reg', (33, 39))
169895	32303675	Immunocytochemistry with anti-tubulin antibody and Hoechst 33342 showed the misalignment of chromosomes at the equatorial plane in cancer cells treated with RAB3GAP1 siRNA (19/33 cells, 57.8%), while no abnormal alignment was observed in cancer cells treated with OPN3 siRNA (0/26 cells, 0%) or scrambled RNA (0/31 cells, 0%) (Fig.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', (238, 244))	('OPN3', 'Gene', (264, 268))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('OPN3', 'Gene', '23596', (264, 268))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('RAB3GAP1 siRNA', 'Var', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (51, 64))	('misalignment', 'CPA', (76, 88))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
169901	32303675	The reduction of ZWINT1 protein was diminished by treatment with MG132, a proteasome inhibitor (Fig.	('ZWINT1', 'Gene', (17, 23))	('MG132', 'Chemical', 'MESH:C072553', (65, 70))	('diminished', 'NegReg', (36, 46))	('MG132', 'Var', (65, 70))	('ZWINT1', 'Gene', '11130', (17, 23))	('reduction', 'NegReg', (4, 13))
169902	32303675	5g), showing that the ZWINT1 protein was strongly degraded in RAB3GAP1-knockdown cells.	('RAB3GAP1-knockdown', 'Var', (62, 80))	('ZWINT1', 'Gene', '11130', (22, 28))	('RAB3GAP1-knockdown', 'Gene', (62, 80))	('ZWINT1', 'Gene', (22, 28))	('degraded', 'NegReg', (50, 58))
169914	32303675	The phosphorylation of hnRNP A0 was aberrantly induced in cancer cells, and the interaction of hnRNP A0 and mitosis-related RAB3GAP1 mRNA was diminished by the deactivation or deletion of the phosphorylated site of hnRNP A0 (Ser84), suggesting that the dysregulation of RNAs through the abnormal phosphorylation of hnRNP A0 leads to tumor progression and is a novel target for cancer treatment (Fig.	('deletion', 'Var', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('deactivation', 'Var', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('hnRNP A0', 'Gene', (315, 323))	('RAB3GAP1', 'Gene', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (377, 383))	('Ser84', 'Chemical', '-', (225, 230))	('leads to', 'Reg', (324, 332))	('hnRNP A0', 'Gene', (95, 103))	('diminished', 'NegReg', (142, 152))	('dysregulation', 'Var', (253, 266))	('tumor', 'Disease', (333, 338))	('phosphorylation', 'MPA', (4, 19))	('interaction', 'Interaction', (80, 91))	('phosphorylation', 'MPA', (296, 311))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('cancer', 'Disease', (377, 383))	('cancer', 'Disease', (58, 64))	('hnRNP A0', 'Gene', (23, 31))
169916	32303675	A comprehensive analysis combining transcriptome and RNA-immunoprecipitation revealed that mRNAs stabilized by hnRNP A0 were completely changed in cancer cells compared to non-tumorous cells, and the hnRNP A0-mRNAs interactions confirmed in cancer cells were diminished by the deactivation or deletion of Ser84 from hnRNP A0, indicating that cancer cells utilize post-transcriptional regulation, including phosphorylation, for their progression as well as genomic modifications.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', (342, 348))	('hnRNP A0', 'Gene', (316, 324))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('mRNAs', 'MPA', (91, 96))	('deletion', 'Var', (293, 301))	('tumor', 'Disease', (176, 181))	('deactivation', 'Var', (277, 289))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('changed', 'Reg', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('interactions', 'Interaction', (215, 227))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('Ser84', 'Gene', (305, 310))	('Ser84', 'Chemical', '-', (305, 310))	('diminished', 'NegReg', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', (147, 153))
169924	32303675	RNA-immunoprecipitation with hnRNP A0 and a gene editing assay of the phosphorylated site of hnRNP A0 revealed that the stabilization of hnRNP A0 interacting mRNAs, including RAB3GAP1, NUDT12, and OPN3, was significantly reduced by the dephosphorylation of hnRNP A0.	('hnRNP A0', 'Gene', (137, 145))	('NUDT12', 'Gene', (185, 191))	('hnRNP A0', 'Gene', (257, 265))	('stabilization', 'MPA', (120, 133))	('NUDT12', 'Gene', '83594', (185, 191))	('reduced', 'NegReg', (221, 228))	('OPN3', 'Gene', (197, 201))	('dephosphorylation', 'Var', (236, 253))	('OPN3', 'Gene', '23596', (197, 201))
169925	32303675	Western blotting showed phosphor-hnRNP A0 to be aberrantly expressed in cancer cells and a comprehensive analysis combining transcriptome and RNA-immunoprecipitation in HCT116 and CoEpiC cells indicated the interacting mRNAs to be completely different between tumor and non-tumorous cells, suggesting that cancer-specific therapy will be achieved by targeting the phosphorylation site (Ser84) of hnRNP A0.	('cancer', 'Disease', (72, 78))	('tumor', 'Disease', (260, 265))	('Ser84', 'Chemical', '-', (386, 391))	('Ser84', 'Var', (386, 391))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('hnRNP A0', 'Gene', (396, 404))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('HCT116', 'CellLine', 'CVCL:0291', (169, 175))	('cancer', 'Disease', (306, 312))
169926	32303675	Our western blotting analysis indicated that phosphor-hnRNP A0 was overexpressed in 3/6 patients (50.0%), none of whom had been treated with anti-tumor agents.	('phosphor-hnRNP', 'Var', (45, 59))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Disease', (146, 151))	('overexpressed', 'PosReg', (67, 80))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
169927	32303675	Interestingly, phosphorylation of hnRNP A0 was strongly observed in stage 1 tumor patients, suggesting that phosphorylation of hnRNP A0 may be a key event in tumorigenesis.	('tumor', 'Disease', (158, 163))	('observed', 'Reg', (56, 64))	('hnRNP A0', 'Gene', (127, 135))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('phosphorylation', 'Var', (108, 123))
169929	32303675	The downregulation of hnRNP A0 (knockdown, dephosphorylation, or deletion of Ser84) induces cell apoptosis through the misalignment of chromosomes at the equatorial plane during cell division in tumor cells but not in non-tumorous cells.	('hnRNP A0', 'Gene', (22, 30))	('tumor', 'Disease', (195, 200))	('cell apoptosis', 'CPA', (92, 106))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('downregulation', 'NegReg', (4, 18))	('dephosphorylation', 'Var', (43, 60))	('Ser84', 'Gene', (77, 82))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('Ser84', 'Chemical', '-', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('deletion', 'Var', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('induces', 'Reg', (84, 91))
170083	28919249	Dose-volume histogram data were analyzed to determine absolute volumes (cc) receiving doses from 10 to 60 Gy (V10, V20, V30, V40, V50, and V60), as well as maximum dose to 2 cc (D2cc), mean dose (MD), and generalized equivalent uniform dose (gEUD).	('V10', 'Var', (110, 113))	('V20', 'Var', (115, 118))	('V60', 'Chemical', 'MESH:C069837', (139, 142))	('V40', 'Var', (125, 128))	('V50', 'Var', (130, 133))	('V60', 'Var', (139, 142))	('V30', 'Var', (120, 123))
170087	28919249	Significant variables on univariate analysis for grade >=2 esophagitis were concurrent chemotherapy, V20, V30, V40, V50, V60, MD, D2cc, and gEUD.	('V60', 'Chemical', 'MESH:C069837', (121, 124))	('esophagitis', 'Phenotype', 'HP:0100633', (59, 70))	('esophagitis', 'Disease', (59, 70))	('V20', 'Var', (101, 104))	('esophagitis', 'Disease', 'MESH:D004941', (59, 70))	('V60', 'Var', (121, 124))	('D2cc', 'Var', (130, 134))	('V40', 'Var', (111, 114))	('V50', 'Var', (116, 119))	('V30', 'Var', (106, 109))
170088	28919249	For grade >=3 esophagitis, the predictive variables were: V30, V40, V50, V60, MD, D2cc, and gEUD.	('V60', 'Chemical', 'MESH:C069837', (73, 76))	('esophagitis', 'Phenotype', 'HP:0100633', (14, 25))	('esophagitis', 'Disease', (14, 25))	('esophagitis', 'Disease', 'MESH:D004941', (14, 25))	('V40', 'Var', (63, 66))	('V60', 'Var', (73, 76))	('D2cc', 'Var', (82, 86))	('V50', 'Var', (68, 71))	('V30', 'Var', (58, 61))
170091	28919249	For an estimated risk of grade >=3 esophagitis of 5%, the threshold values for gEUD and D2cc were 59.3 Gy and 68 Gy, respectively.	('esophagitis', 'Disease', 'MESH:D004941', (35, 46))	('esophagitis', 'Phenotype', 'HP:0100633', (35, 46))	('esophagitis', 'Disease', (35, 46))	('D2cc', 'Var', (88, 92))
170092	28919249	In this study, we report the novel finding that gEUD and D2cc, rather than MD, were the most predictive dose metrics for severe esophagitis.	('gEUD', 'Var', (48, 52))	('esophagitis', 'Phenotype', 'HP:0100633', (128, 139))	('esophagitis', 'Disease', (128, 139))	('esophagitis', 'Disease', 'MESH:D004941', (128, 139))	('D2cc', 'Var', (57, 61))
170111	28919249	Esophageal dose-volume histogram data were analyzed to determine absolute volumes (cc) receiving doses from 10 to 60 Gy (V10, V20, V30, V40, V50, and V60), as well as maximum dose to 2 cc (D2cc), MD to the esophagus, and generalized equivalent uniform dose (gEUD).	('V50', 'Var', (141, 144))	('V60', 'Var', (150, 153))	('V10', 'Var', (121, 124))	('V60', 'Chemical', 'MESH:C069837', (150, 153))	('V40', 'Var', (136, 139))	('V30', 'Var', (131, 134))	('V20', 'Var', (126, 129))
170112	28919249	D2cc was selected as the parameter for maximum dose because it is a well-recognized surrogate for point dose and is a frequently used constraint for rectum and bladder toxicity.	('bladder toxicity', 'Disease', (160, 176))	('bladder toxicity', 'Disease', 'MESH:D001745', (160, 176))	('D2cc', 'Var', (0, 4))
170123	28919249	Mean volumes (cc) for each dose metric were 21.1, 17.0, 14.1, 11.3, 7.6, and 3.3 for V10, V20, V30, V40, V50, V60, respectively; mean gEUD, MD, and D2cc were 46.7 Gy, 23.7 Gy, and 53.4 Gy (Table 2).	('V20', 'Var', (90, 93))	('V40', 'Var', (100, 103))	('V50', 'Var', (105, 108))	('V30', 'Var', (95, 98))	('V10', 'Var', (85, 88))	('V60', 'Var', (110, 113))	('V60', 'Chemical', 'MESH:C069837', (110, 113))
170126	28919249	On univariate analysis, the following variables were found to be predictive of grade >=2 esophagitis: concurrent chemotherapy, V20, V30, V40, V50, V60, MD, D2cc, and gEUD (Table 3).	('esophagitis', 'Phenotype', 'HP:0100633', (89, 100))	('esophagitis', 'Disease', (89, 100))	('V50', 'Var', (142, 145))	('esophagitis', 'Disease', 'MESH:D004941', (89, 100))	('V40', 'Var', (137, 140))	('V60', 'Var', (147, 150))	('D2cc', 'Var', (156, 160))	('gEUD', 'Var', (166, 170))	('V30', 'Var', (132, 135))	('V60', 'Chemical', 'MESH:C069837', (147, 150))	('V20', 'Var', (127, 130))
170127	28919249	For grade >=3 esophagitis, the predictive variables on univariate analysis were: V30, V40, V50, V60, MD, D2cc, and gEUD (Table 4).	('esophagitis', 'Phenotype', 'HP:0100633', (14, 25))	('esophagitis', 'Disease', (14, 25))	('esophagitis', 'Disease', 'MESH:D004941', (14, 25))	('V60', 'Var', (96, 99))	('V40', 'Var', (86, 89))	('D2cc', 'Var', (105, 109))	('V50', 'Var', (91, 94))	('V60', 'Chemical', 'MESH:C069837', (96, 99))	('V30', 'Var', (81, 84))
170130	28919249	For an estimated risk of grade >=3 esophagitis of 5%, the threshold values for gEUD and D2cc were 59.3 Gy and 68 Gy, respectively (Figs 1 and 2).	('esophagitis', 'Disease', 'MESH:D004941', (35, 46))	('esophagitis', 'Phenotype', 'HP:0100633', (35, 46))	('esophagitis', 'Disease', (35, 46))	('D2cc', 'Var', (88, 92))
170132	28919249	A classification tree analysis identified patients with either (1) early development of esophagitis (weeks 1-3) or (2) gEUD >54 Gy and onset of esophagitis within weeks 4 to 5 as being at high risk of subsequent grade 3 esophagitis.	('esophagitis', 'Disease', (144, 155))	('gEUD >54 Gy', 'Var', (119, 130))	('esophagitis', 'Disease', 'MESH:D004941', (144, 155))	('esophagitis', 'Phenotype', 'HP:0100633', (220, 231))	('esophagitis', 'Disease', (220, 231))	('esophagitis', 'Disease', 'MESH:D004941', (220, 231))	('men', 'Species', '9606', (80, 83))	('esophagitis', 'Phenotype', 'HP:0100633', (88, 99))	('esophagitis', 'Disease', (88, 99))	('patients', 'Species', '9606', (42, 50))	('esophagitis', 'Disease', 'MESH:D004941', (88, 99))	('esophagitis', 'Phenotype', 'HP:0100633', (144, 155))
170143	28919249	In 2003, the report of a single institutional retrospective study demonstrated that MD to the esophagus >34 Gy, along with administration of concurrent chemotherapy and maximum dose >58 Gy, were predictive of grade >=3 esophagitis on univariate analysis.	('>34 Gy', 'Var', (104, 110))	('esophagitis', 'Disease', 'MESH:D004941', (219, 230))	('esophagitis', 'Phenotype', 'HP:0100633', (219, 230))	('esophagitis', 'Disease', (219, 230))
170146	28919249	In the present study, we found that, although MD was predictive of grade >=2 and grade >=3 esophagitis, gEUD and D2cc were the most predictive of the dose metrics on ROC analysis.	('esophagitis', 'Disease', (91, 102))	('esophagitis', 'Phenotype', 'HP:0100633', (91, 102))	('esophagitis', 'Disease', 'MESH:D004941', (91, 102))	('D2cc', 'Var', (113, 117))
170148	28919249	Similarly, we found that the predictive ability of the individual dose metrics for grade >=3 esophagitis increases with increasing dose, with D2cc being the most predictive.	('esophagitis increases', 'Disease', 'MESH:D004941', (93, 114))	('esophagitis increases', 'Disease', (93, 114))	('D2cc', 'Var', (142, 146))	('esophagitis', 'Phenotype', 'HP:0100633', (93, 104))
170152	28919249	On multivariable analysis, V60 was the strongest predictor of grade >=2 and >=3 esophagitis with subsequent recursive partitioning analysis dividing patients into low (V60 <0.07%), intermediate (V60 0.07% to 16.99%), and high (V60 >=17%) risk groups.	('patients', 'Species', '9606', (149, 157))	('V60', 'Var', (27, 30))	('esophagitis', 'Phenotype', 'HP:0100633', (80, 91))	('esophagitis', 'Disease', (80, 91))	('esophagitis', 'Disease', 'MESH:D004941', (80, 91))	('V60', 'Chemical', 'MESH:C069837', (168, 171))	('V60', 'Chemical', 'MESH:C069837', (27, 30))	('grade >', 'Disease', (62, 69))	('V60', 'Chemical', 'MESH:C069837', (195, 198))	('V60', 'Chemical', 'MESH:C069837', (227, 230))
170153	28919249	When applied to the validation set, V60 remained significantly predictive only for grade >=3 esophagitis, remarkably similar to our findings for V60, which was the most predictive of the volumetric variables.	('V60', 'Chemical', 'MESH:C069837', (36, 39))	('esophagitis', 'Phenotype', 'HP:0100633', (93, 104))	('esophagitis', 'Disease', (93, 104))	('esophagitis', 'Disease', 'MESH:D004941', (93, 104))	('V60', 'Chemical', 'MESH:C069837', (145, 148))	('V60', 'Var', (36, 39))
170166	28919249	Despite these potential limitations, the finding that high dose metrics are associated with grade >=3 esophagitis is remarkably consistent with the existing literature.	('esophagitis', 'Disease', 'MESH:D004941', (102, 113))	('high dose metrics', 'Var', (54, 71))	('associated', 'Reg', (76, 86))	('esophagitis', 'Phenotype', 'HP:0100633', (102, 113))	('esophagitis', 'Disease', (102, 113))
170168	28919249	In this prospective, multi-institutional observational study for patients with locally advanced lung cancer treated across the state of Michigan, we find that gEUD and D2cc, rather than MD, were the most predictive dose metrics for severe esophagitis.	('D2cc', 'Var', (168, 172))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('lung cancer', 'Disease', (96, 107))	('gEUD', 'Var', (159, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (65, 73))	('esophagitis', 'Disease', (239, 250))	('esophagitis', 'Disease', 'MESH:D004941', (239, 250))	('esophagitis', 'Phenotype', 'HP:0100633', (239, 250))
170217	31488992	High nodal index, prolonged waiting time for surgery after Neo-adjuvant therapy and type of neo-adjuvant therapy (perioperative chemo verse neo-adjuvant chemo XRT) were the risk factors for developing recurrent disease (P <0.05).	('recurrent disease', 'Disease', (201, 218))	('neo', 'Chemical', '-', (140, 143))	('High', 'Var', (0, 4))	('neo', 'Chemical', '-', (92, 95))
170229	30844117	Previously, HOXB7, HOXC6 and HOXC8 were found abnormally upregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with normal mucosa and seen as poor prognostic predictors for ESCC patients, and were shown to promote cell proliferation and anti-apoptosis in ESCC cells.	('ESCC', 'Disease', (193, 197))	('anti-apoptosis', 'CPA', (257, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cell proliferation', 'CPA', (234, 252))	('HOXC8', 'Var', (29, 34))	('patients', 'Species', '9606', (198, 206))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (72, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('promote', 'PosReg', (226, 233))	('HOXB7', 'Var', (12, 17))	('esophageal squamous cell carcinoma', 'Disease', (72, 106))	('HOXC6', 'Var', (19, 24))	('upregulated', 'PosReg', (57, 68))
170231	30844117	The aim of the present study was to explore whether ESCC cells are sensitive to HXR9 disrupting the interaction between multiple HOX proteins and their cofactor PBX, which is required for HOX functions.	('PBX', 'Chemical', '-', (161, 164))	('interaction', 'Interaction', (100, 111))	('disrupting', 'NegReg', (85, 95))	('HXR9', 'Var', (80, 84))	('HOX', 'Chemical', '-', (129, 132))	('HOX', 'Chemical', '-', (188, 191))
170236	30844117	Meanwhile, HXR9 showed an antitumor phenotype, such as inhibiting cell proliferation, inducing cell apoptosis and significantly retarding tumor growth.	('retarding tumor', 'Disease', (128, 143))	('inducing', 'PosReg', (86, 94))	('retarding tumor', 'Disease', 'MESH:D009369', (128, 143))	('tumor', 'Disease', (138, 143))	('cell proliferation', 'CPA', (66, 84))	('cell apoptosis', 'CPA', (95, 109))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('HXR9', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('inhibiting', 'NegReg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
170244	30844117	Moreover, we showed that these HOX genes promoted oncogenic properties in ESCC cells and presented negative survival significance in ESCC patients.14, 15 Specifically, knockdown of HOXB7, HOXC6 or HOXC8 resulted in antiproliferation and proapoptosis phenotype in ESCC cell lines, and induced cell cycle arrest in G1 phase, and inhibited tumor growth in a mice xenograft model.	('HOXC6', 'Var', (188, 193))	('antiproliferation', 'CPA', (215, 232))	('HOXC8', 'Var', (197, 202))	('tumor', 'Disease', (337, 342))	('mice', 'Species', '10090', (355, 359))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('proapoptosis phenotype', 'CPA', (237, 259))	('HOX', 'Chemical', '-', (31, 34))	('arrest', 'Disease', 'MESH:D006323', (303, 309))	('HOX', 'Chemical', '-', (197, 200))	('HOX', 'Chemical', '-', (188, 191))	('inhibited', 'NegReg', (327, 336))	('patients', 'Species', '9606', (138, 146))	('induced', 'Reg', (284, 291))	('HOX', 'Chemical', '-', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('HOXB7', 'Var', (181, 186))	('knockdown', 'Var', (168, 177))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (292, 309))	('arrest', 'Disease', (303, 309))
170261	30844117	Total proteins were extracted by using RIPA lysis buffer with protease inhibitor cocktail and separated by SDS-PAGE, blotted onto PVDF, then immunoreacted with primary antibody overnight at 4 C. The primary antibodies used were anti-PBX (sc-28313 at 1:200; Santa Cruz Biotechnology, Dallas, TX, USA), anti-HOXB7 (ab51237 at 1:50; Abcam, Cambridge, MA, USA), anti-HOXC6 (ab151575 at 1:1000; Abcam), anti-HOXC8 (ab86236 at 1:1000; Abcam), anti-Caspase-3 (#9662 at 1:1000; Cell Signaling Technology, Danvers, MA, USA), anti-poly ADP ribose polymerase (anti-PARP, #5625 at 1:1000; Cell Signaling Technology), anti-c-FOS (sc-447 at 1:200; Santa Cruz Biotechnology), anti-PI3K (#4249 at 1:1000; Cell Signaling Technology), anti-AKT (#9272 at 1:1000; Cell Signaling Technology), anti-p-AKT (#5012 at 1:1000; Cell Signaling Technology), anti-signal transducer and activator of transcription-6 (anti-STAT6, #5397 at 1:1000; Cell Signaling Technology), anti-p-STAT6 (#9364 at 1:1000; Cell Signaling Technology) and anti-GAPDH (ZS-25778 at 1:2000; ZSGB-BIO, Beijing, China).	('AKT', 'Gene', (722, 725))	('PARP', 'Gene', '142', (554, 558))	('AKT', 'Gene', '207', (779, 782))	('poly ADP ribose polymerase', 'Gene', '142', (521, 547))	('GAPDH', 'Gene', '2597', (1010, 1015))	('ZS-25778', 'Var', (1017, 1025))	('Caspase-3', 'Gene', '836', (442, 451))	('c-FOS', 'Gene', '2353', (610, 615))	('PARP', 'Gene', (554, 558))	('STAT6', 'Gene', '6778', (891, 896))	('GAPDH', 'Gene', (1010, 1015))	('STAT6', 'Gene', (950, 955))	('AKT', 'Gene', '207', (722, 725))	('PBX', 'Chemical', '-', (233, 236))	('c-FOS', 'Gene', (610, 615))	('#9364 at 1:1000;', 'Var', (957, 973))	('Caspase-3', 'Gene', (442, 451))	('poly ADP ribose polymerase', 'Gene', (521, 547))	('AKT', 'Gene', (779, 782))	('STAT6', 'Gene', '6778', (950, 955))	('STAT6', 'Gene', (891, 896))
170263	30844117	After being fixed in 3.7% paraformaldehyde for 15 minutes and permeabilized with 0.5% Triton X-100 for 5 minutes, the coverslips were blocked in 5% normal serum and then incubated in primary antibody dilutions overnight at 4 C. The primary antibodies used were anti-PBX (sc-28313 at 1:50, mouse; Santa Cruz Biotechnology), anti-HOXB7 (#40-2000 at 1:50, rabbit; Thermo Fisher Scientific, Waltham, MA, USA), anti-HOXC6 (#PA5-65913 at 4 mug/mL, rabbit; Invitrogen, Carlsbad, CA, USA), and anti-HOXC8 (ab86236 at 1:50, rabbit; Abcam).	('#PA5-65913', 'Var', (418, 428))	('rabbit', 'Species', '9986', (442, 448))	('ab86236', 'Var', (498, 505))	('mouse', 'Species', '10090', (289, 294))	('rabbit', 'Species', '9986', (353, 359))	('PBX', 'Chemical', '-', (266, 269))	('rabbit', 'Species', '9986', (515, 521))
170265	30844117	The secondary antibodies used were FITC-conjugated goat antimouse IgG (F2761 at 1:50; Invitrogen) and TRITC-conjugated goat antirabbit IgG (T2769 at 1:50; Invitrogen).	('rabbit', 'Species', '9986', (128, 134))	('FITC', 'Chemical', 'MESH:D016650', (35, 39))	('goat', 'Species', '9925', (119, 123))	('goat', 'Species', '9925', (51, 55))	('TRITC', 'Chemical', 'MESH:C009434', (102, 107))	('F2761', 'Var', (71, 76))	('T2769', 'Var', (140, 145))	('mouse', 'Species', '10090', (60, 65))
170269	30844117	Each 8-week-old female BALB/c nude mouse was s.c. inoculated with 2.5 x 106 cells of KYSE70 and KYSE150 in 100 muL PBS into the right groin.	('KYSE70', 'Var', (85, 91))	('PBS', 'Chemical', 'MESH:D007854', (115, 118))	('KYSE150', 'Var', (96, 103))	('mouse', 'Species', '10090', (35, 40))
170271	30844117	When the average tumor volume reached approximately 100 mm3 for KYSE70 and 200 mm3 for KYSE150, the mice were randomly divided into two groups and received an initial dose of 100 mg/kg CXR9 or HXR9 (i.v.	('KYSE150', 'Var', (87, 94))	('tumor', 'Disease', (17, 22))	('KYSE70', 'Var', (64, 70))	('mice', 'Species', '10090', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
170277	30844117	After antigen retrieval, the sections were incubated with 10% normal goat serum to block any nonspecific reaction and incubated in primary antibody dilutions overnight at 4 C. The primary antibodies used were anti-Caspase-3 (9662 at 1:1000; Cell Signaling, America), anti-PARP (#5625 at 1:50; Cell Signaling Technology) and anti-c-FOS (TA806833 at 1:250; ZSGB-BIO).	('PARP', 'Gene', '142', (272, 276))	('TA806833', 'Var', (336, 344))	('c-FOS', 'Gene', '2353', (329, 334))	('goat', 'Species', '9925', (69, 73))	('Caspase-3', 'Gene', (214, 223))	('c-FOS', 'Gene', (329, 334))	('PARP', 'Gene', (272, 276))	('Caspase-3', 'Gene', '836', (214, 223))
170281	30844117	It has been shown that ESCC patients with high expression of HOXB7/HOXC6/HOXC8 had poorer prognosis than those with low expression.14, 15 However, no evidence has established their oncogenic function in ESCC.	('ESCC', 'Disease', (203, 207))	('patients', 'Species', '9606', (28, 36))	('HOXB7/HOXC6/HOXC8', 'Var', (61, 78))	('ESCC', 'Disease', (23, 27))
170282	30844117	Results of HOXB7 knockdown in ESCC cells have been reported in our previous study,15 which showed that cell proliferation rate dropped, cell growth rate decreased, colony-formation ability reduced and tumorigenicity reduced remarkably.	('reduced', 'NegReg', (216, 223))	('HOXB7', 'Gene', (11, 16))	('reduced', 'NegReg', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('dropped', 'NegReg', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('decreased', 'NegReg', (153, 162))	('cell proliferation rate', 'CPA', (103, 126))	('colony-formation ability', 'CPA', (164, 188))	('cell growth rate', 'CPA', (136, 152))	('knockdown', 'Var', (17, 26))	('tumor', 'Disease', (201, 206))
170284	30844117	Weight of tumors from HOXC6 and HOXC8 knockdown cells was 218 +- 203 mg and 61 +- 165 mg, respectively, which were significantly lower than those derived from control cells (462 +- 358 mg; P < .01, Figure S1D,E).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('knockdown', 'Var', (38, 47))	('lower', 'NegReg', (129, 134))
170285	30844117	Moreover, knockdown of HOXC6 or HOXC8 induced cell cycle arrest in G1 phase.	('knockdown', 'Var', (10, 19))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (46, 63))	('arrest', 'Disease', (57, 63))	('arrest', 'Disease', 'MESH:D006323', (57, 63))
170293	30844117	In the untreated cells, HOX and PBX protein were observed in the cytoplasm and nucleus, and their colocalization indicated the existence of HOX/PBX dimers, which were decreased remarkably in HXR9-treated cells but not in CXR9-treated cells (Figure 1B).	('dimers', 'Interaction', (148, 154))	('HOX', 'Chemical', '-', (24, 27))	('PBX', 'Chemical', '-', (144, 147))	('PBX', 'Chemical', '-', (32, 35))	('HXR9-treated', 'Var', (191, 203))	('HOX', 'Chemical', '-', (140, 143))	('decreased', 'NegReg', (167, 176))
170294	30844117	In addition, we noticed that HOX mainly localized in the cytoplasm but not in the nucleus for HXR9-treated cells, implying that HXR9 affects the nucleus-cytoplasm translocation of HOX.	('nucleus-cytoplasm translocation', 'MPA', (145, 176))	('HOX', 'Chemical', '-', (180, 183))	('affects', 'Reg', (133, 140))	('HXR9', 'Var', (128, 132))	('HOX', 'Chemical', '-', (29, 32))
170299	30844117	When the average tumor volume reached 100 mm3 for KYSE70 and 200 mm3 for KYSE150, mice were given an initial dose of HXR9 of 100 mg/kg (i.v.	('mice', 'Species', '10090', (82, 86))	('KYSE150', 'Var', (73, 80))	('tumor', 'Disease', (17, 22))	('KYSE70', 'Var', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
170303	30844117	On day 6, tumor growth inhibition (TGI) of xenograft tumor was 52.5% and 32.6% for KYSE70 and KYSE150, respectively.	('KYSE150', 'Var', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('xenograft tumor', 'Disease', (43, 58))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('xenograft tumor', 'Disease', 'MESH:D009369', (43, 58))	('tumor', 'Disease', (53, 58))	('KYSE70', 'Var', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
170304	30844117	On day 18, TGI of xenograft tumor was 59.3% and 65.0% for KYSE70 and KYSE150, respectively.	('KYSE150', 'Var', (69, 76))	('xenograft tumor', 'Disease', 'MESH:D009369', (18, 33))	('KYSE70', 'Var', (58, 64))	('xenograft tumor', 'Disease', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
170315	30844117	Specifically, IL-15, IL-23A, IL-24 were downregulated and MPL was upregulated in response to HXR9 treatment.	('MPL', 'Gene', '4352', (58, 61))	('IL-23A', 'Gene', '51561', (21, 27))	('downregulated', 'NegReg', (40, 53))	('IL-15', 'Gene', (14, 19))	('upregulated', 'PosReg', (66, 77))	('MPL', 'Gene', (58, 61))	('IL-24', 'Gene', (29, 34))	('HXR9', 'Var', (93, 97))	('IL-24', 'Gene', '11009', (29, 34))	('IL-23A', 'Gene', (21, 27))	('IL-15', 'Gene', '3600', (14, 19))
170320	30844117	The results showed that cell viability and colony formation ability were significantly decreased in knockdown cells, as well as enhanced apoptosis, cell cycle arrest in G1 phase, and slowed tumor growth.	('cell viability', 'CPA', (24, 38))	('knockdown', 'Var', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('colony formation ability', 'CPA', (43, 67))	('apoptosis', 'CPA', (137, 146))	('decreased', 'NegReg', (87, 96))	('arrest', 'Disease', 'MESH:D006323', (159, 165))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (148, 165))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('arrest', 'Disease', (159, 165))	('enhanced', 'PosReg', (128, 136))	('tumor', 'Disease', (190, 195))	('slowed', 'NegReg', (183, 189))
170325	30844117	In the present study, we also showed that treating ESCC cells with HXR9 caused apoptosis and inhibited cell proliferation and tumor growth in all of the lines tested.	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('apoptosis', 'CPA', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('inhibited', 'NegReg', (93, 102))	('HXR9', 'Var', (67, 71))	('tumor', 'Disease', (126, 131))
170329	30844117	This means that HOX/PBX inhibition specifically modifies HOX function through diverse mechanisms.	('PBX', 'Chemical', '-', (20, 23))	('HOX', 'Chemical', '-', (16, 19))	('inhibition', 'Var', (24, 34))	('HOX function', 'MPA', (57, 69))	('HOX', 'Chemical', '-', (57, 60))	('modifies', 'Reg', (48, 56))
170332	30844117	Then, at a later stage, STAT activity feeds back directly to HOX, triggering transformation of the HOX cascade into a gene-network during development.36 Thus, we hypothesize that HXR9 may disrupt HOX/PBX functions through modifying cytokine-JAK-STAT pathway activation.	('HXR9', 'Var', (179, 183))	('cytokine-JAK-STAT pathway', 'Pathway', (232, 257))	('functions', 'MPA', (204, 213))	('modifying', 'Reg', (222, 231))	('PBX', 'Chemical', '-', (200, 203))	('HOX/PBX', 'Pathway', (196, 203))	('activation', 'PosReg', (258, 268))	('HOX', 'Chemical', '-', (99, 102))	('HOX', 'Chemical', '-', (61, 64))	('disrupt', 'NegReg', (188, 195))	('HOX', 'Chemical', '-', (196, 199))
170338	30499150	Proliferation of GSTP1 knockdown cells was significantly decreased (P < .01), and the frequency of early apoptosis was increased (P < .05).	('early apoptosis', 'CPA', (99, 114))	('knockdown', 'Var', (23, 32))	('GSTP1', 'Gene', (17, 22))	('GSTP1', 'Gene', '2950', (17, 22))	('Proliferation', 'CPA', (0, 13))	('decreased', 'NegReg', (57, 66))	('increased', 'PosReg', (119, 128))
170339	30499150	Invasion capacity of GSTP1 knockdown cells was slightly decreased in transwell assay.	('knockdown', 'Var', (27, 36))	('decreased', 'NegReg', (56, 65))	('GSTP1', 'Gene', (21, 26))	('GSTP1', 'Gene', '2950', (21, 26))	('transwell assay', 'CPA', (69, 84))	('Invasion capacity', 'CPA', (0, 17))
170343	30499150	Moreover, the frequency of early and late apoptosis in GSTP1 knockdown cells was markedly increased over that of control cells by cisplatin exposure (P < .01).	('increased', 'PosReg', (90, 99))	('GSTP1', 'Gene', (55, 60))	('knockdown', 'Var', (61, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('GSTP1', 'Gene', '2950', (55, 60))
170356	30499150	Taqman Gene Expression Assays (Hs_00943350_g1 for GSTP1, Hs_01060665_g1 for beta-actin) were used as the template in a 20 muL mixture according to the manufacturer's instructions under the following conditions: denaturation at 90 C for 10 minutes; 35 cycles at 90 C for 1 minute, at 60 C for 30 seconds, and at 72 C for 60 seconds; and then a final extension at 72 C for 10 minutes.	('beta-actin', 'Gene', (76, 86))	('GSTP1', 'Gene', '2950', (50, 55))	('Hs_00943350_g1', 'Var', (31, 45))	('Hs_01060665_g1', 'Var', (57, 71))	('beta-actin', 'Gene', '728378', (76, 86))	('GSTP1', 'Gene', (50, 55))
170361	30499150	Two different types of siRNA (Stealth RNAi #HSS104545 and #HSS104546; Invitrogen, Carlsbad, CA, USA) specific for the GSTP1 sequence (GenBank Accession No.	('GSTP1', 'Gene', '2950', (118, 123))	('GSTP1', 'Gene', (118, 123))	('#HSS104546', 'Var', (58, 68))
170364	30499150	KYSE170 and TE13 cells (3 x 104 cells/well) were seeded into six-well plates with 2 mL medium for 24 hours and transfected with 20 nmol/L GSTP1 siRNA (#HSS104546) and a negative control (Stealth siRNA #12935112).	('#HSS104546', 'Var', (151, 161))	('GSTP1', 'Gene', '2950', (138, 143))	('GSTP1', 'Gene', (138, 143))
170387	30499150	Glutathione S-transferase Pi 1 expression in ESCC cell lines was upregulated compared with the normal fibroblast cell line, especially in KYSE170 and TE13, as described in the previous study.19 RNA expression of GSTP1 was reduced by siRNA specific to GSTP1 (si#1: HSS104545, si#2: HSS104546) compared with a negative control (Stealth siRNA: #12935112) in KYSE170 and TE13 cells (Figure 1A).	('GSTP1', 'Gene', (212, 217))	('Glutathione S-transferase Pi 1', 'Gene', '2950', (0, 30))	('GSTP1', 'Gene', (251, 256))	('si#1: HSS104545', 'Var', (258, 273))	('si#', 'Var', (275, 278))	('GSTP1', 'Gene', '2950', (212, 217))	('GSTP1', 'Gene', '2950', (251, 256))	('Glutathione S-transferase Pi 1', 'Gene', (0, 30))	('expression', 'MPA', (198, 208))	('reduced', 'NegReg', (222, 229))
170388	30499150	Protein expression of GSTP1 was obviously reduced by si#2, but not as much by si#1 (Figure 1B).	('reduced', 'NegReg', (42, 49))	('GSTP1', 'Gene', '2950', (22, 27))	('si#2', 'Var', (53, 57))	('Protein expression', 'MPA', (0, 18))	('GSTP1', 'Gene', (22, 27))
170419	30499150	Lin et al described that GSTP1 played a critical role in microRNA (miR)-133b-mediated tumor migration and was substantially related to MMP expression, although the effects on tumor invasion were not investigated.7 In the present study, invasion capacity of ESCC cell lines was decreased by knockdown of GSTP1 expression, whereas migration capacity was not.	('GSTP1', 'Gene', '2950', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (175, 180))	('GSTP1', 'Gene', '2950', (303, 308))	('tumor', 'Disease', (86, 91))	('microRNA (miR)-133b', 'Gene', '442890', (57, 76))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('knockdown', 'Var', (290, 299))	('GSTP1', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('GSTP1', 'Gene', (303, 308))	('microRNA (miR)-133b', 'Gene', (57, 76))	('decreased', 'NegReg', (277, 286))	('invasion capacity', 'CPA', (236, 253))
170423	30499150	Regarding ESCC, few reports have shown the value of GSTP1 as a biomarker for CDDP and 5-FU efficacy.36 In the chemosensitivity assay, viability of GSTP1 knockdown cells was significantly decreased by CDDP treatment, although proliferation was also decreased by GSTP1 knockdown.	('knockdown', 'Var', (153, 162))	('GSTP1', 'Gene', (147, 152))	('CDDP', 'Chemical', '-', (200, 204))	('GSTP1', 'Gene', '2950', (147, 152))	('GSTP1', 'Gene', '2950', (52, 57))	('GSTP1', 'Gene', (261, 266))	('GSTP1', 'Gene', (52, 57))	('CDDP', 'Chemical', '-', (77, 81))	('5-FU', 'Chemical', 'MESH:D005472', (86, 90))	('CDDP', 'Var', (200, 204))	('decreased', 'NegReg', (187, 196))	('viability', 'CPA', (134, 143))	('GSTP1', 'Gene', '2950', (261, 266))
170424	30499150	Moreover, in the apoptosis assay, early and late apoptosis rates by CDDP treatment were strongly increased in GSTP1 knockdown cells.	('GSTP1', 'Gene', '2950', (110, 115))	('increased', 'PosReg', (97, 106))	('knockdown', 'Var', (116, 125))	('CDDP', 'Chemical', '-', (68, 72))	('CDDP', 'Gene', (68, 72))	('GSTP1', 'Gene', (110, 115))
170427	30499150	Glutathione S-transferase Pi 1 prevents JNK activity by forming a complex with JNK in non-stressed cells, while dissociation of the complex occurs under oxidative stress and JNK activity is increased.26 Furthermore, GSTP1 was reported to modulate ERK1/2 rather than JNK under oxidative stress such as CDDP treatment.30 Thus, GSTP1 may play an important role in chemosensitivity through oxidative stress occurred by a DNA-damaging agent such as CDDP rather than 5-FU.	('JNK', 'Gene', (40, 43))	('JNK', 'Gene', (174, 177))	('GSTP1', 'Gene', '2950', (216, 221))	('JNK', 'Gene', '5599', (40, 43))	('Glutathione S-transferase Pi 1', 'Gene', (0, 30))	('JNK', 'Gene', '5599', (174, 177))	('JNK', 'Gene', (79, 82))	('oxidative stress', 'Phenotype', 'HP:0025464', (276, 292))	('ERK1/2', 'Gene', (247, 253))	('ERK1/2', 'Gene', '5595;5594', (247, 253))	('JNK', 'Gene', '5599', (79, 82))	('GSTP1', 'Gene', (216, 221))	('CDDP', 'Chemical', '-', (444, 448))	('CDDP', 'Chemical', '-', (301, 305))	('oxidative stress', 'Phenotype', 'HP:0025464', (386, 402))	('JNK', 'Gene', (266, 269))	('5-FU', 'Chemical', 'MESH:D005472', (461, 465))	('GSTP1', 'Gene', '2950', (325, 330))	('JNK', 'Gene', '5599', (266, 269))	('GSTP1', 'Gene', (325, 330))	('CDDP', 'Var', (444, 448))	('Glutathione S-transferase Pi 1', 'Gene', '2950', (0, 30))	('oxidative stress', 'Phenotype', 'HP:0025464', (153, 169))
170446	29995752	We found that high BMI was closely associated with a higher incidence of wound infection (odds ratio [OR]: 1.41, 95% confidence interval [CI]: 1.02-1.97, P = .04), cardiovascular complications (OR: 2.51, 95% CI, 1.65-3.81, P < .0001), and anastomotic leakage (OR: 1.50, 95% CI, 1.21-1.84, P = .0002), but a lower incidence of chylous leakage (OR: 0.59, 95% CI, 0.40-0.88, P = .01) when compared with normal BMI.	('chylous leakage', 'MPA', (326, 341))	('infection', 'Disease', (79, 88))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (164, 192))	('infection', 'Disease', 'MESH:D007239', (79, 88))	('anastomotic', 'Disease', (239, 250))	('cardiovascular complications', 'Disease', 'MESH:D002318', (164, 192))	('cardiovascular complications', 'Disease', (164, 192))	('high BMI', 'Var', (14, 22))
170447	29995752	The high BMI group was not associated with better or worse overall survival (OS) (hazard ratio [HR]: 0.95, 95% CI, 0.85-1.07, P = .4) and disease-free survival (HR: 0.95, 95% CI, 0.72-1.25, P = .72) than the normal BMI group.	('OS', 'Chemical', '-', (77, 79))	('high', 'Var', (4, 8))	('disease-free survival', 'CPA', (138, 159))	('overall survival', 'CPA', (59, 75))
170448	29995752	However, in the subgroup analysis, the pooled result of HRs generated from multivariate analyses suggested that high BMI could improve OS in EC patients (HR: 0.84, 95% CI, 0.76-0.93, P < .01).	('improve', 'PosReg', (127, 134))	('OS', 'Chemical', '-', (135, 137))	('high BMI', 'Var', (112, 120))	('patients', 'Species', '9606', (144, 152))	('EC', 'Phenotype', 'HP:0011459', (141, 143))
170457	29995752	Furthermore, in comparison with patients with normal BMI, patients with high BMI have more visceral adipose tissue, which might prolong the operative time and cause more blood loss during various types of surgery.	('high BMI', 'Var', (72, 80))	('patients', 'Species', '9606', (32, 40))	('visceral adipose tissue', 'MPA', (91, 114))	('prolong', 'PosReg', (128, 135))	('blood loss', 'Disease', 'MESH:D006473', (170, 180))	('blood loss', 'Disease', (170, 180))	('cause', 'Reg', (159, 164))	('more', 'PosReg', (86, 90))	('patients', 'Species', '9606', (58, 66))	('operative time', 'CPA', (140, 154))
170459	29995752	Several studies have reported that EC patients with high BMI tend to suffer from worse surgical outcomes after esophagectomy, including the increased incidence of severe complications, pulmonary complications, anastomotic leakage, and so on.	('high BMI', 'Var', (52, 60))	('pulmonary complications', 'Disease', 'MESH:D008171', (185, 208))	('patients', 'Species', '9606', (38, 46))	('pulmonary complications', 'Disease', (185, 208))	('EC', 'Phenotype', 'HP:0011459', (35, 37))	('pulmonary complications', 'Phenotype', 'HP:0006532', (185, 208))	('anastomotic', 'Disease', (210, 221))
170462	29995752	Considering several limitations of the published studies on this topic, including single-institutional experience, conflicting data, and small sample sizes, a systematic review and meta-analysis with a large sample size are needed to determine the correlation of high BMI with surgical outcomes and prognosis in postesophagectomy EC patients.	('patients', 'Species', '9606', (333, 341))	('postesophagectomy EC', 'Disease', (312, 332))	('EC', 'Phenotype', 'HP:0011459', (330, 332))	('high', 'Var', (263, 267))
170465	29995752	Two investigators screened the articles with the following inclusion criteria: the patients enrolled in eligible studies with esophageal cancer were histopathologically confirmed; prospective or retrospective studies; and studies assessed the prognostic value of high BMI on survival and postoperative outcomes.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('high BMI', 'Var', (263, 271))	('patients', 'Species', '9606', (83, 91))	('esophageal cancer', 'Disease', (126, 143))
170473	29995752	Sensitivity analyses were carried out by sequentially excluding single studies step by step and subgroup analysis based on tumor histopathological type, study region, cutoff value, and analysis type to explore the possible source of the heterogeneity and to determine the robustness of our results regarding the association between high BMI and the 2 primary endpoints.	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('high BMI', 'Var', (332, 340))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))
170478	29995752	Of these studies, 11 articles with 6790 patients investigated the relationship between high BMI and anastomotic leakage.	('patients', 'Species', '9606', (40, 48))	('high', 'Var', (87, 91))	('anastomotic leakage', 'CPA', (100, 119))
170479	29995752	After merging the data, we observed that the patients with high BMI might have a higher incidence of anastomotic leakage after surgery (OR: 1.50, 95% CI, 1.21-1.84, P = .0002) (Fig.	('patients', 'Species', '9606', (45, 53))	('anastomotic leakage', 'CPA', (101, 120))	('high BMI', 'Var', (59, 67))
170480	29995752	There were 9 articles involving 6078 patients that reported the association of high BMI with chylous leakage, and interestingly the results indicated that high BMI might be a protective factor for postoperative chylous leakage among EC patients (OR: 0.59, 95% CI, 0.40-0.88, P = .01) (Fig.	('high', 'Var', (155, 159))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (236, 244))	('high', 'Var', (79, 83))	('EC', 'Phenotype', 'HP:0011459', (233, 235))	('chylous leakage', 'MPA', (93, 108))	('association', 'Interaction', (64, 75))
170482	29995752	Among 3443 patients in these studies, patients with high BMI might have higher risk of experiencing cardiovascular complications after surgery (OR: 2.51, 95% CI, 1.65-3.81, P < .0001; heterogeneity: I2 = 27%, P = .26) (Fig.	('high BMI', 'Var', (52, 60))	('cardiovascular complications', 'Disease', 'MESH:D002318', (100, 128))	('cardiovascular complications', 'Disease', (100, 128))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (100, 128))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (11, 19))
170495	29995752	From the results of the subgroup analysis, we found that high BMI was still closely correlated with higher incidence of anastomotic leakage in the Asian population (OR = 1.69; 95% CI, 1.31-2.19; P < .01), cutoff value group (25 kg/m2) (OR = 1.52; 95% CI, 1.19-1.94; P < .01), as well as in the EC or esophageal squamous cell carcinoma (ESCC) group (OR = 1.44; 95% CI, 1.14-1.80; P < .01; or OR = 1.89; 95% CI, 1.13-3.17; P < .01) (Table 3).	('high', 'Var', (57, 61))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (300, 334))	('EC', 'Phenotype', 'HP:0011459', (294, 296))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (311, 334))	('anastomotic', 'Disease', (120, 131))	('esophageal squamous cell carcinoma', 'Disease', (300, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))
170496	29995752	It was observed that high BMI was closely correlated with a better OS in the multivariate analysis group (HR = 0.84; 95% CI, 0.76-0.93; P < .01), whereas there was still no significant correlation in the univariate analysis subgroup and other subgroups (Table 3).	('BMI', 'MPA', (26, 29))	('OS', 'Chemical', '-', (67, 69))	('high', 'Var', (21, 25))
170504	29995752	However, our study indicated that there was neither a statistically significant relationship between increased BMI and postoperative mortality, nor marginal trends of higher incidence of mortality exist in high BMI patients undergoing esophagectomy when compared with patients with normal BMI.	('patients', 'Species', '9606', (215, 223))	('esophagectomy', 'Disease', (235, 248))	('increased BMI', 'Phenotype', 'HP:0031418', (101, 114))	('high BMI', 'Var', (206, 214))	('patients', 'Species', '9606', (268, 276))
170505	29995752	Furthermore, it was also observed that high BMI was not associated with better or worse OS and DFS, as compared with normal BMI, and obesity was not linked with better or worse OS in comparison with overweight either.	('obesity', 'Phenotype', 'HP:0001513', (133, 140))	('obesity', 'Disease', 'MESH:D009765', (133, 140))	('overweight', 'Phenotype', 'HP:0025502', (199, 209))	('OS', 'Chemical', '-', (177, 179))	('high BMI', 'Var', (39, 47))	('obesity', 'Disease', (133, 140))	('DFS', 'CPA', (95, 98))	('OS', 'Chemical', '-', (88, 90))
170509	29995752	For instance, as opposed to our study, the meta-analyses conducted by Zhang et al and Pan et al reported that high BMI was a potential predictor of better OS among EC patients overall treated with esophagectomy.	('OS', 'Chemical', '-', (155, 157))	('BMI', 'MPA', (115, 118))	('patients', 'Species', '9606', (167, 175))	('EC', 'Phenotype', 'HP:0011459', (164, 166))	('high', 'Var', (110, 114))	('better OS', 'Disease', (148, 157))
170510	29995752	However, the meta-analysis conducted by Hong et al indicated that high BMI did not improve the prognosis in esophageal adenocarcinoma patients, which was in accordance with our study.	('high BMI', 'Var', (66, 74))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (108, 133))	('esophageal adenocarcinoma', 'Disease', (108, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (108, 133))	('patients', 'Species', '9606', (134, 142))
170512	29995752	Actually, as compared with normal BMI, low BMI usually means that patients have malnutrition and poor tolerance to operations, which might worsen the surgical outcomes and prognosis.	('malnutrition', 'Phenotype', 'HP:0004395', (80, 92))	('malnutrition', 'Disease', (80, 92))	('low BMI', 'Phenotype', 'HP:0045082', (39, 46))	('low', 'Var', (39, 42))	('worsen', 'Reg', (139, 145))	('malnutrition', 'Disease', 'MESH:D044342', (80, 92))	('patients', 'Species', '9606', (66, 74))
170518	29995752	Consistent with this, our meta-analysis showed that high BMI significantly increased the risk of wound infection.	('high BMI', 'Var', (52, 60))	('infection', 'Disease', (103, 112))	('infection', 'Disease', 'MESH:D007239', (103, 112))
170522	29995752	In addition, we also observed that high BMI was correlated with a higher incidence of cardiovascular complications as compared with normal BMI.	('high BMI', 'Var', (35, 43))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (86, 114))	('cardiovascular complications', 'Disease', (86, 114))	('cardiovascular complications', 'Disease', 'MESH:D002318', (86, 114))
170523	29995752	With respect to the incidence of postoperative in-hospital mortality, there was no significant difference between the normal and high BMI groups, although our meta-analysis indicated that high BMI was associated with higher incidence of several surgical outcomes in EC patients treated with esophagectomy, including severe complications, pulmonary complications, anastomotic leakage, cardiovascular complications, and wound infection.	('infection', 'Disease', (424, 433))	('cardiovascular complications', 'Disease', 'MESH:D002318', (384, 412))	('EC', 'Phenotype', 'HP:0011459', (266, 268))	('anastomotic leakage', 'Disease', (363, 382))	('high', 'Var', (188, 192))	('severe complications', 'Disease', (316, 336))	('pulmonary complications', 'Disease', 'MESH:D008171', (338, 361))	('higher', 'PosReg', (217, 223))	('BMI', 'Gene', (193, 196))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (384, 412))	('cardiovascular complications', 'Disease', (384, 412))	('pulmonary complications', 'Phenotype', 'HP:0006532', (338, 361))	('infection', 'Disease', 'MESH:D007239', (424, 433))	('patients', 'Species', '9606', (269, 277))	('pulmonary complications', 'Disease', (338, 361))
170525	29995752	Interestingly, high BMI patients inversely had a substantially reduced incidence of chylous leakage when compared with those with normal BMI.	('patients', 'Species', '9606', (24, 32))	('high BMI', 'Var', (15, 23))	('chylous leakage', 'MPA', (84, 99))	('reduced', 'NegReg', (63, 70))
170526	29995752	One of possible explanations for high BMI as a protective factor for the postoperative chylous leakage might be that high BMI patients have thicker surrounding tissues of esophagus, which leads to a lower risk of misinjury of thoracic duct during esophagus dissection.	('chylous leakage', 'MPA', (87, 102))	('high BMI', 'Var', (117, 125))	('thicker', 'PosReg', (140, 147))	('patients', 'Species', '9606', (126, 134))
170530	29995752	Grotenhius et al showed that obesity significantly improved prognosis and indicated that a higher percentage of tumor-free circumferential resection margins might be obtained during esophagectomy for cancer in high BMI patients because more fat tissue in high BMI patients surround the tumor as compared with patients with normal BMI.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('obesity', 'Disease', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('obesity', 'Disease', 'MESH:D009765', (29, 36))	('high BMI', 'Var', (255, 263))	('patients', 'Species', '9606', (219, 227))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (286, 291))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('patients', 'Species', '9606', (264, 272))	('obesity', 'Phenotype', 'HP:0001513', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('prognosis', 'MPA', (60, 69))	('improved', 'PosReg', (51, 59))	('more', 'PosReg', (236, 240))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patients', 'Species', '9606', (309, 317))	('cancer', 'Disease', (200, 206))
170532	29995752	The results of our meta-analysis suggested that high BMI exerted no impact on OS and DFS in EC patients overall, but the pooled result of HRs generated from multivariate analyses suggested that high BMI could improve OS in EC patients.	('improve', 'PosReg', (209, 216))	('patients', 'Species', '9606', (95, 103))	('high BMI', 'Var', (194, 202))	('EC', 'Phenotype', 'HP:0011459', (92, 94))	('EC', 'Phenotype', 'HP:0011459', (223, 225))	('patients', 'Species', '9606', (226, 234))	('OS', 'Chemical', '-', (78, 80))	('OS', 'Chemical', '-', (217, 219))
170538	29995752	Fourth, only few studies with small sample sizes were available for the pooled analysis of the impact of high BMI on severe complications and DFS as compared with normal BMI, and of obesity on OS when compared with high BMI.	('high BMI', 'Var', (105, 113))	('obesity', 'Phenotype', 'HP:0001513', (182, 189))	('obesity', 'Disease', 'MESH:D009765', (182, 189))	('OS', 'Chemical', '-', (193, 195))	('DFS', 'Disease', (142, 145))	('obesity', 'Disease', (182, 189))	('severe', 'Disease', (117, 123))
170549	28218985	We calculated the individual number of risk factors out of four easily identifiable and significant factors: age >=55 years, current/former alcohol flushing, mean corpuscular volume >=106 fL, and distinct soft palatal melanosis.	('flush', 'Phenotype', 'HP:0031284', (148, 153))	('>=106', 'Var', (182, 187))	('soft palatal melanosis', 'Disease', (205, 227))	('alcohol flushing', 'Disease', (140, 156))	('flushing', 'Phenotype', 'HP:0031284', (148, 156))	('soft palatal melanosis', 'Disease', 'MESH:C562950', (205, 227))	('alcohol flushing', 'Disease', 'MESH:D005483', (140, 156))
170561	28218985	All the alcoholics met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for alcohol dependence.10  The endoscopy examinations were carried out using an Olympus XQ230, Q240, Q240Z, or Q260 panendoscope (Olympus Optical, Tokyo, Japan).	('Mental Disorders', 'Disease', (64, 80))	('Q240', 'Var', (198, 202))	('Mental Disorders', 'Disease', 'MESH:D001523', (64, 80))	('alcohol dependence', 'Disease', 'MESH:D000437', (107, 125))	('alcohol dependence', 'Disease', (107, 125))	('Q240Z', 'SUBSTITUTION', 'None', (204, 209))	('Q260', 'Var', (214, 218))	('Q240Z', 'Var', (204, 209))	('alcohol', 'Chemical', 'MESH:D000438', (107, 114))	('alcohol', 'Chemical', 'MESH:D000438', (8, 15))
170589	28218985	A multivariate analysis showed that the presence of soft palatal melanosis of grade 1+ (OR [95% CI] = 1.58 [1.05-2.38]) or grade 2+/3+ (2.03 [1.20-3.43]) was independently associated with a higher risk of neoplasia in the UAT (Table 5).	('soft palatal melanosis', 'Disease', (52, 74))	('neoplasia', 'Disease', (205, 214))	('associated', 'Reg', (172, 182))	('soft palatal melanosis', 'Disease', 'MESH:C562950', (52, 74))	('grade 2+/3+', 'Var', (123, 134))	('neoplasia', 'Disease', 'MESH:D009369', (205, 214))	('neoplasia', 'Phenotype', 'HP:0002664', (205, 214))
170592	28218985	Increased risks of neoplasia in the UAT were also identified for age (OR = 1.37; 95% CI, 1.17-1.60), current or former flushing (1.57 [1.12-2.21]), and an MCV >=106 fL (1.80 [1.32-2.45]; Table 6).	('neoplasia', 'Disease', (19, 28))	('MCV >=106 fL', 'Var', (155, 167))	('flushing', 'Phenotype', 'HP:0031284', (119, 127))	('flushing', 'Disease', (119, 127))	('flush', 'Phenotype', 'HP:0031284', (119, 124))	('flushing', 'Disease', 'MESH:D005483', (119, 127))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('neoplasia', 'Disease', 'MESH:D009369', (19, 28))
170677	25489937	In particular, the volumes of lung receiving lower doses, such as V5, V10, V15, and V20 are of interest to investigators.	('V20', 'Var', (84, 87))	('V15', 'Gene', (75, 78))	('V15', 'Gene', '28814', (75, 78))	('V10', 'Var', (70, 73))
170683	25489937	Specifically, there was a significant increase in postoperative pulmonary complications when the V10 >= 40%.	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (50, 87))	('increase', 'PosReg', (38, 46))	('postoperative pulmonary complications', 'Disease', (50, 87))	('V10 >= 40%', 'Var', (97, 107))	('pulmonary complications', 'Phenotype', 'HP:0006532', (64, 87))
170688	25489937	The V40 parameter measured in numerous studies had a strong association with increased rates of heart toxicity.	('heart toxicity', 'Disease', 'MESH:D006331', (96, 110))	('V40', 'Var', (4, 7))	('heart toxicity', 'Disease', (96, 110))
170694	25489937	The V30 parameter has been closely associated with the rate of pericardial effusion.	('V30', 'Var', (4, 7))	('pericardial effusion', 'Disease', (63, 83))	('associated', 'Reg', (35, 45))	('pericardial effusion', 'Disease', 'MESH:D010490', (63, 83))	('pericardial effusion', 'Phenotype', 'HP:0001698', (63, 83))
170695	25489937	Specifically, a mean pericardial dose of 26.1 Gy and V30 > 46% has been associated with significantly increased rates of pericardial effusion.	('V30', 'Var', (53, 56))	('pericardial effusion', 'Phenotype', 'HP:0001698', (121, 141))	('pericardial effusion', 'Disease', 'MESH:D010490', (121, 141))	('pericardial effusion', 'Disease', (121, 141))
170697	25489937	Irradiation of the left anterior descending (LAD) artery and left ventricle poses a particular risk to developing coronary artery and ischemic heart disease.	('Irradiation', 'Var', (0, 11))	('coronary artery', 'Disease', (114, 129))	('ischemic heart disease', 'Disease', (134, 156))	('ischemic heart disease', 'Disease', 'MESH:D003324', (134, 156))
170773	25493557	recently reported effective adenoviral-based immunotherapy against esophageal cancer, in which an orthotopic esophageal cancer mouse model established at the gastroesophageal junction using the same technique as we showed in the movie was used.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mouse', 'Species', '10090', (127, 132))	('gastroesophageal junction', 'Disease', (158, 183))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (158, 183))	('esophageal cancer', 'Disease', (67, 84))	('esophageal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('adenoviral-based', 'Var', (28, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
170780	25493557	In our study, using the IVIS imaging system, the luminescent intensity of photons emitted from TE8-Luc subcutaneous tumors strongly correlated with tumor growth.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('correlated', 'Reg', (132, 142))	('TE8-Luc', 'Var', (95, 102))	('tumor', 'Disease', (148, 153))	('luminescent intensity of photons emitted', 'MPA', (49, 89))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (103, 122))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
170797	19798573	For instance, the past decade has witnessed rising prevalence of obesity and overweight in the USA, and body mass index (BMI) has been associated with both symptomatic GERD and BE.	('obesity', 'Phenotype', 'HP:0001513', (65, 72))	('overweight', 'Phenotype', 'HP:0025502', (77, 87))	('GERD', 'Disease', 'MESH:D005764', (168, 172))	('BE', 'Phenotype', 'HP:0100580', (177, 179))	('GERD', 'Disease', (168, 172))	('associated', 'Reg', (135, 145))	('body', 'Var', (104, 108))	('obesity', 'Disease', 'MESH:D009765', (65, 72))	('obesity', 'Disease', (65, 72))
170872	20309880	We found that Let-7g, miR-21, and miR-195p were expressed in all 10 cell lines, miR-9 and miR-20a were not expressed in any of the cell lines, and miR-16-2, miR-30e, miR-34a, miR-126, and miR-200a were expressed in some of the cell lines but not others.	('miR-34a', 'Gene', '407040', (166, 173))	('miR-200a', 'Gene', (188, 196))	('miR-16-2', 'Gene', '406951', (147, 155))	('miR-200a', 'Gene', '406983', (188, 196))	('miR-34a', 'Gene', (166, 173))	('Let-7g', 'Gene', (14, 20))	('miR-126', 'Var', (175, 182))	('miR-30e', 'Gene', '407034', (157, 164))	('miR-30e', 'Gene', (157, 164))	('miR-16-2', 'Gene', (147, 155))	('miR-21', 'Var', (22, 28))	('miR-195p', 'Var', (34, 42))
170874	20309880	Furthermore, we found that miR-126 expression was associated with tumor cell de-differentiation and lymph node metastasis, miR-16-2 was associated with lymph node metastasis, and miR-195p was associated with higher pathologic disease stages in patients with esophageal adenocarcinoma.	('associated', 'Reg', (136, 146))	('miR-195p', 'Var', (179, 187))	('miR-16-2', 'Gene', '406951', (123, 131))	('lymph node metastasis', 'CPA', (152, 173))	('associated', 'Reg', (192, 202))	('expression', 'MPA', (35, 45))	('miR-126', 'Gene', (27, 34))	('patients', 'Species', '9606', (244, 252))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (258, 283))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (258, 283))	('expression', 'Species', '29278', (35, 45))	('esophageal adenocarcinoma', 'Disease', (258, 283))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('lymph node metastasis', 'CPA', (100, 121))	('miR-16-2', 'Gene', (123, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('associated', 'Reg', (50, 60))
170881	20309880	Epidemiologic studies demonstrated that tobacco and alcohol use and low fruit and vegetable consumption are significant risk factors for both esophageal squamous cell carcinoma and esophageal adenocarcinoma, and frequent gastroesophageal reflux, overweight, and obesity are linked to the increasing incidence of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (181, 206))	('low', 'Var', (68, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (181, 206))	('overweight', 'Phenotype', 'HP:0025502', (246, 256))	('obesity', 'Phenotype', 'HP:0001513', (262, 269))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (221, 244))	('esophageal squamous cell carcinoma', 'Disease', (142, 176))	('esophageal adenocarcinoma', 'Disease', (181, 206))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (312, 337))	('gastroesophageal reflux', 'Disease', (221, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (312, 337))	('alcohol', 'Chemical', 'MESH:D000438', (52, 59))	('obesity', 'Disease', (262, 269))	('tobacco', 'Species', '4097', (40, 47))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (142, 176))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (221, 244))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('esophageal adenocarcinoma', 'Disease', (312, 337))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('alcohol use', 'Phenotype', 'HP:0030955', (52, 63))	('obesity', 'Disease', 'MESH:D009765', (262, 269))
170889	20309880	Let-7 is downregulated in human lung cancer and associated with shortened survival in these patients; however, restoration of Let-7 expression induces growth inhibition of lung cancer cells.	('human', 'Species', '9606', (26, 31))	('downregulated', 'NegReg', (9, 22))	('lung cancer', 'Disease', (172, 183))	('patients', 'Species', '9606', (92, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('restoration', 'Var', (111, 122))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('growth inhibition', 'CPA', (151, 168))	('Let-7', 'Gene', (126, 131))	('expression', 'Species', '29278', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('expression', 'MPA', (132, 142))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
170901	20309880	We chose 10 miRNAs (Let-7g, miR-9, miR-16-2, miR-20, miR-21, miR-30e, miR-34a, miR-126, miR-195p, and miR-200a) on the basis of a miRNA microarray study showing that these miRNAs had different expression levels in esophageal cancer tissues and cell lines compared to normal tissues.	('expression', 'Species', '29278', (193, 203))	('miR-16-2', 'Gene', (35, 43))	('miR-34a', 'Gene', '407040', (70, 77))	('miR-34a', 'Gene', (70, 77))	('miR-200a', 'Gene', (102, 110))	('miR-200a', 'Gene', '406983', (102, 110))	('miR-20', 'Var', (45, 51))	('miR-16-2', 'Gene', '406951', (35, 43))	('miR-30e', 'Gene', '407034', (61, 68))	('miR-195p', 'Var', (88, 96))	('miR-9', 'Var', (28, 33))	('esophageal cancer', 'Disease', (214, 231))	('expression levels', 'MPA', (193, 210))	('miR-30e', 'Gene', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('miR-126', 'Var', (79, 86))	('miR-21', 'Var', (53, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (214, 231))
170946	20309880	In particular, Let-7g, miR-21, and miR-195p were expressed in all of the cell lines; miR-9 and miR-20a were not expressed in any of the cell lines; and miR-16-2, miR-30e, miR-34a, miR-126, and miR-200a were expressed in some of the cell lines but not others (Figure 1).	('miR-126', 'Var', (180, 187))	('miR-195p', 'Var', (35, 43))	('miR-21', 'Var', (23, 29))	('miR-30e', 'Gene', '407034', (162, 169))	('miR-16-2', 'Gene', (152, 160))	('miR-30e', 'Gene', (162, 169))	('miR-34a', 'Gene', '407040', (171, 178))	('miR-200a', 'Gene', (193, 201))	('miR-34a', 'Gene', (171, 178))	('miR-16-2', 'Gene', '406951', (152, 160))	('miR-200a', 'Gene', '406983', (193, 201))	('Let-7g', 'Gene', (15, 21))
170948	20309880	Moreover, transactivation of miR-34a by p53 broadly influenced gene expression and promoted apoptosis.	('expression', 'Species', '29278', (68, 78))	('apoptosis', 'CPA', (92, 101))	('miR-34a', 'Gene', '407040', (29, 36))	('transactivation', 'Var', (10, 25))	('p53', 'Gene', (40, 43))	('miR-34a', 'Gene', (29, 36))	('gene expression', 'MPA', (63, 78))	('promoted', 'PosReg', (83, 91))	('influenced', 'Reg', (52, 62))
170956	20309880	The positive staining rates for each miRNA were as follows: Let-7g, 56.7%; miR-9, 78.5%; miR-16-2, 51.9%; miR-20, 73.0%; miR-21, 81.6%; miR-30e, 63.3%; miR-34a, 39.5%; miR-126, 44.3%; miR-195p, 62.4%; and miR-200a, 43.9%.	('miR-16-2', 'Gene', (89, 97))	('miR-20', 'Var', (106, 112))	('miR-34a', 'Gene', '407040', (152, 159))	('miR-16-2', 'Gene', '406951', (89, 97))	('miR-9', 'Var', (75, 80))	('miR-21', 'Var', (121, 127))	('miR-195p', 'Var', (184, 192))	('miR-126', 'Var', (168, 175))	('miR-34a', 'Gene', (152, 159))	('miR-30e', 'Gene', '407034', (136, 143))	('miR-30e', 'Gene', (136, 143))	('miR-200a', 'Gene', (205, 213))	('miR-200a', 'Gene', '406983', (205, 213))	('Let-7g', 'Var', (60, 66))
170958	20309880	We found that miR-126 expression was associated with tumor cell de-differentiation (p = 0.0079) and lymph node metastasis (p = 0.01), miR-16-2 expression was associated with lymph node metastasis (p = 0.03), and miR-195p expression was associated with higher pathologic disease stages (p = 0.0008) in esophageal adenocarcinoma patients.	('expression', 'Species', '29278', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (301, 326))	('expression', 'Species', '29278', (221, 231))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (301, 326))	('expression', 'Species', '29278', (22, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('associated', 'Reg', (158, 168))	('esophageal adenocarcinoma', 'Disease', (301, 326))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('lymph node metastasis', 'CPA', (174, 195))	('associated', 'Reg', (37, 47))	('miR-195p expression', 'Var', (212, 231))	('miR-16-2', 'Gene', (134, 142))	('patients', 'Species', '9606', (327, 335))	('lymph node metastasis', 'CPA', (100, 121))	('miR-16-2', 'Gene', '406951', (134, 142))	('miR-126', 'Gene', (14, 21))	('tumor', 'Disease', (53, 58))
170974	20309880	In addition, our data demonstrated that positive section margins (p = 0.036), advanced clinical disease stage (p=0.025), pathologic disease stage (p=0.0001), poor tumor differentiation (p=0.009), positive lymph nodes (p=0.008), and tumor metastasis (p=0.001) were associated with shorter overall survival in adenocarcinoma patients, and positive section margins (p = 0.029), pathologic disease stage (p= 0.007), and positive lymph nodes (p=0.047) were associated with shorter overall survival in squamous cell carcinoma patients.	('squamous cell carcinoma', 'Disease', (496, 519))	('tumor', 'Disease', (163, 168))	('patients', 'Species', '9606', (323, 331))	('adenocarcinoma', 'Disease', (308, 322))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('poor', 'Var', (158, 162))	('overall', 'MPA', (476, 483))	('tumor', 'Disease', (232, 237))	('shorter', 'NegReg', (280, 287))	('patients', 'Species', '9606', (520, 528))	('tumor metastasis', 'Disease', 'MESH:D009362', (232, 248))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (496, 519))	('adenocarcinoma', 'Disease', 'MESH:D000230', (308, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('tumor metastasis', 'Disease', (232, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (510, 519))	('shorter', 'NegReg', (468, 475))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('overall survival', 'MPA', (288, 304))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (496, 519))
170978	20309880	The expression of some of the miRNAs was associated with tumor cell de-differentiation (miR-126), lymph node metastasis (miR-126 and miR-16-2), or higher pathologic tumor stage (miR-195p) in esophageal adenocarcinoma patients.	('miR-16-2', 'Gene', '406951', (133, 141))	('associated', 'Reg', (41, 51))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (191, 216))	('expression', 'Species', '29278', (4, 14))	('patients', 'Species', '9606', (217, 225))	('esophageal adenocarcinoma', 'Disease', (191, 216))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('expression', 'MPA', (4, 14))	('lymph node metastasis', 'CPA', (98, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (191, 216))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('miR-16-2', 'Gene', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('miR-126', 'Var', (121, 128))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (165, 170))
170984	20309880	They found that the expression levels of some miRNAs were different between esophageal squamous cell carcinoma and normal tissues, and miR-103/107 expression was associated with poor survival.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('expression', 'Species', '29278', (147, 157))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (76, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('miR-103/107', 'Var', (135, 146))	('different', 'Reg', (58, 67))	('associated', 'Reg', (162, 172))	('esophageal squamous cell carcinoma', 'Disease', (76, 110))	('expression levels', 'MPA', (20, 37))	('expression', 'Species', '29278', (20, 30))
170994	20309880	A recent study demonstrated that an ectopic expression of mir-34a in IMR90 cells led to substantial inhibition of growth (i.e., the fraction of S-phase cells decreased, but G1 and G2 cells increased).	('decreased', 'NegReg', (158, 167))	('mir-34a', 'Gene', '407040', (58, 65))	('fraction of S-phase', 'MPA', (132, 151))	('ectopic expression', 'Var', (36, 54))	('IMR90', 'CellLine', 'CVCL:0347', (69, 74))	('inhibition', 'NegReg', (100, 110))	('mir-34a', 'Gene', (58, 65))	('expression', 'Species', '29278', (44, 54))	('growth', 'MPA', (114, 120))	('increased', 'PosReg', (189, 198))
170996	20309880	Our current study confirmed these data in esophageal cancer cells and showed that transfection of miR-34a into various esophageal cancer cell lines suppressed tumor cell growth and expression of c-MET and cyclinD1 although we didn't know whether inhibition of both genes by miR-34a is direct or indirect.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('miR-34a', 'Gene', (274, 281))	('c-MET', 'Protein', (195, 200))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('miR-34a', 'Gene', '407040', (274, 281))	('miR-34a', 'Gene', (98, 105))	('esophageal cancer', 'Disease', (42, 59))	('expression', 'MPA', (181, 191))	('cyclinD1', 'Gene', (205, 213))	('miR-34a', 'Gene', '407040', (98, 105))	('tumor', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('suppressed', 'NegReg', (148, 158))	('transfection', 'Var', (82, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('expression', 'Species', '29278', (181, 191))	('esophageal cancer', 'Disease', (119, 136))
171034	33314197	Consistent with human studies, animal studies have also shown that alcohol drinking or painting on the oro-esophageal epithelium inhibited squamous differentiation and produced squamous hyperproliferation in rodents.	('inhibited', 'NegReg', (129, 138))	('squamous differentiation', 'CPA', (139, 163))	('alcohol', 'Chemical', 'MESH:D000438', (67, 74))	('squamous hyperproliferation', 'Disease', (177, 204))	('human', 'Species', '9606', (16, 21))	('painting', 'Var', (87, 95))	('alcohol drinking', 'Phenotype', 'HP:0030955', (67, 83))	('squamous hyperproliferation', 'Disease', 'MESH:D002294', (177, 204))
171036	33314197	It is believed that ethanol enhances penetration of carcinogens across the epithelium, stimulates cell proliferation, inhibits squamous differentiation, generates oxidative stress, interferes with DNA repair and synthesis, disturbs systemic metabolism of nutrients, impairs immune function, induces chronic inflammation, and promotes angiogenesis.	('cell proliferation', 'CPA', (98, 116))	('inflammation', 'Disease', 'MESH:D007249', (307, 319))	('oxidative stress', 'MPA', (163, 179))	('inhibits', 'NegReg', (118, 126))	('angiogenesis', 'CPA', (334, 346))	('synthesis', 'MPA', (212, 221))	('inflammation', 'Disease', (307, 319))	('impairs', 'NegReg', (266, 273))	('penetration', 'CPA', (37, 48))	('oxidative stress', 'Phenotype', 'HP:0025464', (163, 179))	('immune function', 'CPA', (274, 289))	('induces', 'Reg', (291, 298))	('systemic metabolism of nutrients', 'MPA', (232, 264))	('stimulates', 'PosReg', (87, 97))	('ethanol', 'Chemical', 'MESH:D000431', (20, 27))	('promotes', 'PosReg', (325, 333))	('DNA repair', 'MPA', (197, 207))	('generates', 'Reg', (153, 162))	('ethanol', 'Var', (20, 27))	('squamous differentiation', 'CPA', (127, 151))	('disturbs', 'NegReg', (223, 231))	('enhances', 'PosReg', (28, 36))	('interferes', 'NegReg', (181, 191))	('impairs immune function', 'Phenotype', 'HP:0002721', (266, 289))
171051	33314197	Human ESCC cells (KYSE510, KYSE410, KYSE450, and KYSE70) were obtained from the ATCC (Manassas, VA, USA) and the ECACC (Porton Down, Salisbury, UK) with proper authentication.	('Human', 'Species', '9606', (0, 5))	('KYSE70', 'Var', (49, 55))	('KYSE410', 'Var', (27, 34))	('KYSE510', 'Var', (18, 25))	('KYSE450', 'Var', (36, 43))	('KYSE510', 'CellLine', 'CVCL:1354', (18, 25))
171052	33314197	KYSE510 and KYSE410 were exposed to ethanol, dibenzazepine (DBZ; a chemical NOTCH inhibitor) (Cayman, Ann Arbor, MI, USA), or recombinant human JAG1 (a NOTCH ligand; R&D System, Minneapolis, MN, USA).	('DBZ', 'Chemical', 'MESH:C527817', (60, 63))	('dibenzazepine', 'Chemical', 'MESH:C527817', (45, 58))	('JAG1', 'Gene', (144, 148))	('human', 'Species', '9606', (138, 143))	('ethanol', 'Chemical', 'MESH:D000431', (36, 43))	('KYSE410', 'Var', (12, 19))	('KYSE510', 'CellLine', 'CVCL:1354', (0, 7))	('MN', 'CellLine', 'CVCL:U508', (191, 193))	('JAG1', 'Gene', '182', (144, 148))
171061	33314197	for 5 d) to induce NICD1 overexpression or NOTCH1/NOTCH2 knockout in the esophageal squamous epithelial cells of Sox2CreER;RosaNICD1 or K5CreER;N1fl/fl;N2fl/fl mice, respectively.	('Sox2', 'Gene', '20674', (113, 117))	('knockout', 'Var', (57, 65))	('mice', 'Species', '10090', (160, 164))	('Sox2', 'Gene', (113, 117))	('overexpression', 'PosReg', (25, 39))	('NOTCH1/NOTCH2', 'Gene', (43, 56))	('NICD1', 'Gene', (19, 24))
171089	33314197	A chemical inhibitor of NOTCH signaling, DBZ (25 or 50 muM for 24 h) caused dramatic down-regulation of NICD1, HES1, and PAX9 expression in KYSE510 cells (Figure 2D).	('expression', 'MPA', (126, 136))	('down-regulation', 'NegReg', (85, 100))	('DBZ', 'Chemical', 'MESH:C527817', (41, 44))	('NICD1', 'Gene', (104, 109))	('PAX9', 'Gene', (121, 125))	('KYSE510', 'CellLine', 'CVCL:1354', (140, 147))	('HES1', 'Gene', (111, 115))	('DBZ', 'Var', (41, 44))
171090	33314197	To further determine whether NOTCH perturbation may affect PAX9 expression in vivo, Sox2CreER;ROSANICD1 and K5CreER;N1fl/fl;N2fl/fl mice were exposed to tamoxifen to overexpress NICD1 or knock out Notch1/Notch2 in esophageal squamous epithelial cells.	('expression', 'MPA', (64, 74))	('Notch2', 'Gene', '18129', (204, 210))	('perturbation', 'Var', (35, 47))	('Sox2', 'Gene', '20674', (84, 88))	('PAX9', 'Gene', (59, 63))	('affect', 'Reg', (52, 58))	('mice', 'Species', '10090', (132, 136))	('Sox2', 'Gene', (84, 88))	('overexpress', 'PosReg', (166, 177))	('Notch1', 'Gene', (197, 203))	('Notch1', 'Gene', '18128', (197, 203))	('Notch2', 'Gene', (204, 210))	('knock out', 'Var', (187, 196))	('tamoxifen', 'Chemical', 'MESH:D013629', (153, 162))
171115	33314197	In the normal esophageal epithelium of rodents and humans, NOTCH1, NOTCH2, and NOTCH3 are highly expressed whereas NOTCH4 is expressed at a minimal level.	('NOTCH1', 'Var', (59, 65))	('NOTCH4', 'Gene', (115, 121))	('NOTCH4', 'Gene', '4855', (115, 121))	('NOTCH2', 'Var', (67, 73))	('NOTCH3', 'Var', (79, 85))	('humans', 'Species', '9606', (51, 57))
171119	33314197	These data explain our previous observation that PAX9 in esophageal squamous epithelial cells was downregulated by ethanol exposure and Pax9 deficiency in mouse esophagus promoted cell proliferation and delayed cell differentiation.	('downregulated', 'NegReg', (98, 111))	('Pax9', 'Gene', (136, 140))	('delayed', 'NegReg', (203, 210))	('promoted', 'PosReg', (171, 179))	('cell differentiation', 'CPA', (211, 231))	('PAX9', 'Gene', (49, 53))	('cell proliferation', 'CPA', (180, 198))	('ethanol', 'Chemical', 'MESH:D000431', (115, 122))	('mouse', 'Species', '10090', (155, 160))	('deficiency', 'Var', (141, 151))
171141	33314197	However, in the liver, ethanol activated SHH signaling, and thus promoted carcinogenesis.	('ethanol', 'Var', (23, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (74, 88))	('carcinogenesis', 'Disease', (74, 88))	('promoted', 'PosReg', (65, 73))	('ethanol', 'Chemical', 'MESH:D000431', (23, 30))	('activated', 'PosReg', (31, 40))	('SHH signaling', 'Pathway', (41, 54))
171199	32469462	calculated the proportion of esophageal cancer attributable to drinking, smoking, low vegetable and fruit consumption.	('esophageal cancer', 'Disease', (29, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('low vegetable', 'Var', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
171257	32138170	Furthermore, compared to wild-type endothelial cells, the migration of TSPAN8 knockout endothelial cells was sharply reduced.	('TSPAN8', 'Gene', (71, 77))	('reduced', 'NegReg', (117, 124))	('rat', 'Species', '10116', (61, 64))	('knockout', 'Var', (78, 86))	('migration', 'CPA', (58, 67))
171269	32138170	The knockdown of TSPAN8 attenuates the effects of the EGFR on gastric cancer cell proliferation and invasion.	('effects', 'MPA', (39, 46))	('attenuates', 'NegReg', (24, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('rat', 'Species', '10116', (89, 92))	('TSPAN8', 'Gene', (17, 23))	('EGFR', 'Gene', '1956', (54, 58))	('invasion', 'CPA', (100, 108))	('gastric cancer', 'Disease', (62, 76))	('knockdown', 'Var', (4, 13))	('EGFR', 'Gene', (54, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))
171276	32138170	The knockdown of TSPAN8 reduces cell viability and proliferation, while overexpression of TSPAN8 enhances cell viability and proliferation in NSCLC cells.	('reduces', 'NegReg', (24, 31))	('knockdown', 'Var', (4, 13))	('rat', 'Species', '10116', (132, 135))	('NSCLC', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('TSPAN8', 'Gene', (17, 23))	('cell viability', 'CPA', (32, 46))	('rat', 'Species', '10116', (58, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('TSPAN8', 'Gene', (90, 96))	('overexpression', 'PosReg', (72, 86))	('enhances', 'PosReg', (97, 105))	('cell viability', 'CPA', (106, 120))
171277	32138170	TSPAN8 knockdown leads to G1 arrest and apoptosis by downregulating CDK2, CDK4 and Cyclin D1 and upregulating BCL2 Associated X, Apoptosis Regulator (Bax) and Poly (ADP-ribose) polymerase (PARP).	('apoptosis', 'CPA', (40, 49))	('PARP', 'Gene', (189, 193))	('downregulating', 'NegReg', (53, 67))	('arrest', 'Disease', (29, 35))	('BCL2 Associated X, Apoptosis Regulator', 'Gene', '581', (110, 148))	('Bax', 'Gene', (150, 153))	('CDK4', 'Gene', (74, 78))	('Bax', 'Gene', '581', (150, 153))	('Poly (ADP-ribose) polymerase', 'Gene', '142', (159, 187))	('upregulating', 'PosReg', (97, 109))	('arrest', 'Disease', 'MESH:D006323', (29, 35))	('CDK4', 'Gene', '1019', (74, 78))	('Cyclin D1', 'Gene', '595', (83, 92))	('TSPAN8', 'Gene', (0, 6))	('Cyclin D1', 'Gene', (83, 92))	('Poly (ADP-ribose) polymerase', 'Gene', (159, 187))	('CDK2', 'Gene', '1017', (68, 72))	('knockdown', 'Var', (7, 16))	('PARP', 'Gene', '142', (189, 193))	('CDK2', 'Gene', (68, 72))
171281	32138170	The knockdown of TSPAN8 or competition with purified TSPAN8-LEL protein inhibits EOC cell invasion.	('LEL', 'Chemical', '-', (60, 63))	('TSPAN8', 'Gene', (17, 23))	('inhibits', 'NegReg', (72, 80))	('EOC cell invasion', 'CPA', (81, 98))	('knockdown', 'Var', (4, 13))	('EOC', 'Phenotype', 'HP:0025318', (81, 84))
171283	32138170	The knockdown of TSPAN8 reduces proliferation and migration and increases the sensitivity of temozolomide (TMZ)-induced cell death and the apoptosis of glioma cells.	('reduces', 'NegReg', (24, 31))	('TMZ', 'Chemical', 'MESH:D000077204', (107, 110))	('glioma', 'Disease', (152, 158))	('sensitivity of temozolomide', 'MPA', (78, 105))	('temozolomide', 'Chemical', 'MESH:D000077204', (93, 105))	('rat', 'Species', '10116', (39, 42))	('TSPAN8', 'Gene', (17, 23))	('death', 'Disease', 'MESH:D003643', (125, 130))	('rat', 'Species', '10116', (53, 56))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('proliferation', 'CPA', (32, 45))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('knockdown', 'Var', (4, 13))	('death', 'Disease', (125, 130))	('apoptosis', 'CPA', (139, 148))	('increases', 'PosReg', (64, 73))
171295	32138170	In NPC patients, the expression of TSPAN8 is associated with a reduced survival rate.	('NPC', 'Disease', (3, 6))	('reduced', 'NegReg', (63, 70))	('rat', 'Species', '10116', (80, 83))	('NPC', 'Phenotype', 'HP:0100630', (3, 6))	('expression', 'Var', (21, 31))	('survival rate', 'CPA', (71, 84))	('TSPAN8', 'Gene', (35, 41))	('patients', 'Species', '9606', (7, 15))
171298	32138170	In these cells, TSPAN8 enhances Sonic Hedgehog (SHH) signaling, stabilizes the expression of protein patched homolog 1 (PTCH1) by recruiting ataxin-3 (ATXN3), and promotes cancer stemness.	('ATXN3', 'Gene', '4287', (151, 156))	('PTCH1', 'Gene', (120, 125))	('cancer stemness', 'Disease', 'MESH:D009369', (172, 187))	('SHH', 'Gene', '6469', (48, 51))	('ataxin-3', 'Gene', (141, 149))	('protein patched homolog 1', 'Gene', '5727', (93, 118))	('expression', 'MPA', (79, 89))	('recruiting', 'PosReg', (130, 140))	('TSPAN8', 'Var', (16, 22))	('promotes', 'PosReg', (163, 171))	('cancer stemness', 'Disease', (172, 187))	('ATXN3', 'Gene', (151, 156))	('SHH', 'Gene', (48, 51))	('enhances', 'PosReg', (23, 31))	('Sonic Hedgehog', 'Gene', (32, 46))	('protein patched homolog 1', 'Gene', (93, 118))	('PTCH1', 'Gene', '5727', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('ataxin-3', 'Gene', '4287', (141, 149))	('Sonic Hedgehog', 'Gene', '6469', (32, 46))
171310	32138170	Finally, through in vivo animal models, they confirmed that D6.1 could reduce the tumor growth as well as consumption coagulopathy of D6.1A-overexpressing rat adenocarcinoma cells.	('rat', 'Species', '10116', (155, 158))	('consumption coagulopathy', 'Disease', 'MESH:D004211', (106, 130))	('reduce', 'NegReg', (71, 77))	('coagulopathy', 'Phenotype', 'HP:0003256', (118, 130))	('D6.1A-overexpressing', 'Var', (134, 154))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('D6.1', 'Var', (60, 64))	('consumption coagulopathy', 'Disease', (106, 130))	('consumption coagulopathy', 'Phenotype', 'HP:0005520', (106, 130))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('adenocarcinoma', 'Disease', (159, 173))	('tumor', 'Disease', (82, 87))	('adenocarcinoma', 'Disease', 'MESH:D000230', (159, 173))
171312	32138170	First, we silenced TSPAN8 via TSPAN8 small interfering RNA (siRNA) into HCT116 mCRC cells and observed that TSPAN8 knockdown reduced HCT116 cell invasion.	('HCT116', 'CellLine', 'CVCL:0291', (133, 139))	('TSPAN8', 'Gene', (19, 25))	('CRC', 'Disease', (80, 83))	('TSPAN8', 'Gene', (30, 36))	('CRC', 'Phenotype', 'HP:0030731', (80, 83))	('reduced', 'NegReg', (125, 132))	('HCT116', 'CellLine', 'CVCL:0291', (72, 78))	('CRC', 'Disease', 'MESH:D015179', (80, 83))	('silenced', 'NegReg', (10, 18))	('TSPAN8', 'Gene', (108, 114))	('HCT116 cell invasion', 'CPA', (133, 153))	('knockdown', 'Var', (115, 124))
171314	32138170	Third, a competition assay with purified Fc fusion proteins of each loop (TSPAN8-LEL-Fc and TSPAN8-SEL-Fc) revealed that HCT116 cell invasion was specifically blocked by TSPAN8-LEL-Fc, but not by TSPAN8-SEL-Fc.	('LEL', 'Chemical', '-', (177, 180))	('LEL', 'Chemical', '-', (81, 84))	('HCT116 cell invasion', 'CPA', (121, 141))	('TSPAN8-LEL-Fc', 'Var', (170, 183))	('HCT116', 'CellLine', 'CVCL:0291', (121, 127))	('blocked', 'NegReg', (159, 166))
171321	32138170	We further revealed that TSPAN8-LEL is essential for EOC cell invasion through TSPAN8 siRNA knockdown and a competition assay with purified TSPAN8-LEL-Fc.	('LEL', 'Chemical', '-', (32, 35))	('knockdown', 'Var', (92, 101))	('LEL', 'Chemical', '-', (147, 150))	('EOC', 'Phenotype', 'HP:0025318', (53, 56))	('TSPAN8', 'Gene', (79, 85))
171322	32138170	Moreover, we found that anti-TSPAN8 IgG not only specifically inhibited the invasion of EOC cell lines, including SNU8, SNU251 and SK-OV3 cells, but also wholly and dramatically blocked ovarian cancer cell metastasis by up to around 35% with a single dose.	('ovarian cancer', 'Disease', (186, 200))	('blocked', 'NegReg', (178, 185))	('anti-TSPAN8', 'Var', (24, 35))	('SK-OV3', 'CellLine', 'CVCL:0532', (131, 137))	('inhibited', 'NegReg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('EOC', 'Phenotype', 'HP:0025318', (88, 91))	('ovarian cancer', 'Phenotype', 'HP:0100615', (186, 200))	('ovarian cancer', 'Disease', 'MESH:D010051', (186, 200))	('invasion', 'CPA', (76, 84))
171325	32138170	Furthermore, a radioconjugate 131I-omburtamab, an anti-B7-H3 monoclonal antibody, is being evaluated in clinical studies.	('B7-H3', 'Gene', '80381', (55, 60))	('B7-H3', 'Gene', (55, 60))	('131I-omburtamab', 'Var', (30, 45))
171332	32138170	In conclusion, currently available and accumulating evidence has led us to speculate that antibody-based targeting of TSPAN8 may be an effective strategy to suppress tumor progression and metastasis.	('TSPAN8', 'Gene', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('targeting', 'Var', (105, 114))	('tumor', 'Disease', (166, 171))	('rat', 'Species', '10116', (147, 150))	('suppress', 'NegReg', (157, 165))
171343	31788646	The greatest change in the 15th edition of JGCA staging systems for gastric cancer was the separate inclusion of N3a and N3b.	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gastric cancer', 'Disease', (68, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('N3b', 'Var', (121, 124))	('N3a', 'Var', (113, 116))
171347	31788646	Although at least 16 RLN are recommended for staging in the JGCA and AJCC/UICC TNM classifications, a significant prognostic difference has been reported even between RLN <16 and RLN >=16 in patients with pStage II-III gastric cancer.10 Previous studies have identified that RLN >=25 could eliminate the prognostic effect10 and presented better prognostic staging.11 Indeed, the German S3 guidelines also recommend >=25 RLN as a criterion for a D2 gastrectomy.	('gastric cancer', 'Phenotype', 'HP:0012126', (219, 233))	('patients', 'Species', '9606', (191, 199))	('D2 gastrectomy', 'Disease', (445, 459))	('>=25 RLN', 'Var', (415, 423))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('pStage II-III gastric cancer', 'Disease', (205, 233))	('pStage II-III gastric cancer', 'Disease', 'MESH:D013274', (205, 233))
171362	31788646	Namely, clinical tumor depth staging was divided into three degrees such as: (i) T1, T2; (ii) T3, T4a; and (iii) T4b.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('T4b', 'Var', (113, 116))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))
171368	31788646	Major categories were as follows: (i) clinical questions of surgical resection (CQ1-CQ10); (ii) clinical questions of endoscopic treatments (CQ11-CQ12); (iii) clinical questions for non-resectable or recurrent gastric cancer (CQ13-CQ22); and (iv) clinical questions of perioperative chemotherapy (CQ23-CQ26).	('gastric cancer', 'Disease', 'MESH:D013274', (210, 224))	('gastric cancer', 'Phenotype', 'HP:0012126', (210, 224))	('CQ11-CQ12', 'Chemical', 'MESH:C492468', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('gastric cancer', 'Disease', (210, 224))	('non-resectable', 'Disease', (182, 196))	('CQ13-CQ22', 'Var', (226, 235))
171378	31788646	Regarding patients with only CY1 factor (CQ20) or minute peritoneal metastasis, which is recognized as a clinical status of micro-metastasis, and only a low tumor burden at the peritoneal cavity, perioperative S-1 based chemotherapy for CY126 or HIPEC (hyperthermic intraperitoneal infusion chemotherapy) for CY127 or i.p.	('tumor', 'Disease', (157, 162))	('S-1', 'Gene', '5707', (210, 213))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('S-1', 'Gene', (210, 213))	('CY126', 'Chemical', 'MESH:C098793', (237, 242))	('patients', 'Species', '9606', (10, 18))	('CY127', 'Var', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CY1 factor', 'Var', (29, 39))	('CY127', 'Chemical', 'MESH:C098793', (309, 314))
171389	31788646	eCuraB is en bloc resection status of UL0, undifferentiated type, <2 cm, pT1a, HM0, VM0, Ly0 and V0, or differentiated type, <3 cm, pT1b (SM1), HM0, VM0, Ly0 and V0.	('SM1', 'Gene', (138, 141))	('<3 cm', 'Var', (125, 130))	('SM1', 'Gene', '7911', (138, 141))
171392	31788646	Recently, patients who required radical surgery after endoscopic submucosal dissection for early gastric cancer were investigated.44 The eCura system consists of five clinicopathological factors, which are scored as follows: one point each for tumor size >30 mm, positive vertical margin, venous invasion and SM2 (depth of tumor invasion into the submucosa is >=500 mum from the muscularis mucosa), and three points for lymphatic invasion.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('gastric cancer', 'Disease', (97, 111))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('venous invasion', 'CPA', (289, 304))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('tumor', 'Disease', (244, 249))	('SM2', 'Gene', (309, 312))	('tumor', 'Disease', (323, 328))	('lymphatic invasion', 'CPA', (420, 438))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('>30 mm', 'Var', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (323, 328))	('SM2', 'Gene', '53366', (309, 312))
171400	31788646	Of note, nivolumab, programmed cell death protein 1 (PD-1) immune checkpoint inhibitor has been approved in Japan on the basis of a randomized trial, ATTRACTION-2, showing a significant survival advantage for patients who received nivolumab compared with placebo in the third or later lines of therapy.48, 49 ATTRACTION-2 phase III trial showed that the median overall survival (OS) was significantly better for nivolumab (5.26 months for nivolumab vs 4.14 months for placebo) (HR, 0.63; P < .0001).	('PD-1', 'Gene', (53, 57))	('better', 'PosReg', (401, 407))	('PD-1', 'Gene', '5133', (53, 57))	('overall survival', 'MPA', (361, 377))	('programmed cell death protein 1', 'Gene', (20, 51))	('patients', 'Species', '9606', (209, 217))	('nivolumab', 'Var', (439, 448))	('nivolumab', 'Var', (412, 421))	('programmed cell death protein 1', 'Gene', '5133', (20, 51))
171408	31788646	Regarding postoperative pathophysiology, the influence of non-physiological food passage after Billroth-II and Roux-en-Y reconstruction is recognized as a potential cause of metabolic and absorption disorders such as iron, calcium and fatty acid deficiencies.	('fatty acid deficiencies', 'Disease', 'MESH:C580102', (235, 258))	('calcium', 'Chemical', 'MESH:D002118', (223, 230))	('absorption disorders', 'Disease', (188, 208))	('iron', 'Chemical', 'MESH:D007501', (217, 221))	('non-physiological', 'Var', (58, 75))	('cause', 'Reg', (165, 170))	('calcium', 'Disease', (223, 230))	('absorption disorders', 'Disease', 'MESH:C564600', (188, 208))	('fatty acid deficiencies', 'Disease', (235, 258))	('iron', 'Disease', (217, 221))
171417	31788646	The GS subtype is enriched in a diffuse-type histology and is molecularly characterized by fewer mutations and less overexpression of epithelial mesenchymal transition (EMT)-related genes.64 In contrast, the CIN subtype is enriched in intestinal histology and is molecularly characterized by TP53 mutation and RTK-RAS activation/amplifications.	('CIN', 'Disease', (208, 211))	('mutation', 'Var', (297, 305))	('TP53', 'Gene', '7157', (292, 296))	('TP53', 'Gene', (292, 296))	('RTK-RAS', 'Gene', (310, 317))	('CIN', 'Phenotype', 'HP:0040012', (208, 211))	('activation/amplifications', 'PosReg', (318, 343))
171419	31788646	Thus, some molecular targets with frequent targets have been identified,66 such as gene amplifications of MET and ERBB2; hypermethylation of p16;67, 68 mutations of TP53, APC and E-cadherin;69, 70, 71 oncogenic activation of beta-catenin and K-ras;72 and inactivation of the mismatch repair gene hMLH1, which is associated with MSI.73 However, in clinical settings, only a few genes have been used as diagnostic biomarkers and/or molecular therapeutic targets.74, 75 The development of molecular biomarkers and therapy is urgently required.	('TP53', 'Gene', (165, 169))	('mutations', 'Var', (152, 161))	('E-cadherin', 'Gene', (179, 189))	('E-cadherin', 'Gene', '999', (179, 189))	('ERBB2', 'Gene', '2064', (114, 119))	('K-ras', 'Gene', (242, 247))	('TP53', 'Gene', '7157', (165, 169))	('APC', 'Disease', 'MESH:D011125', (171, 174))	('APC', 'Disease', (171, 174))	('hMLH1', 'Gene', (296, 301))	('hMLH1', 'Gene', '4292', (296, 301))	('p16', 'Gene', (141, 144))	('p16', 'Gene', '1029', (141, 144))	('beta-catenin', 'Gene', (225, 237))	('K-ras', 'Gene', '3845', (242, 247))	('beta-catenin', 'Gene', '1499', (225, 237))	('MSI', 'Gene', (328, 331))	('MSI', 'Gene', '5928', (328, 331))	('ERBB2', 'Gene', (114, 119))
171421	31788646	Liquid biopsy is a less invasive approach for obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression.	('cancer initiation', 'Disease', (124, 141))	('epigenetic aberrations', 'Var', (68, 90))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('associated', 'Reg', (108, 118))	('genetic', 'Var', (56, 63))	('cancer initiation', 'Disease', 'MESH:D009369', (124, 141))
171424	31788646	Identification of the EBV subtype using liquid biopsy could be useful for real-time monitoring of tumor progression and treatment response.78 Also, a recent study identified a blood test, Cancer SEEK, that can detect eight common cancer types including gastric cancer through assessment of the levels of circulating proteins and mutations in cell-free DNA.79  MicroRNAs (miRNA), which are small non-coding RNAs, regulate the translation of specific protein-coding genes.	('gastric cancer', 'Disease', (253, 267))	('translation', 'MPA', (425, 436))	('regulate', 'Reg', (412, 420))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (253, 267))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', (261, 267))	('protein-coding', 'Protein', (449, 463))	('EBV', 'Disease', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (253, 267))	('EBV', 'Disease', 'MESH:D020031', (22, 25))	('Cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (329, 338))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (261, 267))
171428	31788646	Regarding the downregulated tumor suppressor miRNAs in blood, let-7a, miR-101, miR-181b, miR-203, miR-204, miR-218, miR-375, miR-451 and miR-486 might be useful candidates as blood-based biomarkers and oligonucleotide therapeutics for gastric cancer.	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('miR-486', 'Gene', '619554', (137, 144))	('miR-451', 'Gene', '574411', (125, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (235, 249))	('miR-204', 'Gene', '406987', (98, 105))	('miR-21', 'Gene', (107, 113))	('miR-203', 'Gene', (89, 96))	('miR-181b', 'Var', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('downregulated', 'NegReg', (14, 27))	('miR-451', 'Gene', (125, 132))	('gastric cancer', 'Disease', (235, 249))	('miR-375', 'Gene', '494324', (116, 123))	('miR-203', 'Gene', '406986', (89, 96))	('miR-375', 'Gene', (116, 123))	('let-7a', 'Gene', (62, 68))	('miR-101', 'Var', (70, 77))	('miR-204', 'Gene', (98, 105))	('miR-486', 'Gene', (137, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (235, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('miR-21', 'Gene', '406991', (107, 113))
171461	31561465	Epstein-Barr virus-associated tumors usually carrying phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, 2. microsatellite instability (MSI) tumors commonly with PIK3CA, EGFR (epidermal growth factor receptor) and HER2 (human epidermal growth factor receptor 2) mutations, 3. genomically stable gastro-esophageal cancers, characterized by CDH1 and RHOA mutations and the CLDN18-ARHGAP fusion, and finally, 4. chromosomally unstable tumors with TP53 mutations as well as receptor tyrosine kinase (RTK)/RAS, vascular endothelial growth factor receptors (VEGFR), and p110 amplifications.	('gastro-esophageal cancers', 'Disease', 'MESH:D004938', (335, 360))	('EGFR', 'Gene', (210, 214))	('vascular endothelial growth factor receptors', 'Gene', (546, 590))	('RTK', 'Gene', (536, 539))	('p110', 'Gene', '9733', (604, 608))	('EGFR', 'Gene', '1956', (593, 597))	('receptor tyrosine kinase', 'Gene', '5979', (510, 534))	('CDH1', 'Gene', '999', (379, 383))	('RTK', 'Gene', '5979', (536, 539))	('HER2', 'Gene', '2064', (254, 258))	('epidermal growth factor receptor 2', 'Gene', (266, 300))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('TP53', 'Gene', '7157', (484, 488))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('CDH1', 'Gene', (379, 383))	('PIK3CA', 'Gene', (202, 208))	('microsatellite instability (MSI) tumors', 'Disease', 'MESH:D053842', (148, 187))	('PIK3CA', 'Gene', '5290', (126, 132))	('vascular endothelial growth factor receptors', 'Gene', '3791', (546, 590))	('receptor tyrosine kinase', 'Gene', (510, 534))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('VEGFR', 'Gene', '3791', (592, 597))	('tumors', 'Phenotype', 'HP:0002664', (472, 478))	('EGFR', 'Gene', '1956', (210, 214))	('VEGFR', 'Gene', (592, 597))	('CLDN18', 'Gene', (411, 417))	('Epstein-Barr virus-associated tumors', 'Disease', (0, 36))	('tumors', 'Disease', (30, 36))	('epidermal growth factor receptor', 'Gene', '1956', (266, 298))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:C106336', (54, 91))	('tumors', 'Disease', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('mutations', 'Var', (489, 498))	('HER2', 'Gene', (254, 258))	('tumors', 'Disease', (472, 478))	('human', 'Species', '9606', (260, 265))	('EGFR', 'Gene', (593, 597))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('PIK3CA', 'Gene', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('TP53', 'Gene', (484, 488))	('epidermal growth factor receptor', 'Gene', (216, 248))	('Epstein-Barr virus-associated tumors', 'Disease', 'MESH:D020031', (0, 36))	('cancers', 'Phenotype', 'HP:0002664', (353, 360))	('CLDN18', 'Gene', '51208', (411, 417))	('epidermal growth factor receptor', 'Gene', '1956', (216, 248))	('PIK3CA', 'Gene', '5290', (202, 208))	('RHOA', 'Gene', '387', (388, 392))	('epidermal growth factor receptor 2', 'Gene', '2064', (266, 300))	('tumors', 'Disease', 'MESH:D009369', (472, 478))	('RHOA', 'Gene', (388, 392))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('gastro-esophageal cancers', 'Disease', (335, 360))	('p110', 'Gene', (604, 608))
171482	31561465	The underwhelming results of EGFR targeted therapy have led to its loss of appeal as a potential and viable target for EC therapy.	('targeted therapy', 'Var', (34, 50))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('EC', 'Gene', '56838', (119, 121))
171483	31561465	Another promising targeted therapy that had previously been proven effective in the treatment of several GI cancers is the inhibition of vascular endothelial growth factor (VEGF).	('vascular endothelial growth factor', 'Gene', (137, 171))	('vascular endothelial growth factor', 'Gene', '7422', (137, 171))	('inhibition', 'Var', (123, 133))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('VEGF', 'Gene', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('VEGF', 'Gene', '7422', (173, 177))	('cancers', 'Disease', (108, 115))
171501	31561465	As cancer cells mutate, they evolve to evade the anti-tumor immune response (and, more specifically, the tumor-infiltrating CD8 T-cells) by developing immunosuppressive mechanisms that either inhibit, anergise, or trick cytotoxic T-cells into ignoring cancer and commit apoptosis themselves.	('mutate', 'Var', (16, 22))	('trick', 'Reg', (214, 219))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('inhibit', 'NegReg', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CD8', 'Gene', (124, 127))	('evade', 'NegReg', (39, 44))	('cancer', 'Disease', (3, 9))	('CD8', 'Gene', '925', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
171507	31561465	Cancers with high MSI and deficient MMR have a high tumor mutational burden, leading to the development of neo-antigens that facilitate immune recognition.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Cancers', 'Disease', (0, 7))	('tumor', 'Disease', (52, 57))	('facilitate', 'PosReg', (125, 135))	('deficient', 'Var', (26, 35))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('MMR', 'Protein', (36, 39))	('high MSI', 'Var', (13, 21))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('immune recognition', 'MPA', (136, 154))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
171508	31561465	EC cancers often have a high tumor mutational burden, with almost half of the cases displaying p53 mutations (and many other genome abnormalities such as aneuploidy and cyclinA anomalies), likely due to the effects of chronic gastric reflux and inflammation driving continuous cellular and DNA turnover and, thus, eventually tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('inflammation', 'Disease', (245, 257))	('aneuploidy', 'Disease', (154, 164))	('p53', 'Gene', '7157', (95, 98))	('EC', 'Gene', '56838', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('p53', 'Gene', (95, 98))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('anomalies', 'Disease', 'MESH:D000014', (177, 186))	('tumor', 'Disease', (325, 330))	('aneuploidy', 'Disease', 'MESH:D000782', (154, 164))	('gastric reflux', 'Phenotype', 'HP:0002020', (226, 240))	('inflammation', 'Disease', 'MESH:D007249', (245, 257))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('mutations', 'Var', (99, 108))	('cancers', 'Disease', (3, 10))	('tumor', 'Disease', (29, 34))	('anomalies', 'Disease', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
171525	31561465	In the same trial (Checkpoint-032), when compared to nivolumab alone, nivolumab plus ipilimumab combinations had greater progression-free survival (PFS; 10-17% vs 8%) and ORR (13-24% vs 12%) but similar OS, lower 12-month OS rates (24-35% vs 39%), and a significantly increased risk of adverse events (27-47% vs 17%).	('OS rates', 'MPA', (222, 230))	('ORR', 'MPA', (171, 174))	('nivolumab plus ipilimumab', 'Disease', (70, 95))	('combinations', 'Var', (96, 108))	('progression-free survival', 'CPA', (121, 146))	('greater', 'PosReg', (113, 120))	('lower', 'NegReg', (207, 212))	('nivolumab plus ipilimumab', 'Disease', 'MESH:D007625', (70, 95))
171527	31561465	A similar trend was observed for the MSI status, with high-MSI tumors generally responding better than low-MSI ones.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('high-MSI', 'Var', (54, 62))
171593	29238199	One patient had previously received right lower lobectomy due to a benign tumor and two patients had undergone surgery for esophageal cancer, with supra-aortic anastomosis in one case and anastomosis in the neck between the left thoracic incision and neck incision in the other.	('anastomosis', 'Var', (188, 199))	('patient', 'Species', '9606', (88, 95))	('esophageal cancer', 'Disease', (123, 140))	('supra-aortic anastomosis', 'Disease', (147, 171))	('patients', 'Species', '9606', (88, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('patient', 'Species', '9606', (4, 11))	('benign tumor', 'Disease', (67, 79))	('benign tumor', 'Disease', 'MESH:D009369', (67, 79))	('-aortic anastomosis', 'Phenotype', 'HP:0002623', (152, 171))	('supra-aortic anastomosis', 'Disease', 'MESH:D001018', (147, 171))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
171794	28801840	In rats, NNN reproducibly induces head and neck tumors.	('induces', 'Reg', (26, 33))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('NNN', 'Var', (9, 12))	('rats', 'Species', '10116', (3, 7))	('neck tumors', 'Disease', 'MESH:D006258', (43, 54))	('NNN', 'Chemical', 'MESH:C008655', (9, 12))	('head and neck tumors', 'Phenotype', 'HP:0012288', (34, 54))	('neck tumors', 'Disease', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
171796	28801840	However, when administered in drinking water or liquid diet, NNN exposure results in oral, esophageal and nasal tumors.	('nasal tumors', 'Disease', (106, 118))	('nasal tumors', 'Disease', 'MESH:D009669', (106, 118))	('NNN', 'Gene', (61, 64))	('drinking water', 'Chemical', 'MESH:D060766', (30, 44))	('nasal tumors', 'Phenotype', 'HP:0012720', (106, 118))	('results in', 'Reg', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('exposure', 'Var', (65, 73))	('oral', 'Disease', (85, 89))	('NNN', 'Chemical', 'MESH:C008655', (61, 64))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal', 'Disease', (91, 101))
171813	28801840	BaP has been shown to cause skin cancers when topically applied and it causes local tumors when administered subcutaneously.	('cause', 'Reg', (22, 27))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('BaP', 'Chemical', 'MESH:D001564', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('skin cancers', 'Disease', (28, 40))	('skin cancers', 'Phenotype', 'HP:0008069', (28, 40))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('BaP', 'Var', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('skin cancers', 'Disease', 'MESH:D012878', (28, 40))	('causes', 'Reg', (71, 77))
171814	28801840	When given orally, PAH result in tongue and esophageal cancers, tumors of the upper respiratory tract, including nose, larynx and trachea.	('esophageal cancers', 'Disease', (44, 62))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors of the upper respiratory tract', 'Disease', 'MESH:D012141', (64, 101))	('esophageal cancers', 'Disease', 'MESH:D004938', (44, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('result in', 'Reg', (23, 32))	('tumors of the upper respiratory tract', 'Disease', (64, 101))	('PAH', 'Var', (19, 22))	('trachea', 'Disease', (130, 137))	('PAH', 'Chemical', 'MESH:D011084', (19, 22))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('nose', 'Disease', (113, 117))	('tongue', 'Disease', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('larynx', 'Disease', (119, 125))
171849	28801840	There are complex mechanisms of genetic predisposition, carcinogen metabolism and excretion, immunologic competency, and genetic alterations that allow some tobacco users to progress along the carcinogenesis pathway (Figure 8) to develop a cancer while others are able to exit this pathway, for example by excreting the carcinogens or repairing the DNA damage.	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('carcinogenesis', 'Disease', (193, 207))	('tobacco', 'Species', '4097', (157, 164))	('excreting', 'MPA', (306, 315))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('alterations', 'Var', (129, 140))	('cancer', 'Disease', (240, 246))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('develop', 'PosReg', (230, 237))
171851	28801840	Genetic alterations in any of the above defense mechanisms can alter the development of HNSCC.	('Genetic alterations', 'Var', (0, 19))	('alter', 'Reg', (63, 68))	('HNSCC', 'Disease', (88, 93))	('men', 'Species', '9606', (80, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('development of', 'CPA', (73, 87))
171852	28801840	Polymorphisms in the genes encoding for enzymes involved in biotransformation of carcinogens, such as cytochrome P-450s, glutathione S-transferases, UDP glucoronyltransferases, aldehyde dehydrogenase, and alcohol dehydrogenase, have been associated with HNSCC risk.	('HNSCC', 'Phenotype', 'HP:0012288', (254, 259))	('Polymorphisms', 'Var', (0, 13))	('aldehyde dehydrogenase', 'Gene', (177, 199))	('associated', 'Reg', (238, 248))	('aldehyde dehydrogenase', 'Gene', '107777569', (177, 199))	('alcohol', 'Chemical', 'MESH:D000438', (205, 212))	('HNSCC', 'Disease', (254, 259))
171853	28801840	Additionally, polymorphisms of the DNA repair mechanisms, base excision repair, nucleotide excision repair, mismatch repair, and recombination repair, are associated with cancers.	('associated', 'Reg', (155, 165))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('base excision repair', 'MPA', (58, 78))	('polymorphisms', 'Var', (14, 27))	('cancers', 'Disease', (171, 178))	('nucleotide excision repair', 'MPA', (80, 106))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mismatch repair', 'MPA', (108, 123))	('recombination repair', 'MPA', (129, 149))
171855	28801840	If left unrepaired, DNA adducts can cause miscoding and permanent mutations which can activate oncogenes such as K-ras, or inactivate tumor suppressor genes such as p53.	('mutations', 'Var', (66, 75))	('p53', 'Gene', (165, 168))	('inactivate', 'NegReg', (123, 133))	('activate', 'PosReg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('miscoding', 'Disease', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('K-ras', 'Protein', (113, 118))	('tumor', 'Disease', (134, 139))
171859	28801840	In vitro and laboratory animal studies have demonstrated the importance of HPB-releasing adducts in NNK- and NNN-induced carcinogenesis.	('HPB', 'Chemical', 'MESH:C482281', (75, 78))	('adducts', 'Var', (89, 96))	('NNK-', 'Disease', (100, 104))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('NNN', 'Chemical', 'MESH:C008655', (109, 112))	('carcinogenesis', 'Disease', (121, 135))
171860	28801840	Earlier, we described the enhanced carcinogenicity of (S)-NNN compared to (R)-NNN.	('enhanced', 'PosReg', (26, 34))	('(S)-NNN', 'Chemical', 'MESH:C008655', (54, 61))	('carcinogenic', 'Disease', 'MESH:D063646', (35, 47))	('(R)-NNN', 'Chemical', '-', (74, 81))	('carcinogenic', 'Disease', (35, 47))	('S)-NNN', 'Var', (55, 61))
171870	28801840	Future work in this area will aim to address the genetic variation among smokers that may lead to a reduced ability to detoxify the carcinogen exposure that occurs following tobacco use.	('genetic variation', 'Var', (49, 66))	('reduced', 'NegReg', (100, 107))	('ability', 'MPA', (108, 115))	('tobacco', 'Species', '4097', (174, 181))
171982	28915691	High neutrophil proportion in tumor stroma is associated with poor prognoses.	('High neutrophil proportion', 'Var', (0, 26))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor stroma', 'Disease', 'MESH:D009369', (30, 42))	('tumor stroma', 'Disease', (30, 42))
171983	28915691	Neutrophils enhance tumor progression by inducting mutation of cancer suppressive genes, secreting enzymes and cytokines to facilitate malignant cell proliferation and metastasis, and promoting tumor angiogenesis.	('malignant cell proliferation', 'CPA', (135, 163))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('inducting', 'Reg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('promoting', 'PosReg', (184, 193))	('facilitate', 'PosReg', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('mutation', 'Var', (51, 59))	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('enhance', 'PosReg', (12, 19))	('cancer', 'Disease', (63, 69))	('tumor', 'Disease', (20, 25))
172069	27803735	In the final multivariable model, non-aspirin antiplatelet medication use was significantly associated with increased all-cause mortality (HR 2.68, 95% CI 1.17-6.16).	('aspirin', 'Chemical', 'MESH:D001241', (38, 45))	('non-aspirin', 'Var', (34, 45))	('all-cause mortality', 'MPA', (118, 137))
172104	27803735	Studies in colorectal cancer suggest that the effects of aspirin may be influenced by the PI3K pathway as well as other factors such as BRAF mutation status, 15-hydroxyprostaglandin dehydrogenase (HPGD) expression, and circulating macrophage inhibitory cytokine (MIC)-1.	('rectal cancer', 'Phenotype', 'HP:0100743', (15, 28))	('colorectal cancer', 'Disease', 'MESH:D015179', (11, 28))	('HPGD', 'Gene', '873', (197, 201))	('aspirin', 'Chemical', 'MESH:D001241', (57, 64))	('macrophage inhibitory cytokine (MIC)-1', 'Gene', '9518', (231, 269))	('colorectal cancer', 'Phenotype', 'HP:0003003', (11, 28))	('BRAF', 'Gene', '673', (136, 140))	('PI3K pathway', 'Pathway', (90, 102))	('BRAF', 'Gene', (136, 140))	('15-hydroxyprostaglandin dehydrogenase', 'Gene', (158, 195))	('colorectal cancer', 'Disease', (11, 28))	('15-hydroxyprostaglandin dehydrogenase', 'Gene', '873', (158, 195))	('HPGD', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('mutation', 'Var', (141, 149))	('influenced', 'Reg', (72, 82))
172105	27803735	We found that prediagnosis use of non-aspirin antiplatelet medications was associated with significantly increased all-cause mortality, but not with esophageal cancer-specific mortality or development of metastases.	('metastases', 'Disease', (204, 214))	('all-cause mortality', 'MPA', (115, 134))	('metastases', 'Disease', 'MESH:D009362', (204, 214))	('esophageal cancer', 'Disease', (149, 166))	('aspirin', 'Chemical', 'MESH:D001241', (38, 45))	('non-aspirin', 'Var', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('increased', 'PosReg', (105, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))
172129	26688807	Association of Polymorphic Variants of miRNA Processing Genes with Larynx Cancer Risk in a Polish Population Laryngeal cancer (LC) is one of the most prevalent types of head and neck cancer.	('Laryngeal cancer', 'Disease', 'MESH:D007822', (109, 125))	('Larynx Cancer', 'Disease', 'MESH:D007822', (67, 80))	('Polymorphic Variants', 'Var', (15, 35))	('Larynx Cancer', 'Phenotype', 'HP:0012118', (67, 80))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Laryngeal cancer', 'Phenotype', 'HP:0012118', (109, 125))	('Laryngeal cancer', 'Disease', (109, 125))	('head and neck cancer', 'Phenotype', 'HP:0012288', (169, 189))	('LC', 'Phenotype', 'HP:0012118', (127, 129))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('neck cancer', 'Disease', (178, 189))	('neck cancer', 'Disease', 'MESH:D006258', (178, 189))	('Association', 'Interaction', (0, 11))	('miRNA Processing Genes', 'Gene', (39, 61))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('Larynx Cancer', 'Disease', (67, 80))
172132	26688807	Nine polymorphisms of pre-miRNA processing genes, DROSHA (rs6877842), DGCR8 (rs3757, rs417309, and rs1640299), RAN (rs14035), XPO5 (rs11077), DICER1 (rs13078 and rs3742330) and TARBP2 (rs784567), were performed by TaqMan SNP Genotyping Assay.	('rs1640299', 'Mutation', 'rs1640299', (99, 108))	('RAN', 'Gene', (111, 114))	('rs417309', 'Mutation', 'rs417309', (85, 93))	('XPO5', 'Gene', (126, 130))	('rs6877842', 'Mutation', 'rs6877842', (58, 67))	('rs13078', 'Mutation', 'rs13078', (150, 157))	('rs11077', 'Var', (132, 139))	('miR', 'Gene', '220972', (26, 29))	('rs784567', 'Var', (185, 193))	('rs14035', 'Var', (116, 123))	('rs3742330', 'Mutation', 'rs3742330', (162, 171))	('rs3757', 'Var', (77, 83))	('rs11077', 'Mutation', 'rs11077', (132, 139))	('rs417309', 'Var', (85, 93))	('miR', 'Gene', (26, 29))	('rs1640299', 'Var', (99, 108))	('TARBP2', 'Gene', '6895', (177, 183))	('XPO5', 'Gene', '57510', (126, 130))	('TARBP2', 'Gene', (177, 183))	('rs3757', 'Mutation', 'rs3757', (77, 83))	('rs6877842', 'Var', (58, 67))	('rs3742330', 'Var', (162, 171))	('RAN', 'Gene', '5901', (111, 114))	('rs14035', 'Mutation', 'rs14035', (116, 123))	('rs13078', 'Var', (150, 157))	('rs784567', 'Mutation', 'rs784567', (185, 193))	('DGCR8', 'Gene', (70, 75))
172133	26688807	It was found that the frequency of the GT and the TT polymorphic variants of XPO5 gene were higher in LC patients than in controls (p < 0.0001 and p = 0.000183, resp.).	('patients', 'Species', '9606', (105, 113))	('higher', 'PosReg', (92, 98))	('LC', 'Phenotype', 'HP:0012118', (102, 104))	('XPO5', 'Gene', (77, 81))	('XPO5', 'Gene', '57510', (77, 81))	('polymorphic variants', 'Var', (53, 73))
172135	26688807	The TT and the AG of DICER1 gene (p = 0.034697 for rs13078 and p = 0.0004 for rs3742330) as well as the AG and the GG genotypes of TARBP2 gene (p = 0.008335 and p < 0.0001, resp.)	('DICER1', 'Gene', (21, 27))	('rs3742330', 'Mutation', 'rs3742330', (78, 87))	('rs3742330', 'Var', (78, 87))	('TARBP2', 'Gene', (131, 137))	('rs13078', 'Mutation', 'rs13078', (51, 58))	('TARBP2', 'Gene', '6895', (131, 137))	('rs13078', 'Var', (51, 58))
172136	26688807	Our data suggested that polymorphisms of miRNA processing genes might be useful as predictive factors for the LC development.	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('polymorphisms', 'Var', (24, 37))	('LC', 'Phenotype', 'HP:0012118', (110, 112))	('men', 'Species', '9606', (120, 123))
172150	26688807	Aberrant expression of miRNAs contributes to the etiology of many common human diseases, especially cancers.	('Aberrant expression', 'Var', (0, 19))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('contributes', 'Reg', (30, 41))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('etiology', 'Reg', (49, 57))	('human', 'Species', '9606', (73, 78))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
172151	26688807	Some changes, like single nucleotide polymorphisms (SNPs), in the structure of genes encoding miR processing proteins may affect their structure or expression level.	('expression level', 'MPA', (148, 164))	('changes', 'Reg', (5, 12))	('affect', 'Reg', (122, 128))	('miR', 'Gene', '220972', (94, 97))	('structure', 'MPA', (135, 144))	('miR', 'Gene', (94, 97))	('single nucleotide polymorphisms', 'Var', (19, 50))
172153	26688807	Thus, the aim of our study is to evaluate the connection of prevalence of LC with SNPs occurring in the following genes: DROSHA (rs6877842), DGCR8 (rs3757, rs417309, and rs1640299), RAN (rs14035), XPO5 (rs11077), DICER1 (rs13078 and rs3742330), and TARBP2 (rs784567).	('rs784567', 'Var', (257, 265))	('rs13078', 'Var', (221, 228))	('rs6877842', 'Mutation', 'rs6877842', (129, 138))	('rs14035', 'Var', (187, 194))	('XPO5', 'Gene', (197, 201))	('LC', 'Phenotype', 'HP:0012118', (74, 76))	('rs417309', 'Var', (156, 164))	('rs11077', 'Var', (203, 210))	('rs13078', 'Mutation', 'rs13078', (221, 228))	('rs1640299', 'Var', (170, 179))	('rs6877842', 'Var', (129, 138))	('RAN', 'Gene', '5901', (182, 185))	('rs14035', 'Mutation', 'rs14035', (187, 194))	('rs784567', 'Mutation', 'rs784567', (257, 265))	('rs3757', 'Var', (148, 154))	('rs3742330', 'Mutation', 'rs3742330', (233, 242))	('TARBP2', 'Gene', (249, 255))	('rs11077', 'Mutation', 'rs11077', (203, 210))	('TARBP2', 'Gene', '6895', (249, 255))	('RAN', 'Gene', (182, 185))	('rs3757', 'Mutation', 'rs3757', (148, 154))	('XPO5', 'Gene', '57510', (197, 201))	('rs1640299', 'Mutation', 'rs1640299', (170, 179))	('rs3742330', 'Var', (233, 242))	('rs417309', 'Mutation', 'rs417309', (156, 164))
172177	26688807	The aim of this research was to obtain the association of polymorphic variants of genes involved in miRNA processing with the head and neck occurrence risk.	('association', 'Interaction', (43, 54))	('polymorphic variants', 'Var', (58, 78))	('miR', 'Gene', '220972', (100, 103))	('miR', 'Gene', (100, 103))
172178	26688807	In this case-control study, we wanted to evaluate the effects of 9 selected potentially functional single nucleotide polymorphisms (SNPs) in pre-miRNA processing machinery.	('single nucleotide polymorphisms', 'Var', (99, 130))	('miR', 'Gene', '220972', (145, 148))	('miR', 'Gene', (145, 148))
172179	26688807	SNP evaluation was obtained by TaqMan SNP Genotyping Assay with a commercially available primer probe sets (Applied Biosystems, Foster City, CA, USA) and TaqMan Genotyping Master Mix (Applied Biosystems, Foster City, CA, USA) performed on Mx3005P (Agilent Technologies, Santa Clara, CA, USA) according to manufacturer's instructions.	('Mx3005P', 'Var', (239, 246))	('Mix', 'Gene', (179, 182))	('Mix', 'Gene', '83881', (179, 182))
172180	26688807	Assay IDs were as follows: rs6877842-C_1153852_10, rs3757-C_2539471_1_, rs417309-C_2539468_20, rs1640299-C_7543549_20, rs14035-C_11351340_10, rs11077-C_3109165_1_, rs13078-C_7504801_10, rs3742330-C_27475447_10, and rs784567-C_9576934_20.	('rs1640299', 'Mutation', 'rs1640299', (95, 104))	('rs3757-C_2539471_1_', 'Var', (51, 70))	('rs13078', 'Mutation', 'rs13078', (164, 171))	('rs784567-C_9576934_20', 'Var', (215, 236))	('rs13078-C_7504801_10', 'Var', (164, 184))	('rs3757', 'Mutation', 'rs3757', (51, 57))	('rs11077-C_3109165_1_', 'Var', (142, 162))	('rs6877842', 'Mutation', 'rs6877842', (27, 36))	('rs1640299-C_7543549_20', 'Var', (95, 117))	('rs417309', 'Mutation', 'rs417309', (72, 80))	('rs417309-C_2539468_20', 'Var', (72, 93))	('rs14035', 'Mutation', 'rs14035', (119, 126))	('rs784567', 'Mutation', 'rs784567', (215, 223))	('rs3742330-C_27475447_10', 'Var', (186, 209))	('rs3742330', 'Mutation', 'rs3742330', (186, 195))	('rs11077', 'Mutation', 'rs11077', (142, 149))	('rs6877842-C_1153852_10', 'Var', (27, 49))	('rs14035-C_11351340_10', 'Var', (119, 140))
172184	26688807	Among LC patients observed genotype frequencies of some of evaluated single nucleotide polymorphisms (rs6877842, rs14035, rs13078, and rs11077) were not in agreement with HWE.	('rs11077', 'Var', (135, 142))	('patients', 'Species', '9606', (9, 17))	('rs14035', 'Var', (113, 120))	('rs11077', 'Mutation', 'rs11077', (135, 142))	('rs13078', 'Mutation', 'rs13078', (122, 129))	('rs6877842', 'Var', (102, 111))	('rs14035', 'Mutation', 'rs14035', (113, 120))	('rs6877842', 'Mutation', 'rs6877842', (102, 111))	('rs13078', 'Var', (122, 129))	('LC', 'Phenotype', 'HP:0012118', (6, 8))	('men', 'Species', '9606', (161, 164))
172185	26688807	It may be due to genetic changes occurring in tumor tissue during carcinogenesis, for example, loss of heterozygosity as it was described previously or accumulation of mutations that predispose the individual to larynx cancer development.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('larynx cancer', 'Disease', (212, 225))	('larynx cancer', 'Phenotype', 'HP:0012118', (212, 225))	('carcinogenesis', 'Disease', (66, 80))	('larynx cancer', 'Disease', 'MESH:D007822', (212, 225))	('men', 'Species', '9606', (233, 236))	('loss', 'Var', (95, 99))	('mutations', 'Var', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
172188	26688807	We also evaluated a connection between LC and two SNPs of DGCR8 gene: rs3757, rs417309, and rs1640299.	('rs3757', 'Mutation', 'rs3757', (70, 76))	('LC', 'Phenotype', 'HP:0012118', (39, 41))	('rs3757', 'Var', (70, 76))	('rs1640299', 'Var', (92, 101))	('DGCR8', 'Gene', (58, 63))	('rs1640299', 'Mutation', 'rs1640299', (92, 101))	('rs417309', 'Var', (78, 86))	('rs417309', 'Mutation', 'rs417309', (78, 86))
172189	26688807	We did not find any statistically significant connection between LC and any of rs3757 as well as rs1640299 polymorphic variants.	('rs1640299', 'Var', (97, 106))	('rs3757', 'Mutation', 'rs3757', (79, 85))	('rs3757', 'Var', (79, 85))	('rs1640299', 'Mutation', 'rs1640299', (97, 106))	('LC', 'Phenotype', 'HP:0012118', (65, 67))
172190	26688807	GG genotype of DGCR8 rs41709 is less common in LC subjects (OR: 0.3554, 0.95 CI: 0.1401-0.9015, and p = 0.024484).	('LC', 'Phenotype', 'HP:0012118', (47, 49))	('rs41709', 'Var', (21, 28))	('rs41709', 'Mutation', 'rs41709', (21, 28))	('DGCR8', 'Gene', (15, 20))
172192	26688807	On the other hand, the occurrence of XPO5 rs11077 of both GT and TT polymorphic variants was higher in LC individuals than in control subjects (OR: 4.4441, 0.95 CI: 2.4723-7.9883, and p < 0.0001 and OR: 3.3394, 0.95 CI: 1.7544-6.3563, and p = 0.000183; resp.	('higher', 'PosReg', (93, 99))	('XPO5', 'Gene', '57510', (37, 41))	('XPO5', 'Gene', (37, 41))	('rs11077', 'Mutation', 'rs11077', (42, 49))	('rs11077', 'Var', (42, 49))	('LC', 'Phenotype', 'HP:0012118', (103, 105))
172193	26688807	Also both investigated polymorphisms of DICER1 seem to be associated with higher risk of LC occurrence (OR: 2.9762, 0.95 CI: 1.0473-8.4579, and p = 0.034697 [p corr = 0.312] for TT genotype of rs13078 as well as OR: 2.6593, 0.95 CI: 1.5326-4.6144, and p = 0.0004 [p corr = 0.004] for AG genotype of rs3742330).	('polymorphisms', 'Var', (23, 36))	('rs13078', 'Var', (193, 200))	('LC', 'Phenotype', 'HP:0012118', (89, 91))	('rs3742330', 'Mutation', 'rs3742330', (299, 308))	('rs13078', 'Mutation', 'rs13078', (193, 200))	('DICER1', 'Gene', (40, 46))	('rs3742330', 'Var', (299, 308))	('LC occurrence', 'Disease', (89, 102))
172194	26688807	We also found a strong association between the AG and GG genotypes of the TARBP2 rs784567 polymorphism and the risk for LC (OR: 3.0702, 0.95 CI: 1.2935-7.2871, and p = 0.008335 [p corr = 0.075] and OR: 12.1429, 0.95 CI: 4.661-31.6345, and p < 0.0001 [p corr = 0.001], resp.).	('rs784567', 'Mutation', 'rs784567', (81, 89))	('rs784567', 'Var', (81, 89))	('LC', 'Phenotype', 'HP:0012118', (120, 122))	('TARBP2', 'Gene', '6895', (74, 80))	('TARBP2', 'Gene', (74, 80))
172196	26688807	In T1 stage we found a decreased prevalence of AG and GG genotype of DGCR8 rs417309 (OR: 0.087, 0.95 CI: 0.0136-0.5564, and p = 0.011931 [p corr = 0.107] and OR: 0.0517, 0.95 CI: 0.0098-0.2719, and p = 0.001265 [p corr = 0.011], resp., Table 3(a)) as well as RAN rs14035 CT polymorphic variant (OR: 0.2058, 0.95 CI: 0.0415-1.0221, and p = 0.038382 [p corr = 0.345], Table 3(a)).	('RAN', 'Gene', '5901', (259, 262))	('rs14035', 'Var', (263, 270))	('rs417309', 'Mutation', 'rs417309', (75, 83))	('RAN', 'Gene', (259, 262))	('rs14035', 'Mutation', 'rs14035', (263, 270))	('p = 0.038382', 'Var', (335, 347))	('DGCR8', 'Gene', (69, 74))	('decreased', 'NegReg', (23, 32))	('rs417309', 'Var', (75, 83))
172197	26688807	On the other hand, we found an association between T2 in LC patients and high abundance of XPO5 rs11077 GT heterozygote (OR: 4.9697, 0.95 CI: 1.2546-19.686, and p = 0.016786 [p corr = 0.150], Table 3(a)).	('LC', 'Phenotype', 'HP:0012118', (57, 59))	('patients', 'Species', '9606', (60, 68))	('XPO5', 'Gene', (91, 95))	('XPO5', 'Gene', '57510', (91, 95))	('rs11077', 'Var', (96, 103))	('rs11077', 'Mutation', 'rs11077', (96, 103))
172198	26688807	The most interesting here was a fact of a very big difference between allele distribution in cancer and control subjects during analysis of TARBP2 rs784567 polymorphism.	('TARBP2', 'Gene', (140, 146))	('cancer', 'Disease', (93, 99))	('rs784567', 'Var', (147, 155))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('rs784567', 'Mutation', 'rs784567', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('difference', 'Reg', (51, 61))	('TARBP2', 'Gene', '6895', (140, 146))
172199	26688807	Analysis of subjects with T3 stage showed a decrease of CT heterozygote occurrence of RAN rs14035 polymorphism (OR: 0.2401, 0.95 CI: 0.1133-0.509, and p < 0.0001 [p corr = 0.001], Table 3(b)) in LC patients compared to healthy subjects.	('rs14035', 'Mutation', 'rs14035', (90, 97))	('decrease', 'NegReg', (44, 52))	('patients', 'Species', '9606', (198, 206))	('LC', 'Phenotype', 'HP:0012118', (195, 197))	('RAN', 'Gene', '5901', (86, 89))	('polymorphism', 'Var', (98, 110))	('RAN', 'Gene', (86, 89))
172201	26688807	Similar association was found related to AG DICER1 rs3742330 heterozygote (OR: 2.2242, 0.95 CI: 1.0641-4.649, and p = 0.030873 [p corr = 0.277], Table 3(b)) and GG TARBP2 rs7834567 homozygote (OR: 7.9167, 0.95 CI: 2.3694-26.4517, and p = 0.00027 [p corr = 0.002], Table 3(b)).The heterozygote of RAN rs14035 SNP was also found to be negatively associated with T4 (OR: 0.3902, 0.95 CI: 0.1854-0.8216, and p = 0.011477 [p corr = 0.103], Table 3(b)).	('rs14035', 'Mutation', 'rs14035', (300, 307))	('TARBP2', 'Gene', '6895', (164, 170))	('TARBP2', 'Gene', (164, 170))	('RAN', 'Gene', '5901', (296, 299))	('rs7834567', 'Mutation', 'rs7834567', (171, 180))	('rs14035', 'Var', (300, 307))	('rs3742330', 'Mutation', 'rs3742330', (51, 60))	('negatively', 'NegReg', (333, 343))	('SNP', 'Gene', (308, 311))	('RAN', 'Gene', (296, 299))
172202	26688807	On the opposite side, patients with T4 stage of LC were shown to be the carriers of AG DICER1 rs3742330 genotype (OR: 3.0583, 0.95 CI: 1.3452-6.9527, and p = 0.005805 [p corr = 0.052], Table 3(b)) and TARBP2 polymorphic variants (OR: 7.6754, 0.95 CI: 1.0036-58.6983, and p = 0.022201 [p corr = 0.199] for AG and OR: 36.6667, 0.95 CI: 4.6001-292.2647, and p < 0.0001 [p corr = 0.001] for GG, Table 3(b)) more often than control subjects.	('patients', 'Species', '9606', (22, 30))	('TARBP2', 'Gene', '6895', (201, 207))	('TARBP2', 'Gene', (201, 207))	('LC', 'Phenotype', 'HP:0012118', (48, 50))	('p = 0.022201', 'Var', (271, 283))	('p = 0.005805', 'Var', (154, 166))	('polymorphic variants', 'Var', (208, 228))	('rs3742330', 'Mutation', 'rs3742330', (94, 103))	('rs3742330', 'Var', (94, 103))
172203	26688807	RAN rs14035 heterozygote carriers were less likely to have both node positive or negative tumors (OR: 0.3955, 0.95 CI: 0.2264-0.6909, and p = 0.0009 [p corr = 0.008] and OR: 0.131, 0.95 CI: 0.0431-0.3977, and p < 0.0001 [p corr = 0.0009], resp.).	('negative', 'NegReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('RAN', 'Gene', '5901', (0, 3))	('tumors', 'Disease', (90, 96))	('rs14035', 'Var', (4, 11))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('node positive', 'CPA', (64, 77))	('RAN', 'Gene', (0, 3))	('rs14035', 'Mutation', 'rs14035', (4, 11))
172204	26688807	Performed analysis indicated also that XPO5 rs11077 polymorphic variants are associated with tumors without lymph node metastases (OR: 4.2177, 0.95 CI: 2.1965-8.099, and p < 0.0001 [p corr = 0.001] for GT and OR: 3.5542, 0.95 CI: 1.7534-7.2043, and p = 0.000311 [p corr = 0.003] for TT).	('lymph node metastases', 'Disease', 'MESH:D009362', (108, 129))	('rs11077', 'Var', (44, 51))	('lymph node metastases', 'Disease', (108, 129))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('rs11077', 'Mutation', 'rs11077', (44, 51))	('XPO5', 'Gene', '57510', (39, 43))	('XPO5', 'Gene', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))
172205	26688807	Similar correlation was shown also related to DICER1 rs13078 TT genotype (OR: 3.6111, 0.95 CI: 1.0503-12.416, and p = 0.033112 [p corr = 0.298]), DICER1 rs3742330 AG heterozygote (OR: 2.6041, 0.95 CI: 1.4276-4.7502, and p = 0.001483 [p corr = 0.013]), and TARBP2 rs784567 GG homozygote (OR: 8.5714, 0.95 CI: 3.2371-22.6961, and p < 0.0001 [p corr = 0.001]).	('rs3742330', 'Var', (153, 162))	('rs13078', 'Var', (53, 60))	('DICER1', 'Gene', (146, 152))	('DICER1', 'Gene', (46, 52))	('TARBP2', 'Gene', '6895', (256, 262))	('TARBP2', 'Gene', (256, 262))	('rs784567', 'Var', (263, 271))	('rs3742330', 'Mutation', 'rs3742330', (153, 162))	('rs784567', 'Mutation', 'rs784567', (263, 271))	('rs13078', 'Mutation', 'rs13078', (53, 60))
172206	26688807	XPO5 rs11077 and DICER1 rs3742330 heterozygotes were also more likely to have node positive tumors (OR: 5.0584, 0.95 CI: 1.9743-12.9602, and p = 0.000323 [p corr = 0.003] and OR: 3.5476, 0.95 CI: 1.3057-9.6388, and p = 0.009116 [p corr = 0.082], resp.).	('rs11077', 'Mutation', 'rs11077', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('rs3742330', 'Mutation', 'rs3742330', (24, 33))	('rs3742330', 'Var', (24, 33))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('XPO5', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('DICER1', 'Gene', (17, 23))	('XPO5', 'Gene', '57510', (0, 4))
172207	26688807	DGCR8 rs1640299 polymorphic variants were also correlated with N0 LC stage (OR: 4.4602, 0.95 CI: 1.6527-12.0368, and p = 0.0016 [p corr = 0.014] for GT and OR: 32.787, 0.95 CI: 11.1638-96.2956, and p < 0.0001 [p corr = 0.001] for TT).	('rs1640299', 'Mutation', 'rs1640299', (6, 15))	('DGCR8', 'Gene', (0, 5))	('correlated', 'Reg', (47, 57))	('rs1640299', 'Var', (6, 15))	('LC', 'Phenotype', 'HP:0012118', (66, 68))
172210	26688807	We also analyzed the relation between miRNA processing genes polymorphic variants and the stage of cancer (Tables 5(a) and 5(b)).	('polymorphic variants', 'Var', (61, 81))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
172211	26688807	It was found that DICER1 rs3742330 AG heterozygote is connected with LC Stages III and IV (OR: 2.3243, 0.95 CI: 1.0828-4.9893, and p = 0.0276 [p corr = 0.248] and OR: 2.9971, 0.95 CI: 1.4173-6.3378, and p = 0.0031 [p corr = 0.028], resp., Table 5(b)) and DICER1 rs13078 TT genotype is associated with LC Stage III (OR: 9.1667, 0.95 CI: 1.1122-75.5513, and p = 0.01450 [p corr = 0.131], Table 5(b)).	('DICER1', 'Gene', (255, 261))	('LC', 'Phenotype', 'HP:0012118', (301, 303))	('rs13078', 'Mutation', 'rs13078', (262, 269))	('rs3742330', 'Mutation', 'rs3742330', (25, 34))	('LC Stage III', 'Disease', (301, 313))	('rs3742330', 'Var', (25, 34))	('LC', 'Phenotype', 'HP:0012118', (69, 71))
172212	26688807	Moreover, TARBP2 rs784567 AG heterozygote is connected to higher occurrence of LC Stage IV (OR: 9.8246, 0.95 CI: 1.2953-74.5144, and p = 0.0075 [p corr = 0.068], Table 5(b)) and GG polymorphic variant is related to both LC Stage III and Stage IV (OR: 6, 0.95 CI: 1.9403-18.5537, and p = 0.0009 [p corr = 0.008] and OR: 3.3333, 0.95 CI: 5.4718-343.1724, and p < 0.0001 [p corr = 0.001], resp., Table 5(b)).	('rs784567', 'Var', (17, 25))	('TARBP2', 'Gene', '6895', (10, 16))	('TARBP2', 'Gene', (10, 16))	('rs784567', 'Mutation', 'rs784567', (17, 25))	('LC Stage IV', 'Disease', (79, 90))	('LC', 'Phenotype', 'HP:0012118', (220, 222))	('LC', 'Phenotype', 'HP:0012118', (79, 81))	('LC Stage III', 'Disease', (220, 232))
172213	26688807	XPO5 rs11077 GT and TT genotypes are also associated with LC Stage III (OR: 4.9697, 0.95 CI: 2.1259-11.6175, and p < 0.0001 [p corr = 0.001] and OR: 4.2876, 0.95 CI: 1.7271-10.644, and p = 0.001 [p corr = 0.009], resp., Table 5(b)) and LC Stage IV (OR: 4.1573, 0.95 CI: 1.9643-8.799, and p = 0.0001 [p corr = 0.0009] and OR: 2.5973, 0.95 CI: 1.1054-6.1026, and p = 0.0254 [p corr = 0.221], resp., Table 5(b)).	('LC Stage III', 'Disease', (58, 70))	('rs11077', 'Mutation', 'rs11077', (5, 12))	('rs11077', 'Var', (5, 12))	('LC', 'Phenotype', 'HP:0012118', (236, 238))	('LC', 'Phenotype', 'HP:0012118', (58, 60))	('XPO5', 'Gene', (0, 4))	('LC Stage IV', 'Disease', (236, 247))	('XPO5', 'Gene', '57510', (0, 4))
172215	26688807	Such phenomena were observed in patients with Stage III LC and Stage IV, where, respectively, DGCR8 rs417309 AG and GG genotypes (OR: 0.087, 0.95 CI: 0.0136-0.5564, and p = 0.0119 [p corr = 0.107] and OR: 0.0517, 0.95 CI: 0.0098-0.2719, and p = 0.0012 [p corr = 0.011], Table 5(b)) as well as rs1640299 GT heterozygote (OR: 0.0968, 0.95 CI: 0.0165-0.5686, and p = 0.0112 [p corr = 0.101], Table 5(b)) were less likely to be found in cancer subjects than in control group.	('DGCR8', 'Gene', (94, 99))	('rs1640299', 'Var', (293, 302))	('rs417309', 'Var', (100, 108))	('men', 'Species', '9606', (10, 13))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('rs417309', 'Mutation', 'rs417309', (100, 108))	('cancer', 'Disease', 'MESH:D009369', (433, 439))	('rs1640299', 'Mutation', 'rs1640299', (293, 302))	('cancer', 'Disease', (433, 439))	('p =', 'Var', (360, 363))	('LC', 'Phenotype', 'HP:0012118', (56, 58))
172216	26688807	RAN rs14035 CT polymorphic variant was also associated with decreased prevalence in LC patients with Stage I (OR: 0.2058, 0.95 CI: 0.0415-1.0221, and p = 0.0383 [p corr = 0.345], Table 5(a)), Stage III (OR: 0.2476, 0.95 CI: 0.1166-0.5262, and p = 0.0001 [p corr = 0.0009], Table 5(b)), and Stage IV (OR: 0.3478, 0.95 CI: 0.1708-0.7081, and p = 0.0028 [p corr = 0.025], Table 5(b)).	('decreased', 'NegReg', (60, 69))	('LC', 'Phenotype', 'HP:0012118', (84, 86))	('patients', 'Species', '9606', (87, 95))	('RAN', 'Gene', '5901', (0, 3))	('rs14035', 'Var', (4, 11))	('prevalence', 'MPA', (70, 80))	('RAN', 'Gene', (0, 3))	('rs14035', 'Mutation', 'rs14035', (4, 11))
172217	26688807	We performed stratified analysis to estimate the interaction between miRNA processing genes single nucleotide polymorphisms and cigarette smoking (Tables  6-8, Supplementary Materials available online at http://dx.doi.org/10.1155/2015/298378).	('interaction', 'Interaction', (49, 60))	('men', 'Species', '9606', (166, 169))	('single nucleotide polymorphisms', 'Var', (92, 123))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))
172219	26688807	We did not observe any elevated frequency of studied SNPs polymorphic variants correlating with cigarette smoking among LC patients in any of investigated cases.	('SNPs', 'Gene', (53, 57))	('cigarette smoking', 'Disease', (96, 113))	('LC', 'Phenotype', 'HP:0012118', (120, 122))	('polymorphic variants', 'Var', (58, 78))	('patients', 'Species', '9606', (123, 131))
172220	26688807	In this case-control study of 135LC patients and 170 cancer-free controls in a Polish population, we investigated the associations between SNPs of miRNA biosynthesis genes and risk of LC.	('SNPs', 'Var', (139, 143))	('LC', 'Phenotype', 'HP:0012118', (33, 35))	('cancer', 'Disease', (53, 59))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('associations', 'Interaction', (118, 130))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))	('investigated', 'Reg', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('LC', 'Phenotype', 'HP:0012118', (184, 186))
172221	26688807	This is the first report considering the association of the risk of larynx cancer and SNPs of the following polymorphisms: DROSHA (rs6877842), DGCR8 (rs3757, rs417309, and rs1640299), RAN (rs14035), XPO5 (rs11077), DICER1 (rs13078 and rs3742330), and TARBP2 (rs784567).	('larynx cancer', 'Phenotype', 'HP:0012118', (68, 81))	('rs11077', 'Var', (205, 212))	('larynx cancer', 'Disease', 'MESH:D007822', (68, 81))	('rs6877842', 'Mutation', 'rs6877842', (131, 140))	('rs14035', 'Var', (189, 196))	('rs3757', 'Var', (150, 156))	('rs3742330', 'Mutation', 'rs3742330', (235, 244))	('rs11077', 'Mutation', 'rs11077', (205, 212))	('rs417309', 'Var', (158, 166))	('TARBP2', 'Gene', '6895', (251, 257))	('TARBP2', 'Gene', (251, 257))	('rs13078', 'Mutation', 'rs13078', (223, 230))	('rs1640299', 'Var', (172, 181))	('RAN', 'Gene', '5901', (184, 187))	('rs784567', 'Mutation', 'rs784567', (259, 267))	('XPO5', 'Gene', '57510', (199, 203))	('rs3757', 'Mutation', 'rs3757', (150, 156))	('rs6877842', 'Var', (131, 140))	('rs14035', 'Mutation', 'rs14035', (189, 196))	('rs3742330', 'Var', (235, 244))	('larynx cancer', 'Disease', (68, 81))	('RAN', 'Gene', (184, 187))	('rs417309', 'Mutation', 'rs417309', (158, 166))	('rs1640299', 'Mutation', 'rs1640299', (172, 181))	('XPO5', 'Gene', (199, 203))	('rs784567', 'Var', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs13078', 'Var', (223, 230))
172222	26688807	The rs3742330 AG and rs13078 TT genotypes of DICER1 are correlated with increased risk of larynx cancer.	('larynx cancer', 'Disease', (90, 103))	('DICER1', 'Gene', (45, 51))	('larynx cancer', 'Phenotype', 'HP:0012118', (90, 103))	('rs13078', 'Mutation', 'rs13078', (21, 28))	('larynx cancer', 'Disease', 'MESH:D007822', (90, 103))	('rs3742330', 'Mutation', 'rs3742330', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rs13078 TT', 'Var', (21, 31))	('rs3742330 AG', 'Var', (4, 16))
172223	26688807	In turn, the rs14035 RAN CT heterozygote and DGCR8 rs417309 GG genotype were significantly inversely associated with the presence of larynx cancer.	('associated with', 'Reg', (101, 116))	('inversely', 'NegReg', (91, 100))	('rs14035', 'Mutation', 'rs14035', (13, 20))	('RAN', 'Gene', '5901', (21, 24))	('rs417309 GG', 'Var', (51, 62))	('rs417309', 'Mutation', 'rs417309', (51, 59))	('larynx cancer', 'Disease', (133, 146))	('larynx cancer', 'Phenotype', 'HP:0012118', (133, 146))	('larynx cancer', 'Disease', 'MESH:D007822', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('RAN', 'Gene', (21, 24))	('DGCR8', 'Gene', (45, 50))
172224	26688807	In addition, the rs3742330 of DICER1, rs784567 of TARBP2, rs417309 of DGCR8, and rs14035 of RAN as well as rs11077 of XPO5 are associated with the LC progression depending on the tumor size.	('RAN', 'Gene', '5901', (92, 95))	('rs3742330', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('DICER1', 'Gene', (30, 36))	('LC', 'Phenotype', 'HP:0012118', (147, 149))	('XPO5', 'Gene', (118, 122))	('rs417309', 'Mutation', 'rs417309', (58, 66))	('rs784567', 'Mutation', 'rs784567', (38, 46))	('RAN', 'Gene', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('rs11077', 'Var', (107, 114))	('associated with', 'Reg', (127, 142))	('rs14035', 'Var', (81, 88))	('TARBP2', 'Gene', '6895', (50, 56))	('TARBP2', 'Gene', (50, 56))	('rs11077', 'Mutation', 'rs11077', (107, 114))	('XPO5', 'Gene', '57510', (118, 122))	('rs417309', 'Var', (58, 66))	('rs784567', 'Var', (38, 46))	('rs3742330', 'Mutation', 'rs3742330', (17, 26))	('rs14035', 'Mutation', 'rs14035', (81, 88))	('DGCR8', 'Gene', (70, 75))	('tumor', 'Disease', (179, 184))
172225	26688807	Furthermore, the DGCR8 rs1640299, DICER1 rs3742330 and rs13078, RAN rs14035, and XPO5 rs11077 as well as rs784567 of TARBP2 genes single nucleotide polymorphisms have demonstrated an association with tumor progression depending on the lymph node metastases.	('association', 'Reg', (183, 194))	('lymph node metastases', 'Disease', 'MESH:D009362', (235, 256))	('TARBP2', 'Gene', '6895', (117, 123))	('rs1640299', 'Var', (23, 32))	('TARBP2', 'Gene', (117, 123))	('rs11077', 'Mutation', 'rs11077', (86, 93))	('rs784567', 'Var', (105, 113))	('rs3742330', 'Var', (41, 50))	('tumor', 'Disease', (200, 205))	('XPO5', 'Gene', '57510', (81, 85))	('rs13078', 'Mutation', 'rs13078', (55, 62))	('rs1640299', 'Mutation', 'rs1640299', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('RAN', 'Gene', '5901', (64, 67))	('DGCR8', 'Gene', (17, 22))	('rs784567', 'Mutation', 'rs784567', (105, 113))	('rs14035', 'Mutation', 'rs14035', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('lymph node metastases', 'Disease', (235, 256))	('rs3742330', 'Mutation', 'rs3742330', (41, 50))	('XPO5', 'Gene', (81, 85))	('rs11077', 'Var', (86, 93))	('RAN', 'Gene', (64, 67))	('rs13078', 'Var', (55, 62))
172226	26688807	The observed genotype frequencies of rs6877842 and rs417309 alleles were not in agreement with HWE.	('rs417309', 'Var', (51, 59))	('rs6877842', 'Var', (37, 46))	('rs6877842', 'Mutation', 'rs6877842', (37, 46))	('rs417309', 'Mutation', 'rs417309', (51, 59))	('men', 'Species', '9606', (85, 88))
172227	26688807	The above information about genotype and allele frequencies of rs6877842 and rs417309 is consistent with NCBI data that shows that rs6877842 C allele frequency is about 0.018 and rs417309 A allele frequency is lower than 0.08 in population of European descent (NCBI SNP database, access date: January 13th 2015).	('rs6877842', 'Mutation', 'rs6877842', (131, 140))	('rs417309', 'Mutation', 'rs417309', (77, 85))	('rs417309', 'Mutation', 'rs417309', (179, 187))	('rs6877842 C', 'Var', (131, 142))	('rs417309 A', 'Var', (179, 189))	('rs6877842', 'Var', (63, 72))	('rs6877842', 'Mutation', 'rs6877842', (63, 72))
172228	26688807	Our findings suggest, for the first time, that potentially functional polymorphisms of genes encoding proteins of miRNA processing may play a role in the tumors arising at larynx.	('play', 'Reg', (135, 139))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('polymorphisms', 'Var', (70, 83))
172229	26688807	The rs6877842 and the rs784567 polymorphisms are located in the promoter of DROSHA and TRBP2 genes, respectively, and hence can affect the level of protein expression.	('TRBP2', 'Gene', '6895', (87, 92))	('rs784567', 'Mutation', 'rs784567', (22, 30))	('affect', 'Reg', (128, 134))	('level of protein expression', 'MPA', (139, 166))	('TRBP2', 'Gene', (87, 92))	('DROSHA', 'Gene', (76, 82))	('rs6877842', 'Var', (4, 13))	('rs6877842', 'Mutation', 'rs6877842', (4, 13))	('rs784567', 'Var', (22, 30))
172230	26688807	The remaining genes polymorphisms are located in the 3'-UTR, which is the binding site of miRNAs; thereby they may affect the efficiency of miRNA processing.	('affect', 'Reg', (115, 121))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('polymorphisms', 'Var', (20, 33))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))
172232	26688807	On the other hand, it appeared that RAN rs14035 CT polymorphic variant may possess a kind of protective effect on individuals, because a relatively small number of LC patients were carriers of this heterozygote, even in comparison with healthy subjects.	('protective effect', 'CPA', (93, 110))	('RAN', 'Gene', (36, 39))	('rs14035 CT', 'Var', (40, 50))	('patients', 'Species', '9606', (167, 175))	('LC', 'Phenotype', 'HP:0012118', (164, 166))	('rs14035', 'Mutation', 'rs14035', (40, 47))	('RAN', 'Gene', '5901', (36, 39))
172236	26688807	In the present association study, we found that DROSHA polymorphism was not associated with the risk of larynx cancer.	('larynx cancer', 'Disease', (104, 117))	('larynx cancer', 'Phenotype', 'HP:0012118', (104, 117))	('polymorphism', 'Var', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('larynx cancer', 'Disease', 'MESH:D007822', (104, 117))	('DROSHA', 'Gene', (48, 54))
172242	26688807	who proved that variant allele of this polymorphism also increased the overall survival of T-cell lymphoma patients compared to the wild type genotype (HR: 0.27, 0.95 CI: 0.11-0.67, and p = 0.005).	('T-cell lymphoma', 'Disease', 'MESH:D016399', (91, 106))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (91, 106))	('variant', 'Var', (16, 23))	('T-cell lymphoma', 'Disease', (91, 106))	('cell lymphoma', 'Phenotype', 'HP:0012191', (93, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('increased', 'PosReg', (57, 66))	('patients', 'Species', '9606', (107, 115))
172243	26688807	Additionally, a haplotype analysis of DROSHA rs6877842 in Korean patients suggests that ***ACTA is associated with higher POI.	('***ACTA', 'Var', (88, 95))	('higher POI', 'Disease', (115, 125))	('DROSHA', 'Gene', (38, 44))	('patients', 'Species', '9606', (65, 73))	('rs6877842', 'Var', (45, 54))	('rs6877842', 'Mutation', 'rs6877842', (45, 54))	('associated', 'Reg', (99, 109))
172245	26688807	Although there is no information about connection between head and neck cancers and rs6877842, there are some proofs of dysregulation of miRNA processing genes at the expression level.	('rs6877842', 'Var', (84, 93))	('neck cancers', 'Disease', 'MESH:D006258', (67, 79))	('head and neck cancer', 'Phenotype', 'HP:0012288', (58, 78))	('miR', 'Gene', '220972', (137, 140))	('rs6877842', 'Mutation', 'rs6877842', (84, 93))	('miR', 'Gene', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('head and neck cancers', 'Phenotype', 'HP:0012288', (58, 79))	('dysregulation', 'MPA', (120, 133))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('neck cancers', 'Disease', (67, 79))
172261	26688807	We have found an association between risk of laryngeal cancer and two DICER1 SNPs: rs13078 and rs3742330.	('DICER1', 'Gene', (70, 76))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (45, 61))	('rs3742330', 'Mutation', 'rs3742330', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rs3742330', 'Var', (95, 104))	('rs13078', 'Mutation', 'rs13078', (83, 90))	('association', 'Reg', (17, 28))	('laryngeal cancer', 'Disease', 'MESH:D007822', (45, 61))	('laryngeal cancer', 'Disease', (45, 61))	('rs13078', 'Var', (83, 90))
172262	26688807	It was also found that rs13078 (HR = 1.66; 0.95 CI: 1.09-2.52; p = 0.02) was associated with the risk of death of patients with colorectal adenocarcinoma.	('death', 'Disease', 'MESH:D003643', (105, 110))	('death', 'Disease', (105, 110))	('colorectal adenocarcinoma', 'Disease', (128, 153))	('rs13078', 'Var', (23, 30))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (128, 153))	('associated', 'Reg', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('patients', 'Species', '9606', (114, 122))	('rs13078', 'Mutation', 'rs13078', (23, 30))
172264	26688807	In haplotype analysis, haplotypes of DICER showed significant association with RCC survival.	('association', 'Interaction', (62, 73))	('DICER', 'Gene', '23405', (37, 42))	('haplotypes', 'Var', (23, 33))	('DICER', 'Gene', (37, 42))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
172266	26688807	Another study showed that patients with at least one variant allele of SNP rs3742330 in DICER had a significantly increased risk of oral premalignant lesions (OR, 2.09; 95% CI, 1.03-4.24).	('rs3742330', 'Mutation', 'rs3742330', (75, 84))	('SNP rs3742330', 'Var', (71, 84))	('DICER', 'Gene', '23405', (88, 93))	('patients', 'Species', '9606', (26, 34))	('oral premalignant lesions', 'Disease', (132, 157))	('DICER', 'Gene', (88, 93))	('oral premalignant lesions', 'Disease', 'MESH:D020820', (132, 157))
172267	26688807	On the other hand, there was no statistically significant association between rs3742330 and rs13078 SNPs and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs3742330', 'Mutation', 'rs3742330', (78, 87))	('rs13078 SNPs', 'Var', (92, 104))	('rs3742330', 'Var', (78, 87))	('rs13078', 'Mutation', 'rs13078', (92, 99))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
172271	26688807	Because of the direct effect of DGCR8 and RNASEN on miRNA biogenesis and the associations between miRNA expression and cancer development the variations in either gene might affect head and neck cancer occurrence.	('RNASEN', 'Gene', '29102', (42, 48))	('head and neck cancer', 'Phenotype', 'HP:0012288', (181, 201))	('neck cancer', 'Disease', 'MESH:D006258', (190, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('neck cancer', 'Disease', (190, 201))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', '220972', (98, 101))	('cancer', 'Disease', (119, 125))	('RNASEN', 'Gene', (42, 48))	('miR', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('miR', 'Gene', (98, 101))	('cancer', 'Disease', (195, 201))	('variations', 'Var', (142, 152))	('men', 'Species', '9606', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('DGCR8', 'Gene', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('affect', 'Reg', (174, 180))	('associations', 'Interaction', (77, 89))
172272	26688807	In our study we evaluated the role of three DGCR8 SNPs in larynx cancer: rs3757, rs417309, and rs1640299.	('rs1640299', 'Mutation', 'rs1640299', (95, 104))	('larynx cancer', 'Phenotype', 'HP:0012118', (58, 71))	('larynx cancer', 'Disease', 'MESH:D007822', (58, 71))	('rs417309', 'Mutation', 'rs417309', (81, 89))	('rs3757', 'Mutation', 'rs3757', (73, 79))	('DGCR8', 'Gene', (44, 49))	('rs1640299', 'Var', (95, 104))	('rs3757', 'Var', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('rs417309', 'Var', (81, 89))	('larynx cancer', 'Disease', (58, 71))
172277	26688807	have shown that the rs417309 polymorphism of DGCR8 gene was associated with an increased breast cancer risk (OR = 1.50; 95% confidence interval (CI): 1.16-1.93).	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('rs417309', 'Var', (20, 28))	('rs417309', 'Mutation', 'rs417309', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('DGCR8', 'Gene', (45, 50))
172278	26688807	Besides, using luciferase assay, they have found that the variant A allele of rs417309 compared to allele G elevates DGCR8 protein expression.	('elevates', 'PosReg', (108, 116))	('DGCR8', 'Gene', (117, 122))	('protein', 'Protein', (123, 130))	('rs417309', 'Var', (78, 86))	('rs417309', 'Mutation', 'rs417309', (78, 86))
172279	26688807	Because the rs417309 polymorphism is located in the 3'-UTR, which is the binding site of miR-106b and miR-579, it might affect the miRNAs maturation.	('miR-579', 'Gene', '693164', (102, 109))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))	('miR-106b', 'Gene', (89, 97))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('affect', 'Reg', (120, 126))	('rs417309', 'Var', (12, 20))	('rs417309', 'Mutation', 'rs417309', (12, 20))	('miR-106b', 'Gene', '406900', (89, 97))	('miR', 'Gene', '220972', (131, 134))	('miR', 'Gene', (131, 134))	('miR-579', 'Gene', (102, 109))
172282	26688807	Therefore, rs417309 may impair the binding of miRNAs such as miR-106b with DGCR8 and disrupt the process of miRNAs maturation and consequently play an important role in the tumorigenesis.	('miR', 'Gene', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('miR', 'Gene', '220972', (61, 64))	('play', 'Reg', (143, 147))	('miR', 'Gene', (108, 111))	('DGCR8', 'Gene', (75, 80))	('miR', 'Gene', (61, 64))	('binding', 'Interaction', (35, 42))	('miR-106b', 'Gene', '406900', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('rs417309', 'Mutation', 'rs417309', (11, 19))	('miR-106b', 'Gene', (61, 69))	('role', 'Reg', (161, 165))	('miR', 'Gene', '220972', (46, 49))	('impair', 'NegReg', (24, 30))	('rs417309', 'Var', (11, 19))	('tumor', 'Disease', (173, 178))	('miR', 'Gene', '220972', (108, 111))	('disrupt', 'NegReg', (85, 92))	('process', 'MPA', (97, 104))
172286	26688807	Some studies have investigated the associations between rs14035 polymorphism of this gene and risk of several cancers.	('cancers', 'Disease', (110, 117))	('investigated', 'Reg', (18, 30))	('associations', 'Interaction', (35, 47))	('rs14035', 'Mutation', 'rs14035', (56, 63))	('rs14035 polymorphism', 'Var', (56, 76))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
172287	26688807	Evaluation of role of rs14035 in hepatocellular carcinoma showed no statistically significant differences (p < 0.05) between patients and healthy controls.	('rs14035', 'Var', (22, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (33, 57))	('rs14035', 'Mutation', 'rs14035', (22, 29))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (33, 57))	('hepatocellular carcinoma', 'Disease', (33, 57))	('patients', 'Species', '9606', (125, 133))
172289	26688807	On the other hand, data showed an association between occurrence of recessive variant of investigated RAN polymorphism and esophageal cancer (p = 0.024).	('esophageal cancer', 'Disease', (123, 140))	('recessive variant', 'Var', (68, 85))	('RAN', 'Gene', '5901', (102, 105))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('RAN', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
172290	26688807	rs14035 was also evaluated as a predictor of clinical outcomes in colorectal adenocarcinoma patients.	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('rs14035', 'Var', (0, 7))	('colorectal adenocarcinoma', 'Disease', (66, 91))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (66, 91))	('rs14035', 'Mutation', 'rs14035', (0, 7))
172292	26688807	For Stage II diseases, RAN:rs14035 was associated with overall survival with high significance in patients receiving surgery and adjuvant fluoropyrimidine treatment.	('fluoropyrimidine', 'Chemical', '-', (138, 154))	('rs14035', 'Mutation', 'rs14035', (27, 34))	('overall survival', 'MPA', (55, 71))	('RAN', 'Gene', '5901', (23, 26))	('patients', 'Species', '9606', (98, 106))	('RAN', 'Gene', (23, 26))	('associated', 'Reg', (39, 49))	('rs14035', 'Var', (27, 34))	('men', 'Species', '9606', (160, 163))
172295	26688807	Knock-down of XPO5 expression leads to reduced miRNA levels.	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('Knock-down', 'Var', (0, 10))	('reduced', 'NegReg', (39, 46))	('XPO5', 'Gene', (14, 18))	('XPO5', 'Gene', '57510', (14, 18))
172296	26688807	A mutated and inactive XPO5 resulted in reduced miRNA processing and decreased miRNA target inhibition; the restored XPO5 seemed as a tumor suppressor to reverse the impaired export of pre-miRNA in colon cancer.	('XPO5', 'Gene', (23, 27))	('miR', 'Gene', (189, 192))	('colon cancer', 'Disease', (198, 210))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('XPO5', 'Gene', (117, 121))	('reduced', 'NegReg', (40, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (198, 210))	('decreased', 'NegReg', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('XPO5', 'Gene', '57510', (23, 27))	('mutated', 'Var', (2, 9))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', '220972', (48, 51))	('tumor', 'Disease', (134, 139))	('XPO5', 'Gene', '57510', (117, 121))	('colon cancer', 'Disease', 'MESH:D015179', (198, 210))	('miR', 'Gene', '220972', (189, 192))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('miR', 'Gene', (79, 82))	('miR', 'Gene', (48, 51))
172298	26688807	The AC genotype of rs11077, which carries C or A allele, was significantly associated with a better chemotherapy response in patients with non-small cell lung (p = 0.001).	('rs11077', 'Mutation', 'rs11077', (19, 26))	('rs11077', 'Var', (19, 26))	('non-small cell lung', 'Disease', (139, 158))	('better', 'PosReg', (93, 99))	('chemotherapy response', 'CPA', (100, 121))	('patients', 'Species', '9606', (125, 133))
172299	26688807	In addition, rs11077 was independently associated with overall survival in advanced NSCLC patients through multivariate analysis (relative risk 0.457; 95% confidence interval: 0.251-0.831; p = 0.010).	('overall', 'MPA', (55, 62))	('rs11077', 'Var', (13, 20))	('NSCLC', 'Disease', (84, 89))	('rs11077', 'Mutation', 'rs11077', (13, 20))	('associated', 'Reg', (39, 49))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('LC', 'Phenotype', 'HP:0012118', (87, 89))	('patients', 'Species', '9606', (90, 98))
172300	26688807	The altered XPO5 expression may affect the miRNAs, leading to overall downregulation of miRNA expression profiles and thereby mediates the hepatocellular carcinoma survival.	('miR', 'Gene', (88, 91))	('mediates', 'Reg', (126, 134))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('XPO5', 'Gene', (12, 16))	('altered', 'Var', (4, 11))	('XPO5', 'Gene', '57510', (12, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('affect', 'Reg', (32, 38))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (139, 163))	('hepatocellular carcinoma', 'Disease', (139, 163))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (139, 163))	('downregulation', 'NegReg', (70, 84))	('miR', 'Gene', '220972', (88, 91))
172301	26688807	rs11077 CC genotype shows association with reduced Renilla expression in a Renilla luciferase 3'UTR reporter system.	('reduced', 'NegReg', (43, 50))	('rs11077 CC', 'Var', (0, 10))	('Renilla expression', 'MPA', (51, 69))	('rs11077', 'Mutation', 'rs11077', (0, 7))
172304	26688807	Melo and colleagues identified two frameshift mutations in TARBP2 that introduce premature stop codons, resulting in reduced TRBP expression.	('frameshift mutations', 'Var', (35, 55))	('reduced', 'NegReg', (117, 124))	('TRBP', 'Gene', (125, 129))	('TARBP2', 'Gene', '6895', (59, 65))	('TARBP2', 'Gene', (59, 65))	('TRBP', 'Gene', '6895', (125, 129))
172305	26688807	One function of TRBP is regulating DICER1 stability; thus these mutations resulted in reduced DICER1 expression and lower miRNA production and were associated with higher cellular proliferation levels.	('lower', 'NegReg', (116, 121))	('reduced', 'NegReg', (86, 93))	('DICER1', 'Gene', (94, 100))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', (122, 125))	('higher', 'PosReg', (164, 170))	('cellular proliferation', 'CPA', (171, 193))	('mutations', 'Var', (64, 73))	('TRBP', 'Gene', (16, 20))	('expression', 'MPA', (101, 111))	('TRBP', 'Gene', '6895', (16, 20))
172306	26688807	It has been shown that the variant allele of rs784567, which is located in the promoter of the TRBP gene, was associated with neither a risk of bladder cancer (p = 0.07) nor renal cell carcinoma or oral premalignant lesions.	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('rs784567', 'Mutation', 'rs784567', (45, 53))	('rs784567', 'Var', (45, 53))	('associated', 'Reg', (110, 120))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (174, 194))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('bladder cancer', 'Disease', (144, 158))	('renal cell carcinoma or oral premalignant lesions', 'Disease', 'MESH:D051437', (174, 223))	('TRBP', 'Gene', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('renal cell carcinoma or oral premalignant lesions', 'Disease', (174, 223))	('TRBP', 'Gene', '6895', (95, 99))
172308	26688807	On the other hand, rs784567 (HR = 1.59; 95% CI, 1.03 to 2.43; p = 0.04) was also associated with the risk of death in colorectal cancer but lost significance after adjusting for multiple comparison.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('rs784567', 'Mutation', 'rs784567', (19, 27))	('associated', 'Reg', (81, 91))	('rs784567', 'Var', (19, 27))	('colorectal cancer', 'Disease', (118, 135))
172312	26688807	The results indicate that polymorphic variants of these genes may affect not only the development of cancer but also disease progression.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('affect', 'Reg', (66, 72))	('men', 'Species', '9606', (93, 96))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('polymorphic variants', 'Var', (26, 46))	('development of', 'CPA', (86, 100))	('disease progression', 'CPA', (117, 136))
172317	26688807	Our results suggest that rs3742330 of DICER1, rs13078 of DICER1, and rs784567 of TARBP2 as well as rs11077 of XPO5 might be associated with a risk of laryngeal cancer occurrence in the Polish population.	('DICER1', 'Gene', (38, 44))	('rs13078', 'Var', (46, 53))	('rs3742330', 'Var', (25, 34))	('rs11077', 'Var', (99, 106))	('rs784567', 'Mutation', 'rs784567', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rs13078', 'Mutation', 'rs13078', (46, 53))	('XPO5', 'Gene', '57510', (110, 114))	('laryngeal cancer', 'Disease', 'MESH:D007822', (150, 166))	('rs11077', 'Mutation', 'rs11077', (99, 106))	('associated', 'Reg', (124, 134))	('DICER1', 'Gene', (57, 63))	('laryngeal cancer', 'Disease', (150, 166))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (150, 166))	('TARBP2', 'Gene', (81, 87))	('TARBP2', 'Gene', '6895', (81, 87))	('rs784567', 'Var', (69, 77))	('rs3742330', 'Mutation', 'rs3742330', (25, 34))	('XPO5', 'Gene', (110, 114))
172318	26688807	Additionally, rs417309 of DGCR8, rs3742330 and rs13078 of DICER1, and rs784567 of TARBP2 as well as rs11077 of XPO5 are associated with the progression of LC depending on the tumor size and lymph node metastases.	('rs3742330', 'Var', (33, 42))	('rs13078', 'Var', (47, 54))	('rs11077', 'Var', (100, 107))	('rs417309', 'Var', (14, 22))	('rs784567', 'Mutation', 'rs784567', (70, 78))	('rs11077', 'Mutation', 'rs11077', (100, 107))	('DICER1', 'Gene', (58, 64))	('tumor', 'Disease', (175, 180))	('rs13078', 'Mutation', 'rs13078', (47, 54))	('XPO5', 'Gene', '57510', (111, 115))	('associated with', 'Reg', (120, 135))	('lymph node metastases', 'Disease', (190, 211))	('DGCR8', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('TARBP2', 'Gene', '6895', (82, 88))	('rs3742330', 'Mutation', 'rs3742330', (33, 42))	('TARBP2', 'Gene', (82, 88))	('lymph node metastases', 'Disease', 'MESH:D009362', (190, 211))	('rs417309', 'Mutation', 'rs417309', (14, 22))	('rs784567', 'Var', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('LC', 'Phenotype', 'HP:0012118', (155, 157))	('XPO5', 'Gene', (111, 115))
172319	26688807	In addition, the results of our study warrant further functional studies to elucidate the mechanisms by which polymorphisms of miRNA machinery genes affect LC development.	('LC', 'Phenotype', 'HP:0012118', (156, 158))	('affect', 'Reg', (149, 155))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (127, 130))	('men', 'Species', '9606', (166, 169))	('polymorphisms', 'Var', (110, 123))	('LC development', 'CPA', (156, 170))
172320	26688807	An association of the miRNA processing genes single nucleotide polymorphisms with tumor stage of head and neck cancer.	('miR', 'Gene', '220972', (22, 25))	('association', 'Interaction', (3, 14))	('single nucleotide polymorphisms', 'Var', (45, 76))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('head and neck cancer', 'Phenotype', 'HP:0012288', (97, 117))	('neck cancer', 'Disease', 'MESH:D006258', (106, 117))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('neck cancer', 'Disease', (106, 117))	('miR', 'Gene', (22, 25))
172321	26688807	An association of the miRNA processing genes single nucleotide polymorphisms with stage of larynx cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('miR', 'Gene', '220972', (22, 25))	('association', 'Interaction', (3, 14))	('single nucleotide polymorphisms', 'Var', (45, 76))	('larynx cancer', 'Disease', (91, 104))	('larynx cancer', 'Phenotype', 'HP:0012118', (91, 104))	('miR', 'Gene', (22, 25))	('larynx cancer', 'Disease', 'MESH:D007822', (91, 104))
172604	32864805	We found higher rates of grade 2 vomiting and grade 2 and 3 anemia and thrombocytopenia in the double-agent group, which could be possible because cisplatin is highly likely to cause vomiting.	('thrombocytopenia', 'Disease', (71, 87))	('vomiting', 'Disease', (33, 41))	('vomiting', 'Disease', 'MESH:D014839', (33, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('2 vomiting', 'Phenotype', 'HP:0002572', (31, 41))	('anemia', 'Disease', 'MESH:D000740', (60, 66))	('anemia', 'Disease', (60, 66))	('anemia', 'Phenotype', 'HP:0001903', (60, 66))	('thrombocytopenia', 'Disease', 'MESH:D013921', (71, 87))	('grade', 'Disease', (46, 51))	('vomiting', 'Disease', 'MESH:D014839', (183, 191))	('cisplatin', 'Var', (147, 156))	('vomiting', 'Phenotype', 'HP:0002013', (183, 191))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (71, 87))	('vomiting', 'Phenotype', 'HP:0002013', (33, 41))	('vomiting', 'Disease', (183, 191))	('higher', 'PosReg', (9, 15))
172631	32864805	Furthermore, previous retrospective studies showed that single-drug concurrent chemoradiotherapy has lower hematotoxicity than a double-agent regimen concurrent chemoradiotherapy in patients with esophageal cancer [20, 21].	('hematotoxicity', 'Disease', 'MESH:D006402', (107, 121))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('single-drug', 'Var', (56, 67))	('hematotoxicity', 'Disease', (107, 121))	('lower', 'NegReg', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('patients', 'Species', '9606', (182, 190))
172636	33300075	Forkhead box K1 (FOXK1) dysregulation is critical in solid tumors, which serves a pivotal role in the biological characteristics, such as invasion and migration, but its expression and functions in HC are unclear.	('solid tumors', 'Disease', (53, 65))	('migration', 'CPA', (151, 160))	('FOXK1', 'Gene', '221937', (17, 22))	('solid tumors', 'Disease', 'MESH:D009369', (53, 65))	('dysregulation', 'Var', (24, 37))	('FOXK1', 'Gene', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('Forkhead box K1', 'Gene', (0, 15))	('invasion', 'CPA', (138, 146))	('Forkhead box K1', 'Gene', '221937', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
172640	33300075	Silencing FOXK1 in HC cells inhibited invasion and migration, upregulated E-cadherin, and downregulated vimentin, matrix metallopeptidase 9 and Twist in HC cells.	('matrix metallopeptidase 9', 'Gene', (114, 139))	('vimentin', 'Gene', '7431', (104, 112))	('Twist', 'Gene', '7291', (144, 149))	('vimentin', 'Gene', (104, 112))	('E-cadherin', 'Gene', (74, 84))	('FOXK1', 'Gene', (10, 15))	('E-cadherin', 'Gene', '999', (74, 84))	('Twist', 'Gene', (144, 149))	('matrix metallopeptidase 9', 'Gene', '4318', (114, 139))	('upregulated', 'PosReg', (62, 73))	('inhibited', 'NegReg', (28, 37))	('downregulated', 'NegReg', (90, 103))	('Silencing', 'Var', (0, 9))	('FOXK1', 'Gene', '221937', (10, 15))
172641	33300075	Sensitivity to 5-fluorouracil and cisplatin was increased, and glutathione S-transferase pi, multidrug resistance mutation 1 and P-glycoprotein expression levels were downregulated in RBE cells in vitro following FOXK1 knockdown.	('multidrug resistance mutation 1', 'MPA', (93, 124))	('increased', 'PosReg', (48, 57))	('expression levels', 'MPA', (144, 161))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (15, 29))	('knockdown', 'Var', (219, 228))	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('drug resistance', 'Phenotype', 'HP:0020174', (98, 113))	('glutathione S-transferase', 'Gene', (63, 88))	('FOXK1', 'Gene', (213, 218))	('glutathione S-transferase', 'Gene', '373156', (63, 88))	('P-glycoprotein', 'Gene', '5243', (129, 143))	('FOXK1', 'Gene', '221937', (213, 218))	('P-glycoprotein', 'Gene', (129, 143))	('downregulated', 'NegReg', (167, 180))
172648	33300075	The dysregulation of FOXK1 expression and subcellular localization leads to the uncontrolled development and progression of human solid cancer types.	('progression', 'CPA', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('men', 'Species', '9606', (100, 103))	('dysregulation', 'Var', (4, 17))	('FOXK1', 'Gene', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('human', 'Species', '9606', (124, 129))	('cancer', 'Disease', (136, 142))	('uncontrolled development', 'CPA', (80, 104))	('leads to', 'Reg', (67, 75))	('FOXK1', 'Gene', '221937', (21, 26))
172649	33300075	For instance, increasing evidence has demonstrated that FOXK1 knockdown can inhibit cell proliferation, migration and invasion in prostate cancer, hepatocellular carcinoma and esophageal cancer, whereas its enhanced expression facilitates cell proliferation and metastasis in ovarian and esophageal cancer.	('FOXK1', 'Gene', '221937', (56, 61))	('facilitates', 'PosReg', (227, 238))	('migration', 'CPA', (104, 113))	('prostate cancer', 'Disease', (130, 145))	('enhanced', 'PosReg', (207, 215))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (147, 171))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('expression', 'MPA', (216, 226))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (147, 171))	('cell proliferation', 'CPA', (239, 257))	('FOXK1', 'Gene', (56, 61))	('invasion', 'CPA', (118, 126))	('cell proliferation', 'CPA', (84, 102))	('cancer', 'Disease', (299, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('cancer', 'Disease', (139, 145))	('hepatocellular carcinoma', 'Disease', (147, 171))	('inhibit', 'NegReg', (76, 83))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('prostate cancer', 'Disease', 'MESH:D011471', (130, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (130, 145))	('metastasis in ovarian and esophageal cancer', 'Disease', 'MESH:D009362', (262, 305))	('knockdown', 'Var', (62, 71))
172653	33300075	FOXK1 knockdown in vitro inhibited the proliferation and migration of HC cells.	('inhibited', 'NegReg', (25, 34))	('FOXK1', 'Gene', '221937', (0, 5))	('knockdown', 'Var', (6, 15))	('FOXK1', 'Gene', (0, 5))
172673	33300075	Transwell chambers (8 microm pore size; Corning, Inc.) were used to assess the effect of FOXK1 knockdown on cell invasion.	('FOXK1', 'Gene', (89, 94))	('knockdown', 'Var', (95, 104))	('FOXK1', 'Gene', '221937', (89, 94))
172696	33300075	Table I summarizes the association between high FOXK1 expression and clinicopathological variables of HC.	('FOXK1', 'Gene', (48, 53))	('FOXK1', 'Gene', '221937', (48, 53))	('expression', 'MPA', (54, 64))	('high', 'Var', (43, 47))
172697	33300075	A statistically significant association was observed between high FOXK1 expression and tumor invasion and regional LN metastasis.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('significant association', 'Reg', (16, 39))	('FOXK1', 'Gene', '221937', (66, 71))	('regional LN metastasis', 'CPA', (106, 128))	('high', 'Var', (61, 65))	('tumor', 'Disease', (87, 92))	('expression', 'MPA', (72, 82))	('FOXK1', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
172703	33300075	Patients with tumors exhibiting high FOXK1 expression had a significantly shorter DFS than that in patients with low FOXK1 expression (11 vs. 42 months; P<0.001; Fig.	('shorter', 'NegReg', (74, 81))	('high', 'Var', (32, 36))	('FOXK1', 'Gene', '221937', (117, 122))	('DFS', 'MPA', (82, 85))	('FOXK1', 'Gene', (117, 122))	('tumors', 'Disease', (14, 20))	('FOXK1', 'Gene', '221937', (37, 42))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('FOXK1', 'Gene', (37, 42))
172705	33300075	In contrast to the univariate analysis, the multivariate analysis using the Cox proportional hazards model showed that high FOXK1 expression was an independent predictor of tumor recurrence (P=0.014; Table II).	('expression', 'MPA', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('high', 'Var', (119, 123))	('FOXK1', 'Gene', '221937', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('FOXK1', 'Gene', (124, 129))
172707	33300075	However, patients with high FOXK1 expression in tumors had a significantly worse OS than those with low FOXK1 expression (14 months vs. 50 months; P<0.001; Fig.	('patients', 'Species', '9606', (9, 17))	('FOXK1', 'Gene', '221937', (28, 33))	('high', 'Var', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('FOXK1', 'Gene', '221937', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('FOXK1', 'Gene', (28, 33))	('FOXK1', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
172709	33300075	The multivariate analysis also showed that high FOXK1 expression was an independent prognostic factor (P=0.037; Table III).	('FOXK1', 'Gene', (48, 53))	('FOXK1', 'Gene', '221937', (48, 53))	('expression', 'MPA', (54, 64))	('high', 'Var', (43, 47))
172712	33300075	4B shows that the silencing of FOXK1 expression using shRNA was successful in RBE cells (Fig.	('FOXK1', 'Gene', '221937', (31, 36))	('silencing', 'Var', (18, 27))	('FOXK1', 'Gene', (31, 36))
172713	33300075	Silencing endogenous FOXK1 did not affect cell proliferation (Fig.	('Silencing', 'Var', (0, 9))	('FOXK1', 'Gene', (21, 26))	('FOXK1', 'Gene', '221937', (21, 26))
172714	33300075	Western blotting revealed that FOXK1 knockdown resulted in the upregulation of E-cadherin and the downregulation of vimentin, MMP-9 and Twist (Fig.	('MMP-9', 'Gene', (126, 131))	('Twist', 'Gene', '7291', (136, 141))	('FOXK1', 'Gene', '221937', (31, 36))	('downregulation', 'NegReg', (98, 112))	('Twist', 'Gene', (136, 141))	('knockdown', 'Var', (37, 46))	('E-cadherin', 'Gene', (79, 89))	('vimentin', 'Gene', '7431', (116, 124))	('FOXK1', 'Gene', (31, 36))	('vimentin', 'Gene', (116, 124))	('E-cadherin', 'Gene', '999', (79, 89))	('MMP-9', 'Gene', '4318', (126, 131))	('upregulation', 'PosReg', (63, 75))
172716	33300075	It was found that silencing endogenous FOXK1 expression in RBE cells increased their sensitivity to 5-FU and DDP (Fig.	('silencing', 'Var', (18, 27))	('increased', 'PosReg', (69, 78))	('DDP', 'Chemical', 'MESH:D002945', (109, 112))	('5-FU', 'Chemical', 'MESH:D005472', (100, 104))	('FOXK1', 'Gene', '221937', (39, 44))	('FOXK1', 'Gene', (39, 44))
172719	33300075	The data of survival follow-up revealed that its high expression was an independent predictor of tumor recurrence and OS after HC resection.	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('high', 'Var', (49, 53))
172720	33300075	However, the migratory and invasive abilities of RBE cells were inhibited and the expression of several epithelial-mesenchymal transition (EMT)-associated proteins were influenced following knockdown of FOXK1, which provided a novel molecular basis for the key role of FOXK1 in HC development and progression.	('FOXK1', 'Gene', '221937', (203, 208))	('knockdown', 'Var', (190, 199))	('expression', 'MPA', (82, 92))	('influenced', 'Reg', (169, 179))	('inhibited', 'NegReg', (64, 73))	('FOXK1', 'Gene', '221937', (269, 274))	('FOXK1', 'Gene', (203, 208))	('men', 'Species', '9606', (288, 291))	('FOXK1', 'Gene', (269, 274))
172724	33300075	High expression was identified to be associated with tumor invasion and metastasis.	('metastasis', 'CPA', (72, 82))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('associated', 'Reg', (37, 47))	('tumor', 'Disease', (53, 58))
172731	33300075	The survival analysis from the present study showed that high FOXK1 expression in tumors was associated with shorter PFS and worse outcome.	('FOXK1', 'Gene', '221937', (62, 67))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('high', 'Var', (57, 61))	('expression', 'MPA', (68, 78))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('FOXK1', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PFS', 'CPA', (117, 120))	('shorter', 'NegReg', (109, 116))
172735	33300075	Given the association between high FOXK1 expression and tumor invasion or LN metastasis, the present study aimed to detect the role of FOXK1 in cell migration by suppressing its expression and exploring a possible associated mechanism.	('cell migration', 'CPA', (144, 158))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('FOXK1', 'Gene', '221937', (35, 40))	('expression', 'MPA', (41, 51))	('expression', 'MPA', (178, 188))	('tumor', 'Disease', (56, 61))	('FOXK1', 'Gene', '221937', (135, 140))	('high', 'Var', (30, 34))	('FOXK1', 'Gene', (35, 40))	('suppressing', 'NegReg', (162, 173))	('FOXK1', 'Gene', (135, 140))	('LN metastasis', 'CPA', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
172737	33300075	It was identified that silencing endogenous FOXK1 significantly inhibited HC cell migration and invasion, as revealed by the Transwell and wound healing assays.	('FOXK1', 'Gene', (44, 49))	('inhibited', 'NegReg', (64, 73))	('silencing', 'Var', (23, 32))	('invasion', 'CPA', (96, 104))	('FOXK1', 'Gene', '221937', (44, 49))	('HC cell migration', 'CPA', (74, 91))
172739	33300075	It has been demonstrated that the knockdown of FOXK1 inhibits transforming growth factor beta-induced EMT.	('FOXK1', 'Gene', (47, 52))	('FOXK1', 'Gene', '221937', (47, 52))	('knockdown', 'Var', (34, 43))	('inhibits', 'NegReg', (53, 61))	('transforming growth factor beta-induced', 'MPA', (62, 101))
172740	33300075	Its overexpression induces this process by upregulating cysteine-rich angiogenic inducer 61 in colorectal cancer, whereas knockdown prevents an EMT phenotype through the upregulation of E-cadherin and downregulation of N-cadherin in prostate cancer cells.	('prostate cancer', 'Disease', 'MESH:D011471', (233, 248))	('prostate cancer', 'Phenotype', 'HP:0012125', (233, 248))	('N-cadherin', 'Gene', (219, 229))	('N-cadherin', 'Gene', '1000', (219, 229))	('prostate cancer', 'Disease', (233, 248))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('E-cadherin', 'Gene', (186, 196))	('E-cadherin', 'Gene', '999', (186, 196))	('upregulating', 'PosReg', (43, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('knockdown', 'Var', (122, 131))	('cysteine-rich angiogenic inducer 61', 'Gene', '3491', (56, 91))	('overexpression', 'PosReg', (4, 18))	('EMT phenotype', 'CPA', (144, 157))	('colorectal cancer', 'Disease', (95, 112))	('cysteine-rich angiogenic inducer 61', 'Gene', (56, 91))	('downregulation', 'NegReg', (201, 215))	('upregulation', 'PosReg', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))
172746	33300075	Silencing FOXK1 increased sensitivity to 5-FU and DDP, and downregulated the expression of GST-pi, MDR1 and P-gp, which are related to drug resistance, in RBE cells in vitro.	('expression', 'MPA', (77, 87))	('GST-pi', 'Gene', (91, 97))	('DDP', 'Chemical', 'MESH:D002945', (50, 53))	('sensitivity to 5-FU', 'MPA', (26, 45))	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('MDR1', 'Gene', (99, 103))	('downregulated', 'NegReg', (59, 72))	('FOXK1', 'Gene', (10, 15))	('P-gp', 'Gene', '283871', (108, 112))	('MDR1', 'Gene', '5243', (99, 103))	('increased', 'PosReg', (16, 25))	('drug resistance', 'Phenotype', 'HP:0020174', (135, 150))	('P-gp', 'Gene', (108, 112))	('Silencing', 'Var', (0, 9))	('FOXK1', 'Gene', '221937', (10, 15))
172749	33300075	Furthermore, high FOXK1 expression was an independent predictor of tumor recurrence and OS.	('high', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('expression', 'MPA', (24, 34))	('FOXK1', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('FOXK1', 'Gene', '221937', (18, 23))
172809	32824326	Patients with R+ resection, diffuse tumor histology, histologically proven nodal involvement and higher pathological T-stages were at risk of developing PC.	('nodal', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('Patients', 'Species', '9606', (0, 8))	('nodal', 'Gene', '4838', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('R+ resection', 'Var', (14, 26))	('tumor', 'Disease', (36, 41))
172867	30989466	In chemotaxis assays with supernatant from human esophageal epithelial cells, only ONO-AE1-329 but not butaprost or BW245C inhibited the migration of eosinophils.	('migration of eosinophils', 'CPA', (137, 161))	('ONO-AE1-329', 'Var', (83, 94))	('ONO', 'Chemical', 'MESH:C038131', (83, 86))	('inhibited', 'NegReg', (123, 132))	('rat', 'Species', '10116', (140, 143))	('human', 'Species', '9606', (43, 48))
172908	30989466	Eosinophils from healthy donors were incubated with the following compounds: EP4 agonist ONO-AE1-329 (100 nM) or EP4 antagonist ONO-AE3-208 (100 nM; ONO compounds were a generous gift from ONO Pharmaceutical, Osaka, Japan), EP2 agonist butaprost (100 and 300 nM; Cayman Chemicals, Ann Arbor, MI, USA), DP1 agonist BW245C (100 nM), and DP1 antagonist MK0524 (1 microM; Cayman Chemicals).	('EP4', 'Gene', '5734', (113, 116))	('ONO', 'Chemical', 'MESH:C038131', (128, 131))	('EP4', 'Gene', (113, 116))	('DP1', 'Gene', (302, 305))	('ONO', 'Chemical', 'MESH:C038131', (149, 152))	('ONO-AE3-208', 'Var', (128, 139))	('ONO-AE3-208', 'Chemical', 'MESH:C487890', (128, 139))	('EP4', 'Gene', '5734', (77, 80))	('DP1', 'Gene', (335, 338))	('ONO', 'Chemical', 'MESH:C038131', (189, 192))	('EP4', 'Gene', (77, 80))	('DP1', 'Gene', '5729', (335, 338))	('EP2', 'Gene', '10407', (224, 227))	('EP2', 'Gene', (224, 227))	('100', 'Var', (247, 250))	('MK0524', 'Chemical', 'MESH:C518174', (350, 356))	('BW245C (100 nM', 'Var', (314, 328))	('DP1', 'Gene', '5729', (302, 305))	('ONO', 'Chemical', 'MESH:C038131', (89, 92))
172926	30989466	1), with 100 nM of the DP1 agonist BW245C or 1 microM of DP1 antagonist MK0524.	('DP1', 'Gene', '5729', (23, 26))	('DP1', 'Gene', (23, 26))	('DP1', 'Gene', (57, 60))	('BW245C', 'Var', (35, 41))	('DP1', 'Gene', '5729', (57, 60))	('MK0524', 'Chemical', 'MESH:C518174', (72, 78))
172931	30989466	2e) dose-dependently decreased the adhesion of eosinophils to primary esophageal epithelial cells, whereas the DP1 agonist BW245 clearly enhanced eosinophil adhesion (Fig.	('enhanced', 'PosReg', (137, 145))	('eosinophil adhesion', 'CPA', (146, 165))	('DP1', 'Gene', '5729', (111, 114))	('adhesion', 'MPA', (35, 43))	('decreased', 'NegReg', (21, 30))	('BW245', 'Var', (123, 128))	('enhanced eosinophil adhesion', 'Phenotype', 'HP:0008352', (137, 165))	('DP1', 'Gene', (111, 114))
172974	30989466	Although PGE2 induces cell growth in CaCo-2 cells, PGE2 has been also shown to cause disruption of a CaCo-2 cell barrier that involves EP1/EP4 activity supporting our observation that EP4 agonism decreases esophageal epithelial cell barrier.	('EP4', 'Gene', '5734', (139, 142))	('PGE2', 'Gene', (9, 13))	('decreases', 'NegReg', (196, 205))	('EP4', 'Gene', (184, 187))	('PGE2', 'Chemical', 'MESH:D015232', (51, 55))	('EP4', 'Gene', '5734', (184, 187))	('EP4', 'Gene', (139, 142))	('cell growth', 'CPA', (22, 33))	('EP1', 'Gene', '5731', (135, 138))	('PGE2', 'Var', (51, 55))	('PGE2', 'Chemical', 'MESH:D015232', (9, 13))	('EP1', 'Gene', (135, 138))	('esophageal epithelial cell barrier', 'CPA', (206, 240))
172994	29213217	In addition to this, silencing of MARCH8 induced apoptosis in esophageal cancer cells which was measured by cell cycle distribution assay which showed increase in sub G0 and G2/M populations (cell death) and decrease in S-phase population.	('MARCH8', 'Gene', (34, 40))	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('silencing', 'Var', (21, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('S-phase population', 'CPA', (220, 238))	('increase', 'PosReg', (151, 159))	('decrease', 'NegReg', (208, 216))
173004	29213217	In the present study, we have reported aberrant expression of MARCH8 gene in esophageal squamous cell carcinoma (ESCC).	('aberrant expression', 'Var', (39, 58))	('MARCH8', 'Gene', (62, 68))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))
173032	29213217	The migration area among different groups was measured as the average percent of wound closure as compared to that at 0 h. Boyden chamber assay was also performed to check the effect of MARCH8 knockdown on KYSE-410 cell migration and invasion.	('MARCH8', 'Gene', (186, 192))	('KYSE-410', 'CellLine', 'CVCL:1352', (206, 214))	('knockdown', 'Var', (193, 202))	('invasion', 'CPA', (234, 242))
173034	29213217	Unlike migration, Matrigel basement membrane matrix (Corning, Massachusetts, USA) was used to coat the upper side of Boyden chamber to assess the effect of MARCH8 knockdown on invasive capacity of KYSE-410.	('MARCH8', 'Gene', (156, 162))	('KYSE-410', 'CellLine', 'CVCL:1352', (197, 205))	('knockdown', 'Var', (163, 172))
173053	29213217	To check whether MARCH8 silencing modifies migration of KYSE-410 cells, scratch assay was performed.	('KYSE-410', 'CellLine', 'CVCL:1352', (56, 64))	('silencing', 'Var', (24, 33))	('modifies', 'Reg', (34, 42))	('MARCH8', 'Gene', (17, 23))
173062	29213217	In this study, we showed overexpression of MARCH8 in esophageal cancer tissues and its silencing inhibited proliferation, migration, invasion and clonogenicity of EC cells.	('silencing', 'Var', (87, 96))	('invasion', 'CPA', (133, 141))	('proliferation', 'CPA', (107, 120))	('clonogenicity', 'CPA', (146, 159))	('esophageal cancer', 'Disease', (53, 70))	('inhibited', 'NegReg', (97, 106))	('migration', 'CPA', (122, 131))	('overexpression', 'PosReg', (25, 39))	('MARCH8', 'Gene', (43, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
173064	29213217	Our results also demonstrated the effect of MARCH8 knockdown on cellular migration, invasion, growth inhibitory rate, and clonogenic potential of KYSE-410 cells.	('invasion', 'CPA', (84, 92))	('KYSE-410', 'CellLine', 'CVCL:1352', (146, 154))	('clonogenic potential', 'CPA', (122, 142))	('cellular migration', 'CPA', (64, 82))	('effect', 'Reg', (34, 40))	('growth inhibitory rate', 'CPA', (94, 116))	('MARCH8', 'Gene', (44, 50))	('knockdown', 'Var', (51, 60))
173067	29213217	Knockdown of MARCH8 was also found to suppress cancer cell properties like invasion, migration and colony formation ability of KYSE-410 cells.	('MARCH8', 'Gene', (13, 19))	('Knockdown', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('invasion', 'CPA', (75, 83))	('cancer', 'Disease', (47, 53))	('KYSE-410', 'CellLine', 'CVCL:1352', (127, 135))	('migration', 'CPA', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('suppress', 'NegReg', (38, 46))	('colony formation ability', 'CPA', (99, 123))
173249	23418461	In contrast, SnoN expression in the stroma is highly upregulated in the infiltrating inflammatory cells in high-grade esophageal and ovarian tumor samples, suggesting that SnoN may potentially promote malignant progression through modulating the tumor microenvironment in these tumor types.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('promote', 'PosReg', (193, 200))	('malignant progression', 'CPA', (201, 222))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('ovarian tumor', 'Phenotype', 'HP:0100615', (133, 146))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('SnoN', 'Var', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('expression', 'MPA', (18, 28))	('modulating', 'Reg', (231, 241))	('ovarian tumor', 'Disease', (133, 146))	('tumor', 'Disease', (278, 283))	('ovarian tumor', 'Disease', 'MESH:D010051', (133, 146))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('SnoN', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', (141, 146))	('upregulated', 'PosReg', (53, 64))
173251	23418461	However, in human cancer cell lines with amplification of the snoN gene, a strong correlation between increased SnoN copy number and inactivation of p53 was detected, suggesting that the tumor suppressor SnoN-p53 pathway must be inactivated, either through downregulation of SnoN or inactivation of p53, in order to allow cancer cell to proliferate and survive.	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('tumor', 'Disease', (187, 192))	('cancer', 'Disease', (18, 24))	('inactivation', 'Var', (283, 295))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('p53', 'Gene', '7157', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('amplification', 'Var', (41, 54))	('p53', 'Gene', '7157', (299, 302))	('p53', 'Gene', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', (322, 328))	('downregulation', 'NegReg', (257, 271))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('p53', 'Gene', '7157', (209, 212))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('p53', 'Gene', (299, 302))	('SnoN', 'Gene', (275, 279))	('human', 'Species', '9606', (12, 17))	('p53', 'Gene', (209, 212))
173272	23418461	In this report, we examined SnoN expression in four types of normal human tissues and matching cancer tissues of various clinical stages of malignancy to assess whether alterations of SnoN expression correlate with tumor malignancy and/or status of p53 inactivation.	('alterations', 'Var', (169, 180))	('human', 'Species', '9606', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('malignancy', 'Disease', 'MESH:D009369', (140, 150))	('cancer', 'Disease', (95, 101))	('tumor malignancy', 'Disease', (215, 231))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('malignancy', 'Disease', 'MESH:D009369', (221, 231))	('SnoN', 'Gene', (184, 188))	('p53', 'Gene', (249, 252))	('p53', 'Gene', '7157', (249, 252))	('malignancy', 'Disease', (221, 231))	('inactivation', 'Var', (253, 265))	('tumor malignancy', 'Disease', 'MESH:D018198', (215, 231))	('malignancy', 'Disease', (140, 150))
173279	23418461	By examining the location and levels of SnoN expression in these tissues, we hope to gain a better understanding of the functions that SnoN play during tumorigenesis in both the epithelium and stromal environment and how this may correlate with p53 inactivation.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('p53', 'Gene', (245, 248))	('tumor', 'Disease', (152, 157))	('p53', 'Gene', '7157', (245, 248))	('inactivation', 'Var', (249, 261))
173308	23418461	For analysis of potential association of TP53 mutation and SKIL amplification, we performed data mining of the Novartis cell line encyclopedia (CLE) that contains 947 human cancer cell lines, in which copy numbers and mutations of SnoN (SKIL) and p53 genes have been characterized using Affymetrix SNP6 microarray or RNAseq.	('TP53', 'Gene', '7157', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('TP53', 'Gene', (41, 45))	('SKIL', 'Gene', '6498', (237, 241))	('Novartis cell line encyclopedia', 'Disease', (111, 142))	('cancer', 'Disease', (173, 179))	('mutations', 'Var', (218, 227))	('human', 'Species', '9606', (167, 172))	('SKIL', 'Gene', (59, 63))	('p53', 'Gene', '7157', (247, 250))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('SKIL', 'Gene', (237, 241))	('Novartis cell line encyclopedia', 'Disease', 'MESH:C538614', (111, 142))	('SnoN', 'Gene', (231, 235))	('SKIL', 'Gene', '6498', (59, 63))	('p53', 'Gene', (247, 250))
173343	23418461	The model further predicts that in order for tumor cells to overcome the tumor suppressive activity of the SnoN-p53 pathway, they have to either inactivate p53 or delete SnoN.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('delete', 'Var', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (45, 50))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('tumor', 'Disease', (73, 78))	('SnoN', 'Gene', (170, 174))	('p53', 'Gene', (112, 115))	('inactivate', 'NegReg', (145, 155))	('p53', 'Gene', '7157', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
173347	23418461	We analyzed 914 cancer cell lines in the Novartis cell line encyclopedia (CLE), in which copy numbers and mutations of SnoN and p53 genes were characterized using Affymetrix SNP6 microarray or RNAseq technology, to determine whether samples with increased copy number of the SnoN gene also tend to show inactivation of p53 as indicated by a loss of p53 copy number or the presence of known inactivating mutations.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('p53', 'Gene', '7157', (319, 322))	('copy number', 'Var', (256, 267))	('SnoN', 'Gene', (275, 279))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('loss', 'NegReg', (341, 345))	('inactivation', 'NegReg', (303, 315))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('Novartis cell line encyclopedia', 'Disease', 'MESH:C538614', (41, 72))	('copy number', 'MPA', (353, 364))	('increased', 'PosReg', (246, 255))	('p53', 'Gene', (349, 352))	('p53', 'Gene', (319, 322))	('p53', 'Gene', '7157', (349, 352))	('Novartis cell line encyclopedia', 'Disease', (41, 72))
173348	23418461	Based on the mutation status of p53, we classified cell lines into mutant or wild type, and copy number of SnoN were compared among these two groups.	('p53', 'Gene', (32, 35))	('mutation', 'Var', (13, 21))	('p53', 'Gene', '7157', (32, 35))
173349	23418461	As shown in Figure 6A, we identified significant enrichment of SnoN amplification events in p53 mutant or p53 deleted cell lines (p value: 7.25E-009), indicating a potential association between the two genetic events.	('p53', 'Gene', '7157', (106, 109))	('SnoN amplification', 'MPA', (63, 81))	('mutant', 'Var', (96, 102))	('deleted', 'Var', (110, 117))	('p53', 'Gene', (92, 95))	('p53', 'Gene', '7157', (92, 95))	('p53', 'Gene', (106, 109))
173351	23418461	A striking correlation between the frequency of p53 mutation and the frequency of SnoN amplification was detected (The Pearson's correlation coefficient was 0.7), where the lineages with higher incidence of p53 mutation tended to have higher incidence of SnoN amplification (Figure 6B).	('p53', 'Gene', (48, 51))	('SnoN amplification', 'MPA', (255, 273))	('p53', 'Gene', '7157', (48, 51))	('p53', 'Gene', '7157', (207, 210))	('p53', 'Gene', (207, 210))	('mutation', 'Var', (211, 219))
173360	23418461	Together our study suggests that SnoN is likely to play a tumor suppressor role in the initial stages of human cancer development, and inactivation of this pathway by targeting either SnoN itself or p53 is necessary for malignant progression.	('human', 'Species', '9606', (105, 110))	('tumor', 'Disease', (58, 63))	('p53', 'Gene', (199, 202))	('p53', 'Gene', '7157', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('SnoN', 'Gene', (184, 188))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('inactivation', 'Var', (135, 147))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
173377	23418461	Interestingly, the cancers of esophagus and ovary tend to harbor 3q26 amplification and show SnoN copy number increases, and they also display a stronger increase in stroma SnoN levels.	('amplification', 'Var', (70, 83))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('SnoN copy number', 'MPA', (93, 109))	('increases', 'PosReg', (110, 119))	('cancers of esophagus and ovary', 'Disease', 'MESH:D004938', (19, 49))	('stroma', 'MPA', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('increase', 'PosReg', (154, 162))	('3q26', 'Protein', (65, 69))
173383	23418461	Thus, tissues or cells that show elevated SnoN expression (either due to gene amplification or other means) may cease proliferation due to p53-mediated senescence or cell cycle arrest.	('elevated', 'PosReg', (33, 41))	('cease', 'NegReg', (112, 117))	('gene amplification', 'Var', (73, 91))	('cell cycle arrest', 'CPA', (166, 183))	('SnoN', 'Gene', (42, 46))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (166, 183))
173384	23418461	Malignant cells have to overcome this barrier in order to maintain their survival and expansion and may do so by either inactivating/deleting SnoN itself or any downstream steps in the SnoN-p53 pathway.	('inactivating/deleting', 'NegReg', (120, 141))	('SnoN', 'Gene', (142, 146))	('p53', 'Gene', '7157', (190, 193))	('p53', 'Gene', (190, 193))	('inactivating/deleting', 'Var', (120, 141))
173398	33975200	Computed tomography showed a tumor lesion in the lower-third thoracic esophagus; the images also showed irregularities on the surface of the liver, suggestive of coexisting alcoholic liver cirrhosis.	('irregularities', 'Var', (104, 118))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (183, 198))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cirrhosis', 'Phenotype', 'HP:0001394', (189, 198))	('tumor lesion', 'Disease', (29, 41))	('alcoholic liver cirrhosis', 'Disease', 'MESH:D008104', (173, 198))	('tumor lesion', 'Disease', 'MESH:D009369', (29, 41))	('alcoholic liver cirrhosis', 'Disease', (173, 198))
173399	33975200	The preoperative diagnosis was T3N2M0, Stage III esophageal leiomyosarcoma.	('esophageal leiomyosarcoma', 'Disease', (49, 74))	('esophageal leiomyosarcoma', 'Disease', 'MESH:D007890', (49, 74))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (60, 74))	('T3N2M0', 'Var', (31, 37))
173402	33975200	Final histopathological diagnosis was T2N0M0, Stage II esophageal carcinosarcoma.	('esophageal carcinosarcoma', 'Disease', 'MESH:D002296', (55, 80))	('T2N0M0', 'Var', (38, 44))	('esophageal carcinosarcoma', 'Disease', (55, 80))	('esophageal carcinosarcoma', 'Phenotype', 'HP:0011459', (55, 80))
173427	33975200	The preoperative diagnosis was esophageal leiomyosarcoma and the tumor stage (according to the eighth edition of the Union for International Cancer Control) was T3N2M0, Stage III.	('esophageal leiomyosarcoma', 'Disease', (31, 56))	('T3N2M0', 'Var', (161, 167))	('tumor', 'Disease', (65, 70))	('esophageal leiomyosarcoma', 'Disease', 'MESH:D007890', (31, 56))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Cancer', 'Disease', (141, 147))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (42, 56))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
173501	32480340	The initial esophageal cancer stage was pT3N1M0StageIII, and the colon cancer stage was pT2N0M0StageI.	('colon cancer', 'Disease', (65, 77))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('esophageal cancer', 'Disease', (12, 29))	('pT3N1M0StageIII', 'Var', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (12, 29))
173566	29136005	Accordingly, NAC-DCF is a powerful regimen and is expected to achieve pCR in locally advanced esophageal cancer.	('esophageal cancer', 'Disease', (94, 111))	('NAC-DCF', 'Chemical', '-', (13, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NAC-DCF', 'Var', (13, 20))
173615	29136005	It was reported that the expression of IRF-1 inhibited the growth of esophageal cancer cells and that IRF-1 had a potential effect as a tumor suppressor in esophageal cancer.	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('esophageal cancer', 'Disease', (156, 173))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('IRF-1', 'Gene', (39, 44))	('IRF-1', 'Gene', '3659', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('IRF-1', 'Gene', (102, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('IRF-1', 'Gene', '3659', (39, 44))	('inhibited', 'NegReg', (45, 54))	('expression', 'Var', (25, 35))	('tumor', 'Disease', (136, 141))
173622	29136005	A previous study reported that inhibition of the RB/E2F pathway suppressed tumor growth and increased the effect of gemcitabine in pancreatic cancer.	('gemcitabine', 'Chemical', 'MESH:C056507', (116, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('suppressed', 'NegReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('pancreatic cancer', 'Disease', (131, 148))	('increased', 'PosReg', (92, 101))	('inhibition', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('RB/E2F pathway', 'Pathway', (49, 63))	('tumor', 'Disease', (75, 80))	('effect of gemcitabine', 'MPA', (106, 127))
173623	29136005	On the other hand, several reports have indicated that inhibition of the RB/E2F pathway decreased the effect of CDDP in lung cancer and breast cancer and decreased the effect of paclitaxel in lung cancer.	('decreased', 'NegReg', (154, 163))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('lung cancer', 'Disease', (120, 131))	('breast cancer', 'Disease', (136, 149))	('CDDP', 'Chemical', '-', (112, 116))	('decreased', 'NegReg', (88, 97))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('RB/E2F pathway', 'Pathway', (73, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (178, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('CDDP', 'MPA', (112, 116))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('effect', 'MPA', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('inhibition', 'Var', (55, 65))	('effect of paclitaxel', 'MPA', (168, 188))	('lung cancer', 'Disease', (192, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))
173624	29136005	STAT is a TCF activated by JAK in the JAK/STAT pathway.	('JAK', 'Var', (27, 30))	('TCF', 'Gene', (10, 13))	('TCF', 'Gene', '3172', (10, 13))	('JAK/STAT pathway', 'Pathway', (38, 54))
173626	29136005	It has been reported that inactivation of the JAK/STAT pathway inhibited tumor proliferation in esophageal cancer.	('inactivation', 'Var', (26, 38))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('JAK/STAT pathway', 'Pathway', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('inhibited', 'NegReg', (63, 72))
173642	28671623	Cancer is a complex process in which genetic alterations modify the ability of cells to transduce signals, and allow them to acquire new functions, replicate beyond normal limits, evade apoptosis, and ultimately encroach other tissues.	('acquire', 'PosReg', (125, 132))	('modify', 'Reg', (57, 63))	('evade', 'NegReg', (180, 185))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('genetic alterations', 'Var', (37, 56))	('transduce signals', 'MPA', (88, 105))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('apoptosis', 'CPA', (186, 195))
173651	28671623	A greater occurrence of cell surface N-glycans, sialylations, and fucosylations, the abnormal production of mucin, the expression of Lewis X/A structures in glycosphingolipids (identified as a tumor antigen), and the increased expression of galectins constitute the main structural changes that mark the difference between cancer and normal cells.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('lectin', 'Gene', (243, 249))	('mucin', 'Gene', (108, 113))	('lectin', 'Gene', '547726', (243, 249))	('cancer', 'Disease', (323, 329))	('mucin', 'Gene', '100508689', (108, 113))	('cell surface N-glycans', 'Protein', (24, 46))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('expression', 'MPA', (227, 237))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('fucosylations', 'Var', (66, 79))	('N-glycans', 'Chemical', '-', (37, 46))	('tumor', 'Disease', (193, 198))	('increased', 'PosReg', (217, 226))
173668	28671623	However, in a recent study, the topical application of fluorescently labelled wheat germ lectins (WGA) on ex vivo esophagus tissues showed high affinity and specificity for sub-expressed glycans in neoplasia originated from Barrett's esophagus.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (224, 243))	('lectin', 'Gene', (89, 95))	('neoplasia', 'Disease', (198, 207))	('lectin', 'Gene', '547726', (89, 95))	('sub-expressed', 'Var', (173, 186))	('glycans', 'Chemical', 'MESH:D011134', (187, 194))	('wheat', 'Species', '4565', (78, 83))	('neoplasia', 'Phenotype', 'HP:0002664', (198, 207))	('affinity', 'Interaction', (144, 152))	('neoplasia', 'Disease', 'MESH:D009369', (198, 207))	('glycans', 'Protein', (187, 194))
173737	28671623	The phosphorylation of JNK appeared to be responsible for triggering a modification in the ratio of Bax/Bcl-2, Bax translocation, the consequent release of cytochrome c, and ultimately activation of caspase 3.	('caspase 3', 'Gene', '836', (199, 208))	('Bax', 'Gene', '581', (100, 103))	('Bax', 'Gene', (111, 114))	('modification', 'Reg', (71, 83))	('Bcl-2', 'Gene', (104, 109))	('Bcl-2', 'Gene', '596', (104, 109))	('JNK', 'Gene', (23, 26))	('cytochrome c', 'Gene', (156, 168))	('Bax', 'Gene', '581', (111, 114))	('cytochrome c', 'Gene', '54205', (156, 168))	('JNK', 'Gene', '5599', (23, 26))	('activation', 'PosReg', (185, 195))	('Bax', 'Gene', (100, 103))	('phosphorylation', 'Var', (4, 19))	('caspase 3', 'Gene', (199, 208))
173750	28671623	The presence of apoptosis and autophagy was specifically detected by G2/M arrest, as well as the activation of MAPK pathways and caspases-3, -8, and -9 in the apoptotic processes.	('caspases-3, -8, and -9', 'Gene', '836;841;842', (129, 151))	('activation', 'PosReg', (97, 107))	('apoptosis', 'CPA', (16, 25))	('MAPK pathways', 'Pathway', (111, 124))	('G2/M', 'Var', (69, 73))	('autophagy', 'CPA', (30, 39))
173804	28072693	Although similar improvements were not observed for the same comparison using DIR for propagated PET contours from diagnostic PET/CT to planning CT (P > 0.05), for DSC and displacements of COM in the 3D direction of PET contours, the DIR resulted in the improved volume of a large percentage of patients (73.7%; 68.45%; 63.2%) compared with RIR.	('improved', 'PosReg', (254, 262))	('volume', 'MPA', (263, 269))	('displacements', 'Var', (172, 185))	('patients', 'Species', '9606', (295, 303))
173806	28072693	The efficiency of radiotherapy in EC is based on the accuracy and precise quantification of tumor variations and complete identification of the potential tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (92, 97))	('variations', 'Var', (98, 108))	('tumor', 'Disease', (154, 159))
173828	28072693	The 3D vector distance change DeltaV% =  (VDIR - VRIR)/VRIR , VDIR and VRIR represent the 3D vector distance between GTVDIR and GTVRTP and GTVRIR and GTVRTP, respectively.	('DeltaV', 'Var', (30, 36))	('VDIR', 'Gene', '6929', (42, 46))	('VDIR', 'Gene', '6929', (62, 66))	('VDIR', 'Gene', (42, 46))	('VDIR', 'Gene', (62, 66))	('VDIR', 'Gene', '6929', (119, 123))	('VDIR', 'Gene', (119, 123))
173833	28072693	However, for displacements of COM in the 3D direction of PET contours at SUV2.5 and SUV20%, DIR resulted in 73.7% (14/19) and 68.4% (13/19) of patients who improved compared with RIR, respectively.	('SUV20%', 'Var', (84, 90))	('improved', 'PosReg', (156, 164))	('patients', 'Species', '9606', (143, 151))
173838	28072693	However, for DSC and displacements of COM in the 3D direction of PET contours at SUV2.5, SUV20%, and manual contours, DIR resulted in the improved volume of a large percentage of patients (73.7%, 68.45%, 63.2%) compared with RIR.	('DSC', 'Disease', (13, 16))	('SUV20%', 'Var', (89, 95))	('improved', 'PosReg', (138, 146))	('volume', 'MPA', (147, 153))	('displacements', 'Var', (21, 34))	('patients', 'Species', '9606', (179, 187))
173851	27086779	Effects of siRNA-Mediated Knockdown of HDAC1 on the Biological Behavior of Esophageal Carcinoma Cell Lines HDAC1 has been shown to be closely associated with the occurrence of tumors.	('HDAC1', 'Gene', '3065', (107, 112))	('Knockdown', 'Var', (26, 35))	('Esophageal Carcinoma Cell', 'Disease', 'MESH:D000077277', (75, 100))	('HDAC1', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Biological', 'MPA', (52, 62))	('HDAC1', 'Gene', '3065', (39, 44))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('Esophageal Carcinoma Cell', 'Disease', (75, 100))	('HDAC1', 'Gene', (107, 112))	('associated', 'Reg', (142, 152))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('Carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (75, 95))
173852	27086779	We aimed to investigate the effects of siRNA-mediated HDAC1 knockdown on the biological behavior of esophageal carcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('esophageal carcinoma', 'Disease', (100, 120))	('HDAC1', 'Gene', (54, 59))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (100, 120))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (100, 120))	('HDAC1', 'Gene', '3065', (54, 59))	('knockdown', 'Var', (60, 69))
173857	27086779	HDAC1 expression in TE-1, Eca109 and EC9706 cells was significantly higher compared with normal esophageal cell line HEEC (P<0.01).	('EC9706', 'Var', (37, 43))	('HDAC1', 'Gene', (0, 5))	('expression', 'MPA', (6, 16))	('higher', 'PosReg', (68, 74))	('HDAC1', 'Gene', '3065', (0, 5))	('HEEC', 'CellLine', 'None', (117, 121))	('EC9706', 'CellLine', 'CVCL:E307', (37, 43))
173859	27086779	After TE-1 cells were transfected with siRNA-HDAC1, their migration and invasion were significantly lower compared with the controls (P<0.01).	('siRNA-HDAC1', 'Gene', (39, 50))	('lower', 'NegReg', (100, 105))	('transfected', 'Var', (22, 33))	('siRNA-HDAC1', 'Gene', '3065', (39, 50))	('invasion', 'CPA', (72, 80))	('migration', 'CPA', (58, 67))
173861	27086779	The siRNA-mediated HDAC1 knockdown significantly inhibited the proliferation, migration and invasion of TE-1 cells probably by regulating the expression of cell cycle- and EMT-related proteins.	('HDAC1', 'Gene', (19, 24))	('invasion of TE-1 cells', 'CPA', (92, 114))	('regulating', 'Reg', (127, 137))	('HDAC1', 'Gene', '3065', (19, 24))	('migration', 'CPA', (78, 87))	('expression', 'MPA', (142, 152))	('inhibited', 'NegReg', (49, 58))	('knockdown', 'Var', (25, 34))
173882	27086779	Functional abnormity of ZO-1 plays an important role in the occurrence and development of a wide range of diseases.	('ZO-1', 'Gene', '7082', (24, 28))	('ZO-1', 'Gene', (24, 28))	('Functional abnormity', 'Var', (0, 20))
173907	27086779	As shown in Figure 1A, HDAC1 expression in cell line TE-1, Eca109 and EC9706 was significantly higher than that in normal esophageal HEEC cells (P <0.01 or 0.05).	('EC9706', 'Var', (70, 76))	('HEEC', 'CellLine', 'None', (133, 137))	('higher', 'PosReg', (95, 101))	('HDAC1', 'Gene', '3065', (23, 28))	('EC9706', 'CellLine', 'CVCL:E307', (70, 76))	('expression', 'MPA', (29, 39))	('HDAC1', 'Gene', (23, 28))
173917	27086779	Numerous studies have confirmed the close association between HDAC1 dysfunction and the development of a variety of tumors.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('dysfunction', 'Var', (68, 79))	('HDAC1', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('HDAC1', 'Gene', '3065', (62, 67))
173920	27086779	Studies have shown that HDACs inhibitors suppress the proliferation of a variety of cancer cells including liver cancer, lung cancer, cervical cancer, prostate cancer, breast cancer, colon cancer, etc.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('cervical cancer', 'Disease', (134, 149))	('cancer', 'Disease', (175, 181))	('breast cancer', 'Disease', (168, 181))	('cervical cancer', 'Disease', 'MESH:D002583', (134, 149))	('liver cancer', 'Disease', 'MESH:D006528', (107, 119))	('cancer', 'Disease', (113, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('proliferation', 'CPA', (54, 67))	('suppress', 'NegReg', (41, 49))	('colon cancer', 'Phenotype', 'HP:0003003', (183, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('HDAC', 'Gene', '9734', (24, 28))	('cancer', 'Disease', (160, 166))	('liver cancer', 'Phenotype', 'HP:0002896', (107, 119))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('liver cancer', 'Disease', (107, 119))	('HDAC', 'Gene', (24, 28))	('colon cancer', 'Disease', 'MESH:D015179', (183, 195))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('inhibitors', 'Var', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('lung cancer', 'Disease', (121, 132))	('prostate cancer', 'Disease', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (189, 195))	('colon cancer', 'Disease', (183, 195))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
173926	27086779	have confirmed the overexpression of HDAC1 in invasive hepatic cancer tissues and significant inhibition of siRNA-mediated HDAC1 knockdown on cell migration.	('overexpression', 'PosReg', (19, 33))	('inhibition', 'NegReg', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('knockdown', 'Var', (129, 138))	('HDAC1', 'Gene', '3065', (37, 42))	('hepatic cancer', 'Phenotype', 'HP:0002896', (55, 69))	('cell migration', 'CPA', (142, 156))	('HDAC1', 'Gene', (123, 128))	('invasive hepatic cancer', 'Disease', (46, 69))	('HDAC1', 'Gene', '3065', (123, 128))	('invasive hepatic cancer', 'Disease', 'MESH:D008113', (46, 69))	('HDAC1', 'Gene', (37, 42))
173936	27086779	have found that HDAC1 and Snail are important for EMT induced by E-cadherin deficiency during the metastasis of pancreatic cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('HDAC1', 'Gene', (16, 21))	('Snail', 'Gene', (26, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('Snail', 'Gene', '6615', (26, 31))	('HDAC1', 'Gene', '3065', (16, 21))	('deficiency', 'Var', (76, 86))	('pancreatic cancer', 'Disease', (112, 129))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('E-cadherin', 'Gene', (65, 75))	('E-cadherin', 'Gene', '999', (65, 75))
173959	26055624	The inclusion criteria are the following: (1) patients with adenocarcinomas located in esophagogastric junction; (2) patients who underwent surgery and exact pathological details can be achieved; (3) patients without distant metastasis; (4) Patients diagnosed after 2004 (those who can get a more accurate pathologic data); and (5) ICD-O-3 code within the range of 8140-8147, 8210-8214, 8220-8221, 8255, 8260-8263, 8310, and 8480-8481.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('8255', 'Var', (398, 402))	('adenocarcinomas', 'Disease', (60, 75))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (200, 208))	('8210-8214', 'Var', (376, 385))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('8260-8263', 'Var', (404, 413))	('Patients', 'Species', '9606', (241, 249))	('8220-8221', 'Var', (387, 396))	('patients', 'Species', '9606', (117, 125))	('8140-8147', 'Var', (365, 374))	('8480-8481', 'Var', (425, 434))	('adenocarcinomas', 'Disease', 'MESH:D000230', (60, 75))	('8310', 'Var', (415, 419))
174006	25355139	The clinical and biological significance of STAT1 in esophageal squamous cell carcinoma Loss of STAT1 (Signal Transducer and Activator of Transcription-1) has been implicated in the pathobiology of a number of cancer types.	('STAT1', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Loss', 'Var', (88, 92))	('STAT1', 'Gene', '6772', (96, 101))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (53, 87))	('implicated', 'Reg', (164, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('STAT1', 'Gene', (44, 49))	('Signal Transducer and Activator of Transcription-1', 'Gene', '6772', (103, 153))	('cancer', 'Disease', (210, 216))	('esophageal squamous cell carcinoma', 'Disease', (53, 87))	('STAT1', 'Gene', '6772', (44, 49))
174011	25355139	In patients carrying tumors of aggressive cytology (n=50), those with STAT1-strong tumors survived significantly longer than those with STAT1-weak/negative tumors (34.6 months versus 20.5 months, p=0.011).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('longer', 'PosReg', (113, 119))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('patients', 'Species', '9606', (3, 11))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('STAT1-strong', 'Var', (70, 82))	('tumors', 'Disease', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
174015	25355139	Loss of STAT1, which is frequent in ESCC, contributes to the pathogenesis of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('STAT1', 'Gene', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Loss', 'Var', (0, 4))	('ESCC', 'Disease', (36, 40))
174025	25355139	In parallel with this observation, it was reported that the EGF-STAT1 signaling pathway, which is active in normal esophageal epithelial cells, is lost in a considerable fraction of esophageal cancer; furthermore, loss of EGF-STAT1 signaling was found to correlate with a worse clinical outcome.	('EGF-STAT1', 'Gene', '1950;6772', (222, 231))	('EGF-STAT1', 'Gene', (60, 69))	('esophageal cancer', 'Disease', (182, 199))	('EGF-STAT1', 'Gene', '1950;6772', (60, 69))	('lost', 'NegReg', (147, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('loss', 'Var', (214, 218))	('EGF-STAT1', 'Gene', (222, 231))
174046	25355139	After STAT1C transfection, 500 cells/well were plated in six-well plates and incubated 10 days at 37 C. The cells were fixed with 4% buffered formalin for 15 min and then stained with 1% crystal violet (Sigma Aldrich) for 30 min.	('STAT1C', 'Gene', '6772', (6, 12))	('STAT1C', 'Gene', (6, 12))	('crystal violet', 'Chemical', 'MESH:D005840', (187, 201))	('transfection', 'Var', (13, 25))	('formalin', 'Chemical', 'MESH:D005557', (142, 150))
174069	25355139	The expression of STAT1 in a cohort of human ESCC cell lines (EC1, EC109, KYSE150 and KYSE510) as well as a cohort of human immortalized esophageal epithelial cell lines (SHEE, NE2, NE3 and NE6) was examined using Western blots.	('STAT1', 'Gene', (18, 23))	('EC1', 'Gene', (62, 65))	('EC1', 'Gene', '4819', (62, 65))	('KYSE510', 'Var', (86, 93))	('EC109', 'CellLine', 'CVCL:6898', (67, 72))	('EC1', 'Gene', '4819', (67, 70))	('EC1', 'Gene', (67, 70))	('human', 'Species', '9606', (118, 123))	('human', 'Species', '9606', (39, 44))
174072	25355139	In the 6 STAT1-positive cell lines, EC1 and KYSE150 expressed STAT1 relatively weakly, whereas KYSE510, NE2, NE3 and NE6 expressed STAT1 relatively strongly.	('STAT1', 'MPA', (62, 67))	('KYSE510', 'Var', (95, 102))	('weakly', 'NegReg', (79, 85))	('KYSE150', 'Var', (44, 51))	('EC1', 'Gene', (36, 39))	('EC1', 'Gene', '4819', (36, 39))
174073	25355139	Except for EC1, all STAT1-positive cell lines expressed p-STAT1, although all of the immortalized cell lines (including NE2, NE3 and NE6) expressed p-STAT1 relatively weakly.	('EC1', 'Gene', (11, 14))	('p-STAT1', 'Var', (56, 63))	('EC1', 'Gene', '4819', (11, 14))
174078	25355139	As shown in Figure 3C and D, STAT1C transfection in EC1 and EC109 cells led to a significant decrease in colony formation and cell invasion, as compared to cells transfected with the empty vector (p < 0.001 and p < 0.05 in both cell lines).	('cell invasion', 'CPA', (126, 139))	('STAT1C', 'Gene', '6772', (29, 35))	('colony formation', 'CPA', (105, 121))	('STAT1C', 'Gene', (29, 35))	('EC1', 'Gene', '4819', (52, 55))	('EC1', 'Gene', (52, 55))	('decrease', 'NegReg', (93, 101))	('EC109', 'CellLine', 'CVCL:6898', (60, 65))	('EC1', 'Gene', (60, 63))	('transfection', 'Var', (36, 48))	('EC1', 'Gene', '4819', (60, 63))
174082	25355139	Specifically, transfection of STAT1C into EC1 and EC109 substantially upregulated p21Waf1, a negative regulator of G1 cell-cycle progression.	('p21', 'Gene', '644914', (82, 85))	('EC1', 'Gene', (42, 45))	('EC1', 'Gene', '4819', (42, 45))	('transfection', 'Var', (14, 26))	('STAT1C', 'Gene', '6772', (30, 36))	('STAT1C', 'Gene', (30, 36))	('upregulated', 'PosReg', (70, 81))	('EC109', 'CellLine', 'CVCL:6898', (50, 55))	('EC1', 'Gene', '4819', (50, 53))	('p21', 'Gene', (82, 85))	('EC1', 'Gene', (50, 53))
174086	25355139	With this experimental system, we found that siRNA knockdown of STAT1 significantly decreased the number of viable cells, which was assessed by using the trypan blue exclusion assay (p < 0.05 for both cell lines) (Figure 5C).	('number of viable cells', 'CPA', (98, 120))	('men', 'Species', '9606', (16, 19))	('trypan blue', 'Chemical', 'MESH:D014343', (154, 165))	('STAT1', 'Gene', (64, 69))	('decreased', 'NegReg', (84, 93))	('knockdown', 'Var', (51, 60))
174090	25355139	In keeping with this concept, we found that transfection of STAT1C into EC1 and EC109 cells resulted in a substantial decrease in the phosphorylation of NF-kappaB p65, a marker of NF-kappaB activation (Figure 6A).	('transfection', 'Var', (44, 56))	('phosphorylation', 'MPA', (134, 149))	('p65', 'Gene', '5970', (163, 166))	('EC109', 'CellLine', 'CVCL:6898', (80, 85))	('EC1', 'Gene', '4819', (80, 83))	('STAT1C', 'Gene', (60, 66))	('EC1', 'Gene', (80, 83))	('EC1', 'Gene', (72, 75))	('decrease', 'NegReg', (118, 126))	('EC1', 'Gene', '4819', (72, 75))	('STAT1C', 'Gene', '6772', (60, 66))	('p65', 'Gene', (163, 166))	('NF-kappaB', 'Gene', '4790', (153, 162))	('NF-kappaB', 'Gene', '4790', (180, 189))	('NF-kappaB', 'Gene', (180, 189))	('NF-kappaB', 'Gene', (153, 162))
174091	25355139	By subcellular fractionation, we also found that STAT1C transfection induced a dramatic decrease in the nuclear localization of NF-kappaB p65 or phospho-NF-kappaB p65 in both cell lines (Figure 6B).	('decrease', 'NegReg', (88, 96))	('p65', 'Gene', '5970', (138, 141))	('NF-kappaB', 'Gene', (128, 137))	('STAT1C', 'Gene', (49, 55))	('p65', 'Gene', '5970', (163, 166))	('p65', 'Gene', (163, 166))	('STAT1C', 'Gene', '6772', (49, 55))	('NF-kappaB', 'Gene', '4790', (128, 137))	('transfection', 'Var', (56, 68))	('p65', 'Gene', (138, 141))	('NF-kappaB', 'Gene', '4790', (153, 162))	('NF-kappaB', 'Gene', (153, 162))	('nuclear localization', 'MPA', (104, 124))
174094	25355139	As shown in Figure 7A, we found that the expression levels for STAT3 and p-STAT3 were decreased 48 hours after STAT1C transfection into EC109 and EC1 cells.	('STAT1C', 'Gene', (111, 117))	('expression levels', 'MPA', (41, 58))	('STAT1C', 'Gene', '6772', (111, 117))	('EC1', 'Gene', '4819', (136, 139))	('EC1', 'Gene', (136, 139))	('EC1', 'Gene', (146, 149))	('decreased', 'NegReg', (86, 95))	('p-STAT3', 'Var', (73, 80))	('EC109', 'CellLine', 'CVCL:6898', (136, 141))	('EC1', 'Gene', '4819', (146, 149))	('transfection', 'Var', (118, 130))
174095	25355139	We then assessed how STAT1C transfection might affect the physical interaction between STAT1 and STAT3 using co-immunoprecipitation.	('physical interaction', 'Interaction', (58, 78))	('STAT1C', 'Gene', '6772', (21, 27))	('transfection', 'Var', (28, 40))	('affect', 'Reg', (47, 53))	('STAT1C', 'Gene', (21, 27))
174096	25355139	As shown in Figure 7C (right panel), by Western blots, transfection of STAT1C again resulted in 30-40% reduction in the expression of STAT3.	('expression', 'MPA', (120, 130))	('STAT1C', 'Gene', (71, 77))	('transfection', 'Var', (55, 67))	('STAT3', 'Gene', (134, 139))	('STAT1C', 'Gene', '6772', (71, 77))	('reduction', 'NegReg', (103, 112))
174097	25355139	Co-immunoprecipitation studies (left panel) showed that transfection of STAT1C substantially increased the STAT3-STAT1 binding in both EC1 and EC109 cells.	('STAT1C', 'Gene', (72, 78))	('EC1', 'Gene', '4819', (143, 146))	('EC109', 'CellLine', 'CVCL:6898', (143, 148))	('EC1', 'Gene', (143, 146))	('STAT1C', 'Gene', '6772', (72, 78))	('increased', 'PosReg', (93, 102))	('STAT3-STAT1', 'MPA', (107, 118))	('EC1', 'Gene', '4819', (135, 138))	('transfection', 'Var', (56, 68))	('EC1', 'Gene', (135, 138))
174100	25355139	Decreased or loss of STAT1 expression has been observed in many cancer types such as breast cancer, melanoma and leukemia; transfection of STAT1 or STAT1C into cancer cells can arrest their growth by inducing apoptosis and cell-cycle arrest.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('STAT1C', 'Gene', (148, 154))	('STAT1C', 'Gene', '6772', (148, 154))	('arrest', 'PosReg', (177, 183))	('cancer', 'Disease', (160, 166))	('inducing', 'PosReg', (200, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Disease', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('cancer', 'Disease', (92, 98))	('breast cancer', 'Disease', (85, 98))	('apoptosis', 'CPA', (209, 218))	('transfection', 'Var', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('leukemia', 'Phenotype', 'HP:0001909', (113, 121))	('growth', 'MPA', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('STAT1', 'Gene', (139, 144))	('cell-cycle arrest', 'CPA', (223, 240))	('melanoma and leukemia', 'Disease', 'MESH:D008545', (100, 121))
174111	25355139	Specifically, we found that transfection of STAT1C into ESCC induced apoptosis and cell-cycle arrest, with the effect on apoptosis being more pronounced than that on cell proliferation (Figures 3 and 4).	('transfection', 'Var', (28, 40))	('STAT1C', 'Gene', (44, 50))	('apoptosis', 'CPA', (69, 78))	('cell-cycle arrest', 'CPA', (83, 100))	('STAT1C', 'Gene', '6772', (44, 50))
174115	25355139	Thus, gene transfection of STAT1C in fibrosarcoma cell lines was found to induce caspase activation and caspase-dependent apoptosis.	('induce', 'PosReg', (74, 80))	('STAT1C', 'Gene', (27, 33))	('STAT1C', 'Gene', '6772', (27, 33))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (37, 49))	('caspase-dependent apoptosis', 'CPA', (104, 131))	('fibrosarcoma', 'Disease', 'MESH:D005354', (37, 49))	('caspase', 'CPA', (81, 88))	('activation', 'PosReg', (89, 99))	('gene transfection', 'Var', (6, 23))	('fibrosarcoma', 'Disease', (37, 49))
174116	25355139	As we found that STAT1C-induced apoptosis in ESCC correlates with the down-regulation of several pro-survival proteins such as BCL-2 and BCL-xL, previous studies also have shown that STAT1 can promote apoptosis by down-regulating BCL-2 and BCL-xL in multiple myelomas.	('promote', 'PosReg', (193, 200))	('BCL-xL', 'Gene', '598', (137, 143))	('BCL-xL', 'Gene', '598', (240, 246))	('multiple myeloma', 'Phenotype', 'HP:0006775', (250, 266))	('multiple myelomas', 'Phenotype', 'HP:0006775', (250, 267))	('down-regulation', 'NegReg', (70, 85))	('BCL-2', 'Gene', '596', (230, 235))	('BCL-xL', 'Gene', (137, 143))	('BCL-xL', 'Gene', (240, 246))	('BCL-2', 'Gene', (230, 235))	('myelomas', 'Disease', 'MESH:D009101', (259, 267))	('apoptosis', 'CPA', (201, 210))	('STAT1C', 'Gene', '6772', (17, 23))	('STAT1C', 'Gene', (17, 23))	('STAT1', 'Var', (183, 188))	('BCL-2', 'Gene', '596', (127, 132))	('down-regulating', 'NegReg', (214, 229))	('BCL-2', 'Gene', (127, 132))	('myelomas', 'Disease', (259, 267))
174120	25355139	Thus, down-regulation of cyclin D1 induced by STAT1 may partly explain our observation that high STAT1 expression in ESCC is associated with a better clinical outcome.	('high', 'Var', (92, 96))	('cyclin D1', 'Gene', '595', (25, 34))	('expression', 'MPA', (103, 113))	('STAT1', 'Gene', (97, 102))	('ESCC', 'Disease', (117, 121))	('down-regulation', 'NegReg', (6, 21))	('cyclin D1', 'Gene', (25, 34))
174125	25355139	Our findings that modulation of STAT1 expression changed the expression level of phospho-p65, as well as the nuclear localization of p65/phospho-p65, and these findings support the concept that the STAT1 inhibits the growth of ESCC via its suppression of NF-kappaB signaling.	('growth', 'CPA', (217, 223))	('suppression', 'NegReg', (240, 251))	('changed', 'Reg', (49, 56))	('p65', 'Gene', '5970', (145, 148))	('p65', 'Gene', (133, 136))	('p65', 'Gene', (89, 92))	('modulation', 'Var', (18, 28))	('STAT1', 'Var', (198, 203))	('NF-kappaB', 'Gene', '4790', (255, 264))	('nuclear localization', 'MPA', (109, 129))	('p65', 'Gene', '5970', (133, 136))	('inhibits', 'NegReg', (204, 212))	('p65', 'Gene', (145, 148))	('expression level', 'MPA', (61, 77))	('NF-kappaB', 'Gene', (255, 264))	('STAT1', 'Gene', (32, 37))	('p65', 'Gene', '5970', (89, 92))	('ESCC', 'Disease', (227, 231))
174127	25355139	In contrast with STAT1, STAT3 promotes survival, proliferation and motility of cancer cells, and induces immune tolerance.	('survival', 'CPA', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('promotes', 'PosReg', (30, 38))	('proliferation', 'CPA', (49, 62))	('immune tolerance', 'CPA', (105, 121))	('induces', 'PosReg', (97, 104))	('motility', 'CPA', (67, 75))	('STAT3', 'Var', (24, 29))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
174174	21254737	Genetic mutation in alcohol-dehydrogenase 1B (ADH1B) and aldehyd dehydrogenase-2 (ALDH-2), involved in the metabolism of alcohol can result in the development of hypopharynx neoplasia.	('alcohol-dehydrogenase 1B', 'Gene', '125', (20, 44))	('Genetic mutation', 'Var', (0, 16))	('neoplasia', 'Phenotype', 'HP:0002664', (174, 183))	('ADH1B', 'Gene', '125', (46, 51))	('result in', 'Reg', (133, 142))	('hypopharynx neoplasia', 'Disease', (162, 183))	('ALDH-2', 'Gene', '217', (82, 88))	('alcohol-dehydrogenase 1B', 'Gene', (20, 44))	('ALDH-2', 'Gene', (82, 88))	('hypopharynx neoplasia', 'Phenotype', 'HP:0100638', (162, 183))	('ADH1B', 'Gene', (46, 51))
174194	21254737	Genetic polymorphism of enzymes involved in alcohol metabolism (ADH1B, ALDH2) is incriminated in carcinogenic process in hypopharynx.	('carcinogenic process in hypopharynx', 'Disease', (97, 132))	('ALDH2', 'Gene', (71, 76))	('ADH1B', 'Gene', (64, 69))	('carcinogenic process in hypopharynx', 'Disease', 'MESH:D009385', (97, 132))	('Genetic polymorphism', 'Var', (0, 20))	('ALDH2', 'Gene', '217', (71, 76))
174195	21254737	Suppressive  gene p53 mutation has been detected in adenocarcinoma, epidermoid carcinoma and esophageal displasia.	('esophageal displasia', 'Disease', (93, 113))	('p53', 'Gene', (18, 21))	('epidermoid carcinoma', 'Disease', (68, 88))	('mutation', 'Var', (22, 30))	('p53', 'Gene', '7157', (18, 21))	('esophageal displasia', 'Disease', 'MESH:D004941', (93, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('detected', 'Reg', (40, 48))	('adenocarcinoma', 'Disease', (52, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('epidermoid carcinoma', 'Disease', 'MESH:D002294', (68, 88))
174214	31877535	Dysregulation of circRNAs has been reported in many GI cancers and are involved in metastasis and invasion.	('GI cancers', 'Disease', 'MESH:D009369', (52, 62))	('involved', 'Reg', (71, 79))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('reported', 'Reg', (35, 43))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cir', 'Gene', (17, 20))	('GI cancers', 'Disease', (52, 62))	('cir', 'Gene', '9541', (17, 20))	('GI cancer', 'Phenotype', 'HP:0007378', (52, 61))
174220	31877535	Genetic factors such as, APC mutation predisposing to familial adenomatous polyposis, and mutations in E-cadherin leading to hereditary diffuse-type gastric cancer are known risk factors for GI development, but the exact molecular mechanisms underlying the progression and malignancy of other GI cancers remain largely unknown.	('leading to', 'Reg', (114, 124))	('mutation', 'Var', (29, 37))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('GI cancer', 'Phenotype', 'HP:0007378', (293, 302))	('men', 'Species', '9606', (201, 204))	('malignancy of other GI cancers', 'Disease', (273, 303))	('GI', 'Gene', '2770', (191, 193))	('gastric cancer', 'Disease', (149, 163))	('GI', 'Gene', '2770', (293, 295))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (63, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('E-cadherin', 'Gene', (103, 113))	('E-cadherin', 'Gene', '999', (103, 113))	('malignancy of other GI cancers', 'Disease', 'MESH:D009369', (273, 303))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('familial adenomatous polyposis', 'Disease', (54, 84))	('APC', 'Disease', 'MESH:D011125', (25, 28))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (54, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('APC', 'Disease', (25, 28))	('cancers', 'Phenotype', 'HP:0002664', (296, 303))
174248	31877535	More recently, several studies have reported that dysfunction or dysregulation of circRNAs could be associated with the development of human diseases including Alzheimer's and cancer.	('cir', 'Gene', (82, 85))	('associated', 'Reg', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('dysfunction', 'Disease', (50, 61))	('dysregulation', 'Var', (65, 78))	('dysfunction', 'Disease', 'MESH:D009461', (50, 61))	('human', 'Species', '9606', (135, 140))	('Alzheimer', 'Disease', (160, 169))	('cir', 'Gene', '9541', (82, 85))	("Alzheimer's", 'Disease', 'MESH:D000544', (160, 171))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('men', 'Species', '9606', (127, 130))
174292	31877535	The aberrant expression of circRNAs has been linked to many human diseases including cancer.	('linked', 'Reg', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('aberrant expression', 'Var', (4, 23))	('cancer', 'Disease', (85, 91))	('cir', 'Gene', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cir', 'Gene', '9541', (27, 30))	('human', 'Species', '9606', (60, 65))
174327	31877535	Pleckstrin homology-like domain family A member 1 (PHLDA1) overexpression, a direct target of miR-101, decreased the growth and migration of GC cells.	('miR-101', 'Chemical', '-', (94, 101))	('Pleckstrin homology-like domain family A member 1', 'Gene', (0, 49))	('PHLDA1', 'Gene', '22822', (51, 57))	('miR-101', 'Var', (94, 101))	('decreased', 'NegReg', (103, 112))	('overexpression', 'PosReg', (59, 73))	('Pleckstrin homology-like domain family A member 1', 'Gene', '22822', (0, 49))	('PHLDA1', 'Gene', (51, 57))
174351	31877535	In-vitro experiments showed that proliferation, migration, and invasion of GC cells were considerably suppressed by knockdown of hsa_circ_0000467.	('migration', 'CPA', (48, 57))	('cir', 'Gene', (133, 136))	('suppressed', 'NegReg', (102, 112))	('knockdown', 'Var', (116, 125))	('men', 'Species', '9606', (15, 18))	('hsa', 'Gene', '213', (129, 132))	('cir', 'Gene', '9541', (133, 136))	('hsa', 'Gene', (129, 132))	('invasion of GC cells', 'CPA', (63, 83))
174352	31877535	In addition, hsa_circ_0000467 silencing resulted in increased tumor cell apoptosis in-vitro.	('increased', 'PosReg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('cir', 'Gene', (17, 20))	('hsa', 'Gene', '213', (13, 16))	('hsa', 'Gene', (13, 16))	('silencing', 'Var', (30, 39))	('cir', 'Gene', '9541', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
174358	31877535	Most of the hereditary forms of CRC are caused by mutations in genes, including EPCAM,PMS2, MSH6, MSH2or MLH involved in DNA mismatch-repair system, and the adenomatous polyposis coli (APC) gene which handles the Wnt signaling pathway).	('MSH2', 'Gene', (98, 102))	('MLH', 'Gene', (105, 108))	('MSH2', 'Gene', '4436', (98, 102))	('CRC', 'Disease', (32, 35))	('mutations', 'Var', (50, 59))	('EPCAM', 'Gene', '4072', (80, 85))	('caused by', 'Reg', (40, 49))	('APC', 'Disease', 'MESH:D011125', (185, 188))	('PMS2', 'Gene', (86, 90))	('MSH6', 'Gene', (92, 96))	('adenomatous polyposis coli', 'Gene', '324', (157, 183))	('adenomatous polyposis coli', 'Gene', (157, 183))	('PMS2', 'Gene', '5395', (86, 90))	('APC', 'Disease', (185, 188))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (157, 183))	('EPCAM', 'Gene', (80, 85))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (157, 178))	('MSH6', 'Gene', '2956', (92, 96))
174359	31877535	Of note, polyposis is related to mutations in the mutY DNA glycosylase (MUTYH) gene.	('related', 'Reg', (22, 29))	('mutY DNA glycosylase', 'Gene', (50, 70))	('mutY DNA glycosylase', 'Gene', '4595', (50, 70))	('polyposis', 'Disease', 'MESH:D044483', (9, 18))	('mutations', 'Var', (33, 42))	('MUTYH', 'Gene', (72, 77))	('polyposis', 'Disease', (9, 18))	('MUTYH', 'Gene', '4595', (72, 77))
174361	31877535	As its name suggests the deletion of the DCC gene in CRC had been known for more than two decades.	('DCC', 'Gene', (41, 44))	('deletion', 'Var', (25, 33))	('DCC', 'Gene', '1630', (41, 44))
174367	31877535	CircRNA sequencing data in two CRC cell lines,SW620(a metastasis-derived cell line)and SW480 (a primary tumor cell line), and abnormal colorectal cell, NCM460,showed an overall circRNA abundance decreasein CRC cell lines in comparison to normal colonic epithelial cells.	('SW480', 'Var', (87, 92))	('abnormal colorectal cell', 'Disease', 'MESH:D015179', (126, 150))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cir', 'Gene', '9541', (177, 180))	('tumor', 'Disease', (104, 109))	('decreasein', 'NegReg', (195, 205))	('SW480', 'CellLine', 'CVCL:0546', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('Cir', 'Gene', '9541', (0, 3))	('SW620', 'CellLine', 'CVCL:0547', (46, 51))	('Cir', 'Gene', (0, 3))	('abnormal colorectal cell', 'Disease', (126, 150))	('cir', 'Gene', (177, 180))
174370	31877535	Circ-BANP was up-regulated in 35 CRC samples and its knockdown attenuated the proliferation of CRC cells.	('up-regulated', 'PosReg', (14, 26))	('attenuated', 'NegReg', (63, 73))	('proliferation of CRC cells', 'CPA', (78, 104))	('knockdown', 'Var', (53, 62))	('BANP', 'Gene', '54971', (5, 9))	('Cir', 'Gene', '9541', (0, 3))	('BANP', 'Gene', (5, 9))	('Cir', 'Gene', (0, 3))
174387	31877535	CircCCDC66 could function as an oncogene and its knockdown significantly reduced cell migration and metastasis.	('CircCCDC66', 'Gene', (0, 10))	('CircCCDC66', 'Gene', '285331', (0, 10))	('reduced', 'NegReg', (73, 80))	('knockdown', 'Var', (49, 58))
174410	31877535	The AUCs of hsa_circ_0001946 and hsa_circ_0062459 respectively were 0.894 (sensitivity=92%, specificity=80%) and 0.836 (sensitivity=64%, specificity=92%) respectively.	('0.836', 'Var', (113, 118))	('hsa', 'Gene', (12, 15))	('cir', 'Gene', (37, 40))	('hsa', 'Gene', '213', (12, 15))	('cir', 'Gene', '9541', (16, 19))	('hsa', 'Gene', '213', (33, 36))	('hsa', 'Gene', (33, 36))	('0.894', 'Var', (68, 73))	('cir', 'Gene', '9541', (37, 40))	('cir', 'Gene', (16, 19))
174438	31877535	Bioinformatics analysis suggested that circ-TTC17 could play a role in ESCC by sponging microRNAs such as miR-153, -217, -224, and -370.	('TTC17', 'Gene', '55761', (44, 49))	('cir', 'Gene', (39, 42))	('ESCC', 'Disease', (71, 75))	('cir', 'Gene', '9541', (39, 42))	('miR-153', 'Var', (106, 113))	('TTC17', 'Gene', (44, 49))
174447	31877535	In vivo experiments showed that circ0043898 was associated with inhibition of oncogenesis.	('men', 'Species', '9606', (14, 17))	('oncogenesis', 'CPA', (78, 89))	('circ0043898', 'Chemical', '-', (32, 43))	('circ0043898', 'Var', (32, 43))	('inhibition', 'NegReg', (64, 74))
174449	31877535	Evaluation of circRNAs found significant up-regulation of 57 circRNAs and down-regulation of 17 circRNAs in KYSE-150R, a radioresistant EC cell line, compared with the radiosensitive KYSE-150.	('cir', 'Gene', '9541', (14, 17))	('cir', 'Gene', '9541', (96, 99))	('cir', 'Gene', (61, 64))	('down-regulation', 'NegReg', (74, 89))	('cir', 'Gene', (96, 99))	('cir', 'Gene', '9541', (61, 64))	('KYSE-150R', 'Var', (108, 117))	('cir', 'Gene', (14, 17))	('up-regulation', 'PosReg', (41, 54))
174475	31877535	MiR-9 was found to bind tocircMTO1, and circMTO1 silencing in HCC cells could down-modulate p21, the oncogenic miR-9 target, leading to HCC invasion and proliferation promotion.	('p21', 'Gene', '644914', (92, 95))	('silencing', 'Var', (49, 58))	('HCC', 'Gene', (136, 139))	('HCC', 'Gene', (62, 65))	('cir', 'Gene', (26, 29))	('cir', 'Gene', (40, 43))	('cir', 'Gene', '9541', (40, 43))	('cir', 'Gene', '9541', (26, 29))	('proliferation promotion', 'CPA', (153, 176))	('HCC', 'Gene', '619501', (136, 139))	('HCC', 'Gene', '619501', (62, 65))	('down-modulate', 'NegReg', (78, 91))	('p21', 'Gene', (92, 95))
174488	31877535	MAPK14 may facilitate tumor cells proliferation and survival, and contribute to the progression of some tumor types.Yu et al reported that hsa-circ-104718 was physically associated and co-expressed with microRNA-218-5p in HCC.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('hsa', 'Gene', (139, 142))	('MAPK14', 'Gene', (0, 6))	('tumor', 'Disease', (104, 109))	('microRNA-218-5p', 'Var', (203, 218))	('hsa', 'Gene', '213', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cir', 'Gene', (143, 146))	('HCC', 'Gene', '619501', (222, 225))	('MAPK14', 'Gene', '1432', (0, 6))	('tumor', 'Disease', (22, 27))	('cir', 'Gene', '9541', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('HCC', 'Gene', (222, 225))
174491	31877535	Conversely, miR-218-5p over-expression could decrease the proliferation, migration, invasion, and increase apoptosis.	('migration', 'CPA', (73, 82))	('invasion', 'CPA', (84, 92))	('miR-218-5p', 'Var', (12, 22))	('increase', 'PosReg', (98, 106))	('decrease', 'NegReg', (45, 53))	('apoptosis', 'CPA', (107, 116))	('over-expression', 'PosReg', (23, 38))	('miR-218-5p', 'Chemical', '-', (12, 22))
174501	31877535	Silencing of circHIPK3 using siRNA, induced apoptosis and suppressed proliferation and survival of both primary and established human GBC cells.	('induced', 'Reg', (36, 43))	('proliferation', 'CPA', (69, 82))	('apoptosis', 'CPA', (44, 53))	('suppressed', 'NegReg', (58, 68))	('survival', 'CPA', (87, 95))	('human', 'Species', '9606', (128, 133))	('circHIPK3', 'Gene', '10114', (13, 22))	('Silencing', 'Var', (0, 9))	('circHIPK3', 'Gene', (13, 22))
174514	31877535	Bioinformatics analysis predicted that hsa_circ_0005785 (one of the differentially expressed circRNAs) was potentially able to bind miR-181a and miR-181b.	('miR-181a', 'Var', (132, 140))	('cir', 'Gene', '9541', (93, 96))	('cir', 'Gene', (43, 46))	('hsa', 'Gene', '213', (39, 42))	('hsa', 'Gene', (39, 42))	('bind', 'Interaction', (127, 131))	('cir', 'Gene', '9541', (43, 46))	('miR-181b', 'Var', (145, 153))	('cir', 'Gene', (93, 96))	('able', 'Reg', (119, 123))
174534	31877535	Moreover, circRHOT1 knockdown could inhibit pancreatic cancer cell proliferation, invasion and migration.	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('circRHOT1', 'Gene', (10, 19))	('circRHOT1', 'Gene', '55288', (10, 19))	('inhibit', 'NegReg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('knockdown', 'Var', (20, 29))	('pancreatic cancer', 'Disease', (44, 61))
174562	31755241	Similarly, patients with high expression of nuclear Nrf2 exhibited lower ORR compared to those with low expression of nuclear Nrf2.	('Nrf2', 'Gene', '4780', (126, 130))	('Nrf2', 'Gene', '4780', (52, 56))	('Nrf2', 'Gene', (126, 130))	('high expression', 'Var', (25, 40))	('ORR', 'MPA', (73, 76))	('Nrf2', 'Gene', (52, 56))	('patients', 'Species', '9606', (11, 19))	('lower', 'NegReg', (67, 72))	('S', 'Chemical', 'MESH:D013455', (0, 1))
174617	31755241	In addition, the number of cases with low Nrf2 expression [Nrf2(-)] and high Nrf2 expression [Nrf2(+)] was 73(44.5%) and 91(55.5%) respectively.	('Nrf2', 'Gene', '4780', (42, 46))	('Nrf2', 'Gene', '4780', (59, 63))	('expression', 'MPA', (82, 92))	('Nrf2', 'Gene', (77, 81))	('Nrf2', 'Gene', '4780', (77, 81))	('expression', 'MPA', (47, 57))	('Nrf2', 'Gene', '4780', (94, 98))	('Nrf2', 'Gene', (59, 63))	('low', 'NegReg', (38, 41))	('Nrf2', 'Gene', (42, 46))	('Nrf2', 'Gene', (94, 98))	('high', 'Var', (72, 76))
174624	31755241	Similarly, patients with high nuclear Nrf2 expression were associated with a poorer response compared to patients with low expression (83.6% vs. 56.0%, P < 0.001) (Table 3).	('Nrf2', 'Gene', '4780', (38, 42))	('patients', 'Species', '9606', (105, 113))	('Nrf2', 'Gene', (38, 42))	('high', 'Var', (25, 29))	('patients', 'Species', '9606', (11, 19))	('expression', 'MPA', (43, 53))	('poorer', 'NegReg', (77, 83))	('S', 'Chemical', 'MESH:D013455', (0, 1))
174629	31755241	Similarly, high nuclear Nrf2 expression was also associated with poorer long-term survival.	('Nrf2', 'Gene', '4780', (24, 28))	('poorer', 'NegReg', (65, 71))	('Nrf2', 'Gene', (24, 28))	('long-term survival', 'CPA', (72, 90))	('high', 'Var', (11, 15))	('expression', 'MPA', (29, 39))	('S', 'Chemical', 'MESH:D013455', (0, 1))
174647	31755241	ROS induced by radiotherapy could lead to the damage of DNA4 and the oxidation of biomacromolecules such as protein and lipid,5, 6 which mediates the anti-tumor effects of radiotherapy.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('ROS', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('DNA4', 'Protein', (56, 60))	('S', 'Chemical', 'MESH:D013455', (2, 3))	('lead to', 'Reg', (34, 41))	('oxidation of biomacromolecules', 'MPA', (69, 99))	('damage', 'MPA', (46, 52))
174653	31755241	Previous studies related to aberrant activation of Nrf2 mainly focused on the mutation of the NFE2L2 gene, especially in ESCC.	('NFE2L2', 'Gene', (94, 100))	('mutation', 'Var', (78, 86))	('Nrf2', 'Gene', '4780', (51, 55))	('ESCC', 'Disease', 'MESH:C562729', (121, 125))	('NFE2L2', 'Gene', '4780', (94, 100))	('Nrf2', 'Gene', (51, 55))	('ESCC', 'Disease', (121, 125))
174655	31755241	The mutant loci often locate in the regions affecting the binding of Nrf2 to Keap1, which means the mutation of NFE2L2 gene usually decreases the binding affinity between Nrf2 and Keap1 and leads to the constant activation of Nrf2.29, 31, 38 In our study, the tumor tissue samples were collected by esophageal endoscopy and the gene sequencing was not applied due to the limited volume of tissue.	('tumor', 'Disease', (260, 265))	('Nrf2', 'Gene', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('Nrf2', 'Gene', (171, 175))	('Keap1', 'Gene', '9817', (180, 185))	('Keap1', 'Gene', '9817', (77, 82))	('binding affinity', 'Interaction', (146, 162))	('Keap1', 'Gene', (180, 185))	('decreases', 'NegReg', (132, 141))	('leads to', 'Reg', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('NFE2L2', 'Gene', '4780', (112, 118))	('Keap1', 'Gene', (77, 82))	('Nrf2', 'Gene', '4780', (69, 73))	('Nrf2', 'Gene', '4780', (226, 230))	('Nrf2', 'Gene', '4780', (171, 175))	('NFE2L2', 'Gene', (112, 118))	('mutation', 'Var', (100, 108))	('Nrf2', 'Gene', (69, 73))	('activation', 'PosReg', (212, 222))
174662	31755241	Moreover, the high expression of p62 indicates a poor prognosis.21, 22, 39, 40, 41 Therapy targeted p62 gene inhibit the proliferation of hepatocellular carcinoma in vivo and in vitro.19 The over aggregation of p62 is considered as one of reasons for renal cell carcinoma.42 In addition, the elevated expression of p62 induced by constant activation of K-Ras leads to pancreatic ductal adenocarcinoma.43 In contrast, knockdown of p62 gene inhibits pulmonary adenocarcinoma induced by Ras.44 More importantly, recent studies have proved that besides the phosphorylation of p62 by mTORC1, the aggregation of p62 also leads to its self-phosphorylation at S349 and constant activation of Nrf2.19 This promotes the growth of tumors19 and leads to antitumor agent tolerance.24 We speculate that blockage of p62-Keap1-Nrf2 pathway could not only increase the radiosensitivity of ESCC, but also bring long-term benefits.	('p62', 'Gene', (572, 575))	('tumor', 'Phenotype', 'HP:0002664', (746, 751))	('Nrf2', 'Gene', '4780', (684, 688))	('radiosensitivity', 'CPA', (852, 868))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (720, 725))	('p62', 'Gene', '8878', (801, 804))	('carcinoma', 'Phenotype', 'HP:0030731', (463, 472))	('Nrf2', 'Gene', '4780', (811, 815))	('K-Ras', 'Gene', (353, 358))	('p62', 'Gene', (801, 804))	('p62', 'Gene', '8878', (315, 318))	('benefits', 'PosReg', (903, 911))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('p62', 'Gene', (315, 318))	('pancreatic ductal adenocarcinoma', 'Disease', (368, 400))	('tumors', 'Phenotype', 'HP:0002664', (720, 726))	('p62', 'Gene', '8878', (100, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (138, 162))	('p62', 'Gene', (100, 103))	('increase', 'PosReg', (839, 847))	('Keap1', 'Gene', '9817', (805, 810))	('Nrf2', 'Gene', (684, 688))	('tumor', 'Phenotype', 'HP:0002664', (720, 725))	('p62', 'Gene', (211, 214))	('p62', 'Gene', '8878', (211, 214))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (448, 472))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (368, 400))	('Nrf2', 'Gene', (811, 815))	('tumors', 'Disease', (720, 726))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (138, 162))	('ESCC', 'Disease', 'MESH:C562729', (872, 876))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (448, 472))	('tumor', 'Disease', (746, 751))	('K-Ras', 'Gene', '3845', (353, 358))	('Keap1', 'Gene', (805, 810))	('p62', 'Gene', '8878', (606, 609))	('mTORC1', 'Gene', (579, 585))	('p62', 'Gene', (606, 609))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (251, 271))	('S', 'Chemical', 'MESH:D013455', (873, 874))	('pulmonary adenocarcinoma', 'Disease', (448, 472))	('blockage', 'Var', (789, 797))	('tumor', 'Disease', 'MESH:D009369', (746, 751))	('S', 'Chemical', 'MESH:D013455', (652, 653))	('tumors', 'Disease', 'MESH:D009369', (720, 726))	('mTORC1', 'Gene', '382056', (579, 585))	('p62', 'Gene', '8878', (430, 433))	('p62', 'Gene', (430, 433))	('hepatocellular carcinoma', 'Disease', (138, 162))	('ESCC', 'Disease', (872, 876))	('carcinoma', 'Phenotype', 'HP:0030731', (391, 400))	('renal cell carcinoma', 'Disease', (251, 271))	('p62', 'Gene', '8878', (33, 36))	('tumor', 'Disease', (720, 725))	('p62', 'Gene', '8878', (572, 575))	('p62', 'Gene', (33, 36))
174679	31329575	Accumulative evidences have revealed that miRNAs usually negatively regulate gene expression and they play critical roles in various biological processes such as cell proliferation, differentiation, aging and death.	('gene expression', 'MPA', (77, 92))	('regulate', 'Reg', (68, 76))	('death', 'Disease', 'MESH:D003643', (209, 214))	('roles', 'Reg', (116, 121))	('aging', 'CPA', (199, 204))	('cell proliferation', 'CPA', (162, 180))	('death', 'Disease', (209, 214))	('play', 'Reg', (102, 106))	('negatively', 'NegReg', (57, 67))	('miRNAs', 'Var', (42, 48))	('differentiation', 'CPA', (182, 197))
174683	31329575	Besides, deregulation of a set of miRNAs including mir-150, mir-550, mir-124a, mir-518b and mir-539 was shown to be associated with transformation of gastritis into extranodal marginal zone lymphoma.	('mir-518b', 'Gene', '574474', (79, 87))	('gastritis', 'Disease', 'MESH:D005756', (150, 159))	('mir-150', 'Gene', '406942', (51, 58))	('mir-550', 'Var', (60, 67))	('gastritis', 'Phenotype', 'HP:0005263', (150, 159))	('mir-518b', 'Gene', (79, 87))	('lymphoma', 'Disease', 'MESH:D008223', (190, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('mir-150', 'Gene', (51, 58))	('mir-124a', 'Gene', '406907', (69, 77))	('gastritis', 'Disease', (150, 159))	('deregulation', 'Var', (9, 21))	('mir-539', 'Gene', '664612', (92, 99))	('mir-539', 'Gene', (92, 99))	('lymphoma', 'Disease', (190, 198))	('mir-124a', 'Gene', (69, 77))	('associated', 'Reg', (116, 126))
174740	31329575	EDTMDA, LRSSLMDA, PBMDA, MDHGI, HGIMDA, MCMDA, MaxFlow, RLSMDA, HDMP and WBSMDA obtained AUC of 0.9309, 0.9178, 0.9169, 0.8945, 0.8781, 0.8749, 0.8624, 0.8426, 0.8366 and 0.8030 in global LOOCV, respectively; they obtained 0.8524, 0.8418, 0.8341, 0.8240, 0.8077, 0.7718, 0,7774 0.6953, 0.7702 and 0.8031 in global LOOCV, respectively.	('0.8341', 'Var', (239, 245))	('0.7718', 'Var', (263, 269))	('0.8240', 'Var', (247, 253))	('WBSMDA', 'Chemical', '-', (73, 79))	('EDTMDA', 'Chemical', '-', (0, 6))	('PBMDA', 'Chemical', '-', (18, 23))	('0.7702', 'Var', (286, 292))	('HDMP', 'Chemical', '-', (64, 68))	('0.8031', 'Var', (297, 303))	('0.8418', 'Var', (231, 237))	('0.8077', 'Var', (255, 261))
174763	31329575	Moreover, according to the study, the expression of miRNA-382-5p notably increased and miRNA-133a-3p notably decreased in esophageal adenocarcinoma (EAC).	('decreased', 'NegReg', (109, 118))	('increased', 'PosReg', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('miRNA-382-5p', 'Var', (52, 64))	('expression', 'MPA', (38, 48))	('esophageal adenocarcinoma', 'Disease', (122, 147))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (122, 147))	('miRNA-133a-3p', 'Var', (87, 100))	('EAC', 'Phenotype', 'HP:0011459', (149, 152))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (122, 147))
174782	31329575	The AUC of three cross validations including global LOOCV, local LOOCV and 5-fold CV were 0.4939, 0.4413 and 0.5005+/-0.0029 respectively, which indicated that EDTMDA effectively avoided overfitting.	('0.5005+/-0.0029', 'Var', (109, 124))	('EDTMDA', 'Chemical', '-', (160, 166))	('0.4413', 'Var', (98, 104))
174803	30486628	A meta analysis suggested that a higher intake of carotenoids (beta-carotene, alpha- carotene, lycopene, beta-cryptoxanthin, lutein, and zeaxanthin) is associated with lower risk of esophageal cancer (Xiao-Xiao et al., 2013).	('lycopene', 'Chemical', 'MESH:D000077276', (95, 103))	('esophageal cancer', 'Disease', (182, 199))	('lower', 'NegReg', (168, 173))	('beta-cryptoxanthin', 'Chemical', 'MESH:D000072743', (105, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('beta-cryptoxanthin', 'Var', (105, 123))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carotenoids', 'Chemical', 'MESH:D002338', (50, 61))	('beta-carotene', 'Chemical', 'MESH:D019207', (63, 76))	('alpha- carotene', 'Chemical', 'MESH:C041635', (78, 93))
174829	30486628	A significant reduction in DNA synthesis was observed with 5 microM alpha-carotene, beta-carotene, or alpha- plus beta-carotene (P<0.05).	('beta-carotene', 'Chemical', 'MESH:D019207', (114, 127))	('beta-carotene', 'Chemical', 'MESH:D019207', (84, 97))	('reduction', 'NegReg', (14, 23))	('DNA synthesis', 'MPA', (27, 40))	('alpha-carotene', 'Chemical', 'MESH:C041635', (68, 82))	('alpha- plus beta-carotene', 'Var', (102, 127))	('alpha- plus beta-carotene', 'Chemical', '-', (102, 127))
174834	30486628	A significant decrease in HESC cell DNA synthesis was observed with a low concentration of 5microM alpha-carotene (P = 0.024) and 10microM beta-carotene (P = 0.007).	('beta-carotene', 'Chemical', 'MESH:D019207', (139, 152))	('HESC cell DNA synthesis', 'MPA', (26, 49))	('alpha-carotene', 'Chemical', 'MESH:C041635', (99, 113))	('decrease', 'NegReg', (14, 22))	('HESC', 'CellLine', 'CVCL:C777', (26, 30))	('10microM', 'Var', (130, 138))
174855	30486628	Considering the significant inhibition of cellular proliferation of human esophageal cancer cells by a-carotene at a lower concentration, additional studies are needed to elucidate the role of alpha-carotenoids as prophylactic as well as therapeutic agents in esophageal carcinogenesis in human trials and animal studies.	('esophageal carcinogenesis', 'Disease', (260, 285))	('human', 'Species', '9606', (68, 73))	('a-carotene', 'Chemical', '-', (101, 111))	('a-carotene', 'Var', (101, 111))	('esophageal cancer', 'Disease', (74, 91))	('human', 'Species', '9606', (289, 294))	('cellular proliferation', 'CPA', (42, 64))	('alpha-carotenoids', 'Chemical', '-', (193, 210))	('inhibition', 'NegReg', (28, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (260, 285))
174870	30093838	Clinicopathological and prognostic significance of long noncoding RNA MALAT1 in human cancers: a review and meta-analysis The aberrant regulation of MALAT1 has been indicated to be involved in various carcinogenic pathways contributing to the tumourigenesis and progression of cancers.	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('carcinogenic', 'Disease', (201, 213))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('tumour', 'Disease', 'MESH:D009369', (243, 249))	('MALAT1', 'Gene', (70, 76))	('MALAT1', 'Gene', (149, 155))	('tumour', 'Disease', (243, 249))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('carcinogenic', 'Disease', 'MESH:D063646', (201, 213))	('MALAT1', 'Gene', '378938', (70, 76))	('MALAT1', 'Gene', '378938', (149, 155))	('contributing', 'Reg', (223, 235))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('involved', 'Reg', (181, 189))	('cancers', 'Disease', (277, 284))	('aberrant regulation', 'Var', (126, 145))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
174885	30093838	For example, MALAT1 silencing might impede proliferation, migration, and invasion of triple-negative breast cancer (TNBC) cell by reversely mediating MiR-129-5p.	('MiR', 'Gene', '220972', (150, 153))	('BC', 'Phenotype', 'HP:0003002', (118, 120))	('MALAT1', 'Gene', (13, 19))	('impede', 'NegReg', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('proliferation', 'CPA', (43, 56))	('invasion', 'CPA', (73, 81))	('MALAT1', 'Gene', '378938', (13, 19))	('breast cancer', 'Disease', (101, 114))	('silencing', 'Var', (20, 29))	('MiR', 'Gene', (150, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('migration', 'CPA', (58, 67))
174886	30093838	MALAT1 acts as a competitive endogenous RNA (ceRNA) to regulate ZEB1 expression by sponging miR-143-3p, whereas miR-143-3p inhibitor partially impaired the effect of MALAT1 on hepatocellular carcinoma (HCC) cells, and the inhibition of MALAT1 also might inhabit proliferation and invasion of HCC cells.	('proliferation', 'CPA', (262, 275))	('miR', 'Gene', '220972', (92, 95))	('CC', 'Phenotype', 'HP:0002664', (203, 205))	('hepatocellular carcinoma', 'Disease', (176, 200))	('HCC', 'Gene', '619501', (292, 295))	('HCC', 'Phenotype', 'HP:0001402', (292, 295))	('invasion', 'CPA', (280, 288))	('miR', 'Gene', (92, 95))	('ZEB1', 'Gene', '6935', (64, 68))	('MALAT1', 'Gene', (0, 6))	('HCC', 'Gene', (292, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('inhabit', 'Reg', (254, 261))	('MALAT1', 'Gene', (166, 172))	('MALAT1', 'Gene', (236, 242))	('inhibition', 'Var', (222, 232))	('MALAT1', 'Gene', '378938', (0, 6))	('miR', 'Gene', '220972', (112, 115))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('MALAT1', 'Gene', '378938', (166, 172))	('MALAT1', 'Gene', '378938', (236, 242))	('impaired', 'NegReg', (143, 151))	('HCC', 'Gene', '619501', (202, 205))	('HCC', 'Phenotype', 'HP:0001402', (202, 205))	('effect', 'MPA', (156, 162))	('miR', 'Gene', (112, 115))	('HCC', 'Gene', (202, 205))	('ZEB1', 'Gene', (64, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (176, 200))	('CC', 'Phenotype', 'HP:0002664', (293, 295))
174891	30093838	Taken together, emerging evidence manifested that dysregulated MATAT1 is closely related to the development of various types of cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('MATAT1', 'Gene', (63, 69))	('related', 'Reg', (81, 88))	('dysregulated', 'Var', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
174911	30093838	Overexpression of MALAT1 had a higher risk of poor OS (pooled HR = 2.298, 95% CI 1.953-2.704, P = 0.000, I2 = 17.2%).	('OS', 'Chemical', 'MESH:D009992', (51, 53))	('MALAT1', 'Gene', '378938', (18, 24))	('MALAT1', 'Gene', (18, 24))	('poor OS', 'Disease', (46, 53))	('Overexpression', 'Var', (0, 14))
174919	30093838	Additionally, MALAT1 possesses a variety of molecular functions including promotion of EMT, transcriptional dysregulation, pre-mRNA alternative splicing, ceRNA role, epigenetic alteration and transition of cell phenotype via different signaling pathways covering P13k/Akt, Wnt and ERK/MAPK pathways.	('transcriptional dysregulation', 'MPA', (92, 121))	('MALAT1', 'Gene', '378938', (14, 20))	('epigenetic alteration', 'Var', (166, 187))	('Akt', 'Gene', (268, 271))	('Akt', 'Gene', '207', (268, 271))	('EMT', 'Gene', (87, 90))	('ERK', 'Gene', '5594', (281, 284))	('EMT', 'Gene', '3702', (87, 90))	('MALAT1', 'Gene', (14, 20))	('promotion', 'PosReg', (74, 83))	('pre-mRNA alternative splicing', 'MPA', (123, 152))	('ERK', 'Gene', (281, 284))
174933	30093838	For example, knockdown of MALAT1 could induce the EMT by regulating transcriptional factor snail and activating the PI3K/AKT and Wnt pathways.	('AKT', 'Gene', '207', (121, 124))	('MALAT1', 'Gene', (26, 32))	('AKT', 'Gene', (121, 124))	('regulating', 'MPA', (57, 67))	('transcriptional factor snail', 'Protein', (68, 96))	('MALAT1', 'Gene', '378938', (26, 32))	('activating', 'Reg', (101, 111))	('EMT', 'Gene', (50, 53))	('knockdown', 'Var', (13, 22))	('EMT', 'Gene', '3702', (50, 53))	('induce', 'PosReg', (39, 45))
174942	30093838	The results of the study identified that patients with high expression of MALAT1 have a poor OS in univariate and multivariate models.	('OS', 'Chemical', 'MESH:D009992', (93, 95))	('patients', 'Species', '9606', (41, 49))	('MALAT1', 'Gene', '378938', (74, 80))	('high expression', 'Var', (55, 70))	('MALAT1', 'Gene', (74, 80))
174952	30093838	In conclusion, the study revealed that over-expression MALAT1 might be an adverse biomarker for prognostic outcome, lymph node metastasis, distant metastasis, tumour size and TNM stage for cancer patients.	('tumour', 'Disease', (159, 165))	('TNM', 'Gene', '10178', (175, 178))	('distant metastasis', 'CPA', (139, 157))	('over-expression', 'Var', (39, 54))	('MALAT1', 'Gene', '378938', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('TNM', 'Gene', (175, 178))	('patients', 'Species', '9606', (196, 204))	('lymph node metastasis', 'CPA', (116, 137))	('MALAT1', 'Gene', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
174970	29765221	Although these lesions are often benign, BCs can also cause symptoms such as chest pain, cough, dysphagia, and dyspnea due to compression of the surrounding structures.	('cause', 'Reg', (54, 59))	('dyspnea', 'Disease', (111, 118))	('BCs', 'Var', (41, 44))	('dysphagia', 'Disease', (96, 105))	('cough', 'Disease', 'MESH:D003371', (89, 94))	('chest pain', 'Disease', 'MESH:D002637', (77, 87))	('dysphagia', 'Phenotype', 'HP:0002015', (96, 105))	('dyspnea', 'Disease', 'MESH:D004417', (111, 118))	('chest pain', 'Disease', (77, 87))	('cough', 'Phenotype', 'HP:0012735', (89, 94))	('chest pain', 'Phenotype', 'HP:0100749', (77, 87))	('dyspnea', 'Phenotype', 'HP:0002094', (111, 118))	('dysphagia', 'Disease', 'MESH:D003680', (96, 105))	('cough', 'Disease', (89, 94))	('BCs', 'Phenotype', 'HP:0100730', (41, 44))	('pain', 'Phenotype', 'HP:0012531', (83, 87))
174973	29765221	We herein describe an extremely rare case of intramural esophageal BC and hematoma of the gastric wall with positive expressions of CA199 and CA125.	('hematoma', 'Disease', 'MESH:D006406', (74, 82))	('CA199', 'Var', (132, 137))	('intramural esophageal BC', 'Disease', 'MESH:C535869', (45, 69))	('CA199', 'Chemical', '-', (132, 137))	('hematoma', 'Disease', (74, 82))	('intramural esophageal BC', 'Disease', (45, 69))	('CA125', 'Gene', '94025', (142, 147))	('CA125', 'Gene', (142, 147))
174980	29765221	Physical examination did not reveal any obvious abnormal signs, and preoperative laboratory data were within the normal range, with the exception of the tumor markers CA199 and CA125.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('CA199', 'Var', (167, 172))	('CA199', 'Chemical', '-', (167, 172))	('CA125', 'Gene', (177, 182))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('CA125', 'Gene', '94025', (177, 182))
174981	29765221	The serum level of CA199 was > 1,000 U/mL (normal range:<37 U/mL), and CA125 was 4,816 U/mL (normal range: <37 U/mL), while carcinoembryonic antigen (normal range: <5 mug/L) and squamous cell carcinoma antigen (normal range: <1.5 mug/L) were within the normal range.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (178, 201))	('CA199', 'Var', (19, 24))	('squamous cell carcinoma', 'Disease', (178, 201))	('CA199', 'Chemical', '-', (19, 24))	('CA125', 'Gene', (71, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('CA125', 'Gene', '94025', (71, 76))
174993	29765221	We also detected positive expression of CA199 and CA125 in cyst sections by immunohistochemical staining (Figure 4A and B).	('expression', 'MPA', (26, 36))	('CA125', 'Gene', '94025', (50, 55))	('CA199', 'Var', (40, 45))	('CA199', 'Chemical', '-', (40, 45))	('CA125', 'Gene', (50, 55))
175011	29765221	CA199 is the primary marker of choice for pancreatic, colorectal, and hepatocellular cancers, and it is also elevated in pancreatitis, cirrhosis, and obstructive disease of the bile duct.	('pancreatitis', 'Disease', 'MESH:D010195', (121, 133))	('pancreatitis', 'Phenotype', 'HP:0001733', (121, 133))	('colorectal', 'Disease', 'MESH:D015179', (54, 64))	('obstructive disease of the bile duct', 'Disease', (150, 186))	('elevated', 'PosReg', (109, 117))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('colorectal', 'Disease', (54, 64))	('CA199', 'Var', (0, 5))	('cirrhosis', 'Disease', (135, 144))	('pancreatitis', 'Disease', (121, 133))	('CA199', 'Chemical', '-', (0, 5))	('pancreatic', 'Disease', 'MESH:D010195', (42, 52))	('hepatocellular cancers', 'Disease', 'MESH:D006528', (70, 92))	('hepatocellular cancers', 'Disease', (70, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('pancreatic', 'Disease', (42, 52))	('cirrhosis', 'Phenotype', 'HP:0001394', (135, 144))	('cirrhosis', 'Disease', 'MESH:D005355', (135, 144))
175013	29765221	High levels of tumor markers such as CA199 and CA125 are rarely observed in patients with esophageal cysts.	('CA125', 'Gene', '94025', (47, 52))	('patients', 'Species', '9606', (76, 84))	('CA199', 'Var', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('CA199', 'Chemical', '-', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('CA125', 'Gene', (47, 52))	('tumor', 'Disease', (15, 20))	('esophageal cysts', 'Disease', 'MESH:D004934', (90, 106))	('esophageal cysts', 'Disease', (90, 106))
175014	29765221	Reports of high levels of both CA199 and CA125 are extremely rare.	('CA199', 'Chemical', '-', (31, 36))	('CA125', 'Gene', '94025', (41, 46))	('CA125', 'Gene', (41, 46))	('CA199', 'Var', (31, 36))
175016	29765221	These findings suggested that the serum levels of CA199 and CA125 were partly correlated with epithelial cell secretion from the esophageal BC in our patient.	('patient', 'Species', '9606', (150, 157))	('CA125', 'Gene', '94025', (60, 65))	('epithelial cell secretion from the esophageal BC', 'MPA', (94, 142))	('CA199', 'Var', (50, 55))	('CA199', 'Chemical', '-', (50, 55))	('CA125', 'Gene', (60, 65))	('correlated', 'Reg', (78, 88))
175110	26218068	Our results also showed that cancers of the esophagus (SIR, 4.60) and lungs (SIR, 2.01) were the main sites of occurrence of metachronous SPM outside of the head and neck area.	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (29, 53))	('metachronous', 'Var', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers of the esophagus', 'Disease', (29, 53))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (29, 53))
175136	24120473	Incubation with recombinant human (rh)VEGF significantly increased secretion of VEGF protein and cell number; knockdown of PLCG1 markedly reduced the rhVEGF-stimulated increase in levels of phosphorylated PLCG1 and phosphorylated ERK1/2 in neoplastic cells.	('increase', 'PosReg', (168, 176))	('PLCG1', 'Gene', (123, 128))	('knockdown', 'Var', (110, 119))	('reduced', 'NegReg', (138, 145))	('human', 'Species', '9606', (28, 33))	('secretion of VEGF protein', 'MPA', (67, 92))	('PLCG1', 'Gene', '5335', (123, 128))	('levels of phosphorylated', 'MPA', (180, 204))	('PLCG1', 'Gene', (205, 210))	('cell number', 'CPA', (97, 108))	('PLCG1', 'Gene', '5335', (205, 210))
175137	24120473	Esophageal adenocarcinoma tissues showed immunostaining for phosphorylated VEGFR2.	('immunostaining', 'MPA', (41, 55))	('Esophageal adenocarcinoma', 'Disease', (0, 25))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (0, 25))	('phosphorylated', 'Var', (60, 74))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))
175157	24120473	The fact that the anti-tumor effects of VEGFR1 knockout occur in an angiogenesis-independent manner suggests that autocrine VEGF signaling is important in this animal model.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('knockout', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('VEGFR1', 'Gene', (40, 46))
175166	24120473	The mouse VEGF (-807/+118) and VEGFR2 (-620/+304) promoter regions were inserted into the firefly luciferase reporter plasmid pGL3-Basic (Promega, Madison, WI).	('mouse', 'Species', '10090', (4, 9))	('-620/+304', 'Var', (39, 48))	('VEGFR2', 'Gene', (31, 37))
175170	24120473	Cells were treated with the PLC-gamma inhibitor U73122 (Tocris Bioscience, Ellisville, MO) at 2.5 or 5 muM doses or specific PLC-gamma1 siRNA (Thermo Fisher Scientific) (Supplemental methods).	('U73122', 'Chemical', 'MESH:C060229', (48, 54))	('U73122', 'Var', (48, 54))	('PLC', 'Gene', '3339', (28, 31))	('PLC', 'Gene', (28, 31))	('PLC', 'Gene', (125, 128))	('Tocris Bioscience', 'Disease', (56, 73))	('PLC', 'Gene', '3339', (125, 128))	('Tocris Bioscience', 'Disease', 'None', (56, 73))
175183	24120473	VEGF-NA had no effect on BAR-T cell number, but significantly decreased transformed Barrett's (P13R1 and P13R2) and OE33 cell numbers (Supplemental Figure 2A).	('decreased', 'NegReg', (62, 71))	('BAR-T', 'CellLine', 'CVCL:4M95', (25, 30))	('P13R1', 'Var', (95, 100))	('P13R2', 'Var', (105, 110))	('OE33 cell numbers', 'CPA', (116, 133))
175185	24120473	Concentrations of SU1498 >=10 muM caused a significant, dose-dependent decrease in BAR-T cell number, whereas significant decreases in P13R1 cell number were observed with SU1498 in concentrations as low as 5 muM (Supplemental Figure 2B).	('BAR-T cell number', 'CPA', (83, 100))	('SU1498', 'Var', (172, 178))	('decrease', 'NegReg', (71, 79))	('decrease in BAR-T cell number', 'Phenotype', 'HP:0005403', (71, 100))	('BAR-T', 'CellLine', 'CVCL:4M95', (83, 88))	('SU1498', 'Var', (18, 24))	('P13R1 cell number', 'CPA', (135, 152))	('SU1498', 'Chemical', 'MESH:C483044', (172, 178))	('decreases', 'NegReg', (122, 131))	('SU1498', 'Chemical', 'MESH:C483044', (18, 24))
175186	24120473	SU1498 in a concentration of 5 muM also caused significant reductions in P13R2 and OE33 cell numbers (Supplemental Figure 2C).	('SU1498', 'Var', (0, 6))	('OE33 cell numbers', 'CPA', (83, 100))	('P13R2', 'CPA', (73, 78))	('SU1498', 'Chemical', 'MESH:C483044', (0, 6))	('reductions', 'NegReg', (59, 69))
175189	24120473	We found phospho-VEGFR2 predominantly in the nucleus, with lower levels in the cytoplasm of epithelial cells in both the non-neoplastic squamous epithelium (Figure 2A left panels) and in the esophageal adenocarcinomas (Figure 2A right panels).	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('phospho-VEGFR2', 'Var', (9, 23))	('esophageal adenocarcinomas', 'Disease', (191, 217))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (191, 216))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (191, 217))
175192	24120473	In the esophageal adenocarcinoma tissues, staining intensity for phospho-VEGFR2 was strong in 12.5% whereas none of the histologically normal tissues had strong staining for this phospho-protein.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (7, 32))	('esophageal adenocarcinoma tissues', 'Disease', (7, 40))	('phospho-VEGFR2', 'Var', (65, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('esophageal adenocarcinoma tissues', 'Disease', 'MESH:D004938', (7, 40))	('strong', 'PosReg', (84, 90))	('staining intensity', 'MPA', (42, 60))
175196	24120473	VEGFR2 siRNA caused a significant decrease in BrdU incorporation in all the cell lines (Figure 3D), confirming that inhibition of VEGFR2 decreases proliferation in transformed Barrett's and OE33 cells.	('VEGFR2', 'Gene', (130, 136))	('inhibition', 'Var', (116, 126))	('decrease', 'NegReg', (34, 42))	('decreases', 'NegReg', (137, 146))	('BrdU', 'Chemical', 'MESH:D001973', (46, 50))	('BrdU incorporation', 'MPA', (46, 64))	('proliferation', 'CPA', (147, 160))
175206	24120473	Treatment with U73122, a pharmacologic inhibitor of PLC-gamma, caused a significant decrease in VEGF secretion and cell number in both P13R1 and OE33 cells (Supplementary Figure 3A&B).	('decrease', 'NegReg', (84, 92))	('VEGF secretion', 'MPA', (96, 110))	('PLC', 'Gene', (52, 55))	('U73122', 'Chemical', 'MESH:C060229', (15, 21))	('PLC', 'Gene', '3339', (52, 55))	('cell number', 'CPA', (115, 126))	('U73122', 'Var', (15, 21))
175207	24120473	Similarly, reductions in VEGF secretion and BrdU incorporation were observed in both cell lines with PLC-gamma1siRNA (Figure 5C&D).	('VEGF secretion', 'MPA', (25, 39))	('BrdU incorporation', 'CPA', (44, 62))	('reductions', 'NegReg', (11, 21))	('PLC-gamma1siRNA', 'Var', (101, 116))	('BrdU', 'Chemical', 'MESH:D001973', (44, 48))
175209	24120473	To explore the effects of VEGFR2 knockdown on tumor growth in vivo, we produced a stable line of P13R1 cells infected with VEGFR2 shRNA, and confirmed knockdown of VEGFR2 by Western blot both in the population and in a selected clone (B3, data not shown).	('knockdown', 'Var', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('VEGFR2', 'Gene', (164, 170))	('VEGFR2', 'Gene', (123, 129))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
175211	24120473	Unlike the parental cells, xenografts of the population and of the B3 clone of P13R1 cells with VEGFR2 knockdown exhibited no tumor growth whatsoever (Figure 5E).	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('VEGFR2', 'Gene', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('knockdown', 'Var', (103, 112))	('tumor', 'Disease', (126, 131))
175218	24120473	We selected P13R1 because it forms tumors within 10 weeks of inoculation, allowing for a long time course over which to assess the effects of sunitinib.	('sunitinib', 'Chemical', 'MESH:D000077210', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('P13R1', 'Var', (12, 17))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
175223	24120473	the weight of the index tumor plus any additional tumors) for sunitinib-treated mice was significantly lower than that of vehicle-treated control mice (Figure 7D).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor plus any additional tumors', 'Disease', 'MESH:D009369', (24, 56))	('tumor plus any additional tumors', 'Disease', (24, 56))	('sunitinib', 'Chemical', 'MESH:D000077210', (62, 71))	('sunitinib-treated', 'Var', (62, 79))	('lower', 'NegReg', (103, 108))	('mice', 'Species', '10090', (146, 150))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
175229	24120473	Finally, in mice with tumor xenografts, we have shown that knockdown of VEGFR2 abolishes tumor growth, and that treatment with sunitinib delays tumor growth and decreases tumor weight and volume.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('delays tumor growth', 'Disease', 'MESH:D006130', (137, 156))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('decreases tumor', 'Disease', (161, 176))	('knockdown', 'Var', (59, 68))	('sunitinib', 'Chemical', 'MESH:D000077210', (127, 136))	('delays tumor growth', 'Disease', (137, 156))	('decreases tumor', 'Disease', 'MESH:D009369', (161, 176))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('VEGFR2', 'Gene', (72, 78))	('mice', 'Species', '10090', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (22, 27))	('abolishes', 'NegReg', (79, 88))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
175234	24120473	They found phosphorylated VEGFR2 in the cytoplasm and nucleus of disparate cell types in both the normal and tumor tissues from all organs evaluated, with more intense staining in the tumors.	('VEGFR2', 'Gene', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('found', 'Reg', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', (184, 190))	('phosphorylated', 'Var', (11, 25))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
175241	24120473	Compared to non-neoplastic Barrett's cells, growth suppression was achieved with lower concentrations of SU1498 in neoplastic Barrett's cells, and inhibition of their VEGF signaling through multiple methods (VEGF-neutralizing antibody, pharmacologic VEGFR2 inhibition, VEGFR2 siRNA) decreased VEGF production and cell proliferation without significant effects on apoptosis.	('cell proliferation', 'CPA', (313, 331))	('suppression', 'NegReg', (51, 62))	('SU1498', 'Chemical', 'MESH:C483044', (105, 111))	('inhibition', 'Var', (147, 157))	('growth', 'CPA', (44, 50))	('VEGF production', 'MPA', (293, 308))	('decreased', 'NegReg', (283, 292))
175243	24120473	This observation is supported by our finding that VEGFR2 knockdown in transformed Barrett's cells abolished their ability to form tumors in immunodeficient mice.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('immunodeficient', 'Disease', 'MESH:D007153', (140, 155))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('immunodeficient', 'Disease', (140, 155))	('knockdown', 'Var', (57, 66))	('ability', 'CPA', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mice', 'Species', '10090', (156, 160))	('abolished', 'NegReg', (98, 107))	('VEGFR2', 'Gene', (50, 56))
175249	24120473	In agreement with those data, we found that inhibition of PLC-gamma1 decreased phosphorylated ERK expression and cell number in our neoplastic Barrett's cells.	('phosphorylated', 'MPA', (79, 93))	('cell number', 'CPA', (113, 124))	('ERK', 'Gene', (94, 97))	('inhibition', 'Var', (44, 54))	('decreased', 'NegReg', (69, 78))	('PLC-gamma1', 'Gene', (58, 68))	('ERK', 'Gene', '5594', (94, 97))
175265	24120473	We have demonstrated that VEGF produced by neoplastic Barrett's cells activates their VEGFR2, thereby initiating a PLC-PKC-ERK pathway that causes cell proliferation and the production of more VEGF.	('activates', 'PosReg', (70, 79))	('neoplastic', 'Var', (43, 53))	('initiating', 'Reg', (102, 112))	('production', 'MPA', (174, 184))	('PLC', 'Gene', '3339', (115, 118))	('cell proliferation', 'CPA', (147, 165))	('ERK', 'Gene', '5594', (123, 126))	('VEGFR2', 'Gene', (86, 92))	('ERK', 'Gene', (123, 126))	('PLC', 'Gene', (115, 118))	('PKC', 'Gene', (119, 122))	('PKC', 'Gene', '112476', (119, 122))	('causes', 'PosReg', (140, 146))
175324	31333313	Metabolic profiling correlations between esophageal tissues and urine showed that most potential urine biomarkers were correlated with most of the discriminating metabolites in EC tissues, indicating that changes in urine metabolic signature could reflect reprogramming of metabolic pathways in tumor tissues, highlighting the significance of the distinct urinary metabolic profiles as potential novel and nonin-vasive indicators for EC detection.	('changes', 'Var', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('reflect', 'Reg', (248, 255))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', (295, 300))
175362	31333313	Furthermore, the metabolic profiling correlations between esophageal tissues and urine showed that most urine potential biomarkers were correlated with most of the discriminating metabolites in EC tissues, indicating that changes in the urine metabolic signature could reflect reprogramming of metabolic pathways in tumor tissue, high-lighting the significance of the distinct urinary metabolic profiles as potential novel and noninvasive indicators for EC detection.	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('reflect', 'Reg', (269, 276))	('tumor', 'Disease', (316, 321))	('changes', 'Var', (222, 229))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
175407	31073523	These findings suggest that occlusion of the GRS may protect the liver from portosystemic shunt syndrome and have a protective long-term role in preserving hepatic function.	('occlusion', 'Var', (28, 37))	('hepatic function', 'MPA', (156, 172))	('portosystemic shunt syndrome', 'Disease', (76, 104))	('systemic shunt', 'Phenotype', 'HP:0001693', (81, 95))	('portosystemic shunt syndrome', 'Disease', 'MESH:C562830', (76, 104))
175410	30342037	We investigated regulation of ribosomal protein S6 kinase B1 (RPS6KB1) by AURKA and the effects of alisertib, an AURKA inhibitor, in mice xenograft tumors grown from human gastrointestinal cancer cells with mutant, activated forms of KRAS.	('mice', 'Species', '10090', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('human', 'Species', '9606', (166, 171))	('xenograft tumors', 'Disease', 'MESH:D009369', (138, 154))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('gastrointestinal cancer', 'Disease', (172, 195))	('mutant', 'Var', (207, 213))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (172, 195))	('ribosomal protein S6 kinase B1', 'Gene', '6198', (30, 60))	('ribosomal protein S6 kinase B1', 'Gene', (30, 60))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('alisertib', 'Chemical', 'MESH:C550258', (99, 108))	('RPS6KB1', 'Gene', (62, 69))	('xenograft tumors', 'Disease', (138, 154))	('KRAS', 'Gene', (234, 238))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (172, 195))
175411	30342037	We tested the effects of alisertib, or AURKA overexpression or knock down, in 10 upper gastrointestinal or colon cancer cell lines with KRAS mutations or amplifications using the CellTiter-Glo luminescence and clonogenic cell survival assays.	('alisertib', 'Chemical', 'MESH:C550258', (25, 34))	('knock down', 'Var', (63, 73))	('amplifications', 'Var', (154, 168))	('mutations', 'Var', (141, 150))	('upper gastrointestinal or colon cancer', 'Disease', (81, 119))	('tested', 'Reg', (3, 9))	('AURKA', 'Gene', (39, 44))	('KRAS', 'Gene', (136, 140))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('upper gastrointestinal or colon cancer', 'Disease', 'MESH:D015179', (81, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
175416	30342037	We detected AURKA-dependent phosphorylation of RPS6KB1 in cell lines with mutations in KRAS, but not in cells with wild-type Ras.	('KRAS', 'Gene', (87, 91))	('AURKA-dependent phosphorylation', 'MPA', (12, 43))	('mutations', 'Var', (74, 83))	('RPS6KB1', 'Gene', (47, 54))	('phospho', 'Chemical', 'MESH:C033601', (28, 35))
175420	30342037	In studies of gastrointestinal cancer cell lines with activated KRAS, we found AURKA to phosphorylate RPS6KB1 to promote cell proliferation and survival and growth of xenograft tumors in mice.	('growth', 'CPA', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('survival', 'CPA', (144, 152))	('xenograft tumors', 'Disease', (167, 183))	('promote', 'PosReg', (113, 120))	('phospho', 'Chemical', 'MESH:C033601', (88, 95))	('cell proliferation', 'CPA', (121, 139))	('mice', 'Species', '10090', (187, 191))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (14, 37))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('RPS6KB1', 'Gene', (102, 109))	('phosphorylate', 'Var', (88, 101))	('gastrointestinal cancer', 'Disease', (14, 37))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (14, 37))	('xenograft tumors', 'Disease', 'MESH:D009369', (167, 183))
175423	30342037	Activation of oncogenic KRAS by mutations or amplifications is well characterized in luminal gastrointestinal cancers that include colorectal, gastric, and esophageal adenocarcinomas .	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (93, 116))	('colorectal', 'Disease', (131, 141))	('gastric', 'Disease', (143, 150))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (156, 181))	('luminal gastrointestinal cancers', 'Disease', 'MESH:D005770', (85, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('amplifications', 'Var', (45, 59))	('mutations', 'Var', (32, 41))	('Activation', 'PosReg', (0, 10))	('esophageal adenocarcinomas', 'Disease', (156, 182))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004941', (156, 182))	('colorectal', 'Disease', 'MESH:D015179', (131, 141))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('luminal gastrointestinal cancers', 'Disease', (85, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('KRAS', 'Gene', (24, 28))
175429	30342037	Overexpression of AURKA can serve as an independent prognostic marker for poor clinical outcomes in cancer patients .	('AURKA', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patients', 'Species', '9606', (107, 115))
175430	30342037	We and others have reported that aberrant overexpression of AURKA mediates activation of key oncogenic signaling pathways in cancer cells such as NF-kappaB and beta-catenin/WNT signaling.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('oncogenic signaling pathways', 'Pathway', (93, 121))	('activation', 'PosReg', (75, 85))	('beta-catenin', 'Gene', (160, 172))	('beta-catenin', 'Gene', '1499', (160, 172))	('NF-kappaB', 'Gene', '4790', (146, 155))	('overexpression', 'PosReg', (42, 56))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('aberrant', 'Var', (33, 41))	('NF-kappaB', 'Gene', (146, 155))	('AURKA', 'Gene', (60, 65))
175434	30342037	In this study, we demonstrate that AURKA plays a crucial role in phosphorylating RPS6KB1 in KRAS-mutant cancer cells.	('phosphorylating', 'MPA', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('RPS6KB1', 'Gene', (81, 88))	('phospho', 'Chemical', 'MESH:C033601', (65, 72))	('KRAS-mutant', 'Var', (92, 103))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
175460	30342037	To investigate the function of AURKA in promoting KRAS-driven oncogenesis, we evaluated the biological impact of inhibiting AURKA with alisertib, a selective AURKA inhibitor, in a panel of 10 luminal gastrointestinal cancer cell lines harboring KRAS mutations or amplifications (KRAS-driven).	('inhibiting', 'NegReg', (113, 123))	('luminal gastrointestinal cancer', 'Disease', 'MESH:D005770', (192, 223))	('luminal gastrointestinal cancer', 'Disease', (192, 223))	('alisertib', 'Chemical', 'MESH:C550258', (135, 144))	('KRAS', 'Gene', (245, 249))	('AURKA', 'Gene', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('mutations', 'Var', (250, 259))	('amplifications', 'Var', (263, 277))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (200, 223))
175464	30342037	The long-term clonogenic survival assay (15 days), after a single overnight treatment with alisertib, demonstrated a significant reduction in the number of viable cell colonies in gastric cancer cells (ESO26, SNU-1, AGS, SNU-601) and CRC cells (HCT116, SK-CO-1 SW480, SW620, LS180, LS153) (Figure 1 C-F).	('gastric cancer', 'Disease', (180, 194))	('HCT116', 'CellLine', 'CVCL:0291', (245, 251))	('SK-CO-1 SW480', 'CellLine', 'CVCL:0546', (253, 266))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('gastric cancer', 'Disease', 'MESH:D013274', (180, 194))	('SNU-601', 'Chemical', 'MESH:C090841', (221, 228))	('CRC', 'Phenotype', 'HP:0003003', (234, 237))	('reduction', 'NegReg', (129, 138))	('CRC', 'Disease', 'MESH:D015179', (234, 237))	('gastric cancer', 'Phenotype', 'HP:0012126', (180, 194))	('AGS', 'Disease', (216, 219))	('SW620', 'CellLine', 'CVCL:0547', (268, 273))	('AGS', 'Disease', 'MESH:C535607', (216, 219))	('CRC', 'Disease', (234, 237))	('alisertib', 'Chemical', 'MESH:C550258', (91, 100))	('SW620', 'Var', (268, 273))	('LS180', 'CellLine', 'CVCL:0397', (275, 280))
175466	30342037	Treatment with alisertib also increased the percentage of polyploid cells, consistent with earlier reports, (Supplementary Figure S2).	('polyploid', 'Var', (58, 67))	('increased', 'PosReg', (30, 39))	('alisertib', 'Chemical', 'MESH:C550258', (15, 24))
175467	30342037	Collectively, these results indicate that inhibition of AURKA using alisertib can effectively suppress cancer cell viability and induce polyploidy in KRAS-driven GI cancers.	('GI cancer', 'Phenotype', 'HP:0007378', (162, 171))	('induce', 'Reg', (129, 135))	('GI cancers', 'Disease', 'MESH:D009369', (162, 172))	('polyploidy', 'Disease', 'MESH:D011123', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('suppress', 'NegReg', (94, 102))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('inhibition', 'Var', (42, 52))	('AURKA', 'Gene', (56, 61))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('alisertib', 'Chemical', 'MESH:C550258', (68, 77))	('cancer', 'Disease', (103, 109))	('polyploidy', 'Disease', (136, 146))	('GI cancers', 'Disease', (162, 172))
175470	30342037	On the other hand, we found that RPS6KB1 phosphorylation at T389 was the most consistently decreased effector, following alisertib treatment across all GI cancer cell models (ESO26, AGS, SNU-601, SNU-1, HCT116, SW480, SW620) (Figure 2A, B).	('SW620', 'CellLine', 'CVCL:0547', (218, 223))	('effector', 'MPA', (101, 109))	('phosphorylation', 'MPA', (41, 56))	('GI cancer', 'Disease', (152, 161))	('AGS', 'Disease', 'MESH:C535607', (182, 185))	('ESO26', 'Var', (175, 180))	('RPS6KB1', 'Gene', (33, 40))	('SW480', 'Var', (211, 216))	('SW480', 'CellLine', 'CVCL:0546', (211, 216))	('GI cancer', 'Disease', 'MESH:D009369', (152, 161))	('SNU-601', 'Chemical', 'MESH:C090841', (187, 194))	('GI cancer', 'Phenotype', 'HP:0007378', (152, 161))	('alisertib', 'Chemical', 'MESH:C550258', (121, 130))	('SW620', 'Var', (218, 223))	('HCT116', 'CellLine', 'CVCL:0291', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('AGS', 'Disease', (182, 185))	('phospho', 'Chemical', 'MESH:C033601', (41, 48))	('decreased', 'NegReg', (91, 100))
175475	30342037	As shown, our data indicated that following doxycycline treatment, AURKA levels were induced with a notable increase in protein levels of p-RPS6KB1 (T389).	('increase', 'PosReg', (108, 116))	('AURKA levels', 'MPA', (67, 79))	('doxycycline', 'Chemical', 'MESH:D004318', (44, 55))	('protein levels', 'MPA', (120, 134))	('p-RPS6KB1', 'Var', (138, 147))
175477	30342037	Next, we knocked down endogenous AURKA and evaluated the expression of p-RPS6KB1 in GI cancer cell models (ESO26, AGS, SNU-601, SNU-1, HCT116, SW480, SW620).	('AGS', 'Disease', 'MESH:C535607', (114, 117))	('SW620', 'CellLine', 'CVCL:0547', (150, 155))	('p-RPS6KB1', 'Gene', (71, 80))	('SW480', 'Var', (143, 148))	('HCT116', 'Var', (135, 141))	('ESO26', 'Var', (107, 112))	('SW620', 'Var', (150, 155))	('GI cancer', 'Disease', 'MESH:D009369', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('SW480', 'CellLine', 'CVCL:0546', (143, 148))	('SNU-601', 'Chemical', 'MESH:C090841', (119, 126))	('GI cancer', 'Phenotype', 'HP:0007378', (84, 93))	('knocked', 'Reg', (9, 16))	('HCT116', 'CellLine', 'CVCL:0291', (135, 141))	('AGS', 'Disease', (114, 117))	('GI cancer', 'Disease', (84, 93))
175478	30342037	Similar to alisertib results, the knockdown of AURKA induced protein expression of p53 (in p53-wild-type cell lines), p21, BIM, cleaved caspase 3, and cleaved PARP (Supplementary Figure S4A).	('alisertib', 'Chemical', 'MESH:C550258', (11, 20))	('cleaved', 'MPA', (128, 135))	('induced', 'Reg', (53, 60))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('p21', 'Gene', (118, 121))	('p53', 'Gene', (91, 94))	('BIM', 'Gene', '10018', (123, 126))	('PARP', 'Gene', '1302', (159, 163))	('p53', 'Gene', '7157', (91, 94))	('BIM', 'Gene', (123, 126))	('cleaved', 'MPA', (151, 158))	('knockdown', 'Var', (34, 43))	('AURKA', 'Gene', (47, 52))	('p21', 'Gene', '644914', (118, 121))	('PARP', 'Gene', (159, 163))	('caspase 3', 'Protein', (136, 145))	('protein expression', 'MPA', (61, 79))
175481	30342037	Our data indicated that RPS6KB1 knockdown increased the protein level of pro-apoptotic markers such as cleaved caspase 3 and cleaved PARP (Figure 3C).	('PARP', 'Gene', (133, 137))	('increased', 'PosReg', (42, 51))	('cleaved caspase 3', 'MPA', (103, 120))	('knockdown', 'Var', (32, 41))	('protein level of', 'MPA', (56, 72))	('RPS6KB1', 'Gene', (24, 31))	('PARP', 'Gene', '1302', (133, 137))
175482	30342037	The CellTiter-Glo Assay indicated that RPS6KB1 knockdown suppressed cancer cell viability (Figure S4C), consistent with our results showing alisertib-or AURKA knockdown-mediated inhibition of RPS6KB1 phosphorylation.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('phospho', 'Chemical', 'MESH:C033601', (200, 207))	('RPS6KB1', 'Gene', (39, 46))	('knockdown', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('alisertib', 'Chemical', 'MESH:C550258', (140, 149))	('suppressed', 'NegReg', (57, 67))
175484	30342037	Recent studies have shown that aberrant overexpression of AURKA in cancer cells is associated with the gain of oncogenic function due to its kinase activity by which the aberrant overexpressed protein directly binds to and phosphorylates several proteins such as HDM2, IKB, p73, and GSK3beta .	('HDM2', 'Gene', (263, 267))	('kinase activity', 'MPA', (141, 156))	('p73', 'Gene', '7161', (274, 277))	('p73', 'Gene', (274, 277))	('phospho', 'Chemical', 'MESH:C033601', (223, 230))	('HDM2', 'Gene', '4193', (263, 267))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('AURKA', 'Gene', (58, 63))	('aberrant', 'Var', (31, 39))	('binds', 'Interaction', (210, 215))	('GSK3beta', 'Gene', '2931', (283, 291))	('phosphorylates', 'MPA', (223, 237))	('gain', 'PosReg', (103, 107))	('cancer', 'Disease', (67, 73))	('overexpression', 'PosReg', (40, 54))	('GSK3beta', 'Gene', (283, 291))	('protein', 'Protein', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('proteins', 'Protein', (246, 254))	('oncogenic function', 'CPA', (111, 129))	('aberrant', 'Var', (170, 178))
175489	30342037	To further validate that inhibition of AURKA can effectively abrogate phosphorylation of RPS6KB1, we performed immunoprecipitation analysis by pulling down the endogenous total serine and threonine phosphorylated proteins in SW480 and AGS cells, followed by Western blot analysis.	('serine', 'Chemical', 'MESH:C047902', (177, 183))	('AGS', 'Disease', (235, 238))	('threonine', 'Chemical', 'MESH:C061951', (188, 197))	('phospho', 'Chemical', 'MESH:C033601', (198, 205))	('abrogate', 'NegReg', (61, 69))	('AGS', 'Disease', 'MESH:C535607', (235, 238))	('RPS6KB1', 'Gene', (89, 96))	('phosphorylation', 'MPA', (70, 85))	('AURKA', 'Gene', (39, 44))	('inhibition', 'Var', (25, 35))	('pulling down', 'NegReg', (143, 155))	('SW480', 'CellLine', 'CVCL:0546', (225, 230))	('endogenous', 'MPA', (160, 170))	('phospho', 'Chemical', 'MESH:C033601', (70, 77))
175500	30342037	Using lentivirus-mediated shRNA knockdown in cell lines with endogenous mutant (SW480, SNU-1) or amplified (ESO26) KRAS, we detected downregulation of AURKA and p-RPS6KB1 (T389) (Figure 5B).	('mutant', 'Var', (72, 78))	('p-RPS6KB1', 'Protein', (161, 170))	('downregulation', 'NegReg', (133, 147))	('AURKA', 'Protein', (151, 156))	('SW480', 'CellLine', 'CVCL:0546', (80, 85))
175501	30342037	To uncover if AURKA phosphorylates RPS6KB1 only in mutant KRAS cells, we inhibited AURKA by alisertib treatment or genetic knockdown in STKM2 and RKO cells that were engineered to stably express mutant-KRAS, as compared to control.	('AURKA', 'Gene', (83, 88))	('mutant', 'Var', (51, 57))	('alisertib', 'Chemical', 'MESH:C550258', (92, 101))	('mutant-KRAS', 'Var', (195, 206))	('inhibited', 'NegReg', (73, 82))	('phospho', 'Chemical', 'MESH:C033601', (20, 27))
175502	30342037	Consistent with our previous data, inhibition or knockdown of AURKA abolished RPS6KB1 phosphorylation that was induced by mutant KRAS-G12D in these cells (Figure 5D, E).	('abolished', 'NegReg', (68, 77))	('phosphorylation', 'MPA', (86, 101))	('KRAS-G12D', 'Var', (129, 138))	('RPS6KB1', 'Gene', (78, 85))	('phospho', 'Chemical', 'MESH:C033601', (86, 93))	('G12D', 'Mutation', 'rs121913529', (134, 138))	('mutant KRAS-G12D', 'Var', (122, 138))
175503	30342037	Next, we tested whether AURKA knockdown decreases RPS6KB1 phosphorylation in endogenous mutant or wild-type KRAS cells.	('phosphorylation', 'MPA', (58, 73))	('phospho', 'Chemical', 'MESH:C033601', (58, 65))	('RPS6KB1', 'Protein', (50, 57))	('mutant', 'Var', (88, 94))	('knockdown', 'Var', (30, 39))	('decreases', 'NegReg', (40, 49))
175504	30342037	Western blot data demonstrated that AURKA knockdown in mutant KRAS SUN1 (KRAS-G12D) cells dramatically decreased RPS6KB1 phosphorylation (Supplementary Figure S5), whereas AURKA knockdown in wild-type KRAS cells (MKN45 or STKM2) had minimal effects on decreasing RPS6KB1 phosphorylation levels (Supplementary Figure S5).	('RPS6KB1 phosphorylation levels', 'MPA', (263, 293))	('phospho', 'Chemical', 'MESH:C033601', (121, 128))	('decreased', 'NegReg', (103, 112))	('mutant', 'Var', (55, 61))	('G12D', 'Mutation', 'rs121913529', (78, 82))	('phospho', 'Chemical', 'MESH:C033601', (271, 278))	('RPS6KB1 phosphorylation', 'MPA', (113, 136))
175505	30342037	Collectively, these data demonstrate that mutant KRAS, not wild-type, and AURKA are important for phosphorylation of RPS6KB1, suggesting that the AURKA-RPS6KB1 axis is an active druggable downstream effector pathway in mutant KRAS cancer cells.	('mutant', 'Var', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('phospho', 'Chemical', 'MESH:C033601', (98, 105))	('KRAS', 'Gene', (226, 230))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
175506	30342037	To confirm that AURKA is a potential therapeutic target in luminal GI cancers with mutant KRAS, we used four tumor xenograft mouse models (SNU-601, SNU-1, HCT116, and SW480).	('SW480', 'CellLine', 'CVCL:0546', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutant', 'Var', (83, 89))	('SNU-601', 'Chemical', 'MESH:C090841', (139, 146))	('KRAS', 'Gene', (90, 94))	('mouse', 'Species', '10090', (125, 130))	('luminal GI cancers', 'Disease', 'MESH:D009369', (59, 77))	('luminal GI cancers', 'Disease', (59, 77))	('GI cancer', 'Phenotype', 'HP:0007378', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('HCT116', 'CellLine', 'CVCL:0291', (155, 161))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
175511	30342037	Western blot analysis of harvested tumors demonstrated that inhibition of AURKA by alisertib led to decreased expression of p-RPS6KB1 (T389) in tumor xenografts, confirming the in vitro data (Figure 6C).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('p-RPS6KB1', 'Var', (124, 133))	('tumor', 'Disease', (144, 149))	('alisertib', 'Chemical', 'MESH:C550258', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('inhibition', 'NegReg', (60, 70))	('decreased', 'NegReg', (100, 109))	('tumors', 'Disease', (35, 41))	('expression', 'MPA', (110, 120))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('AURKA', 'Gene', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
175513	30342037	Taken together, our results indicate that AURKA-RPS6KB1 is a druggable signaling axis downstream of mutant KRAS luminal GI cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('KRAS', 'Gene', (107, 111))	('mutant', 'Var', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('GI cancer', 'Phenotype', 'HP:0007378', (120, 129))	('luminal GI cancers', 'Disease', (112, 130))	('luminal GI cancers', 'Disease', 'MESH:D009369', (112, 130))
175523	30342037	Mutations in KRAS are frequent early events in colorectal cancers that have been identified in approximately 30% of adenomas.	('colorectal cancers', 'Disease', (47, 65))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('adenomas', 'Disease', 'MESH:D000236', (116, 124))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('adenomas', 'Disease', (116, 124))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (13, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('colorectal cancers', 'Disease', 'MESH:D015179', (47, 65))
175524	30342037	While gastric and esophageal adenocarcinomas have lower frequencies of mutant KRAS, amplifications and non-mutational activation of oncogenic KRAS signatures have been frequently described in these cancers.	('gastric and esophageal adenocarcinoma', 'Disease', 'MESH:D013274', (6, 43))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (18, 43))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('KRAS', 'Gene', (78, 82))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('mutant', 'Var', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('esophageal adenocarcinomas', 'Disease', (18, 44))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004941', (18, 44))
175525	30342037	Mutant KRAS can activate a plethora of oncogenic signaling pathways that include PI3K/AKT, ERK1/2, MEK1/2, and mTOR that promote cancer cell survival leading to poor therapeutic outcomes.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mTOR', 'Gene', '2475', (111, 115))	('AKT', 'Gene', (86, 89))	('mTOR', 'Gene', (111, 115))	('cancer', 'Disease', (129, 135))	('oncogenic signaling pathways', 'Pathway', (39, 67))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('plethora', 'Phenotype', 'HP:0001050', (27, 35))	('Mutant', 'Var', (0, 6))	('ERK1/2', 'Gene', '5595;5594', (91, 97))	('MEK1/2', 'Gene', '5604;5605', (99, 105))	('ERK1/2', 'Gene', (91, 97))	('MEK1/2', 'Gene', (99, 105))	('AKT', 'Gene', '207', (86, 89))	('promote', 'PosReg', (121, 128))	('activate', 'PosReg', (16, 24))	('KRAS', 'Gene', (7, 11))
175526	30342037	In addition, GI tumors with mutant KRAS are resistant to treatment with targeted agent therapies, such as EGFR inhibitors (cetuximab and panitumumab) , MEK inhibitor (CI-1040) , and BRAF inhibitor (vemurafenib) .	('mutant', 'Var', (28, 34))	('GI tumors', 'Disease', 'MESH:D046152', (13, 22))	('KRAS', 'Gene', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('vemurafenib', 'Chemical', 'MESH:C551177', (198, 209))	('MEK', 'Gene', (152, 155))	('BRAF', 'Gene', '673', (182, 186))	('GI tumors', 'Phenotype', 'HP:0007378', (13, 22))	('BRAF', 'Gene', (182, 186))	('MEK', 'Gene', '5609', (152, 155))	('GI tumors', 'Disease', (13, 22))	('EGFR', 'Gene', (106, 110))
175527	30342037	We have shown that pharmacological inhibition of AURKA by alisertib or its knockdown can significantly reduce viability of luminal GI cancer cells with KRAS activation, in vitro and in vivo.	('alisertib', 'Chemical', 'MESH:C550258', (58, 67))	('GI cancer', 'Phenotype', 'HP:0007378', (131, 140))	('AURKA', 'Gene', (49, 54))	('knockdown', 'Var', (75, 84))	('luminal GI cancer', 'Disease', 'MESH:D009369', (123, 140))	('reduce', 'NegReg', (103, 109))	('viability', 'CPA', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('luminal GI cancer', 'Disease', (123, 140))
175538	30342037	However, expression of exogenous mutant KRASG12D induced expression of AURKA and phosphorylation of RPS6KB1 in cancer cells with wild-type KRAS.	('expression', 'MPA', (57, 67))	('phosphorylation', 'MPA', (81, 96))	('AURKA', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('phospho', 'Chemical', 'MESH:C033601', (81, 88))	('G12D', 'Mutation', 'rs121913529', (44, 48))	('induced', 'Reg', (49, 56))	('mutant', 'Var', (33, 39))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('KRASG12D', 'Gene', (40, 48))	('RPS6KB1', 'Gene', (100, 107))
175542	30342037	A study by Tseng, et al revealed that AURKA and mutant RASv are overexpressed in bladder and colon cancers.	('mutant', 'Var', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('colon cancers', 'Phenotype', 'HP:0003003', (93, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('bladder and colon cancers', 'Disease', 'MESH:D001749', (81, 106))	('overexpressed', 'PosReg', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('RASv', 'Gene', (55, 59))
175547	30342037	Using in vitro and in vivo, our results demonstrated that inhibition of AURKA, using alisertib, in KRAS-driven cells inhibited cancer cell growth and significantly reduced tumor volumes.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (172, 177))	('AURKA', 'Gene', (72, 77))	('inhibition', 'Var', (58, 68))	('alisertib', 'Chemical', 'MESH:C550258', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('inhibited', 'NegReg', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('reduced', 'NegReg', (164, 171))
175550	30342037	Our findings suggest that inhibition of AURKA may restore efficacy to selumetinib; however, given the complexity of signaling in cancer cells, additional investigations are needed.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('selumetinib', 'Chemical', 'MESH:C517975', (70, 81))	('AURKA', 'Protein', (40, 45))	('inhibition', 'Var', (26, 36))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('efficacy', 'MPA', (58, 66))
175552	30342037	To this end, we hope that our data will be useful when developing strategies for the treatment of KRAS mutant tumors.	('mutant', 'Var', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('KRAS', 'Gene', (98, 102))
175592	29973582	The tumor targeting and enhanced cancer cell internalization capabilities of the RGD-f-PNPs/EPI are characterized in vitro using EC cells.	('tumor', 'Disease', (4, 9))	('RGD-f-PNPs/EPI', 'Var', (81, 95))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('enhanced', 'PosReg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('f', 'Chemical', 'MESH:D005461', (75, 76))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('f', 'Chemical', 'MESH:D005461', (85, 86))
175595	29973582	In addition, the drug delivery to tumor sites and therapeutic responses could be monitored in vivo with NIR fluorescence from RGD-f-PNPs/EPI.	('NIR fluorescence', 'MPA', (104, 120))	('tumor', 'Disease', (34, 39))	('RGD-f-PNPs/EPI', 'Var', (126, 140))	('f', 'Chemical', 'MESH:D005461', (121, 122))	('f', 'Chemical', 'MESH:D005461', (108, 109))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('f', 'Chemical', 'MESH:D005461', (130, 131))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
175596	29973582	As a result, the RGD-f-PNPs could serve as a biocompatible nanoplatform for both EC imaging and enhanced therapeutic effects.	('RGD-f-PNPs', 'Var', (17, 27))	('f', 'Chemical', 'MESH:D005461', (119, 120))	('enhanced', 'PosReg', (96, 104))	('f', 'Chemical', 'MESH:D005461', (21, 22))	('f', 'Chemical', 'MESH:D005461', (72, 73))	('f', 'Chemical', 'MESH:D005461', (118, 119))	('f', 'Chemical', 'MESH:D005461', (67, 68))	('therapeutic effects', 'CPA', (105, 124))	('f-PNPs', 'Chemical', '-', (21, 27))
175604	29973582	The pi-pi stacking interactions between the tryptophans can serve as the driving force for self-assembly and also increase electronic polarizability.	('pi-pi', 'Var', (4, 9))	('increase', 'PosReg', (114, 122))	('f', 'Chemical', 'MESH:D005461', (87, 88))	('electronic polarizability', 'MPA', (123, 148))	('f', 'Chemical', 'MESH:D005461', (94, 95))	('f', 'Chemical', 'MESH:D005461', (81, 82))	('tryptophans', 'Chemical', 'MESH:D014364', (44, 55))
175629	29973582	Through pi-pi stacking and electrostatic interactions, EPI had a tendency to stack with the aromatic RGD-f-PNPs (Fig.	('EPI', 'Gene', (55, 58))	('EPI', 'Gene', '13851', (55, 58))	('electrostatic interactions', 'CPA', (27, 53))	('f-PNPs', 'Chemical', '-', (105, 111))	('pi-pi', 'Var', (8, 13))
175646	29973582	3b, a strong blue fluorescence with plasma membrane pattern was observed in KYSE-30 cells 30 min after the addition of RGD-f-PNPs/EPI into the culture medium.	('RGD-f-PNPs/EPI', 'Var', (119, 133))	('f', 'Chemical', 'MESH:D005461', (18, 19))	('f', 'Chemical', 'MESH:D005461', (117, 118))	('blue fluorescence', 'MPA', (13, 30))	('f', 'Chemical', 'MESH:D005461', (98, 99))	('f', 'Chemical', 'MESH:D005461', (123, 124))
175649	29973582	These data suggested that RGD peptide moieties enhance the specific binding between nanoparticles and EC cells, which facilitate selective targeting of RGD-f-PNPs/EPI to EC cells vs. normal epithelial cells.	('enhance', 'PosReg', (47, 54))	('facilitate', 'PosReg', (118, 128))	('f', 'Chemical', 'MESH:D005461', (118, 119))	('f', 'Chemical', 'MESH:D005461', (156, 157))	('specific', 'MPA', (59, 67))	('RGD-f-PNPs/EPI', 'Var', (152, 166))	('f', 'Chemical', 'MESH:D005461', (150, 151))	('f', 'Chemical', 'MESH:D005461', (64, 65))
175662	29973582	It is worthwhile to mention that the cell killing effects of RGD-f-PNPs/EPI was significantly higher than EPI alone in KYSE-30 cells, in which RGD-f-PNPs had selective targeting through RGD-integrin alphavbeta3 subunit binding.	('EPI', 'Gene', (106, 109))	('integrin alphavbeta3', 'Gene', (190, 210))	('RGD-f-PNPs', 'Var', (143, 153))	('binding', 'Interaction', (219, 226))	('f', 'Chemical', 'MESH:D005461', (59, 60))	('cell killing effects', 'CPA', (37, 57))	('EPI', 'Gene', '13851', (106, 109))	('f', 'Chemical', 'MESH:D005461', (147, 148))	('f', 'Chemical', 'MESH:D005461', (52, 53))	('f-PNPs', 'Chemical', '-', (65, 71))	('f', 'Chemical', 'MESH:D005461', (65, 66))	('f', 'Chemical', 'MESH:D005461', (51, 52))	('EPI', 'Gene', '13851', (72, 75))	('EPI', 'Gene', (72, 75))	('integrin alphavbeta3', 'Gene', '3685', (190, 210))	('f-PNPs', 'Chemical', '-', (147, 153))	('f', 'Chemical', 'MESH:D005461', (85, 86))	('higher', 'PosReg', (94, 100))
175666	29973582	4d, a much brighter intracellular fluorescence of EPI was observed in cells incubated with RGD-f-PNPs/EPI vs. cells incubated with EPI only, indicating that the RGD-f-PNPs could facilitate the cellular uptake and intracellular accumulation of EPI into the EC cells.	('f', 'Chemical', 'MESH:D005461', (48, 49))	('f-PNPs', 'Chemical', '-', (95, 101))	('EPI', 'Gene', '13851', (131, 134))	('f', 'Chemical', 'MESH:D005461', (95, 96))	('EPI', 'Gene', (243, 246))	('EPI', 'Gene', '13851', (50, 53))	('f', 'Chemical', 'MESH:D005461', (165, 166))	('facilitate', 'PosReg', (178, 188))	('EPI', 'Gene', (131, 134))	('cellular uptake', 'CPA', (193, 208))	('EPI', 'Gene', (50, 53))	('f-PNPs', 'Chemical', '-', (165, 171))	('RGD-f-PNPs', 'Var', (161, 171))	('f', 'Chemical', 'MESH:D005461', (34, 35))	('EPI', 'Gene', '13851', (102, 105))	('f', 'Chemical', 'MESH:D005461', (178, 179))	('f', 'Chemical', 'MESH:D005461', (241, 242))	('intracellular accumulation', 'CPA', (213, 239))	('EPI', 'Gene', (102, 105))	('EPI', 'Gene', '13851', (243, 246))
175670	29973582	When the tumors reached a diameter of about 5 mm, the tumor-bearing mice were randomly divided into four treatment groups: control (saline only), EPI, RGD-f-PNPs, and RGD-f-PNPs/EPI.	('EPI', 'Gene', '13851', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('EPI', 'Gene', '13851', (146, 149))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('EPI', 'Gene', (178, 181))	('mice', 'Species', '10090', (68, 72))	('EPI', 'Gene', (146, 149))	('f-PNPs', 'Chemical', '-', (171, 177))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('f', 'Chemical', 'MESH:D005461', (171, 172))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('f-PNPs', 'Chemical', '-', (155, 161))	('f', 'Chemical', 'MESH:D005461', (100, 101))	('f', 'Chemical', 'MESH:D005461', (155, 156))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('saline', 'Chemical', 'MESH:D012965', (132, 138))	('f', 'Chemical', 'MESH:D005461', (36, 37))	('RGD-f-PNPs', 'Var', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumor', 'Disease', (54, 59))
175680	29973582	The histological data suggested that EPI conjugated with RGD-f-PNPs have less cardiotoxicity.	('cardiotoxicity', 'Disease', (78, 92))	('f-PNPs', 'Chemical', '-', (61, 67))	('RGD-f-PNPs', 'Var', (57, 67))	('EPI', 'Gene', (37, 40))	('cardiotoxicity', 'Disease', 'MESH:D066126', (78, 92))	('EPI', 'Gene', '13851', (37, 40))
175682	29973582	These data showed an enhanced anti-tumor efficacy in vivo, which is likely a result of the specific tumor targeting and efficient delivery of RGD-f-PNPs/EPI.	('f', 'Chemical', 'MESH:D005461', (140, 141))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('f', 'Chemical', 'MESH:D005461', (42, 43))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('f', 'Chemical', 'MESH:D005461', (121, 122))	('f', 'Chemical', 'MESH:D005461', (96, 97))	('enhanced', 'PosReg', (21, 29))	('tumor', 'Disease', (100, 105))	('f', 'Chemical', 'MESH:D005461', (85, 86))	('tumor', 'Disease', (35, 40))	('f', 'Chemical', 'MESH:D005461', (146, 147))	('f', 'Chemical', 'MESH:D005461', (43, 44))	('RGD-f-PNPs/EPI', 'Var', (142, 156))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('f', 'Chemical', 'MESH:D005461', (122, 123))
175695	29973582	In vivo studies further confirmed that RGD-f-PNPs/EPI could achieve similar anti-tumor effects at a lower dose with much less side effects (Fig.	('f', 'Chemical', 'MESH:D005461', (27, 28))	('f', 'Chemical', 'MESH:D005461', (89, 90))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('f', 'Chemical', 'MESH:D005461', (132, 133))	('RGD-f-PNPs/EPI', 'Var', (39, 53))	('f', 'Chemical', 'MESH:D005461', (88, 89))	('f', 'Chemical', 'MESH:D005461', (16, 17))	('f', 'Chemical', 'MESH:D005461', (43, 44))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('f', 'Chemical', 'MESH:D005461', (133, 134))	('tumor', 'Disease', (81, 86))
175699	29973582	After 30 min of RGD-f-PNPs and RGD-f-PNPs/EPI injection, the xenograft tumors were clearly visualized in live animal NIR imaging with relative low background (Fig.	('f', 'Chemical', 'MESH:D005461', (68, 69))	('f', 'Chemical', 'MESH:D005461', (14, 15))	('f-PNPs', 'Chemical', '-', (35, 41))	('xenograft tumors', 'Disease', (61, 77))	('f', 'Chemical', 'MESH:D005461', (35, 36))	('RGD-f-PNPs/EPI', 'Var', (31, 45))	('RGD-f-PNPs', 'Var', (16, 26))	('f', 'Chemical', 'MESH:D005461', (1, 2))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('f-PNPs', 'Chemical', '-', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('xenograft tumors', 'Disease', 'MESH:D009369', (61, 77))	('f', 'Chemical', 'MESH:D005461', (20, 21))
175707	29973582	Clear NIR fluorescence was observed in the tumors isolated from animals injected with RGD-f-PNPs and RGD-f-PNPs/EPI, but not in the control or EPI-treated groups (Fig.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('f', 'Chemical', 'MESH:D005461', (10, 11))	('EPI', 'Gene', (143, 146))	('f-PNPs', 'Chemical', '-', (90, 96))	('EPI', 'Gene', '13851', (143, 146))	('f', 'Chemical', 'MESH:D005461', (59, 60))	('RGD-f-PNPs', 'Var', (86, 96))	('f', 'Chemical', 'MESH:D005461', (90, 91))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('f-PNPs', 'Chemical', '-', (105, 111))	('tumors', 'Disease', (43, 49))	('EPI', 'Gene', (112, 115))	('f', 'Chemical', 'MESH:D005461', (105, 106))	('EPI', 'Gene', '13851', (112, 115))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
175708	29973582	It is worthwhile to note that the tumors isolated from the RGD-f-PNPs/EPI group were much smaller than those from the control and RGD-f-PNP-only groups.	('f', 'Chemical', 'MESH:D005461', (63, 64))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('smaller', 'NegReg', (90, 97))	('RGD-f-PNPs/EPI', 'Var', (59, 73))	('f-PNP', 'Chemical', '-', (134, 139))	('f-PNP', 'Chemical', '-', (63, 68))	('f', 'Chemical', 'MESH:D005461', (50, 51))	('f', 'Chemical', 'MESH:D005461', (109, 110))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('f', 'Chemical', 'MESH:D005461', (134, 135))
175709	29973582	These data demonstrated that the RGD-f-PNPs/EPI could reach, penetrate, and remain in the tumor sites, and the NIR fluorescence from these peptide nanoparticles was bright enough to be visualized using a standard NIR small animal imaging platform.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('f', 'Chemical', 'MESH:D005461', (115, 116))	('f', 'Chemical', 'MESH:D005461', (128, 129))	('f', 'Chemical', 'MESH:D005461', (37, 38))	('f', 'Chemical', 'MESH:D005461', (242, 243))	('RGD-f-PNPs/EPI', 'Var', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
175735	29973582	After removal of the medium, cells were incubated within BSS-Ca2+ (in mM: 140 NaCl, 2.8 KCl, 2 MgCl2, 10 HEPES, 2 Ca2+, pH 7.2) solution containing f-PNPs, EPI, or f-PNPs-EPI, respectively.	('Ca2+', 'Chemical', 'MESH:D000069285', (61, 65))	('NaCl', 'Chemical', 'MESH:D012965', (78, 82))	('EPI', 'Gene', (171, 174))	('HEPES', 'Chemical', 'MESH:D006531', (105, 110))	('f', 'Chemical', 'MESH:D005461', (164, 165))	('f-PNPs', 'Var', (148, 154))	('EPI', 'Gene', '13851', (171, 174))	('f-PNPs', 'Chemical', '-', (148, 154))	('f', 'Chemical', 'MESH:D005461', (148, 149))	('EPI', 'Gene', (156, 159))	('f', 'Chemical', 'MESH:D005461', (1, 2))	('f', 'Chemical', 'MESH:D005461', (15, 16))	('Ca2+', 'Chemical', 'MESH:D000069285', (114, 118))	('EPI', 'Gene', '13851', (156, 159))	('KCl', 'Chemical', 'MESH:D011189', (88, 91))	('f-PNPs', 'Chemical', '-', (164, 170))	('MgCl2', 'Chemical', 'MESH:D015636', (95, 100))
175830	28652771	The overall HR/OR and its 95% CI greater than 1 were considered statistically significant and indicated a worse effect for the group with high/positive COX-2 expression.	('expression', 'MPA', (158, 168))	('COX-2', 'Gene', (152, 157))	('COX-2', 'Gene', '5743', (152, 157))	('high/positive', 'Var', (138, 151))
175835	28652771	The percentage of high/positive COX-2 expression was >50% in 15 studies, and the remaining 10 studies shared the percentage of high/positive COX-2 expression <50%.	('COX-2', 'Gene', (141, 146))	('expression', 'MPA', (38, 48))	('COX-2', 'Gene', '5743', (141, 146))	('COX-2', 'Gene', (32, 37))	('COX-2', 'Gene', '5743', (32, 37))	('high/positive', 'Var', (18, 31))
175840	28652771	When we conducted subgroup analysis by the percentage of high/positive COX-2 expression, we found that both studies with high/positive COX-2 expression >=50% and <50% showed the significant association (high/positive COX-2 >=50%: HR =1.55, 95% CI =1.35-1.78, P<0.001, I2=40.4%, P=0.064; low/negative COX-2 <50%: HR =1.53, 95% CI =1.02-2.29, P=0.038, I2=60.1%, P=0.005).	('COX-2', 'Gene', (300, 305))	('COX-2', 'Gene', '5743', (300, 305))	('COX-2', 'Gene', (135, 140))	('COX-2', 'Gene', '5743', (135, 140))	('COX-2', 'Gene', (71, 76))	('COX-2', 'Gene', '5743', (217, 222))	('COX-2', 'Gene', '5743', (71, 76))	('COX-2', 'Gene', (217, 222))	('low/negative', 'Var', (287, 299))
175841	28652771	When histology type was taken into consideration, high/positive COX-2 expression still had impact on OS in both ESCC and EADC patients (ESCC: HR =1.46, 95% CI =1.17-1.83, P=0.001, I2=52.0%, P=0.007; EADC: HR =2.13, 95% CI =1.62-2.79, P<0.001, I2=26.4%, P=0.246).	('high/positive', 'Var', (50, 63))	('impact', 'Reg', (91, 97))	('EADC', 'Disease', (121, 125))	('ESCC', 'Disease', (112, 116))	('patients', 'Species', '9606', (126, 134))	('COX-2', 'Gene', (64, 69))	('COX-2', 'Gene', '5743', (64, 69))
175842	28652771	Subgroup analysis by sample size (>=100 and <100) also suggested the significant prognostic impact of high/positive COX-2 expression (Table 2).	('high/positive', 'Var', (102, 115))	('expression', 'MPA', (122, 132))	('COX-2', 'Gene', (116, 121))	('COX-2', 'Gene', '5743', (116, 121))
175844	28652771	Our analysis suggested that high/positive COX-2 expression was significantly associated with the depth of invasion (T3/4 vs T1/2: OR =2.36, 95% CI =1.61-63.46, P<0.001, I2=57.8%, P=0.002; Figure 3A), distant metastasis (yes vs no: OR =1.41, 95% CI =1.02-1.95, P=0.037, I2=41.1%, P=0.117; Figure 3B), and TNM stage (III/IV vs I/II: OR =1.84, 95% CI =1.23-2.75, P=0.003, I2=67.1%, P<0.001; Figure 3C).	('COX-2', 'Gene', '5743', (42, 47))	('TNM', 'Gene', (304, 307))	('expression', 'MPA', (48, 58))	('depth of invasion', 'CPA', (97, 114))	('high/positive', 'Var', (28, 41))	('TNM', 'Gene', '10178', (304, 307))	('COX-2', 'Gene', (42, 47))	('distant metastasis', 'CPA', (200, 218))	('associated', 'Reg', (77, 87))
175850	28652771	Peng et al found that COX-2 765G>C polymorphism was associated with colorectal cancer risk.	('colorectal cancer', 'Disease', (68, 85))	('765G>C polymorphism', 'Var', (28, 47))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('765G>C', 'Mutation', 'rs20417', (28, 34))	('associated', 'Reg', (52, 62))	('COX-2', 'Gene', (22, 27))	('COX-2', 'Gene', '5743', (22, 27))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))
175852	28652771	COX-2 765G>C is a functional polymorphism located at 765 bp upstream (2,765 bp) from the transcription starting site.	('COX-2', 'Gene', (0, 5))	('765G>C', 'Var', (6, 12))	('COX-2', 'Gene', '5743', (0, 5))	('765G>C', 'Mutation', 'rs20417', (6, 12))
175867	25709470	XPA A23G polymorphism and risk of digestive system cancers: a meta-analysis Several studies have reported an association between the A23G polymorphism (rs 1800975) in the xeroderma pigmentosum group A (XPA) gene and risk of digestive system cancers.	('XPA', 'Gene', '7507', (0, 3))	('rs 1800975', 'Var', (152, 162))	('XPA', 'Gene', (202, 205))	('A23G', 'Mutation', 'rs1800975', (133, 137))	('system cancers', 'Disease', 'MESH:D009369', (234, 248))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('A23G', 'Mutation', 'rs1800975', (4, 8))	('system cancers', 'Disease', 'MESH:D009369', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('xeroderma pigmentosum group A', 'Gene', '7507', (171, 200))	('xeroderma pigmentosum group A', 'Gene', (171, 200))	('A23G', 'Var', (133, 137))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('system cancers', 'Disease', (44, 58))	('XPA', 'Gene', '7507', (202, 205))	('XPA', 'Gene', (0, 3))	('system cancers', 'Disease', (234, 248))
175868	25709470	In this study, we performed a meta-analysis to assess the association between XPA A23G polymorphism and the risk of digestive system cancers.	('association', 'Interaction', (58, 69))	('A23G', 'Mutation', 'rs1800975', (82, 86))	('polymorphism', 'Var', (87, 99))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('XPA', 'Gene', '7507', (78, 81))	('system cancers', 'Disease', (126, 140))	('XPA', 'Gene', (78, 81))	('system cancers', 'Disease', 'MESH:D009369', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
175871	25709470	Overall, no significant association was found between XPA A23G polymorphism and the risk of digestive system cancers (dominant model: GA + AA versus GG, OR 0.89, 95% CI 0.74-1.08; recessive model: AA versus GA + GG, OR 0.94, 95% CI 0.74-1.20; GA versus GG, OR 0.89, 95% CI 0.77-1.03; and AA versus GG, OR 0.87, 95% CI 0.64-1.19).	('system cancers', 'Disease', 'MESH:D009369', (102, 116))	('GA', 'Chemical', 'MESH:D005708', (243, 245))	('polymorphism', 'Var', (63, 75))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('A23G', 'Mutation', 'rs1800975', (58, 62))	('XPA', 'Gene', '7507', (54, 57))	('XPA', 'Gene', (54, 57))	('GA', 'Chemical', 'MESH:D005708', (207, 209))	('system cancers', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('GA', 'Chemical', 'MESH:D005708', (134, 136))
175872	25709470	In stratified analysis based on tumor type, we also failed to detect any association between XPA A23G polymorphism and the risk of esophageal, gastric, or colorectal cancers.	('polymorphism', 'Var', (102, 114))	('gastric', 'Disease', (143, 150))	('XPA', 'Gene', (93, 96))	('XPA', 'Gene', '7507', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('colorectal cancers', 'Disease', 'MESH:D015179', (155, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('esophageal', 'Disease', (131, 141))	('A23G', 'Mutation', 'rs1800975', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colorectal cancers', 'Disease', (155, 173))	('tumor', 'Disease', (32, 37))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
175873	25709470	This meta-analysis indicates that the XPA A23G polymorphism is not associated with a risk of digestive system cancers.	('XPA', 'Gene', (38, 41))	('XPA', 'Gene', '7507', (38, 41))	('system cancers', 'Disease', 'MESH:D009369', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('A23G', 'Mutation', 'rs1800975', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('polymorphism', 'Var', (47, 59))	('system cancers', 'Disease', (103, 117))
175877	25709470	Deregulation of DNA repair is a crucial factor in the multistep process of carcinogenesis.	('DNA repair', 'Protein', (16, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (75, 89))	('carcinogenesis', 'Disease', (75, 89))	('Deregulation', 'Var', (0, 12))
175882	25709470	In the XPA gene, a polymorphic site has been identified in the 5' untranslated region and consists of an A to G substitution in the fourth nucleotide before the ATG start codon (XPA A23G, rs 1800975).	('XPA', 'Gene', (7, 10))	('A23G', 'Mutation', 'rs1800975', (182, 186))	('rs 1800975', 'Var', (188, 198))	('XPA', 'Gene', '7507', (178, 181))	('XPA', 'Gene', '7507', (7, 10))	('XPA', 'Gene', (178, 181))
175883	25709470	To date, a large number of molecular epidemiologic studies have been conducted to assess the role of A23G polymorphism in XPA gene on various types of cancers, especially those affecting the digestive system.	('A23G polymorphism', 'Var', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('A23G', 'Mutation', 'rs1800975', (101, 105))	('cancers', 'Disease', (151, 158))	('polymorphism', 'Var', (106, 118))	('XPA', 'Gene', (122, 125))	('XPA', 'Gene', '7507', (122, 125))
175885	25709470	Therefore, we conducted a meta-analysis to evaluate the association between XPA A23G polymorphism and the susceptibility to digestive system cancers.	('XPA', 'Gene', '7507', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('XPA', 'Gene', (76, 79))	('system cancers', 'Disease', (134, 148))	('A23G', 'Mutation', 'rs1800975', (80, 84))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('system cancers', 'Disease', 'MESH:D009369', (134, 148))	('polymorphism', 'Var', (85, 97))
175887	25709470	The last search update was August 30, 2014, using the search terms: "xeroderma pigmentosum group A or XPA or DNA repair gene or NER", "genetic polymorphism or polymorphisms or variant", and "digestive system cancer or gastrointestinal cancers or gastric cancer or colorectal cancer or hepatocellular carcinoma or esophageal cancer or pancreatic cancer".	('colorectal cancer', 'Disease', 'MESH:D015179', (264, 281))	('system cancer', 'Disease', (201, 214))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (285, 309))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (218, 242))	('gastric cancer', 'Disease', (246, 260))	('esophageal cancer', 'Disease', 'MESH:D004938', (313, 330))	('pancreatic cancer', 'Disease', (334, 351))	('colorectal cancer', 'Disease', (264, 281))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('variant', 'Var', (176, 183))	('esophageal cancer', 'Disease', (313, 330))	('hepatocellular carcinoma', 'Disease', (285, 309))	('gastrointestinal cancers', 'Disease', (218, 242))	('gastric cancer', 'Disease', 'MESH:D013274', (246, 260))	('XPA', 'Gene', '7507', (102, 105))	('xeroderma pigmentosum group A', 'Gene', '7507', (69, 98))	('xeroderma pigmentosum group A', 'Gene', (69, 98))	('XPA', 'Gene', (102, 105))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (334, 351))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('colorectal cancer', 'Phenotype', 'HP:0003003', (264, 281))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('gastric cancer', 'Phenotype', 'HP:0012126', (246, 260))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (285, 309))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('pancreatic cancer', 'Disease', 'MESH:D010190', (334, 351))	('system cancer', 'Disease', 'MESH:D009369', (201, 214))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
175890	25709470	Studies included in this meta-analysis had to meet the following criteria: studies that evaluated the association between XPA A23G polymorphism and digestive system cancers, in a case-control study design, and had detailed genotype frequency of cases and controls or could be calculated from the article text.	('association', 'Interaction', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('A23G', 'Mutation', 'rs1800975', (126, 130))	('polymorphism', 'Var', (131, 143))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('system cancers', 'Disease', (158, 172))	('XPA', 'Gene', (122, 125))	('system cancers', 'Disease', 'MESH:D009369', (158, 172))	('XPA', 'Gene', '7507', (122, 125))
175892	25709470	The risk of digestive system cancers associated with XPA A23G polymorphism was estimated for each study by odds ratio (OR) and 95% confidence interval (CI).	('A23G', 'Mutation', 'rs1800975', (57, 61))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('polymorphism', 'Var', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('system cancers', 'Disease', (22, 36))	('XPA', 'Gene', '7507', (53, 56))	('XPA', 'Gene', (53, 56))	('system cancers', 'Disease', 'MESH:D009369', (22, 36))
175895	25709470	Therefore, as shown in Table 1, there were 18 case-control studies with 4,170 cases and 6,929 controls concerning XPA A23G polymorphism.	('A23G', 'Mutation', 'rs1800975', (118, 122))	('XPA', 'Gene', (114, 117))	('polymorphism', 'Var', (123, 135))	('XPA', 'Gene', '7507', (114, 117))
175897	25709470	As shown in Table 2, overall no significant association was found between XPA A23G polymorphism and the risk of digestive system cancers (dominant model: OR 0.89, 95% CI 0.74-1.08; recessive model: OR 0.94, 95% CI 0.74-1.20; GA versus GG, OR 0.89, 95% CI 0.77-1.03; and AA versus GG, OR 0.87, 95% CI 0.64-1.19, Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('polymorphism', 'Var', (83, 95))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('XPA', 'Gene', '7507', (74, 77))	('system cancers', 'Disease', (122, 136))	('XPA', 'Gene', (74, 77))	('system cancers', 'Disease', 'MESH:D009369', (122, 136))	('GA', 'Chemical', 'MESH:D005708', (225, 227))	('A23G', 'Mutation', 'rs1800975', (78, 82))
175898	25709470	In subgroup analysis by ethnicity, there was no significant association between XPA A23G polymorphism and the risk of digestive system cancers in either Asians or Caucasians (Table 2, Figure 3).	('polymorphism', 'Var', (89, 101))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('XPA', 'Gene', '7507', (80, 83))	('system cancers', 'Disease', (128, 142))	('system cancers', 'Disease', 'MESH:D009369', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('XPA', 'Gene', (80, 83))	('A23G', 'Mutation', 'rs1800975', (84, 88))
175899	25709470	In addition, only one study focused on hepatocellular carcinoma, and the results showed no association between XPA A23G polymorphism and the risk of hepatocellular carcinoma (Table 2, Figure 4).	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('XPA', 'Gene', (111, 114))	('XPA', 'Gene', '7507', (111, 114))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (149, 173))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('hepatocellular carcinoma', 'Disease', (149, 173))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (149, 173))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('A23G', 'Mutation', 'rs1800975', (115, 119))	('hepatocellular carcinoma', 'Disease', (39, 63))	('polymorphism', 'Var', (120, 132))
175900	25709470	When the analysis was stratified by source of control, we found that XPA A23G polymorphism was associated with a decreased risk of digestive system cancers in population-based models (GA versus GG, OR 0.86, 95% CI 0.77-0.96), but not in other genetic models or hospital-based populations (Table 2).	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('system cancers', 'Disease', (141, 155))	('XPA', 'Gene', (69, 72))	('XPA', 'Gene', '7507', (69, 72))	('system cancers', 'Disease', 'MESH:D009369', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('GA', 'Chemical', 'MESH:D005708', (184, 186))	('A23G', 'Mutation', 'rs1800975', (73, 77))	('polymorphism', 'Var', (78, 90))	('decreased', 'NegReg', (113, 122))
175902	25709470	Substantial heterogeneity was observed between studies for the association between XPA A23G polymorphism and digestive system cancer risk in all genetic models (dominant model: I2=73%, P<0.00001; recessive model: I2=83%, P<0.00001; GA versus GG, I2=52%, P=0.005; and AA versus GG, I2=83%, P<0.00001).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('XPA', 'Gene', '7507', (83, 86))	('XPA', 'Gene', (83, 86))	('system cancer', 'Disease', 'MESH:D009369', (119, 132))	('association', 'Interaction', (63, 74))	('A23G', 'Mutation', 'rs1800975', (87, 91))	('polymorphism', 'Var', (92, 104))	('GA', 'Chemical', 'MESH:D005708', (232, 234))	('system cancer', 'Disease', (119, 132))
175911	25709470	Recently, A23G polymorphism of the XPA gene was reported to confer a risk of digestive system cancers.	('system cancers', 'Disease', (87, 101))	('XPA', 'Gene', (35, 38))	('system cancers', 'Disease', 'MESH:D009369', (87, 101))	('XPA', 'Gene', '7507', (35, 38))	('A23G', 'Mutation', 'rs1800975', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('risk', 'Reg', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('A23G polymorphism', 'Var', (10, 27))
175915	25709470	A recent meta-analysis evaluated the association between XPA A23G polymorphism and cancer risk, and reported that this polymorphism is associated with an increased lung cancer risk and may be a low-penetrant risk factor for development of cancer in people of Asian ethnicity.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('people', 'Species', '9606', (249, 255))	('XPA', 'Gene', '7507', (57, 60))	('XPA', 'Gene', (57, 60))	('A23G', 'Mutation', 'rs1800975', (61, 65))	('lung cancer', 'Disease', (164, 175))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('increased', 'PosReg', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('association', 'Interaction', (37, 48))	('polymorphism', 'Var', (66, 78))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (83, 89))
175916	25709470	Subsequently, Liu et al conducted another meta-analysis to assess the association between A23G polymorphism and risk of cancer, and suggested that the XPA A23G G allele is a low-penetrant risk factor for development of cancer.	('XPA', 'Gene', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('A23G', 'Var', (90, 94))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('A23G', 'Mutation', 'rs1800975', (155, 159))	('cancer', 'Disease', (219, 225))	('A23G', 'Mutation', 'rs1800975', (90, 94))	('XPA', 'Gene', '7507', (151, 154))
175919	25709470	In this meta-analysis, we pooled 18 studies to explore the association between A23G polymorphism and risk of gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (109, 133))	('gastrointestinal cancers', 'Disease', (109, 133))	('A23G', 'Mutation', 'rs1800975', (79, 83))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('polymorphism', 'Var', (84, 96))	('A23G', 'Gene', (79, 83))
175920	25709470	The results demonstrated that XPA A23G polymorphism is not associated with digestive system cancer risk.	('system cancer', 'Disease', 'MESH:D009369', (85, 98))	('A23G', 'Mutation', 'rs1800975', (34, 38))	('system cancer', 'Disease', (85, 98))	('XPA', 'Gene', '7507', (30, 33))	('polymorphism', 'Var', (39, 51))	('XPA', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
175923	25709470	The discrepancies are probably due to the small size of the A23G polymorphism in determining susceptibility to digestive system cancers in the previous meta-analyses.	('A23G', 'Mutation', 'rs1800975', (60, 64))	('system cancers', 'Disease', (121, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('system cancers', 'Disease', 'MESH:D009369', (121, 135))	('A23G', 'Var', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
175931	25709470	In summary, this meta-analysis suggests that XPA A23G polymorphism is not associated with a risk of digestive system cancers.	('XPA', 'Gene', '7507', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('XPA', 'Gene', (45, 48))	('system cancers', 'Disease', (110, 124))	('system cancers', 'Disease', 'MESH:D009369', (110, 124))	('A23G', 'Mutation', 'rs1800975', (49, 53))	('polymorphism', 'Var', (54, 66))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))
175932	24396479	Study of the polymorphisms of cyclooxygenase-2 (-765G>C) and 5-lipoxygenase (1708G>A) in patients with colorectal cancer Colorectal cancer (CRC) is the fourth most common cause of cancer-related mortality worldwide.	('Colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))	('-765G>C', 'Mutation', 'rs20417', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('5-lipoxygenase', 'Gene', '240', (61, 75))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('Colorectal cancer', 'Disease', (121, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('CRC', 'Phenotype', 'HP:0003003', (140, 143))	('colorectal cancer', 'Disease', (103, 120))	('cyclooxygenase-2', 'Gene', '5743', (30, 46))	('cancer', 'Disease', (180, 186))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('1708G>A', 'Var', (77, 84))	('-765G>C', 'Var', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cyclooxygenase-2', 'Gene', (30, 46))	('rectal cancer', 'Phenotype', 'HP:0100743', (107, 120))	('5-lipoxygenase', 'Gene', (61, 75))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('1708G>A', 'Mutation', 'rs957289897', (77, 84))	('cancer', 'Disease', (132, 138))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (114, 120))
175933	24396479	Genetic alterations have been associated with an increased risk of cancer and greater tumor aggressiveness.	('associated', 'Reg', (30, 40))	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor aggressiveness', 'Disease', (86, 106))	('cancer', 'Disease', (67, 73))	('aggressiveness', 'Phenotype', 'HP:0000718', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (86, 106))
175935	24396479	The aim of the present study was to investigate the association between polymorphisms in the COX-2 and 5-LOX genes and the risk of CRC.	('5-LOX', 'Gene', '240', (103, 108))	('CRC', 'Disease', (131, 134))	('COX-2 and 5', 'Gene', '4513', (93, 104))	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('5-LOX', 'Gene', (103, 108))	('polymorphisms', 'Var', (72, 85))
175939	24396479	The heterozygous GC genotype of the COX-2 gene polymorphism was the most common in the two groups (60.0% in CRC patients and 52.7% in controls).	('common', 'Reg', (73, 79))	('patients', 'Species', '9606', (112, 120))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('COX-2', 'Gene', (36, 41))	('COX-2', 'Gene', '5743', (36, 41))	('polymorphism', 'Var', (47, 59))	('CRC', 'Disease', (108, 111))
175947	24396479	The gene transcriptional effect is inhibited by hypermethylation in the promoter region and oxidative damage to nuclear DNA, which are two of the main mechanisms associated with the early stages of colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', (198, 223))	('hypermethylation', 'Var', (48, 64))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (198, 223))	('inhibited', 'NegReg', (35, 44))
175948	24396479	SNPs usually occur in non-coding regions, however, SNPs that occur in the coding regions of genes are frequently associated with various diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('SNPs', 'Var', (51, 55))	('cancer', 'Disease', (157, 163))	('associated', 'Reg', (113, 123))
175949	24396479	Numerous genetic alterations, including polymorphisms in the cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) genes, have been associated with an increased risk of CRC and a poor prognosis, as well as a high fat intake, which increases the risk of developing tumors due to arachidonic acid metabolism that produces proinflammatory substances.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('arachidonic acid', 'Chemical', 'MESH:D016718', (272, 288))	('CRC', 'Disease', (163, 166))	('associated', 'Reg', (126, 136))	('alterations', 'Var', (17, 28))	('fat', 'Gene', '2195', (207, 210))	('tumors', 'Disease', (258, 264))	('polymorphisms', 'Var', (40, 53))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('CRC', 'Phenotype', 'HP:0003003', (163, 166))	('cyclooxygenase (COX)-2', 'Gene', (61, 83))	('5-lipoxygenase', 'Gene', '240', (88, 102))	('cyclooxygenase (COX)-2', 'Gene', '4513', (61, 83))	('5-lipoxygenase', 'Gene', (88, 102))	('fat', 'Gene', (207, 210))
175954	24396479	In 2002, the COX-2 gene -765G>C polymorphism was described by Papafili et al and associated with a higher susceptibility to cancer.	('cancer', 'Disease', (124, 130))	('susceptibility', 'Reg', (106, 120))	('-765G>C', 'Mutation', 'rs20417', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('COX-2', 'Gene', (13, 18))	('gene -765G>C polymorphism', 'Var', (19, 44))	('COX-2', 'Gene', '5743', (13, 18))	('associated', 'Reg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
175960	24396479	The aim of the present study was to analyze the -765G>C polymorphism in the COX-2 gene and the -1708G>A polymorphism in the 5-LOX gene in patients with CRC, and to correlate these polymorphisms with lifestyle and dietary habits.	('CRC', 'Disease', (152, 155))	('COX-2', 'Gene', (76, 81))	('COX-2', 'Gene', '5743', (76, 81))	('the -1708G>A', 'Var', (91, 103))	('5-LOX', 'Gene', '240', (124, 129))	('-765G>C', 'Mutation', 'rs20417', (48, 55))	('CRC', 'Phenotype', 'HP:0003003', (152, 155))	('5-LOX', 'Gene', (124, 129))	('-1708G>A', 'Mutation', 'c.-1708G>A', (95, 103))	('patients', 'Species', '9606', (138, 146))
175979	24396479	Allele C was also associated with a higher risk of cancer (Table II).	('Allele C', 'Var', (0, 8))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
175985	24396479	The present study investigated whether polymorphisms of COX-2 and 5-LOX are associated with the risk of CRC, in addition to the correlation between these polymorphisms and lifestyle.	('CRC', 'Disease', (104, 107))	('polymorphisms', 'Var', (39, 52))	('5-LOX', 'Gene', '240', (66, 71))	('COX-2 and 5', 'Gene', '4513', (56, 67))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('associated', 'Reg', (76, 86))	('5-LOX', 'Gene', (66, 71))
175987	24396479	The consumption of red meat has been associated with an increased production of free radicals, which cause oxidative damage to epithelial cells and genetic mutations.	('free radicals', 'Chemical', 'MESH:D005609', (80, 93))	('oxidative damage', 'MPA', (107, 123))	('production of free radicals', 'MPA', (66, 93))	('cause', 'Reg', (101, 106))	('genetic mutations', 'Var', (148, 165))
175991	24396479	Previous epidemiological studies have shown that acetylsalicylic acid is able to reduce the incidence of CRC by 40-50%.	('reduce', 'NegReg', (81, 87))	('CRC', 'Disease', (105, 108))	('acetylsalicylic acid', 'Var', (49, 69))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('acetylsalicylic acid', 'Chemical', 'MESH:D001241', (49, 69))
175993	24396479	Previously, Pandey et al found no correlation between smoking and COX-2 polymorphisms in patients with cancer of the cervix.	('COX-2', 'Gene', (66, 71))	('COX-2', 'Gene', '5743', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (89, 97))	('polymorphisms', 'Var', (72, 85))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
175994	24396479	Although certain studies have previously reported an association between alcohol, low vitamin intake and cancer, no consensus exists in the literature.	('low vitamin', 'Var', (82, 93))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('alcohol', 'Chemical', 'MESH:D000438', (73, 80))
175996	24396479	COX-2 polymorphisms have been associated with an increased risk of cancer.	('associated', 'Reg', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('polymorphisms', 'Var', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))
175998	24396479	The COX-2 gene -765G>C polymorphism has been shown to modify the gene transcription that may cause an alteration in the binding capacity of specificity protein 1 and consequently, an increased expression of COX-2.	('binding', 'Interaction', (120, 127))	('gene -765G>C polymorphism', 'Var', (10, 35))	('specificity protein 1', 'Gene', '6667', (140, 161))	('increased', 'PosReg', (183, 192))	('specificity protein 1', 'Gene', (140, 161))	('gene transcription', 'MPA', (65, 83))	('COX-2', 'Gene', (207, 212))	('modify', 'Reg', (54, 60))	('-765G>C', 'Mutation', 'rs20417', (15, 22))	('COX-2', 'Gene', (4, 9))	('COX-2', 'Gene', '5743', (207, 212))	('polymorphism', 'Var', (23, 35))	('expression', 'MPA', (193, 203))	('alteration', 'Reg', (102, 112))	('COX-2', 'Gene', '5743', (4, 9))
175999	24396479	The homozygous mutant CC genotype has been associated with a high incidence of leukemia and bladder, breast and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('leukemia', 'Disease', 'MESH:D007938', (79, 87))	('leukemia', 'Disease', (79, 87))	('bladder', 'Disease', (92, 99))	('associated', 'Reg', (43, 53))	('breast and esophageal cancer', 'Disease', 'MESH:D004938', (101, 129))	('homozygous mutant', 'Var', (4, 21))
176002	24396479	Kristinsson et al, studying COX-2 polymorphisms (765G>C and 1195A>G), observed that the GG/GG haplotype was more frequent in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (125, 150))	('GG/GG', 'Var', (88, 93))	('1195A>G', 'Mutation', 'rs689466', (60, 67))	('COX-2', 'Gene', '5743', (28, 33))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (125, 150))	('frequent', 'Reg', (113, 121))	('765G>C', 'Mutation', 'rs20417', (49, 55))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (125, 150))	('COX-2', 'Gene', (28, 33))
176004	24396479	In the current study, the mutant CC genotype of the COX-2 gene polymorphism increased the risk of CRC by ~2-fold (Table II) and by ~5-fold when combined with physical inactivity and consumption of fried foods.	('COX-2', 'Gene', (52, 57))	('COX-2', 'Gene', '5743', (52, 57))	('increased', 'PosReg', (76, 85))	('CRC', 'Disease', (98, 101))	('mutant CC', 'Var', (26, 35))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))
176006	24396479	The polymorphism in the 5-LOX gene, resulting in a change of guanine to adenine at position 1,708, has been studied in CRC and lung, kidney, bladder, pancreas, esophageal and prostate cancer.	('adenine', 'Chemical', 'MESH:D000225', (72, 79))	('esophageal and prostate cancer', 'Disease', 'MESH:D011471', (160, 190))	('kidney', 'Disease', (133, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('pancreas', 'Disease', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('change', 'Reg', (51, 57))	('CRC', 'Disease', (119, 122))	('5-LOX', 'Gene', (24, 29))	('5-LOX', 'Gene', '240', (24, 29))	('bladder', 'Disease', (141, 148))	('CRC', 'Phenotype', 'HP:0003003', (119, 122))	('guanine', 'Chemical', 'MESH:D006147', (61, 68))	('polymorphism', 'Var', (4, 16))
176011	24396479	In addition, Shen et al described an increased risk of lung cancer in the sputum of patients carrying the 12-LOX (GA) polymorphism.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('12-LOX', 'Gene', '246', (106, 112))	('patients', 'Species', '9606', (84, 92))	('12-LOX', 'Gene', (106, 112))	('polymorphism', 'Var', (118, 130))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
176014	24396479	In conclusion, the current study identified a significant difference in the distribution of the COX-2 gene -765CC polymorphism between patients with CRC and controls.	('COX-2', 'Gene', (96, 101))	('COX-2', 'Gene', '5743', (96, 101))	('patients', 'Species', '9606', (135, 143))	('gene -765CC polymorphism', 'Var', (102, 126))	('polymorphism', 'Var', (114, 126))	('CRC', 'Phenotype', 'HP:0003003', (149, 152))
176017	22345985	To evaluate the role of CASP8 polymorphisms in esophageal (EC) and gastric cancers (GC) in the Kashmir valley, we examined the risk due to -652 6N ins/del polymorphism (rs3834129) in the promoter of CASP8 in a case-control study.	('rs3834129', 'Mutation', 'rs3834129', (169, 178))	('esophageal', 'Disease', (47, 57))	('rs3834129', 'Var', (169, 178))	('CASP8', 'Gene', (199, 204))	('CASP8', 'Gene', (24, 29))	('CASP8', 'Gene', '841', (199, 204))	('CASP8', 'Gene', '841', (24, 29))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('GC', 'Phenotype', 'HP:0012126', (84, 86))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('-652 6N ins/del', 'Mutation', 'rs3834129', (139, 154))	('gastric cancers', 'Phenotype', 'HP:0012126', (67, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('gastric cancers', 'Disease', (67, 82))	('gastric cancers', 'Disease', 'MESH:D013274', (67, 82))
176018	22345985	Genotypes of the CASP8 polymorphisms (-652 6N ins/del; rs3834129) were determined for 315 patients (135 EC and 108 GC) and 195 healthy controls by polymerase chain reaction.	('rs3834129', 'Mutation', 'rs3834129', (55, 64))	('CASP8', 'Gene', (17, 22))	('CASP8', 'Gene', '841', (17, 22))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('-652 6N ins/del; rs3834129', 'Var', (38, 64))	('patients', 'Species', '9606', (90, 98))	('rs3834129', 'Var', (55, 64))	('-652 6N ins/del', 'Mutation', 'rs3834129', (38, 53))
176019	22345985	Carriers for the del allele of rs3834129 single nucleotide polymorphism were associated with decreased risk for both EC (odds ratio [OR] = 0.278; 95% confidence interval [95% CI] = 0.090-0.853; P = 0.025) and GC (OR = 0.397; 95% CI = 0.164-0.962; P = 0.041).	('rs3834129 single nucleotide polymorphism', 'Var', (31, 71))	('GC', 'Phenotype', 'HP:0012126', (209, 211))	('rs3834129', 'Mutation', 'rs3834129', (31, 40))	('decreased', 'NegReg', (93, 102))
176021	22345985	However, interaction of CASP8 -652 6N ins/del genotypes with smoking and high consumption of salted tea did not further modulate the risk of EC and GC.	('CASP8', 'Gene', (24, 29))	('CASP8', 'Gene', '841', (24, 29))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('6N ins/del', 'Var', (35, 45))	('modulate', 'Reg', (120, 128))	('-652 6N ins/del', 'Mutation', 'rs3834129', (30, 45))	('salted tea', 'Chemical', '-', (93, 103))
176022	22345985	Polymorphism in CASP8 -652 6N ins/del polymorphism modulates the risk of EC and GC in Kashmir valley.	('Polymorphism', 'Var', (0, 12))	('modulates', 'Reg', (51, 60))	('GC', 'Phenotype', 'HP:0012126', (80, 82))	('-652 6N ins/del', 'Mutation', 'rs3834129', (22, 37))	('6N ins/del polymorphism', 'Var', (27, 50))	('CASP8', 'Gene', (16, 21))	('CASP8', 'Gene', '841', (16, 21))
176030	22345985	There are at least 353 single-nucleotide polymorphisms (SNP) of the CASP8 reported in the dbSNP database (http://www.ncbi.nlm.nih.gov/ SNP/snp_ref.cgi?	('CASP8', 'Gene', '841', (68, 73))	('single-nucleotide polymorphisms', 'Var', (23, 54))	('CASP8', 'Gene', (68, 73))
176031	22345985	choose Rs=allandgo=GoandlocusId=841); however, only two common polymorphic variations, D302H (rs1045485) and 6N ins/del (rs3834129), have been reported to influence the risk of cancer development.	('rs1045485', 'Var', (94, 103))	('6N ins/del', 'Mutation', 'c.delins6', (109, 119))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('D302H', 'Mutation', 'rs1045485', (87, 92))	('D302H (rs1045485', 'Var', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('rs1045485', 'Mutation', 'rs1045485', (94, 103))	('influence', 'Reg', (155, 164))	('rs3834129', 'Var', (121, 130))	('rs3834129', 'Mutation', 'rs3834129', (121, 130))
176033	22345985	Therefore, in the current study, we investigated the roles of CASP8 -652 6N ins/del (rs3834129) polymorphisms in conferring genetic susceptibility to EC and GC in Kashmir valley.	('rs3834129', 'Mutation', 'rs3834129', (85, 94))	('CASP8', 'Gene', '841', (62, 67))	('rs3834129', 'Var', (85, 94))	('CASP8', 'Gene', (62, 67))	('-652 6N ins/del', 'Mutation', 'rs3834129', (68, 83))	('GC', 'Phenotype', 'HP:0012126', (157, 159))
176044	22345985	Observed genotype frequencies for CASP8 -652 6N ins/del polymorphism in controls were examined for deviation from the Hardy-Weinberg equilibrium (HWE) using a goodness-of-fit chi2 -test with one degree of freedom.	('6N ins/del polymorphism', 'Var', (45, 68))	('CASP8', 'Gene', (34, 39))	('-652 6N ins/del', 'Mutation', 'rs3834129', (40, 55))	('CASP8', 'Gene', '841', (34, 39))
176046	22345985	Binary logistic regression analysis was used to fit statistical models to predict the association of CASP8 -652 6N ins/del genotypes with susceptibility to EC and GC.	('-652 6N ins/del', 'Mutation', 'rs3834129', (107, 122))	('GC', 'Phenotype', 'HP:0012126', (163, 165))	('CASP8', 'Gene', (101, 106))	('CASP8', 'Gene', '841', (101, 106))	('6N ins/del', 'Var', (112, 122))
176062	22345985	Studies in a range of human cancers, such as Hodgkin lymphoma, gastric carcinoma and head and neck cancer, have established the role of somatic mutations in CASP genes, which represses apoptosis, leading to illegitimate cell proliferation and anomalous cell survival.	('cancers', 'Disease', (28, 35))	('illegitimate cell proliferation', 'CPA', (207, 238))	('mutations', 'Var', (144, 153))	('CASP', 'Gene', (157, 161))	('head and neck cancer', 'Phenotype', 'HP:0012288', (85, 105))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (63, 80))	('CASP', 'Gene', '9595', (157, 161))	('Hodgkin lymphoma', 'Disease', (45, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('apoptosis', 'CPA', (185, 194))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (45, 61))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (45, 61))	('human', 'Species', '9606', (22, 27))	('represses', 'NegReg', (175, 184))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('gastric carcinoma and head and neck cancer', 'Disease', 'MESH:D006258', (63, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
176063	22345985	These observations provide compelling evidence that low-penetrance genetic variations in CASP genes could also play a substantial role in modifying the risk for various cancers.	('play', 'Reg', (111, 115))	('CASP', 'Gene', (89, 93))	('modifying', 'Reg', (138, 147))	('cancers', 'Disease', (169, 176))	('CASP', 'Gene', '9595', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('low-penetrance genetic variations', 'Var', (52, 85))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
176065	22345985	The 6-bp ins/del polymorphism (-652 6N ins/del; rs3834129) is located in the promoter region of the CASP8 gene and eliminates a Sp1 transcription factor binding site.	('Sp1 transcription factor binding site', 'MPA', (128, 165))	('-652 6N ins/del', 'Mutation', 'rs3834129', (31, 46))	('CASP8', 'Gene', (100, 105))	('CASP8', 'Gene', '841', (100, 105))	('eliminates', 'NegReg', (115, 125))	('rs3834129', 'Mutation', 'rs3834129', (48, 57))	('-652 6N ins/del; rs3834129', 'Var', (31, 57))
176067	22345985	Therefore, a possible mechanism underlying the CASP8 polymorphism associated in the decreased risk in EC and GC in our study is that this polymorphism may reduce apoptotic potential in the T lymphocyte and make malignant cells less likely escape from CTL killing, ultimately protecting against EC and GC.	('CASP8', 'Gene', '841', (47, 52))	('escape', 'CPA', (239, 245))	('CASP8', 'Gene', (47, 52))	('polymorphism', 'Var', (138, 150))	('polymorphism', 'Var', (53, 65))	('GC', 'Phenotype', 'HP:0012126', (301, 303))	('reduce', 'NegReg', (155, 161))	('decreased', 'NegReg', (84, 93))	('protecting', 'Reg', (275, 285))	('GC', 'Phenotype', 'HP:0012126', (109, 111))	('apoptotic potential', 'CPA', (162, 181))
176072	22345985	However, based on our gene environmental interactions, we did not find any significant association of CASP8 -652 6N ins/del genotypes with smoking or high salted tea consumption.	('CASP8', 'Gene', (102, 107))	('6N ins/del', 'Var', (113, 123))	('CASP8', 'Gene', '841', (102, 107))	('-652 6N ins/del', 'Mutation', 'rs3834129', (108, 123))	('salted tea', 'Chemical', '-', (155, 165))
176073	22345985	As it is the first report of genetic susceptibility of EC and GC due to CASP8 -652 6N ins/del polymorphisms in the Kashmiri valley, there is a definite need to perform a similar study in a larger sample size before its clinical application.	('GC', 'Phenotype', 'HP:0012126', (62, 64))	('6N ins/del polymorphisms', 'Var', (83, 107))	('CASP8', 'Gene', (72, 77))	('CASP8', 'Gene', '841', (72, 77))	('-652 6N ins/del', 'Mutation', 'rs3834129', (78, 93))
176078	22087297	Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5) nasopharyngeal, 44% (8/18) esophageal, 76% (13/17) gastric, 50% (2/4) cervical, and 25% (3/12) hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (327, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('human', 'Species', '9606', (68, 73))	('cervical', 'Disease', (287, 295))	('multiple carcinoma cell', 'Disease', (134, 157))	('CpG methylation', 'Var', (180, 195))	('silenced', 'NegReg', (105, 113))	('gastric', 'Disease', (268, 275))	('esophageal', 'Disease', (244, 254))	('downregulated', 'NegReg', (117, 130))	('multiple carcinoma cell', 'Disease', 'MESH:C537656', (134, 157))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (312, 336))	('PRDM5', 'Gene', (37, 42))	('hepatocellular carcinoma', 'Disease', (312, 336))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (312, 336))	('nasopharyngeal', 'Disease', (217, 231))	('methylation', 'Var', (184, 195))
176080	22087297	PRDM5 methylation was frequently detected by methylation-specific PCR (MSP) in multiple primary tumors, including 93% (43/46) nasopharyngeal, 58% (25/43) esophageal, 88% (37/42) gastric and 63% (29/46) hepatocellular tumors.	('gastric', 'Disease', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('esophageal', 'Disease', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('hepatocellular tumors', 'Phenotype', 'HP:0001402', (202, 223))	('detected', 'Reg', (33, 41))	('nasopharyngeal', 'Disease', (126, 140))	('methylation', 'Var', (6, 17))	('hepatocellular tumors', 'Disease', 'MESH:D006528', (202, 223))	('primary tumors', 'Disease', (88, 102))	('hepatocellular tumors', 'Disease', (202, 223))	('PRDM5', 'Gene', (0, 5))	('primary tumors', 'Disease', 'MESH:D009369', (88, 102))
176081	22087297	Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/beta-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('knocking down', 'Var', (210, 223))	('MDM2', 'Gene', '4193', (188, 192))	('CDK4', 'Gene', (171, 175))	('Ectopic', 'Var', (0, 7))	('increased', 'PosReg', (252, 261))	('TWIST1', 'Gene', '7291', (177, 183))	('inhibition', 'NegReg', (94, 104))	('PRDM5', 'Gene', (227, 232))	('TCF', 'Gene', '3172', (108, 111))	('cell proliferation', 'CPA', (262, 280))	('CDK4', 'Gene', '1019', (171, 175))	('tumor', 'Disease', (49, 54))	('downregulation', 'NegReg', (153, 167))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('inhibited', 'NegReg', (39, 48))	('TCF', 'Gene', (108, 111))	('MDM2', 'Gene', (188, 192))	('PRDM5', 'Gene', (8, 13))	('TWIST1', 'Gene', (177, 183))
176083	22087297	Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('involved', 'Reg', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PRDM5', 'Gene', (33, 38))	('epigenetic silencing', 'Var', (9, 29))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
176084	22087297	Tumor-specific epigenetic silencing of tumor suppressor genes (TSGs) through promoter CpG methylation and histone modification is frequently involved in multiple carcinogenesis.	('multiple carcinogenesis', 'Disease', (153, 176))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('multiple carcinogenesis', 'Disease', 'MESH:D063646', (153, 176))	('TSG', 'Gene', '57045', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('histone', 'Protein', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('methylation', 'Var', (90, 101))	('tumor', 'Disease', (39, 44))	('epigenetic silencing', 'Var', (15, 35))	('involved', 'Reg', (141, 149))	('TSG', 'Gene', (63, 66))
176085	22087297	CpG methylation can also be used as an epigenetic biomarker for novel TSG identification and tumor diagnosis.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TSG', 'Gene', (70, 73))	('tumor', 'Disease', (93, 98))	('methylation', 'Var', (4, 15))	('TSG', 'Gene', '57045', (70, 73))	('CpG', 'Protein', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
176086	22087297	A series of TSGs such as p16, RASSF1A, PCDH10 and RASAL, have been identified with epigenetic inactivation in multiple cancers, through promoter CpG methylation.	('RASAL', 'Gene', '8437', (50, 55))	('RASSF1A', 'Gene', '11186', (30, 37))	('RASAL', 'Gene', (50, 55))	('TSG', 'Gene', (12, 15))	('multiple cancers', 'Disease', 'MESH:D009369', (110, 126))	('p16', 'Gene', (25, 28))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('epigenetic inactivation', 'Var', (83, 106))	('TSG', 'Gene', '57045', (12, 15))	('PCDH10', 'Gene', (39, 45))	('p16', 'Gene', '1029', (25, 28))	('RASSF1A', 'Gene', (30, 37))	('multiple cancers', 'Disease', (110, 126))	('PCDH10', 'Gene', '57575', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
176090	22087297	PRDM2 (RIZ1) is the first identified member of methyltransferase family with tumor suppressive function mediated by its PR domain.	('PRDM2', 'Gene', (0, 5))	('PRDM2', 'Gene', '7799', (0, 5))	('PR domain', 'Var', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('RIZ1', 'Gene', '7799', (7, 11))	('tumor', 'Disease', (77, 82))	('RIZ1', 'Gene', (7, 11))
176096	22087297	Ectopic expression of PRDM5 leads to G2/M arrest and apoptosis of tumor cells, although its molecular mechanism is still unclear.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('apoptosis', 'CPA', (53, 62))	('leads to', 'Reg', (28, 36))	('tumor', 'Disease', (66, 71))	('M arrest', 'Disease', 'MESH:D006323', (40, 48))	('Ectopic expression', 'Var', (0, 18))	('M arrest', 'Disease', (40, 48))	('PRDM5', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
176104	22087297	Methylation-specific PCR (MSP) results showed that PRDM5 was frequently methylated in silenced cell lines, including 80% (4/5) nasopharyngeal, 44% (8/18) esophageal, 76% (13/17) gastric, 25% (3/12) hepatocellular, and 50% (2/4) cervical carcinoma cell lines (Figure 2, Table 1), with the exception of only infrequent PRDM5 methylation detected in lung, colon, ovarian and bladder cancer cell lines (Figure S1).	('carcinoma', 'Disease', (237, 246))	('PRDM5', 'Gene', (317, 322))	('PRDM5', 'Gene', (51, 56))	('methylated', 'Var', (72, 82))	('bladder cancer', 'Phenotype', 'HP:0009725', (372, 386))	('carcinoma', 'Disease', 'MESH:D002277', (237, 246))	('colon, ovarian and bladder cancer', 'Disease', 'MESH:D001749', (353, 386))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
176106	22087297	Taken together, these results revealed a strong correlation between PRDM5 promoter CpG methylation and its transcriptional silencing in tumor cell lines.	('PRDM5', 'Gene', (68, 73))	('transcriptional', 'MPA', (107, 122))	('CpG methylation', 'Var', (83, 98))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('methylation', 'Var', (87, 98))	('tumor', 'Disease', (136, 141))
176108	22087297	This pharmacologic demethylation restored PRDM5 expression in all silenced cell lines, accompanied by the increase of demethylated promoter alleles (Figure 3B and 3C), indicating that PRDM5 silencing in tumor cells was directly mediated by promoter methylation.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('PRDM5', 'Gene', (42, 47))	('silencing', 'NegReg', (190, 199))	('demethylation', 'Var', (19, 32))	('expression', 'MPA', (48, 58))	('demethylated promoter alleles', 'MPA', (118, 147))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('increase', 'PosReg', (106, 114))	('restored', 'PosReg', (33, 41))
176114	22087297	MSP detected PRDM5 methylation in 93% (43/46) nasopharyngeal, 58% (25/43) esophageal, 88% (37/42) gastric and 63% (29/46) hepatocellular carcinomas.	('hepatocellular carcinomas', 'Disease', (122, 147))	('PRDM5', 'Gene', (13, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('methylation', 'Var', (19, 30))	('nasopharyngeal', 'Disease', (46, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (122, 147))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (122, 146))	('gastric', 'Disease', (98, 105))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (122, 147))	('esophageal', 'Disease', (74, 84))
176116	22087297	Moreover, quantitative RT-PCR analysis revealed that PRDM5 was frequently downregulated in methylated primary NPC tumors when compared to normal larynx (Figure 6).	('NPC tumors', 'Disease', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('PRDM5', 'Gene', (53, 58))	('NPC tumors', 'Disease', 'MESH:D052556', (110, 120))	('downregulated', 'NegReg', (74, 87))	('methylated', 'Var', (91, 101))
176119	22087297	A mammalian expression vector encoding full-length PRDM5 was transfected into nasopharyngeal, esophageal and gastric cancer cell lines with completely methylated and silenced PRDM5 (HONE1, KYSE140 and MKN28).	('PRDM5', 'Gene', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('silenced', 'Var', (166, 174))	('mammalian', 'Species', '9606', (2, 11))	('HONE1', 'CellLine', 'CVCL:8706', (182, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))
176120	22087297	Consistently, knock-down of endogenous PRDM5 using siRNA in HEK293 cells significantly increased the cell proliferation rate (Figure 7C), suggesting that PRDM5 does function as a tumor suppressor.	('increased', 'PosReg', (87, 96))	('HEK293', 'CellLine', 'CVCL:0045', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cell proliferation rate', 'CPA', (101, 124))	('knock-down', 'Var', (14, 24))	('PRDM5', 'Gene', (39, 44))	('tumor', 'Disease', (179, 184))
176125	22087297	We also examined whether PRDM5 methylation/silencing is correlated with enhanced WNT/beta-catenin signaling in tumor cell lines, and found that the active form of beta-catenin was accumulated in cell lines with methylated and silenced PRDM5, with significant lower level of active beta-catenin detected in PRDM5-expressing cell lines (Figure 8C).	('methylated', 'Var', (211, 221))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('silenced', 'Var', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('PRDM5', 'Gene', (25, 30))	('accumulated', 'PosReg', (180, 191))	('tumor', 'Disease', (111, 116))	('enhanced', 'PosReg', (72, 80))	('PRDM5', 'Gene', (235, 240))	('WNT/beta-catenin signaling', 'MPA', (81, 107))	('methylation/silencing', 'Var', (31, 52))
176126	22087297	We further examined the expression changes of multiple oncogenes and tumor suppressor genes after ectopic PRDM5 expression in both normal and tumor cell lines (HEK293 and HONE1).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('HEK293', 'CellLine', 'CVCL:0045', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('HONE1', 'CellLine', 'CVCL:8706', (171, 176))	('ectopic', 'Var', (98, 105))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('PRDM5', 'Gene', (106, 111))
176129	22087297	Moreover, PRDM5 expression resulted in significant decreased levels of H3K4me3 and acetyl-histone H4 in CDK4 and TWIST1 promoters (Figure 9C), both as active transcription marks.	('expression', 'Var', (16, 26))	('PRDM5', 'Gene', (10, 15))	('acetyl-histone', 'Chemical', '-', (83, 97))	('decreased', 'NegReg', (51, 60))	('levels', 'MPA', (61, 67))	('H3K4me3', 'Protein', (71, 78))	('acetyl-histone H4', 'MPA', (83, 100))	('CDK4', 'Gene', (104, 108))	('CDK4', 'Gene', '1019', (104, 108))	('TWIST1', 'Gene', (113, 119))	('TWIST1', 'Gene', '7291', (113, 119))
176131	22087297	Identification of TSGs silenced by CpG methylation elucidates the molecular mechanisms of carcinogenesis and develops epigenetic biomarkers for cancer detection and prognosis prediction.	('TSG', 'Gene', (18, 21))	('methylation', 'Var', (39, 50))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('TSG', 'Gene', '57045', (18, 21))	('cancer', 'Disease', (144, 150))	('silenced', 'NegReg', (23, 31))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('carcinogenesis', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
176132	22087297	In the present study, we showed that PRDM5, an epigenetic modifier gene, was frequently inactivated by promoter methylation in multiple common cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('promoter methylation', 'Var', (103, 123))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('inactivated', 'NegReg', (88, 99))	('PRDM5', 'Gene', (37, 42))
176133	22087297	Ectopic expression of PRDM5 inhibited tumor cell clonogenicity, at least partially through antagonizing WNT/beta-catenin signaling and oncogene expression such as CDK4, TWIST1, and MDM2.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('CDK4', 'Gene', (163, 167))	('expression', 'MPA', (144, 154))	('WNT/beta-catenin signaling', 'MPA', (104, 130))	('CDK4', 'Gene', '1019', (163, 167))	('MDM2', 'Gene', '4193', (181, 185))	('Ectopic expression', 'Var', (0, 18))	('MDM2', 'Gene', (181, 185))	('oncogene', 'CPA', (135, 143))	('inhibited', 'NegReg', (28, 37))	('TWIST1', 'Gene', (169, 175))	('TWIST1', 'Gene', '7291', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('PRDM5', 'Gene', (22, 27))	('antagonizing', 'NegReg', (91, 103))
176134	22087297	Epigenetic silencing of TSGs is critically involved in the onset and progression of multiple cancers, even preceding genetic changes during tumorigenesis.	('TSG', 'Gene', '57045', (24, 27))	('multiple cancers', 'Disease', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('multiple cancers', 'Disease', 'MESH:D009369', (84, 100))	('TSG', 'Gene', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('involved', 'Reg', (43, 51))	('tumor', 'Disease', (140, 145))
176135	22087297	CpG methylation of TSG promoters is a fundamental epigenetic mechanism leading to their inactivation in tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('methylation', 'Var', (4, 15))	('CpG', 'Var', (0, 3))	('tumors', 'Disease', (104, 110))	('TSG', 'Gene', (19, 22))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('inactivation', 'MPA', (88, 100))	('TSG', 'Gene', '57045', (19, 22))
176136	22087297	Previous studies showed that PRDM5 silencing was mediated by either DNA methylation or trimethylation of H3K27, but with limited cell lines and tumors studied.	('silencing', 'NegReg', (35, 44))	('tumors', 'Disease', (144, 150))	('trimethylation', 'Var', (87, 101))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('H3K27', 'Protein', (105, 110))	('PRDM5', 'Gene', (29, 34))	('DNA methylation', 'Var', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
176138	22087297	Our results showed that aberrant methylation of PRDM5 was associated with its inactivation in multiple tumor cell lines and primary tumors, with the silencing/methylation of PRDM5 in cell lines of gastric cancer (MKN45) and HCC (huH1, Hep3B and HepG2) consistent with previous studies.	('PRDM5', 'Gene', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (132, 137))	('huH1', 'Gene', '25932', (229, 233))	('primary tumors', 'Disease', 'MESH:D009369', (124, 138))	('Hep3B', 'CellLine', 'CVCL:0326', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('gastric cancer', 'Disease', (197, 211))	('HepG2', 'CellLine', 'CVCL:0027', (245, 250))	('aberrant', 'Var', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('silencing/methylation', 'NegReg', (149, 170))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (197, 211))	('inactivation', 'MPA', (78, 90))	('methylation', 'MPA', (33, 44))	('huH1', 'Gene', (229, 233))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('PRDM5', 'Gene', (48, 53))	('primary tumors', 'Disease', (124, 138))	('gastric cancer', 'Phenotype', 'HP:0012126', (197, 211))
176141	22087297	It is likely that methylation of this CpG site would affect the binding of HSF, leading to the disruption of its stress response.	('binding', 'Interaction', (64, 71))	('affect', 'Reg', (53, 59))	('HSF', 'Gene', (75, 78))	('stress response', 'MPA', (113, 128))	('methylation', 'Var', (18, 29))	('disruption', 'MPA', (95, 105))	('HSF', 'Gene', '3569', (75, 78))	('leading to', 'Reg', (80, 90))
176142	22087297	Thus, epigenetic silencing of PRDM5 could abolish cellular protective response to environmental stresses, contributing to tumorigenesis.	('contributing', 'Reg', (106, 118))	('epigenetic silencing', 'Var', (6, 26))	('abolish', 'NegReg', (42, 49))	('cellular protective response', 'CPA', (50, 78))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PRDM5', 'Gene', (30, 35))	('tumor', 'Disease', (122, 127))
176146	22087297	Previous report showed that ectopic PRDM5 expression caused cell cycle G2/M arrest and induced apoptosis in tumor cells, while the molecular mechanisms remain unknown.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('M arrest', 'Disease', 'MESH:D006323', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('apoptosis', 'CPA', (95, 104))	('M arrest', 'Disease', (74, 82))	('tumor', 'Disease', (108, 113))	('ectopic', 'Var', (28, 35))	('caused', 'Reg', (53, 59))	('induced', 'Reg', (87, 94))	('PRDM5', 'Gene', (36, 41))
176148	22087297	Aberrant activation of WNT/beta-catenin signaling is frequently involved in cancers, accompanied with elevated levels of active beta-catenin.	('involved', 'Reg', (64, 72))	('activation', 'PosReg', (9, 19))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', (76, 83))	('WNT/beta-catenin signaling', 'Pathway', (23, 49))	('levels of active beta-catenin', 'MPA', (111, 140))	('elevated', 'PosReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
176149	22087297	In addition to genetic defects, epigenetic silencing of WNT/beta-catenin antagonists also leads to aberrant WNT/beta-catenin signaling in tumors.	('genetic defects', 'Disease', 'MESH:D030342', (15, 30))	('genetic defects', 'Disease', (15, 30))	('WNT/beta-catenin signaling', 'MPA', (108, 134))	('leads to', 'Reg', (90, 98))	('tumors', 'Disease', (138, 144))	('epigenetic silencing', 'Var', (32, 52))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('aberrant', 'PosReg', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
176150	22087297	Frequent methylation-mediated silencing of extracellular (SFRPs and DKKs) and cytosolic (APC, AXIN2 and DACT3) WNT antagonists, nuclear proteins (SOX7 and SOX17), and non-transforming WNT families (WNT5A, WNT7A and WNT9A) occurs in cancers, indicating that the epigenetic inactivation of WNT-signaling negative regulators plays a critical role in tumor pathogenesis.	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('cancers', 'Disease', (232, 239))	('SOX7', 'Gene', '83595', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('silencing', 'NegReg', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('WNT9A', 'Gene', '7483', (215, 220))	('WNT5A', 'Gene', (198, 203))	('WNT7A', 'Gene', '7476', (205, 210))	('AXIN2', 'Gene', (94, 99))	('DACT3', 'Gene', '147906', (104, 109))	('SOX17', 'Gene', '64321', (155, 160))	('WNT7A', 'Gene', (205, 210))	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('WNT9A', 'Gene', (215, 220))	('SOX7', 'Gene', (146, 150))	('DACT3', 'Gene', (104, 109))	('methylation-mediated', 'Var', (9, 29))	('WNT5A', 'Gene', '7474', (198, 203))	('APC', 'Disease', 'MESH:D011125', (89, 92))	('tumor', 'Disease', (347, 352))	('APC', 'Disease', (89, 92))	('SOX17', 'Gene', (155, 160))	('AXIN2', 'Gene', '8313', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (347, 352))
176151	22087297	Our finding that ectopic expression of PRDM5 leads to the inhibition of WNT/beta-catenin signaling in tumor cells, probably through upregulating DKK1, DKK2, and WNT5A , suggests a novel mechanistic link between PRDM5 and WNT signaling in human tumorigenesis.	('WNT/beta-catenin signaling', 'MPA', (72, 98))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('human', 'Species', '9606', (238, 243))	('WNT5A', 'Gene', '7474', (161, 166))	('tumor', 'Disease', (244, 249))	('DKK2', 'Gene', (151, 155))	('WNT5A', 'Gene', (161, 166))	('DKK1', 'Gene', (145, 149))	('DKK2', 'Gene', '27123', (151, 155))	('DKK1', 'Gene', '22943', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PRDM5', 'Gene', (39, 44))	('ectopic expression', 'Var', (17, 35))	('upregulating', 'PosReg', (132, 144))	('inhibition', 'NegReg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
176155	22087297	In summary, we found that PRDM5 was frequently silenced by promoter methylation in multiple tumors.	('PRDM5', 'Gene', (26, 31))	('multiple tumors', 'Disease', (83, 98))	('multiple tumors', 'Disease', 'MESH:D009369', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('silenced', 'NegReg', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('promoter methylation', 'Var', (59, 79))
176157	22087297	The high incidence of PRDM5 methylation in some carcinomas indicates that it is a potential epigenetic biomarker for these tumors.	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('carcinomas', 'Disease', (48, 58))	('carcinomas', 'Disease', 'MESH:D002277', (48, 58))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('PRDM5', 'Gene', (22, 27))	('methylation', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
176171	22087297	Antibodies used were HSF1 (4356, Cell Signaling), FLAG M2 (F3165, Sigma), Histone H3K4me3 (ab8580, Abcam), and acetyl-Histone H4 (06-866, Upstate).	('HSF1', 'Gene', (21, 25))	('F3165', 'Var', (59, 64))	('acetyl-Histone', 'Chemical', '-', (111, 125))	('HSF1', 'Gene', '3297', (21, 25))
176176	22087297	Luciferase reporter construct of CCND1 promoter (+ ~2 kb upstream of transcription start site), or TOPFlash reporter containing 4xTCF-binding sites (kind gift from Dr. Christof Niehrs, German Cancer Research Center (DKFZ)), or FOPFlash reporter containing mutant TCF/LEF binding sites (kind gift from Dr. Jin Dong-Yan, University of Hong Kong) was co-transfected with either pcDNA3.1-PRDM5 or empty vector, together with an internal control Renilla luciferase reporter pRL-CMV vector using FuGene6.	('TCF', 'Gene', '3172', (130, 133))	('TCF/LEF', 'Gene', '3172', (263, 270))	('CCND1', 'Gene', (33, 38))	('TCF/LEF', 'Gene', (263, 270))	('Cancer', 'Disease', (192, 198))	('CCND1', 'Gene', '595', (33, 38))	('Cancer', 'Disease', 'MESH:D009369', (192, 198))	('Cancer', 'Phenotype', 'HP:0002664', (192, 198))	('mutant', 'Var', (256, 262))	('TCF', 'Gene', (263, 266))	('TCF', 'Gene', '3172', (263, 266))	('TCF', 'Gene', (130, 133))
176179	22087297	Antibody used were FLAG M2 (F3165, Sigma), active beta-catenin (05-665, Upstate) and alpha-Tubulin (DM1A, Lab Vision).	('F3165', 'Var', (28, 33))	('alpha-Tubulin', 'Gene', '10376', (85, 98))	('alpha-Tubulin', 'Gene', (85, 98))
176198	21127287	EAC cases were identified using International Classification of Diseases for Oncology (ICD-O-3) topography codes C15.0-C15.9 for esophageal cancer, and histology codes 8140-8573 for adenocarcinoma.	('C15.0-C15.9', 'Var', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('Oncology', 'Phenotype', 'HP:0002664', (77, 85))	('adenocarcinoma', 'Disease', (182, 196))	('adenocarcinoma', 'Disease', 'MESH:D000230', (182, 196))	('esophageal cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('EAC', 'Disease', (0, 3))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
176211	21127287	A recent meta-analysis demonstrated that there is no association between eradication of H. pylori and subsequent risk of GERD symptoms or erosive esophagitis, suggestive that H. pylori may impact risk of EAC at the level of development of BE.	('EAC', 'Phenotype', 'HP:0011459', (204, 207))	('H. pylori', 'Species', '210', (175, 184))	('EAC', 'Disease', (204, 207))	('BE', 'Phenotype', 'HP:0100580', (239, 241))	('esophagitis', 'Phenotype', 'HP:0100633', (146, 157))	('GERD', 'Phenotype', 'HP:0002020', (121, 125))	('esophagitis', 'Disease', (146, 157))	('GERD', 'Disease', 'MESH:D005764', (121, 125))	('H. pylori', 'Var', (175, 184))	('esophagitis', 'Disease', 'MESH:D004941', (146, 157))	('GERD', 'Disease', (121, 125))	('impact', 'Reg', (189, 195))	('H. pylori', 'Species', '210', (88, 97))
176237	33330321	STAT3 protein is activated by tyrosine phosphorylation at residue 705, and p-STAT3 (Tyr705) is able to upregulate the transcription of genes involved in cell proliferation, apoptosis, angiogenesis, invasion and metastasis.	('angiogenesis', 'CPA', (184, 196))	('invasion', 'CPA', (198, 206))	('apoptosis', 'CPA', (173, 182))	('STAT3', 'Gene', '6774', (77, 82))	('metastasis', 'CPA', (211, 221))	('cell proliferation', 'CPA', (153, 171))	('activated', 'PosReg', (17, 26))	('Tyr705', 'Chemical', '-', (84, 90))	('upregulate', 'PosReg', (103, 113))	('STAT3', 'Gene', '6774', (0, 5))	('STAT3', 'Gene', (77, 82))	('tyrosine phosphorylation', 'Var', (30, 54))	('STAT3', 'Gene', (0, 5))	('transcription', 'MPA', (118, 131))	('tyrosine', 'Chemical', 'MESH:D014443', (30, 38))
176286	33330321	Twenty-four hours after carbon ion irradiation, significantly more KYSE150 cells were in S phase arrest after 1, 2 and 4 Gy irradiation, whereas the number of cells in S phase arrest was decreased after 4 Gy (Figure 3B).	('carbon', 'Chemical', 'MESH:D002244', (24, 30))	('arrest', 'Disease', 'MESH:D006323', (176, 182))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('arrest', 'Disease', (176, 182))	('KYSE150', 'Var', (67, 74))	('arrest', 'Disease', (97, 103))	('KYSE150', 'CellLine', 'CVCL:1348', (67, 74))
176303	33330321	Inhibition of the JAK2/STAT3 signal transduction pathway is expected to be an effective way to inhibit tumor growth and promote tumor cell apoptosis.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('STAT3', 'Gene', '6774', (23, 28))	('tumor', 'Disease', (103, 108))	('inhibit', 'NegReg', (95, 102))	('promote', 'PosReg', (120, 127))	('STAT3', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('JAK2', 'Gene', '3717', (18, 22))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('JAK2', 'Gene', (18, 22))
176320	33330321	It has been shown that phosphorylation of STAT3 can increase cell-cell contact, and thus, STAT3 may be an essential gene for the migration and invasiveness of tumor cells.	('STAT3', 'Gene', (42, 47))	('STAT3', 'Gene', '6774', (90, 95))	('cell-cell contact', 'CPA', (61, 78))	('STAT3', 'Gene', (90, 95))	('increase', 'PosReg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('migration', 'CPA', (129, 138))	('phosphorylation', 'Var', (23, 38))	('invasiveness of tumor', 'Disease', (143, 164))	('STAT3', 'Gene', '6774', (42, 47))	('invasiveness of tumor', 'Disease', 'MESH:D009361', (143, 164))
176322	33330321	Inhibition of STAT3 inhibits its target gene MMP2 and inhibits tumor cell invasion.	('STAT3', 'Gene', (14, 19))	('tumor', 'Disease', (63, 68))	('MMP2', 'Gene', (45, 49))	('inhibits', 'NegReg', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('MMP2', 'Gene', '4313', (45, 49))	('Inhibition', 'Var', (0, 10))	('inhibits', 'NegReg', (54, 62))	('STAT3', 'Gene', '6774', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
176324	33330321	In various human malignancies, aberrant activation of the STAT3 signaling pathway is closely associated with tumor EMT, invasion and metastasis.	('malignancies', 'Disease', 'MESH:D009369', (17, 29))	('tumor', 'Disease', (109, 114))	('human', 'Species', '9606', (11, 16))	('aberrant', 'Var', (31, 39))	('malignancies', 'Disease', (17, 29))	('activation', 'PosReg', (40, 50))	('invasion', 'CPA', (120, 128))	('associated', 'Reg', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('STAT3', 'Gene', '6774', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('STAT3', 'Gene', (58, 63))
176325	33330321	Many studies have shown that inducing the inactivation of JAK2 can inhibit STAT3 activation and can thus inhibit STAT3 signaling, which then regulates apoptosis of cancer cells.	('activation', 'MPA', (81, 91))	('inhibit', 'NegReg', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('inhibit', 'NegReg', (105, 112))	('STAT3', 'Gene', '6774', (75, 80))	('regulates', 'Reg', (141, 150))	('inactivation', 'Var', (42, 54))	('inducing', 'Var', (29, 37))	('JAK2', 'Gene', '3717', (58, 62))	('STAT3', 'Gene', '6774', (113, 118))	('STAT3', 'Gene', (75, 80))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('STAT3', 'Gene', (113, 118))	('JAK2', 'Gene', (58, 62))	('apoptosis', 'CPA', (151, 160))
176329	33330321	In melanoma cells, the STAT3 signaling pathway can promote MMP2 expression, while inhibition of phosphorylated STAT3 expression can significantly inhibit MMP2 expression in vivo, which inhibits tumor cell growth and invasion.	('MMP2', 'Gene', (59, 63))	('STAT3', 'Gene', (111, 116))	('STAT3', 'Gene', (23, 28))	('tumor', 'Disease', (194, 199))	('STAT3', 'Gene', '6774', (111, 116))	('MMP2', 'Gene', (154, 158))	('STAT3', 'Gene', '6774', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('inhibition', 'Var', (82, 92))	('expression', 'MPA', (159, 169))	('invasion', 'CPA', (216, 224))	('MMP2', 'Gene', '4313', (59, 63))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('expression', 'MPA', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('MMP2', 'Gene', '4313', (154, 158))	('inhibit', 'NegReg', (146, 153))	('inhibits', 'NegReg', (185, 193))	('promote', 'PosReg', (51, 58))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
176338	32629820	PPT inhibited the viability of ESCC cells in time- and dose-dependent manners.	('inhibited', 'NegReg', (4, 13))	('viability', 'CPA', (18, 27))	('PPT', 'Chemical', 'MESH:C415032', (0, 3))	('PPT', 'Var', (0, 3))	('ESCC', 'Disease', (31, 35))
176339	32629820	PPT induced G2/M phase cell cycle arrest and annexin V-stained cell apoptosis through the activation of the c-Jun N-terminal kinase (JNK)/p38 pathways.	('arrest', 'Disease', (34, 40))	('activation', 'PosReg', (90, 100))	('p38', 'Gene', (138, 141))	('annexin V', 'Gene', '308', (45, 54))	('p38', 'Gene', '1432', (138, 141))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (23, 40))	('annexin V', 'Gene', (45, 54))	('arrest', 'Disease', 'MESH:D006323', (34, 40))	('c-Jun N-terminal kinase', 'Gene', (108, 131))	('JNK', 'Gene', (133, 136))	('c-Jun N-terminal kinase', 'Gene', '5599', (108, 131))	('PPT', 'Var', (0, 3))	('PPT', 'Chemical', 'MESH:C415032', (0, 3))	('JNK', 'Gene', '5599', (133, 136))
176340	32629820	Furthermore, the treatment of KYSE 30 and KYSE 450 ESCC cells with PPT induced apoptosis involving the regulation of endoplasmic reticulum stress- and apoptosis-related proteins by reactive oxygen species (ROS) generation, the loss of mitochondrial membrane potential, and multi-caspase activation.	('regulation', 'MPA', (103, 113))	('loss', 'NegReg', (227, 231))	('endoplasmic reticulum stress-', 'MPA', (117, 146))	('induced', 'Reg', (71, 78))	('ROS', 'Chemical', 'MESH:D017382', (206, 209))	('PPT', 'Chemical', 'MESH:C415032', (67, 70))	('apoptosis', 'CPA', (79, 88))	('mitochondrial membrane potential', 'MPA', (235, 267))	('apoptosis-related', 'Protein', (151, 168))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (181, 204))	('KYSE', 'Var', (42, 46))
176341	32629820	In conclusion, our results indicate that the apoptotic effect of PPT on ESCC cells has the potential to become a new anti-cancer drug by increasing ROS levels and inducing the JNK/p38 signaling pathways.	('JNK', 'Gene', (176, 179))	('JNK', 'Gene', '5599', (176, 179))	('cancer', 'Disease', (122, 128))	('p38', 'Gene', (180, 183))	('increasing', 'PosReg', (137, 147))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('ROS levels', 'MPA', (148, 158))	('inducing', 'Reg', (163, 171))	('ROS', 'Chemical', 'MESH:D017382', (148, 151))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PPT', 'Var', (65, 68))	('PPT', 'Chemical', 'MESH:C415032', (65, 68))	('p38', 'Gene', '1432', (180, 183))
176348	32629820	Recent studies have shown that PPT inhibits microtubule assembly, resulting in antitumor effects without cytotoxicity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('microtubule assembly', 'MPA', (44, 64))	('tumor', 'Disease', (83, 88))	('inhibits', 'NegReg', (35, 43))	('cytotoxicity', 'Disease', 'MESH:D064420', (105, 117))	('PPT', 'Var', (31, 34))	('PPT', 'Chemical', 'MESH:C415032', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cytotoxicity', 'Disease', (105, 117))
176357	32629820	Therefore, we investigate whether PPT can induce apoptosis through the JNK/p38 MAPK pathways in ESCC cells.	('p38', 'Gene', '1432', (75, 78))	('JNK', 'Gene', (71, 74))	('induce', 'PosReg', (42, 48))	('p38', 'Gene', (75, 78))	('JNK', 'Gene', '5599', (71, 74))	('PPT', 'Var', (34, 37))	('PPT', 'Chemical', 'MESH:C415032', (34, 37))	('apoptosis', 'CPA', (49, 58))
176358	32629820	We report here that PPT induces apoptosis in ESCC cells by reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress production, and JNK/p38 activation.	('activation', 'PosReg', (159, 169))	('p38', 'Gene', (155, 158))	('apoptosis', 'CPA', (32, 41))	('induces', 'Reg', (24, 31))	('p38', 'Gene', '1432', (155, 158))	('JNK', 'Gene', (151, 154))	('PPT', 'Var', (20, 23))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (59, 82))	('PPT', 'Chemical', 'MESH:C415032', (20, 23))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('JNK', 'Gene', '5599', (151, 154))
176361	32629820	The mean half-maximal inhibitory concentration (IC50) PPT values indicated a cytotoxic effect toward all ESCC cells (KYSE 30, 0.15 microM; KYSE 70, 0.32 microM; KYSE 410, 0.15 microM; KYSE 450, 0.26 microM; and KYSE 510, 0.24 microM).	('KYSE 410', 'Var', (161, 169))	('PPT', 'Chemical', 'MESH:C415032', (54, 57))	('KYSE 510', 'Var', (211, 219))	('KYSE 70', 'Var', (139, 146))	('KYSE 450', 'Var', (184, 192))	('cytotoxic effect', 'CPA', (77, 93))
176362	32629820	The soft agar assay results showed a similar decrease in cell growth capacity by PPT treatment, which indicated that the anchorage-independent growth of KYSE 30 and KYSE 450 cells was inhibited by PPT treatment (Figure 1G,H).	('PPT', 'Var', (197, 200))	('PPT', 'Var', (81, 84))	('PPT', 'Chemical', 'MESH:C415032', (197, 200))	('PPT', 'Chemical', 'MESH:C415032', (81, 84))	('decrease', 'NegReg', (45, 53))	('anchorage-independent growth', 'CPA', (121, 149))	('cell growth capacity', 'CPA', (57, 77))	('inhibited', 'NegReg', (184, 193))
176363	32629820	We assessed the effects of PPT on cell cycle progression using a Muse  Cell Analyzer (Merck Millipore, Darmstadt, Germany), since PPT inhibited ESCC cell viability.	('inhibited', 'NegReg', (134, 143))	('ESCC', 'Disease', (144, 148))	('PPT', 'Chemical', 'MESH:C415032', (130, 133))	('PPT', 'Var', (130, 133))	('PPT', 'Chemical', 'MESH:C415032', (27, 30))
176365	32629820	The sub-G1 population of PPT-treated cells was significantly increased compared to DMSO-treated controls (Figure 2B).	('sub-G1 population', 'CPA', (4, 21))	('PPT-treated', 'Var', (25, 36))	('increased', 'PosReg', (61, 70))	('DMSO', 'Chemical', 'MESH:D004121', (83, 87))	('PPT', 'Chemical', 'MESH:C415032', (25, 28))
176368	32629820	These results suggest that PPT induced the G2/M phase arrest of ESCC cells.	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('arrest', 'Disease', (54, 60))	('PPT', 'Var', (27, 30))	('PPT', 'Chemical', 'MESH:C415032', (27, 30))
176369	32629820	To identify whether PPT inhibited cell proliferation through apoptosis, we performed an annexin V/7-Aminoactinomycin D (7-AAD) apoptosis detection assay (Figure 3A).	('apoptosis', 'CPA', (61, 70))	('cell proliferation', 'CPA', (34, 52))	('annexin V', 'Gene', '308', (88, 97))	('inhibited', 'NegReg', (24, 33))	('7-Aminoactinomycin D', 'Chemical', 'MESH:C025942', (98, 118))	('annexin V', 'Gene', (88, 97))	('PPT', 'Var', (20, 23))	('PPT', 'Chemical', 'MESH:C415032', (20, 23))	('7-AAD', 'Chemical', '-', (120, 125))
176375	32629820	As shown in Figure 3B, PPT significantly induced the phosphorylation of JNK and p38 proteins in ESCC cells in a dose-dependent manner.	('JNK', 'Gene', (72, 75))	('PPT', 'Var', (23, 26))	('p38', 'Gene', (80, 83))	('PPT', 'Chemical', 'MESH:C415032', (23, 26))	('JNK', 'Gene', '5599', (72, 75))	('induced', 'Reg', (41, 48))	('phosphorylation', 'MPA', (53, 68))	('p38', 'Gene', '1432', (80, 83))
176379	32629820	As shown in Figure 4A, we found that PPT dose-dependently increased the generation of intracellular ROS in the ESCC cells.	('increased', 'PosReg', (58, 67))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('PPT', 'Var', (37, 40))	('PPT', 'Chemical', 'MESH:C415032', (37, 40))	('generation of intracellular ROS', 'MPA', (72, 103))
176383	32629820	The Western blot analysis results demonstrated the concentration-dependent induction of GRP78 and CHOP in response to PPT-treatment (Figure 4B).	('PPT', 'Chemical', 'MESH:C415032', (118, 121))	('CHOP', 'Gene', '1649', (98, 102))	('induction', 'PosReg', (75, 84))	('CHOP', 'Gene', (98, 102))	('GRP78', 'Gene', (88, 93))	('GRP78', 'Gene', '3309', (88, 93))	('PPT-treatment', 'Var', (118, 131))
176388	32629820	The results showed that 0.4 microM PPT led to the depolarization of the MMP of 46.74 +- 1.59% and 44.69 +- 3.29% in the KYSE 30 and KYSE 450 ESCC cells, respectively (Figure 5A).	('depolarization', 'NegReg', (50, 64))	('PPT', 'Chemical', 'MESH:C415032', (35, 38))	('KYSE', 'Var', (120, 124))	('KYSE 450', 'Var', (132, 140))
176389	32629820	The Western blot results revealed that PPT decreased the expression of Bid, Mcl-1, and Bcl-2, and increased the expression of Bax, apoptotic protease activating factor-1(Apaf-1), and cleaved Poly (ADP-Ribose) Polymerase (c-PARP) in the ESCC cells.	('cleaved', 'MPA', (183, 190))	('Bcl-2', 'Gene', '596', (87, 92))	('Bid', 'Gene', '637', (71, 74))	('PPT', 'Chemical', 'MESH:C415032', (39, 42))	('expression', 'MPA', (112, 122))	('expression', 'MPA', (57, 67))	('Poly (ADP-Ribose) Polymerase', 'Gene', '142', (191, 219))	('Mcl-1', 'Gene', '4170', (76, 81))	('increased', 'PosReg', (98, 107))	('Poly (ADP-Ribose) Polymerase', 'Gene', (191, 219))	('Bid', 'Gene', (71, 74))	('PPT', 'Var', (39, 42))	('Apaf-1', 'Gene', '317', (170, 176))	('Apaf-1', 'Gene', (170, 176))	('apoptotic protease activating factor-1', 'Gene', (131, 169))	('Bax', 'Gene', (126, 129))	('PARP', 'Gene', '142', (223, 227))	('Mcl-1', 'Gene', (76, 81))	('Bax', 'Gene', '581', (126, 129))	('Bcl-2', 'Gene', (87, 92))	('apoptotic protease activating factor-1', 'Gene', '317', (131, 169))	('PARP', 'Gene', (223, 227))	('decreased', 'NegReg', (43, 52))
176390	32629820	These data imply that PPT induced MMP dysfunction and mitochondria-mediated apoptosis.	('PPT', 'Var', (22, 25))	('mitochondria-mediated apoptosis', 'CPA', (54, 85))	('PPT', 'Chemical', 'MESH:C415032', (22, 25))	('MMP dysfunction', 'Disease', (34, 49))	('MMP dysfunction', 'Disease', 'MESH:D009461', (34, 49))
176394	32629820	These results suggest that PPT led to the activation of multi-caspases in KYSE 30 and KYSE 450 cells in a dose-dependent manner.	('PPT', 'Var', (27, 30))	('activation', 'PosReg', (42, 52))	('multi-caspases', 'Enzyme', (56, 70))	('PPT', 'Chemical', 'MESH:C415032', (27, 30))
176399	32629820	We demonstrated that PPT suppressed the cell viability (Figure 1B-F) and colony formation (Figure 1G) of the ESCC cells in time- or dose-dependent manners in vitro.	('colony formation', 'CPA', (73, 89))	('suppressed', 'NegReg', (25, 35))	('PPT', 'Var', (21, 24))	('PPT', 'Chemical', 'MESH:C415032', (21, 24))	('cell viability', 'CPA', (40, 54))
176401	32629820	Therefore, PPT can effectively inhibit ESCC cells, and further studies on the inhibitory effects are needed.	('inhibit', 'NegReg', (31, 38))	('PPT', 'Chemical', 'MESH:C415032', (11, 14))	('ESCC', 'Disease', (39, 43))	('PPT', 'Var', (11, 14))
176403	32629820	Cell cycle analysis following the treatment of ESCC cells with different concentrations of PPT showed higher numbers of cells in the G2/M phase compared to the DMSO-treated control cells (Figure 2A).	('DMSO', 'Chemical', 'MESH:D004121', (160, 164))	('cells in the G2/M phase', 'CPA', (120, 143))	('PPT', 'Var', (91, 94))	('PPT', 'Chemical', 'MESH:C415032', (91, 94))	('higher', 'PosReg', (102, 108))	('Cell cycle', 'CPA', (0, 10))
176404	32629820	These results demonstrate that PPT inhibited cell viability by G2/M phase arrest in a dose-dependent manner.	('cell viability', 'CPA', (45, 59))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('inhibited', 'NegReg', (35, 44))	('PPT', 'Var', (31, 34))	('PPT', 'Chemical', 'MESH:C415032', (31, 34))	('arrest', 'Disease', (74, 80))
176414	32629820	In this study, PPT upregulated ROS generation (Figure 4A) and ER stress-mediated protein expression (Figure 4B).	('upregulated', 'PosReg', (19, 30))	('ER stress-mediated protein expression', 'MPA', (62, 99))	('PPT', 'Var', (15, 18))	('PPT', 'Chemical', 'MESH:C415032', (15, 18))	('ROS', 'Chemical', 'MESH:D017382', (31, 34))	('ROS generation', 'MPA', (31, 45))
176417	32629820	Our study results showed that PPT induced MMP dysfunction (Figure 5A) and apoptosis via regulation of mitochondria-associated apoptotic protein (Figure 5B).	('apoptosis', 'CPA', (74, 83))	('mitochondria-associated apoptotic', 'MPA', (102, 135))	('PPT', 'Var', (30, 33))	('PPT', 'Chemical', 'MESH:C415032', (30, 33))	('MMP dysfunction', 'Disease', (42, 57))	('MMP dysfunction', 'Disease', 'MESH:D009461', (42, 57))
176419	32629820	In conclusion, the results of our study revealed that PPT treatment was able to effectively induce apoptosis by regulating anti- and pro-apoptotic proteins in human ESCC cells via the JNK/p38 MAPK signaling pathways, which demonstrated the detailed anti-cancer mechanism of PPT in human ESCC cells.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('regulating', 'Reg', (112, 122))	('PPT', 'Var', (54, 57))	('JNK', 'Gene', (184, 187))	('PPT', 'Chemical', 'MESH:C415032', (54, 57))	('PPT', 'Chemical', 'MESH:C415032', (274, 277))	('p38', 'Gene', '1432', (188, 191))	('apoptosis', 'CPA', (99, 108))	('human', 'Species', '9606', (159, 164))	('JNK', 'Gene', '5599', (184, 187))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (254, 260))	('p38', 'Gene', (188, 191))	('human', 'Species', '9606', (281, 286))	('induce', 'PosReg', (92, 98))
176421	32629820	Fusion of anti-cancer drugs ameliorates efficacy compared to mono-therapy and potentially decreases drug resistance, offering therapeutic anti-cancer benefits such as reducing tumor growth and metastatic potential, cell cycle arrest, and induction of apoptosis.	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('drug resistance', 'Phenotype', 'HP:0020174', (100, 115))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (215, 232))	('reducing', 'NegReg', (167, 175))	('tumor', 'Disease', (176, 181))	('cancer', 'Disease', (143, 149))	('apoptosis', 'CPA', (251, 260))	('ameliorates', 'PosReg', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('arrest', 'Disease', (226, 232))	('cancer', 'Disease', (15, 21))	('efficacy', 'MPA', (40, 48))	('decreases', 'NegReg', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('Fusion', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('arrest', 'Disease', 'MESH:D006323', (226, 232))	('drug resistance', 'MPA', (100, 115))
176422	32629820	The findings of this study suggest that PPT may be valuable as a potential anti-cancer agent and be considered valuable candidates of combination therapy for human ESCC.	('human', 'Species', '9606', (158, 163))	('PPT', 'Chemical', 'MESH:C415032', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PPT', 'Var', (40, 43))	('ESCC', 'Disease', (164, 168))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
176454	32185172	Multiple lines of evidence suggest that numerous risk elements, containing genetic and environmental factors, account for cancer initiation and development, among which the involvement of mis-regulation of non-coding RNAs (ncRNAs) in cancer has aroused extensive attention during the past few decades.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('mis-regulation', 'Var', (188, 202))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer initiation', 'Disease', 'MESH:D009369', (122, 139))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('ncRNA', 'Gene', (223, 228))	('cancer initiation', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (234, 240))	('account', 'Reg', (110, 117))	('ncRNA', 'Gene', '220202', (223, 228))
176464	32185172	lncRNAs are divided into several categories according to genomic organization and relation to coding genes, such as long intergenic non-coding RNAs, antisense RNAs, sense overlapping RNAs, sense intronic RNAs, enhancer RNAs as well as pseudogene-expressed lncRNAs.	('ncRNA', 'Gene', '220202', (257, 262))	('sense overlapping RNAs', 'Var', (165, 187))	('antisense', 'Var', (149, 158))	('ncRNA', 'Gene', '220202', (1, 6))	('sense intronic RNAs', 'Var', (189, 208))	('ncRNA', 'Gene', (257, 262))	('ncRNA', 'Gene', (1, 6))
176469	32185172	Dysregulation of lncRNAs, pseudogenes and circRNAs leads to alteration of abundance of miRNAs, thus affecting their inhibition of downstream target expression.	('Dysregulation', 'Var', (0, 13))	('abundance', 'MPA', (74, 83))	('alteration', 'Reg', (60, 70))	('downstream target expression', 'MPA', (130, 158))	('affecting', 'Reg', (100, 109))	('ncRNA', 'Gene', (18, 23))	('miRNAs', 'Protein', (87, 93))	('ncRNA', 'Gene', '220202', (18, 23))	('inhibition', 'MPA', (116, 126))
176471	32185172	Based on ceRNA mechanism, researchers and scholars have discovered a variety of potential cancer-associated pseudogenes using in silico analysis.	('pseudogenes', 'Var', (108, 119))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
176476	32185172	Dysregulation of pseudogenes and their transcripts has been implicated into initiation and/or progression of human disorders, including cancer.	('human', 'Species', '9606', (109, 114))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('implicated', 'Reg', (60, 70))	('cancer', 'Disease', (136, 142))	('pseudogenes', 'Protein', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
176477	32185172	Among pseudogene-derived lncRNAs, some act as tumor promotors, facilitating cancer development, whereas the other function as tumor suppressors, inhibiting cancer progression.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('ncRNA', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ncRNA', 'Gene', '220202', (26, 31))	('inhibiting', 'NegReg', (145, 155))	('facilitating', 'PosReg', (63, 75))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('pseudogene-derived', 'Var', (6, 24))	('tumor', 'Disease', (126, 131))
176491	32185172	Dysregulation of pseudogenes and their transcripts accounts for the development of chemo-resistance and radio-resistance of HCC which greatly reduces the efficacy of chemotherapy and radiotherapy.	('HCC', 'Phenotype', 'HP:0001402', (124, 127))	('Dysregulation', 'Var', (0, 13))	('reduces', 'NegReg', (142, 149))	('HCC', 'Disease', 'MESH:D006528', (124, 127))	('pseudogenes', 'Protein', (17, 28))	('HCC', 'Disease', (124, 127))
176492	32185172	For example, suggested that PDIAP3 caused doxorubicin resistance of HCC by targeting miR-125/124-TRAF6/NF-KB signaling; found that knockdown of SUMO1P3 markedly enhanced radio-sensitivity in HCC.	('HCC', 'Disease', 'MESH:D006528', (191, 194))	('enhanced', 'PosReg', (161, 169))	('HCC', 'Disease', (191, 194))	('knockdown', 'Var', (131, 140))	('SUMO1P3', 'Gene', '474338', (144, 151))	('doxorubicin', 'MPA', (42, 53))	('HCC', 'Phenotype', 'HP:0001402', (191, 194))	('TRAF6', 'Gene', (97, 102))	('TRAF6', 'Gene', '7189', (97, 102))	('HCC', 'Disease', 'MESH:D006528', (68, 71))	('HCC', 'Disease', (68, 71))	('SUMO1P3', 'Gene', (144, 151))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('HCC', 'Phenotype', 'HP:0001402', (68, 71))	('radio-sensitivity', 'MPA', (170, 187))
176502	32185172	NANOGP8 expression was significantly elevated in gastric cancer and knockdown of NANOGP8 resulted in decreased proliferation and promoted apoptosis of gastric cancer cells.	('promoted', 'PosReg', (129, 137))	('NANOGP8', 'Gene', '388112', (0, 7))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('elevated', 'PosReg', (37, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('decreased', 'NegReg', (101, 110))	('knockdown', 'Var', (68, 77))	('apoptosis', 'CPA', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('expression', 'MPA', (8, 18))	('NANOGP8', 'Gene', (81, 88))	('gastric cancer', 'Disease', (151, 165))	('gastric cancer', 'Disease', (49, 63))	('NANOGP8', 'Gene', '388112', (81, 88))	('NANOGP8', 'Gene', (0, 7))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))
176505	32185172	Overexpression of DUXAP8 promoted cell proliferation and migration of gastric cancer by epigenetically inhibiting PLEKHO1 expression.	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('expression', 'MPA', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PLEKHO1', 'Gene', '51177', (114, 121))	('cell proliferation', 'CPA', (34, 52))	('epigenetically', 'Var', (88, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('DUXAP8', 'Gene', (18, 24))	('migration', 'CPA', (57, 66))	('DUXAP8', 'Gene', '503637', (18, 24))	('promoted', 'PosReg', (25, 33))	('PLEKHO1', 'Gene', (114, 121))	('gastric cancer', 'Disease', (70, 84))
176510	32185172	High expression PTTG3P linked to large tumor size, increased tumor invasiveness and served as an unfavorable prognostic biomarker.	('High expression', 'Var', (0, 15))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PTTG3P', 'Gene', '26255', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor invasiveness', 'Disease', (61, 79))	('tumor invasiveness', 'Disease', 'MESH:D009361', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (39, 44))	('PTTG3P', 'Gene', (16, 22))	('tumor', 'Disease', (61, 66))
176511	32185172	Besides, the abilities of gastric cancer proliferation and invasion were enhanced after ectopic expression of PTTG3P.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('ectopic expression', 'Var', (88, 106))	('PTTG3P', 'Gene', '26255', (110, 116))	('gastric cancer proliferation', 'Disease', (26, 54))	('gastric cancer proliferation', 'Disease', 'MESH:D013274', (26, 54))	('PTTG3P', 'Gene', (110, 116))	('enhanced', 'PosReg', (73, 81))	('invasion', 'CPA', (59, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (26, 40))
176516	32185172	High SUMO1P3 level was reported to be associated with advanced histological stages, metastasis, angiogenesis and poor prognosis of colon cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colon cancer', 'Disease', 'MESH:D015179', (131, 143))	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('SUMO1P3', 'Gene', (5, 12))	('colon cancer', 'Disease', (131, 143))	('metastasis', 'CPA', (84, 94))	('patients', 'Species', '9606', (144, 152))	('angiogenesis', 'CPA', (96, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (131, 143))	('SUMO1P3', 'Gene', '474338', (5, 12))
176517	32185172	Inhibition of SUMO1P3 repressed proliferation, migration, invasion and pro-angiogenesis of colon cancer cells in vitro, and reduced growth, liver metastasis and vascularization of colon cancer in vivo by decreasing cyclin D1, vimentin and VEGFA but increasing E-cadherin expression.	('vimentin', 'Gene', (226, 234))	('colon cancer', 'Disease', 'MESH:D015179', (91, 103))	('E-cadherin', 'Gene', (260, 270))	('VEGFA', 'Gene', (239, 244))	('migration', 'CPA', (47, 56))	('E-cadherin', 'Gene', '999', (260, 270))	('vascularization', 'CPA', (161, 176))	('colon cancer', 'Disease', (180, 192))	('liver metastasis', 'Disease', (140, 156))	('expression', 'MPA', (271, 281))	('colon cancer', 'Disease', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cyclin D1', 'Gene', (215, 224))	('invasion', 'CPA', (58, 66))	('SUMO1P3', 'Gene', (14, 21))	('VEGFA', 'Gene', '7422', (239, 244))	('SUMO1P3', 'Gene', '474338', (14, 21))	('cyclin D1', 'Gene', '595', (215, 224))	('Inhibition', 'Var', (0, 10))	('colon cancer', 'Phenotype', 'HP:0003003', (180, 192))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))	('pro-angiogenesis', 'CPA', (71, 87))	('reduced', 'NegReg', (124, 131))	('increasing', 'PosReg', (249, 259))	('liver metastasis', 'Disease', 'MESH:D009362', (140, 156))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('growth', 'CPA', (132, 138))	('vimentin', 'Gene', '7431', (226, 234))	('decreasing', 'NegReg', (204, 214))	('colon cancer', 'Disease', 'MESH:D015179', (180, 192))
176520	32185172	The authors also indicated that silencing expression of TPTE2P1 resulted in cell cycle arrest at S phase and caused cell apoptosis in colorectal cancer.	('cell cycle arrest at S phase', 'CPA', (76, 104))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('colorectal cancer', 'Disease', (134, 151))	('cell apoptosis', 'CPA', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('silencing', 'Var', (32, 41))	('TPTE2P1', 'Gene', (56, 63))	('caused', 'Reg', (109, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('TPTE2P1', 'Gene', '646405', (56, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))
176522	32185172	DUXAP8 was remarkably overexpressed in colorectal cancer and DUXAP8 knockdown led to inhibited proliferation, migration and invasion and enhanced apoptosis.	('enhanced', 'PosReg', (137, 145))	('DUXAP8', 'Gene', (0, 6))	('inhibited', 'NegReg', (85, 94))	('DUXAP8', 'Gene', '503637', (0, 6))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('knockdown', 'Var', (68, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('DUXAP8', 'Gene', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('invasion', 'CPA', (124, 132))	('apoptosis', 'CPA', (146, 155))	('DUXAP8', 'Gene', '503637', (61, 67))	('colorectal cancer', 'Disease', (39, 56))
176524	32185172	DUXAP10 promoted cell proliferation and cell cycle progression and blocked cell apoptosis by epigenetically silencing expression of p21 and PTEN.	('blocked', 'NegReg', (67, 74))	('cell apoptosis', 'CPA', (75, 89))	('cell proliferation', 'CPA', (17, 35))	('p21', 'Gene', '1026', (132, 135))	('DUXAP10', 'Gene', (0, 7))	('p21', 'Gene', (132, 135))	('epigenetically silencing', 'Var', (93, 117))	('DUXAP10', 'Gene', '503639', (0, 7))	('cell cycle progression', 'CPA', (40, 62))	('PTEN', 'Gene', (140, 144))	('promoted', 'PosReg', (8, 16))	('PTEN', 'Gene', '5728', (140, 144))
176528	32185172	reported that DUXAP8, upregulated in non-small cell lung cancer and an unfavorable prognostic biomarker, significantly facilitated cell growth, migration and invasion, and impaired apoptosis both in vitro and in vivo by epigenetically silencing EGR1 and RHOB.	('upregulated', 'PosReg', (22, 33))	('cell growth', 'CPA', (131, 142))	('epigenetically silencing', 'Var', (220, 244))	('EGR1', 'Gene', (245, 249))	('apoptosis', 'CPA', (181, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('EGR1', 'Gene', '1958', (245, 249))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (37, 63))	('impaired', 'NegReg', (172, 180))	('DUXAP8', 'Gene', (14, 20))	('DUXAP8', 'Gene', '503637', (14, 20))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('RHOB', 'Gene', '388', (254, 258))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (37, 63))	('RHOB', 'Gene', (254, 258))	('facilitated', 'PosReg', (119, 130))	('non-small cell lung cancer', 'Disease', (37, 63))	('invasion', 'CPA', (158, 166))	('migration', 'CPA', (144, 153))
176530	32185172	Functional and mechanistic experiments suggested that DUXAP10 exerted oncogenic roles in non-small cell lung cancer by binding to LSD1 and epigenetic silencing expression of LATS2 and RRAD.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('DUXAP10', 'Gene', (54, 61))	('RRAD', 'Gene', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('RRAD', 'Gene', '6236', (184, 188))	('DUXAP10', 'Gene', '503639', (54, 61))	('LATS2', 'Gene', (174, 179))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (89, 115))	('LATS2', 'Gene', '26524', (174, 179))	('LSD1', 'Gene', '23028', (130, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('non-small cell lung cancer', 'Disease', (89, 115))	('epigenetic silencing', 'Var', (139, 159))	('LSD1', 'Gene', (130, 134))	('binding', 'Interaction', (119, 126))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (89, 115))
176537	32185172	also experimentally confirmed that knockdown of OGFRP1 suppressed the malignant behaviors of endometrial cancer, including suppressed cell viability, enhanced cell apoptosis and inhibited cell migration and invasion.	('knockdown', 'Var', (35, 44))	('OGFRP1', 'Gene', (48, 54))	('enhanced', 'PosReg', (150, 158))	('cell apoptosis', 'CPA', (159, 173))	('malignant behaviors of endometrial cancer', 'Disease', (70, 111))	('suppressed', 'NegReg', (123, 133))	('endometrial cancer', 'Phenotype', 'HP:0012114', (93, 111))	('inhibited', 'NegReg', (178, 187))	('OGFRP1', 'Gene', '388906', (48, 54))	('suppressed', 'NegReg', (55, 65))	('malignant behaviors of endometrial cancer', 'Disease', 'MESH:D016889', (70, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cell viability', 'CPA', (134, 148))
176542	32185172	demonstrated that FTH1P3 was notably upregulated in esophageal squamous cell carcinoma and knockdown of FTH1P3 significantly inhibited proliferation, migration and invasion of esophageal squamous cell carcinoma cells by regulating SP1/NF-kB signaling.	('proliferation', 'CPA', (135, 148))	('invasion', 'CPA', (164, 172))	('migration', 'CPA', (150, 159))	('esophageal squamous cell carcinoma', 'Disease', (176, 210))	('upregulated', 'PosReg', (37, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('knockdown', 'Var', (91, 100))	('regulating', 'Reg', (220, 230))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (52, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (176, 210))	('SP1/NF-kB signaling', 'MPA', (231, 250))	('FTH1P3', 'Gene', (104, 110))	('FTH1P3', 'Gene', (18, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('FTH1P3', 'Gene', '2498', (104, 110))	('FTH1P3', 'Gene', '2498', (18, 24))	('esophageal squamous cell carcinoma', 'Disease', (52, 86))	('inhibited', 'NegReg', (125, 134))
176544	32185172	They also showed that DUXAP10 was positively correlated with poor prognosis and epigenetically silenced p21 by recruiting EZH2 to the promoter of p21, thereby promoting cell proliferation and metastasis.	('EZH2', 'Gene', (122, 126))	('EZH2', 'Gene', '2146', (122, 126))	('p21', 'Gene', '1026', (104, 107))	('p21', 'Gene', '1026', (146, 149))	('promoting', 'PosReg', (159, 168))	('p21', 'Gene', (146, 149))	('p21', 'Gene', (104, 107))	('DUXAP10', 'Gene', '503639', (22, 29))	('recruiting', 'PosReg', (111, 121))	('cell proliferation', 'CPA', (169, 187))	('metastasis', 'CPA', (192, 202))	('epigenetically silenced', 'Var', (80, 103))	('DUXAP10', 'Gene', (22, 29))
176552	32185172	By epigenetically silencing CDKN1A an KLF2, DUXAP8, upregulated in pancreatic cancer, promoted growth of pancreatic cancer.	('KLF2', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('growth', 'MPA', (95, 101))	('epigenetically silencing', 'Var', (3, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('DUXAP8', 'Gene', '503637', (44, 50))	('pancreatic cancer', 'Disease', (105, 122))	('CDKN1A', 'Gene', (28, 34))	('DUXAP8', 'Gene', (44, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (105, 122))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pancreatic cancer', 'Disease', (67, 84))	('CDKN1A', 'Gene', '1026', (28, 34))	('upregulated', 'PosReg', (52, 63))	('promoted', 'PosReg', (86, 94))	('KLF2', 'Gene', '10365', (38, 42))
176554	32185172	They also confirmed that knockdown of DUXAP10 could result in inhibited proliferation, migration, invasion and enhanced apoptosis in renal cell carcinoma through interacting with RNA-binding proteins, EZH2 and LSD1.	('migration', 'CPA', (87, 96))	('proliferation', 'CPA', (72, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('invasion', 'CPA', (98, 106))	('enhanced', 'PosReg', (111, 119))	('LSD1', 'Gene', (210, 214))	('LSD1', 'Gene', '23028', (210, 214))	('RNA-binding proteins', 'Protein', (179, 199))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (133, 153))	('DUXAP10', 'Gene', '503639', (38, 45))	('knockdown', 'Var', (25, 34))	('renal cell carcinoma', 'Disease', (133, 153))	('apoptosis', 'CPA', (120, 129))	('DUXAP10', 'Gene', (38, 45))	('EZH2', 'Gene', '2146', (201, 205))	('inhibited', 'NegReg', (62, 71))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (133, 153))	('EZH2', 'Gene', (201, 205))	('interacting', 'Interaction', (162, 173))
176557	32185172	Furthermore, after knockdown of SUMO1P3, bladder cancer exhibited cell proliferation and migration inhibition and apoptosis induction.	('SUMO1P3', 'Gene', (32, 39))	('knockdown', 'Var', (19, 28))	('cell proliferation', 'CPA', (66, 84))	('migration inhibition', 'CPA', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('SUMO1P3', 'Gene', '474338', (32, 39))	('apoptosis induction', 'CPA', (114, 133))	('bladder cancer', 'Disease', 'MESH:D001749', (41, 55))	('bladder cancer', 'Disease', (41, 55))
176563	32185172	Two pseudogene-derived lncRNAs, TPTE2P1 and Loc344887, have been documented to play oncogenic roles in development of gallbladder cancer.	('TPTE2P1', 'Gene', '646405', (32, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (122, 136))	('gallbladder cancer', 'Disease', (118, 136))	('gallbladder cancer', 'Disease', 'MESH:D005706', (118, 136))	('ncRNA', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Loc344887', 'Var', (44, 53))	('TPTE2P1', 'Gene', (32, 39))	('ncRNA', 'Gene', '220202', (24, 29))	('play', 'Reg', (79, 83))
176564	32185172	Depletion of TPTE2P1 significantly blocked epithelial-mesenchymal transition, migration and invasion of gallbladder cancer.	('epithelial-mesenchymal transition', 'CPA', (43, 76))	('TPTE2P1', 'Gene', (13, 20))	('invasion of gallbladder cancer', 'Disease', 'MESH:D005706', (92, 122))	('Depletion', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('TPTE2P1', 'Gene', '646405', (13, 20))	('migration', 'CPA', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('blocked', 'NegReg', (35, 42))	('invasion of gallbladder cancer', 'Disease', (92, 122))
176565	32185172	Loc344887 was elevated in gallbladder cancer, was positively associated with larger tumor size, and facilitated cell proliferation, cell cycle progression, migration and invasion.	('cell proliferation', 'CPA', (112, 130))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))	('migration', 'CPA', (156, 165))	('tumor', 'Disease', (84, 89))	('gallbladder cancer', 'Disease', (26, 44))	('gallbladder cancer', 'Disease', 'MESH:D005706', (26, 44))	('cell cycle progression', 'CPA', (132, 154))	('facilitated', 'PosReg', (100, 111))	('associated', 'Reg', (61, 71))	('invasion', 'CPA', (170, 178))	('Loc344887', 'Var', (0, 9))	('elevated', 'Reg', (14, 22))
176567	32185172	confirmed FTH1P3 was significantly upregulated in laryngeal squamous cell cancer and positively linked to the poor differentiation, high T classification, positive lymph node metastasis and advanced clinical stage.	('poor differentiation', 'CPA', (110, 130))	('FTH1P3', 'Gene', '2498', (10, 16))	('linked', 'Reg', (96, 102))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D018307', (50, 80))	('positive lymph node metastasis', 'CPA', (155, 185))	('laryngeal squamous cell cancer', 'Disease', (50, 80))	('upregulated', 'PosReg', (35, 46))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (60, 80))	('high', 'Var', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('FTH1P3', 'Gene', (10, 16))
176585	32185172	Apart from PTENP1, some pseudogene-derived lncRNAs were also demonstrated to be downregulated in gastric cancer and play tumor suppressive roles in gastric cancer progression.	('gastric cancer', 'Disease', (97, 111))	('gastric cancer', 'Disease', (148, 162))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('ncRNA', 'Gene', (44, 49))	('tumor', 'Disease', (121, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('downregulated', 'NegReg', (80, 93))	('PTENP1', 'Gene', (11, 17))	('ncRNA', 'Gene', '220202', (44, 49))	('PTENP1', 'Gene', '11191', (11, 17))	('pseudogene-derived', 'Var', (24, 42))
176596	32185172	The investigation performed by the group of Johnson G demonstrated that silencing of NMRAL2P could protect against sulforaphane-mediated inhibition of cell growth, colony formation and migration in colon cancer.	('sulforaphane-mediated inhibition', 'MPA', (115, 147))	('silencing', 'Var', (72, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (198, 210))	('colon cancer', 'Disease', 'MESH:D015179', (198, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('NMRAL2P', 'Gene', (85, 92))	('sulforaphane', 'Chemical', 'MESH:C016766', (115, 127))	('colon cancer', 'Disease', (198, 210))	('NMRAL2P', 'Gene', '344887', (85, 92))	('colony formation', 'CPA', (164, 180))	('cell growth', 'CPA', (151, 162))	('migration', 'CPA', (185, 194))
176606	32185172	Subsequently, they also validated that HERC2P2 overexpression attenuated migration and colony formation abilities of glioma in vitro and inhibited glioma xenograft growth in vivo.	('glioma', 'Disease', (117, 123))	('inhibited', 'NegReg', (137, 146))	('attenuated', 'NegReg', (62, 72))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('HERC2P2', 'Gene', (39, 46))	('HERC2P2', 'Gene', '400322', (39, 46))	('glioma', 'Disease', (147, 153))	('overexpression', 'Var', (47, 61))
176617	32185172	Over the past decades, pseudogenes have been documented to play crucial roles in diverse cancer types in DNA, RNA and protein levels.	('pseudogenes', 'Var', (23, 34))	('DNA', 'MPA', (105, 108))	('protein levels', 'MPA', (118, 132))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('roles', 'Reg', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
176622	32185172	In HCC, long non-coding RNA PTENP1 via its ceRNA interaction with miR-17, miR-19b and miR-20a, and finally suppressed cell growth through inhibited oncogenic PI3K/AKT pathway.	('miR-19b', 'Gene', '406980', (74, 81))	('cell growth', 'CPA', (118, 129))	('miR-17', 'Gene', (66, 72))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('AKT', 'Gene', (163, 166))	('interaction', 'Interaction', (49, 60))	('miR-20a', 'Gene', (86, 93))	('miR-17', 'Gene', '406952', (66, 72))	('HCC', 'Disease', 'MESH:D006528', (3, 6))	('miR-20a', 'Gene', '406982', (86, 93))	('suppressed', 'NegReg', (107, 117))	('inhibited', 'NegReg', (138, 147))	('miR-19b', 'Gene', (74, 81))	('HCC', 'Disease', (3, 6))	('PTENP1', 'Gene', (28, 34))	('long non-coding RNA', 'Var', (8, 27))	('AKT', 'Gene', '207', (163, 166))	('PTENP1', 'Gene', '11191', (28, 34))
176630	32185172	also suggested a FTH1 gene: pseudogene: microRNA modulated tumorigenesis in prostate cancer.	('modulated', 'Reg', (49, 58))	('tumor', 'Disease', (59, 64))	('microRNA', 'Var', (40, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('FTH1', 'Gene', (17, 21))	('FTH1', 'Gene', '2495', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
176633	32185172	confirmed that FLT1P1 antisense transcript suppressed VEGFA by interaction with miR-520a and inhibited tumor cell proliferation and xenograft tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('VEGFA', 'Gene', '7422', (54, 59))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (103, 108))	('interaction', 'Interaction', (63, 74))	('miR-520a', 'Gene', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('antisense', 'Var', (22, 31))	('miR-520a', 'Gene', '574467', (80, 88))	('FLT1P1', 'Gene', (15, 21))	('VEGFA', 'Gene', (54, 59))	('FLT1P1', 'Gene', '391533', (15, 21))	('inhibited', 'NegReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('suppressed', 'NegReg', (43, 53))
176639	32185172	for the first time, reported HMGA1 pseudogenes as candidate proto-oncogenic ceRNAs, including HMGA1P6 and HMGA1P7.	('HMGA1', 'Gene', (29, 34))	('HMGA1', 'Gene', '3159', (29, 34))	('HMGA1P7', 'Gene', (106, 113))	('HMGA1', 'Gene', (106, 111))	('HMGA1P6', 'Gene', '100130029', (94, 101))	('HMGA1P6', 'Gene', (94, 101))	('HMGA1P7', 'Gene', '387065', (106, 113))	('HMGA1', 'Gene', '3159', (106, 111))	('pseudogenes', 'Var', (35, 46))	('HMGA1', 'Gene', (94, 99))	('HMGA1', 'Gene', '3159', (94, 99))
176640	32185172	HMGA1P7 was found to increase H19 and lgf2 expression by acting as decoy for miR-15, miR-16, miR-214, and miR-761.	('H19', 'Gene', (30, 33))	('miR-16', 'Gene', '51573', (85, 91))	('miR-214', 'Gene', (93, 100))	('HMGA1P7', 'Gene', '387065', (0, 7))	('miR-15', 'Var', (77, 83))	('HMGA1P7', 'Gene', (0, 7))	('miR-214', 'Gene', '406996', (93, 100))	('lgf2', 'Gene', (38, 42))	('miR-761', 'Gene', (106, 113))	('miR-16', 'Gene', (85, 91))	('H19', 'Gene', '283120', (30, 33))	('miR-761', 'Gene', '100313892', (106, 113))	('expression', 'MPA', (43, 53))	('increase', 'PosReg', (21, 29))
176644	32185172	OCT4-pg5 also upregulated OCT4 by sponging miR-145 and thus facilitated cell proliferation of endometrial carcinoma.	('sponging', 'Var', (34, 42))	('OCT4-pg5', 'Gene', (0, 8))	('OCT4-pg5', 'Gene', '100009667', (0, 8))	('facilitated', 'PosReg', (60, 71))	('miR-145', 'Gene', (43, 50))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (94, 115))	('OCT4', 'Gene', '5460', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cell proliferation', 'CPA', (72, 90))	('miR-145', 'Gene', '406937', (43, 50))	('endometrial carcinoma', 'Disease', (94, 115))	('upregulated', 'PosReg', (14, 25))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('OCT4', 'Gene', (26, 30))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (0, 4))
176646	32185172	suggested that PTTG3P expression positively associated with PTTG1 expression and may function by sponging miR-129-5p, miR-383-5p, and miR-376c-3p.	('associated', 'Reg', (44, 54))	('miR-376c-3p', 'Var', (134, 145))	('PTTG1', 'Gene', (60, 65))	('miR-383', 'Gene', '494332', (118, 125))	('PTTG1', 'Gene', '9232', (60, 65))	('expression', 'MPA', (66, 76))	('miR-129-5p', 'Gene', '100302178', (106, 116))	('PTTG3P', 'Gene', '26255', (15, 21))	('miR-383', 'Gene', (118, 125))	('miR-129-5p', 'Gene', (106, 116))	('PTTG3P', 'Gene', (15, 21))
176651	32185172	What's more, TUSC2P promotes those functions by binding miR-17, miR-93, miR-299-3p, miR-520a, miR-608, and miR-661 according to the research conducted by.	('miR-93', 'Gene', (64, 70))	('miR-661', 'Gene', (107, 114))	('miR-17', 'Gene', (56, 62))	('promotes', 'PosReg', (20, 28))	('miR-661', 'Gene', '724031', (107, 114))	('miR-17', 'Gene', '406952', (56, 62))	('binding', 'Interaction', (48, 55))	('miR-520a', 'Gene', (84, 92))	('miR-608', 'Gene', (94, 101))	('TUSC2P', 'Gene', (13, 19))	('miR-608', 'Gene', '693193', (94, 101))	('miR-520a', 'Gene', '574467', (84, 92))	('TUSC2P', 'Gene', '359794', (13, 19))	('miR-93', 'Gene', '407051', (64, 70))	('miR-299-3p', 'Var', (72, 82))
176652	32185172	ASS1P3, a pseudogene of ASS1, promoted cell proliferation by functioning as a miRNA decoy for miR-34a-5p in renal cell carcinoma reported by the team of.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('ASS1', 'Gene', '445', (0, 4))	('ASS1', 'Gene', (24, 28))	('ASS1P3', 'Gene', '158452', (0, 6))	('ASS1', 'Gene', '445', (24, 28))	('promoted', 'PosReg', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cell proliferation', 'CPA', (39, 57))	('ASS1P3', 'Gene', (0, 6))	('miR-34a-5p', 'Var', (94, 104))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (108, 128))	('ASS1', 'Gene', (0, 4))	('renal cell carcinoma', 'Disease', (108, 128))
176654	32185172	CYP2A7P was discovered to affect expression of its cognate gene CYP2A6 by functioning as a decoy for miR-126 in human liver.	('CYP2A6', 'Gene', '1548', (64, 70))	('affect', 'Reg', (26, 32))	('CYP2A6', 'Gene', (64, 70))	('miR-126', 'Gene', '406913', (101, 108))	('expression', 'MPA', (33, 43))	('human', 'Species', '9606', (112, 117))	('miR-126', 'Gene', (101, 108))	('CYP2A7P', 'Var', (0, 7))
176657	32185172	By luciferase reporter assay, the authors confirmed that FOXO3P exerted its roles through sponging several miRNAs, including miR-22, miR-136*, miR-138, miR-149*, miR-433, miR-762, miR-3614-5p, and miR-3622b-5p.	('miR-136', 'Gene', '406927', (133, 140))	('miR-149', 'Gene', '406941', (152, 159))	('miR-22', 'Gene', '407004', (125, 131))	('FOXO3', 'Gene', (57, 62))	('miR-3614', 'Gene', '100500827', (180, 188))	('miR-22', 'Gene', (125, 131))	('sponging', 'Reg', (90, 98))	('miR-138', 'Var', (143, 150))	('miR-3622b-5p', 'Var', (197, 209))	('miR-433', 'Gene', (162, 169))	('FOXO3', 'Gene', '2309', (57, 62))	('miR-433', 'Gene', '574034', (162, 169))	('miR-762', 'Gene', (171, 178))	('miR-762', 'Gene', '100313837', (171, 178))	('miR-149', 'Gene', (152, 159))	('miR-3614', 'Gene', (180, 188))	('miR-136', 'Gene', (133, 140))
176658	32185172	GBA encodes lysosomal glucocerebrosidase and its mutations are associated with Parkinson's disease.	('glucocerebrosidase', 'Disease', 'MESH:D005776', (22, 40))	("Parkinson's disease", 'Disease', 'MESH:D010300', (79, 98))	('mutations', 'Var', (49, 58))	('GBA', 'Gene', '2629', (0, 3))	('associated', 'Reg', (63, 73))	('glucocerebrosidase', 'Disease', (22, 40))	('GBA', 'Gene', (0, 3))	("Parkinson's disease", 'Disease', (79, 98))
176673	32185172	Furthermore, seven miRNAs binding with RP11-564D11.3 were predicted, including miR-200b-3p, miR-200a-3p, miR-429, miR-101-3p, miR-9-5p, miR-200c-3p, and miR-141-3p.	('miR-429', 'Gene', (105, 112))	('miR-141-3p', 'Var', (153, 163))	('miR-9-5p', 'Gene', (126, 134))	('miR-9-5p', 'Gene', '407052', (126, 134))	('miR-101-3p', 'Var', (114, 124))	('RP11', 'Gene', (39, 43))	('miR-200b-3p', 'Var', (79, 90))	('RP11', 'Gene', '26121', (39, 43))	('binding', 'Interaction', (26, 33))	('miR-200c-3p', 'Var', (136, 147))	('miR-200a-3p', 'Var', (92, 103))	('miR-429', 'Gene', '554210', (105, 112))
176693	32185172	Expression and/or function dysregulation of these RNA transcripts account for the occurrence of multiple human disorders, containing cancer.	('occurrence', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('function', 'MPA', (18, 26))	('cancer', 'Disease', (133, 139))	('dysregulation', 'Var', (27, 40))	('account', 'Reg', (66, 73))	('human', 'Species', '9606', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
176704	32185172	Of course, the current findings about roles and mechanisms of known pseudogene-derived lncRNAs need to be further precisely validated by basic lab experiments and large clinical trials.	('ncRNA', 'Gene', (88, 93))	('pseudogene-derived', 'Var', (68, 86))	('ncRNA', 'Gene', '220202', (88, 93))
176720	31764785	Previous studies assessing the pathogenesis of PICC-related UEVT mostly analyzed the 3 parameters of Virchow's triad, and suggested that PICC causes vascular endothelial injury and exposes subendothelial collagen to blood, slows blood flow, and aggravates stasis, inducing thrombosis.	('thrombosis', 'Disease', 'MESH:D013927', (273, 283))	('vascular endothelial injury', 'Disease', 'MESH:D057772', (149, 176))	('UEVT', 'Disease', 'MESH:D020246', (60, 64))	('slows', 'NegReg', (223, 228))	('inducing', 'Reg', (264, 272))	('aggravates', 'PosReg', (245, 255))	('stasis', 'MPA', (256, 262))	('PICC', 'Var', (137, 141))	('exposes', 'Reg', (181, 188))	('thrombosis', 'Disease', (273, 283))	('UEVT', 'Disease', (60, 64))	('blood flow', 'MPA', (229, 239))	('causes', 'Reg', (142, 148))	('vascular endothelial injury', 'Disease', (149, 176))
176722	31764785	As an intravascular foreign body, PICC directly activates factor XII and thrombosis initiated by factor XIIa is considered as a contact pathway for thrombus formation.	('thrombus', 'Disease', (148, 156))	('thrombosis', 'Disease', (73, 83))	('thrombus', 'Disease', 'MESH:D013927', (148, 156))	('thrombosis', 'Disease', 'MESH:D013927', (73, 83))	('factor', 'Protein', (58, 64))	('factor XIIa', 'Var', (97, 108))	('activates', 'PosReg', (48, 57))
176734	31764785	The exclusion criteria were: overt predisposition to bleeding having any of the following: platelets < 60 x 109 /L, prothrombin time > 16 seconds (normal 12-13 seconds), activated partial thromboplatin time > 50 seconds (normal 30-40 seconds), thrombin time>22 seconds (normal 15-19 seconds), fibrinogen < 2.0 g/L (normal 2-4 g/L); history of thrombosis with previous thrombolytic therapy; obvious heart, liver, or kidney dysfunction; or failure of PICC indwelling.	('prothrombin', 'Gene', '2147', (116, 127))	('thrombin', 'Gene', (244, 252))	('fibrinogen', 'Gene', '2244', (293, 303))	('< 60 x 109 /L', 'Var', (101, 114))	('bleeding', 'Disease', 'MESH:D006470', (53, 61))	('thrombosis', 'Disease', 'MESH:D013927', (343, 353))	('liver', 'Disease', (405, 410))	('fibrinogen', 'Gene', (293, 303))	('kidney dysfunction', 'Disease', 'MESH:D007674', (415, 433))	('thrombin', 'Gene', '2147', (244, 252))	('bleeding', 'Disease', (53, 61))	('heart', 'Disease', (398, 403))	('thrombin', 'Gene', (119, 127))	('thrombin', 'Gene', '2147', (119, 127))	('thrombosis', 'Disease', (343, 353))	('kidney dysfunction', 'Phenotype', 'HP:0000083', (415, 433))	('prothrombin', 'Gene', (116, 127))	('kidney dysfunction', 'Disease', (415, 433))
176780	31764785	Precisely, times for the occurrence of PICC-related UEVTs were P50 = 15.0 days, P75 = 35.0 days, P90 = 53.0 days, and P95 = 100.0 days, respectively (Fig.	('UEVT', 'Disease', (52, 56))	('P50', 'Var', (63, 66))	('UEVT', 'Disease', 'MESH:D020246', (52, 56))	('P95', 'Var', (118, 121))	('P75', 'Var', (80, 83))
176866	31193834	Genetic predisposition resulting from single-nucleotide polymorphisms of transforming growth factor beta 1 (TGF beta-1) may present an intrinsic factor contributing to the development of severe radiation esophagitis.	('radiation esophagitis', 'Disease', (194, 215))	('radiation esophagitis', 'Disease', 'MESH:D004194', (194, 215))	('esophagitis', 'Phenotype', 'HP:0100633', (204, 215))	('contributing', 'Reg', (152, 164))	('transforming growth factor beta 1', 'Gene', '7040', (73, 106))	('TGF beta-1', 'Gene', '7040', (108, 118))	('single-nucleotide polymorphisms', 'Var', (38, 69))	('TGF beta-1', 'Gene', (108, 118))	('transforming growth factor beta 1', 'Gene', (73, 106))
176896	29868638	Inclusion criteria were: age >= 18 years, histologically verified malignant esophageal tumor (adenocarcinoma or squamous cell cancer), expected survival time >= 3 months, WHO performance status <= 2  , platelets >= 50 billion/L, International Normalized Ratio < 1.5 (medical correction was allowed), and s-creatinine < 150 micromol/L.	('esophageal tumor', 'Disease', (76, 92))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('>= 50 billion/L', 'Var', (212, 227))	('esophageal tumor', 'Phenotype', 'HP:0100751', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('esophageal tumor', 'Disease', 'MESH:D004938', (76, 92))	('International Normalized Ratio', 'MPA', (229, 259))	('adenocarcinoma or squamous cell cancer', 'Disease', 'MESH:D002294', (94, 132))	('adenocarcinoma or squamous cell cancer', 'Disease', (94, 132))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (112, 132))	('s-creatinine', 'MPA', (304, 316))
176920	29868638	The results from gastroscopies and MRI indicate that electrochemotherapy also induces tumor necrosis in that area.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor necrosis', 'Disease', 'MESH:D009336', (86, 100))	('induces', 'Reg', (78, 85))	('tumor necrosis', 'Disease', (86, 100))	('electrochemotherapy', 'Var', (53, 72))
176943	28767564	Numerous studies have established an association between alterations in PET avidity and patient outcomes.	('alterations', 'Var', (57, 68))	('patient', 'Species', '9606', (88, 95))	('PET avidity', 'MPA', (72, 83))
177028	26819081	Quantitative assessment of the association between Fas/FasL gene polymorphism and susceptibility to esophageal carcinoma in a north Chinese population The case-control study aims to investigate the association of Fas and FasL genetic polymorphisms (Fas-670A/G (rs1800682), Fas-1377G/A (rs2234767) and FasL-844T/C (rs763110)) with esophageal carcinoma susceptibility in a north Chinese population.	('rs763110', 'Var', (314, 322))	('Fas-670A/G', 'Gene', (249, 259))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (330, 350))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (100, 120))	('Fas', 'Chemical', 'MESH:C038178', (51, 54))	('association', 'Interaction', (198, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (341, 350))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('esophageal carcinoma', 'Disease', (100, 120))	('Fas', 'Chemical', 'MESH:C038178', (249, 252))	('esophageal carcinoma', 'Disease', (330, 350))	('Fas', 'Chemical', 'MESH:C038178', (273, 276))	('rs763110', 'Mutation', 'rs763110', (314, 322))	('Fas-670A/G', 'Gene', '2189', (249, 259))	('rs1800682', 'Var', (261, 270))	('Fas', 'Chemical', 'MESH:C038178', (301, 304))	('FasL', 'Gene', (55, 59))	('Fas', 'Chemical', 'MESH:C038178', (213, 216))	('FasL', 'Gene', '356', (55, 59))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (100, 120))	('FasL', 'Gene', '356', (221, 225))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (330, 350))	('FasL', 'Gene', (221, 225))	('rs2234767', 'Mutation', 'rs2234767', (286, 295))	('Fas', 'Chemical', 'MESH:C038178', (55, 58))	('FasL', 'Gene', '356', (301, 305))	('FasL', 'Gene', (301, 305))	('Fas', 'Chemical', 'MESH:C038178', (221, 224))	('rs1800682', 'Mutation', 'rs1800682', (261, 270))	('rs2234767', 'Var', (286, 295))
177030	26819081	There were no significant differences in distributions of their genotypes frequencies between patients and controls in Fas-670A/G, Fas-1377G/A and FasL-844T/C polymorphisms (P > 0.05).	('patients', 'Species', '9606', (94, 102))	('Fas-1377G/A', 'Var', (131, 142))	('Fas-670A/G', 'Gene', (119, 129))	('FasL-844T/C', 'Var', (147, 158))	('Fas-670A/G', 'Gene', '2189', (119, 129))
177031	26819081	Stratified analysis showed that no significant association was found between esophageal carcinoma and gene polymorphisms of Fas-670 A/G, Fas-1377G/A, and FasL-844T/C (P > 0.05).	('Fas-670 ', 'Gene', (124, 132))	('Fas-1377G/A', 'Var', (137, 148))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (77, 97))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (77, 97))	('-670 A/G', 'Mutation', 'rs1800682', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('FasL-844T/C', 'Var', (154, 165))	('esophageal carcinoma', 'Disease', (77, 97))	('Fas-670 ', 'Gene', '2189', (124, 132))
177043	26819081	In addition, somatic mutations and functional germline in gene Fas and FasL impair apoptotic signal transduction, which are related to a high risk of cancer 8, 9, 10.	('apoptotic signal transduction', 'MPA', (83, 112))	('Fas', 'Chemical', 'MESH:C038178', (71, 74))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('impair', 'NegReg', (76, 82))	('functional germline', 'Var', (35, 54))	('FasL', 'Gene', (71, 75))	('cancer', 'Disease', (150, 156))	('Fas', 'Chemical', 'MESH:C038178', (63, 66))	('related', 'Reg', (124, 131))	('Fas', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('FasL', 'Gene', '356', (71, 75))
177047	26819081	In addition, aberrant expression of Fas and FasL was also related to differentiation, invasiveness, metastasis, and prognosis of cancer 11, 14.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Fas', 'Chemical', 'MESH:C038178', (36, 39))	('differentiation', 'CPA', (69, 84))	('invasiveness', 'CPA', (86, 98))	('Fas', 'Chemical', 'MESH:C038178', (44, 47))	('aberrant expression', 'Var', (13, 32))	('Fas', 'Gene', (36, 39))	('cancer', 'Disease', (129, 135))	('related', 'Reg', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('FasL', 'Gene', '356', (44, 48))	('FasL', 'Gene', (44, 48))	('metastasis', 'CPA', (100, 110))
177048	26819081	Single-nucleotide polymorphisms have been identified in the promoter region of the Fas gene, A or G at position-670 (Fas-670A/G) and G or A at position-1377 (Fas-1377G/A).	('Fas', 'Gene', (83, 86))	('Fas-1377G/A', 'Var', (158, 169))	('Fas', 'Chemical', 'MESH:C038178', (158, 161))	('Fas-670A/G', 'Var', (117, 127))	('Fas', 'Chemical', 'MESH:C038178', (83, 86))	('Fas', 'Chemical', 'MESH:C038178', (117, 120))
177049	26819081	The Fas-670G allele and the Fas-1377A allele disrupt STAT1and Sp1 transcription factor-binding sites, respectively, and thus diminish promoter activity and decrease Fas gene expression 15, 16.	('Fas gene', 'Gene', (165, 173))	('diminish', 'NegReg', (125, 133))	('disrupt', 'NegReg', (45, 52))	('Sp1', 'Protein', (62, 65))	('Fas-670', 'Gene', '2189', (4, 11))	('promoter activity', 'MPA', (134, 151))	('STAT1', 'Gene', (53, 58))	('Fas-1377A', 'Var', (28, 37))	('Fas', 'Chemical', 'MESH:C038178', (165, 168))	('Fas', 'Chemical', 'MESH:C038178', (4, 7))	('STAT1', 'Gene', '6772', (53, 58))	('Fas', 'Chemical', 'MESH:C038178', (28, 31))	('decrease', 'NegReg', (156, 164))	('Fas-670', 'Gene', (4, 11))
177052	26819081	To date, studies showed that the Fas-670A/G, Fas-1377G/A, and FasL-844T/C polymorphisms might be associated with increased risk of certain cancers, including breast cancer 18, 19, 20, 21, gastric cancer 22, 23, cervical cancer 24, 25, lung cancer 26, 27, etc.	('Fas-670A/G', 'Gene', (33, 43))	('gastric cancer', 'Phenotype', 'HP:0012126', (188, 202))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancers', 'Disease', (139, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('associated', 'Reg', (97, 107))	('cancer', 'Disease', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('breast cancer', 'Disease', (158, 171))	('Fas-670A/G', 'Gene', '2189', (33, 43))	('gastric cancer', 'Disease', (188, 202))	('lung cancer', 'Disease', (235, 246))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('Fas-1377G/A', 'Var', (45, 56))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('gastric cancer', 'Disease', 'MESH:D013274', (188, 202))	('cancer', 'Disease', (220, 226))	('FasL-844T/C', 'Var', (62, 73))	('cancer', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancer', 'Disease', 'MESH:D008175', (235, 246))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
177053	26819081	Several studies have reported the potential association between Fas/ FasL polymorphisms and risk of esophageal cancer 28, 29.	('polymorphisms', 'Var', (74, 87))	('esophageal cancer', 'Disease', (100, 117))	('FasL', 'Gene', (69, 73))	('Fas', 'Chemical', 'MESH:C038178', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('FasL', 'Gene', '356', (69, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('Fas', 'Chemical', 'MESH:C038178', (69, 72))
177054	26819081	In the case-control study, we aim to identify the genotyping of Fas-670A/G, Fas-1377G/A, FasL-844T/C in all cases, and to explore the correlation between three polymorphisms and susceptibility of esophageal carcinoma in north China.	('esophageal carcinoma', 'Disease', (196, 216))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (196, 216))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (196, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('Fas-670A/G', 'Gene', (64, 74))	('Fas-1377G/A', 'Var', (76, 87))	('FasL-844T/C', 'Var', (89, 100))	('Fas-670A/G', 'Gene', '2189', (64, 74))
177063	26819081	Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods were performed for genotyping Fas-670A/G, Fas-1377G/A, FasL-844T/C.	('men', 'Species', '9606', (42, 45))	('Fas-670A/G', 'Gene', (116, 126))	('Fas-1377G/A', 'Var', (128, 139))	('Fas-670A/G', 'Gene', '2189', (116, 126))	('FasL-844T/C', 'Var', (141, 152))
177072	26819081	Fas-670A/G, Fas-1377G/A and FasL-844T/C showed polymorphism in all research subjects.	('FasL-844T/C', 'Var', (28, 39))	('Fas-670A/G', 'Gene', '2189', (0, 10))	('Fas-670A/G', 'Gene', (0, 10))	('Fas-1377G/A', 'Var', (12, 23))	('polymorphism', 'Var', (47, 59))
177073	26819081	And the genotype distributions of Fas-670A/G, Fas-1377G/A and FasL-844T/C in two groups were consistent with Hardy-Weinberg equilibrium (P > 0.05).	('Fas-670A/G', 'Gene', (34, 44))	('Fas-670A/G', 'Gene', '2189', (34, 44))	('FasL-844T/C', 'Var', (62, 73))	('Fas-1377G/A', 'Var', (46, 57))
177074	26819081	For Fas-670A/G polymorphism, the frequencies of GG, AG, and AA genotypes were 12.75%, 50.98%, and 36.27% among the patients and 16.53%, 47.98%, and 35.48% among the controls.	('polymorphism', 'Var', (15, 27))	('patients', 'Species', '9606', (115, 123))	('Fas-670A/G', 'Gene', (4, 14))	('Fas-670A/G', 'Gene', '2189', (4, 14))
177076	26819081	For FasL-844T/C, the frequency of genotype TT, TC, and CC in the esophageal carcinoma patients and in the healthy controls was 3.92%, 39.11%, 56.45% and 4.44%, 39.11%, 56.45%, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal carcinoma', 'Disease', (65, 85))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (65, 85))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (65, 85))	('FasL-844T/C', 'Var', (4, 15))	('patients', 'Species', '9606', (86, 94))
177078	26819081	Frequencies of Fas-670A/G, Fas-1377G/A and FasL-844T/C genotypes among case patients did not differ statistically significantly from those among control subjects.	('patients', 'Species', '9606', (76, 84))	('Fas-670A/G', 'Gene', '2189', (15, 25))	('Fas-1377G/A', 'Var', (27, 38))	('FasL-844T/C', 'Var', (43, 54))	('Fas-670A/G', 'Gene', (15, 25))
177079	26819081	Logistic regression analysis indicated that there was no significant association between esophageal carcinoma and gene polymorphisms of Fas-670A/G, Fas-1377G/A and FasL-844 T/C (Fas-670AG, P = 0.820; Fas-670GG, P = 0.451; Fas-1377AG, P = 0.897; Fas-1377AA, P = 0.881; FasL-844TC, P = 0.119; FasL-844CC, P = 0.454).	('Fas', 'Chemical', 'MESH:C038178', (268, 271))	('FasL', 'Gene', (291, 295))	('FasL', 'Gene', (164, 168))	('Fas-670A/G', 'Gene', (136, 146))	('esophageal carcinoma', 'Disease', (89, 109))	('FasL', 'Gene', '356', (291, 295))	('FasL', 'Gene', '356', (164, 168))	('Fas', 'Chemical', 'MESH:C038178', (291, 294))	('Fas-670', 'Gene', (178, 185))	('Fas', 'Chemical', 'MESH:C038178', (178, 181))	('Fas-670', 'Gene', '2189', (200, 207))	('Fas-670', 'Gene', (136, 143))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (89, 109))	('Fas-670A/G', 'Gene', '2189', (136, 146))	('Fas-670', 'Gene', (200, 207))	('Fas', 'Chemical', 'MESH:C038178', (200, 203))	('Fas', 'Chemical', 'MESH:C038178', (136, 139))	('Fas-1377G/A', 'Var', (148, 159))	('Fas-670', 'Gene', '2189', (178, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('Fas', 'Chemical', 'MESH:C038178', (245, 248))	('Fas', 'Chemical', 'MESH:C038178', (222, 225))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (89, 109))	('FasL', 'Gene', (268, 272))	('FasL', 'Gene', '356', (268, 272))	('Fas', 'Chemical', 'MESH:C038178', (164, 167))	('Fas-670', 'Gene', '2189', (136, 143))	('Fas-1377AA', 'Var', (245, 255))	('Fas', 'Chemical', 'MESH:C038178', (148, 151))
177081	26819081	The results showed that no significant association was found between esophageal carcinoma and gene polymorphisms of Fas-670A/G, Fas-1377G/A, and FasL-844T/C in the north Chinese population (P > 0.05).	('FasL-844T/C', 'Var', (145, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('Fas-670A/G', 'Gene', (116, 126))	('esophageal carcinoma', 'Disease', (69, 89))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (69, 89))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (69, 89))	('Fas-1377G/A', 'Var', (128, 139))	('Fas-670A/G', 'Gene', '2189', (116, 126))
177083	26819081	Among the main causes of esophageal cancer, genetic aberration plays a key role.	('esophageal cancer', 'Disease', 'MESH:D004938', (25, 42))	('genetic aberration', 'Var', (44, 62))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('esophageal cancer', 'Disease', (25, 42))
177084	26819081	The case-control study was conducted to investigate the relationship between polymorphisms in Fas-670A/G, Fas-1377G/A, and FasL-844T/C and the susceptibility to esophageal carcinoma in Anyang, a north Chinese district with a high incidence of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('Fas-1377G/A', 'Var', (106, 117))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (161, 181))	('esophageal cancer', 'Disease', 'MESH:D004938', (243, 260))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (161, 181))	('Fas-670A/G', 'Gene', '2189', (94, 104))	('esophageal cancer', 'Disease', (243, 260))	('FasL-844T/C', 'Var', (123, 134))	('Fas-670A/G', 'Gene', (94, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('esophageal carcinoma', 'Disease', (161, 181))
177085	26819081	Since the identification of polymorphisms in gene Fas and FasL, a variety of case-control studies have been published to explore the possible association between Fas-670A/G, Fas-1377G/A, and FasL-844T/C and risk of cancer 18, 23, 24, 27; however, the reported results were conflicting.	('Fas', 'Chemical', 'MESH:C038178', (191, 194))	('Fas', 'Chemical', 'MESH:C038178', (50, 53))	('Fas-1377G/A', 'Var', (174, 185))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('FasL', 'Gene', (58, 62))	('Fas', 'Gene', (50, 53))	('Fas-670A/G', 'Gene', '2189', (162, 172))	('Fas', 'Chemical', 'MESH:C038178', (174, 177))	('FasL', 'Gene', '356', (58, 62))	('Fas', 'Chemical', 'MESH:C038178', (58, 61))	('polymorphisms', 'Var', (28, 41))	('FasL', 'Gene', '356', (191, 195))	('FasL', 'Gene', (191, 195))	('Fas-670A/G', 'Gene', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('Fas', 'Chemical', 'MESH:C038178', (162, 165))
177086	26819081	In our study, no significant association was found between polymorphisms Fas-670A/G, Fas-1377G/A, and FasL-844T/C and susceptibility to esophageal cancer in Henan Anyang (P > 0.05), suggesting that these polymorphisms might not play an important role in the progression and development of esophageal cancer in this particular population.	('esophageal cancer', 'Disease', (136, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('Fas-670A/G', 'Gene', '2189', (73, 83))	('esophageal cancer', 'Disease', (289, 306))	('esophageal cancer', 'Disease', 'MESH:D004938', (289, 306))	('FasL-844T/C', 'Var', (102, 113))	('Fas-670A/G', 'Gene', (73, 83))	('men', 'Species', '9606', (281, 284))	('Fas-1377G/A', 'Var', (85, 96))
177087	26819081	In another study by Sun et al., subjects with Fas-670GG (OR = 1.72, 95% CI = 1.26-2.34, P < 0.001), Fas-1377AA (OR = 1.79, 95% CI = 1.29-2.48, P < 0.001) and FasL-844CC (OR = 2.06, 95% CI = 1.64-2.59, P < 0.001) genotypes were associated with increased risk of esophageal carcinoma compared with those with Fas-670 AA, Fas-1377 GG, FasL-844 TT genotypes, respectively 29.	('Fas', 'Chemical', 'MESH:C038178', (307, 310))	('esophageal carcinoma', 'Disease', (261, 281))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (261, 281))	('Fas', 'Chemical', 'MESH:C038178', (319, 322))	('Fas-1377AA', 'Var', (100, 110))	('Fas-670', 'Gene', '2189', (46, 53))	('Fas-670 ', 'Gene', (307, 315))	('Fas', 'Chemical', 'MESH:C038178', (158, 161))	('Fas-670', 'Gene', '2189', (307, 314))	('FasL', 'Gene', (332, 336))	('Fas', 'Chemical', 'MESH:C038178', (46, 49))	('FasL', 'Gene', (158, 162))	('Fas-670 ', 'Gene', '2189', (307, 315))	('FasL', 'Gene', '356', (332, 336))	('Fas-670', 'Gene', (46, 53))	('FasL', 'Gene', '356', (158, 162))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (261, 281))	('Fas', 'Chemical', 'MESH:C038178', (332, 335))	('Fas', 'Chemical', 'MESH:C038178', (100, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('Fas-670', 'Gene', (307, 314))
177088	26819081	The frequency of the polymorphisms Fas-670A/G, Fas-1377G/A, and FasL-844 T/C in our study did not show statistical significance when compared to patients and controls.	('patients', 'Species', '9606', (145, 153))	('Fas-670A/G', 'Gene', '2189', (35, 45))	('Fas-1377G/A', 'Var', (47, 58))	('FasL-844', 'Var', (64, 72))	('Fas-670A/G', 'Gene', (35, 45))
177097	26819081	In conclusion, we have shown that the Fas-670A/G, Fas-1377G/A, and FasL-844T/C polymorphisms were not significantly associated with risk of esophageal cancer in a north Chinese population.	('Fas-670A/G', 'Gene', '2189', (38, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('FasL-844T/C', 'Var', (67, 78))	('Fas-670A/G', 'Gene', (38, 48))	('Fas-1377G/A', 'Var', (50, 61))	('esophageal cancer', 'Disease', (140, 157))	('associated', 'Reg', (116, 126))
177099	26629416	Current evidence on the cytotoxic T-lymphocyte antigen 4 + 49G > A polymorphism and digestive system cancer risks: a meta-analysis involving 11,923 subjects Cytotoxic T-lymphocyte antigen (CTLA-4) plays an important role in downregulating T cell activation and proliferation.	('downregulating', 'NegReg', (224, 238))	('system cancer', 'Disease', (94, 107))	('Cytotoxic', 'Disease', 'MESH:D064420', (157, 166))	('Cytotoxic', 'Disease', (157, 166))	('T cell activation', 'CPA', (239, 256))	('4 + 49G > A', 'SUBSTITUTION', 'None', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('downregulating T cell activation', 'Phenotype', 'HP:0005419', (224, 256))	('system cancer', 'Disease', 'MESH:D009369', (94, 107))	('4 + 49G > A', 'Var', (55, 66))
177100	26629416	The CTLA-4 + 49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with many cancer types, but the association between CTLA-4 + 49G > A polymorphism and digestive system cancer risks remain inconclusive.	('CTLA-4', 'Gene', (4, 10))	('49G > A', 'Var', (13, 20))	('49G > A', 'SUBSTITUTION', 'None', (181, 188))	('49G > A', 'Var', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', (130, 136))	('system cancer', 'Disease', 'MESH:D009369', (216, 229))	('association', 'Interaction', (108, 119))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('system cancer', 'Disease', (216, 229))	('cancer', 'Disease', (223, 229))	('49G > A', 'SUBSTITUTION', 'None', (13, 20))
177105	26629416	Our findings suggest that the CTLA-4 + 49G > A polymorphism may be associated with the risk of pancreatic cancer and hepatocellular cell carcinoma.	('CTLA-4', 'Gene', (30, 36))	('hepatocellular cell carcinoma', 'Phenotype', 'HP:0001402', (117, 146))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('associated', 'Reg', (67, 77))	('49G > A', 'SUBSTITUTION', 'None', (39, 46))	('49G > A', 'Var', (39, 46))	('hepatocellular cell carcinoma', 'Disease', (117, 146))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('pancreatic cancer', 'Disease', (95, 112))	('hepatocellular cell carcinoma', 'Disease', 'MESH:D006528', (117, 146))
177109	26629416	This gene is polymorphic, more than 100 single nucleotide polymorphisms have been identified.An AG dimorphism at position 49 in CTLA-4 exon 1 (rs231775), which causes an amino acid change (threonine to alanine) in the peptide leader sequence of the CTLA-4 protein.	('threonine', 'Chemical', 'MESH:D013912', (189, 198))	('rs231775', 'Mutation', 'rs231775', (143, 151))	('alanine', 'Chemical', 'MESH:D000409', (202, 209))	('rs231775', 'Var', (143, 151))	('causes', 'Reg', (160, 166))
177110	26629416	Recent studies indicated that this polymorphism may influence the ability of CTLA-4 to bind with B7.1 and affect T-cell activation subsequently.	('B7.1', 'Gene', (97, 101))	('polymorphism', 'Var', (35, 47))	('B7.1', 'Gene', '941', (97, 101))	('T-cell activation', 'CPA', (113, 130))	('ability', 'MPA', (66, 73))	('influence', 'Reg', (52, 61))	('CTLA-4', 'Gene', (77, 83))	('affect', 'Reg', (106, 112))	('bind', 'Interaction', (87, 91))
177111	26629416	Previous studies have identified that this polymorphism is associated with different cancers including lung cancer, breast cancer, and cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cervical cancer', 'Disease', 'MESH:D002583', (135, 150))	('breast cancer', 'Disease', (116, 129))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('cervical cancer', 'Disease', (135, 150))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('associated', 'Reg', (59, 69))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('polymorphism', 'Var', (43, 55))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
177112	26629416	However, the results of studies on the association between the + 49A > G polymorphism and the risk of digestive system cancers remain inconsistent.	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('system cancers', 'Disease', (112, 126))	('49A > G', 'SUBSTITUTION', 'None', (65, 72))	('system cancers', 'Disease', 'MESH:D009369', (112, 126))	('49A > G', 'Var', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
177114	26629416	In this meta-analysis, a comprehensive literature research of the US National Library of Medicine's Pub Med database, ISI Web of Knowledge, Medline, Embase and Google Scholar Search (update to August, 2014) were conducted using the search terms including "CTLA-4", "polymorphisms", "cancer", and the combined phrases in order to obtain all genetic studies on the relationship of CTLA-4 + 49G/A polymorphism and cancer.	('49G/A', 'SUBSTITUTION', 'None', (388, 393))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancer', 'Disease', (283, 289))	('CTLA-4', 'Gene', (379, 385))	('49G/A', 'Var', (388, 393))	('cancer', 'Disease', (411, 417))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))
177115	26629416	The following criteria were used to select the eligible studies: (1) a case-control study on the association between CTLA-4 + 49G/A polymorphism and cancer, (2) detailed number of different genotypes for estimating an odds ratio (OR) with 95% confidence interval (3) when several publications reported on the same population data, the largest or most complete study was chosen.	('cancer', 'Disease', (149, 155))	('CTLA-4', 'Gene', (117, 123))	('polymorphism', 'Var', (132, 144))	('49G/A', 'Var', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('association', 'Interaction', (97, 108))	('49G/A', 'SUBSTITUTION', 'None', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
177117	26629416	The strength of relationship between CTLA-4 + 49G/A polymorphism and cancer was assessed by using Crude OR with 95% CI.	('49G/A', 'SUBSTITUTION', 'None', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('polymorphism', 'Var', (52, 64))	('CTLA-4', 'Gene', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('49G/A', 'Var', (46, 51))	('cancer', 'Disease', (69, 75))
177118	26629416	We examined the association between the CTLA-4 + 49G/A polymorphism and digestive cancer risks using the following genetic contrasts: homozygote comparison (GG vs. AA), heterozygote comparison (GA vs. AA), dominant genetic model (GG + GA vs. AA), recessive genetic model (GG vs. GA + AA) and allelic comparison (G vs. A).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('49G/A', 'SUBSTITUTION', 'None', (49, 54))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('49G/A', 'Var', (49, 54))	('CTLA-4 +', 'Gene', (40, 48))
177119	26629416	Genotype distribution of the CTLA-4 + 49G/A polymorphism among cancer cases and controls of the 17 studies are shown in Table 2.	('49G/A', 'SUBSTITUTION', 'None', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('CTLA-4', 'Gene', (29, 35))	('polymorphism', 'Var', (44, 56))	('49G/A', 'Var', (38, 43))	('cancer', 'Disease', (63, 69))
177121	26629416	The association strength between CTLA-4 + 49G/A polymorphism and the susceptibility for digestive system cancers are shown in Table 3.	('49G/A', 'SUBSTITUTION', 'None', (42, 47))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('association', 'Interaction', (4, 15))	('polymorphism', 'Var', (48, 60))	('system cancers', 'Disease', (98, 112))	('CTLA-4', 'Gene', (33, 39))	('49G/A', 'Var', (42, 47))	('system cancers', 'Disease', 'MESH:D009369', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
177123	26629416	We then evaluated the effects of CTLA-4 + 49G/A polymorphism according to specific cancer types, different ethnicities and different sources of control.	('49G/A', 'SUBSTITUTION', 'None', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CTLA-4', 'Gene', (33, 39))	('49G/A', 'Var', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
177127	26629416	The result of this meta-analysis suggested that CTLA-4 + 49G/A polymorphism was significantly linked to higher risks for pancreatic cancer.	('CTLA-4', 'Gene', (48, 54))	('pancreatic cancer', 'Disease', (121, 138))	('polymorphism', 'Var', (63, 75))	('linked', 'Reg', (94, 100))	('49G/A', 'Var', (57, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('49G/A', 'SUBSTITUTION', 'None', (57, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))
177128	26629416	Besides, the polymorphism was associated with an increased risk of developing hepatocellular cell carcinoma.	('polymorphism', 'Var', (13, 25))	('hepatocellular cell carcinoma', 'Phenotype', 'HP:0001402', (78, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('hepatocellular cell carcinoma', 'Disease', 'MESH:D006528', (78, 107))	('hepatocellular cell carcinoma', 'Disease', (78, 107))
177129	26629416	The CTLA-4 49G > A SNP has been linked to elevated risk of breast cancer in an Iranian population, and non-Hodgkin's lymphoma in a European Caucasian population.	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (107, 125))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (117, 125))	('breast cancer', 'Disease', (59, 72))	('CTLA-4 49G > A SNP', 'Var', (4, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (103, 125))	("non-Hodgkin's lymphoma", 'Disease', (103, 125))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (103, 125))	('49G > A', 'Mutation', 'rs231775', (11, 18))
177131	26629416	suggested that the CTLA-4 + 49G/A polymorphism was associated with an increased risk of developing solid tumors (including lung caner, breast cancer, colorectal cancer, gastric cancer, skin cancer, thymoma, nasopharyngeal carcinoma, cervical squamous cell carcinoma, esophageal cancer, oral squamous cell carcinoma, HBV-related hepatocellular carcinoma, and renal cell cancer).	('renal cell cancer', 'Disease', (358, 375))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('renal cell cancer', 'Disease', 'MESH:C538614', (358, 375))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('squamous cell carcinoma', 'Disease', (242, 265))	('nasopharyngeal carcinoma', 'Disease', (207, 231))	('49G/A', 'Var', (28, 33))	('esophageal cancer', 'Disease', (267, 284))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('renal cell cancer', 'Phenotype', 'HP:0005584', (358, 375))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('breast cancer', 'Disease', (135, 148))	('solid tumors', 'Disease', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (207, 231))	('skin cancer', 'Disease', (185, 196))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (291, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('lung caner', 'Disease', (123, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (286, 314))	('CTLA-4', 'Gene', (19, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (328, 352))	('thymoma', 'Disease', 'MESH:D013945', (198, 205))	('oral squamous cell carcinoma', 'Disease', (286, 314))	('49G/A', 'SUBSTITUTION', 'None', (28, 33))	('polymorphism', 'Var', (34, 46))	('colorectal cancer', 'Disease', (150, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (242, 265))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('skin cancer', 'Phenotype', 'HP:0008069', (185, 196))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (207, 231))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (291, 314))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (328, 352))	('gastric cancer', 'Disease', (169, 183))	('thymoma', 'Disease', (198, 205))	('thymoma', 'Phenotype', 'HP:0100522', (198, 205))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (242, 265))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('skin cancer', 'Disease', 'MESH:D012878', (185, 196))	('hepatocellular carcinoma', 'Disease', (328, 352))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (267, 284))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
177132	26629416	conducted a meta-analysis and the results indicated that the polymorphism is associated with a decreased risk of lung cancer and breast cancer but not of cervical cancer, colorectal cancer, or gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (193, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('polymorphism', 'Var', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (193, 207))	('decreased', 'NegReg', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cervical cancer', 'Disease', (154, 169))	('cervical cancer', 'Disease', 'MESH:D002583', (154, 169))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (171, 188))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('breast cancer', 'Disease', (129, 142))	('lung cancer', 'Disease', (113, 124))	('gastric cancer', 'Disease', (193, 207))	('colorectal cancer', 'Disease', (171, 188))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
177133	26629416	In our analysis, we first reported that there was no statistically increased risk between the CTLA-4 + 49G/A polymorphism and digestive system cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('49G/A', 'SUBSTITUTION', 'None', (103, 108))	('CTLA-4', 'Gene', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('system cancers', 'Disease', (136, 150))	('system cancers', 'Disease', 'MESH:D009369', (136, 150))	('49G/A', 'Var', (103, 108))
177135	26629416	We also observed the CTLA-4 + 49G/A polymorphism was associated with an increased risk of developing hepatocellular cell carcinoma but not gastric cancer, colorectal cancer and oral cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('CTLA-4', 'Gene', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('49G/A', 'Var', (30, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('polymorphism', 'Var', (36, 48))	('hepatocellular cell carcinoma', 'Phenotype', 'HP:0001402', (101, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('oral cancer', 'Disease', 'MESH:D009062', (177, 188))	('49G/A', 'SUBSTITUTION', 'None', (30, 35))	('oral cancer', 'Disease', (177, 188))	('hepatocellular cell carcinoma', 'Disease', 'MESH:D006528', (101, 130))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('gastric cancer', 'Disease', (139, 153))	('hepatocellular cell carcinoma', 'Disease', (101, 130))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('colorectal cancer', 'Disease', (155, 172))
177139	26629416	In conclusion, our meta-analysis suggested that the CTLA-4 + 49G/A polymorphism may be not associated with an elevated digestive system cancer risks.	('CTLA-4', 'Gene', (52, 58))	('system cancer', 'Disease', 'MESH:D009369', (129, 142))	('49G/A', 'Var', (61, 66))	('system cancer', 'Disease', (129, 142))	('49G/A', 'SUBSTITUTION', 'None', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
177140	25036033	Role of EZH2 Polymorphisms in Esophageal Squamous Cell Carcinoma Risk in Han Chinese Population Gene single nucleotide polymorphisms play a critical role in the development of esophageal squamous cell carcinoma (ESCC).	('SCC', 'Phenotype', 'HP:0002860', (213, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('Esophageal Squamous Cell Carcinoma', 'Disease', (30, 64))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (41, 64))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (176, 210))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (30, 64))	('single nucleotide polymorphisms', 'Var', (101, 132))	('EZH2', 'Gene', '2146', (8, 12))	('Carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('esophageal squamous cell carcinoma', 'Disease', (176, 210))	('EZH2', 'Gene', (8, 12))
177141	25036033	The aim of this study is to investigate the associations between EZH2 gene polymorphisms and ESCC risk.	('polymorphisms', 'Var', (75, 88))	('EZH2', 'Gene', (65, 69))	('EZH2', 'Gene', '2146', (65, 69))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('associations', 'Interaction', (44, 56))	('ESCC', 'Disease', (93, 97))
177142	25036033	We undertook a case-control study to analyze three EZH2 polymorphisms (148505302C > T, 2110 + 6A > C and 626 - 394T > C) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 476 patients with ESCC and 492 control participants, and performed EZH2 genotyping using DNA sequencing.	('626 - 394T > C', 'Mutation', 'rs3757441', (105, 119))	('EZH2', 'Gene', '2146', (51, 55))	('SCC', 'Phenotype', 'HP:0002860', (228, 231))	('EZH2', 'Gene', (51, 55))	('2110 + 6A > C', 'Mutation', 'rs41277434', (87, 100))	('2110 + 6A > C', 'Var', (87, 100))	('148505302C > T', 'Var', (71, 85))	('participants', 'Species', '9606', (248, 260))	('patients', 'Species', '9606', (213, 221))	('EZH2', 'Gene', (276, 280))	('EZH2', 'Gene', '2146', (276, 280))	('148505302C > T', 'Mutation', 'c.148505302C>T', (71, 85))
177143	25036033	The obtained results indicated that overall, no statistically significant association was observed in 148505302C > T and 2110 + 6A > C. However, 626 - 394T > C genotype was at increased risk of ESCCs (p = 0.006; odds ratio (OR) = 1.131, CI 95%: 1.034-1.236).	('148505302C > T', 'Mutation', 'c.148505302C>T', (102, 116))	('SCC', 'Phenotype', 'HP:0002860', (195, 198))	('2110 + 6A > C', 'Mutation', 'rs41277434', (121, 134))	('626 - 394T > C', 'Var', (145, 159))	('626 - 394T > C', 'Mutation', 'rs3757441', (145, 159))	('148505302C > T', 'Var', (102, 116))	('ESCCs', 'Disease', (194, 199))
177145	25036033	In conclusion, polymorphism in 626 - 394T > C was observed to be associated with susceptibility of ESCC.	('626 - 394T > C', 'Mutation', 'rs3757441', (31, 45))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('ESCC', 'Disease', (99, 103))	('associated', 'Reg', (65, 75))	('polymorphism in 626 - 394T > C', 'Var', (15, 45))
177150	25036033	Many studies have suggested the importance of gene single nucleotide polymorphisms (SNPs) that are involved in xenobiotic metabolism that might be responsible for ESCC risk.	('ESCC', 'Disease', (163, 167))	('SCC', 'Phenotype', 'HP:0002860', (164, 167))	('single nucleotide polymorphisms', 'Var', (51, 82))	('responsible', 'Reg', (147, 158))	('xenobiotic metabolism', 'Disease', (111, 132))	('xenobiotic metabolism', 'Disease', 'MESH:D008659', (111, 132))
177152	25036033	It is reported that EZH2 serves as a histone methyl transferase involved in gene silencing, and disruption of EZH2 expression can lead to cancer.	('cancer', 'Disease', (138, 144))	('EZH2', 'Gene', '2146', (20, 24))	('lead to', 'Reg', (130, 137))	('EZH2', 'Gene', (20, 24))	('EZH2', 'Gene', (110, 114))	('EZH2', 'Gene', '2146', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('disruption', 'Var', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
177154	25036033	The abnormalities of EZH2 were observed to correlate closely with tumor aggressiveness and/or poor patient prognosis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patient', 'Species', '9606', (99, 106))	('EZH2', 'Gene', (21, 25))	('EZH2', 'Gene', '2146', (21, 25))	('tumor aggressiveness', 'Disease', (66, 86))	('aggressiveness', 'Phenotype', 'HP:0000718', (72, 86))	('abnormalities', 'Var', (4, 17))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (66, 86))
177156	25036033	The authors concluded that high expression of EZH2 correlates with tumor aggressiveness and adverse patient outcome in ESCC treated with definitive chemoradiotherapy.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (67, 87))	('aggressiveness', 'Phenotype', 'HP:0000718', (73, 87))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('ESCC', 'Disease', (119, 123))	('high', 'Var', (27, 31))	('patient', 'Species', '9606', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor aggressiveness', 'Disease', (67, 87))	('EZH2', 'Gene', '2146', (46, 50))	('EZH2', 'Gene', (46, 50))
177157	25036033	In our previous study, we observed that polymorphism in EZH2 gene 626 - 394T > C was observed to be associated with susceptibility of colorectal cancer.	('colorectal cancer', 'Disease', (134, 151))	('626 - 394T > C', 'Var', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('associated', 'Reg', (100, 110))	('626 - 394T > C', 'Mutation', 'rs3757441', (66, 80))	('polymorphism', 'Var', (40, 52))	('EZH2', 'Gene', '2146', (56, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('EZH2', 'Gene', (56, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))
177158	25036033	However, 148505302C > T polymorphism was indicated to play a protective role in susceptibility to colorectal cancer.	('colorectal cancer', 'Disease', (98, 115))	('148505302C > T', 'Var', (9, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('148505302C > T', 'Mutation', 'c.148505302C>T', (9, 23))
177159	25036033	Thus, in this study, in order to clarify association between EZH2 SNPs rs887569 (g.148505302C > T), rs41277434 (c.2110 + 6A > C) and rs3757441 (c.626 - 394T > C) polymorphisms and ESCC risks, we performed a hospital-based case-control study on Han Chinese population.	('EZH2', 'Gene', (61, 65))	('EZH2', 'Gene', '2146', (61, 65))	('6A > C', 'SUBSTITUTION', 'None', (121, 127))	('rs41277434', 'Mutation', 'rs41277434', (100, 110))	('394T > C', 'Var', (152, 160))	('rs887569', 'Mutation', 'rs887569', (71, 79))	('rs3757441', 'Mutation', 'rs3757441', (133, 142))	('rs887569 (g.148505302C > T', 'Var', (71, 97))	('SCC', 'Phenotype', 'HP:0002860', (181, 184))	('6A > C', 'Var', (121, 127))	('g.148505302C > T', 'Mutation', 'rs887569', (81, 97))	('rs3757441', 'Var', (133, 142))	('ESCC', 'Disease', (180, 184))	('394T > C', 'SUBSTITUTION', 'None', (152, 160))
177162	25036033	The gene polymorphisms of EZH2 rs887569 (g.148505302C > T), rs41277434 (c.2110 + 6A > C) and rs3757441 (c.626 - 394T > C) were successfully amplified in all ESCC and control cases.	('EZH2', 'Gene', '2146', (26, 30))	('6A > C', 'Var', (81, 87))	('SCC', 'Phenotype', 'HP:0002860', (158, 161))	('EZH2', 'Gene', (26, 30))	('394T > C', 'SUBSTITUTION', 'None', (112, 120))	('rs41277434', 'Mutation', 'rs41277434', (60, 70))	('rs887569', 'Mutation', 'rs887569', (31, 39))	('6A > C', 'SUBSTITUTION', 'None', (81, 87))	('ESCC', 'Disease', (157, 161))	('394T > C', 'Var', (112, 120))	('g.148505302C > T', 'Mutation', 'rs887569', (41, 57))	('rs3757441', 'Mutation', 'rs3757441', (93, 102))	('rs887569 (g.148505302C > T', 'Var', (31, 57))
177163	25036033	Overall, no statistically significant association was observed in EZH2 SNP 2110 + 6A > C and 148505302C > T. Individuals with EZH2 626 - 394C/C genotype were more susceptible to ESCCs (p = 0.004, OR = 1.324).	('EZH2', 'Gene', '2146', (126, 130))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('626 - 394C/C', 'Var', (131, 143))	('148505302C > T.', 'Var', (93, 108))	('EZH2', 'Gene', (126, 130))	('EZH2', 'Gene', (66, 70))	('EZH2', 'Gene', '2146', (66, 70))	('ESCCs', 'Disease', (178, 183))	('148505302C > T', 'Mutation', 'c.148505302C>T', (93, 107))	('susceptible', 'Reg', (163, 174))	('2110 + 6A > C', 'Mutation', 'rs41277434', (75, 88))
177164	25036033	Moreover, the variant allele frequency C of EZH2 (626 - 394T > C) was higher in cases as compared with controls (24.2% vs. 21.8%); this result also showed statistical significance (p = 0.006).	('EZH2', 'Gene', (44, 48))	('626 - 394T > C', 'Var', (50, 64))	('higher', 'PosReg', (70, 76))	('626 - 394T > C', 'Mutation', 'rs3757441', (50, 64))	('EZH2', 'Gene', '2146', (44, 48))
177165	25036033	Table 3 shows the association of EZH2 gene 148505302C > T, 2110 + 6A > C and 626 - 394T > C polymorphisms with clinicopathological characteristics, including gender, age at diagnosis, tumor size, differentiation, T stage, lymph node metastasis, and pathological stage of the cancer.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('2110 + 6A > C', 'Mutation', 'rs41277434', (59, 72))	('T stage', 'CPA', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('148505302C > T', 'Var', (43, 57))	('association', 'Interaction', (18, 29))	('tumor', 'Disease', (184, 189))	('lymph node metastasis', 'CPA', (222, 243))	('148505302C > T', 'Mutation', 'c.148505302C>T', (43, 57))	('EZH2', 'Gene', '2146', (33, 37))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('2110 + 6A > C and', 'Var', (59, 76))	('EZH2', 'Gene', (33, 37))	('differentiation', 'CPA', (196, 211))	('cancer', 'Disease', (275, 281))	('626 - 394T > C', 'Mutation', 'rs3757441', (77, 91))
177167	25036033	Our data indicated that EZH2 gene (626 - 394T > C) polymorphism may be a susceptible genotype for ESCC development and may increase the risk of ESCC among the Han Chinese population.	('polymorphism', 'Var', (51, 63))	('EZH2', 'Gene', '2146', (24, 28))	('SCC', 'Phenotype', 'HP:0002860', (145, 148))	('ESCC', 'Disease', (98, 102))	('EZH2', 'Gene', (24, 28))	('626 - 394T > C', 'Mutation', 'rs3757441', (35, 49))	('ESCC', 'Disease', (144, 148))	('increase', 'PosReg', (123, 131))	('626 - 394T > C) polymorphism', 'Var', (35, 63))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))
177168	25036033	Moreover, 626 - 394T > C SNP was observed to be significantly associated with increased risk with tumor size, differentiation, T stage, and pathological stage (p = 0.014, p = 0.001, p = 0.017 and p = 0.037, respectively).	('T stage', 'CPA', (127, 134))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('differentiation', 'CPA', (110, 125))	('626 - 394T > C SNP', 'Var', (10, 28))	('626 - 394T > C', 'Mutation', 'rs3757441', (10, 24))	('pathological stage', 'CPA', (140, 158))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
177169	25036033	However, the 148505302C > T and 2110 + 6A > C polymorphism in EZH2 gene may be not association with ESCC susceptibility.	('148505302C > T', 'Mutation', 'c.148505302C>T', (13, 27))	('EZH2', 'Gene', '2146', (62, 66))	('ESCC', 'Disease', (100, 104))	('EZH2', 'Gene', (62, 66))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('2110 + 6A > C', 'Var', (32, 45))	('2110 + 6A > C', 'Mutation', 'rs41277434', (32, 45))	('148505302C > T', 'Var', (13, 27))
177170	25036033	Although in EZH2 gene 626 - 394T > C the polymorphisms were not related to the presence of lymph nodal metastases, the 626 - 394CC genotype was more common in ESCC of higher advanced pathological staging (stages I & II vs. III & IV, p = 0.037).	('SCC', 'Phenotype', 'HP:0002860', (160, 163))	('lymph nodal metastases', 'Disease', (91, 113))	('ESCC', 'Disease', (159, 163))	('common', 'Reg', (149, 155))	('626 - 394CC', 'Var', (119, 130))	('lymph nodal metastases', 'Disease', 'MESH:D009362', (91, 113))	('EZH2', 'Gene', '2146', (12, 16))	('626 - 394T > C', 'Mutation', 'rs3757441', (22, 36))	('EZH2', 'Gene', (12, 16))
177176	25036033	The abnormal expression of EZH2 is involved in the tumorigenic types of cancer with poor prognoses.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('EZH2', 'Gene', (27, 31))	('EZH2', 'Gene', '2146', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('involved', 'Reg', (35, 43))	('tumor', 'Disease', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancer', 'Disease', (72, 78))
177179	25036033	In one of our previous studies, we undertook a case-control study to analyze associations between EZH2 polymorphisms (148505302C > T, 2110 + 6A > C and 626 - 394T > C) and colorectal cancer (CRC) risk.	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('2110 + 6A > C', 'Var', (134, 147))	('EZH2', 'Gene', (98, 102))	('EZH2', 'Gene', '2146', (98, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('148505302C > T', 'Var', (118, 132))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('colorectal cancer', 'Disease', (172, 189))	('626 - 394T > C', 'Mutation', 'rs3757441', (152, 166))	('CRC', 'Phenotype', 'HP:0003003', (191, 194))	('148505302C > T', 'Mutation', 'c.148505302C>T', (118, 132))	('2110 + 6A > C', 'Mutation', 'rs41277434', (134, 147))
177181	25036033	Nevertheless, 148505302C > T genotype demonstrated a protective effect in CRCs (odds ratio (OR) = 0.777).	('CRC', 'Phenotype', 'HP:0003003', (74, 77))	('148505302C > T', 'Var', (14, 28))	('148505302C > T', 'Mutation', 'c.148505302C>T', (14, 28))	('CRCs', 'Disease', (74, 78))
177182	25036033	Furthermore, 148505302 T allele CRC was more significantly common in patients with smaller tumor size, good differentiation and lower advanced pathological stage.	('common', 'Reg', (59, 65))	('148505302 T', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Disease', (91, 96))
177183	25036033	However, 626 - 394T > C genotype CRCs were more significantly common in patients with tumor size of >5 cm than T allele CRC and in cases of poor differentiation and lower advanced pathological stage.	('CRC', 'Phenotype', 'HP:0003003', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CRC', 'Phenotype', 'HP:0003003', (120, 123))	('tumor', 'Disease', (86, 91))	('626 - 394T > C', 'Mutation', 'rs3757441', (9, 23))	('626 - 394T > C', 'Var', (9, 23))	('poor differentiation', 'CPA', (140, 160))	('CRCs', 'Disease', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('common', 'Reg', (62, 68))	('patients', 'Species', '9606', (72, 80))
177184	25036033	The present study shows that there is no association between the EZH2 gene 148505302C > T SNP, 2110 + 6A > C SNP and ESCCs development, which might indicate genetic diversity linked with tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('2110 + 6A > C', 'Mutation', 'rs41277434', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('EZH2', 'Gene', (65, 69))	('EZH2', 'Gene', '2146', (65, 69))	('tumor', 'Disease', (187, 192))	('148505302C > T', 'Var', (75, 89))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('ESCCs development', 'CPA', (117, 134))	('148505302C > T', 'Mutation', 'c.148505302C>T', (75, 89))
177185	25036033	In another previous study, Crea and colleagues have shown that the haplotypes analysis of 2110 + 6A > C genotype was not related with objective response, progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer patients (mESCC).	('colorectal cancer', 'Disease', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('2110 + 6A > C', 'Mutation', 'rs41277434', (90, 103))	('2110 + 6A > C', 'Var', (90, 103))	('colorectal cancer', 'Disease', 'MESH:D015179', (226, 243))	('patients', 'Species', '9606', (244, 252))	('SCC', 'Phenotype', 'HP:0002860', (256, 259))	('colorectal cancer', 'Phenotype', 'HP:0003003', (226, 243))
177186	25036033	Although the present study did not reveal that the EZH2 g.148505302 T allele has a significant relationship with ESCC risk, Paolicchi and colleagues reported that EZH2 g.148505302 TT genotype was correlated with a significantly longer OS in cholangiocarcinoma (p = 0.026), and moreover, the TT genotype revealed a trend toward a significant association with a reduced risk of mortality.	('ESCC', 'Disease', (113, 117))	('g.148505302', 'Var', (56, 67))	('cholangiocarcinoma', 'Disease', (241, 259))	('EZH2', 'Gene', '2146', (51, 55))	('EZH2', 'Gene', (51, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('EZH2', 'Gene', '2146', (163, 167))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('g.148505302', 'Var', (168, 179))	('EZH2', 'Gene', (163, 167))	('longer', 'PosReg', (228, 234))
177187	25036033	Therefore, the association of EZH2 g.148505302C > T and 2110 + 6A > C polymorphism with susceptibility of ESCCs should be studied in a larger sample size, and the involved molecular mechanisms need further investigation.	('g.148505302C > T', 'Mutation', 'rs887569', (35, 51))	('EZH2', 'Gene', '2146', (30, 34))	('EZH2', 'Gene', (30, 34))	('2110 + 6A > C', 'Mutation', 'rs41277434', (56, 69))	('g.148505302C > T', 'Var', (35, 51))	('ESCCs', 'Disease', (106, 111))	('2110 + 6A > C', 'Var', (56, 69))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))
177192	25036033	revealed that EZH2 gene 626 - 394C > T SNP does not represent a potential predictive marker for bevacizumab efficacy but may play a role as either a prognostic variable or a predictive factor for first-line irinotecan-based chemotherapy in CRC patients.	('play', 'Reg', (125, 129))	('CRC', 'Disease', (240, 243))	('626 - 394C > T', 'Var', (24, 38))	('irinotecan', 'Chemical', 'MESH:D000077146', (207, 217))	('role', 'Reg', (132, 136))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('CRC', 'Phenotype', 'HP:0003003', (240, 243))	('626 - 394C > T', 'SUBSTITUTION', 'None', (24, 38))	('patients', 'Species', '9606', (244, 252))	('bevacizumab', 'Chemical', 'MESH:D000068258', (96, 107))
177193	25036033	In this study, our data for 626 - 394T > C variant showed that the C allele distribution was significantly associated with ESCCs, compared with controls (p = 0.006).	('626 - 394T > C', 'Mutation', 'rs3757441', (28, 42))	('626 - 394T > C', 'Var', (28, 42))	('associated', 'Reg', (107, 117))	('ESCCs', 'Disease', (123, 128))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))
177194	25036033	The homozygous CC variant in our study was observed to be significantly associated with increased risk of tumor size, differentiation, T stage, and pathological stage.	('pathological stage', 'CPA', (148, 166))	('T stage', 'CPA', (135, 142))	('differentiation', 'CPA', (118, 133))	('associated', 'Reg', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('variant', 'Var', (18, 25))
177199	25036033	DNA samples were routinely stored at -20  C. Analysis of EZH2 gene SNPs, rs887569 (g.148505302C > T), rs41277434 (c.2110 + 6A > C) and rs3757441 (c.626 - 394T > C) were performed using multiplex polymerase chain reaction (PCR) with an ABI premix.	('EZH2', 'Gene', (57, 61))	('g.148505302C > T', 'Mutation', 'rs887569', (83, 99))	('rs3757441', 'Mutation', 'rs3757441', (135, 144))	('rs887569 (g.148505302C > T', 'Var', (73, 99))	('6A > C', 'Var', (123, 129))	('394T > C', 'SUBSTITUTION', 'None', (154, 162))	('rs41277434', 'Mutation', 'rs41277434', (102, 112))	('rs887569', 'Mutation', 'rs887569', (73, 81))	('6A > C', 'SUBSTITUTION', 'None', (123, 129))	('394T > C', 'Var', (154, 162))	('EZH2', 'Gene', '2146', (57, 61))
177202	25036033	To conclude, this is the first experience suggesting that an EZH2 polymorphism has significant impact on clinical outcome in ESCC.	('EZH2', 'Gene', (61, 65))	('EZH2', 'Gene', '2146', (61, 65))	('impact', 'Reg', (95, 101))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('polymorphism', 'Var', (66, 78))	('ESCC', 'Disease', (125, 129))
177212	33151397	Incorporation of HER2 and CD44 into clinico-radiomic prediction models improved NCRT response prediction in esophageal cancer.	('NCRT response prediction', 'MPA', (80, 104))	('Incorporation', 'Var', (0, 13))	('CD44', 'Protein', (26, 30))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('HER2', 'Gene', (17, 21))	('cancer', 'Disease', (119, 125))	('HER2', 'Gene', '2064', (17, 21))	('improved', 'PosReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
177217	33151397	Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is the preferred treatment for locally advanced (T1/N1-3/M0; T2-4a/N0-3/M0) curative-intended resectable esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('T2-4a/N0-3/M0', 'Var', (118, 131))	('cancer', 'Disease', (173, 179))
177232	33151397	Patients were eligible for inclusion if they had histologically confirmed locally advanced (T1/N1-3/M0; T2-4a/N0-3/M0) esophageal cancer (according to the seventh tumor-node-metastasis classification system) and if sufficient amounts of pre-treatment biopsy material were available.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('T2-4a/N0-3/M0', 'Var', (104, 117))	('cancer', 'Disease', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
177238	33151397	This grading system classifies the ratio of residual vital tumor cells and the degree of NCRT-induced fibrosis and defines gammapCR; gammapT0N0 (Mandard TRG 1) as no residual vital tumor cells and non-gammapCR (Mandard TRG 5) as no tumor regression at all.	('TRG 1', 'Gene', (153, 158))	('tumor', 'Disease', (181, 186))	('gammapCR', 'Var', (123, 131))	('tumor', 'Disease', (59, 64))	('fibrosis', 'Disease', (102, 110))	('fibrosis', 'Disease', 'MESH:D005355', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (232, 237))	('TRG 5', 'Gene', '7198', (219, 224))	('TRG 1', 'Gene', '7195', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('TRG 5', 'Gene', (219, 224))
177245	33151397	Immunohistochemistry staining was performed on 5-mum tissue sections from archival biopsies using primary antibodies against HER2 (1:100, Fremont), CD44 (1:100, Biolegend), HIF1alpha (1:100, ABCAM), PTCH1 (1:100, ABCAM), and SHH (1:100, ABCAM).	('HER2', 'Gene', (125, 129))	('SHH', 'Gene', '6469', (225, 228))	('1:100', 'Var', (184, 189))	('HER2', 'Gene', '2064', (125, 129))	('HIF1alpha', 'Gene', '3091', (173, 182))	('PTCH1', 'Gene', (199, 204))	('1:100', 'Var', (206, 211))	('SHH', 'Gene', (225, 228))	('1:100', 'Var', (154, 159))	('1:100', 'Var', (131, 136))	('CD44', 'Gene', (148, 152))	('PTCH1', 'Gene', '5727', (199, 204))	('HIF1alpha', 'Gene', (173, 182))
177276	33151397	Although separate incorporation of HER2 or CD44 into the reference models did not improve model performance, incorporating HER2 and CD44 simultaneously yielded substantially improved overall performance (R2M10 = 0.221, R2M11 = 0.270, and R2M12 = 0.225) and discrimination (AUCM10 = 0.759, AUCM11 = 0.857, and AUCM12 = 0.816).	('HER2', 'Gene', (35, 39))	('HER2', 'Gene', '2064', (35, 39))	('R2M11', 'Var', (219, 224))	('HER2', 'Gene', (123, 127))	('AUCM10', 'Var', (273, 279))	('AUCM11', 'Var', (289, 295))	('AUCM12', 'Var', (309, 315))	('R2M12', 'Var', (238, 243))	('HER2', 'Gene', '2064', (123, 127))	('discrimination', 'MPA', (257, 271))	('improved', 'PosReg', (174, 182))	('CD44', 'Gene', (132, 136))
177285	33151397	In vitro, the combination of CD44+/CD24- subpopulation of esophageal cancer cells has shown to be more resistant to NCRT.	('resistant', 'CPA', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CD44+/CD24-', 'Var', (29, 40))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
177303	33370345	Mean lung dose, HAV30% (the proportion of the lung with HAV receiving >=30 Gy), and HAV20% were the top three parameters in lung cancer, while HAV10%, HAV5%, and V10 (the percentage of lung volume receiving 10 Gy or more) were the top three in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('esophageal cancer', 'Disease', (244, 261))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('HAV10%', 'Var', (143, 149))	('HAV5', 'Var', (151, 155))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('HAV20%', 'Var', (84, 90))
177304	33370345	By comparing the differences in the threshold for parameters predicting RP between the two cancers, we saw that HAV30% retained the same value in both cancers.	('HAV30%', 'Var', (112, 118))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancers', 'Disease', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))
177306	33370345	DVH parameters with HAV may have higher commonality than conventional DVH parameters in both patient groups tested.	('commonality', 'MPA', (40, 51))	('patient', 'Species', '9606', (93, 100))	('HAV', 'Var', (20, 23))
177323	33370345	Conventional DVH parameters, including MLD, V2, V5, V10, V20, and V30, and other DVH parameters of high lung attenuation, are described as medians and interquartile ranges.	('V30', 'Var', (66, 69))	('V10', 'Var', (52, 55))	('MLD', 'Disease', 'MESH:D007966', (39, 42))	('MLD', 'Disease', (39, 42))	('V20', 'Var', (57, 60))
177326	33370345	In the univariate analysis of esophageal cancer patients, smoking history, MLD, and V20 were significantly correlated with the occurrence of symptomatic RP (Table 2).	('esophageal cancer', 'Disease', 'MESH:D004938', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('MLD', 'Disease', 'MESH:D007966', (75, 78))	('MLD', 'Disease', (75, 78))	('V20', 'Var', (84, 87))	('correlated with', 'Reg', (107, 122))	('esophageal cancer', 'Disease', (30, 47))	('patients', 'Species', '9606', (48, 56))
177328	33370345	When the predictive performances of DVH parameters for symptomatic RP were compared using the AUC, MLD, HAV30%, and HAV20% were the three best parameters in lung cancer and HAV10%, HAV5%, and V10 were the three best in esophageal cancer (Fig 2).	('esophageal cancer', 'Disease', (219, 236))	('MLD', 'Disease', 'MESH:D007966', (99, 102))	('lung cancer', 'Disease', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('esophageal cancer', 'Disease', 'MESH:D004938', (219, 236))	('MLD', 'Disease', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('HAV30%', 'Var', (104, 110))	('HAV5%', 'Var', (181, 186))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('HAV10%', 'Var', (173, 179))
177330	33370345	When the differences in threshold of parameters between the two cancers were compared, threshold values of HAV30% were found to be almost identical in these cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('HAV30', 'Var', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (64, 71))	('cancers', 'Disease', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
177331	33370345	For all DVH parameters, differences in the threshold between the two cancers were smaller when considering non-emphysematous (MLHAD, HAV30%, HAV20%, HAV10%, and HAV5%) than conventional (MLD, V30, V20, V10, and V5) parameters (Fig 4).	('MLD', 'Disease', (187, 190))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('HAV30%', 'Var', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('non-emphysematous', 'Disease', (107, 124))	('HAV20%', 'Var', (141, 147))	('HAV5%', 'Var', (161, 166))	('HAV10%', 'Var', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))	('MLD', 'Disease', 'MESH:D007966', (187, 190))
177332	33370345	V20 or MLD has been commonly used as an index for the prevention of severe RP in practice.	('V20', 'Var', (0, 3))	('MLD', 'Disease', 'MESH:D007966', (7, 10))	('MLD', 'Disease', (7, 10))
177333	33370345	In various clinical applications of radiotherapy, the limit of MLD or V20 has been described.	('MLD', 'Disease', 'MESH:D007966', (63, 66))	('V20', 'Var', (70, 73))	('MLD', 'Disease', (63, 66))
177336	33370345	Due to the identical threshold values of HAV30% in these two cancer types, this one threshold value could be used in common, at least in lung cancer and esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', (61, 67))	('HAV30%', 'Var', (41, 47))	('cancer', 'Disease', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('esophageal cancer', 'Disease', (153, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))	('cancer', 'Disease', (142, 148))
177348	33370345	The 75% percentiles of HAV20% and V20 and V5 in esophageal cancer were lower than the threshold; therefore, comparing these may not be of much significance.	('esophageal cancer', 'Disease', (48, 65))	('HAV20%', 'Var', (23, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('V20', 'Var', (34, 37))	('lower', 'NegReg', (71, 76))
177369	33370345	As you pointed out, the 75% percentile of HAV20% and V20 and V5 in esophageal cancer were lower than threshold.	('V20', 'Var', (53, 56))	('HAV20%', 'Var', (42, 48))	('lower', 'NegReg', (90, 95))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))
177373	30326253	This may be due to increased resistance (acquired or intrinsic) of tumor cells to chemo/radiotherapies, often caused by aberrant cell cycle, deregulated apoptosis, increases in growth factor signaling pathways, and/or changes in the proteome network.	('deregulated apoptosis', 'CPA', (141, 162))	('growth factor signaling pathways', 'Pathway', (177, 209))	('aberrant', 'Var', (120, 128))	('increases', 'PosReg', (164, 173))	('changes', 'Reg', (218, 225))	('proteome network', 'Pathway', (233, 249))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('caused', 'Reg', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('increased', 'PosReg', (19, 28))	('aberrant cell cycle', 'Phenotype', 'HP:0011018', (120, 139))	('tumor', 'Disease', (67, 72))	('resistance', 'CPA', (29, 39))
177375	30326253	The increased stability and dysregulated expression of miRNAs have been associated with increased resistance to various therapies in several cancers, including esophageal cancer.	('resistance to various therapies', 'CPA', (98, 129))	('stability', 'MPA', (14, 23))	('dysregulated', 'Var', (28, 40))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('associated', 'Reg', (72, 82))	('increased', 'PosReg', (88, 97))	('esophageal cancer', 'Disease', (160, 177))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('increased', 'PosReg', (4, 13))	('cancers', 'Disease', (141, 148))
177382	30326253	These types of cells normally enhance tumor hypoxia, expression of p38 MAPK, production of TGF-beta and Wnt signaling in the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('p38', 'Var', (67, 70))	('tumor', 'Disease', (38, 43))	('production', 'MPA', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Wnt', 'MPA', (104, 107))	('tumor hypoxia', 'Disease', 'MESH:D000860', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor hypoxia', 'Disease', (38, 51))	('TGF-beta', 'Gene', (91, 99))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('expression', 'MPA', (53, 63))	('enhance', 'PosReg', (30, 37))	('TGF-beta', 'Gene', '7039', (91, 99))
177384	30326253	The dysregulated miRNAs disseminate epigenetic changes such as DNA damage, cell cycle arrest and effect sensitivity of tumor cells which are can to contribute to the resistance to therapy.	('contribute', 'Reg', (148, 158))	('tumor', 'Disease', (119, 124))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('arrest', 'Disease', (86, 92))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (75, 92))	('DNA damage', 'Disease', (63, 73))	('disseminate', 'Reg', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('epigenetic changes', 'Var', (36, 54))
177388	30326253	Patients with esophageal tumors, like pancreatic tumors, often require the use of radiotherapy in treatment regimens, and both external and internal beam radiation therapy are used to inactivate the tumor mass prior to surgical resection (also called ablative therapy).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('esophageal tumors', 'Phenotype', 'HP:0100751', (14, 31))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (38, 55))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('esophageal tumors', 'Disease', 'MESH:D004941', (14, 31))	('esophageal tumors', 'Disease', (14, 31))	('pancreatic tumors', 'Disease', 'MESH:D010190', (38, 55))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('pancreatic tumors', 'Disease', (38, 55))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('inactivate', 'Var', (184, 194))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
177398	30326253	(2013) by using qRT-PCR found that miR-21 was up-regulated by ~1.3-fold (Figure 1, Table 1) by treatment with irradiation at 60 Gy in TE-R60 (radioresistant esophageal squamous cancer cells) esophageal squamous cell carcinoma (ESCC)-radioresistant cells relative to that of the TE-1 parental resistant ESCC cells.	('esophageal squamous cell carcinoma', 'Disease', (191, 225))	('TE-R60', 'Var', (134, 140))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (191, 225))	('ESCC', 'Disease', 'MESH:C562729', (227, 231))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (157, 183))	('up-regulated', 'PosReg', (46, 58))	('ESCC', 'Disease', 'MESH:C562729', (302, 306))	('miR-21', 'Gene', (35, 41))	('esophageal squamous cancer', 'Disease', (157, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (202, 225))	('squamous cancer', 'Phenotype', 'HP:0002860', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('ESCC', 'Disease', (302, 306))	('ESCC', 'Disease', (227, 231))	('miR-21', 'Gene', '406991', (35, 41))
177410	30326253	Unlike miR-21, overexpression of miR-31 has been shown to promote cytotoxicity in tumor cells and its levels is often reduced in cancers, perhaps due to deletions or translocation of the fragile location of miR-31 in the genome.	('miR-21', 'Gene', (7, 13))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('miR-31', 'Gene', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('miR-31', 'Gene', '407035', (33, 39))	('fragile', 'Disease', (187, 194))	('cytotoxicity in tumor', 'Disease', (66, 87))	('cytotoxicity in tumor', 'Disease', 'MESH:D064420', (66, 87))	('levels', 'MPA', (102, 108))	('deletions', 'Var', (153, 162))	('miR-31', 'Gene', '407035', (207, 213))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('reduced', 'NegReg', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('fragile', 'Disease', 'MESH:D005600', (187, 194))	('miR-21', 'Gene', '406991', (7, 13))	('overexpression', 'PosReg', (15, 29))	('promote', 'PosReg', (58, 65))	('translocation', 'Var', (166, 179))	('miR-31', 'Gene', (33, 39))
177422	30326253	Esophageal cancer cell lines (TE-1, ECa-109, and EC-9706) express significantly higher amounts (~2.0-fold) (Figure 1, Table 1) of miR-96 compared to normal human esophageal epithelial cells (HECC).	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('EC-9706', 'CellLine', 'CVCL:E307', (49, 56))	('miR-96', 'Var', (130, 136))	('Esophageal cancer', 'Disease', (0, 17))	('human', 'Species', '9606', (156, 161))	('higher', 'PosReg', (80, 86))	('ECa-109', 'CellLine', 'CVCL:6898', (36, 43))
177424	30326253	A significant correlation was noted between tumor volume and metastasis in miR-96 positive cancer patients, though no associations were observed between the ages or gender of patients with regard to miR-96 expression.	('positive', 'Var', (82, 90))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('patients', 'Species', '9606', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('miR-96', 'Gene', (75, 81))	('metastasis', 'CPA', (61, 71))	('patients', 'Species', '9606', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (44, 49))
177426	30326253	Moreover, ectopic expression of miR-96 in TE-1 and ECa-109 esophageal cancer cells promoted cell proliferation compared to control plasmids in cells.	('esophageal cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('ECa-109', 'CellLine', 'CVCL:6898', (51, 58))	('miR-96', 'Gene', (32, 38))	('promoted', 'PosReg', (83, 91))	('ectopic expression', 'Var', (10, 28))	('cell proliferation', 'CPA', (92, 110))
177427	30326253	Further, they found that miR-96-overexpressing esophageal cancer cells exhibited significantly decreased apoptotic rates compared to nonoverexpressing cells following 6 Gy irradiation, suggesting that miR-96 promotes radioresistance.	('decreased', 'NegReg', (95, 104))	('promotes', 'PosReg', (208, 216))	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('miR-96', 'Var', (201, 207))	('radioresistance', 'CPA', (217, 232))	('miR-96-overexpressing', 'Gene', (25, 46))	('esophageal cancer', 'Disease', (47, 64))	('miR-96-overexpressing', 'PosReg', (25, 46))	('apoptotic rates', 'CPA', (105, 120))
177430	30326253	By Western blot analyses, the authors found that RECK was ~5.0-fold higher than in normal cells compared to esophageal cancer cells, indicating that miR-96, in part, in down-regulating RECK in esophageal cancer cells, promoted radioresistance in esophageal cancer.	('promoted', 'PosReg', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('miR-96', 'Var', (149, 155))	('down-regulating', 'NegReg', (169, 184))	('esophageal cancer', 'Disease', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('RECK', 'Gene', (185, 189))	('RECK', 'Gene', (49, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (246, 263))	('radioresistance', 'CPA', (227, 242))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('esophageal cancer', 'Disease', (246, 263))	('esophageal cancer', 'Disease', (193, 210))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('RECK', 'Gene', '8434', (185, 189))	('RECK', 'Gene', '8434', (49, 53))
177448	30326253	The authors found that ectopic expression of miR-124 in TE-1 cells markedly inhibited the proliferation and invasion of cells compared with NC-mimic controls.	('miR', 'Gene', (45, 48))	('inhibited', 'NegReg', (76, 85))	('ectopic expression', 'Var', (23, 41))	('miR', 'Gene', '220972', (45, 48))
177449	30326253	To investigate the role of miR-124 in radiosensitivity, Zhang et al, (2016) overexpressed miR-124 in TE-1 cells exposed to 8 Gy of irradiation, and found that ectopic expression of miR-124 followed by radiotherapy led to a higher percentage of apoptotic cells compared to control scrambled-treated cells.	('ectopic expression', 'Var', (159, 177))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('apoptotic cells', 'CPA', (244, 259))	('miR', 'Gene', (181, 184))	('miR', 'Gene', '220972', (181, 184))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))
177463	30326253	Subsequently, it was proposed that changes in the expression of miR-205 can modulate the activity of the AKT protein at serine 472 in parental cells, while dictating the fate of cells to treatment with radiation.	('serine', 'Chemical', 'MESH:D012694', (120, 126))	('modulate', 'Reg', (76, 84))	('AKT', 'Gene', '207', (105, 108))	('miR-205', 'Gene', (64, 71))	('dictating', 'Reg', (156, 165))	('miR-205', 'Gene', '406988', (64, 71))	('AKT', 'Gene', (105, 108))	('changes', 'Var', (35, 42))	('activity', 'MPA', (89, 97))
177473	30326253	Consistent with this, KYSE450-miR-381 tumors grew slower than KYSE450-control tumors following irradiation of mice with 5 Gy irradiation, demonstrating their radiosensitive nature.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('KYSE450-miR-381', 'Var', (22, 37))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mice', 'Species', '10090', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('grew', 'CPA', (45, 49))	('slower', 'NegReg', (50, 56))
177475	30326253	Surprisingly, overexpression of miR-381 also inhibited tumor growth and was mediated by down-modulation of various signaling factors such as Catenin Beta 1 (CTNB1), Lymphoid Enhancer Binding Factor 1 (LEF1), Cyclin Dependent Kinase 1 (CDK1), X-Linked Inhibitor Of Apoptosis (XIAP), and C-X-C Motif Chemokine Receptor 4 (CXCR4), which are involved in tumor development (Figure 2).	('Cyclin Dependent Kinase 1', 'Gene', (208, 233))	('XIAP', 'Gene', (275, 279))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CDK1', 'Gene', '983', (235, 239))	('CDK1', 'Gene', (235, 239))	('Lymphoid Enhancer Binding Factor 1', 'Gene', (165, 199))	('inhibited', 'NegReg', (45, 54))	('overexpression', 'PosReg', (14, 28))	('LEF1', 'Gene', (201, 205))	('Catenin Beta 1', 'Gene', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Lymphoid Enhancer Binding Factor 1', 'Gene', '51176', (165, 199))	('C-X-C Motif Chemokine Receptor 4', 'Gene', '7852', (286, 318))	('tumor', 'Disease', (350, 355))	('miR-381', 'Var', (32, 39))	('CTNB1', 'Gene', '1499', (157, 162))	('XIAP', 'Gene', '331', (275, 279))	('Cyclin Dependent Kinase 1', 'Gene', '983', (208, 233))	('X-Linked Inhibitor Of Apoptosis', 'Gene', '331', (242, 273))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('CTNB1', 'Gene', (157, 162))	('CXCR4', 'Gene', '7852', (320, 325))	('LEF1', 'Gene', '51176', (201, 205))	('CXCR4', 'Gene', (320, 325))	('X-Linked Inhibitor Of Apoptosis', 'Gene', (242, 273))	('down-modulation', 'NegReg', (88, 103))	('tumor', 'Disease', (55, 60))	('C-X-C Motif Chemokine Receptor 4', 'Gene', (286, 318))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('Catenin Beta 1', 'Gene', '1499', (141, 155))
177476	30326253	Moreover, Zhou et al, found that XIAP is a direct target of miR-381 and binds with its 3'UTR region, dysregulating the enhanced expression of XIAP resulting in increased apoptosis, growth inhibition and radiosensitivity in ESCC cells.	('radiosensitivity', 'CPA', (203, 219))	('ESCC', 'Disease', 'MESH:C562729', (223, 227))	('XIAP', 'Gene', (142, 146))	('increased', 'PosReg', (160, 169))	('XIAP', 'Gene', '331', (142, 146))	('growth inhibition', 'CPA', (181, 198))	('ESCC', 'Disease', (223, 227))	('XIAP', 'Gene', (33, 37))	('XIAP', 'Gene', '331', (33, 37))	('expression', 'MPA', (128, 138))	('dysregulating', 'Var', (101, 114))	('enhanced', 'PosReg', (119, 127))	('apoptosis', 'CPA', (170, 179))
177485	30326253	OE33R-bearing mice developed tumors faster and had larger tumor volumes than those in the OE33P-bearing group.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('larger', 'PosReg', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumors faster', 'Disease', 'MESH:D009369', (29, 42))	('OE33R', 'Chemical', '-', (0, 5))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumors faster', 'Disease', (29, 42))	('OE33R-bearing', 'Var', (0, 13))
177488	30326253	Further, it was identified that ALDH1+ve cells isolated from OE33R cells showed significantly higher resistance to 2 Gy radiation compared to ALDH1-ve populations, and the ALDH1+ve cells showed a higher survival (~1.2-fold) following irradiation with 2 Gy compared to ALDH1-ve cells.	('OE33R', 'Chemical', '-', (61, 66))	('resistance to 2 Gy radiation', 'MPA', (101, 129))	('ALDH1+ve', 'Var', (172, 180))	('survival', 'CPA', (203, 211))	('higher', 'PosReg', (196, 202))	('ALDH1+ve', 'Gene', (32, 40))	('higher', 'PosReg', (94, 100))
177489	30326253	It was also found that OE33R ALDH1+ve cells expressed ~2-fold lower levels of miR-17-5p compared to OE33R ALDH1-ve cells.	('OE33R ALDH1+ve', 'Var', (23, 37))	('OE33R', 'Chemical', '-', (23, 28))	('lower', 'NegReg', (62, 67))	('OE33R', 'Chemical', '-', (100, 105))	('miR-17-5p', 'Gene', '406952', (78, 87))	('levels', 'MPA', (68, 74))	('miR-17-5p', 'Gene', (78, 87))
177513	30326253	miR-338-5p is located on chromosome 17q25.3 and often originates from an intron of the gene encoding the apoptosis-associated tyrosine kinase (AATK).	('miR-338-5p', 'Var', (0, 10))	('miR-338-5p', 'Chemical', '-', (0, 10))	('AATK', 'Gene', (143, 147))	('AATK', 'Gene', '9625', (143, 147))	('apoptosis-associated tyrosine kinase', 'Gene', (105, 141))	('apoptosis-associated tyrosine kinase', 'Gene', '9625', (105, 141))
177515	30326253	In the case of ESCC, miR-338-5p was found to be significantly downregulated (~5.1-fold) in ESCC radioresistant TE-4R cells compared to the sensitive parental TE-4 ESCC cells.	('ESCC', 'Disease', (15, 19))	('ESCC', 'Disease', (163, 167))	('miR-338-5p', 'Chemical', '-', (21, 31))	('miR-338-5p', 'Var', (21, 31))	('radioresistant TE-4R', 'CPA', (96, 116))	('ESCC', 'Disease', (91, 95))	('downregulated', 'NegReg', (62, 75))	('ESCC', 'Disease', 'MESH:C562729', (163, 167))	('ESCC', 'Disease', 'MESH:C562729', (15, 19))	('ESCC', 'Disease', 'MESH:C562729', (91, 95))
177517	30326253	These data clearly indicate that ectopic expression of miR-338-5p renders ESCC cells more sensitive to radiotherapy.	('more', 'PosReg', (85, 89))	('ESCC', 'Disease', (74, 78))	('miR-338-5p', 'Chemical', '-', (55, 65))	('miR-338-5p', 'Var', (55, 65))	('ESCC', 'Disease', 'MESH:C562729', (74, 78))	('sensitive', 'MPA', (90, 99))
177518	30326253	Through western blot analysis, it was found that the miR-338-5p induced the expression of pro-caspase genes such as PARP and caspase-3, thus enhancing apoptosis in radio-exposed ESCC cells, a major factor regulating radioresistance in ESCC.	('ESCC', 'Disease', (235, 239))	('caspase-3', 'Gene', (125, 134))	('ESCC', 'Disease', 'MESH:C562729', (178, 182))	('PARP', 'Gene', (116, 120))	('caspase-3', 'Gene', '836', (125, 134))	('enhancing', 'PosReg', (141, 150))	('miR-338-5p', 'Chemical', '-', (53, 63))	('expression', 'MPA', (76, 86))	('miR-338-5p', 'Var', (53, 63))	('PARP', 'Gene', '142', (116, 120))	('ESCC', 'Disease', 'MESH:C562729', (235, 239))	('ESCC', 'Disease', (178, 182))	('apoptosis', 'CPA', (151, 160))	('induced', 'PosReg', (64, 71))
177519	30326253	To further advance the understanding of the mechanism(s) associated with miR-338-5p induced apoptosis, Park et al (2017), by using bioinformatics identified the survivin gene as one of the targets of miR-338-5p, which was later also confirmed through luciferase-reporter assays.	('survivin', 'Gene', (161, 169))	('miR-338-5p', 'Chemical', '-', (200, 210))	('miR-338-5p', 'Var', (200, 210))	('miR-338-5p', 'Chemical', '-', (73, 83))	('miR-338-5p', 'Var', (73, 83))	('survivin', 'Gene', '11799', (161, 169))
177520	30326253	It was also discovered that miR-338-5p downregulation enhanced the expression of survivin in the radioresistant cell line compared to the parental cells.	('miR-338-5p', 'Var', (28, 38))	('survivin', 'Gene', '11799', (81, 89))	('miR-338-5p', 'Chemical', '-', (28, 38))	('expression', 'MPA', (67, 77))	('enhanced', 'PosReg', (54, 62))	('downregulation', 'NegReg', (39, 53))	('survivin', 'Gene', (81, 89))
177524	30326253	It was found that injection of miR-338-5p into the tumor mass increased the sensitivity to radiation therapy compared to control tumors.	('increased', 'PosReg', (62, 71))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('miR-338-5p', 'Chemical', '-', (31, 41))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('miR-338-5p', 'Var', (31, 41))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (76, 100))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('sensitivity to radiation therapy', 'MPA', (76, 108))
177525	30326253	Additionally, survivin expression was downregulated in the miR-338-5p transfected xenografts of mice.	('miR-338-5p', 'Chemical', '-', (59, 69))	('mice', 'Species', '10090', (96, 100))	('miR-338-5p transfected', 'Var', (59, 81))	('survivin', 'Gene', (14, 22))	('downregulated', 'NegReg', (38, 51))	('survivin', 'Gene', '11799', (14, 22))	('expression', 'MPA', (23, 33))
177526	30326253	Overall, the above findings reveal that downregulation of miR-338-5p plays a critical role in the development of radioresistance in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('radioresistance', 'CPA', (113, 128))	('downregulation', 'NegReg', (40, 54))	('esophageal cancer', 'Disease', (132, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('miR-338-5p', 'Chemical', '-', (58, 68))	('miR-338-5p', 'Var', (58, 68))
177527	30326253	Consistent with this, ectopic overexpression of miR-338-5p was shown to induce apoptosis and sensitivity to radiation treatment by interfering with survivin expression in cells, which is a known inhibitor of apoptosis.	('survivin', 'Gene', '11799', (148, 156))	('miR-338-5p', 'Var', (48, 58))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (93, 117))	('expression', 'MPA', (157, 167))	('induce', 'PosReg', (72, 78))	('interfering', 'NegReg', (131, 142))	('survivin', 'Gene', (148, 156))	('apoptosis', 'CPA', (79, 88))	('miR-338-5p', 'Chemical', '-', (48, 58))
177528	30326253	Therefore, miR-338-5p and survivin together may act as potential biomarkers, and may be explored as target molecules to enhance sensitization of ESCC cells to radiotherapy.	('miR-338-5p', 'Var', (11, 21))	('survivin', 'Gene', (26, 34))	('enhance', 'PosReg', (120, 127))	('miR-338-5p', 'Chemical', '-', (11, 21))	('survivin', 'Gene', '11799', (26, 34))	('ESCC', 'Disease', 'MESH:C562729', (145, 149))	('ESCC', 'Disease', (145, 149))
177529	30326253	Alterations in the expression of both genetic and cellular components have important roles in dictating the fate of tumors following various therapeutic modalities.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('expression', 'MPA', (19, 29))	('dictating', 'Reg', (94, 103))	('Alterations', 'Var', (0, 11))	('roles', 'Reg', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
177531	30326253	Of particular note, molecular targeting of various miRNAs in conjunction with neo-adjuvant therapy may provide a novel approach for restoring immunity against refractory tumors.	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('restoring', 'PosReg', (132, 141))	('molecular', 'Var', (20, 29))	('refractory tumors', 'Disease', 'MESH:D000753', (159, 176))	('refractory tumors', 'Disease', (159, 176))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('immunity', 'MPA', (142, 150))
177532	30326253	Cited literature also supports our claim that modulating microRNA levels in tumor patients is likely to offer sensitization in refractory tumors as well enhancing the immune response.	('microRNA levels', 'MPA', (57, 72))	('refractory tumors', 'Disease', 'MESH:D000753', (127, 144))	('tumor', 'Disease', (138, 143))	('refractory tumors', 'Disease', (127, 144))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('sensitization', 'MPA', (110, 123))	('tumor', 'Disease', (76, 81))	('modulating', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('immune response', 'CPA', (167, 182))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('enhancing', 'PosReg', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
177536	30326253	Modulation of miRNAs levels may provide a new therapeutic approach for esophageal cancer treatment.	('Modulation', 'Var', (0, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('miR', 'Gene', '220972', (14, 17))	('esophageal cancer', 'Disease', (71, 88))	('miR', 'Gene', (14, 17))
177570	30578874	RNA was isolated from esophageal biopsies for quantitative real-time RT-PCR as described previously using TaqMan Gene Expression Assays (Thermo Fisher Scientific, Waltham, MA) for LOX (Hs00942483) and GAPDH (Hs99999905_m1), the latter as an internal control gene.	('GAPDH', 'Gene', '2597', (201, 206))	('Hs00942483', 'Var', (185, 195))	('Hs99999905_m1', 'Var', (208, 221))	('GAPDH', 'Gene', (201, 206))
177629	30578874	We have recently shown that patients with fibrostenotic features of EoE such as history of stricture, impaction, or rings/narrowing on endoscopy display decreased esophageal distensibility measured by the EndoFLIP.	('EoE', 'Phenotype', 'HP:0410151', (68, 71))	('impaction', 'Disease', (102, 111))	('stricture', 'Disease', (91, 100))	('esophageal distensibility measured by the EndoFLIP', 'MPA', (163, 213))	('decreased', 'NegReg', (153, 162))	('rings/narrowing', 'Var', (116, 131))	('patients', 'Species', '9606', (28, 36))
177635	30578874	Inhibiting LOX in murine models of atherosclerosis leads to decreased arterial stiffness despite high fat diets and elevated cholesterol levels.	('cholesterol levels', 'MPA', (125, 143))	('Inhibiting', 'Var', (0, 10))	('atherosclerosis', 'Disease', (35, 50))	('decreased arterial stiffness', 'Disease', (60, 88))	('LOX', 'Gene', (11, 14))	('decreased arterial stiffness', 'Disease', 'MESH:D002303', (60, 88))	('elevated', 'PosReg', (116, 124))	('elevated cholesterol', 'Phenotype', 'HP:0003124', (116, 136))	('atherosclerosis', 'Phenotype', 'HP:0002621', (35, 50))	('atherosclerosis', 'Disease', 'MESH:D050197', (35, 50))	('cholesterol', 'Chemical', 'MESH:D002784', (125, 136))	('murine', 'Species', '10090', (18, 24))
177637	30578874	Taken together, LOX expression in the esophageal epithelium could be propagating fibrosis, stimulating a positive feedback loop resulting in ongoing tissue stiffness and continued remodeling.	('fibrosis', 'Disease', 'MESH:D005355', (81, 89))	('LOX expression', 'Var', (16, 30))	('fibrosis', 'Disease', (81, 89))	('positive feedback loop', 'MPA', (105, 127))	('stimulating', 'Reg', (91, 102))	('tissue stiffness', 'CPA', (149, 165))	('remodeling', 'CPA', (180, 190))
177657	30568145	The typical symptoms of glossopharyngeal neuralgia are paroxysmal, stabbing, electric shock-like pain in the pharynx and/or base of the tongue on swallowing and talking.	('glossopharyngeal neuralgia', 'Disease', 'MESH:D020435', (24, 50))	('shock', 'Phenotype', 'HP:0031273', (86, 91))	('pain', 'Phenotype', 'HP:0012531', (97, 101))	('pain', 'Disease', 'MESH:D010146', (97, 101))	('pain', 'Disease', (97, 101))	('electric shock-like', 'Var', (77, 96))	('paroxysmal', 'Disease', (55, 65))	('glossopharyngeal neuralgia', 'Disease', (24, 50))
177745	29263183	We aimed to enroll 250 subjects, equally divided among men and women, current smokers and nonsmokers, and five levels of mate consumption: none; 1 to 500 mL/day; 501 to 1000 mL/day; 1001 to 2000 mL/day and more than 2000 mL/day.	('men', 'Species', '9606', (55, 58))	('501 to 1000 mL/day', 'Var', (162, 180))	('men', 'Species', '9606', (65, 68))	('1001 to 2000 mL/day', 'Var', (182, 201))	('women', 'Species', '9606', (63, 68))
177815	28319330	Flap endonuclease-1 rs174538 G>A polymorphisms are associated with the risk of esophageal cancer in a Chinese population Esophageal cancer has a high mortality rate, particularly in Asia, and there are obvious racial differences in regard to incidence.	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Flap endonuclease-1', 'Gene', (0, 19))	('rs174538', 'Mutation', 'rs174538', (20, 28))	('Esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('Flap endonuclease-1', 'Gene', '2237', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('associated', 'Reg', (51, 61))	('rs174538 G>A', 'Var', (20, 32))	('Esophageal cancer', 'Disease', (121, 138))
177816	28319330	The purpose of our study was to assess the genetic susceptibility of functional single nucleotide polymorphisms in flap endonuclease-1 (FEN1) in esophageal squamous cell carcinoma ESCC.	('flap endonuclease-1', 'Gene', '2237', (115, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('FEN1', 'Gene', (136, 140))	('single nucleotide polymorphisms', 'Var', (80, 111))	('esophageal squamous cell carcinoma ESCC', 'Disease', (145, 184))	('flap endonuclease-1', 'Gene', (115, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('esophageal squamous cell carcinoma ESCC', 'Disease', 'MESH:D000077277', (145, 184))
177817	28319330	The ligation detection reaction method was used to determine FEN 1 rs174538 G>A genotypes.	('FEN 1', 'Gene', '2237', (61, 66))	('rs174538', 'Mutation', 'rs174538', (67, 75))	('FEN 1', 'Gene', (61, 66))	('rs174538 G>A', 'Var', (67, 79))
177818	28319330	A significantly decreased risk of ESCC was associated with FEN 1 rs174538 GA genotypes among patients under 63 years old.	('rs174538 GA', 'Var', (65, 76))	('rs174538', 'Mutation', 'rs174538', (65, 73))	('ESCC', 'Disease', (34, 38))	('FEN 1', 'Gene', (59, 64))	('FEN 1', 'Gene', '2237', (59, 64))	('patients', 'Species', '9606', (93, 101))	('decreased', 'NegReg', (16, 25))
177819	28319330	Our results suggest that functional polymorphism FEN 1 rs174538 G>A might affect personal susceptibility to ESCC.	('FEN 1', 'Gene', '2237', (49, 54))	('rs174538', 'Mutation', 'rs174538', (55, 63))	('affect', 'Reg', (74, 80))	('ESCC', 'Disease', (108, 112))	('rs174538 G>A', 'Var', (55, 67))	('FEN 1', 'Gene', (49, 54))
177823	28319330	In addition, FEN1 is also involved in apoptosis and can effectively regulate apoptotic products, thus ensuring the smooth progress of apoptosis.11 Previous studies have shown that FEN1 is related to the development of autoimmune diseases, cancer, and other diseases.12  Studies have revealed that a loss of RAD27 (homologue of human FEN-1) stimulates a variety of mutagenic and clastogenic events, including a significant increase in the rate of spontaneous mutation and enhanced sensitivity to DNA damage.11, 13, 14 Meanwhile, the mutant phenotype has been found in yeast cells, suggesting that the FEN1 mutant plays a potential role in mammalian genomic instability and tumorigenesis.7Another study demonstrated that in a mouse model, sporadic tumors, mainly identified as lung cancer, developed in 70% of mice carrying the E160D FEN1 mutation.12 A recent study showed that two single nucleotide polymorphisms (SNPs) of FEN1 genes (-69G>A and 4150G>T) were associated with the risk of lung cancer.15 However, a correlation with the risk of esophageal, liver, stomach, and colorectal cancers has not yet been established.	('FEN1', 'Gene', (922, 926))	('cancer', 'Disease', (780, 786))	('tumor', 'Phenotype', 'HP:0002664', (746, 751))	('tumor', 'Disease', 'MESH:D009369', (672, 677))	('colorectal cancers', 'Disease', 'MESH:D015179', (1074, 1092))	('lung cancer', 'Disease', 'MESH:D008175', (987, 998))	('4150G>T', 'Mutation', 'rs4246215', (945, 952))	('cancer', 'Phenotype', 'HP:0002664', (780, 786))	('tumors', 'Disease', (746, 752))	('liver', 'Disease', (1054, 1059))	('human', 'Species', '9606', (327, 332))	('RAD27', 'Gene', (307, 312))	('cancer', 'Disease', 'MESH:D009369', (1085, 1091))	('mice', 'Species', '10090', (808, 812))	('lung cancer', 'Phenotype', 'HP:0100526', (987, 998))	('-69G>A', 'Mutation', 'rs174538', (934, 940))	('lung cancer', 'Disease', (775, 786))	('FEN-1', 'Gene', (333, 338))	('tumors', 'Disease', 'MESH:D009369', (746, 752))	('tumor', 'Phenotype', 'HP:0002664', (672, 677))	('cancer', 'Disease', (239, 245))	('E160D', 'Mutation', 'p.E160D', (826, 831))	('cancer', 'Disease', (992, 998))	('cancer', 'Disease', 'MESH:D009369', (780, 786))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (992, 998))	('RAD27', 'Gene', '853747', (307, 312))	('tumor', 'Disease', (746, 751))	('colorectal cancers', 'Disease', (1074, 1092))	('autoimmune diseases', 'Disease', 'MESH:D001327', (218, 237))	('cancers', 'Phenotype', 'HP:0002664', (1085, 1092))	('lung cancer', 'Disease', 'MESH:D008175', (775, 786))	('lung cancer', 'Disease', (987, 998))	('yeast', 'Species', '4932', (567, 572))	('tumor', 'Disease', 'MESH:D009369', (746, 751))	('esophageal', 'Disease', (1042, 1052))	('autoimmune diseases', 'Disease', (218, 237))	('cancer', 'Disease', (1085, 1091))	('mammalian', 'Species', '9606', (638, 647))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (218, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (775, 786))	('cancer', 'Phenotype', 'HP:0002664', (1085, 1091))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (992, 998))	('FEN-1', 'Gene', '2237', (333, 338))	('tumors', 'Phenotype', 'HP:0002664', (746, 752))	('-69G>A', 'Var', (934, 940))	('tumor', 'Disease', (672, 677))	('mouse', 'Species', '10090', (724, 729))	('stomach', 'Disease', (1061, 1068))
177824	28319330	We selected 629 patients with ESCC and 686 control samples without cancer to assess FEN1 rs174538 G>A SNP and ESCC risk.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('FEN1', 'Gene', (84, 88))	('cancer', 'Disease', (67, 73))	('rs174538', 'Mutation', 'rs174538', (89, 97))	('patients', 'Species', '9606', (16, 24))	('ESCC', 'Disease', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs174538 G>A', 'Var', (89, 101))	('ESCC', 'Disease', (110, 114))
177825	28319330	We found that the existence of FEN1 rs174538 G>A polymorphisms and susceptibility to ESCC was significantly correlated.	('rs174538', 'Mutation', 'rs174538', (36, 44))	('FEN1', 'Gene', (31, 35))	('rs174538 G>A', 'Var', (36, 48))	('ESCC', 'Disease', (85, 89))
177826	28319330	We performed stratification analyses by age, gender, smoking, and alcohol consumption, and the results showed that age had an effect on the relationship between the polymorphisms and susceptibility to ESCC.	('polymorphisms', 'Var', (165, 178))	('alcohol', 'Chemical', 'MESH:D000438', (66, 73))	('susceptibility', 'Reg', (183, 197))	('relationship', 'Interaction', (140, 152))	('ESCC', 'Disease', (201, 205))
177827	28319330	When the FEN1 rs174538 GG homozygote genotype was used as the reference group, the GA genotype was associated with a borderline statistically significantly decreased risk of ESCC (GA vs. GG: adjusted OR 0.81, 95% CI 0.64-1.04; P = 0.092).	('rs174538', 'Mutation', 'rs174538', (14, 22))	('ESCC', 'Disease', (174, 178))	('decreased', 'NegReg', (156, 165))	('FEN1', 'Gene', (9, 13))	('rs174538 GG', 'Var', (14, 25))
177832	28319330	The samples were genotyped using the ligation detection reaction method, as previously described.17  Differences in the distribution of demographic characteristics, selected variables, and genotypes of the FEN1 rs174538 G>A variant between the patients and controls were evaluated using Student's t and chi 2tests.	('rs174538', 'Mutation', 'rs174538', (211, 219))	('rs174538 G>A', 'Var', (211, 223))	('FEN1', 'Gene', (206, 210))	('patients', 'Species', '9606', (244, 252))
177833	28319330	The connections between the FEN1 rs174538 SNP and risk of ESCC were examined by computing the ORs and 95% CIs using logistic regression analyses and adjusting for age, gender, smoking, and drinking status.	('rs174538', 'Mutation', 'rs174538', (33, 41))	('rs174538 SNP', 'Var', (33, 45))	('FEN1', 'Gene', (28, 32))	('ESCC', 'Disease', (58, 62))
177835	28319330	The genotype distributions of FEN1 rs174538 G>A in the cases and the controls are shown in Table 2.	('rs174538', 'Mutation', 'rs174538', (35, 43))	('rs174538 G>A', 'Var', (35, 47))	('FEN1', 'Gene', (30, 34))
177836	28319330	In the single locus analyses, the genotype frequencies of FEN1 rs174538 G>A were 40.33% (GG), 47.15% (GA), and 12.52% (AA) in the case patients and 36.60% (GG), 52.68% (GA), and 10.72% (AA) in the control subjects; the difference was not statistically significant (P = 0.138).	('patients', 'Species', '9606', (135, 143))	('rs174538', 'Mutation', 'rs174538', (63, 71))	('FEN1', 'Gene', (58, 62))	('rs174538 G>A', 'Var', (63, 75))
177837	28319330	In the recessive model, when the FEN1 rs174538 GG/AA genotypes were used as the reference group, neither the AA homozygote genotype (AA vs. GG/AA: adjusted OR 1.18, 95% CI 0.83-1.68; P = 0.355), nor the GA/AA homozygote genotype (GA/AA vs. GG/AA: adjusted OR 0.85, 95% CI 0.68-1.07; P = 0.176) were associated with a risk of ESCC.	('FEN1', 'Gene', (33, 37))	('ESCC', 'Disease', (325, 329))	('rs174538', 'Mutation', 'rs174538', (38, 46))	('rs174538', 'Var', (38, 46))
177838	28319330	When the FEN1 rs174538 GG homozygote genotype was used as the reference group, the GA genotype was associated with a borderline statistically significantly decreased risk of ESCC (GA vs. GG: adjusted OR 0.81, 95% CI 0.64-1.04; P = 0.092), while the AA genotype was not associated with ESCC risk (AA vs. GG: adjusted OR 1.05, 95% CI 0.72-1.53; P = 0.802).	('ESCC', 'Disease', (174, 178))	('rs174538', 'Mutation', 'rs174538', (14, 22))	('decreased', 'NegReg', (156, 165))	('ESCC', 'Disease', (285, 289))	('FEN1', 'Gene', (9, 13))	('rs174538 GG', 'Var', (14, 25))
177839	28319330	To evaluate the effects of FEN1 rs174538 G>A genotypes on ESCC risk according to age, gender, smoking, and alcohol drinking status, we performed stratification analyses in a recessive model (Table 3).	('rs174538 G>A', 'Var', (32, 44))	('FEN1', 'Gene', (27, 31))	('alcohol drinking', 'Phenotype', 'HP:0030955', (107, 123))	('rs174538', 'Mutation', 'rs174538', (32, 40))	('ESCC', 'Disease', (58, 62))	('alcohol', 'Chemical', 'MESH:D000438', (107, 114))
177840	28319330	A significantly decreased risk of ESCC was associated with the FEN1 rs174538 GA genotypes among patients under 63 years old (GA vs. GG: adjusted OR 0.63, 95% CI 0.45-0.90; P = 0.010, P h = 0.027).	('rs174538', 'Mutation', 'rs174538', (68, 76))	('FEN1', 'Gene', (63, 67))	('ESCC', 'Disease', (34, 38))	('rs174538 GA', 'Var', (68, 79))	('patients', 'Species', '9606', (96, 104))	('decreased', 'NegReg', (16, 25))
177841	28319330	In patients aged under 63 years, when the FEN1 rs174538 GG genotypes were used as the reference group, the FEN1 rs174538 GA/AA genotypes were associated with a significantly lower ESCC risk (GA/AA vs. GG: adjusted OR 0.70, 95% CI 0.50-0.97; P = 0.034, P h = 0.045).	('rs174538', 'Mutation', 'rs174538', (112, 120))	('lower', 'NegReg', (174, 179))	('rs174538', 'Mutation', 'rs174538', (47, 55))	('patients', 'Species', '9606', (3, 11))	('FEN1 rs174538 GA/AA', 'Var', (107, 126))	('ESCC', 'Disease', (180, 184))
177842	28319330	Our multilevel logistic analysis indicated that a significantly decreased risk of ESCC was associated with the FEN1 rs174538 GA genotypes in patients aged under 63 years.	('rs174538', 'Mutation', 'rs174538', (116, 124))	('ESCC', 'Disease', (82, 86))	('FEN1', 'Gene', (111, 115))	('rs174538 GA', 'Var', (116, 127))	('patients', 'Species', '9606', (141, 149))	('decreased', 'NegReg', (64, 73))
177844	28319330	reported that mice homozygous for FEN1 knockout have an embryonic lethal phenotype, but FEN1 heterozygous knockout mice appear to be normal.23 In recent years, a group of researchers have constructed a transgenic mouse model carrying the E160D FEN1mutation, which frequently occurs in cancer.11 As stated above, missing FEN1 leads to the mutator phenotype and apoptotic DNA fragment damage, resulting in genomic instability, chronic inflammation, and the initiation of cancer.12The results of these reports demonstrate that FEN1 is a cancer susceptibility gene.	('FEN1', 'Gene', (524, 528))	('cancer', 'Disease', (534, 540))	('mice', 'Species', '10090', (14, 18))	('inflammation', 'Disease', 'MESH:D007249', (433, 445))	('cancer', 'Phenotype', 'HP:0002664', (534, 540))	('mouse', 'Species', '10090', (213, 218))	('initiation of cancer', 'Disease', 'MESH:D009369', (455, 475))	('cancer', 'Disease', (469, 475))	('E160D', 'Mutation', 'p.E160D', (238, 243))	('mice', 'Species', '10090', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (469, 475))	('cancer', 'Disease', (285, 291))	('initiation of cancer', 'Disease', (455, 475))	('inflammation', 'Disease', (433, 445))	('cancer', 'Disease', 'MESH:D009369', (534, 540))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('missing', 'Var', (312, 319))	('cancer', 'Disease', 'MESH:D009369', (469, 475))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
177845	28319330	Future studies could determine whether SNPs in FEN1 may modify cancer risk by affecting FEN1 expression and function.	('FEN1', 'Gene', (47, 51))	('affecting', 'Reg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('SNPs', 'Var', (39, 43))	('function', 'MPA', (108, 116))	('expression', 'MPA', (93, 103))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('modify', 'Reg', (56, 62))	('cancer', 'Disease', (63, 69))	('FEN1', 'Gene', (88, 92))
177846	28319330	Accumulating evidence reveals that genetic polymorphisms in gene promoter and 3'-UTR regions may affect transcriptional and posttranscriptional expression.24 Recent research has shown that FEN1 rs174538 G and 4150 G alleles can significantly reduce FEN1 messenger RNA expression in normal gastrointestinal tissues, and have been associated with additional gastrointestinal cancer risks compared to FEN1 rs174538A and 4150T alleles.25 In our study, when the FEN1 rs174538 GG homozygote genotype was used as the reference group, the GA genotype was associated with a borderline statistically significantly decreased ESCC risk.	('rs174538', 'Mutation', 'rs174538', (462, 470))	('decreased', 'NegReg', (604, 613))	('additional gastrointestinal cancer', 'Disease', 'MESH:D004067', (345, 379))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('rs174538', 'Mutation', 'rs174538', (403, 411))	('additional gastrointestinal cancer', 'Disease', (345, 379))	('ESCC', 'Disease', (614, 618))	('FEN1 rs174538', 'Var', (457, 470))	('decreased ESCC', 'Phenotype', 'HP:0025022', (604, 618))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (356, 379))	('rs174538', 'Mutation', 'rs174538', (194, 202))
177847	28319330	Previous studies have shown that the FEN1 rs174538G>A SNP located in the promoter region causes increased promoter activity.	('increased', 'PosReg', (96, 105))	('FEN1', 'Gene', (37, 41))	('rs174538G>A', 'Var', (42, 53))	('promoter activity', 'MPA', (106, 123))	('rs174538G>A', 'DBSNP_MENTION', 'None', (42, 53))
177850	28319330	In summary, our results suggest that the functional polymorphism FEN1 rs174538 G>A might affect personal susceptibility to ESCC.	('rs174538 G>A', 'Var', (70, 82))	('ESCC', 'Disease', (123, 127))	('FEN1', 'Gene', (65, 69))	('rs174538', 'Mutation', 'rs174538', (70, 78))	('affect', 'Reg', (89, 95))
177944	24406471	Genetic factors have been identified that clearly increase cancer risk, including Apc mutations that cause familial adenomatous polyposis and E-cadherin mutations that lead to hereditary diffuse-type gastric cancer.	('E-cadherin', 'Gene', (142, 152))	('cancer', 'Disease', (208, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('mutations', 'Var', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('Apc', 'Gene', (82, 85))	('Apc', 'Gene', '11789', (82, 85))	('cause', 'Reg', (101, 106))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('mutations', 'Var', (86, 95))	('lead to', 'Reg', (168, 175))	('gastric cancer', 'Disease', (200, 214))	('familial adenomatous polyposis', 'Disease', (107, 137))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (107, 137))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (116, 137))	('cancer', 'Disease', (59, 65))
177955	24406471	Risk is associated with H pylori strain, variations in host responses governed by genetic diversity, and/or specific interactions between host, microbial, and environmental determinants.	('H pylori', 'Disease', (24, 32))	('variations', 'Var', (41, 51))	('iron', 'Chemical', 'MESH:D007501', (162, 166))	('H pylori', 'Species', '210', (24, 32))	('interactions', 'Interaction', (117, 129))	('associated', 'Reg', (8, 18))
177958	24406471	H pylori strains that harbor the cag PAI (cag+ strains) are associated with a significantly increased risk of distal gastric cancer compared to cag- strains.	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('H pylori', 'Species', '210', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastric cancer', 'Disease', (117, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('cag PAI', 'Var', (33, 40))
177967	24406471	VacA causes a wide assortment of alterations in gastric epithelial cells, including vacuolation, altered plasma and mitochondrial membrane permeability, autophagy, and apoptotic cell death.	('death', 'Disease', (183, 188))	('autophagy', 'CPA', (153, 162))	('vacuolation', 'Disease', (84, 95))	('VacA', 'Var', (0, 4))	('death', 'Disease', 'MESH:D003643', (183, 188))
177969	24406471	Strains that contain type s1, i1 and m1 forms of vacA are associated with a higher risk of gastric cancer than strains that contain type s2, i2 and m2 forms.	('type s1', 'Var', (21, 28))	('gastric cancer', 'Disease', (91, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (91, 105))	('higher risk of gastric cancer', 'Phenotype', 'HP:0006753', (76, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
177977	24406471	Genetic ablation of parietal cells in Leb-expressing transgenic mice permits the gastric epithelial stem cell population to expand, which is accompanied by increased H pylori colonization and inflammation within glandular epithelium.	('gastric epithelial stem cell population', 'CPA', (81, 120))	('transgenic mice', 'Species', '10090', (53, 68))	('increased', 'PosReg', (156, 165))	('inflammation', 'Disease', 'MESH:D007249', (192, 204))	('inflammation', 'Disease', (192, 204))	('H pylori', 'Disease', (166, 174))	('H pylori', 'Species', '210', (166, 174))	('expand', 'PosReg', (124, 130))	('ablation', 'Var', (8, 16))
177984	24406471	Polymorphisms within the IL1beta gene cluster that increase IL1beta production are associated with significant increases in risk for hypochlorhydria, gastric atrophy, and distal gastric adenocarcinoma compared with low-expression IL1b genotypes.	('increase', 'PosReg', (51, 59))	('IL1b', 'Gene', '3553', (60, 64))	('hypochlorhydria', 'Disease', (133, 148))	('IL1b', 'Gene', (60, 64))	('IL1beta', 'Gene', (25, 32))	('IL1b', 'Gene', '3553', (230, 234))	('IL1beta', 'Gene', '3553', (60, 67))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (178, 200))	('Polymorphisms', 'Var', (0, 13))	('IL1b', 'Gene', '3553', (25, 29))	('gastric adenocarcinoma', 'Disease', (178, 200))	('gastric atrophy', 'Disease', (150, 165))	('hypochlorhydria', 'Disease', 'MESH:D000126', (133, 148))	('IL1b', 'Gene', (230, 234))	('gastric atrophy', 'Disease', 'MESH:D013274', (150, 165))	('IL1b', 'Gene', (25, 29))	('IL1beta', 'Gene', (60, 67))	('IL1beta', 'Gene', '3553', (25, 32))
177985	24406471	The presence of a virulent strain of H pylori in a genetically susceptible person further augments the risk for gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('gastric cancer', 'Disease', (112, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('person', 'Species', '9606', (75, 81))	('H pylori', 'Protein', (37, 45))	('augments', 'NegReg', (90, 98))	('presence', 'Var', (4, 12))	('H pylori', 'Species', '210', (37, 45))
177987	24406471	A recent genome-wide association study has identified new targets for studies of gastric carcinogenesis, demonstrating that TLR1 and FCGR2A loci are associated with H pylori sero-prevalence.	('H pylori', 'Disease', (165, 173))	('loci', 'Var', (140, 144))	('H pylori', 'Species', '210', (165, 173))	('associated', 'Reg', (149, 159))	('TLR1', 'Gene', (124, 128))	('gastric carcinogenesis', 'Disease', (81, 103))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (81, 103))	('FCGR2A', 'Gene', (133, 139))
177988	24406471	Dietary factors have recently been shown to accelerate gastric carcinogenesis in rodent models of H pylori infection; specifically iron depletion accelerates the development of gastric dysplasia and cancer by promoting assembly and function of the H pylori cag PAI.	('cancer', 'Disease', (199, 205))	('function', 'MPA', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('H pylori infection', 'Disease', 'MESH:D016481', (98, 116))	('promoting', 'PosReg', (209, 218))	('assembly', 'MPA', (219, 227))	('H pylori infection', 'Phenotype', 'HP:0005202', (98, 116))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('iron', 'Chemical', 'MESH:D007501', (131, 135))	('gastric dysplasia', 'Disease', (177, 194))	('H pylori', 'Species', '210', (98, 106))	('gastric dysplasia', 'Disease', 'MESH:D013274', (177, 194))	('gastric carcinogenesis', 'Disease', (55, 77))	('H pylori', 'Gene', (248, 256))	('H pylori', 'Species', '210', (248, 256))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (55, 77))	('H pylori infection', 'Disease', (98, 116))	('iron depletion', 'Var', (131, 145))	('accelerates', 'PosReg', (146, 157))
178008	24406471	Various H pylori wild-type and mutant strains colonize gerbils well, allowing an examination of the role of virulence determinants on parameters of gastric injury.	('gastric injury', 'Disease', (148, 162))	('mutant', 'Var', (31, 37))	('gastric injury', 'Disease', 'MESH:D013274', (148, 162))	('H pylori', 'Species', '210', (8, 16))	('H pylori', 'Gene', (8, 16))
178021	24406471	In gerbils that were challenged and successfully infected with H pylori, the relative abundance of Clostridium coccoides increased, compared to gerbils not infected with H pylori.	('Clostridium coccoides', 'Species', '1532', (99, 120))	('H pylori', 'Var', (63, 71))	('increased', 'PosReg', (121, 130))	('H pylori', 'Species', '210', (63, 71))	('infected', 'Reg', (49, 57))	('H pylori', 'Species', '210', (170, 178))
178022	24406471	In gerbils that were challenged with H pylori but were not successfully colonized, the proportion of C coccoides, C leptum, and Bifidobacterium was reduced.	('reduced', 'NegReg', (148, 155))	('H pylori', 'Var', (37, 45))	('Bifidobacterium', 'Species', '216816', (128, 143))	('H pylori', 'Species', '210', (37, 45))
178026	24406471	Bacteria other than Helicobacter species have been found to induce gastritis in mice:Acinetobacter lowffi can induce gastric inflammation in the absence of H pylori.	('gastric inflammation', 'Disease', 'MESH:D007249', (117, 137))	('gastritis', 'Phenotype', 'HP:0005263', (67, 76))	('Acinetobacter lowffi', 'Phenotype', 'HP:0032250', (85, 105))	('gastritis', 'Disease', (67, 76))	('Helicobacter', 'Species', '32025', (20, 32))	('Acinetobacter', 'Species', '28090', (85, 98))	('induce', 'Reg', (110, 116))	('gastritis', 'Disease', 'MESH:D005756', (67, 76))	('mice', 'Species', '10090', (80, 84))	('gastric inflammation', 'Disease', (117, 137))	('H pylori', 'Species', '210', (156, 164))	('gastric inflammation', 'Phenotype', 'HP:0005263', (117, 137))	('Acinetobacter', 'Var', (85, 98))
178036	24406471	demonstrated that germ-free INS-GAS mice mono-colonized with H pylori progress more slowly to gastric intraepithelial neoplasia than H pylori-infected specific pathogen-free (SPF) INS-GAS mice.	('mice', 'Species', '10090', (188, 192))	('H pylori', 'Species', '210', (133, 141))	('H pylori', 'Species', '210', (61, 69))	('slowly', 'NegReg', (84, 90))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (102, 127))	('neoplasia', 'Phenotype', 'HP:0002664', (118, 127))	('mice', 'Species', '10090', (36, 40))	('H pylori', 'Var', (61, 69))	('gastric intraepithelial neoplasia', 'Disease', 'MESH:D019048', (94, 127))	('gastric intraepithelial neoplasia', 'Disease', (94, 127))
178040	24406471	Another study demonstrated that progression to gastric neoplasia was similar in SPF INS-GAS mice infected with H pylori and germ-free INS-GAS mice first infected with a restricted Altered Schaedler's Flora (ASF): [ASF 356 (contains Clostridium species), ASF 361 (contains Lactobacillus murinus), and ASF 519 (contains Bacteroides species)], and then challenged with H pylori.	('H pylori', 'Species', '210', (366, 374))	('gastric neoplasia', 'Phenotype', 'HP:0006753', (47, 64))	('Lactobacillus murinus', 'Species', '1622', (272, 293))	('H pylori', 'Species', '210', (111, 119))	('mice', 'Species', '10090', (142, 146))	('neoplasia', 'Phenotype', 'HP:0002664', (55, 64))	('ASF 361', 'Species', '1235801', (254, 261))	('gastric neoplasia', 'Disease', 'MESH:D009369', (47, 64))	('gastric neoplasia', 'Disease', (47, 64))	('Clostridium', 'Species', '1532', (232, 243))	('[ASF 356', 'Var', (213, 221))	('Bacteroides', 'Species', '821', (318, 329))	('mice', 'Species', '10090', (92, 96))
178056	24406471	How can the ability of H pylori strains to increase risk for distal gastric cancer be reconciled with reciprocal effects against GERD, Barrett's esophagus, and esophageal adenocarcinoma?	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (160, 185))	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (135, 154))	('esophageal adenocarcinoma', 'Disease', (160, 185))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (160, 185))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gastric cancer', 'Disease', (68, 82))	('GERD', 'Disease', 'MESH:D005764', (129, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('GERD', 'Disease', (129, 133))	('H pylori', 'Species', '210', (23, 31))	('strains', 'Var', (32, 39))
178059	24406471	Other potential mechanisms include changes in gastric hormone interactions and in T-cell populations induced by the loss of H pylori.	('T-cell populations', 'CPA', (82, 100))	('gastric hormone', 'Protein', (46, 61))	('H pylori', 'Species', '210', (124, 132))	('interactions', 'Interaction', (62, 74))	('H pylori', 'Gene', (124, 132))	('changes', 'Reg', (35, 42))	('loss', 'Var', (116, 120))
178060	24406471	Another possibility is that alterations in the gastric microbiome resulting from the loss of H pylori contribute to an increase in reflux-mediated esophageal adenocarcinoma.	('loss', 'Var', (85, 89))	('alterations', 'Reg', (28, 39))	('H pylori', 'Gene', (93, 101))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (147, 172))	('H pylori', 'Species', '210', (93, 101))	('esophageal adenocarcinoma', 'Disease', (147, 172))	('increase', 'PosReg', (119, 127))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (147, 172))
178070	24406471	Activation of iNOS decreases the basal tone of the lower esophageal sphincter, which, over prolonged periods of time, increases the risk for reflux and its sequelae.	('esophageal sphincter', 'Disease', 'MESH:D009122', (57, 77))	('iNOS', 'Gene', (14, 18))	('reflux', 'MPA', (141, 147))	('increases', 'PosReg', (118, 127))	('Activation', 'Var', (0, 10))	('decreases', 'NegReg', (19, 28))	('esophageal sphincter', 'Disease', (57, 77))
178073	24406471	In contrast to a model that focused on interactions between different strains of H pylori and genetic features of the host, researchers must now consider an alternative model, in which early interactions between H pylori and human tissues alter the structure of the gastric microbiome, by promoting gastric atrophy.	('alter', 'Reg', (239, 244))	('H pylori', 'Species', '210', (212, 220))	('gastric atrophy', 'Disease', 'MESH:D013274', (299, 314))	('H pylori', 'Species', '210', (81, 89))	('promoting', 'PosReg', (289, 298))	('human', 'Species', '9606', (225, 230))	('interactions', 'Interaction', (191, 203))	('H pylori', 'Var', (212, 220))	('structure', 'MPA', (249, 258))	('gastric atrophy', 'Disease', (299, 314))
178075	24406471	Although less information is available about the effects of the microbiome on esophageal cancer, it is plausible that alterations of the gastric microbiome contribute to the increased incidence of esophageal adenocarcinomas:particularly those that arise within the gastroesophageal junction.	('alterations', 'Var', (118, 129))	('gastroesophageal junction', 'Disease', (265, 290))	('esophageal adenocarcinomas', 'Disease', (197, 223))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (265, 290))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (197, 222))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (197, 223))
178079	24406471	Colorectal cancer (CRC) is initiated by mutations in tumor suppressor genes (APC, CTNNB1, p53) and oncogenes (KRAS), which transform healthy mucosa to adenoma and cancer.	('p53', 'Gene', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('p53', 'Gene', '22060', (90, 93))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('APC', 'Disease', 'MESH:D011125', (77, 80))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('APC', 'Disease', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('adenoma', 'Disease', (151, 158))	('Colorectal cancer', 'Disease', (0, 17))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))	('initiated by', 'Reg', (27, 39))	('adenoma', 'Disease', 'MESH:D000236', (151, 158))	('CTNNB1', 'Gene', (82, 88))	('cancer', 'Disease', (163, 169))	('transform', 'Reg', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', (11, 17))
178088	24406471	Disturbances in the composition, distribution, or metabolism of the colon microbiota might shift the homeostatic environment of the colon towards inflammation, dysplasia, and cancer.	('inflammation', 'Disease', 'MESH:D007249', (146, 158))	('shift', 'Reg', (91, 96))	('dysplasia', 'Disease', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('inflammation', 'Disease', (146, 158))	('cancer', 'Disease', (175, 181))	('Disturbances', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('dysplasia', 'Disease', 'MESH:D004476', (160, 169))	('homeostatic environment', 'MPA', (101, 124))	('iron', 'Chemical', 'MESH:D007501', (116, 120))
178124	24406471	Several studies have associated colon neoplasias with genetic polymorphisms in, or changes in expression of, genes that control PRR pathways.	('genetic polymorphisms', 'Var', (54, 75))	('neoplasia', 'Phenotype', 'HP:0002664', (38, 47))	('neoplasias', 'Phenotype', 'HP:0002664', (38, 48))	('colon neoplasias', 'Disease', (32, 48))	('colon neoplasia', 'Phenotype', 'HP:0100273', (32, 47))	('expression', 'MPA', (94, 104))	('colon neoplasias', 'Disease', 'MESH:D009369', (32, 48))
178129	24406471	Although human studies have linked variants in bacterial recognition genes with CRC, there is no clear mechanism by which they alter colon cancer susceptibility.	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('variants', 'Var', (35, 43))	('CRC', 'Disease', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('human', 'Species', '9606', (9, 14))	('colon cancer', 'Disease', (133, 145))	('alter', 'Reg', (127, 132))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))
178130	24406471	Most of these studies have involved mice with disruptions of PRR pathway genes.	('PRR pathway genes', 'Gene', (61, 78))	('disruptions', 'Var', (46, 57))	('mice', 'Species', '10090', (36, 40))
178134	24406471	In mice, TLR4 deletion protects against CRC, whereas overexpression of TLR4 results in beta-catenin activation and increased colitis-associated cancer development following administration of azoxymethane (AOM, a mutagen) and dextran sulfate sodium (DSS, induces colitis).	('colitis-associated cancer', 'Disease', (125, 150))	('TLR4', 'Gene', (9, 13))	('beta-catenin', 'Gene', '12387', (87, 99))	('colitis-associated cancer', 'Disease', 'MESH:D003092', (125, 150))	('colitis', 'Phenotype', 'HP:0002583', (125, 132))	('dextran sulfate sodium', 'Chemical', 'MESH:D016264', (225, 247))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('beta-catenin', 'Gene', (87, 99))	('increased', 'PosReg', (115, 124))	('colitis', 'Disease', (262, 269))	('AOM', 'Chemical', 'MESH:D001397', (205, 208))	('deletion', 'Var', (14, 22))	('TLR4', 'Gene', (71, 75))	('azoxymethane', 'Chemical', 'MESH:D001397', (191, 203))	('colitis', 'Disease', 'MESH:D003092', (262, 269))	('mice', 'Species', '10090', (3, 7))	('colitis', 'Disease', (125, 132))	('CRC', 'Disease', (40, 43))	('CRC', 'Phenotype', 'HP:0003003', (40, 43))	('DSS', 'Chemical', 'MESH:D016264', (249, 252))	('colitis', 'Disease', 'MESH:D003092', (125, 132))	('activation', 'PosReg', (100, 110))	('colitis', 'Phenotype', 'HP:0002583', (262, 269))
178136	24406471	Loss of Myd88, an adapter that transduces most TLR signals, reduces tumor development in mice following administration of only AOM, but increases colitis-associated cancer in mice given AOM and DSS.	('tumor', 'Disease', (68, 73))	('Myd88', 'Gene', '17874', (8, 13))	('mice', 'Species', '10090', (175, 179))	('colitis-associated cancer', 'Disease', (146, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('mice', 'Species', '10090', (89, 93))	('AOM', 'Chemical', 'MESH:D001397', (186, 189))	('Myd88', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('AOM', 'Chemical', 'MESH:D001397', (127, 130))	('reduces', 'NegReg', (60, 67))	('DSS', 'Chemical', 'MESH:D016264', (194, 197))	('Loss', 'Var', (0, 4))	('colitis', 'Phenotype', 'HP:0002583', (146, 153))	('increases', 'PosReg', (136, 145))	('colitis-associated cancer', 'Disease', 'MESH:D003092', (146, 171))
178137	24406471	APCmin/+Myd88-/- mice develop fewer colon tumors than APCmin/+ mice, indicating that bacterial signaling contributes to tumorigenesis in the context of APC mutations.	('APC', 'Disease', 'MESH:D011125', (0, 3))	('APC', 'Disease', (0, 3))	('fewer', 'NegReg', (30, 35))	('APC', 'Disease', 'MESH:D011125', (54, 57))	('APC', 'Disease', (54, 57))	('tumor', 'Disease', (42, 47))	('Myd88', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (120, 125))	('mice', 'Species', '10090', (17, 21))	('mutations', 'Var', (156, 165))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('colon tumors', 'Disease', 'MESH:D015179', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Myd88', 'Gene', '17874', (8, 13))	('colon tumors', 'Phenotype', 'HP:0100273', (36, 48))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('colon tumors', 'Disease', (36, 48))	('APC', 'Disease', 'MESH:D011125', (152, 155))	('APC', 'Disease', (152, 155))
178138	24406471	A subsequent study found that MyD88-dependent activation of ERK stabilizes beta-catenin; in this way, the absence of MyD88 protects against APC-dependent tumors.	('APC-dependent tumors', 'Disease', 'MESH:D011125', (140, 160))	('beta-catenin', 'Gene', '12387', (75, 87))	('MyD88', 'Gene', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('APC-dependent tumors', 'Disease', (140, 160))	('ERK', 'Gene', '13844', (60, 63))	('absence', 'Var', (106, 113))	('ERK', 'Gene', (60, 63))	('beta-catenin', 'Gene', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
178144	24406471	Levels of IL23 and IL17 and tumor growth decrease after antibiotic treatment and deletion of Myd88.	('Levels', 'MPA', (0, 6))	('Myd88', 'Gene', (93, 98))	('tumor', 'Disease', (28, 33))	('growth decrease', 'Phenotype', 'HP:0001510', (34, 49))	('IL17', 'Gene', '16171', (19, 23))	('decrease', 'NegReg', (41, 49))	('deletion', 'Var', (81, 89))	('IL23', 'Gene', (10, 14))	('Myd88', 'Gene', '17874', (93, 98))	('IL17', 'Gene', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('IL23', 'Gene', '83430', (10, 14))
178149	24406471	This is in contrast to humans, in which APC mutations cause colonic tumors.	('APC', 'Disease', 'MESH:D011125', (40, 43))	('cause', 'Reg', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('APC', 'Disease', (40, 43))	('humans', 'Species', '9606', (23, 29))	('mutations', 'Var', (44, 53))	('colonic tumors', 'Disease', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('colonic tumors', 'Disease', 'MESH:D015179', (60, 74))
178151	24406471	Mice with disruptions in specific genes (Il10-/-, Tcrb/p53-/-, Gpx1/Gpx2-/-, and Tgfb1/Rag2-/-) develop fewer tumors under GF than conventional conditions, as do mice exposed to AOM and DSS.	('Tgfb1', 'Gene', '21803', (81, 86))	('Rag2', 'Gene', '19374', (87, 91))	('Tcrb', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('Gpx2', 'Gene', (68, 72))	('Mice', 'Species', '10090', (0, 4))	('Il10', 'Gene', '16153', (41, 45))	('disruptions', 'Var', (10, 21))	('Il10', 'Gene', (41, 45))	('Gpx2', 'Gene', '14776', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('Rag2', 'Gene', (87, 91))	('mice', 'Species', '10090', (162, 166))	('tumors', 'Disease', (110, 116))	('p53', 'Gene', (55, 58))	('Tgfb1', 'Gene', (81, 86))	('Gpx1', 'Gene', '14775', (63, 67))	('Tcrb', 'Gene', '21577', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('p53', 'Gene', '22060', (55, 58))	('AOM', 'Chemical', 'MESH:D001397', (178, 181))	('Gpx1', 'Gene', (63, 67))	('DSS', 'Chemical', 'MESH:D016264', (186, 189))	('fewer', 'NegReg', (104, 109))
178154	24406471	However mono-association with Bacteroides vulgatus reduced colorectal tumorigenesis in Il10-/- mice, compared to conventional Il10-/- mice.	('mono-association', 'Var', (8, 24))	('colorectal tumor', 'Disease', 'MESH:D015179', (59, 75))	('mice', 'Species', '10090', (134, 138))	('reduced', 'NegReg', (51, 58))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Il10', 'Gene', (126, 130))	('Bacteroides', 'Gene', (30, 41))	('Il10', 'Gene', (87, 91))	('colorectal tumor', 'Disease', (59, 75))	('Il10', 'Gene', '16153', (126, 130))	('Il10', 'Gene', '16153', (87, 91))	('Bacteroides vulgatus', 'Species', '821', (30, 50))
178171	24406471	Deletion of the pathogenicity island reduced the rate of invasive tumors but did not change the level of inflammation caused by this E coli strain.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('inflammation', 'Disease', 'MESH:D007249', (105, 117))	('E coli', 'Species', '562', (133, 139))	('invasive tumors', 'Disease', (57, 72))	('inflammation', 'Disease', (105, 117))	('invasive tumors', 'Disease', 'MESH:D009369', (57, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('reduced', 'NegReg', (37, 44))	('Deletion', 'Var', (0, 8))
178180	24406471	Development of CRC involves a combination of inherited and acquired mutations in colonic epithelial cells, along with environmental factors including the intestinal microbiota.	('mutations', 'Var', (68, 77))	('iron', 'Chemical', 'MESH:D007501', (121, 125))	('CRC', 'Phenotype', 'HP:0003003', (15, 18))	('CRC', 'Disease', (15, 18))
178221	20541628	The presence of nodularity in the setting of BE is associated with increased risk of coexistent carcinoma and should be targeted for EMR.	('coexistent', 'Disease', (85, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('nodularity', 'Var', (16, 26))	('carcinoma', 'Disease', (96, 105))	('BE', 'Chemical', 'MESH:D001608', (45, 47))	('carcinoma', 'Disease', 'MESH:D002277', (96, 105))
178276	20541628	The Wiesbaden group has shown that patients with sm1 EAC may be considered for endoscopic resection if the cancers are low grade and do not demonstrate lymphovascular infiltration.	('sm1 EAC', 'Var', (49, 56))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (35, 43))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
178367	20454494	Oda et al., in a multicenter retrospective study of early gastric cancer, observed the incidence of perforation with ESD (3.6%; 11/303) to be significantly higher than that with EMR (1.2%; 5/411).	('gastric cancer', 'Phenotype', 'HP:0012126', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('perforation', 'Disease', (100, 111))	('gastric cancer', 'Disease', (58, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (58, 72))	('ESD', 'Var', (117, 120))
178444	32633082	 LINC00662 promotes cell viability and metastasis in esophageal squamous cell carcinoma by sponging miR-340-5p and upregulating HOXB2 Previous studies have shown that lncRNA LINC00662 plays an important role in pathogenesis of malignancies.	('LINC00662', 'Gene', '148189', (174, 183))	('metastasis', 'CPA', (39, 49))	('LINC00662', 'Gene', (174, 183))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (53, 87))	('sponging', 'Var', (91, 99))	('upregulating', 'PosReg', (115, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('miR-340-5p', 'Chemical', '-', (100, 110))	('HOXB2', 'Gene', '3212', (128, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 87))	('promotes', 'PosReg', (11, 19))	('LINC00662', 'Gene', '148189', (1, 10))	('HOXB2', 'Gene', (128, 133))	('esophageal squamous cell carcinoma', 'Disease', (53, 87))	('LINC00662', 'Gene', (1, 10))	('cell viability', 'CPA', (20, 34))	('miR-340', 'Gene', (100, 107))	('miR-340', 'Gene', '442908', (100, 107))	('malignancies', 'Disease', 'MESH:D009369', (227, 239))	('malignancies', 'Disease', (227, 239))
178450	32633082	For example, silencing of lncRNA SNHG6 inhibited ESCC progression via miR-186/HIF1alpha axis.	('miR-186', 'Gene', (70, 77))	('inhibited', 'NegReg', (39, 48))	('HIF1alpha', 'Gene', '3091', (78, 87))	('SNHG6', 'Gene', '641638', (33, 38))	('ESCC', 'Disease', (49, 53))	('SNHG6', 'Gene', (33, 38))	('HIF1alpha', 'Gene', (78, 87))	('miR-186', 'Gene', '406962', (70, 77))	('silencing', 'Var', (13, 22))
178454	32633082	8 ,  9  Functionally, LINC00662-miR-15b-5p mediated GPR120 dysregulation contributed to osteoarthritis., 10  and lncRNA LINC00662 was found to promote colon cancer tumor growth and metastasis by competitively binding with miR-340-5p to regulate CLDN8 expression.	('binding', 'Interaction', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CLDN8', 'Gene', '9073', (245, 250))	('miR-15b', 'Gene', (32, 39))	('expression', 'MPA', (251, 261))	('osteoarthritis', 'Disease', (88, 102))	('promote', 'PosReg', (143, 150))	('colon cancer tumor', 'Disease', (151, 169))	('miR-15b', 'Gene', '406949', (32, 39))	('colon cancer tumor', 'Disease', 'MESH:D015179', (151, 169))	('colon cancer', 'Phenotype', 'HP:0003003', (151, 163))	('osteoarthritis', 'Disease', 'MESH:D010003', (88, 102))	('GPR120', 'Gene', '338557', (52, 58))	('GPR120', 'Gene', (52, 58))	('metastasis', 'CPA', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('LINC00662', 'Var', (120, 129))	('CLDN8', 'Gene', (245, 250))
178455	32633082	11  miR-340 has been reported to inhibit ESCC cell growth and invasion by targeting phosphoserine aminotransferase 1.	('targeting', 'Reg', (74, 83))	('miR-340', 'Var', (4, 11))	('inhibit', 'NegReg', (33, 40))	('phosphoserine aminotransferase 1', 'Gene', '29968', (84, 116))	('ESCC', 'Disease', (41, 45))	('invasion', 'CPA', (62, 70))	('phosphoserine aminotransferase 1', 'Gene', (84, 116))
178456	32633082	In this study, Homeobox B2 (HOXB2) was predicted to be a potential target for miR-340-5p.	('miR-340-5p', 'Var', (78, 88))	('Homeobox B2', 'Gene', (15, 26))	('Homeobox B2', 'Gene', '3212', (15, 26))
178468	32633082	The 3'-UTR of wild-type or mutant LINC00662 and HOXB2 was inserted into the pGL3 promoter vector (Invitrogen, USA).	('pGL3', 'Gene', (76, 80))	('pGL3', 'Gene', '6391', (76, 80))	('LINC00662', 'Gene', (34, 43))	('mutant', 'Var', (27, 33))
178477	32633082	20 ,  21  Functionally, LINC00662 functioned as an miRNA sponge to promote the prostate cancer tumorigenesis through targeting miR-34a, 22  and LINC00662 was also found to promote proliferation and migration in oral squamous cell carcinoma.	('LINC00662', 'Var', (144, 153))	('oral squamous cell carcinoma', 'Disease', (211, 239))	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('proliferation', 'CPA', (180, 193))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('migration', 'CPA', (198, 207))	('promote', 'PosReg', (172, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('miR-34a', 'Gene', (127, 134))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (211, 239))	('miR-34a', 'Gene', '407040', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('prostate cancer', 'Disease', (79, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (216, 239))	('promote', 'PosReg', (67, 74))
178480	30819240	Evaluation of preoperative risk factors and postoperative indicators for anastomotic leak of minimally invasive McKeown esophagectomy: a single-center retrospective analysis Minimally invasive McKeown esophagectomy is an important surgical approach for esophageal cancer.	('Minimally', 'Var', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('esophageal cancer', 'Disease', (253, 270))	('anastomotic leak', 'Disease', 'MESH:D057868', (73, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (253, 270))	('anastomotic leak', 'Disease', (73, 89))
178606	29375745	In addition, vitamin D was shown to increase interleukin-4 cytokine production, which has been implicated in BE.	('interleukin-4', 'Gene', (45, 58))	('interleukin-4', 'Gene', '3565', (45, 58))	('vitamin D', 'Chemical', 'MESH:D014807', (13, 22))	('increase', 'PosReg', (36, 44))	('BE', 'Phenotype', 'HP:0100580', (109, 111))	('vitamin', 'Var', (13, 20))	('increase interleukin-', 'Phenotype', 'HP:0030783', (36, 57))
178609	29375745	More than 50 vitamin D metabolites have been identified over the past years but only two gained particular attention: 1alpha,25(OH)2D3 and 25(OH)D3.	('1alpha,25(OH)2D3', 'Var', (118, 134))	('vitamin D', 'Chemical', 'MESH:D014807', (13, 22))	('25(OH)D3', 'Chemical', 'MESH:D002112', (139, 147))	('25(OH)D3', 'Var', (139, 147))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (118, 134))
178636	29375745	An association between SNPs in the genes involved in vitamin D pathway and ESCC was also evaluated: Wang et al investigated 12 SNPs in four genes known to be part of the vitamin D pathway: vitamin D binding protein, 7-dehydrocholesterol reductase, 25-hydroxylase and 24-hydroxylase or CYP24A1.	('CYP24A1', 'Gene', (285, 292))	('vitamin D', 'Chemical', 'MESH:D014807', (189, 198))	('vitamin D', 'Chemical', 'MESH:D014807', (170, 179))	('CYP24A1', 'Gene', '1591', (285, 292))	('SNPs', 'Var', (127, 131))	('vitamin D', 'Chemical', 'MESH:D014807', (53, 62))
178665	29375745	Data from animal models have shown that dietary vitamin D is associated with tumor inhibition and reduction of tumor growth, especially in colorectal cancer and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('vitamin D', 'Chemical', 'MESH:D014807', (48, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('colorectal cancer', 'Disease', 'MESH:D015179', (139, 156))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('breast cancer', 'Disease', (161, 174))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('dietary', 'Var', (40, 47))	('reduction', 'NegReg', (98, 107))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (139, 156))	('tumor', 'Disease', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colorectal cancer', 'Disease', (139, 156))
178684	29375745	Variants in the VDR gene were explored and TT homozygotes at rs2238139 and rs2107301 SNPs seemed to have a reduced risk of EAC compared to individual with CC alleles at those sites (OR = 0.26, 95%CI: 0.007, 0.93 and OR = 0.19, 95%CI: 0.06-0.67, respectively).	('rs2107301', 'Mutation', 'rs2107301', (75, 84))	('EAC', 'Phenotype', 'HP:0011459', (123, 126))	('VDR', 'Gene', (16, 19))	('rs2238139', 'Mutation', 'rs2238139', (61, 70))	('reduced', 'NegReg', (107, 114))	('rs2238139', 'Var', (61, 70))	('EAC', 'Gene', '1540', (123, 126))	('EAC', 'Gene', (123, 126))	('VDR', 'Gene', '7421', (16, 19))	('rs2107301 SNPs', 'Var', (75, 89))
178686	29375745	A later study identified two SNPs of the VDR gene associated with reduced risk of reflux esophagitis, BE and EAC.	('esophagitis', 'Phenotype', 'HP:0100633', (89, 100))	('reduced', 'NegReg', (66, 73))	('VDR', 'Gene', '7421', (41, 44))	('SNPs', 'Var', (29, 33))	('EAC', 'Phenotype', 'HP:0011459', (109, 112))	('EAC', 'Gene', '1540', (109, 112))	('reflux esophagitis', 'Disease', (82, 100))	('reflux esophagitis', 'Disease', 'MESH:D005764', (82, 100))	('EAC', 'Gene', (109, 112))	('VDR', 'Gene', (41, 44))	('BE', 'Phenotype', 'HP:0100580', (102, 104))
178687	29375745	Patients with the rs1989969 T/rs2238135 G haplotype had a lower risk for reflux esophagitis (OR = 0.48, 95%CI: 0.28-0.81), BE (OR 0.46, 95%CI: 0.26-0.80) as well as EAC (OR = 0.50, 95%CI: 0.27-0.96).	('EAC', 'Gene', (165, 168))	('lower', 'NegReg', (58, 63))	('rs2238135', 'Mutation', 'rs2238135', (30, 39))	('rs1989969', 'Mutation', 'rs1989969', (18, 27))	('esophagitis', 'Phenotype', 'HP:0100633', (80, 91))	('EAC', 'Gene', '1540', (165, 168))	('EAC', 'Phenotype', 'HP:0011459', (165, 168))	('Patients', 'Species', '9606', (0, 8))	('rs1989969 T/rs2238135 G', 'Var', (18, 41))	('reflux esophagitis', 'Disease', 'MESH:D005764', (73, 91))	('BE', 'Phenotype', 'HP:0100580', (123, 125))	('reflux esophagitis', 'Disease', (73, 91))
178689	29375745	The authors studied the mechanism by which those SNPs work and discovered that the rs1989969 T allele lead to the appearance of a GATA-1 transcription factor binding site, which is known to be a negative transcriptional regulator.	('GATA-1', 'Gene', '2623', (130, 136))	('rs1989969', 'Mutation', 'rs1989969', (83, 92))	('GATA-1', 'Gene', (130, 136))	('rs1989969 T', 'Var', (83, 94))	('binding', 'Interaction', (158, 165))
178730	28861777	After transection of the left sternocleidomastoid muscle, the tumor was easily identified (Fig.	('sternocleidomastoid muscle', 'Phenotype', 'HP:0012036', (30, 56))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('transection', 'Var', (6, 17))	('left sternocleidomastoid muscle', 'Disease', (25, 56))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('left sternocleidomastoid muscle', 'Disease', 'MESH:C535977', (25, 56))
178795	26317542	To further explore the novel mechanisms of ABT-263, proteomic array (RPPAs) were performed and gene set enriched analysis demonstrated that ABT-263 suppresses the expression of many oncogenes including genes that govern stemness pathways.	('suppresses', 'NegReg', (148, 158))	('stemness', 'CPA', (220, 228))	('ABT-263', 'Chemical', 'MESH:C528561', (43, 50))	('ABT-263', 'Chemical', 'MESH:C528561', (140, 147))	('expression', 'MPA', (163, 173))	('ABT-263', 'Var', (140, 147))	('oncogenes', 'Protein', (182, 191))
178797	26317542	Furthermore, ABT263 strongly suppresses cancer stem cell properties in EC cells and the combination of ABT-263 and 5-FU significantly reduced tumor growth in vivo and suppresses the expression of stemness genes.	('ABT-263', 'Var', (103, 110))	('ABT263', 'Var', (13, 19))	('suppresses', 'NegReg', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('EC', 'Phenotype', 'HP:0011459', (71, 73))	('stemness', 'CPA', (196, 204))	('expression', 'MPA', (182, 192))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', (142, 147))	('suppresses', 'NegReg', (167, 177))	('cancer', 'Disease', (40, 46))	('ABT263', 'Chemical', 'MESH:C528561', (13, 19))	('reduced', 'NegReg', (134, 141))	('5-FU', 'Chemical', 'MESH:D005472', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('ABT-263', 'Chemical', 'MESH:C528561', (103, 110))	('combination', 'Var', (88, 99))
178812	26317542	Dysregulation of CSC signaling like Hippo/YAP1, Wnt/beta-catenin, and hedgehog (Hh) have been implicated in the maintenance of tumor and in conferring therapy resistance.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('therapy resistance', 'CPA', (151, 169))	('Hippo/YAP1', 'Gene', (36, 46))	('beta-catenin', 'Gene', (52, 64))	('tumor', 'Disease', (127, 132))	('Dysregulation', 'Var', (0, 13))	('beta-catenin', 'Gene', '1499', (52, 64))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('CSC', 'MPA', (17, 20))	('implicated', 'Reg', (94, 104))
178820	26317542	Thus we explored the effects of ABT-263 alone or combined with 5-FU on a variety of EC cell lines and demonstrated that ABT-263 with 5-FU synergistically enhances the sensitivity and bolsters apoptosis in EC cells and their therapy resistant counterparts.	('5-FU', 'Chemical', 'MESH:D005472', (133, 137))	('EC', 'Phenotype', 'HP:0011459', (84, 86))	('ABT-263', 'Chemical', 'MESH:C528561', (32, 39))	('sensitivity', 'CPA', (167, 178))	('5-FU', 'Chemical', 'MESH:D005472', (63, 67))	('bolsters apoptosis', 'CPA', (183, 201))	('ABT-263', 'Chemical', 'MESH:C528561', (120, 127))	('enhances', 'PosReg', (154, 162))	('ABT-263', 'Var', (120, 127))	('EC', 'Phenotype', 'HP:0011459', (205, 207))
178825	26317542	Most interestingly, when ABT-263 combined with 5-FU, the inhibitory effect was significantly enhanced in six EC cell lines (Figure 1C and Supplementary Figure S3) indicating the synergy between ABT263 and 5-FU.	('ABT263', 'Chemical', 'MESH:C528561', (194, 200))	('EC', 'Phenotype', 'HP:0011459', (109, 111))	('inhibitory effect', 'MPA', (57, 74))	('combined', 'Interaction', (33, 41))	('enhanced', 'PosReg', (93, 101))	('5-FU', 'Chemical', 'MESH:D005472', (205, 209))	('ABT-263', 'Chemical', 'MESH:C528561', (25, 32))	('ABT-263', 'Var', (25, 32))	('5-FU', 'Chemical', 'MESH:D005472', (47, 51))
178831	26317542	However, the combination of ABT-263 and 5-FU resulted in significant increase in sub-G1 phase (apoptosis) indicating that ABT-263 promotes apoptosis in tumor cells arrested in S-phase (containing DNA damage).	('ABT-263', 'Gene', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('increase', 'PosReg', (69, 77))	('arrest', 'Disease', (164, 170))	('promotes', 'PosReg', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('apoptosis', 'CPA', (139, 148))	('tumor', 'Disease', (152, 157))	('5-FU', 'Var', (40, 44))	('arrest', 'Disease', 'MESH:D006323', (164, 170))	('ABT-263', 'Chemical', 'MESH:C528561', (122, 129))	('ABT-263', 'Gene', (122, 129))	('5-FU', 'Chemical', 'MESH:D005472', (40, 44))	('sub-G1 phase', 'CPA', (81, 93))	('ABT-263', 'Chemical', 'MESH:C528561', (28, 35))
178837	26317542	To decipher the novel mechanisms by which ABT-263 enhance the sensitivity of 5-FU in EC cells, we performed RPPA to evaluate 175 proteins expression on EC cells treated with ABT-263 (1 muM) for 48 hours.	('ABT-263', 'Var', (42, 49))	('muM', 'Gene', '56925', (185, 188))	('5-FU', 'Chemical', 'MESH:D005472', (77, 81))	('EC', 'Phenotype', 'HP:0011459', (85, 87))	('muM', 'Gene', (185, 188))	('ABT-263', 'Chemical', 'MESH:C528561', (174, 181))	('sensitivity of 5-FU', 'MPA', (62, 81))	('enhance', 'PosReg', (50, 57))	('ABT-263', 'Chemical', 'MESH:C528561', (42, 49))	('EC', 'Phenotype', 'HP:0011459', (152, 154))
178839	26317542	The quantitative analysis showed a decrease in PI3K/mTOR, survival and stemness signaling (Figure 4B), but the pro-apoptosis and tumor suppressive molecules were up-regulated in ABT-263 treated cells (Figure 4C).	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('stemness signaling', 'CPA', (71, 89))	('up-regulated', 'PosReg', (162, 174))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('survival', 'CPA', (58, 66))	('decrease', 'NegReg', (35, 43))	('ABT-263', 'Chemical', 'MESH:C528561', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ABT-263', 'Var', (178, 185))	('pro-apoptosis', 'CPA', (111, 124))	('tumor', 'Disease', (129, 134))
178857	26317542	Resulted in Figure 6E and Supplementary Figure S2 have shown that the combination of 5-FU and ABT263 led to a significantly decrease in both ALDH1+ and ALDH- cell growth and preferentially inhibition of ALDH1+ cells; while ABT263 or 5-FU alone has minimal effects.	('ABT263', 'Chemical', 'MESH:C528561', (94, 100))	('ALDH1', 'Gene', (141, 146))	('5-FU', 'Chemical', 'MESH:D005472', (233, 237))	('ALDH1', 'Gene', '216', (203, 208))	('5-FU', 'Chemical', 'MESH:D005472', (85, 89))	('ALDH1', 'Gene', '216', (141, 146))	('ABT263', 'Chemical', 'MESH:C528561', (223, 229))	('ABT263', 'Var', (94, 100))	('ALDH- cell growth', 'CPA', (152, 169))	('decrease', 'NegReg', (124, 132))	('combination', 'Interaction', (70, 81))	('ALDH1', 'Gene', (203, 208))	('inhibition', 'NegReg', (189, 199))	('5-FU', 'Var', (85, 89))
178858	26317542	Intriguingly, when SKGT4 (PIN20YAP1, an inducible YAP1 construct) cells with (DOX+) or without (DOX-) induction of YAP-1 and treated with ABT263, 5-FU, or in combination, results in Figure 6F demonstrat that ABT263 alone preferentially inhibited YAP-1 high SKGT-4 cells (DOX+) compared to cells without YAP-1 induction (DOX-) and the combination of ABT263 plus 5-FU produced greatest inhibition on YAP-1 induced SKGT-4 cells.	('SKGT-4', 'CellLine', 'CVCL:2195', (257, 263))	('ABT263', 'Chemical', 'MESH:C528561', (138, 144))	('ABT263', 'Chemical', 'MESH:C528561', (208, 214))	('inhibited', 'NegReg', (236, 245))	('5-FU', 'Chemical', 'MESH:D005472', (146, 150))	('5-FU', 'Chemical', 'MESH:D005472', (361, 365))	('YAP-1', 'Gene', (115, 120))	('DOX', 'Chemical', '-', (78, 81))	('YAP-1', 'Gene', '10413', (398, 403))	('ABT263', 'Var', (208, 214))	('ABT263', 'Chemical', 'MESH:C528561', (349, 355))	('YAP-1', 'Gene', '10413', (303, 308))	('SKGT-4', 'CellLine', 'CVCL:2195', (412, 418))	('YAP-1', 'Gene', '10413', (246, 251))	('DOX', 'Chemical', '-', (320, 323))	('YAP-1', 'Gene', (398, 403))	('YAP-1', 'Gene', (303, 308))	('YAP-1', 'Gene', (246, 251))	('DOX', 'Chemical', '-', (271, 274))	('DOX', 'Chemical', '-', (96, 99))	('YAP-1', 'Gene', '10413', (115, 120))
178861	26317542	This indicates that ABT263 and its combination with 5-FU preferentially inhibits YAP-1 high cell growth due to the suppression of the YAP-1/SOX9 axis.	('YAP-1', 'Gene', '10413', (134, 139))	('YAP-1', 'Gene', (81, 86))	('YAP-1', 'Gene', '10413', (81, 86))	('YAP-1', 'Gene', (134, 139))	('suppression', 'NegReg', (115, 126))	('5-FU', 'Chemical', 'MESH:D005472', (52, 56))	('inhibits', 'NegReg', (72, 80))	('ABT263', 'Chemical', 'MESH:C528561', (20, 26))	('ABT263', 'Var', (20, 26))
178864	26317542	Results from in vivo experiments demonstrated that mice treated with ABT-263 greatly reduced tumor volume and weight in vivo, while the mice treated with ABT-263 in combination with 5-FU, the significant reduction of tumor weights and tumor volumes were observed compared with 5-FU alone (Figure 7A and 7B), while mice body weights did not change significantly.	('reduction', 'NegReg', (204, 213))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Disease', (217, 222))	('mice', 'Species', '10090', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('mice', 'Species', '10090', (314, 318))	('ABT-263', 'Var', (69, 76))	('reduced', 'NegReg', (85, 92))	('ABT-263', 'Chemical', 'MESH:C528561', (69, 76))	('5-FU', 'Chemical', 'MESH:D005472', (277, 281))	('mice', 'Species', '10090', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (93, 98))	('5-FU', 'Chemical', 'MESH:D005472', (182, 186))	('tumor', 'Disease', (235, 240))	('ABT-263', 'Chemical', 'MESH:C528561', (154, 161))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
178871	26317542	EC cell lines and their resistant counterparts when treated with ABT-263, 5-FU, or both demonstrated that there was some dose-dependent effect of single drugs; but combination considerably reduced cell viability by enhancing apoptosis.	('combination', 'Var', (164, 175))	('enhancing', 'PosReg', (215, 224))	('apoptosis', 'CPA', (225, 234))	('reduced', 'NegReg', (189, 196))	('EC', 'Phenotype', 'HP:0011459', (0, 2))	('cell viability', 'CPA', (197, 211))	('ABT-263', 'Chemical', 'MESH:C528561', (65, 72))	('5-FU', 'Chemical', 'MESH:D005472', (74, 78))
178878	26317542	GSEA analysis our RPPA results show that CSC stemness pathways and PI3K/mTOR pathways were inhibited, while proapoptosis and tumor suppressive genes were induced by ABT-263.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('GSEA', 'Chemical', '-', (0, 4))	('mTOR', 'Gene', '2475', (72, 76))	('CSC stemness', 'CPA', (41, 53))	('inhibited', 'NegReg', (91, 100))	('mTOR', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('proapoptosis', 'CPA', (108, 120))	('ABT-263', 'Chemical', 'MESH:C528561', (165, 172))	('ABT-263', 'Var', (165, 172))	('induced', 'PosReg', (154, 161))
178879	26317542	More impressively CSCs have the capacity to repopulate tumors and drive malignant progression and mediate radio- and chemoresistance and dysregulation of CSC signaling like Hippo/YAP1, Wnt/beta-catenin have been implicated in the maintenance of CSC population and confers therapy resistance.	('dysregulation', 'Var', (137, 150))	('beta-catenin', 'Gene', (189, 201))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('beta-catenin', 'Gene', '1499', (189, 201))	('radio-', 'CPA', (106, 112))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('malignant progression', 'CPA', (72, 93))
178881	26317542	In this study, we identified for the first time that ABT263 suppress nuclear expression of YAP-1 and its target SOX9; and inhibits their transcription activity as shown by transfection of YAP-1 and SOX9 promoter activity.	('YAP-1', 'Gene', '10413', (91, 96))	('inhibits', 'NegReg', (122, 130))	('YAP-1', 'Gene', '10413', (188, 193))	('YAP-1', 'Gene', (91, 96))	('ABT263', 'Chemical', 'MESH:C528561', (53, 59))	('YAP-1', 'Gene', (188, 193))	('suppress', 'NegReg', (60, 68))	('ABT263', 'Var', (53, 59))	('transcription activity', 'MPA', (137, 159))	('nuclear expression', 'MPA', (69, 87))
178883	26317542	Similarly, ABT263 was able to decrease beta-catenin and its target CyclinD1 expression and their activity reflected by Super-TOP activity.	('ABT263', 'Var', (11, 17))	('CyclinD1', 'Gene', (67, 75))	('activity', 'MPA', (97, 105))	('decrease', 'NegReg', (30, 38))	('expression', 'MPA', (76, 86))	('beta-catenin', 'Gene', (39, 51))	('CyclinD1', 'Gene', '595', (67, 75))	('beta-catenin', 'Gene', '1499', (39, 51))	('ABT263', 'Chemical', 'MESH:C528561', (11, 17))
178884	26317542	Most importantly, ABT263 reduced CSC population and tumor sphere formation.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('ABT263', 'Chemical', 'MESH:C528561', (18, 24))	('reduced', 'NegReg', (25, 32))	('tumor', 'Disease', (52, 57))	('ABT263', 'Var', (18, 24))	('CSC population', 'CPA', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
178885	26317542	We show that ABT-263 could reduce the CSC population, as noted ABT263 preferentially inhibits ALDH1 positive EC cells tumor sphere formation and decrease the proportion of ALDH1 positive cell population.	('ALDH1', 'Gene', (172, 177))	('inhibits', 'NegReg', (85, 93))	('ABT263', 'Chemical', 'MESH:C528561', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('ALDH1', 'Gene', '216', (172, 177))	('ABT263', 'Var', (63, 69))	('ALDH1', 'Gene', (94, 99))	('EC', 'Phenotype', 'HP:0011459', (109, 111))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('ALDH1', 'Gene', '216', (94, 99))	('tumor', 'Disease', (118, 123))	('ABT-263', 'Chemical', 'MESH:C528561', (13, 20))	('decrease', 'NegReg', (145, 153))
178892	26317542	The synergistic effects of ABT-263 and 5-FU rely on inhibiting CSC signaling components mainly on YAP-1/SOX9 axis and Wnt/beta-catenin signaling in addition to its canonical targets (BCL-2) (Figure 7E).	('YAP-1', 'Gene', (98, 103))	('beta-catenin', 'Gene', '1499', (122, 134))	('inhibiting', 'NegReg', (52, 62))	('5-FU', 'Chemical', 'MESH:D005472', (39, 43))	('5-FU', 'Var', (39, 43))	('CSC signaling components', 'MPA', (63, 87))	('BCL-2', 'Gene', '596', (183, 188))	('BCL-2', 'Gene', (183, 188))	('beta-catenin', 'Gene', (122, 134))	('ABT-263', 'Chemical', 'MESH:C528561', (27, 34))	('ABT-263', 'Gene', (27, 34))	('YAP-1', 'Gene', '10413', (98, 103))
178993	25488897	Erosive esophagitis was seen in several subjects with (35%, 17% LA Grade B, C) and without reflux symptoms (23%, 10% LA grade B, C).	('LA Grade B', 'Var', (64, 74))	('esophagitis', 'Disease', (8, 19))	('esophagitis', 'Phenotype', 'HP:0100633', (8, 19))	('reflux symptoms', 'Phenotype', 'HP:0002020', (91, 106))	('esophagitis', 'Disease', 'MESH:D004941', (8, 19))
179005	25488897	Although a substantial majority of patients who underwent muTNE and huTNE were willing to undergo the test again in future if necessary (78.9% and 83.3%, respectively), acceptability of sEGD was significantly higher (93.4%, p=0.001).	('acceptability', 'MPA', (169, 182))	('muTNE', 'Var', (58, 63))	('higher', 'PosReg', (209, 215))	('muTNE', 'Chemical', '-', (58, 63))	('patients', 'Species', '9606', (35, 43))	('huTNE', 'Chemical', '-', (68, 73))
179009	25488897	Despite this, an important finding of our study was the reduction in recovery and overall patient visit duration achieved by using the muTNE and huTNE techniques compared to sEGD, without any substantial decrement in yield, tolerability and safety.	('muTNE', 'Chemical', '-', (135, 140))	('muTNE', 'Var', (135, 140))	('huTNE', 'Chemical', '-', (145, 150))	('patient', 'Species', '9606', (90, 97))	('recovery', 'MPA', (69, 77))	('reduction', 'NegReg', (56, 65))
179012	25488897	This was lower in the muTNE (79%) and huTNE (83.3%) groups compared to sEGD (100%) (p=0.001), primarily due to inability to intubate the esophagus with the larger biopsy sheath.	('huTNE', 'Chemical', '-', (38, 43))	('muTNE', 'Var', (22, 27))	('muTNE', 'Chemical', '-', (22, 27))	('lower', 'NegReg', (9, 14))
179031	23525727	We also observed the colocalization of p65-NLS and APE-1 in esophageal cancer tissue.	('APE-1', 'Gene', (51, 56))	('APE-1', 'Gene', '328', (51, 56))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('p65-NLS', 'Var', (39, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
179032	23525727	In KYSE220 cells, pretreatment of MG-132 significantly abrogated upregulation of p65 and APE-1 levels induced by MCP-1, and treatment with 10 and 20 nM p65 siRNA significantly inhibited APE-1 mRNA expression.	('abrogated', 'NegReg', (55, 64))	('inhibited', 'NegReg', (176, 185))	('upregulation', 'PosReg', (65, 77))	('MG-132', 'Gene', (34, 40))	('APE-1', 'Gene', (186, 191))	('mRNA expression', 'MPA', (192, 207))	('APE-1', 'Gene', '328', (186, 191))	('p65', 'Var', (152, 155))	('MG-132', 'Chemical', 'MESH:C072553', (34, 40))	('APE-1', 'Gene', (89, 94))	('APE-1', 'Gene', '328', (89, 94))
179033	23525727	siRNA for p65 treatment significantly increased the apoptotic index in 5-FU-treated KYSE220 cells.	('increased', 'PosReg', (38, 47))	('5-FU', 'Chemical', 'MESH:D005472', (71, 75))	('apoptotic index', 'CPA', (52, 67))	('p65', 'Var', (10, 13))
179034	23525727	We conclude that APE-1 is overexpressed and mainly localized in the nuclear compartment of cancer cells, and partly regulated by p65 in the NF-kappaB pathway in ESCC tissue.	('APE-1', 'Gene', (17, 22))	('APE-1', 'Gene', '328', (17, 22))	('NF-kappaB', 'Gene', '4790', (140, 149))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('NF-kappaB', 'Gene', (140, 149))	('regulated', 'Reg', (116, 125))	('ESCC', 'Disease', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('overexpressed', 'PosReg', (26, 39))	('p65', 'Var', (129, 132))
179044	23525727	Then, a recent study revealed that inhibition of NF-kappaB increased the sensitivity of ESCC to chemoradiotherapy.	('ESCC', 'Disease', (88, 92))	('sensitivity', 'MPA', (73, 84))	('NF-kappaB', 'Gene', '4790', (49, 58))	('inhibition', 'Var', (35, 45))	('increased', 'PosReg', (59, 68))	('NF-kappaB', 'Gene', (49, 58))
179047	23525727	Moreover, the nuclear localization sequence of p65 (p65-NLS/active p65) may be useful in monitoring overall NF-kappaB activity in esophageal cancer tissue.	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('activity', 'MPA', (118, 126))	('p65 (p65-NLS/active p65', 'Var', (47, 70))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('NF-kappaB', 'Gene', '4790', (108, 117))	('NF-kappaB', 'Gene', (108, 117))	('esophageal cancer', 'Disease', (130, 147))
179049	23525727	Monocyte chemoattractant protein-1 (MCP-1/CCL2), a member of the C-C chemokine family, is involved in macrophage infiltration and cancer progression and studies have confirmed that MCP-1 activates the NF-kappaB pathway.	('MCP-1', 'Var', (181, 186))	('NF-kappaB', 'Gene', (201, 210))	('CCL2', 'Gene', '6347', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CCL2', 'Gene', (42, 46))	('cancer', 'Disease', (130, 136))	('Monocyte chemoattractant protein-1', 'Gene', (0, 34))	('activates', 'PosReg', (187, 196))	('Monocyte chemoattractant protein-1', 'Gene', '6347', (0, 34))	('NF-kappaB', 'Gene', '4790', (201, 210))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
179056	23525727	The expression of APE-1, p65, p65-NLS and MCP-1 was assessed by immunohistochemical analysis.	('APE-1', 'Gene', (18, 23))	('p65', 'Var', (25, 28))	('APE-1', 'Gene', '328', (18, 23))	('MCP-1', 'Gene', (42, 47))	('p65-NLS', 'Var', (30, 37))
179060	23525727	Colocalization of APE-1 and p65-NLS were confirmed by fluorescence double immunostaining.	('APE-1', 'Gene', '328', (18, 23))	('p65-NLS', 'Var', (28, 35))	('APE-1', 'Gene', (18, 23))
179082	23525727	Spearman rank correlation test was used to determine the correlation of MCP-1 with p65, p65-NLS and APE-1.	('APE-1', 'Gene', (100, 105))	('APE-1', 'Gene', '328', (100, 105))	('p65', 'Var', (83, 86))	('MCP-1', 'Gene', (72, 77))	('p65-NLS', 'Var', (88, 95))
179087	23525727	The levels of APE-1, p65 and p65-NLS expression in the MCP-1-positive tissue samples were significantly higher than in the MCP-1-negative tissue samples (p<0.001; p = 0.001; p<0.05, respectively) (Fig.	('APE-1', 'Gene', (14, 19))	('p65', 'Var', (21, 24))	('APE-1', 'Gene', '328', (14, 19))	('higher', 'PosReg', (104, 110))	('expression', 'MPA', (37, 47))	('p65-NLS', 'Var', (29, 36))	('MCP-1-positive', 'Gene', (55, 69))
179088	23525727	In addition, we found that MCP-1 correlated with p65, p65-NLS and APE-1 expression (p = 0.001; p<0.05; p<0.001, by Spearman rank correlation test, respectively).	('APE-1', 'Gene', (66, 71))	('APE-1', 'Gene', '328', (66, 71))	('p65', 'Var', (49, 52))	('expression', 'MPA', (72, 82))	('MCP-1', 'Gene', (27, 32))	('p65-NLS', 'Var', (54, 61))
179089	23525727	Moreover, we also investigated the colocalization of APE-1 and p65-NLS by fluorescence double immunostaining.	('APE-1', 'Gene', '328', (53, 58))	('APE-1', 'Gene', (53, 58))	('investigated', 'Reg', (18, 30))	('p65-NLS', 'Var', (63, 70))
179093	23525727	Double immunostaining (yellow cells) for p65-NLS and APE-1 could be seen in the nuclei of cancer cells (Fig.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('p65-NLS', 'Var', (41, 48))	('APE-1', 'Gene', (53, 58))	('APE-1', 'Gene', '328', (53, 58))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
179099	23525727	To determine the role of p65 in the regulation of APE-1 expression, we evaluated APE-1 mRNA in KYSE220 cells treated with p65 siRNA.	('mRNA', 'MPA', (87, 91))	('p65', 'Var', (122, 125))	('APE-1', 'Gene', (50, 55))	('APE-1', 'Gene', (81, 86))	('APE-1', 'Gene', '328', (50, 55))	('APE-1', 'Gene', '328', (81, 86))
179100	23525727	Also, 10 nM and 20 nM p65 siRNA significantly inhibited APE-1 mRNA expression compared to unstimulated cells or cells treated with nonsilencing siRNA (p<0.001; p<0.001, Fig.	('inhibited', 'NegReg', (46, 55))	('APE-1', 'Gene', '328', (56, 61))	('p65 siRNA', 'Var', (22, 31))	('APE-1', 'Gene', (56, 61))
179101	23525727	To clarify whether the APE-1-p65 pathway was associated with sensitivity to chemotherapy, we investigated the apoptotic index in 5-FU-incubated KYSE220 cells with or without p65 siRNA.	('investigated', 'Reg', (93, 105))	('APE-1', 'Gene', (23, 28))	('associated', 'Reg', (45, 55))	('APE-1', 'Gene', '328', (23, 28))	('5-FU', 'Chemical', 'MESH:D005472', (129, 133))	('p65', 'Var', (174, 177))
179102	23525727	p65 siRNA treatment significantly increased the apoptotic index in 5-FU (40 and 80 microl/ml)-treated KYSE220 cells compared to cells without p65 siRNA (Fig.	('p65', 'Var', (0, 3))	('apoptotic index', 'CPA', (48, 63))	('increased', 'PosReg', (34, 43))	('5-FU', 'Chemical', 'MESH:D005472', (67, 71))
179104	23525727	Our major findings are: (1) APE-1 was overexpressed and found primarily with nuclear localization in ESCC tissue; (2) APE-1 and p65-NLS were colocalized in the nuclei of cancer cells in ESCC tissue; (3) MCP-1 induced a significant increase in p65 and APE-1 mRNA and protein expression levels in KYSE220 cells; (4) Inhibition of NF-kappaB with MG-132 significantly abrogated the upregulation of p65 and APE-1 induced by MCP-1 in KYSE220 cells; and (5) Knockdown of p65 by siRNA significantly inhibited APE-1 mRNA expression and significantly increased the apoptotic index in 5-FU-treated KYSE220 cells.	('cancer', 'Disease', (170, 176))	('APE-1', 'Gene', '328', (501, 506))	('p65', 'Gene', (464, 467))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('abrogated', 'NegReg', (364, 373))	('APE-1', 'Gene', (501, 506))	('MG-132', 'Chemical', 'MESH:C072553', (343, 349))	('APE-1', 'Gene', '328', (118, 123))	('5-FU', 'Chemical', 'MESH:D005472', (574, 578))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('APE-1', 'Gene', '328', (251, 256))	('APE-1', 'Gene', '328', (28, 33))	('APE-1', 'Gene', '328', (402, 407))	('APE-1', 'Gene', (118, 123))	('increased', 'PosReg', (541, 550))	('APE-1', 'Gene', (251, 256))	('APE-1', 'Gene', (28, 33))	('APE-1', 'Gene', (402, 407))	('NF-kappaB', 'Gene', (328, 337))	('mRNA expression', 'MPA', (507, 522))	('increase', 'PosReg', (231, 239))	('NF-kappaB', 'Gene', '4790', (328, 337))	('Knockdown', 'Var', (451, 460))	('p65', 'MPA', (243, 246))	('inhibited', 'NegReg', (491, 500))	('apoptotic index', 'CPA', (555, 570))
179110	23525727	Considering that p65 siRNA treatment significantly reduced APE-1 mRNA levels while increasing the apoptotic index in 5-FU-treated KYSE220 cells, the APE-1-p65 pathway might be associated with apoptosis in 5-FU-treated esophageal cancer cells.	('p65', 'Var', (17, 20))	('reduced', 'NegReg', (51, 58))	('apoptotic index', 'MPA', (98, 113))	('APE-1', 'Gene', '328', (59, 64))	('APE-1', 'Gene', (149, 154))	('5-FU', 'Chemical', 'MESH:D005472', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('APE-1', 'Gene', '328', (149, 154))	('esophageal cancer', 'Disease', (218, 235))	('5-FU', 'Chemical', 'MESH:D005472', (205, 209))	('APE-1', 'Gene', (59, 64))	('increasing', 'PosReg', (83, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))
179118	23525727	In this study, p65 siRNA treatment significantly inhibited APE-1 expression in KYSE220 cells.	('APE-1', 'Gene', '328', (59, 64))	('expression', 'MPA', (65, 75))	('p65', 'Var', (15, 18))	('APE-1', 'Gene', (59, 64))	('inhibited', 'NegReg', (49, 58))
179119	23525727	In double immunostaining, we could find the colocalization of p65-NLS and APE-1 in esophageal cancer tissue.	('p65-NLS', 'Var', (62, 69))	('esophageal cancer', 'Disease', (83, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('colocalization', 'Interaction', (44, 58))	('APE-1', 'Gene', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('APE-1', 'Gene', '328', (74, 79))
179122	23525727	In our immunohistochemical analysis data, we found that MCP-1 positivity correlated with p65, p65-NLS and APE-1 expression.	('p65', 'Var', (89, 92))	('p65-NLS', 'Var', (94, 101))	('APE-1', 'Gene', '328', (106, 111))	('MCP-1', 'Gene', (56, 61))	('APE-1', 'Gene', (106, 111))	('expression', 'MPA', (112, 122))
179126	23525727	have reported that MCP-1 expression was also linked to poor prognosis in esophageal cancer.	('linked', 'Reg', (45, 51))	('esophageal cancer', 'Disease', (73, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('expression', 'Var', (25, 35))	('MCP-1', 'Gene', (19, 24))
179139	21426561	Accumulating evidence indicates that deregulation of miR is associated with human malignancies including ESCC.	('ESCC', 'Disease', (105, 109))	('miR', 'Gene', (53, 56))	('malignancies', 'Disease', (82, 94))	('human', 'Species', '9606', (76, 81))	('deregulation', 'Var', (37, 49))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))	('associated', 'Reg', (60, 70))
179150	21426561	Accumulating evidence indicates that deregulation of miRs is associated with human malignancies and suggests a causal role of miRs in tumor initiation and progression, since they can function as oncogenes or tumor suppressors.	('tumor initiation', 'Disease', (134, 150))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('malignancies', 'Disease', 'MESH:D009369', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('miRs', 'Protein', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor initiation', 'Disease', 'MESH:D009369', (134, 150))	('associated', 'Reg', (61, 71))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('malignancies', 'Disease', (83, 95))	('deregulation', 'Var', (37, 49))	('miRs', 'Gene', (126, 130))	('tumor', 'Disease', (134, 139))	('human', 'Species', '9606', (77, 82))
179160	21426561	In addition, two miR-205 binding sites were indentified in ZEB2, suggesting EMT could be also regulated by miR-205.	('ZEB2', 'Gene', '9839', (59, 63))	('EMT', 'CPA', (76, 79))	('miR-205', 'Var', (107, 114))	('ZEB2', 'Gene', (59, 63))	('regulated', 'Reg', (94, 103))
179199	21426561	On the other hand, miR-153, -100, -125b, -10a, -99a, -376a, -379, -651, and -146b were significantly lower in expression in the two ESCC cell lines than in Het-1A cells (Figure 1B).	('lower', 'NegReg', (101, 106))	('expression', 'MPA', (110, 120))	('miR-153', 'Chemical', '-', (19, 26))	('miR-153', 'Var', (19, 26))
179202	21426561	Consistent with this, knockdown of miR-205 by anti-miR-205 inhibitor transfection enhanced cellular expression of ZEB2 but not ZEB1 in OE21 cells (Figure 4C).	('ZEB2', 'Gene', (114, 118))	('enhanced', 'PosReg', (82, 90))	('ZEB1', 'Gene', '6935', (127, 131))	('miR-205', 'Gene', (35, 42))	('cellular expression', 'MPA', (91, 110))	('ZEB1', 'Gene', (127, 131))	('anti-miR-205', 'Var', (46, 58))	('ZEB2', 'Gene', '9839', (114, 118))
179206	21426561	Co-transfection of the reporter plasmid along with miR-205 precursor resulted in a significantly reduced ZEB2-3'-UTR-luciferase expression, suggesting that miR-205 is likely to target ZEB2 directly (Figure 5A).	('ZEB2', 'Gene', (184, 188))	('ZEB2', 'Gene', (105, 109))	('reduced', 'NegReg', (97, 104))	('ZEB2', 'Gene', '9839', (184, 188))	('miR-205', 'Var', (156, 163))	('expression', 'MPA', (128, 138))	('ZEB2', 'Gene', '9839', (105, 109))
179222	21426561	Furthermore, breast cancer cell lines expressed lower levels of miR-205 than the non-malignant mammary cells examined in their study.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('miR-205', 'Var', (64, 71))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('lower', 'NegReg', (48, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('levels', 'MPA', (54, 60))
179229	21426561	In the present study, knockdown of miR-205 expression substantially enhanced cellular expression of ZEB2 in ESCC cells.	('enhanced', 'PosReg', (68, 76))	('ZEB2', 'Gene', '9839', (100, 104))	('knockdown', 'Var', (22, 31))	('miR-205', 'Gene', (35, 42))	('cellular expression', 'MPA', (77, 96))	('ZEB2', 'Gene', (100, 104))
179235	21426561	In line with this, cellular E-cadherin expression was substantially reduced, whereas N-cadherin expression emerged in ESCC cells transfected with anti-miR-205 inhibitor to suppress ZEB2, and they were endowed with properties allowing augmented invasion through EMT.	('N-cadherin', 'Gene', (85, 95))	('augmented', 'PosReg', (234, 243))	('ZEB2', 'Gene', '9839', (181, 185))	('N-cadherin', 'Gene', '1000', (85, 95))	('ZEB2', 'Gene', (181, 185))	('E-cadherin', 'Gene', (28, 38))	('E-cadherin', 'Gene', '999', (28, 38))	('reduced', 'NegReg', (68, 75))	('invasion through EMT', 'CPA', (244, 264))	('suppress', 'NegReg', (172, 180))	('anti-miR-205 inhibitor', 'Var', (146, 168))
179250	17927839	Few days later the patient died due to gas exchange dysfunction and circulation instability after a previously unseen combination of drain-erosion of the stomach with subsequent pleurisy and air leak of the left main bronchus.	('patient', 'Species', '9606', (19, 26))	('pleurisy', 'Disease', 'MESH:D010998', (178, 186))	('circulation instability', 'Phenotype', 'HP:0011028', (68, 91))	('circulation instability', 'MPA', (68, 91))	('gas exchange dysfunction', 'Disease', 'MESH:D011007', (39, 63))	('gas exchange dysfunction', 'Disease', (39, 63))	('pleurisy', 'Phenotype', 'HP:0002102', (178, 186))	('pleurisy', 'Disease', (178, 186))	('drain-erosion', 'Var', (133, 146))
179425	30786867	The TNM stages of the primary cancer were pathological or clinical T3N0M0 to T4N1M1, which indicated the primary cancers were advanced, and metastatic when admitted in 4 cases.	('TNM', 'Gene', '10178', (4, 7))	('T4N1M1', 'Var', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (113, 119))	('TNM', 'Gene', (4, 7))	('primary cancers', 'Disease', (105, 120))	('primary cancers', 'Disease', 'MESH:D009369', (105, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('T3N0M0', 'Var', (67, 73))
179453	30594036	Aberrant TGF-beta signaling has been associated with gastrointestinal cancer progression.	('gastrointestinal cancer', 'Disease', (53, 76))	('Aberrant', 'Var', (0, 8))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (53, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (53, 76))	('TGF-beta', 'Protein', (9, 17))	('associated', 'Reg', (37, 47))
179477	30594036	TbetaRs can also activate non-Smad-dependent signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway mediated by p38, c-Jun amino terminal kinase (JNK), extracellular signal-regulated kinases (ERK), nuclear factor-kappaB (NF-kappaB), Rho, and phosphatidylinositol 3-kinase (PI3K)-Akt (Figure 2).	('extracellular signal-regulated kinases', 'Gene', (179, 217))	('NF-kappaB', 'Gene', '4790', (248, 257))	('c-Jun', 'Gene', '3725', (144, 149))	('MAPK', 'Gene', (113, 117))	('ERK', 'Gene', (219, 222))	('c-Jun', 'Gene', (144, 149))	('extracellular signal-regulated kinases', 'Gene', '5594', (179, 217))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (269, 298))	('p38', 'Gene', (139, 142))	('MAPK', 'Gene', '5594', (113, 117))	('nuclear factor-kappaB', 'Gene', '4790', (225, 246))	('phosphatidylinositol 3-kinase', 'Gene', (269, 298))	('activate', 'PosReg', (17, 25))	('TbetaRs', 'Var', (0, 7))	('Akt', 'Gene', (306, 309))	('Rho', 'Pathway', (260, 263))	('Smad', 'Gene', '4092', (30, 34))	('Akt', 'Gene', '207', (306, 309))	('nuclear factor-kappaB', 'Gene', (225, 246))	('p38', 'Gene', '1432', (139, 142))	('ERK', 'Gene', '5594', (219, 222))	('NF-kappaB', 'Gene', (248, 257))	('Smad', 'Gene', (30, 34))
179494	30594036	The accumulation of mutations in TGF-beta signaling pathway components during tumor progression may contribute to the switch in TGF-beta function from tumor-suppressive to tumor-promoting.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('TGF-beta signaling pathway', 'Gene', (33, 59))	('TGF-beta', 'Gene', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
179519	30594036	Additionally, mutations in TbetaRII have been implicated in gastric carcinogenesis.	('implicated', 'Reg', (46, 56))	('TbetaRII', 'Gene', '7048', (27, 35))	('gastric carcinogenesis', 'Disease', (60, 82))	('TbetaRII', 'Gene', (27, 35))	('mutations', 'Var', (14, 23))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (60, 82))
179521	30594036	Various mutations in the promoter regions of TGFB1 and TGFBR2 were associated with the riskofGC in a Chinese population.	('riskofGC', 'Disease', (87, 95))	('TGFB1', 'Gene', '7040', (45, 50))	('TGFBR2', 'Gene', (55, 61))	('mutations', 'Var', (8, 17))	('GC', 'Phenotype', 'HP:0012126', (93, 95))	('TGFB1', 'Gene', (45, 50))	('associated', 'Reg', (67, 77))	('TGFBR2', 'Gene', '7048', (55, 61))
179522	30594036	In addition, an imbalance in Smad4/7 expression was associated with GC cell differentiation, metastasis, and apoptosis.	('GC cell differentiation', 'CPA', (68, 91))	('metastasis', 'CPA', (93, 103))	('apoptosis', 'CPA', (109, 118))	('associated', 'Reg', (52, 62))	('imbalance', 'Var', (16, 25))	('Smad4', 'Gene', (29, 34))	('Smad4', 'Gene', '4089', (29, 34))	('imbalance', 'Phenotype', 'HP:0002172', (16, 25))	('expression', 'MPA', (37, 47))	('GC', 'Phenotype', 'HP:0012126', (68, 70))
179537	30594036	Additionally, mutations in Smad2 and Smad4 have been observed in a small minority of HCC patients.	('observed', 'Reg', (53, 61))	('HCC', 'Disease', (85, 88))	('Smad4', 'Gene', (37, 42))	('Smad4', 'Gene', '4089', (37, 42))	('HCC', 'Phenotype', 'HP:0001402', (85, 88))	('patients', 'Species', '9606', (89, 97))	('Smad2', 'Gene', '4087', (27, 32))	('Smad2', 'Gene', (27, 32))	('mutations', 'Var', (14, 23))
179546	30594036	The miR-200 family of miRNAs was shown to suppress metastasis in human HCC cells, and miR-125b was found to suppress EMT by targeting Smad2 and Smad4.	('suppress', 'NegReg', (42, 50))	('Smad4', 'Gene', '4089', (144, 149))	('human', 'Species', '9606', (65, 70))	('metastasis in human HCC cells', 'CPA', (51, 80))	('miR-125b', 'Chemical', '-', (86, 94))	('EMT', 'CPA', (117, 120))	('HCC', 'Phenotype', 'HP:0001402', (71, 74))	('Smad2', 'Gene', '4087', (134, 139))	('Smad2', 'Gene', (134, 139))	('miR-125b', 'Var', (86, 94))	('suppress', 'NegReg', (108, 116))	('Smad4', 'Gene', (144, 149))
179552	30594036	A recent study demonstrated that abrogation of the posttranscriptional regulation of c-Myc in an epigenetic modification-dependent manner promoted HCC cell resistance to antiproliferative TGF-beta signaling.	('c-Myc', 'Gene', (85, 90))	('abrogation', 'Var', (33, 43))	('HCC', 'Phenotype', 'HP:0001402', (147, 150))	('posttranscriptional regulation', 'MPA', (51, 81))	('HCC', 'Disease', (147, 150))	('promoted', 'PosReg', (138, 146))	('c-Myc', 'Gene', '4609', (85, 90))	('resistance', 'CPA', (156, 166))
179564	30594036	Notably, inhibition of TGF-beta can prevent CRC metastasis by unleashing a cytotoxic T-cell response against cancer cells, implying that TGF-beta signaling suppresses cancer recognition by the immune system.	('unleashing', 'NegReg', (62, 72))	('prevent', 'NegReg', (36, 43))	('suppresses', 'NegReg', (156, 166))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))	('CRC', 'Disease', (44, 47))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (109, 115))	('cytotoxic T-cell', 'MPA', (75, 91))	('TGF-beta', 'Gene', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('inhibition', 'Var', (9, 19))
179565	30594036	For example, mutations in TGFBR2 that abolish TGF-beta signaling have been frequently detected in CRCs.	('CRCs', 'Disease', (98, 102))	('TGFBR2', 'Gene', '7048', (26, 32))	('abolish', 'NegReg', (38, 45))	('detected', 'Reg', (86, 94))	('TGF-beta signaling', 'MPA', (46, 64))	('TGFBR2', 'Gene', (26, 32))	('mutations', 'Var', (13, 22))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))
179566	30594036	More than 80% of CRCs that display microsatellite instability harbor mutations in TGFBR2 (particularly frameshift mutations in exon 3).	('CRCs', 'Disease', (17, 21))	('mutations', 'Var', (69, 78))	('microsatellite instability', 'MPA', (35, 61))	('CRC', 'Phenotype', 'HP:0003003', (17, 20))	('frameshift mutations', 'Var', (103, 123))	('TGFBR2', 'Gene', '7048', (82, 88))	('TGFBR2', 'Gene', (82, 88))
179567	30594036	The exact mechanisms by which TGFBR2 mutations lead to CRC have not been elucidated.	('TGFBR2', 'Gene', '7048', (30, 36))	('lead to', 'Reg', (47, 54))	('CRC', 'Phenotype', 'HP:0003003', (55, 58))	('mutations', 'Var', (37, 46))	('TGFBR2', 'Gene', (30, 36))	('CRC', 'Disease', (55, 58))
179568	30594036	However, a previous study demonstrated that inactivation of TbetaRII induced VEGF-A expression, which enhanced the metastatic potential of CRC cells.	('VEGF-A', 'Gene', '7422', (77, 83))	('enhanced', 'PosReg', (102, 110))	('VEGF-A', 'Gene', (77, 83))	('TbetaRII', 'Gene', '7048', (60, 68))	('metastatic potential of CRC cells', 'CPA', (115, 148))	('TbetaRII', 'Gene', (60, 68))	('CRC', 'Phenotype', 'HP:0003003', (139, 142))	('expression', 'MPA', (84, 94))	('inactivation', 'Var', (44, 56))	('induced', 'Reg', (69, 76))
179569	30594036	TGF-beta signaling was still active in some CRCs that displayed a high level of microsatellite instability despite frameshift mutations in TGFBR2.	('TGFBR2', 'Gene', '7048', (139, 145))	('microsatellite instability', 'MPA', (80, 106))	('TGFBR2', 'Gene', (139, 145))	('frameshift mutations', 'Var', (115, 135))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))
179570	30594036	Mutations in TGFBR1 have also been detected in CRC.	('detected', 'Reg', (35, 43))	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('CRC', 'Disease', (47, 50))	('Mutations', 'Var', (0, 9))	('TGFBR1', 'Gene', (13, 19))	('TGFBR1', 'Gene', '7046', (13, 19))
179571	30594036	For example, loss of three alanine residues within a stretch of nine alanine residues in the N-terminal region of TbetaRI (TGFBR1*6A) was associated with an increased risk of CRC, though these results have not been confirmed.	('CRC', 'Phenotype', 'HP:0003003', (175, 178))	('alanine', 'Chemical', 'MESH:D000409', (27, 34))	('TbetaRI', 'Gene', (114, 121))	('CRC', 'Disease', (175, 178))	('alanine', 'Chemical', 'MESH:D000409', (69, 76))	('TGFBR1', 'Gene', '7046', (123, 129))	('TbetaRI', 'Gene', '7046', (114, 121))	('TGFBR1', 'Gene', (123, 129))	('loss', 'Var', (13, 17))
179574	30594036	Smad4 mutation or loss of expression has been frequently observed in late-stage tumors.	('late-stage tumors', 'Disease', (69, 86))	('late-stage tumors', 'Disease', 'MESH:D062706', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('loss of expression', 'NegReg', (18, 36))	('mutation', 'Var', (6, 14))	('observed', 'Reg', (57, 65))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('Smad4', 'Gene', (0, 5))	('Smad4', 'Gene', '4089', (0, 5))
179575	30594036	Loss of Smad4 could alter BMP signaling to promote CRC metastasis through activation of Rho and Rho-associated protein kinase.	('BMP', 'Gene', '649', (26, 29))	('promote', 'PosReg', (43, 50))	('alter', 'Reg', (20, 25))	('Rho', 'Pathway', (88, 91))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('activation', 'PosReg', (74, 84))	('Smad4', 'Gene', (8, 13))	('Smad4', 'Gene', '4089', (8, 13))	('Rho-associated protein kinase', 'Pathway', (96, 125))	('BMP', 'Gene', (26, 29))	('CRC', 'Disease', (51, 54))	('Loss', 'Var', (0, 4))
179576	30594036	Mutations in Smad2 have been detected in approximately 3%-6% of CRC tumors.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('Smad2', 'Gene', '4087', (13, 18))	('detected', 'Reg', (29, 37))	('Mutations', 'Var', (0, 9))	('CRC tumors', 'Disease', 'MESH:D015179', (64, 74))	('Smad2', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CRC tumors', 'Disease', (64, 74))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))
179577	30594036	Mutations were more frequently observed in early-stage tumors.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('observed', 'Reg', (31, 39))
179580	30594036	Interestingly, a low-frequency coding variant, rs3764482 (c. 83C>T; p. S28F) in Smad7, was associated with the risk of CRC in a Chinese population.	('Smad7', 'Gene', (80, 85))	('S28F', 'Var', (71, 75))	('83C>T', 'Var', (61, 66))	('S28F', 'SUBSTITUTION', 'None', (71, 75))	('Smad7', 'Gene', '4092', (80, 85))	('83C>T', 'SUBSTITUTION', 'None', (61, 66))	('CRC', 'Disease', (119, 122))	('rs3764482', 'Mutation', 'rs3764482', (47, 56))	('CRC', 'Phenotype', 'HP:0003003', (119, 122))	('associated', 'Reg', (91, 101))
179581	30594036	A large-scale meta-analysis demonstrated that several single nucleotide polymorphisms in Smad7 were associated with CRC.	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('associated', 'Reg', (100, 110))	('Smad7', 'Gene', (89, 94))	('single nucleotide polymorphisms', 'Var', (54, 85))	('CRC', 'Disease', (116, 119))	('Smad7', 'Gene', '4092', (89, 94))
179582	30594036	Mutations in Smad3 were also identified and had similar frequencies to those of the Smad2 mutations in sporadic CRCs.	('Smad3', 'Gene', '4088', (13, 18))	('Smad2', 'Gene', (84, 89))	('mutations', 'Var', (90, 99))	('sporadic CRCs', 'Disease', (103, 116))	('Smad3', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('Smad2', 'Gene', '4087', (84, 89))	('CRC', 'Phenotype', 'HP:0003003', (112, 115))
179583	30594036	In addition to the somatic mutations described above, germline mutations in Smads including Smad4 have been observed in several patients with juvenile polyposis syndrome, which can develop into CRC.	('Smad', 'Gene', '4092', (76, 80))	('juvenile polyposis syndrome', 'Disease', 'MESH:C537702', (142, 169))	('juvenile polyposis syndrome', 'Phenotype', 'HP:0004784', (142, 169))	('CRC', 'Disease', (194, 197))	('Smad', 'Gene', (76, 80))	('germline mutations', 'Var', (54, 72))	('develop', 'Reg', (181, 188))	('Smad', 'Gene', '4092', (92, 96))	('Smad4', 'Gene', (92, 97))	('Smad', 'Gene', (92, 96))	('juvenile polyposis syndrome', 'Disease', (142, 169))	('Smad4', 'Gene', '4089', (92, 97))	('CRC', 'Phenotype', 'HP:0003003', (194, 197))	('patients', 'Species', '9606', (128, 136))	('observed', 'Reg', (108, 116))
179584	30594036	Thus, altered TGF-beta signaling plays various stage-specific roles in CRC progression with mutations in TGFBR2 and Smad as the major contributor.	('altered', 'Reg', (6, 13))	('TGFBR2', 'Gene', '7048', (105, 111))	('CRC', 'Disease', (71, 74))	('mutations', 'Var', (92, 101))	('Smad', 'Gene', '4092', (116, 120))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('TGFBR2', 'Gene', (105, 111))	('Smad', 'Gene', (116, 120))
179596	30594036	Overexpression of TGF-beta in early-stage PDACs was associated with reduced tumor cell proliferation and improved survival.	('TGF-beta', 'Gene', (18, 26))	('PDAC', 'Chemical', '-', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PDAC', 'Phenotype', 'HP:0006725', (42, 46))	('Overexpression', 'Var', (0, 14))	('survival', 'CPA', (114, 122))	('improved', 'PosReg', (105, 113))	('reduced', 'NegReg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
179597	30594036	Mutations in TGF-beta pathway proteins may explain the stage-dependent functions of TGF-beta in PDACs.	('PDAC', 'Chemical', '-', (96, 100))	('TGF-beta pathway', 'Gene', (13, 29))	('PDACs', 'Disease', (96, 101))	('Mutations', 'Var', (0, 9))	('TGF-beta', 'Gene', (84, 92))	('PDAC', 'Phenotype', 'HP:0006725', (96, 100))
179598	30594036	Mutations in Smad4 have been observed in approximately 50% of PDACs.	('observed', 'Reg', (29, 37))	('PDACs', 'Disease', (62, 67))	('PDAC', 'Chemical', '-', (62, 66))	('Mutations', 'Var', (0, 9))	('PDAC', 'Phenotype', 'HP:0006725', (62, 66))	('Smad4', 'Gene', (13, 18))	('Smad4', 'Gene', '4089', (13, 18))
179599	30594036	Mutations in TbetaRII have been identified in 4%-7% of pancreatic cancers.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('TbetaRII', 'Gene', '7048', (13, 21))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (55, 73))	('Mutations', 'Var', (0, 9))	('TbetaRII', 'Gene', (13, 21))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('identified', 'Reg', (32, 42))	('pancreatic cancers', 'Disease', 'MESH:D010190', (55, 73))	('pancreatic cancers', 'Disease', (55, 73))
179601	30594036	However, mutation of KRAS alone is not sufficient for malignant transformation.	('KRAS', 'Gene', (21, 25))	('mutation', 'Var', (9, 17))	('KRAS', 'Gene', '3845', (21, 25))
179602	30594036	One recent study demonstrated that mutant KRAS dosage along with other oncogenic gains like Myc drives the early progression of PDAC.	('Myc', 'Gene', '4609', (92, 95))	('KRAS', 'Gene', (42, 46))	('Myc', 'Gene', (92, 95))	('KRAS', 'Gene', '3845', (42, 46))	('PDAC', 'Chemical', '-', (128, 132))	('mutant', 'Var', (35, 41))	('PDAC', 'Phenotype', 'HP:0006725', (128, 132))	('PDAC', 'Disease', (128, 132))
179603	30594036	Additional mutations in tumor suppressors such as Smad4 and CDKN2A are required for PDAC initiation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutations', 'Var', (11, 20))	('PDAC', 'Phenotype', 'HP:0006725', (84, 88))	('tumor', 'Disease', (24, 29))	('CDKN2A', 'Gene', (60, 66))	('Smad4', 'Gene', (50, 55))	('CDKN2A', 'Gene', '1029', (60, 66))	('PDAC', 'Chemical', '-', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('Smad4', 'Gene', '4089', (50, 55))
179605	30594036	In addition, inactivation of retinoblastoma 1 converts TGF-beta from a tumor suppressor to a protumorigenic factor that enhances PDAC cell proliferation.	('retinoblastoma', 'Phenotype', 'HP:0009919', (29, 43))	('TGF-beta', 'Gene', (55, 63))	('inactivation', 'Var', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('PDAC', 'Phenotype', 'HP:0006725', (129, 133))	('retinoblastoma 1', 'Gene', (29, 45))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('enhances', 'PosReg', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('PDAC cell proliferation', 'CPA', (129, 152))	('PDAC', 'Chemical', '-', (129, 133))	('retinoblastoma 1', 'Gene', '5925', (29, 45))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
179609	30594036	Among different gastrointestinal cancers, dysfunction of TbetaR(s) is derived from multiple levels including transcription, translation, and mutation.	('gastrointestinal cancers', 'Disease', (16, 40))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (16, 40))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (16, 39))	('dysfunction', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('TbetaR', 'Gene', (57, 63))	('mutation', 'Var', (141, 149))
179610	30594036	It should be noted that TGFBR(s) mutation is frequently observed in pancreatic cancers, while alternation of TbetaR(s) level often appears in other types of gastrointestinal cancers.	('TGFBR', 'Gene', '7046;7048', (24, 29))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (68, 86))	('observed', 'Reg', (56, 64))	('mutation', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (157, 181))	('pancreatic cancers', 'Disease', (68, 86))	('gastrointestinal cancers', 'Disease', (157, 181))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (157, 180))	('TGFBR', 'Gene', (24, 29))	('pancreatic cancers', 'Disease', 'MESH:D010190', (68, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
179612	30594036	Thus, alternation from these three levels (ligand, receptor, and signal transducer) together contributes to the development of gastrointestinal cancers, and therapeutics that target the TGF-beta signaling pathway may be effective for the treatment of gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('gastrointestinal cancers', 'Disease', (127, 151))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (127, 151))	('gastrointestinal cancers', 'Disease', (251, 275))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (127, 150))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (251, 275))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('alternation', 'Var', (6, 17))	('contributes', 'Reg', (93, 104))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (251, 274))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
179616	30594036	Indeed, small molecule therapeutics, antibodies, and inhibitors against these targets are currently in clinical trials, such as antisense oligonucleotides against TGF-beta or TbetaR to lower their synthesis, TGF-beta-neutralizing monoclonal antibodies and anti-TbetaR monoclonal antibodies to interrupt ligand-receptor interaction, and small molecule inhibitor of TbetaR to prevent signaling transduction.	('antisense', 'Var', (128, 137))	('signaling transduction', 'MPA', (382, 404))	('ligand-receptor interaction', 'Interaction', (303, 330))	('TbetaR', 'Gene', (175, 181))	('lower', 'NegReg', (185, 190))	('prevent', 'Reg', (374, 381))	('TGF-beta', 'Gene', (163, 171))	('synthesis', 'MPA', (197, 206))	('interrupt', 'NegReg', (293, 302))	('oligonucleotides', 'Chemical', 'MESH:D009841', (138, 154))
179620	30594036	Existing research allows for the conclusion that dysregulation of TGF-beta signaling pathway is tightly associated with the development and progression of various gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', (163, 187))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (163, 186))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('TGF-beta signaling pathway', 'Pathway', (66, 92))	('associated', 'Reg', (104, 114))	('dysregulation', 'Var', (49, 62))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (163, 187))
179621	30594036	However, there is still much to learn about the biology of TGF-beta signaling under normal conditions and how its dysfunction contributes to the different types of gastrointestinal cancers.	('TGF-beta', 'Gene', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (164, 188))	('dysfunction', 'Var', (114, 125))	('gastrointestinal cancers', 'Disease', (164, 188))	('contributes', 'Reg', (126, 137))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (164, 187))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))
179637	30116994	The OE-19 cell spheres were drug resistant and EpCAM expression was significantly induced in the OE-19 cell spheres compared to the non-sphere OE-19 cells.	('OE', 'Chemical', 'MESH:C108709', (97, 99))	('induced', 'PosReg', (82, 89))	('OE-19', 'Var', (97, 102))	('OE', 'Chemical', 'MESH:C108709', (143, 145))	('EpCAM', 'Gene', (47, 52))	('OE', 'Chemical', 'MESH:C108709', (4, 6))	('EpCAM', 'Gene', '4072', (47, 52))
179651	30116994	The mechanisms through which EpCAM expression may increase the malignant potential of epithelial cells have been postulated to be associated with cell cycle signaling and up-regulation of proto-oncogenic activities.	('malignant potential of epithelial cells', 'CPA', (63, 102))	('EpCAM', 'Gene', (29, 34))	('increase', 'PosReg', (50, 58))	('cell cycle signaling', 'CPA', (146, 166))	('proto-oncogenic activities', 'CPA', (188, 214))	('up-regulation', 'PosReg', (171, 184))	('EpCAM', 'Gene', '4072', (29, 34))	('expression', 'Var', (35, 45))
179673	30116994	Bar-T cells were maintained in keratinocyte basal medium 2 (KBM-2; Clonetics Walkersville, MD, USA) and OE-19 cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) (Invitrogen, Carlsbad, CA, USA), respectively, supplemented with penicillin (100/ml), streptomycin (100 mug/ml) and 10% FBS (Invitrogen, Carlsbad, CA, USA).	('streptomycin', 'Chemical', 'MESH:D013307', (261, 273))	('FBS', 'Disease', 'MESH:D005198', (295, 298))	('DMEM', 'Chemical', '-', (169, 173))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (135, 167))	('FBS', 'Disease', (295, 298))	('penicillin', 'Chemical', 'MESH:D010406', (240, 250))	('OE', 'Chemical', 'MESH:C108709', (104, 106))	('100', 'Var', (275, 278))
179727	30116994	Consistent with the MTT results, we found that treatment of the OE-19 cell spheres with the individual drugs, as well as with ACF, caused cell death after 48 h. Unexpectedly, we found that the percentage of EpCAM positive cells after ACF treatment was even higher than that after the individual drug treatments, reaching 6%, even though the total amount of surviving cells was less (Fig.	('ACF', 'Var', (234, 237))	('OE', 'Chemical', 'MESH:C108709', (64, 66))	('EpCAM', 'Gene', (207, 212))	('death', 'Disease', (143, 148))	('higher', 'PosReg', (257, 263))	('ACF', 'Chemical', '-', (126, 129))	('MTT', 'Chemical', 'MESH:C070243', (20, 23))	('death', 'Disease', 'MESH:D003643', (143, 148))	('ACF', 'Chemical', '-', (234, 237))	('EpCAM', 'Gene', '4072', (207, 212))
179734	30116994	Specifically, we found that EpCAM was up-regulated by ACF from 6 to 48 h, whereas a decreased EpCAM expression was observed at 72 h (Fig.	('ACF', 'Var', (54, 57))	('EpCAM', 'Gene', (94, 99))	('ACF', 'Chemical', '-', (54, 57))	('EpCAM', 'Gene', '4072', (28, 33))	('EpCAM', 'Gene', '4072', (94, 99))	('EpCAM', 'Gene', (28, 33))	('up-regulated', 'PosReg', (38, 50))
179797	24551170	Tumor xenografts derived from cells pre-exposed to TCA were larger and more vascularized than those derived from control cells.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TCA', 'Chemical', 'MESH:D013656', (51, 54))	('more', 'PosReg', (71, 75))	('vascularized', 'CPA', (76, 88))	('TCA', 'Var', (51, 54))
179815	24551170	also reported that two patients who underwent partial gastrectomy had total bile acids concentration of 14655 microM and 18620 microM.	('rat', 'Species', '10116', (94, 97))	('patients', 'Species', '9606', (23, 31))	('bile acids', 'Chemical', 'MESH:D001647', (76, 86))	('bile acids concentration', 'MPA', (76, 100))	('18620 microM', 'Var', (121, 133))
179834	24551170	#4696, Cell Signaling), Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (D13.14.4E) XP Rabbit mAb (cat.	('Tyr204', 'Chemical', '-', (61, 67))	('Erk1/2', 'Gene', '26417;26413', (45, 51))	('Thr202/Tyr204) (D13.14.4E', 'Var', (54, 79))	('Thr202', 'Chemical', '-', (54, 60))	('Rabbit', 'Species', '9986', (84, 90))	('Phospho-p44/42', 'Var', (24, 38))	('Erk1/2', 'Gene', (45, 51))
179883	24551170	These results showed that TCA exposure increased cell growth by accelerating the entry into the S phase.	('rat', 'Species', '10116', (70, 73))	('accelerating', 'PosReg', (64, 76))	('entry', 'CPA', (81, 86))	('exposure', 'Var', (30, 38))	('increased', 'PosReg', (39, 48))	('TCA', 'Chemical', 'MESH:D013656', (26, 29))	('cell growth', 'CPA', (49, 60))
179888	24551170	Although TCA could not significantly enhance Cox2 expression, the expression level of Cox2 in tca cells was higher than that in control cells.	('expression level', 'MPA', (66, 82))	('tca', 'Chemical', 'MESH:D014238', (94, 97))	('TCA', 'Chemical', 'MESH:D013656', (9, 12))	('tca', 'Var', (94, 97))	('higher', 'PosReg', (108, 114))
179909	24551170	The mean proportion of necrosis was significantly lower in tumors from tca cells than in those from control cells (tca: 2.4+-1.1%; control: 9.8+-3.3%; P = 0.0496; Fig.	('tca', 'Var', (71, 74))	('lower', 'NegReg', (50, 55))	('necrosis', 'Disease', 'MESH:D009336', (23, 31))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tca', 'Chemical', 'MESH:D014238', (115, 118))	('tca', 'Chemical', 'MESH:D014238', (71, 74))	('necrosis', 'Disease', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
179915	24551170	The density of CD31-positive vasculature was higher in tumors from tca cells compared with those from control cells (tca: 102.3+-6.2/mm2; control: 67.9+-0.8/mm2; P = 0.0018; Fig.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CD31-positive', 'Protein', (15, 28))	('tca', 'Chemical', 'MESH:D014238', (117, 120))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tca', 'Chemical', 'MESH:D014238', (67, 70))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('higher', 'PosReg', (45, 51))	('tca', 'Var', (67, 70))
179918	24551170	This phenomenon cannot be explained exclusively by the influence of TCA on DNA damage or carcinogenesis-related pathways because TCA exhibits neither mutagenicity nor genotoxicity.	('toxicity', 'Disease', 'MESH:D064420', (171, 179))	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('toxicity', 'Disease', (171, 179))	('carcinogenesis', 'Disease', (89, 103))	('TCA', 'Var', (129, 132))	('TCA', 'Chemical', 'MESH:D013656', (129, 132))	('TCA', 'Chemical', 'MESH:D013656', (68, 71))
179920	24551170	According to the present data, TCA directly enhances invasiveness of ESCC-DR cells in vitro, which is associated with TGF-beta1 release from cancer cells; TCA also indirectly accelerates tumor growth (by reducing cell loss) in vivo through the promotion of angiogenesis mediated by the migration of vascular endothelial cells.	('tumor', 'Disease', (187, 192))	('TCA', 'Var', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('accelerates', 'PosReg', (175, 186))	('rat', 'Species', '10116', (181, 184))	('cancer', 'Disease', (141, 147))	('promotion', 'PosReg', (244, 253))	('TCA', 'Chemical', 'MESH:D013656', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('TGF-beta1', 'Gene', (118, 127))	('migration of vascular endothelial cells', 'CPA', (286, 325))	('TGF-beta1', 'Gene', '59086', (118, 127))	('rat', 'Species', '10116', (289, 292))	('TCA', 'Chemical', 'MESH:D013656', (155, 158))	('enhances', 'PosReg', (44, 52))	('invasiveness', 'CPA', (53, 65))	('angiogenesis', 'CPA', (257, 269))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('TCA', 'Var', (31, 34))
180020	23875107	Lung transplantation involves vagal nerve transection resulting in sensory and autonomic denervation of the airways and gastroesophageal dysfunction; whether this transient esophageal dysmotility in our case was the effect of limited intra-operative damage to vagus nerve branches or its plexus, patient regained her function after recovery.	('gastroesophageal dysfunction', 'Disease', (120, 148))	('patient', 'Species', '9606', (296, 303))	('intra-operative damage to vagus nerve branches', 'Disease', (234, 280))	('esophageal dysmotility', 'Disease', 'MESH:D015154', (173, 195))	('function', 'MPA', (317, 325))	('intra-operative damage to vagus nerve branches', 'Disease', 'MESH:D020421', (234, 280))	('vagus nerve branches', 'Phenotype', 'HP:0002886', (260, 280))	('esophageal dysmotility', 'Disease', (173, 195))	('gastroesophageal dysfunction', 'Disease', 'MESH:D005764', (120, 148))	('vagal nerve transection', 'Phenotype', 'HP:0002886', (30, 53))	('transection', 'Var', (42, 53))
180032	23875107	The pathophysiology of this rare esophageal spastic nutcracker remained obscure, but the possible etiopathogenesis include hypercontractility precipitated by GERD, started by neurotropic viral infection, initiated by stress induced surgical trauma, induced by outflow obstruction in and around LES, exaggerated by prokinetic and immunosuppressive drugs or complicated by partial vagotomy during LTx that lead to esophageal dysmotility and gastroparesis.	('outflow obstruction', 'Phenotype', 'HP:0032092', (260, 279))	('trauma', 'Disease', (241, 247))	('partial vagotomy', 'Var', (371, 387))	('neurotropic viral infection', 'Disease', (175, 202))	('lead to', 'Reg', (404, 411))	('esophageal spastic', 'Disease', 'MESH:D004941', (33, 51))	('GERD', 'Disease', 'MESH:D005764', (158, 162))	('neurotropic viral infection', 'Disease', 'MESH:D001102', (175, 202))	('gastroparesis', 'Disease', 'MESH:D018589', (439, 452))	('gastroparesis', 'Phenotype', 'HP:0002578', (439, 452))	('esophageal dysmotility', 'Disease', (412, 434))	('GERD', 'Disease', (158, 162))	('esophageal spastic', 'Phenotype', 'HP:0025271', (33, 51))	('gastroparesis', 'Disease', (439, 452))	('LTx', 'Chemical', '-', (395, 398))	('trauma', 'Disease', 'MESH:D014947', (241, 247))	('esophageal dysmotility', 'Disease', 'MESH:D015154', (412, 434))	('esophageal spastic', 'Disease', (33, 51))
180039	33118428	63.9% of cell uptake was achieved by TAB-CIS/5-FU LPHNs, with the best in vivo antitumor ability.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cell uptake', 'CPA', (9, 20))	('tumor', 'Disease', (83, 88))	('TAB-CIS/5-FU LPHNs', 'Chemical', '-', (37, 55))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('TAB-CIS/5-FU', 'Var', (37, 49))
180104	33118428	Figure 4(B) exhibits that 63.9% of cell uptake was achieved by TAB-CIS/5-FU LPHNs, which was higher than that of CIS/5-FU LPHNs (31.6%) (p<.05).	('higher', 'PosReg', (93, 99))	('CIS/5-FU LPHNs', 'Chemical', '-', (67, 81))	('TAB-CIS/5-FU LPHNs', 'Var', (63, 81))	('TAB-CIS/5-FU LPHNs', 'Chemical', '-', (63, 81))	('CIS/5-FU LPHNs', 'Chemical', '-', (113, 127))	('cell uptake', 'CPA', (35, 46))
180115	33118428	However, remarkable reduction in weight was found in free CIS/5-FU group, which is also found an increase of CRE (Table 3).	('free CIS/5-FU', 'Var', (53, 66))	('weight', 'MPA', (33, 39))	('CIS/5-FU', 'Chemical', '-', (58, 66))	('CRE', 'Chemical', 'MESH:D003404', (109, 112))	('CRE', 'Disease', (109, 112))	('reduction', 'NegReg', (20, 29))
180120	33118428	In the present study, TAB was conjugated onto CIS/5-FU LPHNs surface through amido linkage.	('conjugated', 'Interaction', (30, 40))	('CIS/5-FU LPHNs', 'Chemical', '-', (46, 60))	('amido', 'Chemical', '-', (77, 82))	('amido', 'Var', (77, 82))
180126	33118428	These findings were in accordance with the research carried by Ruan et al, who argued that substance P modified nanoparticles achieved higher uptake efficiency that non-modified nanoparticles (Ruan et al.,).	('substance P', 'Gene', (91, 102))	('uptake efficiency', 'MPA', (142, 159))	('higher', 'PosReg', (135, 141))	('substance P', 'Gene', '6863', (91, 102))	('modified', 'Var', (103, 111))
180147	32456621	Overall, high expression of IDO was significantly associated with poor OS (HR 1.92, 95% CI 1.52-2.43, P < 0.001) and TTP (HR 2.25 95% CI 1.58-3.22, P < 0.001).	('high expression', 'Var', (9, 24))	('poor OS', 'Disease', (66, 73))	('IDO', 'Gene', '3620', (28, 31))	('TTP', 'Disease', (117, 120))	('IDO', 'Gene', (28, 31))	('associated', 'Reg', (50, 60))
180149	32456621	The high expression of IDO was significantly associated with the poor prognosis of solid tumors, suggesting that it can be used as a biomarker for tumor prognosis and as a potential target for tumor therapy.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('IDO', 'Gene', '3620', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('IDO', 'Gene', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('associated', 'Reg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('solid tumors', 'Disease', (83, 95))	('high', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
180158	32456621	Depletion of tryptophan causes T cells arrest in the G1 phase of cell cycle, thereby inhibiting T cell proliferation.	('inhibiting', 'NegReg', (85, 95))	('arrest', 'Disease', 'MESH:D006323', (39, 45))	('Depletion', 'Var', (0, 9))	('T cell proliferation', 'CPA', (96, 116))	('arrest', 'Disease', (39, 45))	('tryptophan', 'Chemical', 'MESH:D014364', (13, 23))
180159	32456621	The main metabolite of tryptophan degradation, kynurenine, also has a direct toxic effect on T cells and induces T cell apoptosis.	('induces', 'Reg', (105, 112))	('kynurenine', 'Chemical', 'MESH:D007737', (47, 57))	('kynurenine', 'Var', (47, 57))	('T cell apoptosis', 'CPA', (113, 129))	('tryptophan', 'Chemical', 'MESH:D014364', (23, 33))
180161	32456621	By activating aryl hydrocarbon receptors, kynurenine can regulate the differentiation direction of Th17/Treg cells, thereby promoting the balanced differentiation of Th17/Treg to Treg cells.	('regulate', 'Reg', (57, 65))	('activating', 'Reg', (3, 13))	('promoting', 'PosReg', (124, 133))	('kynurenine', 'Chemical', 'MESH:D007737', (42, 52))	('balanced differentiation', 'CPA', (138, 162))	('kynurenine', 'Var', (42, 52))	('differentiation direction', 'CPA', (70, 95))	('aryl hydrocarbon receptors', 'Protein', (14, 40))
180164	32456621	Tumors with high expression of IDO tend to increase metastatic invasion and have a poor clinical outcome in cancer patients.	('patients', 'Species', '9606', (115, 123))	('metastatic invasion', 'CPA', (52, 71))	('IDO', 'Gene', '3620', (31, 34))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('increase', 'PosReg', (43, 51))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('IDO', 'Gene', (31, 34))	('high expression', 'Var', (12, 27))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
180186	32456621	The results indicated that high expression of IDO was highly correlated with poor prognosis of TTP (pooled HR = 2.25, 95% CI 1.58-3.22, P < 0.001) (Fig.	('IDO', 'Gene', '3620', (46, 49))	('TTP', 'Disease', (95, 98))	('IDO', 'Gene', (46, 49))	('high', 'Var', (27, 31))
180189	32456621	However, in a prospective study group, we found that high expression of IDO was highly correlated with poor OS prognosis (HR1.98, 95% CI 1.57-2.49, P < 0.001) and there was no heterogeneity (I2 = 0%, P = 0.6) (Table 2).	('poor OS', 'Disease', (103, 110))	('IDO', 'Gene', (72, 75))	('high expression', 'Var', (53, 68))	('IDO', 'Gene', '3620', (72, 75))
180194	32456621	Our results showed that high expression of IDO predicted poor OS and TTP in cancer patients.	('poor OS', 'Disease', (57, 64))	('IDO', 'Gene', '3620', (43, 46))	('IDO', 'Gene', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('TTP', 'MPA', (69, 72))
180200	32456621	Our study further enhanced the view that high expression of IDO has a poor prognosis for cancer patients by performing meta-analysis on a large number of research data.	('IDO', 'Gene', (60, 63))	('high expression', 'Var', (41, 56))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('IDO', 'Gene', '3620', (60, 63))
180201	32456621	First, the high expression of IDO may be a universal prognostic biomarker for solid tumors.	('solid tumors', 'Disease', (78, 90))	('IDO', 'Gene', '3620', (30, 33))	('IDO', 'Gene', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('high', 'Var', (11, 15))
180203	32456621	Secondly, we verified that both Asian patients and other country patients harboring high expression of IDO were highly correlated with poor prognosis in patients with solid tumors, which did not vary because of ethnic differences.	('high expression', 'Var', (84, 99))	('solid tumors', 'Disease', (167, 179))	('patients', 'Species', '9606', (153, 161))	('solid tumors', 'Disease', 'MESH:D009369', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('IDO', 'Gene', '3620', (103, 106))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (38, 46))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('IDO', 'Gene', (103, 106))
180215	30401982	Here we report that the genetic or pharmacological inhibition of YAP repressed cancer stem cell (CSC)-like properties, including tumorsphere-forming potential, cell motility, and chemoresistance in vitro, and was sufficient to attenuate tumor growth and CSC marker expression in ESCC xenografts.	('tumors', 'Disease', (129, 135))	('ESCC', 'Disease', 'MESH:C562729', (279, 283))	('inhibition', 'Var', (51, 61))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('attenuate', 'NegReg', (227, 236))	('ESCC', 'Disease', (279, 283))	('cancer', 'Disease', (79, 85))	('chemoresistance', 'CPA', (179, 194))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cell motility', 'CPA', (160, 173))	('tumor', 'Disease', (237, 242))	('YAP', 'Gene', (65, 68))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
180218	30401982	Notably, ESCC samples from The Cancer Genome Atlas (TCGA) dataset had frequent (44%) instances of YAP gene amplification and genetic inactivation of Hippo pathway regulators.	('ESCC', 'Disease', (9, 13))	('Hippo pathway', 'Pathway', (149, 162))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ESCC', 'Disease', 'MESH:C562729', (9, 13))	('YAP gene', 'Gene', (98, 106))	('genetic inactivation', 'Var', (125, 145))
180220	30401982	Together, our findings provide evidence that genetic hyperactivation of YAP unbalances the YAP-SOX9 feedback loop and confers CSC-like features in ESCC, suggesting that this YAP-SOX9 circuit represents a potential therapeutic target.	('CSC-like', 'Disease', (126, 134))	('YAP', 'Gene', (72, 75))	('genetic hyperactivation', 'Var', (45, 68))	('ESCC', 'Disease', (147, 151))	('unbalances', 'NegReg', (76, 86))	('YAP-SOX9 feedback loop', 'MPA', (91, 113))	('ESCC', 'Disease', 'MESH:C562729', (147, 151))
180231	30401982	Importantly, we showed that frequent genetic hyperactivation of YAP disrupted the homeostasis of bidirectional regulation between YAP and SOX9, promoting stemness and ESCC progression.	('homeostasis of bidirectional regulation', 'MPA', (82, 121))	('ESCC', 'Disease', (167, 171))	('stemness', 'CPA', (154, 162))	('disrupted', 'NegReg', (68, 77))	('ESCC', 'Disease', 'MESH:C562729', (167, 171))	('promoting', 'PosReg', (144, 153))	('YAP', 'Gene', (64, 67))	('genetic hyperactivation', 'Var', (37, 60))
180234	30401982	In nonadherent sphere formation assays, knockdown of YAP decreased tumorsphere numbers and size compared with that of the scramble control, whereas ectopic expression of an siRNA-resistant YAP (with synonymous mutations at the siRNA target site) rescued the tumorsphere-forming capacity (Fig.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('knockdown', 'Var', (40, 49))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('decreased', 'NegReg', (57, 66))	('YAP', 'Gene', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('rescued', 'PosReg', (246, 253))
180247	30401982	2e), indicating that inhibition of YAP signaling decreases CSC-like properties in ESCC and therefore attenuates tumor growth.	('ESCC', 'Disease', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('decreases', 'NegReg', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CSC-like properties', 'MPA', (59, 78))	('inhibition', 'Var', (21, 31))	('attenuates', 'NegReg', (101, 111))	('tumor', 'Disease', (112, 117))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))
180252	30401982	YAP knockdown or verteporfin treatment reduced SOX9 promoter activity, whereas mutation of the TEAD1-binding site abrogated the effects of YAP depletion or verteporfin treatment (Fig.	('TEAD1', 'Gene', '7003', (95, 100))	('SOX9', 'Protein', (47, 51))	('verteporfin', 'Chemical', 'MESH:C098350', (156, 167))	('TEAD1', 'Gene', (95, 100))	('abrogated', 'NegReg', (114, 123))	('verteporfin', 'Chemical', 'MESH:C098350', (17, 28))	('mutation', 'Var', (79, 87))	('reduced', 'NegReg', (39, 46))
180259	30401982	Quantitative real-time PCR analysis confirmed the significant increase in the levels of miR-375, miR-506-3p, and miR-622 in Eca109-SOX9 cells, as well as reduced miRNA levels after SOX9 knockdown (Fig.	('miR-622', 'Gene', (113, 120))	('knockdown', 'Var', (186, 195))	('miR-506', 'Gene', '574511', (97, 104))	('miR-506', 'Gene', (97, 104))	('miR-622', 'Gene', '693207', (113, 120))	('miR-375', 'Gene', '494324', (88, 95))	('506-3p', 'Chemical', 'MESH:C012651', (101, 107))	('miRNA levels', 'MPA', (162, 174))	('reduced', 'NegReg', (154, 161))	('miR-375', 'Gene', (88, 95))	('increase', 'PosReg', (62, 70))
180263	30401982	SOX9 knockdown suppressed the activity of MIR506 promoter, whereas loss of the putative SOX9-binding site led to unresponsiveness to SOX9 repression (Fig.	('MIR506', 'Gene', '574511', (42, 48))	('SOX9', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('unresponsiveness', 'MPA', (113, 129))	('MIR506', 'Gene', (42, 48))	('loss', 'NegReg', (67, 71))	('suppressed', 'NegReg', (15, 25))	('activity', 'MPA', (30, 38))
180264	30401982	We then constructed luciferase reporter plasmids containing the YAP 3'-untranslated region (3'-UTR) fragment with wild type or mutated miR-506-3p-binding sites (Fig.	('506-3p', 'Chemical', 'MESH:C012651', (139, 145))	('miR-506', 'Gene', (135, 142))	('mutated', 'Var', (127, 134))	('miR-506', 'Gene', '574511', (135, 142))
180270	30401982	We further examined the impacts of dual inhibition of YAP and SOX9 on cells growth, motility, and chemoresistance to evaluate whether inhibition of SOX9 could potentiate the antitumor effect of YAP repression.	('tumor', 'Disease', (178, 183))	('inhibition', 'Var', (134, 144))	('SOX9', 'Gene', (148, 152))	('potentiate', 'PosReg', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
180271	30401982	Simultaneous knockdown of SOX9 and YAP further sensitized EC9706 and TE-1 cells to cisplatin treatment (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('cisplatin treatment', 'MPA', (83, 102))	('YAP', 'Gene', (35, 38))	('knockdown', 'Var', (13, 22))	('sensitized', 'Reg', (47, 57))
180275	30401982	MST1/2 and LATS1/2, upstream regulators of the Hippo tumor-suppressing signaling, are frequently deleted and mutated, whereas the downstream effectors, YAP and WWTR1 (encoding TAZ), are frequently amplified (Fig.	('MST1', 'Gene', '6789', (0, 4))	('MST1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutated', 'Var', (109, 116))	('WWTR1', 'Gene', (160, 165))	('WWTR1', 'Gene', '25937', (160, 165))	('tumor', 'Disease', (53, 58))	('LATS1', 'Gene', (11, 16))	('LATS1', 'Gene', '9113', (11, 16))
180281	30401982	However, in ESCC tissues, frequent YAP gene amplification and genetic inactivation of Hippo pathway regulators led to aberrant hyperactivation of YAP and disruption of homeostasis, inducing stemness and subsequent cancer development (Fig.	('cancer', 'Disease', (214, 220))	('YAP gene', 'Gene', (35, 43))	('ESCC', 'Disease', (12, 16))	('YAP', 'Gene', (146, 149))	('hyperactivation', 'PosReg', (127, 142))	('amplification', 'Var', (44, 57))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('genetic inactivation', 'Var', (62, 82))	('ESCC', 'Disease', 'MESH:C562729', (12, 16))	('inducing', 'PosReg', (181, 189))	('disruption of homeostasis', 'MPA', (154, 179))	('stemness', 'CPA', (190, 198))
180282	30401982	The Hippo/YAP signaling pathway is involved in the regulation of ESCC initiation and progression, indicated by the frequent genomic amplification of the YAP locus and deletion/mutation of the core Hippo kinases MST and LATS obtained from the TCGA genomic datasets of ESCC patient samples (Fig.	('MST', 'Gene', (211, 214))	('ESCC', 'Disease', (267, 271))	('deletion/mutation', 'Var', (167, 184))	('ESCC', 'Disease', 'MESH:C562729', (65, 69))	('ESCC', 'Disease', (65, 69))	('patient', 'Species', '9606', (272, 279))	('ESCC', 'Disease', 'MESH:C562729', (267, 271))	('YAP locus', 'Gene', (153, 162))
180286	30401982	Until now, two IHC studies have shown that nuclear YAP may serve as a predictive marker for worse outcome in ESCC.	('nuclear YAP', 'Var', (43, 54))	('ESCC', 'Disease', 'MESH:C562729', (109, 113))	('ESCC', 'Disease', (109, 113))
180288	30401982	Unexpectedly, Kaplan-Meier analysis of the TCGA Esophageal Carcinoma dataset indicated that adenocarcinoma patients with high level of YAP mRNA had longer overall survival, although no significant association was observed in squamous cell carcinoma patients (Supplementary Figure 1).	('adenocarcinoma', 'Disease', (92, 106))	('Esophageal Carcinoma', 'Disease', (48, 68))	('high level', 'Var', (121, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('overall', 'MPA', (155, 162))	('adenocarcinoma', 'Disease', 'MESH:D000230', (92, 106))	('patients', 'Species', '9606', (249, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('Esophageal Carcinoma', 'Disease', 'MESH:D004938', (48, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (225, 248))	('Carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (225, 248))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (48, 68))	('squamous cell carcinoma', 'Disease', (225, 248))	('longer', 'PosReg', (148, 154))	('patients', 'Species', '9606', (107, 115))
180291	30401982	ESCC cells with YAP knockdown exhibited decreased SOX9 expression, attenuated sphere-forming potential, and resistance to cytotoxic drugs.	('ESCC', 'Disease', 'MESH:C562729', (0, 4))	('expression', 'MPA', (55, 65))	('sphere-forming potential', 'CPA', (78, 102))	('resistance', 'CPA', (108, 118))	('attenuated', 'NegReg', (67, 77))	('ESCC', 'Disease', (0, 4))	('YAP', 'Gene', (16, 19))	('knockdown', 'Var', (20, 29))	('decreased', 'NegReg', (40, 49))	('SOX9', 'Protein', (50, 54))
180301	30401982	Moreover, YAP-inactivating therapy might yield optimal outcomes when combined with traditional chemotherapies targeting proliferative tumor bulk.	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('YAP-inactivating', 'Var', (10, 26))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
180302	30401982	Frequent aberrant hyperactivation of YAP breaks this feedback loop and disrupts tissue homeostasis in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('aberrant hyperactivation', 'Var', (9, 33))	('disrupts', 'NegReg', (71, 79))	('hyperactivation', 'Var', (18, 33))	('tissue homeostasis', 'MPA', (80, 98))	('breaks', 'NegReg', (41, 47))	('esophageal cancer', 'Disease', (102, 119))	('YAP', 'Gene', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('feedback loop', 'MPA', (53, 66))
180306	30401982	Antibodies against E-cadherin (sc-8426) and vimentin (sc-6260) were purchased from Santa Cruz Biotechnology.	('vimentin', 'Gene', '7431', (44, 52))	('E-cadherin', 'Gene', (19, 29))	('E-cadherin', 'Gene', '999', (19, 29))	('vimentin', 'Gene', (44, 52))	('sc-8426', 'Var', (31, 38))
180323	31543714	Alterations in mitochondria and mitochondrial DNA have been shown to be associated with various cancers, including esophageal cancer.	('mitochondria', 'MPA', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (72, 82))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))	('mitochondrial DNA', 'Protein', (32, 49))
180342	31543714	An inefficient mtDNA repair system also greatly increases the chances of mitochondria harboring mutations, some of which have been shown to drive carcinogenesis.	('carcinogenesis', 'Disease', (146, 160))	('increases', 'PosReg', (48, 57))	('mitochondria', 'MPA', (73, 85))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))	('mutations', 'Var', (96, 105))
180343	31543714	Alterations in mitochondria and mtDNA have been shown to be associated with various cancers, including esophageal cancer.	('esophageal cancer', 'Disease', (103, 120))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('Alterations', 'Var', (0, 11))	('cancers', 'Disease', (84, 91))	('mtDNA', 'Gene', (32, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mitochondria', 'Gene', (15, 27))	('associated', 'Reg', (60, 70))
180366	31543714	They also speculated that TP53 mutation(s) could be a cause of these metabolic alterations in the mitochondria and that the cells with the lowest levels of glycolysis did not eventually progress to cancer.	('TP53', 'Gene', (26, 30))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('mitochondria', 'MPA', (98, 110))	('cancer', 'Disease', (198, 204))	('mutation', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('TP53', 'Gene', '7157', (26, 30))	('metabolic alterations', 'MPA', (69, 90))
180369	31543714	Polymorphisms in the mitochondrial oxidative phosphorylation chain genes have been shown to possess some prognostic value in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('Polymorphisms', 'Var', (0, 13))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('colorectal cancer', 'Disease', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
180370	31543714	Overall, it is likely that metabolic changes involving the mitochondria not only offer a survival benefit to BE cells but also promote the progression of the disease from early BE to EAC.	('EAC', 'Gene', '1540', (183, 186))	('promote', 'PosReg', (127, 134))	('EAC', 'Gene', (183, 186))	('changes', 'Var', (37, 44))	('BE', 'Phenotype', 'HP:0100580', (177, 179))	('BE', 'Phenotype', 'HP:0100580', (109, 111))	('EAC', 'Phenotype', 'HP:0011459', (183, 186))	('survival benefit', 'CPA', (89, 105))
180374	31543714	These changes in MMP are also likely responsible for helping dysplastic and neoplastic cells escape apoptosis.	('changes', 'Var', (6, 13))	('dysplastic', 'Disease', (61, 71))	('dysplastic', 'Disease', 'MESH:D004416', (61, 71))	('MMP', 'Gene', (17, 20))
180377	31543714	More research is warranted to identify strategies to target changes in MMP in BE cells and explore the possibilities of using that knowledge to identify strategies of aiding early detection and efficiently stratifying the risk of progression in BE patients.	('changes', 'Var', (60, 67))	('BE', 'Phenotype', 'HP:0100580', (245, 247))	('BE', 'Phenotype', 'HP:0100580', (78, 80))	('patients', 'Species', '9606', (248, 256))	('MMP', 'Gene', (71, 74))
180384	31543714	indicated that a 4977bp deletion in mtDNA could be a useful biomarker to detect the severity of dysplasia.	('dysplasia', 'Disease', (96, 105))	('mtDNA', 'Gene', (36, 41))	('4977bp deletion', 'Var', (17, 32))	('dysplasia', 'Disease', 'MESH:D004476', (96, 105))
180387	31543714	demonstrated that mtDNA mutations such as with cytochrome c deficiency are an early event in the pathogenesis of BE, preceding the development of dysplasia and cancer.	('c deficiency', 'Disease', 'MESH:D030401', (58, 70))	('dysplasia and cancer', 'Disease', 'MESH:D009369', (146, 166))	('BE', 'Phenotype', 'HP:0100580', (113, 115))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('c deficiency', 'Disease', (58, 70))	('mutations', 'Var', (24, 33))	('mtDNA', 'Gene', (18, 23))
180391	31543714	Despite the advancements in our understanding of the role of mitochondrial dysfunction in cancer, it is still mostly unclear as to how exactly variations and mutations in the mitochondria promote the formation and progression of cancer.	('mitochondrial dysfunction', 'Disease', (61, 86))	('cancer', 'Disease', (229, 235))	('promote', 'PosReg', (188, 195))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('variations', 'Var', (143, 153))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('formation', 'CPA', (200, 209))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (61, 86))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (61, 86))	('mutations', 'Var', (158, 167))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
180399	31543714	Changes in mitochondrial membrane potential and mitochondrial genetic mutations are yet some other ways in which mitochondria could influence the metaplasia-dysplasia-cancer sequence.	('mutations', 'Var', (70, 79))	('mitochondrial membrane potential', 'MPA', (11, 43))	('metaplasia-dysplasia-cancer', 'Disease', 'MESH:D008679', (146, 173))	('mitochondrial genetic', 'Gene', (48, 69))	('metaplasia-dysplasia-cancer', 'Disease', (146, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Changes', 'Reg', (0, 7))	('influence', 'Reg', (132, 141))
180411	30647533	ELISA results showed that GSPE and BAY11-7082 reduced the secretion of inflammatory cytokines interleukin-6 and cyclooxygenase-2.	('BAY11-7082', 'Var', (35, 45))	('reduced', 'NegReg', (46, 53))	('cyclooxygenase-2', 'Gene', (112, 128))	('BAY11-7082', 'Chemical', 'MESH:C434003', (35, 45))	('cyclooxygenase-2', 'Gene', '5743', (112, 128))	('interleukin-6', 'Gene', (94, 107))	('interleukin-6', 'Gene', '3569', (94, 107))
180412	30647533	The results of PCR and western blotting indicated that GSPE and BAY11-7082 activated caspase-3 and attenuated the activation of the NF-kappaB signaling pathway.	('NF-kappaB', 'Gene', (132, 141))	('BAY11-7082', 'Chemical', 'MESH:C434003', (64, 74))	('activated', 'PosReg', (75, 84))	('BAY11-7082', 'Var', (64, 74))	('caspase-3', 'Gene', (85, 94))	('attenuated', 'NegReg', (99, 109))	('NF-kappaB', 'Gene', '4790', (132, 141))	('caspase-3', 'Gene', '836', (85, 94))
180424	30647533	Our previous studies determined that PCs reduced oxidative damage and inflammation.	('inflammation', 'Disease', 'MESH:D007249', (70, 82))	('reduced', 'NegReg', (41, 48))	('oxidative damage', 'MPA', (49, 65))	('PCs', 'Chemical', 'MESH:D044945', (37, 40))	('inflammation', 'Disease', (70, 82))	('PCs', 'Var', (37, 40))
180426	30647533	Although it was found that PCs could induce apoptosis in cancer cells, the role of NF-kappaB in the reversal of EC, as well as the mechanism, remains unclear.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('apoptosis', 'CPA', (44, 53))	('cancer', 'Disease', (57, 63))	('NF-kappaB', 'Gene', '4790', (83, 92))	('EC', 'Phenotype', 'HP:0011459', (112, 114))	('PCs', 'Chemical', 'MESH:D044945', (27, 30))	('induce', 'Reg', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('NF-kappaB', 'Gene', (83, 92))	('PCs', 'Var', (27, 30))
180461	30647533	The measurement of the concentration of IL-6 and COX-2 in ECA109 cells after treatment with GSPE + BAY11-7082 showed that GSPE + BAY11-7082 could inhibit the secretion of inflammatory cytokines in ECA109 cells; furthermore, the inhibitory effect of GSPE + BAY11-7082 was stronger than that caused by GSPE treatment alone (Figures 5(c) and 5(d)).	('inhibit', 'NegReg', (146, 153))	('EC', 'Phenotype', 'HP:0011459', (197, 199))	('COX-2', 'Gene', (49, 54))	('BAY11-7082', 'Chemical', 'MESH:C434003', (256, 266))	('BAY11-7082', 'Chemical', 'MESH:C434003', (129, 139))	('BAY11-7082', 'Chemical', 'MESH:C434003', (99, 109))	('IL-6', 'Gene', (40, 44))	('IL-6', 'Gene', '3569', (40, 44))	('EC', 'Phenotype', 'HP:0011459', (58, 60))	('secretion of inflammatory cytokines', 'MPA', (158, 193))	('COX-2', 'Gene', '4513', (49, 54))	('GSPE', 'Var', (122, 126))
180464	30647533	We examined the effects of GSPE and BAY11-7082 on the mRNA and protein expression of caspase-3 by using PCR and western blotting, respectively.	('BAY11-7082', 'Chemical', 'MESH:C434003', (36, 46))	('BAY11-7082', 'Var', (36, 46))	('caspase-3', 'Gene', (85, 94))	('mRNA and', 'MPA', (54, 62))	('caspase-3', 'Gene', '836', (85, 94))
180466	30647533	With an increased dose of GSPE and the addition of Bay11-7082, the expression level of caspase-3 mRNA and protein increased (Figures 7(a) and 7(b)).	('Bay11-7082', 'Var', (51, 61))	('caspase-3', 'Gene', '836', (87, 96))	('expression level', 'MPA', (67, 83))	('increased', 'PosReg', (114, 123))	('caspase-3', 'Gene', (87, 96))
180467	30647533	This suggested that GSPE and BAY11-7082 promoted the apoptosis of ECA109 cells through the activation of caspase-3.	('BAY11-7082', 'Chemical', 'MESH:C434003', (29, 39))	('apoptosis', 'CPA', (53, 62))	('promoted', 'PosReg', (40, 48))	('BAY11-7082', 'Var', (29, 39))	('activation', 'PosReg', (91, 101))	('caspase-3', 'Gene', (105, 114))	('EC', 'Phenotype', 'HP:0011459', (66, 68))	('caspase-3', 'Gene', '836', (105, 114))
180469	30647533	We used western blotting to detect the protein expression levels of various classical factors, including IKK, IkappaB, p-IkappaB, p50, and p65, in the NF-kappaB pathway.	('p65', 'Gene', (139, 142))	('p65', 'Gene', '5970', (139, 142))	('p50', 'Gene', (130, 133))	('p-IkappaB', 'Var', (119, 128))	('NF-kappaB', 'Gene', '4790', (151, 160))	('p50', 'Gene', '4790', (130, 133))	('NF-kappaB', 'Gene', (151, 160))
180473	30647533	However, we found that the treatment of BAY11-7082 alone did not result in a decrease in IKK mRNA levels (Figure 8(a)).	('decrease', 'NegReg', (77, 85))	('BAY11-7082', 'Chemical', 'MESH:C434003', (40, 50))	('BAY11-7082', 'Var', (40, 50))	('IKK mRNA levels', 'MPA', (89, 104))
180492	30647533	Based on the effects of GSPE, we also investigated the treatment of the NF-kappaB-specific inhibitor BAY11-7082 and found that GSPE + BAY11-7082 was a more effective inhibitor of the phosphorylation level of IkappaB compared with GSPE alone.	('BAY11-7082', 'Chemical', 'MESH:C434003', (134, 144))	('NF-kappaB', 'Gene', '4790', (72, 81))	('IkappaB', 'Protein', (208, 215))	('NF-kappaB', 'Gene', (72, 81))	('phosphorylation level', 'MPA', (183, 204))	('GSPE', 'Var', (127, 131))	('BAY11-7082', 'Chemical', 'MESH:C434003', (101, 111))
180493	30647533	This suggested that the inhibition of NF-kappaB by GSPE was achieved by the inhibition of IkappaB phosphorylation; a similar effect occurred with BAY11-7082, showing that GSPE and BAY11-7082 may have a synergistic inhibitory effect on the NF-kappaB in ECA109 cells.	('BAY11-7082', 'Chemical', 'MESH:C434003', (146, 156))	('inhibition', 'NegReg', (76, 86))	('BAY11-7082', 'Var', (180, 190))	('NF-kappaB', 'Gene', (239, 248))	('IkappaB', 'Protein', (90, 97))	('EC', 'Phenotype', 'HP:0011459', (252, 254))	('NF-kappaB', 'Gene', '4790', (38, 47))	('BAY11-7082', 'Chemical', 'MESH:C434003', (180, 190))	('NF-kappaB', 'Gene', (38, 47))	('inhibition', 'NegReg', (24, 34))	('NF-kappaB', 'Gene', '4790', (239, 248))
180503	30647533	BAY11-7082, a specific inhibitor of NF-kappaB, inhibits the phosphorylation of IkappaB.	('phosphorylation', 'MPA', (60, 75))	('IkappaB', 'Protein', (79, 86))	('NF-kappaB', 'Gene', (36, 45))	('BAY11-7082', 'Chemical', 'MESH:C434003', (0, 10))	('NF-kappaB', 'Gene', '4790', (36, 45))	('inhibits', 'NegReg', (47, 55))	('BAY11-7082', 'Var', (0, 10))
180504	30647533	Therefore, our findings also suggest that GSPE may directly affect IKK, inhibit the activation of IKK, and inhibit the phosphorylation of IkappaB; together, this inhibits the NF-kappaB pathway.	('inhibit', 'NegReg', (107, 114))	('IkappaB', 'Protein', (138, 145))	('NF-kappaB', 'Gene', '4790', (175, 184))	('GSPE', 'Var', (42, 46))	('phosphorylation', 'MPA', (119, 134))	('inhibits', 'NegReg', (162, 170))	('NF-kappaB', 'Gene', (175, 184))	('activation', 'MPA', (84, 94))	('inhibit', 'NegReg', (72, 79))	('affect', 'Reg', (60, 66))	('IKK', 'Pathway', (98, 101))	('IKK', 'Protein', (67, 70))
180577	29552310	The overall results indicated that the loss of p27 protein expression was an independent prognostic biomarker for OS but not for DFS and CSS in patients with DTCs.	('p27', 'Gene', (47, 50))	('OS', 'Chemical', '-', (114, 116))	('patients', 'Species', '9606', (144, 152))	('loss', 'Var', (39, 43))	('CSS', 'Chemical', '-', (137, 140))	('p27', 'Gene', '10671', (47, 50))
180624	29552310	The ORs with 95% CIs were applied to investigate the relationships between p27 expression and lymph node metastasis (negative vs. positive), distant metastasis (negative vs. positive) and pathology grading (G1+G2 vs. G3+G4).	('p27', 'Gene', (75, 78))	('lymph node metastasis', 'CPA', (94, 115))	('G1+G2 vs.', 'Var', (207, 216))	('G3+G4', 'Var', (217, 222))	('p27', 'Gene', '10671', (75, 78))	('distant metastasis', 'CPA', (141, 159))
180642	28445321	However, patients with synchronous tumors and MPMTs of the digestive system showed a shorter survival time.	('shorter', 'NegReg', (85, 92))	('patients', 'Species', '9606', (9, 17))	('synchronous tumors', 'Disease', (23, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('MPMTs', 'Chemical', '-', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('survival time', 'CPA', (93, 106))	('synchronous tumors', 'Disease', 'MESH:D009378', (23, 41))	('MPMTs', 'Var', (46, 51))
180710	28445321	In addition, for both first primary and second primary tumors, the patients with MPMTs of the digestive system showed a shorter survival time than patients with MPMTs of other systems (Fig.	('primary tumors', 'Disease', 'MESH:D009369', (47, 61))	('MPMTs', 'Var', (81, 86))	('shorter', 'NegReg', (120, 127))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('MPMTs', 'Chemical', '-', (161, 166))	('patients', 'Species', '9606', (147, 155))	('MPMTs', 'Chemical', '-', (81, 86))	('primary tumors', 'Disease', (47, 61))	('survival time', 'CPA', (128, 141))
180748	28445321	When analyzed in more detail, MPMTs were most frequently associated with the stomach and the esophagus (synchronous group, n = 16; metachronous group, n = 4) in our study.	('MPMTs', 'Var', (30, 35))	('esophagus', 'Disease', (93, 102))	('stomach', 'Disease', (77, 84))	('MPMTs', 'Chemical', '-', (30, 35))	('associated', 'Reg', (57, 67))
180765	28445321	Specifically, the germline mutations of BRCA1/BRCA2 were associated with increased risk of breast, ovarian, stomach, colorectum, uterus, and pancreas cancers.	('germline mutations', 'Var', (18, 36))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('stomach', 'Disease', (108, 115))	('BRCA2', 'Gene', (46, 51))	('pancreas cancers', 'Disease', 'MESH:D010190', (141, 157))	('uterus', 'Disease', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('colorectum', 'Disease', (117, 127))	('BRCA2', 'Gene', '675', (46, 51))	('BRCA1', 'Gene', '672', (40, 45))	('ovarian', 'Disease', (99, 106))	('breast', 'Disease', (91, 97))	('pancreas cancers', 'Disease', (141, 157))	('associated', 'Reg', (57, 67))	('BRCA1', 'Gene', (40, 45))
180766	28445321	ATM truncations were also detected in many cancer types, mostly in lung, stomach, and prostate cancers.PABL2 gene variation was associated with increased risk of ovarian and stomach carcinoma.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('ovarian and stomach carcinoma', 'Disease', 'MESH:D013274', (162, 191))	('cancer', 'Disease', (43, 49))	('prostate cancers', 'Disease', 'MESH:D011471', (86, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancer', 'Disease', (95, 101))	('stomach carcinoma', 'Phenotype', 'HP:0012126', (174, 191))	('ATM', 'Gene', (0, 3))	('prostate cancers', 'Phenotype', 'HP:0012125', (86, 102))	('associated', 'Reg', (128, 138))	('prostate cancers', 'Disease', (86, 102))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('variation', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('ATM', 'Gene', '472', (0, 3))
180767	28445321	The POLD1 mutation was also associated with colorectal cancer and endometrial cancer predisposition.	('colorectal cancer', 'Disease', (44, 61))	('associated', 'Reg', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('endometrial cancer', 'Phenotype', 'HP:0012114', (66, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('mutation', 'Var', (10, 18))	('endometrial cancer', 'Disease', 'MESH:D016889', (66, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (44, 61))	('POLD1', 'Gene', '5424', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('POLD1', 'Gene', (4, 9))	('endometrial cancer', 'Disease', (66, 84))
180770	28445321	Genetic instability may play an important role in the development of second primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Genetic instability', 'Var', (0, 19))	('men', 'Species', '9606', (61, 64))	('primary tumors', 'Disease', (76, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('primary tumors', 'Disease', 'MESH:D009369', (76, 90))
180801	26273351	Cox multivariate analysis showed that pT3-4a stage (odds ratio [OR] = 3.604, P = 0.027), positive LNM in 2-station (OR = 4.834, P = 0.009) or 2-field (OR = 5.689, P = 0.003) and no adjuvant chemotherapy (OR = 1.594, p = 0.048) were independent risk factors for postoperative recurrence.	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('pT3', 'Gene', '7694', (38, 41))	('positive LNM', 'Var', (89, 101))	('pT3', 'Gene', (38, 41))
180808	26273351	According to our previous study, the five-year survival rate is similar between pN0 (32%) and pN1 (48%), compared to pN2 (12%) and pN3 patients (0%).	('patients', 'Species', '9606', (135, 143))	('pN2', 'Gene', (117, 120))	('pN3', 'Gene', '6336', (131, 134))	('pN0', 'Var', (80, 83))	('pN3', 'Gene', (131, 134))	('pN1', 'Gene', '5270', (94, 97))	('pN2', 'Gene', '351', (117, 120))	('pN1', 'Gene', (94, 97))
180841	26273351	Cox multivariate analysis showed that multi-stations and/or multi-fields of positive lymph node metastasis were independent risk factors for postoperative recurrence.	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('multi-stations', 'Var', (38, 52))
180916	23977217	however, those authors stated that an ALDH2 deficiency does not influence esophageal cancer risk in non-drinkers, implying that topical carcinogen exposure is essential in the pathogenesis of these patients.	('deficiency', 'Var', (44, 54))	('patients', 'Species', '9606', (198, 206))	('ALDH2', 'Gene', '217', (38, 43))	('ALDH2', 'Gene', (38, 43))	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
180917	23977217	There is already evidence showing that deficiencies in ALDH2 are associated with an increased risk of oral cancers.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('associated', 'Reg', (65, 75))	('ALDH2', 'Gene', '217', (55, 60))	('oral cancers', 'Disease', 'MESH:D009062', (102, 114))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('oral cancers', 'Disease', (102, 114))	('deficiencies', 'Var', (39, 51))	('ALDH2', 'Gene', (55, 60))
181066	33334030	On the other hand, the transmembrane glycoproteins of the mucin family, such as mucin 1, 4, and 16, are mesenchymal markers and their expression promotes an increase in migratory and invasive capacity.	('mucin', 'Gene', '100508689', (58, 63))	('mucin 1', 'Gene', (80, 87))	('mucin', 'Gene', '100508689', (80, 85))	('expression', 'Var', (134, 144))	('mucin', 'Gene', (58, 63))	('transmembrane glycoproteins', 'Protein', (23, 50))	('mucin 1', 'Gene', '4582', (80, 87))	('mucin', 'Gene', (80, 85))	('increase', 'PosReg', (157, 165))	('promotes', 'PosReg', (145, 153))
181085	33334030	Over the years, research on the biological function of leptin has increased, showing great interest in the discovery of a possible treatment for obesity and other pathologies mainly related to the reduction of this hormone through combinations of biomolecules or the replacement of leptin.	('obesity', 'Phenotype', 'HP:0001513', (145, 152))	('reduction', 'NegReg', (197, 206))	('leptin', 'Protein', (282, 288))	('combinations', 'Interaction', (231, 243))	('obesity', 'Disease', 'MESH:D009765', (145, 152))	('obesity', 'Disease', (145, 152))	('replacement', 'Var', (267, 278))
181092	33334030	Leptin belongs to the class I long-chain superfamily of cytokines; it has a compact tertiary structure, characterized by two pairs of antiparallel alpha helices, and a disulfide bridge that involves two cysteine residues (Cys 96 and Cys 146), fundamental for binding with its receptor.	('disulfide', 'Chemical', 'MESH:D004220', (168, 177))	('Leptin', 'Gene', (0, 6))	('Cys', 'Chemical', 'MESH:D003545', (222, 225))	('Cys', 'Chemical', 'MESH:D003545', (233, 236))	('Cys 146', 'Var', (233, 240))	('binding', 'Interaction', (259, 266))	('cysteine', 'Chemical', 'MESH:D003545', (203, 211))	('Cys 96', 'Var', (222, 228))
181102	33334030	The onset of the activation of the JAK2-STAT3 signaling pathway occurs with the phosphorylation at Tyr 1138, the recruitment of STAT3 through its SH2 domain (Src homology 2), its phosphorylation at Y705 and its subsequent dimerization and translocation to the nucleus, where it induces gene transcription of the appetite regulating-neuropeptides POMC, AgRP, and NPY and the suppressor of cytokine signaling 3 (SOCS3).	('NPY', 'Gene', (362, 365))	('Src', 'Gene', (158, 161))	('suppressor of cytokine signaling 3', 'Gene', (374, 408))	('STAT3', 'Gene', (128, 133))	('AgRP', 'Gene', '181', (352, 356))	('Tyr', 'Chemical', 'MESH:D014443', (99, 102))	('POMC', 'Gene', '5443', (346, 350))	('JAK2', 'Gene', (35, 39))	('Tyr 1138', 'Var', (99, 107))	('Src', 'Gene', '6714', (158, 161))	('induces', 'PosReg', (278, 285))	('dimerization', 'MPA', (222, 234))	('POMC', 'Gene', (346, 350))	('activation', 'PosReg', (17, 27))	('phosphorylation', 'Var', (80, 95))	('translocation', 'MPA', (239, 252))	('NPY', 'Gene', '4852', (362, 365))	('suppressor of cytokine signaling 3', 'Gene', '9021', (374, 408))	('AgRP', 'Gene', (352, 356))	('phosphorylation', 'MPA', (179, 194))	('gene transcription', 'MPA', (286, 304))	('JAK2', 'Gene', '3717', (35, 39))
181104	33334030	On the other hand, the JAK2-STAT5 pathway initiates the phosphorylation of JAK2 at Tyr1077, followed by activation and translocation to the nucleus of STAT5.	('JAK2', 'Gene', '3717', (75, 79))	('STAT5', 'Gene', (28, 33))	('STAT5', 'Gene', (151, 156))	('JAK2', 'Gene', (23, 27))	('JAK2', 'Gene', (75, 79))	('translocation', 'MPA', (119, 132))	('Tyr1077', 'Chemical', '-', (83, 90))	('STAT5', 'Gene', '6776', (151, 156))	('STAT5', 'Gene', '6776', (28, 33))	('phosphorylation', 'MPA', (56, 71))	('Tyr1077', 'Var', (83, 90))	('JAK2', 'Gene', '3717', (23, 27))
181105	33334030	Deletion of STAT5 has been shown to cause leptin resistance, hyperphagia, and obesity, contributing to leptin-dependent regulation of energy balance and body weight.	('hyperphagia', 'Disease', 'MESH:D006963', (61, 72))	('obesity', 'Disease', 'MESH:D009765', (78, 85))	('cause', 'Reg', (36, 41))	('contributing', 'Reg', (87, 99))	('STAT5', 'Gene', '6776', (12, 17))	('obesity', 'Disease', (78, 85))	('Deletion', 'Var', (0, 8))	('hyperphagia', 'Phenotype', 'HP:0002591', (61, 72))	('STAT5', 'Gene', (12, 17))	('hyperphagia', 'Disease', (61, 72))	('obesity', 'Phenotype', 'HP:0001513', (78, 85))	('leptin resistance', 'Disease', (42, 59))
181106	33334030	The ERK pathway activation depends on the JAK phosphorylation at Tyr985 promoting the interaction between Src homology region 2 domain-containing phosphatase-2 (SHP2), and growth factor receptor-bound protein 2 (GRB-2), resulting in ERK activation and inducing its translocation to the nucleus to mediate the gene expression of c-Fos and of the early growth response protein, EGR-1.	('phosphatase', 'Gene', (146, 157))	('interaction', 'Interaction', (86, 97))	('GRB-2', 'Gene', (212, 217))	('Src', 'Gene', '6714', (106, 109))	('gene expression', 'MPA', (309, 324))	('ERK', 'Gene', (233, 236))	('phosphatase', 'Gene', '5728', (146, 157))	('SHP2', 'Gene', (161, 165))	('c-Fos', 'Gene', (328, 333))	('c-Fos', 'Gene', '2353', (328, 333))	('growth factor receptor-bound protein 2', 'Gene', '2885', (172, 210))	('EGR-1', 'Gene', '1958', (376, 381))	('growth factor receptor-bound protein 2', 'Gene', (172, 210))	('inducing', 'Reg', (252, 260))	('activation', 'PosReg', (237, 247))	('Tyr985', 'Var', (65, 71))	('EGR-1', 'Gene', (376, 381))	('promoting', 'PosReg', (72, 81))	('Src', 'Gene', (106, 109))	('Tyr985', 'Chemical', '-', (65, 71))	('GRB-2', 'Gene', '2885', (212, 217))	('translocation to the nucleus', 'MPA', (265, 293))	('SHP2', 'Gene', '5781', (161, 165))
181115	33334030	AMPK is formed by a catalytic alpha subunit and two regulatory subunits (beta and gamma); its activation depends on the phosphorylation at Thr172, while its inhibition is mediated by the phosphorylation at Ser485/49.	('Ser485', 'Chemical', '-', (206, 212))	('Thr172', 'Chemical', '-', (139, 145))	('Thr172', 'Var', (139, 145))	('AMPK', 'Gene', '5562', (0, 4))	('phosphorylation', 'Var', (120, 135))	('AMPK', 'Gene', (0, 4))	('activation', 'PosReg', (94, 104))
181117	33334030	Inhibition of hypothalamic AMPK is sufficient to reduce food intake and gain weight.	('hypothalamic AMPK', 'Disease', 'MESH:D007027', (14, 31))	('food intake', 'CPA', (56, 67))	('reduce food intake', 'Phenotype', 'HP:0011968', (49, 67))	('gain weight', 'Phenotype', 'HP:0004324', (72, 83))	('gain', 'PosReg', (72, 76))	('Inhibition', 'Var', (0, 10))	('hypothalamic AMPK', 'Disease', (14, 31))	('reduce', 'NegReg', (49, 55))
181122	33334030	In addition to elevated leptin levels, some studies indicate that mutations in leptin, ObR, and signaling pathways are important objects of study to comprehend multiple diseases such as cancer.	('mutations', 'Var', (66, 75))	('elevated leptin', 'Phenotype', 'HP:0031793', (15, 30))	('leptin levels', 'MPA', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('ob', 'Gene', '16846', (129, 131))	('leptin', 'Gene', (79, 85))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
181147	33334030	In an in vitro model of differentiated acini derived from HMT-3522 S1 mammary epithelial cells, and in 3D cultures of nonimmortalized post-stasis human mammary epithelial cells (psHMEC), leptin leads to apical-basal polarity loss by modulating the distribution of the tight junctions (TJ) proteins ZO-1 and claudin-1 and unsettling the cortical F-actin cytoskeleton.	('HMT-3522 S1', 'CellLine', 'CVCL:2499', (58, 69))	('distribution', 'MPA', (248, 260))	('modulating', 'Reg', (233, 243))	('cortical F-actin cytoskeleton', 'CPA', (336, 365))	('loss', 'NegReg', (225, 229))	('ZO-1', 'Gene', (298, 302))	('claudin-1', 'Gene', '9076', (307, 316))	('human', 'Species', '9606', (146, 151))	('unsettling', 'Reg', (321, 331))	('ZO-1', 'Gene', '7082', (298, 302))	('leptin', 'Var', (187, 193))	('apical-basal polarity', 'CPA', (203, 224))	('claudin-1', 'Gene', (307, 316))
181158	33334030	demonstrated the pivotal role of macrophages in the leptin-induced effects in nude BALB/C mice, where leptin promotes the largest tumors and pulmonary metastasis, reduces survival, and also induces IL-8 overexpression.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('IL-8', 'Protein', (198, 202))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('leptin', 'Var', (102, 108))	('survival', 'CPA', (171, 179))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (141, 161))	('reduces', 'NegReg', (163, 170))	('pulmonary metastasis', 'Disease', (141, 161))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('overexpression', 'PosReg', (203, 217))	('induces', 'Reg', (190, 197))	('promotes', 'PosReg', (109, 117))
181171	33334030	In accordance with the in vitro and in vivo analysis carried out by Chang and collaborators, a microarray analysis using normal and malignant breast tissue samples, found a strong correlation between high ObR, leptin, and p-STAT expression and low miR-200c expression, with poorly differentiated high-grade tumors.	('tumors', 'Phenotype', 'HP:0002664', (307, 313))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumors', 'Disease', 'MESH:D009369', (307, 313))	('p-STAT expression', 'MPA', (222, 239))	('expression', 'MPA', (257, 267))	('leptin', 'Protein', (210, 216))	('high ObR', 'Var', (200, 208))	('low', 'NegReg', (244, 247))	('miR-200c', 'Protein', (248, 256))	('tumors', 'Disease', (307, 313))
181202	33334030	Despite the few studies linking leptin to the progression of lung cancer, it has been reported that the polymorphism of the leptin gene LEP-2548 G/A increases the susceptibility to the development of non-small-cell lung cancer (NSCLC), which represents 75-80% of lung cancer.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('lung cancer', 'Disease', (263, 274))	('polymorphism', 'Var', (104, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('LEP-2548', 'Gene', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (215, 226))	('increases', 'PosReg', (149, 158))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (200, 226))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('non-small-cell lung cancer', 'Disease', (200, 226))	('NSCLC', 'Disease', (228, 233))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('NSCLC', 'Disease', 'MESH:D002289', (228, 233))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))
181224	33334030	Overexpression of the leptin receptor ObR in patient tissue samples is associated with bladder carcinogenesis.	('bladder carcinogenesis', 'Disease', (87, 109))	('ObR', 'Gene', (38, 41))	('leptin receptor', 'Gene', (22, 37))	('bladder carcinogenesis', 'Disease', 'MESH:D001749', (87, 109))	('leptin receptor', 'Gene', '3953', (22, 37))	('patient', 'Species', '9606', (45, 52))	('Overexpression', 'Var', (0, 14))	('associated', 'Reg', (71, 81))
181256	33182528	Our previous studies demonstrated that the novel oncolytic adenovirus Ad-TD-nsIL12 (human adenovirus type 5 with E1ACR2, E1B19K, E3gp19K-triple deletions)harboring human non-secretory IL-12 had significant anti-tumor effect, with no toxicity, in a Syrian hamster pancreatic cancer model.	('adenovirus', 'Species', '10508', (90, 100))	('toxicity', 'Disease', (233, 241))	('Ad-TD-nsIL12', 'Chemical', '-', (70, 82))	('tumor', 'Disease', (211, 216))	('adenovirus', 'Species', '10508', (59, 69))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (263, 280))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('Syrian hamster', 'Species', '10036', (248, 262))	('E1B', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('human', 'Species', '9606', (84, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (263, 280))	('toxicity', 'Disease', 'MESH:D064420', (233, 241))	('human adenovirus type 5', 'Species', '28285', (84, 107))	('human', 'Species', '9606', (164, 169))	('pancreatic cancer', 'Disease', (263, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('E1B', 'Gene', '594', (121, 124))	('E3gp19K-triple', 'Var', (129, 143))
181257	33182528	In this study, we evaluated the anti-tumor effect of Ad-TD-nsIL12 in human ESCC.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Ad-TD-nsIL12', 'Var', (53, 65))	('ESCC', 'Disease', (75, 79))	('human', 'Species', '9606', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Ad-TD-nsIL12', 'Chemical', '-', (53, 65))
181258	33182528	The cytotoxicity of Ad-TD-nsIL12, H101 and cisplatin were investigated in two newly established patient-derived tumor cells (PDCs) and a panel of ESCC cell lines in vitro.	('Ad-TD-nsIL12', 'Chemical', '-', (20, 32))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('H101', 'Chemical', '-', (34, 38))	('patient', 'Species', '9606', (96, 103))	('cytotoxicity', 'Disease', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Ad-TD-nsIL12', 'Var', (20, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('tumor', 'Disease', (112, 117))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
181260	33182528	The results showed that Ad-TD-nsIL12 was more cytotixic to and replicated more effectively in human ESCC cell lines than H101.	('cytotixic', 'MPA', (46, 55))	('Ad-TD-nsIL12', 'Chemical', '-', (24, 36))	('human', 'Species', '9606', (94, 99))	('H101', 'Chemical', '-', (121, 125))	('Ad-TD-nsIL12', 'Var', (24, 36))	('replicated', 'CPA', (63, 73))
181261	33182528	Compared with cisplatin and H101, Ad-TD-nsIL12 could significantly inhibit tumor growth and tumor angiogenesis as well as enhance survival rate of animals with no side effects.	('survival rate', 'CPA', (130, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('inhibit', 'NegReg', (67, 74))	('enhance', 'PosReg', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Ad-TD-nsIL12', 'Chemical', '-', (34, 46))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('H101', 'Chemical', '-', (28, 32))	('Ad-TD-nsIL12', 'Var', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (75, 80))
181262	33182528	These findings suggest that Ad-TD-nsIL12 has superior anti-tumor potency against human ESCC with a good safety profile.	('tumor', 'Disease', (59, 64))	('Ad-TD-nsIL12', 'Var', (28, 40))	('Ad-TD-nsIL12', 'Chemical', '-', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('human', 'Species', '9606', (81, 86))	('human ESCC', 'Disease', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
181273	33182528	Unfortunately, H101-related efficacy is poor, largely due to the deletion of the E1B55K and E3B genes, which dramatically reduce the replicative ability of virus and accelerate the clearance rate of virus from tumor tissue.	('deletion', 'Var', (65, 73))	('reduce', 'NegReg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('E1B', 'Gene', '594', (81, 84))	('E1B', 'Gene', (81, 84))	('tumor', 'Disease', (210, 215))	('E3B', 'Gene', (92, 95))	('accelerate', 'PosReg', (166, 176))	('H101', 'Chemical', '-', (15, 19))	('clearance', 'CPA', (181, 190))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('replicative ability of virus', 'CPA', (133, 161))
181274	33182528	Combination of H101 with conventional chemotherapeutic drugs has been investigated to improve clinical efficacy, however the therapeutic effect remains insufficient.	('H101', 'Chemical', '-', (15, 19))	('H101', 'Var', (15, 19))	('improve', 'PosReg', (86, 93))
181275	33182528	Recently, we constructed a novel adenovirus 5-based Ad-TD, which had three gene deletions (E1ACR2, E1B19K and E3gp19K) but retains the E3B gene.	('E1ACR2', 'Var', (91, 97))	('adenovirus 5', 'Species', '28285', (33, 45))	('E1B', 'Gene', '594', (99, 102))	('Ad', 'Chemical', '-', (52, 54))	('E3gp19K', 'Var', (110, 117))	('E1B', 'Gene', (99, 102))
181281	33182528	Our previous studies showed that Ad-TD-nsIL12 was more potent compared to unarmed Ad-TD in Syrian hamster pancreatic cancer models, and the safety was significantly improved compared to that of Ad-TD-IL12.	('safety', 'MPA', (140, 146))	('Syrian hamster', 'Species', '10036', (91, 105))	('improved', 'PosReg', (165, 173))	('pancreatic cancer', 'Disease', 'MESH:D010190', (106, 123))	('Ad', 'Chemical', '-', (194, 196))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Ad-TD-nsIL12', 'Var', (33, 45))	('Ad', 'Chemical', '-', (82, 84))	('Ad', 'Chemical', '-', (33, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (106, 123))	('Ad-TD-nsIL12', 'Chemical', '-', (33, 45))	('pancreatic cancer', 'Disease', (106, 123))
181282	33182528	In order to evaluate the efficacy of Ad-TD-nsIL12 in ESCC, the selection of the evaluation model is critical.	('Ad-TD-nsIL12', 'Var', (37, 49))	('ESCC', 'Disease', (53, 57))	('Ad-TD-nsIL12', 'Chemical', '-', (37, 49))
181290	33182528	In this study, we compared the therapeutic effect of Ad-TD-nsIL12, H101 and traditional cisplatin treatment using primary patient-derived tumor cells and a panel of ESCC cell lines in immune-deficient Syrian hamsters and provide a new strategy for the treatment of esophageal cancer.	('Syrian hamsters', 'Species', '10036', (201, 216))	('cancer', 'Disease', (276, 282))	('tumor', 'Disease', (138, 143))	('Ad-TD-nsIL12', 'Var', (53, 65))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('patient', 'Species', '9606', (122, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Ad-TD-nsIL12', 'Chemical', '-', (53, 65))	('H101', 'Chemical', '-', (67, 71))
181297	33182528	Recombinant adenovirus H101 (human adenovirus type 5 with deletions of the E1B55K and E3B genes) was purchased from Shanghai Sunway Biotech Co., Ltd. (Shanghai, China).	('H101', 'Chemical', '-', (23, 27))	('E1B', 'Gene', '594', (75, 78))	('adenovirus', 'Species', '10508', (12, 22))	('deletions', 'Var', (58, 67))	('E1B', 'Gene', (75, 78))	('E3B', 'Gene', (86, 89))	('human adenovirus type 5', 'Species', '28285', (29, 52))	('adenovirus', 'Species', '10508', (35, 45))
181298	33182528	Recombinant adenovirus 5-based Ad-TD-LUC with E1ACR2, E1B19K, E3gp19K-triple deletions and luciferase insertion, and Ad-TD-nsIL12 with E1ACR2, E1B19K, E3gp19K-triple deletions and non-secreted IL-12 (nsIL12, without signal peptide fragments of IL-12) insertion were constructed in our laboratory as previsously described.	('E1B', 'Gene', (143, 146))	('E3gp19K-triple', 'Var', (62, 76))	('adenovirus 5', 'Species', '28285', (12, 24))	('E1B', 'Gene', '594', (54, 57))	('E3gp19K-triple deletions', 'Var', (151, 175))	('nsIL12', 'Chemical', '-', (123, 129))	('E1B', 'Gene', '594', (143, 146))	('Ad-TD-nsIL12', 'Chemical', '-', (117, 129))	('Ad', 'Chemical', '-', (117, 119))	('Ad', 'Chemical', '-', (31, 33))	('E1ACR2', 'Var', (135, 141))	('E1B', 'Gene', (54, 57))	('nsIL12', 'Chemical', '-', (200, 206))	('E1ACR2', 'Var', (46, 52))
181334	33182528	Primary antibodies were as follows: anti-E1A (1:100 dilution, Clone M58, GeneTex, San Antonio, TX, USA), anti-Ki67 (Clone OTI8H5, ZXGB-BIO, Beijing, China), anti-p63 (Clone 4A4+UMAB4, ZXGB-BIO, Beijing, China), Pan Cytokeratin (AE1/AE3) (Clone MX005, MXB Biotechnologies, Fuzhou, CHN), and anti-CD31 (1:1000 dilution, Clone ab182981, Abcam, Cambridge, MA, USA).	('AE1/AE3', 'Gene', (228, 235))	('MXB', 'Gene', '4600', (251, 254))	('AE1/AE3)', 'Gene', '6521;6508', (228, 236))	('anti-E1A', 'Var', (36, 44))	('CD31', 'Gene', (295, 299))	('CHN', 'Gene', '1123', (280, 283))	('p63', 'Gene', (162, 165))	('CD31', 'Gene', '5175', (295, 299))	('CHN', 'Gene', (280, 283))	('MXB', 'Gene', (251, 254))	('anti-Ki67', 'Var', (105, 114))	('p63', 'Gene', '8626', (162, 165))
181346	33182528	Among the ten detected cells lines and two PDCs, four cell lines including KYSE150, KYSE30, KYSE520 and KYSE410 showed a substantially higher tolerance to cisplatin with the IC50 of (29.6 +- 0.98 mumol/L), (25.54 +- 3.03 mumol/L), (16.98 +- 0.55 mumol/L) and (18.94 +- 0.76 mumol/L) respectively, which were comparable to previously reported IC50 values of ESCC cells for cisplatin (3.39 +- 0.087 mumol/L) (Table S2).	('KYSE520', 'Var', (92, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (372, 381))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('KYSE150', 'Var', (75, 82))	('KYSE410', 'Var', (104, 111))	('KYSE30', 'Var', (84, 90))	('higher', 'PosReg', (135, 141))	('tolerance', 'MPA', (142, 151))
181348	33182528	Two cell lines including KYSE520, KYSE510 and SBRC-EC02 showed a higher tolerance to 5-fluorouracil with the IC50 of (314.63 +- 40.86 mumol/L), (92.08 +- 7.64 mumol/L) and (148.47 +- 9.18 mumol/L) respectively, which were comparable to previously reported IC50 values of ESCC cells for 5-fluorouracil (78.57 +- 2.94 mumol/L) (Table S2).	('KYSE510', 'Var', (34, 41))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (85, 99))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (286, 300))	('higher', 'PosReg', (65, 71))	('tolerance', 'MPA', (72, 81))	('SBRC-EC02', 'CellLine', 'CVCL:W875', (46, 55))
181351	33182528	Ad-TD-nsIL12 exhibited a better cytotoxic effect on the majority of human ESCC cell lines and the PDCs than Ad-TD-LUC and H101.	('Ad-TD-nsIL12', 'Chemical', '-', (0, 12))	('human', 'Species', '9606', (68, 73))	('H101', 'Chemical', '-', (122, 126))	('Ad', 'Chemical', '-', (0, 2))	('Ad-TD-nsIL12', 'Var', (0, 12))	('cytotoxic effect', 'CPA', (32, 48))	('Ad', 'Chemical', '-', (108, 110))
181353	33182528	Ad-TD-nsIL12 showed better replication capability than H101, which replicated poorly in the tumor cells lines tested (Figure 3B-E).	('Ad-TD-nsIL12', 'Chemical', '-', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('H101', 'Chemical', '-', (55, 59))	('replication', 'MPA', (27, 38))	('Ad-TD-nsIL12', 'Var', (0, 12))	('tumor', 'Disease', (92, 97))
181356	33182528	In the early stage of Ad-TD-nsIL12 infection (within 24 h), low levels of IL-12 was detected from supernatants and lysate, which steadily increase from 48 h post infection, but peaked at a maximum level of not more than 6 ng/mL in the supernatant, demonstrating that each cell line supported viral replication and transgene expression, but nsIL-12 was not released in significant amounts from intact cells (Figure S3).	('nsIL-12', 'Chemical', '-', (340, 347))	('Ad-TD-nsIL12', 'Chemical', '-', (22, 34))	('infection', 'Disease', (162, 171))	('Ad-TD-nsIL12', 'Var', (22, 34))	('viral replication', 'CPA', (292, 309))	('infection', 'Disease', (35, 44))	('infection', 'Disease', 'MESH:D007239', (35, 44))	('expression', 'MPA', (324, 334))	('infection', 'Disease', 'MESH:D007239', (162, 171))	('transgene', 'Var', (314, 323))
181360	33182528	In addition, SBRC-EC01 had strong tumorigenicity in the immune-deficient Syrian hamster (ZZU001), but not in B-NDG mice or BALB/c Nude mice, and the pathological structure of subcutaneous tumor was similar to the primary tumor (Figure S4).	('tumor', 'Disease', (188, 193))	('Nude mice', 'Species', '10090', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('SBRC-EC01', 'CellLine', 'CVCL:9726', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (175, 193))	('B-NDG', 'Chemical', '-', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mice', 'Species', '10090', (135, 139))	('SBRC-EC01', 'Var', (13, 22))	('Syrian hamster', 'Species', '10036', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('mice', 'Species', '10090', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
181362	33182528	To determine whether Ad-TD-nsIL12 can inhibit the growth of tumors in vivo, a subcutaneous SBRC-EC01 xenograft tumor model was established in ZZU001 hamsters.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('SBRC-EC01', 'CellLine', 'CVCL:9726', (91, 100))	('hamster', 'Species', '10034', (149, 156))	('Ad-TD-nsIL12', 'Chemical', '-', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Disease', (111, 116))	('Ad-TD-nsIL12', 'Var', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (60, 65))	('inhibit', 'NegReg', (38, 45))	('tumors', 'Disease', (60, 66))
181364	33182528	Animals were each injected intratumorally with Ad-TD-nsIL12 (5 x 108 PFU) or H101 (5 x 108 PFU) or PBS six times.	('H101', 'Chemical', '-', (77, 81))	('Ad-TD-nsIL12', 'Chemical', '-', (47, 59))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Ad-TD-nsIL12', 'Var', (47, 59))	('PBS', 'Chemical', '-', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
181366	33182528	Compared with the PBS group, Ad-TD-nsIL12 had a significant therapeutic effect on subcutaneous xenograft tumors (p < 0.0001).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('Ad-TD-nsIL12', 'Var', (29, 41))	('Ad-TD-nsIL12', 'Chemical', '-', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('PBS', 'Chemical', '-', (18, 21))
181371	33182528	In addition, cisplatin induced a loss in body weight and caused mortality after treatment compared with the virus treatment group (Figure 4A,C,F,G).	('mortality', 'Disease', 'MESH:D003643', (64, 73))	('body weight', 'CPA', (41, 52))	('loss', 'NegReg', (33, 37))	('cisplatin', 'Var', (13, 22))	('mortality', 'Disease', (64, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
181372	33182528	Compared with the Ad-TD-nsIL12 group, the therapeutic effect of H101 was worse (p < 0.001).	('H101', 'Chemical', '-', (64, 68))	('therapeutic', 'MPA', (42, 53))	('Ad-TD-nsIL12', 'Chemical', '-', (18, 30))	('H101', 'Var', (64, 68))
181373	33182528	Although H101 could significantly inhibit the growth of tumor, the tumor did not disappear (Figure 4A,E).	('H101', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('inhibit', 'NegReg', (34, 41))	('H101', 'Chemical', '-', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
181376	33182528	On the 11th day after the first viral injection, high levels of E1A were detected in the tumor tissues of the Ad-TD-nsIL12 and H101 treatment groups.	('H101', 'Chemical', '-', (127, 131))	('H101', 'Var', (127, 131))	('Ad-TD-nsIL12', 'Chemical', '-', (110, 122))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('E1A', 'Protein', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
181377	33182528	On the 21st day, a high level of E1A was still detected in the tumor tissues of the Ad-TD-nsIL12 animals, but none was detected in H101-treated animals at this timepoint.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Ad-TD-nsIL12', 'Var', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Ad-TD-nsIL12', 'Chemical', '-', (84, 96))	('H101', 'Chemical', '-', (131, 135))
181381	33182528	Compared with cisplatin or PBS groups, the percentage of Ki67-positive tumor cells in the Ad-TD-nsIL12 group was significantly decreased at all timepoints (p < 0.05) (Figure 6A), demonstrating that Ad-TD-nsIL12 could effectively inhibit the proliferation of tumor cells.	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('decreased', 'NegReg', (127, 136))	('tumor', 'Disease', (258, 263))	('Ad-TD-nsIL12', 'Var', (198, 210))	('inhibit', 'NegReg', (229, 236))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Ad-TD-nsIL12', 'Chemical', '-', (90, 102))	('PBS', 'Chemical', '-', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', (71, 76))	('Ad-TD-nsIL12', 'Chemical', '-', (198, 210))
181384	33182528	11 days after the first treatment, a marked reduction of vascularity was observed in the Ad-TD-nsIL12 group (p < 0.01), which might be related to the previously defined anti-angiogenic effect of IL-12.	('Ad-TD-nsIL12', 'Var', (89, 101))	('reduction', 'NegReg', (44, 53))	('vascularity', 'MPA', (57, 68))	('Ad-TD-nsIL12', 'Chemical', '-', (89, 101))
181389	33182528	However, given that a major function of E1B55K protein is to promote the nuclear export of the late viral mRNAs to the cytoplasm for viral protein synthesis, deletion of E1B55K affects virus replication, attenuating the potential anti-tumor effect associated with H101.	('affects', 'Reg', (177, 184))	('attenuating', 'NegReg', (204, 215))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('E1B', 'Gene', '594', (170, 173))	('E1B', 'Gene', '594', (40, 43))	('promote', 'PosReg', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('H101', 'Chemical', '-', (264, 268))	('tumor', 'Disease', (235, 240))	('E1B', 'Gene', (170, 173))	('nuclear export of the late viral mRNAs to the', 'MPA', (73, 118))	('E1B', 'Gene', (40, 43))	('deletion', 'Var', (158, 166))	('virus replication', 'MPA', (185, 202))
181390	33182528	Deletion of the E3B gene region also attenuates viral replication and accelerated virus clearance, thus further reducing antitumor efficacy.	('reducing', 'NegReg', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('E3B', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('viral replication', 'CPA', (48, 65))	('tumor', 'Disease', (125, 130))	('attenuates', 'NegReg', (37, 47))	('virus clearance', 'CPA', (82, 97))	('accelerated', 'PosReg', (70, 81))	('Deletion', 'Var', (0, 8))
181392	33182528	Deletion of E1B19K and E3gp19K increases tumor selectivity of the virus.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('E3gp19K', 'Var', (23, 30))	('E1B', 'Gene', '594', (12, 15))	('tumor', 'Disease', (41, 46))	('increases', 'PosReg', (31, 40))	('E1B', 'Gene', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Deletion', 'Var', (0, 8))
181393	33182528	Further, the E3gp19K deletion increases virus replication, cytotoxic T lymphocyte infiltration and antitumor efficacy associated with OAd.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('virus replication', 'CPA', (40, 57))	('E3gp19K', 'Var', (13, 20))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('OAd', 'Disease', (134, 137))	('cytotoxic T lymphocyte infiltration', 'CPA', (59, 94))	('Ad', 'Chemical', '-', (135, 137))	('increases', 'PosReg', (30, 39))
181401	33182528	With the replication of virus restricted to tumor cells, IL-12 produced by the virus accumulates in the cytoplasm of infected cells.	('infected', 'Disease', 'MESH:D007239', (117, 125))	('accumulates', 'PosReg', (85, 96))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('virus', 'Var', (79, 84))	('infected', 'Disease', (117, 125))	('IL-12', 'Gene', (57, 62))	('tumor', 'Disease', (44, 49))
181403	33182528	Using this transgene, only a slight increase of IL-12 in peripheral blood was noted previously and Ad-TD-nsIL12 was shown to have potent antitumor effects, with no systemic toxic side-effects in vivo.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('Ad-TD-nsIL12', 'Var', (99, 111))	('tumor', 'Disease', (141, 146))	('Ad-TD-nsIL12', 'Chemical', '-', (99, 111))
181413	33182528	Higher cytopathic effects were observed for Ad-TD-nsIL12 compared with Ad-TD-LUC and H101 except in KYSE510 and KYSE150.	('Ad', 'Chemical', '-', (71, 73))	('Ad-TD-nsIL12', 'Var', (44, 56))	('H101', 'Chemical', '-', (85, 89))	('Ad', 'Chemical', '-', (44, 46))	('KYSE510', 'Var', (100, 107))	('KYSE150', 'Var', (112, 119))	('Ad-TD-nsIL12', 'Chemical', '-', (44, 56))	('cytopathic effects', 'CPA', (7, 25))
181414	33182528	Viruses could replicate in all the tumor cells and Ad-TD-nsIL12 had stronger replication ability compared to H101.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('H101', 'Chemical', '-', (109, 113))	('replication', 'MPA', (77, 88))	('stronger', 'PosReg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Ad-TD-nsIL12', 'Chemical', '-', (51, 63))	('tumor', 'Disease', (35, 40))	('Ad-TD-nsIL12', 'Var', (51, 63))
181417	33182528	The results showed that Ad-TD-nsIL12 had better cytopathic effect and replication capability in the majority of cell lines and the two PDCs.	('better', 'PosReg', (41, 47))	('Ad-TD-nsIL12', 'Chemical', '-', (24, 36))	('Ad-TD-nsIL12', 'Var', (24, 36))	('cytopathic effect', 'CPA', (48, 65))	('replication capability', 'CPA', (70, 92))
181419	33182528	Having confirmed the efficacy of Ad-TD-nsIL12 in vitro, we next investigated the antitumor efficacy in vivo.	('tumor', 'Disease', (85, 90))	('Ad-TD-nsIL12', 'Var', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Ad-TD-nsIL12', 'Chemical', '-', (33, 45))
181427	33182528	The difference in control of the primary tumor was more marked, with Ad-TD-nsIL12 outperforming cisplatin and H101.	('Ad-TD-nsIL12', 'Var', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('tumor', 'Disease', (41, 46))	('H101', 'Chemical', '-', (110, 114))	('Ad-TD-nsIL12', 'Chemical', '-', (69, 81))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('outperforming', 'PosReg', (82, 95))
181430	33182528	Intratumoral inoculation with Ad-TD-nsIL12 markedly inhibited tumor growth and resulted in 100% survival, and the therapeutic effect of Ad-TD-nsIL12 was better than that of H101.	('H101', 'Chemical', '-', (173, 177))	('Ad-TD-nsIL12', 'Chemical', '-', (30, 42))	('Ad-TD-nsIL12', 'Chemical', '-', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('survival', 'CPA', (96, 104))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('Ad-TD-nsIL12', 'Var', (136, 148))	('Ad-TD-nsIL12', 'Var', (30, 42))	('tumor', 'Disease', (5, 10))	('inhibited', 'NegReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
181432	33182528	This suggests that the therapeutic effect of Ad-TD-nsIL12 on the tumor has not been fully exerted and in the presence of an intact immune system, the therapeutic effect is expected to be even stronger that we have shown here.	('tumor', 'Disease', (65, 70))	('Ad-TD-nsIL12', 'Chemical', '-', (45, 57))	('Ad-TD-nsIL12', 'Var', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
181433	33182528	Of note, there is currently no any Syrian hamster-derived esophageal cancer cell line or in vivo model available for evaluating the antitumour efficacy and safety of Ad-TD-nsIL12 and other immunotherapeutic agent for treatment of esophageal cancer.	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Ad-TD-nsIL12', 'Var', (166, 178))	('tumour', 'Disease', (136, 142))	('Syrian hamster', 'Species', '10036', (35, 49))	('Ad-TD-nsIL12', 'Chemical', '-', (166, 178))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', (69, 75))
181437	33182528	21 days after the first viral injection, E1A protein expression was still detected in the Ad-TD-nsIL12 group, but not in the H101 group.	('H101', 'Chemical', '-', (125, 129))	('Ad-TD-nsIL12', 'Chemical', '-', (90, 102))	('Ad-TD-nsIL12', 'Var', (90, 102))	('E1A protein', 'Protein', (41, 52))
181439	33182528	Thus, H101 has a weaker abililty to replicate and/or a faster clearance rate compared to Ad-TD-nsIL12, as suggested by the functional losses as a result of the E1B55K and E3B gene deletions in H101.	('E1B', 'Gene', '594', (160, 163))	('Ad-TD-nsIL12', 'Chemical', '-', (89, 101))	('H101', 'Gene', (193, 197))	('E3B', 'Var', (171, 174))	('H101', 'Chemical', '-', (6, 10))	('faster', 'PosReg', (55, 61))	('losses', 'NegReg', (134, 140))	('clearance', 'MPA', (62, 71))	('E1B', 'Gene', (160, 163))	('H101', 'Chemical', '-', (193, 197))	('abililty', 'MPA', (24, 32))
181441	33182528	Tumors in the Ad-TD-nsIL12 group showed weaker CD31 expression compared to the other groups.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('weaker', 'NegReg', (40, 46))	('CD31', 'Gene', (47, 51))	('Ad-TD-nsIL12', 'Chemical', '-', (14, 26))	('expression', 'MPA', (52, 62))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CD31', 'Gene', '5175', (47, 51))	('Ad-TD-nsIL12', 'Var', (14, 26))
181442	33182528	The result suggested that Ad-TD-nsIL12 could inhibit angiogenesis of tumor tissues by generating IL-12.	('Ad-TD-nsIL12', 'Chemical', '-', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('IL-12', 'MPA', (97, 102))	('tumor', 'Disease', (69, 74))	('Ad-TD-nsIL12', 'Var', (26, 38))	('inhibit', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
181443	33182528	Both Ad-TD-nsIL12 and H101 could inhibit the proliferation of SBRC-EC01 cells in tumors more strongly than cisplatin.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('H101', 'Chemical', '-', (22, 26))	('proliferation', 'CPA', (45, 58))	('inhibit', 'NegReg', (33, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('Ad-TD-nsIL12', 'Var', (5, 17))	('H101', 'Var', (22, 26))	('SBRC-EC01', 'CellLine', 'CVCL:9726', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('Ad-TD-nsIL12', 'Chemical', '-', (5, 17))
181450	33182528	In conclusion, Ad-TD-nsIL12 can effectively infect and replicate in human ESCC cells, produce cytotoxic effect, and has better therapeutic effect than H101 and conventional chemotherapy in ESCC subcutaneous transplantation tumors, with no associated toxicity.	('therapeutic effect', 'CPA', (127, 145))	('toxicity', 'Disease', 'MESH:D064420', (250, 258))	('toxicity', 'Disease', (250, 258))	('human', 'Species', '9606', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('replicate', 'CPA', (55, 64))	('tumors', 'Disease', (223, 229))	('Ad-TD-nsIL12', 'Var', (15, 27))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('H101', 'Chemical', '-', (151, 155))	('ESCC', 'Disease', (189, 193))	('cytotoxic effect', 'CPA', (94, 110))	('Ad-TD-nsIL12', 'Chemical', '-', (15, 27))
181451	33182528	As such Ad-TD-nsIL12 is a promising candidate anticancer agent for ESCC.	('Ad-TD-nsIL12', 'Var', (8, 20))	('ESCC', 'Disease', (67, 71))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Ad-TD-nsIL12', 'Chemical', '-', (8, 20))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
181453	33182528	Figure S2: Cytotoxicity of AD-TD-LUC, Ad-TD-nsIL12 and H101 in a panel of human ESCC cell lines.	('human', 'Species', '9606', (74, 79))	('Cytotoxicity of AD-TD-LUC', 'Disease', 'MESH:D064420', (11, 36))	('Cytotoxicity of AD-TD-LUC', 'Disease', (11, 36))	('Ad-TD-nsIL12', 'Chemical', '-', (38, 50))	('H101', 'Chemical', '-', (55, 59))	('Ad-TD-nsIL12', 'Var', (38, 50))
181454	33182528	Figure S3: The production of IL-12 by Ad-TD-nsIL-12 in infected tumor cells.	('production of IL-12', 'MPA', (15, 34))	('infected tumor', 'Disease', (55, 69))	('Ad', 'Chemical', '-', (38, 40))	('nsIL-12', 'Chemical', '-', (44, 51))	('infected tumor', 'Disease', 'MESH:D007239', (55, 69))	('Ad-TD-nsIL-12', 'Var', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
181575	30542452	Wild-type (WT) and mutant seeding regions of miR-455-5p in the 3'-UTR of Rab31 were chemically synthesized, following which SpeI and HindIII restriction sites were added and cloned into pMIR-REPORT luciferase reporter plasmids (0.5 microg; Thermo Fisher Scientific, Inc.) with WT or mutant 3'-UTR DNA sequences.	('miR-455', 'Gene', (45, 52))	('miR-455', 'Gene', '619556', (45, 52))	('5p', 'Chemical', '-', (53, 55))	('WT', 'Disease', 'MESH:C536751', (277, 279))	('mutant', 'Var', (283, 289))	('mutant', 'Var', (19, 25))	('Rab31', 'Gene', '11031', (73, 78))	('WT', 'Disease', 'MESH:C536751', (11, 13))	('Rab31', 'Gene', (73, 78))
181580	30542452	miR-455-5p was also significantly downregulated in ESCC tissues from patients with poor differentiation compared with tissues from patients with high or moderate differentiation (P<0.05; Fig.	('patients', 'Species', '9606', (131, 139))	('5p', 'Chemical', '-', (8, 10))	('miR-455', 'Gene', (0, 7))	('downregulated', 'NegReg', (34, 47))	('miR-455', 'Gene', '619556', (0, 7))	('poor differentiation', 'Var', (83, 103))	('ESCC', 'Disease', (51, 55))	('patients', 'Species', '9606', (69, 77))
181597	30542452	5C), whereas Rab31 downregulation induced by miR-455-5p overexpression reduced migration and invasion compared with the miR-NC group (P<0.05; Fig.	('Rab31', 'Gene', '11031', (13, 18))	('miR-455', 'Gene', (45, 52))	('miR', 'Gene', '220972', (120, 123))	('overexpression', 'Var', (56, 70))	('miR', 'Gene', (120, 123))	('miR-455', 'Gene', '619556', (45, 52))	('Rab31', 'Gene', (13, 18))	('5p', 'Chemical', '-', (53, 55))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('reduced', 'NegReg', (71, 78))	('downregulation', 'NegReg', (19, 33))
181604	30542452	It is associated with gene mutation, abnormal expression, epigenetic inheritance and tumor stem cells.	('tumor', 'Disease', (85, 90))	('abnormal expression', 'Var', (37, 56))	('associated', 'Reg', (6, 16))	('gene mutation', 'Var', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('epigenetic inheritance', 'Var', (58, 80))
181642	29946788	A feeling of a foreign body in the esophagus was significantly more common after stenting of the cervical esophagus (p = 0.0001), and hiccup was more common after stenting of the esophagogastric junction (p = 0.02).	('stenting', 'Var', (81, 89))	('hiccup', 'Disease', 'MESH:D006606', (134, 140))	('hiccup', 'Disease', (134, 140))	('hiccup', 'Phenotype', 'HP:0100247', (134, 140))
181687	29946788	Pain occurred more frequently in patients with stents the proximal and middle part of the esophagus (p = 0.004).	('patients', 'Species', '9606', (33, 41))	('Pain', 'Phenotype', 'HP:0012531', (0, 4))	('Pain', 'Disease', 'MESH:D010146', (0, 4))	('stents', 'Var', (47, 53))	('Pain', 'Disease', (0, 4))
181773	29301504	In addition, direct sequencing of extracted DNA from normal mucosa was performed to evaluate single nucleotide polymorphisms in ALDH2 and ADH1B.	('ALDH2', 'Gene', '217', (128, 133))	('single nucleotide polymorphisms', 'Var', (93, 124))	('ADH1B', 'Gene', (138, 143))	('ADH1B', 'Gene', '125', (138, 143))	('ALDH2', 'Gene', (128, 133))
181790	29301504	Patients with FAP exhibit colorectal polyposis and usually harbor adenomatous polyposis coli (APC) gene mutations.	('FAP', 'Disease', (14, 17))	('mutations', 'Var', (104, 113))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (66, 87))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (66, 92))	('colorectal polyposis', 'Disease', (26, 46))	('colorectal polyposis', 'Disease', 'MESH:D011125', (26, 46))	('FAP', 'Disease', 'MESH:C567782', (14, 17))	('adenomatous polyposis coli', 'Disease', (66, 92))	('Patients', 'Species', '9606', (0, 8))	('colorectal polyposis', 'Phenotype', 'HP:0200063', (26, 46))	('APC', 'Gene', (94, 97))	('APC', 'Gene', '324', (94, 97))
181791	29301504	The deletion at codon 1309 in the germline of the APC gene in patients with FAP has been previously reported, especially in profuse-type FAP.	('FAP', 'Disease', 'MESH:C567782', (137, 140))	('APC', 'Gene', '324', (50, 53))	('FAP', 'Disease', (76, 79))	('deletion at codon 1309', 'Var', (4, 26))	('FAP', 'Disease', 'MESH:C567782', (76, 79))	('APC', 'Gene', (50, 53))	('patients', 'Species', '9606', (62, 70))	('FAP', 'Disease', (137, 140))
181793	29301504	In the present case, colorectal lesions were nuclear beta-catenin positive, implying a possible mutation in the APC gene.	('APC', 'Gene', (112, 115))	('APC', 'Gene', '324', (112, 115))	('mutation', 'Var', (96, 104))	('beta-catenin', 'Gene', (53, 65))	('colorectal lesions', 'Disease', (21, 39))	('colorectal lesions', 'Disease', 'MESH:D015179', (21, 39))	('beta-catenin', 'Gene', '1499', (53, 65))
181804	29301504	Two colorectal cancers in the present case harbored KRAS mutations in conjunction with nuclear beta-catenin positivity, indicating an "alternate pathway of carcinogenesis".	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('KRAS', 'Gene', (52, 56))	('carcinogenesis', 'Disease', (156, 170))	('colorectal cancers', 'Disease', 'MESH:D015179', (4, 22))	('KRAS', 'Gene', '3845', (52, 56))	('colorectal cancers', 'Disease', (4, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('beta-catenin', 'Gene', (95, 107))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('beta-catenin', 'Gene', '1499', (95, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (4, 21))
181813	29301504	Patients with ALDH2 gene mutations are known to have a "flusher" phenotype and are reported to be prone to developing esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (25, 34))	('ALDH2', 'Gene', '217', (14, 19))	('prone', 'Reg', (98, 103))	('Patients', 'Species', '9606', (0, 8))	('ALDH2', 'Gene', (14, 19))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))
181814	29301504	Moreover, several studies have reported that genetic polymorphisms of ALDH2 and ADH1B are associated with gastric cancer and colorectal cancer.	('ADH1B', 'Gene', '125', (80, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('ALDH2', 'Gene', '217', (70, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('ADH1B', 'Gene', (80, 85))	('gastric cancer', 'Disease', (106, 120))	('associated', 'Reg', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('genetic polymorphisms', 'Var', (45, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('colorectal cancer', 'Disease', (125, 142))	('ALDH2', 'Gene', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
181815	29301504	The patient's single nucleotide polymorphisms in ALDH2 and ADH1 may have accounted for carcinogenesis in six of his cancers, including the esophageal, gastric and colorectal cancers.	('single nucleotide polymorphisms', 'Var', (14, 45))	('ADH1', 'Gene', (59, 63))	('ADH1', 'Gene', '124', (59, 63))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('colorectal cancers', 'Disease', (163, 181))	('esophageal', 'Disease', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('ALDH2', 'Gene', (49, 54))	('gastric', 'Disease', (151, 158))	('carcinogenesis', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patient', 'Species', '9606', (4, 11))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('ALDH2', 'Gene', '217', (49, 54))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('colorectal cancers', 'Disease', 'MESH:D015179', (163, 181))	('cancers', 'Disease', (116, 123))	('accounted for', 'Reg', (73, 86))
181819	29301504	ADH1B alcohol dehydrogenase ALDH2 acetaldehyde dehydrogenase APC adenomatous polyposis coli DNA deoxyribose nucleic acid FAP familial adenomatous polyposis FFPE formalin fixed paraffin embedded H. pylori  Helicobacter pylori  IHC immunohistochemistry MPMN multiple primary malignant neoplasms MSI microsatellite instability MSS microsatellite stable KA, KH, and TW contributed to the conception and design of the study.	('FAP', 'Disease', (121, 124))	('neoplasms', 'Phenotype', 'HP:0002664', (283, 292))	('formalin', 'Chemical', 'MESH:D005557', (161, 169))	('FAP', 'Disease', 'MESH:C567782', (121, 124))	('microsatellite', 'Var', (328, 342))	('Helicobacter pylori', 'Species', '210', (205, 224))	('ADH1B', 'Gene', '125', (0, 5))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (65, 86))	('MSS', 'Chemical', '-', (324, 327))	('ALDH2', 'Gene', '217', (28, 33))	('malignant neoplasms', 'Disease', 'MESH:D009369', (273, 292))	('APC', 'Gene', '324', (61, 64))	('malignant neoplasms', 'Disease', (273, 292))	('ADH1B', 'Gene', (0, 5))	('alcohol', 'Chemical', 'MESH:D000438', (6, 13))	('paraffin', 'Chemical', 'MESH:D010232', (176, 184))	('familial adenomatous polyposis', 'Disease', (125, 155))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (134, 155))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (125, 155))	('H. pylori', 'Species', '210', (194, 203))	('APC', 'Gene', (61, 64))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (65, 91))	('adenomatous polyposis coli', 'Disease', (65, 91))	('deoxyribose nucleic acid', 'Chemical', '-', (96, 120))	('ALDH2', 'Gene', (28, 33))
181845	27145270	The patients with a high level of cyclin D1 expression exhibited a decreased survival time, compared to patients with a low level of cyclin D1 expression in terms of both OS and DMFS in the training cohort (Figure 2A, 2B).	('survival time', 'CPA', (77, 90))	('DMFS', 'Chemical', '-', (178, 182))	('high', 'Var', (20, 24))	('cyclin D1 expression', 'Var', (34, 54))	('patients', 'Species', '9606', (4, 12))	('decreased', 'NegReg', (67, 76))	('patients', 'Species', '9606', (104, 112))
181847	27145270	A multivariate Cox regression analysis confirmed that a high level of cyclin D1 was an independent factor decreasing both the OS and DMFS in the training cohort (Table S3, S4).	('high level', 'Var', (56, 66))	('decreasing', 'NegReg', (106, 116))	('Cox', 'Gene', '1351', (15, 18))	('DMFS', 'Chemical', '-', (133, 137))	('Cox', 'Gene', (15, 18))
181852	27145270	As predicted, long-term survival also decreased in patients with a high level of cyclin D1 expression, opposed to patients with a low level.	('expression', 'MPA', (91, 101))	('decreased', 'NegReg', (38, 47))	('high', 'Var', (67, 71))	('long-term survival', 'CPA', (14, 32))	('patients', 'Species', '9606', (51, 59))	('patients', 'Species', '9606', (114, 122))	('cyclin D1', 'Protein', (81, 90))
181860	27145270	However, logistic regression analysis of 368 cases in that study indicated that cyclin D1 expression tended to increase the risk of hematogenous recurrence in the node-positive patients, but the p value is not statistically significant (p = 0.072).	('hematogenous', 'Disease', (132, 144))	('increase', 'PosReg', (111, 119))	('patients', 'Species', '9606', (177, 185))	('cyclin D1', 'Protein', (80, 89))	('expression', 'Var', (90, 100))
181891	19363439	Patients with metaplastic esophageal columnar epithelium without goblet cells showed positivity for MUC5AC, MUC2, DAS-1, Villin, and CDX2 in 100%, 0%, 30%, 70%, and 43% of cases, respectively.	('positivity', 'Var', (85, 95))	('MUC5AC', 'Gene', (100, 106))	('CDX2', 'Gene', (133, 137))	('MUC2', 'Gene', '4583', (108, 112))	('CDX2', 'Gene', '1045', (133, 137))	('MUC2', 'Gene', (108, 112))	('Patients', 'Species', '9606', (0, 8))	('MUC5AC', 'Gene', '4586', (100, 106))	('DAS-1', 'Gene', (114, 119))
181894	19363439	In patients with metaplastic esophageal columnar epithelium with goblet cells (BE) a significant increased rate of staining was observed for all markers, except MUC5AC.	('MUC5AC', 'Gene', (161, 167))	('BE', 'Phenotype', 'HP:0100580', (79, 81))	('increased', 'PosReg', (97, 106))	('MUC5AC', 'Gene', '4586', (161, 167))	('patients', 'Species', '9606', (3, 11))	('metaplastic', 'Var', (17, 28))	('staining', 'MPA', (115, 123))
181895	19363439	In addition, both MUC2 and surface Ki67 staining were significantly increased in BE patients with high density goblet cells versus those with low-density goblet cells.	('staining', 'MPA', (40, 48))	('patients', 'Species', '9606', (84, 92))	('high density', 'Var', (98, 110))	('MUC2', 'Gene', (18, 22))	('BE', 'Phenotype', 'HP:0100580', (81, 83))	('MUC2', 'Gene', '4583', (18, 22))	('Ki67', 'Chemical', '-', (35, 39))	('surface Ki67', 'Protein', (27, 39))	('increased', 'PosReg', (68, 77))
181960	19363439	The percentage of cases with DAS-1 and CDX-2 staining was significantly higher (p<0.05) than the gastric controls.	('staining', 'Var', (45, 53))	('higher', 'PosReg', (72, 78))	('DAS-1', 'Gene', (29, 34))	('CDX-2', 'Gene', '1045', (39, 44))	('CDX-2', 'Gene', (39, 44))
181968	19363439	Apart from MUC5AC, which, as indicated above, showed staining in mucinous columnar epithelium from all patient groups in 100% of cases, the percentage of cases that stained with MUC2, DAS-1, Villin, CDX-2, and Ki67 (surface epithelium staining) was increased in mucinous columnar epithelium in areas with goblet cells compared to mucinous columnar epithelium in areas without goblet cells, for both BE subgroups.	('mucin', 'Gene', '100508689', (65, 70))	('MUC5AC', 'Gene', (11, 17))	('BE', 'Phenotype', 'HP:0100580', (399, 401))	('mucin', 'Gene', '100508689', (262, 267))	('CDX-2', 'Gene', '1045', (199, 204))	('CDX-2', 'Gene', (199, 204))	('mucin', 'Gene', '100508689', (330, 335))	('Ki67', 'Chemical', '-', (210, 214))	('MUC2', 'Gene', (178, 182))	('MUC5AC', 'Gene', '4586', (11, 17))	('mucin', 'Gene', (65, 70))	('increased', 'PosReg', (249, 258))	('Ki67', 'Var', (210, 214))	('MUC2', 'Gene', '4583', (178, 182))	('mucin', 'Gene', (262, 267))	('mucin', 'Gene', (330, 335))	('patient', 'Species', '9606', (103, 110))
181969	19363439	In fact, MUC2 staining was observed in non-goblet epithelium in areas devoid of goblet cells in only 2 of 59 (3.3%) patients with metaplastic esophageal columnar epithelium with goblet cells in other areas of the mucosa.	('MUC2', 'Gene', (9, 13))	('metaplastic', 'Var', (130, 141))	('patients', 'Species', '9606', (116, 124))	('MUC2', 'Gene', '4583', (9, 13))
182002	19363439	Recent data also suggests that metaplastic esophageal non-goblet columnar epithelium in patients either with, or without, goblet cells in other portions of the mucosa, shows a variety of molecular and DNA content abnormalities in addition to intestinal differentiation, and, as a result, may be at risk for neoplastic progression.	('patients', 'Species', '9606', (88, 96))	('neoplastic progression', 'CPA', (307, 329))	('abnormalities', 'Var', (213, 226))
182024	33961153	The final preoperative diagnosis was a cT3N0M0 stage II squamous cell carcinoma of the esophagus, according to the Union for International Cancer Control (UICC) TNM classification (version 8) (used for all subsequent cancer classifications).	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('TNM', 'Gene', '10178', (161, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('squamous cell carcinoma', 'Disease', (56, 79))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 79))	('TNM', 'Gene', (161, 164))	('cancer', 'Disease', (217, 223))	('cT3N0M0', 'Var', (39, 46))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('Cancer', 'Disease', (139, 145))	('Cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
182193	33270176	4, Pt-Ir 10% reduces the total equivalent dose in the distance of 2.1 cm from the surface of the water balloon (3.4 cm from the active core) under the allowable limit.	('reduces', 'NegReg', (13, 20))	('Pt', 'Chemical', 'MESH:D010984', (3, 5))	('Pt-Ir', 'Var', (3, 8))	('equivalent dose', 'MPA', (31, 46))	('water', 'Chemical', 'MESH:D014867', (97, 102))
182237	32328462	Excess Fe2+ and H2O2 participate in Fenton reactions, generating reactive oxygen species (ROS),  OH and OH-.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (65, 88))	('Fe2+', 'Chemical', '-', (7, 11))	('Fenton', 'MPA', (36, 42))	('ROS', 'Chemical', 'MESH:D017382', (90, 93))	('Fe', 'Chemical', 'MESH:D007501', (36, 38))	('H2O2', 'Chemical', 'MESH:D006861', (16, 20))	('reactive oxygen species', 'MPA', (65, 88))	('H2O2', 'Var', (16, 20))	('rat', 'Species', '10116', (58, 61))	('Fe', 'Chemical', 'MESH:D007501', (7, 9))	('OH-', 'Var', (104, 107))	('Fe2+', 'Var', (7, 11))
182239	32328462	Furthermore, hydroxyl radicals can cause changes that lead to persistent inflammation and cell survival/proliferation signals.	('inflammation', 'Disease', 'MESH:D007249', (73, 85))	('inflammation', 'Disease', (73, 85))	('cell survival/proliferation signals', 'CPA', (90, 125))	('rat', 'Species', '10116', (111, 114))	('lead to', 'Reg', (54, 61))	('hydroxyl radicals', 'Chemical', 'MESH:D017665', (13, 30))	('hydroxyl radicals', 'Var', (13, 30))
182248	32328462	While a single genetic mutation, amplification or deletion is insufficient to cause metastasis, the accumulation of ROS through Fenton reactions can stimulate widespread modifications to DNA, proteins and lipids which promotes a more aggressive tumor phenotype.	('more', 'PosReg', (229, 233))	('ROS', 'Chemical', 'MESH:D017382', (116, 119))	('promotes', 'PosReg', (218, 226))	('deletion', 'Var', (50, 58))	('Fe', 'Chemical', 'MESH:D007501', (128, 130))	('aggressive tumor', 'Disease', 'MESH:D001523', (234, 250))	('aggressive tumor', 'Disease', (234, 250))	('modifications', 'MPA', (170, 183))	('lipids', 'Chemical', 'MESH:D008055', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('proteins', 'Protein', (192, 200))	('DNA', 'MPA', (187, 190))
182249	32328462	ROS induce metabolic rewiring in cancer cells toward glycolysis, a feature described as the "Warburg effect," however, the byproducts of this process increase intracellular acidity and in response, protons are exported into the extracellular space creating an acidic microenvironment.	('intracellular acidity', 'MPA', (159, 180))	('ROS', 'Var', (0, 3))	('metabolic', 'MPA', (11, 20))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('glycolysis', 'MPA', (53, 63))	('increase intracellular acidity', 'Phenotype', 'HP:0003575', (150, 180))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('increase', 'PosReg', (150, 158))	('protons', 'MPA', (198, 205))
182291	32328462	In contrast, high labile iron induces proteosomal degradation of IRPs, such that translation of ferritin mRNAs and ferroportin are unobstructed, while mRNAs with 3'-UTR IREs are subject to endonuclease attack and degraded.	('high', 'Var', (13, 17))	('IRP', 'Gene', (65, 68))	('proteosomal degradation', 'MPA', (38, 61))	('iron', 'Gene', (25, 29))	('IRP', 'Gene', '7472', (65, 68))	('iron', 'Gene', '102030740', (25, 29))	('induces', 'Reg', (30, 37))
182322	32328462	Surprisingly, lower TS and higher iron-free Tf was observed in stomach cancers, which could be partly explained by Helicobacter pylori infection, which decreases iron absorption and iron is lost through hemorrhagic gastritis.	('iron', 'Gene', (182, 186))	('hemorrhagic gastritis', 'Disease', (203, 224))	('lost', 'NegReg', (190, 194))	('iron', 'Gene', '102030740', (182, 186))	('hemorrhagic gastritis', 'Disease', 'MESH:D005756', (203, 224))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (115, 144))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('Helicobacter pylori', 'Var', (115, 134))	('infection', 'Disease', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('iron', 'Gene', (162, 166))	('infection', 'Disease', 'MESH:D007239', (135, 144))	('stomach cancers', 'Disease', 'MESH:D013274', (63, 78))	('iron', 'Gene', '102030740', (162, 166))	('gastritis', 'Phenotype', 'HP:0005263', (215, 224))	('decreases', 'NegReg', (152, 161))	('Tf', 'Gene', '7018', (44, 46))	('iron', 'Gene', (34, 38))	('Helicobacter pylori', 'Species', '210', (115, 134))	('higher', 'PosReg', (27, 33))	('iron', 'Gene', '102030740', (34, 38))	('stomach cancers', 'Disease', (63, 78))	('stomach cancers', 'Phenotype', 'HP:0012126', (63, 78))	('lower', 'NegReg', (14, 19))
182340	32328462	Hypermethylation of the Lf promoter has been observed in prostate cancer cell lines suggesting epigenetic silencing is a means of Lf loss in epithelial cells.	('prostate cancer', 'Disease', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('Lf', 'Gene', '280846', (24, 26))	('loss', 'NegReg', (133, 137))	('epigenetic silencing', 'Var', (95, 115))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('Lf', 'Gene', '280846', (130, 132))
182342	32328462	Although Lf is often not detectable in tumor tissues, Lf positivity correlates with good prognostic features including low Ki67 proliferation index and high progression-free and overall survival.	('high', 'PosReg', (152, 156))	('rat', 'Species', '10116', (135, 138))	('low', 'NegReg', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Ki67', 'Protein', (123, 127))	('tumor', 'Disease', (39, 44))	('positivity', 'Var', (57, 67))	('Lf', 'Gene', '280846', (54, 56))	('overall survival', 'CPA', (178, 194))	('Lf', 'Gene', '280846', (9, 11))
182349	32328462	In breast and thyroid cancers high LCN2 expression strongly correlated with advanced tumor grade and poor prognosis, but in ovarian, pancreatic and CRC it was associated well-differentiated tumors and a good prognosis.	('expression', 'MPA', (40, 50))	('tumor', 'Disease', (85, 90))	('breast and thyroid cancers', 'Disease', 'MESH:D001943', (3, 29))	('LCN2', 'Gene', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('high', 'Var', (30, 34))	('tumor', 'Disease', (190, 195))	('ovarian, pancreatic', 'Disease', 'MESH:D010195', (124, 143))	('correlated', 'Reg', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumors', 'Disease', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
182356	32328462	found that holo-LCN2 significantly induced migration and spheroid growth of renal cell carcinoma cells whereas iron-free LCN2 inhibited it.	('holo-LCN2', 'Var', (11, 20))	('induced', 'PosReg', (35, 42))	('spheroid growth of renal cell carcinoma', 'Disease', (57, 96))	('rat', 'Species', '10116', (46, 49))	('iron', 'Gene', '102030740', (111, 115))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('migration', 'CPA', (43, 52))	('spheroid growth of renal cell carcinoma', 'Disease', 'MESH:C538614', (57, 96))	('iron', 'Gene', (111, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
182361	32328462	Likewise, antisense oligonucleotides against TfR1 inhibited tumor growth and lung metastases in the 4T1 mammary adenocarcinoma mouse model.	('adenocarcinoma', 'Disease', (112, 126))	('antisense oligonucleotides', 'Var', (10, 36))	('mouse', 'Species', '10090', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('adenocarcinoma', 'Disease', 'MESH:D000230', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('TfR1', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('lung metastases', 'Disease', (77, 92))	('oligonucleotides', 'Chemical', 'MESH:D009841', (20, 36))	('lung metastases', 'Disease', 'MESH:D009362', (77, 92))	('tumor', 'Disease', (60, 65))	('inhibited', 'NegReg', (50, 59))
182362	32328462	Conflicting evidence is reported for CRC with histology showing TfR1 was elevated in tumors but associated with better survival rates and modifying TfR1 expression was said to promote growth, migration and invasion of CRC cell lines and suppress it in other reports.	('suppress', 'NegReg', (237, 245))	('survival', 'CPA', (119, 127))	('TfR1', 'Gene', (64, 68))	('TfR1', 'Gene', (148, 152))	('tumors', 'Disease', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('growth', 'CPA', (184, 190))	('rat', 'Species', '10116', (128, 131))	('invasion', 'CPA', (206, 214))	('modifying', 'Var', (138, 147))	('rat', 'Species', '10116', (195, 198))	('expression', 'MPA', (153, 163))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('promote', 'PosReg', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('elevated', 'PosReg', (73, 81))	('better', 'PosReg', (112, 118))	('migration', 'CPA', (192, 201))
182370	32328462	TfR2 is highly expressed in GBM and correlated with tumor grade, but inversely correlated with patient survival and TfR2 silencing in GBM cells inhibited proliferation and cell cycle progression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TfR2', 'Gene', '7036', (0, 4))	('silencing', 'Var', (121, 130))	('cell cycle progression', 'CPA', (172, 194))	('patient', 'Species', '9606', (95, 102))	('tumor', 'Disease', (52, 57))	('inhibited', 'NegReg', (144, 153))	('TfR2', 'Gene', (116, 120))	('rat', 'Species', '10116', (161, 164))	('TfR2', 'Gene', '7036', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('proliferation', 'CPA', (154, 167))	('TfR2', 'Gene', (0, 4))
182376	32328462	Several reports suggest DMT1 is responsible for intracellular iron accumulation to support CRC proliferation.	('CRC proliferation', 'CPA', (91, 108))	('DMT1', 'Var', (24, 28))	('rat', 'Species', '10116', (102, 105))	('iron', 'Gene', (62, 66))	('iron', 'Gene', '102030740', (62, 66))
182378	32328462	Colon specific knockout of DMT1 reduced tumor burden in CRC mouse models.	('knockout', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('reduced', 'NegReg', (32, 39))	('DMT1', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mouse', 'Species', '10090', (60, 65))
182382	32328462	ZIP14 is important for uptake of NTBI especially by the liver and interestingly, knockdown of p53 which is known to alter iron metabolism, increased iron uptake by ZIP14 in HepG2 liver cancer cells.	('liver cancer', 'Phenotype', 'HP:0002896', (179, 191))	('liver cancer', 'Disease', 'MESH:D006528', (179, 191))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('iron', 'Gene', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('liver cancer', 'Disease', (179, 191))	('NTBI', 'Chemical', '-', (33, 37))	('iron', 'Gene', '102030740', (149, 153))	('increased', 'PosReg', (139, 148))	('HepG2', 'CellLine', 'CVCL:0027', (173, 178))	('knockdown', 'Var', (81, 90))	('iron', 'Gene', '102030740', (122, 126))	('iron', 'Gene', (149, 153))
182412	32328462	Both FTL and FTH1 stained strongly in head and neck cancer tissues compared to normal and higher expression was observed with metastasis, however further analyses of public data found FTL had no prognostic significance but high FTH1 mRNA predicted poor survival.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('FTH1', 'Gene', (228, 232))	('head and neck cancer', 'Phenotype', 'HP:0012288', (38, 58))	('FTL', 'Gene', (184, 187))	('FTL', 'Gene', (5, 8))	('FTL', 'Gene', '2512', (184, 187))	('high', 'Var', (223, 227))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('poor', 'NegReg', (248, 252))	('mRNA', 'MPA', (233, 237))	('FTL', 'Gene', '2512', (5, 8))
182414	32328462	Interestingly, in triple negative breast cancer samples high cytoplasmic and total FTH1 was correlated with favorable prognosis, whereas high nuclear expression was a poor prognostic factor.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('high cytoplasmic', 'Var', (56, 72))	('FTH1', 'Gene', (83, 87))
182417	32328462	It was suggested nuclear FTH1 was protective of the DNA from free iron-induced toxicity and promoted a more aggressive phenotype.	('promoted', 'PosReg', (92, 100))	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('aggressive phenotype', 'CPA', (108, 128))	('toxicity', 'Disease', (79, 87))	('iron', 'Gene', (66, 70))	('FTH1', 'Var', (25, 29))	('iron', 'Gene', '102030740', (66, 70))
182418	32328462	In two separate studies downregulation of FTL with an antisense construct and FTH1 with shRNA in melanoma cells inhibited proliferation and invasion in vitro and tumor growth in vivo.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('melanoma', 'Disease', (97, 105))	('FTH1', 'Gene', (78, 82))	('antisense', 'Var', (54, 63))	('inhibited', 'NegReg', (112, 121))	('tumor', 'Disease', (162, 167))	('rat', 'Species', '10116', (129, 132))	('FTL', 'Gene', '2512', (42, 45))	('downregulation', 'NegReg', (24, 38))	('rat', 'Species', '10116', (11, 14))	('FTL', 'Gene', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
182420	32328462	Similarly, mesothelioma cells overexpress FTH1 to protect against asbestos-induced ROS and its knockdown rendered them more sensitive to apoptosis.	('asbestos', 'Chemical', 'MESH:D001194', (66, 74))	('more', 'PosReg', (119, 123))	('mesothelioma', 'Disease', (11, 23))	('asbestos-induced', 'Disease', (66, 82))	('knockdown', 'Var', (95, 104))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('FTH1', 'Gene', (42, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (11, 23))	('sensitive', 'MPA', (124, 133))	('overexpress', 'PosReg', (30, 41))
182434	32328462	Such an example is beta-phenethyl isothiocyanate, an inhibitor of leukemia cell growth, in part by producing ROS which degrade the Fe-S center of NADH dehydrogenase 3 from respiratory complex I and subsequently suppresses mitochondrial respiration.	('mitochondrial respiration', 'MPA', (222, 247))	('rat', 'Species', '10116', (241, 244))	('rat', 'Species', '10116', (177, 180))	('degrade', 'NegReg', (119, 126))	('suppresses', 'NegReg', (211, 221))	('leukemia', 'Disease', (66, 74))	('leukemia', 'Phenotype', 'HP:0001909', (66, 74))	('leukemia', 'Disease', 'MESH:D007938', (66, 74))	('ROS', 'Chemical', 'MESH:D017382', (109, 112))	('Fe-S', 'MPA', (131, 135))	('Fe-S', 'Chemical', 'MESH:D007501', (131, 135))	('ROS', 'Var', (109, 112))	('beta-phenethyl isothiocyanate', 'Chemical', '-', (19, 48))
182442	32328462	In vitro, 4T1 mouse mammary cells with inducible ferroportin expression had reduced colony forming ability, underwent cell cycle arrest and apoptosis.	('arrest', 'Disease', (129, 135))	('mouse', 'Species', '10090', (14, 19))	('underwent', 'Reg', (108, 117))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('apoptosis', 'CPA', (140, 149))	('colony forming ability', 'CPA', (84, 106))	('reduced', 'NegReg', (76, 83))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('ferroportin', 'Gene', (49, 60))	('inducible', 'Var', (39, 48))
182445	32328462	Cellular iron homeostasis is predominantly controlled by the IRE-IRP system, accordingly, altered expression of IRPs is associated with cancer.	('associated', 'Reg', (120, 130))	('altered', 'Var', (90, 97))	('IRP', 'Gene', '7472', (112, 115))	('iron', 'Gene', '102030740', (9, 13))	('IRP', 'Gene', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('IRP', 'Gene', '7472', (65, 68))	('IRP', 'Gene', (112, 115))	('iron', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('expression', 'MPA', (98, 108))
182446	32328462	For example, both IRP1 and IRP2 are overexpressed in breast cancer, but only knockdown of IRP2 decreased the LIP and inhibited mammary tumor growth in mice.	('decreased', 'NegReg', (95, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('mice', 'Species', '10090', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('knockdown', 'Var', (77, 86))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('inhibited', 'NegReg', (117, 126))	('IRP2', 'Gene', (90, 94))	('LIP', 'MPA', (109, 112))	('decreased the LIP', 'Phenotype', 'HP:0000233', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
182447	32328462	In human lung cancer cells with inducible IRP1 overexpression there was no impact on proliferation in vitro, but when implanted in vivo had suppressed tumor growth.	('suppressed', 'NegReg', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('overexpression', 'PosReg', (47, 61))	('IRP1', 'Gene', (42, 46))	('human', 'Species', '9606', (3, 8))	('tumor', 'Disease', (151, 156))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('rat', 'Species', '10116', (92, 95))	('lung cancer', 'Disease', (9, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('inducible', 'Var', (32, 41))
182449	32328462	In prostate cancer cells IRP2 was consistently overexpressed and knockdown inhibited growth in vitro and in vivo, while IRP1 was detected in some cell lines and knockdown only modestly reduced proliferation in vitro.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('rat', 'Species', '10116', (200, 203))	('inhibited', 'NegReg', (75, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('IRP2', 'Gene', (25, 29))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('growth', 'CPA', (85, 91))	('knockdown', 'Var', (65, 74))	('overexpressed', 'PosReg', (47, 60))
182450	32328462	IRP2 was overexpressed in colon cancer tissues compared to normal and interestingly, correlated with BRAF mutations and it was confirmed in vitro that IRP2 overexpression was driven by hyperactivation of the MAPK pathway.	('BRAF', 'Gene', (101, 105))	('hyperactivation', 'PosReg', (185, 200))	('overexpression', 'PosReg', (156, 170))	('colon cancer', 'Phenotype', 'HP:0003003', (26, 38))	('IRP2', 'Gene', (151, 155))	('colon cancer', 'Disease', 'MESH:D015179', (26, 38))	('MAPK pathway', 'Pathway', (208, 220))	('overexpressed', 'PosReg', (9, 22))	('colon cancer', 'Disease', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (106, 115))	('BRAF', 'Gene', '673', (101, 105))
182487	32328462	reported the iron chelator Dp44mT suppressed colon cancer cell viability, migration, invasion, and reversed TGF-beta-induced EMT through activation of Wnt/beta-catenin as they observed increased target gene expression.	('TGF-beta', 'Gene', (108, 116))	('iron', 'Gene', (13, 17))	('Wnt', 'Gene', '7472', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('iron', 'Gene', '102030740', (13, 17))	('invasion', 'CPA', (85, 93))	('colon cancer', 'Disease', (45, 57))	('rat', 'Species', '10116', (77, 80))	('Dp44mT', 'Var', (27, 33))	('EMT', 'CPA', (125, 128))	('Dp44mT', 'Chemical', 'MESH:C539263', (27, 33))	('activation', 'PosReg', (137, 147))	('increased', 'PosReg', (185, 194))	('beta-catenin', 'Gene', (155, 167))	('beta-catenin', 'Gene', '1499', (155, 167))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('migration', 'CPA', (74, 83))	('suppressed', 'NegReg', (34, 44))	('TGF-beta', 'Gene', '7039', (108, 116))	('Wnt', 'Gene', (151, 154))	('colon cancer', 'Disease', 'MESH:D015179', (45, 57))
182488	32328462	showed that Dp44mT reduced migration and metastasis in vivo, but reduced beta-catenin, c-myc, and cyclin D1.	('beta-catenin', 'Gene', (73, 85))	('reduced', 'NegReg', (65, 72))	('c-myc', 'Gene', '4609', (87, 92))	('c-myc', 'Gene', (87, 92))	('cyclin D1', 'Gene', '595', (98, 107))	('rat', 'Species', '10116', (30, 33))	('beta-catenin', 'Gene', '1499', (73, 85))	('cyclin D1', 'Gene', (98, 107))	('Dp44mT', 'Var', (12, 18))	('reduced', 'NegReg', (19, 26))	('Dp44mT', 'Chemical', 'MESH:C539263', (12, 18))
182489	32328462	Thus, crosstalk between TGF-beta and Wnt/beta-catenin signaling is well-established to promote EMT-induced migration and invasion, but downstream activity may depend on context.	('rat', 'Species', '10116', (110, 113))	('beta-catenin', 'Gene', (41, 53))	('TGF-beta', 'Gene', (24, 32))	('Wnt', 'Gene', (37, 40))	('beta-catenin', 'Gene', '1499', (41, 53))	('Wnt', 'Gene', '7472', (37, 40))	('TGF-beta', 'Gene', '7039', (24, 32))	('EMT-induced migration', 'CPA', (95, 116))	('invasion', 'CPA', (121, 129))	('promote', 'PosReg', (87, 94))	('crosstalk', 'Var', (6, 15))
182495	32328462	Iron-induced hydroxyl radicals and lipid peroxides increased expression of MMP-1 and MMP-3 after UVB irradiation of dermal fibroblasts, which cleave/degrade interstitial collagens, proteoglycans and structural glycoproteins, while DFO treatment degraded these MMPs.	('lipid peroxides', 'Chemical', 'MESH:D008054', (35, 50))	('cleave/degrade', 'NegReg', (142, 156))	('MMP-1', 'Gene', (75, 80))	('men', 'Species', '9606', (240, 243))	('increased', 'PosReg', (51, 60))	('lipid peroxides increased', 'Phenotype', 'HP:0025464', (35, 60))	('Iron', 'Gene', '102030740', (0, 4))	('MMP-3', 'Gene', '4314', (85, 90))	('proteoglycans', 'Protein', (181, 194))	('hydroxyl radicals', 'Chemical', 'MESH:D017665', (13, 30))	('interstitial collagens', 'MPA', (157, 179))	('MMP-3', 'Gene', (85, 90))	('Iron', 'Gene', (0, 4))	('cleave/degrade', 'Var', (142, 156))	('structural glycoproteins', 'Protein', (199, 223))	('DFO', 'Chemical', 'MESH:D003676', (231, 234))	('expression', 'MPA', (61, 71))	('MMP-1', 'Gene', '4312', (75, 80))
182496	32328462	Likewise, Dp44mT abrogates the induction of gelatinase activity (MMP-2) and inhibited liver tumor invasion.	('MMP-2', 'Gene', (65, 70))	('liver tumor', 'Disease', 'MESH:D008113', (86, 97))	('Dp44mT', 'Var', (10, 16))	('gelatinase activity', 'MPA', (44, 63))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Dp44mT', 'Chemical', 'MESH:C539263', (10, 16))	('MMP-2', 'Gene', '4313', (65, 70))	('inhibited', 'NegReg', (76, 85))	('abrogates', 'NegReg', (17, 26))	('liver tumor', 'Phenotype', 'HP:0002896', (86, 97))	('liver tumor', 'Disease', (86, 97))
182504	32328462	Therefore, too much or too little iron can induce migration of endothelial cells and encourage neo-vascularization.	('migration', 'CPA', (50, 59))	('neo-vascularization', 'CPA', (95, 114))	('iron', 'Gene', (34, 38))	('rat', 'Species', '10116', (53, 56))	('induce', 'PosReg', (43, 49))	('encourage', 'PosReg', (85, 94))	('iron', 'Gene', '102030740', (34, 38))	('too', 'Var', (11, 14))
182509	32328462	M2-like macrophages express high levels of ferroportin, however, its knockdown in cultured macrophages did not inhibit the release of iron into the supernatant, nor did it inhibit the proliferation-stimulating effect of the supernatants on breast cancer cells.	('inhibit', 'NegReg', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('rat', 'Species', '10116', (191, 194))	('iron', 'Gene', (134, 138))	('ferroportin', 'Gene', (43, 54))	('breast cancer', 'Disease', (240, 253))	('proliferation-stimulating effect', 'CPA', (184, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('iron', 'Gene', '102030740', (134, 138))	('inhibit', 'NegReg', (172, 179))	('high levels of ferroportin', 'Phenotype', 'HP:0003281', (28, 54))	('knockdown', 'Var', (69, 78))
182511	32328462	Holo-LCN2 accelerated proliferation and migration of lymphatic endothelial cells in 2D culture and promoted lymph vessel sprouting in 3D models.	('rat', 'Species', '10116', (16, 19))	('rat', 'Species', '10116', (43, 46))	('Holo-LCN2', 'Var', (0, 9))	('promoted', 'PosReg', (99, 107))	('rat', 'Species', '10116', (29, 32))	('accelerated', 'PosReg', (10, 21))	('proliferation', 'CPA', (22, 35))	('migration of lymphatic endothelial cells', 'CPA', (40, 80))	('lymph vessel sprouting', 'CPA', (108, 130))
182538	32328462	Although, recently it was found that DFO induces mitochondrial iron accumulation which generates ROS and, therefore, enhanced migration/invasion was driven by mitochondrial ROS.	('ROS', 'MPA', (97, 100))	('rat', 'Species', '10116', (91, 94))	('rat', 'Species', '10116', (129, 132))	('enhanced', 'PosReg', (117, 125))	('iron', 'Gene', (63, 67))	('DFO', 'Var', (37, 40))	('migration/invasion', 'CPA', (126, 144))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('ROS', 'Chemical', 'MESH:D017382', (173, 176))	('DFO', 'Chemical', 'MESH:D003676', (37, 40))	('iron', 'Gene', '102030740', (63, 67))
182552	32328462	Interestingly, iron chelating agents such ciclopirox olamine (CPX) and VLX600, have been shown to inhibit growth of both proliferating and quiescent cancer cells.	('growth', 'CPA', (106, 112))	('cancer', 'Disease', (149, 155))	('ciclopirox', 'Var', (42, 52))	('iron', 'Gene', '102030740', (15, 19))	('ciclopirox olamine', 'Chemical', 'MESH:D000077768', (42, 60))	('CPX', 'Chemical', 'MESH:D000077768', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('inhibit', 'NegReg', (98, 105))	('VLX600', 'Chemical', 'MESH:C000602558', (71, 77))	('VLX600', 'Var', (71, 77))	('rat', 'Species', '10116', (128, 131))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('iron', 'Gene', (15, 19))
182553	32328462	Through chelation of iron, activity of the iron-dependent enzymes that form part of the electron transport chain become impaired resulting in mitochondrial dysfunction.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (142, 167))	('iron', 'Gene', (43, 47))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (142, 167))	('iron', 'Gene', (21, 25))	('mitochondrial dysfunction', 'Disease', (142, 167))	('iron', 'Gene', '102030740', (43, 47))	('impaired', 'NegReg', (120, 128))	('chelation', 'Var', (8, 17))	('iron', 'Gene', '102030740', (21, 25))	('activity', 'MPA', (27, 35))
182601	32328462	These were screened in neuroepithelioma cells with three standout compounds NT, N4mT, N44mT, which showed anti-proliferative activity in additional cancer cell lines, but to a lesser extent in normal cells, such as fibroblasts or macrophages.	('cancer', 'Disease', (148, 154))	('anti-proliferative activity', 'MPA', (106, 133))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('neuroepithelioma', 'Disease', 'MESH:C563168', (23, 39))	('rat', 'Species', '10116', (118, 121))	('neuroepithelioma', 'Disease', (23, 39))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('NT', 'Chemical', '-', (76, 78))	('N44mT', 'Var', (86, 91))	('N4mT', 'Var', (80, 84))
182602	32328462	Based on the success of triapine the DpT series was developed, of which Dp44mT showed high iron chelation and anti-proliferative activity.	('anti-proliferative activity', 'CPA', (110, 137))	('triapine', 'Chemical', 'MESH:C078157', (24, 32))	('iron', 'Gene', (91, 95))	('Dp44mT', 'Var', (72, 78))	('iron', 'Gene', '102030740', (91, 95))	('Dp44mT', 'Chemical', 'MESH:C539263', (72, 78))	('rat', 'Species', '10116', (122, 125))	('DpT', 'Chemical', 'MESH:C059372', (37, 40))
182604	32328462	Dp44mt caused cardiotoxicity and weight loss in mice so efforts to progress to the clinic were halted.	('weight loss', 'Phenotype', 'HP:0001824', (33, 44))	('cardiotoxicity', 'Disease', 'MESH:D066126', (14, 28))	('mice', 'Species', '10090', (48, 52))	('weight loss', 'Disease', 'MESH:D015431', (33, 44))	('Dp44mt', 'Var', (0, 6))	('cardiotoxicity', 'Disease', (14, 28))	('weight loss', 'Disease', (33, 44))
182606	32328462	Bp44mT was also effective for inhibiting growth of lung cancer xenografts with no noticeable cardiotoxicity.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('inhibiting', 'NegReg', (30, 40))	('Bp44mT', 'Chemical', 'MESH:C559854', (0, 6))	('growth', 'CPA', (41, 47))	('Bp44mT', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('cardiotoxicity', 'Disease', 'MESH:D066126', (93, 107))	('cardiotoxicity', 'Disease', (93, 107))
182607	32328462	To date though DpC, an analog of Dp44mt is the most potent and well-tolerated compound showing efficacy both in vitro and in vivo in models of pancreatic, neuroblastoma, and lung cancers.	('neuroblastoma', 'Disease', 'MESH:D009447', (155, 168))	('rat', 'Species', '10116', (72, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('Dp44mt', 'Var', (33, 39))	('neuroblastoma', 'Disease', (155, 168))	('lung cancers', 'Disease', 'MESH:D008175', (174, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('neuroblastoma', 'Phenotype', 'HP:0003006', (155, 168))	('lung cancers', 'Phenotype', 'HP:0100526', (174, 186))	('pancreatic', 'Disease', 'MESH:D010195', (143, 153))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('pancreatic', 'Disease', (143, 153))	('DpC', 'Chemical', 'MESH:C000607942', (15, 18))	('lung cancers', 'Disease', (174, 186))
182612	32328462	In contrast to other iron chelators, such as the thiosemicarbazones, VLX600 does not induce ROS.	('ROS', 'Chemical', 'MESH:D017382', (92, 95))	('iron', 'Gene', (21, 25))	('VLX600', 'Chemical', 'MESH:C000602558', (69, 75))	('VLX600', 'Var', (69, 75))	('thiosemicarbazones', 'Chemical', 'MESH:D013882', (49, 67))	('iron', 'Gene', '102030740', (21, 25))
182629	32328462	These may directly antagonize the receptor (e.g., anti-TfR1 antibodies) to induce cytotoxicity or a non-neutralizing method can be utilized for receptor-mediated internalization of drugs.	('cytotoxicity', 'Disease', (82, 94))	('antagonize', 'NegReg', (19, 29))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('anti-TfR1', 'Var', (50, 59))	('induce', 'PosReg', (75, 81))
182630	32328462	Many clinical trials have been conducted with anti-TfR1 antibodies and show some evidence of anti-tumor efficacy, but immunogenicity remains a major concern.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('antibodies', 'Var', (56, 66))	('tumor', 'Disease', (98, 103))	('anti-TfR1 antibodies', 'Var', (46, 66))
182635	32328462	Similarly, SGT-94 uses the same targeted system to deliver a modified form of the retinoblastoma tumor suppressor gene, RB94, and has recently completed phase I assessment (NCT01517464).	('retinoblastoma', 'Phenotype', 'HP:0009919', (82, 96))	('RB94', 'Gene', (120, 124))	('modified', 'Var', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('retinoblastoma tumor', 'Disease', 'MESH:D012175', (82, 102))	('retinoblastoma tumor', 'Disease', (82, 102))	('men', 'Species', '9606', (167, 170))
182641	32328462	miR-7-5p expression was reduced in pancreatic adenocarcinoma samples and loss of miR-7-5p was proposed to permit TfR1-driven cell proliferation and metabolism.	('loss', 'Var', (73, 77))	('reduced', 'NegReg', (24, 31))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (35, 60))	('miR-7-5p', 'Gene', (81, 89))	('metabolism', 'CPA', (148, 158))	('rat', 'Species', '10116', (137, 140))	('pancreatic adenocarcinoma', 'Disease', (35, 60))	('miR-7-5p', 'Gene', (0, 8))	('expression', 'MPA', (9, 19))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (35, 60))	('miR-7-5p', 'Gene', '407045', (81, 89))	('miR-7-5p', 'Gene', '407045', (0, 8))	('permit', 'Reg', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
182642	32328462	Interestingly, miR-7-5p and miR-141-3p were found to target IREs within 3'-UTR of TfR1, thereby reducing its mRNA and protein expression by competing with the IRE-IRP system.	('miR-7-5p', 'Gene', (15, 23))	('TfR1', 'Gene', (82, 86))	('miR-7-5p', 'Gene', '407045', (15, 23))	('reducing', 'NegReg', (96, 104))	('IRP', 'Gene', (163, 166))	('miR-141-3p', 'Var', (28, 38))	('IRP', 'Gene', '7472', (163, 166))
182644	32328462	Elevated nuclear FTH1 in breast cancer cells, as a result of reduced miR-200b was proposed to protect DNA against oxidative damage, therefore, miR-200b replacement sensitized the cells to the DNA-damaging agent doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (211, 222))	('sensitized', 'Reg', (164, 174))	('men', 'Species', '9606', (159, 162))	('miR-200b', 'Gene', '406984', (143, 151))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('miR-200b', 'Gene', '406984', (69, 77))	('FTH1', 'Gene', (17, 21))	('miR-200b', 'Gene', (143, 151))	('Elevated', 'PosReg', (0, 8))	('breast cancer', 'Disease', (25, 38))	('replacement', 'Var', (152, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('miR-200b', 'Gene', (69, 77))	('reduced', 'NegReg', (61, 68))
182651	32328462	Ferroptosis was identified from screens that detected small molecule inhibitors which were lethal to cultured tumor cells, but the mechanisms were distinct from known programmed death pathways.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('small molecule inhibitors', 'Var', (54, 79))	('inhibitors', 'Var', (69, 79))	('Fe', 'Chemical', 'MESH:D007501', (0, 2))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
182652	32328462	Later was discovered that CD8+ T cells activate tumor ferroptosis during treatment with anti-CTLA4 and anti-PD-L1 immunotherapies.	('PD-L1', 'Gene', (108, 113))	('CD8', 'Gene', '925', (26, 29))	('PD-L1', 'Gene', '29126', (108, 113))	('tumor ferroptosis', 'Disease', 'MESH:D009369', (48, 65))	('anti-CTLA4', 'Var', (88, 98))	('men', 'Species', '9606', (78, 81))	('activate', 'PosReg', (39, 47))	('tumor ferroptosis', 'Disease', (48, 65))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('CD8', 'Gene', (26, 29))
182674	32328462	Dp44mT and DpC overcome resistance to doxorubicin and vinblastine by utilizing lysosomal Pgp transport, where the compounds complex with lysosomal iron, generate ROS which disrupt the lysosomal membrane and induces apoptosis.	('apoptosis', 'CPA', (215, 224))	('disrupt', 'NegReg', (172, 179))	('Pgp', 'Gene', (89, 92))	('Pgp', 'Gene', '5243', (89, 92))	('doxorubicin', 'Chemical', 'MESH:D004317', (38, 49))	('iron', 'Gene', (147, 151))	('DpC', 'Chemical', 'MESH:C000607942', (11, 14))	('ROS', 'Var', (162, 165))	('Dp44mT', 'Chemical', 'MESH:C539263', (0, 6))	('rat', 'Species', '10116', (157, 160))	('vinblastine', 'Chemical', 'MESH:D014747', (54, 65))	('ROS', 'Chemical', 'MESH:D017382', (162, 165))	('iron', 'Gene', '102030740', (147, 151))	('induces', 'Reg', (207, 214))	('lysosomal membrane', 'MPA', (184, 202))
182675	32328462	When Dp44mT was combined with paclitaxel, 5-fluorouracil, doxorubicin, tamoxifen, and 4-hydroperoxycyclophosphamide in vitro the drugs synergistically enhanced cytotoxicity of breast cancer cells.	('tamoxifen', 'Chemical', 'MESH:D013629', (71, 80))	('enhanced', 'PosReg', (151, 159))	('cytotoxicity of breast cancer', 'Disease', (160, 189))	('doxorubicin', 'Chemical', 'MESH:D004317', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (42, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('paclitaxel', 'Chemical', 'MESH:D017239', (30, 40))	('4-hydroperoxycyclophosphamide', 'Chemical', 'MESH:C011272', (86, 115))	('Dp44mT', 'Chemical', 'MESH:C539263', (5, 11))	('cytotoxicity of breast cancer', 'Disease', 'MESH:D064420', (160, 189))	('Dp44mT', 'Var', (5, 11))
182676	32328462	Given the positive proof-of-concept results with Dp44mT, if the results of the DpC clinical trial are encouraging the next logical step would be to assess it in combination with existing cancer treatments.	('men', 'Species', '9606', (199, 202))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('Dp44mT', 'Var', (49, 55))	('Dp44mT', 'Chemical', 'MESH:C539263', (49, 55))	('DpC', 'Chemical', 'MESH:C000607942', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
182682	32328462	Their rationale was that treatment with the ferroptosis inhibitor ferrostatin-1, DFO, or IRP2 knockdown, partially reversed cisplatin-induced toxicity and visually, mitochondrial changes were observed consistent with ferroptosis.	('knockdown', 'Var', (94, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('men', 'Species', '9606', (30, 33))	('toxicity', 'Disease', 'MESH:D064420', (142, 150))	('IRP2', 'Gene', (89, 93))	('toxicity', 'Disease', (142, 150))	('rat', 'Species', '10116', (6, 9))	('ferrostatin-1', 'Chemical', 'MESH:C573944', (66, 79))	('DFO', 'Chemical', 'MESH:D003676', (81, 84))	('reversed', 'NegReg', (115, 123))
182696	32328462	PRIMA-1, a non-genotoxic agent that targets mutant/deleted p53 and activates ferroptotic cell death, enhanced anti-tumor activity of dexamethasone and doxorubicin in multiple myeloma xenografts.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('dexamethasone', 'Chemical', 'MESH:D003907', (133, 146))	('myeloma', 'Disease', 'MESH:D009101', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('multiple myeloma', 'Phenotype', 'HP:0006775', (166, 182))	('activates', 'PosReg', (67, 76))	('myeloma', 'Disease', (175, 182))	('doxorubicin', 'Chemical', 'MESH:D004317', (151, 162))	('PRIMA-1', 'Gene', (0, 7))	('ferroptotic cell death', 'CPA', (77, 99))	('enhanced', 'PosReg', (101, 109))	('mutant/deleted', 'Var', (44, 58))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('PRIMA-1', 'Gene', '145270', (0, 7))
182704	32328462	However, it is still unclear whether dysregulated iron metabolism precedes transformation or is a consequence of it, acting as an adaptive mechanism for tumor progression.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('iron', 'Gene', '102030740', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('dysregulated', 'Var', (37, 49))	('iron', 'Gene', (50, 54))
182748	32155748	Of 79 patients who received a radiotherapy dose < 5000 cGy, 59.5% (n = 47) patients underwent consolidative CRT, while 40.5% (n = 32) patients did not undergo consolidative CRT due to interval metastasis, medically unfit, or patient refusal.	('patient', 'Species', '9606', (6, 13))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (134, 142))	('CRT', 'Gene', '45841', (108, 111))	('CRT', 'Gene', (108, 111))	('CRT', 'Gene', '45841', (173, 176))	('CRT', 'Gene', (173, 176))	('patients', 'Species', '9606', (6, 14))	('< 5000 cGy', 'Var', (48, 58))	('patient', 'Species', '9606', (225, 232))	('patient', 'Species', '9606', (75, 82))	('patient', 'Species', '9606', (134, 141))
182749	32155748	In terms of SUVLN/SUVTumor, time-dependent ROC analysis identified an optimal cutoff value of 0.39 for DMFS (area under the curve 0.754; p < 0.01; 95% CI 0.593-0.916; Figure 2), and the sensitivity and specificity at this value was 74.2% and 80.0%, respectively.	('Tumor', 'Phenotype', 'HP:0002664', (21, 26))	('DMFS', 'Var', (103, 107))	('DMFS', 'Chemical', '-', (103, 107))	('SUVTumor', 'Disease', 'None', (18, 26))	('SUVTumor', 'Disease', (18, 26))
182759	32155748	The univariate model contained eight clinical and three PET-derived parameters (age, performance status, tumor location, initial T stage, initial N stage, tumor length, chemotherapy regimens, radiotherapy dose, SUVTumor, SUVLN, and SUVLN/SUVTumor).	('SUVTumor', 'Disease', (211, 219))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('Tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (155, 160))	('SUVTumor', 'Disease', 'None', (238, 246))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Tumor', 'Phenotype', 'HP:0002664', (214, 219))	('SUVTumor', 'Disease', 'None', (211, 219))	('tumor', 'Disease', (105, 110))	('SUVLN', 'Var', (221, 226))	('SUVTumor', 'Disease', (238, 246))
182831	23846365	CCI-G influenced outcomes with operative time, LOS, cardiovascular complication, and anastomotic leak rate, favoring CCI-G 0 compared to CCI-G 3.	('CCI', 'Chemical', '-', (137, 140))	('CCI', 'Chemical', '-', (0, 3))	('CCI', 'Chemical', '-', (117, 120))	('anastomotic leak', 'Disease', 'MESH:D057868', (85, 101))	('CCI-G', 'Var', (117, 122))	('anastomotic leak', 'Disease', (85, 101))	('cardiovascular complication', 'Disease', 'MESH:D002318', (52, 79))	('cardiovascular complication', 'Phenotype', 'HP:0001626', (52, 79))	('cardiovascular complication', 'Disease', (52, 79))
182832	23846365	Overall survival was worse for CCI-G 1 in comparison with CCI-G 0 [hazard ratio (HR) 1.99, p = 0.027].	('CCI', 'Chemical', '-', (58, 61))	('CCI', 'Chemical', '-', (31, 34))	('CCI-G 1', 'Var', (31, 38))	('worse', 'NegReg', (21, 26))	('Overall survival', 'MPA', (0, 16))
182890	23846365	There was no significant difference between MIE and Open in terms of operative time, but MIE patients had less intraoperative EBL, lymph node harvest was higher, and LOS was shorter (Table 3).	('lymph node harvest', 'CPA', (131, 149))	('higher', 'PosReg', (154, 160))	('MI', 'Phenotype', 'HP:0001658', (89, 91))	('less', 'NegReg', (106, 110))	('MIE', 'Chemical', '-', (89, 92))	('MIE', 'Chemical', '-', (44, 47))	('MI', 'Phenotype', 'HP:0001658', (44, 46))	('MIE', 'Var', (89, 92))	('patients', 'Species', '9606', (93, 101))
182898	23846365	Overall survival was worse for CCI-G 1 in comparison with CCI-G 0.	('CCI', 'Chemical', '-', (58, 61))	('CCI', 'Chemical', '-', (31, 34))	('CCI-G 1', 'Var', (31, 38))	('worse', 'NegReg', (21, 26))	('Overall survival', 'MPA', (0, 16))
182914	23846365	Under multivariate analysis, individuals with CCI-G 1 morbidity were almost two times more likely to die when controlling for gender, age, surgical approach, and BMI, in comparison to those with CCI-G 0 morbidity (p = 0.027, Table 5).	('CCI', 'Chemical', '-', (195, 198))	('CCI-G 1 morbidity', 'Var', (46, 63))	('MI', 'Phenotype', 'HP:0001658', (163, 165))	('die', 'Disease', (101, 104))	('morbidity', 'Var', (54, 63))	('CCI', 'Chemical', '-', (46, 49))
182915	23846365	Individuals with CCI-G 3 morbidity, in comparison to those with CCI-G 0 morbidity, were over three times more likely to die under the same constraints, but this association fell just outside the level of significance (p = 0.056, Table 5).	('morbidity', 'Var', (25, 34))	('CCI', 'Chemical', '-', (17, 20))	('CCI', 'Chemical', '-', (64, 67))	('CCI-G 3 morbidity', 'Var', (17, 34))
182924	23846365	Like others, we have found that MIE is associated with less operative blood loss, a higher lymph node harvest, shorter LOS, and equivalent short- and long-term survival rates.	('blood loss', 'Disease', (70, 80))	('MIE', 'Var', (32, 35))	('MI', 'Phenotype', 'HP:0001658', (32, 34))	('MIE', 'Chemical', '-', (32, 35))	('lymph node harvest', 'CPA', (91, 109))	('blood loss', 'Disease', 'MESH:D006473', (70, 80))	('higher', 'PosReg', (84, 90))
182944	23846365	Our Open group has had a longer follow-up period than our MIE group and it will take ongoing review of our data to determine if the MIE approach improves long-term survival over the open approach.	('improves', 'PosReg', (145, 153))	('MI', 'Phenotype', 'HP:0001658', (132, 134))	('MIE', 'Chemical', '-', (132, 135))	('MIE', 'Var', (132, 135))	('long-term', 'MPA', (154, 163))	('MIE', 'Chemical', '-', (58, 61))	('MI', 'Phenotype', 'HP:0001658', (58, 60))
182948	23846365	Only 13 patients (16 %) had squamous cell histology in the MIE group and 8 (12 %) in the Open group (data not shown).	('squamous cell histology', 'Disease', (28, 51))	('MIE', 'Chemical', '-', (59, 62))	('MIE', 'Var', (59, 62))	('MI', 'Phenotype', 'HP:0001658', (59, 61))	('patients', 'Species', '9606', (8, 16))
182958	32075174	Consequently, aberrant O-linked glycosylation has been extensively demonstrated to affect biological function and protein integrity that directly result in cancer growth and progression of several diseases.	('affect', 'Reg', (83, 89))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('protein', 'Protein', (114, 121))	('aberrant', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('O-linked glycosylation', 'Protein', (23, 45))	('biological function', 'CPA', (90, 109))	('aberrant O-linked glycosylation', 'Phenotype', 'HP:0012358', (14, 45))	('result in', 'Reg', (146, 155))
182977	32075174	The formation of sialyl-Tn results in O-glycan abrogation and has implications in cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('O-glycan', 'Protein', (38, 46))	('implications', 'Reg', (66, 78))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('abrogation', 'NegReg', (47, 57))	('O-glycan', 'Chemical', '-', (38, 46))	('sialyl-Tn', 'Var', (17, 26))
182990	32075174	The branching of O-glycosyltransferases, such as C1GALT1, GCNTs, and B3GNT6, results in the formation of Core branches on glycoproteins, thereby modifying protein function and changing biological processes.	('B3GNT6', 'Var', (69, 75))	('changing', 'Reg', (176, 184))	('modifying', 'Reg', (145, 154))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('results in', 'Reg', (77, 87))	('protein function', 'MPA', (155, 171))	('biological processes', 'CPA', (185, 205))	('glycoproteins', 'Protein', (122, 135))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('C1GALT1', 'Var', (49, 56))
183001	32075174	reported phenotypic changes upon the deletion of T-synthase in a mouse model using a Cre/loxP system.	('changes', 'Reg', (20, 27))	('mouse', 'Species', '10090', (65, 70))	('T-synthase', 'Gene', (49, 59))	('deletion', 'Var', (37, 45))
183005	32075174	reported mutations in the X chromosome-encoded COSMC gene, a chaperone for T-synthase, in multiple tumor cell lines.	('tumor', 'Disease', (99, 104))	('COSMC gene', 'Gene', (47, 57))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
183008	32075174	reported a loss of heterozygosity (LOH) or deletion of cosmc as the major cause for the expression of Tn/STn on cervical cancer.	('cosmc', 'Gene', '29071', (55, 60))	('loss', 'NegReg', (11, 15))	('deletion', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('STn', 'Gene', '1917', (105, 108))	('STn', 'Gene', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cosmc', 'Gene', (55, 60))	('cancer', 'Disease', (121, 127))
183011	32075174	The deletion of C1GALT1 caused an aggressive phenotype in the context of pancreatic ductal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('pancreatic ductal adenocarcinoma', 'Disease', (73, 105))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (73, 105))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (73, 105))	('C1GALT1', 'Gene', (16, 23))	('deletion', 'Var', (4, 12))	('caused', 'Reg', (24, 30))
183012	32075174	To compare the phenotypic difference of C1GALT1, pancreas-specific deletion of C1GALT1 was introduced, along with Kras and p53 mutation, resulting in a KPCC mouse model (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre;C1GALT1-/-).	('C1GALT1', 'Gene', (79, 86))	('Kras', 'Gene', '16653', (114, 118))	('PC', 'Disease', 'MESH:D010190', (153, 155))	('deletion', 'Var', (67, 75))	('Kras', 'Gene', (174, 178))	('Kras', 'Gene', '16653', (174, 178))	('mouse', 'Species', '10090', (157, 162))	('Kras', 'Gene', (114, 118))
183017	32075174	In addition, growth-factor receptors such as EGFR and HER2 were also increased upon the deletion of C1GALT1 in pancreatic cancer cell lines (Figure 2A).	('increased', 'PosReg', (69, 78))	('EGFR', 'Gene', (45, 49))	('deletion', 'Var', (88, 96))	('HER2', 'Gene', (54, 58))	('C1GALT1', 'Gene', (100, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('HER2', 'Gene', '2064', (54, 58))	('pancreatic cancer', 'Disease', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('growth-factor receptors', 'Protein', (13, 36))	('EGFR', 'Gene', '1956', (45, 49))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))
183019	32075174	This study illustrates that COSMC is regulated through epigenetic silencing and not somatic mutations, resulting in glycan-truncation dependent tumorigenicity.	('tumor', 'Disease', (144, 149))	('epigenetic silencing', 'Var', (55, 75))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('thr', 'Chemical', 'MESH:D013912', (47, 50))	('glycan', 'Chemical', 'MESH:D011134', (116, 122))
183021	32075174	In addition to a pancreatic cancer cell line, a non-tumorigenic keratinocyte specific HaCaT cell line has also been shown to induce a highly tumorigenic phenotype upon deletion of COSMC.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (52, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('tumor', 'Disease', (141, 146))	('induce', 'PosReg', (125, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('deletion', 'Var', (168, 176))	('COSMC', 'Gene', (180, 185))
183038	32075174	Truncation of Tn and sialyl-Tn antigens are regarded as the TACA for cancer progression.	('sialyl-Tn antigens', 'Protein', (21, 39))	('Truncation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
183044	32075174	In C1GALT1 knockdown cells, MUC1-N shedding was markedly decreased, suggesting a role of T-antigen on its extracellular translocation (Figure 2B).	('MUC1-N', 'Disease', 'MESH:C536108', (28, 34))	('MUC1-N', 'Disease', (28, 34))	('decreased', 'NegReg', (57, 66))	('knockdown', 'Var', (11, 20))	('C1GALT1', 'Gene', (3, 10))
183050	32075174	The authors found MUC-1 downregulation in C1GALT1-/-/PyMT mice, suggesting a possible involvement in the delayed onset of a tumor.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('mice', 'Species', '10090', (58, 62))	('downregulation', 'NegReg', (24, 38))	('C1GALT1-/-/PyMT', 'Var', (42, 57))	('MUC-1', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
183051	32075174	MUC-1 downstream signaling molecules, such as Src, PI3k, and Akt, were also downregulated in O-glycan deficient mice, indicating a role in decreased proliferation and tumor suppression.	('O-glycan', 'Chemical', '-', (93, 101))	('deficient', 'Var', (102, 111))	('MUC-1 downstream', 'Gene', (0, 16))	('Src', 'Pathway', (46, 49))	('proliferation', 'CPA', (149, 162))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('decreased', 'NegReg', (139, 148))	('downregulated', 'NegReg', (76, 89))	('mice', 'Species', '10090', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('PI3k', 'Pathway', (51, 55))	('tumor', 'Disease', (167, 172))	('Akt', 'Pathway', (61, 64))
183058	32075174	used two colon cancer cell lines, HT29 and SW620, to knockdown T-synthase and examined competition with ST6GalNAc-I and Core 3-synthase (B3GNT6).	('colon cancer', 'Disease', 'MESH:D015179', (9, 21))	('HT29', 'CellLine', 'CVCL:0320;0.011832748844439106', (34, 38))	('knockdown', 'Var', (53, 62))	('colon cancer', 'Disease', (9, 21))	('ST6GalNAc-I', 'Gene', (104, 115))	('T-synthase', 'Enzyme', (63, 73))	('ST6GalNAc-I', 'Gene', '55808', (104, 115))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('Core 3-synthase', 'Gene', '192134', (120, 135))	('Core 3-synthase', 'Gene', (120, 135))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
183066	32075174	The spontaneous duodenal tumor occurrence increased in DKO mice as compared to the wild type mice.	('increased', 'PosReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mice', 'Species', '10090', (59, 63))	('tumor', 'Disease', (25, 30))	('mice', 'Species', '10090', (93, 97))	('duodenal', 'Disease', (16, 24))	('DKO', 'Var', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('duodenal tumor', 'Phenotype', 'HP:0006771', (16, 30))
183089	32075174	In this system, C1GALT1 also induced HGF (Hepatocyte Growth Factor)-dependent dimerization of MET.	('induced', 'Reg', (29, 36))	('C1GALT1', 'Var', (16, 23))	('Hepatocyte Growth Factor', 'Gene', '3082', (42, 66))	('MET', 'Protein', (94, 97))	('HGF', 'Gene', '3082', (37, 40))	('Hepatocyte Growth Factor', 'Gene', (42, 66))	('HGF', 'Gene', (37, 40))
183103	32075174	In addition to galectin-4 modification by sialyl-Tn in metastasis, it is also an essential interaction in CRPC development.	('sialyl-Tn', 'Var', (42, 51))	('metastasis', 'CPA', (55, 65))	('PC', 'Disease', 'MESH:D010190', (108, 110))	('galectin-4', 'Gene', '3960', (15, 25))	('galectin-4', 'Gene', (15, 25))
183104	32075174	Thus, O-glycosylation changes triggered malignant transformations that resulted in metastatic behavior and castrate resistance of cancer cells.	('metastatic behavior', 'CPA', (83, 102))	('resulted in', 'Reg', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('changes', 'Var', (22, 29))	('cancer', 'Disease', (130, 136))	('O-glycosylation changes', 'Var', (6, 29))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('malignant transformations', 'CPA', (40, 65))	('triggered', 'Reg', (30, 39))
183108	32075174	C1GALT1 knockdown resulted in decreased cell growth, migration, and sphere formation in a variety of ovarian cancer cell lines.	('C1GALT1', 'Gene', (0, 7))	('knockdown', 'Var', (8, 17))	('ovarian cancer', 'Disease', (101, 115))	('cell growth', 'CPA', (40, 51))	('sphere formation', 'CPA', (68, 84))	('migration', 'CPA', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('ovarian cancer', 'Disease', 'MESH:D010051', (101, 115))	('decreased', 'NegReg', (30, 39))
183111	32075174	C1GALT1 was found to be an independent attributor for poor OAS of HNSCC patients.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('HNSCC', 'Disease', (66, 71))	('C1GALT1', 'Var', (0, 7))	('poor', 'Disease', (54, 58))	('patients', 'Species', '9606', (72, 80))
183114	32075174	EGFR O-glycans were found to be affected by C1GALT1 knockdown and this further regulated EGF-EGFR binding affinity to promote tumorigenic behavior.	('binding', 'Interaction', (98, 105))	('regulated', 'Reg', (79, 88))	('EGFR', 'Gene', (0, 4))	('promote', 'PosReg', (118, 125))	('EGFR', 'Gene', '1956', (93, 97))	('knockdown', 'Var', (52, 61))	('EGFR', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('C1GALT1', 'Gene', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('affected', 'Reg', (32, 40))	('EGFR', 'Gene', '1956', (0, 4))	('O-glycans', 'Chemical', '-', (5, 14))	('tumor', 'Disease', (126, 131))
183118	32075174	They discovered that the loss of C1GALT1 resulted in increased radiosensitivity of esophageal cancer cells.	('loss', 'Var', (25, 29))	('esophageal cancer', 'Disease', (83, 100))	('radiosensitivity', 'CPA', (63, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('increased', 'PosReg', (53, 62))	('C1GALT1', 'Gene', (33, 40))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (53, 79))
183119	32075174	As O-glycan on beta1-integrin is influenced by C1GALT1, this study also identified beta1-integrin as one of the important oncoglycoproteins regulated by C1GALT1 knockdown.	('beta1-integrin', 'Gene', '3688', (83, 97))	('beta1-integrin', 'Gene', (83, 97))	('influenced', 'Reg', (33, 43))	('C1GALT1', 'Gene', (153, 160))	('beta1-integrin', 'Gene', '3688', (15, 29))	('O-glycan', 'Chemical', '-', (3, 11))	('knockdown', 'Var', (161, 170))	('beta1-integrin', 'Gene', (15, 29))	('C1GALT1', 'Gene', (47, 54))
183121	32075174	This suggests that radiosensitivity of these cancer cells is increased upon truncating O-glycans.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('O-glycans', 'Chemical', '-', (87, 96))	('increased', 'PosReg', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('truncating', 'Var', (76, 86))	('radiosensitivity', 'MPA', (19, 35))	('cancer', 'Disease', (45, 51))	('O-glycans', 'Protein', (87, 96))
183122	32075174	Altogether, the participatory role of O-glycosylation on the beta1-integrin driven signaling pathway was exhibited on cellular radiosensitization.	('O-glycosylation', 'Var', (38, 53))	('beta1-integrin', 'Gene', (61, 75))	('beta1-integrin', 'Gene', '3688', (61, 75))	('cellular radiosensitization', 'Phenotype', 'HP:0010997', (118, 145))
183127	32075174	Core-3 synthase in PC is largely unexplored; however, it warrants further investigation because of the significance Core-3 has on delaying growth and metastasis.	('delaying', 'NegReg', (130, 138))	('Core-3', 'Var', (116, 122))	('PC', 'Disease', 'MESH:D010190', (19, 21))	('delaying growth', 'Phenotype', 'HP:0001510', (130, 145))
183137	32075174	Another study delineated the role of B3GNT6 in colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('B3GNT6', 'Var', (37, 43))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colon cancer', 'Disease', (47, 59))
183139	32075174	The overexpression of B3GNT6 in colon cancer cell lines resulted in diminished MUC1-C nucleus translocation, elevated p53 gene transcription, and the activation of miR-200c (Figure 3A).	('miR-200c', 'Gene', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('elevated', 'PosReg', (109, 117))	('B3GNT6', 'Var', (22, 28))	('colon cancer', 'Disease', (32, 44))	('diminished', 'NegReg', (68, 78))	('activation', 'PosReg', (150, 160))	('colon cancer', 'Disease', 'MESH:D015179', (32, 44))	('MUC1', 'Gene', (79, 83))	('MUC1', 'Gene', '4582', (79, 83))	('colon cancer', 'Phenotype', 'HP:0003003', (32, 44))	('miR-200c', 'Gene', '406985', (164, 172))	('p53 gene', 'Gene', (118, 126))
183143	32075174	Additionally, the altered expression of beta-catenin/TCF-4, c-myc, and cyclin D1 was observed during chemical-induced carcinogenesis, suggesting a possible role of B3GNT6 KO in human colorectal carcinoma.	('carcinogenesis', 'Disease', (118, 132))	('altered', 'Reg', (18, 25))	('B3GNT6 KO', 'Var', (164, 173))	('beta-catenin', 'Gene', (40, 52))	('beta-catenin', 'Gene', '1499', (40, 52))	('human', 'Species', '9606', (177, 182))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('ser', 'Chemical', 'MESH:D012694', (87, 90))	('c-myc', 'Gene', '4609', (60, 65))	('expression', 'MPA', (26, 36))	('cyclin D1', 'Gene', (71, 80))	('TCF-4', 'Gene', (53, 58))	('cyclin D1', 'Gene', '595', (71, 80))	('observed', 'Reg', (85, 93))	('TCF-4', 'Gene', '6925', (53, 58))	('c-myc', 'Gene', (60, 65))	('colorectal carcinoma', 'Disease', (183, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (183, 203))
183148	32075174	In addition, the authors associated the presence of sialylated Core-3 structures mainly to MUC2, independent of the tissue or malignancy.	('MUC2', 'Gene', (91, 95))	('MUC2', 'Gene', '4583', (91, 95))	('malignancy', 'Disease', (126, 136))	('sialylated', 'Var', (52, 62))	('malignancy', 'Disease', 'MESH:D009369', (126, 136))
183150	32075174	In this study, PC3 and LNCaP cell lines were utilized for overexpressing B3GNT6, resulting in reduced migration and invasion in an in vitro assay, suggesting reduced tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('B3GNT6', 'Var', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('reduced', 'NegReg', (94, 101))	('PC3', 'Gene', (15, 18))	('tumor', 'Disease', (166, 171))	('PC3', 'Gene', '3853', (15, 18))	('reduced', 'NegReg', (158, 165))	('LNCaP', 'CellLine', 'CVCL:0395;0.06791921892792452', (23, 28))
183155	32075174	In many instances, truncated glycosylation has been associated with ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (68, 82))	('ovarian cancer', 'Disease', 'MESH:D010051', (68, 82))	('associated', 'Reg', (52, 62))	('truncated glycosylation', 'Var', (19, 42))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ovarian cancer', 'Disease', (68, 82))
183158	32075174	Sialyl-Tn+ ovarian cancer cells had increased colony formation and tumor-sphere formation compared to CD133+ cells.	('Sialyl-Tn+', 'Var', (0, 10))	('colony formation', 'CPA', (46, 62))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (11, 25))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('increased', 'PosReg', (36, 45))	('ovarian cancer', 'Disease', 'MESH:D010051', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Disease', (67, 72))	('ovarian cancer', 'Disease', (11, 25))
183159	32075174	In addition to the in vitro assays, an in vivo xenograft model resulted in reduced tumor burden in the presence of ADC S3F-CL-MMAE.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('reduced', 'NegReg', (75, 82))	('ADC S3F-CL-MMAE', 'Var', (115, 130))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
183160	32075174	Truncated O-linked glycosylation has been considered as a hallmark of pancreatic cancer.	('pancreatic cancer', 'Disease', (70, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('Truncated', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))
183174	32075174	reported increased peritoneal metastasis of sialyl-Tn-expressing gastric carcinoma cell lines when transplanted into nude mice.	('gastric carcinoma', 'Disease', 'MESH:D013274', (65, 82))	('peritoneal metastasis', 'CPA', (19, 40))	('increased', 'PosReg', (9, 18))	('gastric carcinoma', 'Disease', (65, 82))	('sialyl-Tn-expressing', 'Var', (44, 64))	('nude mice', 'Species', '10090', (117, 126))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (65, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
183176	32075174	MUC2 has been shown to be the major carrier of sialyl-Tn on intestinal metaplasia and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('MUC2', 'Gene', (0, 4))	('MUC2', 'Gene', '4583', (0, 4))	('metaplasia', 'Disease', 'MESH:D008679', (71, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('metaplasia', 'Disease', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('sialyl-Tn', 'Var', (47, 56))	('gastric cancer', 'Disease', (86, 100))
183181	32075174	This study highlighted the role of MUC1 VNTR polymorphism with the expression of truncated carbohydrates sialyl-Tn, Tn, and T-antigen.	('T-antigen', 'Protein', (124, 133))	('MUC1', 'Gene', (35, 39))	('polymorphism', 'Var', (45, 57))	('MUC1', 'Gene', '4582', (35, 39))	('carbohydrates', 'Chemical', 'MESH:D002241', (91, 104))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('sialyl-Tn', 'Protein', (105, 114))
183189	32075174	Additionally, sialyl-Tn expression was correlated with poor survival rate, loss of estrogen receptor, and c-erb-B2 oncogene activation.	('c-erb-B2', 'Gene', '2064', (106, 114))	('poor', 'NegReg', (55, 59))	('sialyl-Tn expression', 'Var', (14, 34))	('activation', 'PosReg', (124, 134))	('oncogene', 'Gene', (115, 123))	('c-erb-B2', 'Gene', (106, 114))	('estrogen receptor', 'Gene', (83, 100))	('estrogen receptor', 'Gene', '2099', (83, 100))	('loss', 'NegReg', (75, 79))
183195	32075174	The enzyme activity of ST6GalNAc-I was higher in transfected cells as compared to the mock.	('higher', 'PosReg', (39, 45))	('ST6GalNAc-I', 'Gene', (23, 34))	('ST6GalNAc-I', 'Gene', '55808', (23, 34))	('transfected', 'Var', (49, 60))	('enzyme activity', 'MPA', (4, 19))
183202	32075174	This study also resulted in the generation of CHO cells expressing sialyl-Tn decorated MUC-1.	('CHO', 'CellLine', 'CVCL:0213;0.11185648321825845', (46, 49))	('MUC-1', 'Gene', (87, 92))	('sialyl-Tn decorated', 'Var', (67, 86))	('resulted in', 'Reg', (16, 27))
183208	32075174	Sialyl-Tn-KLH, along with endocrine therapy, resulted in increased overall time to progression (TTP) and OAS of patient groups in comparison to the unconjugated KLH.	('time', 'MPA', (75, 79))	('increased', 'PosReg', (57, 66))	('patient', 'Species', '9606', (112, 119))	('Sialyl-Tn-KLH', 'Var', (0, 13))
183209	32075174	As sialyl-Tn is the most studied glycotype in cancer, recent advancements in the field have resulted in the generation of sialyl-Tn-based immunotherapy.	('cancer', 'Disease', (46, 52))	('sialyl-Tn-based', 'Var', (122, 137))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
183213	32075174	Moreover, sialyl-Tn expressing cells had pronounced BCG-dependent adhesion, internalization, and apoptosis.	('BCG', 'Species', '33892', (52, 55))	('BCG-dependent adhesion', 'CPA', (52, 74))	('sialyl-Tn expressing', 'Var', (10, 30))	('internalization', 'CPA', (76, 91))	('apoptosis', 'CPA', (97, 106))
183214	32075174	To test glycosylation variations in bladder tumors, a novel approach of utilizing cancer cell lines with different genetic backgrounds was tested.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder tumors', 'Disease', 'MESH:D001749', (36, 50))	('bladder tumors', 'Phenotype', 'HP:0009725', (36, 50))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('bladder tumor', 'Phenotype', 'HP:0009725', (36, 49))	('bladder tumors', 'Disease', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('variations', 'Var', (22, 32))
183220	32075174	Sialyl-Tn expression was also associated with poor survival of MIBC.	('Sialyl-Tn expression', 'Var', (0, 20))	('poor', 'NegReg', (46, 50))	('MIBC', 'Disease', 'MESH:D001749', (63, 67))	('MIBC', 'Disease', (63, 67))
183239	32075174	Aberrantly glycosylated forms of mucins participate in a variety of cancer diseases.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer diseases', 'Disease', (68, 83))	('participate', 'Reg', (40, 51))	('cancer diseases', 'Disease', 'MESH:D009369', (68, 83))	('mucin', 'Gene', '100508689', (33, 38))	('Aberrantly glycosylated', 'Var', (0, 23))	('mucin', 'Gene', (33, 38))
183255	32075174	developed a xenograft model of sialyl-Tn expressing bladder tumor with a higher incidence rate.	('bladder tumor', 'Phenotype', 'HP:0009725', (52, 65))	('sialyl-Tn expressing', 'Var', (31, 51))	('bladder tumor', 'Disease', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('bladder tumor', 'Disease', 'MESH:D001749', (52, 65))
183270	32075174	Moreover, a novel finding exhibited the presence of a new splice variant of ST6GalNAc-I (55kDa) in these AR-induced cells as compared to the steroid deprived.	('AR', 'Gene', '367', (105, 107))	('ST6GalNAc-I', 'Gene', (76, 87))	('ST6GalNAc-I', 'Gene', '55808', (76, 87))	('55kDa', 'Var', (89, 94))	('steroid', 'Chemical', 'MESH:D013256', (141, 148))
183280	32075174	GCNT3 was also associated with increased mucin biosynthesis.	('mucin', 'Gene', '100508689', (41, 46))	('GCNT3', 'Var', (0, 5))	('increased', 'PosReg', (31, 40))	('mucin', 'Gene', (41, 46))
183294	32075174	C2GnT-M reduced invasion in matrigel and cell adhesion of collagen-IV and fibronectin.	('C2GnT-M', 'Var', (0, 7))	('fibronectin', 'Gene', '2335', (74, 85))	('fibronectin', 'Gene', (74, 85))	('reduced', 'NegReg', (8, 15))
183308	32075174	Hypomethylation in the GCNT2 variant 2 has been correlated with lymph node metastasis in CRC.	('GCNT2', 'Gene', '2651', (23, 28))	('GCNT2', 'Gene', (23, 28))	('Hypomethylation', 'Var', (0, 15))	('lymph node metastasis', 'CPA', (64, 85))	('CRC', 'Disease', (89, 92))	('correlated with', 'Reg', (48, 63))	('CRC', 'Disease', 'MESH:D015179', (89, 92))
183311	32075174	In particular, a specific polymorphism in C2GnT (valine at 152) was predisposed to PCa.	('C2GnT', 'Gene', '2650', (42, 47))	('valine at 152', 'Var', (49, 62))	('PCa', 'Disease', (83, 86))	('PCa', 'Disease', 'MESH:D011471', (83, 86))	('predisposed', 'Reg', (68, 79))	('C2GnT', 'Gene', (42, 47))	('valine', 'Chemical', 'MESH:D014633', (49, 55))
183313	32075174	However, the in vitro catalytic activity between the valine and isoleucine form resulted in compared catalytic activity.	('valine', 'Chemical', 'MESH:D014633', (53, 59))	('isoleucine', 'Chemical', 'MESH:D007532', (64, 74))	('catalytic activity', 'MPA', (101, 119))	('isoleucine', 'Var', (64, 74))
183316	32075174	C2GnT1 expressing PCa cells have polylactosamine terminated MUC1 chains, which results in the attenuation of NK-PCa cells interactions.	('polylactosamine', 'Chemical', 'MESH:C066929', (33, 48))	('interactions', 'Interaction', (122, 134))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('PCa', 'Disease', 'MESH:D011471', (112, 115))	('C2GnT1', 'Gene', (0, 6))	('PCa', 'Disease', (18, 21))	('MUC1', 'Gene', (60, 64))	('MUC1', 'Gene', '4582', (60, 64))	('PCa', 'Disease', 'MESH:D011471', (18, 21))	('attenuation', 'NegReg', (94, 105))	('C2GnT1', 'Gene', '2650', (0, 6))	('polylactosamine terminated', 'Var', (33, 59))	('PCa', 'Disease', (112, 115))
183318	32075174	Furthermore, O-glycan-terminated MUC1 reduces the adhesive characteristics of PCa cells.	('PCa', 'Disease', (78, 81))	('O-glycan-terminated', 'Var', (13, 32))	('reduces', 'NegReg', (38, 45))	('PCa', 'Disease', 'MESH:D011471', (78, 81))	('MUC1', 'Gene', (33, 37))	('MUC1', 'Gene', '4582', (33, 37))	('O-glycan', 'Chemical', '-', (13, 21))
183326	32075174	Moreover, C2GnT expressing bladder tumors contain polylactosamine chains that are involved in the NKG2D-MICA interaction that is regulated by galectin-3.	('galectin-3', 'Gene', (142, 152))	('MICA', 'Gene', (104, 108))	('C2GnT', 'Gene', (10, 15))	('polylactosamine', 'Chemical', 'MESH:C066929', (50, 65))	('bladder tumors', 'Disease', (27, 41))	('involved', 'Reg', (82, 90))	('C2GnT', 'Gene', '2650', (10, 15))	('MICA', 'Gene', '100507436', (104, 108))	('bladder tumor', 'Phenotype', 'HP:0009725', (27, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('bladder tumors', 'Phenotype', 'HP:0009725', (27, 41))	('NKG2D', 'Gene', '22914', (98, 103))	('galectin-3', 'Gene', '3958', (142, 152))	('bladder tumors', 'Disease', 'MESH:D001749', (27, 41))	('NKG2D', 'Gene', (98, 103))	('polylactosamine chains', 'Var', (50, 72))
183335	32075174	This is an important area of study; further research will reveal the fundamental changes that a loss of glycosyltransferase has on inducing cancerous condition.	('cancerous condition', 'Disease', 'MESH:D009369', (140, 159))	('cancerous condition', 'Phenotype', 'HP:0002664', (140, 159))	('loss', 'Var', (96, 100))	('glycosyltransferase', 'Enzyme', (104, 123))	('cancerous condition', 'Disease', (140, 159))	('inducing', 'Reg', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
183341	32075174	The authors in this manuscript are supported, in parts, by the grants from National Institutes of Health (This work was supported, in parts, by the National Institutes of Health (P01 CA217798, R01 CA210637, R01 CA183459, R01 CA195586, R01 CA201444, R01 CA228524, U01 CA200466, and U01 CA210240).	('N', 'Chemical', 'MESH:D009584', (148, 149))	('R01 CA183459', 'Var', (207, 219))	('R01 CA201444', 'Var', (235, 247))	('P01 CA217798', 'Var', (179, 191))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('R01 CA210637', 'Var', (193, 205))	('U01 CA200466', 'Var', (263, 275))	('R01 CA195586', 'Var', (221, 233))	('R01 CA228524', 'Var', (249, 261))	('U01 CA210240', 'Var', (281, 293))
183368	30360426	Although the product yield of the substituted quinolines was not optimal, its potential for biomedical application was substantial, as the reactivity of compounds might be governed by both steric and electronic nature of the substituents on the aromatic ring of substrates.	('substituted', 'Var', (34, 45))	('governed', 'Reg', (172, 180))	('quinolines', 'Chemical', 'MESH:D011804', (46, 56))
183372	30360426	First, molecules containing bromine atom showed stronger cytotoxicity on cancer cells than that containing trifluoromethyl group or unsubstituted.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cytotoxicity', 'Disease', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bromine', 'Chemical', 'MESH:D001966', (28, 35))	('stronger', 'PosReg', (48, 56))	('bromine atom', 'Var', (28, 40))	('cytotoxicity', 'Disease', 'MESH:D064420', (57, 69))
183374	30360426	Second, regarding the position of bromine atom on quinoline ring (2b-2d), the bromine atom at ortho-position of the aromatic ring was associated with better activity than those at m- or p-position.	('better', 'PosReg', (150, 156))	('bromine', 'Chemical', 'MESH:D001966', (78, 85))	('bromine atom', 'Var', (78, 90))	('bromine', 'Chemical', 'MESH:D001966', (34, 41))	('quinoline', 'Chemical', 'MESH:C037219', (50, 59))	('activity', 'MPA', (157, 165))
183378	30360426	Table 2 presents the bioactivity of the dimeric quinoline derivatives containing sulfonyl group, while the MTS relative values are shown in Figure 2.	('bioactivity', 'MPA', (21, 32))	('sulfonyl group', 'Var', (81, 95))	('sulfonyl', 'Chemical', '-', (81, 89))	('quinoline', 'Chemical', 'MESH:C037219', (48, 57))
183453	24473454	FasL Gene -844T/C Mutation of Esophageal Cancer in South China and Its Clinical Significance In this study, we investigated the association between the FasL -844T/C polymorphism and the risk of developing esophageal squamous cell carcinoma (ESCC) in South China.	('-844T/C', 'SUBSTITUTION', 'None', (157, 164))	('FasL', 'Gene', (0, 4))	('FasL', 'Gene', '356', (0, 4))	('Esophageal Cancer', 'Disease', (30, 47))	('-844T/C', 'Var', (157, 164))	('-844T/C', 'SUBSTITUTION', 'None', (10, 17))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (205, 239))	('-844T/C', 'Mutation', 'rs763110', (157, 164))	('-844T/C', 'Var', (10, 17))	('FasL', 'Gene', '356', (152, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('FasL', 'Gene', (152, 156))	('-844T/C', 'Mutation', 'rs763110', (10, 17))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('esophageal squamous cell carcinoma', 'Disease', (205, 239))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (30, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (216, 239))
183461	24473454	It had been reported that various types of malignant diseases acquired ability to resist cell apoptosis, and that the regulatory defects of this cell-death pathway contribute to tumorigenesis, tumor cell invasion and metastasis.	('tumor', 'Disease', (178, 183))	('malignant diseases', 'Disease', 'MESH:D009369', (43, 61))	('malignant diseases', 'Disease', (43, 61))	('resist cell apoptosis', 'CPA', (82, 103))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('defects', 'Var', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('contribute', 'Reg', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('metastasis', 'CPA', (217, 227))
183462	24473454	Genetic variations of crucial genes in apoptosis pathway may thus influence the susceptibility to cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('influence', 'Reg', (66, 75))	('Genetic variations', 'Var', (0, 18))	('apoptosis', 'Gene', (39, 48))
183464	24473454	Ligation of Fas by either agonistic antibody or its natural ligand transmits a "death signal" to the target cells, potentially triggering apoptosis.	('Fas', 'Chemical', 'MESH:C038178', (12, 15))	('Ligation', 'Var', (0, 8))	('Fas', 'Gene', (12, 15))	('triggering', 'Reg', (127, 137))	('apoptosis', 'CPA', (138, 147))	('transmits a "death signal', 'MPA', (67, 92))
183468	24473454	Single nucleotide polymorphisms (SNPs) have been proposed to play an important role in the genetic susceptibility to cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Single nucleotide polymorphisms', 'Var', (0, 31))
183469	24473454	Many studies have reported that functional SNPs can impact the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('impact', 'Reg', (52, 58))	('functional SNPs', 'Var', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
183470	24473454	The functional mutations in the Fas and FasL genes that impair apoptotic signal transduction have been shown to be associated with an increased risk of many types of cancers, e.g esophageal squamous-cell carcinoma and lung cancer.	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('apoptotic signal transduction', 'MPA', (63, 92))	('Fas', 'Chemical', 'MESH:C038178', (32, 35))	('cancers', 'Disease', (166, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('Fas', 'Chemical', 'MESH:C038178', (40, 43))	('esophageal squamous-cell carcinoma and lung cancer', 'Disease', 'MESH:D000077277', (179, 229))	('Fas', 'Gene', (32, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('mutations', 'Var', (15, 24))	('impair', 'NegReg', (56, 62))	('associated', 'Reg', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('FasL', 'Gene', '356', (40, 44))	('FasL', 'Gene', (40, 44))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
183472	24473454	SNPs of Fas and/or FasL gene have been proposed to be significant in the genetic susceptibility to cancer through altering the expression of gene.	('Fas', 'Gene', (8, 11))	('Fas', 'Chemical', 'MESH:C038178', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('altering', 'Reg', (114, 122))	('cancer', 'Disease', (99, 105))	('SNPs', 'Var', (0, 4))	('expression of gene', 'MPA', (127, 145))	('FasL', 'Gene', (19, 23))	('FasL', 'Gene', '356', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Fas', 'Chemical', 'MESH:C038178', (8, 11))
183473	24473454	The aim of the present study was to analyze whether -844T/C (rs763110) polymorphism in FasL gene (GenBank accession no.	('FasL', 'Gene', (87, 91))	('FasL', 'Gene', '356', (87, 91))	('polymorphism', 'Var', (71, 83))	('rs763110', 'Mutation', 'rs763110', (61, 69))	('-844T/C', 'Mutation', 'rs763110', (52, 59))
183474	24473454	Z96050) promoter confers host's susceptibility to cancers of esophageal squamous cell in south China.	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers of esophageal squamous', 'Disease', 'MESH:D004938', (50, 80))	('Z96050', 'Var', (0, 6))	('susceptibility', 'MPA', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancers of esophageal squamous', 'Disease', (50, 80))
183478	24473454	The genotype and allele distributions of FasL polymorphism in the cases and controls are shown in Table 2.	('FasL', 'Gene', (41, 45))	('polymorphism', 'Var', (46, 58))	('FasL', 'Gene', '356', (41, 45))
183482	24473454	When stratified by age and gender, the FasL gene -844 CC genotype was associated with a decreased risk for the development of ESCC (Adjusted OR = 0.436, 95% CI = 0.271-0.702, P = 0.001) compared with TT genotype.	('men', 'Species', '9606', (118, 121))	('ESCC', 'Disease', (126, 130))	('decreased', 'NegReg', (88, 97))	('gene -844 CC', 'Var', (44, 56))	('FasL', 'Gene', '356', (39, 43))	('FasL', 'Gene', (39, 43))
183497	24473454	Immunohistochemistry was carried out to research whether FasL -844 variation is able to modify the levels of expression of FasL (Fig.	('levels of expression', 'MPA', (99, 119))	('modify', 'Reg', (88, 94))	('FasL', 'Gene', '356', (123, 127))	('FasL', 'Gene', '356', (57, 61))	('FasL', 'Gene', (57, 61))	('variation', 'Var', (67, 76))	('FasL', 'Gene', (123, 127))
183500	24473454	The genotype and allele distributions of FasL polymorphism in the cases and controls are shown in Table 8.	('FasL', 'Gene', (41, 45))	('polymorphism', 'Var', (46, 58))	('FasL', 'Gene', '356', (41, 45))
183502	24473454	The A haplotype remained a significant protective role for ESCC (Adjusted OR = 0.834, 95% CI = 0.727-0.956, P = 0.000), which was comparable to that of G. However, FasL -844 CC combining with Fas -1377 G allele is a protective factor for ESCC (Adjusted OR = 0.488, 95% CI = 0.320-0.743, P = 0.001) (Table 9).	('ESCC', 'Disease', (238, 242))	('FasL', 'Gene', (164, 168))	('Fas -1377 G', 'Var', (192, 203))	('FasL', 'Gene', '356', (164, 168))	('Fas', 'Chemical', 'MESH:C038178', (164, 167))	('Fas', 'Chemical', 'MESH:C038178', (192, 195))	('ESCC', 'Disease', (59, 63))
183509	24473454	The FasL -844 T/C polymorphism may influence FasL expression level and FasL-mediated signaling pathway, and ultimately, the susceptibility to cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('FasL', 'Gene', '356', (71, 75))	('FasL', 'Gene', (45, 49))	('FasL', 'Gene', (4, 8))	('FasL', 'Gene', '356', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('FasL', 'Gene', '356', (4, 8))	('expression level', 'MPA', (50, 66))	('-844 T/C', 'Mutation', 'rs763110', (9, 17))	('susceptibility', 'Reg', (124, 138))	('influence', 'Reg', (35, 44))	('T/C polymorphism', 'Var', (14, 30))	('FasL', 'Gene', (71, 75))	('cancer', 'Disease', (142, 148))
183510	24473454	Many types of tumors express FasL, and aberrant gene expression has been reported to do with cervical carcinogenesis and tumor progression.	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cervical carcinogenesis', 'Disease', 'MESH:D063646', (93, 116))	('aberrant gene expression', 'Var', (39, 63))	('tumor', 'Disease', (121, 126))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('FasL', 'Gene', '356', (29, 33))	('cervical carcinogenesis', 'Disease', (93, 116))	('FasL', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
183513	24473454	An animal model study indicated that after neutralized by human FasL antibody, tumor load and colony formation of tumor cells significantly reduced.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('FasL', 'Gene', (64, 68))	('tumor', 'Disease', (79, 84))	('human', 'Species', '9606', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('neutralized', 'Var', (43, 54))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('FasL', 'Gene', '356', (64, 68))	('reduced', 'NegReg', (140, 147))
183517	24473454	It had been reported that FasL-844T/C gene polymorphism is a risk factor for cervical cancer, lung cancer, bladder cancer, breast cancer, pancreatic cancer.	('risk', 'Reg', (61, 65))	('lung cancer', 'Disease', (94, 105))	('cervical cancer', 'Disease', (77, 92))	('cervical cancer', 'Disease', 'MESH:D002583', (77, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('pancreatic cancer', 'Disease', (138, 155))	('FasL-844T/C gene polymorphism', 'Var', (26, 55))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('bladder cancer', 'Disease', (107, 121))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast cancer', 'Disease', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
183518	24473454	One meta-analysis suggested that the FasL -844 T/C polymorphism was associated with cancer risk.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('associated', 'Reg', (68, 78))	('cancer', 'Disease', (84, 90))	('T/C polymorphism', 'Var', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('-844 T/C', 'Mutation', 'rs763110', (42, 50))	('FasL', 'Gene', (37, 41))	('FasL', 'Gene', '356', (37, 41))
183523	24473454	showed that individuals with both Fas -1377AA and FasL -844 CC genotypes had a higher risk for developing esophageal squamous-cell carcinoma compared with those with both Fas -1377GG and FasL -844 TT genotypes.	('Fas', 'Chemical', 'MESH:C038178', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Fas -1377AA', 'Var', (34, 45))	('esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (106, 140))	('Fas', 'Chemical', 'MESH:C038178', (171, 174))	('esophageal squamous-cell carcinoma', 'Disease', (106, 140))	('FasL', 'Gene', (187, 191))	('Fas', 'Chemical', 'MESH:C038178', (34, 37))	('FasL', 'Gene', '356', (50, 54))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('FasL', 'Gene', '356', (187, 191))	('FasL', 'Gene', (50, 54))	('Fas', 'Chemical', 'MESH:C038178', (187, 190))
183533	24473454	We found that FasL gene polymorphism of esophageal cancer patients is related to T stage, TNM stage, and tumor length.	('patients', 'Species', '9606', (58, 66))	('polymorphism', 'Var', (24, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('FasL', 'Gene', '356', (14, 18))	('FasL', 'Gene', (14, 18))	('TNM', 'Gene', '10178', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('related', 'Reg', (70, 77))	('TNM', 'Gene', (90, 93))	('tumor', 'Disease', (105, 110))	('esophageal cancer', 'Disease', (40, 57))
183554	24473454	The polymorphism of FasL -844 affects the expression of FasL protein in patients' normal esophageal epithelium, esophageal carcinoma and pericancerous tissue cells.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('FasL', 'Gene', (20, 24))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('affects', 'Reg', (30, 37))	('FasL', 'Gene', '356', (56, 60))	('expression', 'MPA', (42, 52))	('FasL', 'Gene', '356', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('FasL', 'Gene', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('esophageal carcinoma', 'Disease', (112, 132))	('cancer', 'Disease', (141, 147))	('polymorphism', 'Var', (4, 16))	('patients', 'Species', '9606', (72, 80))
183560	24473454	We found that Fas -1377 AA genotype is a protection factor for ESCC.	('Fas', 'Chemical', 'MESH:C038178', (14, 17))	('Fas -1377 AA', 'Var', (14, 26))	('ESCC', 'Disease', (63, 67))
183561	24473454	It was reported that Fas -1377A allele disrupt Sp1 transcription factor binding sites, and thus diminish promoter activity and decrease Fas gene expression.	('Sp1 transcription factor', 'Protein', (47, 71))	('Fas gene', 'Gene', (136, 144))	('promoter activity', 'MPA', (105, 122))	('decrease', 'NegReg', (127, 135))	('binding', 'Interaction', (72, 79))	('Fas -1377A', 'Var', (21, 31))	('Fas', 'Chemical', 'MESH:C038178', (136, 139))	('expression', 'MPA', (145, 155))	('Fas', 'Chemical', 'MESH:C038178', (21, 24))	('diminish', 'NegReg', (96, 104))	('disrupt', 'NegReg', (39, 46))
183563	24473454	FasL -844 CC combining with Fas -1377 GG + GA is a protective factor for ESCC.	('Fas -1377 GG + GA', 'Var', (28, 45))	('FasL', 'Gene', (0, 4))	('FasL', 'Gene', '356', (0, 4))	('Fas', 'Chemical', 'MESH:C038178', (0, 3))	('Fas', 'Chemical', 'MESH:C038178', (28, 31))	('ESCC', 'Disease', (73, 77))
183564	24473454	Cells with Fas -1377 G allele express Fas protein normally.	('Fas protein', 'Protein', (38, 49))	('Fas', 'Chemical', 'MESH:C038178', (11, 14))	('Fas', 'Chemical', 'MESH:C038178', (38, 41))	('Fas -1377 G', 'Var', (11, 22))
183566	24473454	On the contrary, cells, including cancer cells with Fas -1377 G allele express low level Fas that will cause immune escape.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Fas', 'Chemical', 'MESH:C038178', (89, 92))	('Fas', 'Protein', (89, 92))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('Fas -1377 G', 'Var', (52, 63))	('cancer', 'Disease', (34, 40))	('cause', 'Reg', (103, 108))	('Fas', 'Chemical', 'MESH:C038178', (52, 55))	('immune escape', 'MPA', (109, 122))
183569	24473454	In this study, we investigated the association between the FasL -844T/C polymorphism on the risk of ESCC in south China.	('FasL', 'Gene', (59, 63))	('FasL', 'Gene', '356', (59, 63))	('-844T/C', 'Mutation', 'rs763110', (64, 71))	('polymorphism', 'Var', (72, 84))	('ESCC', 'Disease', (100, 104))
183570	24473454	FasL -844 CC combining with Fas -1377 G allele is a protective factor for ESCC.	('FasL', 'Gene', (0, 4))	('ESCC', 'Disease', (74, 78))	('FasL', 'Gene', '356', (0, 4))	('Fas', 'Chemical', 'MESH:C038178', (0, 3))	('Fas -1377 G', 'Var', (28, 39))	('Fas', 'Chemical', 'MESH:C038178', (28, 31))
183572	24473454	This polymorphism affects the expression of FasL protein in patients.	('expression', 'MPA', (30, 40))	('patients', 'Species', '9606', (60, 68))	('polymorphism', 'Var', (5, 17))	('affects', 'Reg', (18, 25))	('FasL', 'Gene', '356', (44, 48))	('FasL', 'Gene', (44, 48))
183589	24473454	Fas -1377G/A polymorphism in promoter region was also detected with PCR-RFLP.	('Fas', 'Chemical', 'MESH:C038178', (0, 3))	('PCR-RFLP', 'Disease', (68, 76))	('-1377G/A', 'Mutation', 'rs2234767', (4, 12))	('Fas -1377G/A', 'Var', (0, 12))
183596	24473454	Association between FasL -844 T/C or Fas -1377 G/A polymorphism and ESCC was assessed using chi2 test.	('FasL', 'Gene', (20, 24))	('ESCC', 'Disease', (68, 72))	('FasL', 'Gene', '356', (20, 24))	('Fas', 'Chemical', 'MESH:C038178', (37, 40))	('-844 T/C', 'Mutation', 'rs763110', (25, 33))	('Fas', 'Chemical', 'MESH:C038178', (20, 23))	('Fas', 'Var', (37, 40))	('-1377 G/A', 'Mutation', 'rs2234767', (41, 50))
183598	24473454	We used binary logistic regression (Ascendant Wald method) with each parameter as dependant variable and genotypes of FasL -844 T/C polymorphism with other clinical parameters as independent variables.	('FasL', 'Gene', '356', (118, 122))	('FasL', 'Gene', (118, 122))	('-844 T/C', 'Mutation', 'rs763110', (123, 131))	('T/C polymorphism', 'Var', (128, 144))
183599	24473454	Clinical pathological parameters were dichotomised as follows: grading (well and moderately differentiation versus poorly differentiation), T grade (T1-T2 versus T3-T4), Location of the tumor (Epimere- midportion versus hypomere), tumor length (less than 5 cm versus equal and greater than 5 cm), lymphnode metastasis, nerve involvement, cardiac involvement and vascular tumor thrombus (positive versus negative).	('less', 'Var', (245, 249))	('tumor', 'Disease', (371, 376))	('cardia', 'Disease', 'MESH:D004938', (338, 344))	('tumor', 'Disease', (186, 191))	('nerve involvement', 'CPA', (319, 336))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('lymphnode metastasis', 'CPA', (297, 317))	('tumor', 'Disease', (231, 236))	('vascular tumor thrombus', 'Disease', 'MESH:D013927', (362, 385))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cardia', 'Disease', (338, 344))	('men', 'Species', '9606', (332, 335))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('vascular tumor thrombus', 'Disease', (362, 385))	('vascular tumor', 'Phenotype', 'HP:0100742', (362, 376))	('men', 'Species', '9606', (353, 356))
183615	27902478	Gimeracil antagonizes dihydropyrimidine dehydrogenase (DPD) and inhibits 5-FU degeneration.	('antagonizes', 'NegReg', (10, 21))	('Gimeracil', 'Var', (0, 9))	('DPD', 'Gene', '1806', (55, 58))	('Gimeracil', 'Chemical', 'MESH:C104201', (0, 9))	('5-FU', 'Chemical', 'MESH:D005472', (73, 77))	('5-FU degeneration', 'MPA', (73, 90))	('DPD', 'Gene', (55, 58))	('inhibits', 'NegReg', (64, 72))	('dihydropyrimidine dehydrogenase', 'MPA', (22, 53))
183692	23767030	Meanwhile, laryngitis occurs due to various causes, but most of them display similar appearances by the naked eye with no relation to the causes; LPR can also become an important cause, and laryngitis caused by LPR is referred to as reflux laryngitis.	('laryngitis', 'Disease', 'MESH:D007827', (190, 200))	('laryngitis', 'Disease', 'MESH:D007827', (240, 250))	('reflux laryngitis', 'Disease', 'MESH:D007827', (233, 250))	('laryngitis', 'Disease', (11, 21))	('laryngitis', 'Disease', (240, 250))	('LPR', 'Var', (211, 214))	('reflux laryngitis', 'Disease', (233, 250))	('laryngitis', 'Disease', (190, 200))	('laryngitis', 'Disease', 'MESH:D007827', (11, 21))
183868	20188100	Four previous retrospective cohort studies indicated an association of PPI use and a reduced risk of dysplasia in patients with BE, and one other cohort study of BE also showed that NSAIDs/aspirin usage was protective against the development of EAC.	('PPI', 'Var', (71, 74))	('dysplasia', 'Disease', (101, 110))	('EAC', 'Disease', (245, 248))	('BE', 'Phenotype', 'HP:0100580', (128, 130))	('BE', 'Phenotype', 'HP:0100580', (162, 164))	('dysplasia', 'Disease', 'MESH:D004476', (101, 110))	('aspirin', 'Chemical', 'MESH:D001241', (189, 196))	('EAC', 'Phenotype', 'HP:0011459', (245, 248))	('patients', 'Species', '9606', (114, 122))	('reduced', 'NegReg', (85, 92))	('men', 'Species', '9606', (237, 240))
183900	20188100	In multivariable regression analyses that adjusted for race, number of outpatient encounters, non cancer disease comorbidity index, VA priority level and filled prescriptions for PPI and statin, the inverse association between filled NSAID/aspirin prescription and EAC remained significant (incidence density ratio, 0.64; 95% CI: 0.42-0.97).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('filled', 'Var', (227, 233))	('outpatient', 'Species', '9606', (71, 81))	('cancer disease', 'Disease', 'MESH:D009369', (98, 112))	('aspirin', 'Chemical', 'MESH:D001241', (240, 247))	('EAC', 'Phenotype', 'HP:0011459', (265, 268))	('cancer disease', 'Disease', (98, 112))	('EAC', 'Disease', (265, 268))
184053	33383958	(2019) did not find any evidence for the association between coffee intake and CRC risk but, when using pooled groups, coffee consumption was related with a decreased risk of colon cancer in never-smokers and in Asian countries, and with an increased risk of rectal cancer in the general population, not considering women, never-smokers, and European countries.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('rectal cancer', 'Phenotype', 'HP:0100743', (259, 272))	('coffee', 'Var', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('cancer', 'Disease', (266, 272))	('colon cancer', 'Phenotype', 'HP:0003003', (175, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('colon cancer', 'Disease', 'MESH:D015179', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', (181, 187))	('decreased', 'NegReg', (157, 166))	('colon cancer', 'Disease', (175, 187))	('women', 'Species', '9606', (316, 321))
184085	33383958	Co-cultures of human colorectal adenocarcinoma cell line CaCo2 and 3T3-L1 adipocytes in the presence of caffeine have shown that caffeine inhibits the secretion of inflammatory cytokines interleukin (IL) IL-8 and plasminogen activator inhibitor-1 (PAI-1) and decreases lipid accumulation in adipocytes, whereas it has no effect on 3T3-L1 cells alone.	('-L1', 'CellLine', 'CVCL:S918', (334, 337))	('caffeine', 'Chemical', 'MESH:D002110', (104, 112))	('decreases lipid accumulation', 'Disease', (259, 287))	('IL-8', 'Gene', '3576', (204, 208))	('colorectal adenocarcinoma', 'Disease', (21, 46))	('caffeine', 'Var', (129, 137))	('secretion', 'MPA', (151, 160))	('human', 'Species', '9606', (15, 20))	('-L1', 'CellLine', 'CVCL:S918', (70, 73))	('inhibits', 'NegReg', (138, 146))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (21, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('PAI-1', 'Gene', '5054', (248, 253))	('plasminogen activator inhibitor-1', 'Gene', (213, 246))	('IL-8', 'Gene', (204, 208))	('decreases lipid accumulation', 'Disease', 'MESH:D052439', (259, 287))	('plasminogen activator inhibitor-1', 'Gene', '5054', (213, 246))	('PAI-1', 'Gene', (248, 253))	('caffeine', 'Chemical', 'MESH:D002110', (129, 137))
184104	33383958	(2008) demonstrated that the secretion of IL-8 induced by H2O2 or by tumor necrosis factor-receptor (TNF-R) activation may be blocked by 5-CQA in a dose-dependent manner in human intestinal epithelial CaCo2 cells.	('secretion', 'MPA', (29, 38))	('H2O2', 'Var', (58, 62))	('H2O2', 'Chemical', 'MESH:D006861', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TNF-R', 'Gene', (101, 106))	('tumor necrosis factor-receptor', 'Gene', '7132', (69, 99))	('5-CQA', 'Chemical', '-', (137, 142))	('TNF-R', 'Gene', '7132', (101, 106))	('IL-8', 'Gene', '3576', (42, 46))	('blocked', 'NegReg', (126, 133))	('human', 'Species', '9606', (173, 178))	('tumor necrosis factor-receptor', 'Gene', (69, 99))	('IL-8', 'Gene', (42, 46))	('rat', 'Species', '10116', (14, 17))	('activation', 'PosReg', (108, 118))
184114	33383958	Another important element that influences protein expression are epigenetic marks.	('protein expression', 'MPA', (42, 60))	('pig', 'Species', '9823', (66, 69))	('influences', 'Reg', (31, 41))	('epigenetic marks', 'Var', (65, 81))	('men', 'Species', '9606', (21, 24))
184117	33383958	Finally, polyphenols may also exhibit some effect on epithelial permeability.	('effect', 'Reg', (43, 49))	('polyphenols', 'Var', (9, 20))	('epithelial permeability', 'MPA', (53, 76))	('polyphenols', 'Chemical', 'MESH:D059808', (9, 20))
184224	33383958	The underlying cause of this clinically relevant problem is multiple, including surgical manipulation itself, opioid analgesics, inflammation, electrolyte fluctuations, and imbalances in the autonomic function and gastrointestinal hormonal system.	('imbalances', 'Var', (173, 183))	('electrolyte fluctuations', 'Phenotype', 'HP:0003111', (143, 167))	('inflammation', 'Disease', 'MESH:D007249', (129, 141))	('inflammation', 'Disease', (129, 141))	('imbalances', 'Phenotype', 'HP:0002172', (173, 183))
184229	33383958	The most remarkable results were (1) coffee did not significantly increase complications compared with the control group; (2) coffee significantly decreased the time period until the first bowel movement, as well as the time to tolerance of solid food, the first flatus, and the first defecation; (3) no significant effects were found regarding the length of hospital stay.	('men', 'Species', '9606', (199, 202))	('coffee', 'Var', (126, 132))	('decreased', 'NegReg', (147, 156))	('time period', 'MPA', (161, 172))
184244	33383958	In addition, despite early reports of no effects of caffeine on glial cells, more recent studies have shown that caffeine at 0.01 mM produced an immediate and sustained Ca2+ response in all myenteric glial cells from mouse colon, confirming that they have ryanodine-sensitive Ca2+ stores.	('mouse', 'Species', '10090', (217, 222))	('caffeine', 'Chemical', 'MESH:D002110', (52, 60))	('Ca2+ response', 'MPA', (169, 182))	('caffeine', 'Chemical', 'MESH:D002110', (113, 121))	('caffeine', 'Var', (113, 121))	('ryanodine', 'Chemical', 'MESH:D012433', (256, 265))
184290	33383958	In line with the previous study with SCGs, melanoidins accelerated transit in small intestine (since the caecum was reached significantly more quickly in melanoidin-exposed rats than in control animals) and tended to accelerate fecal pellet formation, although this effect was not significant.	('SCGs', 'Chemical', '-', (37, 41))	('fecal pellet formation', 'CPA', (228, 250))	('rat', 'Species', '10116', (173, 176))	('melanoidin', 'Chemical', 'MESH:C011908', (43, 53))	('accelerate', 'PosReg', (217, 227))	('rat', 'Species', '10116', (61, 64))	('rat', 'Species', '10116', (223, 226))	('melanoidin-exposed', 'Var', (154, 172))	('melanoidin', 'Chemical', 'MESH:C011908', (154, 164))	('melanoidins', 'Chemical', 'MESH:C011908', (43, 54))	('rats', 'Species', '10116', (173, 177))	('accelerated', 'PosReg', (55, 66))
184318	33383958	Of note, although acrylamide activates microglial cells both in vivo and in vitro, leading to the release of proinflammatory cytokines, and consequently contributing to neuronal damage, the involvement of enteric glial cells in enteric neuronal alterations induced by acrylamide has not been specifically evaluated yet, except for the above-mentioned study that used cocultures of intestinal myenteric neurons, smooth muscle cells, and glia, and did not show any acrylamide-induced alterations in this last cell type.	('proinflammatory cytokines', 'MPA', (109, 134))	('acrylamide', 'Var', (18, 28))	('acrylamide', 'Chemical', 'MESH:D020106', (18, 28))	('release', 'MPA', (98, 105))	('rat', 'Species', '10116', (486, 489))	('men', 'Species', '9606', (341, 344))	('rat', 'Species', '10116', (249, 252))	('men', 'Species', '9606', (197, 200))	('neuronal damage', 'Disease', 'MESH:D009410', (169, 184))	('contributing', 'Reg', (153, 165))	('acrylamide', 'Chemical', 'MESH:D020106', (463, 473))	('acrylamide', 'Chemical', 'MESH:D020106', (268, 278))	('neuronal damage', 'Disease', (169, 184))
184370	33383958	Importantly, the aberrant absorption of Trp (which may occur due to cell surface downregulation of ACE2 during chronic stress,, or infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) leads to manifestations of colitis, such as diarrhea.	('Trp', 'Gene', (40, 43))	('aberrant', 'Var', (17, 25))	('colitis', 'Disease', (237, 244))	('Trp', 'Chemical', 'MESH:D014364', (40, 43))	('ACE2', 'Gene', (99, 103))	('severe acute respiratory syndrome coronavirus 2', 'Species', '2697049', (148, 195))	('respiratory syndrome', 'Phenotype', 'HP:0011947', (161, 181))	('diarrhea', 'Phenotype', 'HP:0002014', (254, 262))	('leads to', 'Reg', (210, 218))	('downregulation', 'NegReg', (81, 95))	('colitis', 'Phenotype', 'HP:0002583', (237, 244))	('diarrhea', 'Disease', (254, 262))	('infection', 'Disease', (131, 140))	('diarrhea', 'Disease', 'MESH:D003967', (254, 262))	('ACE2', 'Gene', '59272', (99, 103))	('SARS-CoV-2', 'Species', '2697049', (197, 207))	('infection', 'Disease', 'MESH:D007239', (131, 140))	('colitis', 'Disease', 'MESH:D003092', (237, 244))
184371	33383958	This amino acid is also essential for vitamin B3 (niacin) synthesis, and the deficit of this vitamin causes pellagra, a disease characterized by diarrhea, inflammation, and protein malnutrition, with skin and CNS manifestations.	('causes', 'Reg', (101, 107))	('deficit', 'Var', (77, 84))	('protein malnutrition', 'Disease', (173, 193))	('pellagra', 'Disease', 'MESH:D010383', (108, 116))	('niacin', 'Chemical', 'MESH:D009525', (50, 56))	('pellagra', 'Disease', (108, 116))	('vitamin B3', 'Chemical', 'MESH:D009536', (38, 48))	('diarrhea', 'Phenotype', 'HP:0002014', (145, 153))	('diarrhea', 'Disease', 'MESH:D003967', (145, 153))	('diarrhea', 'Disease', (145, 153))	('malnutrition', 'Phenotype', 'HP:0004395', (181, 193))	('protein malnutrition', 'Disease', 'MESH:D044342', (173, 193))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))	('inflammation', 'Disease', (155, 167))
184381	33383958	Symptoms of some gastrointestinal functional disorders may be due to deregulation of CNS activity, dysregulation at the peripheral level (intestine), or a combination of both (brain-gut axis) by means of neuro-endocrine-immune stimuli.	('gastrointestinal functional disorders', 'Disease', (17, 54))	('CNS', 'Protein', (85, 88))	('gut', 'Gene', (182, 185))	('due to', 'Reg', (62, 68))	('deregulation', 'Var', (69, 81))	('gut', 'Gene', '110006', (182, 185))	('dysregulation', 'MPA', (99, 112))	('gastrointestinal functional disorders', 'Disease', 'MESH:D005767', (17, 54))	('activity', 'MPA', (89, 97))
184385	33383958	Coffee is a source of melatonin, but the bioavailability of this compound in humans is low (around 3%) and caffeine reduces endogenous nocturnal melatonin levels, with a significant impact on duration and quality of sleep.	('reduces', 'NegReg', (116, 123))	('endogenous nocturnal melatonin levels', 'MPA', (124, 161))	('rat', 'Species', '10116', (194, 197))	('caffeine', 'Chemical', 'MESH:D002110', (107, 115))	('humans', 'Species', '9606', (77, 83))	('melatonin', 'Chemical', 'MESH:D008550', (22, 31))	('caffeine', 'Var', (107, 115))	('melatonin', 'Chemical', 'MESH:D008550', (145, 154))
184391	33383958	In the gut, dietary fiber increases fecal bulk, contributes to normal bowel function and to accelerated intestinal transit.	('bowel function', 'CPA', (70, 84))	('fecal bulk', 'MPA', (36, 46))	('accelerated', 'PosReg', (92, 103))	('dietary', 'Var', (12, 19))	('gut', 'Gene', (7, 10))	('fiber', 'Chemical', 'MESH:D004043', (20, 25))	('rat', 'Species', '10116', (98, 101))	('gut', 'Gene', '110006', (7, 10))	('intestinal transit', 'CPA', (104, 122))	('increases', 'PosReg', (26, 35))
184455	31883369	The chi-squared (chi2) test and Fisher exact test showed that Nectin-4 positivity was significantly associated with tumor size (chi2=6.385; P=0.012) and depth of tumor invasion (chi2=7.081; P=0.008).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('Nectin-4', 'Gene', '81607', (62, 70))	('associated', 'Reg', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Nectin-4', 'Gene', (62, 70))	('positivity', 'Var', (71, 81))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
184458	31883369	Patients with positive Nectin-4 expression, determined by Kaplan-Meier and log-rank survival analysis, had significantly lower odds ratios (ORs) compared with patients with negative Nectin-4 expression (Figure 2) (HR=1.747; 95% CI, 1.003-3.044; P<0.05).	('Nectin-4', 'Gene', (23, 31))	('Nectin-4', 'Gene', '81607', (182, 190))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (121, 126))	('positive', 'Var', (14, 22))	('Nectin-4', 'Gene', (182, 190))	('expression', 'MPA', (32, 42))	('patients', 'Species', '9606', (159, 167))	('Nectin-4', 'Gene', '81607', (23, 31))
184459	31883369	As shown in Table 3, the univariate Cox HR model showed that tumor diameter >=4.5 cm (HR=1.674; P=0.044), the depth of invasion (HR=2.950; P=0.008), lymph node involvement (HR=2.518; P=0.003) and Nectin-4 positivity (HR=1.704; P=0.039) were associated with reduced patient prognosis.	('lymph node involvement', 'CPA', (149, 171))	('reduced', 'NegReg', (257, 264))	('Nectin-4', 'Gene', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('patient', 'Species', '9606', (265, 272))	('patient prognosis', 'CPA', (265, 282))	('Cox', 'Gene', '1351', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('positivity', 'Var', (205, 215))	('Cox', 'Gene', (36, 39))	('tumor', 'Disease', (61, 66))	('men', 'Species', '9606', (167, 170))	('Nectin-4', 'Gene', '81607', (196, 204))
184466	31883369	Dysregulated expression of Nectin-4 have been shown in human breast cancer, and pancreatic carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('expression', 'MPA', (13, 23))	('Nectin-4', 'Gene', '81607', (27, 35))	('pancreatic carcinoma', 'Disease', (80, 100))	('human', 'Species', '9606', (55, 60))	('Nectin-4', 'Gene', (27, 35))	('Dysregulated', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (80, 100))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
184467	31883369	The molecular mechanisms underlying the oncogenic effects of Nectin-4 are poorly understood, but overexpression has been shown to promote tumor angiogenesis, activate PI3K/AKT signaling and enhance tumor growth in vivo.	('promote', 'PosReg', (130, 137))	('Nectin-4', 'Gene', '81607', (61, 69))	('AKT', 'Gene', (172, 175))	('tumor', 'Disease', (138, 143))	('activate', 'PosReg', (158, 166))	('Nectin-4', 'Gene', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('AKT', 'Gene', '207', (172, 175))	('overexpression', 'Var', (97, 111))	('enhance', 'PosReg', (190, 197))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
184528	31732509	The PDOX and subcutaneous PDX exhibited somatic single-nucleotide variants (SNVs) in ARID1A (in-frame loss of codon, allelic frequency 34% and 47%) that were not observed in the patient tumor.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('ARID1A', 'Gene', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('patient', 'Species', '9606', (178, 185))	('tumor', 'Disease', (186, 191))	('codon', 'MPA', (110, 115))	('loss of', 'NegReg', (102, 109))	('single-nucleotide variants', 'Var', (48, 74))	('ARID1A', 'Gene', '8289', (85, 91))
184529	31732509	Additional low-frequency SNVs in KDM6A (in-frame gain of codon, allelic frequency 7%) and XPO1 (splice region variant, allelic frequency 6%) were identified in the PDOX, but not in the patient tumor or the subcutaneous PDX (Fig.	('KDM6A', 'Gene', '7403', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('patient', 'Species', '9606', (185, 192))	('KDM6A', 'Gene', (33, 38))	('XPO1', 'Gene', '7514', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('XPO1', 'Gene', (90, 94))	('tumor', 'Disease', (193, 198))	('SNVs', 'Var', (25, 29))	('gain of codon', 'PosReg', (49, 62))
184566	31732509	The minced tumor pieces were immersed in Matrigel (#356230, Corning, Bedford, MA, USA).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('#356230', 'Var', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
184593	31423187	Association between polymorphisms in the CYP1A1, CYP2E1 and GSTM1 genes, and smoking, alcohol and upper digestive tract carcinomas in a high-incidence area of northern China Metabolic gene variants, smoking, and alcohol consumption are important upper digestive tract cancer (UDTC) risk factors.	('tract carcinomas', 'Disease', (114, 130))	('tract cancer', 'Disease', (262, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('alcohol', 'Chemical', 'MESH:D000438', (86, 93))	('upper', 'Disease', (98, 103))	('Association', 'Interaction', (0, 11))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (252, 274))	('CYP1A1', 'Gene', '1543', (41, 47))	('alcohol', 'Chemical', 'MESH:D000438', (212, 219))	('GSTM1', 'Gene', (60, 65))	('CYP2E1', 'Gene', '1571', (49, 55))	('UDTC', 'Chemical', '-', (276, 280))	('tract cancer', 'Disease', 'MESH:D014571', (262, 274))	('variants', 'Var', (189, 197))	('polymorphisms', 'Var', (20, 33))	('GSTM1', 'Gene', '2944', (60, 65))	('CYP2E1', 'Gene', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('tract carcinomas', 'Disease', 'MESH:D012142', (114, 130))	('CYP1A1', 'Gene', (41, 47))
184598	31423187	The cytochrome P4501A1 (CYP1A1) rs4646903 T>C polymorphism increased GCC risk, the cytochrome P4502E1 (CYP2E1) rs2031920 C>T polymorphism increased EC risk, while the GSTM1 null genotype decreased EC risk.	('GSTM1', 'Gene', '2944', (167, 172))	('GCC', 'Chemical', '-', (69, 72))	('cytochrome P4501A1', 'Gene', (4, 22))	('increased', 'PosReg', (59, 68))	('CYP1A1', 'Gene', '1543', (24, 30))	('cytochrome P4502E1', 'Gene', (83, 101))	('increased', 'PosReg', (138, 147))	('rs2031920 C>T', 'Var', (111, 124))	('CYP2E1', 'Gene', '1571', (103, 109))	('cytochrome P4502E1', 'Gene', '1571', (83, 101))	('rs4646903', 'Mutation', 'rs4646903', (32, 41))	('rs2031920', 'Mutation', 'rs2031920', (111, 120))	('GC', 'Phenotype', 'HP:0012126', (69, 71))	('GSTM1', 'Gene', (167, 172))	('rs4646903 T>C', 'Var', (32, 45))	('cytochrome P4501A1', 'Gene', '1543', (4, 22))	('CYP2E1', 'Gene', (103, 109))	('CYP1A1', 'Gene', (24, 30))	('GCC', 'Disease', (69, 72))
184599	31423187	An association existed between the following: CYP1A1 rs4646903 and smoking in EC, GCC and GAC; CYP1A1 rs4646903 and alcohol consumption in EC and GCC; CYP2E1 rs2031920 and smoking in EC, GCC and GAC and CYP2E1 rs2031920 and alcohol consumption in EC and GCC.	('CYP2E1', 'Gene', (151, 157))	('GAC', 'Chemical', '-', (195, 198))	('GAC', 'Chemical', '-', (90, 93))	('CYP1A1', 'Gene', (95, 101))	('rs4646903', 'Var', (53, 62))	('GCC', 'Chemical', '-', (187, 190))	('CYP2E1', 'Gene', (203, 209))	('rs2031920', 'Mutation', 'rs2031920', (210, 219))	('GC', 'Phenotype', 'HP:0012126', (254, 256))	('CYP1A1', 'Gene', (46, 52))	('CYP1A1', 'Gene', '1543', (95, 101))	('GCC', 'Chemical', '-', (146, 149))	('rs4646903', 'Mutation', 'rs4646903', (102, 111))	('alcohol', 'Chemical', 'MESH:D000438', (116, 123))	('GCC', 'Chemical', '-', (82, 85))	('CYP2E1', 'Gene', '1571', (151, 157))	('CYP1A1', 'Gene', '1543', (46, 52))	('GC', 'Phenotype', 'HP:0012126', (187, 189))	('rs4646903', 'Mutation', 'rs4646903', (53, 62))	('rs2031920', 'Mutation', 'rs2031920', (158, 167))	('GC', 'Phenotype', 'HP:0012126', (146, 148))	('CYP2E1', 'Gene', '1571', (203, 209))	('GCC', 'Chemical', '-', (254, 257))	('alcohol', 'Chemical', 'MESH:D000438', (224, 231))	('rs4646903', 'Var', (102, 111))	('GC', 'Phenotype', 'HP:0012126', (82, 84))
184603	31423187	The CYP1A1 rs4646903 and CYP2E1 rs2031920 polymorphisms were risk factors of GCC or EC, and the GSTM1 null genotype may serve a protective role against EC.	('CYP1A1', 'Gene', (4, 10))	('GSTM1', 'Gene', (96, 101))	('GCC', 'Chemical', '-', (77, 80))	('rs4646903', 'Var', (11, 20))	('CYP1A1', 'Gene', '1543', (4, 10))	('CYP2E1', 'Gene', (25, 31))	('GCC', 'Disease', (77, 80))	('risk factors', 'Reg', (61, 73))	('GC', 'Phenotype', 'HP:0012126', (77, 79))	('rs4646903', 'Mutation', 'rs4646903', (11, 20))	('rs2031920', 'Var', (32, 41))	('rs2031920', 'Mutation', 'rs2031920', (32, 41))	('GSTM1', 'Gene', '2944', (96, 101))	('CYP2E1', 'Gene', '1571', (25, 31))
184614	31423187	The CYP1A1 rs4646903 T>C polymorphism (MspI), also known as the m1 allele, is a substitution of T to C in the non-coding 3'-flanking region which appears to be associated with increased enzymatic activity.	('CYP1A1', 'Gene', (4, 10))	('rs4646903 T>C', 'Var', (11, 24))	('increased', 'PosReg', (176, 185))	('CYP1A1', 'Gene', '1543', (4, 10))	('rs4646903', 'Mutation', 'rs4646903', (11, 20))
184615	31423187	The CYP2E1 rs2031920 C>T polymorphism (RsaI) also known as the c2 allele, involves a C to T transition in the 5'-flanking region of the CYP2E1 gene, which appears to be associated with decreased enzymatic activity.	('C to T', 'Var', (85, 91))	('CYP2E1', 'Gene', (4, 10))	('rs2031920 C>T', 'Var', (11, 24))	('rs2031920', 'Mutation', 'rs2031920', (11, 20))	('CYP2E1', 'Gene', '1571', (136, 142))	('CYP2E1', 'Gene', (136, 142))	('CYP2E1', 'Gene', '1571', (4, 10))
184618	31423187	One meta-analysis showed no association between CYP1A1 rs4646903 polymorphism and digestive tract cancers risk, while another meta-analysis confirmed association existed between CYP1A1 rs4646903 and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (199, 213))	('gastric cancer', 'Disease', 'MESH:D013274', (199, 213))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (82, 104))	('CYP1A1', 'Gene', '1543', (48, 54))	('rs4646903', 'Mutation', 'rs4646903', (185, 194))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('rs4646903', 'Var', (55, 64))	('CYP1A1', 'Gene', '1543', (178, 184))	('tract cancers', 'Disease', 'MESH:D014571', (92, 105))	('gastric cancer', 'Disease', (199, 213))	('tract cancers', 'Disease', (92, 105))	('CYP1A1', 'Gene', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('rs4646903', 'Mutation', 'rs4646903', (55, 64))	('rs4646903', 'Var', (185, 194))	('association', 'Interaction', (150, 161))	('CYP1A1', 'Gene', (48, 54))
184619	31423187	Zhang et al indicated that CYP2E1 rs2031920 polymorphisms revealed no association with the risk of GC, however when GSTM1 was null, the association became significant.	('rs2031920', 'Var', (34, 43))	('CYP2E1', 'Gene', (27, 33))	('GSTM1', 'Gene', '2944', (116, 121))	('GSTM1', 'Gene', (116, 121))	('CYP2E1', 'Gene', '1571', (27, 33))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('rs2031920', 'Mutation', 'rs2031920', (34, 43))
184620	31423187	GSTM1/T1 null genotype was reported to increase GC risk, and combination of the CYP1A1 rs4646422 variant allele and GSTM1/T1 null genotypes was also associated with a statistically significant increased risk.	('CYP1A1', 'Gene', (80, 86))	('GC', 'Phenotype', 'HP:0012126', (48, 50))	('CYP1A1', 'Gene', '1543', (80, 86))	('GSTM1', 'Gene', '2944', (116, 121))	('GSTM1', 'Gene', '2944', (0, 5))	('increase', 'PosReg', (39, 47))	('GSTM1', 'Gene', (116, 121))	('GSTM1', 'Gene', (0, 5))	('rs4646422', 'Mutation', 'rs4646422', (87, 96))	('rs4646422', 'Var', (87, 96))
184623	31423187	To clarify the combined effects of CYP1A1 rs4646903, CYP2E1 rs2031920, GSTM1 null polymorphisms and smoking or alcohol consumption on upper digestive tract cancer risk, a population-based case-control study was performed in Anyang, a typical high-incidence area of upper digestive cancer in Northern China.	('CYP1A1', 'Gene', '1543', (35, 41))	('rs4646903', 'Mutation', 'rs4646903', (42, 51))	('CYP2E1', 'Gene', (53, 59))	('rs2031920', 'Mutation', 'rs2031920', (60, 69))	('tract cancer', 'Disease', (150, 162))	('alcohol', 'Chemical', 'MESH:D000438', (111, 118))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (140, 162))	('GSTM1', 'Gene', '2944', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('rs4646903', 'Var', (42, 51))	('rs2031920', 'Var', (60, 69))	('CYP1A1', 'Gene', (35, 41))	('cancer', 'Disease', (156, 162))	('CYP2E1', 'Gene', '1571', (53, 59))	('cancer', 'Disease', (281, 287))	('GSTM1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('tract cancer', 'Disease', 'MESH:D014571', (150, 162))
184631	31423187	Smoking status was stratified into three levels: Never smoked, smoking for <30 years and smoking for >=30 years; alcohol consumption status was stratified into three levels: Never to occasional; >=1 day/week and <150 g/week; >=1 day/week and >150 g/week.	('<150 g/week', 'Var', (212, 223))	('>=1', 'Var', (195, 198))	('alcohol', 'Chemical', 'MESH:D000438', (113, 120))	('>150 g/week', 'Var', (242, 253))
184634	31423187	The polymorphisms of CYP2E1 rs2031920 C>T and GSTM1 were detected by PCR using the Thermal Cycler K640 (Hangzhou Jingle Scientific Instrument Co., Ltd.).	('GSTM1', 'Gene', '2944', (46, 51))	('rs2031920', 'Mutation', 'rs2031920', (28, 37))	('GSTM1', 'Gene', (46, 51))	('CYP2E1', 'Gene', (21, 27))	('rs2031920 C>T', 'Var', (28, 41))	('CYP2E1', 'Gene', '1571', (21, 27))
184645	31423187	A total of 194 EC, 212 GCC and 135 GAC cases, and 212 controls were examined to detect CYP1A1 rs4646903, CYP2E1 rs2031920 and GSTM1 polymorphisms.	('GAC', 'Chemical', '-', (35, 38))	('CYP1A1', 'Gene', (87, 93))	('GCC', 'Chemical', '-', (23, 26))	('CYP2E1', 'Gene', '1571', (105, 111))	('rs4646903', 'Var', (94, 103))	('CYP1A1', 'Gene', '1543', (87, 93))	('GSTM1', 'Gene', '2944', (126, 131))	('GSTM1', 'Gene', (126, 131))	('rs2031920', 'Var', (112, 121))	('rs2031920', 'Mutation', 'rs2031920', (112, 121))	('rs4646903', 'Mutation', 'rs4646903', (94, 103))	('CYP2E1', 'Gene', (105, 111))	('GC', 'Phenotype', 'HP:0012126', (23, 25))
184646	31423187	2 shows the sequencing chromatogram of CYP1A1 rs4646903 and CYP2E1 rs2031920.	('CYP1A1', 'Gene', (39, 45))	('rs4646903', 'Var', (46, 55))	('CYP2E1', 'Gene', '1571', (60, 66))	('CYP1A1', 'Gene', '1543', (39, 45))	('rs2031920', 'Mutation', 'rs2031920', (67, 76))	('CYP2E1', 'Gene', (60, 66))	('rs4646903', 'Mutation', 'rs4646903', (46, 55))
184652	31423187	CYP1A1 rs4646903 polymorphism was significantly associated with GCC risk [CC vs. TT: OR (95% CI)=1.936 (1.035-3.620), P=0.039; CC vs. CT+TT: OR (95% CI)=2.263 (1.272-4.026), P=0.005]; CYP2E1 rs2031920 was significantly associated with EC risk [c1/c2 vs. c1/c1: OR (95% CI)=1.673 (1.111-2.520), P=0.014; c1/c2+c2/c2 vs. c1/c1: OR (95% CI)=1.595 (1.071-2.375), P=0.022] (Tables IV and V).	('c1/c2', 'Gene', '3183', (303, 308))	('CYP2E1', 'Gene', '1571', (184, 190))	('c1/c2', 'Gene', (244, 249))	('rs4646903', 'Var', (7, 16))	('associated', 'Reg', (219, 229))	('CYP1A1', 'Gene', '1543', (0, 6))	('GCC', 'Chemical', '-', (64, 67))	('CYP2E1', 'Gene', (184, 190))	('c1/c2', 'Gene', (303, 308))	('rs4646903', 'Mutation', 'rs4646903', (7, 16))	('rs2031920', 'Mutation', 'rs2031920', (191, 200))	('GCC', 'Disease', (64, 67))	('c1/c2', 'Gene', '3183', (244, 249))	('GC', 'Phenotype', 'HP:0012126', (64, 66))	('CYP1A1', 'Gene', (0, 6))
184653	31423187	Gene-gene and gene-environment association between cigarette smoking, alcohol consumption, and CYP1A1 rs4646903 or CYP2E1 rs2031920 polymorphisms are presented in Table VI.	('rs4646903', 'Mutation', 'rs4646903', (102, 111))	('CYP2E1', 'Gene', '1571', (115, 121))	('CYP1A1', 'Gene', '1543', (95, 101))	('CYP2E1', 'Gene', (115, 121))	('CYP1A1', 'Gene', (95, 101))	('alcohol', 'Chemical', 'MESH:D000438', (70, 77))	('rs4646903', 'Var', (102, 111))	('rs2031920', 'Var', (122, 131))	('rs2031920', 'Mutation', 'rs2031920', (122, 131))
184655	31423187	Compared with non-smokers with wild-type CYP1A1 (TT), smokers with a CYP1A1 heterozygous variant genotype had a 2.597, 4.359 and 3.503-fold increased risk of EC, GCC and GAC, respectively.	('CYP1A1', 'Gene', (69, 75))	('CYP1A1', 'Gene', '1543', (41, 47))	('GCC', 'Chemical', '-', (162, 165))	('GCC', 'Disease', (162, 165))	('GAC', 'Disease', (170, 173))	('CYP1A1', 'Gene', '1543', (69, 75))	('variant', 'Var', (89, 96))	('GC', 'Phenotype', 'HP:0012126', (162, 164))	('GAC', 'Chemical', '-', (170, 173))	('CYP1A1', 'Gene', (41, 47))
184656	31423187	Smokers with a CYP1A1 homozygous variant genotype had a 5.125, 8.618 and 6.070-fold increased risk of EC, GCC and GAC, respectively.	('GAC', 'Disease', (114, 117))	('GC', 'Phenotype', 'HP:0012126', (106, 108))	('GAC', 'Chemical', '-', (114, 117))	('GCC', 'Chemical', '-', (106, 109))	('variant', 'Var', (33, 40))	('CYP1A1', 'Gene', (15, 21))	('CYP1A1', 'Gene', '1543', (15, 21))	('GCC', 'Disease', (106, 109))
184657	31423187	Compared with non-drinkers with wild-type CYP1A1 (TT), alcohol drinkers with a CYP1A1 homozygous variant genotype had a 4.124, 6.820 and 4.489-fold increased risk of EC, GCC and GAC, respectively.	('variant', 'Var', (97, 104))	('GCC', 'Chemical', '-', (170, 173))	('CYP1A1', 'Gene', (79, 85))	('CYP1A1', 'Gene', '1543', (42, 48))	('CYP1A1', 'Gene', '1543', (79, 85))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (55, 71))	('GCC', 'Disease', (170, 173))	('GAC', 'Disease', (178, 181))	('GC', 'Phenotype', 'HP:0012126', (170, 172))	('alcohol', 'Chemical', 'MESH:D000438', (55, 62))	('CYP1A1', 'Gene', (42, 48))	('GAC', 'Chemical', '-', (178, 181))
184661	31423187	These results indicated the association between smoking or alcohol consumption and CYP1A1 rs4646903 or CYP2E1 rs2031920 in UDTC.	('CYP1A1', 'Gene', (83, 89))	('rs4646903', 'Var', (90, 99))	('CYP2E1', 'Gene', (103, 109))	('UDTC', 'Disease', (123, 127))	('association', 'Interaction', (28, 39))	('CYP1A1', 'Gene', '1543', (83, 89))	('rs2031920', 'Mutation', 'rs2031920', (110, 119))	('rs4646903', 'Mutation', 'rs4646903', (90, 99))	('alcohol', 'Chemical', 'MESH:D000438', (59, 66))	('UDTC', 'Chemical', '-', (123, 127))	('CYP2E1', 'Gene', '1571', (103, 109))
184662	31423187	No associations were observed between CYP1A1 rs4646903 and CYP2E1 rs2031920.	('CYP1A1', 'Gene', '1543', (38, 44))	('rs2031920', 'Var', (66, 75))	('rs2031920', 'Mutation', 'rs2031920', (66, 75))	('rs4646903', 'Var', (45, 54))	('CYP2E1', 'Gene', (59, 65))	('CYP2E1', 'Gene', '1571', (59, 65))	('rs4646903', 'Mutation', 'rs4646903', (45, 54))	('CYP1A1', 'Gene', (38, 44))
184664	31423187	In addition, it was indicated that CYP1A1 rs4646903 polymorphisms increased GCC risk, CYP2E1 rs2031920 increased EC risk, while the GSTM1 null genotype decreased EC risk.	('CYP2E1', 'Gene', '1571', (86, 92))	('rs4646903', 'Var', (42, 51))	('CYP1A1', 'Gene', (35, 41))	('GCC', 'Disease', (76, 79))	('increased', 'PosReg', (66, 75))	('increased', 'PosReg', (103, 112))	('GSTM1', 'Gene', '2944', (132, 137))	('CYP2E1', 'Gene', (86, 92))	('rs2031920', 'Var', (93, 102))	('GSTM1', 'Gene', (132, 137))	('CYP1A1', 'Gene', '1543', (35, 41))	('rs2031920', 'Mutation', 'rs2031920', (93, 102))	('GC', 'Phenotype', 'HP:0012126', (76, 78))	('rs4646903', 'Mutation', 'rs4646903', (42, 51))	('GCC', 'Chemical', '-', (76, 79))
184665	31423187	Regarding the gene-gene or gene-environment associations in this study, associations between CYP1A1 rs4646903, CYP2E1 rs2031920 and smoking or alcohol were detected in UDTC.	('CYP1A1', 'Gene', (93, 99))	('associations', 'Interaction', (72, 84))	('UDTC', 'Chemical', '-', (168, 172))	('CYP2E1', 'Gene', (111, 117))	('rs4646903', 'Var', (100, 109))	('CYP1A1', 'Gene', '1543', (93, 99))	('rs2031920', 'Var', (118, 127))	('rs2031920', 'Mutation', 'rs2031920', (118, 127))	('alcohol', 'Chemical', 'MESH:D000438', (143, 150))	('rs4646903', 'Mutation', 'rs4646903', (100, 109))	('CYP2E1', 'Gene', '1571', (111, 117))
184666	31423187	To date, an increasing number of studies have investigated the associations between CYP1A1 rs4646903 polymorphisms and digestive cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('rs4646903', 'Mutation', 'rs4646903', (91, 100))	('CYP1A1', 'Gene', (84, 90))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('investigated', 'Reg', (46, 58))	('CYP1A1', 'Gene', '1543', (84, 90))	('rs4646903', 'Var', (91, 100))
184667	31423187	In a recent meta-analysis, seven articles reported on CYP1A1 rs4646903 polymorphisms in four digestive cancers, and no associations were found in stratified analysis and subgroup analyses.	('polymorphisms', 'Var', (71, 84))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('rs4646903', 'Mutation', 'rs4646903', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rs4646903 polymorphisms', 'Var', (61, 84))	('reported', 'Reg', (42, 50))	('CYP1A1', 'Gene', (54, 60))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('CYP1A1', 'Gene', '1543', (54, 60))	('cancers', 'Disease', (103, 110))
184668	31423187	In addition, in another meta-analysis, CYP1A1 rs4646903 polymorphisms were confirmed to be associated with an increased susceptibility to colorectal cancer, however not to esophageal cancer or gastric cancer.	('susceptibility', 'Reg', (120, 134))	('gastric cancer', 'Disease', (193, 207))	('esophageal cancer', 'Disease', (172, 189))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (193, 207))	('CYP1A1', 'Gene', (39, 45))	('colorectal cancer', 'Disease', (138, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (172, 189))	('rs4646903', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('CYP1A1', 'Gene', '1543', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (193, 207))	('rs4646903', 'Mutation', 'rs4646903', (46, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('associated', 'Reg', (91, 101))
184669	31423187	In the present study, no association between the CYP1A1 rs4646903 CC genotype and EC or GAC were detected, which was consistent with the aforementioned studies.	('CYP1A1', 'Gene', (49, 55))	('CYP1A1', 'Gene', '1543', (49, 55))	('GAC', 'Disease', (88, 91))	('rs4646903 CC', 'Var', (56, 68))	('rs4646903', 'Mutation', 'rs4646903', (56, 65))	('GAC', 'Chemical', '-', (88, 91))
184670	31423187	However, in another meta-analysis, 11 studies about CYP1A1 rs4646903 polymorphisms and GC were included, and significant results were found among a large sample-size subgroup.	('rs4646903', 'Var', (59, 68))	('CYP1A1', 'Gene', '1543', (52, 58))	('GC', 'Phenotype', 'HP:0012126', (87, 89))	('rs4646903', 'Mutation', 'rs4646903', (59, 68))	('CYP1A1', 'Gene', (52, 58))
184671	31423187	Furthermore, evidence was also found to support an association between CYP1A1 rs4646903 polymorphisms and digestive tract cancer in the subgroups of Caucasian and mixed individuals.	('polymorphisms', 'Var', (88, 101))	('tract cancer', 'Disease', (116, 128))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (106, 128))	('CYP1A1', 'Gene', (71, 77))	('rs4646903 polymorphisms', 'Var', (78, 101))	('CYP1A1', 'Gene', '1543', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tract cancer', 'Disease', 'MESH:D014571', (116, 128))	('rs4646903', 'Mutation', 'rs4646903', (78, 87))
184672	31423187	This study found associations between CYP1A1 rs4646903 polymorphisms and GCC.	('GCC', 'Disease', (73, 76))	('CYP1A1', 'Gene', '1543', (38, 44))	('rs4646903', 'Var', (45, 54))	('GCC', 'Chemical', '-', (73, 76))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('rs4646903', 'Mutation', 'rs4646903', (45, 54))	('CYP1A1', 'Gene', (38, 44))	('associations', 'Interaction', (17, 29))
184674	31423187	One report in Linzhou found an association between the CYP1A1 rs4646903 variant allele, and a reduced risk of GCC in people with Dysplasia, who were at high risk for the development of GCC.	('people', 'Species', '9606', (117, 123))	('CYP1A1', 'Gene', (55, 61))	('GCC', 'Disease', (110, 113))	('rs4646903', 'Var', (62, 71))	('GC', 'Phenotype', 'HP:0012126', (185, 187))	('reduced', 'NegReg', (94, 101))	('CYP1A1', 'Gene', '1543', (55, 61))	('GC', 'Phenotype', 'HP:0012126', (110, 112))	('Dysplasia', 'Disease', (129, 138))	('GCC', 'Chemical', '-', (185, 188))	('Dysplasia', 'Disease', 'MESH:D004476', (129, 138))	('rs4646903', 'Mutation', 'rs4646903', (62, 71))	('GCC', 'Chemical', '-', (110, 113))
184677	31423187	However, in this research, CYP2E1 rs2031920 genotypes tended to increase EC risk.	('rs2031920', 'Var', (34, 43))	('CYP2E1', 'Gene', (27, 33))	('increase', 'PosReg', (64, 72))	('CYP2E1', 'Gene', '1571', (27, 33))	('rs2031920', 'Mutation', 'rs2031920', (34, 43))
184678	31423187	One report in Guangzhou Chinese population and another report in a Northern Jiangsu Chinese population also showed that the CYP2E1 rs2031920 polymorphisms could be risk factors for the development of gastric cancer.	('gastric cancer', 'Disease', (200, 214))	('CYP2E1', 'Gene', '1571', (124, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('rs2031920', 'Mutation', 'rs2031920', (131, 140))	('CYP2E1', 'Gene', (124, 130))	('rs2031920 polymorphisms', 'Var', (131, 154))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('risk factors', 'Reg', (164, 176))	('polymorphisms', 'Var', (141, 154))
184679	31423187	Molecular biological evidence has shown that the CYP2E1 rs2031920 variant in the CYP2E1 promoter enhances gene transcriptional activity by altering its binding to its transcription factor, particularly, hepatocyte nuclear factor-1, and influencing its susceptibility to N-nitrosamine-linked carcinogenesis, indicating that the CYP2E1 rs2031920 variant may be associated with an increased cancer risk.	('rs2031920', 'Var', (334, 343))	('rs2031920', 'Var', (56, 65))	('carcinogenesis', 'Disease', (291, 305))	('enhances', 'PosReg', (97, 105))	('hepatocyte nuclear factor-1', 'MPA', (203, 230))	('carcinogenesis', 'Disease', 'MESH:D063646', (291, 305))	('gene transcriptional activity', 'MPA', (106, 135))	('CYP2E1', 'Gene', '1571', (81, 87))	('cancer', 'Disease', (388, 394))	('susceptibility', 'MPA', (252, 266))	('altering', 'Reg', (139, 147))	('CYP2E1', 'Gene', '1571', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('rs2031920', 'Mutation', 'rs2031920', (56, 65))	('CYP2E1', 'Gene', '1571', (327, 333))	('rs2031920', 'Mutation', 'rs2031920', (334, 343))	('binding', 'Interaction', (152, 159))	('CYP2E1', 'Gene', (81, 87))	('N-nitrosamine-linked', 'MPA', (270, 290))	('associated', 'Reg', (359, 369))	('CYP2E1', 'Gene', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('CYP2E1', 'Gene', (327, 333))	('influencing', 'Reg', (236, 247))	('N-nitrosamine', 'Chemical', '-', (270, 283))
184681	31423187	However, increased upper digestive tract cancer risk was associated with GSTM1 non-null genotypes.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tract cancer', 'Disease', 'MESH:D014571', (35, 47))	('GSTM1', 'Gene', (73, 78))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (25, 47))	('tract cancer', 'Disease', (35, 47))	('increased', 'PosReg', (9, 18))	('non-null', 'Var', (79, 87))	('GSTM1', 'Gene', '2944', (73, 78))
184682	31423187	A most recent meta-analysis on four digestive cancers showed that the GSTM1 polymorphism was associated with the risk of the four digestive cancers among the Asian population, as subgroup analyses by cancer site showed that the GSTM1 null genotype increased the total gastric cancer risk in the population.	('GSTM1', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('GSTM1', 'Gene', (228, 233))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('gastric cancer', 'Disease', (268, 282))	('polymorphism', 'Var', (76, 88))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('GSTM1', 'Gene', '2944', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('gastric cancer', 'Disease', 'MESH:D013274', (268, 282))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancer', 'Disease', (276, 282))	('increased', 'PosReg', (248, 257))	('cancers', 'Disease', (46, 53))	('cancer', 'Disease', (46, 52))	('GSTM1', 'Gene', '2944', (228, 233))	('cancer', 'Disease', (140, 146))	('associated', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (268, 282))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancer', 'Disease', (200, 206))
184683	31423187	Another meta-analysis in a Japanese population showed that GSTM1 null, GSTT1 null and GSTM1/T1 both or either null genotypes were associated with increased risk, though this was not statistically significantly.	('GSTT1', 'Gene', (71, 76))	('null', 'Var', (65, 69))	('GSTT1', 'Gene', '2952', (71, 76))	('GSTM1', 'Gene', '2944', (59, 64))	('null', 'Var', (77, 81))	('GSTM1', 'Gene', (59, 64))	('GSTM1', 'Gene', '2944', (86, 91))	('GSTM1', 'Gene', (86, 91))
184684	31423187	However, there are a number of reports showing that cancer risk is associated with GSTM1 non-null genotypes.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('GSTM1', 'Gene', '2944', (83, 88))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('genotypes', 'Var', (98, 107))	('non-null genotypes', 'Var', (89, 107))	('GSTM1', 'Gene', (83, 88))
184687	31423187	Furthermore, it appears that GSTM1 null individuals have higher DNA adduct levels than GSTM1-expressing individuals.	('GSTM1', 'Gene', (87, 92))	('DNA adduct levels', 'MPA', (64, 81))	('GSTM1', 'Gene', '2944', (29, 34))	('higher', 'PosReg', (57, 63))	('GSTM1', 'Gene', (29, 34))	('null', 'Var', (35, 39))	('GSTM1', 'Gene', '2944', (87, 92))
184688	31423187	Regarding the gene-gene or gene-environment associations in this study, an association between CYP1A1 rs4646903, CYP2E1 rs2031920 and smoking or alcohol was detected.	('CYP2E1', 'Gene', (113, 119))	('rs4646903', 'Mutation', 'rs4646903', (102, 111))	('CYP1A1', 'Gene', (95, 101))	('CYP2E1', 'Gene', '1571', (113, 119))	('alcohol', 'Chemical', 'MESH:D000438', (145, 152))	('rs2031920', 'Mutation', 'rs2031920', (120, 129))	('rs4646903', 'Var', (102, 111))	('CYP1A1', 'Gene', '1543', (95, 101))	('rs2031920', 'Var', (120, 129))	('association', 'Interaction', (75, 86))
184689	31423187	Two meta-analyses showed that CYP2E1 rs2031920 may modify the susceptibility to gastric cancer among individuals who have a smoking history, or when GSTM1 or GSTT1 are null, or CYP2E1 rs2031920 is homozygous wild-type.	('GSTM1', 'Gene', '2944', (149, 154))	('modify', 'Reg', (51, 57))	('gastric cancer', 'Disease', (80, 94))	('CYP2E1', 'Gene', '1571', (177, 183))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('rs2031920', 'Mutation', 'rs2031920', (184, 193))	('GSTM1', 'Gene', (149, 154))	('CYP2E1', 'Gene', '1571', (30, 36))	('GSTT1', 'Gene', '2952', (158, 163))	('rs2031920', 'Mutation', 'rs2031920', (37, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('GSTT1', 'Gene', (158, 163))	('CYP2E1', 'Gene', (177, 183))	('rs2031920', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CYP2E1', 'Gene', (30, 36))
184690	31423187	An increased risk was seen in CYP1A1 rs4646422 variant subjects whose smoking was categorized as <=30 pack-years, or whose GSTM1/T1 were both null genotypes, or who were null for either GSTM1/T1 individually.	('GSTM1', 'Gene', '2944', (186, 191))	('GSTM1', 'Gene', (186, 191))	('rs4646422', 'Mutation', 'rs4646422', (37, 46))	('rs4646422', 'Var', (37, 46))	('GSTM1', 'Gene', '2944', (123, 128))	('CYP1A1', 'Gene', (30, 36))	('GSTM1', 'Gene', (123, 128))	('CYP1A1', 'Gene', '1543', (30, 36))
184694	31423187	The differences stem from several factors, including ethnic or geographic differences, as Asian populations have been reported to be more prone compared with Caucasian populations to show significant associations between metabolic gene polymorphisms and carcinogenesis.	('polymorphisms', 'Var', (236, 249))	('associations', 'Interaction', (200, 212))	('carcinogenesis', 'Disease', 'MESH:D063646', (254, 268))	('prone', 'PosReg', (138, 143))	('carcinogenesis', 'Disease', (254, 268))	('metabolic gene', 'Gene', (221, 235))
184702	31423187	The CYP1A1 rs4646903 and CYP2E1 rs2031920 genotypes may contribute to higher GCC and EC susceptibility, respectively.	('CYP1A1', 'Gene', (4, 10))	('GCC', 'Chemical', '-', (77, 80))	('rs4646903', 'Var', (11, 20))	('CYP1A1', 'Gene', '1543', (4, 10))	('CYP2E1', 'Gene', (25, 31))	('GCC', 'Disease', (77, 80))	('GC', 'Phenotype', 'HP:0012126', (77, 79))	('rs4646903', 'Mutation', 'rs4646903', (11, 20))	('rs2031920', 'Var', (32, 41))	('higher', 'PosReg', (70, 76))	('CYP2E1', 'Gene', '1571', (25, 31))	('rs2031920', 'Mutation', 'rs2031920', (32, 41))
184704	31423187	The gene-environment associations present increase the cancer risk.	('increase', 'PosReg', (42, 50))	('associations', 'Var', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gene-environment associations', 'Var', (4, 33))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
184780	30311998	The NLR was associated with lymph node metastasis, pathological (p)TNM stage, tumor length, and radiotherapy, with a preoperative NLR > 2.998 associated with lymph node metastasis (P = 0.0352), radiotherapy (P = 0.0385), a higher pTNM stage (P = 0.0271), and tumor length (P = 0.0317) (Table 1).	('tumor', 'Disease', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('associated with', 'Reg', (142, 157))	('tumor', 'Disease', (78, 83))	('lymph node metastasis', 'CPA', (158, 179))	('> 2.998', 'Var', (134, 141))
184785	30311998	Patients with lymph node metastasis had significantly poorer CSS compared to those without lymph node metastasis (P < 0.001) (Fig 3).	('poorer', 'NegReg', (54, 60))	('CSS', 'MPA', (61, 64))	('Patients', 'Species', '9606', (0, 8))	('lymph node metastasis', 'Var', (14, 35))	('CSS', 'Chemical', '-', (61, 64))
184857	28337661	found fewer liver metastases in the post-MDT group, 6 months after resection, while the study by Freeman et al.	('post-MDT', 'Var', (36, 44))	('MDT', 'Chemical', '-', (41, 44))	('liver metastases', 'Disease', (12, 28))	('liver metastases', 'Disease', 'MESH:D009362', (12, 28))	('fewer', 'NegReg', (6, 11))
185024	28369068	We checked the expression of VEGF, the cells in 10 mumol/L AM80 had a decrease of 20.8%.	('VEGF', 'Gene', '22339', (29, 33))	('decrease', 'NegReg', (70, 78))	('VEGF', 'Gene', (29, 33))	('AM80', 'Var', (59, 63))
185032	28369068	We checked the expression of KDR, the cells in AM80 had a decrease of 18.0%.	('KDR', 'Gene', (29, 32))	('decrease', 'NegReg', (58, 66))	('KDR', 'Gene', '16542', (29, 32))	('AM80', 'Var', (47, 51))
185084	28369068	Inhibition of Tie2 resulted in impaired neoangiogenesis, leading to a delay in hematopoietic recovery.	('Tie2', 'Gene', (14, 18))	('neoangiogenesis', 'CPA', (40, 55))	('delay', 'NegReg', (70, 75))	('hematopoietic recovery', 'CPA', (79, 101))	('Inhibition', 'Var', (0, 10))	('Tie2', 'Gene', '21687', (14, 18))	('impaired', 'NegReg', (31, 39))
185088	28369068	We previously reported that ATRA treatment decreased the expression of vascular endothelial growth factors including VEGF, CD34, and CD105 in EC9706 in vitro and in vivo.	('vascular endothelial growth factor', 'Gene', (71, 105))	('expression', 'MPA', (57, 67))	('VEGF', 'Gene', (117, 121))	('CD105', 'Gene', '13805', (133, 138))	('EC9706', 'Var', (142, 148))	('CD34', 'Gene', (123, 127))	('EC9706', 'CellLine', 'CVCL:E307', (142, 148))	('ATRA', 'Chemical', 'MESH:D014212', (28, 32))	('VEGF', 'Gene', '22339', (117, 121))	('decreased', 'NegReg', (43, 52))	('CD34', 'Gene', '12490', (123, 127))	('CD105', 'Gene', (133, 138))	('vascular endothelial growth factor', 'Gene', '22339', (71, 105))
185095	27147562	We used immunohistochemistry to examine the expression of the EMT-related proteins E-cadherin, N-cadherin and vimentin in samples of T3N1-3M0 ESCC from 155 primary tumors (PTs) with paired metastatic lymph nodes (MLNs) and 58 PTs without paired MLNs.	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('vimentin', 'Gene', '7431', (110, 118))	('N-cadherin', 'Gene', '1000', (95, 105))	('tumors', 'Disease', (164, 170))	('T3N1-3M0', 'Var', (133, 141))	('vimentin', 'Gene', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('N-cadherin', 'Gene', (95, 105))
185096	27147562	Univariate analysis revealed that, for PTs, the EMT phenotype was associated with N-stage (P = 0.039) but not patient survival, and that patients with complete or hybrid type MLNs had better overall survival (OS, P = 0.001) and disease-free survival (DFS, P = 0.005) than patients with null and wild type MLNs, especially those with N1-stage disease (P = 0.017 for OS, and P = 0.017 for DFS, respectively).	('patient', 'Species', '9606', (137, 144))	('EMT', 'CPA', (48, 51))	('MLNs', 'Var', (175, 179))	('patients', 'Species', '9606', (137, 145))	('overall survival', 'CPA', (191, 207))	('better', 'PosReg', (184, 190))	('N-stage', 'Disease', (82, 89))	('N1-stage disease', 'Disease', 'MESH:D058625', (333, 349))	('hybrid type MLNs', 'Var', (163, 179))	('patient', 'Species', '9606', (110, 117))	('patient', 'Species', '9606', (272, 279))	('patients', 'Species', '9606', (272, 280))	('N1-stage disease', 'Disease', (333, 349))	('disease-free survival', 'CPA', (228, 249))
185104	27147562	Complete staining information for three EMT markers, E-cadherin, N-cadherin and vimentin, was obtained in a total of 155 PTs paired with MLNs and 58 PTs without paired MLNs.	('E-cadherin', 'Gene', (53, 63))	('MLNs', 'Var', (137, 141))	('E-cadherin', 'Gene', '999', (53, 63))	('vimentin', 'Gene', '7431', (80, 88))	('N-cadherin', 'Gene', (65, 75))	('vimentin', 'Gene', (80, 88))	('N-cadherin', 'Gene', '1000', (65, 75))
185120	27147562	Multivariate analysis using the Cox proportional hazards regression model with factors significantly affecting survival determined by univariate analysis showed that wild/null type, age >= 58 years and N2-3 stage were all independent predictors of poorer OS and DFS in T3N1-3M0 ESCCs (P < 0.05; Table 2).	('DFS', 'CPA', (262, 265))	('wild/null type', 'Var', (166, 180))	('poorer', 'NegReg', (248, 254))	('Cox', 'Gene', '1351', (32, 35))	('Cox', 'Gene', (32, 35))	('T3N1-3M0', 'Var', (269, 277))
185138	27147562	Selection criteria were 1) histologic proof of thoracic T3N1-3M0 ESCC according to the 7th edition AJCC TNM staging system, 2) availability of formalin-fixed and paraffin-embedded PT and MLN samples, 3) complete surgical resection, 4) no neoadjuvant or adjuvant treatment, 5) and complete follow-up data.	('paraffin', 'Chemical', 'MESH:D010232', (162, 170))	('TNM', 'Gene', '10178', (104, 107))	('formalin', 'Chemical', 'MESH:D005557', (143, 151))	('ESCC', 'Disease', (65, 69))	('T3N1-3M0', 'Var', (56, 64))	('TNM', 'Gene', (104, 107))
185155	24645745	Association Between p21 Ser31Arg Polymorphism and Gastrointestinal Tract Tumor Risk Human p21 gene is characterized by a polymorphism at codon 31 leading to a Serine-to-Arginine (S/R), two different alleles of p21 Ser31Arg (rs 1801270) polymorphism have been shown to differ significantly in their transcriptional efficiency.	('Ser31Arg', 'SUBSTITUTION', 'None', (24, 32))	('Arg', 'Chemical', 'MESH:D001120', (169, 172))	('Gastrointestinal Tract Tumor', 'Phenotype', 'HP:0007378', (50, 78))	('Tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Ser31Arg', 'SUBSTITUTION', 'None', (214, 222))	('p21', 'Gene', '1026', (20, 23))	('p21', 'Gene', '1026', (210, 213))	('p21', 'Gene', '1026', (90, 93))	('Ser31Arg', 'Var', (24, 32))	('Gastrointestinal Tract Tumor', 'Disease', 'MESH:D004067', (50, 78))	('Human', 'Species', '9606', (84, 89))	('Ser31Arg', 'Var', (214, 222))	('Ser', 'Chemical', 'MESH:D012694', (159, 162))	('Serine-to-Arginine', 'MPA', (159, 177))	('transcriptional', 'MPA', (298, 313))	('Gastrointestinal Tract Tumor', 'Disease', (50, 78))	('p21', 'Gene', (20, 23))	('Ser', 'Chemical', 'MESH:D012694', (24, 27))	('p21', 'Gene', (210, 213))	('p21', 'Gene', (90, 93))	('Arg', 'Chemical', 'MESH:D001120', (29, 32))	('Ser', 'Chemical', 'MESH:D012694', (214, 217))	('Arg', 'Chemical', 'MESH:D001120', (219, 222))
185156	24645745	More and more investigations are now being carried out to examine a possible link between the p21 Ser31Arg polymorphism and cancer.	('cancer', 'Disease', (124, 130))	('Ser31Arg', 'Var', (98, 106))	('p21', 'Gene', '1026', (94, 97))	('p21', 'Gene', (94, 97))	('polymorphism', 'Var', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Ser31Arg', 'SUBSTITUTION', 'None', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
185158	24645745	The meta-analysis showed significant association between Ser-allele or Ser/Ser genotype and the susceptibility to gastrointestinal tract tumor in overall studies (Ser-allele vs. Arg-allele: OR = 1.17, 95% CI: 1.04-1.31; Ser/Ser vs. Arg/Arg: OR = 1.38, 95% CI: 1.09-1.75; Ser/Ser vs. Arg/Ser: OR = 1.27, 95% CI: 1.05-1.53; Ser/Ser vs. Arg/Ser + Arg/Arg: OR = 1.29, 95% CI: 1.07-1.54).	('Ser', 'Chemical', 'MESH:D012694', (220, 223))	('Arg', 'Chemical', 'MESH:D001120', (344, 347))	('Ser', 'Chemical', 'MESH:D012694', (275, 278))	('Ser', 'Chemical', 'MESH:D012694', (338, 341))	('Ser', 'Chemical', 'MESH:D012694', (163, 166))	('Arg', 'Chemical', 'MESH:D001120', (232, 235))	('Ser', 'Chemical', 'MESH:D012694', (75, 78))	('gastrointestinal tract tumor', 'Disease', (114, 142))	('Ser', 'Chemical', 'MESH:D012694', (322, 325))	('Arg', 'Chemical', 'MESH:D001120', (334, 337))	('Ser/Ser', 'Var', (322, 329))	('gastrointestinal tract tumor', 'Disease', 'MESH:D004067', (114, 142))	('Ser', 'Chemical', 'MESH:D012694', (271, 274))	('Ser', 'Chemical', 'MESH:D012694', (224, 227))	('Arg', 'Chemical', 'MESH:D001120', (236, 239))	('Arg', 'Chemical', 'MESH:D001120', (348, 351))	('Ser', 'Chemical', 'MESH:D012694', (71, 74))	('Ser', 'Chemical', 'MESH:D012694', (326, 329))	('Ser', 'Chemical', 'MESH:D012694', (287, 290))	('Ser', 'Chemical', 'MESH:D012694', (57, 60))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (114, 142))	('Arg', 'Chemical', 'MESH:D001120', (283, 286))	('Arg', 'Chemical', 'MESH:D001120', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
185159	24645745	Despite the limitations, the results of the present meta-analysis suggested that, in the p21 Ser31Arg polymorphism, Ser-allele and Ser/Ser genotype might be risk factors for gastrointestinal tract tumor in Asian populations.	('gastrointestinal tract tumor', 'Disease', (174, 202))	('Ser', 'Chemical', 'MESH:D012694', (93, 96))	('Ser31Arg', 'SUBSTITUTION', 'None', (93, 101))	('gastrointestinal tract tumor', 'Disease', 'MESH:D004067', (174, 202))	('Ser', 'Chemical', 'MESH:D012694', (131, 134))	('risk factors', 'Reg', (157, 169))	('Ser', 'Chemical', 'MESH:D012694', (135, 138))	('p21', 'Gene', '1026', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Ser31Arg', 'Var', (93, 101))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (174, 202))	('p21', 'Gene', (89, 92))	('Ser', 'Chemical', 'MESH:D012694', (116, 119))
185170	24645745	Several studies showed that p21 polymorphisms might affect protein expression and activity, and play a role in susceptibility to cancer.	('polymorphisms', 'Var', (32, 45))	('p21', 'Gene', '1026', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('role', 'Reg', (103, 107))	('p21', 'Gene', (28, 31))	('protein expression', 'MPA', (59, 77))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('susceptibility', 'Reg', (111, 125))	('activity', 'MPA', (82, 90))	('play', 'Reg', (96, 100))	('affect', 'Reg', (52, 58))
185171	24645745	reported a polymorphism in the p21 codon31 (NM_000389.3:c.93 C>A, dbSNP rs 1801270) that produces a C to A transversion and causes a substitution from serine (Ser) to arginine (Arg), causing a loss of the restriction site and affecting the DNA binding zinc finger motif.	('restriction site', 'MPA', (205, 221))	('DNA binding zinc finger motif', 'MPA', (240, 269))	('p21', 'Gene', '1026', (31, 34))	('affecting', 'Reg', (226, 235))	('p21', 'Gene', (31, 34))	('NM_000389.3:c.93 C>A', 'Mutation', 'rs1801270', (44, 64))	('loss', 'NegReg', (193, 197))	('substitution', 'Var', (133, 145))	('Ser', 'Chemical', 'MESH:D012694', (159, 162))	('Arg', 'Chemical', 'MESH:D001120', (177, 180))	('c.93', 'Var', (56, 60))	('causes', 'Reg', (124, 130))	('dbSNP ', 'Mutation', 'dbSNP', (66, 72))	('transversion', 'MPA', (107, 119))
185172	24645745	It was found that p21 codon 31 (p21 Ser31Arg), which was later proved to be the only SNP in the 3-kb-long coding sequence of p21, both alone and/or in combination with other variants, might have an effect on carcinogenesis.	('p21', 'Gene', '1026', (18, 21))	('carcinogenesis', 'Disease', (208, 222))	('p21', 'Gene', '1026', (125, 128))	('p21', 'Gene', (18, 21))	('p21', 'Gene', '1026', (32, 35))	('Ser31Arg', 'SUBSTITUTION', 'None', (36, 44))	('effect', 'Reg', (198, 204))	('p21', 'Gene', (125, 128))	('p21', 'Gene', (32, 35))	('Ser31Arg', 'Var', (36, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (208, 222))
185173	24645745	A relatively large number of studies evaluated the association between p21 Ser31Arg and the risk of cancers, such as lung cancer, breast cancer, cervical cancer and so on, but the results remain inconclusive.	('Ser31Arg', 'Var', (75, 83))	('lung cancer', 'Disease', (117, 128))	('p21', 'Gene', (71, 74))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('p21', 'Gene', '1026', (71, 74))	('association', 'Interaction', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('cervical cancer', 'Disease', 'MESH:D002583', (145, 160))	('Ser31Arg', 'SUBSTITUTION', 'None', (75, 83))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('cervical cancer', 'Disease', (145, 160))	('cancers', 'Disease', (100, 107))	('breast cancer', 'Disease', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
185174	24645745	Especially there were very few studies about the correlation of p21 Ser31Arg and gastrointestinal tract tumors in Asians reported.	('gastrointestinal tract tumors', 'Phenotype', 'HP:0007378', (81, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Ser31Arg', 'Var', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('gastrointestinal tract tumors', 'Disease', 'MESH:D004067', (81, 110))	('p21', 'Gene', '1026', (64, 67))	('gastrointestinal tract tumors', 'Disease', (81, 110))	('Ser31Arg', 'SUBSTITUTION', 'None', (68, 76))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (81, 109))	('p21', 'Gene', (64, 67))
185175	24645745	Therefore, to derive a more comprehensive and precise estimation of the relationship, we conducted a systematic meta-analysis by including all relevant gastrointestinal system studies focusing on the association between the p21 Ser31Arg and the risk of gastrointestinal tract tumors in Asians.	('Ser31Arg', 'Var', (228, 236))	('gastrointestinal tract tumors', 'Disease', 'MESH:D004067', (253, 282))	('p21', 'Gene', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('gastrointestinal tract tumors', 'Disease', (253, 282))	('Ser31Arg', 'SUBSTITUTION', 'None', (228, 236))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (253, 281))	('gastrointestinal tract tumors', 'Phenotype', 'HP:0007378', (253, 282))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('p21', 'Gene', '1026', (224, 227))
185176	24645745	The search terms included ("P21" OR "CDKN1A"), ("polymorphism" OR "variant"), and ("cancer" OR "carcinoma").	('"polymorphism" OR "variant', 'Var', (48, 74))	('CDKN1A', 'Gene', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('P21', 'Gene', (28, 31))	('CDKN1A', 'Gene', '1026', (37, 43))	('"cancer" OR "carcinoma', 'Disease', (83, 105))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('"cancer" OR "carcinoma', 'Disease', 'MESH:D009369', (83, 105))	('P21', 'Gene', '1026', (28, 31))
185178	24645745	All human-associated studies, regardless of sample size, were included if they met the following criteria: (1) evaluation of p21 Ser31Arg polymorphism and cancer risk; (2) about gastrointestinal tract tumor; (3) case-control studies which use Asia's local population as objects; (4) sufficient data for examining an odds ratio (OR) with 95% confidence interval (95% CI).	('gastrointestinal tract tumor', 'Disease', (178, 206))	('human', 'Species', '9606', (4, 9))	('polymorphism', 'Var', (138, 150))	('Ser31Arg', 'Var', (129, 137))	('p21', 'Gene', '1026', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('gastrointestinal tract tumor', 'Disease', 'MESH:D004067', (178, 206))	('p21', 'Gene', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('Ser31Arg', 'SUBSTITUTION', 'None', (129, 137))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (178, 206))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
185180	24645745	Odds ratios (ORs) and 95% CI were used to assess the strength of association between p21 Ser31Arg polymorphism and gastrointestinal tract tumor.	('Ser31Arg', 'SUBSTITUTION', 'None', (89, 97))	('gastrointestinal tract tumor', 'Disease', 'MESH:D004067', (115, 143))	('Ser31Arg', 'Var', (89, 97))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (115, 143))	('p21', 'Gene', '1026', (85, 88))	('gastrointestinal tract tumor', 'Disease', (115, 143))	('p21', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
185181	24645745	The pooled ORs were performed for allelic contrast (Ser-allele vs. Arg-allele), homozygote comparison (Ser/Ser vs. Arg/Arg), heterozygote comparison (Ser/Ser vs. Arg/Ser, Arg/Ser vs. Arg/Arg), dominant genetic model (Ser/Ser + Arg/Ser vs. Arg/Arg) and recessive genetic model (Ser/Ser vs. Arg/Ser + Arg/Arg).	('Arg', 'Chemical', 'MESH:D001120', (227, 230))	('Arg', 'Chemical', 'MESH:D001120', (289, 292))	('Ser/Ser', 'Var', (277, 284))	('Arg', 'Chemical', 'MESH:D001120', (162, 165))	('Arg', 'Chemical', 'MESH:D001120', (115, 118))	('Ser', 'Chemical', 'MESH:D012694', (154, 157))	('Arg', 'Chemical', 'MESH:D001120', (303, 306))	('Ser', 'Chemical', 'MESH:D012694', (107, 110))	('Ser/Ser', 'Var', (217, 224))	('Arg', 'Chemical', 'MESH:D001120', (183, 186))	('Ser', 'Chemical', 'MESH:D012694', (52, 55))	('Arg', 'Chemical', 'MESH:D001120', (239, 242))	('Arg', 'Chemical', 'MESH:D001120', (119, 122))	('Ser', 'Chemical', 'MESH:D012694', (281, 284))	('Ser', 'Chemical', 'MESH:D012694', (217, 220))	('Ser', 'Chemical', 'MESH:D012694', (231, 234))	('Ser', 'Chemical', 'MESH:D012694', (150, 153))	('Ser', 'Chemical', 'MESH:D012694', (175, 178))	('Arg', 'Chemical', 'MESH:D001120', (299, 302))	('Ser/Ser', 'Var', (150, 157))	('Arg', 'Chemical', 'MESH:D001120', (187, 190))	('Ser', 'Chemical', 'MESH:D012694', (103, 106))	('Arg', 'Chemical', 'MESH:D001120', (67, 70))	('Ser', 'Chemical', 'MESH:D012694', (293, 296))	('Ser', 'Chemical', 'MESH:D012694', (221, 224))	('Ser', 'Chemical', 'MESH:D012694', (166, 169))	('Arg', 'Chemical', 'MESH:D001120', (243, 246))	('Arg', 'Chemical', 'MESH:D001120', (171, 174))	('Ser', 'Chemical', 'MESH:D012694', (277, 280))
185182	24645745	All the investigations were case-control studies including 967 cases and 1723 controls that examined the relationship between p21 Ser31Arg polymorphism and gastrointestinal tract tumor risk.	('gastrointestinal tract tumor', 'Disease', 'MESH:D004067', (156, 184))	('Ser31Arg', 'Var', (130, 138))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (156, 184))	('polymorphism', 'Var', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('Ser31Arg', 'SUBSTITUTION', 'None', (130, 138))	('p21', 'Gene', '1026', (126, 129))	('gastrointestinal tract tumor', 'Disease', (156, 184))	('p21', 'Gene', (126, 129))
185184	24645745	A summary of the meta-analysis findings of the association between p21 Ser31Arg polymorphism and gastrointestinal tract tumor was listed in Table II.	('gastrointestinal tract tumor', 'Disease', 'MESH:D004067', (97, 125))	('p21', 'Gene', '1026', (67, 70))	('Ser31Arg', 'Var', (71, 79))	('p21', 'Gene', (67, 70))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (97, 125))	('gastrointestinal tract tumor', 'Disease', (97, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Ser31Arg', 'SUBSTITUTION', 'None', (71, 79))
185185	24645745	The p21 Ser31Arg polymorphism analysis showed a significant association between Ser-allele and susceptibility to gastrointestinal tract tumor (OR = 1.17, 95% CI: 1.04-1.31) using the fixed effects model (P = 0.010, I2 = 15.4%).	('gastrointestinal tract tumor', 'Disease', (113, 141))	('p21', 'Gene', (4, 7))	('Ser31Arg', 'SUBSTITUTION', 'None', (8, 16))	('susceptibility', 'Reg', (95, 109))	('Ser', 'Chemical', 'MESH:D012694', (8, 11))	('gastrointestinal tract tumor', 'Disease', 'MESH:D004067', (113, 141))	('Ser', 'Chemical', 'MESH:D012694', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (113, 141))	('Ser31Arg', 'Var', (8, 16))	('p21', 'Gene', '1026', (4, 7))
185186	24645745	In the homozygote model comparison, Ser/Ser genotype was more likely to increase gastrointestinal tract tumor risk than Arg/Arg genotype (OR = 1.38, 95% CI: 1.09-1.75).	('Arg', 'Chemical', 'MESH:D001120', (124, 127))	('Ser/Ser', 'Var', (36, 43))	('increase gastrointestinal tract tumor', 'Disease', (72, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('increase gastrointestinal tract tumor', 'Disease', 'MESH:D004067', (72, 109))	('Ser', 'Chemical', 'MESH:D012694', (36, 39))	('Ser', 'Chemical', 'MESH:D012694', (40, 43))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (81, 109))	('Arg', 'Chemical', 'MESH:D001120', (120, 123))
185188	24645745	However, no statistically significant association was found under the other comparisons (Arg/Ser + Ser/Ser vs. Arg/Arg: OR = 1.16, 95% CI: 0.95-1.41; Arg/Ser vs. Arg/Arg: OR = 1.02, 95% CI: 0.83-1.27).	('Arg', 'Chemical', 'MESH:D001120', (162, 165))	('Arg/Ser', 'Var', (150, 157))	('Ser', 'Chemical', 'MESH:D012694', (93, 96))	('Arg', 'Chemical', 'MESH:D001120', (166, 169))	('Arg', 'Chemical', 'MESH:D001120', (111, 114))	('Ser', 'Chemical', 'MESH:D012694', (103, 106))	('Arg/Ser + Ser/Ser', 'Var', (89, 106))	('Arg', 'Chemical', 'MESH:D001120', (115, 118))	('Arg', 'Chemical', 'MESH:D001120', (150, 153))	('Arg', 'Chemical', 'MESH:D001120', (89, 92))	('Ser', 'Chemical', 'MESH:D012694', (154, 157))	('Ser', 'Chemical', 'MESH:D012694', (99, 102))
185189	24645745	The significance of pooled ORs under recessive model of p21 Ser31Arg polymorphism were not influenced excessively by omitting any single study (Figure 3), and the results were stable according to the ORs of fixed effects model and random effects model (Table II).	('p21', 'Gene', '1026', (56, 59))	('Ser31Arg', 'Var', (60, 68))	('p21', 'Gene', (56, 59))	('Ser31Arg', 'SUBSTITUTION', 'None', (60, 68))
185190	24645745	The present meta-analysis, including 967 cases and 1723 controls from 7 publications with 7 case-control studies, explored that the p21 Ser31Arg Ser-allele was significantly associated with an increased gastrointestinal tract tumor risk in Asians.	('Ser', 'Chemical', 'MESH:D012694', (136, 139))	('associated', 'Reg', (174, 184))	('gastrointestinal tract tumor', 'Phenotype', 'HP:0007378', (203, 231))	('Ser', 'Chemical', 'MESH:D012694', (145, 148))	('Ser31Arg', 'Var', (136, 144))	('Asians', 'Disease', (240, 246))	('p21', 'Gene', '1026', (132, 135))	('p21', 'Gene', (132, 135))	('gastrointestinal tract tumor', 'Disease', (203, 231))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('Ser31Arg', 'SUBSTITUTION', 'None', (136, 144))	('gastrointestinal tract tumor', 'Disease', 'MESH:D004067', (203, 231))	('increased gastrointestinal tract', 'Phenotype', 'HP:0011024', (193, 225))
185191	24645745	These findings indicated that p21 Ser31Arg polymorphism may play a role, although modest, in cancer development.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('Ser31Arg', 'Var', (34, 42))	('play', 'Reg', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('p21', 'Gene', '1026', (30, 33))	('p21', 'Gene', (30, 33))	('Ser31Arg', 'SUBSTITUTION', 'None', (34, 42))
185192	24645745	It was biologically plausible that the p21 Ser31Arg polymorphism may modulate the risk of cancers, as p21 plays an important role in cell cycle arrest at the G1 to S phase checkpoint, allowing cells to repair damaged DNA and there by inhibit carcinogenesis.	('cancers', 'Disease', (90, 97))	('carcinogenesis', 'Disease', (242, 256))	('Ser31Arg', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Ser31Arg', 'SUBSTITUTION', 'None', (43, 51))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (133, 150))	('p21', 'Gene', (39, 42))	('p21', 'Gene', '1026', (39, 42))	('arrest', 'Disease', 'MESH:D006323', (144, 150))	('inhibit', 'NegReg', (234, 241))	('p21', 'Gene', '1026', (102, 105))	('modulate', 'Reg', (69, 77))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('p21', 'Gene', (102, 105))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('arrest', 'Disease', (144, 150))	('carcinogenesis', 'Disease', 'MESH:D063646', (242, 256))
185193	24645745	Two different alleles of p21 Ser31Arg polymorphism have been shown to differ significantly in their transcriptional efficiency.	('Ser31Arg', 'Var', (29, 37))	('p21', 'Gene', (25, 28))	('polymorphism', 'Var', (38, 50))	('Ser31Arg', 'SUBSTITUTION', 'None', (29, 37))	('transcriptional efficiency', 'MPA', (100, 126))	('p21', 'Gene', '1026', (25, 28))
185194	24645745	For example, individuals carrying the Arg encoding allele manifest a lower expression.	('Arg', 'Var', (38, 41))	('Arg', 'Chemical', 'MESH:D001120', (38, 41))	('expression', 'MPA', (75, 85))	('lower', 'NegReg', (69, 74))
185195	24645745	showed a significantly increased risk for cancer in white population but decreased risk of esophageal cancer and gastric cancer in Asian population with Arg/Arg genotype.	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('decreased', 'NegReg', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastric cancer', 'Disease', (113, 127))	('cancer', 'Disease', (102, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('Arg', 'Chemical', 'MESH:D001120', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('esophageal cancer', 'Disease', (91, 108))	('Arg/Arg', 'Var', (153, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('cancer', 'Disease', (121, 127))	('Arg', 'Chemical', 'MESH:D001120', (157, 160))
185196	24645745	It actually consisted with our meta-analysis result, in which we found that the effect of the p21 Ser31Arg Ser/Ser genotype was unfavorable toward the development of esophageal, gastric and colorectal cancers in Asians.	('gastric', 'Disease', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('Ser31Arg', 'Var', (98, 106))	('p21', 'Gene', '1026', (94, 97))	('p21', 'Gene', (94, 97))	('Ser', 'Chemical', 'MESH:D012694', (107, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Ser', 'Chemical', 'MESH:D012694', (111, 114))	('Ser31Arg', 'SUBSTITUTION', 'None', (98, 106))	('colorectal cancers', 'Disease', 'MESH:D015179', (190, 208))	('esophageal', 'Disease', (166, 176))	('Ser', 'Chemical', 'MESH:D012694', (98, 101))	('colorectal cancers', 'Disease', (190, 208))
185198	24645745	reported that their overall meta-analysis did not observe any significant association between p21 Ser31Arg polymorphism and lung cancer risk, a significantly increased cancer risk with Ser/Ser genotype in a subgroup existed, which was also in accordant with our analysis results.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('Ser', 'Chemical', 'MESH:D012694', (185, 188))	('Ser31Arg', 'Var', (98, 106))	('p21', 'Gene', '1026', (94, 97))	('Ser', 'Chemical', 'MESH:D012694', (189, 192))	('p21', 'Gene', (94, 97))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('Ser31Arg', 'SUBSTITUTION', 'None', (98, 106))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('Ser', 'Chemical', 'MESH:D012694', (98, 101))
185199	24645745	investigated the association between the p21 Ser31Arg and breast cancer risk among 22109 cases and 29127 controls, but no significant association was found.	('p21', 'Gene', (41, 44))	('Ser31Arg', 'SUBSTITUTION', 'None', (45, 53))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('Ser31Arg', 'Var', (45, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('p21', 'Gene', '1026', (41, 44))
185253	26338103	In this study, we tested the protein expression and activities of EGFR as well as several key nodes on its downstream pathways for ESCC patients and found that expression of p-AKT1, p-AKT2, p-ERK1/2, and p-STAT3 was significantly related to the expression of p-EGFR.	('p-ERK1/2', 'Var', (190, 198))	('STAT3', 'Gene', (206, 211))	('AKT2', 'Gene', (184, 188))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', '1956', (261, 265))	('AKT2', 'Gene', '208', (184, 188))	('EGFR', 'Gene', (261, 265))	('AKT1', 'Gene', '207', (176, 180))	('patients', 'Species', '9606', (136, 144))	('AKT1', 'Gene', (176, 180))	('related', 'Reg', (230, 237))	('STAT3', 'Gene', '6774', (206, 211))	('tested', 'Reg', (18, 24))	('ESCC', 'Disease', (131, 135))
185261	26338103	Our future work will explore whether alterations of EGFR, including gene mutation and amplification, have prognostic values in ESCC.	('EGFR', 'Gene', '1956', (52, 56))	('ESCC', 'Disease', (127, 131))	('EGFR', 'Gene', (52, 56))	('amplification', 'MPA', (86, 99))	('gene mutation', 'Var', (68, 81))
185266	26338103	Besides EGFR stimulation, several other ways of activating AKT1 have been reported, including other growth factor receptors such as VEGF and PDGF, mutations of PI3K or RAS, inactivation of tumor suppressor gene PTEN, and AKT1E17K somatic mutations.	('mutations', 'Var', (147, 156))	('VEGF', 'Gene', (132, 136))	('activating', 'PosReg', (48, 58))	('PTEN', 'Gene', (211, 215))	('EGFR', 'Gene', '1956', (8, 12))	('AKT1', 'Gene', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('inactivation', 'Var', (173, 185))	('PI3K', 'Gene', (160, 164))	('AKT1', 'Gene', '207', (59, 63))	('PTEN', 'Gene', '5728', (211, 215))	('AKT1', 'Gene', (59, 63))	('PDGF', 'Gene', (141, 145))	('EGFR', 'Gene', (8, 12))	('RAS', 'Gene', (168, 171))	('tumor', 'Disease', (189, 194))	('AKT1', 'Gene', '207', (221, 225))	('VEGF', 'Gene', '7422', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
185285	25880782	On the other hand, our previous study had suggested that murine double minute 2 (MDM2) and p16 were associated with chemoradioresistance in ESCC.	('murine double minute 2', 'Gene', '17246', (57, 79))	('chemoradioresistance', 'CPA', (116, 136))	('associated with', 'Reg', (100, 115))	('ESCC', 'Disease', (140, 144))	('murine double minute 2', 'Gene', (57, 79))	('p16', 'Var', (91, 94))
185295	25880782	Moreover, the overall survival with a Ki-67 >= 33.7% was significantly better than that with <33.7% for patients in cStageIII (P = 0.024).	('better', 'PosReg', (71, 77))	('Ki-67 >= 33.7', 'Var', (38, 51))	('patients', 'Species', '9606', (104, 112))
185303	25880782	On the other hand, by investigating the surgical specimens of salvage esophagectomies after dCRT, our previous study had suggested that murine double minute 2 (MDM2) and p16 are associated with chemoradioresistance in ESCC.	('chemoradioresistance', 'CPA', (194, 214))	('dCRT', 'Gene', (92, 96))	('murine double minute 2', 'Gene', '17246', (136, 158))	('associated with', 'Reg', (178, 193))	('ESCC', 'Disease', (218, 222))	('murine double minute 2', 'Gene', (136, 158))	('p16', 'Var', (170, 173))	('dCRT', 'Gene', '45841', (92, 96))
185305	25880782	Overexpression of MDM2 has also been reported to be associated with development of radioresistance in several tumors.	('associated with', 'Reg', (52, 67))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('radioresistance', 'CPA', (83, 98))	('Overexpression', 'Var', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('MDM2', 'Gene', (18, 22))
185306	25880782	p16 is a cyclin-dependent kinase inhibitor and its inactivation is related to carcinogenesis.	('related', 'Reg', (67, 74))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('inactivation', 'Var', (51, 63))	('p16', 'Gene', (0, 3))	('carcinogenesis', 'Disease', (78, 92))
185324	25880782	The percentage of MDM2-, p53-, and Ki-67-positive nuclei, and p16-positive nuclei and/or cytoplasm of tumor cells was evaluated by x 400 magnification microscopy.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('Ki-67-positive', 'Gene', (35, 49))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('MDM2-', 'Var', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
185325	25880782	When determining the cut-off values, we identified the values for abnormal expression as follows: p53 >= 10% and p16 < 5%.	('p16', 'Var', (113, 116))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))
185331	25880782	The number of patients in each clinical stage was as follows: 22 in c-Stage I; 17 in c-Stage II (7, T3N0; 6, T1N1; 4, T2N1); and 40 in c-Stage III (35, T3N1; 5, T3N2).	('T3N0', 'Var', (100, 104))	('patients', 'Species', '9606', (14, 22))	('c-Stage', 'Disease', (68, 75))	('c-Stage', 'Disease', (85, 92))
185341	25880782	The number of patients that were p16 negative was significantly higher in the Failure group than in the CR group in the patients with cStageIII disease (P = 0.010).	('CR', 'Chemical', '-', (104, 106))	('p16 negative', 'Var', (33, 45))	('higher', 'PosReg', (64, 70))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (14, 22))
185346	25880782	In terms of correlation between marker expressions, the MDM2-positive rate tended to be higher in the p16-negative group than in the p16-positive group in the overall group of patients (P = 0.021) and the cStageIII patients (P = 0.086) (Figure 5).	('MDM2-positive', 'Gene', (56, 69))	('higher', 'PosReg', (88, 94))	('patients', 'Species', '9606', (215, 223))	('patients', 'Species', '9606', (176, 184))	('p16-negative', 'Var', (102, 114))
185348	25880782	In terms of MDM2 positivity, the OS of the patients with MDM2 levels >=9.05% was worse than that of the patients with levels <9.05% in the overall cohort (P = 0.08), and patients in cStageI (P = 0.06), and cStageIII (P = 0.15); however, these numbers did not reach statistical significance (Figure 6A).	('patients', 'Species', '9606', (170, 178))	('patients', 'Species', '9606', (43, 51))	('MDM2', 'Gene', (57, 61))	('OS', 'Chemical', '-', (33, 35))	('MDM2 positivity', 'Phenotype', 'HP:0031907', (12, 27))	('levels >=9.05%', 'Var', (62, 76))	('patients', 'Species', '9606', (104, 112))
185350	25880782	In terms of Ki-67, the OS of the patients with Ki-67 levels >=33.7% was significantly better than that of patients with levels <33.7% in the cStageIII group (P = 0.024); however, the findings were opposite in cStageI disease (P = 0.011) (Figure 6B).	('Ki-67 levels >=33.7%', 'Var', (47, 67))	('patients', 'Species', '9606', (33, 41))	('better', 'PosReg', (86, 92))	('patients', 'Species', '9606', (106, 114))	('OS', 'Chemical', '-', (23, 25))
185358	25880782	Although patients with high MDM2 positivity may obtain a CR state clinically, it is still necessary to closely observe them because these patients may be at high risk for cancer recurrence.	('patients', 'Species', '9606', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('MDM2 positivity', 'Phenotype', 'HP:0031907', (28, 43))	('CR', 'Chemical', '-', (57, 59))	('MDM2', 'Gene', (28, 32))	('positivity', 'Var', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('patients', 'Species', '9606', (138, 146))
185363	25880782	Although there were issues that will need to be addressed such as the high number of patients that were p16-negative and the small number of patients in this study, we found that p16 could also be a predictive marker for chemoradiosensitivity in advanced ESCC.	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (141, 149))	('p16', 'Var', (179, 182))	('chemoradiosensitivity', 'Disease', (221, 242))
185374	25880782	Besides inhibiting p53, MDM2 can also inhibit the cell cycle in another route; for example, MDM2 directly inhibits the retinoblastoma protein.	('inhibits', 'NegReg', (106, 114))	('MDM2', 'Var', (92, 96))	('retinoblastoma', 'Phenotype', 'HP:0009919', (119, 133))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('inhibiting', 'NegReg', (8, 18))	('retinoblastoma', 'Disease', 'MESH:D012175', (119, 133))	('cell cycle', 'CPA', (50, 60))	('retinoblastoma', 'Disease', (119, 133))	('inhibit', 'NegReg', (38, 45))
185376	25880782	In conclusion, the results of this study suggest that MDM2 and p16 might have potential as predictive markers for chemoradioresistance in cStageIII ESCC and also that Ki-67 may also have a role as a putative prognostic marker following dCRT in cStageIII ESCC.	('dCRT', 'Gene', (236, 240))	('dCRT', 'Gene', '45841', (236, 240))	('MDM2', 'Gene', (54, 58))	('cStageIII ESCC', 'Disease', (138, 152))	('cStageIII ESCC', 'Disease', (244, 258))	('p16', 'Gene', (63, 66))	('Ki-67', 'Var', (167, 172))	('chemoradioresistance', 'CPA', (114, 134))
185536	31333779	Genome-wide association studies (GWAS) have identified 24 single-nucleotide polymorphisms (SNPs) that could be associated with ESCC in Chinese patients.	('single-nucleotide polymorphisms', 'Var', (58, 89))	('ESCC', 'Disease', (127, 131))	('associated', 'Reg', (111, 121))	('patients', 'Species', '9606', (143, 151))
185538	31333779	It was found that rs12188136 (P=0.027, OR=1.158, 95% CI=1.016-1.319 for AG/AA) was associated with ESCC.	('rs12188136', 'Var', (18, 28))	('associated', 'Reg', (83, 93))	('rs12188136', 'Mutation', 'rs12188136', (18, 28))	('ESCC', 'Disease', (99, 103))
185539	31333779	Binary logistic regression analyses revealed a significant negative association of rs875339 in RORA (P=0.014, OR=0.762, 95% CI=0.613-0.947 for TT/CC).	('rs875339', 'Mutation', 'rs875339', (83, 91))	('negative', 'NegReg', (59, 67))	('RORA', 'Gene', (95, 99))	('RORA', 'Gene', '6095', (95, 99))	('rs875339', 'Var', (83, 91))
185540	31333779	Under the dominant model, rs6854472 was slightly associated with ESCC risk (P=0.048, OR=1.192, 95% CI=1.002-1.418).	('rs6854472', 'Var', (26, 35))	('ESCC', 'Disease', (65, 69))	('rs6854472', 'Mutation', 'rs6854472', (26, 35))
185541	31333779	Under the recessive model, a significant negative association was observed for rs875339 (P=0.010, OR=0.758, 95% CI=0.615-0.935).	('rs875339', 'Var', (79, 87))	('rs875339', 'Mutation', 'rs875339', (79, 87))	('negative', 'NegReg', (41, 49))
185542	31333779	In a word, this large-scale replication study validated that rs12188136 and rs6854472 are associated with ESCC in a Han Chinese subgroup from Eastern China, and that rs875339 is negative associated with ESCC.	('rs875339', 'Var', (166, 174))	('rs6854472', 'Mutation', 'rs6854472', (76, 85))	('rs875339', 'Mutation', 'rs875339', (166, 174))	('ESCC', 'Disease', (106, 110))	('associated', 'Reg', (90, 100))	('rs12188136', 'Var', (61, 71))	('rs12188136', 'Mutation', 'rs12188136', (61, 71))	('rs6854472', 'Var', (76, 85))
185552	31333779	identified rs1050631 in SLC39A6 as being associated with the survival of ESCC patients.	('SLC39A6', 'Gene', '25800', (24, 31))	('rs1050631', 'Var', (11, 20))	('associated', 'Reg', (41, 51))	('SLC39A6', 'Gene', (24, 31))	('rs1050631', 'Mutation', 'rs1050631', (11, 20))	('patients', 'Species', '9606', (78, 86))	('ESCC', 'Disease', (73, 77))
185558	31333779	We selected the 24 top SNPs (rs4478858, rs10881372, rs10801638, rs10173378, rs888103, rs3815501, rs6717108, rs10934685, rs6768588, rs9824873, rs6854472, rs12188136, rs2294693, rs9364414, rs7916519, rs11225815, rs10895458, rs4578395, rs11059556, rs2025245, rs9584006, rs347940, rs875339, and rs12922317) from the reports focusing on ESCC susceptibility loci identified by five GWAS projects in Han Chinese (PubMed search).	('rs2294693', 'Mutation', 'rs2294693', (165, 174))	('rs11059556', 'Mutation', 'rs11059556', (233, 243))	('rs6717108', 'Mutation', 'rs6717108', (97, 106))	('rs10173378', 'Var', (64, 74))	('rs2294693', 'Var', (165, 174))	('rs6768588', 'Mutation', 'rs6768588', (120, 129))	('rs10934685', 'Var', (108, 118))	('rs10801638', 'Var', (52, 62))	('rs10801638', 'Mutation', 'rs10801638', (52, 62))	('rs7916519', 'Var', (187, 196))	('rs9824873', 'Var', (131, 140))	('rs10895458', 'Var', (210, 220))	('rs3815501', 'Mutation', 'rs3815501', (86, 95))	('rs10895458', 'Mutation', 'rs10895458', (210, 220))	('rs2025245', 'Var', (245, 254))	('rs4578395', 'Mutation', 'rs4578395', (222, 231))	('rs888103', 'Mutation', 'rs888103', (76, 84))	('rs11225815', 'Mutation', 'rs11225815', (198, 208))	('rs11059556', 'Var', (233, 243))	('rs12922317', 'Mutation', 'rs12922317', (291, 301))	('rs10173378', 'Mutation', 'rs10173378', (64, 74))	('rs11225815', 'Var', (198, 208))	('rs875339', 'Mutation', 'rs875339', (277, 285))	('rs4478858', 'Var', (29, 38))	('rs347940', 'Mutation', 'rs347940', (267, 275))	('rs10934685', 'Mutation', 'rs10934685', (108, 118))	('rs12188136', 'Var', (153, 163))	('rs888103', 'Var', (76, 84))	('rs9584006', 'Mutation', 'rs9584006', (256, 265))	('rs9364414', 'Var', (176, 185))	('rs4578395', 'Var', (222, 231))	('rs9824873', 'Mutation', 'rs9824873', (131, 140))	('rs347940', 'Var', (267, 275))	('rs9584006', 'Var', (256, 265))	('rs6854472', 'Mutation', 'rs6854472', (142, 151))	('rs6717108', 'Var', (97, 106))	('ESCC', 'Disease', (332, 336))	('rs12188136', 'Mutation', 'rs12188136', (153, 163))	('rs2025245', 'Mutation', 'rs2025245', (245, 254))	('rs10881372', 'Mutation', 'rs10881372', (40, 50))	('rs7916519', 'Mutation', 'rs7916519', (187, 196))	('rs4478858', 'Mutation', 'rs4478858', (29, 38))	('rs9364414', 'Mutation', 'rs9364414', (176, 185))	('rs3815501', 'Var', (86, 95))
185565	31333779	In the single-locus analyses, the allelic frequencies of rs10173378: A>G (0.241 vs. 0.221, P = 0.0409) and rs6854472: G>T (0.072 vs. 0.084, P = 0.0477) were slightly different between the ESCC and control group, but 100,000 permutations showed that there were no significant differences between the two groups.	('rs10173378: A>G', 'Var', (57, 72))	('ESCC', 'Disease', (188, 192))	('rs6854472', 'Mutation', 'rs6854472', (107, 116))	('rs10173378', 'Mutation', 'rs10173378', (57, 67))	('rs6854472: G>T', 'Var', (107, 121))
185566	31333779	The distribution of the rs12188136 (47.4% vs. 50.2%, P = 0.0493) and rs875339 (49.4% vs. 48.4%, P = 0.0341) genotypes showed significant differences between the cases and controls.	('rs875339', 'Var', (69, 77))	('rs12188136', 'Var', (24, 34))	('rs12188136', 'Mutation', 'rs12188136', (24, 34))	('rs875339', 'Mutation', 'rs875339', (69, 77))
185567	31333779	Logistic regression analyses revealed that in the codominant-effect model, the ESCC risk was associated with rs12188136 (P = 0.027, OR = 1.158, 95% CI = 1.016-1.319 for AG/AA).	('rs12188136', 'Var', (109, 119))	('ESCC', 'Disease', (79, 83))	('rs12188136', 'Mutation', 'rs12188136', (109, 119))
185568	31333779	Binary logistic regression analyses revealed a slight negative association of rs10895458 (P = 0.044, OR = 0.547, 95% CI = 0.304-0.983 for CC/AA) and a significant negative association of rs875339 (P = 0.014, OR = 0.762, 95% CI = 0.613-0.947 for TT/CC), but because of the rarity of the homozygous mutant genotype (<3%), the results were invalid for rs10895458.	('rs10895458', 'Mutation', 'rs10895458', (349, 359))	('rs875339', 'Mutation', 'rs875339', (187, 195))	('rs10895458', 'Var', (78, 88))	('CC/AA', 'Disease', (138, 143))	('rs875339', 'Var', (187, 195))	('rs10895458', 'Mutation', 'rs10895458', (78, 88))	('negative', 'NegReg', (54, 62))
185569	31333779	In addition, marginal esophageal cancer risk was found for rs6854472 (P = 0.056, OR = 1.187, 95% CI = 0.995-1.417 for GT/GG) (Table 3).	('rs6854472', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('marginal esophageal cancer', 'Disease', 'MESH:D004938', (13, 39))	('rs6854472', 'Mutation', 'rs6854472', (59, 68))	('marginal esophageal cancer', 'Disease', (13, 39))
185570	31333779	Using the dominant model, significant ESCC risk was observed for rs6854472 (P = 0.048, OR = 1.192, 95% CI = 1.002-1.418).	('rs6854472', 'Var', (65, 74))	('rs6854472', 'Mutation', 'rs6854472', (65, 74))	('ESCC', 'Disease', (38, 42))
185571	31333779	Using the recessive model, a significant negative association was observed for rs875339 (P = 0.010, OR = 0.758, 95% CI = 0.615-0.935) (Table 4).	('rs875339', 'Var', (79, 87))	('rs875339', 'Mutation', 'rs875339', (79, 87))	('negative', 'NegReg', (41, 49))
185573	31333779	The results suggest that rs12188136 and rs6854472 are associated with ESCC in this Han Chinese subgroup, and that rs875339 is negative associated with ESCC.	('rs12188136', 'Mutation', 'rs12188136', (25, 35))	('rs6854472', 'Var', (40, 49))	('rs875339', 'Mutation', 'rs875339', (114, 122))	('rs6854472', 'Mutation', 'rs6854472', (40, 49))	('ESCC', 'Disease', (70, 74))	('rs875339', 'Var', (114, 122))	('associated', 'Reg', (54, 64))	('rs12188136', 'Var', (25, 35))
185575	31333779	Besides rs12188136 and rs6854472 localizing in intergenic areas, RORA could play a role in the development of ESCC.	('RORA', 'Gene', '6095', (65, 69))	('play', 'Reg', (76, 80))	('rs12188136', 'Var', (8, 18))	('rs12188136', 'Mutation', 'rs12188136', (8, 18))	('ESCC', 'Disease', (110, 114))	('rs6854472', 'Mutation', 'rs6854472', (23, 32))	('rs6854472', 'Var', (23, 32))	('RORA', 'Gene', (65, 69))
185578	31333779	This GWAS identified nine new susceptibility loci for ESCC, of which seven (4q23, 16q12.1, 17q21, 22q12, 3q27, 17p13 and 18p11) had a significant marginal effect and two of which (2q22 and 13q33) had a significant association in the gene-alcohol interaction only.	('alcohol interaction', 'Phenotype', 'HP:0030955', (238, 257))	('p11', 'Gene', (123, 126))	('3q27', 'Var', (105, 109))	('ESCC', 'Disease', (54, 58))	('4q23', 'Var', (76, 80))	('17q21', 'Var', (91, 96))	('p11', 'Gene', '6281', (123, 126))	('alcohol', 'Chemical', 'MESH:D000438', (238, 245))
185579	31333779	showed that rs7447927at 5q31.2 and rs1642764 at 17p13.1 were associated with ESCC susceptibility.	('ESCC', 'Disease', (77, 81))	('rs1642764', 'Var', (35, 44))	('rs7447927at', 'Var', (12, 23))	('associated', 'Reg', (61, 71))	('rs1642764', 'Mutation', 'rs1642764', (35, 44))
185580	31333779	showed that rs2274223 was associated with reduced PLCE1 expression and increased risk of ESCC.	('reduced', 'NegReg', (42, 49))	('rs2274223', 'Mutation', 'rs2274223', (12, 21))	('PLCE1', 'Gene', (50, 55))	('rs2274223', 'Var', (12, 21))	('PLCE1', 'Gene', '51196', (50, 55))	('ESCC', 'Disease', (89, 93))	('expression', 'MPA', (56, 66))
185581	31333779	showed that the ADH1B-ADH1C-ADH7 axis was modulated by the rs1042026, rs17033, rs1614972, rs1789903 and rs17028973 SNPs.	('rs17033', 'Var', (70, 77))	('ADH7', 'Gene', (28, 32))	('rs17028973', 'Var', (104, 114))	('rs17033', 'Mutation', 'rs17033', (70, 77))	('ADH1B', 'Gene', (16, 21))	('rs1042026', 'Mutation', 'rs1042026', (59, 68))	('ADH1C', 'Gene', '126', (22, 27))	('ADH1B', 'Gene', '125', (16, 21))	('ADH7', 'Gene', '131', (28, 32))	('rs1789903', 'Var', (90, 99))	('rs1614972', 'Mutation', 'rs1614972', (79, 88))	('ADH1C', 'Gene', (22, 27))	('rs1789903', 'Mutation', 'rs1789903', (90, 99))	('modulated', 'Reg', (42, 51))	('rs1614972', 'Var', (79, 88))	('rs1042026', 'Var', (59, 68))	('rs17028973', 'Mutation', 'rs17028973', (104, 114))
185582	31333779	In the present study, the identified polymorphisms matched those found by the previous studies, and included rs2294693 in 6p21.1, rs11059556 in 12q24, rs6854472 in 4q22, rs12922317 in 16p13.12, and rs9824873 in 3q28.	('rs2294693', 'Mutation', 'rs2294693', (109, 118))	('rs12922317', 'Var', (170, 180))	('rs6854472', 'Mutation', 'rs6854472', (151, 160))	('rs11059556', 'Var', (130, 140))	('rs9824873', 'Mutation', 'rs9824873', (198, 207))	('rs2294693', 'Var', (109, 118))	('rs9824873', 'Var', (198, 207))	('rs6854472', 'Var', (151, 160))	('rs12922317', 'Mutation', 'rs12922317', (170, 180))	('rs11059556', 'Mutation', 'rs11059556', (130, 140))
185585	31333779	This large-scale replication study showed that rs12188136 and rs6854472 are associated with ESCC in a Han Chinese subgroup from Eastern China, and that rs875339 is negative associated with ESCC.	('rs875339', 'Var', (152, 160))	('rs6854472', 'Mutation', 'rs6854472', (62, 71))	('ESCC', 'Disease', (92, 96))	('rs875339', 'Mutation', 'rs875339', (152, 160))	('rs6854472', 'Var', (62, 71))	('rs12188136', 'Var', (47, 57))	('associated', 'Reg', (76, 86))	('rs12188136', 'Mutation', 'rs12188136', (47, 57))
185607	30225745	Thus, we previously conducted a randomized phase II trial to study the effects of Gln plus one pack (80 g) of elemental diet {ED [(Elental ; EA Pharma Co., Ltd.)]}/day: total Gln 8862 mg/day or Gln alone: 8910 mg/day compared to no prevention of OM in patients with esophageal cancer undergoing chemotherapy including FP and triplet regimen.	('esophageal cancer', 'Disease', 'MESH:D004938', (266, 283))	('patients', 'Species', '9606', (252, 260))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('Gln', 'Chemical', 'MESH:D005973', (194, 197))	('esophageal cancer', 'Disease', (266, 283))	('Gln', 'Chemical', 'MESH:D005973', (82, 85))	('Gln', 'Chemical', 'MESH:D005973', (175, 178))	('Gln 8862 mg/day', 'Var', (175, 190))
185627	30225745	The other inclusion criteria were as follows: an Eastern Cooperative Oncology Group performance status of 0-1; a life expectancy of > 12 weeks; and adequate liver, bone marrow, renal, and cardiovascular functions [serum bilirubin <= 1.5 mg/dl; neutrophil count >= 1500/mm3; serum aspartate aminotransferase and alanine aminotransferase levels <= twice the upper limit of normal range; platelet count >= 10 x 104/mm3; hemoglobin >= 8.0 g/dl; and creatinine <= 1.2 mg/dl (or creatinine clearance > 60 ml/min)].	('alanine aminotransferase', 'Gene', (311, 335))	('creatinine clearance', 'MPA', (473, 493))	('alanine aminotransferase', 'Gene', '2875', (311, 335))	('serum bilirubin', 'MPA', (214, 229))	('hemoglobin', 'MPA', (417, 427))	('<= 1.5 mg/dl', 'Var', (230, 242))	('>= 1500/mm3', 'Var', (261, 272))	('creatinine', 'MPA', (445, 455))	('Oncology', 'Phenotype', 'HP:0002664', (69, 77))	('platelet', 'MPA', (385, 393))	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (274, 306))
185731	28404945	The results showed that the overall survival was significantly shorter in patients with uPA-positive stroma expression (n = 132, median survival time 20 months) compared with patients with uPA-negative expression (n = 14, median survival time 36 months) (Figure 3).	('stroma expression', 'CPA', (101, 118))	('overall survival', 'CPA', (28, 44))	('patients', 'Species', '9606', (74, 82))	('shorter', 'NegReg', (63, 70))	('patients', 'Species', '9606', (175, 183))	('uPA-positive', 'Var', (88, 100))
185736	28404945	Cells treated with 20 ng/ml of uPA or CAF CM had significantly accelerated growth rates than cells treated with DMEM control or NF CM.	('growth rates', 'CPA', (75, 87))	('accelerated', 'PosReg', (63, 74))	('DMEM', 'Chemical', '-', (112, 116))	('CAF CM', 'Var', (38, 44))
185744	28404945	When LY294002 or U0126 was added, phosphorylation levels of AKT, GSK3beta, and ERK1/2 were reduced; when both inhibitors were combined, their effects were cooperative (Figure 5A, 5B).	('LY294002', 'Chemical', 'MESH:C085911', (5, 13))	('U0126', 'Chemical', 'MESH:C113580', (17, 22))	('GSK3beta', 'Gene', '2932', (65, 73))	('ERK1/2', 'Gene', (79, 85))	('ERK1/2', 'Gene', '5595;5594', (79, 85))	('AKT', 'Gene', '207', (60, 63))	('phosphorylation levels', 'MPA', (34, 56))	('LY294002', 'Var', (5, 13))	('reduced', 'NegReg', (91, 98))	('U0126', 'Var', (17, 22))	('AKT', 'Gene', (60, 63))	('GSK3beta', 'Gene', (65, 73))
185745	28404945	In the in vitro function assays, we added 1 muM LY294002 and/or U0126 to inhibit PI3k/AKT and/or ERK signaling pathway before treating cells with uPA or CAF CM.	('U0126', 'Chemical', 'MESH:C113580', (64, 69))	('ERK', 'Gene', (97, 100))	('AKT', 'Gene', (86, 89))	('LY294002', 'Var', (48, 56))	('U0126', 'Var', (64, 69))	('LY294002', 'Chemical', 'MESH:C085911', (48, 56))	('AKT', 'Gene', '207', (86, 89))	('ERK', 'Gene', '5594', (97, 100))	('inhibit', 'NegReg', (73, 80))
185746	28404945	However, when EC109 or K30 cells were treated with 1 muM LY294002 or U0126 without uPA or CAF CM treatment, proliferation, migration, and invasion rates were not significantly changed (Supplementary Figure 3).	('LY294002', 'Chemical', 'MESH:C085911', (57, 65))	('U0126', 'Chemical', 'MESH:C113580', (69, 74))	('proliferation', 'CPA', (108, 121))	('U0126', 'Var', (69, 74))	('EC', 'Phenotype', 'HP:0011459', (14, 16))	('LY294002', 'Var', (57, 65))	('migration', 'CPA', (123, 132))	('invasion rates', 'CPA', (138, 152))
185749	28404945	Mice bearing KYSE30 tumors (approximately 100 mm3) were randomized into two groups (n = 5).	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('KYSE30', 'Var', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Mice', 'Species', '10090', (0, 4))
185753	28404945	Further histologic analysis revealed that anti-uPA antibody reduced tumor protein level of the proliferation marker Ki67, and phosphorylation levels of AKT and ERK (Figure 7D).	('tumor', 'Disease', (68, 73))	('AKT', 'Gene', '207', (152, 155))	('ERK', 'Gene', '5594', (160, 163))	('Ki67', 'Gene', (116, 120))	('phosphorylation levels', 'MPA', (126, 148))	('ERK', 'Gene', (160, 163))	('AKT', 'Gene', (152, 155))	('reduced', 'NegReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Ki67', 'Gene', '17345', (116, 120))	('anti-uPA', 'Var', (42, 50))
185771	28404945	Targeting uPA by anti-uPA antibody could effectively neutralize uPA and subsequently deactivate the PI3K/AKT and ERK signaling pathways.	('AKT', 'Gene', '207', (105, 108))	('ERK', 'Gene', '5594', (113, 116))	('ERK', 'Gene', (113, 116))	('AKT', 'Gene', (105, 108))	('uPA', 'Disease', (64, 67))	('deactivate', 'NegReg', (85, 95))	('neutralize', 'Var', (53, 63))
185819	24116039	In contrast to bulk cell studies reported earlier, our study shows significant differences between metaplastic and dysplastic BE cells in both average values and single-cell parameter distributions of mtDNA copy numbers, mitochondrial function, and mRNA expression levels of studied genes.	('copy numbers', 'Var', (207, 219))	('mRNA expression levels', 'MPA', (249, 271))	('mtDNA', 'Gene', (201, 206))	('dysplastic', 'Disease', 'MESH:D004416', (115, 125))	('dysplastic', 'Disease', (115, 125))	('differences', 'Reg', (79, 90))	('mitochondrial function', 'MPA', (221, 243))
185832	24116039	Utilizing single-cell analysis we distinguished differences in mtDNA copy number, mitochondrial membrane potential, and hypoxia response gene expression levels between CP-A and CP-C cells which cannot be predicted by bulk cell analysis.	('CP-A', 'Gene', '1357', (168, 172))	('CP-A', 'Gene', (168, 172))	('hypoxia', 'Disease', (120, 127))	('CP-C', 'Gene', (177, 181))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('CP-C', 'Gene', '529879', (177, 181))	('copy number', 'Var', (69, 80))	('mitochondrial membrane potential', 'MPA', (82, 114))	('differences', 'Reg', (48, 59))	('mtDNA', 'Gene', (63, 68))
185863	24116039	A significant reduction in Ct value of the 16s rRNA gene (p<0.05, n = 24) was observed in hypoxic CP-A single cells, while only slight but statistically significant change was detected in hypoxic CP-C cells (p<0.05, n = 24) (Fig.	('CP-A', 'Gene', (98, 102))	('16s rRNA gene', 'Gene', (43, 56))	('hypoxic CP-C', 'Disease', 'MESH:C566991', (188, 200))	('Ct value', 'MPA', (27, 35))	('hypoxic CP-C', 'Disease', (188, 200))	('hypoxic', 'Var', (90, 97))	('reduction', 'NegReg', (14, 23))	('CP-A', 'Gene', '1357', (98, 102))
185908	24116039	Another potential mechanism contributing to the maintenance of the hyperpolarization of the inner mitochondrial membrane in CP-C cells could be the HIF-1a mediated replacement of the COX4-1 subunit with the COX4-2 isoform which is known to increase the efficiency of COX under hypoxic conditions.	('CP-C', 'Gene', '529879', (124, 128))	('replacement', 'Var', (164, 175))	('COX4-2', 'Gene', (207, 213))	('CP-C', 'Gene', (124, 128))	('hypoxic conditions', 'Disease', 'MESH:D009135', (277, 295))	('COX4-2', 'Gene', '84701', (207, 213))	('HIF-1a', 'Gene', '3091', (148, 154))	('HIF-1a', 'Gene', (148, 154))	('COX4-1', 'Gene', '1327', (183, 189))	('COX4-1', 'Gene', (183, 189))	('hypoxic conditions', 'Disease', (277, 295))
185977	22824243	r-1,t-2,3,c-4-Tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) is a metabolite of phenanthrene, structurally related to carcinogenic PAH.	('PheT', 'Chemical', '-', (59, 63))	('r-1', 'Var', (0, 3))	('phenanthrene', 'Chemical', 'MESH:C031181', (84, 96))	('carcinogenic', 'Disease', 'MESH:D063646', (122, 134))	('carcinogenic', 'Disease', (122, 134))	('PAH', 'Chemical', 'MESH:D011084', (135, 138))	('phenanthrene', 'Chemical', 'MESH:C031181', (45, 57))	('r-1,t-2,3,c-4-Tetrahydroxy-1,2,3,4-tetrahydrophenanthrene', 'Chemical', 'MESH:C502234', (0, 57))
186007	22824243	A higher percentage of NNN-N-glucuronide was also significantly associated with a lower risk of esophageal cancer, after adjustment for the same factors listed above.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('NNN-N-glucuronide', 'Var', (23, 40))	('NNN-N-glucuronide', 'Chemical', '-', (23, 40))	('men', 'Species', '9606', (127, 130))	('lower', 'NegReg', (82, 87))
186028	22824243	These results demonstrate coherence between epidemiologic data in smokers and rat carcinogenicity studies, in which NNN but not NNK, is a potent esophageal carcinogen.	('carcinogenic', 'Disease', 'MESH:D063646', (82, 94))	('carcinogenic', 'Disease', (82, 94))	('rat', 'Species', '10116', (78, 81))	('rat', 'Species', '10116', (21, 24))	('esophageal', 'Disease', (145, 155))	('NNK', 'Chemical', 'MESH:C016583', (128, 131))	('NNN', 'Chemical', 'MESH:C008655', (116, 119))	('NNN', 'Var', (116, 119))
186149	22249096	Removable stents offer the endoscopist and the patient flexibility in handling these stents if they are not tolerated by the patient, misplaced at the time of insertion or if migration occurs, or if tissue in-growth/complications occur.	('patient', 'Species', '9606', (47, 54))	('tissue in-growth/complications', 'CPA', (199, 229))	('rat', 'Species', '10116', (112, 115))	('rat', 'Species', '10116', (178, 181))	('patient', 'Species', '9606', (125, 132))	('misplaced', 'Var', (134, 143))
186155	21468258	The logistic regression analysis for treatment response with various parameters showed that only a high expression of VEGF was significantly associated with a complete response.	('VEGF', 'Gene', '7422', (118, 122))	('associated', 'Reg', (141, 151))	('VEGF', 'Gene', (118, 122))	('high', 'Var', (99, 103))
186166	21468258	The expressions of EGFR has been reported to be associated with better treatment response after CCRT but poor treatment outcomes after primary surgery.	('EGFR', 'Gene', '1956', (19, 23))	('expressions', 'Var', (4, 15))	('CCRT', 'Disease', (96, 100))	('EGFR', 'Gene', (19, 23))
186168	21468258	It has been known that VEGF expression in esophageal carcinoma was associated with more advanced stage or poor prognosis.	('esophageal carcinoma', 'Disease', (42, 62))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (42, 62))	('VEGF', 'Gene', (23, 27))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (42, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('associated', 'Reg', (67, 77))	('expression', 'Var', (28, 38))	('VEGF', 'Gene', '7422', (23, 27))
186216	21468258	However the patients with high COX-2 expression survived significantly shorter than those of low expression (17.6% vs 34.5%, P = 0.03, Fig.	('patients', 'Species', '9606', (12, 20))	('high', 'Var', (26, 30))	('expression', 'MPA', (37, 47))	('shorter', 'NegReg', (71, 78))	('COX-2', 'Protein', (31, 36))
186223	21468258	In a recent study reported by Shimada et al., high pretreatment VEGF expression was associated with a poor response to CCRT and poor survival in patients with ESSC.	('poor', 'NegReg', (128, 132))	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (145, 153))	('expression', 'MPA', (69, 79))	('VEGF', 'Gene', (64, 68))	('ESSC', 'Disease', (159, 163))	('VEGF', 'Gene', '7422', (64, 68))
186226	21468258	The results of this study showed that high VEGF expression was significantly correlated with a complete response to CCRT in ESCC.	('expression', 'MPA', (48, 58))	('correlated', 'Reg', (77, 87))	('high', 'Var', (38, 42))	('VEGF', 'Gene', (43, 47))	('ESCC', 'Disease', (124, 128))	('VEGF', 'Gene', '7422', (43, 47))
186228	21468258	The biological mechanism by which a high VEGF expression could result in improved response to CCRT remains unknown.	('expression', 'MPA', (46, 56))	('VEGF', 'Gene', '7422', (41, 45))	('improved', 'PosReg', (73, 81))	('response to', 'MPA', (82, 93))	('VEGF', 'Gene', (41, 45))	('high', 'Var', (36, 40))
186233	21468258	Oxygenation and drug delivery might be more effective in tumors with high VEGF expression if VEGF was responsible for the hypervascularization of tumors.	('tumors', 'Disease', (146, 152))	('VEGF', 'Gene', '7422', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('VEGF', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('VEGF', 'Gene', (74, 78))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('VEGF', 'Gene', '7422', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('high', 'Var', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
186243	21468258	Although MVD was not evaluated in this study, the high VEGF expression might be correlated with high MVD of the tumor, which could enhance the supply of oxygen and radiosensitizing agents to cancer cells.	('expression', 'MPA', (60, 70))	('VEGF', 'Gene', (55, 59))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('supply of oxygen and', 'MPA', (143, 163))	('VEGF', 'Gene', '7422', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('enhance', 'PosReg', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', (112, 117))	('oxygen', 'Chemical', 'MESH:D010100', (153, 159))	('high', 'Var', (50, 54))
186244	21468258	Based on this postulation, we suggest that high VEGF expression could be associated with more improved response to CCRT.	('response', 'MPA', (103, 111))	('VEGF', 'Gene', (48, 52))	('high', 'Var', (43, 47))	('VEGF', 'Gene', '7422', (48, 52))	('improved', 'PosReg', (94, 102))	('expression', 'MPA', (53, 63))
186251	21468258	Some investigators have found that a high VEGF level was significantly associated with advanced stage disease and a high frequency of distant metastases, as well as a poorer survival.	('high', 'Var', (37, 41))	('metastases', 'Disease', (142, 152))	('advanced stage disease', 'CPA', (87, 109))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('VEGF', 'Gene', '7422', (42, 46))	('VEGF', 'Gene', (42, 46))	('associated', 'Reg', (71, 81))
186252	21468258	The results of this study showed that the OSR and CSSR of patients with higher VEGF expression were not significantly different from patients with lower VEGF expression.	('expression', 'Var', (84, 94))	('VEGF', 'Gene', (153, 157))	('VEGF', 'Gene', '7422', (79, 83))	('patients', 'Species', '9606', (133, 141))	('CSS', 'Chemical', '-', (50, 53))	('VEGF', 'Gene', '7422', (153, 157))	('patients', 'Species', '9606', (58, 66))	('VEGF', 'Gene', (79, 83))
186260	21468258	Thus, the patients with high VEGF expression in this study might have actually had earlier stage of lymph node metastases or clinically undetectable nodal disease.	('metastases', 'Disease', (111, 121))	('nodal disease', 'Disease', 'MESH:D013611', (149, 162))	('VEGF', 'Gene', (29, 33))	('nodal disease', 'Disease', (149, 162))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))	('VEGF', 'Gene', '7422', (29, 33))
186336	32510874	Massive tumors with histological characteristics of squamous cell carcinoma of the esophagus on 4-NQO treated mice were observed but no obvious lesion on the esophagus of control mice was found (Supplementary Figure S1).	('4-NQO', 'Var', (96, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('squamous cell carcinoma', 'Disease', (52, 75))	('mice', 'Species', '10090', (179, 183))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 75))	('4-NQO', 'Chemical', 'MESH:D015112', (96, 101))	('mice', 'Species', '10090', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (66, 92))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))
186380	31889894	Additionally, we confirmed that sulforaphene induces tumor cell apoptosis in mice.	('mice', 'Species', '10090', (77, 81))	('sulforaphene', 'Var', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('sulforaphene', 'Chemical', 'MESH:C473643', (32, 44))
186381	31889894	Interestingly, we also observed the obvious inhibition of cell migration and invasion caused by sulforaphene treatment by inhibiting the expression of cadherin, indicating the complex effects of sulforaphene on the development of esophageal cancer.	('inhibiting', 'NegReg', (122, 132))	('cell migration', 'CPA', (58, 72))	('cadherin', 'Protein', (151, 159))	('expression', 'MPA', (137, 147))	('esophageal cancer', 'Disease', 'MESH:D004938', (230, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('invasion', 'CPA', (77, 85))	('sulforaphene', 'Chemical', 'MESH:C473643', (195, 207))	('sulforaphene', 'Chemical', 'MESH:C473643', (96, 108))	('inhibition', 'NegReg', (44, 54))	('sulforaphene', 'Var', (96, 108))	('esophageal cancer', 'Disease', (230, 247))
186393	31889894	In adipocytes, sulforaphene could suppress adipogenesis through the hedgehog signaling pathway.	('sulforaphene', 'Chemical', 'MESH:C473643', (15, 27))	('hedgehog signaling pathway', 'Pathway', (68, 94))	('sulforaphene', 'Var', (15, 27))	('suppress', 'NegReg', (34, 42))	('adipogenesis', 'MPA', (43, 55))
186395	31889894	Additionally, sulforaphene could eliminate a variety of free radicals, such as hydrogen peroxide and nitrite, and inhibit several bacteria and viruses.	('free radicals', 'MPA', (56, 69))	('inhibit', 'NegReg', (114, 121))	('eliminate', 'NegReg', (33, 42))	('nitrite', 'Chemical', 'MESH:D009573', (101, 108))	('hydrogen peroxide', 'MPA', (79, 96))	('nitrite', 'MPA', (101, 108))	('sulforaphene', 'Chemical', 'MESH:C473643', (14, 26))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (79, 96))	('sulforaphene', 'Var', (14, 26))
186401	31889894	In this study, we revealed that sulforaphene has the potential to induce the apoptosis and inhibit invision of esophageal cancer cells in vitro and in vivo.	('sulforaphene', 'Var', (32, 44))	('inhibit', 'NegReg', (91, 98))	('apoptosis', 'CPA', (77, 86))	('esophageal cancer', 'Disease', (111, 128))	('induce', 'PosReg', (66, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('sulforaphene', 'Chemical', 'MESH:C473643', (32, 44))
186407	31889894	The following antibodies were used: tubulin (1:1000 dilution, #ab8227, Abcam), MSK2 (1:2000 dilution, #ab99411, Abcam), pCREBs133 (1:1000 dilution, #9198S, CST), and Bcl2 (1:1000 dilution, #15071, CST), Cadherin (1:500 dilution, #ab51034, Abcam).	('CST', 'Gene', '106478911', (156, 159))	('MSK2', 'Gene', (79, 83))	('CST', 'Gene', '106478911', (197, 200))	('#ab51034', 'Var', (229, 237))	('CREB', 'Gene', (121, 125))	('Bcl2', 'Gene', (166, 170))	('CST', 'Gene', (156, 159))	('MSK2', 'Gene', '8986', (79, 83))	('CST', 'Gene', (197, 200))	('CREB', 'Gene', '1385', (121, 125))	('Bcl2', 'Gene', '596', (166, 170))
186444	31889894	Similarly, a significant increase in cells with an apoptotic phenotype was detected through the observation of Eca109 cells treated with sulforaphene by transmission electron microscopy (TEM), as shown in Fig.	('sulforaphene', 'Var', (137, 149))	('sulforaphene', 'Chemical', 'MESH:C473643', (137, 149))	('increase', 'PosReg', (25, 33))
186448	31889894	Interestingly, the results showed a significant increase in cells in the G1 phase in the presence of sulforaphene, indicating the arrest of the cell cycle (Fig.	('sulforaphene', 'Var', (101, 113))	('cells in the G1 phase', 'CPA', (60, 81))	('arrest', 'Disease', 'MESH:D006323', (130, 136))	('sulforaphene', 'Chemical', 'MESH:C473643', (101, 113))	('arrest', 'Disease', (130, 136))	('increase', 'PosReg', (48, 56))
186451	31889894	Furthermore, in the Transwell assays, Eca109 cells exhibited significantly decreased migration through the membranes that was caused by sulforaphene treatment (5, 10, or 25 muM), and the cell numbers were obviously decreased (Fig.	('migration through the membranes', 'CPA', (85, 116))	('cell numbers', 'CPA', (187, 199))	('sulforaphene', 'Chemical', 'MESH:C473643', (136, 148))	('sulforaphene', 'Var', (136, 148))	('decreased', 'NegReg', (215, 224))	('decreased', 'NegReg', (75, 84))
186452	31889894	Notably, we detected the invasion capacity of Eca109 cells upon sulforaphene treatment (5, 10, 25 muM) through Matrigel-based transwell assays and found an obvious decrease in the numbers of invading cells (Fig.	('sulforaphene', 'Var', (64, 76))	('decrease', 'NegReg', (164, 172))	('invasion capacity', 'CPA', (25, 42))	('sulforaphene', 'Chemical', 'MESH:C473643', (64, 76))
186458	31889894	Several cancer-related biological processes were found to be significantly affected by sulforaphene treatment, such as the cell cycle, cell apoptosis and cell migration (Fig.	('cell cycle', 'CPA', (123, 133))	('cell apoptosis', 'CPA', (135, 149))	('cancer', 'Disease', (8, 14))	('sulforaphene', 'Var', (87, 99))	('affected', 'Reg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('sulforaphene', 'Chemical', 'MESH:C473643', (87, 99))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cell migration', 'CPA', (154, 168))
186459	31889894	To further explore the molecular mechanism underlying the induction of apoptosis by sulforaphene, the western blot analysis was used and the results revealed that sulforaphene (10 muM) significantly decreased MSK2, pCREB and Bcl-2 protein expression on 6 h, 12 h, 24 h compared with control on 0 h (P < 0.05; Fig.	('sulforaphene', 'Chemical', 'MESH:C473643', (84, 96))	('expression', 'MPA', (239, 249))	('CREB', 'Gene', (216, 220))	('sulforaphene', 'Var', (163, 175))	('decreased', 'NegReg', (199, 208))	('Bcl-2', 'Gene', (225, 230))	('Bcl-2', 'Gene', '596', (225, 230))	('CREB', 'Gene', '1385', (216, 220))	('MSK2', 'Gene', '8986', (209, 213))	('sulforaphene', 'Chemical', 'MESH:C473643', (163, 175))	('MSK2', 'Gene', (209, 213))
186466	31889894	In this study, we demonstrated that sulforaphene induces apoptosis in esophageal cancer cells.	('sulforaphene', 'Chemical', 'MESH:C473643', (36, 48))	('apoptosis', 'CPA', (57, 66))	('esophageal cancer', 'Disease', (70, 87))	('sulforaphene', 'Var', (36, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
186468	31889894	This study is an initial step in the exploration of the role of sulforaphene in esophageal cancer cell apoptosis via the MAPK signaling pathway and reveals that sulforaphene may be a promising therapeutic agent for the treatment of esophageal cancer.	('sulforaphene', 'Chemical', 'MESH:C473643', (64, 76))	('esophageal cancer', 'Disease', (80, 97))	('sulforaphene', 'Chemical', 'MESH:C473643', (161, 173))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('sulforaphene', 'Var', (161, 173))	('esophageal cancer', 'Disease', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('esophageal cancer', 'Disease', 'MESH:D004938', (232, 249))
186470	31889894	It was reported that sulforaphene could decreases human gastric cancer cell viability and induces apoptosis via EGFR, p-ERK1/2 down-regulation pathway.	('EGFR', 'Gene', (112, 116))	('ERK1/2', 'Gene', '5595;5594', (120, 126))	('apoptosis', 'CPA', (98, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('sulforaphene', 'Chemical', 'MESH:C473643', (21, 33))	('sulforaphene', 'Var', (21, 33))	('EGFR', 'Gene', '1956', (112, 116))	('induces', 'Reg', (90, 97))	('down-regulation', 'NegReg', (127, 142))	('human', 'Species', '9606', (50, 55))	('gastric cancer', 'Disease', (56, 70))	('decreases', 'NegReg', (40, 49))	('ERK1/2', 'Gene', (120, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
186471	31889894	Besides, sulforaphene treatment was also demonstrated to induce G2/M phase cell cycle arrest and apoptosis of colon cancer cells, concomitant with phosphorylation of CDK1 and CDC25B at inhibitory sites.	('CDK1', 'Gene', (166, 170))	('colon cancer', 'Disease', (110, 122))	('sulforaphene', 'Chemical', 'MESH:C473643', (9, 21))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('CDC25B', 'Gene', (175, 181))	('phosphorylation', 'MPA', (147, 162))	('sulforaphene', 'Var', (9, 21))	('arrest', 'Disease', (86, 92))	('CDK1', 'Gene', '983', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('colon cancer', 'Disease', 'MESH:D015179', (110, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('induce', 'PosReg', (57, 63))	('CDC25B', 'Gene', '994', (175, 181))	('apoptosis', 'CPA', (97, 106))
186472	31889894	In our study, we also verified that sulforaphene could induce apoptosis in esophageal cancer cells.	('sulforaphene', 'Chemical', 'MESH:C473643', (36, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('sulforaphene', 'Var', (36, 48))	('apoptosis', 'CPA', (62, 71))	('induce', 'PosReg', (55, 61))	('esophageal cancer', 'Disease', (75, 92))
186477	31889894	Our results showed MSK2 and CREB activity were inhibited by sulforaphene in esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('inhibited', 'NegReg', (47, 56))	('sulforaphene', 'Chemical', 'MESH:C473643', (60, 72))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (76, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('MSK2', 'Gene', '8986', (19, 23))	('sulforaphene', 'Var', (60, 72))	('CREB', 'Gene', '1385', (28, 32))	('MSK2', 'Gene', (19, 23))	('CREB', 'Gene', (28, 32))	('activity', 'MPA', (33, 41))	('esophageal squamous cell carcinoma', 'Disease', (76, 110))
186480	31889894	Besides the MAPK signaling pathway, other pathways and mechanisms mediate the occurrence and development of multiple types of tumors induced by sulforaphene.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('sulforaphene', 'Chemical', 'MESH:C473643', (144, 156))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('sulforaphene', 'Var', (144, 156))
186481	31889894	An increasing number of studies have demonstrated that sulforaphene promotes tumorigenesis and metastasis through the regulation of cell proliferation, migration, invasion, and apoptosis.	('apoptosis', 'CPA', (177, 186))	('sulforaphene', 'Var', (55, 67))	('migration', 'CPA', (152, 161))	('promotes', 'PosReg', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('sulforaphene', 'Chemical', 'MESH:C473643', (55, 67))	('metastasis', 'CPA', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cell proliferation', 'CPA', (132, 150))	('tumor', 'Disease', (77, 82))	('invasion', 'CPA', (163, 171))
186484	31889894	Interestingly, sulforaphene induces mitophagic cell death via p62/SQSTM1 accumulation and AMPK inhibition.	('p62', 'Gene', '8878', (62, 65))	('sulforaphene', 'Chemical', 'MESH:C473643', (15, 27))	('SQSTM1', 'Gene', '8878', (66, 72))	('mitophagic cell death', 'CPA', (36, 57))	('p62', 'Gene', (62, 65))	('sulforaphene', 'Var', (15, 27))	('accumulation', 'PosReg', (73, 85))	('AMPK', 'Gene', '5563', (90, 94))	('SQSTM1', 'Gene', (66, 72))	('AMPK', 'Gene', (90, 94))
186485	31889894	Here, we found that sulforaphene could dramatically induce apoptosis and cell cycle arrest in esophageal cancer cells and effectively inhibit tumor growth in mice.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mice', 'Species', '10090', (158, 162))	('tumor', 'Disease', (142, 147))	('inhibit', 'NegReg', (134, 141))	('esophageal cancer', 'Disease', (94, 111))	('arrest', 'Disease', 'MESH:D006323', (84, 90))	('induce', 'PosReg', (52, 58))	('sulforaphene', 'Chemical', 'MESH:C473643', (20, 32))	('apoptosis', 'CPA', (59, 68))	('arrest', 'Disease', (84, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('sulforaphene', 'Var', (20, 32))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
186487	31889894	Additionally, a previous study indicated that sulforaphene caused cytotoxicity and promoted the apoptosis of human hepatocarcinoma HepG2 cells via increases in caspase 3 and 9 activity.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('human', 'Species', '9606', (109, 114))	('increases', 'PosReg', (147, 156))	('hepatocarcinoma', 'Disease', 'None', (115, 130))	('HepG2', 'CellLine', 'CVCL:0027', (131, 136))	('sulforaphene', 'Var', (46, 58))	('caspase 3 and 9', 'Gene', '836;842', (160, 175))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('hepatocarcinoma', 'Disease', (115, 130))	('activity', 'MPA', (176, 184))	('apoptosis', 'CPA', (96, 105))	('promoted', 'PosReg', (83, 91))	('cytotoxicity', 'Disease', (66, 78))	('sulforaphene', 'Chemical', 'MESH:C473643', (46, 58))
186496	31889894	Our findings, together with those of other studies, indicated that sulforaphene could repress MSK2, and CREB, Bcl-2, down-regulate the C-cadherin expression and thereby induced apoptosis and inhibited invasion in esophageal cancer cells.	('Bcl-2', 'Gene', (110, 115))	('MSK2', 'Gene', (94, 98))	('down-regulate', 'NegReg', (117, 130))	('CREB', 'Gene', '1385', (104, 108))	('expression', 'MPA', (146, 156))	('invasion', 'CPA', (201, 209))	('C-cadherin', 'Protein', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('Bcl-2', 'Gene', '596', (110, 115))	('sulforaphene', 'Var', (67, 79))	('MSK2', 'Gene', '8986', (94, 98))	('apoptosis', 'CPA', (177, 186))	('inhibited', 'NegReg', (191, 200))	('repress', 'NegReg', (86, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (213, 230))	('sulforaphene', 'Chemical', 'MESH:C473643', (67, 79))	('CREB', 'Gene', (104, 108))	('induced', 'Reg', (169, 176))	('esophageal cancer', 'Disease', (213, 230))
186498	31889894	To be concluded, sulforaphene could have the potential to serve as an anti-tumor drug through the promotion of tumor cell apoptosis and the inhibition of cell invasion.	('cell invasion', 'CPA', (154, 167))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('sulforaphene', 'Chemical', 'MESH:C473643', (17, 29))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (111, 116))	('promotion', 'PosReg', (98, 107))	('inhibition', 'NegReg', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('sulforaphene', 'Var', (17, 29))	('tumor', 'Disease', (75, 80))
186504	31615079	Mongolians have high incidence and/or prevalence of several diseases linked to low 25(OH)D concentrations, including ischemic heart disease, malignant neoplasms, cirrhosis of the liver, ischemic stroke, lower respiratory tract infections, preterm birth complications, and diabetes mellitus.	('respiratory tract infections', 'Disease', 'MESH:D012141', (209, 237))	('lower respiratory tract infection', 'Phenotype', 'HP:0002783', (203, 236))	('Mongol', 'Chemical', 'None', (0, 6))	('cirrhosis of the liver', 'Disease', 'MESH:D008103', (162, 184))	('ischemic stroke', 'Disease', (186, 201))	('diabetes mellitus', 'Disease', 'MESH:D003920', (272, 289))	('preterm birth complications', 'Disease', (239, 266))	('ischemic heart disease', 'Disease', (117, 139))	('respiratory tract infections', 'Phenotype', 'HP:0011947', (209, 237))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (272, 289))	('lower respiratory tract infections', 'Phenotype', 'HP:0002783', (203, 237))	('ischemic stroke', 'Phenotype', 'HP:0002140', (186, 201))	('respiratory tract infection', 'Phenotype', 'HP:0011947', (209, 236))	('25(OH)D', 'Chemical', 'MESH:C101470', (83, 90))	('ischemic heart disease', 'Disease', 'MESH:D017202', (117, 139))	('malignant neoplasms', 'Disease', (141, 160))	('respiratory tract infections', 'Disease', (209, 237))	('malignant neoplasms', 'Disease', 'MESH:D009369', (141, 160))	('low', 'Var', (79, 82))	('cirrhosis', 'Phenotype', 'HP:0001394', (162, 171))	('stroke', 'Phenotype', 'HP:0001297', (195, 201))	('preterm birth complications', 'Disease', 'MESH:D047928', (239, 266))	('preterm birth', 'Phenotype', 'HP:0001622', (239, 252))	('cirrhosis of the liver', 'Disease', (162, 184))	('neoplasms', 'Phenotype', 'HP:0002664', (151, 160))	('ischemic stroke', 'Disease', 'MESH:D002544', (186, 201))	('diabetes mellitus', 'Disease', (272, 289))
186536	31615079	On the basis of the three studies that accounted for 55% of the size (weight) of the effects of vitamin D status on IHD risk in that meta-analysis, low 25(OH)D was defined as <~16 ng/mL and high as >~30 ng/mL, and similar results were found for early death.	('vitamin D', 'Chemical', 'MESH:D014807', (96, 105))	('death', 'Disease', 'MESH:D003643', (251, 256))	('death', 'Disease', (251, 256))	('25(OH)D', 'Chemical', 'MESH:C101470', (152, 159))	('IHD', 'Disease', 'None', (116, 119))	('IHD', 'Disease', (116, 119))	('<~16 ng/mL', 'Var', (175, 185))
186541	31615079	In a meta-analysis of 16 prospective observational studies, researchers found that low vs. high 25(OH)D concentration was associated with a 32% increased risk of ischemic stroke (relative risk (RR) = 1.32; 95% confidence interval (CI), 1.19 to 1.48).	('low', 'Var', (83, 86))	('ischemic stroke', 'Disease', (162, 177))	('25(OH)D', 'Chemical', 'MESH:C101470', (96, 103))	('ischemic stroke', 'Disease', 'MESH:D002544', (162, 177))	('ischemic stroke', 'Phenotype', 'HP:0002140', (162, 177))	('stroke', 'Phenotype', 'HP:0001297', (171, 177))
186561	31615079	Although the risk of progression to T2DM for vitamin-D-supplemented subjects compared with that of subjects on placebo was not significantly reduced overall (hazard ratio (HR) = 0.88 (95% CI, 0.75 to 1.04; p = 0.12)), it was reduced (as reported in Table 2), significant, or suggestive for several prespecified subgroups.	('DM', 'Phenotype', 'HP:0000819', (38, 40))	('T2DM', 'Disease', (36, 40))	('vitamin-D', 'Chemical', 'MESH:D014807', (45, 54))	('reduced', 'NegReg', (225, 232))	('men', 'Species', '9606', (61, 64))	('vitamin-D-supplemented', 'Var', (45, 67))
186566	31615079	However, screening for hypertension is not widely available, and thus any reductions in hypertension from the long-term prevention of vitamin D deficiency (which suppresses renin production) as has so far only been reported in young men, perhaps because progression of atheromatous disease becomes increasingly irreversible, would be useful.	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (134, 154))	('hypertension', 'Disease', (23, 35))	('suppresses renin production', 'Phenotype', 'HP:0003351', (162, 189))	('hypertension', 'Disease', (88, 100))	('deficiency', 'Var', (144, 154))	('hypertension', 'Phenotype', 'HP:0000822', (23, 35))	('reductions', 'NegReg', (74, 84))	('atheromatous disease', 'Disease', (269, 289))	('atheromatous disease', 'Disease', 'MESH:D058226', (269, 289))	('atheromatous disease', 'Phenotype', 'HP:0002635', (269, 289))	('hypertension', 'Phenotype', 'HP:0000822', (88, 100))	('vitamin D', 'Chemical', 'MESH:D014807', (134, 143))	('suppresses', 'NegReg', (162, 172))	('hypertension', 'Disease', 'MESH:D006973', (23, 35))	('hypertension', 'Disease', 'MESH:D006973', (88, 100))	('men', 'Species', '9606', (233, 236))
186572	31615079	The combination of hypertension and CKD greatly increases the risk of adverse cardiovascular and cerebrovascular outcomes.	('hypertension', 'Disease', (19, 31))	('increases', 'PosReg', (48, 57))	('CKD', 'Var', (36, 39))	('hypertension', 'Phenotype', 'HP:0000822', (19, 31))	('cerebrovascular outcomes', 'CPA', (97, 121))	('hypertension', 'Disease', 'MESH:D006973', (19, 31))	('CKD', 'Phenotype', 'HP:0012622', (36, 39))
186584	31615079	A meta-analysis of data from 21 studies covering 4818 patients and 7175 control subjects reported lower serum 25(OH)D concentrations in COPD patients than in controls (standardized mean difference (SMD), -0.69 (95% CI, -1.00 to -0.38; p < 0.001)), which was most marked in severe COPD (SMD, -0.87 (95% CI, -1.51 to -0.22; p = 0.001)) and in COPD exacerbations (SMD, -0.43 (95% CI, -0.70 to -0.15; p = 0.002)), that is, vitamin D deficiency was associated with increased risk of COPD (OR = 1.77 (95% CI, 1.18 to 2.64; p = 0.006)), with COPD severity (OR = 2.83 (95% CI, 2.00 to 4.00; p < 0.001)) but not with COPD exacerbations (OR = 1.17 (95% CI, 0.86 to 1.59; p = 0.33)), though the heterogeneity of the 25(OH)D assays used affected the associations between vitamin D deficiency and COPD risk.	('COPD', 'Gene', (136, 140))	('COPD', 'Gene', '260431', (341, 345))	('SMD', 'Disease', 'MESH:C537501', (198, 201))	('patients', 'Species', '9606', (54, 62))	('25(OH)D', 'Chemical', 'MESH:C101470', (705, 712))	('COPD', 'Gene', (341, 345))	('25(OH)D', 'Chemical', 'MESH:C101470', (110, 117))	('patients', 'Species', '9606', (141, 149))	('SMD', 'Disease', (286, 289))	('lower', 'NegReg', (98, 103))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (419, 439))	('COPD', 'Gene', '260431', (784, 788))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (759, 779))	('SMD', 'Disease', (198, 201))	('associations', 'Interaction', (738, 750))	('COPD', 'Phenotype', 'HP:0006510', (280, 284))	('COPD', 'Gene', (784, 788))	('SMD', 'Disease', 'MESH:C537501', (361, 364))	('COPD', 'Gene', '260431', (608, 612))	('COPD', 'Phenotype', 'HP:0006510', (535, 539))	('COPD', 'Gene', '260431', (280, 284))	('COPD', 'Phenotype', 'HP:0006510', (478, 482))	('COPD', 'Gene', (608, 612))	('COPD', 'Gene', '260431', (535, 539))	('affected', 'Reg', (725, 733))	('COPD', 'Gene', (280, 284))	('COPD', 'Phenotype', 'HP:0006510', (136, 140))	('vitamin D', 'Chemical', 'MESH:D014807', (419, 428))	('vitamin D', 'Chemical', 'MESH:D014807', (759, 768))	('SMD', 'Disease', (361, 364))	('COPD', 'Gene', (535, 539))	('COPD', 'Gene', '260431', (478, 482))	('deficiency', 'Var', (429, 439))	('COPD', 'Gene', (478, 482))	('COPD', 'Phenotype', 'HP:0006510', (341, 345))	('COPD', 'Gene', '260431', (136, 140))	('SMD', 'Disease', 'MESH:C537501', (286, 289))
186607	31615079	For each 10 ng/mL increment in circulating 25(OH)D, colorectal cancer risk was 19% lower in women (RR = 0.81 [95% CI, 0.75 to 0.87]) and 7% lower in men (RR = 0.93 [95% CI, 0.86 to 1.00]).	('lower', 'NegReg', (140, 145))	('25(OH)D', 'Chemical', 'MESH:C101470', (43, 50))	('men', 'Species', '9606', (149, 152))	('women', 'Species', '9606', (92, 97))	('men', 'Species', '9606', (94, 97))	('circulating 25(OH)D', 'Var', (31, 50))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('lower', 'NegReg', (83, 88))	('men', 'Species', '9606', (23, 26))	('colorectal cancer', 'Disease', (52, 69))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
186608	31615079	A recent meta-analysis of 10 RCTs involving 45,197 participants reported that vitamin D3 supplementation with variable doses and trial durations led to a 15% reduction in cancer mortality rates (risk ratio = 0.85 [95% CI, 0.75 to 0.96]).	('vitamin D3', 'Chemical', 'MESH:D002762', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('supplementation', 'Var', (89, 104))	('cancer', 'Disease', (171, 177))	('participants', 'Species', '9606', (51, 63))	('reduction', 'NegReg', (158, 167))	('men', 'Species', '9606', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('vitamin D3', 'Gene', (78, 88))
186612	31615079	A further review in 2017 reported accumulating evidence from gastric cancer cells, animal models, and clinical trials to suggest that vitamin D deficiency may increase the risk and mortality of gastric cancer, implying that vitamin D supplementation might be a safe and economical way to reduce gastric cancer risks both prospectively and during treatment.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('gastric cancer', 'Disease', 'MESH:D013274', (295, 309))	('gastric cancer', 'Phenotype', 'HP:0012126', (194, 208))	('vitamin D', 'Chemical', 'MESH:D014807', (224, 233))	('men', 'Species', '9606', (240, 243))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (134, 154))	('gastric cancer', 'Disease', (61, 75))	('men', 'Species', '9606', (351, 354))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('gastric cancer', 'Phenotype', 'HP:0012126', (295, 309))	('gastric cancer', 'Disease', (194, 208))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('vitamin D', 'Chemical', 'MESH:D014807', (134, 143))	('increase', 'PosReg', (159, 167))	('vitamin D', 'Gene', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('deficiency', 'Var', (144, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (194, 208))	('gastric cancer', 'Disease', (295, 309))	('reduce gastric cancer', 'Phenotype', 'HP:0006753', (288, 309))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))
186620	31615079	In the first paper, women achieving a serum 25(OH)D concentration >40 ng/mL had a 65% lower all-cancer incidence rate than that of women achieving values <20 ng/mL after a median follow-up of 3.9 years.	('women', 'Species', '9606', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lower', 'NegReg', (86, 91))	('women', 'Species', '9606', (20, 25))	('>40 ng/mL', 'Var', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('25(OH)D', 'Chemical', 'MESH:C101470', (44, 51))	('cancer', 'Disease', (96, 102))
186623	31615079	Although all-cancer incidence was not significantly reduced for the 12,500 people treated with 2000 IU/day of vitamin D3, the reduction was significant for those with a BMI < 25 (HR = 0.76 [95% CI, 0.63 to 0.90]) and for black subjects (HR = 0.77 [95% CI, 0.59 to 1.01]).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('MI', 'Phenotype', 'HP:0001658', (170, 172))	('BMI < 25', 'Var', (169, 177))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('people', 'Species', '9606', (75, 81))	('vitamin D3', 'Chemical', 'MESH:D002762', (110, 120))
186627	31615079	Modest evidence also exists to indicate that vitamin D supplementation in combination with Peg-interferon alpha injection and oral ribavirin improves sustained virus clearance for HCV genotype 1 but not genotypes 2-4.	('HCV', 'Disease', (180, 183))	('genotype', 'Var', (184, 192))	('vitamin D', 'Chemical', 'MESH:D014807', (45, 54))	('ribavirin', 'Chemical', 'MESH:D012254', (131, 140))	('Peg', 'Gene', (91, 94))	('Peg', 'Gene', '5047', (91, 94))	('men', 'Species', '9606', (61, 64))	('sustained virus clearance', 'MPA', (150, 175))	('improves', 'PosReg', (141, 149))
186644	31615079	A recent review reported that observational studies have suggested vitamin D deficiency as a risk factor for AD, Parkinson's disease, vascular dementia, and multiple sclerosis (and other neurological disorders), through variations in vitamin D axis genes and in the actions of vitamin D, whereas ex-vivo studies show that vitamin D activity can both reduce intracerebral amyloid production and increase its clearance from brain tissue in AD.	('AD', 'Disease', 'MESH:D000544', (438, 440))	('dementia', 'Phenotype', 'HP:0000726', (143, 151))	('clearance from brain tissue', 'MPA', (407, 434))	('neurological disorders', 'Disease', (187, 209))	('vitamin D', 'Chemical', 'MESH:D014807', (67, 76))	('deficiency', 'Var', (77, 87))	('AD', 'Phenotype', 'HP:0002511', (109, 111))	('multiple sclerosis', 'Disease', (157, 175))	('AD', 'Disease', (109, 111))	('vascular dementia', 'Disease', 'MESH:D015140', (134, 151))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (67, 87))	('increase', 'PosReg', (394, 402))	('neurological disorders', 'Disease', 'MESH:D009422', (187, 209))	('vitamin', 'Gene', (234, 241))	("Parkinson's disease", 'Disease', (113, 132))	('AD', 'Disease', 'MESH:D000544', (109, 111))	('intracerebral amyloid production', 'MPA', (357, 389))	('vitamin D', 'Chemical', 'MESH:D014807', (277, 286))	('multiple sclerosis', 'Disease', 'MESH:D009103', (157, 175))	('AD', 'Disease', (438, 440))	('variations', 'Var', (220, 230))	('AD', 'Phenotype', 'HP:0002511', (438, 440))	('vascular dementia', 'Disease', (134, 151))	('reduce', 'NegReg', (350, 356))	('vitamin D', 'Chemical', 'MESH:D014807', (322, 331))	("Parkinson's disease", 'Disease', 'MESH:D010300', (113, 132))	('vitamin D', 'Chemical', 'MESH:D014807', (234, 243))
186647	31615079	The classic outcome of vitamin D deficiency during pregnancy and early life is the development of rickets.	('rickets', 'Disease', (98, 105))	('men', 'Species', '9606', (90, 93))	('vitamin D', 'Chemical', 'MESH:D014807', (23, 32))	('rickets', 'Phenotype', 'HP:0002748', (98, 105))	('deficiency', 'Var', (33, 43))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (23, 43))
186651	31615079	The authors also found significant correlations of spontaneous abortion rates with air pollution levels of SO2, NO2, CO, PM10, or PM2.5.	('abortion', 'Disease', 'MESH:D000031', (63, 71))	('NO2', 'Var', (112, 115))	('SO2', 'Chemical', 'MESH:C443440', (107, 110))	('abortion', 'Disease', (63, 71))	('SO2', 'Var', (107, 110))	('NO2', 'Chemical', 'MESH:C021591', (112, 115))	('CO', 'Chemical', 'MESH:D002245', (117, 119))	('PM10', 'Var', (121, 125))	('correlations', 'Interaction', (35, 47))	('PM2.5', 'Var', (130, 135))	('spontaneous abortion', 'Phenotype', 'HP:0005268', (51, 71))
186653	31615079	One of the direct effects of such pollution is increased inflammation, which vitamin D can reduce.	('pollution', 'Var', (34, 43))	('inflammation', 'Disease', 'MESH:D007249', (57, 69))	('increased', 'PosReg', (47, 56))	('vitamin D', 'Chemical', 'MESH:D014807', (77, 86))	('inflammation', 'Disease', (57, 69))
186661	31615079	A meta-analysis involving 21 studies reported that low vs. high maternal 25(OH)D concentration was associated with an OR of 1.62 (95% CI, 1.36 to 1.94) for preeclampsia, the OR for the Asian sub-population being 2.07 (95% CI, 1.51 to 2.85).	('25(OH)D', 'Chemical', 'MESH:C101470', (73, 80))	('preeclampsia', 'Disease', (156, 168))	('low', 'Var', (51, 54))	('preeclampsia', 'Phenotype', 'HP:0100602', (156, 168))
186685	31615079	A Mendelian randomization study reported that variations of SNPs that reduce serum 25(OH)D concentration accounted for a 20% increase in all-cause mortality rate per each 8 ng/mL decrease in serum 25(OH)D. A prospective study of Chinese adults aged >80 years (median age, 93 years) with mean baseline 25(OH)D of 14 ng/mL followed up for 5466 person-years reported that participants with the highest 25(OH)D concentrations had a 39% reduced mortality rate.	('mortality', 'MPA', (440, 449))	('participants', 'Species', '9606', (369, 381))	('25(OH)D', 'Chemical', 'MESH:C101470', (83, 90))	('25(OH)D', 'Chemical', 'MESH:C101470', (399, 406))	('25(OH)D', 'Var', (399, 406))	('person', 'Species', '9606', (342, 348))	('25(OH)D', 'Chemical', 'MESH:C101470', (301, 308))	('25(OH)D', 'Chemical', 'MESH:C101470', (197, 204))	('reduced', 'NegReg', (432, 439))
186718	31615079	However, a vitamin D dosing study conducted by Robert Heaney found that supplementation at 800 IU/day would raise serum 25(OH)D concentration by only 7 ng/mL in adults, and it would be difficult to fortify food in Mongolia to provide intakes of 800 IU/day and, given the low 25(OH)D concentrations seen in winter, this would not result in most people reaching 20 ng/mL.	('Robert Heaney', 'Disease', 'MESH:C535687', (47, 60))	('25(OH)D', 'Chemical', 'MESH:C101470', (120, 127))	('vitamin D', 'Chemical', 'MESH:D014807', (11, 20))	('raise', 'PosReg', (108, 113))	('people', 'Species', '9606', (344, 350))	('Mongol', 'Chemical', 'None', (214, 220))	('Robert Heaney', 'Disease', (47, 60))	('25(OH)D', 'Chemical', 'MESH:C101470', (275, 282))	('men', 'Species', '9606', (78, 81))	('supplementation', 'Var', (72, 87))
186732	29563758	Esophageal PEECS was defined as "mild" meeting one of the following criteria without any obvious perforation: fever (>= 37.8  C), leukocytosis (> 10800 cells/muL), or regional chest pain more than 5/10 points as rated on a numeric pain intensity scale.	('PEECS', 'Chemical', '-', (11, 16))	('pain', 'Disease', 'MESH:D010146', (182, 186))	('pain', 'Disease', (231, 235))	('fever', 'Disease', 'MESH:D005334', (110, 115))	('fever', 'Disease', (110, 115))	('muL', 'Gene', '4591', (158, 161))	('chest pain', 'Phenotype', 'HP:0100749', (176, 186))	('pain', 'Phenotype', 'HP:0012531', (231, 235))	('fever', 'Phenotype', 'HP:0001945', (110, 115))	('pain', 'Disease', (182, 186))	('leukocytosis', 'Disease', (130, 142))	('pain', 'Disease', 'MESH:D010146', (231, 235))	('> 10800', 'Var', (144, 151))	('pain', 'Phenotype', 'HP:0012531', (182, 186))	('leukocytosis', 'Disease', 'MESH:D007964', (130, 142))	('leukocytosis', 'Phenotype', 'HP:0001974', (130, 142))	('muL', 'Gene', (158, 161))	('chest pain', 'Disease', 'MESH:D002637', (176, 186))	('chest pain', 'Disease', (176, 186))	('Esophageal PEECS', 'Disease', (0, 16))
186878	29416674	As demonstrated in Figure 2D, silenced SNHG16 obviously increased the apoptosis rate of ESCC cells, in comparison to negative control cells.	('silenced', 'Var', (30, 38))	('increased', 'PosReg', (56, 65))	('SNHG16', 'Gene', (39, 45))	('SNHG16', 'Gene', '100507246', (39, 45))	('apoptosis rate', 'CPA', (70, 84))
186884	29416674	As obtained in Figure 3B, results from western blot assay revealed that silencing SNHG16 could significantly reduce the level of mesenchymal markers but increase the level of epithelial markers.	('SNHG16', 'Gene', '100507246', (82, 88))	('level of mesenchymal markers', 'MPA', (120, 148))	('silencing', 'Var', (72, 81))	('reduce', 'NegReg', (109, 115))	('SNHG16', 'Gene', (82, 88))	('increase', 'PosReg', (153, 161))	('level of epithelial markers', 'MPA', (166, 193))
186885	29416674	Likewise, immunofluorescence results showed that knockdown of SNHG16 could reverse the EMT phenotype to the MET (Figure 3C).	('knockdown', 'Var', (49, 58))	('SNHG16', 'Gene', '100507246', (62, 68))	('SNHG16', 'Gene', (62, 68))	('EMT', 'Gene', (87, 90))	('EMT', 'Gene', '3702', (87, 90))
186928	29416674	Tumors derived from sh-SNHG16 transfected kyse-70 cells grew more slowly than those derived from control shRNA transfected cells (Figure 8A-8C).	('SNHG16', 'Gene', (23, 29))	('SNHG16', 'Gene', '100507246', (23, 29))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('grew', 'CPA', (56, 60))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('slowly', 'NegReg', (66, 72))	('transfected', 'Var', (30, 41))
186929	29416674	qRT-PCR showed that the level of SNGH16 and ZEB1 in the tumor tissues derived from sh-SNHG16 transfected kyse-70 cells was significantly decreased, while the level of miR-140-5p was obviously increased (Figure 8D-8F).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('level', 'MPA', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('ZEB1', 'Gene', '6935', (44, 48))	('tumor', 'Disease', (56, 61))	('transfected', 'Var', (93, 104))	('SNHG16', 'Gene', '100507246', (86, 92))	('ZEB1', 'Gene', (44, 48))	('miR-140', 'Gene', '406932', (167, 174))	('SNHG16', 'Gene', (86, 92))	('5p', 'Chemical', '-', (175, 177))	('decreased', 'NegReg', (137, 146))	('miR-140', 'Gene', (167, 174))	('SNGH16', 'Gene', (33, 39))	('increased', 'PosReg', (192, 201))
186930	29416674	Immunostaining analysis revealed a lower positive rate of Ki67 in tumors derived from sh-SNHG16 transfected kyse-70 cells compared with the control groups (Figure 8G).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('positive', 'MPA', (41, 49))	('SNHG16', 'Gene', (89, 95))	('transfected', 'Var', (96, 107))	('SNHG16', 'Gene', '100507246', (89, 95))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('lower', 'NegReg', (35, 40))	('Ki67', 'Gene', (58, 62))
186947	29416674	demonstrated that double-negative feedback loop between long non-coding RNA TUG1 and miR-145 promotes epithelial to mesenchymal transition and radioresistance in human bladder cancer cells; and Ji et al.	('TUG1', 'Gene', '55000', (76, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (168, 182))	('radioresistance', 'CPA', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('TUG1', 'Gene', (76, 80))	('miR-145', 'Gene', (85, 92))	('epithelial to mesenchymal transition', 'CPA', (102, 138))	('miR-145', 'Gene', '406937', (85, 92))	('human', 'Species', '9606', (162, 167))	('long non-coding', 'Var', (56, 71))	('promotes', 'PosReg', (93, 101))	('bladder cancer', 'Disease', (168, 182))	('bladder cancer', 'Disease', 'MESH:D001749', (168, 182))
186950	29416674	Consistent with the effect of miR-140-5p mimic, silenced SNHG16 could suppress miR-140-5p target ZEB1.	('5p', 'Chemical', '-', (87, 89))	('ZEB1', 'Gene', (97, 101))	('ZEB1', 'Gene', '6935', (97, 101))	('suppress', 'NegReg', (70, 78))	('miR-140', 'Gene', '406932', (30, 37))	('silenced', 'Var', (48, 56))	('miR-140', 'Gene', (79, 86))	('SNHG16', 'Gene', '100507246', (57, 63))	('5p', 'Chemical', '-', (38, 40))	('SNHG16', 'Gene', (57, 63))	('miR-140', 'Gene', (30, 37))	('miR-140', 'Gene', '406932', (79, 86))
186961	29416674	The ESCC cell lines eca109, EC9706, TE1, Kyse-30 and Kyse-70 and the normal esophageal epithelial cell line HEEC were purchased from Fudan University Shanghai Cell Bank and were cultured at 37  C in a humidified incubator 5% CO2.	('CO2', 'Chemical', '-', (225, 228))	('Kyse-70', 'Var', (53, 60))	('EC9706', 'CellLine', 'CVCL:E307', (28, 34))	('HEEC', 'CellLine', 'None', (108, 112))	('EC9706', 'Var', (28, 34))
187078	23243219	Widespread DNA methylation changes were observed in Barrett's carcinogenesis including  70% of known imprinted genes.	('methylation', 'Var', (15, 26))	("Barrett's carcinogenesis", 'Disease', (52, 76))	('observed', 'Reg', (40, 48))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (52, 76))
187088	23243219	Aberrant DNA methylation is shown to be a characteristic of cancer and these changes are known to occur early during transformation.	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('DNA', 'Protein', (9, 12))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
187090	23243219	However high-throughput array based platforms are now available to identify DNA methylation changes and we have employed this approach to find candidate biomarkers in Barrett's carcinogenesis.	('changes', 'Var', (92, 99))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (167, 191))	("Barrett's carcinogenesis", 'Disease', (167, 191))	('methylation changes', 'Var', (80, 99))
187109	23243219	To compare the difference between groups (BE, BE with dysplasia and EAC) a t-test or one way ANOVA was used for continuous variables (age, segment length and methylation) and chi-square test for categorical variables (gender).	('dysplasia', 'Disease', (54, 63))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('methylation', 'Var', (158, 169))	('BE', 'Phenotype', 'HP:0100580', (46, 48))	('dysplasia', 'Disease', 'MESH:D004476', (54, 63))	('BE', 'Phenotype', 'HP:0100580', (42, 44))
187129	23243219	In the group with 2 genes methylated the proportion of dysplastic cases increased to 42.3% including 11.5% high grade dysplasia/EAC.	('methylated', 'Var', (26, 36))	('dysplastic', 'Disease', (55, 65))	('dysplasia', 'Disease', (118, 127))	('dysplastic', 'Disease', 'MESH:D004416', (55, 65))	('dysplasia', 'Disease', 'MESH:D004476', (118, 127))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))
187130	23243219	In the group with >2 genes methylated 14.5% of cases had LGD and 32.8% had HGD/EAC (combined cases of dysplasia and EAC: 47.3%).	('EAC', 'Phenotype', 'HP:0011459', (116, 119))	('methylated', 'Var', (27, 37))	('HGD/EAC', 'Disease', (75, 82))	('LGD', 'Disease', 'None', (57, 60))	('dysplasia', 'Disease', (102, 111))	('EAC', 'Phenotype', 'HP:0011459', (79, 82))	('LGD', 'Disease', (57, 60))	('dysplasia', 'Disease', 'MESH:D004476', (102, 111))
187148	23243219	Mutations, deletions and LOH of this gene have all been reported in different cancers highlighting its importance in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('reported', 'Reg', (56, 64))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('LOH', 'NegReg', (25, 28))	('Mutations', 'Var', (0, 9))	('deletions', 'Var', (11, 20))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
187152	23243219	Of the other three genes identified by our study; RIN2 encodes a guanine nucleotide exchange factor; PIGR encodes a poly-Ig receptor downregulation of which has been shown to be associated with more frequent lymph node metastasis in gastro-esophageal junctional tumors; and GJA12 encodes a gap junction protein mutations in which have recently been shown to increase the risk for secondary lymphedema after treatment for breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (421, 434))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('gastro-esophageal junctional tumors', 'Disease', (233, 268))	('PIGR', 'Gene', (101, 105))	('lymph node metastasis', 'CPA', (208, 229))	('gastro-esophageal junctional tumors', 'Disease', 'MESH:D005764', (233, 268))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('mutations', 'Var', (311, 320))	('frequent lymph node', 'Phenotype', 'HP:0032536', (199, 218))	('breast cancer', 'Disease', 'MESH:D001943', (421, 434))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (65, 83))	('lymphedema', 'Phenotype', 'HP:0001004', (390, 400))	('breast cancer', 'Disease', (421, 434))	('RIN2', 'Gene', '54453', (50, 54))	('lymphedema', 'Disease', (390, 400))	('downregulation', 'NegReg', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (428, 434))	('lymphedema', 'Disease', 'MESH:D008209', (390, 400))	('RIN2', 'Gene', (50, 54))	('PIGR', 'Gene', '5284', (101, 105))	('GJA12', 'Gene', '57165', (274, 279))	('esophageal junctional tumors', 'Phenotype', 'HP:0100751', (240, 268))	('increase', 'Reg', (358, 366))	('GJA12', 'Gene', (274, 279))
187157	23243219	This suggests that there is a field effect of methylation alterations in keeping with other research in the area of colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('methylation', 'MPA', (46, 57))	('colon cancer', 'Disease', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('alterations', 'Var', (58, 69))
187164	23243219	Using Illumina Infinium arrays to select a methylation signature and pyrosequencing for both retrospective and prospective validation, we have shown that methylation changes can be used alongside histopathology to detect patients who have no visible signs of dysplasia/cancer at high risk of progression.	('patients', 'Species', '9606', (221, 229))	('dysplasia/cancer', 'Disease', 'MESH:D009369', (259, 275))	('methylation changes', 'Var', (154, 173))	('dysplasia/cancer', 'Disease', (259, 275))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))
187192	24408916	The following urinary metabolites were associated with lung cancer risk, independent of smoking intensity and duration: cotinine plus its glucuronide, a biomarker of nicotine uptake; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), a biomarker of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); and r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a biomarker of polycyclic aromatic hydrocarbons (PAH).	('PheT', 'Gene', '9043', (420, 424))	('rat', 'Species', '10116', (112, 115))	('lung cancer', 'Disease', (55, 66))	('associated', 'Reg', (39, 49))	('PAH', 'Chemical', 'MESH:D011084', (476, 479))	('4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone', 'Chemical', 'MESH:C016583', (302, 348))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (442, 474))	('NNK', 'Chemical', 'MESH:C016583', (350, 353))	('r-1-', 'Var', (360, 364))	('phenanthrene', 'Chemical', 'MESH:C031181', (406, 418))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('NNAL', 'Chemical', 'MESH:C099565', (257, 261))	('nicotine', 'Chemical', 'MESH:D009538', (166, 174))	('cotinine', 'Chemical', 'MESH:D003367', (120, 128))	('PheT', 'Gene', (420, 424))	('glucuronides', 'Chemical', 'MESH:D020719', (237, 249))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tobacco', 'Species', '4097', (283, 290))
187233	24408916	Virtually all unburned commercial tobacco products contain NNN and NNK, and they always occur together.	('NNN', 'Chemical', 'MESH:C008655', (59, 62))	('NNK', 'MPA', (67, 70))	('tobacco', 'Species', '4097', (34, 41))	('NNN', 'Var', (59, 62))	('NNK', 'Chemical', 'MESH:C016583', (67, 70))
187247	24408916	r-1,t-2,3,c-4-Tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) is a metabolite of phenanthrene, the simplest PAH with a bay region, a feature that is closely associated with the carcinogenicity.	('r-1', 'Var', (0, 3))	('phenanthrene', 'Chemical', 'MESH:C031181', (84, 96))	('PAH', 'Chemical', 'MESH:D011084', (111, 114))	('PheT', 'Gene', '9043', (59, 63))	('carcinogenic', 'Disease', 'MESH:D063646', (180, 192))	('phenanthrene', 'Chemical', 'MESH:C031181', (45, 57))	('r-1,t-2,3,c-4-Tetrahydroxy-1,2,3,4-tetrahydrophenanthrene', 'Chemical', 'MESH:C502234', (0, 57))	('carcinogenic', 'Disease', (180, 192))	('PheT', 'Gene', (59, 63))
187272	24408916	Our initial report among 155 lung cancer cases and 152 controls showed that current smokers with the highest tertile of urinary total cotinine (>=2615 ng/mg creatinine) had an odds ratio of 3.76 (95% confidence interval = 1.75 - 8.06) relative to smokers with the lowest tertile of total cotinine (35 - <=1196 ng/mg creatinine) after adjustment for number of cigarettes per day, number of years of smoking, and urinary total NNAL (P for trend = 0.002).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('creatinine', 'Chemical', 'MESH:D003404', (157, 167))	('cotinine', 'Chemical', 'MESH:D003367', (134, 142))	('NNAL', 'Chemical', 'MESH:C099565', (425, 429))	('creatinine', 'Chemical', 'MESH:D003404', (316, 326))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('rat', 'Species', '10116', (181, 184))	('>=2615 ng/mg', 'Var', (144, 156))	('lung cancer', 'Disease', (29, 40))	('men', 'Species', '9606', (340, 343))	('cotinine', 'Chemical', 'MESH:D003367', (288, 296))
187280	24408916	Lung cancer risk increased monotonically with increasing serum cotinine levels; odds ratio of lung cancer was 12.4 (95% CI: 7.1, 21.9) for subjects in the highest decile (serum cotinine >1,800 nmol/L or >316.8 ng/mL) relative to nonsmokers (serum cotinine <75 nmol/L or <13.2 ng/mL) after adjustment for number of cigarettes per day.	('cotinine', 'Chemical', 'MESH:D003367', (177, 185))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('cotinine', 'Chemical', 'MESH:D003367', (247, 255))	('increasing serum cotinine levels', 'Phenotype', 'HP:0410171', (46, 78))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('cotinine', 'Chemical', 'MESH:D003367', (63, 71))	('rat', 'Species', '10116', (85, 88))	('lung cancer', 'Disease', (94, 105))	('Lung cancer', 'Disease', (0, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('men', 'Species', '9606', (295, 298))	('serum', 'Var', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
187338	24408916	PheT is a metabolite of the non-carcinogenic PAH phenanthrene, but the metabolism of phenanthrene to PheT closely parallels that of BaP, a strong PAH carcinogen capable of inducing tumors of the lung and other tissues in rodents, and rated as carcinogenic to humans.	('inducing', 'PosReg', (172, 180))	('carcinogenic', 'Disease', (243, 255))	('tumors of the lung', 'Phenotype', 'HP:0100526', (181, 199))	('PheT', 'Gene', (101, 105))	('phenanthrene', 'Chemical', 'MESH:C031181', (85, 97))	('PheT', 'Gene', '9043', (101, 105))	('humans', 'Species', '9606', (259, 265))	('carcinogenic', 'Disease', 'MESH:D063646', (243, 255))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('phenanthrene', 'Chemical', 'MESH:C031181', (49, 61))	('carcinogenic', 'Disease', (32, 44))	('BaP', 'Gene', '11331', (132, 135))	('tumors of the lung', 'Disease', (181, 199))	('non-carcinogenic', 'Disease', 'MESH:C580335', (28, 44))	('phenanthrene', 'Var', (85, 97))	('PAH', 'Chemical', 'MESH:D011084', (45, 48))	('BaP', 'Gene', (132, 135))	('rat', 'Species', '10116', (234, 237))	('carcinogenic', 'Disease', 'MESH:D063646', (32, 44))	('PheT', 'Gene', (0, 4))	('PAH', 'Chemical', 'MESH:D011084', (146, 149))	('PheT', 'Gene', '9043', (0, 4))	('tumors of the lung', 'Disease', 'MESH:D008175', (181, 199))	('non-carcinogenic', 'Disease', (28, 44))
187364	24408916	0.05 mg per cigarette) are associated with reduced carcinogen exposure and reduced nicotine dependence.	('0.05 mg', 'Var', (0, 7))	('carcinogen exposure', 'MPA', (51, 70))	('reduced', 'NegReg', (75, 82))	('nicotine', 'Chemical', 'MESH:D009538', (83, 91))	('reduced', 'NegReg', (43, 50))	('nicotine dependence', 'MPA', (83, 102))
187475	19656375	Several lines of evidence support a role of genetics in cancer survival: FH of colorectal cancer is associated with improved survival in stage III colon cancer; gene polymorphisms have been related to differences in survival of breast cancer cases; and familial UGI cancer cases have shown higher microsatelite instability, greater loss of heterozygosity, and different gene expression patterns from sporadic cases.	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('familial UGI cancer', 'Disease', 'MESH:D009369', (253, 272))	('colon cancer', 'Disease', 'MESH:D015179', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (56, 62))	('microsatelite instability', 'MPA', (297, 322))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('colorectal cancer', 'Disease', (79, 96))	('polymorphisms', 'Var', (166, 179))	('colon cancer', 'Disease', (147, 159))	('breast cancer', 'Disease', 'MESH:D001943', (228, 241))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('breast cancer', 'Disease', (228, 241))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('familial UGI cancer', 'Disease', (253, 272))	('higher', 'PosReg', (290, 296))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('improved', 'PosReg', (116, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', (266, 272))	('colon cancer', 'Phenotype', 'HP:0003003', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', (90, 96))
187547	33381521	For example, abnormally methylated CH25H has been found to be a prognostic marker for lung squamous cell carcinoma patients (Gao et al.,).	('patients', 'Species', '9606', (115, 123))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('abnormally methylated', 'Var', (13, 34))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('CH25H', 'Gene', '9023', (35, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('lung squamous cell carcinoma', 'Disease', (86, 114))	('CH25H', 'Gene', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))
187550	33381521	LOC51089, also called C1QA, was found to be involved in the innate immune system and was associated with the expression of PD-L1 (Olkhov-Mitsel et al.,), and its abnormal expression in tumor tissues was confirmed in head and neck squamous cell carcinoma and clear cell renal cell carcinoma (Yu et al.,; Apanovich et al.,).	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (225, 253))	('associated', 'Reg', (89, 99))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (258, 289))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('tumor', 'Disease', (185, 190))	('C1QA', 'Gene', (22, 26))	('C1QA', 'Gene', '712', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (216, 253))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (258, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('LOC51089', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('clear cell renal cell carcinoma', 'Disease', (258, 289))	('involved', 'Reg', (44, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (269, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('PD-L1', 'Gene', (123, 128))	('neck squamous cell carcinoma', 'Disease', (225, 253))	('PD-L1', 'Gene', '29126', (123, 128))
187552	33381521	Accordingly, kidney renal clear cell carcinoma patients with high expressions of MXRA8 had worse overall survival (Li and Xu,).	('kidney renal clear cell carcinoma', 'Disease', (13, 46))	('MXRA8', 'Gene', '54587', (81, 86))	('overall survival', 'MPA', (97, 113))	('patients', 'Species', '9606', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('high expressions', 'Var', (61, 77))	('MXRA8', 'Gene', (81, 86))	('worse', 'NegReg', (91, 96))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (13, 46))
187553	33381521	RET is an important proto-oncogene that can undergo oncogenic activation through both cytogenetic rearrangement and the activation of point mutations, and alterations in RET have been identified as being oncogenic in multiple malignancies (Subbiah et al.,).	('RET', 'Gene', '5979', (0, 3))	('malignancies', 'Disease', 'MESH:D009369', (226, 238))	('point mutations', 'Var', (134, 149))	('RET', 'Gene', (170, 173))	('alterations', 'Var', (155, 166))	('malignancies', 'Disease', (226, 238))	('RET', 'Gene', '5979', (170, 173))	('RET', 'Gene', (0, 3))
187555	33381521	Alterations in SPI1 lead to cellular proliferation and differentiation arrest, resulting in oncogenic subversion (Roos-Weil et al.,).	('differentiation arrest', 'Disease', (55, 77))	('SPI1', 'Gene', (15, 19))	('Alterations', 'Var', (0, 11))	('differentiation arrest', 'Disease', 'MESH:D006323', (55, 77))	('cellular proliferation', 'CPA', (28, 50))	('SPI1', 'Gene', '6688', (15, 19))	('oncogenic subversion', 'CPA', (92, 112))
187576	33186888	Here, we present a meta-analysis that demonstrates NK cell infiltration is correlated with decreased risk of death across solid tumor origins, grades and stages.	('death across solid tumor', 'Disease', (109, 133))	('NK', 'Chemical', '-', (51, 53))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('death across solid tumor', 'Disease', 'MESH:D003643', (109, 133))	('NK cell infiltration', 'Var', (51, 71))	('decreased', 'NegReg', (91, 100))
187586	33186888	Human NK cells are most often defined and experimentally marked as CD56+CD3- cells, and broadly characterized based on CD56 expression as either circulating, cytokine-producing NK cells (CD57lowCD56bright/CD16-), or tissue-infiltrating, cytotoxic NK cells (CD57brightCD56dim/CD16+).	('CD56', 'Gene', (119, 123))	('Human', 'Species', '9606', (0, 5))	('NK', 'Chemical', '-', (247, 249))	('CD57brightCD56dim/CD16+', 'Var', (257, 280))	('CD57lowCD56bright/CD16-', 'Var', (187, 210))	('NK', 'Chemical', '-', (6, 8))	('NK', 'Chemical', '-', (177, 179))
187590	33186888	Since HLA negatively regulates NK cell activation, loss of "self" HLA lowers the threshold for NK cell activation.	('loss', 'Var', (51, 55))	('threshold for NK cell activation', 'MPA', (81, 113))	('lowers', 'NegReg', (70, 76))	('NK', 'Chemical', '-', (31, 33))	('regulates', 'Reg', (21, 30))	('NK', 'Chemical', '-', (95, 97))
187595	33186888	Current clinical trials investigating adoptive NK cell transfer to treat solid tumors include melanoma (NCT00328861, NCT03470922), kidney cancer (NCT00328861), head and neck cancers (NCT02643550), glioblastoma (NCT02658981), gynecologic malignancies (NCT02459301), and other metastatic (NCT03415100) and non-metastatic solid tumors (NCT01875601, NCT01212341, NCT03940820, NCT02671435, NCT01968109).	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('NCT01212341', 'Var', (346, 357))	('glioblastoma', 'Phenotype', 'HP:0012174', (197, 209))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('NCT02658981', 'Var', (211, 222))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('kidney cancer', 'Phenotype', 'HP:0009726', (131, 144))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('kidney cancer', 'Disease', (131, 144))	('solid tumors', 'Disease', 'MESH:D009369', (319, 331))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('head and neck cancers', 'Phenotype', 'HP:0012288', (160, 181))	('NCT00328861', 'Var', (146, 157))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('NCT01875601', 'Var', (333, 344))	('NCT02671435', 'Var', (372, 383))	('NCT02459301', 'Var', (251, 262))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('NCT03940820', 'Var', (359, 370))	('NCT00328861', 'Var', (104, 115))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('solid tumors', 'Disease', (73, 85))	('NCT03415100', 'Var', (287, 298))	('malignancies', 'Disease', 'MESH:D009369', (237, 249))	('malignancies', 'Disease', (237, 249))	('head and neck cancer', 'Phenotype', 'HP:0012288', (160, 180))	('neck cancers', 'Disease', (169, 181))	('NCT01968109', 'Var', (385, 396))	('glioblastoma', 'Disease', 'MESH:D005909', (197, 209))	('neck cancers', 'Disease', 'MESH:D006258', (169, 181))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('NK', 'Chemical', '-', (47, 49))	('NCT02643550', 'Var', (183, 194))	('solid tumors', 'Disease', (319, 331))	('glioblastoma', 'Disease', (197, 209))	('kidney cancer', 'Disease', 'MESH:D007680', (131, 144))	('NCT03470922', 'Var', (117, 128))	('solid tumors', 'Disease', 'MESH:D009369', (73, 85))
187619	33186888	This statistic indicates that while the majority of studies, across tumor types, found NK cells to be associated with improved OS, additional sub-meta-analyses is warranted by tissue compartment, marker, or within cancer types to strengthen and validate conclusions.	('tumor', 'Disease', (68, 73))	('cancer', 'Disease', (214, 220))	('improved', 'PosReg', (118, 126))	('NK', 'Chemical', '-', (87, 89))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('NK cells', 'Var', (87, 95))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
187643	33186888	Studies staining for CD5638,44,48,50,52,54,55,59,60,69,70,73,84 (n = 16, HR=0.27, 95% CI: 0.18-0.41; p = 0.0001) and CD57 (n = 12, HR=0.38, 95% CI: 0.23-0.63, p = 0.0014) demonstrated a similarly reduced risk of death with NK cell infiltration.	('NK', 'Chemical', '-', (223, 225))	('death', 'Disease', 'MESH:D003643', (212, 217))	('death', 'Disease', (212, 217))	('CD57', 'Var', (117, 121))	('reduced', 'NegReg', (196, 203))
187680	33186888	Three of the five studies identified NK cells by staining for CD56 or CD57 and found that NK cell infiltration significantly improved OS(Table 1, Fig.	('CD56', 'Var', (62, 66))	('CD57', 'Var', (70, 74))	('NK', 'Chemical', '-', (90, 92))	('improved', 'PosReg', (125, 133))	('NK', 'Chemical', '-', (37, 39))
187688	33186888	Two of the studies found that high CD57+ NK cell infiltration into the tumor was associated with significantly improved OS.	('NK', 'Chemical', '-', (41, 43))	('improved', 'PosReg', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('CD57+ NK', 'Var', (35, 43))
187707	33186888	Overall survival was significantly higher in the population with a greater proportional infiltration of CD57+ NK cells (p = 0.001).	('CD57+ NK', 'Var', (104, 112))	('higher', 'PosReg', (35, 41))	('NK', 'Chemical', '-', (110, 112))	('Overall survival', 'CPA', (0, 16))
187716	33186888	In contrast to many of the other cancers examined in this systematic review, NK cells were not significantly associated with improved survival in either of these studies.	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('NK cells', 'Var', (77, 85))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('NK', 'Chemical', '-', (77, 79))
187721	33186888	High numbers of CD57+ NK cells in the peritumoral capsule non-significantly trended towards better OS of soft tissue sarcoma patients (p = 0.797) (Table 1, Fig.	('tumor', 'Disease', (42, 47))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (105, 124))	('NK', 'Chemical', '-', (22, 24))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('sarcoma', 'Disease', (117, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CD57+ NK cells', 'Var', (16, 30))	('sarcoma', 'Disease', 'MESH:D012509', (117, 124))	('better', 'PosReg', (92, 98))	('patients', 'Species', '9606', (125, 133))
187722	33186888	The median survival for high NK cell infiltration in this tumor compartment (29 patients, 36%) was 138 months, compared to 47 months for low expression (50 patients, 63%).	('patients', 'Species', '9606', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('patients', 'Species', '9606', (80, 88))	('high NK', 'Var', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('NK', 'Chemical', '-', (29, 31))
187732	33186888	Those with high NK cell infiltration had significantly longer OS (p = 0.002) compared to those without.	('NK', 'Chemical', '-', (16, 18))	('longer', 'PosReg', (55, 61))	('high', 'Var', (11, 15))
187748	33186888	Notwithstanding, the presence of a single NK cell within a high powered microscopic field was associated with significantly improved OS and DFS in colorectal cancer, HER2+ breast cancer and hepatocellular carcinoma.	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('colorectal cancer', 'Disease', (147, 164))	('NK', 'Chemical', '-', (42, 44))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('improved', 'PosReg', (124, 132))	('HER2+ breast cancer', 'Disease', (166, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('DFS', 'Disease', (140, 143))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (190, 214))	('HER2+ breast cancer', 'Disease', 'MESH:D001943', (166, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (190, 214))	('hepatocellular carcinoma', 'Disease', (190, 214))	('rectal cancer', 'Phenotype', 'HP:0100743', (151, 164))	('presence', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
187777	33186888	Compared with NKp46, definitions of NK cells using CD56 or CD57 were more consistently associated with improved survival.	('NK', 'Chemical', '-', (36, 38))	('survival', 'CPA', (112, 120))	('CD57', 'Var', (59, 63))	('CD56', 'Var', (51, 55))	('NK', 'Chemical', '-', (14, 16))	('improved', 'PosReg', (103, 111))	('NKp46', 'Gene', (14, 19))	('NKp46', 'Gene', '9437', (14, 19))
187789	33186888	Clinical approaches to expand and activate patients' NK cells ex vivo may result in loss of CXCR2 expression, and genetic modification of NK cells to express CXCR2 increases migration to renal cell carcinoma in vitro.	('renal cell carcinoma', 'Disease', (187, 207))	('CXCR2', 'Gene', '3579', (158, 163))	('increases', 'PosReg', (164, 173))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (187, 207))	('NK', 'Chemical', '-', (53, 55))	('patients', 'Species', '9606', (43, 51))	('CXCR2', 'Gene', (158, 163))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (187, 207))	('loss', 'NegReg', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('NK', 'Chemical', '-', (138, 140))	('genetic modification', 'Var', (114, 134))	('CXCR2', 'Gene', '3579', (92, 97))	('CXCR2', 'Gene', (92, 97))
187790	33186888	Across an array of cancer types, infiltration of NK cells is associated with improved response to immunotherapy.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('infiltration', 'Var', (33, 45))	('response to immunotherapy', 'CPA', (86, 111))	('cancer', 'Disease', (19, 25))	('NK', 'Chemical', '-', (49, 51))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('improved', 'PosReg', (77, 85))
187872	29942136	Our findings revealed that, compared with SA, neoadjuvant CRT was associated with improved overall survival (OS) and progression-free survival times, but the 3- and 5-year OS did not show a statistical difference (P>=0.05).	('OS', 'Chemical', '-', (172, 174))	('neoadjuvant', 'Var', (46, 57))	('progression-free', 'CPA', (117, 133))	('overall', 'MPA', (91, 98))	('OS', 'Chemical', '-', (109, 111))	('SA', 'Chemical', '-', (42, 44))	('improved', 'PosReg', (82, 90))
187891	29942136	Lymph node recurrence was significantly lower in the CRT group than in the SA group.	('Lymph node recurrence', 'CPA', (0, 21))	('CRT', 'Var', (53, 56))	('SA', 'Chemical', '-', (75, 77))	('lower', 'NegReg', (40, 45))
187899	29942136	There was a stronger benefit for better OS and PFS in the CRT-surgery arm compared with the surgery arm in this analysis.	('PFS', 'CPA', (47, 50))	('CRT-surgery', 'Var', (58, 69))	('OS', 'Chemical', '-', (40, 42))
188014	29532618	Ku80 overexpression associates with unfavorable prognosis of superficial ESCC patients, and silencing of Ku80 could inhibit the malignant behavior of ESCC cells.	('superficial ESCC', 'Disease', (61, 77))	('silencing', 'Var', (92, 101))	('Ku80', 'Gene', (105, 109))	('overexpression', 'PosReg', (5, 19))	('patients', 'Species', '9606', (78, 86))	('inhibit', 'NegReg', (116, 123))	('malignant behavior of', 'CPA', (128, 149))	('Ku80', 'Gene', (0, 4))
188029	29532618	Ku80, also known as Homo sapiens X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5), is an important and specific components of nonhomologous end joining (NHEJ) 15.	('men', 'Species', '9606', (52, 55))	('XRCC5', 'Gene', (105, 110))	('Chinese hamster', 'Species', '10029', (80, 95))	('XRCC5', 'Gene', '100689306', (105, 110))	('Homo sapiens', 'Species', '9606', (20, 32))	('Ku80', 'Var', (0, 4))
188031	29532618	Our previous studies indicated evaluation of Ku80 promotes management and stratification of ESCC patients 21, 22.	('patients', 'Species', '9606', (97, 105))	('men', 'Species', '9606', (65, 68))	('ESCC', 'Disease', (92, 96))	('Ku80', 'Var', (45, 49))
188078	29532618	The 60 mice were classified into four groups: (1) blank control group: mice were injected with medium; (2) negative control group: mice were injected with ESCC cells; and (3) two experimental groups: mice were injected with nonsilencing shRNA- or Ku80 shRNA-transfected ESCC cells.	('mice', 'Species', '10090', (71, 75))	('men', 'Species', '9606', (185, 188))	('mice', 'Species', '10090', (7, 11))	('mice', 'Species', '10090', (200, 204))	('mice', 'Species', '10090', (131, 135))	('nonsilencing', 'Var', (224, 236))	('Ku80', 'Var', (247, 251))
188089	29532618	Superficial ESCC patients were thereby classified into two groups, namely Ku80 high-level group (n = 64, 59.8%) and Ku80 low-level group (n = 43, 40.2%).	('low-level', 'NegReg', (121, 130))	('patients', 'Species', '9606', (17, 25))	('Superficial ESCC', 'Disease', (0, 16))	('Ku80', 'Var', (116, 120))
188090	29532618	As showed in Table 1, Chi-square test suggested Ku80 expression level was associated with differentiation degree (P = 0.017), T status (P =  0.011), nodal involvement (P = 0.005), TNM stage (P = 0.004), and tumor recurrence (P = 0.008), and not with age (P = 0.420) and gender (P = 0.075).	('TNM', 'Gene', (180, 183))	('differentiation degree', 'CPA', (90, 112))	('Ku80 expression level', 'Var', (48, 69))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('nodal', 'Gene', (149, 154))	('men', 'Species', '9606', (162, 165))	('TNM', 'Gene', '10178', (180, 183))	('nodal', 'Gene', '4838', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('T status', 'CPA', (126, 134))	('associated', 'Reg', (74, 84))
188093	29532618	In the 101 patients with complete 5-year follow-up data, recurrences were observed in 41 of 61 patients (67.2%) with high Ku80 expression and 16 of 40 (40.0%) patients with low Ku80 expression.	('patients', 'Species', '9606', (95, 103))	('expression', 'MPA', (127, 137))	('high', 'Var', (117, 121))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (159, 167))	('Ku80', 'Gene', (122, 126))
188094	29532618	The distant metastases rate in high Ku80 expression group (10/61, 16.4%) was also higher than that in low Ku80 expression group (4/40, 10.0%).	('metastases', 'Disease', (12, 22))	('high Ku80 expression', 'Var', (31, 51))	('higher', 'PosReg', (82, 88))	('metastases', 'Disease', 'MESH:D009362', (12, 22))
188096	29532618	Multivariate analyses indicated that tumor differentiation (P = 0.023), T status (P = 0.003), nodal involvement (P = 0.006), TNM stage (P = 0.005), and Ku80 expression (P = 0.014) were both independent significant indicators of DFS.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('nodal', 'Gene', (94, 99))	('nodal', 'Gene', '4838', (94, 99))	('men', 'Species', '9606', (107, 110))	('Ku80', 'Var', (152, 156))	('TNM', 'Gene', '10178', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('DFS', 'Disease', (228, 231))	('TNM', 'Gene', (125, 128))
188098	29532618	Ku80 protein expression levels were 0.823 +- 0.091, 0.745 +- 0.069, 0.448 +- 0.053, 0.326 +- 0.047, and 0.182 +- 0.027 in untransfected and transfected shRNA scramble, shRNA-1, shRNA-2, and shRNA-3 KYSE150 cells.	('0.745 +- 0.069', 'Var', (52, 66))	('0.182 +- 0.027', 'Var', (104, 118))	('0.448 +- 0.053', 'Var', (68, 82))	('0.326 +- 0.047', 'Var', (84, 98))	('KYSE150', 'CellLine', 'CVCL:1348', (198, 205))
188111	29532618	Additionally, earlier studies have demonstrated that Ku80 is highly expressed and correlates with the progression of gastric cancer, breast cancer, bladder cancer, and colorectal cancer 17, 18, 19, 20.	('breast cancer', 'Disease', (133, 146))	('bladder cancer', 'Disease', 'MESH:D001749', (148, 162))	('bladder cancer', 'Disease', (148, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('bladder cancer', 'Phenotype', 'HP:0009725', (148, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Disease', (168, 185))	('correlates with', 'Reg', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('gastric cancer', 'Disease', (117, 131))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('Ku80', 'Var', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
188123	29532618	Additionally, some interesting findings about the prognostic values of Ku80 in malignant cancers had been reported.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('malignant cancers', 'Disease', (79, 96))	('Ku80', 'Var', (71, 75))	('malignant cancers', 'Disease', 'MESH:D009369', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
188124	29532618	27 demonstrated Ku80 was related to survival of patients with lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('Ku80', 'Var', (16, 20))	('related', 'Reg', (25, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('patients', 'Species', '9606', (48, 56))	('lung adenocarcinoma', 'Disease', (62, 81))
188130	29532618	We also performed experiments in vivo to validate effectiveness of Ku80 knockdown (Fig.	('men', 'Species', '9606', (24, 27))	('knockdown', 'Var', (72, 81))	('Ku80 knockdown', 'Var', (67, 81))
188131	29532618	Chaotic Ku80 expression could cause aberrant DNA damage reaction.	('damage reaction', 'Disease', 'MESH:D004342', (49, 64))	('damage reaction', 'Disease', (49, 64))	('Ku80 expression', 'Var', (8, 23))	('cause', 'Reg', (30, 35))
188134	29532618	Lentiviral-based shRNA might be utilized as an effective cancer therapy 37.	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Lentiviral-based', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
188135	29532618	Additionally, the blockage of tumorigenesis by lentiviral-mediated Ku80 shRNA also supported the effectiveness of this strategy in ESCC.	('blockage', 'NegReg', (18, 26))	('lentiviral-mediated', 'Var', (47, 66))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Ku80', 'Var', (67, 71))	('tumor', 'Disease', (30, 35))	('ESCC', 'Disease', (131, 135))
188137	29532618	Moreover, Ku70 and Ku80 form a heterodimer, Ku protein, which could bind to the DNA ends and act as a DNA repair protein 40.	('Ku80', 'Var', (19, 23))	('Ku70', 'Gene', (10, 14))	('bind', 'Interaction', (68, 72))	('Ku70', 'Gene', '2547', (10, 14))
188139	29532618	In conclusion, this study provided evidence that Ku80 had unrecognized roles in carcinogenesis and development of ESCC.	('Ku80', 'Var', (49, 53))	('carcinogenesis', 'Disease', (80, 94))	('ESCC', 'Disease', (114, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('men', 'Species', '9606', (106, 109))
188140	29532618	Ku80 might serve as an early diagnostic biomarker for dysplasia, carcinoma in situ, and superficial ESCC.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (65, 82))	('superficial ESCC', 'Disease', (88, 104))	('dysplasia', 'Disease', (54, 63))	('dysplasia', 'Disease', 'MESH:D004476', (54, 63))	('carcinoma in situ', 'Disease', 'MESH:D002278', (65, 82))	('carcinoma in situ', 'Disease', (65, 82))	('Ku80', 'Var', (0, 4))
188208	21587177	Recent Studies(  18  ,  26  -  29  ) indicated that there was a certain relationship between the incidence/degree of radiation pneumonia and low-dose irradiation ( Gy).	('low-dose', 'Var', (141, 149))	('pneumonia', 'Phenotype', 'HP:0002090', (127, 136))	('radiation pneumonia', 'Disease', (117, 136))	('radiation pneumonia', 'Disease', 'MESH:D004194', (117, 136))
188234	26868604	With a normal, intact swallow, anterosuperior movement of the hyolaryngeal complex during swallowing enlarges the pharyngeal space, creates negative pressure, and contributes to the mechanical opening of the upper esophageal sphincter.	('negative pressure', 'MPA', (140, 157))	('contributes', 'Reg', (163, 174))	('opening of the upper esophageal sphincter', 'Disease', 'MESH:D009122', (193, 234))	('enlarges', 'PosReg', (101, 109))	('pharyngeal space', 'MPA', (114, 130))	('opening of the upper esophageal sphincter', 'Disease', (193, 234))	('creates', 'Reg', (132, 139))	('anterosuperior', 'Var', (31, 45))
188273	28121921	Hepatitis C virus (HCV) has been identified by the World Health Organization (WHO) as a major health problem; accordingly HCV is a major cause of chronic liver disease, hepatocellular carcinoma, and deaths from liver disease and is the most common indication for liver transplantation worldwide.	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('liver disease', 'Phenotype', 'HP:0001392', (211, 224))	('cause', 'Reg', (137, 142))	('liver disease', 'Disease', 'MESH:D008107', (211, 224))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (169, 193))	('liver disease', 'Disease', (211, 224))	('liver disease', 'Phenotype', 'HP:0001392', (154, 167))	('chronic liver disease', 'Disease', (146, 167))	('Hepatitis', 'Disease', (0, 9))	('liver disease', 'Disease', 'MESH:D008107', (154, 167))	('chronic liver disease', 'Disease', 'MESH:D058625', (146, 167))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (169, 193))	('HCV', 'Species', '11103', (19, 22))	('deaths', 'Disease', (199, 205))	('HCV', 'Species', '11103', (122, 125))	('Hepatitis C virus', 'Species', '11103', (0, 17))	('hepatocellular carcinoma', 'Disease', (169, 193))	('deaths', 'Disease', 'MESH:D003643', (199, 205))	('HCV', 'Var', (122, 125))
188317	26234674	Using miR expression profiling analysis, we found that miR-214-3p is one of the most markedly downregulated miRs in two esophageal squamous cancer cell lines compared to esophageal epithelial cells.	('miRs', 'Gene', (108, 112))	('miR-214-3p', 'Var', (55, 65))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (120, 146))	('esophageal squamous cancer', 'Disease', (120, 146))	('squamous cancer', 'Phenotype', 'HP:0002860', (131, 146))	('downregulated', 'NegReg', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
188318	26234674	Interestingly, using miR target prediction programs, both survivin and CUG-BP1 mRNA were found to contain potential binding sites for miR-214-3p.	('binding', 'Interaction', (116, 123))	('survivin', 'Gene', (58, 66))	('CUG-BP1', 'Gene', (71, 78))	('survivin', 'Gene', '11799', (58, 66))	('miR-214-3p', 'Var', (134, 144))
188319	26234674	Forced expression of miR-214-3p in esophageal cancer cells leads to a decrease in the mRNA and protein levels of both survivin and CUG-BP1.	('miR-214-3p', 'Var', (21, 31))	('CUG-BP1', 'Gene', (131, 138))	('esophageal cancer', 'Disease', (35, 52))	('survivin', 'Gene', (118, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('decrease', 'NegReg', (70, 78))	('survivin', 'Gene', '11799', (118, 126))
188320	26234674	By contrast, silencing miR-214-3p in esophageal epithelial cells leads to an increase in both survivin and CUG-BP1 mRNA and protein.	('silencing miR-214-3p', 'Var', (13, 33))	('survivin', 'Gene', '11799', (94, 102))	('CUG-BP1', 'Gene', (107, 114))	('survivin', 'Gene', (94, 102))	('increase', 'PosReg', (77, 85))	('miR-214-3p', 'Var', (23, 33))
188321	26234674	To determine whether the observed effect of miR-214-3p on survivin expression was direct, mediated through CUG-BP1, or both, binding studies utilizing biotin pull-down assays and heterologous luciferase reporter constructs were performed.	('survivin', 'Gene', (58, 66))	('biotin', 'Chemical', 'MESH:D001710', (151, 157))	('survivin', 'Gene', '11799', (58, 66))	('miR-214-3p', 'Var', (44, 54))	('expression', 'MPA', (67, 77))
188323	26234674	Finally, forced expression of miR-214-3p enhances the sensitivity of esophageal cancer cells to Cisplatin-induced apoptosis.	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('enhances', 'PosReg', (41, 49))	('miR-214-3p', 'Var', (30, 40))	('sensitivity', 'MPA', (54, 65))	('Cisplatin', 'Chemical', 'MESH:D002945', (96, 105))
188325	26234674	These findings suggest that miR-214-3p acts as a tumor suppressor and that its downregulation contributes to chemoresistance in esophageal cancer cells by targeting both survivin and CUG-BP1.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('miR-214-3p', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('esophageal cancer', 'Disease', (128, 145))	('CUG-BP1', 'Gene', (183, 190))	('chemoresistance', 'CPA', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', (49, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('survivin', 'Gene', (170, 178))	('downregulation', 'NegReg', (79, 93))	('survivin', 'Gene', '11799', (170, 178))
188349	26234674	As shown in Figure 2A, transfection efficiency of pre-miR-214-3p was robust in both TE7 and TE10 cells (a).	('TE10', 'CellLine', 'CVCL:1760', (92, 96))	('transfection', 'MPA', (23, 35))	('pre-miR-214-3p', 'Var', (50, 64))
188350	26234674	Following successful transfection of pre-miR-214-3p, both survivin and CUG-BP1 protein levels are markedly decreased in TE7 and TE10 cells (Figure 2B a,b).	('pre-miR-214-3p', 'Var', (37, 51))	('survivin', 'Gene', (58, 66))	('CUG-BP1', 'Gene', (71, 78))	('TE10', 'CellLine', 'CVCL:1760', (128, 132))	('decreased', 'NegReg', (107, 116))	('survivin', 'Gene', '11799', (58, 66))
188352	26234674	Conversely, both survivin and CUG-BP1 protein levels were increased in hESO cells following transfection of anti-miR-214-3p (Figure 2B c).	('increased', 'PosReg', (58, 67))	('anti-miR-214-3p', 'Var', (108, 123))	('survivin', 'Gene', '11799', (17, 25))	('CUG-BP1', 'Gene', (30, 37))	('survivin', 'Gene', (17, 25))
188353	26234674	There was no change in HuR expression following silencing of miR-214-3p in hESO cells.	('HuR', 'Gene', (23, 26))	('silencing', 'Var', (48, 57))	('miR-214-3p', 'Var', (61, 71))	('HuR', 'Gene', '15568', (23, 26))
188354	26234674	To further investigate the mechanism by which miR-214-3p affects survivin and CUGBP1 protein expression, levels of survivin and CUG-BP1 mRNA were assessed following overexpression of pre-miR-214-3p in TE7 and TE10 cells, as well as following transfection of anti-miR-214-3p in hESO cells.	('survivin', 'Gene', '11799', (115, 123))	('survivin', 'Gene', (65, 73))	('CUG-BP1', 'Gene', (128, 135))	('CUGBP1', 'Gene', (78, 84))	('affects', 'Reg', (57, 64))	('expression', 'MPA', (93, 103))	('survivin', 'Gene', (115, 123))	('overexpression', 'PosReg', (165, 179))	('protein', 'Protein', (85, 92))	('survivin', 'Gene', '11799', (65, 73))	('pre-miR-214-3p', 'Var', (183, 197))	('TE10', 'CellLine', 'CVCL:1760', (209, 213))
188355	26234674	As seen in Figure 3A, transfection of pre-miR-214-3p was associated with a decrease in both survivin and CUG-BP1 mRNA levels in both TE7 and TE10 cells.	('decrease', 'NegReg', (75, 83))	('CUG-BP1 mRNA levels', 'MPA', (105, 124))	('TE10', 'CellLine', 'CVCL:1760', (141, 145))	('survivin', 'Gene', '11799', (92, 100))	('pre-miR-214-3p', 'Var', (38, 52))	('survivin', 'Gene', (92, 100))
188356	26234674	In hESO cells, reduction of miR-214-3p expression led to an increase in both survivin and CUG-BP1 mRNA levels (Figure 3B).	('miR-214-3p expression', 'Var', (28, 49))	('reduction', 'NegReg', (15, 24))	('increase', 'PosReg', (60, 68))	('survivin', 'Gene', '11799', (77, 85))	('survivin', 'Gene', (77, 85))	('CUG-BP1 mRNA levels', 'MPA', (90, 109))
188357	26234674	Figure 3C depicts stability of both survivin and CUG-BP1 mRNA following transfection of pre-miR-214-3p in TE7 cells.	('CUG-BP1', 'Gene', (49, 56))	('pre-miR-214-3p', 'Var', (88, 102))	('survivin', 'Gene', '11799', (36, 44))	('stability', 'MPA', (18, 27))	('survivin', 'Gene', (36, 44))
188359	26234674	As seen in these curves, both survivin and CUG-BP1 mRNAs are destabilized following pre-miR-214-3p transfection.	('survivin', 'Gene', (30, 38))	('destabilized', 'NegReg', (61, 73))	('survivin', 'Gene', '11799', (30, 38))	('CUG-BP1', 'Gene', (43, 50))	('pre-miR-214-3p transfection', 'Var', (84, 111))
188360	26234674	The stability curves in Figure 3D demonstrate enhanced stability of both survivin and CUG-BP1 mRNA following silencing of miR-214-3p in hESO cells.	('CUG-BP1', 'Gene', (86, 93))	('survivin', 'Gene', (73, 81))	('survivin', 'Gene', '11799', (73, 81))	('stability', 'MPA', (55, 64))	('silencing', 'Var', (109, 118))	('enhanced', 'PosReg', (46, 54))	('miR-214-3p', 'Var', (122, 132))
188361	26234674	As it was not clear whether the observed effect of miR-214-3p on survivin mRNA and protein expression resulted from a direct interaction with survivin mRNA, indirectly through an interaction with CUG-BP1 mRNA, or both, we next sought to determine whether miR-214-3p bound to both survivin and CUG-BP1 mRNA.	('interaction', 'Interaction', (179, 190))	('miR-214-3p', 'Var', (255, 265))	('survivin', 'Gene', (65, 73))	('survivin', 'Gene', '11799', (280, 288))	('miR-214-3p', 'Var', (51, 61))	('survivin', 'Gene', (142, 150))	('interaction', 'Interaction', (125, 136))	('survivin', 'Gene', (280, 288))	('survivin', 'Gene', '11799', (142, 150))	('survivin', 'Gene', '11799', (65, 73))
188362	26234674	As seen in Figure 4A, there are 3 predicted miR-214-3p binding sites in the 3' untranslated region (UTR) of survivin mRNA.	('binding', 'Interaction', (55, 62))	('miR-214-3p', 'Var', (44, 54))	('survivin', 'Gene', (108, 116))	('survivin', 'Gene', '11799', (108, 116))
188366	26234674	The levels of survivin mRNA and CUG-BP1 mRNA were markedly elevated in the pull-down material isolated from TE7 cells following transfection with biotin-labeled miR-214-3p compared to control (Figure 4B).	('miR-214-3p', 'Var', (161, 171))	('levels', 'MPA', (4, 10))	('CUG-BP1', 'Gene', (32, 39))	('survivin', 'Gene', (14, 22))	('elevated', 'PosReg', (59, 67))	('transfection', 'Var', (128, 140))	('survivin', 'Gene', '11799', (14, 22))	('biotin', 'Chemical', 'MESH:D001710', (146, 152))
188369	26234674	Based on our previous findings that silencing either survivin or CUG-BP1 enhanced the sensitivity of TE7 cells to chemotherapy-induced apoptosis, we predicted similar results following forced expression of miR-214-3p in these cells.	('survivin', 'Gene', '11799', (53, 61))	('sensitivity', 'MPA', (86, 97))	('silencing', 'Var', (36, 45))	('enhanced', 'PosReg', (73, 81))	('survivin', 'Gene', (53, 61))	('CUG-BP1', 'Gene', (65, 72))
188371	26234674	Western blot analysis of lysates harvested 24 hours following Cisplatin exposure revealed a marked increase in caspase-3 protein levels in cells transfected with pre-miR-214-3p compared to control.	('caspase-3', 'Gene', (111, 120))	('caspase-3', 'Gene', '12367', (111, 120))	('pre-miR-214-3p', 'Var', (162, 176))	('increase', 'PosReg', (99, 107))	('Cisplatin', 'Chemical', 'MESH:D002945', (62, 71))
188372	26234674	In order to determine whether the observed enhancement in apoptosis following overexpression of miR-214-3p was due to its reduction in survivin and/or CUG-BP1 levels, rescue experiments were performed.	('survivin', 'Gene', '11799', (135, 143))	('miR-214-3p', 'Var', (96, 106))	('CUG-BP1 levels', 'MPA', (151, 165))	('reduction', 'NegReg', (122, 131))	('enhancement', 'PosReg', (43, 54))	('survivin', 'Gene', (135, 143))	('apoptosis', 'CPA', (58, 67))
188373	26234674	As seen in Figure 7B, overexpression of either survivin or CUG-BP1 following transfection of miR-214-3p restores expression of these proteins.	('expression', 'MPA', (113, 123))	('overexpression', 'PosReg', (22, 36))	('survivin', 'Gene', '11799', (47, 55))	('miR-214-3p', 'Var', (93, 103))	('restores', 'PosReg', (104, 112))	('CUG-BP1', 'Gene', (59, 66))	('survivin', 'Gene', (47, 55))
188375	26234674	To ensure that the observed caspase-3 seen following miR-214-3p overexpression was functional, a caspase-3 ELISA assay was performed under the same conditions.	('caspase-3', 'Gene', (97, 106))	('caspase-3', 'Gene', '12367', (28, 37))	('overexpression', 'PosReg', (64, 78))	('caspase-3', 'Gene', '12367', (97, 106))	('miR-214-3p', 'Var', (53, 63))	('caspase-3', 'Gene', (28, 37))
188378	26234674	Treatment with pre-miR-214-3p alone or control miR plus Cisplatin resulted in approximately 5-10% of cells staining positive for Annexin-V expression, whereas over 50% of TE7 cells transfected with pre-miR-214-3p and exposed to Cisplatin stained positive for Annexin-5 (Figures 7E and 7F).	('pre-miR-214-3p', 'Var', (15, 29))	('Cisplatin', 'Chemical', 'MESH:D002945', (228, 237))	('Annexin-V', 'Gene', '11747', (129, 138))	('Annexin-V', 'Gene', (129, 138))	('Annexin-5', 'Gene', (259, 268))	('Annexin-5', 'Gene', '11747', (259, 268))	('Cisplatin', 'Chemical', 'MESH:D002945', (56, 65))
188379	26234674	Our findings indicate that miR-214-3p is markedly downregulated in esophageal squamous cancer cell lines compared to esophageal epithelial cells.	('miR-214-3p', 'Var', (27, 37))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (67, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('squamous cancer', 'Phenotype', 'HP:0002860', (78, 93))	('esophageal squamous cancer', 'Disease', (67, 93))	('downregulated', 'NegReg', (50, 63))
188380	26234674	We also demonstrate that miR-214-3p regulates survivin expression in these esophageal cancer cells, by both a direct interaction with survivin mRNA, as well as indirectly through an interaction with CUG-BP1 mRNA.	('miR-214-3p', 'Var', (25, 35))	('survivin', 'Gene', '11799', (46, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('interaction', 'Interaction', (182, 193))	('regulates', 'Reg', (36, 45))	('interaction', 'Interaction', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('expression', 'MPA', (55, 65))	('survivin', 'Gene', '11799', (134, 142))	('survivin', 'Gene', (46, 54))	('esophageal cancer', 'Disease', (75, 92))	('survivin', 'Gene', (134, 142))
188381	26234674	Forced expression of miR-214-3p in esophageal cancer cells leads to a decrease in both mRNA and protein levels of survivin and CUG-BP1, associated with decreased mRNA stability of both targets.	('miR-214-3p', 'Var', (21, 31))	('esophageal cancer', 'Disease', (35, 52))	('survivin', 'Gene', (114, 122))	('mRNA stability', 'MPA', (162, 176))	('decrease', 'NegReg', (70, 78))	('decreased', 'NegReg', (152, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CUG-BP1', 'Gene', (127, 134))	('survivin', 'Gene', '11799', (114, 122))
188382	26234674	Finally, overexpression of miR-214-3p results in markedly enhanced sensitivity of esophageal cancer cells to Cisplatin, which is abrogated following rescue expression of either survivin or CUG-BP1.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('overexpression', 'PosReg', (9, 23))	('miR-214-3p', 'Var', (27, 37))	('survivin', 'Gene', '11799', (177, 185))	('enhanced', 'PosReg', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('sensitivity', 'MPA', (67, 78))	('survivin', 'Gene', (177, 185))	('esophageal cancer', 'Disease', (82, 99))
188384	26234674	All five of the miRs (miRs-141, 200c, 203, 205, 429) found to be most upregulated in their study were also upregulated by at least 2 log-fold in both cancer cell lines in our analysis.	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('miRs-141', 'Var', (22, 30))	('cancer', 'Disease', (150, 156))	('upregulated', 'PosReg', (70, 81))	('upregulated', 'PosReg', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
188386	26234674	However, in a study comparing miR expression in 40 esophageal squamous cell cancer specimens and matched normal tissues, miR-214-3p was found to be significantly downregulated in 77.5% of samples.	('miR-214-3p', 'Var', (121, 131))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (62, 82))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (51, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('downregulated', 'NegReg', (162, 175))	('esophageal squamous cell cancer', 'Disease', (51, 82))
188387	26234674	The data presented here not only demonstrate a new role for miR-214-3p as an important post-transcriptional regulator of survivin in esophageal squamous cancer cells, but, by also describing its interaction with CUG-BP1, enhance the understanding of the complex regulatory relationships that exist between miRs and RBPs.	('RBP', 'Gene', (315, 318))	('interaction', 'Interaction', (195, 206))	('squamous cancer', 'Phenotype', 'HP:0002860', (144, 159))	('RBP', 'Gene', '19662', (315, 318))	('survivin', 'Gene', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (133, 159))	('miR-214-3p', 'Var', (60, 70))	('survivin', 'Gene', '11799', (121, 129))	('esophageal squamous cancer', 'Disease', (133, 159))	('CUG-BP1', 'Gene', (212, 219))
188390	26234674	Silencing miR-503 resulted in increased levels of CUG-BP1, which protected cells from TNFalpha -induced apoptosis.	('CUG-BP1', 'MPA', (50, 57))	('TNFalpha', 'Gene', (86, 94))	('miR-503', 'Gene', (10, 17))	('levels', 'MPA', (40, 46))	('increased', 'PosReg', (30, 39))	('Silencing', 'Var', (0, 9))	('miR-503', 'Gene', '723879', (10, 17))	('TNFalpha', 'Gene', '21926', (86, 94))
188392	26234674	Furthermore, simultaneous silencing of miR-503 and CUG-BP1 abolished this increase in c-IAP1 and c-IAP2 levels, providing additional evidence that CUG-BP1 enhances the expression of these anti-apoptotic proteins.	('c-IAP1', 'Gene', (86, 92))	('miR-503', 'Gene', (39, 46))	('c-IAP2', 'Gene', '11797', (97, 103))	('expression', 'MPA', (168, 178))	('abolished', 'NegReg', (59, 68))	('c-IAP1', 'Gene', '11797', (86, 92))	('miR-503', 'Gene', '723879', (39, 46))	('c-IAP2', 'Gene', (97, 103))	('silencing', 'Var', (26, 35))	('enhances', 'PosReg', (155, 163))	('CUG-BP1', 'Var', (147, 154))	('CUG-BP1', 'Gene', (51, 58))
188393	26234674	Our findings indicate that the pro-apoptotic effect observed following forced expression of miR-214-3p, is related at least in part, to the reduction in survivin expression.	('survivin', 'Gene', '11799', (153, 161))	('expression', 'MPA', (162, 172))	('miR-214-3p', 'Var', (92, 102))	('reduction', 'NegReg', (140, 149))	('survivin', 'Gene', (153, 161))
188394	26234674	Alterations in levels of both miR-214-3p and CUG-BP1 have been shown to affect sensitivity to chemotherapy-induced apoptosis in cancer cells, although their expression and targets vary considerably across different malignancies.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('affect', 'Reg', (72, 78))	('malignancies', 'Disease', (215, 227))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('miR-214-3p', 'Var', (30, 40))	('malignancies', 'Disease', 'MESH:D009369', (215, 227))	('CUG-BP1', 'Gene', (45, 52))	('sensitivity to chemotherapy-induced apoptosis', 'MPA', (79, 124))	('cancer', 'Disease', (128, 134))
188395	26234674	In ovarian cancer cells, where miR-214-3p is overexpressed compared to normal tissues, miR-214-3p was shown to downregulate PTEN.	('PTEN', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('miR-214-3p', 'Var', (87, 97))	('ovarian cancer', 'Disease', (3, 17))	('downregulate', 'NegReg', (111, 123))	('PTEN', 'Gene', '19211', (124, 128))
188397	26234674	Similarly, in nasopharyngeal cancer, the upregulation of miR-214-3p led to decreased levels of the pro-apoptotic protein Bim.	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (14, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (14, 35))	('Bim', 'Gene', '12125', (121, 124))	('Bim', 'Gene', (121, 124))	('miR-214-3p', 'Var', (57, 67))	('upregulation', 'PosReg', (41, 53))	('nasopharyngeal cancer', 'Disease', (14, 35))	('decreased', 'NegReg', (75, 84))
188398	26234674	Conversely, miR-214-3p has been shown to be downregulated relative to normal cells in HCC and cervical cancer.	('downregulated', 'NegReg', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR-214-3p', 'Var', (12, 22))	('HCC', 'Disease', (86, 89))	('cervical cancer', 'Disease', (94, 109))	('cervical cancer', 'Disease', 'MESH:D002583', (94, 109))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
188399	26234674	In each case, miR-214-3p was found to target an anti-apoptotic gene; XBP-1 in HCC and Bcl2l2 in cervical cancer, such that the loss of miR-214-3p in these cells resulted in the increased expression of its anti-apoptotic targets.	('loss', 'Var', (127, 131))	('XBP-1', 'Gene', (69, 74))	('miR-214-3p', 'Gene', (135, 145))	('Bcl2l2', 'Gene', '12050', (86, 92))	('anti-apoptotic targets', 'MPA', (205, 227))	('increased', 'PosReg', (177, 186))	('HCC', 'Phenotype', 'HP:0001402', (78, 81))	('cervical cancer', 'Disease', 'MESH:D002583', (96, 111))	('XBP-1', 'Gene', '22433', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('expression', 'MPA', (187, 197))	('cervical cancer', 'Disease', (96, 111))	('Bcl2l2', 'Gene', (86, 92))
188400	26234674	Additionally, forced expression of miR-214-3p in the esophageal squamous cancer cell line Eca109 inhibited expression of the enhancer of zeste homolog 2 (EZH2).	('enhancer of zeste homolog 2', 'Gene', '14056', (125, 152))	('EZH2', 'Gene', '14056', (154, 158))	('EZH2', 'Gene', (154, 158))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (53, 79))	('esophageal squamous cancer', 'Disease', (53, 79))	('miR-214-3p', 'Var', (35, 45))	('expression', 'MPA', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('enhancer of zeste homolog 2', 'Gene', (125, 152))	('squamous cancer', 'Phenotype', 'HP:0002860', (64, 79))	('inhibited', 'NegReg', (97, 106))
188401	26234674	Of note, EZH2 was also found to be a target of miR-214-3p in HCC.	('EZH2', 'Gene', (9, 13))	('HCC', 'Phenotype', 'HP:0001402', (61, 64))	('miR-214-3p', 'Var', (47, 57))	('EZH2', 'Gene', '14056', (9, 13))
188402	26234674	In both reports, overexpression of miR-214-3p led to decreased proliferation and invasion capacity of the transfected cancer cells.	('cancer', 'Disease', (118, 124))	('proliferation', 'CPA', (63, 76))	('miR-214-3p', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('invasion capacity of the transfected', 'CPA', (81, 117))	('overexpression', 'PosReg', (17, 31))	('decreased', 'NegReg', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
188406	26234674	Silencing CUG-BP1 therefore resulted in increased levels of BAD and BAX and enhanced sensitivity to chemotherapy-induced apoptosis.	('CUG-BP1', 'Gene', (10, 17))	('BAX', 'Gene', '12028', (68, 71))	('BAX', 'Gene', (68, 71))	('enhanced', 'PosReg', (76, 84))	('increased', 'PosReg', (40, 49))	('sensitivity to chemotherapy-induced apoptosis', 'MPA', (85, 130))	('Silencing', 'Var', (0, 9))
188408	26234674	Together with our findings, these data regarding targets of miR-214-3p and CUG-BP1 in cancer cells raise the intriguing possibility that miR-214-3p and/or CUG-BP1 could serve as important regulators of multiple anti-apoptotic effectors in esophageal cancer cells.	('miR-214-3p', 'Var', (137, 147))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('esophageal cancer', 'Disease', (239, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))	('cancer', 'Disease', (86, 92))
188437	17173682	Etiological study of esophageal squamous cell carcinoma in an endemic region: a population-based case control study in Huaian, China Continuous exposure to various environmental carcinogens and genetic polymorphisms of xenobiotic-metabolizing enzymes (XME) are associated with many types of human cancers, including esophageal squamous cell carcinoma (ESCC).	('XME', 'Gene', (252, 255))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (316, 350))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (327, 350))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (21, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (341, 350))	('cancers', 'Disease', 'MESH:D009369', (297, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('associated', 'Reg', (261, 271))	('XME', 'Chemical', '-', (252, 255))	('esophageal squamous cell carcinoma', 'Disease', (316, 350))	('xenobiotic-', 'Phenotype', 'HP:0031838', (219, 230))	('human', 'Species', '9606', (291, 296))	('genetic polymorphisms', 'Var', (194, 215))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('cancers', 'Disease', (297, 304))	('esophageal squamous cell carcinoma', 'Disease', (21, 55))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('men', 'Species', '9606', (171, 174))
188444	17173682	Our results demonstrated that dietary and environmental exposures, some demographic parameters and genetic polymorphism of GSTT1 may play important roles in the development of ESCC in Huaian area, China.	('ESCC', 'Disease', (176, 180))	('men', 'Species', '9606', (49, 52))	('play', 'Reg', (133, 137))	('GSTT1', 'Gene', (123, 128))	('genetic polymorphism', 'Var', (99, 119))	('GSTT1', 'Gene', '2952', (123, 128))	('men', 'Species', '9606', (168, 171))	('roles', 'Reg', (148, 153))
188455	17173682	Many studies have suggested that polymorphisms in xenobiotic-metabolizing enzymes (XME) including phase I enzymes such as CYP1A1, CYP1B1, CYP2A6 and CYP2E1, and phase II enzymes such as GSTM1, GSTT1, GSTP1, and microsomal epoxide hydrolase (EPHX) may confer different risks of susceptibility to cancer, including ESCC.	('xenobiotic-', 'Phenotype', 'HP:0031838', (50, 61))	('XME', 'Chemical', '-', (83, 86))	('cancer', 'Disease', (295, 301))	('CYP2E1', 'Gene', (149, 155))	('ESCC', 'Disease', (313, 317))	('EPHX', 'Gene', (241, 245))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('polymorphisms', 'Var', (33, 46))	('GSTM1', 'Gene', (186, 191))	('CYP2A6', 'Gene', (138, 144))	('GSTP1', 'Gene', '2950', (200, 205))	('GSTT1', 'Gene', '2952', (193, 198))	('GSTP1', 'Gene', (200, 205))	('CYP1B1', 'Gene', '1545', (130, 136))	('CYP1B1', 'Gene', (130, 136))	('GSTT1', 'Gene', (193, 198))	('EPHX', 'Gene', '2052', (241, 245))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('CYP1A1', 'Gene', (122, 128))	('microsomal epoxide hydrolase', 'Gene', '2052', (211, 239))	('CYP2A6', 'Gene', '1548', (138, 144))	('microsomal epoxide hydrolase', 'Gene', (211, 239))	('GSTM1', 'Gene', '2944', (186, 191))	('CYP2E1', 'Gene', '1571', (149, 155))	('CYP1A1', 'Gene', '1543', (122, 128))
188488	17173682	However, GSTT1 genotype was marginally associated with ESCC (OR = 1.68; 95% CI = 0.96-2.97; P = 0.07).	('GSTT1', 'Gene', '2952', (9, 14))	('genotype', 'Var', (15, 23))	('associated', 'Reg', (39, 49))	('ESCC', 'Disease', (55, 59))	('GSTT1', 'Gene', (9, 14))
188492	17173682	In the present study, introverted personality, passive smoking, a family history of cancer, esophageal lesion, HP infection, eating fast, fatty meat consumption, pickled vegetables intake, moldy food intake, favor to salty and acrid food were all associated with increased risk of ESCC.	('HP infection', 'Disease', 'MESH:C537262', (111, 123))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('esophageal lesion', 'Disease', (92, 109))	('introverted personality', 'Disease', (22, 45))	('salt', 'Chemical', 'MESH:D012492', (217, 221))	('associated', 'Reg', (247, 257))	('esophageal lesion', 'Disease', 'MESH:D004935', (92, 109))	('HP infection', 'Disease', (111, 123))	('cancer', 'Disease', (84, 90))	('ESCC', 'Disease', (281, 285))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('moldy', 'Var', (189, 194))
188519	17173682	Although this was different from previous studies on ESCC, it is biologically plausible because the presence of the GSTT1 null genotype leads to lower GST enzyme activity levels and, consequently, impaired detoxification of environmental or dietary carcinogens.	('GSTT1', 'Gene', '2952', (116, 121))	('impaired', 'NegReg', (197, 205))	('GSTT1', 'Gene', (116, 121))	('men', 'Species', '9606', (231, 234))	('GS', 'Disease', 'MESH:D011125', (116, 118))	('activity levels', 'MPA', (162, 177))	('lower', 'NegReg', (145, 150))	('GS', 'Disease', 'MESH:D011125', (151, 153))	('presence', 'Var', (100, 108))
188520	17173682	In addition, GSTT1 null has been shown to play a role in esophageal carcinogenesis through a pathway of abnormalities in the p53 tumor suppressor gene, which is highly reported in ESCC.	('role', 'Reg', (49, 53))	('abnormalities', 'Var', (104, 117))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('GSTT1', 'Gene', '2952', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('GSTT1', 'Gene', (13, 18))	('null', 'Var', (19, 23))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (57, 82))	('tumor', 'Disease', (129, 134))	('play', 'Reg', (42, 46))	('esophageal carcinogenesis', 'Disease', (57, 82))
188559	33903283	A spontaneous mutation of Foxn1 gene in athymic nude mice results in the deteriorated or absent thymus.	('absent', 'NegReg', (89, 95))	('Foxn1', 'Gene', '15218', (26, 31))	('mutation', 'Var', (14, 22))	('Foxn1', 'Gene', (26, 31))	('deteriorated', 'CPA', (73, 85))	('absent thymus', 'Phenotype', 'HP:0005359', (89, 102))	('deteriorated or absent thymus', 'Phenotype', 'HP:0010515', (73, 102))	('nude mice', 'Species', '10090', (48, 57))
188562	33903283	The concept of SCID now expands to all severely immunodeficient strains of mice, such as those with Recombination activating gene-1/2 mutation (Rag-1null/Rag-2null).	('mice', 'Species', '10090', (75, 79))	('SCID', 'Gene', '19090', (15, 19))	('Recombination activating gene-1/2', 'Gene', (100, 133))	('Rag-2', 'Gene', (154, 159))	('SCID', 'Gene', (15, 19))	('mutation', 'Var', (134, 142))	('Recombination activating gene-1/2', 'Gene', '19373;19374', (100, 133))	('Rag-1', 'Gene', (144, 149))	('immunodeficient', 'Disease', 'MESH:D007153', (48, 63))	('immunodeficient', 'Disease', (48, 63))	('Rag-2', 'Gene', '19374', (154, 159))	('Rag-1', 'Gene', '19373', (144, 149))
188571	33903283	Nevertheless, no significant improvement in primary EC engraftment has been found using NSG mice compared with NOD-SCID mice.	('mice', 'Species', '10090', (120, 124))	('SCID', 'Gene', '19090', (115, 119))	('SCID', 'Gene', (115, 119))	('NSG', 'Var', (88, 91))	('mice', 'Species', '10090', (92, 96))
188573	33903283	The engraftment rate of human hematopoietic cells in NOG mice are significantly elevated when compared with NOD-SCID mice.	('mice', 'Species', '10090', (57, 61))	('human', 'Species', '9606', (24, 29))	('elevated', 'PosReg', (80, 88))	('SCID', 'Gene', '19090', (112, 116))	('engraftment rate of human hematopoietic cells', 'CPA', (4, 49))	('mice', 'Species', '10090', (117, 121))	('SCID', 'Gene', (112, 116))	('NOG', 'Var', (53, 56))
188592	33903283	Secondly, EC-PDXs are able to mimic the current clinical genetic setting of EC, including mutations in PIK3CA, EGFR, K-Ras, B-Raf and HER2 amplification.	('EC-PDXs', 'Disease', 'MESH:D005955', (10, 17))	('EC-PDXs', 'Disease', (10, 17))	('mutations', 'Var', (90, 99))	('PIK3CA', 'Gene', (103, 109))	('EGFR', 'Gene', (111, 115))	('K-Ras', 'Gene', (117, 122))	('K-Ras', 'Gene', '16653', (117, 122))	('B-Raf', 'Gene', (124, 129))	('HER2', 'Protein', (134, 138))	('B-Raf', 'Gene', '109880', (124, 129))
188595	33903283	However, when PIK3CA mutation was present in the models, Trastuzumab lost the ability to suppress tumor growth, which suggest PIK3CA mutation may be a mechanism of Trastuzumab resistance.	('Trastuzumab', 'Chemical', 'MESH:D000068878', (57, 68))	('mutation', 'Var', (133, 141))	('PIK3CA', 'Gene', (126, 132))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (164, 175))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('lost', 'NegReg', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
188596	33903283	Clinical response to chemotherapy using 5-FU and cisplatin was also compromised in EC-PDX models with PIK3CA mutation.	('PIK3CA', 'Gene', (102, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('5-FU', 'Chemical', 'MESH:D005472', (40, 44))	('compromised', 'NegReg', (68, 79))	('mutation', 'Var', (109, 117))
188621	33903283	The aberrant activation of these receptor tyrosine kinases facilitates the tumorigenesis and progression of multiple malignant tumors, such as EC, lung cancer, gastric cancer, and colon cancer.	('gastric cancer', 'Disease', (160, 174))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('malignant tumors', 'Disease', (117, 133))	('malignant tumors', 'Disease', 'MESH:D009369', (117, 133))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colon cancer', 'Disease', (180, 192))	('gastric cancer', 'Disease', 'MESH:D013274', (160, 174))	('facilitates', 'PosReg', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', (147, 158))	('gastric cancer', 'Phenotype', 'HP:0012126', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('colon cancer', 'Phenotype', 'HP:0003003', (180, 192))	('progression', 'CPA', (93, 104))	('tumor', 'Disease', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('aberrant', 'Var', (4, 12))	('activation', 'PosReg', (13, 23))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('colon cancer', 'Disease', 'MESH:D015179', (180, 192))
188625	33903283	However, PIK3CA mutation or FGFR1 over-expression in PDX attenuated the effect of theliatinib, suggesting care to apply theliatinib to only responsive subsets of patients is required.	('patients', 'Species', '9606', (162, 170))	('mutation', 'Var', (16, 24))	('FGFR1', 'Gene', (28, 33))	('theliatinib', 'Chemical', '-', (120, 131))	('theliatinib', 'Chemical', '-', (82, 93))	('effect', 'MPA', (72, 78))	('FGFR1', 'Gene', '2260', (28, 33))	('PIK3CA', 'Gene', (9, 15))	('attenuated', 'NegReg', (57, 67))	('over-expression', 'PosReg', (34, 49))
188631	33903283	The HER3 might be a potential therapeutic targets for trastuzumab resistant cancer, as inhibition of HER3 could reverse trastuzumab resistance in ESCC and EAC cells.	('reverse', 'NegReg', (112, 119))	('trastuzumab', 'Chemical', 'MESH:D000068878', (54, 65))	('trastuzumab resistance', 'MPA', (120, 142))	('HER3', 'Gene', '13867', (4, 8))	('trastuzumab', 'Chemical', 'MESH:D000068878', (120, 131))	('HER3', 'Gene', (101, 105))	('ESCC', 'Disease', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('EAC', 'Phenotype', 'HP:0011459', (155, 158))	('HER3', 'Gene', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('inhibition', 'Var', (87, 97))	('HER3', 'Gene', '13867', (101, 105))
188633	33903283	EGFR gene amplification or overexpression was a predictor for afatinib sensitivity of ESCC.	('EGFR', 'Gene', (0, 4))	('afatinib', 'Chemical', 'MESH:D000077716', (62, 70))	('amplification', 'Var', (10, 23))	('sensitivity', 'MPA', (71, 82))	('overexpression', 'PosReg', (27, 41))
188635	33903283	In the PDX model of esophagogastric cancer, afatinib resistance could be caused by MET amplification, which might be overcome by MET inhibitor.	('gastric cancer', 'Phenotype', 'HP:0012126', (28, 42))	('resistance', 'MPA', (53, 63))	('MET amplification', 'Var', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('afatinib', 'Gene', (44, 52))	('gastric cancer', 'Disease', (28, 42))	('caused by', 'Reg', (73, 82))	('afatinib', 'Chemical', 'MESH:D000077716', (44, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (28, 42))
188641	33903283	In PDX models of ESCC, APIO-EE-9 effectively inhibited tumor growth with minimal toxicity.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('APIO-EE-9', 'Chemical', '-', (23, 32))	('toxicity', 'Disease', 'MESH:D064420', (81, 89))	('toxicity', 'Disease', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ESCC', 'Disease', (17, 21))	('tumor', 'Disease', (55, 60))	('APIO-EE-9', 'Var', (23, 32))	('inhibited', 'NegReg', (45, 54))
188642	33903283	The inhibition of Aurora-A and -B might be effective in reducing uncontrolled proliferation in ESCC, thus contributing to tumor suppression.	('uncontrolled', 'MPA', (65, 77))	('ESCC', 'Disease', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('inhibition', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('reducing', 'NegReg', (56, 64))	('Aurora-A', 'Gene', (18, 26))	('tumor', 'Disease', (122, 127))
188647	33903283	Suppression of proliferation of EC cells and tumor growth of PDX model were observed following SHR6390 treatment.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('SHR6390', 'Chemical', '-', (95, 102))	('tumor', 'Disease', (45, 50))	('SHR6390', 'Var', (95, 102))	('proliferation', 'CPA', (15, 28))	('Suppression', 'NegReg', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
188648	33903283	The combination of SHR6390 with paclitaxel or cisplatin synergistically inhibited tumor growth in a PDX model.	('SHR6390', 'Var', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (32, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SHR6390', 'Chemical', '-', (19, 26))	('inhibited', 'NegReg', (72, 81))	('combination', 'Interaction', (4, 15))	('tumor', 'Disease', (82, 87))
188654	33903283	Furthermore, the treatment using a CDK9 inhibitor might enhance the cell-killing effect of radiation on EAC.	('CDK9', 'Gene', (35, 39))	('CDK9', 'Gene', '1025', (35, 39))	('enhance', 'PosReg', (56, 63))	('cell-killing effect', 'CPA', (68, 87))	('EAC', 'Phenotype', 'HP:0011459', (104, 107))	('inhibitor', 'Var', (40, 49))	('EAC', 'Disease', (104, 107))
188655	33903283	Synergetic effect of the CDK9 inhibitor, BAY1143572 and radiation were assessed in EAC cell lines and PDX models.	('CDK9', 'Gene', '1025', (25, 29))	('CDK9', 'Gene', (25, 29))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))	('BAY1143572', 'Var', (41, 51))	('BAY1143572', 'Chemical', 'MESH:C000625640', (41, 51))
188656	33903283	By inhibiting CDK9 activation, BAY1143572 could sensitize EAC cells and PDX of EAC to radiation.	('CDK9', 'Gene', '1025', (14, 18))	('BAY1143572', 'Var', (31, 41))	('inhibiting', 'NegReg', (3, 13))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('EAC', 'Phenotype', 'HP:0011459', (79, 82))	('CDK9', 'Gene', (14, 18))	('sensitize', 'Reg', (48, 57))	('BAY1143572', 'Chemical', 'MESH:C000625640', (31, 41))	('activation', 'MPA', (19, 29))
188660	33903283	Aberrant activated STAT3 in cancer cells induces epithelial mesenchymal transition and facilitated metastasis.	('facilitated', 'PosReg', (87, 98))	('epithelial mesenchymal transition', 'CPA', (49, 82))	('induces', 'PosReg', (41, 48))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('STAT3', 'Gene', '6774', (19, 24))	('STAT3', 'Gene', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
188669	33903283	Mutations of MEK/ERK signaling are frequently seen in many human tumors, including EC, lung cancer, and breast cancer.	('human', 'Species', '9606', (59, 64))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('seen', 'Reg', (46, 50))	('tumors', 'Disease', (65, 71))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Disease', (104, 117))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('lung cancer', 'Disease', (87, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MEK/ERK signaling', 'Gene', (13, 30))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
188688	33903283	Aberrant activation of Hedgehog signaling is linked to cancer progression and chemoresistance.	('activation', 'PosReg', (9, 19))	('linked', 'Reg', (45, 51))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Hedgehog signaling', 'Pathway', (23, 41))	('chemoresistance', 'CPA', (78, 93))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
188699	33903283	In the PDX model, CYH33 and radiation inhibited tumor growth, lowered Akt phosphorylation and M2-like macrophage infiltration.	('CYH33', 'Var', (18, 23))	('tumor', 'Disease', (48, 53))	('Akt', 'Gene', (70, 73))	('M2-like macrophage infiltration', 'CPA', (94, 125))	('inhibited', 'NegReg', (38, 47))	('lowered', 'NegReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Akt', 'Gene', '11651', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
188711	33903283	Moreover, inhibition of VEGFR2 using DC101, a murine VEGFR2 inhibitor, delayed tumor growth and prolonged survival of animals with EAC xenografts.	('DC101', 'Chemical', 'MESH:C511761', (37, 42))	('tumor', 'Disease', (79, 84))	('VEGFR2', 'Gene', (24, 30))	('survival', 'CPA', (106, 114))	('murine', 'Species', '10090', (46, 52))	('DC101', 'Gene', (37, 42))	('prolonged', 'PosReg', (96, 105))	('delayed', 'NegReg', (71, 78))	('inhibition', 'Var', (10, 20))	('EAC', 'Phenotype', 'HP:0011459', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
188712	33903283	However, vascular regression induced by DC101 impaired the uptake of intraperitoneally administered nab-paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('impaired', 'NegReg', (46, 54))	('DC101', 'Chemical', 'MESH:C511761', (40, 45))	('nab', 'Chemical', '-', (100, 103))	('DC101', 'Var', (40, 45))	('vascular regression', 'CPA', (9, 28))
188722	33903283	Dysregulation of notch signaling due to NOTCH1, NOTCH2 or NOTCH3 gene mutation has been shown in ESCC.	('NOTCH2', 'Gene', '18129', (48, 54))	('NOTCH1', 'Gene', '18128', (40, 46))	('NOTCH2', 'Gene', (48, 54))	('notch', 'Gene', (17, 22))	('NOTCH3', 'Gene', '18131', (58, 64))	('NOTCH3', 'Gene', (58, 64))	('NOTCH1', 'Gene', (40, 46))	('notch', 'Gene', '18128;18129;18131', (17, 22))	('mutation', 'Var', (70, 78))	('ESCC', 'Disease', (97, 101))
188727	33903283	Inhibition of Notch signaling also decreased the expression of cancer stem-cell markers in EAC cells.	('Notch', 'Gene', '18128;18129;18131', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Notch', 'Gene', (14, 19))	('expression', 'MPA', (49, 59))	('decreased', 'NegReg', (35, 44))	('EAC', 'Phenotype', 'HP:0011459', (91, 94))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
188729	33903283	PPMP (2-[4-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-5-yl]-5-[(2-methylprop- 2-en-1-yl)oxy]phenol), a novel TBA, reduced cell viability, caused cell cycle arrest and apoptosis in ESCC cell lines.	('arrest', 'Disease', 'MESH:D006323', (155, 161))	('PPMP', 'Var', (0, 4))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('cell viability', 'CPA', (121, 135))	('arrest', 'Disease', (155, 161))	('TBA', 'Chemical', '-', (108, 111))	('PPMP', 'Chemical', 'MESH:C026733', (0, 4))	('reduced', 'NegReg', (113, 120))	('apoptosis', 'CPA', (166, 175))	('2-[4-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-5-yl]-5-[(2-methylprop- 2-en-1-yl)oxy]phenol', 'Chemical', '-', (6, 97))
188861	32119928	The serum biomarker panel of leptin, interleukins (IL) IL6, IL8, IL10, and IL12p70 was developed from a case-control study at the Michael DeBakey Veterans Affairs Medical Center.	('IL10', 'Gene', (65, 69))	('IL12p70', 'Var', (75, 82))	('IL10', 'Gene', '3586', (65, 69))	('IL6', 'Gene', '3569', (55, 58))	('IL8', 'Gene', (60, 63))	('IL8', 'Gene', '3576', (60, 63))	('IL6', 'Gene', (55, 58))	('leptin', 'Gene', '3952', (29, 35))	('leptin', 'Gene', (29, 35))
188870	32119928	The serum biomarker score was calculated according to the prior publication: 1 point for each biomarker (leptin, IL6, IL8, IL12p70) that was in the highest quartile of the control group distribution and 1 point for IL10 in the lowest quartile.	('IL8', 'Gene', (118, 121))	('IL6', 'Gene', (113, 116))	('IL12p70', 'Var', (123, 130))	('IL8', 'Gene', '3576', (118, 121))	('leptin', 'Gene', (105, 111))	('IL10', 'Gene', (215, 219))	('IL10', 'Gene', '3586', (215, 219))	('IL6', 'Gene', '3569', (113, 116))	('leptin', 'Gene', '3952', (105, 111))
188879	32119928	Most patients with Barrett's esophagus had short segment (median C0M1; interquartile range C0M1, C0M2; 81.7% < 3 cm).	('patients', 'Species', '9606', (5, 13))	("Barrett's esophagus", 'Disease', (19, 38))	('men', 'Species', '9606', (52, 55))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (19, 38))	('C0M1', 'Var', (65, 69))
188885	32119928	Early neoplasia patients had longer Barrett's esophagus than the first upper endoscopy patients found to have Barrett's esophagus (median C1M3; interquartile range C0M2, C4M6; 46.3% < 3 cm).	('neoplasia', 'Disease', 'MESH:D009369', (6, 15))	('neoplasia', 'Phenotype', 'HP:0002664', (6, 15))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (36, 55))	('patients', 'Species', '9606', (16, 24))	('neoplasia', 'Disease', (6, 15))	('C1M3', 'Var', (138, 142))	('C4M6', 'Var', (170, 174))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (110, 129))	('patients', 'Species', '9606', (87, 95))	('C0M2', 'Var', (164, 168))
188887	32119928	The most severe histological findings at the time of the index procedure was no neoplasia in 8 (9.0%), low grade dysplasia in 8 (9.0%), high grade dysplasia in 25 (28.1%), T1a adenocarcinoma in 31 (34.8%), and adenocarcinoma >= T1b in 11 (12.4%); one patient with pretreatment high grade dysplasia did not undergo any tissue sampling at the time of the index endoscopy but instead underwent radiofrequency ablation.	('men', 'Species', '9606', (272, 275))	('neoplasia', 'Disease', (80, 89))	('high grade', 'Var', (136, 146))	('patient', 'Species', '9606', (251, 258))	('dysplasia', 'Disease', 'MESH:C536170', (288, 297))	('low grade', 'Var', (103, 112))	('dysplasia', 'Disease', 'MESH:C536170', (113, 122))	('neoplasia', 'Disease', 'MESH:D009369', (80, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (80, 89))	('dysplasia', 'Disease', (288, 297))	('adenocarcinoma', 'Disease', (176, 190))	('dysplasia', 'Disease', (113, 122))	('adenocarcinoma', 'Disease', (210, 224))	('dysplasia', 'Disease', 'MESH:C536170', (147, 156))	('adenocarcinoma', 'Disease', 'MESH:D000230', (176, 190))	('adenocarcinoma', 'Disease', 'MESH:D000230', (210, 224))	('dysplasia', 'Disease', (147, 156))
188896	32119928	Among women, M-BERET and Gerson had numerically greater AuROC than GERD symptoms alone, but with imprecise estimates due to the few number of women with Barrett's esophagus.	('AuROC', 'MPA', (56, 61))	('M-BERET', 'Var', (13, 20))	('greater', 'PosReg', (48, 55))	('women', 'Species', '9606', (6, 11))	('women', 'Species', '9606', (142, 147))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (153, 172))
188974	32251457	IsomiRs were identified by differences such as additions or deletions compared with mature miRs.	('miR', 'Gene', (91, 94))	('additions', 'Var', (47, 56))	('', 'Phenotype', 'HP:0030731', (0, 0))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('deletions', 'Var', (60, 69))	('miR', 'Gene', (3, 6))	('miR', 'Gene', '29116', (91, 94))	('miR', 'Gene', '29116', (3, 6))	('', 'Phenotype', 'HP:0002860', (0, 0))
188984	32251457	Table 2 shows the profile of these candidates of miR/isomiRs, read number for ESCC and HC, fold change, and p-value in the 1st and 2nd group.	('', 'Phenotype', 'HP:0030731', (0, 0))	('miR', 'Gene', '29116', (56, 59))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('fold change', 'Var', (91, 102))	('miR', 'Gene', (49, 52))	('p-value', 'Var', (108, 115))	('miR', 'Gene', (56, 59))	('', 'Phenotype', 'HP:0002860', (0, 0))	('miR', 'Gene', '29116', (49, 52))
189014	32251457	Roberts et al reported that circulating small RNA, including isomiR, were associated with colorectal adenoma; and Mjelle et al identified circulating miR/isomiR associated with metastasis of rectal cancer.	('miR', 'Gene', (157, 160))	('rectal cancer', 'Phenotype', 'HP:0100743', (191, 204))	('colorectal adenoma', 'Disease', (90, 108))	('associated with', 'Reg', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0002860', (0, 0))	('', 'Phenotype', 'HP:0030731', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('metastasis of rectal cancer', 'Disease', (177, 204))	('miR', 'Gene', '29116', (150, 153))	('miR', 'Gene', '29116', (64, 67))	('colorectal adenoma', 'Disease', 'MESH:D015179', (90, 108))	('miR', 'Gene', (150, 153))	('miR', 'Gene', (64, 67))	('circulating', 'Var', (138, 149))	('miR', 'Gene', '29116', (157, 160))	('associated', 'Reg', (74, 84))	('metastasis of rectal cancer', 'Disease', 'MESH:D012004', (177, 204))
189020	32251457	According to previous reports, miR-30a-5p plays a dual role in different types of cancer as either an oncogene or onco-suppressor.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('', 'Phenotype', 'HP:0030731', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('miR-30a-5p', 'Chemical', '-', (31, 41))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('miR-30a-5p', 'Var', (31, 41))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0002860', (0, 0))
189049	32251457	You have demonstrated that your diagnostic panel index derived from the regression analysis with miR-30a-5p and isoforms of miR-574-3p and miR-205-5p had high accuracy in the diagnosis of ESCC.	('miR-205', 'Gene', (139, 146))	('', 'Phenotype', 'HP:0030731', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('miR-574-3p', 'Gene', (124, 134))	('ESCC', 'Disease', (188, 192))	('miR-205', 'Gene', '406988', (139, 146))	('miR-574-3p', 'Gene', '693159', (124, 134))	('miR-30a-5p', 'Chemical', '-', (97, 107))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0002860', (0, 0))	('miR-30a-5p', 'Var', (97, 107))
189093	28411855	It has been reported that EGFR protein over-expression and gene amplification are associated with aggressive biological behaviors of esophageal squamous cell carcinoma (ESCC), and the over-expression of EGFR are thought to be common events in ESCC, which contributes to tumor differentiation and lymph node metastasis.	('ESCC', 'Disease', (243, 247))	('EGFR', 'Gene', (203, 207))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('associated with', 'Reg', (82, 97))	('protein', 'Protein', (31, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('EGFR', 'Gene', (26, 30))	('esophageal squamous cell carcinoma', 'Disease', (133, 167))	('EGFR', 'Gene', '1956', (203, 207))	('aggressive biological behaviors', 'CPA', (98, 129))	('over-expression', 'PosReg', (184, 199))	('tumor', 'Disease', (270, 275))	('gene amplification', 'Var', (59, 77))	('aggressive biological behaviors', 'Phenotype', 'HP:0000718', (98, 129))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (133, 167))	('EGFR', 'Gene', '1956', (26, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('over-expression', 'PosReg', (39, 54))
189117	28411855	RIPA lysis buffer, Anti-EGFR IgG, anti-beta-actin IgG, anti-rabbit IgG were from Cell Signaling (USA).	('EGFR', 'Gene', '1956', (24, 28))	('anti-rabbit', 'Var', (55, 66))	('anti-beta-actin', 'Var', (34, 49))	('EGFR', 'Gene', (24, 28))	('Si', 'Chemical', 'MESH:D012825', (86, 88))	('RIPA lysis buffer', 'Chemical', '-', (0, 17))	('rabbit', 'Species', '9986', (60, 66))
189146	28411855	Firstly, we determined the effects of oridonin on ROS production in KYSE-150 cells by flow cytometry, which indicated that oridonin could increase the intracellular ROS level of KYSE-150 cells (Fig.	('increase', 'PosReg', (138, 146))	('oridonin', 'Chemical', 'MESH:C011959', (38, 46))	('ROS', 'Chemical', '-', (165, 168))	('KYSE-150', 'CellLine', 'CVCL:1348', (178, 186))	('KYSE-150', 'CellLine', 'CVCL:1348', (68, 76))	('oridonin', 'Chemical', 'MESH:C011959', (123, 131))	('oridonin', 'Var', (123, 131))	('ROS', 'Chemical', '-', (50, 53))	('intracellular ROS level', 'MPA', (151, 174))
189191	28411855	The above dynamic force spectra allowed us to determine the disso-ciation kinetic parameters of EGF-EGFR complex in KYSE-150 cells under different conditions based on Bell model, which told the relationship between the rupture force F of the ligand-receptor pair and the loading rate gamma as the following equation: Where koff (0) is off-rate constant for dissociation in the absence of external force F, chibeta is the position of the energy barrier that should be overcome during the dissociation (energy barrier width), kB is the Boltzman constant and T is Kelvin temperature.	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))	('KYSE-150', 'CellLine', 'CVCL:1348', (116, 124))	('rupture force', 'Phenotype', 'HP:0100550', (219, 232))	('EGF', 'Gene', (96, 99))	('EGF', 'Gene', (100, 103))	('chibeta', 'Var', (406, 413))	('EGF', 'Gene', '1950', (96, 99))	('EGF', 'Gene', '1950', (100, 103))
189193	28411855	Combing with Bell model, a and b can be calculated as following:  Based on these formulas, the energy barrier width (chibeta) for EGF-EGFR complex in control KYSE-150 cells, 10muM oridonin treated KYSE-150 cells, 30muM oridonin treated KYSE-150 cells, 50muM oridonin treated KYSE-150 cells, 2.5mM MNAC + 50muM oridonin treated KYSE-150 cells and 2.5mM MNAC treated KYSE-150 cells was 0.172 +- 0.003 nm, 0.170 +- 0.009 nm, 0.164 +- 0.013 nm, 0.167 +- 0.016 nm, 0.169 +- 0.006 nm and 0.174 +- 0.002 nm, respectively (Table 1).	('KYSE-150', 'CellLine', 'CVCL:1348', (365, 373))	('KYSE-150', 'CellLine', 'CVCL:1348', (197, 205))	('muM', 'Gene', '56925', (306, 309))	('muM', 'Gene', (306, 309))	('KYSE-150', 'CellLine', 'CVCL:1348', (275, 283))	('KYSE-150', 'CellLine', 'CVCL:1348', (158, 166))	('EGFR', 'Gene', '1956', (134, 138))	('EGF', 'Gene', (134, 137))	('MNAC', 'Chemical', '-', (297, 301))	('KYSE-150', 'CellLine', 'CVCL:1348', (236, 244))	('muM', 'Gene', '56925', (176, 179))	('oridonin', 'Chemical', 'MESH:C011959', (310, 318))	('muM', 'Gene', '56925', (215, 218))	('EGF', 'Gene', '1950', (130, 133))	('muM', 'Gene', (176, 179))	('0.170 +- 0.009 nm', 'Var', (403, 420))	('muM', 'Gene', (215, 218))	('0.172 +- 0.003 nm', 'Var', (384, 401))	('0.164 +- 0.013 nm', 'Var', (422, 439))	('muM', 'Gene', '56925', (254, 257))	('oridonin', 'Chemical', 'MESH:C011959', (180, 188))	('MNAC', 'Chemical', '-', (352, 356))	('muM', 'Gene', (254, 257))	('0.174 +- 0.002 nm', 'Var', (482, 499))	('KYSE-150', 'CellLine', 'CVCL:1348', (327, 335))	('oridonin', 'Chemical', 'MESH:C011959', (219, 227))	('oridonin', 'Chemical', 'MESH:C011959', (258, 266))	('EGFR', 'Gene', (134, 138))	('EGF', 'Gene', (130, 133))	('0.167 +- 0.016 nm', 'Var', (441, 458))	('EGF', 'Gene', '1950', (134, 137))	('0.169 +- 0.006 nm', 'Var', (460, 477))
189231	30787595	The benefit of taxane-based therapies over fluoropyrimidine plus platinum (FP) in the treatment of esophageal cancer: a meta-analysis of clinical studies Fluoropyrimidine plus platinum (FP) is currently the standard treatment for esophageal cancer (EC).	('platinum', 'Chemical', 'MESH:D010984', (65, 73))	('platinum', 'Chemical', 'MESH:D010984', (176, 184))	('esophageal cancer', 'Disease', 'MESH:D004938', (230, 247))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('Fluoropyrimidine', 'Chemical', '-', (154, 170))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Fluoropyrimidine', 'Var', (154, 170))	('taxane', 'Chemical', 'MESH:C080625', (15, 21))	('fluoropyrimidine', 'Chemical', '-', (43, 59))	('esophageal cancer', 'Disease', (230, 247))	('esophageal cancer', 'Disease', (99, 116))
189287	30787595	However, it must be noted that this was based on only one study that compared paclitaxel plus 5-FU with CF, and that cisplatin frequently causes gastrointestinal toxicity (Figure S4).	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (145, 170))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('gastrointestinal toxicity', 'Disease', (145, 170))	('causes', 'Reg', (138, 144))	('paclitaxel', 'Chemical', 'MESH:D017239', (78, 88))	('5-FU', 'Chemical', 'MESH:D005472', (94, 98))	('cisplatin', 'Var', (117, 126))
189313	30787595	In the Medical Research Council OEO2 trial, patients receiving NACT with CF had longer DFS and OS than those receiving surgery alone.	('NACT', 'Var', (63, 67))	('NACT', 'Chemical', '-', (63, 67))	('patients', 'Species', '9606', (44, 52))	('DFS', 'CPA', (87, 90))	('longer', 'PosReg', (80, 86))	('OEO2', 'Chemical', '-', (32, 36))
189332	30787595	While we did not find any benefits of taxane-based NACRT in all EC patients, we did see that taxane-based NACRT improved pCR and OS in SCC when compared with FP regimens.	('SCC', 'Gene', '6317', (135, 138))	('patients', 'Species', '9606', (67, 75))	('taxane-based NACRT', 'Var', (93, 111))	('taxane', 'Chemical', 'MESH:C080625', (93, 99))	('NACRT', 'Chemical', '-', (51, 56))	('pCR', 'Disease', (121, 124))	('SCC', 'Gene', (135, 138))	('taxane', 'Chemical', 'MESH:C080625', (38, 44))	('improved', 'PosReg', (112, 120))	('NACRT', 'Chemical', '-', (106, 111))
189351	26081045	Recently, many somatic and germline mutations of BAP1 have been reported in a broad spectrum of tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('BAP1', 'Gene', (49, 53))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (36, 45))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('reported', 'Reg', (64, 72))	('germline mutations', 'Var', (27, 45))	('BAP1', 'Gene', '8314', (49, 53))
189354	26081045	The deubiquitinase activity and the auto-deubiquitinase activity of F170I-mutant BAP1 were markedly suppressed compared with wild-type BAP1.	('BAP1', 'Gene', '8314', (81, 85))	('BAP1', 'Gene', (81, 85))	('F170I', 'Mutation', 'rs535470039', (68, 73))	('BAP1', 'Gene', '8314', (135, 139))	('F170I-mutant', 'Var', (68, 80))	('suppressed', 'NegReg', (100, 110))	('BAP1', 'Gene', (135, 139))	('auto-deubiquitinase activity', 'MPA', (36, 64))	('deubiquitinase activity', 'MPA', (4, 27))
189355	26081045	In addition, wild-type BAP1 mostly localizes to the nucleus, whereas the F170I mutant preferentially localized in the cytoplasm.	('BAP1', 'Gene', (23, 27))	('localizes', 'MPA', (35, 44))	('F170I', 'Var', (73, 78))	('BAP1', 'Gene', '8314', (23, 27))	('F170I', 'Mutation', 'rs535470039', (73, 78))
189356	26081045	Microarray analysis revealed that expression of the F170I mutant drastically altered gene expression profiles compared with expressed wild-type BAP1.	('F170I', 'Var', (52, 57))	('BAP1', 'Gene', (144, 148))	('gene expression profiles', 'MPA', (85, 109))	('altered', 'Reg', (77, 84))	('F170I', 'Mutation', 'rs535470039', (52, 57))	('BAP1', 'Gene', '8314', (144, 148))
189357	26081045	Gene-ontology analyses indicated that the F170I mutation altered the expression of genes involved in oncogenic pathways.	('expression of genes', 'MPA', (69, 88))	('F170I', 'Mutation', 'rs535470039', (42, 47))	('altered', 'Reg', (57, 64))	('F170I', 'Var', (42, 47))
189358	26081045	We found that one candidate, TCEAL7, previously reported as a putative tumor suppressor gene, was significantly induced by wild-type BAP1 as compared to F170I mutant BAP1.	('TCEAL7', 'Gene', (29, 35))	('F170I', 'Var', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('BAP1', 'Gene', '8314', (166, 170))	('BAP1', 'Gene', '8314', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('BAP1', 'Gene', (166, 170))	('TCEAL7', 'Gene', '56849', (29, 35))	('tumor', 'Disease', (71, 76))	('induced', 'PosReg', (112, 119))	('BAP1', 'Gene', (133, 137))	('F170I', 'Mutation', 'rs535470039', (153, 158))
189365	26081045	BAP1 is frequently mutated in metastasizing uveal melanomas as well as in malignant pleural mesothelioma, renal cell carcinoma and intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('intrahepatic cholangiocarcinoma', 'Disease', (131, 162))	('uveal melanomas', 'Disease', 'MESH:C536494', (44, 59))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (74, 104))	('BAP1', 'Gene', (0, 4))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (144, 162))	('renal cell carcinoma', 'Disease', (106, 126))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (106, 126))	('uveal melanomas', 'Disease', (44, 59))	('uveal melanomas', 'Phenotype', 'HP:0007716', (44, 59))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (84, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('mutated', 'Var', (19, 26))	('malignant pleural mesothelioma', 'Disease', (74, 104))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('BAP1', 'Gene', '8314', (0, 4))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (106, 126))
189366	26081045	Furthermore, a number of germline BAP1 mutations have been reported to predispose to susceptibility to several tumors: the so-called BAP1 cancer syndrome.	('susceptibility', 'Reg', (85, 99))	('cancer syndrome', 'Disease', (138, 153))	('BAP1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('germline', 'Var', (25, 33))	('tumors', 'Disease', (111, 117))	('mutations', 'Var', (39, 48))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('BAP1', 'Gene', '8314', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('predispose', 'Reg', (71, 81))	('BAP1', 'Gene', '8314', (34, 38))	('cancer syndrome', 'Disease', 'MESH:D009369', (138, 153))	('BAP1', 'Gene', (133, 137))
189367	26081045	This suggests that BAP1 mutation can occur in various types of cancers, including as yet unreported malignant diseases.	('occur', 'Reg', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('BAP1', 'Gene', '8314', (19, 23))	('malignant diseases', 'Disease', (100, 118))	('BAP1', 'Gene', (19, 23))	('mutation', 'Var', (24, 32))	('malignant diseases', 'Disease', 'MESH:D009369', (100, 118))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
189370	26081045	Here, we sought to clarify whether genetic alterations in BAP1 are found in ESCC and play an important role in esophageal carcinogenesis.	('genetic alterations', 'Var', (35, 54))	('role', 'Reg', (103, 107))	('BAP1', 'Gene', (58, 62))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (111, 136))	('found', 'Reg', (67, 72))	('play', 'Reg', (85, 89))	('esophageal carcinogenesis', 'Disease', (111, 136))	('ESCC', 'Disease', (76, 80))	('BAP1', 'Gene', '8314', (58, 62))
189379	26081045	MLPA analysis of genomic DNA for each exon of BAP1 gene was carried out using SALSA MLPA BAP1 kit P417-B1-1011 BAP1-v03; probe data are described in SALSA MLPA probemix P417-B1 BAP1 (MRC Holland, Amsterdam, the Netherlands).	('MRC', 'CellLine', 'CVCL:0440', (183, 186))	('BAP1', 'Gene', (89, 93))	('BAP1', 'Gene', '8314', (111, 115))	('BAP1', 'Gene', '8314', (46, 50))	('BAP1', 'Gene', (111, 115))	('BAP1', 'Gene', '8314', (177, 181))	('BAP1', 'Gene', (46, 50))	('BAP1', 'Gene', (177, 181))	('BAP1', 'Gene', '8314', (89, 93))	('P417-B1', 'Var', (169, 176))
189384	26081045	pCY4B-FLAG-BAP1-F170I was generated by site-directed mutagenesis to create the amino acid substitution phenylalanine to isoleucine at codon 170.	('F170I', 'Mutation', 'rs535470039', (16, 21))	('BAP1', 'Gene', '8314', (11, 15))	('BAP1', 'Gene', (11, 15))	('phenylalanine to', 'Var', (103, 119))	('phenylalanine to isoleucine at codon 170', 'Mutation', 'rs535470039', (103, 143))
189390	26081045	Samples were subjected to SDS-PAGE and immunoblotted using anti-Myc (9E10 sc-40, Santa Cruz), anti-FLAG (monoclonal anti-FLAG M2 antibody, Sigma), anti-HA (anti-HA high affinity#1867423, Roche Applied Science) and anti-BAP1 antibodies.	('Myc', 'Gene', '4609', (64, 67))	('Myc', 'Gene', (64, 67))	('BAP1', 'Gene', (219, 223))	('SDS', 'Chemical', 'MESH:D012967', (26, 29))	('anti-FLAG', 'Var', (94, 103))	('anti-HA', 'Var', (147, 154))	('BAP1', 'Gene', '8314', (219, 223))
189396	26081045	Each experiment with wild-type BAP1 or F170I mutant was conducted twice.	('BAP1', 'Gene', '8314', (31, 35))	('BAP1', 'Gene', (31, 35))	('F170I mutant', 'Var', (39, 51))	('F170I', 'Mutation', 'rs535470039', (39, 44))
189397	26081045	Genes were selected by the values of the first component of the vector in principal component analysis, more than 1.428 or less than -1.907, because APOL6 (1.428) and HSPA6 (-1.907) were 1.5-fold differentially expressed between wild-type BAP1 and the F170I mutant, according to the ratio of averaged expression values in heat-map analysis of two independent F170I mutant and wild-type BAP1 transfections.	('APOL6', 'Gene', '80830', (149, 154))	('F170I', 'Mutation', 'rs535470039', (252, 257))	('HSPA6', 'Gene', (167, 172))	('HSPA6', 'Gene', '3310', (167, 172))	('BAP1', 'Gene', '8314', (386, 390))	('BAP1', 'Gene', '8314', (239, 243))	('F170I', 'Var', (252, 257))	('BAP1', 'Gene', (386, 390))	('F170I mutant', 'Var', (359, 371))	('F170I', 'Mutation', 'rs535470039', (359, 364))	('-1.907', 'Var', (174, 180))	('APOL6', 'Gene', (149, 154))	('BAP1', 'Gene', (239, 243))
189406	26081045	To determine the RNA expression level of TCEAL7 gene, we performed a real time RT-PCR assay; in brief, cDNA created with an iScript Advanced cDNA Synthesis Kit for RT-qPCR (BioRad, Hercules, CA, USA) using total RNA extracted from HEK-293T cells transfected with wild-type BAP1 or F170I-mutant were used as a template, then mixed with Supermixes for PCR and Real-Time PCR (BioRad) and TCEAL7-specific primers as well as GAPDH primers, and analyzed using the CFX96 Touch Real-Time PCR Detection System (Bio-Rad).	('TCEAL7', 'Gene', (385, 391))	('HEK-293T', 'CellLine', 'CVCL:0063', (231, 239))	('Rad', 'Gene', '6236', (506, 509))	('F170I', 'Mutation', 'rs535470039', (281, 286))	('Rad', 'Gene', '6236', (376, 379))	('Rad', 'Gene', '6236', (176, 179))	('Rad', 'Gene', (506, 509))	('Rad', 'Gene', (376, 379))	('Rad', 'Gene', (176, 179))	('TCEAL7', 'Gene', '56849', (41, 47))	('F170I-mutant', 'Var', (281, 293))	('TCEAL7', 'Gene', '56849', (385, 391))	('BAP1', 'Gene', '8314', (273, 277))	('TCEAL7', 'Gene', (41, 47))	('BAP1', 'Gene', (273, 277))
189407	26081045	Real-time PCR was performed in triplicate for independent duplicated transfections with either wild-type (Wt) or F170I-mutant BAP1 and the results were analyzed using statistical procedures (SPSS ver.22.0; IBM, Armonk, NY, USA).	('F170I', 'Mutation', 'rs535470039', (113, 118))	('F170I-mutant', 'Var', (113, 125))	('BAP1', 'Gene', '8314', (126, 130))	('BAP1', 'Gene', (126, 130))
189408	26081045	Among 49 patients with ESCC examined by direct sequencing, we identified a somatic non-synonymous mutation of BAP1 in an ESCC tumor.	('patients', 'Species', '9606', (9, 17))	('BAP1', 'Gene', '8314', (110, 114))	('BAP1', 'Gene', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('non-synonymous mutation', 'Var', (83, 106))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ESCC', 'Disease', (121, 125))	('tumor', 'Disease', (126, 131))
189409	26081045	This mutation caused an amino acid substitution from phenylalanine to isoleucine at codon 170 (Fig.1a).	('caused', 'Reg', (14, 20))	('phenylalanine to isoleucine at codon 170', 'Mutation', 'rs535470039', (53, 93))	('amino acid substitution', 'Var', (24, 47))
189414	26081045	As this codon is located in the UCH domain, and phenylalanine at codon 170 is highly conserved across species (Fig.1c,d), we evaluated its effect on the deubiquitinase activity of BAP1.	('deubiquitinase activity', 'MPA', (153, 176))	('phenylalanine', 'Chemical', 'MESH:D010649', (48, 61))	('BAP1', 'Gene', '8314', (180, 184))	('BAP1', 'Gene', (180, 184))	('phenylalanine', 'Var', (48, 61))
189416	26081045	Using an in vivo ubiquitination assay to measure the level of ubiquitinated host cell factor C1 (HCF1), quantified by densitometer as described above in independent triplicated experiments, we showed that deubiquitinase activity was significantly depleted in the F170I mutant compared with wild-type BAP1 (P < 0.05).	('F170I', 'Mutation', 'rs535470039', (263, 268))	('BAP1', 'Gene', '8314', (300, 304))	('host cell factor C1', 'Gene', (76, 95))	('deubiquitinase activity', 'MPA', (205, 228))	('HCF1', 'Gene', '3054', (97, 101))	('depleted', 'NegReg', (247, 255))	('F170I', 'Var', (263, 268))	('HCF1', 'Gene', (97, 101))	('BAP1', 'Gene', (300, 304))	('host cell factor C1', 'Gene', '3054', (76, 95))
189420	26081045	Results obtained from triplicated experiments show that the level of ubiquitinated BAP1 significantly increased by F170I mutation (P < 0.01).	('F170I mutation', 'Var', (115, 129))	('BAP1', 'Gene', (83, 87))	('level of ubiquitinated', 'MPA', (60, 82))	('increased', 'PosReg', (102, 111))	('F170I', 'Mutation', 'rs535470039', (115, 120))	('BAP1', 'Gene', '8314', (83, 87))
189421	26081045	Auto-deubiquitinated BAP1 likely localizes within the nucleus because of the deubiquitinated nuclear localization signals within this protein.	('BAP1', 'Gene', (21, 25))	('deubiquitinated nuclear localization signals', 'MPA', (77, 121))	('Auto-deubiquitinated', 'Var', (0, 20))	('BAP1', 'Gene', '8314', (21, 25))
189422	26081045	Hence, we investigated the subcellular localization of wild-type BAP1 and the F170I mutant.	('F170I', 'Var', (78, 83))	('BAP1', 'Gene', '8314', (65, 69))	('F170I', 'Mutation', 'rs535470039', (78, 83))	('BAP1', 'Gene', (65, 69))
189424	26081045	We showed that F170I mutant preferentially localized within the cytoplasm, whereas wild-type BAP1 mostly localized within the nucleus (Fig.3).	('F170I', 'Mutation', 'rs535470039', (15, 20))	('BAP1', 'Gene', '8314', (93, 97))	('BAP1', 'Gene', (93, 97))	('F170I', 'Var', (15, 20))
189427	26081045	As shown in Figure4(a), expression profiles were dramatically different between wild-type BAP1 and the F170I mutant; clustering analysis revealed that expression profiles could be classified into wild-type and the F170I mutant reproducibly in two independent transfections.	('BAP1', 'Gene', '8314', (90, 94))	('F170I', 'Var', (214, 219))	('F170I', 'Mutation', 'rs535470039', (103, 108))	('BAP1', 'Gene', (90, 94))	('F170I', 'Mutation', 'rs535470039', (214, 219))
189428	26081045	In general, this reproducibly contributed to the differentiation between wild-type BAP1 and the F170I mutant.	('F170I', 'Var', (96, 101))	('BAP1', 'Gene', (83, 87))	('F170I', 'Mutation', 'rs535470039', (96, 101))	('contributed', 'Reg', (30, 41))	('BAP1', 'Gene', '8314', (83, 87))
189429	26081045	Each result indicates that the expression of genes involved in oncogenic pathways was drastically altered by the expression of the F170I mutant compared with that of wild-type BAP1.	('F170I', 'Var', (131, 136))	('BAP1', 'Gene', '8314', (176, 180))	('expression of', 'MPA', (31, 44))	('BAP1', 'Gene', (176, 180))	('F170I', 'Mutation', 'rs535470039', (131, 136))	('altered', 'Reg', (98, 105))
189438	26081045	This view may be supported by our other results; these figures for BAP1-nuclear negative tumors and BAP1 deletion are comparable and BAP1-nuclear negative tumors likely lost allele at BAP1 locus more than BAP1-nuclear positive tumors.	('tumors', 'Disease', (89, 95))	('BAP1', 'Gene', '8314', (205, 209))	('BAP1', 'Gene', (184, 188))	('BAP1', 'Gene', '8314', (133, 137))	('BAP1', 'Gene', '8314', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('BAP1', 'Gene', (205, 209))	('BAP1', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('BAP1', 'Gene', (100, 104))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', (155, 161))	('BAP1', 'Gene', '8314', (67, 71))	('allele', 'MPA', (174, 180))	('deletion', 'Var', (105, 113))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('BAP1', 'Gene', '8314', (184, 188))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('lost', 'NegReg', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('BAP1', 'Gene', (67, 71))
189440	26081045	Several genes that are mutated in ESCC have been described, including TP53 CDKN2A NOTCH1 and NFE2L2.	('TP53', 'Gene', '7157', (70, 74))	('CDKN2A', 'Gene', (75, 81))	('NOTCH1', 'Gene', '4851', (82, 88))	('CDKN2A', 'Gene', '1029', (75, 81))	('TP53', 'Gene', (70, 74))	('mutated', 'Var', (23, 30))	('NOTCH1', 'Gene', (82, 88))	('ESCC', 'Gene', (34, 38))	('NFE2L2', 'Gene', '4780', (93, 99))	('NFE2L2', 'Gene', (93, 99))
189443	26081045	Consistently, in the current study, we observed BAP1 mutation in only 1 case of 49 examined.	('BAP1', 'Gene', '8314', (48, 52))	('BAP1', 'Gene', (48, 52))	('mutation', 'Var', (53, 61))
189446	26081045	Besides, gene expression profiles in oncogenic pathways were markedly different between wild-type BAP1 and the F170I mutant (Fig.4, Table2).	('BAP1', 'Gene', (98, 102))	('gene expression profiles', 'MPA', (9, 33))	('oncogenic pathways', 'Pathway', (37, 55))	('F170I', 'Var', (111, 116))	('different', 'Reg', (70, 79))	('BAP1', 'Gene', '8314', (98, 102))	('F170I', 'Mutation', 'rs535470039', (111, 116))
189447	26081045	Furthermore, although F170I substitution has not been reported previously, F170V and F170L substitutions were reported in renal cell carcinomas in the COSMIC database and by Pena-Llops et al.	('F170V', 'Var', (75, 80))	('F170I', 'Mutation', 'rs535470039', (22, 27))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (122, 143))	('F170L', 'Mutation', 'p.F170L', (85, 90))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (122, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('F170I', 'Var', (22, 27))	('F170L', 'Var', (85, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (122, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('renal cell carcinomas', 'Disease', (122, 143))	('F170V', 'Mutation', 'rs1348195897', (75, 80))
189456	26081045	Alternatively, UBE2O, which has been reported to suppress its function by recruiting BAP1 to the cytosol, is mutated in ESCC and in other esophageal carcinomas (see COSMIC data base).	('UBE2O', 'Gene', (15, 20))	('BAP1', 'Gene', (85, 89))	('UBE2O', 'Gene', '63893', (15, 20))	('recruiting', 'PosReg', (74, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('esophageal carcinomas', 'Disease', (138, 159))	('ESCC', 'Disease', (120, 124))	('mutated', 'Var', (109, 116))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (138, 159))	('BAP1', 'Gene', '8314', (85, 89))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (138, 159))
189457	26081045	It is possible that altered UBE2O behaves as an oncoprotein like activated EGFR or RAS family proteins.	('altered', 'Var', (20, 27))	('UBE2O', 'Gene', (28, 33))	('UBE2O', 'Gene', '63893', (28, 33))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))
189458	26081045	Therefore, BAP1 may be functionally inactivated in these cases with alterations of UBE2O or other genes involved in BAP1 ubiquitination, specifically in nuclear BAP1-negative but cytosolic positive tumors.	('BAP1', 'Gene', (116, 120))	('BAP1', 'Gene', (161, 165))	('BAP1', 'Gene', '8314', (11, 15))	('BAP1', 'Gene', '8314', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('BAP1', 'Gene', (11, 15))	('UBE2O', 'Gene', '63893', (83, 88))	('inactivated', 'NegReg', (36, 47))	('UBE2O', 'Gene', (83, 88))	('tumors', 'Disease', (198, 204))	('alterations', 'Var', (68, 79))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('BAP1', 'Gene', '8314', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
189459	26081045	The detailed mechanism of carcinogenesis by BAP1-negative tumor has not been disclosed so far, but we could show one candidate in downstream of BAP1 by the current study: wild-type BAP1 significantly induces TCEAL7 expression more than F170I mutant BAP1 (Fig.6).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('F170I', 'Mutation', 'rs535470039', (236, 241))	('BAP1', 'Gene', (181, 185))	('TCEAL7', 'Gene', (208, 214))	('BAP1', 'Gene', (144, 148))	('BAP1', 'Gene', '8314', (144, 148))	('BAP1', 'Gene', '8314', (249, 253))	('induces', 'PosReg', (200, 207))	('BAP1', 'Gene', '8314', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('TCEAL7', 'Gene', '56849', (208, 214))	('F170I', 'Var', (236, 241))	('BAP1', 'Gene', '8314', (181, 185))	('BAP1', 'Gene', (249, 253))	('BAP1', 'Gene', (44, 48))	('expression', 'MPA', (215, 225))
189461	26081045	Thus, BAP1 may play a key role in at least a part of esophageal carcinogenesis, not only by somatic mutation or gene deletion, but also by functional inactivation, such as by depleted deubiquitination or by cytoplasmic sequestration.	('esophageal carcinogenesis', 'Disease', (53, 78))	('inactivation', 'NegReg', (150, 162))	('BAP1', 'Gene', (6, 10))	('depleted deubiquitination', 'MPA', (175, 200))	('BAP1', 'Gene', '8314', (6, 10))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (53, 78))	('gene deletion', 'Var', (112, 125))
189516	25117963	In Cameroon, the rate of grade 2 or higher hepatotoxicity experienced by patients receiving nevirapine-based therapy was 16%, and in Malawi, severe hepatotoxicity (defined as greater than 5 times the upper limit of normal) occurred in 9% of patients but did not result in discontinuation of therapy.	('hepatotoxicity', 'Disease', (148, 162))	('nevirapine', 'Chemical', 'MESH:D019829', (92, 102))	('hepatotoxicity', 'Disease', (43, 57))	('nevirapine-based', 'Var', (92, 108))	('patients', 'Species', '9606', (73, 81))	('hepatotoxicity', 'Disease', 'MESH:D056486', (148, 162))	('patients', 'Species', '9606', (241, 249))	('hepatotoxicity', 'Disease', 'MESH:D056486', (43, 57))
189547	25117963	Interventions to reduce the impact of alcohol and substance abuse could have a dramatic impact on liver disease, and where possible, this effect should be incorporated into studies of interventions to reduce alcohol-related harm.	('substance abuse', 'Disease', (50, 65))	('substance abuse', 'Disease', 'MESH:D019966', (50, 65))	('alcohol', 'Chemical', 'MESH:D000438', (208, 215))	('liver disease', 'Phenotype', 'HP:0001392', (98, 111))	('liver disease', 'Disease', (98, 111))	('alcohol', 'Chemical', 'MESH:D000438', (38, 45))	('liver disease', 'Disease', 'MESH:D008107', (98, 111))	('Interventions', 'Var', (0, 13))
189565	25117963	The introduction of therapeutic diets including F-75, F-100, and ready-to-use therapeutic foods (RUTF) has improved the rehabilitation process and reduced hospital stays of children with SAM who are not infected with HIV.	('rehabilitation process', 'CPA', (120, 142))	('F-100', 'Var', (54, 59))	('HIV', 'Species', '12721', (217, 220))	('improved', 'PosReg', (107, 115))	('children', 'Species', '9606', (173, 181))	('hospital stays', 'CPA', (155, 169))	('F-75', 'Var', (48, 52))	('reduced', 'NegReg', (147, 154))
189613	32071920	Flow cytometry analysis (FACS) and wound healing experiments on germacrone treated ESCC cells showed that germacrone could induce apoptosis and inhibit the migration of ESCC cells in a dose-dependent manner.	('ESCC', 'Disease', (169, 173))	('induce', 'PosReg', (123, 129))	('ESCC', 'Disease', 'MESH:C562729', (83, 87))	('apoptosis', 'CPA', (130, 139))	('migration', 'CPA', (156, 165))	('germacrone', 'Chemical', 'MESH:C048393', (64, 74))	('ESCC', 'Disease', 'MESH:C562729', (169, 173))	('inhibit', 'NegReg', (144, 151))	('ESCC', 'Disease', (83, 87))	('germacrone', 'Var', (106, 116))	('germacrone', 'Chemical', 'MESH:C048393', (106, 116))
189614	32071920	In the study on the mechanism of action of germacrone in antiesophageal cancer, we found that germacrone increased the ratio of Bax/Bcl-2 in the cytoplasm of ESCC, resulting in the activation of Caspase-9 and Caspase-3 and decreased the expression of Grp78, thereby reducing the inhibition of Caspase-12 and Caspase-7.	('Caspase-3', 'Gene', (209, 218))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('inhibition', 'MPA', (279, 289))	('Caspase-7', 'Gene', '840', (308, 317))	('esophageal cancer', 'Disease', (61, 78))	('Grp78', 'Gene', '3309', (251, 256))	('Bax', 'Gene', (128, 131))	('decreased', 'NegReg', (223, 232))	('ratio', 'MPA', (119, 124))	('Bax', 'Gene', '581', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Bcl-2', 'Gene', (132, 137))	('Caspase-9', 'Gene', '842', (195, 204))	('ESCC', 'Disease', 'MESH:C562729', (158, 162))	('germacrone', 'Var', (94, 104))	('Caspase-12', 'Enzyme', (293, 303))	('Caspase-3', 'Gene', '836', (209, 218))	('Caspase-9', 'Gene', (195, 204))	('germacrone', 'Chemical', 'MESH:C048393', (94, 104))	('expression', 'MPA', (237, 247))	('germacrone increased', 'Phenotype', 'HP:0012238', (94, 114))	('Caspase-7', 'Gene', (308, 317))	('Bcl-2', 'Gene', '596', (132, 137))	('activation', 'PosReg', (181, 191))	('reducing', 'NegReg', (266, 274))	('increased', 'PosReg', (105, 114))	('Grp78', 'Gene', (251, 256))	('germacrone', 'Chemical', 'MESH:C048393', (43, 53))	('ESCC', 'Disease', (158, 162))
189640	32071920	Wound healing and FACS assays revealed that germacrone inhibited ESCC migration and induced ESCC apoptosis.	('induced', 'Reg', (84, 91))	('ESCC', 'Disease', (92, 96))	('ESCC', 'Disease', 'MESH:C562729', (65, 69))	('germacrone', 'Var', (44, 54))	('ESCC', 'Disease', (65, 69))	('germacrone', 'Chemical', 'MESH:C048393', (44, 54))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))	('inhibited', 'NegReg', (55, 64))
189648	32071920	Caspase-7 (GTX102337), Caspase-12 (GTX132298), and Grp-78 (GTX113340) were purchased from GeneTex (Texas, USA).	('GTX132298', 'Chemical', 'MESH:C038094', (35, 44))	('GTX102337', 'Chemical', 'MESH:C038094', (11, 20))	('GTX102337', 'Var', (11, 20))	('Grp-78', 'Gene', (51, 57))	('Grp-78', 'Gene', '3309', (51, 57))	('GTX113340', 'Chemical', 'MESH:C038094', (59, 68))	('Caspase-7', 'Gene', (0, 9))	('Caspase-7', 'Gene', '840', (0, 9))
189695	32071920	The results were consistent with the above conclusion that germacrone could significantly induce ESCC (Eca109 and EC9706) cell apoptosis.	('germacrone', 'Var', (59, 69))	('germacrone', 'Chemical', 'MESH:C048393', (59, 69))	('ESCC', 'Disease', 'MESH:C562729', (97, 101))	('induce', 'PosReg', (90, 96))	('EC9706', 'CellLine', 'CVCL:E307', (114, 120))	('ESCC', 'Disease', (97, 101))
189700	32071920	All the above results indicated that germacrone could further inhibit ESCC cell proliferation by inducing ESCC cell apoptosis.	('ESCC', 'Disease', 'MESH:C562729', (106, 110))	('germacrone', 'Var', (37, 47))	('ESCC', 'Disease', (106, 110))	('germacrone', 'Chemical', 'MESH:C048393', (37, 47))	('ESCC', 'Disease', 'MESH:C562729', (70, 74))	('inducing', 'Reg', (97, 105))	('inhibit', 'NegReg', (62, 69))	('ESCC', 'Disease', (70, 74))
189707	32071920	Therefore, we used western blot to detect the expression of five key proteins (Bcl-2, Bax, cleaved Caspase-9, cleaved PARP, and cleaved Caspase-3) in ESCC cells after incubation with germacrone.	('Caspase-3', 'Gene', (136, 145))	('Caspase-3', 'Gene', '836', (136, 145))	('Bax', 'Gene', '581', (86, 89))	('Caspase-9', 'Gene', (99, 108))	('germacrone', 'Chemical', 'MESH:C048393', (183, 193))	('cleaved', 'Var', (128, 135))	('PARP', 'Gene', '142', (118, 122))	('cleaved', 'Var', (91, 98))	('ESCC', 'Disease', 'MESH:C562729', (150, 154))	('ESCC', 'Disease', (150, 154))	('Bax', 'Gene', (86, 89))	('Bcl-2', 'Gene', (79, 84))	('Caspase-9', 'Gene', '842', (99, 108))	('Bcl-2', 'Gene', '596', (79, 84))	('PARP', 'Gene', (118, 122))
189716	32071920	Therefore, combining all of the above findings, we conclude that germacrone induces apoptosis in ESCC cells via the intrinsic apoptotic signaling pathway.	('germacrone', 'Var', (65, 75))	('apoptosis', 'CPA', (84, 93))	('germacrone', 'Chemical', 'MESH:C048393', (65, 75))	('ESCC', 'Disease', 'MESH:C562729', (97, 101))	('ESCC', 'Disease', (97, 101))
189720	32071920	Previous studies have found that phosphorylated STAT3 active forms are primarily mediated by phosphorylation at Tyr705.	('STAT3', 'Gene', (48, 53))	('phosphorylation', 'Var', (93, 108))	('mediated by', 'Reg', (81, 92))	('STAT3', 'Gene', '6774', (48, 53))
189723	32071920	Therefore, these findings indicate that germacrone has the potential to inhibit STAT3 phosphorylation in ESCC cells.	('ESCC', 'Disease', (105, 109))	('STAT3', 'Gene', '6774', (80, 85))	('STAT3', 'Gene', (80, 85))	('germacrone', 'Var', (40, 50))	('germacrone', 'Chemical', 'MESH:C048393', (40, 50))	('inhibit', 'NegReg', (72, 79))	('ESCC', 'Disease', 'MESH:C562729', (105, 109))
189732	32071920	Defects in apoptosis mechanisms can destroy the delicate balance of the cell process and might eventually lead to cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Defects', 'Var', (0, 7))	('lead to', 'Reg', (106, 113))	('destroy', 'NegReg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('apoptosis', 'CPA', (11, 20))	('delicate balance of the cell process', 'MPA', (48, 84))	('cancer', 'Disease', (114, 120))
189733	32071920	Some cancers, including ESCC, are highly dependent on survival abnormalities in the apoptotic signaling pathway, but still retain some of the apoptotic mechanisms.	('apoptotic signaling pathway', 'Pathway', (84, 111))	('ESCC', 'Disease', 'MESH:C562729', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('ESCC', 'Disease', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('abnormalities', 'Var', (63, 76))
189774	30034241	The aberrant expression of ECRG4 is associated with hypermethylation in the promoter region and plays an important role in the malignancy of gastric cancer.	('plays', 'Reg', (96, 101))	('hypermethylation in the promoter region', 'MPA', (52, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('ECRG4', 'Gene', (27, 32))	('role', 'Reg', (115, 119))	('malignancy of gastric', 'Phenotype', 'HP:0006753', (127, 148))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('aberrant expression', 'Var', (4, 23))	('malignancy of gastric cancer', 'Disease', (127, 155))	('ECRG4', 'Gene', '84417', (27, 32))	('associated', 'Reg', (36, 46))	('malignancy of gastric cancer', 'Disease', 'MESH:D013274', (127, 155))
189775	30034241	Therefore, ECRG4 may be a potential biomarker for molecular diagnosis of gastric cancer, and the use of 5-Aza-dC to reverse the hypermethylation of ECRG4 may be a new approach to the treatment of gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (196, 210))	('hypermethylation', 'Var', (128, 144))	('ECRG4', 'Gene', '84417', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ECRG4', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('ECRG4', 'Gene', (148, 153))	('ECRG4', 'Gene', '84417', (11, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (196, 210))	('gastric cancer', 'Disease', (196, 210))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (104, 112))	('gastric cancer', 'Disease', (73, 87))
189835	30034241	These results indicated that the inhibition of ECRG4 expression could enhance the growth and invasion of GC cells.	('inhibition', 'Var', (33, 43))	('enhance', 'PosReg', (70, 77))	('ECRG4', 'Gene', '84417', (47, 52))	('ECRG4', 'Gene', (47, 52))
189836	30034241	To determine the effect of ECRG4 expression in altering the cell cycle in GC cells, BGC-823 cells were transfected with pcDNA3.1, pcDNA3.1-ECRG4, siRNA-control, or siRNA-ECRG4.	('BGC-823', 'CellLine', 'CVCL:3360', (84, 91))	('ECRG4', 'Gene', '84417', (139, 144))	('pcDNA3.1', 'Var', (120, 128))	('ECRG4', 'Gene', (27, 32))	('ECRG4', 'Gene', (170, 175))	('ECRG4', 'Gene', '84417', (27, 32))	('ECRG4', 'Gene', (139, 144))	('ECRG4', 'Gene', '84417', (170, 175))
189843	30034241	ECRG4 was hypermethylated in 66.2% (49/74) of the carcinoma tissues but only in 18.9% (14/74) of the paracarcinoma tissues.	('ECRG4', 'Gene', (0, 5))	('carcinoma', 'Disease', 'MESH:D002277', (50, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('carcinoma', 'Disease', 'MESH:D002277', (105, 114))	('ECRG4', 'Gene', '84417', (0, 5))	('carcinoma', 'Disease', (50, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('hypermethylated', 'Var', (10, 25))	('paracarcinoma tissues', 'Disease', 'MESH:D009380', (101, 122))	('carcinoma', 'Disease', (105, 114))	('paracarcinoma tissues', 'Disease', (101, 122))
189874	30034241	Although we did not find an association between ECRG4 methylation and clinicopathological characteristics of GC patients, Wang et al have reported that aberrant ECRG4 promoter methylation could be a predictor of GC pathological stage.	('ECRG4', 'Gene', (48, 53))	('ECRG4', 'Gene', '84417', (161, 166))	('predictor', 'Reg', (199, 208))	('patients', 'Species', '9606', (112, 120))	('ECRG4', 'Gene', '84417', (48, 53))	('aberrant', 'Var', (152, 160))	('promoter', 'MPA', (167, 175))	('ECRG4', 'Gene', (161, 166))
189877	30034241	Therefore, reversing the hypermethylation of ECRG4 with 5-Aza-dC might be a new approach for GC treatment.	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (56, 64))	('hypermethylation', 'Var', (25, 41))	('ECRG4', 'Gene', (45, 50))	('ECRG4', 'Gene', '84417', (45, 50))
189880	30034241	Therefore, we hypothesized that 5-Aza-dC may improve the curative effect of 5-FU to some extent, which would have important clinical significance.	('5-Aza-dC', 'Var', (32, 40))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (32, 40))	('improve', 'PosReg', (45, 52))	('5-FU', 'Chemical', 'MESH:D005472', (76, 80))	('curative effect', 'CPA', (57, 72))
189881	30034241	Our results suggested that ECRG4 is a novel TSG for GC, and DNA methylation of ECRG4 is a potential inducer of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('ECRG4', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('ECRG4', 'Gene', (27, 32))	('inducer', 'Reg', (100, 107))	('tumor', 'Disease', (111, 116))	('DNA', 'Var', (60, 63))	('ECRG4', 'Gene', '84417', (79, 84))	('ECRG4', 'Gene', '84417', (27, 32))
189882	30034241	Inhibition of ECRG4 expression may promote the growth and migration of GC cells.	('ECRG4', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('promote', 'PosReg', (35, 42))	('ECRG4', 'Gene', '84417', (14, 19))	('growth', 'CPA', (47, 53))
189883	30034241	Conversely, demethylation of ECRG4 with 5-Aza-dC could suppress the tumorigenesis of GC cells.	('tumor', 'Disease', (68, 73))	('demethylation', 'Var', (12, 25))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('ECRG4', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('suppress', 'NegReg', (55, 63))	('ECRG4', 'Gene', '84417', (29, 34))
190005	27561635	After this modification, the leakage rate was reduced to 7 % in the last 15 procedures.	('modification', 'Var', (11, 23))	('leakage', 'MPA', (29, 36))	('to 7', 'Species', '1214577', (54, 58))
190009	27561635	We have previously reported on our experience on MIG for advanced GC and CDH1 mutations.	('CDH1', 'Gene', (73, 77))	('GC', 'Phenotype', 'HP:0012126', (66, 68))	('CDH1', 'Gene', '999', (73, 77))	('mutations', 'Var', (78, 87))	('advanced GC', 'Disease', (57, 68))
190163	24244745	Cancer site and histology were defined by the International Classification of Diseases for Oncology (ICD-O) (3rd edition) codes: esophagus (C15.0-C15.9) and adenocarcinoma (8140-8573).	('C15.0-C15.9', 'Var', (140, 151))	('Oncology', 'Phenotype', 'HP:0002664', (91, 99))	('adenocarcinoma', 'Disease', (157, 171))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('adenocarcinoma', 'Disease', 'MESH:D000230', (157, 171))	('esophagus', 'Disease', (129, 138))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('8140-8573', 'Var', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
190221	23365732	Although incidence of nodal metastasis in pT1 tumors was significantly higher in the type Ge tumor group than the type G tumor groups, there was no significant difference in pT2, pT3, and pT4 tumors between two tumor groups.	('higher', 'PosReg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('pT3', 'Gene', '7694', (179, 182))	('pT1', 'Gene', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('pT3', 'Gene', (179, 182))	('nodal metastasis', 'CPA', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('type Ge', 'Var', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
190254	22546272	Endothelial cell tumors in VDR knockout mice grow larger than in wild type mice.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mice', 'Species', '10090', (75, 79))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('VDR', 'Gene', (27, 30))	('knockout', 'Var', (31, 39))	('mice', 'Species', '10090', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
190256	22546272	Additional clinical support is provided by the correlation between a single nucleotide polymorphism in the VDR gene and the risk for colon cancer in human subjects.	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('single nucleotide polymorphism', 'Var', (69, 99))	('colon cancer', 'Disease', (133, 145))	('human', 'Species', '9606', (149, 154))	('VDR', 'Gene', (107, 110))
190286	22546272	Although the primary function of 1,25(OH)2D3 is to regulate calcium absorption and control bone mineralization, upon binding to its cognate VDR, 1,25(OH)2D3 induces cell cycle arrest, differentiation, and apoptosis in normal and transformed cells as well as alters the MAP kinase and Wnt/beta-catenin signaling pathways involved in carcinogenesis.	('apoptosis', 'CPA', (205, 214))	('carcinogenesis', 'Disease', 'MESH:D063646', (332, 346))	('bone mineralization', 'CPA', (91, 110))	('cell cycle arrest', 'CPA', (165, 182))	('induces', 'Reg', (157, 164))	('calcium', 'Chemical', 'MESH:D002118', (60, 67))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (33, 44))	('binding', 'Interaction', (117, 124))	('carcinogenesis', 'Disease', (332, 346))	('alters', 'Reg', (258, 264))	('beta-catenin', 'Gene', (288, 300))	('calcium absorption', 'CPA', (60, 78))	('differentiation', 'CPA', (184, 199))	('1,25(OH)2D3', 'Var', (145, 156))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (165, 182))	('beta-catenin', 'Gene', '1499', (288, 300))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (145, 156))
190287	22546272	High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression, and immunohistochemistry of basal cell carcinoma indicates an increase in VDR staining intensity compared to normal cells.	('cancer', 'Disease', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('prostate cancer', 'Disease', 'MESH:D011471', (137, 152))	('prostate cancer', 'Phenotype', 'HP:0012125', (137, 152))	('High', 'Var', (0, 4))	('increase', 'PosReg', (228, 236))	('VDR', 'Protein', (5, 8))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (194, 214))	('prostate cancer', 'Disease', (137, 152))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('prostate tumors', 'Disease', (23, 38))	('VDR staining intensity', 'MPA', (240, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (194, 214))	('prostate tumors', 'Disease', 'MESH:D011471', (23, 38))	('basal cell carcinoma', 'Disease', (194, 214))	('reduced', 'NegReg', (60, 67))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('vitamin D', 'Chemical', 'MESH:D014807', (116, 125))	('cancer', 'Disease', (83, 89))
190322	16048655	Furthermore, a PPK sufferer has an increased risk of developing ESCC even if there is no family history of esophageal cancer.	('ESCC', 'Disease', (64, 68))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('PPK', 'Var', (15, 18))	('PPK', 'Phenotype', 'HP:0000982', (15, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))
190389	33552962	MPC risk was also associated with betel nut chewing (OR[95% CI]=1.63, 1.14-2.32], p=0.008), the A allele of ALDH2:rs671 (p=0.074 and 0.030 for GA and AA, respectively), the CC genotype in CISH:rs2239751 (OR[95% CI]=1.99 [1.2-3.32], p=0.008), and the G allele of ERCC5:rs17655 (p=0.001 and 0.090 for GC and CC, respectively).	('GA', 'Chemical', 'MESH:D005708', (143, 145))	('ERCC5', 'Gene', '2073', (262, 267))	('CISH', 'Gene', '1154', (188, 192))	('rs671', 'Var', (114, 119))	('betel nut chewing', 'Disease', (34, 51))	('CISH', 'Gene', (188, 192))	('rs17655', 'Mutation', 'rs17655', (268, 275))	('rs2239751', 'Mutation', 'rs2239751', (193, 202))	('betel', 'Chemical', '-', (34, 39))	('ALDH2', 'Gene', '217', (108, 113))	('MPC', 'Disease', (0, 3))	('ALDH2', 'Gene', (108, 113))	('rs671', 'Mutation', 'rs671', (114, 119))	('MPC', 'Chemical', '-', (0, 3))	('ERCC5', 'Gene', (262, 267))
190390	33552962	ADH1B:rs1229984 also correlated with MPC risk (p=0.117).	('rs1229984', 'Mutation', 'rs1229984', (6, 15))	('rs1229984', 'Var', (6, 15))	('MPC', 'Disease', (37, 40))	('ADH1B', 'Gene', (0, 5))	('MPC', 'Chemical', '-', (37, 40))	('ADH1B', 'Gene', '125', (0, 5))	('correlated', 'Reg', (21, 31))
190392	33552962	In conclusion, hereditary variations in ALDH2, CISH, ERCC5, and ADH1B have great potential in predicting the incidence of MPC in EC patients.	('predicting', 'Reg', (94, 104))	('ALDH2', 'Gene', (40, 45))	('CISH', 'Gene', '1154', (47, 51))	('ERCC5', 'Gene', (53, 58))	('ADH1B', 'Gene', (64, 69))	('ERCC5', 'Gene', '2073', (53, 58))	('MPC', 'Disease', (122, 125))	('ADH1B', 'Gene', '125', (64, 69))	('MPC', 'Chemical', '-', (122, 125))	('CISH', 'Gene', (47, 51))	('ALDH2', 'Gene', '217', (40, 45))	('patients', 'Species', '9606', (132, 140))	('variations', 'Var', (26, 36))
190404	33552962	Here, we investigated the association between candidate single-nucleotide polymorphisms (SNPs) and MPC in EC patients.	('single-nucleotide polymorphisms', 'Var', (56, 87))	('patients', 'Species', '9606', (109, 117))	('MPC', 'Disease', (99, 102))	('investigated', 'Reg', (9, 21))	('MPC', 'Chemical', '-', (99, 102))
190408	33552962	The ADH1B SNPs rs1229984 and ALDH2:rs671(G>A, Glu487Lys) are reportedly correlated with the risk of alcohol-related cancers, including hypopharyngeal cancer and EC.	('ALDH2', 'Gene', (29, 34))	('Glu487Lys', 'Var', (46, 55))	('ADH1B', 'Gene', (4, 9))	('hypopharyngeal cancer', 'Disease', (135, 156))	('rs1229984', 'Mutation', 'rs1229984', (15, 24))	('Glu487Lys', 'SUBSTITUTION', 'None', (46, 55))	('correlated with', 'Reg', (72, 87))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('rs671', 'Mutation', 'rs671', (35, 40))	('ADH1B', 'Gene', '125', (4, 9))	('ALDH2', 'Gene', '217', (29, 34))	('rs1229984', 'Var', (15, 24))	('cancers', 'Disease', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('alcohol', 'Chemical', 'MESH:D000438', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (135, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
190409	33552962	Additionally, COX2:rs20417 and CYP1A1:rs1048943 are known to correlate with the risk of both oral cancer and EC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs20417', 'Var', (19, 26))	('CYP1A1', 'Gene', '1543', (31, 37))	('oral cancer', 'Disease', 'MESH:D009369', (93, 104))	('rs1048943', 'Mutation', 'rs1048943', (38, 47))	('COX2', 'Gene', (14, 18))	('rs20417', 'Mutation', 'rs20417', (19, 26))	('COX2', 'Gene', '4513', (14, 18))	('oral cancer', 'Disease', (93, 104))	('CYP1A1', 'Gene', (31, 37))
190410	33552962	SNPs involved in nucleotide excision repair, such as ERCC5:rs17655, have also been found to be associated with the incidence of laryngeal cancer and EC.	('cancer', 'Disease', (138, 144))	('rs17655', 'Var', (59, 66))	('rs17655', 'Mutation', 'rs17655', (59, 66))	('ERCC5', 'Gene', (53, 58))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (128, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('ERCC5', 'Gene', '2073', (53, 58))	('associated with', 'Reg', (95, 110))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
190411	33552962	Finally, GSTP1 rs1695 is also an SNP for the risk of EC and other cancers, such as breast cancer.	('rs1695', 'Var', (15, 21))	('GSTP1', 'Gene', '2950', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('rs1695', 'Mutation', 'rs1695', (15, 21))	('breast cancer', 'Disease', (83, 96))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('GSTP1', 'Gene', (9, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
190439	33552962	Genotyping for rs671, rs243324, and rs2239751 was complete.	('rs2239751', 'Mutation', 'rs2239751', (36, 45))	('rs243324', 'Var', (22, 30))	('rs2239751', 'Var', (36, 45))	('rs243324', 'Mutation', 'rs243324', (22, 30))	('rs671', 'Var', (15, 20))	('rs671', 'Mutation', 'rs671', (15, 20))
190440	33552962	There were six, five, three, four, four, and two patients with unconfirmed data for rs1229984, rs20417, rs1048943, ERCC5:rs17655, GSTP1:rs1695, and SOCS1:rs33932899, respectively.	('SOCS1', 'Gene', '8651', (148, 153))	('GSTP1', 'Gene', (130, 135))	('rs20417', 'Var', (95, 102))	('ERCC5', 'Gene', '2073', (115, 120))	('SOCS1', 'Gene', (148, 153))	('rs17655', 'Mutation', 'rs17655', (121, 128))	('rs1695', 'Mutation', 'rs1695', (136, 142))	('rs33932899', 'Mutation', 'rs33932899', (154, 164))	('rs20417', 'Mutation', 'rs20417', (95, 102))	('GSTP1', 'Gene', '2950', (130, 135))	('rs1229984', 'Mutation', 'rs1229984', (84, 93))	('rs1048943', 'Var', (104, 113))	('rs1048943', 'Mutation', 'rs1048943', (104, 113))	('patients', 'Species', '9606', (49, 57))	('rs1229984', 'Var', (84, 93))	('ERCC5', 'Gene', (115, 120))
190459	33552962	We preliminarily analyzed the association between esophageal cancer MPC and 58 single nucleotide polymorphisms (SNPs) that are related to carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('single nucleotide polymorphisms', 'Var', (79, 110))	('cancer', 'Disease', (61, 67))	('MPC', 'Chemical', '-', (68, 71))	('carcinogenesis', 'Disease', 'MESH:D063646', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('carcinogenesis', 'Disease', (138, 152))	('association', 'Interaction', (30, 41))
190461	33552962	The preliminary results revealed that three SNPs of the suppressor of cytokine signaling (SOCS) family of genes, including CISH:rs2239751, SOCS1:rs33932899, and SOCS1:rs243324, showed a tendency to correlate with increased MPC risk in EC.	('rs33932899', 'Mutation', 'rs33932899', (145, 155))	('CISH', 'Gene', (123, 127))	('SOCS', 'Gene', '1154', (139, 143))	('rs2239751', 'Var', (128, 137))	('SOCS', 'Gene', (139, 143))	('rs243324', 'Var', (167, 175))	('MPC', 'Chemical', '-', (223, 226))	('SOCS', 'Gene', '1154', (161, 165))	('SOCS', 'Gene', (161, 165))	('SOCS1', 'Gene', (139, 144))	('SOCS', 'Gene', '1154', (90, 94))	('SOCS', 'Gene', (90, 94))	('SOCS1', 'Gene', (161, 166))	('CISH', 'Gene', '1154', (123, 127))	('rs2239751', 'Mutation', 'rs2239751', (128, 137))	('SOCS1', 'Gene', '8651', (139, 144))	('SOCS1', 'Gene', '8651', (161, 166))	('rs243324', 'Mutation', 'rs243324', (167, 175))	('MPC', 'Disease', (223, 226))
190465	33552962	In ADH1B:rs1229984, the homologous variant CC was significantly more prevalent in the EC patients than in the normal Taiwanese population; by contrast, TT was significantly less common (23.5% vs. 7.4% for CC; 39.1% vs. 52.2% for TT, p<0.001,  Table 5 ).	('rs1229984', 'Mutation', 'rs1229984', (9, 18))	('patients', 'Species', '9606', (89, 97))	('rs1229984', 'Var', (9, 18))	('ADH1B', 'Gene', (3, 8))	('ADH1B', 'Gene', '125', (3, 8))	('prevalent', 'Reg', (69, 78))
190473	33552962	The heterozygous genotype GC of ERCC5:rs17655 also correlated with increased risk of MPC (p=0.005), HNC (p=0.038), and gastrointestinal cancer (p=0.048).	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (119, 142))	('HNC', 'Disease', (100, 103))	('rs17655', 'Var', (38, 45))	('rs17655', 'Mutation', 'rs17655', (38, 45))	('ERCC5', 'Gene', (32, 37))	('MPC', 'Disease', (85, 88))	('gastrointestinal cancer', 'Disease', (119, 142))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (119, 142))	('ERCC5', 'Gene', '2073', (32, 37))	('MPC', 'Chemical', '-', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
190474	33552962	Moreover, CISH:rs2239751 was found to be significantly correlated with MPC in EC patients (p=0.033), with more than 29% of CC carriers also developing MPC.	('correlated', 'Reg', (55, 65))	('CISH', 'Gene', (10, 14))	('MPC', 'Disease', (71, 74))	('MPC', 'Chemical', '-', (71, 74))	('patients', 'Species', '9606', (81, 89))	('CISH', 'Gene', '1154', (10, 14))	('MPC', 'Chemical', '-', (151, 154))	('rs2239751', 'Mutation', 'rs2239751', (15, 24))	('MPC', 'Disease', (151, 154))	('developing', 'PosReg', (140, 150))	('rs2239751', 'Var', (15, 24))
190476	33552962	ADH1B:rs1229984 only displayed a borderline association with the risk of gastrointestinal cancer (p=0.085).	('rs1229984', 'Mutation', 'rs1229984', (6, 15))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (73, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs1229984', 'Var', (6, 15))	('ADH1B', 'Gene', (0, 5))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (73, 96))	('ADH1B', 'Gene', '125', (0, 5))	('gastrointestinal cancer', 'Disease', (73, 96))
190477	33552962	In multivariate logistic analysis that adjusted for other potential variables, CISH:rs2239751_CC had strong significant correlation with increased risk of MPC and thoracic cancer (OR[95% CI]=1.99 [1.20-3.32], p=0.008 for MPC; OR[95% CI]=5.40 [1.83-15.91], p=0.002 for thoracic cancer,  Table 8 ).	('MPC', 'Chemical', '-', (155, 158))	('CISH', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('MPC', 'Disease', (221, 224))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('MPC', 'Chemical', '-', (221, 224))	('rs2239751', 'Mutation', 'rs2239751', (84, 93))	('CISH', 'Gene', '1154', (79, 83))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('MPC', 'Disease', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('rs2239751_CC', 'Var', (84, 96))
190478	33552962	Patients carrying the AA variant of ALDH2:rs671 had a 3.61-fold increased risk for MPC compared to wildtype GG carriers (OR[95% CI]=3.61[1.13-11.56], p=0.030,  Table 8 ), whereas the AG genotype was significantly correlated with an increased HNC risk (OR[95% CI]=1.82 [1.08-3.07], p=0.030).	('MPC', 'Chemical', '-', (83, 86))	('MPC', 'Disease', (83, 86))	('rs671', 'Var', (42, 47))	('ALDH2', 'Gene', (36, 41))	('rs671', 'Mutation', 'rs671', (42, 47))	('HNC', 'Disease', (242, 245))	('Patients', 'Species', '9606', (0, 8))	('ALDH2', 'Gene', '217', (36, 41))
190480	33552962	Furthermore, ERCC5:rs17655_GC was correlated with a significantly greater risk of MPC and HNC than with CC (OR[95% CI]=2.15 [1.36-3.40], p=0.001 for MPC; OR[95% CI]=2.07 [1.21-3.55], p=0.008 for HNC,  Table 8 ).	('MPC', 'Chemical', '-', (149, 152))	('ERCC5', 'Gene', '2073', (13, 18))	('rs17655_GC', 'Var', (19, 29))	('HNC', 'Disease', (90, 93))	('MPC', 'Chemical', '-', (82, 85))	('MPC', 'Disease', (82, 85))	('ERCC5', 'Gene', (13, 18))	('rs17655', 'Mutation', 'rs17655', (19, 26))
190481	33552962	Moreover, ERCC5:rs17655_GC was also significantly correlated with the risk of metachronous MPC before or after EC (p=0.011 and p=0.022, respectively,  Table 9 ).	('ERCC5', 'Gene', '2073', (10, 15))	('correlated', 'Reg', (50, 60))	('metachronous MPC', 'Disease', (78, 94))	('rs17655', 'Mutation', 'rs17655', (16, 23))	('metachronous MPC', 'Disease', 'MESH:D016609', (78, 94))	('ERCC5', 'Gene', (10, 15))	('rs17655_GC', 'Var', (16, 26))
190482	33552962	Finally, ADH1B:rs1229984_CC was associated with MPC and HNC (p=0.117 and p=0.160, respectively).	('ADH1B', 'Gene', '125', (9, 14))	('MPC', 'Chemical', '-', (48, 51))	('HNC', 'Disease', (56, 59))	('rs1229984', 'Mutation', 'rs1229984', (15, 24))	('rs1229984_CC', 'Var', (15, 27))	('associated', 'Reg', (32, 42))	('ADH1B', 'Gene', (9, 14))	('MPC', 'Disease', (48, 51))
190483	33552962	We defined CISH:rs2239751_CC, ALDH2:rs671_AG/AA, ERCC5:rs17655_GC/GG, and ADH1B: rs1229984_CC as risk genotypes for MPC in EC patients.	('ERCC5', 'Gene', (49, 54))	('rs671', 'Mutation', 'rs671', (36, 41))	('rs2239751', 'Mutation', 'rs2239751', (16, 25))	('rs17655_GC/GG', 'Var', (55, 68))	('CISH', 'Gene', (11, 15))	('ERCC5', 'Gene', '2073', (49, 54))	('ADH1B', 'Gene', '125', (74, 79))	('rs17655', 'Mutation', 'rs17655', (55, 62))	('ALDH2', 'Gene', (30, 35))	('rs2239751_CC', 'Var', (16, 28))	('MPC', 'Disease', (116, 119))	('CISH', 'Gene', '1154', (11, 15))	('patients', 'Species', '9606', (126, 134))	('MPC', 'Chemical', '-', (116, 119))	('rs1229984', 'Mutation', 'rs1229984', (81, 90))	('rs671_AG/AA', 'Var', (36, 47))	('ALDH2', 'Gene', '217', (30, 35))	('ADH1B', 'Gene', (74, 79))
190493	33552962	Both cigarette-smoking and alcohol-drinking were obviously correlated with an increased incidence of MPC according to Chi-square analysis ( Table 2 ), but no significant effect was observed in the multivariate regression model adjusted for other variables ( Table 3 ).	('MPC', 'Disease', (101, 104))	('MPC', 'Chemical', '-', (101, 104))	('alcohol', 'Chemical', 'MESH:D000438', (27, 34))	('alcohol-drinking', 'Phenotype', 'HP:0030955', (27, 43))	('alcohol-drinking', 'Var', (27, 43))
190496	33552962	ALDH2:rs671 and ADH1B:rs1229984 have been frequently demonstrated to strongly correlate with the risk of EC.	('rs1229984', 'Var', (22, 31))	('rs671', 'Var', (6, 11))	('ADH1B', 'Gene', (16, 21))	('rs671', 'Mutation', 'rs671', (6, 11))	('ALDH2', 'Gene', (0, 5))	('ALDH2', 'Gene', '217', (0, 5))	('ADH1B', 'Gene', '125', (16, 21))	('rs1229984', 'Mutation', 'rs1229984', (22, 31))	('correlate with', 'Reg', (78, 92))
190497	33552962	The genotype distribution of ADH1B:rs1229984 also showed no significant difference between the normal Taiwanese and whole East Asian populations (p=0.905); by contrast, there was a significant difference between the EC subjects and the normal Taiwanese population (p<0.001,  Table 5 ).	('rs1229984', 'Var', (35, 44))	('rs1229984', 'Mutation', 'rs1229984', (35, 44))	('ADH1B', 'Gene', '125', (29, 34))	('ADH1B', 'Gene', (29, 34))
190498	33552962	The percentage of ALDH2 deficiency in Taiwan has been ranked number 1 globally, with around 48% of Taiwanese people carrying the variant allele; however, this did not have a statistically significant difference when compared to the whole East-Asian population, according to our analysis (p=0.750).	('ALDH2', 'Gene', '217', (18, 23))	('deficiency', 'Var', (24, 34))	('variant', 'Var', (129, 136))	('people', 'Species', '9606', (109, 115))	('ALDH2', 'Gene', (18, 23))
190499	33552962	Moreover, the genotype distribution of rs671 was significantly different between our EC subjects and the normal Taiwanese population (p<0.001).	('different', 'Reg', (63, 72))	('rs671', 'Var', (39, 44))	('rs671', 'Mutation', 'rs671', (39, 44))
190502	33552962	EC patients carrying the null variant AA also had a significant risk for MPC, especially for synchronous MPC ( Table 9 ).	('MPC', 'Chemical', '-', (73, 76))	('variant', 'Var', (30, 37))	('MPC', 'Chemical', '-', (105, 108))	('patients', 'Species', '9606', (3, 11))	('synchronous MPC', 'Disease', 'MESH:D009378', (93, 108))	('synchronous MPC', 'Disease', (93, 108))	('MPC', 'Disease', (73, 76))
190507	33552962	rs17655 is a non-synonymous SNP in the coding region of ERCC5 and causes a 1104 amino acid change from Asp to His (Asp1104His).	('ERCC5', 'Gene', '2073', (56, 61))	('rs17655', 'Var', (0, 7))	('His', 'Chemical', 'MESH:D006639', (122, 125))	('causes', 'Reg', (66, 72))	('Asp', 'Chemical', 'MESH:D001224', (103, 106))	('His', 'Chemical', 'MESH:D006639', (110, 113))	('Asp1104His', 'SUBSTITUTION', 'None', (115, 125))	('rs17655', 'Mutation', 'rs17655', (0, 7))	('Asp', 'Chemical', 'MESH:D001224', (115, 118))	('ERCC5', 'Gene', (56, 61))	('Asp1104His', 'Var', (115, 125))
190510	33552962	A previous study revealed that the rs17655 heterozygote carriers exhibited an increased risk of laryngeal cancer among heavy smokers.	('laryngeal cancer', 'Phenotype', 'HP:0012118', (96, 112))	('rs17655', 'Mutation', 'rs17655', (35, 42))	('rs17655', 'Var', (35, 42))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
190511	33552962	Thus, the function of rs17655 in MPC of EC patients is possibly due to its impaired repair function in response to environmental toxins, which leads to the development of HNC.	('HNC', 'Disease', (171, 174))	('rs17655', 'Mutation', 'rs17655', (22, 29))	('leads to', 'Reg', (143, 151))	('patients', 'Species', '9606', (43, 51))	('repair', 'MPA', (84, 90))	('MPC', 'Chemical', '-', (33, 36))	('MPC', 'Disease', (33, 36))	('impaired', 'NegReg', (75, 83))	('rs17655', 'Var', (22, 29))
190512	33552962	We found the novel biomarker CISH:rs2239751 to be significantly associated with MPC in EC patients, especially in combination with other thoracic cancers, particularly lung cancer ( Tables 7  and  8 ).	('associated', 'Reg', (64, 74))	('MPC', 'Disease', (80, 83))	('lung cancer', 'Disease', (168, 179))	('rs2239751', 'Mutation', 'rs2239751', (34, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('rs2239751', 'Var', (34, 43))	('CISH', 'Gene', (29, 33))	('MPC', 'Chemical', '-', (80, 83))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('thoracic cancers', 'Disease', (137, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('thoracic cancers', 'Disease', 'MESH:D009369', (137, 153))	('patients', 'Species', '9606', (90, 98))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('CISH', 'Gene', '1154', (29, 33))
190516	33552962	CISH:rs2239751 is a 5'UTR variant in transcript variant-1, which is reportedly correlated with persistent HBV infection.	('rs2239751', 'Var', (5, 14))	('CISH', 'Gene', (0, 4))	('HBV infection', 'Disease', (106, 119))	('correlated with', 'Reg', (79, 94))	('HBV infection', 'Disease', 'MESH:D006509', (106, 119))	('CISH', 'Gene', '1154', (0, 4))	('rs2239751', 'Mutation', 'rs2239751', (5, 14))
190517	33552962	The minor allele C has also been found to be associated with susceptibility to tuberculosis in the Chinese Han population.	('susceptibility', 'Reg', (61, 75))	('associated', 'Reg', (45, 55))	('minor', 'Var', (4, 9))	('tuberculosis', 'Disease', (79, 91))	('tuberculosis', 'Disease', 'MESH:D014376', (79, 91))
190518	33552962	The minor allele frequency of rs2239751 among the global population is only about 0.0914  This frequency also dramatically increases in the East Asia population to about 0.3356, which is close to the minor allele frequency in our population of EC patients at 0.3330.	('rs2239751', 'Mutation', 'rs2239751', (30, 39))	('patients', 'Species', '9606', (247, 255))	('rs2239751', 'Var', (30, 39))	('increases', 'PosReg', (123, 132))
190520	33552962	Whether CISH:rs2239751 is also correlated with the incidence of lung cancer is worthy of future investigation.	('lung cancer', 'Disease', (64, 75))	('CISH', 'Gene', '1154', (8, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs2239751', 'Mutation', 'rs2239751', (13, 22))	('rs2239751', 'Var', (13, 22))	('CISH', 'Gene', (8, 12))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('correlated', 'Reg', (31, 41))
190525	33552962	Taken together, the study demonstrated for the first time that a set of risk SNPs, ALDH2:rs671, CISH:rs2239751, ERCC5:rs17655, and ADH1B:rs1229984, have great potential in predicting the incidence of MPC in EC.	('rs671', 'Var', (89, 94))	('ADH1B', 'Gene', '125', (131, 136))	('CISH', 'Gene', (96, 100))	('MPC', 'Disease', (200, 203))	('rs671', 'Mutation', 'rs671', (89, 94))	('ERCC5', 'Gene', (112, 117))	('rs2239751', 'Mutation', 'rs2239751', (101, 110))	('ALDH2', 'Gene', '217', (83, 88))	('ERCC5', 'Gene', '2073', (112, 117))	('MPC', 'Chemical', '-', (200, 203))	('rs17655', 'Mutation', 'rs17655', (118, 125))	('CISH', 'Gene', '1154', (96, 100))	('ALDH2', 'Gene', (83, 88))	('rs1229984', 'Mutation', 'rs1229984', (137, 146))	('ADH1B', 'Gene', (131, 136))	('rs2239751', 'Var', (101, 110))
190533	33552962	EC, Esophageal cancer; MPCs, Multiple primary cancers; SNPs, Single-nucleotide polymorphisms; HNC, Head and neck cancer; GI ca., Gastrointestinal cancer; SPC, Second primary cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('Gastrointestinal cancer', 'Disease', 'MESH:D004067', (129, 152))	('cancer', 'Disease', (113, 119))	('MPCs', 'Disease', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('neck cancer', 'Disease', 'MESH:D006258', (108, 119))	('neck cancer', 'Disease', (108, 119))	('GI', 'Disease', 'MESH:D005767', (121, 123))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancer', 'Disease', (15, 21))	('cancers', 'Disease', (46, 53))	('cancer', 'Disease', (46, 52))	('HNC', 'Disease', (94, 97))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('Head and neck cancer', 'Phenotype', 'HP:0012288', (99, 119))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('Gastrointestinal cancer', 'Phenotype', 'HP:0007378', (129, 152))	('SNPs', 'Disease', (55, 59))	('Single-nucleotide polymorphisms', 'Var', (61, 92))	('Gastrointestinal cancer', 'Disease', (129, 152))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('MPCs', 'Chemical', '-', (23, 27))
190559	32011517	Then he received second-line oral apatinib (425 mg, once daily) plus S-1 (60 mg, twice daily for 4 weeks with a 2-week drug-free interval, in accordance with his body surface area of 1.7 m2).	('apatinib', 'Chemical', 'MESH:C553458', (34, 42))	('S-1', 'Gene', '5707', (69, 72))	('425', 'Var', (44, 47))	('S-1', 'Gene', (69, 72))
190594	32011517	In addition, the recurrence time of N0/ N1 patients is significantly longer than that of the N2 patients.	('recurrence time', 'CPA', (17, 32))	('patients', 'Species', '9606', (43, 51))	('N0/ N1', 'Var', (36, 42))	('patients', 'Species', '9606', (96, 104))	('longer', 'PosReg', (69, 75))
190622	32175327	Not surprisingly, dysfunction of mucins in their fundamental roles is implicated in disease development at mucosal surfaces, and some mucins have been reported to display diagnostic or prognostic significance in different types of cancer.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('dysfunction', 'Var', (18, 29))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('implicated', 'Reg', (70, 80))
190647	32175327	So far we have observed that high expressions of both EMCN and MUC15 were associated with poor prognosis in GC, and that EMCN and MUC15 displayed the strongest correlation to survival for GC and digestive cancers, respectively (Table 2 and Figure 1).	('high', 'Var', (29, 33))	('EMCN', 'Gene', '51705', (121, 125))	('MUC15', 'Gene', '143662', (63, 68))	('GC', 'Disease', 'MESH:D013274', (108, 110))	('expressions', 'MPA', (34, 45))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('EMCN', 'Gene', (54, 58))	('MUC15', 'Gene', (130, 135))	('cancers', 'Disease', (205, 212))	('EMCN', 'Gene', '51705', (54, 58))	('MUC15', 'Gene', '143662', (130, 135))	('GC', 'Disease', 'MESH:D013274', (188, 190))	('MUC15', 'Gene', (63, 68))	('correlation', 'Interaction', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('EMCN', 'Gene', (121, 125))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
190697	31650732	Cell proliferation was inhibited by LINC01234 knockdown, whereas apoptosis was enhanced.	('LINC01234', 'Gene', '100506465', (36, 45))	('knockdown', 'Var', (46, 55))	('inhibited', 'NegReg', (23, 32))	('LINC01234', 'Gene', (36, 45))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('enhanced', 'PosReg', (79, 87))	('apoptosis', 'CPA', (65, 74))	('Cell proliferation', 'CPA', (0, 18))
190698	31650732	Mice injected with SW480 cells with LINC01234 knockdown displayed decreased tumor volume, weight, and Ki-67 levels compared with those injected with control cells.	('LINC01234', 'Gene', '100506465', (36, 45))	('knockdown', 'Var', (46, 55))	('LINC01234', 'Gene', (36, 45))	('decreased', 'NegReg', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('weight', 'CPA', (90, 96))	('Ki-67', 'Gene', '17345', (102, 107))	('SW480', 'CellLine', 'CVCL:0546', (19, 24))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('Ki-67', 'Gene', (102, 107))
190708	31650732	In fact, dysregulation of lncRNAs has been linked to various cancers.	('lncRNAs', 'Protein', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('linked', 'Reg', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('dysregulation', 'Var', (9, 22))
190719	31650732	All CRC cells, including SW480, HCT116, SW620, and LoVo, as well as a normal colonic cell line, NCM460, were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA).	('SW480', 'Var', (25, 30))	('CRC', 'Disease', 'MESH:D015179', (4, 7))	('SW620', 'Var', (40, 45))	('SW620', 'CellLine', 'CVCL:0547', (40, 45))	('CRC', 'Phenotype', 'HP:0003003', (4, 7))	('SW480', 'CellLine', 'CVCL:0546', (25, 30))	('CRC', 'Disease', (4, 7))	('HCT116', 'CellLine', 'CVCL:0291', (32, 38))
190778	31650732	LINC01234 knockdown significantly inhibited cell viability and colony formation (Fig.	('LINC01234', 'Gene', '100506465', (0, 9))	('inhibited', 'NegReg', (34, 43))	('LINC01234', 'Gene', (0, 9))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('knockdown', 'Var', (10, 19))	('colony formation', 'CPA', (63, 79))	('cell viability', 'CPA', (44, 58))
190779	31650732	In contrast, apoptosis rate was higher in LINC01234 knockdown cells than in control cells (Fig.	('higher', 'PosReg', (32, 38))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('LINC01234', 'Gene', '100506465', (42, 51))	('apoptosis rate', 'CPA', (13, 27))	('LINC01234', 'Gene', (42, 51))	('knockdown', 'Var', (52, 61))
190780	31650732	Correspondingly, several apoptosis-related proteins were upregulated, including cleaved caspase-3, PARP and Bax, whereas Bcl2 was significantly repressed in LINC01234 knockdown cells than in control cells (Fig.	('LINC01234', 'Gene', '100506465', (157, 166))	('PARP', 'Gene', (99, 103))	('cleaved', 'MPA', (80, 87))	('apoptosis-related proteins', 'Protein', (25, 51))	('Bcl2', 'Gene', (121, 125))	('Bax', 'Gene', '581', (108, 111))	('LINC01234', 'Gene', (157, 166))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('caspase-3', 'Gene', (88, 97))	('knockdown', 'Var', (167, 176))	('PARP', 'Gene', '142', (99, 103))	('caspase-3', 'Gene', '836', (88, 97))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('Bcl2', 'Gene', '596', (121, 125))	('Bax', 'Gene', (108, 111))	('upregulated', 'PosReg', (57, 68))
190784	31650732	These results suggest that LINC01234 has a significant inhibitory effect on tumor growth, which was further evidenced by the smaller number of Ki-67-positive cells in LINC01234 knockdown cells than in control cells (Fig.	('LINC01234', 'Gene', '100506465', (167, 176))	('Ki-67', 'Gene', (143, 148))	('LINC01234', 'Gene', (167, 176))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('si', 'Chemical', 'MESH:D012825', (151, 153))	('knockdown', 'Var', (177, 186))	('LINC01234', 'Gene', '100506465', (27, 36))	('inhibitory', 'NegReg', (55, 65))	('smaller', 'NegReg', (125, 132))	('Ki-67', 'Gene', '17345', (143, 148))	('LINC01234', 'Gene', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
190787	31650732	KLF6 mRNA and protein levels were significantly increased in LINC01234 knockdown cells than in control cells (Fig.	('increased', 'PosReg', (48, 57))	('LINC01234', 'Gene', '100506465', (61, 70))	('LINC01234', 'Gene', (61, 70))	('KLF6', 'Gene', '1316', (0, 4))	('knockdown', 'Var', (71, 80))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('KLF6', 'Gene', (0, 4))
190806	31650732	Furthermore, the levels of several apoptosis-related proteins, including caspase-3, PARP, BAX, and BCL2, were altered in LINC01234 knockdown SW480 and HCT116 cells; similar results have also been reported in gastric cancer cells.	('gastric cancer', 'Disease', 'MESH:D013274', (208, 222))	('PARP', 'Gene', '142', (84, 88))	('SW480', 'CellLine', 'CVCL:0546', (141, 146))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('BCL2', 'Gene', '596', (99, 103))	('PARP', 'Gene', (84, 88))	('levels of several apoptosis-related proteins', 'MPA', (17, 61))	('knockdown', 'Var', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('altered', 'Reg', (110, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (208, 222))	('LINC01234', 'Gene', (121, 130))	('BCL2', 'Gene', (99, 103))	('HCT116', 'CellLine', 'CVCL:0291', (151, 157))	('si', 'Chemical', 'MESH:D012825', (165, 167))	('gastric cancer', 'Disease', (208, 222))	('caspase-3', 'Gene', '836', (73, 82))	('BAX', 'Gene', (90, 93))	('BAX', 'Gene', '581', (90, 93))	('LINC01234', 'Gene', '100506465', (121, 130))	('caspase-3', 'Gene', (73, 82))
190814	31650732	Splice variants of KLF6 have been linked with poor prognosis and are considered risk factors in several cancers such as breast, lung, and prostate cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Splice variants', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung', 'Disease', (128, 132))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('prostate cancers', 'Disease', 'MESH:D011471', (138, 154))	('KLF6', 'Gene', '1316', (19, 23))	('KLF6', 'Gene', (19, 23))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('prostate cancers', 'Phenotype', 'HP:0012125', (138, 154))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (147, 154))	('prostate cancers', 'Disease', (138, 154))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('breast', 'Disease', (120, 126))
190818	31650732	Those results are consistent with the present results, as well as reports that KLF6 mutants play important roles in CRC development.	('KLF6', 'Gene', (79, 83))	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('CRC', 'Disease', 'MESH:D015179', (116, 119))	('KLF6', 'Gene', '1316', (79, 83))	('mutants', 'Var', (84, 91))	('roles', 'Reg', (107, 112))	('CRC', 'Disease', (116, 119))	('si', 'Chemical', 'MESH:D012825', (21, 23))
190820	31650732	However, KLF-SV2 mutations antagonize the functions of KLF6, thus promoting cell growth.	('promoting', 'PosReg', (66, 75))	('KLF6', 'Gene', (55, 59))	('cell growth', 'CPA', (76, 87))	('KLF6', 'Gene', '1316', (55, 59))	('KLF-SV2', 'Gene', (9, 16))	('mutations', 'Var', (17, 26))
190821	31650732	Studies found that KLF6 expression contributes only to tumor growth, and not to metastasis or progression through stages, suggesting that dysregulation of KLF6 expression could be an early event in CRC development.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('si', 'Chemical', 'MESH:D012825', (87, 89))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('KLF6', 'Gene', (155, 159))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('CRC', 'Disease', (198, 201))	('tumor', 'Disease', (55, 60))	('KLF6', 'Gene', (19, 23))	('dysregulation', 'Var', (138, 151))	('KLF6', 'Gene', '1316', (155, 159))	('KLF6', 'Gene', '1316', (19, 23))	('CRC', 'Phenotype', 'HP:0003003', (198, 201))	('CRC', 'Disease', 'MESH:D015179', (198, 201))
190847	31281637	Restitution of intravascular volume can induce a rebound increase in portal pressure, which may lead to failure to control bleeding or re-bleeding or both , .	('Restitution', 'Var', (0, 11))	('bleeding', 'Disease', 'MESH:D006470', (123, 131))	('bleeding', 'Disease', (123, 131))	('increase', 'PosReg', (57, 65))	('portal pressure', 'MPA', (69, 84))	('bleeding', 'Disease', 'MESH:D006470', (138, 146))	('bleeding', 'Disease', (138, 146))
190870	31281637	Because PPIs are associated with an increased risk of hepatic encephalopathy , especially in those with recent bacterial infections  and with a high risk of 30-day re-admission , their use (if at all) should not be extended past the hospitalization period.	('encephalopathy', 'Phenotype', 'HP:0001298', (62, 76))	('bacterial infections', 'Disease', (111, 131))	('PPIs', 'Var', (8, 12))	('bacterial infection', 'Phenotype', 'HP:0002718', (111, 130))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (54, 76))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (54, 76))	('hepatic encephalopathy', 'Disease', (54, 76))	('recent bacterial infections', 'Phenotype', 'HP:0002718', (104, 131))	('bacterial infections', 'Disease', 'MESH:D001424', (111, 131))
190894	31281637	Importantly, in this study , high-risk patients were defined as those in the Child C class with a score of 10 to 13 or those in the Child B class with active bleeding at the time of endoscopy.	('score of 10 to 13', 'Var', (98, 115))	('patients', 'Species', '9606', (39, 47))	('bleeding', 'Disease', 'MESH:D006470', (158, 166))	('bleeding', 'Disease', (158, 166))	('Child', 'Species', '9606', (132, 137))	('Child', 'Species', '9606', (77, 82))
190914	31281637	It showed that, in Child A patients (compensated), combination therapy was associated with lower all-source re-bleeding but without an effect on mortality.	('lower', 'NegReg', (91, 96))	('bleeding', 'Disease', (111, 119))	('combination', 'Var', (51, 62))	('patients', 'Species', '9606', (27, 35))	('Child', 'Species', '9606', (19, 24))	('bleeding', 'Disease', 'MESH:D006470', (111, 119))
190918	31281637	The improvement in survival with NSBB is most likely related to a reduction in portal pressure that is associated not only with a reduction in the risk of variceal re-bleeding but also with a reduction in the development of other complications of portal hypertension, such as ascites and spontaneous bacterial peritonitis, as shown in a recent meta-analysis by Turco et al.	('survival', 'MPA', (19, 27))	('portal hypertension', 'Phenotype', 'HP:0001409', (247, 266))	('bacterial peritonitis', 'Disease', 'MESH:D010534', (300, 321))	('ascites', 'Phenotype', 'HP:0001541', (276, 283))	('peritonitis', 'Phenotype', 'HP:0002586', (310, 321))	('bleeding', 'Disease', 'MESH:D006470', (167, 175))	('reduction', 'NegReg', (130, 139))	('improvement', 'PosReg', (4, 15))	('reduction', 'NegReg', (66, 75))	('NSBB', 'Var', (33, 37))	('hypertension', 'Disease', 'MESH:D006973', (254, 266))	('bacterial peritonitis', 'Disease', (300, 321))	('bleeding', 'Disease', (167, 175))	('portal pressure', 'MPA', (79, 94))	('hypertension', 'Disease', (254, 266))	('reduction', 'NegReg', (192, 201))	('ascites', 'Disease', (276, 283))	('NSBB', 'Chemical', '-', (33, 37))	('hypertension', 'Phenotype', 'HP:0000822', (254, 266))	('ascites', 'Disease', 'MESH:D001201', (276, 283))
190920	31281637	These data, obtained from RCTs, are in contrast to those of a cohort study that showed that, in patients with refractory ascites, mortality was higher in NSBB users than in non-users .	('NSBB users', 'Var', (154, 164))	('NSBB', 'Chemical', '-', (154, 158))	('mortality', 'MPA', (130, 139))	('higher', 'PosReg', (144, 150))	('ascites', 'Disease', (121, 128))	('patients', 'Species', '9606', (96, 104))	('ascites', 'Disease', 'MESH:D001201', (121, 128))	('ascites', 'Phenotype', 'HP:0001541', (121, 128))
190955	30574162	FAM201A knockdown enhanced the radiosensitivity of ECA109/ECA109R cells by upregulating ataxia telangiectasia mutated (ATM) and mammalian target of rapamycin (mTOR) expression via the negative regulation of miR-101 expression.	('ataxia telangiectasia mutated', 'Gene', (88, 117))	('miR', 'Gene', '22877', (207, 210))	('enhanced', 'PosReg', (18, 26))	('upregulating', 'PosReg', (75, 87))	('radiosensitivity', 'CPA', (31, 47))	('ATM', 'Gene', (119, 122))	('telangiectasia', 'Phenotype', 'HP:0001009', (95, 109))	('ataxia', 'Phenotype', 'HP:0001251', (88, 94))	('FAM201A', 'Gene', '158228', (0, 7))	('ataxia telangiectasia mutated', 'Gene', '472', (88, 117))	('mTOR', 'Gene', (159, 163))	('mammalian target of rapamycin', 'Gene', '2475', (128, 157))	('FAM201A', 'Gene', (0, 7))	('miR', 'Gene', (207, 210))	('knockdown', 'Var', (8, 17))	('expression', 'MPA', (165, 175))	('mTOR', 'Gene', '2475', (159, 163))	('mammalian target of rapamycin', 'Gene', (128, 157))	('ATM', 'Gene', '472', (119, 122))	('negative regulation', 'NegReg', (184, 203))
190956	30574162	The mouse xenograft model demonstrated that FAM201A knockdown improved the radiosensitivity of ESCC.	('mouse', 'Species', '10090', (4, 9))	('improved', 'PosReg', (62, 70))	('ESCC', 'Disease', (95, 99))	('FAM201A', 'Gene', (44, 51))	('FAM201A', 'Gene', '158228', (44, 51))	('knockdown', 'Var', (52, 61))	('radiosensitivity', 'CPA', (75, 91))
191009	30574162	Based on above data, the ROC curve of the lncRNAs CASC2, FAM201A, and DLX6-AS1 was applied to identify the lncRNA that was the most correlated to radiosensitivity and survival using the area under curve (AUC) were 0.783 (95%CI: 0.609-957, P = 0.005), 0.817 (95%CI: 0.673-960, P = 0.002), and 0.340 (95%CI: 0.150-530, P = 0.110); respectively.	('DLX6-AS1', 'Gene', '285987;1750;5729', (70, 78))	('correlated', 'Reg', (132, 142))	('survival', 'CPA', (167, 175))	('0.340', 'Var', (292, 297))	('radiosensitivity', 'CPA', (146, 162))	('CASC2', 'Gene', '255082', (50, 55))	('CASC2', 'Gene', (50, 55))	('DLX6-AS1', 'Gene', (70, 78))	('0.817', 'Var', (251, 256))	('FAM201A', 'Gene', (57, 64))	('FAM201A', 'Gene', '158228', (57, 64))
191035	30574162	In Eca109/Eca109R cells, the expression of ATM and mTOR was increased while that of miR-101 was decreased in FAM201A-mimic cells when compared with control cells.	('mTOR', 'Gene', (51, 55))	('miR', 'Gene', (84, 87))	('ATM', 'Gene', (43, 46))	('decreased', 'NegReg', (96, 105))	('miR', 'Gene', '22877', (84, 87))	('ATM', 'Gene', '472', (43, 46))	('FAM201A', 'Gene', (109, 116))	('FAM201A', 'Gene', '158228', (109, 116))	('expression', 'MPA', (29, 39))	('mTOR', 'Gene', '2475', (51, 55))	('Eca109/Eca109R', 'Var', (3, 17))	('increased', 'PosReg', (60, 69))
191039	30574162	In this study, they revealed that, when compared with normal para-carcinoma tissue, tumor tissues with a low expression of lncRNA LOC285194 exhibited a larger tumor size, poorer histological grade, had an advanced TNM stage, more lymph node and distant metastases, and was significantly negatively correlated with the pathological response to RT than the LOC285194-high group.	('low', 'NegReg', (105, 108))	('LOC285194', 'Var', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('para-carcinoma', 'Disease', 'MESH:D002277', (61, 75))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('larger', 'PosReg', (152, 158))	('TNM stage', 'CPA', (214, 223))	('correlated', 'Reg', (298, 308))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('negatively', 'NegReg', (287, 297))	('advanced', 'PosReg', (205, 213))	('para-carcinoma', 'Disease', (61, 75))	('tumor', 'Disease', (159, 164))	('metastases', 'Disease', 'MESH:D009362', (253, 263))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (84, 89))	('metastases', 'Disease', (253, 263))	('pathological response', 'CPA', (318, 339))	('more', 'PosReg', (225, 229))
191053	30574162	In vivo, when compared with control groups, FAM201A knockdown significantly blocked xenograft tumor growth (decreased tumor volume and weight), which confirmed that siFAM201A was able enhance radiosensitivity.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('FAM201A', 'Gene', '158228', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('blocked', 'NegReg', (76, 83))	('decreased tumor', 'Disease', (108, 123))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('knockdown', 'Var', (52, 61))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (118, 123))	('FAM201A', 'Gene', (44, 51))	('enhance', 'PosReg', (184, 191))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (184, 208))	('FAM201A', 'Gene', '158228', (44, 51))	('FAM201A', 'Gene', (167, 174))	('decreased tumor', 'Disease', 'MESH:D009369', (108, 123))
191061	30574162	Furthermore, qPCR revealed that overexpression of FAM201A leads to the downregulation of miR-101, the upregulation of ATM and mTOR, and resulted in radioresistance; however, depletion of FAM201A led to the upregulation of miR-101, downregulation of ATM, and mTOR, and resulted in radiosensitivity.	('downregulation', 'NegReg', (71, 85))	('mTOR', 'Gene', (258, 262))	('downregulation', 'NegReg', (231, 245))	('ATM', 'Gene', (249, 252))	('miR', 'Gene', (222, 225))	('FAM201A', 'Gene', (187, 194))	('ATM', 'Gene', '472', (118, 121))	('upregulation', 'PosReg', (206, 218))	('FAM201A', 'Gene', '158228', (50, 57))	('resulted in', 'Reg', (268, 279))	('mTOR', 'Gene', '2475', (258, 262))	('FAM201A', 'Gene', (50, 57))	('miR', 'Gene', '22877', (222, 225))	('upregulation', 'PosReg', (102, 114))	('ATM', 'Gene', (118, 121))	('miR', 'Gene', (89, 92))	('CR', 'Chemical', '-', (15, 17))	('ATM', 'Gene', '472', (249, 252))	('mTOR', 'Gene', (126, 130))	('radioresistance', 'CPA', (148, 163))	('depletion', 'Var', (174, 183))	('miR', 'Gene', '22877', (89, 92))	('radiosensitivity', 'CPA', (280, 296))	('FAM201A', 'Gene', '158228', (187, 194))	('mTOR', 'Gene', '2475', (126, 130))
191129	28638461	demonstrated that the defect in mismatch repair (MMR) was associated with high CD8+ cytotoxic T-cells and Th1-type cells infiltration around the tumor.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('associated', 'Reg', (58, 68))	('CD8+ cytotoxic T-cells', 'CPA', (79, 101))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Th1-type cells infiltration', 'CPA', (106, 133))	('defect', 'Var', (22, 28))	('tumor', 'Disease', (145, 150))	('mismatch', 'Var', (32, 40))
191130	28638461	Colorectal cancer (CRC) with microsatellite instability (MSI) has an exceptionally high mutation burden.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('microsatellite instability', 'Var', (29, 55))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('CR', 'Chemical', '-', (19, 21))	('Colorectal cancer', 'Disease', (0, 17))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))
191139	28638461	reported the preliminary results from the CheckMate-142, a two-staged phase 2 study evaluating nivolumab +/- ipilimumab in metastatic or recurrent CRC with MSI-H or microsatellite stable (MSS).	('CR', 'Chemical', '-', (147, 149))	('CRC', 'Phenotype', 'HP:0003003', (147, 150))	('microsatellite', 'Var', (165, 179))	('nivolumab', 'Chemical', 'MESH:D000077594', (95, 104))	('MSI-H', 'Disease', (156, 161))	('metastatic', 'Disease', (123, 133))	('MSI-H', 'Disease', 'MESH:D000848', (156, 161))	('ipilimumab', 'Chemical', 'MESH:D000074324', (109, 119))	('CRC', 'Disease', (147, 150))
191145	28638461	The combination of modified FOLFOX6 with pembrolizumab has an acceptable safety profile with ORR of 29%.	('pembrolizumab', 'Chemical', 'MESH:C582435', (41, 54))	('modified', 'Var', (19, 27))	('FOLFOX6', 'Gene', (28, 35))	('FOLFOX6', 'Chemical', '-', (28, 35))
191148	28638461	In preclinical model, blockage of the PD-1 receptor combined with administration of immunostimulatory mAbs extends survival in murine model of HCC.	('PD-1', 'Gene', (38, 42))	('extends', 'PosReg', (107, 114))	('murine', 'Species', '10090', (127, 133))	('PD-1', 'Gene', '5133', (38, 42))	('HCC', 'Disease', (143, 146))	('blockage', 'Var', (22, 30))	('HCC', 'Phenotype', 'HP:0001402', (143, 146))	('survival', 'CPA', (115, 123))
191160	28638461	Recently, the cancer genome atlas has identified that gastric cancer can be classified by molecular subtype; Epstein Barr virus (EBV) positive, microsatellite unstable, genomically stable, and chromosomal instability tumors.	('cancer', 'Disease', (14, 20))	('gastric cancer', 'Phenotype', 'HP:0012126', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('gastric cancer', 'Disease', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (54, 68))	('EBV', 'Species', '10376', (129, 132))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('chromosomal instability tumors', 'Disease', 'MESH:D043171', (193, 223))	('microsatellite', 'Var', (144, 158))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('chromosomal instability', 'Phenotype', 'HP:0040012', (193, 216))	('chromosomal instability tumors', 'Disease', (193, 223))
191208	27511066	TDCA-induced increase in TM and H2AX phosphorylation was significantly decreased by knockdown of NOX5-S and overexpression of NOX5-S significantly increased TDCA-induced increase in the tail moment and H2AX phosphorylation.	('DCA', 'Chemical', 'MESH:D003840', (158, 161))	('tail moment', 'CPA', (186, 197))	('NOX5', 'Gene', (97, 101))	('increased', 'PosReg', (147, 156))	('H2AX', 'Gene', '3014', (32, 36))	('increase', 'PosReg', (170, 178))	('knockdown', 'Var', (84, 93))	('H2AX', 'Gene', (32, 36))	('NOX5', 'Gene', '79400', (126, 130))	('H2AX', 'Gene', (202, 206))	('increase', 'PosReg', (13, 21))	('NOX5', 'Gene', '79400', (97, 101))	('H2AX', 'Gene', '3014', (202, 206))	('DCA', 'Chemical', 'MESH:D003840', (1, 4))	('NOX5', 'Gene', (126, 130))	('decreased', 'NegReg', (71, 80))
191209	27511066	Furthermore, TDCA significantly increased cAMP response element binding protein (CREB) phosphorylation in FLO-1 cells.	('cAMP', 'Chemical', 'MESH:D000242', (42, 46))	('DCA', 'Chemical', 'MESH:D003840', (14, 17))	('TDCA', 'Var', (13, 17))	('increased', 'PosReg', (32, 41))
191219	27511066	Persistent DSBs may cause chromosomal abnormalities including translocations and deletions and induce genomic instability, thus contributing to the tumorigenesis.	('DSBs', 'Chemical', '-', (11, 15))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (26, 51))	('deletions', 'Var', (81, 90))	('cause', 'Reg', (20, 25))	('contributing', 'Reg', (128, 140))	('translocations', 'MPA', (62, 76))	('induce', 'Reg', (95, 101))	('tumorigenesis', 'CPA', (148, 161))	('genomic instability', 'CPA', (102, 121))	('chromosomal abnormalities', 'Disease', (26, 51))
191228	27511066	Figure 1 showed that TDCA treatment significantly increased tail moment from 0.2 +- 0.08 to 3.1 +- 0.3 (t test, P < 0.0001), suggesting that TDCA may cause DNA damage in FLO-1 EA cells.	('cause', 'Reg', (150, 155))	('DNA damage', 'MPA', (156, 166))	('increased', 'PosReg', (50, 59))	('DCA', 'Chemical', 'MESH:D003840', (142, 145))	('tail moment', 'MPA', (60, 71))	('DCA', 'Chemical', 'MESH:D003840', (22, 25))	('TDCA', 'Var', (141, 145))
191230	27511066	We found that TDCA significantly increased H2AX phosphorylation in FLO-1 cells (Fig.	('TDCA', 'Var', (14, 18))	('H2AX', 'Gene', '3014', (43, 47))	('increased', 'PosReg', (33, 42))	('H2AX', 'Gene', (43, 47))	('DCA', 'Chemical', 'MESH:D003840', (15, 18))
191231	27511066	1C,D), indicating that TDCA may cause double stranded DNA break.	('double stranded DNA break', 'Disease', (38, 63))	('TDCA', 'Var', (23, 27))	('cause', 'Reg', (32, 37))	('DCA', 'Chemical', 'MESH:D003840', (24, 27))
191234	27511066	Figure 2A showed that knockdown of TGR5 significantly decreased TDCA-induced increase in tail moment from 4.1 +- 0.4 to 2.1 +- 0.3 (ANOVA, P < 0.0001) in FLO-1 cells.	('TGR5', 'Gene', (35, 39))	('DCA', 'Chemical', 'MESH:D003840', (65, 68))	('knockdown', 'Var', (22, 31))	('tail moment', 'MPA', (89, 100))	('decreased', 'NegReg', (54, 63))	('increase', 'PosReg', (77, 85))
191235	27511066	In addition, overexpression of TGR5 by transfection of FLO-1 cells with TGR5 plasmid significantly increased TDCA-induced increase in tail moment from 2.4 +- 0.3 to 3.3 +- 0.4 (ANOVA, P < 0.05, Fig.	('transfection', 'Var', (39, 51))	('TGR5', 'Gene', (72, 76))	('tail moment', 'CPA', (134, 145))	('DCA', 'Chemical', 'MESH:D003840', (110, 113))	('overexpression', 'PosReg', (13, 27))	('increased', 'PosReg', (99, 108))	('increase', 'PosReg', (122, 130))
191236	27511066	Similarly, knockdown of TGR5 significantly decreased TDCA-induced increase in H2AX phosphorylation (Fig.	('increase', 'PosReg', (66, 74))	('DCA', 'Chemical', 'MESH:D003840', (54, 57))	('H2AX', 'Gene', '3014', (78, 82))	('H2AX', 'Gene', (78, 82))	('TGR5', 'Gene', (24, 28))	('TDCA-induced', 'Disease', (53, 65))	('decreased', 'NegReg', (43, 52))	('knockdown', 'Var', (11, 20))
191239	27511066	We have shown that TDCA increases NOX5-S expression and H2O2 production in FLO-1 cells and a Barrett's cell line BAR-T.	('increases', 'PosReg', (24, 33))	('DCA', 'Chemical', 'MESH:D003840', (20, 23))	('H2O2', 'Chemical', 'MESH:D006861', (56, 60))	('NOX5', 'Gene', '79400', (34, 38))	('NOX5', 'Gene', (34, 38))	('H2O2 production', 'MPA', (56, 71))	('TDCA', 'Var', (19, 23))
191242	27511066	We found that TDCA-induced increase in tail moment was significantly reduced by DPI from 3.0 +- 0.3 to 1.0 +- 0.2 (ANOVA, P < 0.0001, Fig.	('DPI', 'Var', (80, 83))	('reduced', 'NegReg', (69, 76))	('tail', 'MPA', (39, 43))	('DPI', 'Chemical', 'MESH:C007517', (80, 83))	('DCA', 'Chemical', 'MESH:D003840', (15, 18))	('increase', 'PosReg', (27, 35))
191245	27511066	Then we used NOX5 siRNA, which had been shown by us to effectively knock down NOX5-S, to knock down NOX5-S.	('NOX5', 'Gene', '79400', (13, 17))	('knock', 'Var', (67, 72))	('NOX5', 'Gene', (78, 82))	('NOX5', 'Gene', (13, 17))	('NOX5', 'Gene', '79400', (100, 104))	('NOX5', 'Gene', '79400', (78, 82))	('knock down', 'NegReg', (89, 99))	('NOX5', 'Gene', (100, 104))
191246	27511066	Figure 5A showed that knockdown of NOX5-S significantly decreased TDCA induced increase in tail moment from 3.4 +- 0.6 to 2.1 +- 0.4 (ANOVA, P < 0.05) in FLO-1 cells (Fig.	('increase', 'PosReg', (79, 87))	('NOX5', 'Gene', (35, 39))	('tail moment', 'MPA', (91, 102))	('decreased', 'NegReg', (56, 65))	('knockdown', 'Var', (22, 31))	('DCA', 'Chemical', 'MESH:D003840', (67, 70))	('NOX5', 'Gene', '79400', (35, 39))	('TDCA', 'Gene', (66, 70))
191257	27511066	Knockdown of CREB significantly decreased TDCA-induced increase in NOX5-S mRNA levels from 209% to 72% control (Fig.	('increase', 'PosReg', (55, 63))	('Knockdown', 'Var', (0, 9))	('NOX5', 'Gene', '79400', (67, 71))	('NOX5', 'Gene', (67, 71))	('DCA', 'Chemical', 'MESH:D003840', (43, 46))	('decreased', 'NegReg', (32, 41))
191259	27511066	In addition, knockdown of CREB significantly decreased TDCA-induced increase in tail moment from 3.6 +- 0.5 to 1.7 +- 0.3 (ANOVA, P < 0.001, Fig.	('CREB', 'Gene', (26, 30))	('decreased', 'NegReg', (45, 54))	('DCA', 'Chemical', 'MESH:D003840', (56, 59))	('increase', 'PosReg', (68, 76))	('knockdown', 'Var', (13, 22))	('tail moment', 'MPA', (80, 91))
191263	27511066	Bile acids have been shown to cause DNA damage, which is mediated by reactive oxygen species (ROS).	('DNA damage', 'Disease', (36, 46))	('ROS', 'Chemical', 'MESH:D017382', (94, 97))	('Bile acids', 'Var', (0, 10))	('Bile acids', 'Chemical', 'MESH:D001647', (0, 10))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (69, 92))
191269	27511066	We found that TGR5 may mediate bile acid-induced DNA damage since 1) knockdown of TGR5 significantly decreased TDCA-induced increase in tail moment and H2AX phosphorylation in FLO-1 cells; 2) overexpression of TGR5 significantly increased TDCA-induced increase in tail moment and H2AX phosphorylation.	('increase', 'PosReg', (124, 132))	('H2AX', 'Gene', '3014', (152, 156))	('bile acid', 'Chemical', 'MESH:D001647', (31, 40))	('H2AX', 'Gene', '3014', (280, 284))	('DCA', 'Chemical', 'MESH:D003840', (240, 243))	('tail moment', 'MPA', (136, 147))	('H2AX', 'Gene', (280, 284))	('decreased', 'NegReg', (101, 110))	('increased', 'PosReg', (229, 238))	('H2AX', 'Gene', (152, 156))	('TGR5', 'Gene', (82, 86))	('overexpression', 'PosReg', (192, 206))	('increase', 'PosReg', (252, 260))	('tail moment', 'MPA', (264, 275))	('knockdown', 'Var', (69, 78))	('DCA', 'Chemical', 'MESH:D003840', (112, 115))	('TGR5', 'Gene', (210, 214))
191282	27511066	We also found that CREB may mediate bile acid-induced increase in NOX5-S expression because knockdown of CREB significantly decreased TDCA-induced increase in NOX5-S mRNA levels.	('NOX5', 'Gene', (159, 163))	('knockdown', 'Var', (92, 101))	('NOX5', 'Gene', '79400', (66, 70))	('decreased', 'NegReg', (124, 133))	('DCA', 'Chemical', 'MESH:D003840', (135, 138))	('increase', 'PosReg', (147, 155))	('TDCA-induced', 'MPA', (134, 146))	('NOX5', 'Gene', '79400', (159, 163))	('bile acid', 'Chemical', 'MESH:D001647', (36, 45))	('CREB', 'Gene', (105, 109))	('NOX5', 'Gene', (66, 70))
191283	27511066	In addition, knockdown of CREB significantly decreased TDCA-induced increase in tail moment in FLO-1 cells and overexpression of CREB significantly increased TDCA-induced increase in tail moment.	('CREB', 'Gene', (26, 30))	('tail moment', 'MPA', (183, 194))	('DCA', 'Chemical', 'MESH:D003840', (159, 162))	('tail', 'MPA', (80, 84))	('decreased', 'NegReg', (45, 54))	('DCA', 'Chemical', 'MESH:D003840', (56, 59))	('increase', 'PosReg', (68, 76))	('knockdown', 'Var', (13, 22))
191285	27511066	In conclusion, bile acid causes DNA damage via activation of TGR5, CREB and NOX5-S in FLO-1 cells.	('bile', 'Var', (15, 19))	('NOX5', 'Gene', (76, 80))	('activation', 'PosReg', (47, 57))	('bile acid', 'Chemical', 'MESH:D001647', (15, 24))	('TGR5', 'Gene', (61, 65))	('NOX5', 'Gene', '79400', (76, 80))	('DNA', 'Disease', (32, 35))
191295	27511066	The primers used were as follows: NOX5-S sense (5'-AAGACTCCATCACGGGGCTGCA-3'), NOX5-S antisense (5'-CCTTCAGCACCTTGGCCAGA-3'), 18S sense (5'-CGGACAGGATTGACAGATTGATAGC-3'), and 18S antisense (5'-TGCCAGAGTCTCGTTCGTTATCG-3').	('NOX5', 'Gene', '79400', (34, 38))	('NOX5', 'Gene', '79400', (79, 83))	("5'-CCTTCAGCACCTTGGCCAGA-3", 'Var', (97, 122))	('NOX5', 'Gene', (34, 38))	('NOX5', 'Gene', (79, 83))	('AAGACTCCATCACGGGGCTGCA', 'Chemical', '-', (51, 73))
191347	27034510	In our study, w = 0 implies no harm to the patient, while w = 100 represents an extent of harm that is imminently life threatening.	('w = 100', 'Var', (58, 65))	('w = 0', 'Var', (14, 19))	('patient', 'Species', '9606', (43, 50))
191372	27034510	Let epsilonTTB denote a small value of Delta(theta, w) and epsilonPFS a small value of deltaxi that are considered clinically insignificant.	('TTB', 'Chemical', '-', (11, 14))	('deltaxi', 'MPA', (87, 94))	('epsilonTTB', 'Var', (4, 14))
191376	27034510	For the RT trial, any improvement in mean TTB or PFS was considered clinically relevant by the participating oncologists, therefore posterior probabilities were computed using epsilonTTB = epsilonPFS = 0.	('TTB', 'Chemical', '-', (42, 45))	('TTB', 'Chemical', '-', (183, 186))	('PFS', 'MPA', (49, 52))	('epsilonTTB', 'Var', (176, 186))	('TTB', 'MPA', (42, 45))
191434	27034510	Among the recurrent toxicity severities, the resulting ESS values ranged from a minimum of 0.68 for severity weight w*2 = 20 (RP of grade< 3) to a maximum of 1.8 for w*7 = 90 (surgical PEF or RP of grade 4).	('w*2 = 20', 'Var', (116, 124))	('w*7 = 90', 'Var', (166, 174))	('toxicity', 'Disease', 'MESH:D064420', (20, 28))	('toxicity', 'Disease', (20, 28))	('ESS', 'Chemical', '-', (55, 58))
191445	27034510	Scenarios 1-12 characterize alternatives chosen randomly to yield a 50% reduction in mean TTB for PBT versus IMRT, with PFS HR   1.	('reduction', 'NegReg', (72, 81))	('TTB', 'Chemical', '-', (90, 93))	('PBT', 'Var', (98, 101))	('TTB', 'MPA', (90, 93))
191492	27034510	The former approach requires Monte Carlo simulation, whereby one generates model parameters from the priors for the baseline model parameters (treatment effects omitted), obtains a prior distribution for mean TTB, and fixes mu0 at the resulting mean.	('TTB', 'MPA', (209, 212))	('TTB', 'Chemical', '-', (209, 212))	('mu0', 'MPA', (224, 227))	('fixes', 'Var', (218, 223))
191508	27034510	The OCs in Tables 5-6 were computed using the following critical values for comparing toxicity rates between modalities using sequential z-tests for a difference in proportions: (3.60563, 3.08866, 2.74145, 2.13505).	('3.60563', 'Var', (179, 186))	('toxicity', 'Disease', 'MESH:D064420', (86, 94))	('toxicity', 'Disease', (86, 94))
191515	25743453	However, it is uncertain if EGJ function and acid clearance are more severely impaired in patients with long-segment Barrett's compared to patients with high-grade esophagitis.	('esophagitis', 'Disease', (164, 175))	('esophagitis', 'Disease', 'MESH:D004941', (164, 175))	('patients', 'Species', '9606', (139, 147))	('long-segment', 'Var', (104, 116))	('Barrett', 'Disease', (117, 124))	('acid clearance', 'MPA', (45, 59))	('impaired', 'Disease', 'MESH:D009422', (78, 86))	('impaired', 'Disease', (78, 86))	('patients', 'Species', '9606', (90, 98))	('EGJ function', 'MPA', (28, 40))	('esophagitis', 'Phenotype', 'HP:0100633', (164, 175))
191577	25743453	In each of these analyses, EGJ contractility was found to be lower in patients with pathological esophageal acid exposure compared to patients with normal acid esophageal exposure.	('patients', 'Species', '9606', (70, 78))	('lower', 'NegReg', (61, 66))	('EGJ contractility', 'CPA', (27, 44))	('patients', 'Species', '9606', (134, 142))	('pathological esophageal acid exposure', 'Var', (84, 121))	('esophageal acid', 'Chemical', '-', (97, 112))
191584	25743453	In a large series of 506 patients with abnormal esophageal acid exposure on 24-h pH monitoring, multivariate analysis demonstrated that abnormal bilirubin exposure was the only factor independently associated with Barrett's esophagus.	("Barrett's esophagus", 'Disease', (214, 233))	('abnormal', 'Var', (136, 144))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (214, 233))	('bilirubin', 'Chemical', 'MESH:D001663', (145, 154))	('patients', 'Species', '9606', (25, 33))	('associated', 'Reg', (198, 208))	('esophageal acid', 'Chemical', '-', (48, 63))
191588	25743453	Finally, it is important to note that patents with long-segment Barrett's esophagus have been reported to have a significantly lower LES pressure than patients with short-segment Barrett's esophagus.	('long-segment', 'Var', (51, 63))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (64, 83))	('lower', 'NegReg', (127, 132))	('patients', 'Species', '9606', (151, 159))	('LES pressure', 'MPA', (133, 145))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (179, 198))	("short-segment Barrett's esophagus", 'Disease', (165, 198))	("short-segment Barrett's esophagus", 'Disease', 'MESH:D001471', (165, 198))
191607	25743453	Impaired esophageal peristaltic function can cause delayed esophageal clearance thereby playing a role in the occurrence of esophagitis and Barrett's esophagus.	('esophageal', 'MPA', (9, 19))	('Impaired esophageal peristaltic function', 'Phenotype', 'HP:0031857', (0, 40))	('esophagitis', 'Disease', (124, 135))	("Barrett's esophagus", 'Disease', (140, 159))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (140, 159))	('esophagitis', 'Phenotype', 'HP:0100633', (124, 135))	('esophagitis', 'Disease', 'MESH:D004941', (124, 135))	('Impaired', 'Var', (0, 8))	('delayed esophageal', 'MPA', (51, 69))
191646	25419901	It has been reported that repairing of IR-induced DNA damage, either double strand breaks or single strand defects, is one important mechanism underlying cancer recurrence and radioresistance.	('cancer', 'Disease', (154, 160))	('double strand breaks', 'Var', (69, 89))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('single strand defects', 'Var', (93, 114))	('radioresistance', 'CPA', (176, 191))
191668	25419901	Gene profiling, in triplicate, was carried out by Illumina Shanghai Corporation using a microarray of Illumine Human-6 V3 and data were collected and analyzed with the Illuminated Beadstudio Application software (GSE61620, GSE61772 and GSE61816).	('Human', 'Species', '9606', (111, 116))	('GSE61772', 'Var', (223, 231))	('GSE61816', 'Var', (236, 244))	('GSE61620', 'Var', (213, 221))
191670	25419901	The relative mRNA levels of the different genes were calculated as follows: DeltaCT (sample)  =  CT (gene) - CT (GAPDH); DeltaDeltaCT  =  DeltaCT (post-irradiation time point) - DeltaCT (0 h); Relative expression  = 2-DeltaDeltaCT.	('GAPDH', 'Gene', '2597', (113, 118))	('GAPDH', 'Gene', (113, 118))	('DeltaDeltaCT', 'Var', (121, 133))
191684	25419901	The male, 4-week-old to 6-week-old nude mice were randomized into two group and injected in the upper portion of a hind limb with a density of 2*106/100 microl of KY170R-shRNA1 and KY170R-scramble cells, respectively.	('nude mice', 'Species', '10090', (35, 44))	('KY170R-shRNA1', 'Var', (163, 176))	('KY170R-scramble', 'Var', (181, 196))
191700	25419901	1C ) analyses confirmed the elevated expression of AKR1C3 in KY170R and TE13R cells, respectively, as compared with their parental cells: ~10-fold at the mRNA level and much higher at the protein level.	('KY170R', 'Var', (61, 67))	('AKR1C3', 'Gene', (51, 57))	('higher', 'PosReg', (174, 180))	('AKR1C3', 'Gene', '8644', (51, 57))	('TE13R', 'Chemical', '-', (72, 77))	('expression', 'MPA', (37, 47))	('elevated', 'PosReg', (28, 36))
191702	25419901	Colony-formation assays verified that KY170R and TE13R were indeed more resistant to IR than their parental KY170 and TE13 cells, with the estimated dose for reduction of survival by 90% for KY170 vs. KY170R as 5.5 Gy vs. 7.8 Gy ( Fig.	('KY170R', 'Var', (38, 44))	('reduction', 'NegReg', (158, 167))	('TE13R', 'Chemical', '-', (49, 54))	('KY170R', 'Var', (201, 207))	('KY170 vs.', 'Var', (191, 200))	('resistant to', 'MPA', (72, 84))
191704	25419901	To examine this issue, the expression levels of AKR1C3 in KY170R and TE13R were down-regulated by shRNAs delivered by lentivector pSD31 and the effects of AKR1C3 knockdown on radioresistance were characterized.	('AKR1C3', 'Gene', (48, 54))	('expression levels', 'MPA', (27, 44))	('KY170R', 'Var', (58, 64))	('AKR1C3', 'Gene', '8644', (48, 54))	('AKR1C3', 'Gene', '8644', (155, 161))	('AKR1C3', 'Gene', (155, 161))	('TE13R', 'Chemical', '-', (69, 74))	('down-regulated', 'NegReg', (80, 94))
191706	25419901	Characterization of AKR1C3 knockdown on cell proliferation indicated that KY170R-shRNA1, KY170R-shRNA2 and KY170R-shRNA3 (three stable cell lines generated by pSD31-mediated transduction) proliferated at almost the same rate as KY170R-scramble cell, which itself had a rate almost identical to that seen in KY170R and KY170 cells (Fig.	('AKR1C3', 'Gene', '8644', (20, 26))	('KY170R-shRNA2', 'Var', (89, 102))	('proliferated', 'CPA', (188, 200))	('KY170R-shRNA1', 'Var', (74, 87))	('KY170R-shRNA3', 'Var', (107, 120))	('AKR1C3', 'Gene', (20, 26))
191719	25419901	Two xenograft models were established by subcutaneously implanting KY170R-shRNA1 and KY170R-scramble cells, separately, in nude mice.	('KY170R-shRNA1', 'Var', (67, 80))	('KY170R-scramble', 'Var', (85, 100))	('nude mice', 'Species', '10090', (123, 132))
191724	25419901	We found all xenografted tumors in 10 irradiated KY170R-shRNA1 mice were sensitive to IR treatment with 8 mice becoming almost tumor-free 5 weeks post irradiation ( Figs.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mice', 'Species', '10090', (106, 110))	('tumors', 'Disease', (25, 31))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (25, 30))	('KY170R-shRNA1', 'Var', (49, 62))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('mice', 'Species', '10090', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
191726	25419901	By contrast, the non-irradiated xenograft tumors in KY170R-shRNA1 and KY170R-scramble mice grew to an average volume of 1000 mm3 with full proliferating cells ( Figs.	('xenograft tumors', 'Disease', (32, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('KY170R-shRNA1', 'Var', (52, 65))	('mice', 'Species', '10090', (86, 90))	('xenograft tumors', 'Disease', 'MESH:D009369', (32, 48))	('KY170R-scramble', 'Var', (70, 85))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
191727	25419901	In the case of the mice with KY170R-scramble xenotransplants, irradiation led to a poor outcome: tumor growth was initially repressed upon irradiation but resumed within two weeks ( Fig.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('KY170R-scramble', 'Var', (29, 44))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('mice', 'Species', '10090', (19, 23))
191731	25419901	It was found that prior to irradiation approximately 2-fold less ROS was in KY170R-scramble than in KY170R-shRNA1 cells ( Figs.	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('less', 'NegReg', (60, 64))	('ROS', 'Protein', (65, 68))	('KY170R-scramble', 'Var', (76, 91))
191732	25419901	Upon irradiation, the level of ROS remained low in KY170R-scramble cells but remarkably increased in KY170R-shRNA1 cells with the difference being almost 3 folds ( Fig.	('KY170R-shRNA1', 'Var', (101, 114))	('ROS', 'MPA', (31, 34))	('increased', 'PosReg', (88, 97))	('ROS', 'Chemical', 'MESH:D017382', (31, 34))
191733	25419901	Coincident with simultaneous AKR1C3 knockdown and ROS increase in irradiated KY170R-shRNA cells, the number of foci of phospho-gamma-histone ( Figs.	('ROS', 'Gene', (50, 53))	('gamma-histone', 'Chemical', '-', (127, 140))	('ROS increase', 'Phenotype', 'HP:0025464', (50, 62))	('increase', 'PosReg', (54, 62))	('AKR1C3', 'Gene', (29, 35))	('knockdown', 'Var', (36, 45))	('AKR1C3', 'Gene', '8644', (29, 35))	('ROS', 'Chemical', 'MESH:D017382', (50, 53))
191754	25419901	In this study, we reported the coincidence of differentiation of AKR1C3 expression, cellular ROS level and DNA damage in radioresistant KY170R vs. non-resistant KY170 cells.	('KY170R', 'Var', (136, 142))	('cellular ROS level', 'MPA', (84, 102))	('AKR1C3', 'Gene', (65, 71))	('ROS', 'Chemical', 'MESH:D017382', (93, 96))	('AKR1C3', 'Gene', '8644', (65, 71))	('DNA damage', 'MPA', (107, 117))
191784	25119898	The results demonstrated that DSC2 knock down by RNAi caused defects in cell-cell adhesion and a concomitant reduction in desmosomal protein expression and adherens junction molecule distribution.	('desmosomal protein expression', 'MPA', (122, 151))	('knock down', 'Var', (35, 45))	('DSC2', 'Gene', '1824', (30, 34))	('reduction', 'NegReg', (109, 118))	('RNAi', 'Gene', (49, 53))	('defects', 'NegReg', (61, 68))	('cell-cell adhesion', 'CPA', (72, 90))	('adherens junction molecule distribution', 'MPA', (156, 195))	('DSC2', 'Gene', (30, 34))
191794	25119898	A previous study of RNA interference (RNAi) in transformed colonic epithelial cells revealed the promotion of tumor cell proliferation in vitro and growth in vivo following knock down of DSC2.	('DSC2', 'Gene', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('promotion', 'PosReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('knock down', 'Var', (173, 183))	('DSC2', 'Gene', '1824', (187, 191))	('growth in', 'CPA', (148, 157))
191800	25119898	The loss of DSC2 initiates tumor cell metastasis by activating the beta-catenin pathway and eventually inducing an epithelial-mesenchymal transition-like process.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('initiates', 'PosReg', (17, 26))	('epithelial-mesenchymal transition-like process', 'CPA', (115, 161))	('tumor', 'Disease', (27, 32))	('DSC2', 'Gene', (12, 16))	('activating', 'Reg', (52, 62))	('inducing', 'Reg', (103, 111))	('DSC2', 'Gene', '1824', (12, 16))	('beta-catenin', 'Gene', (67, 79))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('beta-catenin', 'Gene', '1499', (67, 79))	('loss', 'Var', (4, 8))
191836	25119898	Silencing DSC2 had a marked effect on the membrane localization of these desmosomal proteins and on desmosomal junction formation (Fig.	('DSC2', 'Gene', '1824', (10, 14))	('membrane localization of these', 'MPA', (42, 72))	('desmosomal junction formation', 'MPA', (100, 129))	('Silencing', 'Var', (0, 9))	('DSC2', 'Gene', (10, 14))
191840	25119898	Therefore, the present study investigated the effects of DSC2 knock down on the localization of gamma-catenin and E-cadherin.	('DSC2', 'Gene', '1824', (57, 61))	('E-cadherin', 'Gene', (114, 124))	('knock down', 'Var', (62, 72))	('E-cadherin', 'Gene', '999', (114, 124))	('DSC2', 'Gene', (57, 61))
191844	25119898	Therefore, the present study investigated whether DSC2 depletion affects cytoskeleton rearrangement.	('DSC2', 'Gene', (50, 54))	('affects', 'Reg', (65, 72))	('cytoskeleton', 'MPA', (73, 85))	('investigated', 'Reg', (29, 41))	('depletion', 'Var', (55, 64))	('DSC2', 'Gene', '1824', (50, 54))
191846	25119898	Furthermore, phalloidin-coumarin staining indicated that DSC2 depletion affected the F-actin arrangement (Fig.	('DSC2', 'Gene', '1824', (57, 61))	('coumarin', 'Chemical', 'MESH:C030123', (24, 32))	('depletion', 'Var', (62, 71))	('DSC2', 'Gene', (57, 61))	('phalloidin', 'Chemical', 'MESH:D010590', (13, 23))	('affected', 'Reg', (72, 80))	('F-actin', 'MPA', (85, 92))
191848	25119898	These results indicated that DSC2 depletion resulted in cytoskeleton rearrangement, ultimately promoting cell invasive behavior.	('DSC2', 'Gene', (29, 33))	('cell invasive behavior', 'CPA', (105, 127))	('cytoskeleton rearrangement', 'MPA', (56, 82))	('depletion', 'Var', (34, 43))	('promoting', 'PosReg', (95, 104))	('DSC2', 'Gene', '1824', (29, 33))
191853	25119898	Using various approaches, the present study demonstrated that knock down of DSC2 in these cell lines caused defects in cell-cell adhesion, accompanied by reduced desmosomal junction formation, retraction of keratin intermediate filaments and F-actin cytoskeleton rearrangement.	('knock down', 'Var', (62, 72))	('DSC2', 'Gene', (76, 80))	('reduced', 'NegReg', (154, 161))	('keratin intermediate filaments', 'Protein', (207, 237))	('cell-cell adhesion', 'CPA', (119, 137))	('retraction', 'CPA', (193, 203))	('desmosomal junction formation', 'CPA', (162, 191))	('F-actin cytoskeleton rearrangement', 'CPA', (242, 276))	('actin cytoskeleton rearrangement', 'Phenotype', 'HP:0025200', (244, 276))	('defects', 'NegReg', (108, 115))	('DSC2', 'Gene', '1824', (76, 80))
191855	25119898	DSC2 depletion is highly associated with poor tumor differentiation, regional lymph node metastasis and poor prognosis.	('depletion', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('DSC2', 'Gene', '1824', (0, 4))	('tumor', 'Disease', (46, 51))	('regional lymph node metastasis', 'CPA', (69, 99))	('DSC2', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
191860	25119898	This leads to the conclusion that knocking down the expression of DSC2 by siRNA destabilizes other desmosomal proteins.	('knocking', 'Var', (34, 42))	('DSC2', 'Gene', (66, 70))	('destabilizes', 'NegReg', (80, 92))	('DSC2', 'Gene', '1824', (66, 70))	('expression', 'MPA', (52, 62))
191863	25119898	DSC2 depletion from the desmosome structure may compromise adhesive strength in several ways.	('depletion', 'Var', (5, 14))	('DSC2', 'Gene', '1824', (0, 4))	('compromise', 'NegReg', (48, 58))	('adhesive strength', 'CPA', (59, 76))	('DSC2', 'Gene', (0, 4))
191866	25119898	Uncoupling of these connections results in increased levels of free gamma-catenin and PKP2.	('PKP2', 'Gene', (86, 90))	('levels of free gamma-catenin', 'MPA', (53, 81))	('Uncoupling', 'Var', (0, 10))	('increased', 'PosReg', (43, 52))	('PKP2', 'Gene', '5318', (86, 90))
191894	24455548	Dissection can lead to aneurysmal change and early or late rupture.	('aneurysmal change', 'Phenotype', 'HP:0002617', (23, 40))	('rupture', 'Disease', (59, 66))	('aneurysmal change', 'Disease', (23, 40))	('lead to', 'Reg', (15, 22))	('rupture', 'Disease', 'MESH:D012421', (59, 66))	('Dissection', 'Var', (0, 10))	('aneurysm', 'Phenotype', 'HP:0002617', (23, 31))	('aneurysmal change', 'Disease', 'MESH:D000783', (23, 40))
191924	33932125	The density of CD31+ blood vessels and the expression of vascular endothelial growth factor C (VEGFC) in tumor xenografts were significantly associated with BACH1 levels according to the results of IHC and immunofluorescence (IF) analyses performed in vivo.	('CD31+', 'Var', (15, 20))	('VEGFC', 'Gene', (95, 100))	('BACH1 levels', 'MPA', (157, 169))	('vascular endothelial growth factor C', 'Gene', (57, 93))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('associated', 'Reg', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('vascular endothelial growth factor C', 'Gene', '7424', (57, 93))
191937	33932125	Aberrant expression of BACH1 contributes to tumor metastasis in breast cancer, 7 ,  8 ,  9  colorectal cancer, 10 ,  11 ,  12 ,  13  prostate cancer, 14  ovarian cancer, 15 ,  16  pancreatic cancer, 17  osteosarcoma, 18  and lung cancer.	('tumor metastasis in breast cancer', 'Disease', (44, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (180, 197))	('lung cancer', 'Disease', 'MESH:D008175', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('osteosarcoma', 'Disease', (203, 215))	('pancreatic cancer', 'Disease', (180, 197))	('osteosarcoma', 'Disease', 'MESH:D012516', (203, 215))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ovarian cancer', 'Phenotype', 'HP:0100615', (154, 168))	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('14  ovarian cancer', 'Disease', 'MESH:C535488', (150, 168))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (133, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (180, 197))	('tumor metastasis in breast cancer', 'Disease', 'MESH:D001943', (44, 77))	('colorectal cancer', 'Disease', (92, 109))	('lung cancer', 'Disease', (225, 236))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('prostate cancer', 'Disease', (133, 148))	('osteosarcoma', 'Phenotype', 'HP:0002669', (203, 215))	('BACH1', 'Gene', (23, 28))	('14  ovarian cancer', 'Disease', (150, 168))	('contributes', 'Reg', (29, 40))
191942	33932125	15  In lung cancer, BACH1 expression stimulates glycolysis by activating HK2 transcription and triggers glycolysis-dependent lung cancer metastasis.	('HK2', 'Gene', (73, 76))	('HK2', 'Gene', '3099', (73, 76))	('transcription', 'MPA', (77, 90))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('triggers', 'Reg', (95, 103))	('expression', 'Var', (26, 36))	('lung cancer', 'Disease', (7, 18))	('activating', 'PosReg', (62, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('glycolysis-dependent', 'MPA', (104, 124))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('glycolysis', 'MPA', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('BACH1', 'Gene', (20, 25))	('stimulates', 'PosReg', (37, 47))
191944	33932125	BACH1 knockdown inhibited the migration and invasion of ESCC cells in vitro and the growth and angiogenesis of xenograft tumors in vivo.	('inhibited', 'NegReg', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('knockdown', 'Var', (6, 15))	('BACH1', 'Gene', (0, 5))
191948	33932125	Tissue microarrays of ESCC, HEsoS105Su01 included 50 tumor tissues and paired esophageal epithelial tissues and ZH-ESC 77a included 77 tumor tissues, were purchased from Outdo Biotech and Zhuohao Medical Science and Technology (Shanghai, China).	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('HEsoS105Su01', 'Var', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (135, 140))	('ESCC', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (78, 98))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
191950	33932125	For BACH1, N-cadherin, vimentin and Slug, scores of 0-6, 0-3, 0-8, and 0-8 were considered low expression, and other scores were considered high expression.	('Slug', 'Gene', (36, 40))	('low', 'NegReg', (91, 94))	('0-8', 'Var', (62, 65))	('N-cadherin', 'Gene', (11, 21))	('vimentin', 'Gene', '7431', (23, 31))	('N-cadherin', 'Gene', '1000', (11, 21))	('vimentin', 'Gene', (23, 31))	('Slug', 'Gene', '6591', (36, 40))	('BACH1', 'Gene', (4, 9))
191968	33932125	In the in vivo xenograft experiment, a total of 5x105 KYSE170-shBACH1, KYSE150-BACH1, or corresponding control cells were subcutaneously injected into BALB/c nude mice.	('KYSE170-shBACH1', 'Var', (54, 69))	('KYSE150-BACH1', 'Var', (71, 84))	('KYSE150-BACH1', 'CellLine', 'CVCL:1348', (71, 84))	('nude mice', 'Species', '10090', (158, 167))
191980	33932125	The data of Western blot and qPCR analysis indicated that the expression of BACH1 was relatively higher in KYSE30 and KYSE170 cells and lower in KYSE150 and KYSE510 cells (Figure 2A and 2B), and the data of the IF assays showed that BACH1 was localized in the nucleus and cytoplasm of ESCC cells (Figure 2C).	('lower', 'NegReg', (136, 141))	('higher', 'PosReg', (97, 103))	('KYSE170', 'Var', (118, 125))	('BACH1', 'Gene', (76, 81))	('expression', 'MPA', (62, 72))	('KYSE30', 'Var', (107, 113))	('KYSE510', 'CellLine', 'CVCL:1354', (157, 164))
191983	33932125	BACH1 overexpression resulted in an apparent morphological transition from epithelial to mesenchymal phenotypes in KYSE150-BACH1 cells, and BACH1 depletion using two specific siRNAs resulted in significant epithelial morphology, some cells showed cobblestone-like morphology of KYSE170 and KYSE30 cells (Figure 4A).	('epithelial morphology', 'CPA', (206, 227))	('siRNAs', 'Disease', 'None', (175, 181))	('KYSE150-BACH1', 'CellLine', 'CVCL:1348', (115, 128))	('morphological transition', 'CPA', (45, 69))	('overexpression', 'Var', (6, 20))	('KYSE170', 'CPA', (278, 285))	('cobblestone-like morphology', 'CPA', (247, 274))	('resulted in', 'Reg', (182, 193))	('KYSE30 cells', 'CPA', (290, 302))	('epithelial', 'CPA', (75, 85))	('BACH1', 'Gene', (0, 5))	('siRNAs', 'Disease', (175, 181))
191985	33932125	As shown in Figure 4B-4E, knockdown of BACH1 suppressed the expression of N-cadherin, vimentin, and Slug and upregulated the levels of E-cadherin in KYSE30-siBACH1 and KYSE170-siBACH1 cells.	('expression', 'MPA', (60, 70))	('N-cadherin', 'Gene', (74, 84))	('upregulated', 'PosReg', (109, 120))	('vimentin', 'Gene', '7431', (86, 94))	('N-cadherin', 'Gene', '1000', (74, 84))	('Slug', 'Gene', '6591', (100, 104))	('vimentin', 'Gene', (86, 94))	('suppressed', 'NegReg', (45, 55))	('Slug', 'Gene', (100, 104))	('knockdown', 'Var', (26, 35))	('BACH1', 'Gene', (39, 44))	('E-cadherin', 'Gene', (135, 145))	('E-cadherin', 'Gene', '999', (135, 145))
191995	33932125	To determine whether the BACH1 binding site is involved in CDH2 transcriptional activation, we constructed luciferase reporter vectors with a 350 bp insertion (Chr18:28180381-28180731) of CDH2 promoter regions containing the BACH1-binding sequence or a corresponding mutated version with deletion of the BACH1-binding sequence (Figure 5A).	('deletion', 'Var', (288, 296))	('CDH2', 'Gene', (188, 192))	('CDH2', 'Gene', (59, 63))	('CDH2', 'Gene', '1000', (188, 192))	('CDH2', 'Gene', '1000', (59, 63))
191996	33932125	The relative luciferase activity of the CDH2 wild-type promoter was twofold higher in BACH1-overexpressing KYSE170 cells than that in KYSE170 cells transfected with a control vector (Figure 5D).	('CDH2', 'Gene', (40, 44))	('activity', 'MPA', (24, 32))	('KYSE170', 'Var', (107, 114))	('CDH2', 'Gene', '1000', (40, 44))	('BACH1-overexpressing', 'PosReg', (86, 106))	('BACH1-overexpressing', 'Gene', (86, 106))	('luciferase', 'Enzyme', (13, 23))	('higher', 'PosReg', (76, 82))
191997	33932125	However, the relative luciferase activity of the cells transfected with mutated CDH2 promoters was similar in BACH1-overexpressing and control vector-transfected KYSE170 cells.	('mutated', 'Var', (72, 79))	('CDH2', 'Gene', '1000', (80, 84))	('luciferase', 'Enzyme', (22, 32))	('activity', 'MPA', (33, 41))	('CDH2', 'Gene', (80, 84))
192004	33932125	A xenograft model was generated by subcutaneous injection of KYSE170-shBACH1/KYSE170-shCtrl and KYSE150-BACH1/KYSE150-vector cells into the flanks of nude mice, and xenograft tumors were resected and harvested.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('nude mice', 'Species', '10090', (150, 159))	('KYSE170-shBACH1/KYSE170-shCtrl', 'Var', (61, 91))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('KYSE150-BACH1', 'CellLine', 'CVCL:1348', (96, 109))
192005	33932125	The results showed that knockdown of BACH1 significantly attenuated the tumor growth because the tumors derived from KYSE170-shBACH1 cells were smaller than the tumors derived from the control cells (P < 0.01) (Figure 6A-6C); moreover, overexpression of BACH1 enhanced the tumor growth because the tumors derived from KYSE150-BACH1 cells were larger than the tumors derived from the control cells (P < 0.01) (Figure 6D-6F).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('overexpression', 'PosReg', (236, 250))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (298, 304))	('smaller', 'NegReg', (144, 151))	('BACH1', 'Gene', (37, 42))	('tumors', 'Disease', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (359, 365))	('tumor', 'Disease', (273, 278))	('attenuated', 'NegReg', (57, 67))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (298, 303))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (359, 364))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('KYSE150-BACH1', 'Var', (318, 331))	('tumor', 'Disease', (72, 77))	('KYSE150-BACH1', 'CellLine', 'CVCL:1348', (318, 331))	('tumors', 'Phenotype', 'HP:0002664', (359, 365))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('knockdown', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('BACH1', 'Gene', (254, 259))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('enhanced', 'PosReg', (260, 268))	('tumors', 'Disease', (298, 304))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', (359, 365))
192006	33932125	The results of immunohistochemical staining (IHC) of xenograft tumors derived from KYSE170-shBACH1 and KYSE170-shCtrl cells showed that BACH1 knockdown was accompanied by low expression of N-cadherin, vimentin, and Slug in vivo (Figure 6G and 6H).	('vimentin', 'Gene', '7431', (201, 209))	('expression', 'MPA', (175, 185))	('Slug', 'Gene', '6591', (215, 219))	('low', 'NegReg', (171, 174))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('vimentin', 'Gene', (201, 209))	('N-cadherin', 'Gene', (189, 199))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('N-cadherin', 'Gene', '1000', (189, 199))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('BACH1', 'Gene', (136, 141))	('Slug', 'Gene', (215, 219))	('knockdown', 'Var', (142, 151))
192008	33932125	The results showed that BACH1 knockdown significantly inhibited the density of CD31+ blood vessels and VEGFC expression in xenograft tumor tissues derived from mice subcutaneously injected with KYSE170-shBACH1 cells compared with those derived from mice injected with control KYSE170-shCtrl cells (Figure 6I and 6J).	('inhibited', 'NegReg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('density', 'CPA', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('CD31+ blood vessels', 'CPA', (79, 98))	('mice', 'Species', '10090', (160, 164))	('tumor', 'Disease', (133, 138))	('knockdown', 'Var', (30, 39))	('VEGFC expression', 'Gene', (103, 119))	('mice', 'Species', '10090', (249, 253))	('BACH1', 'Gene', (24, 29))
192015	33932125	The results of the present study indicated that BACH1 promoted the migration and invasion of ESCC cells in vitro and that silencing BACH1 attenuated the growth of xenograft tumors in vivo.	('promoted', 'PosReg', (54, 62))	('BACH1', 'Gene', (48, 53))	('invasion', 'CPA', (81, 89))	('attenuated', 'NegReg', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('BACH1', 'Gene', (132, 137))	('migration', 'CPA', (67, 76))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('silencing', 'Var', (122, 131))
192030	33932125	Inhibition of BACH1 expression markedly repressed the expression of VEGFC in ESCC cells both in vitro and in vivo, attenuated the density of CD31+ blood vessels, and reduced angiogenesis in tumor xenografts in agreement with the results of the previous study that demonstrated that BACH1 significantly promotes tumor growth and angiogenesis in colorectal cancer.	('BACH1', 'Gene', (14, 19))	('VEGFC', 'Gene', (68, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (344, 361))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('angiogenesis', 'CPA', (328, 340))	('colorectal cancer', 'Disease', (344, 361))	('angiogenesis in', 'CPA', (174, 189))	('tumor', 'Disease', (311, 316))	('reduced', 'NegReg', (166, 173))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('tumor', 'Disease', (190, 195))	('colorectal cancer', 'Phenotype', 'HP:0003003', (344, 361))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('density', 'MPA', (130, 137))	('attenuated', 'NegReg', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('promotes', 'PosReg', (302, 310))
192031	33932125	Notably, recent studies have shown that VEGFC is presumably involved in the induction of the EMT, and high VEGFC expression downregulates E-cadherin and upregulates N-cadherin and vimentin.	('E-cadherin', 'Gene', (138, 148))	('vimentin', 'Gene', '7431', (180, 188))	('high', 'Var', (102, 106))	('VEGFC', 'Gene', (107, 112))	('vimentin', 'Gene', (180, 188))	('EMT', 'CPA', (93, 96))	('N-cadherin', 'Gene', (165, 175))	('expression', 'Var', (113, 123))	('N-cadherin', 'Gene', '1000', (165, 175))	('downregulates', 'NegReg', (124, 137))	('upregulates', 'PosReg', (153, 164))	('E-cadherin', 'Gene', '999', (138, 148))
192034	32220892	Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy Esophageal cancer (ESCA) is a deadly malignancy with a 5-year survival rate of only 5-20%, which has remained unchanged for decades.	('Wee1', 'Gene', (0, 4))	('AZD1775', 'Var', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (64, 70))	('Wee1', 'Gene', '7465', (0, 4))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('deadly malignancy', 'Disease', 'MESH:D009369', (117, 134))	('cancer', 'Disease', (98, 104))	('Sensitizes', 'Reg', (42, 52))	('deadly malignancy', 'Disease', (117, 134))	('AZD1775', 'Chemical', 'MESH:C549567', (22, 29))
192035	32220892	ESCA possesses a high frequency of TP53 mutations leading to dysfunctional G1 cell cycle checkpoint, which likely makes ESCA cells highly reliant upon G2/M checkpoint for adaptation to DNA replication stress and DNA damage after radiation.	('TP53', 'Gene', '7157', (35, 39))	('leading to', 'Reg', (50, 60))	('TP53', 'Gene', (35, 39))	('dysfunctional', 'MPA', (61, 74))	('mutations', 'Var', (40, 49))
192039	32220892	AZD1775 (100 nM) as monotherapy did not alter the viability of ESCA cells, but significantly radiosensitized ESCA cells.	('radiosensitized', 'NegReg', (93, 108))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('AZD1775', 'Var', (0, 7))	('ESCA', 'Disease', (109, 113))
192040	32220892	AZD1775 significantly abrogated radiation-induced G2/M phase arrest and attenuation of p-CDK1-Y15.	('arrest', 'Disease', (61, 67))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('CDK1', 'Gene', (89, 93))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('CDK1', 'Gene', '983', (89, 93))	('abrogated', 'NegReg', (22, 31))	('attenuation', 'NegReg', (72, 83))
192041	32220892	Moreover, AZD1775 increased radiation-induced mitotic catastrophe, which was accompanied by increased gammaH2AX levels, and subsequently reduced survival after radiation.	('radiation-induced mitotic catastrophe', 'CPA', (28, 65))	('increased', 'PosReg', (18, 27))	('H2AX', 'Gene', '3014', (107, 111))	('H2AX', 'Gene', (107, 111))	('AZD1775', 'Var', (10, 17))	('AZD1775', 'Chemical', 'MESH:C549567', (10, 17))	('increased', 'PosReg', (92, 101))	('survival', 'CPA', (145, 153))	('reduced', 'NegReg', (137, 144))
192042	32220892	Importantly, AZD1775 in combination with radiotherapy resulted in marked tumor regression of ESCA tumor xenografts.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('AZD1775', 'Chemical', 'MESH:C549567', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (98, 103))	('AZD1775', 'Var', (13, 20))
192044	32220892	Our findings suggest that inhibition of Wee1 by AZD1775 is an effective strategy for radiosensitization in esophageal cancer and warrants clinical testing.	('Wee1', 'Protein', (40, 44))	('esophageal cancer', 'Disease', (107, 124))	('AZD1775', 'Var', (48, 55))	('inhibition', 'NegReg', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('AZD1775', 'Chemical', 'MESH:C549567', (48, 55))
192052	32220892	Aberrant activation of CDKs and hence uncontrolled cell cycle progression is a hallmark of cancer cells.	('CDKs', 'Gene', (23, 27))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CDKs', 'Gene', '983;1017', (23, 27))
192053	32220892	Many human cancers have deficits in G1/S checkpoint due to mutations in the p53 signaling axis including mutations of TP53, CDKN2A, and RB.	('deficits', 'NegReg', (24, 32))	('CDKN2A', 'Gene', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('G1/S checkpoint', 'MPA', (36, 51))	('CDKN2A', 'Gene', '1029', (124, 130))	('TP53', 'Gene', '7157', (118, 122))	('mutations', 'Var', (105, 114))	('TP53', 'Gene', (118, 122))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('mutations', 'Var', (59, 68))	('cancers', 'Disease', (11, 18))	('human', 'Species', '9606', (5, 10))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
192060	32220892	Forced cell cycle progression in the setting of DNA damage perpetuates DNA and chromatin damage, and leads to cell death because of irreparable genetic lesions.	('DNA', 'MPA', (71, 74))	('genetic lesions', 'Disease', 'MESH:D020022', (144, 159))	('damage', 'Var', (52, 58))	('genetic lesions', 'Disease', (144, 159))	('chromatin damage', 'MPA', (79, 95))
192062	32220892	Given the pivotal role for Wee1 in the regulation of CDK1 activity, targeting Wee1 has been proposed for the sensitization of cancer cells to radiotherapy and chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('activity', 'MPA', (58, 66))	('CDK1', 'Gene', '983', (53, 57))	('CDK1', 'Gene', (53, 57))	('targeting', 'Var', (68, 77))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Wee1', 'Gene', (78, 82))
192063	32220892	Large-scale genomic studies have found that esophageal cancer has an extremely high frequency of TP53 mutations, ranging from 44% to 93%.	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('TP53', 'Gene', '7157', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('esophageal cancer', 'Disease', (44, 61))
192064	32220892	Recently, The Cancer Genome Atlas (TCGA) demonstrated that TP53 mutations were the single most common significantly mutated gene in ESCA, occurring in ~71% and ~91% of esophageal adenocarcinoma and esophageal squamous cell carcinoma, respectively.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (168, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('TP53', 'Gene', (59, 63))	('adenocarcinoma', 'Disease', (179, 193))	('adenocarcinoma', 'Disease', 'MESH:D000230', (179, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (198, 232))	('ESCA', 'Disease', (132, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (209, 232))	('mutations', 'Var', (64, 73))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer', 'Disease', (14, 20))	('occurring', 'Reg', (138, 147))	('TP53', 'Gene', '7157', (59, 63))	('Cancer', 'Disease', 'MESH:D009369', (14, 20))	('esophageal squamous cell carcinoma', 'Disease', (198, 232))
192065	32220892	Therefore, esophageal cancer cells may depend on G2/M checkpoint for survival and may be very sensitive to G2/M checkpoint abrogation by Wee1 inhibition.	('esophageal cancer', 'Disease', 'MESH:D004938', (11, 28))	('inhibition', 'Var', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('esophageal cancer', 'Disease', (11, 28))
192066	32220892	AZD1775 is a novel small molecule inhibitor that disrupts G2/M checkpoint by directly inhibiting Wee1 kinase.	('G2/M checkpoint', 'MPA', (58, 73))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('disrupts', 'NegReg', (49, 57))	('inhibiting', 'NegReg', (86, 96))	('Wee1 kinase', 'Pathway', (97, 108))
192069	32220892	In addition to inhibiting G2/M checkpoint, AZD1775 has been shown to induce DNA replication stress via nucleotide exhaustion, and to reduce homologous recombination repair.	('AZD1775', 'Chemical', 'MESH:C549567', (43, 50))	('reduce', 'NegReg', (133, 139))	('nucleotide exhaustion', 'MPA', (103, 124))	('homologous recombination repair', 'MPA', (140, 171))	('DNA replication stress', 'MPA', (76, 98))	('induce', 'PosReg', (69, 75))	('inhibiting', 'NegReg', (15, 25))	('AZD1775', 'Var', (43, 50))	('G2/M', 'Protein', (26, 30))
192071	32220892	Thus, targeting Wee1 may force cells to enter mitosis in the presence of incomplete DNA replication, which might exacerbate replication stress and development of lethal DNA damage.	('incomplete DNA', 'Var', (73, 87))	('mitosis', 'CPA', (46, 53))	('force', 'Reg', (25, 30))	('enter', 'PosReg', (40, 45))	('targeting', 'Var', (6, 15))	('men', 'Species', '9606', (154, 157))	('Wee1', 'Gene', (16, 20))	('exacerbate', 'PosReg', (113, 123))	('replication stress', 'MPA', (124, 142))
192072	32220892	AZD1775 has been tested preclinically in many types of cancers, and has been shown to radiosensitize and chemosensitize certain cancers, including pancreatic, breast, prostate, lung, and glioblastoma cancers.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('AZD1775', 'Var', (0, 7))	('glioblastoma cancers', 'Disease', (187, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('prostate', 'Disease', (167, 175))	('lung', 'Disease', (177, 181))	('glioblastoma', 'Phenotype', 'HP:0012174', (187, 199))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancers', 'Disease', (200, 207))	('glioblastoma cancers', 'Disease', 'MESH:D009369', (187, 207))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('pancreatic', 'Disease', (147, 157))	('cancers', 'Disease', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('radiosensitize', 'CPA', (86, 100))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('breast', 'Disease', (159, 165))	('chemosensitize', 'CPA', (105, 119))
192076	32220892	We found that abrogation of G2/M checkpoint by targeting Wee1 kinase with AZD1775 markedly sensitizes esophageal cancer cells to radiotherapy in vitro and in mouse xenografts.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('targeting', 'Reg', (47, 56))	('mouse', 'Species', '10090', (158, 163))	('AZD1775', 'Chemical', 'MESH:C549567', (74, 81))	('sensitizes', 'Reg', (91, 101))	('radiotherapy', 'CPA', (129, 141))	('Wee1', 'Gene', (57, 61))	('esophageal cancer', 'Disease', (102, 119))	('AZD1775', 'Gene', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('abrogation', 'Var', (14, 24))
192077	32220892	Our findings suggest that AZD1775 in combination with radiotherapy may improve the therapeutic outcome of esophageal cancer patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('therapeutic outcome', 'CPA', (83, 102))	('AZD1775', 'Var', (26, 33))	('esophageal cancer', 'Disease', (106, 123))	('AZD1775', 'Chemical', 'MESH:C549567', (26, 33))	('patients', 'Species', '9606', (124, 132))	('improve', 'PosReg', (71, 78))
192119	32220892	All four cell lines used in our study have TP53 mutation, including esophageal adenocarcinoma cell lines (OE33, SK4, and FLO1) and an esophageal squamous cell carcinoma cell line (KYSE30).	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('SK4', 'Gene', '3783', (112, 115))	('esophageal squamous cell carcinoma', 'Disease', (134, 168))	('SK4', 'Gene', (112, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinoma', 'Disease', (79, 93))	('mutation', 'Var', (48, 56))	('adenocarcinoma', 'Disease', 'MESH:D000230', (79, 93))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (68, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (134, 168))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
192124	32220892	In combination with radiation however, AZD1775 could effectively sensitize ESCA cells to radiation treatment, with dose enhancement ratios (DER) up to 3.14 in SK4 cells, 1.46 in OE33 cells, 1.34 in FLO1 cells, and 1.23 in KYSE cells (Fig.	('AZD1775', 'Chemical', 'MESH:C549567', (39, 46))	('ESCA', 'Disease', (75, 79))	('SK4', 'Gene', (159, 162))	('men', 'Species', '9606', (104, 107))	('enhancement', 'PosReg', (120, 131))	('SK4', 'Gene', '3783', (159, 162))	('AZD1775', 'Var', (39, 46))	('men', 'Species', '9606', (127, 130))	('sensitize', 'Reg', (65, 74))
192127	32220892	We explored whether the radiosensitizing effects of AZD1775 are associated with abrogation of radiation-induced G2/M cell cycle arrest in asynchronously growing cells by flow cytometry assay.	('arrest', 'Disease', 'MESH:D006323', (128, 134))	('AZD1775', 'Var', (52, 59))	('AZD1775', 'Chemical', 'MESH:C549567', (52, 59))	('arrest', 'Disease', (128, 134))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (117, 134))
192129	32220892	However, pre-treatment of cells with AZD1775 at 3 hrs before radiation significantly reduced the accumulation of G2/M phase cells after radiation (Fig.	('AZD1775', 'Chemical', 'MESH:C549567', (37, 44))	('men', 'Species', '9606', (18, 21))	('G2/M phase cells', 'CPA', (113, 129))	('reduced', 'NegReg', (85, 92))	('AZD1775', 'Var', (37, 44))
192131	32220892	Immunoblotting analyses showed AZD1775 inhibited Wee1 and CDK1 phosphorylation in a time-dependent manner, with maximal changes noted 24 hrs after treatment (Fig.	('inhibited', 'NegReg', (39, 48))	('AZD1775', 'Var', (31, 38))	('AZD1775', 'Chemical', 'MESH:C549567', (31, 38))	('men', 'Species', '9606', (152, 155))	('phosphorylation', 'MPA', (63, 78))	('CDK1', 'Gene', (58, 62))	('CDK1', 'Gene', '983', (58, 62))	('Wee1', 'Protein', (49, 53))
192133	32220892	Exposing cells to AZD1775 before radiation attenuated radiation-induced Wee1 and CDK1 phosphorylation, most notable at 24 hrs after radiation.	('Wee1', 'Protein', (72, 76))	('CDK1', 'Gene', '983', (81, 85))	('phosphorylation', 'MPA', (86, 101))	('AZD1775', 'Var', (18, 25))	('CDK1', 'Gene', (81, 85))	('AZD1775', 'Chemical', 'MESH:C549567', (18, 25))	('attenuated', 'NegReg', (43, 53))
192134	32220892	Interestingly, AZD1775 alone induced gammaH2AX expression and enhanced radiation-mediated increase of gammaH2AX particularly after 24 hrs of treatment.	('H2AX', 'Gene', '3014', (42, 46))	('H2AX', 'Gene', '3014', (107, 111))	('H2AX', 'Gene', (42, 46))	('H2AX', 'Gene', (107, 111))	('enhanced', 'PosReg', (62, 70))	('men', 'Species', '9606', (146, 149))	('AZD1775', 'Var', (15, 22))	('induced', 'PosReg', (29, 36))	('AZD1775', 'Chemical', 'MESH:C549567', (15, 22))	('expression', 'MPA', (47, 57))
192135	32220892	Most studies have shown that the therapeutic effects AZD1775 is related to the abrogation of the G2 checkpoint and/or unscheduled mitotic entry.	('AZD1775', 'Chemical', 'MESH:C549567', (53, 60))	('AZD1775', 'Var', (53, 60))	('G2 checkpoint', 'Protein', (97, 110))
192136	32220892	However, emerging evidence suggest that Wee1 inhibition suppresses DNA damage repair and induces replication stress, both of which leads to phosphorylation of H2AX.	('DNA damage repair', 'MPA', (67, 84))	('phosphorylation', 'MPA', (140, 155))	('induces', 'Reg', (89, 96))	('H2AX', 'Gene', '3014', (159, 163))	('H2AX', 'Gene', (159, 163))	('Wee1', 'Gene', (40, 44))	('leads to', 'Reg', (131, 139))	('replication stress', 'CPA', (97, 115))	('inhibition', 'Var', (45, 55))	('suppresses', 'NegReg', (56, 66))
192139	32220892	The abrogation of G2/M phase cell cycle arrest and enhancement of DNA damage by AZD1775 in ESCA cells treated with radiation suggests that AZD1775 can promote irradiated ESCA cells to prematurely enter into cell mitosis before completion of DNA repair.	('enhancement', 'PosReg', (51, 62))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (29, 46))	('AZD1775', 'Gene', (80, 87))	('promote', 'PosReg', (151, 158))	('AZD1775', 'Chemical', 'MESH:C549567', (80, 87))	('DNA', 'MPA', (66, 69))	('arrest', 'Disease', 'MESH:D006323', (40, 46))	('AZD1775', 'Var', (139, 146))	('AZD1775', 'Chemical', 'MESH:C549567', (139, 146))	('arrest', 'Disease', (40, 46))	('men', 'Species', '9606', (58, 61))
192140	32220892	To test this hypothesis, FLO1 and OE33 cells were cultured on cover slides, and treated with vehicle, AZD1775, 4Gy radiation, or the combination of AZD1775 for 3 hrs followed by 4Gy.	('AZD1775', 'Chemical', 'MESH:C549567', (102, 109))	('AZD1775', 'Var', (102, 109))	('AZD1775', 'Var', (148, 155))	('AZD1775', 'Chemical', 'MESH:C549567', (148, 155))
192142	32220892	In comparison to vehicle control, AZD1775 alone did not induce mitotic catastrophe.	('AZD1775', 'Chemical', 'MESH:C549567', (34, 41))	('AZD1775', 'Var', (34, 41))	('mitotic catastrophe', 'CPA', (63, 82))
192143	32220892	Conversely, 4 Gy radiation treatment resulted in accumulation of cells experiencing mitotic catastrophe, which was significantly enhanced by AZD1775 in both cell lines (Fig.	('enhanced', 'PosReg', (129, 137))	('accumulation', 'PosReg', (49, 61))	('AZD1775', 'Var', (141, 148))	('men', 'Species', '9606', (32, 35))	('AZD1775', 'Chemical', 'MESH:C549567', (141, 148))	('cells experiencing mitotic catastrophe', 'CPA', (65, 103))
192144	32220892	Thus, the combination of AZD1775 with radiation resulted in a significantly higher incidence of mitotic catastrophe than radiation treatment alone.	('AZD1775', 'Var', (25, 32))	('AZD1775', 'Chemical', 'MESH:C549567', (25, 32))	('mitotic catastrophe', 'CPA', (96, 115))	('combination', 'Interaction', (10, 21))	('men', 'Species', '9606', (136, 139))
192145	32220892	We found that AZD1775 attenuates radiation-induced G2/M phase arrest, enhances radiation mediated DNA damage, causes premature entrance into mitosis, and finally leads to mitotic cell death.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('AZD1775', 'Var', (14, 21))	('premature entrance', 'MPA', (117, 135))	('arrest', 'Disease', (62, 68))	('AZD1775', 'Chemical', 'MESH:C549567', (14, 21))	('leads to', 'Reg', (162, 170))	('radiation mediated DNA damage', 'MPA', (79, 108))	('causes', 'Reg', (110, 116))	('attenuates', 'NegReg', (22, 32))	('mitotic cell death', 'CPA', (171, 189))	('enhances', 'PosReg', (70, 78))
192151	32220892	2B, exposure of FLO1 or OE33 cells to AZD1775 before and during fractionated radiation still effectively radiosensitized ESCA cells and abrogated cell recovery (Fig.	('radiosensitized', 'NegReg', (105, 120))	('cell recovery', 'CPA', (146, 159))	('AZD1775', 'Var', (38, 45))	('AZD1775', 'Chemical', 'MESH:C549567', (38, 45))	('ESCA', 'Disease', (121, 125))	('abrogated', 'NegReg', (136, 145))
192152	32220892	These results indicate a comparable enhancement of cell death by AZD1775 in ESCA cells when combining AZD1775 with either fractionated or single fraction radiation.	('AZD1775', 'Chemical', 'MESH:C549567', (102, 109))	('AZD1775', 'Var', (65, 72))	('enhancement', 'PosReg', (36, 47))	('AZD1775', 'Chemical', 'MESH:C549567', (65, 72))	('cell death', 'CPA', (51, 61))	('men', 'Species', '9606', (43, 46))
192154	32220892	To determine if Wee1 inhibition could effectively radiosensitize ESCA cells in vivo, we further explored the combined treatment of AZD1775 and radiation in vivo using nude mice xenografts with FLO1 and OE33 cells.	('ESCA', 'Disease', (65, 69))	('nude mice', 'Species', '10090', (167, 176))	('inhibition', 'Var', (21, 31))	('men', 'Species', '9606', (123, 126))	('AZD1775', 'Chemical', 'MESH:C549567', (131, 138))
192155	32220892	When tumors reached 100-150 mm3, the mice were randomized to groups of treatment with vehicle, AZD1775 alone, 4 Gy radiation alone, or the combination of AZD1775 + 4Gy (mice were treated with AZD1775 2 hrs before radiation).	('tumors', 'Disease', (5, 11))	('AZD1775', 'Chemical', 'MESH:C549567', (154, 161))	('AZD1775', 'Chemical', 'MESH:C549567', (95, 102))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('AZD1775', 'Chemical', 'MESH:C549567', (192, 199))	('men', 'Species', '9606', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (169, 173))	('AZD1775', 'Var', (95, 102))	('AZD1775', 'Var', (154, 161))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('mice', 'Species', '10090', (37, 41))
192159	32220892	However, AZD1775 in combination with radiation treatment led to remarkable and sustained tumor regression of both FLO1 and OE33 xenografts (Fig.	('men', 'Species', '9606', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('AZD1775', 'Var', (9, 16))	('AZD1775', 'Chemical', 'MESH:C549567', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
192161	32220892	Consistent with our in vitro data, the combination of AZD1775 and IR significantly increased mitotic catastrophe in tumor xenografts compare to IR treatment alone (Fig.	('increased', 'PosReg', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('men', 'Species', '9606', (152, 155))	('mitotic catastrophe in', 'CPA', (93, 115))	('AZD1775', 'Var', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('AZD1775', 'Chemical', 'MESH:C549567', (54, 61))
192162	32220892	Moreover, the majority of FLO1 and OE33 tumors showed no evidence of tumor recurrence after treatment with AZD1775 in combination with radiation (survival curves shown in Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('FLO1', 'Gene', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', (69, 74))	('men', 'Species', '9606', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('AZD1775', 'Var', (107, 114))	('men', 'Species', '9606', (177, 180))	('AZD1775', 'Chemical', 'MESH:C549567', (107, 114))	('OE33', 'Gene', (35, 39))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumors', 'Disease', (40, 46))
192166	32220892	AZD1775 reduced the phosphorylation of Wee1 and CDK1 as well as the protein levels of cyclin A2, B1, E1 and E2, while increasing levels of phospho-histone H3 (a marker of mitotic cells) (Fig.	('increasing', 'PosReg', (118, 128))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('phospho-histone H3', 'MPA', (139, 157))	('reduced', 'NegReg', (8, 15))	('phosphorylation', 'MPA', (20, 35))	('levels', 'MPA', (129, 135))	('cyclin A2, B1, E1 and E2', 'Gene', '890;891;6080', (86, 110))	('protein levels', 'MPA', (68, 82))	('CDK1', 'Gene', (48, 52))	('Wee1', 'Gene', (39, 43))	('CDK1', 'Gene', '983', (48, 52))
192167	32220892	Taken together, these findings indicate AZD1775 is promoting G2/M phase cell cycle progression.	('AZD1775', 'Var', (40, 47))	('AZD1775', 'Chemical', 'MESH:C549567', (40, 47))	('G2/M phase cell cycle progression', 'CPA', (61, 94))	('promoting', 'PosReg', (51, 60))
192171	32220892	Esophageal cancer cells often lack a functional G1 checkpoint due to a high frequency of TP53 mutations.	('TP53', 'Gene', '7157', (89, 93))	('lack', 'NegReg', (30, 34))	('TP53', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mutations', 'Var', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
192172	32220892	Based on TCGA data, up to 91% of squamous cell carcinoma and 71% of adenocarcinoma esophageal cancers possess a TP53 mutation making them heavily dependent on the G2/M checkpoint to survive DNA damage and replication stress.	('adenocarcinoma esophageal cancers', 'Disease', (68, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (33, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('squamous cell carcinoma', 'Disease', (33, 56))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TP53', 'Gene', '7157', (112, 116))	('mutation', 'Var', (117, 125))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('adenocarcinoma esophageal cancers', 'Disease', 'MESH:D004938', (68, 101))	('TP53', 'Gene', (112, 116))
192174	32220892	In addition, AZD1775 treatment led to a comparable enhancement of cytotoxicity in ESCA cells treated with either fractionated radiation or single dose radiation.	('enhancement', 'PosReg', (51, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('AZD1775', 'Chemical', 'MESH:C549567', (13, 20))	('men', 'Species', '9606', (26, 29))	('cytotoxicity', 'Disease', (66, 78))	('AZD1775', 'Var', (13, 20))	('men', 'Species', '9606', (58, 61))
192175	32220892	Mechanistically, AZD1775 attenuated radiation-induced G2/M phase arrest, which was accompanied by enhanced radiation-induced mitotic catastrophe and DNA damage.	('enhanced', 'PosReg', (98, 106))	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('attenuated', 'NegReg', (25, 35))	('AZD1775', 'Chemical', 'MESH:C549567', (17, 24))	('arrest', 'Disease', (65, 71))	('DNA damage', 'CPA', (149, 159))	('AZD1775', 'Var', (17, 24))
192176	32220892	Our findings suggest that Wee1 kinase specific inhibitor AZD1775 is an effective radiosensitizer for esophageal cancer.	('AZD1775', 'Chemical', 'MESH:C549567', (57, 64))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('AZD1775', 'Var', (57, 64))
192180	32220892	Previous studies have shown that AZD1775 is a potent and selective small molecule inhibitor of Wee1 kinase and has been shown to sensitize tumor cells to both chemotherapy and radiation.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Wee1', 'Enzyme', (95, 99))	('sensitize', 'Reg', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('AZD1775', 'Var', (33, 40))	('AZD1775', 'Chemical', 'MESH:C549567', (33, 40))
192182	32220892	Moreover, we demonstrated that AZD1775 potently inhibited the phosphorylation of both Wee1 and CDK1 in the absence or presence of radiation.	('AZD1775', 'Var', (31, 38))	('Wee1', 'Protein', (86, 90))	('CDK1', 'Gene', (95, 99))	('phosphorylation', 'MPA', (62, 77))	('CDK1', 'Gene', '983', (95, 99))	('AZD1775', 'Chemical', 'MESH:C549567', (31, 38))	('inhibited', 'NegReg', (48, 57))
192183	32220892	Consistent with the role for Wee1 in G2/M checkpoint regulation, AZD1775 prevented IR-induced G2/M phase cell cycle arrest, which was accompanied with enhanced mitotic catastrophe and gammaH2AX, indicative of enhanced cell death and DNA damage.	('mitotic catastrophe', 'CPA', (160, 179))	('H2AX', 'Gene', (189, 193))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (105, 122))	('AZD1775', 'Var', (65, 72))	('enhanced', 'PosReg', (151, 159))	('enhanced', 'PosReg', (209, 217))	('prevented', 'NegReg', (73, 82))	('AZD1775', 'Chemical', 'MESH:C549567', (65, 72))	('arrest', 'Disease', 'MESH:D006323', (116, 122))	('H2AX', 'Gene', '3014', (189, 193))	('arrest', 'Disease', (116, 122))
192184	32220892	Interestingly, we noted AZD1775 caused reductions in E, A, and B-type cyclins.	('cyclins', 'Gene', '891', (70, 77))	('AZD1775', 'Var', (24, 31))	('AZD1775', 'Chemical', 'MESH:C549567', (24, 31))	('reductions', 'NegReg', (39, 49))	('cyclins', 'Gene', (70, 77))	('B-type', 'Protein', (63, 69))
192188	32220892	Taken together, AZD1775 potently inhibits Wee1 in ESCA cells, thereby promoting entry from S and G2 through M phase, and thus preventing Wee1 from protecting ESCA cells from the effects of radiotherapy.	('promoting', 'PosReg', (70, 79))	('AZD1775', 'Var', (16, 23))	('AZD1775', 'Chemical', 'MESH:C549567', (16, 23))	('preventing', 'NegReg', (126, 136))	('inhibits', 'NegReg', (33, 41))	('entry', 'MPA', (80, 85))
192202	32220892	Our results showed that AZD1775 in combination with radiotherapy resulted in virtually complete tumor regression of ESCA tumor xenografts.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('AZD1775', 'Var', (24, 31))	('AZD1775', 'Chemical', 'MESH:C549567', (24, 31))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
192205	32220892	All the four ESCA cell lines used in this study have TP53 mutations.	('mutations', 'Var', (58, 67))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))
192206	32220892	However, besides TP53 mutation, SK4 cells have additional KRAS and PIK3CA mutation (https://portals.broadinstitute.org/ccle).	('KRAS', 'Gene', (58, 62))	('SK4', 'Gene', (32, 35))	('mutation', 'Var', (74, 82))	('PIK3CA', 'Gene', '5290', (67, 73))	('KRAS', 'Gene', '3845', (58, 62))	('TP53', 'Gene', '7157', (17, 21))	('SK4', 'Gene', '3783', (32, 35))	('PIK3CA', 'Gene', (67, 73))	('TP53', 'Gene', (17, 21))
192207	32220892	KRAS and PIK3CA mutations drive tumorigenesis via multiple mechanisms, one of which is to induce DNA replication stress leading to genomic instability.	('drive', 'Reg', (26, 31))	('PIK3CA', 'Gene', '5290', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutations', 'Var', (16, 25))	('genomic instability', 'MPA', (131, 150))	('induce', 'Reg', (90, 96))	('DNA replication stress', 'MPA', (97, 119))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('PIK3CA', 'Gene', (9, 15))	('tumor', 'Disease', (32, 37))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
192209	32220892	Thus, ESCA cells with KRAS and PIK3CA mutations might may have become more dependent on Wee1 kinase for survival due to increased replication stress.	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', '5290', (31, 37))	('KRAS', 'Gene', (22, 26))	('KRAS', 'Gene', '3845', (22, 26))	('mutations', 'Var', (38, 47))
192210	32220892	It will be important to determine whether ESCA with KRAS and/or PIK3CA mutations are hypersensitive to Wee1 inhibitors in future preclinical and clinical studies.	('PIK3CA', 'Gene', (64, 70))	('KRAS', 'Gene', (52, 56))	('ESCA', 'Disease', (42, 46))	('KRAS', 'Gene', '3845', (52, 56))	('PIK3CA', 'Gene', '5290', (64, 70))	('mutations', 'Var', (71, 80))	('hypersensitive', 'Disease', 'MESH:D004342', (85, 99))	('hypersensitive', 'Disease', (85, 99))
192211	32220892	In addition, it will be critical to determine whether TP53 mutant status confers increased sensitivity to AZD1775 and radiation.	('TP53', 'Gene', (54, 58))	('AZD1775', 'Chemical', 'MESH:C549567', (106, 113))	('mutant', 'Var', (59, 65))	('TP53', 'Gene', '7157', (54, 58))	('increased', 'PosReg', (81, 90))	('sensitivity', 'MPA', (91, 102))
192212	32220892	In our preliminary studies, we found that the combination of AZD1775 and radiation did not radiosensitize TP53 intact AGS adenocarcinoma cells (Supplementary Fig.	('AGS adenocarcinoma', 'Disease', 'MESH:C535607', (118, 136))	('TP53', 'Gene', '7157', (106, 110))	('AZD1775', 'Chemical', 'MESH:C549567', (61, 68))	('AGS adenocarcinoma', 'Disease', (118, 136))	('men', 'Species', '9606', (150, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('AZD1775', 'Var', (61, 68))	('TP53', 'Gene', (106, 110))
192213	32220892	Finally, further studies are needed to assess whether AZD1755 sensitizes ESCA cells to DNA-damaging chemotherapies such as platinum-based drugs or other chemotherapeutics which promote replication stress.	('AZD1755', 'Chemical', '-', (54, 61))	('AZD1755', 'Var', (54, 61))	('sensitizes', 'Reg', (62, 72))	('platinum', 'Chemical', 'MESH:D010984', (123, 131))
192216	32220892	This trial was based on preclinical data combining Wee1 inhibitor with gemcitabine and radiation.	('gemcitabine', 'Chemical', 'MESH:C056507', (71, 82))	('Wee1', 'Gene', (51, 55))	('inhibitor', 'Var', (56, 65))
192218	32220892	In summary, our results demonstrated a potent inhibitory role for Wee1 kinase inhibitor AZD1775 in cell cycle checkpoints in response to IR-induced DNA double strand breaks; importantly, AZD1775 enhanced IR-mediated cell death in vitro and maintained the suppression of ESCA mouse xenografts by radiotherapy in vivo.	('suppression', 'CPA', (255, 266))	('mouse', 'Species', '10090', (275, 280))	('enhanced', 'PosReg', (195, 203))	('AZD1775', 'Var', (187, 194))	('ESCA', 'Disease', (270, 274))	('IR-mediated cell death', 'CPA', (204, 226))	('AZD1775', 'Chemical', 'MESH:C549567', (187, 194))	('AZD1775', 'Chemical', 'MESH:C549567', (88, 95))
192220	32220892	Due to the high incidence of TP53 mutations and the dependence on the Wee1-mediated G2/M checkpoint to survive DNA damage, esophageal cancer is a logical site to consider the addition of a Wee1 kinase inhibitor to standard neoadjuvant therapy.	('esophageal cancer', 'Disease', (123, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (34, 43))
192221	32220892	We believe our study warrants a phase I trial testing AZD1775 in combination with radiation or chemoradiation for esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('AZD1775', 'Var', (54, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('AZD1775', 'Chemical', 'MESH:C549567', (54, 61))
192224	32220892	The majority of both esophageal adenocarcinoma and squamous cell carcinomas harbor mutations in TP53, an important tumor suppressor gene that also functions to promote cell cycle arrest in G1/S after DNA damage from radiation.	('arrest', 'Disease', 'MESH:D006323', (179, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('tumor', 'Disease', (115, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (21, 46))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('promote', 'PosReg', (160, 167))	('adenocarcinoma', 'Disease', 'MESH:D000230', (32, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (51, 75))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (168, 185))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TP53', 'Gene', (96, 100))	('arrest', 'Disease', (179, 185))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (51, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('mutations', 'Var', (83, 92))	('squamous cell carcinomas', 'Disease', (51, 75))	('adenocarcinoma', 'Disease', (32, 46))	('TP53', 'Gene', '7157', (96, 100))
192226	32220892	We find that in TP53-mutated cells lacking an effective G1/S checkpoint, AZD1775 markedly radiosensitizes esophageal cancer cells to radiation both in cell culture assays and animal studies.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('AZD1775', 'Var', (73, 80))	('lacking', 'NegReg', (35, 42))	('radiosensitizes', 'NegReg', (90, 105))	('TP53', 'Gene', '7157', (16, 20))	('AZD1775', 'Chemical', 'MESH:C549567', (73, 80))	('esophageal cancer', 'Disease', (106, 123))	('TP53', 'Gene', (16, 20))
192227	32220892	Our results justify a clinical trial to determine the safety and efficacy of combining AZD1775 and radiation in patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('AZD1775', 'Var', (87, 94))	('patients', 'Species', '9606', (112, 120))	('AZD1775', 'Chemical', 'MESH:C549567', (87, 94))	('esophageal cancer', 'Disease', (126, 143))
192314	30864295	Genomic DNA was extracted from formalin-fixed paraffin-embedded sections using a QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany).11 To detect hotspot mutations, BRAF (exon 15), NRAS (exons 1 and 2), and C-kit (exons 9, 11, 13, 17, and 18) were amplified by PCR in at least two separate preparations of genomic DNA.	('BRAF', 'Gene', (166, 170))	('NRAS', 'Gene', '4893', (182, 186))	('mutations', 'Var', (155, 164))	('C-kit', 'Gene', (208, 213))	('paraffin', 'Chemical', 'MESH:D010232', (46, 54))	('C-kit', 'Gene', '3815', (208, 213))	('formalin', 'Chemical', 'MESH:D005557', (31, 39))	('BRAF', 'Gene', '673', (166, 170))	('NRAS', 'Gene', (182, 186))
192325	30864295	Nine (11.8%) patients harbored C-Kit mutations, the most common occurring in exon 18:L862L in three patients, followed by exon 11:V560D in two patients.	('C-Kit', 'Gene', '3815', (31, 36))	('C-Kit', 'Gene', (31, 36))	('patients', 'Species', '9606', (13, 21))	('L862L', 'Mutation', 'rs3733542', (85, 90))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (100, 108))	('L862L', 'Var', (85, 90))	('V560D', 'Mutation', 'rs121913521', (130, 135))	('V560D', 'Var', (130, 135))
192326	30864295	Other mutations included exon 11:L576P, exon 13:G658R, exon 17:N822K, and exon 9:K484K.	('G658R', 'Mutation', 'p.G658R', (48, 53))	('N822K', 'Var', (63, 68))	('G658R', 'Var', (48, 53))	('K484K', 'Var', (81, 86))	('L576P', 'Mutation', 'rs121913513', (33, 38))	('N822K', 'Mutation', 'rs121913514', (63, 68))	('K484K', 'Mutation', 'rs1414417597', (81, 86))	('L576P', 'Var', (33, 38))
192327	30864295	Five (6.6%) were NRAS with five different mutation types: exon 1:G12S, exon 1:G13D, exon 1:G13R, exon 2:Q61H, and exon 2:Q61K.	('G13R', 'Mutation', 'rs121434595', (91, 95))	('G13D', 'Var', (78, 82))	('NRAS', 'Gene', (17, 21))	('G12S', 'Var', (65, 69))	('G12S', 'Mutation', 'rs121913250', (65, 69))	('NRAS', 'Gene', '4893', (17, 21))	('G13D', 'Mutation', 'rs112445441', (78, 82))	('Q61H', 'Mutation', 'rs121913255', (104, 108))	('G13R', 'Var', (91, 95))	('Q61K', 'Mutation', 'rs121913254', (121, 125))	('Q61K', 'Var', (121, 125))
192328	30864295	Five patients (6.6%) had BRAF mutations, most of which were V600E; only one was D594N.	('patients', 'Species', '9606', (5, 13))	('D594N', 'Mutation', 'rs397516896', (80, 85))	('V600E', 'Mutation', 'rs113488022', (60, 65))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))	('V600E', 'Var', (60, 65))
192344	30864295	Cohort TT: Two patients were administered imatinib because they had a C-Kit mutation in exon 11.	('C-Kit', 'Gene', '3815', (70, 75))	('imatinib', 'Chemical', 'MESH:D000068877', (42, 50))	('patients', 'Species', '9606', (15, 23))	('mutation in', 'Var', (76, 87))	('C-Kit', 'Gene', (70, 75))
192345	30864295	One (exon 11:V560D) achieved an eight month partial response (PR) and the other short-term stable disease (SD: 2 months).	('V560D', 'Var', (13, 18))	('partial response', 'NegReg', (44, 60))	('V560D', 'Mutation', 'rs121913521', (13, 18))
192362	30864295	Univariate hazard analysis showed the expected impact of known prognostic variables for melanoma, such as thickness, location of the primary tumor, mutations, and age.	('primary tumor', 'Disease', 'MESH:D009369', (133, 146))	('mutations', 'Var', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('primary tumor', 'Disease', (133, 146))
192386	30864295	Selective inhibition of the mutated RAF kinase with vemurafenib or dabrafenib improves survival of patients with stage IV disease.	('survival', 'MPA', (87, 95))	('inhibition', 'NegReg', (10, 20))	('mutated', 'Var', (28, 35))	('improves', 'PosReg', (78, 86))	('dabrafenib', 'Chemical', 'MESH:C561627', (67, 77))	('RAF', 'Gene', '22882', (36, 39))	('vemurafenib', 'Chemical', 'MESH:D000077484', (52, 63))	('patients', 'Species', '9606', (99, 107))	('RAF', 'Gene', (36, 39))	('stage IV disease', 'Disease', (113, 129))
192388	30864295	Anti-PD-1 antibodies have been demonstrated to be effective in patients with advanced stage melanoma and some data are available on the efficacy in treatment of mucosal melanoma.	('mucosal melanoma', 'Disease', (161, 177))	('Anti-PD-1 antibodies', 'Var', (0, 20))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('mucosal melanoma', 'Disease', 'MESH:D008545', (161, 177))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('men', 'Species', '9606', (153, 156))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('antibodies', 'Var', (10, 20))	('patients', 'Species', '9606', (63, 71))
192406	29113164	Methylation plays an important role in the development and progression of tumors.	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
192449	29113164	Studies on different tumors and cancers have shown that tumor cells and cancer cells are affected by a variety of factors including environmental factors such as various toxic and hazardous substances, radioactive carcinogens, and self-factors such as autoimmune disorders, mutations in tumor suppressor gene and oncogene activation.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (21, 26))	('affected', 'Reg', (89, 97))	('autoimmune disorders', 'Disease', (252, 272))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cancer', 'Disease', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', (287, 292))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (252, 272))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('autoimmune disorders', 'Disease', 'MESH:D001327', (252, 272))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor', 'Disease', (56, 61))	('tumors', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('oncogene', 'CPA', (313, 321))	('activation', 'PosReg', (322, 332))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('mutations', 'Var', (274, 283))
192452	29113164	In addition, tumor suppressor genes can be inactivated by mutations within them or the abnormal regulation network, leading to the occurrence of cancer cells and tumor cells.	('cancer', 'Disease', (145, 151))	('tumor', 'Disease', (13, 18))	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('leading to', 'Reg', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('occurrence', 'Reg', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('inactivated', 'NegReg', (43, 54))
192456	29113164	In the present study, we found that methylation rate of RECK gene in patients with esophageal cancer was significantly higher than that of normal people, indicating that the methylation of RECK gene can promote the occurrence and development of esophageal cancer.	('RECK', 'Gene', '8434', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('esophageal cancer', 'Disease', (83, 100))	('methylation', 'Var', (174, 185))	('RECK', 'Gene', '8434', (56, 60))	('patients', 'Species', '9606', (69, 77))	('higher', 'PosReg', (119, 125))	('people', 'Species', '9606', (146, 152))	('RECK', 'Gene', (189, 193))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('development', 'CPA', (230, 241))	('methylation', 'MPA', (36, 47))	('esophageal cancer', 'Disease', (245, 262))	('promote', 'PosReg', (203, 210))	('RECK', 'Gene', (56, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (245, 262))
192475	27802185	Indeed, two meta-analysis studies suggested that NAC could improve R0 resection rate and overall survival(OS), without affecting perioperative morbidity and mortality.	('NAC', 'Var', (49, 52))	('NAC', 'Chemical', '-', (49, 52))	('improve', 'PosReg', (59, 66))	('R0 resection rate', 'CPA', (67, 84))	('overall survival', 'CPA', (89, 105))
192560	27802185	Functional imaging may offer significant advantages in predicting histopathological response over conventional modality by identifying chemo induced alterations that precede a decline in tumor size.	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('alterations', 'Var', (149, 160))	('tumor', 'Disease', 'MESH:D009369', (187, 192))
192586	27802185	HER2 amplification status in breast and gastric cancer cells, BRAF mutation in colon cancers, KRAS and EGFR mutation in lung cancer have been widely implemented in clinical setting and improved patients' prognosis.	('EGFR', 'Gene', '1956', (103, 107))	('improved', 'PosReg', (185, 193))	('KRAS', 'Gene', (94, 98))	('lung cancer', 'Disease', (120, 131))	('gastric cancer', 'Disease', (40, 54))	('HER2', 'Gene', '2064', (0, 4))	('mutation', 'Var', (67, 75))	('colon cancers', 'Phenotype', 'HP:0003003', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('BRAF', 'Gene', '673', (62, 66))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('BRAF', 'Gene', (62, 66))	('patients', 'Species', '9606', (194, 202))	('colon cancers', 'Disease', 'MESH:D015179', (79, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('EGFR', 'Gene', (103, 107))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('HER2', 'Gene', (0, 4))	('colon cancers', 'Disease', (79, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('KRAS', 'Gene', '3845', (94, 98))	('mutation', 'Var', (108, 116))
192587	27802185	Potential genetic and epigenetic alterations which are involved in chemotherapeutic agents metabolism were thought be implicated in patients' responsiveness to chemotherapy.	('implicated', 'Reg', (118, 128))	('genetic', 'Var', (10, 17))	('patients', 'Species', '9606', (132, 140))	('epigenetic alterations', 'Var', (22, 44))
192597	27802185	assessed GST polymorphisms as predictive markers for cisplatin-based NAC in LAGC.	('NAC', 'Chemical', '-', (69, 72))	('polymorphisms', 'Var', (13, 26))	('GST', 'Gene', (9, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('GST', 'Gene', '373156', (9, 12))
192612	27802185	Their study demonstrated that a concordant methylation of more than three genes classified subgroups of gastric cancer with distinct biological and genetic characteristics.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('methylation', 'Var', (43, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('classified', 'Reg', (80, 90))	('gastric cancer', 'Disease', (104, 118))
192617	27802185	Manipulating the Lin28/let-7 pathway could provide novel therapeutic opportunities for treatment of cancer.	('Lin28', 'Gene', (17, 22))	('Lin28', 'Gene', '79727', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Manipulating', 'Var', (0, 12))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
192678	28273921	The esophagus for 21 patients diagnosed with primary EC were defined in the following four ways: the whole esophagus, including the tumor (ESOwhole); ESOwhole within the treatment field (ESOinfield); ESOinfield, excluding the tumor (ESOinfield-tumor) and ESOwhole, excluding the tumor (ESOwhole-tumor).	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('ESOwhole-tumor', 'Disease', 'MESH:D009369', (286, 300))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (295, 300))	('ESOwhole-tumor', 'Disease', (286, 300))	('tumor', 'Disease', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('ESOinfield', 'Var', (200, 210))	('tumor', 'Disease', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', (226, 231))
192683	28273921	Our study demonstrates that different DEs influence the esophageal toxicity prediction for EC patients administered SIB-IMRT vs. SD-IMRT treatment.	('DEs', 'Chemical', '-', (38, 41))	('patients', 'Species', '9606', (94, 102))	('SIB-IMRT', 'Chemical', '-', (116, 124))	('SD-IMRT', 'Chemical', '-', (129, 136))	('esophageal toxicity', 'Disease', (56, 75))	('influence', 'Reg', (42, 51))	('SIB-IMRT', 'Var', (116, 124))	('esophageal toxicity', 'Disease', 'MESH:D004935', (56, 75))
192687	28273921	Unfortunately, few clinical investigations have been conducted to explore the potential risk of esophageal toxicity using SIB-IMRT vs. standard-dose IMRT (SD-IMRT).	('SIB-IMRT', 'Var', (122, 130))	('esophageal toxicity', 'Disease', (96, 115))	('SIB-IMRT', 'Chemical', '-', (122, 130))	('clinical', 'Species', '191496', (19, 27))	('esophageal toxicity', 'Disease', 'MESH:D004935', (96, 115))	('SD-IMRT', 'Chemical', '-', (155, 162))
192704	28273921	The following dose constraints for OARs were used: spinal cord, Dmax (maximum dose) <45 Gy; PRV for spinal cord, V50 <= 1 cc; lung, V5 < 60%, V10 < 50%, V20 < 30% and mean lung dose (MLD) < 15 Gy, where Vx is percentage of the target volume receiving >= x Gy dose.	('V20 < 30%', 'Var', (153, 162))	('MLD', 'Disease', (183, 186))	('V5 < 60%', 'Var', (132, 140))	('V50 <=', 'Var', (113, 119))	('V10 < 50%', 'Var', (142, 151))	('MLD', 'Disease', 'MESH:D007966', (183, 186))
192710	28273921	The Kwint model derived from 139 patients after CCRT treatment for patients with non-small cell lung cancer (NSCLC) shows a sigmoid-shaped relationship between grade >= 2 AET and V50.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (81, 107))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (67, 75))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (81, 107))	('AET', 'Chemical', '-', (171, 174))	('grade >= 2 AET', 'Var', (160, 174))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (85, 107))	('V50', 'Disease', (179, 182))	('non-small cell lung cancer', 'Disease', (81, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('NSCLC', 'Disease', (109, 114))
192723	28273921	Compared with ESOwhole-tumor and ESOinfield-tumor, the increase of V60 and Dmean was higher for the ESOwhole and ESOinfield definitions.	('V60', 'MPA', (67, 70))	('Dmean', 'MPA', (75, 80))	('increase', 'PosReg', (55, 63))	('ESOwhole', 'Var', (100, 108))	('ESOwhole-tumor', 'Disease', (14, 28))	('higher', 'PosReg', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('ESOinfield', 'Var', (113, 123))	('ESOwhole-tumor', 'Disease', 'MESH:D009369', (14, 28))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (44, 49))
192731	28273921	Compared with ESOwhole-tumor and ESOinfield-tumor, the increase was higher with the ESOwhole and ESOinfield definition.	('increase', 'PosReg', (55, 63))	('ESOwhole-tumor', 'Disease', (14, 28))	('ESOwhole', 'Var', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('ESOwhole-tumor', 'Disease', 'MESH:D009369', (14, 28))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (44, 49))	('ESOinfield definition', 'Var', (97, 118))
192732	28273921	Whether different DEs influence the evaluation of the esophageal toxicity prediction for EC patients administered SIB-IMRT vs. SD-IMRT remains unknown.	('esophageal toxicity', 'Disease', 'MESH:D004935', (54, 73))	('SIB-IMRT', 'Var', (114, 122))	('influence', 'Reg', (22, 31))	('patients', 'Species', '9606', (92, 100))	('SD-IMRT', 'Chemical', '-', (127, 134))	('esophageal toxicity', 'Disease', (54, 73))	('SIB-IMRT', 'Chemical', '-', (114, 122))	('DEs', 'Chemical', '-', (18, 21))
192735	28273921	To the best of our knowledge, this study is the first to investigate the influence of different DEs on the esophageal toxicity prediction for EC patients received SIB-IMRT vs. SD-IMRT.	('patients', 'Species', '9606', (145, 153))	('esophageal toxicity', 'Disease', (107, 126))	('SIB-IMRT', 'Var', (163, 171))	('DEs', 'Chemical', '-', (96, 99))	('esophageal toxicity', 'Disease', 'MESH:D004935', (107, 126))	('SIB-IMRT', 'Chemical', '-', (163, 171))	('SD-IMRT', 'Chemical', '-', (176, 183))
192741	28273921	Although two dosimetric studies demonstrated an improved benefit of SIB-IMRT compared with the SD-IMRT strategy, no further information on esophageal toxicity was provided in the two studies.	('SIB-IMRT', 'Chemical', '-', (68, 76))	('SD-IMRT', 'Chemical', '-', (95, 102))	('esophageal toxicity', 'Disease', (139, 158))	('SIB-IMRT', 'Var', (68, 76))	('esophageal toxicity', 'Disease', 'MESH:D004935', (139, 158))
192745	28273921	Interestingly, we found that two DEs (ESOwhole and ESOinfield) resulted in a similar trend of increase for esophageal toxicity prediction in the SIB-IMRT plans (Table 3), indicating that both of them are comparable for esophageal toxicity evaluation.	('ESOwhole', 'Var', (38, 46))	('esophageal toxicity', 'Disease', (219, 238))	('increase', 'PosReg', (94, 102))	('DEs', 'Chemical', '-', (33, 36))	('esophageal toxicity', 'Disease', (107, 126))	('esophageal toxicity', 'Disease', 'MESH:D004935', (219, 238))	('SIB-IMRT', 'Chemical', '-', (145, 153))	('esophageal toxicity', 'Disease', 'MESH:D004935', (107, 126))	('ESOinfield', 'Var', (51, 61))
192746	28273921	However, we also found that the increase in esophageal toxicity using ESOwhole and ESOinfield was higher than that of the ESOwhole-tumor and ESOinfield-tumor, particularly when the Wijsman model was used (Table 3).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('ESOinfield', 'Var', (83, 93))	('ESOwhole-tumor', 'Disease', 'MESH:D009369', (122, 136))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('ESOwhole', 'Var', (70, 78))	('esophageal toxicity', 'Disease', 'MESH:D004935', (44, 63))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', (131, 136))	('ESOwhole-tumor', 'Disease', (122, 136))	('esophageal toxicity', 'Disease', (44, 63))
192752	28273921	Because AET is enhanced with CCRT, the chemotherapy regimen might partly influence our prediction of esophageal toxicity.	('esophageal toxicity', 'Disease', 'MESH:D004935', (101, 120))	('AET', 'MPA', (8, 11))	('AET', 'Chemical', '-', (8, 11))	('esophageal toxicity', 'Disease', (101, 120))	('influence', 'Reg', (73, 82))	('enhanced', 'PosReg', (15, 23))	('CCRT', 'Var', (29, 33))
192754	28273921	Dose volume parameters, such as V30, V40, V50, V60, Dmax and mean esophagus dose were reported to enable AET prediction.	('V60', 'Var', (47, 50))	('V40', 'Var', (37, 40))	('V30', 'Var', (32, 35))	('Dmax', 'MPA', (52, 56))	('AET', 'Chemical', '-', (105, 108))	('V50', 'Var', (42, 45))
192755	28273921	performed a meta-analysis enrolling the largest population to date (1082 patients) to show that V60 emerged as the best predictor of grade >= 2 and grade >= 3 radiation-induced esophagitis with good calibration and discrimination.	('V60', 'Var', (96, 99))	('esophagitis', 'Phenotype', 'HP:0100633', (177, 188))	('esophagitis', 'Disease', (177, 188))	('esophagitis', 'Disease', 'MESH:D004941', (177, 188))	('patients', 'Species', '9606', (73, 81))
192775	28273921	In summary, our study demonstrated that different DEs influence the esophageal toxicity prediction for EC patients administered SIB-IMRT vs. SD-IMRT.	('SIB-IMRT', 'Var', (128, 136))	('esophageal toxicity', 'Disease', 'MESH:D004935', (68, 87))	('DEs', 'Chemical', '-', (50, 53))	('SIB-IMRT', 'Chemical', '-', (128, 136))	('patients', 'Species', '9606', (106, 114))	('SD-IMRT', 'Chemical', '-', (141, 148))	('esophageal toxicity', 'Disease', (68, 87))	('influence', 'Reg', (54, 63))
192781	26175109	Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for age-specific (<50, 50-59, 60-69, >=70 years) cancer outcomes, as well as interactions by age.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('<50', 'Var', (126, 129))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))
192823	26175109	Conversely, low/moderate alcohol consumption and use of aspirin and NSAIDs were inversely associated with late-onset EA, although effect modifications of these associations by age were not significant.	('late-onset EA', 'Disease', (106, 119))	('EA', 'Phenotype', 'HP:0011459', (117, 119))	('alcohol', 'Chemical', 'MESH:D000438', (25, 32))	('aspirin', 'Chemical', 'MESH:D001241', (56, 63))	('inversely', 'NegReg', (80, 89))	('low/moderate alcohol consumption', 'Var', (12, 44))
192830	26175109	Reflux increases secretion of numerous proinflammatory cytokines such as IL-6 and TNF-alpha and reactive oxygen species.	('reactive oxygen species', 'MPA', (96, 119))	('TNF-alpha', 'Gene', '7124', (82, 91))	('secretion of', 'MPA', (17, 29))	('TNF-alpha', 'Gene', (82, 91))	('IL-6', 'Gene', (73, 77))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (96, 119))	('Reflux', 'Var', (0, 6))	('IL-6', 'Gene', '3569', (73, 77))
192832	26175109	Among a subset of the EA patients included in this study, four SNPs in three apoptosis genes (BCL2, CASP8, and TNFRSF10A) were previously identified as significantly associated with early-onset EA (<=55 vs >55 years).	('associated with', 'Reg', (166, 181))	('TNFRSF10A', 'Gene', (111, 120))	('BCL2', 'Gene', '596', (94, 98))	('CASP8', 'Gene', (100, 105))	('CASP8', 'Gene', '841', (100, 105))	('patients', 'Species', '9606', (25, 33))	('SNPs', 'Var', (63, 67))	('early-onset EA', 'Disease', (182, 196))	('TNFRSF10A', 'Gene', '8797', (111, 120))	('BCL2', 'Gene', (94, 98))	('EA', 'Phenotype', 'HP:0011459', (194, 196))	('EA', 'Phenotype', 'HP:0011459', (22, 24))
192834	26175109	This process could lead to the accumulation of oncogenic mutations in the esophageal cell population, heightening the risk of early-onset EA.	('lead to', 'Reg', (19, 26))	('early-onset EA', 'Disease', (126, 140))	('heightening', 'PosReg', (102, 113))	('mutations', 'Var', (57, 66))	('esophageal', 'Disease', 'MESH:D004941', (74, 84))	('EA', 'Phenotype', 'HP:0011459', (138, 140))	('esophageal', 'Disease', (74, 84))
192850	26263981	LAMP3 DNA copy number was amplified in 70% of ESCC tissues and positive correlated with mRNA expression (p = 0.037).	('ESCC', 'Disease', (46, 50))	('correlated', 'Reg', (72, 82))	('LAMP3', 'Gene', '27074', (0, 5))	('mRNA expression', 'MPA', (88, 103))	('LAMP3', 'Gene', (0, 5))	('copy number', 'Var', (10, 21))
192857	26263981	It has been reported that aberrant expression of several important genes was associated with the poor prognosis of ESCC, such as p53, Bcl-2 and p300.	('ESCC', 'Disease', (115, 119))	('aberrant expression', 'Var', (26, 45))	('p300', 'Gene', (144, 148))	('p53', 'Gene', (129, 132))	('p300', 'Gene', '2033', (144, 148))	('p53', 'Gene', '7157', (129, 132))	('Bcl-2', 'Gene', '596', (134, 139))	('Bcl-2', 'Gene', (134, 139))	('associated', 'Reg', (77, 87))
192871	26263981	Dysregulation of genes in this region might play an important role in the progression and prognosis of cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Dysregulation', 'Var', (0, 13))	('play', 'Reg', (44, 48))	('cancers', 'Disease', (103, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('role', 'Reg', (62, 66))
192887	26263981	This result suggested that the DNA amplification of LAMP3 might result in its transcript over expression in a certain degree.	('DNA', 'Var', (31, 34))	('result', 'Reg', (64, 70))	('transcript', 'MPA', (78, 88))	('LAMP3', 'Gene', '27074', (52, 57))	('over', 'PosReg', (89, 93))	('LAMP3', 'Gene', (52, 57))
192913	26263981	In our study, high expression of LAMP3 was more frequent at the primary sites of patients with lymph node metastasis than in those without metastasis (56.2% vs. 44.1%), although not statistically significant, which might due to the small sample size (50 vs. 30).	('patients', 'Species', '9606', (81, 89))	('LAMP3', 'Gene', (33, 38))	('high', 'Var', (14, 18))	('lymph', 'Disease', (95, 100))	('LAMP3', 'Gene', '27074', (33, 38))
192953	26263981	LAMP3 DNA copy number was positive correlated with its mRNA expression.	('mRNA expression', 'MPA', (55, 70))	('LAMP3', 'Gene', (0, 5))	('copy number', 'Var', (10, 21))	('LAMP3', 'Gene', '27074', (0, 5))
192964	25950810	EC9706 cells with re-localization of ESE3 to the nucleus showed inhibition of proliferation, colony formation, migration, and invasion.	('colony formation', 'CPA', (93, 109))	('rat', 'Species', '10116', (114, 117))	('migration', 'CPA', (111, 120))	('re-localization', 'Var', (18, 33))	('rat', 'Species', '10116', (85, 88))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('ESE3', 'Gene', (37, 41))	('invasion', 'CPA', (126, 134))	('inhibition', 'NegReg', (64, 74))	('proliferation', 'CPA', (78, 91))	('ESE3', 'Gene', '26298', (37, 41))
192976	25950810	ESCC cell lines TE-1 (RIKEN Bio Resource Center, Tsukuba, Japan), EC9706, KYSE150, and KYSE410 (Cancer Institute and Hospital, Chinese Academy of Medical Sciences, China) were cultured in RPMI 1640 medium (Life Technologies, Carlsbad, CA) supplemented with 10% fetal bovine serum (Life Technologies), 100 U/mL penicillin, and 100 mg/mL streptomycin (Life Technologies).	('bovine', 'Species', '9913', (267, 273))	('EC9706', 'CellLine', 'CVCL:E307', (66, 72))	('RPMI 1640 medium', 'Chemical', '-', (188, 204))	('KYSE150', 'Var', (74, 81))	('Cancer', 'Disease', (96, 102))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('streptomycin', 'Chemical', 'MESH:D013307', (336, 348))	('Cancer', 'Disease', 'MESH:D009369', (96, 102))	('penicillin', 'Chemical', 'MESH:D010406', (310, 320))	('KYSE150', 'CellLine', 'CVCL:1348', (74, 81))
193042	25950810	Compared with empty vector-transfected EC9706 cells, re-localization of ESE3 to the nucleus resulted in significantly fewer migratory cells (Fig 7C).	('migratory cells', 'CPA', (124, 139))	('ESE3', 'Gene', (72, 76))	('fewer', 'NegReg', (118, 123))	('re-localization', 'Var', (53, 68))	('ESE3', 'Gene', '26298', (72, 76))	('rat', 'Species', '10116', (127, 130))	('EC9706', 'CellLine', 'CVCL:E307', (39, 45))
193055	25950810	It is downregulated by promoter methylation, leading to inhibition of cell apoptosis in prostate cancer.	('inhibition', 'NegReg', (56, 66))	('prostate cancer', 'Disease', (88, 103))	('downregulated', 'NegReg', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('promoter methylation', 'Var', (23, 43))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('cell apoptosis', 'CPA', (70, 84))
193063	25950810	EGFP-tagged ESE3 showed distinct nuclear localization compared with the even distribution of ESE3 in empty vector-transfected ESCC cells.	('ESE3', 'Gene', (93, 97))	('ESE3', 'Gene', '26298', (12, 16))	('ESE3', 'Gene', (12, 16))	('ESE3', 'Gene', '26298', (93, 97))	('nuclear localization', 'MPA', (33, 53))	('EGFP-tagged', 'Var', (0, 11))
193070	25950810	Consistent with the previous findings in prostate cancer, EC9706 cells with re-localization of ESE3 to the nucleus showed impairments in cell proliferation, colony formation, migration, and invasion.	('rat', 'Species', '10116', (149, 152))	('ESE3', 'Gene', '26298', (95, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (41, 56))	('invasion', 'CPA', (190, 198))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('cell proliferation', 'CPA', (137, 155))	('re-localization', 'Var', (76, 91))	('impairments', 'NegReg', (122, 133))	('EC9706', 'CellLine', 'CVCL:E307', (58, 64))	('ESE3', 'Gene', (95, 99))	('colony formation', 'CPA', (157, 173))	('prostate cancer', 'Disease', (41, 56))	('rat', 'Species', '10116', (178, 181))	('migration', 'CPA', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
193080	25950810	In summary, our study revealed translocation of ESE3 into the cytoplasm of ESCC cells, which acts as a tumor suppressor gene in the carcinogenesis of ESCC.	('ESE3', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('translocation', 'Var', (31, 44))	('ESE3', 'Gene', '26298', (48, 52))	('ESCC', 'Disease', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
193083	25950810	Restoration of the ESE3 localization inhibits ESCC cell growth and colony formation, suggesting a possible novel mechanism of ESCC carcinogenesis by ESE3 re-localization.	('ESE3', 'Gene', (149, 153))	('Restoration', 'Var', (0, 11))	('ESE3', 'Gene', (19, 23))	('rat', 'Species', '10116', (5, 8))	('ESCC', 'Disease', (126, 130))	('ESE3', 'Gene', '26298', (149, 153))	('ESE3', 'Gene', '26298', (19, 23))	('inhibits', 'NegReg', (37, 45))
193093	25588551	In the group treated with chemotherapy combined with anti-EGFR drugs, patients with lowexpression of c-Met had a better OS than those with overexpression of c-Met (OS: 577 d vs 232 d, P = 0.007).	('patients', 'Species', '9606', (70, 78))	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (58, 62))	('c-Met', 'Gene', (101, 106))	('c-Met', 'Gene', '4233', (101, 106))	('lowexpression', 'Var', (84, 97))	('OS', 'Chemical', 'MESH:D009992', (120, 122))	('OS', 'Chemical', 'MESH:D009992', (164, 166))	('c-Met', 'Gene', (157, 162))	('c-Met', 'Gene', '4233', (157, 162))
193155	25588551	In TP plus nimotuzumab group, the OS of patients with c-Met low-expression was significantly better than those with c-Met over-expression (577d vs 232d, P = 0.007).	('patients', 'Species', '9606', (40, 48))	('nimotuzumab', 'Chemical', 'MESH:C501466', (11, 22))	('TP', 'Chemical', 'MESH:C011314', (3, 5))	('better', 'PosReg', (93, 99))	('c-Met', 'Gene', (54, 59))	('OS', 'Chemical', 'MESH:D009992', (34, 36))	('c-Met', 'Gene', (116, 121))	('c-Met', 'Gene', '4233', (54, 59))	('low-expression', 'Var', (60, 74))	('c-Met', 'Gene', '4233', (116, 121))
193160	25588551	The patients with c-Met low-expression had a trend of better prognosis with no statistical significance (P = 0.289).	('c-Met', 'Gene', (18, 23))	('c-Met', 'Gene', '4233', (18, 23))	('low-expression', 'Var', (24, 38))	('patients', 'Species', '9606', (4, 12))	('better', 'PosReg', (54, 60))
193167	25588551	One study reported that an increased expression of c-Met was seen along the metaplasia-adenocarcinoma sequence and patients with esophageal adenocarcinoma with c-Met positive tumors showed lower 6-month survival rates after surgical resection than those with c-Met negative tumors.	('tumors', 'Disease', (175, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('c-Met', 'Gene', '4233', (51, 56))	('c-Met', 'Gene', (259, 264))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('6-month survival rates', 'CPA', (195, 217))	('positive', 'Var', (166, 174))	('c-Met', 'Gene', '4233', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('patients', 'Species', '9606', (115, 123))	('c-Met', 'Gene', (51, 56))	('metaplasia-adenocarcinoma', 'Disease', 'MESH:D008679', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (129, 154))	('c-Met', 'Gene', '4233', (259, 264))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (129, 154))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('expression', 'MPA', (37, 47))	('tumors', 'Disease', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('metaplasia-adenocarcinoma', 'Disease', (76, 101))	('lower', 'NegReg', (189, 194))	('esophageal adenocarcinoma', 'Disease', (129, 154))	('c-Met', 'Gene', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
193176	25588551	In our study, patients with c-Met lowexpression had a better OS than those with c-Met overexpression both in TP plus nimotuzumab group and in TP group.	('lowexpression', 'Var', (34, 47))	('TP', 'Chemical', 'MESH:C011314', (142, 144))	('c-Met', 'Gene', '4233', (28, 33))	('c-Met', 'Gene', (80, 85))	('TP', 'Chemical', 'MESH:C011314', (109, 111))	('c-Met', 'Gene', '4233', (80, 85))	('OS', 'Chemical', 'MESH:D009992', (61, 63))	('nimotuzumab', 'Chemical', 'MESH:C501466', (117, 128))	('patients', 'Species', '9606', (14, 22))	('c-Met', 'Gene', (28, 33))
193181	25588551	However, a study finds out that in lung cancer, amplification of c-Met causes gefitinib resistance by driving ERBB3-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors.	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('c-Met', 'Gene', '4233', (65, 70))	('ERBB', 'Gene', '1956;2064;2065', (110, 114))	('ERBB3', 'Gene', '2065', (110, 115))	('gefitinib', 'Chemical', 'MESH:D000077156', (78, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('gefitinib resistance', 'MPA', (78, 98))	('causes', 'Reg', (71, 77))	('EGFR', 'Gene', '1956', (182, 186))	('ERBB', 'Gene', '1956;2064;2065', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('c-Met', 'Gene', (65, 70))	('activation', 'PosReg', (126, 136))	('lung cancer', 'Disease', (35, 46))	('ERBB3', 'Gene', (110, 115))	('PI3K', 'Pathway', (140, 144))	('ERBB', 'Gene', (110, 114))	('amplification', 'Var', (48, 61))	('EGFR', 'Gene', (182, 186))	('ERBB', 'Gene', (187, 191))
193182	25588551	Recently, another study in colorectal cancer highlights the role of c-Met in mediating primary and secondary resistance to anti-EGFR therapies and encourages the use of c-Met inhibitors in patients displaying resistance as a result of c-Met amplification.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('c-Met', 'Gene', '4233', (68, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('c-Met', 'Gene', (169, 174))	('colorectal cancer', 'Disease', (27, 44))	('c-Met', 'Gene', '4233', (169, 174))	('c-Met', 'Gene', (235, 240))	('amplification', 'Var', (241, 254))	('c-Met', 'Gene', '4233', (235, 240))	('patients', 'Species', '9606', (189, 197))	('c-Met', 'Gene', (68, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
193183	25588551	In the breast cancer, c-Met contributes to trastuzumab resistance, as inhibition of c-Met sensitizes cells to trastuzumab-mediated growth inhibition.	('sensitizes', 'Reg', (90, 100))	('trastuzumab', 'Chemical', 'MESH:D000068878', (43, 54))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('breast cancer', 'Disease', (7, 20))	('trastuzumab', 'Chemical', 'MESH:D000068878', (110, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('c-Met', 'Gene', (84, 89))	('contributes', 'Reg', (28, 39))	('inhibition', 'Var', (70, 80))	('c-Met', 'Gene', '4233', (84, 89))	('c-Met', 'Gene', (22, 27))	('c-Met', 'Gene', '4233', (22, 27))
193184	25588551	High gene copy numbers of c-Met and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive metastatic breast cancer.	('HGF', 'Gene', '3082', (36, 39))	('High gene copy numbers', 'Var', (0, 22))	('HER2', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('trastuzumab', 'Chemical', 'MESH:D000068878', (76, 87))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('HER2', 'Gene', '2064', (113, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('c-Met', 'Gene', (26, 31))	('HGF', 'Gene', (36, 39))	('c-Met', 'Gene', '4233', (26, 31))
193208	24570882	In the East, the predominant type of esophageal cancer is ESCC, which has been associated with alcohol consumption, tobacco use including active and passive smoking, high intake of pickled foods, low intake of fresh fruit and vegetables, low socioeconomic status, poor oral hygiene, frequent consumption of extremely hot drinks, caustic injury, radiation, and achalasia.	('associated', 'Reg', (79, 89))	('alcohol', 'Chemical', 'MESH:D000438', (95, 102))	('tobacco', 'Species', '4097', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('caustic injury', 'Disease', (329, 343))	('achalasia', 'Phenotype', 'HP:0002571', (360, 369))	('hot drinks', 'Phenotype', 'HP:0031217', (317, 327))	('achalasia', 'Disease', (360, 369))	('esophageal cancer', 'Disease', (37, 54))	('ESCC', 'Disease', (58, 62))	('achalasia', 'Disease', 'MESH:D004931', (360, 369))	('poor oral', 'Phenotype', 'HP:0000160', (264, 273))	('low', 'Var', (238, 241))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
193248	24570882	After 12 months, there was no difference in the risk of progression to HGD or EAC in those with LGD as compared to those without LGD (12 patients progressed in each group, absolute risk 2.33% vs. 2.69%).	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('HGD', 'Disease', (71, 74))	('LGD', 'Var', (96, 99))	('patients', 'Species', '9606', (137, 145))	('EAC', 'Disease', (78, 81))
193436	34006988	The granulation tissue was significantly decreased in the PTT groups compared to a control group.	('PTT', 'Chemical', '-', (58, 61))	('PTT', 'Var', (58, 61))	('decreased', 'NegReg', (41, 50))	('granulation tissue', 'CPA', (4, 22))
193463	34006988	Y.C.C., J.M.K, W.P., D.-H.K., J.H.S, D.H.K., and J.-H.P.	('D.-H.K.', 'Var', (21, 28))	('J.H.S', 'CellLine', 'CVCL:M891', (30, 35))	('J.H.S', 'Var', (30, 35))	('D.H.K.', 'Var', (37, 43))
193531	29749455	The cell growth rates of EC9706 for 24 h were 1.5 mg/ml (95.95+-2.67%), 3 mg/ml (86.79+-2.64%), 6 mg/ml (82.76+-3.10%), 12 mg/ml (66.27+-2.74%), 24 mg/ml (58.84+-2.12%), 48 mg/ml (44.99+-4.29%), 96 mg/ml (37.44+-3.07%), respectively.	('EC9706', 'Var', (25, 31))	('cell growth', 'CPA', (4, 15))	('EC9706', 'CellLine', 'CVCL:E307', (25, 31))
193542	29749455	As EC9706 cells are highly differentiated and less malignant, they may not form capillary-like tubes well, while KYSE70 cells have higher malignancy, and were therefore selected.	('malignancy', 'Disease', 'MESH:D009369', (138, 148))	('EC9706', 'CellLine', 'CVCL:E307', (3, 9))	('KYSE70', 'Var', (113, 119))	('malignancy', 'Disease', (138, 148))	('EC9706', 'Var', (3, 9))	('higher', 'PosReg', (131, 137))
193566	29749455	Furthermore, Aidi inhibited peritoneal dissemination in a mouse metastasis model.	('mouse', 'Species', '10090', (58, 63))	('Aidi', 'Chemical', '-', (13, 17))	('inhibited', 'NegReg', (18, 27))	('Aidi', 'Var', (13, 17))
193576	29749455	The present study demonstrated that treatment with Aidi in EC9706 and KYSE70 cells increased the levels of cadherin-1, and decreased the expression of cadherin-2 and vimentin, in a dose-dependent manner, representing the inhibition of EMT signaling.	('EC9706', 'Var', (59, 65))	('Aidi', 'Chemical', '-', (51, 55))	('vimentin', 'Protein', (166, 174))	('expression', 'MPA', (137, 147))	('increased', 'PosReg', (83, 92))	('decreased', 'NegReg', (123, 132))	('levels of cadherin-1', 'MPA', (97, 117))	('cadherin-2', 'Protein', (151, 161))	('EC9706', 'CellLine', 'CVCL:E307', (59, 65))	('KYSE70', 'Var', (70, 76))
193581	29749455	A future direction of research may be to verify whether treatment with Aidi inhibits tumor angiogenesis through an effect on EMT and to further clarify the mechanism of the anti-metastatic effect of treatment with Aidi on ESCC.	('tumor', 'Disease', (85, 90))	('effect', 'Reg', (115, 121))	('EMT', 'CPA', (125, 128))	('inhibits', 'NegReg', (76, 84))	('Aidi', 'Chemical', '-', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Aidi', 'Var', (71, 75))	('Aidi', 'Chemical', '-', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
193585	29749455	Aidi may inhibit tumor metastasis by inhibiting EMT and angiogenesis in human ESCC.	('Aidi', 'Var', (0, 4))	('Aidi', 'Chemical', '-', (0, 4))	('inhibit', 'NegReg', (9, 16))	('tumor metastasis', 'Disease', 'MESH:D009362', (17, 33))	('tumor metastasis', 'Disease', (17, 33))	('human', 'Species', '9606', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('inhibiting', 'NegReg', (37, 47))
193606	25743461	A recent meta-analysis found a lower annual incidence of esophageal adenocarcinoma in short segment Barrett's esophagus patients when compared to all Barrett's esophagus patients in the study (0.19% vs 0.33% per year .	('patients', 'Species', '9606', (170, 178))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (150, 169))	('esophageal adenocarcinoma', 'Disease', (57, 82))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (57, 82))	('short segment', 'Var', (86, 99))	('lower', 'NegReg', (31, 36))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (57, 82))	('patients', 'Species', '9606', (120, 128))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (100, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
193607	25743461	Work from the Northern Ireland Barrett's esophagus register found the risk of progression to adenocarcinoma or high-grade dysplasia increased by seven fold in long segment compared to short segment Barrett's esophagus (hazard ratio 7.1; 95% CI 1.74-29.04) .	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (198, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('long segment', 'Var', (159, 171))	('adenocarcinoma', 'Disease', (93, 107))	('dysplasia', 'Disease', (122, 131))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (31, 50))	('dysplasia', 'Disease', 'MESH:D004476', (122, 131))
193633	25743461	found that indefinite for dysplasia was associated with a similar risk for progression to cancer as was low-grade dysplasia: 14% vs. 20% .	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('dysplasia', 'Disease', (114, 123))	('dysplasia', 'Disease', 'MESH:D004476', (114, 123))	('dysplasia', 'Disease', (26, 35))	('dysplasia', 'Disease', 'MESH:D004476', (26, 35))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('indefinite', 'Var', (11, 21))
193635	25743461	The risk for progression is more pronounced in multifocal indefinite for dysplasia (defined as indefinite for dysplasia in biopsies from more than one level of the esophagus) than in focal indefinite for dysplasia as well as in longer segments with indefinite for dysplasia .	('multifocal', 'Var', (47, 57))	('dysplasia', 'Disease', (264, 273))	('dysplasia', 'Disease', 'MESH:D004476', (73, 82))	('dysplasia', 'Disease', (204, 213))	('dysplasia', 'Disease', (110, 119))	('dysplasia', 'Disease', 'MESH:D004476', (264, 273))	('dysplasia', 'Disease', 'MESH:D004476', (110, 119))	('dysplasia', 'Disease', 'MESH:D004476', (204, 213))	('dysplasia', 'Disease', (73, 82))
193651	25743461	Abnormalities including DNA content abnormalities, chromosomal abnormalities, gene mutations, methylation changes and clonal diversity measurements define patients at increased risk for progression to cancer .	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('chromosomal abnormalities', 'Disease', (51, 76))	('methylation changes', 'Var', (94, 113))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (51, 76))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('patients', 'Species', '9606', (155, 163))	('DNA content', 'MPA', (24, 35))
193653	25743461	Recent promising work in a case control study suggested that aberrant p53 expression, defined as absent or increased expression by immunohistochemistry was associated with an increased risk of neoplastic progression .	('expression', 'MPA', (74, 84))	('aberrant', 'Var', (61, 69))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('neoplastic progression', 'CPA', (193, 215))	('associated', 'Reg', (156, 166))
193655	25743461	Multiple studies have demonstrated the promise of biomarker panels including a recent population-based study using the Northern Ireland Barrett's esophagus register which identified a panel of markers consisting of expert pathologist confirmed low-grade dysplasia, abnormal DNA ploidy as detected by image cytometry, and Aspergillus oryzae lectin immunostaining that could distinguish progressors from nonprogressors to adenocarcinoma or high-grade dysplasia .	('abnormal', 'Var', (265, 273))	('dysplasia', 'Disease', 'MESH:D004476', (254, 263))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (136, 155))	('dysplasia', 'Disease', 'MESH:D004476', (449, 458))	('dysplasia', 'Disease', (449, 458))	('carcinoma', 'Phenotype', 'HP:0030731', (425, 434))	('Aspergillus oryzae', 'Species', '5062', (321, 339))	('adenocarcinoma', 'Disease', (420, 434))	('dysplasia', 'Disease', (254, 263))	('adenocarcinoma', 'Disease', 'MESH:D000230', (420, 434))	('low-grade', 'Var', (244, 253))
193657	25743461	In the future, it is likely that the best predictor for the development of high-grade dysplasia or adenocarcinoma will be a combination of clinical, demographic, histologic, genetic and epigenetic data.	('dysplasia or adenocarcinoma', 'Disease', (86, 113))	('epigenetic', 'Var', (186, 196))	('dysplasia or adenocarcinoma', 'Disease', 'MESH:D000230', (86, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))
193698	25743461	In an Australian case control study, intake of the dietary antioxidants including Vitamin E and beta-carotene were associated with a decreased risk of esophageal adenocarcinoma and dysplastic Barrett's esophagus respectively .	("dysplastic Barrett's esophagus", 'Disease', (181, 211))	('beta-carotene', 'Var', (96, 109))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (181, 211))	('Vitamin E', 'Chemical', 'MESH:D014810', (82, 91))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (192, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (151, 176))	('esophageal adenocarcinoma', 'Disease', (151, 176))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (151, 176))	('decreased', 'NegReg', (133, 142))	('beta-carotene', 'Chemical', 'MESH:D019207', (96, 109))
193704	25743461	A recent meta-analysis of seven observational studies that examined the association between PPI usage and risk of high-grade dysplasia/adenocarcinoma found that PPIs resulted in a 71% reduction in the risk of high-grade dysplasia/adenocarcinoma (OR 0.29; 95% CI 0.12-0.79) .	('reduction', 'NegReg', (184, 193))	('dysplasia/adenocarcinoma', 'Disease', 'MESH:D000230', (220, 244))	('dysplasia/adenocarcinoma', 'Disease', (220, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('dysplasia/adenocarcinoma', 'Disease', 'MESH:D000230', (125, 149))	('dysplasia/adenocarcinoma', 'Disease', (125, 149))	('PPIs', 'Var', (161, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
193723	25743461	In a cohort study of 570 Barrett's esophagus patients from the Netherlands, NSAID use was associated with a decreased risk for progression to high-grade dysplasia/adenocarcinoma (hazard ration 0.47; 95% CI 0.24-0.93), although no effect was seen for low dose aspirin .	('aspirin', 'Chemical', 'MESH:D001241', (259, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('use', 'Var', (82, 85))	('decreased', 'NegReg', (108, 117))	('dysplasia/adenocarcinoma', 'Disease', 'MESH:D000230', (153, 177))	('patients', 'Species', '9606', (45, 53))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (25, 44))	('NSAID', 'Gene', (76, 81))	('dysplasia/adenocarcinoma', 'Disease', (153, 177))
193724	25743461	Finally, a nested case control study from the VA data base found that filled prescriptions for NSAIDs or aspirin in Barrett's esophagus patients was associated with a decreased risk of developing esophageal adenocarcinoma (incidence density ratio 0.64; 95% CI 0.42-0.97) .	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (116, 135))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (196, 221))	('esophageal adenocarcinoma', 'Disease', (196, 221))	('NSAIDs', 'Gene', (95, 101))	('patients', 'Species', '9606', (136, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (196, 221))	('aspirin', 'Chemical', 'MESH:D001241', (105, 112))	('filled prescriptions', 'Var', (70, 90))	('aspirin', 'Gene', (105, 112))	('decreased', 'NegReg', (167, 176))
193813	24602038	This large series reported that death is an uncommon complication associated with catheter ablation of AF, with the incidence of death being 1 of every 1,000 patients.	('death', 'Disease', 'MESH:D003643', (129, 134))	('death', 'Disease', (129, 134))	('catheter ablation', 'Var', (82, 99))	('death', 'Disease', (32, 37))	('AF', 'Disease', 'MESH:D001281', (103, 105))	('AF', 'Phenotype', 'HP:0005110', (103, 105))	('patients', 'Species', '9606', (158, 166))	('death', 'Disease', 'MESH:D003643', (32, 37))
193900	24743601	Chemoresistant sub-lines of EC9706/PTX and EC9706/CDDP showed high expression of 14-3-3sigma protein compared with non-chemoresistant ESCC cell lines and immortalized NEC.	('14-3-3sigma', 'Gene', (81, 92))	('PTX', 'Chemical', '-', (35, 38))	('EC9706', 'CellLine', 'CVCL:E307', (28, 34))	('14-3-3sigma', 'Gene', '2810', (81, 92))	('EC9706/CDDP', 'Var', (43, 54))	('CDDP', 'Chemical', 'MESH:D002945', (50, 54))	('expression', 'MPA', (67, 77))	('EC9706', 'CellLine', 'CVCL:E307', (43, 49))
193953	24743601	The 14-3-3sigma protein level was also determined in an immortalized primary esophageal epithelial cell line (NEC), three ESCC cell lines (EC1, EC109 and EC9706), a paclitaxel-resistant sub-line (EC9706/PTX) and a cisplatin-resistant sub-line (EC9706/CDDP).	('PTX', 'Chemical', '-', (203, 206))	('CDDP', 'Chemical', 'MESH:D002945', (251, 255))	('EC9706', 'CellLine', 'CVCL:E307', (154, 160))	('EC1', 'CellLine', 'CVCL:5V05', (144, 147))	('EC9706', 'CellLine', 'CVCL:E307', (196, 202))	('14-3-3sigma', 'Gene', (4, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('EC9706', 'CellLine', 'CVCL:E307', (244, 250))	('EC9706', 'Var', (154, 160))	('14-3-3sigma', 'Gene', '2810', (4, 15))	('EC1', 'CellLine', 'CVCL:5V05', (139, 142))	('paclitaxel', 'Chemical', 'MESH:D017239', (165, 175))
193955	24743601	However, three ESCC cell lines all expressed moderate levels of 14-3-3sigma protein and the chemoresistant cell lines EC9706/PTX and EC9706/CDDP showed a higher expression of 14-3-3sigma protein when compared with non-chemoresistant ESCC cell lines and immortalized NEC.	('14-3-3sigma', 'Gene', (64, 75))	('CDDP', 'Chemical', 'MESH:D002945', (140, 144))	('EC9706', 'CellLine', 'CVCL:E307', (133, 139))	('14-3-3sigma', 'Gene', (175, 186))	('expression', 'MPA', (161, 171))	('higher', 'PosReg', (154, 160))	('PTX', 'Chemical', '-', (125, 128))	('14-3-3sigma', 'Gene', '2810', (64, 75))	('EC9706/CDDP', 'Var', (133, 144))	('14-3-3sigma', 'Gene', '2810', (175, 186))	('EC9706', 'CellLine', 'CVCL:E307', (118, 124))
193967	24743601	The 5-year overall survival rate in ESCC patients with low (n = 124) and high 14-3-3sigma protein (n = 44) were 25.62% and 43.47%, respectively (log-rank test, chi2 = 8.448, P = 0.004, Figure 3B).	('14-3-3sigma', 'Gene', (78, 89))	('14-3-3sigma', 'Gene', '2810', (78, 89))	('patients', 'Species', '9606', (41, 49))	('low', 'NegReg', (55, 58))	('high', 'Var', (73, 77))	('ESCC', 'Disease', (36, 40))
193971	24743601	When the patients were stratified by lymph node metastasis, those with high expression of 14-3-3sigma had better survival (61.28%) than those with low 14-3-3sigma expression (32.54%) in ESCC without lymph node metastasis (log-rank test, chi2 = 10.023, P = 0.002, Figure 3E), whereas 14-3-3sigma expression was not correlated with lymph node metastasis (log-rank text, chi2 = 0.117, P = 0.732, Figure 3F).	('patients', 'Species', '9606', (9, 17))	('high expression', 'Var', (71, 86))	('14-3-3sigma', 'Gene', '2810', (283, 294))	('better', 'PosReg', (106, 112))	('14-3-3sigma', 'Gene', (151, 162))	('14-3-3sigma', 'Gene', '2810', (90, 101))	('14-3-3sigma', 'Gene', (90, 101))	('14-3-3sigma', 'Gene', '2810', (151, 162))	('14-3-3sigma', 'Gene', (283, 294))	('ESCC', 'Disease', (186, 190))
193983	24743601	First and foremost, the present study demonstrated that dysregulation of 14-3-3sigma expression occurred at pre-malignant stages during the multi-step development and progression of esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (182, 207))	('esophageal carcinogenesis', 'Disease', (182, 207))	('14-3-3sigma', 'Gene', (73, 84))	('dysregulation', 'Var', (56, 69))	('14-3-3sigma', 'Gene', '2810', (73, 84))
193987	24743601	In human epidermal keratinocytes, inactivation of 14-3-3sigma caused immortalization, a fundamental feature of cancer cells.	('caused', 'Reg', (62, 68))	('immortalization', 'CPA', (69, 84))	('inactivation', 'Var', (34, 46))	('14-3-3sigma', 'Gene', '2810', (50, 61))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('14-3-3sigma', 'Gene', (50, 61))
193996	24743601	However, islands of tumor cells with or without 14-3-3sigma expression coexisted sometimes in the same specimen and a paradoxical higher level of 14-3-3sigma expression was observed in adenocarcinomas with high Gleason scores compared with those with low Gleason scores, indicating that cells retaining 14-3-3sigma expression may be selected during disease progression and treatment.	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('higher', 'PosReg', (130, 136))	('high Gleason scores', 'Var', (206, 225))	('adenocarcinomas', 'Disease', 'MESH:D000230', (185, 200))	('14-3-3sigma', 'Gene', '2810', (146, 157))	('adenocarcinomas', 'Disease', (185, 200))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('14-3-3sigma', 'Gene', (303, 314))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('14-3-3sigma', 'Gene', (48, 59))	('14-3-3sigma', 'Gene', (146, 157))	('14-3-3sigma', 'Gene', '2810', (303, 314))	('14-3-3sigma', 'Gene', '2810', (48, 59))	('tumor', 'Disease', (20, 25))
194019	19748854	Detection of promoter hypermethylation of the CpG island of E-cadherin in gastric cardiac adenocarcinoma Abnormal hypermethylation of CpG islands associated with tumor suppressor genes can lead to transcriptional silencing in neoplasia.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('hypermethylation', 'Var', (114, 130))	('gastric cardiac adenocarcinoma', 'Disease', (74, 104))	('tumor', 'Disease', (162, 167))	('E-cadherin', 'Gene', (60, 70))	('E-cadherin', 'Gene', '999', (60, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('neoplasia', 'Disease', (226, 235))	('transcriptional silencing', 'MPA', (197, 222))	('lead to', 'Reg', (189, 196))	('neoplasia', 'Phenotype', 'HP:0002664', (226, 235))	('gastric cardiac adenocarcinoma', 'Disease', 'MESH:D013274', (74, 104))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('neoplasia', 'Disease', 'MESH:D009369', (226, 235))
194022	19748854	E-cadherin was methylated in 63 of 92 (68.5%) tumor specimens, which was significantly higher than that in corresponding normal tissues (P < 0.001).	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('E-cadherin', 'Gene', (0, 10))	('methylated', 'Var', (15, 25))	('E-cadherin', 'Gene', '999', (0, 10))	('higher', 'PosReg', (87, 93))
194026	19748854	80 percent of tumor tissues with E-cadherin gene methylated showed inactivated mRNA expression.	('tumor', 'Disease', (14, 19))	('E-cadherin', 'Gene', (33, 43))	('E-cadherin', 'Gene', '999', (33, 43))	('methylated', 'Var', (49, 59))	('inactivated', 'NegReg', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mRNA expression', 'MPA', (79, 94))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
194027	19748854	High methylation status of the 5' CpG island of E-cadherin gene may be one of the mechanisms in the development of gastric cardiac adenocarcinoma.	('gastric cardiac adenocarcinoma', 'Disease', (115, 145))	('E-cadherin', 'Gene', (48, 58))	('gastric cardiac adenocarcinoma', 'Disease', 'MESH:D013274', (115, 145))	('High methylation status', 'Var', (0, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('E-cadherin', 'Gene', '999', (48, 58))
194034	19748854	It has been shown that germ-line mutations of the E-cadherin gene is related to familial gastric and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('familial gastric', 'Disease', 'MESH:D013274', (80, 96))	('E-cadherin', 'Gene', (50, 60))	('mutations', 'Var', (33, 42))	('E-cadherin', 'Gene', '999', (50, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('familial gastric', 'Disease', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('related', 'Reg', (69, 76))
194035	19748854	Furthermore, somatic mutations of E-cadherin were also found in gastric carcinoma and allelic loss of the E-cadherin locus at 16q22.1 has been reported in different epithelial tumors such as breast, ovarian, endometrial, and prostate carcinomas.	('gastric carcinoma', 'Disease', (64, 81))	('epithelial tumors', 'Disease', (165, 182))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (64, 81))	('epithelial tumors', 'Disease', 'MESH:D002277', (165, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial', 'Disease', (208, 219))	('E-cadherin', 'Gene', (34, 44))	('E-cadherin', 'Gene', '999', (34, 44))	('reported', 'Reg', (143, 151))	('prostate carcinomas', 'Disease', 'MESH:D011472', (225, 244))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('E-cadherin', 'Gene', (106, 116))	('E-cadherin', 'Gene', '999', (106, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('mutations', 'Var', (21, 30))	('found', 'Reg', (55, 60))	('ovarian', 'Disease', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast', 'Disease', (191, 197))	('prostate carcinomas', 'Disease', (225, 244))	('gastric carcinoma', 'Disease', 'MESH:D013274', (64, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (234, 244))
194036	19748854	Except for this genetic alterations, epigenetic alteration include hypermethylation of the 5' CpG island within the promoter of E-cadherin is also responsible for transcriptional repression of the gene.	('E-cadherin', 'Gene', (128, 138))	('E-cadherin', 'Gene', '999', (128, 138))	('transcriptional', 'MPA', (163, 178))	('hypermethylation', 'Var', (67, 83))	('responsible', 'Reg', (147, 158))
194037	19748854	It is known that abnormal hypermethylation of CpG islands associated with tumor suppressor genes can lead to transcriptional silencing in neoplasia.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('neoplasia', 'Disease', 'MESH:D009369', (138, 147))	('neoplasia', 'Phenotype', 'HP:0002664', (138, 147))	('transcriptional silencing', 'MPA', (109, 134))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('neoplasia', 'Disease', (138, 147))	('abnormal hypermethylation', 'Var', (17, 42))	('lead to', 'Reg', (101, 108))
194038	19748854	Indeed, methylation-associated silencing of E-cadherin represents the most common cause for its inactivation in several cancers such as liver, prostate, breast and esophageal.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('inactivation', 'NegReg', (96, 108))	('esophageal', 'Disease', (164, 174))	('liver', 'Disease', (136, 141))	('E-cadherin', 'Gene', (44, 54))	('breast', 'Disease', (153, 159))	('E-cadherin', 'Gene', '999', (44, 54))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('prostate', 'Disease', (143, 151))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('methylation-associated', 'Var', (8, 30))	('silencing', 'NegReg', (31, 40))
194043	19748854	It is now increasingly recognized that epigenetic silencing of gene expression by promoter CpG hypermethylation is an important alternative mechanism in inactivating tumour suppressor genes and tumour associated genes in cancers.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('inactivating', 'NegReg', (153, 165))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('tumour', 'Disease', (166, 172))	('tumour', 'Disease', (194, 200))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancers', 'Disease', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('hypermethylation', 'Var', (95, 111))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('epigenetic silencing', 'Var', (39, 59))
194044	19748854	Mutations of the E-cadherin gene are rare in GCA, thus, in this study, we evaluated the role of methylation of the 5' CpG island of E-cadherin and its correlation with reduced E-cadherin expression in GCA.	('E-cadherin', 'Gene', (132, 142))	('E-cadherin', 'Gene', '999', (132, 142))	('GCA', 'Gene', '25801', (45, 48))	('GCA', 'Gene', (45, 48))	('GCA', 'Gene', '25801', (201, 204))	('Mutations', 'Var', (0, 9))	('GCA', 'Gene', (201, 204))	('E-cadherin', 'Gene', (17, 27))	('E-cadherin', 'Gene', '999', (17, 27))	('expression', 'MPA', (187, 197))	('E-cadherin', 'Gene', (176, 186))	('E-cadherin', 'Gene', '999', (176, 186))	('reduced', 'NegReg', (168, 175))
194055	19748854	A nested PCR approach was used to determine the methylation status within the E-cadherin CpG island in Exon 1 (sequence -126 bp to +144 bp relative to transcription start, GenBank accession number D49685) that has been published previously.	('sequence -126 bp to +144 bp', 'Var', (111, 138))	('E-cadherin', 'Gene', (78, 88))	('E-cadherin', 'Gene', '999', (78, 88))
194060	19748854	The breast cancer cell line MB-MDA-231, which demonstrates methylation and silencing of E-cadherin and reagent blanks were used as positive and negative controls.	('MB-MDA-231', 'CellLine', 'CVCL:0062', (28, 38))	('E-cadherin', 'Gene', (88, 98))	('E-cadherin', 'Gene', '999', (88, 98))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('methylation', 'Var', (59, 70))	('silencing', 'MPA', (75, 84))
194074	19748854	In 63 (68.5%) of 92 GCA tumors E-cadherin methylation was detected, while only in 10 (10.9%) of paired normal tissues E-cadherin methylation was detected.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('GCA', 'Gene', '25801', (20, 23))	('detected', 'Reg', (58, 66))	('GCA', 'Gene', (20, 23))	('tumors', 'Disease', (24, 30))	('E-cadherin', 'Gene', (118, 128))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('E-cadherin', 'Gene', '999', (118, 128))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('methylation', 'Var', (42, 53))	('E-cadherin', 'Gene', (31, 41))	('E-cadherin', 'Gene', '999', (31, 41))
194076	19748854	When stratified for TNM stages, Frequency of E-cadherin gene methylation of GCA patients with stage III and stage IV (78.8%) were significantly higher than GCA patients with stage I and stage II (55%) (chi2 = 5.96, P = 0.01).	('patients', 'Species', '9606', (160, 168))	('methylation', 'Var', (61, 72))	('patients', 'Species', '9606', (80, 88))	('higher', 'PosReg', (144, 150))	('GCA', 'Gene', (156, 159))	('GCA', 'Gene', '25801', (76, 79))	('GCA', 'Gene', (76, 79))	('GCA', 'Gene', '25801', (156, 159))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))
194077	19748854	When stratified for pathological stages, the E-cadherin gene methylation frequencies of moderate, poor-moderate and poor group were 52.4%, 73.5% and 100%, frequency of E-cadherin gene methylation of poor group significantly higher than that in moderate and poor-moderate groups (chi2 = 8.92, P = 0.003) (Table 2).	('methylation', 'Var', (61, 72))	('E-cadherin', 'Gene', (168, 178))	('E-cadherin', 'Gene', '999', (168, 178))	('higher', 'PosReg', (224, 230))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))	('methylation', 'Var', (184, 195))
194084	19748854	The 32 GCA samples including 2 of stage I, 2 of stage II, 8 of stage III and 8 of stage IV of cases in which the tumor was methylated and 12 cases (2 of stage I, 4 of stages II, 4 of stage III and 2 of stage IV) with unmethylated E-cadherin gene.	('GCA', 'Gene', (7, 10))	('tumor', 'Disease', (113, 118))	('methylated', 'Var', (123, 133))	('GCA', 'Gene', '25801', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('E-cadherin', 'Gene', (230, 240))	('E-cadherin', 'Gene', '999', (230, 240))
194086	19748854	16 (1 of stage II, 7 of stage III and 8 of stage IV) cases (80%) of inactivated mRNA expression were observed in 20 tumor samples with E-cadherin gene methylated, the other 4 (2 of stage I, 1 of stage II, 1 of stage III) cases showed positive expression.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('methylated', 'Var', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('E-cadherin', 'Gene', (135, 145))	('E-cadherin', 'Gene', '999', (135, 145))
194094	19748854	Genetic abnormalities of proto-oncogenes and tumor suppressor genes are well-known changes that are frequently involved in cancer pathogenesis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Genetic abnormalities', 'Var', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('proto-oncogenes', 'Gene', (25, 40))	('cancer', 'Disease', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
194095	19748854	However, Epigenetic inactivation of certain tumor suppressor genes by aberrant promoter methylation is frequently observed in several cancers and may play a pivotal role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('aberrant promoter methylation', 'Var', (70, 99))	('cancers', 'Disease', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('Epigenetic inactivation', 'Var', (9, 32))	('play', 'Reg', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('observed', 'Reg', (114, 122))	('role', 'Reg', (165, 169))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
194096	19748854	While genetic abnormalities are associated with changes in DNA sequence, epigenetic events may lead to changes in gene expression that occur without changes in DNA sequence.	('lead to changes', 'Reg', (95, 110))	('genetic abnormalities', 'Disease', 'MESH:D030342', (6, 27))	('genetic abnormalities', 'Disease', (6, 27))	('gene expression', 'MPA', (114, 129))	('epigenetic events', 'Var', (73, 90))
194099	19748854	As a member of cell adhesion molecular, E-cadherin play an important role in maintaining cell adhesion and its dysfunction may result in tumorigenesis.6 The biological consequences of its dysfunction include disruption of intercellular adhesion and impairment of ss-catenin-mediated transactivation.	('impairment', 'NegReg', (249, 259))	('disruption', 'NegReg', (208, 218))	('tumor', 'Disease', (137, 142))	('intercellular adhesion', 'Protein', (222, 244))	('E-cadherin', 'Gene', (40, 50))	('E-cadherin', 'Gene', '999', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('ss-catenin-mediated transactivation', 'MPA', (263, 298))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('dysfunction', 'Var', (188, 199))
194101	19748854	It has been reported that hypermethylation of E-cadherin were associated with gastric cancer and esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (97, 122))	('E-cadherin', 'Gene', (46, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (97, 122))	('associated', 'Reg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('E-cadherin', 'Gene', '999', (46, 56))	('gastric cancer', 'Disease', (78, 92))	('hypermethylation', 'Var', (26, 42))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (97, 122))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
194103	19748854	In this study, we showed that hypermethylation of the 5' CpG island of the E-cadherin promoter occured frequently in GCA tissues (68.5%)and that this methylation change was associated with reduced expression of E-cadherin protein.	('E-cadherin', 'Gene', (211, 221))	('E-cadherin', 'Gene', (75, 85))	('E-cadherin', 'Gene', '999', (211, 221))	('reduced', 'NegReg', (189, 196))	('GCA', 'Gene', '25801', (117, 120))	('E-cadherin', 'Gene', '999', (75, 85))	('GCA', 'Gene', (117, 120))	('hypermethylation', 'Var', (30, 46))	('expression', 'MPA', (197, 207))
194104	19748854	Our data suggested that epigenetic silencing of the E-cadherin promoter via hypermethylation may be one of the critical mechanism for inactivation of this gene in GCA.	('epigenetic silencing', 'Var', (24, 44))	('hypermethylation', 'Var', (76, 92))	('GCA', 'Gene', '25801', (163, 166))	('GCA', 'Gene', (163, 166))	('E-cadherin', 'Gene', (52, 62))	('E-cadherin', 'Gene', '999', (52, 62))	('inactivation', 'NegReg', (134, 146))
194105	19748854	In our study, we found that in the majority of the cases we examined, E-cadherin methylation was tumor specific.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('methylation', 'Var', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('E-cadherin', 'Gene', (70, 80))	('E-cadherin', 'Gene', '999', (70, 80))
194110	19748854	These data strongly suggested that the E-cadherin promoter methylation is an aberrant event.	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('methylation', 'Var', (59, 70))
194112	19748854	In a study of neoplastic progression in Barrett's esophagus, hypermethylation of the tumor suppressor gene p16 was detected in pathologically normal-appearing specimens obtained from a patient who later developed dysplasia.	('tumor', 'Disease', (85, 90))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (40, 59))	('p16', 'Gene', '1029', (107, 110))	('patient', 'Species', '9606', (185, 192))	('detected', 'Reg', (115, 123))	('p16', 'Gene', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('hypermethylation', 'Var', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('dysplasia', 'Disease', (213, 222))	('dysplasia', 'Disease', 'MESH:D004476', (213, 222))
194113	19748854	Therefore, epigenetic inactivation of tumor suppressor genes may be an early feature of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('epigenetic inactivation', 'Var', (11, 34))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
194114	19748854	Our results showed that protein expression of Ecadherin in tumor tissues significantly lower than that in paired normal tissues, however, immunohistochemical staining also showed normal membranous staining of E-cadherin in some tumor samples with E-cadherin methylation.	('protein expression', 'MPA', (24, 42))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('lower', 'NegReg', (87, 92))	('Ecadherin', 'Gene', (46, 55))	('E-cadherin', 'Gene', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('E-cadherin', 'Gene', (247, 257))	('Ecadherin', 'Gene', '999', (46, 55))	('methylation', 'Var', (258, 269))	('tumor', 'Disease', (228, 233))	('E-cadherin', 'Gene', '999', (209, 219))	('E-cadherin', 'Gene', '999', (247, 257))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
194115	19748854	First, This was probably due to the fact that immunohistochemical staining was not as sensitive as PCR in detecting subpopulations of cells with gene methylation and hence downregulation of E-cadherin.	('downregulation', 'NegReg', (172, 186))	('E-cadherin', 'Gene', (190, 200))	('gene methylation', 'Var', (145, 161))	('E-cadherin', 'Gene', '999', (190, 200))
194118	19748854	In our study, we also found positive mRNA expression in some tumor samples with E-cadherin gene methylated.	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '999', (80, 90))	('mRNA expression', 'MPA', (37, 52))	('positive', 'Reg', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('methylated', 'Var', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
194120	19748854	In all, Our study suggested that epigenetic silencing of the E-cadherin promoter via hypermethylation may be one of the mechanism for inactivation of E-cadherin in GCA.	('hypermethylation', 'Var', (85, 101))	('GCA', 'Gene', '25801', (164, 167))	('GCA', 'Gene', (164, 167))	('E-cadherin', 'Gene', (61, 71))	('E-cadherin', 'Gene', (150, 160))	('E-cadherin', 'Gene', '999', (150, 160))	('E-cadherin', 'Gene', '999', (61, 71))	('epigenetic silencing', 'Var', (33, 53))	('inactivation', 'NegReg', (134, 146))
194164	31822054	We identified a cutoff value of 2.716 ng/mL for IGFBP7 to diagnose EJA by using the ROC curve to compare the EJA and normal control groups (Fig.	('2.716 ng/mL', 'Var', (32, 43))	('IGFBP7', 'Gene', '3490', (48, 54))	('EJA', 'Disease', (67, 70))	('EJA', 'Phenotype', 'HP:0011459', (67, 70))	('IGFBP7', 'Gene', (48, 54))	('EJA', 'Phenotype', 'HP:0011459', (109, 112))
194170	31822054	The difference in 3-year OS for EJA patients with high IGFBP7 levels had 72.4% 3-year OS versus 59.7% for patients with low expression (Fig.	('patients', 'Species', '9606', (36, 44))	('IGFBP7', 'Gene', (55, 61))	('IGFBP7', 'Gene', '3490', (55, 61))	('EJA', 'Phenotype', 'HP:0011459', (32, 35))	('patients', 'Species', '9606', (106, 114))	('high', 'Var', (50, 54))
194181	31822054	Methylation of IGFBP7 may reduce the expression of IGFBP7 in gastric cancer and prostate cancer and improve the tumor progression, and administration of IGFBP7 may be therapeutic for reducing breast cancer growth.	('IGFBP7', 'Gene', (51, 57))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('IGFBP7', 'Gene', (153, 159))	('breast cancer', 'Disease', (192, 205))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Methylation', 'Var', (0, 11))	('gastric cancer', 'Disease', (61, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('improve', 'PosReg', (100, 107))	('tumor', 'Disease', (112, 117))	('prostate cancer', 'Disease', (80, 95))	('IGFBP7', 'Gene', '3490', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('IGFBP7', 'Gene', (15, 21))	('expression', 'MPA', (37, 47))	('reduce', 'NegReg', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('IGFBP7', 'Gene', '3490', (51, 57))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('IGFBP7', 'Gene', '3490', (153, 159))
194190	31822054	Overexpression of serum IGFBP7 has been observed in high-grade soft tissue sarcoma, and high levels of serum IGFBP7 have been associated with positive nodal status in non-small cell lung cancer.	('IGFBP7', 'Gene', '3490', (109, 115))	('associated with', 'Reg', (126, 141))	('lung cancer', 'Disease', (182, 193))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('IGFBP7', 'Gene', '3490', (24, 30))	('observed', 'Reg', (40, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('sarcoma', 'Disease', (75, 82))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (171, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('IGFBP7', 'Gene', (109, 115))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (63, 82))	('IGFBP7', 'Gene', (24, 30))	('high levels', 'Var', (88, 99))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (167, 193))
194211	32393474	To date, the only validated predictive biomarkers of response to ICIs used in clinical practice across all solid tumors, including GI cancers, is microsatellite instability high (MSI-H) or DNA mismatch repair deficiency (dMMR).	('MSI-H', 'Chemical', '-', (179, 184))	('solid tumor', 'Disease', 'MESH:D009369', (107, 118))	('GI cancers', 'Disease', 'MESH:D009369', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('deficiency', 'Disease', 'MESH:D007153', (209, 219))	('GI cancer', 'Phenotype', 'HP:0007378', (131, 140))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('dMMR', 'Chemical', '-', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('DNA mismatch', 'Var', (189, 201))	('deficiency', 'Disease', (209, 219))	('solid tumor', 'Disease', (107, 118))	('GI cancers', 'Disease', (131, 141))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
194225	32393474	dMMR determines the accumulation of DNA replication errors which translates into high frequency of frameshift mutations in microsatellite DNA (MSI), leading to a high somatic mutational burden (mutator phenotype).	('frameshift mutations', 'Var', (99, 119))	('somatic mutational burden', 'MPA', (167, 192))	('dMMR', 'Chemical', '-', (0, 4))	('MSI', 'Gene', (143, 146))
194227	32393474	About one-quarter of dMMR CRCs are due to Lynch syndrome, an autosomal dominant hereditary disease characterized by germline mutations in the MMR genes (ie, MLH1, MSH2, MSH6, PMS2 or EPCAM deletions leading to epigenetic inactivation of MSH2), while the remaining cases are defined as 'sporadic'.	('epigenetic inactivation', 'MPA', (210, 233))	('autosomal dominant hereditary disease', 'Disease', (61, 98))	('MLH1', 'Gene', (157, 161))	('dMMR', 'Chemical', '-', (21, 25))	('MMR', 'Gene', (142, 145))	('PMS2', 'Gene', '5395', (175, 179))	('autosomal dominant hereditary disease', 'Disease', 'MESH:D030342', (61, 98))	('MLH1', 'Gene', '4292', (157, 161))	('dMMR CRCs', 'Disease', (21, 30))	('MSH2', 'Gene', (237, 241))	('Lynch syndrome', 'Disease', (42, 56))	('mutations', 'Var', (125, 134))	('EPCAM', 'Gene', '4072', (183, 188))	('MSH2', 'Gene', (163, 167))	('MSH2', 'Gene', '4436', (237, 241))	('due', 'Reg', (35, 38))	('PMS2', 'Gene', (175, 179))	('Lynch syndrome', 'Disease', 'MESH:D003123', (42, 56))	('MSH6', 'Gene', (169, 173))	('deletions', 'Var', (189, 198))	('MSH2', 'Gene', '4436', (163, 167))	('MSH6', 'Gene', '2956', (169, 173))	('EPCAM', 'Gene', (183, 188))
194228	32393474	The majority (80%-90%) of sporadic cases result from epigenetic silencing of the MLH1 gene promoter by hypermethylation, a phenomenon associated with a high CpG island methylation phenotype.	('MLH1', 'Gene', '4292', (81, 85))	('hypermethylation', 'Var', (103, 119))	('MLH1', 'Gene', (81, 85))	('result from', 'Reg', (41, 52))	('epigenetic', 'MPA', (53, 63))
194229	32393474	The concomitant presence of BRAF V600E mutation can be identified in about 30% of dMMR CRC, limited to sporadic MSI.	('BRAF', 'Gene', '673', (28, 32))	('V600E', 'Mutation', 'rs113488022', (33, 38))	('dMMR', 'Chemical', '-', (82, 86))	('V600E', 'Var', (33, 38))	('BRAF', 'Gene', (28, 32))	('dMMR CRC', 'Disease', (82, 90))
194238	32393474	Although MSI-H is conceivably the main driver for TMB-high, other factors may be involved and higher PD-L1 expression was more likely to be seen in MSI-H compared with MSS tumors (20.6% vs 7.8%, p<0.0001).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('MSS tumors', 'Disease', 'MESH:D013132', (168, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('MSI-H', 'Chemical', '-', (9, 14))	('expression', 'MPA', (107, 117))	('MSS tumors', 'Disease', (168, 178))	('MSI-H', 'Chemical', '-', (148, 153))	('MSI-H', 'Var', (148, 153))	('TMB', 'Chemical', '-', (50, 53))	('higher', 'PosReg', (94, 100))	('PD-L1', 'Gene', (101, 106))
194240	32393474	MDM2 amplification has been reported in multiple tumor types and is a hallmark of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('amplification', 'Var', (5, 18))	('reported', 'Reg', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (49, 54))	('MDM2', 'Gene', '4193', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('MDM2', 'Gene', (0, 4))	('tumor', 'Disease', (82, 87))
194241	32393474	Recently MDM2 amplification also has been implicated as a potential marker for accelerated tumor growth after checkpoint inhibitors treatment, a phenomenon known as hyperprogression, affecting approximately 9% of patients who receive PD-1/PD-L1 inhibitors.	('MDM2', 'Gene', '4193', (9, 13))	('MDM2', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (213, 221))	('accelerated', 'PosReg', (79, 90))	('tumor', 'Disease', (91, 96))	('amplification', 'Var', (14, 27))
194242	32393474	To date, hyperprogression after anti-PD-1/PD-L1 agents has been reported by at least four groups, however, the mechanisms that mediate this phenomenon remain unclear and the only markers that have been shown to correlate with this occurrence are MDM2 family gene amplifications and epidermal growth factor receptor (EGFR) alterations.	('MDM2', 'Gene', '4193', (246, 250))	('MDM2', 'Gene', (246, 250))	('EGFR', 'Gene', '1956', (316, 320))	('EGFR', 'Gene', (316, 320))	('epidermal growth factor receptor', 'Gene', (282, 314))	('alterations', 'Var', (322, 333))	('hyperprogression', 'CPA', (9, 25))	('epidermal growth factor receptor', 'Gene', '1956', (282, 314))
194267	32393474	On the other hand, recently reported results from the randomized phase III ATTRACTION-3 study (NCT02569242) showed a significant improvement in OS and a favorable safety profile from the anti-PD-1 nivolumab compared with chemotherapy in previously treated patients with advanced SCC, irrespective of tumor PD-L1 expression.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('nivolumab', 'Chemical', 'MESH:D000077594', (197, 206))	('tumor', 'Disease', (300, 305))	('patients', 'Species', '9606', (256, 264))	('safety', 'MPA', (163, 169))	('SCC', 'Disease', (279, 282))	('improvement', 'PosReg', (129, 140))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('anti-PD-1', 'Var', (187, 196))
194271	32393474	Phase III studies evaluating anti PD-1 treatments (either nivolumab or pembrolizumab, alone or in combination with chemotherapy) in earlier treatment lines and in the adjuvant setting are underway and will provide additional efficacy and biomarker data (ie, NCT02872116, NCT02743494, NCT03189719, NCT03143153).	('NCT02743494', 'Var', (271, 282))	('NCT03143153', 'Var', (297, 308))	('NCT02872116', 'Var', (258, 269))	('NCT03189719', 'Var', (284, 295))	('pembrolizumab', 'Chemical', 'MESH:C582435', (71, 84))	('nivolumab', 'Chemical', 'MESH:D000077594', (58, 67))
194272	32393474	Another strategy under investigation is the use of the anti PD-L1 durvalumab in combination with definitive radiotherapy delivered with oxaliplatin-based chemotherapy in locally advanced unresectable esophageal cancer (NCT03777813).	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (211, 217))	('anti PD-L1', 'Var', (55, 65))	('durvalumab', 'Chemical', 'MESH:C000613593', (66, 76))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (136, 147))
194301	32393474	However, to date, immunotherapy has not proven to be effective in these patients and several studies are ongoing with different approaches: combination of immune checkpoints with (1) chemotherapy (NCT04003636, NCT03111732,), (2) Locoregional treatments such as cryoablation or radiofrequency ablation (RFA) (NCT02821754), (3) radiotherapy (NCT03482102), (4) novel target such as DKK1-neutralizing monoclonal antibody DKN-01 (NCT04057365) and CD-40 (NCT03329950); and adoptive transfer of autologous TILs (NCT03801083).	('NCT04057365', 'Var', (425, 436))	('NCT03329950', 'Var', (449, 460))	('CD-40', 'Gene', (442, 447))	('CD-40', 'Gene', '958', (442, 447))	('NCT03482102', 'Var', (340, 351))	('NCT02821754', 'Var', (308, 319))	('DKK1', 'Gene', '22943', (379, 383))	('DKK1', 'Gene', (379, 383))	('patients', 'Species', '9606', (72, 80))
194304	32393474	However, recently the combination of APX005M, an anti-CD40 antibody, with nivolumab and standard chemotherapy (gemcitabine with nab-paclitaxel) showed manageable safety profiles and promising antitumor activity in untreated metastatic PDAC patients (ORR 58%).	('metastatic PDAC', 'Disease', (224, 239))	('nivolumab', 'Chemical', 'MESH:D000077594', (74, 83))	('tumor', 'Disease', (196, 201))	('CD40', 'Gene', '958', (54, 58))	('paclitaxel', 'Chemical', 'MESH:D017239', (132, 142))	('CD40', 'Gene', (54, 58))	('patients', 'Species', '9606', (240, 248))	('gemcitabine', 'Chemical', 'MESH:C056507', (111, 122))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('nab', 'Chemical', '-', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('APX005M', 'Var', (37, 44))
194312	32393474	An important characteristic of 'hot' tumors is the high TMB, which reflects an increased number of nonsynonymous, single nucleotide variants that may lead to an increased neoantigen production promoting the antitumor immune response.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('neoantigen production', 'MPA', (171, 192))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('single nucleotide variants', 'Var', (114, 140))	('TMB', 'Chemical', '-', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('promoting', 'PosReg', (193, 202))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (37, 43))	('increased', 'PosReg', (161, 170))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
194314	32393474	Patients with alterations in BRCA and additional DNA damage response genes, including ATM, POLE, FANCA, ERCC2 and MSH6, have recently shown correlation with high TMB and improved clinical outcomes to immune checkpoints inhibitors.	('alterations', 'Var', (14, 25))	('ERCC2', 'Gene', '2068', (104, 109))	('ATM', 'Gene', '472', (86, 89))	('TMB', 'MPA', (162, 165))	('FANCA', 'Gene', (97, 102))	('improved', 'PosReg', (170, 178))	('ERCC2', 'Gene', (104, 109))	('clinical outcomes', 'MPA', (179, 196))	('MSH6', 'Gene', (114, 118))	('TMB', 'Chemical', '-', (162, 165))	('Patients', 'Species', '9606', (0, 8))	('BRCA', 'Gene', (29, 33))	('ATM', 'Gene', (86, 89))	('MSH6', 'Gene', '2956', (114, 118))	('FANCA', 'Gene', '2175', (97, 102))
194321	32393474	Tumor-intrinsic mechanisms of immune evasion comprise genetic and epigenetic alterations (immunoediting) that influence the antitumor immune response, including loss of tumor antigen expression, loss of human leukocyte antigen) complex expression and alterations in the antigen processing machinery.	('epigenetic alterations', 'Var', (66, 88))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('immune', 'MPA', (30, 36))	('human', 'Species', '9606', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (169, 174))	('loss', 'NegReg', (161, 165))	('loss', 'NegReg', (195, 199))	('influence', 'Reg', (110, 119))	('alterations', 'Reg', (251, 262))	('expression', 'MPA', (236, 246))
194322	32393474	For instance, loss of beta-2-microglobulin expression (due to deletions, point mutations, or loss of heterozygosity) results in impaired cell surface expression of major histocompatibility class I, which in turn impairs antigen presentation to cytotoxic T cells, thereby inducing resistance to PD-1 and CTLA-4 blockade.	('beta-2-microglobulin', 'Gene', '567', (22, 42))	('resistance', 'MPA', (280, 290))	('loss', 'Var', (93, 97))	('beta-2-microglobulin', 'Gene', (22, 42))	('impairs', 'NegReg', (212, 219))	('antigen presentation', 'MPA', (220, 240))	('major histocompatibility class I', 'Protein', (164, 196))	('cell surface expression', 'MPA', (137, 160))	('deletions', 'Var', (62, 71))	('point mutations', 'Var', (73, 88))	('inducing', 'PosReg', (271, 279))	('impaired', 'NegReg', (128, 136))	('loss', 'NegReg', (14, 18))
194323	32393474	Loss of PTEN, which enhances PI3K signaling, has been found to be associated with resistance to immune checkpoint therapy.	('PI3K', 'MPA', (29, 33))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('enhances', 'PosReg', (20, 28))	('Loss', 'Var', (0, 4))
194324	32393474	Finally, there is now emerging evidence that chromatin remodeling is involved in sensitivity and resistance to ICI, through mutations in SWI/SNF (SWItch/Sucrose Non-Fermentable) complexes, such as loss of ARID1A or inactivation of PBAF subunits.	('PBAF subunits', 'Gene', (231, 244))	('mutations', 'Var', (124, 133))	('ARID1A', 'Gene', (205, 211))	('involved', 'Reg', (69, 77))	('loss', 'Var', (197, 201))	('Sucrose', 'Chemical', 'MESH:D013395', (153, 160))	('ARID1A', 'Gene', '8289', (205, 211))	('inactivation', 'Var', (215, 227))	('SWI/SNF', 'Gene', (137, 144))
194335	32393474	Epigenetic modifications of cancer DNA are known to cause changes in immune-related gene expression, which can impact antigen processing and presentation as well as promote immune evasion.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('antigen processing', 'MPA', (118, 136))	('changes', 'Reg', (58, 65))	('presentation', 'MPA', (141, 153))	('promote', 'PosReg', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('Epigenetic modifications', 'Var', (0, 24))	('immune evasion', 'MPA', (173, 187))	('cancer', 'Disease', (28, 34))	('impact', 'Reg', (111, 117))	('immune-related gene', 'Gene', (69, 88))
194345	32393474	Other likely targets include additional coinhibitory receptors such as TIM3 (a marker for exhausted T cells); T cell immunoglobulin and ITIM domain (TIGIT, which counterbalances the costimulatory function of CD226, that is rapidly induced following T cell activation); B and T lymphocyte attenuator (also known as CD272), which is expressed by T cells and synergizes with herpesvirus entry mediator (also known as TNFRSF14), expressed on antigen-presenting cells; sialic acid-binding Ig-like lectin 9, which is upregulated in TILs and possibly determines a subclass of tumor-specific CD8 +TILs; and V-domain Ig suppressor of T cell activation (VISTA).	('tumor', 'Disease', (569, 574))	('CD8', 'Gene', (584, 587))	('CD226', 'Gene', '10666', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (569, 574))	('sialic acid-binding Ig-like lectin 9', 'Gene', (464, 500))	('TIGIT', 'Gene', '201633', (149, 154))	('CD272', 'Gene', '151888', (314, 319))	('herpesvirus', 'Species', '39059', (372, 383))	('tumor', 'Phenotype', 'HP:0002664', (569, 574))	('V-domain', 'Var', (599, 607))	('CD8', 'Gene', '925', (584, 587))	('sialic acid-binding Ig-like lectin 9', 'Gene', '27180', (464, 500))	('TIGIT', 'Gene', (149, 154))	('CD226', 'Gene', (208, 213))	('TIM3', 'Gene', (71, 75))	('TNFRSF14', 'Gene', '8764', (414, 422))	('TIM3', 'Gene', '84868', (71, 75))	('TNFRSF14', 'Gene', (414, 422))	('CD272', 'Gene', (314, 319))
194402	30362330	The cause-specific hazard frailty model with a separate random effect for every type of event within each cluster (Christian et al., 2016) is: Where XijT and betak are the px1 vector of covariates and px1 vector of regression coefficients, respectively.	('px1', 'Gene', '24145', (172, 175))	('betak', 'Var', (158, 163))	('px1', 'Gene', (172, 175))	('px1', 'Gene', (201, 204))	('px1', 'Gene', '24145', (201, 204))	('XijT', 'Var', (149, 153))
194415	30362330	In Figure 1 Panel (b), two clusters of wards in the central and east part of map with a higher hazard (wards with red colors) and one cluster with lower hazard (wards with blue colors) related to death from other causes can be identified.	('death', 'Disease', (196, 201))	('red colors', 'Var', (114, 124))	('death', 'Disease', 'MESH:D003643', (196, 201))
194447	30362330	The hazard of death from gastrointestinal cancer in patients who had received radiotherapy was lower than those who did not receive radiotherapy.	('lower', 'NegReg', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (25, 48))	('radiotherapy', 'Var', (78, 90))	('death', 'Disease', 'MESH:D003643', (14, 19))	('death', 'Disease', (14, 19))	('gastrointestinal cancer', 'Disease', (25, 48))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (25, 48))	('patients', 'Species', '9606', (52, 60))
194538	28659128	Patients with esophageal cancer staging as cT1N1M0 or cT2-3 N0-1 M0 were enrolled in the study, and it showed better R0 rate (92% vs 69%, P < 0.001), lower node-positive rate (31% vs 75%, P < 0.001) and longer overall survival (49.4 vs 24 months, P = 0.003) in the nCRT group without significant postoperative morbidities and mortalities.	('lower', 'NegReg', (150, 155))	('overall', 'MPA', (210, 217))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cT1N1M0', 'Var', (43, 50))	('esophageal cancer', 'Disease', (14, 31))	('longer', 'PosReg', (203, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (110, 116))	('R0 rate', 'CPA', (117, 124))	('node-positive rate', 'CPA', (156, 174))
194540	28659128	However, accumulating evidence suggested that a significant level of toxicity resulted from nCRT for ESCC.	('toxicity', 'Disease', (69, 77))	('ESCC', 'Gene', (101, 105))	('nCRT', 'Var', (92, 96))	('toxicity', 'Disease', 'MESH:D064420', (69, 77))
194562	28659128	Histologically-confirmed squamous cell carcinoma of the esophagus; Tumors of the esophagus are located in the thoracic cavity; Pre-treatment stage as cT3-4aN0-1M0 (AJCC/UICC 7th Edition) (In case of stage cT4a, curative resectability has to be explicitly verified by the local surgical investigator prior to randomization).	('squamous cell carcinoma of the esophagus', 'Disease', (25, 65))	('Tumors', 'Phenotype', 'HP:0002664', (67, 73))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (25, 65))	('cT3-4aN0-1M0', 'Var', (150, 162))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (39, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))	('Tumors', 'Disease', (67, 73))	('Tumors', 'Disease', 'MESH:D009369', (67, 73))
194575	28659128	The dissected nodes in thoracic cavity should include the upper paraesophageal (no.105), paratracheal (no.106r and 106tb), subcarinal (no.107), middle paraesophageal (no.108), bilateral hilar lymph nodes (no.109), lower paraesophageal (no.110), posterior mediastinal lymph nodes (no.111), and diaphragmatic (no.112) ones.	('middle paraesophageal', 'Disease', 'MESH:D020244', (144, 165))	('upper paraesophageal', 'Disease', (58, 78))	('no.107', 'Var', (135, 141))	('upper paraesophageal', 'Disease', 'MESH:D006551', (58, 78))	('middle paraesophageal', 'Disease', (144, 165))	('no.106r', 'Var', (103, 110))	('no.108', 'Var', (167, 173))
194619	26576752	The incidence of positive margins for patients who underwent esophagogastrectomy without induction therapy for pathologic T1-3N0-1M0 esophageal cancer of the mid and lower esophagus from 2003 to 2006 in the National Cancer Database was analyzed with multivariate logistic regression.	('Cancer', 'Disease', (216, 222))	('Cancer', 'Disease', 'MESH:D009369', (216, 222))	('T1-3N0-1M0', 'Var', (122, 132))	('Cancer', 'Phenotype', 'HP:0002664', (216, 222))	('patients', 'Species', '9606', (38, 46))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
194634	26576752	As long-term survival data for patients in the version of the NCDB used in this study were only available through 2006, all patients diagnosed from 2003 to 2006 with pathologic T1-3N0-1M0 esophageal cancer of the mid and lower esophagus were included for analysis.	('esophageal cancer', 'Disease', 'MESH:D004938', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('T1-3N0-1M0', 'Var', (177, 187))	('patients', 'Species', '9606', (31, 39))	('esophageal cancer', 'Disease', (188, 205))	('patients', 'Species', '9606', (124, 132))
194646	26576752	A total of 3,177 patients with pT1-3N0-1M0 esophageal cancer (adenocarcinomas 83.6% versus squamous cell carcinomas 16.4%) underwent resection during the study period.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (91, 115))	('adenocarcinomas', 'Disease', 'MESH:D000230', (62, 77))	('adenocarcinomas', 'Disease', (62, 77))	('pT1-3N0-1M0', 'Var', (31, 42))	('patients', 'Species', '9606', (17, 25))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (91, 115))	('squamous cell carcinomas', 'Disease', (91, 115))
194706	27436512	Although previous studies have examined the feasibility of using plasma MMP1 as diagnostic or prognostic markers for lung cancers, prostate cancer, thyroid cancer and hepatocellular carcinoma, it has not been investigated as such in esophageal cancer.	('thyroid cancer', 'Disease', (148, 162))	('plasma', 'Var', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('hepatocellular carcinoma', 'Disease', (167, 191))	('esophageal cancer', 'Disease', 'MESH:D004938', (233, 250))	('thyroid cancer', 'Disease', 'MESH:D013964', (148, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('MMP1', 'Gene', (72, 76))	('esophageal cancer', 'Disease', (233, 250))	('thyroid cancer', 'Phenotype', 'HP:0002890', (148, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (167, 191))	('lung cancers', 'Disease', 'MESH:D008175', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancers', 'Disease', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancers', 'Phenotype', 'HP:0100526', (117, 129))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (167, 191))	('prostate cancer', 'Disease', (131, 146))
194716	27436512	The seventeen patients in the GSE20347 dataset had minimum, mean, and maximum values of T/N ratios of 1.51, 90.05, and 466.1064, respectively (Supplementary Fig.	('T/N', 'MPA', (88, 91))	('GSE', 'Chemical', '-', (30, 33))	('patients', 'Species', '9606', (14, 22))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('466.1064', 'Var', (119, 127))
194730	27436512	Studying a set of plasma samples in ESCC patients and their controls, we found a significant association between high plasma MMP1 and ESCC.	('patients', 'Species', '9606', (41, 49))	('high plasma', 'Var', (113, 124))	('ESCC', 'Disease', (134, 138))	('MMP1', 'Gene', (125, 129))
194742	27436512	The association between single nucleotide polymorphisms (SNPs) of MMP1 and lung cancer risk was strongly increased among heavy smokers.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('single nucleotide polymorphisms', 'Var', (24, 55))	('association', 'Interaction', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('increased', 'PosReg', (105, 114))	('MMP1', 'Gene', (66, 70))
194758	27436512	To compare the expression of MMP1 in other studies, we retrieved two publicly available sets of microarray data (GSE23400 and GSE20347) from the Gene Expression Omnibus (GEO) database.	('GSE20347', 'Var', (126, 134))	('GSE23400', 'Var', (113, 121))	('GSE', 'Chemical', '-', (113, 116))	('GSE', 'Chemical', '-', (126, 129))
194759	27436512	GSE23400 and GSE 20347 consist of gene expression data from 53 and 17 Chinese ESCC patients, respectively.	('GSE 20347', 'Var', (13, 22))	('ESCC', 'Disease', (78, 82))	('GSE23400', 'Var', (0, 8))	('patients', 'Species', '9606', (83, 91))	('GSE', 'Chemical', '-', (13, 16))	('GSE', 'Chemical', '-', (0, 3))
194775	27436512	Previous studies, including ours, have found that functional polymorphisms of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase (ALDH2) genes, located on chromosome 4q22 and 12q24, respectively, are highly associated with the risk of ESCC.	('ESCC', 'Disease', (241, 245))	('associated with', 'Reg', (213, 228))	('polymorphisms', 'Var', (61, 74))	('ALDH2', 'Gene', '217', (136, 141))	('alcohol dehydrogenase', 'Gene', '10327', (78, 99))	('ADH1B', 'Gene', '125', (101, 106))	('ALDH2', 'Gene', (136, 141))	('alcohol dehydrogenase', 'Gene', (78, 99))	('ADH1B', 'Gene', (101, 106))
194794	27257562	However, even with recent advancements in voice restoration methods, substitute speech by itself still has lower intelligibility.	('substitute', 'Var', (69, 79))	('lower', 'NegReg', (107, 112))	('intelligibility', 'MPA', (113, 128))	('men', 'Species', '9606', (33, 36))	('substitute speech', 'Phenotype', 'HP:0010529', (69, 86))
194858	26544513	Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('RAS', 'Pathway', (50, 53))	('bladder and esophageal cancer', 'Disease', 'MESH:D001749', (120, 149))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('hyperactivates', 'PosReg', (31, 45))	('mutant', 'Var', (19, 25))	('cancer', 'Disease', (143, 149))	('lung', 'Disease', (114, 118))	('mTOR pathway', 'Pathway', (62, 74))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))	('HRAS', 'Gene', (26, 30))
194859	26544513	HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901.	('HRAS', 'Gene', (0, 4))	('growth inhibition', 'MPA', (32, 49))	('PD0325901', 'Chemical', 'MESH:C506614', (92, 101))	('sensitized', 'Reg', (14, 24))	('MEK162', 'Chemical', 'MESH:C581313', (81, 87))	('mutation', 'Var', (5, 13))	('AZD6244', 'Chemical', 'MESH:C517975', (72, 79))
194860	26544513	Finally, Ba/F3 cells transformed with mutant HRAS isoforms Q61L, Q61R and G12V demonstrated equal sensitivity towards MEK and mTOR inhibition.	('mTOR inhibition', 'MPA', (126, 141))	('sensitivity', 'MPA', (98, 109))	('HRAS', 'Gene', (45, 49))	('G12V', 'Var', (74, 78))	('G12V', 'Mutation', 'rs104894230', (74, 78))	('Q61R', 'Var', (65, 69))	('Q61L', 'Mutation', 'rs121913233', (59, 63))	('Q61R', 'Mutation', 'rs121913233', (65, 69))	('Q61L', 'Var', (59, 63))
194861	26544513	Our results show that HRAS mutations in cancer activate the RAS and mTOR pathways which might serve as a therapeutic option for patients with HRAS mutant tumors.	('mutations', 'Var', (27, 36))	('activate', 'PosReg', (47, 55))	('tumors', 'Disease', (154, 160))	('mTOR pathways', 'Pathway', (68, 81))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('HRAS', 'Gene', (22, 26))
194863	26544513	Mutations in RAS family members lead to hyperactivity of the RAS signaling pathway.	('RAS signaling pathway', 'Pathway', (61, 82))	('hyperactivity', 'Disease', 'MESH:D006948', (40, 53))	('hyperactivity', 'Disease', (40, 53))	('Mutations', 'Var', (0, 9))	('hyperactivity', 'Phenotype', 'HP:0000752', (40, 53))	('RAS', 'Gene', (13, 16))
194866	26544513	Histological subtypes could play a role as a report described a high frequency of HRAS mutations in inverted urothelial papilloma (IUP) - an uncommon neoplasm of the urinary bladder with distinct morphologic features.	('HRAS', 'Gene', (82, 86))	('urothelial papilloma', 'Disease', (109, 129))	('neoplasm', 'Phenotype', 'HP:0002664', (150, 158))	('papilloma', 'Phenotype', 'HP:0012740', (120, 129))	('neoplasm of the urinary bladder', 'Disease', 'MESH:D001749', (150, 181))	('urothelial papilloma', 'Disease', 'MESH:D010212', (109, 129))	('neoplasm of the urinary bladder', 'Disease', (150, 181))	('mutations', 'Var', (87, 96))
194867	26544513	In addition, HRAS mutations seem to be more frequent in squamous cell cancer of the lung (2.8%) than in adenocarcinoma of the lung (1%).	('HRAS', 'Gene', (13, 17))	('squamous cell cancer', 'Disease', (56, 76))	('squamous cell cancer', 'Disease', 'MESH:D002294', (56, 76))	('squamous cell cancer of the lung', 'Phenotype', 'HP:0030359', (56, 88))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('frequent', 'Reg', (44, 52))	('cancer of the lung', 'Phenotype', 'HP:0100526', (70, 88))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (56, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('adenocarcinoma of the lung', 'Disease', (104, 130))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (104, 130))	('mutations', 'Var', (18, 27))
194869	26544513	One recent report described an adenocarcinoma of the lung with HRAS Q61L mutation suffering from rapid progression and deterioration suggesting that HRAS mutations in NSCLC tumors might be aggressive and associated with poor overall prognosis, similar to KRAS mutant NSCL.	('NSCL', 'Gene', (267, 271))	('NSCL', 'Gene', (167, 171))	('KRAS', 'Gene', '3845', (255, 259))	('NSCL', 'Gene', '4807', (267, 271))	('HRAS', 'Gene', (63, 67))	('NSCL', 'Gene', '4807', (167, 171))	('Q61L', 'Mutation', 'rs121913233', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (31, 57))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('HRAS', 'Gene', (149, 153))	('NSCLC tumors', 'Disease', 'MESH:D009369', (167, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (154, 163))	('KRAS', 'Gene', (255, 259))	('mutation', 'Var', (73, 81))	('adenocarcinoma of the lung', 'Disease', (31, 57))	('NSCLC tumors', 'Disease', (167, 179))
194870	26544513	Interestingly, one phase I trial for the novel Mitogen-activated protein kinase kinase (MEK) inhibitor RO5126766 reported a tumor patient with HRAS mutation that showed 20% tumor shrinkage due to MEK inhibitor treatment.	('patient', 'Species', '9606', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('RO5126766', 'Chemical', 'MESH:C577924', (103, 112))	('Mitogen-activated protein kinase kinase', 'Gene', '5609', (47, 86))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('Mitogen-activated protein kinase kinase', 'Gene', (47, 86))	('mutation', 'Var', (148, 156))	('HRAS', 'Gene', (143, 147))
194872	26544513	Typical hotspots for HRAS mutations are found at codon 12, 13 and 61, resulting in G12C/S, G13R/V and Q61R/L mutations.	('G12C', 'SUBSTITUTION', 'None', (83, 87))	('G12C', 'Var', (83, 87))	('HRAS', 'Gene', (21, 25))	('Q61R', 'SUBSTITUTION', 'None', (102, 106))	('Q61R', 'Var', (102, 106))	('mutations', 'Var', (26, 35))	('G13R', 'SUBSTITUTION', 'None', (91, 95))	('G13R', 'Var', (91, 95))
194873	26544513	These positions for mutations of HRAS are at the very same sides as mutations found for NRAS.	('mutations', 'Var', (20, 29))	('NRAS', 'Gene', '4893', (88, 92))	('NRAS', 'Gene', (88, 92))	('HRAS', 'Gene', (33, 37))
194874	26544513	As of today, mutant NRAS has been far better investigated, mainly in melanoma but also in other cancers such as lung cancer and T-cell lymphoma.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('lung cancer', 'Disease', (112, 123))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (128, 143))	('cancers', 'Disease', (96, 103))	('T-cell lymphoma', 'Disease', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('NRAS', 'Gene', '4893', (20, 24))	('cell lymphoma', 'Phenotype', 'HP:0012191', (130, 143))	('melanoma', 'Disease', (69, 77))	('lymphoma', 'Phenotype', 'HP:0002665', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('mutant', 'Var', (13, 19))	('NRAS', 'Gene', (20, 24))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (128, 143))
194875	26544513	NRAS mutations are mostly found at codon 61 and to a fewer extend at codons 12 and 13.	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
194876	26544513	NRAS mutations occur at about 15% to 25% in melanoma patients and are known to activate the RAS-RAF-MEK-ERK pathway.	('RAF', 'Gene', (96, 99))	('RAF', 'Gene', '22882', (96, 99))	('patients', 'Species', '9606', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('activate', 'PosReg', (79, 87))	('mutations', 'Var', (5, 14))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
194879	26544513	Mutant NRAS was also shown to activate the PI3K/mechanistic target of rapamycin (mTOR)-signaling cascade and combined inhibition of MEK and PI3K was synergistic in certain NRAS mutant cell lines of melanoma, lung cancer and neuroblastoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (224, 237))	('mutant', 'Var', (177, 183))	('neuroblastoma', 'Disease', 'MESH:D009447', (224, 237))	('PI3K/mechanistic target of rapamycin', 'Gene', '2475', (43, 79))	('NRAS', 'Gene', '4893', (7, 11))	('activate', 'PosReg', (30, 38))	('NRAS', 'Gene', (172, 176))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('NRAS', 'Gene', '4893', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Mutant', 'Var', (0, 6))	('NRAS', 'Gene', (7, 11))	('PI3K/mechanistic target of rapamycin', 'Gene', (43, 79))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('neuroblastoma', 'Disease', (224, 237))	('lung cancer', 'Disease', (208, 219))
194880	26544513	More important, the concept of targeted treatment of NRAS mutant melanoma could be demonstrated within clinical trials.	('mutant', 'Var', (58, 64))	('NRAS', 'Gene', (53, 57))	('NRAS', 'Gene', '4893', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
194884	26544513	We observed that lung cancer cell lines harboring HRAS mutations showed significant higher sensitivity to MEK inhibitors than HRAS wild-type cell lines.	('lung cancer', 'Disease', (17, 28))	('mutations', 'Var', (55, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('sensitivity to MEK inhibitors', 'MPA', (91, 120))	('HRAS', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('higher', 'PosReg', (84, 90))
194887	26544513	This is reflected by the two lung cancer cell lines KNS-62 (squamous) and NCI-H1915 (adenocarcinoma) which both harbor a Q61L mutation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Q61L', 'Mutation', 'rs121913233', (121, 125))	('Q61L', 'Var', (121, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('NCI-H1915 (adenocarcinoma', 'Disease', 'MESH:D000230', (74, 99))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
194888	26544513	The HRAS G12V mutation is predominant in bladder cancer which was detected in the T24 bladder cancer cell line (Figure 1B).	('bladder cancer', 'Disease', (86, 100))	('HRAS G12V', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('G12V', 'Mutation', 'rs104894230', (9, 13))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('bladder cancer', 'Disease', 'MESH:D001749', (41, 55))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))	('bladder cancer', 'Disease', (41, 55))
194889	26544513	HCC827 is a cell line with described EGFR mutation and HCC78 was found to harbor a ROS1 translocation.	('ROS1', 'Gene', (83, 87))	('ROS1', 'Gene', '6098', (83, 87))	('mutation', 'Var', (42, 50))	('EGFR', 'Gene', '1956', (37, 41))	('HCC78', 'Gene', (55, 60))	('EGFR', 'Gene', (37, 41))
194890	26544513	RAS kinases are well known to activate the RAS-RAF-MEK-ERK cascade and several MEK inhibitors are under clinical development including AZD6244 (Selumetinib) and MEK162 (Binimetinib).	('activate', 'PosReg', (30, 38))	('AZD6244', 'Var', (135, 142))	('Binimetinib', 'Chemical', 'MESH:C581313', (169, 180))	('AZD6244', 'Chemical', 'MESH:C517975', (135, 142))	('Selumetinib', 'Chemical', 'MESH:C517975', (144, 155))	('RAF', 'Gene', '22882', (47, 50))	('RAF', 'Gene', (47, 50))	('MEK162', 'Chemical', 'MESH:C581313', (161, 167))
194892	26544513	We detected that HRAS mutant cell lines KNS-62, NCI-H1915, T24, RL95-2 and KYSE-30 had significantly lower EC50 values for MEK inhibition than HRAS wild-type cells such as CAL12T, HCC44, HCC827 and HCC78 (Figure 1C,1D, Supplementary Figure S1A).	('EC50 values', 'MPA', (107, 118))	('HCC44', 'CellLine', 'CVCL:2060', (180, 185))	('MEK', 'Enzyme', (123, 126))	('NCI-H1915', 'CellLine', 'CVCL:1505', (48, 57))	('lower', 'NegReg', (101, 106))	('mutant', 'Var', (22, 28))	('CAL12T', 'CellLine', 'CVCL:1105', (172, 178))
194894	26544513	In contrast, HRAS mutant cell lines had EC50 values for AZD6244 ranging from 4-5nM (T24 and RL95-2) over 166-258nM (KNS-62, NCI-H1915) to 437nM (KYSE-30) (Figure 1C).	('NCI-H1915', 'CellLine', 'CVCL:1505', (124, 133))	('AZD6244', 'Var', (56, 63))	('EC50', 'MPA', (40, 44))	('AZD6244', 'Chemical', 'MESH:C517975', (56, 63))
194900	26544513	AZD6244, MEK162 and PD0325901 blocked basal ERK phosphorylation in all HRAS mutant cell lines (Figure 1E).	('MEK162', 'Chemical', 'MESH:C581313', (9, 15))	('blocked', 'NegReg', (30, 37))	('PD0325901', 'Var', (20, 29))	('mutant', 'Var', (76, 82))	('PD0325901', 'Chemical', 'MESH:C506614', (20, 29))	('HRAS', 'Disease', (71, 75))	('basal', 'Protein', (38, 43))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))
194901	26544513	Taken together this data shows, that HRAS mutation results in hyperactivation of the RAS pathway in cancer cell lines from various tissues and that this activation sensitizes towards treatment with MEK inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('RAS pathway', 'Pathway', (85, 96))	('mutation', 'Var', (42, 50))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('hyperactivation', 'PosReg', (62, 77))	('HRAS', 'Gene', (37, 41))
194902	26544513	Since MEK inhibitors block cell growth we wanted to analyze whether induction of apoptosis occurs in HRAS mutant cancer cell lines.	('mutant', 'Var', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('HRAS', 'Gene', (101, 105))	('cell growth', 'CPA', (27, 38))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
194903	26544513	Indeed, MEK inhibitor MEK162 induced apoptosis in HRAS mutant cell lines KNS-62, NCI-H1915, T24, RL95-2 and KYSE-30 but not in HRAS wild-type cell lines (Figure 2A, 2B).	('induced', 'Reg', (29, 36))	('apoptosis', 'CPA', (37, 46))	('MEK162', 'Gene', (22, 28))	('mutant', 'Var', (55, 61))	('MEK162', 'Chemical', 'MESH:C581313', (22, 28))	('NCI-H1915', 'CellLine', 'CVCL:1505', (81, 90))
194904	26544513	Previously, it was demonstrated that mutant NRAS melanoma cells are sensitive to the combination of MEK and PI3K inhibitors.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('sensitive', 'Reg', (68, 77))	('NRAS', 'Gene', (44, 48))	('mutant', 'Var', (37, 43))	('NRAS', 'Gene', '4893', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
194906	26544513	Further, pan-PI3K inhibitor BKM120 did not alter phosphorylation of AKT Ser 473 in KNS-62 cell line (Figure 3A).	('Ser', 'Chemical', 'MESH:D012694', (72, 75))	('AKT', 'Gene', '207', (68, 71))	('BKM120', 'Chemical', 'MESH:C571178', (28, 34))	('phosphorylation', 'MPA', (49, 64))	('AKT', 'Gene', (68, 71))	('BKM120', 'Var', (28, 34))
194907	26544513	These findings are in line with a lack of growth inhibition for single pan-PI3K inhibition or combined treatment with MEK162 in HRAS mutant cell lines (Figure 3B).	('HRAS', 'Gene', (128, 132))	('MEK162', 'Chemical', 'MESH:C581313', (118, 124))	('mutant', 'Var', (133, 139))	('inhibition', 'NegReg', (80, 90))
194909	26544513	We conclude that inhibition of the PI3K pathway is not relevant for survival and cell growth of HRAS mutant cancer cells.	('PI3K pathway', 'Pathway', (35, 47))	('HRAS', 'Gene', (96, 100))	('mutant', 'Var', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
194911	26544513	The clinically available mTOR inhibitor Everolimus blocked activity of S6, a kinase downstream of mTOR, in HRAS mutant cell lines (Figure 4A).	('activity', 'MPA', (59, 67))	('HRAS', 'Gene', (107, 111))	('Everolimus', 'Chemical', 'MESH:D000068338', (40, 50))	('mutant', 'Var', (112, 118))	('blocked', 'NegReg', (51, 58))
194912	26544513	This inhibition of the mTOR pathway translated in blockage of cell growth preferentially in HRAS mutant cancer cell lines (Figure 4A).	('mTOR pathway', 'Pathway', (23, 35))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('blockage', 'NegReg', (50, 58))	('mutant', 'Var', (97, 103))	('inhibition', 'NegReg', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (104, 110))	('cell growth preferentially', 'CPA', (62, 88))	('HRAS', 'Gene', (92, 96))
194914	26544513	If used together, combination of Everolimus and AZD6244/MEK162 caused a stronger inhibition of S6 kinase than single use of Everolimus on Western blot (Figure 4B; Supplementary Figure S2A).	('MEK162', 'Chemical', 'MESH:C581313', (56, 62))	('Everolimus', 'Chemical', 'MESH:D000068338', (124, 134))	('AZD6244', 'Chemical', 'MESH:C517975', (48, 55))	('Everolimus', 'Chemical', 'MESH:D000068338', (33, 43))	('inhibition', 'NegReg', (81, 91))	('AZD6244/MEK162', 'Var', (48, 62))
194915	26544513	The combination of Everolimus and AZD6244 / MEK162 also translated in a stronger blockade of cell growth in HRAS mutant cells than single use (Figure 4C; Supplementary Figure S2B).	('AZD6244', 'Chemical', 'MESH:C517975', (34, 41))	('cell growth', 'CPA', (93, 104))	('AZD6244 / MEK162', 'Var', (34, 50))	('HRAS', 'Gene', (108, 112))	('Everolimus', 'Chemical', 'MESH:D000068338', (19, 29))	('MEK162', 'Chemical', 'MESH:C581313', (44, 50))	('mutant', 'Var', (113, 119))	('blockade', 'NegReg', (81, 89))
194919	26544513	To further support the synergistic action of mTOR and MEK inhibitors in HRAS mutant cells we used the novel mTOR1/2 inhibitor AKT8055 which entered early clinical trials.	('mutant', 'Var', (77, 83))	('AKT', 'Gene', (126, 129))	('AKT', 'Gene', '207', (126, 129))	('HRAS', 'Gene', (72, 76))
194922	26544513	Combination of AKT8055 and MEK inhibitors also blocked cell growth synergistically in mutant HRAS cell lines according to Chou-Talalay (Figure 4D; Supplementary Figure S2C).	('AKT', 'Gene', '207', (15, 18))	('MEK', 'Gene', (27, 30))	('mutant', 'Var', (86, 92))	('Chou-Talalay', 'Disease', (122, 134))	('blocked', 'NegReg', (47, 54))	('cell', 'CPA', (55, 59))	('AKT', 'Gene', (15, 18))	('Chou-Talalay', 'Disease', 'None', (122, 134))
194923	26544513	We wanted to study the functional consequences of the different HRAS mutations including Q61L, Q61R and G12V in more detail by testing their abilities to transform interleukin-3 (IL-3)-dependent murine lymphoid Ba/F3 cells to cytokine-independent growth.	('interleukin-3', 'Gene', (164, 177))	('interleukin-3', 'Gene', '16187', (164, 177))	('Q61R', 'Var', (95, 99))	('murine', 'Species', '10090', (195, 201))	('transform', 'Reg', (154, 163))	('Q61R', 'Mutation', 'rs121913233', (95, 99))	('testing', 'Reg', (127, 134))	('G12V', 'Var', (104, 108))	('Q61L', 'Mutation', 'rs121913233', (89, 93))	('Q61L', 'Var', (89, 93))	('HRAS', 'Gene', (64, 68))	('G12V', 'Mutation', 'rs104894230', (104, 108))
194924	26544513	Ba/F3 cells expressing ectopic HRAS Q61L, Q61R or G12V mutations showed strong cell growth whereas Ba/F3 cells with wild-type HRAS or empty vector stopped cell growth (Supplementary Figure S3A).	('Q61R', 'Mutation', 'rs121913233', (42, 46))	('G12V', 'Var', (50, 54))	('G12V', 'Mutation', 'rs104894230', (50, 54))	('Q61L', 'Mutation', 'rs121913233', (36, 40))	('HRAS Q61L', 'Var', (31, 40))	('Q61L', 'Var', (36, 40))	('Q61R', 'Var', (42, 46))	('cell growth', 'CPA', (79, 90))
194925	26544513	Ba/F3 cells expressing mutant versions of HRAS exhibited constitutive phosphorylation of ERK and S6 which was blocked by MEK162 or Everolimus, respectively (Figure 5A, 5B).	('MEK162', 'Chemical', 'MESH:C581313', (121, 127))	('Everolimus', 'Chemical', 'MESH:D000068338', (131, 141))	('HRAS', 'Gene', (42, 46))	('phosphorylation', 'MPA', (70, 85))	('ERK', 'Protein', (89, 92))	('mutant', 'Var', (23, 29))
194926	26544513	All mutant HRAS forms including Q61L, Q61R and G12V sensitized equally towards MEK inhibitor or mTOR inhibitor treatment compared to control vector cell line kept under IL-3 (Figure 5C, 5D).	('Q61L', 'Mutation', 'rs121913233', (32, 36))	('Q61L', 'Var', (32, 36))	('sensitized', 'Reg', (52, 62))	('G12V', 'Var', (47, 51))	('Q61R', 'Var', (38, 42))	('G12V', 'Mutation', 'rs104894230', (47, 51))	('mTOR inhibitor treatment', 'MPA', (96, 120))	('Q61R', 'Mutation', 'rs121913233', (38, 42))
194927	26544513	In both HRAS mutants, Q61L and G12V, combination of MEK and mTOR inhibition caused a synergistic blockade of cell growth (Figure 5E, 5F).	('inhibition', 'NegReg', (65, 75))	('G12V', 'Mutation', 'rs104894230', (31, 35))	('cell growth', 'CPA', (109, 120))	('blockade', 'NegReg', (97, 105))	('Q61L', 'Mutation', 'rs121913233', (22, 26))	('MEK', 'Gene', (52, 55))	('HRAS', 'Gene', (8, 12))	('mTOR', 'Gene', (60, 64))	('Q61L', 'Var', (22, 26))	('G12V', 'Var', (31, 35))
194930	26544513	Treatment of animals with oral AZD6244 or Everolimus resulted in a significant reduction in tumor growth in-vivo (Figure 6A).	('AZD6244', 'Chemical', 'MESH:C517975', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('AZD6244', 'Var', (31, 38))	('Everolimus', 'Chemical', 'MESH:D000068338', (42, 52))	('reduction', 'NegReg', (79, 88))
194931	26544513	In addition, combination of AZD6244 and Everolimus even further reduced tumor growth in-vivo (Figure 6A).	('AZD6244', 'Chemical', 'MESH:C517975', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('combination', 'Interaction', (13, 24))	('Everolimus', 'Chemical', 'MESH:D000068338', (40, 50))	('reduced', 'NegReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('AZD6244', 'Var', (28, 35))
194933	26544513	Again, tumor weight was significantly reduced in AZD6244 and Everolimus treated animals (Figure 6B) and tumor weight was significantly lower in the combination treatment arm (Figure 6B).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('reduced', 'NegReg', (38, 45))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', (104, 109))	('Everolimus', 'Chemical', 'MESH:D000068338', (61, 71))	('lower', 'NegReg', (135, 140))	('AZD6244', 'Var', (49, 56))	('AZD6244', 'Chemical', 'MESH:C517975', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
194934	26544513	We conclude that single and combination treatment of AZD6244 and Everolimus block tumor growth in-vivo.	('Everolimus block tumor', 'Disease', (65, 87))	('AZD6244', 'Var', (53, 60))	('AZD6244', 'Chemical', 'MESH:C517975', (53, 60))	('Everolimus block tumor', 'Disease', 'MESH:D006327', (65, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
194935	26544513	Lung adenocarcinomas have mutually exclusive mutations in receptor tyrosine kinase (RTK) and RAS pathway oncogenes such as EGFR and KRAS.	('EGFR', 'Gene', (123, 127))	('mutations', 'Var', (45, 54))	('KRAS', 'Gene', (132, 136))	('adenocarcinomas', 'Disease', (5, 20))	('KRAS', 'Gene', '3845', (132, 136))	('RTK', 'Gene', (84, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinomas', 'Phenotype', 'HP:0030078', (0, 20))	('EGFR', 'Gene', '1956', (123, 127))	('adenocarcinomas', 'Disease', 'MESH:D000230', (5, 20))
194937	26544513	Targeting 'driver' mutations including EGFR in lung cancer and BRAF in melanoma resulted in great clinical success.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mutations', 'Var', (19, 28))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('BRAF', 'Gene', '673', (63, 67))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('BRAF', 'Gene', (63, 67))
194938	26544513	Whereas targeting mutant KRAS remained difficult, several studies demonstrated that NRAS mutations can be targeted by inhibition of MEK in tumor cell lines.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('inhibition', 'NegReg', (118, 128))	('NRAS', 'Gene', (84, 88))	('MEK', 'Protein', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('NRAS', 'Gene', '4893', (84, 88))	('mutations', 'Var', (89, 98))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
194939	26544513	Inhibition of MEK in NRAS mutant melanoma was also successful in a phase II trial and a large phase III trial is planned.	('NRAS', 'Gene', '4893', (21, 25))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('MEK', 'Gene', (14, 17))	('NRAS', 'Gene', (21, 25))	('mutant', 'Var', (26, 32))
194940	26544513	In this study we were able to show for the first time that HRAS mutant cancer cell lines can be targeted by MEK kinase inhibition (Figure 1).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('HRAS', 'Gene', (59, 63))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MEK', 'Enzyme', (108, 111))	('mutant', 'Var', (64, 70))
194942	26544513	HRAS mutation conferred MEK sensitivity in lung cancer of adenocarcinoma and squamous origin, bladder cancer, endometrium cancer and squamous esophageal cancer cell lines (Figure 1).	('cancer', 'Disease', (153, 159))	('lung cancer of adenocarcinoma', 'Phenotype', 'HP:0030078', (43, 72))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('squamous esophageal cancer', 'Disease', (133, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('lung cancer of adenocarcinoma', 'Disease', 'MESH:D008175', (43, 72))	('cancer', 'Disease', (102, 108))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('lung cancer of adenocarcinoma', 'Disease', (43, 72))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('HRAS', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (122, 128))	('squamous esophageal cancer', 'Disease', 'MESH:D004938', (133, 159))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('mutation', 'Var', (5, 13))	('conferred', 'Reg', (14, 23))
194945	26544513	Both, HRAS and NRAS mutations activate the RAS and the mTOR pathway and induce sensitivity towards MEK inhibitors.	('activate', 'PosReg', (30, 38))	('HRAS', 'Gene', (6, 10))	('sensitivity towards MEK inhibitors', 'MPA', (79, 113))	('NRAS', 'Gene', (15, 19))	('RAS', 'Pathway', (43, 46))	('induce', 'Reg', (72, 78))	('mTOR pathway', 'Pathway', (55, 67))	('NRAS', 'Gene', '4893', (15, 19))	('mutations', 'Var', (20, 29))
194946	26544513	All HRAS mutations studied here are at typical known sites for activating mutations including G12V and Q61L.	('G12V', 'Var', (94, 98))	('Q61L', 'Var', (103, 107))	('HRAS', 'Gene', (4, 8))	('G12V', 'Mutation', 'rs104894230', (94, 98))	('Q61L', 'Mutation', 'rs121913233', (103, 107))
194947	26544513	We found that HRAS mutations at position G12 or Q61 rendered transformed Ba/F3 equally sensitive to MEK inhibitors indicating that all activing mutations at position G12 and Q61 might be eligible for targeted treatment patients with HRAS mutant tumors (Figure 1, 4).	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('HRAS', 'Gene', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('mutations', 'Var', (19, 28))	('Q61', 'Var', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('patients', 'Species', '9606', (219, 227))	('Q61', 'Var', (48, 51))	('tumors', 'Disease', (245, 251))
194949	26544513	HRAS mutations are frequent with about 2.8 - 5.1% in lung and bladder cancer, however, rather infrequent in endometrium and esophageal cancer with about 1% each.	('HRAS', 'Gene', (0, 4))	('esophageal cancer', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('lung', 'Disease', (53, 57))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))
194951	26544513	This was further promoted by experiments in which MEK inhibitors do not only cause growth inhibition but also induced apoptosis in HRAS mutant cancer cells (Figure 2).	('apoptosis', 'CPA', (118, 127))	('mutant', 'Var', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('growth inhibition', 'CPA', (83, 100))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('HRAS', 'Gene', (131, 135))	('induced', 'Reg', (110, 117))	('MEK', 'Gene', (50, 53))
194954	26544513	Patients, but not parents, showed mutations of HRAS at position glycine 12 and 13.	('Patients', 'Species', '9606', (0, 8))	('HRAS', 'Gene', (47, 51))	('mutations', 'Var', (34, 43))	('glycine', 'Chemical', 'MESH:D005998', (64, 71))
194956	26544513	For NRAS mutant cancers the combination of MEK and the dual PI3K/mTOR were described to be synergistic.	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('mutant', 'Var', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('NRAS', 'Gene', (4, 8))	('NRAS', 'Gene', '4893', (4, 8))
194959	26544513	The combination of BKM120 with MEK inhibitor Trametinib failed to achieve a reasonable response in RAS- or BRAF-mutant lung cancer patients in a phase Ib trial.	('patients', 'Species', '9606', (131, 139))	('BRAF', 'Gene', (107, 111))	('BKM120', 'Chemical', 'MESH:C571178', (19, 25))	('Trametinib', 'Chemical', 'MESH:C560077', (45, 55))	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('RAS-', 'Disease', (99, 103))	('BKM120', 'Var', (19, 25))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('BRAF', 'Gene', '673', (107, 111))
194960	26544513	We speculated if mutant HRAS might signal to the mTOR complex directly without involving PI3K/AKT.	('AKT', 'Gene', '207', (94, 97))	('signal', 'Reg', (35, 41))	('HRAS', 'Gene', (24, 28))	('AKT', 'Gene', (94, 97))	('mutant', 'Var', (17, 23))
194961	26544513	This is reflected by our observations showing that the mTOR inhibitor Everolimus alone was sufficient to block cell growth in HRAS mutant cells compared to wild-type cell lines (Figure 4, 5).	('HRAS', 'Gene', (126, 130))	('cell growth', 'CPA', (111, 122))	('mutant', 'Var', (131, 137))	('block', 'NegReg', (105, 110))	('Everolimus', 'Chemical', 'MESH:D000068338', (70, 80))
194962	26544513	The effect of mTOR inhibitors was also minor compared to MEK inhibitors in NRAS mutant melanoma cells.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('mutant', 'Var', (80, 86))	('NRAS', 'Gene', (75, 79))	('NRAS', 'Gene', '4893', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
194964	26544513	One recent report demonstrated that the combination of AZD6244 and the AKT inhibitor MK2206 is tolerable in a phase I trial.	('AZD6244', 'Var', (55, 62))	('AKT', 'Gene', '207', (71, 74))	('AZD6244', 'Chemical', 'MESH:C517975', (55, 62))	('AKT', 'Gene', (71, 74))	('MK2206', 'Chemical', 'MESH:C548887', (85, 91))
194967	26544513	We have shown that mutant HRAS is a potential drug target in different types of cancer including lung cancer and bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('mutant', 'Var', (19, 25))	('bladder cancer', 'Disease', (113, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', (80, 86))	('HRAS', 'Gene', (26, 30))
194984	26544513	Knock-down efficiency was observed after 96 h. Ba/F3 cells were transduced retrovirally with empty pMSCV-Puro (kindly provided by Dr. Balabanov) or pMSCV-Puro expression wild-type HRAS, HRAS Q61L, HRAS Q61R, HRAS G12V with the help of 293T Phoenix cells (ATCC).	('Q61L', 'Mutation', 'rs121913233', (191, 195))	('293T', 'CellLine', 'CVCL:0063', (235, 239))	('HRAS Q61R', 'Var', (197, 206))	('Q61R', 'Mutation', 'rs121913233', (202, 206))	('G12V', 'Mutation', 'rs104894230', (213, 217))	('HRAS Q61L', 'Var', (186, 195))
194991	26544513	Mutations can be found in Cancer Cell Line Encyclopedia (Encyclopedia, 2015).	('Mutations', 'Var', (0, 9))	('Cancer Cell Line Encyclopedia', 'Disease', (26, 55))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (26, 55))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))
194998	26544513	Engrafted tumors reached 150 mm3 after 6 days and animals were randomized into 4 groups: DMSO only (n = 5), AZD6244 (Selumetinib) at 20mg/kg (n = 5), Everolimus at 3.5mg/kg (n = 5), and combined AZD6244 and Everolimus at 20mg/kg and 3.5mg/kg respectively (n = 5).	('AZD6244', 'Chemical', 'MESH:C517975', (195, 202))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('AZD6244', 'Chemical', 'MESH:C517975', (108, 115))	('Everolimus', 'Chemical', 'MESH:D000068338', (207, 217))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('Everolimus', 'Chemical', 'MESH:D000068338', (150, 160))	('DMSO', 'Chemical', 'MESH:D004121', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('Selumetinib', 'Chemical', 'MESH:C517975', (117, 128))	('AZD6244', 'Var', (108, 115))
195040	23658246	The fluorescence spectra for ASY*-FITC and FITC at 100 muM in PBS with 471 nm excitation revealed a peak emission at 519 nm, Fig.	('muM', 'Gene', '56925', (55, 58))	('FITC', 'Chemical', 'MESH:D016650', (43, 47))	('PBS', 'Chemical', 'MESH:D007854', (62, 65))	('muM', 'Gene', (55, 58))	('ASY*-FITC', 'Var', (29, 38))	('ASY*-FITC', 'Chemical', '-', (29, 38))	('FITC', 'Chemical', 'MESH:D016650', (34, 38))
195050	23658246	ASY*-FITC had an association rate constant (k) of 0.2 min-1, Fig.	('ASY*-FITC', 'Var', (0, 9))	('ASY*-FITC', 'Chemical', '-', (0, 9))	('association', 'Interaction', (17, 28))
195053	23658246	Flow cytometry was performed on adenocarcinoma and Q-hTERT cells incubated with ASY*-FITC, control peptides FITC-Ahx-ASYNYDA, GGGAGGGAGGGK-FITC, MNDPIPQ-GGGSK-FITC, AADYYSN-GGGSK-FITC (scrambled) or cells alone to validate peptide specificity (fig.	('MNDPIPQ-GGGSK-FITC', 'Var', (145, 163))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('-FITC', 'Chemical', 'MESH:D016650', (158, 163))	('P', 'Chemical', 'MESH:D010758', (148, 149))	('FITC', 'Chemical', 'MESH:D016650', (159, 163))	('adenocarcinoma', 'Disease', 'MESH:D000230', (32, 46))	('-FITC', 'Chemical', 'MESH:D016650', (84, 89))	('S', 'Chemical', 'MESH:D013455', (170, 171))	('S', 'Chemical', 'MESH:D013455', (156, 157))	('-FITC', 'Chemical', 'MESH:D016650', (138, 143))	('ASY', 'Chemical', '-', (80, 83))	('FITC', 'Chemical', 'MESH:D016650', (108, 112))	('S', 'Chemical', 'MESH:D013455', (176, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('FITC', 'Chemical', 'MESH:D016650', (85, 89))	('-FITC', 'Chemical', 'MESH:D016650', (178, 183))	('FITC', 'Chemical', 'MESH:D016650', (179, 183))	('Ahx', 'Chemical', 'MESH:D015119', (113, 116))	('S', 'Chemical', 'MESH:D013455', (81, 82))	('ASY', 'Chemical', '-', (117, 120))	('P', 'Chemical', 'MESH:D010758', (150, 151))	('FITC', 'Chemical', 'MESH:D016650', (139, 143))	('ASY*-FITC', 'Chemical', '-', (80, 89))	('adenocarcinoma', 'Disease', (32, 46))
195054	23658246	Compared with control peptides, ASY*-FITC showed stronger binding to the adenocarcinoma cells.	('adenocarcinoma', 'Disease', 'MESH:D000230', (73, 87))	('binding', 'Interaction', (58, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('stronger', 'PosReg', (49, 57))	('adenocarcinoma', 'Disease', (73, 87))	('ASY*-FITC', 'Var', (32, 41))	('ASY*-FITC', 'Chemical', '-', (32, 41))
195056	23658246	No difference was observed between ASY*-FITC and the control peptides on binding to Q-hTERT cells.	('ASY*-FITC', 'Var', (35, 44))	('ASY*-FITC', 'Chemical', '-', (35, 44))	('binding', 'Interaction', (73, 80))
195058	23658246	Significantly less signal was measured for control peptides FITC-Ahx-ASY*, GGG*-FITC, MND*-FITC and AAD*-FITC (fig.	('Ahx', 'Chemical', 'MESH:D015119', (65, 68))	('S', 'Chemical', 'MESH:D013455', (70, 71))	('GGG*-FITC', 'Chemical', '-', (75, 84))	('FITC', 'Chemical', 'MESH:D016650', (80, 84))	('AAD*-FITC', 'Var', (100, 109))	('*-FITC', 'Chemical', 'MESH:D016650', (78, 84))	('FITC', 'Chemical', 'MESH:D016650', (60, 64))	('FITC', 'Chemical', 'MESH:D016650', (105, 109))	('*-FITC', 'Chemical', 'MESH:D016650', (103, 109))	('FITC', 'Chemical', 'MESH:D016650', (91, 95))	('MND*-FITC', 'Var', (86, 95))	('*-FITC', 'Chemical', 'MESH:D016650', (89, 95))	('ASY', 'Chemical', '-', (69, 72))	('less', 'NegReg', (14, 18))	('S', 'Chemical', 'MESH:D013455', (0, 1))
195060	23658246	On mass spectrometry, cyclophilin A (CypA) was found to have 50% and 82.3% coverage using photoactive amino acids (L-photo-leucine and L-photo-methionine) and BS3 crosslinking agents, respectively.	('L-photo-leucine', 'Var', (115, 130))	('cyclophilin A', 'Gene', '5478', (22, 35))	('L-photo-methionine', 'Var', (135, 153))	('L-photo-leucine', 'Chemical', '-', (115, 130))	('cyclophilin A', 'Gene', (22, 35))	('L-photo-methionine', 'Chemical', '-', (135, 153))	('CypA', 'Gene', (37, 41))	('S', 'Chemical', 'MESH:D013455', (160, 161))	('CypA', 'Gene', '5478', (37, 41))
195066	23658246	Specific binding of ASY*-FITC to Barrett's neoplasia was confirmed ex vivo using resected human esophageal specimens.	('ASY*-FITC', 'Var', (20, 29))	('S', 'Chemical', 'MESH:D013455', (21, 22))	('ASY*-FITC', 'Chemical', '-', (20, 29))	("Barrett's neoplasia", 'Disease', (33, 52))	('human', 'Species', '9606', (90, 95))	('binding', 'Interaction', (9, 16))	('neoplasia', 'Phenotype', 'HP:0002664', (43, 52))	("Barrett's neoplasia", 'Disease', 'MESH:D001471', (33, 52))	('men', 'Species', '9606', (112, 115))	('S', 'Chemical', 'MESH:D013455', (0, 1))
195074	23658246	We validated specific binding of ASY*-FITC to Barrett's neoplasia on confocal endomicroscopy in vivo in a total of 25 human subjects (22 males, 3 females) (Table 1).	("Barrett's neoplasia", 'Disease', (46, 65))	('neoplasia', 'Phenotype', 'HP:0002664', (56, 65))	('ASY*-FITC', 'Var', (33, 42))	('ASY*-FITC', 'Chemical', '-', (33, 42))	("Barrett's neoplasia", 'Disease', 'MESH:D001471', (46, 65))	('human', 'Species', '9606', (118, 123))	('binding', 'Interaction', (22, 29))
195075	23658246	The surface pathology was assessed in the epithelium where the ASY*-FITC peptide was administered and imaged (depth <=50 mum), whereas the conventional pathology was evaluated from the full mucosal cross-section.	('mum', 'Gene', '56925', (121, 124))	('ASY*-FITC', 'Var', (63, 72))	('mum', 'Gene', (121, 124))	('ASY*-FITC', 'Chemical', '-', (63, 72))
195103	23658246	ASY*-FITC produced a 3.8-fold greater signal for HGD and EAC than for squamous and BE in vivo, highlighting areas for biopsy or therapy.	('ASY*-FITC', 'Var', (0, 9))	('HGD', 'Protein', (49, 52))	('greater', 'PosReg', (30, 37))	('ASY*-FITC', 'Chemical', '-', (0, 9))
195114	23658246	We further validated specific binding of ASY*-FITC to esophageal adenocarcinoma cell lines FLO1, OE19, and OE33.	('ASY*-FITC', 'Var', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (54, 79))	('ASY*-FITC', 'Chemical', '-', (41, 50))	('esophageal adenocarcinoma', 'Disease', (54, 79))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (54, 79))	('binding', 'Interaction', (30, 37))
195116	23658246	We controlled for non-specific binding on in vitro cell validation studies using 4 different peptides: 1) FITC-Ahx-ASY* was developed to block the ASY* binding moiety by moving the FITC fluorophore from the C- to the N-terminus; 2) GGGAGGGAGGGK-FITC was motivated by a previous control peptide that had functional groups removed and charge neutralized, demonstrating that net charge, hydrophobicity, and hydrophilicity of the peptide play an important role in binding; 3) MND*-FITC represents an unrelated peptide; and 4) AAD*-FITC is a scrambled version of the target peptide.	('ASY', 'Chemical', '-', (115, 118))	('AAD*-FITC', 'Var', (522, 531))	('-FITC', 'Chemical', 'MESH:D016650', (476, 481))	('*-FITC', 'Chemical', 'MESH:D016650', (525, 531))	('FITC', 'Chemical', 'MESH:D016650', (245, 249))	('Ahx', 'Chemical', 'MESH:D015119', (111, 114))	('FITC', 'Chemical', 'MESH:D016650', (106, 110))	('FITC', 'Chemical', 'MESH:D016650', (527, 531))	('ASY', 'Chemical', '-', (147, 150))	('FITC', 'Chemical', 'MESH:D016650', (181, 185))	('*-FITC', 'Chemical', 'MESH:D016650', (475, 481))	('-FITC', 'Chemical', 'MESH:D016650', (244, 249))	('-FITC', 'Chemical', 'MESH:D016650', (526, 531))	('FITC', 'Chemical', 'MESH:D016650', (477, 481))	('MND*-FITC', 'Var', (472, 481))
195245	22973319	By comparing these findings, we came to the conclusion that the log-logistic model with gamma frailty is more efficient than the Cox model and log-normal model (with and without gamma frailty).	('Cox', 'Gene', (129, 132))	('gamma frailty', 'Var', (88, 101))	('Cox', 'Gene', '1351', (129, 132))
195288	33717835	In vitro experiments demonstrate that proliferation of esophageal tumor cells is enhanced by knockdown of TAK1 expression and attenuated by elevated expression of TAK1.	('attenuated', 'NegReg', (126, 136))	('TAK1', 'Gene', (106, 110))	('knockdown', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('proliferation', 'CPA', (38, 51))	('enhanced', 'PosReg', (81, 89))	('esophageal tumor', 'Disease', 'MESH:D004938', (55, 71))	('esophageal tumor', 'Disease', (55, 71))	('esophageal tumor', 'Phenotype', 'HP:0100751', (55, 71))
195293	33717835	Taken together, the data reveal that TAK1-mediated phosphorylation of RASSF9 at Ser284 negatively regulates esophageal tumor cell proliferation via inhibition of the RAS/MEK/ERK axis.	('regulates', 'Reg', (98, 107))	('Ser284', 'Var', (80, 86))	('inhibition', 'NegReg', (148, 158))	('RASSF9', 'Gene', '9182', (70, 76))	('Ser284', 'Chemical', '-', (80, 86))	('negatively', 'NegReg', (87, 97))	('ERK', 'Gene', '5594', (174, 177))	('RASSF9', 'Gene', (70, 76))	('esophageal tumor', 'Disease', 'MESH:D004938', (108, 124))	('esophageal tumor', 'Disease', (108, 124))	('ERK', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('phosphorylation', 'Var', (51, 66))	('MEK', 'Gene', (170, 173))	('esophageal tumor', 'Phenotype', 'HP:0100751', (108, 124))	('MEK', 'Gene', '5609', (170, 173))
195295	33717835	In the presence of TAK1, it phosphorylates RASSF9 at Serine284 and this modification disrupts RAS dimerization, leading to a blockade of downstream pathway and cell proliferation.	('Serine284', 'Chemical', '-', (53, 62))	('RASSF9', 'Gene', '9182', (43, 49))	('disrupts', 'NegReg', (85, 93))	('blockade', 'NegReg', (125, 133))	('RAS', 'Protein', (94, 97))	('downstream pathway', 'Pathway', (137, 155))	('TAK1', 'Gene', (19, 23))	('modification', 'Var', (72, 84))	('cell proliferation', 'CPA', (160, 178))	('RASSF9', 'Gene', (43, 49))
195305	33717835	[  8  ] TAK1 promotes tumorigenesis in several types of tumors, including breast cancer, colon cancer, and melanoma,[  9 ,  10  ] and consistent with its role in tumorigenesis, inhibition of TAK1 induces tumor cell apoptosis and reduces its metastatic capacity.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('promotes', 'PosReg', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (162, 167))	('tumors', 'Disease', (56, 62))	('TAK1', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('inhibition', 'Var', (177, 187))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('metastatic capacity', 'CPA', (241, 260))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('induces', 'PosReg', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (56, 61))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('reduces', 'NegReg', (229, 236))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('breast cancer', 'Disease', (74, 87))	('TAK1', 'Gene', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', (22, 27))	('colon cancer', 'Disease', (89, 101))
195306	33717835	[  11 ,  12 ,  13  ] Interestingly, however, several other studies have found that TAK1 appears to function as a tumor suppressor in liver and prostate carcinogenesis[  14 ,  15 ,  16  ] and conditional TAK1 knockout in liver parenchymal cells was reported to induce liver carcinogenesis.	('tumor', 'Disease', (113, 118))	('TAK1', 'Gene', (203, 207))	('knockout', 'Var', (208, 216))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (267, 287))	('liver and prostate carcinogenesis', 'Disease', 'MESH:D011471', (133, 166))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('liver carcinogenesis', 'Disease', (267, 287))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('induce', 'PosReg', (260, 266))
195313	33717835	[  24  ] Several studies have shown that C-RASSFs are suppressed in human cancers and inhibition of individual C-RASSFs promotes tumor progression.	('human', 'Species', '9606', (68, 73))	('RASSF', 'Gene', (113, 118))	('promotes', 'PosReg', (120, 128))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('inhibition', 'Var', (86, 96))	('RASSF', 'Gene', '11186;9770;283349;83593;83937;83593;283349;166824;8045;11228;9182;237504;644943', (113, 118))	('RASSF', 'Gene', '11186;9770;283349;83593;83937;83593;283349;166824;8045;11228;9182;237504;644943', (43, 48))	('tumor', 'Disease', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RASSF', 'Gene', (43, 48))
195317	33717835	Our results further revealed that TAK1-induced phosphorylation of RASSF9 impairs RAS dimerization and leads to a shutdown of downstream signal transduction involving the RAF/MEK/ERK axis.	('RAS', 'Protein', (81, 84))	('MEK', 'Gene', (174, 177))	('shutdown', 'MPA', (113, 121))	('MEK', 'Gene', '5609', (174, 177))	('RASSF9', 'Gene', (66, 72))	('RAF', 'Gene', '22882', (170, 173))	('ERK', 'Gene', '5594', (178, 181))	('RAF', 'Gene', (170, 173))	('phosphorylation', 'Var', (47, 62))	('impairs', 'NegReg', (73, 80))	('dimerization', 'MPA', (85, 97))	('RASSF9', 'Gene', '9182', (66, 72))	('ERK', 'Gene', (178, 181))	('downstream signal transduction', 'MPA', (125, 155))
195328	33717835	Cell proliferation was also enhanced by the gRNA against Map3k7 (Figure 2G,H and Figure S4A,B, Supporting Information).	('gRNA', 'Var', (44, 48))	('Map3k7', 'Gene', '6885', (57, 63))	('Map3k7', 'Gene', (57, 63))	('enhanced', 'PosReg', (28, 36))	('Cell proliferation', 'CPA', (0, 18))
195329	33717835	Consistent with the observations of gRNA-mediated downregulation of TAK1, siRNA-induced TAK1 knockdown also potentiated cell viability, colony formation, and EdU incorporation (Figure 2K-M and Figure S4C,D, Supporting Information).	('knockdown', 'Var', (93, 102))	('potentiated', 'PosReg', (108, 119))	('downregulation', 'NegReg', (50, 64))	('EdU incorporation', 'CPA', (158, 175))	('colony formation', 'CPA', (136, 152))	('EdU', 'Chemical', '-', (158, 161))	('TAK1', 'Gene', (88, 92))	('cell viability', 'CPA', (120, 134))
195330	33717835	Similarly, TAK1 knockdown induced upregulation of cell viability, colony formation and, EdU incorporation in TE-1 and KYSE-150 cells (Figures S5A-E and S6A-E, Supporting Information).	('TAK1', 'Gene', (11, 15))	('knockdown', 'Var', (16, 25))	('EdU', 'Chemical', '-', (88, 91))	('cell viability', 'CPA', (50, 64))	('colony formation', 'CPA', (66, 82))	('EdU incorporation', 'CPA', (88, 105))	('upregulation', 'PosReg', (34, 46))
195335	33717835	Our results showed that elevated expression of TAK1 induced by LV-TAK1 inhibited cell growth, as evidenced by a reduction in tumor volume and weight (Figure  3A).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('inhibited', 'NegReg', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cell growth', 'CPA', (81, 92))	('reduction', 'NegReg', (112, 121))	('tumor', 'Disease', (125, 130))	('expression', 'MPA', (33, 43))	('elevated', 'PosReg', (24, 32))	('LV-TAK1', 'Var', (63, 70))	('TAK1', 'Gene', (47, 51))
195337	33717835	TAK1 expression in LV-TAK1 transduced tumors was confirmed using qRT-PCR (Figure 3D).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('transduced', 'Var', (27, 37))	('tumors', 'Disease', 'MESH:D009369', (38, 44))
195338	33717835	In contrast, TAK1 knockdown by LV-Map3k7 shRNA promoted tumor cell growth (Figure 3E).	('knockdown', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('Map3k7', 'Gene', (34, 40))	('promoted', 'PosReg', (47, 55))	('tumor', 'Disease', (56, 61))	('Map3k7', 'Gene', '6885', (34, 40))	('TAK1', 'Gene', (13, 17))
195340	33717835	Cell proliferation in these tumors was enhanced following TAK1 knockdown (Figure 3G and Figure S8B, Supporting Information).	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('TAK1', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('knockdown', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Cell proliferation', 'CPA', (0, 18))	('enhanced', 'PosReg', (39, 47))
195342	33717835	Our data showed that tumor volume and weight were enhanced by TAK1 knockdown (Figure S9A-E, Supporting Information).	('tumor', 'Disease', (21, 26))	('knockdown', 'Var', (67, 76))	('TAK1', 'Gene', (62, 66))	('enhanced', 'PosReg', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
195346	33717835	[  24 ,  25 ,  27  ] Based on the mass spectra data (Figure S10A,B, Supporting Information), serine residue at 284 (S284) in RASSF9 was found to be phosphorylated.	('S10A', 'SUBSTITUTION', 'None', (60, 64))	('RASSF9', 'Gene', (125, 131))	('phosphorylated', 'MPA', (148, 162))	('S284', 'Var', (116, 120))	('S10A', 'Var', (60, 64))	('serine', 'Chemical', 'MESH:D012694', (93, 99))	('RASSF9', 'Gene', '9182', (125, 131))	('S284', 'Chemical', '-', (116, 120))
195353	33717835	As shown in Figure 4B, TAK1 induced an increase in p-RASSF9 in the cells transfected with wildtype RASSF9; however, TAK1 had no effect on p-RASSF9 in the cells transfected with RASSF9 S284A.	('RASSF9', 'Gene', (140, 146))	('RASSF9', 'Gene', '9182', (177, 183))	('S284A', 'Mutation', 'p.S284A', (184, 189))	('RASSF9', 'Gene', '9182', (53, 59))	('RASSF9', 'Gene', '9182', (99, 105))	('RASSF9', 'Gene', '9182', (140, 146))	('increase', 'PosReg', (39, 47))	('RASSF9', 'Gene', (177, 183))	('S284A', 'Var', (184, 189))	('RASSF9', 'Gene', (53, 59))	('RASSF9', 'Gene', (99, 105))
195354	33717835	We also used (5Z)-7-oxozeaenol (Oxo), a TAK1 inhibitor, to further confirm that TAK1 phosphorylates S284 in RASSF9.	('S284', 'Chemical', '-', (100, 104))	('Oxo', 'Chemical', 'MESH:C403563', (32, 35))	('RASSF9', 'Gene', (108, 114))	('S284', 'Var', (100, 104))	('(5Z)-7-oxozeaenol', 'Chemical', 'MESH:C403563', (13, 30))	('RASSF9', 'Gene', '9182', (108, 114))
195358	33717835	In addition, TAK1-mediated phosphorylation of RASSF9 at S284 could not be recapitulated by a dominant negative form of TAK1 (Figure 4F), in which lysine 63 was mutated into tryptophan (K63W).	('RASSF9', 'Gene', '9182', (46, 52))	('lysine 63 was mutated into tryptophan', 'Mutation', 'p.K63W', (146, 183))	('S284', 'Chemical', '-', (56, 60))	('K63W', 'Chemical', '-', (185, 189))	('RASSF9', 'Gene', (46, 52))	('lysine 63', 'Var', (146, 155))
195359	33717835	Furthermore, in vitro kinase assay also revealed that the S284 in RASSF9 was phosphorylated by TAK1 (Figure 4G).	('S284', 'Chemical', '-', (58, 62))	('S284', 'Var', (58, 62))	('RASSF9', 'Gene', (66, 72))	('RASSF9', 'Gene', '9182', (66, 72))
195362	33717835	Taken together, we conclude that TAK1 phosphorylates RASSF9 at S284 and thus RASSF9 is a downstream target of TAK1.	('S284', 'Chemical', '-', (63, 67))	('RASSF9', 'Gene', '9182', (53, 59))	('RASSF9', 'Gene', '9182', (77, 83))	('S284', 'Var', (63, 67))	('RASSF9', 'Gene', (53, 59))	('RASSF9', 'Gene', (77, 83))
195366	33717835	Our results showed that while RASSF9 overexpression stimulated cell viability, colony formation, and EdU incorporation (Figure  5A-D and Figure S11A,B, Supporting Information), the knockdown of RASSF9 delayed cell growth and proliferation (Figure 5E-I and Figure S11C,D, Supporting Information).	('RASSF9', 'Gene', (30, 36))	('S11C', 'SUBSTITUTION', 'None', (263, 267))	('RASSF9', 'Gene', '9182', (194, 200))	('S11A', 'Var', (144, 148))	('EdU', 'Chemical', '-', (101, 104))	('S11A', 'SUBSTITUTION', 'None', (144, 148))	('RASSF9', 'Gene', '9182', (30, 36))	('delayed cell growth', 'Phenotype', 'HP:0001510', (201, 220))	('stimulated', 'PosReg', (52, 62))	('cell viability', 'CPA', (63, 77))	('S11C', 'Var', (263, 267))	('proliferation', 'CPA', (225, 238))	('cell growth', 'CPA', (209, 220))	('delayed', 'NegReg', (201, 208))	('EdU incorporation', 'CPA', (101, 118))	('knockdown', 'Var', (181, 190))	('RASSF9', 'Gene', (194, 200))	('colony formation', 'CPA', (79, 95))
195367	33717835	Human TCGA database revealed that high expression of RASSF9 was correlated with poorer prognosis in ESCC patients; and conversely, low expression of RASSF9 was associated with longer survival (Figure 5J).	('Human', 'Species', '9606', (0, 5))	('RASSF9', 'Gene', '9182', (149, 155))	('patients', 'Species', '9606', (105, 113))	('RASSF9', 'Gene', '9182', (53, 59))	('RASSF9', 'Gene', (149, 155))	('longer', 'PosReg', (176, 182))	('ESCC', 'Disease', (100, 104))	('high', 'Var', (34, 38))	('expression', 'MPA', (39, 49))	('RASSF9', 'Gene', (53, 59))	('low', 'NegReg', (131, 134))
195369	33717835	We thus employed a cell-based FRET system using CFP (donor) and YFP (acceptor) fusions of KRAS to evaluate the effect of RASSF9 on KRAS dimerization.	('KRAS', 'Gene', (131, 135))	('KRAS', 'Gene', (90, 94))	('RASSF9', 'Gene', (121, 127))	('KRAS', 'Gene', '3845', (90, 94))	('CFP', 'Gene', '5199', (48, 51))	('KRAS', 'Gene', '3845', (131, 135))	('RASSF9', 'Gene', '9182', (121, 127))	('CFP', 'Gene', (48, 51))	('fusions', 'Var', (79, 86))
195370	33717835	[  19  ] We found that the CFP signal increased significantly after YFP bleaching and this increase was further strengthened in the presence of wildtype RASSF9 or the mutant of RASSF9 (Figure  6A).	('RASSF9', 'Gene', '9182', (153, 159))	('RASSF9', 'Gene', '9182', (177, 183))	('CFP', 'Gene', '5199', (27, 30))	('CFP', 'Gene', (27, 30))	('RASSF9', 'Gene', (153, 159))	('mutant', 'Var', (167, 173))	('presence', 'Reg', (132, 140))	('RASSF9', 'Gene', (177, 183))	('strengthened', 'PosReg', (112, 124))	('increased', 'PosReg', (38, 47))
195371	33717835	TAK1 markedly abolished CFP signal enhancement in the presence of wildtype RASSF9 but had no effect in the presence of the mutant of RASSF9 (Figure 6A).	('RASSF9', 'Gene', (75, 81))	('abolished', 'NegReg', (14, 23))	('RASSF9', 'Gene', (133, 139))	('CFP', 'Gene', '5199', (24, 27))	('RASSF9', 'Gene', '9182', (75, 81))	('RASSF9', 'Gene', '9182', (133, 139))	('mutant', 'Var', (123, 129))	('CFP', 'Gene', (24, 27))
195375	33717835	While the mutant of RASSF9 (S284A) similarly stimulated the RAF/MEK/ERK axis, its effect was not altered by TAK1 (Figure 6B,C).	('RASSF9', 'Gene', (20, 26))	('MEK', 'Gene', (64, 67))	('MEK', 'Gene', '5609', (64, 67))	('ERK', 'Gene', '5594', (68, 71))	('RASSF9', 'Gene', '9182', (20, 26))	('S284A', 'Var', (28, 33))	('RAF', 'Gene', (60, 63))	('ERK', 'Gene', (68, 71))	('RAF', 'Gene', '22882', (60, 63))	('stimulated', 'PosReg', (45, 55))	('S284A', 'Mutation', 'p.S284A', (28, 33))
195376	33717835	Accordingly, the increases in cell viability and proliferation induced by RASSF9 were reduced by forced expression of TAK1; however, these increases induced by RASSF9 S284A were not altered by TAK1 (Figure 6D,E and Figure S12, Supporting Information).	('reduced', 'NegReg', (86, 93))	('RASSF9', 'Gene', '9182', (160, 166))	('increases', 'PosReg', (17, 26))	('S284A', 'Var', (167, 172))	('proliferation', 'CPA', (49, 62))	('RASSF9', 'Gene', '9182', (74, 80))	('S284A', 'Mutation', 'p.S284A', (167, 172))	('TAK1', 'Gene', (118, 122))	('RASSF9', 'Gene', (160, 166))	('cell viability', 'CPA', (30, 44))	('RASSF9', 'Gene', (74, 80))
195384	33717835	Similarly, p-MEK was increased by U0126.	('MEK', 'Gene', '5609', (13, 16))	('U0126', 'Chemical', 'MESH:C113580', (34, 39))	('increased', 'PosReg', (21, 30))	('U0126', 'Var', (34, 39))	('MEK', 'Gene', (13, 16))
195385	33717835	RASSF9 induced an increase in p-MEK and this induction was further enhanced by U0126 (Figure 7D).	('increase', 'PosReg', (18, 26))	('U0126', 'Chemical', 'MESH:C113580', (79, 84))	('MEK', 'Gene', '5609', (32, 35))	('RASSF9', 'Gene', (0, 6))	('U0126', 'Var', (79, 84))	('MEK', 'Gene', (32, 35))	('RASSF9', 'Gene', '9182', (0, 6))
195390	33717835	As expected, increased expression of TAK1 induced by LV-TAK1 stimulated p-RASSF9, whereas p-MEK and p-ERK were reduced (Figure 7G).	('MEK', 'Gene', (92, 95))	('MEK', 'Gene', '5609', (92, 95))	('LV-TAK1', 'Var', (53, 60))	('RASSF9', 'Gene', '9182', (74, 80))	('ERK', 'Gene', '5594', (102, 105))	('stimulated', 'PosReg', (61, 71))	('ERK', 'Gene', (102, 105))	('TAK1', 'Gene', (37, 41))	('increased', 'PosReg', (13, 22))	('RASSF9', 'Gene', (74, 80))	('expression', 'MPA', (23, 33))
195391	33717835	On the contrary, TAK1 knockdown induced a decrease in p-RASSF9; meanwhile, p-MEK and p-ERK were increased (Figure 7H).	('TAK1', 'Gene', (17, 21))	('ERK', 'Gene', (87, 90))	('increased', 'PosReg', (96, 105))	('RASSF9', 'Gene', (56, 62))	('knockdown', 'Var', (22, 31))	('decrease', 'NegReg', (42, 50))	('MEK', 'Gene', '5609', (77, 80))	('MEK', 'Gene', (77, 80))	('RASSF9', 'Gene', '9182', (56, 62))	('ERK', 'Gene', '5594', (87, 90))
195397	33717835	Using Kaplan-Meier survival analysis, we found a significant difference (p = 0.002, log-rank test) in 5-year cancer-specific survival between patients with low and high expression of TAK1 (Figure 8D).	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('TAK1', 'Gene', (183, 187))	('cancer', 'Disease', (109, 115))	('high expression', 'Var', (164, 179))	('patients', 'Species', '9606', (142, 150))
195398	33717835	We found that probability of recurrence was lower in patients with high expression of TAK1 compared to those with low expression of TAK1 (Figure 8E).	('lower', 'NegReg', (44, 49))	('TAK1', 'Gene', (86, 90))	('high expression', 'Var', (67, 82))	('patients', 'Species', '9606', (53, 61))
195401	33717835	Accumulating evidence supports an association between dysregulated expression of TAK1 and many human diseases including cancer.	('TAK1', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('human', 'Species', '9606', (95, 100))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('dysregulated', 'Var', (54, 66))	('expression', 'MPA', (67, 77))
195409	33717835	On the contrary, the another study showed that elevated expression of TAK1 correlates with reduced disease free survival in patients diagnosed with primary melanoma or colon cancer, indicating that high expression of TAK1 presents a risk factor for disease progression.	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('high', 'Var', (198, 202))	('melanoma or colon cancer', 'Disease', 'MESH:D015179', (156, 180))	('melanoma or colon cancer', 'Disease', (156, 180))	('elevated', 'PosReg', (47, 55))	('TAK1', 'Gene', (70, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (168, 180))	('expression', 'MPA', (56, 66))	('reduced', 'NegReg', (91, 98))	('disease free survival', 'CPA', (99, 120))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('patients', 'Species', '9606', (124, 132))
195412	33717835	[  14  ] In colon cancers, TAK1 is required for tumor cell viability, and inhibition of TAK1 activity promoted tumor cell apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('inhibition', 'Var', (74, 84))	('tumor', 'Disease', (48, 53))	('activity', 'MPA', (93, 101))	('promoted', 'PosReg', (102, 110))	('colon cancers', 'Disease', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('colon cancers', 'Phenotype', 'HP:0003003', (12, 25))	('colon cancers', 'Disease', 'MESH:D015179', (12, 25))	('colon cancer', 'Phenotype', 'HP:0003003', (12, 24))	('TAK1', 'Gene', (88, 92))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
195413	33717835	[  11  ] Inhibition of TAK1 with Oxo, expression of inactive TAK1, or deletion of Map3k7 were individually sufficient to sensitize melanoma cells to cell death induced by TNFalpha or TRAIL-based combination treatment.	('deletion', 'Var', (70, 78))	('TNFalpha', 'Gene', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('TNFalpha', 'Gene', '7124', (171, 179))	('death', 'Disease', 'MESH:D003643', (154, 159))	('death', 'Disease', (154, 159))	('Map3k7', 'Gene', (82, 88))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('Inhibition', 'NegReg', (9, 19))	('Map3k7', 'Gene', '6885', (82, 88))	('TRAIL', 'Gene', '8743', (183, 188))	('Oxo', 'Chemical', 'MESH:C403563', (33, 36))	('TRAIL', 'Gene', (183, 188))	('sensitize', 'Reg', (121, 130))	('TAK1', 'Gene', (61, 65))
195414	33717835	[  9  ] However, we unexpectedly found that blockade of TAK1 using siRNA- or CRISPR/Cas9-mediated gene silencing largely promoted esophageal squamous tumor cell proliferation, whereas elevated expression of TAK1 retarded cell growth.	('blockade', 'Var', (44, 52))	('squamous tumor', 'Phenotype', 'HP:0002860', (141, 155))	('esophageal squamous tumor', 'Disease', (130, 155))	('TAK1', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('esophageal squamous tumor', 'Disease', 'MESH:D000077277', (130, 155))	('promoted', 'PosReg', (121, 129))	('silencing', 'NegReg', (103, 112))
195425	33717835	Consistent with our results, RASSF7 was found to localize to the centrosome and knockdown of RASSF7 led to a failure in the formation of mitotic spindle and caused mitotic arrest of cells.	('knockdown', 'Var', (80, 89))	('caused', 'Reg', (157, 163))	('mitotic arrest', 'Disease', (164, 178))	('mitotic arrest', 'Disease', 'MESH:D006323', (164, 178))	('RASSF7', 'Gene', '8045', (29, 35))	('failure', 'NegReg', (109, 116))	('RASSF7', 'Gene', (29, 35))	('RASSF7', 'Gene', (93, 99))	('RASSF7', 'Gene', '8045', (93, 99))	('formation of mitotic spindle', 'CPA', (124, 152))
195430	33717835	[  19 ,  38  ] The presence of the RA domain in RASSF9 makes the protein a potentially ideal candidate for inducing RAS dimerization and thus activating the RAF/MEK/ERK axis.	('RAF', 'Gene', (157, 160))	('MEK', 'Gene', (161, 164))	('inducing', 'PosReg', (107, 115))	('RASSF9', 'Gene', (48, 54))	('MEK', 'Gene', '5609', (161, 164))	('RAS', 'Protein', (116, 119))	('dimerization', 'MPA', (120, 132))	('activating', 'Reg', (142, 152))	('RASSF9', 'Gene', '9182', (48, 54))	('ERK', 'Gene', '5594', (165, 168))	('ERK', 'Gene', (165, 168))	('RA domain', 'Var', (35, 44))	('RAF', 'Gene', '22882', (157, 160))
195431	33717835	Consistent with this notion, in this study we showed that elevated expression of RASSF9 induces RAS dimerization, results in a series of trans-phosphorylation of RAF, MEK, and ERK, and eventually increases the expression levels of c-Myc and Fos.	('MEK', 'Gene', (167, 170))	('induces', 'Reg', (88, 95))	('RASSF9', 'Gene', (81, 87))	('increases', 'PosReg', (196, 205))	('RAF', 'Gene', (162, 165))	('c-Myc', 'Gene', (231, 236))	('ERK', 'Gene', '5594', (176, 179))	('results in', 'Reg', (114, 124))	('c-Myc', 'Gene', '4609', (231, 236))	('Fos', 'Gene', (241, 244))	('expression', 'Var', (67, 77))	('RAS', 'Protein', (96, 99))	('dimerization', 'MPA', (100, 112))	('elevated', 'PosReg', (58, 66))	('ERK', 'Gene', (176, 179))	('MEK', 'Gene', '5609', (167, 170))	('expression levels', 'MPA', (210, 227))	('RASSF9', 'Gene', '9182', (81, 87))	('RAF', 'Gene', '22882', (162, 165))	('trans-phosphorylation', 'MPA', (137, 158))	('Fos', 'Gene', '2353', (241, 244))
195433	33717835	We speculate that the inhibitory effect of TAK1 may be due to a conformational change induced by TAK1-mediated phosphorylation of S284 in RASSF9.	('conformational change', 'MPA', (64, 85))	('inhibitory effect', 'MPA', (22, 39))	('RASSF9', 'Gene', (138, 144))	('S284', 'Var', (130, 134))	('S284', 'Chemical', '-', (130, 134))	('phosphorylation', 'MPA', (111, 126))	('RASSF9', 'Gene', '9182', (138, 144))
195436	33717835	We further identified RASSF9 as a downstream target of TAK1 which phosphorylates RASSF9 at S284.	('RASSF9', 'Gene', (81, 87))	('RASSF9', 'Gene', '9182', (22, 28))	('RASSF9', 'Gene', '9182', (81, 87))	('S284', 'Var', (91, 95))	('RASSF9', 'Gene', (22, 28))	('S284', 'Chemical', '-', (91, 95))
195437	33717835	Following phosphorylation of RASSF9 by TAK1, RAS dimerization is disrupted, leading to a blockade of RAF/MEK/ERK signal transduction and retardation of tumor cell growth.	('TAK1', 'Gene', (39, 43))	('blockade', 'NegReg', (89, 97))	('RASSF9', 'Gene', '9182', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('retardation of tumor', 'Disease', 'MESH:D009369', (137, 157))	('retardation of tumor', 'Disease', (137, 157))	('ERK', 'Gene', '5594', (109, 112))	('RAF', 'Gene', '22882', (101, 104))	('ERK', 'Gene', (109, 112))	('RAF', 'Gene', (101, 104))	('RASSF9', 'Gene', (29, 35))	('MEK', 'Gene', (105, 108))	('MEK', 'Gene', '5609', (105, 108))	('phosphorylation', 'Var', (10, 25))
195438	33717835	Taken together, we have revealed a novel role of TAK1 in esophageal squamous tumor cell proliferation and determined that TAK1 mediates this through phosphorylating S284 in RASSF9 to weaken the RAS/RAF/MEK/ERK axis-related signal transduction in cell growth.	('ERK', 'Gene', (206, 209))	('weaken', 'NegReg', (183, 189))	('RASSF9', 'Gene', '9182', (173, 179))	('MEK', 'Gene', (202, 205))	('squamous tumor', 'Phenotype', 'HP:0002860', (68, 82))	('esophageal squamous tumor', 'Disease', (57, 82))	('cell growth', 'CPA', (246, 257))	('MEK', 'Gene', '5609', (202, 205))	('esophageal squamous tumor', 'Disease', 'MESH:D000077277', (57, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('RASSF9', 'Gene', (173, 179))	('phosphorylating', 'Var', (149, 164))	('S284', 'Var', (165, 169))	('RAF', 'Gene', '22882', (198, 201))	('RAF', 'Gene', (198, 201))	('ERK', 'Gene', '5594', (206, 209))	('S284', 'Chemical', '-', (165, 169))
195450	33717835	For the subcutaneous injection model, 2 x 106 ECA-109 cells (TAK1 knockdown or overexpression, and negative control) diluted in 100 microL PBS were implanted into the axilla of BALB/c nude mice (n = 6 to 10 per group).	('PBS', 'Chemical', '-', (139, 142))	('knockdown', 'Var', (66, 75))	('nude mice', 'Species', '10090', (184, 193))	('overexpression', 'PosReg', (79, 93))
195481	32655130	Mechanistically, RNA sequencing coupled with bioinformatics analysis and a series of functional assays revealed that echinatin induced apoptosis and autophagy through inactivation of AKT/mTOR signaling pathway, whereas constitutive activation of AKT significantly abrogated these effects.	('apoptosis', 'CPA', (135, 144))	('AKT', 'Gene', '207', (246, 249))	('mTOR', 'Gene', '2475', (187, 191))	('echinatin', 'Var', (117, 126))	('AKT', 'Gene', (183, 186))	('mTOR', 'Gene', (187, 191))	('AKT', 'Gene', (246, 249))	('autophagy', 'CPA', (149, 158))	('echinatin', 'Chemical', 'MESH:C000623341', (117, 126))	('inactivation', 'NegReg', (167, 179))	('AKT', 'Gene', '207', (183, 186))
195507	32655130	To determine the effect of echinatin on apoptosis in ESCC cells, the cells were treated with echinatin at the indicated concentrations (up to 40 muM) for 24 and 48 h, and the results showed that echinatin-induced apoptosis in a dose-dependent way (Figs.	('echinatin-induced', 'Var', (195, 212))	('muM', 'Gene', '56925', (145, 148))	('echinatin', 'Chemical', 'MESH:C000623341', (195, 204))	('muM', 'Gene', (145, 148))	('apoptosis', 'CPA', (213, 222))	('echinatin', 'Chemical', 'MESH:C000623341', (27, 36))	('echinatin', 'Chemical', 'MESH:C000623341', (93, 102))
195508	32655130	1d and S1A), indicating that echinatin elicited apoptosis in ESCC cells.	('apoptosis', 'CPA', (48, 57))	('echinatin', 'Chemical', 'MESH:C000623341', (29, 38))	('echinatin', 'Var', (29, 38))	('elicited', 'Reg', (39, 47))
195522	32655130	In order to investigate whether echinatin induces autophagy and apoptosis via AKT/mTOR pathway, a vector expressing AKT (T308D/S473D), the constitutively active form of AKT, was transfected into KYSE30 and KYSE270 cells and the anticancer effects of echinatin were determined (Fig.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('T308D', 'SUBSTITUTION', 'None', (121, 126))	('echinatin', 'Chemical', 'MESH:C000623341', (250, 259))	('S473D', 'Mutation', 'p.S473D', (127, 132))	('cancer', 'Disease', (232, 238))	('echinatin', 'Chemical', 'MESH:C000623341', (32, 41))	('AKT', 'Gene', (169, 172))	('KYSE270', 'CellLine', 'CVCL:1350', (206, 213))	('AKT', 'Gene', '207', (78, 81))	('AKT', 'Gene', '207', (116, 119))	('mTOR', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('mTOR', 'Gene', '2475', (82, 86))	('AKT', 'Gene', (78, 81))	('T308D', 'Var', (121, 126))	('AKT', 'Gene', (116, 119))	('AKT', 'Gene', '207', (169, 172))
195523	32655130	The results showed that the ectopic expression of AKT (T308D/S473D) significantly increased the viability of echinatin-treated KYSE30 and KYSE270 cells (Fig.	('S473D', 'Mutation', 'p.S473D', (61, 66))	('AKT', 'Gene', '207', (50, 53))	('echinatin', 'Chemical', 'MESH:C000623341', (109, 118))	('viability', 'CPA', (96, 105))	('KYSE270', 'CellLine', 'CVCL:1350', (138, 145))	('AKT', 'Gene', (50, 53))	('increased', 'PosReg', (82, 91))	('T308D', 'SUBSTITUTION', 'None', (55, 60))	('T308D', 'Var', (55, 60))
195524	32655130	In addition, the echinatin-induced apoptosis was abrogated by AKT (T308D/S473D) overexpression (Fig.	('overexpression', 'PosReg', (80, 94))	('AKT', 'Gene', (62, 65))	('abrogated', 'NegReg', (49, 58))	('T308D', 'Var', (67, 72))	('T308D', 'SUBSTITUTION', 'None', (67, 72))	('echinatin', 'Chemical', 'MESH:C000623341', (17, 26))	('AKT', 'Gene', '207', (62, 65))	('S473D', 'Mutation', 'p.S473D', (73, 78))	('apoptosis', 'CPA', (35, 44))
195525	32655130	3e), and the western blot assay further confirmed that echinatin-induced cleavage of caspase-3 and PARP were significantly decreased in AKT (T308D/S473D)-overexpressing ESCC cells (Fig.	('PARP', 'Gene', (99, 103))	('decreased', 'NegReg', (123, 132))	('S473D', 'Mutation', 'p.S473D', (147, 152))	('PARP', 'Gene', '142', (99, 103))	('AKT', 'Gene', '207', (136, 139))	('caspase-3', 'Gene', (85, 94))	('cleavage', 'MPA', (73, 81))	('T308D', 'SUBSTITUTION', 'None', (141, 146))	('echinatin', 'Chemical', 'MESH:C000623341', (55, 64))	('T308D', 'Var', (141, 146))	('caspase-3', 'Gene', '836', (85, 94))	('AKT', 'Gene', (136, 139))
195526	32655130	Moreover, increased LC3 protein expression upon echinatin treatment was also reversed by AKT (T308D/S473D) overexpression (Fig.	('T308D', 'SUBSTITUTION', 'None', (94, 99))	('LC3', 'Gene', '84557', (20, 23))	('increased LC3', 'Phenotype', 'HP:0003141', (10, 23))	('LC3', 'Gene', (20, 23))	('AKT', 'Gene', '207', (89, 92))	('S473D', 'Mutation', 'p.S473D', (100, 105))	('echinatin', 'Chemical', 'MESH:C000623341', (48, 57))	('overexpression', 'PosReg', (107, 121))	('AKT', 'Gene', (89, 92))	('increased', 'PosReg', (10, 19))	('T308D', 'Var', (94, 99))
195532	32655130	Collectively, these data demonstrated that echinatin can increase the sensitivity of ESCC cells to 5-FU by inducing apoptosis.	('5-FU', 'Chemical', 'MESH:D005472', (99, 103))	('apoptosis', 'CPA', (116, 125))	('echinatin', 'Chemical', 'MESH:C000623341', (43, 52))	('inducing', 'Reg', (107, 115))	('sensitivity', 'MPA', (70, 81))	('increase', 'PosReg', (57, 65))	('echinatin', 'Var', (43, 52))
195536	32655130	In order to investigate whether echinatin inhibits migration and invasion via AKT pathway, the plasmid expression constitutively active form of AKT, AKT (T308D/S473D), was transfected into KYSE30 and KYSE270 cells, the results showed that activation of AKT signaling significantly abrogated the inhibitory effects of echinatin on ESCC cell migration and invasion (Fig.	('AKT', 'Gene', (144, 147))	('echinatin', 'Chemical', 'MESH:C000623341', (32, 41))	('AKT', 'Gene', (149, 152))	('T308D', 'SUBSTITUTION', 'None', (154, 159))	('AKT', 'Gene', '207', (253, 256))	('T308D', 'Var', (154, 159))	('AKT', 'Gene', '207', (78, 81))	('AKT', 'Gene', '207', (149, 152))	('AKT', 'Gene', '207', (144, 147))	('abrogated', 'NegReg', (281, 290))	('invasion', 'CPA', (354, 362))	('ESCC', 'Disease', (330, 334))	('echinatin', 'Chemical', 'MESH:C000623341', (317, 326))	('AKT', 'Gene', (253, 256))	('AKT', 'Gene', (78, 81))	('KYSE270', 'CellLine', 'CVCL:1350', (200, 207))	('S473D', 'Mutation', 'p.S473D', (160, 165))
195544	32655130	The dysregulation of autophagy is closely related to a number of diseases, including cancer, cardiovascular disease, and autoimmunity.	('autophagy', 'CPA', (21, 30))	('cardiovascular disease', 'Disease', 'MESH:D002318', (93, 115))	('cardiovascular disease', 'Disease', (93, 115))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (93, 115))	('cancer', 'Disease', (85, 91))	('related', 'Reg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('autoimmunity', 'Phenotype', 'HP:0002960', (121, 133))
195551	32655130	The rescue experiment by using the AKT (T308D/S473D) plasmid expressing constitutively activation of AKT and the subsequent functional assays indicated that reactivation of AKT/mTOR signaling significantly abrogated the effects of echinatin on apoptosis, proliferation, autophagy, migration, and invasion abilities of cancer cells (Figs.	('cancer', 'Disease', (318, 324))	('proliferation', 'CPA', (255, 268))	('apoptosis', 'CPA', (244, 253))	('AKT', 'Gene', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('reactivation', 'Var', (157, 169))	('autophagy', 'CPA', (270, 279))	('abrogated', 'NegReg', (206, 215))	('mTOR', 'Gene', (177, 181))	('AKT', 'Gene', (101, 104))	('echinatin', 'Chemical', 'MESH:C000623341', (231, 240))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('AKT', 'Gene', '207', (173, 176))	('AKT', 'Gene', (35, 38))	('T308D', 'Var', (40, 45))	('T308D', 'SUBSTITUTION', 'None', (40, 45))	('mTOR', 'Gene', '2475', (177, 181))	('migration', 'CPA', (281, 290))	('AKT', 'Gene', '207', (101, 104))	('S473D', 'Mutation', 'p.S473D', (46, 51))	('AKT', 'Gene', '207', (35, 38))
195569	32655130	Mechanistically, echinatin induces cell autophagy and apoptosis via the AKT/mTOR signaling pathway (Fig.	('apoptosis', 'CPA', (54, 63))	('AKT', 'Gene', '207', (72, 75))	('echinatin', 'Var', (17, 26))	('induces', 'PosReg', (27, 34))	('mTOR', 'Gene', (76, 80))	('mTOR', 'Gene', '2475', (76, 80))	('cell autophagy', 'CPA', (35, 49))	('AKT', 'Gene', (72, 75))	('echinatin', 'Chemical', 'MESH:C000623341', (17, 26))
195574	32655130	The plasmid expressing constitutively active form of AKT, the AKT (T308D/S473D), was a gift from Dr. Robert Weinberg.	('AKT', 'Gene', (62, 65))	('T308D', 'Var', (67, 72))	('T308D', 'SUBSTITUTION', 'None', (67, 72))	('AKT', 'Gene', '207', (53, 56))	('AKT', 'Gene', '207', (62, 65))	('S473D', 'Mutation', 'p.S473D', (73, 78))	('AKT', 'Gene', (53, 56))
195575	32655130	ESCC cells were transfected with AKT (T308D/S473D) or vector control using Lipofectamine 3000 reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions.	('S473D', 'Mutation', 'p.S473D', (44, 49))	('AKT', 'Gene', '207', (33, 36))	('T308D', 'Var', (38, 43))	('T308D', 'SUBSTITUTION', 'None', (38, 43))	('Lipofectamine 3000', 'Chemical', '-', (75, 93))	('AKT', 'Gene', (33, 36))
195616	32182937	To date, most changes involving TRP channels in cancer do not involve mutations in the TRP genes but rather increased or decreased levels of expression of functional TRP proteins, depending on the cancer's stage.	('TRP', 'Gene', (87, 90))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (197, 203))	('decreased', 'NegReg', (121, 130))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('TRP proteins', 'Protein', (166, 178))	('levels of expression of functional', 'MPA', (131, 165))
195644	32182937	The link between the pathophysiology of esophageal cancer and TRP channel expression has been exclusively made for ESCC and includes dysregulation of TRPC6, TRPM7, TRPM8, TRPV1, TRPV2, and TRPV4 expression levels.	('ESCC', 'Disease', (115, 119))	('ESCC', 'Disease', 'MESH:D000077277', (115, 119))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('dysregulation', 'Var', (133, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('TRPV1', 'Gene', (171, 176))	('TRPM8', 'Gene', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('TRPV2', 'Gene', (178, 183))	('TRPM8', 'Gene', '79054', (164, 169))	('TRPC6', 'Gene', (150, 155))	('TRPM7', 'Gene', (157, 162))	('TRPV4', 'Gene', (189, 194))	('TRPV2', 'Gene', '51393', (178, 183))	('esophageal cancer', 'Disease', (40, 57))	('TRP channel', 'Gene', (62, 73))
195653	32182937	Additionally, siRNA-based silencing of TRPM7 in TE6 ESCC cells increased their proliferation, migration, and invasion.	('proliferation', 'CPA', (79, 92))	('invasion', 'CPA', (109, 117))	('increased', 'PosReg', (63, 72))	('TE6 ESCC', 'CellLine', 'CVCL:D568;0.01762100678807292', (48, 56))	('migration', 'CPA', (94, 103))	('TRPM7', 'Gene', (39, 44))	('silencing', 'Var', (26, 35))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))
195656	32182937	The knockdown of TRPV2 in ESCC cells decreased proliferation, cell cycle progression, and the ability to invade and migrate.	('cell cycle progression', 'CPA', (62, 84))	('TRPV2', 'Gene', '51393', (17, 22))	('knockdown', 'Var', (4, 13))	('ESCC', 'Disease', (26, 30))	('ESCC', 'Disease', 'MESH:D000077277', (26, 30))	('SCC', 'Phenotype', 'HP:0002860', (27, 30))	('ability', 'CPA', (94, 101))	('proliferation', 'CPA', (47, 60))	('TRPV2', 'Gene', (17, 22))	('decreased', 'NegReg', (37, 46))
195674	32182937	Another study showed that shRNA-based TRPV2 knockdown in HepG2 cells enhanced spheroid and colony formation, which was restored by the overexpression of TRPV2.	('TRPV2', 'Gene', '51393', (38, 43))	('TRPV2', 'Gene', (153, 158))	('enhanced', 'PosReg', (69, 77))	('TRPV2', 'Gene', '51393', (153, 158))	('knockdown', 'Var', (44, 53))	('TRPV2', 'Gene', (38, 43))
195675	32182937	Additionally, the expression of TRPV2 protein was linked to the stemness of liver cancer cells, as the knockdown of TRPV2 in HepG2 cells induced the expression of liver cancer stem-like cells (LCSLCs) markers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('induced', 'PosReg', (137, 144))	('stemness of liver cancer', 'Disease', 'MESH:D006528', (64, 88))	('TRPV2', 'Gene', (32, 37))	('liver cancer', 'Phenotype', 'HP:0002896', (163, 175))	('liver cancer', 'Disease', 'MESH:D006528', (163, 175))	('linked', 'Reg', (50, 56))	('TRPV2', 'Gene', (116, 121))	('liver cancer', 'Disease', (163, 175))	('TRPV2', 'Gene', '51393', (32, 37))	('expression', 'MPA', (149, 159))	('liver cancer', 'Disease', 'MESH:D006528', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('liver cancer', 'Phenotype', 'HP:0002896', (76, 88))	('stemness of liver cancer', 'Disease', (64, 88))	('TRPV2', 'Gene', '51393', (116, 121))	('knockdown', 'Var', (103, 112))
195684	32182937	Furthermore, in a xenograft mouse model system, the blockage of TRPV4 was shown to decrease tumor size and weight compared to the control group.	('blockage', 'Var', (52, 60))	('mouse', 'Species', '10090', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('decrease', 'NegReg', (83, 91))	('tumor', 'Disease', (92, 97))	('TRPV4', 'Gene', (64, 69))
195688	32182937	Moreover, high TRPC6 expression has been suggested to be associated with a higher Tumor Node Metastasis (TNM) classification of tumors.	('TRPC6', 'Protein', (15, 20))	('TNM', 'Disease', (105, 108))	('expression', 'MPA', (21, 31))	('TNM', 'Disease', 'MESH:D009362', (105, 108))	('Tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('high', 'Var', (10, 14))	('Tumor Node Metastasis', 'Disease', 'MESH:D009362', (82, 103))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('Tumor Node Metastasis', 'Disease', (82, 103))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
195694	32182937	The inhibition or downregulation of TRPC6 significantly decreased drug resistance to all three stimuli, and TRPC6 inhibition could reverse endothelial-mesenchymal transition (EMT), induced by doxorubicin treatment.	('drug resistance to all three stimuli', 'MPA', (66, 102))	('inhibition', 'NegReg', (114, 124))	('TRPC6', 'Gene', (108, 113))	('drug resistance', 'Phenotype', 'HP:0020174', (66, 81))	('reverse', 'NegReg', (131, 138))	('decreased', 'NegReg', (56, 65))	('doxorubicin', 'Chemical', 'MESH:D004317', (192, 203))	('inhibition', 'Var', (4, 14))	('TRPC6', 'Gene', (36, 41))	('downregulation', 'NegReg', (18, 32))
195695	32182937	In line with these findings, TRPC6 interference in vivo enhanced the sensitivity to doxorubicin and led to slower growth of the cells compared to the control cells.	('sensitivity to doxorubicin', 'MPA', (69, 95))	('doxorubicin', 'Chemical', 'MESH:D004317', (84, 95))	('TRPC6', 'Gene', (29, 34))	('growth', 'CPA', (114, 120))	('enhanced', 'PosReg', (56, 64))	('slower', 'NegReg', (107, 113))	('interference', 'Var', (35, 47))
195704	32182937	TRPM2 expression was also shown to enhance proliferation, migration, and invasion of PANC-1 cells, a human pancreatic cancer cell line.	('TRPM2', 'Gene', '7226', (0, 5))	('TRPM2', 'Gene', (0, 5))	('pancreatic cancer', 'Disease', (107, 124))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('enhance', 'PosReg', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('human', 'Species', '9606', (101, 106))	('proliferation', 'CPA', (43, 56))	('invasion', 'CPA', (73, 81))	('expression', 'Var', (6, 16))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))	('migration', 'CPA', (58, 67))
195708	32182937	In addition, high TRPM8 protein expression was found to be associated with lower overall survival and poor disease free survival values for pancreatic cancer patients, as well as positively correlated with the tumor size and stage of pancreatic cancer.	('patients', 'Species', '9606', (158, 166))	('TRPM8', 'Gene', '79054', (18, 23))	('TRPM8', 'Gene', (18, 23))	('lower', 'NegReg', (75, 80))	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('pancreatic cancer', 'Disease', 'MESH:D010190', (234, 251))	('protein', 'Protein', (24, 31))	('high', 'Var', (13, 17))	('disease free survival', 'CPA', (107, 128))	('tumor', 'Disease', (210, 215))	('expression', 'MPA', (32, 42))	('pancreatic cancer', 'Disease', (234, 251))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('pancreatic cancer', 'Disease', (140, 157))	('correlated', 'Reg', (190, 200))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('poor', 'NegReg', (102, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (234, 251))	('overall survival', 'CPA', (81, 97))
195711	32182937	Additionally, TRPM8 knockdown with siRNA resulted in a decrease in cell migration.	('decrease', 'NegReg', (55, 63))	('cell migration', 'CPA', (67, 81))	('knockdown', 'Var', (20, 29))	('TRPM8', 'Gene', (14, 19))	('TRPM8', 'Gene', '79054', (14, 19))
195714	32182937	Additionally, targeting TRPM8 in PANC-1 and BxPC-3 with siRNA resulted in an enhancement of gemcitabine cytotoxicity, which was accompanied by a change in the expression of apoptosis- and gemcitabine metabolism-related proteins.	('cytotoxicity', 'Disease', 'MESH:D064420', (104, 116))	('enhancement', 'PosReg', (77, 88))	('targeting', 'Var', (14, 23))	('apoptosis-', 'MPA', (173, 183))	('expression', 'MPA', (159, 169))	('change', 'Reg', (145, 151))	('cytotoxicity', 'Disease', (104, 116))	('TRPM8', 'Gene', '79054', (24, 29))	('TRPM8', 'Gene', (24, 29))	('gemcitabine', 'Chemical', 'MESH:C056507', (92, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (188, 199))
195718	32182937	Targeting TRPM7 with siRNA in PANC-1 and BxPC-3 resulted in a cell cycle arrest in the G0/G1 phase, accompanied by a change in the expression of p21, cyclin G1, and cyclin B1.	('cyclin B1', 'Gene', '891', (165, 174))	('cyclin B1', 'Gene', (165, 174))	('cyclin G1', 'Gene', '900', (150, 159))	('p21', 'Gene', (145, 148))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))	('change', 'Reg', (117, 123))	('p21', 'Gene', '644914', (145, 148))	('expression', 'MPA', (131, 141))	('cell cycle arrest in the G0/G1 phase', 'CPA', (62, 98))	('Targeting', 'Var', (0, 9))	('cyclin G1', 'Gene', (150, 159))	('TRPM7', 'Gene', (10, 15))
195719	32182937	The role of TRPM7 in the regulation of pancreatic cancer cells proliferation was also connected to Mg2+, as supplementation of the culture medium with Mg2+ reversed the decrease in proliferation caused by the knockdown of TRPM7.	('Mg2', 'Gene', (99, 102))	('Mg2', 'Gene', (151, 154))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('Mg2', 'Gene', '57192', (99, 102))	('knockdown', 'Var', (209, 218))	('TRPM7', 'Gene', (222, 227))	('Mg2', 'Gene', '57192', (151, 154))	('pancreatic cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))
195720	32182937	Targeting TRPM7 enhances cytotoxicity of the conventionally used chemotherapeutic, gemcitabine, which is a pro-apoptotic agent, suggesting that targeting TRPM7 in pancreatic cancer could support standard chemotherapy.	('cytotoxicity', 'Disease', 'MESH:D064420', (25, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (163, 180))	('enhances', 'PosReg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (163, 180))	('cytotoxicity', 'Disease', (25, 37))	('pancreatic cancer', 'Disease', (163, 180))	('Targeting', 'Var', (0, 9))	('TRPM7', 'Gene', (10, 15))
195724	32182937	Furthermore, high TRPM7 staining in pancreatic ductal adenocarcinoma has been associated with higher TRPM7 protein staining in the lymph nodes, suggesting that TRPM7 might be involved in invasion of pancreatic cancer cells.	('pancreatic cancer', 'Disease', (199, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('pancreatic ductal adenocarcinoma', 'Disease', (36, 68))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (36, 68))	('involved', 'Reg', (175, 183))	('high', 'Var', (13, 17))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (36, 68))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('protein', 'Protein', (107, 114))	('TRPM7 protein', 'Protein', (101, 114))	('staining', 'MPA', (24, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('TRPM7', 'Protein', (18, 23))	('higher', 'PosReg', (94, 100))
195725	32182937	Another study showed that in PANC-1 and MIA PaCa-2 cell lines, the TRPM7-mediated cation current regulates Mg2+ homeostasis and cell invasion, as TRPM7 knockdown was shown to reduce invasion along with a decrease in MMP2, uPA, and Hsp90alpha secretion.	('Mg2', 'Gene', '57192', (107, 110))	('decrease', 'NegReg', (204, 212))	('knockdown', 'Var', (152, 161))	('TRPM7', 'Gene', (146, 151))	('MMP2', 'MPA', (216, 220))	('TRPM7-mediated', 'Gene', (67, 81))	('reduce', 'NegReg', (175, 181))	('uPA', 'Gene', '5328', (222, 225))	('uPA', 'Gene', (222, 225))	('cell invasion', 'CPA', (128, 141))	('Mg2', 'Gene', (107, 110))	('Hsp90alpha', 'Gene', (231, 241))	('Hsp90alpha', 'Gene', '3320', (231, 241))	('invasion', 'CPA', (182, 190))	('regulates', 'Reg', (97, 106))
195741	32182937	TRPC6-mediated Ca2+ influx in gastric cancer cell lines is responsible for regulation of the cell cycle, as the inhibition of TRPC6 resulted in cell cycle arrest in the G2/M phase and inhibited cell growth.	('inhibition', 'Var', (112, 122))	('cell cycle arrest in the G2/M phase', 'CPA', (144, 179))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cell growth', 'CPA', (194, 205))	('gastric cancer', 'Disease', 'MESH:D013274', (30, 44))	('gastric cancer', 'Disease', (30, 44))	('Ca2+', 'Chemical', 'MESH:D000069285', (15, 19))	('TRPC6', 'Gene', (126, 131))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (30, 44))	('inhibited', 'NegReg', (184, 193))
195749	32182937	Functional TRPM2 is expressed in gastric cancer cell lines AGS and MKN-45, and its shRNA based knockdown results in the inhibition of proliferation and enhancement of apoptosis.	('gastric cancer', 'Disease', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (33, 47))	('enhancement', 'PosReg', (152, 163))	('TRPM2', 'Gene', (11, 16))	('apoptosis', 'CPA', (167, 176))	('TRPM2', 'Gene', '7226', (11, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('knockdown', 'Var', (95, 104))	('inhibition', 'NegReg', (120, 130))	('proliferation', 'CPA', (134, 147))
195750	32182937	Additionally, TRPM2 knockdown was shown to alter autophagy in AGS cells, which led to mitochondrial dysfunction.	('led to', 'Reg', (79, 85))	('alter', 'Reg', (43, 48))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (86, 111))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (86, 111))	('TRPM2', 'Gene', (14, 19))	('autophagy', 'CPA', (49, 58))	('TRPM2', 'Gene', '7226', (14, 19))	('mitochondrial dysfunction', 'Disease', (86, 111))	('knockdown', 'Var', (20, 29))
195751	32182937	The knockdown of TRPM2 also sensitized AGS and MKN-45 cells to treatment with paclitaxel and doxorubicin, resulting in a further reduction in cell viability.	('sensitized', 'Reg', (28, 38))	('reduction', 'NegReg', (129, 138))	('TRPM2', 'Gene', (17, 22))	('TRPM2', 'Gene', '7226', (17, 22))	('cell viability', 'CPA', (142, 156))	('paclitaxel', 'Chemical', 'MESH:D017239', (78, 88))	('knockdown', 'Var', (4, 13))	('doxorubicin', 'Chemical', 'MESH:D004317', (93, 104))
195770	32182937	The lack of TRPV1 was also accompanied by an increased proliferation of colon cells and higher beta-catenin localization to the nuclei.	('higher', 'PosReg', (88, 94))	('increased', 'PosReg', (45, 54))	('localization to the', 'MPA', (108, 127))	('TRPV1', 'Gene', (12, 17))	('beta-catenin', 'Gene', (95, 107))	('lack', 'Var', (4, 8))	('beta-catenin', 'Gene', '1499', (95, 107))
195775	32182937	In a murine model of multiple intestinal neoplasia (ApcMin/+ mice), TRPV1 deficiency promoted intestinal adenoma formation correlated with a reduced lifespan, which was consistent with previous findings.	('deficiency', 'Var', (74, 84))	('lifespan', 'CPA', (149, 157))	('mice', 'Species', '10090', (61, 65))	('multiple intestinal neoplasia', 'Disease', (21, 50))	('reduced', 'NegReg', (141, 148))	('neoplasia', 'Phenotype', 'HP:0002664', (41, 50))	('murine', 'Species', '10090', (5, 11))	('promoted', 'PosReg', (85, 93))	('TRPV1', 'Gene', (68, 73))	('multiple intestinal neoplasia', 'Disease', 'MESH:D009369', (21, 50))	('multiple intestinal neoplasia', 'Phenotype', 'HP:0200008', (21, 50))	('intestinal adenoma', 'Disease', (94, 112))	('intestinal adenoma', 'Disease', 'MESH:D000236', (94, 112))
195776	32182937	In this model, mice that lack TRPV1 showed higher EGFR phosphorylation and proliferation markers in intestinal epithelial cells, and the deletion of TRPV1 increased the expression of the EGFR-regulated oncogenes, c-Fos and c-Myc.	('c-Fos', 'Gene', '14281', (213, 218))	('c-Myc', 'Protein', (223, 228))	('EGFR phosphorylation', 'MPA', (50, 70))	('TRPV1', 'Gene', (149, 154))	('higher', 'PosReg', (43, 49))	('increased', 'PosReg', (155, 164))	('deletion', 'Var', (137, 145))	('TRPV1', 'Gene', (30, 35))	('c-Fos', 'Gene', (213, 218))	('proliferation markers', 'CPA', (75, 96))	('expression', 'MPA', (169, 179))	('mice', 'Species', '10090', (15, 19))
195803	32182937	Mg2+ was shown to contribute to the regulation of cell proliferation and cell cycle, and Mg2+ deficiency has been shown to induce cell cycle arrest in the G0/G1 phase.	('induce', 'Reg', (123, 129))	('Mg2', 'Gene', (0, 3))	('Mg2', 'Gene', '57192', (89, 92))	('cell cycle arrest in the G0/G1 phase', 'CPA', (130, 166))	('Mg2', 'Gene', '57192', (0, 3))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (130, 147))	('cell cycle', 'CPA', (73, 83))	('deficiency', 'Var', (94, 104))	('Mg2', 'Gene', (89, 92))	('cell proliferation', 'CPA', (50, 68))
195807	32182937	Moreover, a single-nucleotide polymorphism that substitutes TRPM7 threonine 1482 for isoleucine (T1482I) increases the risk of the development of colon cancer, particularly in patients with a high Ca2+/Mg2+ ratio.	('patients', 'Species', '9606', (176, 184))	('Mg2', 'Gene', (202, 205))	('colon cancer', 'Disease', (146, 158))	('T1482I', 'Var', (97, 103))	('single-nucleotide polymorphism', 'Var', (12, 42))	('threonine 1482 for isoleucine', 'Mutation', 'rs8042919', (66, 95))	('TRPM7', 'Gene', (60, 65))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))	('Mg2', 'Gene', '57192', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Ca2+', 'Chemical', 'MESH:D000069285', (197, 201))	('T1482I', 'SUBSTITUTION', 'None', (97, 103))	('increases', 'PosReg', (105, 114))	('colon cancer', 'Disease', 'MESH:D015179', (146, 158))
195808	32182937	It must be noted that this mutation does not influence kinase activity, nor the channel's conductivity, but the channel's sensitivity to Mg2+.	('mutation', 'Var', (27, 35))	('Mg2', 'Gene', '57192', (137, 140))	('Mg2', 'Gene', (137, 140))
195897	30771119	Based on the International Classification of Diseases for Oncology, Third Edition, esophageal and gastric cancers were classified into ESCC (C15, histology codes: 8050-8076), EAC (C15, histology codes: 8140, 8141, 8190-8231, 8260-8263, 8310, 8430, 8480-8490, 8560 and 8570-8572), GCA (C16.0), and GNCA (C16.1-C16.9).	('esophageal and gastric cancer', 'Disease', 'MESH:D013274', (83, 112))	('C16.1-C16.9', 'CellLine', 'CVCL:2322', (303, 314))	('EAC', 'Phenotype', 'HP:0011459', (175, 178))	('8570-8572', 'Var', (268, 277))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('8480-8490', 'Var', (248, 257))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gastric cancers', 'Disease', (98, 113))	('8430', 'Var', (242, 246))	('gastric cancers', 'Disease', 'MESH:D013274', (98, 113))	('gastric cancers', 'Phenotype', 'HP:0012126', (98, 113))	('8310', 'Var', (236, 240))	('EAC', 'Disease', (175, 178))	('8141', 'Var', (208, 212))	('8190-8231', 'Var', (214, 223))	('ESCC', 'Disease', (135, 139))	('GCA', 'Disease', (280, 283))	('8260-8263', 'Var', (225, 234))	('GNCA', 'Disease', (297, 301))	('Oncology', 'Phenotype', 'HP:0002664', (58, 66))	('GC', 'Phenotype', 'HP:0012126', (280, 282))
195936	30771119	Similar model performances were observed when aMED variants with and without alcohol were compared for EAC, GCA, and GNCA risks.	('EAC', 'Disease', (103, 106))	('alcohol', 'Chemical', 'MESH:D000438', (77, 84))	('GCA', 'Disease', (108, 111))	('GNCA', 'Disease', (117, 121))	('variants', 'Var', (51, 59))	('GC', 'Phenotype', 'HP:0012126', (108, 110))	('EAC', 'Phenotype', 'HP:0011459', (103, 106))
195943	30771119	In the US National Institutes of Health-American Association of Retired Persons Diet and Health study, high MD adherence (aMED) was associated with a significantly reduced risk of ESCC, but not EAC, GCA, and GNCA.	('GC', 'Phenotype', 'HP:0012126', (199, 201))	('Persons', 'Species', '9606', (72, 79))	('high', 'Var', (103, 107))	('ESCC', 'Disease', (180, 184))	('EAC', 'Phenotype', 'HP:0011459', (194, 197))	('reduced', 'NegReg', (164, 171))
195960	30771119	While MD adherence was significantly inversely associated with ESCC risk in men, no association was observed with EAC risk.	('associated', 'Interaction', (47, 57))	('inversely', 'NegReg', (37, 46))	('men', 'Species', '9606', (76, 79))	('ESCC', 'Disease', (63, 67))	('adherence', 'Var', (9, 18))	('EAC', 'Phenotype', 'HP:0011459', (114, 117))
195964	30771119	Moreover, polyphenols (e.g., flavonoids) may reduce inflammation and MD adherence has been inversely associated with inflammatory biomarker concentrations.	('inflammation', 'Disease', (52, 64))	('polyphenols', 'Chemical', 'MESH:D059808', (10, 21))	('reduce', 'NegReg', (45, 51))	('polyphenols', 'Var', (10, 21))	('flavonoids', 'Chemical', 'MESH:D005419', (29, 39))	('MD adherence', 'CPA', (69, 81))	('inflammation', 'Disease', 'MESH:D007249', (52, 64))
195980	30771119	However, the validity of tMED and its variants has mainly been established by showing inverse associations with various adverse health outcomes including all-cause mortality and risks of and mortality from cardiovascular diseases and cancer (e.g.,).	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('variants', 'Var', (38, 46))	('cardiovascular diseases', 'Disease', (206, 229))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (206, 229))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (206, 229))	('inverse', 'NegReg', (86, 93))	('tMED', 'Chemical', '-', (25, 29))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('tMED', 'Gene', (25, 29))	('cancer', 'Disease', (234, 240))
195982	30771119	A review published in 2018 showed that 3 out of 4 studies investigating the association of tMED (variants) with postmenopausal estrogen receptor-negative breast cancer risk observed a significant inverse relation.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('association', 'Interaction', (76, 87))	('variants', 'Var', (97, 105))	('tMED', 'Chemical', '-', (91, 95))	('men', 'Species', '9606', (116, 119))
195988	30771119	So far, results for esophageal cancer generally were consistent with high MD adherence being associated with a reduced risk of ESCC, but not EAC.	('esophageal cancer', 'Disease', (20, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ESCC', 'Disease', (127, 131))	('reduced', 'NegReg', (111, 118))	('high', 'Var', (69, 73))	('EAC', 'Phenotype', 'HP:0011459', (141, 144))
195997	28939763	In vitro experiments showed that linc00460 depletion suppressed ESCC cell growth through regulating cell proliferation and cell cycle; in additional, linc00460 depletion accelerated ESCC cell apoptosis.	('cell cycle', 'CPA', (123, 133))	('depletion', 'Var', (160, 169))	('linc00460', 'Gene', '728192', (33, 42))	('accelerated', 'PosReg', (170, 181))	('men', 'Species', '9606', (15, 18))	('linc00460', 'Gene', (33, 42))	('linc00460', 'Gene', '728192', (150, 159))	('cell proliferation', 'CPA', (100, 118))	('ESCC cell growth', 'CPA', (64, 80))	('linc00460', 'Gene', (150, 159))	('ESCC cell apoptosis', 'CPA', (182, 201))	('suppressed', 'NegReg', (53, 63))
196009	28939763	Some of the first identified lncRNAs such as HOX transcript antisense intergenic RNA (HOTAIR), MALAT1, and H19 are highly expressed in multiple tumor tissues and play regulatory roles in chromatin remodeling through histone modification, DNA methylation, or function as competing endogenous RNAs through interacting with microRNAs.	('MALAT1', 'Gene', (95, 101))	('multiple tumor', 'Disease', (135, 149))	('HOTAIR', 'Gene', '100124700', (86, 92))	('methylation', 'Var', (242, 253))	('HOX transcript antisense intergenic RNA', 'Gene', (45, 84))	('H19', 'Gene', (107, 110))	('interacting', 'Interaction', (304, 315))	('multiple tumor', 'Disease', 'MESH:D009369', (135, 149))	('H19', 'Gene', '283120', (107, 110))	('HOX transcript antisense intergenic RNA', 'Gene', '100124700', (45, 84))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('MALAT1', 'Gene', '378938', (95, 101))	('histone', 'Reg', (216, 223))	('DNA', 'MPA', (238, 241))	('play', 'Reg', (162, 166))	('HOTAIR', 'Gene', (86, 92))
196061	28939763	The worse differentiation status of ESCC was correlated with high linc00460 expression (Figure 2E).	('linc00460', 'Gene', (66, 75))	('high', 'Var', (61, 65))	('expression', 'MPA', (76, 86))	('linc00460', 'Gene', '728192', (66, 75))	('ESCC', 'Disease', (36, 40))
196064	28939763	Statistical analysis suggested that linc00460 high-expression group presented more lymph node metastasis and later TNM stage than linc00460 low-expression group.	('more', 'PosReg', (78, 82))	('high-expression', 'Var', (46, 61))	('linc00460', 'Gene', '728192', (36, 45))	('linc00460', 'Gene', '728192', (130, 139))	('TNM', 'Gene', '10178', (115, 118))	('linc00460', 'Gene', (130, 139))	('linc00460', 'Gene', (36, 45))	('lymph node metastasis', 'CPA', (83, 104))	('TNM', 'Gene', (115, 118))
196070	28939763	To our knowledge, EC109 and KYSE450 were established from ESCC surgical specimen with well-differentiated histology, whereas KYSE150 was established from poor differentiated ESCC carcinoma.	('EC109', 'CellLine', 'CVCL:6898', (18, 23))	('ESCC carcinoma', 'Disease', 'MESH:D004938', (174, 188))	('KYSE450', 'Var', (28, 35))	('EC109', 'Var', (18, 23))	('men', 'Species', '9606', (77, 80))	('ESCC', 'Disease', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('ESCC carcinoma', 'Disease', (174, 188))
196071	28939763	So, the particularly high expression of linc00460 in KYSE150 was in accordance with the expression pattern in ESCC tissues.	('expression', 'MPA', (26, 36))	('linc00460', 'Gene', '728192', (40, 49))	('KYSE150', 'Var', (53, 60))	('linc00460', 'Gene', (40, 49))	('high', 'PosReg', (21, 25))
196073	28939763	To investigate the biological functions of linc00460 on ESCC in vitro, three different siRNAs were used to knockdown linc00460 expression in KYSE150 and KYSE450 that had higher level of linc00460.	('knockdown', 'Var', (107, 116))	('linc00460', 'Gene', (117, 126))	('linc00460', 'Gene', '728192', (186, 195))	('linc00460', 'Gene', (186, 195))	('linc00460', 'Gene', '728192', (43, 52))	('linc00460', 'Gene', (43, 52))	('linc00460', 'Gene', '728192', (117, 126))
196077	28939763	EDU proliferation assay showed that the incorporation rate of KYSE150 and KYSE450 decreased after transfected with linc00460 siRNA (Figure 3E and F), demonstrating that depletion of linc00460 damaged ESCC cell proliferation.	('linc00460', 'Gene', '728192', (115, 124))	('depletion', 'Var', (169, 178))	('linc00460', 'Gene', (115, 124))	('ESCC cell proliferation', 'CPA', (200, 223))	('KYSE450', 'Enzyme', (74, 81))	('incorporation rate', 'MPA', (40, 58))	('linc00460', 'Gene', '728192', (182, 191))	('decreased', 'NegReg', (82, 91))	('linc00460', 'Gene', (182, 191))
196079	28939763	The results showed that in KYSE150, linc00460 depletion resulted in the increase in G0/G1-phase distribution and decrease in G2/M-phase distribution (Figure 4A); however, in KYSE450, linc00460 depletion only resulted in decrease of S-phase distribution (Figure 4A).	('depletion', 'Var', (46, 55))	('decrease', 'NegReg', (113, 121))	('S-phase distribution', 'MPA', (232, 252))	('increase', 'PosReg', (72, 80))	('G0/G1-phase distribution', 'MPA', (84, 108))	('linc00460', 'Gene', '728192', (183, 192))	('G2/M-phase distribution', 'MPA', (125, 148))	('linc00460', 'Gene', '728192', (36, 45))	('linc00460', 'Gene', (183, 192))	('linc00460', 'Gene', (36, 45))
196080	28939763	Moreover, cell apoptosis rates in KYSE150 and KYSE450 were increased after linc00460 siRNA transfection (Figure 4B).	('linc00460', 'Gene', '728192', (75, 84))	('cell apoptosis rates', 'CPA', (10, 30))	('linc00460', 'Gene', (75, 84))	('KYSE450', 'Var', (46, 53))	('increased', 'PosReg', (59, 68))
196089	28939763	The results showed that both individual CBP and P300 proteins could bind to linc00460 promoter (Figure 5D); meanwhile, we also detected high acetyl-Histone H3 (Lys18 and Lys27) enrichment signal in linc00460 promoter (Figure 5E).	('linc00460', 'Gene', '728192', (76, 85))	('Lys27', 'Var', (170, 175))	('linc00460', 'Gene', '728192', (198, 207))	('CBP', 'Gene', '1387', (40, 43))	('men', 'Species', '9606', (183, 186))	('linc00460', 'Gene', (76, 85))	('P300', 'Gene', '2033', (48, 52))	('Lys18', 'Var', (160, 165))	('linc00460', 'Gene', (198, 207))	('bind', 'Interaction', (68, 72))	('CBP', 'Gene', (40, 43))	('Lys27', 'Chemical', '-', (170, 175))	('Lys18', 'Chemical', 'MESH:C066704', (160, 165))	('acetyl-Histone', 'MPA', (141, 155))	('acetyl-Histone', 'Chemical', '-', (141, 155))	('P300', 'Gene', (48, 52))
196111	28939763	Thus, we may draw a picture that the above biological pathways alteration result in abnormal gene expression such as linc00460 through CBP/P300 function, and finally causes tumor formation and development.	('result', 'Reg', (74, 80))	('linc00460', 'Gene', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('CBP/P300', 'Gene', (135, 143))	('CBP/P300', 'Gene', '1387;2033', (135, 143))	('men', 'Species', '9606', (200, 203))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('alteration', 'Var', (63, 73))	('causes', 'Reg', (166, 172))	('linc00460', 'Gene', '728192', (117, 126))
196139	28212575	Others have associated a single nucleotide polymorphism in the MUC1 gene to a reduced risk of other upper gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (100, 130))	('upper gastrointestinal cancers', 'Disease', (100, 130))	('single nucleotide polymorphism', 'Var', (25, 55))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('reduced', 'NegReg', (78, 85))	('MUC1', 'Gene', (63, 67))	('MUC1', 'Gene', '4582', (63, 67))
196243	28212575	Positive MUC1 cases were defined as those staining 2+/3+ intensity in >=10% of the pathology examined, following the established classification adopted for HER2.	('HER2', 'Gene', (156, 160))	('HER2', 'Gene', '2064', (156, 160))	('MUC1', 'Gene', '4582', (9, 13))	('MUC1', 'Gene', (9, 13))	('staining', 'Var', (42, 50))
196267	28212575	Before spectra could be used to calculate conjugation efficiency, Molar extinction coefficient (M-1 cm-1) and the peak absorption were calculated for the free dyes in PBS and used as follows PS1 (A280=8896, A687=20594) and Cy5,5 (A280=22479, A674=215826), a generic IgG molar extinction coefficient was used for HuHMFG1 (A280=210000).	('PBS', 'Gene', '1131', (167, 170))	('PS1', 'Gene', '338399', (191, 194))	('A674=215826', 'Var', (242, 253))	('PS1', 'Gene', (191, 194))	('A280=22479', 'Var', (230, 240))	('conjugation', 'MPA', (42, 53))	('PBS', 'Gene', (167, 170))	('A687=20594', 'Var', (207, 217))	('Cy5', 'Chemical', 'MESH:C085321', (223, 226))
196279	28212575	GEO accession numbers: GSE26886, GSE1420, GSE13083, GSE19529.	('GSE1420', 'Chemical', '-', (33, 40))	('GSE19529', 'Var', (52, 60))	('GSE13083', 'Var', (42, 50))	('GSE1420', 'Var', (33, 40))	('GSE26886', 'Var', (23, 31))
196300	25422807	The three analytical steps were as follows: Grouping according to MLNR: The patients were classified into three revised nodal categories: (MLNR0 = 0), (MLNR1 >= 0 to <= 0.1), and (MLNR2 >= 0.1).	('patients', 'Species', '9606', (76, 84))	('MLNR2 >=', 'Var', (180, 188))	('MLNR0 =', 'Var', (139, 146))	('MLNR1 >= 0', 'Var', (152, 162))	('nodal', 'Gene', '4838', (120, 125))	('nodal', 'Gene', (120, 125))
196337	25422807	The OS of patients with SCC of the esophagus can be discriminated based on 3 groups: MLNR0, MLNR1 and MLNR2 and our study clearly has emphatically shown that it can be used as a reliable independent prognostic indicator.	('MLNR2', 'Var', (102, 107))	('MLNR1', 'Var', (92, 97))	('SCC', 'Gene', (24, 27))	('SCC', 'Phenotype', 'HP:0002860', (24, 27))	('SCC', 'Gene', '6317', (24, 27))	('MLNR0', 'Var', (85, 90))	('patients', 'Species', '9606', (10, 18))
196341	23475592	Modeling Gene-Environment Interactions in Oral Cavity and Esophageal Cancers Demonstrates a Role for the p53 R72P Polymorphism in Modulating Susceptibility A large number of epidemiological studies have linked a common single nucleotide polymorphism (SNP) in the human p53 gene to risk for developing a variety of cancers.	('R72P', 'Var', (109, 113))	('R72P', 'Mutation', 'rs1042522', (109, 113))	('p53', 'Gene', (269, 272))	('p53', 'Gene', '22059', (269, 272))	('cancers', 'Disease', 'MESH:D009369', (314, 321))	('cancers', 'Disease', (314, 321))	('single nucleotide polymorphism', 'Var', (219, 249))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '22059', (105, 108))	('Esophageal Cancers', 'Disease', 'MESH:D004938', (58, 76))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancers', 'Phenotype', 'HP:0002664', (69, 76))	('human', 'Species', '9606', (263, 268))	('Esophageal Cancers', 'Disease', (58, 76))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))
196343	23475592	This SNP has also been reported to modulate the development of human papilloma virus (HPV)-driven cancers through differential targeting of the p53 variant proteins by the E6 viral oncoprotein.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('variant', 'Var', (148, 155))	('HPV', 'Species', '10566', (86, 89))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('proteins', 'Protein', (156, 164))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('human papilloma virus', 'Species', '10566', (63, 84))	('cancers', 'Disease', (98, 105))	('papilloma', 'Phenotype', 'HP:0012740', (69, 78))	('human papilloma virus', 'Disease', (63, 84))	('p53', 'Gene', (144, 147))	('modulate', 'Reg', (35, 43))
196344	23475592	Mouse models for the p53 R72P polymorphism have recently been developed but a role for this SNP in modifying cancer risk in response to viral and chemical carcinogens has yet to be established experimentally.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('R72P', 'Var', (25, 29))	('cancer', 'Disease', (109, 115))	('R72P', 'Mutation', 'rs1042522', (25, 29))	('Mouse', 'Species', '10090', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('p53', 'Gene', (21, 24))
196345	23475592	Here we demonstrate that the p53 R72P polymorphism modulates the hyperprolferative, apoptotic and inflammatory phenotypes caused by expression of the HPV16 E6 and E7 oncoproteins.	('R72P', 'Mutation', 'rs1042522', (33, 37))	('HPV16', 'Species', '333760', (150, 155))	('modulates', 'Reg', (51, 60))	('p53', 'Gene', (29, 32))	('HPV16', 'Gene', (150, 155))	('hyperprolferative', 'Disease', (65, 82))	('apoptotic', 'CPA', (84, 93))	('R72P', 'Var', (33, 37))
196346	23475592	Moreover, the R72P SNP also modifies the carcinogenic response to the chemical carcinogen 4NQO, in the presence and absence of the HPV16 transgene.	('HPV16', 'Species', '333760', (131, 136))	('carcinogenic', 'Disease', 'MESH:D063646', (41, 53))	('R72P', 'Mutation', 'rs1042522', (14, 18))	('carcinogenic', 'Disease', (41, 53))	('R72P', 'Var', (14, 18))	('4NQO', 'Chemical', 'MESH:D015112', (90, 94))	('modifies', 'Reg', (28, 36))	('HPV16', 'Gene', (131, 136))
196347	23475592	Our findings confirm several human epidemiological studies associating the codon 72 proline variant with increased risk for certain cancers but also suggest that there are tissue-specific differences in how the R72P polymorphism influences the response to environmental carcinogens.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('R72P', 'Mutation', 'rs1042522', (211, 215))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('human', 'Species', '9606', (29, 34))	('proline', 'Chemical', 'MESH:D011392', (84, 91))	('response to environmental carcinogens', 'MPA', (244, 281))	('R72P', 'Var', (211, 215))	('influences', 'Reg', (229, 239))
196349	23475592	Malfunction of the p53 pathway is an almost universal hallmark of human cancers, although the relative importance of the different p53 activities for tumor suppression is a matter of debate.	('p53 pathway', 'Pathway', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('Malfunction', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('tumor', 'Disease', (150, 155))
196350	23475592	A common polymorphism in the p53 gene results in a protein with either an arginine or proline at amino acid 72.	('arginine', 'Chemical', 'MESH:D001120', (74, 82))	('protein', 'Protein', (51, 58))	('proline', 'Chemical', 'MESH:D011392', (86, 93))	('p53', 'Gene', (29, 32))	('polymorphism', 'Var', (9, 21))	('results in', 'Reg', (38, 48))	('proline', 'MPA', (86, 93))
196351	23475592	Cell culture-based studies have demonstrated that the p53 codon 72 arginine (R72) protein variant has a greater ability to suppress oncogenic transformation and increased apoptotic activity compared to the codon 72 proline (P72) variant.	('arginine', 'Chemical', 'MESH:D001120', (67, 75))	('p53', 'Var', (54, 57))	('apoptotic activity', 'CPA', (171, 189))	('suppress', 'NegReg', (123, 131))	('oncogenic transformation', 'CPA', (132, 156))	('increased', 'PosReg', (161, 170))	('proline', 'Chemical', 'MESH:D011392', (215, 222))
196352	23475592	The p53 R72P polymorphism has been extensively evaluated as a risk modifier for a variety of cancers and other diseases.	('R72P', 'Mutation', 'rs1042522', (8, 12))	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('p53', 'Gene', (4, 7))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('R72P', 'Var', (8, 12))
196353	23475592	Epidemiological studies have often associated the presence of the P72 encoding gene variant to increased risk for some cancers.	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('P72 encoding', 'Var', (66, 78))
196354	23475592	However, in most cases there are conflicting reports and meta-analyses combining studies on lung, breast, and gastric cancers do not support a link between the p53 R72P SNP and cancer risk.	('p53 R72P SNP', 'Var', (160, 172))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('gastric cancers', 'Phenotype', 'HP:0012126', (110, 125))	('R72P', 'Mutation', 'rs1042522', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('gastric cancers', 'Disease', (110, 125))	('gastric cancers', 'Disease', 'MESH:D013274', (110, 125))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
196355	23475592	On the other hand, meta-analyses of studies examining esophageal squamous cell carcinoma (SCC) support the idea that individuals with a P72 variant allele are at greater risk for developing that cancer.	('esophageal squamous cell carcinoma', 'Disease', (54, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))	('SCC', 'Gene', '6317', (90, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('P72', 'Var', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
196356	23475592	A meta-analysis examining risk for cervical cancer also suggests an association with the p53 R72P SNP.	('association', 'Interaction', (68, 79))	('p53 R72P SNP', 'Var', (89, 101))	('cervical cancer', 'Disease', 'MESH:D002583', (35, 50))	('R72P', 'Mutation', 'rs1042522', (93, 97))	('cervical cancer', 'Disease', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
196357	23475592	This possibility was first raised by Storey et al, who proposed that women with the p53 R72/R72 genotype were at increased risk for cervical cancer because the R72 protein variant is preferentially targeted for degradation by the HPV E6 oncoprotein.	('cervical cancer', 'Disease', (132, 147))	('protein', 'Protein', (164, 171))	('cervical cancer', 'Disease', 'MESH:D002583', (132, 147))	('HPV', 'Species', '10566', (230, 233))	('R72/R72', 'Var', (88, 95))	('increased risk for cervical cancer', 'Phenotype', 'HP:0030159', (113, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('preferentially', 'PosReg', (183, 197))	('p53 R72/R72', 'Var', (84, 95))	('degradation', 'MPA', (211, 222))	('women', 'Species', '9606', (69, 74))	('R72', 'Var', (160, 163))
196359	23475592	Moreover, a strong interaction between HPV seropositivity and the R72P SNP for risk of SCC of the oropharynx has been reported.	('SCC', 'Gene', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('HPV', 'Species', '10566', (39, 42))	('R72P', 'Mutation', 'rs1042522', (66, 70))	('SCC', 'Gene', '6317', (87, 90))	('R72P', 'Var', (66, 70))	('HPV', 'Gene', (39, 42))
196360	23475592	However, in the case of HPV-associated head and neck SCC it is the P72-encoding allele of p53 that is associated with increased cancer risk.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('SCC', 'Gene', '6317', (53, 56))	('p53', 'Gene', (90, 93))	('associated with', 'Reg', (102, 117))	('HPV', 'Species', '10566', (24, 27))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('P72-encoding', 'Var', (67, 79))	('SCC', 'Gene', (53, 56))	('cancer', 'Disease', (128, 134))
196362	23475592	Pairs of models generated through different approaches each demonstrate that both human p53 variants are functional in mice.	('p53', 'Gene', (88, 91))	('mice', 'Species', '10090', (119, 123))	('variants', 'Var', (92, 100))	('human', 'Species', '9606', (82, 87))
196363	23475592	Moreover, significant differences between the p53 variants in their abilities to induce apoptosis could be observed in these mouse models.	('p53', 'Gene', (46, 49))	('mouse', 'Species', '10090', (125, 130))	('apoptosis', 'CPA', (88, 97))	('variants', 'Var', (50, 58))
196364	23475592	In one study it was shown that despite a significant difference in the acute apoptotic response to ultraviolet (UV) radiation, there was no significant difference in UV radiation-induced skin carcinogenesis between R72/R72 and P72/P72 genotypes.	('P72/P72', 'Gene', '67040', (227, 234))	('R72/R72', 'Var', (215, 222))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (187, 206))	('P72/P72', 'Gene', (227, 234))	('skin carcinogenesis', 'Disease', (187, 206))
196365	23475592	Another study using similar humanized knock-in mouse models found the R72P SNP made no significant difference in lymphoma development driven by an Emu-myc transgene.	('lymphoma', 'Disease', 'MESH:D008223', (113, 121))	('human', 'Species', '9606', (28, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('R72P', 'Mutation', 'rs1042522', (70, 74))	('R72P', 'Var', (70, 74))	('lymphoma', 'Disease', (113, 121))	('mouse', 'Species', '10090', (47, 52))
196366	23475592	Thus, there is no experimental data, to date, to support a role for the R72P SNP in modulating cancer development using these mouse models.	('mouse', 'Species', '10090', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('R72P', 'Var', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('R72P', 'Mutation', 'rs1042522', (72, 76))
196367	23475592	Here we used human p53 exon 4 knock-in mouse models to examine how the R72P SNP interacts with relevant environmental insults to modify the development of cancers of the oral cavity and esophagus.	('R72P', 'Var', (71, 75))	('human', 'Species', '9606', (13, 18))	('R72P', 'Mutation', 'rs1042522', (71, 75))	('cancers of the oral cavity', 'Phenotype', 'HP:0100649', (155, 181))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('esophagus', 'Disease', (186, 195))	('modify', 'Reg', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('mouse', 'Species', '10090', (39, 44))	('cancers', 'Disease', (155, 162))
196369	23475592	Treatment of these HPV16 transgenic mice with the carcinogen 4-nitroquinoline-1-oxide (4NQO) induced tumor development, which was modified by the R72P polymorphism.	('HPV16', 'Species', '333760', (19, 24))	('4-nitroquinoline-1-oxide', 'Chemical', 'MESH:D015112', (61, 85))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('4NQO', 'Chemical', 'MESH:D015112', (87, 91))	('induced', 'PosReg', (93, 100))	('R72P', 'Var', (146, 150))	('transgenic mice', 'Species', '10090', (25, 40))	('R72P', 'Mutation', 'rs1042522', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
196370	23475592	Moreover, the R72P SNP also affected the development of esophageal cancers in 4NQO treated knock-in mice lacking the HPV16 transgene.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('4NQO', 'Chemical', 'MESH:D015112', (78, 82))	('mice', 'Species', '10090', (100, 104))	('development', 'CPA', (41, 52))	('R72P', 'Mutation', 'rs1042522', (14, 18))	('esophageal cancers', 'Disease', (56, 74))	('affected', 'Reg', (28, 36))	('R72P', 'Var', (14, 18))	('esophageal cancers', 'Disease', 'MESH:D004938', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('HPV16', 'Gene', (117, 122))	('HPV16', 'Species', '333760', (117, 122))	('lacking', 'NegReg', (105, 112))
196371	23475592	Our findings demonstrate that this functional SNP in p53 can modify the response to viral and chemical carcinogens resulting in tissue-specific differences in tumor susceptibility.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('differences', 'Reg', (144, 155))	('modify', 'Reg', (61, 67))	('functional SNP', 'Var', (35, 49))	('SNP', 'Var', (46, 49))	('tumor', 'Disease', (159, 164))	('p53', 'Gene', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
196372	23475592	Human p53 exon 4 knock-in mice encoding either arginine (p53R72/R72) or proline (p53P72/P72) at codon 72 have been described.	('Human', 'Species', '9606', (0, 5))	('p53P72/P72', 'Gene', (81, 91))	('arginine', 'Chemical', 'MESH:D001120', (47, 55))	('proline', 'Chemical', 'MESH:D011392', (72, 79))	('p53R72/R72', 'Var', (57, 67))	('p53P72/P72', 'Gene', '67040', (81, 91))	('mice', 'Species', '10090', (26, 30))
196376	23475592	Genomic DNA isolated from tail snips was used for genotyping the p53 R72P polymorphism as described.	('R72P', 'Var', (69, 73))	('p53', 'Gene', (65, 68))	('R72P', 'Mutation', 'rs1042522', (69, 73))
196395	23475592	Immunoblotting was done using the following primary antibodies: p53 (Vector laboratories, Burlingame, CA); Bax, p21 and actin (Santa Cruz Biotechnology, Santa Cruz, CA).	('p21', 'Gene', '12575', (112, 115))	('p53', 'Var', (64, 67))	('Bax', 'Gene', '12028', (107, 110))	('Bax', 'Gene', (107, 110))	('p21', 'Gene', (112, 115))
196400	23475592	As expected, E6 was expressed in the K14-HPV16 transgenic mice, but not the non-transgenic mice, and the R72P polymorphism did not affect the level of E6 expression.	('R72P', 'Mutation', 'rs1042522', (105, 109))	('transgenic mice', 'Species', '10090', (80, 95))	('R72P', 'Var', (105, 109))	('K14', 'Gene', '16664', (37, 40))	('K14', 'Gene', (37, 40))	('HPV16', 'Species', '333760', (41, 46))	('transgenic mice', 'Species', '10090', (47, 62))
196406	23475592	In contrast, the pro-apoptotic E2F target gene caspase 7 was not elevated in transgenic cells.	('transgenic', 'Species', '10090', (77, 87))	('caspase 7', 'Gene', (47, 56))	('transgenic', 'Var', (77, 87))	('caspase 7', 'Gene', '12369', (47, 56))
196407	23475592	The R72P polymorphism did not significantly affect the expression of these E2F target genes in the presence or absence of the K14-HPV16 transgene.	('HPV16', 'Species', '333760', (130, 135))	('R72P', 'Mutation', 'rs1042522', (4, 8))	('R72P', 'Var', (4, 8))	('expression', 'MPA', (55, 65))	('K14', 'Gene', '16664', (126, 129))	('K14', 'Gene', (126, 129))
196409	23475592	In the epidermis, there was also a statistically significant difference between K14-HPV16;p53P72/P72 and K14-HPV16;p53R72/R72 mice, with the R72 variant associated with higher levels of Ki67 staining.	('higher', 'PosReg', (169, 175))	('Ki67', 'Gene', (186, 190))	('mice', 'Species', '10090', (126, 130))	('p53R72/R72', 'Var', (115, 125))	('HPV16', 'Species', '333760', (109, 114))	('K14', 'Gene', '16664', (105, 108))	('K14', 'Gene', (80, 83))	('K14', 'Gene', '16664', (80, 83))	('R72', 'Var', (141, 144))	('Ki67', 'Gene', '17345', (186, 190))	('K14', 'Gene', (105, 108))	('p53P72/P72', 'Gene', '67040', (90, 100))	('p53P72/P72', 'Gene', (90, 100))	('HPV16', 'Species', '333760', (84, 89))
196420	23475592	In both groups of treated mice, K14-HPV16 transgenic mice with the R72/R72 genotype had increased survival compared to the P72/P72 genotype (Figure 3).	('survival', 'CPA', (98, 106))	('P72/P72', 'Gene', (123, 130))	('K14', 'Gene', '16664', (32, 35))	('K14', 'Gene', (32, 35))	('HPV16', 'Species', '333760', (36, 41))	('increased', 'PosReg', (88, 97))	('P72/P72', 'Gene', '67040', (123, 130))	('transgenic mice', 'Species', '10090', (42, 57))	('R72/R72', 'Var', (67, 74))	('mice', 'Species', '10090', (53, 57))	('mice', 'Species', '10090', (26, 30))
196422	23475592	Oral cavity tumors induced in non-transgenic mice and rats by oral exposure to 4NQO are predominately SCC of the tongue.	('4NQO', 'Var', (79, 83))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('4NQO', 'Chemical', 'MESH:D015112', (79, 83))	('transgenic mice', 'Species', '10090', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Oral cavity tumors', 'Phenotype', 'HP:0100649', (0, 18))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('SCC', 'Gene', (102, 105))	('rats', 'Species', '10116', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
196425	23475592	In our studies, it appears that the combination of the HPV16 transgene and 4NQO resulted in the development of frank SCC in the gingiva.	('combination', 'Var', (36, 47))	('4NQO', 'Chemical', 'MESH:D015112', (75, 79))	('SCC', 'Gene', (117, 120))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('SCC', 'Gene', '6317', (117, 120))	('HPV16', 'Species', '333760', (55, 60))	('resulted in', 'Reg', (80, 91))	('HPV16', 'Gene', (55, 60))
196428	23475592	The R72P polymorphism did not appear to alter tumor incidence or pathology in the oral mucosa.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('R72P', 'Mutation', 'rs1042522', (4, 8))	('tumor', 'Disease', (46, 51))	('R72P', 'Var', (4, 8))	('pathology in the oral', 'Phenotype', 'HP:0100649', (65, 86))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
196429	23475592	Although there was no difference between R72/R72 and P72/P72 mice in SCC of the oral mucosa, there were differences in two other cancers from the K14-HPV16 transgenic mice treated with 4NQO.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('K14', 'Gene', '16664', (146, 149))	('mice', 'Species', '10090', (61, 65))	('HPV16', 'Species', '333760', (150, 155))	('SCC', 'Gene', (69, 72))	('K14', 'Gene', (146, 149))	('R72/R72', 'Var', (41, 48))	('4NQO', 'Chemical', 'MESH:D015112', (185, 189))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Disease', (129, 136))	('transgenic mice', 'Species', '10090', (156, 171))	('P72/P72', 'Gene', '67040', (53, 60))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('SCC', 'Gene', '6317', (69, 72))	('differences', 'Reg', (104, 115))	('P72/P72', 'Gene', (53, 60))	('mice', 'Species', '10090', (167, 171))
196430	23475592	Three out of 25 transgenic mice with the R72/R72 genotype developed SCC of the tongue while no transgenic mice with the P72/P72 genotype (0/24) developed SCC at this site (Figure 4A).	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (154, 157))	('SCC', 'Gene', '6317', (68, 71))	('P72/P72', 'Gene', (120, 127))	('transgenic mice', 'Species', '10090', (16, 31))	('R72/R72', 'Var', (41, 48))	('transgenic mice', 'Species', '10090', (95, 110))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))	('P72/P72', 'Gene', '67040', (120, 127))	('SCC', 'Gene', (154, 157))	('SCC', 'Gene', (68, 71))
196432	23475592	This suggests that the R72P SNP may differentially modulate tumor development in the skin and tongue.	('tumor development in the skin', 'Phenotype', 'HP:0008069', (60, 89))	('R72P', 'Mutation', 'rs1042522', (23, 27))	('R72P', 'Var', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('modulate', 'Reg', (51, 59))
196433	23475592	A previous report analyzing other knock-in mouse models humanized for the R72P polymorphism found that the P72 variant of p53 interacted more efficiently with the NF-kB transcription factor than the R72 variant.	('R72P', 'Mutation', 'rs1042522', (74, 78))	('P72', 'Var', (107, 110))	('NF-kB', 'Protein', (163, 168))	('human', 'Species', '9606', (56, 61))	('interacted', 'Interaction', (126, 136))	('mouse', 'Species', '10090', (43, 48))	('p53', 'Gene', (122, 125))
196434	23475592	This differential association with NF-kB was associated with increased expression of inflammatory genes and an enhanced inflammatory response to lipopolysaccharide (LPS) in mice expressing the p53 P72 variant.	('inflammatory genes', 'Gene', (85, 103))	('expression', 'MPA', (71, 81))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (145, 163))	('NF-kB', 'Gene', (35, 40))	('LPS', 'Disease', 'MESH:C536528', (165, 168))	('inflammatory response to lipopolysaccharide', 'MPA', (120, 163))	('enhanced inflammatory response', 'Phenotype', 'HP:0012649', (111, 141))	('enhanced', 'PosReg', (111, 119))	('increased', 'PosReg', (61, 70))	('p53 P72', 'Var', (193, 200))	('mice', 'Species', '10090', (173, 177))	('LPS', 'Disease', (165, 168))
196441	23475592	Only two esophageal tumors were observed K14-HPV16 transgenic mice treated with 4NQO, one with the p53 R72/R72 genotype and one with the P72/P72 genotype (data not shown).	('transgenic mice', 'Species', '10090', (51, 66))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('esophageal tumors', 'Disease', (9, 26))	('P72/P72', 'Gene', (137, 144))	('p53 R72/R72', 'Var', (99, 110))	('HPV16', 'Species', '333760', (45, 50))	('P72/P72', 'Gene', '67040', (137, 144))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('K14', 'Gene', '16664', (41, 44))	('4NQO', 'Chemical', 'MESH:D015112', (80, 84))	('esophageal tumors', 'Disease', 'MESH:D004938', (9, 26))	('esophageal tumors', 'Phenotype', 'HP:0100751', (9, 26))	('K14', 'Gene', (41, 44))
196442	23475592	To further explore a potential role for the R72P SNP in modulating esophageal carcinogenesis, p53R/72/R72 and p53P72/P72 mice without the K14-HPV16 transgene were treated with 10 mug/ml of 4NQO supplied in the drinking water for 16 weeks.	('esophageal carcinogenesis', 'Disease', (67, 92))	('R72P', 'Mutation', 'rs1042522', (44, 48))	('K14', 'Gene', '16664', (138, 141))	('K14', 'Gene', (138, 141))	('R72P', 'Var', (44, 48))	('4NQO', 'Chemical', 'MESH:D015112', (189, 193))	('p53P72/P72', 'Gene', '67040', (110, 120))	('mice', 'Species', '10090', (121, 125))	('p53P72/P72', 'Gene', (110, 120))	('drinking water', 'Chemical', 'MESH:D060766', (210, 224))	('HPV16', 'Species', '333760', (142, 147))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (67, 92))
196447	23475592	Proliferation in the esophageal tumors was similar between R72/R72 and P72/P72 mice as measured by the number of Ki67-positive cells per field (Figure 6C).	('P72/P72', 'Gene', '67040', (71, 78))	('Ki67', 'Gene', (113, 117))	('mice', 'Species', '10090', (79, 83))	('R72/R72', 'Var', (59, 66))	('esophageal tumors', 'Disease', 'MESH:D004938', (21, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('esophageal tumors', 'Phenotype', 'HP:0100751', (21, 38))	('Ki67', 'Gene', '17345', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('esophageal tumors', 'Disease', (21, 38))	('P72/P72', 'Gene', (71, 78))
196452	23475592	In these studies we have used humanized p53 exon 4 knock-in mouse models to explore how the R72P SNP impacts tumor development in the oral cavity and upper digestive tract.	('impacts', 'Reg', (101, 108))	('human', 'Species', '9606', (30, 35))	('R72P', 'Mutation', 'rs1042522', (92, 96))	('R72P', 'Var', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor development in the oral cavity', 'Phenotype', 'HP:0100649', (109, 145))	('mouse', 'Species', '10090', (60, 65))	('tumor', 'Disease', (109, 114))
196454	23475592	Moreover, 4NQO carcinogenesis produces a spectrum of oral cavity and esophageal lesions that parallel the progression and histological features of human cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('esophageal lesions', 'Disease', 'MESH:D004935', (69, 87))	('cancers', 'Disease', (153, 160))	('human', 'Species', '9606', (147, 152))	('4NQO', 'Chemical', 'MESH:D015112', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('esophageal lesions', 'Disease', (69, 87))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('4NQO', 'Var', (10, 14))
196455	23475592	Using this well-established model we found that mice expressing the p53 P72 variant were more susceptible to esophageal SCC compared to mice encoding the R72 variant.	('p53 P72', 'Var', (68, 75))	('mice', 'Species', '10090', (136, 140))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('mice', 'Species', '10090', (48, 52))	('susceptible', 'Reg', (94, 105))	('esophageal SCC', 'Disease', (109, 123))	('esophageal SCC', 'Disease', 'MESH:D004941', (109, 123))
196456	23475592	This finding is consistent with several epidemiological studies associating the P72 allele with increased risk for esophageal SCC and demonstrates that human cancer susceptibility due to this common polymorphism can be modeled in mice.	('esophageal SCC', 'Disease', (115, 129))	('mice', 'Species', '10090', (230, 234))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('esophageal SCC', 'Disease', 'MESH:D004941', (115, 129))	('P72', 'Var', (80, 83))	('cancer', 'Disease', (158, 164))	('human', 'Species', '9606', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
196458	23475592	It was also suggested that the two p53 protein variants are differentially targeted for degradation by the HPV E6 oncoprotein.	('variants', 'Var', (47, 55))	('p53', 'Gene', (35, 38))	('HPV', 'Species', '10566', (107, 110))	('degradation', 'MPA', (88, 99))	('protein', 'Protein', (39, 46))
196459	23475592	To determine if the R72P SNP modifies the oncogenic effects of HPV, K14-HPV16 transgenic mice were crossed to the p53 exon 4 knock-in models.	('HPV', 'Species', '10566', (63, 66))	('modifies', 'Reg', (29, 37))	('R72P', 'Var', (20, 24))	('R72P', 'Mutation', 'rs1042522', (20, 24))	('transgenic mice', 'Species', '10090', (78, 93))	('HPV', 'Species', '10566', (72, 75))	('HPV16', 'Species', '333760', (72, 77))	('K14', 'Gene', '16664', (68, 71))	('K14', 'Gene', (68, 71))
196460	23475592	We found that the R72P polymorphism made little difference in the levels of p53 or the expression of p53 target genes.	('expression', 'MPA', (87, 97))	('R72P', 'Mutation', 'rs1042522', (18, 22))	('R72P', 'Var', (18, 22))	('levels of p53', 'MPA', (66, 79))
196461	23475592	Nonetheless, the hyperproliferative and apoptotic responses to the HPV16 transgene were modulated by the R72P SNP.	('R72P', 'Mutation', 'rs1042522', (105, 109))	('HPV16', 'Species', '333760', (67, 72))	('R72P', 'Var', (105, 109))	('apoptotic responses', 'CPA', (40, 59))	('HPV16', 'Gene', (67, 72))	('modulated', 'Reg', (88, 97))	('hyperproliferative', 'CPA', (17, 35))
196462	23475592	Interestingly, the R72P SNP appeared to differentially modify cancer susceptibility in different tissues.	('R72P', 'Mutation', 'rs1042522', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('modify', 'Reg', (55, 61))	('R72P', 'Var', (19, 23))
196466	23475592	This finding is consistent with previous epidemiological studies showing that the R72P polymorphism impacts cancer risk in a tissue-specific manner.	('R72P', 'Mutation', 'rs1042522', (82, 86))	('R72P', 'Var', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('impacts', 'Reg', (100, 107))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
196467	23475592	Future studies should address whether the R72P SNP differentially modulates risk for SCC of the tongue and skin in humans, particularly those cancers associated with HPV.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('humans', 'Species', '9606', (115, 121))	('SCC', 'Gene', '6317', (85, 88))	('cancers', 'Disease', (142, 149))	('modulates', 'Reg', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('HPV', 'Species', '10566', (166, 169))	('R72P', 'Mutation', 'rs1042522', (42, 46))	('R72P', 'Var', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('SCC', 'Gene', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))	('skin', 'Disease', (107, 111))
196470	23475592	In addition, the p53 R72P SNP may also modify the inflammatory response associated with tumor development.	('modify', 'Reg', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('p53 R72P SNP', 'Var', (17, 29))	('R72P', 'Mutation', 'rs1042522', (21, 25))	('inflammatory response', 'CPA', (50, 71))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
196473	23475592	This suggests that differential regulation of the inflammatory response by the p53 polymorphic variants may also contribute to differences in cancer susceptibility and progression of at least some tumor types.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('p53', 'Gene', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('contribute', 'Reg', (113, 123))	('differences', 'Reg', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('polymorphic variants', 'Var', (83, 103))	('inflammatory response', 'CPA', (50, 71))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('cancer', 'Disease', (142, 148))
196507	20886398	Subjects in the ablation arm received up to four endoscopic RFA treatments (HALO360 and HALO90, BARRX Medical, Sunnyvale, CA).	('HALO90', 'Var', (88, 94))	('men', 'Species', '9606', (69, 72))	('HALO360', 'Var', (76, 83))	('HALO90', 'CellLine', 'CVCL:1B47', (88, 94))
196523	20886398	In brief, in an intention to treat analysis, we found that among subjects with LGD, 90.5% of those in the RFA group had complete eradication of dysplasia compared with 22.7% of those in the sham group.	('dysplasia', 'Disease', 'MESH:D004476', (144, 153))	('LGD', 'Disease', (79, 82))	('RFA', 'Var', (106, 109))	('eradication', 'NegReg', (129, 140))	('dysplasia', 'Disease', (144, 153))	('LGD', 'Disease', 'None', (79, 82))
196524	20886398	Among subjects with HGD, 81.0% of those in the RFA group had complete eradication of dysplasia compared with 19.0% of those in the sham group.	('RFA', 'Var', (47, 50))	('dysplasia', 'Disease', (85, 94))	('dysplasia', 'Disease', 'MESH:D004476', (85, 94))	('eradication', 'NegReg', (70, 81))
196555	20886398	Because all subjects treated with RFA had either complete eradication of IM or downgrading of disease, there were significant improvements in QoL for the majority of subjects in the RFA group compared to the sham group.	('downgrading', 'NegReg', (79, 90))	('men', 'Species', '9606', (133, 136))	('QoL', 'MPA', (142, 145))	('improvements', 'PosReg', (126, 138))	('RFA', 'Var', (182, 185))
196574	20886398	Eradication of dysplasia by ablation leads to a marked improvement in disease-related QoL in the first 12 months of treatment.	('men', 'Species', '9606', (62, 65))	('men', 'Species', '9606', (121, 124))	('improvement', 'PosReg', (55, 66))	('dysplasia', 'Disease', (15, 24))	('disease-related QoL', 'MPA', (70, 89))	('dysplasia', 'Disease', 'MESH:D004476', (15, 24))	('ablation', 'Var', (28, 36))
196651	12919638	Variceal bleeding occurred more frequent in patients with Child class B and C (Table 2), but differences were not statistically significant (p = 0.9, log-rank test).	('patients', 'Species', '9606', (44, 52))	('bleeding', 'Disease', (9, 17))	('Child', 'Species', '9606', (58, 63))	('Child class B', 'Var', (58, 71))	('bleeding', 'Disease', 'MESH:D006470', (9, 17))
196848	33628625	Due to the biological importance and controversial clinical implications of these markers and cells types, in this study, we used a novel tyramide signal amplification (TSA) multiplexing technique and immunolabeled cells with pancytokeratin (panCK), CD68, CD11c, CD45RO, PD-L1, CD4, CD8A, CD56, granzyme B and forkhead box P3 (FoxP3) in the TME of resected human ESCC and peritumoral uninvolved esophageal tissue samples.	('CD11c', 'Gene', '3687', (256, 261))	('CD68', 'Var', (250, 254))	('CD11c', 'Gene', (256, 261))	('CD4', 'Gene', (278, 281))	('FoxP3', 'Gene', (327, 332))	('PD-L1', 'Gene', (271, 276))	('granzyme B', 'Gene', (295, 305))	('FoxP3', 'Gene', '50943', (327, 332))	('CD8A', 'Gene', '925', (283, 287))	('CD56', 'Gene', (289, 293))	('age', 'Gene', (400, 403))	('CD45RO', 'Gene', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('human', 'Species', '9606', (357, 362))	('ESCC', 'Phenotype', 'HP:0011459', (363, 367))	('CD8A', 'Gene', (283, 287))	('CD45RO', 'Gene', '5788', (263, 269))	('tumoral', 'Disease', (376, 383))	('tumoral', 'Disease', 'MESH:D009369', (376, 383))	('CD4', 'Gene', '920', (263, 266))	('forkhead box P3', 'Gene', '50943', (310, 325))	('forkhead box P3', 'Gene', (310, 325))	('age', 'Gene', '5973', (400, 403))	('CD4', 'Gene', '920', (278, 281))	('granzyme B', 'Gene', '3002', (295, 305))	('CD4', 'Gene', (263, 266))
196862	33628625	Five filter cubes were used for each image capture, including DAPI (440-680 nm), FITC (520-680 nm), CY3 (570-690 nm), CY5 (670-720 nm), and Texas Red (580-700 nm).	('age', 'Gene', (39, 42))	('440-680 nm', 'Var', (68, 78))	('DAPI', 'Chemical', 'MESH:C007293', (62, 66))	('520-680 nm', 'Var', (87, 97))	('age', 'Gene', '5973', (39, 42))	('580-700 nm', 'Var', (151, 161))
196885	33628625	Considering that ECs and TAMs were the major components that expressed PD-L1 in the TME, we also calculated the PD-L1+ EC/EC and PD-L1+ TAM/TAM ratios.	('TAM', 'Gene', (140, 143))	('TAMs', 'Chemical', '-', (25, 29))	('PD-L1', 'Var', (71, 76))	('TAM', 'Gene', '8205', (136, 139))	('TAM', 'Gene', '8205', (25, 28))	('TAM', 'Gene', '8205', (140, 143))	('PD-L1+ EC/EC', 'Disease', (112, 124))	('TAM', 'Gene', (136, 139))	('TAM', 'Gene', (25, 28))	('PD-L1+ EC/EC', 'Disease', 'MESH:D010300', (112, 124))
196920	33628625	Our results revealed that patients in the high Treg infiltration group had a significantly lower infiltration of several antitumor immune effectors, including the CTLs (10.91% vs. 17.26%, P = .02, unpaired t-test) (Figure 6a), aCTLs (4.63% vs. 9.41%, P = .002) (Figure 6b), and NK cells (10.13% vs. 16.48%, P = .008) (Figure 6c) in intraepithelial regions.	('lower', 'NegReg', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Treg', 'Chemical', '-', (47, 51))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Disease', (125, 130))	('high', 'Var', (42, 46))	('infiltration', 'MPA', (97, 109))
196942	33628625	Furthermore, the significantly decreased infiltration of several antitumor immune effectors, including CTLs, aCTLs and NK cells, was observed in patients in the high Treg infiltration group compared to the low infiltration group, in both intraepithelial and stromal regions.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('aCTLs', 'CPA', (109, 114))	('decreased', 'NegReg', (31, 40))	('infiltration', 'MPA', (41, 53))	('high', 'Var', (161, 165))	('CTLs', 'CPA', (103, 107))	('Treg', 'Chemical', '-', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
197016	32548194	Neutrophilic enzymes occlude small vessels, resulting in gangrenous necrosis of the squamous epithelium and the activation of inflammatory cells.	('gangrenous necrosis of the squamous', 'Disease', 'MESH:D005734', (57, 92))	('inflammatory cells', 'CPA', (126, 144))	('activation', 'PosReg', (112, 122))	('gangrenous necrosis of the squamous', 'Disease', (57, 92))	('occlude', 'NegReg', (21, 28))	('small vessels', 'CPA', (29, 42))	('Neutrophilic', 'Var', (0, 12))
197084	31814973	As grade 3 neutropenia was also observed (960/microl), the patient was hospitalized and treated with antibiotics.	('neutropenia', 'Disease', (11, 22))	('960/microl', 'Var', (42, 52))	('patient', 'Species', '9606', (59, 66))	('neutropenia', 'Disease', 'MESH:D009503', (11, 22))	('neutropenia', 'Phenotype', 'HP:0001875', (11, 22))
197165	31444324	show through pharmacological modifications of the microenvironment or signaling pathways of sensitized cells that they can impact tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('impact', 'Reg', (123, 129))	('modifications', 'Var', (29, 42))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
197175	31444324	The preexistence of these junctional cells explains why Barrett's can emerge so rapidly, in a matter of days, upon genetically induced damage to the murine esophagus.	('damage', 'Var', (135, 141))	('Barrett', 'Disease', (56, 63))	('murine', 'Species', '10090', (149, 155))
197177	31444324	As might be expected, most of the Barrett's stem cells had acquired multiple somatic mutations impacting p16, ARIDA1, and other genes seen for Barrett's esophagus, but a third of the Barrett's cases were, like their normal esophageal and gastric counterparts, devoid of somatic mutations.	('p16', 'Gene', (105, 108))	('p16', 'Gene', '13088', (105, 108))	('impacting', 'Reg', (95, 104))	('Barrett', 'Disease', (183, 190))	('mutations', 'Var', (85, 94))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (143, 162))	('ARIDA1', 'Gene', (110, 116))
197187	31444324	Regardless, even with the induction of activated oncogenes and loss of p53, these junctional p63+/Krt5+ cells steadfastly retain their esophageal fate and do not undergo "transcommitment" to Barrett's.	('esophageal fate', 'CPA', (135, 150))	('p63', 'Gene', '22061', (93, 96))	('loss', 'Var', (63, 67))	('Krt5', 'Gene', (98, 102))	('Krt5', 'Gene', '110308', (98, 102))	('ran', 'Gene', (172, 175))	('ran', 'Gene', '19384', (172, 175))	('p53', 'Gene', (71, 74))	('p63', 'Gene', (93, 96))	('p53', 'Gene', '22060', (71, 74))
197197	31444324	They showed that the Cox-2 inhibitor celecoxib reduced the hypercellularity of organoids derived from esophageal progenitors expressing activated Ras in a p53-deficient background, and that the genetic loss of Cox2 in their murine model significantly suppressed tumorigenesis across the esophagus.	('celecoxib', 'Chemical', 'MESH:D000068579', (37, 46))	('p53', 'Gene', (155, 158))	('hypercellularity', 'MPA', (59, 75))	('genetic loss', 'Var', (194, 206))	('Cox2', 'Gene', '17709', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (262, 267))	('suppressed', 'NegReg', (251, 261))	('Cox-2', 'Gene', '17709', (21, 26))	('p53', 'Gene', '22060', (155, 158))	('murine', 'Species', '10090', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('reduced', 'NegReg', (47, 54))	('Cox2', 'Gene', (210, 214))	('Cox-2', 'Gene', (21, 26))
197313	30126380	In the analysis of overall survival (OS), patients with N0-1 status had significantly superior OS compared to those with N2-3 status.	('superior', 'PosReg', (86, 94))	('OS', 'Chemical', '-', (37, 39))	('N0-1 status', 'Var', (56, 67))	('OS', 'Chemical', '-', (95, 97))	('patients', 'Species', '9606', (42, 50))
197379	30126380	The 45 patients who had a day 28/day 5 ratio < 1 had superior OS compared to the 52 patients with a day 28/day 5 ratio > 1 (20.9 months versus 8.6 months, P = 0.002, Fig.	('OS', 'Chemical', '-', (62, 64))	('patients', 'Species', '9606', (84, 92))	('superior', 'PosReg', (53, 61))	('< 1', 'Var', (45, 48))	('patients', 'Species', '9606', (7, 15))
197380	30126380	According to a multivariate comparison, N0-1 status (P = 0.008, hazard ratio: 0.51, 95% confidence interval: 0.31-0.84) was a significant independent factor in better OS.	('better OS', 'Disease', (160, 169))	('OS', 'Chemical', '-', (167, 169))	('N0-1 status', 'Var', (40, 51))
197410	30126380	Patients who had a ratio < 1 at day 5/day 0, day 28/day 0, and day 28/day 5 had superior PFS and OS than those with ratio > 1; however, the difference was only significant for the day 28/day 5 ratios.	('PFS', 'CPA', (89, 92))	('ratio < 1', 'Var', (19, 28))	('superior', 'PosReg', (80, 88))	('OS', 'Chemical', '-', (97, 99))	('Patients', 'Species', '9606', (0, 8))
197425	26892033	Furthermore, ICA treatments upregulated the levels of ERS-related molecules (p-PERK, GRP78, ATF4, p-eIF2alpha, and CHOP) and a pro-apoptotic protein (PUMA) and simultaneously downregulated an anti-apoptotic protein (Bcl2) in the two ESCC cell lines.	('PERK', 'Gene', (79, 83))	('CHOP', 'Gene', (115, 119))	('downregulated', 'NegReg', (175, 188))	('ICA', 'Chemical', 'MESH:C056599', (13, 16))	('ATF4', 'Gene', (92, 96))	('PERK', 'Gene', '9451', (79, 83))	('levels', 'MPA', (44, 50))	('ATF4', 'Gene', '468', (92, 96))	('upregulated', 'PosReg', (28, 39))	('GRP78', 'Gene', (85, 90))	('p-eIF2alpha', 'Var', (98, 109))	('GRP78', 'Gene', '3309', (85, 90))	('CHOP', 'Gene', '1649', (115, 119))
197426	26892033	The downregulation of ERS signaling using eIF2alpha siRNA desensitized EC109 and TE1 cells to ICA treatment, and the upregulation of ERS signaling using thapsigargin sensitized EC109 and TE1 cells to ICA treatment.	('thapsigargin', 'Chemical', 'MESH:D019284', (153, 165))	('eIF2alpha', 'Var', (42, 51))	('ERS signaling', 'MPA', (133, 146))	('ERS signaling', 'MPA', (22, 35))	('ICA', 'Chemical', 'MESH:C056599', (94, 97))	('downregulation', 'NegReg', (4, 18))	('EC109', 'CellLine', 'CVCL:6898', (71, 76))	('EC109', 'CellLine', 'CVCL:6898', (177, 182))	('ICA', 'Chemical', 'MESH:C056599', (200, 203))	('upregulation', 'PosReg', (117, 129))
197455	26892033	Furthermore, adenosine inhibits cell proliferation, increases GRP78 and NF-kappaB p65 expression and induces apoptosis by CHOP and caspase-4 pathways in EC109 cells, which is involved in the ERS pathway.	('GRP78', 'Gene', (62, 67))	('GRP78', 'Gene', '3309', (62, 67))	('increases', 'PosReg', (52, 61))	('EC109', 'CellLine', 'CVCL:6898', (153, 158))	('CHOP', 'Gene', (122, 126))	('NF-kappaB', 'Gene', (72, 81))	('inhibits', 'NegReg', (23, 31))	('adenosine', 'Var', (13, 22))	('p65', 'Gene', (82, 85))	('apoptosis', 'CPA', (109, 118))	('NF-kappaB', 'Gene', '4790', (72, 81))	('induces', 'Reg', (101, 108))	('cell proliferation', 'CPA', (32, 50))	('rat', 'Species', '10116', (44, 47))	('expression', 'MPA', (86, 96))	('p65', 'Gene', '5970', (82, 85))	('CHOP', 'Gene', '1649', (122, 126))	('caspase-4', 'Gene', (131, 140))	('caspase-4', 'Gene', '837', (131, 140))	('adenosine', 'Chemical', 'MESH:D000241', (13, 22))
197484	26892033	ESCC cells were first transfected with eIF2alpha siRNA and then treated with ICA (40 muM) for an additional 24 h. Transfection with eIF2alpha siRNA significantly decreased p-eIF2alpha levels in EC109 and TE1 cells (P < 0.05 compared to transfection with the control siRNA, Fig.	('muM', 'Gene', (85, 88))	('p-eIF2alpha levels', 'MPA', (172, 190))	('decreased', 'NegReg', (162, 171))	('EC109', 'CellLine', 'CVCL:6898', (194, 199))	('eIF2alpha siRNA', 'Var', (132, 147))	('ICA', 'Chemical', 'MESH:C056599', (77, 80))	('muM', 'Gene', '56925', (85, 88))
197485	26892033	The combination of eIF2alpha siRNA and ICA significantly increased cell viability (Fig.	('cell viability', 'CPA', (67, 81))	('ICA', 'Chemical', 'MESH:C056599', (39, 42))	('eIF2alpha', 'Var', (19, 28))	('increased', 'PosReg', (57, 66))
197488	26892033	7C,D) (P < 0.05 compared with the combination of control siRNA and ICA); however, eIF2alpha siRNA alone did not affect cell viability, Caspase 9 activity, ROS generation, or NADPH oxidase activity compared with the control siRNA (P > 0.05).	('rat', 'Species', '10116', (163, 166))	('NADPH', 'Chemical', 'MESH:D009249', (174, 179))	('ROS', 'Chemical', 'MESH:D017382', (155, 158))	('activity', 'MPA', (145, 153))	('Caspase 9', 'Gene', (135, 144))	('ICA', 'Chemical', 'MESH:C056599', (67, 70))	('NADPH oxidase', 'Enzyme', (174, 187))	('activity', 'MPA', (188, 196))	('eIF2alpha', 'Var', (82, 91))	('Caspase 9', 'Gene', '842', (135, 144))	('cell viability', 'CPA', (119, 133))	('ROS', 'MPA', (155, 158))
197489	26892033	In addition, Bcl2 was further upregulated by co-treatment with ICA and eIF2alpha siRNA, whereas PUMA was further downregulated by co-treatment with eIF2alpha siRNA and ICA (P < 0.05 compared with the control siRNA and ICA co-treatment, Fig.	('eIF2alpha siRNA', 'Var', (148, 163))	('ICA', 'Chemical', 'MESH:C056599', (168, 171))	('eIF2alpha siRNA', 'Var', (71, 86))	('ICA', 'Chemical', 'MESH:C056599', (218, 221))	('upregulated', 'PosReg', (30, 41))	('downregulated', 'NegReg', (113, 126))	('Bcl2', 'MPA', (13, 17))	('ICA', 'Chemical', 'MESH:C056599', (63, 66))	('ICA', 'Var', (63, 66))
197566	26892033	For the siRNA transfections, ESCC cells were seeded on 6-well plates at 2 x 105 cells per well in 2 mL of antibiotic-free normal growth medium supplemented with FBS.	('FBS', 'Disease', (161, 164))	('FBS', 'Disease', 'MESH:D005198', (161, 164))	('transfections', 'Var', (14, 27))
197585	26892033	For example, APR-246 upregulated p53 target genes, inhibited clonogenic survival and induced cell cycle arrest as well as apoptosis in oesophageal adenocarcinomas cells harbouring p53 mutations.	('arrest', 'Disease', 'MESH:D006323', (104, 110))	('APR', 'Gene', '5366', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('apoptosis', 'CPA', (122, 131))	('p53', 'Gene', (180, 183))	('mutations', 'Var', (184, 193))	('upregulated', 'PosReg', (21, 32))	('induced', 'Reg', (85, 92))	('p53', 'Gene', '7157', (180, 183))	('arrest', 'Disease', (104, 110))	('oesophageal adenocarcinomas', 'Disease', (135, 162))	('p53', 'Gene', (33, 36))	('oesophageal adenocarcinomas', 'Disease', 'MESH:D005764', (135, 162))	('p53', 'Gene', '7157', (33, 36))	('clonogenic survival', 'CPA', (61, 80))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (136, 161))	('inhibited', 'NegReg', (51, 60))	('APR', 'Gene', (13, 16))
197598	26892033	In addition, some cancer cells express mutant proteins that cannot be correctly folded, which activates the UPR.	('proteins', 'Protein', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('mutant', 'Var', (39, 45))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
197605	26892033	In vitro siRNA-mediated silencing of the ERS response protein eIF2alpha significantly reduced ICA-induced cell death.	('reduced', 'NegReg', (86, 93))	('eIF2alpha', 'Gene', (62, 71))	('ICA', 'Chemical', 'MESH:C056599', (94, 97))	('ICA-induced', 'Disease', (94, 105))	('silencing', 'Var', (24, 33))
197614	26892033	In addition, our experiments confirmed that the inhibition of ERS using eIF2alpha siRNA reversed the effects of ICA on the expression of Bcl2 and PUMA, whereas treatment with the ERS inducers (THA, TM, or DTT) enhanced the effects of ICA on Bcl2 and PUMA expression.	('ICA', 'Chemical', 'MESH:C056599', (112, 115))	('DTT', 'Chemical', 'MESH:D004229', (205, 208))	('THA', 'Chemical', 'MESH:D019284', (193, 196))	('ICA', 'Chemical', 'MESH:C056599', (234, 237))	('TM', 'Chemical', 'MESH:D014415', (198, 200))	('eIF2alpha', 'Var', (72, 81))	('inhibition', 'NegReg', (48, 58))	('Bcl2', 'Gene', (137, 141))
197627	26892033	Additionally, this potentiation of chemosensitivity by ERS may be related to the upregulation of pro-apoptotic pathways and activation of ROS.	('pro-apoptotic pathways', 'Pathway', (97, 119))	('potentiation', 'PosReg', (19, 31))	('activation', 'PosReg', (124, 134))	('ERS', 'Var', (55, 58))	('chemosensitivity', 'CPA', (35, 51))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))	('upregulation', 'PosReg', (81, 93))	('ROS', 'Protein', (138, 141))
197635	24454681	We identified recurrent chromosomal gains and losses and calculated the total copy number abnormality (CNA) count for each tumor as a measure of aneuploidy.	('tumor', 'Disease', (123, 128))	('aneuploidy', 'Disease', (145, 155))	('recurrent chromosomal gain', 'Phenotype', 'HP:0040012', (14, 40))	('losses', 'NegReg', (46, 52))	('aneuploidy', 'Disease', 'MESH:D000782', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('chromosomal', 'Var', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
197638	24454681	SNP arrays facilitate the assessment of recurrent chromosomal gain and loss and allow high resolution, quantitative assessment of segmental aneuploidy (total CNA count).	('chromosomal gain', 'Var', (50, 66))	('segmental aneuploidy', 'Disease', 'MESH:C537538', (130, 150))	('segmental aneuploidy', 'Disease', (130, 150))	('loss', 'NegReg', (71, 75))	('recurrent chromosomal gain', 'Phenotype', 'HP:0040012', (40, 66))
197647	24454681	Genomic instability contributes to malignant transformation by generating the clonal diversity that allows for the development of increased growth rates, invasion and metastasis in cancer cells.	('malignant transformation', 'CPA', (35, 59))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('invasion', 'CPA', (154, 162))	('metastasis', 'CPA', (167, 177))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('Genomic instability', 'Var', (0, 19))	('increased', 'PosReg', (130, 139))	('cancer', 'Disease', (181, 187))	('growth rates', 'CPA', (140, 152))
197648	24454681	Genomic instability and resultant aneuploidy is an early event in the pathogenesis of EAC.	('aneuploidy', 'Disease', 'MESH:D000782', (34, 44))	('Genomic instability', 'Var', (0, 19))	('EAC', 'Gene', '1540', (86, 89))	('aneuploidy', 'Disease', (34, 44))	('EAC', 'Gene', (86, 89))
197651	24454681	This deregulates genes in EAC by several mechanisms, including segmental amplification of oncogenes (e.g.	('EAC', 'Gene', '1540', (26, 29))	('deregulates', 'Reg', (5, 16))	('genes', 'Gene', (17, 22))	('EAC', 'Gene', (26, 29))	('segmental amplification', 'Var', (63, 86))
197653	24454681	CDKN2A, FHIT); and point mutation of tumor suppressor genes (e.g.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('FHIT', 'Gene', (8, 12))	('FHIT', 'Gene', '2272', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('point mutation', 'Var', (19, 33))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))
197654	24454681	TP53) and accompanying copy neutral loss of heterozygosity.	('loss of', 'NegReg', (36, 43))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('copy neutral', 'Var', (23, 35))
197659	24454681	Recent studies have found that the total copy number abnormality (CNA) burden correlates with other measures of chromosomal instability in breast cancer cell lines and is associated with poor prognosis in chronic lymphocytic leukemia and melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('melanoma', 'Disease', (238, 246))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('copy', 'Var', (41, 45))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (205, 233))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (205, 233))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('leukemia', 'Phenotype', 'HP:0001909', (225, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('chromosomal instability', 'Phenotype', 'HP:0040012', (112, 135))	('chronic lymphocytic leukemia', 'Disease', (205, 233))
197706	24454681	Regions of CNA are more likely to be biologically significant when they show extreme copy number change and are identified in multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('multiple tumors', 'Disease', (126, 141))	('multiple tumors', 'Disease', 'MESH:D009369', (126, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('copy number change', 'Var', (85, 103))
197707	24454681	Our results are validated by the fact that a large number of the targets of gain and loss have been previously reported in at least one of three large studies of chromosomal copy number changes in gastric and esophageal adenocarcinoma that examined over 100 tumors using hybridization array platforms.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('changes', 'Var', (186, 193))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('gain', 'PosReg', (76, 80))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('esophageal adenocarcinoma', 'Disease', (209, 234))	('loss', 'NegReg', (85, 89))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (209, 234))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (209, 234))
197708	24454681	We also report several novel targeted gains involving ERBB4, PDGFRA, CDH6 and PTPN11 (Table S3) and focal regions of copy loss overlapping MAML2, JAK2 and ERG (Table S4).	('ERG', 'Gene', '2078', (155, 158))	('PTPN11', 'Gene', (78, 84))	('ERBB4', 'Gene', (54, 59))	('ERG', 'Gene', (155, 158))	('copy', 'Var', (117, 121))	('CDH6', 'Gene', (69, 73))	('CDH6', 'Gene', '1004', (69, 73))	('MAML2', 'Gene', (139, 144))	('JAK2', 'Gene', '3717', (146, 150))	('PDGFRA', 'Gene', '5156', (61, 67))	('PDGFRA', 'Gene', (61, 67))	('PTPN11', 'Gene', '5781', (78, 84))	('MAML2', 'Gene', '84441', (139, 144))	('gains', 'PosReg', (38, 43))	('JAK2', 'Gene', (146, 150))	('ERBB4', 'Gene', '2066', (54, 59))
197712	24454681	In our cases, copy gain in HER2, EGFR and MET receptor tyrosine kinases (Table 2) were generally mutually exclusive.	('EGFR', 'Gene', '1956', (33, 37))	('copy', 'Var', (14, 18))	('EGFR', 'Gene', (33, 37))	('HER2', 'Gene', (27, 31))	('MET receptor tyrosine kinases', 'Enzyme', (42, 71))	('HER2', 'Gene', '2064', (27, 31))
197713	24454681	However, in one case we detected co-amplification of HER2 and EGFR and in one other case there was co-amplification of HER2 and MET.	('EGFR', 'Gene', '1956', (62, 66))	('co-amplification', 'Var', (33, 49))	('HER2', 'Gene', (119, 123))	('EGFR', 'Gene', (62, 66))	('HER2', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (119, 123))	('HER2', 'Gene', '2064', (53, 57))
197717	24454681	Overall, 18/41 (43.9%) cases had copy gain of at least one kinase (HER2, EGFR, MET and KRAS) capable of activating downstream MAP kinase signal transduction.	('KRAS', 'Gene', (87, 91))	('copy', 'Var', (33, 37))	('EGFR', 'Gene', '1956', (73, 77))	('KRAS', 'Gene', '3845', (87, 91))	('EGFR', 'Gene', (73, 77))	('MET', 'Gene', (79, 82))	('HER2', 'Gene', (67, 71))	('HER2', 'Gene', '2064', (67, 71))
197722	24454681	RUNX1 is a transcription factor with frequent inactivating mutations in myeloid leukemia.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (72, 88))	('myeloid leukemia', 'Disease', (72, 88))	('inactivating mutations', 'Var', (46, 68))	('RUNX1', 'Gene', (0, 5))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('myeloid leukemia', 'Disease', 'MESH:D007951', (72, 88))	('RUNX1', 'Gene', '861', (0, 5))
197723	24454681	Cell cycle deregulation appears to be a dominant theme in the pattern of recurrent CNAs in superficial EAC, including recurrent amplification of CCND1, CCNE1 and CDK6 and frequent deletion of CDKN2A.	('CCND1', 'Gene', (145, 150))	('CDK6', 'Gene', '1021', (162, 166))	('deletion', 'Var', (180, 188))	('EAC', 'Gene', (103, 106))	('amplification', 'Var', (128, 141))	('CNAs', 'Disease', (83, 87))	('CCND1', 'Gene', '595', (145, 150))	('CDKN2A', 'Gene', '1029', (192, 198))	('Cell cycle', 'CPA', (0, 10))	('CDKN2A', 'Gene', (192, 198))	('CDK6', 'Gene', (162, 166))	('CCNE1', 'Gene', '898', (152, 157))	('CCNE1', 'Gene', (152, 157))	('EAC', 'Gene', '1540', (103, 106))
197724	24454681	Inactivation of genes known to play a role in sensing and responding to DNA damage is another recurrent theme in superficial EAC.	('EAC', 'Gene', '1540', (125, 128))	('EAC', 'Gene', (125, 128))	('genes', 'Gene', (16, 21))	('Inactivation', 'Var', (0, 12))
197725	24454681	Deletion of FHIT was the most common CNA detected (involving 23/41 cases).	('FHIT', 'Gene', (12, 16))	('FHIT', 'Gene', '2272', (12, 16))	('Deletion', 'Var', (0, 8))
197726	24454681	Loss of FHIT, a tumor suppressor that functions as a sensor of genotoxic stress, may confer resistance to and permit accumulation of DNA damage.	('FHIT', 'Gene', (8, 12))	('FHIT', 'Gene', '2272', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('permit', 'PosReg', (110, 116))	('accumulation of DNA damage', 'MPA', (117, 143))	('tumor', 'Disease', (16, 21))	('resistance to and', 'MPA', (92, 109))	('Loss', 'Var', (0, 4))
197730	24454681	Although mutations in TP53 are among the most common mutations in esophageal adenocarcinoma based on whole exome sequencing, copy number abnormalities involving TP53 were not observed in our cases, a fact that has been previously noted in other reports.	('TP53', 'Gene', (161, 165))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (66, 91))	('mutations', 'Var', (9, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('common', 'Reg', (46, 52))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', '7157', (161, 165))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (66, 91))	('copy number abnormalities', 'Disease', 'MESH:D007674', (125, 150))	('TP53', 'Gene', (22, 26))	('copy number abnormalities', 'Disease', (125, 150))	('esophageal adenocarcinoma', 'Disease', (66, 91))
197733	24454681	There was a significant correlation between copy number by SNP array and EGFR/CEP7 as well as EGFR/nucleus ratios by FISH (Pearson's r = 0.926 and 0.861 respectively, p-value<0.001 for both).	('copy', 'Var', (44, 48))	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (73, 77))	('EGFR', 'Gene', (94, 98))
197743	24454681	The frequency of CNAs ranged from 11 to 433 per tumor (Figure 2) with a median of 82 (IQR, 46-139), indicating a wide variation in genomic complexity in superficial gastroesophageal adenocarcinoma.	('superficial gastroesophageal adenocarcinoma', 'Disease', (153, 196))	('superficial gastroesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (153, 196))	('tumor', 'Disease', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('CNAs', 'Var', (17, 21))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (171, 196))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
197747	24454681	We also evaluated whether total CNA count was associated with chromosome 8 or chromosome 7 copy number (based on centromeric FISH) as an independent, but indirect assessment of tumor ploidy.	('tumor ploidy', 'Disease', (177, 189))	('chromosome', 'Var', (78, 88))	('tumor ploidy', 'Disease', 'MESH:D009369', (177, 189))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))
197750	24454681	FHIT and WWOX genes play a role in regulating response to DNA damage and mutations in these two genes might be more common in tumors with elevated CNA counts.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('WWOX', 'Gene', '51741', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('WWOX', 'Gene', (9, 13))	('common', 'Reg', (116, 122))	('FHIT', 'Gene', (0, 4))	('FHIT', 'Gene', '2272', (0, 4))	('CNA counts', 'MPA', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (73, 82))	('response to DNA damage', 'MPA', (46, 68))
197753	24454681	Similarly, the mean CNA count among cases with FHIT mutation or WWOX mutation was not significantly different from cases lacking these mutations (data not shown, Mann-Whitney U Test p>0.05 for both).	('FHIT', 'Gene', (47, 51))	('WWOX', 'Gene', '51741', (64, 68))	('FHIT', 'Gene', '2272', (47, 51))	('WWOX', 'Gene', (64, 68))	('mutation', 'Var', (69, 77))	('CNA count', 'CPA', (20, 29))
197758	24454681	The Kaplan-Meier survival curves reveal that patients with tumors characterized by intermediate CNA count had significantly worse overall survival outcomes than those falling into the highest or lowest quartiles (p-value = 0.032, Figure 4A).	('overall survival outcomes', 'MPA', (130, 155))	('intermediate CNA', 'Var', (83, 99))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('worse', 'NegReg', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('patients', 'Species', '9606', (45, 53))	('falling', 'Phenotype', 'HP:0002527', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
197764	24454681	Although the spectrum of sequence-level and chromosome-level mutations that contribute to the pathogenesis of EAC are increasingly well characterized, no previous study has explored the clinical significance of chromosomal instability in detail.	('chromosomal instability', 'Phenotype', 'HP:0040012', (211, 234))	('EAC', 'Gene', (110, 113))	('EAC', 'Gene', '1540', (110, 113))	('mutations', 'Var', (61, 70))
197773	24454681	In our analysis of segmental variation in copy number, we did not evaluate tumor ploidy, per se.	('copy', 'Var', (42, 46))	('tumor ploidy', 'Disease', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor ploidy', 'Disease', 'MESH:D009369', (75, 87))
197777	24454681	Chromosomal instability and aneuploidy are most often associated with poor prognosis in cancer, a generalization that is true for multiple cancer types.	('aneuploidy', 'Disease', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (88, 94))	('multiple cancer', 'Disease', (130, 145))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('poor', 'Disease', (70, 74))	('aneuploidy', 'Disease', 'MESH:D000782', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('multiple cancer', 'Disease', 'MESH:D009369', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('Chromosomal instability', 'Var', (0, 23))	('associated', 'Reg', (54, 64))	('cancer', 'Disease', (139, 145))
197778	24454681	One recent study using the CIN70 index to measure chromosomal instability, found a paradoxical relationship between CIN70 scores and survival in estrogen receptor negative breast cancer, ovarian cancer, squamous carcinoma of the lung and gastric adenocarcinoma.	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (203, 221))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (238, 260))	('ovarian cancer', 'Disease', (187, 201))	('squamous carcinoma of the lung', 'Disease', (203, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (212, 233))	('CIN70', 'Gene', (116, 121))	('scores', 'Var', (122, 128))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('squamous carcinoma of the lung', 'Phenotype', 'HP:0030359', (203, 233))	('breast cancer', 'Disease', (172, 185))	('gastric adenocarcinoma', 'Disease', (238, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('squamous carcinoma of the lung', 'Disease', 'MESH:D002294', (203, 233))	('chromosomal instability', 'Phenotype', 'HP:0040012', (50, 73))
197779	24454681	Tumors with the highest quartile CIN70 score had significantly better prognosis than tumors in all three other quartiles.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('CIN70 score', 'Var', (33, 44))	('Tumors', 'Disease', (0, 6))	('prognosis', 'MPA', (70, 79))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('better', 'PosReg', (63, 69))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
197786	24454681	On one hand, chromosomal instability has been shown to facilitate the acquisition of drug resistance in tumor cells.	('chromosomal instability', 'Var', (13, 36))	('acquisition of drug resistance in', 'MPA', (70, 103))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('chromosomal instability', 'Phenotype', 'HP:0040012', (13, 36))	('facilitate', 'PosReg', (55, 65))	('tumor', 'Disease', (104, 109))	('drug resistance', 'Phenotype', 'HP:0020174', (85, 100))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
197787	24454681	On the other hand, experimentally induced chromosomal instability has been shown to sensitize tumor cells to taxol, an anti-mitotic drug that inhibits microtubule formation.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('chromosomal instability', 'Var', (42, 65))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('chromosomal instability', 'Phenotype', 'HP:0040012', (42, 65))	('sensitize', 'Reg', (84, 93))	('microtubule', 'MPA', (151, 162))	('tumor', 'Disease', (94, 99))	('taxol', 'Chemical', 'MESH:D017239', (109, 114))
197793	24454681	Amplification of FGFR2 has been reported to occur in 5-10% of gastric and esophageal adenocarcinomas by SNP array analysis, but we did not see evidence of copy number gain in our cohort.	('FGFR2', 'Gene', (17, 22))	('FGFR2', 'Gene', '2263', (17, 22))	('Amplification', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('esophageal adenocarcinomas', 'Disease', (74, 100))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (74, 99))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (74, 100))
197797	24454681	Although deletion events affecting WWOX and FHIT were marginally more common in tumors with intermediate or high CNA counts (compared to low), the differences were not statistically significant across all three groups.	('WWOX', 'Gene', '51741', (35, 39))	('WWOX', 'Gene', (35, 39))	('FHIT', 'Gene', (44, 48))	('deletion', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CNA counts', 'MPA', (113, 123))	('FHIT', 'Gene', '2272', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('high', 'Var', (108, 112))
197798	24454681	Hence, we cannot suggest a causal role for these fragile site deletions in the overall level of segmental aneuploidy.	('deletions', 'Var', (62, 71))	('segmental aneuploidy', 'Disease', (96, 116))	('segmental aneuploidy', 'Disease', 'MESH:C537538', (96, 116))
197800	24454681	On a qualitative level, amplification events involving HER2 and EGFR were characteristically high copy number with variation in copy number throughout the amplified segment (as depicted in Figure 3).	('high copy number', 'Var', (93, 109))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('HER2', 'Gene', (55, 59))	('HER2', 'Gene', '2064', (55, 59))
197806	24454681	It is an intriguing candidate because PTPN11 is mutated in Noonan and LEOPARD syndromes and activating mutations have been implicated in the pathogenesis of leukemia while inactivating mutation promotes the development of hepatocellular carcinoma.	('promotes', 'PosReg', (194, 202))	('leukemia', 'Phenotype', 'HP:0001909', (157, 165))	('PTPN11', 'Gene', '5781', (38, 44))	('leukemia', 'Disease', 'MESH:D007938', (157, 165))	('leukemia', 'Disease', (157, 165))	('PTPN11', 'Gene', (38, 44))	('inactivating mutation', 'Var', (172, 193))	('LEOPARD', 'Species', '9691', (70, 77))	('implicated', 'Reg', (123, 133))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (222, 246))	('hepatocellular carcinoma', 'Disease', (222, 246))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (222, 246))	('LEOPARD syndromes', 'Disease', (70, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('Noonan', 'Disease', (59, 65))
197810	24454681	Supporting the validity of our data is the fact that we identified a large majority of recurrent copy gains and losses that have been previously identified in esophageal and gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (174, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('losses', 'NegReg', (112, 118))	('gastric cancer', 'Disease', (174, 188))	('esophageal', 'Disease', (159, 169))	('gastric cancer', 'Disease', 'MESH:D013274', (174, 188))	('copy gains', 'Var', (97, 107))
197836	30693974	Thus, in the presence of GTP/GDP TG2 flips closed and in the presence of calcium it flips open.	('calcium', 'Chemical', 'MESH:D002118', (73, 80))	('GTP', 'Chemical', 'MESH:D006160', (25, 28))	('flips', 'Reg', (84, 89))	('TG2', 'Gene', (33, 36))	('GTP/GDP', 'Var', (25, 32))	('flips', 'MPA', (37, 42))	('GDP', 'Chemical', 'MESH:D006153', (29, 32))
197857	30693974	2A) TG2 TGase activity appears to be important for this death response, as TG2 knockdown or treatment with BAPTA-AM (to chelate intracellular calcium) reduces apoptosis and cell death in response to photodynamic therapy.	('cell death', 'CPA', (173, 183))	('calcium', 'Chemical', 'MESH:D002118', (142, 149))	('reduces', 'NegReg', (151, 158))	('TG2', 'Gene', (75, 78))	('BAPTA-AM', 'Chemical', 'MESH:C070379', (107, 115))	('knockdown', 'Var', (79, 88))	('apoptosis', 'CPA', (159, 168))
197863	30693974	This suggests that TG2 inhibitors, which suppress GTP binding by indirectly disordering the TG2 GTP binding site, may be a useful treatment for gastric cancer.	('GTP binding site', 'MPA', (96, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (144, 158))	('disordering', 'NegReg', (76, 87))	('inhibitors', 'Var', (23, 33))	('GTP', 'Protein', (50, 53))	('GTP', 'Chemical', 'MESH:D006160', (96, 99))	('TG2', 'Gene', (19, 22))	('TG2', 'Gene', (92, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (144, 158))	('gastric cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('suppress', 'NegReg', (41, 49))	('GTP', 'Chemical', 'MESH:D006160', (50, 53))
197865	30693974	TG1 expression is increased in patient tumors and in cultured gastric cancer cells, and TG1 knockdown inhibits cell proliferation, enhances apoptosis and increases gastric cancer cell susceptibility to chemotherapeutic agents.	('TG1', 'Gene', (0, 3))	('enhances', 'PosReg', (131, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('knockdown', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('gastric cancer', 'Disease', (62, 76))	('tumors', 'Disease', (39, 45))	('inhibits', 'NegReg', (102, 110))	('increases gastric cancer', 'Disease', 'MESH:D013274', (154, 178))	('apoptosis', 'CPA', (140, 149))	('cell proliferation', 'CPA', (111, 129))	('patient', 'Species', '9606', (31, 38))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('increased', 'PosReg', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('rat', 'Species', '10116', (123, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('increases gastric cancer', 'Phenotype', 'HP:0006753', (154, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('increases gastric cancer', 'Disease', (154, 178))	('TG1', 'Gene', (88, 91))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
197870	30693974	TG3 may have a tumor suppressor role in oral cancer, as proteomic analysis reveals a marked reduction in TG3 levels in oral cancer samples due to hypermethylation of the TG3 gene locus.	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('hypermethylation', 'Var', (146, 162))	('reduction', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TG3 levels', 'MPA', (105, 115))	('TG3', 'Gene', (170, 173))	('tumor', 'Disease', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
197871	30693974	TG3 TGase activity is involved in crosslinking precursor structural proteins to facilitate terminal cell differentiation in stratified epithelia, and so loss of TG3 would be consistent with reduced cell differentiation during cancer progression.	('terminal cell differentiation', 'CPA', (91, 120))	('TG3', 'Gene', (0, 3))	('facilitate', 'PosReg', (80, 90))	('loss', 'Var', (153, 157))	('reduced', 'NegReg', (190, 197))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cell differentiation', 'CPA', (198, 218))	('rat', 'Species', '10116', (126, 129))	('TG3', 'Gene', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
197882	30693974	The authors propose that TG2 forms a complex with keratin 19 and src and that TGase activity modifies keratin 19 to activate src signaling and enhance cancer cell survival (Fig.	('activate', 'PosReg', (116, 124))	('modifies', 'Var', (93, 101))	('enhance', 'PosReg', (143, 150))	('src', 'Gene', (125, 128))	('keratin 19', 'Gene', (50, 60))	('src', 'Gene', '6714', (65, 68))	('keratin 19', 'Gene', '3880', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('complex', 'Interaction', (37, 44))	('keratin 19', 'Gene', (102, 112))	('src', 'Gene', '6714', (125, 128))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('src', 'Gene', (65, 68))	('keratin 19', 'Gene', '3880', (50, 60))
197883	30693974	2B) Thus, it appears that TG2 TGase modification of K19 is necessary to form a scaffold that activates Src signaling.	('modification', 'Var', (36, 48))	('activates', 'PosReg', (93, 102))	('Src', 'Gene', (103, 106))	('Src', 'Gene', '6714', (103, 106))	('K19', 'Gene', '3880', (52, 55))	('K19', 'Gene', (52, 55))
197886	30693974	TG2 knockdown sensitizes cells to docetaxel.	('sensitizes', 'Reg', (14, 24))	('knockdown', 'Var', (4, 13))	('docetaxel', 'Chemical', 'MESH:D000077143', (34, 43))	('TG2', 'Gene', (0, 3))
197887	30693974	TG2 level is increased in breast cancer cells following treatment with rapamycin, an mTOR (mechanistic target of rapamycin complex 1) inhibitor and TG2 knockdown renders these cells hypersensitive to rapamycin.	('breast cancer', 'Disease', (26, 39))	('knockdown', 'Var', (152, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('TG2', 'Gene', (148, 151))	('rapamycin', 'Chemical', 'MESH:D020123', (200, 209))	('rapamycin', 'Chemical', 'MESH:D020123', (71, 80))	('TG2 level', 'MPA', (0, 9))	('rapamycin', 'Chemical', 'MESH:D020123', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mTOR', 'Gene', '2475', (85, 89))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('mTOR', 'Gene', (85, 89))	('increased', 'PosReg', (13, 22))	('hypersensitive', 'PosReg', (182, 196))
197889	30693974	TG2 knockdown also restores breast cancer cell sensitivity to doxorubicin.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('restores', 'PosReg', (19, 27))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('sensitivity to doxorubicin', 'MPA', (47, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('doxorubicin', 'Chemical', 'MESH:D004317', (62, 73))	('breast cancer', 'Disease', (28, 41))	('TG2', 'Gene', (0, 3))	('knockdown', 'Var', (4, 13))
197896	30693974	Both wild-type TG2 and TGase activity-inactive TG2 mutants stimulate NFkappaB leading to HIF-1alpha induction, suggesting that the regulation requires the TG2 GTP-binding domain.	('mutants', 'Var', (51, 58))	('HIF-1alpha', 'Gene', '3091', (89, 99))	('stimulate', 'PosReg', (59, 68))	('TG2', 'Gene', (47, 50))	('NFkappaB', 'Gene', (69, 77))	('GTP', 'Chemical', 'MESH:D006160', (159, 162))	('induction', 'MPA', (100, 109))	('NFkappaB', 'Gene', '4790', (69, 77))	('HIF-1alpha', 'Gene', (89, 99))
197900	30693974	Covalent modification of TG2 can also influence TG2 regulation of NFkappaB.	('TG2 regulation', 'MPA', (48, 62))	('influence', 'Reg', (38, 47))	('TG2', 'Gene', (25, 28))	('NFkappaB', 'Gene', (66, 74))	('NFkappaB', 'Gene', '4790', (66, 74))	('Covalent modification', 'Var', (0, 21))
197901	30693974	For example, protein kinase A phosphorylation of TG2 at serine-216 precedes NFkappaB activation and PTEN downregulation in MCF-7 and T47D cells (Fig.	('PTEN', 'Gene', (100, 104))	('NFkappaB', 'Gene', '4790', (76, 84))	('phosphorylation', 'MPA', (30, 45))	('PTEN', 'Gene', '5728', (100, 104))	('MCF-7', 'CellLine', 'CVCL:0031', (123, 128))	('downregulation', 'NegReg', (105, 119))	('serine', 'Chemical', 'MESH:D012694', (56, 62))	('protein kinase A', 'Enzyme', (13, 29))	('activation', 'PosReg', (85, 95))	('serine-216', 'Var', (56, 66))	('TG2', 'Gene', (49, 52))	('NFkappaB', 'Gene', (76, 84))	('T47D', 'CellLine', 'CVCL:0553', (133, 137))
197903	30693974	Moreover, IL-1beta induces IL-6 production in TG2 overexpressing MCF-7 cells via a mechanism that requires NFkappaB, PI3K and JNK, and leads to enhanced stemness, invasion, survival, and tumor growth, while suppressing IL-6 or IL-1beta production attenuates these events.	('TG2', 'Gene', (46, 49))	('IL-1beta', 'Gene', '3552', (10, 18))	('tumor', 'Disease', (187, 192))	('NFkappaB', 'Gene', '4790', (107, 115))	('invasion', 'CPA', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('enhanced', 'PosReg', (144, 152))	('JNK', 'Gene', (126, 129))	('NFkappaB', 'Gene', (107, 115))	('IL-1beta', 'Gene', (227, 235))	('IL-6', 'Gene', (27, 31))	('survival', 'CPA', (173, 181))	('JNK', 'Gene', '5599', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('IL-1beta', 'Gene', (10, 18))	('MCF-7', 'CellLine', 'CVCL:0031', (65, 70))	('IL-1beta', 'Gene', '3552', (227, 235))	('PI3K', 'Var', (117, 121))	('stemness', 'CPA', (153, 161))
197913	30693974	Treatment of cells with recombinant wild-type TG2 induced non-canonical NFkappaB signaling, but this was not observed with recombinant TG2(C277A), a TGase activity-inactive TG2 mutant, suggesting that TG2 TGase activity is required for malignant spread.	('NFkappaB', 'Gene', (72, 80))	('C277A', 'Var', (139, 144))	('C277A', 'Mutation', 'c.277C>A', (139, 144))	('NFkappaB', 'Gene', '4790', (72, 80))
197916	30693974	These events require interaction of TG2 with fibronectin, as inhibiting the TG2/fibronectin interaction reduces stability of the TGFbeta/fibronectin/TG2 complex to reduce adhesion and biological response.	('stability', 'MPA', (112, 121))	('fibronectin', 'Gene', (45, 56))	('fibronectin', 'Gene', (80, 91))	('TGFbeta', 'Gene', (129, 136))	('reduces', 'NegReg', (104, 111))	('reduce', 'NegReg', (164, 170))	('biological response', 'CPA', (184, 203))	('fibronectin', 'Gene', '2335', (137, 148))	('fibronectin', 'Gene', '2335', (45, 56))	('TGFbeta', 'Gene', '7039', (129, 136))	('fibronectin', 'Gene', '2335', (80, 91))	('inhibiting', 'Var', (61, 71))	('fibronectin', 'Gene', (137, 148))	('interaction', 'Interaction', (92, 103))	('adhesion', 'CPA', (171, 179))
197925	30693974	In A549 lung cancer cells, TG2 knockdown or pharmacologic suppression of JNK activity, reduces TGFbeta1-induced EMT, and additional studies suggest that TG2 activates JNK, via suppression of PP2A activity (Fig.	('JNK', 'Gene', (73, 76))	('TG2', 'Var', (153, 156))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('JNK', 'Gene', '5599', (73, 76))	('PP2A', 'Gene', '5524', (191, 195))	('suppression', 'NegReg', (176, 187))	('activates', 'PosReg', (157, 166))	('JNK', 'Gene', (167, 170))	('JNK', 'Gene', '5599', (167, 170))	('lung cancer', 'Disease', 'MESH:D008175', (8, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (8, 19))	('activity', 'MPA', (196, 204))	('TGFbeta1', 'Gene', '7040', (95, 103))	('PP2A', 'Gene', (191, 195))	('reduces', 'NegReg', (87, 94))	('suppression', 'NegReg', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TGFbeta1', 'Gene', (95, 103))	('lung cancer', 'Disease', (8, 19))	('knockdown', 'Var', (31, 40))
197926	30693974	TG2 also appears to influence drug sensitivity in these tumors, as treatment with TG2 inhibitor or TG2 knockdown restores TRAIL-induced apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TRAIL', 'Gene', (122, 127))	('restores', 'PosReg', (113, 121))	('TG2', 'Gene', (99, 102))	('tumors', 'Disease', (56, 62))	('influence', 'Reg', (20, 29))	('TRAIL', 'Gene', '8743', (122, 127))	('TG2', 'Gene', (82, 85))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('drug sensitivity', 'Phenotype', 'HP:0020174', (30, 46))	('drug sensitivity', 'MPA', (30, 46))	('knockdown', 'Var', (103, 112))
197928	30693974	Screening of the cancer genome atlas indicates a correlation between high TG2 expression and reduced overall patient survival.	('expression', 'MPA', (78, 88))	('patient', 'Species', '9606', (109, 116))	('reduced', 'NegReg', (93, 100))	('TG2', 'Gene', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('high', 'Var', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
197929	30693974	TG2 knockdown in pancreatic ductal adenocarcinoma cells reduces xenograft growth and enhances sensitivity to gemcitabine, and it has been suggested that TG2 released from pancreatic tumor cells activates fibroblasts in the tumor microenvironment to produce laminin which protects the cancer cells by constructing a dense desmoplastic stroma.	('desmoplastic stroma', 'Disease', 'MESH:D018220', (321, 340))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (17, 49))	('knockdown', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('sensitivity to gemcitabine', 'MPA', (94, 120))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (171, 187))	('pancreatic ductal adenocarcinoma', 'Disease', (17, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('xenograft growth', 'CPA', (64, 80))	('tumor', 'Disease', (223, 228))	('cancer', 'Disease', (284, 290))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (17, 49))	('reduces', 'NegReg', (56, 63))	('pancreatic tumor', 'Disease', (171, 187))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('gemcitabine', 'Chemical', 'MESH:C056507', (109, 120))	('pancreatic tumor', 'Disease', 'MESH:D010190', (171, 187))	('tumor', 'Disease', (182, 187))	('desmoplastic stroma', 'Disease', (321, 340))	('TG2', 'Gene', (153, 156))	('enhances', 'PosReg', (85, 93))	('TG2', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
197934	30693974	Moreover, knockdown of eEF2K reduces cell invasion and migration, and reduces TG2 mRNA and protein level.	('eEF2K', 'Gene', (23, 28))	('reduces', 'NegReg', (70, 77))	('eEF2K', 'Gene', '29904', (23, 28))	('rat', 'Species', '10116', (58, 61))	('reduces', 'NegReg', (29, 36))	('cell invasion', 'CPA', (37, 50))	('knockdown', 'Var', (10, 19))	('TG2', 'Protein', (78, 81))
197935	30693974	TG2 appears to have a role in regulating downstream signaling events, as knockdown of either eEF2K, or TG2, reduces Snail and ZEB1 level leading to reduced EMT (Fig.	('TG2', 'Gene', (103, 106))	('Snail', 'Gene', (116, 121))	('eEF2K', 'Gene', '29904', (93, 98))	('reduced', 'NegReg', (148, 155))	('Snail', 'Gene', '6615', (116, 121))	('EMT', 'CPA', (156, 159))	('reduces', 'NegReg', (108, 115))	('ZEB1', 'Gene', (126, 130))	('reduced EMT', 'Phenotype', 'HP:0032198', (148, 159))	('ZEB1', 'Gene', '6935', (126, 130))	('eEF2K', 'Gene', (93, 98))	('knockdown', 'Var', (73, 82))
197937	30693974	TG2 also regulates pancreatic cell morphology, since TG2 silencing reduces the 2-O-tetradecanoylphorbol-13-acetate dependent phosphorylation of keratin 8, and suppresses 2-O-tetradecanoylphorbol-13-acetate dependent keratin filament reorganization in PANC-1 cells.	('2-O-tetradecanoylphorbol-13-acetate', 'Chemical', '-', (79, 114))	('rat', 'Species', '10116', (146, 149))	('pancreatic', 'Disease', 'MESH:D010195', (19, 29))	('keratin 8', 'Gene', (144, 153))	('keratin 8', 'Gene', '3856', (144, 153))	('silencing', 'Var', (57, 66))	('TG2', 'Gene', (53, 56))	('PANC-1', 'CellLine', 'CVCL:0480', (251, 257))	('rat', 'Species', '10116', (218, 221))	('2-O-tetradecanoylphorbol-13-acetate', 'Chemical', '-', (170, 205))	('pancreatic', 'Disease', (19, 29))	('reduces', 'NegReg', (67, 74))	('regulates', 'Reg', (9, 18))	('suppresses', 'NegReg', (159, 169))
197939	30693974	TG2 is highly elevated in epidermal cancer stem cells (ECS cells) and TG2 knockdown or suppression of TG2 function with TG2 inhibitor (NC9) reduces ECS cell survival, spheroid formation, matrigel invasion, migration and EMT (Fig.	('NC9', 'Chemical', '-', (135, 138))	('TG2', 'Gene', (70, 73))	('function', 'MPA', (106, 114))	('migration', 'CPA', (206, 215))	('reduces', 'NegReg', (140, 147))	('suppression', 'NegReg', (87, 98))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('matrigel invasion', 'CPA', (187, 204))	('cancer', 'Disease', (36, 42))	('knockdown', 'Var', (74, 83))	('spheroid formation', 'CPA', (167, 185))	('rat', 'Species', '10116', (209, 212))	('TG2', 'Gene', (102, 105))	('TG2', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('elevated', 'PosReg', (14, 22))
197940	30693974	This reduction in stem cell phenotype is associated with activation of apoptosis, and TG2 mutant studies reveal that TG2 GTP-binding activity, but not TGase activity, is required to maintain the ECS cell phenotype (Fig.	('GTP-binding', 'Protein', (121, 132))	('TG2', 'Gene', (117, 120))	('mutant', 'Var', (90, 96))	('GTP', 'Chemical', 'MESH:D006160', (121, 124))	('activity', 'MPA', (133, 141))	('stem cell phenotype', 'CPA', (18, 37))	('TG2', 'Gene', (86, 89))	('ECS', 'Disease', (195, 198))
197942	30693974	In this cascade TG2 interacts with alpha6/beta4-integrin to stimulate FAK/Src signaling leading to PI3K activation of PDK1.	('PI3K', 'Var', (99, 103))	('alpha6/beta4', 'Gene', '28898', (35, 47))	('PDK1', 'Gene', (118, 122))	('activation', 'PosReg', (104, 114))	('Src', 'Gene', '6714', (74, 77))	('TG2', 'Gene', (16, 19))	('alpha6/beta4', 'Gene', (35, 47))	('stimulate', 'PosReg', (60, 69))	('FAK', 'Gene', '5747', (70, 73))	('interacts', 'Interaction', (20, 29))	('PDK1', 'Gene', '5163', (118, 122))	('Src', 'Gene', (74, 77))	('FAK', 'Gene', (70, 73))
197949	30693974	Studies using ECS cells establish the intracellular mechanism of action of several transglutaminase 2 inhibitors, including NC9, VA4, VA5 and CP4d (Fig.	('transglutaminase 2', 'Gene', (83, 101))	('transglutaminase 2', 'Gene', '7052', (83, 101))	('CP4d', 'Var', (142, 146))	('NC9', 'Chemical', '-', (124, 127))
197958	30693974	Treatment with TG2 inhibitors, KC009 or ERW1227B, sensitives cultured glioblastoma cells to chemotherapeutic agents, and enhances apoptosis in glioblastoma xenografts, and the GK921 TG2 inhibitor suppresses tumor cell transition to the mesenchymal phenotype.	('GK921', 'Var', (176, 181))	('ERW1227B', 'Var', (40, 48))	('TG2', 'Gene', (15, 18))	('GK921', 'Chemical', 'MESH:C000588709', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('glioblastoma', 'Disease', (70, 82))	('enhances', 'PosReg', (121, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('KC009', 'Var', (31, 36))	('KC009', 'Chemical', '-', (31, 36))	('apoptosis', 'CPA', (130, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('tumor', 'Disease', (207, 212))	('glioblastoma', 'Disease', (143, 155))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('TG2', 'Gene', (182, 185))	('suppresses', 'NegReg', (196, 206))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('ERW1227B', 'Chemical', 'MESH:C561342', (40, 48))
197965	30693974	Moreover, TG2 expression is dependent upon retinoic acid which is produced by aldehyde dehydrogenase 1A3 (ALDH1A3), suggesting that ALDH1A3, in glioblastoma stem cells, maintains TG2 level.	('retinoic acid', 'Chemical', 'MESH:D014212', (43, 56))	('TG2 level', 'MPA', (179, 188))	('maintains', 'PosReg', (169, 178))	('glioblastoma', 'Disease', (144, 156))	('ALDH1A3', 'Var', (132, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('aldehyde dehydrogenase 1A3', 'Gene', '56847', (78, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('aldehyde dehydrogenase 1A3', 'Gene', (78, 104))
197973	30693974	Another study reports a substantial increase in TG2 in hepatocellular carcinoma and shows that inhibition of TG2 in HepG2.2.15 or Hep3B cell suppresses cell proliferation, invasion and migration.	('Hep3B', 'CellLine', 'CVCL:0326', (130, 135))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (55, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('hepatocellular carcinoma', 'Disease', (55, 79))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (55, 79))	('inhibition', 'Var', (95, 105))	('increase', 'PosReg', (36, 44))	('TG2', 'Protein', (48, 51))	('TG2', 'Gene', (109, 112))	('rat', 'Species', '10116', (188, 191))	('rat', 'Species', '10116', (164, 167))	('suppresses', 'NegReg', (141, 151))	('cell proliferation', 'CPA', (152, 170))	('HepG2.2.15', 'CellLine', 'CVCL:L855', (116, 126))
197975	30693974	Acrylic retinoids inhibit post-surgery hepatocellular carcinoma recurrence via mechanisms that involve TG2 crosslinking of Sp1 transcription factor in the cell nucleus leading to loss of EGF receptor expression and cell apoptosis.	('EGF receptor', 'Gene', (187, 199))	('inhibit', 'NegReg', (18, 25))	('crosslinking', 'Var', (107, 119))	('cell apoptosis', 'CPA', (215, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('Acrylic retinoids', 'Chemical', '-', (0, 17))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('expression', 'MPA', (200, 210))	('EGF receptor', 'Gene', '1956', (187, 199))	('loss', 'NegReg', (179, 183))	('hepatocellular carcinoma', 'Disease', (39, 63))
197978	30693974	It is interesting that the miR-1285 microRNA regulates TG2 in renal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('renal cancer', 'Disease', (62, 74))	('miR-1285', 'Var', (27, 35))	('miR-1285', 'Chemical', '-', (27, 35))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('regulates', 'Reg', (45, 54))	('renal cancer', 'Disease', 'MESH:D007680', (62, 74))	('TG2', 'Gene', (55, 58))
197980	30693974	Moreover, silencing of TG2 or forced overexpression of miR-1285, reduce TG2 level and cell proliferation.	('miR-1285', 'Gene', (55, 63))	('TG2', 'Gene', (23, 26))	('rat', 'Species', '10116', (98, 101))	('cell proliferation', 'CPA', (86, 104))	('reduce', 'NegReg', (65, 71))	('TG2 level', 'MPA', (72, 81))	('miR-1285', 'Chemical', '-', (55, 63))	('silencing', 'Var', (10, 19))
197981	30693974	TG2 also regulates renal carcinoma cell survival, as TG2 knockdown leads to increased p53 level and enhanced apoptosis in 786-O, A498, CAKI-1 and ACHN cells.	('renal carcinoma', 'Disease', 'MESH:C538614', (19, 34))	('p53', 'Gene', '7157', (86, 89))	('increased', 'PosReg', (76, 85))	('renal carcinoma', 'Disease', (19, 34))	('apoptosis', 'CPA', (109, 118))	('enhanced', 'PosReg', (100, 108))	('knockdown', 'Var', (57, 66))	('TG2', 'Gene', (53, 56))	('renal carcinoma', 'Phenotype', 'HP:0005584', (19, 34))	('regulates', 'Reg', (9, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('p53', 'Gene', (86, 89))
197984	30693974	Moreover, treatment with GK921, a TG2 inhibitor, reduces ACHN and CAKI-1 renal carcinoma cell tumor growth in xenograft models.	('reduces', 'NegReg', (49, 56))	('renal carcinoma', 'Phenotype', 'HP:0005584', (73, 88))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GK921', 'Chemical', 'MESH:C000588709', (25, 30))	('ACHN', 'Protein', (57, 61))	('CAKI-1 renal carcinoma cell tumor', 'Disease', (66, 99))	('CAKI-1 renal carcinoma cell tumor', 'Disease', 'MESH:C538557', (66, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('GK921', 'Var', (25, 30))
197985	30693974	Glycolysis is enhanced in renal carcinoma cells and high TG2 level increases glucose consumption and lactate production, while decreasing mitochondrial aconitase level.	('mitochondrial aconitase', 'Gene', (138, 161))	('mitochondrial aconitase', 'Gene', '50', (138, 161))	('lactate', 'Chemical', 'MESH:D019344', (101, 108))	('renal carcinoma', 'Disease', (26, 41))	('enhanced', 'PosReg', (14, 22))	('renal carcinoma', 'Phenotype', 'HP:0005584', (26, 41))	('glucose', 'Chemical', 'MESH:D005947', (77, 84))	('lactate production', 'MPA', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('decreasing', 'NegReg', (127, 137))	('TG2', 'Gene', (57, 60))	('Glycolysis', 'MPA', (0, 10))	('high', 'Var', (52, 56))	('increases', 'PosReg', (67, 76))	('glucose consumption', 'MPA', (77, 96))	('renal carcinoma', 'Disease', 'MESH:C538614', (26, 41))
197986	30693974	The ubiquitination system also influences TG2 function, as TG2 level is reduced following modification by CHIP (carboxyl-terminus of hsp70-interacting protein), an E3 ubiquitin ligase, and CHIP knockdown is associated with elevated TG2 and aggressive cancer (Fig.	('aggressive cancer', 'Disease', (240, 257))	('reduced', 'NegReg', (72, 79))	('TG2', 'Gene', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('TG2 level', 'MPA', (59, 68))	('influences', 'Reg', (31, 41))	('ubiquitination', 'MPA', (4, 18))	('function', 'MPA', (46, 54))	('CHIP knockdown', 'Var', (189, 203))	('aggressive cancer', 'Disease', 'MESH:D009369', (240, 257))	('elevated', 'PosReg', (223, 231))	('modification', 'Var', (90, 102))
197989	30693974	Silencing of TG2 in renal carcinoma cells reduces actin stress fiber formation and adhesion to fibronectin, collagen type I and laminin, leading to impaired invasion and migration, and reduced cancer stem cell marker expression.	('actin', 'MPA', (50, 55))	('impaired', 'NegReg', (148, 156))	('cancer', 'Disease', (193, 199))	('fibronectin', 'Gene', (95, 106))	('TG2', 'Gene', (13, 16))	('laminin', 'Protein', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('Silencing', 'Var', (0, 9))	('reduced', 'NegReg', (185, 192))	('rat', 'Species', '10116', (173, 176))	('reduces', 'NegReg', (42, 49))	('renal carcinoma', 'Disease', 'MESH:C538614', (20, 35))	('renal carcinoma', 'Phenotype', 'HP:0005584', (20, 35))	('renal carcinoma', 'Disease', (20, 35))	('adhesion', 'CPA', (83, 91))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('fibronectin', 'Gene', '2335', (95, 106))	('invasion', 'CPA', (157, 165))
197995	30693974	TG4 has a role in prostate cancer cell survival, as it stimulates cell motility and N-cadherin expression, changes which are reversed by TG4 knockdown.	('N-cadherin', 'Gene', '1000', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TG4', 'Chemical', '-', (137, 140))	('prostate cancer', 'Disease', 'MESH:D011471', (18, 33))	('TG4', 'Chemical', '-', (0, 3))	('prostate cancer', 'Phenotype', 'HP:0012125', (18, 33))	('TG4', 'Var', (0, 3))	('cell motility', 'CPA', (66, 79))	('N-cadherin', 'Gene', (84, 94))	('stimulates', 'PosReg', (55, 65))	('prostate cancer', 'Disease', (18, 33))	('expression', 'MPA', (95, 105))
197997	30693974	In addition, prostate cancer cells are more motile following forced TG4 expression and this involves TG2 co-localization and interaction with RON, the hepatocyte growth factor-like/macrophage-stimulating protein receptor.	('RON', 'Gene', (142, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))	('more', 'PosReg', (39, 43))	('TG2', 'Gene', (101, 104))	('TG4', 'Chemical', '-', (68, 71))	('interaction', 'Interaction', (125, 136))	('RON', 'Gene', '4486', (142, 145))	('prostate cancer', 'Disease', (13, 28))	('TG4', 'Gene', (68, 71))	('forced', 'Var', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('expression', 'Var', (72, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (13, 28))	('co-localization', 'MPA', (105, 120))
198004	30693974	Consistent with a role of TG2 in meningioma cell survival, TG2 knockdown, or treatment with cystamine, induces meningioma cell death which is associated with reduced Akt signaling.	('meningioma', 'Disease', (33, 43))	('meningioma', 'Phenotype', 'HP:0002858', (33, 43))	('meningioma cell death', 'Disease', 'MESH:D003643', (111, 132))	('meningioma', 'Disease', 'MESH:D008577', (111, 121))	('cystamine', 'Chemical', 'MESH:D003538', (92, 101))	('Akt', 'Gene', '207', (166, 169))	('Akt', 'Gene', (166, 169))	('meningioma', 'Disease', 'MESH:D008577', (33, 43))	('meningioma cell death', 'Disease', (111, 132))	('induces', 'Reg', (103, 110))	('meningioma', 'Disease', (111, 121))	('TG2', 'Gene', (59, 62))	('knockdown', 'Var', (63, 72))	('meningioma', 'Phenotype', 'HP:0002858', (111, 121))
198011	30693974	It is interesting that inhibition of TG2 TGase activity, using calcium blockers, increases interaction of p65 with IkappaBalpha to reduce NFkappaB signaling and enhance mantle cell lymphoma cell sensitivity to bortezomib.	('IkappaBalpha', 'Gene', '4792', (115, 127))	('enhance', 'PosReg', (161, 168))	('NFkappaB', 'Gene', '4790', (138, 146))	('inhibition', 'Var', (23, 33))	('TG2', 'Gene', (37, 40))	('cell lymphoma', 'Phenotype', 'HP:0012191', (176, 189))	('p65', 'Gene', (106, 109))	('IkappaBalpha', 'Gene', (115, 127))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (169, 189))	('bortezomib', 'Chemical', 'MESH:D000069286', (210, 220))	('lymphoma', 'Phenotype', 'HP:0002665', (181, 189))	('mantle cell lymphoma', 'Disease', (169, 189))	('NFkappaB', 'Gene', (138, 146))	('interaction', 'Interaction', (91, 102))	('reduce', 'NegReg', (131, 137))	('p65', 'Gene', '5970', (106, 109))	('calcium', 'Chemical', 'MESH:D002118', (63, 70))	('increases', 'PosReg', (81, 90))
198019	30693974	The pro-cancer action of TG2 appears to require TG2 TGase activity, as expression of wild-type TG2, but not TGase inactive TG2, restores tumor formation in TG2 knockdown MC-1 cells.	('cancer', 'Disease', (8, 14))	('tumor', 'Disease', (137, 142))	('MC-1', 'CellLine', 'CVCL:H810', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('restores', 'PosReg', (128, 136))	('TG2', 'Var', (95, 98))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
198027	30693974	This increase is linked to increased TG2 gene copy number, and TG2 levels are further increased in chemotherapy and radiation-resistant cancer cells.	('copy number', 'Var', (46, 57))	('radiation-resistant cancer', 'Disease', (116, 142))	('TG2', 'MPA', (63, 66))	('increased', 'PosReg', (86, 95))	('increased', 'PosReg', (27, 36))	('TG2', 'Gene', (37, 40))	('radiation-resistant cancer', 'Disease', 'MESH:D009369', (116, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
198035	30693974	In this context, TG2 protects cells from apoptosis by suppressing Bax level and reducing cytochrome c release, and these protective actions are attenuated by TG2 knockdown; however, it is not known if the TG2 TGase activity mediates the change in intracellular distribution of Bax and cytochrome c. Elevated TG2 expression is also associated with osteosarcoma cell cisplatin resistance and TG2 knockdown restores chemosensitivity.	('Bax', 'Gene', '581', (66, 69))	('suppressing', 'NegReg', (54, 65))	('osteosarcoma', 'Disease', (347, 359))	('TG2', 'Gene', (308, 311))	('osteosarcoma', 'Disease', 'MESH:D012516', (347, 359))	('knockdown', 'Var', (394, 403))	('chemosensitivity', 'MPA', (413, 429))	('cytochrome c', 'Gene', '54205', (89, 101))	('expression', 'MPA', (312, 322))	('cytochrome c', 'Gene', '54205', (285, 297))	('cisplatin', 'Chemical', 'MESH:D002945', (365, 374))	('Elevated', 'PosReg', (299, 307))	('Bax', 'Gene', (277, 280))	('osteosarcoma', 'Phenotype', 'HP:0002669', (347, 359))	('cytochrome c', 'Gene', (89, 101))	('associated', 'Reg', (331, 341))	('Bax', 'Gene', '581', (277, 280))	('cytochrome c', 'Gene', (285, 297))	('restores', 'PosReg', (404, 412))	('TG2', 'Gene', (390, 393))	('sarcoma', 'Phenotype', 'HP:0100242', (352, 359))	('Bax', 'Gene', (66, 69))
198040	30693974	TG2 appears to act with oncostatin M receptor to drive tumor cell invasion and migration, and TG2 knockdown attenuates these actions (Fig.	('oncostatin M', 'Gene', '5008', (24, 36))	('oncostatin M', 'Gene', (24, 36))	('TG2', 'Gene', (94, 97))	('migration', 'CPA', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('knockdown', 'Var', (98, 107))	('tumor', 'Disease', (55, 60))	('attenuates', 'NegReg', (108, 118))	('rat', 'Species', '10116', (82, 85))	('drive', 'PosReg', (49, 54))
198045	30693974	TG6 may also have a role in leukemia, as whole exome sequencing revealed a missense mutation in the TG6 gene which co-segregated with the cancer phenotype in a family, but was absent in healthy control patients.	('TG6', 'Gene', (100, 103))	('cancer', 'Disease', (138, 144))	('leukemia', 'Disease', (28, 36))	('leukemia', 'Phenotype', 'HP:0001909', (28, 36))	('leukemia', 'Disease', 'MESH:D007938', (28, 36))	('patients', 'Species', '9606', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('missense mutation', 'Var', (75, 92))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
198048	30693974	Moreover, TG2 knockdown in HT-1080 cells suppresses invasion and migration, and this is associated with reduced NFkappaB, MMP-2 and MMP-9 level and activity.	('MMP-2', 'Gene', (122, 127))	('reduced', 'NegReg', (104, 111))	('NFkappaB', 'Gene', (112, 120))	('HT-1080', 'CellLine', 'CVCL:0317', (27, 34))	('NFkappaB', 'Gene', '4790', (112, 120))	('activity', 'MPA', (148, 156))	('MMP-9', 'Gene', '4318', (132, 137))	('rat', 'Species', '10116', (68, 71))	('MMP-2', 'Gene', '4313', (122, 127))	('suppresses', 'NegReg', (41, 51))	('MMP-9', 'Gene', (132, 137))	('knockdown', 'Var', (14, 23))	('TG2', 'Gene', (10, 13))
198051	30693974	Interestingly, knockdown of TG2 is associated with reduced beta1-integrin interaction with fibronectin and reduced secretion of MMP-9 and MMP-1 (Fig.	('beta1-integrin', 'Gene', '3688', (59, 73))	('fibronectin', 'Gene', '2335', (91, 102))	('reduced', 'NegReg', (51, 58))	('knockdown', 'Var', (15, 24))	('beta1-integrin', 'Gene', (59, 73))	('MMP-1', 'Gene', '4312', (138, 143))	('MMP-9', 'Gene', '4318', (128, 133))	('reduced', 'NegReg', (107, 114))	('MMP-9', 'Gene', (128, 133))	('MMP-1', 'Gene', (138, 143))	('interaction with', 'Interaction', (74, 90))	('fibronectin', 'Gene', (91, 102))	('TG2', 'Gene', (28, 31))
198055	30693974	Analysis of laryngeal squamous cell carcinoma tumors isolated from 148 patients showed that high TG2 expression is associated with reduced survival in patients receiving postoperative radiotherapy, suggesting that TG2 has a role in cancer survival.	('TG2', 'Gene', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('high', 'Var', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('rat', 'Species', '10116', (177, 180))	('cancer', 'Disease', (232, 238))	('patients', 'Species', '9606', (71, 79))	('survival', 'MPA', (139, 147))	('patients', 'Species', '9606', (151, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('reduced', 'NegReg', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('squamous cell carcinoma tumors', 'Disease', 'MESH:D002294', (22, 52))	('expression', 'MPA', (101, 111))	('squamous cell carcinoma tumors', 'Disease', (22, 52))
198061	30693974	TG2 knockdown or treatment with a TG2 inhibitor, in hypoxia-challenged cells, reduces cancer stem cell viability.	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TG2', 'Gene', (0, 3))	('TG2', 'Gene', (34, 37))	('hypoxia', 'Disease', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('knockdown', 'Var', (4, 13))	('reduces', 'NegReg', (78, 85))	('cancer', 'Disease', (86, 92))
198062	30693974	Moreover, TG2 is highly expressed in mesothelioma cancer stem cells and knockdown results in reduced spheroid formation, matrigel invasion, migration and tumor formation (Fig.	('tumor', 'Disease', (154, 159))	('mesothelioma cancer', 'Disease', (37, 56))	('spheroid formation', 'CPA', (101, 119))	('reduced', 'NegReg', (93, 100))	('mesothelioma cancer', 'Phenotype', 'HP:0100001', (37, 56))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('rat', 'Species', '10116', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mesothelioma cancer', 'Disease', 'MESH:D009369', (37, 56))	('TG2', 'Gene', (10, 13))	('migration', 'CPA', (140, 149))	('knockdown', 'Var', (72, 81))	('matrigel invasion', 'CPA', (121, 138))
198063	30693974	In xenograft mesothelioma tumor models, time to tumor first appearance is doubled from nine weeks for wild-type cells, to eighteen weeks for TG2 knockout cells.	('knockout', 'Var', (145, 153))	('tumor', 'Disease', (48, 53))	('mesothelioma tumor', 'Disease', (13, 31))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (13, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('time', 'MPA', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (13, 31))	('tumor', 'Disease', (26, 31))	('TG2', 'Gene', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
198067	30693974	Moreover, TG2 level is markedly elevated in cultured human colon cancer stem cells, and knockdown reduces cell proliferation, invasion, EMT, and stem cell marker (CD133, SOX2, and beta-catenin) expression.	('cell proliferation', 'CPA', (106, 124))	('SOX2', 'Gene', (170, 174))	('SOX2', 'Gene', '6657', (170, 174))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('reduces', 'NegReg', (98, 105))	('rat', 'Species', '10116', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('stem cell', 'CPA', (145, 154))	('colon cancer', 'Disease', (59, 71))	('elevated', 'PosReg', (32, 40))	('beta-catenin', 'Gene', (180, 192))	('knockdown', 'Var', (88, 97))	('TG2 level', 'MPA', (10, 19))	('beta-catenin', 'Gene', '1499', (180, 192))	('human', 'Species', '9606', (53, 58))	('CD133', 'Gene', (163, 168))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('invasion', 'CPA', (126, 134))	('CD133', 'Gene', '8842', (163, 168))	('expression', 'MPA', (194, 204))	('EMT', 'CPA', (136, 139))
198072	30693974	TG2 knockdown in SW480 cells, a modestly aggressive colon cancer cell type, increases invasive behavior in a matrigel invasion assay.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('SW480', 'CellLine', 'CVCL:0546', (17, 22))	('increases', 'PosReg', (76, 85))	('aggressive colon cancer', 'Disease', 'MESH:D015179', (41, 64))	('aggressive colon cancer', 'Disease', (41, 64))	('TG2', 'Gene', (0, 3))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('knockdown', 'Var', (4, 13))	('invasive behavior in a matrigel invasion assay', 'CPA', (86, 132))
198082	30693974	In renal cell carcinoma, cancer cell survival is increased due to TGase modification and inactivation of p53.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('inactivation', 'Var', (89, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('increased', 'PosReg', (49, 58))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('renal cell carcinoma', 'Disease', (3, 23))	('TGase', 'Protein', (66, 71))	('cancer', 'Disease', (25, 31))	('modification', 'Var', (72, 84))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))
198083	30693974	Thus, both GTP-bound/signaling-active and calcium-bound/transamidase-active TG2 conformations have been reported to enhance cancer cell survival.	('cancer', 'Disease', (124, 130))	('TG2', 'Gene', (76, 79))	('enhance', 'PosReg', (116, 123))	('GTP', 'Chemical', 'MESH:D006160', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('conformations', 'Var', (80, 93))	('calcium', 'Chemical', 'MESH:D002118', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
198089	30693974	The first involves expression of TG2 GTP binding-deficient or TGase activity-deficient mutants in cells and assessing the impact on the cancer cell phenotype.	('TGase', 'Gene', (62, 67))	('mutants', 'Var', (87, 94))	('GTP', 'Protein', (37, 40))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('TG2', 'Gene', (33, 36))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('GTP', 'Chemical', 'MESH:D006160', (37, 40))
198100	30693974	In addition, high level expression of TG2 or treating cells with stress agents, that compromise plasma and endoplasmic reticulum membranes to increase intracellular calcium, cause massive activation of the open/extended transamidase-active form leading to crosslinking activation and cell death.	('increase', 'PosReg', (142, 150))	('crosslinking', 'MPA', (256, 268))	('intracellular calcium', 'MPA', (151, 172))	('cell death', 'CPA', (284, 294))	('open/extended transamidase-active form', 'Enzyme', (206, 244))	('increase intracellular calcium', 'Phenotype', 'HP:0003575', (142, 172))	('activation', 'PosReg', (188, 198))	('expression', 'Var', (24, 34))	('TG2', 'Gene', (38, 41))	('calcium', 'Chemical', 'MESH:D002118', (165, 172))	('activation', 'PosReg', (269, 279))
198129	33063132	have previously described synthesis and labeling of 68Ga-FAPI-04 and 68Ga-FAPI-46.	('68Ga-FAPI-04', 'Var', (52, 64))	('68Ga-FAPI-46', 'Var', (69, 81))	('FAPI', 'Chemical', '-', (57, 61))	('FAPI', 'Chemical', '-', (74, 78))
198162	33063132	Due to the very good tumor-to-background ratio, FAPI PET/CT has the potential to improve radiation therapy planning and thereby improve outcomes while reducing therapy-associated toxicity by adapting boost volume definition in preparation for external-beam radiotherapy.	('improve', 'PosReg', (81, 88))	('FAPI PET/CT', 'Var', (48, 59))	('tumor', 'Disease', (21, 26))	('reducing', 'NegReg', (151, 159))	('radiation therapy planning', 'CPA', (89, 115))	('toxicity', 'Disease', 'MESH:D064420', (179, 187))	('outcomes', 'MPA', (136, 144))	('toxicity', 'Disease', (179, 187))	('FAPI', 'Chemical', '-', (48, 52))	('improve', 'PosReg', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
198164	33063132	showed that 68Ga-FAPI-04 PET/CT had a higher detection rate of primary tumors and better sensitivity in the detection of lymph node, bone, and visceral metastases compared with 18F-FDG PET/CT in different types of cancer.	('FAPI', 'Chemical', '-', (17, 21))	('cancer', 'Disease', (214, 220))	('visceral metastases', 'Disease', (143, 162))	('PET/CT', 'Var', (25, 31))	('detection', 'CPA', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('68Ga-FAPI-04 PET/CT', 'Var', (12, 31))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('higher', 'PosReg', (38, 44))	('18F-FDG', 'Chemical', 'MESH:D019788', (177, 184))	('tumors', 'Disease', (71, 77))	('visceral metastases', 'Disease', 'MESH:D009362', (143, 162))	('bone', 'CPA', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
198166	33063132	In contrast to FDG-PET/CT, FAPI-PET/CT is highly specific for tumors and tissues undergoing remodeling.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('FAPI', 'Chemical', '-', (27, 31))	('FAPI-PET/CT', 'Var', (27, 38))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('FDG', 'Chemical', 'MESH:D019788', (15, 18))
198190	33080840	However, nCRT carries the risk of significant gastrointestinal (GI) toxicities, including any-grade nausea (53%), vomiting (25%), diarrhea (18%), constipation (27%), and esophagitis (19%), among others.	('constipation', 'Phenotype', 'HP:0002019', (146, 158))	('diarrhea', 'Disease', (130, 138))	('esophagitis', 'Disease', 'MESH:D004938', (170, 181))	('constipation', 'Disease', 'MESH:D003248', (146, 158))	('diarrhea', 'Disease', 'MESH:D003967', (130, 138))	('nausea', 'Phenotype', 'HP:0002018', (100, 106))	('nausea', 'Disease', (100, 106))	('nCRT', 'Var', (9, 13))	('vomiting', 'Phenotype', 'HP:0002013', (114, 122))	('constipation', 'Disease', (146, 158))	('nausea', 'Disease', 'MESH:D009325', (100, 106))	('esophagitis', 'Disease', (170, 181))	('gastrointestinal (GI) toxicities', 'Disease', 'MESH:D005767', (46, 78))	('esophagitis', 'Phenotype', 'HP:0100633', (170, 181))	('vomiting', 'Disease', (114, 122))	('vomiting', 'Disease', 'MESH:D014839', (114, 122))	('diarrhea', 'Phenotype', 'HP:0002014', (130, 138))
198228	33080840	However, no significant difference in mean albumin loss was noted in those with an FJT vs. those without FJT (0.38 g/dL vs. 0.52 g/dL, p = 0.15).	('albumin', 'Gene', '213', (43, 50))	('loss', 'NegReg', (51, 55))	('FJT', 'Var', (83, 86))	('albumin', 'Gene', (43, 50))
198234	33080840	Patients treated with nCRT with cisplatin/5-FU experienced higher percent weight loss compared to those treated with carboplatin/paclitaxel (p < 0.001).	('weight loss', 'Disease', (74, 85))	('weight loss', 'Phenotype', 'HP:0001824', (74, 85))	('5-FU', 'Chemical', 'MESH:D005472', (42, 46))	('cisplatin/5-FU', 'Var', (32, 46))	('carboplatin', 'Chemical', 'MESH:D016190', (117, 128))	('Patients', 'Species', '9606', (0, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('weight loss', 'Disease', 'MESH:D015431', (74, 85))	('paclitaxel', 'Chemical', 'MESH:D017239', (129, 139))	('nCRT', 'Var', (22, 26))
198252	33080840	Associations between impaired treatment tolerance and malnutrition or sarcopenia have previously been identified with a variety of malignancies and cancer therapies.	('cancer', 'Disease', (148, 154))	('malignancies', 'Disease', (131, 143))	('malnutrition', 'Disease', (54, 66))	('malnutrition', 'Disease', 'MESH:D044342', (54, 66))	('Associations', 'Interaction', (0, 12))	('sarcopenia', 'Disease', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('impaired', 'Var', (21, 29))	('malnutrition', 'Phenotype', 'HP:0004395', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('malignancies', 'Disease', 'MESH:D009369', (131, 143))	('sarcopenia', 'Disease', 'MESH:D055948', (70, 80))
198253	33080840	While not thoroughly studied, potential hypotheses linking these conditions include acquired pharmacokinetic differences in drug metabolism in patients with low lean muscle mass, variations of fat-free mass and volume of distribution, among others.	('drug metabolism', 'MPA', (124, 139))	('volume', 'MPA', (211, 217))	('variations', 'Var', (179, 189))	('low', 'NegReg', (157, 160))	('patients', 'Species', '9606', (143, 151))	('fat-free mass', 'MPA', (193, 206))
198256	33080840	Weight loss was also associated with the type of chemotherapy regimen utilized, with higher rates of weight loss in patients treated with cisplatin/5-FU compared to the more contemporary regimen of carboplatin/paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (210, 220))	('carboplatin', 'Chemical', 'MESH:D016190', (198, 209))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('cisplatin/5-FU', 'Var', (138, 152))	('Weight loss', 'Phenotype', 'HP:0001824', (0, 11))	('patients', 'Species', '9606', (116, 124))	('weight loss', 'Disease', 'MESH:D015431', (101, 112))	('5-FU', 'Chemical', 'MESH:D005472', (148, 152))	('Weight loss', 'Disease', (0, 11))	('Weight loss', 'Disease', 'MESH:D015431', (0, 11))	('weight loss', 'Disease', (101, 112))	('weight loss', 'Phenotype', 'HP:0001824', (101, 112))
198313	32720592	The rate of change in the Diamax ( Dia) was also calculated by  Dia = (Dia x - Dia0)/Dia0 x 100%, where Dia0 was the maximum diameter of the tumor before CRT and x was a time point during or after CRT.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('Diamax', 'Chemical', '-', (26, 32))	('tumor', 'Disease', (141, 146))	('Dia0', 'Var', (104, 108))
198362	32720592	Besides, in our study, pretreatment ADCs of the responders were lower than that of the nonresponders, which was contradicted with the study of Aoyagi et al  who found that the response to CRT and overall survival rate of higher pretreatment ADCs were superior to that of lower pretreatment ADCs.	('ADC', 'Chemical', '-', (241, 244))	('ADC', 'Chemical', '-', (36, 39))	('lower', 'NegReg', (64, 69))	('overall survival rate', 'CPA', (196, 217))	('response to CRT', 'MPA', (176, 191))	('ADC', 'Chemical', '-', (290, 293))	('ADCs', 'Var', (241, 245))
198363	32720592	Correlation analysis between the tumor pretreatment ADCs and the tumor maximum diameter regression rate was made in our study, and the result showed the negative correlation between them; the higher tumor pretreatment ADCs is, the lower the tumor maximum diameter regression rate will be.	('tumor', 'Disease', (199, 204))	('ADCs', 'Var', (218, 222))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (241, 246))	('ADC', 'Chemical', '-', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('ADC', 'Chemical', '-', (218, 221))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('lower', 'NegReg', (231, 236))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
198365	32720592	The tumor tissue with higher pretreatment ADCs may have more necrotic tissues, accompanied by hypoxia, acidosis, and hypoperfusion, and lead to reduced sensitivity to CRT.	('tumor', 'Disease', (4, 9))	('reduced', 'NegReg', (144, 151))	('ADC', 'Chemical', '-', (42, 45))	('acidosis', 'Phenotype', 'HP:0001941', (103, 111))	('sensitivity to CRT', 'MPA', (152, 170))	('necrotic', 'Disease', 'MESH:D009336', (61, 69))	('hypoxia', 'Disease', (94, 101))	('hypoxia', 'Disease', 'MESH:D000860', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('acidosis', 'Disease', 'MESH:D000138', (103, 111))	('ADCs', 'Var', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('necrotic', 'Disease', (61, 69))	('acidosis', 'Disease', (103, 111))
198499	29702599	These interactions are often interconnected, thus aberrant expression of any network component could derail the complex regulatory circuitry, culminating in cancer development and progression.	('aberrant expression', 'Var', (50, 69))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('derail', 'Reg', (101, 107))	('complex regulatory circuitry', 'MPA', (112, 140))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('culminating in', 'Reg', (142, 156))	('cancer', 'Disease', (157, 163))	('progression', 'CPA', (180, 191))
198510	29702599	Deregulation in their expression has been implicated in various diseases, including cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('implicated', 'Reg', (42, 52))	('expression', 'MPA', (22, 32))
198519	29702599	Although most miRNA targets in plants are cleaved due to their almost perfect miRNA complementarity, the miR-399 motif on IPS1 contains a mismatched loop at the miRNA cleavage site that abolishes cleavage.	('miR', 'Gene', (105, 108))	('abolishes', 'NegReg', (186, 195))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('cleavage', 'MPA', (196, 204))	('miR', 'Gene', '220972', (161, 164))	('miR', 'Gene', (161, 164))	('mismatched', 'Var', (138, 148))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (105, 108))
198526	29702599	also reported ceRNA-mediated regulation between proto-oncogene BRAF (B-Raf proto-oncogene, serine/threonine kinase) and its pseudogene BRAFP1 (B-Raf pseudogene 1), and their murine counterparts Braf and Braf-rs1, to induce malignancy in mice, further reinforcing the functionality of pseudogenes.	('malignancy', 'Disease', 'MESH:D009369', (223, 233))	('malignancy', 'Disease', (223, 233))	('Braf', 'Gene', (194, 198))	('rs1', 'Var', (208, 211))	('induce', 'PosReg', (216, 222))	('rs1', 'DBSNP_MENTION', 'None', (208, 211))	('murine', 'Species', '10090', (174, 180))	('BRAF', 'Gene', (63, 67))	('Braf', 'Gene', '109880', (203, 207))	('BRAFP1', 'Gene', (135, 141))	('mice', 'Species', '10090', (237, 241))	('B-Raf proto-oncogene', 'Gene', '109880', (69, 89))	('Braf', 'Gene', '109880', (194, 198))	('Braf', 'Gene', (203, 207))	('B-Raf proto-oncogene', 'Gene', (69, 89))	('BRAFP1', 'Gene', '286494', (135, 141))
198534	29702599	Although there were more copies of miR-16 per cell, each TYRP1 transcript carried three non-canonical miR-16 MREs, thus, the presence of TYRP1 alone could achieve effective target abundance to potentially sponge the entire pool of miR-16 per cell.	('miR-16', 'Gene', (102, 108))	('presence', 'Var', (125, 133))	('miR-16', 'Gene', '51573', (102, 108))	('TYRP1', 'Gene', '7306', (137, 142))	('miR-16', 'Gene', (35, 41))	('TYRP1', 'Gene', (57, 62))	('TYRP1', 'Gene', '7306', (57, 62))	('TYRP1', 'Gene', (137, 142))	('miR-16', 'Gene', '51573', (35, 41))	('miR-16', 'Gene', (231, 237))	('sponge', 'Reg', (205, 211))	('miR-16', 'Gene', '51573', (231, 237))
198541	29702599	Tumor suppressor p53 is also known to epigenetically suppress H19 expression.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('H19', 'Gene', (62, 65))	('epigenetically', 'Var', (38, 52))	('expression', 'MPA', (66, 76))	('H19', 'Gene', '283120', (62, 65))	('suppress', 'NegReg', (53, 61))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
198563	29702599	XIST was shown to exhibit tumor suppressive properties in hepatocellular carcinoma (HCC) by acting as a miRNA decoy for tumor suppressor genes, SMAD7 (SMAD family member 7) and PTEN, by sponging miR-92b and miR-181a, respectively, and suppressing cell proliferation, metastasis, and invasion.	('invasion', 'CPA', (283, 291))	('miR', 'Gene', '220972', (195, 198))	('XIST', 'Gene', '7503', (0, 4))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('suppressing', 'NegReg', (235, 246))	('cell proliferation', 'CPA', (247, 265))	('metastasis', 'CPA', (267, 277))	('sponging', 'Var', (186, 194))	('miR', 'Gene', (195, 198))	('miR', 'Gene', '220972', (104, 107))	('tumor', 'Disease', (26, 31))	('miR-92b', 'Gene', '693235', (195, 202))	('miR', 'Gene', '220972', (207, 210))	('tumor', 'Disease', (120, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('SMAD7', 'Gene', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('HCC', 'Phenotype', 'HP:0001402', (84, 87))	('SMAD', 'Gene', (151, 155))	('PTEN', 'Gene', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('SMAD', 'Gene', (144, 148))	('miR', 'Gene', (104, 107))	('miR', 'Gene', (207, 210))	('hepatocellular carcinoma', 'Disease', (58, 82))	('SMAD', 'Gene', '4092', (151, 155))	('SMAD', 'Gene', '4092', (144, 148))	('miR-92b', 'Gene', (195, 202))	('PTEN', 'Gene', '5728', (177, 181))	('XIST', 'Gene', (0, 4))	('SMAD7', 'Gene', '4092', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
198587	29702599	showed that PVT1 also epigenetically silences miR-200b by recruiting EZH2 to the miR-200b promoter to increase the repressive H3K27me3 mark, resulting in cervical cancer growth and progression.	('epigenetically', 'Var', (22, 36))	('miR-200b', 'Gene', (46, 54))	('PVT1', 'Gene', '5820', (12, 16))	('H3K27me3', 'Protein', (126, 134))	('EZH2', 'Gene', '2146', (69, 73))	('miR-200b', 'Gene', '406984', (81, 89))	('cervical cancer', 'Disease', (154, 169))	('progression', 'CPA', (181, 192))	('miR-200b', 'Gene', (81, 89))	('EZH2', 'Gene', (69, 73))	('cervical cancer', 'Disease', 'MESH:D002583', (154, 169))	('resulting in', 'Reg', (141, 153))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('increase', 'PosReg', (102, 110))	('miR-200b', 'Gene', '406984', (46, 54))	('repressive', 'MPA', (115, 125))	('silences', 'NegReg', (37, 45))	('PVT1', 'Gene', (12, 16))
198591	29702599	Consistent with this function, HOTAIR also epigenetically silences the expression of miRNAs that it sponges.	('expression', 'MPA', (71, 81))	('HOTAIR', 'Gene', '100124700', (31, 37))	('epigenetically', 'Var', (43, 57))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('HOTAIR', 'Gene', (31, 37))
198594	29702599	In a similar fashion, HOTAIR epigenetically silences miR-663b to upregulate its target IGF2 (insulin like growth factor 2) and promote pancreatic cancer growth.	('IGF2', 'Gene', (87, 91))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('miR-663b', 'Gene', (53, 61))	('promote', 'PosReg', (127, 134))	('epigenetically silences', 'Var', (29, 52))	('HOTAIR', 'Gene', (22, 28))	('pancreatic cancer', 'Disease', (135, 152))	('insulin like growth factor 2', 'Gene', '3481', (93, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('IGF2', 'Gene', '3481', (87, 91))	('HOTAIR', 'Gene', '100124700', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('insulin like growth factor 2', 'Gene', (93, 121))	('upregulate', 'PosReg', (65, 75))	('miR-663b', 'Gene', '100313824', (53, 61))
198600	29702599	Furthermore, the last decade has seen the functional characterization of various pseudogenes as regulators of gene expression, mainly by acting as miRNA decoys.	('pseudogenes', 'Var', (81, 92))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))
198613	29702599	Perturbation of the network through a single miRNA or pseudogene disrupted iron homeostasis and enhanced prostate cancer growth, highlighting the delicate balance that governs a multicomponent ceRNA network.	('iron', 'Chemical', 'MESH:D007501', (75, 79))	('disrupted iron homeostasis', 'Phenotype', 'HP:0011031', (65, 91))	('enhanced', 'PosReg', (96, 104))	('prostate cancer', 'Disease', (105, 120))	('miR', 'Gene', '220972', (45, 48))	('Perturbation', 'Var', (0, 12))	('miR', 'Gene', (45, 48))	('disrupted', 'NegReg', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('pseudogene', 'Var', (54, 64))	('iron homeostasis', 'MPA', (75, 91))
198634	29702599	Not surprisingly, circ-ITCH has been reported to antagonize miR-7, miR-17 and miR-214, to upregulate ITCH and impede lung and esophageal squamous cell carcinoma growth by blocking the Wnt/beta-catenin pathway.	('miR-17', 'Gene', (67, 73))	('miR-214', 'Gene', (78, 85))	('ITCH', 'Phenotype', 'HP:0000989', (101, 105))	('ITCH', 'Gene', (23, 27))	('antagonize', 'Var', (49, 59))	('beta-catenin', 'Gene', (188, 200))	('ITCH', 'Gene', (101, 105))	('beta-catenin', 'Gene', '1499', (188, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('impede', 'NegReg', (110, 116))	('esophageal squamous cell carcinoma', 'Disease', (126, 160))	('miR-17', 'Gene', '406952', (67, 73))	('miR-7', 'Gene', (60, 65))	('ITCH', 'Gene', '83737', (23, 27))	('miR-214', 'Gene', '406996', (78, 85))	('upregulate', 'PosReg', (90, 100))	('-ITCH', 'Phenotype', 'HP:0000989', (22, 27))	('ITCH', 'Gene', '83737', (101, 105))	('ITCH', 'Phenotype', 'HP:0000989', (23, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (126, 160))	('blocking', 'NegReg', (171, 179))	('miR-7', 'Gene', '10859', (60, 65))
198641	29702599	Interestingly, circPVT1 expression can be transcriptionally enhanced by the mutant p53/YAP/TEAD complex, and functions as a decoy for miR-497-5p.	('PVT1', 'Gene', (19, 23))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('expression', 'MPA', (24, 34))	('miR', 'Gene', '220972', (134, 137))	('miR', 'Gene', (134, 137))	('YAP', 'Gene', (87, 90))	('mutant', 'Var', (76, 82))	('YAP', 'Gene', '10413', (87, 90))	('PVT1', 'Gene', '5820', (19, 23))	('enhanced', 'PosReg', (60, 68))
198643	29702599	Expression profile screens of bladder carcinoma identified circ-MYLK (myosin light chain kinase) as a highly expressed circRNA which binds miR-29a and derepresses VEGFA (vascular endothelial growth factor A) to activate VEGFA/VEGFR2 (kinase insert domain receptor) signaling and promote growth, angiogenesis and metastasis.	('bladder carcinoma', 'Disease', (30, 47))	('myosin light chain kinase', 'Gene', '4638', (70, 95))	('VEGFR2', 'Gene', (226, 232))	('promote', 'PosReg', (279, 286))	('growth', 'CPA', (287, 293))	('VEGFA', 'Gene', '7422', (220, 225))	('activate', 'PosReg', (211, 219))	('miR-29a', 'Gene', '407021', (139, 146))	('vascular endothelial growth factor A', 'Gene', (170, 206))	('miR-29a', 'Gene', (139, 146))	('VEGFA', 'Gene', '7422', (163, 168))	('VEGFR2', 'Gene', '3791', (226, 232))	('kinase insert domain receptor', 'Gene', (234, 263))	('kinase insert domain receptor', 'Gene', '3791', (234, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('MYLK', 'Gene', (64, 68))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (30, 47))	('MYLK', 'Gene', '4638', (64, 68))	('VEGFA', 'Gene', (220, 225))	('derepresses', 'Var', (151, 162))	('bladder carcinoma', 'Disease', 'MESH:D001749', (30, 47))	('vascular endothelial growth factor A', 'Gene', '7422', (170, 206))	('VEGFA', 'Gene', (163, 168))	('myosin light chain kinase', 'Gene', (70, 95))
198644	29702599	Conversely, circMTO1 was identified as a downregulated circRNA in HCC, and it functions as a tumor suppressor by sponging miR-9 to upregulate p21 and suppress HCC development.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('p21', 'Gene', (142, 145))	('tumor', 'Disease', (93, 98))	('p21', 'Gene', '644914', (142, 145))	('miR', 'Gene', (122, 125))	('circMTO1', 'Var', (12, 20))	('miR', 'Gene', '220972', (122, 125))	('HCC development', 'CPA', (159, 174))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))	('suppress', 'NegReg', (150, 158))	('upregulate', 'PosReg', (131, 141))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
198669	29702599	As a proof of concept, the authors found two NEAT1-related DRCEs in invasive breast cancer that may lead to poor response to tamoxifen therapy for patients with TP53 mutations.	('invasive breast cancer', 'Disease', (68, 90))	('TP53', 'Gene', (161, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('mutations', 'Var', (166, 175))	('NEAT1', 'Gene', '283131', (45, 50))	('invasive breast cancer', 'Disease', 'MESH:D001943', (68, 90))	('patients', 'Species', '9606', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('NEAT1', 'Gene', (45, 50))	('tamoxifen', 'Chemical', 'MESH:D013629', (125, 134))	('TP53', 'Gene', '7157', (161, 165))
198675	29702599	demonstrated effective knockdown KRAS, CXCR4 and PPIB (peptidylprolyl isomerase B) mRNA using Cas13a.	('peptidylprolyl isomerase B', 'Gene', '5479', (55, 81))	('PPIB', 'Gene', (49, 53))	('CXCR4', 'Gene', (39, 44))	('knockdown', 'Var', (23, 32))	('KRAS', 'Gene', (33, 37))	('peptidylprolyl isomerase B', 'Gene', (55, 81))	('PPIB', 'Gene', '5479', (49, 53))	('KRAS', 'Gene', '3845', (33, 37))	('CXCR4', 'Gene', '7852', (39, 44))
198677	29702599	were able to program RNA editing to correct disease-relevant mutations, such as G878A (AVPR2 arginine vasopressin receptor 2) in X-linked nephrogenic diabetes insipidus and G1517A (FANCC Fanconi anemia complementation group C) in Fanconi anemia.	('FANCC Fanconi anemia complementation', 'Phenotype', 'HP:0001994', (181, 217))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (187, 201))	('AVPR2', 'Gene', (87, 92))	('anemia', 'Phenotype', 'HP:0001903', (238, 244))	('X-linked nephrogenic diabetes insipidus', 'Disease', (129, 168))	('nephrogenic diabetes insipidus', 'Phenotype', 'HP:0009806', (138, 168))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (230, 244))	('AVPR2', 'Gene', '554', (87, 92))	('X-linked nephrogenic diabetes insipidus', 'Disease', 'MESH:D018500', (129, 168))	('G878A', 'Mutation', 'rs1064797077', (80, 85))	('anemia', 'Phenotype', 'HP:0001903', (195, 201))	('Fanconi anemia', 'Disease', (187, 201))	('G1517A', 'Var', (173, 179))	('Fanconi anemia', 'Disease', 'MESH:D005199', (187, 201))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (150, 168))	('Fanconi anemia', 'Disease', (230, 244))	('G1517A', 'Mutation', 'c.1517G>A', (173, 179))	('G878A', 'Var', (80, 85))	('Fanconi anemia', 'Disease', 'MESH:D005199', (230, 244))
198735	28465635	A report published in 2016 shows that there are an 477900 and 375000 estimated new EC cases and deaths, respectively, in China.	('deaths', 'Disease', (96, 102))	('375000', 'Var', (62, 68))	('deaths', 'Disease', 'MESH:D003643', (96, 102))
198749	28465635	All primary antibodies, including against p21, Akt, p-Akt (Ser473), mTOR, p-mTOR (Ser2448), p70S6K, p-p70S6K (Thr389), AMPK, p-AMPK (Thr172) and beta-actin, were from Cell Signaling Technology (Danvers, MA, United States).	('p70S6K', 'Gene', '6198', (92, 98))	('Ser2448', 'Var', (82, 89))	('mTOR', 'Gene', (76, 80))	('p21', 'Gene', (42, 45))	('p70S6K', 'Gene', '6198', (102, 108))	('p21', 'Gene', '644914', (42, 45))	('mTOR', 'Gene', '2475', (68, 72))	('Akt', 'Gene', (54, 57))	('Akt', 'Gene', (47, 50))	('Thr389', 'Chemical', '-', (110, 116))	('Ser473', 'Chemical', '-', (59, 65))	('Akt', 'Gene', '207', (54, 57))	('mTOR', 'Gene', '2475', (76, 80))	('Akt', 'Gene', '207', (47, 50))	('beta-actin', 'Gene', (145, 155))	('p70S6K', 'Gene', (92, 98))	('AMPK', 'Gene', '5564', (119, 123))	('p70S6K', 'Gene', (102, 108))	('AMPK', 'Gene', (127, 131))	('AMPK', 'Gene', (119, 123))	('AMPK', 'Gene', '5564', (127, 131))	('Ser2448', 'Chemical', '-', (82, 89))	('mTOR', 'Gene', (68, 72))	('Thr172', 'Chemical', '-', (133, 139))	('beta-actin', 'Gene', '728378', (145, 155))
198763	28465635	After blocking with 5% nonfat dry milk, membranes were incubated at 4  C overnight with each of the following primary antibodies: p21, pAKT (Ser473), AKT, p-mTOR (Ser2448), mTOR, pp70S6K (Thr389), p70S6K, p-AMPK (Thr172), AMPK (all 1:1000 dilution) and beta-actin.	('p21', 'Gene', (130, 133))	('p21', 'Gene', '644914', (130, 133))	('p70S6K', 'Gene', '6198', (197, 203))	('mTOR', 'Gene', '2475', (173, 177))	('beta-actin', 'Gene', (253, 263))	('AKT', 'Gene', (150, 153))	('AKT', 'Gene', '207', (150, 153))	('Thr389', 'Chemical', '-', (188, 194))	('p70S6K', 'Gene', (180, 186))	('AKT', 'Gene', '207', (136, 139))	('Ser2448', 'Chemical', '-', (163, 170))	('AMPK', 'Gene', (207, 211))	('p70S6K', 'Gene', (197, 203))	('AMPK', 'Gene', '5564', (207, 211))	('beta-actin', 'Gene', '728378', (253, 263))	('Ser2448', 'Var', (163, 170))	('mTOR', 'Gene', (157, 161))	('Thr172', 'Chemical', '-', (213, 219))	('Ser473', 'Chemical', '-', (141, 147))	('AMPK', 'Gene', '5564', (222, 226))	('AMPK', 'Gene', (222, 226))	('mTOR', 'Gene', (173, 177))	('p70S6K', 'Gene', '6198', (180, 186))	('mTOR', 'Gene', '2475', (157, 161))	('AKT', 'Gene', (136, 139))
198799	28465635	Our results demonstrated that berberine significantly blocked KYSE-70 cells at the G2/M phase of the cell cycle, suggesting that berberine inhibits KYSE-70 cell proliferation by inducing G2/M cell cycle arrest.	('berberine', 'Chemical', 'MESH:D001599', (129, 138))	('G2/M cell cycle arrest', 'CPA', (187, 209))	('berberine', 'Chemical', 'MESH:D001599', (30, 39))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (192, 209))	('berberine', 'Var', (129, 138))	('inducing', 'PosReg', (178, 186))	('inhibits', 'NegReg', (139, 147))
198829	24621512	Consistently, we observed nuclear translocation and activation of YAP1 by knockdown of CHRNA3, which is a negative regulator of nicotine signaling in bronchial and esophageal cancer cells.	('esophageal cancer', 'Disease', (164, 181))	('CHRNA3', 'Gene', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('YAP1', 'Gene', (66, 70))	('knockdown', 'Var', (74, 83))	('nicotine', 'Chemical', 'MESH:D009538', (128, 136))	('nuclear translocation', 'MPA', (26, 47))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('activation', 'PosReg', (52, 62))
198838	24621512	Recent findings suggest nicotine and its derivatives such as NNN (N-nitrosonornicotine) and NNK((4-methylnitrosamino)-1-(3-pyridyl)-1-butanone) can direct activate nicotinic acetylcholine receptors (nAChRs) to stimulate the growth and angiogenesis and suppress the drug induced apoptosis of the cancer cells.	('apoptosis of the cancer', 'Disease', (278, 301))	('(4-methylnitrosamino)-1-(3-pyridyl)-1-butanone', 'Chemical', 'MESH:C016583', (96, 142))	('apoptosis of the cancer', 'Disease', 'MESH:D009369', (278, 301))	('nAChR', 'Gene', '1137', (199, 204))	('nAChR', 'Gene', (199, 204))	('nicotine', 'Chemical', 'MESH:D009538', (78, 86))	('NNK', 'Var', (92, 95))	('activate', 'PosReg', (155, 163))	('suppress', 'NegReg', (252, 260))	('stimulate', 'PosReg', (210, 219))	('nicotine', 'Chemical', 'MESH:D009538', (24, 32))	('N-nitrosonornicotine', 'Chemical', 'MESH:C008655', (66, 86))	('nicotinic acetylcholine receptors', 'Protein', (164, 197))	('NNN', 'Chemical', 'MESH:C008655', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))
198844	24621512	And amplifications of YAP1 gene locus are observed in intracranial ependymomas, oral squamous cell carcinomas, and medulloblastomas.	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (80, 109))	('oral squamous cell carcinomas', 'Disease', (80, 109))	('intracranial ependymomas', 'Disease', (54, 78))	('amplifications', 'Var', (4, 18))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (85, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('medulloblastomas', 'Disease', 'MESH:D008527', (115, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('medulloblastomas', 'Disease', (115, 131))	('intracranial ependymomas', 'Disease', 'MESH:C531673', (54, 78))	('observed', 'Reg', (42, 50))	('YAP1', 'Gene', (22, 26))
198915	24621512	Because knockdown of CHRNA3 and CHRNA5 increased the proliferation, migration and calcium influx of lung cancer cell lines, as a result of compensatory increase of assembly of alpha7-nAChR on the cytoplasm membrane which had higher permeability to calcium in response to nicotine.	('nAChR', 'Gene', (183, 188))	('calcium', 'Chemical', 'MESH:D002118', (248, 255))	('permeability', 'MPA', (232, 244))	('increase', 'PosReg', (152, 160))	('knockdown', 'Var', (8, 17))	('calcium influx', 'CPA', (82, 96))	('assembly', 'MPA', (164, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('calcium', 'Chemical', 'MESH:D002118', (82, 89))	('lung cancer', 'Disease', (100, 111))	('proliferation', 'CPA', (53, 66))	('increased', 'PosReg', (39, 48))	('nicotine', 'Chemical', 'MESH:D009538', (271, 279))	('nAChR', 'Gene', '1137', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('migration', 'CPA', (68, 77))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
198916	24621512	Thus we employed siRNA approaches to knockdown CHRNA3 in KSYE-510 cell and then examined the effects of CHRNA3 depletion on the growth and migration of KYSE510 cells, and on the activation of YAP1 as well.	('KYSE510', 'CellLine', 'CVCL:1354', (152, 159))	('migration', 'CPA', (139, 148))	('knockdown', 'Var', (37, 46))	('growth', 'CPA', (128, 134))	('KSYE-510', 'CellLine', 'CVCL:1565', (57, 65))	('YAP1', 'Gene', (192, 196))
198917	24621512	We observed an increase of growth rate and migration in KYSE510 cells by CHRNA3 knockdown, which is similar to that seen in the nicotine administration (Figure 2 A, Figure 2 B).	('CHRNA3', 'Gene', (73, 79))	('KYSE510', 'CellLine', 'CVCL:1354', (56, 63))	('knockdown', 'Var', (80, 89))	('growth rate', 'CPA', (27, 38))	('increase', 'PosReg', (15, 23))	('migration', 'CPA', (43, 52))	('nicotine', 'Chemical', 'MESH:D009538', (128, 136))
198929	24621512	As shown in Figure 4, the interactions of YAP1 with alpha-catenin, beta-catenin, 14-3-3, and p63 were disrupted by nicotine administration (Figure 4 A), which is in accordance with our observations that nicotine treatment increased nuclear translocation and activation of YAP1.	('alpha-catenin', 'Protein', (52, 65))	('interactions', 'Interaction', (26, 38))	('nicotine', 'Chemical', 'MESH:D009538', (115, 123))	('YAP1', 'Gene', (42, 46))	('p63', 'Gene', '8626', (93, 96))	('disrupted', 'NegReg', (102, 111))	('increased', 'PosReg', (222, 231))	('p63', 'Gene', (93, 96))	('nicotine', 'Var', (115, 123))	('nuclear translocation', 'MPA', (232, 253))	('activation', 'PosReg', (258, 268))	('nicotine', 'Chemical', 'MESH:D009538', (203, 211))
198932	24621512	As p63 is an important regulator of apoptosis, and altered interaction between YAP1 and p63 would impair the apoptotic responses mediated by p63.	('p63', 'Gene', (3, 6))	('impair', 'NegReg', (98, 104))	('altered', 'Var', (51, 58))	('YAP1', 'Gene', (79, 83))	('interaction', 'Interaction', (59, 70))	('p63', 'Gene', '8626', (88, 91))	('p63', 'Gene', (141, 144))	('apoptotic responses', 'CPA', (109, 128))	('p63', 'Gene', '8626', (3, 6))	('p63', 'Gene', (88, 91))	('p63', 'Gene', '8626', (141, 144))
198942	24621512	Consistently we observed an increased growth rate for esophageal cancer cells by nicotine treatment or through knockdown of CHRNA3.	('increased', 'PosReg', (28, 37))	('knockdown', 'Var', (111, 120))	('nicotine', 'Chemical', 'MESH:D009538', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('growth rate', 'MPA', (38, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('CHRNA3', 'Gene', (124, 130))
198947	24621512	In this study, we have shown that nicotine administration or CHRNA3 depletion lead to an increase of cell growth and migration, and induce resistance to apoptosis in esophageal cancer cells.	('resistance to apoptosis', 'CPA', (139, 162))	('cell growth', 'CPA', (101, 112))	('esophageal cancer', 'Disease', (166, 183))	('induce', 'Reg', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('CHRNA3 depletion', 'Var', (61, 77))	('nicotine', 'Chemical', 'MESH:D009538', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('increase', 'PosReg', (89, 97))
198965	24621512	Whereas, disruption of actin cytoskeleton can activate JNK/SAPK pathway to stabilize p21 monitored by the hippo pathway upstream kinase MST1 and MST2.	('JNK', 'Gene', '5599', (55, 58))	('MST1', 'Gene', '4485', (136, 140))	('MST2', 'Gene', (145, 149))	('activate', 'PosReg', (46, 54))	('MST2', 'Gene', '6788', (145, 149))	('MST1', 'Gene', (136, 140))	('p21', 'Gene', (85, 88))	('disruption', 'Var', (9, 19))	('JNK', 'Gene', (55, 58))	('p21', 'Gene', '644914', (85, 88))
198979	22655262	In winter, red meat intake (beta = 0.208; P = 0.03), processed meat intake (beta = 0.218; P = 0.02), and GSTT1-02 polymorphism ("null" genotype: beta = 0.228; P = 0.02) showed associations with 1-OHPG levels, while CYP1B1-07 polymorphism (GG versus AA + GA genotypes: beta = -0.256; P = 0.008) showed an inverse association.	('1-OHPG levels', 'MPA', (194, 207))	('1-OHPG', 'Chemical', '-', (194, 200))	('polymorphism', 'Var', (114, 126))	('associations', 'Interaction', (176, 188))	('GSTT1-02', 'Gene', (105, 113))	('CYP1B1', 'Gene', '1545', (215, 221))	('CYP1B1', 'Gene', (215, 221))	('GSTT1-02', 'Gene', '2952;2953', (105, 113))
198982	22655262	Polycyclic aromatic hydrocarbons (PAHs) are by-products of incomplete combustion of organic matter and occur as mixtures of complex and variable composition.	('PAHs', 'Chemical', 'MESH:D011084', (34, 38))	('Polycyclic', 'Var', (0, 10))	('organic matter', 'Disease', (84, 98))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (0, 32))	('organic matter', 'Disease', 'MESH:D056784', (84, 98))
198995	22655262	The half-life for urinary excretion of 1-OHPG ranges from 6 to 35 h and peak urine concentration occurs a few hours following exposure (Strickland et al.,).	('1-OHPG', 'Var', (39, 45))	('1-OHPG', 'Chemical', '-', (39, 45))	('urinary excretion', 'MPA', (18, 35))
199017	22655262	Genetic variants including single nucleotide polymorphisms (SNPs) or deletions in the following genes were determined: genes for phase I metabolizing enzymes myeloperoxidase (MPO) and cytochromes P450s (CYP1A1, CYP1A2, CYP1B1, CYP2E1, and CYP3A4) and for phase II metabolizing enzymes glutathione S-transferases (GSTM1, GSTP1, GSTT1), and N-acetyltransferase 2 (NAT2).	('myeloperoxidase', 'Gene', (158, 173))	('myeloperoxidase', 'Gene', '4353', (158, 173))	('CYP1A2', 'Gene', '1544', (211, 217))	('GSTT1', 'Gene', '2952', (327, 332))	('GSTM1', 'Gene', (313, 318))	('GSTP1', 'Gene', '2950', (320, 325))	('CYP1B1', 'Gene', '1545', (219, 225))	('single nucleotide polymorphisms', 'Var', (27, 58))	('CYP2E1', 'Gene', (227, 233))	('CYP1B1', 'Gene', (219, 225))	('CYP3A4', 'Gene', '1576', (239, 245))	('N-acetyltransferase 2', 'Gene', (339, 360))	('GSTP1', 'Gene', (320, 325))	('CYP1A1', 'Gene', (203, 209))	('GSTT1', 'Gene', (327, 332))	('CYP3A4', 'Gene', (239, 245))	('cytochromes P450s', 'Enzyme', (184, 201))	('MPO', 'Gene', '4353', (175, 178))	('CYP1A2', 'Gene', (211, 217))	('GSTM1', 'Gene', '2944', (313, 318))	('N-acetyltransferase 2', 'Gene', '10', (339, 360))	('CYP1A1', 'Gene', '1543', (203, 209))	('MPO', 'Gene', (175, 178))	('NAT2', 'Gene', '10', (362, 366))	('deletions', 'Var', (69, 78))	('CYP2E1', 'Gene', '1571', (227, 233))	('NAT2', 'Gene', (362, 366))
199055	22655262	Red and processed meat intake and GSTT1-02 polymorphism showed correlations with 1-OHPG levels in winter, while CYP1B1-07 polymorphism had an inverse correlation.	('GSTT1-02', 'Gene', (34, 42))	('1-OHPG levels', 'MPA', (81, 94))	('1-OHPG', 'Chemical', '-', (81, 87))	('GSTT1-02', 'Gene', '2952;2953', (34, 42))	('correlations', 'Interaction', (63, 75))	('CYP1B1', 'Gene', '1545', (112, 118))	('polymorphism', 'Var', (43, 55))	('CYP1B1', 'Gene', (112, 118))
199056	22655262	In summer, making bread at home, second-hand smoke, and GSTM1-02 polymorphism were correlated with 1-OHPG levels, but GSTP1-02 polymorphism showed an inverse association; food intake data were not available for this season.	('correlated', 'Reg', (83, 93))	('GSTM1-02', 'Gene', (56, 64))	('polymorphism', 'Var', (65, 77))	('1-OHPG', 'Chemical', '-', (99, 105))	('GSTP1', 'Gene', '2950', (118, 123))	('1-OHPG levels', 'MPA', (99, 112))	('GSTM1-02', 'Gene', '2944;2946', (56, 64))	('GSTP1', 'Gene', (118, 123))
199080	22655262	Several studies have investigated the association between polymorphisms in genes encoding the above enzymes and levels of PAH metabolites in urine, but the results have not been very consistent (Alexandrie et al.,; Schoket et al.,; Apostoli et al.,; Abnet et al.,; Chen et al.,; Chuang and Chang,; Petchpoung et al.,).	('polymorphisms', 'Var', (58, 71))	('PAH', 'Gene', (122, 125))	('PAH', 'Gene', '5053', (122, 125))
199081	22655262	In our study, polymorphisms in some CYP genes were associated with lower levels of 1-OHPG, while deletions in GSTM1 and GSTT1 were associated with elevated levels.	('CYP genes', 'Gene', (36, 45))	('GSTM1', 'Gene', '2944', (110, 115))	('GSTM1', 'Gene', (110, 115))	('GSTT1', 'Gene', (120, 125))	('GSTT1', 'Gene', '2952', (120, 125))	('polymorphisms', 'Var', (14, 27))	('deletions', 'Var', (97, 106))	('lower', 'NegReg', (67, 72))	('1-OHPG', 'Chemical', '-', (83, 89))	('levels of 1-OHPG', 'MPA', (73, 89))
199105	22655262	The multiplexes included the following polymorphisms; series A: CYP1A2-03 (rs762551), NAT2-02 (rs1799931), NAT2-06 (rs1801280), NAT2-08 (rs1799930), GSTM1-02 (deletion), GSTP1-01 (rs1695), GSTP1-02 (rs1138272), and GSTT1-02 (deletion); series B: CYP1A1-01 (rs1048943), CYP1A1-03 (rs1799814), CYP1B1-05 (rs1056836), CYP1B1-07 (rs1800440), CYP2E1-05 (rs6413420), CYP3A4-02 (rs2740574), and MPO-02 (rs2333227).	('NAT2', 'Gene', (86, 90))	('CYP2E1', 'Gene', '1571', (338, 344))	('CYP1B1', 'Gene', (292, 298))	('rs2740574', 'Var', (372, 381))	('GSTP1', 'Gene', '2950', (170, 175))	('rs1801280', 'Var', (116, 125))	('CYP1A1', 'Gene', (246, 252))	('rs2740574', 'Mutation', 'rs2740574', (372, 381))	('rs6413420', 'Mutation', 'rs6413420', (349, 358))	('rs1800440', 'Var', (326, 335))	('rs1056836', 'Var', (303, 312))	('GSTM1-02', 'Gene', '2944;2946', (149, 157))	('rs1138272', 'Var', (199, 208))	('NAT2', 'Gene', '10', (107, 111))	('rs6413420', 'Var', (349, 358))	('rs2333227', 'Var', (396, 405))	('GSTP1', 'Gene', (170, 175))	('rs2333227', 'Mutation', 'rs2333227', (396, 405))	('NAT2', 'Gene', (107, 111))	('CYP1A2', 'Gene', (64, 70))	('rs1799814', 'Mutation', 'rs1799814', (280, 289))	('CYP1A1', 'Gene', (269, 275))	('rs1695', 'Mutation', 'rs1695', (180, 186))	('CYP1B1', 'Gene', '1545', (315, 321))	('CYP1B1', 'Gene', (315, 321))	('CYP2E1', 'Gene', (338, 344))	('NAT2', 'Gene', '10', (128, 132))	('rs1138272', 'Mutation', 'rs1138272', (199, 208))	('rs1801280', 'Mutation', 'rs1801280', (116, 125))	('rs762551', 'Mutation', 'rs762551', (75, 83))	('rs1056836', 'Mutation', 'rs1056836', (303, 312))	('CYP1A1', 'Gene', '1543', (246, 252))	('rs1799930', 'Var', (137, 146))	('NAT2', 'Gene', (128, 132))	('GSTM1-02', 'Gene', (149, 157))	('CYP1B1', 'Gene', '1545', (292, 298))	('MPO', 'Gene', '4353', (388, 391))	('CYP1A1', 'Gene', '1543', (269, 275))	('GSTT1-02', 'Gene', (215, 223))	('rs1800440', 'Mutation', 'rs1800440', (326, 335))	('CYP1A2', 'Gene', '1544', (64, 70))	('rs1048943', 'Mutation', 'rs1048943', (257, 266))	('GSTP1', 'Gene', '2950', (189, 194))	('MPO', 'Gene', (388, 391))	('CYP3A4', 'Gene', '1576', (361, 367))	('GSTT1-02', 'Gene', '2952;2953', (215, 223))	('rs1799814', 'Var', (280, 289))	('GSTP1', 'Gene', (189, 194))	('NAT2', 'Gene', '10', (86, 90))	('CYP3A4', 'Gene', (361, 367))	('rs1799930', 'Mutation', 'rs1799930', (137, 146))	('rs1048943', 'Var', (257, 266))	('rs1799931', 'Mutation', 'rs1799931', (95, 104))
199114	22013481	Patients with high IDO expression and a low number of CD8+ TILs had significantly impaired overall survival time.	('CD8', 'Gene', '925', (54, 57))	('TIL', 'Gene', '7096', (59, 62))	('impaired', 'NegReg', (82, 90))	('overall survival time', 'CPA', (91, 112))	('low number of CD8+', 'Phenotype', 'HP:0005415', (40, 58))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('TIL', 'Gene', (59, 62))	('CD8', 'Gene', (54, 57))	('IDO expression', 'Protein', (19, 33))
199159	22013481	Briefly, 1 x 105 CD8+ T cells were cultured in Eca109-CMs and stimulated with plate-bound anti-CD3 mAb (OKT3, ATCC) and soluble anti-CD28 mAb (BD Bioscience).	('CD28', 'Gene', (133, 137))	('CD8', 'Gene', (17, 20))	('CD8', 'Gene', '925', (17, 20))	('anti-CD3', 'Var', (90, 98))	('CD28', 'Gene', '940', (133, 137))
199175	22013481	Similarly, IDO-high expressing tumors exhibited a significantly lower proportion of stromal CD8+ TILs (range 7-36; median 20.1) compared with IDO-low expressing tumors (range 18-62; median 41.2; P = 0.001; Figure 2(b)).	('CD8', 'Gene', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('lower', 'NegReg', (64, 69))	('tumors', 'Disease', (31, 37))	('IDO-high expressing', 'Var', (11, 30))	('CD8', 'Gene', '925', (92, 95))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('TIL', 'Gene', '7096', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('TIL', 'Gene', (97, 100))
199181	22013481	The median survival of patients with high IDO expression was much shorter (23 months) than those with low IDO expression (33 months).	('patients', 'Species', '9606', (23, 31))	('high IDO expression', 'Var', (37, 56))	('shorter', 'NegReg', (66, 73))
199199	22013481	When exposed to IFNgamma-treated Eca109-CM, the proliferation of CD8+ T cells both from PBMCs and TILs was almost completely restored by the 1MT addition (Figure 5(a)), the functional IDO enzyme activity in IFNgamma-treated Eca109-CM was dramatically inhibited by the 1 MT (Figure 5(b)).	('TIL', 'Gene', '7096', (98, 101))	('IFNgamma', 'Gene', (207, 215))	('IFNgamma', 'Gene', '3458', (207, 215))	('TIL', 'Gene', (98, 101))	('IFNgamma', 'Gene', (16, 24))	('Eca109-CM', 'Var', (224, 233))	('IFNgamma', 'Gene', '3458', (16, 24))	('CD8', 'Gene', (65, 68))	('inhibited', 'NegReg', (251, 260))	('CD8', 'Gene', '925', (65, 68))	('rat', 'Species', '10116', (55, 58))	('IDO enzyme', 'Enzyme', (184, 194))	('activity', 'MPA', (195, 203))
199203	22013481	Similarly, under anti-CD3/CD28 simulation, there was no significant difference in the frequency of apoptotic cells between the cells exposed to IFNgamma-treated and untreated Eca109-CM (Figure 5(c)).	('CD28', 'Gene', (26, 30))	('Eca109-CM', 'Var', (175, 184))	('CD28', 'Gene', '940', (26, 30))	('IFNgamma', 'Gene', '3458', (144, 152))	('IFNgamma', 'Gene', (144, 152))
199227	22013481	One suggests that depleting local L-Try, an essential amino acid for T-cell proliferation, may block the cell cycle in the G1 phase and render T cells susceptible to proliferation arrest, and the other suggests that IDO may suppress T-cell responses by the action of Try metabolites, such as Kyn, which are toxic and proapoptotic for T cells.	('rat', 'Species', '10116', (83, 86))	('L-Try', 'Var', (34, 39))	('rat', 'Species', '10116', (173, 176))	('suppress T-cell responses', 'Phenotype', 'HP:0005419', (224, 249))	('IDO', 'Var', (216, 219))	('essential amino acid', 'Chemical', 'MESH:D000601', (44, 64))	('render', 'Reg', (136, 142))	('depleting', 'Var', (18, 27))	('block', 'NegReg', (95, 100))	('Kyn', 'Chemical', 'MESH:D007737', (292, 295))	('cell cycle in the G1 phase', 'CPA', (105, 131))	('L-Try', 'Chemical', '-', (34, 39))	('suppress', 'NegReg', (224, 232))	('T-cell responses', 'CPA', (233, 249))
199230	22013481	In addition, we presented the evidence that exposure to IDO-expressing Eca109-CM dramatically weakened the cytolytic function of CD8+  T cells from both PBMCs and TILs against target cells, but this attenuation could be abrogated by the addition of the IDO inhibitor 1 MT.	('Eca109-CM', 'Var', (71, 80))	('weakened', 'NegReg', (94, 102))	('CD8', 'Gene', (129, 132))	('cytolytic function', 'MPA', (107, 125))	('CD8', 'Gene', '925', (129, 132))	('TIL', 'Gene', '7096', (163, 166))	('TIL', 'Gene', (163, 166))
199231	22013481	very recently reported that in the experimental rat lung allograft model, IDO creates a local microenvironment that leads to not only reduction in the numbers of CD8+  TILs, but also the loss of cytotoxic activity of the CD8+ effector T cells toward target cells.	('IDO', 'Var', (74, 77))	('TIL', 'Gene', '7096', (168, 171))	('CD8', 'Gene', '925', (221, 224))	('rat', 'Species', '10116', (48, 51))	('CD8', 'Gene', '925', (162, 165))	('loss', 'NegReg', (187, 191))	('reduction', 'NegReg', (134, 143))	('TIL', 'Gene', (168, 171))	('cytotoxic activity', 'CPA', (195, 213))	('CD8', 'Gene', (162, 165))	('CD8', 'Gene', (221, 224))
199235	22013481	These findings, together with our observations, suggest that IDO creates an immune suppression microenvironment not only by suppressing the proliferation of CD8+ TILs but also by impairing the cytotoxic function of CD8+ TILs.	('CD8', 'Gene', '925', (215, 218))	('IDO', 'Var', (61, 64))	('proliferation', 'CPA', (140, 153))	('TIL', 'Gene', '7096', (220, 223))	('cytotoxic function', 'CPA', (193, 211))	('CD8', 'Gene', (157, 160))	('CD8', 'Gene', '925', (157, 160))	('TIL', 'Gene', (220, 223))	('TIL', 'Gene', '7096', (162, 165))	('rat', 'Species', '10116', (147, 150))	('impairing', 'NegReg', (179, 188))	('suppressing', 'NegReg', (124, 135))	('TIL', 'Gene', (162, 165))	('CD8', 'Gene', (215, 218))
199240	22013481	Although the precise role of tumoral IDO in human ESCC remains to be elucidated, our findings suggest that blocking IDO activity may provide a potential means of restoring the host antitumor immunity in the treatment of ESCC.	('tumor', 'Disease', (185, 190))	('human', 'Species', '9606', (44, 49))	('restoring', 'PosReg', (162, 171))	('tumoral', 'Disease', (29, 36))	('tumoral', 'Disease', 'MESH:D009369', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('IDO', 'Protein', (116, 119))	('ESCC', 'Disease', (220, 224))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('blocking', 'Var', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('activity', 'MPA', (120, 128))
199329	32267515	The high prevalence of epidermal growth factor receptor (EGFR) variants among Asian individuals and corresponding molecular-targeted medications may account for this.	('epidermal growth factor receptor', 'Gene', (23, 55))	('variants', 'Var', (63, 71))	('epidermal growth factor receptor', 'Gene', '1956', (23, 55))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', (57, 61))
199330	32267515	The EGFR variant, the most common gene variation in non-small cell lung cancer, is significantly higher among Asian patients with lung cancer than among white patients.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('variant', 'Var', (9, 16))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (56, 78))	('higher', 'Reg', (97, 103))	('EGFR', 'Gene', (4, 8))	('patients', 'Species', '9606', (116, 124))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (52, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('patients', 'Species', '9606', (159, 167))	('lung cancer', 'Disease', (130, 141))	('EGFR', 'Gene', '1956', (4, 8))
199331	32267515	Therefore, Asian patients with lung cancer may benefit most from molecular-targeted therapy with the advent of EGFR inhibitors, which have prolonged survival rates considerably.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('EGFR', 'Gene', '1956', (111, 115))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('EGFR', 'Gene', (111, 115))	('patients', 'Species', '9606', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('molecular-targeted', 'Var', (65, 83))
199344	32267515	Black patients have a higher frequency of KRAS variants in tumors, thereby promoting the aggressiveness of colorectal cancer.	('KRAS', 'Gene', (42, 46))	('variants', 'Var', (47, 55))	('KRAS', 'Gene', '3845', (42, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (59, 65))	('aggressiveness of colorectal cancer', 'Disease', (89, 124))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('patients', 'Species', '9606', (6, 14))	('aggressiveness of colorectal cancer', 'Disease', 'MESH:D015179', (89, 124))	('promoting', 'PosReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
199349	32267515	First, a greater genetic predisposition was found among black women with higher risk allele frequencies at the TERT locus and deleterious BRCA1/2 variants compared with patients from different racial/ethnic groups.	('patients', 'Species', '9606', (169, 177))	('BRCA1/2', 'Gene', (138, 145))	('BRCA1/2', 'Gene', '672;675', (138, 145))	('variants', 'Var', (146, 154))	('TERT', 'Gene', (111, 115))	('TERT', 'Gene', '7015', (111, 115))	('women', 'Species', '9606', (62, 67))
199352	32267515	Nevertheless, white women tend to have magnetic resonance imaging targeting breast cancer and genetic testing of high sensitivity.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('women', 'Species', '9606', (20, 25))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('genetic testing', 'Var', (94, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
199452	31517311	Hence, 52 mice were tested and the results revealed that gGlu-HMRG can improve the endoscopic detection of CAC.	('HMRG', 'Chemical', '-', (62, 66))	('CAC', 'Phenotype', 'HP:0002664', (107, 110))	('mice', 'Species', '10090', (10, 14))	('gGlu-HMRG', 'Var', (57, 66))	('endoscopic detection', 'CPA', (83, 103))	('CAC', 'Disease', (107, 110))	('improve', 'PosReg', (71, 78))
199502	30127973	In total, three sets of gene expression profile data of patients with esophageal cancer were downloaded from the Gene Expression Omnibus (GEO) database : GSE6188 (257 samples), GSE13937 (152 samples) and GSE43732 (238 samples), all representing adenocarcinoma.	('patients', 'Species', '9606', (56, 64))	('GSE43732', 'Var', (204, 212))	('GSE13937', 'Var', (177, 185))	('adenocarcinoma', 'Disease', 'MESH:D000230', (245, 259))	('esophageal cancer', 'Disease', (70, 87))	('GSE6188', 'Chemical', '-', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('adenocarcinoma', 'Disease', (245, 259))	('GSE6188', 'Var', (154, 161))
199532	30127973	It led to ~400,000 mortalities in 2012, accounting for ~5% of all mortality from cancer.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('mortalities', 'Var', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('led to', 'Reg', (3, 9))
199561	29298684	We previously reported an association between the presence of Porphyromonas gingivalis in esophageal squamous cell carcinoma (ESCC) and its progression.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (90, 124))	('Porphyromonas gingivalis', 'Gene', (62, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('presence', 'Var', (50, 58))	('Porphyromonas gingivalis', 'Species', '837', (62, 86))	('esophageal squamous cell carcinoma', 'Disease', (90, 124))
199579	29298684	In another European prospective cohort study, high levels of antibodies to P. gingivalis rendered a > 2-fold increased risk to pancreatic cancer.	('P. gingivalis', 'Gene', (75, 88))	('pancreatic cancer', 'Disease', (127, 144))	('P. gingivalis', 'Species', '837', (75, 88))	('antibodies', 'Var', (61, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))
199600	29298684	seropositivity for at least one subtype of IgG or IgA antibody, produced an AUC of 0.686 with a sensitivity of 68.75% and a specificity of 68.46%, respectively (Fig.	('IgA', 'Gene', '973', (50, 53))	('IgA', 'Gene', (50, 53))	('seropositivity', 'Var', (0, 14))	('IgG', 'Gene', (43, 46))
199609	29298684	The sensitivity of P. gingivalis IgA was higher than that of IgG (86.25% vs. 47.82%) but not the specificity (57.54% vs. 71.92%, Fig.	('P. gingivalis', 'Species', '837', (19, 32))	('IgA', 'Gene', (33, 36))	('higher', 'PosReg', (41, 47))	('P. gingivalis', 'Var', (19, 32))	('IgA', 'Gene', '973', (33, 36))
199613	29298684	The prognostic effect of P. gingivalis IgA resembled that of IgG (log-rank test, x2 = 6.800, P = 0.006, median OS of 19.59 months (n = 16) vs. 34.15 months (n = 64), Fig.	('IgA', 'Gene', '973', (39, 42))	('P. gingivalis', 'Var', (25, 38))	('P. gingivalis', 'Species', '837', (25, 38))	('IgA', 'Gene', (39, 42))
199628	29298684	In sharp contrast, titers of IgG and IgA against P. gingivalis in serum of patients with ESCC increased remarkably compared to patients with esophagitis and healthy controls, which provides direct evidence that P. gingivalis is implicated in the pathogenesis of ESCC.	('IgA', 'Gene', (37, 40))	('IgA', 'Gene', '973', (37, 40))	('titers', 'MPA', (19, 25))	('esophagitis', 'Disease', (141, 152))	('implicated', 'Reg', (228, 238))	('esophagitis', 'Phenotype', 'HP:0100633', (141, 152))	('increased', 'PosReg', (94, 103))	('patients', 'Species', '9606', (75, 83))	('esophagitis', 'Disease', 'MESH:D004941', (141, 152))	('P. gingivalis', 'Species', '837', (49, 62))	('P. gingivalis', 'Var', (49, 62))	('ESCC', 'Disease', (89, 93))	('P. gingivalis', 'Species', '837', (211, 224))	('patients', 'Species', '9606', (127, 135))	('ESCC', 'Disease', (262, 266))
199631	29298684	Combination of IgG and IgA for P. gingivalis had an increased AUC (0.671) compared with an individual IgG or IgA.	('IgA', 'Gene', (23, 26))	('IgA', 'Gene', '973', (109, 112))	('IgA', 'Gene', '973', (23, 26))	('increased', 'PosReg', (52, 61))	('IgA', 'Gene', (109, 112))	('P. gingivalis', 'Species', '837', (31, 44))	('P. gingivalis', 'Var', (31, 44))
199632	29298684	For instance, the positive frequencies of both CYFRA21-1 and SCCA in patients with early stage ESCC (stage 0-II) varied from 4.7% to 24%.	('patients', 'Species', '9606', (69, 77))	('CYFRA21-1', 'Var', (47, 56))	('SCCA', 'Gene', (61, 65))
199640	29298684	ESCC with stage 0-II or negative lymphnode metastasis, patients with high level of P. gingivalis IgG or IgA had a significantly lower OS relative to ESCC patients with low level, and patients with high level of both IgG and IgA had the worst prognosis.	('lymphnode metastasis', 'Disease', 'MESH:D009362', (33, 53))	('P. gingivalis', 'Species', '837', (83, 96))	('P. gingivalis', 'Var', (83, 96))	('lymphnode metastasis', 'Disease', (33, 53))	('IgA', 'Gene', (224, 227))	('IgA', 'Gene', '973', (224, 227))	('patients', 'Species', '9606', (154, 162))	('IgA', 'Gene', (104, 107))	('lower', 'NegReg', (128, 133))	('IgA', 'Gene', '973', (104, 107))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (183, 191))
199644	29298684	IgG and IgA for P. gingivalis are potential serum biomarkers for ESCC and combination of IgG and IgA improves the diagnostic and prognostic performance.	('IgA', 'Gene', '973', (8, 11))	('P. gingivalis', 'Species', '837', (16, 29))	('ESCC', 'Disease', (65, 69))	('IgA', 'Gene', (8, 11))	('IgA', 'Gene', (97, 100))	('IgA', 'Gene', '973', (97, 100))	('improves', 'PosReg', (101, 109))	('combination', 'Var', (74, 85))
199650	28864779	RNAi-mediated TCF-3 gene silencing inhibits proliferation of Eca-109 esophageal cancer cells by inducing apoptosis Esophageal cancer (EC) remains an important health problem in China.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gene', 'Var', (20, 24))	('Esophageal cancer', 'Disease', (115, 132))	('inducing', 'Reg', (96, 104))	('esophageal cancer', 'Disease', (69, 86))	('apoptosis', 'CPA', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('TCF-3', 'Gene', '6929', (14, 19))	('silencing inhibits', 'NegReg', (25, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('TCF-3', 'Gene', (14, 19))	('Esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('proliferation', 'CPA', (44, 57))
199666	28864779	Abnormal gene expressions are associated with the advanced stages of EC, and gene silencing could inhibit the growth and development of EC tumors.	('associated', 'Reg', (30, 40))	('EC tumors', 'Disease', (136, 145))	('gene silencing', 'Var', (77, 91))	('men', 'Species', '9606', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('inhibit', 'NegReg', (98, 105))	('EC tumors', 'Disease', 'MESH:D009369', (136, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
199687	28864779	The optical density (OD) at 570 nm was noted and the growth activity of Eca-109 cell (the effect of TCF-3 gene silencing on the growth of Eca-109 cell) was measured.	('TCF-3', 'Gene', '6929', (100, 105))	('silencing', 'NegReg', (111, 120))	('gene', 'Var', (106, 110))	('TCF-3', 'Gene', (100, 105))
199688	28864779	At the same time, the changes in the morphology of the cells before culturing and after TCF-3 gene silencing were observed via an inverted microscope.	('TCF-3', 'Gene', (88, 93))	('gene silencing', 'Var', (94, 108))	('TCF-3', 'Gene', '6929', (88, 93))
199710	28864779	After membranes were cleaned using TBS with Tween 20 (TBST), extracted protein continued to be added with primary antibodies TCF-3 (#2883, Cell Signaling Technology (CST), Beverly, MA, U.S.A.), Bcl-2 (#2870, CST, Beverly, MA, U.S.A.), Bax (#5023, CST, Beverly, MA, U.S.A.), cleaved-caspase-3 (#9665, CST, Beverly, MA, U.S.A.), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH, as an internal reference) for incubation overnight.	('TBS', 'Chemical', 'MESH:D013725', (35, 38))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (331, 371))	('GAPDH', 'Gene', '2597', (373, 378))	('GAPDH', 'Gene', (373, 378))	('Bax', 'Gene', (235, 238))	('caspase-3', 'Gene', '836', (282, 291))	('Bcl-2', 'Gene', (194, 199))	('TBST', 'Chemical', '-', (54, 58))	('Bcl-2', 'Gene', '596', (194, 199))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (331, 371))	('TCF-3', 'Gene', '6929', (125, 130))	('TBS', 'Chemical', 'MESH:D013725', (54, 57))	('TCF-3', 'Gene', (125, 130))	('Bax', 'Gene', '581', (235, 238))	('#9665', 'Var', (293, 298))	('Tween 20', 'Chemical', 'MESH:D011136', (44, 52))	('caspase-3', 'Gene', (282, 291))
199720	28864779	The result of MTT assay showed that TCF-3 gene silencing could inhibit the proliferation of Eca-109 cells, and the rate of inhibition eventually improved with time and was the highest at 72 h. No such significant difference was found between the control group and the NC group (P=0.68, P=0.73) (Figure 3).	('TCF-3', 'Gene', (36, 41))	('TCF-3', 'Gene', '6929', (36, 41))	('rat', 'Species', '10116', (115, 118))	('gene silencing', 'Var', (42, 56))	('rat', 'Species', '10116', (82, 85))	('MTT', 'Chemical', 'MESH:C070243', (14, 17))	('proliferation', 'CPA', (75, 88))	('inhibit', 'NegReg', (63, 70))
199722	28864779	The BrDU assay demonstrated that TCF-3 gene silencing inhibited the Eca-109 cells proliferation (Figure 5).	('inhibited', 'NegReg', (54, 63))	('gene silencing', 'Var', (39, 53))	('Eca-109 cells proliferation', 'CPA', (68, 95))	('rat', 'Species', '10116', (22, 25))	('rat', 'Species', '10116', (89, 92))	('TCF-3', 'Gene', (33, 38))	('TCF-3', 'Gene', '6929', (33, 38))
199726	28864779	The results showed that TCF-3 gene silencing could arrest Eca-109 cells in G0/G1-phase (Figure 6).	('arrest', 'NegReg', (51, 57))	('gene silencing', 'Var', (30, 44))	('TCF-3', 'Gene', '6929', (24, 29))	('TCF-3', 'Gene', (24, 29))	('Eca-109 cells in G0/G1-phase', 'CPA', (58, 86))
199729	28864779	These results proved that TCF-3 gene silencing could promote apoptosis of Eca-109 cells (P<0.01) (Figure 7).	('TCF-3', 'Gene', '6929', (26, 31))	('apoptosis', 'CPA', (61, 70))	('TCF-3', 'Gene', (26, 31))	('promote', 'PosReg', (53, 60))	('gene silencing', 'Var', (32, 46))
199733	28864779	Our study investigated the role of TCF-3 in Eca-109 cells, and the results indicated that TCF-3 gene silencing could significantly inhibit the proliferation and further growth of Eca-109 cells and induces cell apoptosis.	('cell apoptosis', 'CPA', (205, 219))	('inhibit', 'NegReg', (131, 138))	('rat', 'Species', '10116', (150, 153))	('gene silencing', 'Var', (96, 110))	('TCF-3', 'Gene', '6929', (90, 95))	('TCF-3', 'Gene', (35, 40))	('TCF-3', 'Gene', '6929', (35, 40))	('TCF-3', 'Gene', (90, 95))	('proliferation', 'CPA', (143, 156))	('induces', 'Reg', (197, 204))
199735	28864779	As reflected by another study, it was found that after silencing by RNAi, the mRNA and protein expressions of galectin-3 were decreased.	('decreased', 'NegReg', (126, 135))	('silencing', 'Var', (55, 64))	('galectin-3', 'Gene', (110, 120))	('galectin-3', 'Gene', '3958', (110, 120))
199736	28864779	In general, activating TCF-3 serves as a gene aggravating inflammation.	('TCF-3', 'Gene', (23, 28))	('activating', 'Var', (12, 22))	('inflammation', 'Disease', 'MESH:D007249', (58, 70))	('TCF-3', 'Gene', '6929', (23, 28))	('inflammation', 'Disease', (58, 70))
199737	28864779	This result indicates that silencing TCF-3 gene could decrease the number of cancer cells.	('decrease', 'NegReg', (54, 62))	('silencing', 'Var', (27, 36))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TCF-3', 'Gene', '6929', (37, 42))	('TCF-3', 'Gene', (37, 42))
199738	28864779	Moreover, our study showed that TCF-3 gene silencing induced arrest of Eca-109 cells in G0/G1 cell phase and decreased the proliferation of Eca-109 cells.	('TCF-3', 'Gene', (32, 37))	('proliferation', 'CPA', (123, 136))	('decreased', 'NegReg', (109, 118))	('gene silencing', 'Var', (38, 52))	('arrest', 'CPA', (61, 67))	('rat', 'Species', '10116', (130, 133))	('TCF-3', 'Gene', '6929', (32, 37))	('G0/G1 cell phase', 'CPA', (88, 104))
199739	28864779	had suggested that silencing of TCF-3 contributed to the decrease in the proliferation of prostate cancer cells, and interestingly, the number of cells in the G1-phase significantly increased, whereas the cells in G2-phase decreased, which demonstrated the cell cycle arrest of cancer cells was induced and the proliferation was regressed.	('TCF-3', 'Gene', (32, 37))	('increased', 'PosReg', (182, 191))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('rat', 'Species', '10116', (318, 321))	('cancer', 'Disease', (278, 284))	('prostate cancer', 'Disease', (90, 105))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (257, 274))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('decreased', 'NegReg', (223, 232))	('rat', 'Species', '10116', (80, 83))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('TCF-3', 'Gene', '6929', (32, 37))	('silencing', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('decrease', 'NegReg', (57, 65))	('proliferation', 'CPA', (73, 86))	('cell cycle arrest', 'CPA', (257, 274))	('cancer', 'Disease', (99, 105))	('rat', 'Species', '10116', (247, 250))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
199741	28864779	Abnormal expressions of Wnt signaling pathway components are reported in several cancers, including EC, and it is also involved in cancer development and progression.	('cancer', 'Disease', (131, 137))	('involved', 'Reg', (119, 127))	('Abnormal expressions', 'Phenotype', 'HP:0100022', (0, 20))	('men', 'Species', '9606', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancers', 'Disease', (81, 88))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('Abnormal', 'Var', (0, 8))	('Wnt', 'Gene', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('reported', 'Reg', (61, 69))	('expressions', 'MPA', (9, 20))
199746	28864779	have identified that the high levels of TCF-3 gene are strongly correlated with basal-like tumors and TCF-3 gene silencing decreased the ability of cancer cells for initiation of tumor formation, and contributed to reduced rates of tumor growth.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('TCF-3', 'Gene', (40, 45))	('TCF-3', 'Gene', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', (91, 96))	('rat', 'Species', '10116', (223, 226))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('silencing decreased', 'NegReg', (113, 132))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('reduced', 'NegReg', (215, 222))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (232, 237))	('TCF-3', 'Gene', '6929', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('TCF-3', 'Gene', '6929', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('correlated', 'Reg', (64, 74))	('cancer', 'Disease', (148, 154))	('tumors', 'Disease', (91, 97))	('rates', 'MPA', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gene', 'Var', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (179, 184))
199747	28864779	TCF-3 silencing relatively slowed down the further growth of gastric cancer cells, and the proliferation rate and colony formation of cells were reduced as well.	('reduced', 'NegReg', (145, 152))	('TCF-3', 'Gene', '6929', (0, 5))	('rat', 'Species', '10116', (105, 108))	('gastric cancer', 'Disease', (61, 75))	('TCF-3', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('slowed down', 'NegReg', (27, 38))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('colony formation of cells', 'CPA', (114, 139))	('rat', 'Species', '10116', (98, 101))	('proliferation rate', 'CPA', (91, 109))	('further growth of', 'CPA', (43, 60))	('silencing', 'Var', (6, 15))
199748	28864779	The apoptosis rate of Eca-109 cells was improved after TCF-3 was silenced, and the expression of apoptosis-related protein Bcl-2 decreased, while caspase-3 and Bax expressions increased.	('caspase-3', 'Gene', (146, 155))	('Bcl-2', 'Gene', (123, 128))	('expressions', 'MPA', (164, 175))	('silenced', 'Var', (65, 73))	('increased', 'PosReg', (176, 185))	('Bax', 'Gene', (160, 163))	('caspase-3', 'Gene', '836', (146, 155))	('TCF-3', 'Gene', (55, 60))	('expression', 'MPA', (83, 93))	('improved', 'PosReg', (40, 48))	('apoptosis rate', 'CPA', (4, 18))	('TCF-3', 'Gene', '6929', (55, 60))	('Bax', 'Gene', '581', (160, 163))	('decreased', 'NegReg', (129, 138))	('Bcl-2', 'Gene', '596', (123, 128))	('rat', 'Species', '10116', (14, 17))
199750	28864779	It has been proved that activating TCF-3 was capable of repressing Bax transcription.	('activating', 'Var', (24, 34))	('repressing', 'NegReg', (56, 66))	('Bax', 'Gene', '581', (67, 70))	('TCF-3', 'Gene', (35, 40))	('TCF-3', 'Gene', '6929', (35, 40))	('Bax', 'Gene', (67, 70))
199753	28864779	And it is also suggested that the high expression of Bcl-2 could relatively prevent cell apoptosis and result in blocking apoptosis induced by various agents in different kinds of cells.	('high expression', 'Var', (34, 49))	('apoptosis', 'CPA', (122, 131))	('Bcl-2', 'Gene', (53, 58))	('Bcl-2', 'Gene', '596', (53, 58))	('blocking', 'NegReg', (113, 121))	('prevent', 'NegReg', (76, 83))	('cell apoptosis', 'CPA', (84, 98))
199754	28864779	To sum up, our study proved that as a member of transcription factor family, TCF-3 acts as an advocator and promoter for EC, and the silenced TCF-3 could decrease the growth, viability, colony formation, and proliferation of Eca-109 cells.	('TCF-3', 'Gene', (77, 82))	('TCF-3', 'Gene', '6929', (77, 82))	('colony formation', 'CPA', (186, 202))	('viability', 'CPA', (175, 184))	('rat', 'Species', '10116', (215, 218))	('decrease', 'NegReg', (154, 162))	('proliferation', 'CPA', (208, 221))	('TCF-3', 'Gene', '6929', (142, 147))	('growth', 'CPA', (167, 173))	('TCF-3', 'Gene', (142, 147))	('silenced', 'Var', (133, 141))
199755	28864779	Besides, the apoptosis rate of Eca-109 cells was enhanced after TCF-3 gene was silenced.	('TCF-3', 'Gene', '6929', (64, 69))	('silenced', 'Var', (79, 87))	('enhanced', 'PosReg', (49, 57))	('TCF-3', 'Gene', (64, 69))	('rat', 'Species', '10116', (23, 26))	('apoptosis rate', 'CPA', (13, 27))
199756	28864779	Therefore, silencing TCF-3 gene might serve as a novel target for EC.	('silencing', 'Var', (11, 20))	('TCF-3', 'Gene', (21, 26))	('TCF-3', 'Gene', '6929', (21, 26))
199772	27347110	Abnormalities in the cell cycle are essential in the process of human carcinogenesis, resulting in an increase in cell proliferation and/or a reduction in the death of abnormal cells.	('reduction', 'NegReg', (142, 151))	('human', 'Species', '9606', (64, 69))	('carcinogenesis', 'Disease', (70, 84))	('Abnormalities', 'Var', (0, 13))	('Abnormalities in the cell cycle', 'Phenotype', 'HP:0011018', (0, 31))	('carcinogenesis', 'Disease', 'MESH:D063646', (70, 84))	('increase', 'PosReg', (102, 110))	('cell proliferation', 'CPA', (114, 132))	('death of abnormal cells', 'CPA', (159, 182))
199773	27347110	Several key proteins are required to maintain the integrity of the normal cell cycle, and aberrant expression of proteins such as cyclins A and B1 leads to an abnormal cell cycle.	('expression', 'MPA', (99, 109))	('cyclins A and B1', 'Gene', '379888', (130, 146))	('cell cycle', 'CPA', (168, 178))	('leads to', 'Reg', (147, 155))	('aberrant', 'Var', (90, 98))	('abnormal cell cycle', 'Phenotype', 'HP:0011018', (159, 178))	('expression', 'Species', '29278', (99, 109))
199827	27347110	Thanks to the advances in molecular and cellular biology of tumors, it is well known that the occurrence of EC is partly due to acquired alterations in oncogenes and tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('oncogenes', 'Protein', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (60, 65))	('alterations', 'Var', (137, 148))	('tumors', 'Disease', (60, 66))
199829	27347110	Misregulation of the G1-S transition is an essential component of the cellular transformation process in the cell cycle, and G1-S regulatory defects have been reported in numerous types of human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (195, 207))	('human', 'Species', '9606', (189, 194))	('reported', 'Reg', (159, 167))	('Misregulation', 'Var', (0, 13))	('malignancies', 'Disease', (195, 207))
199840	27347110	The results of survival analysis demonstrated that high expression of Emi1 was strongly correlated with poor prognosis, while multivariate analysis revealed that high expression of Emi1 was an independent unfavorable prognostic factor.	('Emi1', 'Gene', (70, 74))	('expression', 'Species', '29278', (56, 66))	('high', 'Var', (51, 55))	('expression', 'Species', '29278', (167, 177))	('Emi1', 'Gene', (181, 185))
199845	27347110	Furthermore, the present data revealed that silencing Emi1 expression could suppress ECA109 cell proliferation.	('ECA109 cell proliferation', 'CPA', (85, 110))	('suppress', 'NegReg', (76, 84))	('expression', 'Species', '29278', (59, 69))	('Emi1', 'Gene', (54, 58))	('silencing', 'Var', (44, 53))
199848	27347110	The E2F signaling pathway is frequently activated in highly proliferative cells, and the central proteins of the retinoblastoma (Rb)/E2F signaling pathway, including p16INK4a, Rb and cyclin D, are frequently mutated in cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('Rb', 'Phenotype', 'HP:0009919', (129, 131))	('E2F signaling pathway', 'Pathway', (4, 25))	('retinoblastoma', 'Phenotype', 'HP:0009919', (113, 127))	('proteins of the retinoblastoma', 'Disease', 'MESH:D012175', (97, 127))	('proteins of the retinoblastoma', 'Disease', (97, 127))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('Rb', 'Phenotype', 'HP:0009919', (176, 178))	('mutated', 'Var', (208, 215))	('p16INK4a', 'Var', (166, 174))	('cancer', 'Disease', (219, 225))
199850	25583674	Aberrant DNA hypermethylation reduces the expression of the desmosome-related molecule periplakin in esophageal squamous cell carcinoma Periplakin (PPL), a member of the plakin family of proteins that localizes to desmosomes and intermediate filaments, is downregulated in human esophageal squamous cell carcinoma (ESCC).	('downregulated', 'NegReg', (256, 269))	('Aberrant', 'Var', (0, 8))	('human', 'Species', '9606', (273, 278))	('Periplakin', 'Gene', '5493', (136, 146))	('expression', 'MPA', (42, 52))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (279, 313))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (101, 135))	('Periplakin', 'Gene', (136, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('periplakin', 'Gene', '5493', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (290, 313))	('esophageal squamous cell carcinoma', 'Disease', (279, 313))	('esophageal squamous cell carcinoma', 'Disease', (101, 135))	('reduces', 'NegReg', (30, 37))	('periplakin', 'Gene', (87, 97))
199852	25583674	Bisulfite-pyrosequencing of 17 cases demonstrated that the frequency of PPL methylation was higher in ESCC tissues than in normal tissues.	('PPL', 'MPA', (72, 75))	('ESCC', 'Disease', (102, 106))	('higher', 'Reg', (92, 98))	('methylation', 'Var', (76, 87))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))
199863	25583674	In pharyngeal cancer cells, PPL knockdown is related to reduced cellular movement and attachment activity.	('cancer', 'Disease', (14, 20))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (3, 20))	('PPL', 'Gene', (28, 31))	('reduced', 'NegReg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('knockdown', 'Var', (32, 41))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cellular movement', 'CPA', (64, 81))	('attachment activity', 'CPA', (86, 105))
199867	25583674	In squamous cell carcinoma, the hypermethylation of some genes is related to clinicopathological features including poor prognosis and treatment responses.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('hypermethylation', 'Var', (32, 48))	('related', 'Reg', (66, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('squamous cell carcinoma', 'Disease', (3, 26))
199871	25583674	Human ESCC lines KYSE70, KYSE140, KYSE150, KYSE270, KYSE410, and KYSE510 were obtained from the Japanese Collection of Research Bioresources Cell Bank (Osaka, Japan) on 13 August 2013.	('Human', 'Species', '9606', (0, 5))	('KYSE270', 'CellLine', 'CVCL:1350', (43, 50))	('KYSE270', 'Var', (43, 50))	('KYSE140', 'Var', (25, 32))	('KYSE510', 'Var', (65, 72))	('KYSE410', 'Var', (52, 59))	('KYSE150', 'Var', (34, 41))
199877	25583674	The TaqMan Gene-expression assay IDs used in this study for PPL, and EVPL were Hs00160312_m1 and Hs00157430_m1, respectively.	('Hs00160312_m1', 'Var', (79, 92))	('EVPL', 'Gene', '2125', (69, 73))	('EVPL', 'Gene', (69, 73))	('Hs00157430_m1', 'Var', (97, 110))
199894	25583674	Promoter methylation is a frequent event in cancers including ESCC and is associated with transcriptional repression and the subsequent reduction or loss of gene function.	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('Promoter methylation', 'Var', (0, 20))	('ESCC', 'Disease', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('transcriptional', 'MPA', (90, 105))
199898	25583674	In addition, the relative PPL expression levels in tumors were negatively correlated with the increase in DNA methylation levels (Fig.1D), indicating that aberrant hypermethylation of the PPL promoter in ESCC was likely the cause of the downregulated expression.	('DNA methylation levels', 'MPA', (106, 128))	('aberrant hypermethylation', 'Var', (155, 180))	('hypermethylation', 'Var', (164, 180))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('negatively', 'NegReg', (63, 73))	('expression', 'MPA', (251, 261))	('PPL expression levels', 'MPA', (26, 47))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('PPL', 'Gene', (188, 191))
199900	25583674	In all the cell lines, treatment with 5-aza-dC resulted in the trend of increased the expression of PPL mRNA and reached statistically significant levels in five cell lines (Fig.1E).	('5-aza-dC', 'Var', (38, 46))	('increased', 'PosReg', (72, 81))	('PPL', 'Gene', (100, 103))	('expression', 'MPA', (86, 96))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (38, 46))
199901	25583674	The DNA methylation levels of the untreated KYSE270 ESCC cells were as high as 90%, and those of the cells treated with low concentration of 5-aza-dC (0.1 mumol/L) decreased to around 60%.	('decreased', 'NegReg', (164, 173))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (141, 149))	('KYSE270', 'Var', (44, 51))	('KYSE270 ESCC', 'CellLine', 'CVCL:1350', (44, 56))	('DNA methylation levels', 'MPA', (4, 26))
199903	25583674	The methylation and expression levels strongly suggest that PPL expression was silenced by DNA hypermethylation in the PPL promoter in both the tumor samples and the tumor cell lines.	('silenced', 'NegReg', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', (144, 149))	('DNA hypermethylation', 'Var', (91, 111))	('expression', 'MPA', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('PPL', 'Gene', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
199908	25583674	We tested adherence to various extracellular matrices and found that the PPL transfectants adhered more strongly to collagen, fibronectin, or laminin-coated plate compared with the mock transfectants (Fig.3B).	('strongly', 'PosReg', (104, 112))	('fibronectin', 'Gene', (126, 137))	('transfectants', 'Var', (77, 90))	('tested', 'Reg', (3, 9))	('fibronectin', 'Gene', '2335', (126, 137))	('PPL transfectants', 'Var', (73, 90))	('adhered', 'CPA', (91, 98))
199909	25583674	In addition, the wound-healing assay showed that wound closure of the PPL-transfected KYSE270 cells was remarkably delayed compared with that of the mock-transfected cells (Fig.3C).	('KYSE270', 'CellLine', 'CVCL:1350', (86, 93))	('delayed', 'NegReg', (115, 122))	('wound closure', 'CPA', (49, 62))	('PPL-transfected', 'Var', (70, 85))	('wound-healing assay', 'CPA', (17, 36))
199912	25583674	EVPL, another desmosomal protein, forms heterodimer with PPL in epidermal squamous cells, and its somatic mutation is linked to ESCC.	('heterodimer', 'MPA', (40, 51))	('mutation', 'Var', (106, 114))	('linked', 'Reg', (118, 124))	('EVPL', 'Gene', (0, 4))	('ESCC', 'Disease', (128, 132))	('EVPL', 'Gene', '2125', (0, 4))
199914	25583674	The expression of EVPL was strikingly downregulated in both mock and PPL transfectants, and there was no difference between mock and PPL transfectants, indicating that EVPL expression was not induced in PPL transfection.	('EVPL', 'Gene', (168, 172))	('EVPL', 'Gene', (18, 22))	('EVPL', 'Gene', '2125', (168, 172))	('EVPL', 'Gene', '2125', (18, 22))	('expression', 'MPA', (4, 14))	('downregulated', 'NegReg', (38, 51))	('transfectants', 'Var', (73, 86))
199919	25583674	The environmental risk factors affect the condition of the epithelial mucosa, inducing mutations and epigenetic changes, which accumulate, induce mucosal dysplasia, and eventually develop into invasive squamous cell carcinoma.	('invasive squamous cell carcinoma', 'Disease', (193, 225))	('mucosal dysplasia', 'Disease', (146, 163))	('mutations', 'Var', (87, 96))	('mucosal dysplasia', 'Disease', 'MESH:D052016', (146, 163))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (193, 225))	('induce', 'Reg', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('develop', 'Reg', (180, 187))	('epigenetic changes', 'Var', (101, 119))	('inducing', 'Reg', (78, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (202, 225))
199920	25583674	A previous global study using bead arrays to detect promoter-DNA methylation demonstrated that a total of 37 CpG sites were differentially methylated between esophageal squamous cell tumors and background mucosa.	('esophageal squamous cell tumors', 'Disease', 'MESH:D000077277', (158, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('esophageal squamous cell tumors', 'Disease', (158, 189))	('differentially', 'Reg', (124, 138))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('squamous cell tumors', 'Phenotype', 'HP:0002860', (169, 189))	('methylated', 'Var', (139, 149))
199924	25583674	On the other hand, a clear recovery of PPL mRNA was observed in association with the decreased DNA methylation, suggesting that the PPL promoter is likely to be around 50% methylated even in normal cells and that additional hypermethylation in tumors affects PPL expression.	('PPL mRNA', 'MPA', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('PPL expression', 'MPA', (259, 273))	('hypermethylation', 'Var', (224, 240))	('affects', 'Reg', (251, 258))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))
199926	25583674	As a matter of fact, the presence of aberrant DNA hypermethylation in noncancerous esophageal mucosa of ESCC cases was reported in association with smoking history.	('noncancerous esophageal mucosa', 'Disease', 'MESH:D004941', (70, 100))	('aberrant DNA hypermethylation', 'Var', (37, 66))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('noncancerous esophageal mucosa', 'Disease', (70, 100))	('ESCC', 'Disease', (104, 108))
199932	25583674	When the loss of PPL in the cancer cell lines was compensated for, by gene transfection, the cells became smaller and acquired a more cylinder-like shape with the ability to grow in stratified layers, indicating that cells gained the ability to differentiate to squamous epithelial cells.	('PPL', 'Gene', (17, 20))	('gene transfection', 'Var', (70, 87))	('smaller', 'NegReg', (106, 113))	('gained', 'PosReg', (223, 229))	('differentiate', 'CPA', (245, 258))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('loss', 'NegReg', (9, 13))	('acquired', 'PosReg', (118, 126))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
199934	25583674	The authors found that PPL knockdown decreased tumor cell growth, adhesion to ECM.	('ECM', 'Gene', (78, 81))	('knockdown', 'Var', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ECM', 'Gene', '22915', (78, 81))	('decreased', 'NegReg', (37, 46))	('PPL', 'Gene', (23, 26))	('tumor', 'Disease', (47, 52))
199937	25583674	In this sense, PPL loss induced by promoter hypermethylation may contribute to the malignancy of metastatic ESCC.	('promoter hypermethylation', 'Var', (35, 60))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('loss', 'NegReg', (19, 23))	('PPL', 'MPA', (15, 18))	('metastatic ESCC', 'Disease', (97, 112))	('malignancy', 'Disease', (83, 93))	('contribute', 'Reg', (65, 75))
199939	20169125	Later, with the development of monoclonal antibodies, it became possible to recognize, within the T-cells, functional populations:  CD4+ and CD8+.	('CD', 'Phenotype', 'HP:0100280', (141, 143))	('CD8', 'Gene', (141, 144))	('CD4+', 'Var', (132, 136))	('CD8', 'Gene', '925', (141, 144))	('CD', 'Phenotype', 'HP:0100280', (132, 134))
199958	20169125	As a consequence, abnormalities in the number and functions of Tregs have been implicated in the pathogenesis of the abovementioned clinical conditions.	('Tregs', 'CPA', (63, 68))	('functions', 'MPA', (50, 59))	('Tregs', 'Chemical', '-', (63, 68))	('implicated', 'Reg', (79, 89))	('abnormalities', 'Var', (18, 31))
199961	20169125	Mutations in FoxP3 are associated with the inherited autoimmune disease, Scurfy in mice, and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome) in human.	('IPEX', 'Gene', (93, 97))	('autoimmune disease', 'Disease', (53, 71))	('X-linked syndrome', 'Disease', (158, 175))	('autoimmune disease', 'Disease', 'MESH:D001327', (53, 71))	('enteropathy', 'Disease', (141, 152))	('enteropathy', 'Disease', 'MESH:C538273', (141, 152))	('mice', 'Species', '10090', (83, 87))	('Mutations', 'Var', (0, 9))	('IPEX', 'Gene', '50943', (93, 97))	('immune dysregulation', 'Phenotype', 'HP:0002958', (99, 119))	('associated', 'Reg', (23, 33))	('human', 'Species', '9606', (180, 185))	('autoimmune disease', 'Phenotype', 'HP:0002960', (53, 71))	('polyendocrinopathy', 'Disease', 'MESH:D016884', (121, 139))	('Scurfy', 'Disease', (73, 79))	('polyendocrinopathy', 'Disease', (121, 139))	('FoxP3', 'Gene', (13, 18))	('X-linked syndrome', 'Disease', 'MESH:C564486', (158, 175))	('enteropathy', 'Phenotype', 'HP:0002242', (141, 152))
199963	20169125	Beyond IPEX, mutations of FoxP3 have been seen associated also with an absence of Tregs.	('absence', 'NegReg', (71, 78))	('FoxP3', 'Gene', (26, 31))	('Tregs', 'Chemical', '-', (82, 87))	('IPEX', 'Gene', (7, 11))	('absence of Tregs', 'Phenotype', 'HP:0030336', (71, 87))	('IPEX', 'Gene', '50943', (7, 11))	('mutations', 'Var', (13, 22))	('Tregs', 'CPA', (82, 87))
199974	20169125	So, the expression of CD39 in concert with CD73, another ectonucleotidase present on the surface of lymphocytes, can further distinguish CD4+/CD25+/FoxP3+ Treg cells from other T-cells.	('CD', 'Phenotype', 'HP:0100280', (22, 24))	('CD39', 'Gene', (22, 26))	('CD73', 'Gene', (43, 47))	('CD', 'Phenotype', 'HP:0100280', (137, 139))	('CD4+/CD25+/FoxP3+', 'Var', (137, 154))	('CD73', 'Gene', '4907', (43, 47))	('CD', 'Phenotype', 'HP:0100280', (142, 144))	('distinguish', 'Reg', (125, 136))	('CD', 'Phenotype', 'HP:0100280', (43, 45))
199979	20169125	A functionally important proportion of Tregs (the nTregs) originates from the thymus; nevertheless, in 2006, Chatenoud and Bach reported that Tregs are not present as such in the thymus; they derive from peripheral precursors that are CD4+CD25- and differentiate into functional Tregs following adequate stimulation in the presence of the cognate antigen and specialized immunoregulatory cytokines, such as TGF-beta, IL-10, and IL-4; they are generally termed "adaptive" Tregs.	('Bach', 'Gene', '11332', (123, 127))	('Tregs', 'Chemical', '-', (39, 44))	('CD', 'Phenotype', 'HP:0100280', (235, 237))	('CD', 'Phenotype', 'HP:0100280', (239, 241))	('CD4+CD25-', 'Var', (235, 244))	('IL-4', 'Gene', '3565', (428, 432))	('TGF-beta', 'Gene', '7040', (407, 415))	('Bach', 'Gene', (123, 127))	('TGF-beta', 'Gene', (407, 415))	('Tregs', 'Chemical', '-', (471, 476))	('Tregs', 'Chemical', '-', (142, 147))	('Tregs', 'Chemical', '-', (279, 284))	('Tregs', 'Chemical', '-', (51, 56))	('IL-4', 'Gene', (428, 432))
200002	20169125	Moreover, because of the presence of the ectoenzymes CD39 and CD73 on the cellular surface of Tregs, these cells are also able to modulate cellular inhibition, through the production of pericellular adenosine (Ado) from ATP.	('CD', 'Phenotype', 'HP:0100280', (53, 55))	('CD39', 'Var', (53, 57))	('ATP', 'Chemical', 'MESH:D000255', (220, 223))	('CD73', 'Gene', '4907', (62, 66))	('Ado', 'Chemical', 'MESH:D000241', (210, 213))	('cellular inhibition', 'CPA', (139, 158))	('CD', 'Phenotype', 'HP:0100280', (62, 64))	('modulate', 'Reg', (130, 138))	('CD73', 'Gene', (62, 66))	('pericellular adenosine', 'Chemical', '-', (186, 208))	('Tregs', 'Chemical', '-', (94, 99))
200006	20169125	described the role of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a protein highly expressed by Tregs, which inhibits the immune response; CTLA-4 binds the costimulatory molecules CD80 (B7-1) and CD86 (B7-2) with higher affinity than CD28, inhibiting the second signal, necessary to immune activation.	('inhibiting', 'NegReg', (239, 249))	('CD80', 'Gene', (179, 183))	('binds', 'Interaction', (145, 150))	('CTLA-4', 'Var', (138, 144))	('CD86', 'Gene', '942', (195, 199))	('CD86', 'Gene', (195, 199))	('Tregs', 'Chemical', '-', (95, 100))	('cytotoxic T-lymphocyte antigen-4', 'Gene', (22, 54))	('cytotoxic T-lymphocyte antigen-4', 'Gene', '1493', (22, 54))	('CD80', 'Gene', '941', (179, 183))	('CD28', 'Gene', (233, 237))	('CD', 'Phenotype', 'HP:0100280', (179, 181))	('CD', 'Phenotype', 'HP:0100280', (233, 235))	('CD', 'Phenotype', 'HP:0100280', (195, 197))	('second signal', 'MPA', (254, 267))	('CD28', 'Gene', '940', (233, 237))
200008	20169125	In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts.	('autoimmune diseases', 'Disease', 'MESH:D001327', (122, 141))	('human', 'Species', '9606', (185, 190))	('autoimmune diseases', 'Disease', (122, 141))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (122, 141))	('mice', 'Species', '10090', (58, 62))	('autoimmune disease', 'Phenotype', 'HP:0002960', (122, 140))	('blockade', 'Var', (8, 16))	('CTLA-4', 'Gene', (20, 26))
200067	20169125	Compared with healthy patients, patients with gastrointestinal malignancies had a higher proportion of CD4+ CD25+ T-cells in peripheral blood.	('gastrointestinal malignancies', 'Disease', (46, 75))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (22, 30))	('CD', 'Phenotype', 'HP:0100280', (103, 105))	('CD', 'Phenotype', 'HP:0100280', (108, 110))	('CD4+ CD25+', 'Var', (103, 113))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (46, 75))
200108	20169125	Deficiency of vitamin A can lead to exacerbated experimental colitis, and supplementation of vitamin A results in amelioration of diarrhea.	('diarrhea', 'Disease', (130, 138))	('vitamin A', 'Chemical', 'MESH:D014801', (14, 23))	('colitis', 'Phenotype', 'HP:0002583', (61, 68))	('diarrhea', 'Disease', 'MESH:D003967', (130, 138))	('diarrhea', 'Phenotype', 'HP:0002014', (130, 138))	('vitamin A', 'Chemical', 'MESH:D014801', (93, 102))	('exacerbated', 'PosReg', (36, 47))	('colitis', 'Disease', 'MESH:D003092', (61, 68))	('colitis', 'Disease', (61, 68))	('Deficiency of vitamin A', 'Phenotype', 'HP:0004905', (0, 23))	('Deficiency', 'Var', (0, 10))
200113	20169125	According to what was reviewed by O'Connor et al., it has been verified that the absence of IL-17A or IL-17R in T-cells led to an accelerated and severe wasting disease accompanied by higher expression of genes encoding TH1-type of cytokines.	('wasting disease', 'Disease', (153, 168))	('absence', 'Var', (81, 88))	('accelerated', 'PosReg', (130, 141))	('IL-17R', 'Gene', '23765', (102, 108))	('TH1', 'Gene', '51497', (220, 223))	('IL-17A', 'Gene', (92, 98))	('IL-17R', 'Gene', (102, 108))	('wasting disease', 'Disease', 'MESH:D019282', (153, 168))	('higher', 'PosReg', (184, 190))	('TH1', 'Gene', (220, 223))	('expression', 'MPA', (191, 201))	('wasting disease', 'Phenotype', 'HP:0004326', (153, 168))	('IL-17A', 'Gene', '3605', (92, 98))
200115	20169125	This datum indicates that the presence of IL-17 within its receptor (IL-17R) is a favorable prognostic factor in the modulation of the pathogenesis of IBD, diminishing the activation of T-cells in TH1 sense.	('IL-17', 'Gene', '3605', (42, 47))	('IBD', 'Disease', (151, 154))	('TH1', 'Gene', (197, 200))	('IL-17', 'Gene', (69, 74))	('IL-17', 'Gene', '3605', (69, 74))	('IL-17', 'Gene', (42, 47))	('activation', 'MPA', (172, 182))	('diminishing', 'NegReg', (156, 167))	('presence', 'Var', (30, 38))	('TH1', 'Gene', '51497', (197, 200))	('IL-17R', 'Gene', '23765', (69, 75))	('IL-17R', 'Gene', (69, 75))
200119	20169125	Furthermore, helminthes have been demonstrated to protect against colonic inflammation, and Tregs were suggested to be responsible for this protective effect; in fact helminthes impede TH1 and TH2 responses generating an immunoregulatory environment via Treg, IL-10, and/or TGF-beta.	('colonic inflammation', 'Disease', 'MESH:D007249', (66, 86))	('colonic inflammation', 'Disease', (66, 86))	('Tregs', 'Chemical', '-', (92, 97))	('TH1', 'Gene', '51497', (185, 188))	('TGF-beta', 'Gene', '7040', (274, 282))	('immunoregulatory environment', 'MPA', (221, 249))	('TGF-beta', 'Gene', (274, 282))	('impede', 'NegReg', (178, 184))	('helminthes', 'Var', (167, 177))	('TH1', 'Gene', (185, 188))
200143	20169125	Several polymorphisms in the IL-23R gene locus were associated with either susceptibility or resistance to CD.	('IL-23R', 'Gene', (29, 35))	('associated', 'Reg', (52, 62))	('IL-23R', 'Gene', '149233', (29, 35))	('CD', 'Phenotype', 'HP:0100280', (107, 109))	('CD', 'Disease', 'MESH:D006223', (107, 109))	('resistance', 'CPA', (93, 103))	('polymorphisms', 'Var', (8, 21))
200242	32130837	In the current study, chest X-ray images were taken approximately 5 minutes after VFSS, and thus presence of residual barium in esophagus can be considered as abnormal esophageal motility.	('abnormal esophageal motility', 'Phenotype', 'HP:0030895', (159, 187))	('abnormal esophageal motility', 'Disease', (159, 187))	('presence', 'Var', (97, 105))	('barium', 'Chemical', 'MESH:D001464', (118, 124))	('abnormal esophageal motility', 'Disease', 'MESH:D015154', (159, 187))	('barium in esophagus', 'Phenotype', 'HP:0100580', (118, 137))
200300	30941657	However, nCRT was associated with greater tumor downstaging and better DFS.	('DFS', 'MPA', (71, 74))	('tumor', 'Disease', (42, 47))	('nCRT', 'Var', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
200374	30941657	In line with their study, we found that nCRT can lead to more favorable outcomes in SRC patients.	('nCRT', 'Var', (40, 44))	('patients', 'Species', '9606', (88, 96))	('SRC patients', 'Disease', (84, 96))
200437	31105479	As shown in Figure 4A, the lncRNAs TCONS_00062404 and TCONS_00012350 are predicted to cis-regulate the genes Serpina9 and Rnps1, respectively.	('Rnps1', 'Gene', '287113', (122, 127))	('Rnps1', 'Gene', (122, 127))	('TCONS_00012350', 'Var', (54, 68))	('TCONS_00062404', 'Var', (35, 49))	('Serpina9', 'Gene', (109, 117))	('Serpina9', 'Gene', '299274', (109, 117))
200438	31105479	As shown in Figure 4B, 40 interaction relationships were detected between 3 DEL transcripts (TCONS_00076064, TCONS_00008311, and TCONS_00012350) and 34 protein-coding genes in the rat reference genome.	('rat', 'Species', '10116', (180, 183))	('TCONS_00076064', 'Var', (93, 107))	('TCONS_00008311', 'Var', (109, 123))	('TCONS_00012350', 'Var', (129, 143))	('interaction', 'Interaction', (26, 37))
200451	31105479	Studies of epigenetic regulation to potentiate esophageal squamous cell carcinoma have recently emerged.	('epigenetic regulation', 'Var', (11, 32))	('esophageal squamous cell carcinoma', 'Disease', (47, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (47, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('potentiate', 'PosReg', (36, 46))
200471	31019568	The silencing of LINC01419 led to decreased proliferation, increased apoptosis, and enhanced sensitivity to 5-FU in ESCC cells.	('LINC01419', 'Gene', '103352670', (17, 26))	('decreased', 'NegReg', (34, 43))	('5-FU', 'Chemical', 'MESH:D005472', (108, 112))	('LINC01419', 'Gene', (17, 26))	('apoptosis', 'CPA', (69, 78))	('enhanced', 'PosReg', (84, 92))	('increased', 'PosReg', (59, 68))	('sensitivity to 5-FU', 'MPA', (93, 112))	('silencing', 'Var', (4, 13))
200493	31019568	The ECC lines EC9706 and KYSE70 at a density of 2 x 105 were inoculated into six-well plates, and then cultured in Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco Company, Grand Island, NY, USA) comprised of 10% FBS (Sijiqing Biotechnology, Hangzhou, Zhejiang, China) over a subsequent 24 h period.	('EC9706', 'Var', (14, 20))	('FBS', 'Disease', 'MESH:D005198', (222, 225))	('KYSE70', 'Var', (25, 31))	('FBS', 'Disease', (222, 225))	('EC9706', 'CellLine', 'CVCL:E307', (14, 20))
200547	31019568	The results indicated that LINC01419 was highly expressed among the KYSE70, KYSE450, EC109 and EC9706 ESCC cells, with the human ESCC cell EC9706 demonstrating the highest levels (1.934 +- 0.087) and KYSE70 demonstrating the lowest levels [Figure 1(d)].	('EC9706', 'CellLine', 'CVCL:E307', (95, 101))	('LINC01419', 'Gene', '103352670', (27, 36))	('EC9706', 'Var', (139, 145))	('human', 'Species', '9606', (123, 128))	('KYSE70', 'Var', (68, 74))	('EC9706', 'CellLine', 'CVCL:E307', (139, 145))	('EC9706', 'Var', (95, 101))	('LINC01419', 'Gene', (27, 36))
200554	31019568	After the transfection of sh-LINC01419, the antiproliferative effect and proapoptotic effect of 5-FU on ESCC cells were observed to have been strengthened, accompanied by augmented sensitivity of the ESCC cells to 5-FU.	('augmented', 'PosReg', (171, 180))	('LINC01419', 'Gene', (29, 38))	('sensitivity', 'MPA', (181, 192))	('strengthened', 'PosReg', (142, 154))	('5-FU', 'Chemical', 'MESH:D005472', (96, 100))	('antiproliferative effect', 'CPA', (44, 68))	('LINC01419', 'Gene', '103352670', (29, 38))	('transfection', 'Var', (10, 22))	('proapoptotic effect', 'CPA', (73, 92))	('5-FU', 'Chemical', 'MESH:D005472', (214, 218))
200555	31019568	Based on the results obtained we concluded that LINC01419 deletion could inhibit the occurrence of ESCC and improve the sensitivity of the ESCC cells to 5-FU.	('sensitivity', 'MPA', (120, 131))	('LINC01419', 'Gene', '103352670', (48, 57))	('occurrence', 'MPA', (85, 95))	('ESCC', 'Disease', (99, 103))	('improve', 'PosReg', (108, 115))	('LINC01419', 'Gene', (48, 57))	('deletion', 'Var', (58, 66))	('5-FU', 'Chemical', 'MESH:D005472', (153, 157))	('inhibit', 'NegReg', (73, 80))
200564	31019568	The results obtained revealed that the promoter CpG island of the GSTP1 gene was hypermethylated in the LINC01419 oe group, and the methylation level in the sh-LINC01419 group was lower [Figure 3(g and i)].	('hypermethylated', 'Var', (81, 96))	('LINC01419', 'Gene', '103352670', (104, 113))	('LINC01419', 'Gene', '103352670', (160, 169))	('methylation level', 'MPA', (132, 149))	('GSTP1', 'Gene', (66, 71))	('lower', 'NegReg', (180, 185))	('LINC01419', 'Gene', (104, 113))	('LINC01419', 'Gene', (160, 169))	('GSTP1', 'Gene', '2950', (66, 71))
200570	31019568	The results revealed the expression of GSTP1 in the ESCC cells increased significantly after 5-Aza-CdR treatment.	('increased', 'PosReg', (63, 72))	('GSTP1', 'Gene', '2950', (39, 44))	('expression', 'MPA', (25, 35))	('5-Aza-CdR', 'Var', (93, 102))	('GSTP1', 'Gene', (39, 44))
200576	31019568	The above results demonstrated that demethylation of GSTP1 gene decreased ESCC cell proliferation and increased ESCC cell apoptosis, as well as inhibiting the occurrence of ESCC.	('ESCC cell proliferation', 'CPA', (74, 97))	('ESCC', 'Disease', (173, 177))	('GSTP1', 'Gene', '2950', (53, 58))	('demethylation', 'Var', (36, 49))	('inhibiting', 'NegReg', (144, 154))	('decreased', 'NegReg', (64, 73))	('decreased ESCC', 'Phenotype', 'HP:0025022', (64, 78))	('increased', 'PosReg', (102, 111))	('increased ESCC', 'Phenotype', 'HP:0003565', (102, 116))	('GSTP1', 'Gene', (53, 58))
200577	31019568	Following overexpression of GSTP1 or treatment with 5-Aza-CdR, the antiproliferative effect and proapoptotic effect of 5-FU on ESCC cells displayed heightened abilities, indicating that the sensitivity of the ESCC cell to 5-FU was increased after the demethylation of GSTP1 gene.	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('5-FU', 'Chemical', 'MESH:D005472', (222, 226))	('antiproliferative effect', 'MPA', (67, 91))	('GSTP1', 'Gene', (28, 33))	('increased', 'PosReg', (231, 240))	('5-Aza-CdR', 'Var', (52, 61))	('GSTP1', 'Gene', (268, 273))	('sensitivity', 'MPA', (190, 201))	('demethylation', 'Var', (251, 264))	('abilities', 'MPA', (159, 168))	('GSTP1', 'Gene', '2950', (28, 33))	('GSTP1', 'Gene', '2950', (268, 273))
200578	31019568	Taken together, the results suggested that GSTP1 gene demethylation could inhibit the occurrence of ESCC and improve the sensitivity of the ESCC cells to 5-FU.	('GSTP1', 'Gene', (43, 48))	('improve', 'PosReg', (109, 116))	('demethylation', 'Var', (54, 67))	('5-FU', 'Chemical', 'MESH:D005472', (154, 158))	('sensitivity', 'MPA', (121, 132))	('inhibit', 'NegReg', (74, 81))	('ESCC', 'Disease', (100, 104))	('GSTP1', 'Gene', '2950', (43, 48))	('occurrence', 'MPA', (86, 96))
200581	31019568	After treatment with 5-Aza-CdR, compared with the cells transfected with LINC01419 oe only, the ESCC cells (transfected with LINC01419 oe) simultaneously treated with overexpressed GSTP1 or 5-Aza-CdR exhibited significantly decreased cell viability and proliferation ability, and more increased cell apoptosis ability [p < 0.05; Figure 5(a and g)].	('cell apoptosis ability', 'CPA', (295, 317))	('LINC01419', 'Gene', '103352670', (73, 82))	('GSTP1', 'Gene', (181, 186))	('LINC01419', 'Gene', '103352670', (125, 134))	('increased', 'PosReg', (285, 294))	('decreased', 'NegReg', (224, 233))	('cell viability', 'CPA', (234, 248))	('GSTP1', 'Gene', '2950', (181, 186))	('LINC01419', 'Gene', (73, 82))	('overexpressed', 'PosReg', (167, 180))	('proliferation ability', 'CPA', (253, 274))	('LINC01419', 'Gene', (125, 134))	('5-Aza-CdR', 'Var', (190, 199))
200597	31019568	Consistently, reports have indicated that the expression of Lincrna-nr_024015 is expressed in the cytoplasm of ESCC cell, while highlighting an association between the overexpression of Lincrna-nr_024015 and rs8506 A alleles and the survival rate of ESCC patients.	('survival rate', 'CPA', (233, 246))	('Lincrna-nr_024015', 'Var', (186, 203))	('rs8506', 'Mutation', 'rs8506', (208, 214))	('ESCC', 'Disease', (250, 254))	('Lincrna-nr_024015', 'Var', (60, 77))	('patients', 'Species', '9606', (255, 263))	('overexpression', 'PosReg', (168, 182))	('rs8506 A', 'Var', (208, 216))
200601	31019568	Chemotherapy is often combined with 5-FU to treat ESCC, with 5-FU capable of inhibiting ESCC proliferation in a dose-dependent manner.	('inhibiting', 'NegReg', (77, 87))	('ESCC', 'Disease', (88, 92))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('5-FU', 'Chemical', 'MESH:D005472', (36, 40))	('5-FU', 'Var', (61, 65))
200604	31019568	Glutathione S- transferase is widely known to be a carcinogenic substance related to the metabolism of tobacco, while GSTP1 polymorphism has been correlated with the course of ESCC.	('ESCC', 'Disease', (176, 180))	('polymorphism', 'Var', (124, 136))	('GSTP1', 'Gene', (118, 123))	('GSTP1', 'Gene', '2950', (118, 123))	('Glutathione S- transferase', 'Gene', (0, 26))	('carcinogenic', 'Disease', 'MESH:D063646', (51, 63))	('carcinogenic', 'Disease', (51, 63))	('Glutathione S- transferase', 'Gene', '107794811', (0, 26))	('tobacco', 'Species', '4097', (103, 110))	('correlated with', 'Reg', (146, 161))
200605	31019568	A previous study demonstrated that GSTP1 Ile105Val polymorphism was an independent risk factor, and GSTT1-WT was an independent protective factor in ESCC, which was suggestive of a contrary role played by GSTP1 and GSTT1 polymorphisms as risk factors in ESCC.	('ESCC', 'Disease', (149, 153))	('Ile105Val', 'Var', (41, 50))	('polymorphism', 'Var', (51, 63))	('GSTT1', 'Gene', '2952', (215, 220))	('GSTT1', 'Gene', (215, 220))	('GSTP1', 'Gene', '2950', (205, 210))	('GSTP1', 'Gene', (35, 40))	('GSTT1', 'Gene', '2952', (100, 105))	('GSTT1', 'Gene', (100, 105))	('Ile105Val', 'SUBSTITUTION', 'None', (41, 50))	('GSTP1', 'Gene', (205, 210))	('GSTP1', 'Gene', '2950', (35, 40))
200608	31019568	Furthermore, our study revealed that following demethylation of GSTP1 gene, cell proliferation was decreased, while apoptosis was increased, with the occurrence of ESCC being inhibited.	('decreased', 'NegReg', (99, 108))	('GSTP1', 'Gene', (64, 69))	('demethylation', 'Var', (47, 60))	('apoptosis', 'CPA', (116, 125))	('cell proliferation', 'CPA', (76, 94))	('GSTP1', 'Gene', '2950', (64, 69))	('increased', 'PosReg', (130, 139))
200609	31019568	Following treatment with 5-FU, the sensitivity of cancer cells to 5-FU was increased, suggesting that GSTP1 gene demethylation might inhibit the occurrence of ESCC and improve the sensitivity of ESCC cell to 5-FU.	('GSTP1', 'Gene', (102, 107))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('improve', 'PosReg', (168, 175))	('demethylation', 'Var', (113, 126))	('5-FU', 'Chemical', 'MESH:D005472', (25, 29))	('inhibit', 'NegReg', (133, 140))	('5-FU', 'Chemical', 'MESH:D005472', (66, 70))	('GSTP1', 'Gene', '2950', (102, 107))	('occurrence', 'MPA', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('sensitivity', 'MPA', (180, 191))	('5-FU', 'Chemical', 'MESH:D005472', (208, 212))	('ESCC', 'Disease', (159, 163))
200612	31019568	Methylation of the GSTP1 gene CpG island promoter is involved in the occurrence and development of multiple tumors, which could be a biomarker for early screen, diagnosis and prognosis.	('involved', 'Reg', (53, 61))	('GSTP1', 'Gene', '2950', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Methylation', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('multiple tumors', 'Disease', (99, 114))	('multiple tumors', 'Disease', 'MESH:D009369', (99, 114))	('GSTP1', 'Gene', (19, 24))
200618	30674324	We performed circular RNA microarray in 3 pairs of ESCC frozen tumor and non-tumor tissues to identify ESCC-related circRNAs and found 1045 up-regulated and 1032 down-regulated circRNAs among which 6 circRNAs (hsa_circ_0062459, hsa_circ_0076535, hsa_circ_0072215, hsa_circ_0042261, hsa_circ_0001946, and hsa_circ_0043603) displayed consistency with microarray results by qRT-PCR.	('tumor', 'Disease', (63, 68))	('non-tumor', 'Disease', (73, 82))	('hsa_circ_0042261', 'Var', (264, 280))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('non-tumor', 'Disease', 'MESH:D009369', (73, 82))	('hsa_circ_0062459', 'Var', (210, 226))	('hsa_circ_0076535', 'Var', (228, 244))	('down-regulated', 'NegReg', (162, 176))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (77, 82))	('up-regulated', 'PosReg', (140, 152))
200628	30674324	As Additional file 6: Table S2 showed, hsa_circ_0001946 was the only one associated with the recurrence rate of ESCC patients.	('patients', 'Species', '9606', (117, 125))	('hsa_circ_0001946', 'Var', (39, 55))	('ESCC', 'Disease', (112, 116))
200629	30674324	As for disease-free survival (DFS) and overall survival (OS) prediction, patients in the high hsa_circ_0001946 group (according to the median level) had a much shorter DFS and OS (Fig.	('OS', 'Chemical', '-', (176, 178))	('DFS', 'MPA', (168, 171))	('high hsa_circ_0001946', 'Var', (89, 110))	('OS', 'Chemical', '-', (57, 59))	('shorter', 'NegReg', (160, 167))	('patients', 'Species', '9606', (73, 81))
200630	30674324	The results showed that high hsa_circ_0001946 was associated with shorter DFS and OS in K-M curves (Fig.	('DFS', 'MPA', (74, 77))	('OS in K-M curves', 'MPA', (82, 98))	('shorter', 'NegReg', (66, 73))	('high hsa_circ_0001946', 'Var', (24, 45))	('OS', 'Chemical', '-', (82, 84))
200632	30674324	The multivariate Cox proportional hazard models shown that combination of these two group supports the result that hsa_circ_0001946 was a promising and independent prognostic biomarker for ESCC patients in both frozen and FFPE tissues.	('ESCC', 'Disease', (189, 193))	('patients', 'Species', '9606', (194, 202))	('hsa_circ_0001946', 'Var', (115, 131))
200678	28891965	Molecular Mechanisms of Acetaldehyde-Mediated Carcinogenesis in Squamous Epithelium Acetaldehyde is a highly reactive compound that causes various forms of damage to DNA, including DNA adducts, single- and/or double-strand breaks (DSBs), point mutations, sister chromatid exchanges (SCEs), and DNA-DNA cross-links.	('Acetaldehyde', 'Chemical', 'MESH:D000079', (24, 36))	('sister chromatid', 'Disease', (255, 271))	('Acetaldehyde-Mediated Carcinogenesis', 'Disease', (24, 60))	('single-', 'Var', (194, 201))	('adducts', 'Var', (185, 192))	('Acetaldehyde', 'Chemical', 'MESH:D000079', (84, 96))	('Acetaldehyde-Mediated Carcinogenesis', 'Disease', 'MESH:D063646', (24, 60))	('point mutations', 'Var', (238, 253))	('damage', 'MPA', (156, 162))
200679	28891965	Among these, DNA adducts such as N2-ethylidene-2'-deoxyguanosine, N2-ethyl-2'-deoxyguanosine, N2-propano-2'-deoxyguanosine, and N2-etheno-2'-deoxyguanosine are central to acetaldehyde-mediated DNA damage because they are associated with the induction of DNA mutations, DNA-DNA cross-links, DSBs, and SCEs.	('mutations', 'Var', (258, 267))	('DNA', 'Gene', (254, 257))	('DSBs', 'Disease', (290, 294))	("N2-ethylidene-2'-deoxyguanosine", 'Chemical', 'MESH:C525837', (33, 64))	('acetaldehyde', 'Chemical', 'MESH:D000079', (171, 183))	("N2-etheno-2'-deoxyguanosine", 'Chemical', '-', (128, 155))	("N2-propano-2'-deoxyguanosine", 'Chemical', '-', (94, 122))	('SCEs', 'Disease', (300, 304))	('associated', 'Reg', (221, 231))	("N2-ethyl-2'-deoxyguanosine", 'Chemical', 'MESH:C492934', (66, 92))
200681	28891965	Alcohol consumption increases blood and salivary acetaldehyde levels, especially in individuals with ALDH2 polymorphisms, which are highly associated with the risk of squamous cell carcinomas in the upper aerodigestive tract.	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('squamous cell carcinomas', 'Disease', (167, 191))	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (40, 61))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (167, 191))	('acetaldehyde', 'Chemical', 'MESH:D000079', (49, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (167, 190))	('polymorphisms', 'Var', (107, 120))	('associated', 'Reg', (139, 149))	('consumption increases blood', 'Disease', (8, 35))	('Alcohol consumption increases blood and salivary acetaldehyde', 'Phenotype', 'HP:0003533', (0, 61))	('consumption increases blood', 'Disease', 'MESH:D014397', (8, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('ALDH2', 'Gene', (101, 106))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (167, 191))
200693	28891965	ADH1B has two alleles, ADH1B*1 (less active ADH1B) and ADH1B*2 (active ADH1B, Arg47His).	('ADH1B', 'Gene', '125', (55, 60))	('less', 'NegReg', (32, 36))	('ADH1B', 'Gene', (23, 28))	('ADH1B', 'Gene', (71, 76))	('ADH1B', 'Gene', (44, 49))	('ADH1B', 'Gene', '125', (23, 28))	('ADH1B', 'Gene', '125', (71, 76))	('ADH1B', 'Gene', '125', (44, 49))	('ADH1B', 'Gene', (0, 5))	('Arg47His', 'Var', (78, 86))	('active', 'MPA', (37, 43))	('ADH1B', 'Gene', '125', (0, 5))	('Arg47His', 'SUBSTITUTION', 'None', (78, 86))	('ADH1B', 'Gene', (55, 60))
200697	28891965	ALDH2 has two alleles, ALDH2*1 (active ALDH2) and ALDH2*2 (inactive ALDH2, Glu504Lys).	('Glu504Lys', 'Var', (75, 84))	('Glu504Lys', 'SUBSTITUTION', 'None', (75, 84))	('ALDH2', 'Gene', (0, 5))
200698	28891965	Meta-analysis has shown that individuals with ALDH2*1/*2 have a 7.12- and 1.83-fold increased risk of ESCC and HNSCC, respectively, compared with carriers of ALDH2*1/*1.	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('ESCC', 'Disease', (102, 106))	('HNSCC', 'Disease', (111, 116))	('eta', 'Gene', '1909', (1, 4))	('eta', 'Gene', (1, 4))	('ALDH2*1/*2', 'Var', (46, 56))
200699	28891965	Moreover, alcoholics with the ALDH2*1/*2 genotype have a 13.5- and 18.52-fold increased risk of ESCC and HNSCC, respectively, compared with ALDH2*1/*1 genotypes.	('ALDH2', 'Var', (30, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))	('HNSCC', 'Disease', (105, 110))	('ESCC', 'Disease', (96, 100))	('alcohol', 'Chemical', 'MESH:D000438', (10, 17))
200712	28891965	Indeed, alcohol drinking (0.5 g ethanol/kg body weight) increases acetaldehyde concentrations in parotid duct saliva on ALDH2*1/*2 carriers, while it does not affect those on ALDH2*1/*1 carriers.	('increases', 'PosReg', (56, 65))	('carriers', 'Var', (131, 139))	('increases acetaldehyde concentrations', 'Phenotype', 'HP:0003533', (56, 93))	('parotid duct saliva', 'Disease', (97, 116))	('ALDH2', 'Gene', (120, 125))	('ethanol', 'Chemical', 'MESH:D000431', (32, 39))	('alcohol drinking', 'Phenotype', 'HP:0030955', (8, 24))	('parotid duct saliva', 'Disease', 'MESH:D012465', (97, 116))	('acetaldehyde concentrations', 'MPA', (66, 93))	('increases acetaldehyde', 'Phenotype', 'HP:0003533', (56, 78))	('acetaldehyde', 'Chemical', 'MESH:D000079', (66, 78))	('alcohol', 'Chemical', 'MESH:D000438', (8, 15))
200725	28891965	Additionally, blood N2-ethylidene-dG levels in alcoholics with the ALDH2*2 allele are higher than those with the ALDH2*1/*1 allele.	('ALDH2', 'Gene', (67, 72))	('allele', 'Var', (75, 81))	('blood N2-ethylidene-dG levels', 'MPA', (14, 43))	('alcohol', 'Chemical', 'MESH:D000438', (47, 54))	('N2-ethylidene-dG', 'Chemical', '-', (20, 36))	('higher', 'PosReg', (86, 92))
200727	28891965	This evidence indicates that drinking alcohol definitely increases acetaldehyde exposure to the esophageal tissues in individuals with the ALDH2*2 allele.	('increases acetaldehyde', 'Phenotype', 'HP:0003533', (57, 79))	('acetaldehyde', 'Chemical', 'MESH:D000079', (67, 79))	('increases', 'PosReg', (57, 66))	('allele', 'Var', (147, 153))	('alcohol', 'Chemical', 'MESH:D000438', (38, 45))	('acetaldehyde exposure to the esophageal tissues', 'MPA', (67, 114))	('ALDH2*2', 'Gene', (139, 146))
200734	28891965	N2-Et-dG blocks DNA synthesis and induces DNA mutations.	('N2-Et-dG', 'Var', (0, 8))	('DNA synthesis', 'MPA', (16, 29))	('N2-Et-dG', 'Chemical', '-', (0, 8))	('induces', 'Reg', (34, 41))	('DNA mutations', 'MPA', (42, 55))	('blocks', 'NegReg', (9, 15))
200735	28891965	Moreover, N2-Et-dG inhibits translesion DNA synthesis (TLS), which leads to a majority of frameshift deletions and a minority of G:C > T:A transversions in human cells.	('N2-Et-dG', 'Chemical', '-', (10, 18))	('translesion DNA synthesis', 'MPA', (28, 53))	('TLS', 'Gene', '2521', (55, 58))	('G:C > T:A transversions', 'Var', (129, 152))	('inhibits', 'NegReg', (19, 27))	('human', 'Species', '9606', (156, 161))	('N2-Et-dG', 'Var', (10, 18))	('frameshift deletions', 'Var', (90, 110))	('TLS', 'Gene', (55, 58))
200737	28891965	These differences may result in significantly different mutagenic potential between N2-Et-dG and N2-ethylidene-dG.	('mutagenic potential', 'MPA', (56, 75))	('N2-Et-dG', 'Var', (84, 92))	('different', 'Reg', (46, 55))	('N2-ethylidene-dG', 'Chemical', '-', (97, 113))	('N2-Et-dG', 'Chemical', '-', (84, 92))
200746	28891965	To elaborate on details mentioned previously in part, acetaldehyde causes DNA adducts, DNA single-strand breaks, DSBs, point mutations, SCEs, DNA-DNA cross-links, micronuclei, and gross chromosomal aberrations.	('SCEs', 'Disease', (136, 140))	('DNA', 'Disease', (74, 77))	('DSBs', 'Disease', (113, 117))	('eta', 'Gene', (17, 20))	('adducts', 'Var', (78, 85))	('eta', 'Gene', '1909', (56, 59))	('eta', 'Gene', (56, 59))	('cross-links', 'Interaction', (150, 161))	('point', 'Disease', (119, 124))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (186, 209))	('micronuclei', 'CPA', (163, 174))	('eta', 'Gene', '1909', (17, 20))	('acetaldehyde', 'Chemical', 'MESH:D000079', (54, 66))	('gross chromosomal aberrations', 'CPA', (180, 209))
200748	28891965	Exposure of acetaldehyde directly induces mutations, most frequently G:C > A:T transitions in the TP53 gene.	('induces', 'Reg', (34, 41))	('G:C > A:T transitions', 'Var', (69, 90))	('TP53', 'Gene', '7157', (98, 102))	('acetaldehyde', 'Chemical', 'MESH:D000079', (12, 24))	('TP53', 'Gene', (98, 102))
200750	28891965	In addition, G:C > T:A transversions are the most frequent miscoding events induced by CrPdG, followed by G:C > C:G and G:C > A:T mutations.	('transversions', 'Var', (23, 36))	('G:C > C', 'Var', (106, 113))	('CrPdG', 'Gene', (87, 92))	('CrPdG', 'Chemical', 'MESH:C501840', (87, 92))	('G:C > T:A transversions', 'Var', (13, 36))	('G:C > A:T', 'Var', (120, 129))
200758	28891965	This pathway is composed of at least 19 genes (FANCA, B, C, D1, D2, E-G, I, J, L-T) and the deficiency of these genes can cause FA.	('deficiency', 'Var', (92, 102))	('cause', 'Reg', (122, 127))	('FANCA', 'Gene', '2175', (47, 52))	('FANCA', 'Gene', (47, 52))	('FA', 'Phenotype', 'HP:0001994', (128, 130))	('FA', 'Phenotype', 'HP:0001994', (47, 49))
200774	28891965	ALDH2 knockdown resulted in an increase of susceptibility to acetaldehyde.	('acetaldehyde', 'Chemical', 'MESH:D000079', (61, 73))	('ALDH2', 'Gene', (0, 5))	('susceptibility to acetaldehyde', 'Phenotype', 'HP:0003533', (43, 73))	('susceptibility to acetaldehyde', 'MPA', (43, 73))	('knockdown', 'Var', (6, 15))	('increase', 'PosReg', (31, 39))
200775	28891965	Conversely, ALDH2 overexpression prevented acetaldehyde-mediated DNA damage in esophageal keratinocytes, although overexpression of mutant ALDH2 (ALDH2*2) offered no protection.	('ALDH2', 'Gene', (12, 17))	('acetaldehyde', 'Chemical', 'MESH:D000079', (43, 55))	('mutant', 'Var', (132, 138))	('acetaldehyde-mediated DNA damage in', 'MPA', (43, 78))	('prevented', 'NegReg', (33, 42))	('ALDH2', 'Gene', (139, 144))
200868	27465934	In tumor-bearing mice, daily treatment with BCH significantly delayed tumor growth and decreased glucose metabolism, indicating that LAT1 inhibition potentially suppresses esophageal cancer growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (3, 8))	('decreased glucose metabolism', 'Disease', (87, 115))	('esophageal cancer', 'Disease', (172, 189))	('mice', 'Species', '10090', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('delayed', 'NegReg', (62, 69))	('tumor', 'Disease', (70, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('LAT1', 'Gene', (133, 137))	('suppresses', 'NegReg', (161, 171))	('inhibition', 'Var', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('decreased glucose metabolism', 'Disease', 'MESH:D044882', (87, 115))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
200881	27465934	Human esophageal cancer cell lines, KYSE30 (JCRB0188) and KYSE150 (JCRB1095) were purchased from the Health Science Research Resources Bank (Osaka, Japan),21 and routinely maintained in DMEM (Wako Pure Chemical Industries, Osaka, Japan) containing 10% heat-inactivated FBS (AusGeneX, Loganholme, Australia), penicillin (100 units/mL), streptomycin (100 mug/mL), and l-glutamine (2 mM) at 37 C in 5% CO2, 95% air.	('FBS', 'Disease', (269, 272))	('esophageal cancer', 'Disease', (6, 23))	('Human', 'Species', '9606', (0, 5))	('l-glutamine', 'Chemical', 'MESH:D005973', (366, 377))	('CO2', 'Chemical', '-', (399, 402))	('esophageal cancer', 'Disease', 'MESH:D004938', (6, 23))	('penicillin', 'Chemical', 'MESH:D010406', (308, 318))	('FBS', 'Disease', 'MESH:D005198', (269, 272))	('streptomycin', 'Chemical', 'MESH:D013307', (335, 347))	('100 mug/mL', 'Var', (349, 359))	('100 units/mL', 'Var', (320, 332))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
200882	27465934	HEK293-mock and HEK293-hLAT1 established by Khunweeraphong et al.22 were routinely maintained in Eagle's minimum essential medium (Wako Pure Chemical Industries) containing 10% heat-inactivated FBS (AusGeneX), non-essential amino acids (Wako Pure Chemical Industries), penicillin (100 units/mL), streptomycin (100 mug/mL), and l-glutamine (2 mM) at 37 C in 5% CO2, 95% air.	('streptomycin', 'Chemical', 'MESH:D013307', (296, 308))	('hLAT1', 'Gene', '8140', (23, 28))	('100 units/mL', 'Var', (281, 293))	('essential amino acids', 'Chemical', 'MESH:D000601', (214, 235))	('FBS', 'Disease', (194, 197))	('100 mug/mL', 'Var', (310, 320))	('hLAT1', 'Gene', (23, 28))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('penicillin', 'Chemical', 'MESH:D010406', (269, 279))	('l-glutamine', 'Chemical', 'MESH:D005973', (327, 338))	('CO2', 'Chemical', '-', (360, 363))	('essential medium', 'Chemical', '-', (113, 129))	('HEK293', 'CellLine', 'CVCL:0045', (16, 22))	('FBS', 'Disease', 'MESH:D005198', (194, 197))
200883	27465934	Quantitative PCR (qPCR) analysis was carried out to quantify the expression of LAT1, LAT2, LAT3, and LAT4 mRNA in KYSE30 and KYSE150.	('LAT1', 'Gene', (79, 83))	('LAT2', 'Gene', (85, 89))	('LAT3', 'Gene', '9057', (91, 95))	('LAT4', 'Gene', (101, 105))	('KYSE150', 'Var', (125, 132))	('LAT3', 'Gene', (91, 95))	('KYSE30', 'Var', (114, 120))	('LAT2', 'Gene', '7462', (85, 89))	('LAT4', 'Gene', '124935', (101, 105))
200892	27465934	At 1 min after treatment with l-14C-leucine, uptake was terminated by removing the uptake solution followed by washing three times with ice-cold Na+-free HBSS.	('HBSS', 'Chemical', '-', (154, 158))	('uptake solution', 'MPA', (83, 98))	('l-14C-leucine', 'Var', (30, 43))	('uptake', 'MPA', (45, 51))	('l-14C-leucine', 'Chemical', '-', (30, 43))
200902	27465934	Cells were dissolved in sample buffer (25% glycerin, 1% SDS, 62.5 mM Tris-Cl, 10 mM DTT) and incubated at 65 C (LAT1) or 95 C (CD98, beta-actin, mTOR, p-mTOR, 4E-BP-1, p-4E-BP-1, p70S6K, and p-p70S6K) for 15 min.	('glycerin', 'Chemical', 'MESH:D005990', (43, 51))	('p70S6K', 'Gene', '6198', (193, 199))	('4E-BP-1', 'Gene', (159, 166))	('4E-BP-1', 'Gene', '1978', (159, 166))	('CD98', 'Gene', '8140', (127, 131))	('4E-BP-1', 'Gene', (170, 177))	('beta-actin', 'Gene', '728378', (133, 143))	('4E-BP-1', 'Gene', '1978', (170, 177))	('Tris-Cl', 'Chemical', '-', (69, 76))	('beta-actin', 'Gene', (133, 143))	('DTT', 'Chemical', 'MESH:D004229', (84, 87))	('p70S6K', 'Gene', (179, 185))	('p70S6K', 'Gene', '6198', (179, 185))	('p70S6K', 'Gene', (193, 199))	('SDS', 'Chemical', 'MESH:D012967', (56, 59))	('CD98', 'Gene', (127, 131))	('p-mTOR', 'Var', (151, 157))
200904	27465934	Blots were incubated at 4 C overnight in 10 mM Tris-HCl, 100 mM NaCl, 0.1% Tween-20, pH 7.5 (TBST), with 5% skim milk (LAT1, CD98, and beta-actin) or 1% BSA (mTOR, p-mTOR, 4E-BP-1, p-4E-BP-1, p70S6K, and p-p70S6K).	('beta-actin', 'Gene', (135, 145))	('4E-BP-1', 'Gene', (183, 190))	('NaCl', 'Chemical', 'MESH:D012965', (64, 68))	('beta-actin', 'Gene', '728378', (135, 145))	('TBST', 'Chemical', '-', (93, 97))	('CD98', 'Gene', (125, 129))	('4E-BP-1', 'Gene', '1978', (183, 190))	('p70S6K', 'Gene', '6198', (192, 198))	('p70S6K', 'Gene', (192, 198))	('p70S6K', 'Gene', (206, 212))	('p70S6K', 'Gene', '6198', (206, 212))	('4E-BP-1', 'Gene', (172, 179))	('CD98', 'Gene', '8140', (125, 129))	('Tris-HCl', 'Chemical', '-', (47, 55))	('Tween-20', 'Chemical', 'MESH:D011136', (75, 83))	('p-mTOR', 'Var', (164, 170))	('4E-BP-1', 'Gene', '1978', (172, 179))
200922	27465934	l-14C-leucine uptake was higher in KYSE150 than in KYSE30 cells.	('l-14C-leucine uptake', 'MPA', (0, 20))	('l-14C-leucine', 'Chemical', '-', (0, 13))	('KYSE150', 'Var', (35, 42))	('higher', 'PosReg', (25, 31))
200929	27465934	To investigate whether LAT1 inhibition could suppress tumor growth in vivo, BCH (200 mg/kg) was given i.v.	('suppress', 'NegReg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('inhibition', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('LAT1', 'Gene', (23, 27))	('tumor', 'Disease', (54, 59))
200935	27465934	The SUVmax on 18F-FDG-PET images on day 14 was increased in the control group, but decreased in the BCH-treated group, indicating that glucose metabolism of the tumor was decreased by treatment with BCH (Fig.	('decreased', 'NegReg', (171, 180))	('glucose metabolism of the tumor', 'Disease', (135, 166))	('PET', 'Gene', (22, 25))	('BCH', 'Var', (199, 202))	('decreased', 'NegReg', (83, 92))	('glucose metabolism of the tumor', 'Disease', 'MESH:D044882', (135, 166))	('18F-FDG', 'Chemical', 'MESH:D019788', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('PET', 'Gene', '22095', (22, 25))
200943	27465934	The amounts of LAT1 protein in KYSE30 and KYSE150 cells were remarkably different, whereas the amount of CD98 protein was similar.	('CD98', 'Gene', (105, 109))	('KYSE150', 'Var', (42, 49))	('CD98', 'Gene', '8140', (105, 109))	('LAT1 protein', 'Protein', (15, 27))
200946	27465934	The ratio of l-14C-leucine uptake was close to the ratio of CD98.	('l-14C-leucine', 'Var', (13, 26))	('CD98', 'Gene', '8140', (60, 64))	('l-14C-leucine', 'Chemical', '-', (13, 26))	('CD98', 'Gene', (60, 64))
200947	27465934	These results strongly support the formation of heterodimerization of LAT1 with CD98 in esophageal cancer cells, and indicate that the amounts of LAT1 on cell membrane was close between KYSE30 and KYSE150.	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('LAT1', 'Gene', (70, 74))	('heterodimerization', 'MPA', (48, 66))	('KYSE150', 'Var', (197, 204))	('CD98', 'Gene', (80, 84))	('esophageal cancer', 'Disease', (88, 105))	('KYSE30', 'Var', (186, 192))	('formation', 'Reg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('CD98', 'Gene', '8140', (80, 84))
200952	27465934	It has been reported that suppression of mTOR leads to G1 arrest and both p70S6K and 4E-BP1 independently mediate mTOR-dependent G1 phase progression.31 Therefore, it is suggested that LAT1 inhibition with BCH suppressed mTOR signaling, followed by G1 cell cycle arrest and suppression of cell proliferation in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (311, 328))	('arrest', 'Disease', (58, 64))	('p70S6K and 4E-BP1', 'Gene', '6198;1978', (74, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (252, 269))	('arrest', 'Disease', 'MESH:D006323', (263, 269))	('LAT1', 'Gene', (185, 189))	('cell proliferation', 'CPA', (289, 307))	('suppressed', 'NegReg', (210, 220))	('BCH', 'Gene', (206, 209))	('mTOR signaling', 'MPA', (221, 235))	('arrest', 'Disease', (263, 269))	('suppression', 'NegReg', (274, 285))	('esophageal cancer', 'Disease', (311, 328))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('inhibition', 'Var', (190, 200))	('arrest', 'Disease', 'MESH:D006323', (58, 64))
200957	27465934	Both 5-FU and CDDP induce DNA damage, and BCH inhibits amino acids supply and mTOR signaling.	('BCH', 'Var', (42, 45))	('CDDP', 'Chemical', 'MESH:D002945', (14, 18))	('DNA damage', 'MPA', (26, 36))	('CDDP', 'Var', (14, 18))	('inhibits', 'NegReg', (46, 54))	('amino acids supply', 'MPA', (55, 73))	('mTOR signaling', 'MPA', (78, 92))	('5-FU', 'Chemical', 'MESH:D005472', (5, 9))
200965	27465934	Oda et al.17 developed the LAT1-selective inhibitor, KYT-0353, and reported its remarkable antitumor activity in colon cancer-bearing mice.	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('mice', 'Species', '10090', (134, 138))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('colon cancer', 'Disease', (113, 125))	('KYT-0353', 'Var', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('KYT-0353', 'Chemical', 'MESH:C548172', (53, 61))	('tumor', 'Disease', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
200967	27465934	In this study, two types of esophageal cancer cell line were used; KYSE30 is a well-differentiated SCC, and KYSE150 is a poorly differentiated SCC.21 Among them, the expression level of LAT1 was markedly higher in KYSE150 cells.	('SCC', 'Gene', (143, 146))	('esophageal cancer', 'Disease', (28, 45))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('SCC', 'Gene', '6317', (99, 102))	('expression level', 'MPA', (166, 182))	('SCC', 'Gene', '6317', (143, 146))	('LAT1', 'Gene', (186, 190))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('KYSE150', 'Var', (214, 221))	('SCC', 'Gene', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('higher', 'PosReg', (204, 210))
200970	27465934	In conclusion, LAT1 inhibition with BCH suppressed leucine uptake, mTOR signaling, cell cycle progression, and cell proliferation in esophageal cancer cells and significantly delayed tumor growth in tumor-bearing mice.	('mice', 'Species', '10090', (213, 217))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('LAT1', 'Gene', (15, 19))	('leucine uptake', 'MPA', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BCH', 'Gene', (36, 39))	('cell cycle progression', 'CPA', (83, 105))	('suppressed', 'NegReg', (40, 50))	('cell proliferation', 'CPA', (111, 129))	('tumor', 'Disease', (199, 204))	('delayed', 'NegReg', (175, 182))	('leucine', 'Chemical', 'MESH:D007930', (51, 58))	('mTOR signaling', 'MPA', (67, 81))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', (183, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('inhibition', 'Var', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('esophageal cancer', 'Disease', (133, 150))
200971	27465934	Furthermore, LAT1 inhibition could also enhance the antitumor effects of conventional chemotherapeutic drugs in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('enhance', 'PosReg', (40, 47))	('inhibition', 'Var', (18, 28))	('esophageal cancer', 'Disease', (112, 129))	('LAT1', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
201043	26186270	However, there are certain studies that where they have tried to factor out smoking and look at alcohol use and these studies have shown that alcohol by itself can cause esophageal cancer, that HPV infection is associated with the causation of esophageal cancer, and reflux can cause esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('esophageal cancer', 'Disease', (244, 261))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cause', 'Reg', (164, 169))	('esophageal cancer', 'Disease', (170, 187))	('alcohol', 'Var', (142, 149))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('HPV infection', 'Disease', 'MESH:D030361', (194, 207))	('esophageal cancer', 'Disease', (284, 301))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('alcohol', 'Chemical', 'MESH:D000438', (142, 149))	('HPV infection', 'Disease', (194, 207))	('esophageal cancer', 'Disease', 'MESH:D004938', (284, 301))
201122	25160749	We observed that proliferation, clonogenicity and tumorigenesis of CE81T cells were inhibited by Pin1 knockdown.	('Pin1', 'Gene', '5300', (97, 101))	('knockdown', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('CE81T', 'Var', (67, 72))	('Pin1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('clonogenicity', 'CPA', (32, 45))	('tumor', 'Disease', (50, 55))	('inhibited', 'NegReg', (84, 93))
201125	25160749	By immunohistochemistry, we identified that high Pin1 expression was associated with higher primary tumor stage (p = 0.035), higher overall cancer stage (p = 0.047) and poor overall survival (p < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('high', 'Var', (44, 48))	('higher', 'PosReg', (85, 91))	('Pin1', 'Gene', (49, 53))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('overall survival', 'CPA', (174, 190))	('primary tumor', 'Disease', (92, 105))	('higher', 'PosReg', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Pin1', 'Gene', '5300', (49, 53))	('primary tumor', 'Disease', 'MESH:D009369', (92, 105))
201127	25160749	beta-catenin and cyclin D1 were decreased in CE81T cells with Pin1 knockdown.	('beta-catenin', 'Gene', '1499', (0, 12))	('beta-catenin', 'Gene', (0, 12))	('knockdown', 'Var', (67, 76))	('Pin1', 'Gene', (62, 66))	('cyclin D1', 'Gene', '595', (17, 26))	('decreased', 'NegReg', (32, 41))	('Pin1', 'Gene', '5300', (62, 66))	('cyclin D1', 'Gene', (17, 26))
201130	25160749	Pin1 knockdown inhibited aggressiveness of ESCC cells.	('inhibited', 'NegReg', (15, 24))	('Pin1', 'Gene', (0, 4))	('aggressiveness', 'Disease', 'MESH:D001523', (25, 39))	('knockdown', 'Var', (5, 14))	('aggressiveness', 'Disease', (25, 39))	('Pin1', 'Gene', '5300', (0, 4))	('aggressiveness', 'Phenotype', 'HP:0000718', (25, 39))
201139	25160749	In patients treated with definitive chemoradiotherapy, the clinical response in high Pin1 expression group was higher than that of the low expression group.	('Pin1', 'Gene', (85, 89))	('Pin1', 'Gene', '5300', (85, 89))	('patients', 'Species', '9606', (3, 11))	('higher', 'PosReg', (111, 117))	('high', 'Var', (80, 84))	('clinical response', 'CPA', (59, 76))
201153	25160749	Pin1 knockdown was confirmed by western blot and RT-PCR.	('Pin1', 'Gene', (0, 4))	('as c', 'Gene', '412', (16, 20))	('knockdown', 'Var', (5, 14))	('Pin1', 'Gene', '5300', (0, 4))	('as c', 'Gene', (16, 20))
201154	25160749	Western blot analysis was performed using anti-beta-catenin (sc-7963, Santa Cruz), anti-cyclin D1 (sc-718, Santa Cruz; ab16663, Abcam), anti-beta-actin (A5441, Sigma), anti-HA (ab18181, Abcam) and anti-Pin1 (sc-15304, Santa Cruz).	('beta-catenin', 'Gene', '1499', (47, 59))	('Pin1', 'Gene', (202, 206))	('A5441', 'Var', (153, 158))	('cyclin D1', 'Gene', '595', (88, 97))	('cyclin D1', 'Gene', (88, 97))	('Pin1', 'Gene', '5300', (202, 206))	('beta-catenin', 'Gene', (47, 59))
201158	25160749	For evaluating effect of Pin1 knockdown on clonogenicity, cells were plated into 6-well plates with 2 x 103 cells per well.	('Pin1', 'Gene', '5300', (25, 29))	('Pin1', 'Gene', (25, 29))	('knockdown', 'Var', (30, 39))
201170	25160749	MTT assay showed that proliferation of cells with Pin1 knockdown was attenuated (Figure 1B).	('knockdown', 'Var', (55, 64))	('attenuated', 'NegReg', (69, 79))	('Pin1', 'Gene', '5300', (50, 54))	('Pin1', 'Gene', (50, 54))	('MTT', 'Chemical', '-', (0, 3))
201171	25160749	The colony number of cells with Pin1 knockdown was significantly less than that of parental CE81T cells (p <0.01).	('colony number', 'CPA', (4, 17))	('Pin1', 'Gene', '5300', (32, 36))	('knockdown', 'Var', (37, 46))	('Pin1', 'Gene', (32, 36))	('less', 'NegReg', (65, 69))
201173	25160749	This result indicated that Pin1 knockdown inhibited growth of ESCC cells in a dose-dependent manner.	('Pin1', 'Gene', (27, 31))	('growth', 'CPA', (52, 58))	('knockdown', 'Var', (32, 41))	('inhibited', 'NegReg', (42, 51))	('Pin1', 'Gene', '5300', (27, 31))
201175	25160749	The tumor size from cells with Pin1 knockdown was smaller than that from parental CE81T cells (Figure 1D).	('tumor', 'Disease', (4, 9))	('Pin1', 'Gene', '5300', (31, 35))	('Pin1', 'Gene', (31, 35))	('knockdown', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('smaller', 'NegReg', (50, 57))
201176	25160749	These results indicated that Pin1 knockdown inhibited proliferation, clonogenicity and tumorigenesis of ESCC cells.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('inhibited', 'NegReg', (44, 53))	('clonogenicity', 'CPA', (69, 82))	('tumor', 'Disease', (87, 92))	('Pin1', 'Gene', '5300', (29, 33))	('ESCC', 'Disease', (104, 108))	('Pin1', 'Gene', (29, 33))	('proliferation', 'CPA', (54, 67))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('knockdown', 'Var', (34, 43))
201187	25160749	High Pin1 expression was associated with higher primary tumor stage (p = 0.035) and overall cancer stage (p = 0.047).	('primary tumor', 'Disease', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Disease', (92, 98))	('High', 'Var', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('Pin1', 'Gene', '5300', (5, 9))	('primary tumor', 'Disease', 'MESH:D009369', (48, 61))	('expression', 'MPA', (10, 20))	('higher', 'PosReg', (41, 47))	('Pin1', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
201188	25160749	The survival of 50 patients carrying high Pin1 level was significantly worse than that of the 39 patients with low Pin1 expression (p < 0.001; Figure 2D).	('patients', 'Species', '9606', (19, 27))	('high', 'Var', (37, 41))	('Pin1', 'Gene', '5300', (115, 119))	('survival', 'CPA', (4, 12))	('Pin1', 'Gene', (42, 46))	('Pin1', 'Gene', (115, 119))	('worse', 'NegReg', (71, 76))	('Pin1', 'Gene', '5300', (42, 46))	('patients', 'Species', '9606', (97, 105))
201190	25160749	Patients with high Pin1 expression had lower survival rate (p < 0.001; Figure 2E).	('expression', 'MPA', (24, 34))	('survival rate', 'CPA', (45, 58))	('Pin1', 'Gene', '5300', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('Pin1', 'Gene', (19, 23))	('lower', 'NegReg', (39, 44))
201195	25160749	To determine whether Pin1 regulated the aggressiveness of ESCC cells through cyclin D1, we knocked down cyclin D1 in CE81T cells.	('cyclin D1', 'Gene', '595', (104, 113))	('aggressiveness', 'Disease', (40, 54))	('Pin1', 'Gene', (21, 25))	('knocked', 'Var', (91, 98))	('cyclin D1', 'Gene', (104, 113))	('cyclin D1', 'Gene', '595', (77, 86))	('aggressiveness', 'Phenotype', 'HP:0000718', (40, 54))	('cyclin D1', 'Gene', (77, 86))	('aggressiveness', 'Disease', 'MESH:D001523', (40, 54))	('Pin1', 'Gene', '5300', (21, 25))
201196	25160749	The cell proliferation was attenuated and clonogenicity was reduced in cells with cyclin D1 knockdown (Figure 3C and D).	('attenuated', 'NegReg', (27, 37))	('cyclin D1', 'Gene', '595', (82, 91))	('cell proliferation', 'CPA', (4, 22))	('knockdown', 'Var', (92, 101))	('clonogenicity', 'CPA', (42, 55))	('cyclin D1', 'Gene', (82, 91))	('reduced', 'NegReg', (60, 67))
201207	25160749	The proliferation was attenuated and clonogenicity was reduced in CE81T cells with Pin1 knockdown.	('proliferation', 'CPA', (4, 17))	('reduced', 'NegReg', (55, 62))	('Pin1', 'Gene', (83, 87))	('knockdown', 'Var', (88, 97))	('attenuated', 'NegReg', (22, 32))	('clonogenicity', 'CPA', (37, 50))	('Pin1', 'Gene', '5300', (83, 87))
201208	25160749	Our result indicated that Pin1 knockdown inhibited the growth of ESCC cells in a dose-dependent manner.	('Pin1', 'Gene', (26, 30))	('growth', 'CPA', (55, 61))	('Pin1', 'Gene', '5300', (26, 30))	('ESCC', 'Disease', (65, 69))	('inhibited', 'NegReg', (41, 50))	('knockdown', 'Var', (31, 40))
201209	25160749	In xenograft tumor model, we observed that the tumor size from cells with Pin1 knockdown was smaller than that from parental CE81T cells.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', (47, 52))	('xenograft tumor', 'Disease', (3, 18))	('Pin1', 'Gene', '5300', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('smaller', 'NegReg', (93, 100))	('xenograft tumor', 'Disease', 'MESH:D009369', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('knockdown', 'Var', (79, 88))	('Pin1', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
201210	25160749	Collectively, we provided evidence that Pin1 knockdown inhibited proliferation and clonogenicity of ESCC in vitro and tumorigenesis of ESCC in vivo.	('proliferation', 'CPA', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('clonogenicity', 'CPA', (83, 96))	('Pin1', 'Gene', '5300', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('ESCC', 'Disease', (100, 104))	('tumor', 'Disease', (118, 123))	('Pin1', 'Gene', (40, 44))	('inhibited', 'NegReg', (55, 64))	('knockdown', 'Var', (45, 54))
201215	25160749	The percentage of high Pin1 expression in our patients was higher than that of earlier reports, in which 31-37% of ESCC samples exhibited high Pin1 expression.	('ESCC', 'Disease', (115, 119))	('Pin1', 'Gene', (143, 147))	('patients', 'Species', '9606', (46, 54))	('expression', 'MPA', (28, 38))	('Pin1', 'Gene', '5300', (23, 27))	('Pin1', 'Gene', '5300', (143, 147))	('high', 'Var', (18, 22))	('expression', 'MPA', (148, 158))	('Pin1', 'Gene', (23, 27))
201229	25160749	Furthermore, we identified that beta-catenin and cyclin D were downregulated after Pin1 knockdown in CE81T cells.	('Pin1', 'Gene', (83, 87))	('beta-catenin', 'Gene', (32, 44))	('knockdown', 'Var', (88, 97))	('downregulated', 'NegReg', (63, 76))	('beta-catenin', 'Gene', '1499', (32, 44))	('cyclin D', 'Protein', (49, 57))	('Pin1', 'Gene', '5300', (83, 87))
201230	25160749	The beta-catenin transactivation was reduced in cells with Pin1 knockdown but increased after Pin1 re-expression.	('Pin1', 'Gene', '5300', (94, 98))	('beta-catenin', 'Gene', '1499', (4, 16))	('Pin1', 'Gene', (59, 63))	('Pin1', 'Gene', '5300', (59, 63))	('Pin1', 'Gene', (94, 98))	('increased', 'PosReg', (78, 87))	('knockdown', 'Var', (64, 73))	('reduced', 'NegReg', (37, 44))	('beta-catenin', 'Gene', (4, 16))
201231	25160749	In xenograft tumor models, the inhibited tumorigenesis in cells with Pin1 knockdown was partially recovered by cyclin D1 restoration.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (13, 18))	('cyclin D1', 'Gene', (111, 120))	('tumor', 'Disease', (41, 46))	('Pin1', 'Gene', (69, 73))	('xenograft tumor', 'Disease', (3, 18))	('knockdown', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('xenograft tumor', 'Disease', 'MESH:D009369', (3, 18))	('inhibited', 'NegReg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Pin1', 'Gene', '5300', (69, 73))	('cyclin D1', 'Gene', '595', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
201237	25160749	The experimental evidence that Pin1 knockdown inhibited proliferation and clonogenicity of ESCC in vitro and tumorigenesis of ESCC in vivo was provided.	('Pin1', 'Gene', '5300', (31, 35))	('Pin1', 'Gene', (31, 35))	('proliferation', 'CPA', (56, 69))	('knockdown', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('inhibited', 'NegReg', (46, 55))	('clonogenicity', 'CPA', (74, 87))	('tumor', 'Disease', (109, 114))
201248	33692864	Taken together, the present findings demonstrate that Eupafolin has a significant inhibitory effect on the proliferation of EO771 cells, inhibits cell migration and invasion, and promotes cell apoptosis, thereby causing G0/G1 phase arrest, at least partially through the PI3K/Akt/mTOR signaling pathway.	('EO771', 'CellLine', 'CVCL:8349', (124, 129))	('causing', 'Reg', (212, 219))	('Eupafolin', 'Var', (54, 63))	('inhibitory', 'NegReg', (82, 92))	('Akt', 'Gene', (276, 279))	('proliferation', 'CPA', (107, 120))	('mTOR', 'Gene', '2475', (280, 284))	('promotes', 'PosReg', (179, 187))	('Eupafolin', 'Chemical', 'MESH:C503624', (54, 63))	('arrest', 'Disease', 'MESH:D006323', (232, 238))	('cell apoptosis', 'CPA', (188, 202))	('mTOR', 'Gene', (280, 284))	('invasion', 'CPA', (165, 173))	('inhibits', 'NegReg', (137, 145))	('arrest', 'Disease', (232, 238))	('Akt', 'Gene', '207', (276, 279))
201369	33692864	Taken together, the present findings showed that Eupafolin significantly inhibited the proliferation and migration of breast cancer cells, promoted apoptosis, and caused G0/G1 phase arrest, which was achieved by inhibiting the PI3K/Akt/mTOR pathway (Fig.	('Eupafolin', 'Var', (49, 58))	('Akt', 'Gene', '207', (232, 235))	('promoted', 'PosReg', (139, 147))	('Eupafolin', 'Chemical', 'MESH:C503624', (49, 58))	('proliferation', 'CPA', (87, 100))	('arrest', 'Disease', (182, 188))	('Akt', 'Gene', (232, 235))	('caused', 'Reg', (163, 169))	('arrest', 'Disease', 'MESH:D006323', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('inhibiting', 'NegReg', (212, 222))	('mTOR', 'Gene', '2475', (236, 240))	('inhibited', 'NegReg', (73, 82))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('mTOR', 'Gene', (236, 240))	('apoptosis', 'CPA', (148, 157))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
201383	33007263	The detection of variant junctions (each a pair of oriented genomic locations, or breakends, made adjacent in one of four configurations: deletion-like (DEL-like), duplicationlike (DUP-like), inversion-like (INV-like), or translocationlike (TRA-like, Fig.	('DUP', 'Gene', (181, 184))	('translocationlike', 'Var', (222, 239))	('variant', 'Var', (17, 24))	('duplicationlike', 'Var', (164, 179))	('deletion-like', 'Var', (138, 151))	('DUP', 'Gene', '81620', (181, 184))
201399	33007263	Considering clusters harboring three or more junctions, we found low-JCN clusters were significantly more likely to be dominated (> 90% representation of that type) by DEL-like (P < 2.2 x 10-16, z-test, logistic regression) or DUP-like junctions (P < 2.2 x 10-16) (Fig.	('DUP', 'Gene', '81620', (227, 230))	('cluster', 'Species', '100569', (73, 80))	('low-JCN', 'Var', (65, 72))	('cluster', 'Species', '100569', (12, 19))	('DUP', 'Gene', (227, 230))	('DEL-like', 'Var', (168, 176))
201405	33007263	We found a significantly increased burden of pyrgo in endometrial, ovarian, breast, and esophageal adenocarcinoma (ESAD) (Bonferroni P < 0.05, Fisher's Exact test, Fig.	('pyrgo', 'Var', (45, 50))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('breast', 'Disease', (76, 82))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (88, 113))	('endometrial, ovarian', 'Disease', 'MESH:D010049', (54, 74))	('pyrgo', 'Chemical', '-', (45, 50))
201411	33007263	Applying fishHook to find recurrent pyrgo hotspots across 8,642 non-overlapping previously annotated superenhancer regions (see STAR Methods), we found 16 loci were significantly mutated above background (FDR < 0.25) in the setting of a calibrated model fit (lambda = 1.03, Fig.	('STAR', 'Gene', '6770', (128, 132))	('mutated', 'Var', (179, 186))	('pyrgo', 'Chemical', '-', (36, 41))	('STAR', 'Gene', (128, 132))
201416	33007263	We also note that the minority (33%) of pyrgo intersected CGC genes.	('pyrgo', 'Var', (40, 45))	('pyrgo', 'Chemical', '-', (40, 45))	('CGC genes', 'Gene', (58, 67))
201444	33007263	We annotated the resulting 1,703 high-JCN amplicons according to several features: 1) the maximum JCN normalized by the maximal interval CN, 2) the summed JCN associated with fold back inversion junctions (INV-like junctions that terminate and begin at nearly the same location in the genome) relative to the maximal interval CN, and 3) the number of junctions with elevated JCN (JCN>3) (see STAR Methods).	('fold back', 'Phenotype', 'HP:0002808', (175, 184))	('fold back inversion junctions', 'Var', (175, 204))	('STAR', 'Gene', (392, 396))	('STAR', 'Gene', '6770', (392, 396))
201459	33007263	80% of dedifferentiated liposarcomas harbored a tyfonas on chromosome 12q, suggesting that tyfonas represent the genomic footprint of supernumerary ring chromosomes in this tumor type.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('liposarcoma', 'Phenotype', 'HP:0012034', (24, 35))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('tyfonas', 'Chemical', '-', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('liposarcomas', 'Phenotype', 'HP:0012034', (24, 36))	('tyfonas', 'Chemical', '-', (91, 98))	('liposarcomas', 'Disease', 'MESH:D008080', (24, 36))	('liposarcomas', 'Disease', (24, 36))	('tyfonas', 'Var', (48, 55))
201464	33007263	5A, see STAR Methods) revealed a robust peak of hypermutation within the first 1 kbp of breakends on the positive side of the axis.	('hypermutation', 'MPA', (48, 61))	('STAR', 'Gene', (8, 12))	('STAR', 'Gene', '6770', (8, 12))	('breakends', 'Var', (88, 97))
201487	33007263	DDT tumors (defined by high burdens of deletions, duplications, and templated insertion chains) were enriched in triple-negative breast cancer (TNBC) (P < 2.2 x 10-16, OR = 8.80), ovarian cancers (P = 7.03 x 10-16, OR = 6.89), and more broadly sex-hormone driven tumors (P = 3.18 x 10-14, OR = 19.0).	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('ovarian cancers', 'Phenotype', 'HP:0100615', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ovarian cancers', 'Disease', (180, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('ovarian cancers', 'Disease', 'MESH:D010051', (180, 195))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('TNBC', 'Disease', 'None', (144, 148))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('DDT tumors', 'Disease', (0, 10))	('breast cancer', 'Disease', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('deletions', 'Var', (39, 48))	('tumors', 'Disease', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('DDT tumors', 'Disease', 'MESH:D009369', (0, 10))	('tumors', 'Disease', (263, 269))	('TNBC', 'Disease', (144, 148))
201491	33007263	The TYF (tyfonas dominated) cluster was enriched in both luminal breast cancer (P = 4.87 x 10-8, OR = 3.25), HER2+ breast cancer (P < 2.64 x 10-9, OR = 4.96), dedifferentiated liposarcoma (P < 2.2 x 10-16, OR = 24.5), and acral melanoma (P < 1.84 x 10-15, OR = 7.40).	('HER2+', 'Var', (109, 114))	('liposarcoma', 'Disease', 'MESH:D008080', (176, 187))	('cluster', 'Species', '100569', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('acral melanoma', 'Disease', (222, 236))	('luminal breast cancer', 'Disease', (57, 78))	('liposarcoma', 'Disease', (176, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('luminal breast cancer', 'Disease', 'MESH:D001943', (57, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('tyfonas', 'Chemical', '-', (9, 16))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('breast cancer', 'Disease', (115, 128))	('acral melanoma', 'Disease', 'MESH:D008545', (222, 236))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('liposarcoma', 'Phenotype', 'HP:0012034', (176, 187))	('acral melanoma', 'Phenotype', 'HP:0012060', (222, 236))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
201494	33007263	More than 20% of cases in the DDT cluster harbored constitutional (P = 1.60 x 10-4, OR = 3.81) loss of function lesions in BRCA1 (Fig.	('loss of function', 'NegReg', (95, 111))	('lesions', 'Var', (112, 119))	('cluster', 'Species', '100569', (34, 41))	('BRCA1', 'Gene', (123, 128))	('DDT', 'Chemical', 'MESH:D003634', (30, 33))
201495	33007263	BR-cluster tumors were also significantly enriched in somatic TP53 mutations (P < 4.71 x 10-7, OR = 2.06).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('TP53', 'Gene', (62, 66))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('mutations', 'Var', (67, 76))	('tumors', 'Disease', (11, 17))	('cluster', 'Species', '100569', (3, 10))
201496	33007263	S7D), included an enrichment of SMC4 (P = 2.33 x 10-3, OR = 3.11) and RAD21 (P = 1.96 x 10-3, OR = 3.27) mutations in the INVD (inverted duplication dominant) cluster, ARID1AM (P = 1.21 x 10-3, OR = 1.86) mutations in the TIC (templated insertion chain dominant) cluster, and KMT2C (P = 2.89 x 10-3, OR = 1.95) mutations in the TRA (translocation-dominated) cluster.	('cluster', 'Species', '100569', (159, 166))	('cluster', 'Species', '100569', (358, 365))	('mutations', 'Var', (205, 214))	('cluster', 'Species', '100569', (263, 270))	('mutations', 'Var', (105, 114))	('mutations', 'Var', (311, 320))	('TRA', 'Gene', (328, 331))	('RAD21', 'Gene', (70, 75))	('SMC4', 'Gene', (32, 36))	('TIC', 'Phenotype', 'HP:0100033', (222, 225))
201503	33007263	Our data show that rigma likely arise from early and ongoing accumulation of DEL-like junctions at large and late replicating genes.	('DEL-like junctions', 'Var', (77, 95))	('rigma', 'Chemical', '-', (19, 24))	('rigma', 'Disease', (19, 24))
201521	33007263	within a non-canonical context), they may also arise through error prone Pol-alpha fill-in or alt-NHEJ repair, both of which are active at unprotected DNA ends and generate mutations across a wide spectrum of trinucleotide contexts.	('arise', 'Reg', (47, 52))	('trinucleotide', 'Chemical', '-', (209, 222))	('mutations', 'Var', (173, 182))	('fill-in', 'Var', (83, 90))	('Pol-alpha', 'Gene', (73, 82))	('Pol-alpha', 'Gene', '5422', (73, 82))
201535	30349305	Furthermore, in vitro assays, TE10 and KYSE180, of the ESCC cell lines demonstrated that knockdown of circ-DLG1 reduced cell proliferation significantly.	('cell proliferation', 'CPA', (120, 138))	('circ-DLG1', 'Gene', '1739', (102, 111))	('knockdown', 'Var', (89, 98))	('reduced', 'NegReg', (112, 119))	('circ-DLG1', 'Gene', (102, 111))
201543	30349305	Our study is aimed to investigate the association between a new circRNA named circ-DLG1 (hsa_circ_0007203) and ESCC.	('hsa_circ_0007203', 'Var', (89, 105))	('circ-DLG1', 'Gene', '1739', (78, 87))	('circ-DLG1', 'Gene', (78, 87))	('ESCC', 'Disease', (111, 115))
201563	30349305	K180 and T10 cells were transfected with 50 nM si-circ-DLG1 or si-NC.	('circ-DLG1', 'Gene', (50, 59))	('circ-DLG1', 'Gene', '1739', (50, 59))	('T10', 'CellLine', 'CVCL:0190', (9, 12))	('si-NC', 'Var', (63, 68))
201584	30349305	Knocking down of circ-DLG1 expression inhibited cell proliferation significantly, indicating that circ-DLG1 might promote the procession of ESCC.	('Knocking down', 'Var', (0, 13))	('circ-DLG1', 'Gene', (17, 26))	('circ-DLG1', 'Gene', '1739', (98, 107))	('ESCC', 'Disease', (140, 144))	('cell proliferation', 'CPA', (48, 66))	('inhibited', 'NegReg', (38, 47))	('circ-DLG1', 'Gene', '1739', (17, 26))	('circ-DLG1', 'Gene', (98, 107))	('promote', 'PosReg', (114, 121))
201589	30349305	In this study, we found that inhibition of circ-DLG1 expression decreased the proliferation of ESCC cells significantly.	('proliferation of ESCC cells', 'CPA', (78, 105))	('circ-DLG1', 'Gene', '1739', (43, 52))	('circ-DLG1', 'Gene', (43, 52))	('inhibition', 'Var', (29, 39))	('decreased', 'NegReg', (64, 73))
201604	30349305	In addition, they also explored the biological function of miR-630 by targeting Slug and investigated the correlation between miR-630 expression and EMT progression in vivo and in vitro ectopic miR-630 expression could inhibit proliferation, invasion, and metastasis, whereas miR-630 knockdown induced proliferation, invasion, metastasis, and EMT traits.	('miR-630', 'Gene', (194, 201))	('invasion', 'CPA', (242, 250))	('proliferation', 'CPA', (302, 315))	('metastasis', 'CPA', (327, 337))	('Slug', 'Gene', (80, 84))	('induced', 'PosReg', (294, 301))	('miR-630', 'Gene', '693215', (59, 66))	('inhibit', 'NegReg', (219, 226))	('miR-630', 'Gene', '693215', (194, 201))	('EMT traits', 'CPA', (343, 353))	('miR-630', 'Gene', (276, 283))	('proliferation', 'CPA', (227, 240))	('miR-630', 'Gene', (126, 133))	('Slug', 'Gene', '6591', (80, 84))	('invasion', 'CPA', (317, 325))	('miR-630', 'Gene', '693215', (276, 283))	('miR-630', 'Gene', (59, 66))	('metastasis', 'CPA', (256, 266))	('ectopic', 'Var', (186, 193))	('miR-630', 'Gene', '693215', (126, 133))
201658	26426637	The correlation between ERCC1 polymorphisms (rs11615 and rs3212986) and XPD polymorphisms (rs13181 and rs1799793) with the response rate and overall survival of cancer patients who accept neoadjuvant therapy has been extensively investigated.	('rs3212986', 'Mutation', 'rs3212986', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ERCC1', 'Gene', (24, 29))	('rs13181', 'Var', (91, 98))	('ERCC1', 'Gene', '2067', (24, 29))	('rs11615', 'Var', (45, 52))	('rs3212986', 'Var', (57, 66))	('rs1799793', 'Mutation', 'rs1799793', (103, 112))	('XPD', 'Gene', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('rs1799793', 'Var', (103, 112))	('patients', 'Species', '9606', (168, 176))	('XPD', 'Gene', '2068', (72, 75))	('cancer', 'Disease', (161, 167))	('rs13181', 'Mutation', 'rs13181', (91, 98))	('rs11615', 'Mutation', 'rs11615', (45, 52))
201659	26426637	In the present meta-analysis, we demonstrated that the ERCC1 rs3212986 polymorphism was significantly correlated with the response rate of esophageal cancer patients to neoadjuvant therapy (OR = 0.49, 95% CI = 0.31-0.76, heterogeneity P = 0.480).	('rs3212986', 'Var', (61, 70))	('ERCC1', 'Gene', (55, 60))	('patients', 'Species', '9606', (157, 165))	('ERCC1', 'Gene', '2067', (55, 60))	('esophageal cancer', 'Disease', (139, 156))	('correlated', 'Reg', (102, 112))	('rs3212986', 'Mutation', 'rs3212986', (61, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
201660	26426637	Furthermore, a considerable correlation was observed between ERCC1 rs11615 and the response rate of esophageal cancer patients to neoadjuvant therapy (OR = 0.228, 95% CI = 0.125-0.418, heterogeneity P = 0.291).	('ERCC1', 'Gene', '2067', (61, 66))	('esophageal cancer', 'Disease', (100, 117))	('rs11615', 'Mutation', 'rs11615', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('rs11615', 'Var', (67, 74))	('ERCC1', 'Gene', (61, 66))	('patients', 'Species', '9606', (118, 126))
201662	26426637	These findings indicate that the ERCC1 rs11615 and ERCC1 rs312986 polymorphisms may be candidate pharmacogenomic factors capable of predicting the response rate of esophageal cancer patients who accept neoadjuvant therapy.	('esophageal cancer', 'Disease', (164, 181))	('predicting', 'Reg', (132, 142))	('rs312986', 'Var', (57, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('ERCC1', 'Gene', '2067', (51, 56))	('ERCC1', 'Gene', (51, 56))	('rs11615', 'Mutation', 'rs11615', (39, 46))	('ERCC1', 'Gene', (33, 38))	('rs312986', 'Mutation', 'rs312986', (57, 65))	('patients', 'Species', '9606', (182, 190))	('ERCC1', 'Gene', '2067', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('rs11615', 'Var', (39, 46))
201669	26426637	ERCC1 and XPD polymorphisms can reduce the DNA repair capacity.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('reduce', 'NegReg', (32, 38))	('XPD', 'Gene', (10, 13))	('XPD', 'Gene', '2068', (10, 13))	('polymorphisms', 'Var', (14, 27))	('DNA repair capacity', 'CPA', (43, 62))
201670	26426637	Recently, a large number of studies suggested that ERCC1 and XPD polymorphisms predicted the therapeutic response to neoadjuvant treatment and the prognosis in human cancer.	('XPD', 'Gene', (61, 64))	('cancer', 'Disease', (166, 172))	('predicted', 'Reg', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('XPD', 'Gene', '2068', (61, 64))	('polymorphisms', 'Var', (65, 78))	('ERCC1', 'Gene', '2067', (51, 56))	('ERCC1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('human', 'Species', '9606', (160, 165))	('therapeutic response to neoadjuvant treatment', 'CPA', (93, 138))
201673	26426637	Eligibility criteria were as follows: human-based studies; pathologically confirmed cancer receiving neoadjuvant regimens; full text written in English; evaluation of the association between ERCC polymorphisms and clinical outcomes (ie, therapeutic response rate, overall survival (OS) or progression-free survival (PFS)); and the largest study from all studies with overlapping data published by the same investigators was chosen.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('overall survival', 'CPA', (264, 280))	('OS', 'Chemical', '-', (282, 284))	('human', 'Species', '9606', (38, 43))	('cancer', 'Disease', (84, 90))	('association', 'Interaction', (171, 182))	('polymorphisms', 'Var', (196, 209))	('therapeutic response rate', 'CPA', (237, 262))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ERCC', 'Gene', (191, 195))
201680	26426637	The correlation strength of ERCC polymorphisms and response of cancer patients to neoadjuvant treatment was assessed by pooled odds ratios with corresponding 95% CIs.	('patients', 'Species', '9606', (70, 78))	('polymorphisms', 'Var', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ERCC', 'Gene', (28, 32))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
201681	26426637	The hazard ratio (HR) was utilized to estimate the relationship between ERCC variations and the prognosis of cancer patients.	('variations', 'Var', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ERCC', 'Gene', (72, 76))
201684	26426637	ERCC1 rs11615 polymorphism Nine studies were performed to assess the correlation of the ERCC1 rs11615 polymorphism and neoadjuvant therapy.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('rs11615', 'Mutation', 'rs11615', (94, 101))	('rs11615', 'Var', (94, 101))	('rs11615', 'Mutation', 'rs11615', (6, 13))	('ERCC1', 'Gene', '2067', (88, 93))	('ERCC1', 'Gene', (88, 93))
201685	26426637	The genotype data for ERCC1 rs11615 were separated for CC, CT, and TT.	('ERCC1', 'Gene', '2067', (22, 27))	('ERCC1', 'Gene', (22, 27))	('rs11615', 'Var', (28, 35))	('rs11615', 'Mutation', 'rs11615', (28, 35))
201688	26426637	Furthermore, we demonstrated that patients carrying the homozygous CC-TT genotype presented a worse response rate compared with subjects with the heterogeneous CT genotype (OR = 0.228, 95% CI = 0.125-0.418, heterogeneity P = 0.291).	('response', 'MPA', (100, 108))	('CC-TT', 'Var', (67, 72))	('patients', 'Species', '9606', (34, 42))
201689	26426637	ERCC1 rs3212986 polymorphism In this group of genes, subjects with the mutation genotype presented a higher rate of response to neoadjuvant chemotherapy in 4 studies (OR = 1.93, 95% CI = 0.82-4.56, heterogeneity P = 0.847) compared with subjects with the wild-type genotype.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('higher', 'PosReg', (101, 107))	('mutation', 'Var', (71, 79))	('rs3212986', 'Mutation', 'rs3212986', (6, 15))	('response', 'MPA', (116, 124))	('rs3212986 polymorphism', 'Var', (6, 28))
201692	26426637	The results of subgroup analysis by tumor type indicated that a significant correlation was observed between the ERCC1 rs3212986 polymorphism and the response rate of esophageal cancer patients to neoadjuvant therapy (OR = 0.49, 95% CI = 0.31-0.76, heterogeneity P = 0.480) (Fig.	('esophageal cancer', 'Disease', 'MESH:D004938', (167, 184))	('ERCC1', 'Gene', '2067', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('rs3212986', 'Mutation', 'rs3212986', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('rs3212986', 'Var', (119, 128))	('patients', 'Species', '9606', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('esophageal cancer', 'Disease', (167, 184))	('tumor', 'Disease', (36, 41))	('ERCC1', 'Gene', (113, 118))
201693	26426637	The finding demonstrated that subjects carrying ERCC1 rs3212986 with at least one A allele (CA-AA genotype) presented a better response rate than subjects with the CC genotype.	('better', 'PosReg', (120, 126))	('rs3212986', 'Var', (54, 63))	('ERCC1', 'Gene', '2067', (48, 53))	('ERCC1', 'Gene', (48, 53))	('response', 'MPA', (127, 135))	('rs3212986', 'Mutation', 'rs3212986', (54, 63))
201695	26426637	XPD rs1799793 polymorphism A total of 5 studies with 547 subjects were included in this analysis.	('rs1799793', 'Mutation', 'rs1799793', (4, 13))	('XPD', 'Gene', '2068', (0, 3))	('rs1799793 polymorphism', 'Var', (4, 26))	('XPD', 'Gene', (0, 3))
201698	26426637	XPD rs13181 polymorphism (Lys751Gln) The correlation of the XPD polymorphism and response rate of neoadjuvant therapy was explored in 7 studies containing 1687 patients.	('XPD', 'Gene', '2068', (60, 63))	('Lys751Gln', 'SUBSTITUTION', 'None', (26, 35))	('patients', 'Species', '9606', (160, 168))	('XPD', 'Gene', (0, 3))	('Lys751Gln', 'Var', (26, 35))	('XPD', 'Gene', '2068', (0, 3))	('rs13181', 'Mutation', 'rs13181', (4, 11))	('XPD', 'Gene', (60, 63))
201701	26426637	ERCC1 rs11615 polymorphism The ERCC1 rs11615 polymorphism and OS were reported in 5 studies.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('rs11615', 'Var', (37, 44))	('OS', 'Chemical', '-', (62, 64))	('rs11615', 'Var', (6, 13))	('ERCC1', 'Gene', '2067', (31, 36))	('ERCC1', 'Gene', (31, 36))	('rs11615', 'Mutation', 'rs11615', (37, 44))	('rs11615', 'Mutation', 'rs11615', (6, 13))
201705	26426637	Subgroup analysis on the basis of tumor type suggested no significant correlation between the ERCC1 rs11615 polymorphism and NSCLC or osteosarcoma prognosis (Table 3).	('osteosarcoma', 'Disease', (134, 146))	('osteosarcoma', 'Disease', 'MESH:D012516', (134, 146))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('NSCLC', 'Disease', (125, 130))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('rs11615', 'Var', (100, 107))	('ERCC1', 'Gene', (94, 99))	('ERCC1', 'Gene', '2067', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('rs11615', 'Mutation', 'rs11615', (100, 107))	('osteosarcoma', 'Phenotype', 'HP:0002669', (134, 146))
201706	26426637	ERCC1 rs3212986 polymorphism The genotype data were classified into 3 genotypes (CC, CA, and AA).	('rs3212986', 'Var', (6, 15))	('ERCC1', 'Gene', (0, 5))	('ERCC1', 'Gene', '2067', (0, 5))	('rs3212986', 'Mutation', 'rs3212986', (6, 15))
201707	26426637	No significant associations were observed between the ERCC1 rs3212986 polymorphism and OS in the comparison model (CC vs. CA-AA).	('rs3212986', 'Mutation', 'rs3212986', (60, 69))	('OS', 'Chemical', '-', (87, 89))	('rs3212986', 'Var', (60, 69))	('ERCC1', 'Gene', '2067', (54, 59))	('ERCC1', 'Gene', (54, 59))
201708	26426637	No correlation was observed between the rs3212986 polymorphism and neoadjuvant regimens in the subgroup analysis of tumor types.	('rs3212986', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('rs3212986', 'Mutation', 'rs3212986', (40, 49))
201710	26426637	The XPD rs1799793 polymorphism was not of prognostic relevance for neoadjuvant regimens.	('rs1799793', 'Var', (8, 17))	('XPD', 'Gene', (4, 7))	('XPD', 'Gene', '2068', (4, 7))	('rs1799793', 'Mutation', 'rs1799793', (8, 17))
201713	26426637	Analysis of the esophageal cancer subgroup revealed that the XPD rs13181 polymorphism was not significantly associated with OS (HR = 1.01, 95% CI = 0.74-1.38, heterogeneity P = 0.512).	('XPD', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('OS', 'Chemical', '-', (124, 126))	('rs13181', 'Mutation', 'rs13181', (65, 72))	('XPD', 'Gene', '2068', (61, 64))	('esophageal cancer', 'Disease', (16, 33))	('associated', 'Reg', (108, 118))	('rs13181', 'Var', (65, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (16, 33))
201725	26426637	However, the findings of previous studies concerning the predictive impact of ERCC1 and XPD polymorphisms toward neoadjuvant therapy are discordant with one another.	('XPD', 'Gene', '2068', (88, 91))	('polymorphisms', 'Var', (92, 105))	('XPD', 'Gene', (88, 91))	('ERCC1', 'Gene', '2067', (78, 83))	('ERCC1', 'Gene', (78, 83))
201727	26426637	In the present meta-analysis, we demonstrated that the ERCC1 rs11615 and rs3212986 polymorphisms were significantly correlated with the response rate to neoadjuvant therapy in esophageal cancer patients.	('patients', 'Species', '9606', (194, 202))	('rs11615', 'Var', (61, 68))	('esophageal cancer', 'Disease', (176, 193))	('rs3212986', 'Mutation', 'rs3212986', (73, 82))	('ERCC1', 'Gene', (55, 60))	('rs11615', 'Mutation', 'rs11615', (61, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (176, 193))	('ERCC1', 'Gene', '2067', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('correlated', 'Reg', (116, 126))	('rs3212986', 'Var', (73, 82))
201728	26426637	However, no significant correlation was identified between XPD polymorphisms and the response rate of neoadjuvant regimens.	('XPD', 'Gene', (59, 62))	('XPD', 'Gene', '2068', (59, 62))	('polymorphisms', 'Var', (63, 76))
201729	26426637	Meta-analysis of overall survival revealed that subjects carrying the ERCC1 rs11615 genotype CC had a significant tendency toward shorter OS than subjects with genotype CT-TT.	('rs11615', 'Mutation', 'rs11615', (76, 83))	('ERCC1', 'Gene', (70, 75))	('OS', 'Chemical', '-', (138, 140))	('rs11615', 'Var', (76, 83))	('ERCC1', 'Gene', '2067', (70, 75))	('CT-TT', 'Chemical', '-', (169, 174))	('shorter OS', 'MPA', (130, 140))
201730	26426637	However, there was no correlation between other ERCC1 and XPD polymorphisms and OS.	('OS', 'Chemical', '-', (80, 82))	('ERCC1', 'Gene', (48, 53))	('XPD', 'Gene', '2068', (58, 61))	('ERCC1', 'Gene', '2067', (48, 53))	('polymorphisms', 'Var', (62, 75))	('XPD', 'Gene', (58, 61))
201732	26426637	We found that ERCC1 rs3212986 was significantly correlated with the response rate of esophageal cancer patients who received the neoadjuvant regimens.	('ERCC1', 'Gene', '2067', (14, 19))	('ERCC1', 'Gene', (14, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('rs3212986', 'Mutation', 'rs3212986', (20, 29))	('response', 'Disease', (68, 76))	('rs3212986', 'Var', (20, 29))	('correlated', 'Reg', (48, 58))	('patients', 'Species', '9606', (103, 111))	('esophageal cancer', 'Disease', (85, 102))
201734	26426637	The ERCC1 rs3212986 polymorphism is located in the 3' UTR of the gene, which contributes to ERCC1 mRNA stability.	('ERCC1', 'Gene', (92, 97))	('ERCC1', 'Gene', (4, 9))	('ERCC1', 'Gene', '2067', (4, 9))	('rs3212986', 'Mutation', 'rs3212986', (10, 19))	('rs3212986', 'Var', (10, 19))	('ERCC1', 'Gene', '2067', (92, 97))	('mRNA stability', 'MPA', (98, 112))	('contributes', 'Reg', (77, 88))
201735	26426637	Consequently, the rs3212986 polymorphism results in a limited DNA repair capacity, thereby impacting the response to treatment and overall survival.	('response to treatment', 'CPA', (105, 126))	('impacting', 'Reg', (91, 100))	('DNA', 'MPA', (62, 65))	('rs3212986', 'Mutation', 'rs3212986', (18, 27))	('limited', 'NegReg', (54, 61))	('rs3212986', 'Var', (18, 27))
201736	26426637	This finding indicated that ERCC1 rs3212986 might predict the response of esophageal cancer patients to neoadjuvant therapy and offered a minimally invasive and practicable approach to detect the outcome of neoadjuvant regimens.	('ERCC1', 'Gene', '2067', (28, 33))	('ERCC1', 'Gene', (28, 33))	('rs3212986', 'Mutation', 'rs3212986', (34, 43))	('patients', 'Species', '9606', (92, 100))	('predict', 'Reg', (50, 57))	('rs3212986', 'Var', (34, 43))	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
201737	26426637	Additionally, we observed a correlation between ERCC1 rs3212986 and the response rate to neoadjuvant therapy in rectal cancer patients.	('rs3212986', 'Var', (54, 63))	('ERCC1', 'Gene', '2067', (48, 53))	('ERCC1', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('rectal cancer', 'Phenotype', 'HP:0100743', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', (119, 125))	('patients', 'Species', '9606', (126, 134))	('rs3212986', 'Mutation', 'rs3212986', (54, 63))	('response', 'CPA', (72, 80))	('correlation', 'Reg', (28, 39))
201738	26426637	The ERCC1 rs11615 polymorphism is located at codon 118 and may reduce ERCC1 mRNA and protein expression levels, thereby reducing the DNA repair capacity.	('ERCC1', 'Gene', '2067', (4, 9))	('ERCC1', 'Gene', (4, 9))	('ERCC1', 'Gene', (70, 75))	('reducing', 'NegReg', (120, 128))	('ERCC1', 'Gene', '2067', (70, 75))	('rs11615', 'Var', (10, 17))	('reduce', 'NegReg', (63, 69))	('rs11615', 'Mutation', 'rs11615', (10, 17))	('DNA repair capacity', 'MPA', (133, 152))
201739	26426637	Therefore, we investigated whether ERCC1 rs11615 was correlated with the response rate to neoadjuvant therapy in esophageal cancer patients.	('patients', 'Species', '9606', (131, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('rs11615', 'Var', (41, 48))	('ERCC1', 'Gene', (35, 40))	('correlated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ERCC1', 'Gene', '2067', (35, 40))	('esophageal cancer', 'Disease', (113, 130))	('rs11615', 'Mutation', 'rs11615', (41, 48))
201742	26426637	These results were in agreement with Metzger's studies and suggested that ERCC1 rs11615 might predict the response rate to neoadjuvant therapy in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ERCC1', 'Gene', '2067', (74, 79))	('predict', 'Reg', (94, 101))	('rs11615', 'Mutation', 'rs11615', (80, 87))	('esophageal cancer', 'Disease', (146, 163))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('rs11615', 'Var', (80, 87))	('ERCC1', 'Gene', (74, 79))
201743	26426637	On the other hand, our analysis indicated that XPD rs13181 and rs1799793 did not present any correlation with the response rate to neoadjuvant therapy.	('XPD', 'Gene', (47, 50))	('rs13181', 'Mutation', 'rs13181', (51, 58))	('XPD', 'Gene', '2068', (47, 50))	('rs1799793', 'Mutation', 'rs1799793', (63, 72))	('rs1799793', 'Var', (63, 72))
201746	26426637	We demonstrated that ERCC1 rs11615 exhibited a marginal correlation with the OS of patients receiving neoadjuvant therapy (HR = 1.57, 95% CI = 0.95-2.61, heterogeneity P = 0.005), which was similar to the findings of Metzger and Ryu's studies.	('ERCC1', 'Gene', (21, 26))	('ERCC1', 'Gene', '2067', (21, 26))	('rs11615', 'Var', (27, 34))	('OS', 'Chemical', '-', (77, 79))	('patients', 'Species', '9606', (83, 91))	('rs11615', 'Mutation', 'rs11615', (27, 34))
201748	26426637	However, with detecting other ERCC1 and XPD polymorphisms, we were unable to discriminate between shorter OS and longer OS.	('ERCC1', 'Gene', (30, 35))	('XPD', 'Gene', '2068', (40, 43))	('polymorphisms', 'Var', (44, 57))	('XPD', 'Gene', (40, 43))	('OS', 'Chemical', '-', (120, 122))	('OS', 'Chemical', '-', (106, 108))	('ERCC1', 'Gene', '2067', (30, 35))
201751	26426637	In summary, in the present meta-analysis, we tested whether the ERCC1 rs3212986 and rs11615 polymorphisms had the potential capable of predicting the response rate in esophageal cancer patients who received neoadjuvant therapy.	('rs11615', 'Var', (84, 91))	('ERCC1', 'Gene', (64, 69))	('predicting', 'Reg', (135, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('ERCC1', 'Gene', '2067', (64, 69))	('rs11615', 'Mutation', 'rs11615', (84, 91))	('rs3212986', 'Mutation', 'rs3212986', (70, 79))	('tested', 'Reg', (45, 51))	('patients', 'Species', '9606', (185, 193))	('esophageal cancer', 'Disease', (167, 184))	('rs3212986', 'Var', (70, 79))
201768	25874173	NCRT in esophageal cancer could enhance curative resection and eradicate micrometastases, thereby eventually improving overall survival (OS) and disease-free survival.	('NCRT', 'Var', (0, 4))	('curative resection', 'CPA', (40, 58))	('micrometastases', 'CPA', (73, 88))	('improving', 'PosReg', (109, 118))	('eradicate', 'NegReg', (63, 72))	('esophageal cancer', 'Disease', (8, 25))	('disease-free survival', 'CPA', (145, 166))	('overall survival', 'CPA', (119, 135))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('enhance', 'PosReg', (32, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (8, 25))
201822	25874173	Of six RCTs, four RCTs available for evaluating the downstaging effect of NCRT showed that patients who had received NCRT were less likely to have an advanced stage of cancer at pathological examination than were controls.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('patients', 'Species', '9606', (91, 99))	('NCRT', 'Var', (117, 121))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('less', 'NegReg', (127, 131))	('cancer', 'Disease', (168, 174))
201942	24681073	However, the relatively low enthusiasm for aspirin as a chemopreventive strategy in this study may have implications for future EAC prevention strategies:particularly if these evolve in complexity to include polypharmacy such as aspirin plus PPI, or conceivably plus statin therapy, rather than aspirin monotherapy alone.	('PPI', 'Var', (242, 245))	('EAC', 'Disease', (128, 131))	('aspirin', 'Chemical', 'MESH:D001241', (229, 236))	('aspirin', 'Chemical', 'MESH:D001241', (43, 50))	('aspirin', 'Disease', (229, 236))	('aspirin', 'Chemical', 'MESH:D001241', (295, 302))
202058	20112337	Single nucleotide polymorphisms of eight inflammation-related genes and their associations with smoking-related cancers Tobacco smoke and its metabolites are carcinogens that increase tissue oxidative stress and induce target tissue inflammation.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('induce', 'Reg', (212, 218))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('target tissue inflammation', 'MPA', (219, 245))	('Tobacco', 'Species', '4097', (120, 127))	('tissue oxidative stress', 'MPA', (184, 207))	('associations', 'Interaction', (78, 90))	('increase', 'PosReg', (175, 183))	('cancers', 'Disease', (112, 119))	('oxidative stress', 'Phenotype', 'HP:0025464', (191, 207))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
202059	20112337	We hypothesized that genetic variation of inflammatory pathway genes plays a role in tobacco-related carcinogenesis and is modified by tobacco smoking.	('tobacco', 'Species', '4097', (135, 142))	('tobacco', 'Species', '4097', (85, 92))	('carcinogenesis', 'Disease', (101, 115))	('inflammatory pathway genes', 'Gene', (42, 68))	('role', 'Reg', (77, 81))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))	('genetic variation', 'Var', (21, 38))
202061	20112337	After adjusting for age, education, ethnicity, gender, and tobacco smoking, IL10 rs1800871 was inversely associated with oropharyngeal cancer (CT+TT versus CC adjusted odds ratio [aOR]: 0.69, 95% confidence interval [CI]: 0.50-0.95), and among never smokers was positively associated with lung cancer (TT versus CT+CC aOR: 2.5, 95% CI: 1.3-5.1) and inversely with oropharyngeal cancer (CT+TT versus CC aOR: 0.63, 95% CI: 0.41-0.95).	('rs1800871', 'Var', (81, 90))	('rs1800871', 'Mutation', 'rs1800871', (81, 90))	('lung cancer', 'Disease', 'MESH:D008175', (289, 300))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (364, 384))	('IL10', 'Gene', (76, 80))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (121, 141))	('oropharyngeal cancer', 'Disease', (364, 384))	('IL10', 'Gene', '3586', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', (289, 300))	('oropharyngeal cancer', 'Disease', (121, 141))	('tobacco', 'Species', '4097', (59, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (289, 300))	('associated', 'Reg', (273, 283))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
202062	20112337	Among all pooled never smokers (588 cases and 816 controls), TNF rs1799964 was inversely associated with smoking-related cancer (CC versus CT+TT aOR: 0.36, 95% CI: 0.17-0.77).	('associated with', 'Reg', (89, 104))	('TNF', 'Gene', '7124', (61, 64))	('rs1799964', 'Var', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('inversely', 'NegReg', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('rs1799964', 'Mutation', 'rs1799964', (65, 74))	('cancer', 'Disease', (121, 127))	('TNF', 'Gene', (61, 64))
202063	20112337	Bayesian correction for multiple comparisons suggests that chance is unlikely to explain our findings (although epigenetic mechanisms may be in effect), which support our hypotheses, suggesting that IL10 rs1800871 is a susceptibility marker for oropharyngeal and lung cancers, and that TNF rs1799964 is associated with smoking-related cancers among never smokers.	('rs1799964', 'Var', (290, 299))	('IL10', 'Gene', (199, 203))	('cancers', 'Phenotype', 'HP:0002664', (335, 342))	('susceptibility', 'Reg', (219, 233))	('cancers', 'Disease', (335, 342))	('associated', 'Reg', (303, 313))	('rs1800871', 'Mutation', 'rs1800871', (204, 213))	('lung cancers', 'Disease', 'MESH:D008175', (263, 275))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancers', 'Disease', 'MESH:D009369', (268, 275))	('IL10', 'Gene', '3586', (199, 203))	('lung cancers', 'Disease', (263, 275))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('TNF', 'Gene', (286, 289))	('lung cancers', 'Phenotype', 'HP:0100526', (263, 275))	('cancers', 'Disease', 'MESH:D009369', (335, 342))	('rs1799964', 'Mutation', 'rs1799964', (290, 299))	('rs1800871', 'Var', (204, 213))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('cancers', 'Disease', (268, 275))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('TNF', 'Gene', '7124', (286, 289))
202070	20112337	An individual's cancer risk may be affected by genetic variations in essential cell regulatory pathways and inflammatory responses, and tobacco smoking may modify these effects, suggesting that genetic variation may be important susceptibility markers for tobacco-related cancers.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tobacco', 'Species', '4097', (136, 143))	('tobacco', 'Species', '4097', (256, 263))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('cancer', 'Disease', (16, 22))	('inflammatory responses', 'CPA', (108, 130))	('genetic variations', 'Var', (47, 65))	('affected', 'Reg', (35, 43))	('essential cell regulatory pathways', 'Pathway', (69, 103))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('cancer', 'Disease', (272, 278))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('cancers', 'Disease', (272, 279))	('cancers', 'Disease', 'MESH:D009369', (272, 279))
202071	20112337	In the current study, we use a pathway-based approach using data from three case-control studies (Los Angeles [LA] County, Taixing, China, and Memorial Sloan-Kettering Cancer Center [MSKCC]) to test the hypotheses that single nucleotide polymorphisms (SNPs) in inflammation-related genes are associated with smoking-related cancers of the lung, oropharynx, larynx, esophagus, stomach, liver, bladder, and kidney, and that their effects are modified by tobacco smoking.	('larynx', 'Disease', (357, 363))	('bladder', 'Disease', (392, 399))	('kidney', 'Disease', (405, 411))	('single nucleotide polymorphisms', 'Var', (219, 250))	('Memorial Sloan-Kettering Cancer', 'Disease', (143, 174))	('tobacco', 'Species', '4097', (452, 459))	('Memorial Sloan-Kettering Cancer', 'Disease', 'MESH:D008569', (143, 174))	('stomach', 'Disease', (376, 383))	('esophagus', 'Disease', (365, 374))	('associated', 'Reg', (292, 302))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('cancers of the lung', 'Disease', (324, 343))	('Cancer', 'Phenotype', 'HP:0002664', (168, 174))	('oropharynx', 'Disease', (345, 355))	('liver', 'Disease', (385, 390))	('cancers of the lung', 'Disease', 'MESH:D008175', (324, 343))	('cancers', 'Phenotype', 'HP:0002664', (324, 331))	('inflammation-related genes', 'Gene', (261, 287))
202083	20112337	Six SNPs met these criteria across all three studies (IL10 rs1800871; TNF rs1799964 and rs1800629; LTA rs909253; IFNGR1 rs11914; and IFNG rs2069705) while another six met inclusion criteria for at least one of the studies (IL10 rs1800872 and rs1800896; IL1A rs17561; IL1B rs1143627 and rs16944; and IL6 rs1800796).	('IL10', 'Gene', (54, 58))	('TNF', 'Gene', '7124', (70, 73))	('rs1143627', 'Mutation', 'rs1143627', (272, 281))	('rs16944', 'Var', (286, 293))	('rs1800872', 'Mutation', 'rs1800872', (228, 237))	('IL10', 'Gene', '3586', (223, 227))	('rs1800629', 'Var', (88, 97))	('rs1800871', 'Mutation', 'rs1800871', (59, 68))	('IL1B', 'Gene', (267, 271))	('IL10', 'Gene', '3586', (54, 58))	('IL1B', 'Gene', '3553', (267, 271))	('rs909253', 'Mutation', 'rs909253', (103, 111))	('rs1143627', 'Var', (272, 281))	('rs1800629', 'Mutation', 'rs1800629', (88, 97))	('rs1799964', 'Mutation', 'rs1799964', (74, 83))	('rs16944', 'Mutation', 'rs16944', (286, 293))	('rs1800896', 'Mutation', 'rs1800896', (242, 251))	('rs2069705', 'Mutation', 'rs2069705', (138, 147))	('TNF', 'Gene', (70, 73))	('rs17561', 'Mutation', 'rs17561', (258, 265))	('rs1799964', 'Var', (74, 83))	('rs11914', 'Mutation', 'rs11914', (120, 127))	('rs1800796', 'Mutation', 'rs1800796', (303, 312))	('IL10', 'Gene', (223, 227))
202084	20112337	At an alpha level of 0.05, deviation from HWE was suggested for several SNPs (IL1B rs1143627 among Hispanics, IL10 rs1800871 in Asian-Americans, and LTA rs909253 for African-Americans), but none exceeded the Bonferroni-adjusted cut-point of 0.05/12 = 0.0042.	('rs1143627', 'Var', (83, 92))	('IL10', 'Gene', (110, 114))	('IL10', 'Gene', '3586', (110, 114))	('rs909253', 'Var', (153, 161))	('rs909253', 'Mutation', 'rs909253', (153, 161))	('rs1800871', 'Var', (115, 124))	('rs1800871', 'Mutation', 'rs1800871', (115, 124))	('IL1B', 'Gene', (78, 82))	('IL1B', 'Gene', '3553', (78, 82))	('rs1143627', 'Mutation', 'rs1143627', (83, 92))
202085	20112337	Although three SNPs in the IL10 promoter region were within 0.5 kb of each other (rs1800896, rs1800871, and rs1800872), haplotype analysis was not conducted since rs1800896 was not genotyped in the LA and MSKCC studies, and because initial analysis suggested a block size of only two SNPs in the Taixing study.	('rs1800871', 'Var', (93, 102))	('rs1800896', 'Var', (82, 91))	('rs1800896', 'Mutation', 'rs1800896', (163, 172))	('rs1800871', 'Mutation', 'rs1800871', (93, 102))	('rs1800872', 'Var', (108, 117))	('rs1800896', 'Mutation', 'rs1800896', (82, 91))	('rs1800872', 'Mutation', 'rs1800872', (108, 117))	('IL10', 'Gene', (27, 31))	('IL10', 'Gene', '3586', (27, 31))
202087	20112337	SNPs were genotyped using the SNPlex assay (Applied Biosystems [ABI], Foster City, CA); two were also genotyped with ABI's TaqMan assay (IL10 rs1800871 and IFNGR1 rs11914).	('rs11914', 'Mutation', 'rs11914', (163, 170))	('IFNGR1', 'Gene', (156, 162))	('rs1800871', 'Var', (142, 151))	('rs1800871', 'Mutation', 'rs1800871', (142, 151))	('rs11914', 'Var', (163, 170))	('IL10', 'Gene', (137, 141))	('IL10', 'Gene', '3586', (137, 141))
202090	20112337	Concordance for SNPs genotyped on both platforms was 0.943 for IL10 rs1800871 and 0.996 for IFNGR1 rs11914.	('rs11914', 'Var', (99, 106))	('rs1800871', 'Var', (68, 77))	('IL10', 'Gene', (63, 67))	('IL10', 'Gene', '3586', (63, 67))	('rs1800871', 'Mutation', 'rs1800871', (68, 77))	('IFNGR1', 'Gene', (92, 98))	('rs11914', 'Mutation', 'rs11914', (99, 106))
202098	20112337	For SNPs genotyped across all three studies that had point estimates consistent in direction and magnitude over all cancer sites, we investigated whether those SNPs were associated with smoking-related cancer by pooling all cases and controls across all three studies and the different tumor sites.	('SNPs', 'Var', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('associated', 'Reg', (170, 180))
202106	20112337	Oropharyngeal cancer was inversely associated with IL10 rs1800871 among CT heterozygotes (adjusted OR [aOR]: 0.67, 95% CI: 0.48-0.94) and possibly among TT homozygotes (aOR: 0.78, 95% CI: 0.44-1.4), suggesting a dominant inheritance model (aOR: 0.69, 95% CI: 0.50-0.95).	('cancer', 'Disease', (14, 20))	('IL10', 'Gene', (51, 55))	('IL10', 'Gene', '3586', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('rs1800871', 'Var', (56, 65))	('rs1800871', 'Mutation', 'rs1800871', (56, 65))	('associated', 'Interaction', (35, 45))	('inversely', 'NegReg', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
202107	20112337	An inverse association was also observed between IFNG rs2069705 and oropharyngeal cancer (CT and TT versus CC aOR: 0.72, 95% CI: 0.52-1.0).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('oropharyngeal cancer', 'Disease', (68, 88))	('inverse', 'NegReg', (3, 10))	('rs2069705', 'Mutation', 'rs2069705', (54, 63))	('rs2069705', 'Var', (54, 63))	('IFNG', 'Gene', (49, 53))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (68, 88))
202108	20112337	Compared to IL1B rs16944 GG homozygotes, the A allele was more common among lung cancer cases (aOR: 1.3, 95% CI: 1.0-1.8).	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('common', 'Reg', (63, 69))	('rs16944', 'Mutation', 'rs16944', (17, 24))	('lung cancer', 'Disease', (76, 87))	('IL1B', 'Gene', (12, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('IL1B', 'Gene', '3553', (12, 16))	('rs16944', 'Var', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
202110	20112337	Lung cancer was associated with IL10 rs1800871 among never smokers (TT versus CC or CT aOR: 2.5, 95% CI: 1.3-5.1) but not among ever smokers, though there was some heterogeneity across ethnicity.	('associated', 'Interaction', (16, 26))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('IL10', 'Gene', (32, 36))	('IL10', 'Gene', '3586', (32, 36))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('rs1800871', 'Var', (37, 46))	('rs1800871', 'Mutation', 'rs1800871', (37, 46))
202111	20112337	Oropharyngeal cancer was inversely associated with IL10 rs1800871 among ever smokers (CT or TT versus CC aOR: 0.63, 95% CI: 0.41-0.95) and positively associated with IFNG rs2069705 among never smokers (CC versus CT or TT aOR: 1.9, 95% CI: 1.0-3.5).	('cancer', 'Disease', (14, 20))	('IL10', 'Gene', (51, 55))	('IL10', 'Gene', '3586', (51, 55))	('IFNG', 'Gene', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('rs1800871', 'Var', (56, 65))	('rs1800871', 'Mutation', 'rs1800871', (56, 65))	('associated', 'Interaction', (35, 45))	('rs2069705', 'Var', (171, 180))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('rs2069705', 'Mutation', 'rs2069705', (171, 180))	('inversely', 'NegReg', (25, 34))
202112	20112337	Esophageal cancer in the Taixing study was less common among ever smokers who had at least one variant G allele for IL6 rs1800796 (aOR: 0.54, 95% CI: 0.31-0.95).	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('IL6', 'Gene', (116, 119))	('rs1800796', 'Mutation', 'rs1800796', (120, 129))	('rs1800796', 'Var', (120, 129))	('Esophageal cancer', 'Disease', (0, 17))
202114	20112337	Of the six SNPs that were genotyped across all three studies, the most consistent SNP-cancer estimates were observed for TNF rs1799964 among never smokers.	('SNP-cancer', 'Disease', 'MESH:D009369', (82, 92))	('TNF', 'Gene', (121, 124))	('rs1799964', 'Var', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TNF', 'Gene', '7124', (121, 124))	('SNP-cancer', 'Disease', (82, 92))	('rs1799964', 'Mutation', 'rs1799964', (125, 134))
202115	20112337	Smoking-related cancers were much less common among never smokers homozygous for the variant TNF rs1799964 C allele compared to never smokers with at least one T allele (aOR: 0.36, 95% CI: 0.17-0.77).	('cancers', 'Disease', (16, 23))	('TNF', 'Gene', (93, 96))	('rs1799964', 'Mutation', 'rs1799964', (97, 106))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('common', 'Reg', (39, 45))	('TNF', 'Gene', '7124', (93, 96))	('less', 'NegReg', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('rs1799964 C', 'Var', (97, 108))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
202117	20112337	In site-stratified analysis, we observed that the estimated joint effect of recessive IL10 rs1800871 genotype and tobacco smoking was less than what would be expected under the null hypothesis of multiplicativity of effects among lung cancer cases and controls (aROR: 0.31, 95% CI: 0.14-0.69), which persisted across ethnicity, although adjusting for pack-years attenuated the estimate.	('rs1800871', 'Mutation', 'rs1800871', (91, 100))	('lung cancer', 'Disease', (230, 241))	('IL10', 'Gene', (86, 90))	('IL10', 'Gene', '3586', (86, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('less', 'NegReg', (134, 138))	('tobacco', 'Species', '4097', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))	('rs1800871', 'Var', (91, 100))
202118	20112337	There was also an indication of departure from multiplicative effects for IFNGR1 rs11914 esophageal cancer in the Taixing study (aROR: 0.37, 95% CI: 0.13-1.0).	('esophageal cancer', 'Disease', (89, 106))	('rs11914', 'Var', (81, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('IFNGR1', 'Gene', (74, 80))	('rs11914', 'Mutation', 'rs11914', (81, 88))
202119	20112337	In our pooled analysis, there was evidence of greater than multiplicative interaction among individuals recessive for TNF rs1799964 (aROR: 3.4, 95% CI: 1.4-8.6), which was fairly consistent across ethnicity with the exception of African-Americans, whose unstable estimates were a reflection of that group having the least number of individuals homozygous for the rare genotype among controls.	('rs1799964', 'Mutation', 'rs1799964', (122, 131))	('TNF', 'Gene', (118, 121))	('rs1799964', 'Var', (122, 131))	('TNF', 'Gene', '7124', (118, 121))
202120	20112337	Assuming a prior probability of 0.10 and a FPRP cut-point of 0.4, the associations between lung cancer and IL1B rs16944 and between oropharyngeal cancer and polymorphisms of IL10 rs1800871 and IFNG rs2069705 appear to be noteworthy.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('rs2069705', 'Var', (198, 207))	('rs16944', 'Var', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('IL10', 'Gene', (174, 178))	('rs1800871', 'Mutation', 'rs1800871', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('rs2069705', 'Mutation', 'rs2069705', (198, 207))	('IL10', 'Gene', '3586', (174, 178))	('lung cancer', 'Disease', (91, 102))	('rs16944', 'Mutation', 'rs16944', (112, 119))	('IFNG', 'Gene', (193, 197))	('IL1B', 'Gene', '3553', (107, 111))	('IL1B', 'Gene', (107, 111))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (132, 152))	('rs1800871', 'Var', (179, 188))	('associations', 'Interaction', (70, 82))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('oropharyngeal cancer', 'Disease', (132, 152))
202121	20112337	Under the same prior, and assuming that false nondiscovery is four times as costly as false discovery (i.e., a BFDP threshold of 0.8), the association between oropharyngeal cancer and IL10 rs1800871 may be important.	('rs1800871', 'Var', (189, 198))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (159, 179))	('IL10', 'Gene', (184, 188))	('IL10', 'Gene', '3586', (184, 188))	('rs1800871', 'Mutation', 'rs1800871', (189, 198))	('oropharyngeal cancer', 'Disease', (159, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('BFDP', 'Chemical', '-', (111, 115))
202122	20112337	Considering associations that are below both FPRP and BFDP thresholds, IL10 rs1800871 appears to be an important marker for oropharyngeal cancer risk.	('BFDP', 'Chemical', '-', (54, 58))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (124, 144))	('rs1800871', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('oropharyngeal cancer', 'Disease', (124, 144))	('IL10', 'Gene', (71, 75))	('IL10', 'Gene', '3586', (71, 75))	('rs1800871', 'Mutation', 'rs1800871', (76, 85))
202123	20112337	IL10 rs1800871 may also be associated with lung cancer among never smokers and with oropharyngeal cancer among ever smokers.	('IL10', 'Gene', '3586', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('associated', 'Reg', (27, 37))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (84, 104))	('rs1800871', 'Var', (5, 14))	('rs1800871', 'Mutation', 'rs1800871', (5, 14))	('oropharyngeal cancer', 'Disease', (84, 104))	('IL10', 'Gene', (0, 4))
202124	20112337	The TNF rs1799964 SNP, which only appeared to be associated with stomach cancer in site-specific analyses, also seems to be associated with smoking-related cancers among never smokers, even at a 5% prior probability.	('TNF', 'Gene', (4, 7))	('stomach cancer', 'Disease', 'MESH:D013274', (65, 79))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('stomach cancer', 'Phenotype', 'HP:0012126', (65, 79))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('stomach cancer', 'Disease', (65, 79))	('associated', 'Reg', (49, 59))	('TNF', 'Gene', '7124', (4, 7))	('rs1799964', 'Mutation', 'rs1799964', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('associated with', 'Reg', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('rs1799964 SNP', 'Var', (8, 21))
202126	20112337	Among never smokers in our overall study population of 2,097 cases and 1,666 controls, we found that TNF rs1799964 was associated with smoking-related cancer.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('TNF', 'Gene', (101, 104))	('rs1799964', 'Mutation', 'rs1799964', (105, 114))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('TNF', 'Gene', '7124', (101, 104))	('rs1799964', 'Var', (105, 114))	('associated', 'Reg', (119, 129))
202127	20112337	Cancer site-specific analysis suggests that oropharyngeal cancer is inversely associated with IL10 rs1800871 and IFNG rs2069705.	('associated', 'Reg', (78, 88))	('oropharyngeal cancer', 'Disease', (44, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('rs1800871', 'Mutation', 'rs1800871', (99, 108))	('IL10', 'Gene', (94, 98))	('IL10', 'Gene', '3586', (94, 98))	('inversely', 'NegReg', (68, 77))	('IFNG', 'Gene', (113, 117))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('rs2069705', 'Var', (118, 127))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (44, 64))	('rs2069705', 'Mutation', 'rs2069705', (118, 127))	('rs1800871', 'Var', (99, 108))
202129	20112337	TNF rs1799964, for example, seems to be an important SNP among never smokers for smoking-related cancer as a whole, while the IL10 rs1800871 association with lung cancer was observed only among never smokers (aOR: 2.5, 95% CI: 1.3-5.1 versus aOR: 1.0, 95% CI: 0.61-1.7 for ever smokers).	('IL10', 'Gene', (126, 130))	('rs1799964', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('IL10', 'Gene', '3586', (126, 130))	('lung cancer', 'Disease', (158, 169))	('cancer', 'Disease', (97, 103))	('TNF', 'Gene', '7124', (0, 3))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('rs1800871', 'Var', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rs1799964', 'Mutation', 'rs1799964', (4, 13))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('rs1800871', 'Mutation', 'rs1800871', (131, 140))	('cancer', 'Disease', (163, 169))	('TNF', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
202130	20112337	After adjustment for multiple comparisons, the associations between TNF rs1799964 and any smoking-related cancer among never smokers and between IL10 rs1800871 and cancers of the oropharynx and lung do not appear to be due to chance.	('rs1800871', 'Mutation', 'rs1800871', (150, 159))	('IL10', 'Gene', '3586', (145, 149))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('TNF', 'Gene', '7124', (68, 71))	('rs1799964', 'Var', (72, 81))	('rs1800871', 'Var', (150, 159))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('cancer', 'Disease', (164, 170))	('associations', 'Interaction', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers of the oropharynx', 'Phenotype', 'HP:0100638', (164, 189))	('IL10', 'Gene', (145, 149))	('TNF', 'Gene', (68, 71))	('rs1799964', 'Mutation', 'rs1799964', (72, 81))
202131	20112337	Whether IL10 polymorphisms affect lung cancer risk remains to be determined but some reports suggest an association, although differences in models of inheritance and risk estimates suggest some heterogeneity.	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('polymorphisms', 'Var', (13, 26))	('IL10', 'Gene', (8, 12))	('IL10', 'Gene', '3586', (8, 12))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
202132	20112337	A population-based case-cohort study estimated a 60% increase in lung cancer risk for individuals with at least one copy of the IL10 rs1800872 variant A allele (which is in high linkage disequilibrium with rs1800871), and a slightly weaker association among current smokers.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('rs1800872', 'Var', (133, 142))	('IL10', 'Gene', (128, 132))	('rs1800872', 'Mutation', 'rs1800872', (133, 142))	('IL10', 'Gene', '3586', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (65, 76))	('increase', 'PosReg', (53, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('rs1800871', 'Mutation', 'rs1800871', (206, 215))
202133	20112337	A positive association between non-small cell lung cancer (NSCLC) and IL10 rs1800871 was estimated by Van Dyke and colleagues in a population-based case-control study among Caucasian women (aOR: 1.39, 95% CI: 0.96-2.02), and the magnitude of the association was still elevated, though less precisely, among a smaller number of African-American women (aOR: 1.32, 95% CI: 0.60-2.88).	('rs1800871', 'Var', (75, 84))	('rs1800871', 'Mutation', 'rs1800871', (75, 84))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (35, 57))	('IL10', 'Gene', (70, 74))	('women', 'Species', '9606', (183, 188))	('cell lung cancer', 'Disease', (41, 57))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (31, 57))	('IL10', 'Gene', '3586', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('cell lung cancer', 'Disease', 'MESH:D008175', (41, 57))	('NSCLC', 'Disease', (59, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))	('women', 'Species', '9606', (344, 349))
202134	20112337	IL10 rs1800871 was recessively associated with NSCLC in a Chinese population (OR: 1.37, 95% CI: 1.10-2.09) but it is not clear if the estimate was adjusted for tobacco smoking, age, sex, and gender, although those characteristics seemed similarly distributed between cases and controls.	('IL10', 'Gene', '3586', (0, 4))	('tobacco', 'Species', '4097', (160, 167))	('rs1800871', 'Mutation', 'rs1800871', (5, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('associated', 'Reg', (31, 41))	('NSCLC', 'Disease', (47, 52))	('rs1800871', 'Var', (5, 14))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('IL10', 'Gene', (0, 4))
202135	20112337	Weaker associations between rs1800871 and lung cancer have also been reported in a Chinese population for homozygous for the rare allele (aOR: 1.38, 95% CI: 0.57-3.38) and among non-Hispanic Caucasians with at least one variant T allele (aOR: 1.43, 95% CI: 0.78-2.63).	('rs1800871', 'Var', (28, 37))	('rs1800871', 'Mutation', 'rs1800871', (28, 37))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
202136	20112337	Despite differences in interpreting the association between IL10 rs1800871 and lung cancer, point estimates from published studies (i.e., OR ~1.4) are comparable to our own estimate (aOR: 1.5, 95% CI: 0.96-2.2), and the consistency between these estimates (P heterogeneity > 0.99) further suggests that IL10 rs1800871 might be associated with elevated lung cancer risk, but the magnitude is not large.	('rs1800871', 'Mutation', 'rs1800871', (308, 317))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('IL10', 'Gene', (303, 307))	('IL10', 'Gene', '3586', (303, 307))	('lung cancer', 'Disease', 'MESH:D008175', (352, 363))	('rs1800871', 'Var', (65, 74))	('rs1800871', 'Mutation', 'rs1800871', (65, 74))	('rs1800871', 'Var', (308, 317))	('IL10', 'Gene', '3586', (60, 64))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('IL10', 'Gene', (60, 64))	('elevated lung cancer', 'Disease', (343, 363))	('elevated lung cancer', 'Disease', 'MESH:D008175', (343, 363))	('lung cancer', 'Phenotype', 'HP:0100526', (352, 363))
202138	20112337	These studies, however, do not rule out the possibility of association through altered cytokine expression as a result of somatic mutations within the tumor.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cytokine expression', 'MPA', (87, 106))	('tumor', 'Disease', (151, 156))	('mutations', 'Var', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
202139	20112337	Several studies of germline mutations suggest that IL10 polymorphisms, which are associated with periodontitis, may also be associated with tongue cancer and oral neoplasms.	('IL10', 'Gene', (51, 55))	('IL10', 'Gene', '3586', (51, 55))	('neoplasms', 'Phenotype', 'HP:0002664', (163, 172))	('oral neoplasms', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('periodontitis', 'Phenotype', 'HP:0000704', (97, 110))	('tongue cancer', 'Disease', (140, 153))	('oral neoplasms', 'Disease', 'MESH:D009062', (158, 172))	('tongue cancer', 'Disease', 'MESH:D014062', (140, 153))	('associated', 'Reg', (124, 134))	('periodontitis', 'Disease', 'MESH:D010518', (97, 110))	('polymorphisms', 'Var', (56, 69))	('periodontitis', 'Disease', (97, 110))	('associated', 'Reg', (81, 91))
202140	20112337	IL10 rs1800896, which is not in high linkage disequilibrium with rs1800871 (r2 = 0.30), was associated with oral SCC in a hospital-based case-control study (aOR: 2.65, 95% CI: 1.28-5.46).	('associated with', 'Reg', (92, 107))	('oral SCC', 'Disease', (108, 116))	('IL10', 'Gene', '3586', (0, 4))	('rs1800871', 'Mutation', 'rs1800871', (65, 74))	('rs1800896', 'Var', (5, 14))	('rs1800896', 'Mutation', 'rs1800896', (5, 14))	('SCC', 'Phenotype', 'HP:0002860', (113, 116))	('IL10', 'Gene', (0, 4))
202142	20112337	Our results suggest that IL1B rs16944 may predict lung cancer, consistent with published reports, but our association did not hold after correction for multiple comparisons.	('lung cancer', 'Disease', (50, 61))	('IL1B', 'Gene', '3553', (25, 29))	('predict', 'Reg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('rs16944', 'Var', (30, 37))	('rs16944', 'Mutation', 'rs16944', (30, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('IL1B', 'Gene', (25, 29))
202143	20112337	Based on a large, multi-center case-control study, IL1B rs1143627 (linkage disequilibrium with rs16944: r2 = 0.94) was not associated with lung cancer, suggesting that our finding for rs16944 may be due to chance.	('lung cancer', 'Disease', (139, 150))	('associated', 'Reg', (123, 133))	('rs1143627', 'Var', (56, 65))	('IL1B', 'Gene', '3553', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('rs16944', 'Mutation', 'rs16944', (184, 191))	('rs16944', 'Mutation', 'rs16944', (95, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('rs1143627', 'Mutation', 'rs1143627', (56, 65))	('IL1B', 'Gene', (51, 55))
202144	20112337	It is possible, though, that the association of lung cancer with IL1B polymorphisms could involve a pathway that is not primarily mediated by rs1143627.	('IL1B', 'Gene', (65, 69))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('IL1B', 'Gene', '3553', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('polymorphisms', 'Var', (70, 83))	('rs1143627', 'Mutation', 'rs1143627', (142, 151))	('association', 'Interaction', (33, 44))	('involve', 'Reg', (90, 97))
202145	20112337	The involvement of TNF polymorphisms in cancer has been reported for several malignancies, including lymphomas and lung cancer, though more null results have been reported for lung cancer than non-null associations.	('cancer', 'Disease', (120, 126))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('lymphomas', 'Phenotype', 'HP:0002665', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('TNF', 'Gene', (19, 22))	('involvement', 'Reg', (4, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('polymorphisms', 'Var', (23, 36))	('TNF', 'Gene', '7124', (19, 22))	('lymphomas and lung cancer', 'Disease', 'MESH:D008175', (101, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (181, 187))	('lung cancer', 'Disease', (115, 126))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('malignancies', 'Disease', (77, 89))	('lung cancer', 'Disease', (176, 187))
202147	20112337	A meta-analysis of TNF polymorphisms reported positive associations for rs1800629 (summary OR [sOR]: 1.49, 95% CI: 1.11-1.99) and rs1799724 (sOR: 1.57, 95% CI: 0.91-2.70).	('TNF', 'Gene', '7124', (19, 22))	('rs1799724', 'Mutation', 'rs1799724', (130, 139))	('TNF', 'Gene', (19, 22))	('rs1799724', 'Var', (130, 139))	('rs1800629', 'Var', (72, 81))	('rs1800629', 'Mutation', 'rs1800629', (72, 81))
202148	20112337	We observed a similar association for rs1800629 in our gastric cancer sample (aOR: 1.3, 95% CI: 0.74-2.4).	('gastric cancer', 'Disease', (55, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('rs1800629', 'Var', (38, 47))	('rs1800629', 'Mutation', 'rs1800629', (38, 47))
202151	20112337	In our pooled analysis, for example, smoking-related cancers were less common among never smokers with the TNF rs1799964 CC genotype, and the variant C allele did not appear protective among ever smokers (Table 2).	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('rs1799964', 'Mutation', 'rs1799964', (111, 120))	('TNF', 'Gene', (107, 110))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('rs1799964 CC', 'Var', (111, 123))	('TNF', 'Gene', '7124', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('less', 'NegReg', (66, 70))
202152	20112337	Less than multiplicative smoking-SNP interactions were also suggested between lung cancer and IL10 rs1800871, oropharyngeal cancer and IFNG rs2069705, and esophageal cancer and IFNGR1 rs11914.	('IFNG', 'Gene', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (155, 172))	('lung cancer', 'Disease', (78, 89))	('IFNGR1', 'Gene', (177, 183))	('IL10', 'Gene', (94, 98))	('esophageal cancer', 'Disease', (155, 172))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (110, 130))	('rs2069705', 'Var', (140, 149))	('rs1800871', 'Mutation', 'rs1800871', (99, 108))	('IL10', 'Gene', '3586', (94, 98))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('oropharyngeal cancer', 'Disease', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('rs2069705', 'Mutation', 'rs2069705', (140, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('rs11914', 'Mutation', 'rs11914', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rs1800871', 'Var', (99, 108))	('rs11914', 'Var', (184, 191))
202153	20112337	Genetic polymorphisms in the numerous pathways involved in carcinogenesis affect cancer risk, and tobacco smoking may modify these effects.	('tobacco', 'Species', '4097', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (59, 73))	('Genetic polymorphisms', 'Var', (0, 21))	('affect', 'Reg', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('carcinogenesis', 'Disease', (59, 73))
202157	20112337	One of the most commonly studied TNF SNPs is the rs1800629 G-308A polymorphism.	('TNF', 'Gene', '7124', (33, 36))	('rs1800629', 'Mutation', 'rs1800629', (49, 58))	('rs1800629 G-308A', 'Var', (49, 65))	('TNF', 'Gene', (33, 36))	('G-308A', 'Mutation', 'rs1800629', (59, 65))	('G-308A', 'Var', (59, 65))
202158	20112337	The variant rs1799964 C allele, which is not in linkage disequilibrium with the G-308A polymorphism (r2 = 0.07), appears to be associated with increased TNF expression.	('increased', 'PosReg', (143, 152))	('expression', 'MPA', (157, 167))	('rs1799964', 'Mutation', 'rs1799964', (12, 21))	('TNF', 'Gene', (153, 156))	('rs1799964 C', 'Var', (12, 23))	('TNF', 'Gene', '7124', (153, 156))	('G-308A', 'Mutation', 'rs1800629', (80, 86))
202160	20112337	Interestingly, TNF was expressed at higher levels in cells from non-smokers than smokers at all time-points, which lends potential biologic support for our observation that smoking-related cancers were less common among never smokers with the putative high expression TNF rs1799964 CC genotype.	('rs1799964 CC', 'Var', (272, 284))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('high', 'PosReg', (252, 256))	('TNF', 'Gene', (268, 271))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('TNF', 'Gene', (15, 18))	('TNF', 'Gene', '7124', (15, 18))	('TNF', 'Gene', '7124', (268, 271))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('rs1799964', 'Mutation', 'rs1799964', (272, 281))	('cancers', 'Disease', (189, 196))
202161	20112337	Haplotype studies of the gene encoding the anti-inflammatory cytokine IL-10 suggest that the GCC haplotype (i.e., rs1800896 G, rs1800871 C, and rs1800872 C) is associated with high IL-10 production.	('rs1800872 C', 'Var', (144, 155))	('IL-10', 'Gene', '3586', (181, 186))	('rs1800872', 'Mutation', 'rs1800872', (144, 153))	('rs1800871', 'Mutation', 'rs1800871', (127, 136))	('IL-10', 'Gene', '3586', (70, 75))	('rs1800871 C', 'Var', (127, 138))	('rs1800896', 'Mutation', 'rs1800896', (114, 123))	('IL-10', 'Gene', (181, 186))	('IL-10', 'Gene', (70, 75))	('rs1800896 G', 'Var', (114, 125))
202162	20112337	Although haplotype data were unavailable in the LA study, the rs1800871 variant T allele associated with low production appeared to be an important SNP for lung cancer among never smokers while the variant did not seem to increase risk among ever smokers.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('rs1800871', 'Var', (62, 71))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('rs1800871', 'Mutation', 'rs1800871', (62, 71))	('lung cancer', 'Disease', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('low production', 'MPA', (105, 119))
202163	20112337	The Van Dyke study of NSCLC among women reported associations for six SNPs that were also genotyped in our study (IL1B rs1143627 and rs16944; TNF rs1799964 and rs1800629; LTA rs909253; and IL10 rs1800871).	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('IL10', 'Gene', (189, 193))	('LTA', 'Gene', (171, 174))	('associations', 'Interaction', (49, 61))	('rs1800629', 'Var', (160, 169))	('rs16944', 'Var', (133, 140))	('NSCLC', 'Disease', (22, 27))	('rs909253', 'Mutation', 'rs909253', (175, 183))	('rs1800871', 'Mutation', 'rs1800871', (194, 203))	('rs1799964', 'Mutation', 'rs1799964', (146, 155))	('rs1800629', 'Mutation', 'rs1800629', (160, 169))	('IL10', 'Gene', '3586', (189, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('TNF', 'Gene', (142, 145))	('rs1143627', 'Mutation', 'rs1143627', (119, 128))	('rs16944', 'Mutation', 'rs16944', (133, 140))	('TNF', 'Gene', '7124', (142, 145))	('rs1799964', 'Var', (146, 155))	('IL1B', 'Gene', (114, 118))	('IL1B', 'Gene', '3553', (114, 118))	('women', 'Species', '9606', (34, 39))	('rs1143627', 'Var', (119, 128))
202164	20112337	The estimated magnitude and direction of association for these SNPs were similar to our own estimates, both overall and among women, although comparability of our TNF results was affected by the small number of women with the variant C allele, resulting in unstable estimates.	('women', 'Species', '9606', (211, 216))	('TNF', 'Gene', (163, 166))	('TNF', 'Gene', '7124', (163, 166))	('women', 'Species', '9606', (126, 131))	('variant', 'Var', (226, 233))
202165	20112337	While the majority of our SNPs do not result in amino acid substitutions, cancers of the oropharynx and lung appear to be associated with IL10 rs1800871.	('associated', 'Reg', (122, 132))	('lung', 'Disease', (104, 108))	('rs1800871', 'Var', (143, 152))	('IL10', 'Gene', (138, 142))	('IL10', 'Gene', '3586', (138, 142))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('rs1800871', 'Mutation', 'rs1800871', (143, 152))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('cancers of the oropharynx', 'Phenotype', 'HP:0100638', (74, 99))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
202167	20112337	We included ethnicity as a covariate in regression models to address admixture but the effects of population stratification may still residually confound our estimates, particularly for SNPs with allele frequencies that differ greatly between ethnicities, such as IL10 rs1800871 and IFNG rs2069705.	('IL10', 'Gene', (264, 268))	('IL10', 'Gene', '3586', (264, 268))	('confound', 'Reg', (145, 153))	('rs1800871', 'Var', (269, 278))	('rs1800871', 'Mutation', 'rs1800871', (269, 278))	('rs2069705', 'Var', (288, 297))	('rs2069705', 'Mutation', 'rs2069705', (288, 297))
202168	20112337	The association we observed between lung cancer and IL10 rs1800871, for example, might be partially due to uncontrolled differences in ethnicity.	('lung cancer', 'Disease', (36, 47))	('IL10', 'Gene', (52, 56))	('IL10', 'Gene', '3586', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('rs1800871', 'Var', (57, 66))	('rs1800871', 'Mutation', 'rs1800871', (57, 66))
202169	20112337	However, the ethnic diversity of the LA study facilitated examination of ethnicity-specific ratios of odds ratios, which were consistent in magnitude across ethnicity (except for African-Americans, for whom no never smoking lung cancer cases were observed with the risk genotype), suggesting that tobacco smoking and the recessive IL10 rs1800871 genotype may interact on a less than multiplicative scale.	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('rs1800871', 'Mutation', 'rs1800871', (336, 345))	('IL10', 'Gene', (331, 335))	('IL10', 'Gene', '3586', (331, 335))	('lung cancer', 'Disease', (224, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tobacco', 'Species', '4097', (297, 304))	('rs1800871', 'Var', (336, 345))
202172	20112337	The inverse association estimated for the TNF rs1799964 C variant among never smokers reported (Table 2) may reflect a true gene-environment interaction (in which the TNF rs1799964 CC genotype may afford some protection only in the absence of tobacco smoking) but a number of problems need to be considered.	('TNF', 'Gene', (42, 45))	('tobacco', 'Species', '4097', (243, 250))	('TNF', 'Gene', '7124', (167, 170))	('rs1799964', 'Mutation', 'rs1799964', (46, 55))	('TNF', 'Gene', '7124', (42, 45))	('rs1799964', 'Mutation', 'rs1799964', (171, 180))	('rs1799964 C', 'Var', (46, 57))	('rs1799964 CC', 'Var', (171, 183))	('TNF', 'Gene', (167, 170))
202173	20112337	In particular, there were few observations of never smokers with the TNF rs1799964 CC variant genotype (especially true among cases), and none of the confidence intervals for these strata excluded the null when there were less than five observations per cell.	('TNF', 'Gene', (69, 72))	('rs1799964 CC', 'Var', (73, 85))	('TNF', 'Gene', '7124', (69, 72))	('rs1799964', 'Mutation', 'rs1799964', (73, 82))
202179	20112337	Of the four SNPs in the Taixing study with sufficiently high minor allele frequencies to have at least 80% power (IL10 rs1800871, IL10 rs1800872, LTA rs909253, and IL6 rs1800796), the 95% confidence intervals from the multivariate model included both positive and inverse associations.	('rs1800871', 'Mutation', 'rs1800871', (119, 128))	('IL10', 'Gene', (114, 118))	('IL10', 'Gene', '3586', (114, 118))	('IL10', 'Gene', '3586', (130, 134))	('IL10', 'Gene', (130, 134))	('rs909253', 'Mutation', 'rs909253', (150, 158))	('rs1800796', 'Mutation', 'rs1800796', (168, 177))	('rs1800872', 'Var', (135, 144))	('rs1800872', 'Mutation', 'rs1800872', (135, 144))
202180	20112337	One SNP in the MSKCC study with sufficiently high minor allele frequency (IL1B rs1143627) was associated with bladder cancer (aOR = 4.3), but with an extremely wide confidence interval (95% CI: 1.3-14) (the association did not pass multiple comparisons correction) and was therefore not reported.	('bladder cancer', 'Disease', 'MESH:D001749', (110, 124))	('bladder cancer', 'Disease', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('IL1B', 'Gene', (74, 78))	('associated', 'Reg', (94, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('IL1B', 'Gene', '3553', (74, 78))	('rs1143627', 'Mutation', 'rs1143627', (79, 88))	('rs1143627', 'Var', (79, 88))
202184	20112337	Our results if valid suggest that TNF rs1799964 is inversely associated with smoking-related cancers among never smokers, and that IL10 rs1800871 is a susceptibility marker for lung cancer among never smokers, and for oropharyngeal cancer among ever smokers.	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('rs1799964', 'Mutation', 'rs1799964', (38, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('TNF', 'Gene', (34, 37))	('rs1800871', 'Var', (136, 145))	('oropharyngeal cancer', 'Disease', (218, 238))	('inversely', 'NegReg', (51, 60))	('associated', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('rs1799964', 'Var', (38, 47))	('TNF', 'Gene', '7124', (34, 37))	('IL10', 'Gene', (131, 135))	('lung cancer', 'Disease', (177, 188))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('rs1800871', 'Mutation', 'rs1800871', (136, 145))	('cancers', 'Disease', (93, 100))	('IL10', 'Gene', '3586', (131, 135))	('susceptibility', 'Reg', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (218, 238))
202185	20112337	aOR adjusted odds ratio aROR adjusted ratio of odds ratios BFDP Bayesian false discovery probability CI confidence interval cOR crude odds ratio FPRP false positive report probability HWE Hardy-Weinberg equilibrium LA Los Angeles MAF minor allele frequency MSKCC Memorial Sloan-Kettering Cancer Center NSCLC non-small cell lung cancer OR odds ratio ROR ratio of odds ratios SCC squamous cell carcinoma SNP single nucleotide polymorphism sOR summary odds ratio UADT upper aero-digestive tract	('squamous cell carcinoma', 'Disease', (378, 401))	('NSCLC', 'Disease', (302, 307))	('BFDP', 'Chemical', '-', (59, 63))	('single nucleotide polymorphism', 'Var', (406, 436))	('NSCLC', 'Phenotype', 'HP:0030358', (302, 307))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('Cancer', 'Phenotype', 'HP:0002664', (288, 294))	('SCC', 'Phenotype', 'HP:0002860', (374, 377))	('Memorial Sloan-Kettering Cancer', 'Disease', (263, 294))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (312, 334))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (378, 401))	('cell lung cancer', 'Disease', 'MESH:D008175', (318, 334))	('upper aero-digestive', 'Disease', (465, 485))	('Memorial Sloan-Kettering Cancer', 'Disease', 'MESH:D008569', (263, 294))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (378, 401))	('cell lung cancer', 'Disease', (318, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (392, 401))	('NSCLC', 'Disease', 'MESH:D002289', (302, 307))	('UADT', 'Chemical', '-', (460, 464))	('lung cancer', 'Phenotype', 'HP:0100526', (323, 334))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (308, 334))
202258	33445613	An important role for arginine residues has also been reported for other CPPs.	('arginine', 'Var', (22, 30))	('arginine', 'Chemical', 'MESH:D001120', (22, 30))	('CPPs', 'Disease', (73, 77))
202264	33445613	The presence of tryptophan is known to contribute to the uptake efficiency of CPPs, while its position in the sequence modulates it.	('modulates', 'Reg', (119, 128))	('tryptophan', 'Chemical', 'MESH:D014364', (16, 26))	('tryptophan', 'Protein', (16, 26))	('presence', 'Var', (4, 12))	('CPPs', 'Protein', (78, 82))	('contribute', 'PosReg', (39, 49))	('uptake efficiency', 'MPA', (57, 74))
202277	33445613	The analysis of polar contacts (Figure 5B) shows that E9, D17 and to a lesser extent the terminal carboxylate interact frequently with the amine of PE headgroup, while R1,13 and K3,6,10 make salt bridges with the more interior phosphate moieties of the membrane.	('interact', 'Interaction', (110, 118))	('amine', 'Chemical', 'MESH:D000588', (139, 144))	('carboxylate', 'Chemical', '-', (98, 109))	('salt', 'Chemical', 'MESH:D012492', (191, 195))	('D17', 'Var', (58, 61))	('PE', 'Chemical', 'MESH:C483858', (148, 150))	('phosphate', 'Chemical', 'MESH:D010710', (227, 236))	('salt bridges', 'MPA', (191, 203))
202295	33445613	The network of polar interactions reproduces what is observed with POPE, but in this case, the headgroup does not contain an amine and salt bridges involving E9 and D17 are inevitably lost.	('POPE', 'Chemical', 'MESH:C000608529', (67, 71))	('salt', 'Chemical', 'MESH:D012492', (135, 139))	('lost', 'NegReg', (184, 188))	('D17', 'Var', (165, 168))	('salt bridges', 'MPA', (135, 147))	('amine', 'Chemical', 'MESH:D000588', (125, 130))
202304	33445613	The incorporation of peptides affects the interactions among lipids in two main ways.	('incorporation', 'Var', (4, 17))	('peptides', 'Chemical', 'MESH:D010455', (21, 29))	('affects', 'Reg', (30, 37))	('interactions', 'Interaction', (42, 54))	('lipids', 'Chemical', 'MESH:D008055', (61, 67))
202305	33445613	First, the presence of these peptides disrupts part of the hydrogen-bonding networks between PG and PE headgroups.	('presence', 'Var', (11, 19))	('disrupts', 'NegReg', (38, 46))	('PG', 'Chemical', 'MESH:D010715', (93, 95))	('hydrogen-bonding networks', 'MPA', (59, 84))	('PE', 'Chemical', 'MESH:C483858', (100, 102))	('hydrogen', 'Chemical', 'MESH:D006859', (59, 67))	('peptides', 'Chemical', 'MESH:D010455', (29, 37))
202327	33445613	AMPs often exert their antimicrobial activity by cooperativity.	('antimicrobial activity', 'MPA', (23, 45))	('cooperativity', 'Var', (49, 62))	('AMPs', 'Chemical', '-', (0, 4))	('exert', 'Reg', (11, 16))
202328	33445613	Multiple models have been proposed to explain how AMPs can destabilize biological membranes, some of them are carpet model, barrel-stave or toroidal (also called "worm-hole") pore formation, detergent-type micellization, induction of non-lamellar phases, domain formation, non-lytic depolarization and localized thinning.	('non-lytic', 'MPA', (273, 282))	('destabilize', 'NegReg', (59, 70))	('AMPs', 'Var', (50, 54))	('AMPs', 'Chemical', '-', (50, 54))	('domain formation', 'CPA', (255, 271))	('non-lamellar phases', 'CPA', (234, 253))	('carpet', 'Species', '190347', (110, 116))
202338	33445613	Supplementary Figure S8 shows how CXJ can create a significant negative curvature in its target membranes but not in membranes mimicking mammalian cells (POPC and POPC/CHO, Supplementary Figure S8).	('CXJ', 'Var', (34, 37))	('POPC', 'Chemical', '-', (163, 167))	('negative curvature', 'MPA', (63, 81))	('mammalian', 'Species', '9606', (137, 146))	('POPC', 'Chemical', '-', (154, 158))
202340	33445613	It has been shown that amidation of the C-terminus results in increased antimicrobial activity and even better performance in terms of cytotoxicity.	('increased', 'PosReg', (62, 71))	('cytotoxicity', 'Disease', 'MESH:D064420', (135, 147))	('antimicrobial activity', 'CPA', (72, 94))	('amidation', 'Var', (23, 32))	('cytotoxicity', 'Disease', (135, 147))
202342	33445613	Secondly, it should be noted that the absence of the terminal carboxylate should affect the interaction with bacterial and cancerous membranes in two ways: (i) the overall charge becomes more positive, thus increasing the Coulomb attraction to negatively charged membranes such as those of bacteria and cancer cells; (ii) we have shown that in the case of CXJ the terminal carboxylate moiety forms salt bridges with the amine of both PE and PS headgroup.	('CXJ', 'Var', (356, 359))	('increasing', 'PosReg', (207, 217))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous', 'Disease', 'MESH:D009369', (123, 132))	('carboxylate', 'Chemical', '-', (373, 384))	('carboxylate', 'Chemical', '-', (62, 73))	('cancer', 'Disease', (303, 309))	('salt', 'Chemical', 'MESH:D012492', (398, 402))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('cancerous', 'Disease', (123, 132))	('interaction', 'Interaction', (92, 103))	('amine', 'Chemical', 'MESH:D000588', (420, 425))	('affect', 'Reg', (81, 87))	('salt bridges', 'MPA', (398, 410))	('Coulomb attraction', 'MPA', (222, 240))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('cancer', 'Disease', (123, 129))	('PS', 'Chemical', 'MESH:D010718', (441, 443))	('PE', 'Chemical', 'MESH:C483858', (434, 436))
202345	33445613	In CXJN, the only effect is an increase in the involvement of K33 and K37 side chains (belonging to helix II) in the formation of salt bridges with oxygen atoms of the membrane.	('K37', 'Gene', '8688', (70, 73))	('K33', 'Var', (62, 65))	('K37', 'Gene', (70, 73))	('oxygen', 'Chemical', 'MESH:D010100', (148, 154))	('salt', 'Chemical', 'MESH:D012492', (130, 134))	('increase', 'PosReg', (31, 39))
202348	33445613	Both constraints are absent for CXJN, in which helix II can form salt bridges with oxygen atoms of the membrane by means of K33 and K37 side chains and descend deeper in the absence of electrostatic repulsions.	('K37', 'Gene', '8688', (132, 135))	('salt', 'Chemical', 'MESH:D012492', (65, 69))	('K33', 'Var', (124, 127))	('oxygen', 'Chemical', 'MESH:D010100', (83, 89))	('K37', 'Gene', (132, 135))	('salt bridges', 'MPA', (65, 77))
202350	33445613	As discussed earlier, AMPs often increase this order parameter in a first phase (when polar contacts are established) and subsequently lower it when the peptide penetrates more deeply in the bilayers.	('order parameter', 'MPA', (47, 62))	('increase', 'PosReg', (33, 41))	('lower', 'NegReg', (135, 140))	('AMPs', 'Var', (22, 26))	('AMPs', 'Chemical', '-', (22, 26))	('peptide', 'Chemical', 'MESH:D010455', (153, 160))
202351	33445613	Many AMPs can cause a transient permeabilization of the membrane.	('permeabilization', 'MPA', (32, 48))	('AMPs', 'Chemical', '-', (5, 9))	('cause', 'Reg', (14, 19))	('AMPs', 'Var', (5, 9))
202353	33445613	The leading hypothesis to explain this phenomenon is that the accumulation of the peptides in the outer leaflet of the membrane creates an imbalance of mass, charge, surface tension and lateral pressure that eventually leads to a stochastic local dissipation, causing the membrane to become transiently permeable.	('peptides', 'Var', (82, 90))	('lateral pressure', 'MPA', (186, 202))	('leads to', 'Reg', (219, 227))	('accumulation', 'PosReg', (62, 74))	('imbalance of mass', 'MPA', (139, 156))	('imbalance', 'Phenotype', 'HP:0002172', (139, 148))	('stochastic local dissipation', 'MPA', (230, 258))	('membrane', 'MPA', (272, 280))	('become', 'PosReg', (284, 290))	('peptides', 'Chemical', 'MESH:D010455', (82, 90))
202374	33445613	While sequence alignment and MD suggests that helix II might not be essential for the activity, amidation of the C-terminus seems to increase the antibacterial properties of CXJ, probably due to the increase in the net positive charge of the peptide.	('peptide', 'Chemical', 'MESH:D010455', (242, 249))	('amidation', 'Var', (96, 105))	('antibacterial properties', 'MPA', (146, 170))	('net positive charge', 'MPA', (215, 234))	('increase', 'PosReg', (133, 141))	('increase', 'PosReg', (199, 207))
202380	33445613	With the PE headgroup, also present in bacterial and fungal bilayers, CXJ can interact via E9, D17 and E27, forming salt bridges with its protonated amine.	('PE', 'Chemical', 'MESH:C483858', (9, 11))	('amine', 'Chemical', 'MESH:D000588', (149, 154))	('salt bridges', 'MPA', (116, 128))	('D17', 'Var', (95, 98))	('E27', 'Var', (103, 106))	('forming', 'Reg', (108, 115))	('interact', 'Interaction', (78, 86))	('salt', 'Chemical', 'MESH:D012492', (116, 120))
202388	33445613	The integration of biological activity with the analysis of contact map seems to suggest that arginine residues could be responsible for the CPP character of CXJ, while the lysine residues could account for its activity towards mitochondria.	('lysine', 'Chemical', 'MESH:D008239', (173, 179))	('activity', 'MPA', (211, 219))	('arginine residues', 'Var', (94, 111))	('arginine', 'Chemical', 'MESH:D001120', (94, 102))	('CPP', 'MPA', (141, 144))
202399	33050646	Epigenetic dysregulation is an important feature for cancer initiation and progression.	('Epigenetic dysregulation', 'Var', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))
202400	33050646	LncRNA can epigenetically regulate either oncogenes or tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('oncogenes', 'Protein', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('regulate', 'Reg', (26, 34))	('tumor', 'Disease', (55, 60))	('epigenetically', 'Var', (11, 25))
202406	33050646	Based on the genes and the proteins encoded therein, the interactions between the proteins related to cancer have been discovered and studies have been conducted on the mechanisms of occurrence and metastasis of cancer caused by abnormal mutations of these genes or proteins.	('interactions', 'Interaction', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('abnormal mutations', 'Var', (229, 247))	('mutations', 'Var', (238, 247))	('metastasis', 'CPA', (198, 208))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('caused by', 'Reg', (219, 228))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
202407	33050646	Among these non-coding transcripts, long non-coding RNAs (lncRNAs) have a length of 200 bp or more and are epigenetically involved with cancer development in various cells and tissues.	('long non-coding RNAs', 'Var', (36, 56))	('involved with', 'Reg', (122, 135))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
202421	33050646	Studies have been reported on the epigenetic regulations of lncRNA in breast cancer.	('lncRNA', 'Protein', (60, 66))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('epigenetic regulations', 'Var', (34, 56))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
202425	33050646	Downregulated LINC01585 weakens the binding to the non-POU domain-containing octamer-binding protein (NONO) protein and then NONO interacts with cAMP-response element binding protein (CREB)-regulated transcription captivator (CRTC).	('Downregulated', 'Var', (0, 13))	('weakens', 'NegReg', (24, 31))	('non-POU domain-containing octamer-binding protein', 'Gene', (51, 100))	('NONO', 'Gene', '4841', (125, 129))	('LINC01585', 'Gene', (14, 23))	('NONO', 'Gene', (125, 129))	('CRTC', 'Chemical', '-', (226, 230))	('interacts', 'Interaction', (130, 139))	('cAMP-response element binding protein', 'Gene', '1385', (145, 182))	('LINC01585', 'Gene', '101929765', (14, 23))	('non-POU domain-containing octamer-binding protein', 'Gene', '4841', (51, 100))	('NONO', 'Gene', (102, 106))	('NONO', 'Gene', '4841', (102, 106))	('CREB', 'Gene', (184, 188))	('cAMP-response element binding protein', 'Gene', (145, 182))	('binding', 'Interaction', (36, 43))	('CREB', 'Gene', '1385', (184, 188))
202426	33050646	Thus, LINC01585 depletion activates cAMP/CREB-related gene expression via recruitment of the NONO/CRTC complex, and promotes the proliferation of breast cancers.	('CREB', 'Gene', '1385', (41, 45))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cAMP', 'Gene', (36, 40))	('promotes', 'PosReg', (116, 124))	('NONO', 'Gene', '4841', (93, 97))	('CRTC', 'Chemical', '-', (98, 102))	('LINC01585', 'Gene', '101929765', (6, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('breast cancers', 'Disease', (146, 160))	('LINC01585', 'Gene', (6, 15))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('proliferation', 'CPA', (129, 142))	('cAMP', 'Gene', '820', (36, 40))	('NONO', 'Gene', (93, 97))	('CREB', 'Gene', (41, 45))	('depletion', 'Var', (16, 25))	('activates', 'PosReg', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
202437	33050646	Another study suggests that lncRNA SNHG6 binds to EZH2 to methylate the tumor suppressor p21 promoter region and inhibit its expression, which proliferates colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (156, 173))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SNHG6', 'Gene', '641638', (35, 40))	('proliferates', 'PosReg', (143, 155))	('tumor', 'Disease', (72, 77))	('inhibit', 'NegReg', (113, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('expression', 'MPA', (125, 135))	('SNHG6', 'Gene', (35, 40))	('p21', 'Gene', '1026', (89, 92))	('methylate', 'Var', (58, 67))	('EZH2', 'Gene', '2146', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colorectal cancer', 'Disease', (156, 173))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('EZH2', 'Gene', (50, 54))	('p21', 'Gene', (89, 92))
202439	33050646	It is reported that LINC00114/EZH2/DNMT1 complex upregulates the nucleoporin 214 (NUP214) protein, which is related to mitosis, by decreasing miR-133b expression through hypermethylation of the miR-133 promoter region.	('NUP214', 'Gene', (82, 88))	('NUP214', 'Gene', '8021', (82, 88))	('EZH2', 'Gene', '2146', (30, 34))	('LINC00114', 'Gene', '400866', (20, 29))	('miR-133b', 'Gene', '442890', (142, 150))	('DNMT1', 'Gene', '1786', (35, 40))	('LINC00114', 'Gene', (20, 29))	('EZH2', 'Gene', (30, 34))	('miR-133b', 'Gene', (142, 150))	('expression', 'MPA', (151, 161))	('hypermethylation', 'Var', (170, 186))	('mitosis', 'Disease', (119, 126))	('nucleoporin 214', 'Gene', (65, 80))	('mitosis', 'Disease', 'None', (119, 126))	('decreasing', 'NegReg', (131, 141))	('upregulates', 'PosReg', (49, 60))	('nucleoporin 214', 'Gene', '8021', (65, 80))	('DNMT1', 'Gene', (35, 40))
202445	33050646	LncRNA LOC283070 suppresses the androgen receptor (AR) signaling protein function of prohibitin 2 (PHB2) through direct binding.	('LOC283070', 'Chemical', '-', (7, 16))	('binding', 'Interaction', (120, 127))	('androgen receptor', 'Gene', (32, 49))	('PHB2', 'Gene', (99, 103))	('suppresses', 'NegReg', (17, 27))	('PHB2', 'Gene', '11331', (99, 103))	('LOC283070', 'Var', (7, 16))	('AR', 'Gene', '367', (51, 53))	('prohibitin 2', 'Gene', '11331', (85, 97))	('androgen receptor', 'Gene', '367', (32, 49))	('prohibitin 2', 'Gene', (85, 97))
202463	33050646	Aberrant WNT/beta-catenin signaling is related to various cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', '1499', (13, 25))	('related', 'Reg', (39, 46))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('beta-catenin', 'Gene', (13, 25))
202483	33050646	So, we summarized that lncRNA epigenetic regulation progresses through direct binding to protein in migration and invasion of diverse cancers.	('binding', 'Interaction', (78, 85))	('migration', 'CPA', (100, 109))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('epigenetic regulation', 'Var', (30, 51))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('protein', 'Protein', (89, 96))	('invasion', 'CPA', (114, 122))
202513	33050646	Third, lncRNA DANCR catalyzes H3K27me3 in the Fructose-1, 6- biphosphatase (FBP1) promoter region through binding EZH2.	('DANCR', 'Gene', (14, 19))	('binding', 'Interaction', (106, 113))	('DANCR', 'Gene', '57291', (14, 19))	('FBP1', 'Gene', '2203', (76, 80))	('H3K27me3', 'Var', (30, 38))	('EZH2', 'Gene', '2146', (114, 118))	('FBP1', 'Gene', (76, 80))	('EZH2', 'Gene', (114, 118))
202569	33050646	By negative feedback, m6A-modification of GAS5 accelerates the metastasis of colorectal cancer through the degradation of GAS5 transcripts that bind to the YTHDF3 protein (Figure 5).	('GAS5', 'Gene', '60674', (42, 46))	('colorectal cancer', 'Disease', (77, 94))	('metastasis', 'CPA', (63, 73))	('accelerates', 'PosReg', (47, 58))	('m6A-modification', 'Var', (22, 38))	('GAS5', 'Gene', (122, 126))	('degradation', 'MPA', (107, 118))	('YTHDF3', 'Gene', '253943', (156, 162))	('GAS5', 'Gene', '60674', (122, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('YTHDF3', 'Gene', (156, 162))	('GAS5', 'Gene', (42, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('bind', 'Interaction', (144, 148))
202572	33050646	KRT19P3/COPS7A dysregulates the NF-kappaB signaling pathway through the inhibition of IkBa ubiquitination and thus promotes metastasis in gastric cancer.	('gastric cancer', 'Disease', (138, 152))	('COPS7A', 'Gene', '50813', (8, 14))	('COPS7A', 'Gene', (8, 14))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('IkBa', 'Gene', (86, 90))	('NF-kappaB', 'Gene', (32, 41))	('metastasis', 'CPA', (124, 134))	('KRT19P3', 'Gene', '442114', (0, 7))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('dysregulates', 'Var', (15, 27))	('KRT19P3', 'Gene', (0, 7))	('IkBa', 'Gene', '4792', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('promotes', 'PosReg', (115, 123))	('NF-kappaB', 'Gene', '4790', (32, 41))	('inhibition', 'NegReg', (72, 82))
202635	33050646	For instance, seven lncRNAs, such as SNHG1, LINC00467, ATB, VCAN-AS1, LINC00673, P53RRA, and ZFPM2-AS1 are involved in cancer process via modulating the p53 signal pathway.	('SNHG1', 'Gene', '23642', (37, 42))	('modulating', 'Reg', (138, 148))	('p53', 'Gene', '7157', (153, 156))	('AS1', 'Gene', '5729', (65, 68))	('LINC00467', 'Gene', '84791', (44, 53))	('VCAN-AS1', 'Gene', '105379054', (60, 68))	('ZFPM2', 'Gene', '23414', (93, 98))	('P53RRA', 'Var', (81, 87))	('ZFPM2', 'Gene', (93, 98))	('cancer', 'Disease', (119, 125))	('AS1', 'Gene', (99, 102))	('p53', 'Gene', (153, 156))	('VCAN-AS1', 'Gene', (60, 68))	('LINC00467', 'Gene', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('LINC00673', 'Gene', '100499467', (70, 79))	('SNHG1', 'Gene', (37, 42))	('AS1', 'Gene', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('LINC00673', 'Gene', (70, 79))	('AS1', 'Gene', '5729', (99, 102))	('involved', 'Reg', (107, 115))
202638	33050646	identified TLR-related lncRNAs, AP000696.1, LINC00689, LINC00900, and AP000487.1, that are associated with the overall survival of esophageal carcinoma, and Chu et al.	('AP000696.1', 'Var', (32, 42))	('LINC00689', 'Gene', '154822', (44, 53))	('LINC00900', 'Gene', '283143', (55, 64))	('LINC00689', 'Gene', (44, 53))	('LINC00900', 'Gene', (55, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (131, 151))	('esophageal carcinoma', 'Disease', (131, 151))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (131, 151))	('AP000487.1', 'Var', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('associated with', 'Reg', (91, 106))
202639	33050646	also reported three lncRNAs (MCHR2, AC011472.4, and AC063944.1) that regulate TLR signaling.	('MCHR2', 'Gene', (29, 34))	('TLR signaling', 'MPA', (78, 91))	('regulate', 'Reg', (69, 77))	('AC063944.1', 'Var', (52, 62))	('MCHR2', 'Gene', '84539', (29, 34))
202643	32357862	Prdx1 promotes the loss of primary cilia in esophageal squamous cell carcinoma Loss of primary cilia is frequently observed in tumor cells, suggesting that the absence of this organelle may promote tumorigenesis through aberrant signal transduction, the inability to exit the cell cycle, and promotion of tumor cell invasion.	('Prdx1', 'Gene', (0, 5))	('esophageal squamous cell carcinoma', 'Disease', (44, 78))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (305, 310))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('absence', 'Var', (160, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('signal transduction', 'MPA', (229, 248))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (44, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('promote', 'PosReg', (190, 197))	('promotion', 'PosReg', (292, 301))	('aberrant', 'Var', (220, 228))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumor', 'Disease', (198, 203))	('Prdx1', 'Gene', '5052', (0, 5))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
202646	32357862	In this study, we found that silencing Peroxiredoxin 1 (Prdx1) restores primary cilia formation, and over-expressing Prdx1 induces primary cilia loss in ESCC cells.	('cilia loss', 'Disease', (139, 149))	('over-expressing', 'PosReg', (101, 116))	('Prdx1', 'Gene', (117, 122))	('silencing', 'Var', (29, 38))	('Prdx1', 'Gene', (56, 61))	('ESCC', 'Phenotype', 'HP:0011459', (153, 157))	('Peroxiredoxin 1', 'Gene', '5052', (39, 54))	('primary cilia formation', 'CPA', (72, 95))	('cilia loss', 'Disease', 'MESH:C536287', (139, 149))	('Peroxiredoxin 1', 'Gene', (39, 54))	('restores', 'PosReg', (63, 71))
202647	32357862	We also showed that the expression of Prdx1 regulates the action of the HEF1-Aurora A-HDAC6 signaling axis to promote the disassembly of primary cilia, and suppression of Prdx1 results in decreased tumor formation and tumor mass volume in vivo.	('Prdx1', 'Gene', (38, 43))	('decreased tumor', 'Disease', 'MESH:D002303', (188, 203))	('suppression', 'Var', (156, 167))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('decreased tumor', 'Disease', (188, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('promote', 'PosReg', (110, 117))	('disassembly of primary cilia', 'CPA', (122, 150))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (218, 223))	('Prdx1', 'Gene', (171, 176))
202651	32357862	This suggests that inhibition of cilia disassembly or loss in tumor cells or the promotion of ciliary regeneration may inhibit the proliferation and invasion of tumor cells.	('cilia disassembly', 'CPA', (33, 50))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibition', 'Var', (19, 29))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('inhibit', 'NegReg', (119, 126))	('ciliary regeneration', 'CPA', (94, 114))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('promotion', 'PosReg', (81, 90))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
202687	32357862	Genes related to the formation of cellular protrusions (cilia) were significantly activated, and genes influencing the invasion of tumor cells (cell movement of the carcinoma cell line) were significantly inhibited after the inhibition of Prdx1 (Table 1).	('carcinoma', 'Disease', (165, 174))	('inhibited', 'NegReg', (205, 214))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('formation of cellular protrusions', 'CPA', (21, 54))	('activated', 'PosReg', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('carcinoma', 'Disease', 'MESH:D009369', (165, 174))	('tumor', 'Disease', (131, 136))	('Prdx1', 'Gene', (239, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('inhibition', 'Var', (225, 235))
202690	32357862	Studies have shown that FGFR1 knockout can cause ciliary shortening, IGFR1 plays an important role in ciliary elongation, and ABI2 is a tumor suppressor and a cell migration suppressor, participating in human head and neck squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (218, 246))	('cause', 'Reg', (43, 48))	('ABI2', 'Gene', (126, 130))	('human', 'Species', '9606', (203, 208))	('ciliary shortening', 'CPA', (49, 67))	('IGFR1', 'Gene', '100132417', (69, 74))	('knockout', 'Var', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('ABI2', 'Gene', '10152', (126, 130))	('FGFR1', 'Gene', (24, 29))	('FGFR1', 'Gene', '2260', (24, 29))	('ciliary elongation', 'CPA', (102, 120))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('neck squamous cell carcinoma', 'Disease', (218, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))	('tumor', 'Disease', (136, 141))	('IGFR1', 'Gene', (69, 74))
202694	32357862	The above results were consistent with the results of the gene chip detection, which indicated that the inhibition of Prdx1 in the EC9706 cells could promote cilia regeneration and inhibit the invasion capacity of the tumor cells.	('promote', 'PosReg', (150, 157))	('cilia regeneration', 'CPA', (158, 176))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('EC9706', 'CellLine', 'CVCL:E307', (131, 137))	('inhibition', 'Var', (104, 114))	('inhibit', 'NegReg', (181, 188))	('Prdx1', 'Gene', (118, 123))	('tumor', 'Disease', (218, 223))
202695	32357862	In previous work, we demonstrated that inhibition of Prdx1 in EC9706 cells could promote cilia regeneration and down-regulate the expression of the key cilium disassembly protein, Aurora A.	('inhibition', 'Var', (39, 49))	('expression', 'MPA', (130, 140))	('down-regulate', 'NegReg', (112, 125))	('promote', 'PosReg', (81, 88))	('EC9706', 'CellLine', 'CVCL:E307', (62, 68))	('cilia regeneration', 'CPA', (89, 107))	('Prdx1', 'Gene', (53, 58))
202697	32357862	HDAC6 inhibition can enhance the efficacy of anticancer agents in cancers and suppress ESCC proliferation.	('ESCC', 'Phenotype', 'HP:0011459', (87, 91))	('efficacy', 'MPA', (33, 41))	('HDAC6', 'Gene', (0, 5))	('enhance', 'PosReg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('anticancer agents', 'CPA', (45, 62))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('suppress', 'NegReg', (78, 86))	('ESCC', 'Disease', (87, 91))	('inhibition', 'Var', (6, 16))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
202700	32357862	Cells containing the shPrdx1 lentivirus or negative control (shControl) lentivirus were tested and showed that the expression levels of NEDD9, p-Aurora A, and HDAC6 were significantly decreased in Prdx1-inhibited cells (Fig.	('expression levels', 'MPA', (115, 132))	('NEDD9', 'Gene', '4739', (136, 141))	('NEDD9', 'Gene', (136, 141))	('HDAC6', 'Gene', (159, 164))	('decreased', 'NegReg', (184, 193))	('p-Aurora', 'Var', (143, 151))
202705	32357862	We stimulated EC9706 cells with different concentrations of Tripolin A (0, 1.5, 4.5, 7.5, or 10.5 mumol/L) for 12 h, and observed that the expression of p-Aurora A decreased in a dose-dependent manner (Fig.	('decreased', 'NegReg', (164, 173))	('p-Aurora', 'Var', (153, 161))	('Tripolin A', 'Chemical', 'MESH:C583421', (60, 70))	('EC9706', 'CellLine', 'CVCL:E307', (14, 20))	('expression', 'MPA', (139, 149))
202706	32357862	EC9706 cells were stimulated with 4.5 mumol/L Tripolin A for 0, 2, 4, 8, and 12 h, and we observed that the expression of p-Aurora A gradually decreased (Fig.	('decreased', 'NegReg', (143, 152))	('Tripolin A', 'Chemical', 'MESH:C583421', (46, 56))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('p-Aurora', 'Var', (122, 130))	('expression', 'MPA', (108, 118))
202715	32357862	The mice tumor weight and volume also decreased significantly after inhibition of Prdx1 (Fig.	('decreased', 'NegReg', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('mice', 'Species', '10090', (4, 8))	('inhibition', 'Var', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('Prdx1', 'Gene', (82, 87))
202719	32357862	The inhibition of Prdx1 expression promoted cilia regeneration and inhibited the invasion of tumor cells.	('Prdx1', 'Gene', (18, 23))	('inhibited', 'NegReg', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cilia regeneration', 'CPA', (44, 62))	('tumor', 'Disease', (93, 98))	('inhibition', 'Var', (4, 14))	('promoted', 'PosReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
202722	32357862	This was consistent with the above cellular assay results, and further indicated that the action of Prdx1 to promote carcinoma cilium disaggregation and tumor invasion in esophageal squamous cells was achieved by modulation of the NEDD9-Aurora A-HDAC6 signal axis.	('modulation', 'Var', (213, 223))	('NEDD9', 'Gene', '4739', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('NEDD9', 'Gene', (231, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('promote', 'PosReg', (109, 116))	('Prdx1', 'Gene', (100, 105))	('carcinoma', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('carcinoma', 'Disease', 'MESH:D009369', (117, 126))
202723	32357862	Prdx1 is a member of the peroxide oxidation-reduction enzyme family, and its abnormal expression is closely associated with multiple types of tumors.	('Prdx1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('peroxide', 'Chemical', 'MESH:D010545', (25, 33))	('associated', 'Reg', (108, 118))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('abnormal', 'Var', (77, 85))
202724	32357862	Recent studies indicated that the high expression of Prdx1 can promote the occurrence and progression of esophageal carcinoma and that inhibition of Prdx1 expression can promote radiation and chemotherapy sensitivity for esophageal carcinoma treatment.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (105, 125))	('inhibition', 'Var', (135, 145))	('high', 'Var', (34, 38))	('Prdx1', 'Gene', (149, 154))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (221, 241))	('Prdx1', 'Gene', (53, 58))	('esophageal carcinoma', 'Disease', (221, 241))	('promote', 'PosReg', (63, 70))	('esophageal carcinoma', 'Disease', (105, 125))	('progression', 'CPA', (90, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (105, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (221, 241))	('promote', 'PosReg', (170, 177))
202729	32357862	Our results are consistent with other findings that inhibition of Prdx1 can inhibit the occurrence, invasion, and metastasis of tumors.	('occurrence', 'CPA', (88, 98))	('inhibit', 'NegReg', (76, 83))	('Prdx1', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('inhibition', 'Var', (52, 62))	('invasion', 'CPA', (100, 108))	('metastasis of tumors', 'Disease', 'MESH:D009362', (114, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('metastasis of tumors', 'Disease', (114, 134))
202730	32357862	found that Prdx1 knockdown markedly inhibited proximal tubule formation in the pronephros during embryogenesis, significantly increased the cellular levels of reactive oxygen species (ROS), and impaired primary cilia formation, findings that do not agree with our observations.	('inhibited', 'NegReg', (36, 45))	('Prdx1', 'Gene', (11, 16))	('impaired', 'NegReg', (194, 202))	('primary cilia formation', 'CPA', (203, 226))	('ROS', 'Chemical', 'MESH:D017382', (184, 187))	('knockdown', 'Var', (17, 26))	('proximal tubule formation', 'CPA', (46, 71))	('increased', 'PosReg', (126, 135))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (159, 182))
202758	30931376	The set-up for ESD consisted of diagnostic gastroscopes with waterjet function (GIF-H180-J or GIF-HQ190), 4 mm straight distal attachment, water irrigation pump and carbon dioxide insufflation (all from Olympus Medical Systems, Tokyo, Japan).	('water', 'Chemical', 'MESH:D014867', (139, 144))	('GIF-H180-J', 'Var', (80, 90))	('insufflation', 'Disease', (180, 192))	('water', 'Chemical', 'MESH:D014867', (61, 66))	('carbon dioxide', 'Chemical', 'MESH:D002245', (165, 179))	('insufflation', 'Disease', 'None', (180, 192))	('GIF-HQ190', 'Var', (94, 103))
202787	29948420	All patients with a resectable esophageal cancer (cT1N1 or T2-T4a, N0-N3, M0 tumor) and who were fit for nCRT plus surgery, as judged by the surgeon responsible, medical oncologist, and radiation oncologist between July 2008 and December 2013, were eligible for the post-CROSS cohort.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('esophageal cancer', 'Disease', (31, 48))	('T2-T4a', 'Var', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patients', 'Species', '9606', (4, 12))	('cT1N1', 'Var', (50, 55))	('tumor', 'Disease', (77, 82))
202858	29399158	The dysregulation of EGFR has been implicated in the development of resistance to the conventional chemotherapy and poor clinical outcome.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('clinical', 'Species', '191496', (121, 129))	('dysregulation', 'Var', (4, 17))	('men', 'Species', '9606', (60, 63))	('resistance to the conventional chemotherapy', 'CPA', (68, 111))	('implicated', 'Reg', (35, 45))
202859	29399158	Therefore, inhibition of EGFR may be a promising approach for the management of ESCC.	('EGFR', 'Gene', (25, 29))	('men', 'Species', '9606', (72, 75))	('inhibition', 'Var', (11, 21))	('EGFR', 'Gene', '1956', (25, 29))	('ESCC', 'Disease', (80, 84))
202861	29399158	Although EGFR inhibitors have higher efficacies and lower toxicities compared with conventional chemotherapeutic agents, patients have demonstrated highly variable responses to these inhibitors.	('higher', 'PosReg', (30, 36))	('efficacies', 'MPA', (37, 47))	('rat', 'Species', '10116', (142, 145))	('toxicities', 'Disease', 'MESH:D064420', (58, 68))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('inhibitors', 'Var', (14, 24))	('toxicities', 'Disease', (58, 68))	('patients', 'Species', '9606', (121, 129))
202869	29399158	The phosphatiditylinositide-3-kinase (PI3K) signaling pathway is central to growth and survival of numerous types of cancer, and PI3K signaling can be directly activated by genetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('genetic alterations', 'Var', (173, 192))	('phosphatiditylinositide-3-kinase', 'Gene', (4, 36))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('phosphatiditylinositide-3-kinase', 'Gene', '5290', (4, 36))	('rat', 'Species', '10116', (185, 188))
202928	29399158	These results suggested that low miR-1 expression and high PIK3CA expression may be associated with the pathophysiology of ESCC.	('low', 'NegReg', (29, 32))	('high', 'Var', (54, 58))	('ESCC', 'Disease', (123, 127))	('miR-1', 'Gene', (33, 38))	('expression', 'MPA', (66, 76))	('PIK3CA', 'Gene', (59, 65))	('expression', 'MPA', (39, 49))	('PIK3CA', 'Gene', '5290', (59, 65))
202931	29399158	However, the level of PIK3CA protein expression was revealed to be markedly decreased in the cells transfected with miR-1 mimics compared with the cells transfected with control miRNA (Fig.	('mimics', 'Var', (122, 128))	('PIK3CA', 'Gene', '5290', (22, 28))	('level', 'MPA', (13, 18))	('decreased', 'NegReg', (76, 85))	('miR-1', 'Gene', (116, 121))	('PIK3CA', 'Gene', (22, 28))
202941	29399158	In the presence of gefitinib, the apoptotic rate of TE-1 cells transfected with miR-1 mimics was significantly higher compared with TE-1 cells transfected with the control miRNA (P<0.05; Fig.	('apoptotic rate', 'CPA', (34, 48))	('rat', 'Species', '10116', (44, 47))	('gefitinib', 'Chemical', 'MESH:D000077156', (19, 28))	('mimics', 'Var', (86, 92))	('higher', 'PosReg', (111, 117))
202945	29399158	Previous studies by the present authors revealed that miR-1 expression was significantly lower in patients with lung cancer compared with normal tissues, and the low-miR-1 expression group exhibited a significantly higher recurrence rate compared with those in the moderate-miR1 expression level group.	('miR1', 'Gene', '79187', (274, 278))	('expression', 'MPA', (60, 70))	('lower', 'NegReg', (89, 94))	('higher', 'PosReg', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('recurrence rate', 'CPA', (222, 237))	('low-miR-1 expression', 'Var', (162, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('patients', 'Species', '9606', (98, 106))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('rat', 'Species', '10116', (233, 236))	('miR-1', 'Gene', (54, 59))	('rat', 'Species', '10116', (269, 272))	('miR1', 'Gene', (274, 278))
202947	29399158	Similar to the results obtained for patients with NSCLC, the present study demonstrated that the level of miR-1 expression was associated with clinical stage and lymph node metastasis in patients with ESCC, suggesting that low miR-1 expression may be associated with ESCC progression.	('lymph node metastasis', 'CPA', (162, 183))	('patients', 'Species', '9606', (187, 195))	('ESCC', 'Disease', (267, 271))	('clinical stage', 'CPA', (143, 157))	('associated', 'Reg', (127, 137))	('patients', 'Species', '9606', (36, 44))	('associated', 'Reg', (251, 261))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('rat', 'Species', '10116', (82, 85))	('NSCLC', 'Disease', (50, 55))	('clinical', 'Species', '191496', (143, 151))	('ESCC', 'Disease', (201, 205))	('low', 'Var', (223, 226))
202950	29399158	Upon activation of these receptors, PIK3CA binds to its heterodimer p85 and promotes Akt phosphorylation at Thr308 and/or Ser473.	('p85', 'Gene', (68, 71))	('heterodimer', 'MPA', (56, 67))	('promotes', 'PosReg', (76, 84))	('PIK3CA', 'Gene', '5290', (36, 42))	('Akt', 'Gene', '207', (85, 88))	('activation', 'PosReg', (5, 15))	('Ser473', 'Var', (122, 128))	('Akt', 'Gene', (85, 88))	('Thr308', 'Chemical', '-', (108, 114))	('Ser473', 'Chemical', '-', (122, 128))	('p85', 'Gene', '5296', (68, 71))	('binds', 'Interaction', (43, 48))	('PIK3CA', 'Gene', (36, 42))
202959	29399158	Therefore, blockade of EGFR signal transduction appears to be a promising strategy for cancer therapy.	('cancer', 'Disease', (87, 93))	('rat', 'Species', '10116', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('EGFR', 'Gene', '1956', (23, 27))	('blockade', 'Var', (11, 19))	('EGFR', 'Gene', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
202990	28819439	Using epigenetics and miRNA microarray, a few new serum markers were recently found, including the aberrant methylation of genes such as FHIT and the miRNAs miR-507 and miR-634, among others.	('aberrant', 'Var', (99, 107))	('FHIT', 'Gene', (137, 141))	('miR-634', 'Gene', (169, 176))	('methylation', 'MPA', (108, 119))	('FHIT', 'Gene', '2272', (137, 141))	('miR-507', 'Gene', (157, 164))	('miR-634', 'Gene', '693219', (169, 176))	('miR-507', 'Gene', '574512', (157, 164))
203009	28819439	The ESCC cell lines, Eca-109, Kyse30, Kyse140, Kyse180, Kyse510 and Kyse520 (Chinese Academy of Sciences, Shanghai, China), were grown in RPMI 1640 (Invitrogen, USA) supplemented with 10% fetal bovine serum.	('Kyse30', 'Var', (30, 36))	('Kyse180', 'Var', (47, 54))	('Kyse140', 'Var', (38, 45))	('Kyse520', 'Var', (68, 75))	('bovine', 'Species', '9913', (194, 200))	('Kyse510', 'Var', (56, 63))
203046	28819439	By comparison, the mRNA and protein levels of MMP13 were significantly increased in Eca-109, Kyse140, and Kyse180.	('MMP13', 'Gene', (46, 51))	('Eca-109', 'Gene', (84, 91))	('MMP13', 'Gene', '4322', (46, 51))	('Kyse180', 'Var', (106, 113))	('Kyse140', 'Var', (93, 100))	('increased', 'PosReg', (71, 80))
203047	28819439	Similarly, SPP1 mRNA and protein levels were highly expressed in Kyse30, Kyse180, Kyse510 and Kyse520.	('expressed', 'MPA', (52, 61))	('Kyse510', 'Var', (82, 89))	('SPP1', 'Gene', '6696', (11, 15))	('SPP1', 'Gene', (11, 15))	('Kyse30', 'Var', (65, 71))	('Kyse180', 'Var', (73, 80))	('highly', 'PosReg', (45, 51))	('Kyse520', 'Var', (94, 101))
203140	26699425	Nonetheless, when successful, PEG-b-PLA micelles increase the water solubility of anticancer agents by two to three orders of magnitude, enabling > 1.0 mg/mL in water, which is often a requirement for pre-clinical studies on efficacy and toxicity in rodents and eventual testing in human beings.	('water', 'Chemical', 'MESH:D014867', (161, 166))	('PEG-b-PLA', 'Var', (30, 39))	('toxicity', 'Disease', (238, 246))	('b', 'Chemical', 'MESH:D001895', (140, 141))	('b', 'Chemical', 'MESH:D001895', (100, 101))	('nab', 'Chemical', '-', (138, 141))	('cancer', 'Disease', (86, 92))	('b', 'Chemical', 'MESH:D001895', (34, 35))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('water solubility', 'MPA', (62, 78))	('PEG-b-PLA', 'Chemical', '-', (30, 39))	('water', 'Chemical', 'MESH:D014867', (62, 67))	('mice', 'Species', '10090', (40, 44))	('increase', 'PosReg', (49, 57))	('b', 'Chemical', 'MESH:D001895', (288, 289))	('human', 'Species', '9606', (282, 287))	('b', 'Chemical', 'MESH:D001895', (72, 73))	('toxicity', 'Disease', 'MESH:D064420', (238, 246))	('cancer', 'Disease', 'MESH:D009369', (86, 92))
203146	26699425	However, ethanol-Cremophor EL-PEG400 caused 35% mortality within 24 hours, whereas PEG-b-PLA micelles caused no deaths.	('ethanol-Cremophor', 'Var', (9, 26))	('deaths', 'Disease', 'MESH:D003643', (112, 118))	('deaths', 'Disease', (112, 118))	('PEG-b-PLA', 'Chemical', '-', (83, 92))	('mice', 'Species', '10090', (93, 97))	('ethanol-Cremophor EL-PEG400', 'Chemical', '-', (9, 36))
203161	26699425	To enhance drug loading and slow drug release, doxorubicin has been coupled onto the terminal hydroxyl group of PEG-b-PLGA by a carbamate linkage (Figure 2), resulting in PEG-b-PLGA micelles that exhibit a sustained release profile of doxorubicin in comparison to PEG-b-PLGA micelles that contain physically loaded doxorubicin.	('mice', 'Species', '10090', (275, 279))	('mice', 'Species', '10090', (182, 186))	('b', 'Chemical', 'MESH:D001895', (268, 269))	('b', 'Chemical', 'MESH:D001895', (53, 54))	('b', 'Chemical', 'MESH:D001895', (116, 117))	('PEG-b', 'Chemical', '-', (171, 176))	('b', 'Chemical', 'MESH:D001895', (131, 132))	('carbamate', 'Chemical', 'MESH:D002219', (128, 137))	('drug loading', 'MPA', (11, 23))	('enhance', 'PosReg', (3, 10))	('b', 'Chemical', 'MESH:D001895', (321, 322))	('b', 'Chemical', 'MESH:D001895', (123, 124))	('doxorubicin', 'Chemical', 'MESH:D004317', (47, 58))	('b', 'Chemical', 'MESH:D001895', (241, 242))	('doxorubicin', 'Chemical', 'MESH:D004317', (315, 326))	('PEG-b-PLGA', 'Var', (171, 181))	('b', 'Chemical', 'MESH:D001895', (200, 201))	('PEG-b', 'Chemical', '-', (264, 269))	('sustained release profile', 'MPA', (206, 231))	('slow drug release', 'MPA', (28, 45))	('b', 'Chemical', 'MESH:D001895', (175, 176))	('PEG-b', 'Chemical', '-', (112, 117))	('doxorubicin', 'Chemical', 'MESH:D004317', (235, 246))	('b', 'Chemical', 'MESH:D001895', (63, 64))
203169	26699425	In an A549 orthotopic lung cancer model, PEG-b-PLA micelles containing beta-lap-dC3 at 50 mg/kg had a tumor area under the curve over the first 2 hours of 7.3+-0.61 x 106 ng min/g of beta-lapachone, versus 1.4+-0.85 x 106 ng min/g of beta-lapachone for a hydroxypropyl-beta-cyclodextrin formulation of beta-lapachone at maximum tolerated dose (MTD) of 25 mg/kg.	('A549 orthotopic lung cancer', 'Disease', 'MESH:D008175', (6, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mice', 'Species', '10090', (51, 55))	('tumor', 'Disease', (102, 107))	('beta-lapachone', 'Chemical', 'MESH:C014638', (234, 248))	('beta-lapachone', 'Chemical', 'MESH:C014638', (183, 197))	('beta-lap-dC3', 'Chemical', '-', (71, 83))	('hydroxypropyl-beta-cyclodextrin', 'Chemical', 'MESH:D000073738', (255, 286))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('rat', 'Species', '10116', (332, 335))	('beta-lap-dC3', 'Var', (71, 83))	('PEG-b-PLA', 'Chemical', '-', (41, 50))	('A549 orthotopic lung cancer', 'Disease', (6, 33))	('beta-lapachone', 'Chemical', 'MESH:C014638', (302, 316))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
203170	26699425	As a result, antitumor efficacy of PEG-b-PLA micelles containing beta-lap-dC3 significantly prolonged survival of mice in comparison to a hydroxypropyl-beta-cyclodextrin formulation of beta-lapachone.	('beta-lap-dC3', 'Var', (65, 77))	('tumor', 'Disease', (17, 22))	('mice', 'Species', '10090', (45, 49))	('survival', 'CPA', (102, 110))	('beta-lapachone', 'Chemical', 'MESH:C014638', (185, 199))	('hydroxypropyl-beta-cyclodextrin', 'Chemical', 'MESH:D000073738', (138, 169))	('beta-lap-dC3', 'Chemical', '-', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('mice', 'Species', '10090', (114, 118))	('PEG-b-PLA', 'Chemical', '-', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('prolonged', 'PosReg', (92, 101))
203183	26699425	In clinical studies, cases of hypersensitivity reactions have emerged for Genexol-PM , although seemingly less frequently than for Taxol .	('hypersensitivity', 'Disease', (30, 46))	('Genexol-PM', 'Chemical', 'MESH:D017239', (74, 84))	('Genexol-PM', 'Var', (74, 84))	('hypersensitivity', 'Disease', 'MESH:D004342', (30, 46))	('Taxol', 'Chemical', 'MESH:D017239', (131, 136))
203193	26699425	Nab-paclitaxel is approved for breast, non-small cell lung, and pancreatic cancers and it is in clinical trials for melanoma, ovarian and bladder cancers.	('ovarian and bladder cancers', 'Disease', 'MESH:D001749', (126, 153))	('breast', 'Disease', (31, 37))	('pancreatic cancers', 'Disease', (64, 82))	('b', 'Chemical', 'MESH:D001895', (31, 32))	('bladder cancers', 'Phenotype', 'HP:0009725', (138, 153))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('b', 'Chemical', 'MESH:D001895', (138, 139))	('pancreatic cancers', 'Disease', 'MESH:D010190', (64, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('Nab-paclitaxel', 'Var', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('b', 'Chemical', 'MESH:D001895', (2, 3))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('non-small cell lung', 'Disease', (39, 58))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (64, 82))
203223	26699425	Inhibition of mTOR has been widely studied for cancer treatment, noting that the PI3K/Akt signaling pathway is aberrantly activated in many cancers and contributes to cellular resistance to chemotherapy.	('mTOR', 'Gene', '2475', (14, 18))	('Akt', 'Gene', (86, 89))	('cellular resistance to chemotherapy', 'CPA', (167, 202))	('b', 'Chemical', 'MESH:D001895', (158, 159))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('Akt', 'Gene', '207', (86, 89))	('b', 'Chemical', 'MESH:D001895', (4, 5))	('activated', 'PosReg', (122, 131))	('cancer', 'Disease', (47, 53))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('contributes', 'Reg', (152, 163))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (140, 146))	('Inhibition', 'Var', (0, 10))	('b', 'Chemical', 'MESH:D001895', (112, 113))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mTOR', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('b', 'Chemical', 'MESH:D001895', (23, 24))
203227	26699425	Inhibition of mTOR leads to a paradoxical activation of Akt, Ras/MAPK signaling pathway and NFkappaB and therefore drug resistance.	('mTOR', 'Gene', '2475', (14, 18))	('b', 'Chemical', 'MESH:D001895', (4, 5))	('MAPK', 'Gene', '5594', (65, 69))	('NFkappaB', 'Pathway', (92, 100))	('Akt', 'Gene', (56, 59))	('MAPK', 'Gene', (65, 69))	('drug resistance', 'CPA', (115, 130))	('activation', 'PosReg', (42, 52))	('Inhibition', 'Var', (0, 10))	('drug resistance', 'Phenotype', 'HP:0020174', (115, 130))	('Akt', 'Gene', '207', (56, 59))	('mTOR', 'Gene', (14, 18))
203229	26699425	Thus, inhibition of Hsp90 may enhance anti-neoplastic as well as the antiangiogenic activity of mTOR inhibitors.	('mTOR', 'Gene', (96, 100))	('b', 'Chemical', 'MESH:D001895', (10, 11))	('antiangiogenic activity', 'CPA', (69, 92))	('Hsp90', 'Gene', '3320', (20, 25))	('anti-neoplastic', 'CPA', (38, 53))	('inhibition', 'Var', (6, 16))	('enhance', 'PosReg', (30, 37))	('mTOR', 'Gene', '2475', (96, 100))	('b', 'Chemical', 'MESH:D001895', (105, 106))	('Hsp90', 'Gene', (20, 25))
203255	26699425	As a result, tumor priming of liposomal doxorubicin by Taxol  showed the highest therapeutic response based on tumor regression and survival in comparison to liposomal doxorubicin or sequential injection of liposomal doxorubicin followed by Taxol .	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('b', 'Chemical', 'MESH:D001895', (174, 175))	('doxorubicin', 'Chemical', 'MESH:D004317', (168, 179))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('b', 'Chemical', 'MESH:D001895', (46, 47))	('doxorubicin', 'Chemical', 'MESH:D004317', (40, 51))	('b', 'Chemical', 'MESH:D001895', (52, 53))	('Taxol', 'Chemical', 'MESH:D017239', (241, 246))	('survival', 'CPA', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('b', 'Chemical', 'MESH:D001895', (223, 224))	('doxorubicin', 'Chemical', 'MESH:D004317', (217, 228))	('liposomal', 'Var', (30, 39))	('b', 'Chemical', 'MESH:D001895', (238, 239))	('Taxol', 'Chemical', 'MESH:D017239', (55, 60))	('b', 'Chemical', 'MESH:D001895', (102, 103))
203267	26699425	peptides after subcutaneous injection, by far the most significant clinical progress has been made in localized control of cancer as an adjunct to surgery and radiation.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('b', 'Chemical', 'MESH:D001895', (89, 90))	('b', 'Chemical', 'MESH:D001895', (17, 18))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('peptides', 'Var', (0, 8))	('cancer', 'Disease', (123, 129))	('b', 'Chemical', 'MESH:D001895', (39, 40))
203321	26699425	Notably, detected levels of [14C]-paclitaxel were orders of magnitude higher than in vitro lethal levels for brain tumor cell lines, whereas plasma levels of [14C]-paclitaxel were low, indicating little systemic exposure.	('b', 'Chemical', 'MESH:D001895', (109, 110))	('[14C]', 'Chemical', 'MESH:C000615234', (158, 163))	('b', 'Chemical', 'MESH:D001895', (4, 5))	('brain tumor', 'Disease', 'MESH:D001932', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('brain tumor', 'Disease', (109, 120))	('[14C]', 'Chemical', 'MESH:C000615234', (28, 33))	('brain tumor', 'Phenotype', 'HP:0030692', (109, 120))	('paclitaxel', 'Chemical', 'MESH:D017239', (34, 44))	('[14C]-paclitaxel', 'Var', (28, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (164, 174))
203358	24626092	We found that tumor-bearing mice had a relative increase in numbers of circulating CTEC, specifically with increased levels of TEM7 and TEM8 expression.	('tumor', 'Disease', (14, 19))	('increased', 'PosReg', (107, 116))	('mice', 'Species', '10090', (28, 32))	('CTEC', 'Chemical', '-', (83, 87))	('TEM7', 'Var', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('TEM8', 'Var', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('increase', 'PosReg', (48, 56))
203378	24626092	In addition to TEMs, published reports have indicated that CD276 (B7-H3), a leukocyte co-stimulatory molecule, may be over expressed by endothelial cells during pathological but not physiological angiogenesis.	('over expressed', 'PosReg', (118, 132))	('TEM', 'Gene', '1540', (15, 18))	('CD276', 'Var', (59, 64))	('TEM', 'Gene', (15, 18))
203393	24626092	As previously described, in mice CECs were characterized as CD31+CD45-VEGFR-2+CD117-, and CEPs as CD31+CD45-VEGFR-2+CD117+.	('mice', 'Species', '10090', (28, 32))	('CD31+CD45-VEGFR-2+CD117-', 'Var', (60, 84))	('CD31+CD45-VEGFR-2+CD117+', 'Var', (98, 122))
203399	24626092	The following antibodies were used: CD276-PE (R&D Systems), CD146-PerCP-Cy5 (Beckman Coulter), CD31-PECy7 (BD Biosciences), CD133-APC (Miltenyi Biotec), CD45-APC-Cy7(eBiosciences).	('Biotec', 'Chemical', '-', (144, 150))	('CD276-PE', 'Var', (36, 44))	('CD133-APC', 'Disease', 'MESH:D011125', (124, 133))	('CD146', 'Gene', '4162', (60, 65))	('CD133-APC', 'Disease', (124, 133))	('CD146', 'Gene', (60, 65))
203447	24626092	CTECs were defined based on the presence of CEC markers (CD31+CD45-VEGFR-2+CD117-) as well as CD276 or TEM7 immunoreactivity.	('CEC', 'Disease', (44, 47))	('CD31+CD45-VEGFR-2+CD117-', 'Var', (57, 81))	('CTECs', 'Chemical', '-', (0, 5))	('CD276', 'Var', (94, 99))
203448	24626092	CD276 or TEM7 immunoreactivity was detected in 6% to 10% of total endothelial cells from normal skin or lung tissue, but in 30% and 22%, respectively, of tumor ECs (Fig.	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CD276', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
203449	24626092	Therefore, TEM7 and CD276 ECs could be detected on tumor ECs by flow cytometry, and the expression of CD276 could also be detected on ECs from liver tissue in non-tumor-bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TEM7', 'Var', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('CD276', 'Gene', (102, 107))	('tumor', 'Disease', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CD276', 'Var', (20, 25))	('tumor', 'Disease', (163, 168))	('mice', 'Species', '10090', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
203451	24626092	We refer to the CECs co-expressing TEM7 and CD276 as TEM7 CTECs and CD276 CTECs, respectively.	('CTECs', 'Chemical', '-', (74, 79))	('CD276', 'Var', (44, 49))	('CTECs', 'Chemical', '-', (58, 63))	('CD276', 'Var', (68, 73))
203453	24626092	In contrast, the numbers of CD276 CTECs and TEM7 CTECs were significantly increased in the blood of tumor-bearing mice compared with the controls (p = 0.041 and 0.032 respectively) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CTECs', 'Chemical', '-', (34, 39))	('CTECs', 'Chemical', '-', (49, 54))	('tumor', 'Disease', (100, 105))	('TEM7 CTECs', 'CPA', (44, 54))	('increased', 'PosReg', (74, 83))	('CD276', 'Var', (28, 33))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
203455	24626092	In this experiment, 77% of CD276+ CTECs were also TEM7+, and 57% of TEM7+ cells also expressed CD276.	('CD276+', 'Var', (27, 33))	('CD276', 'Var', (95, 100))	('CTECs', 'Chemical', '-', (34, 39))	('men', 'Species', '9606', (14, 17))
203457	24626092	In tumor-bearing mice, the mean percentage of CD276+ or TEM7+ CECs was 31% and 55%, respectively.	('mice', 'Species', '10090', (17, 21))	('tumor', 'Disease', (3, 8))	('TEM7+', 'Var', (56, 61))	('CD276+', 'Var', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
203458	24626092	Whereas, in normal mice the mean percentage of CD276+ or TEM7+ CECs was 16% and 15.8%, respectively.	('CD276+', 'Var', (47, 53))	('TEM7+', 'Var', (57, 62))	('mice', 'Species', '10090', (19, 23))
203461	24626092	The number of TEM7 CTECs in tumor-bearing mice was significantly higher than that in non-tumor-bearing mice that had (VEGF treated) or had not (control) received a VEGF injection (p = 0.018 and 0.020, respectively (Fig.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mice', 'Species', '10090', (103, 107))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('CTECs', 'Chemical', '-', (19, 24))	('higher', 'PosReg', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (89, 94))	('TEM7', 'Var', (14, 18))
203462	24626092	The level of CD276 CTECs was also significantly higher in tumor-bearing than non-tumor-bearing control mice (p = 0.015).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mice', 'Species', '10090', (103, 107))	('CD276', 'Var', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('higher', 'PosReg', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CTECs', 'Chemical', '-', (19, 24))	('tumor', 'Disease', (81, 86))
203465	24626092	We injected mice with H1975 tumor cells subcutaneously, and once tumors reached a volume of 300 mm3, the animals were treated with vehicle only or with the VEGFR tyrosine kinase inhibitor AZD2171 (cediranib) or sunitinib, or the human VEGF monoclonal antibody bevcizumab.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('H1975 tumor', 'Disease', (22, 33))	('tumors', 'Disease', (65, 71))	('cediranib', 'Chemical', 'MESH:C500926', (197, 206))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('human', 'Species', '9606', (229, 234))	('sunitinib', 'Chemical', 'MESH:D000077210', (211, 220))	('mice', 'Species', '10090', (12, 16))	('H1975 tumor', 'Disease', 'MESH:D009369', (22, 33))	('AZD2171', 'Var', (188, 195))	('bevcizumab', 'Chemical', '-', (260, 270))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('AZD2171', 'Chemical', 'MESH:C500926', (188, 195))
203468	24626092	Reduced levels of CD276 CTECs (relative to control) was significantly correlated with the reductions in tumor growth (R2=0.96, p<0.05).	('reductions', 'NegReg', (90, 100))	('CTECs', 'Chemical', '-', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('Reduced', 'NegReg', (0, 7))	('CD276', 'Var', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
203496	24626092	In mouse studies, however, TEM7 expression was demonstrated by RT-PCR in one study of human melanoma and liposarcoma xenografts but not observed in syngeneic melanoma tumors or human colon cancer xenografts by in situ hybridization or by SAGE analysis.	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('syngeneic melanoma tumors', 'Disease', 'MESH:D008545', (148, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (183, 195))	('human', 'Species', '9606', (177, 182))	('SAGE', 'Gene', '55511', (238, 242))	('liposarcoma', 'Disease', (105, 116))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))	('colon cancer', 'Disease', 'MESH:D015179', (183, 195))	('SAGE', 'Gene', (238, 242))	('human', 'Species', '9606', (86, 91))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('liposarcoma', 'Phenotype', 'HP:0012034', (105, 116))	('melanoma', 'Disease', (92, 100))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('colon cancer', 'Disease', (183, 195))	('mouse', 'Species', '10090', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('liposarcoma', 'Disease', 'MESH:D008080', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('syngeneic melanoma tumors', 'Disease', (148, 173))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('TEM7', 'Var', (27, 31))
203502	24626092	In preclinical cancer models, targeting of TEM8 inhibited tumor angiogenesis and tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('targeting', 'Var', (30, 39))	('TEM8', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('inhibited', 'NegReg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('clinical', 'Species', '191496', (6, 14))	('tumor', 'Disease', (81, 86))
203516	24626092	To address whether the increase in CTECs occurred after treatment with agents thought to selectively reduce tumor angiogenesis, we tested the effect of the VEGF pathway inhibitors AZD7121 (cediranib), sunitnib, and bevacizumab in our H1971 xenograft mouse model.	('cediranib', 'Chemical', 'MESH:C500926', (189, 198))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('AZD7121', 'Var', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CTECs', 'Chemical', '-', (35, 40))	('VEGF', 'Gene', (156, 160))	('bevacizumab', 'Chemical', 'MESH:D000068258', (215, 226))	('tumor', 'Disease', (108, 113))	('H1971', 'CellLine', 'CVCL:A518', (234, 239))	('sunitnib', 'Chemical', '-', (201, 209))	('AZD7121', 'Chemical', '-', (180, 187))	('men', 'Species', '9606', (61, 64))	('tested', 'Reg', (131, 137))	('mouse', 'Species', '10090', (250, 255))
203538	24577086	Pharmacological or genetic inhibition of autophagy sensitized ESCC cells to metformin-induced apoptotic cell death.	('autophagy', 'CPA', (41, 50))	('sensitized', 'Reg', (51, 61))	('inhibition', 'Var', (27, 37))	('genetic inhibition', 'Var', (19, 37))	('metformin', 'Chemical', 'MESH:D008687', (76, 85))
203540	24577086	Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced metformin-induced autophagy and apoptosis, and concomitantly enhanced the inhibitory effect of metformin on cell viability.	('enhanced', 'PosReg', (68, 76))	('metformin', 'Chemical', 'MESH:D008687', (77, 86))	('apoptosis', 'CPA', (109, 118))	('small interfering', 'Var', (13, 30))	('metformin-induced', 'Disease', (77, 94))	('enhanced', 'PosReg', (138, 146))	('metformin', 'Chemical', 'MESH:D008687', (172, 181))	('knockdown', 'Var', (58, 67))
203542	24577086	Ectopic expression of Bcl-2 protected cells from metformin-mediated autophagy and apoptosis.	('Bcl-2', 'Gene', (22, 27))	('Ectopic expression', 'Var', (0, 18))	('metformin', 'Chemical', 'MESH:D008687', (49, 58))	('apoptosis', 'CPA', (82, 91))
203543	24577086	In vivo, metformin downregulated Stat3 activity and Bcl-2 expression, induced apoptosis and autophagy, and inhibited tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('metformin', 'Chemical', 'MESH:D008687', (9, 18))	('apoptosis', 'CPA', (78, 87))	('Bcl-2', 'Gene', (52, 57))	('induced', 'PosReg', (70, 77))	('tumor', 'Disease', (117, 122))	('expression', 'MPA', (58, 68))	('autophagy', 'CPA', (92, 101))	('metformin', 'Var', (9, 18))	('inhibited', 'NegReg', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('Stat3 activity', 'MPA', (33, 47))	('downregulated', 'NegReg', (19, 32))
203544	24577086	Together, inactivation of Stat3-Bcl-2 pathway contributes to metformin-induced growth inhibition of ESCC by facilitating crosstalk between apoptosis and autophagy.	('metformin', 'Chemical', 'MESH:D008687', (61, 70))	('inactivation', 'Var', (10, 22))	('autophagy', 'CPA', (153, 162))	('crosstalk', 'Interaction', (121, 130))	('growth inhibition', 'CPA', (79, 96))	('Stat3-Bcl-2 pathway', 'Pathway', (26, 45))	('apoptosis', 'CPA', (139, 148))
203555	24577086	Metformin has also been reported to cause autophagy, suggesting involvement of metformin in coordinating complex interaction between cell survival and growth.	('Metformin', 'Var', (0, 9))	('metformin', 'Chemical', 'MESH:D008687', (79, 88))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('autophagy', 'CPA', (42, 51))
203561	24577086	Metformin, in a concentration range of 1-20 mM, decreased cell viability of both EC109 and EC9706 cells over 24, 48 and 72 h of continuous exposure, as assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (Figures 1a and b), but only marginally reduced the viability of NE3 cells (Figure 1c).	('cell viability', 'CPA', (58, 72))	('MTT', 'Chemical', 'MESH:C070243', (164, 167))	('3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (169, 229))	('decreased', 'NegReg', (48, 57))	('EC9706', 'Var', (91, 97))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('NE3', 'CellLine', 'CVCL:3554', (302, 305))	('EC109', 'CellLine', 'CVCL:6898', (81, 86))	('EC9706', 'CellLine', 'CVCL:E307', (91, 97))
203562	24577086	In addition, in colony formation assays, metformin decreased colony formation compared with control (Figure 1d).	('metformin', 'Var', (41, 50))	('decreased', 'NegReg', (51, 60))	('colony formation', 'CPA', (61, 77))	('colony formation assays', 'CPA', (16, 39))	('metformin', 'Chemical', 'MESH:D008687', (41, 50))
203567	24577086	Consistent with prior reports, the red-to-green fluorescence ratio was found to decrease when cells were treated with metformin for 48 h (Figure 2b), indicating that metformin causes depolarization of the mitochondrial membrane.	('red-to-green fluorescence ratio', 'MPA', (35, 66))	('metformin', 'Chemical', 'MESH:D008687', (118, 127))	('depolarization', 'MPA', (183, 197))	('metformin', 'Var', (166, 175))	('mitochondrial membrane', 'MPA', (205, 227))	('decrease', 'NegReg', (80, 88))	('metformin', 'Chemical', 'MESH:D008687', (166, 175))
203583	24577086	Moreover, induction of autophagy was identified by two well-established measurements of autophagy, that is, enhancement of Beclin-1, a component of the class III phosphatidylinositol 3-kinase complex essential for autophagosome formation, and degradation of p62, a protein facilitating autophagic degradation of ubiquitinated protein aggregation (Figure 3c).	('Beclin-1', 'Gene', (123, 131))	('enhancement', 'PosReg', (108, 119))	('p62', 'Gene', '23636', (258, 261))	('Beclin-1', 'Gene', '8678', (123, 131))	('p62', 'Gene', (258, 261))	('ubiquitinated protein aggregation', 'Disease', (312, 345))	('ubiquitinated protein aggregation', 'Disease', 'MESH:D066263', (312, 345))	('autophagy', 'CPA', (23, 32))	('degradation', 'Var', (243, 254))
203587	24577086	Given that manipulation of autophagy may improve the efficacy of anticancer therapeutics, we were eager to determine whether the metformin-elicited autophagy in ESCC favored cell survival or cell death.	('metformin', 'Chemical', 'MESH:D008687', (129, 138))	('efficacy', 'MPA', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('improve', 'PosReg', (41, 48))	('manipulation', 'Var', (11, 23))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
203593	24577086	Therefore, to corroborate the cytoprotective action of autophagy, the effects of metformin were examined in cells in which Beclin-1 and autophagy-related gene 5 (Atg5), two critical autophagic regulators, were downregulated by small interfering RNA (siRNA).	('Atg5', 'Gene', '9474', (162, 166))	('autophagy-related gene 5', 'Gene', '9474', (136, 160))	('Beclin-1', 'Gene', (123, 131))	('Beclin-1', 'Gene', '8678', (123, 131))	('Atg5', 'Gene', (162, 166))	('small interfering RNA', 'Var', (227, 248))	('metformin', 'Chemical', 'MESH:D008687', (81, 90))	('downregulated', 'NegReg', (210, 223))	('autophagy-related gene 5', 'Gene', (136, 160))
203595	24577086	In agreement with the data derived from pharmacological inhibitors, knockdown of Beclin-1 or Atg5 by siRNA enhanced cleaved PARP, as assayed by western blot analysis (Figure 4e), indicating that autophagy is cytoprotective for metformin-induced apoptotic cell death.	('Atg5', 'Gene', '9474', (93, 97))	('PARP', 'Gene', '1302', (124, 128))	('Beclin-1', 'Gene', (81, 89))	('Beclin-1', 'Gene', '8678', (81, 89))	('enhanced', 'PosReg', (107, 115))	('Atg5', 'Gene', (93, 97))	('PARP', 'Gene', (124, 128))	('knockdown', 'Var', (68, 77))	('metformin', 'Chemical', 'MESH:D008687', (227, 236))	('autophagy', 'CPA', (195, 204))
203601	24577086	In line with metformin treatment, knockdown of Stat3 not only induced apoptosis, as indicated by increased cleaved PARP (Figure 5b), but also resulted in autophagy, as evidenced by conversion of LC3, enhanced Beclin-1 expression and increased punctate GFP-LC-3 fluorescence intensity (Figures 5b and c).	('conversion', 'Var', (181, 191))	('LC3', 'Gene', '84557', (195, 198))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('PARP', 'Gene', '1302', (115, 119))	('enhanced', 'PosReg', (200, 208))	('apoptosis', 'CPA', (70, 79))	('induced', 'Reg', (62, 69))	('Beclin-1', 'Gene', '8678', (209, 217))	('Stat3', 'Gene', (47, 52))	('PARP', 'Gene', (115, 119))	('knockdown', 'Var', (34, 43))	('expression', 'MPA', (218, 228))	('increased', 'PosReg', (233, 242))	('increased', 'PosReg', (97, 106))	('LC3', 'Gene', (195, 198))	('Beclin-1', 'Gene', (209, 217))	('punctate GFP-LC-3 fluorescence intensity', 'MPA', (243, 283))	('autophagy', 'CPA', (154, 163))	('resulted in', 'Reg', (142, 153))
203602	24577086	Moreover, silencing of Stat3 resulted in enhanced metformin-induced decreases in cell viability, as assessed by MTT assay, compared with control (Supplementary Figure 3).	('metformin', 'Chemical', 'MESH:D008687', (50, 59))	('MTT', 'Chemical', 'MESH:C070243', (112, 115))	('decreases', 'NegReg', (68, 77))	('enhanced', 'PosReg', (41, 49))	('Stat3', 'Gene', (23, 28))	('metformin-induced', 'MPA', (50, 67))	('silencing', 'Var', (10, 19))	('cell viability', 'CPA', (81, 95))
203603	24577086	Thus, these data suggest that Stat3 inactivation is involved in metformin-mediated inhibition of growth, and induced autophagy and apoptosis.	('inhibition', 'NegReg', (83, 93))	('autophagy', 'CPA', (117, 126))	('induced', 'Reg', (109, 116))	('growth', 'CPA', (97, 103))	('metformin', 'Chemical', 'MESH:D008687', (64, 73))	('Stat3', 'Gene', (30, 35))	('apoptosis', 'CPA', (131, 140))	('inactivation', 'Var', (36, 48))
203605	24577086	It is noteworthy that Bcl-2, a direct downstream target of Stat3, was repressed by metformin treatment (Figure 2d), whereas Bcl-2 was further downregulated by metformin in Stat3-silenced cells (Figure 5b).	('metformin', 'Var', (83, 92))	('downregulated', 'NegReg', (142, 155))	('metformin', 'Chemical', 'MESH:D008687', (83, 92))	('Bcl-2', 'Gene', (22, 27))	('metformin', 'Chemical', 'MESH:D008687', (159, 168))
203608	24577086	These data indicate that metformin induces apoptosis and autophagy at least partially via inactivation of Stat3 and repression of Bcl-2.	('Bcl-2', 'Gene', (130, 135))	('apoptosis', 'CPA', (43, 52))	('repression', 'NegReg', (116, 126))	('metformin', 'Var', (25, 34))	('inactivation', 'NegReg', (90, 102))	('Stat3', 'Gene', (106, 111))	('autophagy', 'CPA', (57, 66))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))
203615	24577086	Metformin indeed increased p-AMPK, but decreased p-mTOR (Figure 5f).	('mTOR', 'Gene', (51, 55))	('increased', 'PosReg', (17, 26))	('AMPK', 'Gene', (29, 33))	('AMPK', 'Gene', '5564', (29, 33))	('Metformin', 'Var', (0, 9))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('decreased', 'NegReg', (39, 48))	('mTOR', 'Gene', '2475', (51, 55))
203616	24577086	AMPK knockdown partially inhibited metformin-mediated autophagy, as evidenced by decreased conversion of LC3-I to LC3-II (Figure 5f).	('decreased', 'NegReg', (81, 90))	('knockdown', 'Var', (5, 14))	('metformin', 'Chemical', 'MESH:D008687', (35, 44))	('metformin-mediated autophagy', 'CPA', (35, 63))	('LC3-II', 'Gene', '84557', (114, 120))	('conversion', 'MPA', (91, 101))	('LC3', 'Gene', '84557', (114, 117))	('LC3', 'Gene', (114, 117))	('LC3', 'Gene', '84557', (105, 108))	('AMPK', 'Gene', '5564', (0, 4))	('LC3-II', 'Gene', (114, 120))	('AMPK', 'Gene', (0, 4))	('inhibited', 'NegReg', (25, 34))	('LC3', 'Gene', (105, 108))
203617	24577086	Meanwhile, inactivation of Stat3 by metformin was only marginally blocked by AMPK knockdown (Figure 5f).	('inactivation', 'MPA', (11, 23))	('metformin', 'Chemical', 'MESH:D008687', (36, 45))	('Stat3', 'MPA', (27, 32))	('AMPK', 'Gene', '5564', (77, 81))	('knockdown', 'Var', (82, 91))	('AMPK', 'Gene', (77, 81))
203619	24577086	Together, metformin induces apoptosis and autophagy in ESCC largely via crosstalk between Stat3 and Bcl-2.	('metformin', 'Var', (10, 19))	('induces', 'PosReg', (20, 27))	('autophagy', 'CPA', (42, 51))	('crosstalk', 'Interaction', (72, 81))	('apoptosis', 'CPA', (28, 37))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))
203624	24577086	Consistent with in vitro results that metformin treatment decreased the growth of cultured ESCC cells, metformin administration was very effective in inhibiting tumor growth in vivo throughout the course of treatment (Figure 6a), resulting in decreased tumor size and weight (Figure 6b).	('inhibiting', 'NegReg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('decreased', 'NegReg', (58, 67))	('decreased tumor', 'Disease', 'MESH:D009369', (243, 258))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('metformin', 'Var', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('metformin', 'Chemical', 'MESH:D008687', (38, 47))	('metformin', 'Chemical', 'MESH:D008687', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('decreased tumor', 'Disease', (243, 258))	('tumor', 'Disease', (253, 258))	('tumor', 'Disease', (161, 166))
203630	24577086	IHC revealed decreased expression of p-Stat3, and two Stat3 targets, cyclin D1 and Bcl-2, in tumors from mice treated with metformin, as compared with control mice (Figure 6c), whereas total Stat3 levels remained unchanged (data not shown).	('decreased', 'NegReg', (13, 22))	('Bcl-2', 'Gene', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('metformin', 'Var', (123, 132))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('metformin', 'Chemical', 'MESH:D008687', (123, 132))	('p-Stat3', 'Protein', (37, 44))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mice', 'Species', '10090', (159, 163))	('tumors', 'Disease', (93, 99))	('mice', 'Species', '10090', (105, 109))	('cyclin', 'Gene', (69, 75))	('expression', 'MPA', (23, 33))
203636	24577086	We also propose a novel mechanism in which metformin inactivates Stat3 and subsequently represses Bcl-2 to induce autophagy and apoptosis (Figure 7).	('metformin', 'Var', (43, 52))	('metformin', 'Chemical', 'MESH:D008687', (43, 52))	('induce', 'PosReg', (107, 113))	('autophagy', 'CPA', (114, 123))	('inactivates', 'NegReg', (53, 64))	('represses', 'NegReg', (88, 97))	('Stat3', 'Protein', (65, 70))	('apoptosis', 'CPA', (128, 137))	('Bcl-2', 'MPA', (98, 103))
203639	24577086	Although a previous report demonstrates that metformin inhibits proliferation of ESCC cells (KYSE30 and KYSE70) in vitro, our study corroborates and extends these studies to the roles of autophagy and apoptosis and to an in vivo ESCC model.	('inhibits', 'NegReg', (55, 63))	('ESCC', 'Disease', (81, 85))	('metformin', 'Var', (45, 54))	('proliferation', 'CPA', (64, 77))	('autophagy', 'CPA', (187, 196))	('KYSE70', 'Var', (104, 110))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('apoptosis', 'CPA', (201, 210))	('KYSE30', 'Var', (93, 99))
203640	24577086	Given that pharmacological or genetic inhibition of autophagy leads to increased metformin-induced apoptosis, our present data argue that metformin-mediated autophagy is a prosurvival mechanism rather than a cell death mechanism.	('autophagy', 'CPA', (52, 61))	('apoptosis', 'CPA', (99, 108))	('metformin', 'Chemical', 'MESH:D008687', (81, 90))	('inhibition', 'Var', (38, 48))	('increased', 'PosReg', (71, 80))	('metformin', 'Chemical', 'MESH:D008687', (138, 147))	('metformin-induced', 'MPA', (81, 98))
203642	24577086	In contrast, autophagy inhibition by silencing LC3 or Atg5 decreases apoptosis and inhibits the metformin inhibitory effects on melanoma cells.	('LC3', 'Gene', '84557', (47, 50))	('metformin inhibitory effects', 'MPA', (96, 124))	('LC3', 'Gene', (47, 50))	('decreases', 'NegReg', (59, 68))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('inhibits', 'NegReg', (83, 91))	('silencing', 'Var', (37, 46))	('Atg5', 'Gene', '9474', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('apoptosis', 'CPA', (69, 78))	('metformin', 'Chemical', 'MESH:D008687', (96, 105))	('Atg5', 'Gene', (54, 58))	('autophagy', 'CPA', (13, 22))	('melanoma', 'Disease', (128, 136))
203650	24577086	Our in vitro and in vivo findings suggest that metformin exerts antineoplastic activities through downregulation of Stat3 signaling; that is, Stat3 modulates the autophagic process induced by metformin in addition to its participation in cell proliferation and apoptosis.	('Stat3', 'Var', (142, 147))	('downregulation', 'NegReg', (98, 112))	('metformin', 'Chemical', 'MESH:D008687', (47, 56))	('autophagic process', 'CPA', (162, 180))	('modulates', 'Reg', (148, 157))	('antineoplastic activities', 'CPA', (64, 89))	('metformin', 'Chemical', 'MESH:D008687', (192, 201))
203653	24577086	Furthermore, siRNA-mediated knockdown of Stat3 exacerbates metformin-mediated Bcl-2 repression.	('Stat3', 'Gene', (41, 46))	('metformin', 'Chemical', 'MESH:D008687', (59, 68))	('exacerbates', 'PosReg', (47, 58))	('knockdown', 'Var', (28, 37))	('metformin-mediated Bcl-2 repression', 'MPA', (59, 94))
203654	24577086	Prior reports have shown that inactivation of Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis.	('apoptosis', 'CPA', (114, 123))	('Stat3', 'Gene', (46, 51))	('inactivation', 'Var', (30, 42))	('Bax', 'Gene', (82, 85))	('expression', 'MPA', (86, 96))	('induction', 'Reg', (101, 110))	('Bax', 'Gene', '581', (82, 85))	('altered', 'Reg', (68, 75))
203656	24577086	Few studies have directly defined the mechanism of how Stat3 triggers autophagy in cancer cells.	('autophagy', 'CPA', (70, 79))	('Stat3', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('triggers', 'Reg', (61, 69))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
203659	24577086	Therefore, repression of Bcl-2 may dissociate the Bcl-2/Beclin-1 complex and thereby increase cellular autophagy.	('Bcl-2', 'Gene', (25, 30))	('dissociate', 'NegReg', (35, 45))	('cellular autophagy', 'CPA', (94, 112))	('Beclin-1', 'Gene', (56, 64))	('repression', 'Var', (11, 21))	('Beclin-1', 'Gene', '8678', (56, 64))	('increase', 'PosReg', (85, 93))
203660	24577086	It is also evident that Bcl-2 siRNA induces expression of Beclin-1 and Atg5 autophagy-promoting proteins in breast cancer cells, suggesting that inhibition of Bcl-2 induces autophagy through induction of Beclin-1 and Atg5.	('Beclin-1', 'Gene', '8678', (204, 212))	('expression', 'MPA', (44, 54))	('Atg5', 'Gene', '9474', (217, 221))	('Bcl-2', 'Gene', (159, 164))	('Atg5', 'Gene', (71, 75))	('Atg5', 'Gene', (217, 221))	('induces', 'Reg', (165, 172))	('Beclin-1', 'Gene', (58, 66))	('Atg5', 'Gene', '9474', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Beclin-1', 'Gene', '8678', (58, 66))	('autophagy', 'CPA', (173, 182))	('Beclin-1', 'Gene', (204, 212))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('inhibition', 'Var', (145, 155))	('breast cancer', 'Disease', (108, 121))	('induction', 'PosReg', (191, 200))
203661	24577086	In our study, downregulation of Bcl-2 by metformin treatment/Stat3 inactivation leads to liberated or induced Beclin-1/Atg5, thereby triggering autophagy.	('inactivation', 'Var', (67, 79))	('triggering', 'Reg', (133, 143))	('Bcl-2', 'Gene', (32, 37))	('Atg5', 'Gene', '9474', (119, 123))	('Beclin-1', 'Gene', (110, 118))	('Beclin-1', 'Gene', '8678', (110, 118))	('downregulation', 'NegReg', (14, 28))	('metformin', 'Chemical', 'MESH:D008687', (41, 50))	('Atg5', 'Gene', (119, 123))	('autophagy', 'CPA', (144, 153))
203662	24577086	This observation was further confirmed by showing that ectopic expression of Bcl-2 in ESCC cells attenuated metformin-induced autophagy.	('metformin-induced', 'MPA', (108, 125))	('Bcl-2', 'Gene', (77, 82))	('metformin', 'Chemical', 'MESH:D008687', (108, 117))	('attenuated', 'NegReg', (97, 107))	('ectopic expression', 'Var', (55, 73))
203669	24577086	However, AMPK activation does not play a prominent role in metformin-mediated Stat3 inactivation, as metformin robustly inhibits the Stat3 pathway in AMPK-silenced cells, although we cannot exclude direct regulation of cell survival and cell death by AMPK (to Beclin for example) or through other pathways that may also contribute to cell growth and survival (Figure 7).	('inhibits', 'NegReg', (120, 128))	('AMPK', 'Gene', (9, 13))	('cell survival', 'CPA', (219, 232))	('AMPK', 'Gene', '5564', (9, 13))	('cell death', 'CPA', (237, 247))	('Stat3 pathway', 'Pathway', (133, 146))	('AMPK', 'Gene', (150, 154))	('metformin', 'Chemical', 'MESH:D008687', (59, 68))	('AMPK', 'Gene', (251, 255))	('metformin', 'Var', (101, 110))	('AMPK', 'Gene', '5564', (150, 154))	('AMPK', 'Gene', '5564', (251, 255))	('metformin', 'Chemical', 'MESH:D008687', (101, 110))
203696	24577086	After undergoing deparaffinization and rehydration, endogenous peroxidase blocking and antigen retrieval, specimens were incubated overnight at 4 C with anti-p-Stat3 polyclonal antibody (1 : 200), anti-Stat3 polyclonal antibody (1 : 200), anti-cyclin D1 polyclonal antibody, anti-Bcl-2 polyclonal antibody (1 : 100), anti-p62 polyclonal antibody (1 : 200) or anti-PCNA polyclonal antibody (1 : 200).	('p62', 'Gene', (322, 325))	('anti-Stat3', 'Var', (197, 207))	('anti-p-Stat3', 'Var', (153, 165))	('paraffin', 'Chemical', 'MESH:D010232', (19, 27))	('p62', 'Gene', '23636', (322, 325))
203800	20363410	Porfimer sodium PDT with or without previous endoscopic resection has been used with mixed results in this setting, with remission of cancer seen in 20 of 24 (83%) using endoscopic resection followed by PDT, but in only 4 of 9 (44%) subjects using PDT alone.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('endoscopic', 'Var', (170, 180))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
203869	17326708	Esophageal biopsies from 243 patients with BE were evaluated at baseline for TP53 and CDKN2A (p16) alterations, tetraploidy, and aneuploidy using sequencing; loss of heterozygosity (LOH); methylation-specific PCR; and flow cytometry.	('patients', 'Species', '9606', (29, 37))	('aneuploidy', 'Disease', 'MESH:D000782', (129, 139))	('loss of heterozygosity', 'Var', (158, 180))	('p16', 'Gene', '1029', (94, 97))	('CDKN2A', 'Gene', '1029', (86, 92))	('BE', 'Phenotype', 'HP:0100580', (43, 45))	('alterations', 'Var', (99, 110))	('aneuploidy', 'Disease', (129, 139))	('p16', 'Gene', (94, 97))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('CDKN2A', 'Gene', (86, 92))
203870	17326708	At 10 y, all abnormalities, except CDKN2A mutation and methylation, contributed to EA risk significantly by univariate analysis, ranging from 17p LOH (relative risk [RR] = 10.6; 95% confidence interval [CI] 5.2-21.3, p < 0.001) to 9p LOH (RR = 2.6; 95% CI 1.1-6.0, p = 0.03).	('CDKN2A', 'Gene', '1029', (35, 41))	('to 9', 'Species', '1214577', (228, 232))	('EA', 'Phenotype', 'HP:0011459', (83, 85))	('mutation', 'Var', (42, 50))	('contributed', 'Reg', (68, 79))	('methylation', 'Var', (55, 66))	('CDKN2A', 'Gene', (35, 41))
203875	17326708	A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone.	('CDKN2A', 'Gene', '1029', (121, 127))	('abnormalities', 'Var', (50, 63))	('TP53', 'Gene', '7157', (115, 119))	('EA', 'Phenotype', 'HP:0011459', (80, 82))	('TP53', 'Gene', (115, 119))	('CDKN2A', 'Gene', (121, 127))
203876	17326708	NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.	('reduced', 'NegReg', (27, 34))	('molecular abnormalities', 'Disease', 'MESH:C567116', (91, 114))	('patients', 'Species', '9606', (58, 66))	('EA', 'Phenotype', 'HP:0011459', (35, 37))	('molecular abnormalities', 'Disease', (91, 114))	('NSAIDs', 'Var', (0, 6))
203880	17326708	If these altered cells also acquire mutations that allow them to spread around the body, a malignant tumor or cancer results.	('cancer', 'Disease', (110, 116))	('results', 'Reg', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('malignant tumor', 'Disease', (91, 106))	('spread around the body', 'CPA', (65, 87))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('malignant tumor', 'Disease', 'MESH:D018198', (91, 106))
203890	17326708	These proteins normally stop cells dividing but are often inactivated in cancer cells by mutation of one of the two gene copies that encode each of them and also loss of the other copy (so-called "loss of heterozygosity" or LOH).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('loss', 'NegReg', (162, 166))	('inactivated', 'NegReg', (58, 69))	('mutation', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
203892	17326708	After 10 y, the participants whose tissue samples had LOH of the short arms (p) of Chromosome 17 or 9 (the sites of the genes encoding TP53 and CDKN2A, respectively), or an altered DNA content, were more likely to have developed esophageal cancer than those without these abnormalities; those whose samples contained all three abnormalities had the highest risk of developing esophageal cancer.	('developed', 'PosReg', (219, 228))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('TP53', 'Gene', '7157', (135, 139))	('esophageal cancer', 'Disease', (376, 393))	('altered', 'Reg', (173, 180))	('CDKN2A', 'Gene', (144, 150))	('DNA', 'MPA', (181, 184))	('esophageal cancer', 'Disease', 'MESH:D004938', (376, 393))	('short arms', 'Phenotype', 'HP:0009824', (65, 75))	('TP53', 'Gene', (135, 139))	('esophageal cancer', 'Disease', (229, 246))	('CDKN2A', 'Gene', '1029', (144, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (229, 246))	('LOH', 'Var', (54, 57))	('participants', 'Species', '9606', (16, 28))
203900	17326708	Identification of inherited, highly penetrant mutations in some cancer-susceptibility genes is being incorporated into clinical practice as well as cancer-prevention strategies for patients with many familial cancer syndromes, including inherited breast cancer, hereditary nonpolyposis colon cancer, and adenomatous polyposis coli.	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('familial cancer syndromes', 'Disease', (200, 225))	('breast cancer', 'Disease', (247, 260))	('patients', 'Species', '9606', (181, 189))	('cancer', 'Disease', (254, 260))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (200, 225))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('colon cancer', 'Phenotype', 'HP:0003003', (286, 298))	('cancer', 'Disease', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('hereditary nonpolyposis colon cancer', 'Disease', (262, 298))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (304, 330))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (304, 330))	('adenomatous polyposis coli', 'Disease', (304, 330))	('cancer', 'Disease', (148, 154))	('hereditary nonpolyposis colon cancer', 'Disease', 'MESH:D003123', (262, 298))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('cancer', 'Disease', (209, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('hereditary nonpolyposis colon cancer', 'Phenotype', 'HP:0006716', (262, 298))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
203908	17326708	Analysis of genetic progression of BE has identified abnormalities in the tumor-suppressor genes TP53 and CDKN2A, as well as DNA content abnormalities (tetraploidy and aneuploidy) as critical events in the evolution of EA.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('TP53', 'Gene', '7157', (97, 101))	('EA', 'Phenotype', 'HP:0011459', (219, 221))	('tetraploidy and aneuploidy', 'Disease', 'MESH:D057891', (152, 178))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('abnormalities', 'Var', (53, 66))	('TP53', 'Gene', (97, 101))	('CDKN2A', 'Gene', (106, 112))	('tumor', 'Disease', (74, 79))	('abnormalities', 'Var', (137, 150))	('CDKN2A', 'Gene', '1029', (106, 112))	('BE', 'Phenotype', 'HP:0100580', (35, 37))
203932	17326708	For each baseline endoscopy, samples were characterized for 17p LOH spanning TP53, TP53 mutations, DNA content abnormalities including tetraploidy and aneuploidy, 9p LOH spanning the CDKN2A (p16) locus, CDKN2A promoter methylation, and CDKN2A mutation in one biopsy every 2 cm in the Barrett's segment (average = 3.2, range 1-11 biopsies analyzed per study participant).	('TP53', 'Gene', '7157', (83, 87))	('CDKN2A', 'Gene', (183, 189))	('tetraploidy and aneuploidy', 'Disease', 'MESH:D057891', (135, 161))	('mutation', 'Var', (243, 251))	('CDKN2A', 'Gene', (236, 242))	('TP53', 'Gene', (83, 87))	('p16', 'Gene', '1029', (191, 194))	('mutations', 'Var', (88, 97))	('CDKN2A', 'Gene', '1029', (183, 189))	('CDKN2A', 'Gene', (203, 209))	('TP53', 'Gene', (77, 81))	('CDKN2A', 'Gene', '1029', (236, 242))	('CDKN2A', 'Gene', '1029', (203, 209))	('TP53', 'Gene', '7157', (77, 81))	('p16', 'Gene', (191, 194))	('participant', 'Species', '9606', (357, 368))
203937	17326708	Thirteen microsatellite loci were evaluated, including the 17p loci D17S1298 (3.87 Mbp), D17S1537 (6.10 Mbp), TP53-ALU (AAAAT)n in intron 1 (7.77 Mbp), TP53 (CA)n (7.77 Mbp), D17S786 (9.01 Mbp), D17S974 (10.72 Mbp), D17S1303 (11.06 Mbp), and Chromosome 9p loci D9S2169 (5.19 Mbp), D9S935 (5.19 Mbp), D9S925 (18.28 Mbp), D9S932 (24.43 Mbp), D9S1121 (25.39 Mbp), and D9S1118 (31.92 Mbp).	('Mbp', 'Gene', '4155', (210, 213))	('D9S925', 'Var', (300, 306))	('S974', 'CellLine', 'CVCL:U295', (198, 202))	('Mbp', 'Gene', '4155', (83, 86))	('Mbp', 'Gene', (104, 107))	('Mbp', 'Gene', '4155', (146, 149))	('D9S1118', 'Var', (365, 372))	('Mbp', 'Gene', (334, 337))	('D9S935', 'Var', (281, 287))	('Mbp', 'Gene', '4155', (169, 172))	('TP53', 'Gene', '7157', (152, 156))	('Mbp', 'Gene', '4155', (232, 235))	('Mbp', 'Gene', '4155', (314, 317))	('Mbp', 'Gene', (380, 383))	('D17S974', 'Var', (195, 202))	('D17S786', 'Var', (175, 182))	('D9S935', 'CellLine', 'CVCL:V785', (281, 287))	('Mbp', 'Gene', (294, 297))	('Mbp', 'Gene', '4155', (334, 337))	('TP53', 'Gene', '7157', (110, 114))	('Mbp', 'Gene', '4155', (104, 107))	('Mbp', 'Gene', '4155', (380, 383))	('Mbp', 'Gene', '4155', (294, 297))	('D9S932', 'Var', (320, 326))	('Mbp', 'Gene', (275, 278))	('Mbp', 'Gene', (189, 192))	('Mbp', 'Gene', (355, 358))	('TP53', 'Gene', (152, 156))	('Mbp', 'Gene', (210, 213))	('Mbp', 'Gene', '4155', (275, 278))	('Mbp', 'Gene', '4155', (189, 192))	('TP53', 'Gene', (110, 114))	('Mbp', 'Gene', (169, 172))	('Mbp', 'Gene', (83, 86))	('D9S932', 'CellLine', 'CVCL:BS91', (320, 326))	('Mbp', 'Gene', (232, 235))	('D9S2169', 'Var', (261, 268))	('Mbp', 'Gene', (146, 149))	('Mbp', 'Gene', (314, 317))	('Mbp', 'Gene', '4155', (355, 358))	('D9S1121', 'Var', (340, 347))	('S2169', 'CellLine', 'CVCL:K930', (263, 268))
203943	17326708	This patient subset was representative of the entire 243-patient cohort with no statistically significant difference in follow-up time, sex, age, segment length, and cancer outcome between the methylation-assayed group and the non-assayed group.	('methylation-assayed', 'Var', (193, 212))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('patient', 'Species', '9606', (5, 12))	('patient', 'Species', '9606', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
203950	17326708	TP53 mutations from patients with HGD were reported by Prevo et al., and additional new TP53 mutations not previously reported are available from the corresponding author (PCG).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', '7157', (88, 92))	('patients', 'Species', '9606', (20, 28))	('TP53', 'Gene', (88, 92))
203969	17326708	At 10 y, each molecular and DNA content abnormality, when analyzed alone in a patient at baseline, made a significant contribution to prediction of EA risk, with the exception of CDKN2A mutation (10-y RR = 1.8; 95% CI 0.8-4.1, p = 0.13) and CDKN2A methylation (RR = 2.1; 95% CI 0.8-4.1, p = 0.09).	('CDKN2A', 'Gene', '1029', (179, 185))	('patient', 'Species', '9606', (78, 85))	('EA', 'Phenotype', 'HP:0011459', (148, 150))	('CDKN2A', 'Gene', (241, 247))	('methylation', 'Var', (248, 259))	('CDKN2A', 'Gene', (179, 185))	('CDKN2A', 'Gene', '1029', (241, 247))	('mutation', 'Var', (186, 194))
203971	17326708	Although TP53 mutation was highly significant in univariate analysis, it became nonsignificant for EA risk prediction when 17p LOH was included in the model.	('TP53', 'Gene', '7157', (9, 13))	('mutation', 'Var', (14, 22))	('EA', 'Phenotype', 'HP:0011459', (99, 101))	('TP53', 'Gene', (9, 13))
203972	17326708	Tetraploidy was the next selected marker, followed by aneuploidy.	('Tetraploidy', 'Var', (0, 11))	('aneuploidy', 'Disease', 'MESH:D000782', (54, 64))	('aneuploidy', 'Disease', (54, 64))
203973	17326708	CDKN2A methylation provided marginal additional risk but was not statistically significant in the multivariate model (p = 0.28).	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))	('methylation', 'Var', (7, 18))
203974	17326708	CDKN2A mutation did not provide significant additional contribution to EA risk prediction.	('EA', 'Phenotype', 'HP:0011459', (71, 73))	('mutation', 'Var', (7, 15))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))
203975	17326708	The final selected molecular markers that independently contributed to EA risk prediction included 17p LOH, tetraploidy, aneuploidy, and 9p LOH (Table 3).	('aneuploidy', 'Disease', (121, 131))	('tetraploidy', 'Var', (108, 119))	('17p LOH', 'Var', (99, 106))	('9p LOH', 'Var', (137, 143))	('aneuploidy', 'Disease', 'MESH:D000782', (121, 131))	('EA', 'Phenotype', 'HP:0011459', (71, 73))
203976	17326708	TP53 mutation showed strong association with 17p LOH (Phi = 0.63) and aneuploidy (Phi = 0.56).	('aneuploidy', 'Disease', (70, 80))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('association', 'Interaction', (28, 39))	('aneuploidy', 'Disease', 'MESH:D000782', (70, 80))	('17p LOH', 'Disease', (45, 52))	('mutation', 'Var', (5, 13))
203977	17326708	17p LOH is also strongly associated with aneuploidy (Phi = 0.56).	('aneuploidy', 'Disease', 'MESH:D000782', (41, 51))	('17p LOH', 'Var', (0, 7))	('aneuploidy', 'Disease', (41, 51))	('associated', 'Reg', (25, 35))
203978	17326708	Although TP53 mutation was significantly related to EA risk in univariate analysis, it was strongly associated with 17p LOH and aneuploidy, which may explain why it was not retained in the model selection.	('aneuploidy', 'Disease', (128, 138))	('EA', 'Phenotype', 'HP:0011459', (52, 54))	('associated', 'Reg', (100, 110))	('TP53', 'Gene', '7157', (9, 13))	('mutation', 'Var', (14, 22))	('17p LOH', 'Disease', (116, 123))	('TP53', 'Gene', (9, 13))	('related', 'Reg', (41, 48))	('aneuploidy', 'Disease', 'MESH:D000782', (128, 138))
203979	17326708	The adjusted RRs for future EA at 10 y, using the final selected model with 17p LOH, tetraploidy, aneuploidy, and 9p LOH, were RR = 5.4 (95% CI 2.5-12.0), RR = 2.9 (95% CI 1.4-5.9), RR = 3.4 (95% CI 1.6-7.1), and RR = 2.4 (95% CI 1.0-5.5), respectively (Table 3).	('EA', 'Phenotype', 'HP:0011459', (28, 30))	('aneuploidy', 'Disease', (98, 108))	('aneuploidy', 'Disease', 'MESH:D000782', (98, 108))	('tetraploidy', 'Var', (85, 96))
203983	17326708	Tetraploidy and aneuploidy are two measures of DNA content and were treated as a single variable in this section (Figures 1 and 2; Table 4).	('aneuploidy', 'Disease', (16, 26))	('Tetraploidy', 'Var', (0, 11))	('aneuploidy', 'Disease', 'MESH:D000782', (16, 26))
203988	17326708	Participants (22/243) with all three abnormalities (17p LOH, DNA content abnormality, and 9p LOH) had EA incidence rates of 40.2% and 79.12% at 2 and 6 y, respectively.	('EA', 'Phenotype', 'HP:0011459', (102, 104))	('DNA content', 'MPA', (61, 72))	('Participants', 'Species', '9606', (0, 12))	('9p LOH', 'Var', (90, 96))	('17p LOH', 'Var', (52, 59))
203995	17326708	This protective effect was significant in patients with baseline 17p LOH (p = 0.004, Gehan-Wilcoxon test), DNA content abnormalities (tetraploidy and/or aneuploidy) (p = 0.01), and 9p LOH (p <0.001) (Figure 1A-C).	('17p', 'Disease', (65, 68))	('aneuploidy', 'Disease', (153, 163))	('9p LOH', 'Var', (181, 187))	('tetraploidy', 'Var', (134, 145))	('patients', 'Species', '9606', (42, 50))	('DNA', 'MPA', (107, 110))	('aneuploidy', 'Disease', 'MESH:D000782', (153, 163))
204008	17326708	Our results are consistent, however, with previous longitudinal studies of single biomarkers from other centers, including TP53 abnormalities and flow cytometry.	('TP53', 'Gene', '7157', (123, 127))	('abnormalities', 'Var', (128, 141))	('TP53', 'Gene', (123, 127))
204009	17326708	To our knowledge, no previous studies in patients with BE or any other human premalignant condition have prospectively evaluated the contributions of TP53 and CDKN2A gene inactivation (methylation, mutation, and LOH) and DNA content abnormalities in combination with candidate interventions to assess their potential utility as biomarkers for future cancer risk and cancer prevention.	('BE', 'Phenotype', 'HP:0100580', (55, 57))	('TP53', 'Gene', (150, 154))	('human', 'Species', '9606', (71, 76))	('CDKN2A', 'Gene', '1029', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('cancer', 'Disease', 'MESH:D009369', (350, 356))	('abnormalities', 'Var', (233, 246))	('cancer', 'Disease', (366, 372))	('cancer', 'Disease', (350, 356))	('patients', 'Species', '9606', (41, 49))	('mutation', 'Var', (198, 206))	('TP53', 'Gene', '7157', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('CDKN2A', 'Gene', (159, 165))	('inactivation', 'NegReg', (171, 183))
204011	17326708	Perturbations of these genes and the pathways in which they act have profound, mechanistic associations with human cancer based upon evidence accumulated in numerous laboratories.	('numerous laboratories', 'Disease', (157, 178))	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('numerous laboratories', 'Disease', 'MESH:D007757', (157, 178))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Perturbations', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
204012	17326708	TP53 abnormalities typically arise in clones with CDKN2A abnormalities, creating a condition permissive for clonal variants, including tetraploid and aneuploid populations, to survive and expand.	('arise', 'Reg', (29, 34))	('TP53', 'Gene', '7157', (0, 4))	('CDKN2A', 'Gene', (50, 56))	('TP53', 'Gene', (0, 4))	('CDKN2A', 'Gene', '1029', (50, 56))	('abnormalities', 'Var', (5, 18))	('abnormalities', 'Var', (57, 70))
204014	17326708	We simultaneously measured DNA content abnormalities (tetraploidy and aneuploidy), inactivation of TP53 (mutation and LOH), and inactivation of CDKN2A (mutation, methylation, and LOH), all of which have been shown to be mechanistically related to neoplastic progression in BE.	('TP53', 'Gene', (99, 103))	('DNA content abnormalities', 'MPA', (27, 52))	('related', 'Reg', (236, 243))	('inactivation', 'NegReg', (83, 95))	('CDKN2A', 'Gene', (144, 150))	('TP53', 'Gene', '7157', (99, 103))	('tetraploidy and aneuploidy', 'Disease', 'MESH:D057891', (54, 80))	('BE', 'Phenotype', 'HP:0100580', (273, 275))	('inactivation', 'Var', (128, 140))	('CDKN2A', 'Gene', '1029', (144, 150))	('neoplastic progression', 'CPA', (247, 269))
204015	17326708	TP53 abnormalities have been shown in numerous studies to be predictive of EA.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('abnormalities', 'Var', (5, 18))	('EA', 'Phenotype', 'HP:0011459', (75, 77))
204016	17326708	In the present study, TP53 mutations were strongly associated with 17p LOH and aneuploidy and were not selected in the multivariate analysis.	('mutations', 'Var', (27, 36))	('17p LOH', 'Disease', (67, 74))	('aneuploidy', 'Disease', 'MESH:D000782', (79, 89))	('associated', 'Reg', (51, 61))	('TP53', 'Gene', '7157', (22, 26))	('aneuploidy', 'Disease', (79, 89))	('TP53', 'Gene', (22, 26))
204017	17326708	LOH could also be selected as the "second hit" for inactivating TP53 and CDKN2A.	('CDKN2A', 'Gene', '1029', (73, 79))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('inactivating', 'Var', (51, 63))	('CDKN2A', 'Gene', (73, 79))
204019	17326708	reported that clonal diversity measures derived from evolutionary biology retained significant independent EA risk prediction with 17p (TP53) LOH and abnormal ploidy, but 9p LOH became nonsignificant when incorporating evolutionary variables.	('EA', 'Phenotype', 'HP:0011459', (107, 109))	('abnormal ploidy', 'Var', (150, 165))	('LOH', 'NegReg', (142, 145))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))
204021	17326708	For example, expansion of a CDKN2A abnormal clone that is otherwise genetically stable may homogenize the neoplasm, minimizing diversity on which natural selection might act to promote progression.	('neoplasm', 'Disease', 'MESH:D009369', (106, 114))	('neoplasm', 'Phenotype', 'HP:0002664', (106, 114))	('minimizing', 'NegReg', (116, 126))	('diversity', 'MPA', (127, 136))	('CDKN2A', 'Gene', (28, 34))	('expansion', 'Var', (13, 22))	('CDKN2A', 'Gene', '1029', (28, 34))	('neoplasm', 'Disease', (106, 114))
204022	17326708	In contrast, expansion of a CDKN2A abnormal clone predisposed to genetic instability through either environmental or somatic genetic factors would result in increased diversity that could promote progression.	('diversity', 'MPA', (167, 176))	('promote', 'PosReg', (188, 195))	('progression', 'CPA', (196, 207))	('CDKN2A', 'Gene', (28, 34))	('expansion', 'Var', (13, 22))	('increased', 'PosReg', (157, 166))	('CDKN2A', 'Gene', '1029', (28, 34))
204026	17326708	Identification of host genetic factors, including inherited, highly penetrant mutations in cancer susceptibility for hereditary breast cancer (BRCA1, BRCA2), familial polyposis coli (APC), and those predisposing to hereditary non-polyposis colon cancer, among others, in combination with knowledge of environmental factors, have the potential to reduce cancer morbidity and mortality by early detection and prevention.	('familial polyposis coli', 'Disease', 'MESH:D011125', (158, 181))	('colon cancer', 'Phenotype', 'HP:0003003', (240, 252))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (117, 141))	('cancer', 'Disease', (135, 141))	('hereditary non-polyposis colon cancer', 'Phenotype', 'HP:0006716', (215, 252))	('reduce', 'NegReg', (346, 352))	('cancer', 'Disease', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('BRCA2', 'Gene', (150, 155))	('hereditary non-polyposis colon cancer', 'Disease', (215, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('hereditary non-polyposis colon cancer', 'Disease', 'MESH:D015179', (215, 252))	('hereditary breast cancer', 'Disease', (117, 141))	('familial polyposis coli', 'Disease', (158, 181))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('BRCA2', 'Gene', '675', (150, 155))	('BRCA1', 'Gene', '672', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (91, 97))	('BRCA1', 'Gene', (143, 148))	('cancer', 'Disease', (353, 359))	('APC', 'Disease', 'MESH:D011125', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('APC', 'Disease', (183, 186))
204034	17326708	It has recently been shown that the absolute size of aneuploid clones and clones with TP53 lesions is a risk factor for progression to EA.	('lesions', 'Var', (91, 98))	('TP53', 'Gene', '7157', (86, 90))	('aneuploid', 'Var', (53, 62))	('TP53', 'Gene', (86, 90))	('EA', 'Phenotype', 'HP:0011459', (135, 137))
204056	33232284	Loss of FBP1 promotes proliferation, migration, and invasion by regulating fatty acid metabolism in esophageal squamous cell carcinoma Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in China.	('FBP1', 'Gene', (8, 12))	('promotes', 'PosReg', (13, 21))	('regulating', 'Reg', (64, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('fatty acid', 'Chemical', 'MESH:D005227', (75, 85))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (146, 169))	('invasion', 'CPA', (52, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (100, 134))	('migration', 'CPA', (37, 46))	('squamous cell carcinoma', 'Disease', (146, 169))	('proliferation', 'CPA', (22, 35))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 134))	('FBP1', 'Gene', '2203', (8, 12))	('Loss', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('fatty acid metabolism', 'MPA', (75, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('esophageal squamous cell carcinoma', 'Disease', (100, 134))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancers', 'Disease', (203, 210))
204061	33232284	We found loss of FBP1 promoted ESCC cell proliferation, migration and invasion, which correlated with the activated fatty acid metabolism in vitro.	('migration', 'CPA', (56, 65))	('promoted', 'PosReg', (22, 30))	('ESCC cell proliferation', 'CPA', (31, 54))	('FBP1', 'Gene', (17, 21))	('loss', 'Var', (9, 13))	('fatty acid', 'Chemical', 'MESH:D005227', (116, 126))	('invasion', 'CPA', (70, 78))	('FBP1', 'Gene', '2203', (17, 21))
204063	33232284	Furthermore, FBP1 was found to be directly targeted by miR-18b-5p in ESCC cells.	('FBP1', 'Gene', '2203', (13, 17))	('FBP1', 'Gene', (13, 17))	('miR-18b-5p', 'Chemical', '-', (55, 65))	('miR-18b-5p', 'Var', (55, 65))	('targeted', 'Reg', (43, 51))
204064	33232284	In addition, miR-18b-5p inhibitor treatment obviously reversed the increased fatty acid metabolism induced by loss of FBP1 in ESCC cells.	('miR-18b-5p', 'Chemical', '-', (13, 23))	('fatty acid metabolism', 'MPA', (77, 98))	('FBP1', 'Gene', (118, 122))	('loss', 'Var', (110, 114))	('increased', 'PosReg', (67, 76))	('fatty acid', 'Chemical', 'MESH:D005227', (77, 87))	('FBP1', 'Gene', '2203', (118, 122))
204085	33232284	In this study, we found loss of FBP1 promoted ESCC cell proliferation, migration, and invasion in vitro, which was involved in the regulation of miR-18b-5p.	('loss', 'Var', (24, 28))	('FBP1', 'Gene', (32, 36))	('promoted', 'PosReg', (37, 45))	('miR-18b-5p', 'Chemical', '-', (145, 155))	('migration', 'CPA', (71, 80))	('FBP1', 'Gene', '2203', (32, 36))	('ESCC cell proliferation', 'CPA', (46, 69))	('invasion', 'CPA', (86, 94))
204086	33232284	Moreover, the interaction of miR-18b-5p and FBP1 could regulate cell function through inhibiting fatty acid metabolism in ESCC cells.	('FBP1', 'Gene', (44, 48))	('interaction', 'Interaction', (14, 25))	('FBP1', 'Gene', '2203', (44, 48))	('cell function', 'CPA', (64, 77))	('inhibiting', 'NegReg', (86, 96))	('fatty acid', 'Chemical', 'MESH:D005227', (97, 107))	('miR-18b-5p', 'Chemical', '-', (29, 39))	('regulate', 'Reg', (55, 63))	('miR-18b-5p', 'Var', (29, 39))	('fatty acid metabolism', 'MPA', (97, 118))
204095	33232284	To investigate the effect of FBP1 expression on ESCC cells function, Eca109 and ec9706 cells were treated with shFBP1 for 0, 24, 48, 72 h. The results showed that Loss of FBP1 significantly enhanced ESCC cell proliferation compared with the control (Figure 2A and 1B).	('FBP1', 'Gene', '2203', (171, 175))	('Loss', 'Var', (163, 167))	('FBP1', 'Gene', (113, 117))	('FBP1', 'Gene', (29, 33))	('ESCC cell proliferation', 'CPA', (199, 222))	('ec9706', 'CellLine', 'CVCL:E307', (80, 86))	('FBP1', 'Gene', (171, 175))	('FBP1', 'Gene', '2203', (29, 33))	('FBP1', 'Gene', '2203', (113, 117))	('enhanced', 'PosReg', (190, 198))
204096	33232284	We also showed the validation of knockdown of FBP1 in Eca109 cells following shFBP1 transfection for 48 h (Figure 2C).	('FBP1', 'Gene', (46, 50))	('FBP1', 'Gene', '2203', (79, 83))	('knockdown', 'Var', (33, 42))	('FBP1', 'Gene', '2203', (46, 50))	('FBP1', 'Gene', (79, 83))	('transfection', 'Var', (84, 96))
204100	33232284	Furthermore, loss of FBP1 lead to an increase of the content of triglycerides in ESCC cells when compared with the control (Figure 3B).	('FBP1', 'Gene', '2203', (21, 25))	('increase of the content of triglycerides', 'Phenotype', 'HP:0002155', (37, 77))	('FBP1', 'Gene', (21, 25))	('increase', 'PosReg', (37, 45))	('triglycerides', 'Chemical', 'MESH:D014280', (64, 77))	('loss', 'Var', (13, 17))	('content of triglycerides', 'MPA', (53, 77))
204102	33232284	The results demonstrated that loss of FBP1 obviously enhanced the content of neutral lipids detected by flow cytometry (Figure 3C).	('content of neutral lipids', 'MPA', (66, 91))	('FBP1', 'Gene', '2203', (38, 42))	('FBP1', 'Gene', (38, 42))	('lipids', 'Chemical', 'MESH:D008055', (85, 91))	('loss', 'Var', (30, 34))	('enhanced', 'PosReg', (53, 61))
204104	33232284	In addition, following staining with BODIPY 493/503 dye and DAPI, we found loss of FBP1 significantly increased the immunoreaction of BODIPY 493/503 dye compared with the control, which suggested that loss of FBP1 could enhanced the content of neutral lipids (Figure 3E).	('immunoreaction', 'MPA', (116, 130))	('enhanced', 'PosReg', (220, 228))	('loss', 'Var', (201, 205))	('FBP1', 'Gene', '2203', (83, 87))	('FBP1', 'Gene', (209, 213))	('content of neutral lipids', 'MPA', (233, 258))	('BODIPY', 'Chemical', 'MESH:C095489', (37, 43))	('lipids', 'Chemical', 'MESH:D008055', (252, 258))	('BODIPY', 'Chemical', 'MESH:C095489', (134, 140))	('increased', 'PosReg', (102, 111))	('DAPI', 'Chemical', 'MESH:C007293', (60, 64))	('FBP1', 'Gene', (83, 87))	('loss', 'Var', (75, 79))	('FBP1', 'Gene', '2203', (209, 213))
204108	33232284	To explore the detailed mechanism of miR-18b-5p regulating fatty acid metabolism in ESCC cells, the tentative interaction was predicted by the target prediction program Targetscan.	('miR-18b-5p', 'Chemical', '-', (37, 47))	('fatty acid', 'Chemical', 'MESH:D005227', (59, 69))	('fatty acid metabolism', 'MPA', (59, 80))	('miR-18b-5p', 'Var', (37, 47))
204109	33232284	The result showed that FBP1 was predicted to interact with miR-18b-5p from the target analysis (Figure 4B).	('FBP1', 'Gene', (23, 27))	('miR-18b-5p', 'Chemical', '-', (59, 69))	('miR-18b-5p', 'Var', (59, 69))	('interact', 'Reg', (45, 53))	('FBP1', 'Gene', '2203', (23, 27))
204110	33232284	To further testify the relationship between miR-18b-5p and FBP1 in ESCC cells, Eca109 cells were co-transfected with reporter plasmid contained wild type (wt) or mutant type (mut) of 3'UTR of FBP1 and miR-18b-5p mimic.	('FBP1', 'Gene', '2203', (192, 196))	('FBP1', 'Gene', '2203', (59, 63))	('FBP1', 'Gene', (192, 196))	('miR-18b-5p', 'Chemical', '-', (201, 211))	('FBP1', 'Gene', (59, 63))	('miR-18b-5p', 'Chemical', '-', (44, 54))	('mutant type', 'Var', (162, 173))
204111	33232284	The dual luciferase reporter assay showed that miR-18b-5p directly targeted the wt of FBP1 in Eca109 cells (Figure 4C).	('FBP1', 'Gene', (86, 90))	('miR-18b-5p', 'Var', (47, 57))	('FBP1', 'Gene', '2203', (86, 90))	('miR-18b-5p', 'Chemical', '-', (47, 57))
204112	33232284	Moreover, to further explore the relationship between miR-18b-5p and FBP1 in ESCC cells, RNA pull-down analysis was performed in Eca109 cells.	('FBP1', 'Gene', '2203', (69, 73))	('FBP1', 'Gene', (69, 73))	('miR-18b-5p', 'Chemical', '-', (54, 64))	('miR-18b-5p', 'Var', (54, 64))
204114	33232284	Moreover, the relative expression of FBP1 was decreased after treatment with miR-18b-5p mimic, and miR-18b-5p inhibitor significantly increased FBP1 relative expression compared with the respectively control (Figure 4F).	('miR-18b-5p', 'Chemical', '-', (99, 109))	('FBP1', 'Gene', '2203', (144, 148))	('FBP1', 'Gene', (37, 41))	('FBP1', 'Gene', '2203', (37, 41))	('FBP1', 'Gene', (144, 148))	('miR-18b-5p', 'Chemical', '-', (77, 87))	('relative expression', 'MPA', (14, 33))	('decreased', 'NegReg', (46, 55))	('relative expression', 'MPA', (149, 168))	('increased', 'PosReg', (134, 143))	('miR-18b-5p inhibitor', 'Var', (99, 119))
204115	33232284	To explore the effect of miR-18b-5p regulated FBP1 on ESCC cell function, Eca109 cells were treated with miR-18b-5p inhibitor and/or shFBP1.	('miR-18b-5p', 'Var', (105, 115))	('miR-18b-5p', 'Chemical', '-', (25, 35))	('FBP1', 'Gene', (135, 139))	('FBP1', 'Gene', (46, 50))	('FBP1', 'Gene', '2203', (46, 50))	('FBP1', 'Gene', '2203', (135, 139))	('miR-18b-5p', 'Chemical', '-', (105, 115))
204116	33232284	The results showed that miR-18b-5p inhibitor combined with shFBP1 treatment effectively reversed the enhanced proliferation induced by shFBP1 transfection (Figure 5A).	('miR-18b-5p', 'Chemical', '-', (24, 34))	('FBP1', 'Gene', (137, 141))	('FBP1', 'Gene', (61, 65))	('enhanced', 'PosReg', (101, 109))	('transfection', 'Var', (142, 154))	('FBP1', 'Gene', '2203', (137, 141))	('FBP1', 'Gene', '2203', (61, 65))
204126	33232284	In addition, previous studies have shown that low levels of FBP1 are associated with low cancer survival rates and high relapse rates.	('low cancer', 'Disease', 'MESH:D009369', (85, 95))	('relapse rates', 'CPA', (120, 133))	('low cancer', 'Disease', (85, 95))	('FBP1', 'Gene', (60, 64))	('FBP1', 'Gene', '2203', (60, 64))	('low levels', 'Var', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
204129	33232284	To further explore the mechanism of loss of FBP1 mediating ESCC cell function, FBP1 was down-regulated by transfection of shFBP1 in ESCC cells.	('FBP1', 'Gene', (44, 48))	('FBP1', 'Gene', '2203', (124, 128))	('FBP1', 'Gene', '2203', (79, 83))	('transfection', 'Var', (106, 118))	('FBP1', 'Gene', '2203', (44, 48))	('FBP1', 'Gene', (79, 83))	('FBP1', 'Gene', (124, 128))	('down-regulated', 'NegReg', (88, 102))
204130	33232284	We found loss of FBP1 promoted ESCC cell proliferation, migration and invasion in vitro.	('migration', 'CPA', (56, 65))	('promoted', 'PosReg', (22, 30))	('FBP1', 'Gene', (17, 21))	('loss', 'Var', (9, 13))	('ESCC', 'Disease', (31, 35))	('invasion', 'CPA', (70, 78))	('FBP1', 'Gene', '2203', (17, 21))
204132	33232284	Silencing FBP1 can significantly promote the proliferation and metastasis of cancer cells.	('FBP1', 'Gene', '2203', (10, 14))	('promote', 'PosReg', (33, 40))	('proliferation', 'CPA', (45, 58))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('FBP1', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Silencing', 'Var', (0, 9))
204135	33232284	Interestingly, we demonstrated that loss of FBP1 enhanced fatty acid metabolism in ESCC cells.	('FBP1', 'Gene', (44, 48))	('enhanced', 'PosReg', (49, 57))	('loss', 'Var', (36, 40))	('fatty acid metabolism', 'MPA', (58, 79))	('FBP1', 'Gene', '2203', (44, 48))	('fatty acid', 'Chemical', 'MESH:D005227', (58, 68))
204137	33232284	In addition, loss of FBP1 also enhanced the protein expression levels of fatty acid metabolism related FASN, ACC1 and SREBP1C.	('FBP1', 'Gene', '2203', (21, 25))	('enhanced', 'PosReg', (31, 39))	('SREBP1C', 'Gene', '6720', (118, 125))	('FASN', 'Gene', (103, 107))	('fatty acid', 'Chemical', 'MESH:D005227', (73, 83))	('SREBP1C', 'Gene', (118, 125))	('FBP1', 'Gene', (21, 25))	('FASN', 'Gene', '2194', (103, 107))	('loss', 'Var', (13, 17))
204138	33232284	These results suggested that loss of FBP1 might promote ESCC proliferation, migration, and invasion by regulating fatty acid metabolism.	('ESCC', 'Disease', (56, 60))	('fatty acid metabolism', 'MPA', (114, 135))	('invasion', 'CPA', (91, 99))	('migration', 'CPA', (76, 85))	('fatty acid', 'Chemical', 'MESH:D005227', (114, 124))	('FBP1', 'Gene', (37, 41))	('FBP1', 'Gene', '2203', (37, 41))	('loss', 'Var', (29, 33))	('regulating', 'Reg', (103, 113))	('promote', 'PosReg', (48, 55))
204141	33232284	demonstrated that suppressor miR-145 expression was regulated by hypermethylation of the miR-145 promoter region in ESCC.	('hypermethylation', 'Var', (65, 81))	('ESCC', 'Disease', (116, 120))	('miR-145', 'Gene', (29, 36))	('miR-145', 'Gene', '406937', (29, 36))	('miR-145', 'Gene', (89, 96))	('miR-145', 'Gene', '406937', (89, 96))	('expression', 'MPA', (37, 47))	('regulated', 'Reg', (52, 61))
204148	33232284	These results suggested that miR-18b-5p regulated cell function and fatty acid metabolism through targeting FBP1 in ESCC cells.	('fatty acid', 'Chemical', 'MESH:D005227', (68, 78))	('fatty acid metabolism', 'MPA', (68, 89))	('targeting', 'Reg', (98, 107))	('FBP1', 'Gene', '2203', (108, 112))	('regulated', 'Reg', (40, 49))	('cell function', 'MPA', (50, 63))	('miR-18b-5p', 'Chemical', '-', (29, 39))	('miR-18b-5p', 'Var', (29, 39))	('FBP1', 'Gene', (108, 112))
204149	33232284	In conclusion, loss of FBP1 promoted ESCC cell proliferation, migration, and invasion in vitro, which was regulated by miR-18b-5p.	('migration', 'CPA', (62, 71))	('miR-18b-5p', 'Chemical', '-', (119, 129))	('FBP1', 'Gene', (23, 27))	('invasion', 'CPA', (77, 85))	('FBP1', 'Gene', '2203', (23, 27))	('loss', 'Var', (15, 19))	('promoted', 'PosReg', (28, 36))	('ESCC cell proliferation', 'CPA', (37, 60))
204150	33232284	Moreover, loss of FBP1 enhanced fatty acid content and fatty acid metabolism related proteins expression in ESCC cells.	('loss', 'Var', (10, 14))	('enhanced', 'PosReg', (23, 31))	('fatty acid', 'Chemical', 'MESH:D005227', (55, 65))	('FBP1', 'Gene', '2203', (18, 22))	('fatty acid', 'Chemical', 'MESH:D005227', (32, 42))	('fatty acid content', 'MPA', (32, 50))	('fatty acid metabolism related proteins expression', 'MPA', (55, 104))	('FBP1', 'Gene', (18, 22))
204151	33232284	In addition, inhibition of miR-18b-5p counteracted the effect of loss of FBP1 on the cell function and fatty acid metabolism.	('fatty acid', 'Chemical', 'MESH:D005227', (103, 113))	('loss', 'Var', (65, 69))	('FBP1', 'Gene', '2203', (73, 77))	('miR-18b-5p', 'Protein', (27, 37))	('miR-18b-5p', 'Chemical', '-', (27, 37))	('fatty acid metabolism', 'MPA', (103, 124))	('inhibition', 'NegReg', (13, 23))	('FBP1', 'Gene', (73, 77))	('cell function', 'MPA', (85, 98))
204289	31164411	For example, alterations in levels of TP53 protein are highly prevalent in EA and also are associated with the progression of ESCC; therefore, mRNA and protein encoded by TP53 gene are suitable as prognostic biomarkers for both types of malignant esophageal cancer.	('TP53', 'Gene', (171, 175))	('prevalent', 'Reg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('EA', 'Phenotype', 'HP:0011459', (75, 77))	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', '7157', (38, 42))	('malignant esophageal cancer', 'Disease', 'MESH:D004938', (237, 264))	('TP53', 'Gene', '7157', (171, 175))	('malignant esophageal cancer', 'Disease', (237, 264))	('ESCC', 'Disease', (126, 130))	('alterations', 'Var', (13, 24))	('protein', 'Protein', (43, 50))	('associated', 'Reg', (91, 101))
204304	31164411	For example, the alterations in TP53 locus are the most commonly observed type of genetic change in both EA and ESCC.	('TP53', 'Gene', '7157', (32, 36))	('ESCC', 'Disease', (112, 116))	('TP53', 'Gene', (32, 36))	('alterations', 'Var', (17, 28))	('EA', 'Phenotype', 'HP:0011459', (105, 107))
204311	31164411	Expression of UGT2 enzymes in general, as well as respective penzo[a]pyrene metabolizing activity are detectable in esophageal tissue, but expression for a particular UGT2-encoding gene in question, UGT2B17, is not reported in esophagus by Human Protein Atlas (link), possibly due to high frequency of UGT2B17 deletion polymorphism in human populations, especially in Asians (66.7%).	('UGT2', 'Gene', (199, 203))	('human', 'Species', '9606', (335, 340))	('UGT2', 'Gene', (14, 18))	('UGT2B17', 'Gene', '7367', (199, 206))	('penzo[a]pyrene', 'Chemical', '-', (61, 75))	('Human', 'Species', '9606', (240, 245))	('UGT2', 'Gene', '55757', (167, 171))	('UGT2', 'Gene', (302, 306))	('UGT2B17', 'Gene', (199, 206))	('UGT2', 'Gene', '55757', (14, 18))	('UGT2', 'Gene', '55757', (199, 203))	('UGT2', 'Gene', (167, 171))	('UGT2B17', 'Gene', (302, 309))	('UGT2', 'Gene', '55757', (302, 306))	('UGT2B17', 'Gene', '7367', (302, 309))	('deletion polymorphism', 'Var', (310, 331))
204390	30925281	A previous study from Golestan, Iran reported an 8.2-fold increase in ESCC risk for individuals who consume hot tea (>70 C) versus those who drink warm tea (<65 C).	('Golestan', 'Chemical', 'None', (22, 30))	('ESCC', 'Disease', (70, 74))	('>70 C', 'Var', (117, 122))	('ESCC', 'Disease', 'MESH:C562729', (70, 74))
204441	25831092	Due to a point mutation in the gene encoding aldehyde dehydrogenase (ALDH2), its activity is undetectable in homozygotes and far less than half of the normal level in heterozygotes.	('Due', 'Reg', (0, 3))	('point mutation', 'Var', (9, 23))	('undetectable', 'NegReg', (93, 105))	('ALDH2', 'Gene', (69, 74))	('activity', 'MPA', (81, 89))	('aldehyde', 'Chemical', 'MESH:D000447', (45, 53))
204446	25831092	In individuals with the active ALDH2 enzyme, the capacity of the liver to eliminate acetaldehyde formed from ethanol is so efficient that measurable levels of acetaldehyde are not detected in the peripheral blood.	('acetaldehyde', 'Chemical', 'MESH:D000079', (84, 96))	('eliminate acetaldehyde formed from ethanol', 'MPA', (74, 116))	('active', 'Var', (24, 30))	('ethanol', 'Chemical', 'MESH:D000431', (109, 116))	('acetaldehyde', 'Chemical', 'MESH:D000079', (159, 171))	('ALDH2', 'Gene', (31, 36))
204481	25831092	Genotyping for the ALDH2 Glu504Lys polymorphism (rs671) was determined by TaqMan SNP genotyping assays on an Applied Biosystems StepOne real-time PCR system (Foster City, CA, USA).	('Glu504Lys', 'SUBSTITUTION', 'None', (25, 34))	('rs671', 'Mutation', 'rs671', (49, 54))	('ALDH2', 'Gene', (19, 24))	('Glu504Lys', 'Var', (25, 34))
204508	25831092	In ALDH2-active subjects, L-cysteine administration markedly reduced the gastric juice acetaldehyde concentration from the mean peak value of 26.4 +- 3.7 muM (range 9.3-43.0 muM) at 30 min without L-cysteine to a mean peak of 8.4 +- 3.7 muM (range 0.2-35.5 muM) at 30 min with L-cysteine (Fig.	('muM', 'Gene', '56925', (237, 240))	('muM', 'Gene', '56925', (257, 260))	('muM', 'Gene', '56925', (174, 177))	('muM', 'Gene', (174, 177))	('L-cysteine', 'Var', (26, 36))	('muM', 'Gene', (237, 240))	('muM', 'Gene', (257, 260))	('L-cysteine', 'Chemical', 'MESH:D003545', (277, 287))	('L-cysteine', 'Chemical', 'MESH:D003545', (197, 207))	('L-cysteine', 'Chemical', 'MESH:D003545', (26, 36))	('acetaldehyde', 'Chemical', 'MESH:D000079', (87, 99))	('gastric juice acetaldehyde concentration', 'MPA', (73, 113))	('muM', 'Gene', '56925', (154, 157))	('reduced', 'NegReg', (61, 68))	('muM', 'Gene', (154, 157))
204510	25831092	Quantitatively, L-cysteine resulted in a mean decrease of 67% (3-fold) in gastric juice acetaldehyde (AUC) (Fig.	('acetaldehyde', 'Chemical', 'MESH:D000079', (88, 100))	('L-cysteine', 'Var', (16, 26))	('L-cysteine', 'Chemical', 'MESH:D003545', (16, 26))	('gastric juice acetaldehyde', 'MPA', (74, 100))	('decrease', 'NegReg', (46, 54))
204511	25831092	Similarly, L-cysteine greatly reduced the gastric juice acetaldehyde concentration in ALDH2-deficient subjects from a mean peak value of 63.9 +- 7.7muM (range 32.0-96.7 muM) at 30 min without L-cysteine to a mean peak of 26.7 +- 8.1 muM (range 3.8-51.2 muM) at 30 min with L-cysteine (Fig.	('ALDH2-deficient', 'Disease', (86, 101))	('muM', 'Gene', (253, 256))	('ALDH2-deficient', 'Disease', 'MESH:D007153', (86, 101))	('muM', 'Gene', (233, 236))	('L-cysteine', 'Var', (273, 283))	('L-cysteine', 'Chemical', 'MESH:D003545', (192, 202))	('L-cysteine', 'Chemical', 'MESH:D003545', (273, 283))	('muM', 'Gene', '56925', (169, 172))	('muM', 'Gene', '56925', (148, 151))	('gastric juice acetaldehyde concentration', 'MPA', (42, 82))	('muM', 'Gene', '56925', (253, 256))	('L-cysteine', 'Var', (11, 21))	('reduced', 'NegReg', (30, 37))	('muM', 'Gene', (169, 172))	('muM', 'Gene', (148, 151))	('acetaldehyde', 'Chemical', 'MESH:D000079', (56, 68))	('muM', 'Gene', '56925', (233, 236))	('L-cysteine', 'Chemical', 'MESH:D003545', (11, 21))
204512	25831092	Consequently, L-cysteine resulted in a 60% (2.5-fold) reduction in the mean AUC of gastric juice acetaldehyde in ALDH2-deficient subjects (Fig.	('AUC of gastric juice acetaldehyde', 'MPA', (76, 109))	('L-cysteine', 'Chemical', 'MESH:D003545', (14, 24))	('reduction', 'NegReg', (54, 63))	('ALDH2-deficient', 'Disease', 'MESH:D007153', (113, 128))	('ALDH2-deficient', 'Disease', (113, 128))	('acetaldehyde', 'Chemical', 'MESH:D000079', (97, 109))	('L-cysteine', 'Var', (14, 24))
204520	25831092	At 120 min mean salivary acetaldehyde levels ranged from 0.038 +- 0.001 vol% to 0.046 +- 0.002 vol% (from 8.4 +- 0.2 mM to 10.1 +- 0.4 mM).	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (16, 37))	('salivary acetaldehyde levels', 'MPA', (16, 44))	('0.046', 'Var', (80, 85))	('acetaldehyde', 'Chemical', 'MESH:D000079', (25, 37))
204526	25831092	The findings of this study indicate that due to deficient ALDH2, the gastric mucosa is not able to eliminate acetaldehyde produced from ethanol by gastric mucosal ADH enzymes, resulting in the accumulation of acetaldehyde in gastric juice.	('acetaldehyde', 'Chemical', 'MESH:D000079', (109, 121))	('gastric mucosal ADH', 'Disease', 'MESH:D013274', (147, 166))	('acetaldehyde in gastric juice', 'MPA', (209, 238))	('acetaldehyde', 'Chemical', 'MESH:D000079', (209, 221))	('ethanol', 'Chemical', 'MESH:D000431', (136, 143))	('ALDH2', 'Gene', (58, 63))	('deficient', 'Var', (48, 57))	('accumulation', 'MPA', (193, 205))	('accumulation of acetaldehyde', 'Phenotype', 'HP:0003533', (193, 221))	('gastric mucosal ADH', 'Disease', (147, 166))
204545	25831092	A recent animal model study demonstrated increased formation of carcinogenic DNA adducts in the gastric mucosa of ALDH2 knockout mice treated with ethanol.	('carcinogenic', 'Disease', 'MESH:D063646', (64, 76))	('carcinogenic', 'Disease', (64, 76))	('knockout', 'Var', (120, 128))	('formation', 'MPA', (51, 60))	('ethanol', 'Chemical', 'MESH:D000431', (147, 154))	('mice', 'Species', '10090', (129, 133))	('ALDH2', 'Gene', (114, 119))
204578	25831092	Due to the relatively slow gastric emptying rate and effective first pass metabolism of ethanol, these products do not normally lead to significant systemic effects of ethanol, but especially in ALDH2-deficent and/or achlorhydric subjects may result in prolonged exposure of the gastric mucosa to carcinogenic acetaldehyde.	('exposure', 'MPA', (263, 271))	('gastric mucosa to carcinogenic acetaldehyde', 'Disease', (279, 322))	('result in', 'Reg', (243, 252))	('slow gastric emptying', 'Phenotype', 'HP:0002578', (22, 43))	('ALDH2-deficent', 'Var', (195, 209))	('ethanol', 'Chemical', 'MESH:D000431', (88, 95))	('ethanol', 'Chemical', 'MESH:D000431', (168, 175))	('gastric mucosa to carcinogenic acetaldehyde', 'Disease', 'MESH:D013274', (279, 322))
204582	25831092	In addition, high concentration of carcinogenic acetaldehyde produced in the gastric juice of ALDH2-deficent and/or achlorhydric subjects could also be involved in the esophageal carcinogenesis through gastro-esophageal reflux of the gastric contents.	('carcinogenic acetaldehyde', 'Disease', (35, 60))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('ALDH2-deficent', 'Gene', (94, 108))	('esophageal reflux', 'Phenotype', 'HP:0002020', (209, 226))	('esophageal carcinogenesis', 'Disease', (168, 193))	('gastro-esophageal', 'Disease', (202, 219))	('carcinogenic acetaldehyde', 'Disease', 'MESH:D063646', (35, 60))	('involved', 'Reg', (152, 160))	('achlorhydric', 'Var', (116, 128))
204603	25831092	Nondependent changes in gastric juice and salivary acetaldehyde levels caused by ALDH2 deficiency, PPI treatment, and intragastric L-cysteine indicate that the gastric juice acetaldehyde concentration is locally regulated by gastric mucosal ADH- and ALDH2-enzymes and by oral microbes colonizing the acid-free (achlorhydric) stomach.	('L-cysteine', 'Chemical', 'MESH:D003545', (131, 141))	('men', 'Species', '9606', (108, 111))	('PPI', 'Var', (99, 102))	('gastric mucosal ADH', 'Disease', 'MESH:D013274', (225, 244))	('acetaldehyde', 'Chemical', 'MESH:D000079', (174, 186))	('gastric mucosal ADH', 'Disease', (225, 244))	('acetaldehyde', 'Chemical', 'MESH:D000079', (51, 63))	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (42, 63))	('ALDH2 deficiency', 'Disease', 'MESH:D007153', (81, 97))	('ALDH2 deficiency', 'Disease', (81, 97))
204608	21303613	Synthetic biocompatible polymers have been used to improve the efficacy of both small-molecular-weight therapeutics and imaging agents.	('polymers', 'Chemical', 'MESH:D011108', (24, 32))	('small-molecular-weight', 'Var', (80, 102))	('efficacy', 'MPA', (63, 71))
204656	21303613	For example, in a syngeneic murine OCa-1 ovarian carcinoma model, a single dose of PG-TXL in saline (10 mg equivalent paclitaxel/ml) at a dose of 80 mg equivalent paclitaxel/kg caused significant tumor growth delay compared with tumor growth with the same dose of paclitaxel in Cremophor and ethanol.	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor growth delay', 'Disease', 'MESH:D006130', (196, 214))	('paclitaxel', 'Chemical', 'MESH:D017239', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('paclitaxel', 'Chemical', 'MESH:D017239', (264, 274))	('ethanol', 'Chemical', 'MESH:D000431', (292, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('murine', 'Species', '10090', (28, 34))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (41, 58))	('OCa-1 ovarian carcinoma', 'Disease', (35, 58))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('PG-TXL', 'Chemical', '-', (83, 89))	('growth delay', 'Phenotype', 'HP:0001510', (202, 214))	('tumor', 'Disease', (229, 234))	('OCa-1 ovarian carcinoma', 'Disease', 'MESH:D010051', (35, 58))	('saline', 'Chemical', 'MESH:D012965', (93, 99))	('PG-TXL', 'Var', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('paclitaxel', 'Chemical', 'MESH:D017239', (118, 128))	('Cremophor', 'Chemical', 'MESH:C022131', (278, 287))	('tumor growth delay', 'Disease', (196, 214))
204706	21303613	In vivo, PG-TXL showed a biodistribution pattern different from that of free paclitaxel.	('PG-TXL', 'Var', (9, 15))	('paclitaxel', 'Chemical', 'MESH:D017239', (77, 87))	('biodistribution', 'MPA', (25, 40))	('PG-TXL', 'Chemical', '-', (9, 15))
204707	21303613	On the basis of area under the tissue concentration-time curve values, tumor exposure to paclitaxel was five times greater with PG-TXL than with paclitaxel formulated in Cremophor-EL-plus-ethanol vehicle.	('paclitaxel', 'Chemical', 'MESH:D017239', (145, 155))	('PG-TXL', 'Chemical', '-', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('greater', 'PosReg', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Cremophor-EL-plus', 'Chemical', '-', (170, 187))	('ethanol', 'Chemical', 'MESH:D000431', (188, 195))	('paclitaxel', 'Chemical', 'MESH:D017239', (89, 99))	('PG-TXL', 'Var', (128, 134))	('tumor', 'Disease', (71, 76))	('rat', 'Species', '10116', (45, 48))
204709	21303613	Furthermore, in another study in mice, the concentration of free paclitaxel released from PG-TXL remained relatively constant in tumor tissue over a period of 144 h, whereas the concentration of free paclitaxel in tumor tissue of mice injected with paclitaxel in Cremophor-EL-plus-ethanol vehicle was reduced more than sixfold by 144 h after injection.	('paclitaxel', 'Chemical', 'MESH:D017239', (65, 75))	('mice', 'Species', '10090', (230, 234))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('paclitaxel', 'Chemical', 'MESH:D017239', (200, 210))	('rat', 'Species', '10116', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('PG-TXL', 'Chemical', '-', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('paclitaxel', 'Chemical', 'MESH:D017239', (249, 259))	('PG-TXL', 'Var', (90, 96))	('concentration', 'MPA', (43, 56))	('tumor', 'Disease', (214, 219))	('mice', 'Species', '10090', (33, 37))	('tumor', 'Disease', (129, 134))	('Cremophor-EL-plus', 'Chemical', '-', (263, 280))	('rat', 'Species', '10116', (185, 188))	('ethanol', 'Chemical', 'MESH:D000431', (281, 288))
204712	21303613	In addition to the EPR effect, PG-TXL also mediates selective degradation and release of paclitaxl in tumor tissues.	('PG-TXL', 'Chemical', '-', (31, 37))	('degradation', 'MPA', (62, 73))	('release', 'MPA', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('paclitaxl', 'Chemical', '-', (89, 98))	('PG-TXL', 'Var', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
204715	21303613	Significantly, the intracellular concentrations of Glu-2'-TXL and H2N-Glu- Glu-2'-TXL were 100 to 1000 times higher in the RAW 264.7 cells than in the cancer cells.	("Glu-2'-TXL", 'Chemical', '-', (51, 61))	('intracellular concentrations', 'MPA', (19, 47))	('H2N-Glu-', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('higher', 'PosReg', (109, 115))	("Glu-2'-TXL", 'Chemical', '-', (75, 85))	('rat', 'Species', '10116', (40, 43))	('RAW 264.7', 'CellLine', 'CVCL:0493', (123, 132))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
204720	21303613	Using a noninvasive near-infrared (NIR) fluorescence optical imaging technique, we demonstrated selective degradation of L-PG polymer by cysteine proteases, such as cathepsin B and cathepsin L (Figure 3A), selective degradation of L-PG versus D-PG (Figure 3B), and selective inhibition of L-PG degradation in the presence of cathepsin B inhibitor (Figure 3C).	('cathepsin B', 'Gene', (165, 176))	('degradation', 'MPA', (216, 227))	('cathepsin B', 'Gene', (325, 336))	('L-PG', 'Var', (121, 125))	('inhibition', 'NegReg', (275, 285))	('D-PG', 'Chemical', '-', (243, 247))	('L-PG polymer', 'Chemical', '-', (121, 133))	('L-PG', 'Chemical', '-', (289, 293))	('L-PG', 'Chemical', '-', (121, 125))	('cathepsin L', 'Gene', '13039', (181, 192))	('cathepsin B', 'Gene', '13030', (325, 336))	('degradation', 'MPA', (294, 305))	('L-PG', 'Chemical', '-', (231, 235))	('cathepsin L', 'Gene', (181, 192))	('cysteine', 'Enzyme', (137, 145))	('cathepsin B', 'Gene', '13030', (165, 176))	('degradation', 'MPA', (106, 117))	('rat', 'Species', '10116', (90, 93))
204736	21303613	In vivo, PG-DTPA-Gd, as an MRI blood pool imaging agent, showed enhanced vascular contrast in mice up to 2 h after contrast injection.	('PG-DTPA-Gd', 'Var', (9, 19))	('PG-DTPA-Gd', 'Chemical', '-', (9, 19))	('vascular contrast', 'MPA', (73, 90))	('mice', 'Species', '10090', (94, 98))	('enhanced', 'PosReg', (64, 72))
204754	21303613	Results from this study showed that PG-DO3A-Gd-Mce6, a bifunctional polymer conjugate containing both an MRI contrast agent and a photosensitizer, was effective for cancer imaging (contrast-enhanced MRI) and efficacious for treatment with PDT in an animal model.	('polymer', 'Chemical', 'MESH:D011108', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('PG-DO3A-Gd-Mce6', 'Var', (36, 51))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('PG-DO3A-Gd-Mce6', 'Chemical', '-', (36, 51))
204756	21303613	The pegylated conjugate demonstrated longer blood circulation, less liver uptake, and more tumor accumulation than the non-pegylated conjugate, as shown by MRI.	('longer', 'PosReg', (37, 43))	('liver uptake', 'MPA', (68, 80))	('blood circulation', 'CPA', (44, 61))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('pegylated', 'Var', (4, 13))	('tumor', 'Disease', (91, 96))	('less', 'NegReg', (63, 67))	('rat', 'Species', '10116', (31, 34))
204758	21303613	Moreover, animals treated with PDT and pegylated PG-DO3A-Gd-Mce6 showed reduced vascular permeability on dynamic CE-MRI and decreased microvessel density in histological analysis.	('vascular permeability', 'MPA', (80, 101))	('reduced', 'NegReg', (72, 79))	('pegylated PG-DO3A-Gd-Mce6', 'Var', (39, 64))	('PG-DO3A-Gd-Mce6', 'Chemical', '-', (49, 64))	('decreased', 'NegReg', (124, 133))	('PDT', 'Var', (31, 34))	('microvessel density', 'CPA', (134, 153))	('PG-DO3A-Gd-Mce6', 'Var', (49, 64))
204763	21303613	In vitro and in vitro binding studies using DU145 cells, which highly express alphanubeta3 integrin, revealed that the binding affinity of polymer-bound cyclic-RGD-phenylalanine-lysine, or c(RGDfK), had higher binding compared with SLK cells, which was consistent with free c(RGDfK).	('polymer', 'Chemical', 'MESH:D011108', (139, 146))	('binding', 'Interaction', (210, 217))	('DU145', 'CellLine', 'CVCL:0105', (44, 49))	('higher', 'PosReg', (203, 209))	('cyclic-RGD-phenylalanine-lysine', 'Var', (153, 184))	('binding', 'Interaction', (119, 126))
204770	21303613	As discussed previously, PG-TXL has been shown to have significantly higher uptake in tumors and greater antitumor activity than the parent drug, paclitaxel.	('uptake', 'MPA', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (146, 156))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('PG-TXL', 'Var', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('higher', 'PosReg', (69, 75))	('tumor', 'Disease', (109, 114))	('PG-TXL', 'Chemical', '-', (25, 31))
204773	21303613	Interestingly, the fluorescence intensity decreased with increasing amounts of NIR813 dye (Figure 5A).	('NIR813', 'Chemical', 'MESH:C524070', (79, 85))	('fluorescence intensity', 'MPA', (19, 41))	('NIR813 dye', 'Var', (79, 89))	('decreased', 'NegReg', (42, 51))
204776	21303613	Figure 5B shows that L-PG-NIR813, but not D-PG-NIR813, was degraded in tumors with overexpression of cathepsin B.	('D-PG', 'Chemical', '-', (42, 46))	('L-PG-NIR813', 'Var', (21, 32))	('L-PG', 'Chemical', '-', (21, 25))	('PG-NIR', 'Chemical', '-', (44, 50))	('degraded', 'NegReg', (59, 67))	('PG-NIR', 'Chemical', '-', (23, 29))	('cathepsin B', 'Gene', '13030', (101, 112))	('cathepsin B', 'Gene', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('overexpression', 'PosReg', (83, 97))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('NIR813', 'Chemical', 'MESH:C524070', (26, 32))	('tumors', 'Disease', (71, 77))	('NIR813', 'Chemical', 'MESH:C524070', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
204788	21303613	When PG-Gd-NIR813 was injected intralingually in mice bearing DM 14 oral squamous cell carcinomas, MRI could detect not only the presence of PG-Gd-NIR813 but also the pattern of contrast agent distribution, which was different in metastatic and normal lymph nodes (Figure 6).	('PG-Gd-NIR813', 'Chemical', '-', (141, 153))	('mice', 'Species', '10090', (49, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('PG-Gd-NIR813', 'Chemical', '-', (5, 17))	('PG-Gd-NIR813', 'Var', (141, 153))	('DM 14 oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (62, 97))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (73, 97))	('DM 14 oral squamous cell carcinomas', 'Disease', (62, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
204792	21303613	Rats bearing C6 tumors were intravenously injected with PG-Gd-NIR813 and subjected to in vivo imaging 48 h later.	('Rats', 'Species', '10116', (0, 4))	('PG-Gd-NIR813', 'Chemical', '-', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('C6 tumors', 'Disease', 'MESH:C567307', (13, 22))	('C6 tumors', 'Disease', (13, 22))	('PG-Gd-NIR813', 'Var', (56, 68))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
204793	21303613	Figure 7A shows that PG-Gd-NIR813 was distributed toward the central zone of the tumor.	('PG-Gd-NIR813', 'Var', (21, 33))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('PG-Gd-NIR813', 'Chemical', '-', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
204801	21303613	Immunohistochemical evaluation showed colocalization of PG-Gd-NIR813 and CD68+ macrophages in the tumor necrotic regions in the mice not treated with the macrophage-depleting agent.	('CD68', 'Gene', (73, 77))	('PG-Gd-NIR813', 'Chemical', '-', (56, 68))	('tumor necrotic', 'Disease', 'MESH:D009369', (98, 112))	('tumor necrotic', 'Disease', (98, 112))	('mice', 'Species', '10090', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PG-Gd-NIR813', 'Var', (56, 68))	('CD68', 'Gene', '12514', (73, 77))
204802	21303613	Twenty-four hours after macrophage depletion, both PG-Gd-NIR813 and CD68+ macrophages in tumor necrotic areas significantly decreased (Figure 8C, arrows).	('PG-Gd-NIR813', 'Chemical', '-', (51, 63))	('necrotic areas', 'Disease', (95, 109))	('tumor necrotic', 'Disease', 'MESH:D009369', (89, 103))	('CD68', 'Gene', '12514', (68, 72))	('PG-Gd-NIR813', 'Var', (51, 63))	('decreased', 'NegReg', (124, 133))	('tumor necrotic', 'Disease', (89, 103))	('CD68', 'Gene', (68, 72))	('necrotic areas', 'Disease', 'MESH:D009336', (95, 109))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
204806	21303613	Our current data indicate that PG-Gd-NIR813 was phagocytized by the M2 subset of tumor-infiltrating macrophages, which are recruited to the perinecrotic areas of tumors.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('perinecrotic areas of tumors', 'Disease', (140, 168))	('tumor', 'Disease', (162, 167))	('PG-Gd-NIR813', 'Var', (31, 43))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('perinecrotic areas of tumors', 'Disease', 'MESH:D009369', (140, 168))	('rat', 'Species', '10116', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', (81, 86))	('PG-Gd-NIR813', 'Chemical', '-', (31, 43))
204855	33771195	Moreover, postoperative T12-SMA variation and QLQ-C30 scores of the EOF group were higher than those in LOF group (p < 0.05).	('T12-SMA', 'Gene', '923;6606', (24, 31))	('QLQ-C30 scores', 'MPA', (46, 60))	('T12-SMA', 'Gene', (24, 31))	('EOF', 'Var', (68, 71))	('higher', 'PosReg', (83, 89))	('QLQ', 'Chemical', '-', (46, 49))
204906	33771195	The body weight loss of patients in EOF group was lower than that in LOF group in POD 30 (4.23 +- 2.06 VS 5.56 +- 2.86, p = 0.004) (Fig.	('lower', 'NegReg', (50, 55))	('weight loss', 'Phenotype', 'HP:0001824', (9, 20))	('weight loss', 'Disease', 'MESH:D015431', (9, 20))	('EOF', 'Var', (36, 39))	('patients', 'Species', '9606', (24, 32))	('weight loss', 'Disease', (9, 20))
204907	33771195	Moreover, T12-SMA variation (the post/pre ratio) was greater in the EOF group (0.87 +- 0.25 VS 0.79 +- 0.16, p = 0.043) (Fig.	('T12-SMA', 'Gene', (10, 17))	('EOF', 'Var', (68, 71))	('greater', 'PosReg', (53, 60))	('T12-SMA', 'Gene', '923;6606', (10, 17))
204910	33771195	However, 30 days after surgery, the overall health of patients in EOF group was better than that in LOF group (61.33 +- 10.18 VS 53.96 +- 14.87, p = 0.001).	('patients', 'Species', '9606', (54, 62))	('EOF', 'Var', (66, 69))	('better', 'PosReg', (80, 86))
204927	33771195	In this study, we used ALB, PA, TRF, Hb to evaluate the nutrition status and IgA, IgG, IgM to measre the immune status, and results revealed that postoperative nutritional and immune indexes of patients in EOF group were higher than those in LOF group, especially in POD 7 and POD 30.	('patients', 'Species', '9606', (194, 202))	('EOF', 'Var', (206, 209))	('TRF', 'Gene', '3567', (32, 35))	('TRF', 'Gene', (32, 35))	('ALB', 'Gene', '213', (23, 26))	('ALB', 'Gene', (23, 26))	('higher', 'PosReg', (221, 227))
205006	32328198	Our results further confirmed that dysregulated plasma levels of fatty acid-related acylcarnitines may underly the decreased activity of Acetyl-CoA dehydrogenase and the disorder of long-chain fatty acid oxidation observed in ESCC patients.	('Acetyl-CoA dehydrogenase', 'Enzyme', (137, 161))	('dysregulated', 'Var', (35, 47))	('disorder', 'MPA', (170, 178))	('fatty acid', 'Chemical', 'MESH:D005227', (65, 75))	('patients', 'Species', '9606', (231, 239))	('activity', 'MPA', (125, 133))	('ESCC', 'Disease', (226, 230))	('decreased', 'NegReg', (115, 124))	('fatty acid', 'Chemical', 'MESH:D005227', (193, 203))	('acylcarnitines', 'Chemical', 'MESH:C116917', (84, 98))	('plasma levels of', 'MPA', (48, 64))
205039	32328198	A series of studies has shown that dysregulation of LA metabolism takes place in a variety of malignant diseases.	('dysregulation', 'Var', (35, 48))	('malignant diseases', 'Disease', (94, 112))	('LA metabolism', 'MPA', (52, 65))	('malignant diseases', 'Disease', 'MESH:D009369', (94, 112))
205112	32184666	In general, patients who received POCRT suffered more treatment toxicities than those who received PORT (Table 2).	('patients', 'Species', '9606', (12, 20))	('toxicities', 'Disease', 'MESH:D064420', (64, 74))	('POCRT', 'Chemical', '-', (34, 39))	('POCRT', 'Var', (34, 39))	('PORT', 'Chemical', '-', (99, 103))	('toxicities', 'Disease', (64, 74))
205113	32184666	The incidence of grade 3 or higher leukocytopenia was significantly higher in the POCRT group compared with the PORT group (17.2% vs 3.4%, P=0.003; respectively).	('POCRT', 'Var', (82, 87))	('leukocytopenia', 'Disease', 'MESH:D007970', (35, 49))	('PORT', 'Chemical', '-', (112, 116))	('leukocytopenia', 'Disease', (35, 49))	('POCRT', 'Chemical', '-', (82, 87))
205140	32184666	Grade 3 or higher acute toxic reactions, including leukocytopenia and nausea/vomiting, were significantly more common in the POCRT group than in the PORT group.	('vomiting', 'Phenotype', 'HP:0002013', (77, 85))	('PORT', 'Chemical', '-', (149, 153))	('vomiting', 'Disease', (77, 85))	('vomiting', 'Disease', 'MESH:D014839', (77, 85))	('nausea', 'Phenotype', 'HP:0002018', (70, 76))	('leukocytopenia', 'Disease', 'MESH:D007970', (51, 65))	('nausea', 'Disease', (70, 76))	('POCRT', 'Var', (125, 130))	('acute toxic reactions', 'CPA', (18, 39))	('nausea', 'Disease', 'MESH:D009325', (70, 76))	('nausea/vomiting', 'Phenotype', 'HP:0002017', (70, 85))	('POCRT', 'Chemical', '-', (125, 130))	('leukocytopenia', 'Disease', (51, 65))
205145	32184666	However, for postoperative complications, 3FL was associated with significantly more recurrent nerve palsy and anastomosis leakage.	('palsy', 'Disease', (101, 106))	('palsy', 'Disease', 'MESH:D010243', (101, 106))	('3FL', 'Var', (42, 45))	('anastomosis leakage', 'Disease', 'MESH:D003763', (111, 130))	('anastomosis leakage', 'Disease', (111, 130))
205150	32184666	In another large-scale meta-analysis evaluating the effect of POCRT with non-POCRT regimen for esophageal cancer patients, they found that POCRT yielded significant survival benefit (HR: 1.66, 95% CI 1.30-2.11; P<0.0001) and improved local-regional control rate with tolerable toxicities.	('local-regional control rate', 'CPA', (234, 261))	('toxicities', 'Disease', 'MESH:D064420', (277, 287))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (113, 121))	('survival', 'CPA', (165, 173))	('POCRT', 'Chemical', '-', (62, 67))	('improved', 'PosReg', (225, 233))	('POCRT', 'Chemical', '-', (139, 144))	('toxicities', 'Disease', (277, 287))	('POCRT', 'Var', (139, 144))	('esophageal cancer', 'Disease', (95, 112))	('benefit', 'PosReg', (174, 181))	('POCRT', 'Chemical', '-', (77, 82))
205164	32184666	The distant metastasis rate, the mixed (regional lymph node and distant) metastasis rate, and the overall recurrence rate were also significantly lower in the POCRT group than in the PORT group (P<0.05).	('PORT', 'Chemical', '-', (183, 187))	('distant metastasis rate', 'CPA', (4, 27))	('POCRT', 'Var', (159, 164))	('recurrence', 'CPA', (106, 116))	('lower', 'NegReg', (146, 151))	('POCRT', 'Chemical', '-', (159, 164))
205167	32184666	15 (17.2%) patients in the POCRT group got severe leukocytopenia, compared with 3 (3.4%) patients in the PORT group had grade 3 leukocytopenia (P=0.003) in this report.	('leukocytopenia', 'Disease', (128, 142))	('leukocytopenia', 'Disease', (50, 64))	('POCRT', 'Chemical', '-', (27, 32))	('POCRT', 'Var', (27, 32))	('PORT', 'Chemical', '-', (105, 109))	('patients', 'Species', '9606', (89, 97))	('leukocytopenia', 'Disease', 'MESH:D007970', (128, 142))	('patients', 'Species', '9606', (11, 19))	('leukocytopenia', 'Disease', 'MESH:D007970', (50, 64))
205171	32184666	Additionally, as 32% (16/50) of patients in the POCRT group subsequently developed distant metastases compared with 50.8% (33/65) in the PORT group, it seemed reasonable to suggest that systemic adjuvant chemoradiotherapy had a role in controlling distant metastasis.	('patients', 'Species', '9606', (32, 40))	('POCRT', 'Var', (48, 53))	('metastases', 'Disease', (91, 101))	('developed', 'Reg', (73, 82))	('POCRT', 'Chemical', '-', (48, 53))	('PORT', 'Chemical', '-', (137, 141))	('metastases', 'Disease', 'MESH:D009362', (91, 101))
205188	31828980	According to the American Cancer Society, an estimated 17 290 people were reported and 15 850 people eventually died of EC in 2018.1 Patients frequently present with advanced stage disease at first diagnosis, and its overall prognosis remains compromised, even with multimodality interventions.2  Nowadays, several large clinical trials and meta-analysis with high-level evidence have confirmed significantly improved oncological outcomes in patients with locally advanced esophageal carcinoma using neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection.3, 4, 5, 6 Based on these studies, nCRT plus surgery has become the standard treatment procedure for clinical T1bN1-N3 or T2-T4aN-/+M0 patients.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (473, 493))	('T1bN1-N3', 'Var', (678, 686))	('people', 'Species', '9606', (62, 68))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (473, 493))	('Cancer', 'Disease', 'MESH:D009369', (26, 32))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (703, 711))	('patients', 'Species', '9606', (442, 450))	('people', 'Species', '9606', (94, 100))	('EC', 'Phenotype', 'HP:0011459', (120, 122))	('T2-T4aN-/+M0', 'Var', (690, 702))	('EC', 'Disease', 'MESH:D004938', (120, 122))	('esophageal carcinoma', 'Disease', (473, 493))	('carcinoma', 'Phenotype', 'HP:0030731', (484, 493))	('Cancer', 'Disease', (26, 32))
205219	31828980	For example, one of these trials driven from NCDB, included patients with with stage pT3-4Nx-0 or pT1-4N1-3 esophageal carcinoma (squamous cell or adenocarcinoma) without metastatic disease.16 This hospital-based study showed improved long-term oncologic benefits for patients treated with postop RT compared to surgery alone.	('squamous cell or adenocarcinoma', 'Disease', (130, 161))	('improved', 'PosReg', (226, 234))	('squamous cell or adenocarcinoma', 'Disease', 'MESH:D018307', (130, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('pT3', 'Gene', '7694', (85, 88))	('pT3', 'Gene', (85, 88))	('patients', 'Species', '9606', (60, 68))	('esophageal carcinoma', 'Disease', (108, 128))	('postop', 'Var', (290, 296))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (108, 128))	('pT1', 'Gene', '58492', (98, 101))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (108, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('oncologic benefits', 'CPA', (245, 263))	('patients', 'Species', '9606', (268, 276))	('pT1', 'Gene', (98, 101))
205230	31828980	They reported postop RT was associated with decreased survival in node negative patients, and there was no relationship between pT stage and survival outcomes.27 Thus, our study suggest that a significant disadvantage in survival can be attained by pT1 status with postop RT.	('patients', 'Species', '9606', (80, 88))	('survival', 'MPA', (221, 229))	('pT1', 'Gene', '58492', (249, 252))	('postop RT', 'Var', (265, 274))	('disadvantage', 'NegReg', (205, 217))	('pT1', 'Gene', (249, 252))
205236	31828980	However, in the univariable and multivariable analysis for all-cause mortality, according to pT3 subgroup characteristics, postop RT was an independent factor for better OS compared to patients who underwent SA procedure in the subgroup with tumor length >=5 cm.	('postop RT', 'Var', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('pT3', 'Gene', '7694', (93, 96))	('tumor', 'Disease', (242, 247))	('patients', 'Species', '9606', (185, 193))	('pT3', 'Gene', (93, 96))	('better OS', 'Disease', (163, 172))
205307	26866437	Patients with CONUT scores of 0-1 have a normal nutritional status (CONUT 0), those with CONUT scores of 2-4 are at mild risk of malnutrition (CONUT 1), those with CONUT scores of 5-8 are at moderate risk (CONUT 2), and those with CONUT scores of 9-12 are at severe risk of malnutrition (CONUT 3).	('malnutrition', 'Disease', (129, 141))	('malnutrition', 'Disease', (274, 286))	('malnutrition', 'Disease', 'MESH:D044342', (274, 286))	('malnutrition', 'Disease', 'MESH:D044342', (129, 141))	('malnutrition', 'Phenotype', 'HP:0004395', (274, 286))	('malnutrition', 'Phenotype', 'HP:0004395', (129, 141))	('Patients', 'Species', '9606', (0, 8))	('CONUT', 'Var', (14, 19))
205310	26866437	The potential prognostic factors for esophageal cancer were as follows: age (<70 vs. >=70 years), sex (male vs. female), albumin concentration (<3.5 vs. >=3.5 g/dL), CRP (<1.0 vs. >=1.0 mg/dL), pT status (pT 1 vs. pT 2-4), pN status (pN 0 vs. pN 1-2); pStage (1, 2 vs. 3), tumor size (<3 vs. >=3 cm), operation time (<600 vs. >=600 minutes), intraoperative blood loss (<500 vs. >=500 mL), CONUT (CONUT 0 vs. CONUT 1-3), and NLR (0 vs. 1).	('<500', 'Var', (369, 373))	('CRP', 'Gene', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('CRP', 'Gene', '1401', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('intraoperative blood loss', 'Disease', (342, 367))	('CONUT', 'Disease', (389, 394))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (342, 367))	('albumin', 'Gene', (121, 128))	('albumin', 'Gene', '213', (121, 128))	('esophageal cancer', 'Disease', (37, 54))	('tumor', 'Disease', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
205342	26866437	Patients with an elevated NLR have relative lymphocytopenia, which may result in a weaker lymphocyte-mediated immune response to the tumor, thereby worsening their prognosis.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('lymphocytopenia', 'Phenotype', 'HP:0001888', (44, 59))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Patients', 'Species', '9606', (0, 8))	('worsening', 'NegReg', (148, 157))	('tumor', 'Disease', (133, 138))	('weaker', 'NegReg', (83, 89))	('lymphocytopenia', 'Disease', 'MESH:D008231', (44, 59))	('NLR', 'Gene', (26, 29))	('lymphocytopenia', 'Disease', (44, 59))	('elevated', 'Var', (17, 25))
205373	29615660	In this study, we revealed that MSCs-derived B2M significantly induced epithelial-to-mesenchymal transition (EMT) in ESCC cells, and observed its subsequent enhancing effects on cell mobility and tumor-initiation.	('enhancing effects', 'PosReg', (157, 174))	('tumor-initiation', 'Disease', 'MESH:D009369', (196, 212))	('B2M', 'Var', (45, 48))	('induced', 'PosReg', (63, 70))	('cell mobility', 'CPA', (178, 191))	('tumor-initiation', 'Disease', (196, 212))	('epithelial-to-mesenchymal transition', 'CPA', (71, 107))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
205377	29615660	Both MSCNTC and MSCshB2M expressed the same type of surface markers (including CD29, CD44, CD73 and CD105; Fig.	('CD73', 'Gene', (91, 95))	('CD44', 'Gene', '960', (85, 89))	('CD105', 'Var', (100, 105))	('CD29', 'Gene', '3688', (79, 83))	('CD44', 'Gene', (85, 89))	('CD29', 'Gene', (79, 83))	('CD73', 'Gene', '4907', (91, 95))
205385	29615660	Notably, MSCshB2M-CM restored the migration and invasion of ESCC cells, especially in TE-1 cells (Fig.	('restored', 'PosReg', (21, 29))	('TE-1', 'Gene', '57816', (86, 90))	('TE-1', 'Gene', (86, 90))	('invasion', 'CPA', (48, 56))	('MSCshB2M-CM', 'Var', (9, 20))	('migration', 'CPA', (34, 43))
205388	29615660	Western blot analysis showed that the expression of the EMT-related markers, triggered by MSCs-CM, could be inhibited by AG490 (JAK-2 protein tyrosine kinase inhibitor), indicating that the JAK2/STAT3 pathway involved in the EMT process.	('MSCs-CM', 'Var', (90, 97))	('JAK2', 'Gene', (190, 194))	('expression', 'MPA', (38, 48))	('JAK-2', 'Gene', '3717', (128, 133))	('STAT3', 'Gene', '6774', (195, 200))	('AG490', 'Var', (121, 126))	('JAK2', 'Gene', '3717', (190, 194))	('STAT3', 'Gene', (195, 200))	('JAK-2', 'Gene', (128, 133))	('inhibited', 'NegReg', (108, 117))
205394	29615660	Results showed that both MSCNTC-CM and MSCshB2M-CM could significantly promote the formation of tumor spheres including their quantity and dimensions, when compared to the control group (without CM treatment).	('promote', 'PosReg', (71, 78))	('MSCshB2M-CM', 'Var', (39, 50))	('quantity', 'CPA', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
205395	29615660	The anchorage-independent growth ability of ESCC cells under MSCNTC-CM was significantly stronger than that under MSCshB2M-CM treatment (p = 0.004; cells per well with diameter 50 to 100 mum: 116.7 +- 5.8 versus 74.3 +- 7.3, 100 to 200 mum: 138.1 +- 9.8 versus 79.0 +- 2.9, and more than 200 mum: 30.0 +- 2.4 versus 22.3 +- 5.4; Fig.	('mum', 'Gene', (187, 190))	('mum', 'Gene', (236, 239))	('stronger', 'PosReg', (89, 97))	('mum', 'Gene', '56925', (292, 295))	('MSCNTC-CM', 'Var', (61, 70))	('mum', 'Gene', '56925', (187, 190))	('mum', 'Gene', (292, 295))	('mum', 'Gene', '56925', (236, 239))	('anchorage-independent growth ability', 'CPA', (4, 40))
205399	29615660	The results showed that the proportion of SP cells was increased considerably in ESCC cells under MSCNTC-CM treatment compared with the negative control (TE-1: 2.195% versus 1.09%, Eca109: 7.154% versus 0.227%; Fig.	('TE-1', 'Gene', (154, 158))	('SP', 'Chemical', '-', (42, 44))	('increased', 'PosReg', (55, 64))	('ESCC', 'Disease', (81, 85))	('MSCNTC-CM treatment', 'Var', (98, 117))	('TE-1', 'Gene', '57816', (154, 158))
205400	29615660	The SP cells proportion in ESCC cells under MSCshB2M-CM treatment was comparable to the negative control (TE-1: 1.228%, Eca109: 0.312%).	('MSCshB2M-CM', 'Var', (44, 55))	('TE-1', 'Gene', '57816', (106, 110))	('SP', 'Chemical', '-', (4, 6))	('TE-1', 'Gene', (106, 110))
205402	29615660	The results of counting the cell numbers every 12 hours suggested that MSCNTC-CM could significantly promote the proliferation of ESCC cells, exhibiting a 1.5- to 3-fold increase compared with the untreated group (TE-1: p = 0.004 & Eca109: p = 0.011, Fig.	('promote', 'PosReg', (101, 108))	('ESCC', 'Disease', (130, 134))	('increase', 'PosReg', (170, 178))	('TE-1', 'Gene', '57816', (214, 218))	('MSCNTC-CM', 'Var', (71, 80))	('TE-1', 'Gene', (214, 218))	('proliferation', 'CPA', (113, 126))
205406	29615660	The number of dead tumor cells counted by LIVE/DEAD Viability/Cytotoxicity Kit indicated that MSCNTC-CM could significantly enhance the drug-resistant ability of ESCC tumor cells (Eca109: 211.8 +- 42.1 versus 369.4 +- 54.9, p = 0.03; TE-1: 23.2 +- 5.6 versus 98.9 +- 19.6, p = 0.001; Fig.	('Cytotoxicity', 'Disease', 'MESH:D064420', (62, 74))	('TE-1', 'Gene', (234, 238))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('MSCNTC-CM', 'Var', (94, 103))	('drug-resistant ability', 'CPA', (136, 158))	('enhance', 'PosReg', (124, 131))	('ESCC tumor', 'Disease', (162, 172))	('Cytotoxicity', 'Disease', (62, 74))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (19, 24))	('TE-1', 'Gene', '57816', (234, 238))	('ESCC tumor', 'Disease', 'MESH:D004938', (162, 172))	('tumor', 'Disease', (167, 172))
205409	29615660	It suggested that MSCs-CM could affect the ESCC cells' chemo-resistance to carboplatin, but B2M had a minor contribution to this process.	('carboplatin', 'Chemical', 'MESH:D016190', (75, 86))	('MSCs-CM', 'Var', (18, 25))	('chemo-resistance to carboplatin', 'MPA', (55, 86))	('affect', 'Reg', (32, 38))
205410	29615660	Our results of in vitro experiments indicated that B2M of MSCs could promote tumor cells acquiring stem cell-like properties, which may enhance their initiating capability.	('B2M', 'Var', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('initiating', 'MPA', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('promote', 'PosReg', (69, 76))	('enhance', 'PosReg', (136, 143))	('tumor', 'Disease', (77, 82))
205413	29615660	Meanwhile, the induction effect of MSCshB2M was substantially weakened (Eca109: 238.0 +- 148.6 mm3 versus 158.0 +- 115.9 mm3 on day 18 after xenograft, p = 0.32;TE-1: 12.8 +- 11.1 mm3 versus 10.0 +- 5.7 mm3 on day 16 after xenograft, p = 0.059).	('TE-1', 'Gene', '57816', (161, 165))	('MSCshB2M', 'Var', (35, 43))	('TE-1', 'Gene', (161, 165))	('weakened', 'NegReg', (62, 70))
205416	29615660	Specifically, MSCshB2M in vivo seemed to promote TE-1 cells formation into a well-organized tumor structure with decreased cavities (Fig.	('TE-1', 'Gene', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('promote', 'PosReg', (41, 48))	('cavities', 'MPA', (123, 131))	('tumor', 'Disease', (92, 97))	('decreased', 'NegReg', (113, 122))	('MSCshB2M', 'Var', (14, 22))	('TE-1', 'Gene', '57816', (49, 53))
205430	29615660	Our results showed that MSCs-CM could induce a significant EMT phenotype, thereby increase migration, tumor-initiating capability, cell viability and apoptosis resistance of ESCC cells.	('EMT', 'CPA', (59, 62))	('apoptosis resistance', 'CPA', (150, 170))	('tumor', 'Disease', (102, 107))	('cell viability', 'CPA', (131, 145))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('increase', 'PosReg', (82, 90))	('migration', 'CPA', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('MSCs-CM', 'Var', (24, 31))
205434	29615660	reported that B2M overexpression could drive EMT and promote the growth, invasion, and metastasis of human prostate, breast, lung, and renal cancer cells in vitro and in vivo.	('renal cancer', 'Disease', 'MESH:D007680', (135, 147))	('B2M', 'Var', (14, 17))	('metastasis', 'CPA', (87, 97))	('growth', 'CPA', (65, 71))	('breast', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung', 'Disease', (125, 129))	('human', 'Species', '9606', (101, 106))	('renal cancer', 'Disease', (135, 147))	('drive EMT', 'CPA', (39, 48))	('invasion', 'CPA', (73, 81))	('renal cancer', 'Phenotype', 'HP:0009726', (135, 147))	('overexpression', 'PosReg', (18, 32))	('promote', 'PosReg', (53, 60))
205438	29615660	We found in vitro and in vivo that MSCs-derived B2M can enhance the tumor-initiating capability of ESCC cells.	('tumor', 'Disease', (68, 73))	('B2M', 'Var', (48, 51))	('enhance', 'PosReg', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
205443	29615660	For instance, MSCs could inhibit the invasion of U87 cells but enhance the invasion of U373, both of which are glioblastoma cell lines.	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('invasion of U87 cells', 'CPA', (37, 58))	('enhance', 'PosReg', (63, 70))	('U87', 'CellLine', 'CVCL:0022', (49, 52))	('MSCs', 'Var', (14, 18))	('inhibit', 'NegReg', (25, 32))	('glioblastoma', 'Disease', (111, 123))	('glioblastoma', 'Disease', 'MESH:D005909', (111, 123))	('invasion of U373', 'CPA', (75, 91))
205444	29615660	first showed that B2M could activate cAMP-dependent PKA activity by binding to the seven-transmembrane G protein-coupled receptor (GPCR).	('binding', 'Interaction', (68, 75))	('activity', 'MPA', (56, 64))	('cAMP', 'Chemical', 'MESH:D000242', (37, 41))	('B2M', 'Var', (18, 21))	('activate', 'PosReg', (28, 36))	('PKA', 'Enzyme', (52, 55))	('cAMP-dependent', 'MPA', (37, 51))
205451	29615660	Since we observed a decreased expression of snail in MSCshB2M group (Supplementary Fig.	('snail', 'Gene', '6615', (44, 49))	('expression', 'MPA', (30, 40))	('decreased', 'NegReg', (20, 29))	('MSCshB2M', 'Var', (53, 61))	('snail', 'Gene', (44, 49))
205452	29615660	S7), we inferred that B2M may facilitate the nucleus location of p-STAT3 and/or affect downstream DNA transcription as a transcription factor which mechanism need to be further elucidated.	('affect', 'Reg', (80, 86))	('STAT3', 'Gene', '6774', (67, 72))	('B2M', 'Var', (22, 25))	('STAT3', 'Gene', (67, 72))	('nucleus location', 'MPA', (45, 61))	('facilitate', 'PosReg', (30, 40))
205523	29299137	We conducted a hospital-based case-control study to evaluate the combined effects of environmental risk factors and the single nucleotide polymorphisms (SNPs) of ALDH3B2 gene on the development of esophageal squamous carcinoma (ESCC).	('ALDH3B2', 'Gene', '222', (162, 169))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (208, 226))	('ESCC', 'Phenotype', 'HP:0011459', (228, 232))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (197, 226))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (197, 226))	('esophageal squamous carcinoma', 'Disease', (197, 226))	('ALDH3B2', 'Gene', (162, 169))	('single nucleotide polymorphisms', 'Var', (120, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
205526	29299137	Our study suggested that ALDH3B2 rs34589365, rs3741172, rs4646823, rs78402723, rs7947978, rs866907 and rs9787887 polymorphisms were not implicated with altered susceptibility of ESCC according to different age, gender, cigarette smoking and alcohol drinking status.	('rs7947978', 'Var', (79, 88))	('rs34589365', 'Mutation', 'rs34589365', (33, 43))	('ESCC', 'Phenotype', 'HP:0011459', (178, 182))	('rs78402723', 'Mutation', 'rs78402723', (67, 77))	('rs3741172', 'Var', (45, 54))	('rs9787887', 'Mutation', 'rs9787887', (103, 112))	('rs3741172', 'Mutation', 'rs3741172', (45, 54))	('rs4646823', 'Var', (56, 65))	('ALDH3B2', 'Gene', (25, 32))	('ESCC', 'Disease', (178, 182))	('rs4646823', 'Mutation', 'rs4646823', (56, 65))	('rs34589365', 'Var', (33, 43))	('rs866907', 'Var', (90, 98))	('ALDH3B2', 'Gene', '222', (25, 32))	('rs9787887', 'Var', (103, 112))	('alcohol', 'Chemical', 'MESH:D000438', (241, 248))	('rs866907', 'Mutation', 'rs866907', (90, 98))	('rs78402723', 'Var', (67, 77))	('rs7947978', 'Mutation', 'rs7947978', (79, 88))	('alcohol drinking', 'Phenotype', 'HP:0030955', (241, 257))
205531	29299137	The fact that only a subset of cohort that are exposed to the risk factors eventually develop esophageal cancer suggested a critical role of genetic factors, including single nucleotide polymorphisms (SNPs), in the esophageal carcinogenesis.	('single nucleotide polymorphisms', 'Var', (168, 199))	('esophageal cancer', 'Disease', (94, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (215, 240))	('esophageal carcinogenesis', 'Disease', (215, 240))
205540	29299137	Indeed, high ALDH1 expression predicts unfavorable outcomes in patients with ESCC.	('expression', 'MPA', (19, 29))	('high', 'Var', (8, 12))	('ESCC', 'Disease', (77, 81))	('ESCC', 'Phenotype', 'HP:0011459', (77, 81))	('patients', 'Species', '9606', (63, 71))	('ALDH1', 'Gene', (13, 18))	('ALDH1', 'Gene', '216', (13, 18))
205541	29299137	Individuals with ALDH2 Lys allele possess a higher risk of esophageal cancer, in correlation with a higher concentration of blood acetaldehyde after drinking alcohol.	('esophageal cancer', 'Disease', (59, 76))	('Lys', 'Var', (23, 26))	('ALDH2', 'Gene', '217', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('higher concentration of blood acetaldehyde', 'Phenotype', 'HP:0003533', (100, 142))	('alcohol', 'Chemical', 'MESH:D000438', (158, 165))	('acetaldehyde', 'Chemical', 'MESH:D000079', (130, 142))	('concentration of blood acetaldehyde', 'MPA', (107, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('ALDH2', 'Gene', (17, 22))	('higher', 'PosReg', (100, 106))
205542	29299137	There is a strong association between ALDH2 Glu487Lys polymorphism and the risk of esophageal cancer.	('esophageal cancer', 'Disease', (83, 100))	('ALDH2', 'Gene', '217', (38, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('ALDH2', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Glu487Lys', 'Var', (44, 53))	('Glu487Lys', 'SUBSTITUTION', 'None', (44, 53))
205543	29299137	ALDH2 rs671 and rs886205 polymorphisms have also been demonstrated to correlate with ESCC, respectively.	('rs671', 'Var', (6, 11))	('rs671', 'Mutation', 'rs671', (6, 11))	('ALDH2', 'Gene', (0, 5))	('rs886205', 'Var', (16, 24))	('ESCC', 'Disease', (85, 89))	('ESCC', 'Phenotype', 'HP:0011459', (85, 89))	('rs886205', 'Mutation', 'rs886205', (16, 24))	('correlate', 'Reg', (70, 79))	('ALDH2', 'Gene', '217', (0, 5))
205547	29299137	The association between ALDH3B2 polymorphisms and ESCC has not been investigated.	('polymorphisms', 'Var', (32, 45))	('ESCC', 'Phenotype', 'HP:0011459', (50, 54))	('ALDH3B2', 'Gene', (24, 31))	('ALDH3B2', 'Gene', '222', (24, 31))	('ESCC', 'Disease', (50, 54))
205549	29299137	To further evaluate the effects of ALDH3B2 rs34589365, rs3741172, rs4646823, rs78402723, rs7947978, rs866907 and rs9787887 on ESCC risk with different gender, age, smoking and alcohol drinking status, stratification analyses were performed as demonstrated in the Tables 4-10.	('rs866907', 'Var', (100, 108))	('rs7947978', 'Var', (89, 98))	('rs78402723', 'Mutation', 'rs78402723', (77, 87))	('rs3741172', 'Var', (55, 64))	('rs4646823', 'Var', (66, 75))	('ALDH3B2', 'Gene', (35, 42))	('rs866907', 'Mutation', 'rs866907', (100, 108))	('rs3741172', 'Mutation', 'rs3741172', (55, 64))	('rs9787887', 'Mutation', 'rs9787887', (113, 122))	('rs4646823', 'Mutation', 'rs4646823', (66, 75))	('rs34589365', 'Var', (43, 53))	('ALDH3B2', 'Gene', '222', (35, 42))	('rs9787887', 'Var', (113, 122))	('rs78402723', 'Var', (77, 87))	('ESCC', 'Phenotype', 'HP:0011459', (126, 130))	('rs7947978', 'Mutation', 'rs7947978', (89, 98))	('rs34589365', 'Mutation', 'rs34589365', (43, 53))	('ESCC', 'Disease', (126, 130))	('alcohol drinking', 'Phenotype', 'HP:0030955', (176, 192))	('alcohol', 'Chemical', 'MESH:D000438', (176, 183))
205553	29299137	In this hospital-based case-control epidemiological study, we investigated the association between tagging SNPs of ALDH3B2 and the risk of developing esophageal squamous cell carcinoma in a Chinese population.	('SNPs', 'Var', (107, 111))	('esophageal squamous cell carcinoma', 'Disease', (150, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('ALDH3B2', 'Gene', (115, 122))	('ALDH3B2', 'Gene', '222', (115, 122))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (150, 184))
205554	29299137	We found ALDH3B2 rs34589365, rs3741172, rs4646823, rs78402723, rs7947978, rs866907 and rs9787887 polymorphisms were not implicated with altered susceptibility of ESCC according to age, gender, cigarette smoking and alcohol drinking stratification analyses.	('alcohol drinking', 'Phenotype', 'HP:0030955', (215, 231))	('rs7947978', 'Var', (63, 72))	('ESCC', 'Phenotype', 'HP:0011459', (162, 166))	('alcohol', 'Chemical', 'MESH:D000438', (215, 222))	('rs3741172', 'Var', (29, 38))	('rs3741172', 'Mutation', 'rs3741172', (29, 38))	('ESCC', 'Disease', (162, 166))	('rs9787887', 'Mutation', 'rs9787887', (87, 96))	('rs34589365', 'Mutation', 'rs34589365', (17, 27))	('rs866907', 'Var', (74, 82))	('ALDH3B2', 'Gene', (9, 16))	('rs4646823', 'Var', (40, 49))	('rs78402723', 'Mutation', 'rs78402723', (51, 61))	('rs866907', 'Mutation', 'rs866907', (74, 82))	('rs9787887', 'Var', (87, 96))	('rs4646823', 'Mutation', 'rs4646823', (40, 49))	('rs34589365', 'Var', (17, 27))	('ALDH3B2', 'Gene', '222', (9, 16))	('rs7947978', 'Mutation', 'rs7947978', (63, 72))	('rs78402723', 'Var', (51, 61))
205560	29299137	In fact, there is ample evidence showed that subjects with an inactive form of ALDH2 (heterozygous for ALDH2 mutation) have an increased risk of developing various types of head and neck cancers as a consequent of intense exposure to acetaldehyde.	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('neck cancers', 'Disease', (182, 194))	('head and neck cancers', 'Phenotype', 'HP:0012288', (173, 194))	('neck cancers', 'Disease', 'MESH:D006258', (182, 194))	('ALDH2', 'Gene', '217', (79, 84))	('ALDH2', 'Gene', '217', (103, 108))	('acetaldehyde', 'Chemical', 'MESH:D000079', (234, 246))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('ALDH2', 'Gene', (79, 84))	('intense exposure to acetaldehyde', 'Phenotype', 'HP:0003533', (214, 246))	('ALDH2', 'Gene', (103, 108))	('inactive', 'Var', (62, 70))	('mutation', 'Var', (109, 117))
205567	29299137	Deregulation of these enzymes is associated with multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Deregulation', 'Var', (0, 12))	('multiple cancers', 'Disease', 'MESH:D009369', (49, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('associated', 'Reg', (33, 43))	('multiple cancers', 'Disease', (49, 65))
205572	29299137	Although ALDH3B2 rs34589365, rs3741172, rs4646823, rs78402723, rs7947978, rs866907 and rs9787887 were not associated with the susceptibility of ESCC in the current study, the cigarette smoking rate and alcohol drinking rate were significantly higher in the ESCC cases, exemplifying the significance of interaction between the environmental and genetic risk factors in causing esophageal squamous carcinoma.	('rs7947978', 'Var', (63, 72))	('rs3741172', 'Var', (29, 38))	('ESCC', 'Phenotype', 'HP:0011459', (257, 261))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (376, 405))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (387, 405))	('rs3741172', 'Mutation', 'rs3741172', (29, 38))	('ESCC', 'Disease', (257, 261))	('rs9787887', 'Mutation', 'rs9787887', (87, 96))	('rs34589365', 'Mutation', 'rs34589365', (17, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (396, 405))	('alcohol drinking', 'MPA', (202, 218))	('rs866907', 'Var', (74, 82))	('esophageal squamous carcinoma', 'Disease', (376, 405))	('ESCC', 'Phenotype', 'HP:0011459', (144, 148))	('ALDH3B2', 'Gene', (9, 16))	('rs4646823', 'Var', (40, 49))	('rs78402723', 'Mutation', 'rs78402723', (51, 61))	('rs866907', 'Mutation', 'rs866907', (74, 82))	('rs9787887', 'Var', (87, 96))	('alcohol drinking', 'Phenotype', 'HP:0030955', (202, 218))	('higher', 'PosReg', (243, 249))	('rs4646823', 'Mutation', 'rs4646823', (40, 49))	('ESCC', 'Disease', (144, 148))	('alcohol', 'Chemical', 'MESH:D000438', (202, 209))	('rs34589365', 'Var', (17, 27))	('ALDH3B2', 'Gene', '222', (9, 16))	('rs7947978', 'Mutation', 'rs7947978', (63, 72))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (376, 405))	('cigarette smoking', 'MPA', (175, 192))	('rs78402723', 'Var', (51, 61))
205583	29299137	Variations of demographic characteristics and genotypes of the ALDH3B2 rs34589365, rs3741172, rs4646823, rs78402723, rs7947978, rs866907 and rs9787887 between the controls and cases were evaluated using the chi-square (chi2) test to examine the statistical differences.	('rs3741172', 'Var', (83, 92))	('rs3741172', 'Mutation', 'rs3741172', (83, 92))	('rs78402723', 'Mutation', 'rs78402723', (105, 115))	('rs34589365', 'Var', (71, 81))	('rs866907', 'Var', (128, 136))	('rs78402723', 'Var', (105, 115))	('rs7947978', 'Mutation', 'rs7947978', (117, 126))	('rs9787887', 'Mutation', 'rs9787887', (141, 150))	('rs7947978', 'Var', (117, 126))	('rs866907', 'Mutation', 'rs866907', (128, 136))	('rs9787887', 'Var', (141, 150))	('rs4646823', 'Var', (94, 103))	('rs34589365', 'Mutation', 'rs34589365', (71, 81))	('ALDH3B2', 'Gene', (63, 70))	('ALDH3B2', 'Gene', '222', (63, 70))	('rs4646823', 'Mutation', 'rs4646823', (94, 103))
205586	29299137	Our findings that ALDH3B2 rs34589365, rs3741172, rs4646823, rs78402723, rs7947978, rs866907 and rs9787887 polymorphisms were not implicated with altered susceptibility of ESCC in different age, gender, cigarette smoking and alcohol drinking status, when interpreted with caution, could be helpful in evaluating the susceptibility to ESCC.	('rs3741172', 'Mutation', 'rs3741172', (38, 47))	('rs7947978', 'Var', (72, 81))	('ESCC', 'Disease', (171, 175))	('rs34589365', 'Mutation', 'rs34589365', (26, 36))	('rs9787887', 'Mutation', 'rs9787887', (96, 105))	('rs866907', 'Var', (83, 91))	('rs78402723', 'Mutation', 'rs78402723', (60, 70))	('rs866907', 'Mutation', 'rs866907', (83, 91))	('rs4646823', 'Var', (49, 58))	('ALDH3B2', 'Gene', (18, 25))	('rs4646823', 'Mutation', 'rs4646823', (49, 58))	('rs9787887', 'Var', (96, 105))	('rs34589365', 'Var', (26, 36))	('ALDH3B2', 'Gene', '222', (18, 25))	('ESCC', 'Phenotype', 'HP:0011459', (333, 337))	('rs78402723', 'Var', (60, 70))	('rs7947978', 'Mutation', 'rs7947978', (72, 81))	('alcohol drinking', 'Phenotype', 'HP:0030955', (224, 240))	('ESCC', 'Phenotype', 'HP:0011459', (171, 175))	('alcohol', 'Chemical', 'MESH:D000438', (224, 231))	('rs3741172', 'Var', (38, 47))
205714	24397835	Increasing evidence indicated that the presence of neutrophils in tumor tissue be associated with poor prognosis.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('neutrophils', 'Var', (51, 62))
205737	24397835	Double staining of CD66 and CD8 was carried out with DouSP KIT (Maixin-bio, Jinan, China) to analyze the densities and distributions of CD66+ neutrophils and CD8+ lymphocytes following the manufacturer's protocol with some modification.	('CD8', 'Gene', (158, 161))	('CD8', 'Gene', '925', (158, 161))	('CD8', 'Gene', (28, 31))	('CD8', 'Gene', '925', (28, 31))	('CD66+', 'Var', (136, 141))
205779	24397835	The 5-year DFS and OS rates for patients with increased intratumoral CD66+ neutrophils were 20% and 26.7%, compared with 51.1% and 55.5% for patients with decreased intratumoral CD66+ neutrophils, respectively.	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('increased', 'PosReg', (46, 55))	('patients', 'Species', '9606', (141, 149))	('CD66+ neutrophils', 'Var', (69, 86))	('DFS', 'MPA', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
205788	24397835	The presence of tumor-associated neutrophils have been demonstrated to be associated with poor clinical outcomes of several malignancies including clear cell renal cell carcinoma, gastric cancer, colorectal cancer, and hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('associated', 'Reg', (74, 84))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (219, 243))	('gastric cancer', 'Disease', (180, 194))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (147, 178))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (153, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (196, 213))	('cell renal cell carcinoma', 'Disease', (153, 178))	('gastric cancer', 'Disease', 'MESH:D013274', (180, 194))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (219, 243))	('colorectal cancer', 'Disease', (196, 213))	('malignancies', 'Disease', 'MESH:D009369', (124, 136))	('tumor', 'Disease', (16, 21))	('malignancies', 'Disease', (124, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (158, 178))	('presence', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('hepatocellular carcinoma', 'Disease', (219, 243))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (180, 194))	('colorectal cancer', 'Phenotype', 'HP:0003003', (196, 213))
205831	24397835	favoring a more aggressive regimen in tumors with an increased intratumoral neutrophils or misbalance of peritumoral neutrophil and CD8+ lymphocytes.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('increased', 'PosReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('misbalance', 'Var', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))	('tumor', 'Disease', (109, 114))
205834	23946770	HER2 gene amplification in esophageal squamous cell carcinoma is less than in gastroesophageal junction and gastric adenocarcinoma The aim of the present study was to detect the amplification of the human epidermal growth factor receptor 2 (HER2) gene in esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJAC) and gastric cancer (GC), as well as to understand the pathological meaning of HER2 gene amplification with regard to clinico-pathological parameters in these types of cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (351, 365))	('GC', 'Phenotype', 'HP:0012126', (367, 369))	('HER2', 'Gene', '2064', (241, 245))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (298, 323))	('cancer', 'Disease', 'MESH:D009369', (514, 520))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('HER2', 'Gene', (425, 429))	('esophageal squamous cell carcinoma', 'Disease', (27, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('gastric adenocarcinoma', 'Disease', (108, 130))	('HER2', 'Gene', '2064', (0, 4))	('human', 'Species', '9606', (199, 204))	('gastric cancer', 'Phenotype', 'HP:0012126', (351, 365))	('epidermal growth factor receptor 2', 'Gene', '2064', (205, 239))	('esophageal squamous cell carcinoma', 'Disease', (255, 289))	('amplification', 'Var', (178, 191))	('cancer', 'Disease', 'MESH:D009369', (359, 365))	('HER2', 'Gene', (241, 245))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (27, 61))	('gastroesophageal junction adenocarcinoma', 'Disease', 'MESH:D008309', (298, 338))	('cancer', 'Disease', (514, 520))	('epidermal growth factor receptor 2', 'Gene', (205, 239))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (425, 429))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (108, 130))	('cancer', 'Phenotype', 'HP:0002664', (514, 520))	('gastric cancer', 'Disease', (351, 365))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (78, 103))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (255, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('gastroesophageal junction adenocarcinoma', 'Disease', (298, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (329, 338))	('gastroesophageal junction', 'Disease', (78, 103))	('cancer', 'Disease', (359, 365))
205840	23946770	However, in GEJAC and GC, no correlations were observed between HER2 amplification and the gender, age, degree of differentiation, invasion, vascular invasion and lymph node metastases of the patients (all P>0.05).	('vascular invasion', 'CPA', (141, 158))	('patients', 'Species', '9606', (192, 200))	('HER2', 'Gene', (64, 68))	('HER2', 'Gene', '2064', (64, 68))	('GC', 'Phenotype', 'HP:0012126', (22, 24))	('metastases', 'Disease', (174, 184))	('amplification', 'Var', (69, 82))	('metastases', 'Disease', 'MESH:D009362', (174, 184))
205853	23946770	Differences in HER2 dysregulation in primary solid tumors and metastases may, at least partially, explain HER2-targeted therapeutic inconsistencies.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('metastases', 'Disease', 'MESH:D009362', (62, 72))	('HER2', 'Gene', (15, 19))	('HER2', 'Gene', (106, 110))	('solid tumors', 'Disease', (45, 57))	('dysregulation', 'Var', (20, 33))	('HER2', 'Gene', '2064', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('HER2', 'Gene', '2064', (106, 110))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('metastases', 'Disease', (62, 72))
205876	23946770	The rates of HER2 gene amplification in ESCC, GEJAC and GC were 3.9 (3/76), 24.0 (12/50) and 18.8% (9/48), respectively (Figs.	('HER2', 'Gene', (13, 17))	('GC', 'Phenotype', 'HP:0012126', (56, 58))	('amplification', 'Var', (23, 36))	('HER2', 'Gene', '2064', (13, 17))
205884	23946770	Overexpression of HER2 is common in multi-type tumors, such as breast and ovarian cancer.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (63, 88))	('HER2', 'Gene', '2064', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('common', 'Reg', (26, 32))	('multi-type tumors', 'Disease', 'MESH:D046589', (36, 53))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('multi-type tumors', 'Disease', (36, 53))	('HER2', 'Gene', (18, 22))
205886	23946770	Overamplification of the HER2 gene has been shown to have a significant role in tumor development.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('HER2', 'Gene', (25, 29))	('HER2', 'Gene', '2064', (25, 29))	('Overamplification', 'Var', (0, 17))
205891	23946770	The rate of HER2 gene amplification has been recorded as between 6.5 and 7.5% in certain studies, while the results of the majority of studies were within 30%.	('amplification', 'Var', (22, 35))	('HER2', 'Gene', (12, 16))	('HER2', 'Gene', '2064', (12, 16))
205899	23946770	Zhan et al reported that there were correlations between the overexpression of HER2 and the differentiation of the carcinoma, HER2 gene amplification and the differentiation of the carcinoma and tumor stage.	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('HER2', 'Gene', '2064', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('overexpression', 'PosReg', (61, 75))	('differentiation', 'Disease', (92, 107))	('carcinoma and tumor', 'Disease', 'MESH:D009369', (181, 200))	('carcinoma', 'Disease', (115, 124))	('gene amplification', 'Var', (131, 149))	('HER2', 'Gene', (126, 130))	('carcinoma', 'Disease', 'MESH:D002277', (181, 190))	('HER2', 'Gene', '2064', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('HER2', 'Gene', (79, 83))	('carcinoma', 'Disease', 'MESH:D002277', (115, 124))	('carcinoma', 'Disease', (181, 190))
205900	23946770	By contrast, HER2 positivity was associated with reduced tumor aggressiveness and independently associated with improved survival in resected esophageal adenocarcinoma, according to a study at the Mayo Clinic.	('survival', 'MPA', (121, 129))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (142, 167))	('reduced', 'NegReg', (49, 56))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (57, 77))	('HER2', 'Gene', (13, 17))	('positivity', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('Mayo', 'Species', '162683', (197, 201))	('HER2', 'Gene', '2064', (13, 17))	('esophageal adenocarcinoma', 'Disease', (142, 167))	('improved', 'PosReg', (112, 120))	('tumor aggressiveness', 'Disease', (57, 77))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (142, 167))	('aggressiveness', 'Phenotype', 'HP:0000718', (63, 77))
205903	23946770	The present results showed that the rate of HER2 gene amplification was 18.8% in patients with GC.	('amplification', 'Var', (54, 67))	('patients', 'Species', '9606', (81, 89))	('HER2', 'Gene', (44, 48))	('HER2', 'Gene', '2064', (44, 48))	('GC', 'Phenotype', 'HP:0012126', (95, 97))
205912	23946770	By comparing the clinicopathological features of three types of tumor, the features of HER-2 amplification in GEJAC were observed to be more similar to GC.	('amplification', 'Var', (93, 106))	('HER-2', 'Gene', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('GC', 'Phenotype', 'HP:0012126', (152, 154))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('HER-2', 'Gene', '2064', (87, 92))	('GEJAC', 'Disease', (110, 115))
205925	23085486	We had established previously a tumor invasion gene signature derived from mRNA profiling of invading genetically engineered human esophageal cells, transformed with epidermal growth factor receptor (EGFR) overexpression and p53R175H mutation, (EPC2-hTERT-EGFR-p53R175H) that was grown in a 3D organotypic culture (OTC) system.	('p53R175H', 'Var', (225, 233))	('p53R175H', 'Mutation', 'p.R53,175H', (225, 233))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('human', 'Species', '9606', (125, 130))	('epidermal growth factor receptor', 'Gene', '1956', (166, 198))	('hTERT', 'Gene', '7015', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('overexpression', 'PosReg', (206, 220))	('epidermal growth factor receptor', 'Gene', (166, 198))	('p53R175H', 'Mutation', 'p.R53,175H', (261, 269))	('tumor', 'Disease', (32, 37))	('hTERT', 'Gene', (250, 255))
205936	23085486	Fluorescent imaging showed a strong fluorescent signal in TE-11 xenograft tumors expressing periostin (Figure 1E, left panel, white arrow) compared to a low fluorescent signal in TT xenograft tumors (Figure 1E, right panel, white arrow), which do not express periostin.	('fluorescent signal', 'MPA', (36, 54))	('xenograft tumors', 'Disease', (64, 80))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('TT xenograft tumors', 'Disease', (179, 198))	('TT xenograft tumors', 'Disease', 'MESH:D009369', (179, 198))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('xenograft tumors', 'Disease', 'MESH:D009369', (64, 80))	('periostin', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('TE-11', 'Chemical', '-', (58, 63))	('xenograft tumors', 'Disease', 'MESH:D009369', (182, 198))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
205981	23493989	MIE is associated with a significant reduction in hospital stay, with a mean postoperative stay of 12 days (Table 2).	('reduction', 'NegReg', (37, 46))	('MIE', 'Chemical', '-', (0, 3))	('MIE', 'Var', (0, 3))	('hospital stay', 'MPA', (50, 63))
205996	22843625	The decision coefficient (R2) of tumor length difference at the threshold levels of SUV 2.5, SUV 20% and SUV 25% were 0.79, 0.65 and 0.54, respectively.	('SUV 25%', 'Var', (105, 112))	('SUV 2.5', 'Var', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('SUV 20%', 'Var', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
206050	22843625	The decision coefficients (R) of tumor length difference at the threshold levels of SUV 2.5, SUV 20% and SUV 25% were 0.79, 0.65, and 0.54, respectively.	('SUV 25%', 'Var', (105, 112))	('SUV 2.5', 'Var', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
206053	22843625	By comparing eight different threshold levels, the results revealed that GTVPET using a threshold setting of SUV 20% or SUV 2.5 correlated well with tumor length, VR and CI of GTVCT.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('SUV 2.5', 'Var', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('GTV', 'Chemical', '-', (73, 76))	('GTV', 'Chemical', '-', (176, 179))
206073	22843625	compared GTVPET with GTVCT/EUS at the level of the esophageal tumor epicenter, and found that a threshold setting of SUV 2.5 and SUVL4sigma (equal to SUV 2.4) resulted in the highest CI value (0.48 and 0.47, respectively).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('GTV', 'Chemical', '-', (21, 24))	('esophageal tumor', 'Disease', 'MESH:D004938', (51, 67))	('esophageal tumor', 'Disease', (51, 67))	('SUV 2.5', 'Var', (117, 124))	('SUVL4sigma', 'Var', (129, 139))	('esophageal tumor', 'Phenotype', 'HP:0100751', (51, 67))	('GTV', 'Chemical', '-', (9, 12))
206078	22843625	When using smaller cutoff values, such as SUV 2 or SUV 15%, for the threshold setting, more adjacent normal tissue would be included within the GTVPET.	('SUV 2', 'Var', (42, 47))	('SUV 15%', 'Var', (51, 58))	('GTV', 'Chemical', '-', (144, 147))
206086	22843625	The use of threshold levels of SUV 20% or SUV 2.5 achieves the optimal correlation with tumor length, VR and CI.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('SUV 20%', 'Var', (31, 38))	('SUV 2.5', 'Var', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
206194	32226770	After adjustment for the competing risk of death, the 3- and 5-year rates of grade >= 2 events were 28.25 and 28.81% for patients with mean heart dose >= 12 Gy and 11.83 and 15.98% for patients with mean heart dose <12 Gy (p = 0.045; Figure 3A), and similar findings were noted for grade >= 3 cardiac events (p = 0.031, Figure 3B).	('death', 'Disease', 'MESH:D003643', (43, 48))	('grade', 'Disease', (77, 82))	('death', 'Disease', (43, 48))	('>= 12', 'Var', (151, 156))	('patients', 'Species', '9606', (185, 193))	('patients', 'Species', '9606', (121, 129))
206222	32226770	Previous studies found that the most relevant dosimetric factors associated with cardiac events or OS for patients treated with thoracic radiation were diverse, such as mean heart dose, heart V45, heart V50, and heart V55, but did not appear to be the heart V5.	('heart V55', 'Var', (212, 221))	('heart', 'MPA', (186, 191))	('associated', 'Reg', (65, 75))	('patients', 'Species', '9606', (106, 114))	('heart', 'MPA', (197, 202))
206225	32226770	For patients without preexisting ischemic heart disease, high WHO/ISH 10-year risk was significantly associated with a near 2-fold increase in the likelihood of developing of a grade >= 2 cardiac event.	('high', 'Var', (57, 61))	('increase', 'PosReg', (131, 139))	('ischemic heart disease', 'Disease', 'MESH:D003324', (33, 55))	('patients', 'Species', '9606', (4, 12))	('grade >= 2 cardiac event', 'MPA', (177, 201))	('ischemic heart disease', 'Disease', (33, 55))
206235	32226770	In summary, heart dose was significantly associated with an increased cardiac event rate and a worse 5-year OS outcome for patients with stage III esophageal cancer treated with definitive radiotherapy.	('stage III esophageal cancer', 'Disease', (137, 164))	('stage III esophageal cancer', 'Disease', 'MESH:D004938', (137, 164))	('heart dose', 'Var', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cardiac event', 'MPA', (70, 83))	('patients', 'Species', '9606', (123, 131))	('increased', 'PosReg', (60, 69))
206241	31292541	Targeted next-generation sequencing identified 56 non-synonymous alterations in 51 genes including TP53 and APC, which are commonly altered in GEJ cancer.	('TP53', 'Gene', (99, 103))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('non-synonymous alterations', 'Var', (50, 76))	('APC', 'Disease', 'MESH:D011125', (108, 111))	('TP53', 'Gene', '7157', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('APC', 'Disease', (108, 111))
206242	31292541	In addition, multiple copy-number alterations were found including EGFR and K-RAS gene amplifications and loss of CDKN2A and CDKN2B.	('CDKN2A', 'Gene', '1029', (114, 120))	('CDKN2B', 'Gene', '1030', (125, 131))	('amplifications', 'Var', (87, 101))	('K-RAS', 'Gene', '3845', (76, 81))	('K-RAS', 'Gene', (76, 81))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('loss', 'NegReg', (106, 110))	('CDKN2B', 'Gene', (125, 131))	('CDKN2A', 'Gene', (114, 120))
206244	31292541	Finally, pharmacologic inhibition of the EGFR signaling pathway led to downregulation of key downstream kinases and inhibition of cell proliferation in vitro.	('downregulation', 'NegReg', (71, 85))	('EGFR', 'Gene', (41, 45))	('key downstream kinases', 'Pathway', (89, 111))	('inhibition', 'NegReg', (116, 126))	('EGFR', 'Gene', '1956', (41, 45))	('cell proliferation', 'CPA', (130, 148))	('pharmacologic', 'Var', (9, 22))
206259	31292541	The recent TCGA study identified important mutations in TP53, CDKN2A, ARID1A, SMAD4 and ERBB2 in EAC.	('EAC', 'Disease', (97, 100))	('ERBB2', 'Gene', (88, 93))	('ERBB2', 'Gene', '2064', (88, 93))	('SMAD4', 'Gene', (78, 83))	('EAC', 'Disease', 'MESH:D004941', (97, 100))	('TP53', 'Gene', '7157', (56, 60))	('ARID1A', 'Gene', '8289', (70, 76))	('mutations', 'Var', (43, 52))	('ARID1A', 'Gene', (70, 76))	('TP53', 'Gene', (56, 60))	('CDKN2A', 'Gene', (62, 68))	('SMAD4', 'Gene', '4089', (78, 83))	('CDKN2A', 'Gene', '1029', (62, 68))
206260	31292541	Notably, these findings are consistent with previous discoveries that mutations of CDKN2A and TP53 are present in dysplastic Barrett's esophagus.	('mutations', 'Var', (70, 79))	('CDKN2A', 'Gene', '1029', (83, 89))	('TP53', 'Gene', '7157', (94, 98))	('present', 'Reg', (103, 110))	('TP53', 'Gene', (94, 98))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (125, 144))	("dysplastic Barrett's esophagus", 'Disease', (114, 144))	('CDKN2A', 'Gene', (83, 89))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (114, 144))
206261	31292541	Mutations of ERBB2 in tumors lacking ERBB2 amplification can also occur, exemplifying an alternative mechanism of activation of the ERBB2-directed signaling pathway.	('activation', 'PosReg', (114, 124))	('ERBB2', 'Gene', (37, 42))	('ERBB2', 'Gene', (132, 137))	('ERBB2', 'Gene', '2064', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('ERBB2', 'Gene', '2064', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('ERBB2', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (22, 28))	('ERBB2', 'Gene', '2064', (132, 137))
206277	31292541	Targeted gene sequencing of cancer-related genes identified: 1) 56 nonsynonymous variants in approximately 51 genes including TP53 and APC; and 2) multiple copy number alterations including amplification of EGFR and K-RAS and loss of CDKN2A and CDKN2B.	('K-RAS', 'Gene', (216, 221))	('APC', 'Disease', (135, 138))	('amplification', 'Var', (190, 203))	('TP53', 'Gene', (126, 130))	('CDKN2B', 'Gene', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('EGFR', 'Gene', '1956', (207, 211))	('APC', 'Disease', 'MESH:D011125', (135, 138))	('CDKN2B', 'Gene', '1030', (245, 251))	('EGFR', 'Gene', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('CDKN2A', 'Gene', (234, 240))	('loss', 'NegReg', (226, 230))	('cancer', 'Disease', (28, 34))	('K-RAS', 'Gene', '3845', (216, 221))	('TP53', 'Gene', '7157', (126, 130))	('CDKN2A', 'Gene', '1029', (234, 240))
206328	31292541	We identified 56 non-synonymous coding variants in 51 cancer-related genes, including TP53 and APC as previously reported in GEJ cancer (Supplemental Table 2).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('APC', 'Disease', (95, 98))	('TP53', 'Gene', '7157', (86, 90))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', (54, 60))	('TP53', 'Gene', (86, 90))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('non-synonymous coding variants', 'Var', (17, 47))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('APC', 'Disease', 'MESH:D011125', (95, 98))
206329	31292541	3a and summarized in Supplemental Table 3, copy number changes were detected at 17 CNV loci including a 49.1-Mbp gain encompassing the EGFR gene within chromosome 7 (Fig.	('EGFR', 'Gene', '1956', (135, 139))	('copy number', 'Var', (43, 54))	('Mbp', 'Gene', '4155', (109, 112))	('gain', 'PosReg', (113, 117))	('EGFR', 'Gene', (135, 139))	('Mbp', 'Gene', (109, 112))
206340	31292541	To determine whether GEAMP cells in culture express squamous cytokeratins, we performed Western blot analysis of columnar CK8/18, squamous CK13, and squamous CK14 proteins in GEAMP cells as well as in hTERT-immortalized esophageal squamous NES-B10T cells and the esophageal squamous cancer cell line KYSE180.	('CK8/18', 'Gene', (122, 128))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (263, 289))	('CK8/18', 'Gene', '3856;3875', (122, 128))	('squamous cancer', 'Phenotype', 'HP:0002860', (274, 289))	('esophageal squamous cancer', 'Disease', (263, 289))	('B10T', 'SUBSTITUTION', 'None', (244, 248))	('CK14', 'Gene', '3861', (158, 162))	('B10T', 'Var', (244, 248))	('KYSE180', 'CellLine', 'CVCL:1349', (300, 307))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('CK14', 'Gene', (158, 162))	('CK13', 'Gene', '3860', (139, 143))	('squamous NES', 'Phenotype', 'HP:0002860', (231, 243))	('CK13', 'Gene', (139, 143))
206341	31292541	We found columnar marker CK8/18 was more highly expressed in GEAMP cells than in NES-B10T or KYSE180 cells (Fig.	('B10T', 'Var', (85, 89))	('B10T', 'SUBSTITUTION', 'None', (85, 89))	('CK8/18', 'Gene', (25, 31))	('CK8/18', 'Gene', '3856;3875', (25, 31))	('KYSE180', 'CellLine', 'CVCL:1349', (93, 100))	('highly', 'PosReg', (41, 47))
206357	31292541	To test whether a different pharmacologic inhibitor of EGFR decreased the oncogenic signaling pathways in GEAMP cells, GEAMP cells were treated with 5 muM or 10 muM lapatinib for 48 hours.	('lapatinib', 'Chemical', 'MESH:C490728', (165, 174))	('muM', 'Gene', '56925', (151, 154))	('decreased', 'NegReg', (60, 69))	('EGFR', 'Gene', '1956', (55, 59))	('muM', 'Gene', (161, 164))	('EGFR', 'Gene', (55, 59))	('muM', 'Gene', (151, 154))	('inhibitor', 'Var', (42, 51))	('oncogenic signaling pathways', 'Pathway', (74, 102))	('muM', 'Gene', '56925', (161, 164))
206373	31292541	Of note, GEAMP cells contained a frameshift mutation in TP53 and a truncating mutation in APC, both of which are frequently altered in GEJ tumors.	('truncating', 'MPA', (67, 77))	('TP53', 'Gene', '7157', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('frameshift mutation', 'Var', (33, 52))	('TP53', 'Gene', (56, 60))	('APC', 'Disease', 'MESH:D011125', (90, 93))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('APC', 'Disease', (90, 93))
206389	31292541	It was previously reported that EGFR mutation-positive lung adenocarcinoma could transform into squamous cell carcinoma following treatment with EGFR tyrosine kinase inhibitors.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('squamous cell carcinoma', 'Disease', (96, 119))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 119))	('tyrosine kinase', 'Gene', (150, 165))	('mutation-positive', 'Var', (37, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('lung adenocarcinoma', 'Disease', (55, 74))	('EGFR', 'Gene', '1956', (145, 149))	('EGFR', 'Gene', '1956', (32, 36))	('transform', 'Reg', (81, 90))	('EGFR', 'Gene', (145, 149))	('EGFR', 'Gene', (32, 36))	('tyrosine kinase', 'Gene', '7294', (150, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (55, 74))
206397	31322237	Furthermore, DP treatment induced caspase-dependent apoptosis, which could be reversed by exposure to Z-VAD-FMK, a caspase inhibitor.	('caspase-dependent apoptosis', 'CPA', (34, 61))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (102, 111))	('DP treatment', 'Var', (13, 25))	('DP', 'Chemical', 'MESH:C060327', (13, 15))
206426	31322237	9661T), cleaved caspase-7 (1:500; cat.	('caspase-7', 'Gene', (16, 25))	('cleaved', 'Var', (8, 15))	('caspase-7', 'Gene', '840', (16, 25))
206469	31322237	1C, after treatment for 24 h, DP at 80 microM showed reduced toxicity towards LO2 cells compared with the ECA109 cells.	('toxicity', 'Disease', 'MESH:D064420', (61, 69))	('toxicity', 'Disease', (61, 69))	('DP at 80 microM', 'Var', (30, 45))	('reduced', 'NegReg', (53, 60))	('DP', 'Chemical', 'MESH:C060327', (30, 32))	('LO2', 'CellLine', 'CVCL:6926', (78, 81))
206473	31322237	2A, the colony-forming ability of the ECA109 and EC9706 cells decreased significantly in a concentration-dependent manner compared with control group.	('EC9706', 'CellLine', 'CVCL:E307', (49, 55))	('EC9706', 'Var', (49, 55))	('colony-forming ability', 'CPA', (8, 30))	('decreased', 'NegReg', (62, 71))
206483	31322237	In addition, pretreatment for 1 h with Z-VAD-FMK, a broad-spectrum caspase inhibitor, significantly reversed apoptosis induced by DP (80 microM) compared to 80 microM DP treatment alone.	('DP (80 microM', 'Var', (130, 143))	('apoptosis', 'CPA', (109, 118))	('reversed', 'NegReg', (100, 108))	('DP', 'Chemical', 'MESH:C060327', (167, 169))	('DP', 'Chemical', 'MESH:C060327', (130, 132))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (39, 48))
206486	31322237	The role of DP-induced apoptosis in the anti-proliferative effect of this compound was analyzed through pretreatment of ECA109 cells with Z-VAD-FMK before co-incubation with 80 microM DP for 24 h. The results showed that Z-VAD-FMK significantly attenuated the DP-induced reduction in cell viability to 59.8% in ECA109 cells, compared with 36.2% for DP (80 microM) treatment alone (Fig.	('DP', 'Chemical', 'MESH:C060327', (184, 186))	('DP', 'Chemical', 'MESH:C060327', (12, 14))	('Z-VAD-FMK', 'Var', (221, 230))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (138, 147))	('attenuated', 'NegReg', (245, 255))	('DP-induced', 'Disease', (260, 270))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (221, 230))	('DP', 'Chemical', 'MESH:C060327', (260, 262))	('cell viability', 'CPA', (284, 298))	('DP', 'Chemical', 'MESH:C060327', (349, 351))	('reduction', 'NegReg', (271, 280))
206508	31322237	In the present study, it was found that DP treatment significantly induced cell cycle arrest at the G2/M phase in a concentration-dependent manner.	('induced', 'Reg', (67, 74))	('cell cycle arrest at the G2/M phase', 'CPA', (75, 110))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (75, 92))	('DP', 'Chemical', 'MESH:C060327', (40, 42))	('DP treatment', 'Var', (40, 52))
206515	31322237	In the present study, both extrinsic and intrinsic apoptosis were induced by DP treatment in ESCC cells, evidenced by the increased expression of DR4, DR5, cleaved caspase-3/-7/-9, and cleaved PARP, and decreased expression of total PARP, total caspase-3/7, Bcl-2 and caspase-9/-10.	('caspase-3/7', 'Gene', '836;840', (245, 256))	('caspase-3', 'Gene', '836', (245, 254))	('caspase-9/-10', 'Gene', '842;843', (268, 281))	('Bcl-2', 'Gene', (258, 263))	('extrinsic', 'CPA', (27, 36))	('cleaved', 'Var', (185, 192))	('DR5', 'Gene', '8795', (151, 154))	('PARP', 'Gene', '142', (193, 197))	('caspase-3', 'Gene', (245, 254))	('DP', 'Chemical', 'MESH:C060327', (77, 79))	('caspase-9/-10', 'Gene', (268, 281))	('PARP', 'Gene', (193, 197))	('increased', 'PosReg', (122, 131))	('DR5', 'Gene', (151, 154))	('PARP', 'Gene', '142', (233, 237))	('Bcl-2', 'Gene', '596', (258, 263))	('DR4', 'Gene', (146, 149))	('expression', 'MPA', (213, 223))	('caspase-3', 'Gene', '836', (164, 173))	('PARP', 'Gene', (233, 237))	('intrinsic apoptosis', 'CPA', (41, 60))	('caspase-3', 'Gene', (164, 173))	('DR4', 'Gene', '8797', (146, 149))	('decreased', 'NegReg', (203, 212))	('caspase-3/7', 'Gene', (245, 256))	('cleaved', 'Var', (156, 163))	('expression', 'MPA', (132, 142))
206536	31322237	Moreover, the JAK2/STAT3 and AKT/FOXO3a signaling pathways were inhibited by DP treatment.	('DP treatment', 'Var', (77, 89))	('AKT', 'Gene', '207', (29, 32))	('inhibited', 'NegReg', (64, 73))	('STAT3', 'Gene', '6774', (19, 24))	('JAK2', 'Gene', '3717', (14, 18))	('DP', 'Chemical', 'MESH:C060327', (77, 79))	('STAT3', 'Gene', (19, 24))	('AKT', 'Gene', (29, 32))	('JAK2', 'Gene', (14, 18))	('FOXO3a', 'Gene', '2309', (33, 39))	('FOXO3a', 'Gene', (33, 39))
206547	31032230	Treatment with HMGB1 inhibitors prolonged the survival of malignant mesothelioma xenograft mice (14).	('malignant mesothelioma', 'Disease', (58, 80))	('mice', 'Species', '10090', (91, 95))	('prolonged', 'PosReg', (32, 41))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (58, 80))	('inhibitors', 'Var', (21, 31))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (58, 80))	('survival', 'CPA', (46, 54))	('HMGB1', 'Gene', (15, 20))
206551	31032230	Aberrant expression of KRT7 in budding cancer cells represents a modification of the epithelial phenotype (epithelial-epithelial transition) which may be linked to gains in motility and invasive potential (18).	('KRT7', 'Gene', (23, 27))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('invasive potential', 'CPA', (186, 204))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('gains in motility', 'Disease', (164, 181))	('gains in motility', 'Disease', 'MESH:D015430', (164, 181))	('KRT7', 'Gene', '3855', (23, 27))
206561	31032230	PRMT1 "PRMT1 is the main enzyme that mediates the methylation of histone H4, a specific tag for epigenetic transcriptional activation.	('PRMT1', 'Gene', '3276', (7, 12))	('PRMT1', 'Gene', (0, 5))	('histone H4', 'Gene', (65, 75))	('PRMT1', 'Gene', (7, 12))	('histone H4', 'Gene', '8294', (65, 75))	('methylation', 'Var', (50, 61))	('PRMT1', 'Gene', '3276', (0, 5))
206564	31032230	Knockdown of PRMT1 in three NSCLC cell lines was associated with a significant suppression of cell growth (25).	('suppression', 'NegReg', (79, 90))	('NSCLC', 'Disease', (28, 33))	('PRMT1', 'Gene', '3276', (13, 18))	('Knockdown', 'Var', (0, 9))	('PRMT1', 'Gene', (13, 18))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))
206566	31032230	S100P "S100P proteins are localized in the cytoplasm of a wide range of cells and involved in the regulation of several cellular processes such as cell cycle progression and differentiation (34).	('cell cycle progression', 'CPA', (147, 169))	('S100P', 'Var', (7, 12))	('S100P', 'SUBSTITUTION', 'None', (0, 5))	('S100P', 'SUBSTITUTION', 'None', (7, 12))	('involved in', 'Reg', (82, 93))	('proteins', 'Protein', (13, 21))	('differentiation', 'CPA', (174, 189))	('S100P', 'Var', (0, 5))
206567	31032230	Significant correlation was found between high expression and S100P and shorter overall survival (OS) and increased drug resistance in gastric and ovarian cancer (28).	('drug resistance', 'CPA', (116, 131))	('drug resistance', 'Phenotype', 'HP:0020174', (116, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('S100P', 'Var', (62, 67))	('shorter', 'NegReg', (72, 79))	('overall survival', 'MPA', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('high expression', 'Var', (42, 57))	('S100P', 'SUBSTITUTION', 'None', (62, 67))	('gastric and ovarian cancer', 'Disease', 'MESH:D013274', (135, 161))	('increased', 'PosReg', (106, 115))
206568	31032230	S100P also plays a key role in the aggressiveness of pancreatic cancer which is likely mediated by its ability to activate RAGE (29).	('aggressiveness of pancreatic cancer', 'Disease', (35, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('RAGE', 'Gene', '101669765', (123, 127))	('RAGE', 'Gene', (123, 127))	('S100P', 'SUBSTITUTION', 'None', (0, 5))	('aggressiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (35, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('aggressiveness', 'Phenotype', 'HP:0000718', (35, 49))	('S100P', 'Var', (0, 5))
206569	31032230	We found S100P to be expressed at a 7.22x greater level in EAC tumors compared to normal esophagus tissue (P < 0.0001)."	('S100P', 'SUBSTITUTION', 'None', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('S100P', 'Var', (9, 14))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('EAC', 'Disease', (59, 62))
206572	31032230	Knockdown of ANXA1 was found to block the intake of chemotherapy, leading to anticancer drug resistance (11).	('ANXA1', 'Gene', '301', (13, 18))	('drug resistance', 'Phenotype', 'HP:0020174', (88, 103))	('Knockdown', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('leading to', 'Reg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ANXA1', 'Gene', (13, 18))	('intake of chemotherapy', 'MPA', (42, 64))
206578	31032230	On the other hand, patients with high CRNN gene expression were more likely to achieve a pathologic complete response to neoadjuvant chemoradiotherapy (13).	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (19, 27))	('CRNN', 'Gene', (38, 42))	('CRNN', 'Gene', '49860', (38, 42))
206587	31032230	And on the other hand, a high S100A8 expression was found to be a favorable prognostic factor for the survival of oropharyngeal squamous cell carcinoma (38).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('S100A8', 'Gene', (30, 36))	('squamous cell carcinoma', 'Disease', (128, 151))	('S100A8', 'Gene', '6279', (30, 36))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('high', 'Var', (25, 29))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (114, 151))	('expression', 'MPA', (37, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
206595	30286050	Rs4938723 Polymorphism Is Associated with Susceptibility to Hepatocellular Carcinoma Risk and Is a Protective Factor in Leukemia, Colorectal, and Esophageal Cancer Growing evidence indicates that a non-coding RNA named miR-34b/c plays crucial roles in carcinogenesis, and its common polymorphism, pri-miR-34b/c rs4938723, also participates in this process and is associated with cancer susceptibility.	('miR-34b', 'Gene', (301, 308))	('rs4938723', 'Mutation', 'rs4938723', (311, 320))	('carcinogenesis', 'Disease', (252, 266))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (146, 163))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('miR-34b', 'Gene', '407041', (219, 226))	('carcinogenesis', 'Disease', 'MESH:D063646', (252, 266))	('miR-34b', 'Gene', (219, 226))	('Leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('Rs4938723 Polymorphism', 'Var', (0, 22))	('cancer', 'Disease', (379, 385))	('associated', 'Reg', (363, 373))	('Carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Hepatocellular Carcinoma', 'Disease', (60, 84))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('Polymorphism', 'Var', (10, 22))	('Esophageal Cancer', 'Disease', (146, 163))	('rs4938723', 'Var', (311, 320))	('participates', 'Reg', (327, 339))	('Hepatocellular Carcinoma', 'Disease', 'MESH:D006528', (60, 84))	('miR-34b', 'Gene', '407041', (301, 308))	('Factor in Leukemia', 'Disease', 'MESH:D007938', (110, 128))	('Cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Factor in Leukemia', 'Disease', (110, 128))	('cancer', 'Disease', 'MESH:D009369', (379, 385))
206596	30286050	Therefore, we carried out an updated analysis to evaluate this relationship between rs4938723 polymorphism and cancer susceptibility.	('rs4938723', 'Mutation', 'rs4938723', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rs4938723', 'Var', (84, 93))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
206598	30286050	The main results were observed in the stratified analysis subgroups in cancer type subgroup: rs4938723 polymorphism may be a protective factor in leukemia, colorectal cancer, and esophageal cancer; however, C-allele was a risk factor in carriers for hepatocellular carcinoma.	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('rs4938723 polymorphism', 'Var', (93, 115))	('cancer', 'Disease', (167, 173))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (250, 274))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (190, 196))	('esophageal cancer', 'Disease', (179, 196))	('cancer', 'Disease', (71, 77))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (250, 274))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('rs4938723', 'Mutation', 'rs4938723', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (156, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('C', 'Chemical', 'MESH:D002244', (207, 208))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('hepatocellular carcinoma', 'Disease', (250, 274))	('colorectal cancer', 'Disease', (156, 173))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('polymorphism', 'Var', (103, 115))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('leukemia', 'Disease', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
206599	30286050	Current meta-analysis suggested that rs4938723 polymorphism was potentially associated with hepatocellular carcinoma risk, but this polymorphism had a decreased association for susceptibility to esophageal cancer, leukemia, and colorectal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('rs4938723', 'Var', (37, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (228, 245))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('leukemia', 'Phenotype', 'HP:0001909', (214, 222))	('esophageal cancer', 'Disease', (195, 212))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('leukemia', 'Disease', 'MESH:D007938', (214, 222))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('leukemia', 'Disease', (214, 222))	('rs4938723', 'Mutation', 'rs4938723', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('colorectal cancer', 'Disease', 'MESH:D015179', (228, 245))	('decreased', 'NegReg', (151, 160))	('associated', 'Reg', (76, 86))	('hepatocellular carcinoma', 'Disease', (92, 116))	('colorectal cancer', 'Disease', (228, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))
206600	30286050	Furthermore, studies with larger sample sizes and including gene-gene or gene-environment interactions should be carried out to elucidate the role of rs4938723 polymorphism in cancer risk.	('rs4938723', 'Mutation', 'rs4938723', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('rs4938723', 'Var', (150, 159))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
206603	30286050	One of the major reasons for variability among individuals is the presence of single-nucleotide polymorphisms (SNPs), which makes individuals more susceptibility to cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('susceptibility', 'Reg', (147, 161))	('single-nucleotide polymorphisms', 'Var', (78, 109))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('more', 'PosReg', (142, 146))
206605	30286050	There is growing evidence that misalignment of miRNA expression affects tumorigenesis based on activation of either tumor suppressor or oncogene.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('affects', 'Reg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('activation', 'PosReg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('miRNA expression', 'Protein', (47, 63))	('tumor', 'Disease', (116, 121))	('misalignment', 'Var', (31, 43))
206606	30286050	miRNA gene polymorphism affects tumor susceptibility by destroying miRNA biosynthesis and target gene expression, changing mature miRNA, or by affecting its interaction with target genes.	('destroying', 'NegReg', (56, 66))	('interaction', 'Interaction', (157, 168))	('miRNA biosynthesis', 'MPA', (67, 85))	('expression', 'MPA', (102, 112))	('polymorphism', 'Var', (11, 23))	('affecting', 'Reg', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mature miRNA', 'MPA', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('affects', 'Reg', (24, 31))	('tumor', 'Disease', (32, 37))	('miRNA', 'Gene', (0, 5))	('changing', 'Reg', (114, 122))
206607	30286050	For example, in each case, the rs11614913 variant homozygote CC was associated with increased cancer risk.	('rs11614913', 'Var', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rs11614913', 'Mutation', 'rs11614913', (31, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
206608	30286050	Risk of developing oesophageal cancer in Caucasian males and never-smokers was significantly associated with the rs11614913 variant homozygote TT, the minor allele in this population.	('C', 'Chemical', 'MESH:D002244', (41, 42))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('rs11614913', 'Mutation', 'rs11614913', (113, 123))	('associated', 'Reg', (93, 103))	('oesophageal cancer', 'Disease', (19, 37))	('rs11614913', 'Var', (113, 123))	('oesophageal cancer', 'Disease', 'MESH:D009369', (19, 37))
206609	30286050	Rs11614913 is located on the 3' passenger (3p) strand mature sequence of mir-196a-2, thereby possibly affecting both maturation and the repertoire of target mRNAs with which it interacts.	('affecting', 'Reg', (102, 111))	('interacts', 'Interaction', (177, 186))	('Rs11614913', 'Var', (0, 10))	('mir-196a-2', 'Gene', (73, 83))	('mir-196a-2', 'Gene', '406973', (73, 83))	('maturation', 'MPA', (117, 127))	('Rs11614913', 'Mutation', 'Rs11614913', (0, 10))
206610	30286050	Indeed, previous studies have shown that sequence variations in mature and precursor miRNA sequences affect miRNA biogenesis, and levels of mature miR-196a-2 were lower in CC carriers than in TT carriers.	('miR-196a-2', 'Gene', (147, 157))	('miR-196a-2', 'Gene', '406973', (147, 157))	('affect', 'Reg', (101, 107))	('levels', 'MPA', (130, 136))	('sequence variations', 'Var', (41, 60))	('lower', 'NegReg', (163, 168))	('miRNA biogenesis', 'MPA', (108, 124))
206614	30286050	In the promoter region of Pri-miR-34b/c, a potentially functional rs4938723 T/C variant may affect the binding of transcription factor Gata-X, thereby changing the expression of pri-miR-34b/c.	('Gata', 'Gene', (135, 139))	('miR-34b', 'Gene', (30, 37))	('Gata', 'Gene', '55278', (135, 139))	('expression', 'MPA', (164, 174))	('binding', 'Interaction', (103, 110))	('miR-34b', 'Gene', '407041', (30, 37))	('miR-34b', 'Gene', (182, 189))	('changing', 'Reg', (151, 159))	('rs4938723', 'Mutation', 'rs4938723', (66, 75))	('affect', 'Reg', (92, 98))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('miR-34b', 'Gene', '407041', (182, 189))	('rs4938723 T/C', 'Var', (66, 79))
206615	30286050	The rs4938723 T>C variant may potentially influence the expression of miR-34b/c via genetic and epigenetic mechanisms, leading to increased or decreased risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('decreased', 'NegReg', (143, 152))	('rs4938723', 'Mutation', 'rs4938723', (4, 13))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('expression', 'MPA', (56, 66))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('miR-34b', 'Gene', (70, 77))	('influence', 'Reg', (42, 51))	('cancer', 'Disease', (161, 167))	('rs4938723 T>C', 'Var', (4, 17))	('miR-34b', 'Gene', '407041', (70, 77))
206617	30286050	Similar to other kinds of polymorphisms, miR-34b/c rs4938723 polymorphism may influence its own expression, then affect its target genes' expression, finally promoting or inhibiting translation of target proteins to act on several biological functions.	('influence', 'Reg', (78, 87))	('rs4938723', 'Var', (51, 60))	('inhibiting', 'NegReg', (171, 181))	('expression', 'MPA', (96, 106))	('miR-34b', 'Gene', (41, 48))	('expression', 'MPA', (138, 148))	('translation', 'MPA', (182, 193))	('affect', 'Reg', (113, 119))	('rs4938723', 'Mutation', 'rs4938723', (51, 60))	('miR-34b', 'Gene', '407041', (41, 48))	('promoting', 'PosReg', (158, 167))
206618	30286050	For example, Tong (2016) reported rs4938723 CC genotype was significantly associated with reduced lymphoblastic leukemia risk, and C-allele may increase the transcription activity of miR-34b/c.	('leukemia', 'Phenotype', 'HP:0001909', (112, 120))	('reduced', 'NegReg', (90, 97))	('C', 'Chemical', 'MESH:D002244', (131, 132))	('C', 'Chemical', 'MESH:D002244', (45, 46))	('transcription activity', 'MPA', (157, 179))	('rs4938723 CC', 'Var', (34, 46))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (98, 120))	('rs4938723', 'Mutation', 'rs4938723', (34, 43))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (98, 120))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('lymphoblastic leukemia', 'Disease', (98, 120))	('increase', 'PosReg', (144, 152))	('miR-34b', 'Gene', (183, 190))	('miR-34b', 'Gene', '407041', (183, 190))
206619	30286050	However, Chen (2016) found that TC+CC genotype was correlated with an increased risk of hepatocellular carcinoma compared to the TT genotype, which disagrees with Tong's results.	('TC', 'Chemical', 'MESH:D013667', (32, 34))	('TC+CC', 'Var', (32, 37))	('C', 'Chemical', 'MESH:D002244', (9, 10))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('increased risk of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 112))	('C', 'Chemical', 'MESH:D002244', (33, 34))	('C', 'Chemical', 'MESH:D002244', (36, 37))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (88, 112))	('hepatocellular carcinoma', 'Disease', (88, 112))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (88, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
206622	30286050	Li (2017) indicated a rs4938723 polymorphism had a significant relationship with the whole cancer risk.	('rs4938723', 'Mutation', 'rs4938723', (22, 31))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('relationship', 'Reg', (63, 75))	('rs4938723', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
206625	30286050	We considered that it was necessary to re-analyze all case-control studies to assess the association between rs4938723 variant and tumor susceptibility.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('rs4938723', 'Mutation', 'rs4938723', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('rs4938723', 'Var', (109, 118))
206627	30286050	Each publication that assessed the relationship between rs4938723 polymorphism and cancer risk was collected.	('rs4938723', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rs4938723', 'Mutation', 'rs4938723', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
206628	30286050	The selection criteria were: (1) evaluation of pri-miR-34b/c rs4938723 and all types of cancer risks, (2) case-control design, and (3) available genotype frequency.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('rs4938723', 'Mutation', 'rs4938723', (61, 70))	('miR-34b', 'Gene', (51, 58))	('rs4938723', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('miR-34b', 'Gene', '407041', (51, 58))
206630	30286050	Odds ratio (OR) with 95% confidence interval (CI) was used to measure the strength of the association between pri-miR-34b/c rs4938723 and cancers.	('miR-34b', 'Gene', (114, 121))	('miR-34b', 'Gene', '407041', (114, 121))	('rs4938723', 'Var', (124, 133))	('association', 'Interaction', (90, 101))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('rs4938723', 'Mutation', 'rs4938723', (124, 133))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
206631	30286050	We analyzed this correlation by using 5 different genetic models: C-allele vs. T-allele, CC vs. TT, CT vs. TT, CC+CT vs. TT, and CC vs. CT+TT.	('C', 'Chemical', 'MESH:D002244', (66, 67))	('C', 'Chemical', 'MESH:D002244', (100, 101))	('C', 'Chemical', 'MESH:D002244', (111, 112))	('C-allele', 'Var', (66, 74))	('C', 'Chemical', 'MESH:D002244', (90, 91))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('C', 'Chemical', 'MESH:D002244', (112, 113))	('CC vs.', 'Var', (129, 135))	('C', 'Chemical', 'MESH:D002244', (136, 137))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('C', 'Chemical', 'MESH:D002244', (129, 130))
206636	30286050	Finally, 29 different papers describing 30 case-control studies evaluating the relationship between rs4938723 polymorphism and cancer were identified.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs4938723', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('rs4938723', 'Mutation', 'rs4938723', (100, 109))
206644	30286050	mir-34b/c gene is part of the p53 pathway and enhances its tumor suppressor activities; it transcribes microRNA-34 b and c, which inhibit p53 antagonists, cyclin-dependent kinases, and pro-apoptotic proteins.	('enhances', 'PosReg', (46, 54))	('p53', 'Gene', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('inhibit', 'NegReg', (130, 137))	('p53', 'Gene', '7157', (138, 141))	('mir-34b', 'Gene', (0, 7))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('microRNA-34 b', 'Var', (103, 116))	('cyclin-dependent', 'Enzyme', (155, 171))	('mir-34b', 'Gene', '407041', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
206646	30286050	Recently, a SNP located at the promoter region of mir-34b/c gene (rs4938723T/C) was identified, and its role in tumorigenesis has been widely investigated, as it can alter miR-34b/c transcription levels, because it can affect GATA-X binding.	('mir-34b', 'Gene', (50, 57))	('miR-34b', 'Gene', '407041', (172, 179))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('GATA', 'Gene', (226, 230))	('mir-34b', 'Gene', '407041', (50, 57))	('GATA', 'Gene', '55278', (226, 230))	('rs4938723', 'Mutation', 'rs4938723', (66, 75))	('miR-34b', 'Gene', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('rs4938723T/C', 'Var', (66, 78))	('C', 'Chemical', 'MESH:D002244', (77, 78))	('tumor', 'Disease', (112, 117))	('alter', 'Reg', (166, 171))	('affect', 'Reg', (219, 225))
206648	30286050	Our meta-analysis explored the association between pri-miR-34b/c rs4938723 and overall cancer susceptibility, involving 13 950 cancer cases and 16 071 controls.	('miR-34b', 'Gene', '407041', (55, 62))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rs4938723', 'Mutation', 'rs4938723', (65, 74))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('miR-34b', 'Gene', (55, 62))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('rs4938723', 'Var', (65, 74))
206651	30286050	Second, rs4938723 polymorphism might carry out different functions in different types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('rs4938723', 'Var', (8, 17))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('rs4938723', 'Mutation', 'rs4938723', (8, 17))
206658	30286050	Our present analysis found novel evidence that the pri-miR-34b/c rs4938723 polymorphism had 2-tier effects on the risk of different types of cancers: rs493723 polymorphism was associated increased risk of hepatocellular carcinoma and decreased risk of leukemia, colorectal and esophageal cancer.	('miR-34b', 'Gene', '407041', (55, 62))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (205, 229))	('miR-34b', 'Gene', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('rs4938723', 'Gene', (65, 74))	('hepatocellular carcinoma', 'Disease', (205, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('leukemia', 'Phenotype', 'HP:0001909', (252, 260))	('rs493723', 'Mutation', 'rs493723', (150, 158))	('cancers', 'Disease', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rs493723', 'Var', (150, 158))	('leukemia', 'Disease', 'MESH:D007938', (252, 260))	('leukemia', 'Disease', (252, 260))	('decreased', 'NegReg', (234, 243))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (205, 229))	('rs4938723', 'Mutation', 'rs4938723', (65, 74))	('colorectal and esophageal cancer', 'Disease', 'MESH:D015179', (262, 294))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('increased risk of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (187, 229))
206659	30286050	Further studies with larger samples are needed to evaluate associations between rs4938723 polymorphism and each type of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('associations', 'Interaction', (59, 71))	('rs4938723', 'Var', (80, 89))	('type of cancer', 'Disease', 'MESH:D009369', (112, 126))	('rs4938723', 'Mutation', 'rs4938723', (80, 89))	('type of cancer', 'Disease', (112, 126))
206672	29457105	Concurrently, he was receiving weekly carboplatin and paclitaxel for HPV-negative T3N2cM0 base of tongue squamous cell carcinoma.	('carboplatin', 'Chemical', 'MESH:D016190', (38, 49))	('T3N2cM0', 'Var', (82, 89))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (98, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('paclitaxel', 'Chemical', 'MESH:D017239', (54, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 128))	('tongue squamous cell carcinoma', 'Disease', (98, 128))
206703	29457105	This case presented an airway and ventilation challenge as jet ventilation could worsen the tracheoesophageal fistula (TEF) and result in gastric overinflation.	('jet ventilation', 'Var', (59, 74))	('result in', 'Reg', (128, 137))	('worsen', 'PosReg', (81, 87))	('gastric overinflation', 'Disease', (138, 159))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (92, 117))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (92, 117))	('gastric overinflation', 'Disease', 'MESH:D013274', (138, 159))	('TEF', 'Phenotype', 'HP:0002575', (119, 122))	('tracheoesophageal fistula', 'Disease', (92, 117))
206755	27672286	The imbalance produced by loss of VIP- and NO-secreting neurons can lead to irreversible esophageal motor dysfunction.	('esophageal motor dysfunction', 'Disease', (89, 117))	('NO-secreting', 'Protein', (43, 55))	('VIP', 'Gene', '7432', (34, 37))	('lead to', 'Reg', (68, 75))	('imbalance', 'MPA', (4, 13))	('VIP', 'Gene', (34, 37))	('esophageal motor dysfunction', 'Disease', 'MESH:D004941', (89, 117))	('loss', 'Var', (26, 30))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
206783	27672286	Moreover, another study of achalasia patients had shown that the complement complex C5b-C9 (membrane attack complex) and IgM are deposited within or at the ganglion cells of the myenteric plexus.	('C5b-C9', 'Var', (84, 90))	('patients', 'Species', '9606', (37, 45))	('achalasia', 'Phenotype', 'HP:0002571', (27, 36))	('achalasia', 'Disease', (27, 36))	('achalasia', 'Disease', 'MESH:D004931', (27, 36))
206798	27672286	As IFN-gamma is vitally implicated in the regulation of immune response, aberrant regulation of its production can lead to autoimmune diseases.	('IFN-gamma', 'Gene', '3458', (3, 12))	('IFN-gamma', 'Gene', (3, 12))	('autoimmune diseases', 'Disease', (123, 142))	('aberrant regulation', 'Var', (73, 92))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (123, 142))	('production', 'MPA', (100, 110))	('autoimmune disease', 'Phenotype', 'HP:0002960', (123, 141))	('autoimmune diseases', 'Disease', 'MESH:D001327', (123, 142))	('lead to', 'Reg', (115, 122))
206818	27672286	IDO-mediated deprivation of tryptophan halts the proliferation of T cells at mid-G1 phase, which in concert with the pro-apoptotic activity of kynurenine leads to immune tolerance.	('halts', 'NegReg', (39, 44))	('immune tolerance', 'CPA', (163, 179))	('tryptophan', 'Chemical', 'MESH:D014364', (28, 38))	('leads to', 'Reg', (154, 162))	('rat', 'Species', '10116', (56, 59))	('kynurenine', 'Chemical', 'MESH:D007737', (143, 153))	('IDO', 'Gene', '3620', (0, 3))	('IDO', 'Gene', (0, 3))	('deprivation', 'Var', (13, 24))
206821	27672286	Patients with achalasia have shown a higher frequency of pDCregs in the myenteric plexus of esophageal tissue, as compared to control tissues (Figure 4).	('achalasia', 'Phenotype', 'HP:0002571', (14, 23))	('pDCregs', 'Var', (57, 64))	('Patients', 'Species', '9606', (0, 8))	('achalasia', 'Disease', (14, 23))	('achalasia', 'Disease', 'MESH:D004931', (14, 23))
206832	27672286	GAD65 antibodies are reportedly present in approximately 80% of patients with type I diabetes mellitus and in approximately 20% of patients with various organ-specific neurological disorders, including myasthenia gravis, Lambert-Eaton syndrome, autoimmune dysautonomias and encephalopathies.	('myasthenia gravis', 'Disease', (202, 219))	('encephalopathies', 'Disease', 'MESH:D001927', (274, 290))	('present', 'Reg', (32, 39))	('myasthenia', 'Phenotype', 'HP:0003473', (202, 212))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (85, 102))	('encephalopathies', 'Phenotype', 'HP:0001298', (274, 290))	('autoimmune dysautonomias', 'Disease', 'MESH:D054969', (245, 269))	('type I diabetes mellitus', 'Disease', 'MESH:D003922', (78, 102))	('neurological disorders', 'Disease', (168, 190))	('encephalopathies', 'Disease', (274, 290))	('patients', 'Species', '9606', (131, 139))	('myasthenia gravis', 'Disease', 'MESH:D009157', (202, 219))	('type I diabetes mellitus', 'Disease', (78, 102))	('GAD65', 'Gene', (0, 5))	('Lambert-Eaton syndrome', 'Disease', (221, 243))	('GAD65', 'Gene', '2572', (0, 5))	('patients', 'Species', '9606', (64, 72))	('autoimmune dysautonomias', 'Disease', (245, 269))	('neurological disorders', 'Disease', 'MESH:D009422', (168, 190))	('Lambert-Eaton syndrome', 'Disease', 'MESH:D015624', (221, 243))	('antibodies', 'Var', (6, 16))	('type I diabetes', 'Phenotype', 'HP:0100651', (78, 93))	('autoimmune dysautonomias', 'Phenotype', 'HP:0012332', (245, 269))	('dysautonomia', 'Phenotype', 'HP:0012332', (256, 268))
206837	27672286	For example, mutation in the ALADIN 12q13 gene, which is associated with Allgrove syndrome, specifically (Triple-A) in exons 1, 2, 7, 8, 10-14 and 16, and a poly(A) tract, shows clinical manifestations of achalasia, alacrima, and adrenocorticotrophic hormone-resistant adrenal insufficiency.	('alacrima', 'Disease', 'MESH:C562827', (216, 224))	('alacrima', 'Disease', (216, 224))	('ALADIN 12q13', 'Gene', (29, 41))	('achalasia', 'Disease', (205, 214))	('mutation', 'Var', (13, 21))	('achalasia', 'Disease', 'MESH:D004931', (205, 214))	('resistant adrenal insufficiency', 'Phenotype', 'HP:0011734', (259, 290))	('adrenal insufficiency', 'Disease', (269, 290))	('Allgrove syndrome', 'Disease', 'MESH:C536008', (73, 90))	('adrenocorticotrophic hormone-resistant adrenal insufficiency', 'Phenotype', 'HP:0008259', (230, 290))	('Allgrove syndrome', 'Disease', (73, 90))	('achalasia', 'Phenotype', 'HP:0002571', (205, 214))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (269, 290))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (269, 290))	('associated', 'Reg', (57, 67))	('alacrima', 'Phenotype', 'HP:0000522', (216, 224))
206838	27672286	In addition, achalasia has been associated with the multiple endocrine neoplasia type 2 (MEN 2) B syndrome, specifically a germline mutation in exon 16 (M918T) of the RET proto-oncogene on chromosome 10q11 that leads to a methionine-threonine amino acid substitution in the tyrosine kinase domain and thus constitutive activation of the oncogene.	('MEN', 'Species', '9606', (89, 92))	('neoplasia type 2', 'Disease', 'MESH:D009369', (71, 87))	('associated', 'Reg', (32, 42))	('achalasia', 'Disease', 'MESH:D004931', (13, 22))	('RET', 'Gene', '5979', (167, 170))	('mutation in', 'Var', (132, 143))	('M918T', 'Mutation', 'rs74799832', (153, 158))	('activation', 'PosReg', (319, 329))	('achalasia', 'Disease', (13, 22))	('RET', 'Gene', (167, 170))	('achalasia', 'Phenotype', 'HP:0002571', (13, 22))	('M918T', 'Var', (153, 158))	('B syndrome', 'Disease', 'MESH:D006509', (96, 106))	('neoplasia', 'Phenotype', 'HP:0002664', (71, 80))	('B syndrome', 'Disease', (96, 106))	('leads to', 'Reg', (211, 219))	('methionine-threonine amino', 'MPA', (222, 248))	('threonine', 'Chemical', 'MESH:D013912', (233, 242))	('neoplasia type 2', 'Disease', (71, 87))	('methionine', 'Chemical', 'MESH:D008715', (222, 232))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (61, 80))
206839	27672286	The MEN 2 mutation can manifest as one of three types of cancer predisposition, all with an autosomal dominant mode of inheritance; these include the familial medullary thyroid carcinoma, MEN2A and MEN 2B forms.	('MEN 2', 'Gene', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('MEN2A', 'Gene', '5979', (188, 193))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (169, 186))	('MEN', 'Species', '9606', (198, 201))	('MEN', 'Species', '9606', (188, 191))	('cancer', 'Disease', (57, 63))	('MEN2A', 'Gene', (188, 193))	('MEN 2B', 'Gene', '5979', (198, 204))	('MEN', 'Species', '9606', (4, 7))	('thyroid carcinoma', 'Disease', (169, 186))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (169, 186))	('mutation', 'Var', (10, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (159, 186))	('MEN 2B', 'Gene', (198, 204))
206844	27672286	As idiopathic achalasia is a relatively rare disorder, another approach to genetic analysis of these cases has been to identify candidate genes via identification of single nucleotide polymorphisms (SNPs) and classification of their clinical phenotype.	('idiopathic achalasia', 'Disease', 'MESH:D004931', (3, 23))	('rare disorder', 'Disease', 'MESH:D035583', (40, 53))	('achalasia', 'Phenotype', 'HP:0002571', (14, 23))	('idiopathic achalasia', 'Disease', (3, 23))	('rare disorder', 'Disease', (40, 53))	('single nucleotide polymorphisms', 'Var', (166, 197))
206845	27672286	The neuronal nitric oxide synthase (NOS1) gene is located on human chromosome 12q24.2, and a disease-related microsatellite (CA repeat) polymorphism has been found within the 3'-untranslated region (UTR) of exon 29.	('NOS1', 'Gene', '4842', (36, 40))	('polymorphism', 'Var', (136, 148))	('neuronal nitric oxide synthase', 'Gene', (4, 34))	('NOS1', 'Gene', (36, 40))	('neuronal nitric oxide synthase', 'Gene', '4842', (4, 34))	('human', 'Species', '9606', (61, 66))
206849	27672286	It is highly polymorphic, and five SNPs have been reported in patients with late achalasia, including (rs421558) intron-1, (rs437876) intron-4, (rs417387) intron-6, and (rs896 and rs9677) 3'-UTR.	('rs417387', 'Var', (145, 153))	('achalasia', 'Phenotype', 'HP:0002571', (81, 90))	('rs437876', 'Var', (124, 132))	('rs437876', 'Mutation', 'rs437876', (124, 132))	('rs421558', 'Mutation', 'rs421558', (103, 111))	('rs896', 'Var', (170, 175))	('late achalasia', 'Disease', 'MESH:D004931', (76, 90))	('rs421558', 'Var', (103, 111))	('rs896', 'Mutation', 'rs896', (170, 175))	('rs9677', 'Mutation', 'rs9677', (180, 186))	('patients', 'Species', '9606', (62, 70))	('late achalasia', 'Disease', (76, 90))	('rs417387', 'Mutation', 'rs417387', (145, 153))
206851	27672286	One study showed an IL-23R gene polymorphism, wherein arginine replaces glutamine at codon 381, as significantly more common in patients with achalasia than in healthy controls.	('achalasia', 'Disease', 'MESH:D004931', (142, 151))	('common', 'Reg', (118, 124))	('achalasia', 'Phenotype', 'HP:0002571', (142, 151))	('IL-23R', 'Gene', (20, 26))	('arginine', 'Var', (54, 62))	('arginine replaces glutamine at codon 381', 'Mutation', 'rs11209026', (54, 94))	('patients', 'Species', '9606', (128, 136))	('achalasia', 'Disease', (142, 151))	('IL-23R', 'Gene', '149233', (20, 26))
206853	27672286	A SNP in the PTPN22 gene at position 1858C/T, which leads to a replacement of arginine with tryptophan in codon 620, has been shown to increase risk of achalasia in females of Spanish descent.	('arginine with tryptophan in codon 620', 'Mutation', 'rs2476601', (78, 115))	('achalasia', 'Disease', (152, 161))	('achalasia', 'Disease', 'MESH:D004931', (152, 161))	('PTPN22', 'Gene', '26191', (13, 19))	('tryptophan', 'MPA', (92, 102))	('arginine', 'MPA', (78, 86))	('replacement', 'Var', (63, 74))	('achalasia', 'Phenotype', 'HP:0002571', (152, 161))	('increase', 'Reg', (135, 143))	('1858C/T', 'Mutation', 'rs2476601', (37, 44))	('PTPN22', 'Gene', (13, 19))
206854	27672286	Polymorphisms in the IL10 gene have been associated with different autoimmune conditions, such as systemic lupus erythematosus, type 1 diabetes, ulcerative colitis and asthma; for achalasia, however, the GCC haplotype of the IL10 promoter has been associated with a lower risk of the disease.	('ulcerative colitis', 'Phenotype', 'HP:0100279', (145, 163))	('associated', 'Reg', (41, 51))	('achalasia', 'Disease', 'MESH:D004931', (180, 189))	('IL10', 'Gene', (21, 25))	('ulcerative colitis', 'Disease', (145, 163))	('colitis', 'Phenotype', 'HP:0002583', (156, 163))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (98, 126))	('achalasia', 'Disease', (180, 189))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (98, 126))	('Polymorphisms', 'Var', (0, 13))	('diabetes', 'Disease', (135, 143))	('achalasia', 'Phenotype', 'HP:0002571', (180, 189))	('autoimmune conditions', 'Phenotype', 'HP:0002960', (67, 88))	('GCC haplotype', 'Var', (204, 217))	('IL10', 'Gene', '3586', (21, 25))	('asthma', 'Disease', 'MESH:D001249', (168, 174))	('asthma', 'Phenotype', 'HP:0002099', (168, 174))	('ulcerative colitis', 'Disease', 'MESH:D003093', (145, 163))	('IL10', 'Gene', (225, 229))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (128, 143))	('asthma', 'Disease', (168, 174))	('IL10', 'Gene', '3586', (225, 229))	('diabetes', 'Disease', 'MESH:D003920', (135, 143))	('systemic lupus erythematosus', 'Disease', (98, 126))
206855	27672286	Finally, polymorphisms in the IL-33 gene, which encodes the IL-1 cytokine family member IL-33 and is known to play a critical role in chronic inflammatory autoimmune diseases, have been reported as more frequent in females with achalasia, as compared to controls; specifically, the polymorphisms are the rs3939286 SNP and the rs7044343T/rs3939286A risk haplotype.	('autoimmune disease', 'Phenotype', 'HP:0002960', (155, 173))	('rs3939286', 'Mutation', 'rs3939286', (304, 313))	('IL-33', 'Gene', (30, 35))	('autoimmune diseases', 'Disease', 'MESH:D001327', (155, 174))	('IL-33', 'Gene', '90865', (88, 93))	('achalasia', 'Disease', (228, 237))	('rs7044343T/rs3939286A', 'Var', (326, 347))	('achalasia', 'Disease', 'MESH:D004931', (228, 237))	('IL-33', 'Gene', '90865', (30, 35))	('autoimmune diseases', 'Disease', (155, 174))	('rs7044343', 'Mutation', 'rs7044343', (326, 335))	('rs3939286 SNP', 'Var', (304, 317))	('frequent', 'Reg', (203, 211))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (155, 174))	('polymorphisms', 'Var', (9, 22))	('achalasia', 'Phenotype', 'HP:0002571', (228, 237))	('rs3939286', 'Mutation', 'rs3939286', (337, 346))	('IL-33', 'Gene', (88, 93))
206861	27672286	In a study of 1068 cases of achalasia from central Europe, Spain and Italy, an 8-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQbeta1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) was characterized as conferring the strongest risk for achalasia.	('HLA', 'Gene', (146, 149))	('HLA', 'Gene', '3119', (189, 192))	('achalasia', 'Phenotype', 'HP:0002571', (260, 269))	('achalasia', 'Disease', 'MESH:D004931', (28, 37))	('HLA', 'Gene', (170, 173))	('achalasia', 'Phenotype', 'HP:0002571', (28, 37))	('insertion', 'Var', (89, 98))	('HLA-DQB1', 'Gene', (170, 178))	('HLA-DQB1', 'Gene', '3119', (189, 197))	('pain', 'Phenotype', 'HP:0012531', (60, 64))	('HLA', 'Gene', '3119', (146, 149))	('achalasia', 'Disease', (260, 269))	('HLA', 'Gene', '3119', (170, 173))	('achalasia', 'Disease', 'MESH:D004931', (260, 269))	('achalasia', 'Disease', (28, 37))	('HLA', 'Gene', (189, 192))	('HLA-DQB1', 'Gene', '3119', (170, 178))	('HLA-DQB1', 'Gene', (189, 197))
206862	27672286	Two amino acid substitutions in the extracellular domain of HLA-DQalpha1 at position 41 (lysine encoded by HLA-DQA1*01:03) and of HLA-DQbeta1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04) were characterized as independently conferring achalasia risk.	('HLA', 'Gene', (183, 186))	('substitutions', 'Var', (15, 28))	('HLA-DQB1', 'Gene', (202, 210))	('HLA-DQA1', 'Gene', '3117', (107, 115))	('HLA', 'Gene', '3119', (60, 63))	('conferring', 'Reg', (254, 264))	('achalasia', 'Disease', 'MESH:D004931', (265, 274))	('HLA', 'Gene', '3119', (202, 205))	('HLA-DQB1', 'Gene', (183, 191))	('HLA', 'Gene', (60, 63))	('HLA-DQB1', 'Gene', '3119', (202, 210))	('HLA', 'Gene', '3119', (107, 110))	('lysine', 'Chemical', 'MESH:D008239', (89, 95))	('HLA', 'Gene', (202, 205))	('HLA', 'Gene', (107, 110))	('achalasia', 'Disease', (265, 274))	('HLA', 'Gene', '3119', (130, 133))	('HLA-DQA1', 'Gene', (107, 115))	('achalasia', 'Phenotype', 'HP:0002571', (265, 274))	('HLA', 'Gene', '3119', (183, 186))	('HLA', 'Gene', (130, 133))	('HLA-DQB1', 'Gene', '3119', (183, 191))	('glutamic acid', 'Chemical', 'MESH:D018698', (158, 171))
206863	27672286	Moreover, the HLA-DQbeta1 insertion was characterized as a strong risk factor for achalasia and showed a particular geospatial north-south gradient among Europeans.	('risk factor', 'Reg', (66, 77))	('insertion', 'Var', (26, 35))	('achalasia', 'Disease', (82, 91))	('HLA', 'Gene', '3119', (14, 17))	('achalasia', 'Disease', 'MESH:D004931', (82, 91))	('HLA', 'Gene', (14, 17))	('achalasia', 'Phenotype', 'HP:0002571', (82, 91))
206956	26788476	In this study, 100 patients with lower esophageal SCC were included, 50 of whom received NACR and then underwent transhiatal esophagectomy after 3-4 weeks and 50 of whom underwent transhiatal esophagectomy without NACR.	('NACR', 'Var', (89, 93))	('NACR', 'Chemical', '-', (214, 218))	('patients', 'Species', '9606', (19, 27))	('esophageal SCC', 'Disease', (39, 53))	('NACR', 'Chemical', '-', (89, 93))	('esophageal SCC', 'Disease', 'MESH:D004941', (39, 53))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))
206979	22526622	Mutagenesis of Ecrg4 established that cell tethering was mediated by an NH2-terminus hydrophobic leader sequence that enabled both trafficking to the surface and tethering.	('Ecrg4', 'Gene', (15, 20))	('trafficking', 'MPA', (131, 142))	('Mutagenesis', 'Var', (0, 11))	('enabled', 'PosReg', (118, 125))	('Ecrg4', 'Gene', '84417', (15, 20))
206992	22526622	Human embryonic kidney (HEK) and prostate cancer PC3 epithelial cells were maintained in DMEM containing penicillin (100 units/ml), streptomycin (100 mug/ml), and 10% fetal bovine serum (FBS) at 37 C in an incubator supplemented with 5% CO2/95% air.	('Human', 'Species', '9606', (0, 5))	('penicillin', 'Chemical', 'MESH:D010406', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('streptomycin', 'Chemical', 'MESH:D013307', (132, 144))	('HEK', 'Gene', '2042', (24, 27))	('embryonic kidney', 'Disease', 'MESH:D007674', (6, 22))	('PC3', 'Gene', (49, 52))	('PC3', 'Gene', '3853', (49, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (33, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('DMEM', 'Chemical', '-', (89, 93))	('100', 'Var', (146, 149))	('prostate cancer', 'Disease', (33, 48))	('CO2', 'Chemical', '-', (237, 240))	('bovine', 'Species', '9913', (173, 179))	('embryonic kidney', 'Disease', (6, 22))	('FBS', 'Disease', (187, 190))	('HEK', 'Gene', (24, 27))	('FBS', 'Disease', 'MESH:D005198', (187, 190))
207014	22526622	In some experiments, we used an Ad vector containing either a transgene for Ecrg4 (AdEcrg4) or GFP (Adgfp).	('GFP', 'Var', (95, 98))	('Ecrg4', 'Gene', '84417', (85, 90))	('Ecrg4', 'Gene', (76, 81))	('Ecrg4', 'Gene', '84417', (76, 81))	('Ecrg4', 'Gene', (85, 90))
207018	22526622	Plasmids expressing full-length Ecrg4(1-148), Ecrg4(1-132) (CDelta16-Ecrg4), Ecrg4(1-140) (Delta8-Ecrg4), Ecrg4(1-144) (Delta4-Ecrg4), the R67A and K69A mutant (Ala67,69Ecrg4) and P131A and R132A mutant (Ala131,132Ecrg4) were amplified by standard PCR or PCR-mediated site-directed mutagenesis.	('Ecrg4', 'Gene', (46, 51))	('R132A', 'Mutation', 'p.R132A', (190, 195))	('Ecrg4', 'Gene', (32, 37))	('Ecrg4', 'Gene', (214, 219))	('P131A', 'Var', (180, 185))	('Delta8-Ecrg4', 'Gene', (91, 103))	('K69A', 'Mutation', 'p.K69A', (148, 152))	('Ecrg4', 'Gene', (127, 132))	('Ecrg4', 'Gene', '84417', (106, 111))	('Ecrg4', 'Gene', (69, 74))	('Ecrg4', 'Gene', '84417', (98, 103))	('R67A', 'Mutation', 'p.R67A', (139, 143))	('Ecrg4', 'Gene', (77, 82))	('Ala131', 'Chemical', '-', (204, 210))	('Ecrg4', 'Gene', '84417', (169, 174))	('R132A', 'Var', (190, 195))	('Delta4', 'Mutation', 'c.del4', (120, 126))	('R67A', 'Var', (139, 143))	('K69A', 'Var', (148, 152))	('Ecrg4', 'Gene', (98, 103))	('Ecrg4', 'Gene', (106, 111))	('Ecrg4', 'Gene', '84417', (46, 51))	('Ecrg4', 'Gene', '84417', (32, 37))	('Ecrg4', 'Gene', '84417', (214, 219))	('Ecrg4', 'Gene', '84417', (127, 132))	('Ecrg4', 'Gene', '84417', (69, 74))	('Ala67', 'Chemical', '-', (161, 166))	('Ecrg4', 'Gene', (169, 174))	('P131A', 'Mutation', 'p.P131A', (180, 185))	('Ecrg4', 'Gene', '84417', (77, 82))	('Delta8-Ecrg4', 'Gene', '84417', (91, 103))
207052	22526622	However, fusion of the Ecrg4(1-30) leader sequence with GFP leads to a secretory and vesicular distribution.	('Ecrg4', 'Gene', (23, 28))	('Ecrg4', 'Gene', '84417', (23, 28))	('GFP', 'Gene', (56, 59))	('leads to', 'Reg', (60, 68))	('fusion', 'Var', (9, 15))
207058	22526622	To distinguish cell surface tethering from cell surface processing, we evaluated the behavior of a series of Ecrg4 mutants in both HEK (Figure 4, Panel a) and PC3 (Panel b) epithelial cells.	('HEK', 'Gene', (131, 134))	('PC3', 'Gene', '3853', (159, 162))	('mutants', 'Var', (115, 122))	('Ecrg4', 'Gene', (109, 114))	('PC3', 'Gene', (159, 162))	('HEK', 'Gene', '2042', (131, 134))	('Ecrg4', 'Gene', '84417', (109, 114))
207059	22526622	Of the many mutants examined, none conferred HEK cells with an ability to condition their media with Ecrg4 (lanes 17-23).	('Ecrg4', 'Gene', (101, 106))	('mutants', 'Var', (12, 19))	('HEK cell', 'CellLine', 'CVCL:M624', (45, 53))	('Ecrg4', 'Gene', '84417', (101, 106))
207063	22526622	Whereas the mutants were expressed in cells (lanes 3-6) and localized to the cell surface as 14kDa proteins (lanes 9-12), mutagenesis of protein convertase/furin consensus sites at Arg67Lys69 eliminated any low molecular weight fragment of Ecrg4 in conditioned media (lane 17).	('Ecrg4', 'Gene', '84417', (240, 245))	('Arg67Lys69', 'Chemical', '-', (181, 191))	('Arg67Lys69', 'Var', (181, 191))	('eliminated', 'NegReg', (192, 202))	('low molecular weight fragment', 'MPA', (207, 236))	('furin', 'Gene', '5045', (156, 161))	('furin', 'Gene', (156, 161))	('Ecrg4', 'Gene', (240, 245))	('mutagenesis', 'Var', (122, 133))
207064	22526622	This allowed us to tentatively identify the 6-8 kDa product as the result of cleavage at Arg67Lys69 of Ecrg4(1-148).	('Ecrg4', 'Gene', (103, 108))	('Arg67Lys69', 'Chemical', '-', (89, 99))	('Arg67Lys69', 'Var', (89, 99))	('Ecrg4', 'Gene', '84417', (103, 108))	('cleavage', 'Var', (77, 85))
207088	22526622	Neither (1) high salt, which releases ionic interactions like those responsible for binding to cell surface proteoglycans, (2) low pH, which releases ligand-receptor interactions or (3) Na2CO3, which removes all non-covalently bound proteins from the cell surface was able to remove Ecrg4 from the cell surface.	('Na2CO3', 'Var', (186, 192))	('Ecrg4', 'Gene', (283, 288))	('Na2CO3', 'Chemical', 'MESH:C005686', (186, 192))	('ligand-receptor', 'MPA', (150, 165))	('Ecrg4', 'Gene', '84417', (283, 288))	('ionic interactions', 'MPA', (38, 56))	('salt', 'Chemical', 'MESH:D012492', (17, 21))
207095	22526622	First, mutagenesis of Arg67/Lys69 to Ala67,69 and of Pro131/Arg132 to Ala131,132 that target protein convertases and thrombin consensus sequences respectively, had no effect on the appearance of Ecrg4 onto the cell surface of either HEK or PC3 cells (Figure 4).	('thrombin', 'Gene', (117, 125))	('mutagenesis', 'Var', (7, 18))	('Ecrg4', 'Gene', '84417', (195, 200))	('PC3', 'Gene', '3853', (240, 243))	('Arg132', 'Chemical', '-', (60, 66))	('HEK', 'Gene', '2042', (233, 236))	('Lys69', 'Chemical', '-', (28, 33))	('thrombin', 'Gene', '2147', (117, 125))	('Ala131', 'Chemical', '-', (70, 76))	('Ecrg4', 'Gene', (195, 200))	('HEK', 'Gene', (233, 236))	('Arg67', 'Chemical', '-', (22, 27))	('Arg67/Lys69', 'Var', (22, 33))	('Pro131', 'Chemical', '-', (53, 59))	('PC3', 'Gene', (240, 243))	('appearance', 'MPA', (181, 191))	('Ala67', 'Chemical', '-', (37, 42))
207165	33906625	This branching abnormality can cause unexpected vertebral artery damage and bleeding during thoracoscopic esophagectomy.	('bleeding', 'Disease', 'MESH:D006470', (76, 84))	('bleeding', 'Disease', (76, 84))	('vertebral artery damage', 'Disease', 'MESH:C538664', (48, 71))	('vertebral artery damage', 'Disease', (48, 71))	('cause', 'Reg', (31, 36))	('abnormality', 'Var', (15, 26))
207237	32757102	The p40 antibody recognizes DeltaNP63, an isoform of p63, and DeltaNP63 has been suggested to be highly specific for squamous/basal cells.	('DeltaNP63', 'Var', (62, 71))	('p40', 'Gene', (4, 7))	('p63', 'Gene', '8626', (53, 56))	('squamous/basal cells', 'Disease', (117, 137))	('p40', 'Gene', '8626', (4, 7))	('DeltaNP63', 'Var', (28, 37))	('p63', 'Gene', (53, 56))
207299	32235479	Remarkably, a study in gastric cancer indicated that the presence of CTCs can distinguish between cancer patients and healthy controls with a sensitivity of 85.3% and specificity of 90.3%.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (105, 113))	('gastric cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (23, 37))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('presence', 'Var', (57, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (98, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (23, 37))	('cancer', 'Disease', (31, 37))
207309	32235479	Several studies in gastrointestinal cancers showed a positive correlation in between the presence of CTCs at timepoint of diagnosis and local invasion, malignant spread to lymph nodes and distant organs, as well as negative correlation with the progression-free survival and overall survival.	('overall survival', 'CPA', (275, 291))	('malignant spread to lymph nodes', 'CPA', (152, 183))	('local invasion', 'CPA', (136, 150))	('CTCs', 'Gene', (101, 105))	('gastrointestinal cancers', 'Disease', (19, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (19, 43))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (19, 42))	('progression-free survival', 'CPA', (245, 270))	('negative', 'NegReg', (215, 223))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('presence', 'Var', (89, 97))
207310	32235479	Prospective studies revealed that also patients with positive CTC score but without detectable lymph node or distant metastasis were at high risk for tumor recurrence and had a shorter overall survival.	('overall', 'MPA', (185, 192))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('shorter', 'NegReg', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('CTC', 'Gene', (62, 65))	('tumor', 'Disease', (150, 155))	('positive', 'Var', (53, 61))
207327	32235479	showed that in esophageal cancer, ERCC1 expression is associated with better response to neoadjuvant radio chemotherapy.	('ERCC1', 'Gene', (34, 39))	('cancer', 'Disease', (26, 32))	('expression', 'Var', (40, 50))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('ERCC1', 'Gene', '2067', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
207338	32235479	In esophageal cancer, changes in CTC detection after radiotherapy was found to be a prognostic value to predict progression free survival, irrespectively of chemotherapeutic agents.	('cancer', 'Disease', (14, 20))	('changes', 'Var', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('CTC detection', 'MPA', (33, 46))
207350	31235759	In recent years, long non-coding RNAs (lncRNAs) have demonstrated to be novel tumor-associated regulatory factors.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('long non-coding RNAs', 'Var', (17, 37))	('tumor', 'Disease', (78, 83))
207360	31235759	In recent years, non-coding RNA (ncRNA) has been demonstrated to be involved in the progression of disease, including cancer.	('cancer', 'Disease', (118, 124))	('non-coding', 'Var', (17, 27))	('involved', 'Reg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
207386	31235759	It includes 2 upregulated lncRNAs (lnc-GPR50-3 and lnc-PTPN7-3) and 3 downregulated lncRNAs (lnc-AREG-1, lnc-PCP4-2, and lnc-AC233263.1), 2 TFs (E2F4 and KAT2A), and 87 target genes in this map.	('E2F4', 'Gene', (145, 149))	('KAT2A', 'Gene', '2648', (154, 159))	('downregulated', 'NegReg', (70, 83))	('KAT2A', 'Gene', (154, 159))	('upregulated', 'PosReg', (14, 25))	('E2F4', 'Gene', '1874', (145, 149))	('lnc-GPR50-3', 'Var', (35, 46))
207391	31235759	Furthermore, short hairpin RNA (shRNA) mediated by a lentiviral vector (LV) was used to knockdown lnc-KIAA1244-2 in Eca-109 cells.	('KIAA1244', 'Gene', (102, 110))	('KIAA1244', 'Gene', '57221', (102, 110))	('knockdown', 'Var', (88, 97))
207393	31235759	The CCK-8 assays and cell cycle assays indicated that the knockdown of lnc-KIAA1244-2 observably inhibited the proliferation of Eca-109 cells (Fig.	('KIAA1244', 'Gene', (75, 83))	('KIAA1244', 'Gene', '57221', (75, 83))	('proliferation', 'CPA', (111, 124))	('inhibited', 'NegReg', (97, 106))	('knockdown', 'Var', (58, 67))
207394	31235759	Cell cycle analysis demonstrated that lnc-KIAA1244-2 knockdown led to cell cycle arrest at G0/G1 phase (Fig.	('KIAA1244', 'Gene', (42, 50))	('knockdown', 'Var', (53, 62))	('KIAA1244', 'Gene', '57221', (42, 50))	('cell cycle arrest at G0/G1 phase', 'CPA', (70, 102))
207397	31235759	6E,F showed that both the TNFAIP3 mRNA and protein levels were downregulated after lnc-KIAA1244-2 knockdown in Eca-109 cells, indicating lnc-KIAA1244-2 might regulate ESCC cell proliferation via mediating TNFAIP3.	('ESCC cell proliferation', 'CPA', (167, 190))	('TNFAIP3', 'Gene', '7128', (205, 212))	('TNFAIP3', 'Gene', (205, 212))	('knockdown', 'Var', (98, 107))	('TNFAIP3', 'Gene', '7128', (26, 33))	('KIAA1244', 'Gene', '57221', (87, 95))	('TNFAIP3', 'Gene', (26, 33))	('downregulated', 'NegReg', (63, 76))	('regulate', 'Reg', (158, 166))	('KIAA1244', 'Gene', (87, 95))	('KIAA1244', 'Gene', (141, 149))	('KIAA1244', 'Gene', '57221', (141, 149))
207422	31235759	In conclusion, this study demonstrates that the expression patterns of lncRNAs and mRNAs in ESCC tumor tissues are different from those in normal adjacent tissues, and some abnormal expression of lncRNAs may play important roles in the development and progression of ESCC.	('ESCC', 'Disease', (267, 271))	('play', 'Reg', (208, 212))	('expression', 'MPA', (182, 192))	('ESCC tumor', 'Disease', 'MESH:D004938', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('roles', 'Reg', (223, 228))	('abnormal', 'Var', (173, 181))	('ESCC tumor', 'Disease', (92, 102))
207474	31171890	Inhibition of CDK4/6 also can induce the degradation of cyclin D1 and then enhance the sensitivity of cancer cells to radiotherapy.	('CDK4/6', 'Gene', (14, 20))	('induce', 'PosReg', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Inhibition', 'Var', (0, 10))	('CDK4/6', 'Gene', '1019;1021', (14, 20))	('cyclin D1', 'Gene', '595', (56, 65))	('enhance', 'PosReg', (75, 82))	('degradation', 'MPA', (41, 52))	('cyclin D1', 'Gene', (56, 65))
207481	31171890	Recent studies have found that BJOE could inhibit cell proliferation and induce cell apoptosis in various malignancies, such as liver, colon, and ovarian cancers.	('liver', 'Disease', (128, 133))	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('ovarian cancers', 'Disease', 'MESH:D010051', (146, 161))	('BJOE', 'Var', (31, 35))	('ovarian cancers', 'Phenotype', 'HP:0100615', (146, 161))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('malignancies', 'Disease', (106, 118))	('cell proliferation', 'CPA', (50, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (146, 160))	('inhibit', 'NegReg', (42, 49))	('induce', 'PosReg', (73, 79))	('colon', 'Disease', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cell apoptosis', 'CPA', (80, 94))	('ovarian cancers', 'Disease', (146, 161))
207495	31171890	Anti-BCL-2 antibody (ab32124), Anti-P21 antibody (ab109520), Anti-BAX antibody (ab32503), Anti-cyclin D1 antibody (ab16663), Anti-WEE1 antibody (ab203236), Anti-CDK4 antibody (ab199728), Anti-CDK6 antibody (ab124821), and Anti-GAPDH antibody (ab181602) were used as primary antibodies (Abcam, Cambridge, United Kingdom), respectively.	('BCL-2', 'Gene', (5, 10))	('CDK6', 'Gene', '1021', (192, 196))	('P21', 'Gene', (36, 39))	('cyclin D1', 'Gene', '595', (95, 104))	('BAX', 'Gene', (66, 69))	('CDK6', 'Gene', (192, 196))	('ab124821', 'Var', (207, 215))	('BAX', 'Gene', '581', (66, 69))	('cyclin D1', 'Gene', (95, 104))	('CDK4', 'Gene', (161, 165))	('WEE1', 'Gene', (130, 134))	('WEE1', 'Gene', '7465', (130, 134))	('BCL-2', 'Gene', '596', (5, 10))	('P21', 'Gene', '1026', (36, 39))	('CDK4', 'Gene', '1019', (161, 165))
207519	31171890	Here, we investigate the inhibitory effect of BJOE on esophageal cancer and the enhancement of radiosensitivity of esophageal cancer induced by BJOE.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('enhancement', 'PosReg', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', (54, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('radiosensitivity', 'CPA', (95, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('BJOE', 'Var', (144, 148))
207520	31171890	In this study, it was demonstrated that the growth of esophageal cancer can be inhibited significantly by BJOE.	('growth', 'MPA', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('inhibited', 'NegReg', (79, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('BJOE', 'Var', (106, 110))
207705	28077137	Aberrant methylation of DACT1 and DACT2 are associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma The DACT (Dishevelled-associated antagonist of beta-catenin) family of scaffold proteins may play important roles in tumorigenesis.	('methylation', 'Var', (9, 20))	('DACT1', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('DACT2', 'Gene', '168002', (34, 39))	('DACT', 'Chemical', '-', (24, 28))	('tumor', 'Disease', (60, 65))	('beta-catenin', 'Gene', (182, 194))	('beta-catenin', 'Gene', '1499', (182, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (100, 134))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Aberrant methylation', 'Var', (0, 20))	('associated', 'Reg', (44, 54))	('DACT', 'Chemical', '-', (139, 143))	('DACT', 'Chemical', '-', (34, 38))	('esophageal squamous cell carcinoma', 'Disease', (100, 134))	('DACT1', 'Gene', '51339', (24, 29))	('tumor', 'Disease', (252, 257))	('DACT2', 'Gene', (34, 39))
207710	28077137	Decreased mRNA and protein expression of DACT1 and DACT2 were observed in ESCC tumor tissues and were associated with the methylation status of transcription start site (TSS) region.	('DACT2', 'Gene', (51, 56))	('tumor', 'Disease', (79, 84))	('ESCC', 'Disease', (74, 78))	('methylation', 'Var', (122, 133))	('Decreased', 'NegReg', (0, 9))	('DACT1', 'Gene', (41, 46))	('DACT2', 'Gene', '168002', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('DACT1', 'Gene', '51339', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
207712	28077137	The methylation status of TSS region in DACT1 and DACT2 and the protein expression of DACT2 were independently associated with ESCC patients' prognosis.	('DACT2', 'Gene', (86, 91))	('DACT2', 'Gene', '168002', (50, 55))	('ESCC', 'Disease', (127, 131))	('DACT1', 'Gene', '51339', (40, 45))	('DACT1', 'Gene', (40, 45))	('DACT2', 'Gene', (50, 55))	('DACT2', 'Gene', '168002', (86, 91))	('associated with', 'Reg', (111, 126))	('patients', 'Species', '9606', (132, 140))	('methylation status', 'Var', (4, 22))	('protein expression', 'MPA', (64, 82))
207713	28077137	The TSS region hypermethylation may be one of the main mechanisms for reduced expression of DACT1 and DACT2 in ESCC.	('DACT2', 'Gene', '168002', (102, 107))	('expression', 'MPA', (78, 88))	('reduced', 'NegReg', (70, 77))	('DACT1', 'Gene', '51339', (92, 97))	('hypermethylation', 'Var', (15, 31))	('DACT2', 'Gene', (102, 107))	('DACT1', 'Gene', (92, 97))	('ESCC', 'Disease', (111, 115))
207714	28077137	The simultaneous methylation of DACT1 and DACT2 may play important roles in progression of ESCC and may serve as prognostic methylation biomarkers for ESCC patients.	('patients', 'Species', '9606', (156, 164))	('roles', 'Reg', (67, 72))	('DACT1', 'Gene', '51339', (32, 37))	('ESCC', 'Disease', (91, 95))	('methylation', 'Var', (17, 28))	('ESCC', 'Disease', (151, 155))	('DACT2', 'Gene', '168002', (42, 47))	('DACT1', 'Gene', (32, 37))	('DACT2', 'Gene', (42, 47))	('play', 'Reg', (52, 56))
207750	28077137	The membranes were blocked in 5% nonfat milk and incubated with Rabbit anti-human polyclonal antibody for DACT1 (1 mug/ml, ab72078, Abcam, UK) and DACT2(2 mug/ml, ab79042, Abcam, UK), and mouse anti-human monoclonal antibody for beta-actin (1:5000 dilution, ab6276, Abcam, UK) and visualization with enhanced chemiluminescence (ECL) detection reagents (Beyotime, Haimen, Jiangsu, China).	('mouse', 'Species', '10090', (188, 193))	('human', 'Species', '9606', (199, 204))	('beta-actin', 'Gene', '728378', (229, 239))	('DACT2', 'Gene', '168002', (147, 152))	('beta-actin', 'Gene', (229, 239))	('ab6276', 'Var', (258, 264))	('human', 'Species', '9606', (76, 81))	('Rabbit', 'Species', '9986', (64, 70))	('DACT1', 'Gene', '51339', (106, 111))	('DACT2', 'Gene', (147, 152))	('DACT1', 'Gene', (106, 111))
207773	28077137	1d, e, f, g, the mRNA expression of DACT1 and DACT2 were all significantly increased in four esophageal cancer cells after treatment with 5-Aza-Dc, but not with TSA.	('DACT2', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('TSA', 'Chemical', 'MESH:C012589', (161, 164))	('esophageal cancer', 'Disease', (93, 110))	('DACT1', 'Gene', '51339', (36, 41))	('5-Aza-Dc', 'Chemical', 'MESH:D000077209', (138, 146))	('mRNA expression', 'MPA', (17, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('DACT2', 'Gene', '168002', (46, 51))	('5-Aza-Dc', 'Var', (138, 146))	('increased', 'PosReg', (75, 84))	('DACT1', 'Gene', (36, 41))
207774	28077137	However, DACT3 mRNA was not significantly up-regulated after treatment with 5-Aza-Dc or TSA in four esophageal cancer cell lines.	('TSA', 'Chemical', 'MESH:C012589', (88, 91))	('esophageal cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('DACT3', 'Gene', (9, 14))	('5-Aza-Dc', 'Chemical', 'MESH:D000077209', (76, 84))	('DACT3', 'Gene', '147906', (9, 14))	('5-Aza-Dc', 'Var', (76, 84))
207775	28077137	To investigate whether the silencing of DACT1, 2, 3 were associated with their hypermethylation, the MethPrimer program and the CpG island searcher were firstly used to analyze the CpG islands within the sequence of DACT genes.	('DACT', 'Gene', (216, 220))	('silencing', 'Var', (27, 36))	('DACT', 'Chemical', '-', (40, 44))	('DACT', 'Chemical', '-', (216, 220))	('DACT1', 'Gene', (40, 45))	('DACT1', 'Gene', '51339', (40, 45))	('searcher', 'Species', '274808', (139, 147))	('hypermethylation', 'MPA', (79, 95))	('associated', 'Reg', (57, 67))
207786	28077137	2, stable transfection of DACT1/DACT2 or treatment with 5-Aza-Dc resulted in significant inhibition of the proliferation index and reduction of colony numbers in TE1 and TE13 cell lines.	('reduction', 'NegReg', (131, 140))	('DACT2', 'Gene', (32, 37))	('proliferation index', 'CPA', (107, 126))	('DACT1', 'Gene', '51339', (26, 31))	('5-Aza-Dc', 'Chemical', 'MESH:D000077209', (56, 64))	('colony numbers', 'CPA', (144, 158))	('inhibition', 'NegReg', (89, 99))	('transfection', 'Var', (10, 22))	('DACT2', 'Gene', '168002', (32, 37))	('DACT1', 'Gene', (26, 31))
207788	28077137	Cell migration ability was significantly decreased at 12, 24, 36 and 48 h after transfection with DACT1/DACT2 or treatment with 5-Aza-Dc (Fig.	('Cell migration ability', 'CPA', (0, 22))	('DACT2', 'Gene', (104, 109))	('decreased', 'NegReg', (41, 50))	('DACT1', 'Gene', '51339', (98, 103))	('5-Aza-Dc', 'Chemical', 'MESH:D000077209', (128, 136))	('DACT2', 'Gene', '168002', (104, 109))	('transfection', 'Var', (80, 92))	('DACT1', 'Gene', (98, 103))
207801	28077137	But the simultaneous methylation frequency of DACT1 (region2) and DACT2 were associated with clinical stage, LN metastasis and UGIC family history (Table 2).	('DACT2', 'Gene', (66, 71))	('DACT1', 'Gene', '51339', (46, 51))	('UGIC', 'Disease', (127, 131))	('DACT2', 'Gene', '168002', (66, 71))	('clinical stage', 'CPA', (93, 107))	('DACT1', 'Gene', (46, 51))	('methylation frequency', 'Var', (21, 42))	('associated', 'Reg', (77, 87))
207802	28077137	3i and Table 3, the mRNA and protein expression of DACT1, DACT2 in ESCC tissues with hypermethylation of TSS-region were significantly reduced compared to those in ESCC tissues without methylation of this region (P < 0.05); However, the mRNA and protein expression of DACT1 was not different between the ESCC tissues with or without hypermethylation of CGI-shore region (region1) (P > 0.05).	('hypermethylation', 'Var', (85, 101))	('DACT1', 'Gene', '51339', (51, 56))	('DACT1', 'Gene', (268, 273))	('DACT2', 'Gene', '168002', (58, 63))	('DACT1', 'Gene', (51, 56))	('reduced', 'NegReg', (135, 142))	('DACT1', 'Gene', '51339', (268, 273))	('DACT2', 'Gene', (58, 63))
207808	28077137	Furthermore, the ESCC patients with simultaneous methylation of DACT1 and DACT2 showed worst prognosis (P < 0.001, Log-rank test; Fig.	('DACT1', 'Gene', (64, 69))	('ESCC', 'Disease', (17, 21))	('DACT2', 'Gene', (74, 79))	('patients', 'Species', '9606', (22, 30))	('DACT1', 'Gene', '51339', (64, 69))	('simultaneous methylation', 'Var', (36, 60))	('methylation', 'Var', (49, 60))	('DACT2', 'Gene', '168002', (74, 79))
207809	28077137	ESCC patients in stage III / IV or with positive UGIC family history, and with DACT1 or DACT2 methylation showed poor prognosis (Fig.	('DACT1', 'Gene', (79, 84))	('patients', 'Species', '9606', (5, 13))	('DACT2', 'Gene', (88, 93))	('DACT1', 'Gene', '51339', (79, 84))	('methylation', 'Var', (94, 105))	('DACT2', 'Gene', '168002', (88, 93))
207811	28077137	The results indicated that the methylation status of TSS-region in DACT1 or DACT2, the protein expression of DACT2, TNM stage and UGIC family history were independently associated with ESCC patients' survival (Table 4).	('TNM', 'Gene', '10178', (116, 119))	('methylation status', 'Var', (31, 49))	('DACT2', 'Gene', (76, 81))	('DACT2', 'Gene', '168002', (109, 114))	('patients', 'Species', '9606', (190, 198))	('DACT1', 'Gene', '51339', (67, 72))	('protein expression', 'MPA', (87, 105))	('TNM', 'Gene', (116, 119))	('DACT2', 'Gene', '168002', (76, 81))	('ESCC', 'Disease', (185, 189))	('DACT2', 'Gene', (109, 114))	('associated with', 'Reg', (169, 184))	('DACT1', 'Gene', (67, 72))
207818	28077137	The difference may partly due to the fact that histone modification has the tumor cell specific and the precise mechanism of this gene inactivation need to be further studied.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('histone', 'Var', (47, 54))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
207820	28077137	Aberrant methylation of CpG islands in gene promoter has been well-established as a major mechanism for the inactivation of tumor suppressor genes in tumorigenesis.	('methylation', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('inactivation', 'NegReg', (108, 120))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('Aberrant methylation', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
207821	28077137	The hypermethylation of DACT1 in the region near TSS within CpG islands was detected in multiple breast cancer cell lines and primary breast tumors, and the methylation status in this region was a main epigenetic mechanism of DACT1 silencing in breast cancer.	('DACT1', 'Gene', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (245, 258))	('breast cancer', 'Disease', (245, 258))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('detected', 'Reg', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('methylation', 'Var', (157, 168))	('breast tumors', 'Disease', 'MESH:D001943', (134, 147))	('DACT1', 'Gene', '51339', (226, 231))	('breast tumors', 'Disease', (134, 147))	('DACT1', 'Gene', (226, 231))	('breast tumors', 'Phenotype', 'HP:0100013', (134, 147))	('silencing', 'NegReg', (232, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('hypermethylation', 'Var', (4, 20))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('DACT1', 'Gene', '51339', (24, 29))	('breast cancer', 'Disease', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))
207822	28077137	The aberrant methylation of DACT1 in CGI shore region had been detected in primary gastric cancer and the methylated CpG site count in this region had the significant applicability for prognosis evaluation of gastric cancer patients.	('methylation', 'MPA', (13, 24))	('detected', 'Reg', (63, 71))	('DACT1', 'Gene', '51339', (28, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('DACT1', 'Gene', (28, 33))	('aberrant', 'Var', (4, 12))	('gastric cancer', 'Disease', (209, 223))	('gastric cancer', 'Disease', 'MESH:D013274', (209, 223))	('gastric cancer', 'Disease', (83, 97))	('patients', 'Species', '9606', (224, 232))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (209, 223))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
207826	28077137	These results suggested that hypermethylation of TSS-region was more cancer-specific and was associated with the transcriptional inhibition of DACT1.	('DACT1', 'Gene', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('TSS-region', 'Gene', (49, 59))	('associated', 'Reg', (93, 103))	('hypermethylation', 'Var', (29, 45))	('transcriptional', 'MPA', (113, 128))	('DACT1', 'Gene', '51339', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
207828	28077137	The CGI shore-region was more likely to be methylated but may be not necessary for the tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('methylated', 'Var', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
207829	28077137	The TSS-region was selected to analyze the methylation status of DACT2 and there was a significant concordance between the hypermethylation of this gene and its reduced expression in the present study.	('reduced', 'NegReg', (161, 168))	('DACT2', 'Gene', '168002', (65, 70))	('expression', 'MPA', (169, 179))	('hypermethylation', 'Var', (123, 139))	('DACT2', 'Gene', (65, 70))
207830	28077137	found DACT2 was frequently methylated in human gastric cancer and aberrant methylation may be a main mechanism of DACT2 inactiviton.	('DACT2', 'Gene', '168002', (6, 11))	('DACT2', 'Gene', (114, 119))	('gastric cancer', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (41, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('aberrant', 'Var', (66, 74))	('methylation', 'MPA', (75, 86))	('DACT2', 'Gene', (6, 11))	('DACT2', 'Gene', '168002', (114, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))
207832	28077137	When stratified for clinicopathologic characteristics, the methylation status of DACT1 or DACT2 was only associated with UGIC family history, but the simultaneous methylation of DACT1 and DACT2 were associated with clinical stage, LN metastasis and UGIC family history, suggesting that multiple gene methylation may be an ideal cancer biomarker in progression of ESCC and may have definite value on estimating prognosis of ESCC patients.	('DACT1', 'Gene', (178, 183))	('associated', 'Reg', (199, 209))	('DACT2', 'Gene', (90, 95))	('ESCC', 'Disease', (363, 367))	('DACT2', 'Gene', '168002', (188, 193))	('patients', 'Species', '9606', (428, 436))	('DACT1', 'Gene', '51339', (81, 86))	('DACT1', 'Gene', '51339', (178, 183))	('cancer', 'Disease', (328, 334))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('DACT2', 'Gene', '168002', (90, 95))	('UGIC', 'CPA', (249, 253))	('LN metastasis', 'CPA', (231, 244))	('clinical stage', 'CPA', (215, 229))	('methylation', 'Var', (163, 174))	('DACT2', 'Gene', (188, 193))	('DACT1', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))
207834	28077137	In the present study, we showed that protein expression and methylation status of DACT1 and DACT2 were significantly and directly correlated with ESCC patients' survival, suggesting that the inactivation of DACT1 and DACT2 via hypermethylation may confer a growth advantage in ESCC.	('hypermethylation', 'Var', (227, 243))	('DACT1', 'Gene', '51339', (207, 212))	('ESCC', 'Disease', (277, 281))	('DACT2', 'Gene', '168002', (217, 222))	('patients', 'Species', '9606', (151, 159))	('DACT1', 'Gene', '51339', (82, 87))	('DACT2', 'Gene', (92, 97))	('DACT1', 'Gene', (207, 212))	('DACT1', 'Gene', (82, 87))	('growth advantage', 'CPA', (257, 273))	('inactivation', 'Var', (191, 203))	('DACT2', 'Gene', (217, 222))	('DACT2', 'Gene', '168002', (92, 97))
207835	28077137	Therefore, the hypermethylation and inactivation of DACT1 and DACT2 may be considered to be the poor prognostic factors to ESCC patients.	('ESCC', 'Disease', (123, 127))	('DACT1', 'Gene', (52, 57))	('DACT2', 'Gene', '168002', (62, 67))	('hypermethylation', 'Var', (15, 31))	('patients', 'Species', '9606', (128, 136))	('inactivation', 'Var', (36, 48))	('DACT1', 'Gene', '51339', (52, 57))	('DACT2', 'Gene', (62, 67))
207839	28077137	The stage III/IV ESCC patients with DACT1 or DACT2 methylation showed the worse survival, which further indicated the methylation status of DACT1 and DACT2 could be considered as the useful markers for evaluating the prognosis of ESCC.	('DACT2', 'Gene', (45, 50))	('DACT2', 'Gene', '168002', (150, 155))	('DACT1', 'Gene', '51339', (36, 41))	('survival', 'MPA', (80, 88))	('ESCC', 'Disease', (17, 21))	('patients', 'Species', '9606', (22, 30))	('ESCC', 'Disease', (230, 234))	('DACT2', 'Gene', '168002', (45, 50))	('methylation', 'Var', (51, 62))	('DACT2', 'Gene', (150, 155))	('DACT1', 'Gene', '51339', (140, 145))	('worse', 'NegReg', (74, 79))	('DACT1', 'Gene', (36, 41))	('DACT1', 'Gene', (140, 145))
207840	28077137	In the present study, the ESCC patients both with positive UGIC family history and DACT1/DACT2 methylation had been showed the worst survival, indicating the poorer prognosis of DACT1/DACT2 methylation in the high risk populations.	('DACT1', 'Gene', (178, 183))	('DACT2', 'Gene', '168002', (89, 94))	('methylation', 'Var', (95, 106))	('ESCC', 'Disease', (26, 30))	('DACT1', 'Gene', (83, 88))	('DACT2', 'Gene', (184, 189))	('survival', 'MPA', (133, 141))	('patients', 'Species', '9606', (31, 39))	('DACT2', 'Gene', (89, 94))	('DACT1', 'Gene', '51339', (178, 183))	('DACT2', 'Gene', '168002', (184, 189))	('DACT1', 'Gene', '51339', (83, 88))	('worst', 'NegReg', (127, 132))
207841	28077137	In multivariate analysis, the methylation status of TSS-region in DACT1 and DACT2, negative expression of DACT2, tumor stage, and positive UGIC family history provided independent predictive information on ESCC patients' poor survival.	('tumor', 'Disease', (113, 118))	('DACT2', 'Gene', (76, 81))	('patients', 'Species', '9606', (211, 219))	('DACT2', 'Gene', '168002', (106, 111))	('DACT1', 'Gene', (66, 71))	('negative', 'NegReg', (83, 91))	('TSS-region', 'Gene', (52, 62))	('ESCC', 'Disease', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('DACT2', 'Gene', '168002', (76, 81))	('DACT2', 'Gene', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('methylation status', 'Var', (30, 48))	('DACT1', 'Gene', '51339', (66, 71))	('expression', 'MPA', (92, 102))
207842	28077137	In conclusion, the present study suggests that the TSS region hypermethylation may be one of the main mechanisms for reduced expression of DACT1 and DACT2 in ESCC.	('hypermethylation', 'Var', (62, 78))	('DACT1', 'Gene', '51339', (139, 144))	('reduced', 'NegReg', (117, 124))	('DACT2', 'Gene', (149, 154))	('expression', 'MPA', (125, 135))	('ESCC', 'Disease', (158, 162))	('DACT1', 'Gene', (139, 144))	('DACT2', 'Gene', '168002', (149, 154))
207843	28077137	The CGI shore region in DACT1 is more likely to be methylated but is not cancer-specific and isn't related to the transcriptional inhibition of DACT1.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('DACT1', 'Gene', (24, 29))	('DACT1', 'Gene', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('methylated', 'Var', (51, 61))	('DACT1', 'Gene', '51339', (24, 29))	('DACT1', 'Gene', '51339', (144, 149))
207844	28077137	The simultaneous methylation of DACT1 and DACT2 may play important roles in progression of ESCC, and may serve as prognostic biomarkers for ESCC patients.	('patients', 'Species', '9606', (145, 153))	('roles', 'Reg', (67, 72))	('DACT1', 'Gene', '51339', (32, 37))	('ESCC', 'Disease', (91, 95))	('methylation', 'Var', (17, 28))	('DACT2', 'Gene', '168002', (42, 47))	('DACT1', 'Gene', (32, 37))	('DACT2', 'Gene', (42, 47))	('play', 'Reg', (52, 56))
207892	14588079	Based on a limited number of studies, the results show that NSAIDs overall and aspirin in particular are associated with a decreased risk of developing both esophageal cancer and gastric cancer with a magnitude of effect (40 % reduction) comparable to the one observed with colorectal cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('decreased', 'NegReg', (123, 132))	('colorectal cancer', 'Disease', (274, 291))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('colorectal cancer', 'Disease', 'MESH:D015179', (274, 291))	('gastric cancer', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('NSAIDs', 'Var', (60, 66))	('aspirin', 'Chemical', 'MESH:D001241', (79, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (179, 193))	('esophageal cancer', 'Disease', (157, 174))	('colorectal cancer', 'Phenotype', 'HP:0003003', (274, 291))
207926	14588079	There is evidence that supports a similar effect, though to a smaller extent, of NSAIDs in breast cancer whereas such potential in other cancers appears to be slim based on the reviewed literature.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('NSAIDs', 'Var', (81, 87))	('cancers', 'Disease', (137, 144))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
207934	33820882	Furthermore, restoration of expression by treatment with the demethylation agent A + T showed that MT1M downregulation might be closely related to hypermethylation in its promoter region.	('MT1M', 'Gene', '4499', (99, 103))	('hypermethylation', 'Var', (147, 163))	('expression', 'MPA', (28, 38))	('MT1M', 'Gene', (99, 103))	('downregulation', 'NegReg', (104, 118))
207942	33820882	Silencing of tumor suppressor genes (TSGs) by genetic and epigenetic pathways has recently been revealed as an important step in esophageal tumorigenesis.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('TSG', 'Gene', (37, 40))	('esophageal tumor', 'Phenotype', 'HP:0100751', (129, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TSG', 'Gene', '57045', (37, 40))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (140, 145))
207945	33820882	So, study of the function and regulation of silencing TSGs in ESCC is urgently needed.	('silencing', 'Var', (44, 53))	('ESCC', 'Disease', (62, 66))	('TSG', 'Gene', '57045', (54, 57))	('TSG', 'Gene', (54, 57))
207982	33820882	Stable MT1M expressing KYSE150 and control cell three-dimensional (3D) culture were carried out as described by Bissell's protocol.	('KYSE150', 'Var', (23, 30))	('MT1M', 'Gene', '4499', (7, 11))	('MT1M', 'Gene', (7, 11))
207986	33820882	The primary antibodies were used as follows: anti-MT1M antibody (#ab158927; Abcam, USA), PCNA(#ab92592; Abcam), E-cadherin (#ab231303; Abcam), N-cadherin (#ab76011; Abcam), Vimentin (#ab8069; Abcam), SOD1 (#ab51254; Abcam), SOD2 (#13194; Cell Signaling Technology, USA), SOD3 (sc-271170; Santa Cruz Biotechnology, USA), Erk (#4372; Cell Signaling Technology), p-Erk (sc-7383; Santa Cruz Biotechnology), Akt (#4685; Cell Signaling Technology), Nrf2 (sc-365949; Santa Cruz Biotechnology), GPx2 (ab137431; Abcam), p-Akt (sc-4060; Santa Cruz Biotechnology), rabbit polyclonal anti-PI3 kinase p85 alpha (phosphor-Y607, #ab182651; Abcam), cleaved caspase-3 (#9661; Cell Signaling Technology), bcl-2 (#ab32124; Abcam),BAX (#9942; Cell Signaling Technology), and GAPDH (bsm-51010M; BIOSS, China) as a control.	('p85 alpha', 'Gene', '5295', (588, 597))	('Erk', 'Gene', (320, 323))	('SOD2', 'Gene', (224, 228))	('Akt', 'Gene', (403, 406))	('SOD3', 'Gene', '6649', (271, 275))	('Erk', 'Gene', '5594', (320, 323))	('SOD2', 'Gene', '6648', (224, 228))	('p85 alpha', 'Gene', (588, 597))	('Akt', 'Gene', '207', (403, 406))	('GAPDH', 'Gene', '2597', (755, 760))	('Akt', 'Gene', (513, 516))	('cleaved', 'MPA', (633, 640))	('MT1M', 'Gene', '4499', (50, 54))	('PCNA', 'Gene', (89, 93))	('SOD3', 'Gene', (271, 275))	('caspase-3', 'Gene', '836', (641, 650))	('Vimentin', 'Gene', '7431', (173, 181))	('Akt', 'Gene', '207', (513, 516))	('GPx2', 'Gene', '2877', (487, 491))	('GAPDH', 'Gene', (755, 760))	('Nrf2', 'Gene', '4780', (443, 447))	('PI3', 'Gene', '5266', (577, 580))	('E-cadherin', 'Gene', (112, 122))	('bsm-51010M', 'Var', (762, 772))	('caspase-3', 'Gene', (641, 650))	('E-cadherin', 'Gene', '999', (112, 122))	('bcl-2', 'Gene', (687, 692))	('BAX', 'Gene', '581', (711, 714))	('MT1M', 'Gene', (50, 54))	('BAX', 'Gene', (711, 714))	('Vimentin', 'Gene', (173, 181))	('GPx2', 'Gene', (487, 491))	('PCNA', 'Gene', '5111', (89, 93))	('N-cadherin', 'Gene', (143, 153))	('Erk', 'Gene', (362, 365))	('SOD1', 'Gene', (200, 204))	('SOD1', 'Gene', '6647', (200, 204))	('N-cadherin', 'Gene', '1000', (143, 153))	('Nrf2', 'Gene', (443, 447))	('Erk', 'Gene', '5594', (362, 365))	('#ab32124;', 'Var', (694, 703))	('PI3', 'Gene', (577, 580))	('bcl-2', 'Gene', '596', (687, 692))
207990	33820882	Cells were blocked for 1 h with 1% bovine serum albumin and incubated with primary antibodies 4 C overnight, the antibody used were: antibody against Flag (#F9291-.2MG; Sigma-Aldrich), SOD1 (#ab51254; Abcam).	('#F9291-.2MG;', 'Var', (156, 168))	('serum albumin', 'Gene', (42, 55))	('SOD1', 'Gene', '6647', (185, 189))	('F9291-.2MG', 'CellLine', 'CVCL:L875', (157, 167))	('#ab51254;', 'Var', (191, 200))	('serum albumin', 'Gene', '213', (42, 55))	('SOD1', 'Gene', (185, 189))
208005	33820882	By western blot, we have also demonstrated that MT1M was downregulated in three ESCC cell lines KYSE150, KYSE510, KYSE960 compared to 293T human epithelium cell and human lung epithelial BEAS-2B cells (Fig.	('downregulated', 'NegReg', (57, 70))	('human', 'Species', '9606', (165, 170))	('MT1M', 'Gene', (48, 52))	('293T', 'CellLine', 'CVCL:0063', (134, 138))	('KYSE150', 'Var', (96, 103))	('MT1M', 'Gene', '4499', (48, 52))	('KYSE960', 'Var', (114, 121))	('human', 'Species', '9606', (139, 144))	('BEAS-2B', 'CellLine', 'CVCL:0168', (187, 194))	('KYSE960', 'CellLine', 'CVCL:8512', (114, 121))	('KYSE510', 'Var', (105, 112))
208021	33820882	The tumor growth suppressive effects of MT1M on both KYSE150 (P < 0.01) and KYSE960 (P < 0.05) were demonstrated using a MTS assay (Fig.	('tumor', 'Disease', (4, 9))	('KYSE960', 'CellLine', 'CVCL:8512', (76, 83))	('KYSE960', 'Var', (76, 83))	('KYSE150', 'Var', (53, 60))	('MT1M', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('MT1M', 'Gene', '4499', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
208023	33820882	The colonies in MT1M-expressing cells were significantly reduced in both size and quantity in KYSE150 and KYSE960 compared to control cells (Fig.	('KYSE960', 'Var', (106, 113))	('KYSE150', 'Var', (94, 101))	('KYSE960', 'CellLine', 'CVCL:8512', (106, 113))	('MT1M', 'Gene', (16, 20))	('reduced', 'NegReg', (57, 64))	('MT1M', 'Gene', '4499', (16, 20))
208024	33820882	Next, using western blotting, we determined that PCNA, a marker reported to be related to tumor growth, was reduced upon MT1M re-expression (Figs.	('reduced', 'NegReg', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MT1M', 'Gene', (121, 125))	('tumor', 'Disease', (90, 95))	('MT1M', 'Gene', '4499', (121, 125))	('PCNA', 'Gene', (49, 53))	('re-expression', 'Var', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('PCNA', 'Gene', '5111', (49, 53))
208045	33820882	6D), ectopic expression of MT1M significantly evaluated the ROS level, which may, in turn, cause the apoptosis of ESCC cells.	('MT1M', 'Gene', (27, 31))	('MT1M', 'Gene', '4499', (27, 31))	('ROS level', 'MPA', (60, 69))	('ESCC', 'Disease', (114, 118))	('cause', 'Reg', (91, 96))	('ectopic expression', 'Var', (5, 23))	('evaluated', 'NegReg', (46, 55))	('apoptosis', 'CPA', (101, 110))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))
208046	33820882	Because SOD1 is the hub gene in the ROS signaling pathway, we next examined the SOD1 activity through a SOD1 activity assay and verified that SOD1 enzymatic activity was suppressed by MT1M re-expression (P < 0.05; Fig.	('SOD1', 'Gene', (104, 108))	('suppressed', 'NegReg', (170, 180))	('enzymatic activity', 'MPA', (147, 165))	('SOD1', 'Gene', '6647', (104, 108))	('SOD1', 'Gene', (142, 146))	('SOD1', 'Gene', '6647', (142, 146))	('SOD1', 'Gene', (80, 84))	('hub', 'Gene', '1993', (20, 23))	('SOD1', 'Gene', '6647', (80, 84))	('MT1M', 'Gene', (184, 188))	('MT1M', 'Gene', '4499', (184, 188))	('SOD1', 'Gene', (8, 12))	('SOD1', 'Gene', '6647', (8, 12))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('re-expression', 'Var', (189, 202))	('hub', 'Gene', (20, 23))
208053	33820882	Immunofluorescence results suggested that SOD1 was significantly downregulated by the ectopic expression of MT1M (Fig.	('ectopic expression', 'Var', (86, 104))	('SOD1', 'Gene', (42, 46))	('SOD1', 'Gene', '6647', (42, 46))	('MT1M', 'Gene', (108, 112))	('MT1M', 'Gene', '4499', (108, 112))	('downregulated', 'NegReg', (65, 78))
208067	33820882	Downregulation and methylation of MT1M in esophageal cancer suggested that it could be a possible candidate TSGs in ESCC.	('esophageal cancer', 'Disease', (42, 59))	('methylation', 'Var', (19, 30))	('TSG', 'Gene', (108, 111))	('MT1M', 'Gene', '4499', (34, 38))	('ESCC', 'Disease', (116, 120))	('Downregulation', 'NegReg', (0, 14))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('TSG', 'Gene', '57045', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MT1M', 'Gene', (34, 38))
208070	33820882	These data suggested the methylation of MT1M in ESCC was tumor specific and could serve as a potential biomarker in esophageal cancer prognosis.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('biomarker', 'Reg', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('methylation', 'Var', (25, 36))	('MT1M', 'Gene', (40, 44))	('tumor', 'Disease', (57, 62))	('MT1M', 'Gene', '4499', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ESCC', 'Disease', (48, 52))	('esophageal cancer', 'Disease', (116, 133))
208078	33820882	E-cadherin was upregulated after restoration of MT1M expression.	('MT1M', 'Gene', (48, 52))	('upregulated', 'PosReg', (15, 26))	('MT1M', 'Gene', '4499', (48, 52))	('E-cadherin', 'Gene', (0, 10))	('restoration', 'Var', (33, 44))	('expression', 'MPA', (53, 63))	('E-cadherin', 'Gene', '999', (0, 10))
208087	33820882	Paradoxically, as long as intracellular level ROS exceeds the toxicity threshold or the antioxidant system is disturbed, it will induce significant DNA damage and cell apoptosis.	('induce', 'Reg', (129, 135))	('DNA damage', 'MPA', (148, 158))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('disturbed', 'Reg', (110, 119))	('ROS', 'Var', (46, 49))	('toxicity', 'Disease', (62, 70))	('intracellular level', 'MPA', (26, 45))	('ROS', 'Chemical', 'MESH:D017382', (46, 49))	('cell apoptosis', 'CPA', (163, 177))
208093	33820882	These genes can suppress the ROS level and help cancer cell maintain the ROS levels below the toxicity threshold to prevent the cells from undergoing apoptosis or programmed cell death.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('death', 'Disease', 'MESH:D003643', (179, 184))	('death', 'Disease', (179, 184))	('ROS levels', 'MPA', (73, 83))	('genes', 'Var', (6, 11))	('ROS', 'Chemical', 'MESH:D017382', (73, 76))	('suppress', 'NegReg', (16, 24))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('ROS level', 'MPA', (29, 38))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))	('toxicity', 'Disease', (94, 102))
208094	33820882	So, in general, these genes can promote cancer cell proliferation and invasion.	('genes', 'Var', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('promote', 'PosReg', (32, 39))	('invasion', 'CPA', (70, 78))
208095	33820882	However, in contrast to its family members, SOD1 and SOD2, the downregulation of SOD3 has been examined in lung and mammary carcinomas and found to be due to DNA copy number change or hypermethylation in the promoter of methylation.	('carcinomas', 'Disease', 'MESH:D009369', (124, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('lung', 'Disease', (107, 111))	('hypermethylation', 'Var', (184, 200))	('SOD3', 'Gene', (81, 85))	('carcinomas', 'Disease', (124, 134))	('SOD1', 'Gene', (44, 48))	('SOD2', 'Gene', '6648', (53, 57))	('SOD1', 'Gene', '6647', (44, 48))	('SOD2', 'Gene', (53, 57))	('downregulation', 'NegReg', (63, 77))	('SOD3', 'Gene', '6649', (81, 85))
208096	33820882	Overexpressed SOD3 causes hypoxic accumulation of hypoxia-inducible factor (HIF)-1alpha in PDA cells and oncogenic VEGF is also suppressed by SOD3.	('Overexpressed', 'Var', (0, 13))	('SOD3', 'Gene', '6649', (14, 18))	('hypoxic accumulation', 'MPA', (26, 46))	('hypoxia-inducible factor (HIF)-1alpha', 'Gene', '3091', (50, 87))	('VEGF', 'Gene', (115, 119))	('SOD3', 'Gene', '6649', (142, 146))	('SOD3', 'Gene', (14, 18))	('VEGF', 'Gene', '7422', (115, 119))	('SOD3', 'Gene', (142, 146))
208347	32507690	According to the survey of Rocco and colleagues in Europe and North America, as well as the data of the ADJUVANT/CTONG1104 Study in China, there are large treatment strategy differences for IIIA-N2 locally advanced non-small cell lung cancer.	('lung cancer', 'Disease', (230, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('men', 'Species', '9606', (160, 163))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (219, 241))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (215, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))	('IIIA-N2', 'Var', (190, 197))
208439	30445955	In this study, the selection of platinum drugs also played the role in inhibiting RNA and protein synthesis, clinical reports showed that cisplatin has a good anti-cancer effect in the treatment of EC.	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('platinum', 'Chemical', 'MESH:D010984', (32, 40))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cisplatin', 'Var', (138, 147))
208479	29177210	The neoadjuvant use of cisplatin and 5-fluorouracil (5-FU) confers a significant risk of cardiac, renal, and other toxicities, which may impair the ability to withstand subsequent major surgery, and NA treatment-related mortalities are reported.	('impair', 'NegReg', (137, 143))	('toxicities', 'Disease', (115, 125))	('cisplatin', 'Var', (23, 32))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (37, 51))	('renal', 'CPA', (98, 103))	('cardiac', 'CPA', (89, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (23, 32))	('toxicities', 'Disease', 'MESH:D064420', (115, 125))	('5-FU', 'Chemical', 'MESH:D005472', (53, 57))
208545	29177210	The 47 excluded patients with cT1N0 or cT2N0 disease had a 90-day postoperative mortality rate of 4% (2 patients), however, similar to those undergoing chemotherapy.	('cT1N0', 'Var', (30, 35))	('patients', 'Species', '9606', (16, 24))	('cT2N0', 'Var', (39, 44))	('patients', 'Species', '9606', (104, 112))
208578	29089792	Deficiencies of some B vitamins, such as riboflavin, thiamine and pyridoxine, have been proposed as a cause for PVS, though the evidence for this is weak and inconclusive.	('PVS', 'Disease', (112, 115))	('Deficiencies', 'Var', (0, 12))	('cause', 'Reg', (102, 107))	('riboflavin', 'Chemical', 'MESH:D012256', (41, 51))	('pyridoxine', 'Chemical', 'MESH:D011736', (66, 76))	('thiamine', 'Chemical', 'MESH:D013831', (53, 61))
208581	29089792	Riboflavin also plays a key role in several steps during erythropoiesis, including iron absorption and mobilization of ferritin from tissues, and its deficiency could thus contribute to anemia.	('anemia', 'Disease', 'MESH:D000740', (186, 192))	('deficiency', 'Var', (150, 160))	('iron', 'Chemical', 'MESH:D007501', (83, 87))	('iron absorption', 'MPA', (83, 98))	('Riboflavin', 'Chemical', 'MESH:D012256', (0, 10))	('anemia', 'Phenotype', 'HP:0001903', (186, 192))	('contribute to', 'Reg', (172, 185))	('mobilization of ferritin from tissues', 'MPA', (103, 140))	('anemia', 'Disease', (186, 192))
208601	29089792	Abnormal movement of muscles in pharynx and esophagus has also been implicated in web formation.	('Abnormal movement', 'Phenotype', 'HP:0100022', (0, 17))	('web formation', 'Disease', (82, 95))	('Abnormal movement of muscles in pharynx', 'Phenotype', 'HP:0430015', (0, 39))	('Abnormal', 'Var', (0, 8))	('implicated', 'Reg', (68, 78))	('men', 'Species', '9606', (13, 16))
208603	29089792	Impaired heme synthesis, seen in IDA, may induce mitochondrial DNA damage and cause a functional defect in these organelles by a poorly understood mechanism.	('cause', 'Reg', (78, 83))	('functional defect', 'MPA', (86, 103))	('induce', 'Reg', (42, 48))	('heme', 'Chemical', 'MESH:D006418', (9, 13))	('heme', 'Protein', (9, 13))	('Impaired', 'Var', (0, 8))	('mitochondrial DNA damage', 'MPA', (49, 73))
208630	29089792	IDA may be associated with deficiencies of other nutrients, in particular, vitamins, which could manifest as soreness of mouth, glossitis, angular cheilitis, atrophic glossitis (Figure 1), premature loss of teeth, koilonychia (spoon-shaped finger nails), clubbing, seborrheic dermatitis, hyperkeratosis, conjunctivitis, keratitis, blepharitis, paresthesia and/or night blindness.	('atrophic glossitis', 'Disease', (158, 176))	('blepharitis', 'Disease', (331, 342))	('conjunctivitis', 'Disease', 'MESH:D003231', (304, 318))	('glossitis', 'Disease', (128, 137))	('soreness of mouth', 'Disease', 'MESH:D063806', (109, 126))	('night blindness', 'Phenotype', 'HP:0000662', (363, 378))	('glossitis', 'Phenotype', 'HP:0000206', (128, 137))	('clubbing', 'Phenotype', 'HP:0001217', (255, 263))	('seborrheic dermatitis', 'Disease', (265, 286))	('blepharitis', 'Disease', 'MESH:D001762', (331, 342))	('atrophic glossitis', 'Disease', 'MESH:D005928', (158, 176))	('angular cheilitis', 'Phenotype', 'HP:0030318', (139, 156))	('blindness', 'Disease', (369, 378))	('hyperkeratosis', 'Disease', (288, 302))	('angular cheilitis', 'Disease', 'MESH:D002613', (139, 156))	('conjunctivitis', 'Phenotype', 'HP:0000509', (304, 318))	('blepharitis', 'Phenotype', 'HP:0000498', (331, 342))	('paresthesia', 'Disease', (344, 355))	('premature loss of teeth, koilonychia', 'Disease', 'MESH:C537260', (189, 225))	('angular cheilitis', 'Disease', (139, 156))	('deficiencies', 'Var', (27, 39))	('spoon-shaped finger nails', 'Phenotype', 'HP:0001598', (227, 252))	('keratitis', 'Phenotype', 'HP:0000491', (320, 329))	('soreness of mouth', 'Disease', (109, 126))	('hyperkeratosis', 'Disease', 'MESH:D017488', (288, 302))	('glossitis', 'Disease', 'MESH:D005928', (167, 176))	('blindness', 'Phenotype', 'HP:0000618', (369, 378))	('seborrheic dermatitis', 'Phenotype', 'HP:0001051', (265, 286))	('dermatitis', 'Phenotype', 'HP:0011123', (276, 286))	('premature loss of teeth', 'Phenotype', 'HP:0006480', (189, 212))	('cheilitis', 'Phenotype', 'HP:0100825', (147, 156))	('conjunctivitis', 'Disease', (304, 318))	('clubbing', 'Disease', (255, 263))	('glossitis', 'Disease', 'MESH:D005928', (128, 137))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (288, 302))	('atrophic glossitis', 'Phenotype', 'HP:0012473', (158, 176))	('associated', 'Reg', (11, 21))	('seborrheic dermatitis', 'Disease', 'MESH:D012628', (265, 286))	('blindness', 'Disease', 'MESH:D001766', (369, 378))	('koilonychia', 'Phenotype', 'HP:0001598', (214, 225))	('soreness of mouth', 'Phenotype', 'HP:0000155', (109, 126))	('keratitis', 'Disease', (320, 329))	('keratitis', 'Disease', 'MESH:D007634', (320, 329))	('paresthesia', 'Phenotype', 'HP:0003401', (344, 355))	('glossitis', 'Disease', (167, 176))	('glossitis', 'Phenotype', 'HP:0000206', (167, 176))
208679	29089792	The rate of recurrence of dysphagia appears to be lower after endoscopic balloon dilatation than after Savary-Gilliard dilatation.	('lower', 'NegReg', (50, 55))	('dilatation', 'Phenotype', 'HP:0002617', (119, 129))	('dysphagia', 'Disease', 'MESH:D003680', (26, 35))	('endoscopic balloon dilatation', 'Var', (62, 91))	('dysphagia', 'Disease', (26, 35))	('dysphagia', 'Phenotype', 'HP:0002015', (26, 35))	('dilatation', 'Phenotype', 'HP:0002617', (81, 91))
208709	26716904	Further studying CSCs features found that CSCs led to radioresistance, which is associated with intrinsic determinants (DNA repair capability, reactive oxygen species (ROS) levels, cell cycle status, autophagy, apoptosis, regulation of survival pathway) and extrinsic determinants (the influence of hypoxic microenvironment).	('apoptosis', 'CPA', (211, 220))	('ROS', 'Chemical', 'MESH:D017382', (168, 171))	('reactive oxygen species', 'MPA', (143, 166))	('CSCs', 'Var', (42, 46))	('autophagy', 'CPA', (200, 209))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (143, 166))	('led to', 'Reg', (47, 53))	('radioresistance', 'Disease', (54, 69))	('cell cycle', 'CPA', (181, 191))
208714	26716904	Activation of Chk1/2 checkpoint proteins were also found in PC-3RR, DU145RR and LNCaPRR CaP cell lines.	('LNCaPRR CaP', 'CellLine', 'CVCL:0395', (80, 91))	('PC-3RR', 'CellLine', 'CVCL:8757', (60, 66))	('Chk1', 'Gene', (14, 18))	('DU145RR', 'Var', (68, 75))	('PC-3RR', 'Disease', (60, 66))	('Activation', 'PosReg', (0, 10))	('DU145', 'CellLine', 'CVCL:0105', (68, 73))	('Chk1', 'Gene', '1111', (14, 18))
208715	26716904	Inhibition of cell cycle check point protein Chk1 was found to increase radiosensitivity in CD133+CD44+ DU145 CaP cells.	('increase', 'PosReg', (63, 71))	('DU145 CaP', 'CellLine', 'CVCL:0105', (104, 113))	('CD44', 'Gene', '960', (98, 102))	('Chk1', 'Gene', (45, 49))	('CD44', 'Gene', (98, 102))	('CD133', 'Gene', (92, 97))	('radiosensitivity', 'MPA', (72, 88))	('CD133', 'Gene', '8842', (92, 97))	('Inhibition', 'Var', (0, 10))	('Chk1', 'Gene', '1111', (45, 49))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (63, 88))
208726	26716904	Pharmacological depletion of ROS scavengers in Thy1+ CD24+ Lin- CSC-enriched breast cells markedly decreases their clonogenicity and results in radiosensitization.	('decreases', 'NegReg', (99, 108))	('CD24', 'Gene', '100133941', (53, 57))	('depletion', 'Var', (16, 25))	('results in', 'Reg', (133, 143))	('CD24', 'Gene', (53, 57))	('radiosensitization', 'CPA', (144, 162))	('Thy1', 'Gene', '7070', (47, 51))	('clonogenicity', 'CPA', (115, 128))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))	('Thy1', 'Gene', (47, 51))	('ROS', 'Protein', (29, 32))
208728	26716904	Kim et al showed that higher expression of DNA repair and greater number of low-to-intermediate ROS cells after radiation were found in LNCaP prostate spheres (CSCs) compared with adherent LNCaP cells (non-CSCs), further confirming the importance of DNA repair mechanism and ROS level in CaP.	('higher', 'PosReg', (22, 28))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('ROS', 'Chemical', 'MESH:D017382', (275, 278))	('LNCaP', 'CellLine', 'CVCL:0395', (136, 141))	('LNCaP', 'CellLine', 'CVCL:0395', (189, 194))	('LNCaP', 'Var', (136, 141))	('expression', 'MPA', (29, 39))
208739	26716904	Accumulating evidence from human cancer tissues and preclinical studies indicates that different signaling pathways play a critical role in cancer progression, metastasis and chemo/radioresistance via the activation of the pathway proteins or mutation, deletion, epigenetically silence of some pathway genes.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutation', 'Var', (243, 251))	('activation', 'PosReg', (205, 215))	('deletion', 'Var', (253, 261))	('human', 'Species', '9606', (27, 32))	('cancer', 'Disease', (140, 146))	('metastasis', 'CPA', (160, 170))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('epigenetically silence', 'Var', (263, 285))	('pathway genes', 'Gene', (294, 307))	('signaling pathways', 'Pathway', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('chemo/radioresistance', 'CPA', (175, 196))	('pathway', 'Pathway', (223, 230))
208742	26716904	PI3K/Akt/mTOR pathway plays an important role in cell growth and proliferation, and is often dysregulated in cancer due to mutation, amplification, deletion, methylation and post-translational modifications.	('deletion', 'Var', (148, 156))	('mutation', 'Var', (123, 131))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('post-translational modifications', 'Var', (174, 206))	('methylation', 'Var', (158, 169))	('cancer', 'Disease', (109, 115))	('PI3K/Akt/mTOR pathway', 'Pathway', (0, 21))	('amplification', 'Var', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
208745	26716904	Similarly, our recent study also found the PI3K/Akt/mTOR signaling pathway is associated with CaP radioresistance in CaP RR cell lines and enhanced CSC phenotypes (CD44, CD44v6, CD326, ALDH1, Nanog and Snail) (Figure 3).	('CD44', 'Gene', (170, 174))	('ALDH1', 'Gene', '216', (185, 190))	('CD44', 'Gene', '960', (170, 174))	('CD44', 'Gene', '960', (164, 168))	('PI3K/Akt/mTOR signaling pathway', 'Pathway', (43, 74))	('Snail', 'Gene', (202, 207))	('Snail', 'Gene', '6615', (202, 207))	('Nanog', 'Gene', '79923', (192, 197))	('CD44', 'Gene', (164, 168))	('CSC', 'CPA', (148, 151))	('ALDH1', 'Gene', (185, 190))	('CaP radioresistance', 'CPA', (94, 113))	('CD326', 'Var', (178, 183))	('enhanced', 'PosReg', (139, 147))	('Nanog', 'Gene', (192, 197))
208747	26716904	Our recent results showed that combination of dual PI3K/mTOR inhibitors (BEZ235 or PI103) with RT could overcome CaP radioresistance in vitro.	('BEZ235', 'Var', (73, 79))	('PI103', 'Var', (83, 88))	('BEZ235', 'Chemical', 'MESH:C531198', (73, 79))
208748	26716904	We also found that knockdown of CSC marker EpCAM with small interfering RNA (siRNA) could down-regulate the PI3K/Akt/mTOR pathway proteins and enhance radiosensitivity in CaP cells in vitro.	('radiosensitivity', 'CPA', (151, 167))	('enhance', 'PosReg', (143, 150))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (143, 167))	('EpCAM', 'Gene', (43, 48))	('PI3K/Akt/mTOR pathway proteins', 'Pathway', (108, 138))	('down-regulate', 'NegReg', (90, 103))	('EpCAM', 'Gene', '4072', (43, 48))	('small interfering', 'Var', (54, 71))
208750	26716904	Heavey et al recently reviewed that inhibition of this pathway in non-small cell lung cancer (NSCLC) might result in the improvement of RT and overcome radioresistance.	('radioresistance', 'CPA', (152, 167))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('inhibition', 'Var', (36, 46))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (66, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('NSCLC', 'Disease', (94, 99))	('non-small cell lung cancer', 'Disease', (66, 92))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (66, 92))	('improvement', 'PosReg', (121, 132))
208765	26716904	It was reported that this pathway was activated in head and neck squamous cell carcinoma (HNSCC) radioresistance and the expression of p-ERK was found to be decreased by MAPK inhibitor U0126 combined with radiation treatment with increased radiation response.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (60, 88))	('p-ERK', 'Gene', '9451', (135, 140))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('p-ERK', 'Gene', (135, 140))	('activated', 'PosReg', (38, 47))	('expression', 'MPA', (121, 131))	('U0126', 'Var', (185, 190))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (51, 88))	('decreased', 'NegReg', (157, 166))	('inhibitor U0126', 'Var', (175, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('neck squamous cell carcinoma', 'Disease', (60, 88))	('radioresistance', 'CPA', (97, 112))	('U0126', 'Chemical', 'MESH:C113580', (185, 190))
208766	26716904	Affolter et al also showed that U0126 significantly reduced the level of p-ERK and suppressed colony forming ability in radiated oral squamous cancer cells HNSCCUM-02T and lung cancer cells A549.	('U0126', 'Var', (32, 37))	('reduced', 'NegReg', (52, 59))	('squamous cancer', 'Phenotype', 'HP:0002860', (134, 149))	('radiated oral squamous cancer', 'Disease', (120, 149))	('HNSCCUM-02T', 'CellLine', 'CVCL:W875', (156, 167))	('HNSCC', 'Phenotype', 'HP:0012288', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('p-ERK', 'Gene', '9451', (73, 78))	('lung cancer', 'Disease', (172, 183))	('p-ERK', 'Gene', (73, 78))	('A549', 'CellLine', 'CVCL:0023', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))	('level', 'MPA', (64, 69))	('colony forming ability', 'CPA', (94, 116))	('radiated oral squamous cancer', 'Disease', 'MESH:D004194', (120, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('U0126', 'Chemical', 'MESH:C113580', (32, 37))	('suppressed', 'NegReg', (83, 93))
208767	26716904	However, Gupta et al claimed that inhibition of the Raf-MEK-MAPK pathway with PD98059, or the Ras-MEK kinase-p38 pathway with SB203580 had no effect on radiation survival in cells with oncogenic Ras gene.	('p38', 'Gene', '5594', (109, 112))	('MEK', 'Gene', (98, 101))	('Ras', 'Gene', (195, 198))	('MEK', 'Gene', '5609', (98, 101))	('PD98059', 'Chemical', 'MESH:C093973', (78, 85))	('SB203580', 'Chemical', 'MESH:C093642', (126, 134))	('Raf', 'Gene', '22882', (52, 55))	('radiation survival', 'CPA', (152, 170))	('p38', 'Gene', (109, 112))	('MEK', 'Gene', (56, 59))	('MEK', 'Gene', '5609', (56, 59))	('Raf', 'Gene', (52, 55))	('PD98059', 'Var', (78, 85))
208778	26716904	Pitroda et al reported that knockdown of STAT1 with shRNA led to significant growth suppression of irradiated tumors and improved radiosensitization in human squamous cell carcinoma cell line SCC61, accompanied by alterations in glycolysis pathway.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('shRNA', 'Gene', (52, 57))	('improved', 'PosReg', (121, 129))	('STAT1', 'Gene', (41, 46))	('growth suppression of irradiated tumors', 'Disease', (77, 116))	('radiosensitization', 'MPA', (130, 148))	('STAT1', 'Gene', '6772', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('SCC61', 'CellLine', 'CVCL:7118', (192, 197))	('human', 'Species', '9606', (152, 157))	('alterations', 'Reg', (214, 225))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('knockdown', 'Var', (28, 37))	('growth suppression of irradiated tumors', 'Disease', 'MESH:D006130', (77, 116))	('glycolysis pathway', 'Pathway', (229, 247))	('squamous cell carcinoma', 'Disease', (158, 181))
208781	26716904	Our recent findings indicated that increased LDHA was found in CaP RR cells and knockdown of LDHA with siRNA or specific inhibitor FX-11 can increase radiosensitivity in CaP RR cells (unpublished data), suggesting LDHA is associated with CaP radioresistance.	('knockdown', 'Var', (80, 89))	('LDHA', 'Gene', (45, 49))	('increase', 'PosReg', (141, 149))	('LDHA', 'Gene', '3939', (45, 49))	('LDHA', 'Gene', (93, 97))	('LDHA', 'Gene', '3939', (93, 97))	('LDHA', 'Gene', (214, 218))	('radiosensitivity', 'CPA', (150, 166))	('FX-11', 'Chemical', '-', (131, 136))	('associated', 'Reg', (222, 232))	('LDHA', 'Gene', '3939', (214, 218))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (141, 166))	('CaP radioresistance', 'CPA', (238, 257))
208784	26716904	Overexpression of VEGF contributes to the growth and metastasis of solid tumors and inhibition of VEGF pathway offers potential clinical treatment for patients with hematologic malignancies.	('growth', 'CPA', (42, 48))	('metastasis of solid tumors', 'Disease', (53, 79))	('VEGF pathway', 'Pathway', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('patients', 'Species', '9606', (151, 159))	('metastasis of solid tumors', 'Disease', 'MESH:D009362', (53, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('hematologic malignancies', 'Disease', 'MESH:D019337', (165, 189))	('inhibition', 'Var', (84, 94))	('hematologic malignancies', 'Disease', (165, 189))	('VEGF', 'Gene', (18, 22))
208796	26716904	According to Zhang et al, inhibiting Notch-1 could regulate radiation-induced epithelial-mesenchymal transition (EMT) in gastric cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Notch-1', 'Gene', (37, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('regulate', 'Reg', (51, 59))	('gastric cancer', 'Disease', (121, 135))	('inhibiting', 'Var', (26, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
208797	26716904	Inhibiting radiation-induced Notch-1 signaling was found to enhance the RT efficacy in NCI-H1299 and NCI-H460 NSCLC cell lines in vitro and NCI-H1299 s.c xenografts in vivo.	('Inhibiting', 'Var', (0, 10))	('NCI-H1299 and NCI-H460 NSCLC', 'Disease', 'MESH:D002289', (87, 115))	('NCI-H1299', 'CellLine', 'CVCL:0060', (140, 149))	('enhance', 'PosReg', (60, 67))	('NCI-H1299', 'CellLine', 'CVCL:0060', (87, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
208804	26716904	Su et al showed that the up-regulation of the Wnt/beta-catenin pathway is important for KYSE-150 RR esophageal cancer cells.	('up-regulation', 'PosReg', (25, 38))	('esophageal cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('KYSE-150', 'Var', (88, 96))	('beta-catenin', 'Gene', (50, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('beta-catenin', 'Gene', '1499', (50, 62))
208807	26716904	Inhibition of Wnt/beta-catenin pathway could radiosensitize CaP cells through decreasing aldehyde dehydrogenase (ALDH).	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (18, 30))	('decreasing', 'NegReg', (78, 88))	('aldehyde dehydrogenase', 'MPA', (89, 111))	('Inhibition', 'Var', (0, 10))
208815	26716904	In our recent study, total 309 signaling pathway proteins were identified to be significantly different between CaP RR (PC-3RR, DU145RR and LNCaPRR) and control (PC-3, DU145 and LNCaP) cells using the label-free LC-MS/MS method (unpublished data).	('DU145RR', 'Var', (128, 135))	('DU145', 'CellLine', 'CVCL:0105', (128, 133))	('signaling pathway proteins', 'Pathway', (31, 57))	('LNCaP', 'CellLine', 'CVCL:0395', (140, 145))	('LNCaP', 'CellLine', 'CVCL:0395', (178, 183))	('different', 'Reg', (94, 103))	('DU145', 'CellLine', 'CVCL:0105', (168, 173))	('PC-3RR', 'CellLine', 'CVCL:8757', (120, 126))
208886	26049720	This finding is consistent with a previous report, in which a juvenile polyp with SMAD4 mutation showed gastric differentiation (defined by expression of MUC5AC protein).	('mutation', 'Var', (88, 96))	('MUC5AC', 'Gene', '4586', (154, 160))	('SMAD4', 'Gene', (82, 87))	('gastric differentiation', 'CPA', (104, 127))	('juvenile polyp', 'Phenotype', 'HP:0004784', (62, 76))	('MUC5AC', 'Gene', (154, 160))
208911	26273376	However, the MIE group had a significantly lower incidence of functional complication (1.79%, 1/59) than the OE group (32.0%, 16/50, P < 0.01).	('functional', 'MPA', (62, 72))	('MIE', 'Var', (13, 16))	('MIE', 'Chemical', '-', (13, 16))	('OE', 'Chemical', '-', (109, 111))	('lower', 'NegReg', (43, 48))
208934	26273376	The incidence of functional complications was significantly lower in the MIE than in the OE group (P < 0.01).	('OE', 'Chemical', '-', (89, 91))	('MIE', 'Var', (73, 76))	('MIE', 'Chemical', '-', (73, 76))	('functional complications', 'CPA', (17, 41))	('lower', 'NegReg', (60, 65))
208938	26273376	The rate of RLNP was slightly higher in the MIE group than in the OE group, but no statistical significance was observed.	('higher', 'PosReg', (30, 36))	('OE', 'Chemical', '-', (66, 68))	('MIE', 'Var', (44, 47))	('RLNP', 'Disease', (12, 16))	('MIE', 'Chemical', '-', (44, 47))
208947	26273376	These results were consistent with a report by Mamidanna et al., in which they investigated the short-term outcomes following open versus minimally invasive esophagectomy in England, and also found that MIE might help decrease functional morbidity, but not technical problems.	('decrease', 'NegReg', (218, 226))	('MIE', 'Chemical', '-', (203, 206))	('MIE', 'Var', (203, 206))	('functional', 'MPA', (227, 237))
208951	26273376	also observed that the risk of pulmonary infection and respiratory failure was significantly lower after MIE than after OE.	('OE', 'Chemical', '-', (120, 122))	('respiratory failure', 'Disease', 'MESH:D012131', (55, 74))	('respiratory failure', 'Disease', (55, 74))	('risk of pulmonary infection', 'Phenotype', 'HP:0006532', (23, 50))	('MIE', 'Var', (105, 108))	('lower', 'NegReg', (93, 98))	('MIE', 'Chemical', '-', (105, 108))	('pulmonary infection', 'Disease', (31, 50))	('pulmonary infection', 'Phenotype', 'HP:0006532', (31, 50))	('respiratory failure', 'Phenotype', 'HP:0002878', (55, 74))	('pulmonary infection', 'Disease', 'MESH:D008171', (31, 50))
208955	26273376	In our study, the incidence of functional complication in the MIE group was significantly lower than in the OE group (1.7% to 32.0%, P < 0.01).	('lower', 'NegReg', (90, 95))	('MIE', 'Chemical', '-', (62, 65))	('OE', 'Chemical', '-', (108, 110))	('MIE', 'Var', (62, 65))
208965	26273376	In the current study, the rate of anastomosis leakage in the MIE group was 23.7%, significantly higher than in the OE group (12%, P < 0.05).	('MIE', 'Chemical', '-', (61, 64))	('anastomosis leakage', 'MPA', (34, 53))	('MIE', 'Var', (61, 64))	('OE', 'Chemical', '-', (115, 117))	('higher', 'PosReg', (96, 102))
209052	25174943	The CALGB 30105 trial showed that a V20 of 40% was associated with significant grade 3-5 pulmonary toxicity, which would be expected with any other combination treatment, even with radiotherapy alone.	('V20 of 40%', 'Var', (36, 46))	('pulmonary toxicity', 'Disease', 'MESH:D008171', (89, 107))	('pulmonary toxicity', 'Disease', (89, 107))
209152	24312435	An epidemiological study conducted in Taiwan has shown that the odds ratio for esophageal cancer is greater for alcohol drinking than smoking (17.6 vs 5.4).	('esophageal cancer', 'Disease', (79, 96))	('alcohol', 'Chemical', 'MESH:D000438', (112, 119))	('alcohol drinking', 'Phenotype', 'HP:0030955', (112, 128))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('alcohol drinking', 'Var', (112, 128))
209223	33034274	Accumulating evidence indicates that alterations of this protein are involved in human carcinogenesis, especially in the regulation of chemotherapeutic drug response.	('involved', 'Reg', (69, 77))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('alterations', 'Var', (37, 48))	('carcinogenesis', 'Disease', (87, 101))	('human', 'Species', '9606', (81, 86))
209227	33034274	In contrast, loss of Nipped-B-like protein stimulated the growth of EC9706 and Eca-109 cells with high levels of the protein, and resulted in resistance to cisplatin.	('resulted in', 'Reg', (130, 141))	('stimulated', 'PosReg', (43, 53))	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('Nipped-B-like protein', 'Gene', (21, 42))	('resistance to cisplatin', 'MPA', (142, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('growth', 'MPA', (58, 64))	('Nipped-B-like protein', 'Gene', '25836', (21, 42))	('loss', 'Var', (13, 17))
209229	33034274	Restoration of this pro-apoptotic protein in Nipped-B-like protein-overexpressing esophageal squamous cell carcinoma cells effectively increased cisplatin sensitivity.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Nipped-B-like protein', 'Gene', (45, 66))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('Restoration', 'Var', (0, 11))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('Nipped-B-like protein', 'Gene', '25836', (45, 66))	('increased', 'PosReg', (135, 144))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('cisplatin sensitivity', 'MPA', (145, 166))
209230	33034274	Conversely, the silencing of P53-upregulated modulator of apoptosis in Nipped-B-like protein-depleted esophageal squamous cell carcinoma rendered cells resistant to cisplatin.	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('P53', 'Gene', (29, 32))	('Nipped-B-like protein', 'Gene', '25836', (71, 92))	('modulator of', 'MPA', (45, 57))	('resistant', 'CPA', (152, 161))	('P53', 'Gene', '7157', (29, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('silencing', 'Var', (16, 25))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))	('Nipped-B-like protein', 'Gene', (71, 92))
209245	33034274	NIPBL has been implicated in transcriptional regulation, and shows mutations in the majority of individuals afflicted with Cornelia de Lange syndrome (CdLS), a developmental disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and mental retardation.	('Cornelia de Lange syndrome', 'Disease', 'MESH:D003635', (123, 149))	('developmental disorder', 'Phenotype', 'HP:0001263', (160, 182))	('dysmorphic facial', 'Disease', (200, 217))	('limb reduction defects', 'Disease', (242, 264))	('mental retardation', 'Disease', (270, 288))	('limb reduction', 'Phenotype', 'HP:0009826', (242, 256))	('developmental disorder', 'Disease', 'MESH:D002658', (160, 182))	('CdLS', 'Disease', (151, 155))	('growth delay', 'Phenotype', 'HP:0001510', (228, 240))	('Cornelia de Lange syndrome', 'Disease', (123, 149))	('dysmorphic facial features', 'Phenotype', 'HP:0001999', (200, 226))	('developmental disorder', 'Disease', (160, 182))	('NIPBL', 'Gene', (0, 5))	('growth delay', 'CPA', (228, 240))	('CdLS', 'Disease', 'MESH:D003635', (151, 155))	('mental retardation', 'Phenotype', 'HP:0001249', (270, 288))	('mutations', 'Var', (67, 76))	('mental retardation', 'Disease', 'MESH:D008607', (270, 288))	('limb reduction defects', 'Disease', 'MESH:D007022', (242, 264))	('dysmorphic facial', 'Disease', 'None', (200, 217))
209246	33034274	Heterozygous mutations of NIPBL account for 65% of the total cases of CdLS.	('NIPBL', 'Gene', (26, 31))	('CdLS', 'Disease', 'MESH:D003635', (70, 74))	('CdLS', 'Disease', (70, 74))	('Heterozygous mutations', 'Var', (0, 22))
209247	33034274	Increasing evidence has shown that alterations of NIPBL expression are involved in human carcinogenesis, especially in the regulation of chemotherapy sensitivity.	('NIPBL', 'Gene', (50, 55))	('alterations', 'Var', (35, 46))	('involved', 'Reg', (71, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('carcinogenesis', 'Disease', (89, 103))	('human', 'Species', '9606', (83, 88))	('expression', 'MPA', (56, 66))
209248	33034274	Genome-wide functional profiling has shown that the silencing of NIPBL renders breast cancer cells resistant to tamoxifen.	('silencing', 'Var', (52, 61))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('tamoxifen', 'Chemical', 'MESH:D013629', (112, 121))	('NIPBL', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))
209251	33034274	Human ESCC cell lines, including COLO-680N, KYSE-140, KYSE-150, KYSE-180, KYSE-450, TE-10, and TE-13, were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA).	('KYSE', 'Chemical', '-', (44, 48))	('KYSE', 'Chemical', '-', (64, 68))	('KYSE-450', 'Var', (74, 82))	('KYSE-180', 'Var', (64, 72))	('Human', 'Species', '9606', (0, 5))	('TE', 'Chemical', 'MESH:D013691', (84, 86))	('TE', 'Chemical', 'MESH:D013691', (95, 97))	('SA', 'Gene', '6296', (180, 182))	('KYSE', 'Chemical', '-', (54, 58))	('KYSE', 'Chemical', '-', (74, 78))
209285	33034274	previously measured the IC50 of cisplatin in different kinds of ESCC cell lines, including KYSE-140, KYSE-150, TE-1, TE-4, TE-8, TE-10, TE-11, TE-12, and TE-15.	('TE', 'Chemical', 'MESH:D013691', (123, 125))	('TE', 'Chemical', 'MESH:D013691', (143, 145))	('TE', 'Chemical', 'MESH:D013691', (154, 156))	('IC50', 'MPA', (24, 28))	('KYSE-150', 'Var', (101, 109))	('TE', 'Chemical', 'MESH:D013691', (117, 119))	('KYSE', 'Chemical', '-', (91, 95))	('TE-15', 'Disease', 'MESH:D012559', (154, 159))	('TE', 'Chemical', 'MESH:D013691', (111, 113))	('TE-15', 'Disease', (154, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('KYSE', 'Chemical', '-', (101, 105))	('TE', 'Chemical', 'MESH:D013691', (129, 131))	('TE', 'Chemical', 'MESH:D013691', (136, 138))
209293	33034274	On the contrary, NIPBL knockdown decreased cisplatin sensitivity of EC9706 and Eca-109 cells, as measured using flow cytometry (Figure 3C, D) and a cell viability assay (Figure 3E, F), respectively.	('cisplatin sensitivity', 'MPA', (43, 64))	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('NIPBL', 'Gene', (17, 22))	('knockdown', 'Var', (23, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('decreased', 'NegReg', (33, 42))
209298	33034274	Interestingly, PUMA expression in COLO-680N cells was remarkably upregulated after ectopic expression of NIPBL (Figure 4A, B).	('NIPBL', 'Gene', (105, 110))	('PUMA', 'Gene', '27113', (15, 19))	('PUMA', 'Gene', (15, 19))	('upregulated', 'PosReg', (65, 76))	('ectopic expression', 'Var', (83, 101))
209300	33034274	Furthermore, we found that the silencing of PUMA rescues the effect of NIPBL overexpression on cell viability after cisplatin treatment.	('silencing', 'Var', (31, 40))	('overexpression', 'PosReg', (77, 91))	('effect', 'MPA', (61, 67))	('cell viability', 'CPA', (95, 109))	('PUMA', 'Gene', (44, 48))	('rescues', 'PosReg', (49, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('PUMA', 'Gene', '27113', (44, 48))	('NIPBL', 'Gene', (71, 76))
209301	33034274	On the other hand, ectopic expression of PUMA reverses the effect of NIPBL depletion on cell growth after cisplatin treatment (Figure 4E, F).	('ectopic expression', 'Var', (19, 37))	('PUMA', 'Gene', '27113', (41, 45))	('cell growth', 'MPA', (88, 99))	('reverses', 'NegReg', (46, 54))	('PUMA', 'Gene', (41, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('effect', 'MPA', (59, 65))
209306	33034274	Interestingly, several HDACs, including HDAC1, HDAC3, HDAC6, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7, were significantly downregulated following silencing of NIPBL (Figure 5B).	('HDAC1', 'Gene', (40, 45))	('silencing', 'Var', (143, 152))	('SIRT3', 'Gene', '23410', (68, 73))	('SIRT3', 'Gene', (68, 73))	('SIRT7', 'Gene', (93, 98))	('SIRT2', 'Gene', (61, 66))	('HDAC1', 'Gene', '3065', (40, 45))	('HDAC3', 'Gene', '8841', (47, 52))	('SIRT5', 'Gene', (75, 80))	('NIPBL', 'Gene', (156, 161))	('SIRT2', 'Gene', '22933', (61, 66))	('HDAC6', 'Gene', (54, 59))	('SIRT5', 'Gene', '23408', (75, 80))	('HD', 'Disease', 'MESH:D006816', (40, 42))	('downregulated', 'NegReg', (119, 132))	('SIRT7', 'Gene', '51547', (93, 98))	('SIRT6', 'Gene', (82, 87))	('HD', 'Disease', 'MESH:D006816', (54, 56))	('HD', 'Disease', 'MESH:D006816', (23, 25))	('HD', 'Disease', 'MESH:D006816', (47, 49))	('HDAC3', 'Gene', (47, 52))	('HDAC6', 'Gene', '10013', (54, 59))	('SIRT6', 'Gene', '51548', (82, 87))
209313	33034274	In this study, we found that NIPBL-induced dysregulation of PUMA affects cisplatin sensitivity in ESCC.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('dysregulation', 'Var', (43, 56))	('PUMA', 'Gene', (60, 64))	('cisplatin sensitivity', 'MPA', (73, 94))	('affects', 'Reg', (65, 72))	('PUMA', 'Gene', '27113', (60, 64))
209319	33034274	identified heterozygous somatic missense mutations in the SMC1A, SMC4, STAG3, and NIPBL genes in 9 out of 132 patients with colorectal adenocarcinomas.	('missense mutations', 'Var', (32, 50))	('colorectal adenocarcinomas', 'Disease', (124, 150))	('SMC1A', 'Gene', (58, 63))	('SMC4', 'Gene', '10051', (65, 69))	('STAG3', 'Gene', '10734', (71, 76))	('SMC4', 'Gene', (65, 69))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (124, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('STAG3', 'Gene', (71, 76))	('SMC1A', 'Gene', '8243', (58, 63))	('patients', 'Species', '9606', (110, 118))	('NIPBL', 'Gene', (82, 87))
209321	33034274	Subsequently, NIPBL mutations were identified with high microsatellite instability in gastric and colorectal cancers.	('colorectal cancers', 'Disease', (98, 116))	('high microsatellite instability', 'Disease', 'MESH:D053842', (51, 82))	('gastric', 'Disease', (86, 93))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('NIPBL', 'Gene', (14, 19))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('high microsatellite instability', 'Disease', (51, 82))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (20, 29))	('colorectal cancers', 'Disease', 'MESH:D015179', (98, 116))
209322	33034274	Recent cancer genomic analyses discovered a high frequency of NIPBL mutations in a select subset of cancers, including gliomas, endometrial carcinoma, and acute megakaryoblastic leukemia, suggesting that these mutations may underlie the development of human cancers.	('NIPBL', 'Gene', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('acute megakaryoblastic leukemia', 'Disease', 'MESH:D007947', (155, 186))	('acute megakaryoblastic leukemia', 'Disease', (155, 186))	('endometrial carcinoma', 'Disease', (128, 149))	('acute megakaryoblastic leukemia', 'Phenotype', 'HP:0006733', (155, 186))	('cancer', 'Disease', (7, 13))	('cancers', 'Disease', 'MESH:D009369', (258, 265))	('leukemia', 'Phenotype', 'HP:0001909', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('gliomas', 'Disease', (119, 126))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (128, 149))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('human', 'Species', '9606', (252, 257))	('cancers', 'Disease', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (128, 149))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('mutations', 'Var', (68, 77))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('cancers', 'Disease', (258, 265))
209323	33034274	We searched the COSMIC database and found recurrent NIPBL mutations in patients with esophageal cancer (26/1513, 1.72%), with 14 of these mutations occurring in patients with ESCC (Supplementary Figure 2).	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('patients', 'Species', '9606', (71, 79))	('NIPBL', 'Gene', (52, 57))	('patients', 'Species', '9606', (161, 169))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
209324	33034274	The only ESCC cell line used in this study that had a NIPBL mutation was KYSE-450.	('KYSE', 'Chemical', '-', (73, 77))	('mutation', 'Var', (60, 68))	('NIPBL', 'Gene', (54, 59))
209325	33034274	The mutation in KYSE450 is silent, and does not affect the amino acid sequence of NIPBL.	('KYSE450', 'Gene', (16, 23))	('mutation', 'Var', (4, 12))	('KYSE', 'Chemical', '-', (16, 20))
209339	33034274	BBC3 Bcl-2 binding component 3 ChIP Chromatin immunoprecipitation COSMIC Catalogue of Somatic Mutations in Cancer CTCF CCCTC-binding factor ESCC Esophageal squamous cell carcinoma HDACs Histone deacetylases NIPBL Nipped-B-like protein PUMA p53-upregulated modulator of apoptosis SMC Structural maintenance of chromosomes RAD21 double-strand-break repair protein rad21 homolog SA stromal antigen MAU2 MAU2 chromatid cohesion factor homolog SCC sister chromatid cohesion TME Tumor microenvironment.	('CTCF', 'Gene', '10664', (114, 118))	('Nipped-B-like protein', 'Gene', (213, 234))	('MAU2 chromatid cohesion factor homolog', 'Gene', '23383', (400, 438))	('p53', 'Gene', '7157', (240, 243))	('MAU2', 'Gene', (395, 399))	('Bcl-2 binding component 3', 'Gene', '27113', (5, 30))	('RAD21', 'Gene', '5885', (321, 326))	('squamous cell carcinoma', 'Disease', (156, 179))	('Cancer', 'Disease', (107, 113))	('p53', 'Gene', (240, 243))	('MAU2', 'Gene', '23383', (395, 399))	('CTCF', 'Gene', (114, 118))	('rad21', 'Gene', (362, 367))	('stromal antigen', 'Gene', '6296', (379, 394))	('PUMA', 'Gene', '27113', (235, 239))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('SA', 'Gene', '6296', (376, 378))	('MAU2', 'Gene', (400, 404))	('MAU2 chromatid cohesion factor homolog', 'Gene', (400, 438))	('rad21', 'Gene', '5885', (362, 367))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('Nipped-B-like protein', 'Gene', '25836', (213, 234))	('Bcl-2 binding component 3', 'Gene', (5, 30))	('MAU2', 'Gene', '23383', (400, 404))	('BBC3', 'Gene', '27113', (0, 4))	('Mutations', 'Var', (94, 103))	('HD', 'Disease', 'MESH:D006816', (180, 182))	('Tumor', 'Phenotype', 'HP:0002664', (473, 478))	('CCCTC-binding factor', 'Gene', (119, 139))	('CCCTC-binding factor', 'Gene', '10664', (119, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PUMA', 'Gene', (235, 239))	('RAD21', 'Gene', (321, 326))	('stromal antigen', 'Gene', (379, 394))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('BBC3', 'Gene', (0, 4))
209366	32178627	The esophagram displayed stenosis measuring 7 cm in length along with numerous small collections of contrast in the upper portion of the esophageal submucosa, consistent with EIP findings (Fig.	('EIP', 'Disease', (175, 178))	('stenosis', 'Var', (25, 33))	('EIP', 'Disease', 'MESH:C535869', (175, 178))
209370	32178627	Three weeks after dilatation, on follow-up examination, she reported significant improvement in her dysphagia and was tolerating a full regular diet for the first time in 2 years.	('dilatation', 'Var', (18, 28))	('dysphagia', 'Disease', (100, 109))	('dysphagia', 'Phenotype', 'HP:0002015', (100, 109))	('dilatation', 'Phenotype', 'HP:0002617', (18, 28))	('improvement', 'PosReg', (81, 92))	('dysphagia', 'Disease', 'MESH:D003680', (100, 109))
209418	31684999	There was a positive correlation between DeltaADC and early response to treatment (rho = 0.615, P = 0.023), and multivariable logistic regression revealed that DeltaADC was significantly associated with short-term response of CRT in esophageal carcinoma patients.	('DeltaADC', 'Var', (160, 168))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (233, 253))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (233, 253))	('associated with', 'Reg', (187, 202))	('patients', 'Species', '9606', (254, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('esophageal carcinoma', 'Disease', (233, 253))
209432	31684999	In our previous study, we found that the expression level of protein Sirtuin-1 (SIRT1) was higher in CRT non-responder patients with ESCC than in CRT responder patients, and suppression of SIRT1 may inhibit the growth of ESCC cell lines.	('SIRT1', 'Gene', (80, 85))	('patients', 'Species', '9606', (160, 168))	('higher', 'PosReg', (91, 97))	('ESCC', 'Disease', (133, 137))	('patients', 'Species', '9606', (119, 127))	('ESCC', 'Disease', 'MESH:C562729', (221, 225))	('growth', 'CPA', (211, 217))	('suppression', 'Var', (174, 185))	('inhibit', 'NegReg', (199, 206))	('SIRT1', 'Gene', (189, 194))	('ESCC', 'Disease', (221, 225))	('expression level', 'MPA', (41, 57))	('Sirtuin-1', 'Gene', (69, 78))	('Sirtuin-1', 'Gene', '23411', (69, 78))	('ESCC', 'Disease', 'MESH:C562729', (133, 137))
209444	31684999	All MRI examinations contained T1 weighted imaging (TR/TE 423/100 ms, average number 1, FOV 365 x 284 mm, matrix 320, slice thickness 4 mm, skip 1.2-1.6 mm and slice 20), T2 weighted imaging (TR/TE 2000/70 ms, concatenations 2, flip angle 180 , matrix 288, average number 2, FOV 300 x 280 mm, slice thickness 4 mm, slice 20 and skip 1.2-1.6 mm), T1 plus contrast enhanced imaging including sagittal and transverse axial, and then DWI imaging (TR/TE/TI 10,205/70/180 ms, FOV 450 x 366 mm, matrix 256, slice thickness/gap 4/0 mm, slice 20, EPI factor 43).	('FOV', 'Gene', '56287', (470, 473))	('FOV', 'Gene', '56287', (275, 278))	('FOV', 'Gene', (275, 278))	('FOV', 'Gene', (470, 473))	('FOV', 'Gene', '56287', (88, 91))	('FOV', 'Gene', (88, 91))	('TR/TE/TI', 'Var', (443, 451))
209463	31684999	Spearman's rank correlation coefficient demonstrated that pre-ADC, intra-ADC, DeltaADC and the ADCratio were positively correlated with the short-term response (rho = 0.215, 0.595, 0.627 and 0.592 respectively, Table 2), and that only DeltaADC may be an independent factor associated with the short-term response via logistic regression analysis (odds ratio: 875.03, 95%CI: 6.35~1.21E5).	('rat', 'Species', '10116', (352, 355))	('DeltaADC', 'Var', (78, 86))	('rat', 'Species', '10116', (47, 50))	('rat', 'Species', '10116', (98, 101))	('correlated', 'Interaction', (120, 130))
209467	31684999	Intra-ADC, DeltaADC and ADCratio had various strong negative correlations with SIRT1 levels (intra-ADC: r = - 0.748, P = 0.002; DeltaADC: r = - 0.943, P = 0.002; ADCratio: r = - 0.911, P = 0.000), while a weak positive correlation between the pre-ADC and the levels of SIRT1 was observed, and no significant difference in the statistics was found (r = 0.109, P = 0.558) (Fig.	('DeltaADC', 'Var', (11, 19))	('negative', 'NegReg', (52, 60))	('rat', 'Species', '10116', (27, 30))	('SIRT1 levels', 'MPA', (79, 91))	('rat', 'Species', '10116', (165, 168))
209476	31684999	A multicenter trial using diffusion-weighted MRI findings to predict pathologic response in neoadjuvant treatment of breast cancer, change in breast tumour ADC (DeltaADC) after 12 weeks of chemotherapy at MRI predicts complete pathologic response to neoadjuvant chemotherapy.	('breast tumour', 'Disease', (142, 155))	('breast tumour', 'Phenotype', 'HP:0100013', (142, 155))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('complete pathologic response', 'CPA', (218, 246))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (117, 130))	('breast tumour', 'Disease', 'MESH:D001943', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('predicts', 'Reg', (209, 217))	('change', 'Var', (132, 138))
209486	31684999	Previous studies revealed that aberrant expression of SIRT1 has been noted in many solid tumours including esophageal carcinoma, and the overexpression of SIRT1 is responsible for radiation resistance and poor prognosis in patients with esophageal cancer treated with chemotherapy and radiotherapy.	('esophageal cancer', 'Disease', (237, 254))	('SIRT1', 'Gene', (54, 59))	('radiation resistance', 'CPA', (180, 200))	('SIRT1', 'Gene', (155, 160))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('noted', 'Reg', (69, 74))	('aberrant', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (107, 127))	('expression', 'MPA', (40, 50))	('solid tumours', 'Disease', (83, 96))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('overexpression', 'PosReg', (137, 151))	('esophageal carcinoma', 'Disease', (107, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (237, 254))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (107, 127))	('solid tumours', 'Disease', 'MESH:D009369', (83, 96))	('patients', 'Species', '9606', (223, 231))
209496	31684999	LQ15H160012, LY18H160031, LY19H160004 and the General Project of Zhejiang Provincial Health Commission (Grant Nos.2018273652, 2019328882, 2019326095).	('LY19H160004', 'Var', (26, 37))	('LQ15H160012, LY18H160031', 'Chemical', 'MESH:D006859', (0, 24))	('LY18H160031', 'Var', (13, 24))	('LQ15H160012', 'Var', (0, 11))	('LY19', 'CellLine', 'CVCL:1878', (26, 30))
209517	31058847	EGCG can also reduce the recurrence rate of cancers which has attracted research interest.	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('rat', 'Species', '10116', (36, 39))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGCG', 'Var', (0, 4))	('reduce', 'NegReg', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
209544	31058847	Achieving a good result often requires high doses; however, high doses of EGCG triggers a series of toxic side effects.	('EGCG', 'Chemical', 'MESH:C045651', (74, 78))	('high doses', 'Var', (60, 70))	('EGCG', 'Gene', (74, 78))	('triggers', 'Reg', (79, 87))
209546	31058847	ROS can also activate redox-sensitive transcription factor nuclear factor erythrocyte 2-related factor 2 (Nrf2), thereby upregulating the antioxidant response element pathway.	('activate', 'PosReg', (13, 21))	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('Nrf2', 'Gene', (106, 110))	('upregulating', 'PosReg', (121, 133))	('antioxidant response element pathway', 'Pathway', (138, 174))	('nuclear factor erythrocyte 2-related factor 2', 'Gene', '4780', (59, 104))	('nuclear factor erythrocyte 2-related factor 2', 'Gene', (59, 104))	('Nrf2', 'Gene', '4780', (106, 110))
209554	31058847	By inducing oncogene silencing to prevent digestive tract tumors, EGCG can regulate cell cycle hormones, cell cycle-dependent protein kinases (CDKs), CDK inhibitors etc., to stop the growth of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cell', 'MPA', (84, 88))	('oncogene', 'Protein', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('regulate', 'Reg', (75, 83))	('inducing', 'Reg', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tract tumors', 'Disease', 'MESH:D009369', (52, 64))	('stop', 'NegReg', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tract tumors', 'Disease', (52, 64))	('EGCG', 'Chemical', 'MESH:C045651', (66, 70))	('digestive tract tumors', 'Phenotype', 'HP:0007378', (42, 64))	('tumor', 'Disease', (193, 198))	('digestive tract tumor', 'Phenotype', 'HP:0007378', (42, 63))	('silencing', 'Var', (21, 30))
209555	31058847	EGCG can also change survivin expression, phosphatidylinositol-3-kinase (PI3K) and other signaling pathways, induce tumor cell apoptosis, regulate matrix metalloproteinase (MMP) activity, interfere with tumor angiogenesis and ultimately inhibit tumor cell invasion and transformation.	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('inhibit', 'NegReg', (237, 244))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('survivin', 'Protein', (21, 29))	('interfere', 'NegReg', (188, 197))	('regulate', 'Reg', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('change', 'Reg', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('phosphatidylinositol-3-kinase', 'MPA', (42, 71))	('tumor', 'Disease', (245, 250))	('activity', 'MPA', (178, 186))	('induce', 'PosReg', (109, 115))	('metal', 'Chemical', 'MESH:D008670', (154, 159))	('expression', 'MPA', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('EGCG', 'Var', (0, 4))	('tumor', 'Disease', (116, 121))
209559	31058847	EGCG can also induce the conversion of hypophosphorylated cyclin Rb to its hyperphosphorylated form, and upregulate p53 protein expression, leading to tumor cell growth arrest in the G2/M phase and S phase (Figure 2).	('tumor cell growth arrest', 'Disease', 'MESH:D006323', (151, 175))	('protein', 'Protein', (120, 127))	('S phase', 'CPA', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor cell growth arrest', 'Disease', (151, 175))	('upregulate', 'PosReg', (105, 115))	('growth arrest', 'Phenotype', 'HP:0001510', (162, 175))	('cyclin', 'Gene', '5111', (58, 64))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('p53', 'Gene', '7157', (116, 119))	('EGCG', 'Var', (0, 4))	('cyclin', 'Gene', (58, 64))	('expression', 'MPA', (128, 138))	('conversion', 'MPA', (25, 35))	('p53', 'Gene', (116, 119))
209560	31058847	EGCG can change the methylation status of p38, mitogen-activated protein kinase (MAPK) and C-Jun N-terminal kinase in the oral tumor cell, CAL-27, and arrest tumor cell cycle growth.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('p38', 'Gene', (42, 45))	('CAL-27', 'CellLine', 'CVCL:1107', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('oral tumor', 'Phenotype', 'HP:0100649', (122, 132))	('C-Jun', 'Gene', (91, 96))	('arrest tumor', 'Disease', 'MESH:D006323', (151, 163))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('p38', 'Gene', '1432', (42, 45))	('oral tumor', 'Disease', (122, 132))	('arrest tumor', 'Disease', (151, 163))	('EGCG', 'Var', (0, 4))	('change', 'Reg', (9, 15))	('oral tumor', 'Disease', 'MESH:D020820', (122, 132))	('C-Jun', 'Gene', '3725', (91, 96))	('methylation status', 'MPA', (20, 38))
209561	31058847	In human colorectal cancer HT-29 cells, EGCG inhibits the expression of Cyclin D1 protein; stops the cell cycle in the G1 phase; downregulates the Bcl-2 protein; upregulates Bax, caspase-3, and caspase-9; induces cytochrome c release; damages the mitochondrial membrane; and promotes apoptosis of cancer cells.	('EGCG', 'Chemical', 'MESH:C045651', (40, 44))	('apoptosis', 'CPA', (284, 293))	('human', 'Species', '9606', (3, 8))	('stops', 'NegReg', (91, 96))	('cell cycle in the G1 phase', 'CPA', (101, 127))	('expression', 'MPA', (58, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (9, 26))	('promotes', 'PosReg', (275, 283))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('HT-29', 'CellLine', 'CVCL:0320', (27, 32))	('Cyclin D1', 'Gene', '595', (72, 81))	('caspase-9', 'Gene', '842', (194, 203))	('colorectal cancer', 'Disease', (9, 26))	('induces', 'Reg', (205, 212))	('Cyclin D1', 'Gene', (72, 81))	('downregulates', 'NegReg', (129, 142))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('inhibits', 'NegReg', (45, 53))	('Bax', 'Gene', (174, 177))	('damages', 'NegReg', (235, 242))	('Bcl-2', 'Gene', (147, 152))	('Bax', 'Gene', '581', (174, 177))	('caspase-3', 'Gene', '836', (179, 188))	('cytochrome c', 'Gene', '54205', (213, 225))	('caspase-9', 'Gene', (194, 203))	('colorectal cancer', 'Phenotype', 'HP:0003003', (9, 26))	('caspase-3', 'Gene', (179, 188))	('cancer', 'Disease', (20, 26))	('Bcl-2', 'Gene', '596', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', (297, 303))	('EGCG', 'Var', (40, 44))	('mitochondrial membrane', 'MPA', (247, 269))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('cytochrome c', 'Gene', (213, 225))	('upregulates', 'PosReg', (162, 173))
209568	31058847	(4) EGCG increases the amount of cytochrome Cyt-c entering the cytoplasm of the inner mitochondrial membrane of tumor cells, inhibits ATP formation, destroys the membrane potential of the mitochondrial membrane, activates caspase, and promotes the apoptosis of tumor cells.	('ATP', 'Chemical', 'MESH:D000255', (134, 137))	('destroys', 'NegReg', (149, 157))	('activates', 'PosReg', (212, 221))	('promotes', 'PosReg', (235, 243))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('ATP formation', 'MPA', (134, 147))	('caspase', 'Gene', '842', (222, 229))	('inhibits', 'NegReg', (125, 133))	('EGCG', 'Var', (4, 8))	('increases', 'PosReg', (9, 18))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('membrane potential of the mitochondrial', 'MPA', (162, 201))	('EGCG', 'Chemical', 'MESH:C045651', (4, 8))	('apoptosis', 'CPA', (248, 257))	('amount', 'MPA', (23, 29))	('tumor', 'Disease', (261, 266))	('caspase', 'Gene', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('cytochrome Cyt-c entering the cytoplasm', 'MPA', (33, 72))
209570	31058847	In the colorectal cancer cell, HT-29, EGCG inhibits LPS-mediated IKK phosphorylation, blocks the expression of NF-kappaB protein, induces the FLAs-mediated JNK signaling pathway, and destroys mitochondrial membrane potential, changing its permeability for the release of Cyt-c; this activates the activities of caspase-3 and caspase-9, leading to DNA activation in colorectal cancer cells.	('colorectal cancer', 'Phenotype', 'HP:0003003', (7, 24))	('caspase-9', 'Gene', (325, 334))	('activities', 'MPA', (297, 307))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('EGCG', 'Var', (38, 42))	('caspase-3', 'Gene', (311, 320))	('changing', 'Reg', (226, 234))	('NF-kappaB', 'Gene', (111, 120))	('activation', 'PosReg', (351, 361))	('LPS', 'Disease', (52, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (365, 382))	('activates', 'PosReg', (283, 292))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('permeability for the release of Cyt-c', 'MPA', (239, 276))	('NF-kappaB', 'Gene', '4790', (111, 120))	('EGCG', 'Chemical', 'MESH:C045651', (38, 42))	('colorectal cancer', 'Disease', (365, 382))	('induces', 'Reg', (130, 137))	('expression', 'MPA', (97, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (7, 24))	('JNK', 'Gene', (156, 159))	('destroys', 'NegReg', (183, 191))	('colorectal cancer', 'Disease', (7, 24))	('JNK', 'Gene', '5599', (156, 159))	('LPS', 'Disease', 'MESH:C536528', (52, 55))	('HT-29', 'CellLine', 'CVCL:0320', (31, 36))	('inhibits', 'NegReg', (43, 51))	('caspase-9', 'Gene', '842', (325, 334))	('IKK', 'Gene', (65, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (365, 382))	('blocks', 'NegReg', (86, 92))	('IKK', 'Gene', '1147', (65, 68))	('mitochondrial membrane potential', 'MPA', (192, 224))	('caspase-3', 'Gene', '836', (311, 320))
209571	31058847	After treating the esophageal cancer cell line, ECa109, with EGCG, a decrease in cell viability, increase in the apoptotic rate, and demethylation, downregulation and protein expression of the p16 gene, resulted in the induction of increased ECa109 cell apoptosis.	('increase', 'PosReg', (97, 105))	('demethylation', 'Var', (133, 146))	('p16', 'Gene', '1029', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('EGCG', 'Chemical', 'MESH:C045651', (61, 65))	('cell viability', 'CPA', (81, 95))	('ECa109', 'CellLine', 'CVCL:6898', (242, 248))	('ECa109 cell apoptosis', 'CPA', (242, 263))	('decrease', 'NegReg', (69, 77))	('rat', 'Species', '10116', (123, 126))	('esophageal cancer', 'Disease', (19, 36))	('increased', 'PosReg', (232, 241))	('protein expression', 'MPA', (167, 185))	('apoptotic rate', 'CPA', (113, 127))	('p16', 'Gene', (193, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (19, 36))	('ECa109', 'CellLine', 'CVCL:6898', (48, 54))	('downregulation', 'NegReg', (148, 162))
209573	31058847	EGCG can also inhibit the expression of oncogenes Id1 and p68 in the gastric cancer cells, AGS and A2521, change the related metabolic pathways, and induce apoptosis of cancer cells.	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('apoptosis', 'CPA', (156, 165))	('AGS', 'Disease', (91, 94))	('expression', 'MPA', (26, 36))	('p68', 'Gene', '1655', (58, 61))	('p68', 'Gene', (58, 61))	('A2521', 'Var', (99, 104))	('inhibit', 'NegReg', (14, 21))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('gastric cancer', 'Disease', (69, 83))	('cancer', 'Disease', (77, 83))	('AGS', 'Disease', 'MESH:C535607', (91, 94))	('induce', 'PosReg', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Id1', 'Gene', (50, 53))	('Id1', 'Gene', '3397', (50, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('metabolic pathways', 'Pathway', (125, 143))	('change', 'Reg', (106, 112))
209578	31058847	In recent years, several studies have shown that EGCG can inhibit the biological activity of DNA methyltransferase and miRNA expression, which are valuable tools in tumor protection and treatment.	('biological activity', 'MPA', (70, 89))	('DNA methyltransferase', 'Enzyme', (93, 114))	('miRNA expression', 'MPA', (119, 135))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('EGCG', 'Chemical', 'MESH:C045651', (49, 53))	('inhibit', 'NegReg', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('EGCG', 'Var', (49, 53))	('tumor', 'Disease', (165, 170))
209580	31058847	Demethylation of the tumor suppressor genes, p16 and 21, is caused by hypermethylation in digestive tract tumor cells.	('p16', 'Gene', '1029', (45, 48))	('digestive tract tumor', 'Phenotype', 'HP:0007378', (90, 111))	('tumor', 'Disease', (21, 26))	('hypermethylation', 'Var', (70, 86))	('Demethylation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('p16', 'Gene', (45, 48))	('caused by', 'Reg', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
209590	31058847	In two models of digestive tract tumors, 0.16% EGCG in drinking liquid had 47% inhibitory effect on small intestinal tumors in Apcmin/+mice, 70% inhibitory effect on esophageal cancer in rats, and EGCG effectively inhibited the occurrence of intestinal tumors in mice.	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('intestinal tumors', 'Disease', 'MESH:D007414', (242, 259))	('inhibitory', 'NegReg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('small intestinal tumors', 'Phenotype', 'HP:0100833', (100, 123))	('intestinal tumors', 'Disease', 'MESH:D007414', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('digestive tract tumor', 'Phenotype', 'HP:0007378', (17, 38))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('EGCG', 'Chemical', 'MESH:C045651', (47, 51))	('intestinal tumors', 'Disease', (242, 259))	('EGCG', 'Chemical', 'MESH:C045651', (197, 201))	('intestinal tumors', 'Disease', (106, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('digestive tract tumors', 'Phenotype', 'HP:0007378', (17, 39))	('mice', 'Species', '10090', (263, 267))	('inhibited', 'NegReg', (214, 223))	('tract tumors', 'Disease', 'MESH:D009369', (27, 39))	('tract tumors', 'Disease', (27, 39))	('esophageal cancer', 'Disease', (166, 183))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('inhibitory', 'NegReg', (145, 155))	('mice', 'Species', '10090', (135, 139))	('rats', 'Species', '10116', (187, 191))	('0.16', 'Var', (41, 45))
209594	31058847	In human SCLC cells treated with 70 muM EGCG for 24 h, telomerase activity decreased by 50-60%, and apoptosis became apparent at 36 h of treatment.	('EGCG', 'Chemical', 'MESH:C045651', (40, 44))	('SCLC', 'Disease', (9, 13))	('EGCG', 'Var', (40, 44))	('SCLC', 'Disease', 'MESH:D018288', (9, 13))	('human', 'Species', '9606', (3, 8))	('activity', 'MPA', (66, 74))	('apoptosis', 'CPA', (100, 109))	('telomerase', 'Enzyme', (55, 65))	('decreased', 'NegReg', (75, 84))
209600	31058847	EGCG can also block VEGF signal transduction pathways, such as ERK phosphorylation, which induces the phosphorylation-deficient mutants of FOXO to produce FOXO transcriptase activity and inhibit HUVEC cell migration and capillary formation (Figure 3).	('HUVEC', 'CellLine', 'CVCL:2959', (195, 200))	('inhibit', 'NegReg', (187, 194))	('phosphorylation-deficient', 'MPA', (102, 127))	('HUVEC cell migration', 'CPA', (195, 215))	('induces', 'PosReg', (90, 97))	('mutants', 'Var', (128, 135))	('VEGF', 'Gene', '7422', (20, 24))	('VEGF', 'Gene', (20, 24))	('rat', 'Species', '10116', (209, 212))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('FOXO transcriptase', 'Enzyme', (155, 173))	('FOXO', 'Gene', (139, 143))	('produce', 'PosReg', (147, 154))	('ERK', 'Gene', '5594', (63, 66))	('activity', 'MPA', (174, 182))	('ERK', 'Gene', (63, 66))
209604	31058847	EGCG can also inhibit colon cancer by blocking the activation of the epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R) and VEGFR2 of the RTKs family.	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', (162, 166))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('activation', 'PosReg', (51, 61))	('epidermal growth factor receptor', 'Gene', (69, 101))	('VEGFR2', 'Gene', (161, 167))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (110, 147))	('epidermal growth factor receptor', 'Gene', '1956', (69, 101))	('colon cancer', 'Disease', (22, 34))	('VEGFR2', 'Gene', '3791', (161, 167))	('inhibit', 'NegReg', (14, 21))	('IGF-1R', 'Gene', '3480', (149, 155))	('IGF-1R', 'Gene', (149, 155))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (103, 107))	('blocking', 'NegReg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('insulin-like growth factor-1 receptor', 'Gene', (110, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('EGCG', 'Var', (0, 4))
209614	31058847	Altogether, EGCG can effectively mitigate tumor angiogenesis and metastasis, and effectively reduce tumor density.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (42, 47))	('EGCG', 'Var', (12, 16))	('EGCG', 'Chemical', 'MESH:C045651', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (100, 105))	('mitigate', 'NegReg', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('reduce', 'NegReg', (93, 99))
209621	31058847	Activating ERK1/2 signaling and Nrf2 acetylation increase heme oxygenase-1 (HO-1) expression, thereby reducing DSS induced colitis for effective reduction of the incidence of colorectal cancer.	('HO-1', 'Gene', (76, 80))	('ERK1/2', 'Gene', (11, 17))	('ERK1/2', 'Gene', '5595;5594', (11, 17))	('heme oxygenase-1', 'Gene', '3162', (58, 74))	('Nrf2', 'Gene', '4780', (32, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('expression', 'MPA', (82, 92))	('colitis', 'Phenotype', 'HP:0002583', (123, 130))	('colorectal cancer', 'Disease', (175, 192))	('heme oxygenase-1', 'Gene', (58, 74))	('Nrf2', 'Gene', (32, 36))	('reducing', 'NegReg', (102, 110))	('reduction', 'NegReg', (145, 154))	('HO-1', 'CellLine', 'CVCL:1E42', (76, 80))	('acetylation', 'Var', (37, 48))	('colitis', 'Disease', (123, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('increase', 'PosReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colitis', 'Disease', 'MESH:D003092', (123, 130))
209630	31058847	EGCG can induce gene regulation disorders in tumor cells, which lead to an abnormal signal transduction network, and tumor cell growth arrest or apoptosis.	('signal transduction network', 'MPA', (84, 111))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('abnormal', 'Reg', (75, 83))	('gene regulation disorders', 'MPA', (16, 41))	('tumor', 'Disease', (117, 122))	('tumor cell growth arrest', 'Disease', (117, 141))	('tumor', 'Disease', (45, 50))	('lead to', 'Reg', (64, 71))	('induce', 'Reg', (9, 15))	('tumor cell growth arrest', 'Disease', 'MESH:D006323', (117, 141))	('growth arrest', 'Phenotype', 'HP:0001510', (128, 141))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGCG', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('apoptosis', 'CPA', (145, 154))
209644	31058847	In the human gastric tumor cell, AGS, EGCG was shown to inhibit the activation of ERK, JNK and p38 induced by phorbol ester myristate (PMA) in a time-dependent manner, and inhibit downstream nuclear factors, thereby inhibiting digestion and arresting tumor growth.	('p38', 'Gene', '1432', (95, 98))	('arresting tumor', 'Disease', 'MESH:D006323', (241, 256))	('AGS', 'Disease', 'MESH:C535607', (33, 36))	('ERK', 'Gene', '5594', (82, 85))	('EGCG', 'Var', (38, 42))	('digestion', 'CPA', (227, 236))	('phorbol ester myristate', 'Chemical', '-', (110, 133))	('inhibit', 'NegReg', (56, 63))	('JNK', 'Gene', (87, 90))	('JNK', 'Gene', '5599', (87, 90))	('EGCG', 'Chemical', 'MESH:C045651', (38, 42))	('inhibit', 'NegReg', (172, 179))	('ERK', 'Gene', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('arresting tumor', 'Disease', (241, 256))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('activation', 'MPA', (68, 78))	('human', 'Species', '9606', (7, 12))	('inhibiting', 'NegReg', (216, 226))	('p38', 'Gene', (95, 98))	('gastric tumor', 'Disease', (13, 26))	('gastric tumor', 'Disease', 'MESH:D013274', (13, 26))	('gastric tumor', 'Phenotype', 'HP:0006753', (13, 26))	('AGS', 'Disease', (33, 36))	('PMA', 'Chemical', '-', (135, 138))
209654	31058847	EGCG induces the reduction of NF-kB expression and inhibits TNF-alpha and LPS-mediated activation of the NF-kB signaling pathway in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('inhibits', 'NegReg', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('NF-kB', 'Protein', (30, 35))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('tumor', 'Disease', (132, 137))	('LPS', 'Disease', (74, 77))	('EGCG', 'Var', (0, 4))	('TNF-alpha', 'Gene', '7124', (60, 69))	('NF-kB signaling pathway', 'Pathway', (105, 128))	('reduction', 'NegReg', (17, 26))	('LPS', 'Disease', 'MESH:C536528', (74, 77))	('expression', 'MPA', (36, 46))	('TNF-alpha', 'Gene', (60, 69))
209658	31058847	EGCG induces tumor cell apoptosis, which may be related to the stability of p53, and downregulates NF-kappaB activity, leading to the downregulated expression of the anti-apoptotic protein, Bcl-2.	('tumor', 'Disease', (13, 18))	('NF-kappaB', 'Gene', '4790', (99, 108))	('downregulated', 'NegReg', (134, 147))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('downregulates', 'NegReg', (85, 98))	('Bcl-2', 'Gene', (190, 195))	('NF-kappaB', 'Gene', (99, 108))	('Bcl-2', 'Gene', '596', (190, 195))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('activity', 'MPA', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('EGCG', 'Var', (0, 4))	('expression', 'MPA', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('induces', 'Reg', (5, 12))
209670	31058847	EGCG NPs can significantly change the pharmacokinetic characteristics of EGCG and increase its bioavailability by more than 2.4 times.	('pharmacokinetic characteristics', 'MPA', (38, 69))	('EGCG', 'Gene', (73, 77))	('bioavailability', 'MPA', (95, 110))	('NPs', 'Var', (5, 8))	('change', 'Reg', (27, 33))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('increase', 'PosReg', (82, 90))	('EGCG', 'Chemical', 'MESH:C045651', (73, 77))
209673	31058847	After administering EGCG to mice with the tumor, an increase in the growth inhibition of colorectal cancer cells was observed, with EGCG-16 demonstrating the most apparent inhibitory effect.	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('growth inhibition', 'CPA', (68, 85))	('increase', 'PosReg', (52, 60))	('mice', 'Species', '10090', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('EGCG', 'Chemical', 'MESH:C045651', (20, 24))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('rat', 'Species', '10116', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('EGCG-16', 'Chemical', '-', (132, 139))	('EGCG', 'Chemical', 'MESH:C045651', (132, 136))	('EGCG-16', 'Var', (132, 139))
209677	31058847	Structural changes in EGCG have shown promising results in its antibody action.	('antibody action', 'MPA', (63, 78))	('EGCG', 'Chemical', 'MESH:C045651', (22, 26))	('changes', 'Var', (11, 18))	('EGCG', 'Gene', (22, 26))
209683	31058847	Such combinations may also reduce the adverse reactions of cellular chemotherapy drugs and resistance of tumor cells to chemotherapy drugs.	('combinations', 'Var', (5, 17))	('adverse', 'MPA', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cellular chemotherapy drugs', 'CPA', (59, 86))	('reduce', 'NegReg', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
209690	31058847	EGCG administration to genistein-treated APC (min/+) mice showed that genistein increased the levels of EGCG in the small intestine and plasma, and significantly enhanced the cytoplasmic level and growth inhibitory activity of EGCG on human colorectal cancer cells.	('colorectal cancer', 'Disease', (241, 258))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('growth inhibitory activity', 'CPA', (197, 223))	('mice', 'Species', '10090', (53, 57))	('levels', 'MPA', (94, 100))	('genistein', 'Var', (70, 79))	('rat', 'Species', '10116', (13, 16))	('increased the levels of EGCG', 'Phenotype', 'HP:0003496', (80, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (241, 258))	('cytoplasmic level', 'MPA', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('human', 'Species', '9606', (235, 240))	('EGCG', 'Chemical', 'MESH:C045651', (227, 231))	('genistein', 'Chemical', 'MESH:D019833', (23, 32))	('increased', 'PosReg', (80, 89))	('genistein', 'Chemical', 'MESH:D019833', (70, 79))	('enhanced', 'PosReg', (162, 170))	('EGCG', 'Chemical', 'MESH:C045651', (104, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (241, 258))
209716	30957072	Zaidi and colleagues recently published a report in which they assessed the efficacy of a phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor, LY3023414, on established EAC in vivo model.	('LY3023414', 'Chemical', 'MESH:C000621566', (180, 189))	('phosphatidylinositol 3-kinase', 'Gene', (90, 119))	('LY3023414', 'Var', (180, 189))	('mammalian target of rapamycin', 'Gene', '2475', (127, 156))	('mammalian target of rapamycin', 'Gene', (127, 156))	('EAC', 'Phenotype', 'HP:0011459', (206, 209))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (90, 119))	('EAC', 'Disease', (206, 209))
209719	30957072	Tumors volume evaluation by magnetic resonance imaging (MRI) 8 weeks after randomization showed that tumor in control group increased 109.2%, and tumor in LY3023414 group decrease 56.8%.	('LY3023414', 'Var', (155, 164))	('LY3023414', 'Chemical', 'MESH:C000621566', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('decrease', 'NegReg', (171, 179))	('increased', 'PosReg', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (146, 151))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
209723	30957072	TCGA recently reported an integrated genomic landscape in EAC and show that EAC were similar with chromosomal instability (CIN) subtype for gastric cancer characterized by TP53 mutation, ERBB2 amplification, and VEGFA amplification.	('ERBB2', 'Gene', (187, 192))	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('mutation', 'Var', (177, 185))	('CIN', 'Disease', (123, 126))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('CIN', 'Disease', 'MESH:D007674', (123, 126))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('amplification', 'Var', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('VEGFA', 'Gene', '7422', (212, 217))	('CIN', 'Phenotype', 'HP:0040012', (123, 126))	('chromosomal instability', 'Phenotype', 'HP:0040012', (98, 121))	('gastric cancer', 'Disease', (140, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('VEGFA', 'Gene', (212, 217))	('ERBB2', 'Gene', '2064', (187, 192))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))
209726	30957072	Another study of whole-exome sequencing with 149 EACs also showed that the PI3K pathway was altered in 13% by PIK3CA (6%), PIK3R1 (4%) and PTEN (3%) mutation.	('PIK3R1', 'Gene', (123, 129))	('PIK3R1', 'Gene', '5295', (123, 129))	('PTEN', 'Gene', (139, 143))	('PTEN', 'Gene', '5728', (139, 143))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('PI3K pathway', 'Pathway', (75, 87))	('PIK3CA', 'Gene', (110, 116))	('altered', 'Reg', (92, 99))	('mutation', 'Var', (149, 157))	('PIK3CA', 'Gene', '5290', (110, 116))
209729	30957072	showed that PIK3CA mutation was associated with better survival in esophageal squamous cell carcinoma, while Harada et al.	('PIK3CA', 'Gene', '5290', (12, 18))	('mutation', 'Var', (19, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('better', 'PosReg', (48, 54))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (67, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('esophageal squamous cell carcinoma', 'Disease', (67, 101))	('PIK3CA', 'Gene', (12, 18))
209730	30957072	showed that PIK3CA mutation was not associated with survival in gastric cancer.	('PIK3CA', 'Gene', '5290', (12, 18))	('mutation', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gastric cancer', 'Disease', (64, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))	('PIK3CA', 'Gene', (12, 18))
209731	30957072	demonstrated that genetic variations in genes which were related to PI3K/AKT/MTOR pathway correlated with increased recurrence risk in EAC patient who underwent therapy.	('genetic variations', 'Var', (18, 36))	('EAC', 'Disease', (135, 138))	('EAC', 'Phenotype', 'HP:0011459', (135, 138))	('MTOR', 'Gene', (77, 81))	('MTOR', 'Gene', '2475', (77, 81))	('recurrence', 'Disease', (116, 126))	('patient', 'Species', '9606', (139, 146))
209738	30957072	MEK inhibition upregulates PI3K pathway signaling, causing resistance to MEK inhibition.	('PI3K pathway signaling', 'Pathway', (27, 49))	('upregulates', 'PosReg', (15, 26))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('MEK', 'Gene', (73, 76))	('inhibition', 'Var', (4, 14))	('MEK', 'Gene', '5609', (73, 76))
209739	30957072	Tumors harboring RAS or RAF mutation, for example colon cancer, is resistant for single use of growth factor receptor inhibitor.	('RAS', 'Gene', (17, 20))	('RAF', 'Gene', '22882', (24, 27))	('colon cancer', 'Disease', 'MESH:D015179', (50, 62))	('RAF', 'Gene', (24, 27))	('colon cancer', 'Disease', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Tumors', 'Disease', (0, 6))	('mutation', 'Var', (28, 36))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('colon cancer', 'Phenotype', 'HP:0003003', (50, 62))
209740	30957072	The PI3K/AKT pathway was found out to be activated by BRAF inhibitors in BRAF mutated colon cancer, and thus the combination therapy with BRAF inhibitors and PI3K inhibitor has been evaluated in ongoing trial.	('BRAF', 'Gene', '673', (73, 77))	('colon cancer', 'Disease', (86, 98))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('PI3K/AKT pathway', 'Pathway', (4, 20))	('BRAF', 'Gene', '673', (138, 142))	('mutated', 'Var', (78, 85))	('inhibitors', 'Var', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('activated', 'PosReg', (41, 50))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('BRAF', 'Gene', (73, 77))	('BRAF', 'Gene', (138, 142))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))
209778	24048786	MUC5AC protein expression was induced to a greater degree by conjugated bile acids than by unconjugated bile acids, and this occurred at the transcriptional level.	('MUC5AC', 'Gene', (0, 6))	('conjugated bile acids', 'Var', (61, 82))	('induced', 'Reg', (30, 37))	('bile acids', 'Chemical', 'MESH:D001647', (72, 82))	('bile acids', 'Chemical', 'MESH:D001647', (104, 114))	('expression', 'MPA', (15, 25))	('protein', 'Protein', (7, 14))
209781	24048786	The PI3K inhibitor LY294002 and a dominant-negative AKT construct prevented the induction of MUC5AC by conjugated bile acids.	('LY294002', 'Chemical', 'MESH:C085911', (19, 27))	('AKT', 'Gene', (52, 55))	('PI3', 'Gene', '5266', (4, 7))	('bile acids', 'Chemical', 'MESH:D001647', (114, 124))	('prevented', 'NegReg', (66, 75))	('MUC5AC', 'MPA', (93, 99))	('PI3', 'Gene', (4, 7))	('LY294002', 'Var', (19, 27))	('conjugated bile acids', 'MPA', (103, 124))	('AKT', 'Gene', '207', (52, 55))
209816	24048786	The cDNA plasmid for the dominant-negative mutant of AKT (AKT AAA) was provided by Dr. Dimpy Koul (MDACC).	('AKT', 'Gene', '207', (53, 56))	('mutant', 'Var', (43, 49))	('AKT', 'Gene', '207', (58, 61))	('AKT', 'Gene', (53, 56))	('AKT', 'Gene', (58, 61))
209857	24048786	Ly294002, a specific inhibitor of PI3K, blocked GCDC- or TCA-induced MUC5AC expression at concentrations of 5 muM and 10 muM, and this reduction was dose dependent (Fig.	('MUC5AC', 'Protein', (69, 75))	('rat', 'Species', '10116', (97, 100))	('TCA-induced', 'Disease', (57, 68))	('blocked', 'NegReg', (40, 47))	('Ly294002', 'Var', (0, 8))	('TCA', 'Chemical', 'MESH:D014238', (57, 60))	('PI3', 'Gene', '5266', (34, 37))	('GCDC', 'Chemical', 'MESH:C038329', (48, 52))	('GCDC-', 'Disease', (48, 53))	('expression', 'MPA', (76, 86))	('Ly294002', 'Chemical', 'MESH:C085911', (0, 8))	('PI3', 'Gene', (34, 37))
209864	24048786	Conjugated bile acids GCDC and TCA caused a dose-dependent increase in AP-1 activity, which coincided with the induction of MUC5AC (Figure 5A).	('GCDC', 'Chemical', 'MESH:C038329', (22, 26))	('bile acids', 'Chemical', 'MESH:D001647', (11, 21))	('TCA', 'Chemical', 'MESH:D014238', (31, 34))	('AP-1', 'Enzyme', (71, 75))	('GCDC', 'Var', (22, 26))	('MUC5AC', 'MPA', (124, 130))	('increase', 'PosReg', (59, 67))
209869	24048786	The dominant-negative AKT mutant vector completely blocked the AP-1 activity induced by GCDC and TCA and also decreased the basal level of AP-1 transcriptional activity (Fig.	('AP-1', 'Enzyme', (63, 67))	('AP-1 transcriptional activity', 'MPA', (139, 168))	('AKT', 'Gene', '207', (22, 25))	('decreased', 'NegReg', (110, 119))	('basal level', 'MPA', (124, 135))	('AKT', 'Gene', (22, 25))	('TCA', 'Chemical', 'MESH:D014238', (97, 100))	('mutant', 'Var', (26, 32))	('blocked', 'NegReg', (51, 58))	('GCDC', 'Chemical', 'MESH:C038329', (88, 92))
209899	24048786	Alterations in mucin expression are associated with carcinogenesis in various organs of the gastrointestinal tract, and additional studies are needed to investigate the pathological significance of MUC5AC ectopic expression in Barrett's esophagus and its relation to the progression to EA.	('mucin', 'Protein', (15, 20))	('gastrointestinal tract', 'Disease', (92, 114))	('Alterations', 'Var', (0, 11))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (92, 114))	('MUC5AC', 'Gene', (198, 204))	('carcinogenesis', 'Disease', 'MESH:D063646', (52, 66))	('rat', 'Species', '10116', (4, 7))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (227, 246))	('carcinogenesis', 'Disease', (52, 66))	('associated with', 'Reg', (36, 51))
210046	32411232	In previous studies, GASC1 was shown to be a regulator of stemness in CSCs of ESCC via pluripotency-associated genes (PAGs) promoter demethylation, such as NOTCH1 and SOX2, and the high level of GASC1 was closely associated with poor survival of ESCC patients.	('NOTCH1', 'Gene', '4851', (156, 162))	('associated', 'Reg', (213, 223))	('ESCC', 'Disease', (78, 82))	('NOTCH1', 'Gene', (156, 162))	('ESCC', 'Disease', (246, 250))	('demethylation', 'Var', (133, 146))	('GASC1', 'Gene', '23081', (21, 26))	('high', 'Var', (181, 185))	('SOX2', 'Gene', '6657', (167, 171))	('GASC1', 'Gene', (195, 200))	('patients', 'Species', '9606', (251, 259))	('SOX2', 'Gene', (167, 171))	('GASC1', 'Gene', '23081', (195, 200))	('GASC1', 'Gene', (21, 26))
210048	32411232	We found that a high level of GASC1 was closely associated with worse response to NCT and poor survival of ESCC patients, which could provide a theoretical basis for the development of a new therapeutic strategy of ESCC.	('high', 'Var', (16, 20))	('associated', 'Reg', (48, 58))	('GASC1', 'Gene', '23081', (30, 35))	('patients', 'Species', '9606', (112, 120))	('response to NCT', 'MPA', (70, 85))	('GASC1', 'Gene', (30, 35))	('ESCC', 'Disease', (107, 111))
210050	32411232	The target population was locally advanced ESCC, defined as pathologically proven ESCC, with clinical stages of TNM classification, T1bN + M0 and T2-4aN0-2M0, according to the American Joint Committee on Cancer Staging System (UICC-AJCC) (8th edition).	('ESCC', 'Disease', (43, 47))	('Cancer', 'Phenotype', 'HP:0002664', (204, 210))	('TNM', 'Gene', (112, 115))	('locally advanced ESCC', 'Disease', (26, 47))	('Cancer', 'Disease', 'MESH:D009369', (204, 210))	('Cancer', 'Disease', (204, 210))	('T1bN + M0', 'Var', (132, 141))	('TNM', 'Gene', '10178', (112, 115))	('T2-4aN0-2M0', 'Var', (146, 157))
210081	32411232	In the univariate analysis, patients with high GASC1 expression levels showed significantly worse OS than those with GASC1 expression levels.	('GASC1', 'Gene', (117, 122))	('GASC1', 'Gene', '23081', (117, 122))	('GASC1', 'Gene', (47, 52))	('GASC1', 'Gene', '23081', (47, 52))	('high', 'Var', (42, 46))	('patients', 'Species', '9606', (28, 36))	('worse', 'NegReg', (92, 97))
210082	32411232	In the multivariate analysis, the high GASC1 expression level was significantly associated with poor survival (P=0.048) (Table 3).	('GASC1', 'Gene', '23081', (39, 44))	('high', 'Var', (34, 38))	('GASC1', 'Gene', (39, 44))	('poor', 'NegReg', (96, 100))
210085	32411232	Dysregulation of KDM4 demethylases has been documented in a variety of cancers, including lymphoma, medulloblastoma, breast, prostate, colorectal, lung, gastric, esophageal, and renal cancers.	('Dysregulation', 'Var', (0, 13))	('breast', 'Disease', (117, 123))	('KDM4', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('gastric', 'Disease', (153, 160))	('colorectal', 'Disease', (135, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (90, 98))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (184, 191))	('renal cancers', 'Disease', (178, 191))	('cancers', 'Disease', (71, 78))	('medulloblastoma', 'Disease', 'MESH:D008527', (100, 115))	('esophageal', 'Disease', (162, 172))	('medulloblastoma', 'Phenotype', 'HP:0002885', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('medulloblastoma', 'Disease', (100, 115))	('prostate', 'Disease', (125, 133))	('lymphoma', 'Disease', (90, 98))	('lymphoma', 'Disease', 'MESH:D008223', (90, 98))	('renal cancers', 'Disease', 'MESH:D007680', (178, 191))	('lung', 'Disease', (147, 151))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (184, 191))
210088	32411232	We identified tumor initial cells (TICs) from a number of ESCC cell lines and demonstrated increased expression of GASC1 in the ESCC ALDH + TICs and its involvement in TICs maintenance by specific demethylation of H3K9Me3 at the SOX2 and NOTCH1 promoter.	('NOTCH1', 'Gene', (238, 244))	('GASC1', 'Gene', '23081', (115, 120))	('H3K9Me3', 'Protein', (214, 221))	('TICs', 'Disease', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('TICs', 'Disease', 'MESH:D020323', (35, 39))	('NOTCH1', 'Gene', '4851', (238, 244))	('involvement', 'Reg', (153, 164))	('TICs', 'Phenotype', 'HP:0100033', (140, 144))	('TICs', 'Disease', 'MESH:D020323', (168, 172))	('increased', 'PosReg', (91, 100))	('GASC1', 'Gene', (115, 120))	('demethylation', 'Var', (197, 210))	('TICs', 'Disease', (140, 144))	('SOX2', 'Gene', '6657', (229, 233))	('SOX2', 'Gene', (229, 233))	('TICs', 'Phenotype', 'HP:0100033', (35, 39))	('tumor', 'Disease', (14, 19))	('TICs', 'Disease', 'MESH:D020323', (140, 144))	('TICs', 'Phenotype', 'HP:0100033', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('expression', 'MPA', (101, 111))	('TICs', 'Disease', (35, 39))
210089	32411232	Stemness in various types of cancer is the main cause of tumor recurrence, deterioration, and chemoradiotherapy resistance.	('cancer', 'Disease', (29, 35))	('Stemness', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
210090	32411232	Based on this and according to our previous findings, we assumed that ESCC patients with high GASC1 expression in tumor tissue would respond poorly to neoadjuvant chemotherapy in this study.	('poorly', 'NegReg', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('GASC1', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('patients', 'Species', '9606', (75, 83))	('GASC1', 'Gene', '23081', (94, 99))	('expression', 'MPA', (100, 110))	('tumor', 'Disease', (114, 119))	('high', 'Var', (89, 93))	('ESCC', 'Disease', (70, 74))
210096	32411232	According to these findings, the potential biological mechanism of chemotherapy resistance is high GASC1 expression enhancing the proportion and ability of the TICs subpopulation in ESCC.	('GASC1', 'Gene', '23081', (99, 104))	('enhancing', 'PosReg', (116, 125))	('expression', 'Var', (105, 115))	('ESCC', 'Disease', (182, 186))	('GASC1', 'Gene', (99, 104))	('TICs', 'Disease', 'MESH:D020323', (160, 164))	('TICs', 'Disease', (160, 164))	('high', 'Var', (94, 98))	('TICs', 'Phenotype', 'HP:0100033', (160, 164))
210115	32158227	Furthermore, inhibiting SNHG1 decreased xenograft tumor growth by regulating miR-204 and HOXC8.	('SNHG1', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('regulating', 'Reg', (66, 76))	('decreased', 'NegReg', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('HOXC8', 'MPA', (89, 94))	('inhibiting', 'Var', (13, 23))	('tumor', 'Disease', (50, 55))	('miR-204', 'Protein', (77, 84))
210116	32158227	SNHG1 knockdown suppresses migration and invasion but induces apoptosis of esophageal squamous cell cancer cells by increasing miR-204 and decreasing HOXC8.	('SNHG1', 'Gene', (0, 5))	('decreasing', 'NegReg', (139, 149))	('suppresses', 'NegReg', (16, 26))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (75, 106))	('miR-204', 'Protein', (127, 134))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (86, 106))	('esophageal squamous cell cancer', 'Disease', (75, 106))	('increasing', 'PosReg', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('apoptosis', 'CPA', (62, 71))	('knockdown', 'Var', (6, 15))	('HOXC8', 'MPA', (150, 155))	('induces', 'Reg', (54, 61))
210130	32158227	More importantly, recent works indicate that abnormally expressed SNHG1 is involved in the regulation of esophageal squamous cell cancer progression.	('involved', 'Reg', (75, 83))	('esophageal squamous cell cancer', 'Disease', (105, 136))	('SNHG1', 'Gene', (66, 71))	('abnormally expressed', 'Var', (45, 65))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (116, 136))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (105, 136))
210134	32158227	The expression levels of SNHG1, miR-204 and HOXC8 in esophageal cancer were analyzed via TCGA.	('SNHG1', 'Gene', (25, 30))	('esophageal cancer', 'Disease', (53, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('miR-204', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
210138	32158227	The human esophageal squamous cell cancer cell lines (EC9706, KYSE450, KYSE150 and Eca109) and normal esophageal epithelium cell Het-1A were purchased from BeNa Culture Collection (Beijing, China) and verified by the company.	('human', 'Species', '9606', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('KYSE150', 'Var', (71, 78))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (10, 41))	('KYSE150', 'CellLine', 'CVCL:1348', (71, 78))	('esophageal squamous cell cancer', 'Disease', (10, 41))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (21, 41))	('EC9706', 'CellLine', 'CVCL:E307', (54, 60))
210151	32158227	The membranes were blocked with 5% non-fat milk for 2 h, incubated with specific primary antibodies overnight and secondary antibody (ab97051, 1:20,000 dilution) for 2 h. The antibody against HOXC8 (ab86236, 1:1000 dilution) was purchased from Abcam (Cambridge, MA, USA), with beta-actin (ab227387, 1:10,000 dilution) as a loading control.	('beta-actin', 'Gene', '728378', (277, 287))	('beta-actin', 'Gene', (277, 287))	('ab86236', 'Var', (199, 206))
210154	32158227	EC9706 and KYSE150 cells transfected with miR-204 or miR-NC were lysed for RIP assay with a Magna RNA immunoprecipitation kit (Millipore) following the manufacturer's protocols.	('miR-NC', 'Var', (53, 59))	('miR-204', 'Var', (42, 49))	('KYSE150', 'CellLine', 'CVCL:1348', (11, 18))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))
210165	32158227	The patients with high SNHG1 level displayed poor overall survival compared with those in low expression group (P=0.027) (Figure 1C).	('high SNHG1 level', 'Var', (18, 34))	('poor', 'NegReg', (45, 49))	('patients', 'Species', '9606', (4, 12))	('overall survival', 'CPA', (50, 66))
210168	32158227	As shown in Figure 2A and B, the abundance of SNHG1 in EC9706 and KYSE150 cells was effectively decreased 60-65% by transfection of si-SNHG1 in comparison to that in the si-NC group and Blank group.	('KYSE150', 'CellLine', 'CVCL:1348', (66, 73))	('decreased', 'NegReg', (96, 105))	('abundance', 'MPA', (33, 42))	('SNHG1', 'Gene', (46, 51))	('EC9706', 'CellLine', 'CVCL:E307', (55, 61))	('si-SNHG1', 'Var', (132, 140))
210170	32158227	Besides, interference of SNHG1 led to great apoptosis production in EC9706 and KYSE150 cells (Figure 2I and J).	('interference', 'Var', (9, 21))	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('SNHG1', 'Gene', (25, 30))	('KYSE150', 'CellLine', 'CVCL:1348', (79, 86))	('apoptosis production', 'MPA', (44, 64))
210172	32158227	Moreover, the addition of miR-204 led to a markedly increased level of SNHG1 enriched by Ago2 RIP in EC9706 and KYSE150 cells (Figure 3D and E).	('KYSE150', 'CellLine', 'CVCL:1348', (112, 119))	('miR-204', 'Var', (26, 33))	('increased', 'PosReg', (52, 61))	('Ago2', 'Gene', (89, 93))	('level', 'MPA', (62, 67))	('SNHG1', 'Gene', (71, 76))	('Ago2', 'Gene', '27161', (89, 93))	('EC9706', 'CellLine', 'CVCL:E307', (101, 107))
210175	32158227	Besides, miR-204 level in EC9706 and KYSE150 cells was evidently decreased by overexpressing SNHG1 and increased via silencing SNHG1 (Figure 3G and H).	('SNHG1', 'Gene', (127, 132))	('increased', 'PosReg', (103, 112))	('silencing', 'Var', (117, 126))	('decreased', 'NegReg', (65, 74))	('SNHG1', 'Gene', (93, 98))	('overexpressing', 'PosReg', (78, 92))	('KYSE150', 'CellLine', 'CVCL:1348', (37, 44))	('miR-204 level', 'MPA', (9, 22))	('EC9706', 'CellLine', 'CVCL:E307', (26, 32))
210176	32158227	In order to explore whether miR-204 was associated with SNHG1-mediated progression of esophageal squamous cell cancer, EC9706 and KYSE150 cells were transfected with si-NC, si-SNHG1, si-SNHG1 and anti-miR-NC or anti-miR-204.	('anti-miR-204', 'Var', (211, 223))	('si-SNHG1', 'Var', (173, 181))	('EC9706', 'CellLine', 'CVCL:E307', (119, 125))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (97, 117))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (86, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('anti-miR-NC', 'Var', (196, 207))	('esophageal squamous cell cancer', 'Disease', (86, 117))	('si-NC', 'Var', (166, 171))	('KYSE150', 'CellLine', 'CVCL:1348', (130, 137))	('si-SNHG1', 'Var', (183, 191))	('associated', 'Reg', (40, 50))
210177	32158227	After the transfection, the abundance of miR-204 in EC9706 and KYSE150 cells increased by SNHG1 knockdown was obviously decreased by the transfection of anti-miR-204 (Figure 4A and B).	('knockdown', 'Var', (96, 105))	('abundance', 'MPA', (28, 37))	('decreased', 'NegReg', (120, 129))	('anti-miR-204', 'Var', (153, 165))	('KYSE150', 'CellLine', 'CVCL:1348', (63, 70))	('EC9706', 'CellLine', 'CVCL:E307', (52, 58))	('SNHG1', 'Gene', (90, 95))	('miR-204', 'Gene', (41, 48))
210178	32158227	In addition, the suppressive effect of SNHG1 knockdown on migration and invasion of EC9706 and KYSE150 cells was weakened via miR-204 deficiency (Figure 4E-H).	('weakened', 'NegReg', (113, 121))	('deficiency', 'Var', (134, 144))	('migration', 'CPA', (58, 67))	('miR-204', 'Gene', (126, 133))	('suppressive', 'NegReg', (17, 28))	('SNHG1', 'Gene', (39, 44))	('EC9706', 'CellLine', 'CVCL:E307', (84, 90))	('KYSE150', 'CellLine', 'CVCL:1348', (95, 102))	('invasion', 'CPA', (72, 80))	('knockdown', 'Var', (45, 54))
210184	32158227	In addition, the abundance of HOXC8 protein in EC9706 and KYSE150 cells was conspicuously reduced via miR-204 addition and elevated by miR-204 exhaustion (Figure 5G and H).	('EC9706', 'CellLine', 'CVCL:E307', (47, 53))	('miR-204', 'Var', (135, 142))	('reduced', 'NegReg', (90, 97))	('KYSE150', 'CellLine', 'CVCL:1348', (58, 65))	('miR-204', 'Var', (102, 109))	('abundance of HOXC8 protein', 'MPA', (17, 43))	('elevated', 'PosReg', (123, 131))	('EC9706', 'Var', (47, 53))
210187	32158227	To explore whether SNHG1-regulated progression of esophageal squamous cell cancer was mediated by HOXC8, EC9706 and KYSE150 cells were transfected with si-NC, si-SNHG1, si-SNHG1 and pcDNA or HOXC8.	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (50, 81))	('si-SNHG1', 'Var', (169, 177))	('KYSE150', 'CellLine', 'CVCL:1348', (116, 123))	('esophageal squamous cell cancer', 'Disease', (50, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('si-NC', 'Var', (152, 157))	('si-SNHG1', 'Var', (159, 167))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (61, 81))	('EC9706', 'CellLine', 'CVCL:E307', (105, 111))
210188	32158227	As shown in Figure 6A and B, the protein level of HOXC8 in EC9706 and KYSE150 cells was significantly decreased by silencing SNHG1, which was restored by the introduction of HOXC8 overexpression vector.	('KYSE150', 'CellLine', 'CVCL:1348', (70, 77))	('silencing', 'Var', (115, 124))	('SNHG1', 'Gene', (125, 130))	('EC9706', 'CellLine', 'CVCL:E307', (59, 65))	('protein level of', 'MPA', (33, 49))	('decreased', 'NegReg', (102, 111))
210190	32158227	Meanwhile, the inhibition of migration and invasion mediated by SNHG1 knockdown was abated by the restoration of HOXC8 in EC9706 and KYSE150 cells (Figure 6E-H).	('SNHG1', 'Gene', (64, 69))	('inhibition', 'NegReg', (15, 25))	('EC9706', 'CellLine', 'CVCL:E307', (122, 128))	('knockdown', 'Var', (70, 79))	('abated', 'NegReg', (84, 90))	('HOXC8', 'MPA', (113, 118))	('KYSE150', 'CellLine', 'CVCL:1348', (133, 140))
210191	32158227	Additionally, the introduction of HOXC8 significantly relieved the apoptosis of EC9706 and KYSE150 cells induced by silencing SNHG1 (Figure 6I and J).	('apoptosis', 'CPA', (67, 76))	('relieved', 'NegReg', (54, 62))	('EC9706', 'CellLine', 'CVCL:E307', (80, 86))	('KYSE150', 'CellLine', 'CVCL:1348', (91, 98))	('silencing', 'Var', (116, 125))	('SNHG1', 'Gene', (126, 131))
210192	32158227	Besides, knockdown of HOXC8 also weakened the promoting role of SNHG1 in esophageal squamous cell cancer development in vitro (Supplementary Figure 2).	('SNHG1', 'Gene', (64, 69))	('promoting', 'MPA', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('knockdown', 'Var', (9, 18))	('weakened', 'NegReg', (33, 41))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (84, 104))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (73, 104))	('esophageal squamous cell cancer', 'Disease', (73, 104))
210203	32158227	Former findings suggested that SNHG1 could serve as a ceRNA to be implicated in the development of human cancers.	('SNHG1', 'Var', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (99, 104))
210208	32158227	In our study, we also found the tumor suppressive role of miR-204, revealed by which its knockdown abated silencing SNHG1-mediated inhibition of esophageal squamous cell cancer progression.	('SNHG1-mediated', 'Gene', (116, 130))	('miR-204', 'Gene', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (156, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('silencing', 'Var', (106, 115))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (145, 176))	('abated', 'NegReg', (99, 105))	('tumor', 'Disease', (32, 37))	('esophageal squamous cell cancer', 'Disease', (145, 176))	('inhibition', 'NegReg', (131, 141))
210210	32158227	HOXC8 has been regarded as an oncogene and predicts poor prognosis in multiple cancers, including hepatocellular carcinoma, ovarian cancer, non-small cell lung cancer and cervical cancer.	('multiple cancers', 'Disease', (70, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('ovarian cancer', 'Disease', (124, 138))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (140, 166))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cervical cancer', 'Disease', 'MESH:D002583', (171, 186))	('HOXC8', 'Var', (0, 5))	('cervical cancer', 'Disease', (171, 186))	('multiple cancers', 'Disease', 'MESH:D009369', (70, 86))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (98, 122))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('non-small cell lung cancer', 'Disease', (140, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('ovarian cancer', 'Disease', 'MESH:D010051', (124, 138))	('hepatocellular carcinoma', 'Disease', (98, 122))
210212	32158227	Here we first using luciferase reporter assay and RIP confirmed HOXC8 as a target of miR-204 and found that restoration or knockdown of HOXC8 abolished the effect of SNHG1 silence or overexpression on cancer progression, indicating that SNHG1 regulated esophageal squamous cell cancer development by increasing HOXC8 via competitively sponging miR-204.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (264, 284))	('esophageal squamous cell cancer', 'Disease', (253, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Disease', (201, 207))	('regulated', 'Reg', (243, 252))	('HOXC8', 'MPA', (311, 316))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('increasing', 'PosReg', (300, 310))	('cancer', 'Disease', (278, 284))	('SNHG1', 'Var', (237, 242))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (253, 284))
210214	32158227	Hence, we also established the murine xenograft model using esophageal squamous cell cancer cells and found the anti-cancer role of SNHG1 knockdown in this cancer in vivo by regulating miR-204/HOXC8 axis.	('knockdown', 'Var', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('miR-204/HOXC8 axis', 'Pathway', (185, 203))	('esophageal squamous cell cancer', 'Disease', (60, 91))	('regulating', 'Reg', (174, 184))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('SNHG1', 'Gene', (132, 137))	('cancer', 'Disease', (85, 91))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (71, 91))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('murine', 'Species', '10090', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (60, 91))
210301	31969911	However, the median patients' age was higher (73 years), and patients were previously treated against dysphagia with various methods: esophageal dilatation (37%), surgery (14%), EBRT + BT (14%), EBRT (6%) or laser (6%).	('dysphagia', 'Phenotype', 'HP:0002015', (102, 111))	('dysphagia', 'Disease', 'MESH:D003680', (102, 111))	('esophageal dilatation', 'Disease', (134, 155))	('patients', 'Species', '9606', (61, 69))	('EBRT + BT', 'Var', (178, 187))	('dilatation', 'Phenotype', 'HP:0002617', (145, 155))	('dysphagia', 'Disease', (102, 111))	('patients', 'Species', '9606', (20, 28))
210349	30885149	A significantly poorer prognosis was observed in 28 patients with MET FISH-positivity (disease free survival/DFS, P < 0.001 and overall survival/OS, P = 0.001).	('MET FISH-positivity', 'Var', (66, 85))	('OS', 'Chemical', '-', (145, 147))	('patients', 'Species', '9606', (52, 60))	('disease free survival/DFS', 'CPA', (87, 112))
210363	30885149	Aberrant MET activation has been reported in various types of cancer, and promotes tumor cell proliferation, motility, invasion and metastasis.	('promotes', 'PosReg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('metastasis', 'CPA', (132, 142))	('tumor', 'Disease', (83, 88))	('activation', 'PosReg', (13, 23))	('MET', 'Protein', (9, 12))	('motility', 'CPA', (109, 117))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
210365	30885149	Recent studies found different tumors with MET amplification were extraordinarily susceptible to the selective MET tyrosine kinase inhibitor (TKI), and MET amplification was responsible for approximately 20% of the acquired resistance to epidermal growth factor receptor (EGFR) TKI treatment in lung adenocarcinomas.	('epidermal growth factor receptor', 'Gene', '1956', (238, 270))	('EGFR', 'Gene', '1956', (272, 276))	('MET amplification', 'Var', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('EGFR', 'Gene', (272, 276))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('responsible', 'Reg', (174, 185))	('MET', 'Var', (152, 155))	('amplification', 'Var', (47, 60))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('lung adenocarcinomas', 'Disease', (295, 315))	('epidermal growth factor receptor', 'Gene', (238, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('men', 'Species', '9606', (287, 290))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (295, 315))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (295, 315))
210368	30885149	And MET amplification is thought to be associated with metastasis and poorer outcome in gastric, lung and colorectal cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colorectal cancers', 'Disease', (106, 124))	('MET amplification', 'Var', (4, 21))	('lung', 'Disease', (97, 101))	('associated', 'Reg', (39, 49))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('colorectal cancers', 'Disease', 'MESH:D015179', (106, 124))	('gastric', 'Disease', (88, 95))
210395	30885149	MET FISH-positivity was significantly associated with DFS (2.2% in patients without disease progression vs. 8.6% in patients with disease progression, P = 0.002) and OS (2.6% vs. 8.4%, P = 0.005).	('DFS', 'Disease', (54, 57))	('associated', 'Reg', (38, 48))	('patients', 'Species', '9606', (67, 75))	('patients', 'Species', '9606', (116, 124))	('MET FISH-positivity', 'Var', (0, 19))	('OS', 'Chemical', '-', (166, 168))
210400	30885149	The 5-year DFS (17.9%) and OS (17.8%) rates for patients with MET FISH-positivity were significantly lower than the corresponding rates (45.7 and 46.0%) for patients with MET FISH-negativity.	('MET', 'Var', (62, 65))	('OS', 'Chemical', '-', (27, 29))	('DFS', 'MPA', (11, 14))	('patients', 'Species', '9606', (157, 165))	('lower', 'NegReg', (101, 106))	('patients', 'Species', '9606', (48, 56))
210410	30885149	MET FISH-positivity was also associated with DFS (P = 0.020) and OS (P = 0.024) in patients with stage III-IVa ESCC (n = 223) (Fig.	('OS', 'Chemical', '-', (65, 67))	('MET FISH-positivity', 'Var', (0, 19))	('DFS', 'Disease', (45, 48))	('associated', 'Reg', (29, 39))	('patients', 'Species', '9606', (83, 91))
210417	30885149	found the survival outcome of patients with a mean MET gene copy number per cell higher than 5 and higher than 6 was similar, and worse than the other four groups with a mean copy number lower than 5 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('NSCLC', 'Disease', (203, 208))	('MET gene copy number', 'Var', (51, 71))	('patients', 'Species', '9606', (30, 38))
210419	30885149	Since Lennerz etal has demonstrated that 2% of patients (10/489) with esophagogastric adenocarcinoma, who harbored MET amplification and were treated with a MET inhibitor, experienced tumor shrinkage in 2011, MET gene status has gained considerable interest in solid tumors.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('esophagogastric adenocarcinoma', 'Disease', (70, 100))	('solid tumors', 'Disease', (261, 273))	('esophagogastric adenocarcinoma', 'Disease', 'MESH:C537006', (70, 100))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('MET amplification', 'Var', (115, 132))	('tumor', 'Disease', (267, 272))	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (70, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('solid tumors', 'Disease', 'MESH:D009369', (261, 273))
210422	30885149	Moreover, MET FISH-positivity was an independent prognostic factor for both DFS and OS, further indicating increased MET gene copy number is a negative prognostic factor in ESCC.	('negative', 'NegReg', (143, 151))	('ESCC', 'Disease', (173, 177))	('OS', 'Chemical', '-', (84, 86))	('DFS', 'Disease', (76, 79))	('MET gene copy number', 'Var', (117, 137))
210423	30885149	reported in gastric cancer, MET amplification did not have an impact on prognosis in early TNM stage (stage I or II), unlike in advanced TNM stage (stage III or IV).	('early TNM stage', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('gastric cancer', 'Disease', (12, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (12, 26))	('MET amplification', 'Var', (28, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (12, 26))
210503	28469341	Biopsy of representative lesion showed diffuse infiltration of tumor cells in cords and singles, with pleomorphic round to oval nucleus, high N:C ratio and vesicular chromatin in the dermis, along with signet ring-like cells and lymphoplasmacytic infiltrate around blood vessels suggestive of metastatic poorly differentiated adenocarcinoma [Figure 2].	('adenocarcinoma', 'Disease', (326, 340))	('tumor', 'Disease', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('high', 'Var', (137, 141))	('adenocarcinoma', 'Disease', 'MESH:D000230', (326, 340))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
210546	28003023	Hayashi found patients with high BMI showed better overall survival (OS) and disease-free survival (DFS) because of the early clinical diagnosis.	('overall survival', 'CPA', (51, 67))	('better', 'PosReg', (44, 50))	('disease-free survival', 'CPA', (77, 98))	('OS', 'Chemical', '-', (69, 71))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))
210547	28003023	In contrast to this, Yoon pointed out that high BMI was independently associated with two-fold worsening of DFS, and OS after surgery for EAC.	('OS', 'Chemical', '-', (117, 119))	('high BMI', 'Var', (43, 51))	('DFS', 'Disease', (108, 111))	('EAC', 'Phenotype', 'HP:0011459', (138, 141))	('AC', 'Chemical', 'MESH:D000186', (139, 141))
210553	28003023	REE is the sum of the metabolic activities of internal body and can reflect patient's physiques and muscle volumes, and REE per kg total body weight (REE/kg) may reflect the diffusion and metabolic rate of muscle more accurately.	('reflect', 'Reg', (162, 169))	('REE', 'Var', (120, 123))	('diffusion', 'MPA', (174, 183))	('patient', 'Species', '9606', (76, 83))
210587	28003023	There were close relations between REE/kg and weight lost or BMI, patients with high REE/kg have been found to lose more weight (p = 0.006) and have lower BMI (p < 0.001).	('weight lost', 'Phenotype', 'HP:0001824', (46, 57))	('lose', 'NegReg', (111, 115))	('BMI', 'MPA', (155, 158))	('lower BMI', 'Phenotype', 'HP:0045082', (149, 158))	('REE/kg', 'Gene', (85, 91))	('weight', 'MPA', (121, 127))	('lower', 'NegReg', (149, 154))	('high', 'Var', (80, 84))	('patients', 'Species', '9606', (66, 74))
210592	28003023	The spearman correlation analysis found higher serum albumin levels were observed in high BMI, REE and FBG but in low REE/kg groups.	('higher', 'PosReg', (40, 46))	('higher serum albumin levels', 'Phenotype', 'HP:0012117', (40, 67))	('albumin', 'Gene', '213', (53, 60))	('high BMI', 'Var', (85, 93))	('albumin', 'Gene', (53, 60))
210595	28003023	Patients with low BMI, REE, FBG and high REE/kg had significant worse survival.	('FBG', 'Var', (28, 31))	('low BMI', 'Var', (14, 21))	('Patients', 'Species', '9606', (0, 8))	('low BMI', 'Phenotype', 'HP:0045082', (14, 21))	('high REE/kg', 'Var', (36, 47))
210609	28003023	Patients with serum albumin levels <35 g/l had the 5-year survival rate of 26.7 %, compared to 57.8 % in patients with serum albumin > 40 g/l.	('patients', 'Species', '9606', (105, 113))	('albumin', 'Gene', (20, 27))	('albumin', 'Gene', '213', (20, 27))	('Patients', 'Species', '9606', (0, 8))	('<35 g/l', 'Var', (35, 42))	('albumin', 'Gene', (125, 132))	('albumin', 'Gene', '213', (125, 132))
210617	28003023	A few studies focused on the influence of BMI on postoperative outcomes in patients with EC and had shown contradictory results, varying from no differences in postoperative complications and mortality to a higher incidence of individual complications (such as respiratory complications and anastomotic leak) in high BMI patients.	('respiratory complications', 'Disease', (261, 286))	('patients', 'Species', '9606', (321, 329))	('anastomotic leak', 'Disease', 'MESH:D057868', (291, 307))	('respiratory complications', 'Phenotype', 'HP:0011947', (261, 286))	('patients', 'Species', '9606', (75, 83))	('high BMI', 'Var', (312, 320))	('anastomotic leak', 'Disease', (291, 307))	('respiratory complications', 'Disease', 'MESH:D012131', (261, 286))
210632	28003023	To assess the impact of FBG on prognosis in patients with esophageal cancer, both the univariate and multivariate analysis proved that low FBG level (<=90 mg/dL) was independently associated with poor OS.	('low', 'Var', (135, 138))	('patients', 'Species', '9606', (44, 52))	('esophageal cancer', 'Disease', (58, 75))	('poor OS', 'Disease', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('associated', 'Reg', (180, 190))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('OS', 'Chemical', '-', (201, 203))	('FBG', 'Gene', (139, 142))
210642	28003023	So patients with high REE/kg have been found to lose more weight, have lower BMI and have a worse survival, this finding is consistent with the hypothesis.	('lose', 'NegReg', (48, 52))	('high REE/kg', 'Var', (17, 28))	('BMI', 'MPA', (77, 80))	('weight', 'MPA', (58, 64))	('patients', 'Species', '9606', (3, 11))	('lower BMI', 'Phenotype', 'HP:0045082', (71, 80))	('lower', 'NegReg', (71, 76))
210650	28003023	FBG level <=90 mg/dL was independently associated with poor survival for all patients.	('poor', 'NegReg', (55, 59))	('patients', 'Species', '9606', (77, 85))	('<=90 mg/dL', 'Var', (10, 20))
210833	21863136	The authors reported a trend toward higher distal esophageal pressure in the older group for acid exposure <5% and 5-10%; however, this was not found in patients with the highest acid exposure.	('distal esophageal pressure', 'MPA', (43, 69))	('higher', 'PosReg', (36, 42))	('<5%', 'Var', (107, 110))	('patients', 'Species', '9606', (153, 161))
210921	32720208	Other cases with 2-9 eos/hpf were considered non-allergic, and such cases may be diagnosed as GERD or non-specific esophagitis.	('esophagitis', 'Disease', 'MESH:D004938', (115, 126))	('eos/hpf', 'Var', (21, 28))	('allergic', 'Disease', 'MESH:D004342', (49, 57))	('esophagitis', 'Phenotype', 'HP:0100633', (115, 126))	('esophagitis', 'Disease', (115, 126))	('GERD', 'Disease', (94, 98))	('allergic', 'Disease', (49, 57))
210965	32302443	High PET tracer uptake was significantly associated with cancer aggressiveness and hot tumor immune status in ESCC.	('cancer aggressiveness', 'Disease', (57, 78))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('associated', 'Reg', (41, 51))	('High', 'Var', (0, 4))	('tumor', 'Disease', (87, 92))	('aggressiveness', 'Phenotype', 'HP:0000718', (64, 78))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (57, 78))	('ESCC', 'Disease', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
210967	32302443	High positron emission tomography (PET) tracer uptake is significantly correlated with hot tumor immune status (high PD-L1 expression and infiltrative CD8-positive T lymphocytes) in ESCC.	('PD-L1', 'Gene', '29126', (117, 122))	('CD8', 'Gene', (151, 154))	('high', 'Var', (112, 116))	('correlated', 'Reg', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CD8', 'Gene', '925', (151, 154))	('positive T lymphocytes', 'Phenotype', 'HP:0100828', (155, 177))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ESCC', 'Disease', (182, 186))	('PD-L1', 'Gene', (117, 122))	('tumor', 'Disease', (91, 96))
210982	32302443	17 ,  18 ,  19  Tumor immune status with high PD-L1 expression/high numbers of infiltrating immune cells represents an ICI-sensitive "hot tumor," whereas tumor immune status with low PD-L1 expression/poor infiltration of immune cells is considered a "cold tumor" and is associated with poor local immune response and ICI resistance.	('PD-L1', 'Gene', (46, 51))	('PD-L1', 'Gene', (183, 188))	('cold tumor', 'Disease', 'MESH:D000067390', (251, 261))	('poor infiltration of immune cells', 'Phenotype', 'HP:0002721', (200, 233))	('tumor', 'Disease', (138, 143))	('cold tumor', 'Disease', (251, 261))	('PD-L1', 'Gene', '29126', (46, 51))	('PD-L1', 'Gene', '29126', (183, 188))	('high', 'Var', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', (154, 159))
210989	32302443	Another study showed that L-[3-18F]-alpha-methyltyrosine (18F-FAMT) PET, which is based on amino acid metabolism and is associated with the L-type amino acid transporter 1 (LAT1), is useful in the detection of various neoplasms.	('L-type amino acid transporter 1', 'Gene', '8140', (140, 171))	('neoplasms', 'Phenotype', 'HP:0002664', (218, 227))	('LAT1', 'Gene', '8140', (173, 177))	('L-[3-18F', 'Var', (26, 34))	('LAT1', 'Gene', (173, 177))	('L-[3-18F]-alpha-methyltyrosine', 'Chemical', '-', (26, 56))	('neoplasms', 'Disease', 'MESH:D009369', (218, 227))	('L-type amino acid transporter 1', 'Gene', (140, 171))	('neoplasms', 'Disease', (218, 227))	('18F-FAMT', 'Chemical', '-', (58, 66))
211045	32302443	High PD-L1 expression was significantly associated with tumor invasion (P = 0.028), lymphatic invasion (P = 0.032), venous invasion (P = 0.018), stage (P = 0.041), CD8 expression (P < 0.001), GLUT1 expression (P < 0.001), LAT1 expression (P = 0.006), Ki-67 labelling index (P = 0.009) and CD34-positive vessel count (P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('expression', 'MPA', (11, 21))	('GLUT1', 'Gene', '6513', (192, 197))	('LAT1', 'Gene', (222, 226))	('LAT1', 'Gene', '8140', (222, 226))	('associated', 'Reg', (40, 50))	('expression', 'MPA', (168, 178))	('High', 'Var', (0, 4))	('Ki-67 labelling index', 'CPA', (251, 272))	('CD8', 'Gene', '925', (164, 167))	('stage', 'CPA', (145, 150))	('Ki-67', 'Chemical', '-', (251, 256))	('expression', 'MPA', (198, 208))	('CD34', 'Gene', '947', (289, 293))	('PD-L1', 'Gene', (5, 10))	('GLUT1', 'Gene', (192, 197))	('tumor', 'Disease', (56, 61))	('PD-L1', 'Gene', '29126', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CD8', 'Gene', (164, 167))	('lymphatic invasion', 'CPA', (84, 102))	('venous invasion', 'CPA', (116, 131))	('CD34', 'Gene', (289, 293))
211047	32302443	Hot tumor immune status (with high PD-L1 and high CD8) was significantly associated with high GLUT1 expression (P = 0.024) and a high Ki-67 labelling index (P = 0.014).	('tumor', 'Disease', (4, 9))	('CD8', 'Gene', (50, 53))	('Ki-67', 'Chemical', '-', (134, 139))	('PD-L1', 'Gene', '29126', (35, 40))	('CD8', 'Gene', '925', (50, 53))	('expression', 'MPA', (100, 110))	('high', 'Var', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('GLUT1', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('PD-L1', 'Gene', (35, 40))	('GLUT1', 'Gene', '6513', (94, 99))
211049	32302443	ESCC patient groups with high PD-L1, high CD8 or hot tumor immune status were not associated with poor prognosis compared to the other groups.	('patient', 'Species', '9606', (5, 12))	('high', 'Var', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('CD8', 'Gene', (42, 45))	('PD-L1', 'Gene', (30, 35))	('high', 'Var', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('CD8', 'Gene', '925', (42, 45))	('PD-L1', 'Gene', '29126', (30, 35))
211078	32302443	In our study, we showed that high uptake of 18F-FDG and 18F-FAMT by non-invasive PET imaging was significantly associated with a hot tumor phenotype, which has been associated with good response to ICI treatment in several cancers.	('cancers', 'Disease', (223, 230))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('18F-FDG', 'Var', (44, 51))	('tumor', 'Disease', (133, 138))	('associated with', 'Reg', (111, 126))	('18F-FAMT', 'Var', (56, 64))	('18F-FDG', 'Chemical', 'MESH:D019788', (44, 51))	('18F-FAMT', 'Chemical', '-', (56, 64))
211082	32302443	22  GLUT1 and LAT1 are widely expressed in various human cancers, 41 ,  42 ,  43 ,  44 ,  45 ,  46  and PET tracers such as 18F-FDG and 18F-FAMT are imported to tumor cells via GLUT1 and LAT1, respectively.	('GLUT1', 'Gene', (4, 9))	('GLUT1', 'Gene', '6513', (177, 182))	('human', 'Species', '9606', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('LAT1', 'Gene', '8140', (14, 18))	('tumor', 'Disease', (161, 166))	('LAT1', 'Gene', (14, 18))	('LAT1', 'Gene', '8140', (187, 191))	('LAT1', 'Gene', (187, 191))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancers', 'Disease', (57, 64))	('18F-FAMT', 'Var', (136, 144))	('GLUT1', 'Gene', (177, 182))	('GLUT1', 'Gene', '6513', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('18F-FAMT', 'Chemical', '-', (136, 144))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('18F-FDG', 'Chemical', 'MESH:D019788', (124, 131))
211091	32302443	56 ,  57 ,  58  Our study suggested that high PD-L1 ESCC patients had upregulated proliferation capacity and angiogenesis through RTK or HIF1alpha activation.	('PD-L1', 'Gene', (46, 51))	('HIF1alpha', 'Gene', (137, 146))	('RTK', 'Gene', '5979', (130, 133))	('HIF1alpha', 'Gene', '3091', (137, 146))	('proliferation capacity', 'CPA', (82, 104))	('patients', 'Species', '9606', (57, 65))	('angiogenesis', 'CPA', (109, 121))	('PD-L1', 'Gene', '29126', (46, 51))	('high', 'Var', (41, 45))	('ESCC', 'Disease', (52, 56))	('upregulated', 'PosReg', (70, 81))	('RTK', 'Gene', (130, 133))
211107	29259372	Low expression of miR-30a-3p/5p was closely associated with advanced ESCC progression and poor prognosis of patients with ESCC.	('associated', 'Reg', (44, 54))	('miR-30a-3p/5p', 'Var', (18, 31))	('expression', 'MPA', (4, 14))	('ESCC', 'Disease', (69, 73))	('patients', 'Species', '9606', (108, 116))	('Low', 'NegReg', (0, 3))
211110	29259372	Core tip: In this work, we found that low expression of miR-30a-3p/5p was closely associated with advanced esophageal squamous cell carcinoma (ESCC) progression and poor prognosis of patients with ESCC.	('associated with', 'Reg', (82, 97))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('miR-30a-3p/5p', 'Var', (56, 69))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))	('low', 'NegReg', (38, 41))	('patients', 'Species', '9606', (183, 191))
211111	29259372	Furthermore, miR-30a-3p and miR-30a-5p could inhibit the activity of the Wnt signaling pathway by targeting the 3' untranslated regions of Wnt2 and Fzd2, respectively.	('Wnt2', 'Gene', (139, 143))	('miR-30a-3p', 'Var', (13, 23))	('targeting', 'Reg', (98, 107))	('Wnt signaling pathway', 'Pathway', (73, 94))	('miR-30a-5p', 'Var', (28, 38))	('Fzd2', 'Gene', (148, 152))	('Fzd2', 'Gene', '2535', (148, 152))	('activity', 'MPA', (57, 65))	('Wnt2', 'Gene', '7472', (139, 143))	('inhibit', 'NegReg', (45, 52))
211116	29259372	Highly conserved across species, microRNAs not only participate in biological processes, but also in the pathogenesis of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('microRNAs', 'Var', (33, 42))	('human', 'Species', '9606', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('biological processes', 'CPA', (67, 87))	('participate', 'Reg', (52, 63))
211122	29259372	Emerging evidence has indicated that the two strands of miR-30a (miR-30a-3p and miR-30a-5p) are involved in various kinds of cancer.	('cancer', 'Disease', (125, 131))	('involved', 'Reg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('miR-30a', 'Gene', (56, 63))	('miR-30a-5p', 'Var', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
211147	29259372	Statistical analyses further revealed no difference in the miR-30a-3p/5p expression between different differentiation statuses of ESCC (Figure 2A), but miR-30a-3p/5p expression was inversely correlated with classifications of primary tumor and lymphatic metastasis (Figures 2B and C).	('tumor', 'Disease', (234, 239))	('lymphatic metastasis', 'CPA', (244, 264))	('correlated', 'Reg', (191, 201))	('inversely', 'NegReg', (181, 190))	('miR-30a-3p/5p', 'Var', (152, 165))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
211148	29259372	Most importantly, survival analysis indicated that the group of lower miR-30a-3p/5p expression had shorter 5-year overall survival, and was associated with poorer prognosis of patients with ESCC (Figure 2D, log-rank, P < 0.05).	('ESCC', 'Disease', (190, 194))	('shorter', 'NegReg', (99, 106))	('patients', 'Species', '9606', (176, 184))	('lower', 'NegReg', (64, 69))	('miR-30a-3p/5p expression', 'Var', (70, 94))
211149	29259372	As shown in Figure 3A, expression of miR-30a-3p/5p was significantly lower in ESCC cell lines KYSE30 and KYSE150 than in normal esophageal epithelial cell line Het-1A.	('ESCC', 'Disease', (78, 82))	('lower', 'NegReg', (69, 74))	('Het-1A', 'CellLine', 'CVCL:3702', (160, 166))	('KYSE150', 'Var', (105, 112))	('miR-30a-3p/5p', 'Var', (37, 50))	('KYSE30', 'Var', (94, 100))	('KYSE150', 'CellLine', 'CVCL:1348', (105, 112))	('expression', 'MPA', (23, 33))
211151	29259372	MTT and colony formation assays indicated that over-expression of miR-30a-3p/5p significantly repressed the proliferation of HYSE30 cells in comparison with the control group.	('over-expression', 'PosReg', (47, 62))	('repressed', 'NegReg', (94, 103))	('miR-30a-3p/5p', 'Var', (66, 79))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('proliferation', 'CPA', (108, 121))
211152	29259372	It should be noted that the anchorage-independent growth ability of KYSE30 cells was also attenuated by over-expression of miR-30a-3p/5p in the soft-agar assays.	('miR-30a-3p/5p', 'Var', (123, 136))	('anchorage-independent growth ability', 'CPA', (28, 64))	('over-expression', 'PosReg', (104, 119))	('attenuated', 'NegReg', (90, 100))	('agar', 'Chemical', 'MESH:D000362', (149, 153))
211154	29259372	Results showed that the miR-30a-3p/5p over-expression group exhibited remarkably smaller tumor volume and slower tumor growth rate in comparison with the control group (Figures 3F, G, and H).	('smaller', 'NegReg', (81, 88))	('tumor', 'Disease', (113, 118))	('miR-30a-3p/5p', 'Var', (24, 37))	('slower', 'NegReg', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('over-expression', 'PosReg', (38, 53))
211156	29259372	As indicated by the MTT and colony formation assays (Figure 4A bottom and B), inhibition of miR-30a-3p/5p significantly increased the proliferation of KYSE150 cells in comparison with the control groups.	('KYSE150', 'CellLine', 'CVCL:1348', (151, 158))	('miR-30a-3p/5p', 'Gene', (92, 105))	('increased', 'PosReg', (120, 129))	('MTT', 'Chemical', 'MESH:C070243', (20, 23))	('inhibition', 'Var', (78, 88))	('proliferation', 'CPA', (134, 147))
211158	29259372	Tumorigenesis assays performed in the nude mice showed that inhibition of miR-30a-3p/5p increased the tumor volume and tumor growth rate in comparison with the control group (Figure 4D, E, and F).	('tumor', 'Disease', (119, 124))	('inhibition', 'Var', (60, 70))	('miR-30a-3p/5p', 'Gene', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('increased', 'PosReg', (88, 97))	('nude mice', 'Species', '10090', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
211159	29259372	Both in vitro and in vivo experiments indicated that miR-30a-3p/5p served as tumor suppressors in ESCC.	('ESCC', 'Disease', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('miR-30a-3p/5p', 'Var', (53, 66))
211162	29259372	In contrast, inhibition of miR-30a increased the expression of Cyclin D1 and decreased the expression of p27 and p21, both at protein and mRNA levels, as indicated by the results of Western blot and qPCR analyses, respectively (Figures 5C, D, E, and F).	('expression', 'MPA', (91, 101))	('increased', 'PosReg', (35, 44))	('inhibition', 'Var', (13, 23))	('decreased', 'NegReg', (77, 86))	('miR-30a', 'Gene', (27, 34))	('expression', 'MPA', (49, 59))	('Cyclin D1', 'Gene', '595', (63, 72))	('p27', 'Gene', '3429', (105, 108))	('p21', 'Gene', (113, 116))	('Cyclin D1', 'Gene', (63, 72))	('p21', 'Gene', '644914', (113, 116))	('p27', 'Gene', (105, 108))
211163	29259372	Results showed that mRNA expression of Wnt2 was repressed by transfecting miR-30a-3p-mimics, and Fzd2 was inhibited by miR-30a-5p-mimics (Figure 6A).	('miR-30a-5p-mimics', 'Var', (119, 136))	('Wnt2', 'Gene', (39, 43))	('inhibited', 'NegReg', (106, 115))	('miR-30a-3p-mimics', 'Var', (74, 91))	('Fzd2', 'Gene', '2535', (97, 101))	('mRNA expression', 'MPA', (20, 35))	('Fzd2', 'Gene', (97, 101))	('transfecting', 'Var', (61, 73))	('Wnt2', 'Gene', '7472', (39, 43))
211166	29259372	As shown in Figure 6C, over-expression of miR-30a-3p decreased the expression of Wnt2, while inhibition of miR-30a-3p increased it, at both protein and mRNA levels.	('miR-30a-3p', 'Var', (42, 52))	('miR-30a-3p', 'Var', (107, 117))	('increased', 'PosReg', (118, 127))	('Wnt2', 'Gene', (81, 85))	('expression', 'MPA', (67, 77))	('decreased', 'NegReg', (53, 62))	('over-expression', 'PosReg', (23, 38))	('Wnt2', 'Gene', '7472', (81, 85))
211167	29259372	The miR-30a-5p showed the same effects on Fzd2 expression.	('Fzd2', 'Gene', '2535', (42, 46))	('miR-30a-5p', 'Var', (4, 14))	('expression', 'MPA', (47, 57))	('Fzd2', 'Gene', (42, 46))
211168	29259372	Luciferase reporter assays also demonstrated that over-expression of miR-30a-3p significantly reduced luciferase activity of the wild-type Wnt2-3'-UTR in a dose-dependent pattern, while it had no effects on the mutant type.	('Wnt2', 'Gene', (139, 143))	('reduced', 'NegReg', (94, 101))	('luciferase', 'Enzyme', (102, 112))	('miR-30a-3p', 'Var', (69, 79))	('activity', 'MPA', (113, 121))	('Wnt2', 'Gene', '7472', (139, 143))	('over-expression', 'PosReg', (50, 65))
211169	29259372	Likewise, miR-30a-5p had the same effects on the wild-type FZD2-3'-UTR and the mutant one (Figure 6D).	('mutant', 'Var', (79, 85))	('FZD2', 'Gene', '2535', (59, 63))	('FZD2', 'Gene', (59, 63))	('miR-30a-5p', 'Var', (10, 20))
211170	29259372	Emerging evidence has shown that the dysregulation of microRNAs plays an important role in multiple tumor-related processes, such as cell differentiation, proliferation, apoptosis, autophagy, angiogenesis, invasion, and metastasis.	('autophagy', 'CPA', (181, 190))	('microRNAs', 'Protein', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('dysregulation', 'Var', (37, 50))	('role', 'Reg', (83, 87))	('tumor', 'Disease', (100, 105))	('proliferation', 'CPA', (155, 168))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('invasion', 'CPA', (206, 214))	('angiogenesis', 'CPA', (192, 204))	('cell differentiation', 'CPA', (133, 153))	('apoptosis', 'CPA', (170, 179))	('metastasis', 'CPA', (220, 230))
211171	29259372	It was interesting that aberrant expression of miR-30a-3p/5p was found in many kinds of cancer and showed opposite tendencies.	('miR-30a-3p/5p', 'Var', (47, 60))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('found', 'Reg', (65, 70))
211178	29259372	Apart from the expression pattern, it has been observed that miR-30a-3p/5p exhibited multiple roles in the regulation of tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('miR-30a-3p/5p', 'Var', (61, 74))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
211182	29259372	In contrast, miR-30a-5p has been identified as an oncogenic factor in glioma, and knock-down of miR-30a-5p inhibited glioma cell growth and cell invasion, while over-expression of miR-30a-5p had had opposite effects.	('cell invasion', 'CPA', (140, 153))	('glioma', 'Disease', (117, 123))	('glioma', 'Disease', (70, 76))	('knock-down', 'Var', (82, 92))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('miR-30a-5p', 'Var', (96, 106))	('inhibited', 'NegReg', (107, 116))
211183	29259372	Our functional approach showed that miR-30a-3p/5p function as tumor suppressors in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('ESCC', 'Disease', (83, 87))	('miR-30a-3p/5p', 'Var', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
211185	29259372	Colorectal tumorigenesis is initiated by mutations in the Wnt signaling pathway (e.g., APC or beta-catenin) that constitutively activate the pathway, and also by binding a Wnt-protein ligand to a Frizzled family receptor, passing the biological signal to the dishevelled protein inside the cell, and leading to the regulation of gene transcription.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('gene transcription', 'MPA', (329, 347))	('tumor', 'Disease', (11, 16))	('beta-catenin', 'Gene', (94, 106))	('initiated by', 'Reg', (28, 40))	('activate', 'PosReg', (128, 136))	('APC', 'Disease', 'MESH:D011125', (87, 90))	('beta-catenin', 'Gene', '1499', (94, 106))	('binding', 'Interaction', (162, 169))	('regulation', 'MPA', (315, 325))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('APC', 'Disease', (87, 90))	('passing', 'PosReg', (222, 229))	('biological signal', 'MPA', (234, 251))	('leading to', 'Reg', (300, 310))
211188	29259372	In addition, miR-30a-5p has been found to directly suppress PRDM1, resulting in activation of Wnt/beta-catenin (carotene) signaling in glioma.	('suppress', 'NegReg', (51, 59))	('glioma', 'Disease', (135, 141))	('carotene', 'Chemical', 'MESH:D002338', (112, 120))	('miR-30a-5p', 'Var', (13, 23))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('PRDM1', 'Gene', '639', (60, 65))	('activation', 'PosReg', (80, 90))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('beta-catenin', 'Gene', (98, 110))	('beta-catenin', 'Gene', '1499', (98, 110))	('PRDM1', 'Gene', (60, 65))
211189	29259372	We demonstrated that miR-30a-3p and miR-30a-5p directly target the 3'-UTRs of Wnt2 and Fzd2 and inhibit their expression, respectively.	('miR-30a-5p', 'Var', (36, 46))	('Wnt2', 'Gene', (78, 82))	('miR-30a-3p', 'Var', (21, 31))	('Fzd2', 'Gene', '2535', (87, 91))	('Fzd2', 'Gene', (87, 91))	('expression', 'MPA', (110, 120))	('inhibit', 'NegReg', (96, 103))	('Wnt2', 'Gene', '7472', (78, 82))
211190	29259372	In conclusion, low expression of miR-30a-3p/5p was closely associated with advanced ESCC progression and poor prognosis of patients with ESCC.	('expression', 'MPA', (19, 29))	('ESCC', 'Disease', (84, 88))	('patients', 'Species', '9606', (123, 131))	('associated', 'Reg', (59, 69))	('miR-30a-3p/5p', 'Var', (33, 46))	('low', 'NegReg', (15, 18))
211191	29259372	Furthermore, miR-30a-3p and miR-30a-5p could inhibit the activity of the Wnt signaling pathway by targeting the 3'UTRs of WNT2 and FZD2, respectively.	('miR-30a-3p', 'Var', (13, 23))	('targeting', 'Reg', (98, 107))	('Wnt signaling pathway', 'Pathway', (73, 94))	('miR-30a-5p', 'Var', (28, 38))	('FZD2', 'Gene', '2535', (131, 135))	('FZD2', 'Gene', (131, 135))	('WNT2', 'Gene', (122, 126))	('activity', 'MPA', (57, 65))	('inhibit', 'NegReg', (45, 52))	('WNT2', 'Gene', '7472', (122, 126))
211288	27588447	At a false discovery rate of 5%, we identified 16 cis G x BMI interactions (top cis interaction: CHURC1, rs7143432, p = 2.0 x 10-12) and one variant regulating 53 genes in trans (top trans interaction: ZNF423, rs3851570, p = 8.2 x 10-13), all in adipose tissue.	('rs3851570', 'Mutation', 'rs3851570', (210, 219))	('CHURC1', 'Gene', '91612', (97, 103))	('CHURC1', 'Gene', (97, 103))	('cis', 'Gene', (80, 83))	('interactions', 'Interaction', (62, 74))	('cis', 'Gene', (50, 53))	('cis', 'Gene', '1154', (80, 83))	('cis', 'Gene', '1154', (50, 53))	('ZNF423', 'Gene', '23090', (202, 208))	('rs7143432', 'Mutation', 'rs7143432', (105, 114))	('rs3851570', 'Var', (210, 219))	('ZNF423', 'Gene', (202, 208))	('rs7143432', 'Var', (105, 114))
211294	27588447	BMI-associated genetic variants are enriched for hypothalamic processes, which suggests that the variants that cause obesity exert their effects primarily in the brain.	('hypothalamic', 'Disease', (49, 61))	('obesity', 'Phenotype', 'HP:0001513', (117, 124))	('hypothalamic', 'Disease', 'MESH:D007027', (49, 61))	('variants', 'Var', (97, 105))	('variants', 'Var', (23, 31))	('obesity', 'Disease', 'MESH:D009765', (117, 124))	('effects', 'Reg', (137, 144))	('obesity', 'Disease', (117, 124))
211295	27588447	In contrast, variants for many obesity co-morbid traits are primarily thought to regulate genes active in certain peripheral tissues, such as adipose, muscle, and the liver (insulin resistance), the heart and endothelial cells (QT-interval, which is predictive of cardiovascular disease), and adipose (body-fat distribution ), for example.	('variants', 'Var', (13, 21))	('cardiovascular disease', 'Disease', (264, 286))	('obesity', 'Phenotype', 'HP:0001513', (31, 38))	('insulin', 'Gene', (174, 181))	('regulate', 'Reg', (81, 89))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (264, 286))	('insulin', 'Gene', '3630', (174, 181))	('obesity', 'Disease', (31, 38))	('cardiovascular disease', 'Disease', 'MESH:D002318', (264, 286))	('obesity', 'Disease', 'MESH:D009765', (31, 38))	('insulin resistance', 'Phenotype', 'HP:0000855', (174, 192))	('genes', 'Gene', (90, 95))
211300	27588447	Twin studies agnostic to the underlying environment have also identified G x E regulatory variants.	('variants', 'Var', (90, 98))	('G x E regulatory', 'Gene', (73, 89))	('men', 'Species', '9606', (47, 50))
211303	27588447	We then identified 16 significant cis G x BMI interactions (false discovery rate [FDR] = 5%) on the regulation of gene expression in adipose tissue and we provide evidence of replicated examples in an independent adipose tissue cohort (deCODE, n = 754).	('regulation of gene expression', 'MPA', (100, 129))	('cis', 'Gene', (34, 37))	('cis', 'Gene', '1154', (34, 37))	('interactions', 'Var', (46, 58))
211304	27588447	By extending the analysis in trans we were able to identify one cis G x BMI variant that regulates the expression of 53 genes in trans in a BMI-dependent manner.	('G x BMI', 'Gene', (68, 75))	('variant', 'Var', (76, 83))	('regulates', 'Reg', (89, 98))	('expression', 'MPA', (103, 113))	('cis', 'Gene', (64, 67))	('cis', 'Gene', '1154', (64, 67))
211316	27588447	The resulting four significant non-PEER-corrected cis G x BMI variants (rs1464171, rs3851570, rs113368712 and rs35662778; FDR = 5%) were then tested for trans G x BMI effects.	('rs113368712', 'Var', (94, 105))	('rs3851570', 'Mutation', 'rs3851570', (83, 92))	('rs1464171', 'Var', (72, 81))	('rs1464171', 'Mutation', 'rs1464171', (72, 81))	('rs113368712', 'Mutation', 'rs113368712', (94, 105))	('rs35662778', 'Var', (110, 120))	('cis', 'Gene', (50, 53))	('rs3851570', 'Var', (83, 92))	('cis', 'Gene', '1154', (50, 53))	('rs35662778', 'Mutation', 'rs35662778', (110, 120))
211330	27588447	For each of the 1,129 variants, we fitted an interaction (Model 3) and main effect (Model 4) model:andwhere SNPN is SNP1-SNP1,129.	('SNP1', 'Gene', '6625', (121, 125))	('SNP1', 'Gene', (116, 120))	('SNP1', 'Gene', (121, 125))	('SNP1', 'Gene', '6625', (116, 120))	('variants', 'Var', (22, 30))
211337	27588447	To calculate the mediation score, the following four models and equations were implemented:andwhere y = trans gene expression, A = age, A2 = age squared, E = cis gene expression, P = BMI, and G = cis genotype.	('cis', 'Gene', '1154', (158, 161))	('cis', 'Gene', '1154', (196, 199))	('men', 'Species', '9606', (84, 87))	('trans', 'Reg', (104, 109))	('P = BMI', 'Var', (179, 186))	('cis', 'Gene', (158, 161))	('cis', 'Gene', (196, 199))
211354	27588447	Although 11 G x BMI regulated genes showed multi-tissue expression, five genes (PHACTR3, ADH1A, RP11-71E19.1, POU6F2, and SPAG17) have adipose-specific expression within TwinsUK but no detectable expression in blood, skin, or LCLs.	('PHACTR3', 'Gene', '116154', (80, 87))	('POU6F2', 'Gene', '11281', (110, 116))	('SPAG17', 'Gene', (122, 128))	('ADH1A', 'Gene', (89, 94))	('POU6F2', 'Gene', (110, 116))	('SPAG17', 'Gene', '200162', (122, 128))	('RP11-71E19.1', 'Var', (96, 108))	('ADH1A', 'Gene', '124', (89, 94))	('PHACTR3', 'Gene', (80, 87))	('adipose-specific expression', 'MPA', (135, 162))
211355	27588447	The G x BMI variants are enriched for tissue-specific regulatory potential; we tested the 16 variants for enrichment in enhancer activity in the 127 Roadmap Epigenomics cell types and found an enrichment only in purified adipocytes (mesenchymal-stem-cell-derived adipocytes, p = 0.028).	('men', 'Species', '9606', (199, 202))	('variants', 'Var', (93, 101))	('activity', 'MPA', (129, 137))	('men', 'Species', '9606', (112, 115))	('enhancer', 'PosReg', (120, 128))	('tested', 'Reg', (79, 85))
211361	27588447	Variants intronic to PEPD are associated with T2D, adiponectin, triglyceride levels, and fasting insulin; however, the lead GWAS SNPs are in low LD with the G x BMI regulatory variant (r2 = 0.145, D' = 1).	('associated', 'Reg', (30, 40))	('adiponectin', 'Gene', '9370', (51, 62))	('Variants', 'Var', (0, 8))	('PEPD', 'Gene', (21, 25))	('insulin', 'Gene', '3630', (97, 104))	('adiponectin', 'Gene', (51, 62))	('PEPD', 'Gene', '5184', (21, 25))	('triglyceride levels', 'MPA', (64, 83))	('T2D', 'MPA', (46, 49))	('insulin', 'Gene', (97, 104))
211366	27588447	However, individuals with the minor allele of rs7505859 show the opposite relationship (CIDEA is positively correlated with BMI).	('rs7505859', 'Mutation', 'rs7505859', (46, 55))	('rs7505859', 'Var', (46, 55))	('CIDEA', 'Disease', (88, 93))
211368	27588447	A proxy SNP (rs1229977, r2 = 0.63) for the G x BMI variant regulating ADH1A (alcohol dehydrogenase 1A), rs1693457, is associated with esophageal cancer (MIM: 133239) in a large GWAS.	('cancer', 'Disease', (145, 151))	('ADH1A', 'Gene', '124', (70, 75))	('rs1693457', 'Mutation', 'rs1693457', (104, 113))	('ADH1A', 'Gene', (70, 75))	('rs1229977', 'Mutation', 'rs1229977', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('alcohol dehydrogenase 1A', 'Gene', (77, 101))	('rs1693457', 'Var', (104, 113))	('associated with', 'Reg', (118, 133))	('alcohol dehydrogenase 1A', 'Gene', '124', (77, 101))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('rs1229977', 'Var', (13, 22))
211369	27588447	The GWAS association at this locus covers several ADH family genes; however, we show that, in addition to the G x BMI effect, rs1693457 is a main-effect eQTL (beta = -0.89, p = 2.9 x 10-41) for ADH1A.	('ADH', 'Gene', (194, 197))	('ADH', 'Gene', (50, 53))	('ADH1A', 'Gene', '124', (194, 199))	('rs1693457', 'Var', (126, 135))	('ADH1A', 'Gene', (194, 199))	('rs1693457', 'Mutation', 'rs1693457', (126, 135))	('ADH', 'Gene', '124', (194, 197))	('ADH', 'Gene', '124', (50, 53))
211371	27588447	The esophageal cancer GWAS SNP (rs1229977) had an RTC score of 0.98 when tested with either the interaction or main-effect model, indicating that the regulatory and GWAS signals are tagging the same underlying variant.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('rs1229977', 'Var', (32, 41))	('rs1229977', 'Mutation', 'rs1229977', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
211376	27588447	Given that cis eQTLs are enriched for trans-eQTL effects, we utilized a two-step strategy to identify trans G x BMI interactions in adipose tissue, first identifying cis G x BMI interactions and then testing the identified cis G x BMI variants for trans G x BMI effects with all adipose-expressed exons.	('cis', 'Gene', (11, 14))	('cis', 'Gene', '1154', (11, 14))	('cis', 'Gene', (223, 226))	('cis', 'Gene', (166, 169))	('testing', 'Reg', (200, 207))	('cis', 'Gene', '1154', (223, 226))	('cis', 'Gene', '1154', (166, 169))	('variants', 'Var', (235, 243))
211378	27588447	IPA of the 53 genes in the ALG9 G x BMI trans-network revealed enrichment for inhibition of matrix metalloproteases (Benjamini-Hochberg corrected p = 3.6 x 10-8), oxidative phosphorylation (Benjamini-Hochberg corrected p = 3.1 x 10-4), and gene membership of a cardiovascular disease network (Figure 4B), indicating that BMI-dependent regulatory effects at rs3851570 have a wide-ranging role in metabolism and structural remodeling of adipose tissue.	('rs3851570', 'Mutation', 'rs3851570', (357, 366))	('men', 'Species', '9606', (69, 72))	('oxidative phosphorylation', 'MPA', (163, 188))	('cardiovascular disease', 'Disease', (261, 283))	('ALG9', 'Gene', (27, 31))	('rs3851570', 'Var', (357, 366))	('ALG9', 'Gene', '79796', (27, 31))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (261, 283))	('cardiovascular disease', 'Disease', 'MESH:D002318', (261, 283))	('matrix metalloproteases', 'Enzyme', (92, 115))
211384	27588447	We investigated the trans G x BMI effect in a second population by testing rs3851570 against all measured exon expression amounts (n = 168,951) in the deCODE dataset.	('rs3851570', 'Mutation', 'rs3851570', (75, 84))	('rs3851570', 'Var', (75, 84))	('testing', 'Reg', (67, 74))
211385	27588447	Although the 53 trans genes did not replicate in the deCODE dataset, transcriptome-wide we see a significant enrichment for low p values (pi1 = 0.14), demonstrating that rs3851570 has broad effects on adipose gene expression in a BMI-dependent manner in multiple populations.	('pi1', 'Gene', '5265', (138, 141))	('expression', 'MPA', (214, 224))	('rs3851570', 'Mutation', 'rs3851570', (170, 179))	('pi1', 'Gene', (138, 141))	('men', 'Species', '9606', (115, 118))	('effects', 'Reg', (190, 197))	('rs3851570', 'Var', (170, 179))	('adipose gene', 'Gene', (201, 213))
211387	27588447	All 127 G x BMI interactions show an opposite direction of effect between expression and BMI in the two-homozygote classes (for example, PHACTR3, Figure 2).	('effect', 'Reg', (59, 65))	('interactions', 'Var', (16, 28))	('PHACTR3', 'Gene', (137, 144))	('PHACTR3', 'Gene', '116154', (137, 144))
211389	27588447	G x BMI variants are not directly associated with BMI, and no significant enrichment was seen in a BMI GWAS of 339,224 individuals (pi1 = 0), suggesting the G x BMI effects are not the result of indirectly measured gene-by-gene effects.	('men', 'Species', '9606', (80, 83))	('pi1', 'Gene', (132, 135))	('pi1', 'Gene', '5265', (132, 135))	('variants', 'Var', (8, 16))
211398	27588447	All 16 G x BMI interactions (FDR = 5%) showed a similar effect in the G x visceral fat analysis, and despite the drop in sample size, some interactions increased in significance by four orders of magnitude (CAST p = 3.0 x 10-16, PEPD p = 3.0 x 10-15) (Figure 3C), potentially due to the increased sensitivity gained from an accurate machine-measured phenotype.	('interactions', 'Var', (139, 151))	('PEPD', 'Gene', '5184', (229, 233))	('increased', 'PosReg', (152, 161))	('G x visceral fat analysis', 'MPA', (70, 95))	('CAST', 'Gene', (207, 211))	('PEPD', 'Gene', (229, 233))	('CAST', 'Gene', '831', (207, 211))	('interactions', 'Var', (15, 27))
211407	27588447	Characterization of G x BMI regulatory variants and the genes they act upon will help elucidate the downstream consequences of obesity and the molecular pathways leading to associated diseases.	('obesity', 'Phenotype', 'HP:0001513', (127, 134))	('obesity', 'Disease', 'MESH:D009765', (127, 134))	('G x BMI', 'Gene', (20, 27))	('obesity', 'Disease', (127, 134))	('variants', 'Var', (39, 47))
211431	24765533	Esophageal reflux-induced symptoms may develop at a similar rate or more frequently after subtotal gastrectomy compared to that after total gastrectomy, and decrease quality of life in gastric cancer patients.	('gastric cancer', 'Phenotype', 'HP:0012126', (185, 199))	('quality of life', 'CPA', (166, 181))	('subtotal gastrectomy', 'Var', (90, 110))	('Esophageal reflux', 'Phenotype', 'HP:0002020', (0, 17))	('patients', 'Species', '9606', (200, 208))	('Esophageal reflux-induced symptoms', 'Disease', (0, 34))	('decrease', 'NegReg', (157, 165))	('gastric cancer', 'Disease', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('gastric cancer', 'Disease', 'MESH:D013274', (185, 199))
211463	24765533	Although the prevalence of reflux symptoms was higher in patients after subtotal gastrectomy than after total gastrectomy, the difference was not statistically significant (P=0.127).	('reflux symptoms', 'Disease', (27, 42))	('reflux symptoms', 'Phenotype', 'HP:0002020', (27, 42))	('patients', 'Species', '9606', (57, 65))	('higher', 'PosReg', (47, 53))	('subtotal', 'Var', (72, 80))
211465	24765533	With regard to the MID, the difference between the means and MIDs was greater in the domains of the global health status/QoL, which means that the global health status/QoL in the GerdQ (+) group was worse than that in the GerdQ (-) group (Fig.	('MIDs', 'Disease', (61, 65))	('MIDs', 'Disease', 'MESH:C565122', (61, 65))	('worse', 'NegReg', (199, 204))	('GerdQ', 'Var', (179, 184))	('MID', 'Disease', 'None', (19, 22))	('MID', 'Disease', (19, 22))	('global', 'MPA', (147, 153))	('MID', 'Disease', 'None', (61, 64))	('MID', 'Disease', (61, 64))
211475	24765533	Surprisingly, over 20% of the patients with subtotal gastrectomy suffered from significant reflux symptoms, while only 12.3% of the patients with total gastrectomy suffered from GERD symptoms.	('patients', 'Species', '9606', (30, 38))	('subtotal gastrectomy', 'Var', (44, 64))	('reflux symptoms', 'Phenotype', 'HP:0002020', (91, 106))	('suffered', 'Reg', (65, 73))	('reflux symptoms', 'MPA', (91, 106))	('patients', 'Species', '9606', (132, 140))
211495	24765533	However, esophageal reflux symptoms may develop at a similar frequency or more frequently after subtotal gastrectomy than after total gastrectomy.	('subtotal gastrectomy', 'Var', (96, 116))	('reflux symptoms', 'Phenotype', 'HP:0002020', (20, 35))	('esophageal reflux symptoms', 'Disease', 'MESH:D005764', (9, 35))	('esophageal reflux', 'Phenotype', 'HP:0002020', (9, 26))	('esophageal reflux symptoms', 'Disease', (9, 35))
211502	24073846	Introduction of increased beta-catenin signaling, haploid expression of beta-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/beta-catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous beta-catenin expression.	('beta-catenin', 'Gene', '1499', (342, 354))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (267, 287))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (267, 287))	('activation', 'PosReg', (166, 176))	('beta-catenin', 'Gene', '1499', (26, 38))	('HONE1', 'CellLine', 'CVCL:8706', (231, 236))	('beta-catenin', 'Gene', (72, 84))	('beta-catenin', 'Gene', '1499', (72, 84))	('beta-catenin', 'Gene', (184, 196))	('increased', 'PosReg', (16, 25))	('beta-catenin', 'Gene', (342, 354))	('beta-catenin', 'Gene', '1499', (184, 196))	('SLMT1', 'CellLine', 'CVCL:E305', (288, 293))	('beta-catenin', 'Gene', (26, 38))	('esophageal carcinoma', 'Disease', (267, 287))	('dedifferentiation', 'CPA', (210, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('haploid expression', 'Var', (50, 68))
211516	24073846	NPC was reported to have an infrequent mutation of tumor suppressor gene (TSG) p53 and wild-type RB1 expression; they both play critical roles in the control of the reprogramming process, self-renewal, and other cell fate determinations.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('NPC', 'Disease', (0, 3))	('mutation', 'Var', (39, 47))	('RB1', 'Gene', (97, 100))	('self-renewal', 'CPA', (188, 200))	('tumor', 'Disease', (51, 56))	('play', 'Reg', (123, 127))	('reprogramming process', 'CPA', (165, 186))	('TSG', 'Gene', (74, 77))	('RB1', 'Gene', '5925', (97, 100))	('NPC', 'Phenotype', 'HP:0100630', (0, 3))	('TSG', 'Gene', '57045', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
211520	24073846	Because a physiological or basic level of Wnt signaling acts as a determinant factor in the regulation of stem cells and self-renewing tissues and HONE1 cells have very low endogenous expression of beta-catenin, a major mediator of Wnt signaling, we hypothesized that introduction of another copy of the beta-catenin gene (CTNNB1) via single copy transfer of chromosome 3 may generate physiological levels of beta-catenin signaling due to the haploid level of expression of the transferred genes under control by their natural regulators.	('physiological levels', 'MPA', (385, 405))	('beta-catenin', 'Gene', (409, 421))	('beta-catenin', 'Gene', '1499', (304, 316))	('introduction', 'Var', (268, 280))	('CTNNB1', 'Gene', '1499', (323, 329))	('beta-catenin', 'Gene', '1499', (409, 421))	('HONE1', 'CellLine', 'CVCL:8706', (147, 152))	('beta-catenin', 'Gene', (198, 210))	('generate', 'PosReg', (376, 384))	('beta-catenin', 'Gene', (304, 316))	('CTNNB1', 'Gene', (323, 329))	('beta-catenin', 'Gene', '1499', (198, 210))
211535	24073846	The expression of Axin2 was detected in HONE1 hybrid cells, but not in H7 cells and parental HONE1 cells.	('Axin2', 'Gene', '8313', (18, 23))	('HONE1', 'CellLine', 'CVCL:8706', (40, 45))	('HONE1', 'CellLine', 'CVCL:8706', (93, 98))	('H7', 'CellLine', 'CVCL:9772', (71, 73))	('Axin2', 'Gene', (18, 23))	('HONE1 hybrid', 'Var', (40, 52))
211539	24073846	The increased level of beta-catenin protein accumulating around membranes was clearly detected in the majority of hybrid cells compared to parental HONE1 cells by immunofluorescence staining (Figure 1B).	('hybrid', 'Var', (114, 120))	('beta-catenin', 'Gene', (23, 35))	('increased level of beta-', 'Phenotype', 'HP:0003141', (4, 28))	('HONE1', 'CellLine', 'CVCL:8706', (148, 153))	('increased', 'PosReg', (4, 13))	('beta-catenin', 'Gene', '1499', (23, 35))
211541	24073846	Compared with parental HONE1 cells, E-cadherin was up-regulated and N-cadherin was down-regulated in the HONE1 hybrid cells.	('up-regulated', 'PosReg', (51, 63))	('HONE1', 'Var', (105, 110))	('N-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', (36, 46))	('down-regulated', 'NegReg', (83, 97))	('E-cadherin', 'Gene', '999', (36, 46))	('N-cadherin', 'Gene', '1000', (68, 78))	('HONE1', 'CellLine', 'CVCL:8706', (23, 28))	('HONE1', 'CellLine', 'CVCL:8706', (105, 110))
211544	24073846	Immunohistochemical staining of the xenograft tumors demonstrated that beta-catenin, E-cadherin, and Cyclin D1, the target of Wnt signaling, were strongly up-regulated in tumor segregants (TSs) derived from HONE1 hybrids, as compared with control tumors from the parental HONE1 and MCH4.5-2TS cells.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('xenograft tumors', 'Disease', (36, 52))	('MCH4', 'Gene', '843', (282, 286))	('tumors', 'Disease', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('xenograft tumors', 'Disease', 'MESH:D009369', (36, 52))	('E-cadherin', 'Gene', (85, 95))	('E-cadherin', 'Gene', '999', (85, 95))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('HONE1', 'CellLine', 'CVCL:8706', (207, 212))	('up-regulated', 'PosReg', (155, 167))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('MCH4', 'Gene', (282, 286))	('HONE1 hybrids', 'Var', (207, 220))	('hybrids', 'Var', (213, 220))	('tumors', 'Disease', (46, 52))	('beta-catenin', 'Gene', (71, 83))	('Cyclin D1', 'Gene', '595', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('beta-catenin', 'Gene', '1499', (71, 83))	('Cyclin D1', 'Gene', (101, 110))	('tumor', 'Disease', (247, 252))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('HONE1', 'CellLine', 'CVCL:8706', (272, 277))	('tumor', 'Disease', (171, 176))
211562	24073846	CD24+, CD44+, and CD24+/CD44+ populations were markedly increased from 23% to 53.2%, 35.7% to 77.9%, and 42.7% to 77.2%, respectively, in HONE1 hybrid cells compared to parental HONE1 cells (Figure 3B).	('increased', 'PosReg', (56, 65))	('HONE1', 'CellLine', 'CVCL:8706', (178, 183))	('HONE1', 'CellLine', 'CVCL:8706', (138, 143))	('CD44', 'Gene', '960', (7, 11))	('HONE1 hybrid', 'Var', (138, 150))	('CD44', 'Gene', '960', (24, 28))	('CD24', 'Gene', '100133941', (0, 4))	('CD24', 'Gene', (0, 4))	('CD24', 'Gene', '100133941', (18, 22))	('CD44', 'Gene', (7, 11))	('CD44', 'Gene', (24, 28))	('CD24', 'Gene', (18, 22))
211563	24073846	The qPCR array results confirmed that pluripotency genes, Sox2, Klf4, Oct4, and Nanog, are clearly up-regulated in HONE1 hybrid cells, compared with parental HONE1 cells.	('Klf4', 'Gene', '9314', (64, 68))	('Sox2', 'Gene', (58, 62))	('HONE1', 'CellLine', 'CVCL:8706', (158, 163))	('Nanog', 'Gene', (80, 85))	('Nanog', 'Gene', '79923', (80, 85))	('pluripotency', 'MPA', (38, 50))	('Oct4', 'Gene', (70, 74))	('up-regulated', 'PosReg', (99, 111))	('HONE1 hybrid', 'Var', (115, 127))	('HONE1', 'CellLine', 'CVCL:8706', (115, 120))	('Klf4', 'Gene', (64, 68))	('Sox2', 'Gene', '6657', (58, 62))	('Oct4', 'Gene', '5460', (70, 74))
211564	24073846	In addition, many other relevant genes such as HOXA9, RB1, ZIC1, WRN, TDGF1, LIN28B, and WT1 are considerably up-regulated in these HONE1 hybrid cells (Figure 4A), supporting the stem cell-like properties of these cells and activation of known genes related to self-renewal networks.	('WRN', 'Gene', (65, 68))	('WT1', 'Gene', '7490', (89, 92))	('WRN', 'Gene', '7486', (65, 68))	('WT1', 'Gene', (89, 92))	('HOXA9', 'Gene', (47, 52))	('up-regulated', 'PosReg', (110, 122))	('TDGF1', 'Gene', '6997', (70, 75))	('TDGF1', 'Gene', (70, 75))	('LIN28B', 'Gene', (77, 83))	('RB1', 'Gene', (54, 57))	('ZIC1', 'Gene', (59, 63))	('ZIC1', 'Gene', '7545', (59, 63))	('LIN28B', 'Gene', '389421', (77, 83))	('HOXA9', 'Gene', '3205', (47, 52))	('RB1', 'Gene', '5925', (54, 57))	('HONE1', 'CellLine', 'CVCL:8706', (132, 137))	('HONE1', 'Var', (132, 137))
211565	24073846	The exogenous copy of beta-catenin in HONE1 hybrid cells induced signaling cascades involved in multiple pathways such as Wnt, TGF-beta superfamily containing BMP and Activin receptors, pluripotency maintenance, and FGF signaling (Figure 4B).	('beta-catenin', 'Gene', '1499', (22, 34))	('BMP', 'Gene', (159, 162))	('induced', 'Reg', (57, 64))	('HONE1', 'CellLine', 'CVCL:8706', (38, 43))	('FGF signaling', 'MPA', (216, 229))	('signaling cascades', 'MPA', (65, 83))	('TGF-beta', 'Gene', '7040', (127, 135))	('beta-catenin', 'Gene', (22, 34))	('BMP', 'Gene', '649', (159, 162))	('exogenous copy', 'Var', (4, 18))	('TGF-beta', 'Gene', (127, 135))	('pluripotency maintenance', 'MPA', (186, 210))
211585	24073846	The results indicated that tumor cell growth was inhibited by the knockdown of Wnt/beta-catenin signaling in these cells (Figures 6B and 6C), reflecting that activation of tumor suppressive signaling has limited influence to control cell growth in HONE1 hybrid cells.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('beta-catenin', 'Gene', (83, 95))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('beta-catenin', 'Gene', '1499', (83, 95))	('HONE1', 'CellLine', 'CVCL:8706', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('knockdown', 'Var', (66, 75))	('inhibited', 'NegReg', (49, 58))
211595	24073846	Consistent with findings of both components of Wnt pathways and the core stem cell network being expressed or up-regulated in HONE1 hybrid cells, we found that the Wnt signal was clearly increased in HONE1 hybrid cells, as compared with untreated HONE1 cells.	('HONE1', 'CellLine', 'CVCL:8706', (126, 131))	('Wnt signal', 'MPA', (164, 174))	('up-regulated', 'PosReg', (110, 122))	('HONE1', 'CellLine', 'CVCL:8706', (247, 252))	('increased', 'PosReg', (187, 196))	('HONE1 hybrid', 'Var', (200, 212))	('HONE1', 'CellLine', 'CVCL:8706', (200, 205))
211606	24073846	It is also notable that the LIFR- and IL6ST-mediated pluripotency maintenance pathways, as well as BMP receptors and Smad families, were activated in HONE1 hybrid cells.	('IL6ST', 'Gene', (38, 43))	('Smad', 'Gene', (117, 121))	('HONE1', 'Var', (150, 155))	('Smad', 'Gene', '4090;4093', (117, 121))	('HONE1', 'CellLine', 'CVCL:8706', (150, 155))	('IL6ST', 'Gene', '3572', (38, 43))	('activated', 'PosReg', (137, 146))	('BMP', 'Gene', '649', (99, 102))	('BMP', 'Gene', (99, 102))	('LIFR', 'Gene', '3977', (28, 32))	('LIFR', 'Gene', (28, 32))
211612	24073846	There are very limited methods to explore physiological levels of Wnt/beta-catenin signaling in current biology studies and the results of these studies indicate that haploid levels of expression of transferred beta-catenin can induce signaling cascades that include multiple known pathways associated with reprogramming and self-renewal processes.	('beta-catenin', 'Gene', (70, 82))	('haploid levels of expression', 'Var', (167, 195))	('beta-catenin', 'Gene', (211, 223))	('beta-catenin', 'Gene', '1499', (70, 82))	('induce', 'Reg', (228, 234))	('beta-catenin', 'Gene', '1499', (211, 223))	('signaling', 'MPA', (235, 244))
211646	24073846	This work was funded by the Research Grants Council Area of Excellence scheme in Hong Kong (AoE/M-06/08) to MLL and the University of Hong Kong Seed Funding Program for Basic Research (Project Codes: 201007159005 and 201111159142) to YC.	('201111159142', 'Var', (217, 229))	('MLL', 'Gene', (108, 111))	('MLL', 'Gene', '4297', (108, 111))
211685	29992560	East Asian populations have certain polymorphisms in acetaldehyde dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) that alter the formation of the carcinogen acetaldehyde from ethanol, cause a flushing response, and have been demonstrated to modify associations between alcohol intake and cancer .	('ADH', 'Gene', (81, 84))	('polymorphisms', 'Var', (36, 49))	('flushing', 'Disease', (198, 206))	('acetaldehyde', 'Chemical', 'MESH:D000079', (163, 175))	('cause', 'Reg', (190, 195))	('ADH', 'Gene', '124', (81, 84))	('acetaldehyde', 'Chemical', 'MESH:D000079', (53, 65))	('acetaldehyde dehydrogenase', 'Gene', '124', (53, 79))	('cancer', 'Disease', (294, 300))	('alcohol', 'Chemical', 'MESH:D000438', (275, 282))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('ethanol', 'Chemical', 'MESH:D000431', (181, 188))	('associations', 'Interaction', (254, 266))	('acetaldehyde dehydrogenase', 'Gene', (53, 79))	('flushing', 'Disease', 'MESH:D005483', (198, 206))	('alter', 'Reg', (125, 130))	('flushing', 'Phenotype', 'HP:0031284', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('modify', 'Reg', (247, 253))	('formation of the carcinogen acetaldehyde from', 'MPA', (135, 180))
211697	29992560	Both types of adenocarcinomas excluded histologic codes of 8070, 8072, 8240, 8246, 8560, >=8800, 8083, 8050, 8245, and 8512.	('8050', 'Var', (103, 107))	('8560', 'Var', (83, 87))	('8240', 'Var', (71, 75))	('8512', 'Var', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('8246', 'Var', (77, 81))	('8083', 'Var', (97, 101))	('adenocarcinomas', 'Disease', 'MESH:D000230', (14, 29))	('adenocarcinomas', 'Disease', (14, 29))	('>=8800', 'Var', (89, 95))
211714	29992560	In sensitivity analyses, we excluded people who self-reported poor or fair health status as they may have recently altered their alcohol drinking due to ill-health; we excluded those with ICD site codes C16.8 (n=82) and C16.9 (n=169) which refer to overlapping lesions or not otherwise specified lesions of stomach to minimize the misclassification for risk assessment; we excluded cases diagnosed in the first 2 years to assess potential reverse causation; and analyzed the association restricted to alcohol drinkers only.	('alcohol drinkers', 'Phenotype', 'HP:0030955', (501, 517))	('alcohol drinking', 'Phenotype', 'HP:0030955', (129, 145))	('men', 'Species', '9606', (364, 367))	('C16.8', 'Var', (203, 208))	('alcohol', 'Chemical', 'MESH:D000438', (129, 136))	('C16.9', 'CellLine', 'CVCL:2322', (220, 225))	('C16.9', 'Var', (220, 225))	('altered', 'Reg', (115, 122))	('people', 'Species', '9606', (37, 43))	('lesions of stomach', 'Phenotype', 'HP:0006753', (296, 314))	('alcohol', 'Chemical', 'MESH:D000438', (501, 508))
211734	29992560	For example, the SNP rs671 in ALDH2 is a common variant in East Asians, which is associated with the "alcohol flushing response," and is caused by rapid accumulation of the carcinogen acetaldehyde.	('associated with', 'Reg', (81, 96))	('flushing', 'Disease', 'MESH:D005483', (110, 118))	('caused by', 'Reg', (137, 146))	('ALDH2', 'Gene', (30, 35))	('ALDH2', 'Gene', '217', (30, 35))	('rs671', 'Mutation', 'rs671', (21, 26))	('alcohol', 'Chemical', 'MESH:D000438', (102, 109))	('flushing', 'Phenotype', 'HP:0031284', (110, 118))	('SNP rs671', 'Var', (17, 26))	('accumulation', 'PosReg', (153, 165))	('flushing', 'Disease', (110, 118))	('acetaldehyde', 'Chemical', 'MESH:D000079', (184, 196))	('carcinogen acetaldehyde', 'MPA', (173, 196))
211776	31709176	Therefore, blocking PD-L1 with or without the co-blockade of PD-1 is a promising approach to restore the dysfunctional T cells in cancers.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('dysfunctional T', 'Disease', (105, 120))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('PD-L1', 'Gene', (20, 25))	('blocking', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('dysfunctional T', 'Disease', 'MESH:D012735', (105, 120))	('PD-L1', 'Gene', '29126', (20, 25))
211782	31709176	A recent systematic meta-analysis revealed increased rates of hypothyroidism (odds ratio = 7.56, 95% confidence interval 4.53-12.61), pneumonitis (odds ratio = 5.37, 95% confidence interval 2.73-10.56), colitis (odds ratio = 2.88, 95% confidence interval 1.3-6.37), and hypophysitis (odds ratio = 3.38, 95% confidence interval 1.02-11.08) in cancer patients receiving anti-PD-1 treatments compared with standard treatments.	('pneumonitis', 'Disease', 'MESH:D011014', (134, 145))	('colitis', 'Disease', 'MESH:D003092', (203, 210))	('hypothyroidism', 'Disease', (62, 76))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('hypophysitis', 'Disease', 'MESH:D010900', (270, 282))	('colitis', 'Disease', (203, 210))	('patients', 'Species', '9606', (349, 357))	('cancer', 'Disease', (342, 348))	('anti-PD-1', 'Var', (368, 377))	('hypothyroidism', 'Phenotype', 'HP:0000821', (62, 76))	('colitis', 'Phenotype', 'HP:0002583', (203, 210))	('pneumonitis', 'Disease', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('hypothyroidism', 'Disease', 'MESH:D007037', (62, 76))	('hypophysitis', 'Disease', (270, 282))
211815	31709176	Commercial conjugated antibodies used include CD3-Alexa Fluor 700 (344822, BioLegend), CD4-FITC (345768, BD Biosciences), CD8-APC-Cy7 (560179, BD Biosciences), CD160-PE-cy7 (341212, BioLegend), BTLA-APC (344510, BioLegend), PD-1-BV650 (564104, BD Biosciences), Tim3-BV421 (345008, BioLegend), TIGIT-PE (12-9500-42, eBioscience), 2B4-APC (329512, BioLegend), KLRG-1-BV605 (138419, BioLegend), CTLA-4-PE-Cy7 (349914, BioLegend), CD27-PERCP5.5 (356407, BioLegend), CCR7-BV711 (353227, BioLegend), and CD45RA-BV785 (304139, BioLegend).	('CCR7', 'Gene', (462, 466))	('PD-1-BV650', 'Gene', (224, 234))	('CD27', 'Gene', '939', (427, 431))	('Tim', 'Gene', (261, 264))	('2B4', 'Gene', '51744', (329, 332))	('CCR7', 'Gene', '1236', (462, 466))	('eBioscience', 'Disease', 'None', (315, 326))	('CTLA-4', 'Gene', '1493', (392, 398))	('CD8', 'Gene', (122, 125))	('CTLA-4', 'Gene', (392, 398))	('KLRG-1', 'Gene', (358, 364))	('2B4', 'Gene', (329, 332))	('PD-1-BV650', 'Gene', '5133', (224, 234))	('353227', 'Var', (474, 480))	('BTLA', 'Gene', '151888', (194, 198))	('CD27', 'Gene', (427, 431))	('Tim', 'Gene', '26762', (261, 264))	('356407', 'Var', (442, 448))	('KLRG-1', 'Gene', '10219', (358, 364))	('CD8', 'Gene', '925', (122, 125))	('CD160', 'Gene', '11126', (160, 165))	('eBioscience', 'Disease', (315, 326))	('BTLA', 'Gene', (194, 198))	('CD160', 'Gene', (160, 165))
211833	31709176	Further, we discovered that the frequencies of PD-1+ and Tim-3+ cells in peripheral T cells positively correlated with their respective frequencies in TILs (Supplementary Figures 1A-D).	('Tim-3', 'Gene', (57, 62))	('Tim-3', 'Gene', '84868', (57, 62))	('PD-1+', 'Var', (47, 52))
211894	31709176	More importantly, numerous CTLA-4 blockade animal experiments and human clinical trials have suggested that blocking CTLA-4 can lead to high-grade immune-related adverse effects, which are of a more severe magnitude, compared with those of PD-1/PD-L1 blockade.	('CTLA-4', 'Gene', (27, 33))	('PD-L1', 'Gene', (245, 250))	('CTLA-4', 'Gene', (117, 123))	('human', 'Species', '9606', (66, 71))	('PD-L1', 'Gene', '29126', (245, 250))	('blocking', 'Var', (108, 116))	('CTLA-4', 'Gene', '1493', (117, 123))	('high-grade immune-related adverse effects', 'MPA', (136, 177))	('CTLA-4', 'Gene', '1493', (27, 33))
211899	31709176	TIGIT has been reported as a co-regulator of the expansion and function of tumor-specific T cells in advanced melanoma patients, suggesting that co-blockade of PD-1 and TIGIT might elicit potent antitumor responses.	('tumor', 'Disease', (199, 204))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('TIGIT', 'Gene', (169, 174))	('co-blockade', 'Var', (145, 156))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('elicit', 'Reg', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PD-1', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', (75, 80))
211901	31709176	Further, Tim-3 blockade reinvigorated antitumor T-cell responses in lung cancer patients who developed adaptive resistance to PD-1 blockade.	('blockade', 'Var', (15, 23))	('lung cancer', 'Disease', (68, 79))	('tumor', 'Disease', (42, 47))	('patients', 'Species', '9606', (80, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('reinvigorated', 'PosReg', (24, 37))	('Tim-3', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Tim-3', 'Gene', '84868', (9, 14))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
211902	31709176	From 2015 onwards, the safety and toxicity of anti-Tim-3 agents such as TSR-022, Sym023, and MBG453 were evaluated in several phase I clinical trials in multiple types of cancer (NCT02817633, NCT03489343, and NCT02608268).	('NCT02817633', 'Chemical', 'MESH:C079985', (179, 190))	('MBG453', 'Gene', (93, 99))	('NCT03489343', 'Chemical', 'MESH:C079985', (192, 203))	('NCT02817633', 'Var', (179, 190))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('toxicity', 'Disease', 'MESH:D064420', (34, 42))	('toxicity', 'Disease', (34, 42))	('Tim-3', 'Gene', (51, 56))	('cancer', 'Disease', (171, 177))	('Tim-3', 'Gene', '84868', (51, 56))	('NCT03489343', 'Var', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
211903	31709176	Recently, the combinatorial blockade of PD-1 and Tim-3 in a phase II clinical in liver cancer and multiple solid tumors was initiated in 2018 (NCT03680508 and NCT03744468).	('liver cancer', 'Disease', 'MESH:D006528', (81, 93))	('Tim-3', 'Gene', (49, 54))	('liver cancer', 'Disease', (81, 93))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('solid tumors', 'Disease', (107, 119))	('Tim-3', 'Gene', '84868', (49, 54))	('NCT03744468', 'Var', (159, 170))	('PD-1', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('liver cancer', 'Phenotype', 'HP:0002896', (81, 93))	('NCT03680508', 'Var', (143, 154))	('solid tumors', 'Disease', 'MESH:D009369', (107, 119))
211904	31709176	Both our data and a lung cancer study found that Tim-3 and TIGIT are preferentially expressed on PD-1+ CD8 TILs in multiple types of cancer, suggesting that combined blockade of these pathways could be effective to treat diverse tumors.	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('Tim-3', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('CD8', 'Gene', '925', (103, 106))	('cancer', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Tim-3', 'Gene', '84868', (49, 54))	('tumors', 'Disease', (229, 235))	('preferentially', 'PosReg', (69, 83))	('lung cancer', 'Disease', (20, 31))	('cancer', 'Disease', (133, 139))	('PD-1+', 'Var', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('CD8', 'Gene', (103, 106))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TIGIT', 'Gene', (59, 64))
211994	31123456	We previously reported that multiple prior chemotherapy regimens may be associated with the development of hyperammonemia due to fluoropyrimidines.	('fluoropyrimidines', 'Chemical', '-', (129, 146))	('hyperammonemia', 'Disease', 'MESH:D022124', (107, 121))	('associated', 'Reg', (72, 82))	('fluoropyrimidines', 'Var', (129, 146))	('men', 'Species', '9606', (60, 63))	('men', 'Species', '9606', (99, 102))	('hyperammonemia', 'Phenotype', 'HP:0001987', (107, 121))	('hyperammonemia', 'Disease', (107, 121))
212008	23835387	For each of the three pre-stent approximations (IF, VA, and DA), the mean lung and liver doses and the estimated percentages of lung volumes receiving 5 Gy, 10 Gy, 20 Gy, and 30 Gy, and heart volumes receiving 40 Gy were significantly lower (p-values ) than those estimated in the post-stent treatment plans.	('VA', 'Chemical', '-', (52, 54))	('heart', 'MPA', (186, 191))	('DA', 'Chemical', '-', (60, 62))	('men', 'Species', '9606', (297, 300))	('10 Gy', 'Var', (157, 162))	('20 Gy', 'Var', (164, 169))	('IF', 'Chemical', '-', (48, 50))	('lower', 'NegReg', (235, 240))
212027	23835387	We hypothesized that because stenting increases the lumenal diameter of the esophagus, stent placement would also increase the PTV, thus leading to an increased dose to OARs.	('increased', 'PosReg', (151, 160))	('increases', 'PosReg', (38, 47))	('PTV', 'Chemical', '-', (127, 130))	('increase', 'PosReg', (114, 122))	('stenting', 'Var', (29, 37))	('men', 'Species', '9606', (98, 101))	('lumenal diameter of the esophagus', 'MPA', (52, 85))	('PTV', 'MPA', (127, 130))	('men', 'Species', '9606', (54, 57))	('dose', 'MPA', (161, 165))	('stent', 'Var', (87, 92))
212047	23835387	The post-stent SupCyl and InfCyl dimensions were altered by this difference in radii to form new esophageal volumes, Eso-VA Superior and Eso-VA Inferior, and to ultimately make a new PTV (PTV-VA).	('Eso-VA', 'Chemical', '-', (137, 143))	('PTV', 'Chemical', '-', (188, 191))	('men', 'Species', '9606', (35, 38))	('altered', 'Reg', (49, 56))	('difference', 'Var', (65, 75))	('Eso-VA', 'Chemical', '-', (117, 123))	('PTV', 'Chemical', '-', (183, 186))	('PTV-VA', 'Chemical', '-', (188, 194))	('make', 'Reg', (172, 176))
212050	23835387	The post-stent SupCyl and InfCyl were then altered by these differences to create new esophageal volumes, Eso-DA Superior and Eso-DA Inferior, and ultimately make a new PTV (PTV-DA).	('PTV', 'Chemical', '-', (174, 177))	('PTV', 'Chemical', '-', (169, 172))	('make', 'Reg', (158, 162))	('PTV-DA', 'Chemical', '-', (174, 180))	('differences', 'Var', (60, 71))	('Eso-DA', 'Chemical', '-', (126, 132))	('esophageal volumes', 'MPA', (86, 104))	('Eso-DA', 'Chemical', '-', (106, 112))
212085	23835387	Though seemingly intuitive that stent placement, which dilates the esophagus, would increase the target dose field, this is the first study that addresses and quantifies the dosimetry differences between pre- and post-stent placement.	('stent', 'Var', (32, 37))	('target dose field', 'MPA', (97, 114))	('increase', 'PosReg', (84, 92))	('men', 'Species', '9606', (229, 232))	('men', 'Species', '9606', (43, 46))
212111	23835387	This 10% increase in heart dose caused by the stent placement may make it more challenging to achieve the V40 dose constraint, thus increasing the risk of death from cardiac causes.	('increasing', 'PosReg', (132, 142))	('stent', 'Var', (46, 51))	('increase', 'PosReg', (9, 17))	('death', 'Disease', 'MESH:D003643', (155, 160))	('heart dose', 'MPA', (21, 31))	('death', 'Disease', (155, 160))	('men', 'Species', '9606', (57, 60))
212154	28893247	TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification.	('overexpression', 'PosReg', (8, 22))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('gene amplification', 'Var', (40, 58))	('caused by', 'Reg', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('TMEM16A', 'Gene', (0, 7))	('tumors', 'Disease', (67, 73))
212155	28893247	TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('controlled', 'Reg', (27, 37))	('epigenetic regulation', 'Var', (91, 112))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('TMEM16A', 'Gene', (0, 7))	('microRNAs', 'Var', (117, 126))
212158	28893247	Furthermore, TMEM16A overexpression has been reported to promote, inhibit, or produce no effects on cell proliferation and migration in different cancer cells.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('overexpression', 'Var', (21, 35))	('promote', 'PosReg', (57, 64))	('rat', 'Species', '10116', (112, 115))	('cell proliferation', 'CPA', (100, 118))	('inhibit', 'NegReg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('TMEM16A', 'Gene', (13, 20))	('rat', 'Species', '10116', (126, 129))
212162	28893247	This review highlights the cell-type specific mechanisms of TMEM16A in cancer, and envisions the promising use of TMEM16A inhibitors as a potential treatment for TMEM16A-overexpressing cancers.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('TMEM16A', 'Gene', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (71, 77))	('inhibitors', 'Var', (122, 132))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('cancer', 'Disease', (185, 191))
212173	28893247	In addition, TMEM16A dysfunction contributes to many diseases such as cancer, hypertension, gastrointestinal motility disorders, and cystic fibrosis.	('gastrointestinal motility disorders', 'Disease', 'MESH:D005767', (92, 127))	('cystic fibrosis', 'Disease', (133, 148))	('gastrointestinal motility disorders', 'Phenotype', 'HP:0030895', (92, 127))	('dysfunction', 'Var', (21, 32))	('hypertension', 'Disease', (78, 90))	('cystic fibrosis', 'Disease', 'MESH:D003550', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('hypertension', 'Phenotype', 'HP:0000822', (78, 90))	('hypertension', 'Disease', 'MESH:D006973', (78, 90))	('TMEM16A', 'Gene', (13, 20))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('gastrointestinal motility disorders', 'Disease', (92, 127))	('contributes', 'Reg', (33, 44))
212183	28893247	Several studies have examined the copy number of TMEM16A in many tumors including breast cancer, HNSCC, and ESCC, and found that gene amplification commonly accounts for TMEM16A overexpression in these cancers (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('HNSCC', 'Disease', (97, 102))	('tumors', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('TMEM16A', 'Gene', (170, 177))	('overexpression', 'PosReg', (178, 192))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('TMEM16A', 'Gene', (49, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('accounts', 'Reg', (157, 165))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('breast cancer', 'Disease', (82, 95))	('examined', 'Reg', (21, 29))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', (202, 209))	('ESCC', 'Disease', (108, 112))	('gene amplification', 'Var', (129, 147))
212184	28893247	To further confirm TMEM16A gene amplification in cancers, we performed bioinformatics analysis to detect TMEM16A gene alterations using the cBioPortal database (cBioPortal for Cancer Genomic).	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('alterations', 'Var', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('TMEM16A', 'Gene', (105, 112))	('Cancer', 'Disease', (176, 182))	('rat', 'Species', '10116', (122, 125))	('Cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
212185	28893247	TMEM16A gene amplification accounts for the most alterations, and more frequently occurs in HNSCC, ESCC, breast cancer, and lung cancer than in other tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('occurs', 'Reg', (82, 88))	('amplification', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('ESCC', 'Disease', (99, 103))	('lung cancer', 'Disease', (124, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('rat', 'Species', '10116', (53, 56))	('HNSCC', 'Disease', (92, 97))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('TMEM16A', 'Gene', (0, 7))	('breast cancer', 'Disease', (105, 118))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('HNSCC', 'Phenotype', 'HP:0012288', (92, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
212186	28893247	Interestingly, many tumors have missense mutations and deletions in the TMEM16A gene.	('missense mutations', 'Var', (32, 50))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('deletions', 'Var', (55, 64))	('TMEM16A', 'Gene', (72, 79))
212187	28893247	A total of 165 missense mutations have been identified in TMEM16A, and the most frequent mutations are R561L/Q/W, R433Q, and R588G/Q (Fig.	('R561L', 'SUBSTITUTION', 'None', (103, 108))	('R433Q', 'Var', (114, 119))	('R588G', 'Var', (125, 130))	('TMEM16A', 'Gene', (58, 65))	('R561L', 'Var', (103, 108))	('R588G', 'SUBSTITUTION', 'None', (125, 130))	('R433Q', 'Mutation', 'rs778999525', (114, 119))
212191	28893247	reported that TMEM16A gene amplification and protein overexpression were associated with distant metastasis in patients with papillomavirus (HPV)-negative HNSCC.	('TMEM16A', 'Gene', (14, 21))	('HNSCC', 'Phenotype', 'HP:0012288', (155, 160))	('overexpression', 'PosReg', (53, 67))	('protein', 'Protein', (45, 52))	('papillomavirus', 'Disease', 'MESH:D030361', (125, 139))	('papillomavirus', 'Disease', (125, 139))	('distant metastasis', 'CPA', (89, 107))	('associated with', 'Reg', (73, 88))	('amplification', 'Var', (27, 40))	('patients', 'Species', '9606', (111, 119))
212193	28893247	found that TMEM16A gene amplification and protein overexpression was associated with lymph node metastasis and advanced clinical stage in patients with ESCC.	('overexpression', 'PosReg', (50, 64))	('protein', 'Protein', (42, 49))	('associated', 'Reg', (69, 79))	('amplification', 'Var', (24, 37))	('lymph node metastasis', 'CPA', (85, 106))	('TMEM16A', 'Gene', (11, 18))	('ESCC', 'Disease', (152, 156))	('patients', 'Species', '9606', (138, 146))
212197	28893247	Although TMEM16A gene amplification is responsible for TMEM16A overexpression in many tumors, it is clearly not the only mechanism for TMEM16A expression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TMEM16A', 'Gene', (55, 62))	('TMEM16A', 'Gene', (9, 16))	('responsible', 'Reg', (39, 50))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('amplification', 'Var', (22, 35))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('overexpression', 'PosReg', (63, 77))
212206	28893247	Here, we summarize the regulatory mechanisms of TMEM16A expression in cancer cells, and TMEM16A expression is controlled via transcriptional regulation, epigenetic regulation, and microRNAs (Fig.	('epigenetic', 'Var', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('TMEM16A', 'Gene', (88, 95))	('controlled', 'Reg', (110, 120))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
212220	28893247	Histone deacetylase (HDAC) plays an important role in epigenetic regulation of gene expression by deacetylating the lysine residues in the histone, and dysregulation of HDACs has been implicated in the pathogenesis of cancer.	('implicated', 'Reg', (184, 194))	('HDAC', 'Gene', '9734', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('HDAC', 'Gene', (169, 173))	('HDAC', 'Gene', '9734', (169, 173))	('lysine', 'Protein', (116, 122))	('Histone deacetylase', 'Gene', '9734', (0, 19))	('lysine', 'Chemical', 'MESH:D008239', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('Histone deacetylase', 'Gene', (0, 19))	('dysregulation', 'Var', (152, 165))	('deacetylating', 'NegReg', (98, 111))	('HDAC', 'Gene', (21, 25))
212231	28893247	As a CaCC, TMME16A overexpression can result in increased channel function, and opening of TMEM16A chloride channel can lead to changes in intracellular Cl- concentration ([Cl-]i) and membrane potential.	('overexpression', 'PosReg', (19, 33))	('increased', 'PosReg', (48, 57))	('lead to changes', 'Reg', (120, 135))	('channel function', 'MPA', (58, 74))	('TMEM16A', 'Gene', (91, 98))	('membrane potential', 'MPA', (184, 202))	('rat', 'Species', '10116', (164, 167))	('CaCC', 'Gene', (5, 9))	('opening', 'Var', (80, 87))	('CaCC', 'Gene', '1179', (5, 9))
212239	28893247	showing that TMEM16A knockdown reduced EGFR phosphorylation and subsequently inhibited AKT, SRC, and ERK activation in breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('phosphorylation', 'MPA', (44, 59))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('reduced', 'NegReg', (31, 38))	('ERK', 'Gene', '5594', (101, 104))	('ERK', 'Gene', (101, 104))	('AKT', 'Gene', (87, 90))	('breast cancer', 'Disease', (119, 132))	('inhibited', 'NegReg', (77, 86))	('SRC', 'Gene', '6714', (92, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('SRC', 'Gene', (92, 95))	('EGFR', 'Gene', '1956', (39, 43))	('TMEM16A', 'Gene', (13, 20))	('EGFR', 'Gene', (39, 43))	('knockdown', 'Var', (21, 30))	('AKT', 'Gene', '207', (87, 90))	('activation', 'MPA', (105, 115))
212240	28893247	Furthermore, they demonstrated that TMEM16A knockdown reduced the autocrine secretion of EGFR ligands, EGF and TGF-alpha in breast cancer cells, suggesting that TMEM16A can activate EGFR signaling by increasing autocrine secretion of EGFR-ligands.	('EGFR', 'Gene', (234, 238))	('TMEM16A', 'Gene', (36, 43))	('EGF', 'Gene', (182, 185))	('autocrine secretion of', 'MPA', (66, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('activate', 'PosReg', (173, 181))	('EGF', 'Gene', (103, 106))	('EGF', 'Gene', '1950', (234, 237))	('TGF-alpha', 'Gene', (111, 120))	('EGFR', 'Gene', '1956', (182, 186))	('autocrine secretion', 'MPA', (211, 230))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('EGF', 'Gene', '1950', (89, 92))	('breast cancer', 'Disease', (124, 137))	('knockdown', 'Var', (44, 53))	('EGFR', 'Gene', '1956', (234, 238))	('EGFR', 'Gene', (89, 93))	('reduced', 'NegReg', (54, 61))	('TMEM16A', 'Var', (161, 168))	('EGF', 'Gene', (234, 237))	('EGF', 'Gene', '1950', (182, 185))	('increasing', 'PosReg', (200, 210))	('EGF', 'Gene', (89, 92))	('EGF', 'Gene', '1950', (103, 106))	('EGFR', 'Gene', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('TGF-alpha', 'Gene', '7039', (111, 120))	('rat', 'Species', '10116', (25, 28))	('EGFR', 'Gene', '1956', (89, 93))
212243	28893247	Furthermore, they found that TMEM16A overexpression increased calcium/CAMKII phosphorylation, indicating that TMEM16A overexpression activates calcium-dependent CAMKII signaling.	('increased', 'PosReg', (52, 61))	('CAMKII', 'Gene', (161, 167))	('CAMKII', 'Gene', (70, 76))	('CAMKII', 'Gene', '818', (161, 167))	('TMEM16A', 'Gene', (29, 36))	('CAMKII', 'Gene', '818', (70, 76))	('activates', 'PosReg', (133, 142))	('calcium', 'Chemical', 'MESH:D002118', (143, 150))	('overexpression', 'Var', (37, 51))	('calcium', 'Chemical', 'MESH:D002118', (62, 69))
212246	28893247	TMEM16A inhibitors reduced ATP-induced increase in [Ca2+]i, suggesting that Cl- transport through TMEM16A channels may be important for Ca2+ release from the Ca2+ store in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Cl-', 'MPA', (76, 79))	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('[Ca2+]i', 'MPA', (51, 58))	('TMEM16A', 'Gene', (98, 105))	('reduced', 'NegReg', (19, 26))	('cancer', 'Disease', (172, 178))	('TMEM16A', 'Gene', (0, 7))	('inhibitors', 'Var', (8, 18))
212250	28893247	However, TMEM16A overexpression did not induced AKT and ERK5 phosphorylation, suggesting that TMEM16A specifically activates the ERK1/2 signaling pathway.	('activates', 'PosReg', (115, 124))	('AKT', 'Gene', (48, 51))	('ERK1/2', 'Gene', '5595;5594', (129, 135))	('TMEM16A', 'Var', (94, 101))	('ERK1/2', 'Gene', (129, 135))	('AKT', 'Gene', '207', (48, 51))	('ERK5', 'Gene', (56, 60))	('ERK5', 'Gene', '5598', (56, 60))
212251	28893247	reported that TMEM16A knockdown decreased the phosphorylation of MEK and ERK1/2 in human colorectal carcinoma cell lines.	('TMEM16A', 'Gene', (14, 21))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (89, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('MEK', 'Gene', (65, 68))	('MEK', 'Gene', '5609', (65, 68))	('human', 'Species', '9606', (83, 88))	('ERK1/2', 'Gene', (73, 79))	('ERK1/2', 'Gene', '5595;5594', (73, 79))	('knockdown', 'Var', (22, 31))	('colorectal carcinoma', 'Disease', (89, 109))	('phosphorylation', 'MPA', (46, 61))	('decreased', 'NegReg', (32, 41))
212253	28893247	In SMMC-7721 human hepatoma cells, TMEM16A knockdown reduced the p38 and ERK1/2 phosphorylation, but not JNK phosphorylation, suggesting that TMEM16A activated the p38 and ERK1/2 signaling pathways.	('p38', 'Gene', (65, 68))	('ERK1/2', 'Gene', '5595;5594', (172, 178))	('human', 'Species', '9606', (13, 18))	('p38', 'Gene', '5594', (164, 167))	('SMMC-7721', 'CellLine', 'CVCL:0534', (3, 12))	('JNK', 'Gene', (105, 108))	('activated', 'PosReg', (150, 159))	('knockdown', 'Var', (43, 52))	('ERK1/2', 'Gene', (73, 79))	('ERK1/2', 'Gene', '5595;5594', (73, 79))	('reduced', 'NegReg', (53, 60))	('p38', 'Gene', '5594', (65, 68))	('hepatoma', 'Disease', (19, 27))	('JNK', 'Gene', '5599', (105, 108))	('hepatoma', 'Disease', 'MESH:D006528', (19, 27))	('p38', 'Gene', (164, 167))	('TMEM16A', 'Gene', (35, 42))	('ERK1/2', 'Gene', (172, 178))
212261	28893247	Since TMEM16A can form a complex with EGFR and activated the EGFR signaling pathway in HNSCC and breast cancer cells, it remains to be determined whether TMEM16A activates NFkappaB signaling via EGFR.	('EGFR', 'Gene', '1956', (38, 42))	('activates', 'PosReg', (162, 171))	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('EGFR', 'Gene', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('TMEM16A', 'Var', (154, 161))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (195, 199))	('activated', 'PosReg', (47, 56))	('complex', 'Interaction', (25, 32))	('NFkappaB', 'Gene', (172, 180))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('NFkappaB', 'Gene', '4790', (172, 180))	('breast cancer', 'Disease', (97, 110))	('TMEM16A', 'Gene', (6, 13))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
212269	28893247	compared the effect of siRNA-knockdown of TMEM16A on proliferation of HNSCC (BHY and CAL33) cells and colonic epithelial (HT29) cells, and found that TMEM16A knockdown suppressed proliferation in HNSCC cells, but not in HT29 cells.	('TMEM16A', 'Gene', (42, 49))	('proliferation', 'CPA', (179, 192))	('HNSCC', 'Phenotype', 'HP:0012288', (196, 201))	('HT29)', 'CellLine', 'CVCL:0320', (122, 127))	('rat', 'Species', '10116', (186, 189))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('suppressed', 'NegReg', (168, 178))	('rat', 'Species', '10116', (60, 63))	('colonic epithelial', 'Disease', (102, 120))	('TMEM16A', 'Gene', (150, 157))	('colonic epithelial', 'Disease', 'MESH:D002277', (102, 120))	('knockdown', 'Var', (158, 167))	('HT29 cells', 'CellLine', 'CVCL:0320', (220, 230))
212272	28893247	Although TMEM16A overexpression does not affect cell migration in HEK293 cells, TMEM16A promotes cell migration and invasion in various tumors such as HNSCC, hepatocellular carcinoma, lung cancer, glioblastoma, gastric cancer, pancreatic ductal adenocarcinoma, glioma, oral squamous cell carcinoma, and CRC (Table 1), as well as in non-tumor cells such as bronchial epithelial cells and Ehrlich Lettre ascites (ELA) cells.	('tumors', 'Disease', (136, 142))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (227, 259))	('glioblastoma', 'Phenotype', 'HP:0012174', (197, 209))	('glioma', 'Phenotype', 'HP:0009733', (261, 267))	('epithelia', 'Disease', (366, 375))	('Ehrlich Lettre ascites', 'Disease', 'MESH:D002286', (387, 409))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('hepatocellular carcinoma', 'Disease', (158, 182))	('tumor', 'Disease', (336, 341))	('pancreatic ductal adenocarcinoma', 'Disease', (227, 259))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('rat', 'Species', '10116', (56, 59))	('Ehrlich Lettre ascites', 'Disease', (387, 409))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (269, 297))	('ascites', 'Phenotype', 'HP:0001541', (402, 409))	('tumor', 'Disease', (136, 141))	('oral squamous cell carcinoma', 'Disease', (269, 297))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (227, 259))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('HNSCC', 'Disease', (151, 156))	('gastric cancer', 'Disease', (211, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (158, 182))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('CRC', 'Phenotype', 'HP:0003003', (303, 306))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (158, 182))	('cell migration', 'CPA', (97, 111))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('glioblastoma', 'Disease', 'MESH:D005909', (197, 209))	('promotes', 'PosReg', (88, 96))	('glioma', 'Disease', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('HNSCC', 'Phenotype', 'HP:0012288', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('rat', 'Species', '10116', (105, 108))	('glioma', 'Disease', 'MESH:D005910', (261, 267))	('ELA', 'Chemical', '-', (411, 414))	('epithelia', 'Disease', 'None', (366, 375))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('HEK293', 'CellLine', 'CVCL:0045', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('lung cancer', 'Disease', (184, 195))	('glioblastoma', 'Disease', (197, 209))	('TMEM16A', 'Var', (80, 87))
212273	28893247	found that TMEM16A knockdown resulted in a change in the migrating direction in ELA cells, whereas TMEM16F knockdown reduced the speed of migration.	('knockdown', 'Var', (107, 116))	('rat', 'Species', '10116', (141, 144))	('reduced', 'NegReg', (117, 124))	('knockdown', 'Var', (19, 28))	('migrating direction in ELA cells', 'CPA', (57, 89))	('rat', 'Species', '10116', (60, 63))	('speed of migration', 'CPA', (129, 147))	('ELA', 'Chemical', '-', (80, 83))	('TMEM16A', 'Gene', (11, 18))	('TMEM16F', 'Gene', (99, 106))	('TMEM16F', 'Gene', '196527', (99, 106))	('change', 'Reg', (43, 49))
212292	28893247	For example, the serine 970 (S970) residue in the C-terminal tail mediates the interaction of TMEM16A with radixin, and is required for the effect of TMEM16A on cell morphology and epithelial-to-mesenchymal transition (EMT).	('S970', 'Var', (29, 33))	('S970', 'CellLine', 'CVCL:7312', (29, 33))	('serine', 'Chemical', 'MESH:D012694', (17, 23))	('interaction', 'Interaction', (79, 90))	('epithelia', 'Disease', 'None', (181, 190))	('epithelia', 'Disease', (181, 190))	('TMEM16A', 'Gene', (94, 101))
212304	28893247	The cell-specific role of TMEM16A has also been demonstrated by Britschgi et al., showing that knockdown of TMEM16A resulted in decreased secretion of EGFR ligands (EGF and TGF-alpha) in breast cancer cells, but not in HNSCC cells.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('TGF-alpha', 'Gene', (173, 182))	('EGFR', 'Gene', '1956', (151, 155))	('EGFR', 'Gene', (151, 155))	('EGF', 'Gene', (151, 154))	('secretion of', 'MPA', (138, 150))	('HNSCC', 'Phenotype', 'HP:0012288', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('knockdown', 'Var', (95, 104))	('decreased', 'NegReg', (128, 137))	('EGF', 'Gene', (165, 168))	('EGF', 'Gene', '1950', (151, 154))	('TGF-alpha', 'Gene', '7039', (173, 182))	('EGF', 'Gene', '1950', (165, 168))	('rat', 'Species', '10116', (55, 58))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('TMEM16A', 'Gene', (108, 115))	('breast cancer', 'Disease', (187, 200))
212306	28893247	Indeed, TMEM16A has been reported to activate EGFR and CAMKII signaling in breast cancer cells, p38 and ERK1/2 signaling in hepatoma cells, Ras-Raf-MEK-ERK1/2 signaling in UM-SCC1 HNSCC cells and T24 bladder cells, and NFkappaB signaling in glioma cells (Table 1), supporting that TMEM16A activates different signaling pathways in a cell type-dependent way.	('EGFR', 'Gene', '1956', (46, 50))	('CAMKII', 'Gene', '818', (55, 61))	('NFkappaB', 'Gene', '4790', (219, 227))	('MEK', 'Gene', '5609', (148, 151))	('glioma', 'Disease', (241, 247))	('activate', 'PosReg', (37, 45))	('UM-SCC1 HNSCC', 'CellLine', 'CVCL:7707', (172, 185))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hepatoma', 'Disease', (124, 132))	('ERK1/2', 'Gene', (104, 110))	('glioma', 'Disease', 'MESH:D005910', (241, 247))	('ERK1/2', 'Gene', '5595;5594', (104, 110))	('ERK1/2', 'Gene', (152, 158))	('NFkappaB', 'Gene', (219, 227))	('Raf', 'Gene', (144, 147))	('MEK', 'Gene', (148, 151))	('ERK1/2', 'Gene', '5595;5594', (152, 158))	('p38', 'Gene', (96, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('TMEM16A', 'Var', (281, 288))	('EGFR', 'Gene', (46, 50))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('TMEM16A', 'Var', (8, 15))	('breast cancer', 'Disease', (75, 88))	('hepatoma', 'Disease', 'MESH:D006528', (124, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (180, 185))	('Raf', 'Gene', '22882', (144, 147))	('CAMKII', 'Gene', (55, 61))	('p38', 'Gene', '5594', (96, 99))
212309	28893247	In support of this idea, there are consistent results in the literature showing that TMEM16A knockdown in cancer cells with 11q13 amplification decreases cell proliferation in vitro and slows tumor growths in xenograft animals, and TMEM16A gene amplification is associated with poor clinical outcome in patients with HNSCC, ESCC, and breast cancer (Table 1).	('cell proliferation', 'CPA', (154, 172))	('ESCC', 'Disease', (324, 328))	('breast cancer', 'Disease', 'MESH:D001943', (334, 347))	('cancer', 'Disease', (106, 112))	('breast cancer', 'Disease', (334, 347))	('cancer', 'Disease', (341, 347))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('HNSCC', 'Disease', (317, 322))	('rat', 'Species', '10116', (166, 169))	('TMEM16A', 'Gene', (232, 239))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('amplification', 'Var', (130, 143))	('tumor', 'Disease', (192, 197))	('HNSCC', 'Phenotype', 'HP:0012288', (317, 322))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('patients', 'Species', '9606', (303, 311))	('decreases', 'NegReg', (144, 153))	('slows', 'NegReg', (186, 191))	('TMEM16A', 'Gene', (85, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (334, 347))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('rat', 'Species', '10116', (65, 68))
212310	28893247	Thus, 11q13 amplification may cause changes in intrinsic cellular environment that favors proliferation-promoting effect of TMEM16A in cancer cells.	('rat', 'Species', '10116', (97, 100))	('TMEM16A', 'Gene', (124, 131))	('changes', 'Reg', (36, 43))	('cancer', 'Disease', (135, 141))	('intrinsic cellular environment', 'MPA', (47, 77))	('proliferation-promoting effect', 'CPA', (90, 120))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('11q13 amplification', 'Var', (6, 25))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('favors', 'PosReg', (83, 89))
212313	28893247	reported that testosterone upregulated TMEM16A expression via the androgen receptor, and TMEM16A knockdown inhibited testosterone-induced proliferation in prostate cancer cells.	('androgen receptor', 'Gene', (66, 83))	('knockdown', 'Var', (97, 106))	('testosterone-induced proliferation', 'CPA', (117, 151))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (155, 170))	('TMEM16A', 'Gene', (39, 46))	('testosterone', 'Chemical', 'MESH:D013739', (14, 26))	('prostate cancer', 'Phenotype', 'HP:0012125', (155, 170))	('rat', 'Species', '10116', (145, 148))	('androgen receptor', 'Gene', '367', (66, 83))	('TMEM16A', 'Gene', (89, 96))	('upregulated', 'PosReg', (27, 38))	('testosterone', 'Chemical', 'MESH:D013739', (117, 129))	('testosterone upregulated', 'Phenotype', 'HP:0030088', (14, 38))	('inhibited', 'NegReg', (107, 116))	('prostate cancer', 'Disease', (155, 170))	('expression', 'MPA', (47, 57))
212315	28893247	found that TMEM16A was overexpressed in HPV-negative HNSCC cells, and TMEM16A overexpression increased cell proliferation in HPV-negative HNSCC cells with hypomethylation of TMEM16A promoter, but not in HPV-positive HNSCC cells with TMEM16A promoter hypermethylation.	('HNSCC', 'Phenotype', 'HP:0012288', (138, 143))	('rat', 'Species', '10116', (115, 118))	('increased', 'PosReg', (93, 102))	('cell proliferation', 'CPA', (103, 121))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('hypomethylation', 'Var', (155, 170))	('TMEM16A', 'Gene', (174, 181))	('HNSCC', 'Phenotype', 'HP:0012288', (216, 221))	('TMEM16A', 'Gene', (70, 77))
212316	28893247	This finding suggests that DNA hypomethylation status may cause changes in cancer cellular environment that favors proliferation-promoting effect of TMEM16A.	('TMEM16A', 'Gene', (149, 156))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('DNA', 'Var', (27, 30))	('changes', 'Reg', (64, 71))	('cancer', 'Disease', (75, 81))	('hypomethylation status', 'Var', (31, 53))	('proliferation-promoting effect', 'CPA', (115, 145))	('rat', 'Species', '10116', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('favors', 'PosReg', (108, 114))
212317	28893247	reported that TMEM16A expression was decreased in metastatic lymph node tissues compared with primary tumors in patients with HNSCC, and epigenetical inhibition of TMEM16A expression via promoter hypermethylation was believed to cause cytoskeletal arrangement, increased cell migration and subsequent metastasis.	('TMEM16A', 'Gene', (14, 21))	('epigenetical inhibition', 'Var', (137, 160))	('cytoskeletal arrangement', 'CPA', (235, 259))	('increased', 'PosReg', (261, 270))	('promoter hypermethylation', 'Var', (187, 212))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cell migration', 'CPA', (271, 285))	('patients', 'Species', '9606', (112, 120))	('primary tumors', 'Disease', (94, 108))	('TMEM16A', 'Gene', (164, 171))	('metastasis', 'CPA', (301, 311))	('HNSCC', 'Phenotype', 'HP:0012288', (126, 131))	('primary tumors', 'Disease', 'MESH:D009369', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('decreased', 'NegReg', (37, 46))	('cause', 'Reg', (229, 234))	('expression', 'MPA', (22, 32))	('rat', 'Species', '10116', (279, 282))
212319	28893247	In summary, TMEM16A overexpression in cancer is caused by multiple mechanisms including 11q13 gene amplification, transcriptional regulation, epigenetic regulation, and miRNAs, which also alter the expression of many other proteins and thus may constitute heterogeneity of TMEM16A-overexpressing cancer cells.	('miRNAs', 'Var', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('proteins', 'Protein', (223, 231))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('TMEM16A', 'Gene', (12, 19))	('11q13', 'Gene', (88, 93))	('alter', 'Reg', (188, 193))	('overexpression', 'PosReg', (20, 34))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('epigenetic regulation', 'MPA', (142, 163))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Disease', (38, 44))	('expression', 'MPA', (198, 208))	('transcriptional regulation', 'MPA', (114, 140))	('cancer', 'Disease', (296, 302))	('caused by', 'Reg', (48, 57))
212321	28893247	The role of TMEM16A overexpression in cancer cell proliferation and migration has been demonstrated by knockdown of TMEM16A via RNAi-mediated silencing and/or overexpression of TMEM16A-expressing vectors in various cancer cell lines.	('silencing', 'Var', (142, 151))	('cancer', 'Disease', (38, 44))	('overexpression', 'PosReg', (159, 173))	('rat', 'Species', '10116', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('rat', 'Species', '10116', (71, 74))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('rat', 'Species', '10116', (57, 60))	('TMEM16A', 'Gene', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('migration', 'CPA', (68, 77))	('knockdown', 'Var', (103, 112))
212323	28893247	Several studies investigated the role of TMEM16A in cancer cell proliferation using TMEM16A specific inhibitors such as CaCCinh-A01 and T16inh-A01, which inhibits TMEM16A currents, and found that pharmacological inhibition of TMEM16A reduced cell proliferation in TMEM16A-overexpressing cancer cells.	('inhibits', 'NegReg', (154, 162))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('reduced', 'NegReg', (234, 241))	('TMEM16A', 'Gene', (163, 170))	('T16', 'CellLine', 'CVCL:N336', (136, 139))	('T16inh-A01', 'Var', (136, 146))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('rat', 'Species', '10116', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('investigated', 'Reg', (16, 28))	('cancer', 'Disease', (52, 58))	('cell proliferation', 'CPA', (242, 260))	('CaCCinh-A01', 'Chemical', 'MESH:C000607369', (120, 131))	('TMEM16A', 'Gene', (226, 233))	('rat', 'Species', '10116', (254, 257))
212327	28893247	For example, CaCCinh-A01 has been found to inhibit CFTR chloride channels in adult mouse trachea, bestrophin-1 chloride channels stably expressed in CHO, and Ca2+-activated K+ channel (KCa3.1) activity in human red blood cells.	('KCa3.1', 'Gene', '16534', (185, 191))	('bestrophin-1', 'Gene', (98, 110))	('KCa3.1', 'Gene', (185, 191))	('mouse', 'Species', '10090', (83, 88))	('CFTR', 'Gene', '12638', (51, 55))	('inhibit', 'NegReg', (43, 50))	('CFTR', 'Gene', (51, 55))	('CaCCinh-A01', 'Var', (13, 24))	('Ca2+-activated', 'Enzyme', (158, 172))	('human', 'Species', '9606', (205, 210))	('bestrophin-1', 'Gene', '24115', (98, 110))	('CaCCinh-A01', 'Chemical', 'MESH:C000607369', (13, 24))
212328	28893247	CaCCinh-A01 and T16inh-A01 has been found to alter intracellular Ca2+ concentrations in pancreatic ductal adenocarcinoma cell lines and in HEK293 cells overexpressing TMEM16A.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('rat', 'Species', '10116', (77, 80))	('intracellular Ca2+ concentrations', 'MPA', (51, 84))	('pancreatic ductal adenocarcinoma', 'Disease', (88, 120))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (88, 120))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (88, 120))	('CaCCinh-A01', 'Chemical', 'MESH:C000607369', (0, 11))	('alter', 'Reg', (45, 50))	('HEK293', 'CellLine', 'CVCL:0045', (139, 145))	('T16', 'CellLine', 'CVCL:N336', (16, 19))	('CaCCinh-A01', 'Var', (0, 11))	('T16inh-A01', 'Var', (16, 26))
212332	28893247	In addition, several TMEM16A inhibitors that reduced TMEM16A currents but did not affect the protein level of TMEM16A did not inhibit proliferation in TMEM16A-dependent cells.	('inhibitors', 'Var', (29, 39))	('reduced', 'NegReg', (45, 52))	('TMEM16A', 'Gene', (53, 60))	('inhibit', 'NegReg', (126, 133))	('TMEM16A', 'Gene', (21, 28))	('rat', 'Species', '10116', (141, 144))
212334	28893247	To exclude the possible effect of TMEM16A protein levels on cell proliferation, some studies have investigated the role of TMEM16A on cancer cell proliferation, by overexpression of TMEM16A mutants with altered channel function.	('rat', 'Species', '10116', (72, 75))	('rat', 'Species', '10116', (153, 156))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mutants', 'Var', (190, 197))	('overexpression', 'PosReg', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('TMEM16A', 'Gene', (182, 189))
212335	28893247	They found that TMEM16A mutations with reduced channel function inhibited cancer cell proliferation induced by wild-type TMEM16A.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('TMEM16A', 'Gene', (16, 23))	('inhibited', 'NegReg', (64, 73))	('cancer', 'Disease', (74, 80))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('rat', 'Species', '10116', (93, 96))
212341	28893247	If it is true that TMEM16A overexpression decreases [Cl-]i, possibly via increased efflux of Cl-, it is possible that TMEM16A overexpression results in activation of the MAPK signaling pathway, which was observed in UM-SCC1 HNSCC cells, T24 bladder cells, and SMMC-7721 human hepatoma cells.	('increased', 'PosReg', (73, 82))	('activation', 'PosReg', (152, 162))	('TMEM16A overexpression', 'Var', (19, 41))	('overexpression', 'Var', (27, 41))	('hepatoma', 'Disease', (276, 284))	('SMMC-7721', 'CellLine', 'CVCL:0534', (260, 269))	('TMEM16A', 'Gene', (118, 125))	('decreases', 'NegReg', (42, 51))	('overexpression', 'PosReg', (126, 140))	('HNSCC', 'Phenotype', 'HP:0012288', (224, 229))	('hepatoma', 'Disease', 'MESH:D006528', (276, 284))	('MAPK signaling pathway', 'Pathway', (170, 192))	('efflux of Cl-', 'MPA', (83, 96))	('UM-SCC1 HNSCC', 'CellLine', 'CVCL:7707', (216, 229))	('human', 'Species', '9606', (270, 275))	('[Cl-]i', 'MPA', (52, 58))
212348	28893247	Gene amplification and protein overexpression of TMEM16A is associated with poor clinical outcomes in patients with HNSCC, especially in patients with HPV-negative HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (164, 169))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (137, 145))	('Gene amplification', 'Var', (0, 18))	('HNSCC', 'Disease', (116, 121))	('HNSCC', 'Phenotype', 'HP:0012288', (116, 121))	('overexpression', 'PosReg', (31, 45))	('TMEM16A', 'Gene', (49, 56))
212354	28893247	has found that TMEM16A inhibition improves responses to EGFR/HER2-targeted therapy in HNSCC cells.	('HNSCC', 'Disease', (86, 91))	('HNSCC', 'Phenotype', 'HP:0012288', (86, 91))	('inhibition', 'Var', (23, 33))	('EGFR', 'Gene', '1956', (56, 60))	('improves', 'PosReg', (34, 42))	('TMEM16A', 'Gene', (15, 22))	('EGFR', 'Gene', (56, 60))	('HER2', 'Gene', (61, 65))	('responses', 'MPA', (43, 52))	('HER2', 'Gene', '2064', (61, 65))
212360	28893247	Gene amplification is a major contributor to TMEM16A overexpression in many cancers (Table 1, Fig.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('overexpression', 'PosReg', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Gene amplification', 'Var', (0, 18))	('TMEM16A', 'Gene', (45, 52))
212361	28893247	TMEM16A gene alterations vary greatly among different tumors (Fig.	('alterations', 'Var', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('rat', 'Species', '10116', (17, 20))	('tumors', 'Disease', (54, 60))	('TMEM16A', 'Gene', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
212379	28893247	In addition, TMEM16A inhibition by T16A-inhA01 and CaCC-inhA01 has been reported to increase responses to EGFR/HER2-targeted therapy in HNSCC cells.	('HER2', 'Gene', (111, 115))	('T16A', 'Mutation', 'rs1211697061', (35, 39))	('HER2', 'Gene', '2064', (111, 115))	('CaCC', 'Gene', '1179', (51, 55))	('CaCC', 'Gene', (51, 55))	('responses', 'MPA', (93, 102))	('T16A-inhA01', 'Var', (35, 46))	('increase', 'PosReg', (84, 92))	('EGFR', 'Gene', '1956', (106, 110))	('TMEM16A', 'Gene', (13, 20))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('inhibition', 'NegReg', (21, 31))	('EGFR', 'Gene', (106, 110))
212447	28081590	Emergency EVL was identified as a risk factor for rebleeding when compared with elective intervention.	('bleeding', 'Disease', (52, 60))	('EVL', 'Chemical', '-', (10, 13))	('bleeding', 'Disease', 'MESH:D006470', (52, 60))	('Emergency EVL', 'Var', (0, 13))
212492	26196135	Patients undergoing MIO also had significantly reduced incidence of pulmonary complications (PCs) (RR=0.73, 95%CI = 0.63-0.86), pulmonary embolism (PE) (OR=0.71, 95%CI= 0.51-0.99) and arrhythmia (OR=0.79, 95%CI = 0.68-0.92).	('PCs', 'Chemical', '-', (93, 96))	('pulmonary complications', 'Phenotype', 'HP:0006532', (68, 91))	('pulmonary embolism', 'Disease', 'MESH:D011655', (128, 146))	('pulmonary complications', 'Disease', (68, 91))	('Patients', 'Species', '9606', (0, 8))	('pulmonary embolism', 'Disease', (128, 146))	('MIO', 'Chemical', '-', (20, 23))	('arrhythmia', 'Disease', 'MESH:D001145', (184, 194))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (128, 146))	('arrhythmia', 'Phenotype', 'HP:0011675', (184, 194))	('pulmonary complications', 'Disease', 'MESH:D008171', (68, 91))	('reduced', 'NegReg', (47, 54))	('MIO', 'Var', (20, 23))	('arrhythmia', 'Disease', (184, 194))
212501	26196135	Instead, previous meta-analyses, relevant studies and even randomized controlled trials of available evidences have suggested a potential advantage of MIO in reducing the incidence of morbidity, rather than in reducing mortality.	('MIO', 'Var', (151, 154))	('reducing', 'NegReg', (158, 166))	('MIO', 'Chemical', '-', (151, 154))
212526	26196135	A consistent result from the subgroup analysis (RR = 0.69, 95% CI: 0.61-0.77) after removing two studies, which might be the source of heterogeneity, demonstrated that MIO intervention was associated with a difference in the occurrence of PCs (Fig 3), with no significant heterogeneity (I2 = 0%, p = 0.501).	('MIO', 'Chemical', '-', (168, 171))	('MIO', 'Var', (168, 171))	('PCs', 'Chemical', '-', (239, 242))	('PCs', 'Disease', (239, 242))
212531	26196135	It can be seen that the MIO group, as shown in Fig 5, showed a significant decrease in the morbidity of arrhythmia (OR = 0.79, 95%CI = 0.68-0.92), with no heterogeneity among different studies (I2 = 14.5%, P = 0.257).	('MIO', 'Var', (24, 27))	('arrhythmia', 'Phenotype', 'HP:0011675', (104, 114))	('decrease', 'NegReg', (75, 83))	('MIO', 'Chemical', '-', (24, 27))	('arrhythmia', 'Disease', 'MESH:D001145', (104, 114))	('arrhythmia', 'Disease', (104, 114))
212546	26196135	The pooled OR 0.69 demonstrated that MIO could significantly reduce the risk of IHM, when compared with OE, which was consistent with the results from other studies.	('MIO', 'Chemical', '-', (37, 40))	('MIO', 'Var', (37, 40))	('IHM', 'Disease', (80, 83))	('reduce', 'NegReg', (61, 67))
212552	26196135	Therefore, theoretically, we hypothesize that MIO can reduce the rate of PCs and thereby reduce the risk of IHM.	('MIO', 'Chemical', '-', (46, 49))	('IHM', 'Disease', (108, 111))	('reduce', 'NegReg', (54, 60))	('PCs', 'Chemical', '-', (73, 76))	('rate', 'MPA', (65, 69))	('PCs', 'Disease', (73, 76))	('MIO', 'Var', (46, 49))	('reduce', 'NegReg', (89, 95))
212565	26196135	In addition, the perforation of minimally invasive surgery per se could decrease the risk factors leading to postoperative cardiac arrhythmia.	('cardiac arrhythmia', 'Disease', 'MESH:D001145', (123, 141))	('cardiac arrhythmia', 'Phenotype', 'HP:0011675', (123, 141))	('postoperative', 'Disease', (109, 122))	('perforation', 'Var', (17, 28))	('decrease', 'NegReg', (72, 80))	('arrhythmia', 'Phenotype', 'HP:0011675', (131, 141))	('cardiac arrhythmia', 'Disease', (123, 141))
212575	26196135	In conclusion, our research has demonstrated that MIO has superiority in decreasing the incidence of in-hospital mortality, which reinforces the idea that this strategy should be considered as a first-line surgical procedure in esophageal surgery.	('MIO', 'Var', (50, 53))	('in-hospital mortality', 'MPA', (101, 122))	('decreasing', 'NegReg', (73, 83))	('MIO', 'Chemical', '-', (50, 53))
212576	26196135	The decrease in in-hospital mortality by MIO was attributed to the reduction in occurrence of PCs, PE and arrhythmia for patients with resectable esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PCs', 'Chemical', '-', (94, 97))	('PCs', 'Disease', (94, 97))	('esophageal cancer', 'Disease', (146, 163))	('arrhythmia', 'Disease', 'MESH:D001145', (106, 116))	('reduction', 'NegReg', (67, 76))	('decrease', 'NegReg', (4, 12))	('arrhythmia', 'Disease', (106, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('arrhythmia', 'Phenotype', 'HP:0011675', (106, 116))	('MIO', 'Chemical', '-', (41, 44))	('MIO', 'Var', (41, 44))	('patients', 'Species', '9606', (121, 129))
212578	24983628	Telomerase Variant A279T Induces Telomere Dysfunction and Inhibits Non-Canonical Telomerase Activity in Esophageal Carcinomas Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers.	('Variant A279T', 'Var', (11, 24))	('Inhibits', 'NegReg', (58, 66))	('hematologic malignancies', 'Disease', (212, 236))	('cancers', 'Disease', 'MESH:D009369', (307, 314))	('Esophageal Carcinomas', 'Disease', 'MESH:D004938', (104, 125))	('Esophageal Carcinomas', 'Phenotype', 'HP:0011459', (104, 125))	('A279T', 'Mutation', 'rs61748181', (19, 24))	('hematologic malignancies', 'Disease', 'MESH:D019337', (212, 236))	('Induces', 'Reg', (25, 32))	('Esophageal Carcinomas', 'Disease', (104, 125))	('human', 'Species', '9606', (301, 306))	('Carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('Telomere Dysfunction', 'MPA', (33, 53))	('A279T', 'Var', (19, 24))	('inflammatory disorders', 'Disease', (185, 207))	('cancers', 'Phenotype', 'HP:0002664', (307, 314))	('Non-Canonical Telomerase Activity', 'MPA', (67, 100))	('cancers', 'Disease', (307, 314))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('inflammatory disorders', 'Disease', 'MESH:D015212', (185, 207))
212579	24983628	The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas.	('mutations', 'Var', (104, 113))	('esophageal carcinomas', 'Disease', (117, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (117, 138))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (117, 137))	('telomerase', 'Protein', (93, 103))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (117, 138))
212582	24983628	Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and beta-catenin, and to assess expression of cytoskeletal proteins, and cell signaling.	('beta-catenin', 'Gene', '1499', (178, 190))	('interactions', 'Interaction', (116, 128))	('variants', 'Var', (154, 162))	('expression', 'MPA', (206, 216))	('BRG-1', 'Gene', '6597', (168, 173))	('beta-catenin', 'Gene', (178, 190))	('TERT variant', 'CellLine', 'CVCL:7204', (149, 161))	('BRG-1', 'Gene', (168, 173))
212583	24983628	Sequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)].	('A1062T', 'Var', (153, 159))	('TERC', 'Gene', '7012', (58, 62))	('[A279T', 'Var', (114, 120))	('A279T', 'Mutation', 'rs61748181', (115, 120))	('A1062T', 'Mutation', 'rs35719940', (153, 159))	('TERT variant', 'CellLine', 'CVCL:7204', (100, 112))	('TERC', 'Gene', (58, 62))	('TERC', 'Gene', (52, 56))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('TERC', 'Gene', '7012', (52, 56))
212584	24983628	The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01).	('A279T', 'Mutation', 'rs61748181', (34, 39))	('patients', 'Species', '9606', (76, 84))	('EsC', 'Disease', (72, 75))	('higher', 'PosReg', (62, 68))	('A279T', 'Var', (34, 39))
212585	24983628	Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-beta-catenin complex, markedly depleted beta-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells.	('decreased telomere length', 'Phenotype', 'HP:0031413', (26, 51))	('cancer', 'Disease', (177, 183))	('tumor', 'Disease', (371, 376))	('depleted', 'NegReg', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('down-regulated', 'NegReg', (135, 149))	('increased', 'PosReg', (315, 324))	('decreased', 'NegReg', (26, 35))	('A279T', 'Mutation', 'rs61748181', (20, 25))	('depletion', 'NegReg', (247, 256))	('destabilized', 'NegReg', (53, 65))	('impaired chemotaxis', 'Phenotype', 'HP:0040238', (294, 313))	('chemotaxis', 'CPA', (303, 313))	('TERT-BRG-1', 'CellLine', 'CVCL:W881', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('A279T', 'Var', (20, 25))	('decreased', 'NegReg', (222, 231))	('beta-catenin', 'Gene', (117, 129))	('canonical Wnt signaling', 'MPA', (150, 173))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('beta-catenin', 'Gene', '1499', (117, 129))	('impaired', 'NegReg', (294, 302))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', '1499', (77, 89))	('telomere', 'MPA', (36, 44))	('decreased', 'NegReg', (361, 370))	('chemosensitivity', 'CPA', (325, 341))
212586	24983628	A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs) following Zeocin  exposure, as well as Li Fraumeni fibroblasts in the absence of pharmacologically-induced DNA damage.	('mouse', 'Species', '10090', (68, 73))	('A279T expression', 'Var', (0, 16))	('Zeocin', 'Chemical', 'MESH:C105427', (113, 119))	('increased', 'PosReg', (31, 40))	('increased chromosomal aberrations', 'Phenotype', 'HP:0040012', (31, 64))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (41, 64))	('MEFs', 'CellLine', 'CVCL:9115', (97, 101))	('A279T', 'Mutation', 'rs61748181', (0, 5))	('chromosomal aberrations', 'CPA', (41, 64))
212587	24983628	A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal cancer cells.	('non-canonical telomerase', 'Enzyme', (48, 72))	('telomere dysfunction', 'MPA', (14, 34))	('activity', 'MPA', (73, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('induces', 'Reg', (6, 13))	('inhibits', 'NegReg', (39, 47))	('A279T', 'Mutation', 'rs61748181', (0, 5))	('A279T', 'Var', (0, 5))	('esophageal cancer', 'Disease', (85, 102))
212588	24983628	These findings warrant further analysis of A279T expression in esophageal cancers and premalignant esophageal lesions.	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('esophageal cancers', 'Disease', (63, 81))	('esophageal cancers', 'Disease', 'MESH:D004938', (63, 81))	('premalignant esophageal lesions', 'Disease', (86, 117))	('A279T', 'Mutation', 'rs61748181', (43, 48))	('premalignant esophageal lesions', 'Disease', 'MESH:D004935', (86, 117))	('A279T', 'Var', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
212595	24983628	The patient underwent esophagectomy with final pathology revealing T3N0M0 (Stage IIB) adenocarcinoma.	('patient', 'Species', '9606', (4, 11))	('adenocarcinoma', 'Disease', (86, 100))	('T3N0M0', 'Var', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('S', 'Chemical', 'MESH:D013455', (75, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (86, 100))
212597	24983628	Subsequent analysis revealed a germ-line deletion in telomerase RNA component (TERC del 341-360); this loss-of-function mutation was also identified in the proband's son, who at 30 years of age exhibited premature aging, mild anemia, and early cirrhosis.	('anemia', 'Phenotype', 'HP:0001903', (226, 232))	('cirrhosis', 'Phenotype', 'HP:0001394', (244, 253))	('deletion', 'Var', (41, 49))	('loss-of-function', 'NegReg', (103, 119))	('cirrhosis', 'Disease', 'MESH:D005355', (244, 253))	('anemia', 'Disease', (226, 232))	('TERC', 'Gene', (79, 83))	('anemia', 'Disease', 'MESH:D000740', (226, 232))	('TERC', 'Gene', '7012', (79, 83))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('cirrhosis', 'Disease', (244, 253))
212598	24983628	The present study was undertaken to examine the frequency and potential clinical relevance of telomerase complex mutations in sporadic esophageal cancers.	('esophageal cancers', 'Disease', (135, 153))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('esophageal cancers', 'Disease', 'MESH:D004938', (135, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
212616	24983628	Mean telomere length in esophageal cancer cells constitutively expressing wtTERT, A279T, or vector control sequences were analyzed by quantitative polymerase chain reaction (qPCR) techniques.	('esophageal cancer', 'Disease', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('A279T', 'Var', (82, 87))	('A279T', 'Mutation', 'rs61748181', (82, 87))
212621	24983628	The only difference between wtTERT and A279T sequences is a single nucleotide (G to A) change, resulting in the substitution of threonine for alanine at codon 279.	('substitution', 'Var', (112, 124))	('threonine', 'MPA', (128, 137))	('A279T', 'Var', (39, 44))	('A279T', 'Mutation', 'rs61748181', (39, 44))	('threonine for alanine at codon 279', 'Mutation', 'rs61748181', (128, 162))
212622	24983628	Empty pcDNA 3.0 vector as well as pcDNA3 vectors expressing wtTERT, A279T TERT, G260D TERT, A1062T TERT, or TERC del 341-360 were provided by Neal Young.	('A279T', 'Var', (68, 73))	('TERC', 'Gene', '7012', (108, 112))	('A1062T', 'Var', (92, 98))	('A279T', 'SUBSTITUTION', 'None', (68, 73))	('G260D TERT', 'Var', (80, 90))	('TERC', 'Gene', (108, 112))	('G260D', 'Mutation', 'rs148798048', (80, 85))	('A1062T', 'SUBSTITUTION', 'None', (92, 98))
212625	24983628	Effects of wtTERT and A279T expression on Wnt, tumor suppressor and stem cell gene expression were analyzed using human Q-PCR arrays (SA Bioscience; Frederick, MD).	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('A279T', 'Mutation', 'rs61748181', (22, 27))	('human', 'Species', '9606', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('A279T', 'Var', (22, 27))	('S', 'Chemical', 'MESH:D013455', (134, 135))	('tumor', 'Disease', (47, 52))
212629	24983628	HeLa cells were transiently transfected with wtTERT, A279T and G260D mutants and immunoprecipitated with anti-TERT (Rocklands), BRG-1 (Millipore) and beta-catenin (Abcam; Cambridge, MA).	('beta-catenin', 'Gene', '1499', (150, 162))	('BRG-1', 'Gene', (128, 133))	('G260D', 'Mutation', 'rs148798048', (63, 68))	('A279T', 'Var', (53, 58))	('G260D', 'Var', (63, 68))	('A279T', 'Mutation', 'rs61748181', (53, 58))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('beta-catenin', 'Gene', (150, 162))	('BRG-1', 'Gene', '6597', (128, 133))
212642	24983628	EsC2- wtTERT and EsC2-A279T cells were trypsinized, washed in HBSS, suspended in sterile PBS at a concentration of 1x106 cells per 100 microL, and inoculated in contralateral flanks of athymic nude mice.	('EsC2', 'Gene', '84901', (0, 4))	('PBS', 'Chemical', 'MESH:D007854', (89, 92))	('HBSS', 'Chemical', '-', (62, 66))	('nude mice', 'Species', '10090', (193, 202))	('A279T', 'SUBSTITUTION', 'None', (22, 27))	('EsC2', 'Gene', (17, 21))	('A279T', 'Var', (22, 27))	('EsC2', 'Gene', '84901', (17, 21))	('EsC2', 'Gene', (0, 4))
212651	24983628	Parental murine MEF-1 cells and human Li Fraumeni cells or respective cells stably transfected with control vectors, wtTERT, or A279T were grown in normal media (DMEM for MEF-1 cells and MEM for Li Fraumeni cells), and metaphases were arrested by overnight incubation with Colcemid prior to harvest.	('murine', 'Species', '10090', (9, 15))	('MEF-1', 'CellLine', 'CVCL:9115', (16, 21))	('DMEM', 'Chemical', '-', (162, 166))	('MEF-1', 'CellLine', 'CVCL:9115', (171, 176))	('A279T', 'Mutation', 'rs61748181', (128, 133))	('A279T', 'Var', (128, 133))	('metaphases', 'CPA', (219, 229))	('human', 'Species', '9606', (32, 37))
212661	24983628	Direct sequencing analysis revealed two non-synonymous TERT variants (A279T and A1062T) among these 54 patients; one homozygous and 4 heterozygous A279T variants were detected, whereas one heterozygous A1062T variant was identified.	('A279T', 'Var', (70, 75))	('A1062T', 'Mutation', 'rs35719940', (80, 86))	('A279T', 'Mutation', 'rs61748181', (70, 75))	('A1062T', 'Var', (80, 86))	('TERT variant', 'CellLine', 'CVCL:7204', (55, 67))	('patients', 'Species', '9606', (103, 111))	('A1062T', 'Mutation', 'rs35719940', (202, 208))	('A279T', 'Mutation', 'rs61748181', (147, 152))
212662	24983628	To confirm and extend these observations, pyrosequencing techniques were used to analyze the frequency of A279T and A1062T in 89 additional esophageal carcinoma specimens.	('esophageal carcinoma', 'Disease', (140, 160))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (140, 160))	('A1062T', 'Var', (116, 122))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (140, 160))	('A1062T', 'Mutation', 'rs35719940', (116, 122))	('A279T', 'Mutation', 'rs61748181', (106, 111))	('A279T', 'Var', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
212664	24983628	Several additional A279T and A1062T variants were detected in these specimens.	('A1062T', 'Var', (29, 35))	('A1062T', 'Mutation', 'rs35719940', (29, 35))	('A279T', 'Var', (19, 24))	('A279T', 'Mutation', 'rs61748181', (19, 24))	('S', 'Chemical', 'MESH:D013455', (0, 1))
212666	24983628	The overall frequencies of A279T and A1062T variants identified in 143 esophageal cancers are summarized in Table 1.	('A279T', 'Var', (27, 32))	('A1062T', 'Var', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('A279T', 'Mutation', 'rs61748181', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('A1062T', 'Mutation', 'rs35719940', (37, 43))	('esophageal cancers', 'Disease', (71, 89))	('esophageal cancers', 'Disease', 'MESH:D004938', (71, 89))
212667	24983628	The minor allele frequency (mAF) of A279T [SNP database rs61748181] in esophageal cancers (~5%) was significantly higher than that previously observed in a large number of healthy adult blood donors (0.9%), or individuals with aplastic anemia, and was comparable to that previously reported for patients with bone marrow failure and dyskeratosis congenita (DC).	('dyskeratosis congenita', 'Disease', (333, 355))	('aplastic anemia', 'Disease', 'MESH:D000741', (227, 242))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('rs61748181', 'Mutation', 'rs61748181', (56, 66))	('aplastic anemia', 'Disease', (227, 242))	('mAF', 'Gene', '17132', (28, 31))	('aplastic anemia', 'Phenotype', 'HP:0001915', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bone marrow failure', 'Disease', 'MESH:D000080983', (309, 328))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('anemia', 'Phenotype', 'HP:0001903', (236, 242))	('mAF', 'Gene', (28, 31))	('esophageal cancers', 'Disease', (71, 89))	('A279T', 'Mutation', 'rs61748181', (36, 41))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (333, 355))	('bone marrow failure', 'Disease', (309, 328))	('bone marrow failure', 'Phenotype', 'HP:0005528', (309, 328))	('higher', 'PosReg', (114, 120))	('esophageal cancers', 'Disease', 'MESH:D004938', (71, 89))	('A279T [', 'Var', (36, 43))	('patients', 'Species', '9606', (295, 303))
212668	24983628	In contrast, the mAF of A1062T in esophageal cancers was not significantly different than that previously observed in healthy blood donors.	('esophageal cancers', 'Disease', (34, 52))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('esophageal cancers', 'Disease', 'MESH:D004938', (34, 52))	('mAF', 'Gene', (17, 20))	('A1062T', 'Var', (24, 30))	('mAF', 'Gene', '17132', (17, 20))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('A1062T', 'Mutation', 'rs35719940', (24, 30))
212669	24983628	The fact that the mAF of A279T in esophageal cancers was approximately five-fold higher than that observed in peripheral blood from healthy donors suggested that this variant might contribute to the pathogenesis of these malignancies.	('malignancies', 'Disease', (221, 233))	('esophageal cancers', 'Disease', (34, 52))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('A279T', 'Mutation', 'rs61748181', (25, 30))	('A279T', 'Var', (25, 30))	('higher', 'PosReg', (81, 87))	('contribute', 'Reg', (181, 191))	('esophageal cancers', 'Disease', 'MESH:D004938', (34, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))	('mAF', 'Gene', (18, 21))	('mAF', 'Gene', '17132', (18, 21))
212670	24983628	As such, a series of experiments were performed to examine if A279T expression modulated the malignant phenotype of esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('A279T', 'Mutation', 'rs61748181', (62, 67))	('A279T expression', 'Var', (62, 78))	('malignant phenotype of', 'CPA', (93, 115))	('modulated', 'Reg', (79, 88))	('esophageal cancer', 'Disease', (116, 133))
212671	24983628	EsC1 and EsC2 cells, which exhibit low level wtTERT and TERC expression (Table S3), were stably transduced with lentiviral vectors encoding A279T or wtTERT, or control sequences.	('S', 'Chemical', 'MESH:D013455', (79, 80))	('TERC', 'Gene', '7012', (56, 60))	('EsC2', 'Gene', (9, 13))	('EsC2', 'Gene', '84901', (9, 13))	('A279T', 'Var', (140, 145))	('TERC', 'Gene', (56, 60))	('A279T', 'Mutation', 'rs61748181', (140, 145))
212672	24983628	MTS assays revealed that EsC1 and EsC2 cells expressing A279T (EsC1-A279T and EsC2-A279T, respectively) grew significantly slower than cells constitutively expressing wtTERT (EsC1-TERT, and EsC2-TERT, respectively), yet faster than vector controls (Figure 1A).	('A279T', 'Var', (56, 61))	('A279T', 'SUBSTITUTION', 'None', (68, 73))	('EsC2', 'Gene', '84901', (34, 38))	('slower', 'NegReg', (123, 129))	('A279T', 'Mutation', 'rs61748181', (83, 88))	('EsC2-TERT', 'CellLine', 'CVCL:2401', (190, 199))	('A279T', 'SUBSTITUTION', 'None', (56, 61))	('A279T', 'Mutation', 'rs61748181', (68, 73))	('EsC2', 'Gene', (34, 38))	('A279T', 'Var', (83, 88))	('EsC1-TERT', 'CellLine', 'CVCL:2401', (175, 184))	('faster', 'PosReg', (220, 226))	('EsC2', 'Gene', '84901', (190, 194))	('S', 'Chemical', 'MESH:D013455', (2, 3))	('EsC2', 'Gene', '84901', (78, 82))	('A279T', 'Var', (68, 73))	('grew', 'CPA', (104, 108))	('A279T', 'Mutation', 'rs61748181', (56, 61))	('EsC2', 'Gene', (190, 194))	('EsC2', 'Gene', (78, 82))	('A279T', 'SUBSTITUTION', 'None', (83, 88))
212674	24983628	In contrast Ki67 levels in EsC1-A279T and ESC2-A279T were modestly but insignificantly higher than those in vector controls, and significantly lower than those observed in respective TERT-over-expressers.	('ESC2', 'Gene', (42, 46))	('lower', 'NegReg', (143, 148))	('Ki67 levels', 'MPA', (12, 23))	('higher', 'PosReg', (87, 93))	('ESC2', 'Gene', '84901', (42, 46))	('A279T', 'Mutation', 'rs61748181', (32, 37))	('A279T', 'Mutation', 'rs61748181', (47, 52))	('EsC1-A279T', 'Var', (27, 37))
212675	24983628	Annexin V experiments demonstrated a significant increase in apoptotic index in EsC1-A279T and EsC2-A279T cells relative to respective cells over-expressing wtTERT (Figure 1C).	('increase', 'PosReg', (49, 57))	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('A279T', 'Mutation', 'rs61748181', (100, 105))	('A279T', 'Var', (100, 105))	('A279T', 'SUBSTITUTION', 'None', (85, 90))	('apoptotic', 'MPA', (61, 70))	('A279T', 'SUBSTITUTION', 'None', (100, 105))	('A279T', 'Var', (85, 90))	('A279T', 'Mutation', 'rs61748181', (85, 90))
212677	24983628	These preliminary findings suggested that the A279T amino acid substitution simultaneously induced apoptosis and senescence, which attenuated the proliferative effects of telomerase over-expression in esophageal cancer cells.	('proliferative', 'MPA', (146, 159))	('A279T', 'Mutation', 'rs61748181', (46, 51))	('attenuated', 'NegReg', (131, 141))	('A279T amino', 'Var', (46, 57))	('apoptosis', 'CPA', (99, 108))	('esophageal cancer', 'Disease', (201, 218))	('senescence', 'CPA', (113, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (201, 218))	('induced', 'PosReg', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
212678	24983628	Additional experiments were performed to examine if A279T expression modulated telomerase catalytic activity and telomere length in esophageal cancer cells.	('telomere length', 'CPA', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('A279T', 'Mutation', 'rs61748181', (52, 57))	('esophageal cancer', 'Disease', (132, 149))	('A279T expression', 'Var', (52, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('telomerase', 'Enzyme', (79, 89))	('modulated', 'Reg', (69, 78))	('catalytic activity', 'MPA', (90, 108))
212679	24983628	In initial experiments, vectors containing A279T or wtTERT were co-transfected with either TERC del 341-360 (TERCdel) or wtTERC into TERT/TERC-deficient VA-13 cells; telomerase catalytic activity was measured in cell lysates.	('TERC', 'Gene', (109, 113))	('TERC', 'Gene', '7012', (138, 142))	('TERC', 'Gene', (123, 127))	('TERC', 'Gene', (91, 95))	('TERC', 'Gene', '7012', (109, 113))	('TERC', 'Gene', '7012', (91, 95))	('TERC', 'Gene', (138, 142))	('A279T', 'Mutation', 'rs61748181', (43, 48))	('TERC', 'Gene', '7012', (123, 127))	('A279T', 'Var', (43, 48))	('TERCdel', 'Chemical', '-', (109, 116))
212681	24983628	In contrast, A279T did not appear to significantly diminish telomerase catalytic activity under these experimental conditions.	('telomerase', 'Enzyme', (60, 70))	('A279T', 'Var', (13, 18))	('diminish', 'NegReg', (51, 59))	('A279T', 'Mutation', 'rs61748181', (13, 18))
212682	24983628	In subsequent experiments, quantitative PCR techniques were used to examine mean telomere lengths in EsC1 and EsC2 cells stably transduced (>1 year) with wtTERT, A279T, or control vectors.	('EsC2', 'Gene', '84901', (110, 114))	('A279T', 'Mutation', 'rs61748181', (162, 167))	('A279T', 'Var', (162, 167))	('telomere lengths', 'CPA', (81, 97))	('EsC2', 'Gene', (110, 114))
212684	24983628	Mean telomere lengths in A279T-transduced EsC cells were significantly shorter than those observed in wtTERT-transduced cells, and were, in fact, similar to those observed in respective vector controls.	('A279T', 'Mutation', 'rs61748181', (25, 30))	('EsC', 'Disease', (42, 45))	('telomere lengths', 'CPA', (5, 21))	('shorter', 'NegReg', (71, 78))	('A279T-transduced', 'Var', (25, 41))
212685	24983628	Immunoblot analysis using an antibody that recognized wtTERT as well as A279T, demonstrated that the differences in mean telomere lengths observed in A279T-relative to wtTERT transduced esophageal cancer cells were not attributable to consistent differences in telomerase protein levels (Figure 2C).	('telomere', 'MPA', (121, 129))	('A279T', 'Mutation', 'rs61748181', (72, 77))	('esophageal cancer', 'Disease', (186, 203))	('A279T-relative', 'Var', (150, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('A279T', 'Mutation', 'rs61748181', (150, 155))
212686	24983628	Additional immunoblot experiments (Figure 2C) demonstrated that relative to EsC1-TERT and EsC2-TERT, or respective vector controls, EsC1-A279T and EsC2-A279T cells exhibited decreased levels of several shelterin proteins including POT1, which binds to single stranded telomeric 3' overhangs, as well as TIN2, which together with TPP1, connects POT1 to TRP1 to regulate telomere length, and prevent telomeres from activating non-homologous end joining (NHEJ) or other DNA double strand break repair pathways.	('POT1', 'Gene', (344, 348))	('POT1', 'Gene', (231, 235))	('EsC2-TERT', 'CellLine', 'CVCL:2401', (90, 99))	('EsC1-TERT', 'CellLine', 'CVCL:2401', (76, 85))	('A279T', 'SUBSTITUTION', 'None', (152, 157))	('non-homologous end joining', 'Pathway', (424, 450))	('TPP1', 'Gene', (329, 333))	('TRP1', 'Gene', (352, 356))	('activating', 'MPA', (413, 423))	('A279T', 'SUBSTITUTION', 'None', (137, 142))	('DNA double strand break repair pathways', 'Pathway', (467, 506))	('decreased', 'NegReg', (174, 183))	('A279T', 'Mutation', 'rs61748181', (152, 157))	('TIN2', 'Gene', '26277', (303, 307))	('regulate telomere length', 'MPA', (360, 384))	('TPP1', 'Gene', '1200', (329, 333))	('TRP1', 'Gene', '7217', (352, 356))	('POT1', 'Gene', '25913', (344, 348))	('A279T', 'Mutation', 'rs61748181', (137, 142))	('POT1', 'Gene', '25913', (231, 235))	('A279T', 'Var', (152, 157))	('TIN2', 'Gene', (303, 307))	('A279T', 'Var', (137, 142))
212687	24983628	Collectively, these results suggest that A279T-TERT disrupts primary as well as secondary/tertiary telomere structure in esophageal cancer cells.	('A279T-TERT', 'Var', (41, 51))	('A279T', 'Mutation', 'rs61748181', (41, 46))	('esophageal cancer', 'Disease', (121, 138))	('primary', 'MPA', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('secondary/tertiary', 'CPA', (80, 98))
212689	24983628	As such, additional studies were undertaken to ascertain if the TERT A279T variant affected non-canonical TERT activity in esophageal cancer cells.	('esophageal cancer', 'Disease', (123, 140))	('A279T', 'Var', (69, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('affected', 'Reg', (83, 91))	('non-canonical TERT activity', 'MPA', (92, 119))	('A279T', 'SUBSTITUTION', 'None', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
212692	24983628	Compared to wtTERT-transfected HeLa (TERT-HeLa) cells, immunoprecipitates from A279T-HeLa cells had much lower levels of BRG-1 and beta-catenin following pull-down with an anti-TERT antibody.	('BRG-1', 'Gene', (121, 126))	('lower', 'NegReg', (105, 110))	('HeLa', 'CellLine', 'CVCL:0030', (31, 35))	('levels', 'MPA', (111, 117))	('beta-catenin', 'Gene', (131, 143))	('A279T', 'SUBSTITUTION', 'None', (79, 84))	('beta-catenin', 'Gene', '1499', (131, 143))	('HeLa', 'CellLine', 'CVCL:0030', (85, 89))	('HeLa', 'CellLine', 'CVCL:0030', (42, 46))	('BRG-1', 'Gene', '6597', (121, 126))	('TERT-HeLa', 'CellLine', 'CVCL:0030', (37, 46))	('A279T', 'Var', (79, 84))
212693	24983628	Similarly, TERT and BRG-1 levels were lower in beta-catenin immunoprecipitates from A279T-HeLa relative to TERT-HeLa cells.	('beta-catenin', 'Gene', '1499', (47, 59))	('lower', 'NegReg', (38, 43))	('A279T', 'SUBSTITUTION', 'None', (84, 89))	('BRG-1', 'Gene', '6597', (20, 25))	('BRG-1', 'Gene', (20, 25))	('A279T', 'Var', (84, 89))	('TERT-HeLa', 'CellLine', 'CVCL:0030', (107, 116))	('beta-catenin', 'Gene', (47, 59))	('S', 'Chemical', 'MESH:D013455', (0, 1))
212694	24983628	Lastly, beta-catenin and TERT levels were lower in BRG-1 immunoprecipitates from A279T-HeLa cells relative to TERT-HeLa cells.	('beta-catenin', 'Gene', (8, 20))	('lower', 'NegReg', (42, 47))	('A279T', 'SUBSTITUTION', 'None', (81, 86))	('TERT-HeLa', 'CellLine', 'CVCL:0030', (110, 119))	('beta-catenin', 'Gene', '1499', (8, 20))	('TERT levels', 'MPA', (25, 36))	('A279T', 'Var', (81, 86))	('BRG-1', 'Gene', '6597', (51, 56))	('BRG-1', 'Gene', (51, 56))
212695	24983628	These results were not observed in HeLa cells transfected with G260D, a TERT variant frequently detected in hematologic malignancies, which is in the same region of TERT where A279T occurs (Figure 2D).	('HeLa', 'CellLine', 'CVCL:0030', (35, 39))	('hematologic malignancies', 'Disease', (108, 132))	('A279T', 'Mutation', 'rs61748181', (176, 181))	('G260D', 'Mutation', 'rs148798048', (63, 68))	('G260D', 'Var', (63, 68))	('TERT variant', 'CellLine', 'CVCL:7204', (72, 84))	('hematologic malignancies', 'Disease', 'MESH:D019337', (108, 132))
212696	24983628	Furthermore, these results were not observed in HeLa cells transfected with A1062T, another TERT variant associated with hematologic disorders (Figure S2).	('A1062T', 'Mutation', 'rs35719940', (76, 82))	('TERT variant', 'CellLine', 'CVCL:7204', (92, 104))	('hematologic disorders', 'Disease', 'MESH:D006402', (121, 142))	('hematologic disorders', 'Disease', (121, 142))	('hematologic disorders', 'Phenotype', 'HP:0001871', (121, 142))	('HeLa', 'CellLine', 'CVCL:0030', (48, 52))	('A1062T', 'Var', (76, 82))	('S', 'Chemical', 'MESH:D013455', (151, 152))
212697	24983628	Consistent with these findings, immunoblot experiments demonstrated markedly decreased beta-catenin levels in EsC1-A279T as well as EsC2-A279T cells relative to respective vector controls, or EsC cells constitutively expressing wtTERT (Figure 2D; lower panel).	('A279T', 'SUBSTITUTION', 'None', (115, 120))	('A279T', 'Mutation', 'rs61748181', (137, 142))	('beta-catenin', 'Gene', (87, 99))	('A279T', 'Mutation', 'rs61748181', (115, 120))	('A279T', 'Var', (115, 120))	('beta-catenin', 'Gene', '1499', (87, 99))	('A279T', 'SUBSTITUTION', 'None', (137, 142))	('decreased', 'NegReg', (77, 86))	('A279T', 'Var', (137, 142))
212698	24983628	Quantitative RT-PCR experiments demonstrated that changes in beta-catenin levels mediated by A279T in these cells did not coincide with consistent alterations in beta-catenin mRNA levels (data not shown).	('beta-catenin', 'Gene', '1499', (61, 73))	('A279T', 'Var', (93, 98))	('beta-catenin', 'Gene', (162, 174))	('A279T', 'Mutation', 'rs61748181', (93, 98))	('beta-catenin', 'Gene', '1499', (162, 174))	('beta-catenin', 'Gene', (61, 73))
212700	24983628	Immunofluorescence analysis demonstrated that MG132 and ALLN attenuated A279T-mediated decreases in beta-catenin levels in EsC1 and EsC2 cells (Figure 2E).	('beta-catenin', 'Gene', (100, 112))	('decreases', 'NegReg', (87, 96))	('EsC2', 'Gene', (132, 136))	('A279T', 'Mutation', 'rs61748181', (72, 77))	('beta-catenin', 'Gene', '1499', (100, 112))	('EsC2', 'Gene', '84901', (132, 136))	('MG132', 'Var', (46, 51))	('MG132', 'Chemical', 'MESH:C072553', (46, 51))	('A279T-mediated', 'Var', (72, 86))	('attenuated', 'NegReg', (61, 71))
212701	24983628	Collectively, these findings suggest that A279T destabilizes the BRG-1-TERT-beta-catenin complex, resulting in depletion of beta-catenin via proteosomal degradation in esophageal cancer cells.	('destabilizes', 'NegReg', (48, 60))	('A279T', 'Mutation', 'rs61748181', (42, 47))	('esophageal cancer', 'Disease', (168, 185))	('A279T', 'Var', (42, 47))	('beta-catenin', 'Gene', (124, 136))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('beta-catenin', 'Gene', (76, 88))	('beta-catenin', 'Gene', '1499', (124, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('BRG-1', 'Gene', '6597', (65, 70))	('beta-catenin', 'Gene', '1499', (76, 88))	('BRG-1', 'Gene', (65, 70))	('proteosomal degradation', 'MPA', (141, 164))
212703	24983628	Therefore, additional experiments were performed to examine if A279T modulated Wnt activity in cancer cells.	('A279T', 'Var', (63, 68))	('Wnt activity', 'CPA', (79, 91))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('modulated', 'Reg', (69, 78))	('A279T', 'Mutation', 'rs61748181', (63, 68))
212704	24983628	Briefly, HeLa cells transiently expressing either control vector, wtTERT, A279T, G260D or A1062T TERT sequences were transfected with either TOP-FLASH or FOP-FLASH promoter reporters.	('FOP-', 'Phenotype', 'HP:0500062', (154, 158))	('G260D', 'Mutation', 'rs148798048', (81, 86))	('HeLa', 'CellLine', 'CVCL:0030', (9, 13))	('G260D', 'Var', (81, 86))	('A279T', 'Mutation', 'rs61748181', (74, 79))	('S', 'Chemical', 'MESH:D013455', (148, 149))	('A1062T', 'SUBSTITUTION', 'None', (90, 96))	('A279T', 'Var', (74, 79))	('S', 'Chemical', 'MESH:D013455', (161, 162))	('A1062T', 'Var', (90, 96))
212707	24983628	Comparable increases in luciferase activities were observed in HeLa cells expressing G260D as well as A1062T telomerase variants.	('increases', 'PosReg', (11, 20))	('G260D', 'Var', (85, 90))	('activities', 'MPA', (35, 45))	('G260D', 'Mutation', 'rs148798048', (85, 90))	('A1062T', 'Var', (102, 108))	('telomerase', 'Enzyme', (109, 119))	('luciferase', 'Enzyme', (24, 34))	('HeLa', 'CellLine', 'CVCL:0030', (63, 67))	('A1062T', 'Mutation', 'rs35719940', (102, 108))
212708	24983628	In contrast, whereas A279T-HeLa cells also exhibited higher TCF promoter activity compared to vector controls, luciferase levels in A279T-HeLa cells were significantly lower than those observed in wtTERT, G260D or A1062T transfectants.	('A279T', 'Var', (21, 26))	('G260D', 'Mutation', 'rs148798048', (205, 210))	('higher', 'PosReg', (53, 59))	('A1062T', 'Var', (214, 220))	('A279T', 'SUBSTITUTION', 'None', (132, 137))	('lower', 'NegReg', (168, 173))	('A1062T', 'Mutation', 'rs35719940', (214, 220))	('A279T', 'Var', (132, 137))	('A279T', 'SUBSTITUTION', 'None', (21, 26))	('TCF', 'Gene', (60, 63))	('TCF', 'Gene', '3172', (60, 63))	('luciferase', 'Enzyme', (111, 121))
212709	24983628	To extend these observations, immunoblot and qRT-PCR array experiments were performed to examine the effects of A279T expression on Wnt signaling and associated pathways in esophageal cells.	('A279T', 'Var', (112, 117))	('Wnt signaling', 'Pathway', (132, 145))	('A279T', 'Mutation', 'rs61748181', (112, 117))
212710	24983628	Immunoblot experiments demonstrated depletion of beta-catenin in nuclear as well as cytoplasmic extracts from EsC1-A279T and to a lesser extent EsC2-A279T cells relative to respective TERT-transduced cells, or vector controls (Figure 3B).	('beta-catenin', 'Gene', (49, 61))	('A279T', 'SUBSTITUTION', 'None', (115, 120))	('A279T', 'SUBSTITUTION', 'None', (149, 154))	('A279T', 'Mutation', 'rs61748181', (115, 120))	('depletion', 'MPA', (36, 45))	('A279T', 'Var', (115, 120))	('A279T', 'Var', (149, 154))	('beta-catenin', 'Gene', '1499', (49, 61))	('A279T', 'Mutation', 'rs61748181', (149, 154))
212711	24983628	Focused qRT-PCR arrays and confirmatory qRT-PCR experiments (Table 2) demonstrated that relative to wtTERT, A279T mediated repression of several Wnt-related genes in EsC1 and/or EsC2 cells including cyclin D1, a well-established target of canonical Wnt signaling.	('EsC2', 'Gene', (178, 182))	('EsC2', 'Gene', '84901', (178, 182))	('A279T', 'Mutation', 'rs61748181', (108, 113))	('A279T', 'Var', (108, 113))	('repression', 'NegReg', (123, 133))	('cyclin D1', 'Gene', '595', (199, 208))	('Wnt-related genes', 'Gene', (145, 162))	('cyclin D1', 'Gene', (199, 208))
212712	24983628	Furthermore, consistent with recent observations that beta-catenin directly regulates TERT expression, endogenous TERT mRNA levels were lower in A279T-EsC1 and A279T-EsC2 cells relative to EsC1 and EsC2 cells over-expressing wtTERT.	('lower', 'NegReg', (136, 141))	('A279T', 'Mutation', 'rs61748181', (160, 165))	('A279T-EsC1', 'Var', (145, 155))	('EsC2', 'Gene', (166, 170))	('endogenous TERT mRNA levels', 'MPA', (103, 130))	('A279T', 'Mutation', 'rs61748181', (145, 150))	('EsC2', 'Gene', (198, 202))	('EsC2', 'Gene', '84901', (166, 170))	('beta-catenin', 'Gene', (54, 66))	('EsC2', 'Gene', '84901', (198, 202))	('beta-catenin', 'Gene', '1499', (54, 66))
212713	24983628	Additional experiments revealed that a variety of mediators of DNA damage response and apoptosis/senescence including BRCA1, BRCA2, p57, caspase 8, TNF, FAS, IL-6 and IL-8 were induced, whereas JunB was repressed in EsC-1 and/or EsC2 cells expressing A279T relative to wtTERT.	('apoptosis/senescence', 'CPA', (87, 107))	('IL-6', 'Gene', (158, 162))	('p57', 'Gene', '1028', (132, 135))	('TNF', 'Gene', '7124', (148, 151))	('A279T', 'Mutation', 'rs61748181', (251, 256))	('S', 'Chemical', 'MESH:D013455', (155, 156))	('IL-8', 'Gene', (167, 171))	('JunB', 'Gene', (194, 198))	('caspase 8', 'Gene', (137, 146))	('JunB', 'Gene', '3726', (194, 198))	('BRCA2', 'Gene', (125, 130))	('A279T', 'Var', (251, 256))	('EsC2', 'Gene', '84901', (229, 233))	('p57', 'Gene', (132, 135))	('IL-8', 'Gene', '3576', (167, 171))	('EsC2', 'Gene', (229, 233))	('TNF', 'Gene', (148, 151))	('BRCA2', 'Gene', '675', (125, 130))	('FAS', 'Gene', (153, 156))	('BRCA1', 'Gene', '672', (118, 123))	('induced', 'PosReg', (177, 184))	('caspase 8', 'Gene', '841', (137, 146))	('BRCA1', 'Gene', (118, 123))	('IL-6', 'Gene', '3569', (158, 162))
212714	24983628	Because telomerase activity, telomere length, and Wnt/beta-catenin signaling appear to modulate chemoresistance in cancer cells, additional experiments were performed to ascertain if A279T affected sensitivity of esophageal cancer cells to cisplatin and paclitaxel, two agents typically used to treat esophageal carcinomas in clinical settings.	('cisplatin', 'Chemical', 'MESH:D002945', (240, 249))	('A279T', 'Var', (183, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (312, 322))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (301, 321))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('affected', 'Reg', (189, 197))	('beta-catenin', 'Gene', (54, 66))	('beta-catenin', 'Gene', '1499', (54, 66))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (301, 322))	('paclitaxel', 'Chemical', 'MESH:D017239', (254, 264))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (301, 322))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('sensitivity', 'MPA', (198, 209))	('esophageal carcinomas', 'Disease', (301, 322))	('chemoresistance', 'CPA', (96, 111))	('cancer', 'Disease', (115, 121))	('modulate', 'Reg', (87, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (213, 230))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('A279T', 'Mutation', 'rs61748181', (183, 188))	('esophageal cancer', 'Disease', (213, 230))
212715	24983628	As shown in Figure 3C, cisplatin as well as paclitaxel mediated dose-dependent cytotoxicity in EsC1 as well as EsC2 cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('EsC2', 'Gene', (111, 115))	('cisplatin', 'Var', (23, 32))	('EsC2', 'Gene', '84901', (111, 115))	('cytotoxicity', 'Disease', (79, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (23, 32))	('paclitaxel', 'Chemical', 'MESH:D017239', (44, 54))
212716	24983628	Relative to cells expressing wtTERT, EsC1-A279T and EsC2-A279T appeared more sensitive to cisplatin and paclitaxel.	('cisplatin', 'MPA', (90, 99))	('A279T', 'Mutation', 'rs61748181', (42, 47))	('A279T', 'Var', (42, 47))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('A279T', 'SUBSTITUTION', 'None', (57, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('sensitive', 'MPA', (77, 86))	('A279T', 'Var', (57, 62))	('A279T', 'Mutation', 'rs61748181', (57, 62))	('A279T', 'SUBSTITUTION', 'None', (42, 47))
212717	24983628	This phenomenon was more impressive in EsC2 cells; A279T abolished TERT-mediated resistance to cisplatin, and significantly diminished TERT-mediated resistance to paclitaxel.	('A279T', 'Mutation', 'rs61748181', (51, 56))	('A279T', 'Var', (51, 56))	('paclitaxel', 'Chemical', 'MESH:D017239', (163, 173))	('TERT-mediated resistance to paclitaxel', 'MPA', (135, 173))	('EsC2', 'Gene', (39, 43))	('TERT-mediated resistance to cisplatin', 'MPA', (67, 104))	('diminished', 'NegReg', (124, 134))	('EsC2', 'Gene', '84901', (39, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('abolished', 'NegReg', (57, 66))
212719	24983628	As such, additional experiments were performed to ascertain if expression of A279T affected cytoskeletal organization in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cytoskeletal organization', 'CPA', (92, 117))	('affected', 'Reg', (83, 91))	('A279T', 'Var', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('A279T', 'Mutation', 'rs61748181', (77, 82))	('cancer', 'Disease', (121, 127))
212720	24983628	Although some variability was noted between lines, immunoblot experiments (Figure 4A) revealed that relative to cells constitutively expressing wtTERT or control vectors, EsC1- and EsC2- A279T cells not only had decreased beta-catenin levels, but also exhibited reduced expression of vinculin, beta-tubulin, F-actin, and CDH1.	('F-actin', 'Protein', (308, 315))	('decreased', 'NegReg', (212, 221))	('beta-catenin', 'Gene', '1499', (222, 234))	('EsC2', 'Gene', '84901', (181, 185))	('CDH1', 'Gene', '999', (321, 325))	('reduced', 'NegReg', (262, 269))	('A279T', 'Mutation', 'rs61748181', (187, 192))	('beta-tubulin', 'Protein', (294, 306))	('vinculin', 'Gene', (284, 292))	('vinculin', 'Gene', '7414', (284, 292))	('beta-catenin', 'Gene', (222, 234))	('EsC1-', 'Var', (171, 176))	('CDH1', 'Gene', (321, 325))	('EsC2', 'Gene', (181, 185))	('expression', 'MPA', (270, 280))
212721	24983628	Because A279T appeared to disrupt cytoskeletal organization, additional studies were undertaken to directly examine if A279T affected cell motility.	('cell motility', 'CPA', (134, 147))	('A279T', 'Var', (8, 13))	('A279T', 'Mutation', 'rs61748181', (8, 13))	('disrupt', 'NegReg', (26, 33))	('cytoskeletal organization', 'CPA', (34, 59))	('A279T', 'Var', (119, 124))	('A279T', 'Mutation', 'rs61748181', (119, 124))
212722	24983628	Briefly, EsC1 and EsC2 cells constitutively expressing control vector, wtTERT, or A279T were placed in chamber slides and time lapse microscopy techniques were used to evaluate chemotaxis in response to mitogen.	('EsC2', 'Gene', '84901', (18, 22))	('A279T', 'Var', (82, 87))	('EsC2', 'Gene', (18, 22))	('A279T', 'Mutation', 'rs61748181', (82, 87))
212723	24983628	EsC1-TERT and EsC2-TERT, as well as respective vector controls exhibited chemotaxis in response to FBS.	('exhibited', 'Reg', (63, 72))	('EsC2-TERT', 'CellLine', 'CVCL:2401', (14, 23))	('FBS', 'Disease', 'MESH:D005198', (99, 102))	('EsC1-TERT', 'CellLine', 'CVCL:2401', (0, 9))	('chemotaxis', 'CPA', (73, 83))	('EsC1-TERT', 'Var', (0, 9))	('FBS', 'Disease', (99, 102))	('EsC2-TERT', 'Var', (14, 23))
212724	24983628	In contrast, chemotaxis was significantly impaired in EsC1-A279T cells, and was completely abolished in EsC2-A279T cells (p<0.05 for A279T vs. wtTERT).	('A279T', 'Mutation', 'rs61748181', (59, 64))	('A279T', 'SUBSTITUTION', 'None', (133, 138))	('A279T', 'SUBSTITUTION', 'None', (109, 114))	('A279T', 'Mutation', 'rs61748181', (133, 138))	('A279T', 'SUBSTITUTION', 'None', (59, 64))	('A279T', 'Var', (133, 138))	('A279T', 'Var', (109, 114))	('chemotaxis', 'CPA', (13, 23))	('A279T', 'Mutation', 'rs61748181', (109, 114))	('abolished', 'NegReg', (91, 100))	('A279T', 'Var', (59, 64))	('impaired', 'NegReg', (42, 50))
212725	24983628	Additional experiments were performed to ascertain if expression of A279T affected tumorigenicity of esophageal cells.	('A279T', 'Var', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('affected', 'Reg', (74, 82))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('A279T', 'Mutation', 'rs61748181', (68, 73))
212726	24983628	Briefly, EsC2 cells constitutively expressing wtTERT or A279T were inoculated subcutaneously into athymic nude mice.	('A279T', 'Mutation', 'rs61748181', (56, 61))	('EsC2', 'Gene', (9, 13))	('A279T', 'Var', (56, 61))	('EsC2', 'Gene', '84901', (9, 13))	('nude mice', 'Species', '10090', (106, 115))
212727	24983628	EsC2-A279T cells exhibited only 60% tumor take compared to 100% for EsC2-TERT cells.	('A279T', 'SUBSTITUTION', 'None', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('A279T', 'Var', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('EsC2-TERT', 'CellLine', 'CVCL:2401', (68, 77))
212728	24983628	Furthermore, volumes and masses of EsC2-A279T xenografts were significantly less than EsC2-TERT tumors (p<0.05).	('EsC2-TERT tumors', 'Disease', (86, 102))	('less', 'NegReg', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('A279T', 'SUBSTITUTION', 'None', (40, 45))	('EsC2-TERT tumors', 'Disease', 'MESH:D009369', (86, 102))	('volumes', 'CPA', (13, 20))	('A279T', 'Var', (40, 45))
212730	24983628	Fluorescence in-situ hybridization (FISH) experiments were performed to examine if the effects of A279T on tumorigenicity coincided with decreased telomere length in esophageal cancer cells.	('S', 'Chemical', 'MESH:D013455', (38, 39))	('telomere length', 'MPA', (147, 162))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('esophageal cancer', 'Disease', (166, 183))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('A279T', 'Mutation', 'rs61748181', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('A279T', 'Var', (98, 103))	('decreased', 'NegReg', (137, 146))	('decreased telomere length', 'Phenotype', 'HP:0031413', (137, 162))
212735	24983628	Whereas EsC2-A279T xenografts also exhibited strong centromeric signals, these cells lacked red telomeric staining, indicative of short telomeres.	('A279T', 'Var', (13, 18))	('lacked', 'NegReg', (85, 91))	('centromeric signals', 'MPA', (52, 71))	('A279T', 'SUBSTITUTION', 'None', (13, 18))	('short telomeres', 'Phenotype', 'HP:0031413', (130, 145))	('red telomeric staining', 'MPA', (92, 114))
212736	24983628	Results of experiments described above strongly suggested that A279T expression inhibits the malignant phenotype of esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('A279T expression', 'Var', (63, 79))	('inhibits', 'NegReg', (80, 88))	('A279T', 'Mutation', 'rs61748181', (63, 68))	('esophageal cancer', 'Disease', (116, 133))
212737	24983628	On the other hand, the fact that the MAF of A279T was significantly higher in esophageal cancer patients relative to healthy blood donors suggested that expression of this telomerase variant predisposes to malignancy.	('MAF', 'Gene', (37, 40))	('predisposes', 'Reg', (191, 202))	('malignancy', 'Disease', 'MESH:D009369', (206, 216))	('malignancy', 'Disease', (206, 216))	('higher', 'PosReg', (68, 74))	('MAF', 'Gene', '17132', (37, 40))	('patients', 'Species', '9606', (96, 104))	('A279T', 'Mutation', 'rs61748181', (44, 49))	('esophageal cancer', 'Disease', (78, 95))	('A279T', 'Var', (44, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
212738	24983628	In order to reconcile these discrepant observations, experiments were undertaken to examine if A279T affected chromosome integrity in normal cells.	('affected', 'Reg', (101, 109))	('chromosome integrity', 'CPA', (110, 130))	('A279T', 'Mutation', 'rs61748181', (95, 100))	('A279T', 'Var', (95, 100))
212739	24983628	In initial experiments, mouse embryonic fibroblasts (MEF) stably transfected with control vectors, wtTERT, or A279T were cultured for 72 h in normal media with or without Zeocin to induce double strand breaks.	('mouse', 'Species', '10090', (24, 29))	('Zeocin', 'Chemical', 'MESH:C105427', (171, 177))	('induce', 'Reg', (181, 187))	('A279T', 'Mutation', 'rs61748181', (110, 115))	('A279T', 'Var', (110, 115))	('MEF', 'CellLine', 'CVCL:9115', (53, 56))
212741	24983628	Structural aberrations included translocations (t), deletions (del), dicentric (d), and multi-centric (m; three or more centromeres) chromosomes, rings, and other chromosome-breakage exchanges.	('rings', 'CPA', (146, 151))	('chromosome-breakage', 'Phenotype', 'HP:0040012', (163, 182))	('multi-centric', 'CPA', (88, 101))	('deletions', 'Var', (52, 61))	('translocations', 'CPA', (32, 46))	('S', 'Chemical', 'MESH:D013455', (0, 1))
212743	24983628	There were more translocation events and more hyper-tetraploid cells (>4 n) in A279T-MEF cells, but the difference between A279T and control MEF cells was not statistically significant, possibly due to the low number of cells analyzed (average of 15 cells per sample), as well as the fact that murine chromosomes have very long telomeres.	('MEF', 'CellLine', 'CVCL:9115', (85, 88))	('A279T', 'Mutation', 'rs61748181', (123, 128))	('A279T', 'Mutation', 'rs61748181', (79, 84))	('hyper-tetraploid', 'Disease', 'MESH:D057891', (46, 62))	('murine', 'Species', '10090', (294, 300))	('MEF', 'CellLine', 'CVCL:9115', (141, 144))	('more', 'PosReg', (41, 45))	('translocation events', 'CPA', (16, 36))	('hyper-tetraploid', 'Disease', (46, 62))	('A279T', 'SUBSTITUTION', 'None', (123, 128))	('A279T', 'SUBSTITUTION', 'None', (79, 84))	('more', 'PosReg', (11, 15))	('A279T', 'Var', (123, 128))	('A279T', 'Var', (79, 84))
212744	24983628	In contrast, A279T-MEFs treated with Zeocin exhibited significantly higher numbers of structural aberrations relative to Zeocin treated parental, vector control, or wtTERT transfected cells (p = 0.000249, p = 0.001, p = 0.0105, respectively); Zeocin-treated A279T- MEFs had approximately twice the number of rings and multi-centric chromosomes, with virtually every chromosome involved in translocations.	('A279T', 'Var', (258, 263))	('A279T', 'Var', (13, 18))	('A279T', 'Mutation', 'rs61748181', (13, 18))	('Zeocin', 'Chemical', 'MESH:C105427', (243, 249))	('MEFs', 'CellLine', 'CVCL:9115', (19, 23))	('A279T', 'Mutation', 'rs61748181', (258, 263))	('A279T', 'SUBSTITUTION', 'None', (13, 18))	('Zeocin', 'Chemical', 'MESH:C105427', (121, 127))	('A279T', 'SUBSTITUTION', 'None', (258, 263))	('MEFs', 'CellLine', 'CVCL:9115', (265, 269))	('Zeocin', 'Chemical', 'MESH:C105427', (37, 43))
212748	24983628	In contrast, Li Fraumeni fibroblasts constitutively expressing A279T exhibited approximately two-fold higher numbers of multicentric chromosomes, with numerous translocations (p<0.01), indicative of genomic instability.	('A279T', 'Var', (63, 68))	('translocations', 'CPA', (160, 174))	('higher', 'PosReg', (102, 108))	('multicentric chromosomes', 'CPA', (120, 144))	('A279T', 'Mutation', 'rs61748181', (63, 68))
212749	24983628	Mutations or sequence variants within telomerase complex genes have been linked to a variety of benign inflammatory conditions such as pulmonary fibrosis and biliary cirrhosis, inherited bone marrow failure syndromes, as well as aging and cancer.	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (135, 153))	('bone marrow failure', 'Phenotype', 'HP:0005528', (187, 206))	('biliary cirrhosis', 'Phenotype', 'HP:0002613', (158, 175))	('pulmonary fibrosis', 'Disease', (135, 153))	('biliary cirrhosis', 'Disease', 'MESH:D008105', (158, 175))	('sequence variants', 'Var', (13, 30))	('linked', 'Reg', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('telomerase', 'Gene', (38, 48))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (239, 245))	('cirrhosis', 'Phenotype', 'HP:0001394', (166, 175))	('bone marrow failure syndromes', 'Disease', (187, 216))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (135, 153))	('bone marrow failure syndromes', 'Disease', 'MESH:D000080983', (187, 216))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('biliary cirrhosis', 'Disease', (158, 175))
212751	24983628	In malignancy, telomere attrition induces telomere recombination and chromosomal rearrangements through breakage/fusion/bridge mechanisms, as well as tetraploidization, resulting in activation of DNA damage response and early crisis.	('early crisis', 'CPA', (220, 232))	('telomere recombination', 'CPA', (42, 64))	('malignancy', 'Disease', (3, 13))	('induces', 'Reg', (34, 41))	('chromosomal rearrangements', 'CPA', (69, 95))	('telomere attrition', 'Var', (15, 33))	('activation', 'PosReg', (182, 192))	('DNA damage', 'MPA', (196, 206))	('malignancy', 'Disease', 'MESH:D009369', (3, 13))
212752	24983628	Inactivation of Rb and p53 tumor suppressor pathways enables preneoplastic cells with telomere dysfunction to emerge from crisis; subsequent activation of TERT by a variety of mechanisms prevents further telomere shortening during late stages of malignant transformation, and in established cancers.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('telomere shortening', 'MPA', (204, 223))	('telomere shortening', 'Phenotype', 'HP:0031413', (204, 223))	('cancers', 'Disease', (291, 298))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('Inactivation', 'Var', (0, 12))	('prevents', 'NegReg', (187, 195))
212755	24983628	In the present study we sought to examine the frequency and potential clinical relevance of telomerase complex mutations in sporadic esophageal carcinomas after identifying a unique germline TERC deletion in a patient with Barrett's adenocarcinoma.	('mutations', 'Var', (111, 120))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (133, 154))	('TERC', 'Gene', '7012', (191, 195))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (133, 153))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (133, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	("Barrett's adenocarcinoma", 'Disease', 'MESH:D001471', (223, 247))	('patient', 'Species', '9606', (210, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	("Barrett's adenocarcinoma", 'Disease', (223, 247))	('esophageal carcinomas', 'Disease', (133, 154))	('TERC', 'Gene', (191, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
212756	24983628	Although we observed no additional TERC mutations, our analysis identified a telomerase variant (A279T) that occurred nearly five-fold more frequently in esophageal cancer patients compared to healthy blood donors; the frequency of A279T variant expression in esophageal cancers exceeds that of recently described ALK mutations in non-small cell lung cancers.	('esophageal cancers', 'Disease', 'MESH:D004938', (260, 278))	('esophageal cancer', 'Disease', 'MESH:D004938', (260, 277))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('cell lung cancers', 'Disease', 'MESH:D008175', (341, 358))	('lung cancers', 'Phenotype', 'HP:0100526', (346, 358))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('cell lung cancers', 'Disease', (341, 358))	('cancers', 'Phenotype', 'HP:0002664', (351, 358))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('ALK', 'Gene', '238', (314, 317))	('patients', 'Species', '9606', (172, 180))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (331, 358))	('esophageal cancer', 'Disease', (154, 171))	('ALK', 'Gene', (314, 317))	('A279T', 'Mutation', 'rs61748181', (97, 102))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (335, 358))	('A279T', 'Mutation', 'rs61748181', (232, 237))	('esophageal cancers', 'Disease', (260, 278))	('TERC', 'Gene', '7012', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('A279T', 'Var', (232, 237))	('TERC', 'Gene', (35, 39))
212757	24983628	The fact that A279T was observed in tumor as well as corresponding normal esophageal mucosa strongly suggests that this was a germline variant; however, because we did not have corresponding peripheral blood samples to analyze, our results cannot exclude the possibility that A279T was a mutation acquired during field cancerization.	('A279T', 'Mutation', 'rs61748181', (14, 19))	('A279T', 'Var', (14, 19))	('A279T', 'Var', (276, 281))	('A279T', 'Mutation', 'rs61748181', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Disease', (319, 325))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('tumor', 'Disease', (36, 41))
212758	24983628	Additional experiments revealed that A279T decreased telomere length and destabilized the BRG1-TERT-beta-catenin complex, depleting beta-catenin in esophageal cancer cells.	('BRG1', 'Gene', (90, 94))	('beta-catenin', 'Gene', (100, 112))	('beta-catenin', 'Gene', '1499', (100, 112))	('BRG1', 'Gene', '6597', (90, 94))	('telomere', 'MPA', (53, 61))	('beta-catenin', 'Gene', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', (148, 165))	('A279T', 'Mutation', 'rs61748181', (37, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('A279T', 'Var', (37, 42))	('depleting', 'NegReg', (122, 131))	('beta-catenin', 'Gene', '1499', (132, 144))	('decreased telomere length', 'Phenotype', 'HP:0031413', (43, 68))	('decreased', 'NegReg', (43, 52))	('destabilized', 'NegReg', (73, 85))
212759	24983628	Relative to wtTERT, A279T mediated growth inhibition and apoptosis/senescence in-vitro, disrupted cytoskeletal integrity, markedly impaired chemotaxis, increased chemosensitivity and significantly reduced tumorigenicity of esophageal cancer cells.	('impaired chemotaxis', 'Phenotype', 'HP:0040238', (131, 150))	('impaired', 'NegReg', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('esophageal cancer', 'Disease', (223, 240))	('disrupted', 'NegReg', (88, 97))	('increased', 'PosReg', (152, 161))	('chemosensitivity', 'CPA', (162, 178))	('reduced', 'NegReg', (197, 204))	('cytoskeletal', 'MPA', (98, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (223, 240))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('chemotaxis', 'CPA', (140, 150))	('A279T', 'Mutation', 'rs61748181', (20, 25))	('growth inhibition', 'CPA', (35, 52))	('A279T', 'Var', (20, 25))
212760	24983628	To the best of our knowledge, these experiments are the first to identify a telomerase variant in a human malignancy that simultaneously disrupts canonical as well as non-canonical telomerase activities.	('activities', 'MPA', (192, 202))	('disrupts', 'NegReg', (137, 145))	('canonical', 'MPA', (146, 155))	('malignancy', 'Disease', (106, 116))	('human', 'Species', '9606', (100, 105))	('variant', 'Var', (87, 94))	('malignancy', 'Disease', 'MESH:D009369', (106, 116))
212763	24983628	In our study we observed that esophageal cancer cells expressing A279T had short telomeres relative to cells constitutively expressing wtTERT; these findings are consistent with observations by Vulliamy et al that leukocytes from individuals with A279T genotype have short telomeres.	('A279T', 'Var', (247, 252))	('esophageal cancer', 'Disease', 'MESH:D004938', (30, 47))	('A279T', 'Mutation', 'rs61748181', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('A279T', 'Mutation', 'rs61748181', (247, 252))	('short telomeres', 'Phenotype', 'HP:0031413', (75, 90))	('short telomeres', 'Phenotype', 'HP:0031413', (267, 282))	('esophageal cancer', 'Disease', (30, 47))	('A279T', 'Var', (65, 70))
212764	24983628	However, our current results have not precisely defined the mechanisms by which A279T induces telomere dysfunction in esophageal carcinomas.	('telomere dysfunction', 'MPA', (94, 114))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (118, 139))	('induces', 'Reg', (86, 93))	('A279T', 'Mutation', 'rs61748181', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('A279T', 'Var', (80, 85))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (118, 139))	('esophageal carcinomas', 'Disease', (118, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (118, 138))
212765	24983628	A279T occurs in a region of TERT that is not essential for in-vitro activity of telomerase, which may explain our inability to observe effects of A279T on telomerase catalytic activity using TRAPeze assays.	('A279T', 'Mutation', 'rs61748181', (0, 5))	('A279T', 'Mutation', 'rs61748181', (146, 151))	('A279T', 'Var', (0, 5))	('A279T', 'Var', (146, 151))
212766	24983628	Conceivably, deficient repeat addition processivity could contribute to inhibition of telomere length in esophageal cancer cells expressing A279T; however, recent studies by Zaug et al using well-established rabbit reticulocyte lysate experiments have demonstrated no effect of this TERT variant on processivity functions of telomerase.	('TERT variant', 'CellLine', 'CVCL:7204', (283, 295))	('rabbit', 'Species', '9986', (208, 214))	('telomere length', 'MPA', (86, 101))	('esophageal cancer', 'Disease', (105, 122))	('deficient repeat addition', 'Disease', 'MESH:D000647', (13, 38))	('deficient repeat addition', 'Disease', (13, 38))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('A279T', 'Var', (140, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('A279T', 'Mutation', 'rs61748181', (140, 145))	('inhibition', 'NegReg', (72, 82))
212767	24983628	Alternatively, A279T may destabilize interactions of TERT with other telomerase complex proteins, and as suggested by our immunoblot experiments, impair chromosomal capping by shelterin proteins.	('A279T', 'Mutation', 'rs61748181', (15, 20))	('A279T', 'Var', (15, 20))	('destabilize', 'NegReg', (25, 36))	('chromosomal capping', 'CPA', (153, 172))	('interactions', 'Interaction', (37, 49))	('impair', 'NegReg', (146, 152))
212768	24983628	Studies are in progress to further characterize the effects of A279T on telomere biology in normal and cancer cells.	('A279T', 'Var', (63, 68))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('A279T', 'Mutation', 'rs61748181', (63, 68))
212771	24983628	For instance, we observed that beta-catenin was markedly depleted in cancer cells expressing A279T, and that A279T attenuated TERT-mediated chemoresistance in esophageal cancer cells.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('depleted', 'NegReg', (57, 65))	('beta-catenin', 'Gene', (31, 43))	('A279T', 'Var', (93, 98))	('cancer', 'Disease', (170, 176))	('beta-catenin', 'Gene', '1499', (31, 43))	('A279T', 'Mutation', 'rs61748181', (93, 98))	('TERT-mediated chemoresistance', 'CPA', (126, 155))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('attenuated', 'NegReg', (115, 125))	('esophageal cancer', 'Disease', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('A279T', 'Var', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('A279T', 'Mutation', 'rs61748181', (109, 114))	('cancer', 'Disease', (69, 75))
212772	24983628	Whereas inhibition of Wnt/beta-catenin signaling has been shown to sensitize oropharyngeal and prostate cancer cells to cisplatin and paclitaxel, respectively, more recent studies suggest that telomere length determines chemosensitivity in cancer cells.	('beta-catenin', 'Gene', '1499', (26, 38))	('prostate cancer', 'Disease', (95, 110))	('prostate cancer', 'Disease', 'MESH:D011471', (95, 110))	('paclitaxel', 'Chemical', 'MESH:D017239', (134, 144))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('prostate cancer', 'Phenotype', 'HP:0012125', (95, 110))	('sensitize', 'Reg', (67, 76))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('oropharyngeal', 'Disease', (77, 90))	('beta-catenin', 'Gene', (26, 38))	('inhibition', 'Var', (8, 18))	('cancer', 'Disease', (240, 246))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
212773	24983628	Collectively, these findings, together with recent observations that telomerase regulates heterochromatin structure within centromeres and transposons via interactions with BRG-1 and nucleostemin, suggest that the effects of A279T expression in cancer cells are pleiotropic and highly complex, and in all likelihood contingent on genetic/epigenetic landscapes.	('heterochromatin structure', 'MPA', (90, 115))	('nucleostemin', 'Gene', '26354', (183, 195))	('BRG-1', 'Gene', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('interactions', 'Interaction', (155, 167))	('cancer', 'Disease', (245, 251))	('A279T', 'Mutation', 'rs61748181', (225, 230))	('A279T', 'Var', (225, 230))	('nucleostemin', 'Gene', (183, 195))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('BRG-1', 'Gene', '6597', (173, 178))
212774	24983628	Current efforts are focused on identification of cancer cell lines endogenously expressing A279T to further examine these issues.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('A279T', 'Var', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('A279T', 'Mutation', 'rs61748181', (91, 96))	('cancer', 'Disease', (49, 55))
212775	24983628	These observations together with our findings that A279T induced senescence, disrupted cytoskeletal integrity and markedly impaired chemotaxis in esophageal cancer cells raise the possibility that esophageal cancers expressing A279T might have low metastatic potential, hence more favorable clinical behavior.	('esophageal cancers', 'Disease', 'MESH:D004938', (197, 215))	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('impaired', 'NegReg', (123, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('low metastatic potential', 'CPA', (244, 268))	('A279T', 'Mutation', 'rs61748181', (227, 232))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('esophageal cancer', 'Disease', (146, 163))	('senescence', 'MPA', (65, 75))	('cytoskeletal integrity', 'CPA', (87, 109))	('A279T', 'Var', (227, 232))	('A279T', 'Mutation', 'rs61748181', (51, 56))	('esophageal cancers', 'Disease', (197, 215))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('disrupted', 'NegReg', (77, 86))	('chemotaxis', 'CPA', (132, 142))	('A279T', 'Var', (51, 56))	('impaired chemotaxis', 'Phenotype', 'HP:0040238', (123, 142))
212776	24983628	Unfortunately, the relatively small sample size and incomplete data regarding stage, response to therapy and survival of the patients whose tissues were used for this study precluded any assessment of the prognostic or predictive significance of A279T expression in esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('esophageal cancers', 'Disease', 'MESH:D004938', (266, 284))	('A279T', 'Var', (246, 251))	('A279T', 'Mutation', 'rs61748181', (246, 251))	('esophageal cancers', 'Disease', (266, 284))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('patients', 'Species', '9606', (125, 133))
212777	24983628	Such analysis using a larger sample size and tissues linked to complete clinical databases should be undertaken if possible to confirm our initial observations, and define the clinical relevance of A279T expression in esophageal carcinomas.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (218, 238))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (218, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (218, 239))	('A279T', 'Var', (198, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (229, 239))	('A279T', 'Mutation', 'rs61748181', (198, 203))	('esophageal carcinomas', 'Disease', (218, 239))	('S', 'Chemical', 'MESH:D013455', (0, 1))
212778	24983628	Telomere shortening correlates with genomic instability and progression to adenocarcinoma in Barrett's esophagus- a chronic condition in which the squamous epithelia in the distal esophagus is replaced by proliferating, intestinal-type columnar epithelial cells in the context of gastro-esophageal reflux.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (93, 112))	('Telomere shortening', 'Phenotype', 'HP:0031413', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous epithelia', 'Disease', (147, 165))	('gastro-esophageal reflux', 'Disease', (280, 304))	('esophageal reflux', 'Phenotype', 'HP:0002020', (287, 304))	('adenocarcinoma', 'Disease', 'MESH:D000230', (75, 89))	('gastro-esophageal reflux', 'Disease', 'MESH:D005764', (280, 304))	("Barrett's esophagus-", 'Disease', (93, 113))	('squamous epithelia', 'Phenotype', 'HP:0002860', (147, 165))	('squamous epithelia', 'Disease', 'MESH:D002294', (147, 165))	('Telomere', 'Var', (0, 8))	('adenocarcinoma', 'Disease', (75, 89))
212779	24983628	These findings suggest that telomere dysfunction occurs early during esophageal carcinogenesis.	('telomere', 'Var', (28, 36))	('esophageal carcinogenesis', 'Disease', (69, 94))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (69, 94))
212780	24983628	In our study we observed that relative to wtTERT, A279T significantly increased chromosomal aberrations in MEFs with wt p53 following exposure to Zeocin; A279T induced chromosomal instability in p53 deficient Li Fraumeni-fibroblasts in the absence of DNA damage; similar chromosomal aberrations have been identified during oncogene-mediated immortalization of human esophageal epithelial cells.	('p53', 'Gene', (195, 198))	('p53', 'Gene', '7157', (195, 198))	('deficient Li Fraumeni', 'Disease', 'MESH:D016864', (199, 220))	('human', 'Species', '9606', (360, 365))	('induced', 'Reg', (160, 167))	('p53', 'Gene', '7157', (120, 123))	('Zeocin', 'Chemical', 'MESH:C105427', (146, 152))	('chromosomal instability', 'Phenotype', 'HP:0040012', (168, 191))	('increased chromosomal aberrations', 'Phenotype', 'HP:0040012', (70, 103))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (271, 294))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (80, 103))	('MEFs', 'CellLine', 'CVCL:9115', (107, 111))	('chromosomal instability', 'MPA', (168, 191))	('A279T', 'Var', (154, 159))	('p53', 'Gene', (120, 123))	('deficient Li Fraumeni', 'Disease', (199, 220))	('A279T', 'Mutation', 'rs61748181', (154, 159))	('A279T', 'Mutation', 'rs61748181', (50, 55))
212781	24983628	As such, our findings provide a potential mechanism (genomic instability) by which A279T could facilitate esophageal carcinogenesis- particularly in the context of p53 mutations, which are frequently observed in esophageal cancers and their precursor lesions.	('esophageal carcinogenesis', 'Disease', (106, 131))	('A279T', 'Var', (83, 88))	('A279T', 'Mutation', 'rs61748181', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('esophageal cancers', 'Disease', (212, 230))	('esophageal cancers', 'Disease', 'MESH:D004938', (212, 230))	('facilitate', 'PosReg', (95, 105))	('p53', 'Gene', (164, 167))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (106, 131))	('mutations', 'Var', (168, 177))	('p53', 'Gene', '7157', (164, 167))
212782	24983628	Consistent with this notion, we have recently detected p53 mutations in 3 of 4 esophageal cancer samples expressing A279T.	('esophageal cancer', 'Disease', (79, 96))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('detected', 'Reg', (46, 54))	('mutations', 'Var', (59, 68))	('A279T', 'Mutation', 'rs61748181', (116, 121))
212783	24983628	Insufficient genomic DNA prevented us from fully evaluating p53 status relative to A279T expression in the remaining tissue samples.	('p53', 'Gene', (60, 63))	('A279T', 'Var', (83, 88))	('A279T', 'Mutation', 'rs61748181', (83, 88))	('p53', 'Gene', '7157', (60, 63))
212786	24983628	These findings suggest that germline mutations involving telomerase complex predispose to esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('predispose', 'Reg', (76, 86))	('esophageal cancers', 'Disease', (90, 108))	('telomerase complex', 'Protein', (57, 75))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('germline mutations', 'Var', (28, 46))	('esophageal cancers', 'Disease', 'MESH:D004938', (90, 108))
212787	24983628	Unfortunately, we were unable to access samples from the Risques study to determine if germline A279T expression correlates with esophageal cancer risk.	('A279T', 'Mutation', 'rs61748181', (96, 101))	('esophageal cancer', 'Disease', (129, 146))	('A279T expression', 'Var', (96, 112))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
212788	24983628	Such studies should be undertaken if possible to ascertain if A279T is a potential biomarker of progression to cancer in patients with Barrett's esophagus.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (135, 154))	('A279T', 'Var', (62, 67))	('A279T', 'Mutation', 'rs61748181', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Barrett', 'Disease', (135, 142))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (121, 129))	('S', 'Chemical', 'MESH:D013455', (0, 1))
212789	24983628	It is counter-intuitive that A279T-mediated perturbations of telomerase appear to be oncogenic in non-transformed cells, yet tumor suppressive in esophageal cancer cells.	('telomerase', 'Protein', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('esophageal cancer', 'Disease', (146, 163))	('perturbations', 'Var', (44, 57))	('tumor', 'Disease', (125, 130))	('A279T', 'Mutation', 'rs61748181', (29, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('A279T-mediated perturbations', 'Var', (29, 57))
212790	24983628	However, these paradoxical observations are consistent with recent studies demonstrating that constitutive telomerase dysfunction inhibits metastatic progression in murine breast and prostate cancer models.	('dysfunction', 'Var', (118, 129))	('metastatic progression', 'CPA', (139, 161))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (172, 198))	('murine', 'Species', '10090', (165, 171))	('prostate cancer', 'Phenotype', 'HP:0012125', (183, 198))	('inhibits', 'NegReg', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
212791	24983628	Because this was not a case control study, it is possible that our analysis over-estimated the apparent enrichment of A279T in esophageal cancer patients.	('patients', 'Species', '9606', (145, 153))	('esophageal cancer', 'Disease', (127, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('A279T', 'Mutation', 'rs61748181', (118, 123))	('A279T', 'Var', (118, 123))
212792	24983628	Indeed, depending on which database is queried, the mAF of A279T ranges from 0.9% in a large pool of healthy adult blood donors (528 individuals) including Caucasians, Blacks, Latinos and Asians, to 2.2% in patients with diverse pathologic conditions including idiopathic pulmonary fibrosis, aplastic anemia, acute myeloid leukemia, and dyskeratosis congenita in the NHLBI Exome Sequencing Project.	('S', 'Chemical', 'MESH:D013455', (379, 380))	('anemia', 'Phenotype', 'HP:0001903', (301, 307))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (261, 290))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (309, 331))	('A279T', 'Mutation', 'rs61748181', (59, 64))	('mAF', 'Gene', '17132', (52, 55))	('idiopathic pulmonary fibrosis', 'Disease', (261, 290))	('dyskeratosis congenita', 'Disease', (337, 359))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (309, 331))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (272, 290))	('leukemia', 'Phenotype', 'HP:0001909', (323, 331))	('mAF', 'Gene', (52, 55))	('A279T', 'Var', (59, 64))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (315, 331))	('patients', 'Species', '9606', (207, 215))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (337, 359))	('aplastic anemia', 'Disease', 'MESH:D000741', (292, 307))	('acute myeloid leukemia', 'Disease', (309, 331))	('aplastic anemia', 'Disease', (292, 307))	('aplastic anemia', 'Phenotype', 'HP:0001915', (292, 307))
212793	24983628	Despite these limitations, our findings that A279T modulates canonical as well as non-canonical telomerase activities highlight the complexity of telomerase expression in normal cellular homeostasis and human diseases.	('human', 'Species', '9606', (203, 208))	('A279T', 'Mutation', 'rs61748181', (45, 50))	('activities', 'MPA', (107, 117))	('A279T', 'Var', (45, 50))	('modulates', 'Reg', (51, 60))	('canonical', 'MPA', (61, 70))
212794	24983628	Whereas the mechanisms underlying our observations have not been fully delineated, our current findings support additional larger, case control studies to define the frequency and clinical significance of A279T expression in esophageal carcinomas and related preneoplastic lesions.	('esophageal carcinomas', 'Disease', 'MESH:D004938', (225, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('A279T', 'Mutation', 'rs61748181', (205, 210))	('carcinomas', 'Phenotype', 'HP:0030731', (236, 246))	('A279T', 'Var', (205, 210))	('esophageal carcinomas', 'Disease', (225, 246))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (225, 245))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (225, 246))
212823	19637343	The were 1,559 patients with histologically confirmed esophageal cancer and stage 1 (T1N0) or 2 (T2N0, T3N0, T1N1, T2N1).	('patients', 'Species', '9606', (15, 23))	('T2N0', 'Var', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('T3N0', 'Var', (103, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('T1N1', 'Var', (109, 113))
212827	19637343	We identified all patients who underwent an esophagectomy within 4 months of the date of diagnosis, using Current Procedural Terminology (CPT) codes (43100, 43101, 43107, 43108, 43112, 43113, 43116-8, 43121-4) and ICD-9 surgery codes (424, 4240-2, 4399).	('43112', 'Var', (178, 183))	('43107', 'Var', (164, 169))	('esophagectomy', 'Disease', (44, 57))	('43108', 'Var', (171, 176))	('patients', 'Species', '9606', (18, 26))	('43100', 'Var', (150, 155))
212876	19637343	In a SEER analysis by Greenstein et al., black race was associated with a nonsignificant increased risk of death from any cause; however, more than 50% of the patients did not receive either surgery or radiation.	('death', 'Disease', (107, 112))	('patients', 'Species', '9606', (159, 167))	('black race', 'Var', (41, 51))	('death', 'Disease', 'MESH:D003643', (107, 112))
212889	33362384	AI technology will eventually enhance human capability, provide machines genuine autonomy, and reduce errors, and increase productivity and efficiency.	('increase', 'PosReg', (114, 122))	('human', 'Species', '9606', (38, 43))	('reduce', 'NegReg', (95, 101))	('human capability', 'CPA', (38, 54))	('errors', 'MPA', (102, 108))	('AI technology', 'Var', (0, 13))	('enhance', 'PosReg', (30, 37))	('productivity', 'CPA', (123, 135))
212990	32449599	Furthermore, xylogranatin C might induce Eca109 cell apoptosis through joint effects on multiple pathways, including the death receptor and endoplasmic reticulum pathways.	('induce', 'PosReg', (34, 40))	('Eca109 cell apoptosis', 'CPA', (41, 62))	('xylogranatin C', 'Chemical', 'MESH:C516645', (13, 27))	('effects', 'Reg', (77, 84))	('death', 'Disease', 'MESH:D003643', (121, 126))	('death', 'Disease', (121, 126))	('endoplasmic reticulum pathways', 'Pathway', (140, 170))	('xylogranatin C', 'Var', (13, 27))
213037	32449599	9  conducted a study where they isolated and purified compound C22 from the Sea Moth, and this compound displayed activity against human cervical cancer Hela cells.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('activity', 'MPA', (114, 122))	('human', 'Species', '9606', (131, 136))	('Hela cells', 'CellLine', 'CVCL:0030', (153, 163))	('C22', 'Chemical', '-', (63, 66))	('C22', 'Var', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
213039	32449599	10  investigated the R50 compound of Polygonum chinensis, and found that R50 decreased the survival rate of human colorectal cancer HCT16 and HT29 cells, and did so in a mechanism that induced human colorectal cancer HCT16 and HT29 cell apoptosis via the glutathione dependent signaling pathway.	('induced', 'PosReg', (185, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('colorectal cancer', 'Disease', 'MESH:D015179', (199, 216))	('colorectal cancer', 'Disease', (114, 131))	('HT29 cell', 'CellLine', 'CVCL:0320', (142, 151))	('human', 'Species', '9606', (193, 198))	('HCT16', 'CellLine', 'CVCL:M747', (132, 137))	('glutathione', 'Chemical', 'MESH:D005978', (255, 266))	('colorectal cancer', 'Disease', (199, 216))	('HCT16', 'CellLine', 'CVCL:M747', (217, 222))	('survival rate', 'CPA', (91, 104))	('HT29 cell apoptosis', 'CPA', (227, 246))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('HT29 cells', 'CellLine', 'CVCL:0320', (142, 152))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('glutathione dependent signaling pathway', 'Pathway', (255, 294))	('decreased', 'NegReg', (77, 86))	('HT29 cell', 'CellLine', 'CVCL:0320', (227, 236))	('colorectal cancer', 'Phenotype', 'HP:0003003', (199, 216))	('R50', 'Var', (73, 76))	('human', 'Species', '9606', (108, 113))
213045	32449599	14  Caspase family inhibitors can increase the inhibitory effect of xylogranatin C on the proliferation of Eca109 cells in human EC, and such studies verify that xylogranatin C disrupts the proliferation of antitumor cells by inducing tumor cell apoptosis.	('Caspase', 'Gene', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('proliferation', 'CPA', (90, 103))	('xylogranatin C', 'Var', (162, 176))	('xylogranatin C', 'Chemical', 'MESH:C516645', (68, 82))	('human', 'Species', '9606', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('Caspase', 'Gene', '839', (4, 11))	('tumor', 'Disease', (235, 240))	('inhibitory effect', 'MPA', (47, 64))	('proliferation', 'CPA', (190, 203))	('tumor', 'Disease', (211, 216))	('xylogranatin C', 'Chemical', 'MESH:C516645', (162, 176))	('increase', 'PosReg', (34, 42))	('inducing', 'PosReg', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('disrupts', 'NegReg', (177, 185))
213054	32449599	It is speculated that xylogranatin C might induce tumor cell apoptosis via the endogenous apoptosis pathway and the endoplasmic reticulum pathway.	('endogenous apoptosis pathway', 'Pathway', (79, 107))	('xylogranatin C', 'Chemical', 'MESH:C516645', (22, 36))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('induce', 'PosReg', (43, 49))	('xylogranatin', 'Var', (22, 34))
213092	31814116	For example, alcohol use increases circulating sex hormone levels, and this contributes to excess breast cancer risk.13 In addition, acetaldehyde, a metabolite of ethanol classified as a group 1 carcinogen by the International Agency for Research on Cancer, stimulates cell proliferation and induces DNA damage.6, 7, 8, 9, 10, 13, 14 The Japanese have a higher prevalence of polymorphisms in the aldehyde dehydrogenase 2 (ALDH2) enzyme, which makes them slower at metabolizing acetaldehyde.9, 14 Previous studies have indeed suggested an elevated cancer risk from alcohol consumption in the urinary tract and prostate in Japan, which has not been found in Western countries.9, 10, 15, 16, 17, 18, 19 We have hypothesized that there may be an elevated cancer risk at even light to moderate levels of alcohol consumption in Japan due to a higher prevalence of ALDH2 polymorphisms in the Japanese.	('elevated cancer', 'Disease', (742, 757))	('Cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('aldehyde dehydrogenase 2', 'Gene', '217', (396, 420))	('excess breast', 'Phenotype', 'HP:0010313', (91, 104))	('alcohol', 'Chemical', 'MESH:D000438', (13, 20))	('elevated cancer', 'Disease', 'MESH:D009369', (742, 757))	('alcohol', 'Chemical', 'MESH:D000438', (799, 806))	('ALDH2', 'Gene', (422, 427))	('excess breast cancer', 'Disease', 'MESH:D001943', (91, 111))	('ALDH2', 'Gene', (858, 863))	('alcohol use', 'Phenotype', 'HP:0030955', (13, 24))	('aldehyde dehydrogenase 2', 'Gene', (396, 420))	('polymorphisms', 'Var', (864, 877))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('ethanol', 'Chemical', 'MESH:D000431', (163, 170))	('elevated cancer', 'Disease', (538, 553))	('cancer', 'Phenotype', 'HP:0002664', (547, 553))	('higher', 'PosReg', (837, 843))	('cancer', 'Phenotype', 'HP:0002664', (751, 757))	('excess breast cancer', 'Disease', (91, 111))	('ALDH2', 'Gene', '217', (422, 427))	('ALDH2', 'Gene', '217', (858, 863))	('elevated cancer', 'Disease', 'MESH:D009369', (538, 553))	('alcohol', 'Chemical', 'MESH:D000438', (564, 571))
213112	31814116	In addition, we categorized patients into 6 categories by their drink-year levels (0 [lifetime abstainer], >0-20, >20-40, >40-60, >60-90, and >90 drink-years).	('>0-20', 'Var', (107, 112))	('>20-40', 'Var', (114, 120))	('patients', 'Species', '9606', (28, 36))	('>40-60', 'Var', (122, 128))
213235	27310399	The first flatus time, first defecation time, bowel tone recovery time after the operation, and total amount of the gastric juice draining were significantly less in the thoraco-laparoscopic esophagectomy group compared with the routine McKeown operation group (Table 4) (P<0.05, P<0.01).	('first flatus time', 'MPA', (4, 21))	('thoraco-laparoscopic', 'Var', (170, 190))	('bowel', 'Disease', 'MESH:D015212', (46, 51))	('laparoscopic esophagectomy', 'Phenotype', 'HP:0100628', (178, 204))	('first defecation time', 'MPA', (23, 44))	('less', 'NegReg', (158, 162))	('bowel', 'Disease', (46, 51))
213260	27310399	In contrast, VIP relaxes the gastrointestinal smooth muscle, inhibits the secretion of gastric acid and pepsin, and inhibits gastrointestinal motility.	('gastrointestinal motility', 'Disease', (125, 150))	('VIP', 'Var', (13, 16))	('inhibits', 'NegReg', (61, 69))	('gastrointestinal motility', 'Disease', 'MESH:D015835', (125, 150))	('inhibits', 'NegReg', (116, 124))	('gastrointestinal smooth muscle', 'MPA', (29, 59))
213363	25891471	In accordance, the presence of a new malignancy was associated with a high risk of death within the first year after discharge (hazard ration 4.60) in a single-center study conducted in Australia comprising almost 20,000 ICU patients who survived to discharge.	('patients', 'Species', '9606', (225, 233))	('presence', 'Var', (19, 27))	('death', 'Disease', 'MESH:D003643', (83, 88))	('malignancy', 'Disease', 'MESH:D009369', (37, 47))	('death', 'Disease', (83, 88))	('malignancy', 'Disease', (37, 47))
213396	26090365	In this respect, the use of 18F-FDG PET in lymphoma can be considered as an "almost perfect world" as far as quantitative approaches are clinically relevant for assessing therapy response in lymphoma.	('lymphoma', 'Disease', 'MESH:D008223', (191, 199))	('lymphoma', 'Phenotype', 'HP:0002665', (191, 199))	('lymphoma', 'Disease', 'MESH:D008223', (43, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (43, 51))	('18F-FDG', 'Chemical', 'MESH:D019788', (28, 35))	('lymphoma', 'Disease', (191, 199))	('18F-FDG PET', 'Var', (28, 39))	('lymphoma', 'Disease', (43, 51))
213492	26090365	This study confirmed that 18F-FDG PET can be used as an accurate guide for biopsies in suspected transformed tissues: a SUVmax < 11.7 was always associated with indolent lymphoma, whereas a SUVmax > 17 was always associated with histological transformation.	('18F-FDG', 'Chemical', 'MESH:D019788', (26, 33))	('associated', 'Reg', (213, 223))	('SUVmax', 'Var', (120, 126))	('lymphoma', 'Disease', (170, 178))	('associated with', 'Reg', (145, 160))	('lymphoma', 'Disease', 'MESH:D008223', (170, 178))	('lymphoma', 'Phenotype', 'HP:0002665', (170, 178))
213635	23696716	According to the National Comprehensive Cancer Network guidelines, cisplatin is categorized as having a high risk of emesis, whereas nedaplatin is reported to have a moderate emetic risk in the clinical practice guidelines of the Japan Society of Clinical Oncology.	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('nedaplatin', 'Chemical', 'MESH:C053989', (133, 143))	('cisplatin', 'Var', (67, 76))	('Cancer', 'Disease', (40, 46))	('Cancer', 'Disease', 'MESH:D009369', (40, 46))	('Oncology', 'Phenotype', 'HP:0002664', (256, 264))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('emesis', 'Phenotype', 'HP:0002013', (117, 123))	('emesis', 'Disease', 'MESH:D014839', (117, 123))	('emesis', 'Disease', (117, 123))
213651	23696716	Further, deregulation of the genes encoding cytokeratins 14 and 19 reflects the characteristic renal papillary injury associated with nedaplatin.	('nedaplatin', 'Chemical', 'MESH:C053989', (134, 144))	('deregulation', 'Var', (9, 21))	('renal papillary injury', 'Disease', 'MESH:D007681', (95, 117))	('renal papillary injury', 'Disease', (95, 117))
213688	23696716	In patients with advanced NSCLC and high expression of epidermal growth factor receptor, cetuximab in combination with cisplatin-vinorelbine chemotherapy prolonged overall survival.	('high expression', 'Var', (36, 51))	('prolonged', 'PosReg', (154, 163))	('epidermal growth factor receptor', 'Gene', (55, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('vinorelbine', 'Chemical', 'MESH:D000077235', (129, 140))	('patients', 'Species', '9606', (3, 11))	('cetuximab', 'Chemical', 'MESH:D000068818', (89, 98))	('NSCLC', 'Disease', (26, 31))	('overall survival', 'MPA', (164, 180))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
213730	23696716	Gimeracil also has a radiosensitizing effect by inhibiting the repair of double-stranded DNA breaks.	('Gimeracil', 'Var', (0, 9))	('radiosensitizing', 'MPA', (21, 37))	('inhibiting', 'NegReg', (48, 58))	('Gimeracil', 'Chemical', 'MESH:C104201', (0, 9))	('repair of double-stranded DNA breaks', 'MPA', (63, 99))
213761	21455992	A higher risk of RE and EAC was also reported for patients in the highest quartile of saturated fat intake (OR=2.79; 95%CI=1.11-7.04; OR=2.41; 95%CI=1.14-5.08, respectively) and monounsaturated fat intake (OR=2.63; 95%CI=1.01-6.86; OR=5.35; 95%CI=2.14-13.34, respectively).	('EAC', 'Gene', (24, 27))	('monounsaturated fat', 'Chemical', '-', (178, 197))	('saturated fat', 'Chemical', '-', (86, 99))	('patients', 'Species', '9606', (50, 58))	('saturated fat', 'Chemical', '-', (184, 197))	('EAC', 'Phenotype', 'HP:0011459', (24, 27))	('monounsaturated', 'Var', (178, 193))	('EAC', 'Gene', '1540', (24, 27))
213807	21455992	EAC patients - saturated fat and monounsaturated fat, r = 0.58; saturated fat and polyunsaturated fat, r = -0.30; monounsaturated fat and polyunsaturated fat, r = 0.26; all P <0.01.	('monounsaturated', 'Var', (114, 129))	('polyunsaturated fat', 'Chemical', '-', (138, 157))	('monounsaturated fat', 'Chemical', '-', (33, 52))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('saturated fat', 'Chemical', '-', (15, 28))	('saturated fat', 'Chemical', '-', (88, 101))	('polyunsaturated fat', 'Chemical', '-', (82, 101))	('saturated fat', 'Chemical', '-', (64, 77))	('saturated fat', 'Chemical', '-', (39, 52))	('patients', 'Species', '9606', (4, 12))	('saturated fat', 'Chemical', '-', (120, 133))	('monounsaturated fat', 'Chemical', '-', (114, 133))	('EAC', 'Gene', '1540', (0, 3))	('saturated fat', 'Chemical', '-', (144, 157))	('EAC', 'Gene', (0, 3))
213811	21455992	A higher risk of RE and EAC was also reported for patients in the highest quartile of saturated fat intake (OR = 2.79; 95%CI = 1.11-7.04; P for trend = 0.07; OR = 2.41; 95%CI = 1.14-5.08; P for trend = 0.01, respectively) and monounsaturated fat intake (OR = 2.63; 95%CI = 1.01-6.86; P for trend = 0.10; OR = 5.35; 95%CI = 2.14-13.34; P for trend <0.01, respectively).	('EAC', 'Gene', (24, 27))	('saturated fat', 'Chemical', '-', (86, 99))	('patients', 'Species', '9606', (50, 58))	('monounsaturated fat', 'Chemical', '-', (226, 245))	('EAC', 'Phenotype', 'HP:0011459', (24, 27))	('saturated fat', 'Chemical', '-', (232, 245))	('monounsaturated fat', 'Var', (226, 245))	('EAC', 'Gene', '1540', (24, 27))
213812	21455992	Patients in the third quartile of polyunsaturated fat intake had a higher risk of EAC (OR = 2.68; 95%CI = 1.23-5.85), but no further increase in risk, or main effect of intake on risk, was observed beyond this quartile (P for trend = 0.30).	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('EAC', 'Gene', '1540', (82, 85))	('Patients', 'Species', '9606', (0, 8))	('EAC', 'Gene', (82, 85))	('polyunsaturated fat', 'Chemical', '-', (34, 53))	('polyunsaturated fat', 'Var', (34, 53))
213827	21455992	Our data suggested that total fat, saturated fat, and monounsaturated fat intakes were adversely associated with the risk of RE and EAC.	('monounsaturated fat', 'Chemical', '-', (54, 73))	('EAC', 'Gene', '1540', (132, 135))	('EAC', 'Gene', (132, 135))	('saturated fat', 'Chemical', '-', (35, 48))	('monounsaturated fat', 'Var', (54, 73))	('saturated fat', 'Chemical', '-', (60, 73))	('associated', 'Reg', (97, 107))	('EAC', 'Phenotype', 'HP:0011459', (132, 135))
213829	21455992	polyunsaturated fat) were not associated with RE or BE, but there was a suggestion of an adverse association with EAC risk.	('BE', 'Phenotype', 'HP:0100580', (52, 54))	('EAC', 'Gene', (114, 117))	('polyunsaturated fat', 'Var', (0, 19))	('EAC', 'Phenotype', 'HP:0011459', (114, 117))	('polyunsaturated fat', 'Chemical', '-', (0, 19))	('EAC', 'Gene', '1540', (114, 117))
213832	21455992	The results presented in this current study with regards to BE are in agreement with those from a recent case-control study; both studies did not find consistent associations between fat intakes or cholesterol with BE risk, although did report non-significant inverse trends for polyunsaturated fat, which is not evident within this current study.	('polyunsaturated', 'Var', (279, 294))	('associations', 'Interaction', (162, 174))	('cholesterol', 'Chemical', 'MESH:D002784', (198, 209))	('BE', 'Phenotype', 'HP:0100580', (215, 217))	('BE', 'Phenotype', 'HP:0100580', (60, 62))	('polyunsaturated fat', 'Chemical', '-', (279, 298))
213836	21455992	Our results would seem to support these hypotheses because we found total fat, saturated fat, and monounsaturated fat to be strongly associated with increased RE and EAC risk, and the associations observed in this current study for EAC and fat have also been shown in other case-control studies.	('saturated fat', 'Chemical', '-', (79, 92))	('EAC', 'Gene', '1540', (166, 169))	('monounsaturated fat', 'Chemical', '-', (98, 117))	('EAC', 'Gene', '1540', (232, 235))	('increased', 'PosReg', (149, 158))	('EAC', 'Gene', (166, 169))	('saturated fat', 'Chemical', '-', (104, 117))	('EAC', 'Gene', (232, 235))	('monounsaturated fat', 'Var', (98, 117))	('EAC', 'Phenotype', 'HP:0011459', (232, 235))	('EAC', 'Phenotype', 'HP:0011459', (166, 169))
213845	21455992	This was because the adverse associations reported for the case groups tended to be from animal (meat) based fats (saturated fat and monounsaturated fat).	('monounsaturated fat', 'Chemical', '-', (133, 152))	('saturated fat', 'Chemical', '-', (115, 128))	('saturated fat', 'Chemical', '-', (139, 152))	('fats', 'Gene', (109, 113))	('monounsaturated', 'Var', (133, 148))	('fats', 'Gene', '118611', (109, 113))
213853	21455992	However, when we omitted processed meat from the total red meat variable (fresh red meat), it resulted in a significantly positive association being seen between fresh red meat intake and EAC risk.	('EAC', 'Phenotype', 'HP:0011459', (188, 191))	('EAC', 'Gene', '1540', (188, 191))	('positive', 'PosReg', (122, 130))	('EAC', 'Gene', (188, 191))	('fresh red meat', 'Var', (162, 176))
213930	31127885	It has been found out that the anti-carcinogenic effect of the curcuminoid analogues S01, S02, S04, S06, S07, S12- S14 on BGC-823 cell line is 10 folds greater as compared to that of free curcumin.	('carcinogenic', 'Disease', 'MESH:D063646', (36, 48))	('BGC-823', 'CellLine', 'CVCL:3360', (122, 129))	('curcumin', 'Chemical', 'MESH:D003474', (188, 196))	('S12', 'Gene', (110, 113))	('curcumin', 'Chemical', 'MESH:D003474', (63, 71))	('greater', 'PosReg', (152, 159))	('curcuminoid', 'Chemical', 'MESH:D036381', (63, 74))	('S14', 'Gene', '6208', (115, 118))	('S02', 'Var', (90, 93))	('S12', 'Gene', '6268', (110, 113))	('S07', 'Var', (105, 108))	('S01', 'Var', (85, 88))	('S06', 'Var', (100, 103))	('S14', 'Gene', (115, 118))	('S04', 'Var', (95, 98))	('carcinogenic', 'Disease', (36, 48))
213931	31127885	Similarly, the therapeutic activity of analogues S01-S07, S12-S14 and S04, S06, S07, S12 on the cell lines of gastric cancer SGC-7901 and MFC cells is comparatively more than the free curcumin.	('gastric cancer', 'Disease', (110, 124))	('curcumin', 'Chemical', 'MESH:D003474', (184, 192))	('S12', 'Gene', (85, 88))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('S12', 'Gene', '6268', (85, 88))	('rat', 'Species', '10116', (156, 159))	('S12', 'Gene', (58, 61))	('S12', 'Gene', '6268', (58, 61))	('more', 'PosReg', (165, 169))	('S14', 'Gene', (62, 65))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('SGC-7901', 'CellLine', 'CVCL:0520', (125, 133))	('S14', 'Gene', '6208', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('therapeutic activity', 'CPA', (15, 35))	('S04', 'Var', (70, 73))	('S01-S07', 'Var', (49, 56))
213933	31127885	S06 causes the downregulation of the NF-kB signaling and induces apoptosis of the cancerous cells by the expression of cleaved PARP and upregulation od proapoptotic Bax proteins.	('induces', 'Reg', (57, 64))	('downregulation', 'NegReg', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('NF-kB signaling', 'MPA', (37, 52))	('PARP', 'Gene', (127, 131))	('Bax', 'Gene', '581', (165, 168))	('cancerous', 'Disease', (82, 91))	('apoptosis', 'CPA', (65, 74))	('Bax', 'Gene', (165, 168))	('cleaved', 'Var', (119, 126))	('upregulation', 'PosReg', (136, 148))	('cancerous', 'Disease', 'MESH:D009369', (82, 91))	('S06', 'Var', (0, 3))	('PARP', 'Gene', '1302', (127, 131))
213937	31127885	(Peng et al., 2013) EF31 analog of curcumin has a high anticarcinogenic effect than free curcumin.	('carcinogenic', 'Disease', 'MESH:D063646', (59, 71))	('carcinogenic', 'Disease', (59, 71))	('curcumin', 'Chemical', 'MESH:D003474', (89, 97))	('curcumin', 'Chemical', 'MESH:D003474', (35, 43))	('EF31 analog', 'Var', (20, 31))
213939	31127885	EF31 inhibit the NF-kappaB nuclear translocation and lead to downregulation of the inflammatory cytokine mRNA and proteins such as TN-alpha, IL-1B, IL-6.	('IL-6', 'Gene', (148, 152))	('IL-1B', 'Gene', (141, 146))	('EF31', 'Var', (0, 4))	('downregulation', 'NegReg', (61, 75))	('IL-6', 'Gene', '3569', (148, 152))	('TN-alpha', 'Gene', '7123', (131, 139))	('inhibit', 'NegReg', (5, 12))	('TN-alpha', 'Gene', (131, 139))	('NF-kappaB', 'Gene', '4790', (17, 26))	('IL-1B', 'Gene', '3553', (141, 146))	('NF-kappaB', 'Gene', (17, 26))
213941	31127885	Hence, EF31 has the more therapeutic efficiency than free curcumin and it's a more promising analog of curcumin for cancer treatment (Olivera et al., 2012).	('EF31', 'Var', (7, 11))	('therapeutic efficiency', 'CPA', (25, 47))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('curcumin', 'Chemical', 'MESH:D003474', (58, 66))	('curcumin', 'Chemical', 'MESH:D003474', (103, 111))
213945	31127885	Anti-inflammatory property is by the virtue of methoxy groups in its structure which inhibit the cyclooxygenase-2 (COX-2), Lipoxygenase (LOX) and inducible nitric oxide synthase (iNOS) (Bengmark n.d.).	('cyclooxygenase-2', 'Gene', (97, 113))	('COX-2', 'Gene', (115, 120))	('cyclooxygenase-2', 'Gene', '5743', (97, 113))	('iNOS', 'Gene', '4843', (179, 183))	('COX-2', 'Gene', '5743', (115, 120))	('inhibit', 'NegReg', (85, 92))	('inducible nitric oxide synthase', 'Gene', (146, 177))	('inducible nitric oxide synthase', 'Gene', '4843', (146, 177))	('methoxy groups', 'Var', (47, 61))	('Anti-inflammatory', 'MPA', (0, 17))	('Lipoxygenase', 'Enzyme', (123, 135))	('iNOS', 'Gene', (179, 183))
213967	31127885	Treatment with nano curcumin results in reduced expression of cyclin D1 gene and it was followed by significant increase in cytotoxicity and enhanced anti-proliferation potential in KYSE-30 cell line.	('cyclin D1', 'Gene', (62, 71))	('KYSE-30', 'CellLine', 'CVCL:1351', (182, 189))	('cytotoxicity', 'Disease', 'MESH:D064420', (124, 136))	('rat', 'Species', '10116', (162, 165))	('expression', 'MPA', (48, 58))	('nano', 'Var', (15, 19))	('curcumin', 'Chemical', 'MESH:D003474', (20, 28))	('reduced', 'NegReg', (40, 47))	('increase', 'PosReg', (112, 120))	('cytotoxicity', 'Disease', (124, 136))	('enhanced', 'PosReg', (141, 149))	('anti-proliferation potential', 'CPA', (150, 178))	('cyclin D1', 'Gene', '595', (62, 71))
213968	31127885	Other curcumin derived compounds like nano-curcumin are well-known to induce apoptosis in a variety of cells including pancreatic cancer cells (Sahu-Batra and Srivastava, 2009; Jutooru et al., 2010) and it upregulates the expression of pro-apoptotic members of the Bcl-2 family like Bax and Bak, inhibits the anti-apoptotic Bcl-2 proteins, such as Bcl-XL and Bcl-2 and also found to affect several caspases such as caspase-8 (Anto et al., 2002; Singh and Singh, 2011).	('caspases', 'Gene', '841;842', (398, 406))	('Bcl-2', 'Gene', (324, 329))	('Bak', 'Gene', '578', (291, 294))	('nano-curcumin', 'Var', (38, 51))	('pancreatic cancer', 'Disease', (119, 136))	('caspase-8', 'Gene', (415, 424))	('Bcl-2', 'Gene', '596', (324, 329))	('curcumin', 'Chemical', 'MESH:D003474', (43, 51))	('upregulates', 'PosReg', (206, 217))	('Bcl-XL', 'Gene', '598', (348, 354))	('expression', 'MPA', (222, 232))	('Bcl-2', 'Gene', (359, 364))	('Bcl-XL', 'Gene', (348, 354))	('Bcl-2', 'Gene', (265, 270))	('affect', 'Reg', (383, 389))	('induce', 'PosReg', (70, 76))	('Bak', 'Gene', (291, 294))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (119, 136))	('apoptosis', 'Disease', (77, 86))	('nano-curcumin', 'Chemical', '-', (38, 51))	('Bcl-2', 'Gene', '596', (359, 364))	('Bax', 'Gene', (283, 286))	('Bcl-2', 'Gene', '596', (265, 270))	('caspase-8', 'Gene', '841', (415, 424))	('inhibits', 'NegReg', (296, 304))	('caspases', 'Gene', (398, 406))	('curcumin', 'Chemical', 'MESH:D003474', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Bax', 'Gene', '581', (283, 286))	('pancreatic cancer', 'Disease', 'MESH:D010190', (119, 136))
213972	31127885	However, esophageal cancer cells (and cell lines) are either p53 deficient (TE-7) or have mutant non-functional p53 protein (TE-10) (Barnas et al., 1997).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Barnas', 'Species', '202634', (133, 139))	('deficient', 'NegReg', (65, 74))	('mutant', 'Var', (90, 96))	('non-functional', 'MPA', (97, 111))	('esophageal cancer', 'Disease', (9, 26))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '7157', (61, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (9, 26))	('p53', 'Gene', (61, 64))	('p53', 'Gene', '7157', (112, 115))
213978	31127885	This has been proved by fluorescent microscopy as there were equal intra- cellular accumulation in OE19and OE33 (esophageal adenocarcinoma) cell lines as compared to HET-1A (esophageal squamous cells) when treated with same concentration of nano-curcumin.	('nano-curcumin', 'Chemical', '-', (241, 254))	('rat', 'Species', '10116', (231, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (113, 138))	('adenocarcinoma', 'Disease', (124, 138))	('OE33', 'Var', (107, 111))	('adenocarcinoma', 'Disease', 'MESH:D000230', (124, 138))
213979	31127885	Instead, it could be because of the signaling pathways involved in cellular proliferation are aberrantly activated in cancer cells and make them more susceptible to the effects of nano-curcumin and selectively suppress their proliferation as compared to normal cells which merits its exploration for treatment of esophageal cancer (Milano et al., 2013).	('susceptible', 'MPA', (150, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (313, 330))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('more', 'PosReg', (145, 149))	('nano-curcumin', 'Var', (180, 193))	('esophageal cancer', 'Disease', (313, 330))	('suppress', 'NegReg', (210, 218))	('cancer', 'Disease', (324, 330))	('cancer', 'Disease', (118, 124))	('activated', 'PosReg', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('proliferation', 'CPA', (225, 238))	('signaling pathways', 'Pathway', (36, 54))	('rat', 'Species', '10116', (83, 86))	('rat', 'Species', '10116', (289, 292))	('rat', 'Species', '10116', (232, 235))	('nano-curcumin', 'Chemical', '-', (180, 193))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
213981	31127885	Other clinical trials{NCT 00027495 (Colon cancer), NCT 00969085 (Cutaneous T-cell lymphoma), NCT 00094445 (Advanced pancreatic cancer)} with various compositions of Curcumin has showed promised results Except one single event of diarrhea, no adverse events have been recorded.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('diarrhea', 'Disease', 'MESH:D003967', (229, 237))	('NCT 00094445', 'Var', (93, 105))	('cell lymphoma', 'Phenotype', 'HP:0012191', (77, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))	('Colon cancer', 'Disease', 'MESH:D015179', (36, 48))	('pancreatic cancer', 'Disease', (116, 133))	('Curcumin', 'Chemical', 'MESH:D003474', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Cutaneous T-cell lymphoma', 'Disease', 'MESH:D016410', (65, 90))	('diarrhea', 'Phenotype', 'HP:0002014', (229, 237))	('Cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (65, 90))	('Cutaneous T-cell lymphoma', 'Disease', (65, 90))	('Colon cancer', 'Disease', (36, 48))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (75, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('Colon cancer', 'Phenotype', 'HP:0003003', (36, 48))	('diarrhea', 'Disease', (229, 237))
213983	31127885	It has been observed that nano-curcumin has a sensitizing effect on DC-mediated T cell cytotoxicity and leads to increasing cell lysis on EAC cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('increasing', 'PosReg', (113, 123))	('nano-curcumin', 'Var', (26, 39))	('cell lysis', 'CPA', (124, 134))	('cytotoxicity', 'Disease', (87, 99))	('sensitizing', 'MPA', (46, 57))	('nano-curcumin', 'Chemical', '-', (26, 39))
213985	31127885	This suggests that nano-curcumin can potentiate the immune response to the EAC cells.	('potentiate', 'PosReg', (37, 47))	('nano-curcumin', 'Var', (19, 32))	('nano-curcumin', 'Chemical', '-', (19, 32))	('immune response to the EAC cells', 'CPA', (52, 84))
213986	31127885	Treatment with Thera curcumin increases esophageal tumor cells susceptibility to be killed by cytotoxic T cells (Milano et al., 2013) It was found that nano-curcumin also increases the IFN-gamma secretion and decreased the TNF-alpha secretion in the co-culture of OE33 with CTLs and nano-curcumin (Milano et al.	('esophageal tumor', 'Disease', (40, 56))	('TNF-alpha', 'Gene', '7124', (223, 232))	('nano-curcumin', 'Var', (152, 165))	('curcumin', 'Chemical', 'MESH:D003474', (288, 296))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('decreased', 'NegReg', (209, 218))	('esophageal tumor', 'Phenotype', 'HP:0100751', (40, 56))	('TNF-alpha', 'Gene', (223, 232))	('nano-curcumin', 'Chemical', '-', (152, 165))	('curcumin', 'Chemical', 'MESH:D003474', (157, 165))	('curcumin', 'Chemical', 'MESH:D003474', (21, 29))	('nano-curcumin', 'Chemical', '-', (283, 296))	('increases', 'PosReg', (171, 180))	('esophageal tumor', 'Disease', 'MESH:D004938', (40, 56))	('IFN-gamma', 'Gene', '3458', (185, 194))	('IFN-gamma', 'Gene', (185, 194))
213998	31127885	Down regulation of anti-apoptotic genes leads to apoptosis of the cells with damaged DNA which was induced by deoxycholic acid in vitro (Rawat et al., 2012) Furthermore, a pilot study in patients with barrette esophagus showed a trend which suggests that abrogation of IL-8 expression as well as significantly increased levels of apoptosis in the curcumin arm (Bhattacharyya et al., 2010).	('expression', 'MPA', (274, 284))	('patients', 'Species', '9606', (187, 195))	('barrette esophagus', 'Phenotype', 'HP:0100580', (201, 219))	('levels', 'MPA', (320, 326))	('increased', 'PosReg', (310, 319))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (110, 126))	('barrette', 'Disease', (201, 209))	('Down regulation', 'NegReg', (0, 15))	('anti-apoptotic genes', 'Gene', (19, 39))	('curcumin', 'Chemical', 'MESH:D003474', (347, 355))	('IL-8', 'Gene', '3576', (269, 273))	('abrogation', 'Var', (255, 265))	('IL-8', 'Gene', (269, 273))
214003	31127885	Loss of heterozygosity of Smad4 (Ch 18q21.1) was associated with 45% of cases whereas low mRNA levels of TBRII have been associated with 27% of Barrett's adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('adenocarcinoma', 'Disease', (154, 168))	('associated', 'Reg', (121, 131))	('adenocarcinoma', 'Disease', 'MESH:D000230', (154, 168))	('Loss', 'NegReg', (0, 4))	('Smad4', 'Gene', (26, 31))	('Smad4', 'Gene', '4089', (26, 31))	('low', 'Var', (86, 89))
214004	31127885	Dysfunction of TGF-beta signaling leads to aberrant activation of Notch signaling pathway which plays a critical role in the processes of tumor cell proliferation, apoptosis and stem cells maintenance and is closely associated with tumorigenesis in esophageal cancer cell.	('esophageal cancer', 'Disease', 'MESH:D004938', (249, 266))	('rat', 'Species', '10116', (156, 159))	('Dysfunction', 'Var', (0, 11))	('Notch', 'Gene', '4851', (66, 71))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('associated', 'Reg', (216, 226))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('TGF-beta', 'Gene', (15, 23))	('Notch', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('esophageal cancer', 'Disease', (249, 266))	('tumor', 'Disease', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('TGF-beta', 'Gene', '7039', (15, 23))	('activation', 'PosReg', (52, 62))
214010	31127885	Inhibitors of dysfunctional of TGF-beta signaling or Notch inhibitors like curcumin could hold promise for new personalized therapeutic approaches in esophageal adenocarcinoma (Mendelson et al., 2011).	('TGF-beta', 'Gene', (31, 39))	('dysfunctional', 'Disease', (14, 27))	('adenocarcinoma', 'Disease', 'MESH:D000230', (161, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('adenocarcinoma', 'Disease', (161, 175))	('Inhibitors', 'Var', (0, 10))	('TGF-beta', 'Gene', '7039', (31, 39))	('curcumin', 'Chemical', 'MESH:D003474', (75, 83))	('Notch', 'Gene', '4851', (53, 58))	('Notch', 'Gene', (53, 58))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (150, 175))	('dysfunctional', 'Disease', 'MESH:D009461', (14, 27))
214045	30670657	Inhibition of IL-6 reverted the mesenchymal cell state and resensitized tumor cells to therapy.	('mesenchymal cell state', 'CPA', (32, 54))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('Inhibition', 'Var', (0, 10))	('IL-6', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
214050	30670657	Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines.	('patient', 'Species', '9606', (48, 55))	('Inhibition', 'Var', (0, 10))	('drug sensitivity', 'Phenotype', 'HP:0020174', (28, 44))	('IL-6', 'Gene', (14, 18))	('drug sensitivity', 'MPA', (28, 44))
214066	30670657	Stromal IL-6 was identified as the molecule driving this resistance, and targeting IL-6 resulted in resensitization of tumor cells to chemoradiotherapy.	('resensitization', 'CPA', (100, 115))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('IL-6', 'Gene', (83, 87))	('targeting', 'Var', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
214201	29088836	To test the hypothesis that common, germline genetic variants in BAP1 may also contribute to the risk of developing different types of cancer, we genotyped germline single nucleotide polymorphisms (SNPs) for BAP1 in a large population of patients with cancer, including 2,340 with colorectal cancer, 1,436 with bladder cancer, 3,313 with lung cancer, 1,325 with renal cell carcinoma, and 1,162 with esophageal cancer.	('renal cell carcinoma', 'Disease', (362, 382))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (362, 382))	('colorectal cancer', 'Disease', (281, 298))	('cancer', 'Disease', (343, 349))	('BAP1', 'Gene', (65, 69))	('bladder cancer', 'Disease', (311, 325))	('cancer', 'Disease', (319, 325))	('bladder cancer', 'Disease', 'MESH:D001749', (311, 325))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('BAP1', 'Gene', (208, 212))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('cancer', 'Disease', (135, 141))	('bladder cancer', 'Phenotype', 'HP:0009725', (311, 325))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', (338, 349))	('carcinoma', 'Phenotype', 'HP:0030731', (373, 382))	('esophageal cancer', 'Disease', 'MESH:D004938', (399, 416))	('cancer', 'Disease', (292, 298))	('colorectal cancer', 'Phenotype', 'HP:0003003', (281, 298))	('single nucleotide', 'Var', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('cancer', 'Disease', (252, 258))	('contribute', 'Reg', (79, 89))	('esophageal cancer', 'Disease', (399, 416))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (362, 382))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('patients', 'Species', '9606', (238, 246))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('BAP1', 'Gene', '8314', (65, 69))	('lung cancer', 'Disease', 'MESH:D008175', (338, 349))	('BAP1', 'Gene', '8314', (208, 212))	('cancer', 'Disease', (410, 416))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('colorectal cancer', 'Disease', 'MESH:D015179', (281, 298))	('lung cancer', 'Phenotype', 'HP:0100526', (338, 349))	('variants', 'Var', (53, 61))
214202	29088836	We identified significant association of rs11708581 (P = 0.0034) and rs390802 (P = 0.015) with risk of renal cell carcinoma and rs12163565 (P = 0.038) with risk of lung cancer.	('renal cell carcinoma', 'Disease', (103, 123))	('rs390802', 'Var', (69, 77))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (103, 123))	('lung cancer', 'Disease', (164, 175))	('rs12163565', 'Var', (128, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (103, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('rs11708581', 'Mutation', 'rs11708581', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('rs390802', 'Mutation', 'rs390802', (69, 77))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('rs12163565', 'Mutation', 'rs12163565', (128, 138))	('rs11708581', 'Var', (41, 51))
214203	29088836	Expression quantitative trait loci analysis in renal cell carcinoma using publicly available data from TCGA showed that the proxy SNPs for rs11708581 and rs390802 were negatively associated with the expression level of BAP1.	('expression level', 'MPA', (199, 215))	('negatively', 'NegReg', (168, 178))	('rs390802', 'Mutation', 'rs390802', (154, 162))	('BAP1', 'Gene', (219, 223))	('rs11708581', 'Var', (139, 149))	('renal cell carcinoma', 'Disease', (47, 67))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (47, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('rs390802', 'Var', (154, 162))	('rs11708581', 'Mutation', 'rs11708581', (139, 149))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (47, 67))	('BAP1', 'Gene', '8314', (219, 223))
214211	29088836	Recently, several studies have identified somatic and germline BAP1 mutations in a wide-range of cancers, including mesothelioma, uveal melanoma, lung adenocarcinoma, renal cell carcinoma, meningioma, and melanocytic neoplasms.	('mesothelioma', 'Disease', (116, 128))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('uveal melanoma', 'Disease', (130, 144))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (167, 187))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('meningioma', 'Disease', 'MESH:D008577', (189, 199))	('BAP1', 'Gene', (63, 67))	('lung adenocarcinoma', 'Disease', (146, 165))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (205, 226))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (205, 226))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('neoplasms', 'Phenotype', 'HP:0002664', (217, 226))	('melanocytic neoplasms', 'Disease', (205, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (146, 165))	('renal cell carcinoma', 'Disease', (167, 187))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (146, 165))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('meningioma', 'Disease', (189, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('mutations', 'Var', (68, 77))	('meningioma', 'Phenotype', 'HP:0002858', (189, 199))	('BAP1', 'Gene', '8314', (63, 67))
214212	29088836	These studies have shown that rare genetic alterations in BAP1 can be drivers of the tumorigenetic process in these tumors.	('tumors', 'Disease', (116, 122))	('tumor', 'Disease', (85, 90))	('genetic alterations', 'Var', (35, 54))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('BAP1', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))	('BAP1', 'Gene', '8314', (58, 62))
214219	29088836	Although these previous studies have provided the functional characterization of BAP1 and identified rare mutations in several cancers, the role of common germline genetic variants in BAP1 on the risk of developing different types of cancer remains largely unknown.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('BAP1', 'Gene', (81, 85))	('BAP1', 'Gene', '8314', (184, 188))	('variants', 'Var', (172, 180))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('BAP1', 'Gene', (184, 188))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('mutations', 'Var', (106, 115))	('cancers', 'Disease', (127, 134))	('cancer', 'Disease', (234, 240))	('BAP1', 'Gene', '8314', (81, 85))
214220	29088836	A recent large scale meta-analysis showed that common genetic variants in APC and MLH1 genes, two genes known to have high-penetrance mutations contributing to familial colorectal cancer, had strong cumulative epidemiological evidence for a significant association with colorectal cancer risk.	('APC', 'Disease', 'MESH:D011125', (74, 77))	('APC', 'Disease', (74, 77))	('colorectal cancer', 'Disease', (270, 287))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('MLH1', 'Gene', '4292', (82, 86))	('variants', 'Var', (62, 70))	('colorectal cancer', 'Disease', 'MESH:D015179', (169, 186))	('MLH1', 'Gene', (82, 86))	('familial colorectal cancer', 'Disease', 'MESH:D015179', (160, 186))	('colorectal cancer', 'Phenotype', 'HP:0003003', (169, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (270, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('familial colorectal cancer', 'Disease', (160, 186))	('colorectal cancer', 'Phenotype', 'HP:0003003', (270, 287))
214221	29088836	We hypothesized that common, germline genetic variants in BAP1 may also contribute to the risk of developing different types of cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('BAP1', 'Gene', '8314', (58, 62))	('BAP1', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('germline genetic variants', 'Var', (29, 54))	('contribute', 'Reg', (72, 82))	('risk', 'Reg', (90, 94))	('cancer', 'Disease', (128, 134))
214222	29088836	To ensure a comprehensive coverage of common genetic variants in the BAP1 gene, we used the tagging single nucleotide polymorphism (SNP) approach with an r2 of 0.80 and a minor allele frequency of >5% for SNP selection and further supplemented with two additional SNPs based on the basis of putative function.	('BAP1', 'Gene', (69, 73))	('variants', 'Var', (53, 61))	('BAP1', 'Gene', '8314', (69, 73))
214227	29088836	Overall, three BAP1 genetic variants were significant, two with the risk of renal cell carcinoma and one with the risk of lung cancer (Table 2).	('renal cell carcinoma', 'Disease', (76, 96))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', (122, 133))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('variants', 'Var', (28, 36))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (76, 96))	('BAP1', 'Gene', '8314', (15, 19))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('BAP1', 'Gene', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
214229	29088836	A 26% decrease in the risk of developing renal cell carcinoma (95% confidence interval [CI]= 0.61-0.91, P=0.0034) was observed for those carrying either the heterozygous or homozygous variant genotype for rs11708581.	('rs11708581', 'Mutation', 'rs11708581', (205, 215))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (41, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('decrease', 'NegReg', (6, 14))	('rs11708581', 'Var', (205, 215))	('renal cell carcinoma', 'Disease', (41, 61))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (41, 61))
214230	29088836	Significant reduced risk of renal cell carcinoma was observed for those carrying variant alleles of rs390802 (odds ratio [OR]=0.80, 95% CI= 0.67-0.96, P=0.015).	('reduced', 'NegReg', (12, 19))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (28, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('rs390802', 'Mutation', 'rs390802', (100, 108))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (28, 48))	('renal cell carcinoma', 'Disease', (28, 48))	('rs390802', 'Var', (100, 108))
214231	29088836	Individuals carrying variant alleles of rs12163565 had a significantly increased risk of developing lung cancer (OR=1.11, 95% CI= 1.01-1.24, P=0.038) as well as an increased risk of developing bladder cancer (OR=1.17, 95% CI=0.99-1.39, P=0.070), although that increased risk was not statistically significant.	('bladder cancer', 'Disease', 'MESH:D001749', (193, 207))	('rs12163565', 'Mutation', 'rs12163565', (40, 50))	('bladder cancer', 'Disease', (193, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('rs12163565', 'Var', (40, 50))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (193, 207))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
214232	29088836	However, none of the variants were significantly associated with the risk of esophageal cancer and colorectal cancer and the similar results were observed for esophageal cancer with the additional adjustment for alcohol consumption (data not shown).	('variants', 'Var', (21, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('colorectal cancer', 'Disease', (99, 116))	('associated', 'Reg', (49, 59))	('alcohol', 'Chemical', 'MESH:D000438', (212, 219))	('esophageal cancer', 'Disease', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('esophageal cancer', 'Disease', (77, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
214233	29088836	The association for rs11708581 with renal cell carcinoma remained significant even after adjustment for multiple comparison using the Bonferroni correction of 0.01 (=0.05/5 tests) while none of the other associations remained significant after Bonferroni correction.	('renal cell carcinoma', 'Disease', (36, 56))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (36, 56))	('rs11708581', 'Mutation', 'rs11708581', (20, 30))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (36, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('rs11708581', 'Var', (20, 30))
214234	29088836	The protective effects of both rs11708581 and rs390802 against renal cell carcinoma remained significant among male subjects, ever smokers and subjects younger than 65 yrs.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (63, 83))	('rs390802', 'Var', (46, 54))	('rs11708581', 'Var', (31, 41))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (63, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('rs11708581', 'Mutation', 'rs11708581', (31, 41))	('renal cell carcinoma', 'Disease', (63, 83))	('rs390802', 'Mutation', 'rs390802', (46, 54))
214235	29088836	The effect of rs12163565 with the risk of lung cancer remained significant among male and ever smokers.	('rs12163565', 'Var', (14, 24))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('rs12163565', 'Mutation', 'rs12163565', (14, 24))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
214236	29088836	Because rs11708581 and rs390802 were not genotyped by The Cancer Genome Atlas (TCGA), we used 4 proxy SNPs for rs11708581 and 3 proxy SNPs for rs390802 (Table 4) to assess the association of these SNPs with expression level of BAP1.	('rs390802', 'Mutation', 'rs390802', (23, 31))	('BAP1', 'Gene', '8314', (227, 231))	('rs11708581', 'Var', (111, 121))	('rs390802', 'Mutation', 'rs390802', (143, 151))	('Cancer Genome Atlas', 'Disease', (58, 77))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BAP1', 'Gene', (227, 231))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (58, 77))	('association', 'Interaction', (176, 187))	('rs11708581', 'Mutation', 'rs11708581', (111, 121))	('rs390802', 'Var', (143, 151))	('rs11708581', 'Mutation', 'rs11708581', (8, 18))
214237	29088836	We found that BAP1 expression was negatively associated with two proxy SNPs for rs11708581 (rs17052053: r2=0.9, P value=0.006 and rs11713914: r2=1.0, P value=0.05) and one proxy SNP for rs390802 (rs11714402: r2=0.98, P value=0.023).	('BAP1', 'Gene', '8314', (14, 18))	('expression', 'MPA', (19, 29))	('rs11714402', 'Mutation', 'rs11714402', (196, 206))	('rs11713914', 'Var', (130, 140))	('BAP1', 'Gene', (14, 18))	('rs11713914', 'Mutation', 'rs11713914', (130, 140))	('rs17052053', 'Var', (92, 102))	('rs11708581', 'Mutation', 'rs11708581', (80, 90))	('rs390802', 'Mutation', 'rs390802', (186, 194))	('negatively', 'NegReg', (34, 44))	('rs17052053', 'Mutation', 'rs17052053', (92, 102))
214238	29088836	The association of rs17052053 with BAP1 expression remained significant after Bonferroni correction of 0.007 (=0.05/7 tests).	('expression', 'MPA', (40, 50))	('rs17052053', 'Mutation', 'rs17052053', (19, 29))	('BAP1', 'Gene', '8314', (35, 39))	('rs17052053', 'Var', (19, 29))	('BAP1', 'Gene', (35, 39))
214239	29088836	BAP1 has generated much attention owing to the consistent findings of rare germline or somatic mutations in a wide-range of cancer sites.	('cancer', 'Disease', (124, 130))	('BAP1', 'Gene', (0, 4))	('germline', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BAP1', 'Gene', '8314', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
214240	29088836	However, the role of common germline genetic variants in BAP1 on the risk of developing different types of cancer is largely unknown.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('variants', 'Var', (45, 53))	('BAP1', 'Gene', '8314', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('BAP1', 'Gene', (57, 61))	('cancer', 'Disease', (107, 113))
214245	29088836	In addition, various techniques such as comparative genomic hybridization array, targeted next-generation sequencing (NGS), whole exome NGS, sanger sequencing, and immunohistochemical analysis have been used to detect BAP1 mutations.	('BAP1', 'Gene', (218, 222))	('detect', 'Reg', (211, 217))	('mutations', 'Var', (223, 232))	('BAP1', 'Gene', '8314', (218, 222))
214246	29088836	However, due to the limitations of these techniques, detection of BAP1 mutation is still challenging and an ongoing research field.	('mutation', 'Var', (71, 79))	('BAP1', 'Gene', '8314', (66, 70))	('BAP1', 'Gene', (66, 70))
214247	29088836	In this study, we performed an extensive investigation in different types of cancer that included nearly 10,000 cancer cases and 5,000 healthy controls to determine the association of the common germline genetic variants in BAP1 with the risk of developing different types of cancer.	('000 cancer', 'Disease', 'MESH:D009369', (108, 118))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (112, 118))	('BAP1', 'Gene', (224, 228))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Disease', (77, 83))	('BAP1', 'Gene', '8314', (224, 228))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('000 cancer', 'Disease', (108, 118))	('association', 'Interaction', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('variants', 'Var', (212, 220))
214248	29088836	The goal of this study is to establish the role of common variations as susceptibility loci for cancer, providing additional knowledge of the impact of this gene.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('variations', 'Var', (58, 68))
214250	29088836	This genomic region of interest, which was defined at 10 kilobases (kb) upstream and downstream of the BAP1 gene for a total of 28,985 base pairs (bp), contains a total of 135 common germline genetic variants that were genotyped as part of the HapMap project (Phase 3 data).	('BAP1', 'Gene', '8314', (103, 107))	('BAP1', 'Gene', (103, 107))	('variants', 'Var', (200, 208))
214251	29088836	rs123598 is located in the 3'-UTR of BAP1 and rs56238158 was identified as a non-synonymous variant in the whole genome sequencing of J. Craig Venter.	('rs123598', 'Var', (0, 8))	('rs123598', 'Mutation', 'rs123598', (0, 8))	('BAP1', 'Gene', '8314', (37, 41))	('rs56238158', 'Var', (46, 56))	('rs56238158', 'Mutation', 'rs56238158', (46, 56))	('BAP1', 'Gene', (37, 41))
214254	29088836	In the risk analysis by cancer site, the most significant association was for rs11708581 in renal cell carcinoma, resulting in a 26% reduction in risk that remained significant after Bonferroni correction for multiple comparisons.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('rs11708581', 'Mutation', 'rs11708581', (78, 88))	('reduction', 'NegReg', (133, 142))	('renal cell carcinoma', 'Disease', (92, 112))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('rs11708581', 'Var', (78, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (92, 112))
214255	29088836	We also found that rs390802 was associated with a decreased risk of renal cell carcinoma.	('rs390802', 'Var', (19, 27))	('renal cell carcinoma', 'Disease', (68, 88))	('decreased', 'NegReg', (50, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (68, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (68, 88))	('rs390802', 'Mutation', 'rs390802', (19, 27))
214257	29088836	Because of the close proximity of other genes to BAP1, rs11708581 is a synonymous variant of DNAH1 and rs390802 is an intronic variant of DNAH1.	('DNAH1', 'Gene', (138, 143))	('DNAH1', 'Gene', '25981', (93, 98))	('rs390802', 'Var', (103, 111))	('rs11708581', 'Var', (55, 65))	('DNAH1', 'Gene', (93, 98))	('BAP1', 'Gene', (49, 53))	('rs390802', 'Mutation', 'rs390802', (103, 111))	('rs11708581', 'Mutation', 'rs11708581', (55, 65))	('DNAH1', 'Gene', '25981', (138, 143))	('BAP1', 'Gene', '8314', (49, 53))
214258	29088836	Using HaploReg and RegulomeDB from the ENCyclopedia Of DNA Elements (ENCODE) project data, we found that two regions covering these SNPs and their correlated variants (r2>0.8) had a length of 250 kb for rs11708581, including 80 SNPs and 224 kb for rs390802, including 56 SNPs (Supplementary Tables 2 and 3).	('rs11708581', 'Var', (203, 213))	('rs390802', 'Mutation', 'rs390802', (248, 256))	('rs390802', 'Var', (248, 256))	('rs11708581', 'Mutation', 'rs11708581', (203, 213))
214259	29088836	Interestingly, rs123602 (an intronic variant of BAP1) and rs498946 (61 bps 3' of BAP1) are in high linkage disequilibrium (LD) with rs390802 (r2=0.98 and 0.95, respectively) and moderate LD with rs11708581 (r2=0.56 and 0.56, respectively).	('BAP1', 'Gene', '8314', (48, 52))	('rs123602', 'Mutation', 'rs123602', (15, 23))	('BAP1', 'Gene', (81, 85))	('rs390802', 'Var', (132, 140))	('rs11708581', 'Mutation', 'rs11708581', (195, 205))	('BAP1', 'Gene', (48, 52))	('rs123602', 'Var', (15, 23))	('linkage', 'Interaction', (99, 106))	('rs498946', 'Mutation', 'rs498946', (58, 66))	('rs11708581', 'Var', (195, 205))	('BAP1', 'Gene', '8314', (81, 85))	('rs390802', 'Mutation', 'rs390802', (132, 140))
214260	29088836	Because genotyping data for rs11708581 and rs390802 were not available in TCGA for renal cell carcinoma, we used the proxy SNPs in the eQTL analysis and found that two proxy SNPs for rs11708581 and one proxy SNPs for rs390802 exhibited an significantly negative association with the expression level of BAP1.	('negative', 'NegReg', (253, 261))	('rs390802', 'Mutation', 'rs390802', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('rs11708581', 'Mutation', 'rs11708581', (28, 38))	('BAP1', 'Gene', (303, 307))	('rs11708581', 'Var', (183, 193))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (83, 103))	('rs390802', 'Mutation', 'rs390802', (217, 225))	('expression level', 'MPA', (283, 299))	('renal cell carcinoma', 'Disease', (83, 103))	('rs11708581', 'Mutation', 'rs11708581', (183, 193))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (83, 103))	('BAP1', 'Gene', '8314', (303, 307))
214261	29088836	Genotyping data for rs123602 were available but did not show any association with BAP1 expression.	('rs123602', 'Var', (20, 28))	('BAP1', 'Gene', (82, 86))	('BAP1', 'Gene', '8314', (82, 86))	('rs123602', 'Mutation', 'rs123602', (20, 28))
214262	29088836	Both rs11708581 and rs390802 are in the DNase I hypersensitivity region which is a signature of open chromatin that is typically associated with transcriptionally active regions of the genome.	('rs11708581', 'Mutation', 'rs11708581', (5, 15))	('hypersensitivity', 'Disease', 'MESH:D004342', (48, 64))	('hypersensitivity', 'Disease', (48, 64))	('rs390802', 'Mutation', 'rs390802', (20, 28))	('rs11708581', 'Var', (5, 15))	('rs390802', 'Var', (20, 28))
214263	29088836	Therefore, it is possible that rs11708581 and rs390802 affect the risk of developing renal cell carcinoma through BAP1.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (85, 105))	('affect', 'Reg', (55, 61))	('rs390802', 'Var', (46, 54))	('rs11708581', 'Var', (31, 41))	('BAP1', 'Gene', '8314', (114, 118))	('renal cell carcinoma', 'Disease', (85, 105))	('rs11708581', 'Mutation', 'rs11708581', (31, 41))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('BAP1', 'Gene', (114, 118))	('rs390802', 'Mutation', 'rs390802', (46, 54))
214264	29088836	We also found that rs12163565 was associated with an increased risk of developing lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rs12163565', 'Mutation', 'rs12163565', (19, 29))	('rs12163565', 'Var', (19, 29))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))
214265	29088836	Similar to rs11708581, rs12163565 is a missense variant of DNAH1 and is located within 10kb of BAP.	('rs12163565', 'Mutation', 'rs12163565', (23, 33))	('rs11708581', 'Mutation', 'rs11708581', (11, 21))	('BAP', 'Gene', (95, 98))	('rs12163565', 'Var', (23, 33))	('DNAH1', 'Gene', '25981', (59, 64))	('BAP', 'Gene', '11331', (95, 98))	('DNAH1', 'Gene', (59, 64))
214266	29088836	The region covering its correlated variants (r2>0.8) had a length of 201 kb, including five SNPs and none of the SNPs in the BAP1 gene had high LD with rs12163565 (Supplementary Figure 1).	('BAP1', 'Gene', (125, 129))	('rs12163565', 'Var', (152, 162))	('BAP1', 'Gene', '8314', (125, 129))	('rs12163565', 'Mutation', 'rs12163565', (152, 162))
214268	29088836	Overall, the results of this analysis of BAP1 common germline genetic variations in a large population of nearly 10,000 patients with cancer from five different cancer sites support the idea that common germline genetic variants in BAP1 playing a role in mediating the risk of developing renal cell carcinoma and lung cancer.	('cancer', 'Disease', (318, 324))	('BAP1', 'Gene', (41, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (313, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Disease', (161, 167))	('BAP1', 'Gene', (232, 236))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (288, 308))	('playing', 'Reg', (237, 244))	('cancer', 'Disease', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('variations', 'Var', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('renal cell carcinoma and lung cancer', 'Disease', 'MESH:C538614', (288, 324))	('BAP1', 'Gene', '8314', (41, 45))	('variants', 'Var', (220, 228))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('patients', 'Species', '9606', (120, 128))	('BAP1', 'Gene', '8314', (232, 236))
214278	29088836	Four variants were identified as tagging SNPs and an additional two variants were selected based on the basis of putative function: rs123598 and rs56238158 (Table 5).	('rs123598', 'Var', (132, 140))	('rs56238158', 'Var', (145, 155))	('rs56238158', 'Mutation', 'rs56238158', (145, 155))	('rs123598', 'Mutation', 'rs123598', (132, 140))
214281	29088836	The call rates were over 95% for all of the selected polymorphisms except for rs56238158, which was not detectable as a polymorphism in any of our study populations and was excluded from further analysis.	('rs56238158', 'Mutation', 'rs56238158', (78, 88))	('rs56238158', 'Var', (78, 88))	('call rates', 'CPA', (4, 14))
214283	29088836	The effect of rs11708581, rs123598, rs12163565, rs390802, and rs13094687 on the risk of developing different types of cancer was assessed using the dominant model.	('cancer', 'Disease', (118, 124))	('rs123598', 'Var', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('rs11708581', 'Var', (14, 24))	('rs12163565', 'Mutation', 'rs12163565', (36, 46))	('rs123598', 'Mutation', 'rs123598', (26, 34))	('rs13094687', 'Var', (62, 72))	('rs12163565', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs390802', 'Mutation', 'rs390802', (48, 56))	('rs11708581', 'Mutation', 'rs11708581', (14, 24))	('rs13094687', 'Mutation', 'rs13094687', (62, 72))	('rs390802', 'Var', (48, 56))
214284	29088836	We performed eQTL analysis for SNPs rs11708581 and rs390802 to elucidate potential mechanism underlying the association of these SNPs with renal cell carcinoma.	('rs390802', 'Var', (51, 59))	('rs11708581', 'Mutation', 'rs11708581', (36, 46))	('renal cell carcinoma', 'Disease', (139, 159))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (139, 159))	('rs390802', 'Mutation', 'rs390802', (51, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (139, 159))	('association', 'Interaction', (108, 119))	('rs11708581', 'Var', (36, 46))
214290	29088836	In the dbGaP data, SNP rs6809248 did not show high LD with the other proxy SNPs for rs11708581 (r2 range from 0.0 to 0.26) and was removed from further analysis.	('rs6809248', 'Mutation', 'rs6809248', (23, 32))	('rs6809248', 'Var', (23, 32))	('rs11708581', 'Mutation', 'rs11708581', (84, 94))	('rs11708581', 'Var', (84, 94))
214297	28819381	In addition, a lower AGR level was observed more often in patients with a high fibrinogen level than in those with a low fibrinogen level.	('patients', 'Species', '9606', (58, 66))	('low fibrinogen level', 'Phenotype', 'HP:0011900', (117, 137))	('AGR level', 'MPA', (21, 30))	('high', 'Var', (74, 78))	('high fibrinogen', 'Phenotype', 'HP:0011899', (74, 89))	('high fibrinogen level', 'Phenotype', 'HP:0011899', (74, 95))	('fibrinogen', 'Gene', '2244', (79, 89))	('lower', 'NegReg', (15, 20))	('fibrinogen', 'Gene', (79, 89))	('fibrinogen', 'Gene', '2244', (121, 131))	('fibrinogen', 'Gene', (121, 131))
214483	24395382	The presence of HGD or adenocarcinoma following the initial ablation was also associated with an increased risk of recurrence or progression of adenocarcinoma after ablation, with the median time to recurrence following complete remission of 12 months.	('HGD', 'Disease', (16, 19))	('adenocarcinoma', 'Disease', 'MESH:D000230', (23, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('adenocarcinoma', 'Disease', (144, 158))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('presence', 'Var', (4, 12))	('adenocarcinoma', 'Disease', (23, 37))
214505	23741501	Hypermethylation of the promoter regions of the two main human LTBP4 transcriptional forms, LTBP4L and LTBP4S, was found to be involved in LTBP4 silencing.	('silencing', 'NegReg', (145, 154))	('involved', 'Reg', (127, 135))	('LTBP4L', 'Gene', (92, 98))	('Hypermethylation', 'Var', (0, 16))	('LTBP4L', 'Gene', '8425', (92, 98))	('LTBP4S', 'Gene', (103, 109))	('LTBP4', 'Gene', (63, 68))	('LTBP4S', 'Gene', '8425', (103, 109))	('human', 'Species', '9606', (57, 62))
214523	23741501	It has been shown that dysregulated expression of LTBP isoforms is related to the onset of epithelial neoplasms.	('related', 'Reg', (67, 74))	('epithelial neoplasms', 'Phenotype', 'HP:0031492', (91, 111))	('neoplasms', 'Phenotype', 'HP:0002664', (102, 111))	('epithelial neoplasms', 'Disease', (91, 111))	('dysregulated', 'Var', (23, 35))	('LTBP', 'Gene', (50, 54))	('expression', 'Species', '29278', (36, 46))	('epithelial neoplasms', 'Disease', 'MESH:D002277', (91, 111))	('expression', 'MPA', (36, 46))
214528	23741501	However, for LTBP2 it is known that hypermethylation of the promoter is responsible for the downregulation in ESCC and nasopharyngeal carcinomas.	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (119, 143))	('downregulation', 'NegReg', (92, 106))	('nasopharyngeal carcinomas', 'Disease', 'MESH:D000077274', (119, 144))	('nasopharyngeal carcinomas', 'Phenotype', 'HP:0100630', (119, 144))	('hypermethylation', 'Var', (36, 52))	('LTBP2', 'Gene', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ESCC', 'Disease', (110, 114))	('nasopharyngeal carcinomas', 'Disease', (119, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))
214530	23741501	Furthermore, we investigated the potential regulatory mechanism responsible for LTBP4 inactivation in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('LTBP4', 'Gene', (80, 85))	('inactivation', 'Var', (86, 98))	('investigated', 'Reg', (16, 28))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
214534	23741501	In detail, adenocarcinomas of esophagus showed 37%, of stomach 17%, of pancreas 9%, of small intestine 4% and of colon 22% LTBP4 expression (Figure 1A).	('expression', 'Species', '29278', (129, 139))	('LTBP4 expression', 'Var', (123, 139))	('adenocarcinomas', 'Disease', 'MESH:D000230', (11, 26))	('adenocarcinomas', 'Disease', (11, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))
214551	23741501	Epigenetic modifications, such as methylation of cytosine residues in CpG sequences, so called CpG islands, are known to regulate the inactivation of tumor suppressor genes in cancer cells.	('methylation', 'Var', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cytosine', 'Chemical', 'MESH:D003596', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('inactivation', 'MPA', (134, 146))	('regulate', 'Reg', (121, 129))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Disease', (150, 155))
214579	23741501	These results indicate that absence of LTBP4 may play a role in the development of epithelial neoplasms.	('LTBP4', 'Gene', (39, 44))	('neoplasms', 'Phenotype', 'HP:0002664', (94, 103))	('epithelial neoplasms', 'Disease', (83, 103))	('epithelial neoplasms', 'Phenotype', 'HP:0031492', (83, 103))	('epithelial neoplasms', 'Disease', 'MESH:D002277', (83, 103))	('men', 'Species', '9606', (75, 78))	('play', 'Reg', (49, 53))	('absence', 'Var', (28, 35))
214586	23741501	In nasopharyngeal carcinomas and ESCC LTBP2 expression is reduced and re-expression of LTBP2 in ESCC tumor cells suppresses neoplastic capacity in vitro and in vivo .	('nasopharyngeal carcinomas', 'Disease', (3, 28))	('re-expression', 'Var', (70, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('expression', 'MPA', (44, 54))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('expression', 'Species', '29278', (73, 83))	('suppresses', 'NegReg', (113, 123))	('nasopharyngeal carcinomas', 'Disease', 'MESH:D000077274', (3, 28))	('LTBP2', 'Gene', (38, 43))	('nasopharyngeal carcinomas', 'Phenotype', 'HP:0100630', (3, 28))	('neoplastic capacity', 'CPA', (124, 143))	('reduced', 'NegReg', (58, 65))	('LTBP2', 'Gene', (87, 92))	('expression', 'Species', '29278', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
214590	23741501	Demethylation treatment restores LTBP2 expression in ESCC cell lines and high LTBP2 expression correlates with better survival of ESCC patients.	('men', 'Species', '9606', (19, 22))	('patients', 'Species', '9606', (135, 143))	('LTBP2', 'Gene', (33, 38))	('LTBP2', 'Gene', (78, 83))	('ESCC', 'Disease', (130, 134))	('expression', 'Species', '29278', (39, 49))	('better', 'PosReg', (111, 117))	('expression', 'Species', '29278', (84, 94))	('restores', 'PosReg', (24, 32))	('expression', 'MPA', (39, 49))	('expression', 'MPA', (84, 94))	('high', 'Var', (73, 77))
214591	23741501	Thus, epigenetic therapy of esophageal cancer with hypomethylating agents could be one new therapeutic approach, since epigenetic therapies with azacitidine demonstrate first promising results in patients with myelodysplastic syndromes, improving their quality of life and survival.	('esophageal cancer', 'Disease', (28, 45))	('survival', 'CPA', (273, 281))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('azacitidine', 'Chemical', 'MESH:D001374', (145, 156))	('patients', 'Species', '9606', (196, 204))	('quality of life', 'CPA', (253, 268))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (210, 235))	('myelodysplastic syndromes', 'Disease', (210, 235))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (210, 235))	('epigenetic', 'Var', (119, 129))	('improving', 'PosReg', (237, 246))
214604	23741501	Deficiency of E2f4 in mice leads to postnatal death due to an impaired development of the airway epithelium.	('postnatal death', 'Disease', (36, 51))	('postnatal death', 'Disease', 'MESH:D003643', (36, 51))	('impaired', 'NegReg', (62, 70))	('E2f4', 'Gene', (14, 18))	('E2f4', 'Gene', '104394', (14, 18))	('men', 'Species', '9606', (78, 81))	('mice', 'Species', '10090', (22, 26))	('Deficiency', 'Var', (0, 10))
214605	23741501	Interestingly, humans with mutations in LTBP4 show a similar, slightly milder lung phenotype, die in early life due to an impaired pulmonary development and display craniofacial aberrations, including microretrognathia, flat midface, receding forehead and wide fontanelles.	('mutations', 'Var', (27, 36))	('microretrognathia', 'Phenotype', 'HP:0000308', (201, 218))	('craniofacial aberrations', 'Phenotype', 'HP:0004484', (165, 189))	('receding forehead', 'CPA', (234, 251))	('wide fontanelles', 'CPA', (256, 272))	('flat midface', 'CPA', (220, 232))	('impaired pulmonary development', 'Disease', (122, 152))	('humans', 'Species', '9606', (15, 21))	('display craniofacial aberrations', 'Disease', (157, 189))	('display craniofacial aberrations', 'Disease', 'MESH:D019465', (157, 189))	('impaired pulmonary development', 'Disease', 'MESH:D002658', (122, 152))	('receding forehead', 'Phenotype', 'HP:0000340', (234, 251))	('LTBP4', 'Gene', (40, 45))	('flat midface', 'Phenotype', 'HP:0011800', (220, 232))	('wide fontanelles', 'Phenotype', 'HP:0000239', (256, 272))	('microretrognathia', 'Disease', (201, 218))
214617	23741501	Human cDNA of LTBP4L (NM_001042544) and LTBP4S (NM_001042545) were purchased from OriGene (USA) and cloned (primers in Supporting Information S1) into a pcDNA6/myc-His vector (Life Technologies, Germany).	('Human', 'Species', '9606', (0, 5))	('LTBP4S', 'Gene', (40, 46))	('NM_001042545', 'Var', (48, 60))	('LTBP4S', 'Gene', '8425', (40, 46))	('LTBP4L', 'Gene', '8425', (14, 20))	('NM_001042544', 'Var', (22, 34))	('LTBP4L', 'Gene', (14, 20))
214636	23741501	The esophageal cancer cell lines were treated with 5 microM 5-aza-2'-deoxycytidine (Sigma-Aldrich, Germany) for 5 days to determine the significances of hypermethylation in LTBP4 silencing.	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('LTBP4', 'Gene', (173, 178))	('hypermethylation', 'Var', (153, 169))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (60, 82))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal cancer', 'Disease', (4, 21))
214746	32897520	The Child-Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 x 10-4 and 2.42 x 10-4, respectively).	('ALBI grade', 'CPA', (25, 35))	('Child', 'Species', '9606', (4, 9))	('SVR12', 'Var', (75, 80))	('improved', 'PosReg', (50, 58))	('Child-Pugh score', 'CPA', (4, 20))
214747	32897520	Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12.	('SVR12', 'Var', (111, 116))	('branched-chain amino acid', 'Chemical', 'MESH:D000597', (34, 59))	('use of diuretics', 'MPA', (13, 29))	('reduced', 'NegReg', (87, 94))	('branched-chain amino acid preparations', 'MPA', (34, 72))
214788	32897520	Fifty-two and 19 patients were infected with genotype 1 and 2, respectively.	('infected', 'Disease', 'MESH:D007239', (31, 39))	('infected', 'Disease', (31, 39))	('patients', 'Species', '9606', (17, 25))	('genotype', 'Var', (45, 53))
214807	32897520	Of the 20 patients with SVR12, 4 developed recurrent HCC during the follow-up period: 1 underwent radiofrequency ablation for solitary lesion, 1 underwent CyberKnife treatment for solitary lesion, 1 underwent hepatic arterial infusion chemotherapy using a reservoir for portal vein thrombosis, and 1 is awaiting liver transplantation due to deteriorated liver function despite a solitary lesion.	('vein thrombosis', 'Phenotype', 'HP:0004936', (277, 292))	('HCC', 'Disease', (53, 56))	('deteriorated liver function', 'Phenotype', 'HP:0001410', (341, 368))	('deteriorated liver function', 'Disease', (341, 368))	('portal vein thrombosis', 'Phenotype', 'HP:0030242', (270, 292))	('patients', 'Species', '9606', (10, 18))	('vein thrombosis', 'Disease', 'MESH:D020246', (277, 292))	('vein thrombosis', 'Disease', (277, 292))	('SVR12', 'Var', (24, 29))	('deteriorated liver function', 'Disease', 'MESH:D056486', (341, 368))
214810	32897520	In one patient (genotype 1b), no RASs were detected at position L31, Q54, and Y93 at baseline; however, L31V, F37L, and Y93N emerged at relapse.	('Y93N', 'Var', (120, 124))	('Y93N', 'Mutation', 'p.Y93N', (120, 124))	('L31V', 'Var', (104, 108))	('F37L', 'Var', (110, 114))	('patient', 'Species', '9606', (7, 14))	('F37L', 'Mutation', 'p.F37L', (110, 114))	('L31V', 'Mutation', 'p.L31V', (104, 108))
214811	32897520	In the other patient (genotype 2b), Q30K and L31M had already existed at baseline; thereafter, both Q30K and L31M remained at relapse.	('L31M', 'Var', (109, 113))	('Q30K', 'Var', (36, 40))	('patient', 'Species', '9606', (13, 20))	('L31M', 'Var', (45, 49))	('Q30K', 'Mutation', 'p.Q30K', (100, 104))	('L31M', 'Mutation', 'p.L31M', (109, 113))	('Q30K', 'Var', (100, 104))	('Q30K', 'Mutation', 'p.Q30K', (36, 40))	('L31M', 'Mutation', 'p.L31M', (45, 49))
214812	32897520	Neither relapser had NS5B RASs (including S282T) at baseline or relapse.	('S282T', 'Mutation', 'p.S282T', (42, 47))	('NS5B', 'Gene', (21, 25))	('S282T', 'Var', (42, 47))
214819	32897520	Accordingly, the liver functional reserve based on the Child-Pugh classification significantly improved in the patients who achieved SVR12 (p < 0.001; Fig.	('SVR12', 'Var', (133, 138))	('Child', 'Species', '9606', (55, 60))	('improved', 'PosReg', (95, 103))	('liver functional reserve', 'MPA', (17, 41))	('patients', 'Species', '9606', (111, 119))
214823	32897520	Accordingly, the liver functional reserve based on the mALBI grade also significantly improved in patients who achieved SVR12 (p < 0.001; Fig.	('patients', 'Species', '9606', (98, 106))	('SVR12', 'Var', (120, 125))	('improved', 'PosReg', (86, 94))	('liver functional reserve', 'MPA', (17, 41))
214825	32897520	Among the 37 grade 2b patients, e8ight improved to grade 2a and 3 improved to grade 1.	('e8ight', 'Var', (32, 38))	('improved', 'PosReg', (39, 47))	('patients', 'Species', '9606', (22, 30))
214829	32897520	Taken together, improvements in these surrogate parameters indicate that the achievement of SVR12 with SOF/VEL could restore the liver function reserve during the short term of 24 weeks in patients with decompensated cirrhosis.	('cirrhosis', 'Disease', (217, 226))	('liver function reserve', 'MPA', (129, 151))	('SVR12', 'Gene', (92, 97))	('cirrhosis', 'Phenotype', 'HP:0001394', (217, 226))	('SOF/VEL', 'Gene', '388588', (103, 110))	('restore', 'PosReg', (117, 124))	('cirrhosis', 'Disease', 'MESH:D005355', (217, 226))	('SOF/VEL', 'Gene', (103, 110))	('patients', 'Species', '9606', (189, 197))	('achievement', 'Var', (77, 88))
214831	32897520	Given that the serum albumin levels, Child-Pugh scores/classes, and ALBI grades/scores improved in patients who achieved SVR12, we investigated if the diuretic doses and BCAAs were reduced or discontinued with SVR12.	('SVR12', 'Var', (121, 126))	('improved', 'PosReg', (87, 95))	('serum albumin', 'Gene', '213', (15, 28))	('ALBI grades/scores', 'MPA', (68, 86))	('serum albumin', 'Gene', (15, 28))	('patients', 'Species', '9606', (99, 107))	('BCAAs', 'Chemical', 'MESH:D000597', (170, 175))	('Child-Pugh', 'CPA', (37, 47))	('Child', 'Species', '9606', (37, 42))
214839	32897520	These results suggest that achieving SVR12 with SOF/VEL could improve the severity of cirrhosis-related complications, thereby reducing or sparing drug administration dosages for the treatment of complications in patients with decompensated cirrhosis.	('cirrhosis', 'Disease', (241, 250))	('reducing', 'NegReg', (127, 135))	('improve', 'PosReg', (62, 69))	('SVR12', 'Var', (37, 42))	('cirrhosis', 'Disease', (86, 95))	('cirrhosis', 'Phenotype', 'HP:0001394', (86, 95))	('cirrhosis', 'Phenotype', 'HP:0001394', (241, 250))	('SOF/VEL', 'Gene', (48, 55))	('SOF/VEL', 'Gene', '388588', (48, 55))	('patients', 'Species', '9606', (213, 221))	('sparing', 'NegReg', (139, 146))	('cirrhosis', 'Disease', 'MESH:D005355', (241, 250))	('severity', 'MPA', (74, 82))	('cirrhosis', 'Disease', 'MESH:D005355', (86, 95))
214845	32897520	After achieving SVR12, both patients improved the liver functional reserve: Child-Pugh B to A in one and ALBI grade 3 to 2b in both.	('SVR12', 'Var', (16, 21))	('improved', 'PosReg', (37, 45))	('Child', 'Species', '9606', (76, 81))	('liver functional reserve', 'MPA', (50, 74))	('patients', 'Species', '9606', (28, 36))
214970	32494166	The 5-year overall survival rate of patients with high TMI was significantly lower than that of patients with low TMI (P < 0.001).	('lower', 'NegReg', (77, 82))	('high TMI', 'Var', (50, 58))	('overall survival', 'CPA', (11, 27))	('patients', 'Species', '9606', (36, 44))	('TMI', 'Chemical', '-', (55, 58))	('TMI', 'Chemical', '-', (114, 117))	('patients', 'Species', '9606', (96, 104))
214972	32494166	Patients with ESCC with high TMI level who underwent surgery combined with postoperative chemotherapy had a significantly better prognosis than those who underwent surgery alone (P = 0.015).	('Patients', 'Species', '9606', (0, 8))	('ESCC', 'Disease', (14, 18))	('high', 'Var', (24, 28))	('TMI', 'Chemical', '-', (29, 32))	('TMI level', 'MPA', (29, 38))
215024	32494166	Furthermore, the 5-year OS rate in patients with ESCC with a high TMI level was 25.7%, which was significantly lower than that in patients with a low TMI level (50.2%, P < 0.001; Figure 2C).	('TMI', 'Chemical', '-', (66, 69))	('high', 'Var', (61, 65))	('TMI', 'MPA', (66, 69))	('patients', 'Species', '9606', (130, 138))	('lower', 'NegReg', (111, 116))	('ESCC', 'Disease', (49, 53))	('patients', 'Species', '9606', (35, 43))	('TMI', 'Chemical', '-', (150, 153))
215030	32494166	In patients with ESCC who underwent surgery alone, the 5-year OS rate in patients with a high TMI level was 16.9%, which was significantly lower than that in patients with a low TMI level (50.7%, P = 0.001; Figure 3A).	('TMI', 'Chemical', '-', (178, 181))	('ESCC', 'Disease', (17, 21))	('TMI', 'Chemical', '-', (94, 97))	('high', 'Var', (89, 93))	('patients', 'Species', '9606', (3, 11))	('lower', 'NegReg', (139, 144))	('TMI', 'MPA', (94, 97))	('patients', 'Species', '9606', (158, 166))	('patients', 'Species', '9606', (73, 81))
215031	32494166	In patients with ESCC who underwent surgery and postoperative adjuvant chemotherapy, the 5-year OS rate in patients with a high TMI level was significantly lower than that in patients with a low TMI level (31.0% vs. 49.8%, P = 0.006; Figure 3B).	('patients', 'Species', '9606', (107, 115))	('TMI', 'Chemical', '-', (195, 198))	('ESCC', 'Disease', (17, 21))	('high', 'Var', (123, 127))	('TMI', 'Chemical', '-', (128, 131))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (3, 11))	('TMI', 'MPA', (128, 131))	('lower', 'NegReg', (156, 161))
215034	32494166	Our results revealed that, in patients with ESCC with high TMI level, those who underwent surgery combined with postoperative adjuvant chemotherapy had a significantly better prognosis than those who underwent surgery alone (chi2= 5.931, P = 0.015, Figure 4B).	('ESCC', 'Disease', (44, 48))	('TMI level', 'MPA', (59, 68))	('high', 'Var', (54, 58))	('TMI', 'Chemical', '-', (59, 62))	('patients', 'Species', '9606', (30, 38))
215058	32494166	Our results demonstrated that the TMI, by combining CYFRA 21-1 and SCC-Ag, could increase the prognostic evaluation.	('CYFRA 21-1', 'Var', (52, 62))	('TMI', 'Chemical', '-', (34, 37))	('increase', 'PosReg', (81, 89))	('SCC-Ag', 'Gene', (67, 73))	('prognostic evaluation', 'CPA', (94, 115))
215060	32494166	Our results showed that postoperative adjuvant chemotherapy in patients with ESCC with high TMI level prolonged survival compared with surgery alone.	('TMI level', 'MPA', (92, 101))	('prolonged', 'PosReg', (102, 111))	('survival', 'CPA', (112, 120))	('ESCC', 'Disease', (77, 81))	('high', 'Var', (87, 91))	('patients', 'Species', '9606', (63, 71))	('TMI', 'Chemical', '-', (92, 95))
215062	32494166	Our results indicated that patients with ESCC with high TMI level may benefit from postoperative adjuvant chemotherapy.	('benefit', 'PosReg', (70, 77))	('ESCC', 'Disease', (41, 45))	('TMI', 'Chemical', '-', (56, 59))	('patients', 'Species', '9606', (27, 35))	('high', 'Var', (51, 55))	('TMI level', 'MPA', (56, 65))
215076	32215053	The frequencies of perforation, bleeding, and cicatricial stenosis were significantly lower in the MBM group (p < 0.001, p = 0.011, p = 0.009).	('bleeding', 'Disease', 'MESH:D006470', (32, 40))	('bleeding', 'Disease', (32, 40))	('lower', 'NegReg', (86, 91))	('MBM', 'Var', (99, 102))	('MBM', 'Chemical', '-', (99, 102))	('cicatricial stenosis', 'Disease', (46, 66))	('perforation', 'CPA', (19, 30))
215077	32215053	Three local recurrences were observed in the ER-Cap group, while no recurrence was observed in MBM and ESD groups.	('ER-Cap', 'Var', (45, 51))	('MBM', 'Chemical', '-', (95, 98))	('ER-Cap', 'Chemical', '-', (45, 51))	('local', 'CPA', (6, 11))
215160	29930517	No Association Between MicroRNA-608 rs4919510 G>C Polymorphism and Digestive System Cancers Susceptibility: A Meta-Analysis Based on 10,836 Individuals Previous epidemiologic studies have revealed a possible association between microRNA-608 rs4919510 G>C polymorphism and digestive system cancers (DSCs) risk, but the results were not consistent.	('system cancers', 'Disease', (282, 296))	('Cancers', 'Disease', 'MESH:D009369', (84, 91))	('rs4919510', 'Mutation', 'rs4919510', (36, 45))	('system cancers', 'Disease', 'MESH:D009369', (282, 296))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('rs4919510 G>C polymorphism', 'Var', (241, 267))	('microRNA-608', 'Gene', '693193', (228, 240))	('MicroRNA-608', 'Gene', '693193', (23, 35))	('microRNA-608', 'Gene', (228, 240))	('MicroRNA-608', 'Gene', (23, 35))	('rs4919510', 'Mutation', 'rs4919510', (241, 250))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('Cancers', 'Disease', (84, 91))	('Cancers', 'Phenotype', 'HP:0002664', (84, 91))
215161	29930517	We therefore performed an updated meta-analysis to explore the association between microRNA-608 rs4919510 G>C polymorphism and DSCs risk.	('rs4919510 G>C', 'Var', (96, 109))	('DSCs', 'Disease', (127, 131))	('microRNA-608', 'Gene', '693193', (83, 95))	('rs4919510', 'Mutation', 'rs4919510', (96, 105))	('microRNA-608', 'Gene', (83, 95))
215162	29930517	Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the relationship between the microRNA-608 rs4919510 G>C polymorphism and DSCs risk.	('rs4919510', 'Mutation', 'rs4919510', (128, 137))	('rs4919510 G>C', 'Var', (128, 141))	('microRNA-608', 'Gene', '693193', (115, 127))	('microRNA-608', 'Gene', (115, 127))	('DSCs', 'Disease', (159, 163))
215163	29930517	Overall, no significant association was found between microRNA-608 rs4919510 G>C polymorphism and DSCs risk in general populations.	('rs4919510', 'Mutation', 'rs4919510', (67, 76))	('rs4919510 G>C', 'Var', (67, 80))	('microRNA-608', 'Gene', '693193', (54, 66))	('microRNA-608', 'Gene', (54, 66))	('DSCs', 'Disease', (98, 102))
215164	29930517	In summary, current evidence indicates that the microRNA-608 rs4919510 G>C polymorphism maybe an important factor of DSCs susceptibility, especially in Caucasian population.	('microRNA-608', 'Gene', (48, 60))	('rs4919510', 'Mutation', 'rs4919510', (61, 70))	('rs4919510 G>C', 'Var', (61, 74))	('DSCs', 'Disease', (117, 121))	('microRNA-608', 'Gene', '693193', (48, 60))
215171	29930517	Evidences suggested that abnormal gene expression and an alteration of amino acid structure can lead to abnormal biologic activities that result in an imbalance of normal physiologic function and induce the formation of tumors.	('induce', 'Reg', (196, 202))	('abnormal', 'Var', (25, 33))	('imbalance', 'Phenotype', 'HP:0002172', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('alteration', 'Reg', (57, 67))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('lead to', 'Reg', (96, 103))	('formation', 'CPA', (207, 216))	('result in', 'Reg', (138, 147))	('imbalance of normal physiologic function', 'MPA', (151, 191))	('biologic activities', 'CPA', (113, 132))
215172	29930517	Some studies indicated that abnormal microRNA expression could result in tumor occurrence (Valeri et al.,; Tessitore et al.,).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('abnormal', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('microRNA expression', 'MPA', (37, 56))	('tumor', 'Disease', (73, 78))	('result in', 'Reg', (63, 72))
215177	29930517	SNPs alter gene function and/or expression, consequently affecting downstream biologic pathways and increasing cancer risk (Martini et al.,; Niu et al.,).	('affecting', 'Reg', (57, 66))	('alter', 'Reg', (5, 10))	('downstream biologic pathways', 'Pathway', (67, 95))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gene function', 'MPA', (11, 24))	('SNPs', 'Var', (0, 4))	('increasing', 'PosReg', (100, 110))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('expression', 'MPA', (32, 42))
215178	29930517	In microRNA-608, rs4919510 G>C is the most common locus and has attracted increasing attention.	('rs4919510 G>C', 'Var', (17, 30))	('microRNA-608', 'Gene', (3, 15))	('rs4919510', 'Mutation', 'rs4919510', (17, 26))	('microRNA-608', 'Gene', '693193', (3, 15))
215179	29930517	conducted the first case-control study in 2008 and did not find any significant association between the microRNA-608 rs4919510 G>C polymorphism and esophageal cancer (Ye et al.,).	('microRNA-608', 'Gene', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', (148, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('rs4919510', 'Mutation', 'rs4919510', (117, 126))	('rs4919510 G>C', 'Var', (117, 130))	('microRNA-608', 'Gene', '693193', (104, 116))
215180	29930517	Recently, a published meta-analysis addressed the association between microRNA-608 rs4919510 G>C polymorphism and cancer risk (Liu et al.,), but the results were not consistent with subsequent studies, especially in DSCs.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('microRNA-608', 'Gene', (70, 82))	('DSCs', 'Disease', (216, 220))	('microRNA-608', 'Gene', '693193', (70, 82))	('rs4919510', 'Mutation', 'rs4919510', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rs4919510 G>C', 'Var', (83, 96))	('cancer', 'Disease', (114, 120))
215181	29930517	Therefore, we conducted the present meta-analysis to more precisely and comprehensively assess of the association between microRNA-608 rs4919510 G>C polymorphism and DSCs risk.	('association', 'Interaction', (102, 113))	('rs4919510 G>C', 'Var', (135, 148))	('DSCs', 'Disease', (166, 170))	('microRNA-608', 'Gene', '693193', (122, 134))	('microRNA-608', 'Gene', (122, 134))	('rs4919510', 'Mutation', 'rs4919510', (135, 144))
215182	29930517	Five electronic English databases (PubMed, Embase, Web of Science, CNKI and Wanfang) were searched for relevant studies that focused on the association between microRNA-608 rs4919510 G>C polymorphism and DSCs risk from inception up to January 1, 2018.	('association', 'Interaction', (140, 151))	('rs4919510', 'Mutation', 'rs4919510', (173, 182))	('microRNA-608', 'Gene', '693193', (160, 172))	('microRNA-608', 'Gene', (160, 172))	('DSCs', 'Disease', (204, 208))	('rs4919510 G>C polymorphism', 'Var', (173, 199))
215183	29930517	The following search terms and strategy was used (e.g., in PubMed): #1 microRNA 608 #2 microRNA-608 #3 mir 608 #4 mir-608 #5 rs4919510 #6 #1 OR #2 OR #3 OR #4 OR #5 #7 polymorphism #8 variant #9 mutation #10 #7 OR #8 OR #9 #11 cancer #12 tumor #13 neoplasm #14 #11 OR #12 OR #13 #15 #6 AND #10 AND #14 Studies were included based on the following criteria: (1) only case-control studies that focusing on the association between the microRNA-608 rs4919510 G>C polymorphism and DSCs risk; and (2) studies had to provided sufficient frequency data on the genotype distribution to evaluate the crude odds ratios (ORs) and 95% confidence intervals (CIs); and; (3) studies had to be published only in English and Chinese; and (4) only publications with the largest or most recently updated sample data were included when there were some overlapping or duplicate publications on the same theme.	('neoplasm', 'Disease', 'MESH:D009369', (248, 256))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('DSCs', 'Disease', (476, 480))	('neoplasm', 'Disease', (248, 256))	('microRNA-608', 'Gene', (87, 99))	('mir', 'Gene', (114, 117))	('rs4919510 G>C', 'Var', (445, 458))	('mir', 'Gene', '220972', (103, 106))	('microRNA-608', 'Gene', '693193', (87, 99))	('neoplasm', 'Phenotype', 'HP:0002664', (248, 256))	('tumor', 'Disease', (238, 243))	('cancer', 'Disease', (227, 233))	('microRNA-608', 'Gene', (432, 444))	('mir', 'Gene', (103, 106))	('rs4919510', 'Mutation', 'rs4919510', (445, 454))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('mir', 'Gene', '220972', (114, 117))	('microRNA-608', 'Gene', '693193', (432, 444))	('rs4919510', 'Mutation', 'rs4919510', (125, 134))
215185	29930517	We calculated ORs and 95% CIs to assess the association between microRNA-608 rs4919510 G>C polymorphism and DSCs risk.	('rs4919510', 'Mutation', 'rs4919510', (77, 86))	('rs4919510 G>C', 'Var', (77, 90))	('DSCs', 'Disease', (108, 112))	('microRNA-608', 'Gene', '693193', (64, 76))	('microRNA-608', 'Gene', (64, 76))
215189	29930517	Overall, no significant association between the microRNA-608 rs4919510 G>C polymorphism and DSCs risk was observed with the included studies (C vs. G: OR = 1.00, 95% CI = 0.91-1.10, P = 0.98, I2 = 53.4%; GC vs. GG: OR = 1.07, 95% CI = 0.93-1.24, P = 0.35, I2 = 43.0%; CC vs. GG: OR = 1.01, 95% CI = 0.83-1.24, P = 0.90, I2 = 56.4%; GC+CC vs. GG: OR = 1.05, 95% CI = 0.89-1.23, P = 0.58, I2 = 56.4%, (Figure 2); CC vs. GG+GC: OR = 0.99, 95% CI = 0.91-1.09, P = 0.89, I2 = 0%) (Supplementary Figure S1).	('microRNA-608', 'Gene', (48, 60))	('rs4919510 G', 'Var', (61, 72))	('GC', 'Phenotype', 'HP:0012126', (332, 334))	('rs4919510', 'Mutation', 'rs4919510', (61, 70))	('GC', 'Phenotype', 'HP:0012126', (204, 206))	('GC', 'Phenotype', 'HP:0012126', (421, 423))	('microRNA-608', 'Gene', '693193', (48, 60))
215190	29930517	The results of race diversity demonstrated some significant protective effects between microRNA-608 rs4919510 G>C polymorphism and DSCs risk in Caucasian populations (C vs. G: OR = 0.82, 95% CI = 0.68-0.99, P = 0.03, I2 = 0%; CC vs. GG: OR = 0.59, 95% CI = 0.36-0.97, P = 0.04, I2 = 0%; GC+CC vs. GG: OR = 0.61, 95% CI = 0.37-0.99, P = 0.05, I2 = 0%, Figure 2).	('microRNA-608', 'Gene', (87, 99))	('rs4919510 G>C', 'Var', (100, 113))	('DSCs', 'Disease', (131, 135))	('GC', 'Phenotype', 'HP:0012126', (287, 289))	('rs4919510', 'Mutation', 'rs4919510', (100, 109))	('microRNA-608', 'Gene', '693193', (87, 99))
215191	29930517	But the other Subgroup analysis based on control design, cancer type, subject number, and NOS evaluation did not present any significant association between microRNA-608 rs4919510 G>C polymorphism and DSCs risk.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('rs4919510 G>C', 'Var', (170, 183))	('cancer', 'Disease', (57, 63))	('DSCs', 'Disease', (201, 205))	('microRNA-608', 'Gene', '693193', (157, 169))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('microRNA-608', 'Gene', (157, 169))	('rs4919510', 'Mutation', 'rs4919510', (170, 179))
215193	29930517	Some mutations, such as SNPs in microRNAs or their binding site, may alter cancer susceptibility in various tumor types and different populations (Niu et al.,).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Disease', (75, 81))	('tumor', 'Disease', (108, 113))	('SNPs', 'Var', (24, 28))	('alter', 'Reg', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
215198	29930517	Rs4919510 G>C is the most common SNP locus in microRNA-608 and might contribute a different free energy to its binding site of target genes, including INSR,CD4, GHR and RXRB (Landi et al.,).	('GHR', 'Gene', '2690', (161, 164))	('GHR', 'Gene', (161, 164))	('microRNA-608', 'Gene', '693193', (46, 58))	('microRNA-608', 'Gene', (46, 58))	('RXRB', 'Gene', (169, 173))	('INSR', 'Gene', (151, 155))	('Rs4919510', 'Mutation', 'Rs4919510', (0, 9))	('binding', 'Interaction', (111, 118))	('CD4', 'Gene', (156, 159))	('RXRB', 'Gene', '6257', (169, 173))	('CD4', 'Gene', '920', (156, 159))	('contribute', 'Reg', (69, 79))	('free energy', 'MPA', (92, 103))	('Rs4919510 G>C', 'Var', (0, 13))	('INSR', 'Gene', '3643', (151, 155))
215200	29930517	HSF1 is a predicted target of miR-608 and the C-to-G substitution of rs4919510 might weaken the suppression of HSF1 mRNA by miR-608, leading to relatively high expression of HSF1 protein, which could up-regulate the expression of HER2 and facilitated tumorigenesis.	('high', 'PosReg', (155, 159))	('tumor', 'Disease', (251, 256))	('up-regulate', 'PosReg', (200, 211))	('suppression', 'MPA', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('HER2', 'Gene', '2064', (230, 234))	('weaken', 'NegReg', (85, 91))	('rs4919510', 'Var', (69, 78))	('expression', 'MPA', (216, 226))	('miR-608', 'Gene', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('miR-608', 'Gene', '693193', (30, 37))	('expression', 'MPA', (160, 170))	('HSF1', 'Gene', (0, 4))	('facilitated', 'PosReg', (239, 250))	('miR-608', 'Gene', (124, 131))	('HSF1', 'Gene', '3297', (0, 4))	('miR-608', 'Gene', '693193', (124, 131))	('HSF1', 'Gene', (111, 115))	('HER2', 'Gene', (230, 234))	('HSF1', 'Gene', '3297', (111, 115))	('protein', 'Protein', (179, 186))	('HSF1', 'Gene', (174, 178))	('HSF1', 'Gene', '3297', (174, 178))	('rs4919510', 'Mutation', 'rs4919510', (69, 78))
215201	29930517	The above evidence indicated that the alteration of free energy caused by gene mutation between miR-608 and targeted mRNA would influence the protein expression and change the cancer susceptibility (Huang et al.,).	('gene mutation', 'Var', (74, 87))	('influence', 'Reg', (128, 137))	('miR-608', 'Gene', (96, 103))	('change', 'Reg', (165, 171))	('free energy', 'MPA', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('miR-608', 'Gene', '693193', (96, 103))	('protein expression', 'MPA', (142, 160))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('alteration', 'Reg', (38, 48))
215202	29930517	Since 2008, a series of case-control studies focused on microRNA-608 rs4919510 G>C polymorphism and DSCs risk were published, but the conclusions were inconsistent.	('microRNA-608', 'Gene', (56, 68))	('microRNA-608', 'Gene', '693193', (56, 68))	('DSCs', 'Disease', (100, 104))	('rs4919510', 'Mutation', 'rs4919510', (69, 78))	('rs4919510 G>C', 'Var', (69, 82))
215203	29930517	explored the association between microRNA-608 rs4919510 G>C polymorphism and gastric cancer and found an apparently increased risk of gastric cancer in a Latvian population with GG genotype (GG vs. CC, OR = 2.34, 95% CI, 1.08-5.04) (Kupcinskas et al.,).	('association', 'Interaction', (13, 24))	('gastric cancer', 'Disease', (77, 91))	('rs4919510 G>C', 'Var', (46, 59))	('gastric cancer', 'Disease', (134, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('microRNA-608', 'Gene', (33, 45))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('microRNA-608', 'Gene', '693193', (33, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('rs4919510', 'Mutation', 'rs4919510', (46, 55))
215204	29930517	evaluated the microRNA-608 rs4919510 G>C polymorphism in Chinese individuals and concluded that the rs4919510 G-allele and genotype GG were protective factors for stage 0 to II colorectal cancer (CRC) (GG vs. CC, OR = 0.70, 95% CI = 0.55-0.88) (Ying et al.,).	('microRNA-608', 'Gene', (14, 26))	('rs4919510', 'Mutation', 'rs4919510', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('II colorectal cancer', 'Disease', 'MESH:D015179', (174, 194))	('CRC', 'Phenotype', 'HP:0003003', (196, 199))	('rs4919510', 'Var', (100, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('rs4919510', 'Mutation', 'rs4919510', (27, 36))	('II colorectal cancer', 'Disease', (174, 194))	('microRNA-608', 'Gene', '693193', (14, 26))	('stage', 'Disease', (163, 168))
215205	29930517	However, other studies did not find any significant relationship between the microRNA-608 rs4919510 G>C polymorphism and DSCs risk, including these studies by Wang et al.	('rs4919510 G>C', 'Var', (90, 103))	('DSCs', 'Disease', (121, 125))	('microRNA-608', 'Gene', (77, 89))	('microRNA-608', 'Gene', '693193', (77, 89))	('rs4919510', 'Mutation', 'rs4919510', (90, 99))
215206	29930517	and Zhang et al.. How can we conduct a more precise assessment of the association between microRNA-608 rs4919510 G>C polymorphism and DSC risk with these inconsistent results?	('DSC', 'Disease', (134, 137))	('microRNA-608', 'Gene', '693193', (90, 102))	('microRNA-608', 'Gene', (90, 102))	('association', 'Interaction', (70, 81))	('rs4919510', 'Mutation', 'rs4919510', (103, 112))	('rs4919510 G>C', 'Var', (103, 116))
215207	29930517	Therefore, we conducted the meta-analysis with nine published case-control studies to investigate the association between the microRNA-608 rs4919510 G>C polymorphism and DSCs susceptibility.	('rs4919510', 'Mutation', 'rs4919510', (139, 148))	('rs4919510 G>C', 'Var', (139, 152))	('DSCs', 'Disease', (170, 174))	('microRNA-608', 'Gene', (126, 138))	('microRNA-608', 'Gene', '693193', (126, 138))
215209	29930517	The results indicate that the microRNA-608 rs4919510 G>C polymorphism play an important protective effect against DSCs development in Caucasian population only, but not in other subgroup analysis.	('rs4919510', 'Mutation', 'rs4919510', (43, 52))	('rs4919510 G>C', 'Var', (43, 56))	('microRNA-608', 'Gene', '693193', (30, 42))	('DSCs', 'Disease', (114, 118))	('microRNA-608', 'Gene', (30, 42))
215210	29930517	However, according to current results in general population and subgroups, the precise biological mechanism of the association between microRNA-608 rs4919510 G>C polymorphism and DSCs risk were remains unclear.	('microRNA-608', 'Gene', '693193', (135, 147))	('DSCs', 'Disease', (179, 183))	('microRNA-608', 'Gene', (135, 147))	('rs4919510', 'Mutation', 'rs4919510', (148, 157))	('rs4919510 G>C', 'Var', (148, 161))
215211	29930517	To our minds, the possible explanation was that the microRNA-608 rs4919510 G>C polymorphism not participated in cancer susceptibility directly, but play a connected and synergism role during the development of cancer.	('microRNA-608', 'Gene', '693193', (52, 64))	('play', 'Reg', (148, 152))	('microRNA-608', 'Gene', (52, 64))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('rs4919510', 'Mutation', 'rs4919510', (65, 74))	('rs4919510 G>C', 'Var', (65, 78))	('cancer', 'Disease', (210, 216))
215212	29930517	published two meta-analysis assessing the association between the microRNA-608 rs4919510 G>C polymorphism and cancer risk.	('microRNA-608', 'Gene', '693193', (66, 78))	('cancer', 'Disease', (110, 116))	('microRNA-608', 'Gene', (66, 78))	('rs4919510', 'Mutation', 'rs4919510', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rs4919510 G>C', 'Var', (79, 92))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
215215	29930517	suggested that CG genotypes would increase the cancer risk in the Chinese populations.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('genotypes', 'Var', (18, 27))	('cancer', 'Disease', (47, 53))	('CG genotypes', 'Var', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('increase', 'PosReg', (34, 42))
215216	29930517	However, the results of their meta-analysis focused on the general cancer, and the association between the microRNA-608 rs4919510 G>C polymorphism and DSCs risk was not conducted.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('microRNA-608', 'Gene', (107, 119))	('cancer', 'Disease', (67, 73))	('DSCs', 'Disease', (151, 155))	('rs4919510', 'Mutation', 'rs4919510', (120, 129))	('rs4919510 G>C', 'Var', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('microRNA-608', 'Gene', '693193', (107, 119))
215217	29930517	To our knowledge, this is the first meta-analysis to explore the association between the microRNA-608 rs4919510 G>C polymorphism and DSCs risk.	('rs4919510', 'Mutation', 'rs4919510', (102, 111))	('rs4919510 G>C', 'Var', (102, 115))	('microRNA-608', 'Gene', '693193', (89, 101))	('microRNA-608', 'Gene', (89, 101))	('DSCs', 'Disease', (133, 137))
215218	29930517	Additionally, more rigorous methodology, including cumulative and sensitivity analyses and quality evaluation with modified NOS, were used to estimate the genetic effects of the microRNA-608 rs4919510 G>C polymorphism on carcinogenesis.	('rs4919510', 'Mutation', 'rs4919510', (191, 200))	('carcinogenesis', 'CPA', (221, 235))	('rs4919510 G>C', 'Var', (191, 204))	('microRNA-608', 'Gene', '693193', (178, 190))	('microRNA-608', 'Gene', (178, 190))
215219	29930517	This provided a more accurate evaluation of the association between the microRNA-608 rs4919510 G>C polymorphism and DSCs risk.	('DSCs', 'Disease', (116, 120))	('microRNA-608', 'Gene', '693193', (72, 84))	('microRNA-608', 'Gene', (72, 84))	('rs4919510', 'Mutation', 'rs4919510', (85, 94))	('association', 'Interaction', (48, 59))	('rs4919510 G>C', 'Var', (85, 98))
215221	29930517	Second, this meta-analysis only focused on one SNP locus (microRNA-608 rs4919510 G>C), and the results were calculated without gene-gene and gene-environment risk factors, leading to a failure to interpret the potential interaction mechanisms.	('microRNA-608', 'Gene', '693193', (58, 70))	('rs4919510', 'Mutation', 'rs4919510', (71, 80))	('rs4919510 G>C', 'Var', (71, 84))	('microRNA-608', 'Gene', (58, 70))
215222	29930517	In summary, our meta-analysis demonstrated that the microRNA-608 rs4919510 G>C polymorphism might play an important role in DSCs susceptibility.	('microRNA-608', 'Gene', '693193', (52, 64))	('microRNA-608', 'Gene', (52, 64))	('DSCs', 'Disease', (124, 128))	('rs4919510', 'Mutation', 'rs4919510', (65, 74))	('rs4919510 G>C', 'Var', (65, 78))
215288	28373774	The variables shown to be adversely affected were (in decreasing order of severity) body weight loss, esophageal reflux SS, meal-related distress SS, dissatisfaction with meals, necessity for additional meals, and dissatisfaction with daily life SS.	('esophageal reflux', 'Phenotype', 'HP:0002020', (102, 119))	('dissatisfaction', 'Disease', (150, 165))	('dissatisfaction', 'Var', (214, 229))	('weight loss', 'Disease', (89, 100))	('esophageal reflux SS', 'Disease', (102, 122))	('esophageal reflux SS', 'Disease', 'MESH:D005764', (102, 122))	('weight loss', 'Phenotype', 'HP:0001824', (89, 100))	('dissatisfaction with daily life', 'Phenotype', 'HP:0031058', (214, 245))	('weight loss', 'Disease', 'MESH:D015431', (89, 100))
215328	24888779	When cancer tissues are examined, it is important to determine whether the full-length, modified fragments, or different variants of delta-catenin are expressed in the cancer cells and whether the revealed delta-catenin distribution in cancer is dependent upon the choices of antibody applications.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('modified', 'Var', (88, 96))	('cancer', 'Disease', (5, 11))	('variants', 'Var', (121, 129))	('cancer', 'Disease', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
215336	24888779	The rAb25 antibody reacted with the slow migrating and modified high molecular weight form of delta-catenin, although it may or may not overlap with the forms that reacted with rAb62 (Figure 1A).	('delta-catenin', 'Protein', (94, 107))	('slow migrating', 'MPA', (36, 50))	('rAb25', 'Gene', (4, 9))	('modified', 'Var', (55, 63))	('rAb25', 'Gene', '310632', (4, 9))	('reacted', 'Reg', (19, 26))
215352	24888779	Compelling recent evidence has linked CTNND2 SNP or mutations to cancer, myopia, cortical cataract, and Alzheimer's disease.	('mutations', 'Var', (52, 61))	('CTNND2', 'Gene', '1501', (38, 44))	('myopia', 'Disease', (73, 79))	('cortical cataract', 'Disease', 'MESH:D002386', (81, 98))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (104, 123))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('CTNND2', 'Gene', (38, 44))	('myopia', 'Disease', 'MESH:D009216', (73, 79))	("Alzheimer's disease", 'Disease', (104, 123))	('myopia', 'Phenotype', 'HP:0000545', (73, 79))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (104, 123))	('cortical cataract', 'Disease', (81, 98))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cataract', 'Phenotype', 'HP:0000518', (90, 98))	('cortical cataract', 'Phenotype', 'HP:0100019', (81, 98))
215353	24888779	In corroboration with our observations of different variants and fragments and differential distribution of delta-catenin in the cancer cells and tissues reported in this article, it is important for future studies on delta-catenin to recognize that delta-catenin could exist as different forms in cancer tissues and they may exert different roles in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('variants', 'Var', (52, 60))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (298, 304))	('cancer', 'Disease', (351, 357))	('cancer', 'Disease', 'MESH:D009369', (351, 357))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
215354	24888779	The investigations of delta-catenin involved in human disease pathogenesis have accelerated in recent years and strongly support that delta-catenin is a potential cancer biomarker.	('human', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('delta-catenin', 'Var', (134, 147))
215542	29403195	Although epidemiological data remain inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for Vitamin D, results from some correlating studies strongly suggest that Vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding Vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', (423, 429))	('humans', 'Species', '9606', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Vitamin D', 'Chemical', 'MESH:D014807', (225, 234))	('reduce', 'NegReg', (387, 393))	('Vitamin D', 'Chemical', 'MESH:D014807', (154, 163))	('deficiency', 'Var', (235, 245))	('Vitamin', 'Gene', (225, 232))	('cancer', 'Disease', (394, 400))	('increases', 'PosReg', (246, 255))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('Vitamin D', 'Chemical', 'MESH:D014807', (326, 335))	('cancer', 'Disease', 'MESH:D009369', (423, 429))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('Vitamin D deficiency', 'Phenotype', 'HP:0100512', (225, 245))	('improve', 'PosReg', (415, 422))
215583	29403195	A single-nucleotide polymorphism in the promoter of COX-2 may increase the risk of developing esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (94, 119))	('COX-2', 'Gene', (52, 57))	('esophageal adenocarcinoma', 'Disease', (94, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (94, 119))	('single-nucleotide polymorphism', 'Var', (2, 32))	('COX-2', 'Gene', '4513', (52, 57))	('increase', 'PosReg', (62, 70))
215598	29403195	found that direct usage of 1,25(OH)2D3 induces cellular apoptosis in gastric cancer cells and also increased the expression of VDR and CYP24A1 further supporting the antitumoral role that Vitamin D may activate in gastric cancer.	('gastric cancer', 'Disease', (214, 228))	('1,25(OH)2D3', 'Var', (27, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('tumor', 'Disease', (170, 175))	('induces', 'Reg', (39, 46))	('Vitamin D', 'Chemical', 'MESH:D014807', (188, 197))	('expression', 'MPA', (113, 123))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('gastric cancer', 'Disease', 'MESH:D013274', (214, 228))	('CYP24A1', 'Gene', (135, 142))	('VDR', 'Gene', (127, 130))	('increased', 'PosReg', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (27, 38))	('gastric cancer', 'Disease', (69, 83))	('cellular apoptosis', 'CPA', (47, 65))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('CYP24A1', 'Gene', '1591', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (214, 228))	('VDR', 'Gene', '7421', (127, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))
215619	29403195	Vitamin D metabolites suppress TGF-beta-mediated fibrosis through modulating multiple profibrotic proteins, for instance, lowering collagen I and III expression and raising expression levels of matrix metallopeptidase 8, a metalloproteinase that degrades collagen.	('TGF-beta', 'Gene', (31, 39))	('III expression', 'MPA', (146, 160))	('modulating', 'Reg', (66, 76))	('raising', 'PosReg', (165, 172))	('lowering', 'NegReg', (122, 130))	('fibrosis', 'Disease', (49, 57))	('fibrosis', 'Disease', 'MESH:D005355', (49, 57))	('expression levels', 'MPA', (173, 190))	('suppress', 'NegReg', (22, 30))	('matrix metallopeptidase 8', 'Gene', '4317', (194, 219))	('TGF-beta', 'Gene', '7040', (31, 39))	('matrix metallopeptidase 8', 'Gene', (194, 219))	('metabolites', 'Var', (10, 21))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))	('collagen I', 'MPA', (131, 141))
215645	29403195	VDR overexpression in CRC is associated with PI3K-AKT pathway and KRAS mutations.	('VDR', 'Gene', '7421', (0, 3))	('KRAS', 'Gene', '3845', (66, 70))	('CRC', 'Disease', (22, 25))	('mutations', 'Var', (71, 80))	('PI3K-AKT pathway', 'Pathway', (45, 61))	('VDR', 'Gene', (0, 3))	('overexpression', 'PosReg', (4, 18))	('CRC', 'Phenotype', 'HP:0003003', (22, 25))	('associated', 'Reg', (29, 39))	('KRAS', 'Gene', (66, 70))
215647	29403195	Thus, the polymorphisms of the VDR gene may be possible risk factors for colorectal carcinogenesis.	('VDR', 'Gene', '7421', (31, 34))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (73, 98))	('polymorphisms', 'Var', (10, 23))	('risk factors', 'Reg', (56, 68))	('colorectal carcinogenesis', 'Disease', (73, 98))	('VDR', 'Gene', (31, 34))
215649	29403195	Vitamin D deficiency is common in inflammatory bowel diseases (IBD) and colon cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colon cancer', 'Disease', (72, 84))	('Vitamin D', 'Gene', (0, 9))	('colon cancer', 'Phenotype', 'HP:0003003', (72, 84))	('patients', 'Species', '9606', (85, 93))	('inflammatory bowel diseases', 'Disease', 'MESH:D015212', (34, 61))	('Vitamin D deficiency', 'Phenotype', 'HP:0100512', (0, 20))	('inflammatory bowel diseases', 'Phenotype', 'HP:0002037', (34, 61))	('deficiency', 'Var', (10, 20))	('common', 'Reg', (24, 30))	('colon cancer', 'Disease', 'MESH:D015179', (72, 84))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))	('inflammatory bowel diseases', 'Disease', (34, 61))	('IBD', 'Phenotype', 'HP:0002037', (63, 66))
215753	25260491	D5 to the gross tumor volume and clinical target volume was higher with IMPT than with intensity modulated radiation therapy or PSPT (P<.05).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('higher', 'PosReg', (60, 66))	('IMPT', 'Chemical', '-', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('IMPT', 'Var', (72, 76))	('tumor', 'Disease', (16, 21))
215791	25260491	For all patients tested, IMPT plans were associated with lower MLD, lung V5 and V20, heart V40, and esophageal V60 values than were IMRT plans (P<.05) and lower MLD, lung V20, and esophageal V60 than PSPT plans (P<.05) (Fig.	('IMPT', 'Chemical', '-', (25, 29))	('lung V5', 'MPA', (68, 75))	('patients', 'Species', '9606', (8, 16))	('heart V40', 'MPA', (85, 94))	('esophageal V60 values', 'MPA', (100, 121))	('MLD', 'Disease', 'MESH:D007966', (161, 164))	('MLD', 'Disease', (161, 164))	('lower', 'NegReg', (155, 160))	('esophageal V60', 'MPA', (180, 194))	('MLD', 'Disease', 'MESH:D007966', (63, 66))	('lung V20', 'MPA', (166, 174))	('IMPT plans', 'Var', (25, 35))	('MLD', 'Disease', (63, 66))	('V20', 'MPA', (80, 83))	('lower', 'NegReg', (57, 62))
215815	25260491	In proton therapy, unlike photon therapy, the range uncertainty originating from artifacts in the CT image or the conversion of Hounsfield units to stopping powers must be accounted for because that uncertainty can change the proton dose distribution, which can result in target dose misses or overdoses to critical structures.	('target', 'MPA', (272, 278))	('overdoses', 'Disease', (294, 303))	('uncertainty', 'Var', (199, 210))	('overdoses', 'Disease', 'MESH:D062787', (294, 303))	('change', 'Reg', (215, 221))	('result in', 'Reg', (262, 271))	('proton dose distribution', 'MPA', (226, 250))
215833	25435928	In the pDC316-siRNA recombinant vector group, the cells migrated more quickly compared with the siRNA-negative control group, and in the RKIP-expressing adenoviral vector group, the cells migrated more slowly compared with the adenoviral negative control group.	('pDC316-siRNA', 'Var', (7, 19))	('RKIP', 'Gene', '5037', (137, 141))	('slowly', 'NegReg', (202, 208))	('RKIP', 'Gene', (137, 141))	('cells migrated', 'CPA', (50, 64))
215840	25435928	The formation of cholangiocarcinoma often proceeds through several steps, including interaction among the cancer-promoting environmental factors, oncogene activation and tumor-suppressor gene inactivation.	('inactivation', 'Var', (192, 204))	('cholangiocarcinoma', 'Disease', (17, 35))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (17, 35))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (17, 35))	('tumor', 'Disease', (170, 175))	('cancer', 'Disease', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('interaction', 'Interaction', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
215949	25435928	Therefore, positive RKIP expression in cholangiocarcinoma cells may indicate a good prognosis for patients.	('RKIP', 'Gene', (20, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (39, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('patients', 'Species', '9606', (98, 106))	('positive', 'Var', (11, 19))	('cholangiocarcinoma', 'Disease', (39, 57))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 57))	('RKIP', 'Gene', '5037', (20, 24))
215972	25435928	Positive RKIP expression in cholangiocarcinoma cells may be be predictive of a better prognosis.	('cholangiocarcinoma', 'Disease', (28, 46))	('RKIP', 'Gene', '5037', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('RKIP', 'Gene', (9, 13))	('expression', 'MPA', (14, 24))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (28, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('Positive', 'Var', (0, 8))
216323	26687170	Cisplatin, a platinating agent, is used as part of multiple treatment regimens for a multitude of malignancies and can be associated with a decrease in renal function, which is the organ also responsible for its clearance.	('malignancies', 'Disease', (98, 110))	('renal function', 'MPA', (152, 166))	('decrease', 'NegReg', (140, 148))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('Cisplatin', 'Var', (0, 9))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))
216364	26687170	Higher levels of 5-fluorouracil were seen in the plasma as compared to the dialysate:Cmax 567 ug/mL vs. 196 ug/mL and AUC0-696 50.0 ug hr/mL vs. 12.1 ug hr/mL respectively.	('AUC0-696 50.0', 'Var', (118, 131))	('Cmax 567 ug/mL', 'Var', (85, 99))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (17, 31))
216408	26972646	Eligibility criteria included: Clinical stage T2N0M0, T3N0M0, T1-3N1M0 or T1-3N0-1M1A adenocarcinoma of the esophagus guided by the pathologic staging criteria of the AJCC 5.0 staging system, as determined by imaging studies and biopsy where appropriate.	('T3N0M0', 'Var', (54, 60))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (86, 117))	('T1-3N1M0', 'Var', (62, 70))	('T1-3N0-1M1A', 'Var', (74, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('adenocarcinoma of the esophagus', 'Disease', (86, 117))
216477	26972646	These are the results, including long term survival outcome, of E1201 a randomized phase II trial of neoadjuvant preoperative paclitaxel/cisplatin/radiotherapy or irinotecan/cisplatin/RT in locally advanced esophageal adenocarcinoma with, for the two arms: The pathologic complete response were 17% and 15%, respectively, median survival: 21 months and.	('esophageal adenocarcinoma', 'Disease', (207, 232))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (207, 232))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('paclitaxel', 'Chemical', 'MESH:D017239', (126, 136))	('irinotecan', 'Chemical', 'MESH:D000077146', (163, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (174, 183))	('E1201', 'Var', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (207, 232))
216484	22116732	EAC saturated fat, energy adjusted HR (95%CI) 1.79 (1.37-2.33) P for trend <0.01; EAC saturated fat, multivariate adjusted HR (95%CI) 1.27 (0.91-1.78) P for trend=0.28).	('EAC', 'Var', (82, 85))	('fat', 'Gene', (96, 99))	('fat', 'Gene', (14, 17))	('fat', 'Gene', '2195', (96, 99))	('fat', 'Gene', '2195', (14, 17))
216500	22116732	It has been hypothesized that dietary fat intake may be positively linked to reflux and reflux symptoms, thus an increased risk of EAC.	('EAC', 'Disease', (131, 134))	('reflux symptoms', 'Phenotype', 'HP:0002020', (88, 103))	('dietary', 'Var', (30, 37))	('linked', 'Reg', (67, 73))	('reflux', 'Disease', (77, 83))	('fat', 'Gene', (38, 41))	('fat', 'Gene', '2195', (38, 41))	('reflux symptoms', 'Disease', (88, 103))
216514	22116732	Cancer sites were identified by anatomic site and histologic code of the International Classification of Disease for Oncology (ICD-O, third edition); esophageal cancer included topography codes: C15.0-C15.9, gastric cardia cancer included code: C16.0, and gastric non-cardia cancer included codes: C16.1-C16.7, as well as C16.8 (overlapping tumors) and C16.9 (not otherwise specified).	('esophageal cancer', 'Disease', (150, 167))	('tumors', 'Disease', (341, 347))	('C16.9', 'CellLine', 'CVCL:2322', (353, 358))	('C16.9', 'Var', (353, 358))	('C16.1-C16.7', 'CellLine', 'CVCL:2322', (298, 309))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('C16.1-C16.7', 'Var', (298, 309))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('gastric non-cardia cancer', 'Disease', (256, 281))	('C15.0-C15.9', 'Var', (195, 206))	('tumors', 'Disease', 'MESH:D009369', (341, 347))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (208, 229))	('Oncology', 'Phenotype', 'HP:0002664', (117, 125))	('gastric cardia cancer', 'Disease', (208, 229))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('C16.8', 'Var', (322, 327))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('C16.0', 'Var', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('gastric non-cardia cancer', 'Disease', 'MESH:D013274', (256, 281))	('Cancer', 'Disease', (0, 6))
216515	22116732	Esophageal cancers were categorized as squamous cell carcinomas, which included histology codes: 8050-8076, and adenocarcinomas, which included: 8140, 8141, 8190-8231, 8260- 8263, 8310, 8430, 8480-8490, 8560, and 8570-8572.	('8570-8572', 'Var', (213, 222))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (39, 63))	('Esophageal cancers', 'Disease', (0, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (39, 63))	('8050-8076', 'Var', (97, 106))	('8140', 'Var', (145, 149))	('8310', 'Var', (180, 184))	('8430', 'Var', (186, 190))	('8480-8490', 'Var', (192, 201))	('8260- 8263', 'Var', (168, 178))	('squamous cell carcinomas', 'Disease', (39, 63))	('8141', 'Var', (151, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('8190-8231', 'Var', (157, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('Esophageal cancers', 'Disease', 'MESH:D004938', (0, 18))	('adenocarcinomas', 'Disease', 'MESH:D000230', (112, 127))	('8560', 'Var', (203, 207))	('adenocarcinomas', 'Disease', (112, 127))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))
216530	22116732	We further examined specific food sources for each of the main fat types (total fat, saturated fat, monounsaturated fat, and polyunsaturated fat), including red meat, white meat, eggs, and dairy products.	('fat', 'Gene', '2195', (141, 144))	('fat', 'Gene', (80, 83))	('polyunsaturated', 'Var', (125, 140))	('fat', 'Gene', (95, 98))	('fat', 'Gene', '2195', (80, 83))	('fat', 'Gene', '2195', (95, 98))	('fat', 'Gene', (116, 119))	('fat', 'Gene', '2195', (116, 119))	('fat', 'Gene', (141, 144))	('fat', 'Gene', (63, 66))	('fat', 'Gene', '2195', (63, 66))	('monounsaturated', 'MPA', (100, 115))
216549	22116732	In the energy adjusted models, saturated fat and monounsaturated fat intakes were directly associated with risk of EAC, ESCC and gastric cardia adenocarcinoma, but not gastric non-cardia adenocarcinoma (Table 3).	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (129, 158))	('EAC', 'Disease', (115, 118))	('ESCC', 'Disease', (120, 124))	('gastric cardia adenocarcinoma', 'Disease', (129, 158))	('fat', 'Gene', (41, 44))	('fat', 'Gene', '2195', (65, 68))	('fat', 'Gene', (65, 68))	('fat', 'Gene', '2195', (41, 44))	('gastric non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (168, 201))	('gastric non-cardia adenocarcinoma', 'Disease', (168, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('monounsaturated', 'Var', (49, 64))	('associated', 'Reg', (91, 101))
216563	22116732	The association of fat intakes (continuous variable) with cancer risk was also examined by stratum of cigarette use (never, former, or current), alcohol use (drinkers and non-drinkers), and BMI (normal 18.5-<25 kg/m2 or overweight >=25 kg/m2).	('fat', 'Gene', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('fat', 'Gene', '2195', (19, 22))	('cancer', 'Disease', (58, 64))	('alcohol use', 'Phenotype', 'HP:0030955', (145, 156))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('alcohol', 'Chemical', 'MESH:D000438', (145, 152))	('overweight', 'Phenotype', 'HP:0025502', (220, 230))	('normal 18.5-<25 kg/m2', 'Var', (195, 216))
216573	22116732	In some, but not all previous studies, dietary fat has been positively linked to reflux and reflux symptoms, presumably through relaxation of the lower esophageal sphincter.	('reflux symptoms', 'Disease', (92, 107))	('reflux symptoms', 'Phenotype', 'HP:0002020', (92, 107))	('fat', 'Gene', (47, 50))	('esophageal sphincter', 'Disease', (152, 172))	('fat', 'Gene', '2195', (47, 50))	('reflux', 'Disease', (81, 87))	('dietary', 'Var', (39, 46))	('linked', 'Reg', (71, 77))	('esophageal sphincter', 'Disease', 'MESH:D009122', (152, 172))
216581	22116732	The AARP respondents to the questionnaire consumed less fat and red meat and more fiber and fruits and vegetables than comparably aged adults in the general US population, on average.	('fat', 'Gene', '2195', (56, 59))	('more', 'PosReg', (77, 81))	('AARP', 'Var', (4, 8))	('less', 'NegReg', (51, 55))	('fat', 'Gene', (56, 59))
216651	33535583	Although the precise underlying mechanisms are not completely understood, changes in the microbiome composition of a specific body compartment caused by either host intrinsic or external factors (e.g., genetics, infections, diet, or antibiotics) can alter the local homeostasis and induce chronic inflammation, damaging tissues and dysregulating local and systemic immune responses, ultimately leading to disease.	('infections', 'Disease', (212, 222))	('dysregulating', 'Reg', (332, 345))	('local homeostasis', 'MPA', (260, 277))	('alter', 'Reg', (250, 255))	('induce', 'Reg', (282, 288))	('dysregulating local and systemic immune responses', 'Phenotype', 'HP:0002958', (332, 381))	('changes', 'Var', (74, 81))	('damaging', 'Reg', (311, 319))	('inflammation', 'Disease', 'MESH:D007249', (297, 309))	('inflammation', 'Disease', (297, 309))	('infections', 'Disease', 'MESH:D007239', (212, 222))	('leading to', 'Reg', (394, 404))	('disease', 'Disease', (405, 412))	('tissues', 'CPA', (320, 327))
216652	33535583	These pathology-associated alterations are also known as dysbiosis, and they have been linked to several disorders, including cancer.	('dysbiosis', 'Disease', 'MESH:D064806', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('linked', 'Reg', (87, 93))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('dysbiosis', 'Disease', (57, 66))	('alterations', 'Var', (27, 38))
216662	33535583	These findings have led to preclinical and clinical investigations on how to manipulate the microbiome to use it as a therapeutic tool to boost the efficacy of anticancer therapies through different strategies, from dietary interventions and probiotic/antibiotic therapies to fecal microbial transplantation (NCT04264975, NCT01895530, NCT03817125).	('NCT01895530', 'Var', (322, 333))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('NCT04264975', 'Var', (309, 320))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('boost', 'PosReg', (138, 143))	('NCT03817125', 'Var', (335, 346))
216668	33535583	For instance, changes in the relative abundance (RA) of a given group of bacteria has been shown to directly cause DNA damage leading to genetic dysregulation and initiation of tumorigenesis.	('DNA damage', 'MPA', (115, 125))	('genetic dysregulation', 'MPA', (137, 158))	('cause', 'Reg', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('changes', 'Var', (14, 21))	('tumor', 'Disease', (177, 182))	('RA', 'Chemical', '-', (49, 51))
216709	33535583	Escherichia coli, which is a producer of toxin colibactin (pk+), has also raised interest as a driver, since it may cause toxin-induced DNA damage, promoting a specific CRC mutational profile based on insertions and deletions.	('cause', 'Reg', (116, 121))	('promoting', 'PosReg', (148, 157))	('deletions', 'Var', (216, 225))	('CRC', 'Phenotype', 'HP:0003003', (169, 172))	('DNA damage', 'MPA', (136, 146))	('CRC mutational profile', 'MPA', (169, 191))	('Escherichia coli', 'Species', '562', (0, 16))	('colibactin', 'Chemical', 'MESH:C569566', (47, 57))	('insertions', 'Var', (201, 211))
216733	33535583	HPV- and EBV-related cancers: both HPV and EBV are known to initiate the oncogenic process through viral DNA integration into the human genome and through acquisition of cell survival capabilities, causing different tumors depending on the body compartment or organ infected.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (35, 38))	('EBV', 'Species', '10376', (9, 12))	('tumors', 'Disease', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('EBV', 'Species', '10376', (43, 46))	('viral DNA', 'Var', (99, 108))	('infected', 'Disease', 'MESH:D007239', (266, 274))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('causing', 'Reg', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('infected', 'Disease', (266, 274))	('human', 'Species', '9606', (130, 135))
216771	33535583	For example, antibiotics are a known cause of gut dysbiosis, and their use seems to detrimentally impact on the overall survival and progression-free survival of cancer patients, and also impair responses to ICI.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('patients', 'Species', '9606', (169, 177))	('cancer', 'Disease', (162, 168))	('impair', 'NegReg', (188, 194))	('responses to ICI', 'MPA', (195, 211))	('impact', 'Reg', (98, 104))	('detrimentally', 'NegReg', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('antibiotics', 'Var', (13, 24))	('dysbiosis', 'Disease', (50, 59))	('dysbiosis', 'Disease', 'MESH:D064806', (50, 59))	('overall survival', 'CPA', (112, 128))	('progression-free survival', 'CPA', (133, 158))
216806	33535583	Depending upon the tumor type, these could include clinical features of the diagnosed tumors (e.g., diagnostic method and stage, previous surgeries, familial gene mutations, other genetic variants, and diagnostic or prognostic biomarker levels), recent usage of pharmaceutical drugs (e.g., antibiotics, proton-pump inhibitors, metformin, and non-steroidal anti-inflammatories), demographic factors (e.g., place of residence, age, sex, and race/ethnicity), and lifestyle factors (e.g., diet or nutritional status at diagnosis, body weight, tobacco smoking, and alcohol consumption).	('variants', 'Var', (188, 196))	('tobacco', 'Species', '4097', (539, 546))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('alcohol', 'Chemical', 'MESH:D000438', (560, 567))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
216828	32357418	The structure was applied to a biosensor for detecting two different cancerous levels of esophageal cells, namely, OE21 and OE21-1, with a high gain in photocurrent (5.8 and 6.2 times, respectively) and a low detection limit (3000 cells in 50 muL).	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (217, 218))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('OE21-1', 'Var', (124, 130))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('p', 'Chemical', 'MESH:D010758', (20, 21))	('p', 'Chemical', 'MESH:D010758', (188, 189))	('p', 'Chemical', 'MESH:D010758', (19, 20))	('n', 'Chemical', 'MESH:D009584', (238, 239))	('gain', 'PosReg', (144, 148))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('cancerous', 'Disease', 'MESH:D009369', (69, 78))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('photocurrent', 'MPA', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('n', 'Chemical', 'MESH:D009584', (171, 172))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('p', 'Chemical', 'MESH:D010758', (152, 153))	('n', 'Chemical', 'MESH:D009584', (162, 163))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('cancerous', 'Disease', (69, 78))
216829	32357418	We believe that such a p-n heterojunction PEC biosensor could advance biosensor development and provide a promising candidate for biomedical applications.	('p', 'Chemical', 'MESH:D010758', (143, 144))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('p', 'Chemical', 'MESH:D010758', (86, 87))	('advance', 'PosReg', (62, 69))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('biosensor development', 'CPA', (70, 91))	('p', 'Chemical', 'MESH:D010758', (106, 107))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('n', 'Chemical', 'MESH:D009584', (151, 152))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('n', 'Chemical', 'MESH:D009584', (118, 119))	('p', 'Chemical', 'MESH:D010758', (142, 143))	('p', 'Chemical', 'MESH:D010758', (96, 97))	('p', 'Chemical', 'MESH:D010758', (23, 24))	('p-n', 'Var', (23, 26))
216937	32357418	Figure 5b shows that the sample with Cu2O/PEDOT:PSS/ZnO has a higher absorption in 300-500 nm than the sample with Cu2O/ZnO.	('p', 'Chemical', 'MESH:D010758', (106, 107))	('ZnO', 'Chemical', 'MESH:D015034', (52, 55))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('p', 'Chemical', 'MESH:D010758', (28, 29))	('PEDOT', 'Chemical', '-', (42, 47))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('Cu2O', 'Chemical', '-', (115, 119))	('ZnO', 'Chemical', 'MESH:D015034', (120, 123))	('higher', 'PosReg', (62, 68))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('p', 'Chemical', 'MESH:D010758', (74, 75))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('Cu2O', 'Chemical', '-', (37, 41))	('absorption in 300-500 nm', 'MPA', (69, 93))	('PSS/ZnO', 'Var', (48, 55))
216938	32357418	The comparison of the Cu2O/PEDOT:PSS/ZnO and Cu2O with HMTA/PEDOT:PSS/ZnO samples in Figure 5b indicates that HMTA can increase the absorption in 300-500 nm.	('absorption in 300-500 nm', 'MPA', (132, 156))	('HMTA', 'Chemical', 'MESH:D008709', (110, 114))	('HMTA', 'Chemical', 'MESH:D008709', (55, 59))	('p', 'Chemical', 'MESH:D010758', (7, 8))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('Cu2O', 'Chemical', '-', (22, 26))	('p', 'Chemical', 'MESH:D010758', (77, 78))	('ZnO', 'Chemical', 'MESH:D015034', (70, 73))	('HMTA', 'Var', (110, 114))	('ZnO', 'Chemical', 'MESH:D015034', (37, 40))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('p', 'Chemical', 'MESH:D010758', (137, 138))	('PEDOT', 'Chemical', '-', (60, 65))	('PEDOT', 'Chemical', '-', (27, 32))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('increase', 'PosReg', (119, 127))	('Cu2O', 'Chemical', '-', (45, 49))
216939	32357418	In other words, HMTA and PEDOT:PSS enhances the absorption of devices between 300 and 500 nm.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('enhances', 'PosReg', (35, 43))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('PEDOT', 'Chemical', '-', (25, 30))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('p', 'Chemical', 'MESH:D010758', (53, 54))	('HMTA', 'Chemical', 'MESH:D008709', (16, 20))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('PSS', 'Var', (31, 34))	('absorption', 'MPA', (48, 58))
216958	32357418	The photocurrents of OE21 and OE21-1 are 5.8 and 6.2 times higher than that of the case without esophageal cancer cells, respectively.	('p', 'Chemical', 'MESH:D010758', (4, 5))	('p', 'Chemical', 'MESH:D010758', (99, 100))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('OE21-1', 'Var', (30, 36))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('photocurrents', 'MPA', (4, 17))	('p', 'Chemical', 'MESH:D010758', (124, 125))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('higher', 'PosReg', (59, 65))	('cancer', 'Disease', (107, 113))	('OE21', 'Var', (21, 25))
216959	32357418	This result is consistent with the trend of the cancerization of esophageal cancer cells: the carcinogenesis of OE21-1 is more severe than that of OE21.	('p', 'Chemical', 'MESH:D010758', (68, 69))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('OE21-1', 'Var', (112, 118))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('n', 'Chemical', 'MESH:D009584', (137, 138))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('n', 'Chemical', 'MESH:D009584', (17, 18))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', (76, 82))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('carcinogenesis', 'CPA', (94, 108))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
216961	32357418	According to the results in Figure 6b-d, Cu2O with HMTA/PEDOT:PSS/ZnO is the most sensitive structure for detecting esophageal cancer cells, especially OE21, which is the early stage of esophageal cancer and difficult to be diagnosed.	('n', 'Chemical', 'MESH:D009584', (67, 68))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('p', 'Chemical', 'MESH:D010758', (189, 190))	('p', 'Chemical', 'MESH:D010758', (119, 120))	('p', 'Chemical', 'MESH:D010758', (143, 144))	('PEDOT', 'Chemical', '-', (56, 61))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (199, 200))	('cancer', 'Disease', (127, 133))	('ZnO', 'Chemical', 'MESH:D015034', (66, 69))	('HMTA', 'Chemical', 'MESH:D008709', (51, 55))	('Cu2O', 'Chemical', '-', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (197, 203))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('n', 'Chemical', 'MESH:D009584', (228, 229))	('n', 'Chemical', 'MESH:D009584', (205, 206))	('OE21', 'Var', (152, 156))	('cancer', 'Disease', 'MESH:D009369', (127, 133))
216972	32357418	The reason for the slow current drop is that it is affected by PBS or OE21, which still facilitates electronic transmission.	('n', 'Chemical', 'MESH:D009584', (29, 30))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('OE21', 'Var', (70, 74))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('p', 'Chemical', 'MESH:D010758', (35, 36))	('PBS', 'Var', (63, 66))	('electronic transmission', 'MPA', (100, 123))	('facilitates', 'PosReg', (88, 99))	('PBS', 'Chemical', '-', (63, 66))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('n', 'Chemical', 'MESH:D009584', (9, 10))
216983	32357418	Cu2O 25 min + Cu2O with HMTA 5 min/PEDOT:PSS/ZnO heterostructure also exhibits its value in distinguishing OE21 and OE21-1.	('n', 'Chemical', 'MESH:D009584', (90, 91))	('OE21-1', 'Var', (116, 122))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('Cu2O', 'Chemical', '-', (14, 18))	('HMTA', 'Chemical', 'MESH:D008709', (24, 28))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('OE21', 'Var', (107, 111))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('PEDOT', 'Chemical', '-', (35, 40))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('Cu2O', 'Chemical', '-', (0, 4))	('ZnO', 'Chemical', 'MESH:D015034', (45, 48))
216990	32357418	This research was supported by the Ministry of Science and Technology of Taiwan under the Grants MOST 105-2923-E-194-003-MY3, 106-2112-M-194-002, and 108-2823-8-194-002.	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('106-2112-M-194-002', 'Var', (126, 144))	('108-2823-8-194-002', 'Var', (150, 168))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('105-2923-E-194-003-MY3', 'Var', (102, 124))
217086	31452763	A significantly higher expression of CKS2 was found in ULMS tissues than in ULM tissues (P<0.01) and high CKS2 expression was associated with increased tumor size, low progesterone receptor expression and poor prognosis in patients with ULMS.	('higher', 'PosReg', (16, 22))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('CKS2', 'Gene', '1164', (37, 41))	('CKS2', 'Gene', (37, 41))	('low progesterone', 'Phenotype', 'HP:0008233', (164, 180))	('si', 'Chemical', 'MESH:D012825', (216, 218))	('tumor', 'Disease', (152, 157))	('ULMS', 'Phenotype', 'HP:0002891', (55, 59))	('expression', 'MPA', (111, 121))	('si', 'Chemical', 'MESH:D012825', (158, 160))	('ULM', 'Phenotype', 'HP:0000131', (76, 79))	('CKS2', 'Gene', '1164', (106, 110))	('CKS2', 'Gene', (106, 110))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('high', 'Var', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('progesterone receptor', 'Gene', (168, 189))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('progesterone receptor', 'Gene', '5241', (168, 189))	('low', 'NegReg', (164, 167))	('ULMS', 'Phenotype', 'HP:0002891', (237, 241))	('si', 'Chemical', 'MESH:D012825', (196, 198))	('expression', 'MPA', (23, 33))	('increased', 'PosReg', (142, 151))	('ULMS', 'Disease', (237, 241))	('ULM', 'Phenotype', 'HP:0000131', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('ULM', 'Phenotype', 'HP:0000131', (55, 58))	('patients', 'Species', '9606', (223, 231))
217088	31452763	Furthermore, silencing of CKS2 in ULMS cells inhibited cell proliferation, colony formation, migration and invasion, and resulted in cell cycle arrest.	('si', 'Chemical', 'MESH:D012825', (111, 113))	('inhibited', 'NegReg', (45, 54))	('ULM', 'Phenotype', 'HP:0000131', (34, 37))	('ULMS', 'Phenotype', 'HP:0002891', (34, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (133, 150))	('cell proliferation', 'CPA', (55, 73))	('colony formation', 'CPA', (75, 91))	('CKS2', 'Gene', '1164', (26, 30))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('CKS2', 'Gene', (26, 30))	('cell cycle arrest', 'CPA', (133, 150))	('silencing', 'Var', (13, 22))
217102	31452763	Expression arrays from the GEO datasets (GSE64763, GSE764 and GSE36610) showed distinct levels of expression in ULMS and ULM of genes such as cyclin-dependent kinase subunit (CKS)2, thymidylate synthase and putative tenascin-XA.	('ULM', 'Phenotype', 'HP:0000131', (112, 115))	('tenascin', 'Gene', (216, 224))	('ULMS', 'Phenotype', 'HP:0002891', (112, 116))	('CKS)2', 'Gene', '1164', (175, 180))	('tenascin', 'Gene', '3371', (216, 224))	('thymidylate synthase', 'Gene', (182, 202))	('GSE764', 'Chemical', '-', (51, 57))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('ULM', 'Phenotype', 'HP:0000131', (121, 124))	('GSE36610', 'Var', (62, 70))	('thymidylate synthase', 'Gene', '7298', (182, 202))	('GSE64763', 'Var', (41, 49))	('GSE764', 'Var', (51, 57))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('expression', 'MPA', (98, 108))
217131	31452763	Following the transfection of cells with si-CKS2 and si-Ctrl (after 24 h), the cells were seeded at a density of 3x103 per well in a 96-well plate.	('si', 'Chemical', 'MESH:D012825', (53, 55))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('CKS2', 'Gene', '1164', (44, 48))	('CKS2', 'Gene', (44, 48))	('si-Ctrl', 'Var', (53, 60))	('si', 'Chemical', 'MESH:D012825', (41, 43))
217132	31452763	The absorbance was measured at 450 nm by a microplate reader (Bio-Rad Laboratories, Inc.), following incubation in 5% CO2 at 37 C for 2 h. Following 24 h from transfection with si-CKS2 or si-Ctrl, SK-UT-1 or SK-UT-1B cells (500 cells/well) were seeded in 6-well plates and incubated for 14 days to form colonies.	('CO2', 'Chemical', '-', (118, 121))	('CKS2', 'Gene', '1164', (180, 184))	('CKS2', 'Gene', (180, 184))	('SK-UT-1B cells', 'CellLine', 'CVCL:2250', (208, 222))	('si', 'Chemical', 'MESH:D012825', (177, 179))	('si', 'Chemical', 'MESH:D012825', (188, 190))	('SK-UT-1', 'CellLine', 'CVCL:0533', (197, 204))	('SK-UT-1', 'CellLine', 'CVCL:0533', (208, 215))	('si-Ctrl', 'Var', (188, 195))
217138	31452763	Following 24 h transfection with si-RNA, cells (1x105) in 100 microl serum-free medium were placed in the upper chamber, and the lower chamber was filled with 700 microl culture medium with 10% FBS.	('si', 'Chemical', 'MESH:D012825', (33, 35))	('FBS', 'Disease', (194, 197))	('si-RNA', 'Gene', (33, 39))	('FBS', 'Disease', 'MESH:D005198', (194, 197))	('transfection', 'Var', (15, 27))
217141	31452763	The effects of silencing CKS2 on cell cycle progression were assessed using propidium iodide staining and analyzed by flow cytometry.	('propidium iodide', 'Chemical', 'MESH:D011419', (76, 92))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('silencing', 'Var', (15, 24))	('cell cycle progression', 'CPA', (33, 55))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('CKS2', 'Gene', '1164', (25, 29))	('CKS2', 'Gene', (25, 29))
217142	31452763	Cells were seeded in 6-well plates (2x105 per well) and transfected with si-CKS2 and si-Ctrl.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('CKS2', 'Gene', '1164', (76, 80))	('CKS2', 'Gene', (76, 80))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('si-Ctrl', 'Var', (85, 92))
217170	31452763	1E, patients in the CKS2 high-expression group had a markedly poorer survival rate than those in the low-expression group (P=0.03).	('si', 'Chemical', 'MESH:D012825', (111, 113))	('survival rate', 'CPA', (69, 82))	('poorer', 'NegReg', (62, 68))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('high-expression', 'Var', (25, 40))	('patients', 'Species', '9606', (4, 12))	('CKS2', 'Gene', '1164', (20, 24))	('CKS2', 'Gene', (20, 24))
217177	31452763	2C and D, where knockdown of CKS2 decreased the viability of SK-UT-1 and SK-UT-1B cells.	('SK-UT-1B cells', 'CellLine', 'CVCL:2250', (73, 87))	('decreased', 'NegReg', (34, 43))	('SK-UT-1', 'CellLine', 'CVCL:0533', (73, 80))	('CKS2', 'Gene', '1164', (29, 33))	('viability', 'CPA', (48, 57))	('CKS2', 'Gene', (29, 33))	('knockdown', 'Var', (16, 25))	('SK-UT-1', 'CellLine', 'CVCL:0533', (61, 68))
217178	31452763	These results indicate that silencing of CKS2 may inhibit cell proliferation in ULMS cell lines.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('cell proliferation in ULMS cell lines', 'CPA', (58, 95))	('inhibit', 'NegReg', (50, 57))	('ULM', 'Phenotype', 'HP:0000131', (80, 83))	('ULMS', 'Phenotype', 'HP:0002891', (80, 84))	('CKS2', 'Gene', '1164', (41, 45))	('silencing', 'Var', (28, 37))	('CKS2', 'Gene', (41, 45))
217180	31452763	The effect of CKS2 knockdown on the distribution of cells at the different phases of the cell cycle was observed.	('knockdown', 'Var', (19, 28))	('CKS2', 'Gene', '1164', (14, 18))	('CKS2', 'Gene', (14, 18))
217181	31452763	The silencing of CKS2 increased the population of cells at the G1 phase and decreased the cells at S phase (Fig.	('cells at S phase', 'CPA', (90, 106))	('decreased', 'NegReg', (76, 85))	('increased', 'PosReg', (22, 31))	('CKS2', 'Gene', '1164', (17, 21))	('CKS2', 'Gene', (17, 21))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('silencing', 'Var', (4, 13))
217182	31452763	These results suggest that the silencing of CKS2 can cause cell cycle arrest at the G1/S transition phase in ULMS cells.	('cause', 'Reg', (53, 58))	('silencing', 'Var', (31, 40))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('ULM', 'Phenotype', 'HP:0000131', (109, 112))	('CKS2', 'Gene', '1164', (44, 48))	('CKS2', 'Gene', (44, 48))	('cell cycle arrest at the G1/S transition phase', 'CPA', (59, 105))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (59, 76))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('ULMS', 'Phenotype', 'HP:0002891', (109, 113))
217187	31452763	Cells were treated with si-CKS2 or si-Ctrl and investigated in in vitro migration and Matrigel invasion assays.	('si-Ctrl', 'Var', (35, 42))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('CKS2', 'Gene', '1164', (27, 31))	('CKS2', 'Gene', (27, 31))	('investigated', 'Reg', (47, 59))	('si', 'Chemical', 'MESH:D012825', (35, 37))
217190	31452763	Furthermore, the effect of si-CKS2 on the apoptosis of ULMS cells was investigated, by measuring the apoptotic rates of si-Ctrl and si-CKS2 by Annexin V-FITC/PI double-staining assay.	('si', 'Chemical', 'MESH:D012825', (132, 134))	('Annexin V', 'Gene', '308', (143, 152))	('CKS2', 'Gene', '1164', (30, 34))	('Annexin V', 'Gene', (143, 152))	('ULM', 'Phenotype', 'HP:0000131', (55, 58))	('CKS2', 'Gene', '1164', (135, 139))	('CKS2', 'Gene', (135, 139))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('ULMS', 'Phenotype', 'HP:0002891', (55, 59))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('CKS2', 'Gene', (30, 34))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('si-Ctrl', 'Var', (120, 127))
217194	31452763	However, there were no significant changes following the silencing of CKS2 in ULMS cells (data not shown).	('ULM', 'Phenotype', 'HP:0000131', (78, 81))	('CKS2', 'Gene', '1164', (70, 74))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('CKS2', 'Gene', (70, 74))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('silencing', 'Var', (57, 66))	('ULMS', 'Phenotype', 'HP:0002891', (78, 82))
217210	31452763	The CCK-8 and colony-formation assays demonstrated that the silencing of CKS2 decreased cell viability and weakened the colony-forming ability of ULMS cells.	('colony-forming ability of ULMS cells', 'CPA', (120, 156))	('CKS2', 'Gene', (73, 77))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('ULMS', 'Phenotype', 'HP:0002891', (146, 150))	('cell viability', 'CPA', (88, 102))	('ULM', 'Phenotype', 'HP:0000131', (146, 149))	('silencing', 'Var', (60, 69))	('weakened', 'NegReg', (107, 115))	('decreased', 'NegReg', (78, 87))	('CKS2', 'Gene', '1164', (73, 77))
217212	31452763	Flow cytometry analysis indicated that the silencing of CKS2 in ULMS cells increased the cells at the G1 phase and decreased the cells at the S phase.	('ULM', 'Phenotype', 'HP:0000131', (64, 67))	('CKS2', 'Gene', '1164', (56, 60))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('CKS2', 'Gene', (56, 60))	('decreased', 'NegReg', (115, 124))	('silencing', 'Var', (43, 52))	('cells at the G1 phase', 'CPA', (89, 110))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('cells at the S phase', 'CPA', (129, 149))	('increased', 'PosReg', (75, 84))	('ULMS', 'Phenotype', 'HP:0002891', (64, 68))
217213	31452763	Yu et al demonstrated that downregulation of CKS2 resulted in cell cycle arrest in G1/S transition in colorectal cancer, whereas Shen et al found that silencing of CKS2 increased the number of cells at the G2/M phase and decreased the number at G1 and S phase in cholangiocarcinoma.	('CKS2', 'Gene', '1164', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CKS2', 'Gene', (164, 168))	('silencing', 'Var', (151, 160))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (263, 281))	('cell cycle arrest', 'CPA', (62, 79))	('decreased', 'NegReg', (221, 230))	('cholangiocarcinoma', 'Disease', (263, 281))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('si', 'Chemical', 'MESH:D012825', (151, 153))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (263, 281))	('colorectal cancer', 'Disease', (102, 119))	('increased', 'PosReg', (169, 178))	('G1/S transition', 'CPA', (83, 98))	('downregulation', 'NegReg', (27, 41))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('CKS2', 'Gene', '1164', (45, 49))	('CKS2', 'Gene', (45, 49))
217217	31452763	Specifically, the results showed that the knockdown of CKS2 inhibited ULMS cell migration and invasion in vitro.	('CKS2', 'Gene', '1164', (55, 59))	('CKS2', 'Gene', (55, 59))	('ULMS cell migration', 'CPA', (70, 89))	('inhibited', 'NegReg', (60, 69))	('ULMS', 'Phenotype', 'HP:0002891', (70, 74))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('ULM', 'Phenotype', 'HP:0000131', (70, 73))	('invasion in vitro', 'CPA', (94, 111))	('knockdown', 'Var', (42, 51))
217253	30008616	The amplification of ERBB2 leads to an overexpression of HER2 promoting cancer cells survival, growth, migration and proliferation through the activation of the RAS/RAF/mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathways.	('promoting', 'PosReg', (62, 71))	('HER2', 'Gene', '2064', (57, 61))	('mTOR', 'Gene', (304, 308))	('amplification', 'Var', (4, 17))	('cancer', 'Disease', (72, 78))	('PI3', 'Gene', '5266', (295, 298))	('proliferation', 'CPA', (117, 130))	('AKT', 'Gene', (300, 303))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mTOR', 'Gene', '2475', (304, 308))	('growth', 'CPA', (95, 101))	('rat', 'Species', '10116', (124, 127))	('RAF', 'Gene', '22882', (165, 168))	('HER2', 'Gene', (57, 61))	('mammalian target of rapamycin', 'Gene', '2475', (264, 293))	('PI3', 'Gene', (295, 298))	('activation', 'PosReg', (143, 153))	('ERBB2', 'Gene', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('AKT', 'Gene', '207', (300, 303))	('overexpression', 'PosReg', (39, 53))	('RAF', 'Gene', (165, 168))	('ERBB2', 'Gene', '2064', (21, 26))	('mammalian target of rapamycin', 'Gene', (264, 293))	('rat', 'Species', '10116', (106, 109))	('migration', 'CPA', (103, 112))
217260	30008616	Based on the results of this trial trastuzumab in combination with platinum-based chemotherapy has been approved for the first-line treatment of GEA with HER2 overexpression or ERBB2 amplification, and testing for HER2 status is recommended before starting treatment in all patients with advanced GEA who are candidates for HER2-targeted therapy.	('overexpression', 'PosReg', (159, 173))	('HER2', 'Gene', (324, 328))	('ERBB2', 'Gene', (177, 182))	('ERBB2', 'Gene', '2064', (177, 182))	('HER2', 'Gene', (214, 218))	('amplification', 'Var', (183, 196))	('HER2', 'Gene', '2064', (324, 328))	('patients', 'Species', '9606', (274, 282))	('HER2', 'Gene', '2064', (214, 218))	('trastuzumab', 'Chemical', 'MESH:D000068878', (35, 46))	('platinum', 'Chemical', 'MESH:D010984', (67, 75))	('HER2', 'Gene', (154, 158))	('HER2', 'Gene', '2064', (154, 158))
217263	30008616	locally advanced gastric or GEJ HER2-positive tumors: NCT01196390, NCT02205047, NCT02581462), will potentially lead to further testing and treatment indications.	('HER2', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('NCT02581462', 'Var', (80, 91))	('HER2', 'Gene', '2064', (32, 36))	('NCT01196390', 'Var', (54, 65))	('lead', 'Reg', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('NCT02205047', 'Var', (67, 78))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
217272	30008616	The prognostic impact of EGFR amplification remains controversial, as some authors have suggested a negative prognostic value, which has not been confirmed in other series.	('negative', 'NegReg', (100, 108))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', (25, 29))	('amplification', 'Var', (30, 43))
217274	30008616	Mutations or aberrant MET activation are associated with the development of several cancer types including GC.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('associated with', 'Reg', (41, 56))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('aberrant MET activation', 'Var', (13, 36))
217277	30008616	The use of these techniques has allowed the identification of several candidate genes mutations in known cancer-related genes in GC, such as TP53, PTEN, ARID1A, APC, CTNNB1, CDH1, PI3KCA and KMT2C.	('CDH1', 'Gene', '999', (174, 178))	('PI3', 'Gene', (180, 183))	('cancer', 'Disease', (105, 111))	('TP53', 'Gene', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ARID1A', 'Gene', (153, 159))	('PTEN', 'Gene', (147, 151))	('CDH1', 'Gene', (174, 178))	('ARID1A', 'Gene', '8289', (153, 159))	('PTEN', 'Gene', '5728', (147, 151))	('mutations', 'Var', (86, 95))	('KMT2C', 'Gene', '58508', (191, 196))	('KMT2C', 'Gene', (191, 196))	('CTNNB1', 'Gene', '1499', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('TP53', 'Gene', '7157', (141, 145))	('PI3', 'Gene', '5266', (180, 183))	('APC', 'Disease', 'MESH:D011125', (161, 164))	('APC', 'Disease', (161, 164))	('CTNNB1', 'Gene', (166, 172))
217280	30008616	Recently, however, multiple studies have explored the genomic profiling of EAC highlighting the presence of mutations in several cancer-related genes and distinctive gene signatures with could potentially translate in the development of novel biomarkers for targeted treatment.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (108, 117))	('translate in', 'Reg', (205, 217))	('cancer', 'Disease', (129, 135))	('EAC', 'Disease', (75, 78))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
217282	30008616	Additionally, amplifications of several oncogenes such as KRAS (21%), HER2 (19%), EGFR (16%), CND1 (10%) and MET (6%) were identified, as well as loss of SMAD4 (34%), CDKN2A (32%) and ARID1A (10%).	('KRAS', 'Gene', (58, 62))	('loss', 'NegReg', (146, 150))	('EGFR', 'Gene', (82, 86))	('MET', 'Gene', (109, 112))	('HER2', 'Gene', (70, 74))	('KRAS', 'Gene', '3845', (58, 62))	('HER2', 'Gene', '2064', (70, 74))	('CDKN2A', 'Gene', (167, 173))	('CDKN2A', 'Gene', '1029', (167, 173))	('oncogenes', 'Gene', (40, 49))	('SMAD4', 'Gene', (154, 159))	('CND1', 'Gene', (94, 98))	('amplifications', 'Var', (14, 28))	('ARID1A', 'Gene', (184, 190))	('ARID1A', 'Gene', '8289', (184, 190))	('EGFR', 'Gene', '1956', (82, 86))	('SMAD4', 'Gene', '4089', (154, 159))
217283	30008616	Another study compared the gene signature of esophageal squamous cell carcinoma and EAC, highlighting a higher prevalence of HER2 and EGFR amplification, TGF-beta signaling activation and RAS/MEK/MAPK pathway activation in EAC.	('HER2', 'Gene', (125, 129))	('MEK', 'Gene', (192, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('EAC', 'Disease', (223, 226))	('amplification', 'Var', (139, 152))	('HER2', 'Gene', '2064', (125, 129))	('EGFR', 'Gene', (134, 138))	('MEK', 'Gene', '5609', (192, 195))	('activation', 'PosReg', (173, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (45, 79))	('activation', 'PosReg', (209, 219))	('TGF-beta signaling', 'MPA', (154, 172))	('esophageal squamous cell carcinoma', 'Disease', (45, 79))	('EGFR', 'Gene', '1956', (134, 138))
217286	30008616	Results of the analysis showed a wide tumor heterogeneity with high prevalence of copy number alterations and frequent large-scale rearrangements.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('copy number alterations', 'Var', (82, 105))	('rat', 'Species', '10116', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
217287	30008616	Co-amplification of RTKs and/or downstream mitogenic pathways was common (i.e.	('RTK', 'Gene', '5979', (20, 23))	('RTK', 'Gene', (20, 23))	('Co-amplification', 'Var', (0, 16))
217289	30008616	Additionally, in in vitro models, the DDR-impaired subgroup appeared to be sensitive to DNA damage repair-targeted treatment, such as the combination of PARP inhibitors with DNA-damaging agents.	('DDR-impaired', 'Disease', (38, 50))	('inhibitors', 'Var', (158, 168))	('PARP', 'Gene', '1302', (153, 157))	('combination', 'Interaction', (138, 149))	('PARP', 'Gene', (153, 157))	('sensitive', 'Reg', (75, 84))
217308	30008616	A comprehensive analysis of promoter methylation status of 51 gastric carcinoma cases was conducted by Shinozaki and colleagues, who subsequently classified GCs into three epigenotypes characterized by different sets of methylation genes: EBV-positive/extensively high-methylation, EBV-negative/high-methylation and EBV-negative/low-methylation.	('EBV', 'Species', '10376', (282, 285))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (62, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('gastric carcinoma', 'Disease', 'MESH:D013274', (62, 79))	('EBV-negative/high-methylation', 'Var', (282, 311))	('high-methylation', 'Var', (264, 280))	('EBV', 'Species', '10376', (239, 242))	('gastric carcinoma', 'Disease', (62, 79))	('EBV-positive/extensively', 'Var', (239, 263))	('EBV', 'Species', '10376', (316, 319))
217310	30008616	COL9A2, EYA1 and ZNF365 were highly methylated in EBV-positive and EBV-negative/high-methylation subtypes, whereas AMPH, SORC33 and AJAP1 were frequently methylated in all epigenotypes.	('methylated', 'Var', (36, 46))	('EBV', 'Species', '10376', (67, 70))	('EBV', 'Species', '10376', (50, 53))	('COL9A2', 'Gene', (0, 6))	('ZNF365', 'Gene', (17, 23))	('EYA1', 'Gene', (8, 12))	('EBV-positive', 'Disease', (50, 62))
217312	30008616	Interestingly, MLH1 was frequently methylated (46%) in the EBV-negative/high-methylation phenotype, whereas none of the EBV associated GC cases showed MLH1 methylation.	('EBV-negative/high-methylation', 'Var', (59, 88))	('MLH1', 'Gene', '4292', (151, 155))	('methylated', 'Var', (35, 45))	('MLH1', 'Gene', (151, 155))	('EBV', 'Species', '10376', (120, 123))	('MLH1', 'Gene', '4292', (15, 19))	('EBV', 'Species', '10376', (59, 62))	('MLH1', 'Gene', (15, 19))
217319	30008616	This overexpression characterizes the immune signature of EBV-positive GCs, which is known to have a prominent lymphoid infiltration of the stroma and high density of tumor infiltrating lymphocytes (TILs), creating a balance between host immune evasion through PD-L1/2 overexpression, and host immune response.	('rat', 'Species', '10116', (179, 182))	('host immune evasion', 'MPA', (233, 252))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('lymphoid infiltration of the stroma', 'Disease', (111, 146))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('EBV-positive', 'Var', (58, 70))	('rat', 'Species', '10116', (126, 129))	('EBV', 'Species', '10376', (58, 61))	('tumor', 'Disease', (167, 172))	('lymphoid infiltration of the stroma', 'Disease', 'MESH:D017254', (111, 146))
217321	30008616	Somatic mutations unique to EBV-positive GCs include activation of BMP (bone morphogenetic protein) signaling, amplification of JAK2, MET, ERBB2, non-silent PIK3CA mutations, and mutations in ARID1A and BCO.	('JAK2', 'Gene', (128, 132))	('ERBB2', 'Gene', '2064', (139, 144))	('BCO', 'Gene', (203, 206))	('EBV', 'Species', '10376', (28, 31))	('BMP', 'Gene', '649', (67, 70))	('activation', 'PosReg', (53, 63))	('ARID1A', 'Gene', '8289', (192, 198))	('PIK3CA', 'Gene', (157, 163))	('ARID1A', 'Gene', (192, 198))	('BMP', 'Gene', (67, 70))	('MET', 'MPA', (134, 137))	('PIK3CA', 'Gene', '5290', (157, 163))	('mutations', 'Var', (179, 188))	('mutations', 'Var', (164, 173))	('ERBB2', 'Gene', (139, 144))
217322	30008616	TP53 mutations were rare in EBV subtype.	('TP53', 'Gene', '7157', (0, 4))	('EBV', 'Species', '10376', (28, 31))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('EBV', 'Disease', (28, 31))
217324	30008616	In the TCGA analysis, PIK3CA mutations were more dispersed in EBV-positive cancers, but localized in the kinase domain (exon 20) in EBV-negative cancers.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('EBV', 'Species', '10376', (132, 135))	('PIK3CA', 'Gene', '5290', (22, 28))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('mutations', 'Var', (29, 38))	('cancers', 'Disease', (75, 82))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('EBV', 'Species', '10376', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('PIK3CA', 'Gene', (22, 28))
217328	30008616	This can occur in the context of hereditary syndromes, such as Lynch syndrome, with germline mutations in MLH1, MSH2, MSH6 or PMS2, or it can occur sporadically through somatic mutations in MMR genes.	('MSH2', 'Gene', (112, 116))	('mutations', 'Var', (93, 102))	('Lynch syndrome', 'Disease', (63, 77))	('PMS2', 'Gene', (126, 130))	('MSH2', 'Gene', '4436', (112, 116))	('MLH1', 'Gene', '4292', (106, 110))	('MLH1', 'Gene', (106, 110))	('PMS2', 'Gene', '5395', (126, 130))	('Lynch syndrome', 'Disease', 'MESH:D003123', (63, 77))	('MMR', 'Gene', (190, 193))	('MSH6', 'Gene', (118, 122))	('hereditary syndromes', 'Disease', 'MESH:D009386', (33, 53))	('hereditary syndromes', 'Disease', (33, 53))	('MSH6', 'Gene', '2956', (118, 122))
217329	30008616	Epigenetic silencing of MLH1 by promoter hypermethylation is the main mechanism leading to MMR deficiency in both sporadic and familial MSI GC cases.	('promoter hypermethylation', 'Var', (32, 57))	('leading', 'Reg', (80, 87))	('MMR deficiency', 'Disease', (91, 105))	('MMR deficiency', 'Disease', 'MESH:C536143', (91, 105))	('MLH1', 'Gene', '4292', (24, 28))	('Epigenetic silencing', 'Var', (0, 20))	('MLH1', 'Gene', (24, 28))	('familial MSI GC', 'Disease', (127, 142))
217338	30008616	MSI is characterized by elevated mutation rates, including mutations of genes encoding targetable oncogenic signaling proteins.	('MSI', 'Disease', (0, 3))	('rat', 'Species', '10116', (42, 45))	('mutations', 'Var', (59, 68))
217339	30008616	MSI GCs have been shown to harbor more mutations in genes that act as tumor suppressors or oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mutations', 'Var', (39, 48))
217341	30008616	B2 M mutations result in loss of expression of HLA class 1 complexes, which benefits hypermutated tumors by reducing antigen presentation to the immune system.	('benefits', 'PosReg', (76, 84))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('HLA class 1 complexes', 'Protein', (47, 68))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('B2 M', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('reducing', 'NegReg', (108, 116))	('expression', 'MPA', (33, 43))	('loss', 'NegReg', (25, 29))	('antigen presentation to the immune system', 'MPA', (117, 158))
217342	30008616	Targetable amplifications were not identified in MSI, however, mutations in PIK3CA, ERBB3, ERBB2, ARID1A, and EGFR were noted.	('mutations', 'Var', (63, 72))	('ERBB3', 'Gene', '2065', (84, 89))	('ARID1A', 'Gene', '8289', (98, 104))	('ERBB2', 'Gene', '2064', (91, 96))	('ARID1A', 'Gene', (98, 104))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('ERBB2', 'Gene', (91, 96))	('PIK3CA', 'Gene', (76, 82))	('ERBB3', 'Gene', (84, 89))	('PIK3CA', 'Gene', '5290', (76, 82))
217343	30008616	Integrated exome sequencing by Liu and colleagues revealed that MSI GCs have frequent mutations in TP53, ACVR2A, PTEN, PIK3CA, KRAS, ERBB2, ZBTB1, TRAPPC2L, GPR39, GPR85, and CHRM3.	('TRAPPC2L', 'Gene', '51693', (147, 155))	('GPR85', 'Gene', '54329', (164, 169))	('GPR85', 'Gene', (164, 169))	('ERBB2', 'Gene', (133, 138))	('ZBTB1', 'Gene', (140, 145))	('PIK3CA', 'Gene', '5290', (119, 125))	('PTEN', 'Gene', (113, 117))	('TRAPPC2L', 'Gene', (147, 155))	('KRAS', 'Gene', '3845', (127, 131))	('ERBB2', 'Gene', '2064', (133, 138))	('TP53', 'Gene', (99, 103))	('mutations', 'Var', (86, 95))	('rat', 'Species', '10116', (5, 8))	('KRAS', 'Gene', (127, 131))	('CHRM3', 'Gene', (175, 180))	('PTEN', 'Gene', '5728', (113, 117))	('GPR39', 'Gene', (157, 162))	('ACVR2A', 'Gene', '92', (105, 111))	('GPR39', 'Gene', '2863', (157, 162))	('PIK3CA', 'Gene', (119, 125))	('ZBTB1', 'Gene', '22890', (140, 145))	('ACVR2A', 'Gene', (105, 111))	('TP53', 'Gene', '7157', (99, 103))	('CHRM3', 'Gene', '1131', (175, 180))
217351	30008616	From the TCGA data, CDH1 (Cadherin 1, encoding E-cadherin) was found to be mutated in 11% of all GCs, with 37% of all GS GC having a CDH1 mutation.	('CDH1', 'Gene', '999', (133, 137))	('E-cadherin', 'Gene', (47, 57))	('GS', 'Disease', 'MESH:D011125', (118, 120))	('CDH1', 'Gene', '999', (20, 24))	('E-cadherin', 'Gene', '999', (47, 57))	('mutated', 'Var', (75, 82))	('Cadherin 1', 'Gene', '999', (26, 36))	('CDH1', 'Gene', (133, 137))	('Cadherin 1', 'Gene', (26, 36))	('CDH1', 'Gene', (20, 24))
217352	30008616	Genomically stable subtype also had frequent mutations in ARID1A, CLDN18, CDH1, and RHOA (Ras homolog family member A).	('mutations', 'Var', (45, 54))	('RHOA', 'Gene', '387', (84, 88))	('ARID1A', 'Gene', '8289', (58, 64))	('CLDN18', 'Gene', (66, 72))	('ARID1A', 'Gene', (58, 64))	('CLDN18', 'Gene', '51208', (66, 72))	('RHOA', 'Gene', (84, 88))	('CDH1', 'Gene', (74, 78))	('CDH1', 'Gene', '999', (74, 78))
217358	30008616	CLDN18-ARHGAP fusions were found in 15% of GS subtype, and were mutually exclusive from RHOA mutations.	('GS subtype', 'Disease', (43, 53))	('CLDN18', 'Gene', (0, 6))	('RHOA', 'Gene', '387', (88, 92))	('CLDN18', 'Gene', '51208', (0, 6))	('RHOA', 'Gene', (88, 92))	('found', 'Reg', (27, 32))	('fusions', 'Var', (14, 21))	('GS subtype', 'Disease', 'MESH:D011125', (43, 53))
217362	30008616	These unique patterns of mutations in the GS subtype offer new candidate therapeutic targets, which warrant further investigation.	('mutations', 'Var', (25, 34))	('GS subtype', 'Disease', (42, 52))	('GS subtype', 'Disease', 'MESH:D011125', (42, 52))
217365	30008616	CIN subtype tumors are frequent at the gastroesophageal junction/cardia, correlate with the Lauren intestinal histologic variant, show marked aneuploidy, and harbor focal amplifications of RTKs, in addition to recurrent TP53 mutations and RTK-RAS activation.	('gastroesophageal', 'Disease', (39, 55))	('RTK', 'Gene', (189, 192))	('RTK', 'Gene', '5979', (239, 242))	('TP53', 'Gene', '7157', (220, 224))	('TP53', 'Gene', (220, 224))	('mutations', 'Var', (225, 234))	('cardia', 'Disease', 'MESH:D004938', (65, 71))	('cardia', 'Disease', (65, 71))	('aneuploidy', 'Disease', (142, 152))	('RTK', 'Gene', '5979', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('RTK', 'Gene', (239, 242))	('CIN subtype tumors', 'Disease', (0, 18))	('amplifications', 'MPA', (171, 185))	('gastroesophageal', 'Disease', 'MESH:D005764', (39, 55))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('CIN subtype tumors', 'Disease', 'MESH:C535673', (0, 18))	('aneuploidy', 'Disease', 'MESH:D000782', (142, 152))
217368	30008616	As TP53 mutations cause chromosomal instability, it is consistent with the finding from TCGA that CIN GCs have an enrichment of TP53 mutations and recurrent chromosomal amplifications and deletions.	('TP53', 'Gene', '7157', (3, 7))	('CIN', 'Disease', (98, 101))	('TP53', 'Gene', (3, 7))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('CIN', 'Disease', 'MESH:D007674', (98, 101))	('chromosomal instability', 'Phenotype', 'HP:0040012', (24, 47))	('deletions', 'Var', (188, 197))	('mutations', 'Var', (8, 17))	('cause', 'Reg', (18, 23))	('mutations', 'Var', (133, 142))	('chromosomal instability', 'MPA', (24, 47))
217371	30008616	Hence, it is worthwhile to explore the benefits of the HER2 monoclonal antibody, trastuzumab, in CIN tumors harboring ERBB2 amplification.	('trastuzumab', 'Chemical', 'MESH:D000068878', (81, 92))	('ERBB2', 'Gene', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('CIN tumors', 'Disease', (97, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('HER2', 'Gene', (55, 59))	('amplification', 'Var', (124, 137))	('ERBB2', 'Gene', '2064', (118, 123))	('HER2', 'Gene', '2064', (55, 59))	('CIN tumors', 'Disease', 'MESH:D009369', (97, 107))
217376	30008616	Amplification of fibroblast growth factor receptor 2 (FGFR2) is also frequent in CIN GCs, and is of considerable interest due to clinical trials investigating FGFR inhibitors.	('Amplification', 'Var', (0, 13))	('fibroblast growth factor receptor 2', 'Gene', (17, 52))	('CIN', 'Disease', 'MESH:D007674', (81, 84))	('fibroblast growth factor receptor 2', 'Gene', '2263', (17, 52))	('FGFR2', 'Gene', (54, 59))	('FGFR2', 'Gene', '2263', (54, 59))	('frequent', 'Reg', (69, 77))	('CIN', 'Disease', (81, 84))
217379	30008616	FGFR inhibitors have been shown to enhance tumor sensitivity to conventional chemotherapeutic drugs such as 5-fluorouracil, irinotecan, paclitaxel, and etoposide.	('irinotecan', 'Chemical', 'MESH:D000077146', (124, 134))	('etoposide', 'Chemical', 'MESH:D005047', (152, 161))	('FGFR', 'Gene', (0, 4))	('enhance', 'PosReg', (35, 42))	('inhibitors', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('paclitaxel', 'Chemical', 'MESH:D017239', (136, 146))	('tumor', 'Disease', (43, 48))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (108, 122))
217380	30008616	Recent pharmaceutical development has led to highly selective FGFR inhibitors, including drugs such as AZD4547, which, despite encouraging preliminary results, unfortunately failed to improve progression free survival (PFS) versus chemotherapy as second-line treatment in GC with FGFR2 amplification/polysomy.	('progression', 'Disease', (192, 203))	('amplification/polysomy', 'Var', (286, 308))	('AZD4547', 'Chemical', 'MESH:C572463', (103, 110))	('FGFR', 'Gene', (62, 66))	('FGFR2', 'Gene', (280, 285))	('FGFR2', 'Gene', '2263', (280, 285))	('improve', 'PosReg', (184, 191))
217381	30008616	Of note, the authors highlighted a considerable intra-tumor heterogeneity for FGFR2 amplification and poor concordance between FGFR2 amplification/polysomy and FGFR2 expression, suggesting the need for alternative biomarker testing.	('FGFR2', 'Gene', '2263', (127, 132))	('intra-tumor', 'Disease', (48, 59))	('amplification', 'Var', (84, 97))	('concordance', 'MPA', (107, 118))	('poor', 'NegReg', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('FGFR2', 'Gene', (78, 83))	('FGFR2', 'Gene', '2263', (78, 83))	('FGFR2', 'Gene', (160, 165))	('FGFR2', 'Gene', '2263', (160, 165))	('intra-tumor', 'Disease', 'MESH:D009369', (48, 59))	('expression', 'MPA', (166, 176))	('amplification/polysomy', 'Var', (133, 155))	('FGFR2', 'Gene', (127, 132))
217383	30008616	Among these, dovitinib (TKI258) is currently being investigated in several phase I and II clinical trials (NCT01791387, NCT01719549, NCT02268435) including patients with FGFR2 amplification and GC.	('patients', 'Species', '9606', (156, 164))	('TKI258', 'Chemical', 'MESH:C500007', (24, 30))	('FGFR2', 'Gene', (170, 175))	('FGFR2', 'Gene', '2263', (170, 175))	('dovitinib', 'Chemical', 'MESH:C500007', (13, 22))	('amplification', 'Var', (176, 189))
217384	30008616	Overall, FGFR2 amplification in gastroesophageal cancers presents an exciting opportunity for testing these novel drugs, thereby, improving patient prognosis and future outlooks for these patients.	('amplification', 'Var', (15, 28))	('patient', 'Species', '9606', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (32, 56))	('patient', 'Species', '9606', (140, 147))	('FGFR2', 'Gene', '2263', (9, 14))	('FGFR2', 'Gene', (9, 14))	('improving', 'PosReg', (130, 139))	('patients', 'Species', '9606', (188, 196))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('gastroesophageal cancers', 'Disease', (32, 56))
217393	30008616	Regarding the somatic mutations associated with each ACRG group, the authors observed that the MSI subtype, similar to TCGA, was associated with the presence of hypermutation, with mutations in ARID1A (44.2%), the PI3K-PTEN-mTOR pathway (42%), KRAS (23.3%) and ALK (16.3%).	('mTOR', 'Gene', (224, 228))	('PTEN', 'Gene', '5728', (219, 223))	('associated', 'Reg', (129, 139))	('MSI', 'Disease', (95, 98))	('KRAS', 'Gene', '3845', (244, 248))	('PI3', 'Gene', '5266', (214, 217))	('PI3', 'Gene', (214, 217))	('ALK', 'Gene', (261, 264))	('ARID1A', 'Gene', '8289', (194, 200))	('mutations', 'Var', (181, 190))	('ARID1A', 'Gene', (194, 200))	('mTOR', 'Gene', '2475', (224, 228))	('PTEN', 'Gene', (219, 223))	('KRAS', 'Gene', (244, 248))
217395	30008616	The MSS/TP53- subtype showed the highest prevalence of TP53 mutations (60%), with a low frequency of other mutations, as well as focal amplification of ERBB2, EGFR, CCNE1, CCND1 whereas the MSS/TP53+ subtype showed a relatively higher prevalence (compared to MSS/TP53-) of mutations in APC, ARID1A, KRAS, PIK3CA and SMAD4.	('KRAS', 'Gene', (299, 303))	('EGFR', 'Gene', '1956', (159, 163))	('CCNE1', 'Gene', (165, 170))	('TP53', 'Gene', '7157', (263, 267))	('APC', 'Disease', 'MESH:D011125', (286, 289))	('ERBB2', 'Gene', '2064', (152, 157))	('SMAD4', 'Gene', (316, 321))	('APC', 'Disease', (286, 289))	('PIK3CA', 'Gene', (305, 311))	('TP53', 'Gene', '7157', (55, 59))	('MSS', 'Chemical', '-', (190, 193))	('mutations', 'Var', (60, 69))	('CCNE1', 'Gene', '898', (165, 170))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (194, 198))	('SMAD4', 'Gene', '4089', (316, 321))	('MSS', 'Chemical', '-', (259, 262))	('EGFR', 'Gene', (159, 163))	('TP53', 'Gene', (263, 267))	('MSS', 'Chemical', '-', (4, 7))	('ARID1A', 'Gene', (291, 297))	('KRAS', 'Gene', '3845', (299, 303))	('TP53', 'Gene', (55, 59))	('CCND1', 'Gene', '595', (172, 177))	('PIK3CA', 'Gene', '5290', (305, 311))	('TP53', 'Gene', '7157', (194, 198))	('TP53', 'Gene', (8, 12))	('CCND1', 'Gene', (172, 177))	('ERBB2', 'Gene', (152, 157))	('ARID1A', 'Gene', '8289', (291, 297))
217396	30008616	Of note, ERBB2 amplification was seen in 17.4% of MSS/TP53- tumors, compared to MSS/TP53+ (3.0%), MSI (0.0%) and MSS/EMT (0.0%, P = 0.0001).	('TP53', 'Gene', (54, 58))	('amplification', 'Var', (15, 28))	('EMT', 'Gene', (117, 120))	('MSS', 'Chemical', '-', (80, 83))	('MSS', 'Chemical', '-', (50, 53))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('EMT', 'Gene', '3702', (117, 120))	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', '7157', (84, 88))	('MSS', 'Chemical', '-', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('TP53', 'Gene', (84, 88))	('ERBB2', 'Gene', (9, 14))	('ERBB2', 'Gene', '2064', (9, 14))	('tumors', 'Disease', (60, 66))
217401	30008616	In addition, although CDH1 mutations were highly prevalent in the TCGA GS subtype (37%), they were infrequent in the ACRG MSS/EMT subtype (2.8%), suggesting that the TCGA GS type is not equivalent to the ACRG MSS/EMT subtype.	('mutations', 'Var', (27, 36))	('EMT', 'Gene', (126, 129))	('CDH1', 'Gene', '999', (22, 26))	('GS subtype', 'Disease', (71, 81))	('prevalent', 'Reg', (49, 58))	('EMT', 'Gene', '3702', (126, 129))	('GS', 'Disease', 'MESH:D011125', (71, 73))	('MSS', 'Chemical', '-', (209, 212))	('GS', 'Disease', 'MESH:D011125', (171, 173))	('CDH1', 'Gene', (22, 26))	('MSS', 'Chemical', '-', (122, 125))	('EMT', 'Gene', (213, 216))	('GS subtype', 'Disease', 'MESH:D011125', (71, 81))	('EMT', 'Gene', '3702', (213, 216))
217421	30008616	Of note, based on recent molecular subtypes, EBV-positive and MSI-H GCs emerge as the best candidates for immunotherapy based on the increased PD-L1 expression associated with these subtypes and the high tumor mutational load in MSI-H GEA, which has been shown to correlate with a greater benefit from anti-PD-1/PD-L1 blockade.	('MSI-H', 'Disease', 'MESH:D000848', (62, 67))	('MSI-H', 'Disease', (229, 234))	('mutational', 'Var', (210, 220))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('EBV', 'Species', '10376', (45, 48))	('increased PD', 'Phenotype', 'HP:0008151', (133, 145))	('PD-L1', 'Gene', (312, 317))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('MSI-H', 'Disease', 'MESH:D000848', (229, 234))	('tumor', 'Disease', (204, 209))	('PD-L1', 'Gene', (143, 148))	('expression', 'MPA', (149, 159))	('PD-L1', 'Gene', '29126', (312, 317))	('PD-1', 'Gene', (307, 311))	('MSI-H', 'Disease', (62, 67))	('increased', 'PosReg', (133, 142))	('PD-1', 'Gene', '5133', (307, 311))	('PD-L1', 'Gene', '29126', (143, 148))
217424	30008616	VISTA expression was present in 8.8% out of 464 analyzed samples, and was associated with clinical and molecular features such as Lauren phenotype, tumor localization, EBV infection, KRAS and PIK3CA mutational status and PD-L1 expression.	('Lauren phenotype', 'Disease', (130, 146))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('EBV infection', 'Disease', (168, 181))	('KRAS', 'Gene', (183, 187))	('PIK3CA', 'Gene', (192, 198))	('EBV infection', 'Disease', 'MESH:D020031', (168, 181))	('VISTA', 'Gene', (0, 5))	('tumor', 'Disease', (148, 153))	('KRAS', 'Gene', '3845', (183, 187))	('PD-L1', 'Gene', '29126', (221, 226))	('expression', 'MPA', (227, 237))	('PIK3CA', 'Gene', '5290', (192, 198))	('mutational', 'Var', (199, 209))	('VISTA', 'Gene', '64115', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('associated', 'Reg', (74, 84))	('PD-L1', 'Gene', (221, 226))
217431	30008616	Other agents such as pertuzumab and afitinib are currently being evaluated in a phase III (NCT01358877, NCT01774786) and a phase II (NCT01522768) clinical trial, respectively, in the second-line setting following first-line trastuzumab therapy, after the addition of pertuzumab to trastuzumab plus chemotherapy in the first-line setting failed to demonstrate a significant survival benefit.	('NCT01774786', 'Var', (104, 115))	('trastuzumab', 'Chemical', 'MESH:D000068878', (281, 292))	('trastuzumab', 'Chemical', 'MESH:D000068878', (224, 235))	('pertuzumab', 'Chemical', 'MESH:C485206', (267, 277))	('afitinib', 'Chemical', '-', (36, 44))	('NCT01522768', 'Var', (133, 144))	('NCT01358877', 'Var', (91, 102))	('rat', 'Species', '10116', (354, 357))	('pertuzumab', 'Chemical', 'MESH:C485206', (21, 31))
217436	30008616	Notably the co-occurrence of these alterations has been showed to confer resistance to HER2-targeted treatment in vitro, which can be reversed by combined blockade of HER2 and secondary driver mutations, thus suggesting a promising rationale for combined targeted therapies to overcome primary HER2 resistance in HER2 positive tumors.	('HER2', 'Gene', '2064', (87, 91))	('HER2', 'Gene', '2064', (313, 317))	('tumors', 'Disease', 'MESH:D009369', (327, 333))	('alterations', 'Var', (35, 46))	('rat', 'Species', '10116', (232, 235))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('HER2', 'Gene', (294, 298))	('HER2', 'Gene', (167, 171))	('HER2', 'Gene', '2064', (294, 298))	('rat', 'Species', '10116', (39, 42))	('HER2', 'Gene', '2064', (167, 171))	('tumors', 'Disease', (327, 333))	('HER2', 'Gene', (87, 91))	('HER2', 'Gene', (313, 317))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))
217437	30008616	Indeed, in a small case series, a patient with a co-amplification of HER2 and MET was treated with a combination of trastuzumab, crizotinib, and paclitaxel and experienced near-complete disease response, and combined targeted blockade warrants further investigations.	('trastuzumab', 'Chemical', 'MESH:D000068878', (116, 127))	('paclitaxel', 'Chemical', 'MESH:D017239', (145, 155))	('MET', 'Gene', (78, 81))	('crizotinib', 'Chemical', 'MESH:D000077547', (129, 139))	('patient', 'Species', '9606', (34, 41))	('co-amplification', 'Var', (49, 65))	('HER2', 'Gene', (69, 73))	('HER2', 'Gene', '2064', (69, 73))
217440	30008616	A panel of candidate genomic alterations including EGFR, MET, KRAS, PI3K and PTEN mutations and EGFR, MET, and KRAS amplifications was tested in 37 patients treated with trastuzumab (17 responders and 20 patients with primary resistance).	('KRAS', 'Gene', (62, 66))	('EGFR', 'Gene', (51, 55))	('rat', 'Species', '10116', (33, 36))	('PTEN', 'Gene', (77, 81))	('PI3', 'Gene', (68, 71))	('MET', 'Disease', (57, 60))	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (204, 212))	('EGFR', 'Gene', (96, 100))	('PTEN', 'Gene', '5728', (77, 81))	('EGFR', 'Gene', '1956', (51, 55))	('KRAS', 'Gene', '3845', (111, 115))	('trastuzumab', 'Chemical', 'MESH:D000068878', (170, 181))	('MET', 'Var', (102, 105))	('EGFR', 'Gene', '1956', (96, 100))	('KRAS', 'Gene', (111, 115))	('KRAS', 'Gene', '3845', (62, 66))	('PI3', 'Gene', '5266', (68, 71))	('mutations', 'Var', (82, 91))	('tested', 'Reg', (135, 141))
217441	30008616	AMESIA panel alterations were significantly more frequent in resistant patients and in HER2 IHC 2+ compared to HER2 IHC 3+ tumors.	('HER2', 'Gene', (111, 115))	('HER2', 'Gene', '2064', (87, 91))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('HER2', 'Gene', '2064', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('patients', 'Species', '9606', (71, 79))	('rat', 'Species', '10116', (17, 20))	('AMESIA', 'Disease', (0, 6))	('AMESIA', 'Disease', 'None', (0, 6))	('alterations', 'Var', (13, 24))	('frequent', 'Reg', (49, 57))	('HER2', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
217453	30008616	Additionally, recent results of a large-scale profiling study in GC confirmed a high grade of tumor heterogeneity in EBV-positivity and PIK3CA mutations, suggesting caution in the extrapolation of tumor genomic profiling from the analyses of single tissue biopsies.	('PIK3CA', 'Gene', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('EBV', 'Species', '10376', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PIK3CA', 'Gene', '5290', (136, 142))	('tumor', 'Disease', (94, 99))	('EBV-positivity', 'Gene', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('mutations', 'Var', (143, 152))
217458	30008616	Their study included a pilot analysis of cell-free DNA (cfDNA) which showed both concordance and discordance with matched PT and MLs results, as sequencing of cfDNA was able to identify in some cases alterations (i.e.	('rat', 'Species', '10116', (204, 207))	('identify', 'Reg', (177, 185))	('alterations', 'Var', (200, 211))
217464	30008616	Additionally, in this study HER2 amplification in ctDNA were showed to be highly concordant with HER2 amplification in tumor tissue.	('HER2', 'Gene', (97, 101))	('HER2', 'Gene', '2064', (28, 32))	('tumor', 'Disease', (119, 124))	('HER2', 'Gene', '2064', (97, 101))	('amplification', 'Var', (33, 46))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('HER2', 'Gene', (28, 32))
217467	30008616	Epigenetic changes, including DNA methylation, histone modifications and non-coding RNAs, are a common event in cancer and contribute to both carcinogenesis and disease progression.	('carcinogenesis', 'Disease', (142, 156))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('contribute', 'Reg', (123, 133))	('DNA methylation', 'Var', (30, 45))	('non-coding', 'Protein', (73, 83))	('histone', 'MPA', (47, 54))	('carcinogenesis', 'Disease', 'MESH:D063646', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Epigenetic changes', 'Var', (0, 18))
217468	30008616	Aberrant DNA methylation is one of the most studied epigenetic alteration in cancer and it has been proposed as a potential biomarker both for tumor diagnosis, prognosis and treatment response in several cancer types.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('rat', 'Species', '10116', (67, 70))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (143, 148))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('DNA', 'Protein', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
217471	30008616	In EAC, abnormal DNA methylation has been extensively researched as a tool for stratifying Barrett's esophagus patients' risk to develop cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophagus', 'Disease', (101, 110))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (91, 110))	('rat', 'Species', '10116', (81, 84))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('abnormal', 'Var', (8, 16))	('cancer', 'Disease', (137, 143))	('patients', 'Species', '9606', (111, 119))
217472	30008616	Aberrant methylation in several genes, in fact, such as CDKN2A and APC, has been reported as part of the neoplastic progression from Barret's esophagus to EAC).	('part', 'Reg', (93, 97))	('CDKN2A and APC', 'Gene', '1029;324', (56, 70))	('Aberrant methylation', 'Var', (0, 20))	('reported', 'Reg', (81, 89))
217473	30008616	Future research will further address the promising diagnostic and prognostic value of aberrant DNA methylation in GEA and its possible implication in treatment response as well as its potential role as a treatment target in these malignancies.	('malignancies', 'Disease', (230, 242))	('malignancies', 'Disease', 'MESH:D009369', (230, 242))	('DNA', 'Gene', (95, 98))	('aberrant', 'Var', (86, 94))
217480	30008616	Notably, PDX models of tumors harboring alterations in HER-2, MET and FGFR2 signaling pathways have been proven useful for targeted drugs screening and evaluation, highlighting preliminary evidence of activity of the combination of targeted anti-MET and anti-FGFR2 treatment in tumors with co-occurrent amplifications of these genes.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumors', 'Disease', (23, 29))	('HER-2', 'Gene', (55, 60))	('activity', 'MPA', (201, 209))	('tumors', 'Disease', (278, 284))	('FGFR2', 'Gene', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('FGFR2', 'Gene', '2263', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('FGFR2', 'Gene', (259, 264))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('alterations', 'Var', (40, 51))	('rat', 'Species', '10116', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('FGFR2', 'Gene', '2263', (259, 264))	('anti-MET', 'Var', (241, 249))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('HER-2', 'Gene', '2064', (55, 60))
217661	25515326	We also found that, first, NBT + EBRT and concurrent chemotherapy is safe and beneficial in terms of local control in the radical treatment of patients with esophageal cancer, and second, the OS rate was significantly increased, and the late complication rate was significantly decreased in patients who received the TS chemotherapy regimen.	('NBT + EBRT', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('EBRT', 'Chemical', '-', (33, 37))	('local', 'CPA', (101, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('decreased', 'NegReg', (278, 287))	('men', 'Species', '9606', (337, 340))	('late complication', 'CPA', (237, 254))	('increased', 'PosReg', (218, 227))	('men', 'Species', '9606', (135, 138))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (291, 299))	('TS', 'Chemical', '-', (317, 319))	('NBT', 'Chemical', '-', (27, 30))	('esophageal cancer', 'Disease', (157, 174))	('OS rate', 'CPA', (192, 199))
217665	25515326	The present study showed survival benefits from the addition of NBT to EBRT and concurrent chemotherapy in the treatment of locally advanced disease that resulted in short-term effects, and these findings are similar to those in the reports of Montravadl et al.	('EBRT', 'Chemical', '-', (71, 75))	('addition', 'Var', (52, 60))	('survival', 'CPA', (25, 33))	('NBT', 'Chemical', '-', (64, 67))	('benefits', 'PosReg', (34, 42))	('NBT', 'Gene', (64, 67))	('locally advanced disease', 'Disease', (124, 148))	('men', 'Species', '9606', (116, 119))
217677	25515326	Third, we believe that there are at least two factors that made the 252Cf-based NBT more effective than the 192Ir-based HDR, particularly in the treatment of locally advanced esophageal cancer.	('esophageal cancer', 'Disease', (175, 192))	('NBT', 'Chemical', '-', (80, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('252Cf-based', 'Var', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('men', 'Species', '9606', (150, 153))
217682	25515326	In summary, we believe that NBT + EBRT with concurrent chemotherapy is a safe and effective treatment option for patients with thoracic esophageal cancer.	('NBT', 'Var', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('men', 'Species', '9606', (97, 100))	('patients', 'Species', '9606', (113, 121))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (127, 153))	('EBRT', 'Chemical', '-', (34, 38))	('thoracic esophageal cancer', 'Disease', (127, 153))	('NBT', 'Chemical', '-', (28, 31))
217699	25527100	In the seventh edition of the American Joint Committee on Cancer tumor node metastasis (AJCC TNM) staging system for esophageal squamous cell carcinoma issued in 2009, LNs from the neck to the abdomen are defined as regional LNs.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (117, 151))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('TNM', 'Gene', '10178', (93, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('LNs', 'Var', (168, 171))	('esophageal squamous cell carcinoma', 'Disease', (117, 151))	('TNM', 'Gene', (93, 96))	('Cancer tumor', 'Disease', 'MESH:D009369', (58, 70))	('Cancer tumor', 'Disease', (58, 70))
217759	24505369	Matrix Metalloproteinase-1 (MMP-1) Promoter Polymorphisms are Well Linked with Lower Stomach Tumor Formation in Eastern Indian Population Expression of matrix metalloproteinase-1 (MMP-1), an interstitial collagenase, plays a major role in cellular invasion during development of gastric cancer, a leading cause of death worldwide.	('Polymorphisms', 'Var', (44, 57))	('Matrix Metalloproteinase-1', 'Gene', '4312', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('death', 'Disease', 'MESH:D003643', (314, 319))	('gastric cancer', 'Disease', 'MESH:D013274', (279, 293))	('Tumor', 'Phenotype', 'HP:0002664', (93, 98))	('MMP-1', 'Gene', '4312', (180, 185))	('Stomach Tumor', 'Phenotype', 'HP:0006753', (85, 98))	('MMP-1', 'Gene', '4312', (28, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (279, 293))	('Stomach Tumor', 'Disease', (85, 98))	('MMP-1', 'Gene', (180, 185))	('death', 'Disease', (314, 319))	('matrix metalloproteinase-1', 'Gene', '4312', (152, 178))	('MMP-1', 'Gene', (28, 33))	('Stomach Tumor', 'Disease', 'MESH:D013274', (85, 98))	('Matrix Metalloproteinase-1', 'Gene', (0, 26))	('gastric cancer', 'Disease', (279, 293))	('matrix metalloproteinase-1', 'Gene', (152, 178))
217760	24505369	While the importance's of other SNPs in the MMP-1 promoter have not yet been studied in gastric cancer, our aim was to investigate MMP-1 gene promoter polymorphisms and gastric cancer susceptibility in eastern Indian population.	('gastric cancer', 'Disease', (169, 183))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('polymorphisms', 'Var', (151, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('MMP-1', 'Gene', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
217761	24505369	A total of 145 gastric cancer patients and 145 healthy controls were genotyped for MMP-1 -1607 1G/2G (rs1799750) by PCR-restriction fragment length polymorphism (RFLP), while MMP-1 -519 A/G (rs1144393), MMP-1 -422 T/A (rs475007), MMP-1 -340 T/C (rs514921) and MMP-1 -320 T/C (rs494379) were genotyped by DNA sequencing.	('rs1144393', 'Mutation', 'rs1144393', (191, 200))	('rs494379', 'Mutation', 'rs494379', (276, 284))	('gastric cancer', 'Disease', (15, 29))	('-320 T/C', 'Mutation', 'rs494379', (266, 274))	('rs514921', 'Var', (246, 254))	('gastric cancer', 'Disease', 'MESH:D013274', (15, 29))	('rs1144393', 'Var', (191, 200))	('-519 A/G', 'Mutation', 'rs1144393', (181, 189))	('-340 T/C', 'Mutation', 'rs514921', (236, 244))	('rs514921', 'Mutation', 'rs514921', (246, 254))	('-422 T/A', 'Mutation', 'rs475007', (209, 217))	('patients', 'Species', '9606', (30, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('rs494379', 'Var', (276, 284))	('rs475007', 'Mutation', 'rs475007', (219, 227))	('rs475007', 'Var', (219, 227))	('rs1799750', 'Mutation', 'rs1799750', (102, 111))
217762	24505369	A positive association was found with MMP-1 -422 T/A SNP that showed significant risk for regional lymph node metastasis (P = 0.021, Odd's ratio (OR) = 3.044, Confidence intervals (CI) = 1.187-7.807).	('-422 T/A', 'Mutation', 'rs475007', (44, 52))	('regional lymph node metastasis', 'CPA', (90, 120))	('MMP-1 -422 T/A SNP', 'Var', (38, 56))
217763	24505369	In addition, we found a significant association with lower stomach tumor formation among gastric cancer patients for three adjacent polymorphisms near the transcriptional start sites of [MMP-1 -422 T/A (P = 0.043, OR = 2.182, CI = 1.03-4.643), MMP-1 -340 T/C (P = 0.075, OR = 1.97, CI = 0.94-4.158) and MMP-1 -320 T/C (P = 0.034, OR = 2.224, CI = 1.064-40731)].	('stomach tumor', 'Phenotype', 'HP:0006753', (59, 72))	('MMP-1 -320 T/C', 'Var', (303, 317))	('-340 T/C', 'Mutation', 'rs514921', (250, 258))	('patients', 'Species', '9606', (104, 112))	('gastric cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('MMP-1 -340 T/C', 'Var', (244, 258))	('stomach tumor', 'Disease', 'MESH:D013274', (59, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('-320 T/C', 'Mutation', 'rs494379', (309, 317))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('stomach tumor', 'Disease', (59, 72))	('-422 T/A', 'Mutation', 'rs475007', (193, 201))	('lower', 'NegReg', (53, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))
217765	24505369	Furthermore, MMP-1 -519 A/G polymorphism displayed poor cellular differentiation (P = 0.024, OR = 3.8, CI = 1.69-8.56) attributing a higher risk of cancer progression.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('MMP-1 -519 A/G', 'Var', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cellular differentiation', 'CPA', (56, 80))	('poor', 'NegReg', (51, 55))	('-519 A/G', 'Mutation', 'rs1144393', (19, 27))
217778	24505369	Overexpression of MMP-1 protein is associated with poor prognosis of esophageal cancer and colorectal cancer.	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('protein', 'Protein', (24, 31))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('MMP-1', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))
217780	24505369	The presence of a 2G polymorphism could increase transcriptional activity of endogenous MMP-1 because the guanine insertion creates a binding site for a member of the Ets transcription factor family.	('MMP-1', 'Gene', (88, 93))	('transcriptional activity', 'MPA', (49, 73))	('increase', 'PosReg', (40, 48))	('guanine insertion', 'Var', (106, 123))	('presence', 'Var', (4, 12))	('binding', 'Interaction', (134, 141))	('guanine', 'Chemical', 'MESH:D006147', (106, 113))	('polymorphism', 'Var', (21, 33))
217782	24505369	Several other single nucleotide polymorphisms (-519A/G, -422T/A, -340C/T, and -320C/T) in the MMP-1 gene promoter have recently been identified.	('MMP-1', 'Gene', (94, 99))	('-340C/T', 'Mutation', 'rs514921', (65, 72))	('-320C/T', 'Mutation', 'rs494379', (78, 85))	('-422T/A', 'Mutation', 'rs475007', (56, 63))	('-519A/G', 'Mutation', 'rs1144393', (47, 54))	('-519A/G', 'Var', (47, 54))
217785	24505369	In the present study, we conducted a hospital-based case-control study to explore the association of the MMP-1 gene promoter SNPs [-1607 1G/2G (rs1799750) (MMP-1.1), -519A/G (rs1144393) (MMP-1.2), -422T/A (rs475007) (MMP-1.3), -340C/T (rs514921) (MMP-1.4), and -320C/T (rs494379) (MMP-1.5)] and their haplotypes with the risk of gastric cancer development in an eastern Indian population.	('MMP-1.2', 'Gene', '4321', (187, 194))	('MMP-1.1', 'Gene', '4320', (156, 163))	('rs494379', 'Mutation', 'rs494379', (270, 278))	('-340C/T', 'Mutation', 'rs514921', (227, 234))	('MMP-1.4', 'Gene', (247, 254))	('gastric cancer', 'Phenotype', 'HP:0012126', (329, 343))	('MMP-1', 'Gene', (105, 110))	('rs1144393', 'Mutation', 'rs1144393', (175, 184))	('MMP-1.2', 'Gene', (187, 194))	('rs1799750', 'Mutation', 'rs1799750', (144, 153))	('MMP-1.5', 'Gene', (281, 288))	('and -320C/T (rs494379', 'Var', (257, 278))	('-519A/G', 'Mutation', 'rs1144393', (166, 173))	('gastric cancer', 'Disease', (329, 343))	('rs1144393', 'Var', (175, 184))	('rs514921', 'Mutation', 'rs514921', (236, 244))	('MMP-1.1', 'Gene', (156, 163))	('MMP-1.3', 'Gene', '4322', (217, 224))	('MMP-1.5', 'Gene', '4324', (281, 288))	('MMP-1.3', 'Gene', (217, 224))	('-422T/A', 'Mutation', 'rs475007', (197, 204))	('rs475007', 'Mutation', 'rs475007', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('gastric cancer', 'Disease', 'MESH:D013274', (329, 343))	('-320C/T', 'Mutation', 'rs494379', (261, 268))	('MMP-1.4', 'Gene', '4323', (247, 254))
217787	24505369	The study demonstrated the putative association of MMP-1.3, MMP-1.4, and MMP-1.5 polymorphisms with the risk of lower stomach tumor formation in gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (145, 159))	('MMP-1.3', 'Gene', '4322', (51, 58))	('stomach tumor', 'Disease', 'MESH:D013274', (118, 131))	('polymorphisms', 'Var', (81, 94))	('MMP-1.4', 'Gene', (60, 67))	('MMP-1.3', 'Gene', (51, 58))	('stomach tumor', 'Disease', (118, 131))	('MMP-1.5', 'Gene', '4324', (73, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (145, 159))	('gastric cancer', 'Disease', (145, 159))	('stomach tumor', 'Phenotype', 'HP:0006753', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('MMP-1.5', 'Gene', (73, 80))	('MMP-1.4', 'Gene', '4323', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('association', 'Interaction', (36, 47))	('lower', 'NegReg', (112, 117))
217788	24505369	The functional importance of MMP-1 polymorphisms in lower stomach tumor formation was confirmed by haplotype effects of these polymorphisms on MMP-1 expression levels in serum.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('stomach tumor', 'Phenotype', 'HP:0006753', (58, 71))	('lower', 'NegReg', (52, 57))	('MMP-1', 'Gene', (143, 148))	('expression levels', 'MPA', (149, 166))	('polymorphisms', 'Var', (35, 48))	('stomach tumor', 'Disease', 'MESH:D013274', (58, 71))	('stomach tumor', 'Disease', (58, 71))	('MMP-1', 'Gene', (29, 34))
217814	24505369	In analyzing the relationship between the SNP genotypes and disease status of GC, the stage of cancer, histological classification and depth of tumor invasion were transformed to binary data (Stage I+II vs. stage III+IV, well-differentiated+moderately-differentiated vs. Poorly-differentiated, and T1+T2 vs. T3+T4).	('Poorly-differentiated', 'CPA', (271, 292))	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('T1+T2', 'Var', (298, 303))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('well-differentiated+moderately-differentiated', 'CPA', (221, 266))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
217825	24505369	MMP-1.1 polymorphism showed no significant difference in distribution of genotypes (1G1G vs. 1G2G, 2G2G and 1G2G+2G2G) between patients and controls (p = 0.430, p = 0.465 and p = 0.411 respectively).	('MMP-1.1', 'Gene', (0, 7))	('2G2G', 'Var', (99, 103))	('MMP-1.1', 'Gene', '4320', (0, 7))	('1G2G+2G2G', 'Var', (108, 117))	('patients', 'Species', '9606', (127, 135))	('1G1G', 'Var', (84, 88))	('1G2G', 'Var', (93, 97))
217827	24505369	In gastric cancer patients, the frequency of the MMP-1.2 AG, GG and AG+GG genotypes were not significantly different from healthy controls (p = 0.603, p = 0.506 and p = 0.510 respectively) and thus did not confer any significant risk for gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('gastric cancer', 'Disease', (238, 252))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (238, 252))	('AG+GG', 'Var', (68, 73))	('MMP-1.2', 'Gene', (49, 56))	('MMP-1.2', 'Gene', '4321', (49, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (238, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('patients', 'Species', '9606', (18, 26))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
217829	24505369	The genotype frequency distribution, (AA vs. TT, TA and TA+TT) of the MMP-1.3 polymorphism in the patient population was not significantly different from healthy controls (p = 0.626, p = 0.999 and p = 0.806 respectively) and thus did not confer any significant risk for gastric cancer.	('TA', 'Chemical', 'MESH:D013635', (49, 51))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('patient', 'Species', '9606', (98, 105))	('MMP-1.3', 'Gene', (70, 77))	('gastric cancer', 'Disease', (270, 284))	('gastric cancer', 'Disease', 'MESH:D013274', (270, 284))	('gastric cancer', 'Phenotype', 'HP:0012126', (270, 284))	('TA', 'Chemical', 'MESH:D013635', (56, 58))	('MMP-1.3', 'Gene', '4322', (70, 77))	('polymorphism', 'Var', (78, 90))
217837	24505369	MMP-1.1 and MMP-1.2 polymorphisms did not confer any significant risk for tumor location or degree of tumor progression in gastric cancer (Table 3).	('MMP-1.1', 'Gene', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('polymorphisms', 'Var', (20, 33))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('MMP-1.1', 'Gene', '4320', (0, 7))	('MMP-1.2', 'Gene', '4321', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gastric cancer', 'Disease', (123, 137))	('MMP-1.2', 'Gene', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))
217838	24505369	However patients carrying combination of AG and GG genotype of MMP-1.2 polymorphism were significantly distributed among histological subtypes of cancer and showed significantly greater risk for poorly differentiated (PD) carcinomas (p = 0.001, OR = 3.803, CI = 1.69-8.56) (Table 3).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('MMP-1.2', 'Gene', (63, 70))	('PD) carcinomas', 'Disease', 'MESH:D010300', (218, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('MMP-1.2', 'Gene', '4321', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('distributed', 'Reg', (103, 114))	('polymorphism', 'Var', (71, 83))	('patients', 'Species', '9606', (8, 16))
217839	24505369	For MMP-1.3 polymorphism, patients carrying combination of TA and TT genotypes were at more risk of lower stomach cancer (lower & middle body, antrum and pylorus of stomach) (p = 0.043, OR = 2.18, CI = 1.03-4.64).	('MMP-1.3', 'Gene', (4, 11))	('patients', 'Species', '9606', (26, 34))	('lower stomach cancer', 'Disease', 'MESH:D013274', (100, 120))	('polymorphism', 'Var', (12, 24))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lower stomach cancer', 'Disease', (100, 120))	('TA', 'Chemical', 'MESH:D013635', (59, 61))	('stomach cancer', 'Phenotype', 'HP:0012126', (106, 120))	('MMP-1.3', 'Gene', '4322', (4, 11))
217841	24505369	For MMP-1.4 polymorphism, the distribution of TC and CC genotypes among patients with different tumor locations in the stomach was close to reaching a statistical significant association with the risk of lower stomach cancer (p = 0.075, OR = 1.969, CI = 0.94-4.15) (Table 3).	('lower stomach cancer', 'Disease', (204, 224))	('TC', 'Chemical', 'MESH:D013667', (46, 48))	('lower stomach cancer', 'Disease', 'MESH:D013274', (204, 224))	('MMP-1.4', 'Gene', '4323', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('stomach cancer', 'Phenotype', 'HP:0012126', (210, 224))	('tumor', 'Disease', (96, 101))	('polymorphism', 'Var', (12, 24))	('MMP-1.4', 'Gene', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor locations in the stomach', 'Phenotype', 'HP:0006753', (96, 126))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('patients', 'Species', '9606', (72, 80))
217843	24505369	For MMP-1.5 polymorphism, a combination of TC and CC genotypes showed a significant association with location of stomach tumor.	('stomach tumor', 'Phenotype', 'HP:0006753', (113, 126))	('MMP-1.5', 'Gene', '4324', (4, 11))	('TC', 'Chemical', 'MESH:D013667', (43, 45))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('MMP-1.5', 'Gene', (4, 11))	('stomach tumor', 'Disease', 'MESH:D013274', (113, 126))	('polymorphism', 'Var', (12, 24))	('stomach tumor', 'Disease', (113, 126))	('location', 'Disease', (101, 109))
217850	24505369	The extended haplotype frequency distributions of MMP-1 polymorphisms were not significant between gastric cancer patients and controls and none of these haplotypes conferred risk for gastric cancer occurrence (data not shown).	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('MMP-1', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('gastric cancer', 'Disease', (99, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('polymorphisms', 'Var', (56, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('gastric cancer', 'Disease', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('patients', 'Species', '9606', (114, 122))
217851	24505369	The difference in the haplotype frequency was significant between lower stomach gastric cancer patients and upper stomach gastric cancer patients as the number of polymorphic variant alleles were increased resulting in the increase of risk for lower stomach gastric cancer development with highest OR of 2.155, 95% CI = 1.317-3.526, P = 0.0028, chi2 = 9.52 for combined haplotypes containing 4 risk alleles (Table 5).	('gastric cancer', 'Phenotype', 'HP:0012126', (258, 272))	('stomach gastric cancer', 'Disease', 'MESH:D013274', (250, 272))	('stomach gastric cancer', 'Disease', 'MESH:D013274', (114, 136))	('stomach gastric cancer', 'Disease', (250, 272))	('upper stomach gastric cancer', 'Disease', (108, 136))	('increase', 'PosReg', (223, 231))	('patients', 'Species', '9606', (95, 103))	('upper stomach gastric cancer', 'Disease', 'MESH:D013274', (108, 136))	('patients', 'Species', '9606', (137, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('stomach gastric cancer', 'Disease', (72, 94))	('variant', 'Var', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('stomach gastric cancer', 'Disease', 'MESH:D013274', (72, 94))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
217852	24505369	In order to investigate the impact of MMP-1 promoter polymorphisms on the gene function, we compared serum MMP-1 level by serum ELISA in patients having lower stomach cancer with combined risk haplotypes (having at least any one risk allele) vs. upper stomach cancer with the reference haplotype (1G-A-A-T-T).	('1G-A-A-T-T', 'Disease', (297, 307))	('lower stomach cancer', 'Disease', (153, 173))	('upper stomach cancer', 'Disease', (246, 266))	('serum MMP-1 level', 'MPA', (101, 118))	('haplotypes', 'Var', (193, 203))	('stomach cancer', 'Phenotype', 'HP:0012126', (159, 173))	('upper stomach cancer', 'Disease', 'MESH:D013274', (246, 266))	('patients', 'Species', '9606', (137, 145))	('stomach cancer', 'Phenotype', 'HP:0012126', (252, 266))	('compared', 'Reg', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('1G-A-A-T-T', 'Disease', 'MESH:C565824', (297, 307))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('lower stomach cancer', 'Disease', 'MESH:D013274', (153, 173))
217858	24505369	In addition, some polymorphic genes encoding metabolic enzymes and cell cycle regulators, such as methylene tetrahydrofolate reductase, NADPH: quinone oxidoreductase and Cyclin D1 have been documented to confer a susceptibility to gastric cancer.	('NADPH', 'Gene', (136, 141))	('Cyclin D1', 'Gene', (170, 179))	('quinone oxidoreductase', 'Gene', '1429', (143, 165))	('NADPH', 'Gene', '1666', (136, 141))	('gastric cancer', 'Disease', (231, 245))	('susceptibility', 'Reg', (213, 227))	('susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (213, 245))	('gastric cancer', 'Disease', 'MESH:D013274', (231, 245))	('polymorphic', 'Var', (18, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (231, 245))	('quinone oxidoreductase', 'Gene', (143, 165))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('Cyclin D1', 'Gene', '595', (170, 179))
217859	24505369	Therefore, polymorphic genes, alone, in combination with others or through interaction with exogenous risk factors, may be used as predicative parameters for screening individuals at a high risk of gastric cancer.	('high risk of gastric cancer', 'Phenotype', 'HP:0006753', (185, 212))	('gastric cancer', 'Disease', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('polymorphic genes', 'Var', (11, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))
217860	24505369	To the best of our knowledge, this study of the association of MMP-1 variants and the risk of gastric cancer development and progression in an eastern Indian population is the first of its kind with a focus on a -1607 1G/2G polymorphism (MMP-1.1), and an additional four polymorphisms between this SNP and the transcription start site.	('gastric cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('variants', 'Var', (69, 77))	('MMP-1', 'Gene', (63, 68))	('-1607 1G/2G', 'Var', (212, 223))	('association', 'Interaction', (48, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('MMP-1.1', 'Gene', (238, 245))	('progression', 'CPA', (125, 136))	('MMP-1.1', 'Gene', '4320', (238, 245))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))
217861	24505369	Despite this, in our study MMP-1.1 polymorphism and additionally four other SNPs (MMP-1.1, MMP-1.2, MMP-1.3 and MMP-1.4) in the promoter region are not correlated with gastric cancer occurrence, suggesting these promoter variants to be low penetrance risk factors in gastric cancer.	('MMP-1.2', 'Gene', '4321', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('MMP-1.1', 'Gene', '4320', (27, 34))	('MMP-1.4', 'Gene', '4323', (112, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (168, 182))	('MMP-1.1', 'Gene', '4320', (82, 89))	('gastric cancer', 'Disease', (267, 281))	('MMP-1.4', 'Gene', (112, 119))	('MMP-1.2', 'Gene', (91, 98))	('MMP-1.3', 'Gene', '4322', (100, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('MMP-1.3', 'Gene', (100, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (267, 281))	('variants', 'Var', (221, 229))	('MMP-1.1', 'Gene', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('gastric cancer', 'Phenotype', 'HP:0012126', (267, 281))	('gastric cancer', 'Disease', (168, 182))	('MMP-1.1', 'Gene', (82, 89))
217863	24505369	It is well known that the 2G type of SNP at -1607 (MMP-1.1) in the promoter of MMP-1 creates a core recognition sequence (5'-GGAT-3') that represents the binding site for Ets family transcription factors.	('MMP-1.1', 'Gene', '4320', (51, 58))	('MMP-1.1', 'Gene', (51, 58))	('MMP-1', 'Gene', (79, 84))	('SNP at -1607', 'Var', (37, 49))
217865	24505369	Similar results for MMP-1.1 polymorphism have been reported in other investigations on gastric cancer using Japanese populations, gastric cardiac adenocarcinoma (GCA) in a Chinese population, and prostate cancer in a Turkish population.	('prostate cancer', 'Disease', 'MESH:D011471', (196, 211))	('gastric cardiac adenocarcinoma', 'Disease', 'MESH:D013274', (130, 160))	('polymorphism', 'Var', (28, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (196, 211))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('MMP-1.1', 'Gene', (20, 27))	('prostate cancer', 'Disease', (196, 211))	('MMP-1.1', 'Gene', '4320', (20, 27))	('gastric cardiac adenocarcinoma', 'Disease', (130, 160))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
217868	24505369	Patients having combination of the TA and TT genotype for MMP-1.3 polymorphism, a combination of the TC and CC genotype for MMP-1.4 polymorphism, and a combination of the TC and CC genotype for MMP-1.5 polymorphism are at more risk of lower stomach cancer (lower & middle body, antrum and pylorus of stomach), suggesting that these three polymorphisms, separately or in combination may be used as a marker for diagnosing and treating patients having lower stomach cancer in our population.	('lower stomach cancer', 'Disease', (235, 255))	('cancer', 'Phenotype', 'HP:0002664', (464, 470))	('lower stomach cancer', 'Disease', 'MESH:D013274', (450, 470))	('TA', 'Chemical', 'MESH:D013635', (35, 37))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('lower stomach cancer', 'Disease', 'MESH:D013274', (235, 255))	('and pylorus of stomach', 'Disease', (285, 307))	('patients', 'Species', '9606', (434, 442))	('Patients', 'Species', '9606', (0, 8))	('combination', 'Var', (82, 93))	('TC', 'Chemical', 'MESH:D013667', (101, 103))	('MMP-1.5', 'Gene', (194, 201))	('MMP-1.4', 'Gene', '4323', (124, 131))	('TC', 'Chemical', 'MESH:D013667', (171, 173))	('MMP-1.5', 'Gene', '4324', (194, 201))	('MMP-1.3', 'Gene', '4322', (58, 65))	('MMP-1.4', 'Gene', (124, 131))	('MMP-1.3', 'Gene', (58, 65))	('stomach cancer', 'Phenotype', 'HP:0012126', (241, 255))	('stomach cancer', 'Phenotype', 'HP:0012126', (456, 470))	('lower stomach cancer', 'Disease', (450, 470))
217876	24505369	However, stratification analyses with respect to gastric cancer progression in our study shows, those MMP-1 promoter polymorphisms are not significantly associated with invasion, lymph node metastasis, distant metastasis and thus TNM classification of gastric cancer, with some exceptional contradictions.	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('MMP-1', 'Gene', (102, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('gastric cancer', 'Disease', (252, 266))	('polymorphisms', 'Var', (117, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (252, 266))	('associated', 'Reg', (153, 163))	('lymph node metastasis', 'CPA', (179, 200))	('distant metastasis', 'CPA', (202, 220))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gastric cancer', 'Disease', (49, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (252, 266))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))
217878	24505369	MMP-1.4 polymorphism with a combination of the TC and CC genotype shows a negative correlation for regional lymph node metastasis in addition to distant metastasis, contradicting MMP-1.3 polymorphism.	('negative', 'NegReg', (74, 82))	('distant metastasis', 'CPA', (145, 163))	('MMP-1.3', 'Gene', (179, 186))	('TC', 'Chemical', 'MESH:D013667', (47, 49))	('polymorphism', 'Var', (8, 20))	('MMP-1.4', 'Gene', (0, 7))	('regional lymph node metastasis', 'CPA', (99, 129))	('MMP-1.3', 'Gene', '4322', (179, 186))	('MMP-1.4', 'Gene', '4323', (0, 7))
217881	24505369	The MMP-1.1 polymorphism may increase the MMP-1 expression in response to growth factors and cytokines.	('MMP-1.1', 'Gene', (4, 11))	('expression', 'MPA', (48, 58))	('increase', 'PosReg', (29, 37))	('MMP-1', 'Gene', (42, 47))	('polymorphism', 'Var', (12, 24))	('MMP-1.1', 'Gene', '4320', (4, 11))
217883	24505369	So, the presence of polymorphic alleles of the MMP-1 promoter may not necessarily contribute to the degree of tumor invasion and in addition to progression of gastric carcinoma.	('polymorphic', 'Var', (20, 31))	('MMP-1', 'Gene', (47, 52))	('presence', 'Var', (8, 16))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (159, 176))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('gastric carcinoma', 'Disease', 'MESH:D013274', (159, 176))	('gastric carcinoma', 'Disease', (159, 176))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
217884	24505369	However, we found a significant association between the MMP-1.2 polymorphism and the histological classification.	('histological classification', 'CPA', (85, 112))	('MMP-1.2', 'Gene', (56, 63))	('significant association', 'Reg', (20, 43))	('MMP-1.2', 'Gene', '4321', (56, 63))	('polymorphism', 'Var', (64, 76))
217887	24505369	Functional studies showed that the MMP-1 promoter polymorphisms exert haplotype effects on MMP-1 promoter activity in cancer cells.	('cancer', 'Disease', (118, 124))	('MMP-1', 'Gene', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('activity', 'MPA', (106, 114))	('MMP-1', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('polymorphisms', 'Var', (50, 63))
217889	24505369	Three of the five polymorphisms, i.e., MMP-1.2 (rs1144393), MMP-1.3 (rs475007) and MMP-1.4 (rs514921) have been studied in the international HapMap project, and have been shown to be located near a recombination hotspot and thus accounted for low LD.	('rs475007', 'Mutation', 'rs475007', (69, 77))	('MMP-1.2', 'Gene', '4321', (39, 46))	('MMP-1.4', 'Gene', '4323', (83, 90))	('rs514921', 'Var', (92, 100))	('MMP-1.3', 'Gene', '4322', (60, 67))	('rs1144393', 'Mutation', 'rs1144393', (48, 57))	('MMP-1.3', 'Gene', (60, 67))	('rs514921', 'Mutation', 'rs514921', (92, 100))	('MMP-1.4', 'Gene', (83, 90))	('rs1144393', 'Var', (48, 57))	('MMP-1.2', 'Gene', (39, 46))	('rs475007', 'Var', (69, 77))
217892	24505369	However, we have found a functional correlation of MMP-1 promoter polymorphic haplotypes with MMP-1 expression in a locoregional manner of gastric cancer occurrence.	('gastric cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('MMP-1 promoter', 'Gene', (51, 65))	('expression', 'MPA', (100, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('polymorphic haplotypes', 'Var', (66, 88))	('MMP-1', 'Gene', (94, 99))
217895	24505369	In conclusion, our study suggests that MMP-1.3, MMP-1.4 and MMP-1.5 polymorphisms in the MMP-1 promoter enhances the risk of lower stomach tumor formation in an eastern Indian population.	('MMP-1.5', 'Gene', (60, 67))	('stomach tumor', 'Disease', (131, 144))	('MMP-1.4', 'Gene', '4323', (48, 55))	('MMP-1', 'Gene', (89, 94))	('polymorphisms', 'Var', (68, 81))	('MMP-1.5', 'Gene', '4324', (60, 67))	('stomach tumor', 'Phenotype', 'HP:0006753', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('MMP-1.3', 'Gene', '4322', (39, 46))	('MMP-1.4', 'Gene', (48, 55))	('MMP-1.3', 'Gene', (39, 46))	('enhances', 'PosReg', (104, 112))	('stomach tumor', 'Disease', 'MESH:D013274', (131, 144))
217896	24505369	Furthermore, we found that MMP-1.3 polymorphism contributed to the susceptibility of lymph node metastasis.	('MMP-1.3', 'Gene', (27, 34))	('polymorphism', 'Var', (35, 47))	('contributed', 'Reg', (48, 59))	('lymph node metastasis', 'CPA', (85, 106))	('MMP-1.3', 'Gene', '4322', (27, 34))
217930	23436229	He had been diagnosed 1 year earlier with stage II, pT2N0M0 intrathoracic esophageal squamous cell cancer.	('esophageal squamous cell cancer', 'Disease', (74, 105))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (85, 105))	('pT2N0M0', 'Var', (52, 59))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (74, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
217937	23436229	He had been diagnosed 3 years earlier with intrathoracic lower esophageal squamous cell cancer, and underwent esophagectomy with lower mediastinal and abdominal lymph nodal dissection under thoraco-laparotomy with left-sided intra-thoracic gastric tube reconstruction for stage IV, pT3N4M0.	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (63, 94))	('abdominal lymph nodal', 'Disease', 'MESH:D015746', (151, 172))	('abdominal lymph nodal', 'Disease', (151, 172))	('pT3N4M0', 'Var', (282, 289))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (74, 94))	('esophageal squamous cell cancer', 'Disease', (63, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
217969	22221671	Using immunohistochemistry for p63, CK5, CK7, and CDX2, it was confirmed that these carcinomas were pure squamous cell carcinomas, and not EACs or esophageal adenosquamous carcinomas arising from BE.	('carcinomas', 'Disease', (119, 129))	('CDX2', 'Gene', '1045', (50, 54))	('CK5', 'Var', (36, 39))	('CK7', 'Gene', (41, 44))	('carcinomas', 'Disease', (84, 94))	('CDX2', 'Gene', (50, 54))	('carcinomas', 'Disease', (172, 182))	('p63', 'Gene', (31, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('p63', 'Gene', '8626', (31, 34))	('esophageal adenosquamous carcinomas', 'Disease', (147, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('carcinomas', 'Disease', 'MESH:D002277', (119, 129))	('CK7', 'Gene', '3855', (41, 44))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (105, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('carcinomas', 'Disease', 'MESH:D002277', (84, 94))	('esophageal adenosquamous carcinomas', 'Disease', 'MESH:D018196', (147, 182))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (105, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('EAC', 'Phenotype', 'HP:0011459', (139, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('carcinomas', 'Disease', 'MESH:D002277', (172, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('BE', 'Phenotype', 'HP:0100580', (196, 198))	('squamous cell carcinomas', 'Disease', (105, 129))
217970	22221671	Using TP53 mutation and loss of heterozygosity analysis, we established that the ESCCs in BE were not metastases of the previously diagnosed head and neck squamous cell carcinomas but de novo primary ESCCs.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('TP53', 'Gene', (6, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (150, 179))	('SCC', 'Gene', '6317', (201, 204))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (155, 179))	('SCC', 'Gene', '6317', (82, 85))	('BE', 'Phenotype', 'HP:0100580', (90, 92))	('SCC', 'Gene', (201, 204))	('mutation', 'Var', (11, 19))	('SCC', 'Gene', (82, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('TP53', 'Gene', '7157', (6, 10))	('metastases', 'Disease', 'MESH:D009362', (102, 112))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (141, 179))	('metastases', 'Disease', (102, 112))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (141, 178))	('neck squamous cell carcinomas', 'Disease', (150, 179))
217980	22221671	Risk factors for developing EAC in BE include longer duration and higher frequency of gastroesophageal reflux disease, Caucasian and Hispanic race, male sex, advancing age, use of tobacco, and obesity.	('rat', 'Species', '10116', (55, 58))	('obesity', 'Disease', 'MESH:D009765', (193, 200))	('BE', 'Phenotype', 'HP:0100580', (35, 37))	('obesity', 'Disease', (193, 200))	('obesity', 'Phenotype', 'HP:0001513', (193, 200))	('EAC', 'Phenotype', 'HP:0011459', (28, 31))	('Caucasian', 'Var', (119, 128))	('gastroesophageal reflux disease', 'Disease', (86, 117))	('tobacco', 'Species', '4097', (180, 187))	('EAC', 'Disease', (28, 31))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (86, 109))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (86, 117))
217984	22221671	As both patients had been treated for head and neck squamous cell carcinoma (HNSCC) in the past, we furthermore investigated whether these ESCCs were primary cancers that arose in a background of BE or metastases from prior HNSCCs by performing TP53 mutation analysis and loss of heterozygosity (LOH) analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('squamous cell carcinoma', 'Disease', (52, 75))	('primary cancers', 'Disease', 'MESH:D009369', (150, 165))	('metastases', 'Disease', 'MESH:D009362', (202, 212))	('SCC', 'Gene', '6317', (140, 143))	('SCC', 'Gene', '6317', (226, 229))	('SCC', 'Gene', (140, 143))	('metastases', 'Disease', (202, 212))	('BE', 'Phenotype', 'HP:0100580', (196, 198))	('SCC', 'Gene', (226, 229))	('mutation analysis', 'Var', (250, 267))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('TP53', 'Gene', '7157', (245, 249))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (38, 75))	('primary cancers', 'Disease', (150, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('HNSCC', 'Phenotype', 'HP:0012288', (224, 229))	('SCC', 'Gene', '6317', (79, 82))	('patients', 'Species', '9606', (8, 16))	('SCC', 'Gene', (79, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 75))	('SCC', 'Phenotype', 'HP:0002860', (140, 143))	('SCC', 'Phenotype', 'HP:0002860', (226, 229))	('TP53', 'Gene', (245, 249))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))
218028	22221671	Mutation analysis of the TP53 gene showed a point mutation in exon 5 (H179N) in the ESCC and a deletion of 14 nucleotides in exon 6 (c.622_635delGACAGAAA CACTTT, p.D208SfsX3) in the HNSCC (Fig.	('HNSCC', 'Phenotype', 'HP:0012288', (182, 187))	('TP53', 'Gene', (25, 29))	('SCC', 'Gene', '6317', (85, 88))	('H179N', 'Var', (70, 75))	('SCC', 'Gene', '6317', (184, 187))	('p.D208SfsX3', 'Mutation', 'p.D208SfsX3', (162, 173))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('H179N', 'Mutation', 'rs587780070', (70, 75))	('TP53', 'Gene', '7157', (25, 29))	('SCC', 'Gene', (184, 187))	('c.622_635delGACAGAAA', 'Mutation', 'c.622_635delGACAGAAA', (133, 153))	('c.622_635delGACAGAAA', 'Var', (133, 153))	('p.D208SfsX3', 'Var', (162, 173))	('SCC', 'Gene', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))
218039	22221671	The TP53 mutation analysis showed four different mutations in four of the five SCCs in this patient strongly suggesting that the ESCC was an independent tumor.	('SCC', 'Gene', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('patient', 'Species', '9606', (92, 99))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('mutations', 'Var', (49, 58))	('SCC', 'Gene', (79, 82))	('TP53', 'Gene', (4, 8))	('SCC', 'Gene', '6317', (130, 133))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('SCC', 'Gene', '6317', (79, 82))	('TP53', 'Gene', '7157', (4, 8))
218040	22221671	An insertion of one base pair in codon 255 of exon 7 (c.764_765insT, p.I255IfsX9) in the ESCC resulted in a frame shift and premature termination of the protein, responsible for a nonfunctional p53 protein (Table 1).	('premature termination', 'MPA', (124, 145))	('p.I255IfsX9', 'Mutation', 'p.I255IfsX9', (69, 80))	('SCC', 'Gene', (90, 93))	('frame', 'MPA', (108, 113))	('protein', 'Protein', (153, 160))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('p53', 'Gene', (194, 197))	('insertion', 'Var', (3, 12))	('p53', 'Gene', '7157', (194, 197))	('SCC', 'Gene', '6317', (90, 93))	('resulted in', 'Reg', (94, 105))	('c.764_765insT', 'Var', (54, 67))	('c.764_765insT', 'Mutation', 'c.764_765insT', (54, 67))
218046	22221671	In order to investigate whether the ESCCs in BE were primary cancers or metastatic from previously diagnosed HNSCCs, we performed TP53 mutation analysis.	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('SCC', 'Gene', '6317', (37, 40))	('TP53', 'Gene', (130, 134))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('SCC', 'Gene', (111, 114))	('primary cancers', 'Disease', (53, 68))	('TP53', 'Gene', '7157', (130, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (109, 114))	('primary cancers', 'Disease', 'MESH:D009369', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('SCC', 'Gene', (37, 40))	('SCC', 'Gene', '6317', (111, 114))	('mutation', 'Var', (135, 143))	('BE', 'Phenotype', 'HP:0100580', (45, 47))
218050	22221671	Allelic deletions of the chromosome 17p and point mutations of the TP53 gene are frequently found in human cancers, and these may disrupt the p53 pathway.	('point mutations', 'Var', (44, 59))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('human', 'Species', '9606', (101, 106))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('disrupt', 'NegReg', (130, 137))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
218051	22221671	Several studies have reported maintenance of identical TP53 mutations in matched primary and metastatic tumors of the aerodigestive tract.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('mutations', 'Var', (60, 69))
218052	22221671	TP53 mutations are found in approximately 30-50% of HNSCCs and ESCCs.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('SCC', 'Gene', '6317', (54, 57))	('HNSCC', 'Phenotype', 'HP:0012288', (52, 57))	('SCC', 'Gene', '6317', (64, 67))	('mutations', 'Var', (5, 14))	('SCC', 'Gene', (54, 57))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('SCC', 'Gene', (64, 67))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))
218053	22221671	The most common type of TP53 mutations in HNSCC is the missense mutation, accounting for 79% of all mutations.	('SCC', 'Gene', '6317', (44, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('TP53', 'Gene', (24, 28))	('missense mutation', 'Var', (55, 72))	('mutations', 'Var', (29, 38))	('SCC', 'Gene', (44, 47))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('TP53', 'Gene', '7157', (24, 28))
218056	22221671	In contrary, tumors that harbor TP53 missense mutations often show strong and diffuse nuclear accumulation of p53 protein, as the amino acid substitution often results in increased stability of this protein.	('missense mutations', 'Var', (37, 55))	('p53', 'Gene', (110, 113))	('stability', 'MPA', (181, 190))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('p53', 'Gene', '7157', (110, 113))	('TP53', 'Gene', '7157', (32, 36))	('results in', 'Reg', (160, 170))	('protein', 'Protein', (114, 121))	('amino acid substitution', 'Var', (130, 153))	('TP53', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('increased', 'PosReg', (171, 180))	('nuclear accumulation', 'MPA', (86, 106))
218057	22221671	In case of early abrogation of the p53 protein, either through a nonsense or frame shift (insertion/deletion) mutation, complete absence of p53 expression can be found due to a deletion or inactivation of the non-mutated allele.	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('absence', 'NegReg', (129, 136))	('inactivation', 'NegReg', (189, 201))	('expression', 'MPA', (144, 154))	('deletion', 'Var', (177, 185))	('frame shift', 'Var', (77, 88))	('mutation', 'Var', (110, 118))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))
218183	19324126	In addition, another aspect, which is of concern in the pathological diagnosis, is the duplication of the muscularis mucosa, a characteristic finding in BE, that can pose difficulty in proper staging of T1a cancers.	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('T1a cancers', 'Disease', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('duplication', 'Var', (87, 98))	('T1a cancers', 'Disease', 'MESH:D009369', (203, 214))
218258	33379302	The activity of hexokinase-2 was investigated in other malignancies such as non-small cell lung cancer and breast cancer and it was suggested that hexokinase-2 has a negative impact on the treatment of cancer by promoting chemoresistance and the inhibition of glycolysis through hexokinase-2 increases the cancer cells chemotherapy sensitivity.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('non-small cell lung cancer', 'Disease', (76, 102))	('hexokinase-2', 'Gene', '3099', (147, 159))	('hexokinase-2', 'Gene', (279, 291))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('chemoresistance', 'CPA', (222, 237))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('cancer', 'Disease', (96, 102))	('hexokinase-2', 'Gene', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('glycolysis', 'MPA', (260, 270))	('malignancies', 'Disease', 'MESH:D009369', (55, 67))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('hexokinase-2', 'Gene', '3099', (279, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('malignancies', 'Disease', (55, 67))	('hexokinase-2', 'Gene', '3099', (16, 28))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('inhibition', 'Var', (246, 256))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('breast cancer', 'Disease', (107, 120))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (76, 102))	('cancer', 'Disease', (306, 312))	('increases', 'PosReg', (292, 301))	('hexokinase-2', 'Gene', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('cancer', 'Disease', (202, 208))	('promoting', 'PosReg', (212, 221))	('cancer', 'Disease', (114, 120))
218270	33379302	Dysfunction of calcium-permeable channels was revealed as a possible inducer for cancer development, including gastrointestinal tumors.	('Dysfunction', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('calcium', 'Chemical', 'MESH:D002118', (15, 22))	('gastrointestinal tumor', 'Phenotype', 'HP:0007378', (111, 133))	('cancer', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('inducer', 'Reg', (69, 76))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (111, 134))	('gastrointestinal tumors', 'Disease', (111, 134))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (111, 134))
218279	33379302	showed a new epigenetic action of capsaicin capable of regulating cell growth in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('epigenetic', 'Var', (13, 23))	('cell growth', 'CPA', (66, 77))	('regulating', 'Reg', (55, 65))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('capsaicin', 'Chemical', 'MESH:D002211', (34, 43))
218284	33379302	As already mentioned, p53 is an important factor in cancer development, and Helicobacter pylori may cause the inactivation of the P53 gene in gastric cancer through different mechanisms such as mutations or deletions, while capsaicin may counterbalance this negative effect of Helicobacter pylori.	('Helicobacter', 'Disease', (76, 88))	('P53', 'Gene', '7157', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('Helicobacter pylori', 'Species', '210', (277, 296))	('capsaicin', 'Chemical', 'MESH:D002211', (224, 233))	('gastric cancer', 'Disease', (142, 156))	('Helicobacter pylori', 'Species', '210', (76, 95))	('cancer', 'Disease', (150, 156))	('p53', 'Gene', '7157', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('inactivation', 'NegReg', (110, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('p53', 'Gene', (22, 25))	('cancer', 'Disease', (52, 58))	('deletions', 'Var', (207, 216))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('P53', 'Gene', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (194, 203))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))
218286	33379302	It is known that intestinal-type gastric cancer is distinguished by overexpression of HER2 while diffuse-type gastric cancers are characterized by amplification of c-met receptor and aberrations in the EGFR kinase pathway.	('HER2', 'Gene', (86, 90))	('EGFR', 'Gene', (202, 206))	('gastric cancer', 'Disease', 'MESH:D013274', (33, 47))	('aberrations', 'Var', (183, 194))	('amplification', 'PosReg', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('overexpression', 'PosReg', (68, 82))	('EGFR', 'Gene', '1956', (202, 206))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('c-met', 'Gene', (164, 169))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('HER2', 'Gene', '2064', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('gastric cancers', 'Disease', (110, 125))	('gastric cancers', 'Phenotype', 'HP:0012126', (110, 125))	('gastric cancers', 'Disease', 'MESH:D013274', (110, 125))	('gastric cancer', 'Disease', (33, 47))	('c-met', 'Gene', '4233', (164, 169))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))
218306	33379302	Further, TRPV1 initiates direct negative feedback on the EGFR, and blocking EGFR may keep cancer cells from developing and growing.	('TRPV1', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('EGFR', 'Gene', '1956', (76, 80))	('keep', 'PosReg', (85, 89))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', (76, 80))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('EGFR', 'Gene', (57, 61))	('blocking', 'Var', (67, 75))
218307	33379302	Conversely, hyperactivation of EGFR pathways is stimulated by the lack of TRPV1 signaling which may promote cell proliferation increasing the risk of intestinal epithelium malignancies.	('EGFR', 'Gene', '1956', (31, 35))	('promote', 'PosReg', (100, 107))	('TRPV1 signaling', 'Protein', (74, 89))	('malignancies', 'Disease', (172, 184))	('EGFR', 'Gene', (31, 35))	('malignancies', 'Disease', 'MESH:D009369', (172, 184))	('lack', 'Var', (66, 70))	('cell proliferation', 'CPA', (108, 126))
218314	33379302	The p53 mutant gene may have a pro-oncogenic function.	('pro-oncogenic function', 'CPA', (31, 53))	('p53', 'Gene', '7157', (4, 7))	('p53', 'Gene', (4, 7))	('mutant', 'Var', (8, 14))
218315	33379302	It has been shown that oncologic patients with mutations in the p53 gene may develop resistance to chemotherapy.	('resistance', 'CPA', (85, 95))	('patients', 'Species', '9606', (33, 41))	('mutations', 'Var', (47, 56))	('p53', 'Gene', (64, 67))	('develop', 'Reg', (77, 84))	('p53', 'Gene', '7157', (64, 67))
218324	33379302	Furthermore, tNOX knockdown in HCT116 cells inhibits cell migration and proliferation suggesting this mechanism may mediate the oncogenic effect of capsaicin.	('knockdown', 'Var', (18, 27))	('tNOX', 'Gene', '10495', (13, 17))	('capsaicin', 'Chemical', 'MESH:D002211', (148, 157))	('HCT116', 'CellLine', 'CVCL:0291', (31, 37))	('inhibits', 'NegReg', (44, 52))	('tNOX', 'Gene', (13, 17))
218332	33379302	In CCA, capsaicin has yet again demonstrated its anticancer potential in an in vitro study which revealed that capsaicin can block the Hedgehog pathway activation and promote antitumor functions.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('CCA', 'Phenotype', 'HP:0030153', (3, 6))	('capsaicin', 'Chemical', 'MESH:D002211', (111, 120))	('promote', 'PosReg', (167, 174))	('capsaicin', 'Var', (111, 120))	('block', 'NegReg', (125, 130))	('capsaicin', 'Chemical', 'MESH:D002211', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Hedgehog pathway', 'Pathway', (135, 151))	('activation', 'MPA', (152, 162))	('CCA', 'Disease', (3, 6))	('tumor', 'Disease', (179, 184))
218340	33379302	The appearance of mutations in p53, PIK3CA, and beta-catenin are common findings in the development of HCC.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('beta-catenin', 'Gene', (48, 60))	('HCC', 'Phenotype', 'HP:0001402', (103, 106))	('PIK3CA', 'Gene', '5290', (36, 42))	('beta-catenin', 'Gene', '1499', (48, 60))	('HCC', 'Disease', (103, 106))	('PIK3CA', 'Gene', (36, 42))	('mutations', 'Var', (18, 27))
218342	33379302	The P53 mutant gene may have a pro-oncogenic function, p53 being a main cell-cycle catalyst protein that can suffer mutations and promote cancer development not only in the hepatic tissue but in different areas as well.	('promote', 'PosReg', (130, 137))	('cancer', 'Disease', (138, 144))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('mutant', 'Var', (8, 14))	('P53', 'Gene', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('P53', 'Gene', '7157', (4, 7))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
218352	33379302	ROS generation can also lead to the accumulation of ceramide in some cancers, which may alter the cellular metabolism and trigger apoptosis via TRAIL activation; however, these findings have not yet been corroborated in HCC.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cellular metabolism', 'MPA', (98, 117))	('TRAIL', 'Gene', '8743', (144, 149))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('alter', 'Reg', (88, 93))	('apoptosis', 'CPA', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('TRAIL', 'Gene', (144, 149))	('trigger', 'Reg', (122, 129))	('ceramide', 'Chemical', 'MESH:D002518', (52, 60))	('ceramide', 'MPA', (52, 60))	('ROS generation', 'Var', (0, 14))	('lead to', 'Reg', (24, 31))	('accumulation', 'PosReg', (36, 48))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('HCC', 'Phenotype', 'HP:0001402', (220, 223))	('cancers', 'Disease', (69, 76))
218387	33379302	This was achieved most likely by inhibiting the inflammatory process within the pancreatic tissue as well as blocking the activation of the mutant Kras/ERK pathway.	('ERK', 'Gene', '5594', (152, 155))	('inflammatory process', 'CPA', (48, 68))	('pancreatic', 'Disease', (80, 90))	('ERK', 'Gene', (152, 155))	('Kras', 'Gene', (147, 151))	('blocking', 'NegReg', (109, 117))	('Kras', 'Gene', '3845', (147, 151))	('inhibiting', 'NegReg', (33, 43))	('mutant', 'Var', (140, 146))	('pancreatic', 'Disease', 'MESH:D010195', (80, 90))
218408	33363616	Cellular mobility demonstrated that overexpressing HIP1 increased ESCC proliferation, migration and invasion, whereas silencing HIP1 decreased ESCC proliferation, migration and invasion.	('HIP1', 'Gene', (128, 132))	('HIP1', 'Gene', '3092', (51, 55))	('migration', 'CPA', (86, 95))	('invasion', 'CPA', (177, 185))	('ESCC proliferation', 'CPA', (143, 161))	('ESCC proliferation', 'CPA', (66, 84))	('migration', 'CPA', (163, 172))	('increased', 'PosReg', (56, 65))	('increased ESCC', 'Phenotype', 'HP:0003565', (56, 70))	('HIP1', 'Gene', '3092', (128, 132))	('silencing', 'Var', (118, 127))	('invasion', 'CPA', (100, 108))	('HIP1', 'Gene', (51, 55))	('decreased ESCC', 'Phenotype', 'HP:0025022', (133, 147))	('decreased', 'NegReg', (133, 142))
218409	33363616	Furthermore, overexpressing HIP1 induced ESCC cells to enter the S and G2 phases from the G1 phase, whereas HIP1 knockdown arrested the cell cycle in the G1 phase.	('HIP1', 'Gene', (108, 112))	('HIP1', 'Gene', '3092', (28, 32))	('HIP1', 'Gene', '3092', (108, 112))	('G2 phases', 'CPA', (71, 80))	('overexpressing', 'Var', (13, 27))	('HIP1', 'Gene', (28, 32))	('enter', 'PosReg', (55, 60))
218426	33363616	Furthermore, high HIP1 expression was associated with promoting ESCC metastasis, while low HIP1 expression inhibited ESCC metastasis.	('ESCC', 'Disease', (64, 68))	('HIP1', 'Gene', '3092', (91, 95))	('high', 'Var', (13, 17))	('HIP1', 'Gene', '3092', (18, 22))	('promoting', 'PosReg', (54, 63))	('HIP1', 'Gene', (91, 95))	('ESCC', 'Disease', (117, 121))	('inhibited', 'NegReg', (107, 116))	('low', 'Var', (87, 90))	('HIP1', 'Gene', (18, 22))
218457	33363616	1E and F, HIP1 mRNA and protein expression levels are higher in EC109 cells compared with TE-10 cells, and lower in Kyser 0 cells compared with TE-11 cells.	('HIP1', 'Gene', '3092', (10, 14))	('higher', 'PosReg', (54, 60))	('lower', 'NegReg', (107, 112))	('EC109', 'Var', (64, 69))	('HIP1', 'Gene', (10, 14))	('EC109', 'CellLine', 'CVCL:6898', (64, 69))
218487	33363616	The results demonstrated that high positive HIP1 expression was significantly associated with moderate and poor differentiation, TNM stages III-IV and lymph node metastasis, while low positive HIP1 expression was significantly associated with well differentiation (P<0.001), TNM stages I-II (P<0.001)and lymph node non-metastasis (P<0.001) (Table II).	('associated', 'Reg', (78, 88))	('TNM', 'Disease', (275, 278))	('TNM stages III-IV', 'Disease', (129, 146))	('HIP1', 'Gene', (193, 197))	('moderate', 'CPA', (94, 102))	('HIP1', 'Gene', (44, 48))	('expression', 'MPA', (49, 59))	('lymph', 'Disease', (304, 309))	('HIP1', 'Gene', '3092', (193, 197))	('well differentiation', 'CPA', (243, 263))	('HIP1', 'Gene', '3092', (44, 48))	('lymph', 'Disease', (151, 156))	('high positive', 'Var', (30, 43))
218506	33363616	Taken together, these results suggest that inhibiting HIP1 exerts an inhibitory effect on ESCC proliferation by inducing cells to enter the G1 phase from the S phase.	('HIP1', 'Gene', (54, 58))	('inhibiting', 'Var', (43, 53))	('HIP1', 'Gene', '3092', (54, 58))	('ESCC', 'Disease', (90, 94))	('inducing', 'Reg', (112, 120))
218507	33363616	The results of the present study demonstrated that HIP1 mRNA and protein expression levels were lower in Kyse30 cells compared with all other ESCC cell lines.	('lower', 'NegReg', (96, 101))	('HIP1', 'Gene', '3092', (51, 55))	('Kyse30', 'Var', (105, 111))	('HIP1', 'Gene', (51, 55))
218532	33363616	Hsu et al demonstrated that low HIP1 expression is associated with clinical stage and inhibits the metastasis in non-small cell lung cancer.	('HIP1', 'Gene', (32, 36))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('inhibits', 'NegReg', (86, 94))	('associated', 'Reg', (51, 61))	('HIP1', 'Gene', '3092', (32, 36))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('metastasis', 'CPA', (99, 109))	('expression', 'MPA', (37, 47))	('low', 'Var', (28, 31))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
218541	33363616	The results of the present study demonstrated that patients with high HIP1 expression had a significantly shorter survival time than patients with low HIP1 expression.	('HIP1', 'Gene', (70, 74))	('shorter', 'NegReg', (106, 113))	('HIP1', 'Gene', '3092', (151, 155))	('patients', 'Species', '9606', (133, 141))	('HIP1', 'Gene', '3092', (70, 74))	('high', 'Var', (65, 69))	('patients', 'Species', '9606', (51, 59))	('HIP1', 'Gene', (151, 155))	('survival time', 'CPA', (114, 127))
218549	33363616	The results of the MTT, wound healing, and migration and invasion assays demonstrated that overexpressing HIP1 increased the proliferation, migration and invasion of Kyse30 cells, whereas silencing HIP1 decreased the proliferation, migration and invasion of EC109 cells.	('HIP1', 'Gene', '3092', (106, 110))	('EC109', 'CellLine', 'CVCL:6898', (258, 263))	('decreased', 'NegReg', (203, 212))	('increased', 'PosReg', (111, 120))	('MTT', 'Chemical', 'MESH:C070243', (19, 22))	('HIP1', 'Gene', (198, 202))	('invasion', 'CPA', (246, 254))	('proliferation', 'CPA', (125, 138))	('HIP1', 'Gene', (106, 110))	('invasion', 'CPA', (154, 162))	('migration', 'CPA', (232, 241))	('HIP1', 'Gene', '3092', (198, 202))	('migration', 'CPA', (140, 149))	('silencing', 'Var', (188, 197))	('proliferation', 'CPA', (217, 230))
218553	33363616	Taken together, these results suggest that high HIP1 expression is closely associated with the development of esophageal cancer.	('associated with', 'Reg', (75, 90))	('high', 'Var', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('HIP1', 'Gene', '3092', (48, 52))	('esophageal cancer', 'Disease', (110, 127))	('expression', 'MPA', (53, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('men', 'Species', '9606', (102, 105))	('HIP1', 'Gene', (48, 52))
218556	33363616	Notably, high HIP1 expression was associated with poor prognosis.	('HIP1', 'Gene', '3092', (14, 18))	('expression', 'MPA', (19, 29))	('HIP1', 'Gene', (14, 18))	('high', 'Var', (9, 13))
218567	31708778	Furthermore, knockdown of TOPK in KYSE450 cells decreased their sensitivities to eupafolin.	('TOPK', 'Gene', (26, 30))	('eupafolin', 'Chemical', 'MESH:C503624', (81, 90))	('decreased', 'NegReg', (48, 57))	('sensitivities to eupafolin', 'MPA', (64, 90))	('KYSE450', 'CellLine', 'CVCL:1353', (34, 41))	('knockdown', 'Var', (13, 22))
218587	31708778	Antibodies to detect beta-actin, p-histone H3, histone H3, and cleaved caspase-3 were from Cell Signaling Technology (Danvers, MA).	('caspase-3', 'Gene', '836', (71, 80))	('caspase-3', 'Gene', (71, 80))	('p-histone', 'Var', (33, 42))
218621	31708778	The binding model generated by docking simulation indicated that the compound eupafolin was positioned at the hydrophobic pocket of TOPK, surrounded by the residues Tyr-271, Lys-65, Glu-210, Thr-209, and Gly-208, forming a stable hydrophobic binding (Figure 1A).	('Gly-208', 'Var', (204, 211))	('Gly-208', 'Chemical', 'MESH:C047652', (204, 211))	('eupafolin', 'Chemical', 'MESH:C503624', (78, 87))	('Tyr-271', 'Var', (165, 172))	('Glu-210', 'Var', (182, 189))	('eupafolin', 'Gene', (78, 87))	('Thr-209', 'Chemical', 'MESH:C055175', (191, 198))	('binding', 'Interaction', (242, 249))	('Glu', 'Chemical', 'MESH:C094686', (182, 185))	('Lys-65', 'Var', (174, 180))	('Lys', 'Chemical', 'MESH:C026591', (174, 177))	('Tyr-271', 'Chemical', 'MESH:C063610', (165, 172))	('Thr-209', 'Var', (191, 198))
218642	31708778	Different concentrations of the drug were used to treat esophagus cancer cell lines KYSE450, KYSE510, and KYSE70 for 48 h, respectively.	('esophagus cancer', 'Disease', (56, 72))	('KYSE450', 'CellLine', 'CVCL:1353', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophagus cancer', 'Disease', 'MESH:D004938', (56, 72))	('KYSE70', 'Var', (106, 112))
218645	31708778	What's more, neoplastic transformation results showed that eupafolin at 20, 50, and 100 microM inhibited colony formation of KYSE450 cells on 21, 63, and 82%; KYSE510 cells on 12, 35, and 52%; and KYSE70 on 8, 12, and 10% compared with the non-treated cells, respectively (Figures 3C-E).	('KYSE450', 'CellLine', 'CVCL:1353', (125, 132))	('KYSE70', 'Var', (197, 203))	('colony formation', 'CPA', (105, 121))	('inhibited', 'NegReg', (95, 104))	('KYSE510', 'Var', (159, 166))	('eupafolin', 'Chemical', 'MESH:C503624', (59, 68))
218647	31708778	We then examined whether knocking down TOPK expression influences the sensitivity of KYSE450 cancer cells to eupafolin.	('cancer', 'Disease', (93, 99))	('TOPK', 'Gene', (39, 43))	('knocking down', 'Var', (25, 38))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('KYSE450', 'CellLine', 'CVCL:1353', (85, 92))	('eupafolin', 'Chemical', 'MESH:C503624', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('sensitivity', 'MPA', (70, 81))	('influences', 'Reg', (55, 65))
218648	31708778	Moreover, KYSE450 cells transfected with TOPK shRNA1# or mock control were treated with eupafolin or vehicle and subjected to anchorage-independent growth assay.	('KYSE450', 'CellLine', 'CVCL:1353', (10, 17))	('TOPK', 'Var', (41, 45))	('eupafolin', 'Chemical', 'MESH:C503624', (88, 97))	('shRNA1', 'Gene', (46, 52))
218650	31708778	In contrast, the inhibition was only about 17% in KYSE450 cells transfected with shTOPK1#, indicating that KYSE450 cells transfected with shTOPK1# were more resistant to eupafolin treatment (Figure 4B).	('eupafolin', 'Chemical', 'MESH:C503624', (170, 179))	('KYSE450', 'CellLine', 'CVCL:1353', (50, 57))	('resistant', 'MPA', (157, 166))	('shTOPK1#', 'Var', (138, 146))	('KYSE450', 'CellLine', 'CVCL:1353', (107, 114))
218787	25082448	After controlling for potential confounders, contact with ruminants was associated with an 8-fold increase (95% CI: 3.92 - 14.86) in risk of ESCC, and increments in duration of contact raised the risk estimates in a dose-dependent manner.	('men', 'Species', '9606', (156, 159))	('ESCC', 'Disease', (141, 145))	('increments', 'Var', (151, 161))
218849	27821804	Single nucleotide variation at 308 position of Tumor necrosis factor alpha (TNF alpha, also known as TNF) has been proved to be altering the expression of TNF in transcriptional level.	('TNF alpha', 'Gene', (76, 85))	('TNF', 'Gene', (155, 158))	('TNF', 'Gene', '7124', (155, 158))	('TNF', 'Gene', (76, 79))	('TNF', 'Gene', (101, 104))	('altering', 'Reg', (128, 136))	('Tumor necrosis factor alpha', 'Gene', (47, 74))	('expression', 'MPA', (141, 151))	('TNF', 'Gene', '7124', (76, 79))	('Single nucleotide variation at', 'Var', (0, 30))	('TNF', 'Gene', '7124', (101, 104))	('Tumor', 'Phenotype', 'HP:0002664', (47, 52))	('TNF alpha', 'Gene', '7124', (76, 85))	('Tumor necrosis factor alpha', 'Gene', '7124', (47, 74))
218850	27821804	Abnormal in the expression of TNF has been identified to be associated with major depression, Alzheimer's disease, psoriasis, inflammatory bowel disease and cancer.	('TNF', 'Gene', '7124', (30, 33))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (126, 152))	('inflammatory bowel disease', 'Disease', (126, 152))	('psoriasis', 'Disease', (115, 124))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (126, 152))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (94, 113))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	("Alzheimer's disease", 'Disease', (94, 113))	('psoriasis', 'Disease', 'MESH:D011565', (115, 124))	('Abnormal in', 'Var', (0, 11))	('depression', 'Phenotype', 'HP:0000716', (82, 92))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (94, 113))	('expression', 'MPA', (16, 26))	('depression', 'Disease', (82, 92))	('cancer', 'Disease', (157, 163))	('TNF', 'Gene', (30, 33))	('psoriasis', 'Phenotype', 'HP:0003765', (115, 124))	('associated', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('depression', 'Disease', 'MESH:D000275', (82, 92))
218852	27821804	found rs1800629 was not associated with risk of ESCC and EAC.	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('EAC', 'Disease', (57, 60))	('rs1800629', 'Mutation', 'rs1800629', (6, 15))	('rs1800629', 'Var', (6, 15))	('ESCC', 'Disease', (48, 52))
218853	27821804	did not observe association between rs1800629 and risk of ESCC and EAC, which was consistent with the findings of David et al.	('EAC', 'Disease', (67, 70))	('rs1800629', 'Mutation', 'rs1800629', (36, 45))	('rs1800629', 'Var', (36, 45))	('ESCC', 'Disease', (58, 62))	('EAC', 'Phenotype', 'HP:0011459', (67, 70))
218854	27821804	Of these, 323 articles were excluded because they do not investigate the association between rs1800629 and risk of esophageal cancer and 11 articles were screened further.	('rs1800629', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('rs1800629', 'Mutation', 'rs1800629', (93, 102))
218860	27821804	Our meta-analysis, which included 1855 cases and 3762 controls, assessed the association between rs1800629 and the risk of EC.	('rs1800629', 'Var', (97, 106))	('association', 'Interaction', (77, 88))	('rs1800629', 'Mutation', 'rs1800629', (97, 106))
218863	27821804	A previous study has shown that ethnic-specific differences were evident in the association of CASP8-625 6N del and D302H polymorphisms with prostate cancer risk in east Asian and Indian populations.	('D302H', 'SUBSTITUTION', 'None', (116, 121))	('D302H', 'Var', (116, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (141, 156))	('prostate cancer', 'Phenotype', 'HP:0012125', (141, 156))	('association', 'Interaction', (80, 91))	('CASP8-625', 'Gene', (95, 104))	('prostate cancer', 'Disease', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
218866	27821804	The TNF-alpha-308 G/A polymorphism (rs1800629) is located in the promoter region and is associated with increased TNF-alpha production.	('TNF-alpha', 'Gene', (4, 13))	('increased', 'PosReg', (104, 113))	('rs1800629', 'Mutation', 'rs1800629', (36, 45))	('TNF-alpha', 'Gene', '7124', (114, 123))	('rs1800629', 'Var', (36, 45))	('TNF-alpha', 'Gene', (114, 123))	('TNF-alpha', 'Gene', '7124', (4, 13))
218869	27821804	In contrast to the IL-6 and IL-10 genotypes, there is no association between TNFalpha polymorphisms and systemic inflammation.	('systemic inflammation', 'Disease', (104, 125))	('IL-6', 'Gene', (19, 23))	('IL-10', 'Gene', '3586', (28, 33))	('TNFalpha', 'Gene', '7124', (77, 85))	('IL-6', 'Gene', '3569', (19, 23))	('systemic inflammation', 'Disease', 'MESH:D007249', (104, 125))	('IL-10', 'Gene', (28, 33))	('polymorphisms', 'Var', (86, 99))	('TNFalpha', 'Gene', (77, 85))
218878	27821804	Other polymorphisms, such as the interleukin 10-1082 G/A polymorphism, have no association with cervical cancer, esophageal squamous cell carcinoma, or gastric cardiac adenocarcinoma risk.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('gastric cardiac adenocarcinoma', 'Disease', (152, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('10-1082 G/A', 'Var', (45, 56))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('10-1082 G/A', 'SUBSTITUTION', 'None', (45, 56))	('gastric cardiac adenocarcinoma', 'Disease', 'MESH:D013274', (152, 182))	('cervical cancer', 'Disease', 'MESH:D002583', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cervical cancer', 'Disease', (96, 111))
218883	27821804	In conclusion, our meta-analysis shows that TNF-alpha-308 G>A (rs1800629) is not significantly associated with an increased esophageal cancer risk.	('esophageal cancer', 'Disease', (124, 141))	('TNF-alpha-308 G>A', 'Var', (44, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rs1800629', 'Mutation', 'rs1800629', (63, 72))
218886	27821804	Studies that investigate the association between rs1800629 and risk of esophageal cancer were included in this meta-analysis.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('rs1800629', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('rs1800629', 'Mutation', 'rs1800629', (49, 58))	('esophageal cancer', 'Disease', (71, 88))
218887	27821804	The following inclusion criteria were set and reviewed by two independent investigators: (1) an independent case-control design, (2) evaluating the association between rs1800629 and risk of EC, (3) providing the number of genotypes in case-control groups for calculating odds ratio (OR) with 95% confidential intervals (CIs), and (4) genotypes of participants in control groups satisfy Hardy-Weinberg equilibrium (HWE).	('rs1800629', 'Var', (168, 177))	('rs1800629', 'Mutation', 'rs1800629', (168, 177))	('Hardy-Weinberg equilibrium', 'Disease', (386, 412))	('participants', 'Species', '9606', (347, 359))
218888	27821804	The following data were included: first author, publication date, country, ethnicity of the study participants, type of esophageal cancer, number of genotypes in case-control groups and the association between rs1800629 and EC.	('rs1800629', 'Var', (210, 219))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('participants', 'Species', '9606', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('association', 'Interaction', (190, 201))	('esophageal cancer', 'Disease', (120, 137))	('rs1800629', 'Mutation', 'rs1800629', (210, 219))
218905	27465405	Circular RNAs (circRNAs), unlike the well known linear RNA, forms a covalently closed continuous loop.	('cir', 'Gene', (15, 18))	('cir', 'Gene', '9541', (15, 18))	('Circular RNAs', 'Var', (0, 13))
218912	27465405	Our results suggested that the aberrant expression of circRNAs may play a role in transformation of radiation resistance of esophageal cancer cells.	('cir', 'Gene', (54, 57))	('esophageal cancer', 'Disease', (124, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('play', 'Reg', (67, 71))	('aberrant expression', 'Var', (31, 50))	('cir', 'Gene', '9541', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('radiation resistance', 'CPA', (100, 120))
218947	27465405	In this study, there were 57 circRNAs significantly upregulated and 17 circRNAs significantly downregulated in the KYSE-150R cell lines compared with KYSE-150, respectively.	('cir', 'Gene', (71, 74))	('cir', 'Gene', (29, 32))	('cir', 'Gene', '9541', (29, 32))	('cir', 'Gene', '9541', (71, 74))	('downregulated', 'NegReg', (94, 107))	('upregulated', 'PosReg', (52, 63))	('KYSE-150R', 'Var', (115, 124))
218952	27465405	Aberrant expression of circRNAs has been linked to carcinogenesis and the malignant behavior of many different cancer.	('linked', 'Reg', (41, 47))	('Aberrant expression', 'Var', (0, 19))	('cir', 'Gene', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('malignant behavior', 'CPA', (74, 92))	('cir', 'Gene', '9541', (23, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (51, 65))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('carcinogenesis', 'Disease', (51, 65))
218965	27465405	According to our results, we hypothesized that circRNA_001059 may act as an inhibitor of miRNA by binding several specific miRNAs, including miR-30c-1*, miR-30c-2*, miR-122*, miR-139-3p, miR-339-5p and miR-1912.	('miR-1912', 'Gene', '100302144', (202, 210))	('binding', 'Interaction', (98, 105))	('miR-30c-2', 'Gene', '407032', (153, 162))	('miR-339-5p', 'Var', (187, 197))	('miR-122', 'Gene', '406906', (165, 172))	('miR-139-3p', 'Gene', '406931', (175, 185))	('cir', 'Gene', (47, 50))	('miR-30c-1', 'Gene', (141, 150))	('miR-139-3p', 'Gene', (175, 185))	('miR-30c-1', 'Gene', '407031', (141, 150))	('cir', 'Gene', '9541', (47, 50))	('miR-30c-2', 'Gene', (153, 162))	('miR-1912', 'Gene', (202, 210))	('miR-122', 'Gene', (165, 172))
218966	27465405	Our results implied that it is worthwhile to further investigate these novel dysregulated circRNAs as microRNA sponges and their potential biological functions in the development of radiation resistance.	('cir', 'Gene', '9541', (90, 93))	('cir', 'Gene', (90, 93))	('dysregulated', 'Var', (77, 89))
218981	26816494	In the claims database analyses, sodium channel-blocking AED use was inversely associated with diagnoses of colorectal cancer, lung cancer, gastric cancer, and hematological malignancies, with ASRs of 0.72 (95% CI: 0.60 - 0.86), 0.65 (0.51 - 0.81), 0.80 (0.65 - 0.98), and 0.50 (0.37 - 0.66), respectively.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('sodium', 'Protein', (33, 39))	('lung cancer', 'Disease', (127, 138))	('hematological malignancies', 'Disease', 'MESH:D019337', (160, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('SR', 'Chemical', '-', (194, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('AED', 'Var', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('hematological malignancies', 'Phenotype', 'HP:0004377', (160, 186))	('gastric cancer', 'Disease', (140, 154))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('colorectal cancer', 'Disease', (108, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('hematological malignancies', 'Disease', (160, 186))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
218983	26816494	Conclusion: Multi-methodological approaches using different methodologies, algorithms, and databases suggest that sodium channel-blocking AED use is inversely associated with colorectal cancer, lung cancer, gastric cancer, and hematological malignancies.	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('hematological malignancies', 'Phenotype', 'HP:0004377', (227, 253))	('gastric cancer', 'Disease', (207, 221))	('gastric cancer', 'Disease', 'MESH:D013274', (207, 221))	('sodium channel-blocking', 'MPA', (114, 137))	('colorectal cancer', 'Disease', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('associated', 'Reg', (159, 169))	('hematological malignancies', 'Disease', (227, 253))	('lung cancer', 'Disease', 'MESH:D008175', (194, 205))	('hematological malignancies', 'Disease', 'MESH:D019337', (227, 253))	('gastric cancer', 'Phenotype', 'HP:0012126', (207, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('AED', 'Var', (138, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('lung cancer', 'Disease', (194, 205))
218986	26816494	VGSCs are up-regulated in human metastatic disease, and VGSC activity potentiates metastatic cell behavior.	('activity', 'Var', (61, 69))	('VGSC', 'Gene', (56, 60))	('VGSCs', 'Protein', (0, 5))	('potentiates', 'PosReg', (70, 81))	('metastatic cell behavior', 'CPA', (82, 106))	('human', 'Species', '9606', (26, 31))	('up-regulated', 'PosReg', (10, 22))
218987	26816494	Therefore, blockage of these channels may be effective for treatment of cancer.	('blockage', 'Var', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (72, 78))
219008	26816494	The ICD-10 codes of C18 (malignant neoplasm of colon), C19 (malignant neoplasm of rectosigmoid junction) and C20 (malignant neoplasm of rectum) were selected as those defining colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('C18', 'Gene', '27241', (20, 23))	('neoplasm', 'Phenotype', 'HP:0002664', (70, 78))	('malignant neoplasm of colon', 'Disease', (25, 52))	('C20', 'Var', (109, 112))	('neoplasm', 'Phenotype', 'HP:0002664', (124, 132))	('neoplasm of rectum', 'Phenotype', 'HP:0100743', (124, 142))	('colorectal cancer', 'Disease', (176, 193))	('neoplasm of colon', 'Phenotype', 'HP:0100273', (35, 52))	('malignant neoplasm of rectum', 'Disease', 'MESH:D012004', (114, 142))	('C18', 'Gene', (20, 23))	('neoplasm', 'Phenotype', 'HP:0002664', (35, 43))	('malignant neoplasm of rectum', 'Disease', (114, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('malignant neoplasm of colon', 'Disease', 'MESH:D009369', (25, 52))	('malignant neoplasm of rectosigmoid junction', 'Disease', (60, 103))	('C19', 'Var', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('malignant neoplasm of rectosigmoid junction', 'Disease', 'MESH:D011350', (60, 103))
219009	26816494	In addition, the ICD-10 codes of C67 (malignant neoplasm of bladder), C34 (malignant neoplasm of bronchus and lung), C25 (malignant neoplasm of pancreas), C16 (malignant neoplasm of stomach), C15 (malignant neoplasm of esophagus), C81-96 (malignant neoplasms, stated or presumed to be primary, of lymphoid, hematopoietic and related tissue), C43 (malignant melanoma of skin), C50 (malignant neoplasm of breast), and C61 (malignant neoplasm of prostate) were selected as those defining bladder cancer, lung cancer, pancreatic cancer, gastric cancer, esophageal cancer, hematological malignancies, melanoma, breast cancer, and prostate cancer, respectively.	('malignant neoplasm of prostate', 'Disease', (421, 451))	('malignant neoplasm of esophagus', 'Disease', 'MESH:D004938', (197, 228))	('melanoma', 'Phenotype', 'HP:0002861', (596, 604))	('melanoma', 'Disease', (596, 604))	('malignant melanoma of skin', 'Disease', 'MESH:D008545', (347, 373))	('malignant melanoma of skin', 'Disease', (347, 373))	('neoplasm', 'Phenotype', 'HP:0002664', (132, 140))	('malignant neoplasm of stomach', 'Disease', (160, 189))	('melanoma', 'Phenotype', 'HP:0002861', (357, 365))	('cancer', 'Phenotype', 'HP:0002664', (493, 499))	('melanoma', 'Disease', (357, 365))	('pancreatic cancer', 'Disease', (514, 531))	('bladder cancer', 'Disease', 'MESH:D001749', (485, 499))	('cancer', 'Phenotype', 'HP:0002664', (541, 547))	('hematological malignancies', 'Disease', 'MESH:D019337', (568, 594))	('cancer', 'Phenotype', 'HP:0002664', (525, 531))	('malignant neoplasm of prostate', 'Disease', 'MESH:D009369', (421, 451))	('bladder cancer', 'Disease', (485, 499))	('lung cancer', 'Disease', 'MESH:D008175', (501, 512))	('hematological malignancies', 'Phenotype', 'HP:0004377', (568, 594))	('neoplasm', 'Phenotype', 'HP:0002664', (85, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (533, 547))	('neoplasm of bladder', 'Phenotype', 'HP:0009725', (48, 67))	('C50', 'Var', (376, 379))	('neoplasms', 'Phenotype', 'HP:0002664', (249, 258))	('C43', 'Var', (342, 345))	('bladder cancer', 'Phenotype', 'HP:0009725', (485, 499))	('lung cancer', 'Phenotype', 'HP:0100526', (501, 512))	('malignant neoplasm of bladder', 'Disease', (38, 67))	('C15', 'Gene', '51316', (192, 195))	('neoplasm', 'Phenotype', 'HP:0002664', (170, 178))	('malignant neoplasm of bronchus', 'Disease', (75, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (606, 619))	('C15', 'Gene', (192, 195))	('malignant neoplasm of esophagus', 'Disease', (197, 228))	('malignant neoplasm of bladder', 'Disease', 'MESH:D001749', (38, 67))	('C34', 'Var', (70, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (514, 531))	('C61', 'Var', (416, 419))	('malignant neoplasms', 'Disease', (239, 258))	('esophageal cancer', 'Disease', 'MESH:D004938', (549, 566))	('malignant neoplasms', 'Disease', 'MESH:D009369', (239, 258))	('malignant melanoma', 'Phenotype', 'HP:0002861', (347, 365))	('melanoma', 'Disease', 'MESH:D008545', (596, 604))	('gastric cancer', 'Phenotype', 'HP:0012126', (533, 547))	('breast cancer', 'Disease', 'MESH:D001943', (606, 619))	('neoplasm of pancreas', 'Phenotype', 'HP:0002894', (132, 152))	('hematological malignancies', 'Disease', (568, 594))	('neoplasm', 'Phenotype', 'HP:0002664', (207, 215))	('breast cancer', 'Disease', (606, 619))	('melanoma', 'Disease', 'MESH:D008545', (357, 365))	('neoplasm of breast', 'Phenotype', 'HP:0100013', (391, 409))	('prostate cancer', 'Disease', 'MESH:D011471', (625, 640))	('esophageal cancer', 'Disease', (549, 566))	('malignant neoplasm of breast', 'Disease', 'MESH:D001943', (381, 409))	('cancer', 'Phenotype', 'HP:0002664', (560, 566))	('neoplasm of prostate', 'Phenotype', 'HP:0100787', (431, 451))	('malignant neoplasm of bronchus', 'Disease', 'MESH:D009369', (75, 105))	('neoplasm of stomach', 'Phenotype', 'HP:0006753', (170, 189))	('malignant neoplasm of breast', 'Disease', (381, 409))	('prostate cancer', 'Phenotype', 'HP:0012125', (625, 640))	('lung cancer', 'Disease', (501, 512))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('neoplasm of esophagus', 'Phenotype', 'HP:0100751', (207, 228))	('malignant neoplasm of pancreas', 'Disease', (122, 152))	('cancer', 'Phenotype', 'HP:0002664', (506, 512))	('C81-96', 'Var', (231, 237))	('prostate cancer', 'Disease', (625, 640))	('malignant neoplasm of pancreas', 'Disease', 'MESH:D010190', (122, 152))	('C25', 'Var', (117, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (514, 531))	('malignant neoplasm of stomach', 'Disease', 'MESH:D013274', (160, 189))	('gastric cancer', 'Disease', (533, 547))
219040	26816494	In the analyses of individual sodium channel-blocking AEDs, phenytoin was inversely associated with diagnoses of colorectal cancer (ASR: 0.53, 95% CI: 0.33 - 0.83), lung cancer (0.30, 0.17 - 0.50), gastric cancer (0.49, 0.29 - 0.83), hematological malignancies (0.25, 0.13 - 0.47), and breast cancer (0.35, 0.12 - 0.86).	('colorectal cancer', 'Disease', (113, 130))	('gastric cancer', 'Disease', (198, 212))	('phenytoin', 'Chemical', 'MESH:D010672', (60, 69))	('hematological malignancies', 'Disease', 'MESH:D019337', (234, 260))	('breast cancer', 'Disease', 'MESH:D001943', (286, 299))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', (286, 299))	('hematological malignancies', 'Phenotype', 'HP:0004377', (234, 260))	('lung cancer', 'Disease', (165, 176))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('phenytoin', 'Var', (60, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('hematological malignancies', 'Disease', (234, 260))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('SR', 'Chemical', '-', (133, 135))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (286, 299))
219059	26816494	Additionally, some studies have suggested that phenytoin also inhibits migration and secretion in prostate cancer cells.	('phenytoin', 'Chemical', 'MESH:D010672', (47, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('inhibits', 'NegReg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('prostate cancer', 'Disease', (98, 113))	('migration and', 'CPA', (71, 84))	('phenytoin', 'Var', (47, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))
219094	26816494	We applied these methodologies and algorithms to the detection of inverse signals of cancer associated with sodium channel-blocking AED use, and our study detected inverse associations between sodium channel-blocking AED use and several cancers.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('sodium channel-blocking', 'Var', (108, 131))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('inverse', 'NegReg', (164, 171))	('sodium channel-blocking', 'Var', (193, 216))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancer', 'Disease', (85, 91))	('cancers', 'Disease', (237, 244))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('cancer', 'Disease', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
219241	32021422	In tumors that are highly positive for HER2 (3+ on immunohistochemical staining) or positive of florescent-in situ hybridization (FISH), a combination of chemotherapy and trastuzumab is the standard of care.	('positive', 'Reg', (26, 34))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('3+', 'Var', (45, 47))	('HER2', 'Gene', (39, 43))	('HER2', 'Gene', '2064', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
219285	32021422	The pooled analysis concluded that the patients who had baseline high EQ-5D-3L score (better HRQoL) had a better median OS (p<0.01) and PFS (p=0.04) as compared to that of counterparts on multivariate analysis.	('EQ-5D-3L', 'Gene', (70, 78))	('patients', 'Species', '9606', (39, 47))	('PFS', 'MPA', (136, 139))	('better', 'PosReg', (106, 112))	('median OS', 'MPA', (113, 122))	('high', 'Var', (65, 69))
219307	32021422	Also, the patient reported symptoms on the QLQ-C30 were associated with investigator reported symptoms such as loss of appetite, nausea/vomiting, fatigue and diarrhea.	('nausea', 'Phenotype', 'HP:0002018', (129, 135))	('nausea', 'Disease', (129, 135))	('nausea', 'Disease', 'MESH:D009325', (129, 135))	('fatigue', 'Disease', 'MESH:D005221', (146, 153))	('nausea/vomiting', 'Phenotype', 'HP:0002017', (129, 144))	('diarrhea', 'Phenotype', 'HP:0002014', (158, 166))	('loss of appetite', 'Phenotype', 'HP:0004396', (111, 127))	('vomiting', 'Phenotype', 'HP:0002013', (136, 144))	('diarrhea', 'Disease', (158, 166))	('fatigue', 'Disease', (146, 153))	('patient', 'Species', '9606', (10, 17))	('associated', 'Reg', (56, 66))	('diarrhea', 'Disease', 'MESH:D003967', (158, 166))	('fatigue', 'Phenotype', 'HP:0012378', (146, 153))	('vomiting', 'Disease', (136, 144))	('vomiting', 'Disease', 'MESH:D014839', (136, 144))	('loss of appetite', 'Disease', (111, 127))	('QLQ-C30', 'Var', (43, 50))
219327	30290643	The aim of this study was to determine the effect of induction therapy on cT2N0M0 esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('esophageal cancer', 'Disease', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cT2N0M0', 'Var', (74, 81))
219330	30290643	Currentclinical staging for T2N0M0 esophageal carcinoma remains inaccurate.	('T2N0M0', 'Var', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('esophageal carcinoma', 'Disease', (35, 55))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (35, 55))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (35, 55))
219335	30290643	The effect of neoadjuvant CRT on patients with the clinical stage of T2N0M0 esophageal cancer remains uncertain.	('patients', 'Species', '9606', (33, 41))	('T2N0M0', 'Var', (69, 75))	('esophageal cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))
219337	30290643	Killinger et al reported patients with pT2N0M0 disease had a survival rate on par with patients with pT1N0M0, and Song et al reported adjuvant therapy did not improve the survival of pT2N0M0 patients.	('patients', 'Species', '9606', (191, 199))	('patients', 'Species', '9606', (25, 33))	('survival', 'MPA', (61, 69))	('pT2N0M0', 'Var', (39, 46))	('patients', 'Species', '9606', (87, 95))
219339	30290643	Some studies had found that induction therapy did not improve survival of patients with cT2N0 esophageal cancer and recommended surgery alone as the primary treatment approach.	('patients', 'Species', '9606', (74, 82))	('esophageal cancer', 'Disease', (94, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cT2N0', 'Var', (88, 93))
219342	30290643	Therefore, the aim of this study is to determine the effect of induction therapy on cT2N0M0 esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('esophageal cancer', 'Disease', (92, 109))	('cT2N0M0', 'Var', (84, 91))
219347	30290643	Finally, 2646 patients in a total of 8 studies were included in the present met-analysis, among which 961 patients with cT2N0 esophageal carcinoma received induction therapy and 1685 patients did not.	('esophageal carcinoma', 'Disease', (126, 146))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (126, 146))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (126, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (14, 22))	('cT2N0', 'Var', (120, 125))	('patients', 'Species', '9606', (183, 191))
219353	30290643	In this study, the results showed that neoadjuvant therapy for cT2N0M0 esophageal cancer patients did not improve survival.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('patients', 'Species', '9606', (89, 97))	('esophageal cancer', 'Disease', (71, 88))	('cT2N0M0', 'Var', (63, 70))
219358	30290643	Actually, understaged cT2N0M0 is locally advanced stages esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cT2N0M0', 'Var', (22, 29))	('esophageal cancer', 'Disease', (57, 74))
219360	30290643	Dolan also reported that understaged cT2N0M0 patients with postoperative adjuvant therapy had better survival than surgery alone.	('Dolan', 'Chemical', '-', (0, 5))	('cT2N0M0', 'Var', (37, 44))	('patients', 'Species', '9606', (45, 53))	('better', 'PosReg', (94, 100))	('survival', 'CPA', (101, 109))
219361	30290643	However, overstaged cT2N0M0 is T1 stage esophageal cancer.	('cT2N0M0', 'Var', (20, 27))	('esophageal cancer', 'Disease', (40, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
219370	30290643	First, only retrospective studies on induction therapy for cT2N0M0 esophageal cancer have been published.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cT2N0M0', 'Var', (59, 66))	('esophageal cancer', 'Disease', (67, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))
219410	30275998	Body weight loss, vital capacity, and postoperative quality of life were also significantly poorer in the LTA approach group than in the TH approach group.	('weight loss', 'Phenotype', 'HP:0001824', (5, 16))	('LTA', 'Var', (106, 109))	('weight loss', 'Disease', 'MESH:D015431', (5, 16))	('vital capacity', 'CPA', (18, 32))	('weight loss', 'Disease', (5, 16))	('poorer', 'NegReg', (92, 98))
219452	29577671	The results showed that high NFIA expression correlated significantly with poor differentiation, lymph node metastasis, and advanced TNM stage in patients with ESCC.	('ESCC', 'Disease', (160, 164))	('expression', 'MPA', (34, 44))	('lymph node metastasis', 'CPA', (97, 118))	('TNM', 'Gene', (133, 136))	('ESCC', 'Phenotype', 'HP:0011459', (160, 164))	('poor differentiation', 'CPA', (75, 95))	('NFIA', 'Gene', '4774', (29, 33))	('NFIA', 'Gene', (29, 33))	('high', 'Var', (24, 28))	('TNM', 'Gene', '10178', (133, 136))	('patients', 'Species', '9606', (146, 154))
219455	29577671	On the other hand, high NFIB expression correlated with lymph node metastasis, advanced TNM stage, and short OS and DFS in patients with EJA.	('lymph node metastasis', 'CPA', (56, 77))	('high', 'Var', (19, 23))	('EJA', 'Phenotype', 'HP:0011459', (137, 140))	('TNM', 'Gene', (88, 91))	('short OS', 'Disease', (103, 111))	('DFS', 'Disease', (116, 119))	('TNM', 'Gene', '10178', (88, 91))	('advanced', 'CPA', (79, 87))	('patients', 'Species', '9606', (123, 131))	('expression', 'MPA', (29, 39))	('NFIB', 'Gene', (24, 28))
219456	29577671	Finally, multivariate analysis demonstrated that high NFIA expression was an independent prognostic factor for ESCC.	('ESCC', 'Phenotype', 'HP:0011459', (111, 115))	('NFIA', 'Gene', (54, 58))	('NFIA', 'Gene', '4774', (54, 58))	('high', 'Var', (49, 53))	('ESCC', 'Disease', (111, 115))
219471	29577671	The results showed that high NFIA expression correlated with poor differentiation, lymph node metastasis, and short overall survival (OS) and disease-free survival (DFS) in patients with ESCC.	('ESCC', 'Disease', (187, 191))	('expression', 'MPA', (34, 44))	('ESCC', 'Phenotype', 'HP:0011459', (187, 191))	('patients', 'Species', '9606', (173, 181))	('NFIA', 'Gene', '4774', (29, 33))	('NFIA', 'Gene', (29, 33))	('disease-free survival', 'CPA', (142, 163))	('short', 'NegReg', (110, 115))	('poor differentiation', 'CPA', (61, 81))	('high', 'Var', (24, 28))	('overall survival', 'CPA', (116, 132))	('lymph node metastasis', 'CPA', (83, 104))
219494	29577671	Chi-square test revealed that high NFIA expression significantly correlated with poor differentiation (P = 0.046), lymph node metastasis (P = 0.021), and advanced TNM stage (P = 0.045) in ESCC, while high NFIB expression only correlated with poor differentiation degree (P = 0.038) (Table 1).	('lymph node metastasis', 'CPA', (115, 136))	('ESCC', 'Disease', (188, 192))	('NFIA', 'Gene', '4774', (35, 39))	('NFIA', 'Gene', (35, 39))	('TNM', 'Gene', '10178', (163, 166))	('ESCC', 'Phenotype', 'HP:0011459', (188, 192))	('high', 'Var', (30, 34))	('poor differentiation', 'CPA', (81, 101))	('TNM', 'Gene', (163, 166))	('correlated', 'Reg', (65, 75))
219502	29577671	Univariate Cox regression analysis showed that high NFIA expression (hazard ratio (HR) = 3.031, 95% confidence interval (CI) = 1.754-5.239, P < 0.001), tumor size (HR = 1.781, 95% CI = 1.131-2.805, P = 0.013), T-stage (HR = 2.334, 95% CI = 1.304-4.179, P = 0.004), and lymph node metastasis (HR = 3.660, 95% CI = 2.661-5.925, P < 0.001) were prognostic risk factors for OS (Table 2).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('NFIA', 'Gene', '4774', (52, 56))	('NFIA', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('high', 'Var', (47, 51))	('tumor', 'Disease', (152, 157))
219504	29577671	Multivariate Cox proportional hazards regression analysis revealed that high NFIA expression (HR = 3.450, 95% CI = 1.908-6.240, P < 0.001), lymph node metastasis (HR = 2.636, 95% CI = 1.565-4.439, P < 0.001), and T-stage (HR = 2.272, 95% CI = 1.224-4.217, P = 0.009) were independent risk factors for OS in ESCC (Table 3).	('Cox', 'Gene', (13, 16))	('ESCC', 'Phenotype', 'HP:0011459', (307, 311))	('lymph node metastasis', 'CPA', (140, 161))	('NFIA', 'Gene', '4774', (77, 81))	('NFIA', 'Gene', (77, 81))	('ESCC', 'Disease', (307, 311))	('high', 'Var', (72, 76))	('Cox', 'Gene', '1351', (13, 16))
219511	29577671	Chi-square test revealed that high NFIB expression significantly correlated with lymph node metastasis (P = 0.014) and advanced TNM stage (P = 0.036) in EJA (Table 4).	('expression', 'MPA', (40, 50))	('NFIB', 'Gene', (35, 39))	('TNM', 'Gene', '10178', (128, 131))	('high', 'Var', (30, 34))	('lymph node metastasis', 'CPA', (81, 102))	('EJA', 'Phenotype', 'HP:0011459', (153, 156))	('TNM', 'Gene', (128, 131))	('correlated', 'Reg', (65, 75))
219519	29577671	The present study found that high NFIA is an independent prognostic risk factor in ESCC, while NFIB predicts poor outcomes of EJA.	('high', 'Var', (29, 33))	('NFIA', 'Gene', (34, 38))	('EJA', 'Phenotype', 'HP:0011459', (126, 129))	('ESCC', 'Disease', (83, 87))	('ESCC', 'Phenotype', 'HP:0011459', (83, 87))	('NFIA', 'Gene', '4774', (34, 38))
219525	29577671	Consistent with the previous study that NFIA promotes growth of ESCC cells 11, we show here that NFIA is overexpressed in ESCC tissues, and high NFIA expression correlates with poor differentiation, lymph node metastasis, and advanced TNM stage in ESCC.	('TNM', 'Gene', '10178', (235, 238))	('expression', 'MPA', (150, 160))	('poor differentiation', 'CPA', (177, 197))	('TNM', 'Gene', (235, 238))	('NFIA', 'Gene', '4774', (97, 101))	('NFIA', 'Gene', '4774', (145, 149))	('high', 'Var', (140, 144))	('NFIA', 'Gene', (97, 101))	('NFIA', 'Gene', (145, 149))	('NFIA', 'Gene', '4774', (40, 44))	('NFIA', 'Gene', (40, 44))	('ESCC', 'Phenotype', 'HP:0011459', (64, 68))	('ESCC', 'Phenotype', 'HP:0011459', (122, 126))	('ESCC', 'Disease', (248, 252))	('lymph node metastasis', 'CPA', (199, 220))	('ESCC', 'Phenotype', 'HP:0011459', (248, 252))
219530	29577671	The expression of NFIB was also regulated by microRNAs, such as miR-372/373 28, miR-153 29, 30, miR-365 21, and miR-124 31.	('miR-365 21', 'Var', (96, 106))	('miR-372', 'Gene', (64, 71))	('NFIB', 'Gene', (18, 22))	('miR-153 29', 'Var', (80, 90))	('regulated', 'Reg', (32, 41))	('expression', 'MPA', (4, 14))	('miR-372', 'Gene', '442917', (64, 71))	('miR-124 31', 'Var', (112, 122))
219536	29577671	High NFIA expression and high NFIB expression are associated with poor prognosis of patients with ESCC and patients with EJA, respectively.	('patients', 'Species', '9606', (84, 92))	('ESCC', 'Disease', (98, 102))	('expression', 'MPA', (35, 45))	('NFIA', 'Gene', '4774', (5, 9))	('high', 'Var', (25, 29))	('NFIA', 'Gene', (5, 9))	('ESCC', 'Phenotype', 'HP:0011459', (98, 102))	('EJA', 'Phenotype', 'HP:0011459', (121, 124))	('NFIB', 'Gene', (30, 34))	('patients', 'Species', '9606', (107, 115))
219540	28837252	Analysis showed that high expression of CBX8 in 152 muscle invasive bladder cancer specimens was associated with progression of the T, N, and M stages (P = 0.004, 0.005, <0.001, respectively).	('bladder cancer', 'Phenotype', 'HP:0009725', (68, 82))	('CBX8', 'Gene', (40, 44))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (52, 82))	('high', 'Var', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('invasive bladder', 'Phenotype', 'HP:0100645', (59, 75))	('muscle invasive bladder cancer', 'Disease', (52, 82))	('associated', 'Reg', (97, 107))	('M stages', 'CPA', (142, 150))
219541	28837252	Furthermore, Kaplan-Meier survival analysis and log-rank test showed that muscle invasive bladder cancer patients with high CBX8 expression had a poor rate of overall survival (P < 0.001) and 5-year recurrence-free survival (P < 0.001) compared to patients with low CBX8 expression.	('CBX8', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (105, 113))	('overall survival', 'CPA', (159, 175))	('high', 'Var', (119, 123))	('invasive bladder', 'Phenotype', 'HP:0100645', (81, 97))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (74, 104))	('patients', 'Species', '9606', (248, 256))	('poor', 'NegReg', (146, 150))	('muscle invasive bladder cancer', 'Disease', (74, 104))
219542	28837252	High CBX8 expression predicted poor overall survival and 5-year recurrence-free survival in T and N stages of muscle invasive bladder cancer patients.	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('High', 'Var', (0, 4))	('CBX8', 'Gene', (5, 9))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (110, 140))	('overall', 'MPA', (36, 43))	('invasive bladder', 'Phenotype', 'HP:0100645', (117, 133))	('muscle invasive bladder cancer', 'Disease', (110, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('poor', 'NegReg', (31, 35))	('patients', 'Species', '9606', (141, 149))
219543	28837252	Moreover, knockdown of CBX8 inhibited cell proliferation of urothelial carcinoma of the bladder both in vitro and in vivo.	('urothelial carcinoma of the bladder', 'Disease', (60, 95))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (60, 95))	('cell proliferation', 'CPA', (38, 56))	('CBX8', 'Gene', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('inhibited', 'NegReg', (28, 37))	('knockdown', 'Var', (10, 19))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (60, 95))
219544	28837252	In addition, CBX8 depletion resulted in cell cycle delay of urothelial carcinoma cells of the bladder at the G2/M phase by the p53 pathway.	('p53', 'Gene', '7157', (127, 130))	('urothelial carcinoma', 'Disease', (60, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('cell cycle delay', 'CPA', (40, 56))	('CBX8', 'Gene', (13, 17))	('depletion', 'Var', (18, 27))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (60, 80))	('urothelial carcinoma cells of the bladder', 'Phenotype', 'HP:0006740', (60, 101))	('p53', 'Gene', (127, 130))
219545	28837252	The data suggest that high expression of CBX8 plays a critical oncogenic role in aggressiveness of urothelial carcinoma cells of the bladder through promoting cancer cell proliferation by repressing the p53 pathway, and CBX8 could be used as a novel predictor for muscle invasive bladder cancer patients.	('aggressiveness of urothelial carcinoma', 'Disease', 'MESH:D001523', (81, 119))	('cancer', 'Disease', (288, 294))	('promoting', 'PosReg', (149, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (280, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('cancer', 'Disease', (159, 165))	('invasive bladder', 'Phenotype', 'HP:0100645', (271, 287))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('aggressiveness', 'Phenotype', 'HP:0000718', (81, 95))	('CBX8', 'Gene', (41, 45))	('urothelial carcinoma cells of the bladder', 'Phenotype', 'HP:0006740', (99, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('aggressiveness of urothelial carcinoma', 'Disease', (81, 119))	('muscle invasive bladder cancer', 'Disease', (264, 294))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('p53', 'Gene', '7157', (203, 206))	('high expression', 'Var', (22, 37))	('patients', 'Species', '9606', (295, 303))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (264, 294))	('repressing', 'NegReg', (188, 198))	('p53', 'Gene', (203, 206))
219550	28837252	CBX8 was first described in 2000 as a member of the PcG family.3 PcG were initially identified in Drosophila as repressors that silence Hox genes during development.4, 5, 6, 7 Homologous proteins in mammals have subsequently been reported.8, 9, 10 CBX8 functions as a transcriptional repressor that interacts with the RING protein and colocalizes with BMI1 in the PcG body.10 In addition, CBX8 directly binds to the INK4A-ARF locus to promote cell proliferation and to bypass senescence.11, 12 Recent reports have shown that CBX8 is positively associated with glioblastoma, colorectal cancer, and leukemia.13, 14, 15 For example, CBX8 upregulation is associated with TNM staging in esophageal carcinoma, and it acts as a novel DNA repair protein that promotes cell proliferation and protects cancer cells from sensitivity to ionizing radiation or hydrogen peroxide.16 Knockdown of CBX8 inhibits cell proliferation and cell cycle progression by increasing the phosphorylation of p21, Wee1, and CHK1.	('ionizing radiation', 'Disease', (825, 843))	('leukemia', 'Disease', (597, 605))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (682, 702))	('leukemia', 'Disease', 'MESH:D007938', (597, 605))	('increasing', 'PosReg', (944, 954))	('colorectal cancer', 'Disease', 'MESH:D015179', (574, 591))	('p21', 'Gene', '36001', (978, 981))	('BMI1', 'Gene', (352, 356))	('ionizing radiation', 'Disease', 'MESH:D004194', (825, 843))	('CHK1', 'Gene', (993, 997))	('glioblastoma', 'Disease', (560, 572))	('cancer', 'Disease', 'MESH:D009369', (792, 798))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (847, 864))	('PcG', 'Gene', '40358', (65, 68))	('INK4A', 'Gene', '1029', (416, 421))	('colorectal cancer', 'Disease', (574, 591))	('esophageal carcinoma', 'Disease', (682, 702))	('glioblastoma', 'Phenotype', 'HP:0012174', (560, 572))	('Drosophila', 'Species', '7227', (98, 108))	('cell cycle progression', 'CPA', (918, 940))	('ARF', 'Disease', 'MESH:D058186', (422, 425))	('PcG', 'Gene', (364, 367))	('phosphorylation', 'MPA', (959, 974))	('BMI1', 'Gene', '648', (352, 356))	('CHK1', 'Gene', '34993', (993, 997))	('INK4A', 'Gene', (416, 421))	('cancer', 'Disease', (585, 591))	('CBX8', 'Gene', (881, 885))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (682, 702))	('Knockdown', 'Var', (868, 877))	('cancer', 'Phenotype', 'HP:0002664', (585, 591))	('inhibits', 'NegReg', (886, 894))	('Wee1', 'Gene', (983, 987))	('colorectal cancer', 'Phenotype', 'HP:0003003', (574, 591))	('PcG', 'Gene', '40358', (364, 367))	('PcG', 'Gene', (52, 55))	('cancer', 'Disease', (792, 798))	('cancer', 'Phenotype', 'HP:0002664', (792, 798))	('cell proliferation', 'CPA', (895, 913))	('Wee1', 'Gene', '33965', (983, 987))	('carcinoma', 'Phenotype', 'HP:0030731', (693, 702))	('PcG', 'Gene', (65, 68))	('TNM', 'Gene', '10178', (667, 670))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (810, 843))	('ARF', 'Disease', (422, 425))	('cancer', 'Disease', 'MESH:D009369', (585, 591))	('glioblastoma', 'Disease', 'MESH:D005909', (560, 572))	('PcG', 'Gene', '40358', (52, 55))	('TNM', 'Gene', (667, 670))	('p21', 'Gene', (978, 981))
219552	28837252	reported that CBX8 also plays a paradoxical role in colorectal cancer wherein its upregulation is associated with low risk for distant metastasis and good prognosis.14 Knockdown of CBX8 also results in the inhibition of cell proliferation by accelerating the p53 pathway.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))	('cell proliferation', 'CPA', (220, 238))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('Knockdown', 'Var', (168, 177))	('p53', 'Gene', (259, 262))	('p53', 'Gene', '7157', (259, 262))	('CBX8', 'Gene', (181, 185))	('colorectal cancer', 'Disease', (52, 69))	('accelerating', 'PosReg', (242, 254))	('inhibition', 'NegReg', (206, 216))
219555	28837252	Furthermore, knockdown of CBX8 resulted in the inhibition of UCB cell proliferation and cell cycle arrest at the G2/M phase by the p53 pathway.	('UCB cell proliferation', 'CPA', (61, 83))	('cell cycle arrest at the G2/M phase', 'CPA', (88, 123))	('inhibition', 'NegReg', (47, 57))	('UCB', 'Chemical', '-', (61, 64))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (88, 105))	('CBX8', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))
219591	28837252	Bioinformatics analysis was first carried out to evaluate CBX8 gene alterations in UCB using TCGA database.	('UCB', 'Chemical', '-', (83, 86))	('CBX8', 'Gene', (58, 62))	('UCB', 'Disease', (83, 86))	('alterations', 'Var', (68, 79))
219593	28837252	TCGA database shows that more frequent CBX8 amplification predicts poor outcome in UCB patients, indicating that CBX8 may act as an oncogene in UCB.	('amplification', 'Var', (44, 57))	('CBX8', 'Gene', (39, 43))	('UCB', 'Chemical', '-', (144, 147))	('UCB', 'Chemical', '-', (83, 86))	('patients', 'Species', '9606', (87, 95))	('UCB', 'Disease', (83, 86))
219601	28837252	Chi-squared testing suggested that high CBX8 expression was significantly associated with pT stage, pN stage, M stage, and recurrence status of MIBC patients.	('patients', 'Species', '9606', (149, 157))	('CBX8', 'Gene', (40, 44))	('MIBC', 'Chemical', '-', (144, 148))	('M stage', 'Disease', (110, 117))	('pT stage', 'Disease', (90, 98))	('expression', 'MPA', (45, 55))	('pN stage', 'Disease', (100, 108))	('high', 'Var', (35, 39))	('associated', 'Reg', (74, 84))
219603	28837252	Combined with Kaplan-Meier analysis and log-rank test, the analysis showed a significant association of CBX8 expression with OS (P < 0.001), 5-year RFS (P < 0.001), pT2 (P = 0.002), pT3-4 (P < 0.001), pN- (P < 0.001), and pN+ (P = 0.024), suggesting that MIBC patients with high CBX8 expression had lower survival rates than patients with low CBX8 expression (Fig.	('pT3', 'Gene', '7694', (182, 185))	('patients', 'Species', '9606', (325, 333))	('high', 'Var', (274, 278))	('OS', 'Chemical', '-', (125, 127))	('lower', 'NegReg', (299, 304))	('MIBC', 'Chemical', '-', (255, 259))	('expression', 'Var', (284, 294))	('pT3', 'Gene', (182, 185))	('patients', 'Species', '9606', (260, 268))	('survival rates', 'CPA', (305, 319))	('CBX8', 'Gene', (104, 108))	('CBX8', 'Gene', (279, 283))
219606	28837252	Further in vitro investigations involving knocking down CBX8 expression were carried out in the present study to explore the role of CBX8 in promoting UCB cell proliferation.	('CBX8', 'Gene', (56, 60))	('knocking down', 'Var', (42, 55))	('promoting', 'PosReg', (141, 150))	('CBX8', 'Gene', (133, 137))	('UCB', 'Chemical', '-', (151, 154))	('UCB', 'Disease', (151, 154))
219607	28837252	Taken together, these findings indicate that knockdown of CBX8 inhibited UCB cell proliferation.	('UCB', 'Chemical', '-', (73, 76))	('UCB cell proliferation', 'CPA', (73, 95))	('inhibited', 'NegReg', (63, 72))	('CBX8', 'Gene', (58, 62))	('knockdown', 'Var', (45, 54))
219608	28837252	Xenograft BALB/c nude mice were used to investigate whether knockdown of CBX8 inhibits UCB cells proliferation in vivo.	('UCB cells proliferation', 'CPA', (87, 110))	('UCB', 'Chemical', '-', (87, 90))	('knockdown', 'Var', (60, 69))	('nude mice', 'Species', '10090', (17, 26))	('inhibits', 'NegReg', (78, 86))	('CBX8', 'Gene', (73, 77))
219609	28837252	Figure 4d shows that mice infected with T24-CBX8 shRNA generated tumors that were smaller in size and lower in weight than those observed in T24-control mice, indicating that knockdown of CBX8 significantly inhibited tumor growth in vivo.	('lower', 'NegReg', (102, 107))	('T24-CBX8', 'Var', (40, 48))	('smaller', 'NegReg', (82, 89))	('tumor', 'Disease', (217, 222))	('inhibited', 'NegReg', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (65, 70))	('mice', 'Species', '10090', (21, 25))	('CBX8', 'Gene', (188, 192))	('lower in weight', 'Phenotype', 'HP:0004325', (102, 117))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('knockdown', 'Var', (175, 184))	('mice', 'Species', '10090', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
219610	28837252	A recent study involving human esophageal carcinoma EC109 cells showed that depletion of CBX8 results in cell cycle delay at the G2/M phase.16 Therefore, we measured the cell cycle transition to detect whether knockdown of CBX8 affects cell cycle distribution in the UCB cell lines T24 and BIU.	('knockdown', 'Var', (210, 219))	('affects', 'Reg', (228, 235))	('EC109', 'CellLine', 'CVCL:6898', (52, 57))	('UCB', 'Chemical', '-', (267, 270))	('esophageal carcinoma', 'Disease', (31, 51))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (31, 51))	('human', 'Species', '9606', (25, 30))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (31, 51))	('cell cycle', 'CPA', (236, 246))	('CBX8', 'Gene', (223, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
219611	28837252	These findings indicate that knockdown of CBX8 leads to inhibition of G2-M phase transition, which, in turn, contributes to the inhibition of UCB cell proliferation.	('inhibition', 'NegReg', (56, 66))	('inhibition', 'NegReg', (128, 138))	('knockdown', 'Var', (29, 38))	('G2-M phase transition', 'CPA', (70, 91))	('UCB cell proliferation', 'CPA', (142, 164))	('UCB', 'Chemical', '-', (142, 145))	('CBX8', 'Gene', (42, 46))
219614	28837252	Figure 5b shows that the protein expression level of p53 was elevated, whereas that of cdc2/cyclinB1 decreased after knocking down CBX8 expression.	('protein expression level', 'MPA', (25, 49))	('CBX8', 'Gene', (131, 135))	('knocking down', 'Var', (117, 130))	('elevated', 'PosReg', (61, 69))	('decreased', 'NegReg', (101, 110))	('cdc2', 'Gene', '983', (87, 91))	('cdc2', 'Gene', (87, 91))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('cyclinB1', 'Gene', (92, 100))	('cyclinB1', 'Gene', '891', (92, 100))
219617	28837252	Figure 5d shows that the percentage of CBX8-silenced cells in G2 decreased from 25.45% to 12.44% after transfection with p53-siRNA, indicating that knocking down CBX8 inhibits cell cycle progression and is p53-dependent.	('p53', 'Gene', (206, 209))	('p53', 'Gene', '7157', (206, 209))	('knocking down', 'Var', (148, 161))	('cell cycle progression', 'CPA', (176, 198))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('CBX8', 'Gene', (162, 166))	('inhibits', 'NegReg', (167, 175))
219619	28837252	Taken together, these findings indicate that knockdown of CBX8 results in cell cycle arrest at the G2/M phase by the p53 pathway.	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('cell cycle arrest at the G2/M phase', 'CPA', (74, 109))	('CBX8', 'Gene', (58, 62))	('knockdown', 'Var', (45, 54))
219633	28837252	Kaplan-Meier survival analysis and log-rank test showed that patients with high CBX8 expression levels had poorer OS and RFS than patients with low CBX8 expression levels, and a T or N stage with a high CBX8 expression level was associated with poor OS compared to low CBX8 expression.	('CBX8', 'Gene', (80, 84))	('expression levels', 'Var', (85, 102))	('RFS', 'MPA', (121, 124))	('high', 'Var', (75, 79))	('OS', 'Chemical', '-', (114, 116))	('poorer', 'NegReg', (107, 113))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (130, 138))	('OS', 'Chemical', '-', (250, 252))
219636	28837252	We observed that knockdown of CBX8 decreases cell viability and clonogenicity of the UCB cell lines in vitro.	('UCB', 'Chemical', '-', (85, 88))	('cell viability', 'CPA', (45, 59))	('decreases', 'NegReg', (35, 44))	('clonogenicity of the UCB cell lines', 'CPA', (64, 99))	('CBX8', 'Gene', (30, 34))	('knockdown', 'Var', (17, 26))
219637	28837252	Furthermore, xenografting nude mice proved that knockdown of CBX8 inhibits cell growth in vivo.	('cell growth in vivo', 'CPA', (75, 94))	('inhibits', 'NegReg', (66, 74))	('nude mice', 'Species', '10090', (26, 35))	('CBX8', 'Gene', (61, 65))	('knockdown', 'Var', (48, 57))
219638	28837252	A previous study has shown that knockdown of CBX8 represses cancer cell proliferation in vitro and in vivo and results in cell cycle arrest.4, 16 Thus, a flow cytometry assay was carried out to determine cycle distribution, which showed that CBX8 silencing accelerates the G1 to G2 phase transition, which possibly contributes to the inhibition of UCB cell proliferation.	('CBX8', 'Gene', (242, 246))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('G1 to G2 phase transition', 'CPA', (273, 298))	('accelerates', 'PosReg', (257, 268))	('cancer', 'Disease', (60, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('UCB', 'Chemical', '-', (348, 351))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('silencing', 'Var', (247, 256))
219643	28837252	Our findings showed that high expression of CBX8 plays a critical oncogenic role in UCB aggressiveness by promoting cancer cell proliferation by repressing the p53 pathway, and CBX8 could be used as a novel predictor for human UCB patients.	('UCB', 'Chemical', '-', (84, 87))	('repressing', 'NegReg', (145, 155))	('aggressiveness', 'Phenotype', 'HP:0000718', (88, 102))	('patients', 'Species', '9606', (231, 239))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('high expression', 'Var', (25, 40))	('CBX8', 'Gene', (44, 48))	('p53', 'Gene', (160, 163))	('human', 'Species', '9606', (221, 226))	('p53', 'Gene', '7157', (160, 163))	('UCB aggressiveness', 'Disease', 'MESH:D001523', (84, 102))	('UCB', 'Chemical', '-', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('UCB aggressiveness', 'Disease', (84, 102))	('promoting', 'PosReg', (106, 115))
219651	27120796	Patients with positive PD-L1 expression had reduced risk for disease relapse compared to those without PD-L1 expression (Hazard ratio [HR] = 0.75, 95% confidence interval [CI]: 0.56-1.00, P = 0.048).	('expression', 'Var', (29, 39))	('disease relapse', 'CPA', (61, 76))	('PD-L1', 'Gene', (23, 28))	('Patients', 'Species', '9606', (0, 8))	('reduced', 'NegReg', (44, 51))
219665	27120796	However, recent literatures reported that patients with high expression levels in PD-1 and PD-L1 had better prognosis in breast cancer, glioblastoma, metastatic melanoma, colorectal cancer, pulmonary squamous cell carcinoma, and ovarian cancer.	('ovarian cancer', 'Disease', (229, 243))	('pulmonary squamous cell carcinoma', 'Disease', (190, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (229, 243))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))	('better', 'PosReg', (101, 107))	('PD-1', 'Gene', (82, 86))	('pulmonary squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 223))	('PD-1', 'Gene', '5133', (82, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('glioblastoma', 'Disease', 'MESH:D005909', (136, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (171, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('patients', 'Species', '9606', (42, 50))	('ovarian cancer', 'Disease', 'MESH:D010051', (229, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('PD-L1', 'Gene', (91, 96))	('glioblastoma', 'Disease', (136, 148))	('colorectal cancer', 'Disease', (171, 188))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('breast cancer', 'Disease', (121, 134))	('high expression levels', 'Var', (56, 78))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('pulmonary squamous cell carcinoma', 'Phenotype', 'HP:0030359', (190, 223))
219681	27120796	As shown in Table 3, univariate analysis demonstrated that patients with PD-L1 expression had lower risk to relapse than those with no expression (Hazard ratio [HR] = 0.75, 95% confidence interval [CI]: 0.56-1.00, P = 0.048).	('lower', 'NegReg', (94, 99))	('patients', 'Species', '9606', (59, 67))	('expression', 'Var', (79, 89))	('relapse', 'CPA', (108, 115))	('PD-L1', 'Gene', (73, 78))
219683	27120796	The median DFS of the patients with PD-L1 expression was significantly longer than the patients without PD-L1 expression (not reached verse 41.3 months, P = 0.047).	('longer', 'PosReg', (71, 77))	('PD-L1 expression', 'Var', (36, 52))	('DFS', 'MPA', (11, 14))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (87, 95))
219693	27120796	Unlike earlier studies, we observed that patients with PD-L1 expression had longer relapse time and overall survival time in the first 5 years after operation compared to those without PD-L1 expression, and others found similar associations as to ours in different tumor types.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('relapse time', 'CPA', (83, 95))	('tumor', 'Disease', (265, 270))	('expression', 'Var', (61, 71))	('patients', 'Species', '9606', (41, 49))	('longer', 'PosReg', (76, 82))	('survival time', 'CPA', (108, 121))	('PD-L1', 'Gene', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (265, 270))
219696	27120796	PD-L1 was also defined to indicate favorable prognosis in pulmonary squamous cell carcinoma.	('pulmonary squamous cell carcinoma', 'Phenotype', 'HP:0030359', (58, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('pulmonary squamous cell carcinoma', 'Disease', (58, 91))	('PD-L1', 'Var', (0, 5))	('pulmonary squamous cell carcinoma', 'Disease', 'MESH:D002294', (58, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))
219697	27120796	It is known that PD-L1 and PD-1 interaction leads to immune suppression which may partially be responsible for the immune resistance of tumor cells, but high PD-L1 expression may also promote immune responses through PD-L1's binding to unknown receptors other than PD-1, resulting in T-cell proliferation and secretion of certain cytokines such as IL-10 and interferon gamma, which in turn activate strong antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (410, 415))	('PD-1', 'Gene', (27, 31))	('PD-1', 'Gene', '5133', (27, 31))	('promote', 'PosReg', (184, 191))	('tumor', 'Phenotype', 'HP:0002664', (410, 415))	('PD-L1', 'Gene', (158, 163))	('PD-1', 'Gene', (265, 269))	('binding', 'Interaction', (225, 232))	('T-cell proliferation', 'CPA', (284, 304))	('secretion of', 'MPA', (309, 321))	('PD-1', 'Gene', '5133', (265, 269))	('tumor', 'Disease', (136, 141))	('IL-10', 'Gene', (348, 353))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('immune suppression', 'MPA', (53, 71))	('IL-10', 'Gene', '103158318', (348, 353))	('tumor', 'Disease', (410, 415))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('high', 'Var', (153, 157))	('immune responses', 'CPA', (192, 208))
219698	27120796	In addition, it has been shown that localized PD-L1 expression promotes organ-specific autoimmunity.	('PD-L1', 'Gene', (46, 51))	('autoimmunity', 'Disease', (87, 99))	('autoimmunity', 'Disease', 'MESH:D001327', (87, 99))	('promotes', 'PosReg', (63, 71))	('autoimmunity', 'Phenotype', 'HP:0002960', (87, 99))	('expression', 'Var', (52, 62))
219790	26384482	We found that the incidence of anastomotic leak, incision infection, and respiratory complications were more common in the right transthoracic group.	('respiratory complications', 'Disease', (73, 98))	('respiratory complications', 'Phenotype', 'HP:0011947', (73, 98))	('infection', 'Disease', (58, 67))	('infection', 'Disease', 'MESH:D007239', (58, 67))	('anastomotic leak', 'Disease', 'MESH:D057868', (31, 47))	('respiratory complications', 'Disease', 'MESH:D012131', (73, 98))	('anastomotic leak', 'Disease', (31, 47))	('right transthoracic', 'Var', (123, 142))
219820	24163737	This review is intended to summarize recent advances in gaining an understanding of the significance of SBP1 in carcinogenesis, and suggest that SBP1 could be developed as a potential biomarker for cancer progression and prognosis.	('carcinogenesis', 'Disease', 'MESH:D063646', (112, 126))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('carcinogenesis', 'Disease', (112, 126))	('SBP1', 'Var', (145, 149))	('SBP1', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
219824	24163737	In particular, geographic, animal and human epidemiological studies, have shown that lower concentrations of selenium in serum is associated with increased risk of cancer and that selenium supplementation may, in some cases, reduce the risk of several cancer types, including those of the esophagus, colon, prostate and liver .	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('reduce', 'NegReg', (225, 231))	('lower', 'NegReg', (85, 90))	('selenium', 'Chemical', 'MESH:D012643', (180, 188))	('selenium', 'Chemical', 'MESH:D012643', (109, 117))	('cancer', 'Disease', (252, 258))	('human', 'Species', '9606', (38, 43))	('esophagus', 'Disease', (289, 298))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('concentrations', 'MPA', (91, 105))	('cancer', 'Disease', (164, 170))	('colon', 'Disease', (300, 305))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('liver', 'Disease', (320, 325))	('supplementation', 'Var', (189, 204))	('prostate', 'Disease', (307, 315))
219834	24163737	Changes in the levels of GPx1 have been associated with a variety of human diseases.	('human', 'Species', '9606', (69, 74))	('Changes', 'Var', (0, 7))	('associated', 'Reg', (40, 50))	('GPx1', 'Gene', (25, 29))
219841	24163737	has detected two 56 kD SBP1 isoforms in human lung cancers using Tandem mass spectrometry and 2-D western blot analysis, in which an acidic isoform (457AA) was observed at lower levels in lung adenocarcinomas compared with normal lung, with two additional, more acidic SBP1 isoforms only observed in normal lung tissue .	('lung cancers', 'Phenotype', 'HP:0100526', (46, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (188, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('lower', 'NegReg', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung adenocarcinomas', 'Disease', (188, 208))	('lung cancers', 'Disease', (46, 58))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (188, 208))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (188, 208))	('lung cancers', 'Disease', 'MESH:D008175', (46, 58))	('457AA', 'Var', (149, 154))	('human', 'Species', '9606', (40, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
219856	24163737	reported that low levels of the native form SBP1 protein (460aa) was significantly correlated with poor survival among patients with lung cancer .	('lung cancer', 'Disease', (133, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('poor', 'NegReg', (99, 103))	('460aa', 'Var', (58, 63))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('SBP1', 'Gene', (44, 48))
219859	24163737	We have previously reported that SBP1 protein and mRNA expression were dramatically lower in human colorectal cancer  and recent studies have indicated an association between epigenetic changes of SBP1 and its reduced expression.	('mRNA expression', 'MPA', (50, 65))	('epigenetic changes', 'Var', (175, 193))	('reduced', 'NegReg', (210, 217))	('protein', 'Protein', (38, 45))	('colorectal cancer', 'Disease', (99, 116))	('human', 'Species', '9606', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('SBP1', 'Gene', (33, 37))	('lower', 'NegReg', (84, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('expression', 'MPA', (218, 228))	('SBP1', 'Gene', (197, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
219861	24163737	These data clearly demonstrate that SBP1 promoter methylation may be one of the mechanisms responsible for SBP1 downregulation in human colon cancers.	('colon cancers', 'Disease', 'MESH:D015179', (136, 149))	('downregulation', 'NegReg', (112, 126))	('colon cancer', 'Phenotype', 'HP:0003003', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('SBP1', 'Gene', (107, 111))	('colon cancers', 'Disease', (136, 149))	('SBP1', 'Gene', (36, 40))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('colon cancers', 'Phenotype', 'HP:0003003', (136, 149))	('methylation', 'Var', (50, 61))	('human', 'Species', '9606', (130, 135))
219864	24163737	Epigenetic changes in SBP1 were also observed during esophageal carcinogenesis where the proximal regions of the SBP1 promoter was hypermethylated during the progression of Barrett's esophagus to adenocarcinoma as well as in esophageal cancer cell lines .	('esophageal carcinogenesis', 'Disease', (53, 78))	("Barrett's esophagus to adenocarcinoma", 'Disease', 'MESH:D001471', (173, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('esophageal cancer', 'Disease', (225, 242))	("Barrett's esophagus to adenocarcinoma", 'Disease', (173, 210))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (53, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (225, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('SBP1', 'Gene', (113, 117))	('hypermethylated', 'Var', (131, 146))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (173, 192))
219869	24163737	Inhibition of SBP1 by siRNA effectively increased cell motility, promoted cell proliferation, and inhibited apoptosis in hepatacellular carcinoma cell lines .	('cell proliferation', 'CPA', (74, 92))	('hepatacellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('inhibited', 'NegReg', (98, 107))	('SBP1', 'Gene', (14, 18))	('carcinoma', 'Disease', 'MESH:D002277', (136, 145))	('promoted', 'PosReg', (65, 73))	('Inhibition', 'Var', (0, 10))	('increased', 'PosReg', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cell motility', 'CPA', (50, 63))	('apoptosis', 'CPA', (108, 117))	('carcinoma', 'Disease', (136, 145))
219870	24163737	Conversely, ectopic SBP1 expression in colorectal cancer cells resulted in inhibition of cancer cell proliferation and the induction of apoptosis, attenuated cancer cell migration in vitro, and significantly inhibited cancer cell growth in nude mice .	('SBP1', 'Gene', (20, 24))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colorectal cancer', 'Disease', (39, 56))	('inhibited', 'NegReg', (208, 217))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('attenuated cancer', 'Disease', 'MESH:C538265', (147, 164))	('attenuated cancer', 'Disease', (147, 164))	('inhibition', 'NegReg', (75, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('ectopic', 'Var', (12, 19))	('cancer', 'Disease', (218, 224))	('apoptosis', 'CPA', (136, 145))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('nude mice', 'Species', '10090', (240, 249))
219872	24163737	We recently reported that ectopic expression of SBP1 was sufficient to cause an approximately 50% reduction in the activity of the GPx-1 selenoprotein in human HCT116 colon cancer cells without affecting GPx1 mRNA and protein levels .	('human', 'Species', '9606', (154, 159))	('colon cancer', 'Phenotype', 'HP:0003003', (167, 179))	('ectopic expression', 'Var', (26, 44))	('SBP1', 'Gene', (48, 52))	('colon cancer', 'Disease', 'MESH:D015179', (167, 179))	('activity', 'MPA', (115, 123))	('reduction', 'NegReg', (98, 107))	('GPx-1 selenoprotein', 'Enzyme', (131, 150))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('colon cancer', 'Disease', (167, 179))	('HCT116', 'CellLine', 'CVCL:0291', (160, 166))
219928	23762144	(1) Fifty-six patients met criteria for inclusion of small varices level (29 patients in FZHYC group and 27 patients in placebo group) in the follow-up study.	('FZHYC', 'Var', (89, 94))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (14, 22))	('small varices', 'MPA', (53, 66))
219933	23762144	Only Prothrombin time in the FZHYC group (15.14 +- 1.47 s) was shorter than it was in the Propranolol group (16.79 +- 2.32 s, P < 0.05).	('Prothrombin', 'Gene', (5, 16))	('FZHYC', 'Var', (29, 34))	('Propranolol', 'Chemical', 'MESH:D011433', (90, 101))	('shorter', 'NegReg', (63, 70))	('Prothrombin', 'Gene', '2147', (5, 16))
219936	23762144	A total of 6 patients reached the primary end point of esophageal variceal bleeding: 1 of 29 patients in the FZHYC group and 5 of 27 patients in the placebo group.	('esophageal variceal bleeding', 'Disease', 'MESH:D004932', (55, 83))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (133, 141))	('FZHYC', 'Var', (109, 114))	('esophageal variceal bleeding', 'Disease', (55, 83))	('esophageal variceal bleeding', 'Phenotype', 'HP:0002040', (55, 83))	('patients', 'Species', '9606', (93, 101))
219939	23762144	Compared to the Propranolol group (43.0%), there were significant differences in the actuarial probability of esophageal variceal bleeding in FZHYC group (23.9%, P = 0.0131) and the Combination group (12.4%, P = 0.0086).	('Propranolol', 'Chemical', 'MESH:D011433', (16, 27))	('esophageal variceal bleeding', 'Disease', (110, 138))	('esophageal variceal bleeding', 'Phenotype', 'HP:0002040', (110, 138))	('FZHYC', 'Var', (142, 147))	('esophageal variceal bleeding', 'Disease', 'MESH:D004932', (110, 138))
219942	23762144	There was no significant difference in the actuarial probability of survival (95.24% in FZHYC group, 95% in the placebo group, P = 0.7919), suggesting FZHYC has no effect on increasing the survival of the cirrhotic patients with small varices.	('patients', 'Species', '9606', (215, 223))	('FZHYC', 'Var', (151, 156))	('increasing', 'PosReg', (174, 184))
219949	23762144	By the comparison of the Child-Pugh score between the baseline and after treatment of 6th month or 12th month, it was shown that the FZHYC decreased the score.	('decreased', 'NegReg', (139, 148))	('Child', 'Species', '9606', (25, 30))	('FZHYC', 'Var', (133, 138))
219966	23762144	Eight patients did not present varices in the Fuzheng Huayu group, while only 1 patient in the placebo group showed such improvements, and there was significant difference between both groups.	('patient', 'Species', '9606', (6, 13))	('patients', 'Species', '9606', (6, 14))	('varices', 'Disease', (31, 38))	('Fuzheng', 'Var', (46, 53))	('patient', 'Species', '9606', (80, 87))
219969	23762144	The actuarial probability of variceal bleeding was significantly lower and the actuarial probability of survival was significantly higher in the Fuzheng Huayu group than that in the Propranolol group.	('lower', 'NegReg', (65, 70))	('Fuzheng Huayu', 'Var', (145, 158))	('bleeding', 'Disease', 'MESH:D006470', (38, 46))	('Propranolol', 'Chemical', 'MESH:D011433', (182, 193))	('bleeding', 'Disease', (38, 46))	('higher', 'PosReg', (131, 137))
219973	23762144	Through the actions of anti-fibrosis and the nondecrease of cardiac output (the data not show), FZHYC could enhance hepatic blood circulation by increasing the blood flow volume and speed in the liver (the data not shown), thus lowering the risk of bleeding.	('blood flow volume', 'MPA', (160, 177))	('lowering', 'NegReg', (228, 236))	('speed', 'MPA', (182, 187))	('bleeding', 'Disease', 'MESH:D006470', (249, 257))	('bleeding', 'Disease', (249, 257))	('enhance', 'PosReg', (108, 115))	('hepatic blood circulation', 'MPA', (116, 141))	('fibrosis', 'Disease', 'MESH:D005355', (28, 36))	('fibrosis', 'Disease', (28, 36))	('FZHYC', 'Var', (96, 101))	('increasing', 'PosReg', (145, 155))
219975	23762144	The pathological results from three previous clinical trials demonstrated that FZHYC markedly lessened inflammation in the liver, prevented the process of hepatic fibrosis induced by hepatitis B virus, and enhanced the degradation of hepatic fibrosis in patients with hepatic fibrosis.	('inflammation', 'Disease', (103, 115))	('lessened', 'NegReg', (94, 102))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (234, 250))	('degradation', 'MPA', (219, 230))	('hepatic fibrosis', 'Disease', (234, 250))	('hepatitis B virus', 'Species', '10407', (183, 200))	('enhanced', 'PosReg', (206, 214))	('hepatitis', 'Phenotype', 'HP:0012115', (183, 192))	('FZHYC', 'Var', (79, 84))	('lessened inflammation in the liver', 'Phenotype', 'HP:0001410', (94, 128))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (155, 171))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (268, 284))	('inflammation', 'Disease', 'MESH:D007249', (103, 115))	('prevented', 'NegReg', (130, 139))	('hepatic fibrosis', 'Disease', 'MESH:D008103', (234, 250))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (155, 171))	('inflammation in the liver', 'Phenotype', 'HP:0012115', (103, 128))	('hepatic fibrosis', 'Disease', (155, 171))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (268, 284))	('hepatic fibrosis', 'Disease', (268, 284))	('patients', 'Species', '9606', (254, 262))
220094	21796275	We evaluated four RNAs as potential normalizers (U6, RNU44, RNU48 and ath-miR-159a).	('miR', 'Gene', (74, 77))	('miR', 'Gene', '220972', (74, 77))	('U6', 'Var', (49, 51))	('RNU48', 'Gene', (60, 65))	('RNU44', 'Gene', '26806', (53, 58))	('RNU48', 'Gene', '26801', (60, 65))	('RNU44', 'Gene', (53, 58))
220144	31355713	Misspecification of background rates can cause bias in inference about the shape of the dose response, so heterogeneity of background rates might explain at least part of the all solid cancer dose-response difference in curvature between males and females.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('Misspecification', 'Var', (0, 16))
220229	31355713	Even without excluding individual sites of cancer, more-flexible background-rate adjustments (including interaction between distance categories and city in the parametric model or using stratification, which implicitly includes interactions) resulted in lower curvature estimates among males for all solid cancers collectively.	('cancers', 'Phenotype', 'HP:0002664', (306, 313))	('curvature', 'MPA', (260, 269))	('solid cancers', 'Disease', 'MESH:D009369', (300, 313))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('men', 'Species', '9606', (87, 90))	('adjustments', 'Var', (81, 92))	('cancer', 'Disease', (43, 49))	('lower', 'NegReg', (254, 259))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('solid cancers', 'Disease', (300, 313))	('cancer', 'Disease', (306, 312))
220243	31355713	One limitation of our analyses is that stratification of background rates can result in loss of efficiency due to imbalance in apportionment of numbers of events across strata.	('efficiency', 'MPA', (96, 106))	('stratification', 'Var', (39, 53))	('imbalance', 'Phenotype', 'HP:0002172', (114, 123))	('loss', 'NegReg', (88, 92))	('men', 'Species', '9606', (136, 139))
220269	31262333	Biomass fuel is associated with increased risk of Esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Esophageal squamous cell carcinoma', 'Disease', (50, 84))	('Biomass', 'Var', (0, 7))
220278	31262333	An association of biomass smoke with lung cancer is established but suggested with ESCC though polycyclic aromatic hydrocarbons (PAHs), a major component of biomass fuel, have carcinogenic properties on mucosal and endothelial lining of upper aero digestive tract from inhalation.	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (95, 127))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('carcinogenic', 'Disease', 'MESH:D063646', (176, 188))	('polycyclic', 'Var', (95, 105))	('carcinogenic', 'Disease', (176, 188))	('PAHs', 'Chemical', 'MESH:D011084', (129, 133))
220294	31262333	In South Africa, SULT1A1*2/*2, GSTP1 341C/T and T/T genotypes and single nucleotide polymorphisms in miR-423 together with environmental smoke exposure was associated with increased risk of ESCC.	('ESCC', 'Disease', (190, 194))	('miR-423', 'Gene', (101, 108))	('GSTP1', 'Gene', '2950', (31, 36))	('single nucleotide polymorphisms', 'Var', (66, 97))	('SULT1A1', 'Gene', (17, 24))	('T/T', 'Var', (48, 51))	('SULT1A1', 'Gene', '6817', (17, 24))	('miR-423', 'Gene', '494335', (101, 108))	('341C/T', 'Mutation', 'rs1138272', (37, 43))	('GSTP1', 'Gene', (31, 36))
220312	29351209	The Prognostic Significance of Histone Demethylase UTX in Esophageal Squamous Cell Carcinoma The dysregulation of the ubiquitously transcribed TPR gene on the X chromosome (UTX) has been reported to be involved in the oncogenesis of several types of cancers.	('TPR', 'Gene', (143, 146))	('cancers', 'Disease', 'MESH:D009369', (250, 257))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('cancers', 'Disease', (250, 257))	('involved', 'Reg', (202, 210))	('TPR', 'Gene', '7175', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('Carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('Histone Demethylase UTX', 'Gene', (31, 54))	('dysregulation', 'Var', (97, 110))	('Histone Demethylase UTX', 'Gene', '7403', (31, 54))	('Esophageal Squamous Cell Carcinoma', 'Disease', (58, 92))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (58, 92))
220315	29351209	The 5-year OS rates were 39% and 61% in patients with low expression and high expression of UTX, respectively.	('low', 'NegReg', (54, 57))	('patients', 'Species', '9606', (40, 48))	('UTX', 'Gene', (92, 95))	('high expression', 'Var', (73, 88))
220316	29351209	Inhibition of endogenous UTX in ESCC cells increased cell viability and BrdU incorporation, and decreased the expression of epithelial marker E-cadherin.	('E-cadherin', 'Gene', (142, 152))	('E-cadherin', 'Gene', '999', (142, 152))	('BrdU', 'Chemical', 'MESH:D001973', (72, 76))	('decreased', 'NegReg', (96, 105))	('Inhibition', 'Var', (0, 10))	('increased', 'PosReg', (43, 52))	('expression of epithelial marker', 'MPA', (110, 141))	('cell viability', 'CPA', (53, 67))	('BrdU incorporation', 'CPA', (72, 90))
220318	29351209	High UTX expression is independently associated with a better prognosis in patients with ESCC and downregulation of UTX increases ESCC cell growth and decreases E-cadherin expression.	('ESCC', 'Disease', (130, 134))	('decreases', 'NegReg', (151, 160))	('patients', 'Species', '9606', (75, 83))	('ESCC', 'Disease', (89, 93))	('E-cadherin', 'Gene', (161, 171))	('E-cadherin', 'Gene', '999', (161, 171))	('increases', 'PosReg', (120, 129))	('UTX', 'Gene', (116, 119))	('downregulation', 'Var', (98, 112))
220325	29351209	In 2009, inactivated somatic mutations and deletions targeting the UTX gene were identified in a variety of human cancers including multiple myeloma, medulloblastoma, esophageal, colon, bladder, prostate, and renal cancer.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('medulloblastoma', 'Phenotype', 'HP:0002885', (150, 165))	('cancers', 'Disease', (114, 121))	('colon', 'Disease', (179, 184))	('multiple myeloma', 'Phenotype', 'HP:0006775', (132, 148))	('medulloblastoma', 'Disease', (150, 165))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('deletions', 'Var', (43, 52))	('UTX', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('renal cancer', 'Disease', (209, 221))	('myeloma', 'Disease', 'MESH:D009101', (141, 148))	('bladder', 'Disease', (186, 193))	('renal cancer', 'Phenotype', 'HP:0009726', (209, 221))	('prostate', 'Disease', (195, 203))	('esophageal', 'Disease', (167, 177))	('renal cancer', 'Disease', 'MESH:D007680', (209, 221))	('human', 'Species', '9606', (108, 113))	('myeloma', 'Disease', (141, 148))	('medulloblastoma', 'Disease', 'MESH:D008527', (150, 165))
220326	29351209	Constitutional inactivation of UTX causes a specific hereditary disorder called the Kabuki syndrome which may develop into several types of cancer such as neuroblastoma, hepatoblastoma, acute leukemia, and fibromyxoid sarcoma, suggesting that Kabuki syndrome is a cancer predisposition syndrome.	('neuroblastoma', 'Disease', 'MESH:D009447', (155, 168))	('Constitutional inactivation', 'Var', (0, 27))	('UTX', 'Gene', (31, 34))	('Kabuki syndrome', 'Disease', (84, 99))	('Kabuki syndrome', 'Disease', (243, 258))	('acute leukemia', 'Disease', 'MESH:D015470', (186, 200))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('hepatoblastoma', 'Disease', (170, 184))	('cancer', 'Disease', (264, 270))	('hepatoblastoma', 'Disease', 'MESH:D018197', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('fibromyxoid sarcoma', 'Disease', 'MESH:D012509', (206, 225))	('acute leukemia', 'Phenotype', 'HP:0002488', (186, 200))	('Kabuki syndrome', 'Disease', 'MESH:C537705', (84, 99))	('Kabuki syndrome', 'Disease', 'MESH:C537705', (243, 258))	('cancer', 'Disease', (140, 146))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (170, 184))	('hereditary disorder', 'Disease', (53, 72))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('leukemia', 'Phenotype', 'HP:0001909', (192, 200))	('hereditary disorder', 'Disease', 'MESH:D030342', (53, 72))	('neuroblastoma', 'Disease', (155, 168))	('neuroblastoma', 'Phenotype', 'HP:0003006', (155, 168))	('acute leukemia', 'Disease', (186, 200))	('fibromyxoid sarcoma', 'Disease', (206, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (218, 225))
220327	29351209	Kabuki individuals with mutations in UTX have been identified in both female and male patients.	('UTX', 'Gene', (37, 40))	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (86, 94))
220328	29351209	Kabuki syndrome results from hypomorphic female heterozygous mutation and null male hemizygous mutation of UTX.	('UTX', 'Gene', (107, 110))	('hypomorphic female', 'Var', (29, 47))	('Kabuki syndrome', 'Disease', 'MESH:C537705', (0, 15))	('Kabuki syndrome', 'Disease', (0, 15))	('results from', 'Reg', (16, 28))
220329	29351209	However, more precise molecular mechanisms of these UTX mutations in cells or mouse models should be further investigated.	('mouse', 'Species', '10090', (78, 83))	('mutations', 'Var', (56, 65))	('UTX', 'Gene', (52, 55))
220334	29351209	reported that UTX contributes to breast cancer cell proliferation with high levels of UTX being associated with poor prognosis in patients with breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('patients', 'Species', '9606', (130, 138))	('high levels', 'Var', (71, 82))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
220337	29351209	To the best of our knowledge, although UTX defects have been reported in ESCC, the prognostic significance of UTX expression in patients with ESCC remains largely undefined.	('defects', 'Var', (43, 50))	('patients', 'Species', '9606', (128, 136))	('ESCC', 'Disease', (73, 77))	('reported', 'Reg', (61, 69))
220352	29351209	The 5-year OS and DFS rates were 61% and 57% respectively, in patients with high UTX expression, and 39% and 32% respectively, in patients with low UTX expression.	('DFS', 'CPA', (18, 21))	('UTX', 'Protein', (81, 84))	('patients', 'Species', '9606', (130, 138))	('high', 'Var', (76, 80))	('patients', 'Species', '9606', (62, 70))
220355	29351209	The 5-year OS (p = 0.001) and DFS (p < 0.001) rates were 31% and 22%, respectively, in the 36 patients with low UTX and E-cadherin expression, and 57% and 53%, respectively, in the 70 patients without low UTX and E-cadherin expression.	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (184, 192))	('E-cadherin', 'Gene', (120, 130))	('E-cadherin', 'Gene', '999', (120, 130))	('E-cadherin', 'Gene', (213, 223))	('E-cadherin', 'Gene', '999', (213, 223))	('DFS', 'CPA', (30, 33))	('low UTX', 'Var', (108, 115))
220363	29351209	Using exome- or genome-wide sequencing strategies and TCGA databases, various somatic mutations and deletions of UTX have been found in several human cancers, with a prevalence of 24.24% in bladder cancer, 10% in prostate cancer, and 1.85% in esophageal cancer.	('esophageal cancer', 'Disease', (243, 260))	('deletions', 'Var', (100, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('bladder cancer', 'Disease', (190, 204))	('human', 'Species', '9606', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('bladder cancer', 'Phenotype', 'HP:0009725', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('prostate cancer', 'Disease', 'MESH:D011471', (213, 228))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('prostate cancer', 'Phenotype', 'HP:0012125', (213, 228))	('mutations', 'Var', (86, 95))	('prostate cancer', 'Disease', (213, 228))	('UTX', 'Gene', (113, 116))	('found', 'Reg', (127, 132))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (243, 260))
220364	29351209	In addition, in normal fibroblast cells, UTX expression activates the Rb (Retinoblastoma) pathway to suppress cell growth, indicating that UTX may play the role of tumor suppressor in human cancers.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('activates', 'PosReg', (56, 65))	('tumor', 'Disease', (164, 169))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (74, 88))	('cancers', 'Disease', (190, 197))	('suppress', 'NegReg', (101, 109))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('Retinoblastoma', 'Disease', 'MESH:D012175', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('human', 'Species', '9606', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('Retinoblastoma', 'Disease', (74, 88))	('UTX', 'Gene', (41, 44))	('expression', 'Var', (45, 55))	('cell growth', 'CPA', (110, 121))
220366	29351209	UTX knockdown in leukemia cell lines exhibits an anti-growth effect.	('knockdown', 'Var', (4, 13))	('leukemia', 'Disease', (17, 25))	('leukemia', 'Disease', 'MESH:D007938', (17, 25))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('anti-growth effect', 'CPA', (49, 67))	('UTX', 'Gene', (0, 3))
220368	29351209	In the present study, we found that positive UTX expression was associated with better clinical outcomes in 106 patients with ESCC receiving esophagectomy and blockage of endogenous UTX by the siRNA approach led to an increase in cell proliferation and elevation of the BrdU incorporation ability in ESCC cells, suggesting that UTX acts a tumor suppressor in ESCC.	('tumor', 'Disease', (339, 344))	('cell proliferation', 'CPA', (230, 248))	('elevation', 'PosReg', (253, 262))	('UTX', 'Gene', (45, 48))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('increase', 'PosReg', (218, 226))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('positive', 'Var', (36, 44))	('BrdU', 'Chemical', 'MESH:D001973', (270, 274))	('BrdU', 'MPA', (270, 274))
220375	29351209	reported the inactivation of UTX down-regulated E-cadherin gene expression.	('inactivation', 'Var', (13, 25))	('UTX', 'Gene', (29, 32))	('E-cadherin', 'Gene', (48, 58))	('E-cadherin', 'Gene', '999', (48, 58))	('down-regulated', 'NegReg', (33, 47))
220379	29351209	In conclusion, high UTX expression is independently associated with better prognosis in patients with ESCC.	('high', 'Var', (15, 19))	('ESCC', 'Disease', (102, 106))	('patients', 'Species', '9606', (88, 96))	('UTX', 'Protein', (20, 23))
220380	29351209	In ESCC cell lines, downregulation of UTX increases cell growth and decreases E-cadherin expression.	('cell growth', 'CPA', (52, 63))	('increases', 'PosReg', (42, 51))	('downregulation', 'Var', (20, 34))	('decreases', 'NegReg', (68, 77))	('E-cadherin', 'Gene', (78, 88))	('E-cadherin', 'Gene', '999', (78, 88))	('UTX', 'Gene', (38, 41))
220390	29351209	Staining was performed on slides (4 mm) of formalin-fixed, paraffin-embedded tissue sections with primary antibodies against UTX (Clone D3Q1l, 1:400, Cell Signaling Technology, Boston, MA, USA) and E-cadherin (BD610182, 1:2000, BD Biosciences, Sparks, MD,).	('paraffin', 'Chemical', 'MESH:D010232', (59, 67))	('E-cadherin', 'Gene', (198, 208))	('E-cadherin', 'Gene', '999', (198, 208))	('formalin', 'Chemical', 'MESH:D005557', (43, 51))	('BD610182', 'Var', (210, 218))
220458	28779246	We speculate that the pain and discomfort caused by the minilaparotomy diminished the preventive effect of laparoscopy on PPCs.	('PPCs', 'Disease', (122, 126))	('diminished', 'NegReg', (71, 81))	('PPCs', 'Phenotype', 'HP:0006532', (122, 126))	('pain', 'Disease', (22, 26))	('pain', 'Phenotype', 'HP:0012531', (22, 26))	('pain', 'Disease', 'MESH:D010146', (22, 26))	('minilaparotomy', 'Var', (56, 70))	('preventive', 'MPA', (86, 96))
220484	27247885	The inclusion criteria were: (1) Siewert type II or III AEJ, (2) length of esophageal invasion was less than 3 cm, (3) underwent radical proximal or total gastrectomy, (4) with negative proximal margin, (5) pathological T2-4N0-3M0 tumor.	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('T2-4N0-3M0', 'Var', (220, 230))
220503	27247885	showed that there was no difference in overall survival for Siewert type II AEJ between transthoracic and transhiatal approach, but transhiatal approach could decrease pulmonary complications and hospital stay (Wei et al.).	('decrease pulmonary complications', 'Disease', 'MESH:D008171', (159, 191))	('hospital stay', 'CPA', (196, 209))	('decrease pulmonary complications', 'Disease', (159, 191))	('transhiatal approach', 'Var', (132, 152))	('pulmonary complications', 'Phenotype', 'HP:0006532', (168, 191))
220514	27247885	have shown that the median survival time of patients with positive proximal margin was significantly lower than that with negative proximal margin (Mariette et al.).	('lower', 'NegReg', (101, 106))	('patients', 'Species', '9606', (44, 52))	('positive', 'Var', (58, 66))
220524	26380656	Deregulated miRNAs such as miR-221 and miR-31 were found to be statistically significant between the two races.	('miR-221', 'Gene', '407006', (27, 34))	('miR-31', 'Var', (39, 45))	('miR-221', 'Gene', (27, 34))
220525	26380656	Using qRT-PCR, we found that miR-21, miR-146b, miR-221, miR-222, miR-31, and miR-3613 were up-regulated while miR-138 and miR-98 were down-regulated in tumors compared to normal tissues.	('miR-3613', 'Gene', (77, 85))	('miR-146b', 'Gene', (37, 45))	('miR-21', 'Gene', (29, 35))	('tumors', 'Disease', (152, 158))	('miR-31', 'Var', (65, 71))	('miR-98', 'Gene', (122, 128))	('up-regulated', 'PosReg', (91, 103))	('miR-221', 'Gene', (47, 54))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('miR-146b', 'Gene', '574447', (37, 45))	('miR-222', 'Gene', (56, 63))	('miR-3613', 'Gene', '100500908', (77, 85))	('miR-221', 'Gene', '407006', (47, 54))	('miR-138', 'Chemical', '-', (110, 117))	('miR-21', 'Gene', '406991', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('miR-98', 'Gene', '407054', (122, 128))	('miR-222', 'Gene', '407007', (56, 63))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
220534	26380656	Many studies have determined that there are heightened expressions of miR-21, miR-146b, miR-221, miR-222, and miR-31 in PTC.	('miR-146b', 'Gene', '574447', (78, 86))	('miR-31', 'Var', (110, 116))	('miR-222', 'Gene', (97, 104))	('miR-21', 'Gene', '406991', (70, 76))	('PTC', 'Gene', '8030', (120, 123))	('miR-221', 'Gene', '407006', (88, 95))	('miR-21', 'Gene', (70, 76))	('expressions', 'MPA', (55, 66))	('PTC', 'Gene', (120, 123))	('PTC', 'Phenotype', 'HP:0002895', (120, 123))	('miR-221', 'Gene', (88, 95))	('miR-222', 'Gene', '407007', (97, 104))	('miR-146b', 'Gene', (78, 86))	('heightened', 'PosReg', (44, 54))
220544	26380656	Here we report the results of miRNAs expression for miR-21, miR-146b, miR-221, miR-222, miR-31, miR-3613, miR-138, and miR-98.	('miR-221', 'Gene', (70, 77))	('miR-222', 'Gene', (79, 86))	('miR-31', 'Var', (88, 94))	('miR-21', 'Gene', (52, 58))	('miR-138', 'Chemical', '-', (106, 113))	('miR-3613', 'Gene', '100500908', (96, 104))	('miR-98', 'Gene', '407054', (119, 125))	('miR-138', 'Var', (106, 113))	('miR-222', 'Gene', '407007', (79, 86))	('miR-98', 'Gene', (119, 125))	('miR-221', 'Gene', '407006', (70, 77))	('miR-146b', 'Gene', (60, 68))	('miR-21', 'Gene', '406991', (52, 58))	('miR-3613', 'Gene', (96, 104))	('miR-146b', 'Gene', '574447', (60, 68))
220549	26380656	Up-regulated miRNAs included miR-21, miR-146b, miR-221, miR-222, miR-31, and miR-3613.	('miR-31', 'Var', (65, 71))	('miR-146b', 'Gene', '574447', (37, 45))	('miR-21', 'Gene', '406991', (29, 35))	('miR-222', 'Gene', (56, 63))	('miR-3613', 'Gene', '100500908', (77, 85))	('miR-221', 'Gene', '407006', (47, 54))	('Up-regulated', 'PosReg', (0, 12))	('miR-3613', 'Gene', (77, 85))	('miR-222', 'Gene', '407007', (56, 63))	('miR-146b', 'Gene', (37, 45))	('miR-21', 'Gene', (29, 35))	('miR-221', 'Gene', (47, 54))
220550	26380656	Down-regulated miRNAs were miR-138 and miR-98.	('miR-98', 'Gene', '407054', (39, 45))	('miR-98', 'Gene', (39, 45))	('miRNAs', 'MPA', (15, 21))	('miR-138', 'Chemical', '-', (27, 34))	('miR-138', 'Var', (27, 34))	('Down-regulated', 'NegReg', (0, 14))
220564	26380656	Selected miRNAs were miR-21, miR-146b, miR-221, miR-222, miR-3613, miR-31, miR-138, and miR-98.	('miR-3613', 'Gene', '100500908', (57, 65))	('miR-222', 'Gene', (48, 55))	('miR-138', 'Var', (75, 82))	('miR-98', 'Gene', '407054', (88, 94))	('miR-98', 'Gene', (88, 94))	('miR-221', 'Gene', '407006', (39, 46))	('miR-21', 'Gene', (21, 27))	('miR-31', 'Var', (67, 73))	('miR-146b', 'Gene', (29, 37))	('miR-3613', 'Gene', (57, 65))	('miR-221', 'Gene', (39, 46))	('miR-222', 'Gene', '407007', (48, 55))	('miR-21', 'Gene', '406991', (21, 27))	('miR-146b', 'Gene', '574447', (29, 37))	('miR-138', 'Chemical', '-', (75, 82))
220578	26380656	These miRNAs included miR-21, miR-146b, miR-221, miR-222, miR-31, miR-3613, miR-138 and miR-98.	('miR-98', 'Gene', '407054', (88, 94))	('miR-221', 'Gene', '407006', (40, 47))	('miR-222', 'Gene', (49, 56))	('miR-138', 'Chemical', '-', (76, 83))	('miR-98', 'Gene', (88, 94))	('miR-3613', 'Gene', (66, 74))	('miR-146b', 'Gene', '574447', (30, 38))	('miR-222', 'Gene', '407007', (49, 56))	('miR-21', 'Gene', '406991', (22, 28))	('miR-221', 'Gene', (40, 47))	('miR-3613', 'Gene', '100500908', (66, 74))	('miR-31', 'Var', (58, 64))	('miR-21', 'Gene', (22, 28))	('miR-138', 'Var', (76, 83))	('miR-146b', 'Gene', (30, 38))
220587	26380656	These miRNAs were miR-21, miR-146b (Figure 3), miR-221, miR-222 (Figure 4), miR-31, and miR-3613 (Figure 5).	('miR-31', 'Var', (76, 82))	('miR-3613', 'Gene', '100500908', (88, 96))	('miR-21', 'Gene', '406991', (18, 24))	('miR-222', 'Gene', (56, 63))	('miR-146b', 'Gene', '574447', (26, 34))	('miR-3613', 'Gene', (88, 96))	('miR-221', 'Gene', '407006', (47, 54))	('miR-21', 'Gene', (18, 24))	('miR-222', 'Gene', '407007', (56, 63))	('miR-221', 'Gene', (47, 54))	('miR-146b', 'Gene', (26, 34))
220606	26380656	These miRNAs were miR-138 and miR-98 (Figure 6).	('miR-138', 'Var', (18, 25))	('miR-98', 'Gene', (30, 36))	('miR-138', 'Chemical', '-', (18, 25))	('miR-98', 'Gene', '407054', (30, 36))
220639	26380656	One study proposed that the effect of aberrant miR-21 expression led to the suppression of a tumor suppressor gene, programmed cell death 4, or PDCD4.	('expression', 'MPA', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('suppression', 'NegReg', (76, 87))	('aberrant', 'Var', (38, 46))	('tumor', 'Disease', (93, 98))	('PDCD4', 'Gene', (144, 149))	('miR-21', 'Gene', '406991', (47, 53))	('PDCD4', 'Gene', '27250', (144, 149))	('miR-21', 'Gene', (47, 53))
220643	26380656	Therefore the effects of miR-21 knockdown should be studied in PTC in future studies, especially because the knockdown of miR-21 in human breast cancer cell lines has been found to inhibit tumor growth in vivo.	('tumor', 'Disease', (189, 194))	('miR-21', 'Gene', (25, 31))	('human', 'Species', '9606', (132, 137))	('miR-21', 'Gene', '406991', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('knockdown', 'Var', (109, 118))	('PTC', 'Gene', '8030', (63, 66))	('PTC', 'Gene', (63, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('inhibit', 'NegReg', (181, 188))	('PTC', 'Phenotype', 'HP:0002895', (63, 66))	('miR-21', 'Gene', '406991', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('miR-21', 'Gene', (122, 128))
220656	26380656	In breast cancer, miR-221 knockdown reversed EMT and weakened cancer cells' ability to migrate and invade.	('EMT', 'CPA', (45, 48))	('reversed', 'PosReg', (36, 44))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('miR-221', 'Gene', (18, 25))	('weakened', 'NegReg', (53, 61))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('knockdown', 'Var', (26, 35))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('miR-221', 'Gene', '407006', (18, 25))	('cancer', 'Disease', (10, 16))	('rat', 'Species', '10116', (90, 93))
220657	26380656	Further research needs to be done, but optimistically, miR-221 knockdown would have similar effects in PTC, at least, in CA patients.	('PTC', 'Phenotype', 'HP:0002895', (103, 106))	('miR-221', 'Gene', (55, 62))	('PTC', 'Gene', '8030', (103, 106))	('miR-221', 'Gene', '407006', (55, 62))	('knockdown', 'Var', (63, 72))	('PTC', 'Gene', (103, 106))	('patients', 'Species', '9606', (124, 132))
220675	26380656	Investigators who measured levels of phosphorylated protein isoforms in colorectal cancer discovered that there was a two to four-fold decrease in activated signaling molecules (such as p-ERK, p-p38, and p-JNK) in cancers when compared to uninvolved mucosa.	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('p38', 'Gene', (195, 198))	('JNK', 'Gene', '5599', (206, 209))	('p-ERK', 'Var', (186, 191))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Disease', (214, 221))	('p38', 'Gene', '1432', (195, 198))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('colorectal cancer', 'Disease', (72, 89))	('JNK', 'Gene', (206, 209))	('activated signaling molecules', 'MPA', (147, 176))	('decrease', 'NegReg', (135, 143))
220676	26380656	Furthermore, the aberrant expression of protein p21, a cyclin-dependent kinase inhibitor, has been implicated in cancer.	('aberrant', 'Var', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('p21', 'Gene', (48, 51))	('implicated', 'Reg', (99, 109))	('cancer', 'Disease', (113, 119))	('p21', 'Gene', '644914', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
220681	26380656	African American papillary thyroid tumor could have low levels of p21, leading to the potential utility of miR-31 in tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('papillary thyroid tumor', 'Phenotype', 'HP:0002895', (17, 40))	('p21', 'Gene', (66, 69))	('miR-31', 'Var', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (117, 122))	('p21', 'Gene', '644914', (66, 69))	('tumor', 'Disease', (35, 40))	('papillary thyroid tumor', 'Disease', 'MESH:D000077273', (17, 40))	('thyroid tumor', 'Phenotype', 'HP:0100031', (27, 40))	('papillary thyroid tumor', 'Disease', (17, 40))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
220694	26380656	observed differential expressions of miR-31, miR-146b, miR-221, miR-222, and miR-138 between aggressive and non-aggressive PTC.	('miR-138', 'Chemical', '-', (77, 84))	('miR-221', 'Gene', (55, 62))	('miR-146b', 'Gene', (45, 53))	('PTC', 'Gene', '8030', (123, 126))	('PTC', 'Gene', (123, 126))	('miR-146b', 'Gene', '574447', (45, 53))	('miR-222', 'Gene', (64, 71))	('miR-31', 'Gene', (37, 43))	('PTC', 'Phenotype', 'HP:0002895', (123, 126))	('miR-221', 'Gene', '407006', (55, 62))	('miR-222', 'Gene', '407007', (64, 71))	('miR-138', 'Var', (77, 84))
220695	26380656	The expression of miR-146b, miR-221, and miR-222 were up-regulated in aggressive PTC, and miR-138 was down-regulated in aggressive PTC.	('down-regulated', 'NegReg', (102, 116))	('PTC', 'Gene', '8030', (81, 84))	('PTC', 'Gene', (131, 134))	('PTC', 'Gene', (81, 84))	('miR-221', 'Gene', (28, 35))	('PTC', 'Phenotype', 'HP:0002895', (131, 134))	('miR-146b', 'Gene', (18, 26))	('miR-222', 'Gene', '407007', (41, 48))	('expression', 'MPA', (4, 14))	('PTC', 'Phenotype', 'HP:0002895', (81, 84))	('miR-146b', 'Gene', '574447', (18, 26))	('up-regulated', 'PosReg', (54, 66))	('miR-221', 'Gene', '407006', (28, 35))	('miR-138', 'Chemical', '-', (90, 97))	('miR-138', 'Var', (90, 97))	('PTC', 'Gene', '8030', (131, 134))	('miR-222', 'Gene', (41, 48))
220765	25842172	We recently published our institution's initial experience using a biological scaffold to provide extra-luminal reinforcement of the esophageal anastomosis; 37 patients with the reinforcement had a leak rate of 2.7%, compared to a leak rate of 12% in 32 historical control patients who did not receive esophageal reinforcement.	('leak', 'MPA', (198, 202))	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (273, 281))	('reinforcement', 'Var', (178, 191))	('esophageal anastomosis', 'Phenotype', 'HP:0100628', (133, 155))	('esophageal anastomosis', 'Disease', (133, 155))	('esophageal anastomosis', 'Disease', 'MESH:D004941', (133, 155))
220826	25886188	Methylation of RASSF1A gene promoter and the correlation with DNMT1 expression that may contribute to esophageal squamous cell carcinoma Esophageal squamous cell carcinoma is one of the most common malignancies in the world.	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('contribute', 'Reg', (88, 98))	('DNMT1', 'Gene', '1786', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('malignancies', 'Disease', (198, 210))	('RASSF1A', 'Gene', '11186', (15, 22))	('Methylation', 'Var', (0, 11))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (137, 171))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('RASSF1A', 'Gene', (15, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('malignancies', 'Disease', 'MESH:D009369', (198, 210))	('DNMT1', 'Gene', (62, 67))	('Esophageal squamous cell carcinoma', 'Disease', (137, 171))
220828	25886188	The objective is to detect methylation of the RASSF1A gene promoter and the expression of the DNA methyltransferase 1 (DNMT1) protein in esophageal cancer tissue and discuss their relationship with esophageal squamous cell carcinoma.	('RASSF1A', 'Gene', '11186', (46, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('DNA methyltransferase 1', 'Gene', (94, 117))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('methylation', 'Var', (27, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (198, 232))	('DNA methyltransferase 1', 'Gene', '1786', (94, 117))	('DNMT1', 'Gene', (119, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (209, 232))	('RASSF1A', 'Gene', (46, 53))	('DNMT1', 'Gene', '1786', (119, 124))	('esophageal cancer', 'Disease', (137, 154))	('detect', 'Reg', (20, 26))	('esophageal squamous cell carcinoma', 'Disease', (198, 232))
220832	25886188	The RASSF1A gene promoter was highly methylated in cancer tissues, and there were significant differences between normal esophagus tissues and esophageal squamous carcinoma (P < 0.05).	('esophageal squamous carcinoma', 'Disease', (143, 172))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (143, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('RASSF1A', 'Gene', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (154, 172))	('RASSF1A', 'Gene', '11186', (4, 11))	('differences', 'Reg', (94, 105))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (143, 172))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('methylated', 'Var', (37, 47))
220835	25886188	In positive cases for methylation of RASSF1A, the DNMT1 protein had been detected in 41 out of 45 (91%), while in non-methylated cancer cases, 20 out of 55(36.3%), and the difference is significant (P < 0.05).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('RASSF1A', 'Gene', '11186', (37, 44))	('DNMT1', 'Gene', (50, 55))	('protein', 'Protein', (56, 63))	('methylation', 'Var', (22, 33))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('DNMT1', 'Gene', '1786', (50, 55))	('RASSF1A', 'Gene', (37, 44))
220836	25886188	Esophageal squamous carcinoma tumorigenesis may be related with hypermethylation of DNMT1 and RASSF1A promoter CpG island due to their high expression and also their hypermethylation.	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('hypermethylation', 'MPA', (166, 182))	('high', 'PosReg', (135, 139))	('expression', 'MPA', (140, 150))	('DNMT1', 'Gene', (84, 89))	('DNMT1', 'Gene', '1786', (84, 89))	('Esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (0, 29))	('RASSF1A', 'Gene', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (11, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (0, 29))	('hypermethylation', 'Var', (64, 80))	('Esophageal squamous carcinoma', 'Disease', (0, 29))	('RASSF1A', 'Gene', '11186', (94, 101))	('related', 'Reg', (51, 58))	('tumor', 'Disease', (30, 35))
220848	25886188	Using the known positive section as the positive criteria, PBS displaces the primary antibody as the negative criteria.	('displaces', 'NegReg', (63, 72))	('PBS', 'Var', (59, 62))	('PBS', 'Chemical', 'MESH:D007854', (59, 62))
220864	25886188	Previous studies have reported the involvement of RASSF1A promoter methylation in several cancers, including prostate, ovarian, endometrial, gastric, lung, and breast cancer.	('lung', 'Disease', (150, 154))	('cancers', 'Disease', (90, 97))	('endometrial', 'Disease', (128, 139))	('prostate', 'Disease', (109, 117))	('RASSF1A', 'Gene', '11186', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('gastric', 'Disease', (141, 148))	('RASSF1A', 'Gene', (50, 57))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('ovarian', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('breast cancer', 'Disease', (160, 173))	('involvement', 'Reg', (35, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('methylation', 'Var', (67, 78))
220867	25886188	It was conjectured that the promoter CpG island hypermethylation of RASSF1A in human esophageal squamous carcinoma plays a powerful role in the inactivation and transcriptional gene silencing of the RASSF1A gene.	('inactivation', 'NegReg', (144, 156))	('esophageal squamous carcinoma', 'Disease', (85, 114))	('human', 'Species', '9606', (79, 84))	('RASSF1A', 'Gene', (199, 206))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (85, 114))	('RASSF1A', 'Gene', '11186', (68, 75))	('hypermethylation', 'Var', (48, 64))	('RASSF1A', 'Gene', '11186', (199, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (85, 114))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (96, 114))	('RASSF1A', 'Gene', (68, 75))
220868	25886188	But it does not exist in esophageal RASSF1A promoter methylation, and the gene expressed negatively in several patients with the possible mutual adjustment of a bit of a mutation and loss of heterozygosity.	('RASSF1A', 'Gene', '11186', (36, 43))	('mutation', 'Var', (170, 178))	('RASSF1A', 'Gene', (36, 43))	('negatively', 'NegReg', (89, 99))	('patients', 'Species', '9606', (111, 119))
220869	25886188	Not only did we focus on the status of RASSF1A methylation, but we also explored its possible mechanism preliminarily.	('RASSF1A', 'Gene', '11186', (39, 46))	('methylation', 'Var', (47, 58))	('RASSF1A', 'Gene', (39, 46))
220873	25886188	DNMT1 expression abnormalities may be involved in the process of esophageal cancer, but the development in the majority of esophageal cancers is related to multiple factors, genes, and multiple-step processes.	('esophageal cancers', 'Disease', (123, 141))	('esophageal cancer', 'Disease', (65, 82))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('esophageal cancers', 'Disease', 'MESH:D004938', (123, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DNMT1', 'Gene', (0, 5))	('DNMT1', 'Gene', '1786', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('abnormalities', 'Var', (17, 30))
220878	25886188	And furthermore, we also found that in the positive cases for methylation of RASSF1A, the DNMT1 protein had overexpressed in non-methylated cancer cases with significant difference (41 DNMT1 positive cases in 45 RASSF1A positive cases).	('RASSF1A', 'Gene', '11186', (77, 84))	('RASSF1A', 'Gene', (212, 219))	('DNMT1', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('DNMT1', 'Gene', '1786', (90, 95))	('methylation', 'Var', (62, 73))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('overexpressed', 'PosReg', (108, 121))	('RASSF1A', 'Gene', '11186', (212, 219))	('DNMT1', 'Gene', (185, 190))	('DNMT1', 'Gene', '1786', (185, 190))	('RASSF1A', 'Gene', (77, 84))
220883	25886188	Epigenetics may play an important role in tumor diagnosis and treatment gradually.	('Epigenetics', 'Var', (0, 11))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
220887	25886188	On the basis of prophase studies, future research should peg where certain methylation differences are associated with esophageal cancer, establish the esophageal-cancer-related gene methylation spectrum, and focus on DNMT's family roles and specific mechanisms.	('associated', 'Reg', (103, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('esophageal-cancer', 'Disease', 'MESH:D004938', (152, 169))	('DNMT', 'Gene', '1786', (218, 222))	('peg', 'Chemical', '-', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('DNMT', 'Gene', (218, 222))	('methylation differences', 'Var', (75, 98))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal-cancer', 'Disease', (152, 169))	('esophageal cancer', 'Disease', (119, 136))
221015	23901317	Furthermore, although gastroscopic biopsy was performed with suspicion of Borrmann type IV AGC, the positive rate for cancer diagnosis on biopsy specimen was also significantly lower in Borrmann type IV AGC than other Borrmann types of AGC.	('lower', 'NegReg', (177, 182))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('men', 'Species', '9606', (150, 153))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('Borrmann type IV AGC', 'Var', (186, 206))
221030	23901317	Underestimation of the tumor extent can result in either unexpected wider resection of the gastrointestinal tract or tumor involvement at the gastrectomy margins.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('gastrointestinal tract or tumor', 'Disease', (91, 122))	('tumor', 'Disease', (117, 122))	('result in', 'Reg', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('Underestimation', 'Var', (0, 15))	('men', 'Species', '9606', (130, 133))	('gastrointestinal tract or tumor', 'Disease', 'MESH:D004067', (91, 122))
221062	22867052	The enhancer of zeste homolog 2 (EZH2, also called histone lysine methyltransferase) is located at chromosome 7q35 and encodes a member of the Polycomb group proteins, which regulate gene expression via epigenetic modification of chromatin structure including inducing histone acetylation and methylation.	('histone acetylation', 'MPA', (269, 288))	('epigenetic modification', 'Var', (203, 226))	('enhancer of zeste homolog 2', 'Gene', (4, 31))	('regulate', 'Reg', (174, 182))	('methylation', 'MPA', (293, 304))	('enhancer of zeste homolog 2', 'Gene', '2146', (4, 31))	('EZH2', 'Gene', '2146', (33, 37))	('inducing', 'PosReg', (260, 268))	('EZH2', 'Gene', (33, 37))
221106	22867052	In addition, using matrigel-coated transwell assay, we found that the percentages of cells that invaded through the matrigel in miRNAs (miR-98, miR-101 or miR-214) transfected cells were significantly lower than those in the control groups (Figure 5 B).	('cells that invaded through the matrigel', 'CPA', (85, 124))	('miR-214', 'Gene', '406996', (155, 162))	('miR-98', 'Gene', '407054', (136, 142))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('miR', 'Gene', '220972', (155, 158))	('miR-98', 'Gene', (136, 142))	('miR', 'Gene', (155, 158))	('miR', 'Gene', (144, 147))	('miR', 'Gene', (128, 131))	('miR', 'Gene', '220972', (144, 147))	('miR', 'Gene', '220972', (128, 131))	('transfected', 'Var', (164, 175))	('lower', 'NegReg', (201, 206))	('miR-214', 'Gene', (155, 162))
221110	22867052	As shown in Additional file 3: Figure S3, EZH2 protein expression was significantly higher in pcDNA-EZH2 transfected cells than in pcDNA transfected cells.	('protein', 'Protein', (47, 54))	('EZH2', 'Gene', '2146', (100, 104))	('EZH2', 'Gene', '2146', (42, 46))	('EZH2', 'Gene', (100, 104))	('EZH2', 'Gene', (42, 46))	('transfected', 'Var', (105, 116))	('higher', 'PosReg', (84, 90))
221117	22867052	In Eca109 cells, overexpressing miR-98 and miR-214 was found to significantly suppress cell migration and invasion through inhibition of EZH2 expression.	('EZH2', 'Gene', (137, 141))	('miR-98', 'Gene', '407054', (32, 38))	('miR-98', 'Gene', (32, 38))	('miR-214', 'Gene', (43, 50))	('suppress', 'NegReg', (78, 86))	('inhibition', 'NegReg', (123, 133))	('overexpressing', 'Var', (17, 31))	('expression', 'MPA', (142, 152))	('miR-214', 'Gene', '406996', (43, 50))	('EZH2', 'Gene', '2146', (137, 141))
221146	22867052	In Eca109 cells, miR-98 and miR-214 overexpression significantly inhibited cell migration and invasion by repressing EZH2 protein expression.	('protein', 'Protein', (122, 129))	('miR-214', 'Gene', '406996', (28, 35))	('EZH2', 'Gene', (117, 121))	('EZH2', 'Gene', '2146', (117, 121))	('miR-98', 'Gene', '407054', (17, 23))	('inhibited', 'NegReg', (65, 74))	('miR-98', 'Gene', (17, 23))	('miR-214', 'Gene', (28, 35))	('overexpression', 'Var', (36, 50))	('repressing', 'NegReg', (106, 116))
221161	22867052	Mutant EZH2 3'-UTR, which carried a substitution of four nucleotides (AGGU to UCCA for miR-98, UACU to AUGA for miR-101, and CAGC to GUCG for miR-214) within the core binding sites of EZH2 3'-UTR, was obtained using overlapping extension PCR.	('miR-214', 'Gene', (142, 149))	('miR-98', 'Gene', (87, 93))	('substitution', 'Var', (36, 48))	('EZH2', 'Gene', '2146', (7, 11))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('CAGC', 'Gene', '6283', (125, 129))	('EZH2', 'Gene', (7, 11))	('miR-214', 'Gene', '406996', (142, 149))	('EZH2', 'Gene', '2146', (184, 188))	('CAGC', 'Gene', (125, 129))	('miR', 'Gene', '220972', (142, 145))	('miR', 'Gene', (142, 145))	('EZH2', 'Gene', (184, 188))	('miR', 'Gene', (87, 90))	('miR', 'Gene', '220972', (87, 90))	('miR-98', 'Gene', '407054', (87, 93))
221162	22867052	Normal (or mutant) EZH2 3'-UTR was cloned into the SacI-HindIII site of the pMIR-REPORT luciferase vector (Biosystems) and named as Luc-EZH2 (or Luc-EZH2-mut).	('EZH2', 'Gene', (136, 140))	('EZH2', 'Gene', '2146', (136, 140))	('mutant', 'Var', (11, 17))	('EZH2', 'Gene', '2146', (149, 153))	('EZH2', 'Gene', '2146', (19, 23))	('EZH2', 'Gene', (149, 153))	('EZH2', 'Gene', (19, 23))
221211	21483813	A significant association was also identified between the densities of IL-17+ TILs and CD57+ NK cells (r = 0.261, P<0.001, Figure 4B).	('CD57', 'Gene', (87, 91))	('CD57', 'Gene', '27087', (87, 91))	('IL-17+', 'Var', (71, 77))
221219	21483813	Our results are consistent with those of Kryczek et al, who demonstrated that the presence of IL-17+TILs correlated with favorable outcome in and enhanced survival of ovarian cancer patients.	('ovarian cancer', 'Disease', 'MESH:D010051', (167, 181))	('survival', 'CPA', (155, 163))	('ovarian cancer', 'Disease', (167, 181))	('ovarian cancer', 'Phenotype', 'HP:0100615', (167, 181))	('presence', 'Var', (82, 90))	('IL-17+TILs', 'Protein', (94, 104))	('enhanced', 'PosReg', (146, 154))	('patients', 'Species', '9606', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
221254	20865050	However, we found that trastuzumab and HER-2 specific CTLs act synergistically in inducing tumor lysis in OE33 but not in OE19.	('trastuzumab', 'Chemical', 'MESH:D000068878', (23, 34))	('OE33', 'Var', (106, 110))	('OE33', 'Chemical', '-', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('inducing', 'PosReg', (82, 90))	('tumor', 'Disease', (91, 96))	('CTLs', 'Gene', (54, 58))
221257	20865050	Importantly, we demonstrated that by inducing re-expression of TAP-2 in OE19 with INF-gamma treatment or by incubating the cells with INF-gamma producing CTLs, the specific anti HER-2 CTL tumor lysis response and synergistic effect with trastuzumab can be restored.	('tumor', 'Disease', (188, 193))	('trastuzumab', 'Chemical', 'MESH:D000068878', (237, 248))	('TAP-2', 'Gene', (63, 68))	('anti HER-2', 'Var', (173, 183))	('TAP-2', 'Gene', '6891', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('inducing', 'Reg', (37, 45))
221261	20865050	It is overexpressed, mostly via gene amplification, in several aggressive cancers, such as in 25-30% of ovarian and breast cancers, 35-45% of pancreatic carcinomas, and in 30-80% of EAC.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('aggressive cancers', 'Disease', (63, 81))	('EAC', 'Phenotype', 'HP:0011459', (182, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('aggressive cancers', 'Disease', 'MESH:D009369', (63, 81))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (142, 163))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('pancreatic carcinomas', 'Disease', (142, 163))	('breast cancers', 'Phenotype', 'HP:0003002', (116, 130))	('EAC', 'Disease', (182, 185))	('ovarian and breast cancers', 'Disease', 'MESH:D010051', (104, 130))	('gene amplification', 'Var', (32, 50))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
221283	20865050	Investigation of the status of several components of the Antigen Processing Machinery (APM) in this cell line and in EAC tumor biopsy specimens showed that the expression of one of the most important components of the APM, the Transporter Associated with Antigen Processing-2 (TAP-2) is specifically down regulated in OE19 and also in a high percentage of EAC.	('Antigen Processing Machinery', 'Gene', '290', (57, 85))	('TAP-2', 'Gene', (277, 282))	('expression', 'MPA', (160, 170))	('APM', 'Gene', (87, 90))	('Antigen Processing Machinery', 'Gene', (57, 85))	('TAP-2', 'Gene', '6891', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('APM', 'Gene', '290', (218, 221))	('EAC', 'Phenotype', 'HP:0011459', (356, 359))	('tumor', 'Disease', (121, 126))	('down regulated', 'NegReg', (300, 314))	('APM', 'Gene', (218, 221))	('EAC', 'Phenotype', 'HP:0011459', (117, 120))	('EAC', 'Disease', (356, 359))	('APM', 'Gene', '290', (87, 90))	('OE19', 'Var', (318, 322))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
221340	20865050	Determination of the HER-2 status in the OE33, OE19 EAC cell lines and SW620 by DNA FISH revealed that OE33 and OE19 are characterized by a high HER-2 amplification as compared to SW620 that only showed polysomy of chromosome 17 (Fig.1A, Table 1).	('HER-2', 'Protein', (145, 150))	('SW620', 'CellLine', 'CVCL:0547', (71, 76))	('OE19', 'Var', (112, 116))	('OE33', 'Chemical', '-', (41, 45))	('amplification', 'MPA', (151, 164))	('OE33', 'Var', (103, 107))	('SW620', 'CellLine', 'CVCL:0547', (180, 185))	('OE33', 'Chemical', '-', (103, 107))	('EAC', 'Phenotype', 'HP:0011459', (52, 55))
221344	20865050	Cells, which were not treated with trastuzumab, showed a basal cell viability of on average 0.21+-0.02SEM for OE33 and on average 0.34+-0.02SEM for OE19.	('trastuzumab', 'Chemical', 'MESH:D000068878', (35, 46))	('OE19', 'Var', (148, 152))	('OE33', 'Var', (110, 114))	('OE33', 'Chemical', '-', (110, 114))	('basal cell viability', 'CPA', (57, 77))
221345	20865050	Incubations for 24 and 72 hours with trastuzumab already showed significant reductions in cell growth in OE33 and OE19 at a dosage of 2.5 microg of trastuzumab (Paired T-test, p<0.05).	('reductions', 'NegReg', (76, 86))	('trastuzumab', 'Chemical', 'MESH:D000068878', (37, 48))	('OE33', 'Chemical', '-', (105, 109))	('trastuzumab', 'Chemical', 'MESH:D000068878', (148, 159))	('OE19', 'Var', (114, 118))	('trastuzumab', 'Var', (37, 48))	('cell growth', 'CPA', (90, 101))
221381	20865050	It is well known that deficiencies in the expression of APM components can hinder or entirely abolish anticancer immune-responses by preventing proper CTL-induced cell lysis as a consequence of a reduced level of MHC-Class I antigen presentation.	('deficiencies', 'Var', (22, 34))	('abolish', 'NegReg', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('APM', 'Gene', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('MHC-Class I antigen presentation', 'MPA', (213, 245))	('preventing', 'NegReg', (133, 143))	('proper CTL-induced cell lysis', 'CPA', (144, 173))	('hinder', 'NegReg', (75, 81))	('APM', 'Gene', '290', (56, 59))	('reduced', 'NegReg', (196, 203))
221388	20865050	In our study, we examined the HER-2 status of several EAC cell lines and showed that OE33 and OE19 are characterized by high levels of HER-2 gene amplification, confirming previous findings, whereas SW620, a HLA-A2 positive colon cancer cell line taken as control, is characterized by only polysomy of chromosome 17.	('colon cancer', 'Disease', (224, 236))	('EAC', 'Phenotype', 'HP:0011459', (54, 57))	('SW620', 'CellLine', 'CVCL:0547', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('OE33', 'Var', (85, 89))	('OE33', 'Chemical', '-', (85, 89))	('colon cancer', 'Phenotype', 'HP:0003003', (224, 236))	('OE19', 'Var', (94, 98))	('colon cancer', 'Disease', 'MESH:D015179', (224, 236))	('HER-2', 'Protein', (135, 140))
221389	20865050	As expected trastuzumab significantly reduce cell viability and proliferation in OE33 and OE19 as compared to not treated samples, whereas SW620 is not affected by trastuzumab.	('trastuzumab', 'Chemical', 'MESH:D000068878', (164, 175))	('OE33', 'Chemical', '-', (81, 85))	('cell viability', 'CPA', (45, 59))	('reduce', 'NegReg', (38, 44))	('OE19', 'Var', (90, 94))	('trastuzumab', 'Chemical', 'MESH:D000068878', (12, 23))	('SW620', 'CellLine', 'CVCL:0547', (139, 144))
221390	20865050	In contrast, we found that trastuzumab treatment does not result in an increase in apoptosis of OE33 and OE19, confirming prior observations.	('OE33', 'Var', (96, 100))	('OE19', 'Var', (105, 109))	('OE33', 'Chemical', '-', (96, 100))	('trastuzumab', 'Chemical', 'MESH:D000068878', (27, 38))
221393	20865050	Amongst the APM components, the Transporter associated with Antigen Processing 1 and 2 (TAP-1 and 2) polymorphisms and mutations are associated with hindered anticancer responses and poor patient prognosis.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('APM', 'Gene', '290', (12, 15))	('cancer', 'Disease', (162, 168))	('patient', 'Species', '9606', (188, 195))	('APM', 'Gene', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('hindered', 'NegReg', (149, 157))	('TAP-1 and 2', 'Gene', '6890;6891', (88, 99))	('mutations', 'Var', (119, 128))	('polymorphisms', 'Var', (101, 114))
221407	20865050	Finally, it is important to note that NK cells might also be involved in the response of the patient to trastuzumab as treatment of OE33 with trastuzumab increases HER-2 positive PBMCs induced antibody-dependent cell-mediated cytotoxicity (ADCC) on OE33 as compared to untreated cells.	('increases', 'PosReg', (154, 163))	('OE33', 'Chemical', '-', (249, 253))	('cytotoxicity', 'Disease', 'MESH:D064420', (226, 238))	('cytotoxicity', 'Disease', (226, 238))	('trastuzumab', 'Chemical', 'MESH:D000068878', (104, 115))	('trastuzumab', 'Chemical', 'MESH:D000068878', (142, 153))	('patient', 'Species', '9606', (93, 100))	('OE33', 'Var', (132, 136))	('OE33', 'Chemical', '-', (132, 136))	('HER-2 positive', 'Protein', (164, 178))
221497	31564713	Maf deficiency induces down-regulation of vascular cell adhesion molecule 1 in fetal liver macrophages and abrogates erythropoiesis in fetal liver.	('Maf', 'Gene', (0, 3))	('abrogates', 'NegReg', (107, 116))	('vascular cell adhesion molecule 1', 'Gene', '7412', (42, 75))	('vascular cell adhesion molecule 1', 'Gene', (42, 75))	('down-regulation', 'NegReg', (23, 38))	('deficiency', 'Var', (4, 14))	('erythropoiesis', 'MPA', (117, 131))
221501	31564713	In a study using a murine model, Maf overexpression in T lymphocytes induced the development of T-cell lymphoma, suggesting that Maf protein leads to malignant transformation in T lymphocytes.	('murine', 'Species', '10090', (19, 25))	('leads to', 'Reg', (141, 149))	('malignant transformation', 'CPA', (150, 174))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (96, 111))	('cell lymphoma', 'Phenotype', 'HP:0012191', (98, 111))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (96, 111))	('overexpression', 'Var', (37, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('T-cell lymphoma', 'Disease', (96, 111))	('induced', 'Reg', (69, 76))
221518	31564713	Macrophages (2 x 105/well) were then seeded on glass coverslips in a 12-well plate and stimulated with interleukin (IL)-10 (#093-04651, 10 ng/mL, WAKO), interferon (IFN)-alpha (#11200-2, 10 ng/mL, R&D Systems, Minneapolis, MN, USA), IFN-gamma (#IFG4001, 10 ng/mL, WAKO), or lipopolysaccharide (LPS) (#L2654, 100 ng/mL, Sigma, St. Louis, MO, USA) for 1 day.	('IFN-gamma', 'Gene', (233, 242))	('interferon (IFN)-alpha', 'Gene', (153, 175))	(') (#', 'Var', (297, 301))	('interleukin (IL)-10', 'Gene', (103, 122))	('interferon (IFN)-alpha', 'Gene', '3439', (153, 175))	('#11200-2', 'Var', (177, 185))	('interleukin (IL)-10', 'Gene', '3586', (103, 122))	('#093-04651', 'Var', (124, 134))	('IFN-gamma', 'Gene', '3458', (233, 242))
221532	31564713	We also previously showed that expression of indoleamine 2,3-dioxygenase in human monocyte-derived macrophages was elevated by IFN-alpha, IFN-beta, IFN-gamma, and LPS, with the most significant up-regulation induced by IFN-gamma.	('IFN-gamma', 'Gene', (219, 228))	('elevated', 'PosReg', (115, 123))	('IFN-gamma', 'Gene', '3458', (148, 157))	('IFN-gamma', 'Gene', (148, 157))	('up-regulation', 'PosReg', (194, 207))	('IFN-beta', 'Gene', '3456', (138, 146))	('human', 'Species', '9606', (76, 81))	('expression', 'MPA', (31, 41))	('IFN-alpha', 'Gene', '3439', (127, 136))	('IFN-alpha', 'Gene', (127, 136))	('LPS', 'Var', (163, 166))	('IFN-beta', 'Gene', (138, 146))	('indoleamine', 'Chemical', 'None', (45, 56))	('IFN-gamma', 'Gene', '3458', (219, 228))
221610	29909977	Moreover, EBRT may aggravate airway obstruction related to early tumor edema.	('airway obstruction', 'Disease', (29, 47))	('EBRT', 'Var', (10, 14))	('tumor edema', 'Disease', 'MESH:D004487', (65, 76))	('aggravate', 'PosReg', (19, 28))	('EBRT', 'Chemical', '-', (10, 14))	('edema', 'Phenotype', 'HP:0000969', (71, 76))	('airway obstruction', 'Phenotype', 'HP:0002781', (29, 47))	('tumor edema', 'Disease', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
221668	30083064	The overall Ohio EAC incidence rate for men was significantly higher in Ohio than SEER (6.6 and 4.9 per 100 000 men, respectively).	('men', 'Species', '9606', (112, 115))	('EAC', 'Phenotype', 'HP:0011459', (17, 20))	('higher', 'PosReg', (62, 68))	('men', 'Species', '9606', (40, 43))	('Ohio EAC', 'Disease', (12, 20))	('Ohio', 'Var', (72, 76))
221669	30083064	For white men, the EAC incidence rate was significantly higher in Ohio compared with SEER (7.1 and 5.7 per 100 000, respectively).	('men', 'Species', '9606', (10, 13))	('EAC', 'Phenotype', 'HP:0011459', (19, 22))	('EAC', 'Disease', (19, 22))	('Ohio', 'Var', (66, 70))	('higher', 'PosReg', (56, 62))
221671	30083064	The incidence rate of EAC was significantly higher in Ohio women compared with US women (1.0 and 0.6 per 100 000, respectively).	('Ohio', 'Var', (54, 58))	('higher', 'PosReg', (44, 50))	('EAC', 'Disease', (22, 25))	('women', 'Species', '9606', (82, 87))	('women', 'Species', '9606', (59, 64))	('EAC', 'Phenotype', 'HP:0011459', (22, 25))
221676	30083064	The EAC incidence rate for Ohio men was greater than SEER men each year during this 18-year period.	('men', 'Species', '9606', (32, 35))	('EAC', 'Phenotype', 'HP:0011459', (4, 7))	('Ohio', 'Var', (27, 31))	('EAC', 'Disease', (4, 7))	('men', 'Species', '9606', (58, 61))
221678	30083064	However, the increase in the EAC incidence rate was greater in Ohio compared with SEER for both men (Ohio 38% vs United States 15%) and women (Ohio 33% vs United States 17%).	('men', 'Species', '9606', (96, 99))	('EAC', 'Phenotype', 'HP:0011459', (29, 32))	('men', 'Species', '9606', (138, 141))	('EAC', 'Disease', (29, 32))	('women', 'Species', '9606', (136, 141))	('Ohio', 'Var', (63, 67))
221738	26602969	In an ANCOVA analysis, MIE was independently associated with a shorter hospital stay compared to OE (estimated mean difference 1.57 +- 0.53 days, p = 0.003).	('shorter', 'NegReg', (63, 70))	('hospital stay', 'MPA', (71, 84))	('MIE', 'Var', (23, 26))	('OE', 'Chemical', '-', (97, 99))	('MIE', 'Chemical', '-', (23, 26))
221770	26602969	There was no difference in the rate of positive margins, but the median number of nodes examined in the surgical specimen was higher with MIE compared to OE (14 vs 12, p < 0.001).	('MIE', 'Chemical', '-', (138, 141))	('higher', 'PosReg', (126, 132))	('OE', 'Chemical', '-', (154, 156))	('MIE', 'Var', (138, 141))
221771	26602969	Median hospital LOS was also shorter with MIE compared to OE (10.0 days vs 11.0 days, p < 0.001).	('shorter', 'NegReg', (29, 36))	('MIE', 'Chemical', '-', (42, 45))	('MIE', 'Var', (42, 45))	('OE', 'Chemical', '-', (58, 60))
221790	26602969	Multiple other institutional studies showed a wide range of outcomes in terms of mortality and anastomotic leak rate among MIE patients, but not consistently as low as open esophagectomies from Orringer's series.	('anastomotic leak', 'Disease', 'MESH:D057868', (95, 111))	('anastomotic leak', 'Disease', (95, 111))	('mortality', 'CPA', (81, 90))	('patients', 'Species', '9606', (127, 135))	('MIE', 'Chemical', '-', (123, 126))	('MIE', 'Var', (123, 126))
221809	26602969	In the only randomized trial comparing OE and MIE, there were less pulmonary compications with MIE, which was reflected in the shorter hospital LOS by 3 days (14 vs 11 days).	('MIE', 'Chemical', '-', (46, 49))	('MIE', 'Chemical', '-', (95, 98))	('MIE', 'Var', (95, 98))	('pulmonary compications', 'Disease', (67, 89))	('OE', 'Chemical', '-', (39, 41))	('less', 'NegReg', (62, 66))
221822	26602969	MIE may be associated with a slightly shorter hospital length of stay compared to open esophagectomy.	('MIE', 'Chemical', '-', (0, 3))	('MIE', 'Var', (0, 3))	('shorter', 'NegReg', (38, 45))
221823	27723786	Genetic Polymorphisms in the Apoptosis-Associated Gene CASP3 and the Risk of Lung Cancer in Chinese Population Caspase-3 (CASP3) plays a central role in executing cell apoptosis and thus in carcinogenesis.	('carcinogenesis', 'Disease', (190, 204))	('CASP3', 'Gene', (122, 127))	('carcinogenesis', 'Disease', 'MESH:D063646', (190, 204))	('Lung Cancer', 'Disease', (77, 88))	('Lung Cancer', 'Disease', 'MESH:D008175', (77, 88))	('Lung Cancer', 'Phenotype', 'HP:0100526', (77, 88))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Caspase-3', 'Gene', (111, 120))	('CASP3', 'Gene', '836', (55, 60))	('CASP3', 'Gene', (55, 60))	('Caspase-3', 'Gene', '836', (111, 120))	('CASP3', 'Gene', '836', (122, 127))	('cell apoptosis', 'CPA', (163, 177))	('Polymorphisms', 'Var', (8, 21))
221824	27723786	We previously investigated the relationship between functional polymorphisms in CAPS3 829 A>C and 20541 C>T and risk of esophageal squamous cell carcinoma.	('20541 C>T', 'Var', (98, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('20541 C>T', 'Mutation', 'rs1049216', (98, 107))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('829 A>C', 'Mutation', 'rs4647602', (86, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('CAPS3 829 A>C', 'Var', (80, 93))
221825	27723786	However little is known about the role of CASP3 variants in susceptibility to lung cancer.	('lung cancer', 'Disease', (78, 89))	('CASP3', 'Gene', '836', (42, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('variants', 'Var', (48, 56))	('CASP3', 'Gene', (42, 47))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))
221829	27723786	To further explore the possible impact of 829 A>C SNP on CASP3 transcriptional activity, we detected the dual luciferase activity of PGL3-promoter vectors containing 829A or 829C alleles in lung cancer cell lines and found that report gene expressions driven by 829A containing CASP3 promoter were 1.64-fold, 1.94-fold greater than those driven by CASP3 829C containing counterparts in A549 and NCI-H1975 cells (P<0.001).	('CASP3', 'Gene', (57, 62))	('PGL3', 'Gene', '6391', (133, 137))	('CASP3', 'Gene', '836', (278, 283))	('PGL3', 'Gene', (133, 137))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('NCI-H1975', 'CellLine', 'CVCL:1511', (395, 404))	('A549', 'CellLine', 'CVCL:0023', (386, 390))	('CASP3', 'Gene', (278, 283))	('829A', 'Var', (262, 266))	('CASP3', 'Gene', '836', (348, 353))	('CASP3', 'Gene', (348, 353))	('CASP3', 'Gene', '836', (57, 62))	('greater', 'PosReg', (319, 326))	('829 A>C', 'Mutation', 'rs4647602', (42, 49))	('lung cancer', 'Disease', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
221832	27723786	We also found that 829AC or 829CC genotype increased adenocarcinoma risk compared with the AA genotype with OR (95%CI) of 1.33 (1.04-1.70) and 1.51(1.09-2.07).	('adenocarcinoma', 'Disease', (53, 67))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('829AC', 'Var', (19, 24))	('increased', 'PosReg', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('829CC', 'Var', (28, 33))
221833	27723786	CASP3 polymorphism and smoking interaction was demonstrated related with higher risk of lung cancer.	('polymorphism', 'Var', (6, 18))	('CASP3', 'Gene', (0, 5))	('lung cancer', 'Disease', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('CASP3', 'Gene', '836', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
221835	27723786	Among carriers with 20541CT genotype, the ORs (95%CI) of risk with lung cancer for smoking <16, 16-28, or > 28 pack-years were 1.16(0.65-2.07), 1.66(0.98-2.82) and 5.01(3.31-7.58) compared with the 20541CC carriers.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('20541CT', 'Var', (20, 27))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
221836	27723786	These results highlight apoptosis-related CASP3 as an important gene in human carcinogenesis and further support the CASP3 polymorphisms confer to the lung cancer susceptibility.	('CASP3', 'Gene', '836', (42, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('CASP3', 'Gene', '836', (117, 122))	('CASP3', 'Gene', (117, 122))	('CASP3', 'Gene', (42, 47))	('polymorphisms', 'Var', (123, 136))	('carcinogenesis', 'Disease', (78, 92))	('human', 'Species', '9606', (72, 77))	('lung cancer', 'Disease', (151, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))
221842	27723786	Therefore apoptosis may cause the somatic mutations and now thought to contribute to a number of human diseases, ranging from neurodegenerative disorders to malignancy.	('malignancy', 'Disease', 'MESH:D009369', (157, 167))	('malignancy', 'Disease', (157, 167))	('contribute', 'Reg', (71, 81))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (126, 153))	('cause', 'Reg', (24, 29))	('human', 'Species', '9606', (97, 102))	('apoptosis', 'CPA', (10, 19))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (126, 153))	('neurodegenerative disorders', 'Disease', (126, 153))	('mutations', 'Var', (42, 51))
221851	27723786	CASP3 mutations were detected many types of tumor, including colon carcinomas, non-small cell lung cancers, non-Hodgkin lymphomas, stomach carcinomas, hepatocellular carcinomas, and multiple myelomas.	('non-small cell lung cancers', 'Disease', (79, 106))	('lung cancers', 'Phenotype', 'HP:0100526', (94, 106))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (79, 106))	('stomach carcinomas', 'Disease', (131, 149))	('non-Hodgkin lymphomas', 'Disease', (108, 129))	('stomach carcinomas', 'Disease', 'MESH:D013274', (131, 149))	('tumor', 'Disease', (44, 49))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (151, 176))	('CASP3', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (151, 176))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (83, 106))	('CASP3', 'Gene', '836', (0, 5))	('mutations', 'Var', (6, 15))	('non-Hodgkin lymphomas', 'Phenotype', 'HP:0012539', (108, 129))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (79, 106))	('hepatocellular carcinomas', 'Disease', (151, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('non-Hodgkin lymphomas', 'Disease', 'MESH:D008228', (108, 129))	('lymphomas', 'Phenotype', 'HP:0002665', (120, 129))	('multiple myelomas', 'Phenotype', 'HP:0006775', (182, 199))	('Hodgkin lymphomas', 'Phenotype', 'HP:0012189', (112, 129))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('colon carcinomas', 'Disease', (61, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('multiple myelomas', 'Disease', (182, 199))	('multiple myelomas', 'Disease', 'MESH:D009101', (182, 199))	('detected', 'Reg', (21, 29))	('colon carcinomas', 'Disease', 'MESH:D015179', (61, 77))
221853	27723786	They identified three single nucleotide polymorphisms (SNPs), 829 A>C, 17532 A>C, and 20541 C>T, which located in 5'-regulatory region, intron 4, and 3'-regulatory region of CASP3, respectively.	('17532 A>C', 'Var', (71, 80))	('20541 C>T', 'Mutation', 'rs1049216', (86, 95))	('17532 A>C', 'Mutation', 'g.17532A>C', (71, 80))	('CASP3', 'Gene', (174, 179))	('829 A>C', 'Mutation', 'rs4647602', (62, 69))	('20541 C>T', 'Var', (86, 95))	('829 A>C', 'Var', (62, 69))	('CASP3', 'Gene', '836', (174, 179))
221855	27723786	Based on these, we final investigated CASP3 829 A>C and 20541 C>T polymorphisms in this lung cancer case-control study.	('investigated', 'Reg', (25, 37))	('lung cancer', 'Disease', (88, 99))	('CASP3', 'Gene', '836', (38, 43))	('829 A>C', 'Mutation', 'rs4647602', (44, 51))	('CASP3', 'Gene', (38, 43))	('829 A>C', 'Var', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('20541 C>T', 'Var', (56, 65))	('20541 C>T', 'Mutation', 'rs1049216', (56, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
221866	27723786	Briefly, to produce CASP3 region containing the 829 A>C (rs4647602) site, the PCR primer pairs was 5'-TAG TTG CAG GGT TTA AAC TCC AAT GC-3' and 5'-CTA ACT CCT CAC GGC CTG GGA T-3'.	('AAT', 'Gene', (130, 133))	('CASP3', 'Gene', (20, 25))	('829 A>C', 'Mutation', 'rs4647602', (48, 55))	('AAT', 'Gene', '5265', (130, 133))	('CCT', 'Gene', (155, 158))	('rs4647602', 'Mutation', 'rs4647602', (57, 66))	('CASP3', 'Gene', '836', (20, 25))	('rs4647602', 'Var', (57, 66))	('CCT', 'Gene', '907', (155, 158))
221867	27723786	The primer pairs used to amplify CASP3 20541 C>T (rs1049216) was 5'-GTG AAA AAG TTA AAC ATT GAA TTA A-3' and 5'-TTC TTC CAC ATC ATC ATT TCT A-3'.	('20541 C>T', 'Mutation', 'rs1049216', (39, 48))	('20541 C>T (rs1049216', 'Var', (39, 59))	('CASP3', 'Gene', '836', (33, 38))	('rs1049216', 'Var', (50, 59))	('CASP3', 'Gene', (33, 38))	('rs1049216', 'Mutation', 'rs1049216', (50, 59))
221871	27723786	The 829C allele had one BglI restriction site that resulted in two bands (112 bp and 25 bp) and the 20541C allele had one AseI restriction site that resulted in two bands of 82 bp and 21 bp.	('829C', 'Var', (4, 8))	('AseI', 'Chemical', '-', (122, 126))	('resulted in', 'Reg', (51, 62))	('20541C', 'Var', (100, 106))
221872	27723786	The CASP3 829 A>C and 20541 C>T genotypes revealed by PCR-RFLP analysis were further confirmed by direct DNA sequencing (Figs 1B and 2B).	('20541 C>T', 'Var', (22, 31))	('CASP3', 'Gene', (4, 9))	('20541 C>T', 'Mutation', 'rs1049216', (22, 31))	('829 A>C', 'Mutation', 'rs4647602', (10, 17))	('CASP3', 'Gene', '836', (4, 9))
221875	27723786	To produce the luciferase construct containing the 829A allele, a pair of primers 5'-GGT TTAAAC TCCAATTCATTT TCGGCC C-3' and 5'-GAA TTG GAGTTTAAACCC TGCAACTATCTC-3' was used to make the single site mutagenesis (Invitrogen, Carlsbad, CA, USA).	('mutagenesis', 'Var', (198, 209))	('AAT', 'Gene', (99, 102))	('AAT', 'Gene', '5265', (99, 102))
221885	27723786	Table 2 displayed that the genotype distributions of CASP3 829 A>C and 20541 C>T in the cases and controls respectively.	('20541 C>T', 'Var', (71, 80))	('20541 C>T', 'Mutation', 'rs1049216', (71, 80))	('829 A>C', 'Mutation', 'rs4647602', (59, 66))	('CASP3', 'Gene', '836', (53, 58))	('CASP3', 'Gene', (53, 58))
221886	27723786	All observed genotype frequencies of 829 A>C and 20541 C>T in the controls conform to Hardy Weinberg equilibrium (P = 0.915 and P = 0.078, respectively).	('829 A>C', 'Var', (37, 44))	('829 A>C', 'Mutation', 'rs4647602', (37, 44))	('20541 C>T', 'Mutation', 'rs1049216', (49, 58))	('20541 C>T', 'Var', (49, 58))
221888	27723786	No significant changed risk of lung cancer was found to relate to the 20541 C>T genotype.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('20541 C>T', 'Var', (70, 79))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('20541 C>T', 'Mutation', 'rs1049216', (70, 79))
221890	27723786	We operated a multivariate regression model to obtain the association between CASP3 829A>C and 20541 C>T genotypes and risk of lung cancer with adjustment for age, gender and smoking status.	('lung cancer', 'Disease', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('20541 C>T', 'Var', (95, 104))	('20541 C>T', 'Mutation', 'rs1049216', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('829A>C', 'Mutation', 'rs4647602', (84, 90))	('CASP3', 'Gene', '836', (78, 83))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('CASP3', 'Gene', (78, 83))
221893	27723786	We found that 829AC or 829CC genotype increased adenocarcinoma risk compared with the AA genotype with OR (95%CI) of 1.33 (1.04-1.70) and 1.51(1.09-2.07).	('829CC', 'Var', (23, 28))	('adenocarcinoma', 'Disease', (48, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('829AC', 'Var', (14, 19))	('adenocarcinoma', 'Disease', 'MESH:D000230', (48, 62))	('increased', 'PosReg', (38, 47))
221897	27723786	Moreover, these variant genotypes were significantly associated with a two- or three-fold increased risk of lung cancer in smokers (OR = 2.68, 95%CI = 1.89-3.81; OR = 3.23, 95%CI = 2.21-4.92).	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('variant', 'Var', (16, 23))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
221898	27723786	To explored the possible impact of 829 A>C SNP on CASP3 transcriptional activity, we constructed promoter vectors containing 829A or 829C alleles and dual luciferase assay was carried out in lung cancer cell lines, A549 and NCI-H1975.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('829A', 'Var', (125, 129))	('NCI-H1975', 'CellLine', 'CVCL:1511', (224, 233))	('A549', 'CellLine', 'CVCL:0023', (215, 219))	('829C', 'Var', (133, 137))	('lung cancer', 'Disease', (191, 202))	('829 A>C', 'Mutation', 'rs4647602', (35, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('CASP3', 'Gene', '836', (50, 55))	('CASP3', 'Gene', (50, 55))
221899	27723786	Report gene expressions driven by 829A containing CASP3 promoter were 1.64-fold, 1.94-fold greater than those driven by CASP 829C containing counterparts in A549 and NCI-H1975 cells (P<0.001) (Fig 3).	('NCI-H1975', 'CellLine', 'CVCL:1511', (166, 175))	('A549', 'CellLine', 'CVCL:0023', (157, 161))	('829A', 'Var', (34, 38))	('CASP', 'Gene', (50, 54))	('CASP', 'Gene', (120, 124))	('CASP3', 'Gene', (50, 55))	('CASP', 'Gene', '10491', (50, 54))	('greater', 'PosReg', (91, 98))	('CASP3', 'Gene', '836', (50, 55))	('Report gene expressions', 'MPA', (0, 23))	('CASP', 'Gene', '10491', (120, 124))
221900	27723786	These results suggest that the 829 A>C polymorphism influences CASP3 promoter activity.	('CASP3', 'Gene', (63, 68))	('influences', 'Reg', (52, 62))	('829 A>C', 'Mutation', 'rs4647602', (31, 38))	('829 A>C', 'Var', (31, 38))	('CASP3', 'Gene', '836', (63, 68))
221902	27723786	In the current study, we investigated the potential association of CASP3 polymorphisms (829 A>C and 20541 C>T) and with the risk of lung cancer in Chinese population.	('20541 C>T', 'Mutation', 'rs1049216', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('829 A>C', 'Mutation', 'rs4647602', (88, 95))	('association', 'Interaction', (52, 63))	('829 A>C', 'Var', (88, 95))	('CASP3', 'Gene', '836', (67, 72))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('20541 C>T', 'Var', (100, 109))	('CASP3', 'Gene', (67, 72))
221909	27723786	Some research demonstrated the mutation of CASP3 existed in human tumor tissues and cell lines as expected.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CASP3', 'Gene', (43, 48))	('tumor', 'Disease', (66, 71))	('mutation', 'Var', (31, 39))	('CASP3', 'Gene', '836', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('human', 'Species', '9606', (60, 65))
221912	27723786	Mandruzzato and Wang have reported that a large number of caspases mutations in human tumor cells, which caused reduced apoptotic activities.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('caspases', 'Gene', '834;839;841;842;843', (58, 66))	('mutations', 'Var', (67, 76))	('caspases', 'Gene', (58, 66))	('human', 'Species', '9606', (80, 85))	('apoptotic activities', 'CPA', (120, 140))	('reduced', 'NegReg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
221913	27723786	It suggested that the mutation of CASP3 was particularly prone to occur in human cancer tissues, or CASP3 mutation genotype resulted in carcinogenesis.	('CASP3', 'Gene', '836', (34, 39))	('mutation', 'Var', (22, 30))	('CASP3', 'Gene', (34, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('CASP3', 'Gene', '836', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('mutation', 'Var', (106, 114))	('cancer', 'Disease', (81, 87))	('carcinogenesis', 'Disease', (136, 150))	('CASP3', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (75, 80))	('resulted in', 'Reg', (124, 135))
221915	27723786	It is possible that this CASP3 mutation may have resulted that the target tissue operated the apoptosis disadvantageously and thus raised the potential risk of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('disadvantageously', 'NegReg', (104, 121))	('CASP3', 'Gene', '836', (25, 30))	('carcinogenesis', 'Disease', (160, 174))	('operated', 'Reg', (81, 89))	('mutation', 'Var', (31, 39))	('CASP3', 'Gene', (25, 30))	('apoptosis', 'CPA', (94, 103))
221917	27723786	One study determined nine potentially functional polymorphisms in the Caspase on survival of early-stage NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('NSCLC', 'Disease', (105, 110))	('polymorphisms', 'Var', (49, 62))	('Caspase', 'Protein', (70, 77))	('patients', 'Species', '9606', (111, 119))
221918	27723786	Their conclusion was that the CASP7 rs2227310 and CASP9 rs4645981 polymorphisms may affect survival in early-stage NSCLC.	('CASP7', 'Gene', (30, 35))	('rs4645981', 'Var', (56, 65))	('NSCLC', 'Disease', (115, 120))	('rs2227310', 'Mutation', 'rs2227310', (36, 45))	('affect', 'Reg', (84, 90))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('CASP9', 'Gene', (50, 55))	('CASP7', 'Gene', '840', (30, 35))	('CASP9', 'Gene', '842', (50, 55))	('rs4645981', 'Mutation', 'rs4645981', (56, 65))	('rs2227310', 'Var', (36, 45))	('survival', 'Disease', (91, 99))
221919	27723786	Some association studies have suggested possible links between CASP3 polymorphism and the susceptibility to several of cancers, including endometrial cancer, prostrate cancer and head and neck cancer.	('polymorphism', 'Var', (69, 81))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('head and neck cancer', 'Phenotype', 'HP:0012288', (179, 199))	('CASP3', 'Gene', (63, 68))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('association', 'Interaction', (5, 16))	('CASP3', 'Gene', '836', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('endometrial cancer', 'Phenotype', 'HP:0012114', (138, 156))	('head and neck cancer', 'Disease', 'MESH:D006258', (179, 199))	('endometrial cancer', 'Disease', (138, 156))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('endometrial cancer', 'Disease', 'MESH:D016889', (138, 156))	('links', 'Interaction', (49, 54))
221920	27723786	One case-control study was demonstrated that CASP3 rs4647601 TT genotype was related with an increased dangerous impact of squamous cell carcinoma of the Head and Neck.	('squamous cell carcinoma', 'Disease', (123, 146))	('CASP3', 'Gene', '836', (45, 50))	('rs4647601', 'Mutation', 'rs4647601', (51, 60))	('CASP3', 'Gene', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('rs4647601', 'Var', (51, 60))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 146))
221921	27723786	A meta-analysis showed that the homozygote (CC) of rs2705897 (A/C) in the CASP3 gene had a positive association with cancer susceptibility.	('rs2705897', 'Mutation', 'rs2705897', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rs2705897', 'Var', (51, 60))	('CASP3', 'Gene', '836', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('CASP3', 'Gene', (74, 79))
221922	27723786	demonstrated that individuals carried at least one variant allele of the CASP3 -928A>G, 77G>A, and 17532A>C polymorphisms contributed to the genetic susceptibility to lung cancer.	('17532A>C', 'Var', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('77G>A', 'Mutation', 'c.77G>A', (88, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('17532A>C', 'Mutation', 'g.17532A>C', (99, 107))	('CASP3', 'Gene', '836', (73, 78))	('-928A>G', 'Mutation', 'rs751529936', (79, 86))	('susceptibility', 'Reg', (149, 163))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('CASP3', 'Gene', (73, 78))	('77G>A', 'Var', (88, 93))
221923	27723786	Similarity, our present study showed that functional CASP3 829 A>C polymorphism, another significant SNP of CASP3, increased the susceptibility of lung cancer.	('829 A>C polymorphism', 'Var', (59, 79))	('increased', 'PosReg', (115, 124))	('lung cancer', 'Disease', (147, 158))	('CASP3', 'Gene', '836', (108, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('CASP3', 'Gene', '836', (53, 58))	('CASP3', 'Gene', (108, 113))	('CASP3', 'Gene', (53, 58))	('829 A>C', 'Mutation', 'rs4647602', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
221928	27723786	This result implied that the 829 A>C polymorphism caused the decline of CASP3 transcriptional activity and further contribute to the increased risk of developing lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('CASP3', 'Gene', '836', (72, 77))	('829 A>C', 'Mutation', 'rs4647602', (29, 36))	('CASP3', 'Gene', (72, 77))	('829 A>C', 'Var', (29, 36))	('lung cancer', 'Disease', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('decline', 'NegReg', (61, 68))	('transcriptional activity', 'MPA', (78, 102))
221929	27723786	Our findings of a significantly elevated risk, most evident in male and younger subjects with a tendency of increased risk with more variant alleles, suggested that for genetic susceptibility the CASP3 SNPs might be typical markers for lung cancer, because characteristics of genetic susceptibility include an early age of lung cancer onset.	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('CASP3', 'Gene', '836', (196, 201))	('lung cancer', 'Disease', 'MESH:D008175', (323, 334))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('lung cancer', 'Disease', 'MESH:D008175', (236, 247))	('CASP3', 'Gene', (196, 201))	('variant', 'Var', (133, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (323, 334))	('lung cancer', 'Disease', (323, 334))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('lung cancer', 'Disease', (236, 247))
221936	27723786	An analysis of CASP9 promoter polymorphisms contributing to genetic susceptibility to lung cancer suggested that CASP9 polymorphisms and their haplotypes interacted with tobacco smoking.	('CASP9', 'Gene', '842', (113, 118))	('tobacco', 'Species', '4097', (170, 177))	('polymorphisms', 'Var', (119, 132))	('interacted', 'Reg', (154, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('CASP9', 'Gene', (15, 20))	('lung cancer', 'Disease', (86, 97))	('CASP9', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CASP9', 'Gene', '842', (15, 20))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
221937	27723786	One of our published study observed that tobacco smoking worsened the trend of the susceptibility of lung cancer by genetic variant.	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('tobacco', 'Species', '4097', (41, 48))	('genetic variant', 'Var', (116, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
221938	27723786	Therefore we investigated gene-environment interaction between the CASP3 polymorphisms and smoking.	('investigated', 'Reg', (13, 25))	('polymorphisms', 'Var', (73, 86))	('CASP3', 'Gene', '836', (67, 72))	('CASP3', 'Gene', (67, 72))
221939	27723786	An important point of our study was CASP3 polymorphisms had an interaction with cigarette.	('polymorphisms', 'Var', (42, 55))	('CASP3', 'Gene', '836', (36, 41))	('interaction', 'Interaction', (63, 74))	('CASP3', 'Gene', (36, 41))
221988	25563036	In concordance with prior observations, our study found that BE patients in PR 75 years and older have more than double the risk of EAC than those younger than 55 years old (AOR: 2.38, 95% CI = 1.14 - 4.94), and men had more than two-fold the odds (AOR = 2.23, 95% CI: 1.23 - 4.06) of having EAC than women.	('EAC', 'Disease', (132, 135))	('patients', 'Species', '9606', (64, 72))	('women', 'Species', '9606', (301, 306))	('men', 'Species', '9606', (303, 306))	('PR 75 years', 'Var', (76, 87))	('men', 'Species', '9606', (212, 215))
222090	24379010	One in vitro study showed that the oleic acid-rich olive oil-based LE was associated with less lymphocyte apoptosis, necrosis and DNA fragmentation compared with linoleic acid rich in LCT.	('less', 'NegReg', (90, 94))	('LCT', 'Chemical', '-', (184, 187))	('necrosis', 'Disease', (117, 125))	('linoleic acid', 'Chemical', 'MESH:D019787', (162, 175))	('oleic acid-rich', 'Var', (35, 50))	('olive', 'Species', '4146', (51, 56))	('LE', 'Chemical', '-', (67, 69))	('lymphocyte apoptosis', 'CPA', (95, 115))	('necrosis', 'Disease', 'MESH:D009336', (117, 125))	('DNA fragmentation', 'CPA', (130, 147))	('oleic acid', 'Chemical', 'MESH:D019301', (165, 175))	('oleic acid', 'Chemical', 'MESH:D019301', (35, 45))
222100	24379010	The omega-6 PUFA in soybean oil was associated with production of proinflammatory eicosanoids, which tend to regulate additional inflammatory mediators.	('soybean', 'Species', '3847', (20, 27))	('omega-6 PUFA', 'Chemical', '-', (4, 16))	('eicosanoids', 'Chemical', 'MESH:D015777', (82, 93))	('omega-6', 'Var', (4, 11))	('production of proinflammatory eicosanoids', 'MPA', (52, 93))
222141	20191059	A close follow-up of patients with ERFs is important since non-sealing of a fistula after stent placement, and reopening of a fistula after initial sealing, might cause aspiration pneumonia which would certainly lead to the rapid demise of the patient.	('non-sealing', 'Var', (59, 70))	('fistula', 'Disease', (126, 133))	('aspiration pneumonia', 'Disease', (169, 189))	('patient', 'Species', '9606', (21, 28))	('aspiration', 'Phenotype', 'HP:0002835', (169, 179))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (169, 189))	('reopening', 'Var', (111, 120))	('fistula', 'Disease', 'MESH:D005402', (126, 133))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (169, 189))	('patient', 'Species', '9606', (244, 251))	('fistula', 'Disease', 'MESH:D005402', (76, 83))	('patients', 'Species', '9606', (21, 29))	('lead to', 'Reg', (212, 219))	('fistula', 'Disease', (76, 83))	('ERFs', 'Gene', '10767', (35, 39))	('pneumonia', 'Phenotype', 'HP:0002090', (180, 189))	('ERFs', 'Gene', (35, 39))	('cause', 'Reg', (163, 168))
222152	20191059	Mechanical friction between the esophageal and airway stents may cause pressure necrosis of the interposed tissue between the two stents, thereby possibly resulting in a fatal hemorrhage.	('hemorrhage', 'Disease', (176, 186))	('pressure necrosis', 'Phenotype', 'HP:0010885', (71, 88))	('resulting in', 'Reg', (155, 167))	('cause', 'Reg', (65, 70))	('hemorrhage', 'Disease', 'MESH:D006470', (176, 186))	('necrosis', 'Disease', (80, 88))	('pressure', 'Disease', (71, 79))	('Mechanical friction', 'Var', (0, 19))	('necrosis', 'Disease', 'MESH:D009336', (80, 88))
222161	20191059	In a comparative study, health-related quality of life was remarkably improved in the stenting group, compared with the control group and the gastrostomy group in 35 patients with malignant ERFs.	('stenting', 'Var', (86, 94))	('ERFs', 'Gene', '10767', (190, 194))	('improved', 'PosReg', (70, 78))	('health-related quality of life', 'CPA', (24, 54))	('ERFs', 'Gene', (190, 194))	('patients', 'Species', '9606', (166, 174))
222191	33712005	SOCS6 is correlated with better prognosis in ESCC patients.	('SOCS6', 'Var', (0, 5))	('ESCC', 'Disease', (45, 49))	('patients', 'Species', '9606', (50, 58))
222193	33712005	SOCS6 significantly decreased the population of CSCs expressing the surface biomarker CD271 or CD24low/CD44high and their ability of sphere formation.	('decreased', 'NegReg', (20, 29))	('CD24low/CD44high', 'Var', (95, 111))	('CD271', 'Gene', '4804', (86, 91))	('sphere formation', 'CPA', (133, 149))	('CD271', 'Gene', (86, 91))
222205	33712005	In ESCC, our previous study found that HPV is a negative prognostic factor and that HPV attenuates the radiosensitivity of ESCC cells .	('radiosensitivity', 'CPA', (103, 119))	('ESCC', 'Disease', (3, 7))	('attenuates', 'NegReg', (88, 98))	('HPV', 'Species', '10566', (39, 42))	('HPV', 'Species', '10566', (84, 87))	('HPV', 'Var', (84, 87))
222215	33712005	The surface markers CD271 (also named p75NTR) and a CD24low/CD44high phenotype have been reported to be biomarkers for human esophageal CSCs.	('esophageal CSCs', 'Disease', (125, 140))	('CD271', 'Gene', '4804', (20, 25))	('p75NTR', 'Gene', '4804', (38, 44))	('CD271', 'Gene', (20, 25))	('CD24low/CD44high', 'Var', (52, 68))	('p75NTR', 'Gene', (38, 44))	('human', 'Species', '9606', (119, 124))
222218	33712005	In addition, c-Kit is a CSC marker, and inhibition of c-Kit reduces the stemness of cancer cells .	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('c-Kit', 'Gene', (54, 59))	('inhibition', 'Var', (40, 50))	('cancer', 'Disease', (84, 90))	('c-Kit', 'Gene', (13, 18))	('c-Kit', 'Gene', '3815', (54, 59))	('c-Kit', 'Gene', '3815', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('reduces', 'NegReg', (60, 67))
222230	33712005	Membranes were then blocked in 5% nonfat milk and incubated overnight at 4 C with the following monoclonal antibodies: anti-SOCS6 (ab197335, Abcam, 1:500), anti-c-Kit (#3074; Cell Signaling Technology (CST), Beverly, MA, USA; 1:1000), anti-Ku70 (#4588; CST, 1:1000), anti-Ku80 (#2753; CST, 1:1000), anti-RAD51 (#8875; CST, 1:1000), anti-p-ATR (#2853; CST, 1:1000), anti-HPV16 E6 (ab70; Abcam, 1:500), anti-CD24 (18330-1-AP, Proteintech, 1:500), anti-CD44 (15675-1-AP, Proteintech, 1:500), and anti-GAPDH (10494-1-AP, Proteintech, 1:1000).	('Ku80', 'Gene', (272, 276))	('HPV', 'Species', '10566', (370, 373))	('15675-1-AP', 'Var', (456, 466))	('Ku70', 'Gene', (240, 244))	('c-Kit', 'Gene', (161, 166))	('ATR', 'Gene', '545', (339, 342))	('ATR', 'Gene', (339, 342))	('10494-1-AP', 'Var', (505, 515))	('c-Kit', 'Gene', '3815', (161, 166))	('RAD51', 'Gene', (304, 309))	('Ku70', 'Gene', '2547', (240, 244))	('Ku80', 'Gene', '7520', (272, 276))	('RAD51', 'Gene', '5888', (304, 309))
222237	33712005	Cells were incubated with antibodies: anti-SOCS6 (#3074; Santa Cruz Biotechnology, Santa Cruz, CA, USA, 1:200), anti-c-KIT (#3074; CST, 1:200).	('#3074;', 'Var', (124, 130))	('c-KIT', 'Gene', (117, 122))	('c-KIT', 'Gene', '3815', (117, 122))	('anti-SOCS6', 'Var', (38, 48))	('#3074', 'Var', (50, 55))
222254	33712005	The primary antibodies used were anti-SOCS6 (ab197335, Abcam, 1:100) and anti-c-Kit (#3074, CST, 1:100) antibodies.	('c-Kit', 'Gene', (78, 83))	('#3074', 'Var', (85, 90))	('ab197335', 'Var', (45, 53))	('c-Kit', 'Gene', '3815', (78, 83))
222257	33712005	Patients with high SOCS6 expression presented better progression-free survival (PFS, P = 0.023, Fig.	('better', 'PosReg', (46, 52))	('expression', 'MPA', (25, 35))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('SOCS6', 'Gene', (19, 24))	('progression-free survival', 'CPA', (53, 78))
222258	33712005	Since low expression of SOCS6 is correlated with poor prognosis in ESCC patients, we suspected that SOCS6 is a negative regulator of ESCC and that SOCS6 might promote radiosensitivity.	('ESCC', 'Disease', (67, 71))	('SOCS6', 'Gene', (24, 29))	('SOCS6', 'Var', (147, 152))	('expression', 'MPA', (10, 20))	('low', 'NegReg', (6, 9))	('promote', 'PosReg', (159, 166))	('radiosensitivity', 'CPA', (167, 183))	('patients', 'Species', '9606', (72, 80))
222274	33712005	The viability of cells overexpressing SOCS6 was decreased, indicating that SOCS6 can significantly increase cisplatin sensitivity in ESCC cells (Fig.	('cisplatin sensitivity', 'MPA', (108, 129))	('increase', 'PosReg', (99, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('SOCS6', 'Var', (75, 80))
222276	33712005	As for cisplatin sensitivity, knockdown of SOCS6 decreased Eca109 and KYSE-150 cells' sensitivity to cisplatin at some concentrations (Fig.	('KYSE-150', 'CellLine', 'CVCL:1348', (70, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (7, 16))	('sensitivity to cisplatin', 'MPA', (86, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('decreased', 'NegReg', (49, 58))	('knockdown', 'Var', (30, 39))	('SOCS6', 'Gene', (43, 48))
222280	33712005	The number of spheres formed by Eca109-SOCS6 and KYSE-150-SOCS6 cells was obviously decreased compared with the number formed by the corresponding control cells on day 14 (Fig.	('Eca109-SOCS6', 'Var', (32, 44))	('decreased', 'NegReg', (84, 93))	('KYSE-150-SOCS6', 'CellLine', 'CVCL:1348', (49, 63))	('KYSE-150-SOCS6', 'Var', (49, 63))
222282	33712005	CD24low/CD44high is the surface marker phenotype of CSCs, and CD271 is an ESCC stem cell-specific marker.	('CSCs', 'Disease', (52, 56))	('CD24low/CD44high', 'Var', (0, 16))	('CD271', 'Gene', '4804', (62, 67))	('CD271', 'Gene', (62, 67))
222284	33712005	Similarly, the proportion of CD24low/CD44high cells decreased in SOCS6 overexpression group in Eca109 (P < 0.001) and KYSE-150 (P < 0.01) cells (Fig.	('CD24low/CD44high', 'Var', (29, 45))	('overexpression', 'PosReg', (71, 85))	('SOCS6', 'Gene', (65, 70))	('decreased', 'NegReg', (52, 61))	('KYSE-150', 'CellLine', 'CVCL:1348', (118, 126))
222294	33712005	HPV+ Eca109 cells were treated with MG132 (20 microg/mL) for 4 h, and then endogenous c-Kit was immunoprecipitated, and the level of ubiquitylation was monitored by immunoblotting.	('HPV', 'Species', '10566', (0, 3))	('c-Kit', 'Gene', (86, 91))	('MG132', 'Var', (36, 41))	('c-Kit', 'Gene', '3815', (86, 91))	('MG132', 'Chemical', 'MESH:C072553', (36, 41))
222299	33712005	Results showed that SOCS6 could accelerate c-Kit degradation (Fig.	('SOCS6', 'Var', (20, 25))	('c-Kit', 'Gene', (43, 48))	('accelerate', 'PosReg', (32, 42))	('c-Kit', 'Gene', '3815', (43, 48))
222301	33712005	Results showed that SOCS6 could significantly accelerate the degradation of c-Kit in both Eca109 and KYSE-150 cells (Additional file 4: Fig.	('KYSE-150', 'CellLine', 'CVCL:1348', (101, 109))	('accelerate', 'PosReg', (46, 56))	('SOCS6', 'Var', (20, 25))	('degradation', 'MPA', (61, 72))	('c-Kit', 'Gene', (76, 81))	('c-Kit', 'Gene', '3815', (76, 81))
222320	33712005	Survival analysis of 57 ESCC patients showed that SOCS6 is correlated with better prognosis.	('SOCS6', 'Var', (50, 55))	('patients', 'Species', '9606', (29, 37))	('ESCC', 'Disease', (24, 28))
222331	33712005	In this work, flow cytometric analyses and sphere formation assays showed that SOCS6 protein expression sensitizes ESCC cells to radiation and cisplatin by reducing the population of CSCs.	('sensitizes', 'Reg', (104, 114))	('expression', 'Var', (93, 103))	('population of CSCs', 'CPA', (169, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('SOCS6', 'Gene', (79, 84))	('reducing', 'NegReg', (156, 164))	('protein', 'Protein', (85, 92))
222347	33712005	Gain-of-function mutations in c-Kit can promote tumor formation and progression in GIST, AML, mast cell leukemia and melanoma.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('AML', 'Disease', 'MESH:D015470', (89, 92))	('c-Kit', 'Gene', '3815', (30, 35))	('Gain-of-function', 'PosReg', (0, 16))	('AML', 'Phenotype', 'HP:0004808', (89, 92))	('AML', 'Disease', (89, 92))	('mutations', 'Var', (17, 26))	('promote', 'PosReg', (40, 47))	('c-Kit', 'Gene', (30, 35))	('mast cell leukemia', 'Phenotype', 'HP:0100495', (94, 112))	('GIST', 'Disease', (83, 87))	('GIST', 'Phenotype', 'HP:0100723', (83, 87))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mast cell leukemia', 'Disease', 'MESH:D007946', (94, 112))	('mast cell leukemia', 'Disease', (94, 112))	('progression', 'CPA', (68, 79))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
222350	33712005	This study showed that SOCS6 promotes the ubiquitylation and degradation of c-Kit, which may be the mechanism underlying the decrease in CSC properties in ESCC cells overexpressing SOCS6.	('c-Kit', 'Gene', '3815', (76, 81))	('CSC properties', 'MPA', (137, 151))	('SOCS6', 'Var', (181, 186))	('ubiquitylation', 'MPA', (42, 56))	('degradation', 'MPA', (61, 72))	('decrease', 'NegReg', (125, 133))	('SOCS6', 'Gene', (23, 28))	('c-Kit', 'Gene', (76, 81))	('promotes', 'PosReg', (29, 37))
222354	33712005	In our previous study, we found that HPV+ ESCC cells are more resistant to radiation and we demonstrated a novel mechanism by which E6/E7 proteins enhance the stemness of ESCC cells.	('enhance', 'PosReg', (147, 154))	('ESCC', 'Disease', (171, 175))	('E6/E7 proteins', 'Var', (132, 146))	('stemness of', 'CPA', (159, 170))	('HPV', 'Species', '10566', (37, 40))
222489	31933223	Use of neoadjuvant therapy, surgical approach, and hospital volume are modifiable risk factors for margin positivity in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('margin positivity', 'Var', (99, 116))	('esophageal cancer', 'Disease', (120, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))
222536	31933223	Several tumor characteristics are associated with margin positivity and were controlled for in our multivariable model.	('associated', 'Reg', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('margin positivity', 'Var', (50, 67))	('tumor', 'Disease', (8, 13))
222541	31933223	Several directly modifiable risk factors were found to be associated with margin positivity in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('associated', 'Reg', (58, 68))	('margin positivity', 'Var', (74, 91))	('esophageal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
222546	31933223	Positive resection margins are associated with worse overall survival in patients with various malignancies, including esophageal cancer.	('malignancies', 'Disease', 'MESH:D009369', (95, 107))	('malignancies', 'Disease', (95, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('patients', 'Species', '9606', (73, 81))	('overall', 'MPA', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Positive', 'Var', (0, 8))	('worse', 'NegReg', (47, 52))	('esophageal cancer', 'Disease', (119, 136))
222549	31933223	Although margin positivity rates decreased over time, both unmodifiable and modifiable risk factors were found to be associated with margin positivity, including older age, patient comorbidities, and tumor specific factors (clinical T stage, tumor location, tumor grade and tumor size).	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('margin positivity', 'Var', (133, 150))	('tumor', 'Disease', (242, 247))	('patient', 'Species', '9606', (173, 180))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (258, 263))
222566	31933223	Additionally, older and more comorbid patients are less likely to receive neoadjuvant therapy, thereby increasing the likelihood of margin positivity.	('increasing', 'PosReg', (103, 113))	('margin positivity', 'Var', (132, 149))	('patients', 'Species', '9606', (38, 46))
222568	31933223	This study supports these findings with T3, T4, moderately and poorly differentiated tumors, proximal tumors, and tumors greater than 6.0 cm in size being associated with margin positivity.	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('associated', 'Reg', (155, 165))	('moderately', 'CPA', (48, 58))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('margin positivity', 'Var', (171, 188))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
222570	31933223	This study identifies three primarily modifiable risk factors for margin positivity in patients undergoing resection of esophageal cancer: use of neoadjuvant therapy, surgical approach, and hospital volume.	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('margin positivity', 'Var', (66, 83))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('esophageal cancer', 'Disease', (120, 137))
222576	31933223	However, based on the finding that neoadjuvant therapy is associated with decreased odds of margin positivity, even after controlling for clinical stage, providers could consider neoadjuvant therapy for early stage esophageal tumors if margin positivity is a concern based upon tumor location or other factors.	('margin', 'Var', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumor', 'Disease', (278, 283))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('decreased', 'NegReg', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Disease', (226, 231))	('esophageal tumors', 'Phenotype', 'HP:0100751', (215, 232))
222585	31933223	Thus, although we have identified factors associated with margin positivity in esophageal cancer, we are not able to draw conclusions regarding why these factors as associated with margin positivity.	('margin positivity', 'Var', (58, 75))	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (165, 175))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))
222610	32333246	On the cell membrane, AKT is recruited via its PH domain ascribing to the accumulation of PI(3,4,5)P3 and PI(3,4)P2 (less extent), and plays a catalytic role by activating two regulatory sites, including a threonine phosphorylated by PDK1 at Thr308(AKT1), Thr309(AKT2), Thr305(AKT3) and a serine phosphorylated by the mammalian Target of Rapamycin (mTOR) Complex mTORC2 at Ser473(AKT1), Ser474(AKT2), Ser472(AKT3) respectively as well as specifically.	('Ser474', 'Var', (387, 393))	('AKT2', 'Gene', '208', (394, 398))	('activating', 'PosReg', (161, 171))	('AKT', 'Gene', '207', (249, 252))	('AKT', 'Gene', (22, 25))	('AKT3', 'Gene', (277, 281))	('AKT2', 'Gene', (394, 398))	('AKT', 'Gene', (277, 280))	('AKT', 'Gene', (394, 397))	('AKT1', 'Gene', (380, 384))	('AKT', 'Gene', '207', (263, 266))	('AKT', 'Gene', '207', (380, 383))	('PDK1', 'Gene', (234, 238))	('AKT2', 'Gene', '208', (263, 267))	('serine', 'Chemical', 'MESH:D012694', (289, 295))	('AKT1', 'Gene', '207', (249, 253))	('AKT', 'Gene', (408, 411))	('AKT1', 'Gene', '207', (380, 384))	('AKT', 'Gene', '207', (22, 25))	('AKT3', 'Gene', '10000', (408, 412))	('mTORC2', 'Gene', (363, 369))	('AKT2', 'Gene', (263, 267))	('AKT', 'Gene', '207', (394, 397))	('AKT', 'Gene', '207', (277, 280))	('Ser473', 'Var', (373, 379))	('AKT', 'Gene', (249, 252))	('AKT1', 'Gene', (249, 253))	('AKT3', 'Gene', (408, 412))	('Ser472', 'Var', (401, 407))	('PDK1', 'Gene', '5163', (234, 238))	('AKT', 'Gene', '207', (408, 411))	('mammalian Target of Rapamycin', 'Gene', '2475', (318, 347))	('AKT', 'Gene', (380, 383))	('AKT', 'Gene', (263, 266))	('AKT3', 'Gene', '10000', (277, 281))	('mammalian Target of Rapamycin', 'Gene', (318, 347))
222614	32333246	As a lipid phosphatase, PTEN directly suppresses the activation of PI3K/AKT pathway via converting the PIP3 generated by PI3K back to PIP2.	('AKT', 'Gene', '207', (72, 75))	('PTEN', 'Gene', '5728', (24, 28))	('PI3K', 'Var', (121, 125))	('AKT', 'Gene', (72, 75))	('suppresses', 'NegReg', (38, 48))	('PIP3 generated', 'MPA', (103, 117))	('PIP3', 'Chemical', '-', (103, 107))	('PTEN', 'Gene', (24, 28))
222617	32333246	Indeed, the abnormality of PTEN have been validated in diverse cancers, even directly related with carcinogenesis in some cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('PTEN', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('carcinogenesis', 'Disease', (99, 113))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('abnormality', 'Var', (12, 23))	('cancers', 'Disease', (122, 129))	('PTEN', 'Gene', '5728', (27, 31))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
222618	32333246	Following the emerging alterations of PI3K/AKT pathway genes have been widely reported in cancers recently, the inhibitors of PI3K/AKT pathway have brought a new era for targeted therapy of cancer.	('cancer', 'Disease', (190, 196))	('cancers', 'Disease', (90, 97))	('AKT', 'Gene', '207', (131, 134))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('inhibitors', 'Var', (112, 122))	('AKT', 'Gene', '207', (43, 46))	('AKT', 'Gene', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('AKT', 'Gene', (43, 46))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
222629	32333246	Considering that the incidence and mortality of the brain and central nervous system tumors is 1.6% and 2.5% respectively in the worldwide (https://gco.iarc.fr/, Table 1), particularly the most common primary malignant tumor, glioblastoma multiforme (GBM), contributes to the poor prognosis partly for its tolerance of radiation therapy, hyper-activation of PI3K/AKT pathway in GBM caused by the mutations of PIK3CA or PIK3R1 (18.3%) and other PI3K family genes (6.8%) has urged researchers to seek novel targeted treatments to control the disease.	('GBM', 'Disease', (378, 381))	('men', 'Species', '9606', (519, 522))	('PIK3R1', 'Gene', (419, 425))	('AKT', 'Gene', (363, 366))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('central nervous system tumors', 'Disease', (62, 91))	('mutations', 'Var', (396, 405))	('PIK3CA', 'Gene', (409, 415))	('glioblastoma', 'Phenotype', 'HP:0012174', (226, 238))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('malignant tumor', 'Disease', (209, 224))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mortality', 'Disease', (35, 44))	('PIK3R1', 'Gene', '5295', (419, 425))	('AKT', 'Gene', '207', (363, 366))	('glioblastoma multiforme', 'Disease', (226, 249))	('central nervous system tumors', 'Disease', 'MESH:D016543', (62, 91))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (226, 249))	('malignant tumor', 'Disease', 'MESH:D009369', (209, 224))	('hyper-activation', 'PosReg', (338, 354))	('mortality', 'Disease', 'MESH:D003643', (35, 44))
222630	32333246	Moreover, knockdown of PIK3CA or PIK3R1 significantly inhibits cell viability, migration and invasion in GBM cells via hypo-activation of AKT and FAK.	('FAK', 'Gene', (146, 149))	('migration', 'CPA', (79, 88))	('invasion in GBM cells', 'CPA', (93, 114))	('PIK3CA', 'Gene', (23, 29))	('AKT', 'Gene', (138, 141))	('cell viability', 'CPA', (63, 77))	('inhibits', 'NegReg', (54, 62))	('PIK3R1', 'Gene', '5295', (33, 39))	('PIK3R1', 'Gene', (33, 39))	('FAK', 'Gene', '5747', (146, 149))	('knockdown', 'Var', (10, 19))	('AKT', 'Gene', '207', (138, 141))
222632	32333246	PIK3CB knockdown suppresses cell proliferation and induces caspase-dependent apoptosis in GBM in vitro and vivo instead of suppressing GBM cell migration.	('GBM cell migration', 'CPA', (135, 153))	('suppressing', 'NegReg', (123, 134))	('cell proliferation', 'CPA', (28, 46))	('PIK3CB', 'Gene', (0, 6))	('induces', 'Reg', (51, 58))	('caspase-dependent apoptosis', 'MPA', (59, 86))	('suppresses', 'NegReg', (17, 27))	('PIK3CB', 'Gene', '5291', (0, 6))	('knockdown', 'Var', (7, 16))
222634	32333246	Some p110alpha isoform-selective inhibitors, such as A66 or PIK-75, could effectively suppress the GBM cell growth, survival and migration in vitro, while inhibition of p110beta by TGX-221 only arrests cell migration, and inhibition of p110delta by IC87114 or CAL-101 moderately blocks cell proliferation and migration.	('p110beta', 'Gene', '5291', (169, 177))	('IC87114', 'Chemical', 'MESH:C477872', (249, 256))	('suppress', 'NegReg', (86, 94))	('cell migration', 'CPA', (202, 216))	('p110alpha', 'Gene', '5290', (5, 14))	('CAL-101', 'Chemical', 'MESH:C552946', (260, 267))	('p110beta', 'Gene', (169, 177))	('migration', 'CPA', (129, 138))	('GBM cell growth', 'CPA', (99, 114))	('PIK-75', 'Gene', (60, 66))	('cell proliferation', 'CPA', (286, 304))	('p110alpha', 'Gene', (5, 14))	('blocks', 'NegReg', (279, 285))	('TGX-221', 'Gene', (181, 188))	('p110delta', 'Var', (236, 245))
222635	32333246	However, PI3K inhibitors including A66 and BEZ235 are observed to increase the expression of cancer stem cell (CSC) genes (SOX2, OCT4 and MSI1) in GBM CSC models, which exhibit therapy resistance.	('BEZ235', 'Var', (43, 49))	('cancer', 'Disease', (93, 99))	('increase', 'PosReg', (66, 74))	('A66', 'Var', (35, 38))	('MSI1', 'Gene', (138, 142))	('expression', 'MPA', (79, 89))	('PI3K', 'Var', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('OC', 'Phenotype', 'HP:0100615', (129, 131))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('OCT4', 'Gene', '5460', (129, 133))	('OCT4', 'Gene', (129, 133))	('MSI1', 'Gene', '4440', (138, 142))	('SOX2', 'Gene', '6657', (123, 127))	('SOX2', 'Gene', (123, 127))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))
222638	32333246	Notably, building on that 22% genetic alterations of PTEN was detected in GBM (https://www.cbioportal.org, Table 1), especially deep deletion, which caused the loss of function of PTEN tumor suppressor, PTEN was deeply involved in the pathological effects of PI3K/AKT pathway in GBM.	('PTEN', 'Gene', (203, 207))	('PTEN', 'Gene', '5728', (203, 207))	('AKT', 'Gene', (264, 267))	('deep deletion', 'Var', (128, 141))	('PTEN', 'Gene', (180, 184))	('involved', 'Reg', (219, 227))	('PTEN tumor', 'Disease', 'MESH:D006223', (180, 190))	('PTEN tumor', 'Disease', (180, 190))	('PTEN', 'Gene', '5728', (180, 184))	('PTEN', 'Gene', (53, 57))	('PTEN', 'Gene', '5728', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('AKT', 'Gene', '207', (264, 267))	('loss of function', 'NegReg', (160, 176))
222639	32333246	Meanwhile, genetic loss of PTEN is associated with each subtype of GBM.	('associated', 'Reg', (35, 45))	('GBM', 'Disease', (67, 70))	('genetic loss', 'Var', (11, 23))	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (27, 31))
222645	32333246	The loss of FBW7 function increases SOX9 protein levels, increasing the malignancy of cancer and resistance to cisplatin.	('increasing', 'PosReg', (57, 67))	('FBW7', 'Gene', '55294', (12, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('FBW7', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('SOX9', 'Gene', (36, 40))	('resistance', 'CPA', (97, 107))	('malignancy of cancer', 'Disease', 'MESH:D009369', (72, 92))	('increases', 'PosReg', (26, 35))	('SOX9', 'Gene', '6662', (36, 40))	('malignancy of cancer', 'Disease', (72, 92))	('loss', 'Var', (4, 8))
222646	32333246	As a major oncoprotein inhibitor, once FBW7 is deleted or mutated, it can cause tumors to occur directly.	('FBW7', 'Gene', '55294', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('FBW7', 'Gene', (39, 43))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('mutated', 'Var', (58, 65))	('deleted', 'Var', (47, 54))	('cause', 'Reg', (74, 79))
222647	32333246	Moreover, experiments show that combination of PI3K inhibitor, mTOR inhibitor and cisplatin can achieve better therapeutic effect, and how well LY3023414 works in recurrent MBM is being tested in an ongoing clinical trial (NCT03213678, Table 2).	('MBM', 'Disease', (173, 176))	('therapeutic effect', 'MPA', (111, 129))	('men', 'Species', '9606', (16, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('LY3023414', 'Chemical', 'MESH:C000621566', (144, 153))	('LY3023414', 'Var', (144, 153))
222651	32333246	Obviously, the overall genetic alterations of PI3K/AKT pathway in TC are inconspicuous (Table 1), but genetic mutations in PI3K/AKT pathway are common in PDTC and ATC, specifically more common in ATC than in PDTC.	('ATC', 'Disease', (196, 199))	('PDTC', 'Chemical', '-', (154, 158))	('TC', 'Phenotype', 'HP:0002890', (164, 166))	('common', 'Reg', (186, 192))	('TC', 'Phenotype', 'HP:0002890', (66, 68))	('AKT', 'Gene', (51, 54))	('TC', 'Phenotype', 'HP:0002890', (210, 212))	('AKT', 'Gene', (128, 131))	('genetic mutations', 'Var', (102, 119))	('PDTC', 'Chemical', '-', (208, 212))	('TC', 'Phenotype', 'HP:0002890', (156, 158))	('PDTC', 'Disease', (154, 158))	('common', 'Reg', (144, 150))	('AKT', 'Gene', '207', (128, 131))	('TC', 'Phenotype', 'HP:0002890', (197, 199))	('AKT', 'Gene', '207', (51, 54))
222652	32333246	Besides PIK3CA (18% vs. 2%) and PTEN (15% vs. 4%), mutations of PIK3C2G (6% vs. 1%), PIK3CG (6% vs. 1%), PIK3C3 (0 vs. 1%), PIK3R1 (0 vs. 1%), PIK3R2 (3% vs. 0), AKT3 (0 vs. 1%) are also observed in ATC and PDTC respectively.	('PIK3C2G', 'Gene', (64, 71))	('mutations', 'Var', (51, 60))	('PDTC', 'Chemical', '-', (207, 211))	('PIK3C2G', 'Gene', '5288', (64, 71))	('PIK3R1', 'Gene', (124, 130))	('PIK3R2', 'Gene', (143, 149))	('AKT3', 'Gene', '10000', (162, 166))	('PIK3C3', 'Gene', '5289', (105, 111))	('PIK3C3', 'Gene', (105, 111))	('PIK3R2', 'Gene', '5296', (143, 149))	('PDTC', 'Disease', (207, 211))	('AKT3', 'Gene', (162, 166))	('PTEN', 'Gene', (32, 36))	('PIK3R1', 'Gene', '5295', (124, 130))	('PIK3CG', 'Gene', (85, 91))	('ATC', 'Disease', (199, 202))	('PIK3CG', 'Gene', '5294', (85, 91))	('TC', 'Phenotype', 'HP:0002890', (209, 211))	('PTEN', 'Gene', '5728', (32, 36))	('TC', 'Phenotype', 'HP:0002890', (200, 202))
222654	32333246	Actually, exclusive activating mutations of BRAF (60% vs. 33% and 38%) in PTC are more frequently observed than in PDTC and ATC, while mice experiments show that co-mutation of BRAF and PIK3CA can promote the development of lethal ATC, but neither BRAF nor PIK3CA mutations alone can.	('men', 'Species', '9606', (216, 219))	('development of lethal ATC', 'CPA', (209, 234))	('activating', 'PosReg', (20, 30))	('BRAF', 'Gene', (177, 181))	('TC', 'Phenotype', 'HP:0002890', (117, 119))	('BRAF', 'Gene', (44, 48))	('co-mutation', 'Var', (162, 173))	('men', 'Species', '9606', (146, 149))	('TC', 'Phenotype', 'HP:0002890', (125, 127))	('PTC', 'Disease', (74, 77))	('PIK3CA', 'Gene', (186, 192))	('PDTC', 'Chemical', '-', (115, 119))	('mice', 'Species', '10090', (135, 139))	('TC', 'Phenotype', 'HP:0002890', (232, 234))	('TC', 'Phenotype', 'HP:0002890', (75, 77))	('promote', 'PosReg', (197, 204))
222655	32333246	In addition, mutations in BRAF and PIK3CA can activate the MAPK pathway and the PI3K/AKT pathway respectively and lead to the occurrence of ATC, whereas dual blocking PI3K and MAPK pathways can effectively inhibit ATC.	('MAPK pathway', 'Pathway', (59, 71))	('AKT', 'Gene', '207', (85, 88))	('BRAF', 'Gene', (26, 30))	('TC', 'Phenotype', 'HP:0002890', (141, 143))	('PIK3CA', 'Gene', (35, 41))	('activate', 'PosReg', (46, 54))	('AKT', 'Gene', (85, 88))	('mutations', 'Var', (13, 22))	('lead to', 'Reg', (114, 121))	('TC', 'Phenotype', 'HP:0002890', (215, 217))	('ATC', 'Disease', (140, 143))
222662	32333246	Apart from those widely recognized alterations, such as EGFR and KRAS gene mutations, MET amplification, EML4-ALK rearrangements in NSCLC, somatic mutations and amplification in PIK3CA are described in 3-10% vs. 35% of SCC and 0-2.7% vs. 7% of ADC respectively.	('mutations', 'Var', (147, 156))	('EGFR', 'Gene', '1956', (56, 60))	('SCC', 'Disease', (219, 222))	('CC', 'Phenotype', 'HP:0002664', (220, 222))	('PIK3CA', 'Gene', (178, 184))	('KRAS', 'Gene', '3845', (65, 69))	('amplification', 'Var', (161, 174))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('EML4', 'Gene', (105, 109))	('KRAS', 'Gene', (65, 69))	('EML4', 'Gene', '27436', (105, 109))	('ADC', 'Disease', (244, 247))	('NSCLC', 'Disease', (132, 137))	('EGFR', 'Gene', (56, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('ALK', 'Gene', '238', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (219, 222))	('LC', 'Phenotype', 'HP:0100526', (135, 137))	('rearrangements', 'Var', (114, 128))	('ALK', 'Gene', (110, 113))	('men', 'Species', '9606', (123, 126))	('SCLC', 'Phenotype', 'HP:0030357', (133, 137))
222669	32333246	Whether combining daily BKM120 with cisplatin and etoposide was safe and effective in extensive stage SCLC patients had been attempted in a completed clinical trial (NCT02194049, Table 3).	('SCLC', 'Phenotype', 'HP:0030357', (102, 106))	('BKM120', 'Chemical', 'MESH:C571178', (24, 30))	('LC', 'Phenotype', 'HP:0100526', (104, 106))	('etoposide', 'Chemical', 'MESH:D005047', (50, 59))	('SCLC', 'Gene', '7864', (102, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('SCLC', 'Gene', (102, 106))	('BKM120', 'Var', (24, 30))	('patients', 'Species', '9606', (107, 115))
222671	32333246	As expected, NPC has a relatively lower mutational burdens with PIK3CA mutations of 1.8% (Table 1), however, there are still numerous of researches involved in PI3K/AKT pathway in NPC.	('AKT', 'Gene', (165, 168))	('PIK3CA', 'Gene', (64, 70))	('NPC', 'Phenotype', 'HP:0100630', (180, 183))	('NPC', 'Gene', (180, 183))	('NPC', 'Gene', '4864', (180, 183))	('NPC', 'Phenotype', 'HP:0100630', (13, 16))	('mutations', 'Var', (71, 80))	('NPC', 'Gene', (13, 16))	('AKT', 'Gene', '207', (165, 168))	('PC', 'Phenotype', 'HP:0002894', (181, 183))	('PC', 'Phenotype', 'HP:0002894', (14, 16))	('NPC', 'Gene', '4864', (13, 16))
222675	32333246	A series of studies show the mutational events of PI3K pathway (30.5%) in 151 head and neck squamous cell carcinomas (HNSCCs) containing 29 laryngeal squamous cell carcinomas (LSCCs), particularly PIK3CA mutations of 12.6%.	('PIK3CA', 'Gene', (197, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('HNSCC', 'Disease', 'MESH:D000077195', (118, 123))	('squamous cell carcinomas', 'Disease', (150, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('CC', 'Phenotype', 'HP:0002664', (178, 180))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (92, 116))	('CC', 'Phenotype', 'HP:0002664', (121, 123))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (92, 116))	('mutations', 'Var', (204, 213))	('HNSCC', 'Disease', (118, 123))	('PI3K pathway', 'Pathway', (50, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('neck squamous cell carcinomas', 'Disease', (87, 116))	('mutational', 'Var', (29, 39))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (150, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (150, 174))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (87, 116))
222679	32333246	Even more, the safety and efficacy of AKT inhibitor MK2206 in NPC patients had been evaluated in a completed clinical trial (Table 3).	('AKT', 'Gene', (38, 41))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('NPC', 'Phenotype', 'HP:0100630', (62, 65))	('MK2206', 'Var', (52, 58))	('AKT', 'Gene', '207', (38, 41))	('NPC', 'Gene', (62, 65))	('PC', 'Phenotype', 'HP:0002894', (63, 65))	('patients', 'Species', '9606', (66, 74))	('NPC', 'Gene', '4864', (62, 65))
222682	32333246	In general, the genetic alterations of PIK3CA (24%), and PTEN (7%) are observed in ESCA (Table 1), especially the somatic mutations of PIK3CA (7.2% vs 12.5%), PIK3C2A (0.7% vs. 0), PIK3CG (2.9% vs. 4.2%) and PIK3C2G (0 vs. 37.5%) are observed respectively in 139 paired ESCC cases and 24 cell lines.	('PIK3C2G', 'Gene', (208, 215))	('PIK3CG', 'Gene', (181, 187))	('ESCC', 'Disease', (270, 274))	('PIK3C2G', 'Gene', '5288', (208, 215))	('SCC', 'Phenotype', 'HP:0002860', (271, 274))	('PIK3CG', 'Gene', '5294', (181, 187))	('CC', 'Phenotype', 'HP:0002664', (272, 274))	('ESCA', 'Disease', (83, 87))	('PTEN', 'Gene', (57, 61))	('PIK3CA', 'Gene', (135, 141))	('PTEN', 'Gene', '5728', (57, 61))	('mutations', 'Var', (122, 131))	('PIK3C2A', 'Gene', '5286', (159, 166))	('PIK3C2A', 'Gene', (159, 166))
222683	32333246	Even more, PIK3CA mutations are frequent in ESCC associated with chagasic megaesophagus and are associated with a worse patient outcome.	('ESCC', 'Disease', (44, 48))	('associated', 'Reg', (96, 106))	('associated', 'Reg', (49, 59))	('patient', 'Species', '9606', (120, 127))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('PIK3CA', 'Gene', (11, 17))	('chagasic megaesophagus', 'Disease', (65, 87))	('CC', 'Phenotype', 'HP:0002664', (46, 48))	('mutations', 'Var', (18, 27))
222688	32333246	But one research reveals that PI3K/AKT pathway genetic mutations are found in 69 (16%) of the 431 GC patients including PIK3CA (13.2%) and PTEN (4.0%), as well as PIK3CA amplifications are found in 206 (47.8%) of the patients.	('patients', 'Species', '9606', (101, 109))	('PIK3CA', 'Gene', (120, 126))	('AKT', 'Gene', (35, 38))	('mutations', 'Var', (55, 64))	('PTEN', 'Gene', (139, 143))	('PTEN', 'Gene', '5728', (139, 143))	('AKT', 'Gene', '207', (35, 38))	('patients', 'Species', '9606', (217, 225))	('found', 'Reg', (69, 74))
222689	32333246	Another research shows that advanced GC patient have more frequency of PIK3CA mutations in codon 545 than in codon 1047.	('patient', 'Species', '9606', (40, 47))	('advanced GC', 'Disease', (28, 39))	('PIK3CA', 'Gene', (71, 77))	('mutations', 'Var', (78, 87))
222692	32333246	Table 2) and AKT inhibitors (MK2206, GSK2110183 and GDC-0068.	('MK2206', 'Var', (29, 35))	('GDC-0068', 'Chemical', 'MESH:C583616', (52, 60))	('GSK2110183', 'Chemical', 'MESH:C000595148', (37, 47))	('AKT', 'Gene', '207', (13, 16))	('MK2206', 'Chemical', 'MESH:C548887', (29, 35))	('AKT', 'Gene', (13, 16))
222696	32333246	Contrary to predictions, PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC, whereas they are closely associated with KRAS mutations, as well as PIK3CA exon 9 and 20 mutations show different tendencies with respect to BRAF mutation and MSI status.	('CRC', 'Disease', (107, 110))	('associated', 'Reg', (137, 147))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('KRAS', 'Gene', (153, 157))	('PIK3CA', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('PIK3CA', 'Gene', (180, 186))	('KRAS', 'Gene', '3845', (153, 157))
222698	32333246	CXCL12, NLRC3, Wnt/beta-catenin target genes including BAMBI, BOP1, CKS2 and NFIL3, as well as miRNA-135b, Linc00659 and CRNDE are associated with the proliferation, invasion or metastasis of CRC cells via PI3K/AKT signaling.	('CXCL12', 'Gene', (0, 6))	('NFIL3', 'Gene', '4783', (77, 82))	('CKS2', 'Gene', '1164', (68, 72))	('CKS2', 'Gene', (68, 72))	('CRNDE', 'Gene', '643911', (121, 126))	('CRNDE', 'Gene', (121, 126))	('NLRC3', 'Gene', (8, 13))	('BAMBI', 'Gene', (55, 60))	('proliferation', 'CPA', (151, 164))	('NLRC3', 'Gene', '197358', (8, 13))	('AKT', 'Gene', (211, 214))	('BAMBI', 'Gene', '25805', (55, 60))	('BOP1', 'Gene', (62, 66))	('CRC', 'Phenotype', 'HP:0003003', (192, 195))	('metastasis', 'CPA', (178, 188))	('Linc00659', 'Gene', (107, 116))	('Linc00659', 'Gene', '100652730', (107, 116))	('invasion', 'CPA', (166, 174))	('NFIL3', 'Gene', (77, 82))	('BOP1', 'Gene', '23246', (62, 66))	('AKT', 'Gene', '207', (211, 214))	('CXCL12', 'Gene', '6387', (0, 6))	('associated with', 'Reg', (131, 146))	('beta-catenin', 'Gene', (19, 31))	('miRNA-135b', 'Var', (95, 105))	('beta-catenin', 'Gene', '1499', (19, 31))
222700	32333246	As the most common mesenchymal tumor of the digestive system, gastrointestinal stromal tumors (GISTs) mainly harbor mutually exclusive KIT or PDGFRA mutations, which lead to constitutive activation of the encoded receptor tyrosine kinase (RTK) and activation of downstream pathways including PI3K/AKT pathway.	('receptor tyrosine kinase', 'Gene', (213, 237))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('activation', 'PosReg', (187, 197))	('PDGFRA', 'Gene', '5156', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('PDGFRA', 'Gene', (142, 148))	('GISTs', 'Phenotype', 'HP:0100723', (95, 100))	('KIT', 'Gene', '3815', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (62, 93))	('AKT', 'Gene', (297, 300))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (62, 93))	('RTK', 'Gene', (239, 242))	('activation', 'PosReg', (248, 258))	('RTK', 'Gene', '5979', (239, 242))	('mutations', 'Var', (149, 158))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (19, 36))	('gastrointestinal stromal tumors', 'Disease', (62, 93))	('AKT', 'Gene', '207', (297, 300))	('receptor tyrosine kinase', 'Gene', '5979', (213, 237))	('KIT', 'Gene', (135, 138))	('mesenchymal tumor', 'Disease', (19, 36))
222701	32333246	Genetic alterations of PIK3CA and PTEN are observed more frequency in malignant GISTs than in less malignant GISTs in 65 GIST samples with 14/65 overall genetic alterations of PI3K/AKT pathway.	('Genetic alterations', 'Var', (0, 19))	('PIK3CA', 'Gene', (23, 29))	('AKT', 'Gene', (181, 184))	('genetic alterations', 'Var', (153, 172))	('GISTs', 'Phenotype', 'HP:0100723', (109, 114))	('AKT', 'Gene', '207', (181, 184))	('GISTs', 'Phenotype', 'HP:0100723', (80, 85))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))	('malignant', 'Disease', (70, 79))
222702	32333246	It is noted that FASN overexpression often occurs in high-risk and metastatic GISTs, whereas combination therapy with imatinib and C75 targeting FASN has been demonstrated in vitro and vivo to down-regulate the phosphorylation levels of the KIT and PI3K/AKT/mTOR pathway.	('imatinib', 'Chemical', 'MESH:D000068877', (118, 126))	('FASN', 'Gene', (17, 21))	('overexpression', 'PosReg', (22, 36))	('phosphorylation levels', 'MPA', (211, 233))	('AKT', 'Gene', (254, 257))	('FASN', 'Gene', '2194', (17, 21))	('AKT', 'Gene', '207', (254, 257))	('C75', 'Var', (131, 134))	('KIT', 'Gene', '3815', (241, 244))	('FASN', 'Gene', (145, 149))	('FASN', 'Gene', '2194', (145, 149))	('down-regulate', 'NegReg', (193, 206))	('GISTs', 'Phenotype', 'HP:0100723', (78, 83))	('KIT', 'Gene', (241, 244))
222704	32333246	Combination of imatinib mesylate (IM) and MK2206 provide obviously greater efficacy than treatment with IM or MK2206 alone in vitro and vivo preclinical study of GIST.	('MK2206', 'Chemical', 'MESH:C548887', (42, 48))	('men', 'Species', '9606', (94, 97))	('efficacy', 'MPA', (75, 83))	('MK2206', 'Chemical', 'MESH:C548887', (110, 116))	('MK2206', 'Var', (42, 48))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (15, 32))	('greater', 'PosReg', (67, 74))
222709	32333246	A small amount of clinical trials of PI3K inhibitors (SF1126, GSK2636771) and AKT inhibitors (MK2206) in HCC patients may give them an opportunity for relief (Tables 2 and 3).	('HCC', 'Disease', (105, 108))	('patients', 'Species', '9606', (109, 117))	('CC', 'Phenotype', 'HP:0002664', (106, 108))	('HCC', 'Phenotype', 'HP:0001402', (105, 108))	('SF1126', 'Var', (54, 60))	('AKT', 'Gene', '207', (78, 81))	('SF1126', 'Chemical', 'MESH:C526549', (54, 60))	('MK2206', 'Chemical', 'MESH:C548887', (94, 100))	('AKT', 'Gene', (78, 81))	('GSK2636771', 'Chemical', 'MESH:C000627739', (62, 72))	('PI3K', 'Protein', (37, 41))
222710	32333246	Regarding gallbladder cancer (GBC) is the most common malignancy of the biliary tract, the general genetic abnormalities of PIK3CA (10%) and PTEN (2.3%) are found (Table 1), especially the PIK3CA E545K mutation rate (6.15%).	('genetic abnormalities', 'Disease', 'MESH:D030342', (99, 120))	('PTEN', 'Gene', (141, 145))	('PTEN', 'Gene', '5728', (141, 145))	('genetic abnormalities', 'Disease', (99, 120))	('PIK3CA', 'Gene', (189, 195))	('E545K', 'Mutation', 'rs104886003', (196, 201))	('E545K', 'Var', (196, 201))	('PIK3CA', 'Gene', (124, 130))	('BC', 'Phenotype', 'HP:0003002', (31, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('malignancy', 'Disease', 'MESH:D009369', (54, 64))	('gallbladder cancer', 'Disease', (10, 28))	('gallbladder cancer', 'Disease', 'MESH:D005706', (10, 28))	('malignancy', 'Disease', (54, 64))
222711	32333246	Due to ErbB2 and ErbB3 mutations at a frequency of 7-8% in GBC, ErbB2/ErbB3 mutation inducing PD-L1 overexpression can mediate immune escape of tumor cells via PI3K/AKT pathway in vitro.	('mediate', 'Reg', (119, 126))	('BC', 'Phenotype', 'HP:0003002', (60, 62))	('ErbB3', 'Gene', '2065', (17, 22))	('ErbB3', 'Gene', (70, 75))	('mutation', 'Var', (76, 84))	('overexpression', 'PosReg', (100, 114))	('AKT', 'Gene', (165, 168))	('mutations', 'Var', (23, 32))	('ErbB3', 'Gene', '2065', (70, 75))	('ErbB2', 'Gene', '2064', (64, 69))	('ErbB2', 'Gene', '2064', (7, 12))	('PD-L1', 'Gene', (94, 99))	('tumor', 'Disease', (144, 149))	('PD-L1', 'Gene', '29126', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('AKT', 'Gene', '207', (165, 168))	('ErbB3', 'Gene', (17, 22))	('ErbB2', 'Gene', (64, 69))	('ErbB2', 'Gene', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
222713	32333246	Currently, only MK2206 was tested in clinical trials (NCT01859182 and NCT01425879) in GBC patients.	('GBC', 'Disease', (86, 89))	('NCT01859182', 'Var', (54, 65))	('NCT01425879', 'Var', (70, 81))	('MK2206', 'Chemical', 'MESH:C548887', (16, 22))	('BC', 'Phenotype', 'HP:0003002', (87, 89))	('patients', 'Species', '9606', (90, 98))
222718	32333246	Significantly, the mutations of PIK3CG in PDAC are also revealed.	('PIK3CG', 'Gene', (32, 38))	('PIK3CG', 'Gene', '5294', (32, 38))	('PDAC', 'Chemical', '-', (42, 46))	('mutations', 'Var', (19, 28))
222719	32333246	EG-VEGF, TMEM158, miR-107, as well as LncRNA ABHD11-AS1, SNHG1 and AB209630 are involved in proliferation, apoptosis, metastasis or carcinogenesis of PDAC cells through PI3K/AKT pathway.	('TMEM158', 'Gene', '25907', (9, 16))	('PDAC', 'Chemical', '-', (150, 154))	('AS1', 'Gene', '5729', (52, 55))	('EG-VEGF', 'Gene', (0, 7))	('AB209630', 'Var', (67, 75))	('ABHD11', 'Gene', '83451', (45, 51))	('SNHG1', 'Gene', (57, 62))	('carcinogenesis', 'Disease', (132, 146))	('metastasis', 'CPA', (118, 128))	('ABHD11', 'Gene', (45, 51))	('AKT', 'Gene', '207', (174, 177))	('proliferation', 'CPA', (92, 105))	('apoptosis', 'CPA', (107, 116))	('involved', 'Reg', (80, 88))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('AS1', 'Gene', (52, 55))	('miR-107', 'Gene', (18, 25))	('SNHG1', 'Gene', '23642', (57, 62))	('EG-VEGF', 'Gene', '84432', (0, 7))	('TMEM158', 'Gene', (9, 16))	('miR-107', 'Gene', '406901', (18, 25))	('AKT', 'Gene', (174, 177))
222720	32333246	Plenty of clinical trials of PI3K inhibitors (BKM120, BYL719, GSK2636771, PKI-587, BEZ235 and LY3023414.	('BKM120', 'Chemical', 'MESH:C571178', (46, 52))	('LY3023414', 'Chemical', 'MESH:C000621566', (94, 103))	('LY3023414', 'Var', (94, 103))	('BEZ235', 'Chemical', 'MESH:C531198', (83, 89))	('BKM120', 'Var', (46, 52))	('GSK2636771', 'Chemical', 'MESH:C000627739', (62, 72))
222724	32333246	Compared to the recognized genetically diverse of Her2 and TOP2A of BCs, the overall genetic alterations of PI3K/AKT pathway are not uncommon, especially PIK3CA (37%) and PTEN (8%, Table 1).	('Her2', 'Gene', (50, 54))	('TOP2A', 'Gene', (59, 64))	('PIK3CA', 'Var', (154, 160))	('BC', 'Phenotype', 'HP:0003002', (68, 70))	('AKT', 'Gene', '207', (113, 116))	('Her2', 'Gene', '2064', (50, 54))	('PTEN', 'Gene', (171, 175))	('AKT', 'Gene', (113, 116))	('PTEN', 'Gene', '5728', (171, 175))	('TOP2A', 'Gene', '7153', (59, 64))
222725	32333246	Remarkably, hotspot mutations in PIK3CA are frequent in ER+BCs, which account for up to 80% of BCs, and Her2 mutations hyperactivate the HER3/PI3K/AKT/mTOR axis, leading to anti-ER resistance in ER+BCs.	('BC', 'Phenotype', 'HP:0003002', (95, 97))	('BC', 'Phenotype', 'HP:0003002', (198, 200))	('Her2', 'Gene', '2064', (104, 108))	('ER+BCs', 'Disease', (56, 62))	('BC', 'Phenotype', 'HP:0003002', (59, 61))	('AKT', 'Gene', '207', (147, 150))	('HER3', 'Gene', (137, 141))	('PIK3CA', 'Gene', (33, 39))	('mutations', 'Var', (109, 118))	('HER3', 'Gene', '2065', (137, 141))	('Her2', 'Gene', (104, 108))	('leading to', 'Reg', (162, 172))	('hyperactivate', 'PosReg', (119, 132))	('anti-ER resistance', 'MPA', (173, 191))	('mutations', 'Var', (20, 29))	('AKT', 'Gene', (147, 150))
222726	32333246	Hence, dual blockade of the Her2 and ER pathways is necessary for the treatment of ER+/Her2 mutant BCs.	('Her2', 'Gene', '2064', (28, 32))	('Her2', 'Gene', '2064', (87, 91))	('BC', 'Phenotype', 'HP:0003002', (99, 101))	('men', 'Species', '9606', (75, 78))	('mutant', 'Var', (92, 98))	('Her2', 'Gene', (28, 32))	('Her2', 'Gene', (87, 91))
222727	32333246	Moreover, PIK3CA and MAP3K1 alterations reveal Luminal A status in ER+ metastatic BCs and the patients are likely to clinically benefit from BKM120.	('patients', 'Species', '9606', (94, 102))	('BC', 'Phenotype', 'HP:0003002', (82, 84))	('alterations', 'Var', (28, 39))	('Luminal', 'Chemical', 'MESH:D010634', (47, 54))	('PIK3CA', 'Gene', (10, 16))	('MAP3K1', 'Gene', (21, 27))	('BKM120', 'Chemical', 'MESH:C571178', (141, 147))	('MAP3K1', 'Gene', '4214', (21, 27))	('ER+ metastatic BCs', 'Disease', (67, 85))	('Luminal A status', 'MPA', (47, 63))	('reveal', 'Reg', (40, 46))
222728	32333246	On the other hand, top to 70% of patients with breast cancer brain metastases (BCBM) show the activated PI3K pathway, and GDC-0084 induces apoptosis of PIK3CA-mutant BCBM cells by suppressing activation of AKT and p70 S6 kinase.	('AKT', 'Gene', (206, 209))	('breast cancer brain metastases', 'Disease', 'MESH:D001943', (47, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('p70', 'Gene', (214, 217))	('BCBM', 'Chemical', '-', (79, 83))	('suppressing', 'NegReg', (180, 191))	('BCBM', 'Chemical', '-', (166, 170))	('breast cancer brain metastases', 'Disease', (47, 77))	('AKT', 'Gene', '207', (206, 209))	('PIK3CA-mutant', 'Gene', (152, 165))	('apoptosis', 'CPA', (139, 148))	('GDC-0084', 'Var', (122, 130))	('BC', 'Phenotype', 'HP:0003002', (79, 81))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('p70', 'Gene', '84959', (214, 217))	('PI3K pathway', 'Pathway', (104, 116))	('BC', 'Phenotype', 'HP:0003002', (166, 168))	('patients', 'Species', '9606', (33, 41))	('induces', 'PosReg', (131, 138))
222733	32333246	Ovarian serous cystadenocarcinoma (OSC), the leading common subtype of epithelial ovarian cancers (EOC) accounting for 90% of OC, harbors overall genetic alterations of PIK3CA (29%), PIK3R1 (5%), PIK3R2 (9%), AKT1 (5%), AKT2 (8%) and PTEN (7%, Table 1) besides the mutant p53 in high-grade OSC (HGOSC), germline BRCA1 and BRCA2 mutations.	('p53', 'Gene', '7157', (272, 275))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutant', 'Var', (265, 271))	('Ovarian serous cystadenocarcinoma', 'Disease', (0, 33))	('BRCA1', 'Gene', '672', (312, 317))	('PIK3R1', 'Gene', '5295', (183, 189))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (8, 33))	('OC', 'Phenotype', 'HP:0100615', (100, 102))	('PTEN', 'Gene', (234, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('BRCA1', 'Gene', (312, 317))	('high-grade OSC', 'Disease', (279, 293))	('p53', 'Gene', (272, 275))	('OS', 'Phenotype', 'HP:0002669', (297, 299))	('ovarian cancers', 'Phenotype', 'HP:0100615', (82, 97))	('OS', 'Phenotype', 'HP:0002669', (290, 292))	('OS', 'Phenotype', 'HP:0002669', (35, 37))	('PTEN', 'Gene', '5728', (234, 238))	('AKT1', 'Gene', '207', (209, 213))	('PIK3R2', 'Gene', (196, 202))	('epithelial ovarian cancers', 'Disease', (71, 97))	('BRCA2', 'Gene', (322, 327))	('PIK3R1', 'Gene', (183, 189))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('AKT2', 'Gene', '208', (220, 224))	('PIK3R2', 'Gene', '5296', (196, 202))	('AKT1', 'Gene', (209, 213))	('OC', 'Phenotype', 'HP:0100615', (126, 128))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (71, 97))	('mutations', 'Var', (328, 337))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('BRCA2', 'Gene', '675', (322, 327))	('AKT2', 'Gene', (220, 224))	('Ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (0, 33))
222734	32333246	Furthermore, another subtype of EOC, ovarian clear cell carcinomas (OCCCs), shows more frequently mutations of PIK3CA (33%) and PTEN (5%) in overall 97 OCCC cases, especially mutations of PIK3CA (46%) in the 28 cases of affinity purified OCCCs and OCCC cell lines, than the mutation of PIK3CA and PTEN (both < 5%) in HGOSC.	('PIK3CA', 'Gene', (188, 194))	('CC', 'Phenotype', 'HP:0002664', (69, 71))	('mutations', 'Var', (175, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('ovarian clear cell carcinomas', 'Disease', (37, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('OC', 'Phenotype', 'HP:0100615', (68, 70))	('PTEN', 'Gene', (297, 301))	('CC', 'Phenotype', 'HP:0002664', (153, 155))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (37, 66))	('OC', 'Phenotype', 'HP:0100615', (33, 35))	('CC', 'Phenotype', 'HP:0002664', (249, 251))	('PTEN', 'Gene', (128, 132))	('PIK3CA', 'Gene', (111, 117))	('OS', 'Phenotype', 'HP:0002669', (319, 321))	('PTEN', 'Gene', '5728', (297, 301))	('OC', 'Phenotype', 'HP:0100615', (248, 250))	('OC', 'Phenotype', 'HP:0100615', (238, 240))	('OC', 'Phenotype', 'HP:0100615', (152, 154))	('CC', 'Phenotype', 'HP:0002664', (239, 241))	('PTEN', 'Gene', '5728', (128, 132))	('mutations', 'Var', (98, 107))
222738	32333246	Furthermore, aberrant p53/KRASV12/c-Myc or p53/KRASV12/PI3K/AKT signaling is the minimum requirement for fallopian tube secretory epithelial cells (FTSECs) carcinogenesis, and increased copy number of PIK3CA has been observed in six fallopian tube carcinomas (FTCs).	('copy number', 'Var', (186, 197))	('c-Myc', 'Gene', (34, 39))	('fallopian tube carcinomas', 'Disease', 'MESH:D005185', (233, 258))	('EC', 'Phenotype', 'HP:0012114', (151, 153))	('FTCs', 'Phenotype', 'HP:0030394', (260, 264))	('SE', 'Disease', 'None', (150, 152))	('p53', 'Gene', (43, 46))	('c-Myc', 'Gene', '4609', (34, 39))	('men', 'Species', '9606', (96, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (248, 258))	('carcinogenesis', 'Disease', (156, 170))	('TC', 'Phenotype', 'HP:0002890', (261, 263))	('fallopian tube carcinomas', 'Disease', (233, 258))	('p53', 'Gene', '7157', (22, 25))	('PIK3CA', 'Gene', (201, 207))	('AKT', 'Gene', (60, 63))	('KRAS', 'Gene', '3845', (26, 30))	('aberrant', 'Var', (13, 21))	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('TCs', 'Chemical', 'MESH:D013667', (261, 264))	('fallopian tube carcinomas', 'Phenotype', 'HP:0030394', (233, 258))	('fallopian tube carcinoma', 'Phenotype', 'HP:0030394', (233, 257))	('increased', 'PosReg', (176, 185))	('p53', 'Gene', (22, 25))	('KRAS', 'Gene', (26, 30))	('KRAS', 'Gene', '3845', (47, 51))	('AKT', 'Gene', '207', (60, 63))	('EC', 'Gene', '1913', (151, 153))	('KRAS', 'Gene', (47, 51))	('p53', 'Gene', '7157', (43, 46))	('observed', 'Reg', (217, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
222741	32333246	A litany of genetic alterations induced by HPVs in CC activate four major upstream pathways (GFR, Notch receptor, RAS isoforms and p110alpha) to stimulate host cell survival, proliferation and carcinogenesis through the PI3K/AKT/mTOR pathway.	('GFR', 'Gene', (93, 96))	('p110alpha', 'Gene', (131, 140))	('p110alpha', 'Gene', '5290', (131, 140))	('host cell survival', 'CPA', (155, 173))	('AKT', 'Gene', '207', (225, 228))	('carcinogenesis', 'Disease', (193, 207))	('genetic alterations', 'Var', (12, 31))	('CC', 'Phenotype', 'HP:0002664', (51, 53))	('AKT', 'Gene', (225, 228))	('stimulate', 'PosReg', (145, 154))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('HPV', 'Species', '10566', (43, 46))	('proliferation', 'CPA', (175, 188))
222742	32333246	Considerable overall genetic alterations of PI3K/AKT pathway in CC have emerged with PIK3CA (39%) and PTEN (13%, Table 1).	('AKT', 'Gene', (49, 52))	('CC', 'Phenotype', 'HP:0002664', (64, 66))	('PTEN', 'Gene', (102, 106))	('AKT', 'Gene', '207', (49, 52))	('genetic alterations', 'Var', (21, 40))	('PTEN', 'Gene', '5728', (102, 106))
222743	32333246	In particular, the mutations of PIK3CA E542K and E545K promote glycolysis and proliferation of CC in vitro and vivo.	('CC', 'Phenotype', 'HP:0002664', (95, 97))	('E542K', 'Var', (39, 44))	('E545K', 'Mutation', 'rs104886003', (49, 54))	('E545K', 'Var', (49, 54))	('proliferation', 'CPA', (78, 91))	('E542K', 'Mutation', 'rs121913273', (39, 44))	('promote', 'PosReg', (55, 62))	('glycolysis', 'MPA', (63, 73))	('PIK3CA', 'Gene', (32, 38))
222745	32333246	Currently, only preclinical trials of PI3K inhibitor LY294002 has revealed it significantly radiosensitized CC cell lines in vitro and vivo, and the terminated clinical trials of AKT inhibitor GSK2141795 (NCT01958112, Table 3) has tried to display a novel treatment approach to patients of CC.	('AKT', 'Gene', (179, 182))	('men', 'Species', '9606', (261, 264))	('CC', 'Phenotype', 'HP:0002664', (290, 292))	('LY294002', 'Chemical', 'MESH:C085911', (53, 61))	('radiosensitized', 'NegReg', (92, 107))	('LY294002', 'Var', (53, 61))	('CC', 'Phenotype', 'HP:0002664', (108, 110))	('AKT', 'Gene', '207', (179, 182))	('patients', 'Species', '9606', (278, 286))	('GSK2141795', 'Chemical', 'MESH:C000595149', (193, 203))
222747	32333246	Particularly, the endometrioid type of EC (EEC) progressing from intraepithelial endometrial neoplasia in a large proportion of cases belongs to ER-related cancer, and is directly associated with inactivation of PTEN.	('EC', 'Phenotype', 'HP:0012114', (44, 46))	('endometrioid type', 'Disease', (18, 35))	('inactivation', 'Var', (196, 208))	('EC', 'Gene', '1913', (44, 46))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('neoplasia', 'Phenotype', 'HP:0002664', (93, 102))	('EEC', 'Gene', (43, 46))	('associated', 'Reg', (180, 190))	('EC', 'Gene', '1913', (39, 41))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('EEC', 'Gene', '1913', (43, 46))	('PTEN', 'Gene', (212, 216))	('EC', 'Phenotype', 'HP:0012114', (39, 41))	('PTEN', 'Gene', '5728', (212, 216))	('endometrial neoplasia', 'Disease', 'MESH:D014591', (81, 102))	('endometrial neoplasia', 'Disease', (81, 102))
222749	32333246	What's more, it's revealed that the majority of the G3 EEC samples have exhibited PIK3CA mutations (39%) and PTEN mutations (67%).	('EEC', 'Gene', '1913', (55, 58))	('PIK3CA', 'Gene', (82, 88))	('mutations', 'Var', (114, 123))	('PTEN', 'Gene', (109, 113))	('EC', 'Phenotype', 'HP:0012114', (56, 58))	('PTEN', 'Gene', '5728', (109, 113))	('mutations', 'Var', (89, 98))	('EEC', 'Gene', (55, 58))
222750	32333246	Moreover, JQ1, NEDD4, PDCD4, miR-101, -494-3p, Lnc RNA LINP1 and MEG3 have shown their aptitudes for controlling tumorigenesis, proliferation, apoptosis, invasion, progression of EC cells via PI3K/AKT pathway.	('PDCD4', 'Gene', '27250', (22, 27))	('AKT', 'Gene', (197, 200))	('apoptosis', 'CPA', (143, 152))	('proliferation', 'CPA', (128, 141))	('miR-101', 'Var', (29, 36))	('LINP1', 'Gene', '108570035', (55, 60))	('MEG3', 'Gene', '55384', (65, 69))	('EC', 'Gene', '1913', (179, 181))	('invasion', 'CPA', (154, 162))	('NEDD4', 'Gene', (15, 20))	('tumor', 'Disease', (113, 118))	('progression', 'CPA', (164, 175))	('AKT', 'Gene', '207', (197, 200))	('EC', 'Phenotype', 'HP:0012114', (179, 181))	('controlling', 'PosReg', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LINP1', 'Gene', (55, 60))	('PDCD4', 'Gene', (22, 27))	('NEDD4', 'Gene', '4734', (15, 20))	('MEG3', 'Gene', (65, 69))
222753	32333246	Seeing that loss of function of PTEN, resulting in dysregulated activation of the PI3K signaling network, is recognized as one of the most common driving events in PCa development, the overall genetic alterations of PI3K/AKT pathway in PCa have demonstrated with PIK3CA (6%), and visible PTEN (18%, Table 1).	('PCa', 'Phenotype', 'HP:0012125', (236, 239))	('AKT', 'Gene', '207', (221, 224))	('PI3K signaling network', 'Pathway', (82, 104))	('PTEN', 'Gene', (32, 36))	('dysregulated', 'MPA', (51, 63))	('genetic alterations', 'Var', (193, 212))	('PTEN', 'Gene', '5728', (32, 36))	('PC', 'Phenotype', 'HP:0002894', (236, 238))	('AKT', 'Gene', (221, 224))	('PTEN', 'Gene', (288, 292))	('PCa', 'Phenotype', 'HP:0012125', (164, 167))	('PC', 'Phenotype', 'HP:0002894', (164, 166))	('PTEN', 'Gene', '5728', (288, 292))	('activation', 'PosReg', (64, 74))	('loss of function', 'NegReg', (12, 28))	('men', 'Species', '9606', (175, 178))
222764	32333246	Indeed, PIK3CA mutations are considered as an early genetic alteration associated with FGFR3 mutations in superficial papillary NMIBC and the activation of the PI3K/AKT pathway is identified to induce urothelial carcinoma of the renal pelvis.	('AKT', 'Gene', (165, 168))	('mutations', 'Var', (93, 102))	('activation', 'PosReg', (142, 152))	('FGFR3', 'Gene', '2261', (87, 92))	('renal pelvis', 'Phenotype', 'HP:0000125', (229, 241))	('mutations', 'Var', (15, 24))	('induce', 'Reg', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('FGFR3', 'Gene', (87, 92))	('AKT', 'Gene', '207', (165, 168))	('BC', 'Phenotype', 'HP:0003002', (131, 133))	('urothelial carcinoma of the renal pelvis', 'Disease', 'MESH:C538614', (201, 241))	('urothelial carcinoma of the renal pelvis', 'Disease', (201, 241))	('PIK3CA', 'Gene', (8, 14))
222778	32333246	Furthermore, differences related to EBV status or histological subtypes are observed for PI3K signaling in pediatric HL patients by using hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA), where MCCHL and EBV+ cases were less frequently affected by mutations in ITPKB and GNA13 genes.	('EBV', 'Species', '10376', (244, 247))	('ITPKB', 'Gene', (301, 306))	('CC', 'Phenotype', 'HP:0002664', (235, 237))	('HL', 'CellLine', 'CVCL:2492', (117, 119))	('HL', 'Phenotype', 'HP:0012189', (117, 119))	('GNA13', 'Gene', '10672', (311, 316))	('EBV', 'Species', '10376', (36, 39))	('ITPKB', 'Gene', '3707', (301, 306))	('HL', 'Phenotype', 'HP:0012189', (237, 239))	('CHL', 'Disease', (236, 239))	('HL', 'CellLine', 'CVCL:2492', (237, 239))	('CHL', 'Disease', 'MESH:D006689', (236, 239))	('patients', 'Species', '9606', (120, 128))	('GNA13', 'Gene', (311, 316))	('mutations', 'Var', (288, 297))
222786	32333246	Despite the recognized fact that overwhelming majority of FL cases have the characteristic (14;18) translocation involving the IgH/bcl-2 genes, while B-cells "arrested" in germinal centers of FL acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT pathway, and so on.	('translocation', 'Var', (99, 112))	('AKT', 'Gene', (364, 367))	('BC', 'Phenotype', 'HP:0003002', (343, 345))	('IgH', 'Gene', '3492', (127, 130))	('IgH', 'Gene', (127, 130))	('bcl-2', 'Gene', (131, 136))	('bcl-2', 'Gene', '596', (131, 136))	('men', 'Species', '9606', (311, 314))	('AKT', 'Gene', '207', (364, 367))	('influence', 'Reg', (249, 258))
222787	32333246	Especially, the facts that deletion of PIK3CD results in decreased number of marginal zone (MZ) B cells and pleural/peritoneal cavities in mice, as well as the evidences that PIK3CD-depleted B cells also fail to proliferate in vitro in response to BCR or CD40 signals and have impaired both humoral T-cell-dependent and T-cell-independent responses suggest that p110delta plays a critical role in B cell homeostasis and function.	('T-cell-independent responses', 'CPA', (320, 348))	('PIK3CD', 'Gene', (39, 45))	('impaired both humoral T', 'Disease', (277, 300))	('impaired both humoral T', 'Disease', 'MESH:C562390', (277, 300))	('deletion', 'Var', (27, 35))	('mice', 'Species', '10090', (139, 143))	('BC', 'Phenotype', 'HP:0003002', (248, 250))	('CD40', 'Gene', '21939', (255, 259))	('decreased', 'NegReg', (57, 66))	('CD40', 'Gene', (255, 259))
222788	32333246	Consequently, following with the world's first selective PI3Kdelta inhibitor CAL-101 was approved by the FDA for the treatment of FL, CLL and SLL in 2014 [NCT01282424, NCT02136511], the PI3K/AKT inhibitors have shown remarkable activity in an increasing subset of patients with NHL (Tables 2, 3).	('HL', 'CellLine', 'CVCL:2492', (279, 281))	('SLL', 'Gene', (142, 145))	('AKT', 'Gene', '207', (191, 194))	('NCT02136511]', 'Var', (168, 180))	('CAL-101', 'Chemical', 'MESH:C552946', (77, 84))	('HL', 'Phenotype', 'HP:0012189', (279, 281))	('NHL', 'Disease', (278, 281))	('AKT', 'Gene', (191, 194))	('patients', 'Species', '9606', (264, 272))	('SLL', 'Gene', '347734', (142, 145))	('activity', 'MPA', (228, 236))	('PI3Kdelta', 'Gene', (57, 66))	('men', 'Species', '9606', (122, 125))	('PI3Kdelta', 'Gene', '5293', (57, 66))
222791	32333246	One study shows that deregulation of the PI3K/AKT pathway by the inactivation of PTEN are found in 55% of GCB-DLBCL cases, but only in 14% of non-GCB-DLBCL and worsens prognosis in 248 primary DLBCL patients.	('AKT', 'Gene', '207', (46, 49))	('BC', 'Phenotype', 'HP:0003002', (112, 114))	('deregulation', 'PosReg', (21, 33))	('inactivation', 'Var', (65, 77))	('BC', 'Phenotype', 'HP:0003002', (195, 197))	('AKT', 'Gene', (46, 49))	('PTEN', 'Gene', (81, 85))	('GCB-DLBCL', 'Disease', (106, 115))	('patients', 'Species', '9606', (199, 207))	('PTEN', 'Gene', '5728', (81, 85))	('BC', 'Phenotype', 'HP:0003002', (152, 154))
222794	32333246	Preclinical trial of BAY80-6946 in DLBCL cells and the clinical trials of BAY80-6946, INCB050465, CUDC-907 and MK2206 in patients with DLBCL have improved our ability to manage patients with this disorder (Table 2).	('BAY80-6946', 'Chemical', 'MESH:C000589253', (74, 84))	('INCB050465', 'Var', (86, 96))	('patients', 'Species', '9606', (177, 185))	('MK2206', 'Chemical', 'MESH:C548887', (111, 117))	('BC', 'Phenotype', 'HP:0003002', (137, 139))	('BAY80-6946', 'Var', (74, 84))	('improved', 'PosReg', (146, 154))	('BAY80-6946', 'Chemical', 'MESH:C000589253', (21, 31))	('BAY80-6946', 'Var', (21, 31))	('CUDC-907', 'Chemical', 'MESH:C576940', (98, 106))	('MK2206', 'Var', (111, 117))	('DLBCL', 'Disease', (135, 140))	('patients', 'Species', '9606', (121, 129))	('BC', 'Phenotype', 'HP:0003002', (37, 39))
222795	32333246	T/NK-NHL is a heterogeneous group of malignancies often associated with poor clinical outcomes, and each malignancy within this group is characterized by unique clinicopathologic features, while T cell receptor/NF/kB (TCR/NF/kB) signaling highly enriched and dysregulation of JAK/STAT pathway, specifically aberrant STAT3 activation, are the common feature among these lymphomas.	('STAT', 'Gene', '6774', (280, 284))	('lymphoma', 'Phenotype', 'HP:0002665', (369, 377))	('STAT', 'Gene', (280, 284))	('associated', 'Reg', (56, 66))	('STAT3', 'Gene', (316, 321))	('lymphomas', 'Disease', 'MESH:D008223', (369, 378))	('lymphomas', 'Phenotype', 'HP:0002665', (369, 378))	('HL', 'CellLine', 'CVCL:2492', (6, 8))	('STAT3', 'Gene', '6774', (316, 321))	('aberrant', 'Var', (307, 315))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('TC', 'Phenotype', 'HP:0002890', (218, 220))	('STAT', 'Gene', '6774', (316, 320))	('malignancies', 'Disease', 'MESH:D009369', (37, 49))	('STAT', 'Gene', (316, 320))	('HL', 'Phenotype', 'HP:0012189', (6, 8))	('malignancies', 'Disease', (37, 49))	('activation', 'PosReg', (322, 332))	('lymphomas', 'Disease', (369, 378))	('malignancy', 'Disease', (105, 115))	('dysregulation', 'Var', (259, 272))
222796	32333246	A study with 426 adult T cell leukemia/lymphoma (ATL) cases associated with human T cell leukemia virus type-1 (HTLV-1) infection shows that PI3KCD mutation is also observed in 9 of 370 (2.4%) cases besides the highly enriched for TCR/NF/kB signaling, T cell trafficking and other T cell-related pathways.	('KC', 'Phenotype', 'HP:0009726', (144, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (39, 47))	('human T cell leukemia virus type-1 (HTLV-1) infection', 'Disease', 'MESH:D015490', (76, 129))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('adult T cell leukemia/lymphoma', 'Disease', 'MESH:D015459', (17, 47))	('mutation', 'Var', (148, 156))	('PI3KCD mutation', 'Var', (141, 156))	('TCR/NF/kB signaling', 'Pathway', (231, 250))	('TC', 'Phenotype', 'HP:0002890', (231, 233))	('adult T cell leukemia/lymphoma', 'Disease', (17, 47))
222800	32333246	Despite that hotspot mutations of PIK3CA (E542K, E545K and H1047R) and AKT1 genes (E17K) are absent in MM, the R310C mutation of PIK3CA gene is identified in some cases of MM, as well as ROR2 drives the interaction of MM cells with TME through AKT activation.	('R310C', 'Var', (111, 116))	('E545K', 'Var', (49, 54))	('ROR2', 'Gene', '4920', (187, 191))	('ROR2', 'Gene', (187, 191))	('AKT1', 'Gene', (71, 75))	('R310C', 'Mutation', 'rs780572147', (111, 116))	('PIK3CA', 'Gene', (34, 40))	('AKT', 'Gene', '207', (71, 74))	('AKT', 'Gene', (244, 247))	('H1047R', 'Var', (59, 65))	('activation', 'PosReg', (248, 258))	('PIK3CA', 'Gene', (129, 135))	('interaction', 'Interaction', (203, 214))	('H1047R', 'Mutation', 'rs121913279', (59, 65))	('E542K', 'Mutation', 'rs121913273', (42, 47))	('E542K', 'Var', (42, 47))	('AKT', 'Gene', '207', (244, 247))	('E17K', 'Mutation', 'rs121434592', (83, 87))	('E545K', 'Mutation', 'rs104886003', (49, 54))	('AKT', 'Gene', (71, 74))	('AKT1', 'Gene', '207', (71, 75))
222801	32333246	Furthermore, only the blockade of PIK3CA is sufficient to induce cell death in a sizeable subgroup of MM samples, and PIK3CA inhibitor BYL-719 in combination treatments with other compounds establishes anti-myeloma agents resulted in strongly enhanced MM cell death.	('myeloma', 'Disease', (207, 214))	('enhanced', 'PosReg', (243, 251))	('death', 'Disease', 'MESH:D003643', (260, 265))	('PIK3CA', 'Gene', (34, 40))	('blockade', 'Var', (22, 30))	('MM cell death', 'Disease', (252, 265))	('men', 'Species', '9606', (163, 166))	('MM cell death', 'Disease', 'MESH:D003643', (252, 265))	('death', 'Disease', (260, 265))	('myeloma', 'Disease', 'MESH:D009101', (207, 214))	('death', 'Disease', 'MESH:D003643', (70, 75))	('death', 'Disease', (70, 75))	('PIK3CA', 'Gene', (118, 124))	('BYL-719', 'Chemical', 'MESH:C585539', (135, 142))
222802	32333246	Therefore, some preclinical studies have examined PI3K/AKT pathway inhibitors in MM, such as TAS-117, PI-103 and BEZ235.	('PI-103', 'Var', (102, 108))	('AKT', 'Gene', (55, 58))	('BEZ235', 'Chemical', 'MESH:C531198', (113, 119))	('PI-103', 'Chemical', 'MESH:C522973', (102, 108))	('AKT', 'Gene', '207', (55, 58))	('TAS', 'Chemical', 'MESH:D013635', (93, 96))
222803	32333246	Fortunately, some of the clinical trials of PI3K/AKT inhibitors have demonstrated encouraging clinical activity in relapsed and relapsed/refractory (R/R) MM (NCT01002248; NCT01476137; NCT00881946) (Tables 2 and 3).	('AKT', 'Gene', '207', (49, 52))	('NCT01002248', 'Var', (158, 169))	('AKT', 'Gene', (49, 52))
222810	32333246	Since CAL-101 has been approved for marketing in patients with CLL/SLL, the clinical trials of PI3K/AKT inhibitors such as: BAY80-6946, KM120, YY-20394, BEZ235, PKI-587, IPI-145, CAL-101, TGR-1202, MK2206 and GSK2141795 try to seek new therapeutic approach in relapse or refractory patients with CLL or newly diagnosed AML and acute lymphocytic leukemia (ALL, Tables 2 and 3).	('KM120', 'Var', (136, 141))	('AML', 'Disease', 'MESH:D015470', (319, 322))	('AML', 'Disease', (319, 322))	('CAL-101', 'Chemical', 'MESH:C552946', (179, 186))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (327, 353))	('AML', 'Phenotype', 'HP:0004808', (319, 322))	('AKT', 'Gene', (100, 103))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (327, 353))	('IPI-145', 'Chemical', 'MESH:C586691', (170, 177))	('patients', 'Species', '9606', (282, 290))	('GSK2141795', 'Chemical', 'MESH:C000595149', (209, 219))	('leukemia', 'Phenotype', 'HP:0001909', (345, 353))	('MK2206', 'Chemical', 'MESH:C548887', (198, 204))	('patients', 'Species', '9606', (49, 57))	('BAY80-6946', 'Chemical', 'MESH:C000589253', (124, 134))	('AKT', 'Gene', '207', (100, 103))	('SLL', 'Gene', '347734', (67, 70))	('CLL', 'Disease', (296, 299))	('SLL', 'Gene', (67, 70))	('acute lymphocytic leukemia', 'Disease', (327, 353))	('CAL-101', 'Chemical', 'MESH:C552946', (6, 13))	('BEZ235', 'Chemical', 'MESH:C531198', (153, 159))
222814	32333246	Besides the alterations of TP53, RB1, ATRX and DLG2 in OS, total genetic alterations in the PI3K/AKT/mTOR pathway are observed in 14 of 59 (24%) OS patients, and PIK3CA and mTOR are vital for the proliferation and survival of OS cells (Table 1).	('TP53', 'Gene', '7157', (27, 31))	('patients', 'Species', '9606', (148, 156))	('TP53', 'Gene', (27, 31))	('alterations', 'Reg', (73, 84))	('AKT', 'Gene', '207', (97, 100))	('OS', 'Phenotype', 'HP:0002669', (55, 57))	('OS', 'Phenotype', 'HP:0002669', (145, 147))	('alterations', 'Var', (12, 23))	('DLG2', 'Gene', '1740', (47, 51))	('ATRX', 'Gene', (38, 42))	('AKT', 'Gene', (97, 100))	('RB1', 'Gene', (33, 36))	('OS', 'Phenotype', 'HP:0002669', (226, 228))	('ATRX', 'Gene', '546', (38, 42))	('DLG2', 'Gene', (47, 51))	('RB1', 'Gene', '5925', (33, 36))
222815	32333246	Furthermore, dual PI3K/mTOR inhibitors are effective at inducing apoptosis in primary OS cell cultures in vitro in both human and mouse OS, while specific PI3K or mTOR inhibitors are not effective, which is consistent with the preclinical study's result that BEZ235 inhibits proliferation and tumor development of OS cells in vivo.	('human', 'Species', '9606', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('men', 'Species', '9606', (306, 309))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('OS', 'Phenotype', 'HP:0002669', (136, 138))	('inducing', 'Reg', (56, 64))	('tumor', 'Disease', (293, 298))	('apoptosis', 'CPA', (65, 74))	('BEZ235', 'Chemical', 'MESH:C531198', (259, 265))	('inhibits', 'NegReg', (266, 274))	('OS', 'Phenotype', 'HP:0002669', (86, 88))	('PI3K/mTOR', 'Var', (18, 27))	('mouse', 'Species', '10090', (130, 135))	('OS', 'Phenotype', 'HP:0002669', (314, 316))
222819	32333246	In addition, hnRNPM motifs are significantly enriched under the inhibition of the PI3K/AKT/mTOR pathway by BEZ235 in EWS cells.	('EWS', 'Phenotype', 'HP:0012254', (117, 120))	('EWS', 'Gene', '2130', (117, 120))	('EWS', 'Gene', (117, 120))	('AKT', 'Gene', (87, 90))	('BEZ235', 'Var', (107, 113))	('inhibition', 'NegReg', (64, 74))	('BEZ235', 'Chemical', 'MESH:C531198', (107, 113))	('hnRNPM', 'Gene', (13, 19))	('hnRNPM', 'Gene', '4670', (13, 19))	('AKT', 'Gene', '207', (87, 90))
222821	32333246	Currently, pediatric patients of OS or EWS may be beneficial from the ongoing clinical trials of BAY80-6946 (NCT03458728) and LY3023414 (NCT03213678, Table 2).	('BAY80-6946', 'Chemical', 'MESH:C000589253', (97, 107))	('OS', 'Phenotype', 'HP:0002669', (33, 35))	('NCT03458728', 'Var', (109, 120))	('patients', 'Species', '9606', (21, 29))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', (39, 42))	('EWS', 'Phenotype', 'HP:0012254', (39, 42))	('LY3023414', 'Chemical', 'MESH:C000621566', (126, 135))	('BAY80-6946 (NCT03458728', 'Var', (97, 120))	('LY3023414', 'Var', (126, 135))
222824	32333246	Even though solar ultraviolet exposure is the main environmental risk factor for cutaneous melanoma development, there are still genetic susceptibility factors, such as germline mutations in p16 or CDK4, and genesis of melanoma, such as the main genetic drivers BRAF, NF1 and NRAS mutations.	('men', 'Species', '9606', (107, 110))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('CDK4', 'Gene', '1019', (198, 202))	('NRAS', 'Gene', '4893', (276, 280))	('BRAF', 'Gene', (262, 266))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('NF1', 'Gene', '4763', (268, 271))	('p16', 'Gene', (191, 194))	('NF1', 'Gene', (268, 271))	('NRAS', 'Gene', (276, 280))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('p16', 'Gene', '1029', (191, 194))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('melanoma', 'Disease', (219, 227))	('CDK4', 'Gene', (198, 202))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))	('mutations', 'Var', (281, 290))	('cutaneous melanoma', 'Disease', (81, 99))	('mutations', 'Var', (178, 187))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 99))	('men', 'Species', '9606', (58, 61))
222825	32333246	Since BRAFV600E-mutated melanomagenesis is often accompanied by silencing of PTEN, the increasing genetic alterations in PI3K/AKT pathway have been observed in melanoma including: PIK3CA (5%) and PTEN (12%, Table 1).	('BRAFV600E', 'Mutation', 'rs113488022', (6, 15))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('AKT', 'Gene', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (77, 81))	('PTEN', 'Gene', (196, 200))	('silencing', 'NegReg', (64, 73))	('AKT', 'Gene', '207', (126, 129))	('PTEN', 'Gene', '5728', (196, 200))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('BRAFV600E-mutated', 'Var', (6, 23))
222826	32333246	Notably, dysfunction mutations of NF1 induce BRAF inhibitor resistance by activating RAS and its downstreams including both MAPK and PI3K/AKT/mTOR pathways in cutaneous melanoma.	('activating', 'PosReg', (74, 84))	('MAPK', 'Pathway', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('AKT', 'Gene', (138, 141))	('dysfunction mutations', 'Var', (9, 30))	('cutaneous melanoma', 'Disease', (159, 177))	('RAS', 'Pathway', (85, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (159, 177))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (159, 177))	('BRAF inhibitor resistance', 'MPA', (45, 70))	('NF1', 'Gene', (34, 37))	('NF1', 'Gene', '4763', (34, 37))	('AKT', 'Gene', '207', (138, 141))
222827	32333246	Even more, the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma can be forestalled by PI3K blockade.	('MEK', 'Gene', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('MEK', 'Gene', '5609', (24, 27))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('BRAF-mutated', 'Var', (55, 67))
222829	32333246	And now, a limited number of clinical trials of PI3K/AKT pathway inhibitors (BKM120, PX-866, GSK2636771, GSK2141795 and MK2206) try to find new ways other than current classic RAF/MEK/MAPK pathway inhibitors to treat the patients with metastatic or advanced melanomas (Tables 2 and 3).	('patients', 'Species', '9606', (221, 229))	('melanomas', 'Disease', 'MESH:D008545', (258, 267))	('melanomas', 'Disease', (258, 267))	('MEK', 'Gene', '5609', (180, 183))	('RAF', 'Gene', (176, 179))	('PX-866', 'Chemical', 'MESH:C496788', (85, 91))	('MEK', 'Gene', (180, 183))	('AKT', 'Gene', (53, 56))	('melanomas', 'Phenotype', 'HP:0002861', (258, 267))	('MK2206', 'Chemical', 'MESH:C548887', (120, 126))	('BKM120', 'Chemical', 'MESH:C571178', (77, 83))	('GSK2636771', 'Chemical', 'MESH:C000627739', (93, 103))	('RAF', 'Gene', '673;109880', (176, 179))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('GSK2141795', 'Chemical', 'MESH:C000595149', (105, 115))	('metastatic', 'Disease', (235, 245))	('MK2206', 'Var', (120, 126))	('AKT', 'Gene', '207', (53, 56))	('GSK2141795', 'Var', (105, 115))
222830	32333246	In general, ATC, NSCLC, EC, GC, CRC, BC, OC, CC, EC and BLCA exhibit higher frequencies of PIK3CA mutations than other tumors, while PTEN mutations are predominantly found in GBM, EC and PCa (Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('NSCLC', 'Disease', (17, 22))	('EC', 'Phenotype', 'HP:0012114', (24, 26))	('CC', 'Phenotype', 'HP:0002664', (45, 47))	('PCa', 'Disease', (187, 190))	('EC', 'Phenotype', 'HP:0012114', (180, 182))	('PTEN', 'Gene', '5728', (133, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('LC', 'Phenotype', 'HP:0100526', (20, 22))	('PIK3CA', 'Gene', (91, 97))	('tumors', 'Disease', (119, 125))	('GBM', 'Disease', (175, 178))	('SCLC', 'Phenotype', 'HP:0030357', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('CRC', 'Disease', (32, 35))	('TC', 'Phenotype', 'HP:0002890', (13, 15))	('EC', 'Gene', '1913', (49, 51))	('LC', 'Phenotype', 'HP:0100526', (57, 59))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('OC', 'Phenotype', 'HP:0100615', (41, 43))	('BLCA', 'Phenotype', 'HP:0009725', (56, 60))	('BC', 'Phenotype', 'HP:0003002', (37, 39))	('PC', 'Phenotype', 'HP:0002894', (187, 189))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('EC', 'Gene', '1913', (24, 26))	('mutations', 'Var', (98, 107))	('PTEN', 'Gene', (133, 137))	('EC', 'Phenotype', 'HP:0012114', (49, 51))	('EC', 'Gene', '1913', (180, 182))	('PCa', 'Phenotype', 'HP:0012125', (187, 190))
222831	32333246	No matter what kind of the genetic alteration happens in PI3K/AKT pathway, or the factor influences cellular behaviors via PI3K/AKT pathway, it leads to the hyper-activation of PI3K/AKT pathway.	('AKT', 'Gene', (62, 65))	('influences', 'Reg', (89, 99))	('AKT', 'Gene', (128, 131))	('cellular behaviors', 'CPA', (100, 118))	('AKT', 'Gene', '207', (182, 185))	('genetic alteration', 'Var', (27, 45))	('AKT', 'Gene', '207', (62, 65))	('alteration', 'Var', (35, 45))	('AKT', 'Gene', '207', (128, 131))	('hyper-activation', 'PosReg', (157, 173))	('AKT', 'Gene', (182, 185))
222837	32333246	Obviously, CAL-101 not only causes a rapid and sustained reduction in lymphadenopathy, but also regulates the immune environment in CLL.	('immune environment', 'MPA', (110, 128))	('lymphadenopathy', 'Disease', (70, 85))	('men', 'Species', '9606', (124, 127))	('reduction', 'NegReg', (57, 66))	('CAL-101', 'Var', (11, 18))	('lymphadenopathy', 'Disease', 'MESH:D008206', (70, 85))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (70, 85))	('regulates', 'Reg', (96, 105))	('CAL-101', 'Chemical', 'MESH:C552946', (11, 18))
222840	32333246	There are some other embarrassments findings that small molecule PI3K/AKT pathway inhibitors could promote the (re)phosphorylation of AKT2 which is linked to the redistribution and adaptive reprogramming of mitochondria, contributing to drug resistance and metastasis in GBM cells.	('AKT', 'Gene', (134, 137))	('metastasis', 'CPA', (257, 267))	('AKT', 'Gene', '207', (70, 73))	('drug resistance', 'CPA', (237, 252))	('drug resistance', 'Phenotype', 'HP:0020174', (237, 252))	('promote', 'PosReg', (99, 106))	('AKT', 'Gene', (70, 73))	('contributing', 'Reg', (221, 233))	('inhibitors', 'Var', (82, 92))	('AKT2', 'Gene', (134, 138))	('AKT', 'Gene', '207', (134, 137))	('men', 'Species', '9606', (30, 33))	('AKT2', 'Gene', '208', (134, 138))
222843	30376049	RTPDB: a database providing associations between genetic variation or expression and cancer prognosis with radiotherapy-based treatment In recent years, lots of studies have reported the relationship between genetic variation or expression and cancer prognosis with radiotherapy-based treatment.	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('genetic variation', 'Var', (208, 225))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
222846	30376049	It included 775 studies, which consist of 275 Single Nucleotide Polymorphism (SNP) studies with 59 765 patients, 261 genes, 708 SNPs, 16 tumors and 16 treatment types, and 500 expression studies with 55 751 patients, 264 genes, 27 tumors and 15 treatment types.	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('patients', 'Species', '9606', (207, 215))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('Single Nucleotide Polymorphism', 'Var', (46, 76))	('patients', 'Species', '9606', (103, 111))	('tumors', 'Disease', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
222859	30376049	In this paper, we describe the Radiotherapy Prognosis Database (RTPDB), a comprehensive online database established to collect the associations between genetic variants or expression and cancer prognosis of patients who received radiotherapy-based treatment and were documented in biomedical literature.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', (187, 193))	('associations', 'Interaction', (131, 143))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('variants', 'Var', (160, 168))
222863	30376049	Articles published before August 2018 were searched with a combination of mesh term and keywords as follows: Single Nucleotide Polymorphisms, Gene Expression Neoplasms, Radiotherapy and Prognosis.	('Neoplasms', 'Phenotype', 'HP:0002664', (158, 167))	('Neoplasms', 'Disease', 'MESH:D009369', (158, 167))	('Neoplasms', 'Disease', (158, 167))	('Single Nucleotide Polymorphisms', 'Var', (109, 140))
222864	30376049	The literature was included according to the following criteria: (1) studying the relationship between gene variants or expression and cancer prognosis, (2) patients received radiotherapy with or without other treatments and (3) using one of the statistics that Odds Ratio (OR), Hazard Radio (HR) and Risk ratio (RR) and their 95% Confidence Interval (CI) to evaluate the relationship.	('cancer', 'Disease', (135, 141))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('variants', 'Var', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
222878	30376049	To meet the need of RTPDB construction, we selected literatures that provide the association between gene variants or gene expression and cancer prognosis of patients who received radiotherapy-based treatment.	('association', 'Interaction', (81, 92))	('cancer', 'Disease', (138, 144))	('variants', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('patients', 'Species', '9606', (158, 166))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
222886	30376049	Each relationship contains four major items, which are tumor, gene with variant or expression, prognosis with endpoint and OR/HR/RR with 95% CI.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('expression', 'MPA', (83, 93))	('variant', 'Var', (72, 79))
222891	30376049	With the development of studies, more cancer prognosis-related genes and variants are expected to be published and included into RTPDB.	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('variants', 'Var', (73, 81))	('cancer', 'Disease', (38, 44))
222913	26942702	Our previous studies demonstrated that the infiltration of IL-17-producing cells in the cancer nest was correlated with better overall survival (OS) of ESCC patients.	('IL-17', 'Gene', (59, 64))	('IL-17', 'Gene', '3605', (59, 64))	('cancer', 'Disease', (88, 94))	('better', 'PosReg', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('infiltration', 'Var', (43, 55))	('patients', 'Species', '9606', (157, 165))	('overall survival', 'MPA', (127, 143))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ESCC', 'Disease', (152, 156))
223074	25785604	The median survival time was 31.9 months for the high M/C ratio patients, which was significantly longer than the survival time for the low M/C ratio patients (18.8 months) (Fig.	('patients', 'Species', '9606', (150, 158))	('longer', 'PosReg', (98, 104))	('high M/C ratio', 'Var', (49, 63))	('patients', 'Species', '9606', (64, 72))
223078	25785604	In the multivariate Cox's regression analysis adjusted for tumor grade, the M/C of p120ctn with T and N status and M/C of p120ctn with N status alone predicted a 1.84- and 0.49-fold risk of ESCC death, respectively (p = 0.027, 95% CI 1.07-3.18 and p = 0.007, 95% CI 0.29-0.83) (Fig.	('tumor', 'Disease', (59, 64))	('ESCC death', 'Disease', (190, 200))	('M/C', 'Var', (76, 79))	('p120ctn', 'Gene', (122, 129))	('p120ctn', 'Gene', '1500', (122, 129))	('p120ctn', 'Gene', (83, 90))	('ESCC death', 'Disease', 'MESH:D004938', (190, 200))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('p120ctn', 'Gene', '1500', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
223117	33613500	Indeed, H. pylori is believed to be closely involved in the chronic inflammation behind duodenal ulcers and gastric diseases, and therefore it is crucial to understand how H. pylori causes the progression from acute inflammation of the mucosa to GC.	('involved', 'Reg', (44, 52))	('duodenal ulcers', 'Disease', 'MESH:D004381', (88, 103))	('duodenal ulcers', 'Phenotype', 'HP:0002588', (88, 103))	('gastric diseases', 'Disease', (108, 124))	('H. pylori', 'Species', '210', (172, 181))	('gastric diseases', 'Disease', 'MESH:D013272', (108, 124))	('duodenal ulcer', 'Phenotype', 'HP:0002588', (88, 102))	('causes', 'Reg', (182, 188))	('GC', 'Gene', '14473', (246, 248))	('duodenal ulcers', 'Disease', (88, 103))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('inflammation', 'Disease', 'MESH:D007249', (216, 228))	('inflammation', 'Disease', (68, 80))	('GC', 'Phenotype', 'HP:0012126', (246, 248))	('H. pylori', 'Species', '210', (8, 17))	('H. pylori', 'Var', (172, 181))	('inflammation', 'Disease', (216, 228))
223143	33613500	H. pylori can cause chronic gastritis, along with loss of gastric acidity, which leads to bacterial growth in the stomach.	('chronic gastritis', 'Disease', 'MESH:D005756', (20, 37))	('leads to', 'Reg', (81, 89))	('H. pylori', 'Species', '210', (0, 9))	('chronic gastritis', 'Disease', (20, 37))	('loss of gastric acidity', 'Disease', 'MESH:D005764', (50, 73))	('cause', 'Reg', (14, 19))	('gastritis', 'Phenotype', 'HP:0005263', (28, 37))	('loss of gastric acidity', 'Disease', (50, 73))	('H. pylori', 'Var', (0, 9))	('chronic gastritis', 'Phenotype', 'HP:0005231', (20, 37))
223144	33613500	Nowadays, the effects that eradication of H. pylori might have on the risk for GC and esophageal cancer are debatable.	('GC', 'Gene', '14473', (79, 81))	('eradication', 'Var', (27, 38))	('H. pylori', 'Gene', (42, 51))	('GC', 'Phenotype', 'HP:0012126', (79, 81))	('esophageal cancer', 'Disease', (86, 103))	('H. pylori', 'Species', '210', (42, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
223145	33613500	Indeed, GC is not only associated with H. pylori infection, but also with several additional etiological factors and their combinations with H. pylori infection, such as gastric ulcers and adenomatous polyps, blood group, gene mutations, obesity, exposure to dust and metals, tobacco, hookah, and opium use, and alcohol consumption (Figure 2).	('H. pylori infection', 'Phenotype', 'HP:0005202', (39, 58))	('adenomatous polyps', 'Disease', (189, 207))	('obesity', 'Phenotype', 'HP:0001513', (238, 245))	('GC', 'Phenotype', 'HP:0012126', (8, 10))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (189, 207))	('gastric ulcers', 'Disease', 'MESH:D013276', (170, 184))	('H. pylori', 'Species', '210', (39, 48))	('gastric ulcers', 'Phenotype', 'HP:0002592', (170, 184))	('H. pylori', 'Species', '210', (141, 150))	('gene mutations', 'Var', (222, 236))	('adenomatous polyps', 'Disease', 'MESH:D018256', (189, 207))	('pylori infection', 'Disease', 'MESH:D016481', (42, 58))	('associated', 'Reg', (23, 33))	('gastric ulcers', 'Disease', (170, 184))	('obesity', 'Disease', (238, 245))	('pylori infection', 'Disease', 'MESH:D016481', (144, 160))	('obesity', 'Disease', 'MESH:D009765', (238, 245))	('pylori infection', 'Disease', (42, 58))	('alcohol', 'Chemical', 'MESH:D000438', (312, 319))	('GC', 'Gene', '14473', (8, 10))	('H. pylori infection', 'Phenotype', 'HP:0005202', (141, 160))	('pylori infection', 'Disease', (144, 160))	('tobacco', 'Species', '4097', (276, 283))
223148	33613500	Asian populations also show interleukin (IL)-10 and IL-17 polymorphisms that are associated with elevated risk of neoplasia.	('IL-17', 'Gene', '3605', (52, 57))	('neoplasia', 'Disease', (114, 123))	('IL-17', 'Gene', (52, 57))	('interleukin (IL)-10', 'Gene', (28, 47))	('polymorphisms', 'Var', (58, 71))	('neoplasia', 'Disease', 'MESH:D009369', (114, 123))	('neoplasia', 'Phenotype', 'HP:0002664', (114, 123))	('associated', 'Reg', (81, 91))	('interleukin (IL)-10', 'Gene', '3586', (28, 47))
223150	33613500	demonstrated that the polymorphism of IL-17F 7488 is involved in susceptibility to gastric cancer associated with IL-17-induced inflammation in response to H. pylori infection.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (65, 97))	('H. pylori infection', 'Phenotype', 'HP:0005202', (156, 175))	('polymorphism', 'Var', (22, 34))	('IL-17', 'Gene', '3605', (38, 43))	('IL-17', 'Gene', (38, 43))	('gastric cancer', 'Disease', (83, 97))	('pylori infection', 'Disease', 'MESH:D016481', (159, 175))	('H. pylori', 'Species', '210', (156, 165))	('inflammation', 'Disease', 'MESH:D007249', (128, 140))	('susceptibility', 'Reg', (65, 79))	('IL-17F', 'Gene', (38, 44))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('associated', 'Reg', (98, 108))	('pylori infection', 'Disease', (159, 175))	('involved', 'Reg', (53, 61))	('inflammation', 'Disease', (128, 140))	('IL-17F', 'Gene', '112744', (38, 44))	('IL-17', 'Gene', (114, 119))	('IL-17', 'Gene', '3605', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
223151	33613500	These results indicate that genetic variations in inflammation-related genes may play a role in the outcome of H. pylori infection and development of gastric lesions.	('H. pylori infection', 'Phenotype', 'HP:0005202', (111, 130))	('pylori infection', 'Disease', (114, 130))	('inflammation', 'Disease', 'MESH:D007249', (50, 62))	('inflammation', 'Disease', (50, 62))	('play', 'Reg', (81, 85))	('role', 'Reg', (88, 92))	('gastric lesions', 'Disease', 'MESH:D013272', (150, 165))	('pylori infection', 'Disease', 'MESH:D016481', (114, 130))	('H. pylori', 'Species', '210', (111, 120))	('gastric lesions', 'Disease', (150, 165))	('genetic variations', 'Var', (28, 46))
223156	33613500	Salt can erode the protective stomach mucosa, and cultures where diets are rich in salt and pickled foods (e.g., Japan) are associated with high rates of GC.	('protective stomach', 'MPA', (19, 37))	('salt', 'Chemical', 'MESH:D012492', (83, 87))	('Salt', 'Var', (0, 4))	('Salt', 'Chemical', 'MESH:D012492', (0, 4))	('GC', 'Gene', '14473', (154, 156))	('GC', 'Phenotype', 'HP:0012126', (154, 156))	('erode', 'NegReg', (9, 14))
223222	33613500	Considering again the H. pylori virulence factors, it has been shown that a mutation in bacterial cell shape determinants results in a straight rod morphology for H. pylori, which reduces the speed of H. pylori movement by 7-21%.	('H. pylori', 'Species', '210', (22, 31))	('results in', 'Reg', (122, 132))	('straight rod morphology', 'MPA', (135, 158))	('H. pylori', 'Gene', (163, 172))	('reduces', 'NegReg', (180, 187))	('H. pylori', 'Species', '210', (201, 210))	('H. pylori', 'Species', '210', (163, 172))	('mutation', 'Var', (76, 84))	('speed', 'MPA', (192, 197))
223245	33613500	In this regard, high expression of polymorphisms in the gene of toll-like receptor 9 (TLR9), an innate immune receptor which detects DNA motifs located in microbial genomes, has been associated with the onset of premalignant lesions in the stomach.	('TLR9', 'Gene', (86, 90))	('toll-like receptor 9', 'Gene', (64, 84))	('premalignant lesions', 'Disease', (212, 232))	('premalignant lesions in the stomach', 'Phenotype', 'HP:0006753', (212, 247))	('TLR9', 'Gene', '54106', (86, 90))	('expression', 'MPA', (21, 31))	('toll-like receptor 9', 'Gene', '54106', (64, 84))	('polymorphisms', 'Var', (35, 48))	('associated with', 'Reg', (183, 198))
223271	33613500	A recent study revealed a role for gammaGT in increased VacA-dependent vacuolation in epithelial cells, which appears to be mediated through extracellular glutamine hydrolysis.	('VacA', 'Gene', (56, 60))	('glutamine', 'Chemical', 'MESH:D005973', (155, 164))	('increased', 'PosReg', (46, 55))	('gammaGT', 'Var', (35, 42))	('VacA', 'Gene', 'None', (56, 60))
223296	33613500	It has also been suggested that high gene amplification of the EGFR is related to poor patient outcome.	('EGFR', 'Gene', '1956', (63, 67))	('related', 'Reg', (71, 78))	('EGFR', 'Gene', (63, 67))	('high gene amplification', 'Var', (32, 55))	('patient', 'Species', '9606', (87, 94))
223299	33613500	In a comparison with diffuse-type tumors, ErbB2 overexpression showed greater prevalence for intestinal-type and gastroesophageal junction tumors.	('intestinal-type', 'Disease', (93, 108))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('overexpression', 'Var', (48, 62))	('ErbB2', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('ErbB2', 'Gene', '2064', (42, 47))	('gastroesophageal junction tumors', 'Disease', (113, 145))	('gastroesophageal junction tumors', 'Disease', 'MESH:D008309', (113, 145))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
223300	33613500	Many studies have shown ErbB2 positivity to be indicative of poor patient prognosis; however, other studies have also not observed any association between ErbB2 status and patient outcome.	('positivity', 'Var', (30, 40))	('ErbB2', 'Gene', '2064', (155, 160))	('patient', 'Species', '9606', (172, 179))	('patient', 'Species', '9606', (66, 73))	('ErbB2', 'Gene', (24, 29))	('ErbB2', 'Gene', (155, 160))	('ErbB2', 'Gene', '2064', (24, 29))
223308	33613500	This study concluded that CagA appears to be a candidate biomarker for ErbB2 amplification, and might promote development of GC through induction of ErbB2 amplification and overexpression.	('amplification', 'Var', (155, 168))	('overexpression', 'PosReg', (173, 187))	('ErbB2', 'Gene', (71, 76))	('CagA', 'Gene', (26, 30))	('CagA', 'Gene', '6279', (26, 30))	('ErbB2', 'Gene', '2064', (149, 154))	('GC', 'Phenotype', 'HP:0012126', (125, 127))	('amplification', 'Var', (77, 90))	('ErbB2', 'Gene', '2064', (71, 76))	('promote', 'PosReg', (102, 109))	('development', 'CPA', (110, 121))	('ErbB2', 'Gene', (149, 154))	('GC', 'Gene', '14473', (125, 127))
223309	33613500	In contrast, the CagA effects on cell scattering and elongation are antagonized by VacA through inactivation of the EGFRs, including ErbB2, and their downstream signaling, which leads to suppression of MAPK activity and consequently of the "hummingbird" phenotype.	('EGFR', 'Gene', '1956', (116, 120))	('activity', 'MPA', (207, 215))	('ErbB2', 'Gene', '2064', (133, 138))	('inactivation', 'Var', (96, 108))	('CagA', 'Gene', (17, 21))	('CagA', 'Gene', '6279', (17, 21))	('suppression', 'NegReg', (187, 198))	('cell scattering', 'CPA', (33, 48))	('VacA', 'Gene', 'None', (83, 87))	('elongation', 'CPA', (53, 63))	('VacA', 'Gene', (83, 87))	('MAPK', 'Enzyme', (202, 206))	('EGFR', 'Gene', (116, 120))	('ErbB2', 'Gene', (133, 138))
223326	33613500	The hypothesis behind the SUNC effectiveness for eradication of H. pylori infection relies on the ability of the nanoparticles to penetrate through the biofilm extracellular polymeric substances matrix: SUNCs can then disrupt the biofilm to induce cell death, and also promote cell detachment from the surface, and reduce drug resistance.	('pylori infection', 'Disease', 'MESH:D016481', (67, 83))	('death', 'Disease', (253, 258))	('drug resistance', 'Phenotype', 'HP:0020174', (322, 337))	('pylori infection', 'Disease', (67, 83))	('reduce', 'NegReg', (315, 321))	('H. pylori', 'Species', '210', (64, 73))	('SUNCs', 'Var', (203, 208))	('H. pylori infection', 'Phenotype', 'HP:0005202', (64, 83))	('drug resistance', 'MPA', (322, 337))	('induce', 'PosReg', (241, 247))	('biofilm', 'CPA', (230, 237))	('promote', 'PosReg', (269, 276))	('disrupt', 'NegReg', (218, 225))	('cell detachment from the surface', 'CPA', (277, 309))	('death', 'Disease', 'MESH:D003643', (253, 258))
223376	33613500	Indeed, in a meta-analysis by, they showed that a polymorphism in phospholipase C-epsilon1 resulted in significant risk for gastric and esophageal tumors in Asian (Chinese) populations, although this was not seen for Caucasians.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('gastric and esophageal tumors', 'Disease', 'MESH:D013274', (124, 153))	('phospholipase C-epsilon1', 'Gene', '51196', (66, 90))	('esophageal tumors', 'Phenotype', 'HP:0100751', (136, 153))	('polymorphism', 'Var', (50, 62))	('risk', 'Reg', (115, 119))	('phospholipase C-epsilon1', 'Gene', (66, 90))
223382	33613500	Seropositivity for H. pylori was associated with a significantly lower rate of long-segment Barrett's esophagus (odds ratio, 0.42) and a significantly higher rate of short-segment Barrett's esophagus (odds ratio, 1.66).	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (180, 199))	("long-segment Barrett's esophagus", 'Disease', (79, 111))	('lower', 'NegReg', (65, 70))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (92, 111))	('H. pylori', 'Gene', (19, 28))	('H. pylori', 'Species', '210', (19, 28))	('Seropositivity', 'Var', (0, 14))
223407	33613500	It is important to note that microbial infections have for a long time now been considered to be responsible for a range of tumor types, through modulation of host-cell transformation, and hence by promotion of malignant features and inflammation, and disruption of cell integrity through genomic or epigenetic modifications.	('inflammation', 'Disease', (234, 246))	('responsible', 'Reg', (97, 108))	('infections', 'Disease', 'MESH:D007239', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('infections', 'Disease', (39, 49))	('tumor', 'Disease', (124, 129))	('disruption', 'Reg', (252, 262))	('cell integrity', 'CPA', (266, 280))	('promotion', 'PosReg', (198, 207))	('malignant features', 'CPA', (211, 229))	('epigenetic modifications', 'Var', (300, 324))	('inflammation', 'Disease', 'MESH:D007249', (234, 246))	('host-cell transformation', 'CPA', (159, 183))	('genomic', 'Var', (289, 296))	('modulation', 'Reg', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
223413	33613500	In contrast, gradual changes in gastric acidity might also be seen to arise from the histological changes that can be induced by H. pylori, such that other microorganisms might be facilitated in terms of their colonization of the gastric epithelium.	('facilitated', 'PosReg', (180, 191))	('colonization', 'CPA', (210, 222))	('H. pylori', 'Var', (129, 138))	('changes', 'Reg', (21, 28))	('gastric acidity', 'MPA', (32, 47))	('H. pylori', 'Species', '210', (129, 138))
223426	33613500	Hypochlorhydria induced by H. pylori appears to result from loss of parietal cell function, which is seen in particular for patients with more polymorphisms of IL-1beta.	('IL-1beta', 'Gene', (160, 168))	('Hypochlorhydria', 'Disease', 'MESH:D000126', (0, 15))	('polymorphisms', 'Var', (143, 156))	('loss', 'NegReg', (60, 64))	('Hypochlorhydria', 'Disease', (0, 15))	('H. pylori', 'Species', '210', (27, 36))	('parietal cell function', 'CPA', (68, 90))	('IL-1beta', 'Gene', '3552', (160, 168))	('patients', 'Species', '9606', (124, 132))
223427	33613500	However, the changes to the gastric microbiota that arise from absence of H. pylori might also cause an increase in the risk of development of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (143, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('changes', 'Reg', (13, 20))	('esophageal adenocarcinoma', 'Disease', (143, 168))	('H. pylori', 'Gene', (74, 83))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (143, 168))	('absence', 'Var', (63, 70))	('H. pylori', 'Species', '210', (74, 83))
223443	33613500	In conclusion, given that H. pylori remains the most important risk factor for peptic ulcers and GC, its eradication might augment the risk of other diseases and of increased antibiotics resistance.	('augment', 'PosReg', (123, 130))	('peptic ulcer', 'Phenotype', 'HP:0004398', (79, 91))	('H. pylori', 'Species', '210', (26, 35))	('H. pylori', 'Disease', (26, 35))	('peptic ulcers', 'Phenotype', 'HP:0004398', (79, 92))	('GC', 'Gene', '14473', (97, 99))	('peptic ulcers', 'Disease', (79, 92))	('antibiotics resistance', 'MPA', (175, 197))	('eradication', 'Var', (105, 116))	('peptic ulcers', 'Disease', 'MESH:D010437', (79, 92))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('increased', 'PosReg', (165, 174))
223508	31953729	Segmental excision has many potential risks; for example, the risk of tumor recurrence is much higher with fractional resection than with en bloc resection.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('fractional', 'Var', (107, 117))
223557	32256566	Among the 2259 cases, the pathological findings of gastric inflammatory (gastritis group), atrophy (AG group, including intestinal metaplasia), LGIN (LGIN group), and other lesions were 1353, 414, 444, and 48, accounting for 59.89%, 18.33%, 19.65%, and 2.12%, respectively.	('atrophy', 'Disease', 'MESH:D001284', (91, 98))	('gastritis', 'Disease', 'MESH:D005756', (73, 82))	('atrophy', 'Disease', (91, 98))	('1353', 'Var', (186, 190))	('LGIN', 'Disease', (144, 148))	('gastritis', 'Phenotype', 'HP:0005263', (73, 82))	('gastric inflammatory', 'Disease', (51, 71))	('gastritis', 'Disease', (73, 82))
223591	32256566	Antibiotics can reportedly cause changes in the gastric microenvironment and lead to carcinogenesis.	('lead to', 'Reg', (77, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('cause changes', 'Reg', (27, 40))	('carcinogenesis', 'Disease', (85, 99))	('gastric microenvironment', 'MPA', (48, 72))	('Antibiotics', 'Var', (0, 11))
223592	32256566	Antibiotic use seems associated with a slightly elevated breast cancer risk, and antibiotic suppression of intestinal microbiota reduces heme-induced lipoperoxidation associated with colon carcinogenesis, yet the nature of the association remains elusive.	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('cancer', 'Disease', (64, 70))	('antibiotic', 'Var', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('reduces', 'NegReg', (129, 136))	('heme', 'Chemical', 'MESH:D006418', (137, 141))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (183, 203))	('colon carcinogenesis', 'Disease', (183, 203))	('heme-induced lipoperoxidation', 'MPA', (137, 166))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
223595	32256566	As we know, eradication of H. pylori can prevent or reverse the progression of gastric mucosal lesions only in the stage of gastritis.	('gastritis', 'Disease', (124, 133))	('H. pylori', 'Gene', (27, 36))	('gastric mucosal lesions', 'Disease', (79, 102))	('H. pylori', 'Species', '210', (27, 36))	('gastritis', 'Disease', 'MESH:D005756', (124, 133))	('gastric mucosal lesions', 'Disease', 'MESH:D013272', (79, 102))	('gastritis', 'Phenotype', 'HP:0005263', (124, 133))	('eradication', 'Var', (12, 23))
223610	32256566	According to Suzuki et al., H. pylori infection can produce pathological changes similar to LGIN, and after eradication of H. pylori infection, the pathological manifestations of atypical hyperplasia can be improved or even reversed with subsidence of active gastritis.	('infection', 'Disease', (38, 47))	('H. pylori', 'Species', '210', (123, 132))	('H. pylori infection', 'Phenotype', 'HP:0005202', (123, 142))	('subsidence of active gastritis', 'Disease', 'MESH:D005756', (238, 268))	('infection', 'Disease', 'MESH:D007239', (38, 47))	('H. pylori infection', 'Phenotype', 'HP:0005202', (28, 47))	('H. pylori', 'Species', '210', (28, 37))	('hyperplasia', 'Disease', (188, 199))	('subsidence of active gastritis', 'Disease', (238, 268))	('H. pylori', 'Var', (28, 37))	('gastritis', 'Phenotype', 'HP:0005263', (259, 268))	('infection', 'Disease', (133, 142))	('hyperplasia', 'Disease', 'MESH:D006965', (188, 199))	('infection', 'Disease', 'MESH:D007239', (133, 142))
223690	30732126	For subgroups in stages II or I-IIIB or T3 or T3 + T4, the PFS of patients with CTCs > 1 or > 2 was significantly shorter than that of the patients with CTCs <= 1 or CTCs <= 2.	('T3 + T4', 'Var', (46, 53))	('patients', 'Species', '9606', (139, 147))	('PFS', 'MPA', (59, 62))	('shorter', 'NegReg', (114, 121))	('patients', 'Species', '9606', (66, 74))
223691	30732126	In the stage III or T3 + T4 groups, the PFS of patients with CTCs > 0 was significantly shorter than that of patients with CTC = 0.	('shorter', 'NegReg', (88, 95))	('PFS', 'CPA', (40, 43))	('CTCs > 0', 'Var', (61, 69))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (47, 55))	('T3 + T4', 'Var', (20, 27))
223735	30732126	In the subgroup of 50 surgically treated patients, the presence of CTCs was significantly associated with platelet (P = .026) and clinical stages (I-IIIB cf.	('presence', 'Var', (55, 63))	('clinical stages', 'CPA', (130, 145))	('platelet', 'CPA', (106, 114))	('associated', 'Reg', (90, 100))	('patients', 'Species', '9606', (41, 49))	('CTCs', 'Gene', (67, 71))
223739	30732126	PFS was significantly shorter for patients with CTCs > 0 compared with patients with CTC = 0; CTCs > 1 compared with CTCs <= 1; and CTCs > 2 compared with CTCs <= 2 (median survival time: 9 cf.	('CTCs > 2', 'Var', (132, 140))	('CTCs > 1', 'Var', (94, 102))	('PFS', 'MPA', (0, 3))	('patients', 'Species', '9606', (71, 79))	('patients', 'Species', '9606', (34, 42))	('shorter', 'NegReg', (22, 29))
223746	30732126	The multivariate Cox regression analysis showed that patients with CTCs > 2 had significantly shorter PFS than those patients with CTCs <= 2 (P = .003, HR 5.63, 95% CI 1.77-17.887).	('Cox', 'Gene', '1351', (17, 20))	('CTCs > 2', 'Var', (67, 75))	('patients', 'Species', '9606', (53, 61))	('PFS', 'MPA', (102, 105))	('Cox', 'Gene', (17, 20))	('shorter', 'NegReg', (94, 101))	('patients', 'Species', '9606', (117, 125))
223751	30732126	In the 50 surgically treated patients stratified as stage II or I-IIIB or T3 and T3 + T4, the PFS of the patients with CTCs > 1 or CTCs > 2 was significantly shorter than that of patients with CTCs <= 1 or CTCs <= 2, respectively (P < .05; Tables 7 and 8).	('shorter', 'NegReg', (158, 165))	('patients', 'Species', '9606', (29, 37))	('patients', 'Species', '9606', (105, 113))	('CTCs > 1', 'Var', (119, 127))	('PFS', 'MPA', (94, 97))	('patients', 'Species', '9606', (179, 187))	('CTCs > 2', 'Var', (131, 139))
223752	30732126	In stage III and T3 + T4 groups, the PFS of patients with CTCs > 0 was significantly shorter than that of the patients with CTCs = 0 (P < .05).	('shorter', 'NegReg', (85, 92))	('patients', 'Species', '9606', (44, 52))	('CTCs > 0', 'Var', (58, 66))	('T3 + T4', 'Var', (17, 24))	('patients', 'Species', '9606', (110, 118))	('PFS', 'MPA', (37, 40))
223758	30732126	The greater sensitivity of ISET for detecting CTCs compared with the Celltracks AutoPrep system was also observed by Khoja et al in patients with pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CTCs', 'Var', (46, 50))	('pancreatic cancer', 'Disease', (146, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))	('patients', 'Species', '9606', (132, 140))
223767	30732126	CTCs in patients with ESCC may lead to micrometastases that cannot be detected by traditional examination methods.	('ESCC', 'Disease', (22, 26))	('metastases', 'Disease', (44, 54))	('lead to', 'Reg', (31, 38))	('CTCs', 'Var', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (44, 54))	('patients', 'Species', '9606', (8, 16))
223801	28721213	It is in effect a genetic testing for EoE molecular transcriptome and might have both diagnostic and management value in future especially for separating active and inactive disease.	('EoE', 'Gene', (38, 41))	('genetic', 'Var', (18, 25))	('men', 'Species', '9606', (107, 110))
223843	28721213	The second possibility is that PPIs can reduce the level of key mediators of EoE such as eotaxin-3, interleukin 4 and 5 directly.	('PPIs', 'Var', (31, 35))	('reduce', 'NegReg', (40, 46))	('eotaxin-3', 'Gene', (89, 98))	('eotaxin-3', 'Gene', '10344', (89, 98))	('level of key mediators', 'MPA', (51, 73))	('interleukin 4 and 5', 'Gene', '3565;3567', (100, 119))
223881	26273335	Multivariate analysis found that lung infection during radiotherapy, MLD >= 12 Gy, and V30 >= 13% are significantly correlated with an increased risk of RP.	('lung infection', 'Disease', 'MESH:D008171', (33, 47))	('V30 >= 13%', 'Var', (87, 97))	('correlated', 'Reg', (116, 126))	('MLD', 'Disease', 'MESH:D007966', (69, 72))	('lung infection', 'Phenotype', 'HP:0006532', (33, 47))	('lung infection', 'Disease', (33, 47))	('MLD', 'Disease', (69, 72))
223892	26273335	Dose volume histogram (DVH) parameters V20 and V30 (the percentage of lung volume receiving >=20 Gy and >=30 Gy) and mean lung dose (MLD) have long been considered as predictive factors closely correlated with both the risk and severity of RP.	('correlated', 'Reg', (194, 204))	('MLD', 'Disease', 'MESH:D007966', (133, 136))	('V20', 'Var', (39, 42))	('MLD', 'Disease', (133, 136))	('V30', 'Var', (47, 50))
223923	26273335	The dose constraint for the two lungs was V20 <= 30 Gy, mean lung dose (MLD) <=13 Gy.	('MLD', 'Disease', 'MESH:D007966', (72, 75))	('V20 <=', 'Var', (42, 48))	('MLD', 'Disease', (72, 75))
223966	26273335	Other than clinical influence factors, the dosimetric parameters derived from DVH, such as MLD, V5, V10, V13, V20, and V30 have been found to influence both the occurrence and prediction of ARP.	('V13', 'Gene', '28816', (105, 108))	('MLD', 'Disease', 'MESH:D007966', (91, 94))	('V30', 'Var', (119, 122))	('V20', 'Var', (110, 113))	('MLD', 'Disease', (91, 94))	('ARP', 'Disease', (190, 193))	('V13', 'Gene', (105, 108))	('influence', 'Reg', (142, 151))	('V10', 'Var', (100, 103))
223967	26273335	Some studies have reported that an increased risk of RP was associated with MLD >= 14 Gy or > 18 Gy.	('MLD', 'Disease', 'MESH:D007966', (76, 79))	('MLD', 'Disease', (76, 79))	('>= 14 Gy', 'Var', (80, 88))	('> 18 Gy', 'Var', (92, 99))
223973	26273335	Based on univariate analysis, MLD and V5, V10, V15, V20, V25, and V30 were correlated with risks of ARP and SARP.	('ARP', 'Disease', (100, 103))	('V25', 'Var', (57, 60))	('V30', 'Var', (66, 69))	('V10', 'Var', (42, 45))	('V15', 'Gene', '28814', (47, 50))	('V20', 'Var', (52, 55))	('SARP', 'Disease', (108, 112))	('MLD', 'Disease', 'MESH:D007966', (30, 33))	('MLD', 'Disease', (30, 33))	('V15', 'Gene', (47, 50))	('correlated', 'Reg', (75, 85))
223976	26273335	Multivariate analysis in our study has suggested that MLD and V30 are significant predictive factors for RP; MLD is significantly correlated with ARP (P = 0.000), but not significantly correlated with SARP; V30 has greater predictive value for SARP, with significant difference between V30 >= 13% and V30 < 13% (P = 0.022) (Fig.	('MLD', 'Disease', 'MESH:D007966', (54, 57))	('MLD', 'Disease', (54, 57))	('ARP', 'MPA', (146, 149))	('MLD', 'Disease', 'MESH:D007966', (109, 112))	('MLD', 'Disease', (109, 112))	('SARP', 'MPA', (244, 248))	('V30', 'Var', (301, 304))	('RP', 'Disease', (105, 107))	('V30 >= 13%', 'Var', (286, 296))
223979	26273335	Compared to IMRT, using VMAT the lung MLD was higher (P = 0.009) and the low dose region was greater, with statistical difference for V5, V10, V25, and V30 (P < 0.005).	('V25', 'Var', (143, 146))	('V10', 'Var', (138, 141))	('higher', 'PosReg', (46, 52))	('VMAT the lung MLD', 'Disease', 'MESH:D007966', (24, 41))	('V30', 'Var', (152, 155))	('VMAT the lung MLD', 'Disease', (24, 41))
223991	25209371	Potentially functional polymorphisms in the ERCC2 gene and risk of Esophageal Squamous Cell Carcinoma in Chinese populations ERCC2 is indispensable for nucleotide excision repair pathway, and its functional polymorphisms may be associated with cancer risk.	('polymorphisms', 'Var', (23, 36))	('Esophageal Squamous Cell Carcinoma', 'Disease', (67, 101))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (67, 101))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('ERCC2', 'Gene', (125, 130))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('ERCC2', 'Gene', '2068', (44, 49))	('Carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('associated', 'Reg', (228, 238))	('cancer', 'Disease', (244, 250))	('ERCC2', 'Gene', (44, 49))	('ERCC2', 'Gene', '2068', (125, 130))
223992	25209371	In a large case-control study of 1126 esophageal squamous cell carcinomas (ESCC) patients and 1131 controls, we genotyped two SNPs in ERCC2 (rs238406 G > T and rs13181 T > G) and assessed their associations with ESCC risk.	('ERCC2', 'Gene', (134, 139))	('esophageal squamous cell carcinomas', 'Disease', (38, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (38, 73))	('rs238406 G > T', 'Var', (141, 155))	('rs238406', 'Mutation', 'rs238406', (141, 149))	('ESCC', 'Disease', (212, 216))	('patients', 'Species', '9606', (81, 89))	('rs13181 T > G', 'Var', (160, 173))	('associations', 'Interaction', (194, 206))	('ERCC2', 'Gene', '2068', (134, 139))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (49, 73))	('rs13181', 'Mutation', 'rs13181', (160, 167))
223993	25209371	We found a significantly elevated ESCC risk associated with the rs238406 T variant genotypes (adjusted OR = 1.30 and 1.24, 95% CI = 1.02-1.66 and 1.03-1.49 for TG and TG/TT, respectively, compared with GG), particularly in the subgroup of those smoked more than 16 pack-years.	('TG', 'Chemical', '-', (160, 162))	('rs238406', 'Mutation', 'rs238406', (64, 72))	('ESCC', 'Disease', (34, 38))	('elevated', 'PosReg', (25, 33))	('TG', 'Chemical', '-', (167, 169))	('rs238406 T', 'Var', (64, 74))	('elevated ESCC', 'Phenotype', 'HP:0003565', (25, 38))
223994	25209371	Multivariate logistic regression analysis suggested a possible multiplicative gene-environment interaction between rs238406 genotypes and smoking (Pinteraction = 0.026) on ESCC risk.	('rs238406', 'Var', (115, 123))	('rs238406', 'Mutation', 'rs238406', (115, 123))	('ESCC', 'Disease', (172, 176))
223995	25209371	Although no significant risk associations were observed for rs13181, further mini meta-analysis with our and 18 other published studies of 5,012 cases and 8,238 controls found evidence of an association between the rs13181 variant G allele and esophageal cancer risk (TG/GG vs. TT, OR = 1.17; 95% CI = 1.02-1.33).	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('esophageal cancer', 'Disease', (244, 261))	('TG', 'Chemical', '-', (268, 270))	('rs13181', 'Var', (215, 222))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('rs13181', 'Mutation', 'rs13181', (60, 67))	('rs13181', 'Mutation', 'rs13181', (215, 222))
223996	25209371	Interestingly, we consistently found a significant correlation between variant genotypes of these two SNPs and ERCC2 mRNA expression.	('mRNA expression', 'MPA', (117, 132))	('ERCC2', 'Gene', (111, 116))	('variant', 'Var', (71, 78))	('ERCC2', 'Gene', '2068', (111, 116))
223997	25209371	These findings suggest that potentially functional SNPs in ERCC2 may contribute to ESCC risk.	('contribute', 'Reg', (69, 79))	('ERCC2', 'Gene', (59, 64))	('SNPs', 'Var', (51, 55))	('ESCC', 'Disease', (83, 87))	('ERCC2', 'Gene', '2068', (59, 64))
224006	25209371	Since the association of the ERCC2 Lys751Gln (rs13181) polymorphism with ESCC risk was first reported in 2002, there are additional investigations of the association between Lys751Gln and risk of ESCC among different ethnicities, but the results have been mixed or conflicting, likely due to a relatively small sample size in each of the published studies.	('Lys751Gln', 'SUBSTITUTION', 'None', (174, 183))	('ERCC2', 'Gene', '2068', (29, 34))	('ESCC', 'Disease', (196, 200))	('Lys751Gln', 'Var', (174, 183))	('Lys751Gln', 'SUBSTITUTION', 'None', (35, 44))	('ERCC2', 'Gene', (29, 34))	('rs13181', 'Mutation', 'rs13181', (46, 53))	('ESCC', 'Disease', (73, 77))	('Lys751Gln', 'Var', (35, 44))
224007	25209371	Interestingly, published genome-wide association studies (GWASs) of ESCC in Chinese populations did not identify rs13181 SNP as a susceptible locus, perhaps owing to the stringent P values required to avoid false-positive findings, which dramatically decrease the possibility to reveal the modest effect of some common SNPs on risk of cancer, particularly for those SNPs that are potentially functional.	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('decrease', 'NegReg', (251, 259))	('rs13181', 'Var', (113, 120))	('cancer', 'Disease', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('rs13181', 'Mutation', 'rs13181', (113, 120))
224010	25209371	In the single-locus analyses, we found a significantly elevated ESCC risk associated with the rs238406 T variant genotypes (adjusted odds ratio (OR) = 1.30 and 1.24, 95% confidence interval (CI) = 1.02-1.66 and 1.03-1.49 for TG and TG/TT, respectively, compared with GG).	('ESCC', 'Disease', (64, 68))	('rs238406 T', 'Var', (94, 104))	('rs238406', 'Mutation', 'rs238406', (94, 102))	('elevated ESCC', 'Phenotype', 'HP:0003565', (55, 68))	('TG', 'Chemical', '-', (232, 234))	('TG', 'Chemical', '-', (225, 227))	('elevated', 'PosReg', (55, 63))
224012	25209371	In the combined analysis, we categorized all putative risk (OR > 1.0) genotypes from each SNP into a new variable according to the number of risk genotypes (i.e., ERCC2 rs238406 TG/TT + rs13181 TG/GG).	('ERCC2', 'Gene', '2068', (163, 168))	('rs238406', 'Mutation', 'rs238406', (169, 177))	('TG', 'Chemical', '-', (194, 196))	('ERCC2', 'Gene', (163, 168))	('TG', 'Chemical', '-', (178, 180))	('rs13181', 'Mutation', 'rs13181', (186, 193))	('rs238406 TG/TT + rs13181 TG/GG', 'Var', (169, 199))
224013	25209371	In the stratified analysis, we found that those who carried the rs238406 variant TG/TT genotypes had a significant increased risk, particularly in males (adjusted OR = 1.26, 95% CI = 1.02-1.55), subjects with the cumulative smoking dose >16 pack-years (adjusted OR = 1.58, 95% CI = 1.17-2.13) and subjects with BMI >= 25.0 (adjusted OR = 1.40, 95% CI = 1.06-1.84).	('rs238406', 'Mutation', 'rs238406', (64, 72))	('TG/TT', 'Gene', (81, 86))	('TG', 'Chemical', '-', (81, 83))	('rs238406', 'Var', (64, 72))
224016	25209371	Indeed, we did find a statistical evidence for a multiplicative gene-environment interaction between rs238406 genotypes and smoking (Pinteraction = 0.026) on ESCC risk.	('ESCC', 'Disease', (158, 162))	('rs238406', 'Var', (101, 109))	('rs238406', 'Mutation', 'rs238406', (101, 109))
224017	25209371	With the assumption of a prior probability of 0.1, the FPRP values were 0.136, 0.192, 0.091, 0.096 and 0.094, respectively, for associations of rs238406 TG/TT genotypes, 1 combined risk genotype, 2 combined risk genotypes and ">=1" combined risk genotypes with an increased risk of ESCC in all subjects, as well as in the subgroups of the cumulative smoking dose >16 pack-years.	('TG', 'Chemical', '-', (153, 155))	('associations', 'Interaction', (128, 140))	('rs238406', 'Mutation', 'rs238406', (144, 152))	('rs238406 TG/TT', 'Var', (144, 158))	('ESCC', 'Disease', (282, 286))
224018	25209371	In addition to the present association study, we identified 18 other published case-control studies on ERCC2 rs13181 SNP, with the sample sizes ranging between 151 and 1600, for which we performed a mini meta-analysis to assess the association of this SNP with ESCC risk (Supplemental Table 2).	('ERCC2', 'Gene', '2068', (103, 108))	('rs13181', 'Var', (109, 116))	('ERCC2', 'Gene', (103, 108))	('ESCC', 'Disease', (261, 265))	('association', 'Interaction', (232, 243))	('rs13181', 'Mutation', 'rs13181', (109, 116))
224019	25209371	We found that the rs13181 variant G allele was significantly associated with an increased risk of esophageal cancer (OR = 1.17; 95% CI = 1.02-1.33 for TG/GG vs. TT) based on 5,012 cases and 8,238 controls in the pooled analysis as well as in subgroup analysis of these ESCC studies (OR = 1.19; 95% CI = 1.01-1.40 for TG/GG vs. TT) (Table 4, Figure 1).	('rs13181', 'Var', (18, 25))	('TG', 'Chemical', '-', (151, 153))	('TG', 'Chemical', '-', (317, 319))	('rs13181', 'Mutation', 'rs13181', (18, 25))	('esophageal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
224020	25209371	However, we were not able to do a similar mini meta-analysis for rs238406, because there was only one published case-control study on esophageal adenocarcinoma cancer in a European population.	('rs238406', 'Var', (65, 73))	('esophageal adenocarcinoma cancer', 'Disease', 'MESH:D004938', (134, 166))	('esophageal adenocarcinoma cancer', 'Disease', (134, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (134, 159))	('rs238406', 'Mutation', 'rs238406', (65, 73))
224022	25209371	As a result, we found a statistical significance for rs13181 allele T   G on gene transcription expression (Ptrend = 0.005 and 0.001 for CHB and all populations, respectively) (Figure 2), which supports the finding of an association between this SNP and ESCC risk.	('gene transcription expression', 'MPA', (77, 106))	('rs13181', 'Var', (53, 60))	('rs13181', 'Mutation', 'rs13181', (53, 60))	('ESCC', 'Disease', (254, 258))
224023	25209371	For rs238406, however, we found a statistically significant trend for the allele G   T effect on ERCC2 mRNA expression in Europeans (Ptrend = 0.011) but a borderline significance in CHB (Ptrend = 0.098).	('rs238406', 'Var', (4, 12))	('ERCC2', 'Gene', '2068', (97, 102))	('ERCC2', 'Gene', (97, 102))	('rs238406', 'Mutation', 'rs238406', (4, 12))	('mRNA expression', 'MPA', (103, 118))
224025	25209371	rs238406 G > T and rs13181 T > G) were individually or collectively associated with ESCC risk.	('associated', 'Reg', (68, 78))	('ESCC', 'Disease', (84, 88))	('rs13181 T > G', 'Var', (19, 32))	('rs238406', 'Mutation', 'rs238406', (0, 8))	('rs13181', 'Mutation', 'rs13181', (19, 26))	('rs238406 G > T', 'Var', (0, 14))
224026	25209371	We also observed a multiplicative gene-environment interaction between rs238406 genotypes and smoking on ESCC risk.	('rs238406', 'Var', (71, 79))	('ESCC', 'Disease', (105, 109))	('rs238406', 'Mutation', 'rs238406', (71, 79))
224027	25209371	Because many studies have investigated the associations between ERCC2 rs13181 T > G SNP and risk of ESCC cancer, we also performed a mini meta-analysis that provided additional statistical evidence of such an association.	('rs13181 T > G', 'Var', (70, 83))	('ESCC cancer', 'Disease', 'MESH:D004938', (100, 111))	('ESCC cancer', 'Disease', (100, 111))	('rs13181', 'Mutation', 'rs13181', (70, 77))	('ERCC2', 'Gene', '2068', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('associations', 'Interaction', (43, 55))	('ERCC2', 'Gene', (64, 69))
224030	25209371	Mutations in ERCC2 could result in transcription defects and abnormal apoptosis by reducing the BTF2/TFIIH activity, thus leading to a severe but variable depression of NER.	('ERCC2', 'Gene', (13, 18))	('BTF2', 'Gene', (96, 100))	('activity', 'MPA', (107, 115))	('depression', 'Disease', 'MESH:D000275', (155, 165))	('depression', 'Phenotype', 'HP:0000716', (155, 165))	('reducing', 'NegReg', (83, 91))	('TFIIH', 'Gene', '2068', (101, 106))	('depression', 'Disease', (155, 165))	('Mutations', 'Var', (0, 9))	('TFIIH', 'Gene', (101, 106))	('transcription', 'MPA', (35, 48))	('ERCC2', 'Gene', '2068', (13, 18))	('BTF2', 'Gene', '2071', (96, 100))	('result in', 'Reg', (25, 34))	('NER', 'MPA', (169, 172))
224036	25209371	However, the present study found some dominant effects of ERCC2 SNPs on ESCC risk, perhaps owing to complex gene-gene or gene-environment interactions that may have some impact on genetic models for disease risk.	('ERCC2', 'Gene', '2068', (58, 63))	('SNPs', 'Var', (64, 68))	('ERCC2', 'Gene', (58, 63))	('ESCC', 'Disease', (72, 76))
224037	25209371	Previous studies found that ERCC2 rs238406 conferred susceptibility to cancers of the bladder, lung and other organs.	('susceptibility', 'Reg', (53, 67))	('cancers of the bladder', 'Disease', 'MESH:D001749', (71, 93))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('ERCC2', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancers of the bladder', 'Phenotype', 'HP:0009725', (71, 93))	('rs238406', 'Mutation', 'rs238406', (34, 42))	('ERCC2', 'Gene', '2068', (28, 33))	('lung', 'Disease', (95, 99))	('rs238406', 'Var', (34, 42))	('cancers of the bladder', 'Disease', (71, 93))
224038	25209371	Only one reported study focused on esophageal cancer and found no association between rs238406 and esophageal adenocarcinoma risk with only 56 European patients and 95 healthy controls.	('rs238406', 'Mutation', 'rs238406', (86, 94))	('rs238406', 'Var', (86, 94))	('esophageal cancer', 'Disease', (35, 52))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (99, 124))	('esophageal adenocarcinoma', 'Disease', (99, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (99, 124))	('patients', 'Species', '9606', (152, 160))
224039	25209371	In contrast, the present study included over 1000 cases and 1000 controls with a much improved study power and thus found a statistical evidence for a weak association between the rs238406 variant genotypes and increased ESCC risk.	('ESCC', 'Disease', (221, 225))	('increased ESCC', 'Phenotype', 'HP:0003565', (211, 225))	('rs238406', 'Var', (180, 188))	('rs238406', 'Mutation', 'rs238406', (180, 188))
224040	25209371	SNP rs238406, a silent polymorphism in codon 156 of exon 6, does not change the amino acid residue (Arg156Arg).	('rs238406', 'Var', (4, 12))	('Arg156Arg', 'Var', (100, 109))	('rs238406', 'Mutation', 'rs238406', (4, 12))
224042	25209371	However, it is likely that these SNPs may influence ERCC2 protein levels through an effect on mRNA splicing as predicted by the SNPinfo software.	('SNPs', 'Var', (33, 37))	('mRNA splicing', 'MPA', (94, 107))	('ERCC2', 'Gene', (52, 57))	('effect', 'Reg', (84, 90))	('influence', 'Reg', (42, 51))	('ERCC2', 'Gene', '2068', (52, 57))
224044	25209371	Indeed, we found a trend for the rs238406 allele G   T effect on ERCC2 mRNA expression for different populations, indicating that it may be a potentially functional SNP.	('mRNA expression', 'MPA', (71, 86))	('ERCC2', 'Gene', (65, 70))	('rs238406', 'Mutation', 'rs238406', (33, 41))	('rs238406', 'Var', (33, 41))	('ERCC2', 'Gene', '2068', (65, 70))
224045	25209371	For example, we found two SNPs (rs3810366 and rs2097215) located in 5' near gene are in high LD (r2 > 0.8) with rs238406.	('rs2097215', 'Mutation', 'rs2097215', (46, 55))	('rs3810366', 'Mutation', 'rs3810366', (32, 41))	('rs238406', 'Mutation', 'rs238406', (112, 120))	('rs238406', 'Var', (112, 120))	('rs2097215', 'Var', (46, 55))	('rs3810366', 'Var', (32, 41))
224047	25209371	Some meta-analyses have reported that individuals carrying the SNP rs13181 (Lys751Gln) G variant allele had an increased risk of cancers of the lung, stomach, skin and esophagus.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('esophagus', 'Disease', (168, 177))	('skin', 'Disease', (159, 163))	('cancers of the lung', 'Disease', 'MESH:D008175', (129, 148))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('stomach', 'Disease', (150, 157))	('rs13181', 'Mutation', 'rs13181', (67, 74))	('Lys751Gln', 'SUBSTITUTION', 'None', (76, 85))	('Lys751Gln', 'Var', (76, 85))	('cancers of the lung', 'Disease', (129, 148))
224049	25209371	The rs13181 SNP, i.e., the T   G base substitution in exon 23, causes an amino acid alteration from lysine to glycine at codon 751, which leads to a complete change in electronic configuration of the amino acid and thus reduces DNA repair efficiency.	('change', 'Reg', (158, 164))	('amino acid', 'MPA', (73, 83))	('reduces', 'NegReg', (220, 227))	('alteration', 'Reg', (84, 94))	('rs13181', 'Mutation', 'rs13181', (4, 11))	('T   G base', 'Var', (27, 37))	('causes', 'Reg', (63, 69))	('lysine to glycine at codon 751', 'Mutation', 'p.K751G', (100, 130))	('electronic configuration of the amino acid', 'MPA', (168, 210))	('rs13181', 'Var', (4, 11))	('DNA repair', 'MPA', (228, 238))
224051	25209371	In the present study, we also found a significant trend for the rs13181 allele T   G effect on ERCC2 transcript expression levels in different ethnic populations, indicating that the ERCC2 rs13181 SNP may be a underlying genetic determinant of esophageal cancer risk.	('ERCC2', 'Gene', (95, 100))	('transcript expression levels', 'MPA', (101, 129))	('rs13181', 'Mutation', 'rs13181', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('ERCC2', 'Gene', '2068', (183, 188))	('esophageal cancer', 'Disease', (244, 261))	('rs13181', 'Mutation', 'rs13181', (189, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('ERCC2', 'Gene', (183, 188))	('rs13181', 'Var', (64, 71))	('ERCC2', 'Gene', '2068', (95, 100))	('rs13181', 'Var', (189, 196))
224052	25209371	The present study also identified that rs238406 SNP had a significant interaction with tobacco consumption in ESCC risk.	('rs238406 SNP', 'Var', (39, 51))	('tobacco', 'Species', '4097', (87, 94))	('ESCC', 'Disease', (110, 114))	('rs238406', 'Mutation', 'rs238406', (39, 47))
224064	25209371	It is likely that the exact mechanisms by which the ERCC2 variant regulates the gene transcription activity in vivo are not the same as those observed in cell lines in vitro, which warrants additional in vivo mechanistic studies.	('ERCC2', 'Gene', (52, 57))	('gene transcription activity', 'MPA', (80, 107))	('regulates', 'Reg', (66, 75))	('variant', 'Var', (58, 65))	('ERCC2', 'Gene', '2068', (52, 57))
224066	25209371	For example, we failed to find any statistical evidence of an association between rs13181 and ESCC risk, but we did find such a statistical evidence in a subsequent meta-analysis of a much larger sample size.	('rs13181', 'Var', (82, 89))	('ESCC', 'Disease', (94, 98))	('rs13181', 'Mutation', 'rs13181', (82, 89))
224072	25209371	We selected two potentially functional SNPs located in the coding region (i.e., rs13181 T > G and rs238406 G > T) for genotyping, because rs13181 is one of the most reported non-synonymous SNPs that result in an amino acid change, while rs238406 is a synonymous SNP that has a putative function of splicing predicted by the SNP function prediction (FuncPred) software (SNPinfo, http://snpinfo.niehs.nih.gov/).	('rs13181', 'Var', (138, 145))	('rs238406', 'Var', (237, 245))	('rs238406 G', 'Var', (98, 108))	('amino acid change', 'MPA', (212, 229))	('rs13181', 'Mutation', 'rs13181', (138, 145))	('rs238406', 'Mutation', 'rs238406', (98, 106))	('rs13181', 'Mutation', 'rs13181', (80, 87))	('rs238406', 'Mutation', 'rs238406', (237, 245))
224075	25209371	Because there were few reported studies on the association of rs238406 G > T SNP in the ERCC2 gene with ESCC risk, we could not perform its meta-analysis.	('rs238406 G > T', 'Var', (62, 76))	('ERCC2', 'Gene', '2068', (88, 93))	('ESCC', 'Disease', (104, 108))	('ERCC2', 'Gene', (88, 93))	('rs238406', 'Mutation', 'rs238406', (62, 70))
224077	25209371	We computed OR and their 95% CI from univariate and multivariate logistic regression models to estimate the associations of ERCC2 SNPs with ESCC risk, which were also evaluated in subgroup analyses stratified by demographic variables and risk factors.	('ERCC2', 'Gene', '2068', (124, 129))	('associations', 'Interaction', (108, 120))	('ESCC', 'Disease', (140, 144))	('SNPs', 'Var', (130, 134))	('ERCC2', 'Gene', (124, 129))
224093	24765592	Resection of >50% of the circumference was strongly associated and a tobacco use history >=25 pack-years showed a tendency toward stricture formation.	('Resection', 'Var', (0, 9))	('stricture', 'MPA', (130, 139))	('tobacco', 'Species', '4097', (69, 76))
224132	24571804	Thus, IFI may result in reduced incidence of treatment toxicities which enable more patients to tolerate the CCRT.	('IFI', 'Var', (6, 9))	('toxicities', 'Disease', (55, 65))	('CR', 'Chemical', '-', (110, 112))	('patients', 'Species', '9606', (84, 92))	('toxicities', 'Disease', 'MESH:D064420', (55, 65))
224296	19044323	For patients with stage I-II disease, local control rate for patients who received < 80 Gy was 14% at 2 years compared to 88% for those who received >= 80 Gy (p<0.001).	('I-II disease', 'Disease', (24, 36))	('patients', 'Species', '9606', (61, 69))	('I-II disease', 'Disease', 'MESH:D056829', (24, 36))	('< 80', 'Var', (83, 87))	('patients', 'Species', '9606', (4, 12))	('local control', 'CPA', (38, 51))
224307	19044323	The incidence of pulmonary toxicity was not associated with the dose prescribed to the tumor but was significantly associated with mean lung dose, V20, and the normal-tissue complication probability of the lung.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('pulmonary toxicity', 'Disease', (17, 35))	('tumor', 'Disease', (87, 92))	('associated', 'Reg', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('V20', 'Var', (147, 150))	('pulmonary toxicity', 'Disease', 'MESH:D008171', (17, 35))
224309	19044323	RTOG 9311 safely escalated patients with V20 <25% to 83.8 Gy, but the 90.3 Gy dose level was deemed to be too toxic.	('RTOG 9311', 'Gene', (0, 9))	('patients', 'Species', '9606', (27, 35))	('V20', 'Var', (41, 44))	('escalated', 'PosReg', (17, 26))
224382	30298114	Minimising the hiatal widening and repairing preexisting or iatrogenic large hiatal defect are probably the mainstays of the prevention.	('iatrogenic large hiatal defect', 'Disease', 'MESH:D007049', (60, 90))	('Minimising', 'Var', (0, 10))	('iatrogenic large hiatal defect', 'Disease', (60, 90))
224398	27668986	In the past years, candidate-gene studies and genome-wide association studies (GWASs) have discovered important germline variants (especially SNPs) that are associated with cancer risk using case-control designs, indicating sporadic cancers bear genetic components .	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('associated', 'Reg', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', (173, 179))	('variants', 'Var', (121, 129))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Disease', (233, 240))
224406	27668986	(2) SNPs level: 1) non-autosomal chromosomes; 2) call rate < 95%; 3) MAF in controls < 0.05; 4) deviated from Hardy-Weinberg Equilibrium (HWE) in controls (P<0.05); 5) missing rate discrepancies between cases and controls (P<0.05).	('missing rate', 'MPA', (168, 180))	('deviated', 'Var', (96, 104))	('MAF', 'Gene', '4094', (69, 72))	('call rate', 'CPA', (49, 58))	('MAF', 'Gene', (69, 72))	('non-autosomal', 'Var', (19, 32))
224432	27668986	Analogous to other studies for heritability of cancer, we found either known SNPs or known regions (+-250kb or 500kb from the known SNPs) from previous GWAS partitioned a small variance (the value were obtained through subtracting the variance excluding known regions from the total variance).	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('+-250kb', 'Var', (100, 107))	('cancer', 'Disease', (47, 53))
224436	27668986	For example, prevalence of BRCA1 or BRCA2 mutation (important genetic risk factors for ovarian cancer) differs significantly among race/ethnic groups, which is much lower in Chinese or Asian population .	('lower', 'NegReg', (165, 170))	('BRCA1', 'Gene', '672', (27, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRCA1', 'Gene', (27, 32))	('BRCA2', 'Gene', (36, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (87, 101))	('mutation', 'Var', (42, 50))	('BRCA2', 'Gene', '675', (36, 41))	('ovarian cancer', 'Disease', (87, 101))
224444	27668986	Also intriguingly, we found changes after removing SNPs within 500kb of known variants varied among cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('variants', 'Var', (78, 86))	('cancers', 'Disease', (100, 107))
224446	27668986	The possible reason is more SNPs from breast and prostate cancer GWASs have been discovered, for example, nearly 90 variants have been discovered for breast cancer and prostate cancer, respectively.	('prostate cancer', 'Disease', 'MESH:D011471', (168, 183))	('variants', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('breast cancer', 'Disease', (150, 163))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (38, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('prostate cancer', 'Disease', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('discovered', 'Reg', (135, 145))	('prostate cancer', 'Disease', (49, 64))
224448	27668986	For instance, although only 9 variants  have so far been discovered associated with nasopharyngeal cancer, a disease mostly occurs in Southern China , they (250kb and 500kb up and downwards expanded) seem to explain larger proportion of the overall heritability (21.4% and 21.1%).	('nasopharyngeal cancer', 'Disease', (84, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (84, 105))	('250kb', 'Var', (157, 162))
224457	27668986	It is possible that mutate rate differs among chromosomes, and certain chromosomes bear larger numbers or larger effects of mutations towards tendency for different cancers .	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Disease', (165, 172))
224467	27668986	The results indicate polygenic architecture of the nine cancer types (explained heritability ranged from 10.19% to 20.26%).	('cancer', 'Disease', (56, 62))	('polygenic architecture', 'Var', (21, 43))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
224506	28705182	Eligible patients must have a histology-confirmed esophageal squamous cell carcinoma or adenocarcinoma with tumors classified T1-T3, N0 N1, M1a (TNM 6th edition), with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) <=2, aged >=75 years, neutrophil count >=1.8.109/L, platelet count >=100.109/L, hemoglobin >=10 g/L, serum creatinine <=1.25 mumol/L, and forced expiratory volume >= 1 L/s.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('patients', 'Species', '9606', (9, 17))	('Oncology', 'Phenotype', 'HP:0002664', (191, 199))	('serum creatinine', 'MPA', (338, 354))	('hemoglobin', 'MPA', (317, 327))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('>=100.109/L', 'Var', (304, 315))	('TNM', 'Gene', '10178', (145, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('creatinine', 'Chemical', 'MESH:D003404', (344, 354))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('esophageal squamous cell carcinoma or adenocarcinoma', 'Disease', 'MESH:D000077277', (50, 102))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('TNM', 'Gene', (145, 148))	('forced expiratory', 'MPA', (375, 392))
224610	27129160	PPMP inhibited growth of all 3 human esophageal cancer cell lines, KYSE30 (Figure 1B), KYSE450 (Figure 1C), and KYSE510 (Figure 1D), with IC50 values of 5.12 muM, 3.50 muM, and 2.85 muM, respectively.	('KYSE510', 'Var', (112, 119))	('inhibited', 'NegReg', (5, 14))	('muM', 'Gene', (168, 171))	('muM', 'Gene', (182, 185))	('growth', 'MPA', (15, 21))	('muM', 'Gene', (158, 161))	('muM', 'Gene', '56925', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('KYSE510', 'CellLine', 'CVCL:1354', (112, 119))	('human', 'Species', '9606', (31, 36))	('KYSE450', 'Var', (87, 94))	('esophageal cancer', 'Disease', (37, 54))	('PPMP', 'Chemical', 'MESH:C026733', (0, 4))	('muM', 'Gene', '56925', (182, 185))	('muM', 'Gene', '56925', (158, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
224612	27129160	Data indicated that PPMP potently and dose-dependently, inhibited colony formation of all 3 esophageal cancer cell lines, KYSE30 (Figure 2A), KYSE450 (Figure 2B), and KYSE510 (Figure 2C), compared to untreated controls.	('PPMP', 'Var', (20, 24))	('KYSE30', 'Var', (122, 128))	('KYSE510', 'Var', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('KYSE510', 'CellLine', 'CVCL:1354', (167, 174))	('esophageal cancer', 'Disease', (92, 109))	('KYSE450', 'Var', (142, 149))	('inhibited', 'NegReg', (56, 65))	('PPMP', 'Chemical', 'MESH:C026733', (20, 24))	('colony formation', 'CPA', (66, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
224618	27129160	The cleavage of PARP and caspase 3 facilitates cellular disassembly and are considered to be markers for cells undergoing apoptosis.	('PARP', 'Gene', (16, 20))	('cleavage', 'Var', (4, 12))	('caspase 3', 'Gene', (25, 34))	('caspase 3', 'Gene', '836', (25, 34))	('cellular disassembly', 'CPA', (47, 67))	('facilitates', 'PosReg', (35, 46))	('PARP', 'Gene', '1302', (16, 20))
224619	27129160	Consistent with the results of flow cytometry, our Western blot resultsdemonstrated that in the presence of PPMP (5 muM), cleaved PARP or caspase 3 increasingly appeared in KYSE30, KYSE450, and KYSE510 cells over time (Figure 3D).	('PARP', 'Gene', (130, 134))	('caspase 3', 'Gene', (138, 147))	('muM', 'Gene', (116, 119))	('caspase 3', 'Gene', '836', (138, 147))	('PPMP', 'Chemical', 'MESH:C026733', (108, 112))	('KYSE510', 'CellLine', 'CVCL:1354', (194, 201))	('PPMP', 'Var', (108, 112))	('cleaved', 'MPA', (122, 129))	('increasingly appeared', 'PosReg', (148, 169))	('PARP', 'Gene', '1302', (130, 134))	('muM', 'Gene', '56925', (116, 119))
224622	27129160	When KYSE510 cells were treated with PPMP for 24 h, we observed an increased number of cells in G2/M phase that was accompanied by a decreased cell population in the G0/G1 phase of the cell cycle, which was also observed in KYSE30 and KYSE450 cells (Figure 4A-4B).	('cells in G2/M phase', 'CPA', (87, 106))	('KYSE510', 'CellLine', 'CVCL:1354', (5, 12))	('increased', 'PosReg', (67, 76))	('PPMP', 'Chemical', 'MESH:C026733', (37, 41))	('decreased', 'NegReg', (133, 142))	('PPMP', 'Var', (37, 41))
224629	27129160	When esophageal cancer cells were treated with increasing concentrations of PPMP, the amount of polymerized tubulin was decreased, which was accompanied by an increase in depolymerized tubulin (Figure 5A).	('decreased', 'NegReg', (120, 129))	('amount of polymerized tubulin', 'MPA', (86, 115))	('PPMP', 'Chemical', 'MESH:C026733', (76, 80))	('depolymerized tubulin', 'MPA', (171, 192))	('PPMP', 'Var', (76, 80))	('esophageal cancer', 'Disease', (5, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (5, 22))	('increase', 'PosReg', (159, 167))
224645	27129160	Notably, at the end of the study, case EG8 was substantially more sensitive to either a high or low dose of PPMP treatment (tumor volume variation of 50 mg/kg PPMP treatment group vs. vehicle: -89.9%; 10 mg/kg PPMP vs. vehicle: -56.3%; Figure 6B).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('PPMP', 'Chemical', 'MESH:C026733', (108, 112))	('tumor', 'Disease', (124, 129))	('PPMP', 'Chemical', 'MESH:C026733', (159, 163))	('PPMP', 'Var', (159, 163))	('PPMP', 'Chemical', 'MESH:C026733', (210, 214))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
224660	27129160	We examined the effect of PPMP on human esophageal cancer cells and results showed that PPMP markedly inhibited cell viability and anchorage-independent growth of all 3 esophageal cancer cell lines studied (Figures 1, 2).	('human', 'Species', '9606', (34, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('inhibited', 'NegReg', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PPMP', 'Chemical', 'MESH:C026733', (88, 92))	('esophageal cancer', 'Disease', (169, 186))	('PPMP', 'Chemical', 'MESH:C026733', (26, 30))	('cell viability', 'CPA', (112, 126))	('PPMP', 'Var', (88, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (169, 186))	('esophageal cancer', 'Disease', (40, 57))	('anchorage-independent growth', 'CPA', (131, 159))
224665	27129160	Data show that PPMP effectively suppressed tumor growth without affecting mouse body weight (Figure 6).	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('PPMP', 'Chemical', 'MESH:C026733', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mouse', 'Species', '10090', (74, 79))	('PPMP', 'Var', (15, 19))	('tumor', 'Disease', (43, 48))	('suppressed', 'NegReg', (32, 42))
224673	27129160	As a potential CBSI, PPMP exerts its potent effects on the microtubule cytoskeleton and therefore might also produce rapid disruption of tumor blood flow.	('disruption of tumor', 'Disease', 'MESH:D019958', (123, 142))	('PPMP', 'Var', (21, 25))	('produce', 'Reg', (109, 116))	('effects', 'Reg', (44, 51))	('microtubule cytoskeleton', 'MPA', (59, 83))	('disruption of tumor', 'Disease', (123, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('PPMP', 'Chemical', 'MESH:C026733', (21, 25))
224683	27129160	The KYSE30, KYSE450 and KYSE510 human esophageal cancer cell lines were from ATCC.	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('KYSE510', 'Var', (24, 31))	('human', 'Species', '9606', (32, 37))	('KYSE510', 'CellLine', 'CVCL:1354', (24, 31))
224774	27527155	Despite these limits, preliminary studies on CTC status before and after surgery in patients with esophageal squamous cancer showed that the presence of CTCs was an independent predictor of disease recurrence.	('patients', 'Species', '9606', (84, 92))	('presence', 'Var', (141, 149))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (98, 124))	('squamous cancer', 'Phenotype', 'HP:0002860', (109, 124))	('CTCs', 'Gene', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal squamous cancer', 'Disease', (98, 124))
224788	27527155	This result could be due to dissimilar characteristics between esophageal cancer subtypes (SSC vs. EAC), e.g., varied EpCAM expression resulting in diverse CTC detection rates, indicating a potentially clinically relevant difference between the two histotypes.	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('EpCAM', 'Gene', (118, 123))	('CTC detection', 'MPA', (156, 169))	('varied', 'Var', (111, 117))	('EpCAM', 'Gene', '4072', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
224793	27527155	It was concluded that this discrepancy was not due to an intrinsic characteristic of the primary tumor, but most probably to EpCAM knockdown and/or EMT induction.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('knockdown', 'Var', (131, 140))	('EpCAM', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('EpCAM', 'Gene', '4072', (125, 130))
224841	27387830	We propose that more effort should be devoted to improving diagnostic methods of distinguishing T4a and T4b, especially using EUS and its innovations.	('T4a', 'Gene', '6317', (96, 99))	('T4a', 'Gene', (96, 99))	('T4b', 'Var', (104, 107))
224995	28337964	In the current study, we investigated the effects of anti-CD47 treatment on the antitumor immune response in an esophageal squamous cell cancer preclinical model.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('anti-CD47', 'Var', (53, 62))	('esophageal squamous cell cancer', 'Disease', (112, 143))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (112, 143))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (123, 143))
224996	28337964	We found that anti-CD47 treatment enhanced proinflammatory responses and increased CD8+ T-cell infiltration in tumor tissue in the animal model.	('increased', 'PosReg', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('proinflammatory', 'MPA', (43, 58))	('enhanced', 'PosReg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('anti-CD47', 'Var', (14, 23))	('tumor', 'Disease', (111, 116))	('CD8', 'Gene', (83, 86))	('CD8', 'Gene', '925', (83, 86))
224997	28337964	T cells in anti-CD47-treated tumors showed higher PD-1 and CTLA-4 expression, indicating T-cell activation and the rationale of combining anti-CD47 with anti-PD-1 and CLTA-4.	('CTLA-4', 'Gene', (59, 65))	('higher', 'PosReg', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('expression', 'MPA', (66, 76))	('anti-CD47', 'Var', (138, 147))	('anti-CD47-treated', 'Var', (11, 28))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', (29, 35))	('PD-1', 'Gene', (50, 54))	('activation', 'PosReg', (96, 106))
225003	28337964	The ligation of SIRPalpha on phagocytes by CD47-expressed tumor cells results in phosphorylation of SIRPalpha cytoplasmic immunoreceptor tyrosine-based inhibition (ITIM) motifs, leading to a negative regulation of the phagocytosis of tumor cells and, consequently, impairment of antigen presentation.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('phosphorylation', 'MPA', (81, 96))	('tumor', 'Disease', (234, 239))	('SIRPalpha', 'Gene', '19261', (16, 25))	('SIRPalpha', 'Gene', (100, 109))	('impairment', 'NegReg', (265, 275))	('antigen presentation', 'MPA', (279, 299))	('SIRPalpha', 'Gene', '19261', (100, 109))	('SIRPalpha', 'Gene', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tyrosine', 'Chemical', 'MESH:D014443', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('negative regulation', 'NegReg', (191, 210))	('ligation', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
225004	28337964	However, the clinical potential of anti-CD47 in cancer treatment is still under debate.	('anti-CD47', 'Var', (35, 44))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))
225014	28337964	Based on these facts, we aimed to investigate whether anti-CD47 could synergize with current ICBs, therefore being a novel target for esophageal squamous cell cancer treatment.	('esophageal squamous cell cancer', 'Disease', (134, 165))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (145, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ICBs', 'Chemical', '-', (93, 97))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (134, 165))	('anti-CD47', 'Var', (54, 63))
225015	28337964	The mechanisms by which anti-C47 synergizes in cancer immunotherapy were also investigated.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('anti-C47', 'Var', (24, 32))
225049	28337964	Tumors treated with anti-CD47 antibody had an increased number of CD8+ T and TH1 cells, but a decreased number of TH2 cells when compared with the control group (treated with IgG) (Fig.	('TH1', 'Gene', '57314', (77, 80))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TH1', 'Gene', (77, 80))	('increased', 'PosReg', (46, 55))	('CD8', 'Gene', (66, 69))	('anti-CD47', 'Var', (20, 29))	('CD8', 'Gene', '925', (66, 69))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TH2', 'Gene', '15111', (114, 117))	('TH2', 'Gene', (114, 117))
225051	28337964	This evidence suggested that anti-CD47 treatment might enhance the antitumor immunity in a DC-dependent way in esophageal squamous cell cancer.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (111, 142))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('enhance', 'PosReg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('esophageal squamous cell cancer', 'Disease', (111, 142))	('tumor', 'Disease', (71, 76))	('anti-CD47', 'Var', (29, 38))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (122, 142))
225053	28337964	We found that the tumors treated with anti-CD47 antibody had an increased level of proinflammatory cytokines, including IL-2, IFN-gamma, TNF-beta, and IL-12 (Fig.	('IL-12', 'MPA', (151, 156))	('TNF-beta', 'Gene', (137, 145))	('IFN-gamma', 'Gene', '15978', (126, 135))	('anti-CD47 antibody', 'Var', (38, 56))	('TNF-beta', 'Gene', '21926', (137, 145))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('level of proinflammatory cytokines', 'MPA', (74, 108))	('IL-2', 'Gene', '16183', (120, 124))	('increased', 'PosReg', (64, 73))	('IFN-gamma', 'Gene', (126, 135))	('IL-2', 'Gene', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
225055	28337964	However, anti-CD47 did not change the cytokine expression in the CD11c-DTR background mice.	('CD11c', 'Gene', '16411', (65, 70))	('CD11c', 'Gene', (65, 70))	('mice', 'Species', '10090', (86, 90))	('anti-CD47', 'Var', (9, 18))	('cytokine expression', 'MPA', (38, 57))
225056	28337964	Taken together with the data that anti-CD47 increased the number of TH1 cells, we believed that anti-CD47 could trigger a strong antitumor immune response by enhancing inflammation in cancer tissues and that this effect depended on DCs.	('cancer', 'Disease', (184, 190))	('TH1', 'Gene', '57314', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('enhancing', 'PosReg', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('TH1', 'Gene', (68, 71))	('anti-CD47', 'Var', (96, 105))	('tumor', 'Disease', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('inflammation', 'Disease', 'MESH:D007249', (168, 180))	('inflammation', 'Disease', (168, 180))
225058	28337964	The MFIs of PD-1 and CTLA-4 on CD8+ T cells were significantly increased in the tumors treated with anti-CD47 antibody (Fig.	('CTLA-4', 'Gene', (21, 27))	('increased', 'PosReg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('CD8', 'Gene', (31, 34))	('anti-CD47', 'Gene', (100, 109))	('CD8', 'Gene', '925', (31, 34))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('anti-CD47', 'Var', (100, 109))	('PD-1', 'Gene', (12, 16))	('MFIs', 'MPA', (4, 8))
225061	28337964	Considering that anti-CD47 treatment stimulated antitumor immune response and promoted the expression of immune checkpoint proteins, we hypothesized that anti-CD47 treatment might synergize with the anti-PD-1 and anti-CTLA-4 therapy in esophageal squamous cell cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('expression', 'MPA', (91, 101))	('stimulated', 'PosReg', (37, 47))	('esophageal squamous cell cancer', 'Disease', (236, 267))	('tumor', 'Disease', (52, 57))	('anti-CD47', 'Var', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('promoted', 'PosReg', (78, 86))	('anti-CD47', 'Var', (17, 26))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (236, 267))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (247, 267))
225063	28337964	The tumors accepting anti-CD47 antibody treatment plus ICB therapy (anti-CTLA-4 + anti-PD-1 antibodies) had the slowest tumor growth when compared with the tumors treated with either anti-CD47 antibody or ICB antibodies alone (Fig.	('tumor', 'Disease', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('anti-CD47', 'Var', (21, 30))	('tumors', 'Disease', (156, 162))	('ICB', 'Chemical', '-', (55, 58))	('ICB', 'Chemical', '-', (205, 208))	('tumors', 'Disease', (4, 10))	('slowest', 'NegReg', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
225064	28337964	Consistently, the mice treated with anti-CD47 antibody plus ICB antibodies had a better overall survival than the other groups (Fig.	('better', 'PosReg', (81, 87))	('anti-CD47', 'Var', (36, 45))	('mice', 'Species', '10090', (18, 22))	('ICB', 'Chemical', '-', (60, 63))	('overall survival', 'CPA', (88, 104))
225067	28337964	Patients with a high CD47 expression had lower average CD8+ cell density in tumor tissues, validating that high expression of CD47 is a negative immune regulator in esophageal squamous cell cancer patients.	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (165, 196))	('CD47', 'Gene', (21, 25))	('patients', 'Species', '9606', (197, 205))	('expression', 'Var', (26, 36))	('high', 'Var', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('lower', 'NegReg', (41, 46))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (176, 196))	('Patients', 'Species', '9606', (0, 8))	('CD8', 'Gene', (55, 58))	('esophageal squamous cell cancer', 'Disease', (165, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('CD8', 'Gene', '925', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
225074	28337964	The commercialized anti-CD47 antibody used in previous studies is a blockade of the CD47 signaling pathway by competing with SIRPalphas without stimulating the downstream pathways.	('anti-CD47', 'Var', (19, 28))	('CD47 signaling pathway', 'Pathway', (84, 106))	('SIRPalpha', 'Gene', '19261', (125, 134))	('SIRPalpha', 'Gene', (125, 134))
225075	28337964	In the present study, we investigated the potential synergistic effects of anti-CD47 and the currently used ICBs, anti-PD-1, and CTLA-4 in an esophageal squamous cell cancer preclinical model.	('esophageal squamous cell cancer', 'Disease', (142, 173))	('anti-CD47', 'Var', (75, 84))	('ICBs', 'Chemical', '-', (108, 112))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (142, 173))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (153, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
225076	28337964	We first evaluated the effects of anti-CD47 on immune infiltration and antitumor inflammatory response in animal models.	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (75, 80))	('anti-CD47', 'Var', (34, 43))
225077	28337964	Anti-CD47 significantly increased the number of CD8+ T cells, a major indicator of antitumor immune response, in tumor tissues in wild-type host mice.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('Anti-CD47', 'Var', (0, 9))	('CD8', 'Gene', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CD8', 'Gene', '925', (48, 51))	('increased', 'PosReg', (24, 33))
225080	28337964	Here we found that anti-CD47 increased the number of TH1 cells while decreasing the number of TH2 cells in tumors in wild-type host mice.	('anti-CD47', 'Var', (19, 28))	('TH1', 'Gene', '57314', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('TH1', 'Gene', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('increased', 'PosReg', (29, 38))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mice', 'Species', '10090', (132, 136))	('TH2', 'Gene', '15111', (94, 97))	('decreasing', 'NegReg', (69, 79))	('TH2', 'Gene', (94, 97))
225081	28337964	The expression of proinflammatory cytokines, such as IL-2, IL-12, TNF-beta, and IFN-gamma, was also stimulated by anti-CD47 treatment.	('IL-12', 'Gene', (59, 64))	('TNF-beta', 'Gene', '21926', (66, 74))	('expression', 'MPA', (4, 14))	('IFN-gamma', 'Gene', (80, 89))	('IFN-gamma', 'Gene', '15978', (80, 89))	('IL-2', 'Gene', '16183', (53, 57))	('TNF-beta', 'Gene', (66, 74))	('anti-CD47', 'Var', (114, 123))	('stimulated', 'PosReg', (100, 110))	('IL-2', 'Gene', (53, 57))
225082	28337964	However, in the CD11c-DTR mouse model, which has a small number of DCs, the anti-CD47 treatment could only raise a weak response.	('CD11c', 'Gene', '16411', (16, 21))	('mouse', 'Species', '10090', (26, 31))	('anti-CD47', 'Var', (76, 85))	('CD11c', 'Gene', (16, 21))
225083	28337964	These observations implied that anti-CD47 could promote antitumor inflammation and immune response by enhancing the function of DCs.	('function', 'MPA', (116, 124))	('anti-CD47', 'Var', (32, 41))	('inflammation', 'Disease', (66, 78))	('enhancing', 'PosReg', (102, 111))	('promote', 'PosReg', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('DCs', 'Protein', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('immune response', 'CPA', (83, 98))	('tumor', 'Disease', (60, 65))	('inflammation', 'Disease', 'MESH:D007249', (66, 78))
225085	28337964	Thus, we measured the function of CD8+ T cells in tumors treated with anti-CD47.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('measured', 'Reg', (9, 17))	('CD8', 'Gene', (34, 37))	('CD8', 'Gene', '925', (34, 37))	('anti-CD47', 'Gene', (70, 79))	('anti-CD47', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
225086	28337964	It is worth noting that CD8+ T cells in anti-CD47-treated tumors showed a high expression of PD-1 and CTLA-4, two important inhibitory immune checkpoint proteins.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('expression', 'MPA', (79, 89))	('anti-CD47-treated', 'Var', (40, 57))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('CD8', 'Gene', (24, 27))	('CD8', 'Gene', '925', (24, 27))	('PD-1', 'Gene', (93, 97))	('CTLA-4', 'Gene', (102, 108))
225088	28337964	These data indicate that CD8+ T cells in anti-CD47-treated tumors were well activated, but because of upregulation of the inhibitory immune checkpoint, their tumor killing effect was impaired, suggesting that combining anti-CD47 with anti-PD-1 and CTLA-4 may induce a strong tumor-eliminating response.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (275, 280))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('CD8', 'Gene', (25, 28))	('anti-CD47-treated', 'Var', (41, 58))	('upregulation', 'PosReg', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('impaired', 'NegReg', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('anti-CD47', 'Var', (219, 228))	('inhibitory immune', 'MPA', (122, 139))	('induce', 'PosReg', (259, 265))	('tumor', 'Disease', (158, 163))	('tumors', 'Disease', (59, 65))	('CD8', 'Gene', '925', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (158, 163))
225096	28337964	This observation suggests that CD47 expression might negatively influence the antitumor immune response in esophageal squamous cell cancer patients and supports the findings of the animal studies.	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (107, 138))	('patients', 'Species', '9606', (139, 147))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (118, 138))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('expression', 'Var', (36, 46))	('CD47', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('influence', 'Reg', (64, 73))	('negatively', 'NegReg', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('esophageal squamous cell cancer', 'Disease', (107, 138))	('tumor', 'Disease', (82, 87))
225097	28337964	In conclusion, our study indicates that high expression of CD47 is a protective factor for esophageal squamous cell cancer to escape immune killing.	('esophageal squamous cell cancer', 'Disease', (91, 122))	('high expression', 'Var', (40, 55))	('CD47', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (91, 122))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (102, 122))
225098	28337964	Anti-CD47 could enhance antitumor inflammation and T-cell recruitment in a DC-dependent manner.	('inflammation', 'Disease', (34, 46))	('tumor', 'Disease', (28, 33))	('Anti-CD47', 'Var', (0, 9))	('T-cell recruitment', 'CPA', (51, 69))	('enhance', 'PosReg', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('inflammation', 'Disease', 'MESH:D007249', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
225216	31849481	Silencing of TRIM44 inhibits the proliferation, migration and invasion of CRC cells.	('TRIM44', 'Gene', (13, 19))	('inhibits', 'NegReg', (20, 28))	('TRIM44', 'Gene', '54765', (13, 19))	('CRC', 'Phenotype', 'HP:0003003', (74, 77))	('invasion of CRC cells', 'CPA', (62, 83))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('Silencing', 'Var', (0, 9))
225259	31849481	The primary antibodies and dilutions used in this study were anti-TRIM44 antibody (Proteintech Group, Inc., 1:1000); anti-mTOR antibody (1:2000), anti-p-mTOR antibody (1:1500), anti-Akt antibody (1:1000), anti-p-Akt antibody (1:1000), anti-P70 antibody (1:1000), and anti-p-P70 antibody (1:2000) (all from Cell Signal Technology, Beverly, MA, USA).	('P70', 'Gene', (240, 243))	('1:1000', 'Var', (226, 232))	('1:1000', 'Var', (196, 202))	('TRIM44', 'Gene', (66, 72))	('1:2000', 'Var', (137, 143))	('1:1500', 'Var', (168, 174))	('mTOR', 'Gene', (153, 157))	('mTOR', 'Gene', '2475', (153, 157))	('Akt', 'Gene', '207', (182, 185))	('P70', 'Gene', (274, 277))	('P70', 'Gene', '84959', (240, 243))	('Akt', 'Gene', '207', (212, 215))	('mTOR', 'Gene', (122, 126))	('Akt', 'Gene', (182, 185))	('mTOR', 'Gene', '2475', (122, 126))	('Akt', 'Gene', (212, 215))	('TRIM44', 'Gene', '54765', (66, 72))	('P70', 'Gene', '84959', (274, 277))
225290	31849481	The GEPIA survival tool revealed that CRC patients with high mRNA levels of TRIM44 had poorer prognosis (Figure 2A and B).	('TRIM44', 'Gene', '54765', (76, 82))	('CRC', 'Phenotype', 'HP:0003003', (38, 41))	('TRIM44', 'Gene', (76, 82))	('high', 'Var', (56, 60))	('mRNA levels', 'MPA', (61, 72))	('patients', 'Species', '9606', (42, 50))	('si', 'Chemical', 'MESH:D012825', (100, 102))
225301	31849481	TRIM44 protein was upregulated in SW620, LOVO, and HCT116 CRC cells compared with the expression in NCM460 normal intestinal mucosal epithelial cells (Figure 3A).	('upregulated', 'PosReg', (19, 30))	('TRIM44', 'Gene', (0, 6))	('CRC', 'Phenotype', 'HP:0003003', (58, 61))	('SW620', 'CellLine', 'CVCL:0547', (34, 39))	('SW620', 'Var', (34, 39))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('HCT116 CRC', 'CellLine', 'CVCL:0291', (51, 61))	('TRIM44', 'Gene', '54765', (0, 6))	('protein', 'Protein', (7, 14))
225303	31849481	After effective knockdown of TRIM44 expression in the LOVO cells (Figure 3B), we further examined the effects of TRIM44 on CRC cell proliferation, migration, and invasion.	('TRIM44', 'Gene', (113, 119))	('TRIM44', 'Gene', '54765', (29, 35))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('TRIM44', 'Gene', (29, 35))	('knockdown', 'Var', (16, 25))	('TRIM44', 'Gene', '54765', (113, 119))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('CRC', 'Phenotype', 'HP:0003003', (123, 126))
225306	31849481	TRIM44 silencing effectively inhibited the migration and invasion capacities of LOVO cells (Figure 3D).	('inhibited', 'NegReg', (29, 38))	('TRIM44', 'Gene', (0, 6))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('si', 'Chemical', 'MESH:D012825', (7, 9))	('TRIM44', 'Gene', '54765', (0, 6))	('silencing', 'Var', (7, 16))
225308	31849481	The assay demonstrated that knockdown of TRIM44 suppressed the migration of LOVO cells (Figure 3E).	('migration of LOVO cells', 'CPA', (63, 86))	('TRIM44', 'Gene', (41, 47))	('suppressed', 'NegReg', (48, 58))	('knockdown', 'Var', (28, 37))	('TRIM44', 'Gene', '54765', (41, 47))
225320	31849481	Liu et al reported that expression of TRIM44 was markedly upregulated in tissues of cervical cancer than in nearby normal tissues, and that TRIM44 expression was closely related to FIGO stage, lymph node metastasis, and histological grade; and high levels of expression of TRIM44 was correlated to a poor prognosis in cervical cancer patients.	('si', 'Chemical', 'MESH:D012825', (153, 155))	('TRIM44', 'Gene', '54765', (273, 279))	('si', 'Chemical', 'MESH:D012825', (311, 313))	('TRIM44', 'Gene', (273, 279))	('cancer', 'Disease', (327, 333))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('expression', 'MPA', (24, 34))	('upregulated', 'PosReg', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('high', 'Var', (244, 248))	('related', 'Reg', (170, 177))	('FIGO stage', 'Disease', (181, 191))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('TRIM44', 'Gene', '54765', (38, 44))	('patients', 'Species', '9606', (334, 342))	('TRIM44', 'Gene', (38, 44))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('si', 'Chemical', 'MESH:D012825', (211, 213))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('TRIM44', 'Gene', '54765', (140, 146))	('si', 'Chemical', 'MESH:D012825', (265, 267))	('TRIM44', 'Gene', (140, 146))
225322	31849481	TRIM44 is highly expressed in thyroid PTC tissues and cell lines, and silencing of TRIM44 significantly inhibits PTC cell proliferation, migration/invasion, and epithelial-mesenchymal transition (EMT).	('si', 'Chemical', 'MESH:D012825', (70, 72))	('TRIM44', 'Gene', (0, 6))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('epithelial-mesenchymal transition', 'CPA', (161, 194))	('TRIM44', 'Gene', (83, 89))	('silencing', 'Var', (70, 79))	('inhibits', 'NegReg', (104, 112))	('si', 'Chemical', 'MESH:D012825', (188, 190))	('PTC', 'Phenotype', 'HP:0002895', (113, 116))	('PTC', 'Phenotype', 'HP:0002895', (38, 41))	('migration/invasion', 'CPA', (137, 155))	('TRIM44', 'Gene', '54765', (0, 6))	('si', 'Chemical', 'MESH:D012825', (151, 153))	('PTC cell proliferation', 'CPA', (113, 135))	('TRIM44', 'Gene', '54765', (83, 89))
225323	31849481	In other previous studies, the abnormal expression of TRIM44 was closely associated with the progression of malignant tumors, such as gastric cancer, esophageal cancer, and intrahepatic cholangiocarcinoma, thus indicating the poor prognosis of these cancer patients.	('esophageal cancer', 'Disease', (150, 167))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('abnormal', 'Var', (31, 39))	('gastric cancer', 'Disease', (134, 148))	('associated', 'Reg', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('malignant tumors', 'Disease', (108, 124))	('cancer', 'Disease', (161, 167))	('malignant tumors', 'Disease', 'MESH:D009369', (108, 124))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('si', 'Chemical', 'MESH:D012825', (237, 239))	('patients', 'Species', '9606', (257, 265))	('cancer', 'Disease', (142, 148))	('expression', 'MPA', (40, 50))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('si', 'Chemical', 'MESH:D012825', (100, 102))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('cancer', 'Disease', (250, 256))	('TRIM44', 'Gene', '54765', (54, 60))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (173, 204))	('intrahepatic cholangiocarcinoma', 'Disease', (173, 204))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('TRIM44', 'Gene', (54, 60))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (186, 204))
225327	31849481	A series of in vitro assays demonstrated that knockdown of TRIM44 significantly inhibited the proliferation, migration, and invasion abilities of LOVO cells.	('TRIM44', 'Gene', '54765', (59, 65))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('knockdown', 'Var', (46, 55))	('TRIM44', 'Gene', (59, 65))	('invasion abilities of LOVO cells', 'CPA', (124, 156))	('migration', 'CPA', (109, 118))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('inhibited', 'NegReg', (80, 89))
225334	31849481	Based on previous studies and our present bioinformatics predictions, we examined the changes in Akt/mTOR signaling pathway-related molecules after knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('mTOR', 'Gene', (101, 105))	('Akt', 'Gene', (97, 100))	('mTOR', 'Gene', '2475', (101, 105))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('changes', 'Reg', (86, 93))	('TRIM44', 'Gene', '54765', (161, 167))	('Akt', 'Gene', '207', (97, 100))	('knockdown', 'Var', (148, 157))
225403	29928701	However, hereditary factors are rare and affect only 1% to 3% of patients (Lynch syndrome, hereditary diffuse cancer secondary to a mutation of E-cadherin, mutation of BRCA).	('BRCA', 'Gene', (168, 172))	('BRCA', 'Gene', '672', (168, 172))	('hereditary diffuse cancer', 'Disease', 'MESH:D013274', (91, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('E-cadherin', 'Gene', (144, 154))	('Lynch syndrome', 'Disease', (75, 89))	('patients', 'Species', '9606', (65, 73))	('Lynch syndrome', 'Disease', 'MESH:D003123', (75, 89))	('E-cadherin', 'Gene', '999', (144, 154))	('mutation', 'Var', (132, 140))	('hereditary diffuse cancer', 'Disease', (91, 116))	('mutation', 'Var', (156, 164))
225417	29928701	Excluding classical biomarkers, those determining prognosis and the progression of gastric cancer focus on targeting microRNAs, epigenetic alterations and genetic polymorphisms.	('epigenetic alterations', 'Var', (128, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('gastric cancer', 'Disease', (83, 97))	('microRNAs', 'MPA', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('genetic polymorphisms', 'Var', (155, 176))
225456	29928701	Despite increased morbidity and mortality in the Dutch gastric cancer group trial compared to asian series where the procedure is routinely performed (10% vs <1%), D2 dissection was correlated with increased locoregional control and cancer-specific survival.	('gastric cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Dutch gastric cancer', 'Phenotype', 'HP:0011139', (49, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('increased', 'PosReg', (198, 207))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('locoregional control', 'CPA', (208, 228))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('D2 dissection', 'Var', (164, 177))	('cancer', 'Disease', (63, 69))
225479	29928701	However, more treatment interruptions were reported in the 3D-CRT arm than in the IMRT arm (3 versus 0, respectively) as well as a higher elevation of remote serum creatinine (0.2 mg/dL increase in the 3D-CRT group, p = 0.02).	('creatinine', 'Chemical', 'MESH:D003404', (164, 174))	('elevation', 'PosReg', (138, 147))	('remote serum creatinine', 'MPA', (151, 174))	('3D-CRT', 'Var', (59, 65))
225510	29928701	Late toxicity, especially renal and digestive, appeared to be lower with XELOX compared to the MacDonald-treated cohort.	('digestive', 'CPA', (36, 45))	('XELOX', 'Chemical', 'MESH:C519688', (73, 78))	('XELOX', 'Var', (73, 78))	('lower', 'NegReg', (62, 67))	('toxicity', 'Disease', 'MESH:D064420', (5, 13))	('toxicity', 'Disease', (5, 13))
225524	29928701	It seems important to note that in the 10-year follow-up update of patients in the INT 0116 trial, a larger number of second cancers was reported in the postoperative CRT group compared to the control arm (21 versus 8), but it remained non significant (p = 0.21).	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('patients', 'Species', '9606', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('CRT', 'Var', (167, 170))	('postoperative', 'Var', (153, 166))
225544	29928701	Also, combined approach with novel molecules such as check point inhibitors are ongoing: the PROCEED trial (NCT03064490) investigate wether addition of pembrolizumab improves the efficacy of neoadjuvant chemoradiotherapy (45 Gy in 25 fractions with concurrent, weekly carboplatin and paclitaxel).	('addition', 'Var', (140, 148))	('pembrolizumab', 'Chemical', 'MESH:C582435', (152, 165))	('carboplatin', 'Chemical', 'MESH:D016190', (268, 279))	('paclitaxel', 'Chemical', 'MESH:D017239', (284, 294))	('improves', 'PosReg', (166, 174))
225727	29308064	The duration of chylothorax tended to be longer in the no-etilefrine group (n = 5) than in the etilefrine group (n = 11) (27.8 vs. 11.6 days; p = 0.078).	('no-etilefrine', 'Var', (55, 68))	('chylothorax', 'Phenotype', 'HP:0010310', (16, 27))	('etilefrine', 'Chemical', 'MESH:D005039', (95, 105))	('chylothorax', 'Disease', (16, 27))	('etilefrine', 'Chemical', 'MESH:D005039', (58, 68))
225759	29308064	The duration of chylothorax tended to be longer in the no-etilefrine group than in the etilefrine group, but no significant difference between the two groups (27.8 vs. 11.6 days, respectively; p = 0.078).	('no-etilefrine', 'Var', (55, 68))	('chylothorax', 'Phenotype', 'HP:0010310', (16, 27))	('etilefrine', 'Chemical', 'MESH:D005039', (87, 97))	('chylothorax', 'Disease', (16, 27))	('etilefrine', 'Chemical', 'MESH:D005039', (58, 68))
225768	29308064	The use of etilefrine in chylothorax was reported for the first time by Guillem et al.. Etilefrine has both alpha-adrenergic and beta-adrenergic effects and is commonly used to treat conditions such as orthostatic hypotension and priapism.	('etilefrine', 'Chemical', 'MESH:D005039', (11, 21))	('Etilefrine', 'Var', (88, 98))	('orthostatic hypotension', 'Phenotype', 'HP:0001278', (202, 225))	('priapism', 'Phenotype', 'HP:0200023', (230, 238))	('orthostatic hypotension', 'Disease', 'MESH:D007024', (202, 225))	('Etilefrine', 'Chemical', 'MESH:D005039', (88, 98))	('chylothorax', 'Phenotype', 'HP:0010310', (25, 36))	('priapism', 'Disease', 'MESH:D011317', (230, 238))	('hypotension', 'Phenotype', 'HP:0002615', (214, 225))	('orthostatic hypotension', 'Disease', (202, 225))	('priapism', 'Disease', (230, 238))	('alpha-adrenergic', 'MPA', (108, 124))
225775	29308064	In performing TDR, we double-clip the thoracic duct above the diaphragm in patients with cStage II or more advanced esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (75, 83))	('double-clip', 'Var', (22, 33))	('esophageal cancer', 'Disease', (116, 133))
225826	27284372	The membranes were blocked with Tris-buffered saline (Sigma-Aldrich) containing 0.05% Tween-20 (Sigma-Aldrich) and either 5% skim milk or 5% bovine serum albumin (Sigma-Aldrich), and incubated with monoclonal rabbit antibodies against NF-kappaB (#4764; dilution, 1:1,000), AKT (#8596; dilution, 1:1,000) and phosphorylated-AKT (p-AKT; clone Ser473; #4060; dilution, 1:1,000), which were all purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA).	('NF-kappaB', 'Gene', (235, 244))	('AKT', 'Gene', '207', (323, 326))	('AKT', 'Gene', (330, 333))	('#8596;', 'Var', (278, 284))	('AKT', 'Gene', (323, 326))	('bovine', 'Species', '9913', (141, 147))	('AKT', 'Gene', '207', (273, 276))	('rabbit', 'Species', '9986', (209, 215))	('#4764;', 'Var', (246, 252))	('AKT', 'Gene', '207', (330, 333))	('AKT', 'Gene', (273, 276))	('NF-kappaB', 'Gene', '4790', (235, 244))
225850	27284372	Gu et al also reported that reactive oxygen species-mediated autophagy induced by the dysregulation of lipid metabolism protects colorectal cancer cells treated with GA.	('colorectal cancer', 'Disease', (129, 146))	('autophagy', 'CPA', (61, 70))	('reactive oxygen species-mediated', 'MPA', (28, 60))	('lipid', 'Chemical', 'MESH:D008055', (103, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('dysregulation', 'Var', (86, 99))	('GA', 'Chemical', 'MESH:C052659', (166, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('lipid metabolism', 'MPA', (103, 119))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (28, 51))
225908	24466454	Overexpression of miR-221 and miR-222 reduced the levels of p27Kip1 and CDX2, whereas the knockdown of these miRNAs increased the levels of these proteins in the cultured cells.	('CDX2', 'Gene', '1045', (72, 76))	('p27Kip1', 'Gene', (60, 67))	('knockdown', 'Var', (90, 99))	('reduced', 'NegReg', (38, 45))	('miR-221', 'Gene', (18, 25))	('miR-222', 'Gene', (30, 37))	('levels', 'MPA', (50, 56))	('increased', 'PosReg', (116, 125))	('p27Kip1', 'Gene', '1027', (60, 67))	('miR-221', 'Gene', '407006', (18, 25))	('miR-222', 'Gene', '407007', (30, 37))	('CDX2', 'Gene', (72, 76))
225918	24466454	Recently, Guan et al reported that inhibition of FXR suppressed tumor cell viability and induced apoptosis in vitro, and it also reduced tumor formation and growth in nude mouse xenografts.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (137, 142))	('FXR', 'Gene', (49, 52))	('induced', 'Reg', (89, 96))	('mouse', 'Species', '10090', (172, 177))	('growth in', 'CPA', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('inhibition', 'Var', (35, 45))	('suppressed', 'NegReg', (53, 63))	('apoptosis', 'CPA', (97, 106))	('reduced', 'NegReg', (129, 136))
225927	24466454	Novel biomarkers are needed to detect high-risk BE patients with low-grade dysplasia who may eventually develop a progression to EAC.	('low-grade', 'Var', (65, 74))	('EAC', 'Phenotype', 'HP:0011459', (129, 132))	('dysplasia', 'Disease', (75, 84))	('EAC', 'Disease', (129, 132))	('patients', 'Species', '9606', (51, 59))	('dysplasia', 'Disease', 'MESH:D004476', (75, 84))	('BE', 'Phenotype', 'HP:0100580', (48, 50))
225929	24466454	However, the therapeutic application of FXR antagonists or inhibitors of miRNAs have the potency to be beneficial for EAC or BE patients with high risk of developing EAC.	('FXR', 'Protein', (40, 43))	('BE', 'Phenotype', 'HP:0100580', (125, 127))	('beneficial', 'PosReg', (103, 113))	('EAC', 'Disease', (118, 121))	('inhibitors', 'Var', (59, 69))	('patients', 'Species', '9606', (128, 136))	('EAC', 'Phenotype', 'HP:0011459', (118, 121))	('EAC', 'Phenotype', 'HP:0011459', (166, 169))	('miRNAs', 'Gene', (73, 79))
226234	31722716	circGSK3beta promotes metastasis in esophageal squamous cell carcinoma by augmenting beta-catenin signaling Circular RNAs (circRNAs), a novel class of noncoding RNAs, have recently drawn much attention in the pathogenesis of human cancers.	('esophageal squamous cell carcinoma', 'Disease', (36, 70))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (36, 70))	('beta-catenin', 'Gene', '1499', (85, 97))	('promotes', 'PosReg', (13, 21))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('metastasis', 'CPA', (22, 32))	('cancers', 'Disease', (231, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('human', 'Species', '9606', (225, 230))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('beta-catenin', 'Gene', (85, 97))	('augmenting', 'NegReg', (74, 84))	('circGSK3beta', 'Var', (0, 12))
226311	31722716	In addition, as shown in Table 1, high circGSK3beta expression levels were significantly associated with more lymph node metastasis of ESCC (Fig.	('ESCC', 'Disease', (135, 139))	('more', 'PosReg', (105, 109))	('lymph node metastasis', 'CPA', (110, 131))	('expression', 'Species', '29278', (52, 62))	('ESCC', 'Disease', 'MESH:C562729', (135, 139))	('GSK3beta', 'Gene', (43, 51))	('high', 'Var', (34, 38))	('GSK3beta', 'Gene', '2932', (43, 51))
226321	31722716	Depletion of circGSK3beta with siRNA resulted in a significant knockdown in circGSK3beta levels (Additional file 1: Figure S2B & S2D), while the expression level of the host gene, GSK3beta, was not changed by either knockdown or overexpression of circGSK3beta (Additional file 1: Figure S2B - S2E) in ESCC cells.	('S2B', 'Chemical', 'MESH:D013455', (287, 290))	('expression', 'Species', '29278', (233, 243))	('GSK3beta', 'Gene', (180, 188))	('knockdown', 'NegReg', (63, 72))	('GSK3beta', 'Gene', (80, 88))	('ESCC', 'Disease', (301, 305))	('S2B', 'Chemical', 'MESH:D013455', (123, 126))	('expression', 'Species', '29278', (145, 155))	('Depletion', 'Var', (0, 9))	('GSK3beta', 'Gene', '2932', (180, 188))	('GSK3beta', 'Gene', '2932', (80, 88))	('ESCC', 'Disease', 'MESH:C562729', (301, 305))	('GSK3beta', 'Gene', (251, 259))	('GSK3beta', 'Gene', (17, 25))	('siRNA', 'Gene', (31, 36))	('GSK3beta', 'Gene', '2932', (251, 259))	('GSK3beta', 'Gene', '2932', (17, 25))
226333	31722716	Similarly, the Flow cytometry also demonstrated that depletion of circGSK3beta compromised EMT (Fig.	('compromised', 'NegReg', (79, 90))	('depletion', 'Var', (53, 62))	('GSK3beta', 'Gene', (70, 78))	('GSK3beta', 'Gene', '2932', (70, 78))
226357	31722716	The Transwell and Matrigel invasion assay showed that overexpression of beta-catenin compensated the loss of migration and invasion due to depletion of circGSK3beta (Fig.	('expression', 'Species', '29278', (58, 68))	('loss', 'NegReg', (101, 105))	('beta-catenin', 'Gene', (72, 84))	('GSK3beta', 'Gene', (156, 164))	('beta-catenin', 'Gene', '1499', (72, 84))	('GSK3beta', 'Gene', '2932', (156, 164))	('migration', 'CPA', (109, 118))	('depletion', 'Var', (139, 148))
226380	31722716	The AUC of circGSK3beta for ESCC or early stages of ESCC and controls in the validation cohort were 0.8012 (95% CI: 0.7075-0.8950) and 0.8255 (95% CI: 0.6929-0.9581), respectively.	('0.8012', 'Var', (100, 106))	('ESCC', 'Disease', 'MESH:C562729', (28, 32))	('GSK3beta', 'Gene', (15, 23))	('ESCC', 'Disease', 'MESH:C562729', (52, 56))	('0.8255', 'Var', (135, 141))	('GSK3beta', 'Gene', '2932', (15, 23))	('ESCC', 'Disease', (52, 56))	('ESCC', 'Disease', (28, 32))
226409	31722716	Our result indicated that ablation of circGSK3beta inhibits tumor growth which is the direct evidence that the inhibition of circGSK3beta has the potential for ESCC treatments.	('ESCC', 'Disease', (160, 164))	('GSK3beta', 'Gene', '2932', (42, 50))	('GSK3beta', 'Gene', (42, 50))	('inhibits', 'NegReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('GSK3beta', 'Gene', (129, 137))	('ESCC', 'Disease', 'MESH:C562729', (160, 164))	('GSK3beta', 'Gene', '2932', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ablation', 'Var', (26, 34))	('tumor', 'Disease', (60, 65))
226439	24608342	We also provided evidence that OLC1 abnormalities significantly altered the cell proliferation and apoptosis induced by cytotoxic agents.	('OLC1', 'Gene', (31, 35))	('apoptosis', 'CPA', (99, 108))	('cell proliferation', 'CPA', (76, 94))	('abnormalities', 'Var', (36, 49))	('altered', 'Reg', (64, 71))	('OLC1', 'Gene', '9798', (31, 35))
226441	24608342	Our study provides strong evidence suggesting OLC1 abnormalities may contribute to the development of human ESCC and have some important clinical significance.	('ESCC', 'Phenotype', 'HP:0011459', (108, 112))	('human ESCC', 'Disease', (102, 112))	('OLC1', 'Gene', '9798', (46, 50))	('abnormalities', 'Var', (51, 64))	('OLC1', 'Gene', (46, 50))	('contribute', 'Reg', (69, 79))	('human', 'Species', '9606', (102, 107))
226444	24608342	It was previously reported that p53, Cyclin D1, E-cadherin, K-ras, and VEGF have altered expression in ESCC, suggesting that abnormalities in the expression of oncogenes and tumor suppressor genes contributes to esophageal carcinogenesis and malignant development.	('esophageal carcinogenesis', 'Disease', (212, 237))	('abnormalities', 'Var', (125, 138))	('p53', 'Gene', '7157', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (212, 237))	('expression', 'MPA', (89, 99))	('p53', 'Gene', (32, 35))	('K-ras', 'Gene', (60, 65))	('ESCC', 'Phenotype', 'HP:0011459', (103, 107))	('Cyclin D1', 'Gene', '595', (37, 46))	('Cyclin D1', 'Gene', (37, 46))	('malignant development', 'CPA', (242, 263))	('E-cadherin', 'Gene', (48, 58))	('E-cadherin', 'Gene', '999', (48, 58))	('ESCC', 'Disease', (103, 107))	('contributes', 'Reg', (197, 208))	('VEGF', 'Gene', '7422', (71, 75))	('tumor', 'Disease', (174, 179))	('VEGF', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('K-ras', 'Gene', '3845', (60, 65))	('altered', 'Reg', (81, 88))
226461	24608342	We identified relationships between the dysregulation of OLC1 and the effects of cytotoxic agents on cell proliferation and apoptosis.	('dysregulation', 'Var', (40, 53))	('OLC1', 'Gene', '9798', (57, 61))	('OLC1', 'Gene', (57, 61))	('apoptosis', 'CPA', (124, 133))	('cell proliferation', 'CPA', (101, 119))
226464	24608342	The human EC9706, KYSE510, KYSE180, KYSE450 and KYSE150 were the origin of gifted cell lines indicated in our previous published references.	('KYSE150', 'Var', (48, 55))	('human', 'Species', '9606', (4, 9))	('EC9706', 'CellLine', 'CVCL:E307', (10, 16))	('KYSE510', 'Var', (18, 25))	('KYSE180', 'Var', (27, 34))	('EC9706', 'Var', (10, 16))
226475	24608342	Among these patients, 110 were T3N1M0 with lymph-node metastases, and 104 were T3N0M0 without lymph-node metastases, with a gender distribution of 172 male to 42 female.	('patients', 'Species', '9606', (12, 20))	('T3N1M0', 'Var', (31, 37))	('metastases', 'Disease', (105, 115))	('metastases', 'Disease', (54, 64))	('metastases', 'Disease', 'MESH:D009362', (54, 64))	('metastases', 'Disease', 'MESH:D009362', (105, 115))
226492	24608342	For GAPDH, the primers were as follows: 5'-GCTGAGAACGGGAAGCTTGT-3' (forward primer); 5'-GCCAGGGGTGCTAAGCAG-3' (reverse primer), and they resulted in a PCR product of 299 bp.	('GAPDH', 'Gene', (4, 9))	("5'-GCCAGGGGTGCTAAGCAG-3'", 'Var', (85, 109))	('resulted in', 'Reg', (137, 148))	('GAPDH', 'Gene', '2597', (4, 9))
226502	24608342	However, we found no significant differences in OLC1 expression between T3N0M0 (63.46%, 66/104) and T3N1M0 (70.91%, 78/110) in human ESCC tissues (P = 0.394) (Table 1).	('OLC1', 'Gene', '9798', (48, 52))	('human', 'Species', '9606', (127, 132))	('OLC1', 'Gene', (48, 52))	('T3N1M0', 'Var', (100, 106))	('T3N0M0', 'Var', (72, 78))	('ESCC', 'Phenotype', 'HP:0011459', (133, 137))
226509	24608342	KYSE150 cells were transfected with pEGFP-N1-OLC1 or pEGFP-N1, and the stable OLC1-overexpressing cell line was named KYSE150/GFP-OLC1, while the null control clone was named KYSE150/GFP.	('pEGFP-N1-OLC1', 'Gene', (36, 49))	('pEGFP-N1', 'Var', (53, 61))	('KYSE150/GFP-OLC1', 'Gene', (118, 134))	('OLC1', 'Gene', (78, 82))	('OLC1', 'Gene', '9798', (78, 82))	('KYSE150/GFP-OLC1', 'Gene', '9798', (118, 134))	('OLC1', 'Gene', (130, 134))	('OLC1', 'Gene', '9798', (130, 134))	('OLC1', 'Gene', '9798', (45, 49))	('pEGFP-N1-OLC1', 'Gene', '9798', (36, 49))	('OLC1', 'Gene', (45, 49))
226524	24608342	However, less pro-band was seen in KYSE150/GFP compared with OLC-1 cells.	('KYSE150/GFP', 'Var', (35, 46))	('OLC-1', 'Gene', (61, 66))	('OLC-1', 'Gene', '9798', (61, 66))
226527	24608342	EC9706 cells, which express relatively higher levels of endogenous OLC1 (Figure 2A), were transfected with PGCsi-U6/neo/GFP-control or PGCsi-U6/neo/GFP-OLC1.	('GFP-OLC1', 'Gene', '9798', (148, 156))	('OLC1', 'Gene', '9798', (152, 156))	('GFP-OLC1', 'Gene', (148, 156))	('OLC1', 'Gene', (152, 156))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('OLC1', 'Gene', (67, 71))	('OLC1', 'Gene', '9798', (67, 71))	('PGCsi-U6/neo/GFP-control', 'Var', (107, 131))
226532	24608342	CDDP-induced apoptosis in EC9706/pGCsi cells was markedly lower than in OLCsi-1 and OLCsi-2 cells, and they were all in a dose- and time-dependent manner (Figure 4E and 4F).	('CDDP', 'Chemical', 'MESH:D002945', (0, 4))	('EC9706/pGCsi', 'Var', (26, 38))	('lower', 'NegReg', (58, 63))	('apoptosis', 'CPA', (13, 22))	('CDDP-induced', 'Gene', (0, 12))	('EC9706', 'CellLine', 'CVCL:E307', (26, 32))
226538	24608342	Alteration of OLC1 expression could therefore be a critical event during the developmental of human esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('esophageal carcinoma', 'Disease', (100, 120))	('Alteration', 'Var', (0, 10))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (100, 120))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (100, 120))	('human', 'Species', '9606', (94, 99))	('OLC1', 'Gene', (14, 18))	('OLC1', 'Gene', '9798', (14, 18))
226540	24608342	This suggests that the dysregulation of OLC1 may contribute to the development of human ESCC.	('dysregulation', 'Var', (23, 36))	('human ESCC', 'Disease', (82, 92))	('OLC1', 'Gene', '9798', (40, 44))	('OLC1', 'Gene', (40, 44))	('ESCC', 'Phenotype', 'HP:0011459', (88, 92))	('contribute', 'Reg', (49, 59))	('human', 'Species', '9606', (82, 87))
226543	24608342	Here, we provided novel evidence that dysregulation of OLC1 expression significantly alter the cell proliferation and apoptosis induced by cytotoxic agents.	('cell proliferation', 'CPA', (95, 113))	('apoptosis', 'CPA', (118, 127))	('OLC1', 'Gene', (55, 59))	('alter', 'Reg', (85, 90))	('dysregulation', 'Var', (38, 51))	('OLC1', 'Gene', '9798', (55, 59))
226545	24608342	Conversely, we constructed OLC1-knockdown cell lines in EC9706 cells using siRNA, and stable knockdown of endogenous OLC1 inhibited cell growth and sensitized cells to CDDP-induced apoptosis.	('CDDP-induced', 'CPA', (168, 180))	('knockdown', 'Var', (93, 102))	('cell growth', 'CPA', (132, 143))	('OLC1', 'Gene', (117, 121))	('OLC1', 'Gene', '9798', (117, 121))	('inhibited', 'NegReg', (122, 131))	('CDDP', 'Chemical', 'MESH:D002945', (168, 172))	('EC9706', 'CellLine', 'CVCL:E307', (56, 62))	('sensitized', 'Reg', (148, 158))	('OLC1', 'Gene', (27, 31))	('OLC1', 'Gene', '9798', (27, 31))
226549	24608342	Our findings suggest that OLC1 overexpression suppresses cellular apoptosis, possibly by interfering with caspase-3 activation and enhancing Bcl-2 stability.	('Bcl-2', 'Gene', '596', (141, 146))	('suppresses', 'NegReg', (46, 56))	('overexpression', 'Var', (31, 45))	('Bcl-2', 'Gene', (141, 146))	('caspase-3', 'Gene', (106, 115))	('enhancing', 'PosReg', (131, 140))	('OLC1', 'Gene', '9798', (26, 30))	('interfering', 'NegReg', (89, 100))	('OLC1', 'Gene', (26, 30))	('caspase-3', 'Gene', '836', (106, 115))	('activation', 'MPA', (116, 126))	('cellular apoptosis', 'CPA', (57, 75))
226550	24608342	Taken together, these results suggest that the dysregulation of OLC1 disrupts the delicate balance between cell growth and apoptosis.	('dysregulation', 'Var', (47, 60))	('delicate balance between', 'MPA', (82, 106))	('disrupts', 'NegReg', (69, 77))	('OLC1', 'Gene', (64, 68))	('OLC1', 'Gene', '9798', (64, 68))
226551	24608342	Our results therefore help to explain why abnormalities in OLC1 expression contribute to a malignant cellular phenotype in ESCC.	('abnormalities', 'Var', (42, 55))	('contribute', 'Reg', (75, 85))	('ESCC', 'Disease', (123, 127))	('ESCC', 'Phenotype', 'HP:0011459', (123, 127))	('OLC1', 'Gene', '9798', (59, 63))	('OLC1', 'Gene', (59, 63))
226553	24608342	Fibrosarcomas were detected in all animals that were inoculated with OLC1-expressing NIH3T3 cells, but not in the control groups injected with the parental or empty-vector transfected cells.	('Fibrosarcomas', 'Disease', 'MESH:D005354', (0, 13))	('OLC1', 'Gene', (69, 73))	('Fibrosarcomas', 'Disease', (0, 13))	('detected', 'Reg', (19, 27))	('NIH3T3', 'Var', (85, 91))	('NIH3T3', 'CellLine', 'CVCL:0594', (85, 91))	('OLC1', 'Gene', '9798', (69, 73))
226557	24608342	However, more studies are needed to explore the underlying mechanisms of OLC1 dysregulation in esophageal tumorigenesis.	('OLC1', 'Gene', '9798', (73, 77))	('dysregulation', 'Var', (78, 91))	('OLC1', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
226558	24608342	In conclusion, we report that OLC1 is overexpressed in human ESCC; OLC1 abnormalities may contribute to the development of human ESCC and have some important clinical significance.	('ESCC', 'Disease', (129, 133))	('abnormalities', 'Var', (72, 85))	('human', 'Species', '9606', (123, 128))	('human', 'Species', '9606', (55, 60))	('ESCC', 'Phenotype', 'HP:0011459', (129, 133))	('OLC1', 'Gene', (67, 71))	('OLC1', 'Gene', '9798', (67, 71))	('OLC1', 'Gene', '9798', (30, 34))	('ESCC', 'Phenotype', 'HP:0011459', (61, 65))	('contribute', 'Reg', (90, 100))	('OLC1', 'Gene', (30, 34))
226559	24030569	Genetic variation at 8q24, family history of cancer, and upper gastrointestinal cancers in a Chinese population Genetic variation at 8q24 is associated with prostate, bladder, breast, colorectal, thyroid, lung, ovarian, UADT, liver and stomach cancers.	('colorectal', 'Disease', (184, 194))	('liver and stomach cancers', 'Disease', 'MESH:D006528', (226, 251))	('ovarian', 'Disease', (211, 218))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (57, 87))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('ovarian', 'Disease', 'MESH:D010051', (211, 218))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate', 'Disease', (157, 165))	('lung', 'Disease', (205, 209))	('stomach cancer', 'Phenotype', 'HP:0012126', (236, 250))	('associated', 'Reg', (141, 151))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('thyroid', 'Disease', (196, 203))	('breast', 'Disease', (176, 182))	('UADT', 'Disease', (220, 224))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('cancer', 'Disease', (45, 51))	('upper gastrointestinal cancers', 'Disease', (57, 87))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('Genetic variation at', 'Var', (112, 132))	('bladder', 'Disease', (167, 174))	('stomach cancers', 'Phenotype', 'HP:0012126', (236, 251))
226560	24030569	However, a role for variation at 8q24 in familial clustering of upper gastrointestinal cancers has not been studied.	('variation', 'Var', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (64, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('upper gastrointestinal cancers', 'Disease', (64, 94))
226563	24030569	Associations between 8q24 rs1447295, rs16901979, rs6983267 and these cancers were stratified by family history of cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('Associations', 'Interaction', (0, 12))	('rs6983267', 'Var', (49, 58))	('cancers', 'Disease', (69, 76))	('rs1447295', 'Var', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs16901979', 'Mutation', 'rs16901979', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('8q24', 'Gene', (21, 25))	('rs16901979', 'Var', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('rs1447295', 'Mutation', 'rs1447295', (26, 35))	('rs6983267', 'Mutation', 'rs6983267', (49, 58))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', (114, 120))
226566	24030569	In a dominant model, among those with a family history of cancer, rs1447295 was positively associated with liver cancer (ORadj 2.80; 95% CI 1.15-6.80).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('rs1447295', 'Mutation', 'rs1447295', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('liver cancer', 'Disease', 'MESH:D006528', (107, 119))	('liver cancer', 'Phenotype', 'HP:0002896', (107, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('rs1447295', 'Var', (66, 75))	('liver cancer', 'Disease', (107, 119))	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('associated', 'Reg', (91, 101))
226567	24030569	Heterogeneity was observed (Pheterogeneity=0.029) with rs6983267 and liver cancer, with positive association in the dominant model among those with a family history of cancer and positive association in the recessive model among those without a family history of cancer.	('positive', 'PosReg', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('rs6983267', 'Var', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (263, 269))	('cancer', 'Disease', (75, 81))	('liver cancer', 'Phenotype', 'HP:0002896', (69, 81))	('liver cancer', 'Disease', 'MESH:D006528', (69, 81))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('liver cancer', 'Disease', (69, 81))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs6983267', 'Mutation', 'rs6983267', (55, 64))
226569	24030569	These findings suggest that inherited susceptibility to liver cancer may exist in the Taixing population and that variation at 8q24 might be a genetic component of that inherited susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('liver cancer', 'Phenotype', 'HP:0002896', (56, 68))	('liver cancer', 'Disease', 'MESH:D006528', (56, 68))	('liver cancer', 'Disease', (56, 68))	('variation', 'Var', (114, 123))
226576	24030569	Genome-wide association studies (GWAS) and case-control studies have associated variation at 8q24 with prostate, bladder, breast, colorectal, thyroid, lung, ovarian, UADT, liver and stomach cancers.	('stomach cancers', 'Phenotype', 'HP:0012126', (182, 197))	('8q24', 'Gene', (93, 97))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('stomach cancer', 'Phenotype', 'HP:0012126', (182, 196))	('ovarian', 'Disease', 'MESH:D010051', (157, 164))	('lung', 'Disease', (151, 155))	('ovarian', 'Disease', (157, 164))	('bladder', 'Disease', (113, 120))	('colorectal', 'Disease', (130, 140))	('thyroid', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('variation', 'Var', (80, 89))	('liver and stomach cancers', 'Disease', 'MESH:D006528', (172, 197))	('breast', 'Disease', (122, 128))	('UADT', 'Disease', (166, 170))	('prostate', 'Disease', (103, 111))
226578	24030569	Additionally, in a family history-stratified analysis of cancer in a Polish population, 8q24 single nucleotide polymorphism (SNPs) were associated with prostate, laryngeal, lung, and kidney cancers among those with a family history of cancer, with noteworthy heterogeneity in family history-stratified associations for laryngeal and lung cancers.	('prostate', 'Disease', (152, 160))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('associated with', 'Reg', (136, 151))	('cancer', 'Disease', (190, 196))	('lung cancers', 'Disease', 'MESH:D008175', (333, 345))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('kidney cancers', 'Disease', (183, 197))	('kidney cancers', 'Disease', 'MESH:D007680', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('lung cancers', 'Disease', (333, 345))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('8q24', 'Gene', (88, 92))	('lung cancers', 'Phenotype', 'HP:0100526', (333, 345))	('single nucleotide polymorphism', 'Var', (93, 123))	('kidney cancers', 'Phenotype', 'HP:0009726', (183, 197))	('cancers', 'Phenotype', 'HP:0002664', (338, 345))	('lung', 'Disease', (173, 177))	('cancer', 'Disease', (338, 344))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('laryngeal', 'Disease', (162, 171))	('cancer', 'Disease', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
226579	24030569	In this study, we stratified the association of three 8q24 SNPs (rs1447295, rs16901979, rs6983267) and liver, stomach, and esophageal cancers in a Chinese population by family history of cancer.	('rs6983267', 'Mutation', 'rs6983267', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('esophageal cancers', 'Disease', (123, 141))	('rs1447295', 'Mutation', 'rs1447295', (65, 74))	('cancer', 'Disease', (187, 193))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('rs16901979', 'Var', (76, 86))	('stomach', 'Disease', (110, 117))	('esophageal cancers', 'Disease', 'MESH:D004938', (123, 141))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('rs6983267', 'Var', (88, 97))	('rs16901979', 'Mutation', 'rs16901979', (76, 86))	('rs1447295', 'Var', (65, 74))	('liver', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('association', 'Interaction', (33, 44))
226580	24030569	To our knowledge, this is the first study of 8q24 SNPs, family history of cancer, and these three upper GI cancers in a Chinese population.	('8q24 SNPs', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('upper GI cancers', 'Disease', (98, 114))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('upper GI cancers', 'Disease', 'MESH:D009369', (98, 114))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
226589	24030569	Taixing study biospecimens were previously genotyped for three 8q24 SNPs (rs1447295, rs16901979, rs6983267) and main associations reported.	('rs1447295', 'Var', (74, 83))	('rs16901979', 'Mutation', 'rs16901979', (85, 95))	('rs6983267', 'Var', (97, 106))	('rs1447295', 'Mutation', 'rs1447295', (74, 83))	('rs6983267', 'Mutation', 'rs6983267', (97, 106))	('rs16901979', 'Var', (85, 95))
226590	24030569	Genotypic data for all three 8q24 SNPs are included in this study given the location of the SNPs in unique regions of 8q24, published associations in GWAS and case-control studies of colorectal and prostate cancers, and linkage disequilibrium below the threshold of r2=0.80.	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('prostate cancers', 'Phenotype', 'HP:0012125', (198, 214))	('SNPs', 'Var', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('prostate cancer', 'Phenotype', 'HP:0012125', (198, 213))	('colorectal and prostate cancers', 'Disease', 'MESH:D015179', (183, 214))	('associations', 'Interaction', (134, 146))
226593	24030569	We used the TT genotype as the referent for rs6983267 and the CC genotype as the referent for rs1447295 and rs16901979, so that odds ratios were modeled for the genotype homozygous for the cancer risk alleles.	('rs6983267', 'Mutation', 'rs6983267', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('rs16901979', 'Var', (108, 118))	('rs1447295', 'Mutation', 'rs1447295', (94, 103))	('rs16901979', 'Mutation', 'rs16901979', (108, 118))	('rs1447295', 'Var', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('rs6983267', 'Var', (44, 53))	('cancer', 'Disease', (189, 195))
226609	24030569	The 8q24 SNPs included in this study (rs6983267, rs1447295, rs16901979) are not in linkage disequilibrium (r2<0.20) with one another.	('rs16901979', 'Mutation', 'rs16901979', (60, 70))	('rs6983267', 'Mutation', 'rs6983267', (38, 47))	('rs1447295', 'Mutation', 'rs1447295', (49, 58))	('rs1447295', 'Var', (49, 58))	('rs6983267', 'Var', (38, 47))	('rs16901979', 'Var', (60, 70))
226611	24030569	In our previously published study, we did not observe a relationship between the A risk allele of rs1447295 and esophageal, stomach, or liver cancers.	('liver cancer', 'Phenotype', 'HP:0002896', (136, 148))	('stomach', 'Disease', (124, 131))	('liver cancers', 'Phenotype', 'HP:0002896', (136, 149))	('liver cancers', 'Disease', (136, 149))	('liver cancers', 'Disease', 'MESH:D006528', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rs1447295', 'Mutation', 'rs1447295', (98, 107))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('esophageal', 'Disease', (112, 122))	('rs1447295', 'Var', (98, 107))
226612	24030569	In this study, after stratification on family history of cancer (Table 4), we observed a positive association between rs1447295 and liver cancer among those with a family history of cancer (ORadj 2.80; 95% CI 1.15-6.80), in the dominant model, consistent with a departure from multiplicativity (RORadj 2.54; 95% CI 0.94-6.87).	('ROR', 'Gene', '100885779', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('liver cancer', 'Phenotype', 'HP:0002896', (132, 144))	('liver cancer', 'Disease', 'MESH:D006528', (132, 144))	('rs1447295', 'Mutation', 'rs1447295', (118, 127))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('liver cancer', 'Disease', (132, 144))	('ROR', 'Gene', (295, 298))	('rs1447295', 'Var', (118, 127))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
226614	24030569	In this study, we observed family history of cancer as a modifier of the association of rs6983267 and liver cancer (Pheterogeneity=0.029).	('rs6983267', 'Mutation', 'rs6983267', (88, 97))	('liver cancer', 'Disease', 'MESH:D006528', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('liver cancer', 'Disease', (102, 114))	('association', 'Interaction', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('rs6983267', 'Var', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('liver cancer', 'Phenotype', 'HP:0002896', (102, 114))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
226615	24030569	Among those with family history of cancer, the GT heterozygous genotype (ORadj 2.67; 95% CI 1.00-6.82) and rs6983267 in the dominant model (ORadj 2.17; 95% CI 0.89-5.28) are positively associated with liver cancer; however, among those without a family history of cancer, the positive association is observed for the GG rare homozygous genotype (ORadj 2.05; 95% CI 0.96-4.38) and rs6983267 in the recessive model (ORadj 2.15; 95% CI 1.11-4.16).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('rs6983267', 'Var', (107, 116))	('associated', 'Reg', (185, 195))	('rs6983267', 'Mutation', 'rs6983267', (380, 389))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('liver cancer', 'Phenotype', 'HP:0002896', (201, 213))	('liver cancer', 'Disease', 'MESH:D006528', (201, 213))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('rs6983267', 'Mutation', 'rs6983267', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('rs6983267', 'Var', (380, 389))	('liver cancer', 'Disease', (201, 213))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
226618	24030569	No clear association was observed between 8q24 SNPs and stomach and esophageal cancers in family history-stratified analyses.	('8q24 SNPs', 'Var', (42, 51))	('esophageal cancers', 'Disease', (68, 86))	('stomach', 'Disease', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('esophageal cancers', 'Disease', 'MESH:D004938', (68, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))
226622	24030569	We observed that rs1447295 was positively associated with liver cancer among those who reported having a family history of cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('rs1447295', 'Mutation', 'rs1447295', (17, 26))	('liver cancer', 'Phenotype', 'HP:0002896', (58, 70))	('liver cancer', 'Disease', 'MESH:D006528', (58, 70))	('associated', 'Reg', (42, 52))	('rs1447295', 'Var', (17, 26))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('liver cancer', 'Disease', (58, 70))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
226623	24030569	The relationship between the A risk allele of rs1447295and liver cancer in those with a family history of cancer, but not in those without a family history of cancer, is consistent with previously published studies that reported positive associations for rs1447295 and familial prostate cancer.	('cancer', 'Disease', (287, 293))	('liver cancer', 'Disease', 'MESH:D006528', (59, 71))	('familial prostate cancer', 'Disease', (269, 293))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Disease', (106, 112))	('rs1447295', 'Var', (255, 264))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (159, 165))	('liver cancer', 'Phenotype', 'HP:0002896', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('liver cancer', 'Disease', (59, 71))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('prostate cancer', 'Phenotype', 'HP:0012125', (278, 293))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('rs1447295', 'Mutation', 'rs1447295', (255, 264))	('rs1447295', 'Mutation', 'rs1447295', (46, 55))	('rs1447295and', 'Var', (46, 58))	('familial prostate cancer', 'Disease', 'MESH:C537243', (269, 293))
226625	24030569	There is evidence of linkage disequilibrium (LD) between rs1447295 and DG8S737, a microsatellite that is positively associated with prostate cancers, and also the suggestion that both mark a functional causal variant.	('rs1447295', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('associated', 'Reg', (116, 126))	('prostate cancers', 'Disease', 'MESH:D011471', (132, 148))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('rs1447295', 'Mutation', 'rs1447295', (57, 66))	('DG8S737', 'Var', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('prostate cancers', 'Phenotype', 'HP:0012125', (132, 148))	('prostate cancers', 'Disease', (132, 148))
226626	24030569	DG8S737 was not assayed in this study and we could not assess a potential association with liver cancer or potential LD with rs1447295 within this population.	('rs1447295', 'Mutation', 'rs1447295', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('liver cancer', 'Phenotype', 'HP:0002896', (91, 103))	('rs1447295', 'Var', (125, 134))	('liver cancer', 'Disease', 'MESH:D006528', (91, 103))	('liver cancer', 'Disease', (91, 103))
226627	24030569	In addition to our findings with rs1447295, we also observed heterogeneity in the family history-stratified association of rs6983267 and liver cancer that might potentially indicate inherited susceptibility to the risk associated with the recessive G allele in familial cancer clusters.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('liver cancer', 'Disease', (137, 149))	('rs6983267', 'Mutation', 'rs6983267', (123, 132))	('liver cancer', 'Phenotype', 'HP:0002896', (137, 149))	('familial cancer', 'Disease', (261, 276))	('rs1447295', 'Mutation', 'rs1447295', (33, 42))	('association', 'Interaction', (108, 119))	('familial cancer', 'Disease', 'MESH:D009369', (261, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('rs6983267', 'Var', (123, 132))	('liver cancer', 'Disease', 'MESH:D006528', (137, 149))
226628	24030569	Our findings in this candidate gene study of rs6983267 and liver cancer are similar to another recent candidate gene study, where the G allele was associated with thyroid cancer in a recessive inheritance model.	('rs6983267', 'Var', (45, 54))	('liver cancer', 'Phenotype', 'HP:0002896', (59, 71))	('associated', 'Reg', (147, 157))	('thyroid cancer', 'Disease', (163, 177))	('thyroid cancer', 'Phenotype', 'HP:0002890', (163, 177))	('liver cancer', 'Disease', 'MESH:D006528', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('liver cancer', 'Disease', (59, 71))	('rs6983267', 'Mutation', 'rs6983267', (45, 54))	('thyroid cancer', 'Disease', 'MESH:D013964', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
226630	24030569	We did not detect an additive relationship for rs6983267 and liver cancer, among those with a family history of cancer, which might be due to sample size or to a non-additive mechanism.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('rs6983267', 'Mutation', 'rs6983267', (47, 56))	('liver cancer', 'Disease', 'MESH:D006528', (61, 73))	('cancer', 'Disease', (67, 73))	('liver cancer', 'Disease', (61, 73))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs6983267', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('liver cancer', 'Phenotype', 'HP:0002896', (61, 73))
226632	24030569	Functional studies have demonstrated that the G risk allele of rs6983267 enhances transcription of the Myc oncogene, which in turn affects Wnt pathway signaling.	('transcription', 'MPA', (82, 95))	('Wnt pathway signaling', 'Pathway', (139, 160))	('Myc', 'Gene', '4609', (103, 106))	('rs6983267', 'Var', (63, 72))	('rs6983267', 'Mutation', 'rs6983267', (63, 72))	('Myc', 'Gene', (103, 106))	('affects', 'Reg', (131, 138))	('enhances', 'PosReg', (73, 81))
226633	24030569	Beebe-Dimmer and colleagues have published their observations of preferential germline transmission of the G risk allele of rs6983267 in familial prostate cancer cases.	('familial prostate cancer', 'Disease', (137, 161))	('rs6983267', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('familial prostate cancer', 'Disease', 'MESH:C537243', (137, 161))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('rs6983267', 'Mutation', 'rs6983267', (124, 133))
226634	24030569	Tuupanen and colleagues have suggested a role for allelic imbalance at rs6983267 and amplification of the G risk allele by comparing germline rs6983267 genotypes of colorectal cancer patients and their relatives, with somatic rs6983267 genotypes of patients' tumors.	('rs6983267', 'Var', (142, 151))	('imbalance', 'Phenotype', 'HP:0002172', (58, 67))	('rs6983267', 'Mutation', 'rs6983267', (226, 235))	('colorectal cancer', 'Phenotype', 'HP:0003003', (165, 182))	('patients', 'Species', '9606', (249, 257))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('colorectal cancer', 'Disease', (165, 182))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('rs6983267', 'Var', (71, 80))	('Tuupanen', 'Chemical', '-', (0, 8))	('tumors', 'Disease', (259, 265))	('rs6983267', 'Mutation', 'rs6983267', (142, 151))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('colorectal cancer', 'Disease', 'MESH:D015179', (165, 182))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('patients', 'Species', '9606', (183, 191))	('rs6983267', 'Mutation', 'rs6983267', (71, 80))
226646	24030569	In conclusion, this study finds that the association of rs6983267 and rs1447295 with liver cancer varies by family history of cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('rs6983267', 'Var', (56, 65))	('liver cancer', 'Disease', 'MESH:D006528', (85, 97))	('association', 'Interaction', (41, 52))	('liver cancer', 'Disease', (85, 97))	('cancer', 'Disease', (91, 97))	('rs1447295', 'Mutation', 'rs1447295', (70, 79))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('rs6983267', 'Mutation', 'rs6983267', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rs1447295', 'Var', (70, 79))	('liver cancer', 'Phenotype', 'HP:0002896', (85, 97))
226647	24030569	The hypothesis generated in this study, namely that there is an inherited predisposition towards allelic imbalance or loss of heterozygosity at rs6983267, warrants further investigation in larger population-based and family-based studies.	('rs6983267', 'Mutation', 'rs6983267', (144, 153))	('rs6983267', 'Var', (144, 153))	('loss', 'NegReg', (118, 122))	('imbalance', 'Phenotype', 'HP:0002172', (105, 114))	('allelic imbalance', 'MPA', (97, 114))
226648	24030569	Further investigation is also needed into the genetic epidemiology of rs6983267 and rs1447295, in order to understand the potential for linkage with causal markers or possible transmission disequilibrium of risk alleles.	('rs1447295', 'Mutation', 'rs1447295', (84, 93))	('rs6983267', 'Var', (70, 79))	('rs6983267', 'Mutation', 'rs6983267', (70, 79))	('rs1447295', 'Var', (84, 93))
226657	20234107	In women, the risk of digestive cancer mortality was higher among alcohol drinkers than abstainers, but this difference was not statistically significant.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('higher', 'PosReg', (53, 59))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (66, 82))	('cancer', 'Disease', (32, 38))	('alcohol drinkers', 'Var', (66, 82))	('alcohol', 'Chemical', 'MESH:D000438', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('women', 'Species', '9606', (3, 8))
226699	20234107	As compared with no alcohol consumption, high alcohol consumption was associated with a significantly higher risk of mortality from esophageal cancer and colon cancer: the relative risk (95% CI) of mortality was 5.62 (1.45-21.77) for esophageal cancer and 4.59 (1.10-19.20) for colon cancer.	('esophageal cancer', 'Disease', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('alcohol', 'Chemical', 'MESH:D000438', (46, 53))	('colon cancer', 'Disease', (278, 290))	('esophageal cancer', 'Disease', (132, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (234, 251))	('high alcohol consumption', 'Phenotype', 'HP:0030955', (41, 65))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('alcohol', 'Chemical', 'MESH:D000438', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('high alcohol consumption', 'Var', (41, 65))	('colon cancer', 'Disease', 'MESH:D015179', (278, 290))	('colon cancer', 'Disease', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('colon cancer', 'Phenotype', 'HP:0003003', (278, 290))
226702	20234107	An increased risk for all digestive cancers was observed in the high alcohol consumption subgroup, but the association was not statistically significant.	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('high alcohol consumption', 'Phenotype', 'HP:0030955', (64, 88))	('cancers', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('high alcohol consumption', 'Var', (64, 88))	('alcohol', 'Chemical', 'MESH:D000438', (69, 76))
226703	20234107	However, there was a significantly elevated risk for stomach cancer in the high alcohol consumption subgroup.	('high alcohol consumption', 'Phenotype', 'HP:0030955', (75, 99))	('stomach cancer', 'Disease', 'MESH:D013274', (53, 67))	('elevated risk for stomach cancer', 'Phenotype', 'HP:0006753', (35, 67))	('high alcohol consumption', 'Var', (75, 99))	('stomach cancer', 'Phenotype', 'HP:0012126', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('stomach cancer', 'Disease', (53, 67))	('alcohol', 'Chemical', 'MESH:D000438', (80, 87))
226706	20234107	In the high alcohol consumption subgroup, mortality risks for esophageal cancer and colon cancer were greater than those for other digestive cancers: the RR (95% CI) was 6.98 (1.62-30.0) for esophageal cancer and 5.26 (1.10-25.2) for colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', (62, 79))	('high alcohol', 'Var', (7, 19))	('colon cancer', 'Disease', 'MESH:D015179', (234, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('colon cancer', 'Disease', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('alcohol', 'Chemical', 'MESH:D000438', (12, 19))	('cancers', 'Disease', (141, 148))	('colon cancer', 'Disease', (234, 246))	('esophageal cancer', 'Disease', (191, 208))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('high alcohol consumption', 'Phenotype', 'HP:0030955', (7, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (234, 246))	('cancers', 'Disease', 'MESH:D009369', (141, 148))
226712	20234107	Inhalation of acetaldehyde can cause bronchial cancer, as well as esophageal cancer.	('Inhalation', 'Var', (0, 10))	('bronchial cancer', 'Disease', 'MESH:D001982', (37, 53))	('esophageal cancer', 'Disease', (66, 83))	('bronchial cancer', 'Phenotype', 'HP:0030077', (37, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('cause', 'Reg', (31, 36))	('acetaldehyde', 'Chemical', 'MESH:D000079', (14, 26))	('bronchial cancer', 'Disease', (37, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('esophageal cancer.', 'Phenotype', 'HP:0100751', (66, 84))	('Inhalation of acetaldehyde', 'Phenotype', 'HP:0003533', (0, 26))
226715	20234107	However, in a meta-analysis of 16 cohort studies, high alcohol intake was significantly associated with an increased risk of colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (125, 137))	('colon cancer', 'Phenotype', 'HP:0003003', (125, 137))	('colon cancer', 'Disease', (125, 137))	('high alcohol intake', 'Var', (50, 69))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('alcohol', 'Chemical', 'MESH:D000438', (55, 62))
226724	20234107	A recent Japanese study reported that liver cancer risk was actually lower in a high alcohol consumption subgroup.	('liver cancer', 'Phenotype', 'HP:0002896', (38, 50))	('liver cancer', 'Disease', 'MESH:D006528', (38, 50))	('alcohol', 'Chemical', 'MESH:D000438', (85, 92))	('high alcohol consumption', 'Var', (80, 104))	('lower', 'NegReg', (69, 74))	('liver cancer', 'Disease', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('high alcohol consumption', 'Phenotype', 'HP:0030955', (80, 104))
226766	32793451	2B, C) that injury and subsequent leakage of unrecognized thoracic duct tributaries during transthoracic esophagectomy may put the patient at an increased risk of postoperative chyle leakage.	('postoperative', 'MPA', (163, 176))	('leakage', 'Var', (34, 41))	('patient', 'Species', '9606', (131, 138))	('injury', 'Var', (12, 18))
226833	32793451	Low-dose ionizing radiation exhibits anti-inflammatory and apoptotic effects that cause fibrosis or scarring of tissue after trauma, and low-dose radiation can therefore obliterate the chyle leakage point.	('fibrosis', 'Disease', (88, 96))	('obliterate', 'NegReg', (170, 180))	('cause', 'Reg', (82, 87))	('trauma', 'Disease', (125, 131))	('apoptotic', 'CPA', (59, 68))	('scarring', 'Phenotype', 'HP:0100699', (100, 108))	('scarring of tissue', 'CPA', (100, 118))	('low-dose radiation', 'Var', (137, 155))	('chyle leakage point', 'CPA', (185, 204))	('trauma', 'Disease', 'MESH:D014947', (125, 131))	('fibrosis', 'Disease', 'MESH:D005355', (88, 96))
226857	31108196	It is known that risk of LNM is increased in T1b EAC with rates of up to 27% reported; however, even patients with T1a disease may have a 7% risk.	('LNM', 'Disease', (25, 28))	('patients', 'Species', '9606', (101, 109))	('T1b', 'Var', (45, 48))
226915	28713964	In addition, we found that silencing of Msi1 decreased cell proliferation, migration and induced apoptosis in TE-7 and KYSE70 cells.	('Msi1', 'Gene', (40, 44))	('silencing', 'Var', (27, 36))	('induced', 'Reg', (89, 96))	('KYSE70', 'CellLine', 'CVCL:1356', (119, 125))	('decreased', 'NegReg', (45, 54))	('cell proliferation', 'CPA', (55, 73))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('migration', 'CPA', (75, 84))	('apoptosis', 'CPA', (97, 106))	('si', 'Chemical', 'MESH:D012825', (27, 29))
226973	28713964	With paired or unpaired t-tests, we analyzed the expression of Msi1 in cell lines and clinical samples, as well as the difference of proliferation and apoptosis between si-Msi1 cells and the negative control group.	('si', 'Chemical', 'MESH:D012825', (169, 171))	('si', 'Chemical', 'MESH:D012825', (173, 175))	('si-Msi1', 'Var', (169, 176))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('si', 'Chemical', 'MESH:D012825', (157, 159))	('Msi1', 'Gene', (63, 67))	('apoptosis', 'CPA', (151, 160))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('clinical samples', 'Species', '191496', (86, 102))
226986	28713964	2D, P=0.03) and that SOX2 had a significantly different expression in the Msi1 high-expression group compared with the low-expression group (Fig.	('si', 'Chemical', 'MESH:D012825', (90, 92))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('Msi1', 'Gene', (74, 78))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('expression', 'MPA', (56, 66))	('different', 'Reg', (46, 55))	('high-expression', 'Var', (79, 94))	('SOX2', 'Gene', (21, 25))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('SOX2', 'Gene', '6657', (21, 25))
226989	28713964	According to previous studies and the aforementioned results, we hypothesized that Msi1 plays a critical role in ESCC stemness and its characteristics could have an effect on the proliferation and apoptosis of cancer cells.	('proliferation', 'CPA', (179, 192))	('apoptosis', 'CPA', (197, 206))	('effect', 'Reg', (165, 171))	('ESCC stemness', 'Disease', (113, 126))	('ESCC stemness', 'Disease', 'MESH:D004938', (113, 126))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('have', 'Reg', (157, 161))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('Msi1', 'Gene', (83, 87))	('si', 'Chemical', 'MESH:D012825', (203, 205))	('cancer', 'Disease', (210, 216))	('characteristics', 'Var', (135, 150))
226990	28713964	The role of Msi1 in the proliferation and apoptosis of TE-7 and KYSE70 cells was examined following the transfection of an Msi1 siRNA.	('KYSE70', 'CellLine', 'CVCL:1356', (64, 70))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('Msi1', 'Gene', (123, 127))	('transfection', 'Var', (104, 116))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('si', 'Chemical', 'MESH:D012825', (124, 126))
226993	28713964	Notably, we observed that knockdown of Msi1 increased the apoptosis rates in TE-7 and KYSE70 cells (Fig.	('apoptosis rates', 'CPA', (58, 73))	('KYSE70', 'CellLine', 'CVCL:1356', (86, 92))	('Msi1', 'Gene', (39, 43))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('knockdown', 'Var', (26, 35))	('increased', 'PosReg', (44, 53))
226994	28713964	In addition, the proliferation of TE-7 and KYSE70 cells transfected with Msi1-siRNA was observably lower than that of the control group (Fig.	('proliferation', 'CPA', (17, 30))	('KYSE70', 'CellLine', 'CVCL:1356', (43, 49))	('Msi1-siRNA', 'Var', (73, 83))	('lower', 'NegReg', (99, 104))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('si', 'Chemical', 'MESH:D012825', (78, 80))
226995	28713964	Using PCR and western blotting, we further determined that SOX2 expression was also decreased with Msi1 interference (Fig.	('SOX2', 'Gene', (59, 63))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('expression', 'MPA', (64, 74))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('Msi1 interference', 'Var', (99, 116))	('decreased', 'NegReg', (84, 93))	('SOX2', 'Gene', '6657', (59, 63))	('si', 'Chemical', 'MESH:D012825', (100, 102))
226996	28713964	Generally, Msi1 expression could promote the proliferation and decrease the apoptosis of esophageal cancer cell lines.	('Msi1', 'Gene', (11, 15))	('esophageal cancer', 'Disease', (89, 106))	('promote', 'PosReg', (33, 40))	('expression', 'Var', (16, 26))	('proliferation', 'CPA', (45, 58))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('decrease', 'NegReg', (63, 71))	('apoptosis', 'CPA', (76, 85))
226997	28713964	Using the same approach, we detected the influence of knocked down Msi1 expression on the capacity of sphere formation and migration in ESCC cells.	('knocked down', 'Var', (54, 66))	('Msi1', 'Gene', (67, 71))	('sphere formation', 'CPA', (102, 118))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('migration', 'CPA', (123, 132))
226998	28713964	We determined that in the si-Msi1 group the number of spheres formation was markedly decreased (Fig.	('si', 'Chemical', 'MESH:D012825', (30, 32))	('si-Msi1', 'Var', (26, 33))	('decreased', 'NegReg', (85, 94))	('si', 'Chemical', 'MESH:D012825', (26, 28))
227038	28713964	There was a marked increase in apoptosis in the si-Msi1 group and a decrease in proliferation.	('si', 'Chemical', 'MESH:D012825', (37, 39))	('decrease', 'NegReg', (68, 76))	('proliferation', 'CPA', (80, 93))	('increase', 'PosReg', (19, 27))	('si-Msi1', 'Var', (48, 55))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('apoptosis', 'CPA', (31, 40))	('si', 'Chemical', 'MESH:D012825', (48, 50))
227039	28713964	In addition, si-Msi1 had an effect on sphere formation and migration capacity.	('si-Msi1', 'Var', (13, 20))	('migration capacity', 'CPA', (59, 77))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('sphere formation', 'CPA', (38, 54))	('si', 'Chemical', 'MESH:D012825', (13, 15))
227054	28331341	Increased apoptosis and decreased cell proliferation and migration were observed in the anti-PADI2 siRNA-treated MNK-45 cells, and increased cell proliferation and migration and decreased apoptosis were observed in the treated Bel-7402 cells with suppressed PADI2 expression.	('PADI2', 'Gene', (258, 263))	('decreased', 'NegReg', (24, 33))	('increased', 'PosReg', (131, 140))	('cell proliferation', 'CPA', (34, 52))	('rat', 'Species', '10116', (46, 49))	('rat', 'Species', '10116', (153, 156))	('rat', 'Species', '10116', (60, 63))	('MNK', 'Gene', '538', (113, 116))	('cell proliferation', 'CPA', (141, 159))	('Bel-7402', 'CellLine', 'CVCL:5492', (227, 235))	('rat', 'Species', '10116', (167, 170))	('anti-PADI2', 'Var', (88, 98))	('MNK', 'Gene', (113, 116))
227055	28331341	PCR arrays and real-time PCR detected significantly decreased CXCR2 and EPO expression in the MNK-45 cells and Bel-7402 cells, respectively, with the anti-PADI2 siRNA treatments.	('anti-PADI2', 'Var', (150, 160))	('CXCR2', 'Gene', '3579', (62, 67))	('EPO', 'Gene', (72, 75))	('decreased', 'NegReg', (52, 61))	('MNK', 'Gene', (94, 97))	('Bel-7402', 'CellLine', 'CVCL:5492', (111, 119))	('CXCR2', 'Gene', (62, 67))	('EPO', 'Gene', '2056', (72, 75))	('MNK', 'Gene', '538', (94, 97))
227066	28331341	We recently reported that PADI2 is a gene susceptible to breast cancer risk, and its expression contributes to tumorigenesis via ACSL4, BINC3 and CA9 signaling.	('breast cancer', 'Disease', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('BINC3', 'MPA', (136, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('ACSL4', 'Gene', '2182', (129, 134))	('ACSL4', 'Gene', (129, 134))	('contributes', 'Reg', (96, 107))	('CA9', 'Gene', (146, 149))	('tumor', 'Disease', (111, 116))	('expression', 'Var', (85, 95))	('CA9', 'Gene', '768', (146, 149))	('PADI2', 'Gene', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
227097	28331341	MNK-45 and Bel-7402 tumor cells were transfected with the anti-PADI2 siRNAs at 20 nM using the HiPerFect transfection reagent (Qiagen).	('MNK', 'Gene', (0, 3))	('Bel-7402', 'CellLine', 'CVCL:5492', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('anti-PADI2', 'Var', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('MNK', 'Gene', '538', (0, 3))	('tumor', 'Disease', (20, 25))
227135	28331341	Compared with the Allstar siRNA-treated cells, the annexin V/PE and 7-AAD double staining detected significantly increased apoptosis in the anti-PADI2 siRNA-treated MNK-45 cells (P=4.98x10-5), but the analysis measured a considerably decreased apoptosis in the siRNA-treated Bel-7402 cells (P=3x10-4).	('decreased', 'NegReg', (234, 243))	('anti-PADI2', 'Var', (140, 150))	('MNK', 'Gene', (165, 168))	('annexin V', 'Gene', '308', (51, 60))	('7-AAD', 'Chemical', 'MESH:C025942', (68, 73))	('Bel-7402', 'CellLine', 'CVCL:5492', (275, 283))	('annexin V', 'Gene', (51, 60))	('apoptosis', 'CPA', (123, 132))	('PE', 'Chemical', '-', (61, 63))	('MNK', 'Gene', '538', (165, 168))
227137	28331341	The analysis detected a significantly decreased migration of MNK-45 cells when the PADI2 expression was suppressed by anti-PADI2 siRNA compared with the cells treated with Allstar siRNA (P=6.03x10-5); meanwhile, the assay observed a significantly increased cell migration in the siRNA-treated Bel-7402 cells (P=3.6x10-4).	('migration', 'CPA', (48, 57))	('decreased', 'NegReg', (38, 47))	('expression', 'MPA', (89, 99))	('PADI2', 'Gene', (83, 88))	('rat', 'Species', '10116', (51, 54))	('cell migration', 'CPA', (257, 271))	('MNK', 'Gene', '538', (61, 64))	('Bel-7402', 'CellLine', 'CVCL:5492', (293, 301))	('suppressed', 'NegReg', (104, 114))	('anti-PADI2', 'Var', (118, 128))	('increased', 'PosReg', (247, 256))	('rat', 'Species', '10116', (265, 268))	('MNK', 'Gene', (61, 64))
227152	28331341	Our study indicated that the single nucleotide polymorphisms rs2746533, rs2076616 and rs10788656 show significant differences in allele frequency, genotype frequency or both between breast cancer, cervical carcinoma, gastric carcinoma, lung cancer and rectal carcinoma cases and the controls, indicating that PADI2 has genetic susceptibility to these tumor risks.	('cervical carcinoma', 'Disease', (197, 215))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (252, 268))	('cervical carcinoma', 'Disease', 'MESH:D002575', (197, 215))	('lung cancer', 'Disease', (236, 247))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('tumor', 'Disease', (351, 356))	('breast cancer', 'Disease', (182, 195))	('rs2746533', 'Mutation', 'rs2746533', (61, 70))	('rs2076616', 'Mutation', 'rs2076616', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('rectal carcinoma', 'Disease', (252, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('rs10788656', 'Mutation', 'rs10788656', (86, 96))	('lung cancer', 'Disease', 'MESH:D008175', (236, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('rectal carcinoma', 'Disease', 'MESH:D012004', (252, 268))	('rs2746533', 'Var', (61, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('gastric carcinoma', 'Disease', 'MESH:D013274', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('rs2076616', 'Var', (72, 81))	('gastric carcinoma', 'Disease', (217, 234))	('rs10788656', 'Var', (86, 96))	('differences', 'Reg', (114, 125))
227164	28331341	These reports are similar to our observation of decreased cell proliferation and cell migration in anti-PADI2-treated MNK-45 cells while CXCR2 expression was depressed.	('MNK', 'Gene', '538', (118, 121))	('rat', 'Species', '10116', (70, 73))	('CXCR2', 'Gene', '3579', (137, 142))	('cell proliferation', 'CPA', (58, 76))	('CXCR2', 'Gene', (137, 142))	('decreased', 'NegReg', (48, 57))	('MNK', 'Gene', (118, 121))	('rat', 'Species', '10116', (89, 92))	('cell migration', 'CPA', (81, 95))	('anti-PADI2-treated', 'Var', (99, 117))
227175	28331341	These reports correspond to our observation in which increased cell proliferation and cell migration were detected in anti-PADI2 siRNA-treated Bel-7402 cells with inhibited EPO expression.	('Bel-7402', 'CellLine', 'CVCL:5492', (143, 151))	('rat', 'Species', '10116', (94, 97))	('EPO', 'Gene', (173, 176))	('rat', 'Species', '10116', (75, 78))	('anti-PADI2', 'Var', (118, 128))	('cell migration', 'CPA', (86, 100))	('cell proliferation', 'CPA', (63, 81))	('increased', 'PosReg', (53, 62))	('EPO', 'Gene', '2056', (173, 176))	('inhibited', 'NegReg', (163, 172))
227178	28331341	The present study shows decreased cell proliferation and cell migration and increased apoptosis in anti-PADI2 siRNA MNK-45 cells with decreased CXCR2 expression.	('decreased', 'NegReg', (24, 33))	('CXCR2', 'Gene', '3579', (144, 149))	('rat', 'Species', '10116', (46, 49))	('cell proliferation', 'CPA', (34, 52))	('anti-PADI2', 'Var', (99, 109))	('CXCR2', 'Gene', (144, 149))	('apoptosis', 'CPA', (86, 95))	('MNK', 'Gene', '538', (116, 119))	('cell migration', 'CPA', (57, 71))	('MNK', 'Gene', (116, 119))	('rat', 'Species', '10116', (65, 68))
227180	28331341	We previously found that inhibiting PADI2 expression significantly increased the expression of CA9 and decreased the expression of ACSL4 and BIRC3 in MCF-7 cells, originating from breast cancer.	('BIRC3', 'Gene', (141, 146))	('ACSL4', 'Gene', '2182', (131, 136))	('inhibiting', 'Var', (25, 35))	('ACSL4', 'Gene', (131, 136))	('BIRC3', 'Gene', '330', (141, 146))	('expression', 'MPA', (117, 127))	('decreased', 'NegReg', (103, 112))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('increased', 'PosReg', (67, 76))	('MCF-7', 'CellLine', 'CVCL:0031', (150, 155))	('CA9', 'Gene', (95, 98))	('breast cancer', 'Disease', (180, 193))	('PADI2', 'Gene', (36, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('CA9', 'Gene', '768', (95, 98))	('expression', 'MPA', (81, 91))
227181	28331341	Inhibiting PADI2 expression also significantly decreased the cell migration ability of MCF-7 cells but did not affect cell proliferation and apoptosis.	('PADI2', 'Gene', (11, 16))	('Inhibiting', 'Var', (0, 10))	('cell migration ability', 'CPA', (61, 83))	('MCF-7', 'CellLine', 'CVCL:0031', (87, 92))	('rat', 'Species', '10116', (130, 133))	('rat', 'Species', '10116', (69, 72))	('decreased', 'NegReg', (47, 56))
227210	27756877	To this end, we evaluated MTE function in Jurkat cells (T-ALL lines) and lymphocytes from T-ALL patients.We found that MTE strongly inhibited the proliferation and promoted apoptosis in Jurkat cells and lymphocytes from T-ALL patients.	('inhibited', 'NegReg', (132, 141))	('apoptosis', 'CPA', (173, 182))	('ALL', 'Phenotype', 'HP:0006721', (222, 225))	('proliferation', 'CPA', (146, 159))	('Jurkat', 'CellLine', 'CVCL:0065', (186, 192))	('ALL', 'Phenotype', 'HP:0006721', (92, 95))	('T-ALL', 'Phenotype', 'HP:0006727', (220, 225))	('T-ALL', 'Phenotype', 'HP:0006727', (56, 61))	('promoted', 'PosReg', (164, 172))	('MTE', 'Chemical', '-', (26, 29))	('MTE', 'Chemical', '-', (119, 122))	('ALL', 'Phenotype', 'HP:0006721', (58, 61))	('patients', 'Species', '9606', (226, 234))	('patients', 'Species', '9606', (96, 104))	('T-ALL', 'Phenotype', 'HP:0006727', (90, 95))	('MTE', 'Var', (119, 122))	('Jurkat', 'CellLine', 'CVCL:0065', (42, 48))
227221	27756877	To further determine whether decreased viability of leukemia cells treated by MTE was due to the decrease of cell proliferation, we next examined the effects of MTE on cell cycle distribution in Jurkat cells.	('cell proliferation', 'CPA', (109, 127))	('leukemia', 'Disease', (52, 60))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('leukemia', 'Disease', 'MESH:D007938', (52, 60))	('Jurkat', 'CellLine', 'CVCL:0065', (195, 201))	('decreased', 'NegReg', (29, 38))	('MTE', 'Chemical', '-', (78, 81))	('decrease', 'NegReg', (97, 105))	('MTE', 'Chemical', '-', (161, 164))	('MTE', 'Var', (78, 81))
227244	27756877	As shown in Figure 8A and 8B, similar to the T-ALL cell lines, MTE also significantly reduced the cell viability of T-ALL patient's lymphocytes, compared with the healthy people's lymphocytes.	('reduced', 'NegReg', (86, 93))	('MTE', 'Var', (63, 66))	('T-ALL', 'Phenotype', 'HP:0006727', (116, 121))	('ALL', 'Phenotype', 'HP:0006721', (47, 50))	('patient', 'Species', '9606', (122, 129))	('T-ALL', 'Phenotype', 'HP:0006727', (45, 50))	('people', 'Species', '9606', (171, 177))	('cell viability', 'CPA', (98, 112))	('MTE', 'Chemical', '-', (63, 66))	('ALL', 'Phenotype', 'HP:0006721', (118, 121))
227245	27756877	Moreover, MTE also significantly promoted the apoptosis of T-ALL patient's lymphocytes (Figure 8F, 8G, 8H), compared with the healthy ones (Figure 8C, 8D, 8E).	('apoptosis', 'CPA', (46, 55))	('promoted', 'PosReg', (33, 41))	('MTE', 'Var', (10, 13))	('ALL', 'Phenotype', 'HP:0006721', (61, 64))	('T-ALL', 'Phenotype', 'HP:0006727', (59, 64))	('patient', 'Species', '9606', (65, 72))	('MTE', 'Chemical', '-', (10, 13))
227254	27756877	Previous studies have shown that under 24 h treatment with the same MTE as we used, MTE inhibited the proliferation of non-small cell lung cancer cell line, human esophageal carcinoma cell lines KYSE150.	('inhibited', 'NegReg', (88, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))	('esophageal carcinoma', 'Disease', (163, 183))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (119, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('MTE', 'Chemical', '-', (84, 87))	('MTE', 'Chemical', '-', (68, 71))	('non-small cell lung cancer', 'Disease', (119, 145))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (163, 183))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (163, 183))	('MTE', 'Var', (84, 87))	('proliferation', 'CPA', (102, 115))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('human', 'Species', '9606', (157, 162))
227258	27756877	Consistent with these studies, we also found that MTE significantly induced the apoptosis of Jurkat cells based on Annexin V-FITC/PI-stained flow cytometry and TUNEL staining assays (Figure 3).	('MTE', 'Chemical', '-', (50, 53))	('Jurkat', 'CellLine', 'CVCL:0065', (93, 99))	('Annexin V', 'Gene', '308', (115, 124))	('Annexin V', 'Gene', (115, 124))	('MTE', 'Var', (50, 53))	('apoptosis', 'CPA', (80, 89))
227263	27756877	Recent studies have shown that the dysfunctions of PTEN/PIK3/AKT/mTOR pathways are involved in tumorigenesis.	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('PIK3', 'Gene', '5294', (56, 60))	('involved', 'Reg', (83, 91))	('dysfunctions', 'Var', (35, 47))	('PIK3', 'Gene', (56, 60))	('AKT', 'Gene', '207', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('AKT', 'Gene', (61, 64))	('PTEN', 'Gene', (51, 55))	('tumor', 'Disease', (95, 100))	('PTEN', 'Gene', '5728', (51, 55))
227264	27756877	In this signaling cascade, PTEN is an essential tumor suppressor gene, and plays a central negative regulator through removing the D3 phosphate on the inositol ring of PIP3, counteracting PI3K and down-regulating the PI3K/AKT/mTOR signaling pathway which affects cell growth, proliferation and survival.	('PI3K', 'Var', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('removing', 'NegReg', (118, 126))	('tumor', 'Disease', (48, 53))	('PTEN', 'Gene', (27, 31))	('down-regulating', 'NegReg', (197, 212))	('AKT', 'Gene', '207', (222, 225))	('phosphate', 'Chemical', 'MESH:D010710', (134, 143))	('AKT', 'Gene', (222, 225))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mTOR', 'Gene', (226, 230))	('D3 phosphate', 'MPA', (131, 143))	('mTOR', 'Gene', '2475', (226, 230))	('PTEN', 'Gene', '5728', (27, 31))	('inositol', 'Chemical', 'MESH:D007294', (151, 159))
227265	27756877	Impairment of this tumor suppressor pathway potentially became a causal factor for development of malignancies.	('malignancies', 'Disease', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('Impairment', 'Var', (0, 10))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))
227266	27756877	Interestingly, mutant Notch1 can activate c-Myc and PI3K/AKT/mTOR signaling in T-ALL.	('activate', 'PosReg', (33, 41))	('ALL', 'Phenotype', 'HP:0006721', (81, 84))	('c-Myc', 'Gene', (42, 47))	('T-ALL', 'Phenotype', 'HP:0006727', (79, 84))	('AKT', 'Gene', '207', (57, 60))	('Notch1', 'Gene', (22, 28))	('c-Myc', 'Gene', '4609', (42, 47))	('mTOR', 'Gene', (61, 65))	('mutant', 'Var', (15, 21))	('mTOR', 'Gene', '2475', (61, 65))	('Notch1', 'Gene', '4851', (22, 28))	('AKT', 'Gene', (57, 60))
227268	27756877	Loss of function of PTEN mutations leading to constitutive activation of Akt were identified in T-ALL cell lines.	('mutations', 'Var', (25, 34))	('Akt', 'Gene', (73, 76))	('ALL', 'Phenotype', 'HP:0006721', (98, 101))	('activation', 'PosReg', (59, 69))	('Loss of function', 'NegReg', (0, 16))	('T-ALL', 'Phenotype', 'HP:0006727', (96, 101))	('Akt', 'Gene', '207', (73, 76))	('PTEN', 'Gene', (20, 24))	('PTEN', 'Gene', '5728', (20, 24))
227269	27756877	Interestingly, several studies have now described PTEN loss through mutation and/or genomic deletion in up to 35% of pediatric patients with T-ALL.	('genomic deletion', 'Var', (84, 100))	('loss', 'NegReg', (55, 59))	('mutation', 'Var', (68, 76))	('T-ALL', 'Disease', (141, 146))	('ALL', 'Phenotype', 'HP:0006721', (143, 146))	('PTEN', 'Gene', (50, 54))	('PTEN', 'Gene', '5728', (50, 54))	('patients', 'Species', '9606', (127, 135))	('T-ALL', 'Phenotype', 'HP:0006727', (141, 146))
227306	27756877	The primary antibodies were rabbit polyclonal antibodies against PTEN (1:500, CST), or with a monoclonal antibodies against FAS (1:200, Abcam).	('CST', 'Gene', (78, 81))	('PTEN', 'Gene', (65, 69))	('PTEN', 'Gene', '5728', (65, 69))	('CST', 'Gene', '106478911', (78, 81))	('rabbit', 'Species', '9986', (28, 34))	('1:500', 'Var', (71, 76))
227353	26943276	Further multivariate analysis of prognostic factors based on different stages showed that radiotherapy can reduce 72,1% risks of death in localized stage (HR 0.279, 95% CI0.117-0.668), 52.7% risks of death in regional stage (HR 0.473, 95% CI 0.180-1.241) and more than 30% risks of death in distant stage (HR 0.683, 95% CI 0.450-1.037).	('radiotherapy', 'Var', (90, 102))	('death', 'Disease', 'MESH:D003643', (129, 134))	('death', 'Disease', (129, 134))	('death', 'Disease', 'MESH:D003643', (282, 287))	('reduce', 'NegReg', (107, 113))	('death', 'Disease', (282, 287))	('death', 'Disease', 'MESH:D003643', (200, 205))	('localized', 'Disease', (138, 147))	('death', 'Disease', (200, 205))	('regional', 'Disease', (209, 217))
227364	21829465	Whole Genome Expression Array Profiling Highlights Differences in Mucosal Defense Genes in Barrett's Esophagus and Esophageal Adenocarcinoma Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates.	('Differences', 'Var', (51, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Esophageal Adenocarcinoma', 'Disease', (115, 140))	('Mucosal Defense Genes', 'Gene', (66, 87))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (115, 140))	('EAC', 'Phenotype', 'HP:0011459', (168, 171))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (115, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('EAC', 'Gene', '1540', (168, 171))	('Esophageal adenocarcinoma ', 'Gene', '1540', (141, 167))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (91, 110))	('EAC', 'Gene', (168, 171))	('Esophageal adenocarcinoma ', 'Gene', (141, 167))
227428	21829465	In the case of our SDH-54 dataset, we know that both of the EAC tumor samples that were 'misclassified' (Figure 2a) contained substantial copy number changes (data not shown) and around 60% tumor content, clearly distinguishing their DNA from that of either BE or normal squamous sample.	('copy number changes', 'Var', (138, 157))	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('contained', 'Reg', (116, 125))	('EAC', 'Gene', '1540', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('EAC', 'Gene', (60, 63))	('tumor', 'Disease', (190, 195))	('BE', 'Chemical', '-', (258, 260))	('SDH', 'Chemical', '-', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('BE', 'Phenotype', 'HP:0100580', (258, 260))
227467	21829465	Several studies indicate that the TP53 gene is frequently affected by mutation and copy number variation within EAC, and that these changes are likely to increase protein stability, rather than mRNA levels, resulting in abnormal entry into the cell cycle without stopping for DNA repair (reviewed by Fitzgerald 2006 and Reid 2010).	('TP53', 'Gene', (34, 38))	('variation', 'Var', (95, 104))	('abnormal entry into the cell cycle', 'Phenotype', 'HP:0011018', (220, 254))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('EAC', 'Gene', '1540', (112, 115))	('cell cycle', 'CPA', (244, 254))	('copy number variation', 'Var', (83, 104))	('mutation', 'Var', (70, 78))	('EAC', 'Gene', (112, 115))	('affected', 'Reg', (58, 66))	('protein stability', 'MPA', (163, 180))	('increase', 'PosReg', (154, 162))	('entry', 'PosReg', (229, 234))	('TP53', 'Gene', '7157', (34, 38))	('changes', 'Var', (132, 139))
227606	33892181	Emerging evidence had shown that nano-system combined with hypocrellins B could significantly improve their solubility, bioavailability, and enhance their photodynamic efficacy.	('bioavailability', 'MPA', (120, 135))	('enhance', 'PosReg', (141, 148))	('improve', 'PosReg', (94, 101))	('solubility', 'MPA', (108, 118))	('nano-system', 'Var', (33, 44))	('photodynamic', 'MPA', (155, 167))	('hypocrellins B', 'Chemical', 'MESH:C064522', (59, 73))
227723	30012433	Patients with short-segment BE (>=1 cm, <3 cm) have significantly lower annual rates of progression to cancer (0.07%) as compared with long-segment BE (0.25%).	('BE', 'Phenotype', 'HP:0100580', (28, 30))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BE', 'Phenotype', 'HP:0100580', (148, 150))	('lower', 'NegReg', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('BE', 'Disease', 'MESH:D001471', (28, 30))	('Patients', 'Species', '9606', (0, 8))	('men', 'Species', '9606', (23, 26))	('BE', 'Disease', 'MESH:D001471', (148, 150))	('cancer', 'Disease', (103, 109))	('men', 'Species', '9606', (143, 146))	('>=1', 'Var', (32, 35))
227891	30686900	The Baveno VI guidelines suggested a simple algorithm based on LSM < 20 kPa (by transient elastography, TE) and platelet count > 150 G/L for ruling-out VNT in patients with cACLD.	('ACLD', 'Phenotype', 'HP:0100626', (174, 178))	('LSM', 'MPA', (63, 66))	('TE', 'Chemical', '-', (104, 106))	('150 G/L', 'SUBSTITUTION', 'None', (129, 136))	('150 G/L', 'Var', (129, 136))	('cACLD', 'Disease', (173, 178))	('patients', 'Species', '9606', (159, 167))
227893	30686900	Transient elastography (TE) has been widely validated, and the combined TE-based LSM < 20 kPa and platelet count (PLT) > 150 G/L algorithm is able to rule-out varices-needing-treatment (VNTs).	('TE', 'Chemical', '-', (72, 74))	('varices-needing-treatment', 'Disease', (159, 184))	('TE', 'Chemical', '-', (24, 26))	('150 G/L', 'Var', (121, 128))	('150 G/L', 'SUBSTITUTION', 'None', (121, 128))
227895	30686900	In patients with chronic liver diseases, transient elastography (TE) is recommended to screen for cACLD, with values between 10-15 kPa being suggestive and > 15 kPa being highly suggestive for cACLD.	('cACLD', 'Disease', (193, 198))	('liver disease', 'Phenotype', 'HP:0001392', (25, 38))	('TE', 'Chemical', '-', (65, 67))	('liver diseases', 'Disease', (25, 39))	('liver diseases', 'Disease', 'MESH:D008107', (25, 39))	('ACLD', 'Phenotype', 'HP:0100626', (194, 198))	('liver diseases', 'Phenotype', 'HP:0001392', (25, 39))	('patients', 'Species', '9606', (3, 11))	('> 15 kPa', 'Var', (156, 164))	('ACLD', 'Phenotype', 'HP:0100626', (99, 103))	('cACLD', 'Disease', (98, 103))
227898	30686900	Screening for EV is a cornerstone in the management of cirrhotic patients, since the presence of EV indicates a distinct inferior prognosis within cACLD patients.	('EV', 'Phenotype', 'HP:0002040', (97, 99))	('ACLD', 'Phenotype', 'HP:0100626', (148, 152))	('patients', 'Species', '9606', (153, 161))	('EV', 'Phenotype', 'HP:0002040', (14, 16))	('patients', 'Species', '9606', (65, 73))	('inferior', 'NegReg', (121, 129))	('presence', 'Var', (85, 93))
227923	30686900	These guidelines proposed that in cACLD patients with LSM values < 20 kPa and platelet count (PLT) > 150 G/L, screening endoscopy for esophageal varices can be omitted, since these patients have a very low risk for VNT.	('cACLD', 'Disease', (34, 39))	('patients', 'Species', '9606', (40, 48))	('< 20', 'Var', (65, 69))	('150 G/L', 'SUBSTITUTION', 'None', (101, 108))	('150 G/L', 'Var', (101, 108))	('ACLD', 'Phenotype', 'HP:0100626', (35, 39))	('esophageal varices', 'Phenotype', 'HP:0002040', (134, 152))	('patients', 'Species', '9606', (181, 189))
227927	30686900	Since the publication of the Baveno VI guidelines, most studies reported data on the combination algorithm of LSM + PLT (commonly at the cutoff 150G/L) to rule-out VNT.	('LSM', 'Gene', (110, 113))	('150G/L', 'SUBSTITUTION', 'None', (144, 150))	('150G/L', 'Var', (144, 150))
227932	30686900	The surprisingly low number of spared endoscopies could be increased by raising the cut-off for LSM to 25kPa and lowering the PLT threshold to 110 G/L ('expanded Baveno VI criteria').	('LSM', 'MPA', (96, 99))	('110 G/L', 'Var', (143, 150))	('lowering', 'NegReg', (113, 121))	('PLT threshold', 'MPA', (126, 139))	('110 G/L', 'SUBSTITUTION', 'None', (143, 150))
227954	30686900	Indeed, most recently, two meta-analysis on 2D-SWE including 1134 patient and 746 patients have been published that both reported superior accuracy to detect significant fibrosis or cirrhosis using 2D-SWE as compared to TE.	('2D-SWE', 'Var', (198, 204))	('TE', 'Chemical', '-', (220, 222))	('cirrhosis', 'Disease', (182, 191))	('significant', 'Disease', (158, 169))	('patient', 'Species', '9606', (82, 89))	('patients', 'Species', '9606', (82, 90))	('patient', 'Species', '9606', (66, 73))	('cirrhosis', 'Phenotype', 'HP:0001394', (182, 191))	('fibrosis', 'Disease', 'MESH:D005355', (170, 178))	('fibrosis', 'Disease', (170, 178))	('cirrhosis', 'Disease', 'MESH:D005355', (182, 191))
227957	30686900	In a large prospective study investigating 2D-SWE-based liver (L-SWE) and spleen (S-SWE) for the diagnosis of CSPH yielded an AUC of 0.861 for L-SWE (24.6 kPa) and of 0.837 for S-SWE (26.3 kPa), respectively.	('CSPH', 'Chemical', '-', (110, 114))	('CSPH', 'Disease', (110, 114))	('L-SWE', 'Var', (143, 148))
227960	30686900	In a retrospective cohort of 103 cACLD patients 2D-SWE of L-SWE yielded an AUC of 0.887 (cut-off 13.9 kPa) for any EV and 0.880 (cut-off 16.1 kPa) for VNT.	('EV', 'Phenotype', 'HP:0002040', (115, 117))	('patients', 'Species', '9606', (39, 47))	('AUC', 'MPA', (75, 78))	('VNT', 'MPA', (151, 154))	('0.880', 'Var', (122, 127))	('ACLD', 'Phenotype', 'HP:0100626', (34, 38))
227991	30686900	Finally, we have summarized the currently available data and published cut-offs for EV/VNT prediction by TE, pSWE, 2D-SWE and MRE on scale-cards for clinical practice.	('EV/VNT', 'Disease', (84, 90))	('EV', 'Phenotype', 'HP:0002040', (84, 86))	('TE', 'Chemical', '-', (105, 107))	('2D-SWE', 'Var', (115, 121))
227998	30344268	Analyzing the possibility of distinguishing healthy subjects from patients with fibrosis, we have found that the area under the curve is far greater in the HARI index than CysC.	('CysC', 'Gene', (172, 176))	('CysC', 'Gene', '1471', (172, 176))	('greater', 'PosReg', (141, 148))	('fibrosis', 'Disease', 'MESH:D005355', (80, 88))	('fibrosis', 'Disease', (80, 88))	('patients', 'Species', '9606', (66, 74))	('HARI', 'Var', (156, 160))
228081	29055049	We further showed that PAX9 was down-regulated in human oro-esophageal squamous cell carcinoma (OESCC), and its down-regulation was associated with alcohol drinking and promoter hypermethylation.	('PAX9', 'Gene', (23, 27))	('esophageal squamous cell carcinoma', 'Disease', (60, 94))	('promoter hypermethylation', 'Var', (169, 194))	('SCC', 'Gene', '6317', (98, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('human', 'Species', '9606', (50, 55))	('down-regulation', 'NegReg', (112, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (60, 94))	('down-regulated', 'NegReg', (32, 46))	('alcohol', 'Chemical', 'MESH:D000438', (148, 155))	('alcohol drinking', 'Phenotype', 'HP:0030955', (148, 164))	('SCC', 'Gene', (98, 101))
228083	29055049	Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC.	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('Alcohol drinking', 'Phenotype', 'HP:0030955', (0, 16))	('SCC', 'Gene', (93, 96))	('promoter hypermethylation', 'Var', (21, 46))	('SCC', 'Gene', '6317', (93, 96))	('silencing', 'NegReg', (72, 81))	('human', 'Species', '9606', (85, 90))	('PAX9', 'Gene', (67, 71))
228088	29055049	Previous studies have suggested a potential role for the absence of PAX9 in human esophageal squamous cell carcinoma (ESCC) and oral squamous cell carcinoma (OSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('PAX9', 'Gene', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('SCC', 'Gene', '6317', (119, 122))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('absence', 'Var', (57, 64))	('SCC', 'Gene', (159, 162))	('human', 'Species', '9606', (76, 81))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 156))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('SCC', 'Gene', '6317', (159, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('SCC', 'Gene', (119, 122))	('oral squamous cell carcinoma', 'Disease', (128, 156))
228095	29055049	Human ESCC and OSCC tissue samples were obtained from Duke University Medical Center and Beijing Stomatological Hospital, respectively, with informed written consent and institutional IRB approval (Pro39682 and Pro56638).	('SCC', 'Gene', (7, 10))	('Human', 'Species', '9606', (0, 5))	('SCC', 'Gene', '6317', (7, 10))	('SCC', 'Gene', (16, 19))	('Pro39682', 'Var', (198, 206))	('SCC', 'Gene', '6317', (16, 19))	('Pro56638', 'Var', (211, 219))
228101	29055049	Human ESCC cells, KYSE510, KYSE450, and KYSE70, were obtained from ATCC (Manassas, VA, USA) and ECACC (Porton Down, Salisbury, UK) with proper authentication.	('SCC', 'Gene', (7, 10))	('Human', 'Species', '9606', (0, 5))	('KYSE70', 'Var', (40, 46))	('SCC', 'Gene', '6317', (7, 10))	('KYSE450', 'Var', (27, 34))
228131	29055049	Microarray data of four GEO datasets (GSE23400, GSE20347, GSE13601, GSE6631) were downloaded and analyzed to compare PAX9 mRNA expression in cancer versus matched normal tissue.	('GSE20347', 'Var', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mRNA expression', 'MPA', (122, 137))	('GSE6631', 'Var', (68, 75))	('PAX9', 'Gene', (117, 121))	('GSE6631', 'Chemical', '-', (68, 75))	('GSE23400', 'Var', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('compare', 'Reg', (109, 116))	('GSE13601', 'Var', (58, 66))	('cancer', 'Disease', (141, 147))
228143	29055049	Toluidine blue staining showed increased keratohyalin granules in the keratinized cells and palisading of basal cells in the mutant esophagus (Figure 1K, L).	('rat', 'Species', '10116', (72, 75))	('increased', 'PosReg', (31, 40))	('mutant', 'Var', (125, 131))	('palisading', 'CPA', (92, 102))	('rat', 'Species', '10116', (43, 46))	('keratohyalin granules', 'Protein', (41, 62))	('Toluidine blue', 'Chemical', 'MESH:D014048', (0, 14))
228144	29055049	At the fifth day following a BrdU pulse injection, some suprabasal cells of mutant esophagus remained strongly positive for BrdU and Ki67 (Figure 1P, R, T, V; yellow arrows) as compared with the control esophagus (Figure 1O, Q, S, U), suggesting that migration of these cells toward the lumen was impaired.	('migration', 'CPA', (251, 260))	('BrdU', 'Protein', (124, 128))	('Ki67', 'Gene', (133, 137))	('mutant', 'Var', (76, 82))	('impaired', 'NegReg', (297, 305))	('BrdU', 'Chemical', 'MESH:D001973', (124, 128))	('positive', 'Reg', (111, 119))	('BrdU', 'Chemical', 'MESH:D001973', (29, 33))	('Ki67', 'Gene', '17345', (133, 137))	('rat', 'Species', '10116', (254, 257))
228152	29055049	To examine the clinical relevance of PAX9 down-regulation, we analyzed microarray data of four GEO datasets (GSE23400, GSE20347, GSE13601, and GSE6631) and these showed significant down-regulation of PAX9 mRNA in human ESCC (supplementary material, Figure S3A, B) and human OSCC (supplementary material, Figure S3C, D), as compared with matched normal tissues.	('mRNA', 'MPA', (205, 209))	('SCC', 'Gene', (220, 223))	('human', 'Species', '9606', (213, 218))	('GSE23400', 'Var', (109, 117))	('SCC', 'Gene', (275, 278))	('GSE13601', 'Var', (129, 137))	('human', 'Species', '9606', (268, 273))	('SCC', 'Gene', '6317', (220, 223))	('SCC', 'Gene', '6317', (275, 278))	('GSE6631', 'Var', (143, 150))	('PAX9', 'Gene', (200, 204))	('GSE20347', 'Var', (119, 127))	('down-regulation', 'NegReg', (181, 196))	('GSE6631', 'Chemical', '-', (143, 150))
228185	29055049	Promoter hypermethylation was found to be associated with PAX9 silencing in human OESCC.	('SCC', 'Gene', '6317', (84, 87))	('human', 'Species', '9606', (76, 81))	('PAX9', 'Gene', (58, 62))	('SCC', 'Gene', (84, 87))	('silencing', 'NegReg', (63, 72))	('Promoter hypermethylation', 'Var', (0, 25))
228188	29055049	Clinically, PAX9 mutations have been reported in patients with oligodontia and cleft palate.	('cleft palate', 'Disease', (79, 91))	('cleft palate', 'Disease', 'MESH:D002972', (79, 91))	('oligodontia', 'Phenotype', 'HP:0000677', (63, 74))	('oligodontia', 'Disease', 'MESH:C538049', (63, 74))	('cleft palate', 'Phenotype', 'HP:0000175', (79, 91))	('oligodontia', 'Disease', (63, 74))	('patients', 'Species', '9606', (49, 57))	('reported', 'Reg', (37, 45))	('PAX9', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
228198	29055049	Genetic polymorphisms of ethanol-metabolizing genes, such as acetaldehyde dehydrogenase and alcohol dehydrogenase, are also strongly and consistently associated with OESCC.	('SCC', 'Gene', (168, 171))	('associated', 'Reg', (150, 160))	('alcohol', 'Chemical', 'MESH:D000438', (92, 99))	('SCC', 'Gene', '6317', (168, 171))	('acetaldehyde dehydrogenase', 'Gene', (61, 87))	('alcohol dehydrogenase', 'Gene', (92, 113))	('polymorphisms', 'Var', (8, 21))	('ethanol', 'Chemical', 'MESH:D000431', (25, 32))
228210	29055049	It remains unknown whether promoter hypermethylation may be associated with PAX9 down-regulation due to alcohol drinking.	('down-regulation', 'NegReg', (81, 96))	('alcohol drinking', 'Phenotype', 'HP:0030955', (104, 120))	('PAX9', 'Gene', (76, 80))	('alcohol', 'Chemical', 'MESH:D000438', (104, 111))	('promoter hypermethylation', 'Var', (27, 52))
228222	29055049	Transgenic overexpression of SOX2 itself was found to induced SCC in mouse forestomach and lung.	('overexpression', 'Var', (11, 25))	('SCC', 'Gene', '6317', (62, 65))	('mouse', 'Species', '10090', (69, 74))	('SOX2', 'Gene', (29, 33))	('induced', 'PosReg', (54, 61))	('SOX2', 'Gene', '20674', (29, 33))	('SCC', 'Gene', (62, 65))
228233	29254250	We found that AFAP1-AS1 was a risk factor in the prognoses of lung cancer (pooled HR: 1.54; 95% CI: 1.01-2.34), digestive system cancer (pooled HR: 1.87; 95% CI: 1.45-2.41) and nasopharyngeal carcinoma (HR: 11.82; 95% CI: 5.09-27.46).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('system cancer', 'Disease', 'MESH:D009369', (122, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('AFAP1-AS1', 'Var', (14, 23))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (177, 201))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('system cancer', 'Disease', (122, 135))	('nasopharyngeal carcinoma', 'Disease', (177, 201))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (177, 201))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
228234	29254250	AFAP1-AS1 was also a risk factor for RFS in breast cancer (pooled HR = 2.90; 95% CI: 1.69-4.98), as well as TNM stage in both esophageal cancer (pooled OR = 1.90; 95% CI: 1.01-3.57) and colorectal cancer (OR = 6.72; 95% CI: 1.92-23.58).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('colorectal cancer', 'Disease', 'MESH:D015179', (186, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('TNM', 'Gene', '10178', (108, 111))	('AFAP1-AS1', 'Var', (0, 9))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('esophageal cancer', 'Disease', (126, 143))	('TNM', 'Gene', (108, 111))	('colorectal cancer', 'Disease', (186, 203))
228275	29254250	We found that AFAP1-AS1 was a risk factor in the prognosis of lung cancer (pooled HR: 1.54; 95% CI: 1.01-2.34), digestive system cancer (pooled HR: 1.87; 95% CI: 1.45-2.41) and nasopharyngeal carcinoma (HR: 11.82; 95% CI: 5.09-27.46).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('system cancer', 'Disease', 'MESH:D009369', (122, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('AFAP1-AS1', 'Var', (14, 23))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (177, 201))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('system cancer', 'Disease', (122, 135))	('nasopharyngeal carcinoma', 'Disease', (177, 201))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (177, 201))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
228277	29254250	Three studies focused on breast cancer and a subgroup analysis found that AFAP1-AS1 was significantly associated with RFS in breast cancer (pooled HR = 2.90; 95% CI: 1.69-4.98; heterogeneity: Chi2 = 0.76, df = 2 (P = 0.68); I2 = 0%) (Figure 6C).	('RFS', 'Var', (118, 121))	('associated', 'Reg', (102, 112))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('AFAP1-AS1', 'Gene', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', (25, 38))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
228287	29254250	Additionally, high AFAP1-AS1 expression is closely correlated to a poor prognosis of cancer patients.	('AFAP1-AS1', 'Gene', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Disease', (85, 91))	('high', 'Var', (14, 18))	('expression', 'MPA', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('correlated', 'Reg', (51, 61))
228291	29254250	Our group was the first to demonstrate that the specific knock-down of AFAP1-AS1 resulted in AFAP1 expression inhibition.	('expression', 'MPA', (99, 109))	('AFAP1', 'Gene', (71, 76))	('AFAP1', 'Gene', '60312', (71, 76))	('AFAP1', 'Gene', (93, 98))	('AFAP1', 'Gene', '60312', (93, 98))	('knock-down', 'Var', (57, 67))
228294	29254250	By pooled HR values, AFAP1-AS1 was found to be an independent risk factor (pooled HR = 1.58; 95% CI: 1.21-2.21) of OS in tumor patients.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('OS in', 'Disease', (115, 120))	('OS', 'Chemical', '-', (115, 117))	('tumor', 'Disease', (121, 126))	('patients', 'Species', '9606', (127, 135))	('AFAP1-AS1', 'Var', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
228329	27384681	H. pylori can activate the host immune response, thus leading to chronic gastritis and ulcers.	('H. pylori', 'Species', '210', (0, 9))	('ulcers', 'Disease', (87, 93))	('activate', 'PosReg', (14, 22))	('gastritis', 'Disease', 'MESH:D005756', (73, 82))	('ulcers', 'Disease', 'MESH:D014456', (87, 93))	('leading to', 'Reg', (54, 64))	('gastritis', 'Phenotype', 'HP:0005263', (73, 82))	('H. pylori', 'Var', (0, 9))	('chronic gastritis', 'Phenotype', 'HP:0005231', (65, 82))	('host immune response', 'CPA', (27, 47))	('gastritis', 'Disease', (73, 82))
228331	27384681	One mechanism involves H. pylori-mediated generation offree radicals to lead to increasesin gene mutations.	('mutations', 'Var', (97, 106))	('H. pylori', 'Species', '210', (23, 32))	('increasesin gene', 'Gene', (80, 96))	('offree radicals', 'Chemical', '-', (53, 68))	('lead to', 'Reg', (72, 79))
228365	27384681	Immunohistochemical staining detected Ki67 in all non-malignant gastric cardia tissues and GCC patient samples (Figure 3C).	('patient', 'Species', '9606', (95, 102))	('Ki67', 'Var', (38, 42))	('Ki67', 'Chemical', '-', (38, 42))	('gastric cardia tissues', 'Disease', (64, 86))	('detected', 'Reg', (29, 37))	('gastric cardia tissues', 'Disease', 'MESH:D004938', (64, 86))
228368	27384681	Moreover, in GCCsamples, increased Ki67 staining in gastric cardia tissues correlated with increased CDX2 expression.	('staining', 'MPA', (40, 48))	('increased', 'PosReg', (25, 34))	('CDX2', 'Gene', '1045', (101, 105))	('gastric cardia tissues', 'Disease', 'MESH:D004938', (52, 74))	('expression', 'MPA', (106, 116))	('Ki67', 'Var', (35, 39))	('increased', 'PosReg', (91, 100))	('Ki67', 'Chemical', '-', (35, 39))	('CDX2', 'Gene', (101, 105))	('gastric cardia tissues', 'Disease', (52, 74))
228458	27478431	In terms of the depth of invasion, T2, T3, T4a, and T4b occurred in 1 (6.7%), 9 (60%), 3 (20%), and 2 (13.3%) patients, respectively, regional lymph nodes metastases of N1, N2, and N3 occurred in 3 (20%), 1 (6.7%), and 3 (20%) cases, respectively, and stages IB, IIA, IIB, IIIA, IIIB, IIIC, and IV were detected in 1 (6.7%), 5 (33.3%), 2 (13.3%), 1 (6.7%), 3 (20%), 2 (13.3%), and 1 (6.7%) patients, respectively.	('patients', 'Species', '9606', (390, 398))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('T4b', 'Var', (52, 55))	('T4a', 'Var', (43, 46))	('patients', 'Species', '9606', (110, 118))	('metastases', 'Disease', (155, 165))
228504	23717449	ESCC with low or moderate maspin expression had significantly shorter postoperative survival rates compared to those that had high maspin expression (p<0.001).	('shorter', 'NegReg', (62, 69))	('expression', 'Var', (33, 43))	('postoperative survival rates', 'CPA', (70, 98))	('low', 'NegReg', (10, 13))	('maspin', 'Gene', (131, 137))	('maspin', 'Gene', '5268', (131, 137))	('maspin', 'Gene', (26, 32))	('maspin', 'Gene', '5268', (26, 32))
228508	23717449	Maspin expression significantly inhibited cell proliferation, motility and matrigel invasion.	('Maspin', 'Gene', (0, 6))	('inhibited', 'NegReg', (32, 41))	('cell proliferation', 'CPA', (42, 60))	('matrigel invasion', 'CPA', (75, 92))	('expression', 'Var', (7, 17))	('Maspin', 'Gene', '5268', (0, 6))
228580	23717449	Since previous reports in breast and lung cancer for example, suggest that nuclear maspin is associated with better overall patient survival, we also investigated whether maspin subcellular localization correlated with the overall survival.	('breast and lung cancer', 'Disease', 'MESH:D001943', (26, 48))	('nuclear', 'Var', (75, 82))	('maspin', 'Gene', (171, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('maspin', 'Gene', '5268', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('patient survival', 'CPA', (124, 140))	('maspin', 'Gene', (83, 89))	('patient', 'Species', '9606', (124, 131))	('maspin', 'Gene', '5268', (83, 89))	('better', 'PosReg', (109, 115))
228588	23717449	Similar to the observation with early stage ESCC specimens, the level of maspin was not significantly altered in ESCC cell lines that are only weakly or moderately aggressive (T12, E450, KYSE150, and EC109), as judged by Western blotting ( Figure 3A ).	('KYSE150', 'Var', (187, 194))	('E450', 'Var', (181, 185))	('men', 'Species', '9606', (54, 57))	('maspin', 'Gene', (73, 79))	('maspin', 'Gene', '5268', (73, 79))
228591	23717449	The maspin expression in the resulting maspin transfected cells (M-KYSE510) and the mock transfected control (V-KYSE510) are shown in  Figure 4A .	('M-KYSE510', 'Var', (65, 74))	('maspin', 'Gene', (4, 10))	('maspin', 'Gene', '5268', (4, 10))	('maspin', 'Gene', (39, 45))	('maspin', 'Gene', '5268', (39, 45))
228595	23717449	Maspin expression did not significantly alter the colony forming ability, for the colony numbers for M-KYSE510, V-KYSE510 and the parental cells were not significantly different (data not shown).	('V-KYSE510', 'Var', (112, 121))	('Maspin', 'Gene', '5268', (0, 6))	('Maspin', 'Gene', (0, 6))	('M-KYSE510', 'Var', (101, 110))
228596	23717449	To further investigate whether the presence of maspin in ESCC is a gain or loss of other functions in tumor progression, we examined the effect of maspin expression on tumor cell motility and invasion.	('maspin', 'Gene', (47, 53))	('presence', 'Var', (35, 43))	('maspin', 'Gene', '5268', (47, 53))	('tumor', 'Disease', (168, 173))	('ESCC', 'Disease', (57, 61))	('maspin', 'Gene', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('maspin', 'Gene', '5268', (147, 153))	('examined', 'Reg', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
228612	23717449	Upon the transformation and other oncogenic changes, the basal level of maspin expression may not be sufficient to counter-balance the biological effects of oncogenes.	('changes', 'Var', (44, 51))	('maspin', 'Gene', (72, 78))	('maspin', 'Gene', '5268', (72, 78))
228630	23717449	A paradigm based on the studies of classic tumor suppressor genes whose loss or mutation at the genetic level contributes to carcinogenesis and tumor progression would predict that tumor suppressors would be down-regulated as long as the oncogenesis is initiated.	('tumor', 'Disease', (144, 149))	('tumor suppressor', 'Gene', '7248', (181, 197))	('loss', 'NegReg', (72, 76))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor suppressor', 'Gene', (43, 59))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor suppressor', 'Gene', (181, 197))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor suppressor', 'Gene', '7248', (43, 59))	('carcinogenesis', 'Disease', (125, 139))	('tumor', 'Disease', (43, 48))	('down-regulated', 'NegReg', (208, 222))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mutation', 'Var', (80, 88))
228633	23717449	Although maspin is not as frequently mutated as some other well-known tumor suppressor genes such as p53, a specific Ser176 Pro polymorphism has been identified which seems to be frequent in gastric cancer and had reduced tumor suppressive potency as compared to the wild type maspin.	('gastric cancer', 'Disease', (191, 205))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('maspin', 'Gene', (9, 15))	('maspin', 'Gene', '5268', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (191, 205))	('Ser176 Pro polymorphism', 'Var', (117, 140))	('maspin', 'Gene', (277, 283))	('tumor suppressor', 'Gene', (70, 86))	('polymorphism', 'Var', (128, 140))	('p53', 'Gene', '7157', (101, 104))	('reduced', 'NegReg', (214, 221))	('tumor', 'Disease', (222, 227))	('gastric cancer', 'Phenotype', 'HP:0012126', (191, 205))	('Ser176 Pro', 'Mutation', 'rs2289519', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor suppressor', 'Gene', '7248', (70, 86))	('tumor', 'Disease', (70, 75))	('p53', 'Gene', (101, 104))	('frequent', 'Reg', (179, 187))	('maspin', 'Gene', '5268', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
228643	33758232	Volume of low cardiac dose and NLR (baseline and follow-up) were associated with worse patient survival.	('NLR', 'Var', (31, 34))	('patient survival', 'CPA', (87, 103))	('patient', 'Species', '9606', (87, 94))	('worse', 'NegReg', (81, 86))
228680	33758232	Heart V10 > 84% was also associated with worse PFS (p = 0.005), DSS (p = 0.01) and FFDM (p = 0.021), but was not associated with FFLR (see Supplementary Fig.	('Heart V10 > 84%', 'Var', (0, 15))	('PFS', 'MPA', (47, 50))	('DSS', 'Disease', (64, 67))	('FFDM', 'Disease', (83, 87))	('DSS', 'Chemical', '-', (64, 67))
228682	33758232	Follow-up NLR > 7.4 was also associated with worse PFS (p = 0.024) and DSS (p = 0.011) but not associated with FFDM or FFLR (see Supplementary Fig.	('PFS', 'MPA', (51, 54))	('NLR', 'Var', (10, 13))	('DSS', 'Chemical', '-', (71, 74))	('DSS', 'Disease', (71, 74))
228689	33758232	There are limited data about the relationship between heart dose and survival outcomes in esophageal cancer, and heart V30 > 45% is found to be independently associated with worse survival.	('esophageal cancer', 'Disease', (90, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('heart V30 > 45%', 'Var', (113, 128))
228690	33758232	Moreover, based on the data for lung cancer, the RTOG 0617 trial suggested heart V5 and heart V30 were associated with an increased risk of death.	('heart V30', 'Var', (88, 97))	('heart V5', 'Var', (75, 83))	('associated', 'Reg', (103, 113))	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
228730	33006432	The silence of FAM225A attenuated cell viability, migration, and invasion, but facilitated cell apoptosis in ESCC.	('silence', 'Var', (4, 11))	('ESCC', 'Disease', (109, 113))	('cell apoptosis', 'CPA', (91, 105))	('migration', 'CPA', (50, 59))	('FAM225A', 'Gene', '286333', (15, 22))	('FAM225A', 'Gene', (15, 22))	('invasion', 'CPA', (65, 73))	('attenuated', 'NegReg', (23, 33))	('facilitated', 'PosReg', (79, 90))	('cell viability', 'CPA', (34, 48))
228750	33006432	13  MiR-874-3p acts as a prognostic factor and targets STAT3 to exhibit its tumor suppressor in ESCC.	('STAT3', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('MiR-874-3p', 'Var', (4, 14))	('MiR-874-3p', 'Chemical', '-', (4, 14))	('ESCC', 'Disease', (96, 100))	('STAT3', 'Gene', '6774', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
228790	33006432	In addition, cell migration and invasion were both attenuated by FAM225A knockdown (Figure 1E-F).	('FAM225A', 'Gene', (65, 72))	('cell migration', 'CPA', (13, 27))	('FAM225A', 'Gene', '286333', (65, 72))	('attenuated', 'NegReg', (51, 61))	('knockdown', 'Var', (73, 82))	('invasion', 'CPA', (32, 40))
228793	33006432	It was found that Bax and E-cadherin expression was increased, but Bcl-2, PCNA, CyclinD1, MMP-2, MMP-9, and Vimentin expression was decreased by knocking down FAM225A (Figure 1H-I).	('PCNA', 'Gene', (74, 78))	('knocking down', 'Var', (145, 158))	('Bax', 'Gene', (18, 21))	('increased', 'PosReg', (52, 61))	('Bax', 'Gene', '581', (18, 21))	('PCNA', 'Gene', '5111', (74, 78))	('Vimentin', 'Gene', '7431', (108, 116))	('Bcl-2', 'Gene', (67, 72))	('Vimentin', 'Gene', (108, 116))	('MMP-2', 'Gene', '4313', (90, 95))	('FAM225A', 'Gene', '286333', (159, 166))	('E-cadherin', 'Gene', (26, 36))	('MMP-9', 'Gene', '4318', (97, 102))	('CyclinD1', 'Gene', '595', (80, 88))	('MMP-9', 'Gene', (97, 102))	('E-cadherin', 'Gene', '999', (26, 36))	('Bcl-2', 'Gene', '596', (67, 72))	('expression', 'MPA', (37, 47))	('CyclinD1', 'Gene', (80, 88))	('FAM225A', 'Gene', (159, 166))	('MMP-2', 'Gene', (90, 95))	('decreased', 'NegReg', (132, 141))
228815	33006432	The luciferase reporter assay revealed that upregulated expression of FOXP1 notably enhanced the luciferase activities of pGL3-FAM225A-WT vectors, while there was no effect on the luciferase activities of pGL3-FAM225A-Mut vectors (Figure 5D).	('pGL3', 'Gene', '6391', (122, 126))	('FAM225A', 'Gene', (210, 217))	('luciferase', 'Enzyme', (97, 107))	('FAM225A', 'Gene', '286333', (210, 217))	('upregulated', 'PosReg', (44, 55))	('pGL3', 'Gene', (205, 209))	('FOXP1', 'Gene', '27086', (70, 75))	('activities', 'MPA', (108, 118))	('FOXP1', 'Gene', (70, 75))	('FAM225A', 'Gene', '286333', (127, 134))	('pGL3', 'Gene', '6391', (205, 209))	('pGL3', 'Gene', (122, 126))	('enhanced', 'PosReg', (84, 92))	('expression', 'Var', (56, 66))	('FAM225A', 'Gene', (127, 134))
228823	33006432	Suppression of FAM225A significantly enhanced cell apoptosis, which was abolished by NETO2 or FOXP1 overexpression (Figure 6E).	('FOXP1', 'Gene', (94, 99))	('cell apoptosis', 'CPA', (46, 60))	('NETO2', 'Gene', '81831', (85, 90))	('Suppression', 'Var', (0, 11))	('FAM225A', 'Gene', '286333', (15, 22))	('FAM225A', 'Gene', (15, 22))	('FOXP1', 'Gene', '27086', (94, 99))	('enhanced', 'PosReg', (37, 45))	('NETO2', 'Gene', (85, 90))
228824	33006432	Additionally, upregulation of NETO2 or FOXP1 could save the effects of FAM225A knockdown on PCNA, CyclinD1, MMP-2, MMP-9, Bax, Bcl-2, E-cadherin, and Vimentin expression (Figure 6F and G).	('NETO2', 'Gene', '81831', (30, 35))	('PCNA', 'Gene', '5111', (92, 96))	('Bax', 'Gene', (122, 125))	('FOXP1', 'Gene', '27086', (39, 44))	('CyclinD1', 'Gene', '595', (98, 106))	('Bcl-2', 'Gene', '596', (127, 132))	('MMP-2', 'Gene', '4313', (108, 113))	('Vimentin', 'Gene', '7431', (150, 158))	('Bax', 'Gene', '581', (122, 125))	('MMP-9', 'Gene', '4318', (115, 120))	('CyclinD1', 'Gene', (98, 106))	('MMP-9', 'Gene', (115, 120))	('Vimentin', 'Gene', (150, 158))	('upregulation', 'PosReg', (14, 26))	('FOXP1', 'Gene', (39, 44))	('FAM225A', 'Gene', '286333', (71, 78))	('MMP-2', 'Gene', (108, 113))	('NETO2', 'Gene', (30, 35))	('knockdown', 'Var', (79, 88))	('PCNA', 'Gene', (92, 96))	('FAM225A', 'Gene', (71, 78))	('E-cadherin', 'Gene', (134, 144))	('E-cadherin', 'Gene', '999', (134, 144))	('Bcl-2', 'Gene', (127, 132))
228825	33006432	Additionally, the upregulation of NETO2 or FOXP1 could rescue the inhibitory role of FAM225A knockdown on tube formation (Figure 6H).	('NETO2', 'Gene', (34, 39))	('upregulation', 'PosReg', (18, 30))	('knockdown', 'Var', (93, 102))	('FOXP1', 'Gene', '27086', (43, 48))	('FOXP1', 'Gene', (43, 48))	('NETO2', 'Gene', '81831', (34, 39))	('FAM225A', 'Gene', (85, 92))	('FAM225A', 'Gene', '286333', (85, 92))	('tube formation', 'CPA', (106, 120))	('inhibitory', 'MPA', (66, 76))
228838	33006432	The silence of FAM225A attenuated cell viability, migration, and invasion, and promoted cell apoptosis.	('cell apoptosis', 'CPA', (88, 102))	('silence', 'Var', (4, 11))	('migration', 'CPA', (50, 59))	('FAM225A', 'Gene', '286333', (15, 22))	('promoted', 'PosReg', (79, 87))	('FAM225A', 'Gene', (15, 22))	('invasion', 'CPA', (65, 73))	('attenuated', 'NegReg', (23, 33))	('cell viability', 'CPA', (34, 48))
228848	33006432	30  The lncRNA MIR210HG sponges miR-1226-3p to increase mucin-1c expression thus facilitates tumor metastasis in breast cancer.	('increase', 'PosReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('miR-1226-3p', 'Var', (32, 43))	('MIR210HG', 'Gene', '100506211', (15, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('mucin-1c expression', 'MPA', (56, 75))	('tumor metastasis in breast cancer', 'Disease', 'MESH:D001943', (93, 126))	('MIR210HG', 'Gene', (15, 23))	('tumor metastasis in breast cancer', 'Disease', (93, 126))	('facilitates', 'PosReg', (81, 92))
228883	33003374	Indeed, the off-target accumulation of PSs may cause mild but long-lasting phototoxicity, such as light sensitivity leading to burns, swelling pain, and scarring in the normal tissues near the tumor area.	('phototoxicity', 'Disease', 'MESH:D017484', (75, 88))	('swelling pain', 'Disease', (134, 147))	('scarring', 'Phenotype', 'HP:0100699', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('phototoxicity', 'Disease', (75, 88))	('scarring', 'CPA', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('pain', 'Phenotype', 'HP:0012531', (143, 147))	('swelling pain', 'Disease', 'MESH:D010146', (134, 147))	('tumor', 'Disease', (193, 198))	('PSs', 'Var', (39, 42))	('burns', 'Disease', (127, 132))
229014	33003374	NIR-PIT is based on injecting a near-infrared conjugate (IRdye700DX/IR700), a photoactivating chemical, and a monoclonal antibody (mAb), which is the target for expressed antigen on the cancer cell surface.	('NIR-PIT', 'Chemical', '-', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('IRdye700DX/IR700', 'Var', (57, 73))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
229070	33003374	Further, NPs can enhance the targeting ability of PS drugs using the EPR effect to target cancer cells selectively.	('enhance', 'PosReg', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('targeting ability', 'MPA', (29, 46))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('NPs', 'Var', (9, 12))
229136	32917177	Most importantly, with eTHE, the factors regarding oncologic efficacy, such as lymph node harvest, complete resection rate (R0 of 97%), and long-term survival outcomes, were no compromised compared to those of other open or laparoscopic approaches.	('eTHE', 'Chemical', '-', (23, 27))	('eTHE', 'Var', (23, 27))	('lymph node harvest', 'CPA', (79, 97))
229186	32030352	With continued acid exposure, the intestinalized epithelium may accumulate genetic abnormalities, including chromosomal abnormalities, TP53 mutations, and alterations of the CDKN2A, EGFR, and cyclin genes.	('alterations', 'Var', (155, 166))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('genetic abnormalities', 'Disease', (75, 96))	('TP53', 'Gene', '7157', (135, 139))	('CDKN2A', 'Gene', (174, 180))	('cyclin', 'Gene', '5111', (192, 198))	('cyclin', 'Gene', (192, 198))	('TP53', 'Gene', (135, 139))	('CDKN2A', 'Gene', '1029', (174, 180))	('mutations', 'Var', (140, 149))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (108, 133))	('chromosomal abnormalities', 'Disease', (108, 133))	('genetic abnormalities', 'Disease', 'MESH:D030342', (75, 96))
229187	32030352	The accumulation of these genetic abnormalities correlates with histopathologic observation of low-grade dysplasia, high-grade dysplasia, and ultimately invasive adenocarcinoma.	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (153, 176))	('invasive adenocarcinoma', 'Disease', (153, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('genetic abnormalities', 'Var', (26, 47))	('high-grade dysplasia', 'Disease', (116, 136))	('low-grade dysplasia', 'Disease', (95, 114))
229209	29844870	Risks for hypopharyngeal and nasopharyngeal cancers were greatly elevated: (ORQ4vsQ1 = 4.05 (95% CI: 1.24-13.25) for hypopharyngeal cancer and ORQ4vsQ1 = 4.99 (95% CI: 1.14-21.79) for nasopharyngeal cancer.	('hypopharyngeal cancer', 'Disease', (117, 138))	('hypopharyngeal', 'Disease', 'MESH:D007012', (117, 131))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (29, 50))	('ORQ4vsQ1', 'Var', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('nasopharyngeal cancer', 'Disease', (184, 205))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (117, 138))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (29, 50))	('hypopharyngeal', 'Disease', (10, 24))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (184, 205))	('hypopharyngeal', 'Disease', (117, 131))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('hypopharyngeal', 'Disease', 'MESH:D007012', (10, 24))	('cancers', 'Disease', (44, 51))	('nasopharyngeal cancer', 'Disease', (29, 50))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (184, 205))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
229221	29844870	The DII has been associated with various neoplasms including esophageal, laryngeal, pharyngeal, colorectal, prostate, pancreatic, endometrial, and hepatocellular cancers.	('associated', 'Reg', (17, 27))	('neoplasms', 'Disease', 'MESH:D009369', (41, 50))	('pancreatic', 'Disease', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal', 'Disease', (96, 106))	('esophageal', 'Disease', (61, 71))	('neoplasms', 'Disease', (41, 50))	('pharyngeal', 'Disease', (84, 94))	('hepatocellular cancers', 'Disease', 'MESH:D006528', (147, 169))	('prostate', 'Disease', (108, 116))	('DII', 'Var', (4, 7))	('colorectal', 'Disease', 'MESH:D015179', (96, 106))	('neoplasms', 'Phenotype', 'HP:0002664', (41, 50))	('pancreatic', 'Disease', 'MESH:D010195', (118, 128))	('DII', 'Chemical', '-', (4, 7))	('endometrial', 'Disease', (130, 141))	('hepatocellular cancers', 'Disease', (147, 169))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('laryngeal', 'Disease', (73, 82))
229238	29844870	Table 3 shows the association between DII scores and risk for all UATC, and separately for head and neck, and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('DII', 'Var', (38, 41))	('UATC', 'Disease', (66, 70))	('esophageal cancer', 'Disease', (110, 127))	('association', 'Interaction', (18, 29))	('UATC', 'Chemical', '-', (66, 70))	('DII', 'Chemical', '-', (38, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))
229241	29844870	Adjusted ORQ4vsQ1 remained significant for esophageal cancer (1.71; 1.54-1.90); however, a linear trend was attenuated compared with UATC overall (P-trend 0.07).	('UATC', 'Chemical', '-', (133, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('ORQ4vsQ1', 'Var', (9, 17))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
229263	29844870	On the other hand, infection of EBV results in the activation of STAT3 and NF-kappaB signal cascades in target epithelial cells, which induces increased expression of inflammatory cytokines including IL-6 and COX-2.	('increased', 'PosReg', (143, 152))	('infection', 'Var', (19, 28))	('IL-6', 'Gene', (200, 204))	('IL-6', 'Gene', '3569', (200, 204))	('NF-kappaB', 'Gene', (75, 84))	('EBV', 'Species', '10376', (32, 35))	('inflammatory cytokines', 'MPA', (167, 189))	('expression', 'MPA', (153, 163))	('EBV', 'Gene', (32, 35))	('increased expression of inflammatory cytokines', 'Phenotype', 'HP:0012649', (143, 189))	('activation', 'PosReg', (51, 61))	('NF-kappaB', 'Gene', '4790', (75, 84))
229290	29844870	We defined UATC according to the following codes of the International Classification of Diseases and Related Health Problems (ICD10): cancers of the oral cavity and oropharynx (C00.3-C00.9, C01, C02.0-C02.4, C03, C04, C05.0-C05.2, C06, C09 and C10), hypopharynx (C12 and C13), oral cavity-oropharynx-hypopharynx if not otherwise specified (C02.8, C02.9, C05.8, C05.9 and C14), salivary glands (C07 and C08), nasopharynx (C11), larynx (C32) and esophagus (C15).	('C07', 'Var', (394, 397))	('C02.8', 'Var', (340, 345))	('UATC', 'Chemical', '-', (11, 15))	('C00.3-C00.9', 'Var', (177, 188))	('C13', 'Gene', (271, 274))	('C15', 'Gene', '51316', (455, 458))	('C11', 'Gene', '1109', (421, 424))	('C05.8', 'Var', (354, 359))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('C15', 'Gene', (455, 458))	('C14', 'Var', (371, 374))	('C12', 'Var', (263, 266))	('C13', 'Gene', '3229', (271, 274))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('C02.9', 'Var', (347, 352))	('C10', 'Gene', '113246', (244, 247))	('C10', 'Gene', (244, 247))	('C32', 'Gene', (435, 438))	('C32', 'Gene', '51192', (435, 438))	('C01', 'CellLine', 'CVCL:E303', (190, 193))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('C11', 'Gene', (421, 424))	('C05.9 and C14', 'Var', (361, 374))	('cancers of the oral cavity', 'Phenotype', 'HP:0100649', (134, 160))
229388	28823862	But these investigators also reported that the urinary concentration of N'-nitrosonornicotine was very strongly linked to ESCC risk and inferred that this may the causative agent in these tobacco smokers.	('tobacco', 'Species', '4097', (188, 195))	('ESCC', 'Disease', (122, 126))	("N'-nitrosonornicotine", 'Var', (72, 93))	('linked', 'Reg', (112, 118))	("N'-nitrosonornicotine", 'Chemical', 'MESH:C008655', (72, 93))	('urinary concentration', 'MPA', (47, 68))
229432	28823862	Analogous to the hypothesis for folate and colorectal cancer this age interaction may suggest that selenium might prevent ESCC only when it is supplemented before advanced preneoplasia is evident.	('colorectal cancer', 'Disease', (43, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('men', 'Species', '9606', (149, 152))	('preneoplasia', 'Disease', (172, 184))	('colorectal cancer', 'Disease', 'MESH:D015179', (43, 60))	('ESCC only', 'Disease', (122, 131))	('selenium', 'Chemical', 'MESH:D012643', (99, 107))	('preneoplasia', 'Disease', 'None', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('selenium', 'Var', (99, 107))
229433	28823862	An independent chemoprevention trial focused on precancerous lesion reported that selenium could increase regression and reduce regression in subjects with mild esophageal squamous dysplasia.	('regression', 'CPA', (106, 116))	('increase', 'PosReg', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('regression', 'MPA', (128, 138))	('selenium', 'Chemical', 'MESH:D012643', (82, 90))	('esophageal squamous dysplasia', 'Disease', 'MESH:D000077277', (161, 190))	('reduce', 'NegReg', (121, 127))	('selenium', 'Var', (82, 90))	('esophageal squamous dysplasia', 'Disease', (161, 190))	('precancerous lesion', 'Disease', 'MESH:D011230', (48, 67))	('precancerous lesion', 'Disease', (48, 67))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (172, 190))
229463	28823862	Studies that test for the presence of HPV DNA in ESCC tumor tissue have reported a wide range of prevalence estimates, ranging from 0 to nearly 70%, but detecting HPV DNA in the tumor does not mean that it causes tumorigenesis or tumor development.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', (178, 183))	('HPV', 'Species', '10566', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('HPV', 'Species', '10566', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('causes', 'Reg', (206, 212))	('men', 'Species', '9606', (243, 246))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('HPV DNA', 'Var', (163, 170))
229482	28823862	This response occurs because individuals with specific variants in the aldehyde dehydrogenase 2 family gene (ALDH2) and an acetaldehyde dehydrogenase gene (ADH1B) produce high concentrations of acetaldehyde during consumption of alcohol.	('ALDH2', 'Gene', '217', (109, 114))	('alcohol', 'Chemical', 'MESH:D000438', (229, 236))	('variants', 'Var', (55, 63))	('ADH1B', 'Gene', (156, 161))	('acetaldehyde', 'Chemical', 'MESH:D000079', (123, 135))	('high concentrations of acetaldehyde', 'Phenotype', 'HP:0003533', (171, 206))	('ALDH2', 'Gene', (109, 114))	('ADH1B', 'Gene', '125', (156, 161))	('acetaldehyde', 'Chemical', 'MESH:D000079', (194, 206))
229483	28823862	The flushing response is unpleasant, so individuals heterozygous for this variant in ALDH2 tend to avoid alcohol consumption, whereas individuals who are homozygotes for this variant rarely, if ever, consume alcohol; they have a low risk for alcohol-linked diseases including alcoholism.	('avoid alcohol consumption', 'MPA', (99, 124))	('alcohol', 'Chemical', 'MESH:D000438', (276, 283))	('ALDH2', 'Gene', '217', (85, 90))	('alcohol', 'Chemical', 'MESH:D000438', (208, 215))	('alcohol', 'Chemical', 'MESH:D000438', (105, 112))	('variant', 'Var', (74, 81))	('flushing', 'Phenotype', 'HP:0031284', (4, 12))	('alcoholism', 'Disease', (276, 286))	('ALDH2', 'Gene', (85, 90))	('flushing', 'Disease', (4, 12))	('alcohol-linked diseases', 'Disease', (242, 265))	('alcohol-linked diseases', 'Disease', 'MESH:D000437', (242, 265))	('flushing', 'Disease', 'MESH:D005483', (4, 12))	('alcoholism', 'Phenotype', 'HP:0030955', (276, 286))	('alcohol', 'Chemical', 'MESH:D000438', (242, 249))
229484	28823862	If people carrying these polymorphic variants consume alcohol, their risk of ESCC increases as high as 43-fold for moderate drinkers and 73-fold for heavy drinkers.	('alcohol', 'Chemical', 'MESH:D000438', (54, 61))	('polymorphic variants', 'Var', (25, 45))	('ESCC', 'Disease', (77, 81))	('variants', 'Var', (37, 45))	('people', 'Species', '9606', (3, 9))
229485	28823862	Individuals with this variant in ALDH2 who do not consume alcohol have no increase in risk for ESCC.	('ALDH2', 'Gene', (33, 38))	('variant', 'Var', (22, 29))	('alcohol', 'Chemical', 'MESH:D000438', (58, 65))	('ESCC', 'Disease', (95, 99))	('ALDH2', 'Gene', '217', (33, 38))
229487	28823862	The main effects from the Chinese studies have revealed several key SNPs, most notably variants in the phospholipase c epsilon 1 gene (PLCE1).	('phospholipase c epsilon 1', 'Gene', '51196', (103, 128))	('PLCE1', 'Gene', (135, 140))	('PLCE1', 'Gene', '51196', (135, 140))	('variants', 'Var', (87, 95))	('phospholipase c epsilon 1', 'Gene', (103, 128))
229491	28823862	Other identified variants have included genomic regions linked to other cancers including, the region of the caspase 8 gene: a complex region with cancer risk linked to variants in several in-line linkage disequilibrium blocks.	('variants', 'Var', (17, 25))	('linked', 'Reg', (56, 62))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('caspase 8', 'Gene', '841', (109, 118))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('variants', 'Var', (169, 177))	('caspase 8', 'Gene', (109, 118))	('cancer', 'Disease', (72, 78))
229492	28823862	One notable finding was the risk of ESCC linked to a polymorphism in the TP53 gene region.	('linked', 'Reg', (41, 47))	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('polymorphism', 'Var', (53, 65))	('ESCC', 'Disease', (36, 40))
229494	28823862	A few studies have re-examined these polymorphisms in other populations, including a study of polymorphisms in PLCE1 in South Africa, a region with high rates of ESCC.	('PLCE1', 'Gene', (111, 116))	('PLCE1', 'Gene', '51196', (111, 116))	('polymorphisms', 'Var', (94, 107))
229495	28823862	Without this sort of comprehensive assessment, we will not realize the full potential for common genetic variants to help us understand the etiology of ESCC in different populations, nor the potential for these variants to play a role in risk stratification as is being realized in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('breast cancer', 'Disease', 'MESH:D001943', (282, 295))	('breast cancer', 'Disease', (282, 295))	('variants', 'Var', (105, 113))	('variants', 'Var', (211, 219))	('men', 'Species', '9606', (41, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (282, 295))	('ESCC', 'Disease', (152, 156))
229509	28602785	miRNAs play crucial roles in carcinogenesis and cancer development, and a growing body of evidence has shown that many miRNAs are aberrantly expressed and dysfunctional in ESCC.	('carcinogenesis', 'Disease', (29, 43))	('miR', 'Gene', '220972', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('miR', 'Gene', (119, 122))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('aberrantly', 'Var', (130, 140))	('dysfunctional', 'Disease', (155, 168))	('dysfunctional', 'Disease', 'MESH:D006331', (155, 168))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('ESCC', 'Disease', (172, 176))	('carcinogenesis', 'Disease', 'MESH:D063646', (29, 43))
229532	28602785	qPCR analysis showed that the expression of miR-503 was significantly increased by mimic transfection (P < 0.001, Figure1D) and significantly decreased by inhibitor transfection (P < 0.001, Figure1E).	('miR-503', 'Gene', (44, 51))	('expression', 'MPA', (30, 40))	('mimic transfection', 'Var', (83, 101))	('increased', 'PosReg', (70, 79))	('decreased', 'NegReg', (142, 151))	('miR-503', 'Gene', '574506', (44, 51))
229533	28602785	We next conducted cell phenotype assays to evaluate the effects of manipulating miR-503 expression on cell proliferation, migration, and invasion.	('miR-503', 'Gene', (80, 87))	('manipulating', 'Var', (67, 79))	('miR-503', 'Gene', '574506', (80, 87))
229535	28602785	In addition, Transwell assay showed that migration and invasion abilities of YES-2 and KYSE30 cells transfected with miR-503 mimic were significantly decreased compared to the cells transfected with negative control (P < 0.001, Figure2B).	('miR-503', 'Gene', '574506', (117, 124))	('YES-2', 'Gene', (77, 82))	('invasion abilities', 'CPA', (55, 73))	('miR-503', 'Gene', (117, 124))	('KYSE30', 'CellLine', 'CVCL:1351', (87, 93))	('YES-2', 'Gene', '7526', (77, 82))	('mimic', 'Var', (125, 130))	('decreased', 'NegReg', (150, 159))
229537	28602785	As expected, silenced miR-503 expression with inhibitor in KYSE450 and KYSE510 increased cell proliferation, migration, and invasion ability, compared to the cells transfected with the control (Figure 3).	('miR-503', 'Gene', (22, 29))	('increased', 'PosReg', (79, 88))	('cell proliferation', 'CPA', (89, 107))	('KYSE450', 'Var', (59, 66))	('KYSE510', 'CellLine', 'CVCL:1354', (71, 78))	('miR-503', 'Gene', '574506', (22, 29))	('invasion ability', 'CPA', (124, 140))	('migration', 'CPA', (109, 118))	('inhibitor', 'Var', (46, 55))	('KYSE510', 'Var', (71, 78))
229559	28602785	As shown in Figure5C, compared to the cells transfected with the negative control, expression of CCND1 was significantly decreased in the YES-2 and KYSE30 cells transfected with miR-503 mimic or si CCND1.	('CCND1', 'Gene', (97, 102))	('YES-2', 'Gene', '7526', (138, 143))	('miR-503', 'Gene', (178, 185))	('si CCND1', 'Var', (195, 203))	('decreased', 'NegReg', (121, 130))	('YES-2', 'Gene', (138, 143))	('KYSE30', 'CellLine', 'CVCL:1351', (148, 154))	('expression', 'MPA', (83, 93))	('miR-503', 'Gene', '574506', (178, 185))
229573	28602785	Similarly, knocking down expression of CCND1 (si CCND1 + vector) could mimic tumor suppressive effect of miR-503 mimic (mimic + vector) on ESCC cell migration and invasion, whereas overexpression of CCND1 (mimic + CCND1) could partially reverse the tumor suppressive effect of miR-503 on ESCC cell lines (Figure6C).	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('miR-503', 'Gene', (105, 112))	('CCND1', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('miR-503', 'Gene', (277, 284))	('knocking', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('miR-503', 'Gene', '574506', (105, 112))	('tumor', 'Disease', (249, 254))	('miR-503', 'Gene', '574506', (277, 284))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('ESCC', 'Disease', (139, 143))	('invasion', 'CPA', (163, 171))
229588	28602785	There are many factors contributing to the overexpression of cyclin D1 in cancer, such as amplification and abnormal transcription of CCND1 .	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('overexpression', 'PosReg', (43, 57))	('cyclin D1', 'Gene', '595', (61, 70))	('CCND1', 'Gene', (134, 139))	('cancer', 'Disease', (74, 80))	('cyclin D1', 'Gene', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (90, 103))	('abnormal transcription', 'Var', (108, 130))
229590	28602785	Blockage of cyclin D1 expression could induce cell cycle G1/S phase arrest, thus leading to the inhibition of cell proliferation.	('Blockage', 'Var', (0, 8))	('cell cycle G1/S phase arrest', 'CPA', (46, 74))	('cyclin D1', 'Gene', '595', (12, 21))	('cyclin D1', 'Gene', (12, 21))	('cell proliferation', 'CPA', (110, 128))	('inhibition', 'NegReg', (96, 106))	('induce', 'PosReg', (39, 45))
229600	28602785	Moreover, silenced expression of CCND1 could recapitulate the tumor suppressive effect of miR-503 mimic on ESCC, whereas overexpression of CCND1 could partially reverse the tumor suppressive effect of miR-503 mimic on ESCC cells.	('miR-503', 'Gene', '574506', (90, 97))	('miR-503', 'Gene', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('miR-503', 'Gene', '574506', (201, 208))	('CCND1', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('ESCC', 'Disease', (107, 111))	('silenced expression', 'Var', (10, 29))	('miR-503', 'Gene', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
229607	28602785	These include TE12, KYSE510, KYSE450, KYSE410, Colo680N, KYSE180, KYSE140, YES-2, KYSE150, and KYSE30.	('KYSE30', 'Var', (95, 101))	('YES-2', 'Gene', (75, 80))	('KYSE140', 'Var', (66, 73))	('KYSE510', 'Var', (20, 27))	('YES-2', 'Gene', '7526', (75, 80))	('KYSE150', 'Var', (82, 89))	('Colo680N', 'Var', (47, 55))	('KYSE180', 'Var', (57, 64))	('TE12', 'Var', (14, 18))	('KYSE30', 'CellLine', 'CVCL:1351', (95, 101))	('KYSE410', 'Var', (38, 45))	('KYSE510', 'CellLine', 'CVCL:1354', (20, 27))	('KYSE450', 'Var', (29, 36))
229623	27921054	There are very few reports of sunitinib causing severe esophagitis, and only one of them was previously reported as exfoliative esophagitis.	('sunitinib', 'Chemical', 'MESH:D000077210', (30, 39))	('esophagitis', 'Phenotype', 'HP:0100633', (55, 66))	('esophagitis', 'Phenotype', 'HP:0100633', (128, 139))	('esophagitis', 'Disease', (55, 66))	('esophagitis', 'Disease', (128, 139))	('esophagitis', 'Disease', 'MESH:D004941', (55, 66))	('esophagitis', 'Disease', 'MESH:D004941', (128, 139))	('exfoliative esophagitis', 'Disease', (116, 139))	('causing', 'Reg', (40, 47))	('sunitinib', 'Var', (30, 39))	('exfoliative esophagitis', 'Disease', 'MESH:D017889', (116, 139))
229660	27921054	VEGF inhibition results in impaired mucosal healing and increases the vulnerability of the mucosa.	('impaired mucosal healing', 'Disease', 'MESH:D009422', (27, 51))	('increases', 'PosReg', (56, 65))	('inhibition', 'Var', (5, 15))	('impaired mucosal healing', 'Disease', (27, 51))	('VEGF', 'Protein', (0, 4))	('vulnerability of the mucosa', 'CPA', (70, 97))
229661	27921054	Additionally, as seen in rat models, COX-2 is an important inducer of VEGF in the esophageal mucosa and delays ulcer healing when exposed to nonsteroidal anti-inflammatory drugs.	('COX-2', 'Var', (37, 42))	('delays ulcer healing', 'Disease', (104, 124))	('inducer', 'Reg', (59, 66))	('delays ulcer healing', 'Phenotype', 'HP:0001058', (104, 124))	('delays ulcer healing', 'Disease', 'MESH:D014456', (104, 124))	('rat', 'Species', '10116', (25, 28))
229665	31085800	LINC00857 knockdown inhibits cell proliferation and induces apoptosis via involving STAT3 and MET oncogenic proteins in esophageal adenocarcinoma Esophageal adenocarcinoma (EAC) is one of the leading causes of cancer-related death worldwide, and the molecular biology of this cancer remains poorly understood.	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('esophageal adenocarcinoma', 'Disease', (120, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('EAC', 'Phenotype', 'HP:0011459', (173, 176))	('Esophageal adenocarcinoma', 'Disease', (146, 171))	('STAT3', 'Gene', (84, 89))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (146, 171))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (146, 171))	('knockdown', 'Var', (10, 19))	('STAT3', 'Gene', '6774', (84, 89))	('cancer', 'Disease', (276, 282))	('inhibits', 'NegReg', (20, 28))	('apoptosis', 'CPA', (60, 69))	('LINC00857', 'Gene', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cell proliferation', 'CPA', (29, 47))	('induces', 'Reg', (52, 59))	('LINC00857', 'Gene', '439990', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (120, 145))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (120, 145))	('cancer', 'Disease', (210, 216))
229667	31085800	We found that the cell proliferation, colony formation, invasion and migration were decreased after LINC00857 knockdown in EAC cell lines.	('knockdown', 'Var', (110, 119))	('EAC', 'Phenotype', 'HP:0011459', (123, 126))	('LINC00857', 'Gene', '439990', (100, 109))	('migration', 'CPA', (69, 78))	('colony formation', 'CPA', (38, 54))	('cell proliferation', 'CPA', (18, 36))	('decreased', 'NegReg', (84, 93))	('invasion', 'CPA', (56, 64))	('LINC00857', 'Gene', (100, 109))
229668	31085800	We also found that knockdown LINC00857 could induce apoptosis.	('LINC00857', 'Gene', (29, 38))	('knockdown', 'Var', (19, 28))	('induce', 'PosReg', (45, 51))	('LINC00857', 'Gene', '439990', (29, 38))	('apoptosis', 'CPA', (52, 61))
229669	31085800	Mechanistically, we found that the MET, STAT3, c-Myc and p-CREB proteins were decreased after LINC00857 knockdown.	('CREB', 'Gene', (59, 63))	('STAT3', 'Gene', '6774', (40, 45))	('LINC00857', 'Gene', '439990', (94, 103))	('c-Myc', 'Gene', '4609', (47, 52))	('CREB', 'Gene', '1385', (59, 63))	('STAT3', 'Gene', (40, 45))	('c-Myc', 'Gene', (47, 52))	('decreased', 'NegReg', (78, 87))	('MET', 'MPA', (35, 38))	('LINC00857', 'Gene', (94, 103))	('knockdown', 'Var', (104, 113))
229679	31085800	Yang et al reported that dysregulation of HNF1A-AS1 participated in esophageal tumorigenesis, knockdown of HNF1A-AS1 inhibited the proliferation and invasion of esophageal adenocarcinoma cells.	('knockdown', 'Var', (94, 103))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (161, 186))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('HNF1A-AS1', 'Gene', (107, 116))	('HNF1A-AS1', 'Gene', '283460', (107, 116))	('HNF1A-AS1', 'Gene', '283460', (42, 51))	('proliferation', 'CPA', (131, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (161, 186))	('esophageal adenocarcinoma', 'Disease', (161, 186))	('participated', 'Reg', (52, 64))	('dysregulation', 'Var', (25, 38))	('inhibited', 'NegReg', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('HNF1A-AS1', 'Gene', (42, 51))	('invasion', 'CPA', (149, 157))
229685	31085800	We found that knockdown of LINC00857 decreased cell proliferation, invasion and migration, as well as increased apoptosis in EAC cell lines.	('increased', 'PosReg', (102, 111))	('apoptosis', 'CPA', (112, 121))	('invasion', 'CPA', (67, 75))	('migration', 'CPA', (80, 89))	('LINC00857', 'Gene', '439990', (27, 36))	('knockdown', 'Var', (14, 23))	('EAC', 'Phenotype', 'HP:0011459', (125, 128))	('decreased', 'NegReg', (37, 46))	('LINC00857', 'Gene', (27, 36))	('cell proliferation', 'CPA', (47, 65))
229692	31085800	We found 19/26 cell lines have higher LINC00857 expression level more than 1 FPKM value, and OE33, an adenocarcinoma, was the highest one (Figure 1C).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('adenocarcinoma', 'Disease', (102, 116))	('expression level', 'MPA', (48, 64))	('LINC00857', 'Gene', '439990', (38, 47))	('adenocarcinoma', 'Disease', 'MESH:D000230', (102, 116))	('OE33', 'Var', (93, 97))	('LINC00857', 'Gene', (38, 47))	('higher', 'PosReg', (31, 37))
229694	31085800	To test if LINC00857 was functionally involved in EAC, we measured cell proliferation and colony formation followed by LINC00857 knockdown with siRNAs in 3 EAC cell lines, OE19, OE33 and FLO1.	('LINC00857', 'Gene', '439990', (119, 128))	('EAC', 'Phenotype', 'HP:0011459', (156, 159))	('LINC00857', 'Gene', '439990', (11, 20))	('knockdown', 'Var', (129, 138))	('LINC00857', 'Gene', (119, 128))	('LINC00857', 'Gene', (11, 20))	('cell proliferation', 'CPA', (67, 85))	('colony formation', 'CPA', (90, 106))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))
229696	31085800	The cell proliferation was performed using WST-1 assay and the result showed that the cell proliferation was decreased by more than 35% after LINC00857 knockdown at 120 h in OE19, OE33 and FLO1 cell lines (*p < 0.05, Figure 2B).	('decreased', 'NegReg', (109, 118))	('knockdown', 'Var', (152, 161))	('LINC00857', 'Gene', '439990', (142, 151))	('cell proliferation', 'CPA', (86, 104))	('LINC00857', 'Gene', (142, 151))
229698	31085800	Flow cytometry analysis indicated that the cell cycle was arrested at G1 phase after LINC00857 knockdown in OE33 cells (Figure 2E).	('knockdown', 'Var', (95, 104))	('LINC00857', 'Gene', '439990', (85, 94))	('cell cycle', 'CPA', (43, 53))	('LINC00857', 'Gene', (85, 94))
229702	31085800	We found that the cell migration was inhibited by 90% after LINC00857 knockdown in OE33 and FLO-1 cells (**p < 0.01, Figure 3A and 3B).	('LINC00857', 'Gene', '439990', (60, 69))	('knockdown', 'Var', (70, 79))	('inhibited', 'NegReg', (37, 46))	('cell migration', 'CPA', (18, 32))	('LINC00857', 'Gene', (60, 69))
229703	31085800	The cell invasion was down-regulated by 90% in OE33 and FLO-1 followed LINC00857 knockdown (**p < 0.01, Figure 3C and 3D).	('down-regulated', 'NegReg', (22, 36))	('LINC00857', 'Gene', (71, 80))	('cell invasion', 'CPA', (4, 17))	('knockdown', 'Var', (81, 90))	('FLO-1', 'Gene', (56, 61))	('LINC00857', 'Gene', '439990', (71, 80))
229706	31085800	Western blot indicated that the cleavedPARP bands (Figure 4A) occurred only after LINC00857 siRNA treatment, suggesting that inhibition of LINC00857 could induce apoptosis in these cell lines.	('PARP', 'Gene', (39, 43))	('LINC00857', 'Gene', (139, 148))	('LINC00857', 'Gene', '439990', (139, 148))	('LINC00857', 'Gene', (82, 91))	('LINC00857', 'Gene', '439990', (82, 91))	('PARP', 'Gene', '1302', (39, 43))	('apoptosis', 'CPA', (162, 171))	('inhibition', 'Var', (125, 135))
229708	31085800	In a further attempt to dissect potential molecular signaling regulated by LINC00857, we applied Western blot to identify proteins whose expression altered after LINC00857 knockdown in OE33 and FLO1 cells.	('expression', 'MPA', (137, 147))	('LINC00857', 'Gene', (75, 84))	('LINC00857', 'Gene', '439990', (162, 171))	('LINC00857', 'Gene', '439990', (75, 84))	('altered', 'Reg', (148, 155))	('LINC00857', 'Gene', (162, 171))	('knockdown', 'Var', (172, 181))	('proteins', 'Protein', (122, 130))
229709	31085800	We found that several oncogenic proteins including t-MET, p-MET, p-STAT3, c-Myc and p-CREB were decreased after LINC00857 knockdown with siRNA treated cells at 72 hrs in OE33 and FLO1 cells (Figure 4A).	('oncogenic proteins', 'MPA', (22, 40))	('decreased', 'NegReg', (96, 105))	('c-Myc', 'Gene', '4609', (74, 79))	('p-MET', 'MPA', (58, 63))	('STAT3', 'Gene', '6774', (67, 72))	('LINC00857', 'Gene', (112, 121))	('knockdown', 'Var', (122, 131))	('STAT3', 'Gene', (67, 72))	('t-MET', 'MPA', (51, 56))	('CREB', 'Gene', (86, 90))	('c-Myc', 'Gene', (74, 79))	('CREB', 'Gene', '1385', (86, 90))	('LINC00857', 'Gene', '439990', (112, 121))
229713	31085800	While, the mRNA levels of STAT3, c-Myc and CREB were either increased or not changed after LINC00857 knockdown, suggesting these proteins were regulated at post-transcriptional level.	('CREB', 'Gene', (43, 47))	('CREB', 'Gene', '1385', (43, 47))	('c-Myc', 'Gene', '4609', (33, 38))	('knockdown', 'Var', (101, 110))	('STAT3', 'Gene', '6774', (26, 31))	('LINC00857', 'Gene', (91, 100))	('STAT3', 'Gene', (26, 31))	('c-Myc', 'Gene', (33, 38))	('LINC00857', 'Gene', '439990', (91, 100))	('increased', 'PosReg', (60, 69))	('mRNA levels', 'MPA', (11, 22))
229721	31085800	We found that the cell proliferation and colony formation were decreased after LINC00857 knockdown with siRNA in EAC cells.	('EAC', 'Phenotype', 'HP:0011459', (113, 116))	('LINC00857', 'Gene', '439990', (79, 88))	('decreased', 'NegReg', (63, 72))	('knockdown', 'Var', (89, 98))	('LINC00857', 'Gene', (79, 88))	('cell proliferation', 'CPA', (18, 36))	('colony formation', 'CPA', (41, 57))
229722	31085800	The cell apoptosis was also induced upon LINC00857 knockdown, indicating LINC00857 may be involved in EAC tumor growth.	('LINC00857', 'Gene', '439990', (41, 50))	('EAC', 'Phenotype', 'HP:0011459', (102, 105))	('LINC00857', 'Gene', '439990', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('LINC00857', 'Gene', (73, 82))	('cell apoptosis', 'CPA', (4, 18))	('LINC00857', 'Gene', (41, 50))	('tumor', 'Disease', (106, 111))	('knockdown', 'Var', (51, 60))
229725	31085800	We found that the cell migration and invasion ability of EAC cells were significantly decreased after the knockdown of LINC00857, suggesting LINC00857 may be involved in the regulator of metastasis in EAC.	('invasion ability', 'CPA', (37, 53))	('LINC00857', 'Gene', '439990', (119, 128))	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('cell migration', 'CPA', (18, 32))	('LINC00857', 'Gene', '439990', (141, 150))	('LINC00857', 'Gene', (119, 128))	('knockdown', 'Var', (106, 115))	('decreased', 'NegReg', (86, 95))	('EAC', 'Phenotype', 'HP:0011459', (201, 204))	('LINC00857', 'Gene', (141, 150))
229728	31085800	LINC00857 knockdown decreased protein expression of cyclin D1 and cyclin E1 in GC cells.	('cyclin D1', 'Gene', (52, 61))	('cyclin D1', 'Gene', '595', (52, 61))	('decreased', 'NegReg', (20, 29))	('cyclin E1', 'Gene', '898', (66, 75))	('LINC00857', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))	('LINC00857', 'Gene', '439990', (0, 9))	('protein expression', 'MPA', (30, 48))	('cyclin E1', 'Gene', (66, 75))
229730	31085800	In this study, mechanistically, we found that multiple oncogenic proteins such as MET, STAT3, c-Myc and CREB were decreased upon LINC00857 knockdown in EAC cells.	('STAT3', 'Gene', (87, 92))	('c-Myc', 'Gene', '4609', (94, 99))	('LINC00857', 'Gene', (129, 138))	('knockdown', 'Var', (139, 148))	('CREB', 'Gene', (104, 108))	('MET', 'MPA', (82, 85))	('c-Myc', 'Gene', (94, 99))	('decreased', 'NegReg', (114, 123))	('CREB', 'Gene', '1385', (104, 108))	('LINC00857', 'Gene', '439990', (129, 138))	('oncogenic proteins', 'MPA', (55, 73))	('EAC', 'Phenotype', 'HP:0011459', (152, 155))	('STAT3', 'Gene', '6774', (87, 92))
229734	31085800	These results are supporting evidence that LINC00857 abrogation induced apoptosis and decreased migration and invasion ability maybe through the inhibition of MET or STAT3 signaling.	('abrogation', 'Var', (53, 63))	('LINC00857', 'Gene', (43, 52))	('STAT3', 'Gene', (166, 171))	('decreased', 'NegReg', (86, 95))	('apoptosis', 'CPA', (72, 81))	('LINC00857', 'Gene', '439990', (43, 52))	('STAT3', 'Gene', '6774', (166, 171))	('MET', 'MPA', (159, 162))
229762	30131824	For example, researches have implicated that miRNA-7a has clinical significance of high mobility group A2 in human gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (109, 114))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('miRNA-7a', 'Var', (45, 53))	('gastric cancer', 'Disease', (115, 129))
229795	30131824	The results showed that NRLMFMDA obtained the AUC of 0.9068 and 0.8239 in global and local LOOCV, respectively (see Figure 2).	('0.9068', 'Var', (53, 59))	('NRLMFMDA', 'Chemical', '-', (24, 32))	('0.8239', 'Var', (64, 70))
229797	30131824	However, HGIMD, RLSMDA, HDMP, and WBSMDA obtained the AUC of 0.8781, 0.8426, 0.8366 and 0.8030 in global LOOCV, respectively.	('0.8030', 'Var', (88, 94))	('0.8366', 'Var', (77, 83))	('HDMP', 'Chemical', '-', (24, 28))	('0.8426', 'Var', (69, 75))
229811	30131824	For example, among the differentially expressed miRNAs, miR-10b, miR-125b, miR145, miR-21, and miR-155 showed as the most consistently deregulated in breast cancer.	('miR-155', 'Gene', (95, 102))	('miR-21', 'Gene', '406991', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('deregulated', 'PosReg', (135, 146))	('breast cancer', 'Disease', (150, 163))	('miR-21', 'Gene', (83, 89))	('miR-125b', 'Var', (65, 73))	('miR-10b', 'Gene', '406903', (56, 63))	('miR-155', 'Gene', '406947', (95, 102))	('miR145', 'Gene', (75, 81))	('miR-10b', 'Gene', (56, 63))	('miR145', 'Gene', '406937', (75, 81))
229812	30131824	It is worthy noting that miR-10b, miR-125b, and miR-145, were down-regulated and the other two, miR-21 and miR-155, were up-regulated, which means that they can be treated as tumor suppressor genes or oncogenes, respectively (Iorio et al.,).	('miR-145', 'Gene', '406937', (48, 55))	('tumor', 'Disease', (175, 180))	('miR-10b', 'Gene', '406903', (25, 32))	('miR-21', 'Gene', (96, 102))	('miR-155', 'Gene', '406947', (107, 114))	('miR-125b', 'Var', (34, 42))	('up-regulated', 'PosReg', (121, 133))	('down-regulated', 'NegReg', (62, 76))	('miR-10b', 'Gene', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('miR-155', 'Gene', (107, 114))	('miR-21', 'Gene', '406991', (96, 102))	('miR-145', 'Gene', (48, 55))
229817	30131824	The estimated number of new esophageal cancer cases and deaths were 291238 and 218957, respectively.	('esophageal cancer', 'Disease', (28, 45))	('deaths', 'Disease', 'MESH:D003643', (56, 62))	('deaths', 'Disease', (56, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('291238', 'Var', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
229825	30131824	In canine B-cell lymphomas, compared with normal canine peripheral blood mononuclear cells (PBMC) and normal lymph nodes (LN), the expression of miRNA hsa-mir-19a was increased.	('lymphomas', 'Disease', 'MESH:D008223', (17, 26))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (10, 26))	('lymphomas', 'Phenotype', 'HP:0002665', (17, 26))	('miRNA hsa-mir-19a', 'Var', (145, 162))	('expression', 'MPA', (131, 141))	('increased', 'PosReg', (167, 176))	('lymphoma', 'Phenotype', 'HP:0002665', (17, 25))	('canine', 'Species', '9615', (3, 9))	('lymphomas', 'Disease', (17, 26))	('canine', 'Species', '9615', (49, 55))
229832	30131824	Moreover, hsa-mir-146a was ranked first in the top 50 and the recent research has confirmed that a functional polymorphism (rs2910164) in the miR-146a gene is associated with the risk for hepatocellular carcinoma (Xu et al.,).	('miR-146a', 'Gene', '406938', (142, 150))	('rs2910164', 'Var', (124, 133))	('mir-146a', 'Gene', (14, 22))	('rs2910164', 'Mutation', 'rs2910164', (124, 133))	('mir-146a', 'Gene', '406938', (14, 22))	('associated with', 'Reg', (159, 174))	('miR-146a', 'Gene', (142, 150))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (188, 212))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (188, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('hepatocellular carcinoma', 'Disease', (188, 212))
229839	30131824	For example, aberrant expression of miRNAs has been related with various neurological disorders (NDs) in the central nervous system such as Huntington disease, amyotrophic lateral sclerosis, schizophrenia and autism, Alzheimer disease, Parkinson's disease.	('Huntington disease', 'Disease', 'MESH:D006816', (140, 158))	('schizophrenia', 'Disease', 'MESH:D012559', (191, 204))	('autism', 'Disease', (209, 215))	("Parkinson's disease", 'Disease', (236, 255))	('Alzheimer disease', 'Phenotype', 'HP:0002511', (217, 234))	('schizophrenia', 'Phenotype', 'HP:0100753', (191, 204))	('Huntington disease', 'Disease', (140, 158))	('Alzheimer disease', 'Disease', 'MESH:D000544', (217, 234))	('Alzheimer disease', 'Disease', (217, 234))	("Parkinson's disease", 'Disease', 'MESH:D010300', (236, 255))	('related', 'Reg', (52, 59))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (160, 189))	('neurological disorders', 'Disease', (73, 95))	('aberrant expression', 'Var', (13, 32))	('autism', 'Phenotype', 'HP:0000717', (209, 215))	('autism', 'Disease', 'MESH:D001321', (209, 215))	('miRNAs', 'Protein', (36, 42))	('schizophrenia', 'Disease', (191, 204))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (160, 189))	('amyotrophic lateral sclerosis', 'Disease', (160, 189))	('neurological disorders', 'Disease', 'MESH:D009422', (73, 95))
229887	21345220	The clonal selection model of carcinogenesis implies that a random solitary cell undergoes malignant transformation, accumulates multiple mutations and subsequently acquires a survival advantage, which leads to clonal selection.	('undergoes', 'Reg', (81, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (30, 44))	('survival advantage', 'CPA', (176, 194))	('carcinogenesis', 'Disease', (30, 44))	('malignant transformation', 'CPA', (91, 115))	('mutations', 'Var', (138, 147))
229976	21345220	Survival in subgroup with high LgR5 expression in BE (n = 41, p = 0.0278, HR = 3.5145, 95% CI = 1.5050 - 8.2073, Figure 4a), adjacent EACs (n = 41, p = 0.039, HR = 2.8408, 95% CI = 1.2496 - 6.4582) and all EACs (n = 60, p = 0.0325, HR = 2.4175, 95% CI = 1.1719 - 4.9872, Figure 4b) was significantly poorer in comparison to the subgroup of patients with low expression of LgR5 (Table 1 and 2).	('high', 'Var', (26, 30))	('Survival', 'MPA', (0, 8))	('EAC', 'Phenotype', 'HP:0011459', (206, 209))	('EAC', 'Phenotype', 'HP:0011459', (134, 137))	('BE', 'Phenotype', 'HP:0100580', (50, 52))	('poorer', 'NegReg', (300, 306))	('patients', 'Species', '9606', (340, 348))	('LgR5', 'Gene', (31, 35))
229986	21345220	According to a longstanding cancer model, known as the 'clonal evolution model', tumors arise from normal cells that mutate and generate abnormal offspring that do also mutate, forming a mass of genetically varied cancer cells.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutate', 'Var', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
229995	21345220	Therefore targeting of LgR5 signalling might be a potential mechanism to abrogate this inflammation-mediated effect in tumor progression.	('tumor', 'Disease', (119, 124))	('inflammation', 'Disease', (87, 99))	('LgR5 signalling', 'Gene', (23, 38))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('targeting', 'Var', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('inflammation', 'Disease', 'MESH:D007249', (87, 99))	('abrogate', 'NegReg', (73, 81))
230009	34031756	Phase I study of liposomal irinotecan (LY01610) in patients with advanced esophageal squamous cell carcinoma This phase I trial was performed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), preliminary efficacy, and pharmacokinetics (PK) of LY01610, a novel liposome-encapsulated irinotecan, in patients with advanced esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', (74, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (375, 384))	('DLT', 'Gene', (215, 218))	('irinotecan', 'Chemical', 'MESH:D000077146', (27, 37))	('esophageal squamous cell carcinoma', 'Disease', (350, 384))	('irinotecan', 'Chemical', 'MESH:D000077146', (312, 322))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (74, 108))	('patients', 'Species', '9606', (51, 59))	('LY01610', 'Var', (273, 280))	('LY01610', 'Chemical', '-', (273, 280))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (361, 384))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (350, 384))	('patients', 'Species', '9606', (327, 335))	('DLT', 'Gene', '146059', (215, 218))	('toxicities', 'Disease', 'MESH:D064420', (203, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('LY01610', 'Chemical', '-', (39, 46))	('toxicities', 'Disease', (203, 213))
230010	34031756	In the dose-escalation stage, patients with advanced ESCC refractory or intolerant to previous chemotherapy received escalating doses of LY01610.	('patients', 'Species', '9606', (30, 38))	('LY01610', 'Chemical', '-', (137, 144))	('LY01610', 'Var', (137, 144))	('ESCC', 'Disease', (53, 57))
230012	34031756	LY01610 was administered intravenously every 2 weeks, except that the first cycle in dose escalation was 3 weeks to allow observation of DLTs.	('DLT', 'Gene', '146059', (137, 140))	('LY01610', 'Var', (0, 7))	('LY01610', 'Chemical', '-', (0, 7))	('DLT', 'Gene', (137, 140))
230017	34031756	Compared with conventional irinotecan, the PK profile of LY01610 was characterized by increased and prolonged exposure of total irinotecan and the active metabolite SN-38 in plasma.	('increased', 'PosReg', (86, 95))	('irinotecan', 'Chemical', 'MESH:D000077146', (27, 37))	('LY01610', 'Var', (57, 64))	('exposure', 'MPA', (110, 118))	('SN-38', 'Chemical', 'MESH:D000077146', (165, 170))	('LY01610', 'Chemical', '-', (57, 64))	('irinotecan', 'Chemical', 'MESH:D000077146', (128, 138))
230018	34031756	LY01610 demonstrated manageable toxicity and promising anti-tumor activity in patients with advanced ESCC.	('LY01610', 'Var', (0, 7))	('LY01610', 'Chemical', '-', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('patients', 'Species', '9606', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))	('tumor', 'Disease', (60, 65))	('toxicity', 'Disease', (32, 40))	('ESCC', 'Disease', (101, 105))
230019	34031756	Future clinical development of LY01610 as single agent or in combination with other anti-cancer agents in treating ESCC patients is warranted.	('LY01610', 'Var', (31, 38))	('LY01610', 'Chemical', '-', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('patients', 'Species', '9606', (120, 128))	('men', 'Species', '9606', (23, 26))	('ESCC patients', 'Disease', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
230042	34031756	The exclusion criteria included: (i) active systemic infections requiring intravenous antibiotics; (ii) significant cardiovascular diseases, such as myocardial infarction, unstable angina, congestive heart failure (New York Heart Association >= class II), or unstable arrhythmia within 6 months before screening; (iii) uncontrolled ascites or pleural effusions; (iv) pregnancy, lactating or refusal to use effective contraception; (v) a second malignancy within 5 years prior to screening; (vi) symptomatic brain metastasis; (vii) previous exposure to irinotecan; (viii) UGT1A1 *28 homozygous 7/7 variant.	('UGT1A1', 'Gene', '54658', (571, 577))	('congestive heart failure', 'Phenotype', 'HP:0001635', (189, 213))	('ascites', 'Disease', 'MESH:D001201', (332, 339))	('congestive heart failure', 'Disease', 'MESH:D006333', (189, 213))	('variant', 'Var', (597, 604))	('arrhythmia', 'Disease', 'MESH:D001145', (268, 278))	('irinotecan', 'Chemical', 'MESH:D000077146', (552, 562))	('arrhythmia', 'Phenotype', 'HP:0011675', (268, 278))	('viii', 'Gene', '1351', (565, 569))	('malignancy', 'Disease', (444, 454))	('arrhythmia', 'Disease', (268, 278))	('cardiovascular diseases', 'Disease', (116, 139))	('unstable angina', 'Phenotype', 'HP:0001681', (172, 187))	('pleural effusions', 'Disease', (343, 360))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (116, 139))	('ascites', 'Phenotype', 'HP:0001541', (332, 339))	('infections requiring intravenous antibiotics', 'Phenotype', 'HP:0020095', (53, 97))	('pleural effusions', 'Disease', 'MESH:D010996', (343, 360))	('viii', 'Gene', (565, 569))	('infections', 'Disease', 'MESH:D007239', (53, 63))	('infections', 'Disease', (53, 63))	('myocardial infarction', 'Disease', (149, 170))	('unstable angina', 'Disease', 'MESH:D000789', (172, 187))	('congestive heart failure', 'Disease', (189, 213))	('unstable angina', 'Disease', (172, 187))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (116, 139))	('myocardial infarction', 'Phenotype', 'HP:0001658', (149, 170))	('ascites', 'Disease', (332, 339))	('pleural effusions', 'Phenotype', 'HP:0002202', (343, 360))	('malignancy', 'Disease', 'MESH:D009369', (444, 454))	('myocardial infarction', 'Disease', 'MESH:D009203', (149, 170))	('UGT1A1', 'Gene', (571, 577))
230123	34031756	In addition, LY01610 was active in patients with pretreated advanced ESCC, with 1 case of CR and 4 cases of PR among the 24 enrolled patients.	('LY01610', 'Chemical', '-', (13, 20))	('ESCC', 'Disease', (69, 73))	('CR', 'Chemical', '-', (90, 92))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (35, 43))	('LY01610', 'Var', (13, 20))
230127	34031756	Treatment-related adverse events were generally manageable with appropriate supportive care or dose interruptions or reductions, indicating that LY01610 was well tolerated in patients with ESCC.	('LY01610', 'Var', (145, 152))	('LY01610', 'Chemical', '-', (145, 152))	('ESCC', 'Disease', (189, 193))	('patients', 'Species', '9606', (175, 183))	('men', 'Species', '9606', (5, 8))
230133	34031756	Comparing the PK of SN-38 in our present study with that from a phase 1 study evaluating conventional irinotecan at 180 mg/m2, Cmax was significantly lowered with LY01610 at the MTD (90 mg/m2) (Mean: 6.45 vs 26.2 ng/mL), meanwhile, longer T1/2 (39.45 vs 19.7 h) and higher AUCinf (475.81 vs 367.6 ng/mL*h) were observed.	('lowered', 'NegReg', (150, 157))	('LY01610', 'Var', (163, 170))	('LY01610', 'Chemical', '-', (163, 170))	('Cmax', 'MPA', (127, 131))	('irinotecan', 'Chemical', 'MESH:D000077146', (102, 112))	('SN-38', 'Chemical', 'MESH:D000077146', (20, 25))	('T1/2', 'MPA', (239, 243))	('AUCinf', 'MPA', (273, 279))
230134	34031756	Notably, the AUCinf of SN-38 with LY01610 at 60 mg/m2 (455.42 ng/mL*h, listed in Table 4) was already higher than that achieved with 180 mg/m2 conventional irinotecan, suggesting equivalent or improved efficacy with lower toxicities.	('LY01610', 'Var', (34, 41))	('irinotecan', 'Chemical', 'MESH:D000077146', (156, 166))	('LY01610', 'Chemical', '-', (34, 41))	('AUCinf', 'MPA', (13, 19))	('SN-38', 'Chemical', 'MESH:D000077146', (23, 28))	('higher', 'PosReg', (102, 108))	('toxicities', 'Disease', (222, 232))	('toxicities', 'Disease', 'MESH:D064420', (222, 232))
230135	34031756	Indeed, comparing the safety profile with single-agent irinotecan at 180 mg/m2 administered every 14 days in a phase 2 clinical trial, LY01610 at 60 mg/m2 was better tolerated with a numerically lower incidence of grade 3 or 4 neutropenia (14.3% vs 23.3%) and thrombocytopenia (0% vs 3.3%), although the differences were not statistically tested.	('lower', 'NegReg', (195, 200))	('thrombocytopenia', 'Disease', (260, 276))	('neutropenia', 'Disease', 'MESH:D009503', (227, 238))	('neutropenia', 'Phenotype', 'HP:0001875', (227, 238))	('LY01610', 'Var', (135, 142))	('LY01610', 'Chemical', '-', (135, 142))	('irinotecan', 'Chemical', 'MESH:D000077146', (55, 65))	('grade 3', 'Disease', (214, 221))	('thrombocytopenia', 'Disease', 'MESH:D013921', (260, 276))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (260, 276))	('neutropenia', 'Disease', (227, 238))
230141	34031756	However, it is noteworthy that the suspension of the current study during the COVID-19 pandemic in early 2020 might have caused an underestimation of the PFS, since two patients who responded to LY01610 missed the scheduled study treatment during the suspension.	('LY01610', 'Var', (195, 202))	('LY01610', 'Chemical', '-', (195, 202))	('patients', 'Species', '9606', (169, 177))	('COVID-19', 'Disease', 'MESH:C000657245', (78, 86))	('COVID-19', 'Disease', (78, 86))	('men', 'Species', '9606', (235, 238))
230143	34031756	The potential of LY01610 to achieve robust anti-tumor activity at a dose level significantly lower than the MTD suggested a wide therapeutic index.	('tumor', 'Disease', (48, 53))	('LY01610', 'Chemical', '-', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('LY01610', 'Var', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
230145	34031756	In the era of immunotherapy, three randomized phase 3 trials with immune checkpoint inhibitors have established anti-PD-1 antibodies as the standard second-line regimen for advanced ESCC, and thus changed the management of this devastating malignancy.	('men', 'Species', '9606', (165, 168))	('malignancy', 'Disease', 'MESH:D009369', (240, 250))	('antibodies', 'Var', (122, 132))	('changed', 'Reg', (197, 204))	('malignancy', 'Disease', (240, 250))	('men', 'Species', '9606', (215, 218))	('ESCC', 'Disease', (182, 186))	('PD-1', 'Gene', (117, 121))	('PD-1', 'Gene', '5133', (117, 121))
230150	34031756	In conclusion, LY01610 was safe and effective in patients with advanced ESCC refractory or intolerant to previous chemotherapy in our phase 1 study, with slow but prolonged release of total irinotecan and SN-38 as revealed by PK studies.	('SN-38', 'Chemical', 'MESH:D000077146', (205, 210))	('LY01610', 'Var', (15, 22))	('LY01610', 'Chemical', '-', (15, 22))	('patients', 'Species', '9606', (49, 57))	('ESCC', 'Disease', (72, 76))	('irinotecan', 'Chemical', 'MESH:D000077146', (190, 200))
230151	34031756	LY01610 warrants further validation in randomized trials as single agent or in combination with other anti-cancer agents in treating ESCC patients.	('LY01610', 'Var', (0, 7))	('LY01610', 'Chemical', '-', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ESCC', 'Disease', (133, 137))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('patients', 'Species', '9606', (138, 146))
230155	33319855	The 5-year overall survival and disease-free survival for patients with OLNMs were significantly worse than those of IHC-negative patients (P < 0.001), but similar to those of the pN1 patients (P > 0.05).	('pN1', 'Gene', (180, 183))	('overall survival', 'CPA', (11, 27))	('pN1', 'Gene', '5270', (180, 183))	('patients', 'Species', '9606', (184, 192))	('worse', 'NegReg', (97, 102))	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (58, 66))	('disease-free survival', 'CPA', (32, 53))	('OLNMs', 'Var', (72, 77))
230157	33319855	IHC staining in pN0 ESCC patients might help to identify patients at high risk of death after resection, and ITCs in the lymph nodes appear to have a prognostic value equal to that of micrometastases.	('metastases', 'Disease', (189, 199))	('death', 'Disease', 'MESH:D003643', (82, 87))	('death', 'Disease', (82, 87))	('metastases', 'Disease', 'MESH:D009362', (189, 199))	('patients', 'Species', '9606', (57, 65))	('pN0', 'Var', (16, 19))	('ESCC', 'Disease', (20, 24))	('patients', 'Species', '9606', (25, 33))
230231	33319855	The detection of OLNMs in patients with pN0 ESCC might be a useful adjunct to the current TNM stage for ESCC.	('TNM', 'Gene', (90, 93))	('TNM', 'Gene', '10178', (90, 93))	('pN0', 'Var', (40, 43))	('patients', 'Species', '9606', (26, 34))
230360	32653032	Circular RNA circNTRK2 facilitates the progression of esophageal squamous cell carcinoma through up-regulating NRIP1 expression via miR-140-3p Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent gastrointestinal malignancies with high mortality.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('mortality', 'Disease', 'MESH:D003643', (254, 263))	('malignancies', 'Disease', 'MESH:D009369', (231, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('squamous cell carcinoma', 'Disease', (154, 177))	('malignancies', 'Disease', (231, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('up-regulating', 'PosReg', (97, 110))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 88))	('NRIP1', 'Gene', '8204', (111, 116))	('esophageal squamous cell carcinoma', 'Disease', (54, 88))	('expression', 'MPA', (117, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('mortality', 'Disease', (254, 263))	('NRIP1', 'Gene', (111, 116))	('miR-140-3p', 'Var', (132, 142))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 177))	('facilitates', 'PosReg', (23, 34))
230370	32653032	Mechanistic assays disclosed that circNTRK2 could act as a sponge for miR-140-3p to abate its suppression on target NRIP1 expression.	('miR-140-3p', 'Var', (70, 80))	('miR-140-3p', 'Chemical', '-', (70, 80))	('NRIP1', 'Gene', '8204', (116, 121))	('abate', 'NegReg', (84, 89))	('suppression', 'MPA', (94, 105))	('NTRK2', 'Gene', (38, 43))	('NTRK2', 'Gene', '4915', (38, 43))	('NRIP1', 'Gene', (116, 121))
230371	32653032	Moreover, miR-140-3p-induced inhibitory effects on ESCC cell malignant phenotypes were attenuated by the overexpression of circNTRK2.	('inhibitory effects', 'MPA', (29, 47))	('miR-140-3p', 'Chemical', '-', (10, 20))	('attenuated', 'NegReg', (87, 97))	('miR-140-3p-induced', 'Var', (10, 28))	('NTRK2', 'Gene', (127, 132))	('ESCC', 'Disease', (51, 55))	('NTRK2', 'Gene', '4915', (127, 132))
230372	32653032	In addition, depletion of NRIP1 impeded cell proliferation, invasion and EMT, while enhanced apoptosis.	('impeded', 'NegReg', (32, 39))	('invasion', 'CPA', (60, 68))	('EMT', 'CPA', (73, 76))	('NRIP1', 'Gene', (26, 31))	('depletion', 'Var', (13, 22))	('NRIP1', 'Gene', '8204', (26, 31))	('enhanced', 'PosReg', (84, 92))	('apoptosis', 'CPA', (93, 102))	('cell proliferation', 'CPA', (40, 58))
230373	32653032	Furthermore, silencing of circNTRK2 suppressed cell proliferation and invasion through regulating NRIP1 expression.	('suppressed', 'NegReg', (36, 46))	('NRIP1', 'Gene', '8204', (98, 103))	('NTRK2', 'Gene', (30, 35))	('expression', 'MPA', (104, 114))	('NTRK2', 'Gene', '4915', (30, 35))	('NRIP1', 'Gene', (98, 103))	('regulating', 'Reg', (87, 97))	('invasion', 'CPA', (70, 78))	('silencing', 'Var', (13, 22))	('cell proliferation', 'CPA', (47, 65))
230374	32653032	Also, knockdown of circNTRK2 slowed ESCC tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('NTRK2', 'Gene', (23, 28))	('tumor', 'Disease', (41, 46))	('NTRK2', 'Gene', '4915', (23, 28))	('knockdown', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('slowed', 'NegReg', (29, 35))	('ESCC', 'Disease', (36, 40))
230392	32653032	High circNTRIK2 was associated with TNM stage, lymph node metastasis and poor prognosis.	('associated', 'Reg', (20, 30))	('TNM', 'Gene', (36, 39))	('lymph node metastasis', 'CPA', (47, 68))	('High circNTRIK2', 'Var', (0, 15))	('TNM', 'Gene', '10178', (36, 39))
230393	32653032	Functionally, knockdown of circNTRK2 repressed ESCC cell proliferation, invasion and EMT in vitro, and slowed tumor growth in vivo.	('NTRK2', 'Gene', '4915', (31, 36))	('ESCC', 'Disease', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('slowed', 'NegReg', (103, 109))	('NTRK2', 'Gene', (31, 36))	('knockdown', 'Var', (14, 23))	('invasion', 'CPA', (72, 80))	('EMT in vitro', 'CPA', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
230416	32653032	The sequences of siRNAs were listed as follows: si-circ #1, 5'- GCATGAAAGGTGCAAACCCAA - 3'; si-circ #2, 5'- GGCATGAAAGGTGCAAACCCA - 3'; si-circ #3, GTTTGGCATGAAAGGTGCAAA; si-NRIP1, 5'- GAGGAUCAGAACUUUAACATT-3'; si-NC, 5'-UUCUCCGAACGUGUCACGUTT-3'.	('si-NC', 'Var', (211, 216))	('NRIP1', 'Gene', (174, 179))	('NRIP1', 'Gene', '8204', (174, 179))
230430	32653032	After blocking in nonfat milk overnight at 4  C, the membranes were incubated with primary antibody against E-cadherin (1:500, Abcam, Cambridge, MA, USA), vimentin (1:1000, Abcam), Cleaved PARP (1:1000; Abcam), Cleaved caspase-3 (1:500, Abcam), NRIP1 (1:500, Abcam), and GAPDH (1:10,000, Abcam) overnight at 4  C, and then were probed with HRP-conjugated secondary antibody for 2 h at room temprature.	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('1:500', 'Var', (252, 257))	('vimentin', 'Gene', (155, 163))	('GAPDH', 'Gene', '2597', (271, 276))	('NRIP1', 'Gene', '8204', (245, 250))	('caspase-3', 'Gene', '836', (219, 228))	('PARP', 'Gene', '1302', (189, 193))	('GAPDH', 'Gene', (271, 276))	('PARP', 'Gene', (189, 193))	('NRIP1', 'Gene', (245, 250))	('caspase-3', 'Gene', (219, 228))	('vimentin', 'Gene', '7431', (155, 163))
230438	32653032	To evaluate the direct binding between miR-140-3p and circNTRK2, the wild type or mutant sequences containing the binding sites of miR-140-3p in circNTRK2 were inserted into a pmirGLO vector (Promega Corporation, Madison, WI, USA), named as circNTRK2-wt and circNTRK2-mut, respectively.	('miR-140-3p', 'Gene', (131, 141))	('NTRK2', 'Gene', (245, 250))	('NTRK2', 'Gene', '4915', (262, 267))	('miR-140-3p', 'Chemical', '-', (131, 141))	('NTRK2', 'Gene', '4915', (149, 154))	('NTRK2', 'Gene', '4915', (245, 250))	('NTRK2', 'Gene', (149, 154))	('NTRK2', 'Gene', (58, 63))	('miR-140-3p', 'Chemical', '-', (39, 49))	('NTRK2', 'Gene', (262, 267))	('NTRK2', 'Gene', '4915', (58, 63))	('mutant', 'Var', (82, 88))
230440	32653032	Similar procedures were conducted to examine the binding between miR-140-3p and NRIP1.	('miR-140-3p', 'Var', (65, 75))	('miR-140-3p', 'Chemical', '-', (65, 75))	('binding', 'Interaction', (49, 56))	('NRIP1', 'Gene', (80, 85))	('NRIP1', 'Gene', '8204', (80, 85))
230442	32653032	Magna RNA immunoprecipitation kit (Millipore, Billerica, MA, USA) was used to validate the binding between circNTRK2 and miR-140-3p.	('miR-140-3p', 'Chemical', '-', (121, 131))	('NTRK2', 'Gene', '4915', (111, 116))	('kit', 'Gene', (30, 33))	('binding', 'Interaction', (91, 98))	('NTRK2', 'Gene', (111, 116))	('miR-140-3p', 'Var', (121, 131))	('kit', 'Gene', '3815', (30, 33))
230446	32653032	ESCC cells were transfected with the wild type biotin-labelled miR-140-3p (Bio-miR-140-3p-wt), mutant biotin-labeled miR-140-3p (Bio-miR-140-3p-mut), and non-specific negative control (Bio-miR-NC).	('miR', 'Gene', '22877', (79, 82))	('miR-140-3p', 'Chemical', '-', (63, 73))	('miR', 'Gene', '22877', (117, 120))	('miR-140-3p', 'Chemical', '-', (117, 127))	('miR', 'Gene', (133, 136))	('biotin', 'Chemical', 'MESH:D001710', (102, 108))	('miR', 'Gene', (189, 192))	('miR', 'Gene', '22877', (133, 136))	('miR', 'Gene', (79, 82))	('miR', 'Gene', (63, 66))	('mutant', 'Var', (95, 101))	('miR', 'Gene', (117, 120))	('miR-140-3p', 'Chemical', '-', (133, 143))	('miR', 'Gene', '22877', (63, 66))	('miR-140-3p', 'Chemical', '-', (79, 89))	('miR', 'Gene', '22877', (189, 192))	('biotin', 'Chemical', 'MESH:D001710', (47, 53))
230461	32653032	As shown in Table 1, high circNTRK2 expression was demonstrated to be correlated with advanced TNM stage and lymph node metastasis.	('TNM', 'Gene', (95, 98))	('NTRK2', 'Gene', (30, 35))	('TNM', 'Gene', '10178', (95, 98))	('lymph node metastasis', 'CPA', (109, 130))	('high', 'Var', (21, 25))	('NTRK2', 'Gene', '4915', (30, 35))	('expression', 'MPA', (36, 46))	('correlated', 'Reg', (70, 80))
230469	32653032	Colony formation assay further verified the anti-proliferative roles of circNTRK2 knockdown in Eca-109 and KYSE-150 cells and the pro-proliferative effects of circNTRK2 up-regulation in EC-9706 cells (Fig.	('NTRK2', 'Gene', '4915', (76, 81))	('NTRK2', 'Gene', '4915', (163, 168))	('EC-9706', 'CellLine', 'CVCL:E307', (186, 193))	('anti-proliferative', 'CPA', (44, 62))	('knockdown', 'Var', (82, 91))	('up-regulation', 'PosReg', (169, 182))	('KYSE-150', 'CellLine', 'CVCL:1348', (107, 115))	('NTRK2', 'Gene', (76, 81))	('NTRK2', 'Gene', (163, 168))
230470	32653032	As demonstrated by transwell assay, silencing of circNTRK2 led to a decline of invasive ability in Eca-109 and KYSE-150 cells, while enforced expression of circNTRK2 resulted in an enhancement of invasion in EC-9706 cells (Fig.	('KYSE-150', 'CellLine', 'CVCL:1348', (111, 119))	('NTRK2', 'Gene', (53, 58))	('NTRK2', 'Gene', (160, 165))	('invasion', 'CPA', (196, 204))	('NTRK2', 'Gene', '4915', (53, 58))	('EC-9706', 'CellLine', 'CVCL:E307', (208, 215))	('silencing', 'Var', (36, 45))	('NTRK2', 'Gene', '4915', (160, 165))	('decline', 'NegReg', (68, 75))	('invasive ability', 'CPA', (79, 95))	('enhancement', 'PosReg', (181, 192))
230473	32653032	Consistently, knockdown of circNTRK2 in Eca-109 and KYSE-150 cells significantly enhanced the expression of apoptosis-related protein including cleaved PARP and cleaved caspase-3 (Fig.	('apoptosis-related protein', 'Gene', (108, 133))	('enhanced', 'PosReg', (81, 89))	('apoptosis-related protein', 'Gene', '23591', (108, 133))	('caspase-3', 'Gene', (169, 178))	('NTRK2', 'Gene', '4915', (31, 36))	('PARP', 'Gene', '1302', (152, 156))	('caspase-3', 'Gene', '836', (169, 178))	('NTRK2', 'Gene', (31, 36))	('knockdown', 'Var', (14, 23))	('expression', 'MPA', (94, 104))	('PARP', 'Gene', (152, 156))	('cleaved', 'MPA', (144, 151))	('KYSE-150', 'CellLine', 'CVCL:1348', (52, 60))
230474	32653032	Taken together, these results indicated that knockdown of circNTRK2 inhibited ESCC cell proliferation and invasion, and induced apoptosis.	('NTRK2', 'Gene', '4915', (62, 67))	('inhibited', 'NegReg', (68, 77))	('knockdown', 'Var', (45, 54))	('induced', 'Reg', (120, 127))	('invasion', 'CPA', (106, 114))	('NTRK2', 'Gene', (62, 67))	('apoptosis', 'CPA', (128, 137))	('ESCC cell proliferation', 'CPA', (78, 101))
230481	32653032	According to the data from dbDEMC 2.0 (https://www.picb.ac.cn/dbDEMC/search.html), decreased expression of miR-140-3p was observed in esophagus cancer.	('miR-140-3p', 'Chemical', '-', (107, 117))	('decreased', 'NegReg', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('expression', 'MPA', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('miR-140-3p', 'Var', (107, 117))
230484	32653032	Moreover, silencing of circNTRK2 promoted the level of miR-140-3p, while overexpression of circNTRK2 reduced miR-140-3p expression in Eca-109 and KYSE-150 cells (Fig.	('promoted', 'PosReg', (33, 41))	('NTRK2', 'Gene', '4915', (27, 32))	('miR-140-3p', 'Chemical', '-', (55, 65))	('NTRK2', 'Gene', (95, 100))	('NTRK2', 'Gene', (27, 32))	('level of miR-140-3p', 'MPA', (46, 65))	('NTRK2', 'Gene', '4915', (95, 100))	('miR-140-3p', 'Chemical', '-', (109, 119))	('KYSE-150', 'CellLine', 'CVCL:1348', (146, 154))	('silencing', 'Var', (10, 19))
230485	32653032	Nevertheless, circNTRK2 expression was unchanged due to miR-140-3p up-regulation or knockdown (Fig.	('NTRK2', 'Gene', '4915', (18, 23))	('miR-140-3p', 'Var', (56, 66))	('expression', 'MPA', (24, 34))	('miR-140-3p', 'Chemical', '-', (56, 66))	('knockdown', 'Var', (84, 93))	('up-regulation', 'PosReg', (67, 80))	('NTRK2', 'Gene', (18, 23))
230488	32653032	RNA pull-down experiments clarified that in contrast to Bio-miR-NC, Bio-miR-140-3p-wt captured more circNTRK2 in ESCC cells, but the this effect was disappeared when the binding sites on circNTRK2 were mutated (Fig.	('mutated', 'Var', (202, 209))	('miR', 'Gene', '22877', (72, 75))	('NTRK2', 'Gene', (191, 196))	('miR', 'Gene', (60, 63))	('miR-140-3p', 'Chemical', '-', (72, 82))	('NTRK2', 'Gene', '4915', (104, 109))	('miR', 'Gene', '22877', (60, 63))	('NTRK2', 'Gene', '4915', (191, 196))	('miR', 'Gene', (72, 75))	('NTRK2', 'Gene', (104, 109))
230490	32653032	Also, the scatter plot revealed that the level of miR-140-3p was negatively correlated with circNTRK2 expression in ESCC tissues (Fig.	('NTRK2', 'Gene', '4915', (96, 101))	('negatively', 'NegReg', (65, 75))	('miR-140-3p', 'Var', (50, 60))	('miR-140-3p', 'Chemical', '-', (50, 60))	('NTRK2', 'Gene', (96, 101))
230492	32653032	To gain insight into the functions of miR-140-3p, and further address whether it was associated with circNTRK2 in ESCC, Eca-109 and KYSE-150 cells were transfected with miR-140-3p alone or co-transfected with miR-140-3p and circNTRK2.	('NTRK2', 'Gene', (228, 233))	('KYSE-150', 'CellLine', 'CVCL:1348', (132, 140))	('ESCC', 'Disease', (114, 118))	('NTRK2', 'Gene', (105, 110))	('miR-140-3p', 'Var', (169, 179))	('miR-140-3p', 'Chemical', '-', (169, 179))	('NTRK2', 'Gene', '4915', (105, 110))	('NTRK2', 'Gene', '4915', (228, 233))	('miR-140-3p', 'Chemical', '-', (209, 219))	('miR-140-3p', 'Chemical', '-', (38, 48))
230493	32653032	4A, the level of miR-140-3p was significantly up-regulated in Eca-109 and KYSE-109 cells transfected with miR-140-3p, while introduction of circNTRK2 reversed this promotion effect.	('miR-140-3p', 'Chemical', '-', (17, 27))	('miR-140-3p', 'Chemical', '-', (106, 116))	('NTRK2', 'Gene', '4915', (144, 149))	('up-regulated', 'PosReg', (46, 58))	('NTRK2', 'Gene', (144, 149))	('miR-140-3p', 'MPA', (17, 27))	('KYSE-109', 'CellLine', 'CVCL:H602', (74, 82))	('miR-140-3p', 'Var', (106, 116))	('level', 'MPA', (8, 13))
230494	32653032	Functionally, overexpression of miR-140-3p significantly repressed cell viability (Fig.	('miR-140-3p', 'Var', (32, 42))	('miR-140-3p', 'Chemical', '-', (32, 42))	('repressed', 'NegReg', (57, 66))	('cell viability', 'CPA', (67, 81))	('overexpression', 'PosReg', (14, 28))
230496	32653032	Analogously, miR-140-3p mimic dramatically inhibited cell invasion, while this effect were neutralized after co-transfection with circNTRK2 (Fig.	('inhibited', 'NegReg', (43, 52))	('NTRK2', 'Gene', (134, 139))	('cell invasion', 'CPA', (53, 66))	('NTRK2', 'Gene', '4915', (134, 139))	('miR-140-3p mimic', 'Var', (13, 29))	('miR-140-3p', 'Chemical', '-', (13, 23))
230497	32653032	Moreover, E-cadherin expression was increased and Vimentin expression was declined in Eca-109 and KYSE-150 cells with miR-140-3p overexpression, however, these changes were greatly reversed after co-transfection with circNTRK2 and miR-140-3p (Fig.	('E-cadherin', 'Gene', '999', (10, 20))	('NTRK2', 'Gene', '4915', (221, 226))	('overexpression', 'PosReg', (129, 143))	('miR-140-3p', 'Var', (118, 128))	('declined', 'NegReg', (74, 82))	('expression', 'MPA', (21, 31))	('KYSE-150', 'CellLine', 'CVCL:1348', (98, 106))	('miR-140-3p', 'Chemical', '-', (118, 128))	('increased', 'PosReg', (36, 45))	('Vimentin', 'Gene', (50, 58))	('expression', 'MPA', (59, 69))	('miR-140-3p', 'Chemical', '-', (231, 241))	('Vimentin', 'Gene', '7431', (50, 58))	('NTRK2', 'Gene', (221, 226))	('E-cadherin', 'Gene', (10, 20))
230498	32653032	In addition, overexpression of miR-140-3p resulted in an increase of apoptotic rate in Eca-109 and KYSE-109 cells, whereas miR-140-3p-induced apoptosis was relieved following the up-regulation of circNTRK2 (Fig.	('NTRK2', 'Gene', (200, 205))	('miR-140-3p', 'Var', (31, 41))	('miR-140-3p', 'Chemical', '-', (31, 41))	('KYSE-109', 'CellLine', 'CVCL:H602', (99, 107))	('NTRK2', 'Gene', '4915', (200, 205))	('apoptotic rate', 'CPA', (69, 83))	('overexpression', 'PosReg', (13, 27))	('increase', 'PosReg', (57, 65))	('miR-140-3p', 'Chemical', '-', (123, 133))	('up-regulation', 'PosReg', (179, 192))
230503	32653032	The result showed that only NRIP1 expression was declined in both Eca-109 and KYSE-150 cells transfected with miR-140-3p (Fig.	('miR-140-3p', 'Var', (110, 120))	('expression', 'MPA', (34, 44))	('NRIP1', 'Gene', (28, 33))	('miR-140-3p', 'Chemical', '-', (110, 120))	('KYSE-150', 'CellLine', 'CVCL:1348', (78, 86))	('NRIP1', 'Gene', '8204', (28, 33))	('declined', 'NegReg', (49, 57))
230505	32653032	Western blot assays revealed that overexpression of miR-140-3p repressed the protein level of NRIP1 in Eca-109 and KYSE-150 cells (Fig.	('miR-140-3p', 'Var', (52, 62))	('KYSE-150', 'CellLine', 'CVCL:1348', (115, 123))	('miR-140-3p', 'Chemical', '-', (52, 62))	('NRIP1', 'Gene', (94, 99))	('protein level', 'MPA', (77, 90))	('NRIP1', 'Gene', '8204', (94, 99))
230506	32653032	5D, the complementary binding sites between 3'UTR of NTRP1 and miR-140-3p were predicted in two sites (893-900 and 3086-3092).	('893-900', 'Var', (103, 110))	('3086-3092', 'Var', (115, 124))	('miR-140-3p', 'Chemical', '-', (63, 73))	('NTRP1', 'Gene', (53, 58))	('binding', 'Interaction', (22, 29))	('miR-140-3p', 'Var', (63, 73))
230507	32653032	Dual-luciferase reporter assay demonstrated that miR-140-3p mimic significantly decreased the luciferase activity of NRIP1-wt reporter in Eca-109 and KYSE-150 cells.	('miR-140-3p mimic', 'Var', (49, 65))	('NRIP1', 'Gene', (117, 122))	('miR-140-3p', 'Chemical', '-', (49, 59))	('activity', 'MPA', (105, 113))	('decreased', 'NegReg', (80, 89))	('KYSE-150', 'CellLine', 'CVCL:1348', (150, 158))	('NRIP1', 'Gene', '8204', (117, 122))	('luciferase', 'Enzyme', (94, 104))
230511	32653032	Besides, a negative correlation between NRIP1 and miR-140-3p was observed in esophageal carcinoma by using starBase Pan-Cancer Analysis (Fig.	('Cancer', 'Disease', (120, 126))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (77, 97))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (77, 97))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('miR-140-3p', 'Var', (50, 60))	('negative', 'NegReg', (11, 19))	('NRIP1', 'Gene', '8204', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('miR-140-3p', 'Chemical', '-', (50, 60))	('NRIP1', 'Gene', (40, 45))	('esophageal carcinoma', 'Disease', (77, 97))
230519	32653032	Consistently, silencing of NRIP1 lead to an increase of cleaved PARP, cleaved caspase-3 and E-cadherin expression, while a decrease of Vimentin expression (Fig.	('silencing', 'Var', (14, 23))	('PARP', 'Gene', (64, 68))	('decrease', 'NegReg', (123, 131))	('E-cadherin', 'Gene', (92, 102))	('NRIP1', 'Gene', (27, 32))	('caspase-3', 'Gene', (78, 87))	('E-cadherin', 'Gene', '999', (92, 102))	('Vimentin', 'Gene', (135, 143))	('increase', 'PosReg', (44, 52))	('Vimentin', 'Gene', '7431', (135, 143))	('NRIP1', 'Gene', '8204', (27, 32))	('PARP', 'Gene', '1302', (64, 68))	('caspase-3', 'Gene', '836', (78, 87))	('cleaved', 'MPA', (56, 63))
230520	32653032	These data indicated that knockdown of NRIP1 exerted a tumor-suppressive effect in ESCC in vitro.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('NRIP1', 'Gene', '8204', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('knockdown', 'Var', (26, 35))	('ESCC', 'Disease', (83, 87))	('NRIP1', 'Gene', (39, 44))
230521	32653032	To further confirm the detailed mechanism of circNTRK2 in ESCC, rescue experiments were performed in Eca-109 cells by transfection with si-circ #2 or si-circ #2 + NRIP1.	('NRIP1', 'Gene', '8204', (163, 168))	('si-circ #2', 'Var', (136, 146))	('NTRK2', 'Gene', '4915', (49, 54))	('NRIP1', 'Gene', (163, 168))	('NTRK2', 'Gene', (49, 54))
230526	32653032	7A, tumor growth was significantly slowed down by the knockdown of circNTRK2.	('tumor', 'Disease', (4, 9))	('NTRK2', 'Gene', (71, 76))	('knockdown', 'Var', (54, 63))	('slowed down', 'NegReg', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('NTRK2', 'Gene', '4915', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
230529	32653032	Moreover, silencing of circNTRK2 led to a down-regulation of NRIP1 protein level (Fig.	('NTRK2', 'Gene', '4915', (27, 32))	('NRIP1', 'Gene', '8204', (61, 66))	('NTRK2', 'Gene', (27, 32))	('down-regulation', 'NegReg', (42, 57))	('NRIP1', 'Gene', (61, 66))	('protein level', 'MPA', (67, 80))	('silencing', 'Var', (10, 19))
230536	32653032	For example, hsa_circ_0006948 was up-regulated in ESCC, and induced HMGA2 expression to facilitate ESCC progression via miR-490-3p.	('up-regulated', 'PosReg', (34, 46))	('hsa_circ_0006948', 'Var', (13, 29))	('miR', 'Gene', (120, 123))	('HMGA2', 'Gene', '8091', (68, 73))	('ESCC', 'Disease', (99, 103))	('facilitate', 'PosReg', (88, 98))	('HMGA2', 'Gene', (68, 73))	('miR', 'Gene', '22877', (120, 123))	('ESCC', 'Disease', (50, 54))
230537	32653032	Hsa-circ_0000654 expression was increased in ESCC tissues, and knockdown of circ_0000654 repressed cell growth and metastasis through miR-149-5p/STAT3 axis.	('miR-149', 'Gene', (134, 141))	('miR-149', 'Gene', '406941', (134, 141))	('STAT3', 'Gene', (145, 150))	('expression', 'MPA', (17, 27))	('circ_0000654', 'Var', (76, 88))	('repressed', 'PosReg', (89, 98))	('ESCC', 'Disease', (45, 49))	('Hsa-circ_0000654', 'Gene', (0, 16))	('increased', 'PosReg', (32, 41))	('knockdown', 'Var', (63, 72))	('STAT3', 'Gene', '6774', (145, 150))
230541	32653032	Moreover, high circNTRK2 expression was associated with advanced TNM stage, lymph node metastasis and poor prognosis.	('NTRK2', 'Gene', (19, 24))	('lymph node metastasis', 'CPA', (76, 97))	('TNM', 'Gene', '10178', (65, 68))	('expression', 'MPA', (25, 35))	('NTRK2', 'Gene', '4915', (19, 24))	('advanced', 'CPA', (56, 64))	('high', 'Var', (10, 14))	('TNM', 'Gene', (65, 68))	('associated', 'Reg', (40, 50))
230548	32653032	On the basis of the prediction from bioinformatic tools and the data from luciferase reporter, RIP and RNA pull-down assays, miR-140-3p was confirmed as a direct target of circNTRK2.	('miR-140-3p', 'Var', (125, 135))	('NTRK2', 'Gene', '4915', (176, 181))	('NTRK2', 'Gene', (176, 181))	('miR-140-3p', 'Chemical', '-', (125, 135))
230549	32653032	MiR-140-3p was previously demonstrated as a tumor-suppressor in some types of human malignancies, such as squamous cell lung cancer, breast cancer, hepatocellular carcinoma and cervical cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (148, 172))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Disease', (44, 49))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('breast cancer', 'Disease', (133, 146))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (106, 131))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (148, 172))	('MiR-140-3p', 'Var', (0, 10))	('squamous cell lung cancer', 'Disease', (106, 131))	('cancer', 'Disease', (125, 131))	('human', 'Species', '9606', (78, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (140, 146))	('hepatocellular carcinoma', 'Disease', (148, 172))	('MiR-140-3p', 'Chemical', '-', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('cancer', 'Disease', (186, 192))	('malignancies', 'Disease', (84, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
230551	32653032	Functionally, overexpression of miR-140-3p repressed cell proliferation and invasion, and promoted apoptosis, suggesting the anti-tumor effect of miR-140-3p in ESCC.	('ESCC', 'Disease', (160, 164))	('overexpression', 'PosReg', (14, 28))	('miR-140-3p', 'Var', (146, 156))	('miR-140-3p', 'Var', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('apoptosis', 'CPA', (99, 108))	('miR-140-3p', 'Chemical', '-', (146, 156))	('promoted', 'PosReg', (90, 98))	('miR-140-3p', 'Chemical', '-', (32, 42))	('repressed', 'NegReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cell proliferation', 'CPA', (53, 71))	('tumor', 'Disease', (130, 135))	('invasion', 'CPA', (76, 84))
230552	32653032	However, miR-140-3p-induced suppression of cell proliferation and invasion was evidently reversed following the introduction of circNTRK2.	('suppression', 'NegReg', (28, 39))	('miR-140-3p', 'Chemical', '-', (9, 19))	('NTRK2', 'Gene', '4915', (132, 137))	('miR-140-3p-induced', 'Var', (9, 27))	('invasion', 'CPA', (66, 74))	('cell proliferation', 'CPA', (43, 61))	('NTRK2', 'Gene', (132, 137))
230559	32653032	In our study, NRIP1 was verified as a target of miR-140-3p in ESCC cells, and NRIP1 was highly expressed in ESCC tissues.	('miR-140-3p', 'Chemical', '-', (48, 58))	('NRIP1', 'Gene', (14, 19))	('NRIP1', 'Gene', '8204', (78, 83))	('NRIP1', 'Gene', '8204', (14, 19))	('NRIP1', 'Gene', (78, 83))	('miR-140-3p', 'Var', (48, 58))
230563	32653032	Loss-of-function experiments revealed that silencing of NRIP1 suppressed cell proliferation and invasion, but facilitated apoptosis in ESCC.	('ESCC', 'Disease', (135, 139))	('apoptosis', 'CPA', (122, 131))	('NRIP1', 'Gene', (56, 61))	('silencing', 'Var', (43, 52))	('suppressed', 'NegReg', (62, 72))	('invasion', 'CPA', (96, 104))	('cell proliferation', 'CPA', (73, 91))	('NRIP1', 'Gene', '8204', (56, 61))	('facilitated', 'PosReg', (110, 121))
230564	32653032	Moreover, the anti-proliferation and anti-invasion effects induced by circNTRK2 knockdown were greatly abrogated by the overexpression of NRIP1.	('NTRK2', 'Gene', (74, 79))	('knockdown', 'Var', (80, 89))	('abrogated', 'NegReg', (103, 112))	('NRIP1', 'Gene', (138, 143))	('NTRK2', 'Gene', '4915', (74, 79))	('anti-invasion effects', 'CPA', (37, 58))	('NRIP1', 'Gene', '8204', (138, 143))	('anti-proliferation', 'CPA', (14, 32))
230570	32653032	High circNTRK2 expression was correlated with advanced TNM stage, lymph node metastasis and poor prognosis.	('High', 'Var', (0, 4))	('NTRK2', 'Gene', '4915', (9, 14))	('TNM', 'Gene', '10178', (55, 58))	('expression', 'MPA', (15, 25))	('TNM', 'Gene', (55, 58))	('advanced', 'CPA', (46, 54))	('NTRK2', 'Gene', (9, 14))	('lymph node metastasis', 'CPA', (66, 87))
230608	32195341	The complex molecular microenvironment of the wound bed regulates the duration and degree of inflammation in the wound repair process, while its dysregulation leads to impaired healing.	('inflammation', 'Disease', (93, 105))	('healing', 'MPA', (177, 184))	('inflammation', 'Disease', 'MESH:D007249', (93, 105))	('impaired', 'NegReg', (168, 176))	('dysregulation', 'Var', (145, 158))
230610	32195341	We used ECRG4 knockout (KO) mice to establish that the absence of ECRG4 leads to defective neutrophil recruitment with a delay in wound healing.	('absence', 'Var', (55, 62))	('mice', 'Species', '10090', (28, 32))	('neutrophil recruitment', 'CPA', (91, 113))	('defective', 'NegReg', (81, 90))	('delay in wound healing', 'Phenotype', 'HP:0001058', (121, 143))	('delay', 'NegReg', (121, 126))	('ECRG4', 'Gene', (66, 71))	('wound healing', 'CPA', (130, 143))
230612	32195341	In ECRG4 KO mouse leukocytes, there was an increase in CD44 expression, consistent with a model in which ECRG4 negatively regulates CD44 levels.	('expression', 'MPA', (60, 70))	('mouse', 'Species', '10090', (12, 17))	('increase', 'PosReg', (43, 51))	('CD44 levels', 'MPA', (132, 143))	('CD44', 'Gene', (55, 59))	('ECRG4 KO', 'Var', (3, 11))
230615	32195341	Disruption of this inflammation response is associated with delayed wound closure, infection, and scarring.	('scarring', 'Phenotype', 'HP:0100699', (98, 106))	('infection', 'Disease', (83, 92))	('inflammation', 'Disease', 'MESH:D007249', (19, 31))	('infection', 'Disease', 'MESH:D007239', (83, 92))	('delayed wound closure', 'CPA', (60, 81))	('inflammation', 'Disease', (19, 31))	('delayed wound closure', 'Phenotype', 'HP:0000270', (60, 81))	('scarring', 'CPA', (98, 106))	('Disruption', 'Var', (0, 10))
230620	32195341	In injury models, such as cutaneous wounds, pneumonia, noninfectious lung injury, and myocardial infarction, loss of CD44 expression leads to increased and prolonged inflammation, exuberant leukocyte recruitment, failure to clear apoptotic neutrophils, and increased scarring and fibrosis.	('CD44', 'Gene', (117, 121))	('noninfectious lung injury', 'Disease', (55, 80))	('inflammation', 'Disease', 'MESH:D007249', (166, 178))	('increased', 'PosReg', (142, 151))	('increased', 'PosReg', (257, 266))	('inflammation', 'Disease', (166, 178))	('pneumonia', 'Phenotype', 'HP:0002090', (44, 53))	('myocardial infarction', 'Disease', (86, 107))	('loss', 'Var', (109, 113))	('noninfectious lung injury', 'Disease', 'MESH:D000073296', (55, 80))	('failure', 'NegReg', (213, 220))	('myocardial infarction', 'Disease', 'MESH:D009203', (86, 107))	('pneumonia', 'Disease', (44, 53))	('myocardial infarction', 'Phenotype', 'HP:0001658', (86, 107))	('fibrosis', 'Disease', (280, 288))	('pneumonia', 'Disease', 'MESH:D011014', (44, 53))	('scarring', 'Phenotype', 'HP:0100699', (267, 275))	('fibrosis', 'Disease', 'MESH:D005355', (280, 288))
230626	32195341	In murine tumor models, the ability of soluble ECRG4 to increase the recruitment of inflammatory cells is dependent on thrombin cleavage.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('increase', 'PosReg', (56, 64))	('tumor', 'Disease', (10, 15))	('thrombin', 'Gene', '14061', (119, 127))	('recruitment of inflammatory cells', 'MPA', (69, 102))	('murine', 'Species', '10090', (3, 9))	('thrombin', 'Gene', (119, 127))	('soluble', 'Var', (39, 46))	('ECRG4', 'Protein', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
230630	32195341	ECRG4 KO mice had a notable, and statistically significant, delay in early wound closure compared to WT mice, which began at post-wound day 1 (WT 22.5 +- 2.4 mm2 versus KO 30.2 +- 0.7 mm2) and persisted until day 9 (WT 6.8 +- 4.7 mm2 versus KO 15.6 +- 4.2 mm2) (Fig.	('delay', 'NegReg', (60, 65))	('early wound closure', 'CPA', (69, 88))	('mice', 'Species', '10090', (104, 108))	('ECRG4 KO', 'Var', (0, 8))	('mice', 'Species', '10090', (9, 13))
230631	32195341	This highlighted a slower initial rate of wound closure in ECRG4 KO mice after injury that subsequently recovered to the rate of WT mice by day 3.	('mice', 'Species', '10090', (68, 72))	('ECRG4', 'Var', (59, 64))	('mice', 'Species', '10090', (132, 136))	('wound closure', 'CPA', (42, 55))
230632	32195341	We examined the recruitment of Gr1+ granulocytes at the margin of 24-hour wounds and observed decreased Gr1+ staining in the ECRG4 KO mice compared to WT controls (Fig.	('Gr1+', 'Chemical', '-', (31, 35))	('mice', 'Species', '10090', (134, 138))	('ECRG4 KO', 'Var', (125, 133))	('decreased', 'NegReg', (94, 103))	('Gr1+ staining', 'MPA', (104, 117))	('Gr1+', 'Chemical', '-', (104, 108))
230646	32195341	We found that CT16 specifically increased CD11b+Ly6Cint neutrophil recruitment by 35% at 24 hours (Fig.	('Ly6C', 'Gene', (48, 52))	('Ly6C', 'Gene', '17067', (48, 52))	('CT16', 'Var', (14, 18))	('increased', 'PosReg', (32, 41))
230655	32195341	There was no difference in the capacity for whole blood from either ECRG4 KO mice or their WT littermates to kill methicillin-resistant S. aureus (MRSA) as assessed ex vivo.	('mice', 'Species', '10090', (77, 81))	('methicillin-resistant S. aureus', 'MPA', (114, 145))	('S. aureus', 'Species', '1280', (136, 145))	('ECRG4 KO', 'Var', (68, 76))	('methicillin', 'Chemical', 'MESH:D008712', (114, 125))
230658	32195341	The pathway most affected by the expression of ECRG4 in the KEGG analysis was the category of proteoglycans in cancer (Fig.	('expression', 'Var', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('affected', 'Reg', (17, 25))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('ECRG4', 'Gene', (47, 52))
230662	32195341	On the basis of the observation that increased expression of ECRG4 down-regulated CD44 on myelocytes in vitro, we sought to determine whether the loss of ECRG4 in KO mice affected CD44 on leukocytes in vivo.	('ECRG4', 'Gene', (154, 159))	('affected', 'Reg', (171, 179))	('loss', 'Var', (146, 150))	('CD44', 'Gene', (82, 86))	('mice', 'Species', '10090', (166, 170))	('increased', 'PosReg', (37, 46))	('down-regulated', 'NegReg', (67, 81))	('ECRG4', 'Gene', (61, 66))
230663	32195341	Using a flow cytometric analysis of uninjured mice, ECRG4 KO mice demonstrated a 57% increase in the expression of CD44 on blood neutrophils compared to WT controls (Fig.	('mice', 'Species', '10090', (61, 65))	('ECRG4', 'Var', (52, 57))	('CD44', 'Gene', (115, 119))	('mice', 'Species', '10090', (46, 50))	('expression', 'MPA', (101, 111))	('increase', 'PosReg', (85, 93))
230665	32195341	5, D and F) compared to WT mice, with no significant difference in the number of CD45+ cells or CD11b+Ly6G+ neutrophils (Fig.	('mice', 'Species', '10090', (27, 31))	('CD45', 'Gene', (81, 85))	('CD45', 'Gene', '19264', (81, 85))	('CD11b+Ly6G+', 'Var', (96, 107))
230675	32195341	We show that the capacity for ECRG4 to regulate CD44 expression occurs in vivo based on the increased CD44 expression observed on neutrophils from ECRG4 KO mice compared to WT mice and the inverse expression of these genes in the murine wound.	('murine', 'Species', '10090', (230, 236))	('expression', 'MPA', (107, 117))	('mice', 'Species', '10090', (176, 180))	('increased', 'PosReg', (92, 101))	('CD44', 'Gene', (102, 106))	('ECRG4 KO', 'Var', (147, 155))	('mice', 'Species', '10090', (156, 160))	('CD44', 'Gene', (48, 52))
230676	32195341	These findings define ECRG4 as a mediator of CD44 expression and support a model where loss of ECRG4 at the site of injury increases CD44 expression, suggesting a novel mechanism for the regulation of the inflammatory response in cutaneous injury.	('ECRG4', 'Gene', (95, 100))	('loss', 'Var', (87, 91))	('CD44', 'Gene', (133, 137))	('injury increases', 'Disease', (116, 132))	('injury increases', 'Disease', 'MESH:D014947', (116, 132))	('cutaneous injury', 'Disease', (230, 246))	('expression', 'MPA', (138, 148))	('cutaneous injury', 'Disease', 'MESH:D018366', (230, 246))
230687	32195341	While deficient neutrophil mobilization has been shown to inhibit wound healing, which we observed in the ECRG4 KO mouse wound, many studies have demonstrated that prolonged neutrophil recruitment also results in delayed wound closure.	('wound healing', 'CPA', (66, 79))	('mouse', 'Species', '10090', (115, 120))	('deficient', 'Var', (6, 15))	('neutrophil recruitment', 'CPA', (174, 196))	('neutrophil mobilization', 'CPA', (16, 39))	('inhibit', 'NegReg', (58, 65))	('delayed wound closure', 'CPA', (213, 234))	('delayed wound closure', 'Phenotype', 'HP:0000270', (213, 234))
230691	32195341	Its expression and transcriptional responsiveness are down-regulated by hypermethylation of its promoter, accounting for its diminished expression in multiple human cancers.	('expression', 'MPA', (136, 146))	('transcriptional responsiveness', 'MPA', (19, 49))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('expression', 'MPA', (4, 14))	('human', 'Species', '9606', (159, 164))	('hypermethylation', 'Var', (72, 88))	('diminished', 'NegReg', (125, 135))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('down-regulated', 'NegReg', (54, 68))
230694	32195341	Our current study demonstrates that ECRG4 is a factor that helps orchestrate the proper timing of the inflammatory response: First, it facilitates and amplifies early inflammation but then subsequently supports the expression of factors that are essential to injury resolution.	('amplifies', 'PosReg', (151, 160))	('ECRG4', 'Var', (36, 41))	('inflammation', 'Disease', 'MESH:D007249', (167, 179))	('inflammation', 'Disease', (167, 179))	('facilitates', 'PosReg', (135, 146))	('expression', 'MPA', (215, 225))
230783	30477531	Patients who received CCRT suffered more frequent grade 3 or higher leucocytopenia than those who received chemotherapy alone (41.8% versus 24.4%, p = 0.040).	('CCRT', 'Var', (22, 26))	('leucocytopenia', 'Disease', (68, 82))	('Patients', 'Species', '9606', (0, 8))	('CR', 'Chemical', '-', (23, 25))	('grade 3', 'MPA', (50, 57))	('leucocytopenia', 'Disease', 'None', (68, 82))
230831	30477531	The incidence of grade 3 or higher leucopenia was significantly greater in the CCRT group than in the chemotherapy-alone group (41.8% versus 24.4%, p = 0.040).	('CCRT', 'Var', (79, 83))	('leucopenia', 'Disease', (35, 45))	('leucopenia', 'Disease', 'MESH:C536227', (35, 45))	('CR', 'Chemical', '-', (80, 82))
230847	29653516	Degeneration of particular types of skin proteins determines the presence of extracutaneous manifestation, whose range varies among EB subtypes (Fig.	('man', 'Species', '9606', (92, 95))	('extracutaneous manifestation', 'Disease', (77, 105))	('Degeneration', 'Var', (0, 12))
230907	29347960	Unresectable status and M1LYM were significantly associated with poor LRC (p < 0.05) and OS (p < 0.05).	('M1LYM', 'Var', (24, 29))	('poor LRC', 'Disease', (65, 73))	('OS', 'Chemical', '-', (89, 91))
230984	29347960	Unresectable and M1LYM statuses were associated with a poor OS rate [p = 0.025; hazard ratio (HR) = 3.05 (95% CI, 1.15-8.08) and p < 0.0001; HR = 11.5 (95% CI, 3.87-34.0), respectively].	('OS', 'Chemical', '-', (60, 62))	('M1LYM statuses', 'Var', (17, 31))	('poor OS', 'MPA', (55, 62))
230987	29347960	The 5-year LRC rate was 80% (95% CI, 40.9-94.6) for patients with resectable status vs. 30.1% (95% CI, 11.5-51.3) for those with unresectable status and 75.5% (95% CI, 46.9-90.1) for patients with M0 vs. 8.3% (95% CI, 0.5-31.1) for those with M1LYM (Fig.	('LRC', 'CPA', (11, 14))	('patients', 'Species', '9606', (52, 60))	('patients', 'Species', '9606', (183, 191))	('M1LYM', 'Var', (243, 248))
231028	29347960	The cardiovascular diseases after radiotherapy for CESCC were not mentioned except one report, although patients with CESCC possibly have a risk of developing cardiovascular disease because of their lifestyle, similar to patients with squamous cell carcinoma of the head and neck.	('patients', 'Species', '9606', (221, 229))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (4, 26))	('CESCC', 'Chemical', '-', (51, 56))	('cardiovascular diseases', 'Disease', (4, 27))	('cardiovascular disease', 'Disease', 'MESH:D002318', (4, 26))	('CESCC', 'Chemical', '-', (118, 123))	('cardiovascular disease', 'Disease', (159, 181))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (4, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (4, 27))	('CESCC', 'Var', (118, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (235, 258))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (159, 181))	('cardiovascular disease', 'Disease', 'MESH:D002318', (159, 181))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (235, 258))	('squamous cell carcinoma', 'Disease', (235, 258))	('patients', 'Species', '9606', (104, 112))
231043	28606973	From an oncological perspective, his case was relatively straightforward: this 55-year-old male suffered from a T3N0M0 squamous carcinoma of the proximal esophagus.	('squamous carcinoma', 'Disease', 'MESH:D002294', (119, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('squamous carcinoma', 'Disease', (119, 137))	('suffered from', 'Reg', (96, 109))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (119, 137))	('T3N0M0', 'Var', (112, 118))
231045	28606973	At the same time, however, Mr. E had developed an elevated mood with psychotic features and was voluntarily admitted to the psychiatric medical unit (PMU).	('psychotic', 'Disease', (69, 78))	('elevated mood', 'Phenotype', 'HP:0001575', (50, 63))	('psychiatric', 'Disease', (124, 135))	('psychiatric', 'Disease', 'MESH:D001523', (124, 135))	('Mr.', 'Var', (27, 30))	('elevated mood', 'MPA', (50, 63))	('psychotic', 'Disease', 'MESH:D011618', (69, 78))	('psychotic features', 'Phenotype', 'HP:0000725', (69, 87))
231105	28498447	Inhibiting DEC2 may therefore have therapeutic potential for the treatment of esophageal cancer, in combination with cisplatin.	('Inhibiting', 'Var', (0, 10))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('DEC2', 'Gene', (11, 15))	('DEC2', 'Gene', '79365', (11, 15))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
231130	28498447	9542; 1:5,000 dilution), cleaved caspase-3 (Asp175; cat.	('caspase-3', 'Gene', (33, 42))	('caspase-3', 'Gene', '836', (33, 42))	('cleaved', 'Var', (25, 32))
231147	28498447	Expression of DEC2 was decreased with 20 and 50 microM cisplatin, whereas expression of DEC1 was increased in the same conditions (Fig.	('DEC2', 'Gene', (14, 18))	('DEC1', 'Gene', '50514', (88, 92))	('DEC1', 'Gene', (88, 92))	('Expression', 'MPA', (0, 10))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('DEC2', 'Gene', '79365', (14, 18))	('decreased', 'NegReg', (23, 32))	('cisplatin', 'Var', (55, 64))
231148	28498447	Treatment with 10 microM cisplatin induced expression of cleaved PARP, cleaved caspase-8, BimEL, BimL and BimS (Fig.	('caspase-8', 'Gene', (79, 88))	('Bim', 'Gene', (106, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (25, 34))	('caspase-8', 'Gene', '841', (79, 88))	('cleaved', 'Var', (71, 78))	('Bim', 'Gene', '10018', (106, 109))	('PARP', 'Gene', (65, 69))	('Bim', 'Gene', (90, 93))	('Bim', 'Gene', '10018', (90, 93))	('Bim', 'Gene', (97, 100))	('expression', 'MPA', (43, 53))	('cleaved', 'Var', (57, 64))	('Bim', 'Gene', '10018', (97, 100))
231149	28498447	Treatment with 20 and 50 microM cisplatin further increased the amounts of cleaved PARP, cleaved caspase-8, cleaved caspase-3, Bim and Bax, whereas it decreased the expression of Bcl-2 and Bcl-xL (Fig.	('Bcl-xL', 'Gene', '598', (189, 195))	('Bim', 'Gene', (127, 130))	('Bcl-2', 'Gene', (179, 184))	('amounts', 'MPA', (64, 71))	('caspase-8', 'Gene', (97, 106))	('cisplatin', 'Var', (32, 41))	('increased', 'PosReg', (50, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('cleaved', 'MPA', (108, 115))	('Bcl-2', 'Gene', '596', (179, 184))	('caspase-3', 'Gene', '836', (116, 125))	('Bax', 'Gene', (135, 138))	('cleaved', 'MPA', (75, 82))	('caspase-3', 'Gene', (116, 125))	('decreased', 'NegReg', (151, 160))	('Bax', 'Gene', '581', (135, 138))	('expression', 'MPA', (165, 175))	('Bim', 'Gene', '10018', (127, 130))	('cleaved', 'MPA', (89, 96))	('Bcl-xL', 'Gene', (189, 195))	('caspase-8', 'Gene', '841', (97, 106))	('PARP', 'Protein', (83, 87))
231150	28498447	In addition, the ratio of Bax/Bcl-2 protein expression was strongly increased with 50 microM cisplatin (Fig.	('cisplatin', 'Var', (93, 102))	('Bax', 'Gene', (26, 29))	('ratio', 'MPA', (17, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('Bcl-2', 'Gene', (30, 35))	('Bcl-2', 'Gene', '596', (30, 35))	('Bax', 'Gene', '581', (26, 29))	('increased', 'PosReg', (68, 77))
231151	28498447	Treatment of TE-11 cells with 10, 20 and 50 microM cisplatin was demonstrated to significantly reduce cell viability (Fig.	('reduce', 'NegReg', (95, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('TE-11', 'Chemical', '-', (13, 18))	('cisplatin', 'Var', (51, 60))	('cell viability', 'CPA', (102, 116))
231165	28498447	DEC2 overexpression in the presence of cisplatin markedly inhibited multiple apoptotic markers, including all three splice variants of Bim, BimEL, BimL and BimS, as well as cleaved caspase-3, cleaved caspase-8, and cleaved PARP.	('Bim', 'Gene', '10018', (156, 159))	('Bim', 'Gene', (135, 138))	('caspase-3', 'Gene', '836', (181, 190))	('cleaved', 'MPA', (173, 180))	('cisplatin', 'Var', (39, 48))	('overexpression', 'PosReg', (5, 19))	('Bim', 'Gene', '10018', (147, 150))	('caspase-8', 'Gene', (200, 209))	('Bim', 'Gene', '10018', (140, 143))	('apoptotic markers', 'CPA', (77, 94))	('cleaved', 'Var', (215, 222))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('caspase-3', 'Gene', (181, 190))	('inhibited', 'NegReg', (58, 67))	('Bim', 'Gene', (156, 159))	('DEC2', 'Gene', (0, 4))	('Bim', 'Gene', (140, 143))	('Bim', 'Gene', (147, 150))	('DEC2', 'Gene', '79365', (0, 4))	('cleaved', 'MPA', (192, 199))	('PARP', 'Gene', (223, 227))	('caspase-8', 'Gene', '841', (200, 209))	('Bim', 'Gene', '10018', (135, 138))
231182	27329722	Mechanistic investigations revealed that through increasing the levels of intracellular reactive oxygen species (ROS), Gyp-L triggered protein ubiquitination and endoplasm reticulum (ER) stress response, leading to Ca2+ release from ER inositol trisphosphate receptor (IP3R)-operated stores and finally cell death.	('IP3R', 'Gene', (269, 273))	('protein ubiquitination', 'MPA', (135, 157))	('levels of intracellular reactive oxygen species', 'MPA', (64, 111))	('Ca2', 'Gene', '760', (215, 218))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (88, 111))	('Gyp-L', 'Chemical', '-', (119, 124))	('Ca2', 'Gene', (215, 218))	('endoplasm reticulum', 'Disease', 'MESH:D008228', (162, 181))	('increasing', 'PosReg', (49, 59))	('red', 'Chemical', '-', (131, 134))	('endoplasm reticulum', 'Disease', (162, 181))	('IP3R', 'Gene', '3710', (269, 273))	('Gyp-L', 'Var', (119, 124))	('ROS', 'Chemical', 'MESH:D017382', (113, 116))
231185	27329722	Taken together, this work suggested a novel therapeutic option by Gyp-L through the induction of an unconventional ROS-ER-Ca2+-mediated cell death in human esophageal cancer.	('human', 'Species', '9606', (150, 155))	('Gyp-L', 'Var', (66, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('esophageal cancer', 'Disease', (156, 173))	('ROS', 'Chemical', 'MESH:D017382', (115, 118))	('Ca2', 'Gene', '760', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Gyp-L', 'Chemical', '-', (66, 71))	('Ca2', 'Gene', (122, 125))
231193	27329722	Therefore, inhibition of autophagy pathway is an alternative strategy for cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('inhibition', 'Var', (11, 21))	('autophagy pathway', 'CPA', (25, 42))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
231199	27329722	Gyp-L was able to inhibit the growth of esophageal cancer cells, which was accompanied by lysosomal swelling and a halt in the execution of autophagy at the stage of autophagosome-lysosome fusion.	('inhibit', 'NegReg', (18, 25))	('lysosomal swelling', 'CPA', (90, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('autophagy at the stage', 'CPA', (140, 162))	('halt', 'NegReg', (115, 119))	('Gyp-L', 'Var', (0, 5))	('Gyp-L', 'Chemical', '-', (0, 5))	('growth', 'CPA', (30, 36))	('esophageal cancer', 'Disease', (40, 57))
231201	27329722	These results suggested Gyp-L as a novel therapeutic agent to induce an unconventional cell death in human esophageal cancer.	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('human', 'Species', '9606', (101, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('Gyp-L', 'Chemical', '-', (24, 29))	('Gyp-L', 'Var', (24, 29))
231203	27329722	Gyp-L exhibited potent growth inhibitory effect on both cancer cell lines in a dose-dependent manner.	('growth inhibitory effect', 'CPA', (23, 47))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Gyp-L', 'Chemical', '-', (0, 5))	('Gyp-L', 'Var', (0, 5))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
231204	27329722	Besides, treatment with Gyp-L showed a significant increase in cell death, when it was measured by lactate dehydrogenase (LDH) release assay (Figure 1C).	('red', 'Chemical', '-', (92, 95))	('cell death', 'CPA', (63, 73))	('lactate', 'MPA', (99, 106))	('Gyp-L', 'Chemical', '-', (24, 29))	('Gyp-L', 'Var', (24, 29))
231205	27329722	On the contrary, no cell death-inducing effect of Gyp-L on normal cells (HUVEC) or normal esophageal epithelial cells (HEEpiC) was observed (Figure 1D).	('esophageal epithelia', 'Disease', (90, 110))	('esophageal epithelia', 'Disease', 'MESH:D004941', (90, 110))	('HEEpiC', 'CellLine', 'CVCL:S361', (119, 125))	('Gyp-L', 'Chemical', '-', (50, 55))	('Gyp-L', 'Var', (50, 55))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (90, 110))
231206	27329722	The morphological changes were visualized and Gyp-L induced extensive cytoplasmic vacuolation, which affected ~95% of cells after 24 h (Figure 2A).	('Gyp-L', 'Chemical', '-', (46, 51))	('cytoplasmic vacuolation', 'CPA', (70, 93))	('Gyp-L', 'Var', (46, 51))
231211	27329722	Additionally, electron microscopic analysis showed that the ECA-109 cells treated with Gyp-L contained large vacuoles (Figure 2C), and higher magnification electron micrographs clearly showed the presence of partially degraded cytoplasmic materials in the vacuoles (Figure 2C, right panel).	('rad', 'Gene', '6236', (221, 224))	('rad', 'Gene', (221, 224))	('Gyp-L', 'Chemical', '-', (87, 92))	('Gyp-L', 'Var', (87, 92))
231212	27329722	Due to the progressive vacuolar swelling upon treatment with Gyp-L, the nuclear size of ECA-109 or TE-1 cells was reduced by > 40% within 12 h (Figure 2D).	('TE-1', 'CellLine', 'CVCL:1759', (99, 103))	('reduced', 'NegReg', (114, 121))	('Gyp-L', 'Chemical', '-', (61, 66))	('Gyp-L', 'Var', (61, 66))	('vacuolar swelling', 'Disease', 'MESH:C536522', (23, 40))	('nuclear size', 'CPA', (72, 84))	('red', 'Chemical', '-', (114, 117))	('vacuolar swelling', 'Disease', (23, 40))
231213	27329722	In addition, although the LysoTracker signal as well as the level of red fluorescence of acridine orange (AO)-stained cells increased over the first 6 h of treatment with Gyp-L, the signal intensity of both dyes was decreased after 24 h of treatment.	('acridine orange', 'Chemical', 'MESH:D000165', (89, 104))	('increased', 'PosReg', (124, 133))	('red', 'Chemical', '-', (69, 72))	('LysoTracker signal', 'MPA', (26, 44))	('Gyp-L', 'Chemical', '-', (171, 176))	('level of red fluorescence', 'MPA', (60, 85))	('Gyp-L', 'Var', (171, 176))	('AO', 'Chemical', 'MESH:D000165', (106, 108))
231216	27329722	As shown in Figure 3A, Gyp-L barely induced apoptosis, as most of the dead cells belonging to necrosis or other types of cell death.	('necrosis', 'Disease', 'MESH:D009336', (94, 102))	('necrosis', 'Disease', (94, 102))	('Gyp-L', 'Var', (23, 28))	('Gyp-L', 'Chemical', '-', (23, 28))
231218	27329722	Inclusion of Z-VAD-FMK in a non-cytotoxic concentration significantly inhibited caspase activity (Supplementary Figure S3A).	('caspase', 'Gene', (80, 87))	('Z-VAD-FMK', 'Var', (13, 22))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (13, 22))	('inhibited', 'NegReg', (70, 79))	('caspase', 'Gene', '842', (80, 87))
231220	27329722	In contrast, treatment with Z-VAD-FMK enhanced Gyp-L-induced cell death, suggesting that Z-VAD-FMK switches more apoptotic-liked cell death to Gyp-L-mediated cell death.	('Z-VAD-FMK', 'Var', (89, 98))	('switches', 'Reg', (99, 107))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (28, 37))	('enhanced', 'PosReg', (38, 46))	('Gyp-L', 'Chemical', '-', (47, 52))	('apoptotic-liked cell death', 'CPA', (113, 139))	('Gyp-L', 'Chemical', '-', (143, 148))	('Gyp-L-induced cell death', 'CPA', (47, 71))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (89, 98))
231227	27329722	Essentially, treatment with Gyp-L resulted in the accumulation of cells in the G2/M phase, with a concomitant reduction in the proportion of cells in the S phase (Supplementary Figure S3C).	('reduction', 'NegReg', (110, 119))	('red', 'Chemical', '-', (110, 113))	('Gyp-L', 'Chemical', '-', (28, 33))	('accumulation', 'PosReg', (50, 62))	('Gyp-L', 'Var', (28, 33))
231230	27329722	Gyp-L augmented the level of endogenous LC3-II in a time-dependent manner in ECA-109 cells (Figure 4A).	('LC3', 'Gene', (40, 43))	('LC3', 'Gene', '84557', (40, 43))	('Gyp-L', 'Chemical', '-', (0, 5))	('Gyp-L', 'Var', (0, 5))
231231	27329722	The accumulation of LC3-II induced by Gyp-L was also observed in a dose-dependent manner in both ECA-109 and TE-1 cells (Figure 4B).	('LC3', 'Gene', '84557', (20, 23))	('accumulation', 'PosReg', (4, 16))	('LC3', 'Gene', (20, 23))	('Gyp-L', 'Chemical', '-', (38, 43))	('Gyp-L', 'Var', (38, 43))	('TE-1', 'CellLine', 'CVCL:1759', (109, 113))
231232	27329722	We further used ECA-109 cells transiently expressing GFP-tagged LC3 to confirm the autophagy modulatory effect of Gyp-L (Figure 4C).	('Gyp-L', 'Chemical', '-', (114, 119))	('LC3', 'Gene', (64, 67))	('autophagy', 'CPA', (83, 92))	('Gyp-L', 'Var', (114, 119))	('LC3', 'Gene', '84557', (64, 67))
231234	27329722	Suppression of autophagy by knockdown of ATG5, ATG7 or LC3 in ECA-109 cells significantly attenuated Gyp-L-induced cell death (Figure 4D and Supplementary Figure S4A).	('Gyp-L', 'Chemical', '-', (101, 106))	('LC3', 'Gene', '84557', (55, 58))	('ATG7', 'Gene', '10533', (47, 51))	('ATG5', 'Gene', (41, 45))	('Suppression', 'NegReg', (0, 11))	('attenuated', 'NegReg', (90, 100))	('autophagy', 'CPA', (15, 24))	('LC3', 'Gene', (55, 58))	('ATG7', 'Gene', (47, 51))	('Gyp-L-induced cell death', 'CPA', (101, 125))	('knockdown', 'Var', (28, 37))	('ATG5', 'Gene', '9474', (41, 45))
231235	27329722	Finally, inhibition of autophagy by 3-MA (10 mM), a class III PtdIns3-kinase inhibitor that has been widely used as a pharmacological inhibitor in autophagy studies, unexpectedly did not affect Gyp-L-mediated LC3-II accumulation (Supplementary Figure S4B), cytoplasmic vacuolation (Supplementary Figure S4C), as well as cell death (Supplementary Figure S4D).	('LC3', 'Gene', (209, 212))	('Gyp-L', 'Chemical', '-', (194, 199))	('cytoplasmic', 'CPA', (257, 268))	('3-MA', 'Chemical', '-', (36, 40))	('autophagy', 'CPA', (23, 32))	('cell death', 'CPA', (320, 330))	('LC3', 'Gene', '84557', (209, 212))	('inhibition', 'Var', (9, 19))
231242	27329722	To explore this possibility further, we performed an autophagic flux assay by measuring the total cellular amount of p62 to distinguish Gyp-L-mediated LC3 increment.	('LC3', 'Gene', '84557', (151, 154))	('LC3', 'Gene', (151, 154))	('p62', 'Gene', '8878', (117, 120))	('Gyp-L', 'Chemical', '-', (136, 141))	('p62', 'Gene', (117, 120))	('Gyp-L-mediated', 'Var', (136, 150))
231248	27329722	According to this, we suspected whether impaired autophagic flux by Gyp-L may interrupt mitochondrial homeostasis.	('interrupt', 'NegReg', (78, 87))	('mitochondrial homeostasis', 'CPA', (88, 113))	('Gyp-L', 'Chemical', '-', (68, 73))	('red', 'Chemical', '-', (45, 48))	('Gyp-L', 'Var', (68, 73))	('autophagic flux', 'CPA', (49, 64))
231256	27329722	In the presence of Gyp-L, we observed an enhanced formation of yellow puncta without any significant increase in the number of red puncta, as well as CQ-treated cells.	('Gyp-L', 'Chemical', '-', (19, 24))	('red', 'Chemical', '-', (127, 130))	('enhanced', 'PosReg', (41, 49))	('formation of yellow puncta', 'MPA', (50, 76))	('Gyp-L', 'Var', (19, 24))	('CQ', 'Chemical', 'MESH:D002738', (150, 152))
231258	27329722	Therefore, these above results clearly suggested that Gyp-L blocks the fusion between autophagosomes and lysosomes.	('blocks', 'NegReg', (60, 66))	('Gyp-L', 'Var', (54, 59))	('fusion between autophagosomes and', 'CPA', (71, 104))	('Gyp-L', 'Chemical', '-', (54, 59))
231261	27329722	Treatment with Gyp-L significantly up-regulated the expression of RAB5, whereas no change was occurred with the expression of other genes (Supplementary Figure S5C).	('red', 'Chemical', '-', (99, 102))	('RAB5', 'Gene', '5868', (66, 70))	('Gyp-L', 'Chemical', '-', (15, 20))	('RAB5', 'Gene', (66, 70))	('Gyp-L', 'Var', (15, 20))	('expression', 'MPA', (52, 62))	('up-regulated', 'PosReg', (35, 47))
231263	27329722	Besides, knockdown of RAB5 using siRNA has no effect on Gyp-L-induced cell death (Supplementary Figure S5E).	('RAB5', 'Gene', '5868', (22, 26))	('Gyp-L', 'Chemical', '-', (56, 61))	('knockdown', 'Var', (9, 18))	('RAB5', 'Gene', (22, 26))
231264	27329722	To understand the central mechanism through which Gyp-L inhibits autophagic flux and induces lysosome-associated cell death, we analyzed the possible role for ER stress in Gyp-L-promoted cell death.	('induces', 'Reg', (85, 92))	('inhibits', 'NegReg', (56, 64))	('Gyp-L', 'Chemical', '-', (172, 177))	('Gyp-L', 'Chemical', '-', (50, 55))	('Gyp-L', 'Var', (50, 55))	('lysosome-associated cell death', 'CPA', (93, 123))	('autophagic flux', 'CPA', (65, 80))
231265	27329722	Western blot analysis showed that Gyp-L increased polyubiquitinated protein levels in a time- and dose-dependent manner (Figure 6A).	('Gyp-L', 'Chemical', '-', (34, 39))	('increased', 'PosReg', (40, 49))	('Gyp-L', 'Var', (34, 39))	('polyubiquitinated protein levels', 'MPA', (50, 82))
231266	27329722	As expected, the protein levels of several UPR associated proteins were largely increased in a time and dose-dependent way after Gyp-L treatment (Figure 6B).	('protein levels of several', 'MPA', (17, 42))	('Gyp-L', 'Var', (129, 134))	('increased', 'PosReg', (80, 89))	('Gyp-L', 'Chemical', '-', (129, 134))
231268	27329722	Consistently, TUDCA apparently attenuated Gyp-L-mediated cell death in both ECA-109 cells and TE-1 cells (Figure 6E).	('TUDCA', 'Chemical', 'MESH:C031655', (14, 19))	('attenuated', 'NegReg', (31, 41))	('TE-1', 'CellLine', 'CVCL:1759', (94, 98))	('TUDCA', 'Var', (14, 19))	('Gyp-L', 'Chemical', '-', (42, 47))	('Gyp-L-mediated cell death', 'CPA', (42, 67))
231270	27329722	Furthermore, we examined the selectivity of Gyp-L and tested whether Gyp-L induced ER stress in normal esophageal epithelial cells.	('esophageal epithelia', 'Phenotype', 'HP:0012859', (103, 123))	('Gyp-L', 'Var', (69, 74))	('tested', 'Reg', (54, 60))	('esophageal epithelia', 'Disease', (103, 123))	('esophageal epithelia', 'Disease', 'MESH:D004941', (103, 123))	('Gyp-L', 'Chemical', '-', (44, 49))	('Gyp-L', 'Chemical', '-', (69, 74))	('ER stress', 'MPA', (83, 92))
231271	27329722	To our surprise, although Gyp-L induced cytoplasmic vacuolation in higher concentration in HEEpiC cells, only limited cells had vacuole formation and the percentage of cell with vacuoles was largely reduced (Supplementary Figure S6A).	('HEEpiC', 'CellLine', 'CVCL:S361', (91, 97))	('red', 'Chemical', '-', (199, 202))	('Gyp-L', 'Chemical', '-', (26, 31))	('Gyp-L', 'Var', (26, 31))	('cytoplasmic vacuolation', 'MPA', (40, 63))	('reduced', 'NegReg', (199, 206))
231274	27329722	Together, these results suggested that Gyp-L exhibits selectivity toward cancer cells to stimulate non-apoptotic cell death.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Gyp-L', 'Chemical', '-', (39, 44))	('non-apoptotic cell death', 'CPA', (99, 123))	('stimulate', 'PosReg', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Gyp-L', 'Var', (39, 44))
231276	27329722	We next sought to investigate whether Gyp-L perturbed intracellular Ca2+ homeostasis.	('perturbed intracellular Ca2+ homeostasis', 'Phenotype', 'HP:0003575', (44, 84))	('Ca2', 'Gene', '760', (68, 71))	('perturbed', 'Reg', (44, 53))	('Gyp-L', 'Chemical', '-', (38, 43))	('Gyp-L', 'Var', (38, 43))	('Ca2', 'Gene', (68, 71))
231278	27329722	Indeed, incubation with Gyp-L dramatically increased the intracellular Ca2+ levels (Figure 7A).	('Ca2', 'Gene', '760', (71, 74))	('increased the intracellular Ca2+ levels', 'Phenotype', 'HP:0003575', (43, 82))	('increased', 'PosReg', (43, 52))	('Ca2', 'Gene', (71, 74))	('Gyp-L', 'Chemical', '-', (24, 29))	('Gyp-L', 'Var', (24, 29))
231292	27329722	These results revealed that Gyp-L-induced extensive misfolding of new synthesized proteins lead to ER stress and cell death.	('lead to', 'Reg', (91, 98))	('cell death', 'CPA', (113, 123))	('ER stress', 'MPA', (99, 108))	('Gyp-L-induced', 'Var', (28, 41))	('Gyp-L', 'Chemical', '-', (28, 33))	('misfolding of new synthesized proteins', 'MPA', (52, 90))
231294	27329722	In order to further test this, we next examined whether Gyp-L also generates ROS in esophageal cancer cells and, if so, whether this contributes to the ER stress and subsequent cell death.	('ER stress', 'MPA', (152, 161))	('Gyp-L', 'Var', (56, 61))	('contributes', 'Reg', (133, 144))	('ROS', 'MPA', (77, 80))	('generates', 'Reg', (67, 76))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Gyp-L', 'Chemical', '-', (56, 61))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))
231295	27329722	Flow cytometry using a ROS fluorescent probe 2',7'-dichlorofluorescein diacetate (DCF-DA) demonstrated that production of ROS was markedly increased after treatment with Gyp-L for 4 h (Supplementary Figure 9A).	('Gyp-L', 'Chemical', '-', (170, 175))	("2',7'-dichlorofluorescein diacetate", 'Chemical', 'MESH:C029569', (45, 80))	('ROS', 'Chemical', 'MESH:D017382', (122, 125))	('ROS', 'Protein', (122, 125))	('Gyp-L', 'Var', (170, 175))	('increased', 'PosReg', (139, 148))	('ROS', 'Chemical', 'MESH:D017382', (23, 26))	('DCF-DA', 'Chemical', 'MESH:C029569', (82, 88))
231297	27329722	In addition, NAC pretreatment reversed Gyp-L-induced increment of several ER stress proteins (Figure 9C) and the intracellular Ca2+ concentration (Figure 9D).	('increment', 'PosReg', (53, 62))	('NAC', 'Gene', '6622', (13, 16))	('NAC', 'Gene', (13, 16))	('Gyp-L-induced', 'Var', (39, 52))	('Gyp-L', 'Chemical', '-', (39, 44))	('ER stress proteins', 'Protein', (74, 92))	('Ca2', 'Gene', '760', (127, 130))	('Ca2', 'Gene', (127, 130))
231301	27329722	Surprisingly, only TEMPOL was capable to block Gyp-L-induced cell death (Figure 9G), Ca2+ release (Figure 9G) and cytoplasmic vacuolation (Supplementary Figure S7).	('TEMPOL', 'Chemical', 'MESH:C001803', (19, 25))	('cytoplasmic vacuolation', 'CPA', (114, 137))	('Gyp-L', 'Chemical', '-', (47, 52))	('Gyp-L-induced', 'Var', (47, 60))	('Ca2', 'Gene', '760', (85, 88))	('Ca2', 'Gene', (85, 88))
231305	27329722	In the present work, we show that Gyp-L inhibits autophagic flux and induces nonapoptotic, lysosome-associated cell death in human esophageal cancer cells (Supplementary Figure S8).	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('human', 'Species', '9606', (125, 130))	('esophageal cancer', 'Disease', (131, 148))	('induces', 'Reg', (69, 76))	('inhibits', 'NegReg', (40, 48))	('Gyp-L', 'Chemical', '-', (34, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('autophagic flux', 'CPA', (49, 64))	('Gyp-L', 'Var', (34, 39))
231306	27329722	Exposure to Gyp-L was characterized by lysosomal swelling, autophagosome formation and halted autophagosome-lysosome fusion, ultimately leading to cell death.	('Gyp-L', 'Chemical', '-', (12, 17))	('Gyp-L', 'Var', (12, 17))	('leading to', 'Reg', (136, 146))	('lysosomal swelling', 'CPA', (39, 57))	('halted autophagosome-lysosome fusion', 'CPA', (87, 123))	('autophagosome formation', 'CPA', (59, 82))
231307	27329722	More detailed studies found that Gyp-L initially stimulated the generation of ROS, which subsequently triggered ER stress and Ca2+ release from IP3R-operated stores.	('ROS', 'Chemical', 'MESH:D017382', (78, 81))	('Ca2', 'Gene', (126, 129))	('Gyp-L', 'Chemical', '-', (33, 38))	('ER stress', 'MPA', (112, 121))	('IP3R', 'Gene', '3710', (144, 148))	('Gyp-L', 'Var', (33, 38))	('ROS', 'MPA', (78, 81))	('IP3R', 'Gene', (144, 148))	('Ca2', 'Gene', '760', (126, 129))	('red', 'Chemical', '-', (108, 111))	('triggered', 'Reg', (102, 111))
231313	27329722	Herein we provided evidence that Gyp-L-induced cell death correlated with an increase in levels of autophagosomes in human esophageal cancer cells.	('esophageal cancer', 'Disease', (123, 140))	('human', 'Species', '9606', (117, 122))	('Gyp-L-induced', 'Var', (33, 46))	('Gyp-L', 'Chemical', '-', (33, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('increase', 'PosReg', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('levels of autophagosomes', 'MPA', (89, 113))
231314	27329722	In line with this, silencing of autophagy-related genes (ATG5, ATG7 and LC3) protected against Gyp-L cytotoxicity (Figure 4D).	('cytotoxicity', 'Disease', 'MESH:D064420', (101, 113))	('silencing', 'Var', (19, 28))	('LC3', 'Gene', '84557', (72, 75))	('Gyp-L', 'Chemical', '-', (95, 100))	('ATG5', 'Gene', '9474', (57, 61))	('ATG7', 'Gene', '10533', (63, 67))	('LC3', 'Gene', (72, 75))	('cytotoxicity', 'Disease', (101, 113))	('ATG7', 'Gene', (63, 67))	('ATG5', 'Gene', (57, 61))
231315	27329722	However, treatment of Gyp-L resulted in a halt of the execution of autophagy at the stage of autophagosome-lysosome fusion, leading to hallmark accumulation of LC3B-II and p62 (Figure 5).	('LC3B', 'Gene', '81631', (160, 164))	('p62', 'Gene', '8878', (172, 175))	('Gyp-L', 'Chemical', '-', (22, 27))	('accumulation', 'PosReg', (144, 156))	('p62', 'Gene', (172, 175))	('halt', 'NegReg', (42, 46))	('Gyp-L', 'Var', (22, 27))	('autophagy', 'CPA', (67, 76))	('LC3B', 'Gene', (160, 164))
231318	27329722	Therefore, Gyp-L seems to act as a lysosomal inhibitor to exert its anticancer activity by inhibiting the autophagic degradation of cytotoxic and deleterious materials.	('inhibiting', 'NegReg', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rad', 'Gene', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('rad', 'Gene', '6236', (120, 123))	('Gyp-L', 'Chemical', '-', (11, 16))	('Gyp-L', 'Var', (11, 16))	('cancer', 'Disease', (72, 78))
231319	27329722	Besides, Gyp-L-induced cytoplasmic vacuolation associated with increased LC3-II accumulation is similar to previous descriptions in colon, breast, glioblastoma cancer cell lines and mantle cell lymphoma.	('cytoplasmic vacuolation', 'MPA', (23, 46))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (182, 202))	('Gyp-L-induced', 'Var', (9, 22))	('increased', 'PosReg', (63, 72))	('Gyp-L', 'Chemical', '-', (9, 14))	('mantle cell lymphoma', 'Disease', (182, 202))	('lymphoma', 'Phenotype', 'HP:0002665', (194, 202))	('cell lymphoma', 'Phenotype', 'HP:0012191', (189, 202))	('increased LC3', 'Phenotype', 'HP:0003141', (63, 76))	('glioblastoma cancer', 'Disease', (147, 166))	('LC3', 'Gene', '84557', (73, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('LC3', 'Gene', (73, 76))	('glioblastoma cancer', 'Disease', 'MESH:D005909', (147, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
231335	27329722	Together, these findings strongly suggest that autophagic flux inhibition is predominantly a consequence of ER-Ca2+ perturbation.	('red', 'Chemical', '-', (78, 81))	('Ca2', 'Gene', '760', (111, 114))	('autophagic flux', 'CPA', (47, 62))	('Ca2', 'Gene', (111, 114))	('perturbation', 'Var', (116, 128))	('inhibition', 'NegReg', (63, 73))
231336	27329722	In conclusion, our results demonstrated that Gyp-L induced a nonapoptotic, lysosome-associated cell death in human esophageal cancer cells through ROS-ER-Ca2+ signaling.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (109, 114))	('Gyp-L', 'Var', (45, 50))	('ROS', 'Chemical', 'MESH:D017382', (147, 150))	('lysosome-associated cell death', 'CPA', (75, 105))	('Ca2', 'Gene', '760', (154, 157))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('nonapoptotic', 'CPA', (61, 73))	('Ca2', 'Gene', (154, 157))	('Gyp-L', 'Chemical', '-', (45, 50))
231341	27329722	CQ (C6628), TUDCA (T0557), 2-APB (D9754), CHX (C7698) and NAC (A9165) were purchased from Sigma-Aldrich.	('NAC', 'Gene', '6622', (58, 61))	('2-APB', 'Chemical', 'MESH:C109986', (27, 32))	('NAC', 'Gene', (58, 61))	('D9754', 'Var', (34, 39))	('D9754', 'CellLine', 'CVCL:2630', (34, 39))	('CQ', 'Chemical', 'MESH:D002738', (0, 2))	('TUDCA', 'Chemical', 'MESH:C031655', (12, 17))	('T0557', 'Var', (19, 24))	('CHX', 'Chemical', 'MESH:D003513', (42, 45))	('C7698', 'Var', (47, 52))
231342	27329722	Z-VAD-FMK (S7023), Necrostatin-1 (S8037), Rapamycin (S1039) and TEMPOL (S2910) and 3-MA (S2767) were purchased from Selleck.	('TEMPOL', 'Chemical', 'MESH:C001803', (64, 70))	('S1039', 'Var', (53, 58))	('S7023', 'Var', (11, 16))	('S8037', 'Var', (34, 39))	('S2910', 'Var', (72, 77))	('3-MA', 'Chemical', '-', (83, 87))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (0, 9))
231386	27157326	Multivariable regression modeling was used to determine predictors associated with the use of minimally invasive approaches for patients in the National Cancer Data Base who underwent resection of middle and distal clinical T13N03M0 esophageal cancers from 2010 to 2012.	('esophageal cancers', 'Disease', (233, 251))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('T13N03M0', 'Var', (224, 232))	('esophageal cancers', 'Disease', 'MESH:D004938', (233, 251))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('patients', 'Species', '9606', (128, 136))	('Cancer', 'Phenotype', 'HP:0002664', (153, 159))
231406	27157326	Patients with clinical T1-3any NM0 esophageal cancers located in the middle and distal esophagus who underwent esophagectomy from 2010 to 2012 were included in the study.	('T1-3any NM0', 'Var', (23, 34))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('Patients', 'Species', '9606', (0, 8))	('esophageal cancers', 'Disease', (35, 53))	('esophageal cancers', 'Disease', 'MESH:D004938', (35, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
231418	27157326	Patients who underwent MIE were more likely to be treated at an academic facility (p < 0.001), to have a lower clinical T stage (p = 0.029), to have a lower pathologic T stage (p = 0.041), and to have a smaller tumor size (p = 0.007) when compared with patients undergoing OE.	('lower', 'NegReg', (105, 110))	('pathologic T stage', 'CPA', (157, 175))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('clinical T stage', 'CPA', (111, 127))	('patients', 'Species', '9606', (253, 261))	('lower', 'NegReg', (151, 156))	('MIE', 'Var', (23, 26))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('MIE', 'Chemical', '-', (23, 26))
231424	27157326	However, the MIE group was associated with a higher number of lymph nodes harvested (15 versus 13; p = 0.016) and a modest decrease in hospital length of stay (10 days versus 11 days; p = 0.046) (Table 3).	('decrease', 'NegReg', (123, 131))	('MIE', 'Chemical', '-', (13, 16))	('higher number of lymph nodes', 'Phenotype', 'HP:0032536', (45, 73))	('hospital length of stay', 'MPA', (135, 158))	('MIE', 'Var', (13, 16))	('higher', 'PosReg', (45, 51))
231431	27157326	However, patients with squamous cell carcinoma who underwent RAMIE had statistically superior survival (84% versus 56% at 2 years; p = 0.034) (Fig 2D).	('patients', 'Species', '9606', (9, 17))	('RAMIE', 'Species', '83906', (61, 66))	('survival', 'MPA', (94, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('RAMIE', 'Var', (61, 66))	('superior', 'PosReg', (85, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('squamous cell carcinoma', 'Disease', (23, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))
231433	27157326	Additionally, MIE is associated with modest improvements in lymph node harvesting and hospital length of stay without compromising long-term survival.	('MIE', 'Chemical', '-', (14, 17))	('improvements', 'PosReg', (44, 56))	('MIE', 'Var', (14, 17))	('lymph node harvesting', 'CPA', (60, 81))
231456	27157326	In conclusion, MIE is associated with modestly improved perioperative outcomes without compromising survival.	('improved', 'PosReg', (47, 55))	('MIE', 'Chemical', '-', (15, 18))	('MIE', 'Var', (15, 18))
231616	26949124	evaluating the efficacy of metallic esophageal stents in preventing ES after ESD, the mean number of bougie dilations required was 0.45 (range, 0 to 3) for the stent arm as compared to 3.9 (range, 0 to 17) for the arm without the stent.	('ES', 'Phenotype', 'HP:0002043', (68, 70))	('metal', 'Chemical', 'MESH:D008670', (27, 32))	('stent', 'Var', (160, 165))	('ES after ESD', 'Disease', (68, 80))	('ES', 'Phenotype', 'HP:0002043', (77, 79))
231721	26604271	Our results provide a broad catalog of altered miRNAs that merit further investigation in relation to the pathogenesis and diagnosis of EA.	('altered', 'Var', (39, 46))	('miR', 'Gene', (47, 50))	('EA', 'Phenotype', 'HP:0011459', (136, 138))	('miR', 'Gene', '220972', (47, 50))
231756	22302096	The Aurora kinase A inhibitor MLN8237 Enhances Cisplatin-induced Cell Death in Esophageal Adenocarcinoma Cells Esophageal adenocarcinomas (EACs) are poorly responsive to chemotherapeutics.	('Enhances', 'PosReg', (38, 46))	('MLN8237', 'Chemical', 'MESH:C550258', (30, 37))	('MLN8237', 'Var', (30, 37))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('Esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (111, 137))	('Cell Death in Esophageal Adenocarcinoma', 'Disease', (65, 104))	('Cell Death in Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (65, 104))	('Cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('Aurora kinase A', 'Gene', '6790', (4, 19))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (111, 136))	('Cisplatin-induced', 'MPA', (47, 64))	('Aurora kinase A', 'Gene', (4, 19))	('Esophageal adenocarcinomas', 'Disease', (111, 137))	('EAC', 'Phenotype', 'HP:0011459', (139, 142))
231757	22302096	This study aimed to determine the levels of Aurora kinas A (AURKA) and the therapeutic potential of MLN8237, an investigational AURKA inhibitor, alone and in combination with Cisplatin.	('Aurora kinas A', 'MPA', (44, 58))	('AURKA', 'Gene', '6790', (128, 133))	('MLN8237', 'Chemical', 'MESH:C550258', (100, 107))	('AURKA', 'Gene', (128, 133))	('AURKA', 'Gene', '6790', (60, 65))	('Cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('MLN8237', 'Var', (100, 107))	('AURKA', 'Gene', (60, 65))
231760	22302096	Using FLO-1, OE19 and OE33 EAC cell lines, with constitutive AURKA overexpression and mutant-p53, we observed inhibition of colony formation with a single treatment of 0.5muM MLN8237 (p<0.05).	('inhibition', 'NegReg', (110, 120))	('overexpression', 'PosReg', (67, 81))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('MLN8237', 'Chemical', 'MESH:C550258', (175, 182))	('AURKA', 'Gene', '6790', (61, 66))	('MLN8237', 'Var', (175, 182))	('EAC', 'Phenotype', 'HP:0011459', (27, 30))	('men', 'Species', '9606', (160, 163))	('AURKA', 'Gene', (61, 66))	('colony formation', 'CPA', (124, 140))
231762	22302096	24hrs after treatment with the MLN8237 or MLN8237 and Cisplatin, cell cycle analyses demonstrated a sharp increase in the percentage of polyploid cells (p<0.001).	('cell cycle analyses', 'CPA', (65, 84))	('Cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('MLN8237', 'Chemical', 'MESH:C550258', (42, 49))	('MLN8237', 'Chemical', 'MESH:C550258', (31, 38))	('MLN8237', 'Var', (31, 38))	('increase', 'PosReg', (106, 114))	('MLN8237', 'Var', (42, 49))	('men', 'Species', '9606', (17, 20))
231763	22302096	Western blot analysis demonstrated higher induction of TAp73beta, PUMA, NOXA, cleaved caspase 3 and cleaved PARP with the combined treatment, as compared to a single agent treatment.	('cleaved', 'Var', (100, 107))	('caspase 3', 'Gene', (86, 95))	('caspase 3', 'Gene', '836', (86, 95))	('PARP', 'Gene', '1302', (108, 112))	('NOXA', 'Gene', (72, 76))	('NOXA', 'Gene', '5366', (72, 76))	('cleaved', 'MPA', (78, 85))	('men', 'Species', '9606', (177, 180))	('PARP', 'Gene', (108, 112))	('p73', 'Gene', '7161', (57, 60))	('p73', 'Gene', (57, 60))	('men', 'Species', '9606', (136, 139))
231764	22302096	Using xenograft models, we demonstrated an enhanced anti-tumor role for the MLN8237 and Cisplatin combination, as compared to single agent treatments (p<0.001).	('MLN8237', 'Var', (76, 83))	('enhanced', 'PosReg', (43, 51))	('men', 'Species', '9606', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('MLN8237', 'Chemical', 'MESH:C550258', (76, 83))	('tumor', 'Disease', (57, 62))
231765	22302096	In conclusion, this study demonstrates frequent overexpression of AURKA and suggests that MLN8237 could be an effective anti-tumor agent, which can be combined with CDDP for a better therapeutic outcome in EACs.	('AURKA', 'Gene', '6790', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('CDDP', 'Chemical', 'MESH:D002945', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('AURKA', 'Gene', (66, 71))	('EAC', 'Phenotype', 'HP:0011459', (206, 209))	('tumor', 'Disease', (125, 130))	('MLN8237', 'Chemical', 'MESH:C550258', (90, 97))	('overexpression', 'PosReg', (48, 62))	('MLN8237', 'Var', (90, 97))
231769	22302096	Several genomic studies have shown amplification of chromosomal region 20q13 in EAC, a region that harbors Aurora kinase A (AURKA).	('amplification', 'Var', (35, 48))	('AURKA', 'Gene', '6790', (124, 129))	('EAC', 'Disease', (80, 83))	('Aurora kinase A', 'Gene', (107, 122))	('AURKA', 'Gene', (124, 129))	('Aurora kinase A', 'Gene', '6790', (107, 122))	('EAC', 'Phenotype', 'HP:0011459', (80, 83))
231770	22302096	AURKA gene amplification and/or overexpression have also been frequently observed in several malignancies including breast, colon, pancreas, ovaries, bladder, liver, and gastric cancers.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('colon', 'Disease', (124, 129))	('gastric cancers', 'Disease', (170, 185))	('gastric cancers', 'Phenotype', 'HP:0012126', (170, 185))	('gastric cancers', 'Disease', 'MESH:D013274', (170, 185))	('breast', 'Disease', (116, 122))	('AURKA', 'Gene', '6790', (0, 5))	('pancreas', 'Disease', (131, 139))	('amplification', 'Var', (11, 24))	('AURKA', 'Gene', (0, 5))	('ovaries', 'Disease', 'MESH:D010051', (141, 148))	('malignancies', 'Disease', 'MESH:D009369', (93, 105))	('ovaries', 'Disease', (141, 148))	('malignancies', 'Disease', (93, 105))	('overexpression', 'PosReg', (32, 46))	('pancreas', 'Disease', 'MESH:D010190', (131, 139))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('bladder', 'Disease', (150, 157))	('liver', 'Disease', (159, 164))	('observed', 'Reg', (73, 81))
231776	22302096	The mutant p53 tumors confer resistance to a wide-variety of therapeutic regimens.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('mutant', 'Var', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('men', 'Species', '9606', (77, 80))	('resistance', 'CPA', (29, 39))	('tumors', 'Disease', (15, 21))
231778	22302096	MLN8237 is an investigational small molecule inhibitor developed by Millennium Pharmaceuticals, Inc. which selectively inhibits AURKA and has been shown in nonclinical studies to thereby induce cell cycle arrest, polyploidy and mitotic catastrophe.	('mitotic catastrophe', 'CPA', (228, 247))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (194, 211))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('inhibits', 'NegReg', (119, 127))	('AURKA', 'Gene', '6790', (128, 133))	('polyploidy', 'Disease', 'MESH:D011123', (213, 223))	('arrest', 'Disease', 'MESH:D006323', (205, 211))	('MLN8237', 'Var', (0, 7))	('AURKA', 'Gene', (128, 133))	('induce', 'Reg', (187, 193))	('arrest', 'Disease', (205, 211))	('polyploidy', 'Disease', (213, 223))
231779	22302096	Currently, MLN8237 is being tested in various Phase I and Phase II clinical trials for advanced solid tumors and hematological malignancies.	('hematological malignancies', 'Disease', (113, 139))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('solid tumors', 'Disease', (96, 108))	('hematological malignancies', 'Disease', 'MESH:D019337', (113, 139))	('MLN8237', 'Chemical', 'MESH:C550258', (11, 18))	('hematological malignancies', 'Phenotype', 'HP:0004377', (113, 139))	('MLN8237', 'Var', (11, 18))	('solid tumors', 'Disease', 'MESH:D009369', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
231782	22302096	In this study, we investigated the potential therapeutic benefit of MLN8237 alone and in combination with CDDP, using in vitro and in vivo models of mutant-p53 EACs.	('EAC', 'Phenotype', 'HP:0011459', (160, 163))	('MLN8237', 'Chemical', 'MESH:C550258', (68, 75))	('p53', 'Gene', '7157', (156, 159))	('p53', 'Gene', (156, 159))	('MLN8237', 'Var', (68, 75))	('CDDP', 'Chemical', 'MESH:D002945', (106, 110))
231792	22302096	FLO-1 and OE33 cells were treated once with the MLN8237 (0.5muM) and/or CDDP (2.5muM) for 24hr and subsequently incubated for 48hr in drug free DMEM (10% FBS) cell culture medium.	('FBS', 'Disease', 'MESH:D005198', (154, 157))	('CDDP', 'Chemical', 'MESH:D002945', (72, 76))	('FBS', 'Disease', (154, 157))	('MLN8237', 'Chemical', 'MESH:C550258', (48, 55))	('MLN8237', 'Var', (48, 55))	('DMEM', 'Chemical', '-', (144, 148))
231831	22302096	We confirmed the role of AURKA inhibitor MLN8237 in suppressing phosphorylation of AURKA in EAC cells using several time points (2, 4, 8, and 24 hrs).	('phosphorylation', 'MPA', (64, 79))	('AURKA', 'Gene', '6790', (25, 30))	('AURKA', 'Gene', (83, 88))	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('AURKA', 'Gene', (25, 30))	('MLN8237', 'Chemical', 'MESH:C550258', (41, 48))	('MLN8237', 'Var', (41, 48))	('suppressing', 'NegReg', (52, 63))	('AURKA', 'Gene', '6790', (83, 88))
231832	22302096	As shown in Supplemental Figure 1B, MLN8237 inhibited the phosphorylation of AURKA (Thr 288).	('Thr', 'Chemical', 'MESH:D013912', (84, 87))	('MLN8237', 'Var', (36, 43))	('phosphorylation', 'MPA', (58, 73))	('men', 'Species', '9606', (18, 21))	('inhibited', 'NegReg', (44, 53))	('AURKA', 'Gene', '6790', (77, 82))	('MLN8237', 'Chemical', 'MESH:C550258', (36, 43))	('AURKA', 'Gene', (77, 82))
231833	22302096	Because of the frequent overexpression of AURKA in EACs, we utilized in vitro and in vivo methods to test the investigational AURKA inhibitor, MLN8237, alone and in combination with CDDP.	('AURKA', 'Gene', (126, 131))	('CDDP', 'Chemical', 'MESH:D002945', (182, 186))	('MLN8237', 'Chemical', 'MESH:C550258', (143, 150))	('AURKA', 'Gene', (42, 47))	('MLN8237', 'Var', (143, 150))	('overexpression', 'PosReg', (24, 38))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('AURKA', 'Gene', '6790', (126, 131))	('AURKA', 'Gene', '6790', (42, 47))
231835	22302096	The treatment with the MLN8237 and/or CDDP for 24hr significantly reduced the percentage of cells in G1-phase and induced a significant delay in the transition from G2- to M-phase in OE33 (Figure 2A) and FLO-1 (Supplemental Figure.	('reduced', 'NegReg', (66, 73))	('men', 'Species', '9606', (217, 220))	('CDDP', 'Chemical', 'MESH:D002945', (38, 42))	('delay', 'NegReg', (136, 141))	('MLN8237', 'Var', (23, 30))	('transition', 'MPA', (149, 159))	('men', 'Species', '9606', (9, 12))	('CDDP', 'Gene', (38, 42))	('MLN8237', 'Chemical', 'MESH:C550258', (23, 30))
231836	22302096	In addition, treatments with the MLN8237 alone or in combination with CDDP for 24hr led to a significant reduction of cells in the S-phase with an increase in the percentage of cells with polyploidy (Figure 2A and Supplemental Figure.	('MLN8237', 'Chemical', 'MESH:C550258', (33, 40))	('MLN8237', 'Var', (33, 40))	('men', 'Species', '9606', (18, 21))	('polyploidy', 'Disease', 'MESH:D011123', (188, 198))	('CDDP', 'Chemical', 'MESH:D002945', (70, 74))	('men', 'Species', '9606', (220, 223))	('reduction', 'NegReg', (105, 114))	('increase', 'PosReg', (147, 155))	('cells in the S-phase', 'CPA', (118, 138))	('polyploidy', 'Disease', (188, 198))
231837	22302096	At 72hr time point (24hr treatment with subsequent drug free incubation for 48hr), cells with MLN8237 or CDDP single agent treatments demonstrated an increase in the percentage of cells in the sub-G1-phase (p<.05).	('men', 'Species', '9606', (128, 131))	('CDDP', 'Gene', (105, 109))	('CDDP', 'Chemical', 'MESH:D002945', (105, 109))	('MLN8237', 'Chemical', 'MESH:C550258', (94, 101))	('increase', 'PosReg', (150, 158))	('men', 'Species', '9606', (30, 33))	('MLN8237', 'Var', (94, 101))
231840	22302096	These results indicate that one of the early events (24hr) following MLN8237 treatment is the increase in polyploidy and the G2- to M-phase transition delay.	('polyploidy', 'Disease', (106, 116))	('increase', 'PosReg', (94, 102))	('polyploidy', 'Disease', 'MESH:D011123', (106, 116))	('MLN8237', 'Chemical', 'MESH:C550258', (69, 76))	('G2- to M-phase transition delay', 'CPA', (125, 156))	('men', 'Species', '9606', (82, 85))	('MLN8237', 'Var', (69, 76))
231843	22302096	Therefore, it is possible that the combination of MLN8237 and CDDP leads to a delay in G2- to M-phase transition, allowing the activation of the pro-apoptotic machinery and enhanced induction of cell death.	('delay', 'NegReg', (78, 83))	('MLN8237', 'Var', (50, 57))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))	('CDDP', 'Chemical', 'MESH:D002945', (62, 66))	('pro-apoptotic', 'CPA', (145, 158))	('cell death', 'CPA', (195, 205))	('G2-', 'CPA', (87, 90))	('activation', 'PosReg', (127, 137))	('enhanced', 'PosReg', (173, 181))	('CDDP', 'Gene', (62, 66))
231845	22302096	The clonogenic cell survival assay data indicated that MLN8237 (0.5muM) or CDDP (2.5 and 5.0muM) single agent treatment inhibits survival of FLO-1 (MLN 0.5muM: 39.25+-4.15, p<0.05; CDDP 2.5muM: 75.0+-3.98, p<0.05 and CDDP 5.0muM: 20.0+-2.56, p<0.05) (Figure 3A), OE33 (MLN 0.5muM: 48.55+-2.5, p<0.05; CDDP 2.5muM: 75.23+-3.22, p<0.05 and CDDP 5.0muM: 14.7+-5.95, p<0.05) (Figure 3B), and OE19 (MLN 0.5muM: 51.63+-1.52, p<0.05; CDDP 2.5muM: 49.83+-2.89, p<0.05 and CDDP 5.0muM: 2.40+-0.41, p<0.05) (Supplemental Figure.	('inhibits', 'NegReg', (120, 128))	('CDDP', 'Chemical', 'MESH:D002945', (181, 185))	('survival', 'CPA', (129, 137))	('CDDP', 'Chemical', 'MESH:D002945', (464, 468))	('CDDP', 'Chemical', 'MESH:D002945', (217, 221))	('CDDP', 'Chemical', 'MESH:D002945', (338, 342))	('men', 'Species', '9606', (115, 118))	('men', 'Species', '9606', (504, 507))	('MLN8237', 'Chemical', 'MESH:C550258', (55, 62))	('CDDP', 'Chemical', 'MESH:D002945', (427, 431))	('CDDP', 'Chemical', 'MESH:D002945', (75, 79))	('CDDP', 'Chemical', 'MESH:D002945', (301, 305))	('MLN8237', 'Var', (55, 62))
231846	22302096	The treatment with the MLN8237 (0.5muM) and CDDP (2.5 or 5.0muM) combination led to a significantly enhanced inhibition of cell viability and colony formation in FLO-1 (MLN 0.5muM + CDDP 2.5muM: 19.42+-1.3, p<0.01 and MLN 0.5muM + CDDP 5.0muM: 2.23+-0.38, p<0.01) (Figure 3A), OE33 (MLN 0.5muM + CDDP 2.5muM: 24.67+-5.05, p<0.01 and MLN 0.5muM + CDDP 5.0muM: 3.68+-2.19, p<0.01) (Figure 3B), and OE19 (MLN 0.5muM + CDDP 2.5muM: 18.61+-2.10, p<0.01 and MLN 0.5muM + CDDP 5.0muM: 0.66+-0.23, p<0.01) (Supplemental Figure 1C).	('men', 'Species', '9606', (505, 508))	('CDDP', 'Chemical', 'MESH:D002945', (182, 186))	('cell viability', 'CPA', (123, 137))	('MLN8237', 'Var', (23, 30))	('CDDP', 'Chemical', 'MESH:D002945', (415, 419))	('CDDP', 'Chemical', 'MESH:D002945', (296, 300))	('enhanced', 'PosReg', (100, 108))	('men', 'Species', '9606', (9, 12))	('inhibition', 'NegReg', (109, 119))	('CDDP', 'Chemical', 'MESH:D002945', (465, 469))	('CDDP', 'Chemical', 'MESH:D002945', (231, 235))	('MLN8237', 'Chemical', 'MESH:C550258', (23, 30))	('CDDP', 'Chemical', 'MESH:D002945', (44, 48))	('CDDP', 'Chemical', 'MESH:D002945', (346, 350))	('colony formation', 'CPA', (142, 158))
231847	22302096	Therefore, the clonogenic cell survival data suggests that the combination of MLN8237 with CDDP has a significantly higher inhibitory effect on EAC cell survival.	('MLN8237', 'Chemical', 'MESH:C550258', (78, 85))	('inhibitory', 'NegReg', (123, 133))	('higher', 'PosReg', (116, 122))	('EAC cell survival', 'CPA', (144, 161))	('MLN8237', 'Var', (78, 85))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('CDDP', 'Gene', (91, 95))	('CDDP', 'Chemical', 'MESH:D002945', (91, 95))
231848	22302096	The analysis of the phosphorylated T288 amino acid residue of AURKA, following treatment with MLN8237 alone or in combination with CDDP, demonstrated abrogation of phosphorylation of this site, which is indicative of loss of kinase activity (Figure 3C & 3D).	('T288 amino acid', 'Chemical', '-', (35, 50))	('AURKA', 'Gene', (62, 67))	('phosphorylation', 'MPA', (164, 179))	('CDDP', 'Chemical', 'MESH:D002945', (131, 135))	('men', 'Species', '9606', (84, 87))	('MLN8237', 'Chemical', 'MESH:C550258', (94, 101))	('MLN8237', 'Var', (94, 101))	('AURKA', 'Gene', '6790', (62, 67))
231849	22302096	Although, the total AURKA protein levels were apparently upregulated with MLN8237 treatments, the phosphorylated AURKA levels were still low.	('MLN8237', 'Chemical', 'MESH:C550258', (74, 81))	('AURKA', 'Gene', (20, 25))	('men', 'Species', '9606', (87, 90))	('low', 'NegReg', (137, 140))	('MLN8237 treatments', 'Var', (74, 92))	('AURKA', 'Gene', '6790', (113, 118))	('AURKA', 'Gene', '6790', (20, 25))	('AURKA', 'Gene', (113, 118))	('upregulated', 'PosReg', (57, 68))
231851	22302096	The treatment with MLN8237 or CDDP alone induced the expression of TAp73beta protein and its pro-apoptotic targets, NOXA and PUMA.	('CDDP', 'Chemical', 'MESH:D002945', (30, 34))	('MLN8237', 'Chemical', 'MESH:C550258', (19, 26))	('p73', 'Gene', '7161', (69, 72))	('induced', 'PosReg', (41, 48))	('p73', 'Gene', (69, 72))	('MLN8237', 'Var', (19, 26))	('men', 'Species', '9606', (9, 12))	('CDDP', 'Gene', (30, 34))	('expression', 'MPA', (53, 63))	('NOXA', 'Gene', (116, 120))	('NOXA', 'Gene', '5366', (116, 120))
231856	22302096	Taken together, the results support our notion that MLN8237-induced cell death could partly be mediated by apoptosis and can be significantly enhanced when combined with CDDP in EACs.	('MLN8237-induced', 'Var', (52, 67))	('cell death', 'CPA', (68, 78))	('EAC', 'Phenotype', 'HP:0011459', (178, 181))	('CDDP', 'Chemical', 'MESH:D002945', (170, 174))	('enhanced', 'PosReg', (142, 150))	('MLN8237', 'Chemical', 'MESH:C550258', (52, 59))	('apoptosis', 'CPA', (107, 116))
231857	22302096	The aforementioned in vitro results prompted us to determine the anti-tumor activity of MLN8237 and/or CDDP treatments in EAC xenograft mouse models.	('MLN8237', 'Chemical', 'MESH:C550258', (88, 95))	('mouse', 'Species', '10090', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CDDP', 'Chemical', 'MESH:D002945', (103, 107))	('MLN8237', 'Var', (88, 95))	('tumor', 'Disease', (70, 75))	('men', 'Species', '9606', (9, 12))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('men', 'Species', '9606', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
231858	22302096	The in vivo anti-tumor activity analysis demonstrated that treatment with the MLN8237 can significantly inhibit the tumor xenograft growth of OE33 (90.99+-8.92, p<0.05) and FLO-1 (76.66+-6.24, p<0.05) cells, whereas marginal suppression was observed with CDDP treatment (OE33: 178.84+-16.87, p<0.05 and FLO-1: 264.53+-14.81, p<0.05).	('MLN8237', 'Chemical', 'MESH:C550258', (78, 85))	('tumor', 'Disease', (17, 22))	('men', 'Species', '9606', (265, 268))	('MLN8237', 'Var', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('men', 'Species', '9606', (64, 67))	('inhibit', 'NegReg', (104, 111))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('CDDP', 'Chemical', 'MESH:D002945', (255, 259))
231859	22302096	In comparison to the single agent treatments, the combination treatment with the MLN8237 and CDDP led to significantly enhanced inhibition of tumor growth (OE33: 51.47+-9.6, p<0.01, and FLO-1: 10.07+-2.2, p<0.01).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MLN8237', 'Chemical', 'MESH:C550258', (81, 88))	('inhibition', 'NegReg', (128, 138))	('MLN8237', 'Var', (81, 88))	('tumor', 'Disease', (142, 147))	('men', 'Species', '9606', (67, 70))	('CDDP', 'Chemical', 'MESH:D002945', (93, 97))	('men', 'Species', '9606', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('enhanced', 'PosReg', (119, 127))
231860	22302096	The immunohistochemical analysis of tumor xenografts for proliferative (Ki-67) and apoptotic markers (p73 and cleaved caspase 3) after treatment with the MLN8237 and/or CDDP (day 21) also demonstrated a significant reduction in the number of cells positive for Ki67 and an increase in the number of cells with positive p73 and cleaved caspase 3 immunostaining (Figure 5A, 5B, 6A & Supplemental Figure 3).	('men', 'Species', '9606', (140, 143))	('cleaved', 'MPA', (327, 334))	('caspase 3', 'Gene', (335, 344))	('tumor', 'Disease', (36, 41))	('caspase 3', 'Gene', '836', (335, 344))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('p73', 'Gene', '7161', (319, 322))	('p73', 'Gene', (319, 322))	('caspase 3', 'Gene', (118, 127))	('MLN8237', 'Var', (154, 161))	('increase', 'PosReg', (273, 281))	('caspase 3', 'Gene', '836', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('men', 'Species', '9606', (387, 390))	('MLN8237', 'Chemical', 'MESH:C550258', (154, 161))	('reduction', 'NegReg', (215, 224))	('CDDP', 'Chemical', 'MESH:D002945', (169, 173))	('p73', 'Gene', '7161', (102, 105))	('p73', 'Gene', (102, 105))
231865	22302096	Therefore, the in vivo data indicate significantly enhanced anti-tumor activity of MLN and CDDP combination in p53 mutant EAC tumor xenograft models.	('CDDP', 'Chemical', 'MESH:D002945', (91, 95))	('tumor', 'Disease', (65, 70))	('mutant', 'Var', (115, 121))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('enhanced', 'PosReg', (51, 59))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (126, 131))
231868	22302096	In this study we have demonstrated frequent amplification and overexpression of AURKA in EACs and reported therapeutic response to the recently developed AURKA selective inhibitor MLN8237 as a single agent and in combination with CDDP.	('MLN8237', 'Var', (180, 187))	('CDDP', 'Chemical', 'MESH:D002945', (230, 234))	('EAC', 'Phenotype', 'HP:0011459', (89, 92))	('AURKA', 'Gene', '6790', (80, 85))	('AURKA', 'Gene', '6790', (154, 159))	('AURKA', 'Gene', (80, 85))	('overexpression', 'PosReg', (62, 76))	('MLN8237', 'Chemical', 'MESH:C550258', (180, 187))	('AURKA', 'Gene', (154, 159))
231872	22302096	In this study, we have chosen the mutant p53 cell models that included FLO-1, OE19 and OE33 EAC cell lines.	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('p53', 'Gene', '7157', (41, 44))	('mutant', 'Var', (34, 40))	('p53', 'Gene', (41, 44))
231874	22302096	P53 mutant tumors have an aberrant DNA-damage response and are inherently resistant to several chemotherapeutic drugs.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('DNA-damage', 'MPA', (35, 45))	('mutant', 'Var', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))
231878	22302096	Our choice of MLN8237 compound is based on its selective potency as a small molecule AURKA inhibitor.	('MLN8237', 'Chemical', 'MESH:C550258', (14, 21))	('MLN8237', 'Var', (14, 21))	('AURKA', 'Gene', '6790', (85, 90))	('AURKA', 'Gene', (85, 90))
231879	22302096	Using MLN8237 alone, we noticed a significant reduction in the percentage of cells in S-phase at 24 hours.	('MLN8237', 'Chemical', 'MESH:C550258', (6, 13))	('MLN8237', 'Var', (6, 13))	('reduction', 'NegReg', (46, 55))
231881	22302096	Previous reports have shown that AURKA inhibition can inhibit proliferation of leukemic, Ewing, multiple myeloma, neuroblastoma and rhabdomyosarcoma cell lines.	('multiple myeloma', 'Disease', 'MESH:D009101', (96, 112))	('inhibition', 'Var', (39, 49))	('rhabdomyosarcoma', 'Disease', (132, 148))	('multiple myeloma', 'Disease', (96, 112))	('neuroblastoma', 'Disease', 'MESH:D009447', (114, 127))	('leukemic', 'Disease', 'MESH:D007938', (79, 87))	('inhibit', 'NegReg', (54, 61))	('proliferation', 'CPA', (62, 75))	('AURKA', 'Gene', '6790', (33, 38))	('neuroblastoma', 'Disease', (114, 127))	('Ewing', 'CPA', (89, 94))	('AURKA', 'Gene', (33, 38))	('neuroblastoma', 'Phenotype', 'HP:0003006', (114, 127))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (132, 148))	('leukemic', 'Disease', (79, 87))	('multiple myeloma', 'Phenotype', 'HP:0006775', (96, 112))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (132, 148))
231882	22302096	Using long-term clonogenic survival assay, we demonstrated a significant inhibition of cell survival following a single dose of MLN8237.	('cell survival', 'CPA', (87, 100))	('MLN8237', 'Var', (128, 135))	('MLN8237', 'Chemical', 'MESH:C550258', (128, 135))	('inhibition', 'NegReg', (73, 83))
231883	22302096	This finding indicates a long and sustained inhibitory effect of MLN8237 in vitro, which has a particular significance in preclinical studies of anti-cancer drugs.	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('inhibitory effect', 'MPA', (44, 61))	('MLN8237', 'Var', (65, 72))	('MLN8237', 'Chemical', 'MESH:C550258', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
231884	22302096	We have confirmed the inhibition of AURKA activity following MLN8237 treatment, as demonstrated by suppression of T288 amino acid residue phosphorylation in AURKA.	('activity', 'MPA', (42, 50))	('T288 amino acid', 'Chemical', '-', (114, 129))	('MLN8237', 'Chemical', 'MESH:C550258', (61, 68))	('inhibition', 'NegReg', (22, 32))	('T288 amino acid residue phosphorylation', 'MPA', (114, 153))	('AURKA', 'Gene', '6790', (36, 41))	('AURKA', 'Gene', '6790', (157, 162))	('men', 'Species', '9606', (74, 77))	('suppression', 'NegReg', (99, 110))	('AURKA', 'Gene', (36, 41))	('AURKA', 'Gene', (157, 162))	('MLN8237 treatment', 'Var', (61, 78))
231885	22302096	Interestingly, following MLN8237 treatment, there was a modest upregulation of inactive non-phosphorylated AURKA protein levels.	('men', 'Species', '9606', (38, 41))	('AURKA', 'Gene', (107, 112))	('MLN8237', 'Chemical', 'MESH:C550258', (25, 32))	('MLN8237', 'Var', (25, 32))	('upregulation', 'PosReg', (63, 75))	('AURKA', 'Gene', '6790', (107, 112))
231889	22302096	In vitro studies with AURKA selective inhibitors have shown enhanced antitumor activity in combination with other chemotherapeutic agents such as Docetaxel, Nilotinib and Vorinostat.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Nilotinib', 'Chemical', 'MESH:C498826', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Vorinostat', 'Chemical', 'MESH:D000077337', (171, 181))	('AURKA', 'Gene', '6790', (22, 27))	('inhibitors', 'Var', (38, 48))	('tumor', 'Disease', (73, 78))	('Docetaxel', 'Chemical', 'MESH:D000077143', (146, 155))	('AURKA', 'Gene', (22, 27))	('enhanced', 'PosReg', (60, 68))
231891	22302096	Therefore, we decided to test the therapeutic efficacy of MLN8237 and CDDP as single agents and in combination.	('CDDP', 'Gene', (70, 74))	('test', 'Reg', (25, 29))	('MLN8237', 'Chemical', 'MESH:C550258', (58, 65))	('CDDP', 'Chemical', 'MESH:D002945', (70, 74))	('MLN8237', 'Var', (58, 65))
231892	22302096	Interestingly, a recent study has shown that Aurora kinase A critically contributes to the resistance to CDDP in JAK2 V617F mutantinduced transformed cells suggesting that AURKA is most likely critical for resistance to DNA damage.	('Aurora kinase A', 'Gene', (45, 60))	('AURKA', 'Gene', '6790', (172, 177))	('JAK2', 'Gene', (113, 117))	('resistance to CDDP', 'MPA', (91, 109))	('AURKA', 'Gene', (172, 177))	('Aurora kinase A', 'Gene', '6790', (45, 60))	('V617F', 'SUBSTITUTION', 'None', (118, 123))	('CDDP', 'Chemical', 'MESH:D002945', (105, 109))	('contributes', 'Reg', (72, 83))	('JAK2', 'Gene', '3717', (113, 117))	('V617F', 'Var', (118, 123))	('mutantinduced', 'Var', (124, 137))
231893	22302096	Our in vitro and in vivo results suggest a promising therapeutic window for the MLN8237 and CDDP combination as indicated by suppressed cell survival in vitro and significant regression of tumor growth in vivo.	('cell survival', 'CPA', (136, 149))	('tumor', 'Disease', (189, 194))	('MLN8237', 'Var', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('CDDP', 'Gene', (92, 96))	('regression', 'NegReg', (175, 185))	('CDDP', 'Chemical', 'MESH:D002945', (92, 96))	('suppressed', 'NegReg', (125, 135))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('MLN8237', 'Chemical', 'MESH:C550258', (80, 87))
231896	22302096	We have observed a significant increase in the percentage of cells with polyploidy following treatment for 24 hours, suggesting that mitotic catastrophe remains as one of the predominant functions of MLN8237, a finding that is reasonably expected based on the known functions of Aurora kinases during cell cycle.	('MLN8237', 'Var', (200, 207))	('polyploidy', 'Disease', (72, 82))	('mitotic catastrophe', 'CPA', (133, 152))	('polyploidy', 'Disease', 'MESH:D011123', (72, 82))	('men', 'Species', '9606', (98, 101))	('MLN8237', 'Chemical', 'MESH:C550258', (200, 207))
231897	22302096	The treatment with MLN8237 alone and in combination with CDDP led to a significant reduction in percentage of cells in the G1-phase and induction of G2-M-phase arrest in vitro.	('induction', 'Reg', (136, 145))	('MLN8237', 'Chemical', 'MESH:C550258', (19, 26))	('MLN8237', 'Var', (19, 26))	('men', 'Species', '9606', (9, 12))	('arrest', 'Disease', 'MESH:D006323', (160, 166))	('arrest', 'Disease', (160, 166))	('CDDP', 'Chemical', 'MESH:D002945', (57, 61))	('reduction', 'NegReg', (83, 92))
231900	22302096	The fact that MLN8237 led to inhibition of the G2- to M-phase transition could provide a window for activation of pro-apoptotic machinery and induction of apoptosis in cells that acquire DNA damage with CDDP.	('G2-', 'CPA', (47, 50))	('pro-apoptotic machinery', 'MPA', (114, 137))	('CDDP', 'Chemical', 'MESH:D002945', (203, 207))	('inhibition', 'NegReg', (29, 39))	('induction', 'Reg', (142, 151))	('MLN8237', 'Chemical', 'MESH:C550258', (14, 21))	('MLN8237', 'Var', (14, 21))	('activation', 'PosReg', (100, 110))
231903	22302096	It is known that CDDP-induced DNA damage can also result in cell cycle arrest and apoptosis, which could explain the observed added benefit of combining MLN8237 with CDDP.	('result in', 'Reg', (50, 59))	('apoptosis', 'CPA', (82, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('arrest', 'Disease', 'MESH:D006323', (71, 77))	('CDDP', 'Chemical', 'MESH:D002945', (166, 170))	('MLN8237', 'Chemical', 'MESH:C550258', (153, 160))	('arrest', 'Disease', (71, 77))	('CDDP', 'Chemical', 'MESH:D002945', (17, 21))	('MLN8237', 'Var', (153, 160))
231904	22302096	Interestingly, the MLN8237 and CDDP combination demonstrated enhanced activation of TAp73 signaling as indicated by increased TAp73 protein level and upregulation of its downstream transcription targets, NOXA and PUMA.	('p73', 'Gene', (86, 89))	('MLN8237', 'Chemical', 'MESH:C550258', (19, 26))	('transcription', 'MPA', (181, 194))	('p73', 'Gene', '7161', (128, 131))	('p73', 'Gene', (128, 131))	('CDDP', 'Chemical', 'MESH:D002945', (31, 35))	('MLN8237', 'Var', (19, 26))	('NOXA', 'Gene', (204, 208))	('upregulation', 'PosReg', (150, 162))	('increased', 'PosReg', (116, 125))	('NOXA', 'Gene', '5366', (204, 208))	('enhanced activation', 'PosReg', (61, 80))	('p73', 'Gene', '7161', (86, 89))
231907	22302096	Loss of p53 function due to gene mutations or deletions is a known precancerous event observed in about 50% of human malignancies.	('p53', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('p53', 'Gene', '7157', (8, 11))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('human', 'Species', '9606', (111, 116))	('Loss', 'NegReg', (0, 4))	('function', 'MPA', (12, 20))	('malignancies', 'Disease', (117, 129))	('cancer', 'Disease', (70, 76))	('deletions', 'Var', (46, 55))	('gene mutations', 'Var', (28, 42))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
231909	22302096	p73 is expressed as multiple splice variants of which TAp73beta splice variant exhibits more structural resemblance to TAp53 and also induces similar pro-apoptotic targets such as PUMA, NOXA, p21 and p53AIP following DNA damage.	('p73', 'Gene', (0, 3))	('p73', 'Gene', '7161', (56, 59))	('p53', 'Gene', (121, 124))	('p73', 'Gene', (56, 59))	('p53', 'Gene', (200, 203))	('NOXA', 'Gene', (186, 190))	('p53', 'Gene', '7157', (121, 124))	('PUMA', 'MPA', (180, 184))	('structural', 'MPA', (93, 103))	('pro-apoptotic targets', 'MPA', (150, 171))	('p53', 'Gene', '7157', (200, 203))	('NOXA', 'Gene', '5366', (186, 190))	('p21', 'Var', (192, 195))	('induces', 'PosReg', (134, 141))	('p73', 'Gene', '7161', (0, 3))
231911	22302096	Our present findings, using MLN8237, in this context suggest that MLN8237 is expected to be a beneficial approach in both p53 wild-type and mutant EACs.	('p53', 'Gene', '7157', (122, 125))	('EAC', 'Phenotype', 'HP:0011459', (147, 150))	('MLN8237', 'Chemical', 'MESH:C550258', (66, 73))	('MLN8237', 'Chemical', 'MESH:C550258', (28, 35))	('MLN8237', 'Var', (66, 73))	('mutant', 'Var', (140, 146))	('p53', 'Gene', (122, 125))
231912	22302096	In conclusion, our results support the investigation of MLN8237 as a targeted therapy approach for EAC, and likely other malignancies exhibiting overexpression of AURKA.	('MLN8237', 'Var', (56, 63))	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('AURKA', 'Gene', '6790', (163, 168))	('AURKA', 'Gene', (163, 168))	('malignancies', 'Disease', 'MESH:D009369', (121, 133))	('EAC', 'Disease', (99, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (56, 63))	('malignancies', 'Disease', (121, 133))
231913	22302096	The combination of MLN8237 with CDPP results in significantly enhanced anti-tumor activity that is possibly mediated by TAp73beta and mitotic catastrophe events in p53-mutant tumors.	('p73', 'Gene', (122, 125))	('tumors', 'Disease', (175, 181))	('tumor', 'Disease', (175, 180))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('MLN8237', 'Chemical', 'MESH:C550258', (19, 26))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('MLN8237', 'Var', (19, 26))	('tumor', 'Disease', (76, 81))	('enhanced', 'PosReg', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CDPP', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('p53', 'Gene', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('p73', 'Gene', '7161', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('p53', 'Gene', '7157', (164, 167))
231914	22302096	As early phases of clinical trials for MLN8237 are being actively conducted, these data provide useful information for existing and future clinical trials that test MLN8237 in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('MLN8237', 'Chemical', 'MESH:C550258', (39, 46))	('MLN8237', 'Var', (39, 46))	('MLN8237', 'Chemical', 'MESH:C550258', (165, 172))	('human', 'Species', '9606', (176, 181))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('MLN8237', 'Var', (165, 172))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))
231917	33506604	Furthermore, microRNAs (miRNAs) play a pivotal role in the regulation of EMT phenotype, as a result, some miRNAs impact cancer stemness and drug resistance.	('drug resistance', 'CPA', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('drug resistance', 'Phenotype', 'HP:0020174', (140, 155))	('impact', 'Reg', (113, 119))	('cancer stemness', 'Disease', 'MESH:D009369', (120, 135))	('miRNAs', 'Var', (106, 112))	('cancer stemness', 'Disease', (120, 135))
231928	33506604	Nowadays, CD44 [17] and CD133 [18] have been the two most common surface markers used to characterize CSCs.	('CD44 [', 'Var', (10, 16))	('CSCs', 'Disease', (102, 106))	('CD133', 'Gene', (24, 29))	('CD133', 'Gene', '8842', (24, 29))
231929	33506604	Recently, CD73 was found to be correlated with the features of CSC since it elevated the expression of Sox9 in dual ATK-mediated signaling pathways via regulating the expression of c-Myc, and down-regulated glycogen synthase kinase 3beta (GSK-3beta).	('glycogen synthase kinase 3beta', 'Gene', '2932', (207, 237))	('CSC', 'Disease', (63, 66))	('glycogen synthase kinase 3beta', 'Gene', (207, 237))	('expression', 'MPA', (89, 99))	('elevated', 'PosReg', (76, 84))	('CD73', 'Var', (10, 14))	('Sox9', 'Gene', '6662', (103, 107))	('GSK-3beta', 'Gene', '2931', (239, 248))	('down-regulated', 'NegReg', (192, 206))	('Sox9', 'Gene', (103, 107))	('dual ATK-mediated signaling pathways', 'Pathway', (111, 147))	('GSK-3beta', 'Gene', (239, 248))	('c-Myc', 'Gene', '4609', (181, 186))	('expression', 'MPA', (167, 177))	('regulating', 'Reg', (152, 162))	('c-Myc', 'Gene', (181, 186))
231939	33506604	miR-199a-5p conferred its tumor-suppressing function in triple-negative breast cancer by inhibiting EMT and stemness by down-regulating its potential target phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) [33].	('PIK3CD', 'Gene', '5293', (229, 235))	('PIK3CD', 'Gene', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('inhibiting', 'NegReg', (89, 99))	('miR-199a-5p', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta', 'Gene', '5293', (157, 227))	('breast cancer', 'Disease', (72, 85))	('down-regulating', 'NegReg', (120, 135))	('tumor', 'Disease', (26, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
231940	33506604	Loss of miR-205 was found to expand mammary stem cell populations, enhance self-renewal, and promote EMT.	('miR-205', 'Gene', (8, 15))	('self-renewal', 'CPA', (75, 87))	('miR-205', 'Gene', '406988', (8, 15))	('promote', 'PosReg', (93, 100))	('mammary stem cell populations', 'CPA', (36, 65))	('EMT', 'CPA', (101, 104))	('enhance', 'PosReg', (67, 74))	('expand', 'PosReg', (29, 35))	('Loss', 'Var', (0, 4))
231942	33506604	Moreover, the loss of miR-205 induced cell stemness by activating NOTCH2 suggests that there might be a jagged1/miR-205/NOTCH2 signaling pathway that regulates cancer stemness [34, 35].	('loss', 'Var', (14, 18))	('jagged1', 'Gene', '182', (104, 111))	('NOTCH2', 'Gene', (66, 72))	('miR-205', 'Gene', (112, 119))	('miR-205', 'Gene', (22, 29))	('miR-205', 'Gene', '406988', (22, 29))	('NOTCH2', 'Gene', '4853', (120, 126))	('activating', 'PosReg', (55, 65))	('cancer stemness', 'Disease', (160, 175))	('miR-205', 'Gene', '406988', (112, 119))	('jagged1', 'Gene', (104, 111))	('NOTCH2', 'Gene', '4853', (66, 72))	('cell stemness', 'CPA', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('NOTCH2', 'Gene', (120, 126))	('cancer stemness', 'Disease', 'MESH:D009369', (160, 175))
231947	33506604	Additionally, loss of miR-508 resulted in the overexpression of zinc finger E-box binding homeobox 1 (ZEB1), Bmi1, and sal-like protein 4 (SALL4), subsequently leading to EMT and cancer stemness, and poor survival of CRC patients [40].	('patients', 'Species', '9606', (221, 229))	('overexpression', 'PosReg', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('miR-508', 'Gene', '574513', (22, 29))	('ZEB1', 'Gene', (102, 106))	('SALL4', 'Gene', '57167', (139, 144))	('zinc finger E-box binding homeobox 1', 'Gene', '6935', (64, 100))	('loss', 'Var', (14, 18))	('zinc finger E-box binding homeobox 1', 'Gene', (64, 100))	('miR-508', 'Gene', (22, 29))	('leading to', 'Reg', (160, 170))	('sal-like protein 4', 'Gene', '57167', (119, 137))	('cancer stemness', 'Disease', 'MESH:D009369', (179, 194))	('sal-like protein 4', 'Gene', (119, 137))	('SALL4', 'Gene', (139, 144))	('ZEB1', 'Gene', '6935', (102, 106))	('cancer stemness', 'Disease', (179, 194))	('Bmi1', 'Gene', (109, 113))	('Bmi1', 'Gene', '648', (109, 113))
231955	33506604	Besides, silencing miR-203 enhanced the stemness of colon cancer cells, with several EMT activators up-regulated, in which Snail could inhibit miR-203 expression.	('up-regulated', 'PosReg', (100, 112))	('stemness of colon cancer', 'Disease', (40, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('inhibit', 'NegReg', (135, 142))	('silencing', 'Var', (9, 18))	('stemness of colon cancer', 'Disease', 'MESH:D015179', (40, 64))	('enhanced', 'PosReg', (27, 35))	('miR-203', 'Gene', (19, 26))	('expression', 'MPA', (151, 161))	('Snail', 'Gene', (123, 128))	('Snail', 'Gene', '6615', (123, 128))	('miR-203', 'Gene', '406986', (19, 26))	('miR-203', 'Gene', '406986', (143, 150))	('miR-203', 'Gene', (143, 150))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))
231958	33506604	In ovarian cancer, let-7a, miR-200c, and miR-186 could significantly reverse resistin-induced EMT and stemness [48].	('miR-186', 'Gene', '406962', (41, 48))	('miR-186', 'Gene', (41, 48))	('resistin', 'Gene', (77, 85))	('reverse', 'NegReg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('resistin', 'Gene', '56729', (77, 85))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('let-7a', 'Var', (19, 25))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Disease', (3, 17))	('miR-200c', 'Gene', '406985', (27, 35))	('miR-200c', 'Gene', (27, 35))
231960	33506604	In high grade serous ovarian cancer cells with Snail knockdown, let-7 expression was up-regulated, and Nanog and Lin28 were down-regulated, suggesting that Snail/Let-7 axis might be an intersection between stemness and EMT [50].	('Snail', 'Gene', (156, 161))	('serous ovarian cancer', 'Disease', (14, 35))	('Snail', 'Gene', '6615', (47, 52))	('Snail', 'Gene', (47, 52))	('Nanog', 'Gene', (103, 108))	('Snail', 'Gene', '6615', (156, 161))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (14, 35))	('knockdown', 'Var', (53, 62))	('Lin28', 'Gene', '79727', (113, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('let-7', 'Gene', (64, 69))	('expression', 'MPA', (70, 80))	('down-regulated', 'NegReg', (124, 138))	('Lin28', 'Gene', (113, 118))	('Nanog', 'Gene', '79923', (103, 108))	('up-regulated', 'PosReg', (85, 97))
231962	33506604	EMT and CSC properties were involved in the lung cancer risk of PM2.5, and chronic PM2.5 could significantly downregulate the levels of three stemness-associated microRNAs, Let-7a, miR-16 and miR-34a [51].	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('downregulate', 'NegReg', (109, 121))	('miR-16', 'Gene', (181, 187))	('Let-7a', 'Var', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PM2.5', 'Var', (83, 88))	('miR-16', 'Gene', '51573', (181, 187))	('involved', 'Reg', (28, 36))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('miR-34a', 'Gene', '407040', (192, 199))	('levels', 'MPA', (126, 132))	('miR-34a', 'Gene', (192, 199))	('lung cancer', 'Disease', (44, 55))
231989	33506604	Overexpression of teratocarcinoma-derived growth factor 1 (TDGF1), an epidermal growth factor (EGF)-related gene, generated a phenotype of erlotinib resistance, both in epidermal growth factor receptor (EGFR)-mutated and EGFR-tyrosine kinase inhibitor (TKI)-sensitive NSCLC cells, which was confirmed by in-vitro studies, in murine xenograft models and clinical patients.	('patients', 'Species', '9606', (362, 370))	('tyrosine kinase', 'Gene', '7294', (226, 241))	('teratocarcinoma-derived growth factor 1', 'Gene', (18, 57))	('TDGF1', 'Gene', (59, 64))	('teratocarcinoma-derived growth factor 1', 'Gene', '21667', (18, 57))	('erlotinib', 'Chemical', 'MESH:D000069347', (139, 148))	('NSCLC', 'Disease', (268, 273))	('murine', 'Species', '10090', (325, 331))	('gene', 'Var', (108, 112))	('epidermal growth factor receptor', 'Gene', (169, 201))	('epidermal growth factor receptor', 'Gene', '13649', (169, 201))	('erlotinib resistance', 'MPA', (139, 159))	('NSCLC', 'Disease', 'MESH:D002289', (268, 273))	('tyrosine kinase', 'Gene', (226, 241))	('generated', 'Reg', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))
231993	33506604	When PRKCA was directly targeted to repress FAK/Ras/c-Myc signaling pathway, miR-296-3p stimulated its own expression, forming a feedback loop that blocked cisplatin chemoresistance and EMT signaling [74].	('cisplatin chemoresistance', 'MPA', (156, 181))	('FAK', 'Gene', '5747', (44, 47))	('miR-296-3p', 'Chemical', '-', (77, 87))	('c-Myc', 'Gene', '4609', (52, 57))	('stimulated', 'PosReg', (88, 98))	('PRKCA', 'Gene', '5578', (5, 10))	('FAK', 'Gene', (44, 47))	('c-Myc', 'Gene', (52, 57))	('EMT signaling', 'CPA', (186, 199))	('expression', 'MPA', (107, 117))	('miR-296-3p', 'Var', (77, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('PRKCA', 'Gene', (5, 10))	('blocked', 'NegReg', (148, 155))
231995	33506604	It was also reported that silencing c-Myc regulated by miR-451-induced MET in docetaxel-resistant LAD cells through decreasing the expression level of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), Snail, p-ERK as well as p-GSK-3beta and increasing E-cadherin expression.	('ERK', 'Gene', '5594', (232, 235))	('decreasing', 'NegReg', (116, 126))	('GSK-3beta', 'Gene', '2931', (249, 258))	('matrix metalloproteinase-9', 'Gene', '4318', (187, 213))	('c-Myc', 'Gene', '4609', (36, 41))	('Snail', 'Gene', '6615', (223, 228))	('MMP-2', 'Gene', '4313', (179, 184))	('MET', 'Gene', (71, 74))	('miR-451', 'Gene', (55, 62))	('ERK', 'Gene', (232, 235))	('E-cadherin', 'Gene', (274, 284))	('E-cadherin', 'Gene', '999', (274, 284))	('GSK-3beta', 'Gene', (249, 258))	('docetaxel', 'Chemical', 'MESH:D000077143', (78, 87))	('matrix metalloproteinase-2', 'Gene', (151, 177))	('LAD', 'Disease', (98, 101))	('MMP-2', 'Gene', (179, 184))	('Snail', 'Gene', (223, 228))	('MET', 'Gene', '79811', (71, 74))	('matrix metalloproteinase-9', 'Gene', (187, 213))	('increasing', 'PosReg', (263, 273))	('LAD', 'Disease', 'MESH:C535887', (98, 101))	('expression level', 'MPA', (131, 147))	('MMP-9', 'Gene', '4318', (215, 220))	('silencing', 'Var', (26, 35))	('miR-451', 'Gene', '574411', (55, 62))	('MMP-9', 'Gene', (215, 220))	('matrix metalloproteinase-2', 'Gene', '4313', (151, 177))	('c-Myc', 'Gene', (36, 41))
231996	33506604	Furthermore, patients with high miR-451 expression had significantly)P <0.05(more favorable prognosis compared with those with low miR-451 expression.	('miR-451', 'Gene', (32, 39))	('patients', 'Species', '9606', (13, 21))	('miR-451', 'Gene', (131, 138))	('high', 'Var', (27, 31))	('miR-451', 'Gene', '574411', (131, 138))	('miR-451', 'Gene', '574411', (32, 39))
231998	33506604	[76] reported that miR-483-3p reversed EMT to MET and inhibited the invasion, migration, and metastasis of lung cancer cells resistant to gefitinib.	('inhibited', 'NegReg', (54, 63))	('miR-483-3p', 'Var', (19, 29))	('miR-483-3p', 'Chemical', '-', (19, 29))	('metastasis of lung cancer', 'Disease', (93, 118))	('gefitinib', 'Chemical', 'MESH:D000077156', (138, 147))	('invasion', 'CPA', (68, 76))	('MET', 'Gene', '79811', (46, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (93, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('MET', 'Gene', (46, 49))
231999	33506604	In molecular terms, miR-483-3p directly targeted integrin beta3 (ITGB3), and thereby inhibited downstream focal adhesion kinase (FAK)/ERK signaling pathways.	('miR-483-3p', 'Var', (20, 30))	('focal adhesion kinase', 'Gene', (106, 127))	('FAK', 'Gene', '5747', (129, 132))	('inhibited', 'NegReg', (85, 94))	('integrin beta3', 'Gene', (49, 63))	('integrin beta3', 'Gene', '3690', (49, 63))	('miR-483-3p', 'Chemical', '-', (20, 30))	('FAK', 'Gene', (129, 132))	('ITGB3', 'Gene', '3690', (65, 70))	('ERK', 'Gene', '5594', (134, 137))	('ITGB3', 'Gene', (65, 70))	('targeted', 'Reg', (40, 48))	('focal adhesion kinase', 'Gene', '5747', (106, 127))	('ERK', 'Gene', (134, 137))
232023	33506604	Particularly, this study revealed that the inhibition of TGF-beta did not suppress EMT in lung cancer cells but induced an EMT-intermediate state, which overturns the traditional notion about TGF-beta-mediated EMT.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('TGF-beta', 'Gene', '7039', (57, 65))	('inhibition', 'Var', (43, 53))	('TGF-beta', 'Gene', '7039', (192, 200))	('induced', 'Reg', (112, 119))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('EMT-intermediate state', 'MPA', (123, 145))	('TGF-beta', 'Gene', (57, 65))	('TGF-beta', 'Gene', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
232029	33506604	As expected, the E-cadherin expression was down-regulated upon restrictive histone modification, whereas vimentin was up-regulated after active histone modification.	('down-regulated', 'NegReg', (43, 57))	('restrictive histone modification', 'Var', (63, 95))	('up-regulated', 'PosReg', (118, 130))	('expression', 'MPA', (28, 38))	('vimentin', 'Gene', '7431', (105, 113))	('vimentin', 'Gene', (105, 113))	('E-cadherin', 'Gene', (17, 27))	('E-cadherin', 'Gene', '999', (17, 27))
232030	33506604	Besides, this deficiency of miR-155 and miR-200c might be correlated with the epigenetic modifications-induced EMT and might promote the loss of sensitivity to gefitinib irrespective of the secondary EGFR mutation, which some gefitinib-resistant cells possess [87].	('deficiency of miR-155', 'Disease', 'MESH:D007153', (14, 35))	('deficiency of miR-155', 'Disease', (14, 35))	('miR-200c', 'Gene', (40, 48))	('EMT', 'PosReg', (111, 114))	('miR-200c', 'Gene', '406985', (40, 48))	('loss of sensitivity to gefitinib', 'MPA', (137, 169))	('EGFR', 'Gene', (200, 204))	('gefitinib', 'Chemical', 'MESH:D000077156', (160, 169))	('epigenetic modifications-induced', 'MPA', (78, 110))	('gefitinib', 'Chemical', 'MESH:D000077156', (226, 235))	('mutation', 'Var', (205, 213))	('promote', 'PosReg', (125, 132))
232048	33506604	In addition, restoration of TGFBR2, a target of miR-204, could recover resistance to 5-FU in GC cells with miR-204 upregulated [99].	('[99', 'MPA', (127, 130))	('TGFBR2', 'Gene', (28, 34))	('5-FU', 'Chemical', 'MESH:D005472', (85, 89))	('miR-204', 'Gene', (48, 55))	('miR-204', 'Gene', '406987', (48, 55))	('TGFBR2', 'Gene', '7048', (28, 34))	('miR-204', 'Gene', '406987', (107, 114))	('recover', 'PosReg', (63, 70))	('restoration', 'Var', (13, 24))	('resistance to 5-FU', 'MPA', (71, 89))	('miR-204', 'Gene', (107, 114))	('upregulated', 'PosReg', (115, 126))
232055	33506604	Hence, a feedback loop between DNMT1 and miR-30a/c-5p could be a potential signature for addressing EMT and cisplatin resistance in OC, thereby providing a therapeutic strategy for epigenetically improving the responsiveness to anti-cancer agents [102].	('miR-30a', 'Gene', '407029', (41, 48))	('c-5p', 'Gene', '727', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('addressing', 'Reg', (89, 99))	('responsiveness', 'MPA', (210, 224))	('DNMT1', 'Gene', '1786', (31, 36))	('epigenetically', 'Var', (181, 195))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('miR-30a', 'Gene', (41, 48))	('DNMT1', 'Gene', (31, 36))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cisplatin resistance', 'MPA', (108, 128))	('OC', 'Gene', '632', (132, 134))	('improving', 'PosReg', (196, 205))	('c-5p', 'Gene', (49, 53))
232059	33506604	[103] found that miR-1294 dysregulation affected OC cisplatin resistance by regulating IGF1R.	('affected', 'Reg', (40, 48))	('IGF1R', 'Gene', '3480', (87, 92))	('dysregulation', 'Var', (26, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('miR-1294', 'Gene', '100302181', (17, 25))	('regulating', 'Reg', (76, 86))	('IGF1R', 'Gene', (87, 92))	('OC', 'Gene', '632', (49, 51))	('miR-1294', 'Gene', (17, 25))
232060	33506604	IGF1R knockdown could suppress the proliferation, migration, invasion, and EMT of SKOVP/DDP cells.	('proliferation', 'CPA', (35, 48))	('migration', 'CPA', (50, 59))	('invasion', 'CPA', (61, 69))	('IGF1R', 'Gene', (0, 5))	('suppress', 'NegReg', (22, 30))	('EMT', 'CPA', (75, 78))	('knockdown', 'Var', (6, 15))	('IGF1R', 'Gene', '3480', (0, 5))
232064	33506604	It was found that, in cervical cancer, miR-25-3p reversed EMT to MET with enhanced sensitivity to cisplatin in cisplatin-resistant cells by targeting Sema4C [106].	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('MET', 'Gene', '79811', (65, 68))	('Sema4C', 'Gene', '54910', (150, 156))	('targeting', 'Reg', (140, 149))	('sensitivity', 'MPA', (83, 94))	('MET', 'Gene', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('miR-25-3p', 'Chemical', '-', (39, 48))	('Sema4C', 'Gene', (150, 156))	('cancer', 'Disease', (31, 37))	('enhanced', 'PosReg', (74, 82))	('miR-25-3p', 'Var', (39, 48))
232074	33506604	Introducing miR-200c, inhibiting TGF-beta signaling pathways, or silencing either ZEB1 or ZNF217 repressed the invasive capability and enhanced the sensitivity of breast cancer cells to trastuzumab.	('miR-200c', 'Gene', '406985', (12, 20))	('ZEB1', 'Gene', '6935', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('miR-200c', 'Gene', (12, 20))	('enhanced', 'PosReg', (135, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('TGF-beta', 'Gene', '7039', (33, 41))	('invasive capability', 'CPA', (111, 130))	('ZNF217', 'Gene', (90, 96))	('ZNF217', 'Gene', '7764', (90, 96))	('ZEB1', 'Gene', (82, 86))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('trastuzumab', 'Chemical', 'MESH:D000068878', (186, 197))	('TGF-beta', 'Gene', (33, 41))	('breast cancer', 'Disease', (163, 176))	('repressed', 'NegReg', (97, 106))	('silencing', 'Var', (65, 74))	('sensitivity', 'MPA', (148, 159))	('inhibiting', 'NegReg', (22, 32))
232077	33506604	Due to the inhibitory capability of EMT, miR-708-3p was deemed as a tumor-suppressor miRNA in breast cancer.	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('miR-708-3p', 'Var', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('miR-708-3p', 'Chemical', '-', (41, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
232078	33506604	[112] suggested that reintroduction of miR-708-3p might be a promising therapeutic option for overcoming the chemoresistance of breast cancer cells and, at the same time, suppressing breast cancer metastasis.	('cancer metastasis', 'Disease', 'MESH:D009362', (190, 207))	('reintroduction', 'Var', (21, 35))	('miR-708-3p', 'Chemical', '-', (39, 49))	('chemoresistance', 'CPA', (109, 124))	('suppressing', 'NegReg', (171, 182))	('cancer metastasis', 'Disease', (190, 207))	('overcoming', 'PosReg', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('breast cancer', 'Disease', (183, 196))	('miR-708-3p', 'Var', (39, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
232084	33506604	In HCC, miR-125b could overcome the resistance to oxaliplatin through a mechanism involving the reduction of EVA1A-mediated autophagy, with a simultaneous loss of EMT phenotype [114].	('loss', 'NegReg', (155, 159))	('miR-125b', 'Chemical', '-', (8, 16))	('HCC', 'Gene', (3, 6))	('EVA1A', 'Gene', (109, 114))	('EMT phenotype', 'CPA', (163, 176))	('resistance', 'MPA', (36, 46))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (50, 61))	('HCC', 'Gene', '619501', (3, 6))	('miR-125b', 'Var', (8, 16))	('EVA1A', 'Gene', '84141', (109, 114))	('reduction', 'NegReg', (96, 105))
232086	33506604	Furthermore, miR-130a-3p could restore the sensitivity to gemcitabine and inhibit cell growth in gemcitabine-resistant cells [115].	('miR-130a-3p', 'Chemical', '-', (13, 24))	('gemcitabine', 'Chemical', 'MESH:C056507', (58, 69))	('inhibit', 'NegReg', (74, 81))	('restore', 'PosReg', (31, 38))	('miR-130a-3p', 'Var', (13, 24))	('sensitivity to gemcitabine', 'MPA', (43, 69))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('cell growth', 'CPA', (82, 93))
232104	33506604	miR-139-5p and miR-195-5p significantly suppressed the metastasis potential and chemo-resistance of CRC through EMT by targeting BCL2 and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5), respectively [127, 128].	('BCL2', 'Gene', (129, 133))	('chemo-resistance', 'CPA', (80, 96))	('suppressed', 'NegReg', (40, 50))	('metastasis potential', 'CPA', (55, 75))	('GDPD5', 'Gene', '81544', (199, 204))	('targeting', 'Reg', (119, 128))	('miR-139-5p', 'Var', (0, 10))	('glycerophosphodiester phosphodiesterase domain containing 5', 'Gene', '81544', (138, 197))	('BCL2', 'Gene', '596', (129, 133))	('CRC', 'Disease', (100, 103))	('miR-139-5p', 'Chemical', '-', (0, 10))	('miR-195', 'Gene', (15, 22))	('miR-195', 'Gene', '406971', (15, 22))	('GDPD5', 'Gene', (199, 204))
232113	33506604	miR-514b-3p inhibited migration and drug resistance of CRC cells by decreasing the expression of mesenchymal markers and increasing the expression of epithelial markers.	('inhibited', 'NegReg', (12, 21))	('drug resistance of CRC cells', 'CPA', (36, 64))	('expression', 'MPA', (136, 146))	('miR-514b-3p', 'Chemical', '-', (0, 11))	('miR-514b-3p', 'Var', (0, 11))	('epithelial', 'Protein', (150, 160))	('mesenchymal markers', 'Protein', (97, 116))	('decreasing', 'NegReg', (68, 78))	('migration', 'CPA', (22, 31))	('increasing', 'PosReg', (121, 131))	('expression', 'MPA', (83, 93))	('drug resistance', 'Phenotype', 'HP:0020174', (36, 51))
232114	33506604	On the contrary, miR-514b-3p played a pro-metastatic role by speeding up the process of EMT.	('miR-514b-3p', 'Var', (17, 28))	('miR-514b-3p', 'Chemical', '-', (17, 28))	('process of EMT', 'CPA', (77, 91))	('speeding up', 'PosReg', (61, 72))
232115	33506604	For instance, miR-124 could enhance the sensitivity of CRC cells to radiation via inhibiting the expression of a recently-identified EMT regulator and stemness inducer, PRRX1 [132].	('PRRX1', 'Gene', '5396', (169, 174))	('expression', 'MPA', (97, 107))	('inhibiting', 'NegReg', (82, 92))	('PRRX1', 'Gene', (169, 174))	('enhance', 'PosReg', (28, 35))	('miR-124', 'Var', (14, 21))	('sensitivity', 'MPA', (40, 51))
232117	33506604	Moreover, over-expression of miR-125a-3p or miR-3656 played similar role by targeting Fyn and RHOF, respectively [128, 135].	('RHOF', 'Gene', '54509', (94, 98))	('over-expression', 'PosReg', (10, 25))	('RHOF', 'Gene', (94, 98))	('miR-125a-3p', 'Chemical', '-', (29, 40))	('Fyn', 'Gene', '2534', (86, 89))	('Fyn', 'Gene', (86, 89))	('miR-3656', 'Gene', '100500840', (44, 52))	('miR-125a-3p', 'Var', (29, 40))	('targeting', 'Reg', (76, 85))	('miR-3656', 'Gene', (44, 52))
232119	33506604	On the locus of miR-203, the suppressive histone mark H3K27me3 was reduced by the loss of ZEB1.	('ZEB1', 'Gene', '6935', (90, 94))	('ZEB1', 'Gene', (90, 94))	('miR-203', 'Gene', (16, 23))	('miR-203', 'Gene', '406986', (16, 23))	('reduced', 'NegReg', (67, 74))	('suppressive histone mark', 'MPA', (29, 53))	('loss', 'Var', (82, 86))	('H3K27me3', 'Protein', (54, 62))
232131	33506604	In esophageal squamous cell carcinoma, miR-125a-5p up-regulated the E-cadherin and down-regulated the N-cadherin and vimentin expression, with an enhanced cytotoxic effect of cisplatin, whose tumor-suppressive effects on patients were further confirmed by longer survival time and earlier tumor stage.	('patients', 'Species', '9606', (221, 229))	('N-cadherin', 'Gene', (102, 112))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('N-cadherin', 'Gene', '1000', (102, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('miR-125a-5p', 'Var', (39, 50))	('miR-125a-5p', 'Chemical', '-', (39, 50))	('tumor', 'Disease', (289, 294))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('tumor', 'Disease', (192, 197))	('up-regulated', 'PosReg', (51, 63))	('expression', 'MPA', (126, 136))	('cytotoxic effect', 'CPA', (155, 171))	('down-regulated', 'NegReg', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('vimentin', 'Gene', '7431', (117, 125))	('vimentin', 'Gene', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('enhanced', 'PosReg', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
232132	33506604	Remarkably, signal transducer and activator of transcription-3 (STAT3) were targeted by miR-125a-5p.	('miR-125a-5p', 'Var', (88, 99))	('miR-125a-5p', 'Chemical', '-', (88, 99))	('STAT3', 'Gene', '6774', (64, 69))	('signal transducer and activator of transcription-3', 'Gene', '6774', (12, 62))	('STAT3', 'Gene', (64, 69))
232133	33506604	However, IL-6, which was extensively reported to activate the STAT3 signaling pathway, could block the tumor-repressing effect of miR-125a-5p [141, 142].	('STAT3', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('miR-125a-5p', 'Var', (130, 141))	('miR-125a-5p', 'Chemical', '-', (130, 141))	('IL-6', 'Gene', (9, 13))	('tumor', 'Disease', (103, 108))	('block', 'NegReg', (93, 98))	('IL-6', 'Gene', '3569', (9, 13))	('STAT3', 'Gene', '6774', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
232136	33506604	After transfection with miR-139-5p mimics, the expression of mesenchymal markers, such as MMP-9 and Vimentin, was decreased while the expression of epithelial markers, such as ZEB1, beta-cadherin, and E-cadherin, was upregulated in cisplatin-resistant NPC cells.	('E-cadherin', 'Gene', (201, 211))	('ZEB1', 'Gene', (176, 180))	('E-cadherin', 'Gene', '999', (201, 211))	('beta-cadherin', 'Protein', (182, 195))	('expression', 'MPA', (134, 144))	('ZEB1', 'Gene', '6935', (176, 180))	('upregulated', 'PosReg', (217, 228))	('Vimentin', 'Gene', '7431', (100, 108))	('MMP-9', 'Gene', '4318', (90, 95))	('PC', 'Gene', '5091', (253, 255))	('miR-139-5p mimics', 'Var', (24, 41))	('MMP-9', 'Gene', (90, 95))	('miR-139-5p', 'Chemical', '-', (24, 34))	('decreased', 'NegReg', (114, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (232, 241))	('expression', 'MPA', (47, 57))	('Vimentin', 'Gene', (100, 108))
232137	33506604	These results exhibited that miR-139-5p might act as a tumor suppressor in the restoration of the sensitivity of NPC cells to cisplatin by regulating EMT [144].	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miR-139-5p', 'Chemical', '-', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('PC', 'Gene', '5091', (114, 116))	('regulating', 'Reg', (139, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('EMT [', 'CPA', (150, 155))	('miR-139-5p', 'Var', (29, 39))
232138	33506604	miR-296-3p, which was negatively regulated by nicotine, inhibited PI3K/AKT/c-Myc or Ras/BRAF/ERK/MEK/c-Myc pathways to prompt its own expression in an MK2-dependent manner.	('ERK', 'Gene', (93, 96))	('MK2', 'Gene', '9261', (151, 154))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('c-Myc', 'Gene', '4609', (75, 80))	('AKT', 'Gene', '207', (71, 74))	('MK2', 'Gene', (151, 154))	('expression', 'MPA', (134, 144))	('prompt', 'PosReg', (119, 125))	('c-Myc', 'Gene', (101, 106))	('miR-296-3p', 'Chemical', '-', (0, 10))	('MEK', 'Gene', '5609', (97, 100))	('inhibited', 'NegReg', (56, 65))	('ERK', 'Gene', '5594', (93, 96))	('nicotine', 'Chemical', 'MESH:D009538', (46, 54))	('c-Myc', 'Gene', '4609', (101, 106))	('MEK', 'Gene', (97, 100))	('AKT', 'Gene', (71, 74))	('c-Myc', 'Gene', (75, 80))	('miR-296-3p', 'Var', (0, 10))
232139	33506604	Thus, the upregulation of miR-296-3p due to the feedback loop ultimately suppressed NPC cell metastasis and drug resistance partially via EMT.	('upregulation', 'PosReg', (10, 22))	('miR-296-3p', 'Chemical', '-', (26, 36))	('drug resistance', 'CPA', (108, 123))	('drug resistance', 'Phenotype', 'HP:0020174', (108, 123))	('miR-296-3p', 'Var', (26, 36))	('suppressed', 'NegReg', (73, 83))	('PC', 'Gene', '5091', (85, 87))
232140	33506604	Besides, NPC patients with higher miR-296-3p expression had longer overall survival than those with lower miR-296-3p expression [145].	('miR-296-3p expression', 'Var', (34, 55))	('longer', 'PosReg', (60, 66))	('PC', 'Gene', '5091', (10, 12))	('overall survival', 'MPA', (67, 83))	('patients', 'Species', '9606', (13, 21))	('miR-296-3p', 'Chemical', '-', (34, 44))	('miR-296-3p', 'Chemical', '-', (106, 116))
232151	33506604	Knocking down CTSB inhibited mesenchymal transition.	('inhibited', 'NegReg', (19, 28))	('Knocking down', 'Var', (0, 13))	('CTSB', 'Gene', (14, 18))	('mesenchymal transition', 'CPA', (29, 51))	('CTSB', 'Gene', '1508', (14, 18))
232153	33506604	Several studies suggested that miR-125a-3p was involved in the modulation of EMT and chemoresistance in prostate cancer cells [40, 147, 153].	('miR-125a-3p', 'Var', (31, 42))	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('involved', 'Reg', (47, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('miR-125a-3p', 'Chemical', '-', (31, 42))	('prostate cancer', 'Disease', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
232163	33506604	However, the miR-128-3p could increase intracellular oxaliplatin accumulation, by suppressing the EMT pathway.	('miR-128-3p', 'Chemical', '-', (13, 23))	('intracellular oxaliplatin accumulation', 'MPA', (39, 77))	('miR-128-3p', 'Var', (13, 23))	('suppressing', 'NegReg', (82, 93))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (53, 64))	('EMT pathway', 'CPA', (98, 109))	('increase', 'PosReg', (30, 38))
232164	33506604	Importantly, lower expression of miR-128-3p in patients with advanced CRC was associated with weaker responsiveness to oxaliplatin with poor prognosis.	('expression', 'MPA', (19, 29))	('lower', 'NegReg', (13, 18))	('responsiveness to oxaliplatin', 'MPA', (101, 130))	('patients', 'Species', '9606', (47, 55))	('miR-128-3p', 'Chemical', '-', (33, 43))	('miR-128-3p', 'Var', (33, 43))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (119, 130))	('weaker', 'NegReg', (94, 100))	('CRC', 'Disease', (70, 73))
232165	33506604	Moreover, after transfected into human normal colorectal epithelial cells, miR-128-3p was effectively parceled into secreted exosomes, which could be directly transferred to oxaliplatin-resistant cells, leading to an improvement in oxaliplatin response.	('miR-128-3p', 'Var', (75, 85))	('oxaliplatin response', 'MPA', (232, 252))	('human', 'Species', '9606', (33, 38))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (232, 243))	('miR-128-3p', 'Chemical', '-', (75, 85))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (174, 185))	('improvement', 'PosReg', (217, 228))
232166	33506604	The possible mechanism might be that miR-128-3p suppressed oxaliplatin-induced EMT via inhibiting Bmi1 expression and decreased effluent oxaliplatin inside the cell through suppressing the expression of MRP5, a drug transporter [165].	('effluent oxaliplatin inside the', 'MPA', (128, 159))	('oxaliplatin-induced', 'MPA', (59, 78))	('Bmi1', 'Gene', (98, 102))	('expression', 'MPA', (103, 113))	('MRP5', 'Gene', '10057', (203, 207))	('MRP5', 'Gene', (203, 207))	('expression', 'MPA', (189, 199))	('suppressed', 'NegReg', (48, 58))	('Bmi1', 'Gene', '648', (98, 102))	('miR-128-3p', 'Chemical', '-', (37, 47))	('decreased', 'NegReg', (118, 127))	('inhibiting', 'NegReg', (87, 97))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (137, 148))	('miR-128-3p', 'Var', (37, 47))	('suppressing', 'NegReg', (173, 184))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (59, 70))
232178	32208405	DEGs were from 4 Gene Expression Omnibus (GEO) databases (GSE92396, GSE20347, GSE23400, and GSE45168) including 87 esophageal tumor samples and 84 normal samples.	('esophageal tumor', 'Phenotype', 'HP:0100751', (115, 131))	('DEGs', 'Gene', (0, 4))	('GSE23400', 'Var', (78, 86))	('DEGs', 'Gene', '8560', (0, 4))	('esophageal tumor', 'Disease', 'MESH:D004938', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('esophageal tumor', 'Disease', (115, 131))	('GSE20347', 'Var', (68, 76))	('GSE92396', 'Var', (58, 66))	('GSE45168', 'Var', (92, 100))
232185	32208405	Gene set enrichment analysis (GSEA) showed that proteasome and nucleotide excision repair were 2 most differentially enriched pathways in the SPP1 high-expression phenotype, and ECM-receptor interaction and focal adhesion in FN1 high-expression phenotype.	('FN1', 'Gene', (225, 228))	('EC', 'Disease', 'MESH:D005955', (178, 180))	('SPP1', 'Gene', '6696', (142, 146))	('high-expression', 'Var', (147, 162))	('SPP1', 'Gene', (142, 146))	('FN1', 'Gene', '2335', (225, 228))	('GSEA', 'Chemical', '-', (30, 34))	('enriched', 'Reg', (117, 125))
232198	32208405	Kaplan-Meier analysis demonstrated that patients with high expression levels of SPP1 and FN1 had worse overall survival.	('FN1', 'Gene', '2335', (89, 92))	('high expression levels', 'Var', (54, 76))	('overall', 'MPA', (103, 110))	('patients', 'Species', '9606', (40, 48))	('FN1', 'Gene', (89, 92))	('worse', 'NegReg', (97, 102))	('SPP1', 'Gene', '6696', (80, 84))	('SPP1', 'Gene', (80, 84))
232199	32208405	These results indicated that SPP1 and FN1 had the potential to be biomarkers for esophageal cancer, and dysregulation of SPP1 and FN1 was associated with the development and prognosis of this malignancy.	('FN1', 'Gene', '2335', (130, 133))	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('malignancy', 'Disease', (192, 202))	('SPP1', 'Gene', '6696', (29, 33))	('FN1', 'Gene', (130, 133))	('associated with', 'Reg', (138, 153))	('FN1', 'Gene', '2335', (38, 41))	('FN1', 'Gene', (38, 41))	('SPP1', 'Gene', '6696', (121, 125))	('dysregulation', 'Var', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('SPP1', 'Gene', (121, 125))	('esophageal cancer', 'Disease', (81, 98))	('malignancy', 'Disease', 'MESH:D009369', (192, 202))	('SPP1', 'Gene', (29, 33))
232202	32208405	We searched and obtained 1384 items, and gene expression profiling of patients with esophageal cancer GSE92396, GSE20347, GSE23400, and GSE45168 was finally obtained.	('patients', 'Species', '9606', (70, 78))	('GSE45168', 'Var', (136, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('GSE23400', 'Var', (122, 130))	('esophageal cancer', 'Disease', (84, 101))	('GSE92396', 'Var', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('GSE20347', 'Var', (112, 120))
232223	32208405	A total of 1577 genes, 1732 genes, 672 genes, and 1523 genes were identified as DEGs between tumor samples and normal samples after the analysis GSE92396, GSE20347, GSE23400, and GSE45168, respectively (Figure 1B-1E).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('GSE92396', 'Var', (145, 153))	('GSE45168', 'Var', (179, 187))	('GSE20347', 'Var', (155, 163))	('tumor', 'Disease', (93, 98))	('DEGs', 'Gene', (80, 84))	('GSE23400', 'Var', (165, 173))	('DEGs', 'Gene', '8560', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
232237	32208405	Both revealed that the dysregulation of SPP1 and FN1 was associated with tumorigenesis of esophageal carcinoma.	('dysregulation', 'Var', (23, 36))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('esophageal carcinoma', 'Disease', (90, 110))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (90, 110))	('FN1', 'Gene', '2335', (49, 52))	('tumor', 'Disease', (73, 78))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (90, 110))	('FN1', 'Gene', (49, 52))	('SPP1', 'Gene', '6696', (40, 44))	('associated', 'Reg', (57, 67))	('SPP1', 'Gene', (40, 44))
232248	32208405	Plots of the Kaplan-Meier estimator showed that the overexpression of SPP1 and FN1 does not affect the overall survival of patients, while dysregulation of SPP1 and FN1 was remarkably connected with shorter disease-free survival (DFS) and earlier recurrence (P=0.001, HR: 2.2, Figure 7A; P=0.0064, HR: 1.9, Figure 7B).	('shorter', 'NegReg', (199, 206))	('FN1', 'Gene', '2335', (165, 168))	('earlier recurrence', 'CPA', (239, 257))	('disease-free survival', 'CPA', (207, 228))	('patients', 'Species', '9606', (123, 131))	('FN1', 'Gene', '2335', (79, 82))	('FN1', 'Gene', (165, 168))	('FN1', 'Gene', (79, 82))	('SPP1', 'Gene', '6696', (70, 74))	('SPP1', 'Gene', (70, 74))	('SPP1', 'Gene', '6696', (156, 160))	('dysregulation', 'Var', (139, 152))	('SPP1', 'Gene', (156, 160))
232251	32208405	Our results suggest that alterations at the molecular level can identify esophageal cancer with high accuracy, in contrast to studies using only a single dataset.	('alterations', 'Var', (25, 36))	('esophageal cancer', 'Disease', (73, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
232255	32208405	In our study, we found that pathways related to proteasome and nucleotide excision repair were the 2 most differentially enriched in SPP1 high-expression phenotype, and ECM-receptor interaction and focal adhesion were the 2 most differentially enriched in FN1 high-expression phenotype.	('high-expression', 'Var', (138, 153))	('FN1', 'Gene', '2335', (256, 259))	('FN1', 'Gene', (256, 259))	('SPP1', 'Gene', '6696', (133, 137))	('SPP1', 'Gene', (133, 137))	('EC', 'Disease', 'MESH:D005955', (169, 171))
232270	32208405	SPP1 mediates the radioresistance of lung cancer with KRAS mutations, and the loss of SPP1 produces a microenvironment that promotes glioblastoma.	('glioblastoma', 'Disease', (133, 145))	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('SPP1', 'Gene', '6696', (0, 4))	('SPP1', 'Gene', (0, 4))	('KRAS', 'Gene', (54, 58))	('promotes', 'PosReg', (124, 132))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('KRAS', 'Gene', '3845', (54, 58))	('mutations', 'Var', (59, 68))	('loss', 'Var', (78, 82))	('SPP1', 'Gene', '6696', (86, 90))	('radioresistance', 'CPA', (18, 33))	('SPP1', 'Gene', (86, 90))
232282	32208405	It was found that a single-nucleotide polymorphism in FN1 affects tumor migration and metastasis of colon cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FN1', 'Gene', (54, 57))	('tumor', 'Disease', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('metastasis of colon cancer', 'Disease', 'MESH:D015179', (86, 112))	('affects', 'Reg', (58, 65))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('FN1', 'Gene', '2335', (54, 57))	('single-nucleotide polymorphism', 'Var', (20, 50))	('metastasis of colon cancer', 'Disease', (86, 112))
232285	32208405	Studies have shown that loss of SPP1 produces a microenvironment that promotes glioblastoma, which stimulates our interests in studying the relationship between SPP1 and immune microenvironment in esophageal cancer.	('SPP1', 'Gene', (32, 36))	('loss', 'Var', (24, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('SPP1', 'Gene', '6696', (161, 165))	('SPP1', 'Gene', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('glioblastoma', 'Disease', (79, 91))	('glioblastoma', 'Disease', 'MESH:D005909', (79, 91))	('promotes', 'PosReg', (70, 78))	('esophageal cancer', 'Disease', (197, 214))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('SPP1', 'Gene', '6696', (32, 36))
232290	32190735	LINC00152 Knock-down Suppresses Esophageal Cancer by EGFR Signaling Pathway This study aims to explain the role and mechanism of lncRNA LINC00152 in esophageal cancer.	('Esophageal Cancer', 'Disease', (32, 49))	('LINC00152', 'Gene', (136, 145))	('LINC00152', 'Gene', (0, 9))	('Knock-down', 'Var', (10, 20))	('esophageal cancer', 'Disease', (149, 166))	('LINC00152', 'Gene', '112597', (136, 145))	('LINC00152', 'Gene', '112597', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('EGFR', 'Gene', '1956', (53, 57))	('Suppresses', 'NegReg', (21, 31))	('EGFR', 'Gene', (53, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
232294	32190735	Compared with NC groups, the cell proliferation rate of lncRNA groups were significantly suppressed (P<0.05, respectively); the cell apoptosis and G1 phase rates were significantly enhanced in the lncRNA groups (P<0.05, respectively).	('rat', 'Species', '10116', (48, 51))	('rat', 'Species', '10116', (156, 159))	('G1 phase rates', 'CPA', (147, 161))	('enhanced', 'PosReg', (181, 189))	('lncRNA', 'Var', (197, 203))	('rat', 'Species', '10116', (41, 44))	('cell proliferation rate', 'CPA', (29, 52))	('cell apoptosis', 'CPA', (128, 142))
232304	32190735	In this study, we discussed the effects and mechanisms of lncRNA LINC00152 knockdown in Eca 109 and Kyse 150 cells which were two kinds of esophageal cancer in vitro study.	('LINC00152', 'Gene', (65, 74))	('knockdown', 'Var', (75, 84))	('esophageal cancer', 'Disease', (139, 156))	('LINC00152', 'Gene', '112597', (65, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
232323	32190735	After electrophoresis, proteins were transferred to PVDF (Millipore, Bedford, MA, USA) membrane at 4 C. After blocking, the membrane was incubated with primary antibodies: EGFR (1:800) (Abcam, USA), PI3K (1:800) (Abcam, USA), AKT (1:800) (Abcam, USA), P21 (1:800) (Abcam, USA) and GAPDH (1:1000) (Abcam, USA).	('AKT', 'Gene', (226, 229))	('EGFR', 'Gene', '1956', (172, 176))	('PVDF', 'Chemical', 'MESH:C024865', (52, 56))	('EGFR', 'Gene', (172, 176))	('P21', 'Gene', (252, 255))	('PI3K (1:800', 'Var', (199, 210))	('AKT', 'Gene', '207', (226, 229))	('P21', 'Gene', '644914', (252, 255))
232330	32190735	The relative results found that the lncRNA LINC00152 knockdown (si-lncRNA groups) suppressed cells proliferation compared with that of NC groups in Eca 109 (P<0.05,69.69+-5.65 vs.127.33+-5.02, Figure 2A) and Kyse 150 (P<0.05,71.50+-4.48 vs.130.58+-6.00, Figure 2B).	('cells proliferation', 'CPA', (93, 112))	('LINC00152', 'Gene', (43, 52))	('knockdown', 'Var', (53, 62))	('suppressed', 'NegReg', (82, 92))	('LINC00152', 'Gene', '112597', (43, 52))	('rat', 'Species', '10116', (106, 109))
232334	32190735	Compared with NC groups, the G1 phase rate of si-lncRNA groups which the lncRNA LINC00152 were down-regulated were significantly increased in Eca 109 (P<0.05, Figure 4A) and Kyse 150 (P<0.05, Figure 4B).	('down-regulated', 'NegReg', (95, 109))	('G1 phase rate', 'CPA', (29, 42))	('LINC00152', 'Gene', '112597', (80, 89))	('increased', 'PosReg', (129, 138))	('Eca 109', 'Gene', (142, 149))	('LINC00152', 'Gene', (80, 89))	('Kyse 150', 'Var', (174, 182))	('rat', 'Species', '10116', (38, 41))
232335	32190735	The EGFR, PI3K and AKT proteins expressions of si-ln-cRNA groups were significantly suppressed compare with those proteins expression of NC groups in Eca 109 (P<0.05, Figure 5A) and Kyse 150 (P<0.05, Figure 5B).	('EGFR', 'Gene', (4, 8))	('AKT', 'Gene', '207', (19, 22))	('PI3K', 'Protein', (10, 14))	('si-ln-cRNA groups', 'Var', (47, 64))	('AKT', 'Gene', (19, 22))	('suppressed', 'NegReg', (84, 94))	('EGFR', 'Gene', '1956', (4, 8))
232340	32190735	In our present study, the results shown that knock-down of lncRNA LINC00152 suppressed esophageal cancer cell proliferation and enhanced esophageal cancer cell apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rat', 'Species', '10116', (117, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('esophageal cancer', 'Disease', (87, 104))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lncRNA', 'Gene', (59, 65))	('knock-down', 'Var', (45, 55))	('LINC00152', 'Gene', (66, 75))	('suppressed', 'NegReg', (76, 86))	('enhanced', 'PosReg', (128, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('esophageal cancer', 'Disease', (137, 154))	('LINC00152', 'Gene', '112597', (66, 75))
232349	32190735	In our present study, the results were shown that lncRNA LINC00152 knock-down could inhibit EGFR/PI3K/AKT pathway and stimulate P21 expression in esophageal cancer cell lines (Eca 109 and Kyse 150) in vitro study.	('LINC00152', 'Gene', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('P21', 'Gene', (128, 131))	('esophageal cancer', 'Disease', (146, 163))	('inhibit', 'NegReg', (84, 91))	('expression', 'MPA', (132, 142))	('LINC00152', 'Gene', '112597', (57, 66))	('AKT', 'Gene', '207', (102, 105))	('P21', 'Gene', '644914', (128, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('knock-down', 'Var', (67, 77))	('stimulate', 'PosReg', (118, 127))	('AKT', 'Gene', (102, 105))
232351	32190735	In conclusion, lncRNA LINC00152 knock-down might suppress esophageal cancer cell lines Eca 109 and Kyse 150 cell proliferation and induce cell apoptosis.	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('knock-down', 'Var', (32, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('Kyse 150 cell proliferation', 'CPA', (99, 126))	('LINC00152', 'Gene', '112597', (22, 31))	('LINC00152', 'Gene', (22, 31))	('rat', 'Species', '10116', (120, 123))	('induce', 'PosReg', (131, 137))	('cell apoptosis', 'CPA', (138, 152))	('suppress', 'NegReg', (49, 57))
232362	32103875	Patients with high expression of miR-1304 suffered increased rates of tumor >= 3 cm, low differentiation and stage II + III.	('low differentiation', 'CPA', (85, 104))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('miR-1304', 'Gene', (33, 41))	('miR-1304', 'Gene', '100302240', (33, 41))	('increased', 'PosReg', (51, 60))	('stage II + III', 'CPA', (109, 123))	('tumor', 'Disease', (70, 75))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
232412	32103875	No significant differences in gender, age, and lesion location were found between the two groups, and the high miR-1304 expression group had significantly higher rates of tumor size >= 3 cm, low differentiation and stage II + III than the low miR-1304 expression group (aP < 0.05).	('miR-1304', 'Gene', (111, 119))	('miR-1304', 'Gene', '100302240', (111, 119))	('miR-1304', 'Gene', (243, 251))	('stage II + III', 'CPA', (215, 229))	('high', 'Var', (106, 110))	('miR-1304', 'Gene', '100302240', (243, 251))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('higher', 'PosReg', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('low differentiation', 'CPA', (191, 210))
232424	32103875	String analysis of protein co-expression found 269 relationship pairs, of which co-expression with epidermal growth factor (EGF) was the most common (Figure 5 and Tables 8-10).	('epidermal growth factor', 'Gene', '1950', (99, 122))	('EGF', 'Gene', '1950', (124, 127))	('common', 'Reg', (142, 148))	('co-expression', 'Var', (80, 93))	('EGF', 'Gene', (124, 127))	('epidermal growth factor', 'Gene', (99, 122))
232471	32103875	Patients with high expression of miR-1304 had increased rates of tumor >= 3 cm, low differentiation and stage II + III disease.	('miR-1304', 'Gene', (33, 41))	('tumor', 'Disease', (65, 70))	('miR-1304', 'Gene', '100302240', (33, 41))	('increased', 'PosReg', (46, 55))	('low differentiation', 'CPA', (80, 99))	('Patients', 'Species', '9606', (0, 8))	('stage II', 'Disease', (104, 112))	('high expression', 'Var', (14, 29))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
232483	30544482	When the patients were stratified according to country, pathological type, treatment strategies, sample size, and different HR estimate method, high NLR was also significantly correlated with poor OS.	('patients', 'Species', '9606', (9, 17))	('OS', 'Chemical', '-', (197, 199))	('NLR', 'Gene', (149, 152))	('high', 'Var', (144, 148))	('poor OS', 'Disease', (192, 199))	('correlated', 'Reg', (176, 186))
232548	30544482	In our previous meta-analysis, we found high PLR was is associated with poor OS in patients with EC.	('high', 'Var', (40, 44))	('poor OS', 'Disease', (72, 79))	('PLR', 'Gene', (45, 48))	('OS', 'Chemical', '-', (77, 79))	('patients', 'Species', '9606', (83, 91))
232585	29849286	Acids usually cause coagulation necrosis leading to eschar formation and limited deep tissue penetration.	('Acids', 'Var', (0, 5))	('coagulation necrosis', 'Disease', 'MESH:D009336', (20, 40))	('cause', 'Reg', (14, 19))	('coagulation necrosis', 'Disease', (20, 40))	('coagulation necrosis', 'Phenotype', 'HP:0010885', (20, 40))	('eschar', 'Disease', (52, 58))
232586	29849286	Alkalis tend to cause liquefactive necrosis and thrombosis in blood vessels leading to the destruction of deeper tissues.	('thrombosis', 'Disease', (48, 58))	('necrosis', 'Disease', (35, 43))	('necrosis', 'Disease', 'MESH:D009336', (35, 43))	('thrombosis', 'Disease', 'MESH:D013927', (48, 58))	('thrombosis in blood vessels', 'Phenotype', 'HP:0001907', (48, 75))	('Alkalis', 'Var', (0, 7))	('cause', 'Reg', (16, 21))
232642	29375211	Before NACT, endoscopic ultrasound (EUS) and contrast-enhanced computed tomography (CE-CT) had been performed to assess clinical stage and confirm that patients had T2-4N0-3M0 GC, according to the Japanese classification of gastric carcinoma.	('NACT', 'Chemical', '-', (7, 11))	('gastric carcinoma', 'Disease', 'MESH:D013274', (224, 241))	('GC', 'Phenotype', 'HP:0012126', (176, 178))	('gastric carcinoma', 'Disease', (224, 241))	('T2-4N0-3M0 GC', 'Var', (165, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('patients', 'Species', '9606', (152, 160))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (224, 241))
232690	29375211	Although many studies have shown that there is a positive impact from delaying the NACT-surgery interval time on pCR rate and short-term outcomes, the underlying mechanism has never been discussed.	('pCR rate', 'Disease', (113, 121))	('NACT', 'Chemical', '-', (83, 87))	('delaying', 'Var', (70, 78))
232783	28707457	Additionally, high hsa-mir-223 level was associated with a better prognosis in cancer, in contrast to the other miRNAs.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('high', 'Var', (14, 18))	('hsa-mir-223', 'Gene', (19, 30))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('hsa-mir-223', 'Gene', '407008', (19, 30))
232819	28349679	CHB patients with an LSPS >=5.5 had a higher cumulative incidence rate of esophageal variceal bleeding during follow-up, and an LSPS score >=6.5 was an independent risk factor for variceal bleeding from high-risk esophageal varices, indicating that prophylactic treatment should be considered in these high-risk patients.	('variceal bleeding', 'Disease', 'MESH:D014648', (180, 197))	('esophageal variceal bleeding', 'Disease', (74, 102))	('CHB', 'Disease', (0, 3))	('esophageal variceal bleeding', 'Phenotype', 'HP:0002040', (74, 102))	('patients', 'Species', '9606', (312, 320))	('CHB', 'Disease', 'None', (0, 3))	('variceal bleeding', 'Disease', 'MESH:D014648', (85, 102))	('esophageal variceal bleeding', 'Disease', 'MESH:D004932', (74, 102))	('variceal bleeding', 'Disease', (180, 197))	('patients', 'Species', '9606', (4, 12))	('esophageal varices', 'Phenotype', 'HP:0002040', (213, 231))	('LSPS', 'Var', (21, 25))
233071	31950035	Moreover, another study suggested that glutathione peroxidase 7 plays an important physiological role in protecting the healthy esophageal epithelium from acidic bile salt-induced oxidative stress, oxidative DNA damage, and double-stranded DNA breaks.	('glutathione peroxidase 7', 'Gene', '2882', (39, 63))	('double-stranded DNA', 'Var', (224, 243))	('acidic bile salt-induced oxidative stress', 'MPA', (155, 196))	('oxidative DNA damage', 'MPA', (198, 218))	('oxidative stress', 'Phenotype', 'HP:0025464', (180, 196))	('bile salt', 'Chemical', 'MESH:D001647', (162, 171))	('glutathione peroxidase 7', 'Gene', (39, 63))
233073	31950035	Therefore, to identify candidate biomarkers for ESCC, we used a bioinformatics approach to analyze publicly available microarray data (GSE20347, GSE23400, and GSE26886) from the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) database.	('GSE26886', 'Var', (159, 167))	('ESCC', 'Disease', 'MESH:C562729', (48, 52))	('GSE20347', 'Var', (135, 143))	('ESCC', 'Disease', (48, 52))	('GSE23400', 'Var', (145, 153))
233076	31950035	Gene expression profiles (GSE20347, GSE23400, and GSE26886) of cancerous and healthy esophageal tissues were downloaded from the GEO database.	('cancerous', 'Disease', 'MESH:D009369', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('GSE26886', 'Var', (50, 58))	('GSE20347', 'Var', (26, 34))	('cancerous', 'Disease', (63, 72))	('GSE23400', 'Var', (36, 44))
233093	31950035	In accordance with the GO annotation results, the KEGG pathway analysis of the DEGs and the two main clustering modules also suggested that a disordered cell cycle phase, unstable endocytosis, and unbalanced protein digestion and absorption affect the prognosis of patients with ESCC.	('unbalanced', 'Var', (197, 207))	('ESCC', 'Disease', 'MESH:C562729', (279, 283))	('unstable endocytosis', 'MPA', (171, 191))	('disordered cell cycle', 'Phenotype', 'HP:0011018', (142, 163))	('ESCC', 'Disease', (279, 283))	('patients', 'Species', '9606', (265, 273))	('affect', 'Reg', (241, 247))
233095	31950035	In particular, the DEGs identified to be associated with ESCC in the present study were suggested to have an influence on chromosome segregation at the mitosis stage.	('ESCC', 'Disease', (57, 61))	('influence', 'Reg', (109, 118))	('DEGs', 'Var', (19, 23))	('chromosome segregation at the mitosis stage', 'CPA', (122, 165))	('ESCC', 'Disease', 'MESH:C562729', (57, 61))
233096	31950035	Indeed, genes related to the cell cycle (CDKN2A, RB1, NFE2L2, CHEK1, and CHEK2) have been found to contain mutations in 2-10% of ESCC cases.	('NFE2L2', 'Gene', '4780', (54, 60))	('mutations', 'Var', (107, 116))	('RB1', 'Gene', (49, 52))	('ESCC', 'Disease', (129, 133))	('CHEK1', 'Gene', '1111', (62, 67))	('RB1', 'Gene', '5925', (49, 52))	('NFE2L2', 'Gene', (54, 60))	('CHEK2', 'Gene', '11200', (73, 78))	('CHEK1', 'Gene', (62, 67))	('ESCC', 'Disease', 'MESH:C562729', (129, 133))	('CHEK2', 'Gene', (73, 78))	('CDKN2A', 'Gene', (41, 47))	('CDKN2A', 'Gene', '1029', (41, 47))	('contain', 'Reg', (99, 106))
233144	31772577	Mutations in key driver genes : such as those that inactivate genes responsible for DNA repair : are a primary cause of cancer pathogenesis, although the HMP supported the idea that a dysbiotic microbiota can substantially contribute to cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('Mutations', 'Var', (0, 9))	('contribute', 'Reg', (223, 233))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('cause', 'Reg', (111, 116))
233161	31772577	In this condition, other microbes, such as Fusobacterium nucleatum (F. nucleatum), can become opportunistically pathogenic and lead to dysregulated immune response and increased risk to develop periodontal diseases and OSCC.	('SCC', 'Phenotype', 'HP:0002860', (220, 223))	('OSCC', 'Disease', 'MESH:D002294', (219, 223))	('periodontal diseases', 'Phenotype', 'HP:0000704', (194, 214))	('F. nucleatum', 'Species', '851', (68, 80))	('dysregulated immune response', 'Phenotype', 'HP:0002958', (135, 163))	('lead to', 'Reg', (127, 134))	('develop', 'PosReg', (186, 193))	('periodontal diseases', 'Disease', (194, 214))	('Fusobacterium nucleatum', 'Species', '851', (43, 66))	('periodontal diseases', 'Disease', 'MESH:D010510', (194, 214))	('Fusobacterium', 'Var', (43, 56))	('dysregulated immune', 'MPA', (135, 154))	('OSCC', 'Disease', (219, 223))
233164	31772577	It has been recently demonstrated that prolonged infections of oral cancer cells by P. gingivalis promote migratory and invasive properties.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('promote', 'PosReg', (98, 105))	('infections of oral cancer', 'Disease', 'MESH:D009062', (49, 74))	('infections of oral cancer', 'Disease', (49, 74))	('infections of oral cancer', 'Phenotype', 'HP:0100649', (49, 74))	('P. gingivalis', 'Species', '837', (84, 97))	('P. gingivalis', 'Var', (84, 97))	('prolonged infections', 'Phenotype', 'HP:0002719', (39, 59))
233166	31772577	Moreover, P. gingivalis mutant strains lacking the fimbrial protein FimA were attenuated in their ability to activate Zeb1 expression, demonstrating a role for the FimA adhesin in triggering EMT.	('mutant', 'Var', (24, 30))	('P. gingivalis', 'Species', '837', (10, 23))	('Zeb1', 'Gene', (118, 122))	('Zeb1', 'Gene', '6935', (118, 122))	('activate', 'PosReg', (109, 117))	('lacking', 'NegReg', (39, 46))	('attenuated', 'NegReg', (78, 88))
233167	31772577	In addition to mediating these physiological functions, changes in the microbiota composition are often associated with several immunological diseases of the nasal cavity including allergic rhinitis and chronic rhinosinusitis.	('chronic rhinosinusitis', 'Disease', (203, 225))	('diseases of the nasal cavity', 'Phenotype', 'HP:0012720', (142, 170))	('allergic rhinitis', 'Disease', 'MESH:D012220', (181, 198))	('chronic rhinosinusitis', 'Disease', 'MESH:D002908', (203, 225))	('rhinitis', 'Phenotype', 'HP:0012384', (190, 198))	('associated', 'Reg', (104, 114))	('allergic rhinitis', 'Phenotype', 'HP:0003193', (181, 198))	('allergic rhinitis', 'Disease', (181, 198))	('changes', 'Var', (56, 63))
233178	31772577	As an example, a LUAD mouse model carrying Kras mutations and p53 deletion was utilized to compare germ-free and specific pathogen-free conditions, revealing that germ-free mice are significantly protected against LUAD.	('LUAD', 'Disease', 'MESH:C538231', (214, 218))	('Kras', 'Gene', (43, 47))	('p53', 'Gene', '22060', (62, 65))	('Kras', 'Gene', '16653', (43, 47))	('LUAD', 'Disease', (214, 218))	('LUAD', 'Disease', (17, 21))	('mouse', 'Species', '10090', (22, 27))	('LUAD', 'Phenotype', 'HP:0030078', (214, 218))	('LUAD', 'Phenotype', 'HP:0030078', (17, 21))	('p53', 'Gene', (62, 65))	('deletion', 'Var', (66, 74))	('mutations', 'Var', (48, 57))	('mice', 'Species', '10090', (173, 177))	('LUAD', 'Disease', 'MESH:C538231', (17, 21))
233215	31772577	LPS induces innate immune responses by upregulating proinflammatory cytokine genes through the Toll-like receptor (TLR) 4 and the downstream NF-kappaB pathways.	('innate immune responses', 'MPA', (12, 35))	('LPS', 'Var', (0, 3))	('induces', 'Reg', (4, 11))	('NF-kappaB', 'Gene', '4790', (141, 150))	('proinflammatory', 'MPA', (52, 67))	('NF-kappaB', 'Gene', (141, 150))	('upregulating', 'PosReg', (39, 51))
233227	31772577	The signaling pathway induced by Streptococci upon adhesion to CD44 involves cytoskeletal reorganization via Rac1 and ezrin, as well as loss of intercellular junctions by changed distribution of the junctional proteins ZO-1 and E-cadherin.	('ZO-1', 'Gene', '7082', (219, 223))	('distribution', 'MPA', (179, 191))	('ezrin', 'Protein', (118, 123))	('E-cadherin', 'Gene', (228, 238))	('intercellular junctions', 'MPA', (144, 167))	('E-cadherin', 'Gene', '999', (228, 238))	('Rac1', 'Protein', (109, 113))	('ZO-1', 'Gene', (219, 223))	('CD44', 'Gene', (63, 67))	('cytoskeletal reorganization', 'CPA', (77, 104))	('CD44', 'Species', '1151267', (63, 67))	('loss', 'NegReg', (136, 140))	('changed', 'Reg', (171, 178))	('signaling pathway', 'Pathway', (4, 21))	('adhesion', 'Var', (51, 59))
233257	31772577	Accumulating data also support a role for the B. fragilis in inducing tumorigenesis in human and animal models of CRC.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('B. fragilis', 'Species', '817', (46, 57))	('human', 'Species', '9606', (87, 92))	('tumor', 'Disease', (70, 75))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('CRC', 'Disease', 'MESH:D015179', (114, 117))	('inducing', 'Reg', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('CRC', 'Disease', (114, 117))	('B. fragilis', 'Var', (46, 57))
233292	31772577	Alterations of the vaginal microbial community have been also proved to impact pregnancy, bacterial vaginosis, and carcinogenesis.	('Alterations', 'Var', (0, 11))	('bacterial vaginosis', 'Disease', (90, 109))	('pregnancy', 'CPA', (79, 88))	('bacterial vaginosis', 'Disease', 'MESH:D016585', (90, 109))	('carcinogenesis', 'Disease', 'MESH:D063646', (115, 129))	('impact', 'Reg', (72, 78))	('carcinogenesis', 'Disease', (115, 129))	('bacterial vaginosis', 'Phenotype', 'HP:0030683', (90, 109))
233315	31772577	In culture, 6-HAP selectively inhibits the proliferation of tumor cell lines but does not inhibit primary keratinocyte growth.	('6-HAP', 'Chemical', 'MESH:C032610', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('6-HAP', 'Var', (12, 17))	('tumor', 'Disease', (60, 65))	('inhibits', 'NegReg', (30, 38))
233331	31772577	In the intestinal mucosa, B. fragilis induces an inflammatory cascade through IL-17R and Stat3.	('B. fragilis', 'Species', '817', (26, 37))	('IL-17R', 'Gene', '23765', (78, 84))	('IL-17R', 'Gene', (78, 84))	('inflammatory cascade', 'MPA', (49, 69))	('induces', 'Reg', (38, 45))	('B. fragilis', 'Var', (26, 37))	('Stat3', 'MPA', (89, 94))
233422	30485945	In a large population-based research study they demonstrated that cancer patients with low SES were 50% more likely to suffer from another serious disease.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('suffer', 'Reg', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('low SES', 'Var', (87, 94))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Disease', (66, 72))
233442	30485945	Grotenhuis et al., (2010) assessed the delay in diagnostic workup and treatment of esophageal cancer and identified that short-term outcomes such as morbidity and mortality rates are significantly associated with hospital delay while the long-term consequences are less related.	('esophageal cancer', 'Disease', (83, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('men', 'Species', '9606', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('hospital delay', 'Var', (213, 227))	('morbidity', 'Disease', (149, 158))
233450	29434860	The proliferation rates and clone group numbers were significantly higher in HPV16E6-transfected cell groups compared with nonsense-transfected (negative control) cell groups.	('HPV16E6-transfected', 'Var', (77, 96))	('higher', 'PosReg', (67, 73))	('HPV16', 'Species', '333760', (77, 82))	('proliferation rates', 'CPA', (4, 23))	('clone group numbers', 'CPA', (28, 47))
233452	29434860	In conclusion, Eca109 and Eca9706 cell lines with integration of HPV16E6 were successfully established in the present study.	('HPV16', 'Species', '333760', (65, 70))	('integration', 'Var', (50, 61))	('HPV16E6', 'Gene', (65, 72))	('Eca9706', 'CellLine', 'CVCL:E307', (26, 33))
233462	29434860	Also, it was suggested that the level of HPV16E6 protein expression was a key factor maintaining the malignant phenotype of cancer, and it may serve a notable function in the occurrence and course of esophagus cancer.	('cancer', 'Disease', (124, 130))	('function', 'Reg', (159, 167))	('esophagus cancer', 'Disease', (200, 216))	('HPV16E6', 'Var', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophagus cancer', 'Disease', 'MESH:D004938', (200, 216))	('HPV16', 'Species', '333760', (41, 46))	('serve', 'Reg', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
233463	29434860	As the mechanism of HPV16 in causing and promoting cancer is relatively clear in studies concerning cervical cancer, detection of HPV in esophageal cancer cases is worthy of further study, and may have a notable impact on the diagnosis and treatment of esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('HPV16', 'Species', '333760', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('detection', 'Var', (117, 126))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('HPV', 'Species', '10566', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('causing', 'Reg', (29, 36))	('HPV', 'Species', '10566', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('esophageal cancer', 'Disease', (137, 154))	('cancer', 'Disease', (109, 115))	('HPV16', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (253, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('cancer', 'Disease', (148, 154))	('promoting', 'PosReg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('esophageal cancer', 'Disease', (253, 270))	('impact', 'Reg', (212, 218))	('cancer', 'Disease', (51, 57))
233474	29434860	Esophageal cancer cells transfected with nonsense segments were named as Eca109-0 and Eca9706-0 as negative controls.	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Eca9706', 'CellLine', 'CVCL:E307', (86, 93))	('Esophageal cancer', 'Disease', (0, 17))	('nonsense segments', 'Var', (41, 58))
233517	29434860	HPV16E6 esophagus cancer cells were treated separately to establish Eca109-0, Eca109-1, Eca109-b, Eca9706-1, Eca9706-0 and Eca9706-b cells.	('esophagus cancer', 'Disease', (8, 24))	('Eca9706-b', 'Var', (123, 132))	('Eca9706', 'CellLine', 'CVCL:E307', (123, 130))	('HPV16', 'Species', '333760', (0, 5))	('esophagus cancer', 'Disease', 'MESH:D004938', (8, 24))	('Eca9706', 'CellLine', 'CVCL:E307', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('Eca9706-1', 'Var', (98, 107))	('Eca9706-1', 'CellLine', 'CVCL:E307', (98, 107))	('Eca109-b', 'Var', (88, 96))	('Eca9706-0', 'Var', (109, 118))	('Eca9706', 'CellLine', 'CVCL:E307', (109, 116))
233520	29434860	E6 mRNA expression levels were also significantly higher in Eca9706-1 cells compared with Eca9706-0 or Eca9706-b cells (P<0.001; Fig.	('higher', 'PosReg', (50, 56))	('E6 mRNA expression levels', 'MPA', (0, 25))	('Eca9706-1', 'CellLine', 'CVCL:E307', (60, 69))	('Eca9706', 'CellLine', 'CVCL:E307', (90, 97))	('Eca9706', 'CellLine', 'CVCL:E307', (103, 110))	('Eca9706', 'CellLine', 'CVCL:E307', (60, 67))	('Eca9706-1', 'Var', (60, 69))
233525	29434860	For Eca9706 cells, statistically significant differences were observed between different experimental groups (P<0.05), which were ranked as Eca9706-1>Eca9706-b>Eca9706-0, with respect to OD value.	('Eca9706', 'CellLine', 'CVCL:E307', (140, 147))	('Eca9706', 'CellLine', 'CVCL:E307', (4, 11))	('Eca9706-b>', 'Var', (150, 160))	('Eca9706-1>Eca9706-b>', 'Var', (140, 160))	('Eca9706-1>Eca9706', 'CellLine', 'CVCL:E307', (140, 157))	('Eca9706', 'CellLine', 'CVCL:E307', (160, 167))	('Eca9706', 'CellLine', 'CVCL:E307', (150, 157))
233526	29434860	In Eca9706 cells, Eca9706-0 cells exhibited significantly fewer colonies compared with Eca9706-1 (P<0.01) or Eca9706-b (P<0.001) cells.	('Eca9706-1', 'CellLine', 'CVCL:E307', (87, 96))	('Eca9706', 'CellLine', 'CVCL:E307', (3, 10))	('Eca9706', 'CellLine', 'CVCL:E307', (87, 94))	('colonies', 'CPA', (64, 72))	('Eca9706', 'CellLine', 'CVCL:E307', (18, 25))	('Eca9706', 'Var', (3, 10))	('Eca9706', 'CellLine', 'CVCL:E307', (109, 116))	('fewer', 'NegReg', (58, 63))
233527	29434860	Eca9706-1 cells also exhibited significantly fewer colonies compared with Eca9706-b cells (P<0.05).	('Eca9706', 'CellLine', 'CVCL:E307', (0, 7))	('fewer', 'NegReg', (45, 50))	('colonies', 'CPA', (51, 59))	('Eca9706-1', 'Var', (0, 9))	('Eca9706', 'CellLine', 'CVCL:E307', (74, 81))	('Eca9706-1', 'CellLine', 'CVCL:E307', (0, 9))
233528	29434860	In Eca9706 cells, the scratch width ratio in Eca9706-0 was significantly higher compared with Eca9706-1 (P<0.05) and Eca9706-b (P<0.05), while no statistically significant difference was observed between Eca9706-1 and Eca9706-b (P=0.121).	('Eca9706', 'CellLine', 'CVCL:E307', (3, 10))	('Eca9706-0', 'Var', (45, 54))	('scratch width ratio', 'CPA', (22, 41))	('Eca9706', 'CellLine', 'CVCL:E307', (45, 52))	('Eca9706-1', 'CellLine', 'CVCL:E307', (94, 103))	('Eca9706-1', 'CellLine', 'CVCL:E307', (204, 213))	('Eca9706', 'CellLine', 'CVCL:E307', (94, 101))	('Eca9706', 'CellLine', 'CVCL:E307', (117, 124))	('Eca9706', 'Var', (3, 10))	('Eca9706', 'CellLine', 'CVCL:E307', (204, 211))	('Eca9706', 'CellLine', 'CVCL:E307', (218, 225))	('higher', 'PosReg', (73, 79))
233531	29434860	In addition, the transfection group exhibited a significantly higher invasion capacity compared with the negative control group (P<0.01 in Eca109 and P<0.001 in Eca9706).	('Eca9706', 'CellLine', 'CVCL:E307', (161, 168))	('transfection', 'Var', (17, 29))	('invasion capacity', 'CPA', (69, 86))	('higher', 'PosReg', (62, 68))
233533	29434860	Since then, another study demonstrated HPV16E6 is closely is closely associated with tumorigenesis at the gene, mRNA, protein and other levels.	('tumor', 'Disease', (85, 90))	('HPV16', 'Species', '333760', (39, 44))	('associated', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('HPV16E6', 'Var', (39, 46))
233534	29434860	With in-depth studies on oncogenes, it has been identified that HPV16E6 protein serves a critical function in carcinogenic development, as it activates transcription of human telomerase reverse transcriptase, collaborates with E7 protein to inactivate retinoblastoma protein and promotes cell immortalization.	('activates', 'PosReg', (142, 151))	('retinoblastoma', 'Phenotype', 'HP:0009919', (252, 266))	('cell immortalization', 'CPA', (288, 308))	('protein', 'Var', (72, 79))	('HPV16', 'Species', '333760', (64, 69))	('retinoblastoma', 'Disease', (252, 266))	('promotes', 'PosReg', (279, 287))	('retinoblastoma', 'Disease', 'MESH:D012175', (252, 266))	('human', 'Species', '9606', (169, 174))	('carcinogenic', 'Disease', (110, 122))	('transcription', 'MPA', (152, 165))	('inactivate', 'NegReg', (241, 251))	('carcinogenic', 'Disease', 'MESH:D063646', (110, 122))	('HPV16E6', 'Gene', (64, 71))
233538	29434860	Therefore, in the present study, HPV16E6 was used to transfect Eca109 and Eca9706 esophageal cancer cells, and the effects on biological properties of these cell lines were observed.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('HPV16', 'Species', '333760', (33, 38))	('transfect', 'Var', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('esophageal cancer', 'Disease', (82, 99))	('Eca9706', 'CellLine', 'CVCL:E307', (74, 81))
233541	29434860	With respect to function, it was demonstrated with RT-PCR that the transfected esophagus cancer cells contained the target gene, HPV16E6, and HPV16E6mRNA, which was demonstrated at the protein level.	('HPV16', 'Species', '333760', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('esophagus cancer', 'Disease', 'MESH:D004938', (79, 95))	('HPV16', 'Species', '333760', (142, 147))	('HPV16E6', 'Var', (129, 136))	('esophagus cancer', 'Disease', (79, 95))	('HPV16E6mRNA', 'Var', (142, 153))
233542	29434860	It was indicated by the immunofluorescence assay and western blot analysis that HPV16E6 protein was expressed in the transfection group, but not in the blank or negative control group.	('protein', 'Protein', (88, 95))	('HPV16', 'Species', '333760', (80, 85))	('HPV16E6', 'Gene', (80, 87))	('transfection', 'Var', (117, 129))
233548	29434860	Similarly, in the Transwell Matrigel assay, the number of membrane-crossing cells was significantly higher in the experimental groups compared with the negative control groups, suggesting that invasion capacity was increased in HPV16E6-transfected cells.	('HPV16', 'Species', '333760', (228, 233))	('HPV16E6-transfected', 'Var', (228, 247))	('increased', 'PosReg', (215, 224))	('higher', 'PosReg', (100, 106))	('invasion capacity', 'CPA', (193, 210))
233549	29434860	These results suggested that expression of HPV16E6 may be associated with proliferation, invasion and migration of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('expression', 'Var', (29, 39))	('associated', 'Reg', (58, 68))	('HPV16', 'Species', '333760', (43, 48))	('migration', 'CPA', (102, 111))	('invasion', 'CPA', (89, 97))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('proliferation', 'CPA', (74, 87))	('HPV16E6', 'Gene', (43, 50))
233550	29434860	Eca109 cells exhibited higher transfection efficiency but lower proliferation capacity compared with Eca9706 cells, suggesting that HPV16E6 exerts greater effects on well-differentiated Eca9706 compared with poorly-differentiated Eca109.	('proliferation capacity', 'CPA', (64, 86))	('lower', 'NegReg', (58, 63))	('effects', 'MPA', (155, 162))	('Eca9706', 'CellLine', 'CVCL:E307', (101, 108))	('HPV16E6', 'Var', (132, 139))	('Eca9706', 'CellLine', 'CVCL:E307', (186, 193))	('transfection', 'CPA', (30, 42))	('HPV16', 'Species', '333760', (132, 137))
233552	29434860	The reason for this may be that Eca109 cells are poorly differentiated esophageal cancer cells with high malignancy, or that the high transfection efficiency of Eca109 leads to greater effects of HPV16E6.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('transfection', 'MPA', (134, 146))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('HPV16E6', 'Var', (196, 203))	('effects', 'MPA', (185, 192))	('HPV16', 'Species', '333760', (196, 201))	('greater', 'PosReg', (177, 184))	('Eca109', 'Gene', (161, 167))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('esophageal cancer', 'Disease', (71, 88))	('malignancy', 'Disease', (105, 115))
233553	29434860	The current results also identified that non-transfected (blank control) cell lines have slightly stronger proliferation, invasion and migration capacities compared with nonsense transfected (negative control) cell lines, suggesting that transfection causes a certain level of injury to esophageal cancer cells.	('stronger', 'PosReg', (98, 106))	('proliferation', 'CPA', (107, 120))	('injury to esophageal cancer', 'Disease', (277, 304))	('invasion', 'CPA', (122, 130))	('injury to esophageal cancer', 'Disease', 'MESH:D004938', (277, 304))	('migration capacities', 'CPA', (135, 155))	('transfection', 'Var', (238, 250))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
233559	29434860	Therefore, the effects of HPV16E6 on the normal functions of p53 indicate particular significance for carcinogenicity.	('p53', 'Gene', (61, 64))	('carcinogenic', 'Disease', 'MESH:D063646', (102, 114))	('normal functions', 'MPA', (41, 57))	('carcinogenic', 'Disease', (102, 114))	('HPV16', 'Species', '333760', (26, 31))	('effects', 'Reg', (15, 22))	('p53', 'Gene', '7157', (61, 64))	('HPV16E6', 'Var', (26, 33))
233560	29434860	It has also been demonstrated in previous studies that HPV16E6 can allow cells to escape the proliferation limit of senescence and immortalize normal cells by activating telomerase.	('activating', 'PosReg', (159, 169))	('HPV16', 'Species', '333760', (55, 60))	('telomerase', 'Enzyme', (170, 180))	('HPV16E6', 'Var', (55, 62))
233624	29375213	The author reported response rates, resectability rates with curative intent and a survival rate advantage in the NAC group, but, overall, this was not statistically significant.	('survival rate', 'CPA', (83, 96))	('NAC', 'Var', (114, 117))	('NAC', 'Chemical', '-', (114, 117))	('resectability', 'CPA', (36, 49))	('response', 'CPA', (20, 28))	('advantage', 'PosReg', (97, 106))
233633	29375213	The curative resection rate was higher in the NAC + S group than in the SA group.	('S', 'Chemical', 'MESH:D013455', (52, 53))	('S', 'Chemical', 'MESH:D013455', (72, 73))	('higher', 'PosReg', (32, 38))	('NAC + S', 'Var', (46, 53))	('curative resection rate', 'CPA', (4, 27))	('NAC', 'Chemical', '-', (46, 49))	('SA', 'Chemical', '-', (72, 74))
233644	29375213	The 5-year OS rate was improved in the NAC group but this survival benefit was not statistically significant.	('NAC', 'Var', (39, 42))	('NAC', 'Chemical', '-', (39, 42))	('improved', 'PosReg', (23, 31))	('OS', 'Chemical', 'MESH:D009992', (11, 13))
233678	29375213	The trial showed a significantly increased R0 resection and pN0 rates in the NAC arm (P = 0.036) compared to the SA arm, but failed to demonstrate a survival benefit of perioperative treatment.	('SA', 'Chemical', '-', (113, 115))	('increased', 'PosReg', (33, 42))	('NAC', 'Var', (77, 80))	('NAC', 'Chemical', '-', (77, 80))	('R0 resection', 'CPA', (43, 55))	('pN0 rates', 'CPA', (60, 69))
233692	29375213	The R0 resection rate was significantly higher, and the number of lymph node metastases was significantly lower in the NAC arm compared to the SA arm.	('lower', 'NegReg', (106, 111))	('R0 resection rate', 'CPA', (4, 21))	('higher', 'PosReg', (40, 46))	('NAC', 'Chemical', '-', (119, 122))	('lymph node metastases', 'Disease', 'MESH:D009362', (66, 87))	('NAC', 'Var', (119, 122))	('SA', 'Chemical', '-', (143, 145))	('lymph node metastases', 'Disease', (66, 87))
233693	29375213	In addition, the 2-year survival rate was higher in NAC- than in the surgery alone-arm.	('NAC', 'Chemical', '-', (52, 55))	('higher', 'PosReg', (42, 48))	('NAC-', 'Var', (52, 56))
233695	29375213	The curative resection rate was significantly higher in the NAC arm compared to that in the SA arm (84% vs 73%, P = 0.04).	('higher', 'PosReg', (46, 52))	('curative resection', 'CPA', (4, 22))	('SA', 'Chemical', '-', (92, 94))	('NAC', 'Var', (60, 63))	('NAC', 'Chemical', '-', (60, 63))
233696	29375213	A non-significant decrease of lymph node metastases in the NAC arm compared to that of the SA arm was reported (67% vs 80%; P = 0.54).	('NAC', 'Var', (59, 62))	('NAC', 'Chemical', '-', (59, 62))	('lymph node metastases', 'Disease', 'MESH:D009362', (30, 51))	('SA', 'Chemical', '-', (91, 93))	('lymph node metastases', 'Disease', (30, 51))	('decrease', 'NegReg', (18, 26))
233740	29375213	Tumors were stratified by the depth of invasion and by lymph node involvement, and both the OS and DSS were calculated for pT2-pT4 patients and for pT2-pT4 with node-positive patients.	('patients', 'Species', '9606', (131, 139))	('pT2-pT4', 'Var', (123, 130))	('Tumors', 'Disease', (0, 6))	('patients', 'Species', '9606', (175, 183))	('OS', 'Chemical', 'MESH:D009992', (92, 94))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('DSS', 'Chemical', '-', (99, 102))
233784	26491656	Glu504Lys Single Nucleotide Polymorphism of Aldehyde Dehydrogenase 2 Gene and the Risk of Human Diseases Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial enzyme that is known for its important role in oxidation and detoxification of ethanol metabolite acetaldehyde.	('hydrogen', 'Chemical', 'MESH:D006859', (116, 124))	('Aldehyde Dehydrogenase 2', 'Gene', '217', (44, 68))	('Glu504Lys Single Nucleotide Polymorphism', 'Var', (0, 40))	('acetaldehyde', 'Chemical', 'MESH:D000079', (254, 266))	('hydrogen', 'Chemical', 'MESH:D006859', (55, 63))	('Human Diseases', 'Disease', (90, 104))	('ethanol', 'Chemical', 'MESH:D000431', (235, 242))	('Human Diseases', 'Disease', 'MESH:D015658', (90, 104))	('ALDH) 2', 'Gene', (129, 136))	('Aldehyde Dehydrogenase 2', 'Gene', (44, 68))	('Glu504Lys', 'Chemical', '-', (0, 9))
233786	26491656	The Glu504Lys single nucleotide polymorphism (SNP) of ALDH2 gene, which is found in approximately 40% of the East Asian populations, causes defect in the enzyme activity of ALDH2, leading to alterations in acetaldehyde metabolism and alcohol-induced "flushing" syndrome.	('ALDH2', 'Gene', (173, 178))	('defect', 'NegReg', (140, 146))	('Glu504Lys', 'Chemical', '-', (4, 13))	('ALDH2', 'Gene', (54, 59))	('alterations', 'Reg', (191, 202))	('flushing', 'Phenotype', 'HP:0031284', (251, 259))	('acetaldehyde metabolism', 'MPA', (206, 229))	('acetaldehyde', 'Chemical', 'MESH:D000079', (206, 218))	('flushing', 'Disease', (251, 259))	('alcohol', 'Chemical', 'MESH:D000438', (234, 241))	('acetaldehyde metabolism', 'Phenotype', 'HP:0003533', (206, 229))	('enzyme activity', 'MPA', (154, 169))	('rat', 'Species', '10116', (195, 198))	('Glu504Lys single nucleotide polymorphism', 'Var', (4, 44))	('flushing', 'Disease', 'MESH:D005483', (251, 259))
233787	26491656	Evidence suggests that ALDH2 Glu504Lys SNP is a potential candidate genetic risk factor for a variety of chronic diseases such as cardiovascular disease, cancer, and late-onset Alzheimer's disease.	('ALDH2', 'Gene', (23, 28))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (130, 152))	('cardiovascular disease', 'Disease', 'MESH:D002318', (130, 152))	('chronic diseases', 'Disease', 'MESH:D002908', (105, 121))	('chronic diseases', 'Disease', (105, 121))	('cancer', 'Disease', (154, 160))	('Glu504Lys', 'Chemical', '-', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (177, 196))	('cardiovascular disease', 'Disease', (130, 152))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (177, 196))	("Alzheimer's disease", 'Disease', (177, 196))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('Glu504Lys SNP', 'Var', (29, 42))
233788	26491656	In addition, the association between ALDH2 Glu504Lys SNP and the development of these chronic diseases appears to be affected by the interaction between the SNP and lifestyle factors such as alcohol consumption as well as by the presence of other genetic variations.	('interaction', 'Interaction', (133, 144))	('ALDH2', 'Gene', (37, 42))	('chronic diseases', 'Disease', 'MESH:D002908', (86, 102))	('association', 'Interaction', (17, 28))	('Glu504Lys', 'Var', (43, 52))	('men', 'Species', '9606', (72, 75))	('Glu504Lys', 'Chemical', '-', (43, 52))	('affected', 'Reg', (117, 125))	('chronic diseases', 'Disease', (86, 102))	('alcohol', 'Chemical', 'MESH:D000438', (191, 198))
233791	26491656	The Glu504Lys single nucleotide polymorphism (SNP) of ALDH2 gene, which occurs with an incidence of 35-57% in different East Asian subpopulations, causes defect in the enzyme activity of ALDH2, leading to alterations in acetaldehyde metabolism and markedly reduced alcohol tolerance.	('ALDH2', 'Gene', (187, 192))	('defect', 'NegReg', (154, 160))	('Glu504Lys', 'Chemical', '-', (4, 13))	('alcohol tolerance', 'Phenotype', 'HP:0030955', (265, 282))	('reduced', 'NegReg', (257, 264))	('ALDH2', 'Gene', (54, 59))	('alterations', 'Reg', (205, 216))	('acetaldehyde metabolism', 'MPA', (220, 243))	('acetaldehyde', 'Chemical', 'MESH:D000079', (220, 232))	('rat', 'Species', '10116', (209, 212))	('alcohol', 'Chemical', 'MESH:D000438', (265, 272))	('acetaldehyde metabolism', 'Phenotype', 'HP:0003533', (220, 243))	('Glu504Lys single nucleotide polymorphism', 'Var', (4, 44))	('enzyme activity', 'MPA', (168, 183))	('alcohol tolerance', 'CPA', (265, 282))
233792	26491656	Epidemiological studies have linked ALDH2 Glu504Lys SNP with increased risk for human diseases including cardiovascular disease (CVD), cancer, and late-onset Alzheimer's disease (AD).	('cardiovascular disease', 'Disease', 'MESH:D002318', (105, 127))	("Alzheimer's disease", 'Disease', (158, 177))	('ALDH2', 'Gene', (36, 41))	('CVD', 'Phenotype', 'HP:0001626', (129, 132))	('cardiovascular disease', 'Disease', (105, 127))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (158, 177))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('human', 'Species', '9606', (80, 85))	('CVD', 'Disease', (129, 132))	('Glu504Lys', 'Var', (42, 51))	('CVD', 'Disease', 'MESH:D002318', (129, 132))	('AD', 'Disease', (179, 181))	('AD', 'Phenotype', 'HP:0002511', (179, 181))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('Glu504Lys', 'Chemical', '-', (42, 51))	('AD', 'Disease', 'MESH:D000544', (179, 181))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (105, 127))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (158, 177))
233793	26491656	The association between ALDH2 Glu504Lys SNP and the development of these diseases is also related to the effect of the SNP on lifestyle factors such as alcohol consumption and its interaction with other genetic variations.	('Glu504Lys SNP', 'Var', (30, 43))	('ALDH2', 'Gene', (24, 29))	('alcohol', 'Chemical', 'MESH:D000438', (152, 159))	('Glu504Lys', 'Chemical', '-', (30, 39))	('men', 'Species', '9606', (59, 62))
233811	26491656	People carrying the mutant ALDH2 allele display characteristic acetaldehyde-mediated acute effects of alcohol drinking such as facial flushing and increased pulse rate.	('ALDH2', 'Gene', (27, 32))	('rat', 'Species', '10116', (163, 166))	('increased', 'PosReg', (147, 156))	('acetaldehyde-mediated acute effects', 'MPA', (63, 98))	('facial flushing', 'Disease', 'MESH:D005483', (127, 142))	('flushing', 'Phenotype', 'HP:0031284', (134, 142))	('alcohol drinking', 'Phenotype', 'HP:0030955', (102, 118))	('People', 'Species', '9606', (0, 6))	('alcohol', 'Chemical', 'MESH:D000438', (102, 109))	('acetaldehyde', 'Chemical', 'MESH:D000079', (63, 75))	('facial flushing', 'Disease', (127, 142))	('pulse rate', 'MPA', (157, 167))	('mutant', 'Var', (20, 26))
233814	26491656	In wild-type ALDH2 (ALDH2*1), Glu504 forms hydrogen bonds with Arg281 of the same subunit and with Arg492 of the adjacent dimer partner.	('Glu504', 'Var', (30, 36))	('hydrogen', 'Chemical', 'MESH:D006859', (43, 51))	('Glu504', 'Chemical', '-', (30, 36))	('Arg492', 'Chemical', '-', (99, 105))	('hydrogen bonds', 'MPA', (43, 57))	('ALDH2', 'Gene', (13, 18))	('Arg281', 'Chemical', '-', (63, 69))	('Arg281', 'Var', (63, 69))
233815	26491656	The disruption of these interactions by the presence of Lys504 in the mutant (ALDH2*2) perturbs the structure of the subunit with the mutation as well as its dimer partner.	('disruption', 'Reg', (4, 14))	('structure of the subunit', 'MPA', (100, 124))	('ALDH2*2', 'Gene', (78, 85))	('Lys504', 'Chemical', '-', (56, 62))	('interactions', 'Interaction', (24, 36))	('perturbs', 'Reg', (87, 95))	('Lys504', 'Var', (56, 62))
233816	26491656	Binding of the coenzyme NAD+ to ALDH2*2 is impaired, and the mutant enzyme has an increased K m for NAD+ and a decreased k cat, which leads to a very low enzymatic activity in vivo.	('AD', 'Phenotype', 'HP:0002511', (101, 103))	('AD', 'Phenotype', 'HP:0002511', (25, 27))	('decreased', 'NegReg', (111, 120))	('NAD+', 'Chemical', 'MESH:D009243', (24, 28))	('impaired', 'NegReg', (43, 51))	('K m for NAD+', 'MPA', (92, 104))	('NAD+', 'Chemical', 'MESH:D009243', (100, 104))	('mutant', 'Var', (61, 67))	('increased', 'PosReg', (82, 91))	('k cat', 'MPA', (121, 126))	('Binding', 'Interaction', (0, 7))	('ALDH2*2', 'Gene', (32, 39))
233819	26491656	In comparison to ALDH2 * 1/ * 1 homozygotes, individuals with ALDH2 * 1/ * 2 genotype experience significantly higher pulse rate and greater facial flushing as early as 30 min following alcohol consumption and have higher risk of developing hangover symptoms.	('rat', 'Species', '10116', (124, 127))	('facial flushing', 'Disease', (141, 156))	('greater', 'PosReg', (133, 140))	('pulse rate', 'MPA', (118, 128))	('genotype', 'Var', (77, 85))	('facial flushing', 'Disease', 'MESH:D005483', (141, 156))	('ALDH2', 'Gene', (62, 67))	('higher', 'PosReg', (111, 117))	('flushing', 'Phenotype', 'HP:0031284', (148, 156))	('alcohol', 'Chemical', 'MESH:D000438', (186, 193))	('hangover symptoms', 'Disease', (241, 258))
233820	26491656	Electroencephalographs (ECG) show that the increases in P300 latency and decreases in P300 amplitude following alcohol consumption are greater in individuals with ALDH2 * 1/ * 2 genotype than in individuals with ALDH2 * 1/ * 1 genotype, suggesting that their cognitive functioning may be more impaired by alcohol exposure.	('P300', 'Gene', (86, 90))	('P300', 'Gene', (56, 60))	('alcohol', 'Chemical', 'MESH:D000438', (305, 312))	('decreases', 'NegReg', (73, 82))	('genotype', 'Var', (178, 186))	('ALDH2 * 1/ * 2 genotype', 'Var', (163, 186))	('P300', 'Gene', '2033', (86, 90))	('P300', 'Gene', '2033', (56, 60))	('increases', 'PosReg', (43, 52))	('alcohol', 'Chemical', 'MESH:D000438', (111, 118))
233821	26491656	Individuals with ALDH2 * 1/ * 2 genotype also show more impaired psychomotor performance including reaction time to complex visual information, visuomotor coordination, and exact motor ability than those with ALDH2 * 1/ * 1 at 30 and 60 min after moderate alcohol consumption.	('visuomotor coordination', 'CPA', (144, 167))	('impaired psychomotor', 'Disease', 'MESH:D011596', (56, 76))	('impaired psychomotor', 'Disease', (56, 76))	('reaction', 'MPA', (99, 107))	('alcohol', 'Chemical', 'MESH:D000438', (256, 263))	('exact motor ability', 'CPA', (173, 192))	('impaired psychomotor performance', 'Phenotype', 'HP:0025356', (56, 88))	('rat', 'Species', '10116', (251, 254))	('ALDH2 * 1/ * 2', 'Var', (17, 31))
233822	26491656	Because of these acute effects after alcohol ingestion, Glu504Lys SNP of ALDH2 gene is protective against the development of alcoholism and perhaps may decrease the risk of chronic diseases caused by alcohol overconsumption.	('ALDH2', 'Gene', (73, 78))	('chronic diseases', 'Disease', (173, 189))	('alcohol ingestion', 'Phenotype', 'HP:0030955', (37, 54))	('Glu504Lys', 'Chemical', '-', (56, 65))	('alcoholism', 'Disease', (125, 135))	('chronic diseases', 'Disease', 'MESH:D002908', (173, 189))	('alcohol', 'Chemical', 'MESH:D000438', (37, 44))	('men', 'Species', '9606', (117, 120))	('alcoholism', 'Disease', 'MESH:D000437', (125, 135))	('Glu504Lys SNP', 'Var', (56, 69))	('alcoholism', 'Phenotype', 'HP:0030955', (125, 135))	('decrease', 'NegReg', (152, 160))	('alcohol', 'Chemical', 'MESH:D000438', (200, 207))	('alcohol', 'Chemical', 'MESH:D000438', (125, 132))
233823	26491656	On the other hand, individuals carrying Glu504Lys SNP who do drink alcohol may have an increased incidence of alcohol-mediated diseases.	('alcohol', 'Chemical', 'MESH:D000438', (67, 74))	('Glu504Lys SNP', 'Var', (40, 53))	('alcohol-mediated diseases', 'Disease', (110, 135))	('alcohol', 'Chemical', 'MESH:D000438', (110, 117))	('Glu504Lys', 'Chemical', '-', (40, 49))
233824	26491656	Furthermore, for susceptible individuals that drink limited amount of alcohol, defective ALDH2 may cause the accumulation of toxic aldehydes, which can be generated endogenously from metabolism other than ethanol oxidation or directly enter the body from foods and the environment, leading to enhanced oxidative stress and impaired cell function and subsequently affecting the risk of a variety of human chronic diseases.	('accumulation', 'MPA', (109, 121))	('affecting', 'Reg', (363, 372))	('chronic diseases', 'Disease', 'MESH:D002908', (404, 420))	('chronic diseases', 'Disease', (404, 420))	('oxidative stress', 'MPA', (302, 318))	('defective', 'Var', (79, 88))	('cell function', 'CPA', (332, 345))	('ALDH2', 'Gene', (89, 94))	('cause', 'Reg', (99, 104))	('ethanol', 'Chemical', 'MESH:D000431', (205, 212))	('men', 'Species', '9606', (276, 279))	('human', 'Species', '9606', (398, 403))	('enhanced', 'PosReg', (293, 301))	('alcohol', 'Chemical', 'MESH:D000438', (70, 77))	('oxidative stress', 'Phenotype', 'HP:0025464', (302, 318))	('aldehydes', 'Chemical', 'MESH:D000447', (131, 140))	('rat', 'Species', '10116', (159, 162))	('impaired', 'NegReg', (323, 331))
233837	26491656	In contrast, the accumulation of cardiac 4-HNE and the cardiac injury in response to ischemia-reperfusion are exacerbated in ALDH2 knockout mice.	('cardiac 4-HNE', 'MPA', (33, 46))	('knockout', 'Var', (131, 139))	('exacerbated', 'PosReg', (110, 121))	('mice', 'Species', '10090', (140, 144))	('cardiac injury', 'Disease', (55, 69))	('accumulation', 'MPA', (17, 29))	('ischemia', 'Disease', (85, 93))	('cardiac injury', 'Disease', 'MESH:D006331', (55, 69))	('ALDH2', 'Gene', (125, 130))	('ischemia', 'Disease', 'MESH:D007511', (85, 93))	('4-HNE', 'Chemical', 'MESH:C027576', (41, 46))
233838	26491656	These findings suggest that disruption of ALDH2 activity may increase the susceptibility of an individual to CVD.	('CVD', 'Disease', (109, 112))	('activity', 'MPA', (48, 56))	('CVD', 'Phenotype', 'HP:0001626', (109, 112))	('disruption', 'Var', (28, 38))	('CVD', 'Disease', 'MESH:D002318', (109, 112))	('ALDH2', 'Gene', (42, 47))	('increase', 'PosReg', (61, 69))	('susceptibility', 'MPA', (74, 88))
233839	26491656	Recently, two meta-analyses have shown that Glu504Lys SNP of ALDH2 gene in Asian populations is associated with increased risk of coronary artery disease (odds ratio (OR) = 1.36 and 1.28, 95% confidence interval (CI) = 1.06-1.75 and 1.10-1.48, and p = 0.017 and 0.001, resp.)	('coronary artery disease', 'Disease', 'MESH:D003324', (130, 153))	('Glu504Lys SNP', 'Var', (44, 57))	('rat', 'Species', '10116', (160, 163))	('ALDH2', 'Gene', (61, 66))	('coronary artery disease', 'Disease', (130, 153))	('Glu504Lys', 'Chemical', '-', (44, 53))
233841	26491656	It has been reported that ALDH2 * 2 allele is associated with low serum HDL cholesterol levels in Asian populations.	('allele', 'Var', (36, 42))	('low', 'NegReg', (62, 65))	('serum HDL cholesterol levels', 'MPA', (66, 94))	('low serum HDL cholesterol', 'Phenotype', 'HP:0003233', (62, 87))	('cholesterol', 'Chemical', 'MESH:D002784', (76, 87))	('ALDH2 * 2', 'Gene', (26, 35))
233842	26491656	In addition, as ALDH2 also functions in the formation of nitric oxide from nitroglycerin, Glu504Lys SNP of ALDH2 gene eliminates the activity of the enzyme to catalyze the reaction.	('formation of nitric oxide from nitroglycerin', 'MPA', (44, 88))	('nitric oxide', 'Chemical', 'MESH:D009569', (57, 69))	('Glu504Lys', 'Chemical', '-', (90, 99))	('Glu504Lys SNP', 'Var', (90, 103))	('ALDH2', 'Gene', (107, 112))	('nitroglycerin', 'Chemical', 'MESH:D005996', (75, 88))	('activity', 'MPA', (133, 141))	('enzyme', 'Enzyme', (149, 155))	('eliminates', 'NegReg', (118, 128))
233843	26491656	Therefore, it is not surprising that ALDH2 * 2 allele is associated with a lack of an efficacious clinical response to nitroglycerin treatment for coronary heart disease.	('men', 'Species', '9606', (138, 141))	('allele', 'Var', (47, 53))	('ALDH2 * 2', 'Gene', (37, 46))	('coronary heart disease', 'Disease', (147, 169))	('coronary heart disease', 'Phenotype', 'HP:0001677', (147, 169))	('coronary heart disease', 'Disease', 'MESH:D003324', (147, 169))	('nitroglycerin', 'Chemical', 'MESH:D005996', (119, 132))
233845	26491656	ALDH2 * 2 carriers have lower postoperative troponin I levels and inotropic scores as well as shorter length of intensive care unit (ICU) and hospital stay after open-heart surgery.	('troponin I levels', 'MPA', (44, 61))	('rat', 'Species', '10116', (37, 40))	('postoperative troponin I', 'Phenotype', 'HP:0410173', (30, 54))	('lower', 'NegReg', (24, 29))	('inotropic scores', 'MPA', (66, 82))	('carriers', 'Var', (10, 18))	('ALDH2 * 2', 'Gene', (0, 9))
233847	26491656	The increased intracellular GSH levels are also seen in the hearts of ALDH2 * 2 transgenic mice when compared with those of wild-type controls.	('transgenic', 'Var', (80, 90))	('transgenic mice', 'Species', '10090', (80, 95))	('GSH', 'Chemical', 'MESH:D005978', (28, 31))	('ALDH2 * 2', 'Gene', (70, 79))	('intracellular GSH levels', 'MPA', (14, 38))	('increased', 'PosReg', (4, 13))	('increased intracellular GSH', 'Phenotype', 'HP:0003575', (4, 31))
233851	26491656	The effects of Glu504Lys SNP of ALDH2 gene on blood pressure are complicated by alcohol consumption and the presence of other genetic polymorphisms.	('blood pressure', 'MPA', (46, 60))	('ALDH2', 'Gene', (32, 37))	('Glu504Lys', 'Chemical', '-', (15, 24))	('alcohol consumption', 'Disease', (80, 99))	('Glu504Lys SNP', 'Var', (15, 28))	('alcohol', 'Chemical', 'MESH:D000438', (80, 87))
233854	26491656	The authors have found that ALDH2 * 2 carriers have lower incidence of hypertension than ALDH2 * 2 noncarriers (OR = 0.67, 95% CI = 0.47-0.96, p = 0.030), while this correlation is not observed in individuals whose alcohol consumption is below median level or in the group not taking antihypertensive agents.	('carriers', 'Var', (38, 46))	('hypertension', 'Disease', 'MESH:D006973', (71, 83))	('ALDH2 * 2', 'Gene', (28, 37))	('alcohol', 'Chemical', 'MESH:D000438', (215, 222))	('hypertension', 'Disease', (71, 83))	('lower', 'NegReg', (52, 57))	('hypertension', 'Phenotype', 'HP:0000822', (71, 83))
233855	26491656	A case-control study later has shown that ALDH2 * 1/ * 1 genotype is an independent risk factor for essential hypertension among males.	('genotype', 'Var', (57, 65))	('hypertension', 'Disease', 'MESH:D006973', (110, 122))	('risk factor', 'Reg', (84, 95))	('ALDH2', 'Gene', (42, 47))	('hypertension', 'Disease', (110, 122))	('hypertension', 'Phenotype', 'HP:0000822', (110, 122))
233858	26491656	have reported that ALDH2 * 1/ * 1 genotype is an independent predictor for increased systolic (beta-coefficient = 2.96, p = 0.03) and diastolic (beta-coefficient = 2.26, p = 0.01) blood pressure after adjusting for alcohol consumption.	('alcohol', 'Chemical', 'MESH:D000438', (215, 222))	('ALDH2 *', 'Gene', (19, 26))	('genotype', 'Var', (34, 42))	('systolic', 'MPA', (85, 93))	('increased', 'PosReg', (75, 84))
233865	26491656	Individuals carrying both ALDH2 * 2 allele and SOD2 Val/Val genotype have a significantly higher risk of hypertension among drinkers than in nondrinkers (adjusted OR = 6.22, 95% CI = 2.26-17.1, and p < 0.001).	('Val/Val', 'Var', (52, 59))	('hypertension', 'Disease', (105, 117))	('hypertension', 'Phenotype', 'HP:0000822', (105, 117))	('ALDH2 *', 'Gene', (26, 33))	('SOD2', 'Gene', '6648', (47, 51))	('hypertension', 'Disease', 'MESH:D006973', (105, 117))	('SOD2', 'Gene', (47, 51))
233866	26491656	Therefore, both lifestyle factors such as alcohol drinking and other genetic variations may have impacts on the susceptibility of ALDH2 genotypes to hypertension.	('variations', 'Var', (77, 87))	('susceptibility', 'Reg', (112, 126))	('impacts', 'Reg', (97, 104))	('hypertension', 'Disease', (149, 161))	('hypertension', 'Phenotype', 'HP:0000822', (149, 161))	('ALDH2', 'Gene', (130, 135))	('alcohol', 'Chemical', 'MESH:D000438', (42, 49))	('alcohol drinking', 'Phenotype', 'HP:0030955', (42, 58))	('hypertension', 'Disease', 'MESH:D006973', (149, 161))	('genotypes', 'Var', (136, 145))
233871	26491656	The effect of the alteration of ALDH2 activity by Glu504Lys SNP on the risk of cancer has been shown to interact with lifestyle factors, especially alcohol consumption.	('activity', 'MPA', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('rat', 'Species', '10116', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('Glu504Lys', 'Chemical', '-', (50, 59))	('alcohol', 'Chemical', 'MESH:D000438', (148, 155))	('cancer', 'Disease', (79, 85))	('ALDH2', 'Protein', (32, 37))	('Glu504Lys', 'Var', (50, 59))
233873	26491656	Further evaluation of the association of ALDH2 Glu504Lys SNP with esophageal cancer has demonstrated that OR for the ALDH2 * 1/ * 2 and ALDH2 * 2/ * 2 genotypes in comparison to the ALDH2 * 1/ * 1 genotype is 3.43 (95% CI = 1.74-6.75) after adjustment for age, sex, drinking, and smoking status.	('Glu504Lys SNP', 'Var', (47, 60))	('rat', 'Species', '10116', (95, 98))	('esophageal cancer', 'Disease', (66, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ALDH2', 'Gene', (41, 46))	('Glu504Lys', 'Chemical', '-', (47, 56))	('ALDH2', 'Gene', (117, 122))	('association', 'Interaction', (26, 37))	('men', 'Species', '9606', (247, 250))
233877	26491656	And the heavy drinkers (>=1,200 g/year) with ALDH2 * 1/ * 2 genotype have 30.53-fold risk (95% CI = 12.01-77.64) of developing esophageal cancer in comparison to nondrinkers with ALDH2 * 1/ * 1.	('genotype', 'Var', (60, 68))	('esophageal cancer', 'Disease', (127, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('ALDH2', 'Gene', (45, 50))
233878	26491656	ALDH2 Glu504Lys polymorphism has also been shown to interact with the SNPs of other key enzymes in ethanol metabolism in the development of alcohol-associated cancers.	('cancers', 'Disease', (159, 166))	('Glu504Lys', 'Chemical', '-', (6, 15))	('Glu504Lys polymorphism', 'Var', (6, 28))	('ALDH2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('alcohol', 'Chemical', 'MESH:D000438', (140, 147))	('men', 'Species', '9606', (132, 135))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('ethanol', 'Chemical', 'MESH:D000431', (99, 106))	('interact', 'Reg', (52, 60))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
233880	26491656	Arg47His SNP of ADH1B (ADH1B * 2), which exists in more than 90% of East Asians, encodes a superactive subunit of ADH1B that promotes the accumulation of acetaldehyde after alcohol drinking.	('ADH1B', 'Gene', '125', (114, 119))	('ADH1B', 'Gene', (23, 28))	('AD', 'Phenotype', 'HP:0002511', (114, 116))	('ADH1B', 'Gene', (16, 21))	('accumulation of acetaldehyde', 'MPA', (138, 166))	('ADH1B', 'Gene', '125', (23, 28))	('AD', 'Phenotype', 'HP:0002511', (16, 18))	('alcohol drinking', 'Phenotype', 'HP:0030955', (173, 189))	('ADH1B', 'Gene', '125', (16, 21))	('AD', 'Phenotype', 'HP:0002511', (23, 25))	('acetaldehyde', 'Chemical', 'MESH:D000079', (154, 166))	('accumulation of acetaldehyde', 'Phenotype', 'HP:0003533', (138, 166))	('Arg47His', 'Var', (0, 8))	('Arg47His', 'Mutation', 'rs1229984', (0, 8))	('alcohol', 'Chemical', 'MESH:D000438', (173, 180))	('ADH1B', 'Gene', (114, 119))	('promotes', 'PosReg', (125, 133))
233882	26491656	Surprisingly, a study on Japanese alcoholic men (age > 40 y) has shown that individuals with ADH1B * 1/ * 1 genotype (OR = 2.03) have increased risk of esophageal cancer after adjustment for drinking and smoking.	('AD', 'Phenotype', 'HP:0002511', (93, 95))	('esophageal cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('alcohol', 'Chemical', 'MESH:D000438', (34, 41))	('men', 'Species', '9606', (44, 47))	('ADH1B', 'Gene', (93, 98))	('genotype', 'Var', (108, 116))	('men', 'Species', '9606', (182, 185))	('ADH1B', 'Gene', '125', (93, 98))
233889	26491656	It has also been found that there is an interaction between ALDH2 Glu504Lys SNP and alcohol consumption in the development of gastric cancer.	('alcohol', 'Chemical', 'MESH:D000438', (84, 91))	('ALDH2', 'Gene', (60, 65))	('Glu504Lys', 'Chemical', '-', (66, 75))	('gastric cancer', 'Disease', (126, 140))	('men', 'Species', '9606', (118, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('Glu504Lys SNP', 'Var', (66, 79))	('interaction', 'Interaction', (40, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
233890	26491656	The studies on the association of the ALDH2 Glu504Lys SNP with the risk of colorectal cancer have given inconsistent results.	('Glu504Lys SNP', 'Var', (44, 57))	('colorectal cancer', 'Disease', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('ALDH2', 'Gene', (38, 43))	('association', 'Interaction', (19, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('Glu504Lys', 'Chemical', '-', (44, 53))
233891	26491656	Two recent meta-analyses indicate that ALDH2 Glu504Lys SNP may be associated with a decreased risk of colorectal cancer.	('colorectal cancer', 'Disease', (102, 119))	('Glu504Lys', 'Chemical', '-', (45, 54))	('ALDH2', 'Gene', (39, 44))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('Glu504Lys SNP', 'Var', (45, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('decreased', 'NegReg', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
233892	26491656	No significant impact of Glu504Lys SNP of ALDH2 gene on the risk of hepatocellular carcinoma and breast cancer has been found in East Asian populations.	('Glu504Lys', 'Chemical', '-', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Glu504Lys SNP', 'Var', (25, 38))	('ALDH2', 'Gene', (42, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (68, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('hepatocellular carcinoma and breast cancer', 'Disease', 'MESH:D001943', (68, 110))
233897	26491656	It has been found that 4-HNE can induce neuronal death and synapse dysfunction and markedly inhibit microtubule formation and neurite outgrowth.	('4-HNE', 'Var', (23, 28))	('microtubule formation', 'MPA', (100, 121))	('4-HNE', 'Chemical', 'MESH:C027576', (23, 28))	('neuronal death', 'Disease', 'MESH:D009410', (40, 54))	('inhibit', 'NegReg', (92, 99))	('synapse dysfunction', 'Disease', 'MESH:D009461', (59, 78))	('synapse dysfunction', 'Disease', (59, 78))	('neuronal death', 'Disease', (40, 54))	('induce', 'PosReg', (33, 39))
233902	26491656	Similarly, central neurons from transgenic mice overexpressing ALDH2 * 2 gene are more sensitive to 4-HNE-induced toxicity than cells from control animals.	('ALDH2 * 2', 'Gene', (63, 72))	('transgenic mice', 'Species', '10090', (32, 47))	('toxicity', 'Disease', 'MESH:D064420', (114, 122))	('toxicity', 'Disease', (114, 122))	('4-HNE', 'Chemical', 'MESH:C027576', (100, 105))	('overexpressing', 'Var', (48, 62))
233903	26491656	Moreover, these ALDH2 deficient mice exhibit an age-dependent decrease in spatial cognitive ability starting at the age of 6 months.	('ALDH2', 'Gene', (16, 21))	('deficient', 'Var', (22, 31))	('mice', 'Species', '10090', (32, 36))	('decrease', 'NegReg', (62, 70))	('spatial cognitive ability', 'CPA', (74, 99))
233904	26491656	The reduced resistance to oxidative stress has been proposed as one mechanism that leads to the neurodegeneration and memory loss in ALDH2 deficient mice.	('deficient', 'Var', (139, 148))	('resistance to oxidative stress', 'MPA', (12, 42))	('neurodegeneration', 'Disease', (96, 113))	('memory loss', 'Phenotype', 'HP:0002354', (118, 129))	('ALDH2', 'Gene', (133, 138))	('reduced', 'NegReg', (4, 11))	('memory loss', 'Disease', (118, 129))	('neurodegeneration', 'Disease', 'MESH:D019636', (96, 113))	('mice', 'Species', '10090', (149, 153))	('neurodegeneration', 'Phenotype', 'HP:0002180', (96, 113))	('memory loss', 'Disease', 'MESH:D008569', (118, 129))	('oxidative stress', 'Phenotype', 'HP:0025464', (26, 42))
233905	26491656	These results suggest that ALDH2 Glu504Lys SNP could be a genetic risk factor for AD in susceptible populations.	('AD', 'Disease', 'MESH:D000544', (82, 84))	('AD', 'Phenotype', 'HP:0002511', (82, 84))	('Glu504Lys', 'Chemical', '-', (33, 42))	('AD', 'Disease', (82, 84))	('ALDH2', 'Gene', (27, 32))	('Glu504Lys SNP', 'Var', (33, 46))
233909	26491656	Moreover, in LOAD patients homozygous for APOE-epsilon4, the age at onset of LOAD is significantly younger in those with ALDH2 * 2 allele than in those without ALDH2 * 2 allele, and the dosage of the ALDH2 * 2 allele significantly affects the age at onset of the disease.	('APOE', 'Gene', '348', (42, 46))	('younger', 'NegReg', (99, 106))	('AD', 'Phenotype', 'HP:0002511', (79, 81))	('affects', 'Reg', (231, 238))	('AD', 'Disease', 'MESH:D000544', (15, 17))	('AD', 'Disease', (15, 17))	('AD', 'Phenotype', 'HP:0002511', (15, 17))	('ALDH2 * 2 allele', 'Var', (121, 137))	('patients', 'Species', '9606', (18, 26))	('APOE', 'Gene', (42, 46))	('AD', 'Disease', 'MESH:D000544', (79, 81))	('AD', 'Disease', (79, 81))
233911	26491656	Studies have shown that APOE proteins interact with 4-HNE and the strength of binding between APOE isoforms and 4-HNE is different, with the order epsilon2 > epsilon3 > epsilon4.	('binding', 'Interaction', (78, 85))	('4-HNE', 'Chemical', 'MESH:C027576', (112, 117))	('interact', 'Interaction', (38, 46))	('APOE', 'Gene', '348', (94, 98))	('epsilon2', 'Var', (147, 155))	('APOE', 'Gene', (24, 28))	('4-HNE', 'Chemical', 'MESH:C027576', (52, 57))	('APOE', 'Gene', '348', (24, 28))	('APOE', 'Gene', (94, 98))
233918	26491656	Recently, a meta-analysis evaluated the association of ALDH2 variants with the risk of AD in East Asian populations has found that ALDH2   * 1/ * 2 and * 2/ * 2 genotypes are associated with increased AD risk only in subgroup analyses in which male subjects are included (OR = 1.72, 95% CI = 1.10-2.67, and p = 0.02).	('ALDH2', 'Gene', (131, 136))	('* 2/ * 2', 'Var', (152, 160))	('AD', 'Disease', 'MESH:D000544', (201, 203))	('AD', 'Phenotype', 'HP:0002511', (87, 89))	('AD', 'Disease', (201, 203))	('AD', 'Disease', 'MESH:D000544', (87, 89))	('AD', 'Phenotype', 'HP:0002511', (201, 203))	('increased', 'PosReg', (191, 200))	('variants', 'Var', (61, 69))	('ALDH2', 'Gene', (55, 60))	('AD', 'Disease', (87, 89))
233921	26491656	Dysfunction of ALDH2 in individuals carrying ALDH2 Glu504Lys SNP leads to increased accumulation of toxic aldehydes that may result in higher risk of a variety of human diseases including CVD, cancer, and AD.	('cancer', 'Disease', (193, 199))	('CVD', 'Disease', (188, 191))	('accumulation of toxic aldehydes', 'MPA', (84, 115))	('CVD', 'Disease', 'MESH:D002318', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('AD', 'Disease', (205, 207))	('AD', 'Phenotype', 'HP:0002511', (205, 207))	('increased', 'PosReg', (74, 83))	('result', 'Reg', (125, 131))	('ALDH2', 'Gene', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('Dysfunction', 'Var', (0, 11))	('AD', 'Disease', 'MESH:D000544', (205, 207))	('aldehydes', 'Chemical', 'MESH:D000447', (106, 115))	('CVD', 'Phenotype', 'HP:0001626', (188, 191))	('Glu504Lys', 'Var', (51, 60))	('Glu504Lys', 'Chemical', '-', (51, 60))	('human', 'Species', '9606', (163, 168))	('ALDH2', 'Gene', (45, 50))
233924	26491656	In particular, the Glu504Lys SNP of ALDH2 gene is closely related to alcohol drinking behavior.	('ALDH2', 'Gene', (36, 41))	('related', 'Reg', (58, 65))	('alcohol drinking behavior', 'Disease', (69, 94))	('Glu504Lys', 'Chemical', '-', (19, 28))	('alcohol drinking', 'Phenotype', 'HP:0030955', (69, 85))	('alcohol', 'Chemical', 'MESH:D000438', (69, 76))	('Glu504Lys SNP', 'Var', (19, 32))
233926	26491656	On the other hand, the unpleasant flushing syndromes caused by the accumulation of acetaldehyde result in less alcohol consumption and reduced incidence of alcoholism in individuals carrying ALDH2 * 2 allele.	('alcohol', 'Chemical', 'MESH:D000438', (156, 163))	('incidence', 'MPA', (143, 152))	('accumulation of acetaldehyde', 'Phenotype', 'HP:0003533', (67, 95))	('alcohol', 'Chemical', 'MESH:D000438', (111, 118))	('alcohol consumption', 'MPA', (111, 130))	('flushing syndromes', 'Disease', 'MESH:D005483', (34, 52))	('alcoholism', 'Disease', (156, 166))	('flushing', 'Phenotype', 'HP:0031284', (34, 42))	('reduced', 'NegReg', (135, 142))	('ALDH2 * 2', 'Gene', (191, 200))	('less', 'NegReg', (106, 110))	('acetaldehyde', 'Chemical', 'MESH:D000079', (83, 95))	('alcoholism', 'Disease', 'MESH:D000437', (156, 166))	('accumulation', 'Var', (67, 79))	('flushing syndromes', 'Disease', (34, 52))	('alcoholism', 'Phenotype', 'HP:0030955', (156, 166))	('acetaldehyde', 'MPA', (83, 95))
233927	26491656	As a consequence, for pathogenesis directly associated with ethanol consumption, Glu504Lys SNP of ALDH2 gene can be a protective factor for ALDH2 * 2 allele carriers who limit their exposure to ethanol.	('Glu504Lys SNP', 'Var', (81, 94))	('ALDH2', 'Gene', (98, 103))	('ALDH2', 'Gene', (140, 145))	('ethanol', 'Chemical', 'MESH:D000431', (194, 201))	('ethanol', 'Chemical', 'MESH:D000431', (60, 67))	('Glu504Lys', 'Chemical', '-', (81, 90))
233928	26491656	In addition, the effect of Glu504Lys SNP of ALDH2 gene on the development of chronic diseases, which are often multifactorial, can be complicated by other genetic variations.	('men', 'Species', '9606', (69, 72))	('Glu504Lys', 'Chemical', '-', (27, 36))	('ALDH2', 'Gene', (44, 49))	('Glu504Lys SNP', 'Var', (27, 40))	('chronic diseases', 'Disease', 'MESH:D002908', (77, 93))	('chronic diseases', 'Disease', (77, 93))
233929	26491656	In summary, defective ALDH2 activity may compromise the elimination of reactive aldehydes, leading to increased cytotoxicity and oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (129, 145))	('activity', 'MPA', (28, 36))	('cytotoxicity', 'Disease', (112, 124))	('oxidative stress', 'MPA', (129, 145))	('compromise', 'NegReg', (41, 51))	('cytotoxicity', 'Disease', 'MESH:D064420', (112, 124))	('increased', 'PosReg', (102, 111))	('elimination of reactive aldehydes', 'MPA', (56, 89))	('aldehydes', 'Chemical', 'MESH:D000447', (80, 89))	('defective', 'Var', (12, 21))	('ALDH2', 'Protein', (22, 27))
233930	26491656	Other genetic or environmental/life style factors, which promote (or inhibit) the stress caused by defective ALDH2, may increase (or reduce) the susceptibility of individuals carrying ALDH2 * 2 allele to relevant chronic diseases (Figure 1).	('ALDH2', 'Gene', (184, 189))	('stress', 'MPA', (82, 88))	('men', 'Species', '9606', (24, 27))	('defective', 'Var', (99, 108))	('promote', 'PosReg', (57, 64))	('susceptibility', 'MPA', (145, 159))	('reduce', 'NegReg', (133, 139))	('ALDH2', 'Gene', (109, 114))	('chronic diseases', 'Disease', (213, 229))	('increase', 'PosReg', (120, 128))	('inhibit', 'NegReg', (69, 76))	('chronic diseases', 'Disease', 'MESH:D002908', (213, 229))
233931	26491656	More effort should be spent in the future to understand the biochemical and molecular mechanisms underlying the association of ALDH2 Glu504Lys SNP with chronic diseases.	('association', 'Interaction', (112, 123))	('chronic diseases', 'Disease', 'MESH:D002908', (152, 168))	('chronic diseases', 'Disease', (152, 168))	('Glu504Lys', 'Var', (133, 142))	('ALDH2', 'Gene', (127, 132))	('Glu504Lys', 'Chemical', '-', (133, 142))
233932	26491656	Studies using animal and cell models with defective ALDH2 activity will further our knowledge on the molecular basis of human phenotype of ALDH2 variant and provide information for discovery of potential interventions and therapeutics targeting ALDH2.	('human', 'Species', '9606', (120, 125))	('variant', 'Var', (145, 152))	('ALDH2', 'Gene', (139, 144))
233933	26491656	Finally, for those diseases that are prompted synergistically by ALDH2 Glu504Lys SNP and alcohol consumption, individuals carrying ALDH2 * 2 allele should be targeted for reducing alcohol exposure as part of the preventive strategy.	('ALDH2', 'Gene', (131, 136))	('alcohol', 'Chemical', 'MESH:D000438', (89, 96))	('Glu504Lys', 'Var', (71, 80))	('rat', 'Species', '10116', (225, 228))	('Glu504Lys', 'Chemical', '-', (71, 80))	('ALDH2', 'Gene', (65, 70))	('alcohol', 'Chemical', 'MESH:D000438', (180, 187))
233939	25216530	Progression from normal to BE to adenocarcinoma was each associated with specific and mutually exclusive T-UCR signatures that included up-regulation of uc.58-, uc.202-, uc.207-, and uc.223- and down-regulation of uc.214+.	('uc.223-', 'Var', (183, 190))	('uc.214+', 'Gene', (214, 221))	('BE', 'Phenotype', 'HP:0100580', (27, 29))	('adenocarcinoma', 'Disease', 'MESH:D000230', (33, 47))	('up-regulation', 'PosReg', (136, 149))	('uc.58-', 'Gene', (153, 159))	('adenocarcinoma', 'Disease', (33, 47))	('down-regulation', 'NegReg', (195, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('uc.202-', 'Gene', (161, 168))	('uc.207-', 'Var', (170, 177))
233940	25216530	A 9 T-UCR signature characterized BE versus Sq (with the down-regulation of uc.161-, uc.165-, and uc.327-, and the up-regulation of uc.153-, uc.158-, uc.206-, uc.274-, uc.472-, and uc.473-).	('A 9 T', 'Mutation', 'c.9A>T', (0, 5))	('uc.165-', 'Var', (85, 92))	('uc.153-', 'Var', (132, 139))	('down-regulation', 'NegReg', (57, 72))	('uc.472-', 'Var', (168, 175))	('up-regulation', 'PosReg', (115, 128))	('uc.327-', 'Var', (98, 105))	('uc.161-', 'Gene', (76, 83))	('uc.158-', 'Var', (141, 148))	('uc.206-', 'Var', (150, 157))	('BE', 'Phenotype', 'HP:0100580', (34, 36))	('uc.473-', 'Var', (181, 188))	('uc.274-', 'Var', (159, 166))
233946	25216530	The phenotypic changes from native to cancer mucosa result from a composite interaction of genetic dysregulations involving epigenetic silencing, transcription factors, signaling pathways and growth factors.	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('epigenetic silencing', 'Var', (124, 144))	('cancer', 'Disease', (38, 44))
233957	25216530	The up-regulation of uc.158- (Figure 1B), uc.472- (Figure 1C), and uc.473- (Figure 1D), and the down-regulation of uc.165- (Figure 1E) were confirmed by qRT-PCR analysis in an independent series of endoscopic biopsy samples obtained from 50 long-segment BE patients.	('uc.165-', 'Var', (115, 122))	('uc.473-', 'Var', (67, 74))	('BE', 'Phenotype', 'HP:0100580', (254, 256))	('uc.158-', 'Gene', (21, 28))	('patients', 'Species', '9606', (257, 265))	('up-regulation', 'PosReg', (4, 17))	('down-regulation', 'NegReg', (96, 111))
233977	25216530	Most importantly, recent data suggest that T-UCRs are altered at transcriptional level in human tumorigenesis and aberrant T-UCR expression profiles may discriminate between different human cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('expression', 'MPA', (129, 139))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('tumor', 'Disease', (96, 101))	('aberrant', 'Var', (114, 122))	('human', 'Species', '9606', (90, 95))	('discriminate', 'Reg', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('human', 'Species', '9606', (184, 189))	('altered', 'Reg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
233979	25216530	Only very few T-UCRs have been described functionally in vitro, however: uc.73, for example, was found to influence apoptosis in colon cancer cells, and uc.338 to inhibit the growth of hepatocellular carcinoma cells.	('uc.338', 'Var', (153, 159))	('inhibit', 'NegReg', (163, 170))	('colon cancer', 'Phenotype', 'HP:0003003', (129, 141))	('hepatocellular carcinoma', 'Disease', (185, 209))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (185, 209))	('uc.73', 'Gene', (73, 78))	('apoptosis', 'CPA', (116, 125))	('colon cancer', 'Disease', 'MESH:D015179', (129, 141))	('influence', 'Reg', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colon cancer', 'Disease', (129, 141))	('growth', 'CPA', (175, 181))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (185, 209))
233980	25216530	Although UCRs are significantly depleted among segmental duplications and copy-number variants, the deletion of some of these regions in knock-out mice was not associated to any notable phenotypic abnormality.	('depleted', 'NegReg', (32, 40))	('mice', 'Species', '10090', (147, 151))	('copy-number variants', 'Var', (74, 94))	('UCRs', 'CPA', (9, 13))
234035	24872713	In GIST, sunitinib against wild-type and exon 9-mutant Kit was superior to that of imatinib in vitro, whereas both drugs exhibited similar potency against Kit exon-11 mutant kinases.	('sunitinib', 'Chemical', 'MESH:D000077210', (9, 18))	('GIST', 'Phenotype', 'HP:0100723', (3, 7))	('exon 9-mutant', 'Var', (41, 54))	('Kit', 'Gene', (55, 58))	('imatinib', 'Chemical', 'MESH:D000068877', (83, 91))
234039	24872713	FLT3 is another TKI that when mutated may lead to the development of a specific type of leukemia, known as acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (107, 129))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (113, 129))	('FLT3', 'Gene', '2322', (0, 4))	('leukemia', 'Disease', (121, 129))	('mutated', 'Var', (30, 37))	('leukemia', 'Disease', 'MESH:D007938', (121, 129))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (107, 129))	('lead to', 'Reg', (42, 49))	('acute myeloid leukemia', 'Disease', (107, 129))	('FLT3', 'Gene', (0, 4))	('leukemia', 'Disease', (88, 96))	('leukemia', 'Disease', 'MESH:D007938', (88, 96))
234040	24872713	Furthermore, sunitinib targets mutant RET, which is involved in the multiple endocrine neoplasia types 2A and 2B autosomal-dominant syndromes, familial medullary thyroid carcinoma, and perhaps sporadic NETs.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (162, 179))	('mutant', 'Var', (31, 37))	('sunitinib', 'Chemical', 'MESH:D000077210', (13, 22))	('RET', 'Gene', '5979', (38, 41))	('neoplasia', 'Disease', 'MESH:D009369', (87, 96))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (152, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('neoplasia', 'Phenotype', 'HP:0002664', (87, 96))	('thyroid carcinoma', 'Disease', (162, 179))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (162, 179))	('multiple', 'Disease', (68, 76))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (77, 96))	('RET', 'Gene', (38, 41))	('involved', 'Reg', (52, 60))	('neoplasia', 'Disease', (87, 96))
234095	24872713	Moreover, a number of more selective VEGFR inhibitors were also found to induce PUMA and apoptosis in colon cancer cells, supporting the non-angiogenic role of anti-VEGFR therapies.	('inhibitors', 'Var', (43, 53))	('VEGFR', 'Gene', '3791', (165, 170))	('VEGFR', 'Gene', (37, 42))	('apoptosis', 'CPA', (89, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('PUMA', 'CPA', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('VEGFR', 'Gene', (165, 170))	('colon cancer', 'Disease', (102, 114))	('VEGFR', 'Gene', '3791', (37, 42))	('induce', 'PosReg', (73, 79))
234107	24872713	Further studies are required to confirm that targeting EMMPRIN in RCC inhibits tumor angiogenesis, progression, and resistance to TKIs and mammalian target-of-rapamycin inhibitors.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('resistance', 'CPA', (116, 126))	('progression', 'CPA', (99, 110))	('tumor', 'Disease', (79, 84))	('mammalian target-of-rapamycin', 'Gene', '2475', (139, 168))	('inhibits', 'NegReg', (70, 78))	('EMMPRIN', 'Gene', '682', (55, 62))	('EMMPRIN', 'Gene', (55, 62))	('targeting', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('RCC', 'Disease', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mammalian target-of-rapamycin', 'Gene', (139, 168))
234120	24872713	In vitro, sunitinib inhibited VEGF-dependent proliferation and migration of human umbilical endothelial cells and disrupted capillary tube formation, and in in vivo models of cancer angiogenesis, sunitinib decreased tumor-microvessel density, blocked vascularization in the vascular window tumor model, and decreased the metastatic potential of several cancers, such as Lewis lung cancer.	('sunitinib', 'Var', (196, 205))	('VEGF', 'Gene', '7422', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('cancer', 'Disease', (175, 181))	('metastatic potential', 'CPA', (321, 341))	('inhibited', 'NegReg', (20, 29))	('Lewis lung cancer', 'Disease', (370, 387))	('VEGF', 'Gene', (30, 34))	('Lewis lung cancer', 'Disease', 'MESH:D018827', (370, 387))	('lung cancer', 'Phenotype', 'HP:0100526', (376, 387))	('tumor', 'Disease', (290, 295))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', (216, 221))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('blocked', 'NegReg', (243, 250))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('cancers', 'Disease', 'MESH:D009369', (353, 360))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('cancer', 'Disease', (381, 387))	('sunitinib', 'Chemical', 'MESH:D000077210', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('decreased', 'NegReg', (206, 215))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('decreased', 'NegReg', (307, 316))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('vascularization', 'CPA', (251, 266))	('sunitinib', 'Chemical', 'MESH:D000077210', (10, 19))	('cancers', 'Phenotype', 'HP:0002664', (353, 360))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', (353, 360))	('cancer', 'Disease', (353, 359))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('migration', 'CPA', (63, 72))
234208	21338875	Complex diseases are caused by many genetic and environmental factors working together, and GWAS has permitted the discovery of hundreds of genetic variants that alter the risk of developing multiple complex diseases, including type 2 diabetes, Crohn's disease, and Parkinson's disease.	("Crohn's disease", 'Disease', (245, 260))	("Parkinson's disease", 'Disease', (266, 285))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (228, 243))	("Parkinson's disease", 'Disease', 'MESH:D010300', (266, 285))	("Crohn's disease", 'Phenotype', 'HP:0100280', (245, 260))	('variants', 'Var', (148, 156))	('man', 'Species', '9606', (31, 34))	("Crohn's disease", 'Disease', 'MESH:D003424', (245, 260))	('diabetes', 'Disease', (235, 243))	('alter', 'Reg', (162, 167))	('diabetes', 'Disease', 'MESH:D003920', (235, 243))
234213	21338875	The strongest genetic contribution to nicotine dependence comes from variation in the nicotinic receptor subunits, and the most compelling genetic evidence is provided by several large-scale GWAS meta-analyses of smoking behavior.	('variation', 'Var', (69, 78))	('nicotine dependence', 'Disease', (38, 57))	('nicotine', 'Chemical', 'MESH:D009538', (38, 46))	('nicotinic receptor subunits', 'Protein', (86, 113))
234216	21338875	The SNP rs16969968 is unequivocally associated with smoking behavior (p=5.57 x 10-72).	('rs16969968', 'Mutation', 'rs16969968', (8, 18))	('associated with', 'Reg', (36, 51))	('smoking behavior', 'Disease', (52, 68))	('rs16969968', 'Var', (8, 18))
234217	21338875	Variation in an independent group of nicotinic receptors is also associated with the development of heavy smoking and nicotine dependence.	('nicotinic receptors', 'Protein', (37, 56))	('associated with', 'Reg', (65, 80))	('nicotine dependence', 'Disease', (118, 137))	('heavy smoking', 'Disease', (100, 113))	('Variation', 'Var', (0, 9))	('nicotine', 'Chemical', 'MESH:D009538', (118, 126))
234220	21338875	In addition to genetic variants in the nicotinic receptors contributing to the development of nicotine dependence, genetic variation in nicotine metabolism plays an important role in cigarette consumption and nicotine dependence.	('genetic variants', 'Var', (15, 31))	('nicotinic receptors', 'Protein', (39, 58))	('nicotine', 'Chemical', 'MESH:D009538', (94, 102))	('contributing', 'Reg', (59, 71))	('nicotine dependence', 'Disease', (94, 113))	('genetic variation', 'Var', (115, 132))	('nicotine', 'Chemical', 'MESH:D009538', (136, 144))	('nicotine', 'Chemical', 'MESH:D009538', (209, 217))	('role', 'Reg', (175, 179))	('nicotine', 'MPA', (136, 144))	('cigarette consumption', 'Disease', (183, 204))	('nicotine dependence', 'Disease', (209, 228))
234223	21338875	The importance of nicotine metabolism and variation in the CYP2a6 region on chromosome 19 was recently reinforced by the GWAS meta-analysis studies in which variants in this region were associated with number of cigarettes smoked per day.	('variation', 'Var', (42, 51))	('associated', 'Reg', (186, 196))	('CYP2a6', 'Gene', '1548', (59, 65))	('CYP2a6', 'Gene', (59, 65))	('nicotine', 'Chemical', 'MESH:D009538', (18, 26))	('variants', 'Var', (157, 165))
234224	21338875	The most significant SNP reported in this region, the intergenic variant rs41405144, lies within two large deletions (defined as CYP2a6*4 and CYP2a6*12).	('rs41405144', 'Mutation', 'rs41405144', (73, 83))	('CYP2a6', 'Gene', '1548', (129, 135))	('CYP2a6', 'Gene', (129, 135))	('rs41405144', 'Var', (73, 83))	('CYP2a6', 'Gene', '1548', (142, 148))	('CYP2a6', 'Gene', (142, 148))
234225	21338875	This variant, rs41405144, is correlated with rs1801272, a non-synonymous SNP that defines the CYP2a6*2 loss of function allele.	('rs1801272', 'Mutation', 'rs1801272', (45, 54))	('rs41405144', 'Var', (14, 24))	('rs1801272', 'Var', (45, 54))	('loss of function', 'NegReg', (103, 119))	('CYP2a6', 'Gene', '1548', (94, 100))	('CYP2a6', 'Gene', (94, 100))	('rs41405144', 'Mutation', 'rs41405144', (14, 24))
234226	21338875	These findings confirm that variation in nicotine metabolism contributes to the number of cigarettes smoked daily and the development of nicotine dependence.	('contributes', 'Reg', (61, 72))	('nicotine dependence', 'Disease', (137, 156))	('nicotine metabolism', 'MPA', (41, 60))	('variation', 'Var', (28, 37))	('nicotine', 'Chemical', 'MESH:D009538', (137, 145))	('nicotine', 'Chemical', 'MESH:D009538', (41, 49))
234228	21338875	Polymorphisms in the alcohol metabolizing enzymes are the most strongly associated genetic variants that influence alcohol consumption and alcohol dependence.	('alcohol', 'Chemical', 'MESH:D000438', (139, 146))	('influence', 'Reg', (105, 114))	('alcohol consumption and alcohol dependence', 'Disease', 'MESH:D000437', (115, 157))	('Polymorphisms', 'Var', (0, 13))	('associated', 'Reg', (72, 82))	('alcohol metabolizing enzymes', 'Enzyme', (21, 49))	('alcohol dependence', 'Phenotype', 'HP:0030955', (139, 157))	('alcohol', 'Chemical', 'MESH:D000438', (21, 28))	('alcohol', 'Chemical', 'MESH:D000438', (115, 122))
234234	21338875	For instance, ADH1B*2, or rs1229984, diminishes ADH1b enzymatic activity several fold, and ALDH2*2, or rs671, results in a nearly inactive enzyme.	('rs1229984', 'Mutation', 'rs1229984', (26, 35))	('rs671', 'Var', (103, 108))	('ALDH2', 'Gene', (91, 96))	('ADH1b', 'Gene', (48, 53))	('ADH1b', 'Gene', '125', (48, 53))	('ADH1B', 'Gene', '125', (14, 19))	('rs671', 'Mutation', 'rs671', (103, 108))	('diminishes', 'NegReg', (37, 47))	('enzymatic activity', 'MPA', (54, 72))	('ADH1B', 'Gene', (14, 19))	('rs1229984', 'Var', (26, 35))	('ALDH2', 'Gene', '217', (91, 96))
234236	21338875	The mechanism by which variants of these enzymes influence the risk of developing alcohol dependence is hypothesized to be through an elevation of acetaldehyde levels after drinking, leading to facial flushing, nausea, and other adverse reactions.	('facial flushing', 'Disease', 'MESH:D005483', (194, 209))	('nausea', 'Disease', 'MESH:D009325', (211, 217))	('acetaldehyde levels', 'MPA', (147, 166))	('leading to', 'Reg', (183, 193))	('alcohol dependence', 'Phenotype', 'HP:0030955', (82, 100))	('alcohol dependence', 'Disease', (82, 100))	('alcohol', 'Chemical', 'MESH:D000438', (82, 89))	('elevation', 'PosReg', (134, 143))	('acetaldehyde', 'Chemical', 'MESH:D000079', (147, 159))	('facial flushing', 'Disease', (194, 209))	('flushing', 'Phenotype', 'HP:0031284', (201, 209))	('variants', 'Var', (23, 31))	('influence', 'Reg', (49, 58))	('elevation of acetaldehyde levels', 'Phenotype', 'HP:0003533', (134, 166))	('nausea', 'Phenotype', 'HP:0002018', (211, 217))	('nausea', 'Disease', (211, 217))
234241	21338875	For instance, rs1229984 and rs671 are not genotyped on many of the initial GWAS chips (www.broadinstitute.org/mpg/snap).	('rs1229984', 'Mutation', 'rs1229984', (14, 23))	('rs671', 'Var', (28, 33))	('rs1229984', 'Var', (14, 23))	('rs671', 'Mutation', 'rs671', (28, 33))	('man', 'Species', '9606', (55, 58))	('mpg', 'Gene', (110, 113))	('mpg', 'Gene', '4350', (110, 113))
234246	21338875	Ethanol enhances GABAA receptor function and electrophysiologic studies implicate GABAA receptors as targets for the effect of ethanol in the central nervous system.	('GABA', 'Chemical', 'MESH:D005680', (82, 86))	('GABA', 'Chemical', 'MESH:D005680', (17, 21))	('Ethanol', 'Chemical', 'MESH:D000431', (0, 7))	('GABAA receptor', 'Protein', (17, 31))	('ethanol', 'Chemical', 'MESH:D000431', (127, 134))	('function', 'MPA', (32, 40))	('enhances', 'PosReg', (8, 16))	('Ethanol', 'Var', (0, 7))
234247	21338875	Multiple candidate gene reports show an association between variants in GABRA2 and alcohol dependence.	('GABRA2', 'Gene', '2555', (72, 78))	('alcohol dependence', 'Phenotype', 'HP:0030955', (83, 101))	('alcohol dependence', 'Disease', (83, 101))	('GABRA2', 'Gene', (72, 78))	('variants', 'Var', (60, 68))	('alcohol', 'Chemical', 'MESH:D000438', (83, 90))
234257	21338875	Similarly, the endogeneous opioid system clearly plays a role in addiction, and an amino acid change in the mu opioid receptor (OPRM1) displays functional changes with up to threefold variation in the affinity of the receptor to bind beta-endorphin, the endogenous opioid.	('amino acid change', 'Var', (83, 100))	('bind', 'Interaction', (229, 233))	('OPRM1', 'Gene', (128, 133))	('OPRM1', 'Gene', '4988', (128, 133))	('addiction', 'Disease', (65, 74))	('variation', 'Reg', (184, 193))	('beta-endorphin', 'Gene', '5443', (234, 248))	('changes', 'Reg', (155, 162))	('beta-endorphin', 'Gene', (234, 248))	('affinity', 'MPA', (201, 209))
234259	21338875	For instance, variants in the alcohol metabolizing genes specifically contribute to differences in alcohol consumption and alcohol dependence, but not to other addictive behaviors.	('alcohol metabolizing genes', 'Gene', (30, 56))	('alcohol dependence', 'Phenotype', 'HP:0030955', (123, 141))	('alcohol', 'Chemical', 'MESH:D000438', (30, 37))	('differences', 'Reg', (84, 95))	('variants', 'Var', (14, 22))	('alcohol', 'Chemical', 'MESH:D000438', (99, 106))	('alcohol', 'Chemical', 'MESH:D000438', (123, 130))	('addictive behavior', 'Phenotype', 'HP:0030858', (160, 178))	('alcohol consumption and alcohol dependence', 'Disease', 'MESH:D000437', (99, 141))	('addictive behaviors', 'Phenotype', 'HP:0030858', (160, 179))	('contribute', 'Reg', (70, 80))
234260	21338875	Similarly, the variation in nicotine metabolizing genes contributes to smoking behavior and cigarettes smoked per day, but not alcoholism or other drug addiction.	('alcoholism', 'Disease', (127, 137))	('cigarettes smoked', 'CPA', (92, 109))	('nicotine', 'Chemical', 'MESH:D009538', (28, 36))	('alcoholism', 'Disease', 'MESH:D000437', (127, 137))	('alcoholism', 'Phenotype', 'HP:0030955', (127, 137))	('nicotine metabolizing genes', 'Gene', (28, 55))	('variation', 'Var', (15, 24))	('contributes', 'Reg', (56, 67))	('smoking behavior', 'CPA', (71, 87))
234261	21338875	In fact, twin studies have convincingly shown that most of the genetic variation to addiction is shared across the liability to develop nicotine, alcohol, and illicit drug addiction.	('genetic variation', 'Var', (63, 80))	('develop', 'PosReg', (128, 135))	('illicit drug addiction', 'Disease', (159, 181))	('nicotine', 'Chemical', 'MESH:D009538', (136, 144))	('alcohol', 'Chemical', 'MESH:D000438', (146, 153))	('alcohol', 'Disease', (146, 153))
234262	21338875	The chromosome 15 variant in the alpha5 nicotinic receptor, rs16969968, which influences the development of nicotine dependence, has also been independently shown to contribute to the occurrence of alcohol and cocaine dependence.	('nicotine', 'Chemical', 'MESH:D009538', (108, 116))	('contribute to', 'Reg', (166, 179))	('influences', 'Reg', (78, 88))	('occurrence', 'Reg', (184, 194))	('alcohol', 'Chemical', 'MESH:D000438', (198, 205))	('rs16969968', 'Var', (60, 70))	('cocaine', 'Chemical', 'MESH:D003042', (210, 217))	('rs16969968', 'Mutation', 'rs16969968', (60, 70))
234263	21338875	The minor allele of rs16969968 that is correlated with an increased risk for nicotine dependence is associated with a decreased risk for alcohol and cocaine dependence.	('alcohol', 'Chemical', 'MESH:D000438', (137, 144))	('nicotine', 'Chemical', 'MESH:D009538', (77, 85))	('decreased', 'NegReg', (118, 127))	('rs16969968', 'Var', (20, 30))	('nicotine dependence', 'Disease', (77, 96))	('cocaine', 'Chemical', 'MESH:D003042', (149, 156))	('rs16969968', 'Mutation', 'rs16969968', (20, 30))
234265	21338875	These data reinforce the importance of variation in the CHRNA5-CHRNA3-CHRNB3 gene cluster for risk of dependence on multiple substances, although the direction of the effects varies across substances.	('CHRNB3', 'Gene', '1142', (70, 76))	('CHRNA5', 'Gene', (56, 62))	('dependence on multiple substances', 'MPA', (102, 135))	('CHRNA3', 'Gene', '1136', (63, 69))	('CHRNA5', 'Gene', '1138', (56, 62))	('CHRNB3', 'Gene', (70, 76))	('CHRNA3', 'Gene', (63, 69))	('variation', 'Var', (39, 48))
234266	21338875	In addition, variants in this region influence the initial responses to alcohol and nicotine in adolescents.	('nicotine', 'Chemical', 'MESH:D009538', (84, 92))	('variants', 'Var', (13, 21))	('alcohol', 'Chemical', 'MESH:D000438', (72, 79))	('influence', 'Reg', (37, 46))
234270	21338875	For example, the well known genetic variants that alter alcohol metabolism, rs1229984 in ADH1b and rs671 in ALDH2, are not queried on most of the commercial GWAS chips.	('ADH1b', 'Gene', (89, 94))	('ADH1b', 'Gene', '125', (89, 94))	('rs671', 'Mutation', 'rs671', (99, 104))	('rs1229984', 'Var', (76, 85))	('rs1229984', 'Mutation', 'rs1229984', (76, 85))	('ALDH2', 'Gene', '217', (108, 113))	('rs671', 'Var', (99, 104))	('alcohol', 'Chemical', 'MESH:D000438', (56, 63))	('alcohol metabolism', 'MPA', (56, 74))	('ALDH2', 'Gene', (108, 113))
234271	21338875	For smoking behavior, for example, we know that individual genetic variants contribute only a small effect to the development of nicotine dependence.	('nicotine', 'Chemical', 'MESH:D009538', (129, 137))	('nicotine dependence', 'Disease', (129, 148))	('variants', 'Var', (67, 75))
234272	21338875	For example, in our study from the Collaborative Genetic Study of Nicotine Dependence, approximately 9 variants in the nicotinic receptors explain 5% of the phenotypic variance in the sample.	('variants', 'Var', (103, 111))	('nicotinic receptors', 'Protein', (119, 138))	('Nicotine', 'Chemical', 'MESH:D009538', (66, 74))
234277	21338875	Two of the top genetic findings -rs16969968 in CHRNA5 and rs6474412 in CHRNB3:showed significance levels of 5.57 x 10-72 with a sample size of N = 73,853 (TAG, 2010) and 1.4 x 10-8 with a sample size of N = 84,956.	('CHRNB3', 'Gene', (71, 77))	('CHRNB3', 'Gene', '1142', (71, 77))	('rs6474412', 'Var', (58, 67))	('rs6474412', 'Mutation', 'rs6474412', (58, 67))	('rs16969968', 'Mutation', 'rs16969968', (33, 43))	('CHRNA5', 'Gene', (47, 53))	('CHRNA5', 'Gene', '1138', (47, 53))	('-rs16969968', 'Var', (32, 43))
234278	21338875	In our COGEND sample of 2,062 subjects of European descent, we have a significance level of 4 x 10-7 for the CHRNA5 variant and 1.37 x 10-3 for the variant in CHRNB3, representing a 3 and 10 fold increase in the power to detect genetic variation compared to a more heterogeneous GWAS.	('variant', 'Var', (148, 155))	('CHRNA5', 'Gene', (109, 115))	('variant', 'Var', (116, 123))	('CHRNB3', 'Gene', (159, 165))	('increase', 'PosReg', (196, 204))	('CHRNA5', 'Gene', '1138', (109, 115))	('CHRNB3', 'Gene', '1142', (159, 165))
234281	21338875	In the chromosome 15 region, the most biologically credible variant associated with nicotine dependence is rs16969968, a polymorphism that causes an amino acid change from aspartic acid to asparagine (Asp398Asn) in the alpha5 nicotine receptor subunit.	('amino', 'MPA', (149, 154))	('Asp398Asn', 'Var', (201, 210))	('associated', 'Reg', (68, 78))	('rs16969968', 'Mutation', 'rs16969968', (107, 117))	('nicotine', 'Chemical', 'MESH:D009538', (84, 92))	('aspartic acid', 'Chemical', 'MESH:D001224', (172, 185))	('aspartic acid', 'MPA', (172, 185))	('nicotine', 'Chemical', 'MESH:D009538', (226, 234))	('Asn', 'Chemical', 'MESH:D001216', (207, 210))	('nicotine dependence', 'Disease', (84, 103))	('asparagine', 'Chemical', 'MESH:D001216', (189, 199))
234283	21338875	An in vitro functional study found that alpha4alpha5beta2 receptors that only differed by the asparagine amino acid substitution exhibited altered response to a nicotine agonist compared with receptors containing the aspartic acid amino acid.	('aspartic acid amino acid', 'Chemical', '-', (217, 241))	('asparagine amino acid', 'Chemical', '-', (94, 115))	('asparagine amino acid substitution', 'Var', (94, 128))	('alpha4alpha5beta2 receptors', 'Protein', (40, 67))	('response to a nicotine agonist', 'MPA', (147, 177))	('altered', 'Reg', (139, 146))	('nicotine', 'Chemical', 'MESH:D009538', (161, 169))
234284	21338875	Further studies of the nicotinic receptors show that the alpha5 Asn 398 protein (high risk variant) in the nicotinic acetylcholine receptor lowers Ca2+permeability and increases short-term desensitization in (alpha4beta2)alpha5, but does not alter the receptor sensitivity to activation.	('short-term desensitization', 'MPA', (178, 204))	('increases', 'PosReg', (168, 177))	('Ca2+permeability', 'MPA', (147, 163))	('alpha5', 'Var', (57, 63))	('Asn', 'Chemical', 'MESH:D001216', (64, 67))	('lowers', 'NegReg', (140, 146))	('Ca2+', 'Chemical', 'MESH:D000069285', (147, 151))
234286	21338875	In the chromosome 15 region, the second independent genetic association with nicotine dependence is marked by rs880395, and functional studies suggest a distinct biological mechanism: altered alpha5 nicotinic receptor mRNA expression.	('rs880395', 'Var', (110, 118))	('alpha5 nicotinic receptor', 'Protein', (192, 217))	('rs880395', 'Mutation', 'rs880395', (110, 118))	('nicotine', 'Chemical', 'MESH:D009538', (77, 85))	('altered', 'Reg', (184, 191))
234287	21338875	Variants tagged by rs880395, which are more than 10kb upstream of CHRNA5, result in a 2.5 to 4 fold difference in alpha5 nicotinic receptor mRNA expression in the brain.	('Variants', 'Var', (0, 8))	('difference', 'Reg', (100, 110))	('CHRNA5', 'Gene', '1138', (66, 72))	('alpha5 nicotinic receptor mRNA expression', 'MPA', (114, 155))	('CHRNA5', 'Gene', (66, 72))	('rs880395', 'Mutation', 'rs880395', (19, 27))
234294	21338875	These genetic associations with nicotine and alcohol dependence and proposed mechanisms of biologic action including neurotransmission and metabolism provide new insights to the underlying biology associated with addiction.	('nicotine', 'Chemical', 'MESH:D009538', (32, 40))	('nicotine', 'Disease', (32, 40))	('alcohol dependence', 'Phenotype', 'HP:0030955', (45, 63))	('alcohol dependence', 'Disease', (45, 63))	('genetic', 'Var', (6, 13))	('alcohol', 'Chemical', 'MESH:D000438', (45, 52))
234297	21338875	Large-scale genetic studies demonstrate that the same variants on chromosome 15 that are associated with smoking behavior are also the strongest genetic risk factors for lung cancer and COPD.	('COPD', 'Disease', (186, 190))	('associated', 'Reg', (89, 99))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('COPD', 'Phenotype', 'HP:0006510', (186, 190))	('COPD', 'Disease', 'MESH:D029424', (186, 190))	('variants', 'Var', (54, 62))	('lung cancer', 'Disease', (170, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
234300	21338875	Evidence in favor of a direct biological effect are that this genetic risk for lung cancer and COPD association with these variants remains after statistically accounting for duration of smoking history and number of cigarettes smoked per day.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('COPD', 'Disease', 'MESH:D029424', (95, 99))	('COPD', 'Disease', (95, 99))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('variants', 'Var', (123, 131))	('COPD', 'Phenotype', 'HP:0006510', (95, 99))
234303	21338875	This implies that the smokers with the risk variants are inhaling more intensely and increasing their exposure to nicotine and other carcinogens in cigarette smoke.	('nicotine', 'Chemical', 'MESH:D009538', (114, 122))	('increasing', 'PosReg', (85, 95))	('intensely', 'PosReg', (71, 80))	('variants', 'Var', (44, 52))	('exposure to nicotine', 'MPA', (102, 122))
234305	21338875	A parallel finding is seen with genetic variants that influence alcohol consumption, alcohol dependence, and esophageal cancer.	('alcohol dependence', 'Phenotype', 'HP:0030955', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('alcohol dependence', 'Disease', (85, 103))	('alcohol consumption', 'Disease', (64, 83))	('alcohol', 'Chemical', 'MESH:D000438', (64, 71))	('alcohol', 'Chemical', 'MESH:D000438', (85, 92))	('esophageal cancer', 'Disease', (109, 126))	('variants', 'Var', (40, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))	('influence', 'Reg', (54, 63))
234306	21338875	Large studies of esophageal cancer, a cancer related to alcohol use, identify two genetic variants in alcohol metabolizing genes that influence alcohol consumption and alcohol dependence (ADH1b variant, rs1229984, and ALDH2 variant, rs671) and also contribute to the risk of esophageal cancer.	('rs1229984', 'Var', (203, 212))	('ALDH2', 'Gene', (218, 223))	('ADH1b', 'Gene', '125', (188, 193))	('alcohol', 'Chemical', 'MESH:D000438', (144, 151))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('alcohol', 'Chemical', 'MESH:D000438', (56, 63))	('alcohol consumption and alcohol dependence', 'Disease', 'MESH:D000437', (144, 186))	('cancer', 'Disease', (286, 292))	('alcohol dependence', 'Phenotype', 'HP:0030955', (168, 186))	('influence', 'Reg', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('alcohol', 'Chemical', 'MESH:D000438', (102, 109))	('alcohol use', 'Phenotype', 'HP:0030955', (56, 67))	('cancer', 'Disease', (38, 44))	('ALDH2', 'Gene', '217', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('rs1229984', 'Mutation', 'rs1229984', (203, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (17, 34))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Disease', (28, 34))	('rs671', 'Var', (233, 238))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('esophageal cancer', 'Disease', (17, 34))	('ADH1b', 'Gene', (188, 193))	('esophageal cancer', 'Disease', 'MESH:D004938', (275, 292))	('rs671', 'Mutation', 'rs671', (233, 238))	('alcohol', 'Chemical', 'MESH:D000438', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('esophageal cancer', 'Disease', (275, 292))
234307	21338875	Even after controlling for alcohol consumption in the analyses, the protective effects of these variants for esophageal cancer remain strong.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('variants', 'Var', (96, 104))	('alcohol', 'Chemical', 'MESH:D000438', (27, 34))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
234308	21338875	This implies that variants in alcohol metabolizing genes not only reduce alcohol consumption and decrease the risk for alcohol dependence, but also lower the susceptibility to esophageal cancer, perhaps by reducing the carcinogenic effects of alcohol, its metabolites and other toxins.	('susceptibility', 'MPA', (158, 172))	('alcohol dependence', 'Phenotype', 'HP:0030955', (119, 137))	('alcohol dependence', 'Disease', (119, 137))	('decrease', 'NegReg', (97, 105))	('alcohol', 'Chemical', 'MESH:D000438', (30, 37))	('reducing', 'NegReg', (206, 214))	('alcohol consumption', 'MPA', (73, 92))	('esophageal cancer', 'Disease', (176, 193))	('alcohol', 'Chemical', 'MESH:D000438', (243, 250))	('alcohol', 'Chemical', 'MESH:D000438', (119, 126))	('variants', 'Var', (18, 26))	('lower', 'NegReg', (148, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (176, 193))	('carcinogenic', 'Disease', 'MESH:D063646', (219, 231))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('carcinogenic', 'Disease', (219, 231))	('reduce', 'NegReg', (66, 72))	('alcohol', 'Chemical', 'MESH:D000438', (73, 80))
234314	21338875	It also remains unclear if the mechanism of these associations of cancer with the genetic variants can be completely explained through addictive behaviors, or if biologic mechanisms act in the brain to increase the risk of addiction while also acting in the lung and esophagus to increase the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('addictive behavior', 'Phenotype', 'HP:0030858', (135, 153))	('cancer', 'Disease', (301, 307))	('increase', 'PosReg', (280, 288))	('addiction', 'Disease', (223, 232))	('addictive behaviors', 'Phenotype', 'HP:0030858', (135, 154))	('variants', 'Var', (90, 98))	('associations', 'Interaction', (50, 62))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('increase', 'PosReg', (202, 210))	('cancer', 'Disease', (66, 72))
234315	21338875	Only through animal models will we be able to separate the genetic influence of these variants on the development of dependence from the genetic contribution to the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (180, 186))	('variants', 'Var', (86, 94))
234317	21338875	Similarly, the polymorphisms that cause amino acid changes in alcohol metabolizing genes, rs671 and rs1229984, are common in Asian populations, but are rare in populations of European and African descent.	('amino acid changes', 'Var', (40, 58))	('rs1229984', 'Mutation', 'rs1229984', (100, 109))	('alcohol metabolizing genes', 'Gene', (62, 88))	('rs671', 'Var', (90, 95))	('rs1229984', 'Var', (100, 109))	('alcohol', 'Chemical', 'MESH:D000438', (62, 69))	('rs671', 'Mutation', 'rs671', (90, 95))
234318	21338875	Thus, rs16969968 will play a larger role in the development of heavy smoking and nicotine dependence in populations of European ancestry compared to populations of African and Asian ancestry.	('rs16969968', 'Mutation', 'rs16969968', (6, 16))	('heavy smoking', 'Disease', (63, 76))	('nicotine', 'Chemical', 'MESH:D009538', (81, 89))	('nicotine dependence', 'Disease', (81, 100))	('rs16969968', 'Var', (6, 16))
234319	21338875	Similarly, rs671 and rs1229984 will more strongly influence alcohol consumption and alcohol dependence in Asian populations compared to European and African populations.	('rs1229984', 'Mutation', 'rs1229984', (21, 30))	('rs671', 'Var', (11, 16))	('rs1229984', 'Var', (21, 30))	('alcohol consumption and alcohol dependence', 'Disease', 'MESH:D000437', (60, 102))	('rs671', 'Mutation', 'rs671', (11, 16))	('alcohol dependence', 'Phenotype', 'HP:0030955', (84, 102))	('influence', 'Reg', (50, 59))
234321	21338875	The strongest specific genetic contributors to dependence are related to the pharmacologic responses to nicotine and alcohol and include variation in nicotinic receptor genes, nicotine metabolizing genes, and alcohol metabolizing genes.	('nicotine', 'Chemical', 'MESH:D009538', (176, 184))	('alcohol', 'Chemical', 'MESH:D000438', (209, 216))	('variation', 'Var', (137, 146))	('alcohol', 'Chemical', 'MESH:D000438', (117, 124))	('nicotine metabolizing genes', 'Gene', (176, 203))	('nicotinic receptor genes', 'Gene', (150, 174))	('nicotine', 'Chemical', 'MESH:D009538', (104, 112))	('dependence', 'Disease', (47, 57))
234322	21338875	If the progress in other medical disorders can be used as an example, the "big science" consortia that include the study of tens of thousands and potentially hundreds of thousands of people will soon discover new variants that contribute to addiction.	('addiction', 'Disease', (241, 250))	('variants', 'Var', (213, 221))	('people', 'Species', '9606', (183, 189))	('contribute', 'Reg', (227, 237))
234332	21338875	We may be able to utilize the variation in nicotinic receptors and nicotine metabolizing genes to improve our treatments for smoking.	('nicotinic receptors', 'Protein', (43, 62))	('nicotine metabolizing genes', 'Gene', (67, 94))	('variation', 'Var', (30, 39))	('nicotine', 'Chemical', 'MESH:D009538', (67, 75))
234333	33920562	MTHFR C677T and A1298C Polymorphisms in Breast Cancer, Gliomas and Gastric Cancer: A Review Folate (vitamin B9) is found in some water-soluble foods or as a synthetic form of folic acid and is involved in many essential biochemical processes.	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('water', 'Chemical', 'MESH:D014867', (129, 134))	('MTHFR', 'Gene', (0, 5))	('Folate', 'Chemical', 'MESH:D005492', (92, 98))	('vitamin B9', 'Chemical', 'MESH:D005492', (100, 110))	('C677T', 'Mutation', 'rs1801133', (6, 11))	('Gliomas and Gastric Cancer', 'Disease', 'MESH:D013274', (55, 81))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (67, 81))	('Breast Cancer', 'Disease', 'MESH:D001943', (40, 53))	('A1298C', 'SUBSTITUTION', 'None', (16, 22))	('folic acid', 'Chemical', 'MESH:D005492', (175, 185))	('MTHFR', 'Gene', '4524', (0, 5))	('Breast Cancer', 'Disease', (40, 53))	('A1298C', 'Var', (16, 22))	('C677T', 'Var', (6, 11))	('Glioma', 'Phenotype', 'HP:0009733', (55, 61))	('Breast Cancer', 'Phenotype', 'HP:0003002', (40, 53))	('Gliomas', 'Phenotype', 'HP:0009733', (55, 62))
234336	33920562	MTHFR polymorphisms result in reduced enzyme activity and altered levels of DNA methylation and synthesis.	('MTHFR', 'Gene', '4524', (0, 5))	('polymorphisms', 'Var', (6, 19))	('synthesis', 'MPA', (96, 105))	('MTHFR', 'Gene', (0, 5))	('levels of DNA methylation', 'MPA', (66, 91))	('reduced', 'NegReg', (30, 37))	('enzyme activity', 'MPA', (38, 53))	('altered', 'Reg', (58, 65))
234337	33920562	MTHFR polymorphisms have been linked to increased risks of several pathologies, including cancer.	('MTHFR', 'Gene', '4524', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('polymorphisms', 'Var', (6, 19))	('MTHFR', 'Gene', (0, 5))	('linked to', 'Reg', (30, 39))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
234340	33920562	This review discusses the relationship between the MTHFR C677T and A1298C polymorphisms and the increased risk of breast cancer, gliomas, and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('gastric cancer', 'Disease', (142, 156))	('C677T', 'Mutation', 'rs1801133', (57, 62))	('A1298C', 'Var', (67, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('C677T', 'Var', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('MTHFR', 'Gene', '4524', (51, 56))	('gliomas', 'Disease', (129, 136))	('gliomas', 'Disease', 'MESH:D005910', (129, 136))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('gliomas', 'Phenotype', 'HP:0009733', (129, 136))	('A1298C', 'SUBSTITUTION', 'None', (67, 73))	('MTHFR', 'Gene', (51, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
234352	33920562	In addition to the effects of methylation in DNA and possible subsequent damage to molecules, disturbances in the metabolism of carbon-1 cause DNA damage via effects on nucleotide synthesis.	('metabolism', 'MPA', (114, 124))	('nucleotide synthesis', 'MPA', (169, 189))	('carbon', 'Chemical', 'MESH:D002244', (128, 134))	('effects', 'Reg', (158, 165))	('disturbances', 'Var', (94, 106))
234353	33920562	In folate deficiency, uracil is incorporated into DNA molecules; during repair, breaks may occur in DNA molecules by uracil glycosylase (UDG), causing damage and chromosomal translocations, a hallmark of genomic instability that may contribute to tumor progression.	('folate deficiency', 'Phenotype', 'HP:0100507', (3, 20))	('folate deficiency', 'Disease', (3, 20))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('folate deficiency', 'Disease', 'MESH:C562799', (3, 20))	('chromosomal translocations', 'CPA', (162, 188))	('uracil', 'Chemical', 'MESH:D014498', (117, 123))	('tumor', 'Disease', (247, 252))	('breaks', 'Var', (80, 86))	('contribute', 'Reg', (233, 243))	('damage', 'MPA', (151, 157))	('UDG', 'Gene', (137, 140))	('UDG', 'Gene', '7374', (137, 140))	('uracil', 'Chemical', 'MESH:D014498', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('DNA molecules', 'Gene', (100, 113))	('causing', 'Reg', (143, 150))
234365	33920562	Global DNA hypomethylation is associated with low folate intake in animals and experimental studies with human models.	('low', 'NegReg', (46, 49))	('Global DNA', 'Var', (0, 10))	('human', 'Species', '9606', (105, 110))	('folate', 'Chemical', 'MESH:D005492', (50, 56))	('low folate intake', 'Phenotype', 'HP:0100507', (46, 63))
234366	33920562	Three processes characterize the contribution of changes in the patterns of DNA methylation in the initiation and progression of cancer: (i) global hypomethylation promotes chromosomal instability by the reactivation of transposable elements and loss of imprinting; (ii) local hypomethylation induces the activation of oncogenes; and (iii) most of the time, hypermethylation promotes the silencing of tumor suppressor genes.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('silencing', 'MPA', (388, 397))	('hypermethylation', 'Var', (358, 374))	('initiation', 'Disease', (99, 109))	('chromosomal instability', 'MPA', (173, 196))	('activation', 'PosReg', (305, 315))	('imprinting', 'Gene', (254, 264))	('cancer', 'Disease', (129, 135))	('promotes', 'PosReg', (164, 172))	('initiation', 'Disease', 'MESH:D007319', (99, 109))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('oncogenes', 'Gene', (319, 328))	('local hypomethylation', 'Var', (271, 292))	('chromosomal instability', 'Phenotype', 'HP:0040012', (173, 196))	('tumor', 'Disease', (401, 406))
234371	33920562	In this context, this review discusses the relationship of changes in the folate pathway resulting from the C677T and A1298C polymorphisms of the MTHFR gene with the process of breast, glioma and gastric carcinogenesis.	('folate', 'Chemical', 'MESH:D005492', (74, 80))	('A1298C', 'Var', (118, 124))	('glioma and gastric carcinogenesis', 'Disease', 'MESH:D063646', (185, 218))	('MTHFR', 'Gene', '4524', (146, 151))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('A1298C', 'SUBSTITUTION', 'None', (118, 124))	('breast', 'Disease', (177, 183))	('MTHFR', 'Gene', (146, 151))	('C677T', 'Mutation', 'rs1801133', (108, 113))	('C677T', 'Var', (108, 113))	('folate pathway', 'Pathway', (74, 88))
234374	33920562	The occurrence of polymorphisms in enzymes encoding genes of the folate pathway provides a functional impact on metabolism.	('folate', 'Chemical', 'MESH:D005492', (65, 71))	('occurrence', 'Reg', (4, 14))	('metabolism', 'MPA', (112, 122))	('impact', 'Reg', (102, 108))	('polymorphisms', 'Var', (18, 31))
234376	33920562	MTHFR polymorphisms have been extensively investigated to assess their association in various medical conditions, primarily cardiovascular disease, thrombosis, pregnancy complications, neural tube defects, cancer risk, and psychiatric disease.	('psychiatric disease', 'Disease', 'MESH:D001523', (223, 242))	('MTHFR', 'Gene', (0, 5))	('psychiatric disease', 'Phenotype', 'HP:0000708', (223, 242))	('tube defects', 'Disease', (192, 204))	('neural tube defects', 'Phenotype', 'HP:0045005', (185, 204))	('cancer', 'Disease', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('polymorphisms', 'Var', (6, 19))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (124, 146))	('thrombosis', 'Disease', 'MESH:D013927', (148, 158))	('cardiovascular disease', 'Disease', 'MESH:D002318', (124, 146))	('MTHFR', 'Gene', '4524', (0, 5))	('tube defects', 'Disease', 'MESH:D005184', (192, 204))	('cardiovascular disease', 'Disease', (124, 146))	('thrombosis', 'Disease', (148, 158))	('pregnancy complications', 'Disease', (160, 183))	('psychiatric disease', 'Disease', (223, 242))	('association', 'Interaction', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
234377	33920562	There are two polymorphisms of the MTHFR gene already well described as associated with numerous pathologies: C677T and A1298C.	('A1298C', 'SUBSTITUTION', 'None', (120, 126))	('MTHFR', 'Gene', '4524', (35, 40))	('associated', 'Reg', (72, 82))	('A1298C', 'Var', (120, 126))	('C677T', 'Mutation', 'rs1801133', (110, 115))	('MTHFR', 'Gene', (35, 40))	('C677T', 'Var', (110, 115))
234378	33920562	The C677T polymorphism is an exchange at position 677 of the MTHFR gene whose exchange of nucleotide cysteine for thymine culminates in the replacement of alanine by valine in the MTHFR enzyme.	('nucleotide cysteine', 'Chemical', '-', (90, 109))	('MTHFR', 'Gene', (61, 66))	('alanine', 'Chemical', 'MESH:D000409', (155, 162))	('C677T', 'Mutation', 'rs1801133', (4, 9))	('valine', 'Chemical', 'MESH:D014633', (166, 172))	('MTHFR', 'Gene', '4524', (180, 185))	('C677T', 'Var', (4, 9))	('thymine', 'Chemical', 'MESH:D013941', (114, 121))	('MTHFR', 'Gene', (180, 185))	('MTHFR', 'Gene', '4524', (61, 66))	('alanine', 'MPA', (155, 162))	('replacement', 'Var', (140, 151))	('exchange', 'MPA', (78, 86))
234380	33920562	The reduction in enzyme activity leads to an increase in plasma homocysteine levels in mutant homozygous subjects and high plasma homocysteine levels; in heterozygotes, homocysteine levels are high compared with normal individuals but lower than homozygotes.	('activity', 'MPA', (24, 32))	('homocysteine', 'Chemical', 'MESH:D006710', (169, 181))	('plasma homocysteine levels', 'MPA', (57, 83))	('high plasma homocysteine levels', 'MPA', (118, 149))	('enzyme', 'Enzyme', (17, 23))	('homocysteine', 'Chemical', 'MESH:D006710', (64, 76))	('mutant', 'Var', (87, 93))	('homocysteine', 'Chemical', 'MESH:D006710', (130, 142))	('reduction', 'NegReg', (4, 13))	('increase', 'PosReg', (45, 53))
234381	33920562	The MTHFR A1298C polymorphism occurs in exon 7 and results in glutamate transformation into alanine at codon 429.	('A1298C', 'Var', (10, 16))	('glutamate transformation into alanine', 'MPA', (62, 99))	('MTHFR', 'Gene', (4, 9))	('A1298C', 'SUBSTITUTION', 'None', (10, 16))	('glutamate', 'Chemical', 'MESH:D018698', (62, 71))	('alanine', 'Chemical', 'MESH:D000409', (92, 99))	('results in', 'Reg', (51, 61))	('MTHFR', 'Gene', '4524', (4, 9))
234383	33920562	Unlike the C677T polymorphism, the effect of the A1298C polymorphism on plasma homocysteine levels is inconsistent.	('A1298C', 'SUBSTITUTION', 'None', (49, 55))	('C677T', 'Mutation', 'rs1801133', (11, 16))	('homocysteine', 'Chemical', 'MESH:D006710', (79, 91))	('plasma homocysteine levels', 'MPA', (72, 98))	('A1298C', 'Var', (49, 55))
234387	33920562	Studies have shown that folate deficiencies and the presence of polymorphisms in genes related to the folate pathway increase the incidence of cancer.	('folate', 'Chemical', 'MESH:D005492', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('increase', 'PosReg', (117, 125))	('folate', 'Chemical', 'MESH:D005492', (102, 108))	('presence', 'Var', (52, 60))	('folate deficiencies', 'Phenotype', 'HP:0100507', (24, 43))	('deficiencies', 'Var', (31, 43))	('folate', 'MPA', (24, 30))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('folate pathway increase', 'Phenotype', 'HP:0032164', (102, 125))	('polymorphisms', 'Var', (64, 77))
234389	33920562	Therefore, MTHFR polymorphisms may directly affect the incidence of cancer, likely by causing an imbalance in maintaining the epigenome.	('causing', 'Reg', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('imbalance', 'Phenotype', 'HP:0002172', (97, 106))	('MTHFR', 'Gene', '4524', (11, 16))	('imbalance in maintaining the epigenome', 'MPA', (97, 135))	('polymorphisms', 'Var', (17, 30))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('MTHFR', 'Gene', (11, 16))	('cancer', 'Disease', (68, 74))	('affect', 'Reg', (44, 50))
234390	33920562	However, data regarding the association between the MTHFR polymorphism status and cancer risk have also been conflicting.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('polymorphism', 'Var', (58, 70))	('MTHFR', 'Gene', '4524', (52, 57))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('MTHFR', 'Gene', (52, 57))
234391	33920562	Several types of tumors have been associated with the presence of polymorphisms in MTHFR.	('associated', 'Reg', (34, 44))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('MTHFR', 'Gene', '4524', (83, 88))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('presence', 'Var', (54, 62))	('MTHFR', 'Gene', (83, 88))	('polymorphisms', 'Var', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
234392	33920562	The MTHFR gene polymorphisms show a relationship with leukemias and lymphomas with a more marked presence of the C677T polymorphism than A1298G in studies with significant results obtained.	('relationship', 'Reg', (36, 48))	('C677T', 'Mutation', 'rs1801133', (113, 118))	('lymphomas', 'Phenotype', 'HP:0002665', (68, 77))	('leukemias', 'Phenotype', 'HP:0001909', (54, 63))	('C677T', 'Var', (113, 118))	('MTHFR', 'Gene', (4, 9))	('A1298G', 'Mutation', 'rs1060500125', (137, 143))	('leukemias and lymphomas', 'Disease', 'MESH:D008223', (54, 77))	('MTHFR', 'Gene', '4524', (4, 9))
234393	33920562	In a meta-analysis of 134 case-control studies, the MTHFR C677T polymorphism was significantly associated with an increased risk of tumors, and stratified analyses showed an increased risk of stomach and esophageal cancer in addition to an increased risk in Asian ethnicities.	('cancer', 'Disease', (215, 221))	('associated', 'Reg', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('C677T', 'Mutation', 'rs1801133', (58, 63))	('MTHFR', 'Gene', '4524', (52, 57))	('C677T', 'Var', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('increased risk of stomach', 'Phenotype', 'HP:0005207', (174, 199))	('tumors', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('MTHFR', 'Gene', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
234394	33920562	Other meta-analyses have shown an association of esophageal cancer in individuals with the MTHFR C677T CT and TT genotypes with low folate intake, and these effects could be largely modified using tobacco.	('association', 'Interaction', (34, 45))	('low folate intake', 'Phenotype', 'HP:0100507', (128, 145))	('MTHFR', 'Gene', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('folate', 'Chemical', 'MESH:D005492', (132, 138))	('C677T', 'Mutation', 'rs1801133', (97, 102))	('low', 'NegReg', (128, 131))	('C677T', 'Var', (97, 102))	('MTHFR', 'Gene', '4524', (91, 96))	('tobacco', 'Species', '4097', (197, 204))
234396	33920562	The status of the C677T homozygous polymorphism has also been linked to an increase in gastric cancer, and this risk is increased in individuals with low folate intake.	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('low folate intake', 'Phenotype', 'HP:0100507', (150, 167))	('C677T', 'Var', (18, 23))	('C677T', 'Mutation', 'rs1801133', (18, 23))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('folate', 'Chemical', 'MESH:D005492', (154, 160))	('increase in gastric cancer', 'Phenotype', 'HP:0006753', (75, 101))
234397	33920562	In adenomatous polyposis, a precursor stage of colorectal adenocarcinoma, the 677TT MTHFR variant is associated with a reduced risk of developing carcinoma in the presence of high doses of folic acid and vitamins B6, B12 and/or B2 in subjects with a low intake of alcohol.	('carcinoma', 'Disease', 'MESH:D009369', (146, 155))	('MTHFR', 'Gene', '4524', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('colorectal adenocarcinoma', 'Disease', (47, 72))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (3, 24))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (3, 24))	('vitamins B6', 'Chemical', 'MESH:D025101', (204, 215))	('B12', 'Chemical', 'MESH:C034730', (217, 220))	('carcinoma', 'Disease', (63, 72))	('folic acid', 'Chemical', 'MESH:D005492', (189, 199))	('reduced', 'NegReg', (119, 126))	('MTHFR', 'Gene', (84, 89))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (47, 72))	('carcinoma', 'Disease', 'MESH:D009369', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('677TT', 'Var', (78, 83))	('carcinoma', 'Disease', (146, 155))	('alcohol', 'Chemical', 'MESH:D000438', (264, 271))	('adenomatous polyposis', 'Disease', (3, 24))
234398	33920562	This reduces 677TT variant MTHFR enzyme activity and can deflect methyl groups available via DNA methylation in DNA synthesis, irreversibly committing 1-carbon units for the methylation cycle and away from the synthesis of thymidylate and purine.	('methyl groups available', 'MPA', (65, 88))	('MTHFR', 'Gene', '4524', (27, 32))	('methylation cycle', 'MPA', (174, 191))	('1-carbon units', 'MPA', (151, 165))	('variant', 'Var', (19, 26))	('purine', 'Chemical', 'MESH:C030985', (239, 245))	('MTHFR', 'Gene', (27, 32))	('activity', 'MPA', (40, 48))	('carbon', 'Chemical', 'MESH:D002244', (153, 159))	('677TT variant', 'Var', (13, 26))	('reduces', 'NegReg', (5, 12))	('deflect', 'NegReg', (57, 64))
234400	33920562	The overall hypomethylation is associated with hypermethylation of tumor suppressor genes, particularly in subjects with MTHFR 677TT.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('hypermethylation', 'MPA', (47, 63))	('MTHFR', 'Gene', '4524', (121, 126))	('hypomethylation', 'Var', (12, 27))	('associated', 'Reg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('MTHFR', 'Gene', (121, 126))
234402	33920562	Therefore, functional polymorphisms in MTHFR seem to be somewhat related to several cancer types.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('MTHFR', 'Gene', (39, 44))	('polymorphisms', 'Var', (22, 35))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('MTHFR', 'Gene', '4524', (39, 44))	('related', 'Reg', (65, 72))
234404	33920562	It is characterized by the expression of aberrant genes that confer heterogeneous morphology and aggressiveness to the tumor in addition to varied clinical manifestations.	('tumor', 'Disease', (119, 124))	('aberrant', 'Var', (41, 49))	('aggressiveness', 'Phenotype', 'HP:0000718', (97, 111))	('aggressiveness', 'Disease', 'MESH:D001523', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('aggressiveness', 'Disease', (97, 111))
234407	33920562	Several environmental and genetic elements are involved in different BC types, and various mutations in tumor suppressor genes and oncogenes are involved in the process of carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('iron', 'Chemical', 'MESH:D007501', (11, 15))	('carcinogenesis', 'Disease', 'MESH:D063646', (172, 186))	('mutations', 'Var', (91, 100))	('involved', 'Reg', (145, 153))	('carcinogenesis', 'Disease', (172, 186))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('oncogenes', 'Gene', (131, 140))
234409	33920562	Importantly, variations in the MTHFR genotype reduce the catalytic activity of MTHFR, and this activity is essential for DNA synthesis, methylation and repair.	('catalytic activity', 'MPA', (57, 75))	('reduce', 'NegReg', (46, 52))	('MTHFR', 'Gene', '4524', (79, 84))	('variations', 'Var', (13, 23))	('MTHFR', 'Gene', '4524', (31, 36))	('MTHFR', 'Gene', (79, 84))	('MTHFR', 'Gene', (31, 36))
234410	33920562	Functional polymorphisms in MTHFR have been shown to influence the risk of BC, although this finding remains controversial, and the data from the evaluated studies are shown in Table 1.	('polymorphisms', 'Var', (11, 24))	('influence', 'Reg', (53, 62))	('MTHFR', 'Gene', '4524', (28, 33))	('MTHFR', 'Gene', (28, 33))
234411	33920562	In a case-control study conducted in China with 560 patients diagnosed with BC and 560 healthy individuals, a significant association was observed between the homozygous TT genotype for the C677T polymorphism of the MTHFR gene and the risk of BC compared with the wild homozygous genotype CC (p = 0.007).	('MTHFR', 'Gene', '4524', (216, 221))	('C677T', 'Var', (190, 195))	('MTHFR', 'Gene', (216, 221))	('C677T', 'Mutation', 'rs1801133', (190, 195))	('patients', 'Species', '9606', (52, 60))
234413	33920562	Another group showed a 1.7 times higher incidence of breast cancer in individuals with the polymorphic T allele and 2.5 times higher for homozygous TT individuals than for individuals with the wild genotype.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('polymorphic T allele', 'Var', (91, 111))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
234414	33920562	However, they were not observed in the distribution of the A1298C MTHFR polymorphism between cases and controls in the risk of BC.	('A1298C', 'SUBSTITUTION', 'None', (59, 65))	('A1298C', 'Var', (59, 65))	('MTHFR', 'Gene', (66, 71))	('MTHFR', 'Gene', '4524', (66, 71))
234415	33920562	Analyses of the C677T polymorphism from peripheral blood samples obtained from 100 Iranian women with BC and 142 healthy women showed that the T allele and TT genotype had a higher prevalence in patients (p < 0.0001).	('C677T', 'Mutation', 'rs1801133', (16, 21))	('C677T', 'Var', (16, 21))	('higher prevalence', 'PosReg', (174, 191))	('women', 'Species', '9606', (91, 96))	('T allele', 'Var', (143, 151))	('patients', 'Species', '9606', (195, 203))	('women', 'Species', '9606', (121, 126))
234417	33920562	previously verified the role of the single-nucleotide polymorphism (SNP) T of the C677T polymorphism in vitro in folate metabolism as a risk factor for BC and suggested the use of SNPs as possible pharmacogenetics for chemotherapy treatment.	('folate', 'Chemical', 'MESH:D005492', (113, 119))	('C677T', 'Var', (82, 87))	('C677T', 'Mutation', 'rs1801133', (82, 87))	('risk', 'Reg', (136, 140))	('single-nucleotide polymorphism', 'Var', (36, 66))	('folate metabolism', 'MPA', (113, 130))
234418	33920562	Controversially, a study of 1459 women aged between 25 and 64 years revealed no statistically significant correlation between the risk of BC and the C677T polymorphism, although breast cancer was more prevalent in women with the T allele and low folate intake, suggesting that the polymorphic allele can be considered an important risk factor for breast cancer.	('T allele', 'Var', (229, 237))	('low', 'Var', (242, 245))	('prevalent', 'Reg', (201, 210))	('women', 'Species', '9606', (214, 219))	('women', 'Species', '9606', (33, 38))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (347, 360))	('low folate intake', 'Phenotype', 'HP:0100507', (242, 259))	('breast cancer', 'Disease', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (347, 360))	('breast cancer', 'Disease', (347, 360))	('folate', 'Chemical', 'MESH:D005492', (246, 252))	('C677T', 'Mutation', 'rs1801133', (149, 154))	('C677T', 'Var', (149, 154))
234419	33920562	A meta-analysis publication performed by He and colleagues observed a strong tendency toward the risk of BC in women with polymorphic homozygous (TT) and heterozygous (CT) genotypes for the MTHFR C677T polymorphism.	('women', 'Species', '9606', (111, 116))	('MTHFR', 'Gene', '4524', (190, 195))	('C677T', 'Mutation', 'rs1801133', (196, 201))	('C677T', 'Var', (196, 201))	('MTHFR', 'Gene', (190, 195))
234420	33920562	This risk was increased in women of Asian and Caucasian ethnicities, suggesting that polymorphism may be a risk factor for tumorigenesis.	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('women', 'Species', '9606', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('polymorphism', 'Var', (85, 97))
234424	33920562	Considering the possible relationship between the polymorphism and Caucasian and Asian ethnicities, another group evaluated the influence of the C677T and A1298C polymorphisms in Latin American populations and found a high risk for the development of BC in homozygous, recessive and allelic genetic models for the C677T polymorphism (p = 0.02, p = 0.04, and p = 0.01, respectively).	('A1298C', 'SUBSTITUTION', 'None', (155, 161))	('C677T', 'Mutation', 'rs1801133', (145, 150))	('A1298C', 'Var', (155, 161))	('C677T', 'Var', (145, 150))	('C677T', 'Mutation', 'rs1801133', (314, 319))	('C677T', 'Var', (314, 319))
234429	33920562	Interestingly, the AC and CC genotypes of the A1298C polymorphism have been linked to a decreased risk of BC in Kazakhstan women.	('A1298C', 'SUBSTITUTION', 'None', (46, 52))	('A1298C', 'Var', (46, 52))	('decreased', 'NegReg', (88, 97))	('women', 'Species', '9606', (123, 128))
234430	33920562	However, the association of the 677TT polymorphism with alcohol consumption and BC incidence was observed in Brazilian women aged older than 50 years.	('677TT', 'Var', (32, 37))	('alcohol', 'Chemical', 'MESH:D000438', (56, 63))	('association', 'Interaction', (13, 24))	('women', 'Species', '9606', (119, 124))
234432	33920562	Another group that evaluated 253 Brazilian women with BC and 257 healthy women aged older than 50 years found an association of the C677T polymorphism with distant metastases (CC versus CT + TT, p = 0.028; CT versus CC + TT, p = 0.031) and with the expression of ER (p = 0.02).	('metastases', 'Disease', 'MESH:D009362', (164, 174))	('C677T', 'Var', (132, 137))	('association', 'Interaction', (113, 124))	('women', 'Species', '9606', (73, 78))	('ER', 'Gene', '2069', (263, 265))	('women', 'Species', '9606', (43, 48))	('metastases', 'Disease', (164, 174))	('C677T', 'Mutation', 'rs1801133', (132, 137))
234433	33920562	Interestingly, analyses of the A1298C polymorphism performed by the same group showed an association of the wild-type homozygous (AA) genotype with higher degrees of severity of sporadic breast cancer given the lower prevalence of patients with this genotype in stage 0 of the disease.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('patients', 'Species', '9606', (231, 239))	('A1298C', 'SUBSTITUTION', 'None', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('A1298C', 'Var', (31, 37))	('breast cancer', 'Disease', (187, 200))
234434	33920562	The authors suggested that the C677T and A1298C polymorphisms were not associated with the risk of BC, but might modulate the severity of the disease.	('A1298C', 'SUBSTITUTION', 'None', (41, 47))	('modulate', 'Reg', (113, 121))	('C677T', 'Mutation', 'rs1801133', (31, 36))	('A1298C', 'Var', (41, 47))	('C677T', 'Var', (31, 36))
234436	33920562	Additionally, the polymorphic homozygote (CC) showed a higher risk of developing BC than the wild homozygote (AA), suggesting a significant association of the MTHFR A1298C polymorphism with the risk of developing BC.	('association', 'Interaction', (140, 151))	('A1298C', 'SUBSTITUTION', 'None', (165, 171))	('MTHFR', 'Gene', '4524', (159, 164))	('A1298C', 'Var', (165, 171))	('MTHFR', 'Gene', (159, 164))
234437	33920562	In a recent case-control study carried out with women from the North of Brazil, no significant associations were observed between the C677T and A1298G polymorphisms with the risk of BC.	('C677T', 'Var', (134, 139))	('C677T', 'Mutation', 'rs1801133', (134, 139))	('A1298G', 'Mutation', 'rs1060500125', (144, 150))	('A1298G', 'Var', (144, 150))	('women', 'Species', '9606', (48, 53))
234438	33920562	However, the group found a strong association between polymorphism in a gene encoding thymidylate synthase (TYMS) and the risk of developing more aggressive BC subtypes.	('thymidylate synthase', 'Gene', '7298', (86, 106))	('TYMS', 'Gene', (108, 112))	('polymorphism', 'Var', (54, 66))	('thymidylate synthase', 'Gene', (86, 106))	('TYMS', 'Gene', '7298', (108, 112))
234439	33920562	Importantly, TYMS displaces the accumulated MTHFR substrate (5,10-methylenetetrahydrofolate) in response to decreased enzyme activity for DNA synthesis and contributes to methylation imbalance and the results of this group suggest that the decrease in MTHFR activity and the levels of global methylation can occur in response to the displacement of the substrate for DNA synthesis in response to TYMS polymorphisms.	('global methylation', 'MPA', (285, 303))	('activity', 'MPA', (258, 266))	('TYMS', 'Gene', '7298', (396, 400))	('MTHFR', 'Gene', '4524', (252, 257))	('MTHFR', 'Gene', (44, 49))	('enzyme activity', 'MPA', (118, 133))	('polymorphisms', 'Var', (401, 414))	('TYMS', 'Gene', '7298', (13, 17))	('MTHFR', 'Gene', (252, 257))	('decrease', 'NegReg', (240, 248))	('5,10-methylenetetrahydrofolate', 'Chemical', 'MESH:C013123', (61, 91))	('imbalance', 'Phenotype', 'HP:0002172', (183, 192))	('TYMS', 'Gene', (396, 400))	('decreased', 'NegReg', (108, 117))	('methylation imbalance', 'MPA', (171, 192))	('TYMS', 'Gene', (13, 17))	('MTHFR', 'Gene', '4524', (44, 49))
234440	33920562	In a case-control study with 58 women with IBC and 58 healthy women, a trend was observed for the association between the most aggressive BC biotypes (HER-2 and TN) and the mutant allele variants of the C677T and A1298C polymorphisms.	('association', 'Interaction', (98, 109))	('HER-2', 'Gene', (151, 156))	('A1298C', 'SUBSTITUTION', 'None', (213, 219))	('women', 'Species', '9606', (32, 37))	('C677T', 'Mutation', 'rs1801133', (203, 208))	('C677T', 'Var', (203, 208))	('A1298C', 'Var', (213, 219))	('HER-2', 'Gene', '2064', (151, 156))	('women', 'Species', '9606', (62, 67))
234441	33920562	The association of the biophenotype and polymorphisms highlighted the risk of presenting a more aggressive biophenotype two or three times higher in patients with the C677T and A1298C polymorphisms, respectively, suggesting an association of the polymorphisms with tumor progression.	('patients', 'Species', '9606', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('C677T', 'Var', (167, 172))	('C677T', 'Mutation', 'rs1801133', (167, 172))	('association', 'Interaction', (227, 238))	('tumor', 'Disease', (265, 270))	('A1298C', 'Var', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('A1298C', 'SUBSTITUTION', 'None', (177, 183))	('higher', 'PosReg', (139, 145))
234442	33920562	Additionally, the group also showed an association of the A1298C polymorphism with the risk of lymph node metastasis and an increased risk of developing BC in patients with polymorphic homozygous (CC) genotypes and overweight individuals.	('overweight', 'Phenotype', 'HP:0025502', (215, 225))	('A1298C', 'SUBSTITUTION', 'None', (58, 64))	('association', 'Reg', (39, 50))	('lymph node metastasis', 'CPA', (95, 116))	('A1298C', 'Var', (58, 64))	('patients', 'Species', '9606', (159, 167))
234446	33920562	In addition the strong presence of the TC mutant haplotype associated with overexpression of the HER-2 receptor, the presence of tumor cells in the lymph nodes and the size of the tumor suggests a relationship between the C677T and A1298G polymorphisms with BC aggressiveness and the use of the evaluation of these polymorphisms as possible markers predictive and prognostic factors for the development of BC.	('TC', 'Chemical', 'MESH:D013667', (39, 41))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mutant', 'Var', (42, 48))	('tumor', 'Disease', (129, 134))	('C677T', 'Mutation', 'rs1801133', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('overexpression', 'PosReg', (75, 89))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('BC aggressiveness', 'Disease', 'MESH:D001523', (258, 275))	('A1298G', 'Mutation', 'rs1060500125', (232, 238))	('A1298G', 'Var', (232, 238))	('BC aggressiveness', 'Disease', (258, 275))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('aggressiveness', 'Phenotype', 'HP:0000718', (261, 275))	('HER-2', 'Gene', '2064', (97, 102))	('C677T', 'Var', (222, 227))	('HER-2', 'Gene', (97, 102))	('tumor', 'Disease', (180, 185))	('associated', 'Reg', (59, 69))
234447	33920562	Recently, a case-control study in a South Asian population showed for the first time an association between the homozygous polymorphic T genotype of the C677T polymorphism and the risk of breast cancer in older patients (>35 years) suggesting that the reduction of enzyme activity of MTHFR for breast cancer risk may be related, among other epigenetic factors, to age.	('enzyme activity', 'MPA', (265, 280))	('breast cancer', 'Disease', (294, 307))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('patients', 'Species', '9606', (211, 219))	('breast cancer', 'Disease', (188, 201))	('MTHFR', 'Gene', (284, 289))	('breast cancer', 'Disease', 'MESH:D001943', (294, 307))	('reduction', 'NegReg', (252, 261))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('C677T', 'Mutation', 'rs1801133', (153, 158))	('MTHFR', 'Gene', '4524', (284, 289))	('breast cancer', 'Phenotype', 'HP:0003002', (294, 307))	('C677T', 'Var', (153, 158))
234448	33920562	Interestingly, in the same study, the lack of the CC genotype in patients suggests a protective effect of the A1298C polymorphism against breast cancer.	('A1298C', 'Var', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('A1298C', 'SUBSTITUTION', 'None', (110, 116))	('patients', 'Species', '9606', (65, 73))	('breast cancer', 'Disease', (138, 151))
234462	33920562	As previously detailed, MTHFR C677T and MTHFR A1298C polymorphisms confer lower functioning MTHFR enzymes and are associated with increased cancer risk.	('MTHFR', 'Gene', '4524', (24, 29))	('C677T', 'Mutation', 'rs1801133', (30, 35))	('MTHFR', 'Gene', (92, 97))	('A1298C', 'Var', (46, 52))	('C677T', 'Var', (30, 35))	('MTHFR', 'Gene', (40, 45))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('MTHFR', 'Gene', (24, 29))	('associated', 'Reg', (114, 124))	('MTHFR', 'Gene', '4524', (92, 97))	('A1298C', 'SUBSTITUTION', 'None', (46, 52))	('lower', 'NegReg', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('functioning', 'MPA', (80, 91))	('MTHFR', 'Gene', '4524', (40, 45))
234465	33920562	Several studies have associated genomic hypomethylation with tumorigenesis by promoting genomic instability, the loss of imprinting and oncogene activation.	('genomic hypomethylation', 'Var', (32, 55))	('loss', 'NegReg', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('promoting', 'PosReg', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('genomic instability', 'CPA', (88, 107))	('tumor', 'Disease', (61, 66))
234466	33920562	Thus, we intend to summarize and critically explore available literature reports on MTHFR polymorphisms in CNS tumors.	('MTHFR', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('CNS tumors', 'Disease', 'MESH:D016543', (107, 117))	('MTHFR', 'Gene', '4524', (84, 89))	('CNS tumor', 'Phenotype', 'HP:0100006', (107, 116))	('polymorphisms', 'Var', (90, 103))	('CNS tumors', 'Disease', (107, 117))
234467	33920562	In pediatric tumors, a case-control study of 73 Thai children with different types of brain tumors demonstrated that the CC allele of the MTHFR A1298C polymorphism was associated with a 3.9-fold increased risk of embryonic tumors such as medulloblastoma, pineoblastoma and primitive neuroectodermal tumor (PNET).	('medulloblastoma', 'Disease', (238, 253))	('pineoblastoma', 'Phenotype', 'HP:0030408', (255, 268))	('associated', 'Reg', (168, 178))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('pineoblastoma', 'Disease', 'MESH:D010871', (255, 268))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('MTHFR', 'Gene', '4524', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (283, 304))	('tumors', 'Disease', (92, 98))	('embryonic tumors', 'Disease', 'MESH:D009373', (213, 229))	('brain tumor', 'Phenotype', 'HP:0030692', (86, 97))	('pineoblastoma', 'Disease', (255, 268))	('A1298C', 'SUBSTITUTION', 'None', (144, 150))	('tumors', 'Disease', (13, 19))	('embryonic tumors', 'Phenotype', 'HP:0002898', (213, 229))	('neuroectodermal tumor', 'Disease', (283, 304))	('A1298C', 'Var', (144, 150))	('MTHFR', 'Gene', (138, 143))	('brain tumors', 'Disease', 'MESH:D001932', (86, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('brain tumors', 'Phenotype', 'HP:0030692', (86, 98))	('embryonic tumors', 'Disease', (213, 229))	('neuroectodermal tumor', 'Disease', 'MESH:D017599', (283, 304))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (273, 304))	('children', 'Species', '9606', (53, 61))	('medulloblastoma', 'Disease', 'MESH:D008527', (238, 253))	('medulloblastoma', 'Phenotype', 'HP:0002885', (238, 253))	('brain tumors', 'Disease', (86, 98))
234469	33920562	They also observed a 5.2-fold increased risk of glial tumors for the homozygous TT allele of MTHFR C677T; however, this increase was not statistically significant.	('C677T', 'Mutation', 'rs1801133', (99, 104))	('C677T', 'Var', (99, 104))	('MTHFR', 'Gene', '4524', (93, 98))	('glial tumors', 'Disease', 'MESH:D005910', (48, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('glial tumors', 'Disease', (48, 60))	('MTHFR', 'Gene', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
234470	33920562	Conversely, Salnikova and colleagues (2013) found no association of the MTHFR polymorphism and pediatric brain tumor risk.	('brain tumor', 'Disease', 'MESH:D001932', (105, 116))	('brain tumor', 'Disease', (105, 116))	('polymorphism', 'Var', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('brain tumor', 'Phenotype', 'HP:0030692', (105, 116))	('MTHFR', 'Gene', '4524', (72, 77))	('association', 'Interaction', (53, 64))	('MTHFR', 'Gene', (72, 77))
234475	33920562	An appropriate diet might compensate for the reduced enzymatic activity conferred by MTHFR polymorphisms, reducing tumor risk.	('MTHFR', 'Gene', '4524', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('reducing', 'NegReg', (106, 114))	('polymorphisms', 'Var', (91, 104))	('tumor', 'Disease', (115, 120))	('MTHFR', 'Gene', (85, 90))	('enzymatic activity', 'MPA', (53, 71))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
234476	33920562	The geographical distribution of folate-rich nutrients may be associated with the MTHFR C677T polymorphism frequency.	('C677T', 'Var', (88, 93))	('MTHFR', 'Gene', (82, 87))	('folate', 'Chemical', 'MESH:D005492', (33, 39))	('MTHFR', 'Gene', '4524', (82, 87))	('C677T', 'Mutation', 'rs1801133', (88, 93))
234481	33920562	One literature report observed no significant difference in the serum folic acid and vitamin B12 levels concerning MTHFR polymorphisms.	('serum folic acid', 'MPA', (64, 80))	('vitamin B12 levels', 'MPA', (85, 103))	('folic acid', 'Chemical', 'MESH:D005492', (70, 80))	('MTHFR', 'Gene', '4524', (115, 120))	('polymorphisms', 'Var', (121, 134))	('vitamin B12', 'Chemical', 'MESH:D014805', (85, 96))	('MTHFR', 'Gene', (115, 120))
234482	33920562	Additionally, they found no association between meningioma or glioma risk and the MTHFR C677T polymorphism in the Indian population.	('meningioma', 'Disease', 'MESH:D008577', (48, 58))	('C677T', 'Var', (88, 93))	('MTHFR', 'Gene', (82, 87))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('meningioma', 'Disease', (48, 58))	('meningioma', 'Phenotype', 'HP:0002858', (48, 58))	('MTHFR', 'Gene', '4524', (82, 87))	('glioma', 'Disease', (62, 68))	('C677T', 'Mutation', 'rs1801133', (88, 93))
234483	33920562	This literature report supports that the MTHFR C677T polymorphism does not increase the risk of cancer development when there is adequate folate intake.	('C677T', 'Mutation', 'rs1801133', (47, 52))	('C677T', 'Var', (47, 52))	('adequate folate intake', 'Phenotype', 'HP:0100507', (129, 151))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MTHFR', 'Gene', '4524', (41, 46))	('folate', 'Chemical', 'MESH:D005492', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('MTHFR', 'Gene', (41, 46))	('cancer', 'Disease', (96, 102))
234486	33920562	Using rodent models of gliomagenesis, treatment with folate limits the development of glioma, inhibits tumor growth, and reduces overall methylation gain.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('gliomagenesis', 'Disease', (23, 36))	('glioma', 'Disease', (86, 92))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('methylation gain', 'MPA', (137, 153))	('tumor', 'Disease', (103, 108))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', (23, 29))	('folate', 'Var', (53, 59))	('reduces', 'NegReg', (121, 128))	('limits', 'NegReg', (60, 66))	('inhibits', 'NegReg', (94, 102))	('gliomagenesis', 'Disease', 'None', (23, 36))	('folate', 'Chemical', 'MESH:D005492', (53, 59))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
234491	33920562	Notably, the influence of ethnicity in MTHFR polymorphisms is associated with glioma risk.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('MTHFR', 'Gene', (39, 44))	('associated', 'Reg', (62, 72))	('polymorphisms', 'Var', (45, 58))	('glioma', 'Disease', (78, 84))	('MTHFR', 'Gene', '4524', (39, 44))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
234492	33920562	The genotypic frequency of MTHFR polymorphisms differs among ethnicities and can be a bias source in risk assessment.	('MTHFR', 'Gene', (27, 32))	('polymorphisms', 'Var', (33, 46))	('MTHFR', 'Gene', '4524', (27, 32))
234495	33920562	The authors also stratified samples by histological grade (I-IV), but no significant difference was observed between the MTHFR 677CC and 677CT genotypes.	('MTHFR', 'Gene', (121, 126))	('MTHFR', 'Gene', '4524', (121, 126))	('677CT', 'Var', (137, 142))
234502	33920562	Two meta-analyses demonstrated no enhanced risk of glioma development based on the MTHFR C667T polymorphism.	('glioma', 'Disease', (51, 57))	('MTHFR', 'Gene', '4524', (83, 88))	('C667T', 'Var', (89, 94))	('C667T', 'Mutation', 'rs1801133', (89, 94))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('MTHFR', 'Gene', (83, 88))
234504	33920562	Carriers of MTHFR TC present an increased risk of meningioma.	('meningioma', 'Disease', (50, 60))	('MTHFR', 'Gene', (12, 17))	('meningioma', 'Phenotype', 'HP:0002858', (50, 60))	('meningioma', 'Disease', 'MESH:D008577', (50, 60))	('Carriers', 'Var', (0, 8))	('MTHFR', 'Gene', '4524', (12, 17))	('TC', 'Chemical', 'MESH:D013667', (18, 20))
234506	33920562	A meta-analysis was conducted to evaluate the impact of the MTHFR A1298C polymorphism on meningioma and glioma risk.	('MTHFR', 'Gene', '4524', (60, 65))	('meningioma', 'Disease', (89, 99))	('MTHFR', 'Gene', (60, 65))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('A1298C', 'SUBSTITUTION', 'None', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('meningioma', 'Phenotype', 'HP:0002858', (89, 99))	('meningioma', 'Disease', 'MESH:D008577', (89, 99))	('glioma', 'Disease', (104, 110))	('A1298C', 'Var', (66, 72))
234507	33920562	They found that heterozygous (AC versus AA) and dominant (CC + AC versus AA) variants were associated with an increased risk of meningiomas and gliomas, although only gliomas presented an increased risk associated with any MTHFR A1298C genotype.	('variants', 'Var', (77, 85))	('meningiomas', 'Disease', 'MESH:D008577', (128, 139))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('meningiomas', 'Disease', (128, 139))	('MTHFR', 'Gene', '4524', (223, 228))	('A1298C', 'Var', (229, 235))	('MTHFR', 'Gene', (223, 228))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('A1298C', 'SUBSTITUTION', 'None', (229, 235))	('gliomas', 'Disease', (167, 174))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('gliomas', 'Disease', 'MESH:D005910', (144, 151))	('meningiomas', 'Phenotype', 'HP:0002858', (128, 139))	('gliomas', 'Phenotype', 'HP:0009733', (144, 151))	('gliomas', 'Disease', (144, 151))	('meningioma', 'Phenotype', 'HP:0002858', (128, 138))
234508	33920562	However, an Indian population-based study demonstrated that the CC genotype had a 38% reduced chance of meningioma compared with the AA genotype of the MTHFR A1298C polymorphism.	('A1298C', 'SUBSTITUTION', 'None', (158, 164))	('meningioma', 'Phenotype', 'HP:0002858', (104, 114))	('reduced', 'NegReg', (86, 93))	('meningioma', 'Disease', 'MESH:D008577', (104, 114))	('MTHFR', 'Gene', '4524', (152, 157))	('A1298C', 'Var', (158, 164))	('meningioma', 'Disease', (104, 114))	('MTHFR', 'Gene', (152, 157))
234509	33920562	Additionally, no enhanced risk was found when other SNPs were combined, such as MTHFR C677T and polymorphisms in MTRR and MTR.	('MTR', 'Gene', (113, 116))	('MTHFR', 'Gene', (80, 85))	('MTRR', 'Gene', (113, 117))	('MTR', 'Gene', (122, 125))	('MTRR', 'Gene', '4552', (113, 117))	('MTHFR', 'Gene', '4524', (80, 85))	('polymorphisms', 'Var', (96, 109))	('C677T', 'Mutation', 'rs1801133', (86, 91))	('MTR', 'Gene', '4552', (113, 116))	('C677T', 'Var', (86, 91))	('MTR', 'Gene', '4552', (122, 125))
234511	33920562	One study observed that meningiomas have a lower frequency of MTHFR 677TT and the T allele, while the other observed a significantly higher frequency.	('meningiomas', 'Disease', 'MESH:D008577', (24, 35))	('T allele', 'Var', (82, 90))	('MTHFR', 'Gene', '4524', (62, 67))	('meningiomas', 'Phenotype', 'HP:0002858', (24, 35))	('meningioma', 'Phenotype', 'HP:0002858', (24, 34))	('meningiomas', 'Disease', (24, 35))	('MTHFR', 'Gene', (62, 67))	('lower', 'NegReg', (43, 48))
234512	33920562	Both reports demonstrated no difference in the MTHFR A1298C polymorphism.	('MTHFR', 'Gene', (47, 52))	('MTHFR', 'Gene', '4524', (47, 52))	('A1298C', 'SUBSTITUTION', 'None', (53, 59))	('A1298C', 'Var', (53, 59))
234514	33920562	Similarly, the MTHFR A1298C polymorphism was associated with an increased meningioma risk only in the Caucasian population.	('increased meningioma risk', 'Phenotype', 'HP:0005381', (64, 89))	('A1298C', 'SUBSTITUTION', 'None', (21, 27))	('MTHFR', 'Gene', (15, 20))	('meningioma', 'Disease', (74, 84))	('meningioma', 'Phenotype', 'HP:0002858', (74, 84))	('MTHFR', 'Gene', '4524', (15, 20))	('meningioma', 'Disease', 'MESH:D008577', (74, 84))	('A1298C', 'Var', (21, 27))
234516	33920562	A large case-control study with 1005 glioma cases, 631 meningioma cases and 1098 controls demonstrated that the heterozygosity for MTHFR A1298C and MTHFR C677T was associated with an increased risk of meningioma.	('A1298C', 'SUBSTITUTION', 'None', (137, 143))	('meningioma', 'Disease', 'MESH:D008577', (55, 65))	('meningioma', 'Phenotype', 'HP:0002858', (201, 211))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('glioma', 'Disease', (37, 43))	('MTHFR', 'Gene', '4524', (148, 153))	('C677T', 'Mutation', 'rs1801133', (154, 159))	('meningioma', 'Disease', 'MESH:D008577', (201, 211))	('MTHFR', 'Gene', '4524', (131, 136))	('meningioma', 'Disease', (201, 211))	('A1298C', 'Var', (137, 143))	('meningioma', 'Disease', (55, 65))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('meningioma', 'Phenotype', 'HP:0002858', (55, 65))	('MTHFR', 'Gene', (131, 136))	('MTHFR', 'Gene', (148, 153))
234517	33920562	Glioma risk was increased only by MTHFR A1298C heterozygosity.	('MTHFR', 'Gene', '4524', (34, 39))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('A1298C', 'Var', (40, 46))	('MTHFR', 'Gene', (34, 39))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('A1298C', 'SUBSTITUTION', 'None', (40, 46))
234519	33920562	They demonstrated that the MTHFR A1298C polymorphism was mostly associated with GBM and oligodendrocytes increased the risk.	('associated', 'Reg', (64, 74))	('A1298C', 'Var', (33, 39))	('MTHFR', 'Gene', '4524', (27, 32))	('GBM', 'Disease', (80, 83))	('MTHFR', 'Gene', (27, 32))	('A1298C', 'SUBSTITUTION', 'None', (33, 39))	('increased', 'PosReg', (105, 114))	('oligodendrocytes increased', 'Phenotype', 'HP:0100709', (88, 114))
234520	33920562	Regarding GBM, another study found no association between the MTHFR C677T polymorphism and disease risk.	('MTHFR', 'Gene', (62, 67))	('MTHFR', 'Gene', '4524', (62, 67))	('C677T', 'Mutation', 'rs1801133', (68, 73))	('C677T', 'Var', (68, 73))
234521	33920562	Linnebank and colleagues demonstrated that the T-allele of the MTHFR C677T polymorphism is associated with poorer overall survival in GBM, likely mediated by reduced enzymatic activity.	('MTHFR', 'Gene', '4524', (63, 68))	('poorer', 'NegReg', (107, 113))	('overall', 'MPA', (114, 121))	('C677T', 'Var', (69, 74))	('MTHFR', 'Gene', (63, 68))	('C677T', 'Mutation', 'rs1801133', (69, 74))
234522	33920562	The MTHFR c.677TT genotype is an independent poor prognostic factor in the younger patient group (<60 years).	('c.677TT', 'Var', (10, 17))	('MTHFR', 'Gene', (4, 9))	('patient', 'Species', '9606', (83, 90))	('MTHFR', 'Gene', '4524', (4, 9))
234526	33920562	Cadieux and colleagues (2006) evaluated the association of the MTHFR C677T polymorphism with DNA hypomethylation in GBM cell lines and patient samples.	('patient', 'Species', '9606', (135, 142))	('MTHFR', 'Gene', '4524', (63, 68))	('C677T', 'Var', (69, 74))	('MTHFR', 'Gene', (63, 68))	('C677T', 'Mutation', 'rs1801133', (69, 74))	('association', 'Interaction', (44, 55))	('DNA hypomethylation', 'MPA', (93, 112))
234533	33920562	In the present review, we detailed studies with controversial results regarding the impact of MTHFR polymorphisms on glioma risk.	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('MTHFR', 'Gene', (94, 99))	('MTHFR', 'Gene', '4524', (94, 99))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('polymorphisms', 'Var', (100, 113))	('glioma', 'Disease', (117, 123))
234535	33920562	Despite the effort of several studies to address the ethnic impact in the risk assessment of MTHFR polymorphisms, small patient samples have limited the results.	('polymorphisms', 'Var', (99, 112))	('MTHFR', 'Gene', (93, 98))	('patient', 'Species', '9606', (120, 127))	('MTHFR', 'Gene', '4524', (93, 98))
234536	33920562	A comprehensive evaluation in a larger cohort is essential to elucidate the influence of these factors on the relationship between MTHFR polymorphisms and glioma risk.	('polymorphisms', 'Var', (137, 150))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('MTHFR', 'Gene', '4524', (131, 136))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('MTHFR', 'Gene', (131, 136))	('glioma', 'Disease', (155, 161))
234542	33920562	Similarly, the Asian Cancer Research Group (ACRG) has characterized gastric adenocarcinoma into four subtypes: tumors with microsatellite stable/epithelial-to-mesenchymal transition (MSS/EMT), tumors with microsatellite instability (MSI), microsatellite stable/TP53 activity (MSS/TP53+) tumors, and microsatellite stable/TP53 inactivity (MSS/TP53-) tumors.	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Cancer', 'Disease', (21, 27))	('tumors', 'Disease', (111, 117))	('TP53', 'Gene', (261, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('TP53', 'Gene', '7157', (342, 346))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('tumors', 'Disease', (349, 355))	('gastric adenocarcinoma', 'Disease', (68, 90))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('TP53', 'Gene', (280, 284))	('TP53', 'Gene', (321, 325))	('tumors', 'Disease', 'MESH:D009369', (349, 355))	('TP53', 'Gene', '7157', (261, 265))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('microsatellite', 'Var', (239, 253))	('TP53', 'Gene', (342, 346))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (68, 90))	('TP53', 'Gene', '7157', (280, 284))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('TP53', 'Gene', '7157', (321, 325))	('tumors', 'Disease', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumors', 'Disease', (287, 293))
234544	33920562	The relationship between the presence of C677T and A1298C polymorphisms and risk of GC among different populations is shown in Table 3.	('C677T', 'Mutation', 'rs1801133', (41, 46))	('A1298C', 'SUBSTITUTION', 'None', (51, 57))	('A1298C', 'Var', (51, 57))	('C677T', 'Var', (41, 46))
234545	33920562	A prospective study performed with an eastern Turkish population assessed the relationship between the MTHFR A1298C and C677T polymorphisms in gastrointestinal tumor development and included 70 GC patients.	('gastrointestinal tumor', 'Phenotype', 'HP:0007378', (143, 165))	('patients', 'Species', '9606', (197, 205))	('MTHFR', 'Gene', '4524', (103, 108))	('C677T', 'Mutation', 'rs1801133', (120, 125))	('C677T', 'Var', (120, 125))	('A1298C', 'Var', (109, 115))	('gastrointestinal tumor', 'Disease', 'MESH:D004067', (143, 165))	('gastrointestinal tumor', 'Disease', (143, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('MTHFR', 'Gene', (103, 108))	('A1298C', 'SUBSTITUTION', 'None', (109, 115))
234548	33920562	Recently, in a case (n = 307) control (n = 560) study in a Chinese Han population, patients carrying the TT genotype of C677T polymorphism were associated with a decreased risk of GC in older individuals and patients who never drank alcohol Moreover, the relationship of the MTHFR C677T polymorphism and the combined use of alcohol and smoking have a coordinate effect influencing GC risk.	('C677T', 'Mutation', 'rs1801133', (281, 286))	('patients', 'Species', '9606', (208, 216))	('C677T', 'Mutation', 'rs1801133', (120, 125))	('decreased', 'NegReg', (162, 171))	('C677T', 'Var', (120, 125))	('MTHFR', 'Gene', '4524', (275, 280))	('alcohol', 'Chemical', 'MESH:D000438', (233, 240))	('alcohol', 'Chemical', 'MESH:D000438', (324, 331))	('patients', 'Species', '9606', (83, 91))	('MTHFR', 'Gene', (275, 280))
234549	33920562	However, a meta-analysis of 5757 cases and 8501 controls of Asian and Caucasian patients found different results: a significant association was found between the GC and MTHFR C677T polymorphisms (homozygous model [TT vs. CC]: OR, 1.39; 95% CI, 1.20-1.62; heterozygous model [CT vs. CC]: OR, 1.18; 95% CI, 1.05-1.32; dominant model [TT + CT vs. CC]: OR, 1.23; 95% CI, 1.10-1.38; recessive model [TT vs. CC + CT]: OR, 1.26; 95% CI, 1.12-1.42).	('MTHFR', 'Gene', (169, 174))	('patients', 'Species', '9606', (80, 88))	('C677T', 'Mutation', 'rs1801133', (175, 180))	('C677T', 'Var', (175, 180))	('MTHFR', 'Gene', '4524', (169, 174))
234550	33920562	Further investigations also indicated an elevated risk of GC in Asian individuals carrying the MTHFR C677T polymorphism but not in Caucasian populations.	('MTHFR', 'Gene', (95, 100))	('C677T', 'Var', (101, 106))	('MTHFR', 'Gene', '4524', (95, 100))	('C677T', 'Mutation', 'rs1801133', (101, 106))
234552	33920562	Similar results were found in a study of genetic susceptibility to cancer involving GC samples (n = 2727), where MTHFR C677T was associated with GC (TT vs. CT + CC; OR: 1.52, 95% CI: 1.31-1.77, p-value = 4.9 x 10-8).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('MTHFR', 'Gene', '4524', (113, 118))	('C677T', 'Mutation', 'rs1801133', (119, 124))	('cancer', 'Disease', (67, 73))	('C677T', 'Var', (119, 124))	('MTHFR', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
234553	33920562	In a meta-analysis involving 6572 cases and 9584 controls comprising Caucasian, Asian and mixed ethnicity samples, the MTHFR C677T polymorphism significantly increased the susceptibility to GC, but no significant correlation was found with the A1298C polymorphism.	('susceptibility', 'MPA', (172, 186))	('MTHFR', 'Gene', '4524', (119, 124))	('A1298C', 'Var', (244, 250))	('A1298C', 'SUBSTITUTION', 'None', (244, 250))	('MTHFR', 'Gene', (119, 124))	('C677T', 'Mutation', 'rs1801133', (125, 130))	('C677T', 'Var', (125, 130))	('increased', 'PosReg', (158, 167))
234554	33920562	Furthermore, the authors found that MTHFR C677T but not MTHFR A1298C was associated with an increased risk of GC in Asian and Caucasian populations.	('A1298C', 'SUBSTITUTION', 'None', (62, 68))	('MTHFR', 'Gene', '4524', (36, 41))	('MTHFR', 'Gene', (36, 41))	('MTHFR', 'Gene', '4524', (56, 61))	('C677T', 'Mutation', 'rs1801133', (42, 47))	('MTHFR', 'Gene', (56, 61))	('A1298C', 'Var', (62, 68))
234555	33920562	Another divergent result was found in a meta-analysis performed by Dong and colleagues, who evaluated 4070/6462 cases/controls for C677T and 1923/3561 cases/controls for the A1298C polymorphism.	('A1298C', 'Var', (174, 180))	('C677T', 'Var', (131, 136))	('C677T', 'Mutation', 'rs1801133', (131, 136))	('A1298C', 'SUBSTITUTION', 'None', (174, 180))
234556	33920562	No significant association was found in the CC genotype of A1298C; however, the C677T allele T compared with allele C was associated with a 17.3% increased risk.	('A1298C', 'SUBSTITUTION', 'None', (59, 65))	('A1298C', 'Var', (59, 65))	('C677T', 'Var', (80, 85))	('C677T', 'Mutation', 'rs1801133', (80, 85))
234559	33920562	MTHFR polymorphisms also play important roles in the response of GC patients to treatments.	('MTHFR', 'Gene', (0, 5))	('patients', 'Species', '9606', (68, 76))	('MTHFR', 'Gene', '4524', (0, 5))	('polymorphisms', 'Var', (6, 19))
234562	33920562	No association was found between the C677T polymorphism and response rate [TT/(CC + CT) OR = 1.31, 95% CI: 0.62-2.76] or overall survival [(CT + TT)/CC HR = 1.05, 95% CI: 0.86-1.26; TT/(CT + CC) HR = 1.48, 95% CI: 0.53-4.15].	('C677T', 'Var', (37, 42))	('C677T', 'Mutation', 'rs1801133', (37, 42))	('overall survival', 'CPA', (121, 137))
234565	33920562	Other GC treatments seem to be influenced by MTHFR polymorphisms.	('MTHFR', 'Gene', '4524', (45, 50))	('polymorphisms', 'Var', (51, 64))	('influenced', 'Reg', (31, 41))	('MTHFR', 'Gene', (45, 50))
234566	33920562	In the Netherlands, a multicenter phase 2 study investigated the use of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine as a first-line treatment for advanced HER2-negative GC patients and found that the MTHFR C677T polymorphism was related to outcomes in which patients carrying the TT genotype had inferior progression-free survival (vs CC/CT: HR, 4.7; 95% CI, 1.75-12.8 [p = 0.0007]) and OS (vs CC/CT: HR, 5.9; 95% CI, 2.12-16.5 [p = 0.0001].	('C677T', 'Var', (229, 234))	('MTHFR', 'Gene', '4524', (223, 228))	('patients', 'Species', '9606', (281, 289))	('inferior', 'NegReg', (319, 327))	('patients', 'Species', '9606', (195, 203))	('MTHFR', 'Gene', (223, 228))	('HER2', 'Gene', (178, 182))	('C677T', 'Mutation', 'rs1801133', (229, 234))	('progression-free survival', 'CPA', (328, 353))	('HER2', 'Gene', '2064', (178, 182))
234567	33920562	Additionally, in a study of a German population, the MTHFR A1298C polymorphism was an independent prognostic factor associated with a poor prognosis in neoadjuvantly treated GC patients.	('A1298C', 'Var', (59, 65))	('MTHFR', 'Gene', (53, 58))	('A1298C', 'SUBSTITUTION', 'None', (59, 65))	('patients', 'Species', '9606', (177, 185))	('MTHFR', 'Gene', '4524', (53, 58))
234568	33920562	MTHFR polymorphisms also impact the severity of atrophic gastritis, which is a GC precursor lesion.	('MTHFR', 'Gene', '4524', (0, 5))	('atrophic gastritis', 'Disease', 'MESH:D005757', (48, 66))	('atrophic gastritis', 'Disease', (48, 66))	('polymorphisms', 'Var', (6, 19))	('MTHFR', 'Gene', (0, 5))	('impact', 'Reg', (25, 31))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (48, 66))	('gastritis', 'Phenotype', 'HP:0005263', (57, 66))
234569	33920562	Helicobacter pylori-negative patients carrying the TT genotype showed an increased risk of moderate-to-severe lesions; thus, MTHFR C677T may act as a predictive factor for GC precancerous lesions.	('patients', 'Species', '9606', (29, 37))	('GC precancerous lesions', 'Disease', (172, 195))	('Helicobacter pylori', 'Species', '210', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('GC precancerous lesions', 'Disease', 'MESH:D011230', (172, 195))	('MTHFR', 'Gene', '4524', (125, 130))	('moderate-to-severe', 'Disease', (91, 109))	('C677T', 'Mutation', 'rs1801133', (131, 136))	('Helicobacter', 'Disease', (0, 12))	('C677T', 'Var', (131, 136))	('MTHFR', 'Gene', (125, 130))
234570	33920562	Saberi and colleagues found an increased risk of GC in a case (n = 450) control (n = 780) study of an Iranian population in patients carrying the MTHFR C677T polymorphism who were also positive for Helicobacter pylori infection.	('C677T', 'Mutation', 'rs1801133', (152, 157))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (198, 227))	('Helicobacter pylori', 'Disease', (198, 217))	('MTHFR', 'Gene', '4524', (146, 151))	('infection', 'Disease', (218, 227))	('C677T', 'Var', (152, 157))	('Helicobacter pylori', 'Species', '210', (198, 217))	('MTHFR', 'Gene', (146, 151))	('infection', 'Disease', 'MESH:D007239', (218, 227))	('patients', 'Species', '9606', (124, 132))
234572	33920562	As discussed above, the effect of the MTHFR polymorphisms in GC is not homogeneous among the populations.	('polymorphisms', 'Var', (44, 57))	('MTHFR', 'Gene', (38, 43))	('MTHFR', 'Gene', '4524', (38, 43))
234573	33920562	This complex variation may be caused by the interaction of genetic and environmental factors, such as variant alleles, dietary habits, smoking, folate intake, alcohol consumption, Helicobacter pylori infection, and the molecular background specific to each population.	('folate', 'Chemical', 'MESH:D005492', (144, 150))	('caused by', 'Reg', (30, 39))	('variant', 'Var', (102, 109))	('Helicobacter pylori', 'Species', '210', (180, 199))	('infection', 'Disease', (200, 209))	('iron', 'Chemical', 'MESH:D007501', (74, 78))	('infection', 'Disease', 'MESH:D007239', (200, 209))	('alcohol', 'Chemical', 'MESH:D000438', (159, 166))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (180, 209))	('Helicobacter pylori', 'Disease', (180, 199))
234574	33920562	Thus, it is difficult to draw conclusions about MTHFR polymorphisms and the risk of GC.	('MTHFR', 'Gene', (48, 53))	('polymorphisms', 'Var', (54, 67))	('MTHFR', 'Gene', '4524', (48, 53))
234575	33920562	In the present review, we detailed studies with controversial results regarding the impact of MTHFR polymorphisms on breast cancer, glioma and gastric cancer risk.	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('MTHFR', 'Gene', '4524', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('polymorphisms', 'Var', (100, 113))	('MTHFR', 'Gene', (94, 99))	('glioma and gastric cancer', 'Disease', 'MESH:D013274', (132, 157))
234576	33920562	In addition to the controversial literature, we observed a more relevant influence of the MTHFR C677T polymorphism, particularly in the Caucasian and Asian populations, on the risk of developing BC.	('C677T', 'Mutation', 'rs1801133', (96, 101))	('MTHFR', 'Gene', '4524', (90, 95))	('C677T', 'Var', (96, 101))	('MTHFR', 'Gene', (90, 95))
234577	33920562	However, the MTHFR A1298C polymorphism also showed relevance in some cases concerning the risk of breast cancer and relation to more aggressive phenotypes or lymphonodal metastases.	('MTHFR', 'Gene', '4524', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('lymphonodal metastases', 'Disease', 'MESH:D009362', (158, 180))	('breast cancer', 'Disease', (98, 111))	('lymphonodal metastases', 'Disease', (158, 180))	('A1298C', 'Var', (19, 25))	('MTHFR', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('A1298C', 'SUBSTITUTION', 'None', (19, 25))
234578	33920562	MTHFR C677T polymorphisms are more associated with an increased meningioma risk, primarily in Caucasian populations.	('MTHFR', 'Gene', '4524', (0, 5))	('increased meningioma risk', 'Phenotype', 'HP:0005381', (54, 79))	('C677T', 'Mutation', 'rs1801133', (6, 11))	('meningioma', 'Disease', (64, 74))	('associated', 'Reg', (35, 45))	('C677T', 'Var', (6, 11))	('MTHFR', 'Gene', (0, 5))	('meningioma', 'Phenotype', 'HP:0002858', (64, 74))	('meningioma', 'Disease', 'MESH:D008577', (64, 74))
234579	33920562	Regarding MTHFR A1298C polymorphisms, it appears to be more associated with glioma risk, mainly the heterozygous genotype.	('polymorphisms', 'Var', (23, 36))	('glioma', 'Disease', (76, 82))	('MTHFR', 'Gene', '4524', (10, 15))	('A1298C', 'Var', (16, 22))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('MTHFR', 'Gene', (10, 15))	('A1298C', 'SUBSTITUTION', 'None', (16, 22))	('associated', 'Reg', (60, 70))
234580	33920562	The effect of the MTHFR polymorphisms in GC is heterogeneous and may be associated with epigenetic and environmental factors.	('iron', 'Chemical', 'MESH:D007501', (106, 110))	('MTHFR', 'Gene', '4524', (18, 23))	('associated', 'Reg', (72, 82))	('polymorphisms', 'Var', (24, 37))	('MTHFR', 'Gene', (18, 23))
234581	33920562	In a metabolomic study performed using serum samples from Greek women who were BC controls, a significant interaction was observed between the MTHFR C677T polymorphism and a Mediterranean diet rich in fruits and vegetables and the modulation of the serum levels of the 5-MTHFR enzyme.	('MTHFR', 'Gene', '4524', (143, 148))	('C677T', 'Mutation', 'rs1801133', (149, 154))	('modulation', 'Reg', (231, 241))	('MTHFR', 'Gene', '4524', (271, 276))	('serum levels', 'MPA', (249, 261))	('women', 'Species', '9606', (64, 69))	('MTHFR', 'Gene', (143, 148))	('MTHFR', 'Gene', (271, 276))	('C677T', 'Var', (149, 154))
234582	33920562	Another group evaluated gene-environment interactions and predictors of colorectal cancer and suggested that interactions of the environment would be related to MTHFR polymorphism and the prevention and/or induction of colorectal cancer.	('interactions', 'Interaction', (109, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (219, 236))	('related', 'Reg', (150, 157))	('iron', 'Chemical', 'MESH:D007501', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('MTHFR', 'Gene', '4524', (161, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('MTHFR', 'Gene', (161, 166))	('colorectal cancer', 'Disease', (219, 236))	('iron', 'Chemical', 'MESH:D007501', (32, 36))	('colorectal cancer', 'Disease', (72, 89))	('polymorphism', 'Var', (167, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (219, 236))
234584	33920562	Additionally, comprehensive evaluation in a larger cohort stratified by ethnicity, histological subtype and considering vitamins B6 and B12 and folate levels is crucial to further understand the association of MTHFR polymorphisms and BC and glioma and CG risk.	('folate', 'Chemical', 'MESH:D005492', (144, 150))	('B12', 'Chemical', 'MESH:C034730', (136, 139))	('association', 'Interaction', (195, 206))	('glioma', 'Disease', 'MESH:D005910', (241, 247))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('MTHFR', 'Gene', '4524', (210, 215))	('polymorphisms', 'Var', (216, 229))	('vitamins B6', 'Chemical', 'MESH:D025101', (120, 131))	('MTHFR', 'Gene', (210, 215))	('glioma', 'Disease', (241, 247))
234609	32969511	First, Fucci-S/G2/M Green vector (AM-V9010M; MBL Life Science) was transfected into TE2 cells.	('MBL', 'Gene', '50639', (45, 48))	('V9010M', 'SUBSTITUTION', 'None', (37, 43))	('TE2', 'Chemical', '-', (84, 87))	('V9010M', 'Var', (37, 43))	('MBL', 'Gene', (45, 48))
234612	32969511	Next, Fucci-G1 Orange vector (AM-V9003M; MBL Life Science) was transfected into Fucci-S/G2/M-expressing TE2 cells, as above, and cells were treated with neomycin and selected in a similar manner.	('Fucci-S/G2/M-expressing', 'Gene', (80, 103))	('V9003M', 'Var', (33, 39))	('TE2', 'Chemical', '-', (104, 107))	('V9003M', 'SUBSTITUTION', 'None', (33, 39))	('MBL', 'Gene', (41, 44))	('neomycin', 'Chemical', 'MESH:D009355', (153, 161))	('MBL', 'Gene', '50639', (41, 44))
234644	32969511	Furthermore, the presence of CD9, CD63, and CD81, common markers for exosomes, and the absence of calnexin, a major marker of the endosome, were confirmed by western blot analysis of the exosomes or of cell protein isolated from TE2 cells (Figure S1C).	('calnexin', 'Gene', (98, 106))	('CD9', 'Gene', (29, 32))	('CD63', 'Var', (34, 38))	('CD9', 'Gene', '928', (29, 32))	('TE2', 'Chemical', '-', (229, 232))	('CD81', 'Var', (44, 48))	('calnexin', 'Gene', '821', (98, 106))	('absence', 'NegReg', (87, 94))
234656	32969511	The numbers of G1-phase cells (orange) and S/G2/M-phase cells (green) were assessed after 0, 12, and 24 h of culture with or without treatment with a high density of cancer-derived exosomes (10 mug/mL; Figure 5A,B).	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('S/G2', 'Var', (43, 47))	('S/G2', 'SUBSTITUTION', 'None', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
234663	32969511	3  In addition, tumor-derived microRNA-1246 was transferred to lymph nodes near the tumor via exosomes.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (16, 21))	('microRNA-1246', 'Var', (30, 43))
234677	32969511	The exosome uptake assay suggested that uptake of exosomes by T.Tn cells was faster than that by TE2 cells.	('Tn', 'Chemical', 'MESH:C009497', (64, 66))	('TE2', 'Chemical', '-', (97, 100))	('uptake', 'MPA', (40, 46))	('T.Tn', 'Var', (62, 66))	('faster', 'PosReg', (77, 83))
234683	32969511	16 ,  17  In addition, other studies have shown that G0/G1-phase cancer cells also have an upregulated migration ability compared with S/G2/M-phase cells according to Fucci imaging.	('upregulated', 'PosReg', (91, 102))	('S/G2', 'Var', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('S/G2', 'SUBSTITUTION', 'None', (135, 139))	('migration ability', 'CPA', (103, 120))	('G0/G1-phase', 'Var', (53, 64))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
234689	32969511	Exosomes contain many types of miRNAs (eg miR-21, miR 93-5, miR-339-5p, and miR-1246), especially exosomes from patients with ESCC or from ESCC cell lines, and these miRNAs are related to many signal pathways.	('miR-1246', 'Gene', (76, 84))	('related', 'Reg', (177, 184))	('miR-21', 'Gene', (42, 48))	('miR 93-5', 'Gene', (50, 58))	('patients', 'Species', '9606', (112, 120))	('miR-339-5p', 'Var', (60, 70))	('miR 93-5', 'Gene', '100126325', (50, 58))	('ESCC', 'Disease', (126, 130))	('miR-21', 'Gene', '406991', (42, 48))	('miR-1246', 'Gene', '100302142', (76, 84))
234697	31477842	The chemical modifications imposed onto SOX2 are inherently heterogeneous, comprising singular or clustered events of phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, PARPylation, and O-glycosylation that reciprocally affect each other and critically impact SOX2 functionality, often in a tissue and species-specific manner.	('functionality', 'MPA', (286, 299))	('acetylation', 'MPA', (148, 159))	('SUMOylation', 'MPA', (177, 188))	('glycosyl', 'Chemical', 'MESH:D017261', (209, 217))	('impact', 'Reg', (274, 280))	('PARP', 'Gene', '142', (190, 194))	('ubiquitination', 'MPA', (161, 175))	('O-glycosylation', 'MPA', (207, 222))	('man', 'Species', '9606', (340, 343))	('SOX2', 'Enzyme', (281, 285))	('methylation', 'MPA', (135, 146))	('PARP', 'Gene', (190, 194))	('phosphorylation', 'MPA', (118, 133))	('affect', 'Reg', (241, 247))	('modifications', 'Var', (13, 26))
234699	31477842	Here we provide a comprehensive review of the current knowledge on SOX2 protein modifications, their proposed relationship to the PI3K/AKT pathway, and regulatory influence on SOX2 with regards to stemness, reprogramming, and cancer.	('stemness', 'Disease', 'MESH:D020295', (197, 205))	('stemness', 'Disease', (197, 205))	('protein', 'Protein', (72, 79))	('PI3', 'Gene', '5266', (130, 133))	('modifications', 'Var', (80, 93))	('PI3', 'Gene', (130, 133))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('SOX2', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
234717	31477842	In particular: Deletion of Sox2 in the zygote results in early embryonic lethality with concomitant malformation of the epiblast.	('results in', 'Reg', (46, 56))	('embryonic lethality', 'Disease', 'MESH:D020964', (63, 82))	('Deletion', 'Var', (15, 23))	('embryonic lethality', 'Disease', (63, 82))	('Sox2', 'Gene', (27, 31))
234719	31477842	Underscoring a critical role in ES cell maintenance, both deletion and overexpression of Sox2 impose ES cell differentiation in vitro.	('Sox2', 'Gene', (89, 93))	('ES cell differentiation', 'CPA', (101, 124))	('overexpression', 'PosReg', (71, 85))	('impose', 'Reg', (94, 100))	('deletion', 'Var', (58, 66))	('ES', 'CellLine', 'CVCL:M564', (101, 103))	('ES', 'CellLine', 'CVCL:M564', (32, 34))
234722	31477842	Underscoring conserved functions in man, hereditary SOX2 haplo-insufficiency was associated with syndromic microphthalmia type 3 (MCOPS3), a disease characterized by micro- or an-ophthalmia and concomitant cognitive and/or developmental impairment.	('haplo-insufficiency', 'Var', (57, 76))	('MCOPS3', 'Gene', '6657', (130, 136))	('SOX2', 'Gene', (52, 56))	('ophthalmia', 'Disease', 'MESH:D009877', (111, 121))	('syndromic microphthalmia type 3', 'Phenotype', 'HP:0500052', (97, 128))	('microphthalmia', 'Phenotype', 'HP:0000568', (107, 121))	('man', 'Species', '9606', (36, 39))	('syndromic microphthalmia', 'Disease', 'MESH:D008850', (97, 121))	('developmental impairment', 'Phenotype', 'HP:0001263', (223, 247))	('ophthalmia', 'Disease', (179, 189))	('MCOPS3', 'Gene', (130, 136))	('syndromic microphthalmia', 'Disease', (97, 121))	('associated', 'Reg', (81, 91))	('ophthalmia', 'Disease', (111, 121))	('ophthalmia', 'Disease', 'MESH:D009877', (179, 189))
234724	31477842	During the last decade, aberrant SOX2 expression has been further associated with various forms of cancer, particularly of epithelial or neuronal origin, for review see.	('expression', 'MPA', (38, 48))	('SOX2', 'Protein', (33, 37))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('associated', 'Reg', (66, 76))	('aberrant', 'Var', (24, 32))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
234748	31477842	Accordingly, mechanisms that overactivate the PI3K/AKT axis or impair its inactivation (such as mutations in PIK3CA and/or PTEN genes, for example) range amongst the most prominent molecular aberrations in cancer and resemble mutational hot spots for resistance development.	('PIK3CA', 'Gene', (109, 115))	('PI3', 'Gene', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('PIK3CA', 'Gene', '5290', (109, 115))	('impair', 'NegReg', (63, 69))	('PTEN', 'Gene', (123, 127))	('inactivation', 'MPA', (74, 86))	('PTEN', 'Gene', '5728', (123, 127))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('PI3', 'Gene', '5266', (46, 49))	('mutations', 'Var', (96, 105))	('overactivate', 'PosReg', (29, 41))
234756	31477842	In cancer finally, such growth regulatory mechanisms may be largely uncoupled and overruled by mutations inducing and sustaining clonal expansion (e.g., involving aberrant PI3K/AKT/mTORC1 signaling).	('mTORC1', 'Gene', '382056', (181, 187))	('PI3', 'Gene', '5266', (172, 175))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('inducing', 'Reg', (105, 113))	('mutations', 'Var', (95, 104))	('mTORC1', 'Gene', (181, 187))	('PI3', 'Gene', (172, 175))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
234759	31477842	This is remarkable, as several lines of experimental evidence gathered in healthy and transformed cell matter, clearly underscore an interdependence between PI3K/AKT signaling on the one hand and SOX2-imposed (cancer) stem cell characteristics on the other: Mutations in PTEN for example support the outgrowth of healthy and malignant mammary epithelium derived stem cells, which can be antagonized by the PI3K/AKT cross-reactive inhibitor perifosine.	('cancer', 'Disease', (210, 216))	('outgrowth', 'CPA', (300, 309))	('PI3', 'Gene', '5266', (157, 160))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PI3', 'Gene', (406, 409))	('support', 'PosReg', (288, 295))	('Mutations', 'Var', (258, 267))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('PI3', 'Gene', (157, 160))	('perifosine', 'Chemical', 'MESH:C105905', (440, 450))	('PTEN', 'Gene', (271, 275))	('PI3', 'Gene', '5266', (406, 409))	('PTEN', 'Gene', '5728', (271, 275))
234760	31477842	Effectively separating these effects, either inhibition of PI3 kinase or knock-down of downstream AKT1 were later shown to impair the survival of tumor initiating supposed breast carcinoma stem cells.	('breast carcinoma', 'Phenotype', 'HP:0003002', (172, 188))	('AKT1', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('impair', 'NegReg', (123, 129))	('survival', 'CPA', (134, 142))	('breast carcinoma', 'Disease', (172, 188))	('tumor', 'Disease', (146, 151))	('PI3', 'Gene', '5266', (59, 62))	('breast carcinoma', 'Disease', 'MESH:D001943', (172, 188))	('knock-down', 'Var', (73, 83))	('inhibition', 'Var', (45, 55))	('AKT1', 'Gene', '207', (98, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('PI3', 'Gene', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
234762	31477842	These observations were further substantialized in man, where AKT-driven phosphorylation was shown to sustain SOX2 protein stability, nuclear localization, and thereby regulate in vitro clonogenicity and in vivo tumorigenicity of breast carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('phosphorylation', 'Var', (73, 88))	('breast carcinoma', 'Disease', 'MESH:D001943', (230, 246))	('breast carcinoma', 'Disease', (230, 246))	('SOX2 protein', 'Protein', (110, 122))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('clonogenicity', 'CPA', (186, 199))	('regulate', 'Reg', (168, 176))	('man', 'Species', '9606', (51, 54))	('sustain', 'PosReg', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('breast carcinoma', 'Phenotype', 'HP:0003002', (230, 246))	('tumor', 'Disease', (212, 217))	('nuclear localization', 'MPA', (134, 154))
234772	31477842	However, inhibition of mTORC1 has also been described to attenuate SOX2 and further downstream SOX9 expression in glioma, and both PI3K inhibitors and rapamycin reported to suppress SOX2-driven tumorigenicity from esophageal squamous cells in a murine xenografts.	('SOX9', 'Gene', (95, 99))	('tumor', 'Disease', (194, 199))	('SOX2', 'Gene', (67, 71))	('inhibition', 'Var', (9, 19))	('SOX2-driven', 'MPA', (182, 193))	('murine', 'Species', '10090', (245, 251))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('glioma', 'Disease', (114, 120))	('PI3', 'Gene', (131, 134))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('attenuate', 'NegReg', (57, 66))	('rapamycin', 'Chemical', 'MESH:D020123', (151, 160))	('suppress', 'NegReg', (173, 181))	('mTORC1', 'Gene', (23, 29))	('expression', 'MPA', (100, 110))	('PI3', 'Gene', '5266', (131, 134))	('mTORC1', 'Gene', '382056', (23, 29))
234776	31477842	Intriguingly, shRNA-mediated knock-down of LRRN1 associated with impaired AKT activity and thereby nuclear depletion and proteasomal degradation of SOX2, OCT4, and NANOG.	('AKT activity', 'CPA', (74, 86))	('nuclear depletion', 'MPA', (99, 116))	('proteasomal degradation', 'MPA', (121, 144))	('LRRN1', 'Gene', '57633', (43, 48))	('NANOG', 'Gene', '79923', (164, 169))	('LRRN1', 'Gene', (43, 48))	('NANOG', 'Gene', (164, 169))	('OCT4', 'Gene', '5460', (154, 158))	('impaired', 'NegReg', (65, 73))	('knock-down', 'Var', (29, 39))	('OCT4', 'Gene', (154, 158))
234787	31477842	In other Sox proteins by contrast the motif is either functionally compromised by loss of a hydroxy acceptor chain (SoxF), structurally distorted by insertion of proline residues (SoxB2, SoxG, and SoxH classes), charge modified by arginine to glutamine replacement (SoxE), or further derivatized by exchange of the acceptor threonine for serine (Sox12 and Sox15) thus modifying the steric context of the phosphorylation site.	('Sox', 'Gene', (197, 200))	('modifying', 'Reg', (368, 377))	('Sox', 'Gene', '104009', (197, 200))	('Sox', 'Gene', (356, 359))	('Sox', 'Gene', '104009', (356, 359))	('Sox12', 'Gene', '6666', (346, 351))	('Sox', 'Gene', (187, 190))	('threonine', 'Chemical', 'MESH:C061951', (324, 333))	('Sox', 'Gene', (180, 183))	('Sox', 'Gene', '104009', (187, 190))	('Sox15', 'Gene', (356, 361))	('Sox', 'Gene', (266, 269))	('Sox', 'Gene', '104009', (180, 183))	('Sox', 'Gene', '104009', (266, 269))	('Sox', 'Gene', (346, 349))	('Sox', 'Gene', '104009', (346, 349))	('glutamine', 'Chemical', 'MESH:C578860', (243, 252))	('Sox', 'Gene', (116, 119))	('Sox', 'Gene', '104009', (116, 119))	('SoxB', 'Gene', (180, 184))	('loss', 'NegReg', (82, 86))	('proline', 'Protein', (162, 169))	('proline', 'Chemical', 'MESH:C489032', (162, 169))	('insertion', 'Var', (149, 158))	('Sox15', 'Gene', '6665', (356, 361))	('arginine', 'Chemical', 'MESH:D001127', (231, 239))	('hydroxy', 'Chemical', 'MESH:D006880', (92, 99))	('serine', 'Chemical', 'MESH:C047902', (338, 344))	('SoxB', 'Gene', '6658', (180, 184))	('Sox', 'Gene', (9, 12))	('steric context of the phosphorylation site', 'MPA', (382, 424))	('Sox', 'Gene', '104009', (9, 12))	('Sox12', 'Gene', (346, 351))	('distorted', 'NegReg', (136, 145))
234789	31477842	However, while phosphorylation of mouse Thr118 sustains Sox2 driven transcription in ES and iPS cells, alanine replacement analysis revealed that Thr116 is not stringently required for the nuclear localization of human SOX2.	('iPS', 'Disease', (92, 95))	('human', 'Species', '9606', (213, 218))	('Thr118', 'Gene', (40, 46))	('ES', 'CellLine', 'CVCL:M564', (85, 87))	('mouse', 'Species', '10090', (34, 39))	('phosphorylation', 'Var', (15, 30))	('iPS', 'Disease', 'OMIM:613661', (92, 95))	('alanine', 'Chemical', 'MESH:D000409', (103, 110))	('sustains', 'PosReg', (47, 55))	('Sox2 driven', 'Gene', (56, 67))
234792	31477842	Additional phosphorylation sites described for SOX2 comprise the residues Ser249, Ser250, and Ser251 originally identified in a phospho-proteomic analysis of human ESCs.	('ES', 'CellLine', 'CVCL:M564', (164, 166))	('human', 'Species', '9606', (158, 163))	('Ser', 'Chemical', 'MESH:C530429', (94, 97))	('Ser250', 'Var', (82, 88))	('Ser249', 'Var', (74, 80))	('Ser251', 'Var', (94, 100))	('Ser', 'Chemical', 'MESH:C530429', (74, 77))	('Ser', 'Chemical', 'MESH:C530429', (82, 85))
234794	31477842	Proposed as being functionally redundant, all three phosphorylation sites relate to nearby Lys245/247 that is a target of protein SUMOylation.	('Lys', 'Chemical', 'MESH:C026591', (91, 94))	('Lys245/247', 'Var', (91, 101))	('relate', 'Reg', (74, 80))
234795	31477842	While a conservative amino acid replacement at this position (i.e., K247R) has no evident effect on Sox2 protein stability or localization, SUMOylation at Lys247 coincides with reduced Sox2 binding to an Fgf4 enhancer element in the context of Oct3/4 co-expression, so that a transcription modulatory significantly was proposed for this residue modification.	('K247R', 'Mutation', 'p.K247R', (68, 73))	('Oct3/4', 'Gene', '5460', (244, 250))	('Fgf4', 'Gene', '2249', (204, 208))	('Lys', 'Chemical', 'MESH:C026591', (155, 158))	('reduced', 'NegReg', (177, 184))	('Oct3/4', 'Gene', (244, 250))	('Sox2', 'MPA', (185, 189))	('SUMOylation', 'Var', (140, 151))	('K247R', 'Var', (68, 73))	('binding', 'Interaction', (190, 197))	('Fgf4', 'Gene', (204, 208))
234796	31477842	Documenting functional connectivity of phosphorylation and nearby SUMOylation events in this segment, a SOX2(S249-251D) mutant mimicking constitutive phosphorylation at the indicated residues strongly induced SUMOylation of SOX2, whereas a phosphorylation incompetent SOX2(S249-251A) mutant impairs this modification.	('S249-251A', 'Var', (273, 282))	('S2', 'CellLine', 'CVCL:Z232', (273, 275))	('S2', 'CellLine', 'CVCL:Z232', (109, 111))	('induced', 'PosReg', (201, 208))	('SUMOylation', 'MPA', (209, 220))	('SOX2', 'Protein', (224, 228))	('mutant', 'Var', (120, 126))
234797	31477842	SUMOylation was fully obstructed though only in a SOX2(K245A) mutant, thus reconfirming Lys245 as the target site for SOX2 SUMOylation.	('obstructed', 'NegReg', (22, 32))	('K245A', 'Var', (55, 60))	('SOX2', 'Gene', (50, 54))	('Lys', 'Chemical', 'MESH:C026591', (88, 91))	('SUMOylation', 'MPA', (0, 11))	('K245A', 'Mutation', 'p.K245A', (55, 60))
234802	31477842	This analysis uncovered p300/CBP-imposed in vitro acetylation on various Sox2 sites including lysine residues K37, K60, K67, K75, K89, K97, K105, K111, K117, K119, and K123 that all match the HMG domain except for K123.	('CBP', 'Gene', '1977', (29, 32))	('K75', 'Gene', (125, 128))	('CBP', 'Gene', (29, 32))	('K75', 'Gene', '9119', (125, 128))	('K123', 'Chemical', 'MESH:D011188', (168, 172))	('p300', 'Gene', (24, 28))	('K67', 'Var', (120, 123))	('K123', 'Chemical', 'MESH:D011188', (214, 218))	('p300', 'Gene', '2033', (24, 28))	('K37', 'Gene', '8688', (110, 113))	('lysine', 'Chemical', 'MESH:C114808', (94, 100))	('K117', 'Var', (152, 156))	('K37', 'Gene', (110, 113))	('K67', 'Chemical', 'MESH:D011188', (120, 123))	('K97', 'Var', (135, 138))	('K111', 'Var', (146, 150))	('K119', 'Var', (158, 162))	('acetylation', 'MPA', (50, 61))	('K123', 'Var', (168, 172))	('K89', 'Var', (130, 133))	('K60', 'Var', (115, 118))	('K60', 'Chemical', 'MESH:D011188', (115, 118))	('K105', 'Var', (140, 144))
234804	31477842	The Sox2 NES motif was identified on basis of sequence homology to Sry and Sox9, where a nuclear export activity had first been identified and functionally validated by impaired sexual differentiation in mice expressing NES-mutant alleles.	('Sox9', 'Gene', (75, 79))	('Sry', 'Gene', '21674', (67, 70))	('impaired sexual differentiation', 'Disease', (169, 200))	('impaired sexual differentiation', 'Disease', 'MESH:D012735', (169, 200))	('Sry', 'Gene', (67, 70))	('ES', 'CellLine', 'CVCL:M564', (10, 12))	('NES-mutant', 'Var', (220, 230))	('mice', 'Species', '10090', (204, 208))	('ES', 'CellLine', 'CVCL:M564', (221, 223))	('Sox9', 'Gene', '20682', (75, 79))
234806	31477842	Confirming functional relevance, an interaction with the nuclear export receptor, Crm1, is impaired in NES mutant forms of Sox2 thus causing their subcellular mislocalization.	('Crm1', 'Gene', (82, 86))	('mutant', 'Var', (107, 113))	('impaired', 'NegReg', (91, 99))	('Crm1', 'Gene', '7514', (82, 86))	('ES', 'CellLine', 'CVCL:M564', (104, 106))	('NES', 'Gene', (103, 106))	('interaction', 'Interaction', (36, 47))	('causing', 'Reg', (133, 140))	('Sox2', 'Gene', (123, 127))	('subcellular mislocalization', 'MPA', (147, 174))
234807	31477842	Finally connecting these findings to acetylation events, K75A (acetylation null) and K75Q (acetylation mimicry) alleles were cloned and found to modulate Crm1-docking and Sox2 nucleo-cytoplasmatic distribution, indeed.	('Crm1', 'Gene', (154, 158))	('K75A', 'Var', (57, 61))	('K75A', 'Mutation', 'p.K75A', (57, 61))	('modulate', 'Reg', (145, 153))	('K75Q', 'Mutation', 'p.K75Q', (85, 89))	('Sox2 nucleo-cytoplasmatic distribution', 'MPA', (171, 209))	('Crm1', 'Gene', '7514', (154, 158))	('K75Q', 'Var', (85, 89))
234809	31477842	A methylation at this site was proposed to enforce Sox2 homo-dimerization and functionally linked to the expression of Sox2 target genes, while chromatin binding blocks methylation of arginine 113.	('arginine', 'Chemical', 'MESH:D001127', (184, 192))	('homo-dimerization', 'MPA', (56, 73))	('methylation', 'MPA', (169, 180))	('Sox2', 'Protein', (51, 55))	('enforce', 'PosReg', (43, 50))	('linked', 'Reg', (91, 97))	('blocks', 'NegReg', (162, 168))	('expression', 'MPA', (105, 115))	('methylation', 'Var', (2, 13))
234811	31477842	While these notions were first elaborated in murine ESCs and human cancer cells (e.g., breast and esophageal carcinoma cell lines), Wong and co-workers embed these findings into following intriguing regulatory concept: The aforementioned Thr116/118 phosphorylation site is flanked by two lysine residues (one on either side, see Fig.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('murine', 'Species', '10090', (45, 51))	('Thr116/118', 'Var', (238, 248))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (98, 118))	('cancer', 'Disease', (67, 73))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (98, 118))	('ES', 'CellLine', 'CVCL:M564', (52, 54))	('lysine', 'Chemical', 'MESH:C114808', (288, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('human', 'Species', '9606', (61, 66))	('esophageal carcinoma', 'Disease', (98, 118))
234812	31477842	The C-proximal of these residues (Lys119) is subject to Set7 imposed protein methylation that fosters WWP2-driven ubiquitination and cytosolic proteasomal decay of Sox2.	('WWP2-driven ubiquitination', 'MPA', (102, 128))	('cytosolic proteasomal decay', 'MPA', (133, 160))	('Lys119', 'Var', (34, 40))	('fosters', 'PosReg', (94, 101))	('Lys', 'Chemical', 'MESH:C026591', (34, 37))
234816	31477842	Moreover, while K115 may be a target of ubiquitination in human SOX2, this very residue has also been associated with acetylation in murine ESCs (i.e., K117ac), similarly to nearby K119 that has been proposed as a target of Set7 imposed methylation.	('ES', 'CellLine', 'CVCL:M564', (140, 142))	('associated', 'Reg', (102, 112))	('human', 'Species', '9606', (58, 63))	('K117ac', 'Var', (152, 158))	('murine', 'Species', '10090', (133, 139))	('acetylation', 'MPA', (118, 129))
234823	31477842	Finally, SOX2/Sox2 is subject to protein O-glycosylation (O-GlcNAcylation, more specifically) at residue Ser246/248 as shown in the human pancreatic cancer cell line S2VP10, as well as in murine ESCs and iPSCs.	('S2', 'CellLine', 'CVCL:Z232', (166, 168))	('pancreatic cancer', 'Disease', (138, 155))	('ES', 'CellLine', 'CVCL:M564', (195, 197))	('iPS', 'Disease', 'OMIM:613661', (204, 207))	('protein O-glycosylation', 'MPA', (33, 56))	('glycosyl', 'Chemical', 'MESH:D017261', (43, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('O-GlcNAc', 'Gene', '8473', (58, 66))	('murine', 'Species', '10090', (188, 194))	('subject', 'Reg', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('O-GlcNAc', 'Gene', (58, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('human', 'Species', '9606', (132, 137))	('Ser', 'Chemical', 'MESH:C530429', (105, 108))	('iPS', 'Disease', (204, 207))	('Ser246/248', 'Var', (105, 115))
234825	31477842	As with the aforementioned PI3K/AKT imposed phosphor-regulation, protein O-glycosylation also likely represents a recurring molecular theme amongst pluripotency inducing TFs since related modifications were identified in Oct4 and further potential O-GlcNAcylation sites proposed for Sox2 (i.e., Thr258 and Ser259).	('Ser259', 'Chemical', 'MESH:C530429', (306, 312))	('glycosyl', 'Chemical', 'MESH:D017261', (75, 83))	('PI3', 'Gene', '5266', (27, 30))	('Oct4', 'Gene', (221, 225))	('modifications', 'Var', (188, 201))	('O-GlcNAc', 'Gene', (248, 256))	('PI3', 'Gene', (27, 30))	('O-GlcNAc', 'Gene', '8473', (248, 256))	('Thr258', 'Chemical', 'MESH:C055175', (295, 301))
234829	31477842	Firstly, chemical modification sites described for SOX2 do not randomly scatter throughout the protein's primary sequence, but cluster in particularly conserved stretches of regulatory significance (i.e., nuclear export sequence (NES), nuclear localization sequence (NLS), and a phosphorylation-dependent SUMOylation motif (PDSM)).	('ES', 'CellLine', 'CVCL:M564', (231, 233))	('nuclear export', 'MPA', (205, 219))	('nuclear localization', 'MPA', (236, 256))	('cluster', 'Reg', (127, 134))	('sites', 'Var', (31, 36))
234832	31477842	Such structural information may guide rational-based drug design against SOX2-driven cancer or improve reprogramming efficacy through molecular fine-tuning of SOX2.	('improve', 'PosReg', (95, 102))	('SOX2', 'Gene', (159, 163))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('reprogramming efficacy', 'CPA', (103, 125))	('cancer', 'Disease', (85, 91))	('fine-tuning', 'Var', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
234860	31259752	Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited.	('BMPR1A', 'Gene', (159, 165))	('BMPR1A', 'Gene', (238, 244))	('juvenile polyposis syndrome', 'Disease', 'MESH:C537702', (172, 199))	('BMPR1A', 'Gene', '657', (122, 128))	('Loss-of-function', 'NegReg', (129, 145))	('Deletion', 'Var', (110, 118))	('Patients', 'Species', '9606', (80, 88))	('JPS', 'Disease', 'MESH:C537702', (201, 204))	('Gastric Involvement', 'Disease', 'MESH:D013274', (54, 73))	('Juvenile Polyposis Syndrome', 'Disease', (21, 48))	('Juvenile Polyposis Syndrome', 'Disease', 'MESH:C537702', (21, 48))	('juvenile polyposis syndrome', 'Disease', (172, 199))	('JPS', 'Disease', (201, 204))	('BMPR1A', 'Gene', (122, 128))	('juvenile polyposis syndrome', 'Phenotype', 'HP:0004784', (172, 199))	('BMPR1A', 'Gene', '657', (159, 165))	('BMPR1A', 'Gene', '657', (238, 244))	('mutations', 'Var', (146, 155))	('JPS', 'Phenotype', 'HP:0004784', (201, 204))	('Gastric Involvement', 'Disease', (54, 73))	('Juvenile Polyposis Syndrome', 'Phenotype', 'HP:0004784', (21, 48))
234861	31259752	We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A.	('BMPR1A', 'Gene', (149, 155))	('deletion', 'Var', (109, 117))	('BMPR1A', 'Gene', '657', (149, 155))
234863	31259752	Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes.	('JPS', 'Phenotype', 'HP:0004784', (14, 17))	('deletion of 429 kb', 'Var', (72, 90))	('BMPR1A', 'Gene', '657', (109, 115))	('JPS', 'Disease', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('BMPR1A', 'Gene', (109, 115))	('JPS', 'Disease', 'MESH:C537702', (14, 17))	('Bukharin', 'Chemical', 'None', (37, 45))
234869	31259752	Up to 60% of individuals with clinically defined JPS are now found to exhibit mutations in SMAD4 or BMPR1A genes.	('JPS', 'Phenotype', 'HP:0004784', (49, 52))	('exhibit', 'Reg', (70, 77))	('BMPR1A', 'Gene', (100, 106))	('SMAD4', 'Gene', (91, 96))	('JPS', 'Disease', (49, 52))	('mutations', 'Var', (78, 87))	('JPS', 'Disease', 'MESH:C537702', (49, 52))	('SMAD4', 'Gene', '4089', (91, 96))	('BMPR1A', 'Gene', '657', (100, 106))
234871	31259752	Although dysplastic polyps may appear with variable histology, one study reported "mixed polyposis syndrome" with polyps containing variable pathology of adenomatous, hyperplastic, and juvenile features caused by small base pair deletions in the BMPR1A gene; adenomas comprise less than 10% of JPS polyps.	('JPS', 'Disease', (294, 297))	('polyps', 'Disease', 'MESH:D011127', (114, 120))	('polyposis syndrome', 'Disease', (89, 107))	('dysplastic polyps', 'Disease', (9, 26))	('small base pair deletions', 'Var', (213, 238))	('BMPR1A', 'Gene', (246, 252))	('JPS', 'Phenotype', 'HP:0004784', (294, 297))	('adenomas', 'Disease', 'MESH:D000236', (259, 267))	('polyps', 'Disease', (20, 26))	('adenomas', 'Disease', (259, 267))	('polyps', 'Disease', (298, 304))	('polyps', 'Disease', 'MESH:D011127', (20, 26))	('polyps', 'Disease', (114, 120))	('dysplastic polyps', 'Disease', 'MESH:D011127', (9, 26))	('BMPR1A', 'Gene', '657', (246, 252))	('polyps', 'Disease', 'MESH:D011127', (298, 304))	('polyposis syndrome', 'Disease', 'MESH:D044483', (89, 107))	('JPS', 'Disease', 'MESH:C537702', (294, 297))	('caused by', 'Reg', (203, 212))	('adenomatous', 'Disease', (154, 165))	('adenomatous', 'Disease', 'MESH:D011125', (154, 165))
234873	31259752	Although colonic phenotype is similar between patients with SMAD4 and BMPR1A mutations, upper GI and gastric polyposis is much more common in SMAD4 mutation.	('SMAD4', 'Gene', '4089', (60, 65))	('patients', 'Species', '9606', (46, 54))	('BMPR1A', 'Gene', (70, 76))	('common', 'Reg', (132, 138))	('gastric polyposis', 'Disease', (101, 118))	('SMAD4', 'Gene', (60, 65))	('colonic', 'Disease', 'MESH:D015179', (9, 16))	('SMAD4', 'Gene', '4089', (142, 147))	('gastric polyposis', 'Phenotype', 'HP:0004394', (101, 118))	('mutations', 'Var', (77, 86))	('BMPR1A', 'Gene', '657', (70, 76))	('gastric polyposis', 'Disease', 'MESH:C562464', (101, 118))	('mutation', 'Var', (148, 156))	('SMAD4', 'Gene', (142, 147))	('colonic', 'Disease', (9, 16))
234874	31259752	As reported by Aretz et al., SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis than did patients with BMPR1A mutations (83% vs 8%, respectively).	('higher frequency of gastric polyposis', 'Phenotype', 'HP:0004394', (73, 110))	('SMAD4', 'Gene', (29, 34))	('gastric polyposis', 'Disease', (93, 110))	('BMPR1A', 'Gene', '657', (134, 140))	('gastric polyposis', 'Phenotype', 'HP:0004394', (93, 110))	('SMAD4', 'Gene', '4089', (29, 34))	('gastric polyposis', 'Disease', 'MESH:C562464', (93, 110))	('patients', 'Species', '9606', (120, 128))	('mutation', 'Var', (35, 43))	('BMPR1A', 'Gene', (134, 140))
234875	31259752	All cases of gastric cancer occurred in families with SMAD4 mutations.	('occurred', 'Reg', (28, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('SMAD4', 'Gene', (54, 59))	('gastric cancer', 'Disease', (13, 27))	('gastric cancer', 'Disease', 'MESH:D013274', (13, 27))	('mutations', 'Var', (60, 69))	('SMAD4', 'Gene', '4089', (54, 59))
234878	31259752	The molecular alterations involved in polyp and tumor formation in JPS are attributed to defective BMP signaling, where aberrant BMP signaling disrupts stem cell self-renewal and differentiation, contributing to tumor formation.	('disrupts', 'NegReg', (143, 151))	('BMP', 'Gene', '649', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('JPS', 'Disease', 'MESH:C537702', (67, 70))	('aberrant', 'Var', (120, 128))	('defective', 'NegReg', (89, 98))	('BMP', 'Gene', '649', (129, 132))	('JPS', 'Disease', (67, 70))	('BMP', 'Gene', (99, 102))	('tumor', 'Disease', (48, 53))	('polyp', 'Disease', (38, 43))	('JPS', 'Phenotype', 'HP:0004784', (67, 70))	('BMP', 'Gene', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (212, 217))	('contributing', 'Reg', (196, 208))	('stem cell self-renewal', 'CPA', (152, 174))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
234881	31259752	Most pathogenic variants in BMPR1A are point mutations or small deletions.	('BMPR1A', 'Gene', (28, 34))	('point mutations', 'Var', (39, 54))	('pathogenic', 'Reg', (5, 15))	('BMPR1A', 'Gene', '657', (28, 34))	('variants', 'Var', (16, 24))
234883	31259752	Contiguous gene deletions may lead to more pronounced manifestations; however, the rarity and variability of BMPR1A deletions not including PTEN have made genotype-phenotype relationships of large BMPR1A deletions difficult to assess.	('BMPR1A', 'Gene', '657', (197, 203))	('deletions', 'Var', (116, 125))	('BMPR1A', 'Gene', '657', (109, 115))	('BMPR1A', 'Gene', (197, 203))	('BMPR1A', 'Gene', (109, 115))	('PTEN', 'Gene', (140, 144))	('PTEN', 'Gene', '5728', (140, 144))
234884	31259752	We identified a deletion of the entire coding region of the BMPR1A gene among and investigated the clinical features in over 50 individuals from 7 unrelated families.	('BMPR1A', 'Gene', (60, 66))	('deletion', 'Var', (16, 24))	('BMPR1A', 'Gene', '657', (60, 66))
234887	31259752	BROCA multigene panel was used for testing for genes known or suggested to harbor mutations leading to solid tumors.	('leading to', 'Reg', (92, 102))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))	('mutations', 'Var', (82, 91))	('solid tumors', 'Disease', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
234888	31259752	With the exception of the BMPR1A deletion, no potentially damaging variants were detected in any family in any of the 65 genes sequenced.	('deletion', 'Var', (33, 41))	('BMPR1A', 'Gene', '657', (26, 32))	('BMPR1A', 'Gene', (26, 32))
234889	31259752	The breakpoints of BMPR1A copy number variations were identified by analysis of the split reads obtained by local realignment using Burrows-Wheeler Aligner-mem v0.7.12 and visualization within integrative genomics viewer.	('BMPR1A', 'Gene', (19, 25))	('variations', 'Var', (38, 48))	('BMPR1A', 'Gene', '657', (19, 25))
234916	31259752	Multigene testing detected the large deletion in BMPR1A.	('BMPR1A', 'Gene', '657', (49, 55))	('detected', 'Reg', (18, 26))	('BMPR1A', 'Gene', (49, 55))	('deletion', 'Var', (37, 45))
234935	31259752	Describing multiple individuals (up to 50 individuals with polyposis) harboring the same BMPR1A mutation allows the delineation of features associated with a large BMPR1A deletion and assessment of phenotypic variability in carriers of the same mutation.	('BMPR1A', 'Gene', (164, 170))	('polyposis', 'Disease', (59, 68))	('mutation', 'Var', (96, 104))	('deletion', 'Var', (171, 179))	('BMPR1A', 'Gene', '657', (89, 95))	('BMPR1A', 'Gene', '657', (164, 170))	('polyposis', 'Disease', 'MESH:D044483', (59, 68))	('BMPR1A', 'Gene', (89, 95))
234950	31259752	Large gene deletions in cancer predisposition syndromes may be associated with more severe or earlier phenotypic onset, such as MSH2-associated Lynch syndrome and neurofibromatosis type 1.	('Lynch syndrome', 'Disease', 'MESH:D003123', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('Large gene deletions', 'Var', (0, 20))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (163, 180))	('associated', 'Reg', (63, 73))	('neurofibromatosis type 1', 'Gene', '4763', (163, 187))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('MSH2', 'Gene', (128, 132))	('neurofibromatosis type 1', 'Gene', (163, 187))	('MSH2', 'Gene', '4436', (128, 132))	('Lynch syndrome', 'Disease', (144, 158))
234951	31259752	For BMPR1A deletions, it has been suggested that the contiguous deletion involving PTEN is responsible for a more sever phenotype.	('PTEN', 'Gene', '5728', (83, 87))	('BMPR1A', 'Gene', (4, 10))	('deletions', 'Var', (11, 20))	('BMPR1A', 'Gene', '657', (4, 10))	('PTEN', 'Gene', (83, 87))
234952	31259752	The phenotypic variability shown in here is not indicative for a more severe phenotype associated with a BMPR1A deletion.	('BMPR1A', 'Gene', (105, 111))	('deletion', 'Var', (112, 120))	('BMPR1A', 'Gene', '657', (105, 111))
234955	31259752	Although other mechanisms of loss of function were not excluded, the presence of both BMPR1A alleles in the tumors suggests that, as with SMAD4, complete somatic loss of BMPR1A may not be required for BMPR1A-associated cancer.	('BMPR1A', 'Gene', '657', (170, 176))	('BMPR1A', 'Gene', '657', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('SMAD4', 'Gene', '4089', (138, 143))	('BMPR1A', 'Gene', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('loss', 'Var', (162, 166))	('BMPR1A', 'Gene', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Disease', (108, 114))	('BMPR1A', 'Gene', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('BMPR1A', 'Gene', '657', (86, 92))	('SMAD4', 'Gene', (138, 143))
234956	31259752	In summary, among patients with genomic deletion of the BMPR1A gene, JPS was almost fully penetrant, but age at onset, polyp burden and histology, and cancer occurrence were highly variable, with unexpected upper GI involvement.	('JPS', 'Phenotype', 'HP:0004784', (69, 72))	('BMPR1A', 'Gene', '657', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('deletion', 'Var', (40, 48))	('BMPR1A', 'Gene', (56, 62))	('polyp burden', 'Disease', 'MESH:D011127', (119, 131))	('JPS', 'Disease', (69, 72))	('cancer', 'Disease', (151, 157))	('polyp burden', 'Disease', (119, 131))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('patients', 'Species', '9606', (18, 26))	('JPS', 'Disease', 'MESH:C537702', (69, 72))	('upper GI involvement', 'Disease', 'MESH:D005767', (207, 227))	('upper GI involvement', 'Disease', (207, 227))
235030	29508217	Standardization of EGD and EUS reports, in accordance with the published guidelines, will increase QI compliance rates and potentially improve patient care by enhancing communication among all involved providers, decreasing the need to repeat procedures and improving the ability to appropriately tailor treatment options.	('increase', 'PosReg', (90, 98))	('compliance', 'Var', (102, 112))	('patient', 'Species', '9606', (143, 150))	('decreasing', 'NegReg', (213, 223))	('enhancing', 'PosReg', (159, 168))	('communication', 'MPA', (169, 182))	('improving', 'PosReg', (258, 267))	('patient care', 'MPA', (143, 155))	('improve', 'PosReg', (135, 142))
235108	28740353	These elevated expressions were substantially enhanced by the BHSST treatment, with bax and caspase 3 expression being decreased to a level near that seen in the normal (P < 0.05 and < 0.01, respectively).	('expressions', 'MPA', (15, 26))	('BHSST', 'Var', (62, 67))	('decreased', 'NegReg', (119, 128))	('bax', 'Gene', '24887', (84, 87))	('expression', 'MPA', (102, 112))	('caspase 3', 'Gene', (92, 101))	('BHSST', 'Chemical', '-', (62, 67))	('enhanced', 'PosReg', (46, 54))	('bax', 'Gene', (84, 87))	('caspase 3', 'Gene', '25402', (92, 101))
235111	28740353	The present study provided evidence that supplementation of BHSST significantly ameliorated CARE-induced esophageal ulcer.	('esophageal ulcer', 'Disease', (105, 121))	('supplementation', 'Var', (41, 56))	('esophageal ulcer', 'Phenotype', 'HP:0004791', (105, 121))	('BHSST', 'Gene', (60, 65))	('esophageal ulcer', 'Disease', 'MESH:D014456', (105, 121))	('ameliorated', 'PosReg', (80, 91))	('rat', 'Species', '10116', (86, 89))	('BHSST', 'Chemical', '-', (60, 65))
235124	28740353	Importantly, the CARE modeled rats that were treated with BHSST showed remarkably less damage than their untreated CARE control counterparts.	('BHSST', 'Chemical', '-', (58, 63))	('rats', 'Species', '10116', (30, 34))	('less', 'NegReg', (82, 86))	('damage', 'MPA', (87, 93))	('BHSST', 'Var', (58, 63))
235140	28740353	Moreover, BHSST was found to increase transcription of the gene encoding the anti-apoptotic Bcl-2-like protein, which would serve to inhibit the pro-apoptotic factor bax and to attenuate the transcription of genes encoding for pro-apoptotic proteins, such as bax.	('bax', 'Gene', '24887', (259, 262))	('transcription', 'MPA', (38, 51))	('BHSST', 'Chemical', '-', (10, 15))	('bax', 'Gene', (166, 169))	('increase', 'PosReg', (29, 37))	('Bcl-2-like protein', 'Gene', (92, 110))	('inhibit', 'NegReg', (133, 140))	('Bcl-2-like protein', 'Gene', '24224', (92, 110))	('bax', 'Gene', (259, 262))	('attenuate', 'NegReg', (177, 186))	('transcription', 'MPA', (191, 204))	('bax', 'Gene', '24887', (166, 169))	('BHSST', 'Var', (10, 15))
235212	28211499	The survey showed a significant correlation (HR: 1.47, 95% CI: 1.14-1.89) between high expression of CTLA-4 and OS in the subgroup of single nucleotide polymorphisms (SNPs).	('CTLA-4', 'Gene', '1493', (101, 107))	('sur', 'Gene', (4, 7))	('sur', 'Gene', '6833', (4, 7))	('high expression', 'PosReg', (82, 97))	('CTLA-4', 'Gene', (101, 107))	('single nucleotide polymorphisms', 'Var', (134, 165))
235242	28211499	IFN-gamma, IL-2, and -13 productions were observed to be sharply reduced following B7/CTLA-4/CD28 cross-linkage, while IL-10 and TGF-beta increased.	('IFN-gamma', 'Gene', (0, 9))	('IL-2, and -13', 'Gene', '3558;3596', (11, 24))	('CD28', 'Gene', '940', (93, 97))	('CTLA-4', 'Gene', (86, 92))	('reduced', 'NegReg', (65, 72))	('IL-10', 'Gene', '3586', (119, 124))	('cross-linkage', 'Var', (98, 111))	('TGF-beta', 'Gene', '7040', (129, 137))	('IL-10', 'Gene', (119, 124))	('TGF-beta', 'Gene', (129, 137))	('CTLA-4', 'Gene', '1493', (86, 92))	('IFN-gamma', 'Gene', '3458', (0, 9))	('CD28', 'Gene', (93, 97))
235244	28211499	Besides, several studies indicated that the expression of sCTLA-4 is associated with proinflammatory cytokine levels.	('CTLA-4', 'Gene', (59, 65))	('proinflammatory cytokine levels', 'MPA', (85, 116))	('associated', 'Reg', (69, 79))	('expression', 'Var', (44, 54))	('CTLA-4', 'Gene', '1493', (59, 65))
235253	28211499	The CTLA-4 gene has more than one hundred SNPs, among which the most studied phenotypes was +49 A/G located in exon 1, and CT60 AA genotype, located in the 30-untranslated region of the gene.	('CTLA-4', 'Gene', (4, 10))	('CT60', 'Gene', '348120', (123, 127))	('+49 A/G', 'Mutation', 'rs231775', (92, 99))	('CT60', 'Gene', (123, 127))	('CTLA-4', 'Gene', '1493', (4, 10))	('+49 A/G', 'Var', (92, 99))
235257	28211499	The 49AA genotype is associated with increased expression of CTLA-4 mRNA and protein, which has enhanced interaction with B7 ligands and an enhanced effect on T cell inhibition.	('T cell inhibition', 'CPA', (159, 176))	('B7 ligands', 'Protein', (122, 132))	('CTLA-4', 'Gene', '1493', (61, 67))	('enhanced', 'PosReg', (96, 104))	('enhanced effect', 'PosReg', (140, 155))	('mRNA', 'Protein', (68, 72))	('increased', 'PosReg', (37, 46))	('CTLA-4', 'Gene', (61, 67))	('interaction', 'Interaction', (105, 116))	('expression', 'MPA', (47, 57))	('49AA', 'Var', (4, 8))
235274	28211499	Several of studies have notified the correlation between CTLA-4 lymphocyte variants and its susceptibility to autoimmunity and cancer.	('CTLA-4', 'Gene', '1493', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('autoimmunity', 'Disease', (110, 122))	('autoimmunity', 'Disease', 'MESH:D001327', (110, 122))	('CTLA-4', 'Gene', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('autoimmunity', 'Phenotype', 'HP:0002960', (110, 122))	('variants', 'Var', (75, 83))
235380	26350171	Subjects randomized to the Z3P3 arm had significantly greater femoral neck bone loss (-0.80 vs. 0.24 %; p=0.0009), and those in the Z6 arm had fewer morphometric spine fractures (RR=0.51, 95% CI 0.26 to 0.95; p=0.035, (see Appendix IVB, Black JBMR 2012, Figure 4).	('fractures', 'Disease', 'MESH:D050723', (168, 177))	('spine fractures', 'Phenotype', 'HP:0002953', (162, 177))	('loss', 'NegReg', (80, 84))	('greater femoral neck', 'Phenotype', 'HP:0006429', (54, 74))	('Z3P3', 'Var', (27, 31))	('fractures', 'Disease', (168, 177))	('femoral neck bone', 'CPA', (62, 79))	('greater', 'PosReg', (54, 61))	('bone loss', 'Phenotype', 'HP:0002797', (75, 84))	('fewer', 'NegReg', (143, 148))
235414	26350171	By univariate analysis, the incidence of morphometric vertebral fractures in the Z3P3 group was predicted by femoral neck and total hip T-score <= -2.5, (see Appendix IVB, Cosman 2014, Figure 1).	('vertebral fractures', 'Disease', (54, 73))	('<= -2.5', 'Var', (144, 151))	('Z3P3', 'Var', (81, 85))	('vertebral fracture', 'Phenotype', 'HP:0002953', (54, 72))	('femoral neck', 'CPA', (109, 121))	('vertebral fractures', 'Disease', 'MESH:D050723', (54, 73))	('vertebral fractures', 'Phenotype', 'HP:0002953', (54, 73))
235417	26350171	Finally, neither age >= 75 yr, nor weight <= 60 kg, when entered as single categorical variables, was predictive of new morphometric or non-vertebral fractures in the Z3P3 subjects.	('vertebral fractures', 'Phenotype', 'HP:0002953', (140, 159))	('Z3P3', 'Var', (167, 171))	('non-vertebral fractures', 'Disease', 'MESH:D050723', (136, 159))	('non-vertebral fractures', 'Disease', (136, 159))	('-vertebral fracture', 'Phenotype', 'HP:0002953', (139, 158))	('vertebral fracture', 'Phenotype', 'HP:0002953', (140, 158))
235437	26350171	Fasting serum PINP, measured in 1140 women at entry in the HORIZON extension, was not a predictor of morphometric or non-vertebral fractures in the Z3P3 group.	('vertebral fracture', 'Phenotype', 'HP:0002953', (121, 139))	('women', 'Species', '9606', (37, 42))	('-vertebral fracture', 'Phenotype', 'HP:0002953', (120, 139))	('vertebral fractures', 'Phenotype', 'HP:0002953', (121, 140))	('non-vertebral fractures', 'Disease', 'MESH:D050723', (117, 140))	('Z3P3', 'Var', (148, 152))	('non-vertebral fractures', 'Disease', (117, 140))
235450	26350171	These factors were independently evaluated in the FLEX study, and while older age and low BMI were predictors of bone loss at the spine and hip after discontinuation of ALN therapy, no model based on these risk factors was able to identify women likely to lose more bone over the next 5 years.	('BMI', 'MPA', (90, 93))	('loss', 'NegReg', (118, 122))	('ALN', 'Chemical', 'MESH:D019386', (169, 172))	('lose', 'NegReg', (256, 260))	('bone loss', 'Phenotype', 'HP:0002797', (113, 122))	('women', 'Species', '9606', (240, 245))	('low BMI', 'Phenotype', 'HP:0045082', (86, 93))	('low', 'Var', (86, 89))	('bone', 'CPA', (113, 117))
235511	26350171	The risk of fractures is substantially decreased by BPs, and remains much higher than that of developing risk of ONJ (185 fold) or AFF (4835 fold) (Figure 1).	('fractures', 'Disease', 'MESH:D050723', (12, 21))	('BPs', 'Var', (52, 55))	('decreased', 'NegReg', (39, 48))	('BPs', 'Chemical', 'MESH:D004164', (52, 55))	('fractures', 'Disease', (12, 21))
235548	26350171	In addition, in a subgroup analysis, hip fracture risk was decreased by 36% in women over age 74 years who had a femoral neck T-score < -3.	('decreased', 'NegReg', (59, 68))	('hip fracture', 'Disease', 'MESH:D006620', (37, 49))	('< -3', 'Var', (134, 138))	('women', 'Species', '9606', (79, 84))	('hip fracture', 'Disease', (37, 49))
235556	26350171	In addition, there is some evidence that vascular disease may be decreased in patients treated with BPs, as manifested by lower risk of stroke and myocardial infarction.	('stroke', 'Phenotype', 'HP:0001297', (136, 142))	('myocardial infarction', 'Disease', (147, 168))	('myocardial infarction', 'Disease', 'MESH:D009203', (147, 168))	('stroke', 'Disease', (136, 142))	('decreased', 'NegReg', (65, 74))	('vascular disease', 'Disease', (41, 57))	('BPs', 'Var', (100, 103))	('patients', 'Species', '9606', (78, 86))	('myocardial infarction', 'Phenotype', 'HP:0001658', (147, 168))	('stroke', 'Disease', 'MESH:D020521', (136, 142))	('vascular disease', 'Disease', 'MESH:D000783', (41, 57))	('BPs', 'Chemical', 'MESH:D004164', (100, 103))
235557	26350171	There are also some reports that mortality is reduced in patients treated with BPs, although not all studies are positive.	('mortality', 'MPA', (33, 42))	('patients', 'Species', '9606', (57, 65))	('BPs', 'Var', (79, 82))	('BPs', 'Chemical', 'MESH:D004164', (79, 82))	('reduced', 'NegReg', (46, 53))
235680	21381009	Risk estimates for buccal, esophagus, and liver cancers were also adjusted for alcoholism because inclusion of this variable in the regression models resulted in a >10% change in the risk estimates for a number of autoimmune diseases and alimentary tract cancers.	('liver cancers', 'Disease', 'MESH:D006528', (42, 55))	('autoimmune diseases', 'Disease', 'MESH:D001327', (214, 233))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('autoimmune diseases', 'Disease', (214, 233))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (214, 233))	('alimentary tract cancers', 'Disease', 'MESH:C563519', (238, 262))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('autoimmune disease', 'Phenotype', 'HP:0002960', (214, 232))	('liver cancers', 'Phenotype', 'HP:0002896', (42, 55))	('alcoholism', 'Phenotype', 'HP:0030955', (79, 89))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('alcoholism', 'Disease', (79, 89))	('alimentary tract cancers', 'Disease', (238, 262))	('alcoholism', 'Disease', 'MESH:D000437', (79, 89))	('liver cancer', 'Phenotype', 'HP:0002896', (42, 54))	('liver cancers', 'Disease', (42, 55))	('change', 'Reg', (169, 175))	('inclusion', 'Var', (98, 107))
235723	21381009	It is plausible that these changes increase risk for esophageal cancer, and previous literature supports associations between these autoimmune conditions and esophageal cancer.	('autoimmune conditions', 'Phenotype', 'HP:0002960', (132, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('associations', 'Interaction', (105, 117))	('esophageal cancer', 'Disease', (53, 70))	('changes', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('esophageal cancer', 'Disease', (158, 175))
235751	33949239	Our study showed that CTPG significantly inhibited the growth of HepG2 and BEL-7404 cells through the induction of cell cycle arrest and apoptosis, which was associated with the activation of MAPK pathways characterized by the up-regulated phosphorylation of p38, JNK, and ERK1/2 and mitochondria-dependent pathway characterized by the reduction of mitochondrial membrane potential.	('arrest', 'Disease', (126, 132))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (115, 132))	('JNK', 'Gene', '5599', (264, 267))	('phosphorylation', 'MPA', (240, 255))	('activation', 'PosReg', (178, 188))	('p38', 'Gene', (259, 262))	('mitochondrial membrane potential', 'MPA', (349, 381))	('MAPK pathways', 'Pathway', (192, 205))	('reduction', 'NegReg', (336, 345))	('arrest', 'Disease', 'MESH:D006323', (126, 132))	('p38', 'Gene', '5594', (259, 262))	('up-regulated', 'PosReg', (227, 239))	('apoptosis', 'CPA', (137, 146))	('CTPG', 'Chemical', '-', (22, 26))	('growth', 'CPA', (55, 61))	('inhibited', 'NegReg', (41, 50))	('mitochondria-dependent pathway', 'Pathway', (284, 314))	('BEL-7404', 'CellLine', 'CVCL:6568', (75, 83))	('ERK1/2', 'Gene', (273, 279))	('ERK1/2', 'Gene', '5595;5594', (273, 279))	('CTPG', 'Var', (22, 26))	('HepG2', 'CellLine', 'CVCL:0027', (65, 70))	('JNK', 'Gene', (264, 267))
235752	33949239	The release of cytochrome c and the cleavage of caspase-3, -7, -9, and PARP were subsequently increased by CTPG treatment.	('increased', 'PosReg', (94, 103))	('caspase-3, -7, -9', 'Gene', '836;840;842', (48, 65))	('CTPG', 'Var', (107, 111))	('cytochrome c', 'Gene', (15, 27))	('PARP', 'Gene', '142', (71, 75))	('CTPG', 'Chemical', '-', (107, 111))	('cytochrome c', 'Gene', '54205', (15, 27))	('cleavage', 'MPA', (36, 44))	('PARP', 'Gene', (71, 75))
235753	33949239	Moreover, CTPG significantly suppressed the migration of HepG2 through reducing the levels of matrix metalloproteinase-2 and vascular endothelial growth factor.	('HepG2', 'Protein', (57, 62))	('CTPG', 'Var', (10, 14))	('matrix metalloproteinase-2', 'Gene', '4313', (94, 120))	('reducing', 'NegReg', (71, 79))	('HepG2', 'CellLine', 'CVCL:0027', (57, 62))	('vascular endothelial growth factor', 'Gene', '7422', (125, 159))	('CTPG', 'Chemical', '-', (10, 14))	('vascular endothelial growth factor', 'Gene', (125, 159))	('migration', 'CPA', (44, 53))	('matrix metalloproteinase-2', 'Gene', (94, 120))	('suppressed', 'NegReg', (29, 39))
235755	33949239	In H22 tumor mouse model, CTPG combined with cisplatin further inhibited the growth of H22 cells and reduced the side effects of cisplatin.	('mouse', 'Species', '10090', (13, 18))	('H22', 'CellLine', 'CVCL:1E32', (3, 6))	('tumor', 'Disease', (7, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('growth', 'MPA', (77, 83))	('CTPG', 'Chemical', '-', (26, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('side effects', 'MPA', (113, 125))	('H22', 'CellLine', 'CVCL:1E32', (87, 90))	('reduced', 'NegReg', (101, 108))	('inhibited', 'NegReg', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('CTPG', 'Var', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
235756	33949239	Taken together, CTPG inhibited the growth of HCC through direct antitumor effect and indirect immunoenhancement effect, and improved the antitumor efficacy of cisplatin.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('HCC', 'Phenotype', 'HP:0001402', (45, 48))	('CTPG', 'Chemical', '-', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('improved', 'PosReg', (124, 132))	('growth', 'CPA', (35, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('tumor', 'Disease', (141, 146))	('HCC', 'Protein', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('inhibited', 'NegReg', (21, 30))	('CTPG', 'Var', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
235768	33949239	We found that CTPG could inhibit the growth of HepG2 and BEL-7404 cells through mitochondria-dependent apoptosis and the MAPK signaling pathway.	('MAPK signaling pathway', 'Pathway', (121, 143))	('CTPG', 'Var', (14, 18))	('mitochondria-dependent apoptosis', 'MPA', (80, 112))	('BEL-7404', 'CellLine', 'CVCL:6568', (57, 65))	('CTPG', 'Chemical', '-', (14, 18))	('HepG2', 'CellLine', 'CVCL:0027', (47, 52))	('growth', 'CPA', (37, 43))	('inhibit', 'NegReg', (25, 32))
235769	33949239	CTPG significantly inhibited the migration of HepG2 cells by reducing the levels of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF).	('reducing', 'NegReg', (61, 69))	('matrix metalloproteinase-2', 'Gene', '4313', (84, 110))	('vascular endothelial growth factor', 'Gene', (123, 157))	('CTPG', 'Var', (0, 4))	('matrix metalloproteinase-2', 'Gene', (84, 110))	('inhibited', 'NegReg', (19, 28))	('HepG2', 'CellLine', 'CVCL:0027', (46, 51))	('VEGF', 'Gene', (159, 163))	('MMP-2', 'Gene', '4313', (112, 117))	('migration', 'CPA', (33, 42))	('CTPG', 'Chemical', '-', (0, 4))	('vascular endothelial growth factor', 'Gene', '7422', (123, 157))	('VEGF', 'Gene', '7422', (159, 163))	('MMP-2', 'Gene', (112, 117))
235770	33949239	In addition, CTPG promoted the proliferation and activation of immune cells, and enhanced the immunity of mice.	('activation', 'CPA', (49, 59))	('immunity of mice', 'CPA', (94, 110))	('mice', 'Species', '10090', (106, 110))	('CTPG', 'Chemical', '-', (13, 17))	('enhanced', 'PosReg', (81, 89))	('proliferation', 'CPA', (31, 44))	('promoted', 'PosReg', (18, 26))	('CTPG', 'Var', (13, 17))
235771	33949239	Importantly, CTPG combined with cisplatin can further inhibit the growth of H22 cells in vivo and reduced the side effects of cisplatin.	('side effects', 'MPA', (110, 122))	('CTPG', 'Chemical', '-', (13, 17))	('inhibit', 'NegReg', (54, 61))	('H22', 'CellLine', 'CVCL:1E32', (76, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('reduced', 'NegReg', (98, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('CTPG', 'Var', (13, 17))	('growth of H22 cells in vivo', 'CPA', (66, 93))
235821	33949239	The splenocytes were collected, counted, and stained with anti-CD3-APC and anti-CD19-PE or anti-CD4-FITC and anti-CD8-APC or anti-CD11b-PE and anti-Gr-1-APC or anti-CD4-FITC, anti-CD25-APC, and anti-Foxp3-PE (BD Biosciences).	('FITC', 'Chemical', 'MESH:D016650', (169, 173))	('APC', 'Gene', (185, 188))	('CD8', 'Gene', (114, 117))	('APC', 'Gene', (153, 156))	('APC', 'Gene', '324', (67, 70))	('APC', 'Gene', (118, 121))	('FITC', 'Chemical', 'MESH:D016650', (100, 104))	('anti-CD11b-PE', 'Var', (125, 138))	('CD19', 'Gene', (80, 84))	('anti-Foxp3-PE', 'Var', (194, 207))	('APC', 'Gene', (67, 70))	('APC', 'Gene', '324', (185, 188))	('CD8', 'Gene', '925', (114, 117))	('Gr-1', 'Gene', '546644', (148, 152))	('anti-CD4-FITC', 'Var', (91, 104))	('Gr-1', 'Gene', (148, 152))	('APC', 'Gene', '324', (153, 156))	('CD19', 'Gene', '930', (80, 84))	('anti-CD4-FITC', 'Var', (160, 173))	('APC', 'Gene', '324', (118, 121))
235825	33949239	The MTT assay showed that CTPG significantly reduced the viability of BEL-7404 and HepG2 cells in a dose- and time-dependent manner (Figure 1A).	('reduced', 'NegReg', (45, 52))	('CTPG', 'Chemical', '-', (26, 30))	('CTPG', 'Var', (26, 30))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('HepG2 cells', 'CPA', (83, 94))	('viability', 'CPA', (57, 66))	('HepG2', 'CellLine', 'CVCL:0027', (83, 88))	('BEL-7404', 'CellLine', 'CVCL:6568', (70, 78))
235832	33949239	The phosphorylation of ERK (P-ERK) was down-regulated by 200 and 400 mug/mL CTPG treatment, while P-ERK was up-regulated under 600 mug/mL CTPG treatment (Figure 1D).	('up-regulated', 'PosReg', (108, 120))	('ERK', 'Gene', '5594', (30, 33))	('phosphorylation', 'MPA', (4, 19))	('CTPG', 'Var', (76, 80))	('ERK', 'Gene', (23, 26))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'Gene', (30, 33))	('ERK', 'Gene', '5594', (100, 103))	('CTPG', 'Chemical', '-', (138, 142))	('CTPG', 'Chemical', '-', (76, 80))	('down-regulated', 'NegReg', (39, 53))	('ERK', 'Gene', (100, 103))
235834	33949239	These results suggested that CTPG might inhibit the proliferation of HCC cells through the MAPK signaling pathway.	('proliferation', 'CPA', (52, 65))	('inhibit', 'NegReg', (40, 47))	('HCC cells', 'CPA', (69, 78))	('CTPG', 'Var', (29, 33))	('MAPK signaling pathway', 'Pathway', (91, 113))	('CTPG', 'Chemical', '-', (29, 33))	('HCC', 'Phenotype', 'HP:0001402', (69, 72))
235835	33949239	We further analyzed whether CTPG inhibited HCC cell proliferation through induction of cell cycle arrest.	('arrest', 'Disease', (98, 104))	('CTPG', 'Var', (28, 32))	('HCC', 'Phenotype', 'HP:0001402', (43, 46))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))	('cell cycle', 'CPA', (87, 97))	('CTPG', 'Chemical', '-', (28, 32))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('HCC cell proliferation', 'CPA', (43, 65))	('inhibited', 'NegReg', (33, 42))
235837	33949239	Similarly, CTPG also induced HepG2 cell cycle arrest at S-phase and the frequencies increased from 40.66% in the control group to 61.90% in the 600 mug/mL CTPG treated group (Figure 2A).	('HepG2', 'CellLine', 'CVCL:0027', (29, 34))	('CTPG', 'Var', (11, 15))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('CTPG', 'Chemical', '-', (11, 15))	('increased', 'PosReg', (84, 93))	('arrest', 'Disease', (46, 52))	('CTPG', 'Chemical', '-', (155, 159))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (35, 52))
235841	33949239	These results suggested that CTPG suppressed HCC cell proliferation by inducing cell cycle arrest.	('inducing', 'Reg', (71, 79))	('HCC', 'Phenotype', 'HP:0001402', (45, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('suppressed', 'NegReg', (34, 44))	('HCC cell proliferation', 'CPA', (45, 67))	('arrest', 'Disease', 'MESH:D006323', (91, 97))	('CTPG', 'Var', (29, 33))	('CTPG', 'Chemical', '-', (29, 33))	('arrest', 'Disease', (91, 97))
235845	33949239	As shown in Figure 3C, the control HepG2 cells were homogeneously stained while HepG2 cells treated with CTPG showed chromatin condensation and fragmentation in a dose-dependent manner, which were similar with HepG2 cells treated with cisplatin.	('fragmentation', 'CPA', (144, 157))	('HepG2', 'CellLine', 'CVCL:0027', (35, 40))	('HepG2', 'CellLine', 'CVCL:0027', (80, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (235, 244))	('chromatin condensation', 'CPA', (117, 139))	('CTPG', 'Var', (105, 109))	('CTPG', 'Chemical', '-', (105, 109))	('HepG2', 'CellLine', 'CVCL:0027', (210, 215))
235846	33949239	These results indicated that CTPG induced apoptosis of HCC cells.	('apoptosis', 'CPA', (42, 51))	('CTPG', 'Var', (29, 33))	('HCC', 'Phenotype', 'HP:0001402', (55, 58))	('CTPG', 'Chemical', '-', (29, 33))
235847	33949239	The integrity of the outer mitochondrial membrane is strictly regulated by the Bcl-2 family and the reduction of Deltapsim promotes the release of cytochrome c that activates the caspase cascade to induce apoptosis.	('cytochrome c', 'Gene', '54205', (147, 159))	('apoptosis', 'CPA', (205, 214))	('activates', 'Reg', (165, 174))	('caspase', 'Gene', '841;842', (179, 186))	('caspase', 'Gene', (179, 186))	('induce', 'PosReg', (198, 204))	('cytochrome c', 'Gene', (147, 159))	('Bcl-2', 'Gene', (79, 84))	('reduction', 'Var', (100, 109))	('Bcl-2', 'Gene', '596', (79, 84))	('Deltapsim', 'Gene', (113, 122))
235849	33949239	As shown Figure 4A, the green fluorescence intensity of the FL-1 channel was dose-dependently increased by CTPG treatment while the red fluorescence intensity of the FL-2 channel was dose-dependently decreased in both BEL-7404 and HepG2 cells.	('HepG2', 'CellLine', 'CVCL:0027', (231, 236))	('increased', 'PosReg', (94, 103))	('BEL-7404', 'CellLine', 'CVCL:6568', (218, 226))	('CTPG', 'Var', (107, 111))	('green fluorescence intensity', 'MPA', (24, 52))	('red fluorescence intensity', 'MPA', (132, 158))	('CTPG', 'Chemical', '-', (107, 111))	('FL-1', 'Gene', (60, 64))
235850	33949239	Inverted fluorescence microscope observation exhibited a similar result (Figure 4B), indicating that CTPG reduces the Deltapsim of HCC cells.	('reduces', 'NegReg', (106, 113))	('HCC', 'Phenotype', 'HP:0001402', (131, 134))	('CTPG', 'Var', (101, 105))	('Deltapsim', 'MPA', (118, 127))	('CTPG', 'Chemical', '-', (101, 105))
235851	33949239	Subsequently, we observed that levels of cytochrome c were increased in both BEL-7404 and HepG2 cells after CTPG treatment (Figure 4C), which further confirmed the reduction of Deltapsim in CTPG treated HCC cells.	('HepG2', 'CellLine', 'CVCL:0027', (90, 95))	('cytochrome c', 'Gene', '54205', (41, 53))	('CTPG', 'Var', (108, 112))	('BEL-7404', 'CellLine', 'CVCL:6568', (77, 85))	('Deltapsim', 'MPA', (177, 186))	('CTPG', 'Chemical', '-', (108, 112))	('increased', 'PosReg', (59, 68))	('CTPG', 'Chemical', '-', (190, 194))	('HCC', 'Phenotype', 'HP:0001402', (203, 206))	('cytochrome c', 'Gene', (41, 53))
235859	33949239	The results demonstrated that CTPG induced apoptosis of HCC cells by mitochondria-dependent pathway.	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('apoptosis', 'CPA', (43, 52))	('CTPG', 'Chemical', '-', (30, 34))	('mitochondria-dependent pathway', 'Pathway', (69, 99))	('CTPG', 'Var', (30, 34))
235868	33949239	As shown in Supplemental Figure 2A, CTPG significantly increased the proliferation of T cells and B cells in a dose-dependent manner, even in the presence of cisplatin.	('CTPG', 'Chemical', '-', (36, 40))	('proliferation', 'CPA', (69, 82))	('increased', 'PosReg', (55, 64))	('CTPG', 'Var', (36, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))
235889	33949239	The tumor weight in the CTPG + cisplatin group was lower than that in other groups.	('tumor', 'Disease', (4, 9))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('CTPG +', 'Var', (24, 30))	('lower', 'NegReg', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CTPG', 'Chemical', '-', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
235894	33949239	Compared with the untreated group, spleen indexes were significantly decreased and increased by cisplatin and CTPG, respectively.	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('increased', 'PosReg', (83, 92))	('CTPG', 'Var', (110, 114))	('decreased', 'NegReg', (69, 78))	('CTPG', 'Chemical', '-', (110, 114))	('spleen indexes', 'MPA', (35, 49))	('cisplatin', 'Var', (96, 105))
235895	33949239	CTPG + cisplatin recovered spleen indexes compared with cisplatin alone.	('cisplatin', 'Chemical', 'MESH:D002945', (7, 16))	('CTPG', 'Var', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('CTPG', 'Chemical', '-', (0, 4))	('spleen indexes', 'MPA', (27, 41))	('recovered', 'PosReg', (17, 26))
235897	33949239	We further investigated whether the antitumor effect of CTPG + cisplatin was correlated with enhanced immunity.	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('enhanced', 'PosReg', (93, 101))	('CTPG +', 'Var', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('CTPG', 'Chemical', '-', (56, 60))	('immunity', 'CPA', (102, 110))
235902	33949239	Compared with the control group, CTPG alone also partly increased the numbers of CD4+ and CD8+ T cells although there was no significant difference.	('increased', 'PosReg', (56, 65))	('CD8', 'Gene', (90, 93))	('CTPG', 'Var', (33, 37))	('CD8', 'Gene', '925', (90, 93))	('CTPG', 'Chemical', '-', (33, 37))
235908	33949239	These results suggested that the antitumor effect of CTPG + cisplatin might be correlated with the enhanced immunity characterized by the increased numbers of T cells and the decreased numbers of MDSCs and Tregs.	('CTPG', 'Chemical', '-', (53, 57))	('increased', 'PosReg', (138, 147))	('T cells', 'CPA', (159, 166))	('CTPG +', 'Var', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('enhanced', 'PosReg', (99, 107))	('immunity', 'CPA', (108, 116))	('Tregs', 'CPA', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('decreased', 'NegReg', (175, 184))
235909	33949239	It has been reported that TCM could induce apoptosis of various tumor cells through different pathways, including the extrinsic death receptor, intrinsic mitochondrial and endoplasmic reticulum (ER) stress pathways.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('death', 'Disease', (128, 133))	('tumor', 'Disease', (64, 69))	('apoptosis', 'CPA', (43, 52))	('TCM', 'Var', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('intrinsic mitochondrial', 'Pathway', (144, 167))	('death', 'Disease', 'MESH:D003643', (128, 133))	('induce', 'PosReg', (36, 42))
235911	33949239	We also reported that CTPG inhibited the growth of melanoma B16-F10 cells and esophageal carcinoma Eca-109 cells through the induction of apoptosis via a mitochondrial-dependent pathway.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (78, 98))	('B16-F10', 'CellLine', 'CVCL:0159', (60, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('growth', 'CPA', (41, 47))	('CTPG', 'Chemical', '-', (22, 26))	('mitochondrial-dependent pathway', 'Pathway', (154, 185))	('apoptosis', 'CPA', (138, 147))	('inhibited', 'NegReg', (27, 36))	('CTPG', 'Var', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('esophageal carcinoma', 'Disease', (78, 98))	('melanoma', 'Disease', (51, 59))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (78, 98))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
235914	33949239	In the present study, we found that CTPG inhibited the growth of human HCC HepG2 and BEL-7404 cells through activation of the MAPK signaling pathway and induction of apoptosis via the mitochondria-dependent pathway.	('CTPG', 'Chemical', '-', (36, 40))	('HCC HepG2', 'CellLine', 'CVCL:0027', (71, 80))	('human', 'Species', '9606', (65, 70))	('HCC', 'Phenotype', 'HP:0001402', (71, 74))	('growth', 'CPA', (55, 61))	('CTPG', 'Var', (36, 40))	('BEL-7404', 'CellLine', 'CVCL:6568', (85, 93))	('induction', 'Reg', (153, 162))	('inhibited', 'NegReg', (41, 50))	('mitochondria-dependent pathway', 'Pathway', (184, 214))	('apoptosis', 'CPA', (166, 175))	('MAPK signaling pathway', 'Pathway', (126, 148))	('activation', 'PosReg', (108, 118))
235916	33949239	Here, we found that CTPG increased the expression of Bax and reduced the expression of Bcl-2 in HepG2 and BEL-7404 cells, which resulted in the reduction of Deltapsim and the release of cytochrome c to activate the caspase cascade.	('Bcl-2', 'Gene', '596', (87, 92))	('CTPG', 'Var', (20, 24))	('HepG2', 'CellLine', 'CVCL:0027', (96, 101))	('activate', 'PosReg', (202, 210))	('cytochrome c', 'Gene', (186, 198))	('expression', 'MPA', (73, 83))	('expression', 'MPA', (39, 49))	('caspase', 'Gene', (215, 222))	('CTPG', 'Chemical', '-', (20, 24))	('Deltapsim', 'MPA', (157, 166))	('caspase', 'Gene', '841;842', (215, 222))	('reduction', 'NegReg', (144, 153))	('Bcl-2', 'Gene', (87, 92))	('increased', 'PosReg', (25, 34))	('Bax', 'Gene', (53, 56))	('cytochrome c', 'Gene', '54205', (186, 198))	('BEL-7404', 'CellLine', 'CVCL:6568', (106, 114))	('Bax', 'Gene', '581', (53, 56))	('reduced', 'NegReg', (61, 68))
235918	33949239	However, our previous study showed that CTPG induced the apoptosis of H22 cells through both intrinsic and extrinsic pathways.	('extrinsic pathways', 'Pathway', (107, 125))	('apoptosis', 'CPA', (57, 66))	('intrinsic', 'Pathway', (93, 102))	('H22', 'CellLine', 'CVCL:1E32', (70, 73))	('CTPG', 'Var', (40, 44))	('CTPG', 'Chemical', '-', (40, 44))
235919	33949239	These results suggested that CTPG might inhibit the growth of tumor cells through multiple targets and pathways.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibit', 'NegReg', (40, 47))	('tumor', 'Disease', (62, 67))	('CTPG', 'Var', (29, 33))	('CTPG', 'Chemical', '-', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
235924	33949239	We found that CTPG up-regulated the phosphorylated levels of p38, JNK, and ERK, suggesting that the MAPK signaling pathway might be involved in the apoptosis of HCC cells induced by CTPG.	('JNK', 'Gene', '5599', (66, 69))	('ERK', 'Gene', '5594', (75, 78))	('CTPG', 'Var', (14, 18))	('p38', 'Gene', '5594', (61, 64))	('ERK', 'Gene', (75, 78))	('CTPG', 'Chemical', '-', (14, 18))	('CTPG', 'Chemical', '-', (182, 186))	('HCC', 'Phenotype', 'HP:0001402', (161, 164))	('phosphorylated levels', 'MPA', (36, 57))	('HCC', 'Disease', (161, 164))	('up-regulated', 'PosReg', (19, 31))	('JNK', 'Gene', (66, 69))	('involved', 'Reg', (132, 140))	('p38', 'Gene', (61, 64))
235930	33949239	In the H22 tumor mouse model, CTPG + cisplatin not only showed the best antitumor effect but also reduced the side effects of cisplatin.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('side effects', 'MPA', (110, 122))	('H22', 'CellLine', 'CVCL:1E32', (7, 10))	('mouse', 'Species', '10090', (17, 22))	('tumor', 'Disease', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CTPG', 'Chemical', '-', (30, 34))	('CTPG + cisplatin', 'Var', (30, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('reduced', 'NegReg', (98, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
235932	33949239	The increased numbers of T cells might be corrected with their proliferation promoted by CTPG and their decreased apoptosis protected by CTPG.	('CTPG', 'Chemical', '-', (137, 141))	('CTPG', 'Chemical', '-', (89, 93))	('apoptosis', 'CPA', (114, 123))	('CTPG', 'Var', (89, 93))
235934	33949239	In conclusion, CTPG induced apoptosis in HCC cells through both the mitochondria-dependent and MAPK signaling pathways in vitro and inhibited the growth of HCC through direct antitumor effects and indirect immune enhancement in combination with cisplatin.	('HCC', 'Disease', (156, 159))	('inhibited', 'NegReg', (132, 141))	('mitochondria-dependent', 'Pathway', (68, 90))	('HCC', 'Phenotype', 'HP:0001402', (156, 159))	('MAPK signaling pathways', 'Pathway', (95, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (245, 254))	('growth', 'CPA', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('CTPG', 'Var', (15, 19))	('enhancement', 'PosReg', (213, 224))	('HCC', 'Phenotype', 'HP:0001402', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('CTPG', 'Chemical', '-', (15, 19))	('tumor', 'Disease', (179, 184))
235982	32912295	This includes base modifications, single and double strand breaks of varying complexity, DNA crosslinks, and bulky lesions which arise from direct ionization events or are indirectly mediated by free reactive oxygen species (ROS), respectively.	('ROS', 'Chemical', 'MESH:D017382', (225, 228))	('single', 'Disease', (34, 40))	('base modifications', 'Var', (14, 32))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (200, 223))
235988	32912295	Moreover, DNA damage-induced senescence and death of AT I and AT II cells result in a loss of barrier function and reduced surfactant production, decreased surface tension, and possible atelectasis due to the lack of surfactant eventually leading to interstitial edema, exudation of proteins into the alveolar space, and further reduction of the alveolar septa.	('senescence', 'Var', (29, 39))	('lack', 'NegReg', (209, 213))	('loss', 'NegReg', (86, 90))	('surfactant production', 'MPA', (123, 144))	('reduced', 'NegReg', (115, 122))	('exudation of', 'MPA', (270, 282))	('death of AT I', 'Disease', (44, 57))	('atelectasis', 'CPA', (186, 197))	('decreased', 'NegReg', (146, 155))	('edema', 'Disease', 'MESH:D004487', (263, 268))	('death of AT I', 'Disease', 'MESH:D003643', (44, 57))	('edema', 'Phenotype', 'HP:0000969', (263, 268))	('reduction', 'NegReg', (329, 338))	('proteins', 'Protein', (283, 291))	('atelectasis', 'Phenotype', 'HP:0100750', (186, 197))	('edema', 'Disease', (263, 268))	('surface tension', 'MPA', (156, 171))	('barrier', 'MPA', (94, 101))
236052	32912295	For SBRT, V20 > 10% and MLD > 6 Gy were associated with higher risk of grade 2-4 RIP.	('V20 > 10%', 'Var', (10, 19))	('SBRT', 'Chemical', '-', (4, 8))	('MLD', 'Disease', 'MESH:D007966', (24, 27))	('grade 2-4 RIP', 'Disease', (71, 84))	('MLD', 'Disease', (24, 27))
236055	32912295	Programmed cell death 1 (PD-1)/ Programmed cell death 1 ligand 1 (PD-L1) inhibition alone can cause immune-mediated pneumonitis in less than 5%.	('PD-L1', 'Gene', '574058', (66, 71))	('pneumonitis', 'Disease', 'MESH:D011014', (116, 127))	('PD-1', 'Gene', (25, 29))	('Programmed cell death 1 ligand 1', 'Gene', (32, 64))	('Programmed cell death 1 ligand 1', 'Gene', '574058', (32, 64))	('pneumonitis', 'Disease', (116, 127))	('cause', 'Reg', (94, 99))	('PD-L1', 'Gene', (66, 71))	('inhibition', 'Var', (73, 83))
236058	32912295	Unfortunately, predictive biomarkers and/or patient- or disease-related characteristics that can identify patients with elevated risk of RIP with ICI treatment are currently not available, but several ongoing studies are investigating these multi-modal treatment approaches and aim at establishing such biomarkers (NCT03519971 (PACIFIC-2), NCT04245514 (SAKK 16/18), NCT03801902 (NRG-LU004), NCT03217071).	('men', 'Species', '9606', (155, 158))	('men', 'Species', '9606', (258, 261))	('patient', 'Species', '9606', (44, 51))	('NCT03217071', 'Var', (391, 402))	('patient', 'Species', '9606', (106, 113))	('NCT04245514', 'Var', (340, 351))	('NCT03801902', 'Var', (366, 377))	('patients', 'Species', '9606', (106, 114))	('NCT03519971', 'Var', (315, 326))
236086	32912295	Thus, inhibition of TGF-beta and/or its downstream signaling cascades represents an attractive strategy to prevent radiation-induced lung toxicity.	('TGF-beta', 'Protein', (20, 28))	('lung toxicity', 'Disease', (133, 146))	('lung toxicity', 'Disease', 'MESH:D008171', (133, 146))	('inhibition', 'Var', (6, 16))
236087	32912295	Several in vivo studies described reduced inflammation and lung fibrosis upon TGF-beta receptor inhibition with LY2109761, a TGF-beta receptor I/II kinase inhibitor which interferes with SMAD1/2 phosphorylation, attenuates TGF-beta signaling, and suppresses production of the pro-inflammatory cytokines IL-6, IL-7R, and IL-8.	('attenuates', 'NegReg', (212, 222))	('IL-7R', 'Gene', '3575', (309, 314))	('SMAD1/2', 'Gene', (187, 194))	('interferes', 'NegReg', (171, 181))	('IL-8', 'Gene', (320, 324))	('reduced', 'NegReg', (34, 41))	('LY2109761', 'Chemical', 'MESH:C530108', (112, 121))	('suppresses', 'NegReg', (247, 257))	('lung fibrosis', 'Disease', 'MESH:D005355', (59, 72))	('LY2109761', 'Var', (112, 121))	('inflammation', 'Disease', 'MESH:D007249', (42, 54))	('IL-6', 'Gene', '3569', (303, 307))	('TGF-beta receptor', 'Gene', (78, 95))	('production', 'MPA', (258, 268))	('IL-6', 'Gene', (303, 307))	('TGF-beta signaling', 'MPA', (223, 241))	('IL-8', 'Gene', '3576', (320, 324))	('inflammation', 'Disease', (42, 54))	('lung fibrosis', 'Disease', (59, 72))	('lung fibrosis', 'Phenotype', 'HP:0002206', (59, 72))	('phosphorylation', 'MPA', (195, 210))	('SMAD1/2', 'Gene', '4086;4087', (187, 194))	('IL-7R', 'Gene', (309, 314))	('inhibition', 'NegReg', (96, 106))
236088	32912295	LY2157299 (galunisertib) more specifically inhibits TGF-beta receptor I and has already convinced in phase II clinical trials for idiopathic pulmonary fibrosis (IPF) with manageable toxicity.	('LY2157299', 'Var', (0, 9))	('LY2157299', 'Chemical', 'MESH:C557799', (0, 9))	('galunisertib', 'Chemical', 'MESH:C557799', (11, 23))	('toxicity', 'Disease', 'MESH:D064420', (182, 190))	('toxicity', 'Disease', (182, 190))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (130, 159))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (141, 159))	('TGF-beta receptor I', 'Protein', (52, 71))	('inhibits', 'NegReg', (43, 51))	('idiopathic pulmonary fibrosis', 'Disease', (130, 159))
236094	32912295	However, in clinical trials for idiopathic pulmonary fibrosis (IPF), PDGF inhibitors, such as imatinib, failed to prolong survival and/or improve lung function - in contrast to nintedanib which appears safe and slowed down IPF progression considerably.	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (43, 61))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (32, 61))	('inhibitors', 'Var', (74, 84))	('PDGF', 'Gene', (69, 73))	('imatinib', 'Chemical', 'MESH:D000068877', (94, 102))	('lung function', 'MPA', (146, 159))	('idiopathic pulmonary fibrosis', 'Disease', (32, 61))	('improve', 'PosReg', (138, 145))	('nintedanib', 'Chemical', 'MESH:C530716', (177, 187))	('improve lung function', 'Phenotype', 'HP:0005952', (138, 159))	('inhibitors', 'Chemical', '-', (74, 84))	('IPF', 'Disease', (223, 226))
236097	32912295	In vivo experiments demonstrated that CTGF inhibition can attenuate the development of radiation-induced lung fibrosis and even to revert the fibrotic processes in a therapeutic setting.	('men', 'Species', '9606', (79, 82))	('CTGF', 'Gene', (38, 42))	('inhibition', 'Var', (43, 53))	('fibrotic processes', 'CPA', (142, 160))	('men', 'Species', '9606', (14, 17))	('attenuate', 'NegReg', (58, 67))	('lung fibrosis', 'Disease', 'MESH:D005355', (105, 118))	('lung fibrosis', 'Disease', (105, 118))	('revert', 'NegReg', (131, 137))	('lung fibrosis', 'Phenotype', 'HP:0002206', (105, 118))
236134	29942193	The highly hydrophobic bile acids such as chenodeoxycholic acid (CD) and deoxycholic acid can promote carcinogenesis and stimulate the invasion of colon cancer cells.	('deoxycholic acid', 'Var', (73, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('CD', 'Chemical', 'MESH:D002635', (65, 67))	('carcinogenesis', 'Disease', (102, 116))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (47, 63))	('promote', 'PosReg', (94, 101))	('colon cancer', 'Disease', 'MESH:D015179', (147, 159))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (73, 89))	('colon cancer', 'Phenotype', 'HP:0003003', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('stimulate', 'PosReg', (121, 130))	('colon cancer', 'Disease', (147, 159))	('chenodeoxycholic acid', 'Chemical', 'MESH:D002635', (42, 63))	('bile acids', 'Chemical', 'MESH:D001647', (23, 33))	('invasion', 'CPA', (135, 143))
236155	29942193	Interestingly, UDCA inhibits proliferation and induces apoptosis in colon cancer cells.	('induces', 'Reg', (47, 54))	('inhibits', 'NegReg', (20, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('proliferation', 'CPA', (29, 42))	('colon cancer', 'Disease', (68, 80))	('UDCA', 'Chemical', 'MESH:D014580', (15, 19))	('apoptosis', 'CPA', (55, 64))	('UDCA', 'Var', (15, 19))
236157	29942193	Moreover, UDCA inhibits proliferation and induce apoptosis in colon cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('proliferation', 'CPA', (24, 37))	('colon cancer', 'Disease', (62, 74))	('UDCA', 'Chemical', 'MESH:D014580', (10, 14))	('induce', 'PosReg', (42, 48))	('UDCA', 'Var', (10, 14))	('colon cancer', 'Phenotype', 'HP:0003003', (62, 74))	('inhibits', 'NegReg', (15, 23))	('apoptosis', 'CPA', (49, 58))	('colon cancer', 'Disease', 'MESH:D015179', (62, 74))
236203	29942193	Furthermore, UDCA suppresses CD-induced PGE2 production without affecting COX-2 expression.	('CD-induced PGE2 production', 'MPA', (29, 55))	('UDCA', 'Chemical', 'MESH:D014580', (13, 17))	('UDCA', 'Var', (13, 17))	('CD', 'Chemical', 'MESH:D002635', (29, 31))	('suppresses', 'NegReg', (18, 28))	('PGE2', 'Chemical', 'MESH:D015232', (40, 44))
236231	29942193	In colon cancer, the highly hydrophobic bile acids such as CD promote carcinogenesis and stimulate the invasion; UDCA, a less hydrophobic stereoisomer of CD, inhibits proliferation and induces apoptosis.	('inhibits', 'NegReg', (158, 166))	('apoptosis', 'CPA', (193, 202))	('bile acids', 'Chemical', 'MESH:D001647', (40, 50))	('CD', 'Chemical', 'MESH:D002635', (59, 61))	('stimulate', 'PosReg', (89, 98))	('induces', 'Reg', (185, 192))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('promote', 'PosReg', (62, 69))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('UDCA', 'Chemical', 'MESH:D014580', (113, 117))	('carcinogenesis', 'Disease', 'MESH:D063646', (70, 84))	('proliferation', 'CPA', (167, 180))	('carcinogenesis', 'Disease', (70, 84))	('invasion', 'CPA', (103, 111))	('CD', 'Chemical', 'MESH:D002635', (154, 156))	('UDCA', 'Var', (113, 117))	('colon cancer', 'Disease', (3, 15))
236235	27892671	Association between the XRCC3 Thr241Met Polymorphism and Gastrointestinal Cancer Risk: A Meta-Analysis The x-ray repair cross-complementing group 3 (XRCC3) encodes a protein involved in the homologous recombination repair (HRR) pathway for double-strand DNA repair.	('x-ray repair cross-complementing group 3', 'Gene', '7517', (107, 147))	('XRCC3', 'Gene', '7517', (149, 154))	('x-ray repair cross-complementing group 3', 'Gene', (107, 147))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Thr241Met', 'Var', (30, 39))	('XRCC3', 'Gene', '7517', (24, 29))	('Gastrointestinal Cancer', 'Disease', 'MESH:D004067', (57, 80))	('XRCC3', 'Gene', (24, 29))	('Gastrointestinal Cancer', 'Disease', (57, 80))	('Polymorphism', 'Var', (40, 52))	('Association', 'Interaction', (0, 11))	('Thr241Met', 'SUBSTITUTION', 'None', (30, 39))	('XRCC3', 'Gene', (149, 154))	('Gastrointestinal Cancer', 'Phenotype', 'HP:0007378', (57, 80))
236236	27892671	Associations of the XRCC3 Thr241Met polymorphism with various cancers have been widely reported.	('Associations', 'Interaction', (0, 12))	('Thr241Met', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('XRCC3', 'Gene', (20, 25))	('XRCC3', 'Gene', '7517', (20, 25))	('polymorphism', 'Var', (36, 48))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('Thr241Met', 'SUBSTITUTION', 'None', (26, 35))	('cancers', 'Disease', (62, 69))
236237	27892671	However, published data on links between XRCC3 Thr241Met and gastrointestinal (GI) cancer risk are inconsistent.	('Thr241Met', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Thr241Met', 'SUBSTITUTION', 'None', (47, 56))	('links', 'Interaction', (27, 32))	('XRCC3', 'Gene', (41, 46))	('XRCC3', 'Gene', '7517', (41, 46))	('gastrointestinal (GI) cancer', 'Disease', 'MESH:D004067', (61, 89))
236238	27892671	A meta-analysis was conducted to characterize the relationship between XRCC3 Thr241Met polymorphisms and GI cancer risk.	('XRCC3', 'Gene', (71, 76))	('Thr241Met', 'Var', (77, 86))	('XRCC3', 'Gene', '7517', (71, 76))	('GI cancer', 'Disease', 'MESH:D009369', (105, 114))	('GI cancer', 'Phenotype', 'HP:0007378', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('polymorphisms', 'Var', (87, 100))	('Thr241Met', 'SUBSTITUTION', 'None', (77, 86))	('GI cancer', 'Disease', (105, 114))
236239	27892671	The results of the overall meta-analysis suggested a borderline association between the XRCC3 Thr241Met polymorphism and GI cancer susceptibility (T vs. C: OR=1.18, 9 % CI=1.0-1.4, POR=0.04; TT vs. CT+CC: OR=1.3, 95 % CI=1.0-1.6, POR=0.04).	('POR', 'Gene', (181, 184))	('GI cancer', 'Phenotype', 'HP:0007378', (121, 130))	('XRCC3', 'Gene', (88, 93))	('polymorphism', 'Var', (104, 116))	('Thr241Met', 'SUBSTITUTION', 'None', (94, 103))	('XRCC3', 'Gene', '7517', (88, 93))	('GI cancer', 'Disease', 'MESH:D009369', (121, 130))	('POR', 'Gene', '5447', (230, 233))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('GI cancer', 'Disease', (121, 130))	('POR', 'Gene', '5447', (181, 184))	('Thr241Met', 'Var', (94, 103))	('POR', 'Gene', (230, 233))
236241	27892671	When stratified by ethnicity, source of controls or cancer type, although some associations between XRCC3 Thr241Met polymorphism and GI cancer susceptibility were detected, these associations no longer existed after removing studies not conforming to HWE.	('polymorphism', 'Var', (116, 128))	('GI cancer', 'Disease', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('associations', 'Interaction', (79, 91))	('Thr241Met', 'Var', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('GI cancer', 'Disease', 'MESH:D009369', (133, 142))	('cancer', 'Disease', (136, 142))	('Thr241Met', 'SUBSTITUTION', 'None', (106, 115))	('GI cancer', 'Phenotype', 'HP:0007378', (133, 142))	('XRCC3', 'Gene', '7517', (100, 105))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('XRCC3', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
236242	27892671	Our meta-analysis suggests that the XRCC3 Thr241Met polymorphism is not associated with risk of GI cancer based on current evidence.	('Thr241Met', 'SUBSTITUTION', 'None', (42, 51))	('XRCC3', 'Gene', (36, 41))	('XRCC3', 'Gene', '7517', (36, 41))	('GI cancer', 'Disease', (96, 105))	('Thr241Met', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('GI cancer', 'Disease', 'MESH:D009369', (96, 105))	('GI cancer', 'Phenotype', 'HP:0007378', (96, 105))
236247	27892671	Allelic variations in oncogenes are nomination genetic risk factors that may vary the onset and outcome of GI cancer.	('GI cancer', 'Phenotype', 'HP:0007378', (107, 116))	('Allelic variations', 'Var', (0, 18))	('oncogenes', 'Gene', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('GI cancer', 'Disease', (107, 116))	('vary', 'Reg', (77, 81))	('GI cancer', 'Disease', 'MESH:D009369', (107, 116))
236248	27892671	There has been evidence that human susceptibility to cancer could be influenced by single nucleotide polymorphisms (SNPs) located in DNA repair genes (Chiurillo, 2014).	('DNA repair', 'Gene', (133, 143))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('single nucleotide polymorphisms', 'Var', (83, 114))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('human', 'Species', '9606', (29, 34))	('influenced', 'Reg', (69, 79))
236253	27892671	Many single nucleotide polymorphisms in the XRCC3 gene have been reported.	('single nucleotide polymorphisms', 'Var', (5, 36))	('XRCC3', 'Gene', '7517', (44, 49))	('XRCC3', 'Gene', (44, 49))
236254	27892671	Moreover, a common polymorphism in XRCC3 gene is at nucleotide 1,8607C/T (rs861,539) that results in substitution of amino acid threonine to methionine at codon 241 (Thr241Met) in exon seven of XRCC3 gene.	('XRCC3', 'Gene', '7517', (194, 199))	('rs861', 'Var', (74, 79))	('Thr241Met', 'SUBSTITUTION', 'None', (166, 175))	('rs861', 'DBSNP_MENTION', 'None', (74, 79))	('XRCC3', 'Gene', (194, 199))	('XRCC3', 'Gene', (35, 40))	('XRCC3', 'Gene', '7517', (35, 40))	('threonine to methionine at codon 241', 'Mutation', 'rs861539', (128, 164))	('Thr241Met', 'Var', (166, 175))	('8607C/T', 'Mutation', 'g.8607C>T', (65, 72))	('results in', 'Reg', (90, 100))	('substitution', 'Var', (101, 113))
236256	27892671	To date, several case-control studies have been conducted to assess the role of XRCC3 Thr241Met polymorphism in predisposition to GI cancer but the published results are controversial and inconsistent.	('GI cancer', 'Disease', (130, 139))	('polymorphism', 'Var', (96, 108))	('Thr241Met', 'SUBSTITUTION', 'None', (86, 95))	('XRCC3', 'Gene', '7517', (80, 85))	('GI cancer', 'Disease', 'MESH:D009369', (130, 139))	('GI cancer', 'Phenotype', 'HP:0007378', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Thr241Met', 'Var', (86, 95))	('XRCC3', 'Gene', (80, 85))
236257	27892671	found that gastric cancer occurrence was associated with the XRCC3 Met/Met polymorphic variant (OR=1.8, 95% CI=1.1-2.9 for TT genotype) in a Chinese population (Huang et al., 2006) and Mucha et al.	('associated', 'Reg', (41, 51))	('XRCC3', 'Gene', (61, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (11, 25))	('XRCC3', 'Gene', '7517', (61, 66))	('Met/Met', 'Var', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (11, 25))	('gastric cancer', 'Disease', (11, 25))
236258	27892671	(2013) suggested significant association of heterozygotes (OR=0.6, 95% CI=0.4-0.9) and the Met allele (OR=0.7, 95% CI=0.5-0.9) with reduced colorectal cancer risk (Mucha et al., 2013).	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('colorectal cancer', 'Disease', (140, 157))	('reduced', 'NegReg', (132, 139))	('Met', 'Var', (91, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))
236259	27892671	reported that XRCC3 Thr241Met polymorphism may not play a significant role in the risk of gastric cancer in Italian population (OR=0.8 and 95% CI= 0.7-1.78 for TT genotype) (Palli et al., 2010)and Moghtit et al.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('Thr241Met', 'Var', (20, 29))	('XRCC3', 'Gene', '7517', (14, 19))	('XRCC3', 'Gene', (14, 19))	('Thr241Met', 'SUBSTITUTION', 'None', (20, 29))	('gastric cancer', 'Disease', (90, 104))
236260	27892671	(2014) suggested that the XRCC3 Thr241Met polymorphism may not be associated with the colorectal cancer risk in West Algerian population (Moghtit et al., 2014).	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('Thr241Met', 'Var', (32, 41))	('XRCC3', 'Gene', (26, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('XRCC3', 'Gene', '7517', (26, 31))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Thr241Met', 'SUBSTITUTION', 'None', (32, 41))
236262	27892671	A literature research was conducted using PubMed Database updated on March 2016 for all publications on the association between XRCC3 Thr241Met polymorphism and GI cancer susceptibility.	('polymorphism', 'Var', (144, 156))	('XRCC3', 'Gene', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('GI cancer', 'Disease', (161, 170))	('XRCC3', 'Gene', '7517', (128, 133))	('Thr241Met', 'Var', (134, 143))	('association', 'Interaction', (108, 119))	('GI cancer', 'Disease', 'MESH:D009369', (161, 170))	('Thr241Met', 'SUBSTITUTION', 'None', (134, 143))	('GI cancer', 'Phenotype', 'HP:0007378', (161, 170))
236263	27892671	The search strategy was performed by combination of the following keywords: polymorphism, Thr241Met, XRCC3, esophageal, gastric, colorectal, carcinoma and cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('gastric', 'Disease', (120, 127))	('XRCC3', 'Gene', '7517', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Thr241Met', 'SUBSTITUTION', 'None', (90, 99))	('polymorphism', 'Var', (76, 88))	('esophageal', 'Disease', (108, 118))	('colorectal, carcinoma', 'Disease', 'MESH:D015179', (129, 150))	('Thr241Met', 'Var', (90, 99))	('XRCC3', 'Gene', (101, 106))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
236264	27892671	The eligible studies included in present meta-analysis had to comprise all the following inclusion criteria: (a) the study was published in English, (b) case-control studies about the association of XRCC3 Thr241Met polymorphism with GI cancer risk, (c) the study provided sufficient genotype distribution data to compute odds ratios (ORs) and 95% confidence intervals (CIs).	('Thr241Met', 'Var', (205, 214))	('GI cancer', 'Disease', 'MESH:D009369', (233, 242))	('GI cancer', 'Disease', (233, 242))	('XRCC3', 'Gene', (199, 204))	('XRCC3', 'Gene', '7517', (199, 204))	('Thr241Met', 'SUBSTITUTION', 'None', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('association', 'Interaction', (184, 195))	('GI cancer', 'Phenotype', 'HP:0007378', (233, 242))
236265	27892671	The risk of GI cancer associated with the XRCC3 Thr241Met polymorphism was estimated for each study by the odds ratio (OR) and 95.0% confidence interval (CI) under the Allelic model (T vs. C), heterozygote model (CT vs. CC), homozygote model (TT vs. CC), dominant model (TT+ CT vs. CC) and recessive model (TT vs. CT+CC).	('Thr241Met', 'SUBSTITUTION', 'None', (48, 57))	('GI cancer', 'Phenotype', 'HP:0007378', (12, 21))	('GI cancer', 'Disease', 'MESH:D009369', (12, 21))	('Thr241Met', 'Var', (48, 57))	('XRCC3', 'Gene', '7517', (42, 47))	('XRCC3', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('GI cancer', 'Disease', (12, 21))
236269	27892671	For the meta-analysis of XRCC3 Thr241Met polymorphism for GI cancer, there were four studies on esophageal cancer (Casson et al., 2005; Ye et al., 2006; Djansugurova et al., 2013), 10 studies on gastric cancer (Shen et al., 2004; Duarte et al., 2005; Huang et al., 2005; Huang et al., 2006; Ye et al., 2006; Ruzzo et al., 2007; Canbay et al., 2010; Palli et al., 2010; Zhao et al., 2011; Cheng et al., 2015), and 16 study on colorectal cancer (Krupa and Blasiak, 2004; Tranah et al., 2004; Jin et al., 2005; Stern et al., 2005; Yeh et al., 2005; Moreno et al., 2006; Skjelbred et al., 2006; Improta et al., 2008; Wang et al., 2010; Canbay et al., 2011; Krupa et al., 2011; Gil et al., 2012; Zhao et al., 2012; Mucha et al., 2013; Moghtit et al., 2014; Nissar et al., 2014).	('GI cancer', 'Disease', (58, 67))	('XRCC3', 'Gene', (25, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (425, 442))	('gastric cancer', 'Disease', (195, 209))	('Thr241Met', 'Var', (31, 40))	('GI cancer', 'Disease', 'MESH:D009369', (58, 67))	('GI cancer', 'Phenotype', 'HP:0007378', (58, 67))	('Thr241Met', 'SUBSTITUTION', 'None', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (195, 209))	('colorectal cancer', 'Disease', 'MESH:D015179', (425, 442))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('XRCC3', 'Gene', '7517', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Disease', (425, 442))	('esophageal cancer', 'Disease', (96, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (195, 209))
236270	27892671	Table 2 listed the main results of the association between XRCC3 polymorphism and GI cancer risk.	('polymorphism', 'Var', (65, 77))	('GI cancer', 'Disease', 'MESH:D009369', (82, 91))	('XRCC3', 'Gene', (59, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (82, 91))	('XRCC3', 'Gene', '7517', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('GI cancer', 'Disease', (82, 91))	('association', 'Interaction', (39, 50))
236271	27892671	The overall results of meta-analysis showed borderline association between the XRCC3 Thr241Met polymorphism and increased GI cancer susceptibility in allelic and recessive genetic models (T vs. C: OR=1.2, 95 % CI=1.0-1.4, POR=0.04; TT vs. CT+CC: OR=1.3, 95 % CI=1.04-1.6, POR=0.04).	('GI cancer', 'Disease', (122, 131))	('POR', 'Gene', '5447', (222, 225))	('POR', 'Gene', (272, 275))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('GI cancer', 'Disease', 'MESH:D009369', (122, 131))	('Thr241Met', 'Var', (85, 94))	('XRCC3', 'Gene', (79, 84))	('POR', 'Gene', '5447', (272, 275))	('GI cancer', 'Phenotype', 'HP:0007378', (122, 131))	('increased', 'PosReg', (112, 121))	('polymorphism', 'Var', (95, 107))	('XRCC3', 'Gene', '7517', (79, 84))	('POR', 'Gene', (222, 225))	('Thr241Met', 'SUBSTITUTION', 'None', (85, 94))
236273	27892671	Stratified analysis by ethnicity, source of controls and cancer type detected some associations between Thr241Met polymorphism and cancer susceptibility.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('associations', 'Interaction', (83, 95))	('polymorphism', 'Var', (114, 126))	('cancer', 'Disease', (57, 63))	('Thr241Met', 'SUBSTITUTION', 'None', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Thr241Met', 'Var', (104, 113))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
236274	27892671	In stratified analysis by ethnicity, the present meta-analysis showed that the Thr241Met polymorphism was associated with increased GI cancer risk in Asians (T vs. C: OR =1.5, 95 % CI=1.1-2.1, POR=0.009; TT vs. CC: OR=2.1, 95 % CI=1.2-3.4, POR=0.004; CT vs. CC: OR=1.6, 95 % CI=1.1-2.4, POR=0.014; TT+CT vs. CC: OR=1.6, 95 % CI=1.1-2.4, POR=0.014; TT vs. CT+CC: OR=2.2, 95 % CI=1.8-2.7, POR<0.001) In stratified analysis according to source of control, significant increased GI cancer risk was found in hospital-based studies (TT vs. CC: OR=1.6, 95 % CI=1.0-2.6, POR=0.049; TT vs. CT+CC: OR=1.6, 95 % CI=1.1-2.3, POR=0.013), but not in population-based studies.	('POR', 'Gene', '5447', (287, 290))	('POR', 'Gene', '5447', (563, 566))	('POR', 'Gene', (337, 340))	('increased', 'PosReg', (465, 474))	('POR', 'Gene', (193, 196))	('Thr241Met', 'Var', (79, 88))	('POR', 'Gene', (240, 243))	('GI cancer', 'Disease', 'MESH:D009369', (132, 141))	('Thr241Met', 'SUBSTITUTION', 'None', (79, 88))	('GI cancer', 'Phenotype', 'HP:0007378', (132, 141))	('POR', 'Gene', '5447', (387, 390))	('cancer', 'Phenotype', 'HP:0002664', (478, 484))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('POR', 'Gene', (613, 616))	('POR', 'Gene', (563, 566))	('POR', 'Gene', (287, 290))	('GI cancer', 'Disease', (475, 484))	('POR', 'Gene', '5447', (337, 340))	('POR', 'Gene', '5447', (193, 196))	('POR', 'Gene', (387, 390))	('polymorphism', 'Var', (89, 101))	('POR', 'Gene', '5447', (240, 243))	('GI cancer', 'Disease', (132, 141))	('GI cancer', 'Phenotype', 'HP:0007378', (475, 484))	('POR', 'Gene', '5447', (613, 616))	('GI cancer', 'Disease', 'MESH:D009369', (475, 484))
236277	27892671	Statistical analysis demonstrated no significant association between Thr241Met XRCC3 and GI cancer in all genetic models (Table 3).	('Thr241Met', 'SUBSTITUTION', 'None', (69, 78))	('GI cancer', 'Disease', (89, 98))	('GI cancer', 'Disease', 'MESH:D009369', (89, 98))	('XRCC3', 'Gene', (79, 84))	('GI cancer', 'Phenotype', 'HP:0007378', (89, 98))	('XRCC3', 'Gene', '7517', (79, 84))	('Thr241Met', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
236278	27892671	Significant heterogeneity revealed among literatures for the XRCC3 Thr241Met polymorphism and GI cancer risk (allelic: P <0.001, I2=87.9%; homozygous: P <0.001, I2=77.9%; heterozygous: P <0.001, I2=82.7%, dominant: P <0.001, I2=86.7% and recessive: P <0.001, I2=70.1).	('GI cancer', 'Disease', 'MESH:D009369', (94, 103))	('Thr241Met', 'Var', (67, 76))	('GI cancer', 'Phenotype', 'HP:0007378', (94, 103))	('XRCC3', 'Gene', (61, 66))	('XRCC3', 'Gene', '7517', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('GI cancer', 'Disease', (94, 103))	('Thr241Met', 'SUBSTITUTION', 'None', (67, 76))
236280	27892671	Deficiency in the repair capacity because of polymorphisms or mutations in genes involved in DNA repair can ultimate genomic instability that lead to chromosomal instability syndromes and increased risk of developing different types of cancer (Manuguerra et al., 2006).	('chromosomal instability', 'Phenotype', 'HP:0040012', (150, 173))	('ultimate', 'Reg', (108, 116))	('chromosomal instability syndromes', 'MPA', (150, 183))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('repair', 'MPA', (18, 24))	('mutations', 'Var', (62, 71))	('cancer', 'Disease', (236, 242))	('genomic instability', 'MPA', (117, 136))	('Deficiency', 'Disease', 'MESH:D007153', (0, 10))	('polymorphisms', 'Var', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('Deficiency', 'Disease', (0, 10))	('lead to', 'Reg', (142, 149))
236281	27892671	Double strand breaks (DSBs) are the most dangerous DNA damage and XRCC3 is required for the formation of the protein complex necessary for homologous recombination repair (HRR) of DNA DSB (Brenneman et al., 2000).	('XRCC3', 'Gene', (66, 71))	('XRCC3', 'Gene', '7517', (66, 71))	('Double strand breaks', 'Var', (0, 20))
236282	27892671	The Thr241Met (T241M) is the most frequent polymorphism in XRCC3, resulting in the amino acid substitution of threonine to methionine in codon 241, which may modify the function of enzyme and its interaction with other proteins involved in the DNA repair mechanisms.	('Thr241Met', 'SUBSTITUTION', 'None', (4, 13))	('proteins', 'Protein', (219, 227))	('interaction', 'Interaction', (196, 207))	('threonine to methionine in codon 241', 'Mutation', 'rs861539', (110, 146))	('Thr241Met', 'Var', (4, 13))	('XRCC3', 'Gene', (59, 64))	('enzyme', 'Enzyme', (181, 187))	('modify', 'Reg', (158, 164))	('XRCC3', 'Gene', '7517', (59, 64))	('T241M', 'Mutation', 'rs861539', (15, 20))	('function', 'MPA', (169, 177))
236283	27892671	Mounting evidence by meta-analysis indicates that XRCC3 Thr241Met polymorphism is associated with risk of particularly cancer (e.g., melanoma skin cancer (Fan et al., 2015), prostate cancer (Xuan et al., 2015), lung cancer (Bei et al., 2015), and hepatocellular carcinoma (Wu et al., 2013).	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('XRCC3', 'Gene', (50, 55))	('cancer', 'Disease', (216, 222))	('Thr241Met', 'Var', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('cancer', 'Disease', (183, 189))	('Thr241Met', 'SUBSTITUTION', 'None', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (247, 271))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('prostate cancer', 'Phenotype', 'HP:0012125', (174, 189))	('polymorphism', 'Var', (66, 78))	('XRCC3', 'Gene', '7517', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('skin cancer', 'Phenotype', 'HP:0008069', (142, 153))	('cancer', 'Disease', (147, 153))	('hepatocellular carcinoma', 'Disease', (247, 271))
236284	27892671	Several previous studies have evaluated the association between the XRCC3 Thr241Met polymorphism and GI cancer susceptibility; however, existing results are inconsistent.	('Thr241Met', 'Var', (74, 83))	('GI cancer', 'Phenotype', 'HP:0007378', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('XRCC3', 'Gene', (68, 73))	('XRCC3', 'Gene', '7517', (68, 73))	('Thr241Met', 'SUBSTITUTION', 'None', (74, 83))	('GI cancer', 'Disease', (101, 110))	('GI cancer', 'Disease', 'MESH:D009369', (101, 110))
236285	27892671	This meta-analysis was performed to derive a more precise estimation of the association between Thr241Met polymorphism and GI cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Thr241Met', 'SUBSTITUTION', 'None', (96, 105))	('GI cancer', 'Disease', (123, 132))	('association', 'Interaction', (76, 87))	('Thr241Met', 'Var', (96, 105))	('GI cancer', 'Disease', 'MESH:D009369', (123, 132))	('GI cancer', 'Phenotype', 'HP:0007378', (123, 132))	('polymorphism', 'Var', (106, 118))
236286	27892671	The overall results indicated a borderline association between the Thr241Met polymorphism and increased GI cancer susceptibility in allelic and recessive genetic models.	('GI cancer', 'Phenotype', 'HP:0007378', (104, 113))	('Thr241Met', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('increased', 'PosReg', (94, 103))	('GI cancer', 'Disease', (104, 113))	('Thr241Met', 'SUBSTITUTION', 'None', (67, 76))	('GI cancer', 'Disease', 'MESH:D009369', (104, 113))
236288	27892671	The different effect of XRCC3 Thr241Met polymorphism between ethnicity may result from different genetic background and environmental exposures, which may contribute to the discrepancy.	('Thr241Met', 'Var', (30, 39))	('XRCC3', 'Gene', (24, 29))	('polymorphism', 'Var', (40, 52))	('XRCC3', 'Gene', '7517', (24, 29))	('Thr241Met', 'SUBSTITUTION', 'None', (30, 39))
236291	27892671	When excluding the studies that deviated from HWE, a borderline association between XRCC3 polymorphism and GI cancer susceptibility altered in allelic and recessive genetic models in overall results.	('XRCC3', 'Gene', (84, 89))	('XRCC3', 'Gene', '7517', (84, 89))	('GI cancer', 'Phenotype', 'HP:0007378', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('altered', 'Reg', (132, 139))	('GI cancer', 'Disease', (107, 116))	('polymorphism', 'Var', (90, 102))	('GI cancer', 'Disease', 'MESH:D009369', (107, 116))
236292	27892671	Also, all significant associations between XRCC3 Thr241Met and GI cancer in Asian, hospital based studies and colorectal cancer subgroup were disappeared.	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('XRCC3', 'Gene', (43, 48))	('XRCC3', 'Gene', '7517', (43, 48))	('GI cancer', 'Disease', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Thr241Met', 'SUBSTITUTION', 'None', (49, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('GI cancer', 'Disease', 'MESH:D009369', (63, 72))	('Thr241Met', 'Var', (49, 58))	('colorectal cancer', 'Disease', (110, 127))	('GI cancer', 'Phenotype', 'HP:0007378', (63, 72))
236293	27892671	First, 7,649.0 cases and 11,123.0 controls were included in this meta-analysis; the sample size was relatively small and may not have provided sufficient statistical power to estimate the association between XRRC3 Thr241Met polymorphism and GI cancer risk.	('Thr241Met', 'Var', (214, 223))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('Thr241Met', 'SUBSTITUTION', 'None', (214, 223))	('GI cancer', 'Phenotype', 'HP:0007378', (241, 250))	('GI cancer', 'Disease', (241, 250))	('GI cancer', 'Disease', 'MESH:D009369', (241, 250))	('XRRC3', 'Gene', (208, 213))
236294	27892671	In addition, Because of limited available data about association between XRCC3 Thr241Met polymorphism and GI cancer in Asian population and esophageal cancer, our results should be interpreted with caution.	('GI cancer', 'Disease', (106, 115))	('polymorphism', 'Var', (89, 101))	('XRCC3', 'Gene', '7517', (73, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('Thr241Met', 'SUBSTITUTION', 'None', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('GI cancer', 'Disease', 'MESH:D009369', (106, 115))	('Thr241Met', 'Var', (79, 88))	('GI cancer', 'Phenotype', 'HP:0007378', (106, 115))	('association', 'Interaction', (53, 64))	('XRCC3', 'Gene', (73, 78))	('esophageal cancer', 'Disease', (140, 157))
236297	27892671	According to our knowledge, this is the first meta-analysis to investigate the association of xrcc3 Thr241Met polymorphism with GI cancer, and the influence of this gene polymorphism on GI cancer susceptibility in different ethnic populations.	('GI cancer', 'Disease', 'MESH:D009369', (186, 195))	('GI cancer', 'Disease', 'MESH:D009369', (128, 137))	('polymorphism', 'Var', (110, 122))	('GI cancer', 'Phenotype', 'HP:0007378', (128, 137))	('GI cancer', 'Phenotype', 'HP:0007378', (186, 195))	('Thr241Met', 'SUBSTITUTION', 'None', (100, 109))	('xrcc3', 'Gene', '7517', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('association', 'Interaction', (79, 90))	('GI cancer', 'Disease', (186, 195))	('Thr241Met', 'Var', (100, 109))	('xrcc3', 'Gene', (94, 99))	('GI cancer', 'Disease', (128, 137))
236298	27892671	In conclusion, present meta-analysis suggested that the XRCC3 Thr241Met polymorphism might influence GI cancer risk in Asians, although after removing studies not conforming to HWE, this association disappeared.	('GI cancer', 'Phenotype', 'HP:0007378', (101, 110))	('Thr241Met', 'SUBSTITUTION', 'None', (62, 71))	('influence', 'Reg', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Thr241Met', 'Var', (62, 71))	('XRCC3', 'Gene', '7517', (56, 61))	('GI cancer', 'Disease', (101, 110))	('XRCC3', 'Gene', (56, 61))	('GI cancer', 'Disease', 'MESH:D009369', (101, 110))
236458	21385931	Results showed that the tumor:normal expression ratio directionality was the same for most of the genes (88%), however, the magnitude of the fold changes was markedly higher in the micro-dissected as opposed to the non-micro-dissected samples (8K cDNA and U133A/B set chip studies).	('micro-dissected', 'Var', (181, 196))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('higher', 'PosReg', (167, 173))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
236470	21385931	Xue et al did evaluate normal, dysplastic, and invasive ESCCs within esophagectomies from the same cases and observed that protein expression positivity increased across this morphologic progression from 13% to 41% to 62%, respectively, suggesting some discrimination between clinically and diagnostically important categories.	('protein expression', 'MPA', (123, 141))	('dysplastic', 'Disease', 'MESH:D004416', (31, 41))	('increased', 'PosReg', (153, 162))	('dysplastic', 'Disease', (31, 41))	('positivity', 'Var', (142, 152))
236540	16620376	Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer The roles of mitochondria in energy metabolism, the generation of ROS, aging, and the initiation of apoptosis have implicated their importance in tumorigenesis.	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('ROS', 'Chemical', 'MESH:D017382', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mitochondrial DNA', 'Gene', (60, 77))	('tumor', 'Disease', (245, 250))	('mutations', 'Var', (24, 33))	('esophageal cancer', 'Disease', (81, 98))
236541	16620376	In this study we aim to establish the mutation spectrum and to understand the role of somatic mtDNA mutations in esophageal cancer.	('mutations', 'Var', (100, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('mtDNA', 'Gene', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal cancer', 'Disease', (113, 130))
236542	16620376	The entire mitochondrial genome was screened for somatic mutations in 20 pairs (18 esophageal squamous cell carcinomas, one adenosquamous carcinoma and one adenocarcinoma) of tumor/surrounding normal tissue of esophageal cancers, using temporal temperature gradient gel electrophoresis (TTGE), followed by direct DNA sequencing to identify the mutations.	('esophageal cancers', 'Disease', (210, 228))	('mutations', 'Var', (57, 66))	('esophageal squamous cell carcinomas', 'Disease', (83, 118))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (83, 118))	('esophageal cancers', 'Disease', 'MESH:D004938', (210, 228))	('adenocarcinoma', 'Disease', (156, 170))	('adenosquamous carcinoma', 'Disease', (124, 147))	('tumor', 'Disease', (175, 180))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (124, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('adenocarcinoma', 'Disease', 'MESH:D000230', (156, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (94, 118))
236543	16620376	Fourteen somatic mtDNA mutations were identified in 55% (11/20) of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively.	('missense mutations', 'Var', (102, 120))	('ATP6', 'Gene', (156, 160))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('ATP6', 'Gene', '4508', (156, 160))	('ND4L', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ND4', 'Gene', (150, 153))	('ND4', 'Gene', '4538', (150, 153))	('ND4', 'Gene', (174, 177))	('ND4', 'Gene', '4538', (174, 177))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('ND4L', 'Gene', '4539', (150, 154))	('tumors', 'Disease', (67, 73))	('frameshift mutation', 'Var', (127, 146))
236545	16620376	Our results demonstrate that somatic mtDNA mutations in esophageal cancers are frequent.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('mtDNA', 'Gene', (37, 42))	('esophageal cancers', 'Disease', (56, 74))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('esophageal cancers', 'Disease', 'MESH:D004938', (56, 74))
236546	16620376	Some missense and frameshift mutations may play an important role in the tumorigenesis of esophageal carcinoma.	('frameshift mutations', 'Var', (18, 38))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('esophageal carcinoma', 'Disease', (90, 110))	('play', 'Reg', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (90, 110))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (90, 110))	('tumor', 'Disease', (73, 78))	('missense', 'Var', (5, 13))
236551	16620376	Neoplastic transformation is a multi-step process in that alterations in multiple nuclear genes have been extensively documented.	('Neoplastic transformation', 'Disease', (0, 25))	('Neoplastic transformation', 'Disease', 'MESH:D002471', (0, 25))	('alterations', 'Var', (58, 69))
236553	16620376	However, unlike the common mtDNA mutations in maternally inherited mitochondrial disease, the functional significance and pathogenic mechanism of somatic mtDNA mutations in cancer development remains unclear despite the vast evidence of their occurrence in various types of tumors.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('mutations', 'Var', (160, 169))	('occurrence', 'Reg', (243, 253))	('cancer', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('mitochondrial disease', 'Disease', (67, 88))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mtDNA', 'Gene', (154, 159))	('mitochondrial disease', 'Disease', 'MESH:D028361', (67, 88))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumors', 'Disease', (274, 280))
236555	16620376	Extensive analysis of the mitochondrial genome using direct sequencing has revealed that approximately 30-70% of all types of tumors harbor mtDNA alterations.	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('alterations', 'Var', (146, 157))	('mtDNA', 'Gene', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
236556	16620376	Previous reports demonstrated that most of the somatic mtDNA mutations found in cancer were in the homoplasmic form.	('mtDNA', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
236557	16620376	This observation led to the conclusion that mutant mitochondria gained a replicative advantage during tumorigenesis and became homoplasmic within a few generations.	('replicative advantage', 'CPA', (73, 94))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('mutant', 'Var', (44, 50))
236558	16620376	Our recent investigation of somatic mtDNA mutations in breast, oral, and brain tumors revealed that mutations in the coding region did occur and there were significant number of heteroplasmic alterations.	('brain tumors', 'Phenotype', 'HP:0030692', (73, 85))	('mutations', 'Var', (100, 109))	('brain tumors', 'Disease', (73, 85))	('heteroplasmic alterations', 'Disease', (178, 203))	('breast', 'Disease', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mtDNA', 'Gene', (36, 41))	('heteroplasmic alterations', 'Disease', 'MESH:D004408', (178, 203))	('brain tumors', 'Disease', 'MESH:D001932', (73, 85))	('mutations', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
236560	16620376	Somatic mtDNA mutations in the non-coding D-loop region occurred in 5 and 34% of primary esophageal tumors reported by two Japanese studies.	('occurred', 'Reg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('esophageal tumors', 'Disease', 'MESH:D004938', (89, 106))	('mtDNA', 'Gene', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('esophageal tumors', 'Disease', (89, 106))	('esophageal tumors', 'Phenotype', 'HP:0100751', (89, 106))	('mutations', 'Var', (14, 23))
236561	16620376	A similar investigation of Chinese patients from Shanxi province also reported D-loop mtDNA mutations in 33% of esophageal tumors.	('esophageal tumors', 'Disease', 'MESH:D004938', (112, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('mtDNA', 'Gene', (86, 91))	('esophageal tumors', 'Phenotype', 'HP:0100751', (112, 129))	('D-loop', 'Var', (79, 85))	('esophageal tumors', 'Disease', (112, 129))	('mutations', 'Var', (92, 101))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
236564	16620376	In this report, we use TTGE mutation scanning method to study somatic mtDNA mutations in the entire mitochondrial genome of 20 esophageal tumors and their surrounding tissue.	('mtDNA', 'Gene', (70, 75))	('mutations', 'Var', (76, 85))	('esophageal tumors', 'Disease', 'MESH:D004938', (127, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('esophageal tumors', 'Phenotype', 'HP:0100751', (127, 144))	('esophageal tumors', 'Disease', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
236576	16620376	Sequence variations found in both tumor and matched normal mtDNA but different from that recorded in the GenBank were scored as germline variations.	('variations', 'Var', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
236581	16620376	Fisher's exact test is used to analyze whether there is association between the mtDNA content change in tumors and the presence of mutations.	('mutations', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('mtDNA', 'Gene', (80, 85))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
236582	16620376	Non-parametric Mann-Whitney test was also used to test if mtDNA content alteration in tumor is different in patients with or without mtDNA mutations.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (139, 148))	('tumor', 'Disease', (86, 91))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
236585	16620376	Eleven out of 20 (55%) tumors harbored somatic mtDNA mutations with a total of 14 mutations.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mtDNA', 'Gene', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
236587	16620376	All nine mutations in the D-loop involved an insertion or deletion within the poly C stretch of the nucleotide positions (np) 303-309 hot spot region.	('involved', 'Reg', (33, 41))	('mutations', 'Var', (9, 18))	('insertion', 'Var', (45, 54))	('deletion', 'Var', (58, 66))	('poly C', 'Chemical', 'MESH:D011066', (78, 84))
236590	16620376	Two of the somatic mutations changed from the homoplasmic state in surrounding tissue to a mutant homoplasmic state in tumor.	('tumor', 'Disease', (119, 124))	('mutations', 'Var', (19, 28))	('changed', 'Reg', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
236593	16620376	Among them, the most remarkable is A11976C in NADH dehydrogenase subunit 4 (ND4) where tyrosine at amino acid position 406 is replaced by serine.	('ND4', 'Gene', (76, 79))	('tyrosine', 'Chemical', 'MESH:D014443', (87, 95))	('NADH dehydrogenase subunit 4', 'Gene', (46, 74))	('ND4', 'Gene', '4538', (76, 79))	('A11976C', 'Mutation', 'g.11976A>C', (35, 42))	('serine', 'Chemical', 'MESH:D012694', (138, 144))	('serine', 'MPA', (138, 144))	('tyrosine', 'MPA', (87, 95))	('A11976C', 'Var', (35, 42))	('NADH dehydrogenase subunit 4', 'Gene', '4538', (46, 74))
236594	16620376	Other novel missense variations are M47T in NADH dehydrogenase subunit 4 (ND4L), S531T in NADH dehydrogenase subunit 5 (ND5), S219N in ATP synthase subunit 6 (ATPase 6), and E109D in cytochrome c oxidase subunit II (COII).	('ND5', 'Gene', '4540', (120, 123))	('S219N', 'Var', (126, 131))	('ATPase 6', 'Gene', '4508', (159, 167))	('NADH dehydrogenase subunit 5', 'Gene', (90, 118))	('COII', 'Gene', '4513', (216, 220))	('NADH dehydrogenase subunit 4', 'Gene', (44, 72))	('E109D', 'Var', (174, 179))	('M47T', 'Mutation', 'rs200487531', (36, 40))	('S219N', 'Mutation', 'p.S219N', (126, 131))	('ATP synthase subunit 6', 'Gene', (135, 157))	('ND4L', 'Gene', '4539', (74, 78))	('cytochrome c oxidase subunit II', 'Gene', (183, 214))	('COII', 'Gene', (216, 220))	('ATPase 6', 'Gene', (159, 167))	('NADH dehydrogenase subunit 5', 'Gene', '4540', (90, 118))	('S531T', 'Mutation', 'rs28359184', (81, 86))	('cytochrome c oxidase subunit II', 'Gene', '4513', (183, 214))	('S531T', 'Var', (81, 86))	('NADH dehydrogenase subunit 4', 'Gene', '4538', (44, 72))	('ATP synthase subunit 6', 'Gene', '4508', (135, 157))	('ND5', 'Gene', (120, 123))	('ND4L', 'Gene', (74, 78))	('E109D', 'Mutation', 'p.E109D', (174, 179))	('M47T', 'Var', (36, 40))
236595	16620376	Other frequent germ-line polymorphisms are C16233T, T16189C, T16519C in D-loop region, and C12705T in ND5, and T9540C in cytochrome c oxidase subunit II (COII) are silent variations with no amino acid change.	('ND5', 'Gene', (102, 105))	('T16189C', 'Var', (52, 59))	('T9540C', 'Var', (111, 117))	('COII', 'Gene', (154, 158))	('T16519C', 'Var', (61, 68))	('C12705T', 'Mutation', 'g.12705C>T', (91, 98))	('C16233T', 'Mutation', 'g.16233C>T', (43, 50))	('COII', 'Gene', '4513', (154, 158))	('C12705T', 'Var', (91, 98))	('C16233T', 'Var', (43, 50))	('T16189C', 'Mutation', 'g.16189T>C', (52, 59))	('cytochrome c oxidase subunit II', 'Gene', '4513', (121, 152))	('T9540C', 'Mutation', 'g.9540T>C', (111, 117))	('cytochrome c oxidase subunit II', 'Gene', (121, 152))	('ND5', 'Gene', '4540', (102, 105))	('T16519C', 'Mutation', 'g.16519T>C', (61, 68))
236598	16620376	G10500A somatic mutation changes a moderately conserved alanine residue to threonine in ND4L (Fig.	('moderately conserved alanine residue', 'MPA', (35, 71))	('ND4L', 'Gene', (88, 92))	('G10500A', 'Mutation', 'g.10500G>A', (0, 7))	('alanine', 'Chemical', 'MESH:D000409', (56, 63))	('changes', 'Reg', (25, 32))	('G10500A', 'Var', (0, 7))	('ND4L', 'Gene', '4539', (88, 92))	('threonine', 'Chemical', 'MESH:D013912', (75, 84))
236599	16620376	The A9182G mutation in ATPase6 is a back change from asparagine to serine.	('A9182G', 'Var', (4, 10))	('back change from asparagine to serine', 'MPA', (36, 73))	('A9182G', 'Mutation', 'g.9182A>G', (4, 10))	('asparagine', 'Chemical', 'MESH:D001216', (53, 63))	('ATPase6', 'Gene', (23, 30))	('ATPase6', 'Gene', '4508', (23, 30))	('serine', 'Chemical', 'MESH:D012694', (67, 73))
236601	16620376	One silent mutation G9377A in COIII (cytochrome c oxidase subunit III) does not change the amino acid.	('G9377A', 'Var', (20, 26))	('cytochrome c oxidase subunit III', 'Gene', '4514', (37, 69))	('COIII', 'Gene', '4514', (30, 35))	('cytochrome c oxidase subunit III', 'Gene', (37, 69))	('G9377A', 'Mutation', 'g.9377G>A', (20, 26))	('COIII', 'Gene', (30, 35))
236602	16620376	Another mutation, A1544T in 12S rRNA occurs at a stem region.	('12S rRNA', 'Gene', (28, 36))	('A1544T', 'Mutation', 'c.1544A>T', (18, 24))	('A1544T', 'Var', (18, 24))
236603	16620376	For instance, A11976C changes an evolutionary highly conserved hydrophobic tyrosine to hydrophilic serine at amino acid position 406 of ND4 subunit (Fig.	('changes', 'Reg', (22, 29))	('A11976C', 'Mutation', 'g.11976A>C', (14, 21))	('ND4', 'Gene', (136, 139))	('ND4', 'Gene', '4538', (136, 139))	('tyrosine', 'Chemical', 'MESH:D014443', (75, 83))	('serine', 'Chemical', 'MESH:D012694', (99, 105))	('A11976C', 'Var', (14, 21))
236604	16620376	Another example is the E109D mutation in COII (Fig.	('COII', 'Gene', '4513', (41, 45))	('COII', 'Gene', (41, 45))	('E109D', 'Var', (23, 28))	('E109D', 'Mutation', 'p.E109D', (23, 28))
236605	16620376	Although it involves a conserved amino acid change, the shortening of hydrocarbon chain may have subtle effects on mitochondrial function.	('effects', 'Reg', (104, 111))	('mitochondrial function', 'MPA', (115, 137))	('hydrocarbon', 'Chemical', 'MESH:D006838', (70, 81))	('shortening', 'Var', (56, 66))
236607	16620376	All five novel missense germline variations were not detected in 19 breast cancers, 31 neurofibromas, and 15 medulloblastomas, all of Caucasian origin in previous studies.	('neurofibromas', 'Phenotype', 'HP:0001067', (87, 100))	('breast cancers', 'Disease', 'MESH:D001943', (68, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('breast cancers', 'Disease', (68, 82))	('15 medulloblastomas', 'Disease', 'MESH:D008527', (106, 125))	('neurofibromas', 'Disease', 'MESH:D009455', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('15 medulloblastomas', 'Disease', (106, 125))	('missense', 'Var', (15, 23))	('breast cancers', 'Phenotype', 'HP:0003002', (68, 82))	('neurofibromas', 'Disease', (87, 100))
236611	16620376	The mean value of tumor/normal mtDNA ratio in the tumors with mtDNA mutation was 1.32 +- 0.31 and that of the tumors without mtDNA mutation was 1.45 +- 0.22.	('mtDNA', 'Gene', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', (18, 23))	('mutation', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
236612	16620376	Thus, tumor with or without somatic mtDNA mutations show no significant difference (p value = 0.59 using non-parametric Mann-Whitney test) in mtDNA content change from normal to tumors.	('tumor', 'Disease', (178, 183))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('mtDNA', 'Gene', (36, 41))	('mtDNA content', 'MPA', (142, 155))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mutations', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
236613	16620376	The majority (6 out of 11) of tumors with somatic mtDNA mutations have either elevated (>2) or reduced (<0.5) mtDNA content in tumors compared to surrounding normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('mutations', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('elevated', 'PosReg', (78, 86))	('mtDNA', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('reduced', 'NegReg', (95, 102))	('mtDNA content', 'MPA', (110, 123))
236614	16620376	The patient (case E18) whose mtDNA content is severely reduced in tumor harbored a frameshift deleterious mutation (10941 del 11bp).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('10941 del 11bp', 'Mutation', 'c.10941del11', (116, 130))	('tumor', 'Disease', (66, 71))	('patient', 'Species', '9606', (4, 11))	('10941 del 11bp', 'Var', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
236618	16620376	The patient (case E05) who had the most reduced mtDNA content in tumor, harbored the A1544T novel mutation in 12S rRNA gene.	('mtDNA content in', 'MPA', (48, 64))	('12S rRNA', 'Gene', (110, 118))	('tumor', 'Disease', (65, 70))	('patient', 'Species', '9606', (4, 11))	('A1544T', 'Mutation', 'c.1544A>T', (85, 91))	('A1544T', 'Var', (85, 91))	('reduced', 'NegReg', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
236626	16620376	Eight out of 11 tumors with mtDNA mutations became metastatic, whereas only 4 out of 9 tumors without somatic mtDNA mutations became metastatic.	('mtDNA', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', (16, 22))	('mutations', 'Var', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
236627	16620376	The analysis of odds ratio showed that the patients with somatic mtDNA mutation has 3.33 times higher risk of metastasis compared to patients without somatic mutations.	('metastasis', 'Disease', 'MESH:D009362', (110, 120))	('metastasis', 'Disease', (110, 120))	('mutation', 'Var', (71, 79))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (133, 141))	('mtDNA', 'Gene', (65, 70))
236629	16620376	We screened the entire mitochondrial genome of 20 esophageal primary tumors and their surrounding tissues for the presence of somatic mutations using the TTGE mutation detection method.	('esophageal primary tumors', 'Disease', (50, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (134, 143))	('esophageal primary tumors', 'Disease', 'MESH:D004938', (50, 75))
236630	16620376	Fourteen somatic mtDNA mutations were found in 11 (55%) tumors.	('mtDNA', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
236632	16620376	Although the sensitivity of detecting nuclear gene mutations has been reported to be around 97%, the detection rate for mtDNA may be lower due to low percentage of heteroplasmy and the limit of DNA sequencing.	('mutations', 'Var', (51, 60))	('heteroplasmy', 'Disease', 'None', (164, 176))	('heteroplasmy', 'Disease', (164, 176))	('mtDNA', 'Disease', (120, 125))	('lower', 'NegReg', (133, 138))
236633	16620376	Thus, the mutations detected represent an underestimate of the total somatic mutation load in the tumor mtDNAs.	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
236636	16620376	These results, although contradicted with the previous report that majority of the mutations involved in homoplasmy to homoplasmy changes, were consistent with random occurrence of mtDNA alterations at different times during tumorigenesis, or, mutations that might become homoplasmic at different rate.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('alterations', 'Var', (187, 198))	('tumor', 'Disease', (225, 230))	('homoplasmy to homoplasmy change', 'Disease', (105, 136))	('mtDNA', 'Gene', (181, 186))	('homoplasmy to homoplasmy change', 'Disease', 'MESH:D009402', (105, 136))
236637	16620376	Heteroplasmic mutations have been found in other tumors.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('Heteroplasmic mutations', 'Var', (0, 23))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))
236638	16620376	Our results suggest that mtDNA alterations may potentially be good biomarkers for early detection and/or prognosis of cancer.	('alterations', 'Var', (31, 42))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mtDNA', 'Gene', (25, 30))
236642	16620376	This phenomenon was also observed in liver cancer where tumors bearing somatic mtDNA mutation had either markedly reduced or elevated mtDNA content in tumor.	('elevated', 'PosReg', (125, 133))	('liver cancer', 'Disease', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mtDNA content', 'MPA', (134, 147))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (151, 156))	('mutation', 'Var', (85, 93))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('liver cancer', 'Phenotype', 'HP:0002896', (37, 49))	('liver cancer', 'Disease', 'MESH:D006528', (37, 49))	('mtDNA', 'Gene', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
236645	16620376	This compensatory mechanism may be beneficial as observed in patients E04 and in mitochondrial disease.	('E04', 'Var', (70, 73))	('patients', 'Species', '9606', (61, 69))	('mitochondrial disease', 'Disease', (81, 102))	('mitochondrial disease', 'Disease', 'MESH:D028361', (81, 102))
236646	16620376	Thus, in the late onset of a disease such as cancer, mtDNA polymorphisms can potentially play a role in modifying the cancer risk.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('modifying', 'Reg', (104, 113))	('polymorphisms', 'Var', (59, 72))	('mtDNA', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('play', 'Reg', (89, 93))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
236647	16620376	The missense variations, Y406S in ND4, M47T in ND4L, S219N in ATPase 6, and E109D in COII, might function as cancer predisposition factors.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('ATPase 6', 'Gene', (62, 70))	('ND4', 'Gene', '4538', (47, 50))	('ND4', 'Gene', (47, 50))	('E109D', 'Mutation', 'p.E109D', (76, 81))	('S219N', 'Var', (53, 58))	('COII', 'Gene', (85, 89))	('ND4L', 'Gene', (47, 51))	('S219N', 'Mutation', 'p.S219N', (53, 58))	('Y406S', 'Mutation', 'p.Y406S', (25, 30))	('E109D', 'Var', (76, 81))	('ATPase 6', 'Gene', '4508', (62, 70))	('function', 'Reg', (97, 105))	('cancer', 'Disease', (109, 115))	('Y406S', 'Var', (25, 30))	('ND4', 'Gene', '4538', (34, 37))	('ND4', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('M47T', 'Var', (39, 43))	('COII', 'Gene', '4513', (85, 89))	('ND4L', 'Gene', '4539', (47, 51))	('M47T', 'Mutation', 'rs200487531', (39, 43))
236648	16620376	Our unpublished observations have demonstrated that certain mtDNA haplogroups and mtDNA variations (polymorphisms and mutations) modify an individual's cancer risk.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('modify', 'Reg', (129, 135))	('mtDNA', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('variations', 'Var', (88, 98))
236649	16620376	In order to understand the actual functional effect of the mtDNA mutations on susceptibility to cancer and tumorigenic process, functional analysis of mitochondrial bearing such mutations or polymorphisms in a transmitochondrial cybrid system will be necessary.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('mtDNA', 'Gene', (59, 64))	('mutations', 'Var', (178, 187))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (65, 74))
236650	16620376	We used TTGE to scan the entire mitochondrial genome for somatic mtDNA mutations in esophageal cancer, followed by DNA sequencing to identify the exact mutations and found that 55% of the tumors harbored somatic mtDNA mutations.	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (218, 227))	('harbored', 'Reg', (195, 203))	('mutations', 'Var', (71, 80))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mtDNA', 'Gene', (212, 217))	('mtDNA', 'Gene', (65, 70))
236651	16620376	Since reduction in mtDNA content is not the only mechanism leading to down-regulation of mitochondrial function in cancer, the possibility that a mutant protein generated by somatic mtDNA mutation plays a role in tumor formation can not be ruled out.	('tumor', 'Disease', (213, 218))	('cancer', 'Disease', (115, 121))	('mtDNA', 'Gene', (182, 187))	('mutation', 'Var', (188, 196))	('mitochondrial function', 'MPA', (89, 111))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('down-regulation', 'NegReg', (70, 85))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
236654	16620376	Both germline and somatic mtDNA mutations appeared to have effects in modifying cancer risk or are directly involved in the pathogenic mechanism of tumorigenesis.	('effects', 'Reg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (148, 153))	('mutations', 'Var', (32, 41))	('involved', 'Reg', (108, 116))	('mtDNA', 'Gene', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Disease', (80, 86))
236695	33236315	As discussed above, alterations in the ratio of Streptococcus species to gram negative species is associated with reflux-related conditions.	('alterations', 'Var', (20, 31))	('Streptococcus', 'Species', '1328', (48, 61))	('associated', 'Reg', (98, 108))	('reflux-related conditions', 'Disease', (114, 139))
236703	33236315	Interestingly, patients with Helicobacter pylori were found to have a decreased risk of developing EOE.	('patients', 'Species', '9606', (15, 23))	('EOE', 'Disease', (99, 102))	('Helicobacter pylori', 'Var', (29, 48))	('EOE', 'Phenotype', 'HP:0410151', (99, 102))	('decreased', 'NegReg', (70, 79))	('Helicobacter pylori', 'Species', '210', (29, 48))
236707	33236315	PPIs act directly on the proton pumps in the stomach, leading to changes in the acidic environment, which may adversely affect the natural microenvironments of commensal bacteria.	('leading to changes', 'Reg', (54, 72))	('proton pump', 'Gene', (25, 36))	('proton pump', 'Gene', '479', (25, 36))	('PPIs', 'Var', (0, 4))	('acidic environment', 'MPA', (80, 98))
236710	33236315	It is thought that the high gastric pH gives rise to a significant increase in oral bacteria in the stomach, such as such as Pepto-streptococcus stomatis, Streptococcus anginosus, Parvimonas micra, Slackia exigua and Dialister pneumosintes.	('oral bacteria', 'CPA', (79, 92))	('Streptococcus anginosus', 'Disease', (155, 178))	('high', 'Var', (23, 27))	('streptococcus', 'Species', '1328', (131, 144))	('Dialister pneumosintes', 'Species', '39950', (217, 239))	('Parvimonas micra', 'Disease', (180, 196))	('increase', 'PosReg', (67, 75))	('Parvimonas micra', 'Species', '33033', (180, 196))	('Slackia exigua', 'Disease', (198, 212))	('Streptococcus anginosus', 'Species', '1328', (155, 178))	('Slackia exigua', 'Species', '84109', (198, 212))	('Dialister pneumosintes', 'Disease', (217, 239))	('Pepto-streptococcus stomatis', 'Disease', (125, 153))
236711	33236315	A separate study in 2019 by Yi-Chao Shi et al examined the association between PPI use and microbiota in GERD patients versus healthy controls and found that PPI use in GERD patients had lowered relative bacterial diversity of gastric microbiota.	('relative bacterial diversity of gastric microbiota', 'MPA', (195, 245))	('PPI', 'Var', (158, 161))	('patients', 'Species', '9606', (174, 182))	('lowered', 'NegReg', (187, 194))	('patients', 'Species', '9606', (110, 118))
236712	33236315	They reported higher abundances of Planococcaceae, Oxalobacteraceae, and Sphingomonadaceae in the gastric microbiota with PPI use in GERD patients, and decreased abundance of Desulfuromonadaceae and Shewanellaceae compared to non-PPI users.	('decreased', 'NegReg', (152, 161))	('use', 'Var', (126, 129))	('PPI use', 'Var', (122, 129))	('abundances', 'MPA', (21, 31))	('patients', 'Species', '9606', (138, 146))	('higher', 'PosReg', (14, 20))
236759	33544706	Individuals diagnosed with liver cirrhosis (K703) or hepatitis (K746) were also excluded.	('K746', 'Var', (64, 68))	('hepatitis', 'Disease', 'MESH:D056486', (53, 62))	('liver cirrhosis', 'Disease', 'MESH:D008103', (27, 42))	('K703', 'Var', (44, 48))	('liver cirrhosis', 'Disease', (27, 42))	('hepatitis', 'Phenotype', 'HP:0012115', (53, 62))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (27, 42))	('hepatitis', 'Disease', (53, 62))
236765	33544706	The glycemic status was categorized in accordance with FBG (non-DM, FBG < 100 mg/dL; impaired fasting glucose (IFG), 100 <= FBG < 126 mg/dL; and DM, FBG >= 126 mg/dL).	('impaired fasting glucose', 'Disease', (85, 109))	('FBG', 'Disease', (55, 58))	('DM', 'Disease', 'MESH:D009223', (64, 66))	('impaired fasting glucose', 'Disease', 'MESH:D018149', (85, 109))	('impaired fasting glucose', 'Phenotype', 'HP:0040270', (85, 109))	('IFG', 'Chemical', '-', (111, 114))	('DM', 'Disease', 'MESH:D009223', (145, 147))	('100 <=', 'Var', (117, 123))
236804	33544706	Cohort studies from Austria and Sweden revealed that subjects with high serum GGT levels had an increased risk of gastrointestinal cancer, and a meta-analysis found a positive association between serum GGT levels and the risk of gastrointestinal cancer.	('GGT', 'Gene', (78, 81))	('high', 'Var', (67, 71))	('gastrointestinal cancer', 'Disease', (229, 252))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (114, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('GGT', 'Gene', (202, 205))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (229, 252))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (114, 137))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (229, 252))	('GGT', 'Gene', '728441', (78, 81))	('gastrointestinal cancer', 'Disease', (114, 137))	('GGT', 'Gene', '728441', (202, 205))
236884	32776152	We also showed that knockdown of NRF2 or ACSS2 led to decreased ACSS2 expression, which in turn reduced the levels of acetyl-CoA and ATP with or without ethanol exposure.	('ATP', 'Chemical', 'MESH:D000255', (133, 136))	('ethanol', 'Chemical', 'MESH:D000431', (153, 160))	('ATP', 'MPA', (133, 136))	('ACSS2', 'Gene', (64, 69))	('expression', 'MPA', (70, 80))	('decreased', 'NegReg', (54, 63))	('NRF2', 'Gene', (33, 37))	('knockdown', 'Var', (20, 29))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (118, 128))	('ACSS2', 'Gene', (41, 46))	('reduced', 'NegReg', (96, 103))
236896	32776152	Recently, studies on human ESCC samples from China, Japan and Malawi with next-generation sequencing have identified driver mutations of ESCC.	('ESCC', 'Disease', (137, 141))	('mutations', 'Var', (124, 133))	('human', 'Species', '9606', (21, 26))
236901	32776152	Somatic mutations of NRF2, KEAP1, or CUL3 result in the constitutive transcription of NRF2 cytoprotective genes in cancer cells, which leads to increased metabolism, proliferation, and chemoradioresistance in these cells.	('NRF2', 'Gene', (21, 25))	('KEAP1', 'Gene', '9817', (27, 32))	('cancer', 'Disease', (115, 121))	('CUL3', 'Gene', (37, 41))	('CUL3', 'Gene', '8452', (37, 41))	('proliferation', 'CPA', (166, 179))	('constitutive', 'MPA', (56, 68))	('mutations', 'Var', (8, 17))	('NRF2', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('KEAP1', 'Gene', (27, 32))	('chemoradioresistance', 'CPA', (185, 205))	('metabolism', 'MPA', (154, 164))	('leads to', 'Reg', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('increased', 'PosReg', (144, 153))
236902	32776152	NRF2 is mutated in ~10% of ESCC cases, while genes encoding its regulators CUL3 and KEAP1 are mutated in ~3% and 4% of ESCC cases, respectively.	('NRF2', 'Gene', (0, 4))	('CUL3', 'Gene', '8452', (75, 79))	('mutated', 'Var', (8, 15))	('CUL3', 'Gene', (75, 79))	('ESCC', 'Disease', (27, 31))	('KEAP1', 'Gene', '9817', (84, 89))	('KEAP1', 'Gene', (84, 89))
236904	32776152	NRF2 mutations are mostly located in the KEAP1 binding domain at the N-terminus of the NRF2 protein, and therefore decrease the binding affinity of KEAP1 and subsequent degradation of NRF2.	('NRF2', 'Gene', (0, 4))	('degradation', 'MPA', (169, 180))	('KEAP1', 'Gene', '9817', (41, 46))	('KEAP1', 'Gene', '9817', (148, 153))	('mutations', 'Var', (5, 14))	('KEAP1', 'Gene', (41, 46))	('binding', 'Interaction', (128, 135))	('KEAP1', 'Gene', (148, 153))	('decrease', 'NegReg', (115, 123))
236905	32776152	More recently, it has been reported that ESCC patients with high nuclear NRF2 expression have significantly poorer prognosis.	('ESCC', 'Disease', (41, 45))	('NRF2', 'Gene', (73, 77))	('high nuclear', 'Var', (60, 72))	('patients', 'Species', '9606', (46, 54))
236920	32776152	siRNA transfection was done using Lipofectamine RNAiMax (Invitrogen, Waltham, MA), Optimem limited serum media (Gibco), ACSS2 siRNA (AM16708, ID177990, Invitrogen), NFE2L2 siRNA (4392421, IDs9491, Invitrogen), or KEAP1 siRNA (4392420, IDs18982, Invitrogen).	('4392421', 'Var', (179, 186))	('4392420', 'Var', (226, 233))	('NFE2L2', 'Gene', '4780', (165, 171))	('KEAP1', 'Gene', (213, 218))	('AM16708', 'Var', (133, 140))	('NFE2L2', 'Gene', (165, 171))	('Lipofectamine', 'Chemical', 'MESH:C086724', (34, 47))	('Optimem limited serum media', 'Chemical', '-', (83, 110))	('ID177990', 'Var', (142, 150))	('KEAP1', 'Gene', '9817', (213, 218))
236963	32776152	When KYSE70 cells were transfected with NRF2 siRNA, there was a significant decrease in the expression of NRF2, ACSS2, and ACSS3 (Fig.	('ACSS2', 'Gene', (112, 117))	('NRF2', 'Gene', (40, 44))	('ACSS3', 'Gene', '79611', (123, 128))	('transfected', 'Var', (23, 34))	('decrease', 'NegReg', (76, 84))	('ACSS3', 'Gene', (123, 128))	('NRF2', 'Gene', (106, 110))	('expression', 'MPA', (92, 102))
236968	32776152	Sox2CreER;LSL-Nrf2E79Q/+mouse expressed a high level of NRF2 in the esophagus due to the expression of a mutant allele (E79Q) after tamoxifen induction.	('E79Q', 'Var', (120, 124))	('Sox2', 'Gene', (0, 4))	('mouse', 'Species', '10090', (24, 29))	('tamoxifen', 'Chemical', 'MESH:D013629', (132, 141))	('E79Q', 'Mutation', 'rs1057519922', (120, 124))	('Sox2', 'Gene', '20674', (0, 4))	('E79Q', 'Mutation', 'rs1057519922', (18, 22))
236969	32776152	Indeed, ACSS2 was overexpressed in the Sox2CreER;LSL-Nrf2E79Q/+ esophagus (Fig.	('overexpressed', 'PosReg', (18, 31))	('Sox2', 'Gene', (39, 43))	('LSL-Nrf2E79Q/+', 'Var', (49, 63))	('Sox2', 'Gene', '20674', (39, 43))
236970	32776152	Using Western blotting, we confirmed ACSS2 and ACSS3 upregulation in Keap1-/- esophagi as compared to wild-type esophagi (Fig.	('ACSS2', 'Gene', (37, 42))	('ACSS3', 'Gene', '79611', (47, 52))	('upregulation', 'PosReg', (53, 65))	('ACSS3', 'Gene', (47, 52))	('Keap1-/-', 'Var', (69, 77))
236983	32776152	When NRF2 was upregulated in KYSE410 cells, cellular acetate decreased, while acetyl-CoA production increased (Fig.	('acetate', 'Chemical', 'MESH:D000085', (53, 60))	('cellular acetate', 'MPA', (44, 60))	('increased', 'PosReg', (100, 109))	('KYSE410', 'Var', (29, 36))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (78, 88))	('acetyl-CoA production', 'MPA', (78, 99))	('NRF2', 'Gene', (5, 9))	('upregulated', 'PosReg', (14, 25))	('KYSE410', 'CellLine', 'CVCL:1352', (29, 36))	('decreased', 'NegReg', (61, 70))
237000	32776152	5D, NRF2 hyperactivation led to a significant increase in baseline OXPHOS in KYSE410 cells.	('NRF2', 'Gene', (4, 8))	('increase', 'PosReg', (46, 54))	('hyperactivation', 'Var', (9, 24))	('KYSE410', 'CellLine', 'CVCL:1352', (77, 84))	('baseline OXPHOS', 'MPA', (58, 73))
237002	32776152	NRF2 hyperactivation led to increased ECAR, while its downregulation led to decreased ECAR (Fig.	('increased', 'PosReg', (28, 37))	('NRF2', 'Gene', (0, 4))	('downregulation', 'NegReg', (54, 68))	('CA', 'Gene', '12310', (87, 89))	('decreased', 'NegReg', (76, 85))	('CA', 'Gene', '12310', (39, 41))	('hyperactivation', 'Var', (5, 20))
237004	32776152	NRF2 hyperactivation also produced a more energetic phenotype in KYSE410 cells (Fig.	('NRF2', 'Gene', (0, 4))	('more', 'PosReg', (37, 41))	('KYSE410', 'CellLine', 'CVCL:1352', (65, 72))	('energetic phenotype', 'MPA', (42, 61))	('hyperactivation', 'Var', (5, 20))	('KYSE410', 'Var', (65, 72))
237007	32776152	Baseline ECAR was significantly decreased when ACSS2 was either knocked down or when the ACSS2 enzyme was inhibited (Fig.	('knocked down', 'Var', (64, 76))	('CA', 'Gene', '12310', (10, 12))	('ACSS2', 'Gene', (47, 52))	('inhibited', 'NegReg', (106, 115))	('ACSS2', 'Gene', (89, 94))	('decreased', 'NegReg', (32, 41))
237013	32776152	The increase of free fatty acid was significantly decreased when either ACSS2 or NRF2 was knocked down (Fig.	('free fatty acid', 'MPA', (16, 31))	('decreased', 'NegReg', (50, 59))	('knocked', 'Var', (90, 97))	('free fatty acid', 'Chemical', 'MESH:D005230', (16, 31))	('increase', 'PosReg', (4, 12))	('NRF2', 'Gene', (81, 85))	('ACSS2', 'Gene', (72, 77))
237014	32776152	However, NRF2 hyperactivation led to significantly increased lipid synthesis after ethanol exposure (Fig.	('hyperactivation', 'Var', (14, 29))	('ethanol', 'Chemical', 'MESH:D000431', (83, 90))	('increased', 'PosReg', (51, 60))	('lipid synthesis', 'MPA', (61, 76))	('NRF2', 'Gene', (9, 13))	('increased lipid', 'Phenotype', 'HP:0003077', (51, 66))	('lipid', 'Chemical', 'MESH:D008055', (61, 66))
237024	32776152	Previous studies on alcohol-associated cancer have mainly focused on acetaldehyde due to its reactive nature and its ability to induce genetic mutations as well as protein aberrations.	('protein', 'Protein', (164, 171))	('genetic mutations', 'Var', (135, 152))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('induce', 'Reg', (128, 134))	('alcohol', 'Chemical', 'MESH:D000438', (20, 27))	('acetaldehyde', 'Chemical', 'MESH:D000079', (69, 81))
237032	32776152	When ethanol and acetaldehyde contact esophageal epithelial cells, ethanol perturbs the lipid bilayer of the cell membrane and interferes with the function of intrinsic membrane proteins, such as TLR4, Notch, Shh, and Wnt pathway receptors, and thus activates or inhibits downstream signaling.	('interferes', 'NegReg', (127, 137))	('perturbs', 'NegReg', (75, 83))	('intrinsic membrane proteins', 'MPA', (159, 186))	('downstream signaling', 'MPA', (272, 292))	('TLR4', 'Gene', '7099', (196, 200))	('TLR4', 'Gene', (196, 200))	('Wnt pathway', 'Pathway', (218, 229))	('acetaldehyde', 'Chemical', 'MESH:D000079', (17, 29))	('lipid bilayer of the cell membrane', 'MPA', (88, 122))	('ethanol', 'Chemical', 'MESH:D000431', (67, 74))	('Shh', 'Gene', (209, 212))	('ethanol', 'Chemical', 'MESH:D000431', (5, 12))	('activates', 'PosReg', (250, 259))	('lipid bilayer', 'Chemical', 'MESH:D008051', (88, 101))	('ethanol', 'Var', (67, 74))	('function', 'MPA', (147, 155))	('inhibits', 'NegReg', (263, 271))	('Notch', 'Protein', (202, 207))	('Shh', 'Gene', '6469', (209, 212))
237033	32776152	Inside epithelial cells, ethanol metabolism causes oxidative damages to DNA, proteins, and lipids, and modulates fatty acid metabolism as well.	('fatty acid metabolism', 'MPA', (113, 134))	('modulates', 'Reg', (103, 112))	('oxidative damages', 'MPA', (51, 68))	('ethanol metabolism', 'Var', (25, 43))	('fatty acid', 'Chemical', 'MESH:D005227', (113, 123))	('lipids', 'Chemical', 'MESH:D008055', (91, 97))	('proteins', 'Protein', (77, 85))	('DNA', 'MPA', (72, 75))	('ethanol', 'Chemical', 'MESH:D000431', (25, 32))
237039	32776152	Activation of NRF2 prevents ethanol-induced oxidative stress, lipid accumulation, and accelerated acetaldehyde metabolism.	('oxidative stress', 'Phenotype', 'HP:0025464', (44, 60))	('NRF2', 'Gene', (14, 18))	('lipid accumulation', 'MPA', (62, 80))	('acetaldehyde metabolism', 'MPA', (98, 121))	('prevents', 'NegReg', (19, 27))	('acetaldehyde', 'Chemical', 'MESH:D000079', (98, 110))	('lipid', 'Chemical', 'MESH:D008055', (62, 67))	('acetaldehyde metabolism', 'Phenotype', 'HP:0003533', (98, 121))	('oxidative stress', 'MPA', (44, 60))	('Activation', 'Var', (0, 10))	('accelerated', 'PosReg', (86, 97))	('ethanol', 'Chemical', 'MESH:D000431', (28, 35))
237062	32776152	This upregulated lipid synthesis in KYSE70 cells was dependent on the NRF2/ACSS2 axis as shown by the significant decrease in lipid synthesis due to NRF2KD, ACSS2KD or ACSS2 inhibition (Fig.	('upregulated', 'PosReg', (5, 16))	('NRF2KD', 'Gene', (149, 155))	('lipid', 'Chemical', 'MESH:D008055', (126, 131))	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('decrease', 'NegReg', (114, 122))	('ACSS2 inhibition', 'Var', (168, 184))	('ACSS2KD', 'Gene', '55902', (157, 164))	('ACSS2KD', 'Gene', (157, 164))	('NRF2KD', 'Gene', '4780', (149, 155))	('lipid synthesis', 'MPA', (126, 141))
237096	31788277	Arterial blood gas analysis showed pH 7.463 (normal range: pH 7.35-7.45), pCO2 38.4 mm Hg (3-45 mm Hg), pO2 57 mm Hg (83-108 mm Hg), HCO3 27.5 mmol/L (22-26 mmol/L), and O2 saturation on room air 91% (95%-100%).	('O2', 'Chemical', 'MESH:D013481', (76, 78))	('pO2', 'Var', (104, 107))	('pO2', 'Chemical', 'MESH:D013481', (104, 107))	('HCO3', 'Chemical', 'MESH:C504136', (133, 137))	('Hg', 'Chemical', 'MESH:D008628', (87, 89))	('O2', 'Chemical', 'MESH:D013481', (170, 172))	('Hg', 'Chemical', 'MESH:D008628', (128, 130))	('Hg', 'Chemical', 'MESH:D008628', (114, 116))	('O2', 'Chemical', 'MESH:D013481', (105, 107))	('pH 7.463', 'Var', (35, 43))	('Hg', 'Chemical', 'MESH:D008628', (99, 101))	('pCO2', 'Var', (74, 78))
237213	29905337	EUS-RFA induced a decrease in vascularity and central necrosis in the 2 NET patients, but no decrease in tumor diameter was observed.	('patients', 'Species', '9606', (76, 84))	('EUS-RFA', 'Var', (0, 7))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('necrosis', 'Disease', (54, 62))	('decrease', 'NegReg', (18, 26))	('vascularity', 'CPA', (30, 41))	('necrosis', 'Disease', 'MESH:D009336', (54, 62))
237230	29905337	Relevant current procedural technology (CPT) codes for RFA include 43270 (EGD with ablation of tumor, polyp, or other lesion(s) (includes predilation and postdilation and guidewire passage, when performed) and 43229 (esophagoscopy with ablation).	('43270', 'Var', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('43229', 'Var', (210, 215))
237240	29390576	Patients with endoscope traversable cancer showed a significantly higher 3-year overall survival and 3-year relapse-free survival than patients who were endoscope non-traversable (53.8% vs 17.3%, P < .001 and 71.1% vs 45.3%, P = .003, respectively).	('patients', 'Species', '9606', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('overall survival', 'CPA', (80, 96))	('cancer', 'Disease', (36, 42))	('relapse-free', 'CPA', (108, 120))	('endoscope traversable', 'Var', (14, 35))	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
237362	25487184	Primary invasive esophageal cancers were classified according to histologic type as SCC (histology codes 8050-8078, 8083-8084) or adenocarcinoma (histology codes 8140-8141, 8143-8145, 8190-8231, 8260-8263, 8310, 8401, 8480-8490, 8550-8551, 8570-8574, 8576).	('8570-8574', 'Var', (240, 249))	('Primary invasive esophageal cancers', 'Disease', (0, 35))	('adenocarcinoma', 'Disease', (130, 144))	('8401', 'Var', (212, 216))	('SCC', 'Gene', '6317', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (130, 144))	('8143-8145', 'Var', (173, 182))	('8310', 'Var', (206, 210))	('Primary invasive esophageal cancers', 'Disease', 'MESH:D004938', (0, 35))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('8260-8263', 'Var', (195, 204))	('SCC', 'Gene', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('8190-8231', 'Var', (184, 193))	('8550-8551', 'Var', (229, 238))	('8480-8490', 'Var', (218, 227))
237409	25487184	Foreign-born Asian-Americans are more likely to be Helicobacter pylori seropositive than US-born Asians, and there is evidence that the absence of H. pylori may be a risk factor for esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (182, 207))	('Helicobacter pylori', 'Species', '210', (51, 70))	('absence', 'Var', (136, 143))	('H. pylori', 'Gene', (147, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('H. pylori', 'Species', '210', (147, 156))	('esophageal adenocarcinoma', 'Disease', (182, 207))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (182, 207))	('risk', 'Reg', (166, 170))
237429	28430598	In subgroup analysis, SATB1 expression is significantly correlated with poor prognosis in gastrointestinal cancer in Asian population.	('SATB1', 'Gene', (22, 27))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (90, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (90, 113))	('expression', 'Var', (28, 38))	('gastrointestinal cancer', 'Disease', (90, 113))	('SATB1', 'Gene', '6304', (22, 27))
237443	28430598	Overexpression of SATB1 correlated with adverse clinical parameters and poor prognosis.	('SATB1', 'Gene', (18, 23))	('SATB1', 'Gene', '6304', (18, 23))	('Overexpression', 'Var', (0, 14))
237446	28430598	In prostate and bladder cancer, overexpression of SATB1 can induce epithelial-mesenchymal transition (EMT) which leads to cancer cell invasion and metastasis.	('induce', 'PosReg', (60, 66))	('SATB1', 'Gene', (50, 55))	('SATB1', 'Gene', '6304', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('bladder cancer', 'Disease', 'MESH:D001749', (16, 30))	('bladder cancer', 'Disease', (16, 30))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('leads to', 'Reg', (113, 121))	('cancer', 'Disease', (24, 30))	('overexpression', 'Var', (32, 46))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))	('prostate', 'Disease', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('metastasis', 'CPA', (147, 157))	('epithelial-mesenchymal transition', 'CPA', (67, 100))
237449	28430598	Moreover, Fromberg and colleagues reported that knockdown of SATB1 in colorectal cell lines can interfere with numerous gene expressions such as MMP7, VEGF, N-cadherin, Slug, Twist, beta-catenin etc, which involve in proliferation, cell cycle, EMT, invasion and cell survival.	('SATB1', 'Gene', (61, 66))	('SATB1', 'Gene', '6304', (61, 66))	('MMP7', 'Gene', (145, 149))	('beta-catenin', 'Gene', '1499', (182, 194))	('beta-catenin', 'Gene', (182, 194))	('N-cadherin', 'Protein', (157, 167))	('MMP7', 'Gene', '727698', (145, 149))	('Twist', 'MPA', (175, 180))	('VEGF', 'Gene', '493845', (151, 155))	('interfere', 'NegReg', (96, 105))	('VEGF', 'Gene', (151, 155))	('gene expressions', 'MPA', (120, 136))	('knockdown', 'Var', (48, 57))
237466	28430598	However, SATB1 expression was significantly associated with advanced (stage III/IV) TNM stage (1756 patients; pooled OR: 1.81, 95% CI 1.24-2.65, p = 0.002), advanced (T3/T4) T stage (2227 patients; pooled OR: 1.64, 95% CI 1.17-2.29, p = 0.004), lymph node metastasis (2453 patients; pooled OR: 1.73, 95% CI 1.26-2.36, p = 0.0007) and distant metastasis (2042 patients; pooled OR: 1.56, 95% CI 1.00-2.45, p = 0.05) (Figure 7B-7E).	('associated', 'Reg', (44, 54))	('TNM', 'Gene', '10178', (84, 87))	('expression', 'Var', (15, 25))	('TNM', 'Gene', (84, 87))	('lymph node metastasis', 'CPA', (245, 266))	('patients', 'Species', '9606', (273, 281))	('patients', 'Species', '9606', (359, 367))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (100, 108))	('SATB1', 'Gene', (9, 14))	('SATB1', 'Gene', '6304', (9, 14))	('distant metastasis', 'CPA', (334, 352))
237489	28430598	Heterogeneity between studies included: Sohaily found that the association between loss of SATB1expression and poor OS was even stronger in right colon cancer patients, which implied that although colorectal cancer is usually considered as a single disease, differences still exist between right-sided, left-sided, sigmoid and rectal cancer both in clinical and biological aspects, however in Sun et al and Meng et al, they only included rectal cancer patients.	('patients', 'Species', '9606', (452, 460))	('rectal cancer', 'Disease', 'MESH:D012004', (201, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))	('SATB1', 'Gene', '6304', (91, 96))	('SATB1', 'Gene', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('right colon cancer', 'Disease', (140, 158))	('rectal cancer', 'Disease', 'MESH:D012004', (327, 340))	('rectal cancer', 'Disease', 'MESH:D012004', (438, 451))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('loss', 'Var', (83, 87))	('colorectal cancer', 'Disease', 'MESH:D015179', (197, 214))	('rectal cancer', 'Phenotype', 'HP:0100743', (201, 214))	('patients', 'Species', '9606', (159, 167))	('colorectal cancer', 'Disease', (197, 214))	('right colon cancer', 'Disease', 'MESH:D015179', (140, 158))	('poor OS', 'Disease', (111, 118))	('rectal cancer', 'Disease', (327, 340))	('rectal cancer', 'Phenotype', 'HP:0100743', (327, 340))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))	('rectal cancer', 'Disease', (438, 451))	('rectal cancer', 'Phenotype', 'HP:0100743', (438, 451))
237495	28430598	Surprisingly in our subgroup studies, we found that SATB1 expression was positively correlated with poor OS in Asian population (combined HR: 2.00, p < 0.00001).	('poor OS', 'Disease', (100, 107))	('correlated', 'Reg', (84, 94))	('SATB1', 'Gene', '6304', (52, 57))	('expression', 'Var', (58, 68))	('SATB1', 'Gene', (52, 57))
237523	28319436	Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('heart disease', 'Disease', 'MESH:D006331', (292, 305))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('reduces', 'NegReg', (161, 168))	('women', 'Species', '9606', (253, 258))	('heart disease', 'Disease', (292, 305))	('Breast Cancer', 'Disease', 'MESH:D001943', (24, 37))	('cause', 'Reg', (267, 272))	('Breast Cancer', 'Disease', (24, 37))	('cancer', 'Disease', (197, 203))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (282, 288))	('Breast Cancer', 'Phenotype', 'HP:0003002', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('Radiotherapy', 'Var', (148, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
237535	28319436	Tamoxifen can cause endometrial cancer, cytotoxic drugs can cause leukemia, and trastuzumab and anthracyclines can cause cardiac disease.	('cardiac disease', 'Disease', (121, 136))	('cause', 'Reg', (60, 65))	('endometrial cancer', 'Disease', 'MESH:D016889', (20, 38))	('Tamoxifen', 'Var', (0, 9))	('endometrial cancer', 'Phenotype', 'HP:0012114', (20, 38))	('cardiac disease', 'Disease', 'MESH:D006331', (121, 136))	('cause', 'Reg', (14, 19))	('leukemia', 'Disease', (66, 74))	('trastuzumab', 'Chemical', 'MESH:D000068878', (80, 91))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('leukemia', 'Disease', 'MESH:D007938', (66, 74))	('leukemia', 'Phenotype', 'HP:0001909', (66, 74))	('cause', 'Reg', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('anthracyclines', 'Chemical', 'MESH:D018943', (96, 110))	('endometrial cancer', 'Disease', (20, 38))
237567	28319436	The contralateral breast cancer RR was greater in the old trials of orthovoltage (low-energy) radiotherapy (RR, 1.57; 95% CI, 1.24 to 1.99) than in the other trials (RR, 1.12; 95% CI, 1.00 to 1.26; Data Supplement Figs S4, S5).	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('contralateral breast cancer', 'Disease', (4, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (4, 31))	('orthovoltage', 'Var', (68, 80))
237576	28319436	All-cause mortality among women without breast cancer recurrence was increased by radiotherapy (RR, 1.15; 95% CI, 1.09 to 1.22; Table 2; Data Supplement Figs S1-S3, Table S4), predominantly because of cardiac disease (RR, 1.30; 95% CI, 1.15 to 1.46).	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('All-cause mortality', 'MPA', (0, 19))	('increased', 'PosReg', (69, 78))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('women', 'Species', '9606', (26, 31))	('cardiac disease', 'Disease', (201, 216))	('radiotherapy', 'Var', (82, 94))	('cardiac disease', 'Disease', 'MESH:D006331', (201, 216))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
237629	28404917	Silencing of Lgr5 expression in the ESCC cell line KYSE450 by small interfering RNA (siRNA) strongly inhibited cell proliferation, migration and invasion ability, the expression of CSCs-related genes and Wnt/beta-catenin signaling.	('Lgr5', 'Gene', '8549', (13, 17))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('si', 'Chemical', 'MESH:D012825', (149, 151))	('migration', 'CPA', (131, 140))	('expression', 'MPA', (167, 177))	('si', 'Chemical', 'MESH:D012825', (173, 175))	('si', 'Chemical', 'MESH:D012825', (221, 223))	('Silencing', 'Var', (0, 9))	('CSCs-related genes', 'Gene', (181, 199))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('cell proliferation', 'CPA', (111, 129))	('beta-catenin', 'Gene', '1499', (208, 220))	('beta-catenin', 'Gene', (208, 220))	('invasion ability', 'CPA', (145, 161))	('inhibited', 'NegReg', (101, 110))	('Lgr5', 'Gene', (13, 17))
237644	28404917	The Wnt/beta-catenin signaling pathway plays a critical role in the regulation of stem and cancer stem cells, and abnormally activated Wnt/beta-catenin pathway is usually associated with tumorigenesis, including ESCC.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('beta-catenin', 'Gene', (8, 20))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', (91, 97))	('abnormally', 'Var', (114, 124))	('ESCC', 'Disease', (212, 216))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('si', 'Chemical', 'MESH:D012825', (197, 199))	('beta-catenin', 'Gene', (139, 151))	('tumor', 'Disease', (187, 192))	('beta-catenin', 'Gene', '1499', (8, 20))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('beta-catenin', 'Gene', '1499', (139, 151))	('associated', 'Reg', (171, 181))
237651	28404917	Our findings demonstrated that Lgr5 was progressively expressed in esophageal carcinogenesis, and Lgr5 expression promoted cell proliferation, cell migration and invasion, the expression of CSCs-related genes, and activated the Wnt/beta-catenin signaling pathway.	('Lgr5', 'Gene', (31, 35))	('cell proliferation', 'CPA', (123, 141))	('beta-catenin', 'Gene', (232, 244))	('CSCs-related genes', 'Gene', (190, 208))	('expression', 'MPA', (176, 186))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('beta-catenin', 'Gene', '1499', (232, 244))	('invasion', 'CPA', (162, 170))	('Lgr5', 'Gene', '8549', (31, 35))	('si', 'Chemical', 'MESH:D012825', (182, 184))	('Lgr5', 'Gene', (98, 102))	('esophageal carcinogenesis', 'Disease', (67, 92))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('si', 'Chemical', 'MESH:D012825', (245, 247))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (67, 92))	('promoted', 'PosReg', (114, 122))	('expression', 'Var', (103, 113))	('activated', 'PosReg', (214, 223))	('cell migration', 'CPA', (143, 157))	('Lgr5', 'Gene', '8549', (98, 102))
237660	28404917	Kaplan-Meier analysis suggested that prognosis was poor for patients with high Lgr5 expression (Figure 1D).	('si', 'Chemical', 'MESH:D012825', (90, 92))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('high', 'Var', (74, 78))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('patients', 'Species', '9606', (60, 68))	('Lgr5', 'Gene', '8549', (79, 83))	('expression', 'MPA', (84, 94))	('Lgr5', 'Gene', (79, 83))
237667	28404917	The results of qRT-PCR and western blot indicated that the protein and mRNA levels of Lgr5 were elevated in ESCC KYSE450 spheroid body cells, compared with ESCC KYSE450 parental cells.	('Lgr5', 'Gene', (86, 90))	('ESCC KYSE450', 'Var', (108, 120))	('mRNA levels', 'MPA', (71, 82))	('elevated', 'PosReg', (96, 104))	('Lgr5', 'Gene', '8549', (86, 90))	('protein', 'MPA', (59, 66))	('KYSE450', 'Var', (113, 120))
237668	28404917	Flow cytometric analysis revealed that KYSE450 spheroid body cells contained a high proportion of Lgr5+ cells, while parental cells had a smaller Lgr5+ fraction.	('Lgr5', 'Gene', (146, 150))	('Lgr5', 'Gene', '8549', (98, 102))	('Lgr5', 'Gene', '8549', (146, 150))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('Lgr5', 'Gene', (98, 102))	('KYSE450', 'Var', (39, 46))
237692	28404917	The mRNA and protein levels of SOX2, ALDH1A1 and NANOG were reduced in the si-Lgr5 group compared with NC group and CON group, implying that the silencing of Lgr5 in ESCC cells may reduce CSCs properties (Figure 6A).	('si', 'Chemical', 'MESH:D012825', (145, 147))	('SOX2', 'Gene', (31, 35))	('ALDH1A1', 'Gene', '216', (37, 44))	('silencing', 'Var', (145, 154))	('SOX2', 'Gene', '6657', (31, 35))	('Lgr5', 'Gene', '8549', (158, 162))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('NANOG', 'Gene', '79923', (49, 54))	('Lgr5', 'Gene', (78, 82))	('reduce', 'NegReg', (181, 187))	('reduced', 'NegReg', (60, 67))	('CSCs properties', 'CPA', (188, 203))	('NANOG', 'Gene', (49, 54))	('ALDH1A1', 'Gene', (37, 44))	('Lgr5', 'Gene', (158, 162))	('Lgr5', 'Gene', '8549', (78, 82))
237718	28404917	Accumulating data has demonstrated that the silencing of Lgr5 influences the functional and molecular outcome of colorectal cancer cells, breast cancer cells, cervical cancer and ovarian cancer; for example, previous reports indicated that knocking down endogenous Lgr5 in cultured colorectal cancer cell lines reduced their proliferation, migration, invasion, growth rates and colony formation capability.	('Lgr5', 'Gene', '8549', (57, 61))	('colorectal cancer', 'Disease', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('ovarian cancer', 'Disease', (179, 193))	('reduced', 'NegReg', (311, 318))	('migration', 'CPA', (340, 349))	('colony formation capability', 'CPA', (378, 405))	('proliferation', 'CPA', (325, 338))	('ovarian cancer', 'Phenotype', 'HP:0100615', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal cancer', 'Phenotype', 'HP:0003003', (282, 299))	('influences', 'Reg', (62, 72))	('growth rates', 'CPA', (361, 373))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('invasion', 'CPA', (351, 359))	('si', 'Chemical', 'MESH:D012825', (355, 357))	('Lgr5', 'Gene', (265, 269))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('Lgr5', 'Gene', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('breast cancer', 'Disease', (138, 151))	('silencing', 'Var', (44, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (282, 299))	('ovarian cancer', 'Disease', 'MESH:D010051', (179, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('colorectal cancer', 'Disease', (282, 299))	('cervical cancer', 'Disease', 'MESH:D002583', (159, 174))	('Lgr5', 'Gene', '8549', (265, 269))	('cervical cancer', 'Disease', (159, 174))	('knocking down', 'Var', (240, 253))
237719	28404917	In order to investigate the biological role of Lgr5 in ESCC cells, we verified that silencing of Lgr5 could inhibit cell proliferation, migration and invasion, and the levels of CSC-related genes, which act together to promote tumorigenesis and accelerate the progression of ESCC.	('Lgr5', 'Gene', '8549', (47, 51))	('tumor', 'Disease', (227, 232))	('Lgr5', 'Gene', (97, 101))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('si', 'Chemical', 'MESH:D012825', (267, 269))	('silencing', 'Var', (84, 93))	('promote', 'PosReg', (219, 226))	('ESCC', 'Disease', (275, 279))	('accelerate', 'PosReg', (245, 255))	('Lgr5', 'Gene', (47, 51))	('si', 'Chemical', 'MESH:D012825', (237, 239))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('Lgr5', 'Gene', '8549', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('levels', 'MPA', (168, 174))	('inhibit', 'NegReg', (108, 115))	('cell proliferation', 'CPA', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
237726	28404917	In this study, we show that silencing of Lgr5 reduces the expression of beta-catenin and its effector genes cyclinD1 and c-Myc in ESCC cells.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('c-Myc', 'Gene', '4609', (121, 126))	('cyclinD1', 'Gene', (108, 116))	('beta-catenin', 'Gene', (72, 84))	('expression', 'MPA', (58, 68))	('Lgr5', 'Gene', '8549', (41, 45))	('cyclinD1', 'Gene', '595', (108, 116))	('beta-catenin', 'Gene', '1499', (72, 84))	('c-Myc', 'Gene', (121, 126))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('Lgr5', 'Gene', (41, 45))	('silencing', 'Var', (28, 37))	('reduces', 'NegReg', (46, 53))
237761	28404917	Silencing of endogenous Lgr5 was carried out in human esophageal cancer-derived cell lines KYSE450, KYSE70, Eca109 and Eca9706.	('Eca9706', 'CellLine', 'CVCL:E307', (119, 126))	('human', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('Lgr5', 'Gene', '8549', (24, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('Silencing', 'Var', (0, 9))	('Lgr5', 'Gene', (24, 28))
237770	28404917	Total RNA was extracted from pools of parental esophageal cancer-derived cell lines, spheroid body cells, and cells after si-Lgr5 transfection was quantified, using TRIzol reagent (Invitrogen, USA).	('TRIzol', 'Chemical', 'MESH:C411644', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Lgr5', 'Gene', (125, 129))	('transfection', 'Var', (130, 142))	('si', 'Chemical', 'MESH:D012825', (160, 162))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('parental esophageal cancer', 'Disease', 'MESH:D004938', (38, 64))	('Lgr5', 'Gene', '8549', (125, 129))	('parental esophageal cancer', 'Disease', (38, 64))
237777	28404917	Parental cells, spheroid body cells, and cells after si-Lgr5 transfection were lysed as described previously.	('transfection', 'Var', (61, 73))	('Lgr5', 'Gene', (56, 60))	('Lgr5', 'Gene', '8549', (56, 60))	('si', 'Chemical', 'MESH:D012825', (53, 55))
237884	26314845	MMP-14 is not or low expressed in majority of normal tissues, but widely expressed and critical to the acquisition of the invasive and metastatic phenotype of prostate, breast, melanoma and ovarian carcinomas; therefore, targeting MMP-14 is an effective approach to cancer therapy.	('MMP-14', 'Gene', (231, 237))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (190, 208))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('MMP-14', 'Gene', '4323', (0, 6))	('cancer', 'Disease', (266, 272))	('MMP-14', 'Gene', '4323', (231, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('MMP-14', 'Gene', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('breast', 'Disease', (169, 175))	('melanoma and ovarian carcinomas', 'Disease', 'MESH:D008545', (177, 208))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('prostate', 'Disease', (159, 167))	('targeting', 'Var', (221, 230))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))
237886	26314845	Previous studies have shown that when the balance between TIMPs and MMPs is altered, it could bring about the degradation of the extracellular matrix and induce tumor cell invasion, migration or other receptor-mediated changes.	('migration', 'CPA', (182, 191))	('induce', 'Reg', (154, 160))	('bring about', 'Reg', (94, 105))	('MMPs', 'Gene', (68, 72))	('degradation of the extracellular matrix', 'MPA', (110, 149))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('altered', 'Var', (76, 83))	('MMPs', 'Gene', '4313;4323', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
237934	26314845	Determined by the end of the experiment, LDP(AE)-TIMP2 at doses of 0.20 mg/kg, 0.35 mg/kg and 0.50 mg/kg inhibited the growth of KYSE150 xenograft by 64%, 76% and 82%, respectively; while LDM inhibited tumor growth by 60%.	('tumor', 'Disease', (202, 207))	('inhibited', 'NegReg', (105, 114))	('LDP', 'Gene', '10404', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('LDP', 'Gene', (41, 44))	('0.35 mg/kg', 'Var', (79, 89))	('growth', 'CPA', (119, 125))
237938	26314845	As shown in Figure 6C, LDP(AE)-TIMP2 suppressed the growth of HT1080 xenograft by 62%, 70% and 75%, respectively, at doses of 0.20 mg/kg, 0.40 mg/kg and 0.60 mg/kg; while LDM by 49%.	('HT1080', 'Gene', '8872', (62, 68))	('LDP', 'Gene', '10404', (23, 26))	('growth', 'CPA', (52, 58))	('LDP', 'Gene', (23, 26))	('0.40 mg/kg', 'Var', (138, 148))	('HT1080', 'Gene', (62, 68))	('0.20', 'Var', (126, 130))	('suppressed', 'NegReg', (37, 47))
237944	26314845	This provides evidence that TIMP2 can bind to MMP-14 in a unique manner, accordingly, TIMP2 may be able to serve as a MMP-14 directed carrier for targeted drug delivery.	('MMP-14', 'Gene', '4323', (118, 124))	('MMP-14', 'Gene', '4323', (46, 52))	('TIMP2', 'Var', (86, 91))	('MMP-14', 'Gene', (118, 124))	('MMP-14', 'Gene', (46, 52))
237948	26314845	Moreover, uneven or defective vascular system can generate distinct TME, promoting tumor heterogeneity and finally affecting the pre-clinical or clinical therapeutic effects.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('promoting', 'PosReg', (73, 82))	('defective', 'Var', (20, 29))	('tumor', 'Disease', (83, 88))	('affecting', 'Reg', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('pre-clinical or clinical therapeutic effects', 'CPA', (129, 173))
237952	26314845	TIMP2 can reduce the phosphorylation of ERK and AKT, subsequently, suppress endothelial growth and angiogenesis.	('TIMP2', 'Var', (0, 5))	('AKT', 'Gene', (48, 51))	('suppress', 'NegReg', (67, 75))	('phosphorylation', 'MPA', (21, 36))	('ERK', 'Gene', (40, 43))	('ERK', 'Gene', '2048', (40, 43))	('reduce', 'NegReg', (10, 16))	('AKT', 'Gene', '207', (48, 51))
237967	26314845	As shown in Figure 1A, the full gene fragments of the fusion proteins LDP-TIMP2 and TIMP2-LDP mainly consist of the gene encoding TIMP2 (194 amino acids), apoprotein LDP (110 amino acids) and the linker peptide (GlyGlyGlyGlySer)2.	('LDP', 'Gene', (90, 93))	('GlyGlyGlyGlySer', 'Chemical', '-', (212, 227))	('LDP', 'Gene', (70, 73))	('194', 'Var', (137, 140))	('LDP', 'Gene', (166, 169))	('LDP', 'Gene', '10404', (70, 73))	('LDP', 'Gene', '10404', (90, 93))	('LDP', 'Gene', '10404', (166, 169))	('TIMP2', 'Gene', (130, 135))
238050	26021191	When patients with Barrett's are compared to those without, the BE patients have abundant evidence of aberrant acid exposure -longer episodes of acid exposure, and lower pH, and also weak peristaltic contractions and decreased baseline LES tone.	('peristaltic contractions', 'MPA', (188, 212))	('decreased', 'NegReg', (217, 226))	('weak', 'NegReg', (183, 187))	('lower', 'NegReg', (164, 169))	('acid exposure', 'MPA', (145, 158))	('patients', 'Species', '9606', (67, 75))	('patients', 'Species', '9606', (5, 13))	('BE', 'Phenotype', 'HP:0100580', (64, 66))	('acid exposure', 'MPA', (111, 124))	('baseline LES tone', 'MPA', (227, 244))	('episodes of acid exposure', 'Phenotype', 'HP:0004911', (133, 158))	('aberrant', 'Var', (102, 110))
238062	26021191	Edelstein et al, in a case control study in 2007, found that the overall risk of BE was significantly greater in those with high WHR (OR 2.4); the risk of LSBE in these patients was even higher (OR 4.3).	('greater', 'PosReg', (102, 109))	('high WHR', 'Phenotype', 'HP:0031819', (124, 132))	('patients', 'Species', '9606', (169, 177))	('OR 2.4', 'Gene', '26479', (134, 140))	('BE', 'Phenotype', 'HP:0100580', (81, 83))	('LSBE', 'Disease', (155, 159))	('high WHR', 'Var', (124, 132))	('OR 2.4', 'Gene', (134, 140))	('BE', 'Phenotype', 'HP:0100580', (157, 159))
238085	26021191	The presence of the cytotoxin-associated gene (CagA) identifies Hp strains more likely to induce gastritis, more extensive gastric inflammation, and gastric cancer.	('gastric cancer', 'Disease', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CagA', 'Gene', (47, 51))	('gastric inflammation', 'Disease', (123, 143))	('CagA', 'Gene', '6279', (47, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('gastric inflammation', 'Phenotype', 'HP:0005263', (123, 143))	('Hp', 'Species', '210', (64, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('induce', 'Reg', (90, 96))	('gastritis', 'Disease', 'MESH:D005756', (97, 106))	('gastric inflammation', 'Disease', 'MESH:D007249', (123, 143))	('gastritis', 'Phenotype', 'HP:0005263', (97, 106))	('presence', 'Var', (4, 12))	('gastritis', 'Disease', (97, 106))
238117	26021191	In a prospective cohort study design, Abnet et al compared those with BMI 18.5 - 25 (normal body weight) to those with obesity (BMI > 30.0) and found that the risk of EAC was increased by more than a factor of two (HR 2.1).	('obesity', 'Disease', 'MESH:D009765', (119, 126))	('BMI 18.5 - 25', 'Var', (70, 83))	('EAC', 'Phenotype', 'HP:0011459', (167, 170))	('obesity', 'Disease', (119, 126))	('EAC', 'Disease', (167, 170))	('obesity', 'Phenotype', 'HP:0001513', (119, 126))
238142	26021191	Dysplasia in BE is a histologic diagnosis suggesting that epithelial cells have acquired genetic or epigenetic alterations which predispose them to the development of malignancy.	('epigenetic alterations', 'Var', (100, 122))	('genetic', 'Var', (89, 96))	('Dysplasia', 'Disease', 'MESH:D004476', (0, 9))	('men', 'Species', '9606', (159, 162))	('BE', 'Phenotype', 'HP:0100580', (13, 15))	('malignancy', 'Disease', 'MESH:D009369', (167, 177))	('predispose', 'Reg', (129, 139))	('Dysplasia', 'Disease', (0, 9))	('malignancy', 'Disease', (167, 177))
238151	26021191	Furthermore, non-adherence was associated with a significant reduction in dysplasia detection (summary OR 0.53).	('reduction in dysplasia', 'Disease', 'MESH:D015431', (61, 83))	('reduction in dysplasia', 'Disease', (61, 83))	('non-adherence', 'Var', (13, 26))
238185	26021191	Kastelein et al studied the effect of aberrant p53 expression in a nested case-control study and found striking results.	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('aberrant', 'Var', (38, 46))
238188	26021191	LGD alone was far less predictive of progression (RR 2.4, 95% CI: 0.9, 6.0), and the positive predictive value of progression was 15% with LGD alone compared to 33% in patients with both LGD and aberrant p53 expression.	('aberrant', 'Var', (195, 203))	('p53', 'Gene', '7157', (204, 207))	('patients', 'Species', '9606', (168, 176))	('p53', 'Gene', (204, 207))
238194	26021191	In that study, low-grade dysplasia, abnormal DNA ploidy, and Aspergillus oryzae lectin (AOL) were all risk factors for progression.	('low-grade dysplasia', 'Disease', (15, 34))	('Aspergillus oryzae', 'Species', '5062', (61, 79))	('low-grade dysplasia', 'Disease', 'MESH:D008228', (15, 34))	('abnormal', 'Var', (36, 44))
238196	26021191	Another retrospective study found that among 322 patients with BE, aneupoloidy and/or tetraploidy, when assessed by flow cytometry, was associated with a RR of 11.7 for neoplastic progression to cancer.	('tetraploidy', 'Var', (86, 97))	('aneupoloidy', 'Var', (67, 78))	('BE', 'Phenotype', 'HP:0100580', (63, 65))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
238199	26021191	They found that p53 abnormalities detected by immunohistochemistry (OR 17, 95% 3.2, 96) and FISH (OR 7.3, 95% CI: 1.3, 41) were both independent predictors of progression.	('p53', 'Gene', '7157', (16, 19))	('p53', 'Gene', (16, 19))	('abnormalities', 'Var', (20, 33))
238419	23026274	Also, areas of irregularities should be separately biopsied because nodularity is associated with higher risk of prevalent malignancy.	('nodularity', 'Var', (68, 78))	('malignancy', 'Disease', (123, 133))	('malignancy', 'Disease', 'MESH:D009369', (123, 133))
238433	23026274	The length of the BE segment may be a risk factor for progression, with 1 recent multicenter cohort study reporting that the risk of progression in nondysplastic BE subjects with a BE segment greater than 6 cm was significantly higher (0.65% per patient year) compared with those with segment lengths shorter than 6 cm (0.09% per patient year).	('patient', 'Species', '9606', (246, 253))	('men', 'Species', '9606', (24, 27))	('higher', 'PosReg', (228, 234))	('BE', 'Phenotype', 'HP:0100580', (18, 20))	('BE', 'Phenotype', 'HP:0100580', (162, 164))	('greater', 'Var', (192, 199))	('men', 'Species', '9606', (187, 190))	('men', 'Species', '9606', (288, 291))	('patient', 'Species', '9606', (330, 337))	('BE', 'Phenotype', 'HP:0100580', (181, 183))
238437	23026274	The presence of nodularity in the BE segment also portends a higher likelihood of prevalent advanced neoplasia and higher rate of progression to EAC.	('EAC', 'Gene', '1540', (145, 148))	('neoplasia', 'Disease', (101, 110))	('EAC', 'Gene', (145, 148))	('nodularity', 'Var', (16, 26))	('neoplasia', 'Disease', 'MESH:D009369', (101, 110))	('neoplasia', 'Phenotype', 'HP:0002664', (101, 110))	('EAC', 'Phenotype', 'HP:0011459', (145, 148))	('men', 'Species', '9606', (40, 43))	('BE', 'Phenotype', 'HP:0100580', (34, 36))
238445	23026274	Biomarkers studied include loss of heterozygosity (LOH) for chromosome p17, aneuploidy/tetraploidy, and methylation-based markers.	('loss', 'Var', (27, 31))	('p17', 'Gene', (71, 74))	('aneuploidy/tetraploidy', 'Disease', (76, 98))	('p17', 'Gene', '653820', (71, 74))	('aneuploidy/tetraploidy', 'Disease', 'MESH:D057891', (76, 98))
238446	23026274	Patients with aneuploidy or tetraploidy present on biopsy had an increased incidence of 5-year cancer risk than those without, 0% versus 28% respectively.	('aneuploidy', 'Disease', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tetraploidy', 'Var', (28, 39))	('cancer', 'Disease', (95, 101))	('Patients', 'Species', '9606', (0, 8))	('aneuploidy', 'Disease', 'MESH:D000782', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
238448	23026274	One study concluded that subjects with 17p LOH had increased rates of progression to cancer with a relative risk of 16 compared with those with 2 intact 17p alleles.	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('17p LOH', 'Var', (39, 46))
238449	23026274	This same group looked at using a panel of aneuploidy/tetraploidy, 17p LOH, and 9p LOH, and found a 6-year incidence of cancer of 80% for those with all 3 abnormalities, compared with an incidence of 12% at 10 years for those without any abnormalities.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('abnormalities', 'Var', (155, 168))	('aneuploidy/tetraploidy', 'Disease', 'MESH:D057891', (43, 65))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('aneuploidy/tetraploidy', 'Disease', (43, 65))
238451	23026274	Patients with methylation of p16, RUNX3, and HPP1 were shown to have an increased risk of progression to both HGD and EAC.	('HPP1', 'Gene', (45, 49))	('p16', 'Gene', (29, 32))	('EAC', 'Gene', '1540', (118, 121))	('RUNX3', 'Gene', (34, 39))	('RUNX3', 'Gene', '864', (34, 39))	('EAC', 'Gene', (118, 121))	('p16', 'Gene', '1029', (29, 32))	('Patients', 'Species', '9606', (0, 8))	('methylation', 'Var', (14, 25))	('HPP1', 'Gene', '780897', (45, 49))	('HGD', 'Disease', (110, 113))	('EAC', 'Phenotype', 'HP:0011459', (118, 121))
238484	23026274	PDT was shown superior when compared with omeprazole and surveillance in a randomized controlled trial, in terms of reducing the rate of progression to EAC and eliminating HGD.	('EAC', 'Gene', '1540', (152, 155))	('reducing', 'NegReg', (116, 124))	('PDT', 'Var', (0, 3))	('EAC', 'Gene', (152, 155))	('omeprazole', 'Chemical', 'MESH:D009853', (42, 52))	('HGD', 'Disease', (172, 175))	('EAC', 'Phenotype', 'HP:0011459', (152, 155))
238487	23026274	In this randomized controlled trial, RFA was well tolerated, with only 6% of patients developing strictures; additionally, in those treated with RFA, the rate of progression to EAC was reduced in the RFA arm compared with the sham arm.	('EAC', 'Gene', '1540', (177, 180))	('RFA', 'Var', (145, 148))	('EAC', 'Gene', (177, 180))	('RFA', 'Var', (200, 203))	('patients', 'Species', '9606', (77, 85))	('EAC', 'Phenotype', 'HP:0011459', (177, 180))	('reduced', 'NegReg', (185, 192))
238502	23026274	There are some nonrandomized observational studies showing that PPIs may reduce the rate of progression in BE and patients who use them have an overall lower incidence of EAC; however, it is currently not recommended to use doses of PPIs over the amount needed to prevent symptomatic reflux as a form of chemoprevention.	('men', 'Species', '9606', (210, 213))	('EAC', 'Phenotype', 'HP:0011459', (171, 174))	('PPIs', 'Var', (64, 68))	('lower', 'NegReg', (152, 157))	('EAC', 'Gene', '1540', (171, 174))	('patients', 'Species', '9606', (114, 122))	('EAC', 'Gene', (171, 174))	('reduce', 'NegReg', (73, 79))	('BE', 'Phenotype', 'HP:0100580', (107, 109))
238520	22815788	MiR-214 was the most upregulated (150 fold) and miR-146b-5b, 146a, 145, 142-3p and 21 were upregulated by at least 10 fold.	('MiR-214', 'Gene', (0, 7))	('miR-146b', 'Gene', (48, 56))	('145', 'Var', (67, 70))	('upregulated', 'PosReg', (21, 32))	('miR-146b', 'Gene', '574447', (48, 56))	('146a', 'Var', (61, 65))	('MiR-214', 'Gene', '406996', (0, 7))
238521	22815788	Out of 12 miRNAs chosen for validation by qRT-PCR, five (miR-214, 146b-5p, 146a, 142-3p and 21) were confirmed and 11 shared the same trend.	('miR-214', 'Gene', (57, 64))	('146a', 'Var', (75, 79))	('miR-214', 'Gene', '406996', (57, 64))
238548	22815788	Five miRNAs (miR-214, miR-146b-5p, miR-146a, miR-142-3p and miR-21) were confirmed with statistical significance (P-value <0.05) and 11 of the miRNAs (except miR489) shared the same regulatory trends (Table 3 and Figure 2).	('miR-214', 'Gene', '406996', (13, 20))	('miR489', 'Gene', (158, 164))	('miR-146b', 'Gene', '574447', (22, 30))	('miR-21', 'Gene', (13, 19))	('miR-142-3p', 'Var', (45, 55))	('miR-214', 'Gene', (13, 20))	('miR-146a', 'Gene', (35, 43))	('miR489', 'Gene', '574442', (158, 164))	('miR-21', 'Gene', '406991', (60, 66))	('miR-21', 'Gene', '406991', (13, 19))	('miR-146b', 'Gene', (22, 30))	('miR-21', 'Gene', (60, 66))	('miR-146a', 'Gene', '406938', (35, 43))
238560	22815788	The differential expression of certain of these miRNAs such as miR-214, miR-142-3p and miR-29b appear to be influenced much more significantly by the treatment as opposed to the allergic process alone.	('influenced', 'Reg', (108, 118))	('miR-142-3p', 'Var', (72, 82))	('miR-29b', 'Gene', '407024', (87, 94))	('differential expression', 'MPA', (4, 27))	('miR-214', 'Gene', '406996', (63, 70))	('miR-29b', 'Gene', (87, 94))	('miR-214', 'Gene', (63, 70))
238595	22815788	The identified gene expression changes provide additional diagnostic and therapeutic targets for EoE and other eosinophilic epithelial diseases.	('eosinophilic epithelial diseases', 'Disease', 'MESH:D004802', (111, 143))	('EoE', 'Disease', (97, 100))	('eosinophilic epithelial diseases', 'Disease', (111, 143))	('changes', 'Var', (31, 38))
238767	33907415	Silencing of LINC00184 significantly suppressed OC cell growth and cisplatin resistance in vivo (p<0.01).	('LINC00184', 'Gene', '100302691', (13, 22))	('OC', 'Phenotype', 'HP:0100615', (48, 50))	('cisplatin resistance', 'MPA', (67, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('Silencing', 'Var', (0, 9))	('LINC00184', 'Gene', (13, 22))	('suppressed', 'NegReg', (37, 47))
238768	33907415	LINC00184 silencing inhibited Ki67 and CNTN1 expression and promoted apoptosis of xenograft tumors.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('promoted', 'PosReg', (60, 68))	('LINC00184', 'Gene', '100302691', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Ki67', 'Gene', (30, 34))	('expression', 'MPA', (45, 55))	('inhibited', 'NegReg', (20, 29))	('apoptosis', 'CPA', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('silencing', 'Var', (10, 19))	('LINC00184', 'Gene', (0, 9))	('tumors', 'Disease', (92, 98))	('CNTN1', 'Gene', (39, 44))
238783	33907415	Miao et al demonstrated that the silencing of lncRNA ANRIL enhanced OC cell apoptosis and cisplatin sensitivity by targeting the let-7a/HMGA2 axis.	('ANRIL', 'Gene', (53, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('HMGA2', 'Gene', '8091', (136, 141))	('OC', 'Phenotype', 'HP:0100615', (68, 70))	('silencing', 'Var', (33, 42))	('enhanced', 'PosReg', (59, 67))	('HMGA2', 'Gene', (136, 141))	('cisplatin sensitivity', 'MPA', (90, 111))	('ANRIL', 'Gene', '100048912', (53, 58))	('targeting', 'Reg', (115, 124))
238784	33907415	MALAT-1 knockdown promoted cisplatin sensitivity in OC cells by suppressing the Notch1 signaling pathway.	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('suppressing', 'NegReg', (64, 75))	('knockdown', 'Var', (8, 17))	('Notch1', 'Gene', (80, 86))	('MALAT-1', 'Gene', '378938', (0, 7))	('Notch1', 'Gene', '4851', (80, 86))	('cisplatin sensitivity', 'MPA', (27, 48))	('OC', 'Phenotype', 'HP:0100615', (52, 54))	('promoted', 'PosReg', (18, 26))	('MALAT-1', 'Gene', (0, 7))
238789	33907415	High expression of LINC00184 is associated with a worse 10-year survival for patients with breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('High', 'Var', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('LINC00184', 'Gene', (19, 28))	('patients', 'Species', '9606', (77, 85))	('worse', 'NegReg', (50, 55))	('LINC00184', 'Gene', '100302691', (19, 28))
238820	33907415	A2780-DDP, SKOV3-DDP, A2780 and SKOV3 cells were plated in six-well plates with 1x105 cells per well.	('A2780', 'Var', (22, 27))	('SKOV3', 'CellLine', 'CVCL:0532', (11, 16))	('A2780-DDP', 'Var', (0, 9))	('SKOV3', 'CellLine', 'CVCL:0532', (32, 37))
238825	33907415	miR-1305 mimic and negative control (miR-NC) (GenePharma, Shanghai, China) were applied to transfect A2780 and SKOV3 cells.	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('transfect', 'Var', (91, 100))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('miR-1305', 'Gene', (0, 8))	('miR-1305', 'Gene', '100302270', (0, 8))	('SKOV3', 'CellLine', 'CVCL:0532', (111, 116))
238827	33907415	A2780-DDP cells underwent cotransfection with siNC and NC-inh, or siLINC00184 and NC-inh, or siLINC00184 and miR-1305 inhibitor.	('siNC', 'Chemical', 'MESH:C052464', (46, 50))	('miR-1305', 'Gene', (109, 117))	('A2780-DDP', 'Var', (0, 9))	('LINC00184', 'Gene', '100302691', (95, 104))	('miR-1305', 'Gene', '100302270', (109, 117))	('LINC00184', 'Gene', '100302691', (68, 77))	('LINC00184', 'Gene', (95, 104))	('LINC00184', 'Gene', (68, 77))
238914	33907415	In addition, LINC00184 expression in A2780, SKOV3, A2780-DDP and SKOV3-DDP cell lines was remarkably more up-regulated than that in the IOSE80 cell line (p<0.01).	('SKOV3', 'CellLine', 'CVCL:0532', (44, 49))	('LINC00184', 'Gene', '100302691', (13, 22))	('A2780', 'Var', (37, 42))	('SKOV3', 'CellLine', 'CVCL:0532', (65, 70))	('A2780-DDP', 'Var', (51, 60))	('up-regulated', 'PosReg', (106, 118))	('LINC00184', 'Gene', (13, 22))	('expression', 'MPA', (23, 33))
238915	33907415	Notably, A2780-DDP and SKOV3-DDP cell lines exhibited markedly more up-regulated LINC00184 expression than that in A2780 and SKOV3 cell lines (p<0.01) (Figure 1D).	('expression', 'MPA', (91, 101))	('SKOV3', 'CellLine', 'CVCL:0532', (23, 28))	('LINC00184', 'Gene', '100302691', (81, 90))	('LINC00184', 'Gene', (81, 90))	('up-regulated', 'PosReg', (68, 80))	('SKOV3', 'CellLine', 'CVCL:0532', (125, 130))	('A2780-DDP', 'Var', (9, 18))
238922	33907415	As shown in Figure 2B, SKOV3, SKOV3-DDP, A2780 and A2780-DDP cells were resistant to cisplatin in a dose-dependent manner.	('resistant', 'MPA', (72, 81))	('SKOV3', 'CellLine', 'CVCL:0532', (23, 28))	('A2780', 'Var', (41, 46))	('SKOV3', 'CellLine', 'CVCL:0532', (30, 35))	('A2780-DDP', 'Var', (51, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
238923	33907415	Notably, the IC50 values for SKOV3, SKOV3-DDP, A2780 and A2780-DDP cells were 44.49, 192.5, 14.39 and 109.5 muM, respectively.	('SKOV3', 'CellLine', 'CVCL:0532', (29, 34))	('A2780-DDP', 'Var', (57, 66))	('SKOV3', 'CellLine', 'CVCL:0532', (36, 41))	('A2780', 'Var', (47, 52))
238925	33907415	For A2780-DDP and SKOV3-DDP cells, obviously decreased proliferation was found in the siLINC00184 group and siNC + cisplatin group compared with the siNC group (p<0.01).	('LINC00184', 'Gene', '100302691', (88, 97))	('siNC', 'Chemical', 'MESH:C052464', (149, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('proliferation', 'CPA', (55, 68))	('decreased', 'NegReg', (45, 54))	('A2780-DDP', 'Var', (4, 13))	('LINC00184', 'Gene', (88, 97))	('SKOV3', 'CellLine', 'CVCL:0532', (18, 23))	('siNC', 'Chemical', 'MESH:C052464', (108, 112))
238927	33907415	For A2780 and SKOV3 cells, relative to the oeNC group, the proliferation was greatly increased in the oeLINC00184 group and significantly deceased in the oeNC + cisplatin group (p<0.01).	('proliferation', 'CPA', (59, 72))	('A2780', 'Var', (4, 9))	('deceased', 'NegReg', (138, 146))	('LINC00184', 'Gene', (104, 113))	('SKOV3', 'CellLine', 'CVCL:0532', (14, 19))	('increased', 'PosReg', (85, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('LINC00184', 'Gene', '100302691', (104, 113))
238929	33907415	For A2780-DDP and SKOV3-DDP cells, the siLINC00184 group and siNC + cisplatin group exhibited markedly higher apoptotic ratios than the siNC group (p<0.05 or p<0.01).	('LINC00184', 'Gene', (41, 50))	('apoptotic ratios', 'CPA', (110, 126))	('siNC', 'Chemical', 'MESH:C052464', (136, 140))	('siNC', 'Chemical', 'MESH:C052464', (61, 65))	('A2780-DDP', 'Var', (4, 13))	('LINC00184', 'Gene', '100302691', (41, 50))	('SKOV3', 'CellLine', 'CVCL:0532', (18, 23))	('higher', 'PosReg', (103, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
238931	33907415	For A2780 and SKOV3 cells, compared to the oeNC group, the apoptotic ratio was remarkably decreased in the oeLINC00184 group and markedly increased in the oeNC + cisplatin group (p<0.01).	('A2780', 'Var', (4, 9))	('increased', 'PosReg', (138, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('LINC00184', 'Gene', '100302691', (109, 118))	('decreased', 'NegReg', (90, 99))	('apoptotic ratio', 'CPA', (59, 74))	('LINC00184', 'Gene', (109, 118))	('SKOV3', 'CellLine', 'CVCL:0532', (14, 19))
238940	33907415	A2780-DDP and SKOV3-DDP cells of the siLINC00184 group showed significantly increased miR-1305 expression compared with those of the siNC group (p <0.01).	('miR-1305', 'Gene', (86, 94))	('LINC00184', 'Gene', '100302691', (39, 48))	('miR-1305', 'Gene', '100302270', (86, 94))	('increased', 'PosReg', (76, 85))	('A2780-DDP', 'Var', (0, 9))	('siNC', 'Chemical', 'MESH:C052464', (133, 137))	('LINC00184', 'Gene', (39, 48))	('SKOV3', 'CellLine', 'CVCL:0532', (14, 19))	('expression', 'MPA', (95, 105))
238948	33907415	For A2780 and SKOV3 cells of the miR-1305 mimic group, CNTN1 protein expression was aberrantly down-regulated compared with that of the miR-NC group (p<0.01) (Figure 4C).	('miR', 'Gene', '220972', (33, 36))	('A2780', 'Var', (4, 9))	('miR', 'Gene', (33, 36))	('down-regulated', 'NegReg', (95, 109))	('miR-1305', 'Gene', '100302270', (33, 41))	('miR', 'Gene', '220972', (136, 139))	('miR-1305', 'Gene', (33, 41))	('miR', 'Gene', (136, 139))	('SKOV3', 'CellLine', 'CVCL:0532', (14, 19))	('CNTN1', 'Gene', (55, 60))	('protein', 'Protein', (61, 68))
238949	33907415	In contrast, seriously up-regulated CNTN1 protein expression was observed in A2780-DDP and SKOV3-DDP cells of the oeLINC00184 group relative to the oeNC group (p<0.01) (Figure 4D).	('CNTN1', 'Gene', (36, 41))	('A2780-DDP', 'Var', (77, 86))	('LINC00184', 'Gene', '100302691', (116, 125))	('SKOV3', 'CellLine', 'CVCL:0532', (91, 96))	('LINC00184', 'Gene', (116, 125))	('up-regulated', 'PosReg', (23, 35))	('expression', 'MPA', (50, 60))
238955	33907415	For A2780-DDP cells of the siLINC00184 + NC-inh group, the CNTN1 protein expression was markedly decreased compared with that of the siNC group, NC-inh group and siNC + NC-inh group (p<0.01).	('LINC00184', 'Gene', '100302691', (29, 38))	('LINC00184', 'Gene', (29, 38))	('siNC', 'Chemical', 'MESH:C052464', (133, 137))	('CNTN1', 'Gene', (59, 64))	('A2780-DDP', 'Var', (4, 13))	('decreased', 'NegReg', (97, 106))	('siNC', 'Chemical', 'MESH:C052464', (162, 166))
238956	33907415	Relative to the siLINC00184 + NC-inh group, significantly increased CNTN1 protein expression was found in A2780-DDP cells of the siLINC00184 + miR-1305 inhibitor group (p<0.01) (Figure 5A).	('LINC00184', 'Gene', (18, 27))	('increased', 'PosReg', (58, 67))	('LINC00184', 'Gene', (131, 140))	('A2780-DDP', 'Var', (106, 115))	('CNTN1', 'Gene', (68, 73))	('LINC00184', 'Gene', '100302691', (18, 27))	('miR-1305', 'Gene', '100302270', (143, 151))	('LINC00184', 'Gene', '100302691', (131, 140))	('miR-1305', 'Gene', (143, 151))
238972	33907415	CNTN1 protein expression in xenograft tumors of the shNC + cisplatin group was much higher than in the shLINC00184 + cisplatin group (p<0.01) (Figure 6C).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('protein', 'Protein', (6, 13))	('tumors', 'Disease', (38, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('LINC00184', 'Gene', '100302691', (105, 114))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('CNTN1', 'Gene', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('expression', 'MPA', (14, 24))	('LINC00184', 'Gene', (105, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('shNC', 'Var', (52, 56))	('higher', 'PosReg', (84, 90))
238977	33907415	Conversely, much lower CNTN1 protein expression was found in A2780-DDP and SKOV3-DDP cells of the siCNTN1 group relative to the siCtrl group (p<0.01).	('A2780-DDP', 'Var', (61, 70))	('siCNTN1', 'Gene', (98, 105))	('lower', 'NegReg', (17, 22))	('SKOV3', 'CellLine', 'CVCL:0532', (75, 80))	('CNTN1 protein', 'Protein', (23, 36))	('expression', 'MPA', (37, 47))
238979	33907415	However, A2780 and SKOV3 cells of the oeCtrl + cisplatin group displayed obviously lower proliferation than those of the oeCtrl group (p<0.01).	('proliferation', 'CPA', (89, 102))	('SKOV3 cells', 'CPA', (19, 30))	('SKOV3', 'CellLine', 'CVCL:0532', (19, 24))	('lower', 'NegReg', (83, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('A2780', 'Var', (9, 14))
238981	33907415	In addition, the proliferation was remarkably decreased in A2780-DDP and SKOV3-DDP cells of the siCNTN1 group and siCtrl + cisplatin group relative to the siCtrl group (p<0.05 or p<0.01).	('proliferation', 'CPA', (17, 30))	('SKOV3', 'CellLine', 'CVCL:0532', (73, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('A2780-DDP', 'Var', (59, 68))	('siCNTN1', 'Gene', (96, 103))	('decreased', 'NegReg', (46, 55))
238983	33907415	For A2780 and SKOV3 cells, significantly lower apoptosis in the oeCNTN1 group and higher apoptosis in the oeCtrl + cisplatin group occurred compared with the oeCtrl group (p<0.01).	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('A2780', 'Var', (4, 9))	('SKOV3', 'CellLine', 'CVCL:0532', (14, 19))	('lower', 'NegReg', (41, 46))
238985	33907415	For A2780-DDP and SKOV3-DDP cells, dramatically higher apoptosis was exhibited in the siCNTN1 group and siCtrl + cisplatin group compared with the siCtrl group (p<0.01).	('A2780-DDP', 'Var', (4, 13))	('siCNTN1', 'Gene', (86, 93))	('higher', 'PosReg', (48, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('SKOV3', 'CellLine', 'CVCL:0532', (18, 23))	('apoptosis', 'CPA', (55, 64))
238986	33907415	However, in comparison with the siCNTN1 group, apoptosis was distinctly increased in A2780-DDP and SKOV3-DDP cells of the siCNTN1 + cisplatin group (p<0.01) (Figure 7F).	('increased', 'PosReg', (72, 81))	('A2780-DDP', 'Var', (85, 94))	('apoptosis', 'CPA', (47, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('SKOV3', 'CellLine', 'CVCL:0532', (99, 104))
239002	33907415	LINC00184 silencing inhibited the malignant phenotype of A2780 and A2780-DDP cells, including reducing proliferation and enhancing apoptosis.	('A2780-DDP', 'Var', (67, 76))	('LINC00184', 'Gene', (0, 9))	('malignant phenotype', 'CPA', (34, 53))	('LINC00184', 'Gene', '100302691', (0, 9))	('enhancing', 'PosReg', (121, 130))	('inhibited', 'NegReg', (20, 29))	('apoptosis', 'CPA', (131, 140))	('reducing', 'NegReg', (94, 102))	('A2780', 'Var', (57, 62))	('silencing', 'Var', (10, 19))
239003	33907415	However, the transfection with miR-1305 inhibitor reversed these effects on A2780 and A2780-DDP cells.	('miR-1305', 'Gene', '100302270', (31, 39))	('A2780-DDP', 'Var', (86, 95))	('miR-1305', 'Gene', (31, 39))
239012	33907415	It is worth noting that miR-1305 inhibition reversed the inhibiting effect of LINC00184 knockdown on OC progression.	('inhibiting', 'NegReg', (57, 67))	('miR-1305', 'Gene', (24, 32))	('LINC00184', 'Gene', '100302691', (78, 87))	('LINC00184', 'Gene', (78, 87))	('knockdown', 'Var', (88, 97))	('miR-1305', 'Gene', '100302270', (24, 32))	('OC', 'Phenotype', 'HP:0100615', (101, 103))
239018	33907415	High expression of CNTN1 was associated with poor overall survival and disease-free survival in hepatocellular carcinoma patients.	('disease-free survival', 'CPA', (71, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('hepatocellular carcinoma', 'Disease', (96, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('High', 'Var', (0, 4))	('overall survival', 'CPA', (50, 66))	('poor', 'NegReg', (45, 49))	('patients', 'Species', '9606', (121, 129))	('CNTN1', 'Gene', (19, 24))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))
239032	33907415	LINC00184 silencing could promote apoptosis and weaken proliferation and cisplatin resistance of OC cells both in vitro and in vivo.	('promote', 'PosReg', (26, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('OC', 'Phenotype', 'HP:0100615', (97, 99))	('LINC00184', 'Gene', '100302691', (0, 9))	('proliferation', 'CPA', (55, 68))	('weaken', 'NegReg', (48, 54))	('apoptosis', 'CPA', (34, 43))	('cisplatin resistance', 'MPA', (73, 93))	('LINC00184', 'Gene', (0, 9))	('silencing', 'Var', (10, 19))
239040	32578508	Overall survival was higher in patients who had received radiation therapy than in patients who did not receive radiation therapy (hazard ratio: 3.574; 95% CI: 1.501-8.510; P = .002).	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (31, 39))	('higher', 'PosReg', (21, 27))	('radiation therapy', 'Var', (57, 74))	('Overall survival', 'MPA', (0, 16))
239050	32578508	In the presence of molecular oxygen, the energy transfer can lead to a series of photochemical reactions and generation of various cytotoxic species and other reactive oxygen species, and consequently induce apoptosis and/or necrosis of targeted lesion.	('apoptosis', 'CPA', (208, 217))	('lead to', 'Reg', (61, 68))	('oxygen', 'Chemical', 'MESH:D010100', (168, 174))	('necrosis', 'Disease', (225, 233))	('induce', 'Reg', (201, 207))	('oxygen', 'Chemical', 'MESH:D010100', (29, 35))	('energy transfer', 'Var', (41, 56))	('necrosis', 'Disease', 'MESH:D009336', (225, 233))	('photochemical reactions', 'MPA', (81, 104))	('cytotoxic species', 'MPA', (131, 148))
239055	32578508	The main components are hematoporphyrin, porphyrin polymer, hydroxyethyl-vinylporphyrin, and a small amount of protoporphyrin.	('porphyrin polymer', 'Protein', (41, 58))	('hydroxyethyl-vinylporphyrin', 'Chemical', '-', (60, 87))	('hydroxyethyl-vinylporphyrin', 'Var', (60, 87))	('porphyrin polymer', 'Chemical', '-', (41, 58))	('protoporphyrin', 'Chemical', 'MESH:C028025', (111, 125))	('hematoporphyrin', 'Chemical', 'MESH:D006415', (24, 39))
239058	32578508	The inclusion criteria (1) ineligible for surgery or RT, (2) recurrence after surgery or RT, (3) any reason for refusing surgery or RT, (4) advanced esophageal cancer (T3-4N1-3M0, Union for International Cancer Control [UICC] seventh), (5) received PDT in our institution, and (6) signed the PDT research consent form.	('advanced', 'Reg', (140, 148))	('T3-4N1-3M0', 'Var', (168, 178))	('Cancer', 'Phenotype', 'HP:0002664', (204, 210))	('esophageal cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('Cancer', 'Disease', (204, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('Cancer', 'Disease', 'MESH:D009369', (204, 210))
239059	32578508	The exclusion criteria (1) early esophageal cancer (T1-2N0-1M0, UICC seventh), (2) did not receive PDT in our institution, and (3) underwent esophageal stenting.	('esophageal cancer', 'Disease', (33, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('T1-2N0-1M0', 'Var', (52, 62))
239118	32578508	The dysphagia score for all patients decreased from 3.43 +- 0.73 to 1.79 +- 0.53 one month after PDT (P < .05).	('dysphagia', 'Disease', (4, 13))	('dysphagia', 'Phenotype', 'HP:0002015', (4, 13))	('dysphagia', 'Disease', 'MESH:D003680', (4, 13))	('PDT', 'Var', (97, 100))	('patients', 'Species', '9606', (28, 36))	('decreased', 'NegReg', (37, 46))
239126	32578508	Patients with KPS score >=80 had greater OS than patients with KPS score <80 (hazard ratio [HR]: 2.626; 95% CI: 1.091-6.322; P = .024; Figure 3).	('Patients', 'Species', '9606', (0, 8))	('KPS score >=80', 'Var', (14, 28))	('greater', 'PosReg', (33, 40))	('patients', 'Species', '9606', (49, 57))
239131	32578508	Li et al  conducted a controlled study of 90 patients with stage III and IV esophageal cancer, including 27 patients who underwent PDT (group A), 33 patients who were treated with PDT plus chemotherapy (group B), and 30 patients treated with chemotherapy (group C).	('patients', 'Species', '9606', (149, 157))	('esophageal cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('patients', 'Species', '9606', (220, 228))	('patients', 'Species', '9606', (45, 53))	('PDT', 'Var', (131, 134))	('patients', 'Species', '9606', (108, 116))
239146	32578508	Yoon et al  reported that 4 weeks after PDT, 90% of patients observed a significant improvement in dysphagia grading scores from 2.75 +- 0.91 to 1.05 +- 0.83 (P < .05).	('PDT', 'Var', (40, 43))	('dysphagia', 'Disease', 'MESH:D003680', (99, 108))	('dysphagia', 'Disease', (99, 108))	('patients', 'Species', '9606', (52, 60))	('dysphagia', 'Phenotype', 'HP:0002015', (99, 108))
239148	32578508	Many studies have observed that PDT can improve patients' quality of life and prolong their survival.	('survival', 'CPA', (92, 100))	('quality of life', 'CPA', (58, 73))	('PDT', 'Var', (32, 35))	('prolong', 'NegReg', (78, 85))	('patients', 'Species', '9606', (48, 56))	('improve', 'PosReg', (40, 47))
239156	32578508	Patients with high KPS score generally have better tolerance to PDT, which thus provides survival benefits.	('better', 'PosReg', (44, 50))	('tolerance', 'MPA', (51, 60))	('benefits', 'PosReg', (98, 106))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('survival', 'MPA', (89, 97))	('KPS', 'Gene', (19, 22))
239187	31516617	Chang et al found that the high expression of TPX2 in cervical cancer cells causes a more active proliferation of cancer cells and predicts the deterioration of cervical cancer, leading to speculation that the high expression of TPX2 may be a tumorigenic mechanism.	('TPX2', 'Gene', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tumor', 'Disease', (243, 248))	('cancer', 'Disease', (170, 176))	('more', 'PosReg', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('high', 'Var', (27, 31))	('active proliferation', 'CPA', (90, 110))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('deterioration of cervical cancer', 'Disease', 'MESH:D002583', (144, 176))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('deterioration of cervical cancer', 'Disease', (144, 176))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('cancer', 'Disease', (114, 120))
239189	31516617	NIK-IKK-beta binding protein (NIBP), which has gained attention in the medical field, is highly expressed in various tumor tissues such as colon, gastric, and esophageal cancer, and has proved to promote the proliferation and invasion of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('NIK-IKK-beta', 'Var', (0, 12))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('colon', 'Disease', 'MESH:D015179', (139, 144))	('promote', 'PosReg', (196, 203))	('esophageal cancer', 'Disease', (159, 176))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('proliferation', 'CPA', (208, 221))	('gastric', 'Disease', (146, 153))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('colon', 'Disease', (139, 144))
239190	31516617	In their study on NIBP expression in colon cancer, Xu et al found that NIBP is overexpressed in colon cancer, and patients with high NIBP expression have much lower overall survival than patients with lower levels of NIBP.	('patients', 'Species', '9606', (187, 195))	('colon cancer', 'Phenotype', 'HP:0003003', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colon cancer', 'Disease', 'MESH:D015179', (37, 49))	('colon cancer', 'Disease', (37, 49))	('NIBP', 'Gene', (133, 137))	('lower', 'NegReg', (159, 164))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('high', 'Var', (128, 132))	('overall survival', 'MPA', (165, 181))	('patients', 'Species', '9606', (114, 122))	('colon cancer', 'Disease', (96, 108))
239247	31516617	Hsu et al found that high expression of TPX2 is an independent prognostic factor for patients with esophageal cancer, and knocking down TPX2 levels can significantly suppress cancer cell proliferation.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('TPX2', 'Gene', (40, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('suppress', 'NegReg', (166, 174))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('TPX2', 'Gene', (136, 140))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('knocking down', 'Var', (122, 135))	('esophageal cancer', 'Disease', (99, 116))
239248	31516617	Liu et al discovered that high expression of TPX2 is a risk factor for lymph node metastasis of esophageal carcinoma, and TPX2 can be used as a biomarker for early diagnosis and prognosis of esophageal cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('high expression', 'Var', (26, 41))	('risk factor', 'Reg', (55, 66))	('esophageal carcinoma', 'Disease', (96, 116))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (96, 116))	('lymph', 'Disease', (71, 76))	('TPX2', 'Gene', (45, 49))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (96, 116))	('esophageal cancer', 'Disease', (191, 208))
239249	31516617	In this study, TPX2 expression was upregulated in cancer tissues, and TPX2 expression was closely related to tumor TNM grade, lymph node metastasis and degree of infiltration; TPX2 was a risk factor for lymph node metastasis of esophageal cancer, similar to the above results.	('TPX2', 'Var', (176, 180))	('cancer', 'Disease', (50, 56))	('TPX2', 'Gene', (15, 19))	('expression', 'MPA', (20, 30))	('lymph node metastasis of esophageal cancer', 'Disease', (203, 245))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('lymph node metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (203, 245))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancer', 'Disease', (239, 245))	('upregulated', 'PosReg', (35, 46))	('TNM', 'Gene', '10178', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', (109, 114))	('TNM', 'Gene', (115, 118))
239251	31516617	Liu et al showed that inhibition of TPX2 gene expression can effectively inhibit the invasion and metastasis of esophageal cancer cell line EC9706, promote tumor cell apoptosis, and may be a new way to treat esophageal cancer.	('inhibition', 'Var', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('TPX2', 'Gene', (36, 40))	('EC9706', 'CellLine', 'CVCL:E307', (140, 146))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (98, 129))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('esophageal cancer', 'Disease', (208, 225))	('metastasis of esophageal cancer', 'Disease', (98, 129))	('promote', 'PosReg', (148, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))	('inhibit', 'NegReg', (73, 80))
239259	31516617	According to the results of this study, the high expression of TPX2 and NIBP promotes the development of esophageal cancer.	('NIBP', 'Gene', (72, 76))	('high', 'Var', (44, 48))	('promotes', 'PosReg', (77, 85))	('esophageal cancer', 'Disease', (105, 122))	('TPX2', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))
239322	28452206	According to studies about the pathogenesis of GERD in obesity, several mechanisms, such as visceral fat at the gastroesophageal junction (GEJ), increased circulating hormones (e.g., estrogen), increased gastric pressure caused by the pressure within the intra-abdominal organ, disruption of the GEJ, and increased transient LES have been suggested to elucidate the association between GERD and obesity.	('obesity', 'Phenotype', 'HP:0001513', (395, 402))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (112, 137))	('obesity', 'Disease', 'MESH:D009765', (55, 62))	('increased', 'PosReg', (145, 154))	('increased gastric', 'Phenotype', 'HP:0005207', (194, 211))	('obesity', 'Phenotype', 'HP:0001513', (55, 62))	('increased', 'PosReg', (194, 203))	('obesity', 'Disease', 'MESH:D009765', (395, 402))	('disruption', 'Var', (278, 288))	('obesity', 'Disease', (395, 402))	('gastric pressure', 'MPA', (204, 220))	('gastroesophageal junction', 'Disease', (112, 137))	('obesity', 'Disease', (55, 62))
239350	28024648	The largest decrease in mortality hazard in upfront esophagectomy patients was detected with >=25 LN sampled (HR 0.77, 95% CI 0.67 - 0.89, p<0.001), while for induction therapy patients, >=10 or 15 LN was associated with optimal survival benefit (HR 0.81, 95% CI 0.74 - 0.90, p<0.001).	('>=25 LN', 'Var', (93, 100))	('esophagectomy', 'Disease', (52, 65))	('mortality', 'MPA', (24, 33))	('patients', 'Species', '9606', (177, 185))	('decrease', 'NegReg', (12, 20))	('patients', 'Species', '9606', (66, 74))
239398	28024648	An institutional review at Cornell with over 260 upfront esophagectomy patients found a mortality reduction for patients that received a lymphadenectomy for any of the highest three quartiles (34% decrease for patients with 17-25 nodes, 48% decrease with 26-40 nodes, and 49% decrease with >=40 nodes) when compared to the lowest quartile (<=16 lymph nodes).	('26-40 nodes', 'Var', (255, 266))	('patients', 'Species', '9606', (71, 79))	('mortality', 'MPA', (88, 97))	('reduction', 'NegReg', (98, 107))	('patients', 'Species', '9606', (112, 120))	('decrease', 'NegReg', (241, 249))	('patients', 'Species', '9606', (210, 218))	('decrease', 'NegReg', (276, 284))	('decrease', 'NegReg', (197, 205))
239402	28024648	An institutional analysis at Duke University found that there was no threshold number of examined lymph nodes for induction therapy patients with pathologic T1-T2 tumors, while for pathologic T3-T4 tumors, significant improvements in survival were detected with >=7 lymph nodes.	('T1-T2', 'Var', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('improvements', 'PosReg', (218, 230))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('survival', 'MPA', (234, 242))	('patients', 'Species', '9606', (132, 140))
239442	28115730	Inhibiting EGFR pathway can inhibit tumor cell proliferation, differentiation, tumor angiogenesis, and promote treatment response of chemotherapy and radiation.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('differentiation', 'CPA', (62, 77))	('Inhibiting', 'Var', (0, 10))	('tumor', 'Disease', (79, 84))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('promote', 'PosReg', (103, 110))	('treatment response', 'CPA', (111, 129))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (36, 41))	('inhibit', 'NegReg', (28, 35))
239493	28115730	In an open-label multicenter, phase III, randomized clinical trial, patients with advanced gastroesophageal junction tumor with Her2 high expression received trastuzumab plus combined chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('gastroesophageal junction tumor', 'Disease', 'MESH:D008309', (91, 122))	('trastuzumab', 'Chemical', 'MESH:D000068878', (158, 169))	('gastroesophageal junction tumor', 'Disease', (91, 122))	('high expression', 'Var', (133, 148))	('Her2', 'Gene', '2064', (128, 132))	('patients', 'Species', '9606', (68, 76))	('Her2', 'Gene', (128, 132))
239579	33673581	In addition, texture-modified diets are lower in nutrients than a regular diet and are more likely to induce malnutrition and sarcopenia than a regular diet.	('malnutrition', 'Disease', (109, 121))	('induce', 'Reg', (102, 108))	('texture-modified diets', 'Var', (13, 35))	('sarcopenia', 'Disease', 'MESH:D055948', (126, 136))	('malnutrition', 'Phenotype', 'HP:0004395', (109, 121))	('sarcopenia', 'Disease', (126, 136))	('nutrients', 'MPA', (49, 58))	('lower', 'NegReg', (40, 45))
239580	33673581	Malnutrition leads to systemic muscle mass loss and atrophy of the muscles used to swallow, and this ultimately leads to dysphagia.	('atrophy', 'Disease', 'MESH:D001284', (52, 59))	('Malnutrition', 'Var', (0, 12))	('dysphagia', 'Disease', (121, 130))	('atrophy', 'Disease', (52, 59))	('dysphagia', 'Phenotype', 'HP:0002015', (121, 130))	('dysphagia', 'Disease', 'MESH:D003680', (121, 130))	('loss', 'NegReg', (43, 47))	('Malnutrition', 'Phenotype', 'HP:0004395', (0, 12))	('leads to', 'Reg', (112, 120))	('atrophy of the muscles', 'Phenotype', 'HP:0003202', (52, 74))
239665	33536555	In a recent publication, Menya and colleagues found that moderate and severe dental fluorosis may increase the risk of esophageal squamous cell carcinoma (ESCC) in Africa.	('dental fluorosis', 'Var', (77, 93))	('esophageal squamous cell carcinoma', 'Disease', (119, 153))	('moderate', 'Var', (57, 65))	('S', 'Chemical', 'MESH:D013455', (156, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('severe dental fluorosis', 'Phenotype', 'HP:0000166', (70, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (119, 153))
239683	33536555	The hypervariable region V4 of bacterial 16S rRNA gene was amplified using KOD-plus-Neo DNA polymerase (Toyobo, Tokyo, Japan) and the universal primers (515F: 5'-GTG YCA GCM GCC GCG GTA A-3' and 806R: 5'-GTG GAC TAC HVG GGT WTC TAA-3').	('GTG', 'Gene', '2678', (204, 207))	('GTG', 'Gene', (204, 207))	('GTG', 'Gene', '2678', (162, 165))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('515F:', 'Var', (153, 158))	('GTG', 'Gene', (162, 165))
239740	33536555	Thus, S. mitis is directly associated with dental caries formation.	('S. mitis', 'Var', (6, 14))	('associated with', 'Reg', (27, 42))	('dental caries', 'Phenotype', 'HP:0000670', (43, 56))	('dental caries formation', 'Disease', (43, 66))	('S. mitis', 'Species', '28037', (6, 14))
239742	33536555	There appears to be no evidence that demonstrates L. lactis is strongly associated with dental caries.	('L. lactis', 'Species', '1358', (50, 59))	('L. lactis', 'Var', (50, 59))	('dental caries', 'Disease', (88, 101))	('dental caries', 'Phenotype', 'HP:0000670', (88, 101))	('associated', 'Reg', (72, 82))
239747	33536555	Most recently, Menya suggested that moderate/severe dental fluorosis was strongly associated with a 9.4-fold increased risk of esophageal squamous cell carcinoma (ESCC) compared with a no dental fluorosis population in Africa.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (127, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('esophageal squamous cell carcinoma', 'Disease', (127, 161))	('severe dental fluorosis', 'Phenotype', 'HP:0000166', (45, 68))	('S', 'Chemical', 'MESH:D013455', (164, 165))	('moderate/severe dental fluorosis', 'Var', (36, 68))
239778	30706012	G4L was significantly higher in patients who received XRT versus those who received PRT (56% vs 22%; P < .01).	('higher', 'PosReg', (22, 28))	('XRT', 'Var', (54, 57))	('G4L', 'MPA', (0, 3))	('patients', 'Species', '9606', (32, 40))
239786	30706012	A recent series from one institution investigating the relationship between RT modality and lymphopenia in EC showed a decrease in lymphopenia rates for patients treated with PRT compared with photon RT (XRT).	('decrease', 'NegReg', (119, 127))	('lymphopenia', 'Disease', (131, 142))	('patients', 'Species', '9606', (153, 161))	('lymphopenia', 'Phenotype', 'HP:0001888', (92, 103))	('lymphopenia', 'Disease', (92, 103))	('lymphopenia', 'Disease', 'MESH:D008231', (131, 142))	('lymphopenia', 'Phenotype', 'HP:0001888', (131, 142))	('lymphopenia', 'Disease', 'MESH:D008231', (92, 103))	('PRT', 'Var', (175, 178))
239819	30706012	Here, we demonstrate that PRT compared with XRT may be one such way to reduce treatment-induced lymphopenia in patients with EC and potentially other disease sites.	('reduce', 'NegReg', (71, 77))	('lymphopenia', 'Phenotype', 'HP:0001888', (96, 107))	('lymphopenia', 'Disease', 'MESH:D008231', (96, 107))	('PRT', 'Var', (26, 29))	('lymphopenia', 'Disease', (96, 107))	('patients', 'Species', '9606', (111, 119))
239835	30558313	Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (43, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('neuroblastoma', 'Phenotype', 'HP:0003006', (68, 81))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (32, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mixed', 'Reg', (21, 26))	('neuroblastomas', 'Phenotype', 'HP:0003006', (68, 82))	('neuroblastomas', 'Disease', 'MESH:D009447', (68, 82))	('pancreatic neuroendocrine tumors', 'Disease', (32, 64))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (32, 64))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (43, 63))	('neuroblastomas', 'Disease', (68, 82))	('PPGLs', 'Var', (15, 20))
239842	30558313	Similarly, PPGLs are separated into 4 groups named after their molecular characteristics: pseudohypoxia related to succinate dehydrogenase or VHL/EPAS1 disturbances, wnt-altered and kinase-signaling pathways.	('pseudohypoxia', 'Disease', 'None', (90, 103))	('VHL', 'Disease', 'MESH:D006623', (142, 145))	('EPAS1', 'Gene', '2034', (146, 151))	('VHL', 'Disease', (142, 145))	('EPAS1', 'Gene', (146, 151))	('disturbances', 'Var', (152, 164))	('pseudohypoxia', 'Disease', (90, 103))
239882	30558313	Results showed a separation into two clusters, one consisting of low and high grade gliomas and a second including NBL, PNET, and PPGL (Figure 4, Supplementary Figures S10A-C and S11A-C).	('NBL', 'Phenotype', 'HP:0003006', (115, 118))	('S11A', 'Var', (179, 183))	('S10A', 'Var', (168, 172))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('S11A', 'SUBSTITUTION', 'None', (179, 183))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('S10A', 'SUBSTITUTION', 'None', (168, 172))
239900	30558313	This includes presence of both telomerase activation and alternative lengthening of telomeres due to ATRX or DAXX truncation as well as somatic or germline driver mutations in MEN1.	('telomerase', 'Enzyme', (31, 41))	('mutations', 'Var', (163, 172))	('DAXX', 'Gene', '1616', (109, 113))	('MEN1', 'Gene', (176, 180))	('MEN1', 'Gene', '4221', (176, 180))	('activation', 'PosReg', (42, 52))	('ATRX', 'Gene', (101, 105))	('DAXX', 'Gene', (109, 113))	('ATRX', 'Gene', '546', (101, 105))
240035	26412319	Home interventions, nutritional counseling, early provider-initiated telephone follow-up, and other discharge planning strategies have been shown to reduce readmissions and emergency department visits among medically-managed patients.	('nutritional counseling', 'Var', (20, 42))	('patients', 'Species', '9606', (225, 233))	('emergency', 'CPA', (173, 182))	('readmissions', 'CPA', (156, 168))	('reduce', 'NegReg', (149, 155))
240092	25236485	In univariate comparisons, patients undergoing EUS were younger (p<0.0001), more likely to be white (p=0.0002), and were more likely to demonstrate EAC on histology (p<0.0001) compared with the "no EUS or CT-PET" group.	('patients', 'Species', '9606', (27, 35))	('EAC', 'Disease', (148, 151))	('EUS', 'Var', (47, 50))
240105	25236485	Compared with patients not undergoing any staging modality, patients receiving EUS+CT-PET were more likely to be younger (p<0.0001), white (p=0.004), demonstrate EAC histology (p<0.001), and have locoregional disease (p<0.001) (Supplementary Table 1).	('locoregional disease', 'Disease', (196, 216))	('EUS+CT-PET', 'Var', (79, 89))	('patients', 'Species', '9606', (60, 68))	('EAC histology', 'CPA', (162, 175))	('patients', 'Species', '9606', (14, 22))	('men', 'Species', '9606', (234, 237))
240106	25236485	Receipt of EUS+CT-PET resulted in improved survival for all stages (p<0.01 for all univariate comparisons) with the exception of patients with Stage 0 disease.	('survival', 'MPA', (43, 51))	('improved', 'PosReg', (34, 42))	('patients', 'Species', '9606', (129, 137))	('EUS+CT-PET', 'Var', (11, 21))
240111	25236485	Similarly, receipt of CT-PET was a significant predictor of improved 1-year (HR 0.57, 95% CI 0.51-0.64, p<0.0001), 3-year (HR 0.66, 95% CI 0.60-0.73, p<0.0001) and 5-year (HR 0.67, 95% CI 0.62-0.74, p<0.0001) year survival in the 2002 to 2008 cohort of patients with esophageal cancer (Table 3).	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('patients', 'Species', '9606', (253, 261))	('CT-PET', 'Var', (22, 28))	('esophageal cancer', 'Disease', (267, 284))	('improved', 'PosReg', (60, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (267, 284))
240137	25236485	This study demonstrates an improved survival in a cohort of patients undergoing CT-PET staging, compared to the no EUS or CT-PET group, and that CT-PET was associated with a higher rate of treatment with chemoradiation.	('CT-PET', 'Var', (145, 151))	('CT-PET staging', 'Var', (80, 94))	('improved', 'PosReg', (27, 35))	('patients', 'Species', '9606', (60, 68))	('men', 'Species', '9606', (194, 197))	('survival', 'CPA', (36, 44))
240147	25236485	The incremental yield of EUS-FNA in staging of esophageal cancer by interrogating peri-esophageal and, in particular, celiac nodes were not evaluated in this study because of relatively small number of patients undergoing EUS-FNA precluding an accurate evaluation of its true benefit in terms of survival.	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('men', 'Species', '9606', (9, 12))	('patients', 'Species', '9606', (202, 210))	('EUS-FNA', 'Var', (222, 229))	('esophageal cancer', 'Disease', (47, 64))
240148	25236485	However, EUS-FNA for lymph node staging in esophageal cancer has been shown to enhance overall staging accuracy, compared to EUS alone and thus, our conclusion about the positive impact of EUS on outcome should be still valid.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('EUS-FNA', 'Var', (9, 16))	('enhance', 'PosReg', (79, 86))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('staging accuracy', 'CPA', (95, 111))
240233	24664246	The Kd values for Ec-LDP-Hr bound to EC9706 and KYSE150 cells were 5.283 mumol/L and 3.562 mumol/L, respectively (Fig.	('bound', 'Interaction', (28, 33))	('EC9706', 'Var', (37, 43))	('LDP', 'Gene', '10404', (21, 24))	('KYSE150', 'CellLine', 'CVCL:1348', (48, 55))	('LDP', 'Gene', (21, 24))	('EC9706', 'CellLine', 'CVCL:E307', (37, 43))
240243	24664246	Control cells (EC9706 and KYSE150) distributed in G2-M phase were 10.51%+-0.98% and 6.26%+-1.96% respectively, whereas cells treated with 0.1 nmol/L of Ec-LDP-Hr-AE distributed in G2-M phase were 86.00%+-0.98% and 89.36%+-0.71% respectively.	('LDP', 'Gene', (155, 158))	('EC9706', 'Var', (15, 21))	('LDP', 'Gene', '10404', (155, 158))	('KYSE150', 'CellLine', 'CVCL:1348', (26, 33))	('EC9706', 'CellLine', 'CVCL:E307', (15, 21))
240249	24664246	4B, the ratios of apoptotic EC9706 cells after treatment with 0.1, 0.5 and 1 nmol/L of Ec-LDP-Hr-AE were 15.06%+-0.29%, 38.10%+-0.64% and 50.00%+-0.39% respectively, which showed significant increases compared with control cells (P<0.01).	('LDP', 'Gene', (90, 93))	('EC9706', 'Var', (28, 34))	('LDP', 'Gene', '10404', (90, 93))	('EC9706', 'CellLine', 'CVCL:E307', (28, 34))
240272	24664246	Vallera and co-workers have developed novel bispecific molecules by fusing two distinct targeting ligands to a single toxin with the aim to improve specificity, and the results demonstrated that bispecific molecules showed either enhanced antitumor activity or broader spectrum of reactivity than the monospecific molecules.	('enhanced', 'PosReg', (230, 238))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('bispecific', 'Var', (195, 205))	('specificity', 'MPA', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
240302	24664246	These data suggested that comparing with "naked" LDM, the bispecific fusion protein showed elevated antitumor efficacy and decreased toxicity.	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('toxicity', 'Disease', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('elevated', 'PosReg', (91, 99))	('decreased', 'NegReg', (123, 132))	('LDM', 'Chemical', 'MESH:C058024', (49, 52))	('tumor', 'Disease', (104, 109))	('bispecific', 'Var', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
240325	20713185	At moderate levels, ROS/RNS may affect many cell biological processes by transcriptional regulation through certain redox-sensitive transcription factors including NF-kappaB, P53, Nrf-2, and HIF, or by directly modifying protein/enzyme molecules such as TRX, AKt, PTEN, Bcl-2 involved in cell proliferation, transformation or survival.	('P53', 'Gene', (175, 178))	('modifying', 'Reg', (211, 220))	('TRX', 'Gene', '7295', (254, 257))	('transcriptional regulation', 'MPA', (73, 99))	('cell biological', 'CPA', (44, 59))	('Nrf-2', 'Gene', '4780', (180, 185))	('protein/enzyme', 'Protein', (221, 235))	('AKt', 'Gene', (259, 262))	('P53', 'Gene', '7157', (175, 178))	('PTEN', 'Gene', (264, 268))	('NF-kappaB', 'Gene', (164, 173))	('RNS', 'Chemical', 'MESH:D026361', (24, 27))	('TRX', 'Gene', (254, 257))	('Nrf-2', 'Gene', (180, 185))	('PTEN', 'Gene', '5728', (264, 268))	('NF-kappaB', 'Gene', '4790', (164, 173))	('ROS', 'Chemical', 'MESH:D017382', (20, 23))	('affect', 'Reg', (32, 38))	('Bcl-2', 'Gene', (270, 275))	('AKt', 'Gene', '207', (259, 262))	('ROS/RNS', 'Var', (20, 27))
240326	20713185	At highly elevated levels, ROS/RNS can cause severe oxidative damage to biolipid membranes, DNA, and protein, leading to cell injury and cell death.	('leading to', 'Reg', (110, 120))	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('cell injury and cell death', 'Disease', 'MESH:D001926', (121, 147))	('oxidative damage', 'MPA', (52, 68))	('DNA', 'MPA', (92, 95))	('biolipid membranes', 'MPA', (72, 90))	('RNS', 'Chemical', 'MESH:D026361', (31, 34))	('ROS/RNS', 'Var', (27, 34))
240331	20713185	This cell death process can be further amplified by caspase-mediated cleavage of Bid, which is then translocated to mitochondria to induce the release of apoptosis factors such as cytochrome c, AIF, and Smac/DIABLO from mitochondria into cytosol.	('Bid', 'Gene', (81, 84))	('Bid', 'Gene', '637', (81, 84))	('Smac', 'Gene', '56616', (203, 207))	('cleavage', 'Var', (69, 77))	('cytochrome c', 'Gene', (180, 192))	('DIABLO', 'Gene', (208, 214))	('release', 'MPA', (143, 150))	('apoptosis', 'MPA', (154, 163))	('induce', 'Reg', (132, 138))	('AIF', 'Gene', '9131', (194, 197))	('DIABLO', 'Gene', '56616', (208, 214))	('cytochrome c', 'Gene', '54205', (180, 192))	('AIF', 'Gene', (194, 197))	('Smac', 'Gene', (203, 207))
240333	20713185	Considering the important roles of mitochondria in various cell death pathways, it is not surprising that compounds that target mitochondria may significantly affect cell viability by inducing apoptosis, necrosis, or autophagy.	('apoptosis', 'CPA', (193, 202))	('compounds', 'Var', (106, 115))	('affect', 'Reg', (159, 165))	('necrosis', 'Disease', (204, 212))	('cell viability', 'CPA', (166, 180))	('inducing', 'Reg', (184, 192))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('necrosis', 'Disease', 'MESH:D009336', (204, 212))	('autophagy', 'CPA', (217, 226))
240335	20713185	Several factors, including mitochondrial DNA mutations, oncogenic stress, loss of p53 tumor suppressor, and aberrant expression of metabolic enzymes, are thought to contribute to mitochondrial abnormalities.	('metabolic', 'Enzyme', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', (86, 91))	('expression', 'MPA', (117, 127))	('mitochondrial', 'Gene', (27, 40))	('aberrant', 'Var', (108, 116))	('loss', 'NegReg', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('contribute', 'Reg', (165, 175))	('mitochondrial abnormalities', 'Disease', 'MESH:D028361', (179, 206))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('mitochondrial abnormalities', 'Phenotype', 'HP:0012103', (179, 206))	('mitochondrial abnormalities', 'Disease', (179, 206))	('S', 'Chemical', 'MESH:D013455', (0, 1))
240336	20713185	Since mitochondria play major roles in energy metabolism, ROS generation and redox signaling, and regulation of cell death, dysfunction of these cellular organelles would cause alterations in these important cellular processes, which may provide a biochemical basis for preferentially impacting cancer cells.	('cause alterations', 'Reg', (171, 188))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Disease', (295, 301))	('dysfunction', 'Var', (124, 135))	('ROS', 'MPA', (58, 61))	('redox signaling', 'MPA', (77, 92))	('S', 'Chemical', 'MESH:D013455', (60, 61))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('S', 'Chemical', 'MESH:D013455', (0, 1))
240347	20713185	Mitochondrial dysfunction caused by mitochondrial DNA mutations, oncogenic signals, and ROS stress may be an important event that forces cancer cells to be more rely on the glycolytic pathway for energy production and for generation of metabolic intermediates for biogenesis.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (54, 63))	('Mitochondrial dysfunction', 'Disease', (0, 25))	('Mitochondrial dysfunction', 'Disease', 'MESH:D028361', (0, 25))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('Mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (0, 25))	('cancer', 'Disease', (137, 143))	('glycolytic pathway', 'Pathway', (173, 191))	('ROS', 'Chemical', 'MESH:D017382', (88, 91))	('mitochondrial DNA', 'Gene', (36, 53))
240355	20713185	Mutations in those genes are linked to phaeochromocytoma, paraganglioma or leiomyoma.	('paraganglioma', 'Phenotype', 'HP:0002668', (58, 71))	('Mutations', 'Var', (0, 9))	('linked', 'Reg', (29, 35))	('phaeochromocytoma, paraganglioma or leiomyoma', 'Disease', 'MESH:D007889', (39, 84))
240356	20713185	Interestingly, tumors such as paraganglioma that contain this type of mutations are relatively benign.	('tumors', 'Disease', (15, 21))	('mutations', 'Var', (70, 79))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('paraganglioma', 'Phenotype', 'HP:0002668', (30, 43))	('paraganglioma', 'Disease', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('paraganglioma', 'Disease', 'MESH:D010235', (30, 43))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
240362	20713185	HIF-1alpha deregulation or sustained stability under normoxia condition has been related to many cancer types.	('sustained stability', 'MPA', (27, 46))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('deregulation', 'Var', (11, 23))	('related', 'Reg', (81, 88))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HIF-1alpha', 'Gene', (0, 10))
240363	20713185	The HIF-1alpha level is high in RCC4 renal carcinoma cell line due to a mutation in von Hippel-Lindau (VHL) ubiqutin ligase.	('von Hippel-Lindau', 'Gene', '7428', (84, 101))	('HIF-1alpha', 'Gene', (4, 14))	('RCC4 renal carcinoma', 'Disease', 'MESH:C538614', (32, 52))	('renal carcinoma', 'Phenotype', 'HP:0005584', (37, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('RCC4 renal carcinoma', 'Disease', (32, 52))	('HIF-1alpha', 'Gene', '3091', (4, 14))	('VHL', 'Disease', (103, 106))	('VHL', 'Disease', 'MESH:D006623', (103, 106))	('mutation', 'Var', (72, 80))	('von Hippel-Lindau', 'Gene', (84, 101))
240364	20713185	By reintroducing VHL into RCC4 cells, HIF-1alpha is destabilized, which leads to a substantial decrease in aerobic glucose consumption.	('decrease', 'NegReg', (95, 103))	('aerobic glucose consumption', 'Disease', (107, 134))	('RCC4', 'Gene', (26, 30))	('reintroducing', 'Var', (3, 16))	('aerobic glucose consumption', 'Disease', 'MESH:C538054', (107, 134))	('VHL', 'Disease', (17, 20))	('VHL', 'Disease', 'MESH:D006623', (17, 20))	('HIF-1alpha', 'Gene', '3091', (38, 48))	('RCC4', 'Gene', '84925', (26, 30))	('HIF-1alpha', 'Gene', (38, 48))
240368	20713185	Wild-type p53 represses GLUT1 and GLUT4 gene transcription, while mutations within the DNA binding domain of p53 impair the repressive effect on GLUT transcription, leading to increased glucose metabolism.	('mutations', 'Var', (66, 75))	('represses', 'NegReg', (14, 23))	('p53', 'Gene', '7157', (10, 13))	('GLUT1', 'Gene', '6513', (24, 29))	('GLUT4', 'Gene', (34, 39))	('p53', 'Gene', (10, 13))	('repressive effect', 'MPA', (124, 141))	('GLUT', 'Gene', '6513', (34, 38))	('increased glucose', 'Phenotype', 'HP:0003074', (176, 193))	('GLUT', 'Gene', '6513', (145, 149))	('p53', 'Gene', '7157', (109, 112))	('GLUT', 'Gene', (34, 38))	('GLUT4', 'Gene', '6517', (34, 39))	('GLUT', 'Gene', '6513', (24, 28))	('increased', 'PosReg', (176, 185))	('glucose', 'Chemical', 'MESH:D005947', (186, 193))	('transcription', 'MPA', (45, 58))	('glucose metabolism', 'MPA', (186, 204))	('GLUT', 'Gene', (145, 149))	('GLUT1', 'Gene', (24, 29))	('p53', 'Gene', (109, 112))	('GLUT', 'Gene', (24, 28))	('impair', 'NegReg', (113, 119))
240369	20713185	In hepatoma cells, over-expression of mutant p53 protein binds to the p53 response elements on the type II hexokinase promoter region and activates its expression.	('mutant', 'Var', (38, 44))	('p53', 'Gene', (45, 48))	('hepatoma', 'Disease', 'MESH:D006528', (3, 11))	('p53', 'Gene', '7157', (45, 48))	('protein', 'Protein', (49, 56))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('hepatoma', 'Disease', (3, 11))	('binds', 'Interaction', (57, 62))	('over-expression', 'PosReg', (19, 34))	('expression', 'MPA', (152, 162))	('activates', 'PosReg', (138, 147))
240372	20713185	When p53 is mutated, glycolysis is increased due to a lack of TIGAR.	('increased', 'PosReg', (35, 44))	('TIGAR', 'Gene', (62, 67))	('mutated', 'Var', (12, 19))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '7157', (5, 8))	('glycolysis', 'MPA', (21, 31))	('TIGAR', 'Gene', '57103', (62, 67))
240377	20713185	Glioblastoma cells with high Akt activity displayed an increased rate of glycolysis, while those cells lacking Akt show low glycolytic activity.	('glycolysis', 'MPA', (73, 83))	('Glioblastoma', 'Disease', (0, 12))	('Akt', 'Gene', (111, 114))	('Akt', 'Gene', '207', (29, 32))	('increased', 'PosReg', (55, 64))	('rate', 'MPA', (65, 69))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('Akt', 'Gene', (29, 32))	('activity', 'MPA', (33, 41))	('high', 'Var', (24, 28))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Akt', 'Gene', '207', (111, 114))
240386	20713185	Likewise, attenuation of LDH-A expression has been shown to compromise glycolysis, increase mitochondrial respiration, and diminish tumorigenicity.	('LDH-A', 'Gene', '3939', (25, 30))	('increase', 'PosReg', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('compromise', 'NegReg', (60, 70))	('glycolysis', 'MPA', (71, 81))	('LDH-A', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('diminish', 'NegReg', (123, 131))	('tumor', 'Disease', (132, 137))	('attenuation', 'Var', (10, 21))	('mitochondrial respiration', 'MPA', (92, 117))
240391	20713185	For example, deficiency in functional p53 resulting in instability of mitochondrial genome was associated with the increased cellular ROS stress.	('instability', 'MPA', (55, 66))	('increased cellular ROS', 'Phenotype', 'HP:0025464', (115, 137))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('ROS', 'Chemical', 'MESH:D017382', (134, 137))	('increased', 'PosReg', (115, 124))	('deficiency', 'Var', (13, 23))	('cellular ROS stress', 'MPA', (125, 144))	('mitochondrial genome', 'MPA', (70, 90))	('associated', 'Reg', (95, 105))
240392	20713185	Mitochondrial DNA (mtDNA) mutations have also been shown to be correlated with increased ROS levels in several types of cancer cells both in solid tumors and leukemia.	('ROS', 'Chemical', 'MESH:D017382', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('increased', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('increased ROS levels', 'Phenotype', 'HP:0025464', (79, 99))	('solid tumors', 'Disease', 'MESH:D009369', (141, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('leukemia', 'Disease', (158, 166))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('leukemia', 'Disease', 'MESH:D007938', (158, 166))	('mutations', 'Var', (26, 35))	('solid tumors', 'Disease', (141, 153))	('ROS levels', 'MPA', (89, 99))
240394	20713185	Mutation of mitochondrial DNA could result in malformation of electron transport chain and thus compromise the electron transporting process, leading to an increased leakage of electrons and superoxide formation.	('result in malformation', 'Reg', (36, 58))	('superoxide', 'Chemical', 'MESH:D013481', (191, 201))	('superoxide formation', 'MPA', (191, 211))	('Mutation', 'Var', (0, 8))	('increased', 'PosReg', (156, 165))	('electron transporting process', 'MPA', (111, 140))	('leakage of electrons', 'MPA', (166, 186))	('electron transport chain', 'MPA', (62, 86))	('compromise', 'NegReg', (96, 106))	('mitochondrial DNA', 'Gene', (12, 29))
240398	20713185	It seems that oxidative stress may play a significant role in the acquisition of the hallmarks of cancer, immortalization and transformation, cancer cell proliferation, mitogenic signaling, cell survival and disruption of cell death signaling, epithelial-mesenchymal transition and metastasis, angiogenesis, and chemoresistance.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('metastasis', 'CPA', (282, 292))	('immortalization', 'CPA', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('epithelial-mesenchymal transition', 'CPA', (244, 277))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('angiogenesis', 'CPA', (294, 306))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('oxidative stress', 'Phenotype', 'HP:0025464', (14, 30))	('disruption', 'Var', (208, 218))	('cancer', 'Disease', (98, 104))	('cell survival', 'CPA', (190, 203))	('chemoresistance', 'CPA', (312, 327))	('cancer', 'Disease', (142, 148))
240400	20713185	When the increase of ROS reaches a certain threshold level that exceeds the cellular antioxidant capacity, ROS may exert a cytotoxic effect leading to oxidative damage and the death of tumor cells and thus suppress cancer progression.	('oxidative damage', 'MPA', (151, 167))	('cytotoxic effect', 'MPA', (123, 139))	('ROS', 'Chemical', 'MESH:D017382', (21, 24))	('death of tumor', 'Disease', (176, 190))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ROS', 'Gene', (21, 24))	('ROS', 'Chemical', 'MESH:D017382', (107, 110))	('ROS', 'Var', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('suppress', 'NegReg', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('death of tumor', 'Disease', 'MESH:D003643', (176, 190))
240405	20713185	As such, manipulating ROS levels by redox modulation seems to be a feasible way to selectively kill cancer cells with less toxicity to normal cells.	('toxicity', 'Disease', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('ROS', 'Chemical', 'MESH:D017382', (22, 25))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))	('manipulating', 'Var', (9, 21))
240407	20713185	For example, Arsenic trioxide, which is capable of impairing the respiratory chain function and promote superoxide generation, has been shown to effectively kill leukemia cells.	('superoxide', 'Chemical', 'MESH:D013481', (104, 114))	('impairing', 'NegReg', (51, 60))	('Arsenic', 'Var', (13, 20))	('promote', 'PosReg', (96, 103))	('superoxide generation', 'MPA', (104, 125))	('leukemia', 'Disease', (162, 170))	('leukemia', 'Phenotype', 'HP:0001909', (162, 170))	('leukemia', 'Disease', 'MESH:D007938', (162, 170))	('Arsenic trioxide', 'Chemical', 'MESH:D000077237', (13, 29))	('respiratory chain', 'Enzyme', (65, 82))
240410	20713185	For example, resistance to arsenic trioxide was found to be associated with an upregulation of hemoxygenase I, SOD1 and glutathione.	('hemoxygenase I', 'Enzyme', (95, 109))	('resistance', 'Var', (13, 23))	('SOD1', 'Gene', (111, 115))	('glutathione', 'Chemical', 'MESH:D005978', (120, 131))	('oxygen', 'Chemical', 'MESH:D010100', (98, 104))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (27, 43))	('SOD1', 'Gene', '6647', (111, 115))	('glutathione', 'MPA', (120, 131))	('upregulation', 'PosReg', (79, 91))
240417	20713185	Dysregulation of Bcl-2 family is often observed in various types of human cancer, including renal, ovarian, stomach, and brain tumors and leukemia.	('brain tumor', 'Phenotype', 'HP:0030692', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('brain tumors', 'Disease', (121, 133))	('stomach', 'Disease', (108, 115))	('human', 'Species', '9606', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('Dysregulation', 'Var', (0, 13))	('observed', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('leukemia', 'Disease', (138, 146))	('leukemia', 'Disease', 'MESH:D007938', (138, 146))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('ovarian', 'Disease', (99, 106))	('renal', 'Disease', (92, 97))	('brain tumors', 'Phenotype', 'HP:0030692', (121, 133))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('brain tumors', 'Disease', 'MESH:D001932', (121, 133))
240426	20713185	Abnormalities in PTP have been implicated in pathological conditions such as cancer, neurodegeneration, ischemia/reperfusion and aging.	('implicated', 'Reg', (31, 41))	('ischemia', 'Disease', 'MESH:D007511', (104, 112))	('Abnormalities', 'Var', (0, 13))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('neurodegeneration', 'Phenotype', 'HP:0002180', (85, 102))	('PTP', 'Gene', (17, 20))	('ischemia', 'Disease', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('neurodegeneration', 'Disease', (85, 102))	('neurodegeneration', 'Disease', 'MESH:D019636', (85, 102))
240451	20713185	Inhibition of the GSH antioxidant system by PEITC in cancer cells may cause a severe accumulation of ROS due to the high basal ROS output in these cells, especially in those cells with mitochondrial dysfunction, and trigger massive cell death either by c-jun kinase-induced apoptosis and/or by direct damage to cellular components, such as membranes, proteins and DNA.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (185, 210))	('cell death', 'CPA', (232, 242))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (185, 210))	('ROS', 'Chemical', 'MESH:D017382', (127, 130))	('cancer', 'Disease', (53, 59))	('GSH', 'Chemical', '-', (18, 21))	('ROS', 'MPA', (101, 104))	('basal ROS output', 'MPA', (121, 137))	('mitochondrial dysfunction', 'Disease', (185, 210))	('accumulation', 'PosReg', (85, 97))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('PEITC', 'Chemical', 'MESH:C058305', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('trigger', 'Reg', (216, 223))	('Inhibition', 'Var', (0, 10))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))
240452	20713185	As GSH also has a crucial role in regulating the function of proteins through thiol modifications, the abrogation of the GSH system can also inactivate the pro-survival signals, such as nuclear factor kappaB (NF-kappaB) and MCL-1, and thus further facilitate cell death (Trachootham et al.,).	('GSH', 'Chemical', '-', (3, 6))	('GSH', 'Chemical', '-', (121, 124))	('NF-kappaB', 'Gene', '4790', (209, 218))	('thiol', 'Chemical', 'MESH:D013438', (78, 83))	('MCL-1', 'Gene', '4170', (224, 229))	('facilitate', 'PosReg', (248, 258))	('MCL-1', 'Gene', (224, 229))	('function', 'MPA', (49, 57))	('NF-kappaB', 'Gene', (209, 218))	('pro-survival signals', 'MPA', (156, 176))	('proteins', 'Protein', (61, 69))	('abrogation', 'Var', (103, 113))	('GSH', 'Gene', (121, 124))	('inactivate', 'NegReg', (141, 151))	('cell death', 'CPA', (259, 269))
240453	20713185	Inhibition of ROS-scavenging systems and inactivation of pro-survival pathways can together effectively kill cancer cells.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('inactivation', 'Var', (41, 53))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('cancer', 'Disease', (109, 115))	('pro-survival pathways', 'Pathway', (57, 78))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ROS-scavenging', 'Protein', (14, 28))
240457	20713185	A previous study showed that PEITC can conjugate with glutathione and cause its export from the cells, thus leading to a depletion of intracellular glutathione pool.	('export from the cells', 'MPA', (80, 101))	('PEITC', 'Chemical', 'MESH:C058305', (29, 34))	('glutathione', 'Chemical', 'MESH:D005978', (54, 65))	('leading to', 'Reg', (108, 118))	('glutathione', 'Chemical', 'MESH:D005978', (148, 159))	('cause', 'Reg', (70, 75))	('depletion of intracellular glutathione pool', 'Phenotype', 'HP:0003343', (121, 164))	('conjugate', 'Interaction', (39, 48))	('depletion of intracellular glutathione pool', 'MPA', (121, 164))	('glutathione', 'Protein', (54, 65))	('PEITC', 'Var', (29, 34))
240464	20713185	Thus, PEITC can cause a rapid depletion of GSH through the export mechanism while glutathione depletion by BSO is a slow process due to the presence of the GSSG-GSH recycling system.	('GSH', 'MPA', (43, 46))	('glutathione', 'Chemical', 'MESH:D005978', (82, 93))	('glutathione depletion', 'MPA', (82, 103))	('PEITC', 'Var', (6, 11))	('export mechanism', 'MPA', (59, 75))	('depletion', 'MPA', (30, 39))	('GSH', 'Chemical', '-', (43, 46))	('PEITC', 'Chemical', 'MESH:C058305', (6, 11))	('GSSG', 'Chemical', 'MESH:D019803', (156, 160))	('BSO', 'Chemical', 'MESH:D019328', (107, 110))	('GSH', 'Chemical', '-', (161, 164))
240469	20713185	Because PEITC is an electrophile, it may stimulate the cellular stress response through the keap-1/Nrf-2 system at low concentrations tolerable by the cells.	('Nrf-2', 'Gene', '4780', (99, 104))	('PEITC', 'Chemical', 'MESH:C058305', (8, 13))	('cellular stress response', 'CPA', (55, 79))	('Nrf-2', 'Gene', (99, 104))	('keap-1', 'Gene', '9817', (92, 98))	('stimulate', 'PosReg', (41, 50))	('keap-1', 'Gene', (92, 98))	('PEITC', 'Var', (8, 13))
240486	20713185	Paradoxically, other studies suggested that honokiol could induce an increase in ROS levels in various cell lines.	('increase', 'PosReg', (69, 77))	('honokiol', 'Var', (44, 52))	('honokiol', 'Chemical', 'MESH:C005499', (44, 52))	('ROS levels', 'MPA', (81, 91))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))
240502	20713185	Consistently, siRNA knockdown of CypD also reduced the sensitivity to honokiol (Chen et al., 2009).	('C', 'Chemical', 'MESH:D002244', (80, 81))	('sensitivity to honokiol', 'MPA', (55, 78))	('CypD', 'Gene', '10105', (33, 37))	('CypD', 'Gene', (33, 37))	('C', 'Chemical', 'MESH:D002244', (33, 34))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('knockdown', 'Var', (20, 29))	('reduced', 'NegReg', (43, 50))	('honokiol', 'Chemical', 'MESH:C005499', (70, 78))
240521	20713185	It has been shown that EGCG was able to rapidly cause apoptotic cell death in various malignant B-cell lines by triggering the mitochondria-related cell death events including loss of mitochondrial transmembrane potential (Deltapsim); release of various mitochondrial apoptogenic proteins (cytochrome c, Smac/DIABLO, and AIF), activation of caspases, and ROS generation.	('caspases', 'Gene', '841;842', (341, 349))	('EGCG', 'Var', (23, 27))	('cytochrome c', 'Gene', (290, 302))	('cause', 'Reg', (48, 53))	('EGCG', 'Chemical', 'MESH:C045651', (23, 27))	('release', 'MPA', (235, 242))	('AIF', 'Gene', '9131', (321, 324))	('DIABLO', 'Gene', '56616', (309, 315))	('AIF', 'Gene', (321, 324))	('loss', 'NegReg', (176, 180))	('ROS generation', 'CPA', (355, 369))	('mitochondria-related', 'MPA', (127, 147))	('activation', 'PosReg', (327, 337))	('Smac', 'Gene', (304, 308))	('cytochrome c', 'Gene', '54205', (290, 302))	('ROS', 'Chemical', 'MESH:D017382', (355, 358))	('Smac', 'Gene', '56616', (304, 308))	('mitochondrial transmembrane potential', 'MPA', (184, 221))	('triggering', 'Reg', (112, 122))	('DIABLO', 'Gene', (309, 315))	('caspases', 'Gene', (341, 349))
240580	20713185	Since many of the mitochondrial functions are essential for the viability of the normal cells, a compound that directly and completely inhibits one of these essential functions may be detrimental to the normal cells and would likely to have a significant toxic side effect.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('compound', 'Var', (97, 105))	('detrimental', 'NegReg', (184, 195))	('inhibits', 'NegReg', (135, 143))
240585	20713185	Such mechanistic studies and the identification and testing of new agents capable of preferentially targeting the aberrant mitochondria in cancer cells and/or their metabolic alterations are important tasks in future research.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('aberrant mitochondria', 'Phenotype', 'HP:0012103', (114, 135))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('aberrant', 'Var', (114, 122))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('cancer', 'Disease', (139, 145))
240622	31289612	Genomic characterization of early-stage esophageal squamous cell carcinoma in a Japanese population Major risk factors for esophageal squamous cell carcinoma (ESCC) are smoking, alcohol consumption, and single nucleotide polymorphisms in ADH1B and ALDH2.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('ADH1B', 'Gene', (238, 243))	('single nucleotide polymorphisms', 'Var', (203, 234))	('esophageal squamous cell carcinoma', 'Disease', (40, 74))	('ALDH2', 'Gene', '217', (248, 253))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('esophageal squamous cell carcinoma', 'Disease', (123, 157))	('ADH1B', 'Gene', '125', (238, 243))	('alcohol', 'Chemical', 'MESH:D000438', (178, 185))	('ALDH2', 'Gene', (248, 253))	('SCC', 'Gene', (160, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (40, 74))	('SCC', 'Gene', '6317', (160, 163))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (123, 157))
240626	31289612	We found significantly more somatic mutations in TP53 and NOTCH1, CDKN2A deletions, and CCND1 amplifications in cancerous areas than in non-cancerous areas, consistent with previous studies that have characterized them as tumor suppressors and oncogenes.	('TP53', 'Gene', '7157', (49, 53))	('non-cancerous', 'Disease', (136, 149))	('cancerous areas', 'Disease', 'MESH:D009369', (140, 155))	('cancerous areas', 'Disease', (112, 127))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('CCND1', 'Gene', '595', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CDKN2A', 'Gene', (66, 72))	('CCND1', 'Gene', (88, 93))	('cancerous areas', 'Disease', (140, 155))	('deletions', 'Var', (73, 82))	('amplifications', 'Var', (94, 108))	('CDKN2A', 'Gene', '1029', (66, 72))	('more', 'PosReg', (23, 27))	('TP53', 'Gene', (49, 53))	('tumor', 'Disease', (222, 227))	('NOTCH1', 'Gene', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('cancerous areas', 'Disease', 'MESH:D009369', (112, 127))	('mutations', 'Var', (36, 45))	('NOTCH1', 'Gene', '4851', (58, 64))	('non-cancerous', 'Disease', 'MESH:D009369', (136, 149))
240627	31289612	These data suggest that mutations, deletions, and amplifications, which alter the function of TP53, NOTCH1, CDKN2A, and CCND1, are the key changes that promote the transformation of esophageal mucosa to ESCC.	('SCC', 'Gene', '6317', (204, 207))	('function', 'MPA', (82, 90))	('esophageal mucosa', 'Disease', (182, 199))	('CDKN2A', 'Gene', '1029', (108, 114))	('promote', 'PosReg', (152, 159))	('CDKN2A', 'Gene', (108, 114))	('TP53', 'Gene', '7157', (94, 98))	('CCND1', 'Gene', (120, 125))	('TP53', 'Gene', (94, 98))	('SCC', 'Gene', (204, 207))	('deletions', 'Var', (35, 44))	('NOTCH1', 'Gene', '4851', (100, 106))	('mutations', 'Var', (24, 33))	('transformation', 'CPA', (164, 178))	('amplifications', 'Var', (50, 64))	('NOTCH1', 'Gene', (100, 106))	('CCND1', 'Gene', '595', (120, 125))
240632	31289612	The genetic risk factors for ESCC are well known; common germline variants for ESCC are rs1229984 on ADH1B and rs671 on ALDH2.	('ALDH2', 'Gene', '217', (120, 125))	('SCC', 'Gene', '6317', (80, 83))	('SCC', 'Gene', '6317', (30, 33))	('ADH1B', 'Gene', '125', (101, 106))	('rs1229984', 'Mutation', 'rs1229984', (88, 97))	('ALDH2', 'Gene', (120, 125))	('rs671', 'Var', (111, 116))	('rs671', 'Mutation', 'rs671', (111, 116))	('SCC', 'Gene', (80, 83))	('SCC', 'Gene', (30, 33))	('rs1229984', 'Var', (88, 97))	('ADH1B', 'Gene', (101, 106))
240633	31289612	In addition, somatic mutations and copy-number variants (CNVs) have been implicated in the development and proliferation of ESCC.	('implicated', 'Reg', (73, 83))	('copy-number variants', 'Var', (35, 55))	('proliferation', 'CPA', (107, 120))	('SCC', 'Gene', (125, 128))	('SCC', 'Gene', '6317', (125, 128))
240637	31289612	Therefore, identifying mutations associated with the development of SCC in the background mucosa and IN is essential.	('mutations', 'Var', (23, 32))	('SCC', 'Gene', (68, 71))	('associated', 'Reg', (33, 43))	('SCC', 'Gene', '6317', (68, 71))
240639	31289612	reported mutations and gene copy-number changes in non-tumor, IN, and ESCC samples, collected from 70 advanced-ESCC patients.	('non-tumor', 'Disease', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SCC', 'Gene', '6317', (112, 115))	('mutations', 'Var', (9, 18))	('patients', 'Species', '9606', (116, 124))	('gene copy-number changes', 'Var', (23, 47))	('non-tumor', 'Disease', 'MESH:D009369', (51, 60))	('SCC', 'Gene', (71, 74))	('SCC', 'Gene', '6317', (71, 74))	('SCC', 'Gene', (112, 115))
240643	31289612	In light of the lack of the said research, we evaluated the somatic mutations and copy-number variants in 42 T1 or High-grade IN (HGIN) patients to study the genetic changes in the early-stage development of ESCC.	('SCC', 'Gene', '6317', (209, 212))	('patients', 'Species', '9606', (136, 144))	('copy-number variants', 'Var', (82, 102))	('SCC', 'Gene', (209, 212))
240647	31289612	Genotyping indicated that 5 patients harbored the rs1229984 GG allele in ADH1B, and 29 patients harbored the rs671 GA allele in ALDH2.	('rs671', 'Mutation', 'rs671', (109, 114))	('ADH1B', 'Gene', '125', (73, 78))	('rs1229984', 'Mutation', 'rs1229984', (50, 59))	('rs1229984 GG', 'Var', (50, 62))	('ALDH2', 'Gene', '217', (128, 133))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (87, 95))	('ADH1B', 'Gene', (73, 78))	('rs671 GA', 'Var', (109, 117))	('ALDH2', 'Gene', (128, 133))
240648	31289612	Therefore, 7 cases had no risk SNPs (rs671 AA or GG and rs1229984 AA or GA), 33 cases had 1 risk SNP (rs671 GA or rs1229984 GG), and 2 cases had 2 risk SNPs (rs671 GA and rs1229984 GG).	('rs671', 'Mutation', 'rs671', (102, 107))	('rs671 GA', 'Var', (102, 110))	('rs1229984', 'Mutation', 'rs1229984', (56, 65))	('rs1229984 AA', 'Var', (56, 68))	('rs671', 'Mutation', 'rs671', (158, 163))	('rs1229984 GG', 'Var', (114, 126))	('rs671 GA', 'Var', (158, 166))	('rs1229984', 'Mutation', 'rs1229984', (114, 123))	('rs671', 'Mutation', 'rs671', (37, 42))	('rs671 AA', 'Var', (37, 45))	('rs1229984', 'Mutation', 'rs1229984', (171, 180))	('rs1229984 GG', 'Var', (171, 183))
240652	31289612	Similar to previous findings for many cancer types, the predominant substitution across all ESCN samples was C to T involving the CpG dinucleotide (Supplementary Figure 3A).	('C to T', 'Var', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (130, 146))	('cancer', 'Disease', (38, 44))
240653	31289612	Among all 1,182 genes, we identified 89 that had non-synonymous somatic mutations and indels in at least two patients (Supplementary Tables 4 and 5).	('indels', 'Var', (86, 92))	('non-synonymous somatic mutations', 'Var', (49, 81))	('patients', 'Species', '9606', (109, 117))
240662	31289612	We found that the frequency of mutations in MLL2 and TP53, observed in advanced-ESCC patients, was significantly higher than that in T1 ESCC patients.	('SCC', 'Gene', '6317', (81, 84))	('mutations', 'Var', (31, 40))	('MLL2', 'Gene', '9757', (44, 48))	('SCC', 'Gene', '6317', (137, 140))	('MLL2', 'Gene', (44, 48))	('higher', 'PosReg', (113, 119))	('patients', 'Species', '9606', (85, 93))	('TP53', 'Gene', '7157', (53, 57))	('SCC', 'Gene', (81, 84))	('patients', 'Species', '9606', (141, 149))	('TP53', 'Gene', (53, 57))	('SCC', 'Gene', (137, 140))
240665	31289612	The frequency of mutations in TP53 and NOTCH1 was higher in the cancerous samples than in the non-cancerous samples (p < 0.01, p = 0.038, respectively).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancerous', 'Disease', 'MESH:D009369', (64, 73))	('TP53', 'Gene', (30, 34))	('NOTCH1', 'Gene', (39, 45))	('TP53', 'Gene', '7157', (30, 34))	('non-cancerous', 'Disease', 'MESH:D009369', (94, 107))	('NOTCH1', 'Gene', '4851', (39, 45))	('cancerous', 'Disease', (98, 107))	('higher', 'Reg', (50, 56))	('cancerous', 'Disease', (64, 73))	('non-cancerous', 'Disease', (94, 107))	('mutations', 'Var', (17, 26))	('cancerous', 'Disease', 'MESH:D009369', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
240666	31289612	We analyzed 26 paired ESCC and non-cancerous samples for the presence of recurrent focal copy-number variants (CNVs) via SureCall Copy Number Methods.	('non-cancerous', 'Disease', 'MESH:D009369', (31, 44))	('SCC', 'Gene', '6317', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('non-cancerous', 'Disease', (31, 44))	('SCC', 'Gene', (23, 26))	('copy-number variants', 'Var', (89, 109))
240668	31289612	The genes most frequently affected in cancerous areas were CDKN2A/2B (deleted in 61.5%) and CCND1 (amplified in 42.3%), followed by ATM (deletion 19.3%), TERT (amplified in 19.3%), SOX2 (amplified in 19.3%), KDM6A (deletion 19.3%), LRP1B (deleted in 15.3%), ERBB2 (amplified in 15.3%), PIK3CA (amplified 15.3%), and EGFR (amplified in 11.5%) (Figure 3).	('affected', 'Reg', (26, 34))	('deletion', 'Var', (215, 223))	('cancerous areas', 'Disease', (38, 53))	('LRP1B', 'Gene', '53353', (232, 237))	('KDM6A', 'Gene', (208, 213))	('PIK3CA', 'Gene', '5290', (286, 292))	('CDKN2A/2B', 'Gene', '1029', (59, 68))	('EGFR', 'Gene', '1956', (316, 320))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('TERT', 'Gene', (154, 158))	('CDKN2A/2B', 'Gene', (59, 68))	('ERBB2', 'Gene', (258, 263))	('TERT', 'Gene', '7015', (154, 158))	('PIK3CA', 'Gene', (286, 292))	('CCND1', 'Gene', '595', (92, 97))	('SOX2', 'Gene', '6657', (181, 185))	('LRP1B', 'Gene', (232, 237))	('SOX2', 'Gene', (181, 185))	('KDM6A', 'Gene', '7403', (208, 213))	('CCND1', 'Gene', (92, 97))	('EGFR', 'Gene', (316, 320))	('ERBB2', 'Gene', '2064', (258, 263))	('cancerous areas', 'Disease', 'MESH:D009369', (38, 53))
240669	31289612	We identified the following CNVs: RB1 deletions and PIK3CA amplifications in 3 non-cancerous tissues; and CCND1 amplification and CDKN2A and LRP1B deletion in 1 non-cancerous sample (Figure 3).	('LRP1B', 'Gene', '53353', (141, 146))	('non-cancerous', 'Disease', (161, 174))	('CDKN2A', 'Gene', (130, 136))	('RB1', 'Gene', '5925', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('PIK3CA', 'Gene', '5290', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('PIK3CA', 'Gene', (52, 58))	('deletions', 'Var', (38, 47))	('CDKN2A', 'Gene', '1029', (130, 136))	('deletion', 'Var', (147, 155))	('non-cancerous', 'Disease', (79, 92))	('CCND1', 'Gene', (106, 111))	('LRP1B', 'Gene', (141, 146))	('non-cancerous', 'Disease', 'MESH:D009369', (161, 174))	('RB1', 'Gene', (34, 37))	('non-cancerous', 'Disease', 'MESH:D009369', (79, 92))	('CCND1', 'Gene', '595', (106, 111))
240674	31289612	Moreover, the frequencies of CCND1 amplification and CDKN2A deletion in T1 ESCC areas were significantly higher than those in non-cancerous areas (p < 0.001 for both) (Supplementary Figure 4C).	('amplification', 'Var', (35, 48))	('CDKN2A', 'Gene', (53, 59))	('cancerous areas', 'Disease', 'MESH:D009369', (130, 145))	('higher', 'PosReg', (105, 111))	('deletion', 'Var', (60, 68))	('non-cancerous', 'Disease', (126, 139))	('CCND1', 'Gene', (29, 34))	('cancerous areas', 'Disease', (130, 145))	('SCC', 'Gene', (76, 79))	('CDKN2A', 'Gene', '1029', (53, 59))	('CCND1', 'Gene', '595', (29, 34))	('SCC', 'Gene', '6317', (76, 79))	('non-cancerous', 'Disease', 'MESH:D009369', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
240675	31289612	These results suggested that CNVs occurred in the early stages of carcinogenesis and that CCND1 amplification and CDKN2A deletion played important roles in the development of carcinogenesis in the early stage of ESCC.	('CCND1', 'Gene', (90, 95))	('CDKN2A', 'Gene', '1029', (114, 120))	('carcinogenesis', 'Disease', 'MESH:D063646', (175, 189))	('SCC', 'Gene', '6317', (213, 216))	('CCND1', 'Gene', '595', (90, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('roles', 'Reg', (147, 152))	('carcinogenesis', 'Disease', (175, 189))	('carcinogenesis', 'Disease', (66, 80))	('SCC', 'Gene', (213, 216))	('deletion', 'Var', (121, 129))	('CDKN2A', 'Gene', (114, 120))
240683	31289612	reported that non-cancerous esophageal mucosa with multiple lugol-voiding lesions had low frequencies of TP53 mutations.	('non-cancerous esophageal', 'Disease', (14, 38))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('non-cancerous esophageal', 'Disease', 'MESH:D004938', (14, 38))	('cancerous esophageal mucosa', 'Disease', (18, 45))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('cancerous esophageal mucosa', 'Disease', 'MESH:D004938', (18, 45))
240688	31289612	We found that somatic mutations in TP53 and NOTCH1, CDKN2A deletions, and CCND1 amplifications play critical roles in the development of ESCC.	('SCC', 'Gene', (138, 141))	('NOTCH1', 'Gene', '4851', (44, 50))	('CCND1', 'Gene', (74, 79))	('deletions', 'Var', (59, 68))	('TP53', 'Gene', '7157', (35, 39))	('roles', 'Reg', (109, 114))	('TP53', 'Gene', (35, 39))	('NOTCH1', 'Gene', (44, 50))	('SCC', 'Gene', '6317', (138, 141))	('mutations', 'Var', (22, 31))	('CDKN2A', 'Gene', (52, 58))	('CCND1', 'Gene', '595', (74, 79))	('CDKN2A', 'Gene', '1029', (52, 58))
240691	31289612	Moreover, loss of epidermal NOTCH1 promotes skin tumorigenesis by impacting the stromal microenvironment.	('epidermal NOTCH1', 'Gene', (18, 34))	('loss', 'Var', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('promotes', 'PosReg', (35, 43))	('tumor', 'Disease', (49, 54))	('impacting', 'Reg', (66, 75))	('stromal microenvironment', 'CPA', (80, 104))
240694	31289612	However, mutations in TP53 and NOTCH1 were not mutually exclusive in the esophageal tumors that we evaluated.	('esophageal tumors', 'Disease', 'MESH:D004938', (73, 90))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TP53', 'Gene', '7157', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('NOTCH1', 'Gene', '4851', (31, 37))	('NOTCH1', 'Gene', (31, 37))	('esophageal tumors', 'Phenotype', 'HP:0100751', (73, 90))	('TP53', 'Gene', (22, 26))	('esophageal tumors', 'Disease', (73, 90))
240695	31289612	Overexpression and somatic mutations of CCND1 often contribute to transformation; they can either directly or indirectly promote constitutive cyclin D1 nuclear localization, which is a critical oncogenic event.	('mutations', 'Var', (27, 36))	('cyclin D1', 'Gene', (142, 151))	('transformation', 'CPA', (66, 80))	('nuclear localization', 'MPA', (152, 172))	('CCND1', 'Gene', (40, 45))	('contribute', 'Reg', (52, 62))	('CCND1', 'Gene', '595', (40, 45))	('promote', 'PosReg', (121, 128))	('cyclin D1', 'Gene', '595', (142, 151))
240696	31289612	In ESCC, CCND1 amplification or overexpression is also significantly correlated with lymph node metastasis.	('SCC', 'Gene', (4, 7))	('CCND1', 'Gene', (9, 14))	('correlated', 'Reg', (69, 79))	('overexpression', 'PosReg', (32, 46))	('amplification', 'Var', (15, 28))	('SCC', 'Gene', '6317', (4, 7))	('CCND1', 'Gene', '595', (9, 14))	('lymph node metastasis', 'CPA', (85, 106))
240698	31289612	Therefore, we hypothesize that CCND1 alterations occur in the early stages of carcinogenesis.	('CCND1', 'Gene', (31, 36))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('CCND1', 'Gene', '595', (31, 36))	('carcinogenesis', 'Disease', (78, 92))	('alterations', 'Var', (37, 48))
240701	31289612	Finally, we focused on the change in the frequency of TP53 mutations as a result of cancer progression.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('TP53', 'Gene', '7157', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (59, 68))	('TP53', 'Gene', (54, 58))
240702	31289612	The frequency of TP53 mutations in each early stage ESCC was higher than that in inflamed esophageal mucosa, which correlated with the transformation of inflamed esophageal mucosa to ESCC.	('SCC', 'Gene', '6317', (53, 56))	('SCC', 'Gene', (184, 187))	('mutations', 'Var', (22, 31))	('SCC', 'Gene', (53, 56))	('SCC', 'Gene', '6317', (184, 187))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
240704	31289612	Previous studies indicated that TP53 expression was altered in some patients with dysplasia and that mutations in TP53 arose early during ESCC development.	('SCC', 'Gene', '6317', (139, 142))	('mutations', 'Var', (101, 110))	('altered', 'Reg', (52, 59))	('TP53', 'Gene', '7157', (32, 36))	('dysplasia', 'Disease', (82, 91))	('TP53', 'Gene', '7157', (114, 118))	('patients', 'Species', '9606', (68, 76))	('TP53', 'Gene', (32, 36))	('SCC', 'Gene', (139, 142))	('TP53', 'Gene', (114, 118))	('expression', 'MPA', (37, 47))	('dysplasia', 'Disease', 'MESH:D004476', (82, 91))
240705	31289612	characterized the genomic alterations in ESCC precursor lesions, delineated clonal evolution in ESCC development, and suggested that the complete inactivation of TP53 is essential for the development of ESCC.	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('SCC', 'Gene', (42, 45))	('SCC', 'Gene', (97, 100))	('inactivation', 'Var', (146, 158))	('SCC', 'Gene', (204, 207))	('SCC', 'Gene', '6317', (42, 45))	('SCC', 'Gene', '6317', (97, 100))	('SCC', 'Gene', '6317', (204, 207))
240727	31289612	The T1 data from 26 ESCC patients with mutations in each representative ESCC driver gene were collected only during the replication stage.	('SCC', 'Gene', (21, 24))	('SCC', 'Gene', '6317', (21, 24))	('SCC', 'Gene', (73, 76))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (25, 33))	('SCC', 'Gene', '6317', (73, 76))
240730	31289612	The advanced-cancer data indicated the CNVs in all exons in Sawada's advanced-ESCC data and Chen et al.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('SCC', 'Gene', (79, 82))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('SCC', 'Gene', '6317', (79, 82))	('CNVs', 'Var', (39, 43))
240734	31289612	We compared our patients' data with that of the results of somatic mutations in all exons in the Japanese advanced-ESCC data via the chi-square and Fisher's exact tests in order to observe the differences in the frequency of patients with somatic mutations and CNVs in each gene.	('SCC', 'Gene', (116, 119))	('patients', 'Species', '9606', (225, 233))	('patients', 'Species', '9606', (16, 24))	('SCC', 'Gene', '6317', (116, 119))	('mutations', 'Var', (67, 76))
240737	31289612	SCC squamous cell carcinoma ESCC esophageal squamous cell carcinoma ESCN esophageal squamous cell neoplasm IN intraepithelial neoplasia HGIN high-grade IN WES whole-exome sequencing MAF mutation allele frequency CNV copy-number variants	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('squamous cell neoplasm', 'Phenotype', 'HP:0002860', (84, 106))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (4, 27))	('SCC', 'Gene', '6317', (29, 32))	('MAF', 'Gene', (182, 185))	('intraepithelial neoplasia', 'Disease', (110, 135))	('SCC', 'Gene', (29, 32))	('esophageal squamous cell carcinoma', 'Disease', (33, 67))	('mutation', 'Var', (186, 194))	('squamous cell carcinoma', 'Disease', (4, 27))	('esophageal squamous cell neoplasm', 'Disease', 'MESH:D000077277', (73, 106))	('neoplasm', 'Phenotype', 'HP:0002664', (98, 106))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (110, 135))	('SCC', 'Gene', '6317', (0, 3))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (33, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (4, 27))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (110, 135))	('esophageal squamous cell neoplasm', 'Disease', (73, 106))	('neoplasia', 'Phenotype', 'HP:0002664', (126, 135))	('SCC', 'Gene', (0, 3))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
240739	30425579	Metformin also can enhance tumor radiosensitivity in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('Metformin', 'Var', (0, 9))	('enhance tumor radiosensitivity', 'Phenotype', 'HP:0010997', (19, 49))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('enhance', 'PosReg', (19, 26))
240745	30425579	The results indicated that the tumor response was higher in patients who also were treated with metformin than in those who were not (OR, 0.48; 95% CI, 0.22-1.07; P=0.07) and nondiabetic (OR, 0.27; 95% CI, 0.07-0.98; P=0.05).	('higher', 'PosReg', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('nondiabetic', 'Disease', (175, 186))	('tumor', 'Disease', (31, 36))	('metformin', 'Var', (96, 105))	('nondiabetic', 'Disease', 'MESH:D005923', (175, 186))	('patients', 'Species', '9606', (60, 68))	('metformin', 'Chemical', 'MESH:D008687', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
240746	30425579	Moreover, patients who received metformin had survival benefits compared with patients not treated with metformin (2y-OS: OR, 0.48; 95% CI, 0.29-0.80; P=0.005; 5y-OS: OR, 0.38; 95% CI, 0.25-0.56; P<0.00001).	('metformin', 'Var', (32, 41))	('metformin', 'Chemical', 'MESH:D008687', (32, 41))	('patients', 'Species', '9606', (78, 86))	('5y-OS', 'Chemical', '-', (160, 165))	('2y-OS', 'Chemical', '-', (115, 120))	('patients', 'Species', '9606', (10, 18))	('benefits', 'PosReg', (55, 63))	('survival', 'CPA', (46, 54))	('metformin', 'Chemical', 'MESH:D008687', (104, 113))
240757	30425579	Epidemiologic findings have demonstrated that the incidence of cancer in patients with DM who received metformin was lower than among nondiabetics or patients with DM who received a drug other than metformin to control blood glucose.	('metformin', 'Chemical', 'MESH:D008687', (198, 207))	('nondiabetic', 'Disease', (134, 145))	('DM', 'Disease', 'MESH:D009223', (164, 166))	('glucose', 'Chemical', 'MESH:D005947', (225, 232))	('nondiabetic', 'Disease', 'MESH:D005923', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lower', 'NegReg', (117, 122))	('metformin', 'Var', (103, 112))	('patients', 'Species', '9606', (150, 158))	('metformin', 'Chemical', 'MESH:D008687', (103, 112))	('DM', 'Disease', 'MESH:D009223', (87, 89))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Disease', (63, 69))
240762	30425579	Metformin has been found to increase radiosensitivity to non-small cell lung cancer in vitro.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (57, 83))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('Metformin', 'Var', (0, 9))	('non-small cell lung cancer', 'Disease', (57, 83))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (28, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('radiosensitivity', 'CPA', (37, 53))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))	('increase', 'PosReg', (28, 36))
240763	30425579	Specifically, metformin reduces oxygen consumption and increases oxygenation in tumor cells by directly inhibiting mitochondrial metabolism; this mitigates radiation resistance associated with tumor hypoxia.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor hypoxia', 'Disease', 'MESH:D000860', (193, 206))	('mitochondrial metabolism', 'MPA', (115, 139))	('radiation', 'MPA', (156, 165))	('tumor', 'Disease', (193, 198))	('oxygen consumption', 'MPA', (32, 50))	('reduces', 'NegReg', (24, 31))	('oxygenation', 'MPA', (65, 76))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (80, 85))	('inhibiting', 'NegReg', (104, 114))	('tumor hypoxia', 'Disease', (193, 206))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('metformin', 'Var', (14, 23))	('oxygen', 'Chemical', 'MESH:D010100', (65, 71))	('increases', 'PosReg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('oxygen', 'Chemical', 'MESH:D010100', (32, 38))	('mitigates', 'NegReg', (146, 155))
240801	30425579	Specifically, metformin combined with radiation was found to enhance DNA damage in vitro, as measured by indices such as phosphorylation of histone protein H2AX and the olive tail moment.	('enhance', 'PosReg', (61, 68))	('metformin', 'Var', (14, 23))	('phosphorylation', 'MPA', (121, 136))	('DNA damage', 'CPA', (69, 79))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('olive', 'Species', '4146', (169, 174))	('olive tail moment', 'CPA', (169, 186))
240803	30425579	The molecular mechanisms that regulate metformin-enhanced radiosensitivity involve p53- and AMPK-mediated signaling pathways.	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('AMPK', 'Gene', '5562', (92, 96))	('metformin', 'Chemical', 'MESH:D008687', (39, 48))	('radiosensitivity', 'CPA', (58, 74))	('AMPK', 'Gene', (92, 96))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (49, 74))	('metformin-enhanced', 'Var', (39, 57))
240805	30425579	Skinner et al found that metformin radiosensitization was related to the expression of mutant p53.	('p53', 'Gene', (94, 97))	('metformin radiosensitization', 'MPA', (25, 53))	('p53', 'Gene', '7157', (94, 97))	('related', 'Reg', (58, 65))	('mutant', 'Var', (87, 93))	('expression', 'MPA', (73, 83))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))
240815	30425579	In the comparison of 5y-OS, the D+M group had no survival advantage over the N-M group.	('5y-OS', 'Chemical', '-', (21, 26))	('D+M', 'Var', (32, 35))	('survival', 'CPA', (49, 57))
240830	30250546	Growth inhibition and chemo-radiosensitization of esophageal squamous cell carcinoma by survivin-shRNA lentivirus transfection Esophageal cancer is one of the most common types of cancer worldwide, and it has a poor prognosis.	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (180, 186))	('Esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('survivin', 'Gene', '11799', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('survivin', 'Gene', (88, 96))	('transfection', 'Var', (114, 126))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('Esophageal cancer', 'Disease', (127, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))
240837	30250546	Survivin knockdown induced apoptosis in esophageal cancer KYSE-150 and ECA-109 cell lines when exposed to the aforementioned chemo-radiotherapy treatments.	('knockdown', 'Var', (9, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('Survivin', 'Gene', '11799', (0, 8))	('induced', 'Reg', (19, 26))	('Survivin', 'Gene', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('apoptosis', 'CPA', (27, 36))	('esophageal cancer', 'Disease', (40, 57))
240839	30250546	Targeted survivin ablation may be a promising strategy against esophageal tumor relapse and chemo-radioresistance.	('survivin', 'Gene', '11799', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('esophageal tumor', 'Disease', 'MESH:D004938', (63, 79))	('survivin', 'Gene', (9, 17))	('esophageal tumor', 'Disease', (63, 79))	('ablation', 'Var', (18, 26))	('esophageal tumor', 'Phenotype', 'HP:0100751', (63, 79))
240857	30250546	The present study demonstrated that lentivirus-mediated knockdown of survivin in ESC cell lines suppressed the tumorigenic capacity of these cells, and enhanced the sensitivity to conventional chemotherapy and radiotherapy in vitro.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('survivin', 'Gene', (69, 77))	('tumor', 'Disease', (111, 116))	('suppressed', 'NegReg', (96, 106))	('enhanced', 'PosReg', (152, 160))	('survivin', 'Gene', '11799', (69, 77))	('ESC', 'Phenotype', 'HP:0011459', (81, 84))	('knockdown', 'Var', (56, 65))
240878	30250546	ab76424, ab227387 and ab32561, respectively; all from Abcam, Cambridge, UK) overnight at 4 C. Subsequent to washing 3 times with TBST and incubated with peroxidase conjugated anti-rabbit secondary antibody (1:10,000; cat.	('ab227387', 'Var', (9, 17))	('rabbit', 'Species', '9986', (180, 186))	('ab32561', 'Var', (22, 29))
240894	30250546	1B) indicates that survivin was knocked down efficiently in all 4 cell lines, with ~50% at day 1 and up to 80% at day 3.	('survivin', 'Gene', '11799', (19, 27))	('knocked', 'Var', (32, 39))	('survivin', 'Gene', (19, 27))
240897	30250546	Consistent with the Matrigel  invasion assay, the wound healing assay additionally confirmed that survivin knockdown affected ESC cell migration (Fig.	('survivin', 'Gene', (98, 106))	('knockdown', 'Var', (107, 116))	('ESC', 'Phenotype', 'HP:0011459', (126, 129))	('ESC', 'Disease', (126, 129))	('survivin', 'Gene', '11799', (98, 106))	('affected', 'Reg', (117, 125))
240911	30250546	Compared to negative controls or cont-lent virus infection, drug treatment or svv-lent transfection significantly increased the proportion of apoptotic cells, indicating the role of survivin in ESC cell survival.	('virus infection', 'Disease', 'MESH:D015658', (43, 58))	('survivin', 'Gene', (182, 190))	('increased', 'PosReg', (114, 123))	('virus infection', 'Disease', (43, 58))	('survivin', 'Gene', '11799', (182, 190))	('transfection', 'Var', (87, 99))	('ESC', 'Phenotype', 'HP:0011459', (194, 197))
240912	30250546	Cells pretreated with svv-lent to knock down survivin, then exposed to paclitaxel (Fig.	('survivin', 'Gene', '11799', (45, 53))	('knock down', 'Var', (34, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (71, 81))	('survivin', 'Gene', (45, 53))
240915	30250546	Similarly, survivin knockdown sensitized the KYSE-150 and ECA-109 cells to radiation.	('knockdown', 'Var', (20, 29))	('survivin', 'Gene', '11799', (11, 19))	('sensitized', 'Reg', (30, 40))	('survivin', 'Gene', (11, 19))
240927	30250546	Survivin knockdown significantly inhibited ESC cells colony formation, migration and invasion (Fig.	('knockdown', 'Var', (9, 18))	('Survivin', 'Gene', '11799', (0, 8))	('ESC', 'Phenotype', 'HP:0011459', (43, 46))	('ESC cells colony formation', 'CPA', (43, 69))	('Survivin', 'Gene', (0, 8))	('migration', 'CPA', (71, 80))	('invasion', 'CPA', (85, 93))	('inhibited', 'NegReg', (33, 42))
240933	30250546	The results of the present study also indicated that survivin knockdown in ESC cell lines increased their sensitivity to chemo-radiotherapy (Fig.	('sensitivity to chemo-radiotherapy', 'MPA', (106, 139))	('increased', 'PosReg', (90, 99))	('survivin', 'Gene', '11799', (53, 61))	('survivin', 'Gene', (53, 61))	('ESC', 'Phenotype', 'HP:0011459', (75, 78))	('knockdown', 'Var', (62, 71))
240934	30250546	When ESC cells were exposed to paclitaxel, cisplatin or radiation, survivin knockdown increased the proportion of apoptotic cells, as measured by a TUNEL assay and verified by an elevated cleaved PARP1 level.	('PARP1', 'Gene', '142', (196, 201))	('PARP1', 'Gene', (196, 201))	('knockdown', 'Var', (76, 85))	('increased', 'PosReg', (86, 95))	('paclitaxel', 'Chemical', 'MESH:D017239', (31, 41))	('survivin', 'Gene', '11799', (67, 75))	('elevated', 'PosReg', (179, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('survivin', 'Gene', (67, 75))	('ESC', 'Phenotype', 'HP:0011459', (5, 8))
241041	27537591	Recently, Ishikawa et al reported that combining intraluminal brachytherapy (ILBT) with EBRT was more effective than EBRT alone in patients with medically inoperable T1b esophageal cancer, with the higher 5-year CSS rate in the ILBT group (86% vs 62%; P = 0.04).	('patients', 'Species', '9606', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('EBRT', 'Chemical', '-', (88, 92))	('esophageal cancer', 'Disease', (170, 187))	('CSS', 'MPA', (212, 215))	('EBRT', 'Chemical', '-', (117, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))	('T1b', 'Var', (166, 169))	('ILBT', 'Chemical', '-', (228, 232))	('CSS', 'Chemical', '-', (212, 215))	('ILBT', 'Chemical', '-', (77, 81))
241043	27537591	In their study, the LC rate of the EBRT + ILBT group was superior to that of the EBRT-alone group, although the difference was not statistically significant.	('EBRT + ILBT', 'Var', (35, 46))	('EBRT', 'Chemical', '-', (81, 85))	('ILBT', 'Chemical', '-', (42, 46))	('LC rate', 'CPA', (20, 27))	('superior', 'PosReg', (57, 65))	('EBRT', 'Chemical', '-', (35, 39))
241056	27537591	The 3 and 5-year LC rates were higher in the hypofractionation group (81.4% and 50.0% vs 71.8% and 44.1%; P = 0.02, respectively), whereas the 3 and 5-year OS rates were not different between the groups (43.2% and 38.8% vs 38.2% and 28.0%; P = 0.268, respectively).	('higher', 'PosReg', (31, 37))	('LC rates', 'CPA', (17, 25))	('OS', 'Chemical', '-', (156, 158))	('hypofractionation', 'Var', (45, 62))
241081	27328734	Several therapeutic options have been developed for clinical T1N0M0 (UICC-TNM classification, 7th edition) thoracic esophageal squamous cell carcinoma (ESCC): surgery, radiotherapy (RT), chemoradiotherapy (CRT), endoscopic resection (ER) including endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD).	('esophageal squamous cell carcinoma', 'Disease', (116, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('endoscopic submucosal dissection', 'Disease', (288, 320))	('T1N0M0', 'Var', (61, 67))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (116, 150))	('endoscopic mucosal resection', 'Disease', (248, 276))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))
241091	27328734	They concluded that based on the rate of lymph node metastasis, clinical T1N0M0 ESCC invading the MM or SM should be distinguished from EP/LPM cancer.	('LPM cancer', 'Disease', 'MESH:D009369', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('LPM cancer', 'Disease', (139, 149))	('MM', 'Disease', 'MESH:D009101', (98, 100))	('T1N0M0', 'Var', (73, 79))	('ESCC', 'Disease', (80, 84))
241092	27328734	In organ-conserving treatments for clinical T1N0M0 ESCC, the depth of tumor invasion is closely related to the treatment approach.	('T1N0M0 ESCC', 'Var', (44, 55))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
241165	27328734	The present analysis of organ-conserving treatment for patients with clinical T1N0M0 thoracic ESCC demonstrated that PS was an independent prognostic factor for both DSS and DFS.	('DFS', 'Disease', (174, 177))	('patients', 'Species', '9606', (55, 63))	('T1N0M0', 'Var', (78, 84))	('PS', 'Chemical', '-', (117, 119))	('DSS', 'Chemical', '-', (166, 169))	('DSS', 'Disease', (166, 169))
241170	27328734	reported that CRT resulted in increased OS rate compared to RT alone, but their trial included locally advanced squamous cell carcinoma and adenocarcinoma cases.	('OS rate', 'MPA', (40, 47))	('CRT', 'Var', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('adenocarcinoma', 'Disease', (140, 154))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 135))	('increased', 'PosReg', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Disease', (112, 135))
241200	27328734	In our multivariate analysis for patients with clinical T1N0M0 thoracic ESCC invading the MM or SM, ER showed significance regarding the local control rate.	('T1N0M0', 'Var', (56, 62))	('patients', 'Species', '9606', (33, 41))	('MM', 'Disease', 'MESH:D009101', (90, 92))	('local control', 'CPA', (137, 150))
241208	27328734	analyzed 53 patients with T1N0-T4N1 ESCC without distant metastases treated with RT, and they concluded that the omission of ENI was not associated with a significant amount of failure in lymph node regions.	('patients', 'Species', '9606', (12, 20))	('T1N0-T4N1', 'Var', (26, 35))	('metastases', 'Disease', (57, 67))	('failure', 'Disease', 'MESH:D017093', (177, 184))	('ENI', 'Chemical', '-', (125, 128))	('failure', 'Disease', (177, 184))	('metastases', 'Disease', 'MESH:D009362', (57, 67))
241213	27328734	The results of this study showed that PS was an independent prognostic factor for both DSS and DFS in patients with clinical T1N0M0 thoracic ESCC invading the MM or SM.	('patients', 'Species', '9606', (102, 110))	('DSS', 'Chemical', '-', (87, 90))	('PS', 'Chemical', '-', (38, 40))	('DSS', 'Disease', (87, 90))	('MM', 'Disease', 'MESH:D009101', (159, 161))	('T1N0M0', 'Var', (125, 131))
241238	25006285	The eligibility criteria included age 18-70 years, Eastern Cooperative Oncology Group (ECOG) status <=2, histopathologically proven T1 to T4 ESCC with N1 status (AJCC 2010, Stage IIB and III), hematological and biochemical parameters suitable for radiotherapy or chemotherapy, no tracheoesophageal fistula, no prior chest radiotherapy or chemotherapy or definitive surgery, no other primary cancer and no other diseases that needed hospitalization.	('cancer', 'Phenotype', 'HP:0002664', (391, 397))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (280, 305))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (280, 305))	('Oncology', 'Phenotype', 'HP:0002664', (71, 79))	('tracheoesophageal fistula', 'Disease', (280, 305))	('cancer', 'Disease', (391, 397))	('cancer', 'Disease', 'MESH:D009369', (391, 397))	('<=2', 'Var', (100, 103))
241289	25006285	In this trial, 172 eligible patients aged 70 years or more with T3-4N0-1M0 squamous cell cancers of the esophagus were randomized to pre-operative therapy (three cycles of 5-FU, leucovorin, etoposide, and cisplatin, followed by concurrent etoposide, cisplatin, plus 40 Gy) followed by surgery versus chemoradiation alone (the same chemotherapy but the RT dose was increased to 60 to 65 Gy +/- brachytherapy).	('leucovorin', 'Chemical', 'MESH:D002955', (178, 188))	('etoposide', 'Chemical', 'MESH:D005047', (190, 199))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (89, 113))	('etoposide', 'Chemical', 'MESH:D005047', (239, 248))	('T3-4N0-1M0', 'Var', (64, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (205, 214))	('5-FU', 'Chemical', 'MESH:D005472', (172, 176))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (75, 96))	('squamous cell cancers', 'Disease', (75, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (250, 259))	('patients', 'Species', '9606', (28, 36))	('squamous cell cancers', 'Disease', 'MESH:D002294', (75, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
241308	17546048	Loss of 16q23 occurs frequently in multiple tumors, indicating the presence of critical TSGs at this locus, such as the well-studied WWOX.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('multiple tumors', 'Disease', (35, 50))	('multiple tumors', 'Disease', 'MESH:D009369', (35, 50))	('WWOX', 'Gene', '51741', (133, 137))	('16q23', 'Gene', (8, 13))	('TSG', 'Gene', (88, 91))	('TSG', 'Gene', '57045', (88, 91))	('WWOX', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Loss', 'Var', (0, 4))
241311	17546048	Instead, methylation of the ADAMTS18 promoter CpG Island was frequently detected with methylation-specific PCR and bisulfite genome sequencing in multiple carcinoma cell lines and primary carcinomas, but not in any non-tumor cell line and normal epithelial tissue.	('methylation', 'Var', (9, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('non-tumor', 'Disease', 'MESH:D009369', (215, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('ADAMTS18', 'Gene', '170692', (28, 36))	('detected', 'Reg', (72, 80))	('non-tumor', 'Disease', (215, 224))	('bisulfite', 'Chemical', 'MESH:C042345', (115, 124))	('ADAMTS18', 'Gene', (28, 36))	('multiple carcinoma cell lines and primary carcinomas', 'Disease', 'MESH:C537656', (146, 198))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))
241312	17546048	Both pharmacological and genetic demethylation dramatically induced ADAMTS18 expression, indicating that CpG methylation directly contributes to the tumor-specific silencing of ADAMTS18.	('expression', 'MPA', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('demethylation', 'Var', (33, 46))	('ADAMTS18', 'Gene', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('ADAMTS18', 'Gene', (68, 76))	('ADAMTS18', 'Gene', '170692', (177, 185))	('tumor', 'Disease', (149, 154))	('silencing', 'NegReg', (164, 173))	('induced', 'PosReg', (60, 67))	('ADAMTS18', 'Gene', '170692', (68, 76))
241313	17546048	Ectopic ADAMTS18 expression leads to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells lacking the expression.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('ADAMTS18', 'Gene', '170692', (8, 16))	('carcinoma cell', 'Disease', 'MESH:C538614', (115, 129))	('carcinoma cell', 'Disease', (115, 129))	('Ectopic', 'Var', (0, 7))	('inhibition', 'NegReg', (49, 59))	('ADAMTS18', 'Gene', (8, 16))
241319	17546048	Inactivation of TSGs in human tumors is usually achieved through either the combination of one genetic change mainly chromosomal deletion, with another genetic or epigenetic change such as promoter methylation that silences gene transcription, or through epigenetic inactivation of both alleles.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('human', 'Species', '9606', (24, 29))	('chromosomal deletion', 'Var', (117, 137))	('epigenetic inactivation', 'Var', (255, 278))	('TSG', 'Gene', (16, 19))	('gene transcription', 'MPA', (224, 242))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('TSG', 'Gene', '57045', (16, 19))	('silences', 'NegReg', (215, 223))	('promoter methylation', 'Var', (189, 209))
241320	17546048	Frequently, TSGs identification begins with the detection of chromosomal deletions in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TSG', 'Gene', (12, 15))	('tumor', 'Disease', (86, 91))	('chromosomal deletions', 'Var', (61, 82))	('TSG', 'Gene', '57045', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
241330	17546048	We further found that the tumor-specific downregulation of ADAMTS18 is mediated by promoter methylation rather than genetic deletion.	('promoter methylation', 'Var', (83, 103))	('ADAMTS18', 'Gene', '170692', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('ADAMTS18', 'Gene', (59, 67))	('downregulation', 'NegReg', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
241340	17546048	Consistent with previous conventional CGH results (Table 1), we did detect a hemizygous 16q23.1 deletion (~2 Mb) in 3 out of 15 carcinoma cell lines examined (10 esophageal and 5 nasopharyngeal carcinoma) (Figure 2c, Ying & Tao, in preparation).	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (179, 203))	('nasopharyngeal carcinoma', 'Disease', (179, 203))	('15 carcinoma', 'Disease', (125, 137))	('16q23.1', 'Gene', (88, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (179, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal', 'Disease', (162, 172))	('15 carcinoma', 'Disease', 'MESH:C567193', (125, 137))	('deletion', 'Var', (96, 104))	('carcinoma cell', 'Disease', 'MESH:C538614', (128, 142))	('carcinoma cell', 'Disease', (128, 142))
241343	17546048	TSGs can also be frequently inactivated through epigenetic mechanisms, mainly methylation of promoter CpG Islands (CGI) that are generally unmethylated in normal tissues.	('TSG', 'Gene', (0, 3))	('TSG', 'Gene', '57045', (0, 3))	('methylation', 'Var', (78, 89))
241344	17546048	A typical CGI was found near the ADAMTS18 exon 1 by CpG Island Searcher (http://ccnt.hsc.usc.edu/cpgislands2), using the following criteria: GC content >55%, Obs CpG/Exp CpG >0.65, and length ~500 bp (Figure 3a), indicating that ADAMTS18 is vulnerable to methylation-mediated silencing.	('>55', 'Var', (152, 155))	('ADAMTS18', 'Gene', (33, 41))	('ADAMTS18', 'Gene', '170692', (229, 237))	('ADAMTS18', 'Gene', '170692', (33, 41))	('Searcher', 'Species', '274808', (63, 71))	('Obs', 'Var', (158, 161))	('ADAMTS18', 'Gene', (229, 237))
241348	17546048	In contrast, no methylation was detected in all 5 non-tumor epithelial cell lines (Figure 3b), indicating that ADAMTS18 CGI methylation is tumor-specific.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('ADAMTS18', 'Gene', '170692', (111, 119))	('non-tumor', 'Disease', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('non-tumor', 'Disease', 'MESH:D009369', (50, 59))	('methylation', 'Var', (124, 135))	('ADAMTS18', 'Gene', (111, 119))
241355	17546048	These results confirm that ADAMTS18 downregulation is directly mediated by CGI methylation.	('ADAMTS18', 'Gene', '170692', (27, 35))	('downregulation', 'NegReg', (36, 50))	('methylation', 'Var', (79, 90))	('ADAMTS18', 'Gene', (27, 35))
241357	17546048	Methylation was detected in a variety of tumors but seldom in the corresponding non-tumor tissues (Figure 5 and Table 2), highlighting the importance of tumor-specific ADAMTS18 methylation in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('non-tumor', 'Disease', (80, 89))	('tumors', 'Disease', (41, 47))	('non-tumor', 'Disease', 'MESH:D009369', (80, 89))	('ADAMTS18', 'Gene', (168, 176))	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (192, 197))	('ADAMTS18', 'Gene', '170692', (168, 176))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (84, 89))	('detected', 'Reg', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
241361	17546048	We report here that ADAMTS18 is downregulated in multiple carcinomas through promoter methylation rather than genetic deletion.	('downregulated', 'NegReg', (32, 45))	('ADAMTS18', 'Gene', '170692', (20, 28))	('multiple carcinomas', 'Disease', 'MESH:C537656', (49, 68))	('multiple carcinomas', 'Disease', (49, 68))	('ADAMTS18', 'Gene', (20, 28))	('promoter methylation', 'Var', (77, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
241367	17546048	However, we detected significantly more micro-deletions with much better resolution, thus greatly reducing the number of candidate genes for further functional validation and novel TSG identification.	('reducing', 'NegReg', (98, 106))	('TSG', 'Gene', '57045', (181, 184))	('TSG', 'Gene', (181, 184))	('micro-deletions', 'Var', (40, 55))
241368	17546048	On the other side, however, TSGs are more frequently inactivated through epigenetic mechanisms or a combination of genetic and epigenetic aberrations, than through biallelic genetic inactivation.	('TSG', 'Gene', '57045', (28, 31))	('inactivated', 'NegReg', (53, 64))	('epigenetic', 'Var', (73, 83))	('TSG', 'Gene', (28, 31))
241388	17546048	On the other hand, genetic mutations may also inactivate ADAMTS18.	('ADAMTS18', 'Gene', '170692', (57, 65))	('genetic mutations', 'Var', (19, 36))	('inactivate', 'NegReg', (46, 56))	('ADAMTS18', 'Gene', (57, 65))
241389	17546048	A very recent comprehensive mutation study reported 2 missense mutations (R382K and K455T, both within the metalloproteinase catalytic domain) of ADAMTS18 in 2/11 colon tumors.	('K455T', 'Var', (84, 89))	('colon tumors', 'Disease', 'MESH:D015179', (163, 175))	('ADAMTS18', 'Gene', '170692', (146, 154))	('K455T', 'Mutation', 'rs776584074', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('R382K', 'Var', (74, 79))	('colon tumors', 'Disease', (163, 175))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('R382K', 'Mutation', 'rs368783738', (74, 79))	('ADAMTS18', 'Gene', (146, 154))	('colon tumors', 'Phenotype', 'HP:0100273', (163, 175))
241390	17546048	However, the biologic implication of these mutations in tumorigenesis remains to be further investigated.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
241391	17546048	Multiple studies have shown that aberrant CGI methylation can be used as a sensitive marker for cancer diagnosis and prognosis prediction.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('CGI', 'Protein', (42, 45))	('aberrant', 'Var', (33, 41))	('cancer', 'Disease', (96, 102))
241412	17546048	48 hours later, the transfectants were replated in triplicate and cultured for 10-15 days in complete RPMI1640 medium containing G418 (400 mug/ml), without (colony formation assay) or with 0.33% agar (soft agar assay).	('colon', 'Disease', (157, 162))	('agar', 'Chemical', 'MESH:D000362', (195, 199))	('G418', 'Var', (129, 133))	('agar', 'Chemical', 'MESH:D000362', (206, 210))	('RPMI1640 medium', 'Chemical', '-', (102, 117))	('colon', 'Disease', 'MESH:D015179', (157, 162))	('G418', 'Chemical', 'MESH:C010680', (129, 133))
241428	31963924	Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk.	('gastric atrophy', 'Disease', 'MESH:D013274', (189, 204))	('gastritis', 'Disease', 'MESH:D005756', (161, 170))	('gastritis', 'Phenotype', 'HP:0005263', (161, 170))	('patients', 'Species', '9606', (60, 68))	('chronic H.', 'Var', (143, 153))	('H. pylori', 'Species', '210', (151, 160))	('gastritis', 'Disease', (161, 170))	('H. pylori gastritis', 'Phenotype', 'HP:0005202', (151, 170))	('gastric atrophy', 'Disease', (189, 204))
241448	31963924	Most are classified as Grade 1 (G1) on the WHO scale, with a Ki-67 index (if any) of <3%: they regress with resection of the gastric antrum, the location of the G-cells, which produce the gastrin.	('gastrin', 'Gene', '2520', (188, 195))	('resection', 'Var', (108, 117))	('gastrin', 'Gene', (188, 195))	('regress', 'NegReg', (95, 102))	('Grade 1 (G1', 'Gene', '5544', (23, 34))
241455	31963924	In the case of type-2 tumors, in patients with MEN-1, a hereditary condition caused by mutations which inactivate the tumor suppressor gene MEN1, the tumorigenic influence of gastrin may be accentuated by reduced tumor suppression, an additional factor in inducing carcinoids, although it must also be pointed out that despite the fact that using villin-Cre to delete the MEN1 locus in the gastrointestinal epithelium generated hypergastrinemia, G-cell hyperplasia and epithelial dysplasia, no ECL tumors developed.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('MEN-1', 'Gene', (47, 52))	('hyperplasia', 'Disease', 'MESH:D006965', (453, 464))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('delete', 'Var', (361, 367))	('gastrin', 'Gene', '2520', (433, 440))	('MEN1', 'Gene', '4221', (372, 376))	('inactivate', 'Var', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (428, 444))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('ECL', 'Gene', (494, 497))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('mutations', 'Var', (87, 96))	('ECL', 'Gene', '6366', (494, 497))	('tumor', 'Phenotype', 'HP:0002664', (498, 503))	('hypergastrinemia', 'Disease', (428, 444))	('MEN1', 'Gene', (372, 376))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('carcinoid', 'Phenotype', 'HP:0100570', (265, 274))	('epithelial dysplasia', 'Disease', (469, 489))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('hypergastrinemia', 'Disease', 'None', (428, 444))	('tumors', 'Phenotype', 'HP:0002664', (498, 504))	('gastrin', 'Gene', (433, 440))	('tumors', 'Disease', (22, 28))	('MEN1', 'Gene', '4221', (140, 144))	('gastrin', 'Gene', '2520', (175, 182))	('carcinoids', 'Disease', 'MESH:D002276', (265, 275))	('carcinoids', 'Disease', (265, 275))	('tumors', 'Disease', (498, 504))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (213, 218))	('MEN1', 'Gene', (140, 144))	('MEN-1', 'Gene', '4221', (47, 52))	('patients', 'Species', '9606', (33, 41))	('tumor', 'Disease', (498, 503))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('carcinoids', 'Phenotype', 'HP:0100570', (265, 275))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Disease', (118, 123))	('gastrin', 'Gene', (175, 182))	('tumors', 'Disease', 'MESH:D009369', (498, 504))	('tumor', 'Disease', (22, 27))	('hyperplasia', 'Disease', (453, 464))	('tumor', 'Disease', 'MESH:D009369', (498, 503))	('epithelial dysplasia', 'Disease', 'MESH:C567703', (469, 489))
241456	31963924	This suggests that more than one alteration to this genome may be required for the genesis of type-2 NETs in MEN-1, or that deletions or heterozygosity in the somatostatin genome may also be involved.	('MEN-1', 'Gene', '4221', (109, 114))	('MEN-1', 'Gene', (109, 114))	('NETs', 'Disease', 'MESH:D018358', (101, 105))	('heterozygosity', 'Var', (137, 151))	('deletions', 'Var', (124, 133))	('NETs', 'Disease', (101, 105))
241463	31963924	In a rare human disease, that closely resembles exposure to prolonged PPI therapy, members of a Spanish family, homozygous for an inactivating mutation in the gene ATP4A that regulates expression of the alpha subunit of H+/K+ ATPase, have the inability to secrete gastric acid and consequently have life-long hypochlorhydria and hypergastrinemia.	('ATP4A', 'Gene', (164, 169))	('human', 'Species', '9606', (10, 15))	('expression', 'MPA', (185, 195))	('ATPase', 'Gene', (226, 232))	('ATP4A', 'Gene', '495', (164, 169))	('inactivating mutation in', 'Var', (130, 154))	('inability', 'NegReg', (243, 252))	('secrete gastric acid', 'MPA', (256, 276))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (329, 345))	('life-long hypochlorhydria and hypergastrinemia', 'Disease', 'MESH:D000126', (299, 345))	('ATPase', 'Gene', '1769', (226, 232))
241469	31963924	Recent studies, however, have shown that FSG levels in PPI users do not reflect the 4- or 5-fold elevations in mean serum gastrin concentrations that occur and persist after meals, particularly in females.	('PPI', 'Var', (55, 58))	('gastrin', 'Gene', (122, 129))	('gastrin', 'Gene', '2520', (122, 129))
241487	31963924	Other factors may emerge that specifically identify subpopulations at an enhanced risk of developing PPI-associated carcinoids including: presence of chronic gastritis (short of corpus atrophy) due to autoimmunity or H. pylori infection:the latter perhaps accelerated by PPI therapy; the dose or duration of PPI therapy; the presence of a PPI slow-metabolizer phenotype; or the presence of mutations in other genes e.g., MEN-1 or those affecting somatostatin responses.	('atrophy', 'Disease', (185, 192))	('MEN-1', 'Gene', (421, 426))	('chronic gastritis', 'Disease', (150, 167))	('mutations', 'Var', (390, 399))	('carcinoids', 'Disease', 'MESH:D002276', (116, 126))	('pylori infection', 'Disease', (220, 236))	('carcinoids', 'Disease', (116, 126))	('H. pylori infection', 'Phenotype', 'HP:0005202', (217, 236))	('chronic gastritis', 'Phenotype', 'HP:0005231', (150, 167))	('carcinoids', 'Phenotype', 'HP:0100570', (116, 126))	('gastritis', 'Phenotype', 'HP:0005263', (158, 167))	('autoimmunity', 'Disease', (201, 213))	('chronic gastritis', 'Disease', 'MESH:D005756', (150, 167))	('MEN-1', 'Gene', '4221', (421, 426))	('PPI-associated', 'Disease', (101, 115))	('accelerated', 'PosReg', (256, 267))	('presence', 'Reg', (378, 386))	('H. pylori', 'Species', '210', (217, 226))	('autoimmunity', 'Disease', 'MESH:D001327', (201, 213))	('pylori infection', 'Disease', 'MESH:D016481', (220, 236))	('atrophy', 'Disease', 'MESH:D001284', (185, 192))	('autoimmunity', 'Phenotype', 'HP:0002960', (201, 213))	('carcinoid', 'Phenotype', 'HP:0100570', (116, 125))
241506	31963924	Together, these observations suggest that by causing hypergastrinemia, widespread use of PPIs, often for many years and particularly in patients with intractable reflux disease, may be contributing to increase in the occurrence of many cancers, both within and outside the gastrointestinal tract.	('man', 'Species', '9606', (105, 108))	('causing', 'Reg', (45, 52))	('increase', 'PosReg', (201, 209))	('hypergastrinemia', 'Disease', (53, 69))	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('reflux disease', 'Phenotype', 'HP:0002020', (162, 176))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('cancers', 'Disease', (236, 243))	('patients', 'Species', '9606', (136, 144))	('hypergastrinemia', 'Disease', 'None', (53, 69))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('PPIs', 'Var', (89, 93))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (53, 69))	('man', 'Species', '9606', (231, 234))
241520	31963924	While the trophic effect of gastrin leading to ECL cell hyperplasia may be a necessary factor in increasing tumor development, it may not be the sole factor involved; loss or impaired expression of the tumor-suppressor gene menin (even in heterozygous subjects), dysregulation of somatostatin response genes or those regulating chromogranin A, Reg-1 protein expression, phenotype for PPI-degradation, or presence of acquired diseases such as H. pylori or auto-immune chronic gastritis, may all modify the effects of PPIs in different susceptible individuals.	('effects', 'MPA', (505, 512))	('gastrin', 'Gene', '2520', (28, 35))	('tumor', 'Disease', (108, 113))	('trophic effect', 'Phenotype', 'HP:0010834', (10, 24))	('chronic gastritis', 'Disease', (467, 484))	('loss', 'Disease', 'MESH:D016388', (167, 171))	('H. pylori', 'Disease', (442, 451))	('men', 'Species', '9606', (224, 227))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (202, 207))	('hyperplasia', 'Disease', (56, 67))	('men', 'Species', '9606', (121, 124))	('chromogranin A', 'Gene', (328, 342))	('Reg-1', 'Gene', '80149', (344, 349))	('gastrin', 'Gene', (28, 35))	('hyperplasia', 'Disease', 'MESH:D006965', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('menin', 'Gene', '4221', (224, 229))	('dysregulation', 'Var', (263, 276))	('chronic gastritis', 'Phenotype', 'HP:0005231', (467, 484))	('H. pylori', 'Species', '210', (442, 451))	('menin', 'Gene', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('chromogranin A', 'Gene', '1113', (328, 342))	('gastritis', 'Phenotype', 'HP:0005263', (475, 484))	('ECL', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('loss', 'Disease', (167, 171))	('ECL', 'Gene', '6366', (47, 50))	('chronic gastritis', 'Disease', 'MESH:D005756', (467, 484))	('modify', 'Reg', (494, 500))	('Reg-1', 'Gene', (344, 349))
241526	31963924	The PPI-induced, growth-promoting effects of gastrin, on tumors in the stomach, increasingly appears to affect gastric cancers as well as gastric carcinoids, and may well extend to cancers in other organs.	('carcinoid', 'Phenotype', 'HP:0100570', (146, 155))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('gastrin', 'Gene', (45, 52))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumors in the stomach', 'Phenotype', 'HP:0006753', (57, 78))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('PPI-induced', 'Var', (4, 15))	('cancers', 'Disease', (119, 126))	('growth-promoting', 'PosReg', (17, 33))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gastric carcinoids', 'Disease', 'MESH:D002276', (138, 156))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('gastric carcinoids', 'Disease', (138, 156))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Disease', (181, 188))	('gastric cancers', 'Disease', 'MESH:D013274', (111, 126))	('gastric cancers', 'Disease', (111, 126))	('affect', 'Reg', (104, 110))	('gastric cancers', 'Phenotype', 'HP:0012126', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('gastrin', 'Gene', '2520', (45, 52))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('carcinoids', 'Phenotype', 'HP:0100570', (146, 156))	('tumors', 'Disease', (57, 63))
241540	31963924	Additional staining of the excised tumor revealed the presence of synaptophysin, CgA, vesicular monoamine transporter 2 (VMAT 2), and positivity on Sevier-Mungar staining, all indicating an ECL cell origin.	('CgA', 'Gene', '1113', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('synaptophysin', 'Gene', '6855', (66, 79))	('vesicular monoamine transporter 2', 'Gene', (86, 119))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CgA', 'Gene', (81, 84))	('tumor', 'Disease', (35, 40))	('vesicular monoamine transporter 2', 'Gene', '6571', (86, 119))	('ECL', 'Gene', (190, 193))	('VMAT 2', 'Gene', '6571', (121, 127))	('ECL', 'Gene', '6366', (190, 193))	('synaptophysin', 'Gene', (66, 79))	('VMAT 2', 'Gene', (121, 127))	('positivity', 'Var', (134, 144))
241549	31963924	Serum gastrin (191 pmol/L) and serum chromogranin (19.7 nmol/L) were both elevated while taking PPI, but both normalized 3 months after drug use ceased.	('PPI', 'Var', (96, 99))	('elevated', 'PosReg', (74, 82))	('gastrin', 'Gene', '2520', (6, 13))	('gastrin', 'Gene', (6, 13))
241556	31963924	Three months after stopping PPI, both serum gastrin and chromogranin A had returned to normal and ECL-cell hyperplasia had disappeared, but diffuse ECL-density was still present.	('hyperplasia', 'Disease', (107, 118))	('chromogranin A', 'Gene', (56, 70))	('gastrin', 'Gene', (44, 51))	('ECL', 'Gene', (148, 151))	('disappeared', 'NegReg', (123, 134))	('returned', 'PosReg', (75, 83))	('ECL', 'Gene', '6366', (148, 151))	('hyperplasia', 'Disease', 'MESH:D006965', (107, 118))	('PPI', 'Var', (28, 31))	('ECL', 'Gene', (98, 101))	('gastrin', 'Gene', '2520', (44, 51))	('chromogranin A', 'Gene', '1113', (56, 70))	('ECL', 'Gene', '6366', (98, 101))
241602	31554233	In this study, we examined the role of ATP6V0C in glucose metabolism in ECCs.	('glucose metabolism', 'Disease', 'MESH:D044882', (50, 68))	('ATP6V0C', 'Var', (39, 46))	('glucose metabolism', 'Disease', (50, 68))
241603	31554233	The ATP6V0C depletion attenuated ECC proliferation, invasion, and suppressed glucose metabolism, as indicated by reduced glucose uptake and decreased lactate and adenosine triphosphate (ATP) production in cells.	('decreased', 'NegReg', (140, 149))	('glucose metabolism', 'Disease', 'MESH:D044882', (77, 95))	('glucose', 'Chemical', 'MESH:D005947', (121, 128))	('lactate', 'Chemical', 'MESH:D019344', (150, 157))	('suppressed glucose metabolism', 'Phenotype', 'HP:0040270', (66, 95))	('glucose metabolism', 'Disease', (77, 95))	('glucose', 'Chemical', 'MESH:D005947', (77, 84))	('ATP', 'Chemical', 'MESH:D000255', (4, 7))	('invasion', 'CPA', (52, 60))	('suppressed', 'NegReg', (66, 76))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (162, 184))	('ECC proliferation', 'CPA', (33, 50))	('attenuated', 'NegReg', (22, 32))	('ATP6V0C depletion', 'Var', (4, 21))	('reduced', 'NegReg', (113, 120))	('glucose uptake', 'MPA', (121, 135))	('ATP', 'Chemical', 'MESH:D000255', (186, 189))
241604	31554233	Consistent with this, expression of glycolytic enzyme and the extracellular acidification rate (ECAR) were also decreased by ATP6V0C knockdown.	('knockdown', 'Var', (133, 142))	('expression', 'Species', '29278', (22, 32))	('extracellular acidification rate', 'MPA', (62, 94))	('decreased', 'NegReg', (112, 121))	('glycolytic enzyme', 'Enzyme', (36, 53))	('expression', 'MPA', (22, 32))	('ATP6V0C knockdown', 'Var', (125, 142))
241605	31554233	Mechanistically, ATP6V0C interacted with pyruvate kinase isoform M2 (PKM2), a key regulator of glycolysis in ECCs.	('pyruvate', 'Chemical', 'MESH:D011773', (41, 49))	('interacted', 'Reg', (25, 35))	('ATP6V0C', 'Var', (17, 24))	('PKM2', 'Gene', (69, 73))
241626	31554233	Consistent with this result, fibroblast cells overexpressing ATP6V0C exhibit high invasiveness along with matrix metalloproteinase 2 (MMP-2) secretion.	('matrix metalloproteinase 2', 'Gene', '17390', (106, 132))	('matrix metalloproteinase 2', 'Gene', (106, 132))	('MMP-2', 'Gene', '17390', (134, 139))	('invasiveness', 'CPA', (82, 94))	('ATP6V0C', 'Var', (61, 68))	('MMP-2', 'Gene', (134, 139))
241642	31554233	3827), p-Jun N-terminal kinase (p-JNK) (Thr183/Tyr185; cat.	('p-Jun N-terminal kinase', 'MPA', (7, 30))	('Thr183/Tyr185;', 'Var', (40, 54))	('JNK', 'Gene', '26419', (34, 37))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('JNK', 'Gene', (34, 37))	('Thr183', 'Chemical', 'MESH:C083647', (40, 46))
241691	31554233	The proliferation of ENFs was unaffected by ATP6V0C depletion when compared to cells treated with NS (Figure S2).	('N', 'Chemical', 'MESH:D009584', (98, 99))	('ATP6V0C depletion', 'Var', (44, 61))	('ENFs', 'CPA', (21, 25))	('N', 'Chemical', 'MESH:D009584', (22, 23))
241692	31554233	In exploring whether ATP6V0C regulates the expression of cell-cycle regulators and cell survival-related proteins in TE8 cells, we found that reducing levels of ATP6V0C decreased the expression of cyclin E, cyclin-dependent kinase 2 (cdk2), and b-cell lymphoma (bcl-2), indicating G1 phase arrest (Figure 1D).	('ATP6V0C', 'Var', (161, 168))	('cyclin-dependent kinase 2', 'Gene', (207, 232))	('G1 phase arrest', 'CPA', (281, 296))	('cyclin-dependent kinase 2', 'Gene', '12566', (207, 232))	('b-cell lymphoma', 'Disease', (245, 260))	('lymphoma', 'Phenotype', 'HP:0002665', (252, 260))	('b-cell lymphoma', 'Phenotype', 'HP:0012191', (245, 260))	('bcl-2', 'Gene', '12043', (262, 267))	('expression', 'Species', '29278', (183, 193))	('bcl-2', 'Gene', (262, 267))	('b-cell lymphoma', 'Disease', 'MESH:D016399', (245, 260))	('cyclin', 'Protein', (197, 203))	('expression', 'MPA', (183, 193))	('expression', 'Species', '29278', (43, 53))	('decreased', 'NegReg', (169, 178))	('cdk2', 'Gene', (234, 238))	('cdk2', 'Gene', '12566', (234, 238))
241693	31554233	However, in ENFs, the levels of cleaved caspase 3, poly (ADP-ribose) polymerase (PARP), apoptosis-related proteins, and bcl-2, a regulator of cell survival, were unchanged by ATP6V0C depletion (Figure S2).	('bcl-2', 'Gene', (120, 125))	('PARP', 'Gene', (81, 85))	('PARP', 'Gene', '11545', (81, 85))	('levels of cleaved caspase 3', 'MPA', (22, 49))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('ATP6V0C depletion', 'Var', (175, 192))	('poly (ADP-ribose)', 'Chemical', 'MESH:D011064', (51, 68))	('apoptosis-related', 'MPA', (88, 105))	('bcl-2', 'Gene', '12043', (120, 125))
241694	31554233	Moreover, apoptosis in ENFs was not significantly reduced by the depletion of ATP6V0C, as revealed by Annexin V staining (Figure S2).	('Annexin V', 'Gene', (102, 111))	('Annexin V', 'Gene', '11747', (102, 111))	('apoptosis', 'CPA', (10, 19))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('depletion', 'Var', (65, 74))	('ATP6V0C', 'Var', (78, 85))
241696	31554233	The ATP6V0C depletion led to a reduction in proliferation of neuroblastoma SH-SY5SY, cervix adenocarcinoma HeLa, melanoma SK-MEL-1, and osteosarcoma U2OS cells (Figure S3).	('reduction', 'NegReg', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('SK-MEL-1', 'CellLine', 'CVCL:0068', (122, 130))	('ATP6V0C depletion', 'Var', (4, 21))	('osteosarcoma', 'Phenotype', 'HP:0002669', (136, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('neuroblastoma', 'Disease', (61, 74))	('U2OS', 'CellLine', 'CVCL:0042', (149, 153))	('adenocarcinoma HeLa', 'Disease', (92, 111))	('neuroblastoma', 'Phenotype', 'HP:0003006', (61, 74))	('SH-SY5SY', 'CellLine', 'CVCL:7028', (75, 83))	('proliferation', 'CPA', (44, 57))	('osteosarcoma', 'Disease', (136, 148))	('osteosarcoma', 'Disease', 'MESH:D012516', (136, 148))	('neuroblastoma', 'Disease', 'MESH:D009447', (61, 74))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('adenocarcinoma HeLa', 'Disease', 'MESH:D000230', (92, 111))
241697	31554233	Interestingly, the expression levels of ATP6V0C varied depending on the cancer cell line (Figure S3), suggesting a potential role for ATP6V0C in various cancers.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancer', 'Disease', (153, 159))	('cancers', 'Disease', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('expression levels', 'MPA', (19, 36))	('ATP6V0C', 'Var', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('expression', 'Species', '29278', (19, 29))	('cancer', 'Disease', (72, 78))
241699	31554233	The ATP6V0C depletion resulted in a 40% decrease in the proliferation of TE8 cells compared to cells treated with non-silencing siRNA (NS) under high-glucose condition (Figure 1E).	('decrease', 'NegReg', (40, 48))	('proliferation', 'CPA', (56, 69))	('glucose', 'Chemical', 'MESH:D005947', (150, 157))	('high-glucose', 'Phenotype', 'HP:0003074', (145, 157))	('ATP6V0C depletion', 'Var', (4, 21))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('N', 'Chemical', 'MESH:D009584', (135, 136))
241700	31554233	Similarly, after ATP6V0C depletion, we found a 50% decrease in the TE8 cell number under low-glucose conditions (Figure 1E).	('TE8 cell number', 'CPA', (67, 82))	('glucose', 'Chemical', 'MESH:D005947', (93, 100))	('low-glucose', 'Phenotype', 'HP:0001943', (89, 100))	('decrease', 'NegReg', (51, 59))	('ATP6V0C depletion', 'Var', (17, 34))
241701	31554233	These results suggested that ECC viability is sensitive to glucose availability and ATP6V0C depletion results in a decrease in the survival of ECCs; this was not observed with ENFs.	('N', 'Chemical', 'MESH:D009584', (177, 178))	('ATP6V0C depletion', 'Var', (84, 101))	('decrease', 'NegReg', (115, 123))	('survival', 'CPA', (131, 139))	('glucose', 'Chemical', 'MESH:D005947', (59, 66))
241703	31554233	Therefore, we examined whether depletion of ATP6V0C, which is a pH regulator, affects TE8 cell motility and invasiveness under high- or low-glucose conditions.	('invasiveness', 'CPA', (108, 120))	('low-glucose', 'Phenotype', 'HP:0001943', (136, 147))	('affects', 'Reg', (78, 85))	('ATP6V0C', 'Var', (44, 51))	('glucose', 'Chemical', 'MESH:D005947', (140, 147))
241704	31554233	In addition, low-glucose condition and ATP6V0C depletion decreased further both migration and invasion of TE8 cells by 50% (Figure 2A,B).	('ATP6V0C depletion', 'Var', (39, 56))	('migration', 'CPA', (80, 89))	('low-glucose', 'Phenotype', 'HP:0001943', (13, 24))	('invasion of TE8 cells', 'CPA', (94, 115))	('glucose', 'Chemical', 'MESH:D005947', (17, 24))	('decreased', 'NegReg', (57, 66))
241706	31554233	We found that combining ATP6V0C depletion and 2DG resulted in greater inhibition of migration and invasion of TE8 cells compared to 2DG treatment alone, suggesting that both ATP6V0C and glucose are critical for migration and invasion of ECCs (Figure 2C,D).	('inhibition', 'NegReg', (70, 80))	('glucose', 'Chemical', 'MESH:D005947', (186, 193))	('invasion', 'CPA', (98, 106))	('migration', 'CPA', (84, 93))	('ATP6V0C depletion', 'Var', (24, 41))
241709	31554233	The ATP6V0C depletion led to pronounced inhibition of TE8 cell adhesion, as revealed by decreased levels of phosphorylated paxillin (Figure 2E,F).	('inhibition', 'NegReg', (40, 50))	('paxillin', 'Gene', (123, 131))	('decreased', 'NegReg', (88, 97))	('ATP6V0C depletion', 'Var', (4, 21))	('TE8 cell adhesion', 'CPA', (54, 71))	('paxillin', 'Gene', '19303', (123, 131))
241710	31554233	We also assessed the phosphorylation status of signaling components that mediate motility and adhesion in ATP6V0C-depleted TE8 cells and found that ATP6V0C depletion inhibits phosphorylation of FAK, ERK, and c-JNK in ECCs (Figure 2G).	('FAK', 'Gene', (194, 197))	('ATP6V0C depletion', 'Var', (148, 165))	('JNK', 'Gene', (210, 213))	('ERK', 'Gene', '26413', (199, 202))	('FAK', 'Gene', '14083', (194, 197))	('phosphorylation', 'MPA', (175, 190))	('JNK', 'Gene', '26419', (210, 213))	('inhibits', 'NegReg', (166, 174))	('ERK', 'Gene', (199, 202))	('depletion', 'Var', (156, 165))
241711	31554233	These results indicate that ATP6V0C induces phosphorylation of signaling components, including ERK, JNK, and FAK, during ECC adhesion and movement.	('phosphorylation', 'MPA', (44, 59))	('ATP6V0C', 'Var', (28, 35))	('FAK', 'Gene', '14083', (109, 112))	('FAK', 'Gene', (109, 112))	('ERK', 'Gene', (95, 98))	('JNK', 'Gene', '26419', (100, 103))	('ERK', 'Gene', '26413', (95, 98))	('JNK', 'Gene', (100, 103))	('induces', 'Reg', (36, 43))
241714	31554233	We observed that ATP6V0C depletion significantly reduced ATP and lactate production compared to cells treated with NS under both high- and low-glucose conditions (Figure 3A,B).	('lactate production', 'MPA', (65, 83))	('low-glucose', 'Phenotype', 'HP:0001943', (139, 150))	('reduced', 'NegReg', (49, 56))	('ATP', 'Chemical', 'MESH:D000255', (57, 60))	('N', 'Chemical', 'MESH:D009584', (115, 116))	('ATP', 'Chemical', 'MESH:D000255', (17, 20))	('lactate', 'Chemical', 'MESH:D019344', (65, 72))	('glucose', 'Chemical', 'MESH:D005947', (143, 150))	('ATP6V0C depletion', 'Var', (17, 34))
241715	31554233	In addition, ATP6V0C depletion resulted in a significant decrease in glucose uptake under high- and low-glucose conditions (Figure 3C).	('decrease', 'NegReg', (57, 65))	('glucose', 'Chemical', 'MESH:D005947', (69, 76))	('low-glucose', 'Phenotype', 'HP:0001943', (100, 111))	('ATP6V0C depletion', 'Var', (13, 30))	('glucose uptake', 'MPA', (69, 83))	('glucose', 'Chemical', 'MESH:D005947', (104, 111))
241718	31554233	We found that ATP6V0C depletion resulted in decreased expression of glycolytic genes such as Glut1, HIF-1, HK2, phosphofructokinase-1 (PFK1), enolase 1 (ENO1), PKM2, LDHA, and pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK1), under both high- and low-glucose conditions (Figure 3D,E), suggesting that ATP6V0C positively regulates the expression of HIF 1-dependent glycolytic genes.	('HK2', 'Gene', (107, 110))	('Glut1', 'Gene', (93, 98))	('expression', 'Species', '29278', (54, 64))	('expression', 'MPA', (342, 352))	('regulates', 'Reg', (328, 337))	('HK2', 'CellLine', 'CVCL:0302', (107, 110))	('LDHA', 'Gene', (166, 170))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('glucose', 'Chemical', 'MESH:D005947', (259, 266))	('ATP6V0C', 'Var', (309, 316))	('low-glucose', 'Phenotype', 'HP:0001943', (255, 266))	('LDHA', 'Gene', '16828', (166, 170))	('expression', 'Species', '29278', (342, 352))	('glycolytic genes', 'Gene', (68, 84))	('expression', 'MPA', (54, 64))	('ATP6V0C', 'Var', (14, 21))	('pyruvate', 'Chemical', 'MESH:D011773', (176, 184))	('Glut1', 'Gene', '20525', (93, 98))	('decreased', 'NegReg', (44, 53))
241721	31554233	However, upon glucose stimulation, depletion of ATP6V0C resulted in a significant reduction of ECAR (Figure 3F).	('depletion', 'MPA', (35, 44))	('reduction', 'NegReg', (82, 91))	('ATP6V0C', 'Var', (48, 55))	('ECAR', 'MPA', (95, 99))	('glucose', 'Chemical', 'MESH:D005947', (14, 21))
241722	31554233	When oligomycin, which inhibits ATP synthase in mitochondria, was added, ECAR was further decreased by ATP6V0C depletion (Figure 3F).	('oligomycin', 'Chemical', 'MESH:C031004', (5, 15))	('decreased', 'NegReg', (90, 99))	('ATP', 'Chemical', 'MESH:D000255', (32, 35))	('ATP', 'Chemical', 'MESH:D000255', (103, 106))	('ATP6V0C depletion', 'Var', (103, 120))	('ECAR', 'MPA', (73, 77))
241723	31554233	Similarly, ATP6V0C knockdown led to lower ECAR compared with the NS control after treatment with FCCP which induces proton leak, or rotenone, a complex I inhibitor to shut down electron transport chain (Figure 3F).	('rotenone', 'Chemical', 'MESH:D012402', (132, 140))	('lower', 'NegReg', (36, 41))	('induces', 'Reg', (108, 115))	('proton leak', 'MPA', (116, 127))	('ATP6V0C knockdown', 'Var', (11, 28))	('ECAR', 'MPA', (42, 46))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('FCCP', 'Chemical', 'MESH:D002259', (97, 101))
241725	31554233	Thus, these results suggest that ATP6V0C is critical for glycolysis rather than mitochondrial respiration in ECCs in the presence of glucose.	('mitochondrial respiration', 'MPA', (80, 105))	('glycolysis', 'MPA', (57, 67))	('ATP6V0C', 'Var', (33, 40))	('glucose', 'Chemical', 'MESH:D005947', (133, 140))
241727	31554233	In this study, we examined the effects of ATP6V0C depletion on phosphorylation levels of AKT, S6K1, and AMPK.	('ATP6V0C', 'Var', (42, 49))	('S6K1', 'Gene', '72508', (94, 98))	('AKT', 'Pathway', (89, 92))	('S6K1', 'Gene', (94, 98))	('phosphorylation levels', 'MPA', (63, 85))
241728	31554233	The ATP6V0C depletion decreased AKT and S6K1 phosphorylation but increased AMPK phosphorylation, while the total levels of AKT, S6K1, and AMPK remained unchanged (Figure 3H), indicating that ATP6V0C enhances signaling related to energy metabolism for ECC growth.	('increased', 'PosReg', (65, 74))	('S6K1', 'Gene', '72508', (128, 132))	('ATP6V0C', 'Var', (4, 11))	('S6K1', 'Gene', '72508', (40, 44))	('phosphorylation', 'MPA', (45, 60))	('enhances', 'PosReg', (199, 207))	('ATP6V0C', 'Var', (191, 198))	('AMPK phosphorylation', 'MPA', (75, 95))	('S6K1', 'Gene', (128, 132))	('S6K1', 'Gene', (40, 44))	('AKT', 'MPA', (32, 35))	('signaling', 'MPA', (208, 217))	('decreased', 'NegReg', (22, 31))
241729	31554233	Taken together, the results of this study suggest that ATP6V0C increases aerobic glycolysis and maintains ECC proliferation under both high- and low-glucose conditions.	('aerobic glycolysis', 'MPA', (73, 91))	('increases', 'PosReg', (63, 72))	('glucose', 'Chemical', 'MESH:D005947', (149, 156))	('ATP6V0C', 'Var', (55, 62))	('low-glucose', 'Phenotype', 'HP:0001943', (145, 156))	('ECC proliferation', 'CPA', (106, 123))
241731	31554233	The PKM2 mutant R399E, common in cancer cells, disrupts tetramer formation of PKM2, thereby producing dimers and decreasing its pyruvate kinase activity, eventually resulting in increased cancer cell proliferation.	('cancer', 'Disease', (33, 39))	('tetramer formation', 'MPA', (56, 74))	('pyruvate kinase activity', 'MPA', (128, 152))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('PKM2', 'Gene', (78, 82))	('R399E', 'Var', (16, 21))	('disrupts', 'NegReg', (47, 55))	('dimers', 'MPA', (102, 108))	('R399E', 'Mutation', 'p.R399E', (16, 21))	('increased', 'PosReg', (178, 187))	('producing', 'Reg', (92, 101))	('PKM2', 'Gene', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutant R399E', 'Var', (9, 21))	('decreasing', 'NegReg', (113, 123))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('pyruvate', 'Chemical', 'MESH:D011773', (128, 136))
241733	31554233	The ATP6V0C was associated more strongly with the Flag-PKM2 mutant R399E compared to Flag-PKM2 WT (Figure 4B), suggesting that ATP6V0C interacts with dimeric PKM2.	('R399E', 'Var', (67, 72))	('interacts', 'Interaction', (135, 144))	('mutant R399E', 'Var', (60, 72))	('Flag-PKM2', 'Gene', (50, 59))	('R399E', 'Mutation', 'p.R399E', (67, 72))
241735	31554233	Interestingly, compared to high-glucose conditions, endogenous ATP6V0C strongly interacted with Flag-PKM2 (Figure 4C) and interacted more with endogenous PKM2 in TE8 cells (Figure 4D) under low-glucose condition.	('low-glucose', 'Phenotype', 'HP:0001943', (190, 201))	('high-glucose', 'Phenotype', 'HP:0003074', (27, 39))	('glucose', 'Chemical', 'MESH:D005947', (32, 39))	('interacted', 'Interaction', (80, 90))	('glucose', 'Chemical', 'MESH:D005947', (194, 201))	('interacted', 'Reg', (122, 132))	('endogenous', 'Var', (52, 62))
241736	31554233	The PKM2 domain containing amino acids 1-116 includes catalytic active sites, such as tyrosine residue 105 (Tyr105) and tyrosine residue 148 (Tyr148), which are significant in cancer cell metabolism and growth.	('Tyr148', 'Chemical', 'MESH:C059343', (142, 148))	('tyrosine', 'Chemical', 'None', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tyrosine', 'Chemical', 'None', (120, 128))	('cancer', 'Disease', (176, 182))	('tyrosine residue 105 (Tyr105', 'Var', (86, 114))	('tyrosine residue 148', 'Var', (120, 140))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('Tyr105', 'Var', (108, 114))
241737	31554233	The results demonstrated that the N-terminal domain of PKM2 containing amino acids 1-116 interacts strongly with ATP6V0C, whereas other PKM2 portions containing amino acids 116-218, 218-389, or 389-531 are not associated with ATP6V0C (Figure 4E).	('interacts', 'Interaction', (89, 98))	('amino acids 1-116', 'Var', (71, 88))	('ATP6V0C', 'Disease', (113, 120))	('N', 'Chemical', 'MESH:D009584', (34, 35))
241738	31554233	These results also indicate that ATP6V0C preferably binds to the N-terminal domain of PKM2 containing amino acids 1-116.	('preferably', 'PosReg', (41, 51))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('ATP6V0C', 'Var', (33, 40))	('binds', 'Interaction', (52, 57))
241739	31554233	Tyrosine phosphorylation (Tyr105) of PKM2 increases PKM2 activity, leading to enhanced aerobic glycolysis.	('aerobic glycolysis', 'MPA', (87, 105))	('Tyrosine', 'Var', (0, 8))	('increases', 'PosReg', (42, 51))	('Tyr105', 'Var', (26, 32))	('activity', 'MPA', (57, 65))	('Tyrosine', 'Chemical', 'None', (0, 8))	('PKM2', 'Enzyme', (52, 56))	('PKM2', 'Gene', (37, 41))	('enhanced', 'PosReg', (78, 86))
241742	31554233	In addition, ATP6V0C depletion decreased PKM2 phosphorylation under both high- and low-glucose conditions (Figure 4G,H).	('glucose', 'Chemical', 'MESH:D005947', (87, 94))	('decreased', 'NegReg', (31, 40))	('low-glucose', 'Phenotype', 'HP:0001943', (83, 94))	('ATP6V0C depletion', 'Var', (13, 30))	('PKM2 phosphorylation', 'Enzyme', (41, 61))
241745	31554233	Intriguingly, ATP6V0C was partially co-localized with Calnexin, Lamp-1 or Cox-1 (Figure S4), indicating its potential role in other organelles such as the ER, lysosome, or mitochondria in ECCs.	('Calnexin', 'Gene', '12330', (54, 62))	('ATP6V0C', 'Var', (14, 21))	('Cox-1', 'Gene', '17708', (74, 79))	('Lamp-1', 'Gene', (64, 70))	('Lamp-1', 'Gene', '16783', (64, 70))	('Cox-1', 'Gene', (74, 79))	('Calnexin', 'Gene', (54, 62))
241746	31554233	We investigated using the ChIP assay whether ATP6V0C stimulates PKM2 recruitment to hypoxia response element (HRE) sites of LDHA.	('recruitment', 'MPA', (69, 80))	('hypoxia', 'Disease', (84, 91))	('stimulates', 'PosReg', (53, 63))	('hypoxia', 'Disease', 'MESH:D000860', (84, 91))	('ATP6V0C', 'Var', (45, 52))	('LDHA', 'Gene', '16828', (124, 128))	('LDHA', 'Gene', (124, 128))	('PKM2', 'Gene', (64, 68))
241747	31554233	Generating lactate ATP6V0C depletion significantly decreased PKM2 accumulation at the LDHA HRE site but not at RPL13A (the non-HIF-1 target gene), in TE8 cells (Figure 5C), suggesting that ATP6V0C enhances PKM2 association to the LDHA HRE site.	('LDHA', 'Gene', (230, 234))	('enhances', 'PosReg', (197, 205))	('LDHA', 'Gene', '16828', (230, 234))	('ATP6V0C', 'Var', (189, 196))	('PKM2', 'Enzyme', (61, 65))	('RPL13A', 'Gene', (111, 117))	('decreased', 'NegReg', (51, 60))	('LDHA', 'Gene', (86, 90))	('LDHA', 'Gene', '16828', (86, 90))	('accumulation', 'MPA', (66, 78))	('lactate', 'Chemical', 'MESH:D019344', (11, 18))	('association', 'Interaction', (211, 222))	('RPL13A', 'Gene', '22121', (111, 117))
241749	31554233	Genetic changes in ATP6V0C, particularly its deletion or amplification, were frequently found in esophageal cancer, underscoring the significance of ATP6V0C in tumors (Figure 5D).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('ATP6V0C', 'Gene', (19, 26))	('changes', 'Var', (8, 15))	('found', 'Reg', (88, 93))	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('tumors', 'Disease', (160, 166))	('deletion', 'Var', (45, 53))	('amplification', 'MPA', (57, 70))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
241754	31554233	In this study, we showed that ATP6V0C depletion resulted in a decreased proliferation accompanied by increased apoptosis of ECCs but had no effect on the viability of ENFs.	('decreased', 'NegReg', (62, 71))	('increased', 'PosReg', (101, 110))	('proliferation', 'CPA', (72, 85))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('ATP6V0C depletion', 'Var', (30, 47))	('apoptosis', 'CPA', (111, 120))
241756	31554233	Similarly, recent studies have demonstrated that ATP6V1C1 knockdown does not affect the growth of mouse embryonic fibroblasts, C3H10T1/2, while reducing the proliferation of breast cancer cells such as MCF-7, MDA-MB-231, and MDA-MB-435S.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (209, 219))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('MDA-MB-435S', 'CellLine', 'CVCL:0622', (225, 236))	('reducing', 'NegReg', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('MCF-7', 'CellLine', 'CVCL:0031', (202, 207))	('C3H10T1', 'CellLine', 'CVCL:0190', (127, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('proliferation', 'CPA', (157, 170))	('ATP6V1C1', 'Gene', '66335', (49, 57))	('ATP6V1C1', 'Gene', (49, 57))	('mouse', 'Species', '10090', (98, 103))	('knockdown', 'Var', (58, 67))
241758	31554233	In addition, ATP6V0C depletion also led to a reduction in the proliferation of various cancer cells, such as SH-SY5SY, HeLa, SK-MEL-1, and U2OS cells.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('proliferation', 'CPA', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('HeLa', 'CellLine', 'CVCL:0030', (119, 123))	('U2OS', 'CellLine', 'CVCL:0042', (139, 143))	('SK-MEL-1', 'CellLine', 'CVCL:0068', (125, 133))	('ATP6V0C depletion', 'Var', (13, 30))	('reduction', 'NegReg', (45, 54))	('SH-SY5SY', 'CellLine', 'CVCL:7028', (109, 117))
241762	31554233	In addition, overexpression of ATP6V0C induces the secretion of neurotransmitters such as acetylcholine, serotonin, and dopamine.	('ATP6V0C', 'Var', (31, 38))	('expression', 'Species', '29278', (17, 27))	('acetylcholine', 'MPA', (90, 103))	('acetylcholine', 'Chemical', 'MESH:D000109', (90, 103))	('dopamine', 'MPA', (120, 128))	('secretion of neurotransmitters', 'MPA', (51, 81))	('serotonin', 'Chemical', 'MESH:D012701', (105, 114))	('serotonin', 'MPA', (105, 114))	('dopamine', 'Chemical', 'MESH:D004298', (120, 128))	('induces', 'Reg', (39, 46))
241764	31554233	Our study further demonstrated that ATP6V0C positively regulates glucose metabolism, which produces main energy sources for esophageal cancer cells.	('esophageal cancer', 'Disease', (124, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('glucose metabolism', 'Disease', 'MESH:D044882', (65, 83))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ATP6V0C', 'Var', (36, 43))	('regulates', 'Reg', (55, 64))	('glucose metabolism', 'Disease', (65, 83))
241765	31554233	Lowering levels of ATP6V0C resulted in reduced glucose uptake and decreased lactate and ATP production under both high- and low-glucose conditions, leading to downregulation of glycolysis.	('ATP', 'Chemical', 'MESH:D000255', (88, 91))	('glucose', 'Chemical', 'MESH:D005947', (128, 135))	('ATP', 'Chemical', 'MESH:D000255', (19, 22))	('glucose uptake', 'MPA', (47, 61))	('lactate', 'Chemical', 'MESH:D019344', (76, 83))	('decreased', 'NegReg', (66, 75))	('glycolysis', 'MPA', (177, 187))	('lactate', 'MPA', (76, 83))	('ATP production', 'MPA', (88, 102))	('reduced', 'NegReg', (39, 46))	('ATP6V0C', 'Var', (19, 26))	('downregulation', 'NegReg', (159, 173))	('glucose', 'Chemical', 'MESH:D005947', (47, 54))	('low-glucose', 'Phenotype', 'HP:0001943', (124, 135))
241766	31554233	These results suggested that ATP6V0C might prevent cell death by enhancing glycolysis under low-glucose conditions.	('low-glucose', 'Phenotype', 'HP:0001943', (92, 103))	('glycolysis', 'MPA', (75, 85))	('enhancing', 'PosReg', (65, 74))	('ATP6V0C', 'Var', (29, 36))	('cell death', 'CPA', (51, 61))	('glucose', 'Chemical', 'MESH:D005947', (96, 103))
241769	31554233	Consistent with this, ATP6V0C depletion prevented low-glucose-induced expression of glycolytic enzymes.	('prevented', 'NegReg', (40, 49))	('low-glucose', 'Phenotype', 'HP:0001943', (50, 61))	('expression', 'Species', '29278', (70, 80))	('glucose', 'Chemical', 'MESH:D005947', (54, 61))	('ATP6V0C depletion', 'Var', (22, 39))	('low-glucose-induced expression of', 'MPA', (50, 83))	('glycolytic', 'Enzyme', (84, 94))
241770	31554233	In addition, ATP6V0C depletion decreased the ECAR, an indicator of aerobic glycolysis, whereas there was no significant difference in OCR between the NS and ATP6V0C knockdown cells after treatment with mitochondrial inhibitors, suggesting that ATP6V0C is crucial for glycolysis in ECCs.	('N', 'Chemical', 'MESH:D009584', (150, 151))	('decreased', 'NegReg', (31, 40))	('depletion', 'Var', (21, 30))	('ECAR', 'MPA', (45, 49))	('ATP6V0C depletion', 'Var', (13, 30))
241771	31554233	The ATP6V0C depletion inhibits the expression of glycolytic enzymes and decreases glycolysis, the first step in glucose oxidation.	('inhibits', 'NegReg', (22, 30))	('glycolytic enzymes', 'Enzyme', (49, 67))	('expression', 'Species', '29278', (35, 45))	('expression', 'MPA', (35, 45))	('glucose', 'Chemical', 'MESH:D005947', (112, 119))	('ATP6V0C depletion', 'Var', (4, 21))	('decreases glycolysis', 'Disease', 'MESH:C564972', (72, 92))	('decreases glycolysis', 'Phenotype', 'HP:0012270', (72, 92))	('decreases glycolysis', 'Disease', (72, 92))
241772	31554233	Studies have revealed that glucose deprivation contributes to mutations in the KRAS pathway and induces the Warburg effect.	('Warburg effect', 'CPA', (108, 122))	('mutations', 'Var', (62, 71))	('induces', 'Reg', (96, 103))	('glucose', 'Chemical', 'MESH:D005947', (27, 34))	('KRAS', 'Gene', (79, 83))	('KRAS', 'Gene', '16653', (79, 83))
241774	31554233	Therefore, these and our own results suggest that ATP6V0C enhances glycolytic metabolism, depending on glucose availability.	('glycolytic metabolism', 'MPA', (67, 88))	('glucose', 'Chemical', 'MESH:D005947', (103, 110))	('enhances', 'PosReg', (58, 66))	('ATP6V0C', 'Var', (50, 57))
241777	31554233	The PKM2 tetramer favors ATP production through the tricarboxylic acid cycle, while the PKM2 dimer leads to increased levels of intermediates (e.g., glycerate 3-P, glyceraldehyde 3-P, and glucose 6-P) in glycolysis, suggesting that the PKM2 dimer is necessary for high rates of cell proliferation.	('levels of', 'MPA', (118, 127))	('favors', 'PosReg', (18, 24))	('ATP production', 'MPA', (25, 39))	('tricarboxylic acid cycle', 'MPA', (52, 76))	('glycerate 3-P', 'MPA', (149, 162))	('glyceraldehyde 3-P', 'Chemical', 'MESH:D005985', (164, 182))	('increased', 'PosReg', (108, 117))	('ATP', 'Chemical', 'MESH:D000255', (25, 28))	('PKM2 dimer', 'Var', (88, 98))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (52, 70))	('glucose', 'Chemical', 'MESH:D005947', (188, 195))	('PKM2', 'Var', (4, 8))
241779	31554233	Our findings revealed that ATP6V0C associates preferentially with the PKM2 mutant R399E compared to WT PKM2.	('R399E', 'Var', (82, 87))	('PKM2', 'Gene', (70, 74))	('preferentially', 'PosReg', (46, 60))	('R399E', 'Mutation', 'p.R399E', (82, 87))	('mutant R399E', 'Var', (75, 87))
241780	31554233	The PKM2 mutant R399E exists as a dimer and appears to be catalytically inactive for the conversion of phosphoenolpyruvic acid (PEP) to pyruvate.	('phosphoenolpyruvic acid', 'Chemical', 'MESH:D000596', (103, 126))	('PKM2', 'Gene', (4, 8))	('pyruvate', 'Chemical', 'MESH:D011773', (136, 144))	('R399E', 'Mutation', 'p.R399E', (16, 21))	('inactive', 'NegReg', (72, 80))	('PEP', 'Chemical', 'MESH:C073248', (128, 131))	('R399E', 'Var', (16, 21))
241781	31554233	The inactive PKM2 dramatically facilitates the proliferation and growth of tumor cells from the SW480 cell line.	('facilitates', 'PosReg', (31, 42))	('SW480', 'CellLine', 'CVCL:0546', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('PKM2', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('proliferation', 'CPA', (47, 60))	('tumor', 'Disease', (75, 80))
241782	31554233	In addition, PKM2 overexpression is significantly associated with the advanced tumor grade of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('PKM2', 'Var', (13, 17))	('expression', 'Species', '29278', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('associated', 'Reg', (50, 60))	('ESCC', 'Disease', (94, 98))	('overexpression', 'PosReg', (18, 32))
241783	31554233	Therefore, it is possible that ATP6V0C interacts with the PKM2 mutant R399E or PKM2, driving glucose metabolism and leading to high-grade esophageal cancer.	('esophageal cancer', 'Disease', (138, 155))	('driving', 'PosReg', (85, 92))	('R399E', 'Mutation', 'p.R399E', (70, 75))	('glucose metabolism', 'Disease', 'MESH:D044882', (93, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('PKM2', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('leading to', 'Reg', (116, 126))	('R399E', 'Var', (70, 75))	('glucose metabolism', 'Disease', (93, 111))	('mutant R399E', 'Var', (63, 75))	('PKM2', 'Var', (79, 83))
241785	31554233	The assembly of the vacuolar H+-ATPase complex occurs when high levels of glucose are available, whereas glucose depletion induces V-ATPase disassembly leading to the inhibition of V-ATPase activity.	('V-ATPase', 'Gene', '242341', (131, 139))	('high levels of glucose', 'Phenotype', 'HP:0003074', (59, 81))	('disassembly', 'NegReg', (140, 151))	('ATP', 'Chemical', 'MESH:D000255', (133, 136))	('induces', 'Reg', (123, 130))	('assembly', 'MPA', (4, 12))	('inhibition', 'NegReg', (167, 177))	('activity', 'MPA', (190, 198))	('depletion', 'Var', (113, 122))	('V-ATPase', 'Gene', (181, 189))	('glucose', 'Chemical', 'MESH:D005947', (105, 112))	('V-ATPase', 'Gene', '242341', (181, 189))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))	('ATP', 'Chemical', 'MESH:D000255', (183, 186))	('ATP', 'Chemical', 'MESH:D000255', (32, 35))	('V-ATPase', 'Gene', (131, 139))
241786	31554233	Interestingly, the interaction between ATP6V0C and PKM2 was stronger under low- compared to high-glucose conditions.	('glucose', 'Chemical', 'MESH:D005947', (97, 104))	('PKM2', 'Enzyme', (51, 55))	('ATP6V0C', 'Var', (39, 46))	('high-glucose', 'Phenotype', 'HP:0003074', (92, 104))	('interaction', 'Interaction', (19, 30))	('stronger', 'PosReg', (60, 68))
241788	31554233	Based on our results and other studies, the positive role of ATP6V0C in glycolysis is predominant when glucose availability is low along with a decrease of V-ATPase activity.	('V-ATPase', 'Gene', '242341', (156, 164))	('activity', 'MPA', (165, 173))	('positive', 'PosReg', (44, 52))	('glucose', 'Chemical', 'MESH:D005947', (103, 110))	('decrease', 'NegReg', (144, 152))	('glucose availability', 'MPA', (103, 123))	('V-ATPase', 'Gene', (156, 164))	('glycolysis', 'MPA', (72, 82))	('ATP6V0C', 'Var', (61, 68))
241792	31554233	In addition, the PKM2 Y105F mutation leads to a reduction in lactate production and an increase in oxidative phosphorylation, pointing to the significance of phosphorylated PKM2 at Tyr105.	('PKM2', 'Gene', (17, 21))	('increase', 'PosReg', (87, 95))	('lactate', 'Chemical', 'MESH:D019344', (61, 68))	('lactate production', 'MPA', (61, 79))	('oxidative phosphorylation', 'MPA', (99, 124))	('Y105F', 'Mutation', 'p.Y105F', (22, 27))	('reduction', 'NegReg', (48, 57))	('Y105F', 'Var', (22, 27))
241793	31554233	Considering both that an increase in PKM2 phosphorylation at Tyr105 is positively associated with nuclear localization of PKM2 and our data, ATP6V0C is likely to induce nuclear translocation of PKM2 by enhancing PKM2 phosphorylation at Tyr105, although the kinase responsible has not yet been identified in esophageal cancer cells.	('increase', 'PosReg', (25, 33))	('ATP6V0C', 'Var', (141, 148))	('esophageal cancer', 'Disease', (307, 324))	('phosphorylation', 'MPA', (217, 232))	('PKM2', 'Enzyme', (212, 216))	('nuclear translocation', 'MPA', (169, 190))	('enhancing', 'PosReg', (202, 211))	('esophageal cancer', 'Disease', 'MESH:D004938', (307, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('induce', 'PosReg', (162, 168))	('nuclear localization', 'MPA', (98, 118))
241794	31554233	The ChIP analysis revealed that ATP6V0C depletion results in reduced recruitment of PKM2 to HRE sites, the gene promoter for transactivation of LDHA, which catalyzes the intra-conversion of pyruvate and lactate to enhance glycolysis.	('recruitment', 'MPA', (69, 80))	('LDHA', 'Gene', (144, 148))	('PKM2', 'Enzyme', (84, 88))	('glycolysis', 'MPA', (222, 232))	('LDHA', 'Gene', '16828', (144, 148))	('ATP6V0C depletion', 'Var', (32, 49))	('pyruvate', 'Chemical', 'MESH:D011773', (190, 198))	('enhance', 'PosReg', (214, 221))	('lactate', 'Chemical', 'MESH:D019344', (203, 210))	('reduced', 'NegReg', (61, 68))
241795	31554233	In conclusion, glucose-sensitive ATP6V0C interacts with the catalytic domain of PKM2 containing Tyr105 and leads to nuclear translocation of PKM2 to LDHA HRE sites, enhancing transcriptional activation of glycolytic genes and, thus, inducing metabolic reprogramming and movement of ECCs.	('metabolic reprogramming', 'CPA', (242, 265))	('enhancing', 'PosReg', (165, 174))	('glucose', 'Chemical', 'MESH:D005947', (15, 22))	('Tyr105', 'Var', (96, 102))	('glycolytic genes', 'Gene', (205, 221))	('movement', 'CPA', (270, 278))	('leads to', 'Reg', (107, 115))	('LDHA', 'Gene', '16828', (149, 153))	('LDHA', 'Gene', (149, 153))	('transcriptional activation', 'MPA', (175, 201))	('inducing', 'PosReg', (233, 241))	('nuclear translocation', 'MPA', (116, 137))
241796	31554233	Therefore, targeting ATP6V0C could be an effective therapeutic approach for controlling deregulated glucose metabolism in ECCs.	('ATP6V0C', 'Var', (21, 28))	('glucose metabolism', 'Disease', (100, 118))	('glucose metabolism', 'Disease', 'MESH:D044882', (100, 118))	('targeting ATP6V0C', 'Var', (11, 28))
241798	31554233	Figure S3: ATP6V0C depletion attenuates proliferation of various cancer cell lines.	('depletion', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('attenuates', 'NegReg', (29, 39))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
241855	31700229	Esophageal necrosis may be secondary to a combination of low cardiac output and profound vasoconstriction caused by low body temperature, especially in the splanchnic region, resulting in esophageal ischemia.	('Esophageal necrosis', 'Disease', 'MESH:D004941', (0, 19))	('vasoconstriction', 'MPA', (89, 105))	('low body temperature', 'Phenotype', 'HP:0002045', (116, 136))	('Esophageal necrosis', 'Disease', (0, 19))	('esophageal ischemia', 'Disease', (188, 207))	('low', 'Var', (116, 119))	('esophageal ischemia', 'Disease', 'MESH:D007511', (188, 207))	('low cardiac output', 'Disease', 'MESH:D002303', (57, 75))	('low cardiac output', 'Disease', (57, 75))
241882	31700229	There are also cases of AEN associated with orthotopic liver transplantation, either in the immediate postoperative period, secondary to hemorrhagic shock caused by inadvertent laceration of the phrenic artery, or some days later in association with hypotensive ischemic insult.	('hemorrhagic shock', 'Disease', (137, 154))	('shock', 'Phenotype', 'HP:0031273', (149, 154))	('AEN', 'Disease', (24, 27))	('AEN', 'Disease', 'MESH:D004941', (24, 27))	('laceration', 'Var', (177, 187))	('hypotensive ischemic', 'Disease', 'MESH:D007022', (250, 270))	('hemorrhagic shock', 'Disease', 'MESH:D012771', (137, 154))	('hypotensive ischemic', 'Disease', (250, 270))
241982	31369212	Adult height was estimated by height at 20 years of age and was considered a stable variable in adulthood.25 BMI status was categorized based on Chinese standards for BMI thresholds (unit: kg/m2): underweight (<18.5), normal (>=18.5 and <24), overweight (>=24 and <28), and obese (>=28).	('obese', 'Disease', 'MESH:D009765', (274, 279))	('overweight', 'Phenotype', 'HP:0025502', (243, 253))	('>=18.5', 'Var', (226, 232))	('obese', 'Disease', (274, 279))	('>=24', 'Var', (255, 259))
241986	31369212	For the fully adjusted regression models, we adjusted for age (continuous), sex, education (illiteracy/primary school/junior high school/high school or above), marital status (unmarried/married/divorced or widowed), occupation (farmer/worker/other), family wealth score (quintiles), missing and filled teeth (none/ <6/ >=6), daily frequency of brushing teeth (<2/ >=2), tea temperature (never/warm/hot/very hot), family history of esophageal cancer among first-degree relatives (yes/no), smoking pack-years (never/ <=30/ >30) and alcohol drinking intensity (never/ <=80/ >80 g/day).	('alcohol', 'Chemical', 'MESH:D000431', (530, 537))	('esophageal cancer', 'Disease', 'MESH:D004938', (431, 448))	('never/ <=80/', 'Var', (558, 570))	('brushing teeth', 'Disease', (344, 358))	('adjusted', 'Reg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (442, 448))	('esophageal cancer', 'Disease', (431, 448))	('brushing teeth', 'Disease', 'MESH:D014071', (344, 358))	('alcohol drinking', 'Phenotype', 'HP:0030955', (530, 546))	('brushing teeth', 'Phenotype', 'HP:0000670', (344, 358))
241991	31369212	Table 1 presents the general distribution of height at 20 years of age, BMI at 20 years of age, BMI 10 years prior to ascertainment, Stunkard body shape at 20 years of age, and Stunkard body shape 10 years prior to ascertainment among controls and ESCC cases.	('men', 'Species', '9606', (224, 227))	('ESCC', 'Disease', 'MESH:C562729', (248, 252))	('Stunkard', 'Var', (177, 185))	('ESCC', 'Disease', (248, 252))	('men', 'Species', '9606', (127, 130))
242003	31369212	However, participants with body shape 1 and 2, 10 years prior to ascertainment, had higher risks of ESCC than those with other body shape types (compared with body shape 3, the OR of body shape 1 was 2.83, 95% CI: 1.92~4.17, P value for trend less than 0.001, Figure 3B).	('body shape 1', 'Var', (27, 39))	('ESCC', 'Disease', 'MESH:C562729', (100, 104))	('ESCC', 'Disease', (100, 104))	('men', 'Species', '9606', (74, 77))	('end', 'Disease', (239, 242))	('participants', 'Species', '9606', (9, 21))	('end', 'Disease', 'MESH:D007676', (239, 242))
242015	31369212	Multiple cohort studies reported that adult height is positively associated with risks of all-site cancers and cancer-related deaths, but they did not identify the association between height and ESCC risk.30, 31, 32  The evidence for low BMI status or thinness as a risk factor for ESCC has been documented over the recent decades.	('low BMI', 'Phenotype', 'HP:0045082', (234, 241))	('ESCC', 'Disease', 'MESH:C562729', (282, 286))	('men', 'Species', '9606', (300, 303))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (99, 105))	('cancers', 'Disease', (99, 106))	('ESCC', 'Disease', (195, 199))	('low', 'Var', (234, 237))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('ESCC', 'Disease', (282, 286))	('thinness', 'Disease', 'MESH:D013851', (252, 260))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('thinness', 'Disease', (252, 260))	('ESCC', 'Disease', 'MESH:C562729', (195, 199))
242023	31369212	In a prospective study exploring trajectory of perceived body shape across the lifespan in relation to all-site cancer risk, body adiposity significantly increases the EAC risk in males,20 which is similar to the relationship between BMI and EAC risk.	('increases', 'PosReg', (154, 163))	('cancer', 'Disease', (112, 118))	('EAC', 'Disease', (242, 245))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('EAC', 'Phenotype', 'HP:0011459', (168, 171))	('EAC', 'Disease', 'MESH:D004941', (242, 245))	('EAC', 'Disease', 'MESH:D004941', (168, 171))	('EAC', 'Disease', (168, 171))	('body adiposity', 'Var', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('EAC', 'Phenotype', 'HP:0011459', (242, 245))
242029	31369212	It is noteworthy that the risk patterns of body size at age 20 years and body size at 10 years prior to ascertainment for ESCC risk were different, which were consistent with previous reports.14, 33, 34 Martincorena et al35 recently reported that somatic mutations accumulated with age in normal esophageal mucosa, and cancer-associated mutant clones in middle-aged and elderly donors covered most areas of the epithelium.	('mutant', 'Var', (337, 343))	('ESCC', 'Disease', (122, 126))	('cancer', 'Disease', (319, 325))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('men', 'Species', '9606', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('ESCC', 'Disease', 'MESH:C562729', (122, 126))
242030	31369212	This implies that body size, a changeable exposure, measured at different time and its individual long-term change have different effects for the somatic carcinogenic mutation or epigenetic modification.	('somatic carcinogenic', 'Disease', (146, 166))	('effects', 'Reg', (130, 137))	('epigenetic modification', 'Var', (179, 202))	('somatic carcinogenic', 'Disease', 'MESH:D013001', (146, 166))
242036	31369212	In our study, very lean body size was significantly associated with an increased risk of ESCC, especially in older people.	('ESCC', 'Disease', 'MESH:C562729', (89, 93))	('people', 'Species', '9606', (115, 121))	('ESCC', 'Disease', (89, 93))	('very lean', 'Var', (14, 23))
242056	30356041	Low fiber intake was associated with increased relative abundance of several Gram-negative bacteria, including Prevotella, Neisseria, and Eikenella.	('Prevotella', 'Disease', (111, 121))	('fiber', 'Chemical', 'MESH:D004043', (4, 9))	('Neisseria', 'Disease', (123, 132))	('increased', 'PosReg', (37, 46))	('Low fiber', 'Var', (0, 9))
242066	30356041	Conversely, dietary fiber contributes to different microbial alterations, and is associated with reduced weight gain and improved glycemic and lipid control.	('reduced weight', 'Phenotype', 'HP:0004325', (97, 111))	('reduced weight gain', 'Phenotype', 'HP:0001508', (97, 116))	('lipid', 'Chemical', 'MESH:D008055', (143, 148))	('improved', 'PosReg', (121, 129))	('weight gain', 'Phenotype', 'HP:0004324', (105, 116))	('dietary', 'Var', (12, 19))	('reduced', 'NegReg', (97, 104))	('microbial alterations', 'MPA', (51, 72))	('weight gain', 'Disease', (105, 116))	('fiber', 'Chemical', 'MESH:D004043', (20, 25))	('weight gain', 'Disease', 'MESH:D015430', (105, 116))
242070	30356041	High fiber consumption may confer a lower risk of Fusobacterium nucleatum-positive, but not F. nucleatum-negative, colon cancer, suggesting that the effect of diet on cancer risk is mediated in part by microbiome composition.	('lower', 'NegReg', (36, 41))	('fiber', 'Chemical', 'MESH:D004043', (5, 10))	('High fiber', 'Var', (0, 10))	('Fusobacterium nucleatum-positive', 'Disease', (50, 82))	('colon cancer', 'Disease', (115, 127))	('F. nucleatum', 'Species', '851', (92, 104))	('colon cancer', 'Disease', 'MESH:D015179', (115, 127))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (167, 173))	('Fusobacterium nucleatum', 'Species', '851', (50, 73))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (115, 127))	('cancer', 'Disease', (121, 127))
242126	30356041	PPIs are known to impact the upper gastrointestinal microbiome, so it is possible that this exposure either acts synergistically with dietary fiber to magnify the impact on the microbiome or makes the microbiome more susceptible to effects of fiber.	('upper gastrointestinal', 'Disease', 'MESH:D005767', (29, 51))	('impact', 'Reg', (18, 24))	('fiber', 'Chemical', 'MESH:D004043', (243, 248))	('makes', 'Reg', (191, 196))	('fiber', 'Chemical', 'MESH:D004043', (142, 147))	('upper gastrointestinal', 'Disease', (29, 51))	('PPIs', 'Var', (0, 4))	('microbiome', 'MPA', (177, 187))
242134	30356041	Low fiber intake can lead to weight gain and obesity, and high fiber intake may contribute to increased SCFA production in the colon and improved systemic insulin sensitivity; these changes might in turn have effects on the esophageal microbiome.	('weight gain', 'Disease', 'MESH:D015430', (29, 40))	('obesity', 'Phenotype', 'HP:0001513', (45, 52))	('weight gain', 'Phenotype', 'HP:0004324', (29, 40))	('increased', 'PosReg', (94, 103))	('fiber', 'Chemical', 'MESH:D004043', (4, 9))	('lead to', 'Reg', (21, 28))	('weight gain', 'Disease', (29, 40))	('fiber', 'Chemical', 'MESH:D004043', (63, 68))	('obesity', 'Disease', 'MESH:D009765', (45, 52))	('improved', 'PosReg', (137, 145))	('insulin', 'Gene', (155, 162))	('SCFA production', 'MPA', (104, 119))	('obesity', 'Disease', (45, 52))	('effects', 'Reg', (209, 216))	('high fiber', 'Var', (58, 68))	('insulin', 'Gene', '3630', (155, 162))	('Low fiber', 'Var', (0, 9))
242154	30356041	These findings may indicate an association between low fiber intake and an esophageal microbiome that promotes chronic inflammation.	('promotes', 'PosReg', (102, 110))	('inflammation', 'Disease', 'MESH:D007249', (119, 131))	('low fiber', 'Var', (51, 60))	('inflammation', 'Disease', (119, 131))	('fiber', 'Chemical', 'MESH:D004043', (55, 60))
242180	30139375	Immunohistochemical analysis showed positivity for CD56, chromogranin, and synaptophysin in the NEC component (Fig.	('synaptophysin', 'Gene', (75, 88))	('CD56', 'Gene', (51, 55))	('chromogranin', 'Protein', (57, 69))	('NEC', 'Phenotype', 'HP:0100634', (96, 99))	('synaptophysin', 'Gene', '6855', (75, 88))	('positivity', 'Var', (36, 46))	('CD56', 'Gene', '4684', (51, 55))
242229	28518141	Aberrant expressions of chemokines and their cognate receptors were associated with several human diseases such as cancer, autoimmune and inflammatory diseases.	('cancer', 'Disease', (115, 121))	('associated', 'Reg', (68, 78))	('Aberrant', 'Var', (0, 8))	('human diseases', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('chemokines', 'Protein', (24, 34))	('autoimmune', 'Disease', (123, 133))	('inflammatory diseases', 'Disease', (138, 159))	('human', 'Species', '9606', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('expressions', 'MPA', (9, 20))
242245	28518141	Furthermore, we found the expressions of CXCL1 and its receptor CXCR2 were significantly increased 30 min after 8 Gy of radiation in KYSE-150 and KYSE-30, which may cause a constitutively activated CXCL1/CXCR2 signaling in tumor cells (Figures 1d and e).	('expressions', 'MPA', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('KYSE-30', 'Var', (146, 153))	('CXCR2', 'Gene', (64, 69))	('KYSE-150', 'Var', (133, 141))	('activated', 'PosReg', (188, 197))	('CXCL1', 'MPA', (41, 46))	('CXCR2', 'Gene', '3579', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('increased', 'PosReg', (89, 98))	('CXCR2', 'Gene', (204, 209))	('CXCR2', 'Gene', '3579', (64, 69))
242250	28518141	We found the expression of gamma-H2AX, a marker of DNA double-strand breaks, which are one major form of cellular damage induced by radiation, was decreased after 8 Gy of radiation in KYSE-30 and KYSE-150 that were cultured in CAF medium for 24 h; meanwhile, cellular DNA damage repair proteins including p-ATM, Rad50, p-Chk2, Ku80 and DNA-PKcs were upregulated after 8 Gy of radiation in KYSE-30 and KYSE-150 that were cultured in CAF medium for 24 h (Figure 2c and Supplementary Figure S3).	('ATM', 'Gene', (307, 310))	('Ku80', 'Gene', (327, 331))	('ATM', 'Gene', '472', (307, 310))	('expression', 'MPA', (13, 23))	('gamma-H2AX', 'Chemical', '-', (27, 37))	('Rad50', 'Gene', '10111', (312, 317))	('decreased', 'NegReg', (147, 156))	('Chk2', 'Gene', '11200', (321, 325))	('upregulated', 'PosReg', (350, 361))	('Chk2', 'Gene', (321, 325))	('Rad50', 'Gene', (312, 317))	('DNA-PKcs', 'Gene', '5591', (336, 344))	('KYSE-150', 'Var', (401, 409))	('cellular', 'MPA', (259, 267))	('DNA-PKcs', 'Gene', (336, 344))	('Ku80', 'Gene', '7520', (327, 331))
242254	28518141	Furthermore, treatment with 10 muM ATM kinase inhibitor Ku55933 significantly decreased clonogenic survival of KYSE-150 and KYSE-30 that were cultured in CAF medium before radiation (Figure 3).	('ATM', 'Gene', '472', (35, 38))	('Ku55933', 'Var', (56, 63))	('Ku55933', 'Chemical', 'MESH:C495818', (56, 63))	('ATM', 'Gene', (35, 38))	('decreased', 'NegReg', (78, 87))	('clonogenic survival', 'CPA', (88, 107))
242256	28518141	When KYSE-30 and KYSE-150 were cultured in CAF medium, reactive oxygen species (ROS) was obviously increased 15 min after 8 Gy of radiation compared with when cultured in normal medium (Supplementary Figure S4).	('KYSE-30', 'Var', (5, 12))	('increased', 'PosReg', (99, 108))	('KYSE-150', 'Var', (17, 25))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (55, 78))
242271	28518141	Furthermore, treatment with 10 muM Mek1/2 kinase inhibitor U0126 significantly decreased clonogenic survival of KYSE-150 and KYSE-30 that were cultured in CAF medium before radiation ((Figure 5d).	('U0126', 'Chemical', 'MESH:C113580', (59, 64))	('Mek1/2', 'Gene', (35, 41))	('decreased', 'NegReg', (79, 88))	('Mek1/2', 'Gene', '5604;5605', (35, 41))	('U0126', 'Var', (59, 64))	('clonogenic survival', 'CPA', (89, 108))
242276	28518141	When treated with the combination therapy with radiotherapy and CXCL1 antibody, the volume and weight of xenograft tumors were both decreased in comparison with radiotherapy alone (Figure 6).	('xenograft tumors', 'Disease', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('xenograft tumors', 'Disease', 'MESH:D009369', (105, 121))	('CXCL1', 'Var', (64, 69))	('decreased', 'NegReg', (132, 141))
242277	28518141	These results suggested inhibition of CAF-secreted CXCL1 reversed tumor radioresistance in vivo.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('inhibition', 'Var', (24, 34))	('CAF-secreted CXCL1', 'MPA', (38, 56))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
242283	28518141	Survival analysis showed the prognosis of ESCC patients with positive CXCL1 expression in CAFs was significantly poorer than those with negative CXCL1 expression in CAFs (Figures 7b and c).	('poorer', 'NegReg', (113, 119))	('ESCC', 'Disease', (42, 46))	('patients', 'Species', '9606', (47, 55))	('positive CXCL1 expression', 'Var', (61, 86))
242298	28518141	In human cancers such as gastric, colorectal and pancreatic cancer, CXCL1 was demonstrated to mediate angiogenesis and promote tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('pancreatic cancer', 'Disease', (49, 66))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('pancreatic cancer', 'Disease', 'MESH:D010190', (49, 66))	('cancers', 'Disease', (9, 16))	('gastric', 'Disease', (25, 32))	('tumor', 'Disease', (127, 132))	('promote', 'PosReg', (119, 126))	('human', 'Species', '9606', (3, 8))	('colorectal', 'Disease', 'MESH:D015179', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CXCL1', 'Var', (68, 73))	('colorectal', 'Disease', (34, 44))	('angiogenesis', 'CPA', (102, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
242305	28518141	Inhibition of DNA damage repair improved the radiosensitivity of several human cancers.	('cancers', 'Disease', (79, 86))	('radiosensitivity', 'CPA', (45, 61))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('human', 'Species', '9606', (73, 78))	('improved', 'PosReg', (32, 40))	('Inhibition', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
242309	28518141	Aberrant ROS status correlated with several human diseases including cancer, diabetes and aging as ROS was able to activate several cellular signaling pathways involved in DNA damage repair, cell proliferation, differentiation, survival and metabolism, and antioxidant, anti-inflammation response.	('human', 'Species', '9606', (44, 49))	('diabetes', 'Disease', (77, 85))	('survival', 'CPA', (228, 236))	('diabetes', 'Disease', 'MESH:D003920', (77, 85))	('ROS', 'Gene', (99, 102))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cellular signaling pathways', 'Pathway', (132, 159))	('activate', 'PosReg', (115, 123))	('differentiation', 'CPA', (211, 226))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('cell proliferation', 'CPA', (191, 209))	('inflammation', 'Disease', 'MESH:D007249', (275, 287))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('ROS', 'Chemical', 'MESH:D017382', (99, 102))	('cancer', 'Disease', (69, 75))	('inflammation', 'Disease', (275, 287))
242324	28518141	Furthermore, DNA damage sensor ATM was involved in radiation-induced Erk activation; in turn, inhibition of Erk activation attenuates radiation-induced ATM phosphorylation and the recruitment of ATM to DNA damage foci, suggesting there is a positive feedback loop involved in Erk/ATM signaling following radiation.	('ATM', 'Gene', '472', (31, 34))	('ATM', 'Gene', (280, 283))	('damage foci', 'Disease', (206, 217))	('attenuates', 'NegReg', (123, 133))	('ATM', 'Gene', (152, 155))	('recruitment', 'MPA', (180, 191))	('ATM', 'Gene', (31, 34))	('ATM', 'Gene', '472', (195, 198))	('Erk', 'Gene', (276, 279))	('Erk', 'Gene', '5594', (276, 279))	('ATM', 'Gene', '472', (280, 283))	('inhibition', 'Var', (94, 104))	('damage foci', 'Disease', 'MESH:C565785', (206, 217))	('Erk', 'Gene', (69, 72))	('Erk', 'Gene', (108, 111))	('Erk', 'Gene', '5594', (69, 72))	('Erk', 'Gene', '5594', (108, 111))	('ATM', 'Gene', '472', (152, 155))	('ATM', 'Gene', (195, 198))
242331	28518141	Our study found the cross talk of CAFs and tumor cells induced CXCL1 expression in an autocrine/paracrine signaling loop, which further enhanced the pathological roles of CXCL1 in ESCC.	('enhanced', 'PosReg', (136, 144))	('cross', 'Var', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('induced', 'Reg', (55, 62))	('ESCC', 'Disease', (180, 184))
242342	28518141	Antibodies against p-ATM (Ser1981, #5883), Ku80 (#2180), Rad50 (#3247), p-RAD50 (Ser635, #14223), p-Chk2 (Thr68, #2197), Erk1/2 (#9102), p-Erk1/2 (Thr202/Tyr204, #4370), p-Mek1/2 (Ser217/221, #9154), E-cadherin (#3195S), Vimentin (5741S), SOD1 (#2770) and GAPDH (#2118) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('Erk1/2', 'Gene', '5595;5594', (139, 145))	('Vimentin', 'Gene', '7431', (221, 229))	('Ku80', 'Gene', (43, 47))	('Thr202/Tyr204', 'Var', (147, 160))	('GAPDH', 'Gene', '2597', (256, 261))	('RAD50', 'Gene', '10111', (74, 79))	('ATM', 'Gene', '472', (21, 24))	('Ser635', 'Var', (81, 87))	('Erk1/2', 'Gene', '5595;5594', (121, 127))	('Vimentin', 'Gene', (221, 229))	('Chk2', 'Gene', '11200', (100, 104))	('Mek1/2', 'Gene', (172, 178))	('GAPDH', 'Gene', (256, 261))	('E-cadherin', 'Gene', (200, 210))	('E-cadherin', 'Gene', '999', (200, 210))	('#2770', 'Var', (245, 250))	('5741S', 'Var', (231, 236))	('ATM', 'Gene', (21, 24))	('Erk1/2', 'Gene', (139, 145))	('Ser217/221', 'Var', (180, 190))	('Mek1/2', 'Gene', '5604;5605', (172, 178))	('Ku80', 'Gene', '7520', (43, 47))	('Rad50', 'Gene', '10111', (57, 62))	('Erk1/2', 'Gene', (121, 127))	('SOD1', 'Gene', (239, 243))	('Rad50', 'Gene', (57, 62))	('SOD1', 'Gene', '6647', (239, 243))	('RAD50', 'Gene', (74, 79))	('Chk2', 'Gene', (100, 104))
242344	28518141	Antibodies against gamma-H2AX (S139, #ab26350), DNA-PKcs (#ab32566), p-DNA-PKcs (S2056, #ab124918), FAP (#ab28244), alpha-SMA (#ab5694) and Ki-67 (#ab92742) were purchased from Abcam (Cambridge, UK).	('S139', 'Var', (31, 35))	('FAP', 'Disease', (100, 103))	('S2056', 'CellLine', 'CVCL:K818', (81, 86))	('DNA-PKcs', 'Gene', (48, 56))	('#ab32566', 'Var', (58, 66))	('DNA-PKcs', 'Gene', '5591', (71, 79))	('FAP', 'Disease', 'MESH:C567782', (100, 103))	('#ab28244', 'Var', (105, 113))	('S2056', 'Var', (81, 86))	('#ab5694', 'Var', (127, 134))	('DNA-PKcs', 'Gene', '5591', (48, 56))	('DNA-PKcs', 'Gene', (71, 79))	('gamma-H2AX', 'Chemical', '-', (19, 29))
242388	28104365	Defective mitochondrial dynamics play important roles in human diseases.	('Defective mitochondrial dynamics', 'Phenotype', 'HP:0003287', (0, 32))	('Defective', 'Var', (0, 9))	('human', 'Species', '9606', (57, 62))	('mitochondrial dynamics', 'MPA', (10, 32))
242396	28104365	MtDNA mutations, deletions or impaired DNA replication are the most common cause of mitochondrial dysfunction .	('cause', 'Reg', (75, 80))	('DNA', 'MPA', (39, 42))	('deletions', 'Var', (17, 26))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (84, 109))	('MtDNA', 'Gene', (0, 5))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (84, 109))	('impaired', 'NegReg', (30, 38))	('mitochondrial dysfunction', 'Disease', (84, 109))	('mutations', 'Var', (6, 15))
242413	28104365	Hypoxia and mutations in subunits have been associated with increased ROS production from complex I. Mitochondria play an important role in Calcium homeostasis.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('mutations', 'Var', (12, 21))	('ROS production', 'MPA', (70, 84))	('increased ROS production', 'Phenotype', 'HP:0025464', (60, 84))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('Calcium', 'Chemical', 'MESH:D002118', (140, 147))	('increased', 'PosReg', (60, 69))
242419	28104365	Excessive ROS production induced by photo-excitation of cytochrome c oxidase in ASTC-1 and COS7 cells resulted in increased fragmentation of mitochondria.	('cytochrome c', 'Gene', (56, 68))	('COS7', 'CellLine', 'CVCL:0224', (91, 95))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('photo-excitation', 'Var', (36, 52))	('increased', 'PosReg', (114, 123))	('cytochrome c', 'Gene', '54205', (56, 68))	('ROS production', 'MPA', (10, 24))	('fragmentation of mitochondria', 'MPA', (124, 153))	('Excessive ROS production', 'Phenotype', 'HP:0025464', (0, 24))
242423	28104365	In control cells mitochondria are densely packed in the periphery of the nuclear envelope, whereas in cells with reduced mtDNA content (either by ethidium bromide treatment or silencing Tfam mRNA), the mitochondria are fewer in number, markedly smaller in size, appear fragmented and distributed throughout the cellular cytoplasm (Fig 1B).	('silencing', 'Var', (176, 185))	('Tfam mRNA', 'Gene', (186, 195))	('fewer', 'NegReg', (219, 224))	('ethidium bromide', 'Chemical', 'MESH:D004996', (146, 162))	('smaller', 'NegReg', (245, 252))
242432	28104365	Mitochondrial fusion results in extended mitochondrial networks, which provides advantage to cells under high energy demands and disruption of mitochondrial fusion has been shown to result in mitochondrial dysfunction.	('mitochondrial dysfunction', 'Disease', (192, 217))	('extended', 'PosReg', (32, 40))	('mitochondrial networks', 'CPA', (41, 63))	('disruption', 'Var', (129, 139))	('result', 'Reg', (182, 188))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (192, 217))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (192, 217))
242454	28104365	Experimental targeting of misfolded ornithine transcarbomoylase to mitochondrial matrix resulted in upregulation of several heat shock proteins like HSP60, HSP10 and chaperones without affecting cytosolic or ER stress response.	('shock', 'Disease', 'MESH:D012769', (129, 134))	('HSP10', 'Gene', (156, 161))	('HSP60', 'Gene', (149, 154))	('shock', 'Disease', (129, 134))	('HSP60', 'Gene', '3329', (149, 154))	('shock', 'Phenotype', 'HP:0031273', (129, 134))	('misfolded', 'Var', (26, 35))	('HSP10', 'Gene', '3336', (156, 161))	('upregulation', 'PosReg', (100, 112))	('chaperones', 'CPA', (166, 176))
242455	28104365	Similarly, presence of mutant EndoG in intermembrane space resulted in Akt phosphorylation mediated activation of estrogen receptor alpha and induction of quality control proteases localized to IMS.	('Akt', 'Gene', '207', (71, 74))	('estrogen receptor alpha', 'Gene', '2099', (114, 137))	('quality control', 'MPA', (155, 170))	('Akt', 'Gene', (71, 74))	('EndoG', 'Gene', '2021', (30, 35))	('induction', 'PosReg', (142, 151))	('EndoG', 'Gene', (30, 35))	('activation', 'PosReg', (100, 110))	('estrogen receptor alpha', 'Gene', (114, 137))	('mutant', 'Var', (23, 29))
242457	28104365	The peptides activate a transcriptional response mediated by ATFS-1 that localizes to nucleus and along with two other factors DVE-1 and Ubl-5 induce expression of genes involved in mitochondrial quality control and cellular metabolism.	('transcriptional', 'MPA', (24, 39))	('expression', 'MPA', (150, 160))	('localizes', 'MPA', (73, 82))	('induce', 'PosReg', (143, 149))	('Ubl-5', 'Gene', (137, 142))	('peptides', 'Var', (4, 12))	('ATFS-1', 'Gene', (61, 67))	('Ubl-5', 'Gene', '59286', (137, 142))
242459	28104365	Aberrant growth and exposure to adverse conditions like hypoxia are common feature of cancer cells and likely result in very high rates of oxidatively damaged and misfolded proteins inside mitochondria, conditions that could initiate unfolded protein response.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('oxidatively damaged', 'MPA', (139, 158))	('proteins', 'Protein', (173, 181))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('Aberrant growth', 'Phenotype', 'HP:0001507', (0, 15))	('result', 'Reg', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('hypoxia', 'Disease', (56, 63))	('cancer', 'Disease', (86, 92))
242474	28104365	Supporting evidence for the defective mitochondria in cancer tissue has been shown by both genetic screening for mtDNA defects and by providing experimental support by using cybrids .	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('defective', 'NegReg', (28, 37))	('defects', 'Var', (119, 126))	('mtDNA', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
242475	28104365	Low copy number of mtDNA has been observed in many cancers including breast, colon, hepatocellular carcinomas, astrocytomas and prostate cancers .	('colon', 'Disease', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('astrocytomas and prostate cancers', 'Disease', 'MESH:D011471', (111, 144))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast', 'Disease', (69, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (128, 143))	('prostate cancers', 'Phenotype', 'HP:0012125', (128, 144))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('mtDNA', 'Gene', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('Low copy number', 'Var', (0, 15))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (84, 109))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (84, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('observed', 'Reg', (34, 42))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('cancers', 'Disease', (51, 58))	('hepatocellular carcinomas', 'Disease', (84, 109))
242476	28104365	Experimentally induced mtDNA depletion in colorectal and prostate cancer cells promotes aggressive cancers .	('depletion', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('colorectal and prostate cancer', 'Disease', 'MESH:D015179', (42, 72))	('promotes', 'PosReg', (79, 87))	('aggressive cancers', 'Disease', (88, 106))	('aggressive cancers', 'Disease', 'MESH:D009369', (88, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
242478	28104365	Mutations in mitochondrial DNA has been reported in several cancers including breast, renal adenocarcinoma, thyroid tumors, colon cancer, head and neck cancer and prostate cancer .	('prostate cancer', 'Disease', (163, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('breast', 'Disease', (78, 84))	('colon cancer', 'Disease', (124, 136))	('renal adenocarcinoma', 'Disease', (86, 106))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (86, 106))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('head and neck cancer', 'Phenotype', 'HP:0012288', (138, 158))	('thyroid tumors', 'Disease', (108, 122))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('reported', 'Reg', (40, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (124, 136))	('head and neck cancer', 'Disease', 'MESH:D006258', (138, 158))	('mitochondrial DNA', 'Gene', (13, 30))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancers', 'Disease', (60, 67))	('renal adenocarcinoma', 'Disease', 'MESH:C538614', (86, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (163, 178))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colon cancer', 'Disease', 'MESH:D015179', (124, 136))	('thyroid tumors', 'Disease', 'MESH:D013959', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
242479	28104365	Although the causal role of mitochondrial DNA defect in tumorigenesis has not been clearly established, cybrid cell lines generated by fusing cytoplasts and nuclei from different cell lines provide a means for testing the role of WT and mutant mtDNA under the same nuclear genetic background.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutant', 'Var', (237, 243))	('tumor', 'Disease', (56, 61))	('testing', 'Reg', (210, 217))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
242480	28104365	Mutations in complex I subunit ND6 increased the metastatic potential by producing excessive ROS, whereas an ND5 mutation promoted tumorigenesis by oxidative stress and Akt activation .	('mutation', 'Var', (113, 121))	('increased', 'PosReg', (35, 44))	('ROS', 'MPA', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('Akt', 'Gene', (169, 172))	('ND6', 'Gene', (31, 34))	('activation', 'PosReg', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('ROS', 'Chemical', 'MESH:D017382', (93, 96))	('promoted', 'PosReg', (122, 130))	('tumor', 'Disease', (131, 136))	('Mutations', 'Var', (0, 9))	('oxidative stress', 'Phenotype', 'HP:0025464', (148, 164))	('ND5', 'Gene', '4540', (109, 112))	('Akt', 'Gene', '207', (169, 172))	('metastatic potential', 'CPA', (49, 69))	('ND5', 'Gene', (109, 112))
242481	28104365	Mutations in SDH subunits and FH genes have been observed in paragangliomas, pheochromocytomas, multiple cutaneous and uterine leiomyomatas and aggressive forms of renal cell cancer.	('pheochromocytomas', 'Disease', 'MESH:D010673', (77, 94))	('paragangliomas', 'Phenotype', 'HP:0002668', (61, 75))	('leiomyomatas and aggressive forms of renal cell cancer', 'Disease', 'MESH:C538614', (127, 181))	('paraganglioma', 'Phenotype', 'HP:0002668', (61, 74))	('SDH', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('paragangliomas', 'Disease', 'MESH:D010235', (61, 75))	('renal cell cancer', 'Phenotype', 'HP:0005584', (164, 181))	('Mutations', 'Var', (0, 9))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (77, 94))	('SDH', 'Gene', '6390', (13, 16))	('observed', 'Reg', (49, 57))	('uterine leiomyomatas', 'Phenotype', 'HP:0000131', (119, 139))	('paragangliomas', 'Disease', (61, 75))	('FH', 'Disease', 'MESH:D006938', (30, 32))	('pheochromocytomas', 'Disease', (77, 94))
242483	28104365	Heterozygous missense mutations in IDH have been shown in gliomas, chondromas and astrocytomas.	('IDH', 'Gene', (35, 38))	('chondromas', 'Disease', (67, 77))	('astrocytomas', 'Disease', (82, 94))	('shown', 'Reg', (49, 54))	('IDH', 'Gene', '3417', (35, 38))	('chondromas', 'Disease', 'MESH:D002812', (67, 77))	('Heterozygous missense mutations', 'Var', (0, 31))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('astrocytomas', 'Disease', 'MESH:D001254', (82, 94))
242484	28104365	Heterodimers of mutant IDH1 and IDH3 have been shown to increase accumulation of 2-hydroxyglutarate that has been shown to affect methylation and other epigenetic modifications .	('increase', 'PosReg', (56, 64))	('methylation', 'MPA', (130, 141))	('IDH1', 'Gene', (23, 27))	('IDH', 'Gene', (32, 35))	('mutant', 'Var', (16, 22))	('IDH1', 'Gene', '3417', (23, 27))	('IDH', 'Gene', '3417', (32, 35))	('IDH', 'Gene', (23, 26))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (81, 99))	('affect', 'Reg', (123, 129))	('accumulation of 2-hydroxyglutarate', 'MPA', (65, 99))	('epigenetic modifications', 'MPA', (152, 176))	('IDH', 'Gene', '3417', (23, 26))
242488	28104365	Depletion of mtDNA resulting in mitochondrial dysfunction induced an epithelial to mesenchymal transition in multiple cell lines including MCF 10A breast cancer cells.	('MCF 10A', 'CellLine', 'CVCL:0598', (139, 146))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('breast cancer', 'Disease', (147, 160))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (32, 57))	('induced', 'Reg', (58, 65))	('Depletion', 'Var', (0, 9))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (32, 57))	('mtDNA', 'Gene', (13, 18))	('mitochondrial dysfunction', 'Disease', (32, 57))	('epithelial to mesenchymal transition', 'CPA', (69, 105))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
242489	28104365	Mutation in complex I subunit ND6 was shown to increase the metastatic potential of a mouse lung carcinoma cell line.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung carcinoma', 'Disease', 'MESH:D008175', (92, 106))	('mouse', 'Species', '10090', (86, 91))	('Mutation', 'Var', (0, 8))	('lung carcinoma', 'Disease', (92, 106))	('increase', 'PosReg', (47, 55))	('ND6', 'Gene', (30, 33))
242495	28104365	Interestingly most of the available literature shows dysregulated Drp1 action as responsible for excessive fission.	('dysregulated', 'Var', (53, 65))	('Drp1', 'Gene', (66, 70))	('Drp1', 'Gene', '10059', (66, 70))	('fission', 'CPA', (107, 114))
242497	28104365	Moreover, inhibition of this phosphorylation in xenografts is sufficient to block tumor growth.	('inhibition', 'Var', (10, 20))	('block tumor', 'Disease', 'MESH:D006327', (76, 87))	('block tumor', 'Disease', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
242503	28104365	As mentioned earlier, mtDNA depletion in C2C12 cells induces mitochondrial retrograde signaling that transforms them to tumorigenic cells.	('C2C12', 'CellLine', 'CVCL:0188', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('depletion', 'Var', (28, 37))	('transforms', 'Reg', (101, 111))	('mitochondrial retrograde signaling', 'MPA', (61, 95))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))	('induces', 'Reg', (53, 60))
242504	28104365	We recently observed in these cells that mitochondrial dysfunction caused by mtDNA depletion leads to increased Drp1 mitochondrial localization and reduced OPA1 expression, accompanied with fragmented mitochondria.	('OPA1', 'Gene', '4976', (156, 160))	('mitochondrial dysfunction', 'Disease', (41, 66))	('Drp1', 'Gene', (112, 116))	('reduced', 'NegReg', (148, 155))	('mitochondrial localization', 'MPA', (117, 143))	('expression', 'MPA', (161, 171))	('depletion', 'Var', (83, 92))	('increased', 'PosReg', (102, 111))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (41, 66))	('Drp1', 'Gene', '10059', (112, 116))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (41, 66))	('OPA1', 'Gene', (156, 160))
242505	28104365	As shown in Fig 1 and 2, mtDNA depletion (either by EtBr or knock down of Tfam mRNA) induced higher levels of mitochondrial fission.	('higher', 'PosReg', (93, 99))	('Tfam mRNA', 'Gene', (74, 83))	('EtBr', 'Gene', (52, 56))	('knock down', 'Var', (60, 70))	('EtBr', 'Gene', '1910', (52, 56))	('mitochondrial fission', 'MPA', (110, 131))
242509	28104365	Dysfunctional mitochondria, either due to specific defects in mitochondrial enzymes or general effects like hypoxia, loss of membrane potential or mtDNA depletion exhibit characteristic accumulation of metabolites.	('mitochondrial enzymes', 'Enzyme', (62, 83))	('loss', 'Var', (117, 121))	('metabolites', 'MPA', (202, 213))	('membrane potential', 'MPA', (125, 143))	('hypoxia', 'Disease', 'MESH:D000860', (108, 115))	('accumulation', 'PosReg', (186, 198))	('hypoxia', 'Disease', (108, 115))	('defects', 'NegReg', (51, 58))
242511	28104365	One of the metabolites, lauryl carnitine was shown to increase expression of pro inflammatory cytokines in bone marrow derived macrophages.	('lauryl carnitine', 'Var', (24, 40))	('lauryl carnitine', 'Chemical', 'MESH:C091947', (24, 40))	('increase', 'PosReg', (54, 62))	('expression', 'MPA', (63, 73))
242514	28104365	Mutations in enzymes of TCA cycle, components of the electron transport chain and mtDNA defects affect mitochondrial metabolism and alter the metabolome.	('TCA cycle', 'Gene', (24, 33))	('affect', 'Reg', (96, 102))	('metabolome', 'MPA', (142, 152))	('mitochondrial metabolism', 'MPA', (103, 127))	('mtDNA', 'Gene', (82, 87))	('TCA', 'Chemical', 'MESH:D014238', (24, 27))	('Mutations', 'Var', (0, 9))	('alter', 'Reg', (132, 137))
242515	28104365	Metabolic profiling of hereditary paraganglioma and phenochromocytoma harboring mutations in succinate dehydrogenase showed increased levels of succinate, which has been shown to inhibit prolyl hydroxylases (PHD) and stabilize HIF1 .	('PHD', 'Disease', (208, 211))	('prolyl hydroxylases', 'MPA', (187, 206))	('succinate', 'Chemical', 'MESH:D019802', (93, 102))	('succinate dehydrogenase', 'Gene', (93, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (34, 47))	('mutations', 'Var', (80, 89))	('increased', 'PosReg', (124, 133))	('HIF1', 'Gene', '3091', (227, 231))	('succinate', 'Chemical', 'MESH:D019802', (144, 153))	('levels of succinate', 'MPA', (134, 153))	('HIF1', 'Gene', (227, 231))	('inhibit', 'NegReg', (179, 186))	('hereditary paraganglioma and phenochromocytoma', 'Disease', 'MESH:D010235', (23, 69))	('PHD', 'Disease', 'MESH:D011547', (208, 211))
242516	28104365	Heriditary leiomyomatosis and renal cell cancers that have a high frequency of mutation in Fumarate hydratase similarly accumulate millimolar levels of fumarate, which has been shown to also inhibit PHDs and histone demethylases .	('Fumarate hydratase', 'Gene', (91, 109))	('Fumarate hydratase', 'Gene', '2271', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('renal cell cancer', 'Phenotype', 'HP:0005584', (30, 47))	('inhibit', 'NegReg', (191, 198))	('PHD', 'Disease', 'MESH:D011547', (199, 202))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('PHD', 'Disease', (199, 202))	('mutation', 'Var', (79, 87))	('accumulate', 'PosReg', (120, 130))	('millimolar levels', 'MPA', (131, 148))	('histone demethylases', 'Enzyme', (208, 228))	('fumarate', 'Chemical', 'MESH:D005650', (152, 160))	('Heriditary leiomyomatosis and renal cell cancers', 'Disease', 'MESH:C535516', (0, 48))
242518	28104365	Isocitrate dehydrogenase is another enzyme of the TCA cycle that is mutated in many human cancers like colon cancer, gliomas, AML and osteosarcoma.	('osteosarcoma', 'Disease', (134, 146))	('cancers', 'Disease', (90, 97))	('gliomas', 'Disease', (117, 124))	('colon cancer', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (134, 146))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('mutated', 'Var', (68, 75))	('citrate', 'Chemical', 'MESH:D019343', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('TCA', 'Chemical', 'MESH:D014238', (50, 53))	('osteosarcoma', 'Phenotype', 'HP:0002669', (134, 146))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('AML', 'Disease', 'MESH:D015470', (126, 129))	('human', 'Species', '9606', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('colon cancer', 'Disease', 'MESH:D015179', (103, 115))	('AML', 'Disease', (126, 129))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))
242519	28104365	Mutations in IDH generates a neomorphic enzyme that converts isocitrate to 2-hydroxyglutarate (2-HG) instead of oxo-glutarate .	('IDH', 'Gene', '3417', (13, 16))	('2-HG', 'Chemical', 'MESH:C019417', (95, 99))	('oxo-glutarate', 'Chemical', 'MESH:D007656', (112, 125))	('Mutations', 'Var', (0, 9))	('isocitrate', 'Chemical', 'MESH:C034219', (61, 71))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (75, 93))	('IDH', 'Gene', (13, 16))	('isocitrate', 'MPA', (61, 71))
242520	28104365	2-HG has been shown to be oncogenic through its action on PHDs, and can bring about epigenetic changes .	('epigenetic changes', 'MPA', (84, 102))	('PHD', 'Disease', 'MESH:D011547', (58, 61))	('bring about', 'Reg', (72, 83))	('PHD', 'Disease', (58, 61))	('2-HG', 'Chemical', 'MESH:C019417', (0, 4))	('2-HG', 'Var', (0, 4))	('oncogenic', 'CPA', (26, 35))
242521	28104365	mtDNA depletion mediated mitochondrial dysfunction induces stress signaling that transforms non-tumorigenic cells to acquire tumorigenic phenotype.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (25, 50))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (25, 50))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('induces', 'Reg', (51, 58))	('tumor', 'Disease', (96, 101))	('stress signaling', 'MPA', (59, 75))	('tumor', 'Disease', (125, 130))	('mitochondrial dysfunction', 'Disease', (25, 50))	('depletion', 'Var', (6, 15))	('transforms', 'Reg', (81, 91))	('mtDNA', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
242525	28104365	It is well documented that mitochondrial dysfunction influences pathological phenotypes and morphological changes has been postulated to be an adaptive cellular response to the mitochondrial stress Reports from our laboratory and others have shown that immortalized mammary cells harboring mitochondrial defects undergo cellular morphological reprograming similar to an epithelial-mesenchymal transition .	('undergo', 'Reg', (312, 319))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (27, 52))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (27, 52))	('mitochondrial dysfunction', 'Disease', (27, 52))	('mitochondrial', 'Gene', (290, 303))	('defects', 'Var', (304, 311))	('cellular morphological reprograming', 'CPA', (320, 355))
242529	28104365	In primary esophageal cells derived from Tfamfl/fl mice, we observed, cells transduced ex vivo with adenoviral Cre contained >95% reduced Tfam mRNA and also with reduced mtDNA content compared to cells transduced with the adenoviral vector expressing GFP (Fig 6A,B).	('Tfam', 'Protein', (138, 142))	('adenoviral', 'Var', (100, 110))	('mice', 'Species', '10090', (51, 55))	('reduced', 'NegReg', (162, 169))	('reduced', 'NegReg', (130, 137))	('mtDNA content', 'MPA', (170, 183))
242532	28104365	Organoids derived from Tfam knockout Tfamfl/fl/+Cre murine primary esophageal cells as described in the above section, were fewer in numbers and showed reduced basal and parabasal cells.	('fewer', 'NegReg', (124, 129))	('reduced', 'NegReg', (152, 159))	('Tfam', 'Gene', (23, 27))	('knockout', 'Var', (28, 36))	('murine', 'Species', '10090', (52, 58))
242535	28104365	The second part of the hypothesis suggesting a role for defective mitochondrial function as a possible cause of cancer initiation or progression remains contentious, despite intense investigations in many laboratories.	('defective mitochondrial function', 'Phenotype', 'HP:0003287', (56, 88))	('cancer initiation', 'Disease', 'MESH:D009369', (112, 129))	('defective', 'Var', (56, 65))	('cancer initiation', 'Disease', (112, 129))	('mitochondrial function', 'Protein', (66, 88))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
242536	28104365	Although clinical studies show strong correlation between mitochondrial dysfunction, including respiratory defects, mtDNA mutations and low mtDNA contents in a variety of human cancers, the cause or effect relationship remains unclear.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (58, 83))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (58, 83))	('respiratory defects', 'Disease', (95, 114))	('cancers', 'Disease', (177, 184))	('mitochondrial dysfunction', 'Disease', (58, 83))	('mutations', 'Var', (122, 131))	('respiratory defects', 'Disease', 'MESH:D012131', (95, 114))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('mtDNA', 'Gene', (116, 121))	('human', 'Species', '9606', (171, 176))
242537	28104365	Many studies including ours have shown that partial depletion of mtDNA, heteroplasmic mtDNA mutations, or disruption of Complex I and complex IV induce tumorigenic phenotypes in immortalized epithelial cells.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mtDNA', 'Gene', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('mutations', 'Var', (92, 101))
242574	26252284	The aberrant expression or function of cell adhesion molecules results in the loss of tissue architecture, thus providing an opportunity for tumor cells to invade and progression.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('progression', 'CPA', (167, 178))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('expression', 'MPA', (13, 23))	('function', 'MPA', (27, 35))	('aberrant', 'Var', (4, 12))	('tissue architecture', 'CPA', (86, 105))	('tumor', 'Disease', (141, 146))	('loss', 'NegReg', (78, 82))	('invade', 'CPA', (156, 162))	('cell adhesion molecules', 'Protein', (39, 62))
242602	26252284	The pooled results showed that high expression of CD44v6 was associated with poor prognosis in patients with esophageal cancer (HR = 2.47, 95% CI = 1.56-3.92, I2 = 38.4%, P = 0.165; see Figure 3).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('patients', 'Species', '9606', (95, 103))	('CD44', 'Gene', (50, 54))	('esophageal cancer', 'Disease', (109, 126))	('high expression', 'Var', (31, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))	('CD44', 'Gene', '960', (50, 54))
242608	26252284	CD44v6:a CD44 variant:changes the composition and function of adhesion molecules.	('CD44', 'Gene', (9, 13))	('changes', 'Reg', (22, 29))	('CD44', 'Gene', '960', (0, 4))	('CD44', 'Gene', (0, 4))	('composition', 'MPA', (34, 45))	('function of adhesion molecules', 'MPA', (50, 80))	('CD44', 'Gene', '960', (9, 13))	('variant', 'Var', (14, 21))
242612	26252284	Moreover, Nozoe et al showed that high expression of CD44v6 was associated with lymph node metastasis.	('associated', 'Reg', (64, 74))	('lymph node metastasis', 'CPA', (80, 101))	('CD44', 'Gene', '960', (53, 57))	('CD44', 'Gene', (53, 57))	('high', 'Var', (34, 38))
242616	26252284	Our results also found that the high expression of CD44v6 was associated with poor survival in esophageal cancer patients with lymphoid nodal metastasis, which suggests that the abnormal expression of CD44v6 in tumor cells may enhance their potential for metastasis in the regional lymph nodes.	('CD44', 'Gene', (201, 205))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('lymphoid nodal metastasis', 'Disease', (127, 152))	('lymphoid nodal metastasis', 'Disease', 'MESH:D009362', (127, 152))	('patients', 'Species', '9606', (113, 121))	('enhance', 'PosReg', (227, 234))	('poor', 'NegReg', (78, 82))	('CD44', 'Gene', '960', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('CD44', 'Gene', (51, 55))	('expression', 'MPA', (37, 47))	('CD44', 'Gene', '960', (201, 205))	('esophageal cancer', 'Disease', (95, 112))	('abnormal', 'Var', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
242623	26252284	In conclusion, this meta-analysis indicates that high expression of CD44v6 is associated with a poor survival and lymphoid nodal metastasis in patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('CD44', 'Gene', '960', (68, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('CD44', 'Gene', (68, 72))	('patients', 'Species', '9606', (143, 151))	('high expression', 'Var', (49, 64))	('lymphoid nodal metastasis', 'Disease', (114, 139))	('poor', 'NegReg', (96, 100))	('esophageal cancer', 'Disease', (157, 174))	('lymphoid nodal metastasis', 'Disease', 'MESH:D009362', (114, 139))
242727	25134008	MRM quantitation of glycopeptides is based on the use of oxonium ions as transitions including m/z values at 138 (HexNAc-2H2O-CH2O), 274 (NeuAc-H2O), 366 (HexNAc+Hex), and 657 (HexNAc+Hex+NeuAc).	('Hex', 'Gene', '3087', (114, 117))	('Hex', 'Gene', '3087', (162, 165))	('Hex', 'Gene', '3087', (177, 180))	('H2O', 'Chemical', 'MESH:D014867', (127, 130))	('NeuAc', 'Chemical', 'MESH:D019158', (188, 193))	('H2O', 'Chemical', 'MESH:D014867', (144, 147))	('NeuAc', 'Chemical', 'MESH:D019158', (138, 143))	('Hex', 'Gene', (114, 117))	('Hex', 'Gene', (162, 165))	('CH2O', 'Chemical', '-', (126, 130))	('Hex', 'Gene', (177, 180))	('Hex', 'Gene', '3087', (184, 187))	('oxonium', 'Chemical', 'MESH:C027727', (57, 64))	('HexNAc', 'Chemical', '-', (155, 161))	('Hex', 'Gene', (184, 187))	('NeuAc-H2O', 'Var', (138, 147))	('HexNAc', 'Chemical', '-', (114, 120))	('HexNAc', 'Chemical', '-', (177, 183))	('2H2O', 'Chemical', '-', (121, 125))	('Hex', 'Gene', '3087', (155, 158))	('H2O', 'Chemical', 'MESH:D014867', (122, 125))	('274 (NeuAc-H2O', 'Var', (133, 147))	('Hex', 'Gene', (155, 158))
242755	25134008	Confirmed assignment of glycopeptides was based on the detection of diagnostic ions of N-lined glycopeptides (oxonium ions) in HCD MS/MS, such as m/z values of 138, 204, 274, 292, 366, 657, and so on.	('292', 'Var', (175, 178))	('HCD', 'Disease', (127, 130))	('274', 'Var', (170, 173))	('lined glycopeptides', 'Chemical', '-', (89, 108))	('366', 'Var', (180, 183))
242784	25134008	For example, the glycosylation on N552 associated with FINC shows a very low abundance or nondetection from some of the subjects in HGD or EAC.	('FINC', 'Gene', (55, 59))	('N552', 'Var', (34, 38))	('FINC', 'Gene', '2335', (55, 59))	('EAC', 'Phenotype', 'HP:0011459', (139, 142))
242785	25134008	The glycosylation on N882 from CFAH was observed with 1.70 times higher in HGD compared with DF.	('CFAH', 'Chemical', '-', (31, 35))	('N882', 'Chemical', '-', (21, 25))	('glycosylation', 'MPA', (4, 17))	('N882', 'Var', (21, 25))	('higher', 'PosReg', (65, 71))
242786	25134008	Two glycosylation sites on N81 and N51 were associated with ITIH4, representing down-regulation by 0.48 and 0.64 times in EAC, respectively.	('N81', 'Var', (27, 30))	('ITIH4', 'Gene', '3700', (60, 65))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('ITIH4', 'Gene', (60, 65))	('N51', 'Var', (35, 38))	('down-regulation', 'NegReg', (80, 95))
242787	25134008	In Figure 6A, monosialylated biantennary glycopeptide attached to N43 on CO8A was detected with down-regulation for HGD (0.53 times lower) and EAC (0.62 times lower) compared with DF.	('HGD', 'Protein', (116, 119))	('EAC', 'Phenotype', 'HP:0011459', (143, 146))	('CO8A', 'Chemical', '-', (73, 77))	('lower', 'NegReg', (159, 164))	('lower', 'NegReg', (132, 137))	('monosialylated', 'Var', (14, 28))	('down-regulation', 'NegReg', (96, 111))
242788	25134008	Disialylated biantennary glycopeptide attached to N328 from IPSP was observed with up-regulation in HGD (2.36 times higher) and EAC (1.71 times higher) compared with DF.	('N328', 'Var', (50, 54))	('up-regulation', 'PosReg', (83, 96))	('Disialylated biantennary glycopeptide', 'Phenotype', 'HP:0410365', (0, 37))	('N328', 'Chemical', '-', (50, 54))	('HGD', 'Disease', (100, 103))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))
242789	25134008	By HC enrichment, two glycosylation sites of N138 and N397 associated with CERU were determined to be statistically validated between DF versus HGD and DF versus EAC.	('CERU', 'Chemical', '-', (75, 79))	('N397', 'Var', (54, 58))	('N138', 'Chemical', '-', (45, 49))	('N138', 'Var', (45, 49))	('EAC', 'Phenotype', 'HP:0011459', (162, 165))	('CERU', 'Disease', (75, 79))
242790	25134008	Another glycosylation site on N555 from F13B also shows down-regulation by 0.34 times in HGD and 0.52 times in EAC compared with DF.	('down-regulation', 'NegReg', (56, 71))	('F13B', 'Gene', '2165', (40, 44))	('HGD', 'Disease', (89, 92))	('N555', 'Var', (30, 34))	('F13B', 'Gene', (40, 44))	('EAC', 'Phenotype', 'HP:0011459', (111, 114))
242798	23270334	All microdissected targets with dysplasia had mutations, with a high ML consistently present in high grade dysplasia targets.	('dysplasia', 'Disease', (107, 116))	('mutations', 'Var', (46, 55))	('dysplasia', 'Disease', 'MESH:D004476', (107, 116))	('dysplasia', 'Disease', (32, 41))	('dysplasia', 'Disease', 'MESH:D004476', (32, 41))
242800	23270334	Assessment of mutational load using our panel of LOH mutational markers may be a useful adjunct to microscopic inspection of biopsy specimens, and thereby, improve patient management.	('patient', 'Species', '9606', (164, 171))	('mutational load', 'Var', (14, 29))	('improve', 'PosReg', (156, 163))
242802	23270334	During BE carcinogenesis, genetic alterations that favor unregulated cell growth, such as activation of oncogenes and inactivation of tumor suppressor genes, cause morphologic changes in esophageal tissue .	('oncogenes', 'Gene', (104, 113))	('activation', 'PosReg', (90, 100))	('cause', 'Reg', (158, 163))	('inactivation', 'Var', (118, 130))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
242803	23270334	Various studies have firmly established that mutational change involving tumor suppressor genes occurs at the histological onset of BE .	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('mutational change', 'Var', (45, 62))
242818	23270334	Previous work using microdissection-guided broad panel profiling for loss of heterozygosity (LOH) mutations in proximity to tumor suppressor genes has shown clinical utility for a variety of cancer applications .	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('loss of heterozygosity', 'NegReg', (69, 91))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
242842	23270334	Esophageal biopsies were examined for LOH mutational profiles adjacent to tumor suppressor genes.	('LOH mutational profiles', 'Var', (38, 61))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
242844	23270334	While most mutations found in HGD targets were high clonality, mutations found in non-dysplastic histological classifications (intestinal metaplasia, "indefinite for dysplasia") were typically low clonality.	('mutations', 'Var', (11, 20))	('intestinal metaplasia', 'Disease', (127, 148))	('dysplasia', 'Disease', (166, 175))	('dysplasia', 'Disease', 'MESH:D004476', (166, 175))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (127, 148))	('HGD', 'Gene', (30, 33))
242845	23270334	Microdissected targets histologically classified with dysplasia had the highest frequency of mutations at 17p (TP53), with mutations present in 14/16 (88%) HGD targets, 27/39 (69%) LGD targets, and 49/138 (36%) "indefinite for dysplasia" targets.	('dysplasia', 'Disease', (227, 236))	('mutations', 'Var', (93, 102))	('dysplasia', 'Disease', (54, 63))	('TP53', 'Gene', '7157', (111, 115))	('dysplasia', 'Disease', 'MESH:D004476', (227, 236))	('TP53', 'Gene', (111, 115))	('dysplasia', 'Disease', 'MESH:D004476', (54, 63))	('mutations', 'Var', (123, 132))
242847	23270334	Mutational load (Table 2, Figure 2) for a microdissected target represents the accumulation of clonally expanded LOH mutations next to tumor suppressor genes.	('mutations', 'Var', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Mutational', 'Var', (0, 10))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
242848	23270334	Using the frequency with which mutational load was observed in intestinal metaplasia we established three levels of Mutational Load (ML) with respect to each histological classification (Figure 2B).	('Mutational Load', 'Var', (116, 131))	('intestinal metaplasia', 'Disease', (63, 84))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (63, 84))
242852	23270334	Accumulation of genomic instability within and next to oncogenes and tumor suppressor genes is associated with unregulated cell growth that can result in expansion of clonal cell populations and, ultimately, progression to cancer .	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Disease', (69, 74))	('clonal cell populations', 'CPA', (167, 190))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('expansion', 'PosReg', (154, 163))	('cancer', 'Disease', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('genomic instability', 'Var', (16, 35))
242853	23270334	In this study, we surveyed the presence and extent of genomic instability by assessing the presence and clonality of LOH mutations adjacent to tumor suppressor genes in microdissected tissue targets with a range of histological classifications.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (121, 130))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
242854	23270334	BE microdissected targets with a histological classification of intestinal metaplasia were used to define three levels of Mutational Load (ML) with respect to each histological class: no ML, low ML and high ML (Figure 2B, Table 3).	('intestinal metaplasia', 'Disease', (64, 85))	('Mutational', 'Var', (122, 132))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (64, 85))
242858	23270334	Specimens histologically classified as intestinal metaplasia and "indefinite for dysplasia" spanned a similar spectrum of LOH mutational load (no ML through high ML).	('intestinal metaplasia', 'Disease', 'MESH:D008679', (39, 60))	('LOH mutational load', 'Var', (122, 141))	('dysplasia', 'Disease', (81, 90))	('intestinal metaplasia', 'Disease', (39, 60))	('dysplasia', 'Disease', 'MESH:D004476', (81, 90))
242859	23270334	We found that 78% of intestinal metaplasia microdissected targets had detectable mutations, despite the absence of morphological changes indicative of dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (151, 160))	('intestinal metaplasia', 'Disease', (21, 42))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (21, 42))	('mutations', 'Var', (81, 90))	('dysplasia', 'Disease', (151, 160))
242860	23270334	These results are consistent with a large body of work suggesting that DNA alterations in BE precede the overt morphological development of dysplasia .	('dysplasia', 'Disease', (140, 149))	('alterations', 'Var', (75, 86))	('dysplasia', 'Disease', 'MESH:D004476', (140, 149))
242863	23270334	As with intestinal metaplasia, some "indefinite for dysplasia" microdissected targets may have mutations that precede morphological changes consistent with dysplasia.	('dysplasia', 'Disease', (52, 61))	('dysplasia', 'Disease', (156, 165))	('dysplasia', 'Disease', 'MESH:D004476', (52, 61))	('dysplasia', 'Disease', 'MESH:D004476', (156, 165))	('mutations', 'Var', (95, 104))	('intestinal metaplasia', 'Disease', (8, 29))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (8, 29))
242866	23270334	In our previous experience across other organ groups using a similar LOH panel to examine mutations located near tumor suppressor genes, cell populations that lacked detectable LOH mutations were strongly correlated with benign, reactive processes .	('tumor', 'Disease', (113, 118))	('mutations', 'Var', (90, 99))	('benign', 'CPA', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mutations', 'Var', (181, 190))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('correlated with', 'Reg', (205, 220))
242867	23270334	Although gene panels employed in this study and previous ones are not a complete examination of the entire genome, the absence of clonally expanded LOH mutations next to the large number of tumor suppressor genes surveyed in our panel is strong evidence that the microdissected targets examined did not have extensive genomic instability.	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutations', 'Var', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))
242868	23270334	Microdissected targets that displayed low ML and were histologically classified as normal squamous epithelium and epithelium containing non-intestinalized columnar cells (10% of normal squamous epithelial targets; 39% of columnar, non-Barrett's epithelial targets) could represent actual mutations within histologically normal appearing mucosa or detection of mutated DNA from adjacent cells or intercellular fluids.	('epithelia', 'Disease', 'None', (245, 254))	('epithelia', 'Disease', (245, 254))	('epithelia', 'Disease', 'None', (194, 203))	('epithelia', 'Disease', (194, 203))	('mutated', 'Var', (360, 367))
242869	23270334	The mutational load in these squamous and columnar epithelial microdissected targets could also represent chromosomal aberrations that have yet to become morphologically visible by histology.	('epithelia', 'Disease', 'None', (51, 60))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (106, 129))	('mutational load', 'Var', (4, 19))	('epithelia', 'Disease', (51, 60))
242872	23270334	This supports the association of high levels of genomic instability with more severe histological classifications of BE and is in line with the concept that patients with high ML may also be at greater risk of progression to EAC.	('patients', 'Species', '9606', (157, 165))	('high ML', 'Var', (171, 178))	('EAC', 'Disease', (225, 228))	('association', 'Interaction', (18, 29))
242873	23270334	Consistently, the presence of three or more DNA abnormalities in patients has been associated with a greater risk of progression towards cancer .	('presence', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('patients', 'Species', '9606', (65, 73))
242875	23270334	Our study is consistent with others that have described LOH mutations adjacent to TP53 and CDKN2A tumor suppressor genes, which together have been associated with greater risk of BE progression to cancer .	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('associated', 'Reg', (147, 157))	('CDKN2A', 'Gene', (91, 97))	('LOH mutations', 'Var', (56, 69))	('cancer', 'Disease', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('CDKN2A', 'Gene', '1029', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (60, 69))
242878	23270334	In addition to enhancing histological classification, this type of mutational profiling may also facilitate patient monitoring using sequential biopsies taken over varying periods of time prior to determining if ablation is needed.	('patient', 'Species', '9606', (108, 115))	('enhancing', 'PosReg', (15, 24))	('histological', 'CPA', (25, 37))	('mutational', 'Var', (67, 77))
242880	23270334	We demonstrate that various levels of mutational load (no ML, low ML, and high ML) adjacent to tumor suppressor genes exist within each histological classification (intestinal metaplasia, "indefinite for dysplasia", LGD, HGD).	('intestinal metaplasia', 'Disease', (165, 186))	('dysplasia', 'Disease', (204, 213))	('tumor', 'Disease', (95, 100))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (165, 186))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('dysplasia', 'Disease', 'MESH:D004476', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutational', 'Var', (38, 48))
242883	23270334	EAC: Esophageal Adenocarcinoma; BE: Barrett's Esophagus; LGD: High Grade Dysplasia; HGD: Low Grade Dysplasia; ML: Mutational Load; LOH: Loss of Heterozygosity; FFPE: Formalin Fixed, Paraffin Embedded; H&E: Hematoxylin and Eosin; GI: Gastrointestinal; RFA: Radiofrequency Ablation.	('Low Grade Dysplasia', 'Disease', (89, 108))	('Dysplasia', 'Disease', (73, 82))	('Eosin', 'Chemical', 'MESH:D004801', (222, 227))	('Dysplasia', 'Disease', 'MESH:D004476', (73, 82))	('Paraffin', 'Chemical', 'MESH:D010232', (182, 190))	('Esophageal Adenocarcinoma', 'Disease', (5, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (5, 30))	('Mutational', 'Var', (114, 124))	('Loss', 'NegReg', (136, 140))	('H&E', 'Chemical', '-', (201, 204))	('Formalin', 'Chemical', 'MESH:D005557', (166, 174))	('Low Grade Dysplasia', 'Disease', 'MESH:D008228', (89, 108))	('Hematoxylin', 'Chemical', 'MESH:D006416', (206, 217))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (5, 30))	('Dysplasia', 'Disease', (99, 108))	('Dysplasia', 'Disease', 'MESH:D004476', (99, 108))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (36, 55))
243060	19036143	Radiotherapy, especially concurrent with chemotherapy can lead to acute esophagitis.	('esophagitis', 'Disease', (72, 83))	('Radiotherapy', 'Var', (0, 12))	('esophagitis', 'Phenotype', 'HP:0100633', (72, 83))	('lead to', 'Reg', (58, 65))	('esophagitis', 'Disease', 'MESH:D004941', (72, 83))
243166	32675704	ESD for T1a or T1b SESCC showed comparable survival and recurrence rates with surgery.	('T1a', 'Gene', (8, 11))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('T1b', 'Var', (15, 18))	('T1a', 'Gene', '10630', (8, 11))
243171	32675704	In the National Comprehensive Cancer Network and Japanese guidelines, adjuvant therapy after ESD is recommended for T1b or T1a-MM with LVI.	('Cancer', 'Disease', 'MESH:D009369', (30, 36))	('Cancer', 'Disease', (30, 36))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('T1b', 'Var', (116, 119))	('T1a', 'Gene', '10630', (123, 126))	('T1a', 'Gene', (123, 126))
243236	32290321	In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('alter', 'Reg', (53, 58))	('dysfunctions', 'Var', (26, 38))	('tumor', 'Disease', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('epigenetic modifications', 'Var', (94, 118))	('genetic', 'Var', (79, 86))	('expression', 'MPA', (65, 75))	('cancer', 'Disease', (3, 9))	('PRDM genes', 'Gene', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
243237	32290321	They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed.	('imbalance', 'Phenotype', 'HP:0002172', (152, 161))	('alternative splicing', 'Var', (29, 49))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
243250	32290321	Some evidence suggests that PRDMs are involved in human malignancy through modulation of several processes such as epigenetic modifications, genetic reprogramming, inflammation, and metabolic homeostasis.	('inflammation', 'Disease', (164, 176))	('malignancy', 'Disease', 'MESH:D009369', (56, 66))	('modulation', 'Reg', (75, 85))	('involved', 'Reg', (38, 46))	('PRDMs', 'Chemical', '-', (28, 33))	('malignancy', 'Disease', (56, 66))	('genetic reprogramming', 'CPA', (141, 162))	('inflammation', 'Disease', 'MESH:D007249', (164, 176))	('metabolic homeostasis', 'CPA', (182, 203))	('epigenetic modifications', 'Var', (115, 139))	('human', 'Species', '9606', (50, 55))
243251	32290321	These two isoforms, generated by either alternative splicing or alternative use of different promoters, play opposite roles, particularly in cancer.	('alternative splicing', 'Var', (40, 60))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
243253	32290321	The imbalance in favor of PR- is observed in many human malignancies and it can be due to inactivating mutations or silencing of the complete form and/or to increased expression of the PR- form.	('inactivating mutations', 'Var', (90, 112))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('human', 'Species', '9606', (50, 55))	('increased', 'PosReg', (157, 166))	('silencing', 'Var', (116, 125))	('malignancies', 'Disease', (56, 68))	('expression', 'MPA', (167, 177))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
243255	32290321	An overview of cancer-specific alterations affecting PRDM family members, taking into account putative causes, produced effects, and underlying molecular mechanisms, is detailed below and summarized in Table 1.	('alterations', 'Var', (31, 42))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('PRDM', 'Gene', (53, 57))
243260	32290321	Initially, in 2006, structural alterations inactivating PRDM1/BLIMP1 were identified in DLBCLs in two independent studies.	('BCL', 'Phenotype', 'HP:0012191', (90, 93))	('BLIMP1', 'Gene', '639', (62, 68))	('inactivating', 'Var', (43, 55))	('DLBCLs', 'Disease', (88, 94))	('BLIMP1', 'Gene', (62, 68))
243262	32290321	Particularly, disruption of PRDM1/BLIMP1 function is frequently observed in the activated B-cell-like (ABC) subtype of DLBCL by distinct mechanisms including inactivating mutations, chromosomal deletion, and epigenetic silencing.	('BCL', 'Phenotype', 'HP:0012191', (121, 124))	('inactivating mutations', 'Var', (158, 180))	('BLIMP1', 'Gene', '639', (34, 40))	('function', 'MPA', (41, 49))	('ABC', 'Gene', (103, 106))	('ABC', 'Gene', '10058', (103, 106))	('activated B-cell-like', 'Disease', (80, 101))	('epigenetic silencing', 'Var', (208, 228))	('BLIMP1', 'Gene', (34, 40))	('chromosomal deletion', 'Var', (182, 202))	('disruption', 'NegReg', (14, 24))
243263	32290321	Of note, a more recent study demonstrated that its genetic loss could contribute to the overall poor prognosis for ABC-DLBCL but not germinal center B-cell-like (GCB)-DLBCLs.	('BCL', 'Phenotype', 'HP:0012191', (121, 124))	('BCL', 'Phenotype', 'HP:0012191', (169, 172))	('ABC', 'Gene', (115, 118))	('ABC', 'Gene', '10058', (115, 118))	('genetic loss', 'Var', (51, 63))
243264	32290321	Furthermore, the lack of BLIMP1 expression correlated with an impaired p53 signaling pathway and Myc overexpression; gene expression profiling data also indicated that inactivated BLIMP1 could facilitate DLBCL progression through Myc and BCR (B cell receptor) signaling, which are essential for ABC-DLBCL survival.	('DLBCL', 'Disease', (204, 209))	('BLIMP1', 'Gene', (25, 31))	('BCL', 'Phenotype', 'HP:0012191', (301, 304))	('BLIMP1', 'Gene', (180, 186))	('ABC', 'Gene', '10058', (295, 298))	('BLIMP1', 'Gene', '639', (25, 31))	('BLIMP1', 'Gene', '639', (180, 186))	('BCL', 'Phenotype', 'HP:0012191', (206, 209))	('inactivated', 'Var', (168, 179))	('facilitate', 'PosReg', (193, 203))	('Myc', 'MPA', (230, 233))	('ABC', 'Gene', (295, 298))
243267	32290321	In addition, PRDM1 ectopic expression in a DLBCL-derived cell line triggered cell cycle arrest.	('PRDM1', 'Gene', (13, 18))	('ectopic expression', 'Var', (19, 37))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('arrest', 'Disease', (88, 94))	('BCL', 'Phenotype', 'HP:0012191', (45, 48))	('triggered', 'Reg', (67, 76))
243269	32290321	Consistently, an in vivo study showed that mouse Prdm1 deletion cooperated with constitutive activation of the NF-kappaB pathway to support a neoplastic phenotype.	('activation', 'PosReg', (93, 103))	('support', 'PosReg', (132, 139))	('Prdm1', 'Gene', '12142', (49, 54))	('NF-kappaB', 'Gene', '18033', (111, 120))	('Prdm1', 'Gene', (49, 54))	('deletion', 'Var', (55, 63))	('neoplastic phenotype', 'CPA', (142, 162))	('mouse', 'Species', '10090', (43, 48))	('NF-kappaB', 'Gene', (111, 120))
243271	32290321	For instance, array comparative genomic hybridization and gene expression profiling in extranodal NK/T-cell lymphoma (EN-NK/T) revealed that the most frequently deleted chromosomal region 6q21-6q25, induced a downregulation of several tumor-suppressor genes including PRDM1.	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (101, 116))	('NK/T-cell lymphoma', 'Disease', 'MESH:D054391', (98, 116))	('NK/T-cell lymphoma', 'Disease', (98, 116))	('downregulation', 'NegReg', (209, 223))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cell lymphoma', 'Phenotype', 'HP:0012191', (103, 116))	('tumor-suppressor', 'Gene', (235, 251))	('PRDM1', 'Gene', (268, 273))	('6q21-6q25', 'Var', (188, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (108, 116))	('tumor-suppressor', 'Gene', '7248', (235, 251))
243275	32290321	PRDM1 mutations occurred in patients with plasmablastic lymphoma; interestingly, in this rare neoplasm, PRDM1 genetic alterations did not impair terminal B-cell differentiation, but contributed to the oncogenicity of MYC, which is usually dysregulated by translocation or amplification.	('lymphoma', 'Phenotype', 'HP:0002665', (56, 64))	('plasmablastic lymphoma', 'Disease', (42, 64))	('MYC', 'Gene', '4609', (217, 220))	('MYC', 'Gene', (217, 220))	('genetic alterations', 'Var', (110, 129))	('neoplasm', 'Disease', (94, 102))	('plasmablastic lymphoma', 'Disease', 'MESH:D000069293', (42, 64))	('PRDM1', 'Gene', (104, 109))	('oncogenicity', 'MPA', (201, 213))	('neoplasm', 'Disease', 'MESH:D009369', (94, 102))	('neoplasm', 'Phenotype', 'HP:0002664', (94, 102))	('patients', 'Species', '9606', (28, 36))	('contributed to', 'Reg', (182, 196))
243277	32290321	This is in accordance with the study on ABC-DLBCL patients where the lack of BLIMP1 expression correlated with Myc overexpression.	('BLIMP1', 'Gene', '639', (77, 83))	('patients', 'Species', '9606', (50, 58))	('BCL', 'Phenotype', 'HP:0012191', (46, 49))	('correlated', 'Reg', (95, 105))	('ABC', 'Gene', (40, 43))	('BLIMP1', 'Gene', (77, 83))	('lack', 'Var', (69, 73))	('expression', 'MPA', (84, 94))	('Myc overexpression', 'Disease', (111, 129))	('ABC', 'Gene', '10058', (40, 43))
243288	32290321	In colorectal tumor cells, PRDM1 knockdown by small-interfering RNA (siRNA) results in both apoptosis and growth arrest through regulation of p53 transcription.	('apoptosis', 'CPA', (92, 101))	('p53', 'Gene', (142, 145))	('growth arrest', 'Disease', (106, 119))	('knockdown', 'Var', (33, 42))	('growth arrest', 'Disease', 'MESH:D006323', (106, 119))	('PRDM1', 'Gene', (27, 32))	('regulation', 'Reg', (128, 138))	('growth arrest', 'Phenotype', 'HP:0001510', (106, 119))	('transcription', 'MPA', (146, 159))	('colorectal tumor', 'Disease', (3, 19))	('colorectal tumor', 'Disease', 'MESH:D015179', (3, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('small-interfering', 'Var', (46, 63))
243289	32290321	Interestingly, both p53 mRNA and protein levels are considerably increased after PRDM1/BLIMP1 depletion, which is accompanied by the induction of p53 target genes.	('BLIMP1', 'Gene', (87, 93))	('BLIMP1', 'Gene', '639', (87, 93))	('depletion', 'Var', (94, 103))	('increased', 'PosReg', (65, 74))
243296	32290321	In addition, PRDM1 reduced the expression of DKK1 thus exerting its antitumor effect via antagonizing the activity of Wnt/beta-catenin pathway (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('beta-catenin', 'Gene', '1499', (122, 134))	('tumor', 'Disease', (72, 77))	('antagonizing', 'NegReg', (89, 101))	('DKK1', 'Gene', '22943', (45, 49))	('DKK1', 'Gene', (45, 49))	('activity', 'MPA', (106, 114))	('expression', 'MPA', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('reduced', 'NegReg', (19, 26))	('PRDM1', 'Var', (13, 18))	('beta-catenin', 'Gene', (122, 134))
243298	32290321	Specifically, the ectopic expression of the transcription factor Aiolos induced anoikis resistance to cancer cells by downregulating PRDM1.	('Aiolos', 'Gene', '22806', (65, 71))	('ectopic expression', 'Var', (18, 36))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('induced', 'PosReg', (72, 79))	('PRDM1', 'Gene', (133, 138))	('cancer', 'Disease', (102, 108))	('downregulating', 'NegReg', (118, 132))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Aiolos', 'Gene', (65, 71))
243301	32290321	Additionally, mutations were revealed in some solid tumors, such as skin cutaneous melanoma and uterine carcinosarcoma, which displayed more than 5% of patients carrying PRDM1 mutations.	('revealed', 'Reg', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('skin cutaneous melanoma', 'Disease', (68, 91))	('mutations', 'Var', (176, 185))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('carcinosarcoma', 'Disease', 'MESH:D002296', (104, 118))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (96, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('PRDM1', 'Gene', (170, 175))	('carcinosarcoma', 'Disease', (104, 118))	('mutations', 'Var', (14, 23))	('patients', 'Species', '9606', (152, 160))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (68, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
243307	32290321	Indeed, both genetic inactivation or epigenetic silencing of RIZ1 and/or an increase of RIZ2 expression levels were frequently revealed in many human cancer tissues and cell lines.	('increase', 'PosReg', (76, 84))	('human', 'Species', '9606', (144, 149))	('revealed', 'Reg', (127, 135))	('genetic inactivation', 'Var', (13, 33))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('expression levels', 'MPA', (93, 110))	('cancer', 'Disease', (150, 156))	('RIZ2', 'Gene', '7799', (88, 92))	('RIZ2', 'Gene', (88, 92))	('RIZ1', 'Gene', (61, 65))	('epigenetic silencing', 'Var', (37, 57))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
243311	32290321	Riz1 knockout mice, carrying normal Riz2, were tumor prone in both wild-type and mutant p53 genetic backgrounds.	('prone', 'PosReg', (53, 58))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('p53', 'Gene', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutant', 'Var', (81, 87))	('Riz2', 'Gene', '7799', (36, 40))	('Riz2', 'Gene', (36, 40))	('tumor', 'Disease', (47, 52))
243312	32290321	Indeed, an accelerated tumorigenesis was associated with Riz1 deficiency (Riz1-/-) on the p53+/- background.	('Riz1', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('deficiency', 'Var', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('accelerated', 'PosReg', (11, 22))	('tumor', 'Disease', (23, 28))
243315	32290321	Indeed, frameshift mutations of microsatellite repeats localized in the C-terminal coding region were frequently detected in colorectal, gastric, endometrial, and pancreatic microsatellite instability (MIN) positive cancers.	('gastric', 'Disease', (137, 144))	('colorectal', 'Disease', (125, 135))	('endometrial', 'Disease', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('frameshift mutations', 'Var', (8, 28))	('pancreatic microsatellite instability (MIN) positive cancers', 'Disease', 'MESH:D053842', (163, 223))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('detected', 'Reg', (113, 121))
243319	32290321	Despite their high occurrence, the functional significance in tumorigenesis of these C-terminal PRDM2 truncated forms induced by frameshift mutations is still unknown and deserves investigation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('PRDM2', 'Gene', (96, 101))	('frameshift mutations', 'Var', (129, 149))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('induced', 'Reg', (118, 125))
243320	32290321	Interestingly, the restoration of the wild-type PRDM2 gene sequence of one mutant c.4467delA allele by genome editing in homozygous mutant human colorectal cancer cells, repaired its H3K9me2 activity, impaired tumor cell growth, reduced anchorage-independent growth, cellular migration, and colony forming ability in vitro, as well as decreased the tumor growth in a mouse xenograft model.	('colony forming ability in vitro', 'CPA', (291, 322))	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('mouse', 'Species', '10090', (367, 372))	('activity', 'MPA', (191, 199))	('impaired tumor', 'Disease', 'MESH:D060825', (201, 215))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('colorectal cancer', 'Disease', (145, 162))	('decreased', 'NegReg', (335, 344))	('tumor', 'Disease', (210, 215))	('H3K9me2', 'Protein', (183, 190))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('c.4467delA', 'Var', (82, 92))	('PRDM2', 'Gene', (48, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('reduced', 'NegReg', (229, 236))	('repaired', 'NegReg', (170, 178))	('cellular migration', 'CPA', (267, 285))	('tumor', 'Disease', (349, 354))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('mutant', 'Var', (132, 138))	('anchorage-independent growth', 'CPA', (237, 265))	('impaired tumor', 'Disease', (201, 215))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('human', 'Species', '9606', (139, 144))	('c.4467delA', 'Mutation', 'rs57173229', (82, 92))
243321	32290321	Furthermore, H3K9me2 activity restoration determined the downregulation of several genes involved in cancer pathways, mostly of EMT, thus contributing to a more aggressive cancer phenotype (Figure 1E).	('downregulation', 'NegReg', (57, 71))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('H3K9me2', 'Protein', (13, 20))	('cancer', 'Disease', (101, 107))	('aggressive cancer', 'Disease', 'MESH:D009369', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('restoration', 'Var', (30, 41))	('cancer', 'Disease', (172, 178))	('aggressive cancer', 'Disease', (161, 178))	('more', 'PosReg', (156, 160))
243322	32290321	In addition, frameshift mutations in the (A)9 tract were also found in samples of malignant melanoma and nevi and in leukemia cell lines.	('nevi', 'Disease', (105, 109))	('malignant melanoma', 'Disease', 'MESH:D008545', (82, 100))	('malignant melanoma', 'Disease', (82, 100))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('leukemia', 'Disease', 'MESH:D007938', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('nevi', 'Phenotype', 'HP:0003764', (105, 109))	('leukemia', 'Disease', (117, 125))	('frameshift mutations', 'Var', (13, 33))	('found', 'Reg', (62, 67))	('malignant melanoma', 'Phenotype', 'HP:0002861', (82, 100))	('A)9', 'Gene', (42, 45))
243323	32290321	Interestingly, in most cases of MIN pathway cancers these frameshift mutations were biallelic or homozygous/hemizygous, indicating that PRDM2 follows the two-hit model of tumor suppressor genes, with one hit achieved either by mutations/deletions affecting the PR domain or by frameshift mutations in the 3' end affecting the interactions between the N-terminal PR domain of RIZ1 and its C-terminal region, including the PR-binding motif.	('affecting', 'Reg', (312, 321))	('RIZ1', 'Gene', (375, 379))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('mutations/deletions', 'Var', (227, 246))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('frameshift mutations', 'Var', (277, 297))	('interactions', 'Interaction', (326, 338))
243325	32290321	Interestingly, some PRDM2 polymorphisms have also been associated with carcinogenesis.	('polymorphisms', 'Var', (26, 39))	('PRDM2', 'Gene', (20, 25))	('carcinogenesis', 'Disease', (71, 85))	('associated', 'Reg', (55, 65))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
243327	32290321	A CpG island in the PRDM2/RIZ1 promoter is frequently methylated in many cancer types, such as breast carcinomas and liver tumors, as well as in colon and lung cancer cell lines.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', (160, 166))	('liver tumors', 'Disease', 'MESH:D008113', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('liver tumors', 'Phenotype', 'HP:0002896', (117, 129))	('breast carcinomas', 'Disease', 'MESH:D001943', (95, 112))	('methylated', 'Var', (54, 64))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('breast carcinomas', 'Disease', (95, 112))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('liver tumors', 'Disease', (117, 129))	('PRDM2/RIZ1', 'Gene', (20, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('breast carcinomas', 'Phenotype', 'HP:0003002', (95, 112))	('colon and lung cancer', 'Disease', 'MESH:D008175', (145, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))
243328	32290321	Additionally, epigenetic silencing of RIZ1 expression was also detected in pituitary adenomas and nasopharyngeal carcinoma specimens.	('detected', 'Reg', (63, 71))	('epigenetic silencing', 'Var', (14, 34))	('carcinoma', 'Disease', 'MESH:D009369', (113, 122))	('men', 'Species', '9606', (128, 131))	('pituitary adenomas', 'Disease', 'MESH:D010911', (75, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (98, 122))	('RIZ1', 'Gene', (38, 42))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (75, 93))	('carcinoma', 'Disease', (113, 122))	('pituitary adenomas', 'Disease', (75, 93))
243335	32290321	Noteworthy, a later study demonstrated that estradiol induced the preferential synthesis of transcripts with exon 9a, whereas it reduced those containing exons 9b and 10.	('synthesis', 'MPA', (79, 88))	('preferential', 'PosReg', (66, 78))	('exon 9a', 'Var', (109, 116))	('reduced', 'NegReg', (129, 136))	('estradiol', 'Chemical', 'MESH:D004958', (44, 53))
243344	32290321	Specifically, tumor suppressor function requires the establishment of the H4K20me1-H3K9me1 trans-tail 'histone code' at specific loci through the direct interaction of RIZ1 PR-binding motif to PR-Set7 monomethyltransferase, an essential component of the mammalian cell cycle, which is needed for proper DNA replication and mitosis, thus hypothesizing an additional mechanism of action.	('men', 'Species', '9606', (62, 65))	('mitosis', 'Disease', 'None', (323, 330))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('interaction', 'Interaction', (153, 164))	('mammalian', 'Species', '9606', (254, 263))	('PR-Set7', 'Gene', (193, 200))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('H4K20me1-H3K9me1', 'Var', (74, 90))	('PR-Set7', 'Gene', '387893', (193, 200))	('RIZ1', 'Gene', (168, 172))	('mitosis', 'Disease', (323, 330))
243346	32290321	Since the loss of PR-Set7 produced persistent DNA double-strand breaks (DSBs), it was conceivable that H4K20me1, and possibly Riz1-mediated H3K9me1, had a role in DNA repair.	('loss', 'Var', (10, 14))	('DNA double-strand breaks', 'MPA', (46, 70))	('DSBs', 'Chemical', '-', (72, 76))	('H4K20me1', 'Var', (103, 111))	('PR-Set7', 'Gene', (18, 25))	('PR-Set7', 'Gene', '387893', (18, 25))
243357	32290321	It is well established that chromosomal rearrangements or proviral insertion at the PRDM3 locus gene, MECOM, are found in up to 10% of acute myeloid leukemia (AML) cases with poor survival outcomes.	('men', 'Species', '9606', (49, 52))	('AML', 'Phenotype', 'HP:0004808', (159, 162))	('AML', 'Disease', (159, 162))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (135, 157))	('MECOM', 'Gene', (102, 107))	('found', 'Reg', (113, 118))	('leukemia', 'Phenotype', 'HP:0001909', (149, 157))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (141, 157))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (135, 157))	('AML', 'Disease', 'MESH:D015470', (159, 162))	('acute myeloid leukemia', 'Disease', (135, 157))	('chromosomal rearrangements', 'Var', (28, 54))
243361	32290321	Later, in ovarian tumors a high frequency of aberrant EVI1 splicing, generating novel isoforms, could contribute to the pathophysiology of these cancers.	('cancers', 'Disease', (145, 152))	('ovarian tumors', 'Disease', (10, 24))	('EVI1', 'Gene', (54, 58))	('ovarian tumors', 'Phenotype', 'HP:0100615', (10, 24))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('aberrant', 'Var', (45, 53))	('ovarian tumors', 'Disease', 'MESH:D010051', (10, 24))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('isoforms', 'MPA', (86, 94))	('contribute', 'Reg', (102, 112))	('EVI1', 'Gene', '14013', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
243362	32290321	EVI1 is usually upregulated through the generation of oncogenic fusion proteins as a consequence of rearrangements; alternatively, it can also be upregulated by leukemogenic factors at the transcriptional level.	('upregulated', 'PosReg', (16, 27))	('rearrangements', 'Var', (100, 114))	('EVI1', 'Gene', (0, 4))	('upregulated', 'PosReg', (146, 157))	('men', 'Species', '9606', (109, 112))	('EVI1', 'Gene', '14013', (0, 4))
243373	32290321	For instance, the proximal set of EVI1 zinc fingers is able to bind the N-terminal domain of the zinc finger transcription factor hypermethylated in cancer 1 (HIC1); in turn, this interaction deregulates the DNA binding and transcriptional activity of EVI1 on the BCL-XL promoter, thus compromising the anti-apoptotic activity of EVI1 (Figure 2).	('transcriptional', 'MPA', (224, 239))	('hypermethylated in cancer 1', 'Gene', (130, 157))	('EVI1', 'Gene', (252, 256))	('EVI1', 'Gene', '14013', (252, 256))	('BCL-XL', 'Gene', (264, 270))	('compromising', 'NegReg', (286, 298))	('anti-apoptotic activity', 'CPA', (303, 326))	('EVI1', 'Gene', (34, 38))	('deregulates', 'NegReg', (192, 203))	('HIC1', 'Gene', (159, 163))	('EVI1', 'Gene', '14013', (34, 38))	('BCL-XL', 'Gene', '598', (264, 270))	('hypermethylated in cancer 1', 'Gene', '3090', (130, 157))	('interaction', 'Var', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DNA binding', 'Interaction', (208, 219))	('HIC1', 'Gene', '3090', (159, 163))	('EVI1', 'Gene', (330, 334))	('BCL', 'Phenotype', 'HP:0012191', (264, 267))	('EVI1', 'Gene', '14013', (330, 334))
243376	32290321	EVI1 knockdown impaired PC cell proliferation through a cell cycle progression blockade.	('blockade', 'NegReg', (79, 87))	('cell cycle progression', 'CPA', (56, 78))	('impaired', 'NegReg', (15, 23))	('knockdown', 'Var', (5, 14))	('PC', 'Phenotype', 'HP:0012125', (24, 26))	('EVI1', 'Gene', (0, 4))	('EVI1', 'Gene', '14013', (0, 4))
243377	32290321	Mechanistically, these changes might be at least in part mediated by reactivation of SMAD3, a known transcriptional target of EVI1.	('SMAD3', 'Gene', '4088', (85, 90))	('SMAD3', 'Gene', (85, 90))	('EVI1', 'Gene', (126, 130))	('reactivation', 'Var', (69, 81))	('EVI1', 'Gene', '14013', (126, 130))
243378	32290321	EVI1 knockdown in PC cells also reduced migratory potential and anchorage-independent growth while enhancing apoptosis sensitivity.	('enhancing', 'PosReg', (99, 108))	('anchorage-independent growth', 'CPA', (64, 92))	('apoptosis sensitivity', 'CPA', (109, 130))	('migratory potential', 'CPA', (40, 59))	('knockdown', 'Var', (5, 14))	('reduced', 'NegReg', (32, 39))	('EVI1', 'Gene', (0, 4))	('PC', 'Phenotype', 'HP:0012125', (18, 20))	('EVI1', 'Gene', '14013', (0, 4))
243389	32290321	In addition, EVI1 knockdown demonstrated its requirement for metastasis of colon cancer cells.	('knockdown', 'Var', (18, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('men', 'Species', '9606', (52, 55))	('EVI1', 'Gene', (13, 17))	('metastasis of colon cancer', 'Disease', (61, 87))	('EVI1', 'Gene', '14013', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('metastasis of colon cancer', 'Disease', 'MESH:D015179', (61, 87))
243394	32290321	Recent findings have suggested MECOM as a novel candidate gene for hereditary hematological malignancies; indeed, a novel germline mutation within the ninth zinc finger motif was reported in a family with developed myeloid malignancies.	('reported', 'Reg', (179, 187))	('myeloid malignancies', 'Disease', 'MESH:D009369', (215, 235))	('hematological malignancies', 'Phenotype', 'HP:0004377', (78, 104))	('hereditary hematological malignancies', 'Disease', (67, 104))	('myeloid malignancies', 'Disease', (215, 235))	('hereditary hematological malignancies', 'Disease', 'MESH:D019337', (67, 104))	('germline mutation within', 'Var', (122, 146))
243395	32290321	As for PRDM2 gene, a mononucleotide repeat (A7) in exon 8 of MECOM coding sequences was found to be a target for frameshift mutation (loss-of-function mutation) in colorectal cancers with MIN.	('colorectal cancer', 'Phenotype', 'HP:0003003', (164, 181))	('colorectal cancers', 'Disease', 'MESH:D015179', (164, 182))	('mononucleotide', 'Chemical', '-', (21, 35))	('colorectal cancers', 'Disease', (164, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('frameshift mutation', 'Var', (113, 132))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
243396	32290321	In the same study, the authors also observed intratumor heterogeneity (an important cancer hallmark) of MECOM mutations in four of 16 analyzed cases (25%).	('MECOM', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('cancer hallmark', 'Disease', (84, 99))	('cancer hallmark', 'Disease', 'MESH:D009369', (84, 99))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
243406	32290321	Later, epigenetic PRDM5 silencing was also shown in gastric and colorectal cancers, where its ectopic expression determined a cell growth suppression.	('colorectal cancers', 'Disease', 'MESH:D015179', (64, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('colorectal cancers', 'Disease', (64, 82))	('epigenetic PRDM5', 'Var', (7, 23))	('gastric', 'Disease', (52, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('silencing', 'NegReg', (24, 33))	('cell growth', 'CPA', (126, 137))
243407	32290321	Of note, PRDM5 promoter methylation was detected in both primary colorectal and gastric cancers but not in noncancerous tissue specimens collected from areas adjacent to the tumors.	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('cancerous', 'Disease', (110, 119))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (65, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('detected', 'Reg', (40, 48))	('methylation', 'Var', (24, 35))	('men', 'Species', '9606', (132, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('PRDM5', 'Gene', (9, 14))	('cancerous', 'Disease', 'MESH:D009369', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('gastric cancers', 'Phenotype', 'HP:0012126', (80, 95))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
243410	32290321	Recently, a significant PRDM5 promoter methylation was observed in BRAF mutant cancers of the serrated pathway whereas minimal levels of methylation were detected in the BRAF wild-type cancers of the traditional pathway; moreover, PRDM5 methylation was evident in a small proportion of serrated type polyps indicating that this may be an early event in tumorigenesis.	('polyps', 'Disease', (300, 306))	('serrated pathway', 'Pathway', (94, 110))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('tumor', 'Disease', (353, 358))	('mutant', 'Var', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('serrated type', 'Disease', (286, 299))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('polyps', 'Disease', 'MESH:D011127', (300, 306))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PRDM5', 'Gene', (231, 236))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('BRAF', 'Gene', '673', (170, 174))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (170, 174))	('PRDM5', 'Gene', (24, 29))	('serrated type polyps', 'Phenotype', 'HP:0032222', (286, 306))	('BRAF', 'Gene', (67, 71))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
243412	32290321	For example, aberrant DNA methylation reduced PRDM5 expression in about 40.5% of cervical cancers, whereas normal tissues were unmethylated.	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cervical cancers', 'Disease', (81, 97))	('PRDM5', 'Gene', (46, 51))	('cervical cancers', 'Disease', 'MESH:D002583', (81, 97))	('expression', 'MPA', (52, 62))	('DNA', 'Protein', (22, 25))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('aberrant', 'Var', (13, 21))
243413	32290321	Similarly, PRDM5 was frequently silenced by promoter methylation in multiple cancer cell lines and tumor specimens, including nasopharyngeal, esophageal, gastric, cervical, and hepatocellular carcinoma.	('tumor', 'Disease', (99, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('silenced', 'NegReg', (32, 40))	('men', 'Species', '9606', (110, 113))	('cancer', 'Disease', (77, 83))	('PRDM5', 'Gene', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (177, 201))	('promoter methylation', 'Var', (44, 64))	('nasopharyngeal', 'Disease', (126, 140))	('hepatocellular carcinoma', 'Disease', (177, 201))	('cervical', 'Disease', (163, 171))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (177, 201))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('esophageal', 'Disease', (142, 152))	('gastric', 'Disease', (154, 161))
243419	32290321	Accordingly, this concept is also supported by a study in which repression of PRDM5 function, due to deletions in its locus along with miR-182 sequence amplification, was shown to play a co-operative role in ovarian cancers.	('ovarian cancers', 'Disease', 'MESH:D010051', (208, 223))	('miR-182', 'Gene', '406958', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('ovarian cancers', 'Disease', (208, 223))	('repression', 'NegReg', (64, 74))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (208, 222))	('PRDM5', 'Gene', (78, 83))	('ovarian cancers', 'Phenotype', 'HP:0100615', (208, 223))	('deletions', 'Var', (101, 110))	('miR-182', 'Gene', (135, 142))
243425	32290321	Noteworthy, a meta-analysis of genome-wide association studies correlated a single nucleotide polymorphism in PRDM6 gene with both mammographic density and breast cancer susceptibility.	('PRDM6', 'Gene', (110, 115))	('PRDM6', 'Gene', '93166', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('single nucleotide polymorphism', 'Var', (76, 106))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('mammographic density', 'Disease', (131, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))
243429	32290321	A whole-exome sequencing analysis on a small group of pituitary adenomas revealed genetic variants in several genes, including PRDM8.	('pituitary adenomas', 'Disease', (54, 72))	('PRDM8', 'Gene', (127, 132))	('variants', 'Var', (90, 98))	('pituitary adenomas', 'Disease', 'MESH:D010911', (54, 72))	('PRDM8', 'Gene', '56978', (127, 132))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (54, 72))
243441	32290321	Indeed, meiotic recombination is crucial for accurate chromosomal disjunction and genomic stability maintenance during meiosis; likewise, homologous recombination also promotes genomic stability by repairing DSBs in cells undergoing mitosis.	('homologous recombination', 'Var', (138, 162))	('meiosis', 'Disease', 'MESH:C536875', (119, 126))	('DSBs', 'Chemical', '-', (208, 212))	('DSBs', 'MPA', (208, 212))	('promotes', 'PosReg', (168, 176))	('genomic stability', 'CPA', (177, 194))	('mitosis', 'Disease', (233, 240))	('repairing', 'NegReg', (198, 207))	('mitosis', 'Disease', 'None', (233, 240))	('meiosis', 'Disease', (119, 126))
243442	32290321	Furthermore, the two processes involve overlapping molecular machinery and comparable mechanisms whose dysregulation can often lead to diseases, including cancer.	('diseases', 'Disease', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lead to', 'Reg', (127, 134))	('dysregulation', 'Var', (103, 116))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
243448	32290321	Since PRDM9 variability has been suggested to influence genomic instability, the authors of this study argued that these rare allelic forms could be involved in the development of preleukemic clones in B-ALL patients and proposed that an altered PRDM9 function in the parental germline could lead to the genomic instability associated with childhood ALL.	('PRDM9', 'Gene', '56979', (6, 11))	('function', 'MPA', (252, 260))	('LL', 'Phenotype', 'HP:0005526', (351, 353))	('patients', 'Species', '9606', (208, 216))	('childhood ALL', 'Disease', (340, 353))	('LL', 'Phenotype', 'HP:0005526', (205, 207))	('genomic instability', 'MPA', (304, 323))	('B-ALL', 'Phenotype', 'HP:0004812', (202, 207))	('altered', 'Var', (238, 245))	('PRDM9', 'Gene', (246, 251))	('lead to', 'Reg', (292, 299))	('PRDM9', 'Gene', '56979', (246, 251))	('involved', 'Reg', (149, 157))	('PRDM9', 'Gene', (6, 11))	('men', 'Species', '9606', (172, 175))
243449	32290321	PRDM9 mutations have also been correlated with specific solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('PRDM9', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('correlated', 'Reg', (31, 41))	('PRDM9', 'Gene', '56979', (0, 5))
243450	32290321	Indeed, in a study defining a landscape of non-coding RNA (ncRNA) in the head and neck squamous cell carcinoma (HNSCC), 307 non-coding transcripts differentially expressed in HNSCC were significantly correlated with patient survival, and associated with known gene mutations and chromosome alterations, including PRDM9 mutations; particularly, piR-34736 was upregulated two-fold in HNSCC and correlated to patient survival and PRDM9 mutation.	('neck squamous cell carcinoma', 'Disease', (82, 110))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (82, 110))	('HNSCC', 'Disease', (382, 387))	('mutation', 'Var', (433, 441))	('PRDM9', 'Gene', (427, 432))	('patient', 'Species', '9606', (216, 223))	('mutations', 'Var', (319, 328))	('PRDM9', 'Gene', '56979', (427, 432))	('patient', 'Species', '9606', (406, 413))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('PRDM9', 'Gene', (313, 318))	('PRDM9', 'Gene', '56979', (313, 318))	('correlated', 'Reg', (200, 210))	('HNSCC', 'Phenotype', 'HP:0012288', (382, 387))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (175, 180))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (73, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('upregulated', 'PosReg', (358, 369))	('piR-34736', 'Var', (344, 353))
243451	32290321	Very recently, a mutation analysis of histone lysine methyltransferases in bladder cancer from TCGA datasets identified PRDM9 among the six genes with a potential critical role in oncogenesis and prognosis of this cancer type.	('PRDM9', 'Gene', '56979', (120, 125))	('cancer', 'Disease', (214, 220))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutation', 'Var', (17, 25))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('PRDM9', 'Gene', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
243452	32290321	Noteworthy, our pan-cancer mutation analysis recognized PRDM9 as one of the most mutated genes of the PRDM family with frequencies ranging from 0.5% to 15.4% and higher than 5% in multiple cancers, such as DLBCL, HNSCC, endometrial, esophageal, stomach, and colon carcinomas, kidney and lung tumors, and melanoma.	('colon carcinomas', 'Disease', (258, 274))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('BCL', 'Phenotype', 'HP:0012191', (208, 211))	('lung tumors', 'Phenotype', 'HP:0100526', (287, 298))	('multiple cancers', 'Disease', (180, 196))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('mutation', 'Var', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('colon carcinomas', 'Disease', 'MESH:D003110', (258, 274))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('lung tumors', 'Disease', (287, 298))	('melanoma', 'Disease', 'MESH:D008545', (304, 312))	('DLBCL', 'Disease', (206, 211))	('HNSCC', 'Disease', (213, 218))	('esophageal', 'Disease', (233, 243))	('cancer', 'Disease', (20, 26))	('multiple cancers', 'Disease', 'MESH:D009369', (180, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('HNSCC', 'Phenotype', 'HP:0012288', (213, 218))	('endometrial', 'Disease', (220, 231))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PRDM9', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('melanoma', 'Disease', (304, 312))	('PRDM9', 'Gene', '56979', (56, 61))	('lung tumors', 'Disease', 'MESH:D008175', (287, 298))	('stomach', 'Disease', (245, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('carcinomas', 'Phenotype', 'HP:0030731', (264, 274))
243453	32290321	In a newly published pan-cancer analysis of TCGA data the authors revealed that aberrant expression of PRDM9 was associated with an enrichment of somatic structural variants at sites of binding and activity in several cancer types, thus hypothesizing a novel mechanism underlying genomic instability during tumorigenesis based on the possibility that there are putative uncharacterized genomic features and binding sites leading to these variants.	('PRDM9', 'Gene', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('expression', 'MPA', (89, 99))	('variants', 'Var', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', (218, 224))	('men', 'Species', '9606', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('PRDM9', 'Gene', '56979', (103, 108))	('tumor', 'Disease', (307, 312))	('activity', 'MPA', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('binding', 'Interaction', (186, 193))	('cancer', 'Disease', (25, 31))	('aberrant', 'Var', (80, 88))	('associated', 'Reg', (113, 123))
243455	32290321	Using RNA-seq and other methodologies, analysis of 84 soft tissue sarcomas revealed that a significant subset of low-grade undifferentiated pleomorphic sarcoma (UPS) showed a gene fusion of PRDM10 either with MED12 or CITED2, suggesting that these rearrangements were specific for this less aggressive UPS subset.	('undifferentiated pleomorphic sarcoma', 'Disease', (123, 159))	('men', 'Species', '9606', (257, 260))	('aggressive UPS', 'Disease', 'MESH:D017118', (291, 305))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('CITED2', 'Gene', '10370', (218, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('gene fusion', 'Var', (175, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('MED12', 'Gene', (209, 214))	('PRDM10', 'Gene', '56980', (190, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (54, 74))	('sarcomas', 'Disease', (66, 74))	('MED12', 'Gene', '9968', (209, 214))	('PRDM10', 'Gene', (190, 196))	('aggressive UPS', 'Disease', (291, 305))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (123, 159))	('CITED2', 'Gene', (218, 224))
243459	32290321	In childhood ALL, whole-exome-sequencing and whole-genome-sequencing revealed that homozygous non-synonymous coding mutations negatively affected PRDM11 function.	('non-synonymous coding mutations', 'Var', (94, 125))	('PRDM11', 'Gene', (146, 152))	('LL', 'Phenotype', 'HP:0005526', (14, 16))	('affected', 'Reg', (137, 145))	('PRDM11', 'Chemical', '-', (146, 152))	('negatively', 'NegReg', (126, 136))	('function', 'MPA', (153, 161))
243461	32290321	Indeed, deletion of PRDM11 accelerated Myc-driven lymphomagenesis, while its overexpression induced apoptosis and delayed lymphoma onset.	('PRDM11', 'Chemical', '-', (20, 26))	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('overexpression', 'PosReg', (77, 91))	('delayed lymphoma', 'Disease', (114, 130))	('lymphoma', 'Disease', (122, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('PRDM11', 'Gene', (20, 26))	('lymphoma', 'Disease', 'MESH:D008223', (122, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('accelerated', 'PosReg', (27, 38))	('delayed lymphoma', 'Disease', 'MESH:D008223', (114, 130))	('lymphoma', 'Disease', (50, 58))	('apoptosis', 'CPA', (100, 109))	('deletion', 'Var', (8, 16))
243466	32290321	Several studies indicated that PRDM12 might act as a tumor suppressor gene in human chronic myeloid leukemia with derivative chromosome 9 deletions or rearrangements.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (92, 108))	('chronic myeloid leukemia', 'Disease', (84, 108))	('rearrangements', 'Var', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('PRDM12', 'Gene', '59335', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PRDM12', 'Gene', (31, 37))	('deletions', 'Var', (138, 147))	('tumor', 'Disease', (53, 58))	('men', 'Species', '9606', (160, 163))	('human', 'Species', '9606', (78, 83))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (84, 108))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (84, 108))
243481	32290321	The analysis of gene copy number suggested that the mechanism could be gene amplification on chromosome 8q13, a region frequently altered in a wide variety of human tumors.	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('gene amplification', 'Var', (71, 89))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
243483	32290321	In vitro experiments showed that while ectopic PRDM14 expression enhanced cancer cell growth and resistance to chemotherapeutic drugs, PRDM14 knockdown was able to induce apoptosis and increase sensitivity to chemotherapeutic drugs.	('increase', 'PosReg', (185, 193))	('PRDM14', 'Gene', (47, 53))	('sensitivity to chemotherapeutic drugs', 'MPA', (194, 231))	('ectopic', 'Var', (39, 46))	('induce', 'PosReg', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('apoptosis', 'CPA', (171, 180))	('enhanced', 'PosReg', (65, 73))	('resistance to chemotherapeutic drugs', 'MPA', (97, 133))	('cancer', 'Disease', (74, 80))	('men', 'Species', '9606', (15, 18))	('PRDM14', 'Gene', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('knockdown', 'Var', (142, 151))
243484	32290321	More recently, in vitro and in vivo experiments were set up to ascertain whether and how PRDM14 could also confer stem cell-like properties and epigenetic changes to cancer cells.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('men', 'Species', '9606', (42, 45))	('stem cell-like properties', 'CPA', (114, 139))	('epigenetic changes', 'Var', (144, 162))	('PRDM14', 'Gene', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
243488	32290321	PRDM14 silencing strongly reduced the stem cell phenotype and inhibited breast cancer cell line proliferation, tumorsphere formation, and suppressed cell growth in the presence of low concentrations of anticancer drugs.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('PRDM14', 'Gene', (0, 6))	('reduced', 'NegReg', (26, 33))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('silencing', 'Var', (7, 16))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', (79, 85))	('cell growth', 'CPA', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('inhibited', 'NegReg', (62, 71))	('stem cell phenotype', 'CPA', (38, 57))	('suppressed', 'NegReg', (138, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
243491	32290321	In particular, miR-424 knockdown induces cdc42 expression that in turn positively regulates PRDM14 through the activation of p-21-activated kinase 1 (pak1) and stat5 (Figure 1F).	('activation', 'PosReg', (111, 121))	('pak1', 'Gene', '5058', (150, 154))	('regulates', 'Reg', (82, 91))	('knockdown', 'Var', (23, 32))	('p-21-activated kinase 1', 'Gene', '5058', (125, 148))	('stat5', 'Gene', (160, 165))	('cdc42', 'Gene', '998', (41, 46))	('p-21-activated kinase 1', 'Gene', (125, 148))	('pak1', 'Gene', (150, 154))	('miR-424', 'Gene', '494336', (15, 22))	('cdc42', 'Gene', (41, 46))	('miR-424', 'Gene', (15, 22))	('induces', 'PosReg', (33, 40))	('stat5', 'Gene', '6776', (160, 165))	('expression', 'MPA', (47, 57))	('PRDM14', 'Gene', (92, 98))
243498	32290321	As in human ALL, mice with LL induced by Prdm14 aberrant expression showed widespread aneuploidy and copy number alterations, indicating significant chromosomal damage due to failure to activate genes involved in chromosomal stability and DNA repair pathways.	('human', 'Species', '9606', (6, 11))	('mice', 'Species', '10090', (17, 21))	('aneuploidy', 'Disease', (86, 96))	('LL', 'Phenotype', 'HP:0005526', (13, 15))	('aneuploidy', 'Disease', 'MESH:D000782', (86, 96))	('aberrant expression', 'Var', (48, 67))	('copy number alterations', 'CPA', (101, 124))	('activate', 'PosReg', (186, 194))	('Prdm14', 'Gene', (41, 47))	('LL', 'Phenotype', 'HP:0005526', (27, 29))
243506	32290321	Consistently, PRDM14 overexpression promoted cell migration through extracellular matrix degradation in a human lung cancer cell line.	('human', 'Species', '9606', (106, 111))	('overexpression', 'Var', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('cell migration', 'CPA', (45, 59))	('extracellular matrix degradation', 'CPA', (68, 100))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('PRDM14', 'Gene', (14, 20))	('promoted', 'PosReg', (36, 44))
243509	32290321	More recently, overexpression of PRDM14 was observed also in pancreatic cancer, where it could sustain cell pluripotency; indeed, PRDM14 knockdown suppressed cancer stem-like phenotypes, including liver metastasis, via miR-125a-3p regulating Fyn expression (Figure 1F).	('PRDM14', 'Gene', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('suppressed', 'NegReg', (147, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('cancer', 'Disease', (158, 164))	('knockdown', 'Var', (137, 146))	('Fyn', 'Gene', (242, 245))	('liver metastasis', 'Disease', 'MESH:D009362', (197, 213))	('Fyn', 'Gene', '2534', (242, 245))	('expression', 'MPA', (246, 256))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('liver metastasis', 'Disease', (197, 213))	('pancreatic cancer', 'Disease', (61, 78))	('cancer', 'Disease', (72, 78))
243511	32290321	Alterations of the 8q13.2 region with PRDM14 copy number gain were also found in intracranial germ cell tumors and in head and neck cancer.	('head and neck cancer', 'Disease', 'MESH:D006258', (118, 138))	('found', 'Reg', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('head and neck cancer', 'Phenotype', 'HP:0012288', (118, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PRDM14', 'Gene', (38, 44))	('tumors', 'Disease', (104, 110))	('copy number', 'Var', (45, 56))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('germ cell tumors', 'Phenotype', 'HP:0100728', (94, 110))	('gain', 'PosReg', (57, 61))
243517	32290321	Later, PRDM14 silencing was found through hypermethylation of its promoter in HPV-positive cancers, and ectopic expression of PRDM14 in HPV16-positive cancer cell lines induced apoptosis, possibly due to a direct upregulation of the pro-apoptotic genes NOXA and PUMA.	('hypermethylation', 'Var', (42, 58))	('PRDM14', 'Gene', (126, 132))	('PUMA', 'Gene', '27113', (262, 266))	('PRDM14', 'Gene', (7, 13))	('HPV-positive cancers', 'Disease', 'MESH:D030361', (78, 98))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', (151, 157))	('upregulation', 'PosReg', (213, 225))	('PUMA', 'Gene', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('HPV16', 'Species', '333760', (136, 141))	('HPV-positive cancers', 'Disease', (78, 98))	('NOXA', 'Gene', '5366', (253, 257))	('ectopic expression', 'Var', (104, 122))	('apoptosis', 'CPA', (177, 186))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Disease', (91, 97))	('induced', 'PosReg', (169, 176))	('NOXA', 'Gene', (253, 257))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('silencing', 'NegReg', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
243524	32290321	PRDM15 was identified as a candidate tumor suppressor gene, since localized homozygous deletions were revealed at 21q22 chromosome region in several pancreatic cancer cell lines.	('PRDM15', 'Gene', (0, 6))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('tumor', 'Disease', (37, 42))	('deletions', 'Var', (87, 96))	('pancreatic cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('PRDM15', 'Gene', '63977', (0, 6))
243533	32290321	Moreover, the aberrant expression of MEL1S/sPRDM16, associated with DNA hypomethylation, was correlated with dysregulation of TGF-beta-mediated signaling suggesting that MEL1S might be responsible for TGF-beta resistance in leukemogenesis of adult T-cell leukemia.	('TGF-beta', 'Gene', (126, 134))	('leukemogenesis of adult T-cell leukemia', 'Disease', (224, 263))	('MEL1', 'Gene', (170, 174))	('MEL1', 'Gene', '63976', (170, 174))	('leukemogenesis of adult T-cell leukemia', 'Disease', 'MESH:D015459', (224, 263))	('correlated', 'Reg', (93, 103))	('leukemia', 'Phenotype', 'HP:0001909', (255, 263))	('TGF-beta', 'Gene', '7039', (126, 134))	('MEL1', 'Gene', (37, 41))	('associated', 'Reg', (52, 62))	('TGF-beta', 'Gene', (201, 209))	('MEL1', 'Gene', '63976', (37, 41))	('aberrant', 'Var', (14, 22))	('dysregulation', 'MPA', (109, 122))	('TGF-beta', 'Gene', '7039', (201, 209))	('expression', 'MPA', (23, 33))
243537	32290321	In addition, cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion were detected in a case of progressive CML suggesting that different mechanisms of chromosomal rearrangement may occur in these malignancies.	('CML', 'Phenotype', 'HP:0005506', (154, 157))	('men', 'Species', '9606', (219, 222))	('malignancies', 'Disease', (243, 255))	('CML', 'Disease', (154, 157))	('t(1;21)(p36;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (71, 87))	('cryptic', 'Gene', '55997', (13, 20))	('RUNX1', 'Gene', (57, 62))	('PRDM16', 'Gene', (46, 52))	('cryptic', 'Gene', (13, 20))	('partial deletions', 'Var', (25, 42))	('RUNX1', 'Gene', (95, 100))	('RUNX1', 'Gene', '861', (57, 62))	('RUNX1', 'Gene', '861', (95, 100))	('detected', 'Reg', (120, 128))	('malignancies', 'Disease', 'MESH:D009369', (243, 255))
243538	32290321	Successively, additional PRDM16 translocation partners, fusion transcripts and other rearrangements have been detected in leukemia cases with a poor prognosis, most of them showing an upregulation of this gene as a common feature.	('detected', 'Reg', (110, 118))	('PRDM16', 'Gene', (25, 31))	('leukemia', 'Disease', (122, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('men', 'Species', '9606', (94, 97))	('upregulation', 'PosReg', (184, 196))	('fusion transcripts', 'Var', (56, 74))
243539	32290321	Actually, several studies have established that high PRDM16 expression is independently associated with adverse outcomes in both adult and pediatric AML patients.	('expression', 'MPA', (60, 70))	('AML', 'Disease', (149, 152))	('AML', 'Phenotype', 'HP:0004808', (149, 152))	('patients', 'Species', '9606', (153, 161))	('PRDM16', 'Gene', (53, 59))	('AML', 'Disease', 'MESH:D015470', (149, 152))	('high', 'Var', (48, 52))	('associated with', 'Reg', (88, 103))
243544	32290321	The mouse model of conditional Prdm16 deletion elucidated the role of these two isoforms in normal and leukemic hematopoiesis and identified sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia.	('leukemic hematopoiesis', 'Disease', (103, 125))	('mouse', 'Species', '10090', (4, 9))	('inflammation', 'Disease', 'MESH:D007249', (197, 209))	('leukemia', 'Disease', (213, 221))	('leukemia', 'Phenotype', 'HP:0001909', (213, 221))	('leukemia', 'Disease', 'MESH:D007938', (213, 221))	('inflammation', 'Disease', (197, 209))	('leukemic hematopoiesis', 'Disease', 'MESH:C536227', (103, 125))	('Prdm16', 'Gene', (31, 37))	('deletion', 'Var', (38, 46))
243545	32290321	To date, rearrangements of the chromosomal region encompassing PRDM16 have been observed not only in hematopoietic malignancies but also in several solid tumors though with different and/or conflicting results, which altogether indicate this gene may function as both oncogene and tumor suppressor gene.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('PRDM16', 'Gene', (63, 69))	('observed', 'Reg', (80, 88))	('men', 'Species', '9606', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('rearrangements', 'Var', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('malignancies', 'Disease', (115, 127))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', (154, 159))
243546	32290321	For instance, genome-wide array based comparative genomic hybridization (array-CGH) defined distinct amplifications in osteosarcoma, involving PRDM16.	('osteosarcoma', 'Disease', 'MESH:D012516', (119, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('amplifications', 'Var', (101, 115))	('osteosarcoma', 'Disease', (119, 131))	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))	('PRDM16', 'Gene', (143, 149))
243547	32290321	Otherwise, array-CGH integrated with gene expression analysis of leiomyosarcoma revealed a frequent loss at 1p36, which contains PRDM16, suggesting that this defect could promote muscle differentiation in this context.	('p36', 'Gene', (109, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (65, 79))	('p36', 'Gene', '51251', (109, 112))	('promote', 'PosReg', (171, 178))	('leiomyosarcoma', 'Disease', (65, 79))	('muscle differentiation', 'CPA', (179, 201))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (65, 79))	('defect', 'Var', (158, 164))	('loss', 'NegReg', (100, 104))	('PRDM16', 'Gene', (129, 135))
243548	32290321	Similarly, integrated analysis of uterine leiomyosarcoma revealed PRDM16 deletions and/or reduced expression.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('reduced', 'NegReg', (90, 97))	('PRDM16', 'Gene', (66, 72))	('leiomyosarcoma', 'Disease', (42, 56))	('deletions', 'Var', (73, 82))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (34, 56))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (42, 56))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (42, 56))	('expression', 'MPA', (98, 108))
243554	32290321	A possible role as a tumor suppressor gene has been proposed in lung cancer where PRDM16 is aberrantly methylated and its expression is low or absent.	('lung cancer', 'Disease', (64, 75))	('PRDM16', 'Gene', (82, 88))	('absent', 'NegReg', (143, 149))	('expression', 'MPA', (122, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('tumor', 'Disease', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('aberrantly methylated', 'Var', (92, 113))	('low', 'NegReg', (136, 139))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
243555	32290321	Accordingly, the median overall survival of both non-small cell lung cancer and LUAD patients with high levels of PRDM16 was significantly longer than that of cases with low levels of this gene.	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PRDM16', 'Gene', (114, 120))	('patients', 'Species', '9606', (85, 93))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('longer', 'PosReg', (139, 145))	('high levels', 'Var', (99, 110))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (49, 75))	('non-small cell lung cancer', 'Disease', (49, 75))
243560	32290321	Altogether, these findings indicate that PRDM16 methylation status, both hypermethylation and hypomethylation, is often affected in distinct cancers, where this gene can play alternatively a role as an oncogene or as a tumor suppressor gene.	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('PRDM16', 'Gene', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('hypermethylation', 'Var', (73, 89))	('tumor', 'Disease', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('affected', 'Reg', (120, 128))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('hypomethylation', 'MPA', (94, 109))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cancers', 'Disease', (141, 148))
243562	32290321	Additionally, PRDM16 is highly overexpressed also in atypical teratoid/rhabdoid tumor, a highly malignant brain tumor predominantly arising in infants; moreover, it could have a functional role in human rhabdoid tumor cells since PRDM16 knockdown resulted in reduced metabolic activity and proliferation.	('knockdown', 'Var', (237, 246))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (71, 85))	('rhabdoid tumor', 'Disease', (71, 85))	('PRDM16', 'Gene', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('infants', 'Species', '9606', (143, 150))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (203, 217))	('brain tumor', 'Phenotype', 'HP:0030692', (106, 117))	('malignant brain tumor', 'Disease', 'MESH:D001932', (96, 117))	('malignant brain tumor', 'Disease', (96, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('proliferation', 'CPA', (290, 303))	('metabolic activity', 'CPA', (267, 285))	('reduced', 'NegReg', (259, 266))	('rhabdoid tumor', 'Disease', (203, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('human', 'Species', '9606', (197, 202))
243570	32290321	Moreover, knockdown of ciRS-133 reduced cancer cachexia in tumor-implanted mice, decreasing oxygen consumption and heat production.	('oxygen consumption', 'MPA', (92, 110))	('mice', 'Species', '10090', (75, 79))	('tumor', 'Disease', (59, 64))	('ciRS-133 reduced cancer cachexia', 'Disease', (23, 55))	('decreasing', 'NegReg', (81, 91))	('heat production', 'MPA', (115, 130))	('cachexia', 'Phenotype', 'HP:0004326', (47, 55))	('ciRS-133 reduced cancer cachexia', 'Disease', 'MESH:D002100', (23, 55))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('knockdown', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
243572	32290321	Our TCGA analysis found that PRDM16 gene was mutated in about 6-7% of DLBCL and it was frequently altered in many cases of skin cutaneous melanoma (7.8%) and endometrial carcinoma (5.6%).	('endometrial carcinoma', 'Disease', 'MESH:D016889', (158, 179))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('BCL', 'Phenotype', 'HP:0012191', (72, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('skin cutaneous melanoma', 'Disease', (123, 146))	('endometrial carcinoma', 'Disease', (158, 179))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (158, 179))	('PRDM16', 'Gene', (29, 35))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (128, 146))	('DLBCL', 'Disease', (70, 75))	('altered', 'Reg', (98, 105))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (123, 146))	('mutated', 'Var', (45, 52))
243592	32290321	Moreover, high expression of ZFPM1 was related with good prognosis of LUAD through the analysis of RNA-seq, DNA methylation, and miRNA-seq data of squamous cell cancer samples downloaded from TCGA.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('related', 'Reg', (39, 46))	('LUAD', 'Disease', (70, 74))	('LUAD', 'Phenotype', 'HP:0030078', (70, 74))	('expression', 'MPA', (15, 25))	('squamous cell cancer', 'Disease', (147, 167))	('high', 'Var', (10, 14))	('ZFPM1', 'Gene', (29, 34))	('squamous cell cancer', 'Disease', 'MESH:D002294', (147, 167))	('ZFPM1', 'Gene', '161882', (29, 34))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (147, 167))
243594	32290321	Indeed, our pan-cancer analysis revealed ZFPM1/FOG1 mutation occurrence in about 50% of ACC patients.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('ZFPM1', 'Gene', (41, 46))	('patients', 'Species', '9606', (92, 100))	('ACC', 'Disease', (88, 91))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('ZFPM1', 'Gene', '161882', (41, 46))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
243595	32290321	Interestingly, these mutations were localized in a hotspot region and OncodriveCLUST results suggested it could be putatively considered a cancer driver gene in this malignancy.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutations', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('malignancy', 'Disease', 'MESH:D009369', (166, 176))	('malignancy', 'Disease', (166, 176))	('cancer', 'Disease', (139, 145))
243596	32290321	These results were confirmed by a complete analysis of the mutational data of ACC, which was performed on the same public database and validated through further algorithms (Mutsig and 20/20 rule); this study identified a new ACC-specific gene mutation signature, also comprising ZFPM1 among the six genes.	('ACC', 'Phenotype', 'HP:0006744', (225, 228))	('mutation', 'Var', (243, 251))	('ACC-specific', 'Disease', (225, 237))	('ZFPM1', 'Gene', (279, 284))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('ZFPM1', 'Gene', '161882', (279, 284))
243597	32290321	In addition, in our analysis we found that ZFPM1 is mutated also in colorectal cancers at relatively high frequencies.	('colorectal cancers', 'Disease', 'MESH:D015179', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutated', 'Var', (52, 59))	('colorectal cancers', 'Disease', (68, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('ZFPM1', 'Gene', '161882', (43, 48))	('ZFPM1', 'Gene', (43, 48))
243604	32290321	It is known that GATA3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation; FOG2 was shown to act during mammary development even though the consequences of Gata3 gene ablation in murine models were more severe than that of Fog2, whose excision induced premature mammary gland involution.	('induced', 'Reg', (283, 290))	('Fog2', 'Gene', '22762', (262, 266))	('murine', 'Species', '10090', (218, 224))	('Fog2', 'Gene', (262, 266))	('gene', 'Var', (201, 205))	('Gata3', 'Gene', (195, 200))	('Gata3', 'Gene', '14462', (195, 200))	('men', 'Species', '9606', (158, 161))
243608	32290321	Bioinformatics analysis of microarray data and genotyping of a ZFPM2 polymorphism indicated its possible role in glioma and glioblastoma.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('polymorphism', 'Var', (69, 81))	('ZFPM2', 'Gene', (63, 68))	('role', 'Reg', (105, 109))	('glioma', 'Disease', (113, 119))	('glioblastoma', 'Disease', (124, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))
243615	32290321	Indeed, we found that, after PRDM9, ZFPM2/FOG2 was the most mutated PRDM gene with pan-cancer frequencies of protein-affecting mutations higher than 1%; specifically, we detected mutation frequencies higher than 5% in patients with skin cutaneous melanoma, lung tumors, uterine carcinosarcoma, esophageal carcinoma, and stomach and rectum adenocarcinomas.	('skin cutaneous melanoma', 'Disease', (232, 255))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('PRDM9', 'Gene', (29, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (344, 354))	('mutation', 'Var', (179, 187))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('PRDM9', 'Gene', '56979', (29, 34))	('lung tumors', 'Disease', (257, 268))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (294, 314))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (270, 292))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (237, 255))	('mutations', 'Var', (127, 136))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (232, 255))	('cancer', 'Disease', (87, 93))	('rectum adenocarcinomas', 'Disease', 'MESH:D012004', (332, 354))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carcinosarcoma', 'Disease', (278, 292))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (294, 314))	('carcinosarcoma', 'Disease', 'MESH:D002296', (278, 292))	('lung tumors', 'Disease', 'MESH:D008175', (257, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('lung tumors', 'Phenotype', 'HP:0100526', (257, 268))	('esophageal carcinoma', 'Disease', (294, 314))	('rectum adenocarcinomas', 'Disease', (332, 354))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
243620	32290321	In this scenario, being involved in a multitude of pathways regulating several cancer-related processes, ranging from cell metabolism to stemness, the pharmacological control of PRDM epigenetic modulators represent a potential multi-target approach in cancer therapy (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (252, 258))	('epigenetic modulators', 'Var', (183, 204))	('PRDM', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
243621	32290321	A hallmark of cancer is the genomic instability that accounts for the increase in mutation frequency.	('cancer', 'Disease', (14, 20))	('increase', 'PosReg', (70, 78))	('mutation', 'Var', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
243625	32290321	For instance, PRDM2a/RIZ1 was shown to counteract the IGF-1 receptor and the downstream components ERK1/2 and AKT (Figure 3B).	('AKT', 'Gene', (110, 113))	('IGF-1', 'Gene', '3479', (54, 59))	('IGF-1', 'Gene', (54, 59))	('ERK1/2', 'Gene', '5595;5594', (99, 105))	('ERK1/2', 'Gene', (99, 105))	('PRDM2a/RIZ1', 'Var', (14, 25))	('AKT', 'Gene', '207', (110, 113))
243649	32290321	PRDM14 knockdown decreased cancer stem-like phenotypes through upregulation of miR-125a-3p that subsequently downregulated Fyna mechanism that is reported to regulate tumor phenotypes in pancreatic cancer (Figure 1F).	('Fyn', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (187, 204))	('PRDM14', 'Gene', (0, 6))	('upregulation', 'PosReg', (63, 75))	('decreased', 'NegReg', (17, 26))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('pancreatic cancer', 'Disease', 'MESH:D010190', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', (167, 172))	('Fyn', 'Gene', '2534', (123, 126))	('miR-125a-3p', 'Gene', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('pancreatic cancer', 'Disease', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('downregulated', 'NegReg', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Disease', (27, 33))	('knockdown', 'Var', (7, 16))
243657	32290321	Indeed, its silencing in breast cancer cells reduces cancer stem cells phenotype and tumorsphere formation (Table 1 and Figure 1).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (32, 38))	('reduces', 'NegReg', (45, 52))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('silencing', 'Var', (12, 21))	('breast cancer', 'Disease', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
243661	32290321	MAGL blockade impairs migration, invasiveness, and tumorigenicity in aggressive human cancer.	('blockade', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MAGL', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (51, 56))	('invasiveness', 'CPA', (33, 45))	('migration', 'CPA', (22, 31))	('impairs', 'NegReg', (14, 21))	('human', 'Species', '9606', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancer', 'Disease', (86, 92))
243666	32290321	Additionally, since some PRDMs (e.g., PRDM1, 9, 11, 14, 16) are able to orchestrate the differentiation of B and T lymphocytes, their involvement in the control of a more incisive immune response to neoplasia cannot be excluded.	('PRDM1', 'Var', (38, 43))	('neoplasia', 'Phenotype', 'HP:0002664', (199, 208))	('men', 'Species', '9606', (141, 144))	('neoplasia', 'Disease', 'MESH:D009369', (199, 208))	('neoplasia', 'Disease', (199, 208))	('PRDMs', 'Chemical', '-', (25, 30))
243668	32290321	Currently, as reported for other families, many studies have highlighted the consequences of aberrant isoform expression in triggering tumorigenesis and drug resistance, suggesting that dysregulation of alternative transcription may be a key mechanism leading to cancer progression and drug resistance.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', (263, 269))	('tumor', 'Disease', (135, 140))	('drug resistance', 'CPA', (286, 301))	('leading', 'Reg', (252, 259))	('aberrant', 'Var', (93, 101))	('drug resistance', 'CPA', (153, 168))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('drug resistance', 'Phenotype', 'HP:0020174', (286, 301))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('dysregulation', 'Var', (186, 199))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
243786	30449806	18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG/PET-CT) revealed the accumulation of FDG in the right shoulder, lumbar spinous processes, both ischial tuberosities, and both hips and greater trochanters, indicating polymyalgia rheumatica (PMR).	('-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (3, 22))	('polymyalgia rheumatica', 'Disease', 'MESH:D011111', (248, 270))	('greater trochanters', 'Phenotype', 'HP:0002822', (216, 235))	('ischial tuberosities', 'Disease', (176, 196))	('polymyalgia rheumatica', 'Disease', (248, 270))	('FDG', 'Var', (118, 121))	('ischial tuberosities', 'Disease', 'MESH:D014402', (176, 196))
243795	30449806	However, little is known about the pathophysiology of paraneoplastic syndrome that causes PMR-like symptoms and what types of findings present on 18F-FDG/PET-CT. We herein report a case of paraneoplastic syndrome in which 18F-FDG/PET-CT showed findings suggestive of PMR but a subsequent detailed examination indicated the presence of esophageal carcinoma.	('paraneoplastic syndrome', 'Disease', (54, 77))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (335, 355))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (335, 355))	('PMR', 'Disease', (267, 270))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (54, 77))	('18F-FDG/PET-CT', 'Var', (222, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('paraneoplastic syndrome', 'Disease', (189, 212))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (189, 212))	('esophageal carcinoma', 'Disease', (335, 355))
243820	30449806	The 18F-FDG/PET-CT findings associated with PMR include the accumulation of FDG in both shoulders, lumbar spinous processes, both ischial tuberosities, both hips, and both greater trochanters, indicating bursitis.	('ischial tuberosities', 'Disease', (130, 150))	('bursitis', 'Disease', 'MESH:D002062', (204, 212))	('bursitis', 'Disease', (204, 212))	('PMR', 'Disease', (44, 47))	('greater trochanters', 'Phenotype', 'HP:0002822', (172, 191))	('ischial tuberosities', 'Disease', 'MESH:D014402', (130, 150))	('bursitis', 'Phenotype', 'HP:0025232', (204, 212))	('FDG', 'Var', (76, 79))
243821	30449806	A previous study investigating the usefulness of 18F-FDG/PET-CT in the diagnosis of PMR revealed that when the accumulation of FDG was found in two or more locations (ischial tuberosities, greater trochanters, and lumbar spinous processes), the diagnostic probabilities (sensitivity 85.7%, specificity 88.2%) were high.	('ischial tuberosities', 'Disease', (167, 187))	('ischial tuberosities', 'Disease', 'MESH:D014402', (167, 187))	('FDG', 'Var', (127, 130))	('greater trochanters', 'Phenotype', 'HP:0002822', (189, 208))	('accumulation', 'PosReg', (111, 123))
243827	30449806	A previous study indicated that PMR does not increase the risk of malignancies, whereas another study conversely found that PMR does indeed increase the risk of malignancies, particularly in the first 6 to 12 months after the diagnosis.	('PMR', 'Var', (124, 127))	('malignancies', 'Disease', (161, 173))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('malignancies', 'Disease', (66, 78))	('increase', 'PosReg', (140, 148))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
243848	30657231	Moreover, silencing of REV7 induced increased reactive oxygen species levels postirradiation.	('reactive oxygen species levels', 'MPA', (46, 76))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (46, 69))	('REV7', 'Gene', (23, 27))	('increased reactive oxygen species levels', 'Phenotype', 'HP:0025464', (36, 76))	('increased', 'PosReg', (36, 45))	('silencing', 'Var', (10, 19))
243894	30657231	The glass slides were incubated with anti-REV7 mAb (Abcam), anti-gammaH2AX mAb (Abcam) and/or anti-PRDX2 mAb (Abnova, Taipei, Taiwan) at a dilution of 1:200 overnight in a humidified chamber.	('anti-gammaH2AX', 'Var', (60, 74))	('anti-REV7', 'Var', (37, 46))	('gammaH2AX', 'Chemical', '-', (65, 74))
243910	30657231	We first confirmed that REV7 knockdown (KD) or overexpression negatively impacted cell viability and migration ability (Figure S1).	('cell viability', 'CPA', (82, 96))	('knockdown', 'Var', (29, 38))	('negatively', 'NegReg', (62, 72))	('impacted', 'Reg', (73, 81))	('REV7', 'Gene', (24, 28))	('migration ability', 'CPA', (101, 118))	('rat', 'Species', '10116', (104, 107))
243911	30657231	Next we noted that REV7 KD cells had a significant reduction in colony forming ability (SER = 1.38 for Eca109 cells, SER = 1.15 for TE-1 cells) postirradiation (Figure 2B).	('reduction', 'NegReg', (51, 60))	('REV7 KD', 'Var', (19, 26))	('SER', 'Chemical', '-', (117, 120))	('TE-1', 'CellLine', 'CVCL:1759', (132, 136))	('colony forming ability', 'CPA', (64, 86))	('SER', 'Chemical', '-', (88, 91))
243920	30657231	As shown by Figure 3C,D, REV7 KD resulted in a significant decrease in tumor weight compared to the control group, whereas REV7 overexpression resulted in an increase in these parameters compared to the pcDNA3.1 group.	('REV7', 'Gene', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('REV7 KD', 'Var', (25, 32))	('decrease', 'NegReg', (59, 67))	('tumor', 'Disease', (71, 76))	('increase', 'PosReg', (158, 166))
243921	30657231	IHC analysis showed that REV7 KD promoted apoptosis due to increased Bax and decreased Bcl-2 expression (Figure 3E,F).	('Bcl-2', 'Gene', (87, 92))	('Bcl-2', 'Gene', '596', (87, 92))	('Bax', 'Gene', '581', (69, 72))	('apoptosis', 'CPA', (42, 51))	('REV7 KD', 'Var', (25, 32))	('Bax', 'Gene', (69, 72))	('increased', 'PosReg', (59, 68))	('decreased', 'NegReg', (77, 86))
243926	30657231	Meanwhile, REV7 KD reduced more than 30% of cellular NADPH in irradiated ESCC cells (Figure 4B).	('NADPH', 'Gene', '1666', (53, 58))	('REV7 KD', 'Var', (11, 18))	('NADPH', 'Gene', (53, 58))	('reduced', 'NegReg', (19, 26))
243931	30657231	These results support that REV7 KD-induced radiosensitization of ESCC cells is impacted by increased ROS level.	('radiosensitization', 'CPA', (43, 61))	('REV7 KD-induced', 'Var', (27, 42))	('increased ROS level', 'Phenotype', 'HP:0025464', (91, 110))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('ROS level', 'MPA', (101, 110))	('increased', 'PosReg', (91, 100))
243937	30657231	In NADPH assays, silencing PRDX2 exhausted NAPDH (more than 55% of shNC cells; Figure S5); thus, REV7 KD contributes to oxidative stress postirradiation through suppression of nuclear PRDX2.	('NADPH', 'Gene', (3, 8))	('PRDX2', 'Gene', (27, 32))	('nuclear PRDX2', 'Protein', (176, 189))	('oxidative stress', 'Phenotype', 'HP:0025464', (120, 136))	('NADPH', 'Gene', '1666', (3, 8))	('oxidative stress', 'MPA', (120, 136))	('REV7 KD', 'Var', (97, 104))	('silencing', 'Var', (17, 26))	('suppression', 'NegReg', (161, 172))
243939	30657231	As shown in Figure 6C, the majority of nuclear PRDX2 localization resembles DSB (marked by gammaH2AX) postirradiation, peaking at 2 hours then gradually returning to baseline at 24 hours following radiation, whereas REV7 KD significantly preserved more DSB (more than twice that of shNC cells), which was retained at 24 hours post-radiation (Figure 6C,D).	('REV7 KD', 'Var', (216, 223))	('DSB', 'MPA', (253, 256))	('gammaH2AX', 'Chemical', '-', (91, 100))	('PRDX2', 'Gene', (47, 52))
243940	30657231	To confirm the function of this hallmark, REV7 KD was performed and found to sensitize ESCC to radiation through activation of apoptosis in ESCC cell lines and tumor xenografts, whereas REV7 overexpression went the opposite way.	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('apoptosis', 'CPA', (127, 136))	('activation', 'PosReg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('REV7 KD', 'Var', (42, 49))	('tumor', 'Disease', (160, 165))
243945	30657231	Exposure to irradiation increases DNA lesions, dysfunction of organelles and intracellular free radicals.42 In the ROS assay, we found that REV7 KD increased ROS postirradiation while overexpression of REV7 decreased ROS (Figure 4A).	('increased', 'PosReg', (148, 157))	('ROS', 'Chemical', 'MESH:D017382', (217, 220))	('REV7 KD', 'Var', (140, 147))	('ROS', 'MPA', (158, 161))	('ROS', 'Chemical', 'MESH:D017382', (115, 118))	('ROS', 'Chemical', 'MESH:D017382', (158, 161))
243946	30657231	Physiologically, PRDX2 possesses robust reductive ability through providing reductive electrons via thiol oxidation for the NADPH-dependent thioredoxin (Trx)/Trx-reductase system.45 Consistently, upregulated PRDX2 protected cells from H2O2-induced oxidative stress,50 whereas PRDX2 knockdown was found to increase ROS and to impair cell cycle progression and proliferation.51 It has been well established that PRDX2 functions as a radio-protector as PRDX2 expression increases immediately in rat skin after UV radiation52 and is highly inducible by therapeutic radiation in cancer cells,53 correspondingly null of PRDX2 enhances oxidized DNA damage in vivo or vitro.54 In our work, knockdown of PRDX2 induced over 50% NADPH loss (Figure S5) and REV7 KD suppressed nuclear PRDX2 augmentation (Figure 5E,F), hence contributing to oxidative stress.	('cancer', 'Disease', (574, 580))	('NADPH', 'Gene', (718, 723))	('cancer', 'Phenotype', 'HP:0002664', (574, 580))	('NADPH', 'Gene', '1666', (718, 723))	('contributing', 'Reg', (812, 824))	('NADPH', 'Gene', (124, 129))	('rat', 'Species', '10116', (366, 369))	('REV7 KD', 'Var', (745, 752))	('NADPH', 'Gene', '1666', (124, 129))	('rat', 'Species', '10116', (492, 495))	('suppressed', 'NegReg', (753, 763))	('Trx', 'Gene', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (574, 580))	('oxidative stress', 'MPA', (828, 844))	('Trx', 'Gene', (158, 161))	('nuclear', 'MPA', (764, 771))	('loss', 'NegReg', (724, 728))	('augmentation', 'PosReg', (778, 790))	('knockdown', 'Var', (682, 691))	('Trx', 'Gene', '116484', (153, 156))	('oxidative stress', 'Phenotype', 'HP:0025464', (828, 844))	('PRDX2', 'Gene', (695, 700))	('oxidative stress', 'Phenotype', 'HP:0025464', (248, 264))	('ROS', 'Chemical', 'MESH:D017382', (314, 317))	('Trx', 'Gene', '116484', (158, 161))
243993	30005630	However, the dissection of RLN nodes caused a 14-30% increase in RLN injury.	('increase', 'PosReg', (53, 61))	('RLN injury', 'Disease', 'MESH:D058186', (65, 75))	('RLN injury', 'Disease', (65, 75))	('dissection', 'Var', (13, 23))
244128	28981100	In our previous studies, we have reported that STAT1 is an important tumor suppressor in esophageal squamous cell carcinoma (ESCC), where loss of STAT1 contributes to the pathogenesis of these tumors and correlates with a worse clinical outcome.	('STAT1', 'Gene', '6772', (47, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('loss', 'Var', (138, 142))	('STAT1', 'Gene', (146, 151))	('tumor', 'Disease', (69, 74))	('esophageal squamous cell carcinoma', 'Disease', (89, 123))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('STAT1', 'Gene', '6772', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('STAT1', 'Gene', (47, 52))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (89, 123))
244137	28981100	within support of this concept, loss of STAT1beta in ESCC tumors correlates with a significantly worse clinical outcome.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('STAT1', 'Gene', '6772', (40, 45))	('ESCC tumors', 'Disease', 'MESH:D004938', (53, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('loss', 'Var', (32, 36))	('ESCC tumors', 'Disease', (53, 64))	('STAT1', 'Gene', (40, 45))
244143	28981100	As shown in the middle panel of Figure 1b, following STAT1beta transfection, IFN-gamma addition resulted in a rapid and dramatic increase in STAT1alpha as well as p-STAT1Y701.	('STAT1', 'Gene', (165, 170))	('STAT1', 'Gene', '6772', (165, 170))	('STAT1', 'Gene', (141, 146))	('p-STAT1', 'Gene', '6772', (163, 170))	('transfection', 'Var', (63, 75))	('STAT1', 'Gene', '6772', (141, 146))	('STAT1', 'Gene', (53, 58))	('increase', 'PosReg', (129, 137))	('IFN-gamma', 'Gene', (77, 86))	('IFN-gamma', 'Gene', '3458', (77, 86))	('STAT1', 'Gene', '6772', (53, 58))	('p-STAT1', 'Gene', (163, 170))
244147	28981100	In contrast, in STAT1beta-transfected cells, a strong nuclear p-STAT1Y701 signal was detectable at 1 h, after IFN-gamma addition, then declined by 24 h. Similar findings were found following STAT1alpha transfection, although the p-STAT1Y701 signal was slightly more intense than that resulting from STAT1beta transfection.	('p-STAT1', 'Gene', '6772', (62, 69))	('STAT1', 'Gene', '6772', (64, 69))	('STAT1', 'Gene', (299, 304))	('p-STAT1', 'Gene', (229, 236))	('STAT1', 'Gene', '6772', (299, 304))	('IFN-gamma', 'Gene', '3458', (110, 119))	('IFN-gamma', 'Gene', (110, 119))	('transfection', 'Var', (202, 214))	('p-STAT1', 'Gene', '6772', (229, 236))	('STAT1', 'Gene', (231, 236))	('STAT1', 'Gene', '6772', (231, 236))	('p-STAT1', 'Gene', (62, 69))	('STAT1', 'Gene', (16, 21))	('STAT1', 'Gene', (191, 196))	('STAT1', 'Gene', '6772', (16, 21))	('STAT1', 'Gene', '6772', (191, 196))	('STAT1', 'Gene', (64, 69))
244152	28981100	By quantitative RT-PCR, we found a significant decrease in STAT1alpha mRNA after STAT1beta transfection in both ESCC cell lines, whereas transfection of the STAT1betaY701F mutant did not have any appreciable effect (Figure 2a).	('STAT1', 'Gene', (59, 64))	('transfection', 'Var', (91, 103))	('STAT1', 'Gene', '6772', (81, 86))	('STAT1', 'Gene', '6772', (157, 162))	('STAT1', 'Gene', '6772', (59, 64))	('decrease', 'NegReg', (47, 55))	('Y701F', 'Mutation', 'p.Y701F', (166, 171))	('STAT1', 'Gene', (81, 86))	('STAT1', 'Gene', (157, 162))
244155	28981100	As shown in Figure 2b, we found that transfection of STAT1beta almost completely abrogated STAT1alpha ubiquitination.	('STAT1', 'Gene', '6772', (91, 96))	('STAT1', 'Gene', (53, 58))	('abrogated', 'NegReg', (81, 90))	('STAT1', 'Gene', (91, 96))	('STAT1', 'Gene', '6772', (53, 58))	('transfection', 'Var', (37, 49))
244156	28981100	Consistent with our previous data, the Y701F mutation of STAT1beta lacked this effect.	('Y701F', 'Mutation', 'p.Y701F', (39, 44))	('Y701F', 'Var', (39, 44))	('STAT1', 'Gene', (57, 62))	('lacked', 'NegReg', (67, 73))	('STAT1', 'Gene', '6772', (57, 62))
244164	28981100	As shown in Figure 3a, STAT1beta transfection significantly increased the transcriptional activity of STAT1, as compared to that of empty vector (P<0.05).	('transfection', 'Var', (33, 45))	('increased', 'PosReg', (60, 69))	('STAT1', 'Gene', (23, 28))	('transcriptional activity', 'MPA', (74, 98))	('STAT1', 'Gene', '6772', (23, 28))	('STAT1', 'Gene', (102, 107))	('STAT1', 'Gene', '6772', (102, 107))
244167	28981100	To test whether the increased transcriptional activity of STAT1 mediated by STAT1beta transfection was caused by an increase in STAT1-DNA binding, we performed pull-down experiments using a biotinylated probe containing the STAT1 DNA-binding consensus sequence.	('increased', 'PosReg', (20, 29))	('STAT1', 'Gene', (58, 63))	('STAT1', 'Gene', (224, 229))	('STAT1', 'Gene', '6772', (58, 63))	('men', 'Species', '9606', (176, 179))	('STAT1', 'Gene', (76, 81))	('STAT1', 'Gene', '6772', (224, 229))	('STAT1', 'Gene', (128, 133))	('transfection', 'Var', (86, 98))	('STAT1', 'Gene', '6772', (76, 81))	('biotin', 'Chemical', 'MESH:D001710', (190, 196))	('STAT1', 'Gene', '6772', (128, 133))	('transcriptional activity', 'MPA', (30, 54))
244175	28981100	Upon STAT1 siRNA knockdown, both EC1 and KYSE150 cells showed a significant increase in the number of colonies.	('increase', 'PosReg', (76, 84))	('STAT1', 'Gene', (5, 10))	('knockdown', 'Var', (17, 26))	('STAT1', 'Gene', '6772', (5, 10))	('EC1', 'Gene', (33, 36))	('EC1', 'Gene', '4819', (33, 36))
244176	28981100	However, enforced STAT1beta expression significantly attenuated the biological effect of STAT1 siRNA knockdown (lane 3).	('STAT1', 'Gene', (89, 94))	('STAT1', 'Gene', (18, 23))	('STAT1', 'Gene', '6772', (89, 94))	('STAT1', 'Gene', '6772', (18, 23))	('biological effect', 'CPA', (68, 85))	('attenuated', 'NegReg', (53, 63))	('knockdown', 'Var', (101, 110))
244178	28981100	Western blotting revealed that transfection of STAT1beta led to the expression of cleaved poly-ADP ribose polymerase (PARP) in ESCC cells stimulated with IFN-gamma (Figure 4c).	('STAT1', 'Gene', '6772', (47, 52))	('expression', 'MPA', (68, 78))	('poly-ADP ribose polymerase', 'Gene', (90, 116))	('PARP', 'Gene', '142', (118, 122))	('transfection', 'Var', (31, 43))	('poly-ADP ribose polymerase', 'Gene', '142', (90, 116))	('IFN-gamma', 'Gene', (154, 163))	('STAT1', 'Gene', (47, 52))	('IFN-gamma', 'Gene', '3458', (154, 163))	('PARP', 'Gene', (118, 122))
244179	28981100	Also, STAT1beta transfection synergized with 5-fluorouracil (5-FU) and cisplatin in decreasing colony formation (Figure 4d), as well as the number of viable cells in an MTS assay (Figure 4e).	('STAT1', 'Gene', (6, 11))	('decreasing', 'NegReg', (84, 94))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('STAT1', 'Gene', '6772', (6, 11))	('colony formation', 'CPA', (95, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))	('transfection', 'Var', (16, 28))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (45, 59))
244202	28981100	In keeping with this concept, infection with Mycobacterium tuberculosis and Leishmania Mexicana has been found to increase the expression and phosphorylation of STAT1beta, leading to an inhibition of STAT1 signaling.	('Leishmania Mexicana', 'Species', '5665', (76, 95))	('infection', 'Disease', (30, 39))	('increase', 'PosReg', (114, 122))	('inhibition', 'NegReg', (186, 196))	('infection', 'Disease', 'MESH:D007239', (30, 39))	('expression', 'MPA', (127, 137))	('Mycobacterium tuberculosis', 'Var', (45, 71))	('STAT1', 'Gene', (200, 205))	('STAT1', 'Gene', '6772', (200, 205))	('phosphorylation', 'MPA', (142, 157))	('STAT1', 'Gene', (161, 166))	('STAT1', 'Gene', '6772', (161, 166))
244216	28981100	Researchers also demonstrated prolonged phosphorylation of STAT1 after STAT1beta transfection, and that this effect is related to a reduction of SOCS1, which is a negative regulator of the JAK-STAT1 pathway.	('STAT1', 'Gene', (59, 64))	('SOCS1', 'Gene', '8651', (145, 150))	('prolonged', 'PosReg', (30, 39))	('STAT1', 'Gene', '6772', (59, 64))	('reduction', 'NegReg', (132, 141))	('transfection', 'Var', (81, 93))	('SOCS1', 'Gene', (145, 150))	('STAT1', 'Gene', (193, 198))	('STAT1', 'Gene', (71, 76))	('STAT1', 'Gene', '6772', (193, 198))	('STAT1', 'Gene', '6772', (71, 76))	('phosphorylation', 'MPA', (40, 55))
244219	28981100	In support of the concept that STAT1beta potentiates the tumor suppressor effect of STAT1alpha, we find that loss of STAT1beta expression significantly correlates with a worse clinical outcome in a large cohort of ESCC patients.	('ESCC', 'Disease', (214, 218))	('STAT1', 'Gene', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('STAT1', 'Gene', (31, 36))	('STAT1', 'Gene', '6772', (117, 122))	('STAT1', 'Gene', '6772', (31, 36))	('loss', 'Var', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('STAT1', 'Gene', (84, 89))	('STAT1', 'Gene', '6772', (84, 89))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Disease', (57, 62))
244224	28981100	Thus, gene transfection of STAT3beta results in increasing STAT3alpha transcription activity.	('STAT3', 'Gene', (27, 32))	('STAT3', 'Gene', '6774', (59, 64))	('gene transfection', 'Var', (6, 23))	('increasing', 'PosReg', (48, 58))	('STAT3', 'Gene', (59, 64))	('STAT3', 'Gene', '6774', (27, 32))
244256	28981100	The ESCC cell lines were transfected with STAT1beta, mutant STAT1betaY701A or empty vector.	('STAT1', 'Gene', (42, 47))	('STAT1', 'Gene', '6772', (42, 47))	('mutant', 'Var', (53, 59))	('STAT1', 'Gene', (60, 65))	('STAT1', 'Gene', '6772', (60, 65))
244264	28981100	Cells were grown on cover slips coated with poly-L-lysine (Sigma Aldrich) in a six-well plate and fixed with 3% paraformaldehyde in PBS (pH 7.4).	('PBS', 'Disease', 'MESH:D011535', (132, 135))	('PBS', 'Disease', (132, 135))	('poly-L-lysine', 'Chemical', '-', (44, 57))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (112, 128))	('poly-L-lysine', 'Var', (44, 57))
244269	28981100	After STAT1beta or empty vector transfection, cells were inoculated in six-well plates, at a density of 500 cells/well and incubated for 10 days at 37  C. The cells were fixed with 4% buffered formalin for 15 min and then stained with 1% crystal violet (Sigma Aldrich) for 30 min.	('STAT1', 'Gene', (6, 11))	('crystal violet', 'Chemical', 'MESH:D005840', (238, 252))	('STAT1', 'Gene', '6772', (6, 11))	('transfection', 'Var', (32, 44))	('formalin', 'Chemical', 'MESH:D005557', (193, 201))
244311	26491354	Association between the COMT Val158Met polymorphism and risk of cancer: evidence from 99 case-control studies Catechol-O-methyltransferase (COMT) plays a central role in DNA repair and estrogen-induced carcinogenesis.	('Val158Met', 'SUBSTITUTION', 'None', (29, 38))	('Catechol-O-methyltransferase', 'Gene', (110, 138))	('Catechol-O-methyltransferase', 'Gene', '1312', (110, 138))	('cancer', 'Disease', (64, 70))	('COMT', 'Gene', (140, 144))	('COMT', 'Gene', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('carcinogenesis', 'Disease', 'MESH:D063646', (202, 216))	('Val158Met', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('carcinogenesis', 'Disease', (202, 216))	('estrogen-induced', 'CPA', (185, 201))	('COMT', 'Gene', '1312', (140, 144))	('COMT', 'Gene', '1312', (24, 28))
244312	26491354	Many recent epidemiologic studies have investigated the association between the COMT Val158Met polymorphism and cancer risk, but the results are inconclusive.	('Val158Met', 'Var', (85, 94))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('COMT', 'Gene', '1312', (80, 84))	('Val158Met', 'SUBSTITUTION', 'None', (85, 94))	('investigated', 'Reg', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('COMT', 'Gene', (80, 84))
244313	26491354	In this study, we performed a meta-analysis to investigate the association between cancer susceptibility and COMT Val158Met in different genetic models.	('Val158Met', 'SUBSTITUTION', 'None', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (83, 89))	('COMT', 'Gene', '1312', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Val158Met', 'Var', (114, 123))	('COMT', 'Gene', (109, 113))
244314	26491354	Overall, no significant associations were found between COMT Val158Met polymorphism and cancer risk (homozygote model: odds ratio [OR] =1.05, 95% confidence interval [CI] = [0.98, 1.13]; heterozygote model: OR =1.01, 95% CI = [0.98, 1.04]; dominant model: OR =1.02, 95% CI [0.97, 1.06], and recessive model: OR =1.03, 95% CI [0.97, 1.09]).	('Val158Met', 'Var', (61, 70))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('COMT', 'Gene', '1312', (56, 60))	('Val158Met', 'SUBSTITUTION', 'None', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('COMT', 'Gene', (56, 60))
244315	26491354	In the subgroup analysis of cancer type, COMT Val158Met was significantly associated with increased risks of bladder cancer in recessive model, and esophageal cancer in homozygote model, heterozygote model, and dominant model.	('cancer', 'Disease', (159, 165))	('COMT', 'Gene', '1312', (41, 45))	('Val158Met', 'SUBSTITUTION', 'None', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('COMT', 'Gene', (41, 45))	('esophageal cancer', 'Disease', (148, 165))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('bladder cancer', 'Disease', (109, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Val158Met', 'Var', (46, 55))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (28, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
244316	26491354	Subgroup analyses based on ethnicities, COMT Val158Met was significantly associated with increased risk of cancer in homozygote and recessive model among Asians.	('COMT', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Val158Met', 'Var', (45, 54))	('COMT', 'Gene', '1312', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Val158Met', 'SUBSTITUTION', 'None', (45, 54))	('cancer', 'Disease', (107, 113))
244317	26491354	In addition, homozygote, recessive, and dominant models were significantly associated with increased cancer risk in the subgroup of allele-specific polymerase chain reaction genotyping.	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('homozygote', 'Var', (13, 23))
244318	26491354	In summary, this meta-analysis suggested that COMT Val158Met polymorphism might not be a risk factor for overall cancer risk, but it might be involved in cancer development at least in some ethnic groups (Asian) or some specific cancer types (bladder and esophageal cell cancer).	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', (113, 119))	('COMT', 'Gene', '1312', (46, 50))	('bladder and esophageal cell cancer', 'Disease', 'MESH:D001749', (243, 277))	('cancer', 'Disease', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('involved', 'Reg', (142, 150))	('Val158Met', 'SUBSTITUTION', 'None', (51, 60))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('COMT', 'Gene', (46, 50))	('esophageal cell cancer', 'Phenotype', 'HP:0011459', (255, 277))	('cancer', 'Disease', (154, 160))	('Val158Met', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
244323	26491354	The most common form of genetic variation, that is, single-nucleotide polymorphisms, is known to contribute individual susceptibility to cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('contribute', 'Reg', (97, 107))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('single-nucleotide polymorphisms', 'Var', (52, 83))
244328	26491354	Therefore, the loss of or changes in COMT is supposed to contribute to genomic instability and tumor genesis.	('changes', 'Var', (26, 33))	('COMT', 'Gene', (37, 41))	('contribute', 'Reg', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('loss of', 'NegReg', (15, 22))	('genomic instability', 'CPA', (71, 90))	('COMT', 'Gene', '1312', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
244329	26491354	In line with these considerations, it has been hypothesized that COMT Val158Met might influence the development of all cancers.	('Val158Met', 'SUBSTITUTION', 'None', (70, 79))	('COMT', 'Gene', '1312', (65, 69))	('development of', 'CPA', (100, 114))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('COMT', 'Gene', (65, 69))	('Val158Met', 'Var', (70, 79))	('influence', 'Reg', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
244330	26491354	Up to now, many researches have indicated the link between COMT polymorphism and cancer susceptibility.	('link', 'Reg', (46, 50))	('COMT', 'Gene', '1312', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('COMT', 'Gene', (59, 63))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('polymorphism', 'Var', (64, 76))
244331	26491354	Several polymorphisms have been identified, including the widely studied polymorphism Val158Met(rs4680).	('rs4680', 'Var', (96, 102))	('Val158Met(rs4680', 'Var', (86, 102))	('rs4680', 'Mutation', 'rs4680', (96, 102))
244333	26491354	It is biologically reasonable to hypothesize that women who carry mutant COMT-Met allele may have higher cancer risks.	('COMT', 'Gene', '1312', (73, 77))	('mutant', 'Var', (66, 72))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('women', 'Species', '9606', (50, 55))	('COMT', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
244334	26491354	In recent years, many studies have investigated the relationship between COMT Val158Met polymorphism in different races and different types of cancer, but the results were inconclusive or controversial.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('COMT', 'Gene', '1312', (73, 77))	('investigated', 'Reg', (35, 47))	('Val158Met', 'SUBSTITUTION', 'None', (78, 87))	('COMT', 'Gene', (73, 77))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('Val158Met', 'Var', (78, 87))
244335	26491354	The inconsistent conclusions may be due to a possible minor effect of the polymorphism on cancer or the small sample size in studies with inadequate statistical power of complex traits.	('polymorphism', 'Var', (74, 86))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
244337	26491354	Although some previous meta-analyses have reported the association between COMT Val158Met polymorphism and ovarian cancer (up to eight case-control studies included), breast cancer (up to 56 case-control studies included), endometrial cancer (up to seven case-control studies included), prostate cancer (up to six case-control studies included), and lung cancer (evidence from six case-control studies), only specific cancer types or race populations were included, which led to their limitations.	('breast cancer', 'Disease', (167, 180))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('lung cancer', 'Disease', (350, 361))	('endometrial cancer', 'Disease', 'MESH:D016889', (223, 241))	('cancer', 'Disease', 'MESH:D009369', (418, 424))	('prostate cancer', 'Disease', 'MESH:D011471', (287, 302))	('Val158Met', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('prostate cancer', 'Phenotype', 'HP:0012125', (287, 302))	('ovarian cancer', 'Disease', (107, 121))	('prostate cancer', 'Disease', (287, 302))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('COMT', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (355, 361))	('lung cancer', 'Disease', 'MESH:D008175', (350, 361))	('lung cancer', 'Phenotype', 'HP:0100526', (350, 361))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('polymorphism', 'Var', (90, 102))	('cancer', 'Disease', (418, 424))	('COMT', 'Gene', '1312', (75, 79))	('Val158Met', 'SUBSTITUTION', 'None', (80, 89))	('cancer', 'Disease', (115, 121))	('endometrial cancer', 'Phenotype', 'HP:0012114', (223, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('cancer', 'Disease', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('ovarian cancer', 'Disease', 'MESH:D010051', (107, 121))	('endometrial cancer', 'Disease', (223, 241))	('cancer', 'Disease', (296, 302))	('cancer', 'Disease', 'MESH:D009369', (355, 361))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
244338	26491354	To update the results of previous meta-analyses and to provide a more precise assessment of the association between COMT Val158Met and cancer risk, we performed a comprehensive meta-analysis by including the most recent and relevant articles.	('cancer', 'Disease', (135, 141))	('COMT', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Val158Met', 'Var', (121, 130))	('COMT', 'Gene', '1312', (116, 120))	('Val158Met', 'SUBSTITUTION', 'None', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
244339	26491354	A comprehensive literature search was performed using the PubMed, Cochrane Library, Chinese National Knowledge Infrastructure, and EMBASE database for relevant articles published (the last search update was February 15, 2015) with keywords "COMT", "Catechol-O-methyltransferase", "Val158Met", "rs4680", "single nucleotide polymorphism", "polymorphism", "Variant", "Mutation", "Cancer", "tumor", "neoplasm", "malignancy", or "Carcinoma".	('Cancer', 'Phenotype', 'HP:0002664', (377, 383))	('tumor', 'Phenotype', 'HP:0002664', (387, 392))	('Carcinoma', 'Phenotype', 'HP:0030731', (425, 434))	('Cancer', 'Disease', (377, 383))	('neoplasm', 'Disease', 'MESH:D009369', (396, 404))	('Val158Met', 'SUBSTITUTION', 'None', (281, 290))	('COMT', 'Gene', (241, 245))	('Catechol-O-methyltransferase', 'Gene', '1312', (249, 277))	('malignancy', 'Disease', 'MESH:D009369', (408, 418))	('neoplasm', 'Disease', (396, 404))	('Cancer', 'Disease', 'MESH:D009369', (377, 383))	('tumor', 'Disease', (387, 392))	('"Carcinoma', 'Disease', (424, 434))	('Val158Met', 'Var', (281, 290))	('rs4680', 'Mutation', 'rs4680', (294, 300))	('COMT', 'Gene', '1312', (241, 245))	('malignancy', 'Disease', (408, 418))	('Catechol-O-methyltransferase', 'Gene', (249, 277))	('"Carcinoma', 'Disease', 'MESH:D002277', (424, 434))	('tumor', 'Disease', 'MESH:D009369', (387, 392))	('neoplasm', 'Phenotype', 'HP:0002664', (396, 404))
244341	26491354	We included all the case-control studies and cohort studies that have investigated the association between COMT Val158Met polymorphisms and cancer risk with genotyping data.	('polymorphisms', 'Var', (122, 135))	('Val158Met', 'Var', (112, 121))	('COMT', 'Gene', '1312', (107, 111))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('Val158Met', 'SUBSTITUTION', 'None', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('COMT', 'Gene', (107, 111))
244343	26491354	All studies were included if they met the following criteria: 1) only the case-control studies or cohort studies were considered, 2) studies that investigated the COMT Val158Met polymorphism and the risk of cancer susceptibility were included, and 3) the genotype distribution of the polymorphism in cases and controls was described in details, and the results were expressed as odds ratio (OR) and corresponding 95% confidence interval (95% CI).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('Val158Met', 'Var', (168, 177))	('COMT', 'Gene', '1312', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('COMT', 'Gene', (163, 167))	('Val158Met', 'SUBSTITUTION', 'None', (168, 177))
244344	26491354	Major reasons for exclusion of studies were as follows: 1) not for cancer research, 2) only case population, 3) duplicate of previous publication, and 4) review articles, editorials, case reports, studies with preliminary results not on COMT Val158Met polymorphism or outcome, and investigations of the role of COMT expression related to disease.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Val158Met', 'SUBSTITUTION', 'None', (242, 251))	('cancer', 'Disease', (67, 73))	('COMT', 'Gene', (311, 315))	('COMT', 'Gene', '1312', (237, 241))	('COMT', 'Gene', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('COMT', 'Gene', '1312', (311, 315))	('Val158Met', 'Var', (242, 251))
244346	26491354	ORs and their 95% CIs were used to determine the strength of association between the COMT Val158Met polymorphism and cancer risk.	('Val158Met', 'SUBSTITUTION', 'None', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('COMT', 'Gene', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Val158Met', 'Var', (90, 99))	('cancer', 'Disease', (117, 123))	('COMT', 'Gene', '1312', (85, 89))
244353	26491354	Overall, no significant associations between COMT Val158Met and cancer risk were found using homozygote model (OR =1.05, 95% CI [0.98, 1.13]), heterozygote model (OR =1.01, 95% CI [0.98, 1.04]), dominant model (OR =1.02, 95% CI [0.97, 1.06]), or recessive model (OR =1.03, 95% CI [0.97, 1.09]).	('COMT', 'Gene', '1312', (45, 49))	('Val158Met', 'SUBSTITUTION', 'None', (50, 59))	('COMT', 'Gene', (45, 49))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Val158Met', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
244354	26491354	Significant heterogeneity was observed among the 99 studies on COMT Val158Met polymorphism.	('Val158Met', 'SUBSTITUTION', 'None', (68, 77))	('COMT', 'Gene', '1312', (63, 67))	('Val158Met', 'Var', (68, 77))	('COMT', 'Gene', (63, 67))
244356	26491354	In the subgroup analysis on cancer type, COMT Val158Met was significantly associated with an increased risk of bladder cancer in recessive model (OR =1.30, 95% CI [1.02, 1.66]), esophageal cell cancer in homozygote model (OR =1.77, 95% CI [1.07, 2.93]), heterozygote model (OR =1.40, 95% CI [1.01, 1.92]), and dominant model (OR =1.46, 95% CI [1.08, 1.98]).	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('Val158Met', 'Var', (46, 55))	('bladder cancer', 'Disease', 'MESH:D001749', (111, 125))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('bladder cancer', 'Disease', (111, 125))	('COMT', 'Gene', (41, 45))	('cancer', 'Disease', (119, 125))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('esophageal cell cancer', 'Disease', (178, 200))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('esophageal cell cancer', 'Phenotype', 'HP:0011459', (178, 200))	('cancer', 'Disease', (28, 34))	('COMT', 'Gene', '1312', (41, 45))	('Val158Met', 'SUBSTITUTION', 'None', (46, 55))	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('esophageal cell cancer', 'Disease', 'MESH:D004938', (178, 200))
244358	26491354	These studies were further stratified on the basis of ethnicities, and the results showed that COMT Val158-Met polymorphism may be a risk factor for cancer in Asian populations in the homozygote model (OR =1.25, 95% CI [1.03, 1.51]) and recessive model (OR =1.20, 95% CI [1.01, 1.43]).	('Val158-Met polymorphism', 'Var', (100, 123))	('cancer', 'Disease', (149, 155))	('COMT', 'Gene', (95, 99))	('polymorphism', 'Var', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Val158-Met', 'Mutation', 'rs4680', (100, 110))	('risk factor', 'Reg', (133, 144))	('COMT', 'Gene', '1312', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
244359	26491354	We failed to detect any association between the COMT Val158Met polymorphism and African, Caucasian, and mixed populations.	('COMT', 'Gene', (48, 52))	('Val158Met', 'Var', (53, 62))	('Val158Met', 'SUBSTITUTION', 'None', (53, 62))	('COMT', 'Gene', '1312', (48, 52))
244363	26491354	At present, >1,369 susceptibility loci associated with cancer risk have been identified by genome-wide association study, but none of these studies had reported significant associations between cancer susceptibility and COMT Val158Met polymorphisms.	('COMT', 'Gene', '1312', (220, 224))	('cancer', 'Disease', (194, 200))	('Val158Met', 'SUBSTITUTION', 'None', (225, 234))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('COMT', 'Gene', (220, 224))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Val158Met', 'Var', (225, 234))	('cancer', 'Disease', (55, 61))
244364	26491354	We searched the manufacturers' websites (http://www.affymetrix.com/index.affx and http://www.illumina.com) and the relevant PubMed databases (Probe, Database of Genotypes and Phenotypes, and Gene Expression Omnibus DataSets) and found that the COMT Val158Met polymorphism was not included in the platforms commonly used in genome-wide association studies.	('COMT', 'Gene', '1312', (244, 248))	('Val158Met', 'SUBSTITUTION', 'None', (249, 258))	('COMT', 'Gene', (244, 248))	('Val158Met', 'Var', (249, 258))
244365	26491354	But since the identification of COMT Val158Met polymorphism, the role of COMT Val158Met in cancers risk has been reported in an increasing number of studies, but the results remained controversial.	('COMT', 'Gene', '1312', (73, 77))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('polymorphism', 'Var', (47, 59))	('Val158Met', 'SUBSTITUTION', 'None', (37, 46))	('cancers', 'Disease', (91, 98))	('Val158Met', 'SUBSTITUTION', 'None', (78, 87))	('COMT', 'Gene', (73, 77))	('COMT', 'Gene', '1312', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('COMT', 'Gene', (32, 36))	('Val158Met', 'Var', (78, 87))	('Val158Met', 'Var', (37, 46))
244367	26491354	Hence, the association between the COMT Val158Met polymorphism and the risk of cancer remains unknown.	('Val158Met', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('COMT', 'Gene', '1312', (35, 39))	('COMT', 'Gene', (35, 39))	('Val158Met', 'SUBSTITUTION', 'None', (40, 49))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
244368	26491354	Therefore, meta-analysis can provide a quantitative summary of the available data supporting the association between COMT Val158Met and cancer risk.	('Val158Met', 'Var', (122, 131))	('COMT', 'Gene', '1312', (117, 121))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('Val158Met', 'SUBSTITUTION', 'None', (122, 131))	('COMT', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
244370	26491354	The results indicated no significant association between COMT Val158Met polymorphism and overall cancer risk in any genetic comparison model tested.	('cancer', 'Disease', (97, 103))	('COMT', 'Gene', (57, 61))	('polymorphism', 'Var', (72, 84))	('Val158Met', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('COMT', 'Gene', '1312', (57, 61))	('Val158Met', 'SUBSTITUTION', 'None', (62, 71))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
244371	26491354	In further subgroup analysis by cancer type, COMT Val158Met was significantly associated with an increased risk of bladder cancer and esophageal cancer in some specific genetic models.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('COMT', 'Gene', '1312', (45, 49))	('Val158Met', 'SUBSTITUTION', 'None', (50, 59))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('associated', 'Reg', (78, 88))	('Val158Met', 'Var', (50, 59))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('COMT', 'Gene', (45, 49))	('cancer', 'Disease', (123, 129))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('esophageal cancer', 'Disease', (134, 151))
244373	26491354	In line with most previous meta-analyses for single cancer, Zhang et al, Du et al and Mao et al have reported that the COMT Val158Met polymorphism may not contribute to the risk of prostate cancer, ovarian cancer, or breast cancer in any of the assessed genetic model.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', (190, 196))	('Val158Met', 'SUBSTITUTION', 'None', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (206, 212))	('ovarian cancer', 'Disease', 'MESH:D010051', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('COMT', 'Gene', (119, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('Val158Met', 'Var', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('prostate cancer', 'Disease', 'MESH:D011471', (181, 196))	('prostate cancer', 'Phenotype', 'HP:0012125', (181, 196))	('ovarian cancer', 'Disease', (198, 212))	('breast cancer', 'Disease', (217, 230))	('prostate cancer', 'Disease', (181, 196))	('ovarian cancer', 'Phenotype', 'HP:0100615', (198, 212))	('COMT', 'Gene', '1312', (119, 123))
244374	26491354	However, the significant association between the COMT Val158Met polymorphism and cancer risk remains to be determined in Asians.	('Val158Met', 'SUBSTITUTION', 'None', (54, 63))	('COMT', 'Gene', '1312', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('COMT', 'Gene', (49, 53))	('Val158Met', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
244378	26491354	In conclusion, the present meta-analysis suggested that COMT Val158Met polymorphism might not be a risk factor for overall cancer risk, but it might be involved in cancer development at least in some ethnic groups (Asian) or some specific cancer types (bladder and esophageal cancer).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Val158Met', 'Var', (61, 70))	('bladder and esophageal cancer', 'Disease', 'MESH:D001749', (253, 282))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('COMT', 'Gene', '1312', (56, 60))	('Val158Met', 'SUBSTITUTION', 'None', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('COMT', 'Gene', (56, 60))	('involved', 'Reg', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
244381	23880852	Moreover, preclinical data have shown that inhibition of Hh signaling has the potential to reduce prostate cancer invasiveness and metastatic potential.	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('inhibition', 'Var', (43, 53))	('Hh signaling', 'Protein', (57, 69))	('prostate cancer invasiveness', 'Disease', (98, 126))	('reduce', 'NegReg', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('metastatic potential', 'CPA', (131, 151))	('prostate cancer invasiveness', 'Disease', 'MESH:D011471', (98, 126))	('reduce prostate', 'Phenotype', 'HP:0008687', (91, 106))
244397	23880852	The presence of active Smo in the tip of the cilium induces a functional change in the organelle that fundamentally alters the manner in which the members of the Gli family of transcription factors (Gli1, Gli2, Gli3) are post-translationally processed, involving protein phosphorylation, proteasome-mediated proteolysis and cytoplasmic-nuclear shuttling.	('alters', 'Reg', (116, 122))	('men', 'Species', '9606', (107, 110))	('Gli', 'Gene', (162, 165))	('Gli3', 'Gene', (211, 215))	('Gli2', 'Gene', (205, 209))	('Gli', 'Gene', '2735', (199, 202))	('Smo', 'Gene', (23, 26))	('protein phosphorylation', 'MPA', (263, 286))	('cytoplasmic-nuclear shuttling', 'CPA', (324, 353))	('Gli', 'Gene', '2735', (205, 208))	('Gli', 'Gene', (199, 202))	('Gli', 'Gene', (205, 208))	('Gli2', 'Gene', '2736', (205, 209))	('induces', 'Reg', (52, 59))	('Gli', 'Gene', '2735', (211, 214))	('presence', 'Var', (4, 12))	('Gli3', 'Gene', '2737', (211, 215))	('Gli', 'Gene', (211, 214))	('Gli', 'Gene', '2735', (162, 165))
244399	23880852	The presence of activated Smo within the primary cilium suppresses the generation of Gli-R forms.	('suppresses', 'NegReg', (56, 66))	('presence', 'Var', (4, 12))	('Gli', 'Gene', '2735', (85, 88))	('Gli', 'Gene', (85, 88))
244407	23880852	In recent years, it has become increasingly clear that aberrant Hh signaling plays a major role in cancer initiation and progression to more advanced stages.	('Hh signaling', 'Protein', (64, 76))	('aberrant', 'Var', (55, 63))	('cancer initiation', 'Disease', 'MESH:D009369', (99, 116))	('cancer initiation', 'Disease', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
244409	23880852	This disease is mainly caused by mutations in the PTCH1 gene, but also mutations in SMO and SUFU have been described.	('PTCH1', 'Gene', (50, 55))	('SUFU', 'Gene', '51684', (92, 96))	('caused by', 'Reg', (23, 32))	('mutations', 'Var', (33, 42))	('PTCH1', 'Gene', '5727', (50, 55))	('SMO', 'Gene', '6608', (84, 87))	('SMO', 'Gene', (84, 87))	('SUFU', 'Gene', (92, 96))
244412	23880852	Ligand-independent Hh signaling has mainly been described in BCC and MB and can either be due to loss-of-function mutations (PTCH1, SUFU) or otherwise caused by gain-of-function mutations (SHH, SMO or GLI1/2).	('PTCH1', 'Gene', '5727', (125, 130))	('SHH', 'Gene', (189, 192))	('GLI1/2', 'Gene', '2735;2736', (201, 207))	('mutations', 'Var', (114, 123))	('GLI1/2', 'Gene', (201, 207))	('SUFU', 'Gene', (132, 136))	('gain-of-function', 'PosReg', (161, 177))	('SMO', 'Gene', '6608', (194, 197))	('SUFU', 'Gene', '51684', (132, 136))	('PTCH1', 'Gene', (125, 130))	('SHH', 'Gene', '6469', (189, 192))	('SMO', 'Gene', (194, 197))	('loss-of-function', 'NegReg', (97, 113))	('Ligand-independent Hh signaling', 'MPA', (0, 31))
244421	23880852	Disruption of the primary cilia in Smo-activated tumors inhibits tumor growth, whereas tumor growth is accelerated in Gli2-dependent tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', (49, 55))	('accelerated', 'PosReg', (103, 114))	('Disruption', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Disease', (65, 70))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Gli2', 'Gene', (118, 122))	('tumors', 'Disease', (133, 139))	('tumor', 'Disease', (87, 92))	('tumors inhibits tumor', 'Disease', (49, 70))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (133, 138))	('tumors inhibits tumor', 'Disease', 'MESH:D009369', (49, 70))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('Gli2', 'Gene', '2736', (118, 122))
244427	23880852	Nevertheless, loss-of function mutations in SUFU are the only known mutations in the Hh pathway in prostatic tumor tissues thus far (Figure 1A).	('Hh pathway', 'Pathway', (85, 95))	('SUFU', 'Gene', '51684', (44, 48))	('mutations', 'Var', (31, 40))	('prostatic tumor', 'Disease', (99, 114))	('SUFU', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('prostatic tumor', 'Disease', 'MESH:D011471', (99, 114))	('loss-of function', 'NegReg', (14, 30))
244428	23880852	In general, however, aberrant Hh signaling in prostate tumors is believed to be ligand-dependent.	('aberrant', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('prostate tumor', 'Phenotype', 'HP:0100787', (46, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('prostate tumors', 'Disease', 'MESH:D011471', (46, 61))	('Hh signaling', 'MPA', (30, 42))	('prostate tumors', 'Disease', (46, 61))
244443	23880852	Moreover, Hh signaling also correlated with Ki67 and vascular epithelial growth factor (VEGF), but not with CD31.	('Ki67', 'Var', (44, 48))	('CD31', 'Gene', '5175', (108, 112))	('vascular epithelial growth factor', 'Gene', '7422', (53, 86))	('VEGF', 'Gene', (88, 92))	('vascular epithelial growth factor', 'Gene', (53, 86))	('VEGF', 'Gene', '7422', (88, 92))	('Hh signaling', 'MPA', (10, 22))	('CD31', 'Gene', (108, 112))	('correlated', 'Reg', (28, 38))
244462	23880852	Moreover, combination of ADT and chemotherapy also resulted in an increased epithelial Bcl2 and nuclear pAKT expression, emphasizing the role of Hh signaling activation in tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('ADT', 'Chemical', '-', (25, 28))	('increased', 'PosReg', (66, 75))	('AKT', 'Gene', '207', (105, 108))	('Bcl2', 'Gene', (87, 91))	('tumor', 'Disease', (172, 177))	('AKT', 'Gene', (105, 108))	('ADT', 'Var', (25, 28))	('Bcl2', 'Gene', '596', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
244472	23880852	Knockout of GLI2 in PCa cells suppressed tumor growth both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('suppressed', 'NegReg', (30, 40))	('tumor', 'Disease', (41, 46))	('GLI2', 'Gene', (12, 16))	('GLI2', 'Gene', '2736', (12, 16))	('Knockout', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
244474	23880852	Ectopic expression of GLI2 led to an accelerated cell cycle progression, especially through the G2-M phase, consequently resulting in an increased cell growth.	('cell cycle progression', 'CPA', (49, 71))	('accelerated', 'PosReg', (37, 48))	('Ectopic expression', 'Var', (0, 18))	('increased', 'PosReg', (137, 146))	('GLI2', 'Gene', (22, 26))	('GLI2', 'Gene', '2736', (22, 26))	('cell growth', 'CPA', (147, 158))
244478	23880852	Inhibition of Hh signaling and stathmin1 both decreased PCa cell proliferation, but no additive effect was observed, indicating that Hh signaling presumably functions through regulation of stathmin1.	('stathmin1', 'Gene', '3925', (189, 198))	('stathmin1', 'Gene', '3925', (31, 40))	('stathmin1', 'Gene', (31, 40))	('Inhibition', 'Var', (0, 10))	('decreased', 'NegReg', (46, 55))	('PCa cell proliferation', 'CPA', (56, 78))	('stathmin1', 'Gene', (189, 198))
244493	23880852	This prompted the development of small-molecule Hh pathway modulators with improved potency and druggability.	('modulators', 'Var', (59, 69))	('Hh pathway', 'Pathway', (48, 58))	('men', 'Species', '9606', (25, 28))
244497	23880852	When the cilia are lost, high Hh ligand levels are no longer relevant and a secondary mutation downstream of the cilia (e.g., inactivating mutation of SUFU) would be required to sustain pathway activation.	('inactivating mutation', 'Var', (126, 147))	('SUFU', 'Gene', '51684', (151, 155))	('SUFU', 'Gene', (151, 155))
244501	23880852	As for the treatment of PCa, several preclinical studies have shown that inhibition of Hh signaling reduces tumor growth as well as PCa invasiveness and metastatic potential.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('PCa invasiveness', 'Disease', 'MESH:D009362', (132, 148))	('PCa invasiveness', 'Disease', (132, 148))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('reduces', 'NegReg', (100, 107))	('metastatic potential', 'CPA', (153, 173))	('tumor', 'Disease', (108, 113))	('men', 'Species', '9606', (16, 19))	('inhibition', 'Var', (73, 83))
244505	23880852	indicated that GDC-0449 also inhibits tumor proliferation of PCa xenograft mice.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mice', 'Species', '10090', (75, 79))	('GDC-0449', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('inhibits', 'NegReg', (29, 37))	('GDC-0449', 'Chemical', 'MESH:C538724', (15, 23))
244507	23880852	Moreover, a reduction in proliferation was seen after GDC-0449 treatment by means of decreased Ki67 expression level; however, no change in tumor volume was observed.	('decreased', 'NegReg', (85, 94))	('GDC-0449', 'Chemical', 'MESH:C538724', (54, 62))	('tumor', 'Disease', (140, 145))	('GDC-0449', 'Var', (54, 62))	('proliferation', 'MPA', (25, 38))	('reduction', 'NegReg', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('men', 'Species', '9606', (68, 71))	('Ki67 expression level', 'MPA', (95, 116))
244508	23880852	A phase I clinical trial testing the use of the GDC-0449 as a single agent in patients with BCC, MB and other advanced solid tumor types, including PCa, reported a complete or partial tumor response in patients with BCC (19/33) and MB (1/1).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('BCC', 'Disease', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('partial', 'NegReg', (176, 183))	('patients', 'Species', '9606', (78, 86))	('BCC', 'Disease', (216, 219))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (184, 189))	('patients', 'Species', '9606', (202, 210))	('GDC-0449', 'Chemical', 'MESH:C538724', (48, 56))	('PCa', 'Disease', (148, 151))	('GDC-0449', 'Var', (48, 56))
244513	23880852	Other Smo inhibitors (LDE-225, TAK-441, PF-04449913, IPI-926, BMS-833923, LY2940680, LEQ506 itraconazole and vitamin D3) are currently being evaluated in clinical trials for the treatment of MB, BCC and other advanced tumor types, including PCa.	('LDE-225', 'Var', (22, 29))	('vitamin D3', 'Chemical', 'MESH:D002762', (109, 119))	('PCa', 'Disease', (241, 244))	('men', 'Species', '9606', (183, 186))	('IPI-926', 'Var', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('LEQ506 itraconazole', 'Var', (85, 104))	('BMS-833923', 'Var', (62, 72))	('LY2940680', 'Var', (74, 83))	('LY2940680', 'Chemical', 'MESH:C581399', (74, 83))	('BCC', 'Disease', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('IPI-926', 'Chemical', 'MESH:C541444', (53, 60))	('tumor', 'Disease', (218, 223))	('itraconazole', 'Chemical', 'MESH:D017964', (92, 104))	('PF-04449913', 'Var', (40, 51))
244521	23880852	Acquired resistance to Smo inhibition has been linked to distinct mechanisms, such as mutations in SMO (e.g., D473H), amplifications of downstream target genes (e.g., GLI1/2) or up-regulation of synergistic signals such as PI3K signaling.	('mutations', 'Var', (86, 95))	('D473H', 'Var', (110, 115))	('GLI1/2', 'Gene', '2735;2736', (167, 173))	('GLI1/2', 'Gene', (167, 173))	('SMO', 'Gene', (99, 102))	('SMO', 'Gene', '6608', (99, 102))	('D473H', 'Mutation', 'rs17710891', (110, 115))	('amplifications', 'Var', (118, 132))	('up-regulation', 'PosReg', (178, 191))	('inhibition', 'NegReg', (27, 37))
244526	23880852	Inhibition of Hh signaling in esophageal, pancreatic and non-small cell lung cancer cell lines, either chemically or through siRNA-mediated silencing also resulted in radiosensitization.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (57, 83))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))	('Inhibition', 'NegReg', (0, 10))	('radiosensitization', 'CPA', (167, 185))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('non-small cell lung cancer', 'Disease', (57, 83))	('pancreatic', 'Disease', 'MESH:D010195', (42, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('silencing', 'Var', (140, 149))	('pancreatic', 'Disease', (42, 52))
244534	23880852	Hh signaling components (e.g., Ptch1, Gli1/2) have been linked to genomic instability, inactivation of homologous recombination (HR), non-homologous end joining (NHEJ) and defects in checkpoint activation.	('genomic instability', 'CPA', (66, 85))	('linked', 'Reg', (56, 62))	('checkpoint activation', 'CPA', (183, 204))	('inactivation', 'Var', (87, 99))	('Gli1/2', 'Gene', (38, 44))	('defects', 'NegReg', (172, 179))	('Gli1/2', 'Gene', '2735;2736', (38, 44))	('Ptch1', 'Gene', (31, 36))
244539	23880852	Furthermore, activation of Shh may impair the early DNA damage repair and thereby protect human cancer cells against IR in an autocrine manner.	('activation', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('impair', 'NegReg', (35, 41))	('human', 'Species', '9606', (90, 95))	('Shh', 'Gene', (27, 30))	('protect', 'Reg', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('early DNA damage', 'MPA', (46, 62))	('cancer', 'Disease', (96, 102))
244545	23880852	that inhibition of Hh signaling in combination with IR results in G1 arrest, thereby decreasing the number of cells in the radioresistant S phase of the cell cycle.	('results in', 'Reg', (55, 65))	('arrest', 'Disease', 'MESH:D006323', (69, 75))	('inhibition', 'Var', (5, 15))	('decreasing', 'NegReg', (85, 95))	('arrest', 'Disease', (69, 75))
244555	23880852	Moreover, Hh inhibition with cyclopamine or IPI-926) increased tumor perfusion through depletion of the tumor-associated stromal tissue, which resulted in more effective delivery of chemotherapeutic agents.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('depletion of', 'MPA', (87, 99))	('delivery of', 'MPA', (170, 181))	('tumor', 'Disease', (104, 109))	('IPI-926', 'Var', (44, 51))	('increased', 'PosReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('more', 'PosReg', (155, 159))	('inhibition', 'NegReg', (13, 23))	('IPI-926', 'Chemical', 'MESH:C541444', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('cyclopamine', 'Chemical', 'MESH:C000541', (29, 40))
244567	23880852	Alterations in P53 are detected in more than 50% of human cancers, including PCa.	('P53', 'Gene', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('P53', 'Gene', '7157', (15, 18))	('Alterations', 'Var', (0, 11))	('human', 'Species', '9606', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('detected', 'Reg', (23, 31))	('cancers', 'Disease', (58, 65))	('PCa', 'Disease', (77, 80))
244568	23880852	The role of p53 inactivation in evasion of apoptosis and DNA repair is well established, but p53 also seems to be involved in chemo- and radioresistance.	('DNA repair', 'MPA', (57, 67))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('inactivation', 'Var', (16, 28))	('involved', 'Reg', (114, 122))	('evasion of apoptosis', 'MPA', (32, 52))
244570	23880852	Inhibition of Hh signaling recovered p53 activity in breast cancer cells lines, leading to DNA damage-induced apoptosis.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('DNA', 'Disease', (91, 94))	('p53', 'Gene', (37, 40))	('Inhibition', 'Var', (0, 10))	('p53', 'Gene', '7157', (37, 40))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('activity', 'MPA', (41, 49))	('breast cancer', 'Disease', (53, 66))	('leading to', 'Reg', (80, 90))
244577	23880852	The effectiveness of chemotherapy is challenged by distinct mechanisms that mediate drug resistance at cellular level, i.e., genetic changes (mutations, amplifications, epigenetics) that influence drug uptake, metabolism or export, but also limited drug delivery due to the microenvironment plays an essential role.	('mutations', 'Var', (142, 151))	('metabolism', 'MPA', (210, 220))	('influence', 'Reg', (187, 196))	('men', 'Species', '9606', (286, 289))	('drug uptake', 'MPA', (197, 208))	('export', 'MPA', (224, 230))	('drug resistance', 'Phenotype', 'HP:0020174', (84, 99))	('limited drug delivery', 'Phenotype', 'HP:0020173', (241, 262))
244588	23880852	has demonstrated that inhibition of Hh signaling with the Smo inhibitor NVP-LDE-225 (Erismodegib) down-regulates pluripotency-maintaining factors Nanog, Oct4, Sox2, c-Myc and thereby inhibits CSC tumor growth.	('inhibition', 'Var', (22, 32))	('c-Myc', 'Gene', (165, 170))	('Oct4', 'Gene', '5460', (153, 157))	('Sox2', 'Gene', '6657', (159, 163))	('tumor', 'Disease', (196, 201))	('Nanog', 'Gene', (146, 151))	('Sox2', 'Gene', (159, 163))	('Erismodegib', 'Chemical', 'MESH:C561435', (85, 96))	('NVP-LDE-225', 'Gene', (72, 83))	('inhibits', 'NegReg', (183, 191))	('pluripotency', 'Disease', (113, 125))	('pluripotency', 'Disease', 'None', (113, 125))	('Oct4', 'Gene', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('c-Myc', 'Gene', '4609', (165, 170))	('Nanog', 'Gene', '79923', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('down-regulates', 'NegReg', (98, 112))
244591	23880852	They have shown that inhibition of GLI2 significantly enhanced the effect of paclitaxel on PCa cells both in vitro as in vivo presumably through synergistic effects on apoptosis.	('effect', 'MPA', (67, 73))	('GLI2', 'Gene', (35, 39))	('GLI2', 'Gene', '2736', (35, 39))	('inhibition', 'Var', (21, 31))	('paclitaxel', 'Chemical', 'MESH:D017239', (77, 87))	('enhanced', 'PosReg', (54, 62))
244592	23880852	demonstrated that co-targeting of the Hh and EGFR pathway in combination with chemotherapeutic agents results in increased anti-proliferative, anti-invasive and apoptotic effects on different metastatic PCa cell lines compared to the single or two-drug strategies, indicating that targeting both signaling pathways could enhance chemosensitivity.	('EGFR', 'Gene', (45, 49))	('anti-proliferative', 'CPA', (123, 141))	('co-targeting', 'Var', (18, 30))	('apoptotic effects', 'CPA', (161, 178))	('enhance', 'PosReg', (321, 328))	('increased', 'PosReg', (113, 122))	('EGFR', 'Gene', '1956', (45, 49))	('anti-invasive', 'CPA', (143, 156))
244606	23880852	Moreover, the combined treatment with Smo and PI3K inhibitors significantly delayed the development of resistance, although no differential effect was seen on tumor growth.	('men', 'Species', '9606', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PI3K inhibitors', 'Var', (46, 61))	('development of resistance', 'CPA', (88, 113))	('tumor', 'Disease', (159, 164))	('men', 'Species', '9606', (95, 98))	('delayed', 'NegReg', (76, 83))	('Smo', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
244632	23880852	Moreover, inhibition of Hh signaling seems to increase tumor perfusion and could thereby improve delivery of the chemotherapeutic agent to the tumor and also synergistic effects of Hh inhibition and chemotherapy on apoptosis have previously been described.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('improve', 'PosReg', (89, 96))	('tumor', 'Disease', (143, 148))	('increase', 'PosReg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('delivery of the chemotherapeutic agent to the', 'MPA', (97, 142))	('tumor', 'Disease', (55, 60))	('inhibition', 'Var', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
244640	23326344	Breast cancer susceptibility gene 1 (BRCA1) expression has been found to switch the response to cisplatin- or paclitaxel-based chemotherapy.	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('paclitaxel', 'Chemical', 'MESH:D017239', (110, 120))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('expression', 'Var', (44, 54))	('BRCA1', 'Gene', '672', (37, 42))	('switch', 'Reg', (73, 79))	('Breast cancer', 'Disease', (0, 13))	('BRCA1', 'Gene', (37, 42))
244641	23326344	It remains unclear how variations in BRCA1 expression influence clinical outcomes in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('BRCA1', 'Gene', '672', (37, 42))	('influence', 'Reg', (54, 63))	('variations', 'Var', (23, 33))	('esophageal cancer', 'Disease', (85, 102))	('BRCA1', 'Gene', (37, 42))
244644	23326344	Multivariate analysis revealed that low BRCA1 expression was an independent prognostic factor in cisplatin-based chemotherapy (HR 0.29; 95%CI 0.12-0.71; P = 0.007) or chemoradiotherapy (HR 0.12; 95%CI 0.04-0.37; P<0.001) group and higher risk for mortality in docetaxel-based chemotherapy (HR 5.02; 95%CI 2.05-12.28; P<0.001) or chemoradiotherapy (HR 7.02; 95%CI 2.37-27.77; P<0.001) group.	('low', 'Var', (36, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('cisplatin-based chemotherapy', 'Disease', (97, 125))	('BRCA1', 'Gene', '672', (40, 45))	('docetaxel', 'Chemical', 'MESH:D000077143', (260, 269))	('expression', 'MPA', (46, 56))	('BRCA1', 'Gene', (40, 45))
244659	23326344	It was also confirmed in clinic that BRCA1 mutations or alterations in BRCA1 mRNA and protein expression switch the response to cisplatin- or paclitaxel-based chemotherapy as well as influence the survivals in a number of malignancies, including breast cancer, ovarian cancer, gastric cancer and lung cancer.	('ovarian cancer', 'Disease', (261, 275))	('lung cancer', 'Disease', 'MESH:D008175', (296, 307))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('ovarian cancer', 'Phenotype', 'HP:0100615', (261, 275))	('gastric cancer', 'Disease', (277, 291))	('lung cancer', 'Phenotype', 'HP:0100526', (296, 307))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('breast cancer', 'Disease', (246, 259))	('influence', 'Reg', (183, 192))	('gastric cancer', 'Disease', 'MESH:D013274', (277, 291))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('malignancies', 'Disease', 'MESH:D009369', (222, 234))	('switch', 'Reg', (105, 111))	('survivals', 'CPA', (197, 206))	('mRNA and', 'MPA', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('malignancies', 'Disease', (222, 234))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('lung cancer', 'Disease', (296, 307))	('ovarian cancer', 'Disease', 'MESH:D010051', (261, 275))	('BRCA1', 'Gene', '672', (71, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (277, 291))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('BRCA1', 'Gene', (71, 76))	('alterations', 'Var', (56, 67))	('paclitaxel', 'Chemical', 'MESH:D017239', (142, 152))	('mutations', 'Var', (43, 52))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA1', 'Gene', (37, 42))
244660	23326344	In our previous studies, high levels of BRCA1 mRNA were negatively associated with cisplatin sensitivity but positively associated with docetaxel sensitivity in gastric cancer patients.	('patients', 'Species', '9606', (176, 184))	('associated', 'Reg', (120, 130))	('gastric cancer', 'Phenotype', 'HP:0012126', (161, 175))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('negatively', 'NegReg', (56, 66))	('docetaxel sensitivity', 'MPA', (136, 157))	('BRCA1', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('high', 'Var', (25, 29))	('cisplatin sensitivity', 'MPA', (83, 104))	('gastric cancer', 'Disease', (161, 175))	('BRCA1', 'Gene', '672', (40, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (161, 175))	('docetaxel', 'Chemical', 'MESH:D000077143', (136, 145))	('associated', 'Interaction', (67, 77))
244661	23326344	Those advanced gastric carcinoma patients with high BRCA1 expression had significantly longer overall survivals compared to those with low expression (25.8 vs 9.5 months, P = 0.006) who received second-line docetaxel-based chemotherapy after first-line FOLFOX chemotherapy.	('BRCA1', 'Gene', '672', (52, 57))	('patients', 'Species', '9606', (33, 41))	('high', 'Var', (47, 51))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (15, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('BRCA1', 'Gene', (52, 57))	('docetaxel', 'Chemical', 'MESH:D000077143', (207, 216))	('gastric carcinoma', 'Disease', 'MESH:D013274', (15, 32))	('FOLFOX', 'Chemical', '-', (253, 259))	('longer', 'PosReg', (87, 93))	('gastric carcinoma', 'Disease', (15, 32))
244663	23326344	However, no studies have addressed how variations in BRCA1 expressions influence clinical outcomes in patients with esophageal cancer treated with these chemotherapeutic agents.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('influence', 'Reg', (71, 80))	('patients', 'Species', '9606', (102, 110))	('BRCA1', 'Gene', '672', (53, 58))	('variations', 'Var', (39, 49))	('BRCA1', 'Gene', (53, 58))	('esophageal cancer', 'Disease', (116, 133))
244678	23326344	All primers and probes sequence were as follows: beta-actin (NM_001101.3) forward 5' TGAGCGCGGCTACAGCTT 3', reverse 5' TCCTTAATGTCACGCACGATTT 3', and probe 6FAM -5'ACCACCA CGGCCGAGCGG 3' TAMRA; BRCA1 (NM_007294) forward 5'GGCTATCCTCTCAGAGTGACATTTTA 3', reverse 5'GCTTTATCAGGTTATGTTGCATGGT 3', and probe 6FAM -5'CCACTCAGCAGAGGG 3' MGB.	('BRCA1', 'Gene', '672', (194, 199))	('BRCA1', 'Gene', (194, 199))	('beta-actin', 'Gene', '728378', (49, 59))	('NM_001101.3', 'Var', (61, 72))	('beta-actin', 'Gene', (49, 59))
244699	23326344	In the chemotherapy group, patients with low BRCA1 expression had increased RR (57.1 vs 15.4%, P = 0.025) and mOS (15.0 vs 7.0, P = 0.002; Figure 2A) compared to those with high expression when treated with cisplatin-based chemotherapy; whereas when treated with docetaxel-based chemotherapy, patients with high BRCA1 mRNA expression had increased RR (69.2 vs 25.0%, P = 0.017) and mOS (16.0 vs 7.0, P<0.001; Figure 2B) compared to those with low expression (Table 3).	('increased', 'PosReg', (66, 75))	('mOS', 'Gene', (110, 113))	('BRCA1', 'Gene', '672', (45, 50))	('increased', 'PosReg', (338, 347))	('mOS', 'Gene', (382, 385))	('BRCA1', 'Gene', (45, 50))	('low', 'Var', (41, 44))	('BRCA1', 'Gene', '672', (312, 317))	('mOS', 'Gene', '17451', (382, 385))	('cisplatin', 'Chemical', 'MESH:D002945', (207, 216))	('mOS', 'Gene', '17451', (110, 113))	('patients', 'Species', '9606', (27, 35))	('docetaxel', 'Chemical', 'MESH:D000077143', (263, 272))	('high', 'Var', (307, 311))	('patients', 'Species', '9606', (293, 301))	('BRCA1', 'Gene', (312, 317))
244701	23326344	Patients with low BRCA1 expression had the best clinical results when treated with cisplatin/5-Fu compared to docetaxel/5-Fu or cisplatin/docetaxel regimens [RR were 57.1, 25.0 (P = 0.073) and 28.6% (P = 0.217), respectively; mOS were 15.0, 7.0 (P = 0.002) and 15.0 months (P = 0.450), respectively; Figure 2C].	('BRCA1', 'Gene', '672', (18, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('mOS', 'Gene', '17451', (226, 229))	('docetaxel', 'Chemical', 'MESH:D000077143', (138, 147))	('expression', 'MPA', (24, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('BRCA1', 'Gene', (18, 23))	('docetaxel', 'Chemical', 'MESH:D000077143', (110, 119))	('5-Fu', 'Chemical', 'MESH:D005472', (93, 97))	('Patients', 'Species', '9606', (0, 8))	('5-Fu', 'Chemical', 'MESH:D005472', (120, 124))	('low', 'Var', (14, 17))	('mOS', 'Gene', (226, 229))
244702	23326344	For those patients with high BRCA1 expression levels, regimen of docetaxel/5-Fu became the optimization choice in comparison with cisplatin/5-Fu or cisplatin/docetaxel regimens [RR were 69.2, 15.4 (P = 0.024) and 33.3% (P = 0.096), respectively; mOS were 16.0, 7.0 (P = 0.001) and11.8 months (P = 0.081), respectively; Figure 2D] (Table 4).	('docetaxel', 'Chemical', 'MESH:D000077143', (158, 167))	('5-Fu', 'Chemical', 'MESH:D005472', (140, 144))	('docetaxel', 'Chemical', 'MESH:D000077143', (65, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('expression', 'MPA', (35, 45))	('BRCA1', 'Gene', '672', (29, 34))	('mOS', 'Gene', (246, 249))	('high', 'Var', (24, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('BRCA1', 'Gene', (29, 34))	('mOS', 'Gene', '17451', (246, 249))	('patients', 'Species', '9606', (10, 18))	('5-Fu', 'Chemical', 'MESH:D005472', (75, 79))
244703	23326344	No significant differences were observed in RR (72.7 vs 60.0%, P = 0.516) and mOS (15.0 vs 12.0 months, P = 0.839; Figure 3A) between patients with low and high BRCA1 expression who were treated with radiotherapy alone.	('BRCA1', 'Gene', (161, 166))	('low', 'Var', (148, 151))	('patients', 'Species', '9606', (134, 142))	('BRCA1', 'Gene', '672', (161, 166))	('mOS', 'Gene', (78, 81))	('high', 'Var', (156, 160))	('mOS', 'Gene', '17451', (78, 81))
244704	23326344	Nevertheless, when treated with concurrent chemoradiotherapy, patients with low BRCA1 expression had increased RR (87.5 vs 46.2%, P = 0.017) and mOS (24.0 vs 11.3 months, P<0.001; Figure 3B) compared to those with high expressions in the cisplatin-based chemoradiotherapy subgroup; and those with high BRCA1 expression had increased RR (89.5 vs 50.0%, P = 0.024) and mOS (19.5 vs 7.5 months, P<0.001; Figure 3C) compared to those with low expressions in the docetaxel-based chemoradiotherapy subgroup (Table 3).	('low', 'Var', (76, 79))	('mOS', 'Gene', '17451', (367, 370))	('increased', 'PosReg', (323, 332))	('high', 'Var', (297, 301))	('mOS', 'Gene', (145, 148))	('increased', 'PosReg', (101, 110))	('BRCA1', 'Gene', '672', (302, 307))	('BRCA1', 'Gene', '672', (80, 85))	('mOS', 'Gene', '17451', (145, 148))	('cisplatin', 'Chemical', 'MESH:D002945', (238, 247))	('BRCA1', 'Gene', (302, 307))	('docetaxel', 'Chemical', 'MESH:D000077143', (458, 467))	('BRCA1', 'Gene', (80, 85))	('expression', 'Var', (86, 96))	('mOS', 'Gene', (367, 370))	('patients', 'Species', '9606', (62, 70))
244707	23326344	Cox proportional hazard analysis revealed that low BRCA1 expression as an independent prognostic factor was significant associated with increased mOS in cisplatin-based chemotherapy (HR 0.29; 95%CI 0.12-0.71; P = 0.007) or chemoradiotherapy (HR 0.12; 95%CI 0.04-0.37; P<0.001) group, whereas low BRCA1 expression emerged conversely as higher risk for mortality associated with decreased mOS in docetaxel-based chemotherapy ( HR 5.02; 95%CI 2.05-12.28; P<0.001) or chemoradiotherapy (HR 7.02; 95%CI 2.37-27.77; P<0.001) group (Table 5).	('docetaxel', 'Chemical', 'MESH:D000077143', (394, 403))	('mOS', 'Gene', '17451', (387, 390))	('decreased', 'NegReg', (377, 386))	('BRCA1', 'Gene', '672', (296, 301))	('expression', 'Var', (57, 67))	('mOS', 'Gene', (146, 149))	('BRCA1', 'Gene', '672', (51, 56))	('low', 'Var', (47, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('BRCA1', 'Gene', (296, 301))	('BRCA1', 'Gene', (51, 56))	('mOS', 'Gene', '17451', (146, 149))	('increased', 'PosReg', (136, 145))	('low', 'Var', (292, 295))	('mOS', 'Gene', (387, 390))
244714	23326344	As a predictive marker in previous studies, overexpression of BRCA1 was significantly correlated with higher RR and progression-free survival (PFS) but not with mOS in non-small-cell lung cancer (NSCLC) treated with docetaxel-gemcitabine as first-line chemotherapy; BRCA1 mutation appeared to be related with high pathologic complete response in breast cancer treated with platinum-based neoadjuvant therapy.	('gemcitabine', 'Chemical', 'MESH:C056507', (226, 237))	('mOS', 'Gene', (161, 164))	('BRCA1', 'Gene', '672', (266, 271))	('BRCA1', 'Gene', (266, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (346, 359))	('mOS', 'Gene', '17451', (161, 164))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('mutation', 'Var', (272, 280))	('platinum', 'Chemical', 'MESH:D010984', (373, 381))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('breast cancer', 'Disease', 'MESH:D001943', (346, 359))	('NSCLC', 'Disease', (196, 201))	('breast cancer', 'Disease', (346, 359))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('BRCA1', 'Gene', '672', (62, 67))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('BRCA1', 'Gene', (62, 67))	('lung cancer', 'Disease', (183, 194))	('docetaxel', 'Chemical', 'MESH:D000077143', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))
244715	23326344	Meanwhile, as a prognostic marker, low BRCA1 expression correlated with improved survival in advanced ovarian cancer who received platinum-based chemotherapy and high BRCA1 expression correlated with longer mOS in gastric cancer patients treated with second-line docetaxel-based chemotherapy after first-line FOLFOX chemotherapy.	('patients', 'Species', '9606', (229, 237))	('gastric cancer', 'Disease', (214, 228))	('mOS', 'Gene', (207, 210))	('docetaxel', 'Chemical', 'MESH:D000077143', (263, 272))	('platinum', 'Chemical', 'MESH:D010984', (130, 138))	('gastric cancer', 'Disease', 'MESH:D013274', (214, 228))	('improved', 'PosReg', (72, 80))	('survival', 'MPA', (81, 89))	('longer', 'PosReg', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('BRCA1', 'Gene', '672', (167, 172))	('mOS', 'Gene', '17451', (207, 210))	('BRCA1', 'Gene', (167, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('BRCA1', 'Gene', '672', (39, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (214, 228))	('expression', 'MPA', (173, 183))	('high', 'Var', (162, 166))	('BRCA1', 'Gene', (39, 44))	('FOLFOX', 'Chemical', '-', (309, 315))	('expression', 'MPA', (45, 55))	('ovarian cancer', 'Disease', (102, 116))	('low', 'NegReg', (35, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))
244724	23326344	Cisplatin- and docetaxel-based treatments were found to be the optimized choices for patients with low and high expression of BRCA1 to get more clinical benefits in the present study, respectively.	('BRCA1', 'Gene', (126, 131))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('patients', 'Species', '9606', (85, 93))	('docetaxel', 'Chemical', 'MESH:D000077143', (15, 24))	('high expression', 'Var', (107, 122))	('BRCA1', 'Gene', '672', (126, 131))
244726	23326344	In this retrospective study, patients with stage III-IV had longer mOS of 15.0 months (95% CI: 10.7-19.3) when treated with cisplatin-based chemotherapy for low BRCA1 expression and 16.0 months (95% CI: 11.7-20.3) when treated with docetaxel-based chemotherapy for high BRCA1 expression.	('BRCA1', 'Gene', (161, 166))	('BRCA1', 'Gene', (270, 275))	('patients', 'Species', '9606', (29, 37))	('longer', 'PosReg', (60, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('mOS', 'Gene', (67, 70))	('low', 'Var', (157, 160))	('mOS', 'Gene', '17451', (67, 70))	('docetaxel', 'Chemical', 'MESH:D000077143', (232, 241))	('BRCA1', 'Gene', '672', (161, 166))	('BRCA1', 'Gene', '672', (270, 275))	('expression', 'MPA', (167, 177))
244728	23326344	Meanwhile, no clinical benefits were observed in patients with low BRCA1 expression who received docetaxel-based treatments and patients with high BRCA1 expression who received cisplatin-based treatments (Table 4).	('expression', 'Var', (73, 83))	('BRCA1', 'Gene', '672', (147, 152))	('docetaxel', 'Chemical', 'MESH:D000077143', (97, 106))	('BRCA1', 'Gene', (147, 152))	('cisplatin', 'Chemical', 'MESH:D002945', (177, 186))	('BRCA1', 'Gene', '672', (67, 72))	('patients', 'Species', '9606', (49, 57))	('low', 'Var', (63, 66))	('patients', 'Species', '9606', (128, 136))	('BRCA1', 'Gene', (67, 72))
244729	23326344	Patients with low BRCA1 expression treated with cisplatin/docetaxel chemotherapy had similar OS (15.0 vs 15.0 months, P = 0.450, Figure 2C) compared to cispalin/5-Fu chemotherapy and patients with high BRCA1 expression treated with cisplatin/docetaxel chemotherapy also had no better OS (11.8 vs 16.0 months, P = 0.081, Figure 2D) compared to docetaxel/5-Fu chemotherapy (Table 4).	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('docetaxel', 'Chemical', 'MESH:D000077143', (58, 67))	('BRCA1', 'Gene', '672', (202, 207))	('BRCA1', 'Gene', '672', (18, 23))	('OS', 'Gene', '17451', (93, 95))	('BRCA1', 'Gene', (18, 23))	('BRCA1', 'Gene', (202, 207))	('5-Fu', 'Chemical', 'MESH:D005472', (353, 357))	('OS', 'Gene', '17451', (284, 286))	('Patients', 'Species', '9606', (0, 8))	('docetaxel', 'Chemical', 'MESH:D000077143', (242, 251))	('cisplatin', 'Chemical', 'MESH:D002945', (232, 241))	('cispalin', 'Chemical', '-', (152, 160))	('docetaxel', 'Chemical', 'MESH:D000077143', (343, 352))	('low', 'Var', (14, 17))	('patients', 'Species', '9606', (183, 191))	('5-Fu', 'Chemical', 'MESH:D005472', (161, 165))
244734	23326344	In present study, there was no significant difference in clinical outcomes between patients with low and high BRCA1 expression when treated with radiotherapy alone.	('expression', 'MPA', (116, 126))	('high', 'Var', (105, 109))	('BRCA1', 'Gene', '672', (110, 115))	('BRCA1', 'Gene', (110, 115))	('patients', 'Species', '9606', (83, 91))	('low', 'NegReg', (97, 100))
244735	23326344	This result was in agreement to the previous study of breast cancer, which showed no evidence of increased radiation sensitivity in breast tissue heterozygous for a BRCA1/2 germline mutation.	('germline', 'Var', (173, 181))	('breast cancer', 'Disease', (54, 67))	('BRCA1/2', 'Gene', '672;675', (165, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('BRCA1/2', 'Gene', (165, 172))
244761	19293308	The ICD-O-3 codes for the histology-specific analyses were squamous cell carcinoma (8050-8078, 8083-8084); adenocarcinoma (8140-8231, 8250-8551, 8570-8574, 8576); small cell lung cancer (8002, 8040-8045, 8240, 8246); large cell lung cancer (8012); hepatocellular carcinoma (8170-8175); melanoma (8720-8780); soft tissue tumors and sarcoma (8680-8711, 8800-8936, 8980-8981, 8990-8991, 9040-9044, 9120-9133, 9150-9252, 9370-9372, 9490, 9540-9581); transitional cell carcinoma (8120-8139); neuroepithelial tumors (9360-9362, 9381-9421, 9424-9451, 9470-9474, 9490-9501, 9505-9508, 9522-9523); papillary tumors (8050, 8260, 8340-8344, 8350, 8450-8460); and anus, anal canal and anorectum squamous cell carcinoma (8050-8078, 8083-8084, 8124; includes cloacogenic tumors).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (163, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('hepatocellular carcinoma', 'Disease', (248, 272))	('papillary tumors', 'Disease', 'MESH:D002291', (589, 605))	('papillary tumors', 'Disease', (589, 605))	('neuroepithelial tumors', 'Disease', 'MESH:D018302', (487, 509))	('tumors', 'Disease', 'MESH:D009369', (320, 326))	('cell carcinoma', 'Disease', 'MESH:C538614', (459, 473))	('8050', 'Var', (607, 611))	('tumors', 'Disease', 'MESH:D009369', (757, 763))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('cell lung cancer', 'Disease', 'MESH:D008175', (169, 185))	('melanoma', 'Phenotype', 'HP:0002861', (286, 294))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (683, 706))	('melanoma', 'Disease', (286, 294))	('squamous cell carcinoma', 'Disease', (59, 82))	('adenocarcinoma', 'Disease', (107, 121))	('tumors', 'Phenotype', 'HP:0002664', (599, 605))	('tumors', 'Phenotype', 'HP:0002664', (503, 509))	('cell carcinoma', 'Disease', 'MESH:C538614', (68, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (697, 706))	('anorectum squamous cell carcinoma', 'Disease', 'MESH:D002294', (673, 706))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (248, 272))	('neuroepithelial tumors', 'Disease', (487, 509))	('small cell lung cancer', 'Disease', 'MESH:D055752', (163, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('anorectum squamous cell carcinoma', 'Disease', (673, 706))	('tumor', 'Phenotype', 'HP:0002664', (599, 604))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('cell carcinoma', 'Disease', 'MESH:C538614', (692, 706))	('large cell lung cancer', 'Phenotype', 'HP:0030360', (217, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (331, 338))	('tumor', 'Phenotype', 'HP:0002664', (503, 508))	('small cell lung cancer', 'Disease', (163, 185))	('cell lung cancer', 'Disease', 'MESH:D008175', (223, 239))	('tumors', 'Disease', (599, 605))	('tumors', 'Phenotype', 'HP:0002664', (757, 763))	('tumors', 'Disease', (503, 509))	('8050-8078', 'Var', (708, 717))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (446, 473))	('carcinoma', 'Phenotype', 'HP:0030731', (464, 473))	('9360-9362', 'Var', (511, 520))	('neuroepithelial tumors', 'Phenotype', 'HP:0030063', (487, 509))	('melanoma', 'Disease', 'MESH:D008545', (286, 294))	('cell carcinoma', 'Disease', (459, 473))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (248, 272))	('soft tissue tumors and sarcoma', 'Disease', 'MESH:D012509', (308, 338))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('cell lung cancer', 'Disease', (223, 239))	('tumors', 'Disease', (320, 326))	('tumor', 'Phenotype', 'HP:0002664', (757, 762))	('tumors', 'Disease', (757, 763))	('tumors', 'Disease', 'MESH:D009369', (599, 605))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (308, 326))	('tumors', 'Disease', 'MESH:D009369', (503, 509))	('papillary tumors', 'Phenotype', 'HP:0007482', (589, 605))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (683, 706))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
244822	19293308	Putative differences between the sexes that may explain the male predominance of esophageal adenocarcinoma include android obesity, production and concentration of gastric acid, hiatal hernia, defective lower-esophageal sphincter, and higher intra-abdominal and intra-gastric pressures.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('esophageal adenocarcinoma', 'Disease', (81, 106))	('esophageal', 'Disease', 'MESH:D004941', (81, 91))	('android obesity', 'Phenotype', 'HP:0012743', (115, 130))	('android obesity', 'Disease', 'MESH:D009765', (115, 130))	('hiatal hernia', 'Disease', 'MESH:D006551', (178, 191))	('hiatal hernia', 'Disease', (178, 191))	('hernia', 'Phenotype', 'HP:0100790', (185, 191))	('higher', 'PosReg', (235, 241))	('esophageal', 'Disease', (209, 219))	('hiatal hernia', 'Phenotype', 'HP:0002036', (178, 191))	('defective', 'Var', (193, 202))	('obesity', 'Phenotype', 'HP:0001513', (123, 130))	('esophageal', 'Disease', (81, 91))	('android obesity', 'Disease', (115, 130))	('intra-abdominal and intra-gastric pressures', 'Disease', 'MESH:D059325', (242, 285))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (81, 106))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (81, 106))	('esophageal', 'Disease', 'MESH:D004941', (209, 219))
244827	19293308	Major risk factors for HCC in the United States are chronic infection with hepatitis C virus and hepatitis B virus, as well as alcoholic liver disease.	('hepatitis B virus', 'Species', '10407', (97, 114))	('chronic infection with hepatitis C virus', 'Disease', 'MESH:D019698', (52, 92))	('chronic infection with hepatitis C virus', 'Disease', (52, 92))	('HCC', 'Disease', (23, 26))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (127, 150))	('hepatitis', 'Phenotype', 'HP:0012115', (97, 106))	('chronic infection', 'Phenotype', 'HP:0031035', (52, 69))	('HCC', 'Phenotype', 'HP:0001402', (23, 26))	('liver disease', 'Phenotype', 'HP:0001392', (137, 150))	('alcoholic liver disease', 'Disease', (127, 150))	('hepatitis', 'Var', (97, 106))	('hepatitis', 'Phenotype', 'HP:0012115', (75, 84))
244897	19888422	Patients with ECV depletion generally have hyperuricemia, because proximal tubules avidly reabsorb sodium together with urate.	('urate', 'MPA', (120, 125))	('ECV depletion', 'Var', (14, 27))	('sodium', 'Chemical', 'MESH:D012964', (99, 105))	('hyperuricemia', 'Disease', 'MESH:D033461', (43, 56))	('Patients', 'Species', '9606', (0, 8))	('reabsorb sodium', 'MPA', (90, 105))	('urate', 'Chemical', 'MESH:D014527', (120, 125))	('hyperuricemia', 'Phenotype', 'HP:0002149', (43, 56))	('hyperuricemia', 'Disease', (43, 56))
244932	33026466	Results showed a significantly lower rate of major complications (36%), especially pulmonary complications (18%), in the hybrid group compared with the open transthoracic esophagectomy group (64% and 30%, respectively).	('hybrid', 'Var', (121, 127))	('pulmonary complications', 'Disease', 'MESH:D008171', (83, 106))	('major complications', 'CPA', (45, 64))	('lower', 'NegReg', (31, 36))	('pulmonary complications', 'Disease', (83, 106))	('pulmonary complications', 'Phenotype', 'HP:0006532', (83, 106))
244944	33026466	It found a reduction of overall postoperative complications in patients treated with MIE (41.5%) vs. OE (48.2%).	('reduction', 'NegReg', (11, 20))	('MIE', 'Var', (85, 88))	('postoperative complications', 'CPA', (32, 59))	('patients', 'Species', '9606', (63, 71))
244945	33026466	Specifically, pulmonary complications (OR = 0.527, 95% CI = 0431~0.645, p < 0.05), cardiovascular complications (OR = 0.770, 95% CI = 0.681~0.872, p < 0.05), and surgical technology-related (STR) complications (OR = 0.639, 95% CI = 0.522~0.781, p < 0.05), as well as in-hospital mortality (OR = 0.668, 95% CI = 0.539~0.827, p < 0.05), were found to be lower in the MIE group.	('mortality', 'Disease', (279, 288))	('pulmonary complications', 'Disease', 'MESH:D008171', (14, 37))	('cardiovascular complications', 'Disease', (83, 111))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (83, 111))	('pulmonary complications', 'Phenotype', 'HP:0006532', (14, 37))	('cardiovascular complications', 'Disease', 'MESH:D002318', (83, 111))	('MIE', 'Var', (365, 368))	('mortality', 'Disease', 'MESH:D003643', (279, 288))	('lower', 'NegReg', (352, 357))	('surgical technology-related', 'CPA', (162, 189))	('pulmonary complications', 'Disease', (14, 37))
244955	33026466	In addition to that, postoperative pain, short-term quality of life, and short-term postoperative functional recovery were significantly better in RAMIE group.	('postoperative pain', 'Disease', 'MESH:D010149', (21, 39))	('better', 'PosReg', (137, 143))	('pain', 'Phenotype', 'HP:0012531', (35, 39))	('postoperative pain', 'Disease', (21, 39))	('RAMIE', 'Var', (147, 152))
244997	31255713	For the use case of detecting relevant phenotypic characterizations for given PH related phenotypes, HPOEmb-Orphanet outperformed the other three HPO embeddings by achieving the highest average P@5 of 0.81 and the highest P@10 of 0.79.	('P@5', 'Gene', '347051', (194, 197))	('HPOEmb-Orphanet', 'Var', (101, 116))	('outperformed', 'PosReg', (117, 129))	('P@5', 'Gene', (194, 197))	('HPOEmb-Orphanet', 'Chemical', '-', (101, 116))
245067	31255713	Figure 4.1 depicts a cluster generated by HPOEmb-Original including the greatest number of phenotypic terms with coarse granularity in the HPO graph, such as abnormal epiphyseal ossification, abnormal lung morphology, abnormality of muscle morphology, abnormal proportion of double-negative alpha-beta regulatory T cell.	('abnormal epiphyseal ossification', 'Phenotype', 'HP:0010656', (158, 190))	('abnormality of muscle morphology', 'Phenotype', 'HP:0011805', (218, 250))	('abnormal proportion of double-negative alpha-beta regulatory T cell', 'Phenotype', 'HP:0031399', (252, 319))	('abnormality', 'Var', (218, 229))	('muscle morphology', 'CPA', (233, 250))	('abnormal epiphyseal ossification', 'Disease', (158, 190))	('double-negative alpha-beta regulatory T cell', 'CPA', (275, 319))	('abnormal epiphyseal ossification', 'Disease', 'MESH:D009999', (158, 190))	('abnormal lung morphology', 'Phenotype', 'HP:0002088', (192, 216))	('abnormal lung morphology', 'CPA', (192, 216))	('abnormal epiphyseal', 'Phenotype', 'HP:0005930', (158, 177))
245108	31255713	For example, 7 of 10 inferred phenotypes for stage 5 chronic kidney diseases were high level nodes with coarse granularity: abnormality of the musculature of the lower limbs, abnormality of the phalanges of the 5th finger, abnormal macular morphology, abnormality of epiphysis morphology, abnormal tongue morphology, abnormality of phalanx of finger, and abnormality of muscle morphology.	('abnormality', 'Var', (175, 186))	('abnormal', 'Var', (223, 231))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (53, 75))	('stage 5 chronic kidney diseases', 'Phenotype', 'HP:0003774', (45, 76))	('abnormality of the phalanges of the 5th finger', 'Phenotype', 'HP:0004213', (175, 221))	('abnormality', 'Var', (317, 328))	('abnormal tongue morphology', 'Phenotype', 'HP:0030809', (289, 315))	('stage 5 chronic kidney disease', 'Phenotype', 'HP:0003774', (45, 75))	('abnormality', 'Var', (252, 263))	('abnormality of epiphysis morphology', 'Phenotype', 'HP:0005930', (252, 287))	('kidney disease', 'Phenotype', 'HP:0000112', (61, 75))	('abnormality', 'Var', (124, 135))	('abnormality', 'Var', (355, 366))	('abnormality of muscle morphology', 'Phenotype', 'HP:0011805', (355, 387))	('kidney diseases', 'Phenotype', 'HP:0000112', (61, 76))	('abnormality of the phalanges', 'Phenotype', 'HP:0005918', (175, 203))	('abnormality of the musculature of the lower limbs', 'Phenotype', 'HP:0001437', (124, 173))	('macular morphology', 'CPA', (232, 250))	('abnormality of phalanx of finger', 'Phenotype', 'HP:0005918', (317, 349))	('abnormal tongue', 'Phenotype', 'HP:0000157', (289, 304))	('chronic kidney diseases', 'Disease', (53, 76))	('chronic kidney diseases', 'Disease', 'MESH:D051436', (53, 76))	('lower limbs', 'Phenotype', 'HP:0006385', (162, 173))	('abnormality of the musculature', 'Phenotype', 'HP:0003011', (124, 154))	('chronic kidney diseases', 'Phenotype', 'HP:0012622', (53, 76))	('abnormal macular morphology', 'Phenotype', 'HP:0001103', (223, 250))
245127	30643947	Patients with FDG-avid nodes were more likely to have incurable disease (51.4% versus 15.5%; p < 0.001), and a worse prognosis if not: multivariate hazard ratio 2.19 (1.23-3.91; p = 0.008).	('FDG', 'Chemical', 'MESH:D019788', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('FDG-avid', 'Var', (14, 22))	('incurable', 'Disease', (54, 63))
245135	30643947	Beyond avoiding futile investigations and radical treatment in this 5%, we found patients with FDG-avid nodes (metabolic nodal stage, mN) to have a worse disease-free survival after gastrectomy.	('disease-free survival', 'CPA', (154, 175))	('patients', 'Species', '9606', (81, 89))	('worse', 'NegReg', (148, 153))	('FDG', 'Chemical', 'MESH:D019788', (95, 98))	('FDG-avid', 'Var', (95, 103))
245140	30643947	We found that patients with FDG-avid nodes within a standard lymphadenectomy field had a higher risk of disease progression before surgery and recurrence and death afterwards.	('FDG', 'Chemical', 'MESH:D019788', (28, 31))	('disease progression', 'CPA', (104, 123))	('death', 'Disease', 'MESH:D003643', (158, 163))	('FDG-avid', 'Var', (28, 36))	('death', 'Disease', (158, 163))	('patients', 'Species', '9606', (14, 22))
245159	30643947	An economic model was developed using 2017 UK National Health Service (NHS) tariffs for laparoscopy ($735), 3 cycles ECX ($8004), gastrectomy ($10,402), PET-CT ($980), liver MRI ($145), mediastinoscopy ($1432), and ultrasound-guided fine needle aspiration ($599).	('aspiration', 'Phenotype', 'HP:0002835', (245, 255))	('$145', 'Var', (179, 183))	('ECX', 'Chemical', '-', (117, 120))	('mediastinoscopy', 'Disease', (186, 201))	('gastrectomy', 'Disease', (130, 141))	('$980', 'Var', (161, 165))	('$1432', 'Var', (203, 208))
245164	30643947	An avid tumor was more likely with advancing T stage: T2-3 multivariate OR 3.38 (2.28-5.02; p = 0.002) and T4 7.46 (3.38-14.7; p = 0.003).	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('T2-3', 'Var', (54, 58))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))
245207	30643947	On multivariable analysis (Table 4), relative to pN0mN0 disease, patients with pN >= 1mN0 disease (i.e., non-avid nodal metastases) had a worse DFS (HR 2.44 [1.20-4.96]; p = 0.013).	('pN >= 1mN0', 'Var', (79, 89))	('nodal metastases', 'Disease', (114, 130))	('DFS', 'MPA', (144, 147))	('nodal metastases', 'Disease', 'MESH:D009362', (114, 130))	('patients', 'Species', '9606', (65, 73))
245209	30643947	We found that routinely staging all patients with gastric cancer with 18F-FDG PET-CT was useful, both identifying unsuspected metastases and risk-stratifying patients.	('18F-FDG', 'Var', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patients', 'Species', '9606', (36, 44))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('metastases', 'Disease', (126, 136))	('FDG', 'Chemical', 'MESH:D019788', (74, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('patients', 'Species', '9606', (158, 166))	('metastases', 'Disease', 'MESH:D009362', (126, 136))
245211	30643947	One quarter of patients had FDG-avid nodes, which conferred a worse prognosis: a significantly higher risk of coincident incurable disease at staging and worse disease-free survival following surgery if curable (independent of clinical and pathological nodal stage).	('FDG', 'Chemical', 'MESH:D019788', (28, 31))	('patients', 'Species', '9606', (15, 23))	('FDG-avid', 'Var', (28, 36))	('disease-free survival', 'CPA', (160, 181))	('worse', 'NegReg', (154, 159))
245218	30643947	Coupe et al previously reported FDG-avid nodes to confer a worse prognosis in 68 patients with GOJ or gastric cancer, although did not assess the staging utility of PET-CT and also included patients undergoing non-curative treatment.	('FDG-avid nodes', 'Var', (32, 46))	('patients', 'Species', '9606', (190, 198))	('patients', 'Species', '9606', (81, 89))	('gastric cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('FDG', 'Chemical', 'MESH:D019788', (32, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('GOJ', 'Disease', (95, 98))
245220	30643947	The latter suggests a mechanism by which FDG-avid nodes confer a worse prognosis, as a surrogate for a more aggressive and metastatic cancer phenotype.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('FDG-avid nodes', 'Var', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('FDG', 'Chemical', 'MESH:D019788', (41, 44))
245229	30643947	Our cohort was insufficient to determine whether restaging patients with PET-CT rather than CT is preferable, but intuitively the greater sensitivity of PET-CT should translate to restaging (as we previously reported in esophageal cancer).	('esophageal cancer', 'Disease', (220, 237))	('insufficient', 'Disease', (15, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (220, 237))	('restaging', 'Disease', (180, 189))	('patients', 'Species', '9606', (59, 67))	('PET-CT', 'Var', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('insufficient', 'Disease', 'MESH:D000309', (15, 27))
245242	29856759	Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation A key challenge in the development of precision medicine is defining the phenotypic consequences of pharmacological modulation of specific target macromolecules.	('SMYD3', 'Gene', '64754', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutagenesis', 'Var', (42, 53))	('autonomous cancer', 'Disease', (116, 133))	('SMYD2', 'Gene', (71, 76))	('autonomous cancer', 'Disease', 'MESH:D009369', (116, 133))	('SMYD2', 'Gene', '56950', (71, 76))	('SMYD3', 'Gene', (81, 86))
245246	29856759	By site-specific modification of histone lysine or arginine amino acid side chains, these enzymes effect chromatin structural changes that in turn control programs of gene transcription.	('chromatin', 'MPA', (105, 114))	('modification', 'Var', (17, 29))	('arginine', 'Protein', (51, 59))	('programs of gene transcription', 'MPA', (155, 185))	('histone lysine', 'Protein', (33, 47))	('control', 'Reg', (147, 154))	('arginine amino acid', 'Chemical', '-', (51, 70))	('lysine', 'Chemical', 'MESH:D008239', (41, 47))
245248	29856759	Small molecule inhibitors for a number of these enzymes have been reported over the past decade and inhibitors against three PMT targets (DOT1L, EZH2 and PRMT5) have transitioned to clinical trials as therapeutic agents against different human cancers.	('DOT1L', 'Gene', '84444', (138, 143))	('human', 'Species', '9606', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('PRMT5', 'Gene', (154, 159))	('EZH2', 'Gene', '2146', (145, 149))	('DOT1L', 'Gene', (138, 143))	('PRMT5', 'Gene', '10419', (154, 159))	('EZH2', 'Gene', (145, 149))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('inhibitors', 'Var', (100, 110))	('cancers', 'Disease', (244, 251))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))
245252	29856759	Consistent with its role in tumorigenesis, knockdown of SMYD2 in esophageal, bladder and gastric cancer models is reported to attenuate proliferation in a variety of tissue culture cells.	('tumor', 'Disease', (28, 33))	('attenuate', 'NegReg', (126, 135))	('bladder', 'Disease', (77, 84))	('knockdown', 'Var', (43, 52))	('gastric cancer', 'Disease', (89, 103))	('esophageal', 'Disease', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('SMYD2', 'Gene', (56, 61))	('proliferation in a variety of tissue culture cells', 'CPA', (136, 186))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))	('bladder', 'Disease', 'MESH:D001745', (77, 84))
245259	29856759	BAY-598 inhibits SMYD2 with an IC50 of 27 nM, inhibits intracellular substrate methylation with an IC50 of 58 nM, but has little impact on cell proliferation or induction of apoptosis in cell lines found to be sensitive to LLY-507.	('BAY-598', 'Var', (0, 7))	('inhibits', 'NegReg', (8, 16))	('LLY-507', 'Chemical', 'MESH:C000600304', (223, 230))	('intracellular substrate methylation', 'MPA', (55, 90))	('inhibits', 'NegReg', (46, 54))	('SMYD2', 'Gene', (17, 22))	('BAY-598', 'Chemical', '-', (0, 7))
245265	29856759	SMYD3 has also been shown to regulate MAPK pathways by methylating MAP3K2.	('MAP3K2', 'Gene', '10746', (67, 73))	('MAPK pathways', 'Pathway', (38, 51))	('methylating', 'Var', (55, 66))	('MAP3K2', 'Gene', (67, 73))	('regulate', 'Reg', (29, 37))
245267	29856759	Nevertheless, and in contrast to many of the earlier studies summarized above, these SMYD2 and SMYD3 inhibitors show no impact on the cell proliferation of more than 240 cancer cell lines regardless of genetic or histological background.	('cell proliferation', 'CPA', (134, 152))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('inhibitors', 'Var', (101, 111))	('cancer', 'Disease', (170, 176))	('SMYD2', 'Gene', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('SMYD3', 'Gene', (95, 100))
245268	29856759	Similarly, knockout of these genes with CRISPR/Cas9 across 313 cell lines shows no proliferative effects.	('knockout', 'Var', (11, 19))	('SPR', 'Gene', (43, 46))	('proliferative effects', 'CPA', (83, 104))	('SPR', 'Gene', '6697', (43, 46))
245270	29856759	The isoform of SMYD3 containing Lys at position 13 was used for the biochemical assays, SPR and ITC while the SMYD3 isoform containing Asn at position 13 was utilized for x-ray crystal structures.	('SPR', 'Gene', (88, 91))	('Lys', 'Chemical', 'MESH:D008239', (32, 35))	('SPR', 'Gene', '6697', (88, 91))	('Asn', 'Chemical', 'MESH:D001216', (135, 138))	('Lys at position 13', 'Var', (32, 50))
245294	29856759	Enzyme and substrate concentrations used for the mechanism of EPZ028862 inhibition of SMYD3 are described in S3 Table.	('SMYD3', 'Gene', (86, 91))	('EPZ028862', 'Chemical', '-', (62, 71))	('EPZ028862', 'Var', (62, 71))	('inhibition', 'NegReg', (72, 82))
245304	29856759	Structures have been deposited into the Protein Data Bank (SMYD2-EPZ033294 = 5V3H; SMYD3-EPZ028862 = 5V37).	('EPZ028862', 'Chemical', '-', (89, 98))	('SMYD2-EPZ033294', 'Var', (59, 74))	('SMYD3-EPZ028862', 'Var', (83, 98))	('EPZ033294', 'Chemical', '-', (65, 74))
245305	29856759	The SPR binding assay for EPZ033294/SMYD2 was performed at 15 C using the SensiQ system (SensiQ Technoogies, Inc., Oklahoma City, OK).	('Oklahoma City', 'Disease', (115, 128))	('EPZ033294', 'Chemical', '-', (26, 35))	('Oklahoma City', 'Disease', 'MESH:C537147', (115, 128))	('EPZ033294/SMYD2', 'Var', (26, 41))	('SPR', 'Gene', (4, 7))	('SPR', 'Gene', '6697', (4, 7))
245308	29856759	The SPR binding assay for EZ028862/SMYD3 was performed at 15 C using the Biacore T200 system (GE Healthcare, Marlborough, MA).	('SPR', 'Gene', (4, 7))	('EZ028862', 'Chemical', '-', (26, 34))	('SPR', 'Gene', '6697', (4, 7))	('EZ028862/SMYD3', 'Var', (26, 40))
245335	29856759	Fig 1A illustrates the chemical structures of SMYD2 inhibitors that have been reported previously and of EPZ033294 and EPZ032597, new inhibitors representing a completely novel pharmacophore series.	('EPZ032597', 'Chemical', '-', (119, 128))	('EPZ033294', 'Var', (105, 114))	('EPZ033294', 'Chemical', '-', (105, 114))	('EPZ032597', 'Var', (119, 128))	('inhibitors', 'MPA', (52, 62))	('SMYD2', 'Gene', (46, 51))
245336	29856759	EPZ033294 is an inhibitor of SMYD2 that was optimized from an initial hit from Epizyme's proprietary histone methyltransferase-biased library using a radiometric assay with tritiated SAM and an H3 peptide as substrates.	('SMYD2', 'Gene', (29, 34))	('peptide', 'Chemical', 'MESH:D010455', (197, 204))	('EPZ033294', 'Var', (0, 9))	('EPZ033294', 'Chemical', '-', (0, 9))	('SAM', 'Chemical', 'MESH:D012436', (183, 186))
245337	29856759	EPZ033294 inhibits the enzymatic activity of SMYD2 with a potency of 3.9 nM (Fig 2A) and is noncompetitive with respect to peptide substrate (Fig 2B) and either noncompetitive or uncompetitive with respect to SAM.	('SAM', 'Chemical', 'MESH:D012436', (209, 212))	('inhibits', 'NegReg', (10, 18))	('EPZ033294', 'Var', (0, 9))	('EPZ033294', 'Chemical', '-', (0, 9))	('peptide', 'Chemical', 'MESH:D010455', (123, 130))	('enzymatic activity', 'MPA', (23, 41))	('SMYD2', 'Gene', (45, 50))	('peptide substrate', 'MPA', (123, 140))
245341	29856759	In addition, EPZ033294 and EPZ032597 were tested against a panel of 15 additional methyltransferase enzymes to check the selectivity of the compounds for SMYD2.	('methyltransferase enzymes', 'Enzyme', (82, 107))	('EPZ032597', 'Chemical', '-', (27, 36))	('EPZ033294', 'Var', (13, 22))	('EPZ032597', 'Var', (27, 36))	('EPZ033294', 'Chemical', '-', (13, 22))	('tested', 'Reg', (42, 48))
245345	29856759	Compared to all other published SMYD2 inhibitors, EPZ033294 binds in a distinct and unique manner, traversing the peptide binding site and inducing a pocket into which the hydrophobic tail of the molecule is inserted (S1 Fig).	('peptide', 'Protein', (114, 121))	('EPZ033294', 'Chemical', '-', (50, 59))	('inducing', 'Reg', (139, 147))	('EPZ033294', 'Var', (50, 59))	('peptide', 'Chemical', 'MESH:D010455', (114, 121))	('traversing', 'Reg', (99, 109))
245347	29856759	Western blot analysis of intracellular levels of BTF3me1 as a function of EPZ033294 concentration demonstrated a concentration-dependent inhibition of this mark with an IC50 of 2.9 nM (Fig 2D, Table 1).	('BTF3me1', 'Gene', (49, 56))	('inhibition', 'NegReg', (137, 147))	('EPZ033294', 'Chemical', '-', (74, 83))	('EPZ033294', 'Var', (74, 83))
245348	29856759	Despite relatively potent inhibition of SMYD2 biochemical activity (Table 1), the previously reported compounds AZ505 and LLY-507 demonstrated inhibition of intracellular BTF3me1 (Table 1), and were significantly less potent in this assay than EPZ033294 or the reported cellular methylation activity of BAY-598 (Table 1).	('SMYD2', 'Gene', (40, 45))	('AZ505', 'Var', (112, 117))	('AZ505', 'Chemical', 'MESH:C568821', (112, 117))	('LLY-507', 'Var', (122, 129))	('inhibition', 'NegReg', (26, 36))	('intracellular BTF3me1', 'MPA', (157, 178))	('EPZ033294', 'Chemical', '-', (244, 253))	('less', 'NegReg', (213, 217))	('inhibition', 'NegReg', (143, 153))	('LLY-507', 'Chemical', 'MESH:C000600304', (122, 129))	('BAY-598', 'Chemical', '-', (303, 310))
245351	29856759	We next tested proliferation in response to EPZ032597, a compound similar to EPZ033294 in structure with a cellular IC50 of 31 nM (Fig 3B, Table 1), for effects against a panel of 240 cell lines (Eurofins Panlabs Oncopanel) representing a broad variety of cancer cell lines of differing origin (see S6 Table for more information).	('tested', 'Reg', (8, 14))	('EPZ032597', 'Var', (44, 53))	('EPZ033294', 'Chemical', '-', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Disease', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('EPZ032597', 'Chemical', '-', (44, 53))
245352	29856759	EPZ032597 was inactive as an anti-proliferative agent in nearly all tested cell types with a proliferative IC50 not observed at concentrations up to 10 muM in a 10-day assay (Fig 3C).	('muM', 'Gene', '56925', (152, 155))	('EPZ032597', 'Var', (0, 9))	('muM', 'Gene', (152, 155))	('EPZ032597', 'Chemical', '-', (0, 9))
245358	29856759	The oxindole sulfonamides and sulfamides, EPZ030456 and EPZ031686, show low nanomolar inhibition of SMYD3 enzymatic activity and intracellular concentration-dependent inhibition of methylation of the SMYD3 substrate MAP3K2, originally identified by Mazur et al.. Structure-activity relationship studies of SMYD3 inhibitors led to the isoxazole sulfonamide series exemplified by EPZ028862, another molecule displaying similarly potency against SMYD3 in biochemical and cellular assays with physicochemical properties suitable for in vivo studies (Fig 4A and 4B; Table 1 and S2 Table).	('EPZ028862', 'Var', (378, 387))	('MAP3K2', 'Gene', (216, 222))	('isoxazole sulfonamide', 'Chemical', '-', (334, 355))	('amide', 'Chemical', 'MESH:D000577', (19, 24))	('EPZ028862', 'Chemical', '-', (378, 387))	('amide', 'Chemical', 'MESH:D000577', (350, 355))	('amide', 'Chemical', 'MESH:D000577', (34, 39))	('MAP3K2', 'Gene', '10746', (216, 222))
245359	29856759	In addition, EPZ028862 was tested against a panel of 15 methyltransferase enzymes to check the selectivity of the compound for SMYD3.	('EPZ028862', 'Var', (13, 22))	('tested', 'Reg', (27, 33))	('methyltransferase', 'Enzyme', (56, 73))	('EPZ028862', 'Chemical', '-', (13, 22))
245365	29856759	It is important to note that the EC50 measured by CETSA represents the binding affinity of EPZ028862 to SMYD3 at 47 degrees and likely underestimates the potency at the physiologically relevant temperature of 37 degrees.	('EPZ028862', 'Var', (91, 100))	('EPZ028862', 'Chemical', '-', (91, 100))	('binding affinity', 'Interaction', (71, 87))	('EC50', 'MPA', (33, 37))
245366	29856759	With verification of inhibition of SMYD3 in cells, we then specifically tested how inhibition of SMYD3 by EPZ028862 affected cell proliferation in vitro.	('inhibition', 'NegReg', (83, 93))	('EPZ028862', 'Chemical', '-', (106, 115))	('SMYD3', 'Gene', (97, 102))	('cell proliferation', 'CPA', (125, 143))	('tested', 'Reg', (72, 78))	('EPZ028862', 'Var', (106, 115))
245368	29856759	Treatment of NSCLC and other lung cancer cell lines with and without KRAS mutations at concentrations as high as 25 microM had no impact on proliferation (S5 Table).	('KRAS', 'Gene', (69, 73))	('NSCLC', 'Disease', (13, 18))	('proliferation', 'CPA', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('mutations', 'Var', (74, 83))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
245380	29856759	Hep3B cells infected with SMYD3 sgRNA virus have undetectable levels of SMYD3 but showed similar growth characteristics to controls indicating that loss of this enzyme is well tolerated by this cell line (Fig 5C and 5D).	('SMYD3', 'MPA', (72, 77))	('loss', 'Var', (148, 152))	('undetectable levels', 'MPA', (49, 68))	('Hep3B', 'CellLine', 'CVCL:0326', (0, 5))
245382	29856759	The findings that SMYD2 and SMYD3 targeted CRISPR-Cas9 knockout are well tolerated in every cell line tested and inhibitors of SMYD2 and SMYD3 have almost no detectable effects on cell proliferation, we conclude that neither the activity nor expression of these enzymes is required for in vitro cancer cell proliferation.	('SPR', 'Gene', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('SPR', 'Gene', '6697', (46, 49))	('cancer', 'Disease', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('knockout', 'Var', (55, 63))
245386	29856759	demonstrate that SMYD3 deficiency reduces tumorigenesis induced by mutant KRAS in both pancreas and lung.	('deficiency', 'Var', (23, 33))	('SMYD3', 'Gene', (17, 22))	('tumor', 'Disease', (42, 47))	('reduces', 'NegReg', (34, 41))	('KRAS', 'Gene', (74, 78))	('pancreas', 'Disease', (87, 95))	('mutant', 'Var', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('pancreas', 'Disease', 'MESH:D010190', (87, 95))
245438	27231920	For those already diagnosed with oral cancer, reduction (<79 g alcohol/week) or cessation in alcohol drinking resulted in a significant decrease in mortality at three (p < 0.001) and five (p < 0.001) years.	('oral cancer', 'Disease', (33, 44))	('reduction', 'NegReg', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('<79', 'Var', (57, 60))	('decrease', 'NegReg', (136, 144))	('alcohol drinking', 'Phenotype', 'HP:0030955', (93, 109))	('alcohol', 'Chemical', 'MESH:D000438', (63, 70))	('oral cancer', 'Disease', 'MESH:D009062', (33, 44))	('alcohol', 'Chemical', 'MESH:D000438', (93, 100))	('mortality', 'MPA', (148, 157))
245447	27231920	Data showed that subjects carrying the GG variant homozygote of alcohol dehydrogenase-2 (ADH2) G48A had a higher EC risks among Asian populations, and heavy drinking made it worse, whereas researchers found that functional genotypes of enzymes involved in alcohol metabolism were not significantly related to EAC or ESCC in a European population.	('alcohol dehydrogenase-2', 'Gene', '125', (64, 87))	('alcohol', 'Chemical', 'MESH:D000438', (256, 263))	('ESCC', 'Disease', (316, 320))	('alcohol', 'Chemical', 'MESH:D000438', (64, 71))	('G48A', 'Mutation', 'c.48G>A', (95, 99))	('EAC', 'Phenotype', 'HP:0011459', (309, 312))	('ADH2', 'Gene', (89, 93))	('ADH2', 'Gene', '125', (89, 93))	('alcohol dehydrogenase-2', 'Gene', (64, 87))	('EAC', 'Disease', (309, 312))	('variant', 'Var', (42, 49))	('G48A', 'Var', (95, 99))
245451	27231920	A study showed that high folate intake ameliorated the relationship between alcohol consumption and HCC incidence.	('alcohol', 'Chemical', 'MESH:D000438', (76, 83))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))	('folate', 'Chemical', 'MESH:D005492', (25, 31))	('high folate intake', 'Phenotype', 'HP:0032164', (20, 38))	('high', 'Var', (20, 24))	('HCC', 'Disease', (100, 103))	('rat', 'Species', '10116', (45, 48))
245457	27231920	A study even suggested that moderate alcohol consumption was associated with decreased risk of colorectal in both men (OR, 0.35; 95% CI, 0.16-0.74) and women (OR, 0.40; 95% CI, 0.18-0.91).	('women', 'Species', '9606', (152, 157))	('colorectal', 'Disease', 'MESH:D015179', (95, 105))	('rat', 'Species', '10116', (32, 35))	('alcohol', 'Chemical', 'MESH:D000438', (37, 44))	('men', 'Species', '9606', (114, 117))	('colorectal', 'Disease', (95, 105))	('men', 'Species', '9606', (154, 157))	('moderate alcohol consumption', 'Var', (28, 56))	('decreased', 'NegReg', (77, 86))
245462	27231920	Another study on the combined effects of XRCC1 polymorphisms and alcohol consumption also supported the role of gene-environment interactions in colorectal cancer susceptibility.	('interactions', 'Interaction', (129, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('polymorphisms', 'Var', (47, 60))	('XRCC1', 'Gene', '7515', (41, 46))	('men', 'Species', '9606', (124, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('XRCC1', 'Gene', (41, 46))	('alcohol', 'Chemical', 'MESH:D000438', (65, 72))	('colorectal cancer', 'Disease', (145, 162))
245476	27231920	Heavy drinking has been widely accepted to be a major cause of chronic pancreatitis and a risk factor of type 2 diabetes mellitus, both of which are associated with pancreatic cancer.	('type 2 diabetes', 'Disease', (105, 120))	('cause', 'Reg', (54, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('chronic pancreatitis', 'Disease', (63, 83))	('type 2 diabetes', 'Disease', 'MESH:D003924', (105, 120))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (105, 120))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (112, 129))	('associated', 'Reg', (149, 159))	('pancreatitis', 'Phenotype', 'HP:0001733', (71, 83))	('Heavy drinking', 'Var', (0, 14))	('diabetes mellitus', 'Disease', (112, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (63, 83))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (63, 83))	('diabetes mellitus', 'Disease', 'MESH:D003920', (112, 129))	('pancreatic cancer', 'Disease', (165, 182))
245493	27231920	Due to the preservation of grape skin during maceration, the concentration of total phenolics in red wine (1378-2681 mg/L gallic acid equivalents) is much higher than that in white wine (<50 mg/L gallic acid equivalents).	('red wine', 'Chemical', '-', (97, 105))	('maceration', 'Phenotype', 'HP:0032007', (45, 55))	('gallic acid', 'Chemical', 'MESH:D005707', (122, 133))	('1378-2681 mg/L', 'Var', (107, 121))	('rat', 'Species', '10116', (68, 71))	('gallic acid', 'Chemical', 'MESH:D005707', (196, 207))	('concentration', 'MPA', (61, 74))	('rat', 'Species', '10116', (49, 52))	('higher', 'PosReg', (155, 161))
245512	27231920	In an nude mouse model transplanted with the ER-MDA-MB231 breast cancer cells, reduced tumor growth, suppression of genes of the NF-kappaB pathway as well as up-regulation of cell cycle arrest related genes (CDK5RAP1, RBBP8, and SERTAD1) were all observed after the red wine extracts treatment (100 mg/kg body weight equivalent of polyphenols).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('men', 'Species', '9606', (289, 292))	('SERTAD1', 'Gene', (229, 236))	('red wine', 'Chemical', '-', (266, 274))	('CDK5RAP1', 'Gene', (208, 216))	('polyphenols', 'Chemical', 'MESH:D059808', (331, 342))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (175, 192))	('up-regulation', 'PosReg', (158, 171))	('RBBP8', 'Gene', (218, 223))	('cell', 'Gene', (175, 179))	('CDK5RAP1', 'Gene', '66971', (208, 216))	('reduced', 'NegReg', (79, 86))	('tumor', 'Disease', (87, 92))	('SERTAD1', 'Gene', '55942', (229, 236))	('suppression', 'NegReg', (101, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('genes', 'MPA', (116, 121))	('mouse', 'Species', '10090', (11, 16))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('NF-kappaB pathway', 'Pathway', (129, 146))	('ER-MDA-MB231', 'Var', (45, 57))	('RBBP8', 'Gene', '225182', (218, 223))	('breast cancer', 'Disease', (58, 71))	('MDA-MB231', 'CellLine', 'CVCL:0062', (48, 57))
245546	27231920	Folate depletion could lead to alterations in DNA and RNA methylation, disruption of DNA integrity and DNA repair, therefore promoting carcinogenensis.	('lead', 'Reg', (23, 27))	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('promoting', 'PosReg', (125, 134))	('Folate', 'MPA', (0, 6))	('carcinogenensis', 'CPA', (135, 150))	('disruption', 'NegReg', (71, 81))	('depletion', 'Var', (7, 16))	('rat', 'Species', '10116', (35, 38))	('alterations', 'Reg', (31, 42))	('Folate depletion', 'Phenotype', 'HP:0100507', (0, 16))
245609	27231920	For male, though lacking statistically significant association, there was a trend toward increased hypertension risks with low to moderate drinking, and heavy drinking significantly elevated hypertension risks (31-40 g/day: RR, 1.77; 95% CI, 1.39-2.26 and >50 g/day: RR, 1.61; 95% CI, 1.38-1.87).	('hypertension', 'Phenotype', 'HP:0000822', (191, 203))	('heavy drinking', 'Var', (153, 167))	('hypertension', 'Disease', (99, 111))	('hypertension', 'Phenotype', 'HP:0000822', (99, 111))	('rat', 'Species', '10116', (134, 137))	('hypertension', 'Disease', 'MESH:D006973', (191, 203))	('low to moderate drinking', 'Var', (123, 147))	('elevated', 'PosReg', (182, 190))	('hypertension', 'Disease', 'MESH:D006973', (99, 111))	('hypertension', 'Disease', (191, 203))
245618	27231920	In addition, a meta-analysis suggested that light to moderate alcohol consumption was inversely associated with risks of heart failure (RR, 0.85; 95% CI: 0.78-0.93).	('heart failure', 'Disease', 'MESH:D006333', (121, 134))	('light to moderate alcohol consumption', 'Var', (44, 81))	('heart failure', 'Disease', (121, 134))	('rat', 'Species', '10116', (57, 60))	('alcohol', 'Chemical', 'MESH:D000438', (62, 69))	('inversely', 'NegReg', (86, 95))	('heart failure', 'Phenotype', 'HP:0001635', (121, 134))
245624	27231920	The dysfunction of the NO pathway is involved in the development of many cardiovascular diseases, such as hypertension, atherosclerosis and cerebral hypoperfusion.	('hypertension', 'Disease', 'MESH:D006973', (106, 118))	('dysfunction', 'Var', (4, 15))	('cardiovascular diseases', 'Disease', (73, 96))	('hypertension', 'Disease', (106, 118))	('atherosclerosis', 'Phenotype', 'HP:0002621', (120, 135))	('atherosclerosis and cerebral hypoperfusion', 'Disease', 'MESH:D002537', (120, 162))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (73, 96))	('hypertension', 'Phenotype', 'HP:0000822', (106, 118))	('NO pathway', 'Pathway', (23, 33))	('men', 'Species', '9606', (60, 63))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (73, 96))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (73, 95))	('involved', 'Reg', (37, 45))
245634	27231920	These changes might increase collateral blood flow to prevent further ischemic insult as well as compensate for the ischemic myocardium.	('ischemic myocardium', 'Disease', 'MESH:D003324', (116, 135))	('changes', 'Var', (6, 13))	('ischemic insult', 'Disease', (70, 85))	('ischemic insult', 'Disease', 'MESH:D007511', (70, 85))	('ischemic myocardium', 'Disease', (116, 135))	('collateral blood flow', 'CPA', (29, 50))	('increase', 'PosReg', (20, 28))
245639	27231920	An experimental study among healthy adults reported reduced cardiovascular responsiveness associated with moderate alcohol consumption (<15.8 g alcohol for female and <23.7 g alcohol for male).	('rat', 'Species', '10116', (110, 113))	('<15.8', 'Var', (136, 141))	('reduced', 'NegReg', (52, 59))	('men', 'Species', '9606', (9, 12))	('alcohol', 'Chemical', 'MESH:D000438', (144, 151))	('alcohol', 'Chemical', 'MESH:D000438', (175, 182))	('cardiovascular responsiveness', 'MPA', (60, 89))	('alcohol', 'Chemical', 'MESH:D000438', (115, 122))
245653	27231920	An in vitro study also suggested that the endothelial dependent vasorelaxant effect of alcohol free red wine (100 and 300 mug/mL) was correlated with increased NO concentration.	('endothelial dependent vasorelaxant effect', 'MPA', (42, 83))	('rat', 'Species', '10116', (170, 173))	('100', 'Var', (110, 113))	('NO concentration', 'MPA', (160, 176))	('alcohol free red wine', 'Chemical', '-', (87, 108))
245655	27231920	The cardioprotective ability of many drugs, such as acetylsalicylic acid, is correlated with suppression of platelet aggregation.	('cardioprotective ability', 'CPA', (4, 28))	('platelet aggregation', 'Disease', (108, 128))	('suppression', 'NegReg', (93, 104))	('platelet aggregation', 'Disease', 'MESH:D001791', (108, 128))	('acetylsalicylic acid', 'Var', (52, 72))	('platelet aggregation', 'Phenotype', 'HP:0003540', (108, 128))	('acetylsalicylic acid', 'Chemical', 'MESH:D001241', (52, 72))
245688	27231920	According to a prospective study, diabetic patients who reported moderate drinking (<=21 drinks/week for men and <=14 drinks/week for women) presented decreased risks of cardiovascular accidents (adjusted HR, 0.83; 95% CI, 0.72-0.95; p = 0.008), micro vascular complications (adjusted HR, 0.85; 95% CI, 0.73-0.99; p = 0.03) as well as all-cause mortality (adjusted HR, 0.87; 95% CI, 0.75-1.00; p = 0.05).	('cardiovascular accidents', 'Disease', 'MESH:D002318', (170, 194))	('<=14 drinks/week', 'Var', (113, 129))	('all-cause mortality', 'CPA', (335, 354))	('patients', 'Species', '9606', (43, 51))	('diabetic', 'Disease', 'MESH:D003920', (34, 42))	('decreased', 'NegReg', (151, 160))	('cardiovascular accidents', 'Disease', (170, 194))	('women', 'Species', '9606', (134, 139))	('men', 'Species', '9606', (105, 108))	('vascular complications', 'Disease', (252, 274))	('diabetic', 'Disease', (34, 42))	('rat', 'Species', '10116', (69, 72))	('men', 'Species', '9606', (136, 139))	('vascular complications', 'Disease', 'MESH:D000783', (252, 274))
245734	27231920	The induction of pancreatic beta-cell dysfunction and apoptosis by chronic alcohol administration might act through nitration and downregulation of glucokinase.	('apoptosis', 'CPA', (54, 63))	('nitration', 'Var', (116, 125))	('pancreatic beta-cell dysfunction', 'Disease', 'MESH:D010195', (17, 49))	('rat', 'Species', '10116', (91, 94))	('downregulation', 'NegReg', (130, 144))	('glucokinase', 'Gene', '2645', (148, 159))	('alcohol', 'Chemical', 'MESH:D000438', (75, 82))	('rat', 'Species', '10116', (119, 122))	('beta-cell dysfunction', 'Phenotype', 'HP:0006279', (28, 49))	('pancreatic beta-cell dysfunction', 'Disease', (17, 49))	('glucokinase', 'Gene', (148, 159))
245751	27231920	Heavy drinking was reported to provide additional risks of obesity, and alcohol-derived calories might play an important role in these increased risks.	('obesity', 'Phenotype', 'HP:0001513', (59, 66))	('alcohol', 'Chemical', 'MESH:D000438', (72, 79))	('Heavy drinking', 'Var', (0, 14))	('obesity', 'Disease', 'MESH:D009765', (59, 66))	('obesity', 'Disease', (59, 66))
245767	27231920	Estrogen could affect lipid accumulation in adipocytes, inhibiting lipogenesis and facilitating lipolysis.	('lipid', 'Chemical', 'MESH:D008055', (22, 27))	('affect', 'Reg', (15, 21))	('Estrogen', 'Var', (0, 8))	('inhibiting', 'NegReg', (56, 66))	('lipid accumulation', 'MPA', (22, 40))	('lipolysis', 'MPA', (96, 105))	('lipogenesis', 'MPA', (67, 78))
245786	27231920	It is of note that binge drinking was associated with major cardiovascular accidents, such as myocardial infarction and stroke.	('myocardial infarction', 'Phenotype', 'HP:0001658', (94, 115))	('stroke', 'Phenotype', 'HP:0001297', (120, 126))	('associated', 'Reg', (38, 48))	('cardiovascular accidents', 'Disease', 'MESH:D002318', (60, 84))	('stroke', 'Disease', (120, 126))	('binge drinking', 'Var', (19, 33))	('myocardial infarction', 'Disease', (94, 115))	('stroke', 'Disease', 'MESH:D020521', (120, 126))	('cardiovascular accidents', 'Disease', (60, 84))	('myocardial infarction', 'Disease', 'MESH:D009203', (94, 115))	('binge drinking', 'Phenotype', 'HP:0100739', (19, 33))
245796	22606415	Although mortality is not high, there is a highly related morbidity rate: caustic ingestion may thus cause perforations and necrosis in the acute phase, while the late complications include stricture formation, especially in the esophagus and the antrum, and the development of esophageal and, rarely, gastric carcinoma.	('bid', 'Gene', '637', (61, 64))	('stricture', 'Disease', (190, 199))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (302, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('necrosis', 'Disease', (124, 132))	('caustic ingestion', 'Var', (74, 91))	('esophageal', 'Disease', (278, 288))	('gastric carcinoma', 'Disease', 'MESH:D013274', (302, 319))	('necrosis', 'Disease', 'MESH:D009336', (124, 132))	('cause', 'Reg', (101, 106))	('gastric carcinoma', 'Disease', (302, 319))	('bid', 'Gene', (61, 64))	('perforations', 'CPA', (107, 119))
245829	22606415	Alkali ingestion causes more commonly esophageal injuries, whereas the damage caused by acids is maximal in the stomach, and the esophagus is minimally affected.	('esophageal injuries', 'Disease', 'MESH:D004941', (38, 57))	('esophageal injuries', 'Disease', (38, 57))	('causes', 'Reg', (17, 23))	('Alkali', 'Var', (0, 6))
245904	33573059	Compared to people younger than 30 years old, the adjusted risks were 297.55, 53.88, 1250.63, 2154.44, and 164.61 for breast, cervix, lung, esophagus cancer, and all cancers, respectively (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Disease', (166, 173))	('cancer', 'Disease', (166, 172))	('lung', 'Disease', (134, 138))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('2154.44', 'Var', (94, 101))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('people', 'Species', '9606', (12, 18))	('breast', 'Disease', (118, 124))	('cancer', 'Disease', (150, 156))	('cervix', 'Disease', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
245930	33573059	A study conducted in Israel also found that low-frequency electromagnetic fields contribute to breast cancer development.	('low-frequency', 'Var', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('contribute', 'Reg', (81, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('men', 'Species', '9606', (116, 119))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
245940	33573059	However, there are many other risk factors, such as aging, genetic mutations, reproductive history, dense breasts, past history of breast disease, previous treatment with radiotherapy, sedentary lifestyle, overweight or obesity after menopause, alcohol intake, and use of hormones and some oral contraceptives.	('alcohol', 'Chemical', 'MESH:D000438', (245, 252))	('obesity', 'Phenotype', 'HP:0001513', (220, 227))	('dense breasts', 'Disease', (100, 113))	('men', 'Species', '9606', (234, 237))	('obesity after menopause', 'Phenotype', 'HP:0008209', (220, 243))	('genetic mutations', 'Var', (59, 76))	('obesity', 'Disease', 'MESH:D009765', (220, 227))	('overweight', 'Phenotype', 'HP:0025502', (206, 216))	('obesity', 'Disease', (220, 227))	('breast disease', 'Disease', 'MESH:D001943', (131, 145))	('overweight', 'Disease', (206, 216))	('men', 'Species', '9606', (161, 164))	('breast disease', 'Disease', (131, 145))	('sedentary', 'Disease', (185, 194))
246115	32884347	Boggs et al indicated that primary GTV of esophagus is a more powerful predictor of patient outcomes than traditional TNM staging and GTV >85cc and GTV>46 cc were correlated with an increased risk of local failure and distant failure respectively.	('TNM', 'Gene', (118, 121))	('local failure', 'CPA', (200, 213))	('GTV >85cc', 'Var', (134, 143))	('distant failure', 'CPA', (218, 233))	('GTV', 'Chemical', '-', (134, 137))	('GTV', 'Chemical', '-', (35, 38))	('TNM', 'Gene', '10178', (118, 121))	('GTV>46 cc', 'Var', (148, 157))	('GTV', 'Chemical', '-', (148, 151))	('patient', 'Species', '9606', (84, 91))
246134	32884347	GTVe reduction ratio (RR) compared with pretreatment GTVe was calculated to reveal changes of tumor volume by time, taking twentieth fraction of radiotherapy as example, RR=100x(pretreatment GTVe -GTVe at twenthieth fraction of radiotherapy)/pretreatment GTVe.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('GTVe', 'Chemical', '-', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GTVe', 'Chemical', '-', (197, 201))	('GTVe', 'Chemical', '-', (53, 57))	('tumor', 'Disease', (94, 99))	('GTVe', 'Chemical', '-', (255, 259))	('GTVe', 'Chemical', '-', (0, 4))	('RR=100x', 'Var', (170, 177))
246200	32448253	Furthermore, patients with pathologic lymph node LN metastasis have a significantly lower survival rate than patients without LN metastasis.	('lymph node LN metastasis', 'Var', (38, 62))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (13, 21))	('survival rate', 'CPA', (90, 103))	('lower', 'NegReg', (84, 89))
246207	32448253	Therefore, this retrospective study examined whether S + CT or S + CRT were associated with improved survival among patients with pN+ ESCC.	('survival', 'MPA', (101, 109))	('patients', 'Species', '9606', (116, 124))	('CRT', 'Gene', '799', (67, 70))	('CRT', 'Gene', (67, 70))	('improved', 'PosReg', (92, 100))	('S + CT', 'Var', (53, 59))
246234	32448253	The S + CT group was more likely to have pT3 status than the S + CRT group (p = 0.021).	('CRT', 'Gene', '799', (65, 68))	('pT3 status', 'Disease', (41, 51))	('S + CT', 'Var', (4, 10))	('CRT', 'Gene', (65, 68))
246253	32448253	Moreover, the independent predictors of OS and DFS were S + CRT, KPS score, and pathological T/N status.	('KPS score', 'Var', (65, 74))	('CRT', 'Gene', (60, 63))	('CRT', 'Gene', '799', (60, 63))	('DFS', 'Disease', (47, 50))
246268	32448253	For example, patients with KPS 90-100 can benefit from the S + CRT.	('CRT', 'Gene', '799', (63, 66))	('benefit', 'PosReg', (42, 49))	('CRT', 'Gene', (63, 66))	('patients', 'Species', '9606', (13, 21))	('KPS 90-100', 'Var', (27, 37))
246358	32256779	FPD was significantly earlier in 0.5-EI-4 compared with the other five groups (P=0.024, P<0.001, P<0.001, P<0.001 and P<0.001 for 0.5-EI-4 compared with 1-EI-4, 1-C-37, 0.5-C-4, 0.25-T-37 and 0.125-T-4, respectively), and it was earlier in 1-EI-4 compared with 1-C-37, 0.5-C-4, 0.25-T-37 and 0.125-T-4 (P<0.001, P<0.001, P<0.001 and P<0.001, respectively; Fig.	('FPD', 'Disease', 'MESH:C563324', (0, 3))	('P', 'Chemical', 'MESH:D010758', (312, 313))	('P', 'Chemical', 'MESH:D010758', (321, 322))	('P', 'Chemical', 'MESH:D010758', (333, 334))	('P', 'Chemical', 'MESH:D010758', (106, 107))	('FPD', 'Disease', (0, 3))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('0.5-EI-4', 'Var', (33, 41))	('P', 'Chemical', 'MESH:D010758', (97, 98))	('P', 'Chemical', 'MESH:D010758', (118, 119))	('P', 'Chemical', 'MESH:D010758', (1, 2))	('P', 'Chemical', 'MESH:D010758', (303, 304))	('P', 'Chemical', 'MESH:D010758', (88, 89))
246430	32256779	These smooth muscle markers (alpha-SMA, desmin and vimentin) may be involved in the regulation of smooth muscle movement, and SMCs in vitro may have lost motility, such that the conversion from contractile to synthetic phenotypes could be triggered in vitro.	('alpha-SMA', 'Gene', '58', (29, 38))	('motility', 'CPA', (154, 162))	('vimentin', 'Gene', (51, 59))	('involved', 'Reg', (68, 76))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('desmin', 'Gene', '1674', (40, 46))	('vimentin', 'Gene', '7431', (51, 59))	('alpha-SMA', 'Gene', (29, 38))	('S', 'Chemical', 'MESH:D013455', (126, 127))	('SMCs', 'Var', (126, 130))	('men', 'Species', '9606', (53, 56))	('lost', 'NegReg', (149, 153))	('desmin', 'Gene', (40, 46))	('men', 'Species', '9606', (116, 119))
246487	32023907	In terms of carcinogenesis, IMP2 expression leads to elevated levels of IGF2, which can activate the signaling pathways of MAPK and Jak-STAT.	('levels', 'MPA', (62, 68))	('expression', 'Var', (33, 43))	('IGF2', 'Gene', (72, 76))	('elevated', 'PosReg', (53, 61))	('elevated levels of IGF2', 'Phenotype', 'HP:0030269', (53, 76))	('IMP2', 'Gene', '10644', (28, 32))	('IMP2', 'Gene', (28, 32))	('MAPK', 'Pathway', (123, 127))	('activate', 'PosReg', (88, 96))	('signaling pathways', 'Pathway', (101, 119))	('IGF2', 'Gene', '3481', (72, 76))
246493	32023907	Both studies concluded that DKK is responsible for migration, invasion, and lymph node metastasis in esophageal adenocarcinoma.	('lymph node metastasis', 'CPA', (76, 97))	('esophageal adenocarcinoma', 'Disease', (101, 126))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (101, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('migration', 'CPA', (51, 60))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (101, 126))	('invasion', 'CPA', (62, 70))	('DKK', 'Var', (28, 31))
246502	32023907	could demonstrate that aberrant Gli1/2 expression was significantly associated with increased EMT and AKT pathway activity in EAC cell lines.	('activity', 'MPA', (114, 122))	('Gli1/2', 'Gene', (32, 38))	('EMT', 'CPA', (94, 97))	('EAC', 'Disease', (126, 129))	('EAC', 'Disease', 'MESH:D004941', (126, 129))	('EAC', 'Phenotype', 'HP:0011459', (126, 129))	('Gli1/2', 'Gene', '2735;2736', (32, 38))	('increased EMT', 'Phenotype', 'HP:0008151', (84, 97))	('AKT', 'Gene', '207', (102, 105))	('increased', 'PosReg', (84, 93))	('expression', 'MPA', (39, 49))	('aberrant', 'Var', (23, 31))	('AKT', 'Gene', (102, 105))
246523	32023907	The amplification and overexpression of ERBB2 (or HER2/neu) lead to several intracellular signals such as the activation of the MAPK signaling pathway and is very common in intestinal-type but not in diffuse-type gastric carcinomas.	('ERBB2', 'Gene', '2064', (40, 45))	('activation', 'PosReg', (110, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('overexpression', 'PosReg', (22, 36))	('ERBB2', 'Gene', (40, 45))	('HER2/neu', 'Gene', '2064', (50, 58))	('intracellular signals', 'MPA', (76, 97))	('MAPK signaling pathway', 'Pathway', (128, 150))	('HER2/neu', 'Gene', (50, 58))	('amplification', 'Var', (4, 17))	('gastric carcinomas', 'Disease', 'MESH:D013274', (213, 231))	('gastric carcinomas', 'Disease', (213, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (221, 231))	('intestinal-type', 'Disease', (173, 188))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (213, 230))
246524	32023907	It was further demonstrated that HER2/neu mutations occur especially in metastatic gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('HER2/neu', 'Gene', '2064', (33, 41))	('occur', 'Reg', (52, 57))	('HER2/neu', 'Gene', (33, 41))	('gastric cancer', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('mutations', 'Var', (42, 51))
246530	32023907	The authors found that TP53 mutations were significantly higher among patients with hepatic metastases compared to patients without metastasis.	('hepatic metastases', 'Disease', (84, 102))	('hepatic metastases', 'Disease', 'MESH:D009362', (84, 102))	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (115, 123))	('higher', 'Reg', (57, 63))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
246531	32023907	The TP53 mutations were present in both the liver metastasis tissue and primary gastric tumor, suggesting an organ-specific metastasis mechanism of TP53.	('gastric tumor', 'Disease', 'MESH:D013274', (80, 93))	('TP53', 'Gene', (4, 8))	('TP53', 'Gene', '7157', (148, 152))	('mutations', 'Var', (9, 18))	('TP53', 'Gene', (148, 152))	('gastric tumor', 'Phenotype', 'HP:0006753', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('gastric tumor', 'Disease', (80, 93))	('TP53', 'Gene', '7157', (4, 8))
246763	32054931	Although their function has not been clear, in recent years it has been demonstrated that miRs are combined with mRNA with a complementary sequence, and that they inhibit targets by translation inhibition and cleavage (degradation).	('inhibit', 'NegReg', (163, 170))	('miRs', 'Var', (90, 94))	('targets', 'MPA', (171, 178))	('men', 'Species', '9606', (131, 134))	('cleavage', 'MPA', (209, 217))	('translation', 'MPA', (182, 193))
246849	31571914	AKT allosteric inhibitor MK2206 and dual PI3K and mTOR inhibitor BEZ235 are promising drug candidates with potential anti-tumor effects.	('MK2206', 'Chemical', 'MESH:C548887', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('BEZ235', 'Chemical', 'MESH:C531198', (65, 71))	('AKT', 'Pathway', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('MK2206', 'Var', (25, 31))	('tumor', 'Disease', (122, 127))
246850	31571914	In this study, we aimed to detect the activation of PI3K/AKT/mTOR pathway and assess the efficacy of MK2206 and BEZ235 in inhibiting esophageal cancer growth.	('inhibiting', 'NegReg', (122, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('MK2206', 'Var', (101, 107))	('PI3K/AKT/mTOR pathway', 'Pathway', (52, 73))	('activation', 'PosReg', (38, 48))	('esophageal cancer', 'Disease', (133, 150))	('MK2206', 'Chemical', 'MESH:C548887', (101, 107))	('BEZ235', 'Chemical', 'MESH:C531198', (112, 118))
246853	31571914	MK2206 and BEZ235 inhibited cell proliferation, enhanced apoptosis, and induced cell-cycle arrest through downstream effectors SKP2, MCL-1, and cyclin D1 in esophageal SCC cells.	('cell-cycle arrest', 'CPA', (80, 97))	('apoptosis', 'CPA', (57, 66))	('esophageal SCC', 'Disease', (157, 171))	('BEZ235', 'Var', (11, 17))	('SKP2', 'Gene', '6502', (127, 131))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('enhanced', 'PosReg', (48, 56))	('cell proliferation', 'CPA', (28, 46))	('BEZ235', 'Chemical', 'MESH:C531198', (11, 17))	('rat', 'Species', '10116', (40, 43))	('esophageal SCC', 'Disease', 'MESH:C562729', (157, 171))	('MCL-1', 'Gene', '4170', (133, 138))	('cyclin D1', 'Gene', '595', (144, 153))	('MCL-1', 'Gene', (133, 138))	('inhibited', 'NegReg', (18, 27))	('cyclin D1', 'Gene', (144, 153))	('SKP2', 'Gene', (127, 131))	('MK2206', 'Var', (0, 6))
246854	31571914	MK2206 and BEZ235 also inhibited tumor growth in xenograft mice through the inhibition of AKT phosphorylation.	('inhibition', 'NegReg', (76, 86))	('mice', 'Species', '10090', (59, 63))	('inhibited', 'NegReg', (23, 32))	('BEZ235', 'Var', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('BEZ235', 'Chemical', 'MESH:C531198', (11, 17))	('AKT phosphorylation', 'Pathway', (90, 109))	('tumor', 'Disease', (33, 38))	('MK2206', 'Var', (0, 6))	('phospho', 'Chemical', 'MESH:C033601', (94, 101))
246855	31571914	MK2206/BEZ235 combination showed greater anti-tumor effect than MK2206 or BEZ235 alone.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('MK2206/BEZ235', 'Var', (0, 13))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('BEZ235', 'Chemical', 'MESH:C531198', (7, 13))	('tumor', 'Disease', (46, 51))	('BEZ235', 'Chemical', 'MESH:C531198', (74, 80))	('MK2206', 'Chemical', 'MESH:C548887', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
246856	31571914	The enhanced efficacy of the combination was associated with the inhibition of phosphorylation ATK on both Thr308 and Ser473.	('inhibition', 'NegReg', (65, 75))	('Ser473', 'Var', (118, 124))	('enhanced', 'PosReg', (4, 12))	('efficacy', 'MPA', (13, 21))	('Ser', 'Chemical', 'MESH:C530429', (118, 121))	('phosphorylation ATK', 'MPA', (79, 98))	('phospho', 'Chemical', 'MESH:C033601', (79, 86))
246857	31571914	The combination of MK2206 and BEZ235 exhibits potent antitumor effects and may have important clinical applications for esophageal SCC treatment.	('BEZ235', 'Chemical', 'MESH:C531198', (30, 36))	('BEZ235', 'Var', (30, 36))	('esophageal SCC', 'Disease', 'MESH:C562729', (120, 134))	('MK2206', 'Var', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('esophageal SCC', 'Disease', (120, 134))	('tumor', 'Disease', (57, 62))	('MK2206', 'Chemical', 'MESH:C548887', (19, 25))
246863	31571914	The highly selective AKT inhibitor MK2206 has shown antitumor effects by promoting dephosphorylation of AKT in breast, gastric, neuroendocrine, endometrial, and other cancers.	('neuroendocrine', 'Disease', (128, 142))	('gastric', 'Disease', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('promoting', 'PosReg', (73, 82))	('breast', 'Disease', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('phospho', 'Chemical', 'MESH:C033601', (85, 92))	('tumor', 'Disease', (56, 61))	('dephosphorylation', 'MPA', (83, 100))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('MK2206', 'Chemical', 'MESH:C548887', (35, 41))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('endometrial', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('AKT', 'Pathway', (104, 107))	('MK2206', 'Var', (35, 41))
246865	31571914	Both MK2206 and BEZ235 have proven to be competitive candidates for cancer therapy in clinical trials.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('MK2206', 'Var', (5, 11))	('BEZ235', 'Var', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('BEZ235', 'Chemical', 'MESH:C531198', (16, 22))	('MK2206', 'Chemical', 'MESH:C548887', (5, 11))
246867	31571914	As a dual PI3K and mTORC1/2 inhibitor, BEZ235 may show greater antitumor activity because blocking PI3K can initiate mTOR inhibition and compensatory activation of AKT.	('PI3K', 'Var', (99, 103))	('mTOR', 'Pathway', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('activation', 'PosReg', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('inhibition', 'NegReg', (122, 132))	('AKT', 'Pathway', (164, 167))	('mTORC1/2', 'Gene', '74343;382056', (19, 27))	('blocking PI3K', 'Var', (90, 103))	('tumor', 'Disease', (67, 72))	('BEZ235', 'Chemical', 'MESH:C531198', (39, 45))	('mTORC1/2', 'Gene', (19, 27))
246868	31571914	The combination of MK2206 with trastuzumab, mitogen-activated protein kinase (MEK) inhibitor AZD6244, farnesyltransferase FTI-2153 all showed high efficacy both in vitro and in vivo.	('MEK', 'Gene', (78, 81))	('MEK', 'Gene', '5609', (78, 81))	('AZD6244', 'Chemical', 'MESH:C517975', (93, 100))	('MK2206', 'Var', (19, 25))	('mitogen-activated protein kinase', 'Gene', (44, 76))	('mitogen-activated protein kinase', 'Gene', '5609', (44, 76))	('combination', 'Interaction', (4, 15))	('MK2206', 'Chemical', 'MESH:C548887', (19, 25))
246870	31571914	MK2206 or BEZ235 in combination with an mTOR inhibitor, such as rapamycin and everolimus, exerts synergistic antitumor activity in preclinical cancer models.	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('BEZ235', 'Var', (10, 16))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('BEZ235', 'Chemical', 'MESH:C531198', (10, 16))	('everolimus', 'Chemical', 'MESH:C107135', (78, 88))	('rapamycin', 'Chemical', 'MESH:D020123', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('MK2206', 'Var', (0, 6))
246871	31571914	Overall, these results suggest that the combination of MK2206 and BEZ235 might have synergistic antitumor effects.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BEZ235', 'Gene', (66, 72))	('tumor', 'Disease', (100, 105))	('BEZ235', 'Chemical', 'MESH:C531198', (66, 72))	('MK2206', 'Chemical', 'MESH:C548887', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('MK2206', 'Var', (55, 61))
246874	31571914	We also investigated the antitumor effects of MK2206 and BEZ235 alone and in combination in esophageal SCC cell lines and xenograft animal model.	('esophageal SCC', 'Disease', 'MESH:C562729', (92, 106))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('MK2206', 'Var', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('investigated', 'Reg', (8, 20))	('esophageal SCC', 'Disease', (92, 106))	('tumor', 'Disease', (29, 34))	('MK2206', 'Chemical', 'MESH:C548887', (46, 52))	('BEZ235', 'Chemical', 'MESH:C531198', (57, 63))
246897	31571914	Results showed that compared to the HET-1A normal esophageal cell line, the esophageal SCC cell lines (KYSE 70, KYSE 150, KYWE 270, KYSE 410) exhibited elevated expression of p-AKTT308, p-mTORS2448, p100alpha PI3K, p110beta PI3K, and p85 PI3K (Figure 1A).	('p85', 'Gene', '5296', (234, 237))	('p110beta', 'Gene', '5291', (215, 223))	('elevated', 'PosReg', (152, 160))	('esophageal SCC', 'Disease', (76, 90))	('expression', 'MPA', (161, 171))	('p110beta', 'Gene', (215, 223))	('p-AKTT308', 'Var', (175, 184))	('p-mTORS2448', 'Var', (186, 197))	('p85', 'Gene', (234, 237))	('p100alpha PI3K', 'Var', (199, 213))	('esophageal SCC', 'Disease', 'MESH:C562729', (76, 90))
246900	31571914	Next, we examined the inhibitory effects of MK2206 or BEZ235 on proliferation of esophageal SCC cell lines.	('MK2206', 'Chemical', 'MESH:C548887', (44, 50))	('rat', 'Species', '10116', (71, 74))	('esophageal SCC', 'Disease', 'MESH:C562729', (81, 95))	('MK2206', 'Var', (44, 50))	('esophageal SCC', 'Disease', (81, 95))	('BEZ235', 'Chemical', 'MESH:C531198', (54, 60))
246901	31571914	Results highlighted that MK2206 and BEZ235 significantly inhibited cell proliferation in KYSE150 (Figure 2A and B).	('BEZ235', 'Var', (36, 42))	('MK2206', 'Chemical', 'MESH:C548887', (25, 31))	('inhibited', 'NegReg', (57, 66))	('cell proliferation in KYSE150', 'CPA', (67, 96))	('rat', 'Species', '10116', (79, 82))	('MK2206', 'Var', (25, 31))	('BEZ235', 'Chemical', 'MESH:C531198', (36, 42))
246902	31571914	Specifically, both p-AKTT308 and p-AKTS473 were significantly decreased after MK2206 treatment, but p-AKTS473 was less decreased than p-AKTT308.	('decreased', 'NegReg', (62, 71))	('p-AKTS473', 'Var', (33, 42))	('MK2206', 'Var', (78, 84))	('p-AKTT308', 'Var', (19, 28))	('MK2206', 'Chemical', 'MESH:C548887', (78, 84))
246903	31571914	In accordance with these results, the p-S6 was decreased by MK2206.	('p-S6', 'Gene', (38, 42))	('MK2206', 'Var', (60, 66))	('p-S6', 'Gene', '338413', (38, 42))	('MK2206', 'Chemical', 'MESH:C548887', (60, 66))	('decreased', 'NegReg', (47, 56))
246905	31571914	p-AKTT308, p-AKTS473, p-mTOR, and p-P70S6K were all significantly decreased after BEZ235 treatment (Figure 2D).	('P70S6K', 'Gene', '6198', (36, 42))	('BEZ235', 'Chemical', 'MESH:C531198', (82, 88))	('decreased', 'NegReg', (66, 75))	('P70S6K', 'Gene', (36, 42))	('p-AKTT308', 'Var', (0, 9))	('p-mTOR', 'MPA', (22, 28))	('BEZ235', 'Gene', (82, 88))	('p-AKTS473', 'Var', (11, 20))
246906	31571914	Moreover, compared with MK2206, p-AKTS473, p-mTOR, and p-P70S6K decreased more after BEZ235 treatment.	('BEZ235', 'Chemical', 'MESH:C531198', (85, 91))	('BEZ235', 'Var', (85, 91))	('MK2206', 'Chemical', 'MESH:C548887', (24, 30))	('P70S6K', 'Gene', (57, 63))	('p-AKTS473', 'Var', (32, 41))	('P70S6K', 'Gene', '6198', (57, 63))	('decreased', 'NegReg', (64, 73))
246907	31571914	We next determined whether MK2206 or BEZ235 increased apoptosis in esophageal cancer cells.	('apoptosis', 'CPA', (54, 63))	('MK2206', 'Var', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('MK2206', 'Chemical', 'MESH:C548887', (27, 33))	('esophageal cancer', 'Disease', (67, 84))	('BEZ235', 'Var', (37, 43))	('increased', 'PosReg', (44, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('BEZ235', 'Chemical', 'MESH:C531198', (37, 43))
246909	31571914	Results showed that both MK2206 and BEZ235 induced cell apoptosis dose-dependently.	('BEZ235', 'Var', (36, 42))	('MK2206', 'Chemical', 'MESH:C548887', (25, 31))	('MK2206', 'Var', (25, 31))	('cell apoptosis', 'CPA', (51, 65))	('BEZ235', 'Chemical', 'MESH:C531198', (36, 42))
246910	31571914	The 3 muM dose of MK2206 and the 10 nM dose of BEZ235 both independently induced significant apoptosis in KYSE150 cells (Figure 3A and B).	('BEZ235', 'Chemical', 'MESH:C531198', (47, 53))	('MK2206', 'Chemical', 'MESH:C548887', (18, 24))	('apoptosis', 'CPA', (93, 102))	('MK2206', 'Var', (18, 24))	('induced', 'Reg', (73, 80))
246912	31571914	The decreased MCL-1 and increased cleaved-caspase-3 were in line with increased apoptosis after MK2206 or BEZ235 treatment (Figure 3C and D).	('MCL-1', 'Gene', '4170', (14, 19))	('decreased', 'NegReg', (4, 13))	('MCL-1', 'Gene', (14, 19))	('MK2206', 'Chemical', 'MESH:C548887', (96, 102))	('BEZ235', 'Chemical', 'MESH:C531198', (106, 112))	('caspase-3', 'Gene', '836', (42, 51))	('decreased MCL', 'Phenotype', 'HP:0025066', (4, 17))	('MK2206', 'Var', (96, 102))	('increased', 'PosReg', (24, 33))	('caspase-3', 'Gene', (42, 51))
246913	31571914	As indicated in Figure 4A and B, MK2206 or BEZ235 treatment resulted in the accumulation of KYSE150 in the G2/M phase.	('MK2206', 'Var', (33, 39))	('accumulation', 'PosReg', (76, 88))	('BEZ235', 'Gene', (43, 49))	('MK2206', 'Chemical', 'MESH:C548887', (33, 39))	('KYSE150', 'MPA', (92, 99))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))
246914	31571914	Western blot analyses showed that cell cycle checkpoint proteins SKP2, CDK2 and cyclin D1 were decreased after MK2206 or BEZ235 treatment (Figure 4C and D).	('decreased', 'NegReg', (95, 104))	('SKP2', 'Gene', (65, 69))	('CDK2', 'Gene', '1017', (71, 75))	('cyclin D1', 'Gene', (80, 89))	('BEZ235', 'Gene', (121, 127))	('MK2206', 'Chemical', 'MESH:C548887', (111, 117))	('BEZ235', 'Chemical', 'MESH:C531198', (121, 127))	('SKP2', 'Gene', '6502', (65, 69))	('cell cycle checkpoint proteins', 'MPA', (34, 64))	('MK2206', 'Var', (111, 117))	('cyclin D1', 'Gene', '595', (80, 89))	('CDK2', 'Gene', (71, 75))
246915	31571914	Given that the combination of inhibitors targeted more than one molecule in a signaling pathway, we examined the efficiency of the combination of MK2206/BEZ235 in esophageal cancer cells.	('targeted', 'Reg', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('esophageal cancer', 'Disease', (163, 180))	('MK2206', 'Chemical', 'MESH:C548887', (146, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('MK2206/BEZ235', 'Var', (146, 159))	('BEZ235', 'Chemical', 'MESH:C531198', (153, 159))
246917	31571914	Our results showed that the combination of MK2206 and BEZ235 significantly inhibited cell proliferation compared with the high dose of MK2206 or BEZ235 alone in KYSE 150 (Figure 5A).	('BEZ235', 'Chemical', 'MESH:C531198', (54, 60))	('rat', 'Species', '10116', (97, 100))	('cell proliferation', 'CPA', (85, 103))	('MK2206', 'Var', (43, 49))	('inhibited', 'NegReg', (75, 84))	('MK2206', 'Chemical', 'MESH:C548887', (135, 141))	('MK2206', 'Chemical', 'MESH:C548887', (43, 49))	('BEZ235', 'Chemical', 'MESH:C531198', (145, 151))	('BEZ235', 'Var', (54, 60))
246918	31571914	Western blot analyses further showed that expression of p-AKTT308, p-AKTS473, and p-mTOR decreased more by MK2206 plus BEZ235 compared to MK2206 or BEZ235 alone (Figure 5B).	('BEZ235', 'Var', (119, 125))	('BEZ235', 'Chemical', 'MESH:C531198', (119, 125))	('MK2206', 'Chemical', 'MESH:C548887', (107, 113))	('expression', 'MPA', (42, 52))	('p-AKTS473', 'Var', (67, 76))	('MK2206', 'Chemical', 'MESH:C548887', (138, 144))	('p-AKTT308', 'Var', (56, 65))	('BEZ235', 'Chemical', 'MESH:C531198', (148, 154))	('p-mTOR', 'Gene', (82, 88))	('MK2206 plus BEZ235', 'Var', (107, 125))	('decreased', 'NegReg', (89, 98))
246919	31571914	We next determined whether the combination of MK2206 and BEZ235 induces apoptosis and cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('induces', 'Reg', (64, 71))	('MK2206', 'Var', (46, 52))	('cell cycle arrest', 'CPA', (86, 103))	('MK2206', 'Chemical', 'MESH:C548887', (46, 52))	('apoptosis', 'CPA', (72, 81))	('BEZ235', 'Gene', (57, 63))	('BEZ235', 'Chemical', 'MESH:C531198', (57, 63))
246920	31571914	Results showed that 20 muM MK2206, 1000 nM BEZ235, and the combination of 3 muM MK2206 plus 100 nM BEZ235 induced cell apoptosis by 22.5%, 30.8%, and 42.3% in KYSE 150, respectively (Figure 5C).	('MK2206', 'Chemical', 'MESH:C548887', (27, 33))	('MK2206', 'Var', (80, 86))	('MK2206', 'Chemical', 'MESH:C548887', (80, 86))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))	('MK2206', 'Var', (27, 33))	('cell apoptosis', 'CPA', (114, 128))	('BEZ235', 'Chemical', 'MESH:C531198', (99, 105))
246921	31571914	In cells treated with MK2206 or BEZ235 alone, we showed an increased number of cells in G2/M phase (Figure 5D).	('MK2206', 'Var', (22, 28))	('G2/M phase', 'CPA', (88, 98))	('BEZ235', 'Var', (32, 38))	('MK2206', 'Chemical', 'MESH:C548887', (22, 28))	('increased', 'PosReg', (59, 68))	('BEZ235', 'Chemical', 'MESH:C531198', (32, 38))
246922	31571914	Our data showed that 20 muM MK2206, 1000 nM BEZ235, and 3 muM MK2206+100 nM BEZ235 led to 5.2%, 28.7%, and 33.5% of the cells accumulated in the G2/M phase, respectively.	('BEZ235', 'Chemical', 'MESH:C531198', (44, 50))	('MK2206', 'Chemical', 'MESH:C548887', (28, 34))	('MK2206', 'Chemical', 'MESH:C548887', (62, 68))	('BEZ235', 'Chemical', 'MESH:C531198', (76, 82))	('MK2206+100', 'Var', (62, 72))	('MK2206', 'Var', (28, 34))
246923	31571914	We also examined whether the MK2206/BEZ235 combination had better antitumor effects than the single inhibitor in a KYSE 150 xenograft mouse model in vivo.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('MK2206', 'Chemical', 'MESH:C548887', (29, 35))	('MK2206/BEZ235', 'Var', (29, 42))	('BEZ235', 'Chemical', 'MESH:C531198', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mouse', 'Species', '10090', (134, 139))
246924	31571914	As shown in Figure 6, MK2206 or BEZ235 alone only showed a slight inhibition of tumor growth, which was not significant compared to the control animals.	('MK2206', 'Chemical', 'MESH:C548887', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('MK2206', 'Var', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('BEZ235', 'Var', (32, 38))	('inhibition', 'NegReg', (66, 76))	('BEZ235', 'Chemical', 'MESH:C531198', (32, 38))
246925	31571914	The combination of MK2206 and BEZ235 at lower dose, however, significantly inhibited tumor growth compared to the control animals.	('tumor', 'Disease', (85, 90))	('BEZ235', 'Chemical', 'MESH:C531198', (30, 36))	('MK2206', 'Var', (19, 25))	('inhibited', 'NegReg', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('BEZ235', 'Var', (30, 36))	('MK2206', 'Chemical', 'MESH:C548887', (19, 25))
246926	31571914	Combined with the in vitro study, these results verify the efficacy of the combination of MK2206 and BEZ235 on apoptosis and tumor inhibition in esophageal SCC.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('esophageal SCC', 'Disease', (145, 159))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MK2206', 'Chemical', 'MESH:C548887', (90, 96))	('tumor', 'Disease', (125, 130))	('esophageal SCC', 'Disease', 'MESH:C562729', (145, 159))	('MK2206', 'Var', (90, 96))	('apoptosis', 'CPA', (111, 120))	('BEZ235', 'Chemical', 'MESH:C531198', (101, 107))
246929	31571914	Furthermore, results show that MK2206 and BEZ235 inhibit proliferation, increase apoptosis, and induce cell cycle arrest in esophageal SCC.	('BEZ235', 'Var', (42, 48))	('increase', 'PosReg', (72, 80))	('MK2206', 'Chemical', 'MESH:C548887', (31, 37))	('esophageal SCC', 'Disease', (124, 138))	('induce', 'Reg', (96, 102))	('cell cycle arrest', 'CPA', (103, 120))	('apoptosis', 'CPA', (81, 90))	('BEZ235', 'Chemical', 'MESH:C531198', (42, 48))	('rat', 'Species', '10116', (64, 67))	('proliferation', 'CPA', (57, 70))	('esophageal SCC', 'Disease', 'MESH:C562729', (124, 138))	('MK2206', 'Var', (31, 37))	('inhibit', 'NegReg', (49, 56))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (103, 120))
246930	31571914	More importantly, the combination of MK2206 and BEZ235 exhibits enhanced antitumor effects as compared to MK2206 or BEZ235 alone.	('BEZ235', 'Chemical', 'MESH:C531198', (116, 122))	('BEZ235', 'Var', (48, 54))	('MK2206', 'Chemical', 'MESH:C548887', (106, 112))	('MK2206', 'Var', (37, 43))	('BEZ235', 'Chemical', 'MESH:C531198', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MK2206', 'Chemical', 'MESH:C548887', (37, 43))	('tumor', 'Disease', (77, 82))	('enhanced', 'PosReg', (64, 72))
246932	31571914	Phosphorylations at Thr308 and at Ser473 are both necessary for fully AKT activation.	('activation', 'PosReg', (74, 84))	('Ser', 'Chemical', 'MESH:C530429', (34, 37))	('Thr308', 'Var', (20, 26))
246933	31571914	Activated AKT can phosphorylate multiple substrates to regulate cellular processes, including proliferation, survival, motility, angiogenesis, and metabolism/glucose homeostasis Our results show that both MK2206 and BEZ235 inhibit esophageal SCC cell proliferation, increase apoptosis and that is associated with G2/M cell cycle accumulation.	('BEZ235', 'Var', (216, 222))	('rat', 'Species', '10116', (46, 49))	('rat', 'Species', '10116', (101, 104))	('esophageal SCC', 'Disease', 'MESH:C562729', (231, 245))	('MK2206', 'Var', (205, 211))	('BEZ235', 'Chemical', 'MESH:C531198', (216, 222))	('increase', 'PosReg', (266, 274))	('apoptosis', 'CPA', (275, 284))	('MK2206', 'Chemical', 'MESH:C548887', (205, 211))	('esophageal SCC', 'Disease', (231, 245))	('glucose', 'Chemical', 'MESH:D005947', (158, 165))	('rat', 'Species', '10116', (258, 261))	('phospho', 'Chemical', 'MESH:C033601', (18, 25))	('G2/M cell cycle accumulation', 'CPA', (313, 341))	('inhibit', 'NegReg', (223, 230))
246934	31571914	MK2206 and BEZ235 may inhibit AKT phosphorylations at Thr308 and Ser473.	('BEZ235', 'Var', (11, 17))	('inhibit', 'NegReg', (22, 29))	('AKT', 'Pathway', (30, 33))	('Ser', 'Chemical', 'MESH:C530429', (65, 68))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('Thr308', 'Var', (54, 60))	('BEZ235', 'Chemical', 'MESH:C531198', (11, 17))	('MK2206', 'Var', (0, 6))	('phospho', 'Chemical', 'MESH:C033601', (34, 41))	('Ser473', 'Var', (65, 71))
246935	31571914	Specifically, the expression levels of SKP2, MCL-1, and cyclin D1 are suppressed by MK2206 or BEZ235 treatment.	('SKP2', 'Gene', '6502', (39, 43))	('expression levels', 'MPA', (18, 35))	('MK2206', 'Var', (84, 90))	('MCL-1', 'Gene', '4170', (45, 50))	('MCL-1', 'Gene', (45, 50))	('suppressed', 'NegReg', (70, 80))	('MK2206', 'Chemical', 'MESH:C548887', (84, 90))	('SKP2', 'Gene', (39, 43))	('BEZ235', 'Chemical', 'MESH:C531198', (94, 100))	('cyclin D1', 'Gene', '595', (56, 65))	('cyclin D1', 'Gene', (56, 65))
246938	31571914	MCL-1 inhibits apoptotic cell death through ligation of the proapoptotic Bcl-2 family member Bak.	('apoptotic cell death', 'CPA', (15, 35))	('inhibits', 'NegReg', (6, 14))	('Bcl-2', 'Gene', (73, 78))	('ligation', 'Var', (44, 52))	('Bcl-2', 'Gene', '596', (73, 78))	('MCL-1', 'Gene', '4170', (0, 5))	('MCL-1', 'Gene', (0, 5))	('Bak', 'Gene', (93, 96))
246939	31571914	MCL can lead to constitutive transcription of cyclin D1, one of the cell cycle regulatory switches in actively proliferating cells Apoptosis and cell proliferation are linked by cell-cycle regulators such as cyclins and CDKs.	('cyclin D1', 'Gene', '595', (46, 55))	('CDKs', 'Gene', '983;1017', (220, 224))	('rat', 'Species', '10116', (118, 121))	('cyclin D1', 'Gene', (46, 55))	('CDKs', 'Gene', (220, 224))	('rat', 'Species', '10116', (157, 160))	('lead to', 'Reg', (8, 15))	('MCL', 'Var', (0, 3))
246940	31571914	Our data indicate that MK2206 and BEZ235 impact cell cycle and apoptosis, at least in part, through modulating cell-cycle regulators.	('MK2206', 'Chemical', 'MESH:C548887', (23, 29))	('BEZ235', 'Var', (34, 40))	('BEZ235', 'Chemical', 'MESH:C531198', (34, 40))	('cell cycle', 'CPA', (48, 58))	('cell-cycle regulators', 'MPA', (111, 132))	('modulating', 'Reg', (100, 110))	('MK2206', 'Var', (23, 29))	('apoptosis', 'CPA', (63, 72))	('impact', 'Reg', (41, 47))
246941	31571914	MK2206 binds to PH domain and it does not interact with the ATP-binding pocket to prevent the AKT membrane translocation and subsequent activation.	('ATP', 'Chemical', 'MESH:D000255', (60, 63))	('binds', 'Interaction', (7, 12))	('prevent', 'NegReg', (82, 89))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('activation', 'PosReg', (136, 146))	('MK2206', 'Var', (0, 6))	('AKT', 'Pathway', (94, 97))
246942	31571914	We found that the phosphorylation of AKT at Thr308 is significantly reduced by MK2206.	('AKT', 'Pathway', (37, 40))	('MK2206', 'Chemical', 'MESH:C548887', (79, 85))	('phosphorylation', 'MPA', (18, 33))	('reduced', 'NegReg', (68, 75))	('MK2206', 'Var', (79, 85))	('phospho', 'Chemical', 'MESH:C033601', (18, 25))
246943	31571914	S6 is a ribosomal protein, the downstream effector of AKT, which is inhibited by MK2206 in esophageal cancer cells.	('MK2206', 'Chemical', 'MESH:C548887', (81, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MK2206', 'Var', (81, 87))	('inhibited', 'NegReg', (68, 77))	('esophageal cancer', 'Disease', (91, 108))
246944	31571914	The phosphorylation of AKT at Ser473 was only slightly reduced by MK2206.	('AKT', 'Pathway', (23, 26))	('reduced', 'NegReg', (55, 62))	('MK2206', 'Chemical', 'MESH:C548887', (66, 72))	('phosphorylation', 'MPA', (4, 19))	('phospho', 'Chemical', 'MESH:C033601', (4, 11))	('MK2206', 'Var', (66, 72))	('Ser', 'Chemical', 'MESH:C530429', (30, 33))
246945	31571914	As we mentioned earlier, phosphorylation at Thr308 and at Ser473 is both necessary for full AKT activation.	('Ser', 'Chemical', 'MESH:C530429', (58, 61))	('AKT', 'Pathway', (92, 95))	('phospho', 'Chemical', 'MESH:C033601', (25, 32))	('phosphorylation', 'Var', (25, 40))	('activation', 'PosReg', (96, 106))
246946	31571914	A slight inhibition of phosphorylation at Ser473 may explain the less encouraging clinical benefits observed for single treatment of MK2206.	('inhibition', 'NegReg', (9, 19))	('MK2206', 'Chemical', 'MESH:C548887', (133, 139))	('phosphorylation', 'MPA', (23, 38))	('phospho', 'Chemical', 'MESH:C033601', (23, 30))	('Ser', 'Chemical', 'MESH:C530429', (42, 45))	('Ser473', 'Var', (42, 48))
246947	31571914	As a dual PI3K-mTOR inhibitor, BEZ235 inhibits the activity of PI3K and mTORC1 as well as mTORC2.	('activity', 'MPA', (51, 59))	('BEZ235', 'Var', (31, 37))	('inhibits', 'NegReg', (38, 46))	('mTORC1', 'Gene', '382056', (72, 78))	('BEZ235', 'Chemical', 'MESH:C531198', (31, 37))	('PI3K', 'Pathway', (63, 67))	('mTORC2', 'Gene', '74343', (90, 96))	('mTORC2', 'Gene', (90, 96))	('mTORC1', 'Gene', (72, 78))
246948	31571914	P70S6K, the downstream effector of mTOR is significantly decreased by BEZ235, which indicates mTOR inhibition role of BEZ235 in esophageal SCC.	('BEZ235', 'Var', (70, 76))	('esophageal SCC', 'Disease', (128, 142))	('P70S6K', 'Gene', '6198', (0, 6))	('BEZ235', 'Chemical', 'MESH:C531198', (70, 76))	('P70S6K', 'Gene', (0, 6))	('BEZ235', 'Chemical', 'MESH:C531198', (118, 124))	('esophageal SCC', 'Disease', 'MESH:C562729', (128, 142))	('decreased', 'NegReg', (57, 66))
246949	31571914	Our results show that compared with MK2206, BEZ235 inhibits AKT phosphorylation at Thr308 and Ser473, and decreases the phosphorylation of mTOR significantly.	('BEZ235', 'Chemical', 'MESH:C531198', (44, 50))	('inhibits', 'NegReg', (51, 59))	('AKT', 'Pathway', (60, 63))	('phosphorylation', 'MPA', (120, 135))	('phospho', 'Chemical', 'MESH:C033601', (64, 71))	('Ser', 'Chemical', 'MESH:C530429', (94, 97))	('phospho', 'Chemical', 'MESH:C033601', (120, 127))	('mTOR', 'MPA', (139, 143))	('MK2206', 'Chemical', 'MESH:C548887', (36, 42))	('BEZ235', 'Var', (44, 50))	('decreases', 'NegReg', (106, 115))	('Ser473', 'Var', (94, 100))
246953	31571914	After being fully activated, AKT mediates the phosphorylation of TSC2 to inhibit the TSC1/2 complex then activates mTORC1 signaling.The inhibition of mTOR could induce insulin receptor substrate-1 expression to activate AKT.	('mTORC1', 'Gene', (115, 121))	('TSC2', 'Gene', '7249', (65, 69))	('induce', 'Reg', (161, 167))	('inhibition', 'Var', (136, 146))	('phospho', 'Chemical', 'MESH:C033601', (46, 53))	('TSC2', 'Gene', (65, 69))	('TSC1/2', 'Gene', '7248;7249', (85, 91))	('AKT', 'Pathway', (220, 223))	('mTORC1', 'Gene', '382056', (115, 121))	('TSC1/2', 'Gene', (85, 91))	('insulin receptor substrate-1', 'Gene', (168, 196))	('activate', 'PosReg', (211, 219))	('insulin receptor substrate-1', 'Gene', '3667', (168, 196))	('expression', 'MPA', (197, 207))	('mTOR', 'Gene', (150, 154))
246954	31571914	When p-mTOR is blocked in parallel with the inhibition of AKT phosphorylations at Thr308 and Ser473, BEZ235 at nmol level shows better inhibition on cell proliferation, apoptosis, and cell cycle arrest than MK2206 at mmol level.	('apoptosis', 'CPA', (169, 178))	('Ser473', 'Var', (93, 99))	('inhibition', 'NegReg', (135, 145))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (184, 201))	('cell cycle arrest', 'CPA', (184, 201))	('Ser', 'Chemical', 'MESH:C530429', (93, 96))	('phospho', 'Chemical', 'MESH:C033601', (62, 69))	('Thr308', 'Var', (82, 88))	('cell proliferation', 'CPA', (149, 167))	('BEZ235', 'Var', (101, 107))	('rat', 'Species', '10116', (161, 164))	('AKT', 'Protein', (58, 61))	('MK2206', 'Chemical', 'MESH:C548887', (207, 213))	('BEZ235', 'Chemical', 'MESH:C531198', (101, 107))
246955	31571914	The xenograft mouse model analysis also shows reduced tumor size in the BEZ235 treatment group than MK2206 treatment group, although the difference did not reach statistical significance.	('mouse', 'Species', '10090', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('MK2206', 'Chemical', 'MESH:C548887', (100, 106))	('BEZ235', 'Chemical', 'MESH:C531198', (72, 78))	('BEZ235', 'Var', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('reduced', 'NegReg', (46, 53))	('tumor', 'Disease', (54, 59))
246956	31571914	When combined with other chemotherapy or target therapy, MK2206 and BEZ235 have shown encouraging efficacy in several cancers both in vitro and in vivo.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('BEZ235', 'Chemical', 'MESH:C531198', (68, 74))	('MK2206', 'Var', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MK2206', 'Chemical', 'MESH:C548887', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
246957	31571914	In this study, we investigated the efficacy of MK2206/BEZ235 combination in esophageal SCC.	('MK2206/BEZ235', 'Var', (47, 60))	('esophageal SCC', 'Disease', (76, 90))	('esophageal SCC', 'Disease', 'MESH:C562729', (76, 90))	('BEZ235', 'Chemical', 'MESH:C531198', (54, 60))	('MK2206', 'Chemical', 'MESH:C548887', (47, 53))
246958	31571914	Our study verifies increased antitumor efficacy in MK2206/BEZ235 combination compared with MK2206 or BEZ235 alone in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('BEZ235', 'Chemical', 'MESH:C531198', (58, 64))	('MK2206', 'Chemical', 'MESH:C548887', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('increased', 'PosReg', (19, 28))	('tumor', 'Disease', (33, 38))	('MK2206/BEZ235', 'Gene', (51, 64))	('MK2206/BEZ235', 'Var', (51, 64))	('MK2206', 'Chemical', 'MESH:C548887', (91, 97))	('BEZ235', 'Chemical', 'MESH:C531198', (101, 107))
246959	31571914	The combination of MK2206 and BEZ235 shows better inhibition effects on phosphorylation of AKT at Thr308 and Ser473.	('BEZ235', 'Chemical', 'MESH:C531198', (30, 36))	('AKT', 'Pathway', (91, 94))	('MK2206', 'Var', (19, 25))	('inhibition', 'NegReg', (50, 60))	('Ser473', 'Var', (109, 115))	('phosphorylation', 'MPA', (72, 87))	('phospho', 'Chemical', 'MESH:C033601', (72, 79))	('BEZ235', 'Var', (30, 36))	('Ser', 'Chemical', 'MESH:C530429', (109, 112))	('MK2206', 'Chemical', 'MESH:C548887', (19, 25))
246961	31571914	Blocking the PI3K/AKT/mTOR pathway by MK2206 and BEZ235 could inhibit cell proliferation, induce cell apoptosis and cause cell cycle arrest through the inhibition of AKT phosphorylation, and downstream effectors SKP2, MCL-1, and cyclin D1.	('inhibition', 'NegReg', (152, 162))	('SKP2', 'Gene', '6502', (212, 216))	('induce', 'PosReg', (90, 96))	('BEZ235', 'Chemical', 'MESH:C531198', (49, 55))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('MK2206', 'Var', (38, 44))	('inhibit', 'NegReg', (62, 69))	('cyclin D1', 'Gene', (229, 238))	('cell apoptosis', 'CPA', (97, 111))	('cause', 'Reg', (116, 121))	('cyclin D1', 'Gene', '595', (229, 238))	('BEZ235', 'Var', (49, 55))	('cell proliferation', 'CPA', (70, 88))	('MCL-1', 'Gene', '4170', (218, 223))	('AKT', 'Pathway', (166, 169))	('cell cycle arrest', 'CPA', (122, 139))	('MK2206', 'Chemical', 'MESH:C548887', (38, 44))	('PI3K/AKT/mTOR pathway', 'Pathway', (13, 34))	('phospho', 'Chemical', 'MESH:C033601', (170, 177))	('MCL-1', 'Gene', (218, 223))	('rat', 'Species', '10116', (82, 85))	('SKP2', 'Gene', (212, 216))
246962	31571914	The combination of MK2206 and BEZ235 showed better antitumor effects than MK2206 or BEZ235 alone.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('BEZ235', 'Chemical', 'MESH:C531198', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MK2206', 'Var', (19, 25))	('tumor', 'Disease', (55, 60))	('BEZ235', 'Chemical', 'MESH:C531198', (84, 90))	('BEZ235', 'Var', (30, 36))	('MK2206', 'Chemical', 'MESH:C548887', (74, 80))	('MK2206', 'Chemical', 'MESH:C548887', (19, 25))
246963	31571914	The inhibition on phosphorylation ATK on Thr308 and Ser473 is critical for the antitumor effects in esophageal SCC.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('esophageal SCC', 'Disease', 'MESH:C562729', (100, 114))	('esophageal SCC', 'Disease', (100, 114))	('tumor', 'Disease', (83, 88))	('phosphorylation', 'MPA', (18, 33))	('Ser', 'Chemical', 'MESH:C530429', (52, 55))	('Ser473', 'Var', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('phospho', 'Chemical', 'MESH:C033601', (18, 25))	('Thr308', 'Var', (41, 47))
246964	31571914	The better efficacy of MK2206/BEZ235 combination is associated with the inhibition of phosphorylation ATK on Thr308 and Ser473.	('MK2206/BEZ235', 'Var', (23, 36))	('BEZ235', 'Chemical', 'MESH:C531198', (30, 36))	('Ser', 'Chemical', 'MESH:C530429', (120, 123))	('MK2206', 'Chemical', 'MESH:C548887', (23, 29))	('Ser473', 'Var', (120, 126))	('phosphorylation ATK', 'MPA', (86, 105))	('phospho', 'Chemical', 'MESH:C033601', (86, 93))	('inhibition', 'NegReg', (72, 82))
246965	31571914	This study importantly has clinical application for MK2206/BEZ235 combination treatment in esophageal SCC.	('esophageal SCC', 'Disease', 'MESH:C562729', (91, 105))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('BEZ235', 'Chemical', 'MESH:C531198', (59, 65))	('esophageal SCC', 'Disease', (91, 105))	('MK2206/BEZ235', 'Var', (52, 65))
246975	30997729	Helical tomotherapy (HT) is a dose delivery technique, in which the treatment couch moves in the direction of the gantry rotation axis, and the high-speed driving of 64 multileaf collimators allow the fluence to be finely modulated.1 Studies have shown that HT and volume-modulated arc radiotherapy help improve the dose concentration at the target for cervical esophageal cancers.2, 3, 4, 5 However, their use may increase the risk of radiation pneumonitis and pulmonary complications compared to using three-dimensional (3D) conformal radiation therapy or intensity modulated radiotherapy, because of the increased low-dose area in the lung.6, 7, 8 Nomura et al6 reported that the volumes receiving at least 5, 10, 15, and 20 Gy (V5Gy, V10Gy, V15Gy, and V20Gy, respectively) and mean lung dose were significantly associated with the development of symptomatic radiation pneumonitis.	('pneumonitis', 'Disease', 'MESH:D011014', (872, 883))	('pulmonary complications', 'Phenotype', 'HP:0006532', (462, 485))	('rotation axis', 'Disease', 'MESH:C566610', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('pneumonitis', 'Disease', 'MESH:D011014', (446, 457))	('pulmonary complications', 'Disease', (462, 485))	('cancers', 'Phenotype', 'HP:0002664', (373, 380))	('pulmonary complications', 'Disease', 'MESH:D008171', (462, 485))	('V20Gy', 'Var', (756, 761))	('cervical esophageal cancers', 'Disease', 'MESH:D004938', (353, 380))	('rotation axis', 'Disease', (121, 134))	('pneumonitis', 'Disease', (872, 883))	('V15Gy', 'Var', (745, 750))	('pneumonitis', 'Disease', (446, 457))	('cervical esophageal cancers', 'Disease', (353, 380))	('V10Gy', 'Var', (738, 743))	('associated', 'Reg', (815, 825))
247027	31031809	ESCC patients with a high level of GASC1 presented a significantly worse survival rate.	('survival', 'MPA', (73, 81))	('patients', 'Species', '9606', (5, 13))	('worse', 'NegReg', (67, 72))	('GASC1', 'Var', (35, 40))
247028	31031809	Furthermore, blockade of GASC1 decreased NOTCH1 expression via increase of NOTCH1 promoter H3K9me2 and H3K9me3.	('GASC1', 'Gene', (25, 30))	('increase', 'PosReg', (63, 71))	('blockade', 'Var', (13, 21))	('NOTCH1', 'Gene', '4851', (75, 81))	('NOTCH1', 'Gene', (75, 81))	('expression', 'MPA', (48, 58))	('decreased', 'NegReg', (31, 40))	('H3K9me3', 'Protein', (103, 110))	('NOTCH1', 'Gene', '4851', (41, 47))	('NOTCH1', 'Gene', (41, 47))	('H3K9me2', 'Protein', (91, 98))
247029	31031809	Moreover, the impaired stemness after blockade of GASC1 could be reversed after transfection of NOTCH1 overexpression lentiviral vector.	('impaired stemness', 'Disease', 'MESH:D009422', (14, 31))	('GASC1', 'Gene', (50, 55))	('impaired stemness', 'Disease', (14, 31))	('blockade', 'Var', (38, 46))	('NOTCH1', 'Gene', '4851', (96, 102))	('NOTCH1', 'Gene', (96, 102))
247036	31031809	Human ESCC cell lines including KYSE70, KYSE140, KYSE30, and KYSE150 were requested by Dr. Shimada from Kyoto University.	('Human', 'Species', '9606', (0, 5))	('KYSE150', 'Var', (61, 68))	('KYSE150', 'CellLine', 'CVCL:1348', (61, 68))	('KYSE30', 'Var', (49, 55))
247041	31031809	KYSE150 cells were stably transfected with a vector containing a GASC1-specific small hairpin RNA (shRNA) to knockdown GASC1 expression (shGASC1 KYSE150 cells).	('KYSE150', 'CellLine', 'CVCL:1348', (0, 7))	('KYSE150', 'CellLine', 'CVCL:1348', (145, 152))	('expression', 'MPA', (125, 135))	('GASC1', 'Gene', (119, 124))	('knockdown', 'Var', (109, 118))
247053	31031809	Anti-GASC1, anti-ALDH1L1, anti-NOTCH1 (Abcam, USA), anti-H3K9Me2, and anti-H3K9me3 (Millipore, USA) antibodies were used as primary antibodies.	('ALDH1L1', 'Gene', '10840', (17, 24))	('anti-H3K9Me2', 'Var', (52, 64))	('anti-H3K9me3', 'Var', (70, 82))	('NOTCH1', 'Gene', '4851', (31, 37))	('NOTCH1', 'Gene', (31, 37))	('ALDH1L1', 'Gene', (17, 24))
247062	31031809	The genes that decreased by >=20% following GASC1 knockdown in KYSE150 cells were analyzed by the DAVID Functional Annotation Tool, compared with a background of the total genes expressed in scramble shRNA control KYSE150 cells.	('KYSE150', 'CellLine', 'CVCL:1348', (63, 70))	('knockdown', 'Var', (50, 59))	('GASC1', 'Gene', (44, 49))	('decreased', 'NegReg', (15, 24))	('KYSE150', 'CellLine', 'CVCL:1348', (214, 221))
247063	31031809	In order to explore whether GASC1 could affect the level of methylation modification of histone H3K9me2/me3 in NOTCH1 promoter region, we performed ChIP assay in ALDH+ KYSE150 cells with GASC1 knockdown or CA treatment.	('KYSE150', 'CellLine', 'CVCL:1348', (168, 175))	('GASC1', 'Gene', (187, 192))	('knockdown', 'Var', (193, 202))	('affect', 'Reg', (40, 46))	('NOTCH1', 'Gene', '4851', (111, 117))	('methylation', 'MPA', (60, 71))	('NOTCH1', 'Gene', (111, 117))
247066	31031809	Firstly, we analyzed the expression of GASC1 in ESCC cell lines (KYSE30, KYSE70, KYSE140, and KYSE150) by qPCR and western blotting, respectively.	('KYSE150', 'Var', (94, 101))	('KYSE150', 'CellLine', 'CVCL:1348', (94, 101))	('GASC1', 'Gene', (39, 44))	('KYSE30', 'Var', (65, 71))	('KYSE70', 'Var', (73, 79))	('KYSE140', 'Var', (81, 88))
247067	31031809	The results showed that mRNA expression of GASC1 in KYSE30 and KYSE150 cells was significantly higher than that in SHEE (human immortalized esophageal epithelial cell line, as a control), KYSE70, and KYSE140 cells (P<0.05, Figure 1(a)).	('KYSE150', 'CellLine', 'CVCL:1348', (63, 70))	('higher', 'PosReg', (95, 101))	('GASC1', 'Gene', (43, 48))	('KYSE30', 'Var', (52, 58))	('human', 'Species', '9606', (121, 126))	('mRNA expression', 'MPA', (24, 39))	('KYSE150', 'Var', (63, 70))
247076	31031809	In addition, we analyzed the relationship between GASC1 expression and the survival of ESCC patients and found that patients with a high level of GASC1 presented a significantly worse survival rate (P=0.0146, Figure 3(g)).	('GASC1', 'Gene', (146, 151))	('worse', 'NegReg', (178, 183))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (92, 100))	('survival', 'MPA', (184, 192))	('high level', 'Var', (132, 142))
247077	31031809	Therefore, these results suggest that high level of GASC1 is closely correlated with poor survival in ESCC patients, and is a prognostic indicator of ESCC patients.	('ESCC', 'Disease', (102, 106))	('poor', 'NegReg', (85, 89))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (107, 115))	('high level', 'Var', (38, 48))	('GASC1', 'Gene', (52, 57))
247080	31031809	After knockdown of GASC1 expression in KYSE150 cells and treatment with CA, the percentages of ALDH+ cells were obviously decreased compared to control (P<0.05, Figure 4(c)).	('GASC1', 'Gene', (19, 24))	('KYSE150', 'CellLine', 'CVCL:1348', (39, 46))	('knockdown', 'Var', (6, 15))	('ALDH+ cells', 'CPA', (95, 106))	('decreased', 'NegReg', (122, 131))
247081	31031809	Meanwhile, immunofluorescence result showed that ALDH expression in KYSE150 cells was markedly decreased after blockade of GASC1 (Figure 4(d)).	('expression', 'MPA', (54, 64))	('decreased', 'NegReg', (95, 104))	('KYSE150', 'CellLine', 'CVCL:1348', (68, 75))	('blockade', 'Var', (111, 119))	('ALDH', 'Gene', (49, 53))	('GASC1', 'Gene', (123, 128))
247085	31031809	Flow cytometry results showed that knockdown of GASC1 in KYSE150 cells inhibited cell progress from G1 stage to S stage compared to control (Supplementary Figure S3).	('knockdown', 'Var', (35, 44))	('inhibited', 'NegReg', (71, 80))	('KYSE150', 'CellLine', 'CVCL:1348', (57, 64))	('cell progress from G1 stage to S stage', 'CPA', (81, 119))	('GASC1', 'Gene', (48, 53))
247087	31031809	As a result, the tumor volume of shGASC1 ALDH+ KYSE150 cell-derived xenografts was significantly lower than control group (P<0.05, Figure 4(e), Supplementary Figure S4A).	('tumor', 'Disease', (17, 22))	('lower', 'NegReg', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('shGASC1', 'Var', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('KYSE150', 'CellLine', 'CVCL:1348', (47, 54))
247089	31031809	To clarify the mechanism of GASC1 involving in the regulation of CSC-like properties in ESCC cells, we used the Agilent Human Genome Microarray to analyze the different gene expression between shGASC1 KYSE150 and scramble shRNA control cells.	('KYSE150', 'Var', (201, 208))	('Human', 'Species', '9606', (120, 125))	('KYSE150', 'CellLine', 'CVCL:1348', (201, 208))	('shGASC1', 'Gene', (193, 200))
247093	31031809	Western blotting results showed that NOTCH1 protein level in shGASC1 ESCC cells was dramatically decreased compared to that in SHEE control cells (Supplementary Figure S5).	('shGASC1', 'Var', (61, 68))	('decreased', 'NegReg', (97, 106))	('NOTCH1', 'Gene', '4851', (37, 43))	('NOTCH1', 'Gene', (37, 43))
247095	31031809	These findings indicate that NOTCH1 is decreased after knockdown of GASC1 in ESCC cells.	('NOTCH1', 'Gene', (29, 35))	('knockdown', 'Var', (55, 64))	('GASC1', 'Gene', (68, 73))	('decreased', 'NegReg', (39, 48))	('NOTCH1', 'Gene', '4851', (29, 35))
247096	31031809	To further evaluate downregulation of NOTCH1 during GASC1 blockade is linked to histone modification, we investigated whether blockade of GASC1 affect selected global histone methylation states in ALDH+ KYSE150 cells.	('KYSE150', 'CellLine', 'CVCL:1348', (203, 210))	('blockade', 'Var', (126, 134))	('downregulation', 'NegReg', (20, 34))	('NOTCH1', 'Gene', '4851', (38, 44))	('NOTCH1', 'Gene', (38, 44))	('affect', 'Reg', (144, 150))	('global histone methylation states', 'MPA', (160, 193))	('GASC1', 'Gene', (138, 143))
247097	31031809	ChIP analysis was performed using antibodies that individually recognize either H3K9me2 and H3K9me3 and the primers amplifying the regions of NOTCH1 promoter.	('H3K9me2', 'Var', (80, 87))	('H3K9me3', 'Var', (92, 99))	('NOTCH1', 'Gene', '4851', (142, 148))	('NOTCH1', 'Gene', (142, 148))
247098	31031809	GASC1 knockdown was found to cause substantial increases of H3K9me2 and H3K9me3 levels at NOTCH1 promoter in ALDH+ KYSE150 cells (Figures 6(a)-6(c)).	('H3K9me2', 'MPA', (60, 67))	('NOTCH1', 'Gene', '4851', (90, 96))	('GASC1', 'Gene', (0, 5))	('H3K9me3 levels', 'MPA', (72, 86))	('KYSE150', 'CellLine', 'CVCL:1348', (115, 122))	('increases', 'PosReg', (47, 56))	('knockdown', 'Var', (6, 15))	('NOTCH1', 'Gene', (90, 96))
247101	31031809	The results of cellular immunofluorescence assay showed that blockade of GASC1 including GASC1 knockdown and CA treatment significantly increased H3K9me2 (Figure 6(g)) and H3K9me3 (Figure 6(h)) levels compared to control groups, indicating a demethylation effect of GASC1 on NOTCH1 promoter.	('H3K9me2', 'MPA', (146, 153))	('GASC1', 'Gene', (73, 78))	('blockade', 'Var', (61, 69))	('knockdown', 'Var', (95, 104))	('GASC1', 'Gene', (89, 94))	('increased', 'PosReg', (136, 145))	('H3K9me3', 'MPA', (172, 179))	('NOTCH1', 'Gene', '4851', (275, 281))	('NOTCH1', 'Gene', (275, 281))
247102	31031809	Summary, these data suggest that blockade of GASC1 induces NOTCH1 promoter methylation.	('GASC1', 'Gene', (45, 50))	('blockade', 'Var', (33, 41))	('promoter methylation', 'MPA', (66, 86))	('NOTCH1', 'Gene', '4851', (59, 65))	('NOTCH1', 'Gene', (59, 65))
247104	31031809	After knockdown of NOTCH1 in KYSE150 cells, the sphere forming ability was significantly decreased compared to control (P<0.05, Figures 7(a) and 7(b)).	('NOTCH1', 'Gene', '4851', (19, 25))	('NOTCH1', 'Gene', (19, 25))	('sphere forming ability', 'CPA', (48, 70))	('knockdown', 'Var', (6, 15))	('KYSE150', 'CellLine', 'CVCL:1348', (29, 36))	('decreased', 'NegReg', (89, 98))
247113	31031809	Importantly, GASC1 knockdown and JAK2 inhibition caused cell death.	('JAK2', 'Gene', (33, 37))	('knockdown', 'Var', (19, 28))	('cell death', 'CPA', (56, 66))	('inhibition', 'NegReg', (38, 48))	('GASC1', 'Gene', (13, 18))	('JAK2', 'Gene', '3717', (33, 37))
247123	31031809	H3K9me2/me3, the promoter of NOTCH1, was upregulated via GASC1 knockdown, indicating that the mechanism of ESCC stemness induced by GASC1 could be mediated via NOTCH1 promoter demethylation.	('NOTCH1', 'Gene', (29, 35))	('NOTCH1', 'Gene', '4851', (160, 166))	('NOTCH1', 'Gene', (160, 166))	('upregulated', 'PosReg', (41, 52))	('GASC1', 'Gene', (57, 62))	('knockdown', 'Var', (63, 72))	('ESCC', 'Disease', (107, 111))	('H3K9me2/me3', 'Var', (0, 11))	('NOTCH1', 'Gene', '4851', (29, 35))
247124	31031809	Increasing evidences support the fact that GASC1 upregulates the expression of important oncogene MDM2 and myc and stem cell key transcription factor NANOG through H3K9 methylation.	('H3K9 methylation', 'Var', (164, 180))	('NANOG', 'Gene', '79923', (150, 155))	('MDM2', 'Gene', '4193', (98, 102))	('MDM2', 'Gene', (98, 102))	('NANOG', 'Gene', (150, 155))	('myc', 'Gene', (107, 110))	('GASC1', 'Gene', (43, 48))	('expression', 'MPA', (65, 75))	('methylation', 'Var', (169, 180))	('myc', 'Gene', '4609', (107, 110))	('upregulates', 'PosReg', (49, 60))
247127	31031809	By means of human genome microarray analysis and ChIP, we found that ALDH+ CSCs could induce rapid increase of H3K9me3 level in target gene NOTCH1 promoter region after GASC1 expression was reduced.	('NOTCH1', 'Gene', '4851', (140, 146))	('NOTCH1', 'Gene', (140, 146))	('H3K9me3 level', 'MPA', (111, 124))	('human', 'Species', '9606', (12, 17))	('ALDH+', 'Var', (69, 74))	('increase', 'PosReg', (99, 107))
247130	31031809	In conclusion, we found that high level of GASC1 was closely associated with poor survival of ESCC patients.	('poor', 'NegReg', (77, 81))	('high level', 'Var', (29, 39))	('GASC1', 'Gene', (43, 48))	('patients', 'Species', '9606', (99, 107))	('associated', 'Reg', (61, 71))	('ESCC', 'Disease', (94, 98))
247133	25703328	Cigarette Smoke Mediates Epigenetic Repression of miR-217 During Esophageal Adenocarcinogenesis Although microRNAs (miRs) have been implicated in the pathogenesis of various human malignancies, limited information is available regarding mechanisms by which these noncoding RNAs contribute to initiation and progression of tobacco-induced esophageal cancers.	('esophageal cancers', 'Disease', 'MESH:D004938', (338, 356))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('human', 'Species', '9606', (174, 179))	('tobacco', 'Species', '4097', (322, 329))	('cancers', 'Phenotype', 'HP:0002664', (349, 356))	('miR-217', 'Gene', '406999', (50, 57))	('malignancies', 'Disease', 'MESH:D009369', (180, 192))	('miR-217', 'Gene', (50, 57))	('esophageal cancers', 'Disease', (338, 356))	('Epigenetic', 'Var', (25, 35))	('contribute', 'Reg', (278, 288))	('Esophageal Adenocarcinogenesis', 'Disease', 'MESH:D004941', (65, 95))	('Esophageal Adenocarcinogenesis', 'Disease', (65, 95))	('malignancies', 'Disease', (180, 192))
247140	25703328	Deoxyazacytidine induced miR-217 expression, and down-regulated KLK7 in EACC; deoxyazacytidine also attenuated CSC-mediated miR-217 repression and up-regulation of KLK7 in IEE and EACC.	('KLK7', 'Gene', (164, 168))	('deoxyazacytidine', 'Var', (78, 94))	('miR-217', 'Gene', '406999', (25, 32))	('EAC', 'Gene', '1540', (180, 183))	('miR-217', 'Gene', '406999', (124, 131))	('EAC', 'Gene', '1540', (72, 75))	('miR-217', 'Gene', (124, 131))	('EAC', 'Gene', (180, 183))	('attenuated', 'NegReg', (100, 110))	('EAC', 'Gene', (72, 75))	('deoxyazacytidine', 'Chemical', 'MESH:D000077209', (78, 94))	('down-regulated', 'NegReg', (49, 63))	('Deoxyazacytidine', 'Chemical', 'MESH:D000077209', (0, 16))	('KLK7', 'Gene', (64, 68))	('up-regulation', 'PosReg', (147, 160))	('expression', 'MPA', (33, 43))	('miR-217', 'Gene', (25, 32))
247142	25703328	Collectively, these data demonstrate that epigenetic repression of miR-217 contributes to the pathogenesis of EAC via up-regulation of KLK7, and suggest that restoration of miR-217 expression may be a novel treatment strategy for these malignancies.	('EAC', 'Gene', (110, 113))	('miR-217', 'Gene', '406999', (173, 180))	('miR-217', 'Gene', (173, 180))	('up-regulation', 'PosReg', (118, 131))	('malignancies', 'Disease', (236, 248))	('miR-217', 'Gene', '406999', (67, 74))	('miR-217', 'Gene', (67, 74))	('KLK7', 'Gene', (135, 139))	('epigenetic repression', 'Var', (42, 63))	('restoration', 'Var', (158, 169))	('EAC', 'Gene', '1540', (110, 113))	('malignancies', 'Disease', 'MESH:D009369', (236, 248))
247150	25703328	In addition to genetic as well as epigenetic aberrations , a variety of microRNA (miR) alterations have been identified in EAC .	('microRNA', 'MPA', (72, 80))	('alterations', 'Var', (87, 98))	('EAC', 'Gene', '1540', (123, 126))	('EAC', 'Gene', (123, 126))	('identified', 'Reg', (109, 119))
247151	25703328	For instance, miR-21, miR-143-145, miR-192, miR-194, and miR-215 appear to be consistently up-regulated, whereas let7c, miR-203, miR-205 and miR-375 are down-regulated in EAC as well as Barrett's epithelia; these alterations in microRNA expression inhibit death signaling, and promote cell cycle progression, as well as invasion and metastatic potential of cancer cells (reviewed in ref.	('miR-21', 'Gene', '406991', (14, 20))	('cell cycle progression', 'CPA', (285, 307))	('let7c', 'Gene', (113, 118))	('miR-205', 'Gene', (129, 136))	('miR-192', 'Gene', (35, 42))	('miR-215', 'Gene', '406997', (57, 64))	('miR-375', 'Gene', '494324', (141, 148))	('miR-194', 'Var', (44, 51))	('miR-375', 'Gene', (141, 148))	('miR-21', 'Gene', '406991', (57, 63))	('miR-215', 'Gene', (57, 64))	('miR-21', 'Gene', (14, 20))	('up-regulated', 'PosReg', (91, 103))	('cancer', 'Disease', (357, 363))	('death signaling', 'CPA', (256, 271))	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('promote', 'PosReg', (277, 284))	('miR-192', 'Gene', '406967', (35, 42))	('miR-205', 'Gene', '406988', (129, 136))	('miR-203', 'Gene', (120, 127))	('miR-21', 'Gene', (57, 63))	('alterations', 'Var', (213, 224))	('miR-143', 'Gene', '406935', (22, 29))	('let7c', 'Gene', '406885', (113, 118))	('miR-143', 'Gene', (22, 29))	('EAC', 'Gene', '1540', (171, 174))	('down-regulated', 'NegReg', (153, 167))	('cancer', 'Disease', 'MESH:D009369', (357, 363))	('miR-203', 'Gene', '406986', (120, 127))	('EAC', 'Gene', (171, 174))	('inhibit', 'NegReg', (248, 255))
247152	25703328	Whereas some of these alterations appear to be associated with particular risk factors or overall prognosis of EAC patients , the precise mechanisms and clinical implications of miR dysregulation during esophageal adenocarcinogenesis have not been fully defined.	('patients', 'Species', '9606', (115, 123))	('EAC', 'Gene', '1540', (111, 114))	('EAC', 'Gene', (111, 114))	('alterations', 'Var', (22, 33))	('esophageal adenocarcinogenesis', 'Disease', (203, 233))	('associated', 'Reg', (47, 57))	('esophageal adenocarcinogenesis', 'Disease', 'MESH:D004941', (203, 233))
247168	25703328	qRT-PCR analysis demonstrated 7.6-33 fold increases and 18.9-26.4 fold decreases in miR-217 levels in the aforementioned cells exhibiting over-expression or knockdown of miR-217, respectively (Supplementary Figure S3).	('increases', 'PosReg', (42, 51))	('over-expression', 'PosReg', (138, 153))	('miR-217', 'Gene', '406999', (84, 91))	('miR-217', 'Gene', '406999', (170, 177))	('miR-217', 'Gene', (170, 177))	('miR-217', 'Gene', (84, 91))	('knockdown', 'Var', (157, 166))	('decreases', 'NegReg', (71, 80))
247172	25703328	Knock-down of miR-217 only modestly increased KLK7 mRNA levels in IEEC and EACC cultured in control media, and did not appear to significantly enhance induction of KLK7 by cigarette smoke, suggesting that the effects of miR-217 knockdown and CSC exposure on KLK-7 expression were mediated at least in part by redundant mechanisms.	('miR-217', 'Gene', '406999', (14, 21))	('miR-217', 'Gene', '406999', (220, 227))	('KLK-7', 'Gene', '5650', (258, 263))	('miR-217', 'Gene', (14, 21))	('miR-217', 'Gene', (220, 227))	('Knock-down', 'Var', (0, 10))	('KLK-7', 'Gene', (258, 263))	('EAC', 'Gene', '1540', (75, 78))	('EAC', 'Gene', (75, 78))	('increased', 'PosReg', (36, 45))	('KLK7 mRNA levels', 'MPA', (46, 62))
247173	25703328	Modulation of miR-217 did not affect expression of KLK6, a related kallikrein family member, which is not a predicted target of miR-217 and is not modulated by CSC (Supplementary Figure S4).	('Modulation', 'Var', (0, 10))	('miR-217', 'Gene', '406999', (14, 21))	('miR-217', 'Gene', (14, 21))	('miR-217', 'Gene', '406999', (128, 135))	('miR-217', 'Gene', (128, 135))	('KLK6', 'Gene', '5653', (51, 55))	('expression', 'MPA', (37, 47))	('KLK6', 'Gene', (51, 55))
247179	25703328	Immunoblot experiments demonstrated that over-expression of miR-217 decreased, whereas knock-down of miR-217 increased KLK7-but not KLK6 protein levels, respectively, in Het-1A, EsC1, and EsC2 cells (Figure 2C; corresponding densitometry analysis summarized in Supplementary Table S2).	('KLK6', 'Gene', (132, 136))	('decreased', 'NegReg', (68, 77))	('over-expression', 'PosReg', (41, 56))	('miR-217', 'Gene', '406999', (101, 108))	('miR-217', 'Gene', (101, 108))	('miR-217', 'Gene', '406999', (60, 67))	('EsC2', 'Gene', (188, 192))	('miR-217', 'Gene', (60, 67))	('knock-down', 'Var', (87, 97))	('EsC2', 'Gene', '84901', (188, 192))	('KLK6', 'Gene', '5653', (132, 136))	('increased', 'PosReg', (109, 118))	('KLK7-but', 'MPA', (119, 127))
247195	25703328	Direct cell count experiments (Figure 3A) demonstrated that constitutive over-expression of KLK7 increased proliferation of EACC by 23-37% relative to respective controls (P< 0.05); in contrast, knock-down of KLK7 decreased proliferation of these cells by 29-40% (P < 0.05).	('EAC', 'Gene', (124, 127))	('proliferation', 'CPA', (224, 237))	('increased', 'PosReg', (97, 106))	('knock-down', 'Var', (195, 205))	('proliferation', 'CPA', (107, 120))	('over-expression', 'PosReg', (73, 88))	('KLK7', 'Gene', (92, 96))	('decreased', 'NegReg', (214, 223))	('KLK7', 'Gene', (209, 213))	('EAC', 'Gene', '1540', (124, 127))
247196	25703328	Subsequent matrigel experiments (Figure 3B) demonstrated that overexpression of KLK7 increased, whereas knock-down of KLK7 inhibited invasion of EACC, respectively; Het-1A do not invade matrigel, hence, were not used for this experiment.	('EAC', 'Gene', '1540', (145, 148))	('EAC', 'Gene', (145, 148))	('KLK7', 'Gene', (80, 84))	('KLK7', 'Gene', (118, 122))	('inhibited', 'NegReg', (123, 132))	('overexpression', 'PosReg', (62, 76))	('increased', 'PosReg', (85, 94))	('knock-down', 'Var', (104, 114))
247201	25703328	First, in-vitro growth assays were performed using Het-1A, EsC1, EsC2, OE19, and OE33 cells following over-expression or knock-down of miR-217.	('EsC2', 'Gene', '84901', (65, 69))	('miR-217', 'Gene', (135, 142))	('knock-down', 'Var', (121, 131))	('miR-217', 'Gene', '406999', (135, 142))	('EsC2', 'Gene', (65, 69))	('over-expression', 'PosReg', (102, 117))
247202	25703328	As shown in Figure 4A, constitutive over-expression of miR-217 decreased proliferation of EACC by ~25-45% relative to vector controls; in contrast, knock-down of miR-217 increased proliferation of Het-1A, EsC2, and OE19 cells by approximately 39.5%, 20.7%, and 21.6%, respectively, but did not appear to enhance proliferation of EsC1 or OE19 cells.	('miR-217', 'Gene', '406999', (55, 62))	('EsC2', 'Gene', (205, 209))	('EAC', 'Gene', (90, 93))	('miR-217', 'Gene', '406999', (162, 169))	('miR-217', 'Gene', (55, 62))	('proliferation', 'CPA', (180, 193))	('miR-217', 'Gene', (162, 169))	('EsC2', 'Gene', '84901', (205, 209))	('increased', 'PosReg', (170, 179))	('EAC', 'Gene', '1540', (90, 93))	('knock-down', 'Var', (148, 158))
247207	25703328	Knock-down of miR-217 did not reproducibly increase invasion of control EAC cells or enhance invasion of CSC-treated EAC cells, suggesting that the effects of miR-217 repression and CSC treatment were mediated, at least in part, by redundant mechanisms.	('miR-217', 'Gene', '406999', (14, 21))	('EAC', 'Gene', (117, 120))	('miR-217', 'Gene', (14, 21))	('miR-217', 'Gene', (159, 166))	('miR-217', 'Gene', '406999', (159, 166))	('repression', 'NegReg', (167, 177))	('EAC', 'Gene', '1540', (72, 75))	('EAC', 'Gene', (72, 75))	('Knock-down', 'Var', (0, 10))	('EAC', 'Gene', '1540', (117, 120))
247234	25703328	Similar to what was observed for DNMT3b, levels of EZH2, SUZ12 and H3K27Me3 within the miR-217 regulatory region were higher in EAC as well as normal esophageal mucosa from smokers relative to non-smokers.	('higher', 'PosReg', (118, 124))	('miR-217', 'Gene', '406999', (87, 94))	('EAC', 'Gene', (128, 131))	('miR-217', 'Gene', (87, 94))	('EZH2', 'Gene', '2146', (51, 55))	('EZH2', 'Gene', (51, 55))	('DNMT3b', 'Gene', '1789', (33, 39))	('EAC', 'Gene', '1540', (128, 131))	('SUZ12', 'Gene', (57, 62))	('SUZ12', 'Gene', '23512', (57, 62))	('H3K27Me3', 'Var', (67, 75))	('DNMT3b', 'Gene', (33, 39))
247238	25703328	Knock-down of NF-1 significantly diminished miR-217 expression in Het-1A, EsC1, EsC2 and OE19 cells (Figure 7B).	('NF-1', 'Gene', '4763', (14, 18))	('diminished', 'NegReg', (33, 43))	('EsC2', 'Gene', (80, 84))	('Knock-down', 'Var', (0, 10))	('EsC2', 'Gene', '84901', (80, 84))	('NF-1', 'Gene', (14, 18))	('expression', 'MPA', (52, 62))	('miR-217', 'Gene', (44, 51))	('miR-217', 'Gene', '406999', (44, 51))
247254	25703328	Additional knock-out of DNMT1 (DKO cells) only modestly augmented the effects of DNMT3b knock-out regarding endogenous levels of miR-217 or abrogation of CSC-mediated repression of this miR.	('DNMT3b', 'Gene', (81, 87))	('DNMT1', 'Gene', '1786', (24, 29))	('knock-out', 'Var', (88, 97))	('miR-217', 'Gene', (129, 136))	('DNMT3b', 'Gene', '1789', (81, 87))	('miR-217', 'Gene', '406999', (129, 136))	('abrogation', 'NegReg', (140, 150))	('DNMT1', 'Gene', (24, 29))	('CSC-mediated repression', 'MPA', (154, 177))
247258	25703328	Although alterations in micro-RNA expression have been implicated in the pathogenesis of a variety of human cancers , the mechanisms by which these non-coding RNAs mediate initiation and progression of esophageal cancers have not been fully delineated.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('esophageal cancers', 'Disease', (202, 220))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('micro-RNA', 'Protein', (24, 33))	('esophageal cancers', 'Disease', 'MESH:D004938', (202, 220))	('alterations', 'Var', (9, 20))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('implicated', 'Reg', (55, 65))	('cancers', 'Disease', (213, 220))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))	('human', 'Species', '9606', (102, 107))
247259	25703328	In the present study we sought to characterize micro-RNAs in esophageal epithelia and esophageal adenocarcinoma cells, which are modulated by cigarette smoke - a well-established risk factor for ESCC that only recently has been implicated in esophageal adenocarcinogenesis.	('esophageal adenocarcinoma', 'Disease', (86, 111))	('esophageal epithelia', 'Disease', 'MESH:D004941', (61, 81))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (86, 111))	('esophageal adenocarcinogenesis', 'Disease', (242, 272))	('micro-RNAs', 'Var', (47, 57))	('esophageal adenocarcinogenesis', 'Disease', 'MESH:D004941', (242, 272))	('ESCC', 'Disease', (195, 199))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (86, 111))	('esophageal epithelia', 'Disease', (61, 81))
247261	25703328	Interestingly, cigarette smoke did not appear to repress DA732292- the host gene for miR-217, nor diminish expression of miR-216, which is upstream of miR-217 within the same host gene.	('DA732292-', 'Var', (57, 66))	('miR-216', 'Gene', (121, 128))	('expression', 'MPA', (107, 117))	('diminish', 'NegReg', (98, 106))	('miR-217', 'Gene', '406999', (85, 92))	('miR-217', 'Gene', (85, 92))	('miR-216', 'Gene', '406998', (121, 128))	('miR-217', 'Gene', '406999', (151, 158))	('miR-217', 'Gene', (151, 158))
247264	25703328	Constitutive over-expression of miR-217 inhibited, whereas knockdown of miR-217 increased growth of EACC in vitro and in vivo.	('miR-217', 'Gene', (72, 79))	('inhibited', 'NegReg', (40, 49))	('miR-217', 'Gene', '406999', (32, 39))	('increased', 'PosReg', (80, 89))	('miR-217', 'Gene', (32, 39))	('EAC', 'Gene', '1540', (100, 103))	('miR-217', 'Gene', '406999', (72, 79))	('knockdown', 'Var', (59, 68))	('growth', 'MPA', (90, 96))	('EAC', 'Gene', (100, 103))	('over-expression', 'PosReg', (13, 28))
247265	25703328	To the best of our knowledge, these experiments are the first to implicate epigenetic repression of miR-217 in the pathogenesis of EAC.	('miR-217', 'Gene', (100, 107))	('EAC', 'Gene', '1540', (131, 134))	('epigenetic repression', 'Var', (75, 96))	('EAC', 'Gene', (131, 134))	('implicate', 'Reg', (65, 74))	('miR-217', 'Gene', '406999', (100, 107))
247277	25703328	In addition, KLK7 catalyzes formation of an active, truncated MMP9 variant that is not produced by other proteases.	('MMP9', 'Gene', '4318', (62, 66))	('variant', 'Var', (67, 74))	('MMP9', 'Gene', (62, 66))	('active', 'MPA', (44, 50))
247282	25703328	However our present findings do not exclude the possibility that some of the inhibitory effects of miR-217 in EACC are mediated by down-regulation of KRAS and E2F3 , or subtle epigenetic alterations due to down-regulation of DNNMT3a.	('down-regulation', 'NegReg', (131, 146))	('EAC', 'Gene', (110, 113))	('DNNMT3a', 'Gene', (225, 232))	('EAC', 'Gene', '1540', (110, 113))	('E2F3', 'Gene', (159, 163))	('E2F3', 'Gene', '1871', (159, 163))	('miR-217', 'Gene', '406999', (99, 106))	('miR-217', 'Gene', (99, 106))	('down-regulation', 'NegReg', (206, 221))	('KRAS', 'Gene', (150, 154))	('epigenetic alterations', 'Var', (176, 198))	('KRAS', 'Gene', '3845', (150, 154))
247302	28380443	The pooled results of 14 studies indicated that high expression of UCA1 was significantly associated with poorer OS in patients with digestive system cancers (HR: 1.89, 95 % CI: 1.52-2.26).	('poorer OS', 'Disease', (106, 115))	('system cancers', 'Disease', 'MESH:D009369', (143, 157))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('patients', 'Species', '9606', (119, 127))	('UCA1', 'Gene', '652995', (67, 71))	('UCA1', 'Gene', (67, 71))	('HR', 'Phenotype', 'HP:0001402', (159, 161))	('high expression', 'Var', (48, 63))	('system cancers', 'Disease', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
247329	28380443	Overall, the pooled results confirmed that there was a significant association between high UCA1expression and poor OS in digestive system cancer (HR: 1.89, 95 % CI: 1.52-2.26, p<= 0.001) (Figure 2A).	('system cancer', 'Disease', (132, 145))	('HR', 'Phenotype', 'HP:0001402', (147, 149))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('UCA1', 'Gene', '652995', (92, 96))	('poor OS', 'Disease', (111, 118))	('UCA1', 'Gene', (92, 96))	('high', 'Var', (87, 91))	('system cancer', 'Disease', 'MESH:D009369', (132, 145))
247336	28380443	The association between UCA1 and OS of patients was significant in studies with sample size both equal or greater than 100 (HR: 1.67, 95 % CI: 1.15-2.20, p<= 0.001) and less than 100 (HR: 2.10, 95 % CI: 1.57-2.63, p<= 0.001).	('patients', 'Species', '9606', (39, 47))	('HR', 'Phenotype', 'HP:0001402', (124, 126))	('HR', 'Phenotype', 'HP:0001402', (184, 186))	('less than 100', 'Var', (169, 182))	('UCA1', 'Gene', '652995', (24, 28))	('OS of patients', 'Disease', (33, 47))	('UCA1', 'Gene', (24, 28))
247339	28380443	The pooled meta-analysis confirmed that high UCA1 expression was a significant independent predictor of poor OS in digestive system malignancies (HR: 1.85, 95 % CI: 1.45-2.25, p<= 0.001) (Figure 3A).	('high', 'Var', (40, 44))	('poor OS', 'Disease', (104, 111))	('system malignancies', 'Disease', (125, 144))	('HR', 'Phenotype', 'HP:0001402', (146, 148))	('system malignancies', 'Disease', 'MESH:D009369', (125, 144))	('UCA1', 'Gene', '652995', (45, 49))	('UCA1', 'Gene', (45, 49))	('expression', 'MPA', (50, 60))
247346	28380443	The results showed that there was a significant association between high expression level of UCA1 and poor DFS in digestive system malignancies (HR = 2.50; 95 % CI = 1.30-3.69; p<= 0.001) (Figure 4).	('UCA1', 'Gene', (93, 97))	('system malignancies', 'Disease', 'MESH:D009369', (124, 143))	('HR', 'Phenotype', 'HP:0001402', (145, 147))	('system malignancies', 'Disease', (124, 143))	('high expression level', 'Var', (68, 89))	('poor', 'Disease', (102, 106))	('UCA1', 'Gene', '652995', (93, 97))
247352	28380443	While high UCA1 expression was found to be significantly associated with advanced TNM stage (OR: 3.81, 95 % CI: 1.87-7.76, p= 0.0002).	('TNM', 'Gene', '10178', (82, 85))	('associated', 'Reg', (57, 67))	('TNM', 'Gene', (82, 85))	('high', 'Var', (6, 10))	('UCA1', 'Gene', '652995', (11, 15))	('expression', 'MPA', (16, 26))	('UCA1', 'Gene', (11, 15))
247357	28380443	In colorectal cancer, high UCA1 expression was significantly related to differentiation grade (OR: 2.60, 95 % CI: 1.67- 4.03, p<0.0001), lymph node metastasis (OR: 3.88, 95 % CI: 1.71- 8.83, p = 0.001) and distant metastasis(OR: 2.67, 95 % CI: 1.32-5.38, p = 0.006) and TNM stage (OR: 2.45, 95 % CI: 1.62-3.70, p <0.0001).	('differentiation grade', 'CPA', (72, 93))	('TNM', 'Gene', (270, 273))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('high', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lymph node metastasis', 'CPA', (137, 158))	('related', 'Reg', (61, 68))	('colorectal cancer', 'Disease', (3, 20))	('TNM', 'Gene', '10178', (270, 273))	('distant metastasis', 'CPA', (206, 224))	('expression', 'MPA', (32, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('UCA1', 'Gene', '652995', (27, 31))	('UCA1', 'Gene', (27, 31))
247371	28380443	The patients with high UCA1 expression had a poorer OS compared to patients with low UCA1 expression.	('patients', 'Species', '9606', (67, 75))	('UCA1', 'Gene', '652995', (23, 27))	('UCA1', 'Gene', (23, 27))	('UCA1', 'Gene', '652995', (85, 89))	('expression', 'Var', (28, 38))	('UCA1', 'Gene', (85, 89))	('patients', 'Species', '9606', (4, 12))	('high', 'Var', (18, 22))
247394	28380443	For gastric cancer, UCA1 was observed to be highly expressed, while the silence of UCA1 could decrease proliferation of tumor cells.	('silence', 'Var', (72, 79))	('decrease', 'NegReg', (94, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (4, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (4, 18))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('UCA1', 'Gene', '652995', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('gastric cancer', 'Disease', (4, 18))	('UCA1', 'Gene', '652995', (83, 87))	('UCA1', 'Gene', (83, 87))	('tumor', 'Disease', (120, 125))	('UCA1', 'Gene', (20, 24))
247426	27698906	The result of transwell assay showed that the numbers of cells travelled through the micropore membrane was significantly decreased as HDAC1 expression was knockdown.	('knockdown', 'Var', (156, 165))	('HDAC1', 'Gene', '3065', (135, 140))	('expression', 'MPA', (141, 151))	('HDAC1', 'Gene', (135, 140))	('decreased', 'NegReg', (122, 131))
247427	27698906	Moreover, HDAC1 knockdown inhibited the migration of EC109 cells as determining by scratch test.	('inhibited', 'NegReg', (26, 35))	('HDAC1', 'Gene', (10, 15))	('knockdown', 'Var', (16, 25))	('migration of EC109 cells', 'CPA', (40, 64))	('EC109', 'CellLine', 'CVCL:6898', (53, 58))	('HDAC1', 'Gene', '3065', (10, 15))
247428	27698906	Additionally, enhancement of cisplatin-stimulated apoptosis was detected by HDAC1 knockdown.	('HDAC1', 'Gene', '3065', (76, 81))	('knockdown', 'Var', (82, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('HDAC1', 'Gene', (76, 81))	('apoptosis', 'CPA', (50, 59))	('enhancement', 'PosReg', (14, 25))
247431	27698906	Numerous studies have showed that aberrant histone modifications and the deregulation of gene expression are involved in the process of transformation and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('deregulation of gene expression', 'MPA', (73, 104))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('aberrant', 'Var', (34, 42))	('histone', 'Protein', (43, 50))	('tumor', 'Disease', (155, 160))	('transformation', 'CPA', (136, 150))	('involved', 'Reg', (109, 117))
247445	27698906	To further test HDAC1 inhibition for cancer treatment, the gene expression of HDAC1 was knockdown mediated by a lentivirus system, which has been intensively applied for gene transferring.	('HDAC1', 'Gene', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('HDAC1', 'Gene', (78, 83))	('cancer', 'Disease', (37, 43))	('knockdown', 'Var', (88, 97))	('HDAC1', 'Gene', '3065', (16, 21))	('HDAC1', 'Gene', '3065', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
247448	27698906	We found that inhibition of HDAC1 enhanced the chemosensitivity in esophageal cancer cells.	('enhanced', 'PosReg', (34, 42))	('HDAC1', 'Gene', (28, 33))	('chemosensitivity in', 'CPA', (47, 66))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('inhibition', 'Var', (14, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('HDAC1', 'Gene', '3065', (28, 33))
247474	27698906	Result of realtime RT-PCR showed HDAC1 mRNA was efficiently knockdown in cell clone Si-HDAC1-2, while none was observed in the other cell clone (Fig.2B).	('HDAC1', 'Gene', (33, 38))	('HDAC1', 'Gene', '3065', (33, 38))	('HDAC1', 'Gene', (87, 92))	('knockdown', 'Var', (60, 69))	('HDAC1', 'Gene', '3065', (87, 92))
247480	27698906	Further analysis of cell cycle distribution showed that decreased S-phase and increased G2-phase population was observed as HDAC1 was knockdown (Fig.3B).	('HDAC1', 'Gene', '3065', (124, 129))	('decreased', 'NegReg', (56, 65))	('G2-phase population', 'CPA', (88, 107))	('knockdown', 'Var', (134, 143))	('increased', 'PosReg', (78, 87))	('HDAC1', 'Gene', (124, 129))	('S-phase', 'CPA', (66, 73))
247481	27698906	These indicated that knockdown of HDAC1 affected the biological character of EC109 cells.	('affected', 'Reg', (40, 48))	('biological character of EC109 cells', 'CPA', (53, 88))	('HDAC1', 'Gene', (34, 39))	('EC109', 'CellLine', 'CVCL:6898', (77, 82))	('HDAC1', 'Gene', '3065', (34, 39))	('knockdown', 'Var', (21, 30))
247483	27698906	The result of transwell assay showed that the numbers of cells travelled through the micropore membrane was significantly decreased as HDAC1 expression was knockdown (Fig.4A).	('knockdown', 'Var', (156, 165))	('HDAC1', 'Gene', '3065', (135, 140))	('expression', 'MPA', (141, 151))	('HDAC1', 'Gene', (135, 140))	('decreased', 'NegReg', (122, 131))
247484	27698906	Moreover, HDAC1 knockdown inhibited the migration of EC109 cells as determining by scratch test (Fig.4B).	('inhibited', 'NegReg', (26, 35))	('HDAC1', 'Gene', (10, 15))	('knockdown', 'Var', (16, 25))	('migration of EC109 cells', 'CPA', (40, 64))	('EC109', 'CellLine', 'CVCL:6898', (53, 58))	('HDAC1', 'Gene', '3065', (10, 15))
247485	27698906	These data suggested that HDAC1 knockdown inhibited cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('HDAC1', 'Gene', (26, 31))	('cancer metastasis', 'Disease', (52, 69))	('knockdown', 'Var', (32, 41))	('inhibited', 'NegReg', (42, 51))	('HDAC1', 'Gene', '3065', (26, 31))	('cancer metastasis', 'Disease', 'MESH:D009362', (52, 69))
247486	27698906	As acetylation of core histones is governed by opposing actions of a variety of HATs and HDACs, HDAC1 knockdown led to histone hyperacetylation, which was similar to that of HDAC inhibitors (HDACis) such as TSA and SAHA.	('HDAC', 'Gene', (89, 93))	('HDAC', 'Gene', '9734', (174, 178))	('HDAC', 'Gene', '9734', (96, 100))	('HDAC1', 'Gene', '3065', (96, 101))	('HDAC', 'Gene', '9734', (89, 93))	('SAHA', 'Chemical', 'MESH:D000077337', (215, 219))	('hyperacetylation', 'PosReg', (127, 143))	('HDAC', 'Gene', (191, 195))	('knockdown', 'Var', (102, 111))	('acetylation', 'MPA', (3, 14))	('HDAC', 'Gene', '9734', (191, 195))	('HDAC1', 'Gene', (96, 101))	('TSA', 'Chemical', 'MESH:C012589', (207, 210))	('HDACs', 'Chemical', '-', (89, 94))	('histone', 'MPA', (119, 126))	('HDAC', 'Gene', (96, 100))	('HDAC', 'Gene', (174, 178))
247488	27698906	As shown in Fig.5A, cell viability after exposure to cisplatin was much lower in HDAC1 knockdown group, compared with that of control.	('HDAC1', 'Gene', (81, 86))	('cell viability', 'CPA', (20, 34))	('lower', 'NegReg', (72, 77))	('HDAC1', 'Gene', '3065', (81, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('knockdown group', 'Var', (87, 102))
247492	27698906	The apoptosis executer induced by cisplatin was also significantly increased in SiHDAC group, compared with that of NC group (Fig.5C).	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('SiHDAC', 'Var', (80, 86))	('apoptosis executer', 'CPA', (4, 22))	('increased', 'PosReg', (67, 76))	('SiHDAC', 'Chemical', '-', (80, 86))
247493	27698906	These data clearly indicated that HDAC1 knockdown enhanced the chemosensitivity of DNA-damaging drugs.	('chemosensitivity of DNA-damaging drugs', 'MPA', (63, 101))	('knockdown', 'Var', (40, 49))	('HDAC1', 'Gene', (34, 39))	('HDAC1', 'Gene', '3065', (34, 39))	('enhanced', 'PosReg', (50, 58))
247497	27698906	The most interesting finding of this work is that HDAC knockdown enhanced the cell death induced by cisplatin.	('knockdown', 'Var', (55, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('cell death', 'CPA', (78, 88))	('HDAC', 'Gene', (50, 54))	('enhanced', 'PosReg', (65, 73))	('HDAC', 'Gene', '9734', (50, 54))
247509	27698906	Overexpression of HDAC1 was linked to a higher proliferation rate of cancer cells.	('HDAC1', 'Gene', '3065', (18, 23))	('higher', 'PosReg', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('proliferation rate', 'CPA', (47, 65))	('HDAC1', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
247510	27698906	found high HDAC1 expression was associated with increased cell proliferation of prostate cancer.	('increased', 'PosReg', (48, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('expression', 'MPA', (17, 27))	('cell proliferation', 'CPA', (58, 76))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('HDAC1', 'Gene', (11, 16))	('HDAC1', 'Gene', '3065', (11, 16))	('high', 'Var', (6, 10))	('prostate cancer', 'Disease', (80, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
247512	27698906	Consequently, inhibition of HDAC1 could lead to growth arrest and activation of cell cycle inhibitor such as p21 and p27.	('growth arrest', 'Phenotype', 'HP:0001510', (48, 61))	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('cell cycle', 'CPA', (80, 90))	('arrest', 'Disease', (55, 61))	('HDAC1', 'Gene', (28, 33))	('p27', 'Gene', (117, 120))	('p27', 'Gene', '3429', (117, 120))	('p21', 'Gene', (109, 112))	('inhibition', 'Var', (14, 24))	('p21', 'Gene', '644914', (109, 112))	('HDAC1', 'Gene', '3065', (28, 33))	('activation', 'PosReg', (66, 76))
247513	27698906	In this work, we found a significant decrease of cell growth as HDAC1 was knockdown by shRNA.	('decrease', 'NegReg', (37, 45))	('HDAC1', 'Gene', (64, 69))	('knockdown', 'Var', (74, 83))	('HDAC1', 'Gene', '3065', (64, 69))	('cell growth', 'CPA', (49, 60))
247514	27698906	Cell cycle analysis revealed an altered distribution associated with HDAC1 knockdown (Fig.3).	('HDAC1', 'Gene', '3065', (69, 74))	('distribution', 'MPA', (40, 52))	('knockdown', 'Var', (75, 84))	('altered', 'Reg', (32, 39))	('HDAC1', 'Gene', (69, 74))
247515	27698906	In line with the altered cell growth, cancer metastasis of EC109 cells was also significantly decreased as HDAC1 expression was knockdown, as determined by cell migration and invasion assay.	('HDAC1', 'Gene', '3065', (107, 112))	('expression', 'MPA', (113, 123))	('EC109', 'CellLine', 'CVCL:6898', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer metastasis', 'Disease', (38, 55))	('knockdown', 'Var', (128, 137))	('cancer metastasis', 'Disease', 'MESH:D009362', (38, 55))	('decreased', 'NegReg', (94, 103))	('HDAC1', 'Gene', (107, 112))
247519	27698906	found that TSA and FK228 potentiated induction of apoptosis by cisplatin.	('FK228', 'Chemical', 'MESH:C087123', (19, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('TSA', 'Chemical', 'MESH:C012589', (11, 14))	('potentiated', 'PosReg', (25, 36))	('FK228', 'Var', (19, 24))	('apoptosis', 'CPA', (50, 59))
247521	27698906	We observed decreased cell viability and increased cell apoptosis induced by cisplatin as HDAC1 was knockdown (Fig.5), which was inconsistent with other studies.	('knockdown', 'Var', (100, 109))	('increased', 'PosReg', (41, 50))	('HDAC1', 'Gene', '3065', (90, 95))	('decreased', 'NegReg', (12, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('cell viability', 'CPA', (22, 36))	('HDAC1', 'Gene', (90, 95))	('cell apoptosis', 'CPA', (51, 65))
247530	25813822	In addition, somatic LZTS1 mutations and promoter methylation were assessed to determine an association with clinicopathological data from IMPC patients.	('mutations', 'Var', (27, 36))	('LZTS1', 'Gene', '11178', (21, 26))	('patients', 'Species', '9606', (144, 152))	('LZTS1', 'Gene', (21, 26))	('association', 'Interaction', (92, 103))
247537	25813822	Risk factors of breast cancer include female gender, old age, inherited mutations (such as BRCA1 and BRCA2), family history of breast cancer, high breast tissue density, overweight or obese after menopause, use of menopausal hormone therapy (MHT), physical inactivity, and alcohol consumption (Global Cancer Facts & Figures, 2nd Edition, American Cancer Society).	('overweight', 'Phenotype', 'HP:0025502', (170, 180))	('obese', 'Disease', (184, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('BRCA1', 'Gene', '672', (91, 96))	('obese', 'Disease', 'MESH:D009765', (184, 189))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('BRCA1', 'Gene', (91, 96))	('mutations', 'Var', (72, 81))	('breast cancer', 'Disease', (16, 29))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('Cancer', 'Phenotype', 'HP:0002664', (301, 307))	('BRCA2', 'Gene', (101, 106))	('Cancer', 'Phenotype', 'HP:0002664', (347, 353))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('alcohol', 'Chemical', 'MESH:D000438', (273, 280))	('BRCA2', 'Gene', '675', (101, 106))	('obese after menopause', 'Phenotype', 'HP:0008209', (184, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
247550	25813822	Hypermethylation of LZTS1 CpG islands could be responsible for the reduced expression of LZTS1 in cancer cells.	('LZTS1', 'Gene', '11178', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('LZTS1', 'Gene', (89, 94))	('LZTS1', 'Gene', (20, 25))	('reduced', 'NegReg', (67, 74))	('cancer', 'Disease', (98, 104))	('LZTS1', 'Gene', '11178', (20, 25))	('expression', 'MPA', (75, 85))
247552	25813822	In addition, we determined whether somatic LZTS1 mutations and promoter methylation were associated with clinicopathological data from IMPC patients.	('associated', 'Reg', (89, 99))	('mutations', 'Var', (49, 58))	('LZTS1', 'Gene', (43, 48))	('IMPC', 'Disease', (135, 139))	('patients', 'Species', '9606', (140, 148))	('LZTS1', 'Gene', '11178', (43, 48))
247566	25813822	The sections were finally reviewed under a microscope independently by two pathologists and blindly scored for LZTS1 immunoreactivity into four categories using a previously reported scoring method: +++ or strong (96-100 % positive cells); ++ or moderate (51-95 % positive cells); + or weak (2-50 % positive cells); and:or absent (<2 % positive cells).	('+++', 'Var', (199, 202))	('LZTS1', 'Gene', (111, 116))	('LZTS1', 'Gene', '11178', (111, 116))
247567	25813822	We performed DHPLC analysis to sequence LZTS1 mutations.	('DHPLC', 'Chemical', '-', (13, 18))	('LZTS1', 'Gene', (40, 45))	('LZTS1', 'Gene', '11178', (40, 45))	('mutations', 'Var', (46, 55))
247585	25813822	In contrast, 62 % (62/100) of the IMPC tissue had LZTS1 protein loss or down-regulation (14 +++, 24 ++, 29 +, and 33 -) and significantly lower than normal tissues (chi2 = 25.655, P = 0.000; Table 2).	('protein loss', 'Disease', (56, 68))	('14 +++', 'Var', (89, 95))	('LZTS1', 'Gene', (50, 55))	('lower', 'NegReg', (138, 143))	('protein loss', 'Disease', 'MESH:D011488', (56, 68))	('LZTS1', 'Gene', '11178', (50, 55))	('down-regulation', 'NegReg', (72, 87))
247590	25813822	In IMPC tissue samples, mutations were localized on exon 3 (C3927G, Leu>Val).	('C3927G', 'Var', (60, 66))	('C3927G', 'Mutation', 'rs1055252269', (60, 66))	('Leu>Val', 'Var', (68, 75))
247597	25813822	We found that 18/18 (100 %) of the IMPC samples had LZTS1 promoter methylation.	('IMPC', 'Disease', (35, 39))	('LZTS1', 'Gene', (52, 57))	('LZTS1', 'Gene', '11178', (52, 57))	('methylation', 'Var', (67, 78))
247598	25813822	In contrast, 0/9 (0 %) of the normal breast tissue samples had LZTS1 promoter methylation.	('LZTS1', 'Gene', (63, 68))	('LZTS1', 'Gene', '11178', (63, 68))	('methylation', 'Var', (78, 89))
247599	25813822	Furthermore, Statistical analysis revealed LZTS1 promoter methylation was associated with the loss of LZTS1 protein expression (Table 4, P < 0.05).	('expression', 'MPA', (116, 126))	('loss', 'NegReg', (94, 98))	('LZTS1', 'Gene', (43, 48))	('protein', 'Protein', (108, 115))	('LZTS1', 'Gene', (102, 107))	('methylation', 'Var', (58, 69))	('LZTS1', 'Gene', '11178', (43, 48))	('LZTS1', 'Gene', '11178', (102, 107))
247603	25813822	In addition, reduced LZTS1 expression was associated with LZTS1 promoter methylation or mutation.	('mutation', 'Var', (88, 96))	('LZTS1', 'Gene', '11178', (21, 26))	('LZTS1', 'Gene', '11178', (58, 63))	('expression', 'MPA', (27, 37))	('promoter methylation', 'Var', (64, 84))	('LZTS1', 'Gene', (58, 63))	('LZTS1', 'Gene', (21, 26))	('reduced', 'NegReg', (13, 20))
247604	25813822	After that, we determined whether somatic LZTS1 mutations were associated with clinicopathological data from IMPC patients.	('LZTS1', 'Gene', '11178', (42, 47))	('associated', 'Reg', (63, 73))	('IMPC', 'Disease', (109, 113))	('LZTS1', 'Gene', (42, 47))	('patients', 'Species', '9606', (114, 122))	('mutations', 'Var', (48, 57))
247605	25813822	To date, studies have detected LZTS1 mutations in different cancers, but they are uncommon.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('LZTS1', 'Gene', '11178', (31, 36))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('mutations', 'Var', (37, 46))	('detected', 'Reg', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('LZTS1', 'Gene', (31, 36))
247608	25813822	found a missense mutation in one case of gastric carcinoma that also had LZTS1 loss.	('loss', 'NegReg', (79, 83))	('gastric carcinoma', 'Disease', 'MESH:D013274', (41, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('LZTS1', 'Gene', (73, 78))	('gastric carcinoma', 'Disease', (41, 58))	('LZTS1', 'Gene', '11178', (73, 78))	('missense mutation in', 'Var', (8, 28))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (41, 58))
247610	25813822	In this study, we also found one of these 53 IMPC samples had a mutation at exon 3, while 25 of the 53 IMPC samples had a base change in the intron region of LZTS1.	('LZTS1', 'Gene', (158, 163))	('mutation', 'Var', (64, 72))	('LZTS1', 'Gene', '11178', (158, 163))	('base change', 'MPA', (122, 133))
247611	25813822	But LZTS1 mutation was not the main cause for loss of LZTS1 expression in IMPC.	('LZTS1', 'Gene', (54, 59))	('mutation', 'Var', (10, 18))	('LZTS1', 'Gene', (4, 9))	('LZTS1', 'Gene', '11178', (54, 59))	('IMPC', 'Disease', (74, 78))	('LZTS1', 'Gene', '11178', (4, 9))
247614	25813822	However, LZTS1 promoter was more frequently methylated in IMPC samples and was associated with reduced levels of LZTS1 expression, indicating that LZTS1 plays a role in promoting IMPC progression at least through the promoter methylation-mediated transcriptional repressor.	('methylated', 'Var', (44, 54))	('IMPC', 'Disease', (179, 183))	('LZTS1', 'Gene', '11178', (147, 152))	('IMPC', 'Disease', (58, 62))	('LZTS1', 'Gene', (113, 118))	('LZTS1', 'Gene', '11178', (9, 14))	('promoting', 'PosReg', (169, 178))	('LZTS1', 'Gene', (147, 152))	('reduced', 'NegReg', (95, 102))	('LZTS1', 'Gene', '11178', (113, 118))	('LZTS1', 'Gene', (9, 14))	('levels', 'MPA', (103, 109))
247615	25813822	Therefore, we hypothesized that reactivation of the methylation-silenced gene could restore LZTS1 expression and inhibit IMPC metastasis.	('reactivation', 'Var', (32, 44))	('LZTS1', 'Gene', (92, 97))	('inhibit', 'NegReg', (113, 120))	('IMPC metastasis', 'CPA', (121, 136))	('LZTS1', 'Gene', '11178', (92, 97))	('restore', 'PosReg', (84, 91))	('expression', 'MPA', (98, 108))
247617	25813822	Indeed, our previous study showed that re-expression of LZTS1 in the highly metastatic MDA-MB-231 cell line resulted in an inhibition of cancer cell proliferation, migration and invasion, and suppression of epithelial-to-mesenchymal transition.	('suppression', 'NegReg', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('re-expression', 'Var', (39, 52))	('LZTS1', 'Gene', '11178', (56, 61))	('epithelial-to-mesenchymal transition', 'CPA', (207, 243))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (87, 97))	('inhibition', 'NegReg', (123, 133))	('cancer', 'Disease', (137, 143))	('LZTS1', 'Gene', (56, 61))
247621	24558407	Meta-Analysis of the Aldehyde Dehydrogenases-2 (ALDH2) Glu487Lys Polymorphism and Colorectal Cancer Risk A number of studies have explored the association of the aldehyde dehydrogenases-2 (ALDH2) Glu487Lys polymorphism and risk of colorectal cancer; however, the results are inconsistent.	('association', 'Interaction', (143, 154))	('Glu487Lys', 'Var', (55, 64))	('Glu487Lys', 'SUBSTITUTION', 'None', (196, 205))	('ALDH2', 'Gene', '217', (189, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (231, 248))	('ALDH2', 'Gene', '217', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (82, 99))	('Glu487Lys', 'SUBSTITUTION', 'None', (55, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (231, 248))	('ALDH2', 'Gene', (189, 194))	('ALDH2', 'Gene', (48, 53))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (82, 99))	('colorectal cancer', 'Disease', (231, 248))	('Glu487Lys', 'Var', (196, 205))	('Colorectal Cancer', 'Disease', (82, 99))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))
247624	24558407	Our results suggested that the ALDH2 Glu487Lys polymorphism may be associated with a decreased risk of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('decreased', 'NegReg', (85, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('Glu487Lys', 'Var', (37, 46))	('ALDH2', 'Gene', '217', (31, 36))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Glu487Lys', 'SUBSTITUTION', 'None', (37, 46))	('ALDH2', 'Gene', (31, 36))
247627	24558407	Many gene polymorphisms are associated with risk of colorectal cancer risk.	('associated', 'Reg', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('polymorphisms', 'Var', (10, 23))	('colorectal cancer', 'Disease', (52, 69))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
247631	24558407	ALDH2 (aldehyde dehydrogenases-2) is the major enzyme for acetaldehyde elimination, and its polymorphisms determine blood acetaldehyde concentrations after alcohol consumption.	('determine', 'Reg', (106, 115))	('alcohol', 'Chemical', 'MESH:D000438', (156, 163))	('polymorphisms', 'Var', (92, 105))	('ALDH2', 'Gene', (0, 5))	('acetaldehyde', 'Chemical', 'MESH:D000079', (122, 134))	('blood acetaldehyde concentrations', 'Phenotype', 'HP:0003533', (116, 149))	('acetaldehyde', 'Chemical', 'MESH:D000079', (58, 70))	('blood acetaldehyde concentrations', 'MPA', (116, 149))	('ALDH2', 'Gene', '217', (0, 5))
247632	24558407	The Glu487Lys polymorphism (also named Glu504Lys, or rs671, with the Glutamate corresponding to *1 allele, and Lysine corresponding to *2 allele, the exact position of the variant is 457 of NP_001191818.1 and 504 of NP_000681.2) has been the most frequently studied.	('Glu487Lys', 'SUBSTITUTION', 'None', (4, 13))	('Glu504Lys', 'Var', (39, 48))	('Glu504Lys', 'SUBSTITUTION', 'None', (39, 48))	('Glu487Lys', 'Var', (4, 13))	('Lysine', 'Chemical', 'MESH:D008239', (111, 117))	('rs671', 'Mutation', 'rs671', (53, 58))	('Glutamate', 'Chemical', 'MESH:D018698', (69, 78))
247633	24558407	A single nucleotide polymorphism at codon 487 in the ALDH2 gene leads to the substitution of glutamate (Glu) by lysine (Lys), which is highly prevalent among east Asians.	('single nucleotide polymorphism', 'Var', (2, 32))	('Glu', 'Chemical', 'MESH:D018698', (104, 107))	('ALDH2', 'Gene', (53, 58))	('Lys', 'Chemical', 'MESH:D008239', (120, 123))	('Glu', 'Protein', (104, 107))	('lysine', 'Chemical', 'MESH:D008239', (112, 118))	('substitution', 'Var', (77, 89))	('glutamate', 'Chemical', 'MESH:D018698', (93, 102))	('ALDH2', 'Gene', '217', (53, 58))	('leads to', 'Reg', (64, 72))
247634	24558407	Such a polymorphism (Glu to Lys, or G to A, or *1 to *2) generates an ALDH2 with much lower activity and causes much higher blood levels of acetaldehyde, which may contribute to susceptibility to carcinogenesis.	('Glu', 'Chemical', 'MESH:D018698', (21, 24))	('higher blood levels of acetaldehyde', 'Phenotype', 'HP:0003533', (117, 152))	('susceptibility', 'Reg', (178, 192))	('Lys', 'Chemical', 'MESH:D008239', (28, 31))	('Glu to Lys', 'Var', (21, 31))	('acetaldehyde', 'Chemical', 'MESH:D000079', (140, 152))	('blood levels of acetaldehyde', 'MPA', (124, 152))	('lower', 'NegReg', (86, 91))	('carcinogenesis', 'Disease', 'MESH:D063646', (196, 210))	('ALDH2', 'Gene', '217', (70, 75))	('contribute', 'Reg', (164, 174))	('carcinogenesis', 'Disease', (196, 210))	('higher', 'PosReg', (117, 123))	('activity', 'MPA', (92, 100))	('ALDH2', 'Gene', (70, 75))
247635	24558407	The Glu487Lys polymorphism has been reported to be associated with many types of cancer, such as esophageal cancer, head and neck cancer, gastric cancer and colorectal cancer.	('cancer', 'Disease', (146, 152))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('head and neck cancer', 'Phenotype', 'HP:0012288', (116, 136))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('Glu487Lys', 'SUBSTITUTION', 'None', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('colorectal cancer', 'Disease', (157, 174))	('esophageal cancer', 'Disease', (97, 114))	('head and neck cancer', 'Disease', 'MESH:D006258', (116, 136))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (108, 114))	('gastric cancer', 'Disease', (138, 152))	('cancer', 'Disease', (130, 136))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Glu487Lys', 'Var', (4, 13))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))
247637	24558407	Chiang's study found that the allele frequency of ALDH2 A was significantly higher in colorectal cancer cases; however, Miyasaka's study found that the A/A genotype of ALDH2 might not be a risk factor for colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('colorectal cancer', 'Disease', 'MESH:D015179', (205, 222))	('ALDH2', 'Gene', '217', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('ALDH2', 'Gene', (50, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (205, 222))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('A/A', 'Var', (152, 155))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ALDH2', 'Gene', (168, 173))	('colorectal cancer', 'Disease', (205, 222))	('higher', 'PosReg', (76, 82))	('ALDH2', 'Gene', '217', (50, 55))
247639	24558407	In view of the uncertain association between ALDH2 Glu487Lys polymorphism and colorectal cancer risk, we sought to obtain more precise information by conducting a meta-analysis including all of the evidence produced to date.	('Glu487Lys', 'SUBSTITUTION', 'None', (51, 60))	('ALDH2', 'Gene', '217', (45, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('colorectal cancer', 'Disease', (78, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ALDH2', 'Gene', (45, 50))	('Glu487Lys', 'Var', (51, 60))
247641	24558407	For an article to be included in the meta-analysis, it had to provide the following information: 1) the number of colorectal cancer cases and controls; and 2) the number of individuals with Glu/Glu, Glu/Lys and Lys/Lys in both colorectal cancer cases and controls.	('colorectal cancer', 'Phenotype', 'HP:0003003', (227, 244))	('Glu', 'Chemical', 'MESH:D018698', (199, 202))	('Glu/Lys', 'Var', (199, 206))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Lys/Lys', 'Var', (211, 218))	('Lys', 'Chemical', 'MESH:D008239', (215, 218))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('colorectal cancer', 'Disease', (227, 244))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('Glu', 'Chemical', 'MESH:D018698', (190, 193))	('Lys', 'Chemical', 'MESH:D008239', (211, 214))	('Glu', 'Chemical', 'MESH:D018698', (194, 197))	('Glu/Glu', 'Var', (190, 197))	('colorectal cancer', 'Disease', (114, 131))	('Lys', 'Chemical', 'MESH:D008239', (203, 206))	('colorectal cancer', 'Disease', 'MESH:D015179', (227, 244))
247643	24558407	The strength of the association between the ALDH2 Glu487Lys polymorphism and risk of colorectal cancer was assessed by odds ratios (ORs) with the corresponding 95%CI for each study.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('Glu487Lys', 'Var', (50, 59))	('ALDH2', 'Gene', (44, 49))	('Glu487Lys', 'SUBSTITUTION', 'None', (50, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('ALDH2', 'Gene', '217', (44, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
247647	24558407	Moreover, the p values from Begg's test and Egger's test were all greater than 0.05 (Table S2), indicating no publication bias To the best of our knowledge, this is the first meta-analysis to evaluate the association between an ALDH2 polymorphism and risk of colorectal cancer.	('polymorphism', 'Var', (234, 246))	('ALDH2', 'Gene', (228, 233))	('colorectal cancer', 'Disease', 'MESH:D015179', (259, 276))	('colorectal cancer', 'Phenotype', 'HP:0003003', (259, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('ALDH2', 'Gene', '217', (228, 233))	('colorectal cancer', 'Disease', (259, 276))
247664	24558407	Secondly, there was heterogeneity between studies of ALDH2 polymorphisms, and and meta-regression analysis was failed to find the potential heterogeneity.	('ALDH2', 'Gene', '217', (53, 58))	('polymorphisms', 'Var', (59, 72))	('ALDH2', 'Gene', (53, 58))
247665	24558407	Thirdly, all of the studies were conducted in Japan and China, and other high risk areas of CRC did not explore the relationship between ALDH2 polymorphism and CRC.	('CRC', 'Disease', (160, 163))	('ALDH2', 'Gene', (137, 142))	('polymorphism', 'Var', (143, 155))	('ALDH2', 'Gene', '217', (137, 142))
247666	24558407	In conclusion, this comprehensive meta-analysis has evaluated all published data currently available on the ALDH2 Glu487Lys polymorphism and risk of colorectal cancer.	('Glu487Lys', 'Var', (114, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('ALDH2', 'Gene', '217', (108, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('Glu487Lys', 'SUBSTITUTION', 'None', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colorectal cancer', 'Disease', (149, 166))	('ALDH2', 'Gene', (108, 113))
247667	24558407	Our meta-analysis suggested that the GA and GA+AA genotypes may reduce the risk of CRC compared with the GG genotype, which may be explained by the unpleasant symptoms of ALDH2 A carriers preventing them from consuming alcohol.	('reduce', 'NegReg', (64, 70))	('ALDH2', 'Gene', (171, 176))	('alcohol', 'Chemical', 'MESH:D000438', (219, 226))	('GA+AA', 'Var', (44, 49))	('preventing', 'NegReg', (188, 198))	('ALDH2', 'Gene', '217', (171, 176))	('CRC', 'Disease', (83, 86))
247754	21935353	We found one such target site at a cryptic "shadow" enhancer 7 kilobases (kb) downstream of the Cdx2 gene, where Rfx1 restricts transcriptional activation by FoxA.	('FoxA', 'Gene', (158, 162))	('transcriptional activation', 'MPA', (128, 154))	('shadow', 'Gene', (44, 50))	('restricts', 'NegReg', (118, 127))	('shadow', 'Gene', '44858', (44, 50))	('Cdx2', 'Gene', (96, 100))	('Rfx1', 'Var', (113, 117))
247760	21935353	Cdx2 encodes a transcription factor that promotes intestinal differentiation; ectopic expression of Cdx2 in the esophagus can help promote metaplasia and cancer.	('metaplasia', 'Disease', 'MESH:D008679', (139, 149))	('Cdx2', 'Gene', (100, 104))	('metaplasia', 'Disease', (139, 149))	('ectopic expression', 'Var', (78, 96))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('promote', 'PosReg', (131, 138))
247768	21935353	Indeed, chronic esophageal damage from reflux of gastro-duodenal contents can result in the aberrant expression of Cdx2 in the esophageal foregut epithelium and, together with other molecular changes, promotes metaplasia of the cells to an intestinal phenotype (Barrett's Esophagus) and subsequent adenocarcinoma.	('aberrant', 'Var', (92, 100))	('reflux of gastro', 'Phenotype', 'HP:0002020', (39, 55))	('result', 'Reg', (78, 84))	('adenocarcinoma', 'Disease', (298, 312))	('esophageal damage', 'Disease', (16, 33))	('Cdx2', 'Gene', (115, 119))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (262, 281))	('esophageal damage', 'Disease', 'MESH:D004935', (16, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (298, 312))	('metaplasia', 'Disease', 'MESH:D008679', (210, 220))	('promotes', 'PosReg', (201, 209))	('expression', 'MPA', (101, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('metaplasia', 'Disease', (210, 220))
247784	21935353	In contrast, the transcription factor motifs enriched at silent genes included those for Rfx (motif M00975), type II nuclear hormone receptors (motif M00964), USF (motif M00217), PAX5 (motif M00143), and CDC5 (motif M00478) (Figure 2C).	('USF', 'Gene', (159, 162))	('motif M00964', 'Var', (144, 156))	('USF', 'Gene', '7391', (159, 162))	('PAX5', 'Gene', (179, 183))	('PAX5', 'Gene', '5079', (179, 183))	('CDC5', 'Gene', '988', (204, 208))	('Rfx', 'Gene', (89, 92))	('motif M00975', 'Var', (94, 106))	('CDC5', 'Gene', (204, 208))	('Rfx', 'Gene', '5989', (89, 92))	('motif M00217', 'Var', (164, 176))	('motif M00478', 'Var', (210, 222))	('motif M00143', 'Var', (185, 197))
247795	21935353	We then created a series of luciferase reporter constructs with a wild type copy of the 500 bp+7 kb element, as well as variant elements with clustered mutations of the FoxA or Rfx sites, inserted downstream of the reporter (Figure 4C).	('Rfx', 'Gene', '5989', (177, 180))	('FoxA', 'Gene', (169, 173))	('Rfx', 'Gene', (177, 180))	('mutations', 'Var', (152, 161))
247796	21935353	In three independent HepG2 transfection experiments, each quantified in duplicate, the wild-type Cdx2 +7 kb enhancer elicited a ten-fold greater activity than the control plasmid in HepG2 cells (Figure 4C, "wt Cdx2 +7 kb").	('enhancer', 'PosReg', (108, 116))	('activity', 'MPA', (145, 153))	('Cdx2 +7 kb', 'Var', (97, 107))	('HepG2', 'CellLine', 'CVCL:0027', (182, 187))	('HepG2', 'CellLine', 'CVCL:0027', (21, 26))	('greater', 'PosReg', (137, 144))
247797	21935353	Mutation of the FoxA sites resulted in loss of enhancer activity (Figure 4B, "FoxA mut"), consistent with our results in transgenic mice.	('Mutation', 'Var', (0, 8))	('loss', 'NegReg', (39, 43))	('enhancer activity', 'MPA', (47, 64))	('transgenic mice', 'Species', '10090', (121, 136))	('FoxA', 'Gene', (16, 20))
247798	21935353	Strikingly, mutation of the Rfx site resulted in an increase in reporter activity, compared to the wild type element, demonstrating that factors that bind the site repress the Cdx2 enhancer (Figure 4B, "Rfx1 mut").	('enhancer', 'PosReg', (181, 189))	('Rfx', 'Gene', '5989', (203, 206))	('Rfx', 'Gene', '5989', (28, 31))	('increase', 'PosReg', (52, 60))	('Cdx2', 'Gene', (176, 180))	('reporter activity', 'MPA', (64, 81))	('mutation', 'Var', (12, 20))	('Rfx', 'Gene', (203, 206))	('Rfx', 'Gene', (28, 31))	('repress', 'NegReg', (164, 171))
247799	21935353	Simultaneous mutation of both the Rfx and FoxA sites resulted in a loss of enhancer activity, indicating that FoxA binding is necessary for the cryptic activity when the Rfx1 site is lost.	('Rfx', 'Gene', '5989', (34, 37))	('Rfx', 'Gene', (170, 173))	('mutation', 'Var', (13, 21))	('loss', 'NegReg', (67, 71))	('Rfx', 'Gene', '5989', (170, 173))	('enhancer activity', 'MPA', (75, 92))	('Rfx', 'Gene', (34, 37))
247815	21935353	Notably, though, upon Rfx1 knock-down we observed a 50% decrease in the CK14 and Sox2 mRNA levels (Figure 6).	('CK14', 'Gene', (72, 76))	('knock-down', 'Var', (27, 37))	('Rfx1', 'Gene', (22, 26))	('Sox2', 'Gene', '6657', (81, 85))	('CK14', 'Gene', '3861', (72, 76))	('decrease', 'NegReg', (56, 64))	('Sox2', 'Gene', (81, 85))
247816	21935353	Taken together with our observation that there is a marked decrease of Rfx1 expression in the epithelium of Barrett's esophagus with dysplasia, our findings suggest that Rfx1 helps control the maintenance of the squamous epithelial cell identity in the esophagus and hence antagonizes dysplasia.	('squamous epithelia', 'Disease', (212, 230))	('dysplasia', 'Disease', (285, 294))	('Rfx1', 'Gene', (71, 75))	('dysplasia', 'Disease', 'MESH:D004476', (285, 294))	('dysplasia', 'Disease', (133, 142))	('expression', 'MPA', (76, 86))	('decrease', 'NegReg', (59, 67))	('squamous epithelia', 'Disease', 'MESH:D002294', (212, 230))	('squamous epithelia', 'Phenotype', 'HP:0002860', (212, 230))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (108, 127))	('dysplasia', 'Disease', 'MESH:D004476', (133, 142))	('Rfx1', 'Var', (170, 174))
247820	21935353	We observed RXR enrichment at the Cdx2 +7 kb element as compared to a control site in the TTF1 gene (Figure 7A).	('RXR', 'Gene', '6256', (12, 15))	('RXR', 'Gene', (12, 15))	('TTF1', 'Gene', (90, 94))	('TTF1', 'Gene', '7270', (90, 94))	('Cdx2 +7 kb', 'Var', (34, 44))
247821	21935353	The extent of RXR enrichment at the Cdx2 +7 kb element was similar to that at the Cyp7a1 promoter, which contains a known type II nuclear hormone receptor binding site.	('RXR', 'Gene', (14, 17))	('Cyp7a1', 'Gene', '1581', (82, 88))	('Cyp7a1', 'Gene', (82, 88))	('RXR', 'Gene', '6256', (14, 17))	('Cdx2 +7 kb', 'Var', (36, 46))
247826	21935353	Indeed, FoxA1 has been implicated as a tumor promoting factor and is upregulated in a subset of esophageal cancers as a result of genomic amplification.	('FoxA1', 'Gene', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('esophageal cancers', 'Disease', (96, 114))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('esophageal cancers', 'Disease', 'MESH:D004938', (96, 114))	('upregulated', 'PosReg', (69, 80))	('tumor', 'Disease', (39, 44))	('genomic amplification', 'Var', (130, 151))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('FoxA1', 'Gene', '3169', (8, 13))
247827	21935353	In our studies, partial knock-down of Rfx1 was insufficient to alter FoxA1 levels (data not shown).	('insufficient', 'Disease', (47, 59))	('insufficient', 'Disease', 'MESH:D000309', (47, 59))	('knock-down', 'Var', (24, 34))	('alter', 'Reg', (63, 68))	('FoxA1', 'Gene', '3169', (69, 74))	('Rfx1', 'Gene', (38, 42))	('FoxA1', 'Gene', (69, 74))
247830	21935353	With regard to the small fraction of adenocarcinomas that retain Rfx1 expression, we suggest that either Rfx1 loss is not absolutely necessary for such progression or, like many other genes that are involved with cancer, the samples could, for example, contain point mutations that are not reflected in changes in protein abundance.	('adenocarcinomas', 'Disease', (37, 52))	('loss', 'NegReg', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Rfx1', 'Gene', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('point mutations', 'Var', (261, 276))	('cancer', 'Disease', (213, 219))	('contain', 'Reg', (253, 260))	('adenocarcinomas', 'Disease', 'MESH:D000230', (37, 52))
247832	21935353	For example, a meta-analysis showed that K-ras mutations progress from an occurrence in 36-44% of early stage pancreatic neoplasias to 87% in later stage cancers.	('K-ras', 'Gene', (41, 46))	('pancreatic neoplasias', 'Phenotype', 'HP:0002894', (110, 131))	('K-ras', 'Gene', '3845', (41, 46))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('neoplasias', 'Phenotype', 'HP:0002664', (121, 131))	('mutations', 'Var', (47, 56))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('pancreatic neoplasias', 'Disease', (110, 131))	('cancers', 'Disease', (154, 161))	('pancreatic neoplasias', 'Disease', 'MESH:D009369', (110, 131))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
247833	21935353	Mutations in p53 occur in frequencies of 25-80% in various cancers tested and mutation in APC occur in up to 83% of colorectal tumors tested; in both cases using tissue sample numbers comparable to those used here.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('colorectal tumors', 'Disease', 'MESH:D015179', (116, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal tumors', 'Disease', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Mutations', 'Var', (0, 9))	('APC', 'Disease', 'MESH:D011125', (90, 93))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('p53', 'Gene', (13, 16))	('cancers', 'Disease', (59, 66))	('APC', 'Disease', (90, 93))	('p53', 'Gene', '7157', (13, 16))
247838	21935353	Rfx1 expression was found to be down-regulated in gliomas as a result of promoter methylation and the reintroduction of Rfx1 in transfected glioma cells resulted in decreased cell proliferation, suggesting that Rfx1 may play a role as a tumor suppressor in glioma tumorigenesis.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('expression', 'MPA', (5, 15))	('Rfx1', 'Gene', (0, 4))	('Rfx1', 'Gene', (120, 124))	('down-regulated', 'NegReg', (32, 46))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('glioma', 'Disease', (257, 263))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('cell proliferation', 'CPA', (175, 193))	('tumor', 'Disease', (264, 269))	('gliomas', 'Disease', (50, 57))	('glioma', 'Disease', 'MESH:D005910', (257, 263))	('glioma', 'Disease', (50, 56))	('reintroduction', 'Var', (102, 116))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('decreased', 'NegReg', (165, 174))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', (237, 242))	('promoter methylation', 'Var', (73, 93))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('glioma', 'Disease', (140, 146))
247883	31556243	Patients with stage T0, T1a, and T1b ESCC were included in the study.	('ESCC', 'Disease', (37, 41))	('ESCC', 'Phenotype', 'HP:0011459', (37, 41))	('Patients', 'Species', '9606', (0, 8))	('T1a', 'Disease', (24, 27))	('ESCC', 'Disease', 'MESH:C562729', (37, 41))	('T1b', 'Var', (33, 36))
247900	31556243	However, the depth of tumor invasion was significantly different with the ESD group having more M1 lesions, while the MIE group had more SM1-3 lesions (P = 0.000).	('tumor invasion', 'Disease', 'MESH:D009361', (22, 36))	('SM1', 'Gene', '7911', (137, 140))	('SM1', 'Gene', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor invasion', 'Disease', (22, 36))	('M1 lesions', 'Var', (96, 106))
247952	31527639	FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy Definitive chemoradiotherapy (dCRT) is the major treatment for esophageal squamous cell carcinoma (ESCC), and prediction of the response to dCRT is important so as not to miss an opportunity to cure an ESCC.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('esophageal squamous cell carcinoma', 'Disease', (44, 78))	('ESCC', 'Disease', (313, 317))	('ESCC', 'Disease', (210, 214))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (174, 208))	('FGF5', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('FGF5', 'Gene', '2250', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('methylation', 'Var', (5, 16))	('dCRT', 'Gene', (251, 255))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (44, 78))	('esophageal squamous cell carcinoma', 'Disease', (174, 208))	('dCRT', 'Gene', (141, 145))	('ESCC', 'Disease', 'MESH:C562729', (210, 214))	('dCRT', 'Gene', '45841', (251, 255))	('ESCC', 'Disease', 'MESH:C562729', (313, 317))	('dCRT', 'Gene', '45841', (141, 145))
247954	31527639	In the screening cohort (n = 41), somatic mutations in 114 genes showed no association with dCRT response.	('somatic mutations', 'Var', (34, 51))	('dCRT', 'Gene', '45841', (92, 96))	('dCRT', 'Gene', (92, 96))	('association', 'Interaction', (75, 86))
247956	31527639	Among them, FGF5 methylation was validated to be associated with dCRT response (n = 34; P = 0.001), and further re-validated (n = 42; P = 0.020) by bisulfite-pyrosequencing.	('FGF5', 'Gene', '2250', (12, 16))	('methylation', 'Var', (17, 28))	('FGF5', 'Gene', (12, 16))	('dCRT', 'Gene', '45841', (65, 69))	('dCRT', 'Gene', (65, 69))	('associated with', 'Reg', (49, 64))	('bisulfite', 'Chemical', 'MESH:C042345', (148, 157))
247957	31527639	The sensitivity and specificity in the combined validation and re-validation sets (n = 76) were 45% and 90%, respectively, by using the cut-off value established in the screening set, and FGF5 methylation had predictive power independent from clinicopathological parameters.	('methylation', 'Var', (193, 204))	('FGF5', 'Gene', (188, 192))	('FGF5', 'Gene', '2250', (188, 192))
247958	31527639	In ESCC cell lines, FGF5 promoter methylation repressed its expression.	('expression', 'MPA', (60, 70))	('methylation', 'Var', (34, 45))	('ESCC', 'Disease', 'MESH:C562729', (3, 7))	('ESCC', 'Disease', (3, 7))	('FGF5', 'Gene', (20, 24))	('FGF5', 'Gene', '2250', (20, 24))
247962	31527639	These results showed that FGF5 methylation is a validated marker for ESCC sensitivity to dCRT.	('dCRT', 'Gene', '45841', (89, 93))	('ESCC', 'Disease', 'MESH:C562729', (69, 73))	('FGF5', 'Gene', '2250', (26, 30))	('dCRT', 'Gene', (89, 93))	('methylation', 'Var', (31, 42))	('FGF5', 'Gene', (26, 30))	('ESCC', 'Disease', (69, 73))
247970	31527639	Indeed, associations of the response with a genotype (GALNT14), gene expression (MDM2, LOC285194, and SIM2), and gene methylation (ZNF695) have been reported.	('gene expression', 'MPA', (64, 79))	('LOC285194', 'Chemical', 'MESH:C492399', (87, 96))	('GALNT14', 'Gene', (54, 61))	('SIM2', 'Gene', (102, 106))	('ZNF695', 'Gene', (131, 137))	('SIM2', 'Gene', '6493', (102, 106))	('LOC285194', 'Var', (87, 96))	('MDM2', 'Gene', '4193', (81, 85))	('associations', 'Interaction', (8, 20))	('MDM2', 'Gene', (81, 85))	('GALNT14', 'Gene', '79623', (54, 61))	('ZNF695', 'Gene', '57116', (131, 137))	('response', 'MPA', (28, 36))
248010	31527639	To the above 41 ESCC samples analyzed for the mutations, we added three samples of peripheral leukocytes and 12 samples of normal esophageal mucosae.	('ESCC', 'Disease', (16, 20))	('mutations', 'Var', (46, 55))	('ESCC', 'Disease', 'MESH:C562729', (16, 20))
248019	31527639	These results in the screening, validation, and re-validation sets demonstrated that FGF5 methylation was associated with the response to dCRT with a high specificity.	('associated with', 'Reg', (106, 121))	('dCRT', 'Gene', '45841', (138, 142))	('dCRT', 'Gene', (138, 142))	('methylation', 'Var', (90, 101))	('FGF5', 'Gene', (85, 89))	('FGF5', 'Gene', '2250', (85, 89))
248021	31527639	Univariate analyses showed that gender, clinical T stage, clinical N stage, clinical M stage, and FGF5 methylation were significantly associated with the response to dCRT (Table 1).	('associated', 'Reg', (134, 144))	('clinical', 'Species', '191496', (58, 66))	('clinical', 'Species', '191496', (76, 84))	('FGF5', 'Gene', (98, 102))	('clinical', 'Species', '191496', (40, 48))	('FGF5', 'Gene', '2250', (98, 102))	('dCRT', 'Gene', '45841', (166, 170))	('methylation', 'Var', (103, 114))	('dCRT', 'Gene', (166, 170))
248022	31527639	A multivariate logistic regression analysis involving gender, clinical T stage, clinical N stage, clinical M stage, and FGF5 methylation showed that FGF5 methylation was an independent predictive factor for the response to dCRT (OR 6.17, 95% CI 2.06-18.34, P = 0.001).	('response', 'MPA', (211, 219))	('clinical', 'Species', '191496', (62, 70))	('FGF5', 'Gene', (149, 153))	('methylation', 'Var', (154, 165))	('FGF5', 'Gene', '2250', (149, 153))	('dCRT', 'Gene', '45841', (223, 227))	('dCRT', 'Gene', (223, 227))	('clinical', 'Species', '191496', (80, 88))	('FGF5', 'Gene', (120, 124))	('FGF5', 'Gene', '2250', (120, 124))	('clinical', 'Species', '191496', (98, 106))
248030	31527639	These showed that FGF5 promoter methylation repressed its expression, as is observed for methylation of promoter CpG islands of many genes.	('FGF5', 'Gene', (18, 22))	('methylation', 'Var', (32, 43))	('FGF5', 'Gene', '2250', (18, 22))	('expression', 'MPA', (58, 68))
248033	31527639	In contrast, in KYSE-170 and 180 cells with high FGF5 methylation, FGF5 expression was not induced, even after CDDP treatment (Fig.	('high', 'Var', (44, 48))	('methylation', 'Var', (54, 65))	('FGF5', 'Gene', '2250', (67, 71))	('CDDP', 'Chemical', 'MESH:D002945', (111, 115))	('expression', 'MPA', (72, 82))	('FGF5', 'Gene', (67, 71))	('FGF5', 'Gene', (49, 53))	('FGF5', 'Gene', '2250', (49, 53))
248035	31527639	Further, the impact of FGF5 expression on sensitivity to CDDP was analyzed by expressing FGF5 in KYSE-180 cells with FGF5 promoter hypermethylation (Fig.	('CDDP', 'Chemical', 'MESH:D002945', (57, 61))	('FGF5', 'Gene', (117, 121))	('hypermethylation', 'Var', (131, 147))	('FGF5', 'Gene', (23, 27))	('FGF5', 'Gene', '2250', (23, 27))	('FGF5', 'Gene', (89, 93))	('FGF5', 'Gene', '2250', (89, 93))	('FGF5', 'Gene', '2250', (117, 121))
248037	31527639	This suggested that FGF5 is induced by dCRT and confers resistance, but that its methylation disables the induction and confers sensitivity.	('dCRT', 'Gene', (39, 43))	('disables', 'NegReg', (93, 101))	('confers', 'NegReg', (120, 127))	('methylation', 'Var', (81, 92))	('induction', 'MPA', (106, 115))	('sensitivity', 'MPA', (128, 139))	('FGF5', 'Gene', (20, 24))	('FGF5', 'Gene', '2250', (20, 24))	('resistance', 'MPA', (56, 66))	('dCRT', 'Gene', '45841', (39, 43))
248040	31527639	The FGF5 methylation in normal esophageal mucosae, being 9.4% at the highest, suggested that the FGF5 methylation was the consequence of its low expression in normal esophageal mucosae.	('FGF5', 'Gene', (97, 101))	('FGF5', 'Gene', '2250', (97, 101))	('methylation', 'Var', (102, 113))	('expression', 'MPA', (145, 155))	('FGF5', 'Gene', '2250', (4, 8))	('FGF5', 'Gene', (4, 8))
248042	31527639	In the present study, we discovered that FGF5 methylation is a sensitivity marker of ESCC to dCRT.	('methylation', 'Var', (46, 57))	('ESCC', 'Disease', (85, 89))	('dCRT', 'Gene', '45841', (93, 97))	('FGF5', 'Gene', (41, 45))	('FGF5', 'Gene', '2250', (41, 45))	('dCRT', 'Gene', (93, 97))	('ESCC', 'Disease', 'MESH:C562729', (85, 89))
248044	31527639	Therefore, patients who are predicted to be sensitive to dCRT by FGF5 methylation should respond to dCRT with a high probability.	('FGF5', 'Gene', (65, 69))	('dCRT', 'Gene', '45841', (57, 61))	('dCRT', 'Gene', (57, 61))	('dCRT', 'Gene', '45841', (100, 104))	('dCRT', 'Gene', (100, 104))	('methylation', 'Var', (70, 81))	('patients', 'Species', '9606', (11, 19))	('FGF5', 'Gene', '2250', (65, 69))
248045	31527639	Therefore, FGF5 methylation is a promising sensitivity marker for ESCC to dCRT.	('FGF5', 'Gene', (11, 15))	('ESCC', 'Disease', 'MESH:C562729', (66, 70))	('ESCC', 'Disease', (66, 70))	('dCRT', 'Gene', '45841', (74, 78))	('methylation', 'Var', (16, 27))	('FGF5', 'Gene', '2250', (11, 15))	('dCRT', 'Gene', (74, 78))
248046	31527639	FGF5 methylation was in its promoter CpG island, and, when methylation was present, it consistently repressed FGF5 expression.	('repressed', 'NegReg', (100, 109))	('methylation', 'Var', (5, 16))	('expression', 'MPA', (115, 125))	('FGF5', 'Gene', (0, 4))	('FGF5', 'Gene', '2250', (0, 4))	('FGF5', 'Gene', (110, 114))	('FGF5', 'Gene', '2250', (110, 114))
248052	31527639	If FGF5 is methylated, FGF5 cannot be induced, and this will lead to cell death and thus clinical response.	('lead to', 'Reg', (61, 68))	('FGF5', 'Gene', (23, 27))	('FGF5', 'Gene', '2250', (23, 27))	('methylated', 'Var', (11, 21))	('death', 'Disease', 'MESH:D003643', (74, 79))	('clinical response', 'CPA', (89, 106))	('FGF5', 'Gene', '2250', (3, 7))	('clinical', 'Species', '191496', (89, 97))	('FGF5', 'Gene', (3, 7))	('death', 'Disease', (74, 79))
248054	31527639	The importance of FGF5 expression for resistance to dCRT suggests that inhibition of FGF5 or its pathway may have therapeutic benefit in increasing the response to dCRT of ESCC, especially when FGF5 is not methylated.	('FGF5', 'Gene', (18, 22))	('inhibition', 'Var', (71, 81))	('FGF5', 'Gene', (194, 198))	('FGF5', 'Gene', '2250', (194, 198))	('dCRT', 'Gene', '45841', (164, 168))	('ESCC', 'Disease', 'MESH:C562729', (172, 176))	('increasing', 'PosReg', (137, 147))	('dCRT', 'Gene', (164, 168))	('dCRT', 'Gene', '45841', (52, 56))	('dCRT', 'Gene', (52, 56))	('FGF5', 'Gene', (85, 89))	('FGF5', 'Gene', '2250', (85, 89))	('ESCC', 'Disease', (172, 176))	('FGF5', 'Gene', '2250', (18, 22))
248056	31527639	Therefore, if an ESCC develops from an esophageal cell with FGF5 methylation, the ESCC is expected to be sensitive to dCRT (Fig.	('ESCC', 'Disease', 'MESH:C562729', (17, 21))	('ESCC', 'Disease', (82, 86))	('ESCC', 'Disease', (17, 21))	('FGF5', 'Gene', (60, 64))	('FGF5', 'Gene', '2250', (60, 64))	('methylation', 'Var', (65, 76))	('dCRT', 'Gene', '45841', (118, 122))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))	('dCRT', 'Gene', (118, 122))
248058	31527639	In general, it is reported that a gene tends to be methylated when it is not expressed, and accumulation of aberrant DNA methylation of various genes, including drivers and passengers, leads to predisposition to cancer.	('aberrant', 'Var', (108, 116))	('leads to predisposition', 'Reg', (185, 208))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
248059	31527639	Taken together, it was considered that the lack of FGF5 expression in normal esophageal mucosa facilitated FGF5 methylation to creep into some esophageal cells, and that, when an ESCC happened to develop from such a cell with FGF5 methylation, the ESCC paradoxically showed sensitivity to dCRT.	('FGF5', 'Gene', (107, 111))	('FGF5', 'Gene', '2250', (107, 111))	('ESCC', 'Disease', 'MESH:C562729', (179, 183))	('ESCC', 'Disease', 'MESH:C562729', (248, 252))	('lack', 'Var', (43, 47))	('facilitated', 'PosReg', (95, 106))	('ESCC', 'Disease', (179, 183))	('dCRT', 'Gene', '45841', (289, 293))	('FGF5', 'Gene', (226, 230))	('FGF5', 'Gene', '2250', (226, 230))	('dCRT', 'Gene', (289, 293))	('FGF5', 'Gene', (51, 55))	('FGF5', 'Gene', '2250', (51, 55))	('methylation', 'MPA', (112, 123))	('ESCC', 'Disease', (248, 252))
248061	31527639	We identified that FGF5 methylation was associated with the sensitivity of ESCC to dCRT.	('FGF5', 'Gene', (19, 23))	('FGF5', 'Gene', '2250', (19, 23))	('ESCC', 'Disease', (75, 79))	('dCRT', 'Gene', (83, 87))	('methylation', 'Var', (24, 35))	('dCRT', 'Gene', '45841', (83, 87))	('sensitivity', 'Disease', (60, 71))	('associated', 'Reg', (40, 50))	('ESCC', 'Disease', 'MESH:C562729', (75, 79))
248062	31527639	Collections of samples: J.I., T.K., T.T., I.O., K.K., H.I., Y.T., H.D., H.N., Y.-C.L.	('T.T', 'Disease', 'MESH:D001260', (36, 39))	('T.T', 'Disease', (36, 39))	('H.I.', 'Var', (54, 58))	('K.K.', 'Var', (48, 52))
248176	31116509	In addition, knockdown of MALAT1 attenuated the stemness of ESCC cells, as evidenced by a decrease in spheroid formation capacity, stemness marker expression and aldehyde dehydrogenase 1 activity.	('decrease', 'NegReg', (90, 98))	('MALAT1', 'Gene', (26, 32))	('aldehyde dehydrogenase 1', 'Gene', '216', (162, 186))	('expression', 'MPA', (147, 157))	('activity', 'MPA', (187, 195))	('aldehyde dehydrogenase 1', 'Gene', (162, 186))	('attenuated', 'NegReg', (33, 43))	('spheroid formation capacity', 'CPA', (102, 129))	('stemness marker', 'CPA', (131, 146))	('stemness of', 'CPA', (48, 59))	('knockdown', 'Var', (13, 22))
248178	31116509	Overexpression of YAP partially rescued the effect of MALAT1 knockdown on stemness and radiosensitivity of ESCC cells.	('stemness', 'CPA', (74, 82))	('YAP', 'Gene', (18, 21))	('radiosensitivity', 'CPA', (87, 103))	('knockdown', 'Var', (61, 70))	('MALAT1', 'Gene', (54, 60))	('YAP', 'Gene', '10413', (18, 21))
248190	31116509	Mesenchymal stem cells could induce lncRNA MACC1-AS1 expression, which promotes the fatty acid oxidation-dependent stemness of gastric cancer cells 8.	('MACC1', 'Gene', (43, 48))	('stemness of gastric cancer', 'Disease', 'MESH:D013274', (115, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('MACC1', 'Gene', '346389', (43, 48))	('promotes', 'PosReg', (71, 79))	('fatty acid', 'Chemical', 'MESH:D005227', (84, 94))	('lncRNA', 'Var', (36, 42))	('stemness of gastric cancer', 'Disease', (115, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('fatty acid oxidation-dependent', 'MPA', (84, 114))	('AS1', 'Gene', '5729', (49, 52))	('AS1', 'Gene', (49, 52))
248198	31116509	In addition to being regulated by the upstream Hippo pathway, YAP activity is regulated by other factors, for example, statin blocks the YAP-CD44 axis and subsequently attenuates the stemness of malignant mesothelioma cells 17.	('attenuates', 'NegReg', (168, 178))	('stemness of malignant mesothelioma', 'Disease', 'MESH:C562839', (183, 217))	('blocks', 'NegReg', (126, 132))	('statin', 'Var', (119, 125))	('YAP', 'Gene', (62, 65))	('YAP', 'Gene', '10413', (137, 140))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (195, 217))	('CD44', 'Gene', '960', (141, 145))	('YAP', 'Gene', '10413', (62, 65))	('stemness of malignant mesothelioma', 'Disease', (183, 217))	('YAP', 'Gene', (137, 140))	('CD44', 'Gene', (141, 145))
248220	31116509	As expected, knockdown of MALAT1 reduced the expression of stemness markers (SOX2 and Nanog) in ESCC cells (Fig.	('Nanog', 'Gene', (86, 91))	('MALAT1', 'Gene', (26, 32))	('expression', 'MPA', (45, 55))	('SOX2', 'Gene', (77, 81))	('reduced', 'NegReg', (33, 40))	('SOX2', 'Gene', '6657', (77, 81))	('Nanog', 'Gene', '79923', (86, 91))	('knockdown', 'Var', (13, 22))
248225	31116509	As expected, knockdown of MALAT1 decreased YAP transcriptional activity, which is characterized by the decrease in 8xGTIIC-luciferase plasmid activity (Fig.	('MALAT1', 'Gene', (26, 32))	('YAP', 'Gene', '10413', (43, 46))	('YAP', 'Gene', (43, 46))	('8xGTIIC-luciferase plasmid activity', 'MPA', (115, 150))	('decreased', 'NegReg', (33, 42))	('decrease', 'NegReg', (103, 111))	('knockdown', 'Var', (13, 22))
248226	31116509	Consistently, knockdown of MALAT1 decreased expression of connective tissue growth factor, a target of YAP (Fig.	('connective tissue growth factor', 'Gene', '1490', (58, 89))	('YAP', 'Gene', '10413', (103, 106))	('expression', 'MPA', (44, 54))	('decreased', 'NegReg', (34, 43))	('connective tissue growth factor', 'Gene', (58, 89))	('YAP', 'Gene', (103, 106))	('MALAT1', 'Gene', (27, 33))	('knockdown', 'Var', (14, 23))
248227	31116509	Furthermore, knockdown of MALAT1 reduced YAP protein level (Fig.	('YAP', 'Gene', (41, 44))	('MALAT1', 'Gene', (26, 32))	('reduced', 'NegReg', (33, 40))	('YAP', 'Gene', '10413', (41, 44))	('knockdown', 'Var', (13, 22))
248229	31116509	Notably, the level of mRNA and promoter activity of YAP were unaffected by knockdown of MALAT1 (Fig.	('YAP', 'Gene', (52, 55))	('knockdown', 'Var', (75, 84))	('mRNA', 'MPA', (22, 26))	('MALAT1', 'Gene', (88, 94))	('promoter activity', 'MPA', (31, 48))	('YAP', 'Gene', '10413', (52, 55))
248234	31116509	5B-D, overexpression of YAP saved the expression of stemness markers which was decreased by knockdown of MALAT1.	('stemness markers', 'CPA', (52, 68))	('YAP', 'Gene', (24, 27))	('knockdown', 'Var', (92, 101))	('expression of', 'MPA', (38, 51))	('YAP', 'Gene', '10413', (24, 27))
248235	31116509	Additionally, the reduced capacity of spheroid formation induced by knockdown of MALAT1 was partially nullified by YAP overexpression (Fig.	('MALAT1', 'Gene', (81, 87))	('YAP', 'Gene', '10413', (115, 118))	('reduced', 'NegReg', (18, 25))	('YAP', 'Gene', (115, 118))	('knockdown', 'Var', (68, 77))	('spheroid formation', 'CPA', (38, 56))
248238	31116509	Moreover, the enhanced radiosensitivity induced by knockdown of MALAT1 was partially reversed by YAP overexpression (Fig.	('YAP', 'Gene', '10413', (97, 100))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (14, 39))	('enhanced', 'PosReg', (14, 22))	('YAP', 'Gene', (97, 100))	('radiosensitivity', 'CPA', (23, 39))	('MALAT1', 'Gene', (64, 70))	('knockdown', 'Var', (51, 60))
248245	31116509	Additionally, MALAT1 suppresses glioma progression via reduction of extracellular signal-regulated kinase/mitogen-activated protein kinase signaling activity and expression of matrix metalloproteinase 2 33.	('reduction', 'NegReg', (55, 64))	('glioma', 'Disease', (32, 38))	('matrix metalloproteinase 2', 'Gene', '4313', (176, 202))	('expression', 'MPA', (162, 172))	('matrix metalloproteinase 2', 'Gene', (176, 202))	('suppresses', 'NegReg', (21, 31))	('MALAT1', 'Var', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))
248253	31116509	It is speculated that MALAT1 might enhance YAP protein stability and suppress its degradation, but this needs further investigation.	('MALAT1', 'Var', (22, 28))	('YAP', 'Gene', '10413', (43, 46))	('enhance', 'PosReg', (35, 42))	('degradation', 'MPA', (82, 93))	('YAP', 'Gene', (43, 46))	('suppress', 'NegReg', (69, 77))
248297	30142158	Another example is that aberrant expression level of hsa-mir-16 (3rd in the prediction list) could suppress cell apoptosis while promote growth by regulating the reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and the ex-determining region Y-related high-mobility-group box transcription factor 6 (SOX6) which play important roles in the pathogenesis of ESCC.	('RECK', 'Gene', (222, 226))	('mir-16', 'Gene', '51573', (57, 63))	('promote', 'PosReg', (129, 136))	('aberrant', 'Var', (24, 32))	('SOX6', 'Gene', (316, 320))	('RECK', 'Gene', '8434', (222, 226))	('SOX6', 'Gene', '55553', (316, 320))	('suppress', 'NegReg', (99, 107))	('expression', 'MPA', (33, 43))	('mir-16', 'Gene', (57, 63))	('growth', 'CPA', (137, 143))	('ESCC', 'Disease', (372, 376))	('cell apoptosis', 'CPA', (108, 122))
248315	30142158	Taking first-ranked hsa-let-7e as an example, research confirmed that umonji/Arid1 B (JARID1B) promoted breast tumor cell cycle progression through epigenetic repression of hsa-let-7e.	('promoted', 'PosReg', (95, 103))	('hsa-let-7e', 'Gene', '406887', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('hsa-let-7e', 'Gene', (173, 183))	('breast tumor', 'Disease', (104, 116))	('JARID1B', 'Gene', '10765', (86, 93))	('JARID1B', 'Gene', (86, 93))	('hsa-let-7e', 'Gene', '406887', (20, 30))	('Arid1 B', 'Gene', (77, 84))	('breast tumor', 'Phenotype', 'HP:0100013', (104, 116))	('hsa-let-7e', 'Gene', (20, 30))	('epigenetic repression', 'Var', (148, 169))	('Arid1 B', 'Gene', '57492', (77, 84))	('breast tumor', 'Disease', 'MESH:D001943', (104, 116))
248367	24724600	The prevalence of hiatal hernia was significantly higher in subjects of Turkmen ethnicity (18.5%) than in non-Turkmens (9.8%; P value=0.03).	('hiatal hernia', 'Disease', 'MESH:D006551', (18, 31))	('higher', 'PosReg', (50, 56))	('hiatal hernia', 'Disease', (18, 31))	('men', 'Species', '9606', (114, 117))	('hernia', 'Phenotype', 'HP:0100790', (25, 31))	('men', 'Species', '9606', (76, 79))	('hiatal hernia', 'Phenotype', 'HP:0002036', (18, 31))	('Turkmen ethnicity', 'Var', (72, 89))
248389	24724600	In our study, the prevalence of hiatal hernia and GERD were approximately twice higher in Turkmen than non-Turkmen subjects.	('men', 'Species', '9606', (111, 114))	('men', 'Species', '9606', (94, 97))	('Turkmen', 'Var', (90, 97))	('hiatal hernia', 'Disease', 'MESH:D006551', (32, 45))	('GERD', 'Disease', 'MESH:D005764', (50, 54))	('hiatal hernia', 'Disease', (32, 45))	('hernia', 'Phenotype', 'HP:0100790', (39, 45))	('GERD', 'Disease', (50, 54))	('higher', 'PosReg', (80, 86))	('hiatal hernia', 'Phenotype', 'HP:0002036', (32, 45))
248395	28404937	Genetic polymorphisms are associated with the risk of gastric and colorectal cancers in a Han Chinese population Here, we genotyped eleven single-nucleotide polymorphisms (SNPs) and evaluated their association with the risk of developing gastric cancer (GC) or colorectal cancer (CRC) in 1,790 Han Chinese participants (588 GC patients, 499 CRC patients, and 703 healthy controls).	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('gastric cancer', 'Disease', (238, 252))	('colorectal cancers', 'Disease', 'MESH:D015179', (66, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (261, 278))	('participants', 'Species', '9606', (306, 318))	('single-nucleotide polymorphisms', 'Var', (139, 170))	('gastric cancer', 'Disease', 'MESH:D013274', (238, 252))	('GC', 'Phenotype', 'HP:0012126', (324, 326))	('GC', 'Phenotype', 'HP:0012126', (254, 256))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('CRC', 'Phenotype', 'HP:0003003', (280, 283))	('colorectal cancer', 'Disease', 'MESH:D015179', (261, 278))	('patients', 'Species', '9606', (345, 353))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('colorectal cancers', 'Disease', (66, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (238, 252))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (261, 278))	('patients', 'Species', '9606', (327, 335))	('CRC', 'Phenotype', 'HP:0003003', (341, 344))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
248396	28404937	Statistically analysis showed that the "C" allele of rs2689154 in MIPEPP2 was associated with a decreased risk of GC (odds ratio [OR] = 0.81, 95 % confidence interval [CI]: 0.66-0.99, P = 0.041), whereas the "T" allele of rs12615966 in LOC284998 was associated with a 1.29-fold increase in the risk of GC (OR = 1.29, 95% CI: 1.03-1.63, P = 0.029).	('GC', 'Phenotype', 'HP:0012126', (302, 304))	('rs2689154', 'Mutation', 'rs2689154', (53, 62))	('decreased', 'NegReg', (96, 105))	('rs12615966', 'Mutation', 'rs12615966', (222, 232))	('MIPEPP2', 'Gene', '100130099', (66, 73))	('GC', 'Phenotype', 'HP:0012126', (114, 116))	('MIPEPP2', 'Gene', (66, 73))	('rs2689154', 'Var', (53, 62))
248397	28404937	Additionally, genetic model analyses showed that rs2689154 was associated with a reduced risk of GC under the recessive model (adjusted OR = 0.46, 95% CI: 0.22-0.98, P = 0.037), and rs12615966 in FOXF1 was associated with an increased risk of GC in both the dominant and log-additive models after adjusted for age and gender (adjusted OR = 1.36, 95% CI: 1.02-1.81, P = 0.033; adjusted OR = 1.36, 95% CI: 1.05-1.75, P = 0.018, respectively).	('rs12615966', 'Var', (182, 192))	('rs12615966', 'Mutation', 'rs12615966', (182, 192))	('FOXF1', 'Gene', '2294', (196, 201))	('rs2689154', 'Var', (49, 58))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('reduced', 'NegReg', (81, 88))	('FOXF1', 'Gene', (196, 201))	('rs2689154', 'Mutation', 'rs2689154', (49, 58))	('GC', 'Phenotype', 'HP:0012126', (243, 245))
248398	28404937	We also observed that rs2178146 in FOXF1 was associated with an increased risk of CRC in the recessive model (adjusted OR = 1.90, 95% CI: 1.05-3.45, P = 0.034).	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('FOXF1', 'Gene', (35, 40))	('FOXF1', 'Gene', '2294', (35, 40))	('CRC', 'Disease', (82, 85))	('rs2178146', 'Var', (22, 31))	('rs2178146', 'Mutation', 'rs2178146', (22, 31))
248399	28404937	Our results confirmed that rs2689154 in MIPEPP2 was significantly decreased GC risk, but rs12615966 in LOC284998 was significantly increased GC risk, and rs2178146 in FOXF1 was associated with increased CRC risk in the Han Chinese population.	('rs12615966', 'Var', (89, 99))	('MIPEPP2', 'Gene', '100130099', (40, 47))	('increased', 'PosReg', (131, 140))	('MIPEPP2', 'Gene', (40, 47))	('rs12615966', 'Mutation', 'rs12615966', (89, 99))	('rs2689154', 'Var', (27, 36))	('decreased', 'NegReg', (66, 75))	('rs2689154', 'Mutation', 'rs2689154', (27, 36))	('CRC', 'Phenotype', 'HP:0003003', (203, 206))	('GC', 'Phenotype', 'HP:0012126', (141, 143))	('GC', 'Phenotype', 'HP:0012126', (76, 78))	('FOXF1', 'Gene', (167, 172))	('CRC', 'Disease', (203, 206))	('rs2178146', 'Mutation', 'rs2178146', (154, 163))	('rs2178146', 'Var', (154, 163))	('FOXF1', 'Gene', '2294', (167, 172))
248405	28404937	Genome-wide association studies (GWAS) have demonstrated that rs2689154 (MIPEPP2), rs4927850 (LOC105374300), rs2255280 (DAB2), rs12615966 (LOC284998), rs7574865 (STAT4), and rs3790844 (NR5A2) SNPs are associated with an increased risk of pancreatic cancer in Japanese and Chinese population.	('STAT4', 'Gene', (162, 167))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 255))	('pancreatic cancer', 'Disease', (238, 255))	('rs2689154', 'Mutation', 'rs2689154', (62, 71))	('DAB2', 'Gene', '1601', (120, 124))	('MIPEPP2', 'Gene', '100130099', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('rs2255280', 'Mutation', 'rs2255280', (109, 118))	('rs2255280', 'Var', (109, 118))	('rs7574865', 'Var', (151, 160))	('rs4927850', 'Mutation', 'rs4927850', (83, 92))	('DAB2', 'Gene', (120, 124))	('rs7574865', 'Mutation', 'rs7574865', (151, 160))	('rs3790844', 'Var', (174, 183))	('MIPEPP2', 'Gene', (73, 80))	('rs12615966', 'Var', (127, 137))	('rs2689154', 'Var', (62, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (238, 255))	('rs4927850', 'Var', (83, 92))	('NR5A2', 'Gene', '2494', (185, 190))	('NR5A2', 'Gene', (185, 190))	('STAT4', 'Gene', '6775', (162, 167))	('rs3790844', 'Mutation', 'rs3790844', (174, 183))	('pancreatic cancer', 'Disease', 'MESH:D010190', (238, 255))	('rs12615966', 'Mutation', 'rs12615966', (127, 137))
248406	28404937	Additionally, some reports have shown that rs12100561 (C14orf143), rs2178146 (FOXF1), and rs1050631 (SLC39A6) are associated with increased susceptibility to hepatocellular carcinoma, esophageal adenocarcinoma, and esophageal squamous-cell carcinoma, respectively.	('esophageal adenocarcinoma', 'Disease', (184, 209))	('esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (215, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('esophageal squamous-cell carcinoma', 'Disease', (215, 249))	('hepatocellular carcinoma', 'Disease', (158, 182))	('rs12100561', 'Mutation', 'rs12100561', (43, 53))	('rs1050631', 'Var', (90, 99))	('rs1050631', 'Mutation', 'rs1050631', (90, 99))	('rs2178146', 'Var', (67, 76))	('SLC39A6', 'Gene', '25800', (101, 108))	('rs12100561', 'Var', (43, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('SLC39A6', 'Gene', (101, 108))	('rs2178146', 'Mutation', 'rs2178146', (67, 76))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (226, 249))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (158, 182))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (184, 209))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (184, 209))	('FOXF1', 'Gene', (78, 83))	('C14orf143', 'Gene', (55, 64))	('FOXF1', 'Gene', '2294', (78, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (158, 182))	('C14orf143', 'Gene', '90141', (55, 64))
248407	28404937	For example, although the SPARCL1 gene is associated with the risk of GC and CRC, the association between rs4610302 and susceptibility to GC and CRC in the Han Chinese population has not yet been examined.	('associated', 'Reg', (42, 52))	('CRC', 'Disease', (77, 80))	('CRC', 'Phenotype', 'HP:0003003', (145, 148))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('GC', 'Phenotype', 'HP:0012126', (138, 140))	('rs4610302', 'Var', (106, 115))	('SPARCL1', 'Gene', '8404', (26, 33))	('SPARCL1', 'Gene', (26, 33))	('rs4610302', 'Mutation', 'rs4610302', (106, 115))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))
248408	28404937	In addition, The SNP rs4591517 (SALL4P5-RPL24P7) has been associated with the risk of CRC, but the association between this SNP and the risk of GC remains unknown.	('GC', 'Phenotype', 'HP:0012126', (144, 146))	('associated', 'Reg', (58, 68))	('RPL24P7', 'Gene', '100270963', (40, 47))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('rs4591517', 'Var', (21, 30))	('SALL4P5', 'Gene', '100130785', (32, 39))	('RPL24P7', 'Gene', (40, 47))	('rs4591517', 'Mutation', 'rs4591517', (21, 30))	('SALL4P5', 'Gene', (32, 39))	('CRC', 'Disease', (86, 89))
248409	28404937	In this case-control study, we investigated whether eleven SNPs (rs3790844, rs2689154, rs12615966, rs7574865, rs4591517, rs4927850, rs4610302, rs2255280, rs12100561, rs2178146, and rs1050631) were associated with susceptibility to GC and CRC in a Han Chinese population.	('rs3790844', 'Var', (65, 74))	('rs2255280', 'Mutation', 'rs2255280', (143, 152))	('rs12615966', 'Mutation', 'rs12615966', (87, 97))	('rs2178146', 'Mutation', 'rs2178146', (166, 175))	('rs2255280', 'Var', (143, 152))	('rs4591517', 'Var', (110, 119))	('GC', 'Phenotype', 'HP:0012126', (231, 233))	('rs4591517', 'Mutation', 'rs4591517', (110, 119))	('rs12100561', 'Mutation', 'rs12100561', (154, 164))	('rs4610302', 'Mutation', 'rs4610302', (132, 141))	('rs3790844', 'Mutation', 'rs3790844', (65, 74))	('associated', 'Reg', (197, 207))	('rs2689154', 'Mutation', 'rs2689154', (76, 85))	('CRC', 'Disease', (238, 241))	('CRC', 'Phenotype', 'HP:0003003', (238, 241))	('rs12100561', 'Var', (154, 164))	('rs12615966', 'Var', (87, 97))	('rs4927850', 'Mutation', 'rs4927850', (121, 130))	('rs1050631', 'Var', (181, 190))	('rs7574865', 'Var', (99, 108))	('rs1050631', 'Mutation', 'rs1050631', (181, 190))	('rs4610302', 'Var', (132, 141))	('susceptibility', 'Reg', (213, 227))	('rs2178146', 'Var', (166, 175))	('rs2689154', 'Var', (76, 85))	('rs7574865', 'Mutation', 'rs7574865', (99, 108))	('rs4927850', 'Var', (121, 130))
248414	28404937	The "C" allele of rs2689154 in MIPEPP2 was associated with a decreased risk of GC (OR = 0.81, 95 % CI: 0.66-0.99, P = 0.041), while the "T" allele of rs12615966 in LOC284998 was associated with a 1.29-fold increase in the risk of GC (OR = 1.29, 95% CI: 1.03-1.63, P = 0.029).	('GC', 'Phenotype', 'HP:0012126', (230, 232))	('rs2689154', 'Var', (18, 27))	('GC', 'Phenotype', 'HP:0012126', (79, 81))	('rs12615966', 'Mutation', 'rs12615966', (150, 160))	('MIPEPP2', 'Gene', '100130099', (31, 38))	('rs2689154', 'Mutation', 'rs2689154', (18, 27))	('decreased', 'NegReg', (61, 70))	('MIPEPP2', 'Gene', (31, 38))
248415	28404937	The rs2689154 SNP in MIPEPP2 was associated with a reduced risk of GC in both the recessive model after adjusted for age and gender (adjusted OR = 0.46, 95% CI: 0.22-0.98, P = 0.037) and the log-additive model without adjustment (OR = 0.81, 95% CI: 0.66-0.99, P = 0.038).	('reduced', 'NegReg', (51, 58))	('rs2689154 SNP', 'Var', (4, 17))	('MIPEPP2', 'Gene', '100130099', (21, 28))	('rs2689154', 'Mutation', 'rs2689154', (4, 13))	('MIPEPP2', 'Gene', (21, 28))	('GC', 'Phenotype', 'HP:0012126', (67, 69))
248416	28404937	In contrast, the rs12615966 SNP in LOC284998 was associated with an increased risk of GC in both the dominant model (adjusted OR = 1.36, 95% CI: 1.02-1.81, P = 0.033) and the log-additive model (adjusted OR = 1.36, 95% CI: 1.05-1.75, P = 0.018) after adjusted for age and gender.	('GC', 'Phenotype', 'HP:0012126', (86, 88))	('rs12615966 SNP', 'Var', (17, 31))	('LOC284998', 'Gene', (35, 44))	('rs12615966', 'Mutation', 'rs12615966', (17, 27))
248417	28404937	Finally, rs2178146 in FOXF1 was associated with an increased risk of CRC in the recessive model both before and after adjustment for age and gender (OR = 2.05, 95% CI: 1.22-3.45, P = 0.007; adjusted OR =1.90, 95% CI: 1.05-3.45, P = 0.034).	('CRC', 'Phenotype', 'HP:0003003', (69, 72))	('FOXF1', 'Gene', (22, 27))	('rs2178146', 'Mutation', 'rs2178146', (9, 18))	('rs2178146', 'Var', (9, 18))	('CRC', 'Disease', (69, 72))	('FOXF1', 'Gene', '2294', (22, 27))
248419	28404937	We found that the rs2689154 SNP in MIPEPP2 was protective against GC.	('GC', 'Phenotype', 'HP:0012126', (66, 68))	('rs2689154 SNP', 'Var', (18, 31))	('MIPEPP2', 'Gene', '100130099', (35, 42))	('rs2689154', 'Mutation', 'rs2689154', (18, 27))	('MIPEPP2', 'Gene', (35, 42))
248420	28404937	In contrast, the rs12615966 SNP in LOC284998 was associated with an increased risk of GC.	('GC', 'Phenotype', 'HP:0012126', (86, 88))	('rs12615966 SNP', 'Var', (17, 31))	('LOC284998', 'Gene', (35, 44))	('rs12615966', 'Mutation', 'rs12615966', (17, 27))
248421	28404937	In addition, the rs2178146 SNP in FOXF1 was associated with an increased risk of CRC.	('associated', 'Reg', (44, 54))	('FOXF1', 'Gene', '2294', (34, 39))	('CRC', 'Disease', (81, 84))	('rs2178146 SNP', 'Var', (17, 30))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('FOXF1', 'Gene', (34, 39))	('rs2178146', 'Mutation', 'rs2178146', (17, 26))
248422	28404937	Previous genome-wide association studies demonstrated that the rs2689154 SNP in MIPEPP2 and the rs12615966 SNP in LOC284998 are associated with the risk of developing pancreatic cancer in Chinese and Japanese populations, respectively.	('rs12615966', 'Mutation', 'rs12615966', (96, 106))	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('MIPEPP2', 'Gene', (80, 87))	('LOC284998', 'Gene', (114, 123))	('rs12615966 SNP', 'Var', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('rs2689154 SNP', 'Var', (63, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('associated', 'Reg', (128, 138))	('rs2689154', 'Mutation', 'rs2689154', (63, 72))	('MIPEPP2', 'Gene', '100130099', (80, 87))	('pancreatic cancer', 'Disease', (167, 184))
248424	28404937	Here, we found that rs2689154 was protective against GC, while rs12615966 was associated with an increased risk of GC, in a Han Chinese patient population; additional studies should be conducted with larger sample sizes and in other populations to confirm these findings.	('rs12615966', 'Mutation', 'rs12615966', (63, 73))	('patient', 'Species', '9606', (136, 143))	('rs12615966', 'Var', (63, 73))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('rs2689154', 'Mutation', 'rs2689154', (20, 29))	('GC', 'Phenotype', 'HP:0012126', (53, 55))	('rs2689154', 'Var', (20, 29))
248425	28404937	In a previous study, the SNP rs2178146 in FOXF1, a member of the forkhead family of transcription factors, was associated with susceptibility to esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (145, 170))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (145, 170))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (145, 170))	('susceptibility', 'Reg', (127, 141))	('FOXF1', 'Gene', '2294', (42, 47))	('SNP rs2178146', 'Var', (25, 38))	('associated', 'Reg', (111, 121))	('rs2178146', 'Mutation', 'rs2178146', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('FOXF1', 'Gene', (42, 47))
248426	28404937	FOXF1, a potential tumor suppressor gene that is epigenetically silenced in breast cancer, plays a critical role in embryonic development as well as in cell cycle processes that maintain genomic stability.	('epigenetically silenced', 'Var', (49, 72))	('FOXF1', 'Gene', '2294', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('FOXF1', 'Gene', (0, 5))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('tumor', 'Disease', (19, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
248427	28404937	In addition, FOXF1 is a novel gene target of the p53 family, and ectopic expression and inactivation of FOXF1 inhibited and stimulated, respectively, cancer cell invasion and migration.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('FOXF1', 'Gene', (104, 109))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('FOXF1', 'Gene', '2294', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('FOXF1', 'Gene', '2294', (104, 109))	('FOXF1', 'Gene', (13, 18))	('migration', 'CPA', (175, 184))	('inhibited', 'NegReg', (110, 119))	('ectopic expression', 'Var', (65, 83))	('inactivation', 'Var', (88, 100))	('stimulated', 'PosReg', (124, 134))
248428	28404937	Furthermore, FOXF1 expression is largely silenced in colorectal cancer cell lines with inactive p53, and knockdown of FOXF1 caused genomic instability in colorectal cancer cells with a defect in the p53-p21WAF1 checkpoint, suggesting that FOXF1 plays an essential role in colorectal tumorigenesis.	('p53', 'Gene', '7157', (96, 99))	('FOXF1', 'Gene', (118, 123))	('colorectal cancer', 'Disease', (154, 171))	('FOXF1', 'Gene', (13, 18))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('FOXF1', 'Gene', '2294', (118, 123))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (199, 202))	('defect', 'NegReg', (185, 191))	('FOXF1', 'Gene', '2294', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('p53', 'Gene', (199, 202))	('colorectal tumor', 'Disease', 'MESH:D015179', (272, 288))	('FOXF1', 'Gene', (239, 244))	('knockdown', 'Var', (105, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('genomic instability', 'MPA', (131, 150))	('silenced', 'NegReg', (41, 49))	('FOXF1', 'Gene', '2294', (239, 244))	('colorectal tumor', 'Disease', (272, 288))	('colorectal cancer', 'Disease', (53, 70))	('p21', 'Gene', (203, 206))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('caused', 'Reg', (124, 130))	('p21', 'Gene', '644914', (203, 206))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))
248433	28404937	It is therefore plausible that the rs2178146 SNP in FOXF1 may increase the risk of developing CRC by decreasing the anti-malignant effects of MSC fusion, influencing Hedgehog signaling, or inhibiting vascular tube formation.	('vascular tube formation', 'CPA', (200, 223))	('decreasing', 'NegReg', (101, 111))	('rs2178146', 'Mutation', 'rs2178146', (35, 44))	('inhibiting', 'NegReg', (189, 199))	('FOXF1', 'Gene', (52, 57))	('anti-malignant effects', 'CPA', (116, 138))	('FOXF1', 'Gene', '2294', (52, 57))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('Hedgehog', 'MPA', (166, 174))	('rs2178146 SNP', 'Var', (35, 48))	('influencing', 'Reg', (154, 165))	('CRC', 'Disease', (94, 97))
248435	28404937	In conclusion, we found that the rs2689154 SNP in MIPEPP2 and the rs12615966 SNP in LOC284998 were associated with susceptibility to GC, while the rs2178146 SNP in FOXF1 was associated with an increased risk of CRC, in a Han Chinese population.	('GC', 'Phenotype', 'HP:0012126', (133, 135))	('rs2178146', 'Mutation', 'rs2178146', (147, 156))	('rs12615966', 'Mutation', 'rs12615966', (66, 76))	('rs12615966', 'Var', (66, 76))	('MIPEPP2', 'Gene', (50, 57))	('rs2689154', 'Mutation', 'rs2689154', (33, 42))	('CRC', 'Disease', (211, 214))	('FOXF1', 'Gene', '2294', (164, 169))	('rs2689154 SNP', 'Var', (33, 46))	('susceptibility', 'Reg', (115, 129))	('FOXF1', 'Gene', (164, 169))	('CRC', 'Phenotype', 'HP:0003003', (211, 214))	('MIPEPP2', 'Gene', '100130099', (50, 57))	('rs2178146', 'Var', (147, 156))	('associated', 'Reg', (99, 109))
248441	28404937	The eleven SNPs (rs3790844, rs2689154, rs12615966, rs7574865, rs4591517, rs4927850, rs4610302, rs2255280, rs12100561, rs2178146, and rs1050631) associated with pancreatic cancer, esophageal cancer, and other digestive system cancers were randomly chosen from previous GWAS reports for examination.	('rs2255280', 'Var', (95, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('associated', 'Reg', (144, 154))	('rs4591517', 'Var', (62, 71))	('rs4610302', 'Mutation', 'rs4610302', (84, 93))	('rs2178146', 'Var', (118, 127))	('rs4591517', 'Mutation', 'rs4591517', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('rs3790844', 'Var', (17, 26))	('esophageal cancer', 'Disease', (179, 196))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (160, 177))	('rs2178146', 'Mutation', 'rs2178146', (118, 127))	('rs12615966', 'Var', (39, 49))	('rs2689154', 'Mutation', 'rs2689154', (28, 37))	('system cancers', 'Disease', 'MESH:D009369', (218, 232))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('rs4610302', 'Var', (84, 93))	('rs4927850', 'Mutation', 'rs4927850', (73, 82))	('system cancers', 'Disease', (218, 232))	('rs1050631', 'Var', (133, 142))	('rs12100561', 'Mutation', 'rs12100561', (106, 116))	('pancreatic cancer', 'Disease', 'MESH:D010190', (160, 177))	('rs3790844', 'Mutation', 'rs3790844', (17, 26))	('rs1050631', 'Mutation', 'rs1050631', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('rs2689154', 'Var', (28, 37))	('rs7574865', 'Var', (51, 60))	('rs12615966', 'Mutation', 'rs12615966', (39, 49))	('rs4927850', 'Var', (73, 82))	('rs12100561', 'Var', (106, 116))	('pancreatic cancer', 'Disease', (160, 177))	('rs7574865', 'Mutation', 'rs7574865', (51, 60))	('rs2255280', 'Mutation', 'rs2255280', (95, 104))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
248446	27016410	Herein we showed the clinical relevance of ANO1 alterations with ESCC and esophageal precancerous lesion progression.	('esophageal precancerous lesion', 'Disease', 'MESH:D011230', (74, 104))	('alterations', 'Var', (48, 59))	('ESCC', 'Disease', (65, 69))	('esophageal precancerous lesion', 'Disease', (74, 104))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ANO1', 'Gene', (43, 47))
248448	27016410	ANO1 expression was significantly associated with a shorter overall survival (OS), especially in patients with moderately differentiated and stage IIA tumors.	('ANO1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('expression', 'Var', (5, 15))	('moderately differentiated', 'CPA', (111, 136))	('shorter', 'NegReg', (52, 59))	('IIA tumors', 'Disease', 'MESH:C536042', (147, 157))	('patients', 'Species', '9606', (97, 105))	('overall survival', 'MPA', (60, 76))	('IIA tumors', 'Disease', (147, 157))
248464	27016410	Amplification and/or overexpression of ANO1 have been frequently observed in gastrointestinal stromal tumors (GISTs), breast cancer, head and neck squamous cell carcinoma (HNSCCs) and gastric carcinomas In ANO1-amplified cancer cell lines bearing 11q13 amplification, knockdown of ANO1 inhibited cell proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts via deactivating EGFR and CAMK signaling.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (133, 170))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cell proliferation', 'CPA', (296, 314))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('apoptosis', 'CPA', (324, 333))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('gastric carcinomas', 'Disease', (184, 202))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('EGFR', 'Gene', '1956', (410, 414))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('GISTs', 'Phenotype', 'HP:0100723', (110, 115))	('cancer', 'Disease', (125, 131))	('deactivating', 'NegReg', (397, 409))	('induced', 'Reg', (316, 323))	('breast cancer', 'Disease', (118, 131))	('ANO1', 'Gene', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (77, 108))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (77, 108))	('cancer', 'Disease', (221, 227))	('CAMK', 'Gene', (419, 423))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('CAMK', 'Gene', '818', (419, 423))	('reduced', 'NegReg', (339, 346))	('tumor', 'Disease', (102, 107))	('inhibited', 'NegReg', (286, 295))	('tumor', 'Disease', (347, 352))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (133, 170))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('gastrointestinal stromal tumors', 'Disease', (77, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('EGFR', 'Gene', (410, 414))	('ANO1', 'Gene', (281, 285))	('cancer', 'Disease', (375, 381))	('gastric carcinomas', 'Disease', 'MESH:D013274', (184, 202))	('knockdown', 'Var', (268, 277))
248471	27016410	Kaplan-Meier curves showed that patients with positive ANO1 expression had a shorter OS compared to those with undetectable expression (P= 0.0015, Figure 1).	('patients', 'Species', '9606', (32, 40))	('ANO1', 'Gene', (55, 59))	('expression', 'Var', (60, 70))	('shorter', 'NegReg', (77, 84))	('positive', 'Var', (46, 54))
248480	27016410	In the second cohort, ANO1 expression was observed in three of four cases with SD and one with CIS (Figure 3B), but undetectable in all the 43 mD, 6 MD and 94 chronic esophagitis.	('esophagitis', 'Disease', (167, 178))	('CIS', 'Phenotype', 'HP:0030075', (95, 98))	('esophagitis', 'Disease', 'MESH:D004941', (167, 178))	('SD', 'Disease', 'MESH:D029461', (79, 81))	('ANO1', 'Var', (22, 26))	('esophagitis', 'Phenotype', 'HP:0100633', (167, 178))
248483	27016410	Taken together, the precancerous lesions with positive ANO1 expression mostly had progressed in both the two cohort (80% and 100%), and the vast majority of those with negative ANO1 expression were no progression (87.8% and 100%) (Supplementary Table S4).	('ANO1', 'Gene', (55, 59))	('expression', 'Var', (60, 70))	('precancerous lesions', 'Disease', 'MESH:D011230', (20, 40))	('precancerous lesions', 'Disease', (20, 40))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('positive', 'Var', (46, 54))
248503	27016410	Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 could abrogate the growth effect of ANO1.	('ERK', 'Gene', '5594', (32, 35))	('genetic inactivation', 'Var', (40, 60))	('ERK', 'Gene', (32, 35))	('ERK', 'Gene', '5594', (64, 67))	('growth effect', 'CPA', (90, 103))	('MEK', 'Gene', (28, 31))	('MEK', 'Gene', '5609', (28, 31))	('abrogate', 'NegReg', (77, 85))	('ERK', 'Gene', (64, 67))
248505	27016410	We previously reported that knock-down of ANO1 significantly inhibited the proliferation of KYSE30 and KYSE510 cells.	('KYSE510', 'CellLine', 'CVCL:1354', (103, 110))	('inhibited', 'NegReg', (61, 70))	('ANO1', 'Gene', (42, 46))	('knock-down', 'Var', (28, 38))	('KYSE510 cells', 'CPA', (103, 116))
248533	26839536	The abundant ROS may react with proteins, lipids, carbohydrates, and nucleic acids, resulting in cell membrane damage, DNA base modifications, deoxyribose damage, and single- and double-stranded DNA breaks.	('DNA base modifications', 'MPA', (119, 141))	('lipids', 'Chemical', 'MESH:D008055', (42, 48))	('carbohydrates', 'Chemical', 'MESH:D002241', (50, 63))	('deoxyribose damage', 'Disease', 'MESH:C565112', (143, 161))	('ROS', 'Gene', (13, 16))	('deoxyribose damage', 'Disease', (143, 161))	('cell membrane damage', 'CPA', (97, 117))	('resulting', 'Reg', (84, 93))	('single-', 'Var', (167, 174))
248558	26839536	Thus, DOUX2 may also contribute to esophageal cancer in addition to NOX5, which was shown to promote cell proliferation in esophageal cancer.	('DOUX2', 'Var', (6, 11))	('esophageal cancer', 'Disease', (123, 140))	('esophageal cancer', 'Disease', (35, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('NOX5', 'Gene', (68, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('contribute', 'Reg', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cell proliferation', 'CPA', (101, 119))	('NOX5', 'Gene', '79400', (68, 72))
248562	26839536	Increased DUOX2 expression may help to eradicate Hp colonization and infection as suggested by the persistent Helicobacter infection in mice deficient in DUOX2 activity.	('mice', 'Species', '10090', (136, 140))	('eradicate', 'NegReg', (39, 48))	('Helicobacter infection', 'Phenotype', 'HP:0005202', (110, 132))	('Increased', 'PosReg', (0, 9))	('DUOX2', 'Gene', (10, 15))	('deficient', 'Var', (141, 150))	('Helicobacter infection', 'Disease', (110, 132))	('expression', 'MPA', (16, 26))	('infection', 'CPA', (69, 78))
248674	25106775	Inflammatory processes also lead to generation of reactive oxygen species (ROS) which may cause inactivating mutations in tumor suppressor genes or post-translational modifications in DNA repair proteins, thus promoting carcinogenesis.	('inactivating mutations', 'Var', (96, 118))	('promoting', 'PosReg', (210, 219))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (50, 73))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('carcinogenesis', 'Disease', 'MESH:D063646', (220, 234))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('DNA repair proteins', 'Protein', (184, 203))	('mutations', 'Var', (109, 118))	('lead to', 'Reg', (28, 35))	('ROS', 'Chemical', 'MESH:D017382', (75, 78))	('carcinogenesis', 'Disease', (220, 234))	('tumor', 'Disease', (122, 127))
248713	25106775	Although it is more conventional to adjust for the effects of obesity by adjusting for BMI, we chose to adjust for WHR (a measure of central adiposity) in the current analyses as there is good evidence that WHR is more strongly associated with BE as compared to BMI.	('WHR', 'Var', (207, 210))	('obesity', 'Phenotype', 'HP:0001513', (62, 69))	('obesity', 'Disease', 'MESH:D009765', (62, 69))	('BE as', 'Disease', (244, 249))	('associated', 'Reg', (228, 238))	('obesity', 'Disease', (62, 69))
248765	25106775	Although a recent study showed that presence of long-segment BE carried a sevenfold increased risk of progression to EA, BE segment length is only modestly associated with the risk of EA in our cohort.	('long-segment', 'Var', (48, 60))	('presence', 'Var', (36, 44))	('men', 'Species', '9606', (56, 59))	('men', 'Species', '9606', (127, 130))
248833	33541291	That is to say, patients with protein degradation, RNA degradation and splicing effects were more inclined to a poor prognosis (Fig.	('RNA degradation', 'MPA', (51, 66))	('protein degradation', 'MPA', (30, 49))	('splicing effects', 'Var', (71, 87))	('patients', 'Species', '9606', (16, 24))
248857	33541291	The splice variant of oncostatin M receptor beta is overexpressed in human esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('esophageal squamous cell carcinoma', 'Disease', (75, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('splice variant', 'Var', (4, 18))	('overexpressed', 'PosReg', (52, 65))	('human', 'Species', '9606', (69, 74))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (75, 109))
248863	33541291	Mutations in genes encoding splice proteins are frequently found in cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (59, 64))	('cancer', 'Disease', (68, 74))
248918	31908722	Chen et al reported that the locoregional recurrence rate for patients receiving PORT was significantly lower than that of patients who had undergone surgery alone.	('locoregional recurrence rate', 'CPA', (29, 57))	('PORT', 'Var', (81, 85))	('patients', 'Species', '9606', (123, 131))	('lower', 'NegReg', (104, 109))	('patients', 'Species', '9606', (62, 70))
248976	31908722	Our result also revealed a better DFS for patients in the S + R arm than those in the S arm.	('S', 'Chemical', 'MESH:D013455', (58, 59))	('S', 'Chemical', 'MESH:D013455', (86, 87))	('S + R', 'Var', (58, 63))	('DFS', 'MPA', (34, 37))	('better', 'PosReg', (27, 33))	('S', 'Chemical', 'MESH:D013455', (36, 37))	('patients', 'Species', '9606', (42, 50))
248988	31908722	Second, patients in the S + R arm were fewer than those in the S arm, possibly influencing DFS; a longer follow-up and more enrolled patients are needed.	('S', 'Chemical', 'MESH:D013455', (63, 64))	('S + R', 'Var', (24, 29))	('S', 'Chemical', 'MESH:D013455', (93, 94))	('influencing', 'Reg', (79, 90))	('patients', 'Species', '9606', (133, 141))	('S', 'Chemical', 'MESH:D013455', (24, 25))	('DFS', 'Disease', (91, 94))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('patients', 'Species', '9606', (8, 16))
249036	31245158	The Japanese treatment guidelines, however, refer to the predominant location of the tumor, whether it is in the stomach (G) or esophagus (E), resulting in a description as G, E, GE, EG, or E=G (Fig.	('tumor', 'Disease', (85, 90))	('E=G', 'Var', (190, 193))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
249182	30281702	Known cancer risk factors include social determinants, lifestyle factors, occupational exposures, infectious agents, and genetic and epigenetic alterations.	('cancer', 'Disease', (6, 12))	('epigenetic alterations', 'Var', (133, 155))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))
249285	30281702	Currently, alcohol consumption is recognized to cause cancer of the oral cavity, pharynx, larynx, esophagus, colorectum, liver (hepatocellular carcinoma) and breast (in females).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (128, 152))	('cancer of the oral cavity', 'Phenotype', 'HP:0100649', (54, 79))	('colorectum', 'Disease', (109, 119))	('larynx', 'Disease', (90, 96))	('hepatocellular carcinoma', 'Disease', (128, 152))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (128, 152))	('alcohol consumption', 'Var', (11, 30))	('cancer', 'Disease', (54, 60))	('cause', 'Reg', (48, 53))	('alcohol', 'Chemical', 'MESH:D000438', (11, 18))	('esophagus', 'Disease', (98, 107))	('liver', 'Disease', (121, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('breast', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
249287	30281702	Studies on gene-environment interactions (GxEs) consistently found a higher risk of alcohol-related cancers among individuals with deficiencies in the oxidation of acetaldehyde to acetate.	('alcohol', 'Chemical', 'MESH:D000438', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('acetaldehyde', 'Chemical', 'MESH:D000079', (164, 176))	('deficiencies', 'Var', (131, 143))	('men', 'Species', '9606', (23, 26))	('oxidation of acetaldehyde to acetate', 'MPA', (151, 187))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('acetate', 'Chemical', 'MESH:D000085', (180, 187))	('cancers', 'Disease', (100, 107))
249299	30281702	A recent systematic review of the literature on cancer at 22 body sites, which included 541 studies, found a consistent association between physical activity and decreased incidence and mortality rates of both colon and breast cancer.	('physical activity', 'Var', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('decreased', 'NegReg', (162, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('colon and breast cancer', 'Disease', 'MESH:D001943', (210, 233))
249343	30281702	Results from meta-analyses have suggested that the eradication of H. pylori might prevent gastric cancer and that this approach is most likely more successful in healthy individuals than in those with noncancer gastric diseases or symptoms, although the authors noted that more studies are needed to confirm this conclusion.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('prevent', 'NegReg', (82, 89))	('H. pylori', 'Gene', (66, 75))	('gastric diseases', 'Disease', (211, 227))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('gastric diseases', 'Disease', 'MESH:D013274', (211, 227))	('H. pylori', 'Species', '210', (66, 75))	('eradication', 'Var', (51, 62))	('cancer', 'Disease', (98, 104))	('gastric cancer', 'Disease', (90, 104))
249366	30281702	Currently, advances in genomics and other -omics technologies have allowed the character of genomic and epigenomic variations in humans and pathogens, as well as the relationships of these variations with environmental factors, to be assessed in the setting of carcinogenesis.	('humans', 'Species', '9606', (129, 135))	('variations', 'Var', (189, 199))	('carcinogenesis', 'Disease', 'MESH:D063646', (261, 275))	('carcinogenesis', 'Disease', (261, 275))	('men', 'Species', '9606', (212, 215))
249375	30281702	For example, in studies using this approach, acetaldehyde-metabolizing genes have been linked to head and neck cancer, and genetic scores for higher adult BMIs were correlated with increased risks of colorectal, ovarian and lung cancer.	('genetic scores', 'Var', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('linked', 'Reg', (87, 93))	('colorectal, ovarian and lung cancer', 'Disease', 'MESH:D015179', (200, 235))	('acetaldehyde', 'Chemical', 'MESH:D000079', (45, 57))	('head and neck cancer', 'Phenotype', 'HP:0012288', (97, 117))	('acetaldehyde-metabolizing genes', 'Gene', (45, 76))	('neck cancer', 'Disease', 'MESH:D006258', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('neck cancer', 'Disease', (106, 117))
249400	29190924	Mechanistic studies demonstrated that decreased PTTG1 mitigated the expression levels of GLI1 in vitro and in vivo and ChIP assay also indicated that PTTG1 cooperated with GLI1 by binding to its promoter.	('GLI1', 'Gene', (89, 93))	('GLI1', 'Gene', (172, 176))	('decreased', 'Var', (38, 47))	('PTTG1', 'Gene', (150, 155))	('mitigated', 'NegReg', (54, 63))	('PTTG1', 'Gene', (48, 53))	('rat', 'Species', '10116', (27, 30))	('rat', 'Species', '10116', (161, 164))	('binding', 'Interaction', (180, 187))	('expression levels', 'MPA', (68, 85))	('GLI1', 'Gene', '2735', (172, 176))	('GLI1', 'Gene', '2735', (89, 93))
249431	29190924	The mRNA and protein expression levels of PTTG1 and GLI1 in EC-1, EC9706, Eca-109 and SHEE were shown in Figure 1C, 1D.	('GLI1', 'Gene', '2735', (52, 56))	('GLI1', 'Gene', (52, 56))	('EC-1', 'Gene', (60, 64))	('EC9706', 'CellLine', 'CVCL:E307', (66, 72))	('PTTG1', 'Gene', (42, 47))	('EC-1', 'Gene', '4819', (60, 64))	('EC9706', 'Var', (66, 72))
249440	29190924	After transfected with PTTG1 siRNA, the number of colonies formed by EC-1 and Eca-109 were also significantly decreased (Figure 2E).	('colon', 'Disease', (50, 55))	('transfected', 'Var', (6, 17))	('decreased', 'NegReg', (110, 119))	('EC-1 and Eca-109', 'Gene', '4819', (69, 85))	('colon', 'Disease', 'MESH:D015179', (50, 55))	('PTTG1', 'Gene', (23, 28))
249461	29190924	The levels of vimentin and N-cadherin were all reduced in PTTG1 siRNA transfected EC-1 or Eca-109 cells' groups relative to the control tumors, while the most important marker of EMT, E-cadherin, expressed higher in PTTG1 siRNA transfected EC-1 or Eca-109 cells' groups compared to those in control groups (Figure 5C), indicating decreased EMT in PTTG1 down-regulation tumors.	('tumors', 'Disease', (136, 142))	('decreased EMT', 'Phenotype', 'HP:0032198', (330, 343))	('higher', 'PosReg', (206, 212))	('EMT', 'CPA', (340, 343))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('N-cadherin', 'Gene', (27, 37))	('PTTG1', 'Gene', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (369, 375))	('N-cadherin', 'Gene', '1000', (27, 37))	('E-cadherin', 'Gene', (184, 194))	('E-cadherin', 'Gene', '999', (184, 194))	('transfected', 'Var', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('down-regulation', 'NegReg', (353, 368))	('tumors', 'Disease', (369, 375))	('reduced', 'NegReg', (47, 54))	('EC-1', 'Gene', '4819', (82, 86))	('vimentin', 'Gene', '7431', (14, 22))	('levels', 'MPA', (4, 10))	('EC-1', 'Gene', '4819', (240, 244))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('EC-1', 'Gene', (82, 86))	('vimentin', 'Gene', (14, 22))	('decreased', 'NegReg', (330, 339))	('EC-1', 'Gene', (240, 244))	('tumors', 'Disease', 'MESH:D009369', (369, 375))	('PTTG1', 'Gene', (347, 352))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
249469	29190924	The high expression of E-cadherin and low expression of vimentin and N-cadherin could be partially reversed in EC-1 and Eca-109 cells transfected with PTTG1 siRNA and 2 mumol/L purmorphamine together compared with those treated by PTTG1 siRNA separately.	('vimentin', 'Gene', '7431', (56, 64))	('PTTG1 siRNA', 'Var', (151, 162))	('vimentin', 'Gene', (56, 64))	('EC-1 and Eca-109', 'Gene', '4819', (111, 127))	('E-cadherin', 'Gene', (23, 33))	('N-cadherin', 'Gene', (69, 79))	('expression', 'MPA', (9, 19))	('E-cadherin', 'Gene', '999', (23, 33))	('rat', 'Species', '10116', (247, 250))	('purmorphamine', 'Chemical', 'MESH:C470893', (177, 190))	('N-cadherin', 'Gene', '1000', (69, 79))
249473	29190924	We found that up regulation of GLI1 promoted invasion and migration of EC-1 and Eca-109 cells treated by PTTG1 siRNA and 2 mumol/L purmorphamine simultaneously compared with those treated by PTTG1 siRNA separately (Figure 6C, 6D).	('up regulation', 'PosReg', (14, 27))	('EC-1 and Eca-109', 'Gene', '4819', (71, 87))	('GLI1', 'Gene', '2735', (31, 35))	('rat', 'Species', '10116', (207, 210))	('purmorphamine', 'Chemical', 'MESH:C470893', (131, 144))	('GLI1', 'Gene', (31, 35))	('rat', 'Species', '10116', (61, 64))	('PTTG1 siRNA', 'Var', (105, 116))	('invasion', 'CPA', (45, 53))	('promoted', 'PosReg', (36, 44))	('migration', 'CPA', (58, 67))
249482	29190924	Our studies demonstrated that inhibition of PTTG1 was also critical for the restrain of EMT.	('PTTG1', 'Gene', (44, 49))	('restrain of EMT', 'CPA', (76, 91))	('inhibition', 'Var', (30, 40))	('rat', 'Species', '10116', (19, 22))
249484	29190924	Furthermore, PTTG1 deficient mice demonstrated suppression of tumor growth and EMT.	('EMT', 'CPA', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('PTTG1', 'Gene', (13, 18))	('mice', 'Species', '10090', (29, 33))	('rat', 'Species', '10116', (41, 44))	('suppression', 'NegReg', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('deficient', 'Var', (19, 28))
249492	29190924	Our previous studies showed that high-expression of GLI1 dampened expression of E-cadherin and enhanced the expression of vimentin, and it also improved the expression of Snail, indicative of its role in EMT occurrence.	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '999', (80, 90))	('Snail', 'Gene', (171, 176))	('GLI1', 'Gene', '2735', (52, 56))	('dampened', 'NegReg', (57, 65))	('improved', 'PosReg', (144, 152))	('GLI1', 'Gene', (52, 56))	('expression', 'MPA', (157, 167))	('high-expression', 'Var', (33, 48))	('Snail', 'Gene', '6615', (171, 176))	('expression', 'MPA', (66, 76))	('expression', 'MPA', (108, 118))	('vimentin', 'Gene', '7431', (122, 130))	('enhanced', 'PosReg', (95, 103))	('vimentin', 'Gene', (122, 130))
249493	29190924	So we thought PTTG1 could participate in EMT in ESCC via activating GLI1.	('GLI1', 'Gene', (68, 72))	('ESCC', 'Disease', (48, 52))	('activating', 'Var', (57, 67))	('GLI1', 'Gene', '2735', (68, 72))
249507	29190924	ESCC cell lines: EC-1, EC9706 and ECa109 and immortalized human esophageal epithelial cell line SHEE were all preserved in our laboratory in the Department of Oncology, the First Affiliated Hospital of Zhengzhou University.	('EC9706', 'CellLine', 'CVCL:E307', (23, 29))	('rat', 'Species', '10116', (131, 134))	('human', 'Species', '9606', (58, 63))	('EC-1', 'Gene', (17, 21))	('EC9706', 'Var', (23, 29))	('Oncology', 'Phenotype', 'HP:0002664', (159, 167))	('EC-1', 'Gene', '4819', (17, 21))
249696	27294188	The genes which harbor mutation conferring benefit to survival of tumor cell are called driver genes.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutation', 'Var', (23, 31))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('benefit', 'PosReg', (43, 50))
249700	27294188	The mutation of KDM6A is involved in various types of cancer across both solid and liquid tumors.	('involved', 'Reg', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mutation', 'Var', (4, 12))	('cancer', 'Disease', (54, 60))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('solid', 'Disease', (73, 78))	('KDM6A', 'Gene', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
249708	27294188	As part of an H3K4-methyltransferase complex containing MLL2, PTIP, ASC2, ASH2, RBQ3, and WDR5, KDM6A can promote H3K4 methylation.	('H3K4', 'Protein', (114, 118))	('RBQ3', 'Gene', '5929', (80, 84))	('KDM6A', 'Var', (96, 101))	('RBQ3', 'Gene', (80, 84))	('promote', 'PosReg', (106, 113))	('PTIP', 'Gene', '22976', (62, 66))	('ASC2', 'Gene', '23054', (68, 72))	('ASC2', 'Gene', (68, 72))	('methylation', 'MPA', (119, 130))	('PTIP', 'Gene', (62, 66))
249709	27294188	Clinically, KDM6A or MLL4 was associated with poor prognosis in patients with breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('patients', 'Species', '9606', (64, 72))	('MLL4', 'Gene', (21, 25))	('MLL4', 'Gene', '9757', (21, 25))	('KDM6A', 'Var', (12, 17))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
249715	27084641	For 21 patients, SIB plans with a physical dose prescription of 2 Gy or 2.5 Gy/fraction in 25 fractions to planning target volume (PTV)50Gy or PTV62.5Gy (primary tumor with 0.5 cm margins) were created and evaluated for robustness to random setup errors and proton range errors.	('PTV62.5Gy', 'Var', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('PTV', 'Chemical', '-', (143, 146))	('tumor', 'Disease', (162, 167))	('PTV', 'Chemical', '-', (131, 134))	('patients', 'Species', '9606', (7, 15))
249720	27084641	Setup error robustness was patient anatomy dependent, and the potential minimum dose per fraction was always lower with SFO than with VMAT.	('error robustness', 'Disease', 'MESH:D012030', (6, 22))	('lower', 'NegReg', (109, 114))	('SFO', 'Var', (120, 123))	('patient', 'Species', '9606', (27, 34))	('error robustness', 'Disease', (6, 22))	('VMAT', 'Disease', 'None', (134, 138))	('VMAT', 'Disease', (134, 138))
249745	27084641	A PTV62.5Gy median dose (D50%) was used for plan normalization in the standard plans and showed no statistically significant difference between the VMAT and SFO plans.	('VMAT', 'Disease', 'None', (148, 152))	('VMAT', 'Disease', (148, 152))	('PTV', 'Chemical', '-', (2, 5))	('PTV62.5Gy', 'Var', (2, 11))
249759	27084641	The target dose coverage was acceptable for all patients, with a D98% of CTV50Gy >95% of the prescribed dose (PD), a median CTV50Gy D98% of 48.9 Gy (range 48.3-49.9), and median GTV D98% of 62.6 Gy (range 62.4-62.9).	('CTV50Gy D98', 'Var', (124, 135))	('D98%', 'Var', (65, 69))	('CTV50Gy', 'Gene', (73, 80))	('GTV', 'Chemical', '-', (178, 181))	('PD', 'Disease', 'MESH:D010300', (110, 112))	('patients', 'Species', '9606', (48, 56))	('D98', 'Var', (132, 135))
249772	27084641	The VMAT and SFO plans were normalized such that the PTV62.5Gy median dose equaled the PD, although the VMAT plan GTV dose was slightly greater than the SFO dose.	('VMAT', 'Disease', (4, 8))	('VMAT', 'Disease', (104, 108))	('PD', 'Disease', 'MESH:D010300', (87, 89))	('VMAT', 'Disease', 'None', (4, 8))	('PTV62.5Gy', 'Var', (53, 62))	('GTV', 'Chemical', '-', (114, 117))	('VMAT', 'Disease', 'None', (104, 108))	('PTV', 'Chemical', '-', (53, 56))
249777	27084641	The minimum GTV D98 values with the SFO setup errors were lower than the VMAT values by 0.3% to 2.2% of the prescribed GTV dose.	('GTV', 'Chemical', '-', (119, 122))	('VMAT', 'Disease', (73, 77))	('lower', 'NegReg', (58, 63))	('errors', 'Var', (46, 52))	('GTV', 'MPA', (12, 15))	('VMAT', 'Disease', 'None', (73, 77))	('GTV', 'Chemical', '-', (12, 15))
249787	27084641	Our comparison of RT techniques for midesophageal cancer indicated that SFO offers improved cardiopulmonary sparing and equivalent target coverage compared with VMAT.	('improved', 'PosReg', (83, 91))	('SFO', 'Var', (72, 75))	('midesophageal cancer', 'Disease', 'MESH:D009369', (36, 56))	('VMAT', 'Disease', 'None', (161, 165))	('midesophageal cancer', 'Disease', (36, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cardiopulmonary sparing', 'CPA', (92, 115))	('VMAT', 'Disease', (161, 165))
249818	26555375	 FGFR1 Amplification Is Often Homogeneous and Strongly Linked to the Squamous Cell Carcinoma Subtype in Esophageal Carcinoma Amplification of the fibroblast growth factor receptor 1 (FGFR1) is believed to predict response to multi-kinase inhibitors targeting FGFR1.	('FGFR1', 'Gene', (259, 264))	('Linked', 'Reg', (55, 61))	('fibroblast growth factor receptor 1', 'Gene', (146, 181))	('FGFR1', 'Gene', '2260', (1, 6))	('FGFR1', 'Gene', '2260', (183, 188))	('FGFR1', 'Gene', '2260', (259, 264))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('predict', 'Reg', (205, 212))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (104, 124))	('fibroblast growth factor receptor 1', 'Gene', '2260', (146, 181))	('Carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('Squamous Cell Carcinoma Subtype in Esophageal Carcinoma', 'Disease', 'MESH:D000077277', (69, 124))	('Carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('Amplification', 'Var', (125, 138))	('FGFR1', 'Gene', (1, 6))	('FGFR1', 'Gene', (183, 188))
249820	26555375	This study was designed to investigate the prevalence and clinical significance of FGFR1 amplification in a tissue microarray containing 346 adenocarcinomas and 254 squamous cell carcinomas of the esophagus, using dual-labeling fluorescence in situ hybridization (FISH) analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (165, 189))	('squamous cell carcinomas', 'Disease', (165, 189))	('adenocarcinomas', 'Disease', 'MESH:D000230', (141, 156))	('carcinomas of the esophagus', 'Disease', 'MESH:D004938', (179, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('adenocarcinomas', 'Disease', (141, 156))	('FGFR1', 'Gene', (83, 88))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (165, 189))	('amplification', 'Var', (89, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('FGFR1', 'Gene', '2260', (83, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('carcinomas of the esophagus', 'Disease', (179, 206))
249821	26555375	FGFR1 amplification, defined as a ratio of FGFR1:centromere 8 copy numbers >= 2.0, was more frequently seen in squamous cell carcinoma (8.9% of 202 interpretable cases) than in adenocarcinoma (1.6% of 308; p<0.0001).	('FGFR1', 'Gene', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('seen', 'Reg', (103, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('adenocarcinoma', 'Disease', 'MESH:D000230', (177, 191))	('FGFR1', 'Gene', '2260', (43, 48))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 134))	('squamous cell carcinoma', 'Disease', (111, 134))	('amplification', 'Var', (6, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('adenocarcinoma', 'Disease', (177, 191))
249822	26555375	There was no association between FGFR1 amplification and tumor phenotype or clinical outcome.	('FGFR1', 'Gene', '2260', (33, 38))	('amplification', 'Var', (39, 52))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('FGFR1', 'Gene', (33, 38))
249824	26555375	This analysis revealed complete homogeneity of FGFR1 amplification in 20 (86.9%) primary tumors and in all available lymph node metastases.	('metastases', 'Disease', (128, 138))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('FGFR1', 'Gene', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('amplification', 'Var', (53, 66))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('FGFR1', 'Gene', '2260', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
249826	26555375	In conclusion, FGFR1 amplification occurs in a relevant subgroup of carcinomas of the esophagus and may play a particular role for development of squamous cell cancers.	('FGFR1', 'Gene', '2260', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('squamous cell cancers', 'Disease', (146, 167))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (146, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('squamous cell cancers', 'Disease', 'MESH:D002294', (146, 167))	('carcinomas of the esophagus', 'Disease', (68, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('role', 'Reg', (122, 126))	('play', 'Reg', (104, 108))	('carcinomas of the esophagus', 'Disease', 'MESH:D004938', (68, 95))	('amplification', 'Var', (21, 34))	('FGFR1', 'Gene', (15, 20))
249836	26555375	An important mechanism of oncogenic FGFR1 activation is amplification of its gene locus at chromosome 8p11, which is found in 10-20% of squamous cell carcinomas of the lung, in about 10% of hormone receptor positive breast carcinoma, 10-17% head and neck squamous cell carcinomas and 6% of small cell carcinomas of the lung.	('breast carcinoma', 'Disease', 'MESH:D001943', (216, 232))	('activation', 'PosReg', (42, 52))	('squamous cell carcinomas of the lung', 'Phenotype', 'HP:0030359', (136, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('squamous cell carcinomas of the lung', 'Disease', (136, 172))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (241, 279))	('FGFR1', 'Gene', '2260', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('carcinomas', 'Phenotype', 'HP:0030731', (301, 311))	('breast carcinoma', 'Phenotype', 'HP:0003002', (216, 232))	('neck squamous cell carcinomas', 'Disease', (250, 279))	('small cell carcinomas of the lung', 'Disease', 'MESH:D055752', (290, 323))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('squamous cell carcinomas of the lung', 'Disease', 'MESH:D002294', (136, 172))	('breast carcinoma', 'Disease', (216, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinomas', 'Phenotype', 'HP:0030731', (269, 279))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (250, 279))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (255, 279))	('small cell carcinomas of the lung', 'Disease', (290, 323))	('amplification', 'Var', (56, 69))	('FGFR1', 'Gene', (36, 41))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (150, 172))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (301, 323))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (136, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('small cell carcinomas of the lung', 'Phenotype', 'HP:0030357', (290, 323))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
249837	26555375	Little is known about the clinical significance of FGFR1 amplification in esophageal cancer or about possible differences between histological subtypes.	('amplification', 'Var', (57, 70))	('esophageal cancer', 'Disease', (74, 91))	('FGFR1', 'Gene', (51, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('FGFR1', 'Gene', '2260', (51, 56))
249839	26555375	Only one study on Asian ESCC patients suggested that FGFR1 amplification might be linked to poor outcome.	('FGFR1', 'Gene', (53, 58))	('patients', 'Species', '9606', (29, 37))	('FGFR1', 'Gene', '2260', (53, 58))	('amplification', 'Var', (59, 72))	('linked', 'Reg', (82, 88))	('Asian ESCC', 'Disease', (18, 28))
249862	26555375	Examples of tumor spots with and without FGFR1 amplification are shown in Fig 1 (Fig 1).	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('amplification', 'Var', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('FGFR1', 'Gene', '2260', (41, 46))	('FGFR1', 'Gene', (41, 46))	('tumor', 'Disease', (12, 17))
249867	26555375	Heterogeneity was defined as presence of FGFR1 non-amplified and amplified tumor areas within the same cancer (Fig 1B).	('non-amplified', 'Var', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor areas within the same cancer', 'Disease', (75, 109))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))	('tumor areas within the same cancer', 'Disease', 'MESH:D001929', (75, 109))
249877	26555375	Low- and high-level FGFR1 amplifications were significantly more frequent in ESCC (18 of 202, 8.9%) than in EADC (5 of 308, 1.6%, p<0.0001).	('FGFR1', 'Gene', '2260', (20, 25))	('ESCC', 'Disease', (77, 81))	('FGFR1', 'Gene', (20, 25))	('amplifications', 'Var', (26, 40))
249879	26555375	Due to these strong differences in amplification frequencies between squamous cell- and adenocarcinomas, associations to phenotype and clinical outcome were calculated separately in each subgroup.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('amplification', 'Var', (35, 48))	('adenocarcinomas', 'Disease', (88, 103))	('squamous cell-', 'Disease', (69, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('adenocarcinomas', 'Disease', 'MESH:D000230', (88, 103))
249880	26555375	These analyses did not reveal significant associations between FGFR1 amplification and tumor phenotype or clinical outcome, neither in the subset of 202 ESCC, nor in the subset of 308 EADC (Fig 2).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('amplification', 'Var', (69, 82))
249881	26555375	A total of 21 squamous cell carcinomas and 4 adenocarcinomas harbored FGFR1 copy number increases that did not reach the predefined threshold for amplification, including 15 cancers with polyploidy of chromosome 8 (15 ESCC) and 10 cancers with FGFR1 gains (6 ESCC and 4 EADC).	('adenocarcinomas', 'Disease', 'MESH:D000230', (45, 60))	('adenocarcinomas', 'Disease', (45, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (14, 38))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (231, 238))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (14, 38))	('cancers', 'Disease', (174, 181))	('FGFR1', 'Gene', (244, 249))	('FGFR1', 'Gene', (70, 75))	('increases', 'PosReg', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('15 cancers', 'Disease', (171, 181))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('squamous cell carcinomas', 'Disease', (14, 38))	('gains', 'PosReg', (250, 255))	('polyploidy', 'Disease', (187, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('copy number', 'Var', (76, 87))	('polyploidy', 'Disease', 'MESH:D011123', (187, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('15 cancers', 'Disease', 'MESH:C567447', (171, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('FGFR1', 'Gene', '2260', (244, 249))	('FGFR1', 'Gene', '2260', (70, 75))
249885	26555375	Remarkably, FGFR1 amplification was also observed in 6 of 8 patients (75%) where areas of dysplastic squamous epithelium were found adjacent to invasive cancer.	('FGFR1', 'Gene', (12, 17))	('invasive cancer', 'Disease', (144, 159))	('FGFR1', 'Gene', '2260', (12, 17))	('patients', 'Species', '9606', (60, 68))	('invasive cancer', 'Disease', 'MESH:D009362', (144, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('observed', 'Reg', (41, 49))	('dysplastic squamous epithelium', 'Disease', (90, 120))	('dysplastic squamous epithelium', 'Disease', 'MESH:C536309', (90, 120))	('amplification', 'Var', (18, 31))
249886	26555375	mRNA expression results were retained from 8 of 10 FGFR1 amplified and FGFR1 non-amplified each.	('FGFR1', 'Gene', (71, 76))	('FGFR1', 'Gene', '2260', (71, 76))	('mRNA expression', 'MPA', (0, 15))	('amplified', 'Var', (57, 66))	('FGFR1', 'Gene', (51, 56))	('FGFR1', 'Gene', '2260', (51, 56))
249887	26555375	The average mRNA expression level was 14919.4 in FGFR1 amplified as compared to 5485.8 in FGFR1 non-amplified (p = 0.1869).	('amplified', 'Var', (55, 64))	('mRNA expression level', 'MPA', (12, 33))	('FGFR1', 'Gene', (49, 54))	('FGFR1', 'Gene', (90, 95))	('FGFR1', 'Gene', '2260', (90, 95))	('FGFR1', 'Gene', '2260', (49, 54))
249888	26555375	Of note, most FGFR1 amplified cancers had expression levels that were in the range of FGFR1 non-amplified samples.	('expression levels', 'MPA', (42, 59))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancers', 'Disease', (30, 37))	('FGFR1', 'Gene', (14, 19))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('FGFR1', 'Gene', (86, 91))	('FGFR1', 'Gene', '2260', (14, 19))	('FGFR1', 'Gene', '2260', (86, 91))	('amplified', 'Var', (20, 29))
249895	26555375	Data from The Cancer Genome Atlas (TCGA https://tcga-data.nci.nih.gov/tcga) on esophageal carcinomas (September 2015) indicate FGFR1 amplification in 11.1% of 45 squamous cell carcinomas with data on copy number alterations, which is also well in line with 8.9% in our study.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('amplification', 'Reg', (133, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('esophageal carcinomas', 'Disease', (79, 100))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (79, 100))	('copy number alterations', 'Var', (200, 223))	('FGFR1', 'Gene', (127, 132))	('FGFR1', 'Gene', '2260', (127, 132))	('Cancer Genome Atlas', 'Disease', (14, 33))	('squamous cell carcinomas', 'Disease', (162, 186))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (162, 186))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (14, 33))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (79, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (162, 186))
249897	26555375	TCGA data, moreover, suggest that FGFR1 mutations are rare events (< 2%) in this tumor type.	('FGFR1', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutations', 'Var', (40, 49))	('FGFR1', 'Gene', '2260', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
249898	26555375	It is, therefore, likely that the putative oncogenic function of amplified FGFR1 is typically mediated by the wild type gene.	('FGFR1', 'Gene', '2260', (75, 80))	('FGFR1', 'Gene', (75, 80))	('amplified', 'Var', (65, 74))
249901	26555375	These findings suggest that gene amplification is one important mechanism for FGFR1 overexpression but also indicates that other mechanisms can lead to a significant up-regulation of FGFR1 expression.	('FGFR1', 'Gene', (78, 83))	('overexpression', 'PosReg', (84, 98))	('gene amplification', 'Var', (28, 46))	('FGFR1', 'Gene', '2260', (183, 188))	('up-regulation', 'PosReg', (166, 179))	('FGFR1', 'Gene', '2260', (78, 83))	('expression', 'MPA', (189, 199))	('FGFR1', 'Gene', (183, 188))
249902	26555375	We found a striking predominance of FGFR1 amplification in squamous cell cancers (8.9%) as compared to adenocarcinomas (1.6%) in our study on 510 esophageal cancers.	('squamous cell cancers', 'Phenotype', 'HP:0002860', (59, 80))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('FGFR1', 'Gene', (36, 41))	('squamous cell cancers', 'Disease', 'MESH:D002294', (59, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('FGFR1', 'Gene', '2260', (36, 41))	('adenocarcinomas', 'Disease', 'MESH:D000230', (103, 118))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('adenocarcinomas', 'Disease', (103, 118))	('amplification', 'Var', (42, 55))	('esophageal cancers', 'Disease', (146, 164))	('esophageal cancers', 'Disease', 'MESH:D004938', (146, 164))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('squamous cell cancers', 'Disease', (59, 80))
249903	26555375	A higher prevalence of FGFR1 amplification in ESCC as compared to EADC had also been suggested in a previous study comparing 70 ESCC and 189 EADC.	('FGFR1', 'Gene', (23, 28))	('FGFR1', 'Gene', '2260', (23, 28))	('amplification', 'Var', (29, 42))
249908	26555375	It is, thus, tempting to speculate that amplification and overexpression of these genes results in activation of specific genetic programs that favor development of the one ore the other histological subtype of esophageal carcinomas.	('esophageal carcinomas', 'Disease', 'MESH:D004938', (211, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('activation', 'PosReg', (99, 109))	('genetic programs', 'CPA', (122, 138))	('overexpression', 'PosReg', (58, 72))	('amplification', 'Var', (40, 53))	('esophageal carcinomas', 'Disease', (211, 232))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (211, 232))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('favor', 'PosReg', (144, 149))
249909	26555375	In fact, amplification of GATA4 and GATA6 is often found in adenocarcinomas from other origins.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('adenocarcinomas', 'Disease', (60, 75))	('amplification', 'Var', (9, 22))	('GATA6', 'Gene', '2627', (36, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('GATA6', 'Gene', (36, 41))	('GATA4', 'Gene', '2626', (26, 31))	('GATA4', 'Gene', (26, 31))	('adenocarcinomas', 'Disease', 'MESH:D000230', (60, 75))	('found', 'Reg', (51, 56))
249912	26555375	We found FGFR1 amplification in six of eight samples of squamous cell dysplasia adjacent to FGFR1 amplified cancers, and 15 of 18 FGFR1 amplified ESCC showed homogeneous amplification.	('FGFR1', 'Gene', (92, 97))	('FGFR1', 'Gene', '2260', (9, 14))	('FGFR1', 'Gene', (130, 135))	('amplification', 'Reg', (15, 28))	('FGFR1', 'Gene', '2260', (92, 97))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (56, 79))	('FGFR1', 'Gene', '2260', (130, 135))	('amplified', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('squamous cell dysplasia', 'Disease', 'MESH:D002294', (56, 79))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('FGFR1', 'Gene', (9, 14))	('squamous cell dysplasia', 'Disease', (56, 79))	('cancers', 'Disease', (108, 115))
249913	26555375	These findings, despite the low number of cases, might suggest that FGFR1 amplification is an early event in ESCC.	('FGFR1', 'Gene', (68, 73))	('FGFR1', 'Gene', '2260', (68, 73))	('ESCC', 'Disease', (109, 113))	('amplification', 'Var', (74, 87))
249915	26555375	For example, FGFR1 amplification was found in in-situ carcinomas and low-grade ER positive breast cancers and in early stage lung cancers.	('stage lung cancers', 'Disease', (119, 137))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('situ carcinomas', 'Disease', (49, 64))	('FGFR1', 'Gene', '2260', (13, 18))	('stage lung cancers', 'Disease', 'MESH:D008175', (119, 137))	('breast cancers', 'Disease', 'MESH:D001943', (91, 105))	('breast cancers', 'Disease', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('amplification', 'Var', (19, 32))	('breast cancers', 'Phenotype', 'HP:0003002', (91, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('FGFR1', 'Gene', (13, 18))	('situ carcinomas', 'Disease', 'MESH:D002278', (49, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('found', 'Reg', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (125, 137))
249918	26555375	Preclinical studies have demonstrated the efficacy of AZD4547 and BGJ398 on FGFR gene:amplified cancers both in cell line and mouse models.	('mouse', 'Species', '10090', (126, 131))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('FGFR gene', 'Gene', (76, 85))	('BGJ398', 'Chemical', 'MESH:C568950', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('amplified', 'PosReg', (86, 95))	('AZD4547', 'Var', (54, 61))	('BGJ398', 'Gene', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('AZD4547', 'Chemical', 'MESH:C572463', (54, 61))	('cancers', 'Disease', (96, 103))
249919	26555375	In a phase II clinical trial (NCT01795768), AZD4547 showed therapeutic efficacy as a second-line treatment in patients with FGFR1- and FGFR2-amplified breast cancer, squamous cell carcinoma of the lung, or gastro-esophageal adenocarcinoma.	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (166, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (213, 238))	('FGFR1', 'Gene', '2260', (124, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('AZD4547', 'Var', (44, 51))	('breast cancer', 'Disease', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('FGFR2', 'Gene', (135, 140))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (180, 201))	('gastro-esophageal adenocarcinoma', 'Disease', 'MESH:D005764', (206, 238))	('AZD4547', 'Chemical', 'MESH:C572463', (44, 51))	('FGFR1', 'Gene', (124, 129))	('gastro-esophageal adenocarcinoma', 'Disease', (206, 238))	('squamous cell carcinoma of the lung', 'Disease', (166, 201))	('FGFR2', 'Gene', '2263', (135, 140))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (166, 201))	('patients', 'Species', '9606', (110, 118))
249921	26555375	The lack of relevant intratumoral heterogeneity of FGFR1 amplifications in our study suggests that anti-FGFR1 therapies may be effective in esophageal cancers harboring this alteration, and encourages future clinical trials in FGFR1 amplified ESCC.	('esophageal cancers', 'Disease', (140, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('alteration', 'Var', (174, 184))	('esophageal cancers', 'Disease', 'MESH:D004938', (140, 158))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('FGFR1', 'Gene', (227, 232))	('FGFR1', 'Gene', '2260', (104, 109))	('FGFR1', 'Gene', (51, 56))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('FGFR1', 'Gene', '2260', (227, 232))	('tumor', 'Disease', (26, 31))	('FGFR1', 'Gene', (104, 109))	('FGFR1', 'Gene', '2260', (51, 56))
249923	26555375	Additional data on the clinical relevance of FGFR1 alterations in ESCC are only available from Asian patients.	('alterations', 'Var', (51, 62))	('patients', 'Species', '9606', (101, 109))	('FGFR1', 'Gene', (45, 50))	('ESCC', 'Disease', (66, 70))	('FGFR1', 'Gene', '2260', (45, 50))
249924	26555375	Two studies on 526 Korean and 79 Japanese patients report associations between FGFR1 amplification and immunohistochemical overexpression and shorted overall survival.	('associations', 'Interaction', (58, 70))	('shorted', 'NegReg', (142, 149))	('overexpression', 'PosReg', (123, 137))	('FGFR1', 'Gene', (79, 84))	('amplification', 'Var', (85, 98))	('FGFR1', 'Gene', '2260', (79, 84))	('patients', 'Species', '9606', (42, 50))
249926	26555375	Such ethnical differences have been described for various relevant molecular cancer features, including HER2 amplification in breast cancer, TMPRSS2-ERG gene fusion in prostate cancer, and MET mutation in lung cancer.	('cancer', 'Disease', (177, 183))	('ERG', 'Gene', '2078', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('amplification', 'Var', (109, 122))	('TMPRSS2', 'Gene', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', (205, 216))	('prostate cancer', 'Disease', 'MESH:D011471', (168, 183))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('MET mutation', 'Var', (189, 201))	('breast cancer', 'Disease', (126, 139))	('prostate cancer', 'Disease', (168, 183))	('HER2', 'Gene', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('lung cancer', 'Disease', 'MESH:D008175', (205, 216))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('ERG', 'Gene', (149, 152))	('HER2', 'Gene', '2064', (104, 108))	('cancer', 'Disease', (210, 216))	('TMPRSS2', 'Gene', '7113', (141, 148))
249929	26555375	In fact, there is a large number of studies using TMAs with one 0.6 mm cores that confirm the known prognostic relevance of virtually all previously established clinically useful biomarkers, for instance, between alterations of HER2 or p53 and survival in breast cancer, between vimentin expression and prognosis in kidney cancer, and even between heterogeneous markers such as Ki67 labeling index and prognosis in urinary bladder cancer, breast cancer and prostate cancer.	('breast cancer', 'Disease', (256, 269))	('HER2', 'Gene', (228, 232))	('bladder cancer', 'Phenotype', 'HP:0009725', (423, 437))	('urinary bladder cancer', 'Disease', (415, 437))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('vimentin', 'Gene', '7431', (279, 287))	('vimentin', 'Gene', (279, 287))	('cancer', 'Phenotype', 'HP:0002664', (446, 452))	('p53', 'Gene', '7157', (236, 239))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (415, 437))	('kidney cancer', 'Disease', 'MESH:D007680', (316, 329))	('p53', 'Gene', (236, 239))	('HER2', 'Gene', '2064', (228, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (439, 452))	('cancer', 'Phenotype', 'HP:0002664', (466, 472))	('alterations', 'Var', (213, 224))	('TMAs', 'Chemical', '-', (50, 54))	('prostate cancer', 'Disease', 'MESH:D011471', (457, 472))	('breast cancer', 'Disease', 'MESH:D001943', (439, 452))	('breast cancer', 'Phenotype', 'HP:0003002', (256, 269))	('breast cancer', 'Disease', (439, 452))	('prostate cancer', 'Phenotype', 'HP:0012125', (457, 472))	('kidney cancer', 'Phenotype', 'HP:0009726', (316, 329))	('prostate cancer', 'Disease', (457, 472))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('kidney cancer', 'Disease', (316, 329))	('breast cancer', 'Disease', 'MESH:D001943', (256, 269))
249930	26555375	Data from The Cancer Genome Atlas (TCGA) on 70 esophageal carcinomas (45 ESCC and 25 EADC) suggest that FGFR1 mutations are rare events (< 2%) in this tumor type.	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (47, 68))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mutations', 'Var', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (47, 68))	('tumor', 'Disease', (151, 156))	('Cancer Genome Atlas', 'Disease', (14, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (14, 33))	('esophageal carcinomas', 'Disease', (47, 68))	('FGFR1', 'Gene', (104, 109))	('FGFR1', 'Gene', '2260', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
249932	26555375	In summary, the results of our study provide strong evidence that FGFR1 amplification is an early molecular event linked to the squamous cell subtype of esophageal cancers.	('amplification', 'Var', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('linked', 'Reg', (114, 120))	('squamous cell subtype', 'Disease', (128, 149))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('FGFR1', 'Gene', (66, 71))	('esophageal cancers', 'Disease', (153, 171))	('FGFR1', 'Gene', '2260', (66, 71))	('esophageal cancers', 'Disease', 'MESH:D004938', (153, 171))
249944	26462879	Tobacco use, alcohol consumption and mutations of enzymes that metabolizing alcohol have been the primary causes of ESCC, however, alcohol consumption is not considered as a risk factor for EAC.	('alcohol', 'Chemical', 'MESH:D000438', (131, 138))	('EAC', 'Phenotype', 'HP:0011459', (190, 193))	('alcohol', 'Chemical', 'MESH:D000438', (76, 83))	('ESCC', 'Disease', (116, 120))	('alcohol', 'Chemical', 'MESH:D000438', (13, 20))	('causes', 'Reg', (106, 112))	('mutations', 'Var', (37, 46))	('Tobacco', 'Species', '4097', (0, 7))
249996	25439272	Beyond demographics, the major risk factors for EAC are gastroesophageal reflux disease (GERD), cigarette smoking, obesity, and low fruit and vegetable consumption.	('obesity', 'Disease', (115, 122))	('obesity', 'Disease', 'MESH:D009765', (115, 122))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (56, 87))	('low fruit', 'Var', (128, 137))	('obesity', 'Phenotype', 'HP:0001513', (115, 122))	('EAC', 'Phenotype', 'HP:0011459', (48, 51))	('gastroesophageal reflux disease', 'Disease', (56, 87))	('EAC', 'Disease', (48, 51))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (56, 79))
250015	25439272	In a murine model, inhibition of COX-2 reduced progression of BE to EAC.	('inhibition', 'Var', (19, 29))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('murine', 'Species', '10090', (5, 11))	('reduced', 'NegReg', (39, 46))	('COX-2', 'Enzyme', (33, 38))	('BE', 'Phenotype', 'HP:0100580', (62, 64))
250018	25439272	Blockade of NF-kappaB activity has been shown to reduce the acid-induced inflammatory response in cell lines derived from EAC.	('NF-kappaB', 'Gene', (12, 21))	('Blockade', 'Var', (0, 8))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('reduce', 'NegReg', (49, 55))	('acid-induced inflammatory response', 'MPA', (60, 94))	('NF-kappaB', 'Gene', '4790', (12, 21))
250047	25439272	No statistical differences were found between groups with regards to the presence of HPV, the presence of high- vs low-risk subtypes, or immunohistochemistry for P16INK4a (a viral product that is used as a marker for activity of infection).	('infection', 'Disease', (229, 238))	('infection', 'Disease', 'MESH:D007239', (229, 238))	('HPV', 'Species', '10566', (85, 88))	('P16INK4a', 'Var', (162, 170))
250056	25439272	However, eradication of H. pylori does not induce new cases of GERD, nor does it worsen GERD symptoms (except in patients with hiatal hernia and corpus gastritis).	('H. pylori', 'Gene', (24, 33))	('hernia', 'Phenotype', 'HP:0100790', (134, 140))	('hiatal hernia and corpus gastritis', 'Disease', 'MESH:D006551', (127, 161))	('GERD', 'Disease', (63, 67))	('H. pylori', 'Species', '210', (24, 33))	('patients', 'Species', '9606', (113, 121))	('hiatal hernia', 'Phenotype', 'HP:0002036', (127, 140))	('gastritis', 'Phenotype', 'HP:0005263', (152, 161))	('eradication', 'Var', (9, 20))	('GERD', 'Disease', (88, 92))
250060	25439272	Likewise, it cannot be determined whether this variant microbiome caused disease by induction of abnormal lower esophageal sphincter function, accelerated disease by potentiating inflammation via interaction with TLRs, predisposed towards disease by altering the immune response to incipient cancer, or resulted from changes in the local microenvironment related to acid exposure.	('disease', 'Disease', (155, 162))	('caused', 'Reg', (66, 72))	('TLRs', 'Protein', (213, 217))	('accelerated', 'PosReg', (143, 154))	('inflammation', 'Disease', 'MESH:D007249', (179, 191))	('changes', 'Reg', (317, 324))	('interaction', 'Interaction', (196, 207))	('esophageal sphincter function', 'Disease', 'MESH:D046628', (112, 141))	('cancer', 'Disease', (292, 298))	('altering', 'Reg', (250, 258))	('inflammation', 'Disease', (179, 191))	('esophageal sphincter function', 'Disease', (112, 141))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('disease', 'Disease', (73, 80))	('variant', 'Var', (47, 54))	('disease', 'Disease', (239, 246))	('induction', 'Reg', (84, 93))	('potentiating', 'PosReg', (166, 178))	('cancer', 'Disease', 'MESH:D009369', (292, 298))
250188	32856860	Malnutrition may lead to cachexia which is responsible for up to 20 percent of cancer deaths (Gullett et al., 2011; Ryan et al., 2016).	('Malnutrition', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cachexia', 'Phenotype', 'HP:0004326', (25, 33))	('lead to', 'Reg', (17, 24))	('cancer deaths', 'Disease', 'MESH:D009369', (79, 92))	('cancer deaths', 'Disease', (79, 92))	('cachexia', 'Disease', 'MESH:D002100', (25, 33))	('Malnutrition', 'Phenotype', 'HP:0004395', (0, 12))	('cachexia', 'Disease', (25, 33))
250257	32856860	The twelve-month mortality was significantly associated with BMI<18.5 before treatment (52% vs. 26%) (p-value=0.032).	('mortality', 'Disease', (17, 26))	('mortality', 'Disease', 'MESH:D003643', (17, 26))	('men', 'Species', '9606', (82, 85))	('BMI<18.5', 'Var', (61, 69))
250282	32856860	Elevated RDW predicts poor prognosis in patients with oral SCC and hepatocellular carcinoma.	('patients', 'Species', '9606', (40, 48))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('oral SCC and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 91))	('RDW', 'MPA', (9, 12))	('Elevated', 'Var', (0, 8))
250309	33381546	AC079467.1 and DIRC3 were considered to be positively correlated with overall survival.	('DIRC3', 'Gene', '729582', (15, 20))	('AC079467.1', 'Var', (0, 10))	('overall', 'CPA', (70, 77))	('correlated', 'Reg', (54, 64))	('DIRC3', 'Gene', (15, 20))
250311	33381546	Long noncoding RNA has been confirmed to be associated with poor prognosis in lung cancer, gastric cancer, liver cancer, and other cancers.	('lung cancer', 'Disease', (78, 89))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancers', 'Disease', (131, 138))	('gastric cancer', 'Disease', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (91, 105))	('liver cancer', 'Disease', 'MESH:D006528', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('liver cancer', 'Phenotype', 'HP:0002896', (107, 119))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('Long noncoding RNA', 'Var', (0, 18))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('liver cancer', 'Disease', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
250314	33381546	The overexpression of lncRNA HAND2-AS1 may inhibit the proliferation, migration, and invasion of cancer cells in ESCC by downregulating miRNA-21.	('miRNA-21', 'Gene', (136, 144))	('ESCC', 'Disease', (113, 117))	('downregulating', 'NegReg', (121, 135))	('migration', 'CPA', (70, 79))	('invasion of cancer cells', 'CPA', (85, 109))	('proliferation', 'CPA', (55, 68))	('inhibit', 'NegReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('miRNA-21', 'Gene', '406991', (136, 144))	('lncRNA HAND2-AS1', 'Var', (22, 38))	('overexpression', 'PosReg', (4, 18))
250327	33262384	Our data indicate that 252Cf-NBT+EBRT produces favorable local control for patients with local recurrent esophageal cancer after CRT, with tolerable side effects.	('252Cf-NBT+EBRT', 'Var', (23, 37))	('EBRT', 'Chemical', '-', (33, 37))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('patients', 'Species', '9606', (75, 83))	('local', 'MPA', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CR', 'Chemical', '-', (129, 131))	('252Cf-NBT', 'Chemical', '-', (23, 32))
250339	33262384	Evidence from randomized trials has revealed that the outcome of single-fraction intraluminal brachytherapy is better than that of stents, in which intraluminal brachytherapy improves dysphagia and quality of life associated with the delayed onset of symptomatic relief.	('dysphagia', 'Disease', (184, 193))	('quality of life', 'CPA', (198, 213))	('improves', 'PosReg', (175, 183))	('intraluminal brachytherapy', 'Var', (148, 174))	('dysphagia', 'Phenotype', 'HP:0002015', (184, 193))	('dysphagia', 'Disease', 'MESH:D003680', (184, 193))
250372	33262384	Furthermore, patients in the NBT+EBRT group exhibited significantly better responses than those in the EBRT group.	('EBRT', 'Chemical', '-', (33, 37))	('better', 'PosReg', (68, 74))	('NBT', 'Chemical', '-', (29, 32))	('NBT+EBRT', 'Var', (29, 37))	('patients', 'Species', '9606', (13, 21))	('EBRT', 'Chemical', '-', (103, 107))	('responses', 'MPA', (75, 84))
250379	33262384	Though not statistically significant (p = 0.667 with a 95% confidence interval), the median FRS duration for the NBT+EBRT group was 13 months (10.2 to 13.9 months), whereas that for the EBRT alone group was 12 months (10.6 to 14.6 months).	('NBT', 'Chemical', '-', (113, 116))	('NBT+EBRT', 'Var', (113, 121))	('FRS duration', 'CPA', (92, 104))	('EBRT', 'Chemical', '-', (117, 121))	('EBRT', 'Chemical', '-', (186, 190))
250403	33262384	Some papers have reported that EBRT+NBT can improve PFS and OS in patients with advanced cervical and esophageal carcinomas.	('esophageal carcinomas', 'Disease', (102, 123))	('improve', 'PosReg', (44, 51))	('NBT', 'Chemical', '-', (36, 39))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (102, 122))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (102, 123))	('PFS', 'Disease', (52, 55))	('cervical', 'Disease', (89, 97))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (102, 123))	('EBRT+NBT', 'Var', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('EBRT', 'Chemical', '-', (31, 35))	('patients', 'Species', '9606', (66, 74))
250409	33262384	Therefore, with a high reirradiation dose in our cohort, the dose of EBRT was 54-60 Gy/30 f., and that of NBT+EBRT was 12 Gy-eq/3 f. + 41.4 Gy/23 f. or 12 Gy-eq/3 f. + 46 Gy/23 f. Consistent with previous studies, recurrence markedly shortened the survival duration.	('shortened', 'NegReg', (234, 243))	('survival duration', 'CPA', (248, 265))	('NBT', 'Chemical', '-', (106, 109))	('EBRT', 'Chemical', '-', (110, 114))	('EBRT', 'Chemical', '-', (69, 73))	('recurrence', 'Var', (214, 224))
250422	33262384	So in our study the EBRT+NBT may be suited to patients with short-term recrudescence or the nearby normal tissues dose must be low, and received a significantly lower IMRT(41.4-46 Gy, four fractions/week, one fraction/day, and 1.8-2.0 Gy/fraction, for total of 23 fractions), this can be addressed by reference to the additional dose from the NBT.	('lower', 'NegReg', (161, 166))	('patients', 'Species', '9606', (46, 54))	('NBT', 'Chemical', '-', (343, 346))	('EBRT+NBT', 'Var', (20, 28))	('EBRT', 'Chemical', '-', (20, 24))	('NBT', 'Chemical', '-', (25, 28))
250424	33262384	In the present study, the main causes of death were different between the NBT+EBRT group and the EBRT group.	('EBRT', 'Chemical', '-', (78, 82))	('NBT', 'Chemical', '-', (74, 77))	('NBT+EBRT', 'Var', (74, 82))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('EBRT', 'Chemical', '-', (97, 101))
250430	33262384	However, NBT+EBRT for recurrent esophageal carcinoma after CRT is an effective treatment option, and it is especially suitable for patients with short-term recrudescence.	('patients', 'Species', '9606', (131, 139))	('CR', 'Chemical', '-', (59, 61))	('NBT', 'Chemical', '-', (9, 12))	('recurrent', 'Disease', (22, 31))	('NBT+EBRT', 'Var', (9, 17))	('EBRT', 'Chemical', '-', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('esophageal carcinoma', 'Disease', (32, 52))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (32, 52))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (32, 52))
250435	33243974	By comparing miRNA profiles of the highly metastatic ESCC cell sublines, we established through serial in vivo selection with the parental cells, we found that the expression level of miR-515-3p was lower in ESCC tumor tissues than adjacent normal tissues, further decreased in metastatic tumors, and moreover, markedly associated with advanced stage, metastasis and patient survival.	('patient survival', 'CPA', (367, 383))	('lower', 'NegReg', (199, 204))	('ESCC tumor', 'Disease', 'MESH:D004938', (208, 218))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('metastasis', 'CPA', (352, 362))	('patient', 'Species', '9606', (367, 374))	('decreased', 'NegReg', (265, 274))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('associated with', 'Reg', (320, 335))	('tumors', 'Disease', (289, 295))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('advanced stage', 'CPA', (336, 350))	('ESCC tumor', 'Disease', (208, 218))	('miR-515-3p', 'Var', (184, 194))	('miR-515-3p', 'Chemical', '-', (184, 194))	('expression level', 'MPA', (164, 180))
250436	33243974	The in vitro and in vivo assays suggested that miR-515-3p could increase the expression of the epithelial markers as well as decrease the expression of the mesenchymal markers, and more importantly, suppress invasion and metastasis of ESCC cells.	('ESCC', 'Disease', (235, 239))	('expression', 'MPA', (77, 87))	('epithelial markers', 'Protein', (95, 113))	('miR-515-3p', 'Var', (47, 57))	('miR-515-3p', 'Chemical', '-', (47, 57))	('increase', 'PosReg', (64, 72))	('expression', 'MPA', (138, 148))	('mesenchymal markers', 'CPA', (156, 175))	('decrease', 'NegReg', (125, 133))	('suppress', 'NegReg', (199, 207))
250437	33243974	Mechanistically, we revealed that miR-515-3p directly regulated vimentin and matrix metalloproteinase-3 (MMP3) expression by binding to the coding sequence and 3'untranslated region, respectively.	('regulated', 'Reg', (54, 63))	('matrix metalloproteinase-3', 'Gene', '4314', (77, 103))	('MMP3', 'Gene', (105, 109))	('matrix metalloproteinase-3', 'Gene', (77, 103))	('miR-515-3p', 'Var', (34, 44))	('miR-515-3p', 'Chemical', '-', (34, 44))	('vimentin', 'Protein', (64, 72))	('expression', 'MPA', (111, 121))	('binding', 'Interaction', (125, 132))
250438	33243974	In addition, the data from whole-genome methylation sequencing and methylation-specific PCR indicated that the CpG island within miR-515-3p promoter was markedly hypermethylated in ESCC cell lines and ESCC tumor tissues, which may lead to deregulation of miR-515-3p expression in ESCC.	('ESCC', 'Disease', (280, 284))	('hypermethylated', 'Var', (162, 177))	('ESCC tumor', 'Disease', 'MESH:D004938', (201, 211))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('miR-515-3p', 'Chemical', '-', (129, 139))	('miR-515-3p', 'Gene', (255, 265))	('deregulation', 'MPA', (239, 251))	('miR-515-3p', 'Chemical', '-', (255, 265))	('ESCC', 'Disease', (181, 185))	('ESCC tumor', 'Disease', (201, 211))
250439	33243974	Furthermore, our preclinical experiment provides solid evidence that systemic delivery of miR-515-3p oligonucleotide obviously suppressed the metastasis of ESCC cells in nude mice.	('metastasis of', 'CPA', (142, 155))	('nude mice', 'Species', '10090', (170, 179))	('miR-515-3p oligonucleotide', 'Chemical', '-', (90, 116))	('miR-515-3p oligonucleotide', 'Var', (90, 116))	('suppressed', 'NegReg', (127, 137))	('ESCC', 'Disease', (156, 160))
250440	33243974	Taken together, this study demonstrates that miR-515-3p suppresses tumor metastasis and thus represents a promising prognostic biomarker and therapeutic strategy in ESCC.	('ESCC', 'Disease', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('miR-515-3p', 'Var', (45, 55))	('miR-515-3p', 'Chemical', '-', (45, 55))	('suppresses', 'NegReg', (56, 66))	('tumor metastasis', 'Disease', 'MESH:D009362', (67, 83))	('tumor metastasis', 'Disease', (67, 83))
250448	33243974	Among the candidate miRNAs, miR-515-3p expression was confirmed to be downregulated in the highly invasive and metastatic sublines and correlated with metastasis status and prognosis of the cancer patients.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('patients', 'Species', '9606', (197, 205))	('correlated', 'Reg', (135, 145))	('miR-515-3p expression', 'Var', (28, 49))	('miR-515-3p', 'Chemical', '-', (28, 38))	('downregulated', 'NegReg', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('metastasis status', 'CPA', (151, 168))
250449	33243974	However, up to now, the biological function of miR-515-3p in cancer metastasis and its upstream regulatory mechanism has not been reported.	('miR-515-3p', 'Var', (47, 57))	('miR-515-3p', 'Chemical', '-', (47, 57))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
250451	33243974	Here, a series of gain- and loss-of-function experiments and in vivo and in vitro functional experiments were performed to examine the effect of miR-515-3p on cancer invasion and metastasis as well as the potential upstream and downstream mechanisms.	('cancer', 'Disease', (159, 165))	('gain-', 'PosReg', (18, 23))	('loss-of-function', 'NegReg', (28, 44))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('miR-515-3p', 'Var', (145, 155))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('miR-515-3p', 'Chemical', '-', (145, 155))
250452	33243974	The therapeutic potential of systemically delivered miR-515-3p oligonucleotide in the treatment of cancer metastasis was examined.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('miR-515-3p', 'Var', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('miR-515-3p oligonucleotide', 'Chemical', '-', (52, 78))
250454	33243974	Expression levels of some well-known metastasis-suppressive miRNAs such as miR-124 and miR-708, were markedly decreased in the highly metastatic ESCC subline, strongly suggesting that this model is useful in profiling metastasis-associated miRNAs.	('Expression levels', 'MPA', (0, 17))	('miR-708', 'Gene', (87, 94))	('decreased', 'NegReg', (110, 119))	('metastasis-suppressive', 'CPA', (37, 59))	('miR-124', 'Var', (75, 82))	('miR-708', 'Gene', '100126333', (87, 94))
250456	33243974	In this study, the results showed that miR-515-3p overexpression obviously repressed the invasive potential of KYSE150-Luc-LM3 cells (Supplementary Fig.	('miR-515-3p', 'Var', (39, 49))	('repressed', 'PosReg', (75, 84))	('miR-515-3p', 'Chemical', '-', (39, 49))	('invasive potential', 'CPA', (89, 107))
250457	33243974	And miR-515-3p expression was lower in ESCC cells as compared with the normal immortalized esophageal epithelial cells (Fig.	('miR-515-3p', 'Chemical', '-', (4, 14))	('lower', 'NegReg', (30, 35))	('ESCC', 'Disease', (39, 43))	('miR-515-3p', 'Var', (4, 14))
250458	33243974	S1b) through serial in vitro selection, and found that miR-515-3p expression further decreased in the highly invasive and metastatic sublines KYSE410-Luc-I6 and KYSE150-Luc-LM3 (Fig.	('decreased', 'NegReg', (85, 94))	('KYSE150-Luc-LM3', 'Var', (161, 176))	('expression', 'MPA', (66, 76))	('KYSE410-Luc-I6', 'Var', (142, 156))	('miR-515-3p', 'Gene', (55, 65))	('miR-515-3p', 'Chemical', '-', (55, 65))
250463	33243974	More importantly, patients with low expression of miR-515-3p had obviously shorter survival (median survival = 22.4 months) than the patients with high miR-515-3p expression (median survival = 57.0 months) (Fig.	('low', 'NegReg', (32, 35))	('miR-515-3p', 'Var', (50, 60))	('miR-515-3p', 'Chemical', '-', (50, 60))	('patients', 'Species', '9606', (133, 141))	('shorter', 'NegReg', (75, 82))	('patients', 'Species', '9606', (18, 26))	('miR-515-3p', 'Chemical', '-', (152, 162))	('survival', 'MPA', (83, 91))
250466	33243974	Analysis of data from the OncomiR Cancer Database indicated that miR-515-3p expression was markedly correlated with the survival of the patients with esophageal cancer (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('miR-515-3p expression', 'Var', (65, 86))	('correlated with', 'Reg', (100, 115))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('patients', 'Species', '9606', (136, 144))	('miR-515-3p', 'Chemical', '-', (65, 75))	('cancer', 'Disease', (161, 167))	('OncomiR Cancer', 'Disease', (26, 40))	('OncomiR Cancer', 'Disease', 'MESH:D009369', (26, 40))
250467	33243974	Moreover, miR-515-3p expression was also associated with clinical parameters and survival in several other cancer types such as kidney renal papillary cell carcinoma (Supplementary Tables 1 and 2).	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('kidney renal papillary cell carcinoma', 'Disease', (128, 165))	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (128, 165))	('miR-515-3p expression', 'Var', (10, 31))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('miR-515-3p', 'Chemical', '-', (10, 20))	('cancer', 'Disease', (107, 113))
250468	33243974	These data indicated that miR-515-3p may be a novel biomarker for cancer diagnosis and prognosis.	('miR-515-3p', 'Var', (26, 36))	('miR-515-3p', 'Chemical', '-', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
250472	33243974	Notably, the results from methylation-specific PCR revealed that the CpG island within miR-515-3p was significantly hypermethylated in ESCC cell lines examined, but not in immortalized normal esophageal epithelial cells (Fig.	('miR-515-3p', 'Chemical', '-', (87, 97))	('ESCC', 'Disease', (135, 139))	('hypermethylated', 'Var', (116, 131))
250474	33243974	We also determined the methylation level and expression level of miR-515-3p in 28 pairs of ESCC tumor and normal tissues (Fig.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ESCC tumor', 'Disease', 'MESH:D004938', (91, 101))	('expression', 'MPA', (45, 55))	('methylation level', 'MPA', (23, 40))	('miR-515-3p', 'Var', (65, 75))	('miR-515-3p', 'Chemical', '-', (65, 75))	('ESCC tumor', 'Disease', (91, 101))
250475	33243974	miR-515-3p was found significantly hypermethylated in 60.7% (17/28) of the ESCC tissues compared with their paired normal tissues (Fig.	('hypermethylated', 'Var', (35, 50))	('ESCC', 'Disease', (75, 79))	('miR-515-3p', 'Chemical', '-', (0, 10))	('miR-515-3p', 'Var', (0, 10))
250477	33243974	We found that miR-515-3p expression was negatively associated with its methylation level in 28 pairs of ESCC tissues and normal tissues (r = - 0.46, p < 0.05) (Fig.	('miR-515-3p', 'Chemical', '-', (14, 24))	('methylation level', 'MPA', (71, 88))	('miR-515-3p expression', 'Var', (14, 35))	('negatively', 'NegReg', (40, 50))
250478	33243974	These data implied that promoter hypermethylation leads to the deregulation of miR-515-3p expression in ESCC.	('miR-515-3p', 'Gene', (79, 89))	('miR-515-3p', 'Chemical', '-', (79, 89))	('ESCC', 'Disease', (104, 108))	('deregulation', 'MPA', (63, 75))	('promoter hypermethylation', 'Var', (24, 49))
250479	33243974	The function of miR-515-3p in ESCC invasion and metastasis has not been reported previously.	('ESCC', 'Disease', (30, 34))	('miR-515-3p', 'Var', (16, 26))	('miR-515-3p', 'Chemical', '-', (16, 26))
250480	33243974	miR-515-3p-overexpressing stable cell lines were generated in the highly invasive and metastatic ESCC cells, KYSE410-Luc-I6 and KYSE150-Luc-LM3, which we established previously (Fig.	('KYSE150-Luc-LM3', 'Var', (128, 143))	('miR-515-3p', 'Chemical', '-', (0, 10))	('KYSE410-Luc-I6', 'Var', (109, 123))
250481	33243974	The results showed that KYSE410-Luc-I6-miR-515-3p and KYSE150-Luc-LM3-miR-515-3p cells had lower invasive, migration and adhesion ability, as compared with corresponding parental cell lines expressing scrambled miRNAs (Fig.	('lower', 'NegReg', (91, 96))	('miR-515-3p', 'Chemical', '-', (39, 49))	('invasive', 'CPA', (97, 105))	('KYSE150-Luc-LM3-miR-515-3p', 'Var', (54, 80))	('KYSE410-Luc-I6-miR-515-3p', 'Var', (24, 49))	('miR-515-3p', 'Chemical', '-', (70, 80))	('adhesion ability', 'CPA', (121, 137))
250483	33243974	EMT marker expression were analyzed, decreased fibronectin and N-cadherin expression as well as increased E-cadherin and ZO-1 expression were observed in miR-515-3p-overexpressing ESCC cells (Fig.	('expression', 'MPA', (74, 84))	('increased', 'PosReg', (96, 105))	('decreased fibronectin', 'Phenotype', 'HP:0032463', (37, 58))	('ZO-1', 'Gene', '7082', (121, 125))	('expression', 'MPA', (126, 136))	('miR-515-3p', 'Chemical', '-', (154, 164))	('miR-515-3p-overexpressing', 'Var', (154, 179))	('fibronectin', 'Gene', '2335', (47, 58))	('N-cadherin', 'Gene', (63, 73))	('E-cadherin', 'Gene', (106, 116))	('E-cadherin', 'Gene', '999', (106, 116))	('N-cadherin', 'Gene', '1000', (63, 73))	('fibronectin', 'Gene', (47, 58))	('decreased', 'NegReg', (37, 46))	('ZO-1', 'Gene', (121, 125))
250485	33243974	S3b, inhibition of miR-515-3p expression increased the invasive, migration, and adhesion ability of ESCC cells.	('migration', 'CPA', (65, 74))	('increased', 'PosReg', (41, 50))	('inhibition', 'Var', (5, 15))	('miR-515-3p', 'Chemical', '-', (19, 29))	('miR-515-3p expression', 'Protein', (19, 40))	('invasive', 'CPA', (55, 63))	('adhesion ability', 'CPA', (80, 96))
250486	33243974	We also found decreased E-cadherin and ZO-1 as well as increased fibronectin and N-cadherin expression in miR-515-3p-knockdown ESCC cells, as compared with their control cells respectively (Fig.	('decreased', 'NegReg', (14, 23))	('ZO-1', 'Gene', (39, 43))	('fibronectin', 'Gene', (65, 76))	('N-cadherin', 'Gene', '1000', (81, 91))	('miR-515-3p-knockdown', 'Var', (106, 126))	('increased', 'PosReg', (55, 64))	('miR-515-3p', 'Chemical', '-', (106, 116))	('E-cadherin', 'Gene', (24, 34))	('fibronectin', 'Gene', '2335', (65, 76))	('increased fibronectin', 'Phenotype', 'HP:0032463', (55, 76))	('ZO-1', 'Gene', '7082', (39, 43))	('E-cadherin', 'Gene', '999', (24, 34))	('expression', 'MPA', (92, 102))	('N-cadherin', 'Gene', (81, 91))
250490	33243974	The results showed that miR-515-3p significantly suppressed lung metastasis, which was confirmed by hematoxylin and eosin (H & E) staining of lung sections (Fig.	('miR-515-3p', 'Var', (24, 34))	('lung metastasis', 'CPA', (60, 75))	('miR-515-3p', 'Chemical', '-', (24, 34))	('hematoxylin', 'Chemical', 'MESH:D006416', (100, 111))	('suppressed', 'NegReg', (49, 59))	('eosin', 'Chemical', 'MESH:D004801', (116, 121))	('H & E', 'Chemical', 'MESH:D006371', (123, 128))
250491	33243974	In contrast, loss-of-function experiment showed that knockdown of miR-515-3p significantly promoted lung metastasis (Fig.	('miR-515-3p', 'Var', (66, 76))	('promoted', 'PosReg', (91, 99))	('miR-515-3p', 'Chemical', '-', (66, 76))	('lung metastasis', 'CPA', (100, 115))
250492	33243974	Collectively, these results indicated for the first time that miR-515-3p may be a novel suppressor of cancer cell invasion and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('miR-515-3p', 'Var', (62, 72))	('miR-515-3p', 'Chemical', '-', (62, 72))	('suppressor', 'NegReg', (88, 98))
250494	33243974	S5a), and 173 transcripts were found to be downregulated in KYSE150-Luc-LM3-miR-515-3p cells (fold change > 1.5) (Supplementary Fig.	('downregulated', 'NegReg', (43, 56))	('KYSE150-Luc-LM3-miR-515-3p', 'Var', (60, 86))	('S5a', 'Gene', '5710', (0, 3))	('S5a', 'Gene', (0, 3))	('miR-515-3p', 'Chemical', '-', (76, 86))
250498	33243974	Among the five overlapped genes, vimentin and MMP3, which have been widely recognized as key regulators in promoting cancer invasion and metastasis, drew our great attention to postulate that miR-515-3p may exert its suppressive effect on cancer mobility through its regulation on vimentin and MMP3.	('MMP3', 'Gene', (294, 298))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('miR-515-3p', 'Var', (192, 202))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('miR-515-3p', 'Chemical', '-', (192, 202))	('regulation', 'Reg', (267, 277))	('cancer', 'Disease', (239, 245))	('vimentin', 'Protein', (281, 289))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('suppressive', 'NegReg', (217, 228))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
250499	33243974	Computational analysis suggested the possible direct binding sites for miR-515-3p to be in the coding sequence (CDS) of vimentin and 3'-UTR of MMP3, respectively (Fig.	('miR-515-3p', 'Var', (71, 81))	('miR-515-3p', 'Chemical', '-', (71, 81))	('MMP3', 'Gene', (143, 147))	('binding', 'Interaction', (53, 60))	('vimentin', 'Protein', (120, 128))
250500	33243974	For verification, using 3'-UTR luciferase reporter assays, we found that transfection of miR-515-3p mimic in KYSE150 cells led to an obvious decrease in the relative luciferase activity of vimentin CDS and MMP3 3'-UTR, but there was no inhibition of luciferase activity when miR-515-3p mimic was co-transfected with mutant MMP3 3'-UTR or vimentin CDS (Fig.	('luciferase', 'Enzyme', (166, 176))	('miR-515-3p mimic', 'Var', (89, 105))	('miR-515-3p', 'Chemical', '-', (89, 99))	('activity', 'MPA', (177, 185))	('miR-515-3p', 'Chemical', '-', (275, 285))	('decrease', 'NegReg', (141, 149))
250501	33243974	Significant decreases in vimentin and MMP3 expression at mRNA and protein levels were observed in the highly invasive and metastatic cell lines with stable overexpression of miR-515-3p (Fig.	('vimentin', 'Protein', (25, 33))	('overexpression', 'PosReg', (156, 170))	('miR-515-3p', 'Var', (174, 184))	('miR-515-3p', 'Chemical', '-', (174, 184))	('MMP3', 'Gene', (38, 42))	('decreases', 'NegReg', (12, 21))	('expression', 'MPA', (43, 53))
250502	33243974	Conversely, expression levels of vimentin and MMP3 were upregulated in the ESCC cells with stable knockdown of miR-515-3p (Fig.	('vimentin', 'Protein', (33, 41))	('MMP3', 'Gene', (46, 50))	('expression levels', 'MPA', (12, 29))	('miR-515-3p', 'Chemical', '-', (111, 121))	('miR-515-3p', 'Var', (111, 121))	('upregulated', 'PosReg', (56, 67))
250503	33243974	Moreover, gain- and loss-of-function experiments and western blotting analysis revealed that transient transfection of miR-515-3p mimic or miR-515-3p-expressing plasmid not only markedly reduced vimentin and MMP3 expression at mRNA and protein levels, but also decreased fibronectin and N-cadherin expression in ESCC cell lines (Fig.	('fibronectin', 'Gene', (271, 282))	('MMP3', 'Protein', (208, 212))	('expression', 'MPA', (213, 223))	('miR-515-3p-expressing', 'Var', (139, 160))	('N-cadherin', 'Gene', '1000', (287, 297))	('decreased', 'NegReg', (261, 270))	('miR-515-3p', 'Var', (119, 129))	('miR-515-3p', 'Chemical', '-', (119, 129))	('reduced', 'NegReg', (187, 194))	('fibronectin', 'Gene', '2335', (271, 282))	('miR-515-3p', 'Chemical', '-', (139, 149))	('decreased fibronectin', 'Phenotype', 'HP:0032463', (261, 282))	('vimentin', 'Protein', (195, 203))	('N-cadherin', 'Gene', (287, 297))
250504	33243974	S6a, b), whereas silencing of miR-515-3p with inhibitor had opposite effect on vimentin, MMP3 and EMT markers (Fig.	('miR-515-3p', 'Var', (30, 40))	('miR-515-3p', 'Chemical', '-', (30, 40))	('EMT markers', 'CPA', (98, 109))	('silencing', 'Var', (17, 26))	('MMP3', 'CPA', (89, 93))	('vimentin', 'Protein', (79, 87))
250505	33243974	These data make it obvious that miR-515-3p affects the expression levels of vimentin and MMP3 by binding to CDS and 3'-UTR region, respectively, thus suggesting that downregulation of miR-515-3p may lead to vimentin- and MMP3-mediated cancer invasion and metastasis.	('metastasis', 'CPA', (255, 265))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('affects', 'Reg', (43, 50))	('expression levels', 'MPA', (55, 72))	('binding', 'Interaction', (97, 104))	('lead to', 'Reg', (199, 206))	('MMP3', 'Gene', (89, 93))	('miR-515-3p', 'Var', (184, 194))	('miR-515-3p', 'Chemical', '-', (184, 194))	('downregulation', 'NegReg', (166, 180))	('miR-515-3p', 'Chemical', '-', (32, 42))
250507	33243974	The I6 and LM3 cells co-overexpressing miR-515-3p and vimentin, or miR-515-3p and MMP3, or miR-515-3p, vimentin and MMP3 (KYSE150-Luc-LM3-miR-515-3p-vimentin, KYSE150-Luc-LM3-miR-515-3p-MMP3, KYSE150-Luc-LM3-miR-515-3p-vimentin+MMP3, KYSE410-Luc-I6-miR-515-3p-vimentin, KYSE410-Luc-I6-miR-515-3p-MMP3, KYSE410-Luc-I6-miR-515-3p-vimentin+MMP3), or miR-515-3p alone (KYSE150-Luc-LM3-miR-515-3p-CON, KYSE410-Luc-I6-miR-515-3p-CON), and the control cells (KYSE150-Luc-LM3-miR-CON-CON, KYSE410-Luc-I6-miR-CON-CON) were compared for the expression levels of EMT markers and their invasive and migration ability.	('miR-515-3p', 'Chemical', '-', (67, 77))	('KYSE410-Luc-I6-miR-515-3p-CON', 'Var', (397, 426))	('miR-515-3p', 'Chemical', '-', (39, 49))	('miR-515-3p', 'Chemical', '-', (249, 259))	('miR-515-3p', 'Chemical', '-', (91, 101))	('miR-515-3p', 'Chemical', '-', (175, 185))	('miR-CON', 'Chemical', '-', (468, 475))	('miR-515-3p', 'Chemical', '-', (347, 357))	('miR-515-3p', 'Chemical', '-', (381, 391))	('miR-515-3p', 'Chemical', '-', (412, 422))	('miR-515-3p', 'Chemical', '-', (285, 295))	('miR-515-3p', 'Chemical', '-', (138, 148))	('miR-515-3p', 'Chemical', '-', (208, 218))	('miR-515-3p', 'Chemical', '-', (317, 327))	('expression levels', 'MPA', (531, 548))	('miR-CON', 'Chemical', '-', (496, 503))
250508	33243974	Decreased fibronectin and N-cadherin expression and increased E-cadherin and ZO-1 expression were observed in the miR-515-3p-overexpressing cells, and these effects were abolished by ectopic expression of vimentin or MMP3 alone, or vimentin and MMP3 (Fig.	('N-cadherin', 'Gene', (26, 36))	('fibronectin', 'Gene', (10, 21))	('increased', 'PosReg', (52, 61))	('expression', 'MPA', (82, 92))	('N-cadherin', 'Gene', '1000', (26, 36))	('ZO-1', 'Gene', (77, 81))	('Decreased', 'NegReg', (0, 9))	('ZO-1', 'Gene', '7082', (77, 81))	('E-cadherin', 'Gene', (62, 72))	('fibronectin', 'Gene', '2335', (10, 21))	('expression', 'MPA', (37, 47))	('miR-515-3p', 'Chemical', '-', (114, 124))	('miR-515-3p-overexpressing', 'Var', (114, 139))	('Decreased fibronectin', 'Phenotype', 'HP:0032463', (0, 21))	('E-cadherin', 'Gene', '999', (62, 72))
250510	33243974	On the contrary, the expression of vimentin and MMP3 in miR-515-3p-knockdwon ESCC cell lines (KYSE150-Luc-ZIP-miR-515-3p, EC109-ZIP-miR-515-3p) was further inhibited with shRNA (Fig.	('miR-515-3p-knockdwon', 'Gene', (56, 76))	('EC109-ZIP-miR-515-3p', 'Var', (122, 142))	('expression', 'MPA', (21, 31))	('MMP3', 'Gene', (48, 52))	('miR-515-3p', 'Chemical', '-', (56, 66))	('miR-515-3p', 'Chemical', '-', (110, 120))	('miR-515-3p', 'Chemical', '-', (132, 142))	('vimentin', 'Protein', (35, 43))	('inhibited', 'NegReg', (156, 165))
250511	33243974	S7b, knockdown of vimentin or MMP3 significantly abrogated the effects of miR-515-3p knockdown on cell invasion, migration and expressions of EMT markers in ESCC cells.	('cell invasion', 'CPA', (98, 111))	('miR-515-3p', 'Chemical', '-', (74, 84))	('abrogated', 'NegReg', (49, 58))	('expressions', 'MPA', (127, 138))	('knockdown', 'Var', (5, 14))	('MMP3', 'Gene', (30, 34))	('ESCC', 'Disease', (157, 161))	('migration', 'CPA', (113, 122))
250512	33243974	Taken together, we proved that miR-515-3p suppresses cancer invasion and metastasis by directly targeting vimentin and MMP3.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('MMP3', 'Gene', (119, 123))	('suppresses', 'NegReg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('targeting', 'Reg', (96, 105))	('miR-515-3p', 'Var', (31, 41))	('miR-515-3p', 'Chemical', '-', (31, 41))	('vimentin', 'Protein', (106, 114))
250514	33243974	First, we investigated the effect of miR-515-3p oligonucleotide in ESCC cells, the cells transfected with miR-515-3p oligonucleotide had lower invasion, migration, and adhesion ability than the cells transfected with miR-CON oligonucleotide (Supplementary Fig.	('miR-CON', 'Chemical', '-', (217, 224))	('oligonucleotide', 'Chemical', 'MESH:D009841', (117, 132))	('lower', 'NegReg', (137, 142))	('invasion', 'CPA', (143, 151))	('migration', 'CPA', (153, 162))	('oligonucleotide', 'Chemical', 'MESH:D009841', (48, 63))	('miR-515-3p oligonucleotide', 'Chemical', '-', (37, 63))	('miR-515-3p oligonucleotide', 'Chemical', '-', (106, 132))	('oligonucleotide', 'Chemical', 'MESH:D009841', (225, 240))	('adhesion ability', 'CPA', (168, 184))	('miR-515-3p oligonucleotide', 'Var', (106, 132))
250515	33243974	Decreased fibronectin and N-cadherin expression as well as increased E-cadherin and ZO-1 expression were observed in cells transfected miR-515-3p oligonucleotide (Supplementary Fig.	('N-cadherin', 'Gene', (26, 36))	('E-cadherin', 'Gene', '999', (69, 79))	('fibronectin', 'Gene', (10, 21))	('expression', 'MPA', (89, 99))	('ZO-1', 'Gene', (84, 88))	('miR-515-3p oligonucleotide', 'Chemical', '-', (135, 161))	('N-cadherin', 'Gene', '1000', (26, 36))	('Decreased', 'NegReg', (0, 9))	('miR-515-3p oligonucleotide', 'Var', (135, 161))	('ZO-1', 'Gene', '7082', (84, 88))	('fibronectin', 'Gene', '2335', (10, 21))	('E-cadherin', 'Gene', (69, 79))	('increased', 'PosReg', (59, 68))	('Decreased fibronectin', 'Phenotype', 'HP:0032463', (0, 21))
250518	33243974	The results showed that systemically delivered miR-515-3p oligonucleotide significantly decreased the metastatic burden in the lungs, as compared with the group treated with miR-CON (Fig.	('miR-CON', 'Chemical', '-', (174, 181))	('miR-515-3p', 'Var', (47, 57))	('metastatic burden in the lungs', 'CPA', (102, 132))	('miR-515-3p oligonucleotide', 'Chemical', '-', (47, 73))	('decreased', 'NegReg', (88, 97))
250519	33243974	6b, c), suggesting that miR-515-3p may be a potential therapeutic molecule for treatment of metastatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR-515-3p', 'Var', (24, 34))	('miR-515-3p', 'Chemical', '-', (24, 34))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
250522	33243974	Despite many treatment strategies have been developed, metastatic spread, drug resistance, and recurrence lead to poor prognosis of the cancer patients.	('drug resistance', 'Var', (74, 89))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('patients', 'Species', '9606', (143, 151))	('cancer', 'Disease', (136, 142))	('drug resistance', 'Phenotype', 'HP:0020174', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('metastatic spread', 'CPA', (55, 72))
250526	33243974	In our study, we identified that 6 candidate miRNAs may be involved in cancer metastasis and miR-369-3p, miR-515-3p as well as miR-331-5p were found to obviously suppress the ESCC cell invasion (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('miR-515-3p', 'Var', (105, 115))	('miR-515-3p', 'Chemical', '-', (105, 115))	('suppress', 'NegReg', (162, 170))	('cancer', 'Disease', (71, 77))	('ESCC cell invasion', 'CPA', (175, 193))	('miR-369-3p', 'Gene', (93, 103))	('miR-369-3p', 'Gene', '442914', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-331', 'Gene', '442903', (127, 134))	('miR-331', 'Gene', (127, 134))
250527	33243974	Among the three miRNAs, the miR-515-3p rarely reported in cancer became our research focus.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('miR-515-3p', 'Var', (28, 38))	('miR-515-3p', 'Chemical', '-', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
250528	33243974	At present, the function and upstream regulatory mechanism of miR-515-5p were reported in lung cancer and breast cancer.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('lung cancer', 'Disease', (90, 101))	('miR-515-5p', 'Var', (62, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('miR-515-5p', 'Chemical', '-', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('reported', 'Reg', (78, 86))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
250529	33243974	It has been indicated that miR-515-5p can directly bind to 3' UTR of sphingosine kinase 1 to inhibit breast cancer cell proliferation.	('inhibit', 'NegReg', (93, 100))	('miR-515-5p', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('miR-515-5p', 'Chemical', '-', (27, 37))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('sphingosine kinase 1', 'Gene', '8877', (69, 89))	('breast cancer', 'Disease', (101, 114))	('sphingosine kinase 1', 'Gene', (69, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('bind', 'Interaction', (51, 55))
250530	33243974	Moreover, in non-small cell lung cancer, miR-515-5p was found to suppress cell migration, survival and metastasis by directly targeting MARK4 and CXCL6 respectively.	('cell migration', 'CPA', (74, 88))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (13, 39))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('miR-515-5p', 'Var', (41, 51))	('targeting', 'Reg', (126, 135))	('CXCL6', 'Gene', (146, 151))	('MARK4', 'Gene', (136, 141))	('miR-515-5p', 'Chemical', '-', (41, 51))	('MARK4', 'Gene', '57787', (136, 141))	('lung cancer', 'Disease', (28, 39))	('CXCL6', 'Gene', '6372', (146, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('suppress', 'NegReg', (65, 73))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (17, 39))
250531	33243974	These studies suggest that miR-515-5p may an effective biomarker in cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('miR-515-5p', 'Var', (27, 37))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('miR-515-5p', 'Chemical', '-', (27, 37))	('cancer', 'Disease', (68, 74))
250532	33243974	However, the function and underlying mechanism of miR-515-3p in cancer have not been reported.	('miR-515-3p', 'Var', (50, 60))	('miR-515-3p', 'Chemical', '-', (50, 60))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
250533	33243974	In our work, we identified abnormal expression of miR-515-3p in metastatic ESCC for the first time (Fig.	('miR-515-3p', 'Chemical', '-', (50, 60))	('miR-515-3p', 'Var', (50, 60))	('metastatic ESCC', 'Disease', (64, 79))
250535	33243974	6d, we here provided for the first time that miR-515-3p significantly inhibits ESCC cell invasion and metastasis through directly binding to vimentin and MMP3, rendering a significant mechanistic and functional significance in the research of miRNA in ESCC metastasis.	('vimentin', 'Protein', (141, 149))	('inhibits', 'NegReg', (70, 78))	('miR-515-3p', 'Var', (45, 55))	('ESCC', 'Disease', (79, 83))	('miR-515-3p', 'Chemical', '-', (45, 55))	('MMP3', 'Protein', (154, 158))	('binding', 'Interaction', (130, 137))
250540	33243974	Here, we revealed for the first time that vimentin and MMP3 are target genes of miR-515-3p.	('miR-515-3p', 'Var', (80, 90))	('vimentin', 'Protein', (42, 50))	('MMP3', 'Gene', (55, 59))	('miR-515-3p', 'Chemical', '-', (80, 90))
250541	33243974	To our knowledge, the function and action mechanism of miR-515-3p in cancer is unknown up to now.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('miR-515-3p', 'Var', (55, 65))	('miR-515-3p', 'Chemical', '-', (55, 65))	('cancer', 'Disease', (69, 75))
250542	33243974	We verified that ectopic miR-515-3p expression significantly decreased the vimentin and MMP3 expression, whereas silencing of miR-515-3p increased their expression.	('MMP3', 'Gene', (88, 92))	('miR-515-3p', 'Chemical', '-', (126, 136))	('miR-515-3p', 'Gene', (25, 35))	('miR-515-3p', 'Chemical', '-', (25, 35))	('vimentin', 'Protein', (75, 83))	('expression', 'MPA', (93, 103))	('increased', 'PosReg', (137, 146))	('expression', 'MPA', (153, 163))	('decreased', 'NegReg', (61, 70))	('silencing', 'Var', (113, 122))
250543	33243974	We also verified that miR-515-3p-overexpressing cells co-overexpressing vimentin and MMP3 showed higher invasive and migration ability as compared with the miR-515-3p-overexpressing cells overexpressing vimentin or MMP3 alone, and almost completely restored the suppressive effect of miR-515-3p on ESCC invasive and migration.	('miR-515-3p', 'Chemical', '-', (22, 32))	('miR-515-3p', 'Chemical', '-', (156, 166))	('higher', 'PosReg', (97, 103))	('MMP3', 'Var', (85, 89))	('miR-515-3p', 'Chemical', '-', (284, 294))	('miR-515-3p-overexpressing', 'Var', (22, 47))	('ESCC', 'Disease', (298, 302))
250544	33243974	These data suggest that vimentin and MMP3 may not regulate each other, but have an obviously additive effect in mediating the role of miR-515-3p in invasive and metastatic potential of ESCC cells.	('miR-515-3p', 'Chemical', '-', (134, 144))	('ESCC', 'Disease', (185, 189))	('miR-515-3p', 'Var', (134, 144))
250545	33243974	We further used in vitro and in vivo assays to show that miR-515-3p directly binds to both the CDS and 3'-UTR region of vimentin and MMP3, respectively, suppressing the invasion and metastasis in ESCC (Figs.	('miR-515-3p', 'Var', (57, 67))	('miR-515-3p', 'Chemical', '-', (57, 67))	('MMP3', 'Gene', (133, 137))	('ESCC', 'Disease', (196, 200))	('suppressing', 'NegReg', (153, 164))
250546	33243974	These findings mechanistically illustrated miR-515-3p to be a novel regulator of EMT to restrain cancer metastasis, providing a useful therapeutic target for ESCC treatment.	('cancer', 'Disease', (97, 103))	('ESCC', 'Disease', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('miR-515-3p', 'Var', (43, 53))	('miR-515-3p', 'Chemical', '-', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
250550	33243974	In this study, given that miR-515-3p can reduce vimentin and MMP3 expression, successfully delivered miR-515-3p was expected to target vimentin and MMP3 simultaneously, which may achieve a better therapeutic effect for advanced ESCC.	('miR-515-3p', 'Var', (26, 36))	('miR-515-3p', 'Var', (101, 111))	('ESCC', 'Disease', (228, 232))	('vimentin', 'Protein', (48, 56))	('miR-515-3p', 'Chemical', '-', (101, 111))	('miR-515-3p', 'Chemical', '-', (26, 36))	('MMP3', 'Protein', (61, 65))	('reduce', 'NegReg', (41, 47))
250551	33243974	Our results from animal experiment confirmed that intravenous injection of miRNA-515-3p oligonucleotide significantly inhibited the metastatic spread in mice (Fig.	('inhibited', 'NegReg', (118, 127))	('-515-3p', 'Chemical', '-', (80, 87))	('mice', 'Species', '10090', (153, 157))	('miRNA-515-3p', 'Var', (75, 87))	('metastatic spread in mice', 'CPA', (132, 157))	('-3p oligonucleotide', 'Chemical', '-', (84, 103))
250552	33243974	6), demonstrating the potential therapeutic significance of miRNA-515-3p in ESCC treatment.	('miRNA-515-3p', 'Var', (60, 72))	('ESCC', 'Disease', (76, 80))	('-515-3p', 'Chemical', '-', (65, 72))
250553	33243974	This study also revealed that miR-515-3p is a useful biomarker for ESCC diagnosis and prognosis.	('ESCC', 'Disease', (67, 71))	('miR-515-3p', 'Var', (30, 40))	('miR-515-3p', 'Chemical', '-', (30, 40))
250554	33243974	1, in situ hybridization analysis of miR-515-3p expression in tissue microarray suggested that downregulation of miR-515-3p in ESCC can predict lymph node metastasis and unfavorable prognosis.	('ESCC', 'Disease', (127, 131))	('miR-515-3p', 'Var', (113, 123))	('miR-515-3p', 'Chemical', '-', (113, 123))	('downregulation', 'NegReg', (95, 109))	('unfavorable prognosis', 'CPA', (170, 191))	('lymph node metastasis', 'CPA', (144, 165))	('miR-515-3p', 'Chemical', '-', (37, 47))
250555	33243974	The expression of miR-515-3p was clearly correlated to ESCC stages and progresses, and more significantly correlated to cancer survival of ESCC (Fig.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('expression', 'MPA', (4, 14))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('miR-515-3p', 'Chemical', '-', (18, 28))	('miR-515-3p', 'Var', (18, 28))	('ESCC', 'Disease', (55, 59))	('progresses', 'CPA', (71, 81))	('correlated', 'Reg', (41, 51))	('correlated', 'Reg', (106, 116))
250556	33243974	These observations imply that miR-515-3p can be further explored to be a meaningful biomarker for ESCC.	('miR-515-3p', 'Var', (30, 40))	('miR-515-3p', 'Chemical', '-', (30, 40))	('ESCC', 'Disease', (98, 102))
250557	33243974	In conclusion, this study demonstrates that miR-515-3p can suppress the invasive and metastatic potential of ESCC cells by directly targeting vimentin and MMP3.	('targeting', 'Reg', (132, 141))	('vimentin', 'Protein', (142, 150))	('miR-515-3p', 'Var', (44, 54))	('ESCC', 'Disease', (109, 113))	('miR-515-3p', 'Chemical', '-', (44, 54))	('MMP3', 'Gene', (155, 159))	('suppress', 'NegReg', (59, 67))
250558	33243974	Promoter hypermethylation leads to the downregulation of miR-515-3p in ESCC, which correlates with unfavorable clinicopathological characteristics and poor survival of cancer patients, suggesting that miR-515-3p may be a novel diagnostic and prognostic biomarker.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('miR-515-3p', 'Gene', (57, 67))	('miR-515-3p', 'Chemical', '-', (57, 67))	('ESCC', 'Disease', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Disease', (168, 174))	('miR-515-3p', 'Chemical', '-', (201, 211))	('downregulation', 'NegReg', (39, 53))	('Promoter hypermethylation', 'Var', (0, 25))
250559	33243974	The preclinical data testify that systemic delivery of miR-515-3p can exert inhibitory effect on tumor metastasis, indicating the potential of developing miR-515-3p to be a new therapeutic strategy for ESCC treatment.	('inhibitory effect', 'MPA', (76, 93))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('miR-515-3p', 'Chemical', '-', (154, 164))	('ESCC', 'Disease', (202, 206))	('tumor metastasis', 'Disease', 'MESH:D009362', (97, 113))	('miR-515-3p', 'Var', (55, 65))	('miR-515-3p', 'Chemical', '-', (55, 65))	('tumor metastasis', 'Disease', (97, 113))
250575	33243974	miRNA-target prediction: One software program miRanda (http://www.microrna.org/microrna/getExprForm.do) was used to predict the putative binding sites on the CDS of vimentin and 3'UTR of MMP3 for miR-515-3p.	('binding', 'Interaction', (137, 144))	('miR-515-3p', 'Var', (196, 206))	('miR-515-3p', 'Chemical', '-', (196, 206))	('MMP3', 'Gene', (187, 191))	('vimentin', 'Protein', (165, 173))
250582	33243974	The plasmids expressing mutant CDS of vimentin and 3'UTR of MMP3 were constructed using site-directed mutagenesis kit (Agilent Technologies, Santa Clara, CA).	('mutant', 'Var', (24, 30))	('MMP3', 'Gene', (60, 64))	('kit', 'Gene', '3815', (114, 117))	('kit', 'Gene', (114, 117))
250617	31897341	In the largest effort to determine genetic predictors of response to systemic therapies in esophageal and gastric cancer, tumor tissue from 187 patients affected with HER2-negative esophageal cancer and receiving first-line treatment with a fluoropyrimidine plus platinum combination was analyzed by using MSK-IMPACT, a capture-based, new generation sequencing platform that can detect mutations, copy-number alterations, and rearrangements.	('esophageal cancer', 'Disease', (181, 198))	('detect', 'Reg', (379, 385))	('HER2', 'Gene', '2064', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('copy-number alterations', 'Var', (397, 420))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('tumor', 'Disease', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('platinum', 'Chemical', 'MESH:D010984', (263, 271))	('fluoropyrimidine', 'Chemical', 'MESH:C029269', (241, 257))	('rearrangements', 'Var', (426, 440))	('mutations', 'Var', (386, 395))	('HER2', 'Gene', (167, 171))	('gastric cancer', 'Disease', (106, 120))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('patients', 'Species', '9606', (144, 152))
250625	31897341	Conversely 16.3% of patients with microsatellite stable (MSS) or MSI-low (MSI-L) tumors treated with chemotherapy had a tumor regression grade of 1 or 2.	('microsatellite stable', 'Var', (34, 55))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('MSI-low (MSI-L) tumors', 'Disease', 'MESH:D053842', (65, 87))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (81, 86))
250653	31897341	When HER2 is mutated or amplified, its activation also occurs in a ligand-independent manner.	('amplified', 'Var', (24, 33))	('HER2', 'Gene', (5, 9))	('activation', 'PosReg', (39, 49))	('HER2', 'Gene', '2064', (5, 9))	('mutated', 'Var', (13, 20))
250655	31897341	The amplification of ERBB2 leads to an increased expression of HER2 protein, which plays a pivotal role in cell proliferation and survival in several types of cancer, including gastric cancer.	('cancer', 'Disease', (159, 165))	('gastric cancer', 'Disease', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('gastric cancer', 'Disease', 'MESH:D013274', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('expression', 'MPA', (49, 59))	('ERBB2', 'Gene', '2064', (21, 26))	('increased', 'PosReg', (39, 48))	('amplification', 'Var', (4, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (177, 191))	('ERBB2', 'Gene', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('HER2', 'Gene', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (185, 191))	('HER2', 'Gene', '2064', (63, 67))
250656	31897341	In gastric cancer, HER2 amplification is more often associated with proximal tumors (34%) compared to distal forms (20%).	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('HER2', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HER2', 'Gene', '2064', (19, 23))	('associated', 'Reg', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('amplification', 'Var', (24, 37))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
250658	31897341	In the TCGA classification, tumors with chromosomal instability more often express HER2 as consequence of gene amplification (24%).	('express', 'Reg', (75, 82))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('gene amplification', 'Var', (106, 124))	('HER2', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('chromosomal instability', 'Phenotype', 'HP:0040012', (40, 63))	('HER2', 'Gene', '2064', (83, 87))
250661	31897341	In first line of therapy, treatment of metastatic gastric cancer patients with high expression of HER2 (IHC3+ or IHC2+/FISH+) with trastuzumab in addition to chemotherapy of a fluoropyrimidine (capecitabine or 5-FU) plus cisplatin has shown an advantage in OS compared to chemotherapy alone.	('capecitabine', 'Chemical', 'MESH:C110904', (194, 206))	('IHC2+/FISH+', 'Var', (113, 124))	('IHC3+', 'Chemical', 'MESH:C053584', (104, 109))	('IHC2+', 'Chemical', 'MESH:C053584', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (221, 230))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('advantage', 'PosReg', (244, 253))	('HER2', 'Gene', (98, 102))	('5-FU', 'Chemical', 'MESH:D005472', (210, 214))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('HER2', 'Gene', '2064', (98, 102))	('patients', 'Species', '9606', (65, 73))	('high expression', 'Var', (79, 94))	('fluoropyrimidine', 'Chemical', 'MESH:C029269', (176, 192))	('IHC3+', 'Var', (104, 109))
250671	31897341	Currently, at least 2 clinical trials are exploring the association of peri-operative chemotherapy in association with anti-HER2 agents in gastric and esophagogastric junction cancer: the EORTC INNOVATION (NCT02205047) and the AIO-FLOT6 PETRARCA (NCT02581462) studies (Table 2).	('HER2', 'Gene', '2064', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('NCT02205047', 'Var', (206, 217))	('AIO-FLOT6 PETRARCA', 'Chemical', 'MESH:C436719', (227, 245))	('HER2', 'Gene', (124, 128))	('gastric and esophagogastric junction cancer', 'Disease', 'MESH:D013274', (139, 182))
250688	31897341	The AMNESIA study is a multicenter, prospective, case-control study, which has shown the negative predictive impact of a panel of genomic aberrations, including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications in HER2 positive metastatic gastric cancer patients eligible for first line therapy whit trastuzumab plus cisplatin and fluoropyrimidine chemotherapy.	('PTEN', 'Gene', (180, 184))	('HER2', 'Gene', '2064', (231, 235))	('gastric cancer', 'Disease', 'MESH:D013274', (256, 270))	('KRAS', 'Gene', '3845', (170, 174))	('EGFR', 'Gene', (161, 165))	('amplifications', 'Var', (213, 227))	('KRAS', 'Gene', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cisplatin', 'Chemical', 'MESH:D002945', (334, 343))	('PTEN', 'Gene', '5728', (180, 184))	('KRAS', 'Gene', '3845', (208, 212))	('gastric cancer', 'Phenotype', 'HP:0012126', (256, 270))	('HER2', 'Gene', (231, 235))	('EGFR', 'Gene', (199, 203))	('KRAS', 'Gene', (208, 212))	('patients', 'Species', '9606', (271, 279))	('EGFR', 'Gene', '1956', (161, 165))	('fluoropyrimidine', 'Chemical', 'MESH:C029269', (348, 364))	('gastric cancer', 'Disease', (256, 270))	('mutations', 'Var', (185, 194))	('EGFR', 'Gene', '1956', (199, 203))
250697	31897341	Silencing of RPS6 expression or pharmacological inhibition of PI3K/AKT/mTOR was associated with reduced cellular viability and expression level of NRF2, suggesting a pivotal role of this pathway in anti-HER2 drug resistance.	('AKT', 'Gene', '207', (67, 70))	('NRF2', 'Gene', (147, 151))	('RPS6', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('RPS6', 'Gene', '6194', (13, 17))	('AKT', 'Gene', (67, 70))	('HER2', 'Gene', '2064', (203, 207))	('mTOR', 'Gene', '2475', (71, 75))	('drug resistance', 'Phenotype', 'HP:0020174', (208, 223))	('mTOR', 'Gene', (71, 75))	('expression level', 'MPA', (127, 143))	('cellular viability', 'CPA', (104, 122))	('NRF2', 'Gene', '4780', (147, 151))	('HER2', 'Gene', (203, 207))	('reduced', 'NegReg', (96, 103))
250698	31897341	Moreover, this study retrospectively analyzed a cohort of patients with HER2 amplified locally advanced or metastatic gastric cancer treated with trastuzumab in combination with platinum-based chemotherapy.	('HER2', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (58, 66))	('HER2', 'Gene', '2064', (72, 76))	('gastric cancer', 'Disease', (118, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('locally advanced or', 'Disease', (87, 106))	('amplified', 'Var', (77, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('platinum', 'Chemical', 'MESH:D010984', (178, 186))
250699	31897341	In this analysis, patients with high NRF2 expression had worse prognosis than patients with low NRF2 expression.	('high', 'Var', (32, 36))	('NRF2', 'Gene', (96, 100))	('patients', 'Species', '9606', (78, 86))	('NRF2', 'Gene', '4780', (37, 41))	('patients', 'Species', '9606', (18, 26))	('NRF2', 'Gene', (37, 41))	('NRF2', 'Gene', '4780', (96, 100))
250701	31897341	Co-alterations in genes coding for proteins members of different tyrosine-kinase receptor intracellular pathways are emerging as relevant mechanisms of intrinsic and acquired resistance to anti-HER2 therapeutic strategies.	('mechanisms', 'Reg', (138, 148))	('HER2', 'Gene', '2064', (194, 198))	('HER2', 'Gene', (194, 198))	('tyrosine', 'Chemical', 'None', (65, 73))	('Co-alterations', 'Var', (0, 14))
250704	31897341	A recent study showed that 50% of esophagogastric junction cancer with MET amplifications were associated with HER2/EGFR amplifications in the same tumor cells.	('HER2', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('HER2', 'Gene', '2064', (111, 115))	('tumor', 'Disease', (148, 153))	('junction cancer', 'Disease', 'MESH:D009369', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('MET amplifications', 'Var', (71, 89))	('EGFR', 'Gene', '1956', (116, 120))	('associated', 'Reg', (95, 105))	('EGFR', 'Gene', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('junction cancer', 'Disease', (50, 65))
250709	31897341	In this study, we found that gastric cancer models selected for resistance to trastuzumab, in addition to a loss of HER2 expression, were associated with overexpression of FGFR3, FGF9 and phosphorylated AKT.	('FGF9', 'Gene', (179, 183))	('loss', 'NegReg', (108, 112))	('phosphorylated', 'Var', (188, 202))	('gastric cancer', 'Disease', (29, 43))	('AKT', 'Gene', (203, 206))	('FGF9', 'Gene', '2254', (179, 183))	('gastric cancer', 'Disease', 'MESH:D013274', (29, 43))	('expression', 'MPA', (121, 131))	('FGFR3', 'Gene', (172, 177))	('overexpression', 'PosReg', (154, 168))	('HER2', 'Gene', (116, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('HER2', 'Gene', '2064', (116, 120))	('AKT', 'Gene', '207', (203, 206))
250729	31897341	We demonstrated HOXB9 is a crucial transcription factor in sustaining tumor resistance to bevacizumab, and that silencing its expression could be a promising approach to modulate this resistance.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('expression', 'MPA', (126, 136))	('tumor', 'Disease', (70, 75))	('silencing', 'Var', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
250731	31897341	Silencing HOXB9 in bevacizumab-resistant models significantly reduced Angptl2, CXCL1, IL-8, and TGF-beta levels, reverted their mesenchymal phenotype, and restored, in turn, sensitivity to bevacizumab.	('IL-8', 'Gene', (86, 90))	('TGF-beta', 'Gene', (96, 104))	('reverted', 'PosReg', (113, 121))	('TGF-beta', 'Gene', '7040', (96, 104))	('CXCL1', 'Gene', '2919', (79, 84))	('restored', 'PosReg', (155, 163))	('mesenchymal phenotype', 'CPA', (128, 149))	('IL-8', 'Gene', '3576', (86, 90))	('CXCL1', 'Gene', (79, 84))	('Angptl2', 'Gene', (70, 77))	('Silencing', 'Var', (0, 9))	('sensitivity to bevacizumab', 'MPA', (174, 200))	('Angptl2', 'Gene', '23452', (70, 77))	('reduced', 'NegReg', (62, 69))	('HOXB9', 'Gene', (10, 15))
250736	31897341	Moreover, the expression of HOXB9 might serve as potential biomarker for selecting patients with gastric cancer that are more likely to benefit from this therapeutic strategy.	('expression', 'Var', (14, 24))	('HOXB9', 'Gene', (28, 33))	('gastric cancer', 'Disease', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (83, 91))
250741	31897341	Currently, there are 2 ongoing clinical trials of perioperative chemotherapy plus immunotherapy in gastric cancer and esophagogastric junction adenocarcinoma: KEYNOTE-585 (NCT03221426) and DANTE trail (NCT03421288).	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('KEYNOTE-585', 'Chemical', 'MESH:C024325', (159, 170))	('junction adenocarcinoma', 'Disease', (134, 157))	('NCT03421288', 'Chemical', 'MESH:C079985', (202, 213))	('gastric cancer', 'Disease', (99, 113))	('NCT03421288', 'Var', (202, 213))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('NCT03221426', 'Var', (172, 183))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (118, 157))	('NCT03221426', 'Chemical', 'MESH:C079985', (172, 183))	('junction adenocarcinoma', 'Disease', 'MESH:D000230', (134, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
250762	31897341	In addition, a significantly higher ORR was observed in patients with PD-L1 >=1% compared to patients with PD-L1 negative (50.0% vs. 0.0%, P<0.001).	('higher', 'PosReg', (29, 35))	('patients', 'Species', '9606', (56, 64))	('PD-L1', 'Gene', '29126', (70, 75))	('PD-L1', 'Gene', '29126', (107, 112))	('>=1%', 'Var', (76, 80))	('ORR', 'MPA', (36, 39))	('PD-L1', 'Gene', (107, 112))	('patients', 'Species', '9606', (93, 101))	('PD-L1', 'Gene', (70, 75))
250767	31897341	However, data from post-hoc analyses suggested that pembrolizumab had antitumor activity in patients whose tumors had high levels of MSI irrespective of the combined positive score (hazard ratio, 0.42; 95% confidence interval [CI], 0.13-1.31; median OS not reached [95% CI, 5.6 months-not reached] vs. 8.1 months [2.0-16.7]).	('pembrolizumab', 'Var', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('MSI', 'Disease', 'MESH:D053842', (133, 136))	('MSI', 'Disease', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
250770	31897341	Epigenomic promoter alterations have been described as a mechanism of immune escape and as negative predictive biomarkers in gastric cancer patients who receive checkpoint inhibitors.	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('immune escape', 'CPA', (70, 83))	('Epigenomic promoter alterations', 'Var', (0, 31))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('patients', 'Species', '9606', (140, 148))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
250772	31897341	Patients with high alternate promoter utilization had lower markers of T cell cytolytic activity, and lower response rate and survival than patients with low alternate promoter utilization.	('lower', 'NegReg', (102, 107))	('response rate', 'CPA', (108, 121))	('survival', 'CPA', (126, 134))	('Patients', 'Species', '9606', (0, 8))	('T cell cytolytic activity', 'MPA', (71, 96))	('patients', 'Species', '9606', (140, 148))	('high alternate promoter utilization', 'Var', (14, 49))	('lower', 'NegReg', (54, 59))
250781	31897341	However, angiogenesis, HER2 amplification, MSI, and EBV+ status are early events in the development of gastric cancer and it is reasonable to conceive that their predictive value could be relevant also in the preoperative setting.	('angiogenesis', 'CPA', (9, 21))	('MSI', 'Disease', 'MESH:D053842', (43, 46))	('MSI', 'Disease', (43, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('HER2', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('HER2', 'Gene', '2064', (23, 27))	('gastric cancer', 'Disease', (103, 117))	('EBV', 'Disease', 'MESH:D020031', (52, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('amplification', 'Var', (28, 41))	('EBV', 'Disease', (52, 55))
250784	31897341	Co-alterations in tyrosine kinase receptors, including FGFR3, might contribute to intrinsic and acquired resistance to trastuzumab.	('tyrosine', 'Chemical', 'None', (18, 26))	('Co-alterations', 'Var', (0, 14))	('FGFR3', 'Gene', (55, 60))	('contribute', 'Reg', (68, 78))
250914	29262640	Furthermore, this modification enhances the burden of esophageal cancer and do not increase the incidence of gastric cancer, thus providing a false perception of better gastric cancer control.	('gastric cancer', 'Disease', (169, 183))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('burden', 'MPA', (44, 50))	('increase the incidence of gastric cancer', 'Phenotype', 'HP:0006753', (83, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('esophageal cancer', 'Disease', (54, 71))	('enhances', 'PosReg', (31, 39))	('modification', 'Var', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))
250989	26058041	Nitrosamines and nutritional deficiencies are among the main causes of squamous-cell carcinoma, while gastroesophageal reflux disease (GERD) and obesity are linked to adenocarcinoma.	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (167, 181))	('gastroesophageal reflux disease', 'Disease', (102, 133))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (102, 133))	('GERD', 'Disease', 'MESH:D005764', (135, 139))	('obesity', 'Disease', (145, 152))	('Nitrosamines', 'Var', (0, 12))	('obesity', 'Disease', 'MESH:D009765', (145, 152))	('squamous-cell carcinoma', 'Disease', (71, 94))	('nutritional deficiencies', 'Disease', 'MESH:D044342', (17, 41))	('causes', 'Reg', (61, 67))	('Nitrosamines', 'Chemical', 'MESH:D009602', (0, 12))	('squamous-cell carcinoma', 'Disease', 'MESH:D002294', (71, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('nutritional deficiencies', 'Disease', (17, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('adenocarcinoma', 'Disease', (167, 181))	('obesity', 'Phenotype', 'HP:0001513', (145, 152))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (102, 125))	('GERD', 'Disease', (135, 139))
250991	26058041	Mutations in multiple genes including p53, FasL, and EGFR have been reported to be associated with the onset and development of esophageal cancer.	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('esophageal cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (83, 93))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('FasL', 'Gene', (43, 47))	('FasL', 'Gene', '356', (43, 47))
250992	26058041	Changes in gene expression levels have also been linked to the cancer; for example, induced expression of MAL was found in esophageal cancer and inactivation of RUNX3 may correlate with esophageal carcinogenesis.	('MAL', 'Gene', '4118', (106, 109))	('esophageal cancer', 'Disease', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('cancer', 'Disease', (134, 140))	('RUNX3', 'Gene', '864', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('MAL', 'Gene', (106, 109))	('inactivation', 'Var', (145, 157))	('induced', 'PosReg', (84, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (186, 211))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('esophageal carcinogenesis', 'Disease', (186, 211))	('RUNX3', 'Gene', (161, 166))	('cancer', 'Disease', (63, 69))	('expression', 'MPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
251020	26058041	Its aberrant expression in esophageal squamous cell carcinoma is associated with invasion or metastasis.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (27, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('metastasis', 'CPA', (93, 103))	('invasion', 'CPA', (81, 89))	('aberrant expression', 'Var', (4, 23))	('associated', 'Reg', (65, 75))	('esophageal squamous cell carcinoma', 'Disease', (27, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))
251028	26058041	Mutations in Axin1 are associated with many types of cancer, with a 12% deletion frequency in medulloblastoma and detrimental mutations in HCC (hepatocellular carcinomas).	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (144, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('Axin1', 'Gene', (13, 18))	('cancer', 'Disease', (53, 59))	('hepatocellular carcinomas', 'Disease', (144, 169))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('Mutations', 'Var', (0, 9))	('medulloblastoma and detrimental', 'Disease', 'MESH:D008527', (94, 125))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('medulloblastoma', 'Phenotype', 'HP:0002885', (94, 109))	('Axin1', 'Gene', '8312', (13, 18))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (144, 169))	('HCC', 'Gene', (139, 142))	('associated', 'Reg', (23, 33))	('deletion', 'Var', (72, 80))
251029	26058041	Rare mutations of Axin1 were detected in esophageal SCC, while reduced expression of Axin was observed in oesophageal squamous cell carcinoma.	('expression', 'MPA', (71, 81))	('esophageal SCC', 'Disease', (41, 55))	('Axin1', 'Gene', '8312', (18, 23))	('Axin', 'Gene', (85, 89))	('reduced', 'NegReg', (63, 70))	('Axin', 'Gene', '8312', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('Axin1', 'Gene', (18, 23))	('Axin', 'Gene', (18, 22))	('mutations', 'Var', (5, 14))	('detected', 'Reg', (29, 37))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (106, 141))	('Axin', 'Gene', '8312', (85, 89))	('oesophageal squamous cell carcinoma', 'Disease', (106, 141))
251046	26058041	H2O2 acts as a direct or indirect signal molecule in regulation of PKC, MAPK, JAK, Ras, NF-kB, c-Myc and AP-1, which are closely correlated with carcinogenesis, including esophageal cancer.	('AP-1', 'Gene', (105, 109))	('c-Myc', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('JAK', 'Gene', (78, 81))	('PKC', 'Enzyme', (67, 70))	('correlated', 'Reg', (129, 139))	('c-Myc', 'Gene', '4609', (95, 100))	('NF-kB', 'Gene', (88, 93))	('MAPK', 'Gene', (72, 76))	('carcinogenesis', 'Disease', 'MESH:D063646', (145, 159))	('AP-1', 'Gene', '2353', (105, 109))	('carcinogenesis', 'Disease', (145, 159))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))	('esophageal cancer', 'Disease', (171, 188))
251047	26058041	Increased production of H2O2 may stimulate the activity of tyrosine phosphorylation, MAP kinase and DNA synthesis in a manner that can be reversed by H2O2 inhibitors.	('H2O2', 'Var', (24, 28))	('tyrosine', 'Chemical', 'MESH:D014443', (59, 67))	('H2O2', 'Chemical', 'MESH:D006861', (24, 28))	('tyrosine phosphorylation', 'MPA', (59, 83))	('MAP kinase', 'Enzyme', (85, 95))	('activity', 'MPA', (47, 55))	('H2O2', 'Chemical', 'MESH:D006861', (150, 154))	('DNA synthesis', 'MPA', (100, 113))	('stimulate', 'PosReg', (33, 42))
251048	26058041	H2O2 production stimulates the transcription of MMPs and the adhesion of cancer cells, which can be inhibited by catalase (CAT).	('stimulates', 'PosReg', (16, 26))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('catalase', 'Gene', '847', (113, 121))	('transcription', 'MPA', (31, 44))	('CAT', 'Gene', (123, 126))	('CAT', 'Gene', '847', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MMPs', 'Gene', '4322', (48, 52))	('catalase', 'Gene', (113, 121))	('MMPs', 'Gene', (48, 52))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))
251050	26058041	Furthermore, H2O2 may be a chemical carcinogenesis factor in metal-mediated DNA damage and genetic alteration in normal epithelial cells and cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('carcinogenesis', 'Disease', (36, 50))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('H2O2', 'Chemical', 'MESH:D006861', (13, 17))	('H2O2', 'Var', (13, 17))	('cancer', 'Disease', (141, 147))	('metal', 'Chemical', 'MESH:D008670', (61, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (36, 50))
251057	26058041	Dietary experiments showed that TRIS can induce benign or malignant tumors of the forestomach and lung in female and male mice, the kidney in male mice and the liver in female mice.	('mice', 'Species', '10090', (147, 151))	('malignant tumors of the forestomach', 'Disease', (58, 93))	('mice', 'Species', '10090', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('TRIS', 'Chemical', 'MESH:C012085', (32, 36))	('mice', 'Species', '10090', (176, 180))	('malignant tumors of the forestomach', 'Disease', 'MESH:D013274', (58, 93))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('TRIS', 'Var', (32, 36))	('benign', 'CPA', (48, 54))
251104	26058041	Disruption of this pathway is also associated with other cancers.	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('associated', 'Reg', (35, 45))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Disruption', 'Var', (0, 10))
251106	26058041	Dysregulation of these processes can cause abnormal cell growth and movement, which can lead to tumor development.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('abnormal cell growth', 'CPA', (43, 63))	('lead to', 'Reg', (88, 95))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cause', 'Reg', (37, 42))
251107	26058041	Inhibition of Wnt signaling may prove to be an effective method for inhibition of the uncontrolled renewal that drives cancers, including esophageal cancer.	('esophageal cancer', 'Disease', (138, 155))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('Wnt', 'Gene', '7471', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancers', 'Disease', (119, 126))	('Inhibition', 'Var', (0, 10))	('Wnt', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
251109	26058041	Many cancer-associated mutations of components of the MAPK signaling pathways have been found in Ras and B-Raf, both of which participate in the ERK signaling pathway.	('ERK', 'Gene', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('B-Raf', 'Gene', '673', (105, 110))	('Ras', 'Gene', (97, 100))	('B-Raf', 'Gene', (105, 110))	('cancer', 'Disease', (5, 11))	('mutations', 'Var', (23, 32))	('participate', 'Reg', (126, 137))	('ERK', 'Gene', '5594', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
251164	19423024	In terms of detecting malignancy, any nodular areas within the Barrett's segment, especially if high grade dysplasia has previously been found, are associated with a higher frequency of malignancy.	('dysplasia', 'Disease', (107, 116))	('malignancy', 'Disease', 'MESH:D009369', (186, 196))	('dysplasia', 'Disease', 'MESH:D004476', (107, 116))	('men', 'Species', '9606', (76, 79))	('malignancy', 'Disease', 'MESH:D009369', (22, 32))	('malignancy', 'Disease', (186, 196))	('malignancy', 'Disease', (22, 32))	('nodular areas', 'Var', (38, 51))
251189	19423024	Adequate assessment of endocytoscopic images was impossible in 49% of the area with magnification x450 and in 22% with magnification x1125.	('men', 'Species', '9606', (15, 18))	('x450', 'Var', (98, 102))	('magnification x450', 'Var', (84, 102))
251192	19423024	Positive and negative predictive values for high grade intraepithelial neoplasia or cancer were 0.29 and 0.83, respectively, for magnification x450 and 0.44 and 0.83, respectively, for magnification x1125.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (55, 80))	('magnification x1125', 'Var', (185, 204))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('magnification x450', 'Var', (129, 147))	('neoplasia', 'Phenotype', 'HP:0002664', (71, 80))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (55, 80))	('intraepithelial neoplasia', 'Disease', (55, 80))
251217	23977381	A number of researches propose LNR as a novel and independent prognostic factor that can reduce the phenomenon of stage migration in some other kinds of cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('reduce', 'NegReg', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('LNR', 'Var', (31, 34))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
251263	23940674	Here, we investigate the correlation between CD166 positivity in digestive system cancers and clinicopathological features using meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('positivity', 'Var', (51, 61))	('system cancers', 'Disease', (75, 89))	('system cancers', 'Disease', 'MESH:D009369', (75, 89))	('CD166', 'Gene', (45, 50))
251266	23940674	In colorectal cancer specifically, the results of a fixed-effects model indicated that CD166-positive expression was an independent marker associated with a smaller tumor burden (T category; RR = 0.93, 95%, CI: 0.88-0.98) but worse spread to nearby lymph nodes (N category; RR = 1.17, 95% CI: 1.05-1.30).	('smaller', 'NegReg', (157, 164))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('CD166-positive expression', 'Var', (87, 112))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('colorectal cancer', 'Disease', (3, 20))	('N', 'Chemical', 'MESH:D009584', (262, 263))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('worse', 'PosReg', (226, 231))	('tumor', 'Disease', (165, 170))
251276	23940674	Two earlier studies by Weichert and Horst et al reported positive expression of CD166 in colorectal cancer and that CD166 was an independent prognostic marker associated with poor survival rates.	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('CD166', 'Var', (116, 121))	('positive', 'PosReg', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('associated', 'Reg', (159, 169))	('expression', 'MPA', (66, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('CD166', 'Gene', (80, 85))
251299	23940674	However, in colorectal cancer specifically, CD166 expression was associated with more advanced T category (RR = 0.93, 95% CI: 0.88-0.98) and N-positive status (RR = 1.17, 95%CI 1.05-1.30), and it did not show any relationship with other kinds of digestive tumors.	('colorectal cancer', 'Disease', (12, 29))	('T category', 'CPA', (95, 105))	('CD166', 'Var', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('digestive tumors', 'Phenotype', 'HP:0007378', (246, 262))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('tumors', 'Disease', 'MESH:D009369', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('N-positive status', 'CPA', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumors', 'Disease', (256, 262))	('N', 'Chemical', 'MESH:D009584', (141, 142))
251309	23940674	The other three studies in this meta-analysis that focused on membranous staining including colorectal and pancreatic cancer, all concluded that high CD166 expression is a positive marker for good prognosis.	('pancreatic cancer', 'Disease', (107, 124))	('CD166', 'Gene', (150, 155))	('colorectal', 'Disease', (92, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'MPA', (156, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))	('high', 'Var', (145, 149))
251312	23940674	These data suggest that high CD166 expression could impede cancer cell release from a local lesion.	('CD166', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('expression', 'MPA', (35, 45))	('high', 'Var', (24, 28))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('impede', 'NegReg', (52, 58))
251316	23940674	Specifically, soluble CD166/ALCAM (sALCAM) binds to scFv I/F8 to form a chimera, which induces endocytosis of the membrane-bound CD166/ALCAM.	('CD166/ALCAM', 'Gene', (129, 140))	('ALCAM', 'Gene', '214', (135, 140))	('I/F8', 'SUBSTITUTION', 'None', (57, 61))	('CD166/ALCAM', 'Gene', '214', (22, 33))	('endocytosis', 'MPA', (95, 106))	('I/F8', 'Var', (57, 61))	('ALCAM', 'Gene', (28, 33))	('CD166/ALCAM', 'Gene', '214', (129, 140))	('induces', 'Reg', (87, 94))	('ALCAM', 'Gene', (135, 140))	('ALCAM', 'Gene', '214', (36, 41))	('CD166/ALCAM', 'Gene', (22, 33))	('ALCAM', 'Gene', '214', (28, 33))	('ALCAM', 'Gene', (36, 41))
251318	23940674	Van Kempen et al also found that disruption of CD166 self-interaction was associated with tumor cell motility and metastasis.	('disruption', 'Var', (33, 43))	('metastasis', 'CPA', (114, 124))	('self-interaction', 'Interaction', (53, 69))	('CD166', 'Gene', (47, 52))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('associated', 'Reg', (74, 84))
251322	23940674	These observations suggest that specific subcellular localization of CD166 could be used as a clinical prognostic marker because the loss of CD166 cell surface expression appears to be a precursor for tumor progression.	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('loss', 'Var', (133, 137))	('CD166', 'Gene', (141, 146))
251327	23940674	Variation in sALCAM among studies may have multiple causes: sALCAM must pass through the barrier of tumor tissue and vascular endothelial cells to be flushed into the blood stream, and sequential sectioning has failed to establish a direct relationship between ADAM17/TACE and ALCAM.	('ALCAM', 'Gene', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('TACE', 'Gene', '6868', (268, 272))	('tumor', 'Disease', (100, 105))	('ALCAM', 'Gene', (14, 19))	('TACE', 'Gene', (268, 272))	('flushed', 'Phenotype', 'HP:0031284', (150, 157))	('ALCAM', 'Gene', '214', (277, 282))	('ADAM17', 'Gene', '6868', (261, 267))	('ALCAM', 'Gene', '214', (61, 66))	('Variation', 'Var', (0, 9))	('ADAM17', 'Gene', (261, 267))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('ALCAM', 'Gene', '214', (14, 19))	('ALCAM', 'Gene', (61, 66))
251354	20596708	On the other hand, it might be hypothesized that in patients with a high BMI (and increased visceral fatty tissue), a higher percentage of tumor-free circumferential resection margins might be achieved because of the presence of more fatty tissue surrounding the tumor compared with patients with a low BMI when performing esophagectomy for cancer.	('more', 'PosReg', (229, 233))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('high', 'Var', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('patients', 'Species', '9606', (283, 291))	('low BMI', 'Phenotype', 'HP:0045082', (299, 306))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (263, 268))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('cancer', 'Disease', (341, 347))	('patients', 'Species', '9606', (52, 60))
251387	20596708	Advanced pT stage was seen significantly more often in patients with a low or normal BMI (p < 0.01).	('BMI', 'MPA', (85, 88))	('low', 'Var', (71, 74))	('Advanced pT', 'Disease', (0, 11))	('patients', 'Species', '9606', (55, 63))
251407	20596708	It is known that transthoracic esophagectomy is associated with more pulmonary complications compared with the transhiatal approach.	('transthoracic', 'Var', (17, 30))	('pulmonary complications', 'Disease', (69, 92))	('pulmonary complications', 'Phenotype', 'HP:0006532', (69, 92))	('pulmonary complications', 'Disease', 'MESH:D008171', (69, 92))
251408	20596708	In this study advanced pT stage was seen significantly more often in patients with a low or normal BMI compared with patients with a high BMI (p = 0.02).	('low', 'NegReg', (85, 88))	('advanced', 'CPA', (14, 22))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (117, 125))	('normal', 'Var', (92, 98))	('BMI', 'Gene', (99, 102))
251424	33290111	Risk factors for tumor recurrence in patients with pT3N0M0 thoracic esophageal squamous cell carcinoma after esophagectomy To analyze the factors contributing to recurrence in patients with pT3N0M0 thoracic esophageal squamous cell carcinoma (ESCC).	('pT3N0M0', 'Var', (51, 58))	('patients', 'Species', '9606', (176, 184))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('tumor', 'Disease', (17, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('patients', 'Species', '9606', (37, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (218, 241))	('pT3N0M0', 'Var', (190, 197))	('esophageal squamous cell carcinoma', 'Disease', (68, 102))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (207, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('esophageal squamous cell carcinoma', 'Disease', (207, 241))
251435	33290111	also confirmed that NCRT could increase the radical resection rate and lower the occurrence of complications, thereby prolonging the survival time for ESCC patients.	('survival time', 'CPA', (133, 146))	('NCRT', 'Var', (20, 24))	('patients', 'Species', '9606', (156, 164))	('radical resection rate', 'CPA', (44, 66))	('prolonging', 'NegReg', (118, 128))	('occurrence of complications', 'MPA', (81, 108))	('ESCC', 'Disease', (151, 155))	('lower', 'NegReg', (71, 76))	('increase', 'PosReg', (31, 39))
251475	33290111	Statistically, POCT was associated with reduced TR [hazard ratio (HR) = 0.682; p = 0.004] and LR (HR = 0.665; p = 0.008), and PORT was associated with reduced LR (HR = 0.580; p = 0.027).	('TR', 'Gene', '2149', (48, 50))	('reduced', 'NegReg', (151, 158))	('POCT', 'Var', (15, 19))	('reduced', 'NegReg', (40, 47))	('LR', 'Chemical', '-', (94, 96))	('LR', 'Chemical', '-', (159, 161))
251476	33290111	We performed a subgroup analysis to determine the benefits of PORT and POCT among different subgroups of pT3N0M0 ESCC patients based on tumor location.	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('pT3N0M0', 'Var', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('patients', 'Species', '9606', (118, 126))
251477	33290111	We found that PORT was significantly associated with reduced TR (p = 0.011) and LR (p = 0.029) for upper ESCC alone and unexpectedly associated with higher DM for middle ESCC (HR = 1.944; p = 0.043).	('DM', 'Disease', 'MESH:D009223', (156, 158))	('LR', 'Chemical', '-', (80, 82))	('reduced', 'NegReg', (53, 60))	('TR', 'Gene', '2149', (61, 63))	('PORT', 'Var', (14, 18))	('higher', 'PosReg', (149, 155))
251478	33290111	POCT was significantly associated with reduced TR (p = 0.011) and LR (p = 0.038) for middle ESCC (Table 4).	('middle ESCC', 'Disease', (85, 96))	('reduced', 'NegReg', (39, 46))	('TR', 'Gene', '2149', (47, 49))	('LR', 'Chemical', '-', (66, 68))	('POCT', 'Var', (0, 4))
251482	33290111	In this study, we observed that the TR rate among pT3N0M0 thoracic ESCC patients was as high as 40%.	('pT3N0M0', 'Var', (50, 57))	('TR', 'Gene', '2149', (36, 38))	('thoracic ESCC', 'Disease', (58, 71))	('patients', 'Species', '9606', (72, 80))
251488	33290111	We found that the higher number of dissected lymph nodes was associated with higher TR among pT3N0M0 ESCC patients.	('higher', 'PosReg', (77, 83))	('patients', 'Species', '9606', (106, 114))	('TR', 'Gene', '2149', (84, 86))	('pT3N0M0 ESCC', 'Var', (93, 105))
251496	33290111	found that PORT for the supraclavicular, upper mediastinal lymphatic drainage regions, and tumor bed could reduce intrathoracic lymph node recurrence in pT2-3N0M0 ESCC patients.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (168, 176))	('reduce', 'NegReg', (107, 113))	('pT2-3N0M0 ESCC', 'Var', (153, 167))	('tumor', 'Disease', (91, 96))	('intrathoracic lymph node recurrence', 'MPA', (114, 149))
251497	33290111	concluded that PORT with T field irradiation was associated with reduced tumor bed LR without any improvement in the OS of pT1-4N0M0 ESCC patients, and many other studies have suggested that PORT could significantly improve OS and disease-free survival (DFS) among pT3N0M0 thoracic ESCC patients.	('patients', 'Species', '9606', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('reduced', 'NegReg', (65, 72))	('LR', 'Chemical', '-', (83, 85))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('improve', 'PosReg', (216, 223))	('patients', 'Species', '9606', (287, 295))	('pT1', 'Gene', '58492', (123, 126))	('tumor', 'Disease', (73, 78))	('pT1', 'Gene', (123, 126))	('disease-free survival', 'CPA', (231, 252))	('pT3N0M0', 'Var', (265, 272))
251498	33290111	In addition, this study showed that POCT was associated with significantly reduced TR and LR, especially in the middle thoracic segment in ESCC patients.	('LR', 'Chemical', '-', (90, 92))	('TR', 'Gene', '2149', (83, 85))	('POCT', 'Var', (36, 40))	('reduced', 'NegReg', (75, 82))	('patients', 'Species', '9606', (144, 152))	('ESCC', 'Disease', (139, 143))
251499	33290111	Subgroup analysis showed that POCT was associated with reduced LR in the mediastinum.	('reduced', 'NegReg', (55, 62))	('LR in the mediastinum', 'CPA', (63, 84))	('LR', 'Chemical', '-', (63, 65))	('POCT', 'Var', (30, 34))
251510	33290111	In summary, LR was the main cause of treatment failure in pT3N0M0 thoracic ESCC patients after two-field dissection.	('patients', 'Species', '9606', (80, 88))	('thoracic ESCC patients', 'Disease', (66, 88))	('pT3N0M0', 'Var', (58, 65))	('LR', 'Chemical', '-', (12, 14))
251512	33290111	PORT could decrease LR in the upper third of the thoracic cavity in pT3N0M0 patients, and POCT could reduce LR in the middle thoracic segment in pT3N0M0 patients.	('reduce', 'NegReg', (101, 107))	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (153, 161))	('LR in the middle thoracic segment', 'MPA', (108, 141))	('decrease', 'NegReg', (11, 19))	('LR', 'Chemical', '-', (20, 22))	('pT3N0M0', 'Var', (68, 75))	('LR', 'Chemical', '-', (108, 110))
251514	32118743	412 patients with resectable (cT1N1M0 or cT2-4N0-3M0) esophageal or GEJ cancer treated at the MDACC between October 2002 and June 2016 were analyzed.	('cT1N1M0', 'Var', (30, 37))	('esophageal', 'Disease', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('patients', 'Species', '9606', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cT2-4N0-3M0', 'Var', (41, 52))	('cancer', 'Disease', (72, 78))
251533	32118743	We included all patients who fulfilled the following key eligibility criteria: age >=18 years; histologically confirmed SCC or EAC Siewert type I, II or involving the esophagus by the 7th edition (2010) of the American Joint Committee on Cancer TNM staging system; cT1N1M0 or cT2-4N0-3M0 tumors; patient treated with preoperative CRT with a chemotherapy based on DF or FOX followed by surgery; and patients receiving induction chemotherapy were included.	('TNM', 'Gene', (245, 248))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('patient', 'Species', '9606', (398, 405))	('SCC', 'Disease', (120, 123))	('patients', 'Species', '9606', (16, 24))	('cT2-4N0-3M0', 'Var', (276, 287))	('patient', 'Species', '9606', (296, 303))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('EAC', 'Phenotype', 'HP:0011459', (127, 130))	('cT1N1M0', 'Var', (265, 272))	('TNM', 'Gene', '10178', (245, 248))	('Cancer', 'Phenotype', 'HP:0002664', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('Cancer', 'Disease', (238, 244))	('patient', 'Species', '9606', (16, 23))	('patients', 'Species', '9606', (398, 406))	('tumors', 'Disease', (288, 294))	('Cancer', 'Disease', 'MESH:D009369', (238, 244))
251557	32118743	Patients were primarily men (88%), overweight or obese (78%), with baseline T3/T4 (88%) and N+ (64%) tumors.	('obese', 'Disease', (49, 54))	('men', 'Species', '9606', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('T3/T4', 'Var', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Patients', 'Species', '9606', (0, 8))	('obese', 'Disease', 'MESH:D009765', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('overweight', 'Phenotype', 'HP:0025502', (35, 45))	('tumors', 'Disease', (101, 107))
251584	32118743	For example, almost all cancers of the lower 3rd esophagus were chromosomally unstable, with especially ERBB2 and VEGFA amplification or TP53 mutation, whereas a small proportion of GEJ tumors had microsatellite instability, considered as a good prognostic factor.	('GEJ tumors', 'Disease', 'MESH:D009369', (182, 192))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('VEGFA', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('GEJ tumors', 'Disease', (182, 192))	('amplification', 'Var', (120, 133))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('ERBB2', 'Gene', '2064', (104, 109))	('TP53', 'Gene', '7157', (137, 141))	('mutation', 'Var', (142, 150))	('VEGFA', 'Gene', '7422', (114, 119))	('ERBB2', 'Gene', (104, 109))	('microsatellite', 'MPA', (197, 211))	('cancers', 'Disease', (24, 31))	('TP53', 'Gene', (137, 141))
251587	32118743	Second, the CROSS trial only included patients with T1N1 or T2-3N0-1 tumors, and a recent suspicion of worsened outcomes emerged when original eligibility criteria were extended to patients with more advanced diseases.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('T1N1', 'Var', (52, 56))	('patients', 'Species', '9606', (181, 189))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('patients', 'Species', '9606', (38, 46))
251588	32118743	However, we reported here excellent survival data among patients with T2-4N0-3 tumors.	('patients', 'Species', '9606', (56, 64))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('T2-4N0-3', 'Var', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
251609	32588681	Silencing or downregulating PRR11 expression can suppress cellular proliferation, inhibit tumor metastasis, and reduce tumor growth in vivo.	('tumor', 'Disease', (119, 124))	('reduce', 'NegReg', (112, 118))	('PRR11', 'Gene', '55771', (28, 33))	('PRR11', 'Gene', (28, 33))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (90, 95))	('inhibit', 'NegReg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor metastasis', 'Disease', 'MESH:D009362', (90, 106))	('tumor metastasis', 'Disease', (90, 106))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cellular proliferation', 'CPA', (58, 80))	('suppress', 'NegReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('downregulating', 'NegReg', (13, 27))
251675	32323771	Transfection of KYSE150 esophageal squamous cell carcinoma (ESCC) cells with miR-200a mimics significantly increased their proliferative, migratory and invasive ability, whereas the opposite cell behaviors were observed in ESCC cells transfected with a miR-200a inhibitor.	('miR-200a', 'Gene', (253, 261))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (24, 58))	('miR-200a', 'Gene', '406983', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('invasive ability', 'CPA', (152, 168))	('miR-200a', 'Gene', (77, 85))	('increased', 'PosReg', (107, 116))	('esophageal squamous cell carcinoma', 'Disease', (24, 58))	('KYSE150', 'CellLine', 'CVCL:1348', (16, 23))	('mimics', 'Var', (86, 92))	('proliferative', 'CPA', (123, 136))	('miR-200a', 'Gene', '406983', (253, 261))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))
251688	32323771	Multiple other miRNAs, including miR-133a, miR-138, miR-375 and miR-593 serve as tumor suppressors, whereas miR-16, miR-21, miR-31, miR-34b, miR-208, miR-223, miR-373 and miR-423 exhibit oncogenic abilities.	('miR-373', 'Gene', (159, 166))	('miR-593', 'Gene', '693178', (64, 71))	('miR-423', 'Gene', '494335', (171, 178))	('miR-223', 'Gene', (150, 157))	('miR-21', 'Gene', (116, 122))	('miR-373', 'Gene', '442918', (159, 166))	('miR-34b', 'Gene', '407041', (132, 139))	('oncogenic abilities', 'CPA', (187, 206))	('miR-423', 'Gene', (171, 178))	('miR-16', 'Gene', (108, 114))	('miR-593', 'Gene', (64, 71))	('miR-34b', 'Gene', (132, 139))	('tumor', 'Disease', (81, 86))	('miR-208', 'Gene', '406990', (141, 148))	('miR-223', 'Gene', '407008', (150, 157))	('miR-31', 'Gene', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('miR-16', 'Gene', '51573', (108, 114))	('miR-375', 'Gene', '494324', (52, 59))	('miR-375', 'Gene', (52, 59))	('miR-208', 'Gene', (141, 148))	('miR-138', 'Var', (43, 50))	('miR-21', 'Gene', '406991', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('miR-31', 'Gene', '407035', (124, 130))
251689	32323771	It has been reported that miR-106b, miR-204, miR-371-3p, miR-574-3p, miR-886-3p, miR-1203, miR-1303 and miR-1909 were differentially expressed between patients with and without tumor relapse following surgery.	('miR-106b', 'Gene', (26, 34))	('miR-1303', 'Gene', '100302284', (91, 99))	('miR-574-3p', 'Gene', (57, 67))	('miR-1203', 'Gene', (81, 89))	('miR-886-3p', 'Var', (69, 79))	('miR-1203', 'Gene', '100302211', (81, 89))	('tumor', 'Disease', (177, 182))	('miR-204', 'Gene', (36, 43))	('miR-1909', 'Gene', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('miR-371-3p', 'Gene', '100500855', (45, 55))	('miR-1909', 'Gene', '100302210', (104, 112))	('miR-371-3p', 'Gene', (45, 55))	('miR-1303', 'Gene', (91, 99))	('patients', 'Species', '9606', (151, 159))	('miR-106b', 'Gene', '406900', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('miR-574-3p', 'Gene', '693159', (57, 67))	('miR-204', 'Gene', '406987', (36, 43))
251724	32323771	A total of 1x104 KYSE150 cells/well were seeded into 24-well plates and incubated for 24 h at 37 C. Wild-type or mutant miR-200a target gene 3'-UTR vectors, combined with the miR-200a mimic, were subsequently co-transfected into KYSE150 cells using Lipofectamine  3000 (Invitrogen; Thermo Fisher Scientific, Inc.), according to the manufacturer's protocol.	('miR-200a', 'Gene', '406983', (120, 128))	('miR-200a', 'Gene', (175, 183))	('miR-200a', 'Gene', (120, 128))	('Lipofectamine', 'Chemical', 'MESH:C086724', (249, 262))	('miR-200a', 'Gene', '406983', (175, 183))	('mutant', 'Var', (113, 119))	('KYSE150', 'CellLine', 'CVCL:1348', (229, 236))	('KYSE150', 'CellLine', 'CVCL:1348', (17, 24))
251725	32323771	The construction of the miR-200a target genes' 3'-UTR wild-type or mutant reporter genes were performed using the miRNA databases (Fig.	('miR-200a', 'Gene', (24, 32))	('mutant', 'Var', (67, 73))	('miR-200a', 'Gene', '406983', (24, 32))
251735	32323771	miR-200a mimics transfection significantly increased the migratory and invasive ability of ESCC cells compared with the scramble control, whereas the miR-200a inhibitor-transfected cells exhibited significantly reduced migratory and invasive capacity compared with the scramble control (Fig.	('invasive capacity', 'CPA', (233, 250))	('miR-200a', 'Gene', (150, 158))	('miR-200a', 'Gene', (0, 8))	('miR-200a', 'Gene', '406983', (150, 158))	('miR-200a', 'Gene', '406983', (0, 8))	('migratory', 'CPA', (57, 66))	('reduced', 'NegReg', (211, 218))	('invasive ability', 'CPA', (71, 87))	('increased', 'PosReg', (43, 52))	('transfection', 'Var', (16, 28))
251750	32323771	The results indicated that KYSE150 ESCC cells transfected with the miR-200a mimic significantly suppressed the luciferase activity of the wild-type reporters containing the 3'-UTR of all target genes (CTNNB1, CDH1, APC, PTEN, CTNNA1 and SOD2) compared with the scramble control; this inhibition disappeared when the miR-200a target site was mutated (Fig.	('CTNNB1', 'Gene', '1499', (201, 207))	('miR-200a', 'Gene', '406983', (67, 75))	('suppressed', 'NegReg', (96, 106))	('miR-200a', 'Gene', (316, 324))	('APC', 'Gene', (215, 218))	('PTEN', 'Gene', '5728', (220, 224))	('CTNNB1', 'Gene', (201, 207))	('mimic', 'Var', (76, 81))	('CTNNA1', 'Gene', (226, 232))	('miR-200a', 'Gene', (67, 75))	('CDH1', 'Gene', '999', (209, 213))	('SOD2', 'Gene', (237, 241))	('CTNNA1', 'Gene', '1495', (226, 232))	('KYSE150', 'CellLine', 'CVCL:1348', (27, 34))	('activity', 'MPA', (122, 130))	('miR-200a', 'Gene', '406983', (316, 324))	('CDH1', 'Gene', (209, 213))	('APC', 'Gene', '324', (215, 218))	('SOD2', 'Gene', '6648', (237, 241))	('APC', 'Phenotype', 'HP:0005227', (215, 218))	('PTEN', 'Gene', (220, 224))	('luciferase', 'Enzyme', (111, 121))
251751	32323771	miRNAs have been widely reported to be associated with tumor development, and are often regarded as disease biomarkers; it has been demonstrated that miRNAs affect ESCC cell behaviors, including cell proliferation, migration and invasion.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('invasion', 'CPA', (229, 237))	('cell proliferation', 'CPA', (195, 213))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('miRNAs', 'Var', (150, 156))	('ESCC', 'Disease', (164, 168))	('migration', 'CPA', (215, 224))	('affect', 'Reg', (157, 163))
251756	32323771	In another study, out of a total of 136 DEMs identified in EC, the top five DEMs were revealed to be miRNA-21, miRNA-93, miRNA-196a-1, miRNA-196a-2 and miRNA-4746.	('miRNA-21', 'Gene', '406991', (101, 109))	('miRNA-4746', 'Var', (152, 162))	('miRNA-93', 'Gene', (111, 119))	('miRNA-21', 'Gene', (101, 109))	('miRNA-93', 'Gene', '407051', (111, 119))	('miRNA-196a-1', 'Var', (121, 133))	('miRNA-196a-2', 'Var', (135, 147))
251757	32323771	In addition, within a cohort of 102 patients with EC, miR-451a, miR-144-3p and miR-144-5p were identified; other miRNAs including miR-133a miR-138, miR-375 and miR-593 were observed to serve as tumor suppressors, whereas miR-16, miR-21, miR-31, miR-34b, miR-208, miR-223, miR-373 and miR-423 exhibited oncogenic properties.	('miR-423', 'Gene', (284, 291))	('miR-34b', 'Gene', '407041', (245, 252))	('miR-16', 'Gene', (221, 227))	('tumor', 'Disease', (194, 199))	('miR-223', 'Gene', (263, 270))	('miR-21', 'Gene', (229, 235))	('miR-373', 'Gene', '442918', (272, 279))	('miR-451a', 'Gene', '574411', (54, 62))	('miR-31', 'Gene', (237, 243))	('miR-34b', 'Gene', (245, 252))	('miR-144', 'Gene', '406936', (64, 71))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('miR-593', 'Gene', (160, 167))	('miR-133a', 'Var', (130, 138))	('miR-144', 'Gene', '406936', (79, 86))	('miR-16', 'Gene', '51573', (221, 227))	('miR-208', 'Gene', '406990', (254, 261))	('miR-375', 'Gene', '494324', (148, 155))	('miR-375', 'Gene', (148, 155))	('miR-223', 'Gene', '407008', (263, 270))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('oncogenic properties', 'CPA', (302, 322))	('miR-31', 'Gene', '407035', (237, 243))	('miR-423', 'Gene', '494335', (284, 291))	('miR-451a', 'Gene', (54, 62))	('miR-138', 'Var', (139, 146))	('miR-208', 'Gene', (254, 261))	('miR-144', 'Gene', (64, 71))	('miR-21', 'Gene', '406991', (229, 235))	('miR-593', 'Gene', '693178', (160, 167))	('miR-144', 'Gene', (79, 86))	('miR-373', 'Gene', (272, 279))
251758	32323771	Meanwhile, researchers identified miR-28-5p, miR-34a-5p and miR-186-5p as the significant biomarkers of ESCC.	('miR-28', 'Gene', '407020', (34, 40))	('miR-28', 'Gene', (34, 40))	('miR-186', 'Gene', '406962', (60, 67))	('ESCC', 'Disease', (104, 108))	('miR-186', 'Gene', (60, 67))	('miR-34a-5p', 'Var', (45, 55))
251759	32323771	For instance, miRNA-10b can promote ESCC cell proliferation, migration, invasion and colony formation, as well as metastasis; miRNA-548 and miRNA-576 enhance the migration and invasion of ESCC cells; miRNA-1 can suppress the proliferation, migration and invasion of ESCC cells.	('metastasis', 'CPA', (114, 124))	('migration', 'CPA', (162, 171))	('ESCC', 'Disease', (188, 192))	('miRNA-10b', 'Gene', (14, 23))	('miRNA-576', 'Var', (140, 149))	('proliferation', 'CPA', (225, 238))	('suppress', 'NegReg', (212, 220))	('enhance', 'PosReg', (150, 157))	('colony formation', 'CPA', (85, 101))	('migration', 'CPA', (61, 70))	('invasion', 'CPA', (254, 262))	('miRNA-548', 'Var', (126, 135))	('miRNA-10b', 'Gene', '406903', (14, 23))	('migration', 'CPA', (240, 249))	('invasion', 'CPA', (72, 80))	('invasion', 'CPA', (176, 184))
251774	32323771	The present study investigated the putative target genes of miR-200a, as miRNAs function in the development of ESCC via binding to the UTR region of target genes: miRNA-10b targeting FOXO3, micRNA-548 and miRNA-576 downregulating NRIP1 and miRNA-1 binding to Notch2.	('miR-200a', 'Gene', '406983', (60, 68))	('micRNA-548', 'Gene', (190, 200))	('FOXO3', 'Gene', '2309', (183, 188))	('ESCC', 'Disease', (111, 115))	('Notch2', 'Gene', '4853', (259, 265))	('FOXO3', 'Gene', (183, 188))	('miRNA-10b', 'Gene', '406903', (163, 172))	('miRNA-1', 'Protein', (240, 247))	('binding', 'Interaction', (248, 255))	('miRNA-576', 'Var', (205, 214))	('NRIP1', 'Gene', '8204', (230, 235))	('miRNA-10b', 'Gene', (163, 172))	('downregulating', 'NegReg', (215, 229))	('Notch2', 'Gene', (259, 265))	('NRIP1', 'Gene', (230, 235))	('miR-200a', 'Gene', (60, 68))
251784	32323771	The dephosphorylation of tyrosine-phosphorylated focal adhesion kinase inhibits focal adhesion formation, cell migration and integrin-mediated cell spreading.	('integrin-mediated cell spreading', 'CPA', (125, 157))	('tyrosine-phosphorylated', 'Var', (25, 48))	('dephosphorylation', 'Var', (4, 21))	('inhibits', 'NegReg', (71, 79))	('focal adhesion formation', 'CPA', (80, 104))	('cell migration', 'CPA', (106, 120))	('tyrosine', 'Chemical', 'MESH:D014443', (25, 33))
251812	31939000	We extracted the data for patients diagnosed with thoracic esophageal cancer (C151, C153-155) and treated surgically at a registered hospital for thoracic esophageal cancer, and for patients diagnosed at another hospital but treated surgically at a registered hospital for thoracic esophageal cancer.	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (273, 299))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('thoracic esophageal cancer', 'Disease', (50, 76))	('C153-155', 'Var', (84, 92))	('thoracic esophageal cancer', 'Disease', (273, 299))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (146, 172))	('patients', 'Species', '9606', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('patients', 'Species', '9606', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('thoracic esophageal cancer', 'Disease', (146, 172))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (50, 76))
251836	31939000	Cox proportional hazard regression analyses stratified by the type of adjuvant treatment showed that patients receiving treatment at an AIBCES had a significantly lower hazard ratio (HR 0.82, 95% CI 0.75-0.90) than those treated at a Non-AIBCES.	('patients', 'Species', '9606', (101, 109))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('AIBCES', 'Chemical', '-', (136, 142))	('AIBCES', 'Chemical', '-', (238, 244))	('hazard ratio', 'MPA', (169, 181))	('AIBCES', 'Var', (136, 142))	('lower', 'NegReg', (163, 168))
251838	31939000	Cox proportional hazard regression analyses before and after propensity score matching showed that, in consideration of clinical factors, patients receiving treatment at an AIBCES had a significantly lower hazard ratio than those treated at a Non-AIBCES.	('AIBCES', 'Chemical', '-', (247, 253))	('hazard ratio', 'MPA', (206, 218))	('Cox', 'Gene', (0, 3))	('Cox', 'Gene', '1351', (0, 3))	('lower', 'NegReg', (200, 205))	('AIBCES', 'Var', (173, 179))	('patients', 'Species', '9606', (138, 146))	('AIBCES', 'Chemical', '-', (173, 179))
251946	30613310	S100A8 and S100A9 (MRP14) usually co-exist in the form of heterodimer, known as calprotectin, that is constitutively expressed in neutrophils and monocytes.	('S100A8', 'Var', (0, 6))	('MRP14', 'Gene', (19, 24))	('MRP14', 'Gene', '94195', (19, 24))	('S100A9', 'Var', (11, 17))
251947	30613310	Interestingly, studies of ESCC patients observed decreased levels of S100A8 and S100A9 in ESCC tumors compared to that in normal esophageal mucosa, whereas their expression levels increased in NMBA-induced esophageal tumors in rats.	('levels', 'MPA', (59, 65))	('NMBA', 'Chemical', 'MESH:C014707', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('expression levels', 'MPA', (162, 179))	('S100A9', 'Var', (80, 86))	('ESCC tumors', 'Disease', (90, 101))	('S100A8', 'Var', (69, 75))	('decreased', 'NegReg', (49, 58))	('rats', 'Species', '10116', (227, 231))	('patients', 'Species', '9606', (31, 39))	('esophageal tumors', 'Disease', 'MESH:D004938', (206, 223))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('esophageal tumors', 'Phenotype', 'HP:0100751', (206, 223))	('esophageal tumor', 'Phenotype', 'HP:0100751', (206, 222))	('ESCC tumors', 'Disease', 'MESH:D004938', (90, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('esophageal tumors', 'Disease', (206, 223))
251985	29849506	NR_004053 was one of the major SOX2OT transcripts aberrantly expressed in ESCC tissues and cells.	('ESCC', 'Disease', (74, 78))	('SOX2OT', 'Gene', '347689', (31, 37))	('SOX2OT', 'Gene', (31, 37))	('NR_004053', 'Var', (0, 9))
251986	29849506	Overexpression of SOX2OT (NR_004053) promoted ESCC cell growth, antagonized the effect of DDP and increased cell proliferation ratio.	('NR_004053', 'Var', (26, 35))	('promoted', 'PosReg', (37, 45))	('ESCC cell growth', 'CPA', (46, 62))	('SOX2OT', 'Gene', '347689', (18, 24))	('cell proliferation ratio', 'CPA', (108, 132))	('SOX2OT', 'Gene', (18, 24))	('DDP', 'Chemical', 'MESH:D002945', (90, 93))	('increased', 'PosReg', (98, 107))
251987	29849506	Ectopic expression of SOX2 could increase the luciferase activity of SOX2OT-pGL3/Basic and SOX2OT expression, while overexpression of SOX2OT (NR_004053) had no effect on SOX2 expression.	('pGL3', 'Gene', (76, 80))	('SOX2', 'Gene', (170, 174))	('SOX2', 'Gene', '6657', (170, 174))	('SOX2OT', 'Gene', (69, 75))	('activity', 'MPA', (57, 65))	('SOX2', 'Gene', '6657', (91, 95))	('pGL3', 'Gene', '6391', (76, 80))	('SOX2', 'Gene', (91, 95))	('SOX2OT', 'Gene', (91, 97))	('luciferase', 'Enzyme', (46, 56))	('SOX2OT', 'Gene', '347689', (69, 75))	('Ectopic expression', 'Var', (0, 18))	('SOX2OT', 'Gene', '347689', (91, 97))	('SOX2', 'Gene', '6657', (134, 138))	('SOX2', 'Gene', (134, 138))	('SOX2OT', 'Gene', (134, 140))	('SOX2', 'Gene', (69, 73))	('SOX2', 'Gene', '6657', (69, 73))	('increase', 'PosReg', (33, 41))	('SOX2', 'Gene', '6657', (22, 26))	('SOX2', 'Gene', (22, 26))	('SOX2OT', 'Gene', '347689', (134, 140))
251988	29849506	Our study demonstrates that the major isoform of SOX2OT in ESCC, SOX2OT (NR_004053) contributes to cell growth.	('SOX2OT', 'Gene', '347689', (65, 71))	('SOX2OT', 'Gene', '347689', (49, 55))	('NR_004053', 'Var', (73, 82))	('SOX2OT', 'Gene', (65, 71))	('SOX2OT', 'Gene', (49, 55))	('cell growth', 'CPA', (99, 110))	('ESCC', 'Disease', (59, 63))
252011	29849506	The sequence of SOX2OT transcript variant 4 (NR_004053) was synthesized and cloned into eukaryotic expression vector pcDNA3.1 (+).	('SOX2OT', 'Gene', '347689', (16, 22))	('NR_004053', 'Var', (45, 54))	('SOX2OT', 'Gene', (16, 22))
252030	29849506	To identify differentially expressed isoforms in ESCC, PCR was used to detect SOX2OT transcript variants in ESCC tissue and cells.	('SOX2OT', 'Gene', '347689', (78, 84))	('SOX2OT', 'Gene', (78, 84))	('variants', 'Var', (96, 104))
252031	29849506	NR_075092, NR_075089 and NR_004053 were the major SOX2OT transcripts uniquely elevated in ESCC tissues, which were also found in KYSE150 and KYSE450 cells (Fig.	('elevated', 'PosReg', (78, 86))	('NR_004053', 'Var', (25, 34))	('SOX2OT', 'Gene', '347689', (50, 56))	('NR_075089', 'Var', (11, 20))	('SOX2OT', 'Gene', (50, 56))	('ESCC', 'Disease', (90, 94))	('NR_075092', 'Var', (0, 9))
252037	29849506	Edu assays showed that ectopic expression of SOX2OT raised the proliferation ratio of ESCC cells (Fig.	('ESCC cells', 'CPA', (86, 96))	('ectopic expression', 'Var', (23, 41))	('SOX2OT', 'Gene', (45, 51))	('proliferation ratio', 'CPA', (63, 82))	('Edu', 'Chemical', '-', (0, 3))	('raised', 'PosReg', (52, 58))	('SOX2OT', 'Gene', '347689', (45, 51))
252041	29849506	qPCR and Western Blot analyses found that ectopic expression SOX2 promoted SOX2OT expression (Fig.	('SOX2', 'Gene', (61, 65))	('SOX2', 'Gene', (75, 79))	('SOX2OT', 'Gene', '347689', (75, 81))	('SOX2', 'Gene', '6657', (75, 79))	('ectopic expression', 'Var', (42, 60))	('promoted', 'PosReg', (66, 74))	('SOX2', 'Gene', '6657', (61, 65))	('SOX2OT', 'Gene', (75, 81))
252043	29849506	Furthermore, luciferase reporter assay showed that ectopic expression of SOX2 could increase the luciferase activity of SOX2OT-pGL3/Basic, suggesting that SOX2 may promote SOX2OT expression at transcriptional level.	('SOX2', 'Gene', (172, 176))	('SOX2', 'Gene', '6657', (155, 159))	('luciferase', 'Enzyme', (97, 107))	('SOX2', 'Gene', '6657', (172, 176))	('SOX2', 'Gene', (155, 159))	('SOX2OT', 'Gene', (172, 178))	('SOX2OT', 'Gene', '347689', (172, 178))	('SOX2', 'Gene', '6657', (73, 77))	('SOX2', 'Gene', (73, 77))	('increase', 'PosReg', (84, 92))	('SOX2', 'Gene', (120, 124))	('pGL3', 'Gene', (127, 131))	('SOX2', 'Gene', '6657', (120, 124))	('pGL3', 'Gene', '6391', (127, 131))	('SOX2OT', 'Gene', (120, 126))	('ectopic expression', 'Var', (51, 69))	('activity', 'MPA', (108, 116))	('promote', 'PosReg', (164, 171))	('SOX2OT', 'Gene', '347689', (120, 126))	('expression', 'MPA', (179, 189))
252047	29849506	Our study identified that NR_004053 is one of the major SOX2OT isoforms differentially expressed in ESCC tissues and cells.	('NR_004053', 'Var', (26, 35))	('ESCC', 'Disease', (100, 104))	('SOX2OT', 'Gene', (56, 62))	('SOX2OT', 'Gene', '347689', (56, 62))
252059	29849506	In conclusion, our study identifies NR_004053 as the one of the major SOX2OT isoforms in ESCC and reveals that SOX2OT (NR_004053) contributes to the growth of ESCC.	('contributes', 'PosReg', (130, 141))	('SOX2OT', 'Gene', '347689', (111, 117))	('SOX2OT', 'Gene', '347689', (70, 76))	('NR_004053', 'Var', (119, 128))	('SOX2OT', 'Gene', (111, 117))	('SOX2OT', 'Gene', (70, 76))	('growth', 'MPA', (149, 155))	('NR_004053', 'Var', (36, 45))	('ESCC', 'Disease', (159, 163))
252174	29769143	Overall survival and grade 5 toxicities were significantly associated with a Charlson score > 1, indicating that comorbidity may play a more important role than age per se.	('Charlson', 'Var', (77, 85))	('toxicities', 'Disease', 'MESH:D064420', (29, 39))	('toxicities', 'Disease', (29, 39))	('Overall survival', 'CPA', (0, 16))
252183	29769143	High T stage is well known to be associated with decreased survival as shown by others and was also identified as a negative prognostic for OS in our series according to multivariate analysis.	('decreased', 'NegReg', (49, 58))	('High T', 'Var', (0, 6))	('survival', 'MPA', (59, 67))	('OS', 'Chemical', 'MESH:D009992', (140, 142))
252215	29416734	Furthermore, increasing numbers of miRNAs have been experimentally shown to be associated with the development processes of various human diseases.	('associated', 'Reg', (79, 89))	('miRNAs', 'Var', (35, 41))	('human', 'Species', '9606', (132, 137))
252238	29416734	For example, the AUCs obtained from MCMDA, HGIMDA, RLSMDA, HDMP, WBSMDA were 0.8749, 0.8781, 0.8426, 0.8366, 0.8030 in global LOOCV and 0.7718, 0.8077, 0.6953, 0.7702, 0.8031 in local LOOCV, respectively.	('0.8426', 'Var', (93, 99))	('0.6953', 'Var', (152, 158))	('0.8031', 'Var', (168, 174))	('WBSMDA', 'Chemical', '-', (65, 71))	('0.8749', 'Var', (77, 83))	('0.7718', 'Var', (136, 142))	('0.8366', 'Var', (101, 107))	('0.8077', 'Var', (144, 150))	('0.8030', 'Var', (109, 115))	('0.8781', 'Var', (85, 91))	('HDMP', 'Chemical', '-', (59, 63))	('0.7702', 'Var', (160, 166))
252253	29416734	For example, among the differentially expressed miRNAs, miR-10b, miR-125b, miR145, miR-21, and miR-155 emerged to be the most consistently deregulated in breast neoplasm.	('miR-155', 'Gene', (95, 102))	('miR-21', 'Gene', '406991', (83, 89))	('neoplasm', 'Phenotype', 'HP:0002664', (161, 169))	('breast neoplasm', 'Phenotype', 'HP:0100013', (154, 169))	('breast neoplasm', 'Disease', (154, 169))	('deregulated', 'Reg', (139, 150))	('miR-21', 'Gene', (83, 89))	('miR-125b', 'Var', (65, 73))	('miR-10b', 'Gene', '406903', (56, 63))	('breast neoplasm', 'Disease', 'MESH:D001943', (154, 169))	('miR145', 'Gene', (75, 81))	('miR-155', 'Gene', '406947', (95, 102))	('miR-10b', 'Gene', (56, 63))	('miR145', 'Gene', '406937', (75, 81))
252254	29416734	Three of them, miR-10b, miR-125b, and miR-145, were down-regulated and the remaining two, miR-21 and miR-155, were up-regulated, suggesting that they may potentially act as tumor suppressor genes or oncogenes, respectively.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('miR-10b', 'Gene', '406903', (15, 22))	('miR-10b', 'Gene', (15, 22))	('up-regulated', 'PosReg', (115, 127))	('miR-21', 'Gene', (90, 96))	('down-regulated', 'NegReg', (52, 66))	('miR-125b', 'Var', (24, 32))	('tumor', 'Disease', (173, 178))	('miR-155', 'Gene', '406947', (101, 108))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('miR-155', 'Gene', (101, 108))	('miR-145', 'Gene', (38, 45))	('miR-21', 'Gene', '406991', (90, 96))	('miR-145', 'Gene', '406937', (38, 45))
252261	29416734	Furthermore, recent researches have shown that the expression of miRNAs has tight associations with the development of esophageal neoplasm.	('neoplasm', 'Phenotype', 'HP:0002664', (130, 138))	('esophageal neoplasm', 'Phenotype', 'HP:0100751', (119, 138))	('miRNAs', 'Gene', (65, 71))	('esophageal neoplasm', 'Disease', (119, 138))	('associations', 'Reg', (82, 94))	('expression', 'Var', (51, 61))	('esophageal neoplasm', 'Disease', 'MESH:D004938', (119, 138))
252271	29416734	Recent experimental studies showed that profound mRNA expression changes of potential target genes involving cell cycle control, apoptosis and B-cell differentiation was concerned with the down-regulation of miR-16, miR-26a, miR-101, miR-29c and miR138 in the t(14;18)-negative follicular lymphoma subset.	('miR-26a', 'Gene', (216, 223))	('follicular lymphoma', 'Disease', 'MESH:D008224', (278, 297))	('follicular lymphoma', 'Disease', (278, 297))	('miR-16', 'Gene', (208, 214))	('miR-101', 'Var', (225, 232))	('miR138', 'Gene', (246, 252))	('mRNA expression', 'MPA', (49, 64))	('miR-29c', 'Gene', (234, 241))	('miR-16', 'Gene', '51573', (208, 214))	('miR-29c', 'Gene', '407026', (234, 241))	('lymphoma', 'Phenotype', 'HP:0002665', (289, 297))	('miR-26a', 'Gene', '407015', (216, 223))	('down-regulation', 'NegReg', (189, 204))
252291	29416734	In view of reasons mentioned above, SSCMDA could improve the prediction accuracy in comparison with the previous proposed methods.	('improve', 'PosReg', (49, 56))	('SSCMDA', 'Var', (36, 42))	('SSCMDA', 'Chemical', '-', (36, 42))	('prediction', 'MPA', (61, 71))
252320	29172270	Among the analyzed MTVs, a statistically significant correlation with GTVCT was revealed for MTV10%SUVmax (r = 0.63; p = 0.0014), MTVliv (r = 0.60; p = 0.0021), MTVSUV2.5 (r = 0.54; p = 0.0063); MTV20%SUVmax (r = 0.44; p = 0.0344); MTV30%SUVmax (r = 0.44; p = 0.0373).	('MTV', 'Chemical', '-', (195, 198))	('MTV10%', 'Var', (93, 99))	('MTV', 'Chemical', '-', (232, 235))	('MTV', 'Chemical', '-', (93, 96))	('MTV30%SUVmax', 'Var', (232, 244))	('MTV', 'Chemical', '-', (19, 22))	('MTV30', 'Species', '43266', (232, 237))	('MTV', 'Chemical', '-', (130, 133))	('MTV', 'Chemical', '-', (161, 164))
252369	29172270	MTVs were determined as follows: MTV2.5 (threshold: SUV >= 2.5), MTVliv [>= mean SUV of the patient's liver +- 2 standard deviations (SD)], MTV10 (>= 10% of SUVmax), MTV20, MTV30, MTV40, MTV50, MTV60, and MTV70, respectively, according to the definitions above.	('MTV', 'Chemical', '-', (187, 190))	('MTV', 'Chemical', '-', (180, 183))	('MTV', 'Chemical', '-', (140, 143))	('MTV20', 'Var', (166, 171))	('MTV', 'Chemical', '-', (194, 197))	('MTV50', 'Var', (187, 192))	('MTV', 'Chemical', '-', (65, 68))	('MTV30', 'Species', '43266', (173, 178))	('MTV40', 'Var', (180, 185))	('MTVliv', 'Var', (65, 71))	('MTV', 'Chemical', '-', (33, 36))	('MTV60', 'Var', (194, 199))	('MTV70', 'Var', (205, 210))	('MTV', 'Chemical', '-', (0, 3))	('patient', 'Species', '9606', (92, 99))	('MTV30', 'Var', (173, 178))	('MTV', 'Chemical', '-', (173, 176))	('MTV', 'Chemical', '-', (166, 169))	('MTV', 'Chemical', '-', (205, 208))	('SD', 'Disease', 'MESH:D029461', (134, 136))
252409	29172270	Among the auto-segmented MTV volumes, the best compatibility with GTVCT had MTV10, which was immediately followed by MTVliv and MTV2,5, as shown in the diagrams (Figure 2B, C, D).	('men', 'Species', '9606', (18, 21))	('MTV', 'Chemical', '-', (117, 120))	('MTV', 'Chemical', '-', (128, 131))	('MTV10', 'Var', (76, 81))	('MTV', 'Chemical', '-', (76, 79))	('compatibility', 'Interaction', (47, 60))	('MTV', 'Chemical', '-', (25, 28))
252512	29172270	In cases of very low SUVmax (e.g., in DT gastric cancer) MTV10% corresponds to almost the entire area covered by the ROI, in addition to the physiological uptake in the background region such as by the liver.	('MTV', 'Chemical', '-', (57, 60))	('MTV10%', 'Var', (57, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('DT', 'Chemical', 'MESH:D013936', (38, 40))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('gastric cancer', 'Disease', (41, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
252578	28740892	Patients were required to be Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, meet the following laboratory criteria within 14 days before registration: white blood cells >=3000/mm3; platelet count >=10x104/mm3; hemoglobin level >=8.0 g/dL; aspartate aminotransferase and alanine aminotransferase <=100 IU/L; total bilirubin <=1.5 mg/dL; serum creatinine <=2.0 mg/dL; and oxygen saturation >=93%.	('creatinine', 'Chemical', 'MESH:D003404', (364, 374))	('serum creatinine', 'MPA', (358, 374))	('aspartate', 'MPA', (261, 270))	('total bilirubin', 'MPA', (329, 344))	('>=10x104/mm3', 'Var', (218, 230))	('hemoglobin level', 'MPA', (232, 248))	('Patients', 'Species', '9606', (0, 8))	('Oncology', 'Phenotype', 'HP:0002664', (49, 57))	('oxygen saturation', 'MPA', (392, 409))	('>=3000/mm3', 'Var', (191, 201))	('alanine aminotransferase', 'Enzyme', (292, 316))	('bilirubin', 'Chemical', 'MESH:D001663', (335, 344))
252583	28740892	Chemotherapy was delayed because of toxicities until recovery to the following conditions: absolute neutrophil count >=1000/mm3; platelet count >=7.5x104/mm3; aspartate aminotransferase and alanine aminotransferase <= 100 IU/L; total bilirubin <=2.5 mg/dL; serum creatinine <=2.5 mg/dL; and grade 2 or lower nausea, vomiting, anorexia, esophagitis, diarrhea, or radiation pneumonitis.	('pneumonitis', 'Disease', (372, 383))	('esophagitis', 'Disease', 'MESH:D004941', (336, 347))	('nausea', 'Disease', 'MESH:D009325', (308, 314))	('aspartate aminotransferase', 'MPA', (159, 185))	('<= 100 IU/L', 'Var', (215, 226))	('toxicities', 'Disease', (36, 46))	('toxicities', 'Disease', 'MESH:D064420', (36, 46))	('>=7.5x104/mm3', 'Var', (144, 157))	('vomiting', 'Disease', 'MESH:D014839', (316, 324))	('esophagitis', 'Phenotype', 'HP:0100633', (336, 347))	('total bilirubin', 'MPA', (228, 243))	('>=1000/mm3', 'Var', (117, 127))	('vomiting', 'Phenotype', 'HP:0002013', (316, 324))	('anorexia', 'Disease', 'MESH:D000855', (326, 334))	('vomiting', 'Disease', (316, 324))	('diarrhea', 'Phenotype', 'HP:0002014', (349, 357))	('nausea', 'Phenotype', 'HP:0002018', (308, 314))	('bilirubin', 'Chemical', 'MESH:D001663', (234, 243))	('diarrhea', 'Disease', 'MESH:D003967', (349, 357))	('lower', 'NegReg', (302, 307))	('creatinine', 'Chemical', 'MESH:D003404', (263, 273))	('anorexia', 'Phenotype', 'HP:0002039', (326, 334))	('nausea', 'Disease', (308, 314))	('serum creatinine', 'MPA', (257, 273))	('diarrhea', 'Disease', (349, 357))	('pneumonitis', 'Disease', 'MESH:D011014', (372, 383))	('anorexia', 'Disease', (326, 334))	('esophagitis', 'Disease', (336, 347))
252661	28118321	Over-expression of SOX4 could partly abrogated propofol-mediated inhibition of EC9706 cell migration and invasion.	('inhibition', 'NegReg', (65, 75))	('SOX4', 'Gene', (19, 23))	('SOX4', 'Gene', '6659', (19, 23))	('EC9706', 'CellLine', 'CVCL:E307', (79, 85))	('abrogated', 'NegReg', (37, 46))	('Over-expression', 'Var', (0, 15))	('propofol', 'Chemical', 'MESH:D015742', (47, 55))
252705	28118321	We found that propofol markedly inhibited EC9706s migration after 18 h in a dose-dependent manner (Figure 1A, P<0.01).	('inhibited', 'NegReg', (32, 41))	('EC9706s', 'Var', (42, 49))	('EC9706', 'CellLine', 'CVCL:E307', (42, 48))	('propofol', 'Chemical', 'MESH:D015742', (14, 22))
252718	28118321	Identical to the effect of propofol (5 mug/L), inhibition of SOX4 by SOX4-siRNA could also decrease EC9706 migration and invasion (Figure 4C and 4D, P<0.05).	('SOX4', 'Gene', '6659', (69, 73))	('propofol', 'Chemical', 'MESH:D015742', (27, 35))	('inhibition', 'Var', (47, 57))	('EC9706', 'CellLine', 'CVCL:E307', (100, 106))	('EC9706 migration', 'CPA', (100, 116))	('SOX4', 'Gene', (61, 65))	('SOX4', 'Gene', '6659', (61, 65))	('invasion', 'CPA', (121, 129))	('SOX4', 'Gene', (69, 73))	('decrease', 'NegReg', (91, 99))
252726	28118321	In addition, over-expression of SOX4 could also reverse the propofol-induced decreased expression and activity of MMP-2/9 (Figure 5E, 5F, P<0.01).	('SOX4', 'Gene', (32, 36))	('MMP-2/9', 'Gene', '4313;4318', (114, 121))	('over-expression', 'Var', (13, 28))	('MMP-2/9', 'Gene', (114, 121))	('SOX4', 'Gene', '6659', (32, 36))	('propofol', 'Chemical', 'MESH:D015742', (60, 68))	('expression', 'MPA', (87, 97))	('activity', 'MPA', (102, 110))	('decreased', 'NegReg', (77, 86))
252741	28118321	Alterations in transcriptional activities that result in imbalance between oncogenes and tumor suppressor genes finally cause initiation and progression of cancer.	('imbalance', 'MPA', (57, 66))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cause', 'Reg', (120, 125))	('Alterations', 'Var', (0, 11))	('transcriptional', 'MPA', (15, 30))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('imbalance', 'Phenotype', 'HP:0002172', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('oncogenes', 'Protein', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
252745	28118321	What's more, a lot of studies found that miRNAs like miR-133a, miR-132, and miR-211 played that anti-cancer role by targeting SOX4.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('targeting', 'Reg', (116, 125))	('miR-132', 'Gene', (63, 70))	('miR-133a', 'Var', (53, 61))	('cancer', 'Disease', (101, 107))	('miR-211', 'Gene', (76, 83))	('miR-211', 'Gene', '406993', (76, 83))	('miR-132', 'Gene', '406921', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('SOX4', 'Gene', (126, 130))	('SOX4', 'Gene', '6659', (126, 130))
252746	28118321	Therefore, we supposed that propofol inhibited EC9706 cell migration and invasion by down-regulation of SOX4.	('EC9706', 'CellLine', 'CVCL:E307', (47, 53))	('inhibited', 'NegReg', (37, 46))	('propofol', 'Chemical', 'MESH:D015742', (28, 36))	('down-regulation', 'NegReg', (85, 100))	('EC9706', 'Var', (47, 53))	('invasion', 'CPA', (73, 81))	('SOX4', 'Gene', (104, 108))	('SOX4', 'Gene', '6659', (104, 108))
252747	28118321	In this study, we found that knock down of SOX4 by siRNA had the same effect as propofol on EC9706, including suppressing cell migration and invasion, inhibiting the expression and activity of MMP-2/9, and increasing the expression TIMP-1, which indicated that SOX4 played an important role in the regulation of EC9706 cell migration and invasion.	('invasion', 'CPA', (141, 149))	('EC9706', 'CellLine', 'CVCL:E307', (312, 318))	('increasing', 'PosReg', (206, 216))	('SOX4', 'Gene', '6659', (43, 47))	('cell migration', 'CPA', (122, 136))	('knock down', 'Var', (29, 39))	('MMP-2/9', 'Gene', '4313;4318', (193, 200))	('EC9706', 'CellLine', 'CVCL:E307', (92, 98))	('activity', 'MPA', (181, 189))	('SOX4', 'Gene', (261, 265))	('propofol', 'Chemical', 'MESH:D015742', (80, 88))	('expression', 'MPA', (221, 231))	('expression', 'MPA', (166, 176))	('SOX4', 'Gene', '6659', (261, 265))	('TIMP-1', 'Gene', (232, 238))	('SOX4', 'Gene', (43, 47))	('suppressing', 'NegReg', (110, 121))	('inhibiting', 'NegReg', (151, 161))	('MMP-2/9', 'Gene', (193, 200))	('TIMP-1', 'Gene', '7076', (232, 238))
252764	26911980	A PVTT in the main portal trunk was predictive of rebleeding (hazard ratio 3.706, p = .0223), and alpha-fetoprotein-L3 levels <37.4 % (hazard ratio 0.464, p = 0.015) and Child-Pugh class A/B (hazard ratio 0.398, p = 0.007) were associated with overall survival.	('portal trunk', 'Phenotype', 'HP:0025154', (19, 31))	('alpha-fetoprotein', 'Gene', (98, 115))	('overall', 'MPA', (244, 251))	('PVTT', 'Var', (2, 6))	('alpha-fetoprotein', 'Gene', '174', (98, 115))	('Child', 'Species', '9606', (170, 175))	('associated', 'Reg', (228, 238))	('PVTT', 'Phenotype', 'HP:0030242', (2, 6))	('rebleeding', 'CPA', (50, 60))
252805	26911980	Among all patients, 56 % had a PVTT in the main portal trunk, and 27 % had extrahepatic metastasis.	('PVTT', 'Var', (31, 35))	('extrahepatic metastasis', 'CPA', (75, 98))	('PVTT', 'Phenotype', 'HP:0030242', (31, 35))	('patients', 'Species', '9606', (10, 18))	('portal trunk', 'Phenotype', 'HP:0025154', (48, 60))
252820	26911980	The median rebleeding-free survival time was 24 days in the patient group with a PVTT in the main portal trunk and 34 days in the patient group with a PVTT in the first or second branches of the portal vein (p = 0.6313).	('patient', 'Species', '9606', (60, 67))	('patient', 'Species', '9606', (130, 137))	('portal trunk', 'Phenotype', 'HP:0025154', (98, 110))	('PVTT', 'Phenotype', 'HP:0030242', (81, 85))	('PVTT', 'Phenotype', 'HP:0030242', (151, 155))	('PVTT', 'Var', (81, 85))	('rebleeding-free survival time', 'CPA', (11, 40))
252842	26911980	In HCC patients with a PVTT in the main trunk, varices are exacerbated due to the marked elevation of portal vein pressure, leading to rebleeding despite initial hemostasis.	('PVTT', 'Phenotype', 'HP:0030242', (23, 27))	('rebleeding', 'Disease', (135, 145))	('leading to', 'Reg', (124, 134))	('HCC', 'Gene', (3, 6))	('elevation', 'PosReg', (89, 98))	('varices', 'Disease', (47, 54))	('HCC', 'Gene', '619501', (3, 6))	('portal vein pressure', 'MPA', (102, 122))	('PVTT in', 'Var', (23, 30))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('exacerbated', 'PosReg', (59, 70))	('patients', 'Species', '9606', (7, 15))
252852	26911980	After initial hemostasis success using EVL, rebleeding-free survival was predicted by the presence of a PVTT in the main trunk influencing portal vein pressure, and overall survival was predicted by Child-Pugh class and AFP-L3 levels, which are not directly related to variceal severity, but rather reflect liver function and the malignant potential of the HCC a determinant of prognosis.	('presence', 'Var', (90, 98))	('HCC', 'Gene', (357, 360))	('portal vein pressure', 'MPA', (139, 159))	('Child', 'Species', '9606', (199, 204))	('PVTT', 'Phenotype', 'HP:0030242', (104, 108))	('AFP', 'Gene', (220, 223))	('HCC', 'Gene', '619501', (357, 360))	('HCC', 'Phenotype', 'HP:0001402', (357, 360))	('AFP', 'Gene', '174', (220, 223))	('rebleeding-free survival', 'CPA', (44, 68))	('EVL', 'Chemical', '-', (39, 42))	('influencing', 'Reg', (127, 138))
252859	26911980	A PVTT in the main portal trunk was predictive of rebleeding, and AFP-L3 levels and Child-Pugh class were predictive of overall survival.	('AFP', 'Gene', '174', (66, 69))	('portal trunk', 'Phenotype', 'HP:0025154', (19, 31))	('rebleeding', 'Disease', (50, 60))	('PVTT', 'Var', (2, 6))	('AFP', 'Gene', (66, 69))	('Child', 'Species', '9606', (84, 89))	('PVTT', 'Phenotype', 'HP:0030242', (2, 6))
253028	24206575	For COX-2, VEGF, cyclin D1, p53, E-cadherin and SCC-Ag, the results indicated that fixed-effects estimates and/or random effects estimate before and after the deletion of each study were similar at large, suggesting high stability of the meta-analysis results.	('p53', 'Gene', (28, 31))	('VEGF', 'Gene', (11, 15))	('cyclin D1', 'Gene', '595', (17, 26))	('E-cadherin', 'Gene', (33, 43))	('p53', 'Gene', '7157', (28, 31))	('E-cadherin', 'Gene', '999', (33, 43))	('SCC', 'Gene', (48, 51))	('VEGF', 'Gene', '7422', (11, 15))	('COX-2', 'Gene', (4, 9))	('SCC', 'Gene', '6317', (48, 51))	('deletion', 'Var', (159, 167))	('COX-2', 'Gene', '5743', (4, 9))	('cyclin D1', 'Gene', (17, 26))
253043	24206575	Among the four markers associated with limitless replicative potential, cylin D1 and p53 are the most consistently associated with OS.	('p53', 'Gene', (85, 88))	('OS', 'Chemical', '-', (131, 133))	('cylin D1', 'Var', (72, 80))	('p53', 'Gene', '7157', (85, 88))	('associated with', 'Reg', (115, 130))
253055	24206575	We further show that high CRP expression is significantly correlated with poor survival in EC.	('CRP', 'Gene', '1401', (26, 29))	('expression', 'MPA', (30, 40))	('CRP', 'Gene', (26, 29))	('high', 'Var', (21, 25))
253067	32850794	Of them, four TLR-related lncRNAs (AP000696.1, LINC00689, LINC00900, and AP000487.1) are significantly associated with the overall survival (OS) of ESCA patients, and utilizing this four-lncRNA signature is capable of stratifying patients into high-risk and low-risk groups with significantly different OS in the discovery set.	('LINC00900', 'Gene', '283143', (58, 67))	('AP000487.1', 'Var', (73, 83))	('LINC00900', 'Gene', (58, 67))	('patients', 'Species', '9606', (153, 161))	('LINC00689', 'Gene', (47, 56))	('ESCA', 'Phenotype', 'HP:0011459', (148, 152))	('ESCA', 'Disease', (148, 152))	('overall survival', 'MPA', (123, 139))	('patients', 'Species', '9606', (230, 238))	('associated with', 'Reg', (103, 118))	('AP000696.1', 'Var', (35, 45))	('LINC00689', 'Gene', '154822', (47, 56))
253091	32850794	To identify potential TLR-related lncRNA biomarkers for predicting OS, we performed feature selection for 357 lncRNAs in the TLR-related lncRNAs-mRNA network in the discovery set, and identified four TLR-related lncRNAs (AP000696.1, LINC00689, LINC00900, and AP000487.1) as optimal biomarkers, which were significantly associated with OS of ESCA patients (Table 2).	('AP000696.1', 'Var', (221, 231))	('LINC00689', 'Gene', '154822', (233, 242))	('AP000487.1', 'Var', (259, 269))	('patients', 'Species', '9606', (346, 354))	('ESCA', 'Phenotype', 'HP:0011459', (341, 345))	('ESCA', 'Disease', (341, 345))	('LINC00689', 'Gene', (233, 242))	('LINC00900', 'Gene', '283143', (244, 253))	('LINC00900', 'Gene', (244, 253))	('associated', 'Reg', (319, 329))
253092	32850794	Then these four TLR-related lncRNAs biomarkers were integrated into a signature using the linear sum of expression levels of lncRNAs biomarkers and the weights derived from multivariate Cox regression analysis as follows: four TLR-related lncRNAs signature (four-TLR-lncRNA signature) = (0.239 x expression level of AP000696.1) + (-0.240 x expression level of LINC00689) + (0.124 x expression level of LINC00900) + (0.239 x expression level of AP000487.1).	('LINC00900', 'Gene', (402, 411))	('LINC00689', 'Gene', '154822', (360, 369))	('LINC00689', 'Gene', (360, 369))	('0.239', 'Var', (288, 293))	('LINC00900', 'Gene', '283143', (402, 411))
253097	32850794	As shown in Figure 2C, three lncRNAs (AP000696.1, LINC00900, and AP000487.1) are associated with high-risk and are up-regulated expressed in high-risk patients, and one lncRNAs (LINC00689) tended to be a protective factor and is up-regulated in the low-risk group.	('LINC00689', 'Gene', '154822', (178, 187))	('LINC00900', 'Gene', '283143', (50, 59))	('up-regulated', 'PosReg', (115, 127))	('LINC00900', 'Gene', (50, 59))	('patients', 'Species', '9606', (151, 159))	('AP000696.1', 'Var', (38, 48))	('LINC00689', 'Gene', (178, 187))	('AP000487.1', 'Var', (65, 75))
253103	32850794	Three lncRNAs (AP000696.1, LINC00900, and AP000487.1) are risk factors, whereas the lncRNAs LINC00689 is a protective factor.	('LINC00900', 'Gene', '283143', (27, 36))	('LINC00900', 'Gene', (27, 36))	('LINC00689', 'Gene', (92, 101))	('AP000487.1', 'Var', (42, 52))	('LINC00689', 'Gene', '154822', (92, 101))	('AP000696.1', 'Var', (15, 25))
253108	32850794	Three lncRNAs (AP000696.1, LINC00900 and AP000487.1) are risk factors, whereas the lncRNAs LINC00689 is a protective factor.	('LINC00900', 'Gene', '283143', (27, 36))	('LINC00689', 'Gene', '154822', (91, 100))	('LINC00900', 'Gene', (27, 36))	('LINC00689', 'Gene', (91, 100))	('AP000487.1', 'Var', (41, 51))	('AP000696.1', 'Var', (15, 25))
253116	32850794	To further explore potential clinical implication of TLR-related lncRNAs in ESCA, we performed LASSO analysis for feature selection and identified four prognostic lncRNAs (AP000696.1, LINC00689, LINC00900, and AP000487.1) from the lists of 357 TLR-related lncRNAs.	('ESCA', 'Phenotype', 'HP:0011459', (76, 80))	('LINC00689', 'Gene', '154822', (184, 193))	('AP000696.1', 'Var', (172, 182))	('ESCA', 'Disease', (76, 80))	('LINC00900', 'Gene', '283143', (195, 204))	('LINC00900', 'Gene', (195, 204))	('LINC00689', 'Gene', (184, 193))
253129	32148661	Cisplatin-Based Chemotherapy of Human Cancers Cisplatin (cis-diammine-dichloro-platinum II) was initially discovered to prevent the growth of Escherichia coli and was further recognized for its anti-neoplastic and cytotoxic effects on cancer cells.	('Cisplatin', 'Var', (46, 55))	('Cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('prevent', 'NegReg', (120, 127))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('cis-diammine-dichloro-platinum II', 'Chemical', 'MESH:D002945', (57, 90))	('Cancers', 'Phenotype', 'HP:0002664', (38, 45))	('Cancers', 'Disease', (38, 45))	('Cancers', 'Disease', 'MESH:D009369', (38, 45))	('growth', 'MPA', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('Escherichia coli', 'Species', '562', (142, 158))	('Human', 'Species', '9606', (32, 37))
253151	32148661	Evidence from tissue culture studies reveals that drug resistance may stem from epigenetic modifications at both cellular and molecular levels; including high levels of DNA damage repair (DDR), modifications in DNA methylation progress, uprooted and low regulation of mRNA expression levels, impairment in transcriptional regulation, and interference with apoptosis.	('impairment', 'NegReg', (292, 302))	('low', 'NegReg', (250, 253))	('stem from', 'Reg', (70, 79))	('drug resistance', 'Phenotype', 'HP:0020174', (50, 65))	('uprooted', 'PosReg', (237, 245))	('apoptosis', 'CPA', (356, 365))	('modifications', 'Var', (194, 207))	('drug', 'Disease', (50, 54))	('mRNA expression levels', 'MPA', (268, 290))	('DNA methylation progress', 'Gene', (211, 235))	('interference', 'NegReg', (338, 350))	('transcriptional regulation', 'MPA', (306, 332))	('men', 'Species', '9606', (298, 301))	('DNA damage repair', 'MPA', (169, 186))
253154	32148661	Moreover, once ATM is activated it maintains and phosphorylates tumor suppressor gene p53 which may induce transactivation of several genes inclusing p21 gene responsible for cell cycle growth arrest, DNA damage inducible gene 45 (GADD45) involved in DNA repair, and Bax to facilitate in apoptosis.	('ATM', 'Gene', '472', (15, 18))	('arrest', 'Disease', 'MESH:D006323', (193, 199))	('GADD45', 'Gene', '1647', (231, 237))	('p21', 'Gene', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('p21', 'Gene', '644914', (150, 153))	('GADD45', 'Gene', (231, 237))	('p53', 'Gene', '7157', (86, 89))	('p53', 'Gene', (86, 89))	('ATM', 'Gene', (15, 18))	('arrest', 'Disease', (193, 199))	('tumor', 'Disease', (64, 69))	('phosphorylates', 'Var', (49, 63))	('transactivation', 'MPA', (107, 122))	('Bax', 'Gene', (267, 270))	('growth arrest', 'Phenotype', 'HP:0001510', (186, 199))	('apoptosis', 'CPA', (288, 297))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Bax', 'Gene', '581', (267, 270))
253187	32148661	However, cisplatin is also known to induce unfavorable side effects and drug resistance, especially after long-term exposure.	('cisplatin', 'Var', (9, 18))	('drug resistance', 'CPA', (72, 87))	('drug resistance', 'Phenotype', 'HP:0020174', (72, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))
253208	32148661	In addition, refusal of cisplatin in PC3 cell lines is assumed to be due to the mutation and/or the nonoperation of p53 gene.	('p53', 'Gene', (116, 119))	('PC3', 'CellLine', 'CVCL:0035', (37, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))	('mutation', 'Var', (80, 88))	('p53', 'Gene', '7157', (116, 119))
253470	27579034	Procedures were performed using a single-channel upper gastrointestinal endoscope with a water-jet system (GIF-Q260J; Olympus).	('upper gastrointestinal endoscope', 'Disease', (49, 81))	('Q260J', 'SUBSTITUTION', 'None', (111, 116))	('water', 'Chemical', 'MESH:D014867', (89, 94))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (49, 81))	('Q260J', 'Var', (111, 116))
253477	24433541	STMN-1 is a potential marker of lymph node metastasis in distal esophageal adenocarcinomas and silencing its expression can reverse malignant phenotype of tumor cells Distal esophageal adenocarcinoma is a highly aggressive neoplasm.	('aggressive neoplasm', 'Disease', (212, 231))	('tumor', 'Disease', (155, 160))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (174, 199))	('silencing', 'Var', (95, 104))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (174, 199))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('aggressive neoplasm', 'Disease', 'MESH:D001523', (212, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (64, 90))	('esophageal adenocarcinoma', 'Disease', (174, 199))	('esophageal adenocarcinomas', 'Disease', (64, 90))	('STMN-1', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('STMN-1', 'Gene', '3925', (0, 6))	('expression', 'MPA', (109, 119))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (64, 89))	('neoplasm', 'Phenotype', 'HP:0002664', (223, 231))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (64, 89))
253483	24433541	Lentivirus-mediated RNAi was employed to knock-down STMN-1 expression in Human esophageal adenocarcinoma cells.	('STMN-1', 'Gene', (52, 58))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('knock-down', 'Var', (41, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('expression', 'MPA', (59, 69))	('esophageal adenocarcinoma', 'Disease', (79, 104))	('Human', 'Species', '9606', (73, 78))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))
253489	24433541	Esophageal adenocarcinoma cells stably transfected with STMN-1 shRNA significantly reduced tumor xenografts volume in vivo.	('Esophageal adenocarcinoma', 'Disease', (0, 25))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (0, 25))	('reduced', 'NegReg', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('STMN-1', 'Var', (56, 62))	('tumor', 'Disease', (91, 96))
253527	24433541	STMN-1 protein expression was higher in node positive vs. node negative specimen (P = 0.001) and locally advanced (T3 + T4a) versus minimally advanced (T1 + T2) distal esophageal adenocarcinoma (P = 0.004) but there was no positive correlation with other clinicopathological characteristics.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (168, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('higher', 'PosReg', (30, 36))	('men', 'Species', '9606', (77, 80))	('esophageal adenocarcinoma', 'Disease', (168, 193))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (168, 193))	('STMN-1', 'Gene', (0, 6))	('T3 + T4a', 'Var', (115, 123))
253538	24433541	Cell migration was evaluated in the Boyden migration assay two days after esophageal adenocarcinoma cells were transfected with Non-silencing shRNA infected cells or STMN1shRNA.	('STMN1shRNA', 'Var', (166, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (74, 99))	('esophageal adenocarcinoma', 'Disease', (74, 99))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (74, 99))
253541	24433541	The Flow cytometery results demonstrated that, STMN-1 shRNA treated cells induce an accumulation of esophageal adenocarcinoma cells in the G1/S phase of the cell cycle (Figure 4C, D).	('STMN-1', 'Var', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (100, 125))	('accumulation', 'PosReg', (84, 96))	('esophageal adenocarcinoma', 'Disease', (100, 125))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (100, 125))
253542	24433541	These results demonstrate that knockdown of STMN-1 induces G1/S phase arrest in esophageal adenocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (80, 105))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('induces', 'Reg', (51, 58))	('G1/S phase arrest', 'CPA', (59, 76))	('STMN-1', 'Gene', (44, 50))	('knockdown', 'Var', (31, 40))	('esophageal adenocarcinoma', 'Disease', (80, 105))
253543	24433541	These data indicated that knockdown of STMN-1 expression induced apoptosis in the esophageal adenocarcinoma cells.	('STMN-1 expression', 'Gene', (39, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (82, 107))	('esophageal adenocarcinoma', 'Disease', (82, 107))	('apoptosis', 'CPA', (65, 74))	('knockdown', 'Var', (26, 35))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (82, 107))
253545	24433541	Esophageal adenocarcinoma cells infected with non-silencing shRNA and STMN1 shRNA or untreated were injected into mice, (Figure 6C, D).	('Esophageal adenocarcinoma', 'Disease', (0, 25))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (0, 25))	('STMN1', 'Var', (70, 75))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('mice', 'Species', '10090', (114, 118))	('non-silencing', 'Var', (46, 59))
253546	24433541	These results demonstrate that in vivo tumor growth was inhibited by shRNA-mediated knockdown of STMN-1 expression in esophageal adenocarcinoma cells.	('esophageal adenocarcinoma', 'Disease', (118, 143))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (118, 143))	('STMN-1', 'Gene', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('knockdown', 'Var', (84, 93))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (118, 143))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tumor', 'Disease', (39, 44))	('inhibited', 'NegReg', (56, 65))
253562	24433541	We found that stable knockdown of STMN-1 led to reduced proliferation rates and migration in vitro, and decreased in vivo tumorigenicity.	('reduced', 'NegReg', (48, 55))	('decreased', 'NegReg', (104, 113))	('proliferation rates', 'CPA', (56, 75))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('migration in vitro', 'CPA', (80, 98))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('STMN-1', 'Gene', (34, 40))	('knockdown', 'Var', (21, 30))	('tumor', 'Disease', (122, 127))
253563	24433541	Apoptosis, is a carefully regulated process that can be induced by a variety of stimuli, including programmed tissue remodeling, cell detachment (anoikis), genomic damage, hypoxia, signaling pathway derangement, growth factor or cytokine limitations, and infection.	('men', 'Species', '9606', (140, 143))	('signaling', 'Pathway', (181, 190))	('Apoptosis', 'Disease', (0, 9))	('hypoxia', 'Disease', 'MESH:D000860', (172, 179))	('cell detachment', 'CPA', (129, 144))	('infection', 'Disease', (255, 264))	('infection', 'Disease', 'MESH:D007239', (255, 264))	('hypoxia', 'Disease', (172, 179))	('derangement', 'Var', (199, 210))	('men', 'Species', '9606', (206, 209))
253564	24433541	Dysregulation of apoptosis contributes to the development of cancer, as decreased rates of cell death facilitate an overall increase in cell number.	('increase', 'PosReg', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Dysregulation', 'Var', (0, 13))	('decreased', 'NegReg', (72, 81))	('cancer', 'Disease', (61, 67))	('apoptosis', 'CPA', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('men', 'Species', '9606', (53, 56))	('rates', 'MPA', (82, 87))	('cell number', 'CPA', (136, 147))
253575	24433541	STMN-1 is an indicator of lymph node metastasis in distal esophageal adenocarcinomas and its silencing reverses the malignant biological behavior in esophageal adenocarcinoma cells.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (149, 174))	('silencing', 'Var', (93, 102))	('esophageal adenocarcinoma', 'Disease', (149, 174))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (149, 174))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (58, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('malignant biological', 'CPA', (116, 136))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (58, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (58, 83))	('esophageal adenocarcinomas', 'Disease', (58, 84))
253582	24433541	The potential outcome of STMN-1 inhibition in cancer therapy is promising, Our clinical data shows that increased STMN-1 expression is associated with more aggressive disease, Thus, STMN-1 is an indicator of lymph node metastasis in distal esophageal adenocarcinomas and it has oncogenic effects in cell lines and xenografts.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('aggressive disease', 'Disease', 'MESH:D001523', (156, 174))	('increased', 'PosReg', (104, 113))	('cancer', 'Disease', (46, 52))	('STMN-1', 'Gene', (114, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (240, 265))	('aggressive disease', 'Disease', (156, 174))	('expression', 'MPA', (121, 131))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (240, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('associated', 'Reg', (135, 145))	('STMN-1', 'Var', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('esophageal adenocarcinomas', 'Disease', (240, 266))
253585	24433541	Further investigations are required to test which routes of delivery (e.g., direct intratumoral injections or systemic administration) of STMN-1 shRNA would be most efficient for esophageal cancer therapy.	('esophageal cancer', 'Disease', (179, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('STMN-1', 'Var', (138, 144))	('tumor', 'Disease', (88, 93))
253712	16515704	Since TD5/5 (prediction radiation-dose of normal tissue complication probability at 5% within 5 years after radiotherapy) of the stomach is 60 Gy and since one of our patients died of necrosis of the stomach, which had been used for thoracic esophageal substitution, 6 months after the end of 66 Gy radiotherapy, we avoid irradiation to the gastric tube with a total dose of more than 60 Gy.	('TD5/5', 'Var', (6, 11))	('patients', 'Species', '9606', (167, 175))	('gastric tube', 'Disease', 'MESH:D013274', (341, 353))	('gastric tube', 'Disease', (341, 353))	('necrosis', 'Disease', (184, 192))	('necrosis', 'Disease', 'MESH:D009336', (184, 192))
253743	33880577	Notably, U0126, a specific MEK inhibitor, decreased MEK and ERK expression, and blocked the promotive effects of BANCR overexpression on the proliferation, migration and invasion of ESCC cells.	('BANCR', 'Gene', (113, 118))	('blocked', 'NegReg', (80, 87))	('expression', 'MPA', (64, 74))	('decreased', 'NegReg', (42, 51))	('MEK', 'Gene', (27, 30))	('MEK', 'Gene', '5609', (27, 30))	('ERK', 'Gene', '5594', (60, 63))	('migration', 'CPA', (156, 165))	('U0126', 'Chemical', 'MESH:C113580', (9, 14))	('ERK', 'Gene', (60, 63))	('proliferation', 'CPA', (141, 154))	('BANCR', 'Gene', '100885775', (113, 118))	('MEK', 'Gene', (52, 55))	('MEK', 'Gene', '5609', (52, 55))	('promotive', 'MPA', (92, 101))	('U0126', 'Var', (9, 14))	('invasion', 'CPA', (170, 178))
253750	33880577	lncRNAs serve a crucial role in a variety of processes in diseases, and their alterations are recognized as drivers or suppressors for cancer progression, including ESCC.	('cancer', 'Disease', (135, 141))	('ESCC', 'Disease', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('alterations', 'Var', (78, 89))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
253756	33880577	It has been reported that BANCR mediates ESCC progression by regulating insulin-like growth factor 1 receptor expression via microRNA-338-3p.	('regulating', 'Reg', (61, 71))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (72, 109))	('microRNA-338-3p', 'Var', (125, 140))	('BANCR', 'Gene', '100885775', (26, 31))	('ESCC', 'Disease', (41, 45))	('insulin-like growth factor 1 receptor', 'Gene', (72, 109))	('expression', 'MPA', (110, 120))	('BANCR', 'Gene', (26, 31))
253804	33880577	In contrast to BANCR overexpression, BANCR silencing significantly suppressed the viability and proliferative ability of Eca-109 cells (Fig.	('BANCR', 'Gene', '100885775', (37, 42))	('BANCR', 'Gene', '100885775', (15, 20))	('silencing', 'Var', (43, 52))	('BANCR', 'Gene', (15, 20))	('BANCR', 'Gene', (37, 42))	('viability', 'CPA', (82, 91))	('suppressed', 'NegReg', (67, 77))	('proliferative ability', 'CPA', (96, 117))
253812	33880577	In addition, U0126 treatment significantly suppressed the viability and proliferative ability of Eca-109 cells transfected with BANCR (Fig.	('proliferative ability', 'CPA', (72, 93))	('BANCR', 'Gene', '100885775', (128, 133))	('viability', 'CPA', (58, 67))	('U0126', 'Var', (13, 18))	('BANCR', 'Gene', (128, 133))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))	('suppressed', 'NegReg', (43, 53))
253816	33880577	At present, a variety of lncRNAs have been identified as master regulators of gene expression, and their alterations drive or impede cancer progression.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('drive', 'Reg', (117, 122))	('cancer', 'Disease', (133, 139))	('alterations', 'Var', (105, 116))	('impede', 'NegReg', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
253832	33880577	In the current study, U0126, a specific MEK inhibitor, decreased MEK and ERK expression, and blocked the promotive effects of BANCR overexpression on the proliferation, migration and invasion of ESCC cells.	('blocked', 'NegReg', (93, 100))	('MEK', 'Gene', '5609', (40, 43))	('expression', 'MPA', (77, 87))	('U0126', 'Var', (22, 27))	('ERK', 'Gene', (73, 76))	('MEK', 'Gene', (65, 68))	('migration', 'CPA', (169, 178))	('MEK', 'Gene', '5609', (65, 68))	('BANCR', 'Gene', '100885775', (126, 131))	('decreased', 'NegReg', (55, 64))	('U0126', 'Chemical', 'MESH:C113580', (22, 27))	('invasion', 'CPA', (183, 191))	('proliferation', 'CPA', (154, 167))	('BANCR', 'Gene', (126, 131))	('promotive', 'MPA', (105, 114))	('MEK', 'Gene', (40, 43))	('ERK', 'Gene', '5594', (73, 76))
253833	33880577	Overall, the present results strongly suggested that lncRNA BANCR accelerated proliferation, migration and invasion of ESCC cells via the Raf/MEK/ERK signaling pathway.	('ERK', 'Gene', '5594', (146, 149))	('migration', 'CPA', (93, 102))	('ERK', 'Gene', (146, 149))	('lncRNA', 'Var', (53, 59))	('Raf', 'Gene', '22882', (138, 141))	('MEK', 'Gene', (142, 145))	('MEK', 'Gene', '5609', (142, 145))	('BANCR', 'Gene', '100885775', (60, 65))	('proliferation', 'CPA', (78, 91))	('accelerated', 'PosReg', (66, 77))	('invasion', 'CPA', (107, 115))	('BANCR', 'Gene', (60, 65))	('Raf', 'Gene', (138, 141))
253840	31692873	To test if mtDNA defects are a contributing factor in ESCC, we used oncogenic stimuli such as ESCC carcinogen 4-nitroquinoline oxide (4-NQO) treatment, or expressing p53R175H oncogenic driver mutation.	('p53R175H', 'Var', (166, 174))	('4-nitroquinoline oxide', 'Chemical', 'MESH:D015112', (110, 132))	('ESCC', 'Disease', (54, 58))	('ESCC', 'Disease', 'MESH:C562729', (94, 98))	('ESCC', 'Disease', 'MESH:C562729', (54, 58))	('4-NQO', 'Chemical', 'MESH:D015112', (134, 139))	('ESCC', 'Disease', (94, 98))
253842	31692873	Our studies show that mtDNA copy number depletion, activates a mitochondrial retrograde response, potentiates telomere defects, and increases the oncogenic susceptibility towards ESCC.	('telomere defects', 'MPA', (110, 126))	('ESCC', 'Disease', 'MESH:C562729', (179, 183))	('activates', 'PosReg', (51, 60))	('ESCC', 'Disease', (179, 183))	('oncogenic susceptibility', 'CPA', (146, 170))	('mtDNA', 'Gene', (22, 27))	('increases', 'PosReg', (132, 141))	('potentiates', 'PosReg', (98, 109))	('copy number depletion', 'Var', (28, 49))	('mitochondrial retrograde response', 'MPA', (63, 96))
253848	31692873	The most prevalent genetic alterations identified in ESCC include TP53R175H or EGFR mutations.	('ESCC', 'Disease', (53, 57))	('EGFR', 'Gene', (79, 83))	('prevalent', 'Reg', (9, 18))	('EGFR', 'Gene', '13649', (79, 83))	('TP53R175H', 'Var', (66, 75))	('ESCC', 'Disease', 'MESH:C562729', (53, 57))
253853	31692873	Mitochondrial (mt) DNA mutations, deletions or impaired mtDNA replication are common causes of mitochondrial dysfunction.	('mtDNA', 'Gene', (56, 61))	('mitochondrial dysfunction', 'Disease', (95, 120))	('deletions', 'Var', (34, 43))	('mutations', 'Var', (23, 32))	('impaired', 'NegReg', (47, 55))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (95, 120))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (95, 120))
253856	31692873	It is established that mitochondrial dysfunction resulting from mutations in mtDNA, and nuclear DNA encoded genes for mitochondrial proteins, are associated with various types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('mtDNA', 'Gene', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (23, 48))	('mutations', 'Var', (64, 73))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (23, 48))	('associated', 'Reg', (146, 156))	('mitochondrial dysfunction', 'Disease', (23, 48))
253857	31692873	However, the contribution of mtDNA copy number reduction in the initiation or progression of ESCC remains unclear.	('reduction', 'NegReg', (47, 56))	('ESCC', 'Disease', 'MESH:C562729', (93, 97))	('mtDNA', 'Gene', (29, 34))	('ESCC', 'Disease', (93, 97))	('copy number', 'Var', (35, 46))
253858	31692873	To determine the role of dysfunctional mitochondria in ESCC progression, we utilized two different mouse models of mtDNA depletion: 1) MPV17-/- which contains tissue-specific mtDNA depletion and 2) Tfam-/+ mice.	('dysfunctional mitochondria', 'Disease', (25, 51))	('MPV17-/-', 'Var', (135, 143))	('mouse', 'Species', '10090', (99, 104))	('Tfam', 'Gene', '21780', (198, 202))	('mice', 'Species', '10090', (206, 210))	('ESCC', 'Disease', 'MESH:C562729', (55, 59))	('Tfam', 'Gene', (198, 202))	('dysfunctional mitochondria', 'Disease', 'MESH:C565498', (25, 51))	('ESCC', 'Disease', (55, 59))
253860	31692873	Loss of MPV17 (MPV17-/-) causes mtDNA depletion and impairs oxidative phosphorylation (OXPHOS) in humans and mice, while the heterozygous (MPV17+/-) mice have mtDNA content and mitochondrial functions comparable to the wild type mice.	('MPV17', 'Gene', (8, 13))	('mtDNA', 'MPA', (32, 37))	('depletion', 'NegReg', (38, 47))	('oxidative phosphorylation', 'MPA', (60, 85))	('mice', 'Species', '10090', (149, 153))	('humans', 'Species', '9606', (98, 104))	('impairs', 'NegReg', (52, 59))	('mice', 'Species', '10090', (229, 233))	('Loss', 'Var', (0, 4))	('mice', 'Species', '10090', (109, 113))
253867	31692873	We observed that primary cells and 3D organoids derived from esophageal epithelia of mice containing partial mitochondrial DNA (mtDNA) depletion shows the activation of the mitochondrial retrograde signaling (MtRS) pathway and cellular alterations that resemble oncogenic transition.	('mice', 'Species', '10090', (85, 89))	('depletion', 'Var', (135, 144))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (61, 81))	('cellular alterations', 'CPA', (227, 247))	('partial', 'Var', (101, 108))	('activation', 'PosReg', (155, 165))
253868	31692873	In the MPV17-/- model of mtDNA depletion we observed telomere defects and chromosomal defects typical of tumor cells.	('chromosomal defects', 'Disease', 'MESH:D002869', (74, 93))	('telomere defects', 'CPA', (53, 69))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('chromosomal defects', 'Disease', (74, 93))	('tumor', 'Disease', (105, 110))	('MPV17-/-', 'Var', (7, 15))
253871	31692873	We harvested the esophagi from either wild type mice (WT, MPV17+/+), MPV17 heterozygotes (+/-) and homozygous knockout (-/-) mice (genotype shown in Supplementary Figure 1A).	('mice', 'Species', '10090', (48, 52))	('MPV17+/+', 'Var', (58, 66))	('MPV17', 'Var', (69, 74))	('mice', 'Species', '10090', (125, 129))
253873	31692873	The EECs in MPV17-/- show 80% reduction in mtDNA content compared to WT (Figure 1A), whereas, the mtDNA content of EECs in MPV17+/- mice is similar to WT mice.	('MPV17-/-', 'Var', (12, 20))	('mice', 'Species', '10090', (154, 158))	('mtDNA content', 'MPA', (43, 56))	('mice', 'Species', '10090', (132, 136))	('reduction', 'NegReg', (30, 39))
253876	31692873	We further tested the contribution of mitochondrial stress in ESCC progression using human esophageal (epithelial) keratinocyte cell line EPC2-hTERT (EPC2) and EPC2-hTERT cells expressing the most prevalent ESCC mutation in gene TP53R175H.	('ESCC', 'Disease', (207, 211))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (138, 148))	('ESCC', 'Disease', (62, 66))	('ESCC', 'Disease', 'MESH:C562729', (62, 66))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (160, 170))	('mutation', 'Var', (212, 220))	('EPC2-hTERT (EPC2', 'CellLine', 'CVCL:4361', (138, 154))	('ESCC', 'Disease', 'MESH:C562729', (207, 211))	('tested', 'Reg', (11, 17))	('TP53R175H', 'Gene', (229, 238))	('human', 'Species', '9606', (85, 90))
253878	31692873	The esophageal epithelial cells (EECs) from WT and MPV17 +/- or MPV17-/- mice were harvested and enzymatically dissociated into single cells and grown either as two-dimensional cultures, or were suspended in Matrigel  as detailed in Materials and Methods to generate 3D organoids.	('mice', 'Species', '10090', (73, 77))	('MPV17 +/-', 'Var', (51, 60))	('MPV17-/-', 'Var', (64, 72))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (4, 24))
253883	31692873	Interestingly, EPC2 cells expressing oncogenic TP53R175H mutation, exhibit similar morphological and actin reorganization as observed in mtDNA-depleted EPC2 cells suggesting that mtDNA depletion-induced mitochondrial stress mimics the oncogenic cellular transformation induced by tumor suppressor gene mutations in ESCC.	('ESCC', 'Disease', 'MESH:C562729', (315, 319))	('mutations', 'Var', (302, 311))	('TP53R175H', 'Var', (47, 56))	('ESCC', 'Disease', (315, 319))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumor', 'Disease', (280, 285))	('oncogenic cellular transformation', 'CPA', (235, 268))
253887	31692873	We observed that MPV17 -/- animals did not develop any tumors in vivo and there are no reports from other laboratories of spontaneous tumors in MPV17-/- mice.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MPV17', 'Var', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('mice', 'Species', '10090', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
253891	31692873	We observed that MPV17-/- animals exhibited loss of body weight (nearly 20%) while there was no significant weight loss in either the WT or MPV17-/+ mice suggesting that 4NQO treatment had substantially higher deleterious effects on the MPV17-/- mice (Supplementary Figure 5A).	('weight loss', 'Disease', 'MESH:D015431', (108, 119))	('loss', 'NegReg', (44, 48))	('MPV17-/-', 'Var', (17, 25))	('mice', 'Species', '10090', (149, 153))	('body weight', 'CPA', (52, 63))	('weight loss', 'Disease', (108, 119))	('weight loss', 'Phenotype', 'HP:0001824', (108, 119))	('4NQO', 'Chemical', 'MESH:D015112', (170, 174))	('mice', 'Species', '10090', (246, 250))
253892	31692873	There were visible lesions in the esophagus of the MPV17-/- mice while no abnormality was observed in esophagus in WT or MPV17-/+ mice.	('mice', 'Species', '10090', (130, 134))	('abnormality', 'Disease', (74, 85))	('abnormality', 'Disease', 'MESH:D002869', (74, 85))	('mice', 'Species', '10090', (60, 64))	('MPV17-/-', 'Var', (51, 59))
253893	31692873	Histopathological analysis of the esophageal sections indicated pre-cancerous lesions including esophageal hyperplasia and dysplasia in MPV17-/- mice without any abnormality in esophagi of WT mice.	('cancerous lesions', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mice', 'Species', '10090', (192, 196))	('esophageal hyperplasia and dysplasia', 'Disease', 'MESH:D004941', (96, 132))	('abnormality', 'Disease', (162, 173))	('cancerous lesions', 'Disease', 'MESH:D009369', (68, 85))	('abnormality', 'Disease', 'MESH:D002869', (162, 173))	('MPV17-/-', 'Var', (136, 144))	('abnormality in esophagi', 'Phenotype', 'HP:0002031', (162, 185))	('mice', 'Species', '10090', (145, 149))
253894	31692873	Mild hyperplasia with basal layer activity and some minor dysplasia indicated by a mild cell polarization alteration, some hyperchromatic nuclei and mild changes in nuclear size and shape were observed in MPV17-/- mouse esophagi (Supplementary Figure 5B).	('minor', 'CPA', (52, 57))	('cell polarization alteration', 'CPA', (88, 116))	('MPV17-/-', 'Var', (205, 213))	('dysplasia', 'Disease', (58, 67))	('nuclear size', 'CPA', (165, 177))	('hyperchromatic nuclei', 'Disease', 'MESH:C566014', (123, 144))	('hyperplasia', 'Disease', (5, 16))	('changes', 'Reg', (154, 161))	('basal layer activity', 'CPA', (22, 42))	('mouse', 'Species', '10090', (214, 219))	('dysplasia', 'Disease', 'MESH:D015792', (58, 67))	('hyperplasia', 'Disease', 'MESH:D006965', (5, 16))	('hyperchromatic nuclei', 'Disease', (123, 144))
253896	31692873	H&E staining of the organoid cross sections demonstrate that MPV17-/- organoids have dysplastic mucosa consistent with neoplastic transformation (Figure 2C).	('neoplastic transformation', 'Disease', 'MESH:D002471', (119, 144))	('have dysplastic', 'CPA', (80, 95))	('that', 'Var', (56, 60))	('neoplastic transformation', 'Disease', (119, 144))
253900	31692873	The mitochondrial retrograde signaling (MtRS) pathway can be triggered by mtDNA depletion or by loss of nuclear encoded mitochondrial electron transport chain protein CcOIVi1,.	('CcOIVi1', 'Gene', (167, 174))	('CcO', 'Chemical', 'MESH:C066468', (167, 170))	('triggered', 'Reg', (61, 70))	('loss', 'NegReg', (96, 100))	('depletion', 'Var', (80, 89))
253902	31692873	In response to 4NQO treatment, we observed increased levels of MtRS factors IGF-1R, hnRNPA2, phospho-hnRNPA2 and reduced CcOIVi1 in MPV17-/- organoids compared to WT organoids (Figure 3A).	('CcOIVi1', 'MPA', (121, 128))	('MPV17-/-', 'Var', (132, 140))	('hnRNPA2', 'Gene', '3181', (101, 108))	('IGF-1R', 'Gene', '16001', (76, 82))	('hnRNPA2', 'Gene', '3181', (84, 91))	('levels', 'MPA', (53, 59))	('CcO', 'Chemical', 'MESH:C066468', (121, 124))	('hnRNPA2', 'Gene', (101, 108))	('increased', 'PosReg', (43, 52))	('hnRNPA2', 'Gene', (84, 91))	('reduced', 'NegReg', (113, 120))	('IGF-1R', 'Gene', (76, 82))	('4NQO', 'Chemical', 'MESH:D015112', (15, 19))
253903	31692873	The mRNA levels for the MtRS markers, hnRNPA2 and TGFbeta and IGF1R protein level are higher in MPV17-/- EEC compared to WT (Figure 3B and 3C) suggesting that mitochondrial stress potentiates the effect of nuclear oncogenic mutations in eliciting an oncogenic response.	('protein level', 'MPA', (68, 81))	('mRNA levels', 'MPA', (4, 15))	('hnRNPA2', 'Gene', (38, 45))	('TGFbeta', 'Gene', (50, 57))	('eliciting', 'Reg', (237, 246))	('IGF1R', 'Gene', (62, 67))	('potentiates', 'PosReg', (180, 191))	('oncogenic response', 'CPA', (250, 268))	('IGF1R', 'Gene', '16001', (62, 67))	('TGFbeta', 'Gene', '21803', (50, 57))	('higher', 'PosReg', (86, 92))	('MPV17-/- EEC', 'Var', (96, 108))	('hnRNPA2', 'Gene', '3181', (38, 45))
253905	31692873	As expected, WT EECs expressing the oncogenic TP53R175H mutation showed remodeling of actin filaments exhibiting filopodia typically observed in cancer cells.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('actin filaments exhibiting filopodia', 'MPA', (86, 122))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('remodeling', 'MPA', (72, 82))	('TP53R175H', 'Var', (46, 55))
253906	31692873	Notably, both the MPV17-/- and MPV17-/-+ TP53R175H EECs undergo actin reorganization similar to migratory cancer cells (Figure 4A).	('MPV17-/-+ TP53R175H', 'Var', (31, 50))	('actin', 'MPA', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('TP53R175H', 'Var', (41, 50))	('cancer', 'Disease', (106, 112))	('undergo', 'Reg', (56, 63))	('MPV17-/-', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
253907	31692873	Based on our results above suggesting an oncogenic potential in MPV17-/- EECs, we assessed their invasive potential by an in vitro Matrigel  invasion assay which recapitulates the capacity of cells to invade through a Matrigel  layer enriched with components of the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('MPV17-/-', 'Var', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (266, 271))
253908	31692873	Furthermore, our Telo-FISH results in Figure 4C show that compared to WT mice, which showed normal telomeres, MPV17-/-+ TP53R175H primary EECs showed no significant reduction in telomere signals.	('telomere signals', 'MPA', (178, 194))	('MPV17-/-+ TP53R175H', 'Var', (110, 129))	('mice', 'Species', '10090', (73, 77))	('reduction', 'NegReg', (165, 174))
253909	31692873	This shows that mtDNA reduction combined with a nuclear oncogenic mutation induces severe telomere loss, which potentially can cause chromosomal aberrations frequently observed in ESCCs.	('telomere', 'MPA', (90, 98))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (133, 156))	('cause', 'Reg', (127, 132))	('reduction', 'NegReg', (22, 31))	('ESCC', 'Disease', 'MESH:C562729', (180, 184))	('loss', 'NegReg', (99, 103))	('mutation', 'Var', (66, 74))	('ESCC', 'Disease', (180, 184))
253916	31692873	Notably, reports show that inhibition of fission inhibits cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('inhibits', 'NegReg', (49, 57))	('inhibition', 'Var', (27, 37))	('fission', 'CPA', (41, 48))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
253917	31692873	In MPV17-/- EECs, we observed higher levels of the fission protein DRP1 (Figure 5B).	('DRP1', 'Gene', '74006', (67, 71))	('higher', 'PosReg', (30, 36))	('DRP1', 'Gene', (67, 71))	('levels', 'MPA', (37, 43))	('MPV17-/- EECs', 'Var', (3, 16))
253919	31692873	In agreement, MPV17-/- cells have reduced protein levels of the mitochondrial fusion marker, MFN1 (Figure 5C).	('MFN1', 'Gene', '67414', (93, 97))	('reduced', 'NegReg', (34, 41))	('MPV17-/-', 'Var', (14, 22))	('protein levels', 'MPA', (42, 56))	('MFN1', 'Gene', (93, 97))
253922	31692873	Mitochondrial genome defects have been associated with various aggressive cancers.	('aggressive cancers', 'Disease', (63, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('aggressive cancers', 'Disease', 'MESH:D009369', (63, 81))	('associated', 'Reg', (39, 49))	('defects', 'Var', (21, 28))	('Mitochondrial genome', 'Gene', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
253924	31692873	Reports show that mtDNA copy number changes including high or low, mtDNA mutations and deletions in tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('low', 'NegReg', (62, 65))	('deletions', 'Var', (87, 96))	('mtDNA', 'Gene', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (73, 82))
253925	31692873	In fact, frequent mtDNA mutations in the D-loop 4977 bp, a common deletion, was detected in 92% of esophageal tumors and as high as 182 mutations in the protein coding genes have been reported in human esophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('esophageal cancers', 'Disease', (202, 220))	('esophageal tumors', 'Disease', 'MESH:D004941', (99, 116))	('human', 'Species', '9606', (196, 201))	('esophageal cancers', 'Disease', 'MESH:D004938', (202, 220))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('esophageal tumors', 'Phenotype', 'HP:0100751', (99, 116))	('detected', 'Reg', (80, 88))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('esophageal tumors', 'Disease', (99, 116))	('mutations in', 'Var', (24, 36))	('mtDNA', 'Gene', (18, 23))
253927	31692873	Our prior studies have shown that mtDNA copy number depletion and dysfunctional mitochondria activate mitochondria to nucleus retrograde signaling (MtRS) pathway, which reprograms immortalized skeletal myoblasts into tumorigenic phenotype as well as contributes to the metastatic phenotype of cancers of the mammary, lung and osteosarcomas.	('activate', 'PosReg', (93, 101))	('osteosarcomas', 'Disease', 'MESH:D012516', (326, 339))	('tumor', 'Disease', (217, 222))	('lung', 'Disease', (317, 321))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('cancers', 'Phenotype', 'HP:0002664', (293, 300))	('osteosarcomas', 'Disease', (326, 339))	('cancers', 'Disease', (293, 300))	('dysfunctional mitochondria', 'Disease', 'MESH:C565498', (66, 92))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('mtDNA', 'Gene', (34, 39))	('osteosarcomas', 'Phenotype', 'HP:0002669', (326, 339))	('dysfunctional mitochondria', 'Disease', (66, 92))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('metastatic', 'CPA', (269, 279))	('mitochondria to nucleus retrograde signaling', 'Pathway', (102, 146))	('copy number depletion', 'Var', (40, 61))	('cancers', 'Disease', 'MESH:D009369', (293, 300))	('contributes', 'Reg', (250, 261))
253928	31692873	In this study, we demonstrate that mtDNA copy number depletion in murine primary esophageal epithelial cells can activate MtRS and result in oncogenic transformation.	('mtDNA', 'Gene', (35, 40))	('result in', 'Reg', (131, 140))	('oncogenic transformation', 'CPA', (141, 165))	('MtRS', 'CPA', (122, 126))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (81, 101))	('copy number depletion', 'Var', (41, 62))	('murine', 'Species', '10090', (66, 72))	('activate', 'PosReg', (113, 121))
253930	31692873	Alterations in these processes are frequently encountered in cancer, during both initiation and progression and alterations in mitochondrial dynamics is associated with cancer development.	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('associated', 'Reg', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mitochondrial dynamics', 'MPA', (127, 149))	('alterations', 'Var', (112, 123))	('Alterations', 'Reg', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
253932	31692873	Our results here showing that inhibition of mitochondrial fission by mDivi-1 reversed the cellular phenotype of the MPV17-/- cells, is in agreement with the dogma that increased mitochondrial fission is an adaptive mechanism of cancer cells and that pharmacologic inhibition of fission by mDivi-1 may prove therapeutically beneficial in ESCC patients.	('cancer', 'Disease', (228, 234))	('inhibition', 'Var', (30, 40))	('patients', 'Species', '9606', (342, 350))	('ESCC', 'Disease', 'MESH:C562729', (337, 341))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('ESCC', 'Disease', (337, 341))	('mitochondrial', 'MPA', (178, 191))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
253935	31692873	We observed preneoplastic transformations in the MPV17-/- esophageal epithelium in less than 8 weeks.	('neoplastic transformation', 'Disease', (15, 40))	('neoplastic transformation', 'Disease', 'MESH:D002471', (15, 40))	('MPV17-/-', 'Var', (49, 57))
253936	31692873	This shorter treatment duration required to induce carcinogenic alteration in MPV17-/- compared to the WT or MPV17-/+ mice suggests that mitochondrial dysfunction is an additive factor in potentiating the carcinogenic effect of 4NQO.	('4NQO', 'Chemical', 'MESH:D015112', (228, 232))	('carcinogenic alteration', 'Disease', (51, 74))	('MPV17-/-', 'Var', (78, 86))	('carcinogenic alteration', 'Disease', 'MESH:D004408', (51, 74))	('carcinogenic', 'Disease', 'MESH:D063646', (205, 217))	('potentiating', 'PosReg', (188, 200))	('carcinogenic', 'Disease', 'MESH:D063646', (51, 63))	('carcinogenic', 'Disease', (51, 63))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (137, 162))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (137, 162))	('mice', 'Species', '10090', (118, 122))	('mitochondrial dysfunction', 'Disease', (137, 162))	('carcinogenic', 'Disease', (205, 217))
253939	31692873	A study demonstrated that mtDNA haplotype influences mitochondrial dysfunction and associated aging parameters such as telomere attrition in conplastic mice.	('haplotype', 'Var', (32, 41))	('influences', 'Reg', (42, 52))	('telomere attrition', 'MPA', (119, 137))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (53, 78))	('mice', 'Species', '10090', (152, 156))	('mtDNA', 'Gene', (26, 31))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (53, 78))	('mitochondrial dysfunction', 'Disease', (53, 78))
254006	31069143	The median overall survival in VISTA positive patients was 84.6 months (95%CI 27.2-141.9 months) compared to 22.1 months (95%CI 15.1-29.0 months) in VISTA negative patients (p = 0.024).	('VISTA', 'Gene', (31, 36))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (164, 172))	('positive', 'Var', (37, 45))
254011	31069143	For the entire validation cohort, VISTA expression was associated with a prolonged overall survival with a median overall survival of 41.9 months (95%CI 18.0-65.9 months) vs. 25.7 months in VISTA negative patients (95% CI 19.1-32.3 months) (p = 0.046) (Figure 3(e)).	('overall survival', 'MPA', (83, 99))	('patients', 'Species', '9606', (205, 213))	('expression', 'Var', (40, 50))	('VISTA', 'Gene', (34, 39))	('prolonged', 'PosReg', (73, 82))
254020	31069143	No survival differences were observed for patients with low or high CD3 expression with respect to VISTA expression (Supplementary Figure 1).	('CD3', 'Gene', (68, 71))	('patients', 'Species', '9606', (42, 50))	('high', 'Var', (63, 67))
254024	31069143	In tumors with high VISTA expression 10 patients showed HER2 amplification, but a correlation via cross-table analysis did not reveal a significant association between VISTA and HER2 amplification (p = 0.236).	('high', 'Var', (15, 19))	('HER2', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('HER2', 'Gene', '2064', (56, 60))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('patients', 'Species', '9606', (40, 48))	('HER2', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('HER2', 'Gene', '2064', (178, 182))
254027	31069143	Furthermore, we do not find any correlation of VISTA with important molecular alterations like TP53 mutational status and HER2 amplification status, as well as with further important biomarkers of the tumor microenvironment like the number of T-cells (CD3) and previously examined LAG3 expression on TILs (Data are currently under revision).	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('LAG3', 'Gene', (281, 285))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('LAG3', 'Gene', '3902', (281, 285))	('HER2', 'Gene', (122, 126))	('HER2', 'Gene', '2064', (122, 126))	('tumor', 'Disease', (201, 206))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('mutational', 'Var', (100, 110))
254039	31069143	In oral squamous cell cancer, high VISTA expression in combination with low CD8 expression is associated with poor prognosis and lymph node metastases.	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (3, 28))	('oral squamous cell cancer', 'Disease', (3, 28))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (8, 28))	('metastases', 'Disease', (140, 150))	('high', 'Var', (30, 34))	('expression', 'MPA', (80, 90))	('CD8', 'Gene', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('CD8', 'Gene', '925', (76, 79))	('metastases', 'Disease', 'MESH:D009362', (140, 150))
254066	31069143	These data were statistically correlated with molecular data like TP53 mutational and the HER2 amplification status.	('HER2', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (66, 70))	('HER2', 'Gene', '2064', (90, 94))	('TP53', 'Gene', (66, 70))	('mutational', 'Var', (71, 81))
254092	30746370	Perioperative albumin level in the DGE group was lower than that in the control group (P < 0.05).	('DGE', 'Phenotype', 'HP:0002578', (35, 38))	('albumin', 'Gene', (14, 21))	('albumin', 'Gene', '213', (14, 21))	('lower', 'NegReg', (49, 54))	('DGE', 'Var', (35, 38))
254110	30746370	Postoperative DGE not only prolongs hospital stay and recovery time, but also increases the incidence of aspiration pneumonia.	('pneumonia', 'Phenotype', 'HP:0002090', (116, 125))	('aspiration pneumonia', 'Disease', (105, 125))	('aspiration', 'Phenotype', 'HP:0002835', (105, 115))	('recovery time', 'CPA', (54, 67))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (105, 125))	('DGE', 'Phenotype', 'HP:0002578', (14, 17))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (105, 125))	('prolongs', 'PosReg', (27, 35))	('increases', 'PosReg', (78, 87))	('DGE', 'Var', (14, 17))
254131	30746370	Among them, age, the intraoperative blood loss, chest drainage time, portion of anxiety score >= 45 points, portion of analgesia pump use, postoperative to enteral nutrition interval, and postoperative fluid volume in the DGE group were higher than those in the control group.	('analgesia', 'Disease', (119, 128))	('anxiety', 'Disease', 'MESH:D001008', (80, 87))	('analgesia', 'Disease', 'MESH:D000699', (119, 128))	('DGE', 'Var', (222, 225))	('chest drainage time', 'CPA', (48, 67))	('intraoperative blood loss', 'Disease', (21, 46))	('higher', 'PosReg', (237, 243))	('anxiety', 'Disease', (80, 87))	('anxiety', 'Phenotype', 'HP:0000739', (80, 87))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (21, 46))	('DGE', 'Phenotype', 'HP:0002578', (222, 225))
254132	30746370	The perioperative albumin level in the DGE group was lower than that in the control group.	('DGE', 'Var', (39, 42))	('albumin', 'Gene', (18, 25))	('albumin', 'Gene', '213', (18, 25))	('DGE', 'Phenotype', 'HP:0002578', (39, 42))	('lower', 'NegReg', (53, 58))
254146	30746370	The anxiety score of the DGE group was significantly higher than that of the control group.	('anxiety', 'Disease', (4, 11))	('higher', 'PosReg', (53, 59))	('DGE', 'Phenotype', 'HP:0002578', (25, 28))	('anxiety', 'Phenotype', 'HP:0000739', (4, 11))	('DGE', 'Var', (25, 28))	('anxiety', 'Disease', 'MESH:D001008', (4, 11))
254153	30746370	By comparing perioperative albumin levels between the DGE group and control group, it was found that albumin level was significantly lower in the DGE group.	('DGE', 'Var', (146, 149))	('albumin', 'Gene', '213', (27, 34))	('albumin', 'Gene', (27, 34))	('DGE', 'Phenotype', 'HP:0002578', (146, 149))	('DGE', 'Phenotype', 'HP:0002578', (54, 57))	('albumin', 'Gene', (101, 108))	('albumin', 'Gene', '213', (101, 108))	('lower', 'NegReg', (133, 138))
254240	27766787	In multivariate analyses for OS, GTV >= 60 cc (P = 0.00040), RDI < 50% (P = 0.00034), and cN2-3 (P = 0.0020) were associated with significantly worse OS.	('GTV >= 60 cc', 'Var', (33, 45))	('GTV', 'Chemical', '-', (33, 36))	('RDI < 50%', 'Var', (61, 70))	('OS', 'Chemical', '-', (29, 31))	('cN2-3', 'Var', (90, 95))	('OS', 'Chemical', '-', (150, 152))
254261	27766787	The explanatory variables included age (<68 vs. >=68 years), tumor length (>=5 cm vs. <5 cm), cT stage, cN stage, cM stage, GTV (>= 60cc vs. < 60cc), KPS (<90% vs. >=90%), histopathological type (SCC vs. other), and RDI (>=50% vs. <50%).	('SCC', 'Gene', (196, 199))	('>= 60cc', 'Var', (129, 136))	('SCC', 'Gene', '6317', (196, 199))	('cT stage', 'Disease', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('GTV', 'Chemical', '-', (124, 127))	('tumor', 'Disease', (61, 66))	('cN stage', 'Disease', (104, 112))
254274	27766787	GTV >= 60cc (hazard ratio [HR] 4.35; P = 0.00040), RDI <= 50% (HR 3.52; P = 0.00034), and cN-stage (HR 3.40; P = 0.0020) remained associated with significantly poor prognosis.	('RDI', 'MPA', (51, 54))	('cN-stage', 'CPA', (90, 98))	('GTV', 'Chemical', '-', (0, 3))	('GTV >= 60cc', 'Var', (0, 11))
254280	27766787	Tumor length was determined as a prognostic factor of EC.5, 6, 7, 8, 9, 10, 11, 12 Data from the Japanese esophageal carcinoma registration database between 1969 and 1980 demonstrated that the depth of tumor invasion correlated with the 10-year survival of EC patients more than the superficial extent of the tumor.6, 13 Recent publications have suggested that pathologic esophageal tumor length is directly correlated with long-term survival; however, most of these data originated in western countries, and the cancer type was predominantly adenocarcinoma.8, 11, 12, 14, 15, 16 The finding that GTV > 60 cc was associated with a significantly poor OS prognosis may be related to the fact that tumor length is a prognostic factor for survival.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (695, 700))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (106, 126))	('GTV', 'Chemical', '-', (597, 600))	('carcinoma', 'Phenotype', 'HP:0030731', (548, 557))	('cancer', 'Disease', 'MESH:D009369', (513, 519))	('esophageal tumor', 'Disease', (372, 388))	('esophageal tumor', 'Phenotype', 'HP:0100751', (372, 388))	('tumor', 'Disease', (202, 207))	('adenocarcinoma', 'Disease', (543, 557))	('OS', 'Chemical', '-', (650, 652))	('tumor', 'Phenotype', 'HP:0002664', (695, 700))	('patients', 'Species', '9606', (260, 268))	('tumor', 'Disease', (383, 388))	('poor', 'NegReg', (645, 649))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (309, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (383, 388))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (106, 126))	('esophageal tumor', 'Disease', 'MESH:D004938', (372, 388))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('GTV > 60 cc', 'Var', (597, 608))	('adenocarcinoma', 'Disease', 'MESH:D000230', (543, 557))	('cancer', 'Disease', (513, 519))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('esophageal carcinoma', 'Disease', (106, 126))	('tumor', 'Phenotype', 'HP:0002664', (383, 388))	('cancer', 'Phenotype', 'HP:0002664', (513, 519))	('tumor', 'Disease', (695, 700))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
254327	26801375	Cases with T1b and greater tumor depth, lymph node involvement, or metastatic disease at presentation were excluded.	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('T1b', 'Var', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
254339	26801375	EUS was identified from outpatient and physician-supplier files with the following CPT codes: 43231, 43232, 43242, 43259, 76975.	('43242', 'Var', (108, 113))	('43259', 'Var', (115, 120))	('outpatient', 'Species', '9606', (24, 34))	('43232', 'Var', (101, 106))	('43231', 'Var', (94, 99))	('76975', 'Var', (122, 127))
254341	26801375	Adverse events were identified using the following ICD-9-CM diagnosis codes and procedure codes (ICD-9-CM and CPT): hemorrhage complicating a procedure (998.1), accidental puncture or laceration during a procedure (998.2), retrieval of retained foreign body (CPT 49085; ICD-9 54.92), management of postoperative shock/hemorrhage (ICD-9 39.98), management of abdominal infection (CPT 49020, 49021, 49040, 49041, 49060, 49061, 49080, 49081, 75989; ICD-9 54.0, 54.91, 54.19), repair of an organ injury/laceration (CPT 38100, 44602, 44603; ICD-9 31.71, 33.41, 41.5, 42.82, 44.61, 46.71, 46.73, 50.61, 51.91), reoperative laparotomy (CPT 49002, 49000, 49010; ICD-9 54.12, 54.11, 54.21), management of wound adverse event (CPT 10060, 10061, 10120, 10121, 10140, 10180, 12020, 13160, 97601, 97602; ICD-9 54.61, 86.22), and management of bowel obstruction (CPT 44050).	('10180', 'Var', (756, 761))	('hemorrhage', 'Disease', 'MESH:D006470', (116, 126))	('postoperative shock/hemorrhage', 'Disease', 'MESH:D019106', (298, 328))	('postoperative shock/hemorrhage', 'Disease', (298, 328))	('CPT 10060', 'Var', (717, 726))	('organ injury', 'Disease', 'MESH:D019965', (486, 498))	('bowel obstruction', 'Disease', 'MESH:D015212', (830, 847))	('abdominal infection', 'Disease', (358, 377))	('abdominal infection', 'Disease', 'MESH:D015746', (358, 377))	('organ injury', 'Disease', (486, 498))	('bowel obstruction', 'Disease', (830, 847))	('hemorrhage', 'Disease', (318, 328))	('hemorrhage', 'Disease', 'MESH:D006470', (318, 328))	('bowel obstruction', 'Phenotype', 'HP:0005214', (830, 847))	('shock', 'Phenotype', 'HP:0031273', (312, 317))	('10120', 'Var', (735, 740))	('hemorrhage', 'Disease', (116, 126))	('CPT 44050', 'Var', (849, 858))
254345	26801375	Receipt of chemotherapy was identified from MedPAR, physician-supplier, and SAF files with the following codes: chemotherapy administration (99.25), antineoplastic chemotherapy encounter (V58.11), cancer chemotherapy follow-up (V67.2), convalescence and palliative care after chemotherapy (V66.2), outpatient or physician administration of chemotherapy (Q0083 - Q0085), chemotherapeutic agents (Healthcare Common Procedure Coding System codes J9000 - J9999), and revenue center codes (0331, 0332, 0335).	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('Q0083 - Q0085', 'Var', (354, 367))	('outpatient', 'Species', '9606', (298, 308))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('J9999', 'CellLine', 'CVCL:M891', (451, 456))	('SAF', 'Chemical', '-', (76, 79))
254368	26801375	A Cox model censoring patients dying within 60 days of the procedure developed to evaluate the impact of perioperative mortality on long-term survival demonstrated that endoscopic treatment was associated with decreased mortality through 2 years after adjusting for other factors (HR, 0.61; 95% CI, 0.45 - 0.85).	('patients', 'Species', '9606', (22, 30))	('decreased', 'NegReg', (210, 219))	('endoscopic treatment', 'Var', (169, 189))	('mortality', 'MPA', (220, 229))	('Cox', 'Gene', '1351', (2, 5))	('Cox', 'Gene', (2, 5))
254370	26801375	Among patients diagnosed between 2002 and 2009 (a time period accounting for most endoscopically treated cases), endoscopic treatment was associated with decreased mortality (HR, 0.51; 95% CI, 0.36 - 0.74) after adjusting for other factors.	('endoscopic treatment', 'Var', (113, 133))	('decreased', 'NegReg', (154, 163))	('patients', 'Species', '9606', (6, 14))	('mortality', 'MPA', (164, 173))
254437	24177052	NF-kappaB1 (p50) and NF-kappaB2 (p52) are generated by processing of the precursor proteins p105 and p100, respectively, and lack TADs but can positively regulate transcription by interacting with other proteins or negatively regulate transcription by competing for DNA binding.	('competing', 'Interaction', (252, 261))	('p52', 'Gene', '4791', (33, 36))	('TADs', 'Protein', (130, 134))	('DNA binding', 'Interaction', (266, 277))	('p105', 'Gene', '4790', (92, 96))	('p52', 'Gene', (33, 36))	('proteins', 'Protein', (203, 211))	('rat', 'Species', '10116', (46, 49))	('p50', 'Gene', '4790', (12, 15))	('regulate', 'Reg', (226, 234))	('p100', 'Var', (101, 105))	('positively', 'PosReg', (143, 153))	('transcription', 'MPA', (235, 248))	('p50', 'Gene', (12, 15))	('regulate', 'Reg', (154, 162))	('negatively', 'NegReg', (215, 225))	('transcription', 'MPA', (163, 176))	('p105', 'Gene', (92, 96))	('interacting', 'Interaction', (180, 191))
254463	24177052	PI3K and epidermal growth factor receptor (EGFR), which is overexpressed in about 90% of HNSCC, can also activate NF-kappaB signaling, leading to IL-8 and VEGF production.	('HNSCC', 'Phenotype', 'HP:0012288', (89, 94))	('NF-kappaB signaling', 'MPA', (114, 133))	('epidermal growth factor receptor', 'Gene', '1956', (9, 41))	('PI3K', 'Var', (0, 4))	('leading to', 'Reg', (135, 145))	('VEGF', 'Gene', (155, 159))	('EGFR', 'Gene', '1956', (43, 47))	('VEGF', 'Gene', '7422', (155, 159))	('SCC', 'Gene', (91, 94))	('IL-8', 'Gene', '3576', (146, 150))	('epidermal growth factor receptor', 'Gene', (9, 41))	('EGFR', 'Gene', (43, 47))	('activate', 'PosReg', (105, 113))	('IL-8', 'Gene', (146, 150))	('SCC', 'Gene', '6317', (91, 94))
254464	24177052	Ultimately, carcinogen and ROS related genetic and epigenetic alterations affecting upstream signaling leads to aberrant activation of IKK and NF-kappaB (Figure 1).	('genetic', 'Var', (39, 46))	('IKK', 'Protein', (135, 138))	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('activation', 'PosReg', (121, 131))	('rat', 'Species', '10116', (66, 69))	('NF-kappaB', 'Protein', (143, 152))	('epigenetic alterations', 'Var', (51, 73))
254478	24177052	CTAR2 activates the canonical NF-kappaB pathway by TRAF6-mediated IkappaBalpha phosphorylation, while CTAR1 activates the alternative pathway by inducing processing of p100 to p52.	('IkappaBalpha phosphorylation', 'MPA', (66, 94))	('TRAF6', 'Gene', (51, 56))	('processing', 'MPA', (154, 164))	('p100', 'Var', (168, 172))	('inducing', 'PosReg', (145, 153))	('TRAF6', 'Gene', '7189', (51, 56))	('p52', 'Gene', (176, 179))	('p52', 'Gene', '4791', (176, 179))	('CTAR2', 'Gene', (0, 5))	('activates', 'PosReg', (6, 15))	('CTAR1', 'Gene', (102, 107))	('alternative pathway', 'Pathway', (122, 141))
254498	24177052	show that genetic variants of the PI3K/PTEN/Akt/mTOR pathway can identify patients at high risk for SPT and predict response to 13-cRA.	('mTOR', 'Gene', '2475', (48, 52))	('Akt', 'Gene', '207', (44, 47))	('mTOR', 'Gene', (48, 52))	('predict', 'Reg', (108, 115))	('patients', 'Species', '9606', (74, 82))	('cRA', 'Gene', (131, 134))	('genetic variants', 'Var', (10, 26))	('Akt', 'Gene', (44, 47))	('PTEN', 'Gene', (39, 43))	('PTEN', 'Gene', '5728', (39, 43))	('cRA', 'Gene', '51747', (131, 134))	('SPT', 'Disease', (100, 103))
254500	24177052	EGFR amplification or phosphorylation is detected in over 90% of human HNSCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (65, 70))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('HNSCC tumors', 'Disease', (71, 83))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (71, 76))	('EGFR', 'Gene', '1956', (0, 4))	('phosphorylation', 'MPA', (22, 37))
254501	24177052	Additionally, EGFR overexpression or phosphorylation in HNSCC is associated with malignant transformation and poor clinical prognosis.	('overexpression', 'PosReg', (19, 33))	('SCC', 'Gene', (58, 61))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('HNSCC', 'Phenotype', 'HP:0012288', (56, 61))	('SCC', 'Gene', '6317', (58, 61))	('phosphorylation', 'Var', (37, 52))	('associated', 'Reg', (65, 75))	('malignant transformation', 'CPA', (81, 105))
254502	24177052	It is well-established that EGFR phosphorylation can stimulate NF-kappaB activity in head and neck cancer.	('head and neck cancer', 'Phenotype', 'HP:0012288', (85, 105))	('EGFR', 'Gene', '1956', (28, 32))	('stimulate', 'PosReg', (53, 62))	('activity', 'MPA', (73, 81))	('phosphorylation', 'Var', (33, 48))	('EGFR', 'Gene', (28, 32))	('neck cancer', 'Disease', (94, 105))	('neck cancer', 'Phenotype', 'HP:0012288', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('neck cancer', 'Disease', 'MESH:D006258', (94, 105))	('NF-kappaB', 'Protein', (63, 72))
254506	24177052	S536 is considered the most important site for p65 transactivation by IkappaB kinase beta of the classical IkappaB kinase complex.	('S536', 'Var', (0, 4))	('p65', 'Gene', (47, 50))	('IkappaB kinase beta', 'Gene', '3551', (70, 89))	('IkappaB kinase beta', 'Gene', (70, 89))	('transactivation', 'PosReg', (51, 66))	('p65', 'Gene', '5970', (47, 50))
254520	24177052	Their results show that while EGCG alone does not significantly affect expression of cell cycle regulatory proteins, when combined with erlotinib, EGCG treatment is able to decrease expression of p65 and many of its transcriptional targets.	('decrease', 'NegReg', (173, 181))	('transcriptional targets', 'MPA', (216, 239))	('expression', 'MPA', (182, 192))	('EGCG', 'Chemical', 'MESH:C045651', (147, 151))	('p65', 'Gene', (196, 199))	('EGCG', 'Chemical', 'MESH:C045651', (30, 34))	('erlotinib', 'Chemical', 'MESH:D000069347', (136, 145))	('EGCG', 'Var', (147, 151))	('p65', 'Gene', '5970', (196, 199))
254542	24177052	COX-2 inhibition can decrease proliferation and invasion of HNSCC cells and modulate the expression of proteins integral to angiogenesis and apoptosis in favoring chemoprevention.	('modulate', 'Reg', (76, 84))	('expression of', 'MPA', (89, 102))	('decrease', 'NegReg', (21, 29))	('SCC', 'Gene', '6317', (62, 65))	('proteins', 'Protein', (103, 111))	('rat', 'Species', '10116', (37, 40))	('HNSCC', 'Phenotype', 'HP:0012288', (60, 65))	('inhibition', 'Var', (6, 16))	('invasion', 'CPA', (48, 56))	('COX-2', 'Gene', (0, 5))	('proliferation', 'CPA', (30, 43))	('COX-2', 'Gene', '5743', (0, 5))	('SCC', 'Gene', (62, 65))
254568	24177052	Rapamycin also inhibited development of chemically induced skin and oral SCC, and HNSCC that develop spontaneously in genetically engineered KrasG12D/p53-/-, Pten-/-, or Pten-/-/Tgfbr1-/- mice in vivo.	('Tgfbr1', 'Gene', (178, 184))	('inhibited', 'NegReg', (15, 24))	('SCC', 'Gene', '6317', (84, 87))	('Pten', 'Gene', (170, 174))	('mice', 'Species', '10090', (188, 192))	('KrasG12D/p53-/-', 'Var', (141, 156))	('Rapamycin', 'Chemical', 'MESH:D020123', (0, 9))	('Pten', 'Gene', '19211', (170, 174))	('Tgfbr1', 'Gene', '21812', (178, 184))	('HNSCC', 'Phenotype', 'HP:0012288', (82, 87))	('SCC', 'Gene', (73, 76))	('development', 'CPA', (25, 36))	('Pten', 'Gene', (158, 162))	('SCC', 'Gene', '6317', (73, 76))	('Pten', 'Gene', '19211', (158, 162))	('SCC', 'Gene', (84, 87))
254575	24177052	While the mechanisms whereby TZDs hamper NF-kappaB activity have been teased out in colorectal, prostate, leukemia, lung, and breast cancers, there is currently little to no evidence to show the effects on NF-kappaB in HNSCC.	('teased out', 'Phenotype', 'HP:0001061', (70, 80))	('leukemia', 'Disease', (106, 114))	('leukemia', 'Disease', 'MESH:D007938', (106, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('TZDs', 'Chemical', 'MESH:D045162', (29, 33))	('NF-kappaB activity', 'MPA', (41, 59))	('colorectal', 'Disease', (84, 94))	('TZDs', 'Var', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('lung', 'Disease', (116, 120))	('SCC', 'Gene', '6317', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancers', 'Disease', 'MESH:D001943', (126, 140))	('breast cancers', 'Disease', (126, 140))	('leukemia', 'Phenotype', 'HP:0001909', (106, 114))	('SCC', 'Gene', (221, 224))	('prostate', 'Disease', (96, 104))	('hamper', 'NegReg', (34, 40))	('breast cancers', 'Phenotype', 'HP:0003002', (126, 140))	('colorectal', 'Disease', 'MESH:D015179', (84, 94))	('HNSCC', 'Phenotype', 'HP:0012288', (219, 224))
254585	24177052	A clinical trial using soy isoflavones is ongoing at the University of Michigan Cancer Center to assess HNSCC biomarker expression of p53, p16, EGFR, VEGF, Bcl-xL and COX-2, and risk of SPT (NCT01028001).	('Bcl-xL', 'Gene', (156, 162))	('Bcl-xL', 'Gene', '598', (156, 162))	('COX-2', 'Gene', '5743', (167, 172))	('p16', 'Gene', (139, 142))	('SCC', 'Gene', '6317', (106, 109))	('SPT', 'Disease', (186, 189))	('p16', 'Gene', '1029', (139, 142))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('SCC', 'Gene', (106, 109))	('EGFR', 'Gene', (144, 148))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('VEGF', 'Gene', (150, 154))	('Cancer', 'Disease', (80, 86))	('VEGF', 'Gene', '7422', (150, 154))	('isoflavones', 'Chemical', 'MESH:D007529', (27, 38))	('COX-2', 'Gene', (167, 172))	('p53', 'Var', (134, 137))	('EGFR', 'Gene', '1956', (144, 148))	('Cancer', 'Disease', 'MESH:D009369', (80, 86))
254669	21554722	The topography for gastric cancer was grouped into three categories: proximal third (cardia) in the gastroesophageal junction or upper third of the stomach (ICD-O codes C16.0 and C16.1), distal stomach or lower two thirds of the stomach (ICD-O codes C16.2-C16.7), and unknown or unspecified/overlapping lesion (ICD-O codes C16.8 and C16.9).	('gastric cancer', 'Disease', (19, 33))	('C16.9', 'CellLine', 'CVCL:2322', (333, 338))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('C16.9', 'Var', (333, 338))	('gastric cancer', 'Disease', 'MESH:D013274', (19, 33))	('C16.2-C16.7', 'CellLine', 'CVCL:2322', (250, 261))	('gastroesophageal junction', 'Disease', (100, 125))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (100, 125))	('unspecified', 'Species', '32644', (279, 290))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('C16.1', 'CellLine', 'CVCL:2322', (179, 184))	('cardia', 'Disease', 'MESH:D004938', (85, 91))	('cardia', 'Disease', (85, 91))
254708	21554722	Genetic variation may be responsible for differences in tumor-host interactions, such as the micro-architecture of tumors and the complex process of metastasis, both of which are influenced by host genetic polymorphisms.	('Genetic variation', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (115, 120))	('tumors', 'Disease', (115, 121))	('influenced', 'Reg', (179, 189))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
254724	21554722	Our study also confirms the findings of an earlier study in BC that reported better survival outcomes for gastric cancer patients with Asian ethnicity compared to the general population.	('better', 'PosReg', (77, 83))	('survival', 'MPA', (84, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('gastric cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Asian ethnicity', 'Var', (135, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('patients', 'Species', '9606', (121, 129))
254726	21554722	A comparison between registries from Shanghai (China) and Madras (India) shows that the 5-year relative survival for gastric (20% versus 7.5%) and esophageal cancer (9.0% versus 6.9%) is better in Shanghai.	('esophageal cancer', 'Disease', (147, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('Shanghai', 'Var', (197, 205))	('gastric', 'Disease', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
254785	12500826	The reintubation injury was due to malposition of the stylet of the endotracheal tube.	('injury', 'Disease', 'MESH:D058186', (17, 23))	('injury', 'Disease', (17, 23))	('malposition', 'Var', (35, 46))	('reintubation', 'Disease', (4, 16))
254815	29871681	The patient used tobacco and alcohol before he underwent left pneumonectomy for a pT2N0M0 primary squamous cell lung cancer 12 years ago, which was followed by 4 cycles of gemcitabine/carboplatin doublet chemotherapy.	('alcohol', 'Chemical', 'MESH:D000438', (29, 36))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (98, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gemcitabine', 'Chemical', 'MESH:C056507', (172, 183))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (98, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('tobacco', 'Species', '4097', (17, 24))	('patient', 'Species', '9606', (4, 11))	('pT2N0M0', 'Var', (82, 89))	('squamous cell lung cancer', 'Disease', (98, 123))	('carboplatin', 'Chemical', 'MESH:D016190', (184, 195))
254837	28504813	In vivo, OE33 cells led to 63.6 and 100% tumor nodules after orthotopic (n=12) and subcutaneous (n=8) injection, respectively.	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('OE33 cells', 'Var', (9, 19))
254843	28504813	A subpopulation obtained through in vivo selection, OACM5 1.C SC1, gives a significant higher take rate, ectopically.	('OACM5 1.C', 'Var', (52, 61))	('take rate', 'MPA', (94, 103))	('SC1', 'Gene', (62, 65))	('SC1', 'Gene', '6941', (62, 65))	('higher', 'PosReg', (87, 93))
254854	28504813	A total of 9 different esophageal squamous cell carcinoma (ESSC) cell lines (81-T, KYSE30, KYSE150, SLMT-1, TE1, TE8, TE4, TE10 and T.Tn) and 3 esophageal adenocarcinoma (EAC) cell lines [(OE19), PT1590 and OE33 ] have been described for orthotopic use.	('TE4', 'Var', (118, 121))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (144, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('KYSE150', 'Var', (91, 98))	('TE10', 'Var', (123, 127))	('KYSE30', 'Var', (83, 89))	('esophageal adenocarcinoma', 'Disease', (144, 169))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (23, 57))	('T.Tn', 'Var', (132, 136))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (144, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (34, 57))	('SC', 'Gene', '6941', (61, 63))	('TE1', 'Var', (108, 111))	('TE8', 'Var', (113, 116))	('esophageal squamous cell carcinoma', 'Disease', (23, 57))
254858	28504813	Moreover, OE19 overexpresses Her2, which is found in only a minority of EAC patients [17-32% of gastroesophageal junction (GEJ) tumors ].	('patients', 'Species', '9606', (76, 84))	('Her2', 'Gene', (29, 33))	('OE19', 'Var', (10, 14))	('EAC', 'Disease', (72, 75))	('Her2', 'Gene', '2064', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('gastroesophageal junction (GEJ) tumors', 'Disease', 'MESH:D008309', (96, 134))	('overexpresses', 'PosReg', (15, 28))
254928	28504813	Five mice were subcutaneously injected bilaterally with OACM5 1.C SC1 cells, resulting in 10 macroscopically visible tumors (Table I).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('OACM5 1.C', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('SC1', 'Gene', (66, 69))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('SC1', 'Gene', '6941', (66, 69))	('mice', 'Species', '10090', (5, 9))
254967	28504813	The unsuccessful in vivo selection of OE33 was probably due to the small amount of tumor cells in the excised tumors and the low clonogenic potential of the cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('clonogenic potential', 'CPA', (129, 149))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumors', 'Disease', (110, 116))	('OE33', 'Var', (38, 42))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
254975	28504813	It would be interesting to transfect the investigated EAC cell lines with luciferase, such as shown by Gros et al, to perform in vivo fluorescence imaging in case of stable nodules, and be able to differentiate viable tumor cells from scar tissue and Matrigel.	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('scar', 'Phenotype', 'HP:0100699', (235, 239))	('differentiate', 'Reg', (197, 210))	('transfect', 'Var', (27, 36))	('tumor', 'Disease', (218, 223))
255002	27363029	We also compared GEJAC with and without BE, and tEAC with and without BE across clinical parameters and found that for both tumor subsets the presence of BE was associated with a higher frequency of early stage tumors, as has been published previously.	('presence', 'Var', (142, 150))	('BE', 'Phenotype', 'HP:0100580', (70, 72))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('stage tumors', 'Disease', 'MESH:D062706', (205, 217))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Disease', (124, 129))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('BE', 'Phenotype', 'HP:0100580', (40, 42))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('BE', 'Phenotype', 'HP:0100580', (154, 156))	('stage tumors', 'Disease', (205, 217))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
255004	27363029	Figure 1A shows no significant differences in the total number of non-silent, protein-coding mutations between GEJAC and tEAC tumor groups, while Figure 1B shows that GEJAC mutations are significantly (p=0.02 Wilcoxon Rank-sum test) less likely to involve the ApA dinucleotide, a signature mutation associated with EAC.	('ApA', 'Gene', (260, 263))	('EAC', 'Phenotype', 'HP:0011459', (315, 318))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (173, 182))	('EAC', 'Disease', (315, 318))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('less', 'NegReg', (233, 237))	('ApA', 'Gene', '2028', (260, 263))	('involve', 'Reg', (248, 255))	('tumor', 'Disease', (126, 131))
255006	27363029	Of the top 26 genes, only MYST3 showed a notably higher mutation rate in GEJAC (9.8%; 4/41) compared to tEAC (<2%; 1/53).	('MYST3', 'Gene', '7994', (26, 31))	('mutation', 'Var', (56, 64))	('GEJAC', 'Disease', (73, 78))	('higher', 'PosReg', (49, 55))	('EAC', 'Phenotype', 'HP:0011459', (105, 108))	('MYST3', 'Gene', (26, 31))
255007	27363029	We then considered GEJACs without BE vs tEACs with BE and saw the above results recapitulated, with a significantly lower fraction of ApA mutations in GEJAC without BE (p=0.023 by Wilcoxon Rank-sum test) and a significant difference in the distribution of mutations across the same 26 genes (p=0.04 by paired T-test), as well as similar individual gene profiles to those of the parent dataset listed above (Supplementary Figure S1).	('lower', 'NegReg', (116, 121))	('ApA', 'Gene', '2028', (134, 137))	('BE', 'Phenotype', 'HP:0100580', (51, 53))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('ApA', 'Gene', (134, 137))	('BE', 'Phenotype', 'HP:0100580', (34, 36))	('BE', 'Phenotype', 'HP:0100580', (165, 167))	('mutations', 'Var', (138, 147))
255023	27363029	Among these 13 genes the highest risk ratio was 5, for the pseudogene GTF2IP1, and the lowest was 0.4 to PIGW (Supplementary Table S8).	('PIGW', 'Gene', '284098', (105, 109))	('GTF2IP1', 'Gene', (70, 77))	('pseudogene', 'Var', (59, 69))	('PIGW', 'Gene', (105, 109))	('GTF2IP1', 'Gene', '2970', (70, 77))
255030	27363029	In the univariate analyses of tumor location (GEJAC vs tEAC) we saw that GEJAC was associated with a slight but significant improvement in overall survival by log-rank statistic (p=0.0044; Figure 3D and Supplementary Figure S6A).	('improvement', 'PosReg', (124, 135))	('overall survival', 'MPA', (139, 155))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('GEJAC', 'Var', (73, 78))	('EAC', 'Phenotype', 'HP:0011459', (56, 59))	('tumor', 'Disease', (30, 35))
255071	27363029	used FISH to demonstrate that the presence of chromosomal gain involving ZNF217 predicted stage-independent survival in 130 EAC patients.	('chromosomal gain', 'Var', (46, 62))	('predicted', 'Reg', (80, 89))	('ZNF217', 'Gene', (73, 79))	('stage-independent survival', 'CPA', (90, 116))	('ZNF217', 'Gene', '7764', (73, 79))	('EAC', 'Phenotype', 'HP:0011459', (124, 127))	('patients', 'Species', '9606', (128, 136))	('EAC', 'Disease', (124, 127))
255072	27363029	Several lines of evidence implicate ZNF217 as a key player in the regulation of the epithelial to mesenchymal transition (EMT), including the discovery of CDH1 as a direct repression target and that ZNF217 expression can be directly regulated by several EMT-related miRNAs, including miR-24, miR-203 and miR200c.	('miR-24', 'Var', (284, 290))	('miR200c', 'Gene', (304, 311))	('CDH1', 'Gene', (155, 159))	('expression', 'MPA', (206, 216))	('ZNF217', 'Gene', (36, 42))	('CDH1', 'Gene', '999', (155, 159))	('ZNF217', 'Gene', '7764', (36, 42))	('regulated', 'Reg', (233, 242))	('miR-203', 'Gene', '406986', (292, 299))	('miR-203', 'Gene', (292, 299))	('miR200c', 'Gene', '406985', (304, 311))	('ZNF217', 'Gene', (199, 205))	('ZNF217', 'Gene', '7764', (199, 205))
255090	27363029	Height and weight data, at the time of surgery, were extracted from patient records and used to determine BMI category as follows: 'underweight' (BMI < 18.5), 'normal' (BMI 18.5 to 24.9), 'overweight' (BMI 25 to 29.9) and 'obese' (BMI 30.0 and above).	("'obese'", 'Disease', 'MESH:D009765', (222, 229))	('patient', 'Species', '9606', (68, 75))	('BMI', 'Var', (202, 205))	("'obese'", 'Disease', (222, 229))
255171	24219164	Several findings imply the potential relevance of DSB repair defects in the tumorigenesis of esophageal squamous cell carcinoma (ESCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal squamous cell carcinoma', 'Disease', (93, 127))	('defects', 'Var', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
255173	24219164	Of these eight cell lines, the clonogenic survival of one (TE-6) was reduced by AZD2281 to the level of DSB repair-defective Capan-1 and HCC1937 cells.	('TE', 'Chemical', 'MESH:D013691', (59, 61))	('reduced', 'NegReg', (69, 76))	('Capan-1', 'CellLine', 'CVCL:0237', (125, 132))	('AZD2281', 'Chemical', 'MESH:C531550', (80, 87))	('HCC1937', 'CellLine', 'CVCL:0290', (137, 144))	('clonogenic survival', 'CPA', (31, 50))	('AZD2281', 'Var', (80, 87))
255188	24219164	Poly(ADP-ribose) polymerase (PARP) inhibitors induce the accumulation of DNA single-strand breaks (SSB), which cause the formation of DNA double-strand breaks (DSB) after the stalling and collapse of progressing DNA replication folks.	('Poly(ADP-ribose) polymerase', 'Gene', (0, 27))	('Poly(ADP-ribose) polymerase', 'Gene', '142', (0, 27))	('PARP', 'Gene', '142', (29, 33))	('inhibitors', 'Var', (35, 45))	('cause', 'Reg', (111, 116))	('PARP', 'Gene', (29, 33))
255191	24219164	BRCA1 and BRCA2 are key components of the HRR machinery, and the abnormality of these genes is known to cause sporadic and hereditary breast and ovarian cancers.	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', '675', (10, 15))	('abnormality', 'Var', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('ovarian cancers', 'Phenotype', 'HP:0100615', (145, 160))	('sporadic', 'Disease', (110, 118))	('cause', 'Reg', (104, 109))	('hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (123, 160))	('BRCA2', 'Gene', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
255195	24219164	Although the direct relevance has not been well investigated, several findings suggest that a defect in the HRR pathway contributes to the tumorigenesis of ESCC.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('defect', 'Var', (94, 100))	('HRR pathway', 'Pathway', (108, 119))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('ESCC', 'Disease', (156, 160))
255207	24219164	To evaluate the formation of 53BP1 and RAD51 nuclear foci, cells grown on mu-Dish35 mm,low (ibidi) were treated with an anti-53BP1 rabbit polyclonal antibody (Abcam, Cambridge, UK) or an anti-RAD51 rabbit polyclonal antibody (Santa Cruz Biotechnology) followed by an Alexa Flour 488 donkey anti-rabbit IgG (H + L) (Invitrogen, Carlsbad, CA, USA).	('rabbit', 'Species', '9986', (131, 137))	('rabbit', 'Species', '9986', (198, 204))	('RAD51', 'Gene', '5888', (192, 197))	('Alexa Flour 488', 'Chemical', '-', (267, 282))	('donkey', 'Species', '9793', (283, 289))	('RAD51', 'Gene', (39, 44))	('anti-53BP1', 'Var', (120, 130))	('rabbit', 'Species', '9986', (295, 301))	('RAD51', 'Gene', '5888', (39, 44))	('RAD51', 'Gene', (192, 197))
255215	24219164	The IC50 values for HCC1937 and Capan-1 cells, which have deletions or mutations in the BRCA genes and are reported to be sensitive to PARP inhibitors, were 0.2 and 0.6 muM, respectively.	('muM', 'Gene', '56925', (169, 172))	('Capan-1', 'CellLine', 'CVCL:0237', (32, 39))	('PARP', 'Gene', '142', (135, 139))	('deletions', 'Var', (58, 67))	('HCC1937', 'CellLine', 'CVCL:0290', (20, 27))	('mutations', 'Var', (71, 80))	('muM', 'Gene', (169, 172))	('BRCA', 'Gene', '672', (88, 92))	('PARP', 'Gene', (135, 139))	('BRCA', 'Gene', (88, 92))
255219	24219164	Because AZD2281 and BSI-201 suppressed the growth of the TE-6 cells as efficiently as it suppressed the growth of the BRCA-deficient, PARP-inhibitor-sensitive cell lines and failed to suppress the growth of the TE-1 cells; we designated TE-6 as a PARP inhibitor-sensitive ESCC cell line and TE-1 as a PARP inhibitor-resistant cell line.	('PARP', 'Gene', (301, 305))	('BRCA-deficient', 'Disease', 'OMIM:604370', (118, 132))	('suppressed', 'NegReg', (89, 99))	('PARP', 'Gene', (134, 138))	('AZD2281', 'Chemical', 'MESH:C531550', (8, 15))	('BRCA-deficient', 'Disease', (118, 132))	('growth', 'MPA', (43, 49))	('TE', 'Chemical', 'MESH:D013691', (237, 239))	('PARP', 'Gene', '142', (247, 251))	('TE', 'Chemical', 'MESH:D013691', (291, 293))	('BSI-201', 'Chemical', 'MESH:C090712', (20, 27))	('PARP', 'Gene', (247, 251))	('TE-1', 'Gene', '57816', (211, 215))	('suppressed', 'NegReg', (28, 38))	('TE-1', 'Gene', (211, 215))	('TE-1', 'Gene', '57816', (291, 295))	('TE', 'Chemical', 'MESH:D013691', (211, 213))	('growth', 'MPA', (104, 110))	('TE-1', 'Gene', (291, 295))	('BSI-201', 'Gene', (20, 27))	('PARP', 'Gene', '142', (301, 305))	('AZD2281', 'Var', (8, 15))	('TE', 'Chemical', 'MESH:D013691', (57, 59))	('PARP', 'Gene', '142', (134, 138))
255221	24219164	Treatment with 1 and 5 muM of AZD2281 for 12 h increased the population with 4n DNA content from 36.7% to 40.7% and 40.6%, respectively.	('AZD2281', 'Var', (30, 37))	('population with 4n DNA content', 'MPA', (61, 91))	('AZD2281', 'Chemical', 'MESH:C531550', (30, 37))	('increased', 'PosReg', (47, 56))	('muM', 'Gene', '56925', (23, 26))	('muM', 'Gene', (23, 26))
255227	24219164	Both the percentage of gamma-H2AX positive cells determined by visual inspection and the average fluorescence intensity of gamma-H2AX staining per cell increased significantly in a dose-dependent manner in TE-6 cells, but not in TE-1 cells, suggesting that AZD2281 induced an accumulation of DNA damage in TE-6 cells (Fig.	('gamma-H2AX', 'Chemical', '-', (23, 33))	('AZD2281', 'Chemical', 'MESH:C531550', (257, 264))	('TE', 'Chemical', 'MESH:D013691', (206, 208))	('gamma-H2AX', 'Chemical', '-', (123, 133))	('TE-1', 'Gene', '57816', (229, 233))	('AZD2281', 'Var', (257, 264))	('TE', 'Chemical', 'MESH:D013691', (306, 308))	('TE-1', 'Gene', (229, 233))	('accumulation', 'PosReg', (276, 288))	('TE', 'Chemical', 'MESH:D013691', (229, 231))	('DNA damage', 'MPA', (292, 302))
255228	24219164	The Western blotting and immunofluorescence data also suggested that the baseline gamma-H2AX level was higher in the AZD2281-sensitive TE-6 cells than in the resistant TE-1 cells (Fig.	('gamma-H2AX', 'Chemical', '-', (82, 92))	('AZD2281', 'Chemical', 'MESH:C531550', (117, 124))	('TE-1', 'Gene', (168, 172))	('TE', 'Chemical', 'MESH:D013691', (168, 170))	('AZD2281-sensitive', 'Var', (117, 134))	('TE', 'Chemical', 'MESH:D013691', (135, 137))	('gamma-H2AX level', 'MPA', (82, 98))	('higher', 'PosReg', (103, 109))	('TE-1', 'Gene', '57816', (168, 172))
255245	24219164	To identify the molecular mechanism underlying the impaired DNA repair in TE-6 cells, we performed whole-exome sequencing of TE-6 and TE-1 cells and selected the DNA repair-related genes that were mutated in the genomic DNA of TE-6 cells but not TE-1 cells.	('TE', 'Chemical', 'MESH:D013691', (227, 229))	('TE', 'Chemical', 'MESH:D013691', (125, 127))	('DNA repair-related genes', 'Gene', (162, 186))	('mutated', 'Var', (197, 204))	('TE-1', 'Gene', '57816', (246, 250))	('TE', 'Chemical', 'MESH:D013691', (246, 248))	('TE-1', 'Gene', '57816', (134, 138))	('TE', 'Chemical', 'MESH:D013691', (134, 136))	('TE-1', 'Gene', (246, 250))	('TE', 'Chemical', 'MESH:D013691', (74, 76))	('TE-1', 'Gene', (134, 138))
255246	24219164	In total, 16 722 and 16 543 single nucleotide variants (SNV) were identified from the exomes of TE-1 and TE-6 cells, respectively (Tables S1 and S2).	('TE-1', 'Gene', (96, 100))	('TE', 'Chemical', 'MESH:D013691', (96, 98))	('TE', 'Chemical', 'MESH:D013691', (105, 107))	('single nucleotide variants', 'Var', (28, 54))	('TE-1', 'Gene', '57816', (96, 100))
255249	24219164	We further evaluated the impact of amino acid substitutions using the Polyphen2 prediction program; we focused in particular on the T448M missense mutation of RNF8, which is an E3-ligase polyubiquitylating gamma-H2AX.	('RNF8', 'Gene', (159, 163))	('gamma-H2AX', 'Chemical', '-', (206, 216))	('T448M', 'Mutation', 'rs200185110', (132, 137))	('T448M missense', 'Var', (132, 146))
255256	24219164	The following findings support the idea that the PARP inhibitor induced growth retardation in the DSB repair-impaired background of TE-6 cells: (i) AZD2281 induced the accumulation of DNA damage, as evaluated by gamma-H2AX expression levels.	('PARP', 'Gene', '142', (49, 53))	('growth retardation', 'Phenotype', 'HP:0001510', (72, 90))	('DNA damage', 'MPA', (184, 194))	('AZD2281', 'Chemical', 'MESH:C531550', (148, 155))	('gamma-H2AX', 'Chemical', '-', (212, 222))	('TE', 'Chemical', 'MESH:D013691', (132, 134))	('growth retardation', 'Disease', 'MESH:D006130', (72, 90))	('PARP', 'Gene', (49, 53))	('AZD2281', 'Var', (148, 155))	('growth retardation', 'Disease', (72, 90))
255260	24219164	Though the presence or absence of BRCA1 and BRCA2 alterations most strikingly distinguishes the PARP inhibitor-sensitive cells and patients, no pathogenetic mutations in either gene were identified in the TE-6 cells (Table S1).	('patients', 'Species', '9606', (131, 139))	('PARP', 'Gene', (96, 100))	('BRCA1', 'Gene', (34, 39))	('alterations', 'Var', (50, 61))	('BRCA2', 'Gene', (44, 49))	('TE', 'Chemical', 'MESH:D013691', (205, 207))	('BRCA2', 'Gene', '675', (44, 49))	('PARP', 'Gene', '142', (96, 100))
255262	24219164	The alteration of other genes, such as 53BP1, RAD51, PTEN and USP11, also reportedly affects the sensitivity to PARP inhibitors.	('PARP', 'Gene', (112, 116))	('affects', 'Reg', (85, 92))	('RAD51', 'Gene', (46, 51))	('USP11', 'Gene', (62, 67))	('alteration', 'Var', (4, 14))	('RAD51', 'Gene', '5888', (46, 51))	('PARP', 'Gene', '142', (112, 116))	('USP11', 'Gene', '8237', (62, 67))	('PTEN', 'Gene', (53, 57))	('PTEN', 'Gene', '5728', (53, 57))	('53BP1', 'Gene', (39, 44))
255264	24219164	Because a paired non-tumor genome is not available for the TE-series cells, we subtracted previously identified germline variants from our set of total SNVs and indels to enrich for potential somatic mutations.	('TE', 'Chemical', 'MESH:D013691', (59, 61))	('tumor', 'Disease', (21, 26))	('variants', 'Var', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
255266	24219164	It was reported that RNF8-/- p53-/- mice had increased levels of genomic instability and a remarkably elevated tumor incidence compared to p53-/- mice, that the knockdown of RNF8 sensitized cells to ionizing radiation, and that disruption of the RING domains of RNF8 impaired DSB-associated ubiquitylation and inhibited retention of 53BP1 and BRCA1 at the DSBs sites.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('impaired', 'NegReg', (267, 275))	('genomic instability', 'MPA', (65, 84))	('p53', 'Gene', (139, 142))	('mice', 'Species', '10090', (36, 40))	('disruption', 'Var', (228, 238))	('p53', 'Gene', '22060', (139, 142))	('levels', 'MPA', (55, 61))	('increased', 'PosReg', (45, 54))	('mice', 'Species', '10090', (146, 150))	('RNF8', 'Gene', (262, 266))	('DSBs', 'Chemical', '-', (356, 360))	('tumor', 'Disease', (111, 116))	('DSB-associated ubiquitylation', 'MPA', (276, 305))	('inhibited', 'NegReg', (310, 319))	('retention', 'MPA', (320, 329))	('53BP1', 'Protein', (333, 338))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('elevated', 'PosReg', (102, 110))	('p53', 'Gene', (29, 32))	('p53', 'Gene', '22060', (29, 32))
255267	24219164	The PolyPhen-2 program predicts a probable deleterious impact of the T448M substitution on the structure and function of RNF8.	('structure', 'MPA', (95, 104))	('T448M', 'Var', (69, 74))	('T448M', 'Mutation', 'rs200185110', (69, 74))	('deleterious', 'Reg', (43, 54))	('function', 'MPA', (109, 117))	('RNF8', 'Gene', (121, 125))
255268	24219164	Although the effect of the T448M mutation on the polyubiquitination ability of RNF8 has not yet been confirmed, the observation that the increase in ubiquitination after X-ray irradiation in the TE-6 cells was less than that of the TE-1 cells suggests that RNF8 is impaired in the TE-6 cells.	('TE', 'Chemical', 'MESH:D013691', (195, 197))	('TE', 'Chemical', 'MESH:D013691', (281, 283))	('T448M', 'Mutation', 'rs200185110', (27, 32))	('TE-1', 'Gene', '57816', (232, 236))	('T448M', 'Var', (27, 32))	('TE', 'Chemical', 'MESH:D013691', (232, 234))	('RNF8', 'Gene', (79, 83))	('ubiquitination', 'MPA', (149, 163))	('TE-1', 'Gene', (232, 236))	('polyubiquitination', 'MPA', (49, 67))
255269	24219164	The impact of the mutation or loss of RNF8 to PARP inhibitor sensitivity has to be further evaluated.	('PARP', 'Gene', '142', (46, 50))	('RNF8', 'Gene', (38, 42))	('mutation', 'Var', (18, 26))	('loss', 'NegReg', (30, 34))	('PARP', 'Gene', (46, 50))
255272	24219164	Meanwhile, the sensitivity of the TE-series cells to AZD2281 is altered by gradation and most cells exhibited intermediate sensitivity.	('TE', 'Chemical', 'MESH:D013691', (34, 36))	('AZD2281', 'Var', (53, 60))	('AZD2281', 'Chemical', 'MESH:C531550', (53, 60))	('sensitivity', 'MPA', (15, 26))
255275	24219164	We noticed a strong correlation between AZD2281 sensitivity and gamma-H2Ax levels in the cells without treatment; this effect might represent the extent of baseline DNA damage.	('AZD2281', 'Chemical', 'MESH:C531550', (40, 47))	('AZD2281', 'Var', (40, 47))	('gamma-H2Ax levels', 'MPA', (64, 81))
255288	25187728	The miRNA-RNA-induced silencing complex binds to specific mRNA targets via imperfect base pairing in the 3'-untranslated region, leading to translational repression or degradation of these mRNAs.	('miR', 'Gene', (4, 7))	('imperfect', 'Var', (75, 84))	('miR', 'Gene', '220972', (4, 7))	('base pairing', 'MPA', (85, 97))	('binds', 'Interaction', (40, 45))	('translational repression', 'MPA', (140, 164))	('degradation', 'MPA', (168, 179))
255294	25187728	Both genetic and epigenetic alterations affect the expression of miRNAs in cancer.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('expression', 'MPA', (51, 61))	('affect', 'Reg', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('epigenetic alterations', 'Var', (17, 39))
255304	25187728	This epigenetic regulation of miR-129 has also been demonstrated by different groups in hepatocellular carcinoma (HCC).	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('demonstrated', 'Reg', (52, 64))	('HCC', 'Phenotype', 'HP:0001402', (114, 117))	('epigenetic regulation', 'Var', (5, 26))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (88, 112))	('HCC', 'Gene', (114, 117))	('hepatocellular carcinoma', 'Disease', (88, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('HCC', 'Gene', '619501', (114, 117))
255309	25187728	miR-129 expression was reduced by epigenetic repression, which leads to the upregulation of SOX4 in endometrial cancer.	('upregulation', 'PosReg', (76, 88))	('endometrial cancer', 'Disease', (100, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (100, 118))	('epigenetic repression', 'Var', (34, 55))	('SOX4', 'Gene', (92, 96))	('miR', 'Gene', (0, 3))	('endometrial cancer', 'Disease', 'MESH:D016889', (100, 118))	('SOX4', 'Gene', '6659', (92, 96))	('miR', 'Gene', '220972', (0, 3))	('expression', 'MPA', (8, 18))	('reduced', 'NegReg', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
255313	25187728	It appears that epigenetic silencing of miR-129 in gastric cancer is a key event leading to the upregulation of SOX4 during tumorigenesis.	('miR', 'Gene', '220972', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('miR', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('gastric cancer', 'Phenotype', 'HP:0012126', (51, 65))	('SOX4', 'Gene', (112, 116))	('epigenetic silencing', 'Var', (16, 36))	('SOX4', 'Gene', '6659', (112, 116))	('upregulation', 'PosReg', (96, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (51, 65))	('gastric cancer', 'Disease', (51, 65))
255325	25187728	It is logical to reason that restoration of miR-129 expression will have tumor-suppressive potential, either alone or in combination with chemotherapy for developing novel therapeutic strategies for treating advanced colorectal cancer, liver cancer, and gastric cancer.	('miR', 'Gene', '220972', (44, 47))	('liver cancer', 'Disease', 'MESH:D006528', (236, 248))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('restoration', 'Var', (29, 40))	('colorectal cancer', 'Disease', (217, 234))	('gastric cancer', 'Disease', 'MESH:D013274', (254, 268))	('liver cancer', 'Phenotype', 'HP:0002896', (236, 248))	('miR', 'Gene', (44, 47))	('liver cancer', 'Disease', (236, 248))	('gastric cancer', 'Phenotype', 'HP:0012126', (254, 268))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('expression', 'MPA', (52, 62))	('gastric cancer', 'Disease', (254, 268))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))
255326	25187728	Our recent studies demonstrated that restoration of miR-129 in vivo can sensitize colon cancer tumor xenografts to 5-FU treatment.	('sensitize', 'Reg', (72, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (82, 94))	('colon cancer tumor', 'Disease', (82, 100))	('colon cancer tumor', 'Disease', 'MESH:D015179', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('restoration', 'Var', (37, 48))	('miR', 'Gene', '220972', (52, 55))	('5-FU', 'Chemical', 'MESH:D005472', (115, 119))	('miR', 'Gene', (52, 55))
255336	25187728	The reduced expression of miR-129 has been shown in colorectal cancer via epigenetic silencing by promoter methylation.	('miR', 'Gene', '220972', (26, 29))	('epigenetic', 'MPA', (74, 84))	('miR', 'Gene', (26, 29))	('reduced', 'NegReg', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('colorectal cancer', 'Disease', (52, 69))	('promoter methylation', 'Var', (98, 118))	('expression', 'MPA', (12, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
255362	20300841	Patients enrolled in the MAGIC trial (n=503, 75% gastric adenocarcinoma and 25% esophageal and GEJ tumors) were randomized to perioperative epirubicin, cisplatin and 5-fluorouracil with a significant improvement in 5-year survival rate (36% vs. 23%) but no improvement for purely adjuvant chemotherapy.	('epirubicin', 'Var', (140, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('GEJ tumors', 'Disease', (95, 105))	('improvement', 'PosReg', (200, 211))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('epirubicin', 'Chemical', 'MESH:D015251', (140, 150))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (49, 71))	('gastric adenocarcinoma', 'Disease', (49, 71))	('GEJ tumors', 'Disease', 'MESH:D009369', (95, 105))	('cisplatin', 'Var', (152, 161))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (166, 180))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
255374	20300841	Despite the complexity of cancer cells, their growth and survival can often be impaired by the inactivation of a single oncogene.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('growth', 'CPA', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('impaired', 'NegReg', (79, 87))	('inactivation', 'Var', (95, 107))
255377	20300841	Experimental evidence surprisingly illustrates that the inactivation of even a single oncogene can be sufficient to induce sustained tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('inactivation', 'Var', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
255379	20300841	Understanding when and how oncogene inactivation induces apoptosis is important when developing effective strategies for the treatment of cancer.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('induces', 'Reg', (49, 56))	('inactivation', 'Var', (36, 48))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
255386	20300841	Deoxycholic acid, a major component of human bile, results in ligand-dependent EGFR activation and CDX2 induction, even in the absence of acidic pH.	('Deoxycholic acid', 'Var', (0, 16))	('Deoxycholic acid', 'Chemical', 'MESH:D003840', (0, 16))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('activation', 'PosReg', (84, 94))	('CDX2', 'Gene', (99, 103))	('induction', 'PosReg', (104, 113))	('CDX2', 'Gene', '1045', (99, 103))	('human', 'Species', '9606', (39, 44))
255388	20300841	Activating EGFR mutations in exons 18 and 21, first found in non-small cell lung cancers, have also been identified in a subset of patients with Barrett's esophagus, high-grade dysplasia, and esophageal adenocarcinoma.	('Activating', 'PosReg', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('non-small cell lung cancers', 'Disease', (61, 88))	("Barrett's esophagus", 'Disease', (145, 164))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (61, 88))	('lung cancers', 'Phenotype', 'HP:0100526', (76, 88))	('EGFR', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('dysplasia', 'Disease', (177, 186))	('dysplasia', 'Disease', 'MESH:D004476', (177, 186))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (145, 164))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (145, 164))	('patients', 'Species', '9606', (131, 139))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (192, 217))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (65, 88))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (192, 217))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (61, 88))	('EGFR', 'Gene', '1956', (11, 15))	('esophageal adenocarcinoma', 'Disease', (192, 217))
255404	20300841	It is possible that the subset of patients who would benefit from EGFR inhibitors have not been properly identified; the presence of EGFR in a tumor may not be sufficient to ensure response to EGFR inhibitors.	('tumor', 'Disease', (143, 148))	('presence', 'Var', (121, 129))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', '1956', (193, 197))	('EGFR', 'Gene', (193, 197))	('EGFR', 'Gene', '1956', (133, 137))	('patients', 'Species', '9606', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('EGFR', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
255405	20300841	In addition, K-RAS mutations, which predict for EGFR inhibitor resistance, are found in almost one-third of esophageal adenocarcinomas.	('K-RAS', 'Gene', '3845', (13, 18))	('K-RAS', 'Gene', (13, 18))	('esophageal adenocarcinomas', 'Disease', (108, 134))	('EGFR', 'Gene', '1956', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (108, 133))	('EGFR', 'Gene', (48, 52))	('mutations', 'Var', (19, 28))	('found', 'Reg', (79, 84))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (108, 134))
255413	20300841	Specific polymorphisms in VEGF were associated with an increased odds ratio for esophageal adenocarcinoma via logistic regression among a cohort of patients with esophageal adenocarcinoma and healthy controls.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('patients', 'Species', '9606', (148, 156))	('esophageal adenocarcinoma', 'Disease', (162, 187))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (80, 105))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (162, 187))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('VEGF', 'Gene', (26, 30))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (162, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('polymorphisms', 'Var', (9, 22))	('associated', 'Reg', (36, 46))	('VEGF', 'Gene', '7422', (26, 30))	('esophageal adenocarcinoma', 'Disease', (80, 105))
255439	20300841	AURKA polymorphisms, not studied in EAC, have been associated with elevated breast cancer risk and earlier onset of pancreatic adenocarcinoma.	('AURKA', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (116, 141))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('polymorphisms', 'Var', (6, 19))	('associated', 'Reg', (51, 61))	('EAC', 'Phenotype', 'HP:0011459', (36, 39))	('AURKA', 'Gene', '6790', (0, 5))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (116, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('elevated breast cancer', 'Disease', (67, 89))	('elevated breast cancer', 'Disease', 'MESH:D001943', (67, 89))	('pancreatic adenocarcinoma', 'Disease', (116, 141))
255441	20300841	Furthermore, AURKA expression results in GSK-3beta phosphorylation, in turn resulting in decreased beta-catenin phosphorylation and accumulation and activation of the oncogenic beta-catenin/TCF transcription complex.	('AURKA', 'Gene', (13, 18))	('GSK-3beta', 'Gene', (41, 50))	('GSK-3beta', 'Gene', '2932', (41, 50))	('beta-catenin', 'Gene', '1499', (99, 111))	('beta-catenin', 'Gene', '1499', (177, 189))	('expression', 'Var', (19, 29))	('phosphorylation', 'MPA', (51, 66))	('beta-catenin', 'Gene', (177, 189))	('beta-catenin', 'Gene', (99, 111))	('accumulation', 'PosReg', (132, 144))	('AURKA', 'Gene', '6790', (13, 18))	('activation', 'PosReg', (149, 159))	('decreased', 'NegReg', (89, 98))
255443	20300841	MK-0547 has been effective in xenograft models of ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ovarian cancer', 'Disease', (50, 64))	('MK-0547', 'Var', (0, 7))	('MK-0547', 'Chemical', '-', (0, 7))	('ovarian cancer', 'Phenotype', 'HP:0100615', (50, 64))
255457	16095543	In addition, the average time required to perform a DNA ploidy analysis was shorter with the ACIS (30-40 min) than with the CAS 200 (40-70 min).	('shorter', 'NegReg', (76, 83))	('ACIS', 'Var', (93, 97))	('CAS', 'Gene', (124, 127))	('CAS', 'Gene', '9564', (124, 127))
255463	16095543	In addition to changes in chromosome copy numbers, cancer cells may also experience a change in the size of individual chromosomes, due to chromosomal translocations, deletions, and duplications.	('deletions', 'Var', (167, 176))	('changes', 'Reg', (15, 22))	('change', 'Reg', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('chromosomal', 'CPA', (139, 150))	('duplications', 'Var', (182, 194))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (51, 57))	('size', 'MPA', (100, 104))
255471	16095543	Recently, a more automated system, the Automated Cellular Imaging System (ACIS) (ChromaVision Medical System, Inc., San Juan Capistrano, CA) was introduced for the analysis of DNA ploidy, but results using this system have not been validated against the conventional CAS 200 system.	('DNA', 'Var', (176, 179))	('CAS', 'Gene', (267, 270))	('CAS', 'Gene', '9564', (267, 270))
255541	16095543	The diagnosis of an aneuploid G0/G1 peak depends on its distinct separation from the normal diploid peak.	('rat', 'Species', '10116', (69, 72))	('G0/G1', 'Gene', (30, 35))	('aneuploid', 'Var', (20, 29))
255562	34022830	Thoracic cancer patients who were treated with thoracic radiation from Jan 2018 to Jan 2019 in Shandong Cancer Hospital and Institute were enrolled prospectively.	('cancer', 'Disease', (9, 15))	('Jan', 'Var', (83, 86))	('patients', 'Species', '9606', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Cancer', 'Disease', (104, 110))	('Cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))
255585	34022830	Previous studies have shown the importance of clinical characteristics, dosimetric parameters factors as well as laboratory indicators, such as pack-years, baseline pulmonary function, a history of lung resection, mean lung dose (MLD), total or ipsilateral lung volume receiving more than 2000 cGy (V20), total lung V10, total lung V13, ipsilateral lung V5, interleukin-8, recombinant human eotaxin-2, recombinant human eotaxin-22, recombinant human eotaxin-17 and so on.	('recombinant human', 'Var', (402, 419))	('recombinant human eotaxin-17', 'Var', (432, 460))	('human', 'Species', '9606', (385, 390))	('V13', 'Gene', '28816', (332, 335))	('eotaxin-2', 'Gene', (420, 429))	('eotaxin-2', 'Gene', '6369', (391, 400))	('human', 'Species', '9606', (414, 419))	('interleukin-8', 'Gene', '3576', (358, 371))	('human', 'Species', '9606', (444, 449))	('recombinant human', 'Var', (373, 390))	('MLD', 'Disease', (230, 233))	('MLD', 'Disease', 'MESH:D007966', (230, 233))	('V13', 'Gene', (332, 335))	('interleukin-8', 'Gene', (358, 371))	('eotaxin-2', 'Gene', '6369', (420, 429))	('eotaxin-2', 'Gene', (391, 400))
255586	34022830	In addition, genetic variants of pulmonary surfactant-associated glycoprotein D, homeodomain interacting protein kinase 2 and interleukin-4 were also reported to be associated with RP development.	('glycoprotein D', 'Gene', (65, 79))	('homeodomain interacting protein kinase 2', 'Gene', '28996', (81, 121))	('homeodomain interacting protein kinase 2', 'Gene', (81, 121))	('genetic variants', 'Var', (13, 29))	('associated', 'Reg', (165, 175))	('interleukin-4', 'Gene', (126, 139))	('glycoprotein D', 'Gene', '2532', (65, 79))	('interleukin-4', 'Gene', '3565', (126, 139))
255631	34022830	The results of this study demonstrated SARE, ILMLD (> 1186.78 cGy), MED were associated with SRP.	('SRP', 'Disease', (93, 96))	('MLD', 'Disease', 'MESH:D007966', (47, 50))	('MLD', 'Disease', (47, 50))	('SARE', 'Chemical', '-', (39, 43))	('SRP', 'Chemical', '-', (93, 96))	('> 1186.78 cGy', 'Var', (52, 65))	('associated', 'Reg', (77, 87))
255663	34022830	Numerous lung related DVH parameters for RP have been widely verified in previous studies, such as total or ipsilateral lung V5, V10, V13 and V20.	('V13', 'Gene', '28816', (134, 137))	('V20', 'Var', (142, 145))	('V13', 'Gene', (134, 137))
255681	33536782	Many studies have reported that Dkk1 is abnormally expressed in tumor cells, and abnormal expression of Dkk1 can inhibit cell proliferation or induce apoptosis through pro-apoptotic factors, However, due to the differences in tumor environment and the complex regulatory mechanisms in different tumors, Dkk1 has different effects on the progression of different tumors.	('tumors', 'Disease', (295, 301))	('apoptosis', 'CPA', (150, 159))	('cell proliferation', 'CPA', (121, 139))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', (362, 367))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('tumors', 'Phenotype', 'HP:0002664', (362, 368))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (295, 300))	('induce', 'Reg', (143, 149))	('Dkk1', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('tumors', 'Disease', (362, 368))	('effects', 'Reg', (322, 329))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('abnormal expression', 'Var', (81, 100))	('tumor', 'Disease', (64, 69))	('inhibit', 'NegReg', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (362, 368))	('tumor', 'Disease', (226, 231))
255682	33536782	In many tumors, high expression of Dkk1 may promote tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('promote', 'PosReg', (44, 51))	('high', 'Var', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor metastasis', 'Disease', 'MESH:D009362', (52, 68))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('Dkk1', 'Gene', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumor metastasis', 'Disease', (52, 68))
255697	33536782	IP3 triggers the release of calcium ions (Ca2+) from the endoplasmic reticulum activating calmodulin and subsequently CAMKII (calcium/calmodulin-dependent kinase II), TAK-1 (TGF-beta activated kinase 1) and NLK (Nemo-like kinase) thereby inhibiting the canonical Wnt pathway.	('TGF-beta activated kinase 1', 'Gene', (174, 201))	('calcium/calmodulin-dependent kinase II', 'Gene', (126, 164))	('CAMKII', 'Gene', '818', (118, 124))	('calcium', 'Chemical', 'MESH:D002118', (28, 35))	('IP3', 'Var', (0, 3))	('Nemo-like kinase', 'Gene', '51701', (212, 228))	('calcium/calmodulin-dependent kinase II', 'Gene', '818', (126, 164))	('Ca2+', 'Chemical', 'MESH:D000069285', (42, 46))	('Nemo-like kinase', 'Gene', (212, 228))	('TAK-1', 'Gene', '6885', (167, 172))	('release', 'MPA', (17, 24))	('inhibiting', 'NegReg', (238, 248))	('NLK', 'Gene', '51701', (207, 210))	('NLK', 'Gene', (207, 210))	('Wnt', 'Gene', (263, 266))	('Wnt', 'Gene', '114487', (263, 266))	('CAMKII', 'Gene', (118, 124))	('calcium', 'Chemical', 'MESH:D002118', (126, 133))	('TGF-beta activated kinase 1', 'Gene', '6885', (174, 201))	('TAK-1', 'Gene', (167, 172))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))
255699	33536782	In the Wnt pathway, mutations at key sites, methylation of the promoter and stability of beta-catenin have been shown to be associated with tumor progression and low survival in patients: The progression of chronic phase CML toward blastic crisis phase due to GSK3beta mutations and beta-catenin stabilization in GMP cells (granulocyte-macrophage progenitor cells).	('CML', 'Disease', (221, 224))	('mutations', 'Var', (269, 278))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (178, 186))	('Wnt', 'Gene', (7, 10))	('associated', 'Reg', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('GSK3beta', 'Gene', (260, 268))	('GSK3beta', 'Gene', '2931', (260, 268))	('Wnt', 'Gene', '114487', (7, 10))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', (140, 145))
255700	33536782	And Wnt pathway inhibitor promoters (ie, SFRP,DKK and WIF-1) are hypermethylated in ALL and AML and are associated with low survival in patients.	('survival', 'MPA', (124, 132))	('AML', 'Disease', 'MESH:D015470', (92, 95))	('WIF-1', 'Gene', '11197', (54, 59))	('DKK', 'Gene', (46, 49))	('low', 'NegReg', (120, 123))	('patients', 'Species', '9606', (136, 144))	('Wnt', 'Gene', (4, 7))	('hypermethylated', 'Var', (65, 80))	('AML', 'Disease', (92, 95))	('WIF-1', 'Gene', (54, 59))	('Wnt', 'Gene', '114487', (4, 7))
255701	33536782	Loss-of-function mutations in APC and RNF43 and gain-of-function mutations in RSPO (characterized by gene fusions) and CTNNB1 was reported in the vast majority of colorectal cancers (CRC).	('Loss-of-function', 'NegReg', (0, 16))	('APC', 'Disease', 'MESH:D011125', (30, 33))	('APC', 'Disease', (30, 33))	('CTNNB1', 'Gene', (119, 125))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('RSPO', 'Gene', (78, 82))	('CTNNB1', 'Gene', '1499', (119, 125))	('colorectal cancers', 'Disease', 'MESH:D015179', (163, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('gain-of-function', 'PosReg', (48, 64))	('RNF43', 'Gene', '54894', (38, 43))	('colorectal cancers', 'Disease', (163, 181))	('RNF43', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('mutations', 'Var', (17, 26))	('RSPO', 'Gene', '284654', (78, 82))	('mutations', 'Var', (65, 74))
255704	33536782	But in other tumors, the expression of Dkk1 exists as a tumor suppressor.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (13, 19))	('Dkk1', 'Gene', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('expression', 'Var', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
255712	33536782	The data showed that CSC phenotype was related to VM and Dkk1 overexpression, and in vivo studies showed that lung cancer cells overexpressing Dkk1 had more CSC phenotype and more invasiveness than normal lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('Dkk1', 'Var', (143, 147))	('more', 'PosReg', (175, 179))	('lung cancer', 'Disease', 'MESH:D008175', (205, 216))	('invasiveness', 'CPA', (180, 192))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('lung cancer', 'Disease', (205, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('CSC', 'Disease', (157, 160))	('more', 'PosReg', (152, 156))
255717	33536782	Cox regression analysis showed that antibodies against Pep B subtype were independent prognostic factors of NSCLC.	('antibodies', 'Var', (36, 46))	('NSCLC', 'Disease', (108, 113))	('Pep B', 'Gene', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('Pep B', 'Gene', '5182', (55, 60))
255726	33536782	By comparing the serum Dkk1 levels of 831 test cohort participants and 453 validation cohort participants, and the liver tissue Dkk1 mRNA and protein levels of HCC patients and non-cancer patients, Professor Qin Wenxin found that Dkk1 can complement the measurement of AFP in HCC diagnosis, improve the differentiation of AFP-negative HCC patients, and distinguish HCC from non-malignant chronic liver disease.	('AFP', 'Gene', (322, 325))	('AFP', 'Gene', '174', (322, 325))	('patients', 'Species', '9606', (188, 196))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('chronic liver disease', 'Disease', (388, 409))	('Qin', 'Gene', '2290', (208, 211))	('HCC', 'Disease', (276, 279))	('HCC', 'Disease', (365, 368))	('chronic liver disease', 'Disease', 'MESH:D058625', (388, 409))	('Qin', 'Gene', (208, 211))	('patients', 'Species', '9606', (339, 347))	('patients', 'Species', '9606', (164, 172))	('improve', 'PosReg', (291, 298))	('AFP', 'Gene', (269, 272))	('cancer', 'Disease', (181, 187))	('AFP', 'Gene', '174', (269, 272))	('participants', 'Species', '9606', (54, 66))	('liver disease', 'Phenotype', 'HP:0001392', (396, 409))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('distinguish', 'Reg', (353, 364))	('Dkk1', 'Var', (230, 234))	('participants', 'Species', '9606', (93, 105))
255734	33536782	It was found that after TACE treatment, the serum Dkk1 and CTCs in the reaction group were significantly lower than those before treatment, and the overall survival time, disease-free survival time and 5-year survival rate of patients with positive serum Dkk1 and CTC before treatment were significantly lower than those before treatment.	('lower', 'NegReg', (105, 110))	('TACE', 'Chemical', '-', (24, 28))	('CTCs', 'MPA', (59, 63))	('positive serum Dkk1', 'Var', (240, 259))	('patients', 'Species', '9606', (226, 234))	('5-year survival rate', 'CPA', (202, 222))	('lower', 'NegReg', (304, 309))	('serum', 'MPA', (44, 49))	('overall survival time', 'CPA', (148, 169))	('disease-free survival time', 'CPA', (171, 197))
255741	33536782	The proportion of S phase and G2/M phase increased, while the proportion of G0/G1 decreased, and the overexpression of Dkk1 led to the enhancement of invasive ability of EC9706 cells.	('overexpression', 'PosReg', (101, 115))	('Dkk1', 'Var', (119, 123))	('invasive ability', 'CPA', (150, 166))	('enhancement', 'PosReg', (135, 146))	('S phase', 'CPA', (18, 25))	('G2/M phase', 'CPA', (30, 40))	('EC9706', 'CellLine', 'CVCL:E307', (170, 176))
255744	33536782	The expression of Dkk1 protein in resected specimens of ESCC patients was compared with various clinicopathological parameters and prognosis (the relationship between disease-free survival (DFS)) showed that the DFS of patients with Dkk1-positive tumors was worse than that of ESCC-negative patients (5-year DFS;1.5% vs 53.6% DFS;1.5% 0.0062), indicating that Dkk1 can be used as a new predictor of poor prognosis in patients with ESCC after radical resection.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Disease', (247, 253))	('worse', 'NegReg', (258, 263))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('ESCC', 'Disease', (431, 435))	('patients', 'Species', '9606', (61, 69))	('Dkk1', 'Var', (360, 364))	('patients', 'Species', '9606', (291, 299))	('patients', 'Species', '9606', (219, 227))	('patients', 'Species', '9606', (417, 425))
255758	33536782	After examining the relationship between the co-expression of Dkk1 and beta-catenin in gastric cancer and clinical prognosis, it was found that the co-expression of Dkk1 and beta-catenin was significantly correlated with high N stage (N2 and N3).	('high N stage', 'Disease', (221, 233))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('correlated', 'Reg', (205, 215))	('Dkk1', 'Gene', (165, 169))	('beta-catenin', 'Protein', (174, 186))	('co-expression', 'Var', (148, 161))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))
255759	33536782	The overall survival (OS) and DFS of patients with high expression of Dkk1 were poor.	('overall survival', 'CPA', (4, 20))	('poor', 'NegReg', (80, 84))	('patients', 'Species', '9606', (37, 45))	('high expression', 'Var', (51, 66))	('Dkk1', 'Gene', (70, 74))
255760	33536782	Multivariate analysis showed that high expression of Dkk1 alone or high expression of Dkk1 with beta-catenin positive were independent prognostic factors for tumor recurrence and overall survival, indicating that high expression of Dkk1 was an important prognostic factor for tumor recurrence and survival in resected AGC patients, regardless of the positivity of beta-catenin.	('Dkk1', 'Gene', (232, 236))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('patients', 'Species', '9606', (322, 330))	('tumor', 'Disease', (276, 281))	('high', 'Var', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Dkk1', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
255764	33536782	After Dkk1 was introduced into CD44+ cells, it effectively inhibited the endogenous Wnt/beta-catenin signal transduction and reduced the tumorigenicity of CD44+ cells in vivo, which verified the effectiveness of gene therapy targeting Wnt/beta-catenin signal pathway in CSC cells.	('Wnt', 'Gene', (84, 87))	('tumor', 'Disease', (137, 142))	('Wnt', 'Gene', (235, 238))	('inhibited', 'NegReg', (59, 68))	('Dkk1', 'Var', (6, 10))	('reduced', 'NegReg', (125, 132))	('Wnt', 'Gene', '114487', (84, 87))	('Wnt', 'Gene', '114487', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
255772	33536782	At the same time, in vitro culture showed that HCT116 with overexpression of Dkk1 inhibited the formation of the tubular structure of human umbilical vein endothelial cells and down-regulated the expression of VEGF, and the tumor size, microvessel density and VEGF expression of CRC cells with high expression of Dkk1 decreased.	('HCT116', 'CellLine', 'CVCL:0291', (47, 53))	('Dkk1', 'Gene', (77, 81))	('down-regulated', 'NegReg', (177, 191))	('VEGF', 'Gene', '7422', (260, 264))	('human', 'Species', '9606', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('inhibited', 'NegReg', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('VEGF', 'Gene', '7422', (210, 214))	('tumor', 'Disease', (224, 229))	('expression', 'MPA', (196, 206))	('HCT116', 'Var', (47, 53))	('expression', 'MPA', (265, 275))	('microvessel density', 'CPA', (236, 255))	('VEGF', 'Gene', (260, 264))	('decreased', 'NegReg', (318, 327))	('VEGF', 'Gene', (210, 214))
255776	33536782	Microarray analysis of CRC cell lines showed that the expression of Dkk1 and the level of Dkk1 protein depended on the increase of Dkk1 secretion after CSN5 gene knockout, which affected the Wnt signal transduction of SW480 cells.	('SW480', 'CellLine', 'CVCL:0546', (218, 223))	('Wnt', 'Gene', (191, 194))	('Dkk1 secretion', 'MPA', (131, 145))	('Wnt', 'Gene', '114487', (191, 194))	('CSN5', 'Gene', (152, 156))	('increase', 'PosReg', (119, 127))	('CSN5', 'Gene', '10987', (152, 156))	('knockout', 'Var', (162, 170))
255781	33536782	Knocking down miR-410 can promote the expression of Dkk1, inhibit the proliferation, migration and invasion of CRC cells, and induce apoptosis, while the overexpression of miR-410 shows the contrary.	('promote', 'PosReg', (26, 33))	('induce', 'Reg', (126, 132))	('miR-410', 'Gene', (14, 21))	('miR-410', 'Gene', '574434', (172, 179))	('Knocking down', 'Var', (0, 13))	('miR-410', 'Gene', '574434', (14, 21))	('expression', 'MPA', (38, 48))	('apoptosis', 'CPA', (133, 142))	('proliferation', 'CPA', (70, 83))	('inhibit', 'NegReg', (58, 65))	('Dkk1', 'Gene', (52, 56))	('miR-410', 'Gene', (172, 179))
255783	33536782	Silencing the expression of HotTip can inhibit the migration and invasion of colorectal cancer cells.	('HotTip', 'Gene', '100316868', (28, 34))	('colorectal cancer', 'Disease', (77, 94))	('inhibit', 'NegReg', (39, 46))	('expression', 'MPA', (14, 24))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HotTip', 'Gene', (28, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('Silencing', 'Var', (0, 9))
255791	33536782	Further in vitro experiment found that the invasiveness of PC tumor cells with Dkk1 knockout was significantly decreased.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('knockout', 'Var', (84, 92))	('decreased', 'NegReg', (111, 120))	('Dkk1', 'Gene', (79, 83))	('invasiveness of PC tumor', 'Disease', 'MESH:D015324', (43, 67))	('invasiveness of PC tumor', 'Disease', (43, 67))
255792	33536782	In terms of the mechanism of Dkk1 regulating PC, gene chip analysis showed that Dkk1 was an abnormal gene associated with GATA6 gene knockout.	('GATA6', 'Gene', (122, 127))	('knockout', 'Var', (133, 141))	('GATA6', 'Gene', '2627', (122, 127))	('Dkk1', 'Gene', (80, 84))
255794	33536782	In the case of low GATA6 knock down, it was found that the mRNA expression of Dkk1 and the secretion of Dkk1 protein increased.	('knock down', 'Var', (25, 35))	('GATA6', 'Gene', (19, 24))	('increased', 'PosReg', (117, 126))	('secretion', 'MPA', (91, 100))	('GATA6', 'Gene', '2627', (19, 24))	('mRNA expression', 'MPA', (59, 74))	('Dkk1', 'Gene', (78, 82))
255797	33536782	This study found that serum Dkk1 and CA19-9 were increased in patients with advanced PC and chronic pancreatitis, but Dkk1 was more effective in distinguishing PC from chronic pancreatitis than CA19-9, and the survival rate of patients with high expression of Dkk1 was significantly lower than that of patients with low expression of Dkk1.	('pancreatitis', 'Phenotype', 'HP:0001733', (176, 188))	('pancreatitis', 'Disease', 'MESH:D010195', (176, 188))	('pancreatitis', 'Disease', (100, 112))	('survival rate', 'CPA', (210, 223))	('CA19-9', 'Chemical', 'MESH:C086528', (194, 200))	('pancreatitis', 'Disease', (176, 188))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (92, 112))	('high expression', 'Var', (241, 256))	('CA19-9', 'Chemical', 'MESH:C086528', (37, 43))	('pancreatitis', 'Disease', 'MESH:D010195', (100, 112))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (168, 188))	('lower', 'NegReg', (283, 288))	('pancreatitis', 'Phenotype', 'HP:0001733', (100, 112))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (302, 310))	('patients', 'Species', '9606', (227, 235))
255798	33536782	Kaplan-Meier analysis of Dkk1 expression and patient clinical data showed that OS and relapse-free survival (RFS) decreased in patients with high Dkk1 expression, and the expression of Dkk1 was significantly correlated with T stage and lymph node metastasis.	('relapse-free survival', 'CPA', (86, 107))	('correlated', 'Reg', (208, 218))	('patient', 'Species', '9606', (127, 134))	('RFS', 'Disease', 'MESH:D005198', (109, 112))	('expression', 'MPA', (151, 161))	('patients', 'Species', '9606', (127, 135))	('lymph node metastasis', 'CPA', (236, 257))	('decreased', 'NegReg', (114, 123))	('patient', 'Species', '9606', (45, 52))	('Dkk1', 'Gene', (146, 150))	('T stage', 'CPA', (224, 231))	('high', 'Var', (141, 145))	('RFS', 'Disease', (109, 112))
255811	33536782	It can be used for the detection and diagnosis of CC, and for the prognosis evaluation of CC patients In view of the important role of lncRNA in the pathological process of cancer, some scholars have studied the role of lncRNA in CC and found that the promoting effect of SNHG7 on the development of CC depends on the activation of Wnt pathway mediated by Dkk1, while the binding of EZH2 and Dkk1 promoter and the share of H3K27me3 in Dkk1 promoter are decreased after SNHG7 silencing.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('Wnt', 'Gene', (332, 335))	('SNHG7', 'Gene', '84973', (469, 474))	('EZH2', 'Gene', '2146', (383, 387))	('promoting', 'PosReg', (252, 261))	('Wnt', 'Gene', '114487', (332, 335))	('EZH2', 'Gene', (383, 387))	('patients', 'Species', '9606', (93, 101))	('died', 'Disease', (203, 207))	('silencing', 'Var', (475, 484))	('decreased', 'NegReg', (453, 462))	('SNHG7', 'Gene', (272, 277))	('cancer', 'Disease', (173, 179))	('SNHG7', 'Gene', (469, 474))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('died', 'Disease', 'MESH:D003643', (203, 207))	('binding', 'Interaction', (372, 379))	('Dkk1', 'Protein', (392, 396))	('H3K27me3', 'Var', (423, 431))	('SNHG7', 'Gene', '84973', (272, 277))
255828	33536782	It was found that overexpression of DKN-01 had no significant effect on tumor cell phenotype and tumor load, but overexpression of Dkk1 reduced the infiltration of CD45+ leukocytes into the peritoneum and omentum, reduced natural killer (NK) and CD8T cells, and decreased the expression of interferon-gamma (IFN-gamma) on activated CD8T cells.	('infiltration', 'CPA', (148, 160))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (72, 77))	('interferon-gamma', 'Gene', '3458', (290, 306))	('decreased', 'NegReg', (262, 271))	('tumor', 'Disease', (97, 102))	('interferon-gamma', 'Gene', (290, 306))	('IFN-gamma', 'Gene', (308, 317))	('IFN-gamma', 'Gene', '3458', (308, 317))	('reduced', 'NegReg', (214, 221))	('reduced', 'NegReg', (136, 143))	('Dkk1', 'Var', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('natural killer', 'CPA', (222, 236))
255841	33536782	In the study of mesenchymal stem cell (MSC), it was found that MSCs from the rib perichondrium (PMSCs)-conditioned medium could significantly inhibit the growth, migration and invasion of breast cancer cells, and down-regulate the expression of Wnt/beta-catenin pathway and its target genes, while neutralizing Dkk1 in PMSC-conditioned medium could significantly reduce its inhibitory effect on tumor cells.	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('tumor', 'Disease', (395, 400))	('Wnt', 'Gene', (245, 248))	('inhibit', 'NegReg', (142, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('breast cancer', 'Disease', (188, 201))	('neutralizing', 'Var', (298, 310))	('down-regulate', 'NegReg', (213, 226))	('Dkk1', 'Gene', (311, 315))	('Wnt', 'Gene', '114487', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (395, 400))	('invasion', 'CPA', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (395, 400))	('growth', 'CPA', (154, 160))	('expression', 'MPA', (231, 241))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
255843	33536782	By comparing the serum Dkk1 and CA15-3 between breast cancer patients and healthy subjects, it was found that in the early stage of breast cancer, the sensitivity and specificity of Dkk1 were higher than that of CA15-3, while the expression of Dkk1 in HER-2-, ER-, and PR-positive patients was lower than that in HER-2-, ER- and PR- negative patients.	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('CA15-3', 'Gene', (212, 218))	('Dkk1', 'Var', (182, 186))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('breast cancer', 'Disease', (47, 60))	('HER-2', 'Gene', '2064', (252, 257))	('patients', 'Species', '9606', (61, 69))	('HER-2', 'Gene', (252, 257))	('HER-2', 'Gene', '2064', (313, 318))	('HER-2', 'Gene', (313, 318))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('specificity', 'MPA', (167, 178))	('CA15-3', 'Gene', '4582', (32, 38))	('sensitivity', 'MPA', (151, 162))	('patients', 'Species', '9606', (281, 289))	('expression', 'MPA', (230, 240))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lower', 'NegReg', (294, 299))	('CA15-3', 'Gene', (32, 38))	('patients', 'Species', '9606', (342, 350))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('higher', 'PosReg', (192, 198))	('CA15-3', 'Gene', '4582', (212, 218))
255854	33536782	Multivariate analysis showed that serum Dkk1 was an independent prognostic factor for OS of bladder cancer.	('OS of bladder cancer', 'Disease', 'MESH:D001749', (86, 106))	('Dkk1', 'Protein', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('OS of bladder cancer', 'Disease', (86, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))	('serum', 'Var', (34, 39))
255855	33536782	Gao et al demonstrated that up-regulation of miR-543-3p in bladder cancer can activate Wnt/beta-catenin signal by directly targeting Dkk1, while the expression of miR-543-3p is up-regulated in bladder cancer tissues and cells, and is positively correlated with high-grade bladder cancer, suggesting a potential tumor intervention target.	('Dkk1', 'Gene', (133, 137))	('Wnt', 'Gene', '114487', (87, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (193, 207))	('bladder cancer', 'Phenotype', 'HP:0009725', (272, 286))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('bladder cancer', 'Disease', (193, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('bladder cancer', 'Phenotype', 'HP:0009725', (193, 207))	('targeting', 'Reg', (123, 132))	('tumor', 'Disease', (311, 316))	('correlated', 'Reg', (245, 255))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('up-regulation', 'PosReg', (28, 41))	('miR-543-3p', 'Var', (45, 55))	('miR-543-3p', 'Var', (163, 173))	('up-regulated', 'PosReg', (177, 189))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('Wnt', 'Gene', (87, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (272, 286))	('bladder cancer', 'Disease', (272, 286))	('activate', 'PosReg', (78, 86))	('bladder cancer', 'Disease', (59, 73))
255859	33536782	Specifically, through the above research, we can find that Dkk1 has been shown to promote tumor metastasis in the following tumors: NSCLC, HCC, EC, GC, PC, CC, Breast cancer, and BUC.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('HCC', 'Disease', (139, 142))	('promote', 'PosReg', (82, 89))	('BUC', 'Disease', (179, 182))	('Breast cancer', 'Disease', (160, 173))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Dkk1', 'Var', (59, 63))	('tumor metastasis', 'Disease', 'MESH:D009362', (90, 106))	('tumor metastasis', 'Disease', (90, 106))	('tumors', 'Disease', (124, 130))	('NSCLC', 'Disease', (132, 137))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('Breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Breast cancer', 'Disease', 'MESH:D001943', (160, 173))
255861	33536782	By comparing the serum samples of tumor patients and normal subjects, we also confirmed the protective effect of high expression of Dkk1 on CRC patients.	('tumor', 'Disease', (34, 39))	('high expression', 'Var', (113, 128))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (144, 152))	('CRC', 'Disease', (140, 143))	('Dkk1', 'Gene', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
255862	33536782	However, high expression of Dkk1 was shown in other tumors to promote tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (70, 75))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('Dkk1', 'Gene', (28, 32))	('promote', 'PosReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('high', 'Var', (9, 13))
255872	33536782	However, in other tumor studies, it has been found that Dkk1 can inhibit the biological effect of tumor.	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (98, 103))	('inhibit', 'NegReg', (65, 72))	('Dkk1', 'Var', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
255874	33536782	In this case, it can be assumed that Dkk1 cannot inhibit the transduction of the classical Wnt signal pathway, thus eliminating its potential antitumor activity.	('Wnt', 'Gene', (91, 94))	('Dkk1', 'Var', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('Wnt', 'Gene', '114487', (91, 94))	('transduction', 'MPA', (61, 73))	('eliminating', 'NegReg', (116, 127))	('inhibit', 'NegReg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
255876	33536782	The close relationship between the expression level of Dkk1 in serum of clinical tumor patients and prognosis makes Dkk1 an attractive target for tumor therapy, and blocking the activity of Dkk1 in mice can significantly reduce the ability of tumor invasion and metastasis in vivo.	('reduce', 'NegReg', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('blocking', 'Var', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mice', 'Species', '10090', (198, 202))	('activity', 'MPA', (178, 186))	('Dkk1', 'Gene', (190, 194))	('patients', 'Species', '9606', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (243, 248))
255949	31501152	In autoimmune gastritis, APCA antibodies progressively destroy the parietal cells, leading to reduced or absent acid production (hypochlorhydria or achlorhydria) and an increased gastric pH.	('gastric pH', 'CPA', (179, 189))	('hypochlorhydria', 'Disease', (129, 144))	('autoimmune gastritis', 'Disease', 'MESH:D005756', (3, 23))	('APCA', 'Gene', (25, 29))	('reduced', 'NegReg', (94, 101))	('antibodies', 'Var', (30, 40))	('increased', 'PosReg', (169, 178))	('destroy', 'NegReg', (55, 62))	('achlorhydria', 'Disease', 'MESH:D000126', (148, 160))	('hypochlorhydria', 'Disease', 'MESH:D000126', (129, 144))	('acid production', 'MPA', (112, 127))	('gastritis', 'Phenotype', 'HP:0005263', (14, 23))	('increased gastric', 'Phenotype', 'HP:0005207', (169, 186))	('autoimmune gastritis', 'Disease', (3, 23))	('achlorhydria', 'Disease', (148, 160))	('achlorhydria', 'Phenotype', 'HP:0032448', (148, 160))	('absent', 'NegReg', (105, 111))
255953	31501152	These findings may be analogous to the reduction in H. pylori whole cell antibody titers as gastric atrophy becomes more severe, and the observation that the greatest risk of GNCA is found in patients with a low PGI/II ratio who are H. pylori CagA antibody positive (showing a history of H. pylori exposure) and H. pylori whole cell antibody negative.	('H. pylori', 'Species', '210', (312, 321))	('H. pylori', 'Species', '210', (288, 297))	('low', 'Var', (208, 211))	('H. pylori', 'Species', '210', (233, 242))	('patients', 'Species', '9606', (192, 200))	('reduction', 'NegReg', (39, 48))	('PGI/II', 'Gene', (212, 218))	('gastric atrophy', 'Disease', (92, 107))	('H. pylori', 'Species', '210', (52, 61))	('gastric atrophy', 'Disease', 'MESH:D013274', (92, 107))	('GNCA', 'Disease', (175, 179))
255961	31501152	In conclusion, we found that serum positivity for APCA was statistically significantly associated with low PG I/II ratios, which was a serological marker for prevalent atrophic gastritis, but inversely associated with later development of gastric cardia adenocarcinoma in a high-risk Chinese population.	('PG I/II ratios', 'MPA', (107, 121))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (239, 268))	('atrophic gastritis', 'Disease', (168, 186))	('associated with', 'Reg', (202, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('inversely', 'NegReg', (192, 201))	('serum positivity', 'Var', (29, 45))	('APCA', 'Gene', (50, 54))	('gastric cardia adenocarcinoma', 'Disease', (239, 268))	('low', 'NegReg', (103, 106))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (168, 186))	('atrophic gastritis', 'Disease', 'MESH:D005757', (168, 186))	('gastritis', 'Phenotype', 'HP:0005263', (177, 186))
255962	31501152	Individuals with low PG I/II ratios who were also seronegative for APCA had the highest risk of both gastric cardia and non-cardia adenocarcinomas.	('PG I/II', 'Gene', (21, 28))	('low', 'Var', (17, 20))	('gastric cardia and non-cardia adenocarcinomas', 'Disease', 'MESH:D004938', (101, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
256006	31323215	The cumulative incidence of recurrence at 2 years was 2.5%, 6.1% and 12% for T1a, T1b and T2, respectively.	('T1a', 'Gene', '10630', (77, 80))	('T1b', 'Var', (82, 85))	('T1a', 'Gene', (77, 80))
256102	31485440	The Pre-AMC was significantly associated with overall survival (OS) (HR, 2.145; 95% CI, 1.124-4.095; P = 0.021), but not to disease-free survival (DFS) (HR, 1.853; 95% CI, 0.883-3.889; P = 0.103).	('associated', 'Reg', (30, 40))	('AMC', 'Phenotype', 'HP:0012311', (8, 11))	('AMC', 'Chemical', '-', (8, 11))	('overall survival', 'MPA', (46, 62))	('Pre-AMC', 'Var', (4, 11))
256210	28348478	A recent trial also showed improved survival in the group of patients who received a TIPS, on top of reduced risk of recurrent ascites.	('improved', 'PosReg', (27, 35))	('TIPS', 'Var', (85, 89))	('ascites', 'Disease', 'MESH:D001201', (127, 134))	('ascites', 'Disease', (127, 134))	('ascites', 'Phenotype', 'HP:0001541', (127, 134))	('patients', 'Species', '9606', (61, 69))	('survival', 'MPA', (36, 44))
256244	28355360	Infection with HP is one cause of duodenal or gastric ulcers (reported to develop in 1 to 10% of infected patients), gastric cancer (in 0.1 to 3%), and gastric mucosa-associated lymphoid-tissue (MALT) lymphoma (in <0.01%).	('lymphoma', 'Phenotype', 'HP:0002665', (201, 209))	('gastric ulcers', 'Disease', 'MESH:D013276', (46, 60))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('gastric ulcers', 'Disease', (46, 60))	('HP', 'Species', '210', (15, 17))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastric ulcers', 'Phenotype', 'HP:0002592', (46, 60))	('patients', 'Species', '9606', (106, 114))	('Infection', 'Var', (0, 9))	('gastric cancer', 'Disease', (117, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('lymphoid-tissue (MALT) lymphoma', 'Disease', 'MESH:D018442', (178, 209))	('duodenal', 'Disease', (34, 42))
256246	28355360	Furthermore, an inverse association has been established between Cag A-positive HP infection and the risk of esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (109, 134))	('HP infection', 'Disease', (80, 92))	('esophageal adenocarcinoma', 'Disease', (109, 134))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (109, 134))	('Cag A-positive', 'Var', (65, 79))	('inverse', 'NegReg', (16, 23))	('HP infection', 'Disease', 'MESH:C537262', (80, 92))
256362	32100077	Human fluorochrome-conjugated antibodies, anti-CD127, anti-CD4, anti-CD3, anti-CD11c, anti-Siglec-8, anti-IL17A, anti-IFNgamma, anti-TNF-alpha, anti-IL22, anti-FOXP3, anti-IL10 all were purchased from BioLegend.	('IFNgamma', 'Gene', '3458', (118, 126))	('Human', 'Species', '9606', (0, 5))	('IL17A', 'Gene', '3605', (106, 111))	('FOXP3', 'Gene', '50943', (160, 165))	('CD11c', 'Gene', '3687', (79, 84))	('CD11c', 'Gene', (79, 84))	('CD4', 'Gene', '920', (59, 62))	('Siglec-8', 'Gene', '27181', (91, 99))	('IL10', 'Gene', (172, 176))	('Siglec-8', 'Gene', (91, 99))	('IL22', 'Gene', (149, 153))	('CD4', 'Gene', (59, 62))	('IL22', 'Gene', '50616', (149, 153))	('IL17A', 'Gene', (106, 111))	('FOXP3', 'Gene', (160, 165))	('anti-CD3', 'Var', (64, 72))	('CD127', 'Gene', '3575', (47, 52))	('IL10', 'Gene', '3586', (172, 176))	('CD127', 'Gene', (47, 52))	('TNF-alpha', 'Gene', '7124', (133, 142))	('TNF-alpha', 'Gene', (133, 142))	('IFNgamma', 'Gene', (118, 126))
256418	32100077	When correlating mRNA expression with overall survival rates in univariate analysis, high IL10 levels in both tumor and peritumoral samples were significantly associated with worse patient prognosis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('IL10', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('patient', 'Species', '9606', (181, 188))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', (124, 129))	('high', 'Var', (85, 89))	('IL10', 'Gene', '3586', (90, 94))	('tumoral', 'Disease', (124, 131))	('tumoral', 'Disease', 'MESH:D009369', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
256419	32100077	In peritumoral samples, high expression levels of PD1 were also associated with worse survival (Fig.	('tumoral', 'Disease', (7, 14))	('tumoral', 'Disease', 'MESH:D009369', (7, 14))	('PD1', 'Gene', (50, 53))	('expression levels', 'MPA', (29, 46))	('high', 'Var', (24, 28))	('worse', 'NegReg', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
256455	32100077	However, we found an increase in PD1+ T cells in high-grade dysplasia and in EACs themselves.	('dysplasia', 'Disease', 'MESH:C536170', (60, 69))	('increase', 'PosReg', (21, 29))	('PD1+', 'Var', (33, 37))	('dysplasia', 'Disease', (60, 69))
256470	32100077	In contrast, IL-22 also bears anti-tumor effects since blocking of IL-22 in early tumor initiation stages during DSS colitis leads to a reduced tumor burden.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (144, 149))	('DSS colitis', 'Disease', (113, 124))	('IL-22', 'Gene', '50616', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IL-22', 'Gene', (67, 72))	('IL-22', 'Gene', '50616', (13, 18))	('DSS colitis', 'Disease', 'MESH:D015417', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (35, 40))	('blocking', 'Var', (55, 63))	('IL-22', 'Gene', (13, 18))	('colitis', 'Phenotype', 'HP:0002583', (117, 124))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('reduced', 'NegReg', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
256503	26904687	Metformin Synergistically Enhances Cisplatin-Induced Cytotoxicity in Esophageal Squamous Cancer Cells under Glucose-Deprivation Conditions Previous studies suggest that metformin may exert a protective effect on cisplatin-induced cytotoxicity in cancer cells, and this finding has led to a caution for considering metformin use in the treatment of cancer patients.	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('Cytotoxicity', 'Disease', 'MESH:D064420', (53, 65))	('Metformin', 'Var', (0, 9))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('Cisplatin-Induced', 'MPA', (35, 52))	('Esophageal Squamous Cancer', 'Disease', (69, 95))	('metformin', 'Chemical', 'MESH:D008687', (314, 323))	('patients', 'Species', '9606', (355, 363))	('cancer', 'Disease', (246, 252))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cytotoxicity', 'Disease', (230, 242))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('cytotoxicity', 'Disease', 'MESH:D064420', (230, 242))	('metformin', 'Chemical', 'MESH:D008687', (169, 178))	('cancer', 'Disease', (348, 354))	('Esophageal Squamous Cancer', 'Disease', 'MESH:D004938', (69, 95))	('Squamous Cancer', 'Phenotype', 'HP:0002860', (80, 95))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('Cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('Cytotoxicity', 'Disease', (53, 65))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('Glucose-Deprivation Conditions', 'Disease', (108, 138))	('Enhances', 'PosReg', (26, 34))	('Glucose-Deprivation Conditions', 'Disease', 'MESH:D012892', (108, 138))
256504	26904687	However, in this paper we provide the first demonstration that metformin synergistically augments cisplatin cytotoxicity in the esophageal squamous cancer cell line, ECA109, under glucose-deprivation conditions, which may be more representative of the microenvironment within solid tumors; this effect is very different from the previously reported cytoprotective effect of metformin against cisplatin in commonly used high glucose incubation medium.	('glucose-deprivation conditions', 'Disease', 'MESH:D012892', (180, 210))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (128, 154))	('glucose', 'Chemical', 'MESH:D005947', (180, 187))	('solid tumors', 'Disease', 'MESH:D009369', (276, 288))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('augments', 'NegReg', (89, 97))	('glucose-deprivation conditions', 'Disease', (180, 210))	('high glucose', 'Phenotype', 'HP:0003074', (419, 431))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('metformin', 'Var', (63, 72))	('metformin', 'Chemical', 'MESH:D008687', (374, 383))	('glucose', 'Chemical', 'MESH:D005947', (424, 431))	('metformin', 'Chemical', 'MESH:D008687', (63, 72))	('cytotoxicity', 'Disease', (108, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (392, 401))	('cytotoxicity', 'Disease', 'MESH:D064420', (108, 120))	('esophageal squamous cancer', 'Disease', (128, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('squamous cancer', 'Phenotype', 'HP:0002860', (139, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('solid tumors', 'Disease', (276, 288))
256516	26904687	A growing body of data suggests that metformin may elicit antitumor effects alone or synergistically improve the response of radiotherapy or chemotherapy.	('metformin', 'Chemical', 'MESH:D008687', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('response', 'CPA', (113, 121))	('tumor', 'Disease', (62, 67))	('improve', 'PosReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('metformin', 'Var', (37, 46))
256534	26904687	In glucose-deprivation medium, metformin showed significantly enhanced cytotoxicity and synergistically augmented the cytotoxicity of DDP.	('glucose-deprivation', 'Disease', 'MESH:D012892', (3, 22))	('cytotoxicity', 'Disease', (71, 83))	('DDP', 'Gene', (134, 137))	('cytotoxicity', 'Disease', 'MESH:D064420', (118, 130))	('augmented', 'PosReg', (104, 113))	('enhanced', 'PosReg', (62, 70))	('metformin', 'Var', (31, 40))	('metformin', 'Chemical', 'MESH:D008687', (31, 40))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))	('DDP', 'Gene', '1678', (134, 137))	('cytotoxicity', 'Disease', (118, 130))	('glucose-deprivation', 'Disease', (3, 22))
256544	26904687	This protective effect of metformin was slightly, albeit significantly, higher than that observed in the cells treated with 1 muM DDP alone, as demonstrated by the t-test and p values, which reached 0.022 and 0.006, respectively.	('muM', 'Gene', '56925', (126, 129))	('DDP', 'Gene', (130, 133))	('metformin', 'Chemical', 'MESH:D008687', (26, 35))	('muM', 'Gene', (126, 129))	('protective effect', 'CPA', (5, 22))	('higher', 'PosReg', (72, 78))	('DDP', 'Gene', '1678', (130, 133))	('metformin', 'Var', (26, 35))
256549	26904687	Similarly, a moderate level of cytotoxicity was observed in cells treated with 100 muM metformin, while it was synergistically augmented when this treatment was combined with 1 muM DDP, as demonstrated by the finding that the cytotoxicity of the combined treatment was significantly greater than the cytotoxicities observed with each individual treatment.	('cytotoxicity', 'Disease', 'MESH:D064420', (31, 43))	('cytotoxicities', 'Disease', 'MESH:D064420', (300, 314))	('DDP', 'Gene', (181, 184))	('metformin', 'Var', (87, 96))	('muM', 'Gene', '56925', (83, 86))	('cytotoxicity', 'Disease', (226, 238))	('muM', 'Gene', '56925', (177, 180))	('greater', 'PosReg', (283, 290))	('cytotoxicity', 'Disease', (31, 43))	('muM', 'Gene', (83, 86))	('metformin', 'Chemical', 'MESH:D008687', (87, 96))	('DDP', 'Gene', '1678', (181, 184))	('cytotoxicity', 'Disease', 'MESH:D064420', (226, 238))	('muM', 'Gene', (177, 180))	('cytotoxicities', 'Disease', (300, 314))
256553	26904687	In glucose-deprivation medium, metformin caused a significant reduction of ATP synthesis and interfered with the AMPK and AKT signaling pathways in ECA109 cells.	('glucose-deprivation', 'Disease', 'MESH:D012892', (3, 22))	('AMPK', 'Gene', (113, 117))	('interfered', 'NegReg', (93, 103))	('metformin', 'Var', (31, 40))	('AKT', 'Gene', '207', (122, 125))	('ATP synthesis', 'MPA', (75, 88))	('metformin', 'Chemical', 'MESH:D008687', (31, 40))	('AMPK', 'Gene', '5563', (113, 117))	('reduction', 'NegReg', (62, 71))	('glucose-deprivation', 'Disease', (3, 22))	('ATP', 'Chemical', 'MESH:D000255', (75, 78))	('AKT', 'Gene', (122, 125))
256559	26904687	As for AKT, the addition of 200 muM metformin slightly inhibited AKT phosphorylation in high glucose medium, whereas the addition of 200 muM metformin under glucose-deprivation conditions led to a significant inhibition of AKT phosphorylation.	('glucose-deprivation conditions', 'Disease', 'MESH:D012892', (157, 187))	('AKT', 'Gene', (7, 10))	('AKT', 'Gene', (223, 226))	('AKT', 'Gene', '207', (65, 68))	('high glucose', 'Phenotype', 'HP:0003074', (88, 100))	('glucose', 'Chemical', 'MESH:D005947', (157, 164))	('metformin', 'Var', (36, 45))	('glucose-deprivation conditions', 'Disease', (157, 187))	('muM', 'Gene', '56925', (137, 140))	('muM', 'Gene', (137, 140))	('glucose', 'Chemical', 'MESH:D005947', (93, 100))	('metformin', 'Chemical', 'MESH:D008687', (36, 45))	('muM', 'Gene', '56925', (32, 35))	('AKT', 'Gene', '207', (7, 10))	('muM', 'Gene', (32, 35))	('AKT', 'Gene', '207', (223, 226))	('inhibition', 'NegReg', (209, 219))	('AKT', 'Gene', (65, 68))	('metformin', 'Chemical', 'MESH:D008687', (141, 150))	('inhibited', 'NegReg', (55, 64))
256584	26904687	Additionally, we showed that metformin synergistically augments DPP-induced cytotoxicity under glucose-deprivation conditions.	('metformin', 'Chemical', 'MESH:D008687', (29, 38))	('glucose-deprivation conditions', 'Disease', 'MESH:D012892', (95, 125))	('cytotoxicity', 'Disease', 'MESH:D064420', (76, 88))	('DPP', 'Chemical', 'MESH:C038694', (64, 67))	('metformin', 'Var', (29, 38))	('cytotoxicity', 'Disease', (76, 88))	('augments', 'PosReg', (55, 63))	('glucose-deprivation conditions', 'Disease', (95, 125))
256586	26904687	Previous works suggested that metformin exerts its biochemical effect in cancer cells primarily via inhibition of respiratory-chain complex 1 in a dose-dependent manner, thus reducing mitochondrial oxidative phosphorylation (OXPHOS) and ATP production.	('cancer', 'Disease', (73, 79))	('respiratory-chain complex 1', 'Enzyme', (114, 141))	('metformin', 'Var', (30, 39))	('ATP production', 'MPA', (237, 251))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('reducing', 'NegReg', (175, 183))	('ATP', 'Chemical', 'MESH:D000255', (237, 240))	('metformin', 'Chemical', 'MESH:D008687', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('inhibition', 'NegReg', (100, 110))
256593	26904687	suggests that metformin reduces DDP-induced anticancer activity in vitro through the AMPK-independent upregulation of the AKT survival pathway, because metformin induces AKT activation in DDP-treated cells and treatment with an AKT inhibitor abolishes the antioxidant and antiapoptotic effects of metformin.	('AKT', 'Gene', '207', (170, 173))	('AMPK', 'Gene', (85, 89))	('AKT', 'Gene', (228, 231))	('cancer', 'Disease', (48, 54))	('AKT', 'Gene', '207', (122, 125))	('DDP', 'Gene', '1678', (188, 191))	('DDP', 'Gene', (188, 191))	('metformin', 'Chemical', 'MESH:D008687', (297, 306))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('metformin', 'Var', (152, 161))	('metformin', 'Chemical', 'MESH:D008687', (152, 161))	('reduces', 'NegReg', (24, 31))	('AKT', 'Gene', '207', (228, 231))	('AKT', 'Gene', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('activation', 'PosReg', (174, 184))	('AKT', 'Gene', (122, 125))	('AMPK', 'Gene', '5563', (85, 89))	('DDP', 'Gene', '1678', (32, 35))	('antiapoptotic', 'CPA', (272, 285))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('DDP', 'Gene', (32, 35))
256603	26904687	showed that, in patients of esophageal cancer, use of metformin was associated with significantly improved overall survival, significantly increased distant metastasis-free survival, and a higher complete response rate.	('esophageal cancer', 'Disease', (28, 45))	('metformin', 'Chemical', 'MESH:D008687', (54, 63))	('complete response', 'CPA', (196, 213))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('patients', 'Species', '9606', (16, 24))	('increased', 'PosReg', (139, 148))	('distant metastasis-free survival', 'CPA', (149, 181))	('overall', 'MPA', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('metformin', 'Var', (54, 63))	('improved', 'PosReg', (98, 106))
256605	26904687	In contrast to the cytoprotective effect of metformin observed under high glucose conditions, we showed that metformin synergistically augments the cytotoxicity of DDP in cells cultured under glucose-deprivation conditions.	('augments', 'PosReg', (135, 143))	('glucose-deprivation conditions', 'Disease', (192, 222))	('metformin', 'Var', (109, 118))	('high glucose', 'Phenotype', 'HP:0003074', (69, 81))	('cytotoxicity', 'Disease', 'MESH:D064420', (148, 160))	('DDP', 'Gene', (164, 167))	('metformin', 'Chemical', 'MESH:D008687', (109, 118))	('glucose-deprivation conditions', 'Disease', 'MESH:D012892', (192, 222))	('metformin', 'Chemical', 'MESH:D008687', (44, 53))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))	('glucose', 'Chemical', 'MESH:D005947', (192, 199))	('DDP', 'Gene', '1678', (164, 167))	('cytotoxicity', 'Disease', (148, 160))
256609	29934340	PET-avidity is indicative of high glucose utilization and is nearly universal in EAC.	('EAC', 'Phenotype', 'HP:0011459', (81, 84))	('high glucose utilization', 'MPA', (29, 53))	('EAC', 'Disease', (81, 84))	('high glucose', 'Phenotype', 'HP:0003074', (29, 41))	('PET-avidity', 'Var', (0, 11))	('glucose', 'Chemical', 'MESH:D005947', (34, 41))
256617	29934340	TXNIP overexpression increased whereas knockdown abrogated DNA damage and apoptosis following cisplatin treatment.	('apoptosis', 'CPA', (74, 83))	('abrogated', 'NegReg', (49, 58))	('knockdown', 'Var', (39, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('DNA damage', 'MPA', (59, 69))
256627	29934340	This 'Warburg effect' which decreases ATP production (2 vs 36 per mole glucose) and increases lactate production appears counterintuitive; however, these metabolic alterations facilitate biosynthesis of macromolecules such as proteins, nucleotides, and lipids through the mitochondria.	('ATP production', 'MPA', (38, 52))	('decreases', 'NegReg', (28, 37))	('mole', 'Phenotype', 'HP:0003764', (208, 212))	('lactate production', 'MPA', (94, 112))	('facilitate', 'PosReg', (176, 186))	('glucose', 'Chemical', 'MESH:D005947', (71, 78))	('lipids', 'Chemical', 'MESH:D008055', (253, 259))	('ATP', 'Chemical', 'MESH:D000255', (38, 41))	('increases', 'PosReg', (84, 93))	('alterations', 'Var', (164, 175))	('biosynthesis of macromolecules', 'MPA', (187, 217))	('lactate', 'Chemical', 'MESH:D019344', (94, 101))	('mole', 'Phenotype', 'HP:0003764', (66, 70))	('proteins', 'Protein', (226, 234))
256639	29934340	In contrast, glutamine inhibits TXNIP expression, thus facilitating glucose uptake.	('glucose uptake', 'CPA', (68, 82))	('TXNIP expression', 'MPA', (32, 48))	('glucose', 'Chemical', 'MESH:D005947', (68, 75))	('glutamine', 'Chemical', 'MESH:D005973', (13, 22))	('facilitating', 'PosReg', (55, 67))	('inhibits', 'NegReg', (23, 31))	('glutamine', 'Var', (13, 22))
256642	29934340	TXNIP expression in EAC has been associated with higher tumor differentiation, lack of lymph node metastases, and reduced perineural invasion.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('reduced', 'NegReg', (114, 121))	('tumor', 'Disease', (56, 61))	('lack of lymph node', 'Phenotype', 'HP:0002732', (79, 97))	('EAC', 'Phenotype', 'HP:0011459', (20, 23))	('metastases', 'Disease', (98, 108))	('TXNIP expression', 'Var', (0, 16))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('perineural invasion', 'CPA', (122, 141))	('higher', 'PosReg', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('EAC', 'Gene', (20, 23))
256643	29934340	High TXNIP expression also correlated with improved disease-specific survival in EAC patients receiving anthracycline-based chemotherapy prior to esophagectomy.	('EAC', 'Phenotype', 'HP:0011459', (81, 84))	('High', 'Var', (0, 4))	('anthracycline', 'Chemical', 'MESH:D018943', (104, 117))	('TXNIP', 'Protein', (5, 10))	('expression', 'MPA', (11, 21))	('patients', 'Species', '9606', (85, 93))	('disease-specific survival', 'CPA', (52, 77))	('improved', 'PosReg', (43, 51))
256693	29934340	However, glutamine almost completely abrogated glucose-mediated induction of TXNIP.	('glucose-mediated induction', 'MPA', (47, 73))	('glutamine', 'Chemical', 'MESH:D005973', (9, 18))	('glutamine', 'Var', (9, 18))	('abrogated', 'NegReg', (37, 46))	('glucose', 'Chemical', 'MESH:D005947', (47, 54))	('TXNIP', 'MPA', (77, 82))
256698	29934340	Additionally, knockdown of TXNIP in Esc2 did not alter ECAR (Supplemental Figure 3).	('ECAR', 'MPA', (55, 59))	('Esc2', 'Gene', (36, 40))	('Esc2', 'Gene', '84901', (36, 40))	('knockdown', 'Var', (14, 23))
256699	29934340	Consistent with results of SeaHorse experiments, TXNIP over-expression significantly (albeit relatively modestly) decreased glucose uptake in Flo-1 but not Esc2 cells (Supplemental Figure 4).	('glucose', 'Chemical', 'MESH:D005947', (124, 131))	('Esc2', 'Gene', '84901', (156, 160))	('TXNIP', 'Var', (49, 54))	('over-expression', 'PosReg', (55, 70))	('decreased', 'NegReg', (114, 123))	('Esc2', 'Gene', (156, 160))	('glucose uptake', 'MPA', (124, 138))
256700	29934340	However, TXNIP expression decreased lactate secretion in Flo-1 and Esc2 cells indicating a global decrease in glycolysis (Figure 2B).	('decrease', 'NegReg', (98, 106))	('lactate secretion', 'MPA', (36, 53))	('lactate', 'Chemical', 'MESH:D019344', (36, 43))	('TXNIP', 'Var', (9, 14))	('Esc2', 'Gene', '84901', (67, 71))	('decreased', 'NegReg', (26, 35))	('glycolysis', 'MPA', (110, 120))	('Esc2', 'Gene', (67, 71))
256705	29934340	Additionally, knockdown of TXNIP in Esc2 did not alter OCR (Supplemental Figure 7).	('Esc2', 'Gene', (36, 40))	('OCR', 'MPA', (55, 58))	('Esc2', 'Gene', '84901', (36, 40))	('knockdown', 'Var', (14, 23))
256708	29934340	Given that glutamine markedly represses TXNIP expression and significantly inhibits EACC proliferation, we asked whether TXNIP acts primarily as a tumor suppressor rather than a metabolic regulator in EACC.	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('glutamine', 'Chemical', 'MESH:D005973', (11, 20))	('tumor', 'Disease', (147, 152))	('EACC', 'Chemical', '-', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('EACC proliferation', 'CPA', (84, 102))	('EAC', 'Phenotype', 'HP:0011459', (201, 204))	('glutamine', 'Var', (11, 20))	('EACC', 'Chemical', '-', (84, 88))	('TXNIP', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('expression', 'MPA', (46, 56))	('represses', 'NegReg', (30, 39))	('inhibits', 'NegReg', (75, 83))
256715	29934340	As shown in Figures 3 C, D and E, volumes and masses of subcutaneous xenografts established from Esc2 overexpressing TXNIP were significantly smaller than tumors derived from vector control cells.	('overexpressing TXNIP', 'Var', (102, 122))	('TXNIP', 'Var', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('Esc2', 'Gene', (97, 101))	('smaller', 'NegReg', (142, 149))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('Esc2', 'Gene', '84901', (97, 101))
256720	29934340	In light of observations that TXNIP expression in gastroesophageal carcinomas has been associated with improved survival in patients treated with induction chemotherapy prior to esophagectomy, we queried whether standard therapy modulated the expression of TXNIP.	('gastroesophageal carcinomas', 'Disease', (50, 77))	('gastroesophageal carcinomas', 'Disease', 'MESH:D005764', (50, 77))	('improved', 'PosReg', (103, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('survival', 'MPA', (112, 120))	('TXNIP', 'Var', (30, 35))	('patients', 'Species', '9606', (124, 132))
256725	29934340	CDDP also increased TNXIP protein levels in EACC.	('EAC', 'Phenotype', 'HP:0011459', (44, 47))	('EACC', 'Chemical', '-', (44, 48))	('CDDP', 'Var', (0, 4))	('TNXIP protein levels', 'MPA', (20, 40))	('CDDP', 'Chemical', '-', (0, 4))	('increased', 'PosReg', (10, 19))
256727	29934340	Additionally, knock-down of TXNIP significantly attenuated CDDP-mediated induction of TXNIP in EACC (Figure 4C).	('EAC', 'Phenotype', 'HP:0011459', (95, 98))	('attenuated', 'NegReg', (48, 58))	('EACC', 'Chemical', '-', (95, 99))	('knock-down', 'Var', (14, 24))	('CDDP', 'Chemical', '-', (59, 63))
256728	29934340	These findings show that cisplatin robustly induces TXNIP regardless of its baseline expression in EACC.	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('cisplatin', 'Chemical', 'MESH:D002945', (25, 34))	('TXNIP', 'MPA', (52, 57))	('EACC', 'Chemical', '-', (99, 103))	('cisplatin', 'Var', (25, 34))	('induces', 'Reg', (44, 51))
256735	29934340	Consistent with these observations, knockdown of TXNIP markedly attenuated CDDP-mediated apoptosis in EACC (Figure 4F).	('EAC', 'Phenotype', 'HP:0011459', (102, 105))	('CDDP-mediated apoptosis', 'CPA', (75, 98))	('knockdown', 'Var', (36, 45))	('EACC', 'Chemical', '-', (102, 106))	('CDDP', 'Chemical', '-', (75, 79))	('attenuated', 'NegReg', (64, 74))
256736	29934340	Results described thus far demonstrate that EACC are dependent on glutamine, and that glutamine represses TXNIP expression in these cells.	('represses', 'NegReg', (96, 105))	('glutamine', 'Var', (86, 95))	('glutamine', 'Chemical', 'MESH:D005973', (86, 95))	('EAC', 'Phenotype', 'HP:0011459', (44, 47))	('EACC', 'Chemical', '-', (44, 48))	('TXNIP expression', 'MPA', (106, 122))	('glutamine', 'Chemical', 'MESH:D005973', (66, 75))
256738	29934340	Restoration of TXNIP expression markedly inhibits growth of EACC in-vitro and in-vivo, and sensitizes these cells to CDDP-mediated DNA damage and apoptosis.	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('inhibits', 'NegReg', (41, 49))	('CDDP', 'Chemical', '-', (117, 121))	('sensitizes', 'Reg', (91, 101))	('Restoration', 'Var', (0, 11))	('TXNIP', 'Gene', (15, 20))	('EACC', 'Chemical', '-', (60, 64))	('growth', 'CPA', (50, 56))
256744	29934340	Indeed, knockdown of TXNIP significantly abrogated the induction of apoptosis by the combination of CDDP and entinostat (Figure 5D and Supplemental Figure 14).	('abrogated', 'NegReg', (41, 50))	('knockdown', 'Var', (8, 17))	('apoptosis', 'CPA', (68, 77))	('entinostat', 'Chemical', 'MESH:C118739', (109, 119))	('CDDP', 'Chemical', '-', (100, 104))
256748	29934340	When the site is not cleaved, the Ubi domain results in proteasome degradation of GFP, whereas, if caspase 3 site is cleaved, then GFP will not be degraded and is detectable.	('proteasome degradation', 'MPA', (56, 78))	('caspase 3', 'Gene', (99, 108))	('caspase 3', 'Gene', '836', (99, 108))	('Ubi domain', 'Var', (34, 44))	('results in', 'Reg', (45, 55))
256770	29934340	We also observed that overexpression of TXNIP significantly decreased proliferation, clonogenicity, and tumorigenicity suggesting that TXNIP functions as a tumor suppressor in EACC.	('EACC', 'Chemical', '-', (176, 180))	('decreased', 'NegReg', (60, 69))	('clonogenicity', 'CPA', (85, 98))	('EACC', 'Disease', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('TXNIP', 'Var', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (104, 109))	('proliferation', 'CPA', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('EAC', 'Phenotype', 'HP:0011459', (176, 179))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
256777	29934340	Vendetti and colleagues demonstrated that in NSCLC, epigenetic priming with entinostat prior to irinotecan sensitized A549 xenografts and enhanced tumor response in a patient-derived xenograft model.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('entinostat', 'Chemical', 'MESH:C118739', (76, 86))	('NSCLC', 'Disease', (45, 50))	('entinostat', 'Gene', (76, 86))	('sensitized', 'Reg', (107, 117))	('patient', 'Species', '9606', (167, 174))	('enhanced', 'PosReg', (138, 146))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('irinotecan', 'Chemical', 'MESH:D000077146', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('A549', 'CellLine', 'CVCL:0023', (118, 122))	('epigenetic priming', 'Var', (52, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))
256782	29934340	We provide evidence that glutamine is required for EACC proliferation and that glutamine suppresses TXNIP.	('glutamine', 'Chemical', 'MESH:D005973', (25, 34))	('glutamine', 'Var', (79, 88))	('TXNIP', 'MPA', (100, 105))	('suppresses', 'NegReg', (89, 99))	('EACC', 'Chemical', '-', (51, 55))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('glutamine', 'Chemical', 'MESH:D005973', (79, 88))
256783	29934340	In EACC, we report that TXNIP acts as a tumor suppressor and can sensitize these cells to chemotherapeutics.	('TXNIP', 'Var', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('EACC', 'Chemical', '-', (3, 7))
256805	32342878	Second, radiation therapy, especially when delivered concurrently with chemotherapy, may cause lymphopenia which is likely to persist over the course of therapy, resulting in immunosuppression and thus increased susceptibility to the virus.	('increased', 'PosReg', (202, 211))	('susceptibility', 'MPA', (212, 226))	('lymphopenia', 'Disease', (95, 106))	('immunosuppression', 'MPA', (175, 192))	('radiation therapy', 'Var', (8, 25))	('lymphopenia', 'Phenotype', 'HP:0001888', (95, 106))	('lymphopenia', 'Disease', 'MESH:D008231', (95, 106))
256967	15535453	demonstrated that outpatients receiving a nutritional support product (1,000 kcal, 34 grams protein) through a feeding tube (i.e., enteral nutritional support) had significantly improved protein intake and significantly fewer hospitalizations.	('improved', 'PosReg', (178, 186))	('hospitalizations', 'MPA', (226, 242))	('1,000', 'Var', (71, 76))	('protein intake', 'MPA', (187, 201))	('patients', 'Species', '9606', (21, 29))	('fewer', 'NegReg', (220, 225))
256977	15535453	In this study, mortality was reduced by nearly 50 percent in patients receiving PTU.	('mortality', 'MPA', (15, 24))	('patients', 'Species', '9606', (61, 69))	('reduced', 'NegReg', (29, 36))	('PTU', 'Chemical', 'MESH:D011441', (80, 83))	('PTU', 'Var', (80, 83))
257002	15535453	Research demonstrates a strong rationale for using many of these CAM agents, such as S-adenosylmethionine, but shows that others may have no efficacy or may even cause harm, including liver injury.	('S-adenosylmethionine', 'Var', (85, 105))	('liver injury', 'Disease', (184, 196))	('liver injury', 'Disease', 'MESH:D056486', (184, 196))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (85, 105))	('cause', 'Reg', (162, 167))
257076	15535453	An analysis of 11 prospective studies evaluating the effectiveness of nonselective beta blockers at preventing initial variceal bleeding showed that beta blockers decreased the risk of first bleed by at least 40 percent (25 percent in control subjects vs. 15 percent in the treatment group) after a median of 2 years.	('bleeding', 'Disease', (128, 136))	('bleeding', 'Disease', 'MESH:D006470', (128, 136))	('decreased', 'NegReg', (163, 172))	('beta blockers', 'Var', (149, 162))
257091	15535453	Despite the fact that TIPS is more effective than endoscopic therapy in decreasing rebleeding from esophageal varices (19 percent rebleeding with TIPS vs. 47 percent with endoscopic therapy), 1 in 3 of these patients will develop hepatic encephalopathy after TIPS, and this intervention does not affect survival rates.	('develop', 'PosReg', (222, 229))	('bleeding', 'Disease', 'MESH:D006470', (132, 140))	('patients', 'Species', '9606', (208, 216))	('bleeding', 'Disease', (132, 140))	('bleeding', 'Disease', 'MESH:D006470', (85, 93))	('esophageal varices', 'Phenotype', 'HP:0002040', (99, 117))	('encephalopathy', 'Phenotype', 'HP:0001298', (238, 252))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (230, 252))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (230, 252))	('hepatic encephalopathy', 'Disease', (230, 252))	('bleeding', 'Disease', (85, 93))	('decreasing', 'NegReg', (72, 82))	('TIPS', 'Var', (259, 263))
257186	28289510	Between January 2004 and December 2013, 105 patients underwent total gastrectomy (TG) (n = 42, 40%) or subtotal gastrectomy (SG) (n = 63, 60%) (Figure 2).	('TG', 'Chemical', '-', (82, 84))	('subtotal', 'Var', (103, 111))	('patients', 'Species', '9606', (44, 52))	('total gastrectomy', 'Disease', (63, 80))
257210	28289510	In our series, the Ivor-Lewis approach to esophagectomy was associated with lower feeding tube utilization rates at discharge compared to the transhiatal approach (25.0% vs 59.8%, respectively; P < 0.0001).	('lower', 'NegReg', (76, 81))	('feeding tube utilization rates', 'MPA', (82, 112))	('Ivor-Lewis approach', 'Var', (19, 38))	('feed', 'Chemical', '-', (82, 86))
257231	28289510	Specific resections were associated with need for tube feed supplementation, as patients who underwent transhiatal esophagectomy more frequently required nutritional supplementation at that time of discharge compared to Ivor-Lewis esophagectomy (59.8% vs 25.0%, respectively; P < 0.0001).	('transhiatal', 'Var', (103, 114))	('nutritional supplementation', 'MPA', (154, 181))	('patients', 'Species', '9606', (80, 88))	('feed', 'Chemical', '-', (55, 59))
257253	27384996	Although dysregulated activity of cell growth regulators is often associated with cancer, the prognostic significance and metabolic roles of V-ATPase in esophageal cancer progression remain unclear.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('V-ATPase', 'Gene', '242341', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('associated', 'Reg', (66, 76))	('dysregulated', 'Var', (9, 21))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('esophageal cancer', 'Disease', (153, 170))	('activity', 'MPA', (22, 30))	('V-ATPase', 'Gene', (141, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
257254	27384996	Here, we show that high levels of V-ATPase subunit V1E1 (V-ATPase V1E1) were significantly associated with shortened disease-free survival in patients with esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('high', 'Var', (19, 23))	('V-ATPase', 'Gene', (34, 42))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (156, 190))	('V-ATPase', 'Gene', '242341', (57, 65))	('shortened', 'NegReg', (107, 116))	('disease-free survival', 'CPA', (117, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (167, 190))	('V-ATPase', 'Gene', '242341', (34, 42))	('esophageal squamous cell carcinoma', 'Disease', (156, 190))	('patients', 'Species', '9606', (142, 150))	('V-ATPase', 'Gene', (57, 65))
257257	27384996	Consistent with these results, the Cancer Genome Atlas (TCGA) data and Gene Set Enrichment Analysis (GSEA) showed a high frequency of copy number alterations of the V-ATPase V1E1 gene, and identified a correlation between levels of V-ATPase V1E1 mRNA and Pyruvate Kinase M2 (PKM2) in ESCC.	('V-ATPase', 'Gene', (232, 240))	('ESCC', 'Disease', (284, 288))	('V-ATPase', 'Gene', '242341', (232, 240))	('V-ATPase', 'Gene', (165, 173))	('GSEA', 'Chemical', '-', (101, 105))	('Pyruvate Kinase M2', 'Gene', '18746', (255, 273))	('Cancer Genome Atlas', 'Disease', (35, 54))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (35, 54))	('V-ATPase', 'Gene', '242341', (165, 173))	('Pyruvate Kinase M2', 'Gene', (255, 273))	('copy number alterations', 'Var', (134, 157))
257264	27384996	In addition, expression of Hexokinase-1 (HK1), another glycolytic enzyme, is associated with disease progression, invasion, and poor survival of patients with ESCC.	('poor', 'NegReg', (128, 132))	('patients', 'Species', '9606', (145, 153))	('Hexokinase-1', 'Gene', '3098', (27, 39))	('glycolytic enzyme', 'Gene', (55, 72))	('HK1', 'Gene', '3098', (41, 44))	('expression', 'Var', (13, 23))	('Hexokinase-1', 'Gene', (27, 39))	('HK1', 'Gene', (41, 44))	('glycolytic enzyme', 'Gene', '3098', (55, 72))	('invasion', 'CPA', (114, 122))	('associated with', 'Reg', (77, 92))	('ESCC', 'Disease', (159, 163))
257283	27384996	In addition, we assessed the effects of V-ATPase V1E1 depletion on esophageal cancer cell viability, aerobic glycolysis, glycolytic gene expression, and oxygen consumption.	('depletion', 'Var', (54, 63))	('aerobic glycolysis', 'MPA', (101, 119))	('V-ATPase', 'Gene', '242341', (40, 48))	('glycolytic gene expression', 'MPA', (121, 147))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('oxygen', 'Chemical', 'MESH:D010100', (153, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('V-ATPase', 'Gene', (40, 48))
257286	27384996	We first validated the specificity of antibodies by immunostaining sections containing TE8 esophageal cancer cells, in which V-ATPase V1E1 was knocked down or not with siRNA or non-silencing siRNA (control).	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TE8 esophageal cancer', 'Phenotype', 'HP:0011459', (87, 108))	('knocked', 'Var', (143, 150))	('V-ATPase', 'Gene', (125, 133))	('esophageal cancer', 'Disease', (91, 108))	('V-ATPase', 'Gene', '242341', (125, 133))
257298	27384996	High V-ATPase V1E1 levels were more significantly associated with reduced disease-free survival in early-stage ESCC patients (P = 0.005) than in late-stage patients (P = 0.414) (Figure 2B, 2C).	('patients', 'Species', '9606', (156, 164))	('reduced', 'NegReg', (66, 73))	('disease-free survival', 'CPA', (74, 95))	('V-ATPase', 'Gene', '242341', (5, 13))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (116, 124))	('V-ATPase', 'Gene', (5, 13))	('ESCC', 'Disease', (111, 115))
257300	27384996	This conclusion is supported by the fact that high expression of V-ATPase V1E1 was significantly associated with reduced disease-free survival (P = 0.004; Figure 2D) and reduced overall survival (Supplementary Figure S1B).	('high', 'Var', (46, 50))	('reduced', 'NegReg', (170, 177))	('V-ATPase', 'Gene', (65, 73))	('disease-free survival', 'CPA', (121, 142))	('reduced', 'NegReg', (113, 120))	('V-ATPase', 'Gene', '242341', (65, 73))	('overall survival', 'CPA', (178, 194))
257304	27384996	Moreover, disease-free (HR, 0.722; 95% CI; 0.6-0.9, P = 0.004) and overall survival (HR, 0.732; 95% CI; 0.6-0.9, P = 0.010) of patients with recurrent esophageal cancer treated with radiation therapy was poorer in patients with high V-ATPase V1E1 expression (Table 3).	('esophageal cancer', 'Disease', (151, 168))	('high', 'Var', (228, 232))	('patients', 'Species', '9606', (214, 222))	('expression', 'MPA', (247, 257))	('V-ATPase', 'Gene', (233, 241))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('patients', 'Species', '9606', (127, 135))	('poorer', 'NegReg', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('V-ATPase', 'Gene', '242341', (233, 241))
257308	27384996	However, knockdown of V-ATPase V1E1 resulted in decreased proliferation of TE8 esophageal cancer cells (Figure 3A).	('V-ATPase', 'Gene', (22, 30))	('esophageal cancer', 'Disease', (79, 96))	('knockdown', 'Var', (9, 18))	('proliferation', 'CPA', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('TE8 esophageal cancer', 'Phenotype', 'HP:0011459', (75, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('V-ATPase', 'Gene', '242341', (22, 30))	('decreased', 'NegReg', (48, 57))
257312	27384996	Moreover, levels of apoptotic proteins including cleaved caspase 3 and Poly [ADP-ribose] polymerase 1 (PARP) were increased substantially by V-ATPase V1E1 depletion (Figure 3B).	('cleaved caspase 3', 'MPA', (49, 66))	('Poly [ADP-ribose] polymerase 1', 'Gene', '11545', (71, 101))	('V-ATPase', 'Gene', '242341', (141, 149))	('increased', 'PosReg', (114, 123))	('levels of apoptotic proteins', 'MPA', (10, 38))	('PARP', 'Gene', (103, 107))	('Poly [ADP-ribose] polymerase 1', 'Gene', (71, 101))	('PARP', 'Gene', '11545', (103, 107))	('V-ATPase', 'Gene', (141, 149))	('depletion', 'Var', (155, 164))
257316	27384996	In addition, V-ATPase V1E1 depletion led to reduced expression of Vimentin, Matrix Metalloproteinases 2 (MMP2), and Matrix Metalloproteinases 7 (MMP7), which mediate epithelial-to-mesenchymal transition (EMT) (Figure 4C).	('V-ATPase', 'Gene', (13, 21))	('Vimentin', 'Gene', (66, 74))	('MMP2', 'Gene', '17390', (105, 109))	('Matrix Metalloproteinases 7', 'Gene', '17393', (116, 143))	('Vimentin', 'Gene', '22352', (66, 74))	('expression', 'MPA', (52, 62))	('V-ATPase', 'Gene', '242341', (13, 21))	('epithelial-to-mesenchymal', 'CPA', (166, 191))	('MMP7', 'Gene', '17393', (145, 149))	('Matrix Metalloproteinases 2', 'Gene', (76, 103))	('depletion', 'Var', (27, 36))	('Matrix Metalloproteinases 7', 'Gene', (116, 143))	('MMP7', 'Gene', (145, 149))	('reduced', 'NegReg', (44, 51))	('MMP2', 'Gene', (105, 109))	('Matrix Metalloproteinases 2', 'Gene', '17390', (76, 103))
257317	27384996	EMT is the first step in the process of metastasis, and converts the adherent phenotype of epithelial cancer cells to an invasive, migratory mesenchymal phenotype.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('epithelial cancer', 'Phenotype', 'HP:0031492', (91, 108))	('epithelial cancer', 'Disease', 'MESH:D000077216', (91, 108))	('epithelial cancer', 'Disease', (91, 108))	('EMT', 'Var', (0, 3))
257319	27384996	Based on this finding, we examined whether V-ATPase V1E1 knockdown affected focal adhesion of TE8 esophageal cancer cells.	('affected', 'Reg', (67, 75))	('V-ATPase', 'Gene', '242341', (43, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))	('knockdown', 'Var', (57, 66))	('focal adhesion', 'CPA', (76, 90))	('esophageal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('TE8 esophageal cancer', 'Phenotype', 'HP:0011459', (94, 115))	('V-ATPase', 'Gene', (43, 51))
257320	27384996	V-ATPase V1E1 depletion led to pronounced inhibition of focal adhesion formation as revealed by less densely stained phosphorylated paxillin, which mediates the interaction between the actin cytoskeleton and integrin (Figure 4D, 4E).	('V-ATPase', 'Gene', (0, 8))	('paxillin', 'Gene', (132, 140))	('paxillin', 'Gene', '19303', (132, 140))	('depletion', 'Var', (14, 23))	('focal adhesion formation', 'CPA', (56, 80))	('V-ATPase', 'Gene', '242341', (0, 8))	('inhibition', 'NegReg', (42, 52))
257325	27384996	We measured levels of lactate and ATP, major sources of energy generated from aerobic glycolysis, in TE8 cells after V-ATPase V1E1 knockdown.	('V-ATPase', 'Gene', '242341', (117, 125))	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('knockdown', 'Var', (131, 140))	('lactate', 'Chemical', 'MESH:D019344', (22, 29))	('ATP', 'Chemical', 'MESH:D000255', (34, 37))	('lactate', 'MPA', (22, 29))	('ATP', 'MPA', (34, 37))	('V-ATPase', 'Gene', (117, 125))
257326	27384996	The levels of lactate and ATP were markedly decreased in V-ATPase V1E1 depleted cells compared to cells treated with non-silencing siRNA (Figure 5A, 5B), indicating that V-ATPase V1E1 acts to shift metabolic flux toward aerobic glycolysis and away from mitochondrial respiration.	('depleted', 'Var', (71, 79))	('ATP', 'Chemical', 'MESH:D000255', (26, 29))	('levels', 'MPA', (4, 10))	('V-ATPase', 'Gene', '242341', (170, 178))	('V-ATPase', 'Gene', '242341', (57, 65))	('ATP', 'Chemical', 'MESH:D000255', (172, 175))	('ATP', 'Chemical', 'MESH:D000255', (59, 62))	('metabolic flux', 'MPA', (198, 212))	('decreased', 'NegReg', (44, 53))	('V-ATPase', 'Gene', (170, 178))	('shift', 'PosReg', (192, 197))	('lactate', 'Chemical', 'MESH:D019344', (14, 21))	('aerobic glycolysis', 'MPA', (220, 238))	('V-ATPase', 'Gene', (57, 65))
257327	27384996	Furthermore, V-ATPase V1E1 depletion led to suppression of glucose uptake (Figure 5C), which is linked to reduced levels of lactate in V-ATPase V1E1 knockdown cells.	('V-ATPase', 'Gene', '242341', (135, 143))	('V-ATPase', 'Gene', (13, 21))	('levels of lactate', 'MPA', (114, 131))	('glucose', 'MPA', (59, 66))	('V-ATPase', 'Gene', '242341', (13, 21))	('depletion', 'Var', (27, 36))	('V-ATPase', 'Gene', (135, 143))	('suppression', 'NegReg', (44, 55))	('reduced', 'NegReg', (106, 113))	('glucose', 'Chemical', 'MESH:D005947', (59, 66))	('lactate', 'Chemical', 'MESH:D019344', (124, 131))
257329	27384996	V-ATPase V1E1 depletion resulted in decreased expression of glycolytic enzymes, Glut1, PKM2, and LDHA (Figure 5D), which are key drivers of the metabolic switch from oxidative phosphorylation to aerobic glycolysis.	('glycolytic enzyme', 'Gene', '3098', (60, 77))	('V-ATPase', 'Gene', (0, 8))	('Glut1', 'Gene', '20525', (80, 85))	('PKM2', 'Gene', (87, 91))	('glycolytic enzyme', 'Gene', (60, 77))	('Glut1', 'Gene', (80, 85))	('LDHA', 'Gene', '16828', (97, 101))	('LDHA', 'Gene', (97, 101))	('depletion', 'Var', (14, 23))	('V-ATPase', 'Gene', '242341', (0, 8))	('expression', 'MPA', (46, 56))	('decreased', 'NegReg', (36, 45))
257338	27384996	V-ATPase V1E1 depletion resulted in decreased phosphorylation levels of AKT at ser473 and of PKM2 at Tyr105, while total AKT and PKM2 levels remained unchanged (Figure 5G), suggesting that V1E1 promotes glycolysis through AKT and PKM2.	('AKT', 'Gene', '11651', (121, 124))	('promotes', 'PosReg', (194, 202))	('AKT', 'Gene', '11651', (72, 75))	('phosphorylation levels', 'MPA', (46, 68))	('V-ATPase', 'Gene', (0, 8))	('AKT', 'Gene', (121, 124))	('AKT', 'Gene', (72, 75))	('V1E1', 'Protein', (9, 13))	('AKT', 'Gene', '11651', (222, 225))	('ser473', 'Chemical', '-', (79, 85))	('depletion', 'Var', (14, 23))	('Tyr105', 'Chemical', '-', (101, 107))	('V-ATPase', 'Gene', '242341', (0, 8))	('glycolysis', 'MPA', (203, 213))	('V1E1', 'Var', (189, 193))	('AKT', 'Gene', (222, 225))	('decreased', 'NegReg', (36, 45))
257339	27384996	To determine whether the expression of V-ATPase V1E1 was associated with PKM2, we measured the concomitant expression of V-ATPase V1E1, p-PKM2, PKM2, and mTOR in esophageal cancer tissues (Figure 5H).	('V-ATPase', 'Gene', (39, 47))	('esophageal cancer', 'Disease', (162, 179))	('V-ATPase', 'Gene', '242341', (39, 47))	('p-PKM2', 'Var', (136, 142))	('V-ATPase', 'Gene', (121, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('V-ATPase', 'Gene', '242341', (121, 129))	('associated', 'Reg', (57, 67))
257346	27384996	Genetic alterations, especially amplification of V-ATPase V1E1, were frequently found in ESCC compared with other types of cancer.	('found', 'Reg', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('V-ATPase', 'Gene', (49, 57))	('amplification', 'Var', (32, 45))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('ESCC', 'Disease', (89, 93))	('cancer', 'Disease', (123, 129))	('V-ATPase', 'Gene', '242341', (49, 57))
257351	27384996	We found that gene expression signatures related to cancer metabolism, including hypoxia (NES = 1.8) and glycolysis signaling (NES = 1.4), were enriched in patients expressing high V1E1 levels (Figure 6C).	('patients', 'Species', '9606', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('hypoxia', 'Disease', (81, 88))	('V1E1 levels', 'MPA', (181, 192))	('hypoxia', 'Disease', 'MESH:D000860', (81, 88))	('glycolysis signaling', 'MPA', (105, 125))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('high', 'Var', (176, 180))
257354	27384996	To assess the clinical relevance of this finding, we performed an immunohistochemical examination of the protein levels of V-ATPase V1E1 and p-PKM2 in cancer tissues from a distinct ESCC cohort (n = 302) (Supplementary Table S1).	('V-ATPase', 'Gene', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('V-ATPase', 'Gene', '242341', (123, 131))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('p-PKM2', 'Var', (141, 147))
257357	27384996	This analysis showed a strong correlation between levels of V-ATPase V1E1 and p-PKM2 (P < 0.001) (Figure 7A).	('V-ATPase', 'Gene', (60, 68))	('V-ATPase', 'Gene', '242341', (60, 68))	('p-PKM2', 'Var', (78, 84))
257362	27384996	Consistent with the role of V-ATPase on nutrient sensing with mTORC1, malfunction or overexpression of V-ATPase has been reported in breast cancer and other diseases, including inherited distal renal tubular acidosis, sensorineural deafness, and osteopetrosis.	('distal renal tubular acidosis', 'Disease', (187, 216))	('malfunction', 'Var', (70, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('overexpression', 'PosReg', (85, 99))	('osteopetrosis', 'Disease', (246, 259))	('acidosis', 'Phenotype', 'HP:0001941', (208, 216))	('V-ATPase', 'Gene', '242341', (28, 36))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('breast cancer', 'Disease', (133, 146))	('sensorineural deafness', 'Phenotype', 'HP:0000407', (218, 240))	('osteopetrosis', 'Phenotype', 'HP:0011002', (246, 259))	('reported', 'Reg', (121, 129))	('V-ATPase', 'Gene', (28, 36))	('deafness', 'Phenotype', 'HP:0000365', (232, 240))	('distal renal tubular acidosis', 'Phenotype', 'HP:0008341', (187, 216))	('sensorineural deafness', 'Disease', (218, 240))	('renal tubular acidosis', 'Phenotype', 'HP:0001947', (194, 216))	('mTORC1', 'Gene', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('V-ATPase', 'Gene', '242341', (103, 111))	('mTORC1', 'Gene', '382056', (62, 68))	('osteopetrosis', 'Disease', 'MESH:D010022', (246, 259))	('sensorineural deafness', 'Disease', 'MESH:D006313', (218, 240))	('V-ATPase', 'Gene', (103, 111))	('distal renal tubular acidosis', 'Disease', 'MESH:D000141', (187, 216))
257368	27384996	In addition, knockdown of V-ATPase subunit V1G or treatment with the V-ATPase inhibitor, archazolid, results in apoptosis in glioblastoma and bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('apoptosis', 'CPA', (112, 121))	('V-ATPase', 'Gene', (26, 34))	('archazolid', 'Chemical', '-', (89, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('V-ATPase', 'Gene', (69, 77))	('V-ATPase', 'Gene', '242341', (26, 34))	('glioblastoma', 'Disease', (125, 137))	('V-ATPase', 'Gene', '242341', (69, 77))	('knockdown', 'Var', (13, 22))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))
257372	27384996	In line with this, we showed that knockdownof V-ATPase V1E1 resulted in a reduction of migration and invasion of esophageal squamous cell carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('V-ATPase', 'Gene', '242341', (46, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('knockdownof', 'Var', (34, 45))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('reduction', 'NegReg', (74, 83))	('V-ATPase', 'Gene', (46, 54))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('V1E1', 'Var', (55, 59))	('invasion', 'CPA', (101, 109))
257373	27384996	In addition, recent studies showed that the expression of V-ATPase subunits V1A, V1G and V0a are associated with metastasis of ovarian cancer, glioma, and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (155, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (127, 141))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (155, 169))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('V-ATPase', 'Gene', (58, 66))	('metastasis of ovarian cancer', 'Disease', (113, 141))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('associated with', 'Reg', (97, 112))	('glioma', 'Disease', (143, 149))	('V-ATPase', 'Gene', '242341', (58, 66))	('gastric cancer', 'Disease', (155, 169))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (113, 141))	('V0a', 'Var', (89, 92))	('V1A, V1G', 'Gene', '54140', (76, 84))
257377	27384996	We found that knockdown of V-ATPase V1E1 led to a reduction in phosphorylation of FAK and paxillin, which enhanced focal adhesion assembly.	('enhanced', 'PosReg', (106, 114))	('reduction', 'NegReg', (50, 59))	('paxillin', 'Gene', (90, 98))	('paxillin', 'Gene', '19303', (90, 98))	('V-ATPase', 'Gene', (27, 35))	('FAK', 'Protein', (82, 85))	('V-ATPase', 'Gene', '242341', (27, 35))	('focal adhesion assembly', 'CPA', (115, 138))	('phosphorylation', 'MPA', (63, 78))	('knockdown', 'Var', (14, 23))
257389	27384996	We found that V-ATPase V1E1 depletion induced a metabolic switch that led to decreased phosphorylation of PKM2 Tyr 105.	('PKM2 Tyr 105', 'Enzyme', (106, 118))	('Tyr', 'Chemical', 'MESH:D014443', (111, 114))	('V-ATPase', 'Gene', (14, 22))	('depletion', 'Var', (28, 37))	('phosphorylation', 'MPA', (87, 102))	('induced', 'Reg', (38, 45))	('metabolic switch', 'MPA', (48, 64))	('V-ATPase', 'Gene', '242341', (14, 22))	('decreased', 'NegReg', (77, 86))
257391	27384996	Moreover, the Cancer Genome Atlas (TCGA) data and Gene Set Enrichment Analysis (GSEA) indicated that genomic alteration of V-ATPase V1E1 was frequently observed in ESCC, and V-ATPase V1E1 expression was significantly associated with gene signatures of cancer metabolism.	('observed', 'Reg', (152, 160))	('V-ATPase', 'Gene', (123, 131))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('V-ATPase', 'Gene', (174, 182))	('associated', 'Reg', (217, 227))	('alteration', 'Var', (109, 119))	('cancer', 'Disease', (252, 258))	('GSEA', 'Chemical', '-', (80, 84))	('V-ATPase', 'Gene', '242341', (123, 131))	('V-ATPase', 'Gene', '242341', (174, 182))	('ESCC', 'Disease', (164, 168))	('Cancer Genome Atlas', 'Disease', (14, 33))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (14, 33))
257392	27384996	Consistent with this, high expression of both V-ATPase V1E1 and p-PKM2 was associated with poorer prognosis in ESCC, implicating V-ATPase V1E1 in deregulation of glucose metabolism in the development of ESCC.	('V-ATPase', 'Gene', '242341', (46, 54))	('V-ATPase', 'Gene', (129, 137))	('glucose', 'Chemical', 'MESH:D005947', (162, 169))	('deregulation', 'MPA', (146, 158))	('glucose metabolism', 'MPA', (162, 180))	('V-ATPase', 'Gene', '242341', (129, 137))	('p-PKM2', 'Var', (64, 70))	('V-ATPase', 'Gene', (46, 54))	('poorer', 'NegReg', (91, 97))	('ESCC', 'Disease', (111, 115))
257393	27384996	Similar to our results, high expression of PKM2 and vascular endothelial growth factor-C, an important molecule in angiogenesis and lymphangiogenesis, correlated significantly with poor prognosis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('breast cancer', 'Disease', 'MESH:D001943', (199, 212))	('breast cancer', 'Disease', (199, 212))	('vascular endothelial growth factor-C', 'Gene', '22341', (52, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))	('PKM2', 'Var', (43, 47))	('vascular endothelial growth factor-C', 'Gene', (52, 88))	('expression', 'MPA', (29, 39))
257395	27384996	Our current data demonstrate that the expression of V-ATPase V1E1 is associated with poor clinical outcome of patients with early stage of ESCC.	('associated', 'Reg', (69, 79))	('expression', 'Var', (38, 48))	('V-ATPase', 'Gene', (52, 60))	('patients', 'Species', '9606', (110, 118))	('ESCC', 'Disease', (139, 143))	('V-ATPase', 'Gene', '242341', (52, 60))
257398	27384996	Our findings suggest that therapeutic strategies designed to modulate V-ATPase V1E1 expression may be beneficial for the treatment of esophageal squamous cell carcinoma.	('V-ATPase', 'Gene', '242341', (70, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('esophageal squamous cell carcinoma', 'Disease', (134, 168))	('modulate', 'Var', (61, 69))	('V-ATPase', 'Gene', (70, 78))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (134, 168))
257444	28210138	Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair Esophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality.	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (123, 148))	('EAC', 'Phenotype', 'HP:0011459', (150, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('nucleotide excision', 'Var', (96, 115))	('Gastroesophageal junction adenocarcinoma displays abnormalities', 'Disease', 'MESH:D008309', (0, 63))	('Esophageal adenocarcinoma (EAC)', 'Gene', '1540', (123, 154))	('Esophageal adenocarcinoma (EAC', 'Gene', (123, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
257447	28210138	DNA repair defects have been described in various malignancies.	('malignancies', 'Disease', 'MESH:D009369', (50, 62))	('defects', 'Var', (11, 18))	('described', 'Reg', (29, 38))	('malignancies', 'Disease', (50, 62))
257453	28210138	Alterations in the expression of EME1, a structure-specific endonuclease involved in HR, were the most prevalent, with messenger (m)RNA overexpression in six of the EAC samples.	('EAC', 'Gene', (165, 168))	('EME1', 'Gene', '146956', (33, 37))	('Alterations', 'Var', (0, 11))	('overexpression', 'PosReg', (136, 150))	('EME1', 'Gene', (33, 37))	('EAC', 'Phenotype', 'HP:0011459', (165, 168))	('EAC', 'Gene', '1540', (165, 168))
257455	28210138	Our study identified DNA repair dysregulation in EAC involving two critical pathways, HR and NER, and is the first demonstration of EME1 upregulation in any cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('EAC', 'Gene', (49, 52))	('dysregulation', 'Var', (32, 45))	('EME1', 'Gene', (132, 136))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('cancer', 'Disease', (157, 163))	('EME1', 'Gene', '146956', (132, 136))	('EAC', 'Gene', '1540', (49, 52))
257456	28210138	These DNA repair abnormalities have the potential to affect a number of processes such as genomic instability and therapy response, and the consequences of these defects deserve further study in EAC.	('genomic instability', 'CPA', (90, 109))	('DNA repair', 'Gene', (6, 16))	('affect', 'Reg', (53, 59))	('therapy response', 'CPA', (114, 130))	('EAC', 'Phenotype', 'HP:0011459', (195, 198))	('EAC', 'Gene', '1540', (195, 198))	('abnormalities', 'Var', (17, 30))	('EAC', 'Gene', (195, 198))
257464	28210138	DNA repair defects characterizing a number of malignancies are being increasingly identified.	('malignancies', 'Disease', 'MESH:D009369', (46, 58))	('defects', 'Var', (11, 18))	('malignancies', 'Disease', (46, 58))
257465	28210138	For example, homologous recombination (HR) defects were noted in 50% of high-grade serous ovarian tumors.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('noted', 'Reg', (56, 61))	('ovarian tumors', 'Phenotype', 'HP:0100615', (90, 104))	('homologous', 'Var', (13, 23))	('serous ovarian tumors', 'Phenotype', 'HP:0012887', (83, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('serous ovarian tumors', 'Disease', 'MESH:D010051', (83, 104))	('defects', 'Var', (43, 50))	('serous ovarian tumors', 'Disease', (83, 104))
257466	28210138	Nucleotide excision repair (NER) deficiency has been previously described in sporadic stage 1 breast cancers, testicular cancers, and lung cancers and has been linked to carcinogenesis and genomic instability.	('testicular cancer', 'Phenotype', 'HP:0010788', (110, 127))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancers', 'Phenotype', 'HP:0003002', (94, 108))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('carcinogenesis', 'Disease', (170, 184))	('NER', 'Gene', (28, 31))	('testicular cancers', 'Disease', 'MESH:D013736', (110, 128))	('testicular cancers', 'Phenotype', 'HP:0010788', (110, 128))	('linked', 'Reg', (160, 166))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('testicular cancers', 'Disease', (110, 128))	('lung cancers', 'Disease', 'MESH:D008175', (134, 146))	('deficiency', 'Var', (33, 43))	('lung cancers', 'Disease', (134, 146))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancers', 'Phenotype', 'HP:0100526', (134, 146))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancers', 'Disease', 'MESH:D001943', (94, 108))	('breast cancers', 'Disease', (94, 108))	('described', 'Reg', (64, 73))
257467	28210138	Ataxia telangiectasia mutated deficiency has been found in mantle cell lymphomas and gastric cancers.	('lymphomas', 'Phenotype', 'HP:0002665', (71, 80))	('deficiency', 'Var', (30, 40))	('gastric cancers', 'Disease', 'MESH:D013274', (85, 100))	('mantle cell lymphomas', 'Disease', 'MESH:D020522', (59, 80))	('mantle cell lymphomas', 'Disease', (59, 80))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('gastric cancers', 'Disease', (85, 100))	('gastric cancers', 'Phenotype', 'HP:0012126', (85, 100))	('found', 'Reg', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (71, 79))	('telangiectasia', 'Phenotype', 'HP:0001009', (7, 21))	('Ataxia', 'Phenotype', 'HP:0001251', (0, 6))	('Ataxia telangiectasia', 'Disease', (0, 21))	('Ataxia telangiectasia', 'Disease', 'MESH:D001260', (0, 21))
257470	28210138	Exploring DNA repair abnormalities in esophageal cancer has largely focused on the analysis of DNA repair polymorphisms and their association with cancer susceptibility or therapy response.	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('polymorphisms', 'Var', (106, 119))	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (147, 153))	('association', 'Interaction', (130, 141))
257475	28210138	Our data highlight a number of DNA repair alterations that can have a critical effect on both EAC biology and DNA repair.	('EAC', 'Gene', (94, 97))	('alterations', 'Var', (42, 53))	('effect', 'Reg', (79, 85))	('EAC', 'Phenotype', 'HP:0011459', (94, 97))	('EAC', 'Gene', '1540', (94, 97))
257503	28210138	Defects in a number of HR genes have been described in solid organ malignancies and have been shown to mediate sensitivity to a variety of chemotherapy agents including platinum, crosslinking agents, and poly(ADP-ribose) polymerase inhibitors.	('described', 'Reg', (42, 51))	('malignancies', 'Disease', (67, 79))	('Defects', 'Var', (0, 7))	('HR genes', 'Gene', (23, 31))	('platinum', 'Chemical', 'MESH:D010984', (169, 177))	('mediate', 'Reg', (103, 110))	('sensitivity', 'MPA', (111, 122))	('malignancies', 'Disease', 'MESH:D009369', (67, 79))
257529	28210138	The observation of NER deficiency in all EAC samples analyzed is extremely intriguing, especially with the role of this pathway in repair of DNA damage resulting from various sources.	('deficiency', 'Var', (23, 33))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('NER', 'Gene', (19, 22))	('EAC', 'Gene', '1540', (41, 44))	('EAC', 'Gene', (41, 44))
257530	28210138	Underexpression of NER components has been tied to poor prognosis in cancer, with clinical data suggesting it is more likely observed in higher stages of cancer as compared with earlier stages.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('Underexpression', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (69, 75))
257541	28210138	Multiple studies have highlighted genetic alterations in EAC, revealing mutations in the frequently mutated genes such as TP53 and PIK3CA, as well as less common mutations in SPG20, TLR4, ELMO1, and DOCK2.	('mutations', 'Var', (72, 81))	('TP53', 'Gene', (122, 126))	('PIK3CA', 'Gene', '5290', (131, 137))	('TLR4', 'Gene', (182, 186))	('DOCK2', 'Gene', '1794', (199, 204))	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('SPG20', 'Gene', '23111', (175, 180))	('SPG20', 'Gene', (175, 180))	('EAC', 'Gene', '1540', (57, 60))	('ELMO1', 'Gene', '9844', (188, 193))	('EAC', 'Gene', (57, 60))	('PIK3CA', 'Gene', (131, 137))	('DOCK2', 'Gene', (199, 204))	('TP53', 'Gene', '7157', (122, 126))	('ELMO1', 'Gene', (188, 193))	('TLR4', 'Gene', '7099', (182, 186))
257542	28210138	Limited data exist describing the DNA repair alterations present in EAC and with the fundamental role of chemotherapy and radiation in this disease, understanding those alterations has the potential of further refining therapies and improving patient outcomes.	('alterations', 'Var', (45, 56))	('patient', 'Species', '9606', (243, 250))	('men', 'Species', '9606', (90, 93))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('EAC', 'Gene', '1540', (68, 71))	('EAC', 'Gene', (68, 71))
257547	28210138	Defective NER, through reduced expression of some of its components, especially XPA and ERCC1, has been postulated to be one of the main mechanisms of hypersensitivity of testicular cancer, including in the metastatic stage to cisplatin therapy.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (227, 236))	('hypersensitivity of', 'Disease', (151, 170))	('XPA', 'Gene', '7507', (80, 83))	('hypersensitivity of', 'Disease', 'MESH:D004342', (151, 170))	('testicular cancer', 'Phenotype', 'HP:0010788', (171, 188))	('testicular cancer', 'Disease', 'MESH:D013736', (171, 188))	('XPA', 'Gene', (80, 83))	('expression', 'MPA', (31, 41))	('Defective', 'Var', (0, 9))	('ERCC1', 'Gene', (88, 93))	('ERCC1', 'Gene', '2067', (88, 93))	('reduced', 'NegReg', (23, 30))	('testicular cancer', 'Disease', (171, 188))	('NER', 'Gene', (10, 13))
257566	28210138	MUS81/EME1's contribution to the recovery of stalled replication forks, a crucial step in preserving genome stability, suggests MUS81/EME1 defects would possibly mediate genomic instability, a bona fide hallmark of cancer.	('MUS81', 'Gene', (0, 5))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('MUS81', 'Gene', '80198', (0, 5))	('genomic', 'MPA', (170, 177))	('defects', 'Var', (139, 146))	('MUS81', 'Gene', '80198', (128, 133))	('EME1', 'Gene', '146956', (6, 10))	('EME1', 'Gene', '146956', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('EME1', 'Gene', (134, 138))	('MUS81', 'Gene', (128, 133))	('mediate', 'Reg', (162, 169))	('EME1', 'Gene', (6, 10))
257567	28210138	This is supported by a number of observations including the associated increase of spontaneous gross chromosomal rearrangements in the setting of defective MUS81 or EME1.	('MUS81', 'Gene', '80198', (156, 161))	('EME1', 'Gene', '146956', (165, 169))	('defective', 'Var', (146, 155))	('increase', 'PosReg', (71, 79))	('EME1', 'Gene', (165, 169))	('MUS81', 'Gene', (156, 161))	('men', 'Species', '9606', (122, 125))
257570	28210138	These defects possibly contribute to the genomic instability of EAC and potentially mediate resistance to chemotherapy and radiation that remains a challenge in caring for these patients.	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('patients', 'Species', '9606', (178, 186))	('contribute', 'Reg', (23, 33))	('EAC', 'Gene', '1540', (64, 67))	('EAC', 'Gene', (64, 67))	('defects', 'Var', (6, 13))
257571	28210138	Discovering the implications of DNA repair abnormalities in EAC carcinogenesis and therapy response has the potential to improve outcomes of EAC.	('EAC', 'Gene', (141, 144))	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('EAC', 'Gene', '1540', (60, 63))	('carcinogenesis', 'Disease', (64, 78))	('EAC', 'Gene', (60, 63))	('abnormalities', 'Var', (43, 56))	('EAC', 'Phenotype', 'HP:0011459', (141, 144))	('improve', 'PosReg', (121, 128))	('EAC', 'Gene', '1540', (141, 144))
257578	27193578	Complications were associated both with increased early (90 days) mortality (OR = 4.25, 95 % CI = 2.78-6.50), and reduced overall survival when patients suffering early mortality were excluded (HR = 1.23, 95 % CI = 1.01-1.50).	('reduced', 'NegReg', (114, 121))	('Complications', 'Var', (0, 13))	('overall survival', 'MPA', (122, 138))	('patients', 'Species', '9606', (144, 152))
257591	27193578	Only cases with an appropriate cancer diagnosis (ICD-10: C15*, C16* and C25* respectively, where * denotes all sub-codes) applied within eight weeks from surgery were included.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('C16*', 'SUBSTITUTION', 'None', (63, 67))	('C25*', 'SUBSTITUTION', 'None', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('C15*', 'Var', (57, 61))	('C25*', 'Var', (72, 76))	('C15*', 'SUBSTITUTION', 'None', (57, 61))	('cancer', 'Disease', (31, 37))	('C16*', 'Var', (63, 67))
257653	25647058	Some of those with GERD may develop Barrett esophagus, which can lead to esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (73, 98))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (36, 53))	('GERD', 'Var', (19, 23))	('Barrett esophagus', 'Disease', (36, 53))	('lead to', 'Reg', (65, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (73, 98))	('esophageal adenocarcinoma', 'Disease', (73, 98))
257725	25647058	Wang et al also found that the annual detection rate of type I EGJA seemed to be positively correlated with reflux esophagitis in time trend.	('correlated', 'Reg', (92, 102))	('type', 'Var', (56, 60))	('reflux esophagitis', 'Disease', (108, 126))	('EGJA', 'Phenotype', 'HP:0011459', (63, 67))	('esophagitis', 'Phenotype', 'HP:0100633', (115, 126))	('reflux esophagitis', 'Disease', 'MESH:D005764', (108, 126))
257761	25801241	The sVEGF-C/D levels of patients with GBC were significantly higher than those of people with healthy gallbladders (p < 0.001 and p = 0.001, respectively) and cholesterol polyp (p = 0.032 and p = 0.004, respectively).	('cholesterol polyp', 'Disease', 'MESH:D011127', (159, 176))	('VEGF-C/D', 'Gene', '7424;2277', (5, 13))	('higher', 'PosReg', (61, 67))	('GBC', 'Var', (38, 41))	('cholesterol polyp', 'Disease', (159, 176))	('VEGF-C/D', 'Gene', (5, 13))	('sVEGF-C', 'Chemical', '-', (4, 11))	('patients', 'Species', '9606', (24, 32))	('people', 'Species', '9606', (82, 88))
257765	25801241	The mean survival time with high sVEGF-C was significantly shorter than that with low sVEGF-C (p < 0.001), which was also true for low sVEGF-D (p = 0.032).	('sVEGF-C', 'Chemical', '-', (33, 40))	('shorter', 'NegReg', (59, 66))	('high sVEGF-C', 'Var', (28, 40))	('sVEGF', 'Chemical', '-', (86, 91))	('sVEGF-C', 'Chemical', '-', (86, 93))	('VEGF-D', 'Gene', '2277', (136, 142))	('sVEGF', 'Chemical', '-', (135, 140))	('sVEGF', 'Chemical', '-', (33, 38))	('VEGF-D', 'Gene', (136, 142))	('survival time', 'CPA', (9, 22))
257810	25801241	In GBC patients, the sVEGF-C levels for patients with LNM were significantly higher than those observed for patients without LNM (8477.65 +- 2018.32 vs 6807.64 +- 1663.66 pg/ml, p = 0.018).	('LNM', 'Var', (54, 57))	('higher', 'PosReg', (77, 83))	('GBC', 'Disease', (3, 6))	('patients', 'Species', '9606', (40, 48))	('sVEGF-C', 'Chemical', '-', (21, 28))	('patients', 'Species', '9606', (108, 116))	('sVEGF-C levels', 'MPA', (21, 35))	('patients', 'Species', '9606', (7, 15))
257816	25801241	When the cutoff values of sVEGF-C/D for the diagnosis of GBC patients were 7054.83 and 595.13 pg/ml, the diagnostic values were as follows: sensitivities of 71.0 and 74.2 %, specificities of 80.0 and 85.0 %, accuracies of 74.5 and 78.4 %, and AUCs of 0.785 and 0.838, respectively.	('VEGF-C/D', 'Gene', (27, 35))	('sensitivities', 'MPA', (140, 153))	('sVEGF-C', 'Chemical', '-', (26, 33))	('patients', 'Species', '9606', (61, 69))	('7054.83', 'Var', (75, 82))	('VEGF-C/D', 'Gene', '7424;2277', (27, 35))	('GBC', 'Disease', (57, 60))
257857	25801241	In our study, when the sVEGF-C/D levels reached the cutoff values of 7054.83 and 595.13 pg/ml, the diagnosis values for the presence of malignancy were sensitivities of 71 and 74.2 % and specificities of 80.0 and 85.0 %, but no significant difference was found between sVEGF-C and sVEGF-D when they were used as biomarkers of GBC.	('malignancy', 'Disease', (136, 146))	('VEGF-D', 'Gene', '2277', (282, 288))	('7054.83', 'Var', (69, 76))	('VEGF-C/D', 'Gene', (24, 32))	('sVEGF-C', 'Chemical', '-', (23, 30))	('sVEGF', 'Chemical', '-', (269, 274))	('sVEGF-C', 'Chemical', '-', (269, 276))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('sVEGF', 'Chemical', '-', (23, 28))	('VEGF-C/D', 'Gene', '7424;2277', (24, 32))	('sVEGF', 'Chemical', '-', (281, 286))	('VEGF-D', 'Gene', (282, 288))
257867	25801241	In our study, when the cutoff values of the sVEGF-C/D levels as the markers of LNM were 7667.27 and 674.88 pg/ml, respectively, the predicted values were as follows: sensitivities of 81.2 and 87.5 % and specificities of 73.3 and 80 %.	('sVEGF-C', 'Chemical', '-', (44, 51))	('VEGF-C/D', 'Gene', (45, 53))	('7667.27', 'Var', (88, 95))	('VEGF-C/D', 'Gene', '7424;2277', (45, 53))
257871	25801241	In this study, we observed that the mean survival time with high sVEGF-C was significantly shorter than that observed with low sVEGF-C, as well as high sVEGF-D.	('sVEGF', 'Chemical', '-', (65, 70))	('survival time', 'CPA', (41, 54))	('sVEGF', 'Chemical', '-', (127, 132))	('VEGF-D', 'Gene', '2277', (153, 159))	('VEGF-D', 'Gene', (153, 159))	('sVEGF', 'Chemical', '-', (152, 157))	('sVEGF-C', 'Chemical', '-', (127, 134))	('sVEGF-C', 'Chemical', '-', (65, 72))	('shorter', 'NegReg', (91, 98))	('high sVEGF-C', 'Var', (60, 72))
257873	25801241	These findings were consistent with those reports showing that a high sVEGF-C level was related to poor prognosis in patients with breast tumors and gastric cancer.	('gastric cancer', 'Disease', (149, 163))	('breast tumors', 'Disease', 'MESH:D001943', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('breast tumors', 'Disease', (131, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('high', 'Var', (65, 69))	('sVEGF-C', 'Chemical', '-', (70, 77))	('breast tumors', 'Phenotype', 'HP:0100013', (131, 144))	('patients', 'Species', '9606', (117, 125))	('sVEGF-C', 'Gene', (70, 77))
257875	25801241	These studies suggested that sVEGF-C/D could be useful in predicting the prognosis of GBC patients, which could be because high sVEGF-C/D levels in GBC patients increase the risk of LNM, distant metastasis, and advanced stage, thereby decreasing the chance of radical resection and resulting in poor outcomes.	('radical resection', 'CPA', (260, 277))	('VEGF-C/D', 'Gene', (30, 38))	('distant metastasis', 'CPA', (187, 205))	('sVEGF-C', 'Chemical', '-', (29, 36))	('decreasing', 'NegReg', (235, 245))	('high', 'Var', (123, 127))	('VEGF-C/D', 'Gene', '7424;2277', (129, 137))	('advanced stage', 'CPA', (211, 225))	('patients', 'Species', '9606', (152, 160))	('increase', 'PosReg', (161, 169))	('VEGF-C/D', 'Gene', '7424;2277', (30, 38))	('VEGF-C/D', 'Gene', (129, 137))	('patients', 'Species', '9606', (90, 98))	('LNM', 'Disease', (182, 185))	('sVEGF-C', 'Chemical', '-', (128, 135))
257876	25801241	However, colorectal cancer patients with low sVEGF-C levels showed a poorer overall survival than did those with high sVEGF-C levels.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('overall survival', 'MPA', (76, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (9, 26))	('poorer', 'NegReg', (69, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (9, 26))	('patients', 'Species', '9606', (27, 35))	('low', 'Var', (41, 44))	('sVEGF-C', 'Chemical', '-', (45, 52))	('colorectal cancer', 'Disease', (9, 26))	('sVEGF-C', 'Chemical', '-', (118, 125))
257947	25424871	Patients with T1/2 disease had a better 3-year OS than stage T3 and T4 tumors (36.1% vs. 30.4% vs. 12.5% p =0.001).	('Patients', 'Species', '9606', (0, 8))	('T1/2', 'Var', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('OS', 'Chemical', '-', (47, 49))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
257948	25424871	The 3-year PFS of patients with T1/T2 disease was significantly better than that of patients with T3 and T4 disease (30.7% vs. 21.3% vs. 6.3%; p =0.002).	('better', 'PosReg', (64, 70))	('patients', 'Species', '9606', (84, 92))	('PFS', 'MPA', (11, 14))	('patients', 'Species', '9606', (18, 26))	('T1/T2 disease', 'Var', (32, 45))
257951	25424871	The 3-year OS and PFS of patients who received cisplatin and 5-FU were 14.5% and 13.1%, respectively (p =0.003), while the 3-year OS and PFS rates of patients who received other regimens were 13.3% and 11.0%, respectively (p =0.034).	('OS', 'Chemical', '-', (11, 13))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('cisplatin', 'Var', (47, 56))	('patients', 'Species', '9606', (150, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('PFS', 'CPA', (18, 21))	('OS', 'Chemical', '-', (130, 132))	('patients', 'Species', '9606', (25, 33))	('5-FU', 'Var', (61, 65))
257972	25424871	In our study, the survival of patients with T1/2 disease is better than that of those with a T3 lesion, and the prognosis of patients with T3 disease is better than that of those with T4 lesions.	('better', 'PosReg', (60, 66))	('T1/2', 'Var', (44, 48))	('T3 disease', 'Disease', 'MESH:C537047', (139, 149))	('T3 disease', 'Disease', (139, 149))	('patients', 'Species', '9606', (30, 38))	('survival', 'CPA', (18, 26))	('patients', 'Species', '9606', (125, 133))
258166	21698030	For example, a thickness variation of only 1 nm in each of the TiO2 layers, relative to what was initially designed, is enough to move the peak to a different central wavelength.	('move', 'Reg', (130, 134))	('variation', 'Var', (25, 34))	('TiO2', 'Chemical', 'MESH:C009495', (63, 67))	('peak', 'MPA', (139, 143))
258192	33760397	SHR-1316 plus liposomal irinotecan and 5-fluorouracil has a promising efficacy and manageable safety profile, and could be a new first-line treatment approach for patients with unresectable locally advanced or distant metastatic ESCC.	('ESCC', 'Disease', (229, 233))	('SHR-1316', 'Var', (0, 8))	('patients', 'Species', '9606', (163, 171))	('SHR-1316', 'Chemical', '-', (0, 8))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (39, 53))	('irinotecan', 'Chemical', 'MESH:D000077146', (24, 34))
258201	33760397	11 ,  12 ,  13  Several anti-PD-1 antibodies have demonstrated promising efficacy and manageable safety in the treatment of advanced ESCC patients.	('PD-1', 'Gene', '5133', (29, 33))	('PD-1', 'Gene', (29, 33))	('ESCC', 'Disease', (133, 137))	('antibodies', 'Var', (34, 44))	('patients', 'Species', '9606', (138, 146))
258203	33760397	18 ,  19  In the first-line setting, pembrolizumab plus chemotherapy versus chemotherapy plus placebo provided a statistically significant and clinically meaningful improvement in OS in the phase 3 KEYNOTE-590 study, suggesting a synergistic effect of chemotherapy in combination with ICIs.	('KEYNOTE-590', 'Chemical', '-', (198, 209))	('pembrolizumab', 'Var', (37, 50))	('improvement', 'PosReg', (165, 176))	('pembrolizumab', 'Chemical', 'MESH:C582435', (37, 50))
258230	33760397	The primary endpoint of the study was PFS in the intention-to-treat population, defined as the time period between treatment initiation and the first documented disease progression or death of any cause, with censoring for patients alive and progression-free at data cut-off.	('patients', 'Species', '9606', (223, 231))	('death', 'Disease', 'MESH:D003643', (184, 189))	('death', 'Disease', (184, 189))	('PFS', 'Var', (38, 41))
258258	33760397	Eighteen patients provided evaluable tissue samples for the assessment of baseline tumor cell PD-L1 expression, among which 16 (88.9%), 13 (72.2%), 12 (66.7%), and four (22.2%) patients had PD-L1 expression >=1%, >=5%, >=10%, and >=25%, respectively.	('had', 'Gene', '23498', (186, 189))	('PD-L1', 'Gene', (94, 99))	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('PD-L1', 'Gene', (190, 195))	('tumor', 'Disease', (83, 88))	('patients', 'Species', '9606', (177, 185))	('PD-L1', 'Gene', '29126', (190, 195))	('PD-L1', 'Gene', '29126', (94, 99))	('had', 'Gene', (186, 189))	('>=10%', 'Var', (219, 224))	('>=5%', 'Var', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
258263	33760397	Our findings indicate that SHR-1316 combined with liposomal irinotecan and 5-fluorouracil has promising efficacies and manageable safety profiles in the first-line treatment of advanced ESCC.	('SHR-1316', 'Var', (27, 35))	('irinotecan', 'Chemical', 'MESH:D000077146', (60, 70))	('SHR-1316', 'Chemical', '-', (27, 35))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (75, 89))	('ESCC', 'Disease', (186, 190))
258291	33760397	18  In the KEYNOTE-590 trial, although the improvement in OS with pembrolizumab plus chemotherapy versus chemotherapy alone in untreated patients with ESCC and esophageal adenocarcinoma was independent of PD-L1 CPS status, patients with CPS >=10 achieved greater benefit (CPS >=10 HR 0.62, 95% CI 0.49-0.78 vs. CPS < 10 HR 0.86, 95% CI 0.68-1.10).	('adenocarcinoma', 'Disease', (171, 185))	('patients', 'Species', '9606', (223, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('pembrolizumab', 'Chemical', 'MESH:C582435', (66, 79))	('PD-L1', 'Gene', (205, 210))	('adenocarcinoma', 'Disease', 'MESH:D000230', (171, 185))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (160, 185))	('ESCC', 'Disease', (151, 155))	('patients', 'Species', '9606', (137, 145))	('KEYNOTE-590', 'Chemical', '-', (11, 22))	('PD-L1', 'Gene', '29126', (205, 210))	('CPS', 'Var', (237, 240))	('esophageal', 'Disease', (160, 170))
258298	32005028	Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA Backgrounds: Emerging evidences has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) is critically involved in esophageal squamous cell carcinoma (ESCC) progression.	('esophageal squamous cell carcinoma', 'Disease', (256, 290))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (256, 290))	('ESCC', 'Disease', 'MESH:C562729', (292, 296))	('EZH2', 'Gene', '2146', (107, 111))	('PSMA3-AS1', 'Gene', (20, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (267, 290))	('dysregulation', 'Var', (182, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('involved', 'Reg', (244, 252))	('EZH2', 'Gene', (107, 111))	('ESCC', 'Disease', (292, 296))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (20, 29))
258312	32005028	The dysregulation of oncogenes and tumor suppressor genes plays important roles in the process of ESCC progression.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('dysregulation', 'Var', (4, 17))	('ESCC', 'Disease', (98, 102))	('tumor', 'Disease', (35, 40))	('ESCC', 'Disease', 'MESH:C562729', (98, 102))	('oncogenes', 'Protein', (21, 30))
258329	32005028	Multivariate analysis revealed that a high PSMA3-AS1 expression status was an independent indicator for poor prognosis in esophageal cancer patients (Tables 1 and 2).	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('PSMA3-AS1', 'Gene', (43, 52))	('high', 'Var', (38, 42))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (43, 52))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
258336	32005028	Next, to further verify the biological roles of PSMA3-AS1in esophageal cancer cells, we established stable PSMA3-AS1 knockdown via lentiviral infection in EC9706 and EC109 cell lines (which have high PSMA3-AS1 expression) and validated the down-regulation of PSMA3-AS1 by RT-qPCR (Figure 3A).	('PSMA3-AS1', 'Gene', (259, 268))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (48, 57))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (107, 116))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (200, 209))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (259, 268))	('EC109', 'CellLine', 'CVCL:6898', (166, 171))	('esophageal cancer', 'Disease', (60, 77))	('infection', 'Disease', (142, 151))	('EC9706', 'CellLine', 'CVCL:E307', (155, 161))	('infection', 'Disease', 'MESH:D007239', (142, 151))	('PSMA3-AS1', 'Gene', (48, 57))	('PSMA3-AS1', 'Gene', (107, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('down-regulation', 'NegReg', (240, 255))	('knockdown', 'Var', (117, 126))	('PSMA3-AS1', 'Gene', (200, 209))
258337	32005028	CCK-8, colony formation, wound healing and transwell assays were then performed to monitor the proliferation and migration function of esophageal cancer cells in response to PSMA3-AS1 knockdown.	('knockdown', 'Var', (184, 193))	('PSMA3-AS1', 'Gene', (174, 183))	('esophageal cancer', 'Disease', (135, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('migration', 'CPA', (113, 122))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (174, 183))
258338	32005028	The results showed that PSMA3-AS1 knockdown specifically suppressed the proliferation and migration of EC9706 and EC109 cells (which have high PSMA3-AS1 expression) in vitro (Figure 3B-3E).	('migration', 'CPA', (90, 99))	('EC109', 'CellLine', 'CVCL:6898', (114, 119))	('proliferation', 'CPA', (72, 85))	('EC9706', 'CellLine', 'CVCL:E307', (103, 109))	('PSMA3-AS1', 'Gene', (143, 152))	('PSMA3-AS1', 'Gene', (24, 33))	('knockdown', 'Var', (34, 43))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (24, 33))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (143, 152))	('suppressed', 'NegReg', (57, 67))
258340	32005028	Next, we found that PSMA3-AS1 knockdown significantly up-regulated miR-101 expression in esophageal cancer cells, whereas PSMA3-AS1 overexpression reduced miR-101 expression (Figure 4B and 4C).	('esophageal cancer', 'Disease', (89, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PSMA3-AS1', 'Gene', (122, 131))	('PSMA3-AS1', 'Gene', (20, 29))	('miR-101', 'Chemical', '-', (67, 74))	('up-regulated', 'PosReg', (54, 66))	('expression', 'MPA', (163, 173))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (122, 131))	('knockdown', 'Var', (30, 39))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (20, 29))	('expression', 'MPA', (75, 85))	('miR-101', 'Gene', (67, 74))	('miR-101', 'Chemical', '-', (155, 162))
258342	32005028	Moreover, PSMA3-AS1 was pulled down by biotinylated miR-101, whereas mutagenesis of the binding sites for PSMA3-AS1 in miR-101 abolished this interaction (Figure 4E).	('PSMA3-AS1', 'Gene', '379025;5684;5729', (10, 19))	('mutagenesis', 'Var', (69, 80))	('miR-101', 'Chemical', '-', (52, 59))	('PSMA3-AS1', 'Gene', (106, 115))	('PSMA3-AS1', 'Gene', (10, 19))	('miR-101', 'Chemical', '-', (119, 126))	('miR-101', 'Gene', (52, 59))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (106, 115))	('biotinylated', 'Var', (39, 51))	('biotin', 'Chemical', 'MESH:D001710', (39, 45))
258345	32005028	Furthermore, AGO2 knockdown increased PSMA3-AS1 expression in esophageal cancer KYSE150 and KYSE450 cells (Figure 4G and 4H).	('increased', 'PosReg', (28, 37))	('knockdown', 'Var', (18, 27))	('esophageal cancer', 'Disease', (62, 79))	('AGO2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('PSMA3-AS1', 'Gene', (38, 47))	('AGO2', 'Gene', '27161', (13, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (38, 47))
258348	32005028	Next, we constructed luciferase reporter vectors containing the wild-type (wt) or mutant (mu) EZH2 3'-UTR (Figure 5A).	('EZH2', 'Gene', '2146', (94, 98))	('EZH2', 'Gene', (94, 98))	('mutant', 'Var', (82, 88))
258350	32005028	The luciferase activity of the WT reporter was increased by transfecting miR-101 siRNA in contrast to transfection with miR-101 mimic (Figure 5C).	('miR-101', 'Chemical', '-', (73, 80))	('miR-101', 'Var', (73, 80))	('activity', 'MPA', (15, 23))	('increased', 'PosReg', (47, 56))	('transfecting', 'Var', (60, 72))	('luciferase', 'Enzyme', (4, 14))	('miR-101', 'Chemical', '-', (120, 127))
258354	32005028	However, the results showed that up-regulation of mutant PSMA3-AS1 did not increase the expression of EZH2 in esophageal cancer cells (Figure 5H and 5I).	('EZH2', 'Gene', (102, 106))	('EZH2', 'Gene', '2146', (102, 106))	('PSMA3-AS1', 'Gene', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('up-regulation', 'PosReg', (33, 46))	('esophageal cancer', 'Disease', (110, 127))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (57, 66))	('mutant', 'Var', (50, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))
258355	32005028	All of the above results indicated that PSMA3-AS1, miR-101 and EZH2 acted together via a ceRNA mechanism Next, we successfully performed CRISPR/Cas9 gene editing of EZH2 in KYSE150 and KYSE450cells as confirmed by a significant reduction in EZH2 protein expression (Figure 6A).	('EZH2', 'Gene', (165, 169))	('reduction', 'NegReg', (228, 237))	('EZH2', 'Gene', '2146', (165, 169))	('EZH2', 'Gene', '2146', (63, 67))	('PSMA3-AS1', 'Gene', (40, 49))	('editing', 'Var', (154, 161))	('EZH2', 'Gene', (63, 67))	('EZH2', 'Gene', '2146', (241, 245))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (40, 49))	('EZH2', 'Gene', (241, 245))	('protein', 'Protein', (246, 253))	('miR-101', 'Chemical', '-', (51, 58))
258356	32005028	CCK-8 and colony formation assays showed that PSMA3-AS1 overexpression did not affect the proliferation of esophageal cancer cells with EZH2 knocked out (Figure 6B and 6C).	('EZH2', 'Gene', (136, 140))	('EZH2', 'Gene', '2146', (136, 140))	('esophageal cancer', 'Disease', (107, 124))	('PSMA3-AS1', 'Gene', '379025;5684;5729', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('knocked out', 'Var', (141, 152))	('PSMA3-AS1', 'Gene', (46, 55))
258362	32005028	Recent investigations have shown that dysregulated lncRNAs play critical roles in modulating tumor progression.	('modulating', 'Reg', (82, 92))	('dysregulated', 'Var', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('lncRNAs', 'Protein', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
258371	32005028	Moreover, patients with high LUCAT1 expression had a worse prognosis than patients with low LUCAT1 expression.	('LUCAT1', 'Gene', '100505994', (29, 35))	('LUCAT1', 'Gene', (29, 35))	('LUCAT1', 'Gene', '100505994', (92, 98))	('LUCAT1', 'Gene', (92, 98))	('patients', 'Species', '9606', (74, 82))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))
258374	32005028	Importantly, it was confirmed that miR-101 inhibited cell proliferation directly by inhibiting the expression of EZH2intransitional cell carcinomas, lung cancer, and embryonal rhabdomyosarcoma cells.	('expression', 'MPA', (99, 109))	('cell carcinomas', 'Disease', (132, 147))	('cell carcinomas', 'Disease', 'MESH:D002292', (132, 147))	('lung cancer', 'Disease', (149, 160))	('miR-101', 'Chemical', '-', (35, 42))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (166, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('miR-101', 'Var', (35, 42))	('inhibited', 'NegReg', (43, 52))	('embryonal rhabdomyosarcoma', 'Disease', (166, 192))	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (176, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('cell proliferation', 'CPA', (53, 71))	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (166, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('inhibiting', 'NegReg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('EZH2', 'Gene', '2146', (113, 117))	('EZH2', 'Gene', (113, 117))
258376	32005028	Furthermore, it was reported that miR-101 inhibited cell metastasis by down-regulating EZH2 expression in lung cancer and osteosarcoma.	('osteosarcoma', 'Disease', (122, 134))	('osteosarcoma', 'Phenotype', 'HP:0002669', (122, 134))	('miR-101', 'Var', (34, 41))	('lung cancer', 'Disease', (106, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (122, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('EZH2', 'Gene', '2146', (87, 91))	('cell metastasis', 'CPA', (52, 67))	('down-regulating', 'NegReg', (71, 86))	('EZH2', 'Gene', (87, 91))	('inhibited', 'NegReg', (42, 51))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('miR-101', 'Chemical', '-', (34, 41))	('expression', 'MPA', (92, 102))
258381	32005028	Dysregulation of EZH2 is implicated in ESCC cisplatin resistance, proliferation, invasion, and metastasis, and is associated with poor outcome in ESCC.	('EZH2', 'Gene', (17, 21))	('ESCC', 'Disease', (39, 43))	('Dysregulation', 'Var', (0, 13))	('invasion', 'CPA', (81, 89))	('ESCC', 'Disease', 'MESH:C562729', (146, 150))	('proliferation', 'CPA', (66, 79))	('ESCC', 'Disease', 'MESH:C562729', (39, 43))	('metastasis', 'CPA', (95, 105))	('associated', 'Reg', (114, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('implicated', 'Reg', (25, 35))	('ESCC', 'Disease', (146, 150))	('EZH2', 'Gene', '2146', (17, 21))	('cisplatin resistance', 'MPA', (44, 64))
258397	29752726	Genomic data suggest that gene mutations and several other mechanisms result in NRF2 hyperactivation in human ESCC.	('mutations', 'Var', (31, 40))	('ESCC', 'Disease', 'MESH:C562729', (110, 114))	('NRF2', 'Gene', (80, 84))	('human', 'Species', '9606', (104, 109))	('ESCC', 'Disease', (110, 114))	('hyperactivation', 'PosReg', (85, 100))
258400	29752726	Genomic data suggest that gene mutations and several other mechanisms result in NRF2 hyperactivation in human esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (110, 144))	('mutations', 'Var', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('ESCC', 'Disease', 'MESH:C562729', (146, 150))	('NRF2', 'Gene', (80, 84))	('human', 'Species', '9606', (104, 109))	('hyperactivation', 'PosReg', (85, 100))	('esophageal squamous cell carcinoma', 'Disease', (110, 144))	('ESCC', 'Disease', (146, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
258407	29752726	Genetic targeting of the NRF2 signaling pathway impaired tumorigenesis in the lung, pancreas, and colon.	('Genetic targeting', 'Var', (0, 17))	('impaired', 'NegReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('NRF2 signaling pathway', 'Pathway', (25, 47))
258409	29752726	Genetic activation of NRF2 in Keap1-/- mice resulted in esophageal hyperproliferation and hyperkeratosis.	('Genetic activation', 'Var', (0, 18))	('esophageal hyperproliferation and hyperkeratosis', 'Disease', 'MESH:D004941', (56, 104))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (90, 104))	('NRF2', 'Gene', (22, 26))	('mice', 'Species', '10090', (39, 43))
258411	29752726	The esophageal phenotype of Keap1-/- mice was further attributable to constitutive activation of NRF2 with the assistance of small Maf proteins.	('esophageal', 'Disease', (4, 14))	('Keap1-/-', 'Var', (28, 36))	('NRF2', 'Gene', (97, 101))	('mice', 'Species', '10090', (37, 41))	('activation', 'PosReg', (83, 93))
258412	29752726	Tissue-specific deletion of esophageal NRF2 in Keap1-/- mice (K5Cre Nrf2fl/fl Keap1-/-) allowed survival until adulthood.	('deletion', 'Var', (16, 24))	('mice', 'Species', '10090', (56, 60))	('esophageal NRF2', 'Gene', (28, 43))
258421	29752726	Keap1-/- esophagus had an increased expression of keratinization genes, PI3K/Akt pathway genes, and PPARbeta/delta.	('keratinization genes', 'Gene', (50, 70))	('PPARbeta', 'Gene', '5467', (100, 108))	('PI3K/Akt pathway', 'Pathway', (72, 88))	('esophagus', 'Disease', (9, 18))	('increased', 'PosReg', (26, 35))	('PPARbeta', 'Gene', (100, 108))	('Keap1-/-', 'Var', (0, 8))	('expression', 'MPA', (36, 46))
258427	29752726	Activating NRF2 may potentially strengthen esophageal epithelial barrier function as a therapeutic approach for gastroesophageal reflux disease.	('gastroesophageal reflux disease', 'Disease', (112, 143))	('NRF2', 'Gene', (11, 15))	('esophageal epithelial barrier function', 'CPA', (43, 81))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (112, 135))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (112, 143))	('Activating', 'Var', (0, 10))	('strengthen', 'PosReg', (32, 42))
258428	29752726	Que's group further demonstrated that basal progenitor cell-specific expression of constitutively active bone morphogenetic protein (BMP) promoted squamous differentiation in mouse esophagus.	('squamous differentiation', 'CPA', (147, 171))	('BMP', 'Gene', '649', (133, 136))	('promoted', 'PosReg', (138, 146))	('BMP', 'Gene', (133, 136))	('mouse', 'Species', '10090', (175, 180))	('expression', 'Var', (69, 79))
258434	29752726	Mutations in other genes of the NRF2 signaling pathway (KEAP1 and CUL3) were relatively less common.	('CUL3', 'Gene', (66, 70))	('Mutations', 'Var', (0, 9))	('NRF2 signaling pathway', 'Pathway', (32, 54))	('CUL3', 'Gene', '8452', (66, 70))
258435	29752726	NRF2 mutations and KEAP1 mutations were mutually exclusive in human lung cancer cell lines.	('lung cancer', 'Disease', (68, 79))	('NRF2', 'Gene', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('human', 'Species', '9606', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (5, 14))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))
258442	29752726	NRF2 mutations have not been reported in esophageal squamous hyperplasia and non-tumorous dysplasia.	('NRF2', 'Gene', (0, 4))	('squamous hyperplasia', 'Phenotype', 'HP:0002860', (52, 72))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('esophageal squamous hyperplasia and non-tumorous dysplasia', 'Disease', 'MESH:C562729', (41, 99))
258444	29752726	Phylogenetic analysis showed that NRF2 mutation as a driver mutation tended to be located on the branches of the tumor phylogenetic tree, while mutations of tumor suppressor genes (e.g., p53) tended to be located on the trunk, suggesting that NRF2 mutation may be a relatively late event during the development of ESCC.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (113, 118))	('NRF2', 'Gene', (34, 38))	('ESCC', 'Disease', (314, 318))	('mutation', 'Var', (39, 47))	('p53', 'Gene', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('p53', 'Gene', '7157', (187, 190))	('ESCC', 'Disease', 'MESH:C562729', (314, 318))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
258445	29752726	Genomic mutations of the NRF2 signaling pathway correlated with the transcriptional activity of the NRF2 signaling pathway in ESCC.	('ESCC', 'Disease', 'MESH:C562729', (126, 130))	('NRF2', 'Gene', (25, 29))	('NRF2 signaling pathway', 'Pathway', (100, 122))	('Genomic mutations', 'Var', (0, 17))	('ESCC', 'Disease', (126, 130))	('correlated', 'Reg', (48, 58))	('transcriptional activity', 'MPA', (68, 92))
258447	29752726	Other than mutations, at least five additional mechanisms are known to activate NRF2 in cancer: hypomethylation of KEAP1, accumulation of disruptor proteins, increased production of NRF2, electrophoretic attack of KEAP1 by oncometabolites, and downregulation of NRF2-targeting microRNAs (miRNAs).	('activate', 'PosReg', (71, 79))	('mutations', 'Var', (11, 20))	('cancer', 'Disease', (88, 94))	('increased', 'PosReg', (158, 167))	('accumulation', 'PosReg', (122, 134))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('production', 'MPA', (168, 178))	('hypomethylation', 'MPA', (96, 111))	('NRF2', 'Gene', (80, 84))	('NRF2', 'Protein', (182, 186))	('downregulation', 'NegReg', (244, 258))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('electrophoretic attack', 'MPA', (188, 210))
258450	29752726	Mutant NRF2 conferred increased cell proliferation, attachment-independent survival, and resistance to 5-fluorouracil and gamma-irradiation.	('resistance', 'CPA', (89, 99))	('NRF2', 'Gene', (7, 11))	('increased', 'PosReg', (22, 31))	('attachment-independent survival', 'CPA', (52, 83))	('Mutant', 'Var', (0, 6))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (103, 117))	('cell proliferation', 'CPA', (32, 50))
258451	29752726	Blockage of NRF2 suppresses the migration and invasion of ESCC cells in a hypoxic microenvironment.	('Blockage', 'Var', (0, 8))	('ESCC', 'Disease', 'MESH:C562729', (58, 62))	('suppresses', 'NegReg', (17, 27))	('hypoxic', 'Disease', 'MESH:D000860', (74, 81))	('migration', 'CPA', (32, 41))	('ESCC', 'Disease', (58, 62))	('NRF2', 'Gene', (12, 16))	('hypoxic', 'Disease', (74, 81))
258453	29752726	We hypothesized that NRF2 hyperactivation caused esophageal hyperproliferation and hyperkeratosis through gene transcriptional regulation in esophageal squamous epithelial cells.	('NRF2', 'Gene', (21, 25))	('caused', 'Reg', (42, 48))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (83, 97))	('hyperactivation', 'Var', (26, 41))	('esophageal hyperproliferation and hyperkeratosis', 'Disease', 'MESH:D004941', (49, 97))
258465	29752726	Recent next-generation sequencing studies have confirmed PIK3CA mutations as drivers in ESCC.	('ESCC', 'Disease', (88, 92))	('PIK3CA', 'Gene', '5290', (57, 63))	('mutations', 'Var', (64, 73))	('ESCC', 'Disease', 'MESH:C562729', (88, 92))	('PIK3CA', 'Gene', (57, 63))
258466	29752726	Phospho-Akt levels were increased in the KEAP1-/- esophagus.	('Phospho-Akt levels', 'MPA', (0, 18))	('increased', 'PosReg', (24, 33))	('Phospho', 'Chemical', 'MESH:C033601', (0, 7))	('KEAP1-/-', 'Var', (41, 49))
258467	29752726	In the literature, transgenic overexpression of EGF ligand or receptor (AREG, ERBB2) and a constitutively active Akt or transgenic knockout of PTEN (an inhibitor of the PI3K/Akt pathway) caused esophageal hyperkeratosis in mice.	('ERBB2', 'Gene', '13866', (78, 83))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (205, 219))	('AREG', 'Gene', (72, 76))	('knockout', 'Var', (131, 139))	('esophageal hyperkeratosis', 'Disease', (194, 219))	('ERBB2', 'Gene', (78, 83))	('mice', 'Species', '10090', (223, 227))	('overexpression', 'PosReg', (30, 44))	('caused', 'Reg', (187, 193))	('transgenic', 'Species', '10090', (19, 29))	('esophageal hyperkeratosis', 'Disease', 'MESH:D004941', (194, 219))	('transgenic', 'Species', '10090', (120, 130))	('PTEN', 'Gene', (143, 147))	('AREG', 'Gene', '11839', (72, 76))
258468	29752726	Since PI3K/Akt mutations and activation are commonly seen in human ESCC, it would be interesting to further understand how these two signaling pathways interact with each other.	('activation', 'PosReg', (29, 39))	('ESCC', 'Disease', (67, 71))	('mutations', 'Var', (15, 24))	('ESCC', 'Disease', 'MESH:C562729', (67, 71))	('human', 'Species', '9606', (61, 66))	('PI3K/Akt', 'Gene', (6, 14))
258471	29752726	However, tissue of origin and environment are critical factors implicated in carcinogenesis driven by genetic alterations.	('carcinogenesis', 'Disease', (77, 91))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('genetic alterations', 'Var', (102, 121))
258482	29752726	It should be noted that the location of NRF2 mutations on the branches of tumor phylogenetic trees suggests that targeting NRF2 may not be as effective as targeting the trunks (e.g., p53).	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('NRF2', 'Gene', (40, 44))	('tumor', 'Disease', (74, 79))	('NRF2', 'Gene', (123, 127))
258483	29752726	In fact, Clemons proposed targeting the glutathione biosynthesis pathway (or NRF2 signaling pathway) in p53-mutanted cancers, considering that more than 80% of ESCCs harbor mutations in the p53 gene.	('p53', 'Gene', (104, 107))	('ESCC', 'Disease', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('p53', 'Gene', '7157', (104, 107))	('p53', 'Gene', (190, 193))	('ESCC', 'Disease', 'MESH:C562729', (160, 164))	('mutations', 'Var', (173, 182))	('p53', 'Gene', '7157', (190, 193))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('glutathione', 'Chemical', 'MESH:D005978', (40, 51))	('cancers', 'Disease', (117, 124))
258488	30271485	Comparison of treatment plan quality of VMAT for esophageal carcinoma with: flattening filter beam versus flattening filter free beam Purpose: To investigate the difference in treatment plan quality of volumetric modulated arc treatment (VMAT) for esophageal carcinoma with flattening filter beam (FF) and flattening filter free beam (FFF).	('VMAT', 'Disease', 'None', (40, 44))	('men', 'Species', '9606', (232, 235))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (49, 69))	('VMAT', 'Disease', (40, 44))	('flattening filter free beam', 'Var', (306, 333))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (248, 268))	('men', 'Species', '9606', (19, 22))	('VMAT', 'Disease', 'None', (238, 242))	('FF', 'Chemical', '-', (298, 300))	('VMAT', 'Disease', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (49, 69))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (248, 268))	('flattening', 'Var', (274, 284))	('FF', 'Chemical', '-', (335, 337))	('men', 'Species', '9606', (181, 184))	('esophageal carcinoma', 'Disease', (49, 69))	('esophageal carcinoma', 'Disease', (248, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))
258489	30271485	Material and methods: A total of fifty-six treatment plans were generated for twenty eight esophageal carcinoma patients with flattening filter beam and flattening filter free beam, using same optimal parameters.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (91, 111))	('men', 'Species', '9606', (48, 51))	('flattening', 'Var', (153, 163))	('patients', 'Species', '9606', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('esophageal carcinoma', 'Disease', (91, 111))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (91, 111))
258492	30271485	Results: A significant decreasing in peripheral dose around targets was found using FFF beams while the dose distributions in targets were equivalent to the plans with FF beams.	('FF', 'Chemical', '-', (84, 86))	('peripheral dose', 'MPA', (37, 52))	('decreasing', 'NegReg', (23, 33))	('FFF beams', 'Var', (84, 93))	('FF', 'Chemical', '-', (168, 170))
258495	30271485	Conclusions: For esophageal carcinoma, the research showed that the treatment plans with FFF beams could get comparable dose distribution in targets and could significantly reduce the peripheral dose around targets compared to the plans with FF beams.	('dose distribution', 'MPA', (120, 137))	('esophageal carcinoma', 'Disease', (17, 37))	('reduce', 'NegReg', (173, 179))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (17, 37))	('FF', 'Chemical', '-', (242, 244))	('men', 'Species', '9606', (73, 76))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (17, 37))	('FFF', 'Var', (89, 92))	('peripheral dose around', 'MPA', (184, 206))	('FF', 'Chemical', '-', (89, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))
258499	30271485	Several studies have demonstrated that volumetric modulated arc therapy has the ability to reduce monitor units and treatment time when compared with intensity-modulated radiation therapy [3.4.5.6].	('reduce', 'NegReg', (91, 97))	('men', 'Species', '9606', (121, 124))	('treatment time', 'CPA', (116, 130))	('monitor units', 'MPA', (98, 111))	('volumetric', 'Var', (39, 49))
258523	30271485	For the PTVs, the parameters analyzed were D 2%, D 98%, V 100%, V 95%, and homogeneity index (HI) and conformal index (CI).	('homogeneity', 'MPA', (75, 86))	('D 98', 'Var', (49, 53))	('PTV', 'Chemical', '-', (8, 11))	('D 2', 'Var', (43, 46))	('HI', 'Disease', 'MESH:C538424', (94, 96))
258527	30271485	Peripheral doses around PTVs were analyzed via comparison of volume outside PTV2 covered by 45 Gy, 30 Gy, and 20 Gy (V45Gy, V30Gy,V20Gy).	('V30Gy', 'Var', (124, 129))	('PTV', 'Chemical', '-', (76, 79))	('V20Gy', 'Var', (130, 135))	('PTV', 'Chemical', '-', (24, 27))
258540	30271485	For peripheral dose around PTV2, a significant reduction of V45Gy, V30Gy and V20Gy were observed on average by 6.46%, 8.18% and 4.40%, respectively.	('PTV2', 'Gene', (27, 31))	('PTV', 'Chemical', '-', (27, 30))	('reduction', 'NegReg', (47, 56))	('V30Gy', 'Var', (67, 72))	('V45Gy', 'Var', (60, 65))	('V20Gy', 'Var', (77, 82))
258544	30271485	The D2% which indicated hot dose in targets were 6416.3cGy and 6420.4cGy for FF beams and FFF beams, respectively, both bellowed 108% of prescripts dose.	('6420.4cGy', 'Var', (63, 72))	('FF', 'Chemical', '-', (90, 92))	('FF', 'Chemical', '-', (77, 79))	('6416.3cGy', 'Var', (49, 58))
258550	30271485	In this study, the V10Gy, V20Gy and V30Gy were used for evaluation of pulmonary toxicity.	('pulmonary toxicity', 'Disease', 'MESH:D008171', (70, 88))	('V20Gy', 'Var', (26, 31))	('V30Gy', 'Var', (36, 41))	('pulmonary toxicity', 'Disease', (70, 88))	('V10Gy', 'Var', (19, 24))
258551	30271485	Mary V.G stated when the total lung V20Gy is <25%, the very low risk of pneumonitis would occur.	('pneumonitis', 'Disease', 'MESH:D011014', (72, 83))	('<25%', 'Var', (45, 49))	('pneumonitis', 'Disease', (72, 83))
258552	30271485	For these two contrast plan groups with FF beams and FFF beams, the average values of V20Gy and V30Gy are both very close, meanwhile, the V20Gy is less than 30% and V30Gy is less than 20%, they are all within dose constrain tolerance and no significant statistic difference for both plans.	('V30Gy', 'Var', (96, 101))	('FF', 'Chemical', '-', (53, 55))	('FF', 'Chemical', '-', (40, 42))	('V20Gy', 'Var', (138, 143))	('less', 'NegReg', (147, 151))	('V20Gy', 'Var', (86, 91))	('less', 'NegReg', (174, 178))	('V30Gy', 'Var', (165, 170))
258558	30271485	Although the V40Gy,V30Gy of FFF beams plans had a slightly decreasing trend compared to the FF beams plans, they were all within 3%.	('FF', 'Chemical', '-', (28, 30))	('V30Gy', 'Var', (19, 24))	('FF', 'Chemical', '-', (92, 94))	('V40Gy', 'Var', (13, 18))
258564	30271485	For FFF beam plans, the peripheral dose such as V45 Gy, V30 Gy and V20Gy were reduced by 6.46%, 8.18% and 4.40%, respectively compared to the FF beam plans.	('V20Gy', 'Var', (67, 72))	('FF', 'Chemical', '-', (142, 144))	('V30 Gy', 'Var', (56, 62))	('reduced', 'NegReg', (78, 85))	('FF', 'Chemical', '-', (4, 6))	('V45 Gy', 'Var', (48, 54))
258579	30106155	MicroRNA-675-3p promotes esophageal squamous cell cancer cell migration and invasion Esophageal cancer ranks fourth in cancer-associated mortality in China and the incidence of esophageal adenocarcinoma has risen dramatically over the past two decades.	('promotes', 'PosReg', (16, 24))	('cancer', 'Disease', (50, 56))	('esophageal adenocarcinoma', 'Disease', (177, 202))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (96, 102))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (25, 56))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MicroRNA-675-3p', 'Var', (0, 15))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (36, 56))	('esophageal squamous cell cancer', 'Disease', (25, 56))	('Esophageal cancer', 'Disease', (85, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (177, 202))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (177, 202))	('Esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))
258617	30106155	MiRNA-675 represses the expression of tumor suppressor retinoblastoma in a classical way and promotes the proliferation of colon cancer cells.	('MiRNA-675', 'Var', (0, 9))	('tumor', 'Disease', (38, 43))	('represses', 'NegReg', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('MiRNA-675', 'Chemical', '-', (0, 9))	('retinoblastoma', 'Disease', (55, 69))	('retinoblastoma', 'Disease', 'MESH:D012175', (55, 69))	('expression', 'MPA', (24, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (123, 135))	('colon cancer', 'Disease', 'MESH:D015179', (123, 135))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('colon cancer', 'Disease', (123, 135))	('retinoblastoma', 'Phenotype', 'HP:0009919', (55, 69))	('promotes', 'PosReg', (93, 101))	('proliferation', 'CPA', (106, 119))
258640	30106155	The protein concentrations of matrix metalloproteinase (MMP)2, MMP9 and E-cadherin were measured by ELISA assay (Hangzhou Multisciences, Biotech Co., Ltd, Zhejiang, China, catalog number: EK1M022-96T, EK1M092-96T, EK12352-96T, respectively) following the manufacturer's protocol.	('MMP9', 'Gene', '4318', (63, 67))	('MMP9', 'Gene', (63, 67))	('EK1M022-96T', 'Var', (188, 199))	('Hangzhou Multisciences', 'Disease', (113, 135))	('matrix metalloproteinase (MMP)2', 'Gene', '4313', (30, 61))	('Hangzhou Multisciences', 'Disease', 'None', (113, 135))	('EK1M092-96T', 'Var', (201, 212))	('EK12352-96T', 'Var', (214, 225))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))
258710	28858114	The Radiation Therapy Oncology Group trial 85-01 established the superiority of chemoradiation with cisplatin and 5-fluorouracil over RT alone in patients treated without surgery and showed that CRT improved both 5-year survival (26% vs 0% at 5 years) and median survival (12.5 vs 9 months) compared with RT alone.	('improved', 'PosReg', (199, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (114, 128))	('Oncology', 'Phenotype', 'HP:0002664', (22, 30))	('median', 'MPA', (256, 262))	('CR', 'Chemical', '-', (195, 197))	('patients', 'Species', '9606', (146, 154))	('CRT', 'Var', (195, 198))
258750	28858114	Similarly, the median OS was also significantly longer in CRT group (24.6 months, 95% CI, 19.4-29.4 months) than that in the RT group (19.4 months, 95% CI, 13.7-25.0 months, P = .018).	('CR', 'Chemical', '-', (58, 60))	('OS', 'Chemical', '-', (22, 24))	('longer', 'PosReg', (48, 54))	('CRT', 'Var', (58, 61))
258794	27956804	FGFR1 and MYC amplifications were observed in 21.4% (37/173) and 54.2% (91/168) of patients, respectively, while MYC expression was observed in 58.9% (106/180) of patients.	('patients', 'Species', '9606', (163, 171))	('MYC', 'Gene', (10, 13))	('patients', 'Species', '9606', (83, 91))	('FGFR1', 'Gene', (0, 5))	('MYC', 'Gene', '4609', (113, 116))	('FGFR1', 'Gene', '2260', (0, 5))	('amplifications', 'Var', (14, 28))	('MYC', 'Gene', '4609', (10, 13))	('observed', 'Reg', (34, 42))	('MYC', 'Gene', (113, 116))
258796	27956804	Although FGFR1 amplification was not associated with MYC amplification or expression, 12.3% (20/163) of patients exhibited both FGFR1 amplification and MYC expression.	('FGFR1', 'Gene', (128, 133))	('FGFR1', 'Gene', '2260', (128, 133))	('MYC', 'Gene', '4609', (152, 155))	('FGFR1', 'Gene', '2260', (9, 14))	('MYC', 'Gene', '4609', (53, 56))	('amplification', 'Var', (134, 147))	('MYC', 'Gene', (152, 155))	('MYC', 'Gene', (53, 56))	('exhibited', 'Reg', (113, 122))	('FGFR1', 'Gene', (9, 14))	('patients', 'Species', '9606', (104, 112))
258797	27956804	There was also a correlation in FGFR1 amplification status between matched primary tumors and metastatic lymph nodes (P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('FGFR1', 'Gene', (32, 37))	('FGFR1', 'Gene', '2260', (32, 37))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('correlation', 'Reg', (17, 28))	('amplification status', 'Var', (38, 58))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
258800	27956804	FGFR1 amplification was an independent predictor for prolonged OS in all patients (P = 0.029) and in those who did not receive adjuvant therapy (P = 0.013).	('OS', 'Chemical', '-', (63, 65))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('prolonged OS', 'Disease', (53, 65))	('amplification', 'Var', (6, 19))	('patients', 'Species', '9606', (73, 81))
258801	27956804	Combined FGFR1 amplification and MYC expression predicted better OS in patients who did not receive adjuvant therapy (P = 0.034) but not in those who did receive adjuvant therapy.	('FGFR1', 'Gene', '2260', (9, 14))	('OS', 'Chemical', '-', (65, 67))	('amplification', 'Var', (15, 28))	('better', 'PosReg', (58, 64))	('MYC', 'Gene', '4609', (33, 36))	('patients', 'Species', '9606', (71, 79))	('MYC', 'Gene', (33, 36))	('FGFR1', 'Gene', (9, 14))
258802	27956804	FGFR1 amplification and MYC expression have prognostic implications in resected ESCCs with respect to adjuvant therapy.	('implications', 'Reg', (55, 67))	('SCC', 'Gene', '6317', (81, 84))	('MYC', 'Gene', (24, 27))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (6, 19))	('SCC', 'Gene', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('MYC', 'Gene', '4609', (24, 27))
258806	27956804	FGFR1 and MYC amplifications were observed in 21.4% and 54.2% of patients with ESCC, respectively, while 12.3% exhibited both FGFR1 amplification and MYC expression.	('SCC', 'Gene', '6317', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('MYC', 'Gene', (10, 13))	('FGFR1', 'Gene', (126, 131))	('MYC', 'Gene', '4609', (150, 153))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplifications', 'Var', (14, 28))	('FGFR1', 'Gene', '2260', (126, 131))	('MYC', 'Gene', '4609', (10, 13))	('patients', 'Species', '9606', (65, 73))	('SCC', 'Gene', (80, 83))	('observed', 'Reg', (34, 42))	('MYC', 'Gene', (150, 153))
258807	27956804	MYC expression and FGFR1 amplification were significantly associated with prolonged survival.	('MYC', 'Gene', (0, 3))	('associated', 'Reg', (58, 68))	('FGFR1', 'Gene', '2260', (19, 24))	('MYC', 'Gene', '4609', (0, 3))	('prolonged', 'PosReg', (74, 83))	('amplification', 'Var', (25, 38))	('FGFR1', 'Gene', (19, 24))
258808	27956804	Combined FGFR1 amplification and MYC expression was a predictor of better survival in patients who did not receive adjuvant therapy, but not in those who did.	('FGFR1', 'Gene', '2260', (9, 14))	('amplification', 'Var', (15, 28))	('MYC', 'Gene', '4609', (33, 36))	('expression', 'MPA', (37, 47))	('MYC', 'Gene', (33, 36))	('FGFR1', 'Gene', (9, 14))	('better', 'PosReg', (67, 73))	('patients', 'Species', '9606', (86, 94))
258812	27956804	Recently, genomic and molecular alterations have been discovered in ESCC, including activation of the receptor tyrosine kinase (RTK) pathway, cell cycle dysregulation, activation of Wnt and Notch signaling pathways and epigenetic modifications.	('RTK', 'Gene', (128, 131))	('receptor tyrosine kinase', 'Gene', '5979', (102, 126))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (142, 166))	('activation', 'PosReg', (84, 94))	('SCC', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('epigenetic modifications', 'Var', (219, 243))	('SCC', 'Gene', '6317', (69, 72))	('RTK', 'Gene', '5979', (128, 131))	('activation', 'PosReg', (168, 178))	('cell cycle dysregulation', 'CPA', (142, 166))	('receptor tyrosine kinase', 'Gene', (102, 126))
258819	27956804	However, the prognostic significance of FGFR1 amplification in patients with ESCC remains controversial.	('amplification', 'Var', (46, 59))	('SCC', 'Gene', '6317', (78, 81))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('patients', 'Species', '9606', (63, 71))	('SCC', 'Gene', (78, 81))	('SCC', 'Phenotype', 'HP:0002860', (78, 81))
258820	27956804	Pulmonary squamous cell carcinoma (SCC) is another cancer frequently showing FGFR1 amplification.	('FGFR1', 'Gene', (77, 82))	('SCC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('FGFR1', 'Gene', '2260', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('SCC', 'Gene', '6317', (35, 38))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('Pulmonary squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 33))	('Pulmonary squamous cell carcinoma', 'Disease', (0, 33))	('cancer', 'Disease', (51, 57))	('amplification', 'Var', (83, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))	('Pulmonary squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 33))
258834	27956804	The entire tumor area was scanned for hot spots representing increased FGFR1 copy numbers.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('FGFR1', 'Gene', (71, 76))	('increased FGFR1', 'Phenotype', 'HP:0030269', (61, 76))	('tumor', 'Disease', (11, 16))	('copy numbers', 'Var', (77, 89))	('FGFR1', 'Gene', '2260', (71, 76))	('increased', 'PosReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
258849	27956804	In ESCCs, FGFR1 amplification was detected in 21.4% (37/173) of patients (high amplification in 19.7%, n = 34 and low amplification in 1.7%, n = 3; Figure 1A and B).	('detected', 'Reg', (34, 42))	('SCC', 'Gene', (4, 7))	('patients', 'Species', '9606', (64, 72))	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('SCC', 'Gene', '6317', (4, 7))	('amplification', 'Var', (16, 29))	('FGFR1', 'Gene', (10, 15))	('FGFR1', 'Gene', '2260', (10, 15))
258853	27956804	FGFR1 amplification status was not associated with MYC amplification or protein expression.	('MYC', 'Gene', (51, 54))	('protein expression', 'MPA', (72, 90))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (6, 19))	('MYC', 'Gene', '4609', (51, 54))
258855	27956804	ESCC patients with FGFR1 amplification were younger than those without FGFR1 amplification (mean +- SD, 62.3 +- 8.4 years versus 65.6 +- 7.4 years, P = 0.022).	('FGFR1', 'Gene', (71, 76))	('patients', 'Species', '9606', (5, 13))	('FGFR1', 'Gene', '2260', (19, 24))	('FGFR1', 'Gene', '2260', (71, 76))	('SCC', 'Gene', (1, 4))	('SCC', 'Gene', '6317', (1, 4))	('SCC', 'Phenotype', 'HP:0002860', (1, 4))	('amplification', 'Var', (25, 38))	('FGFR1', 'Gene', (19, 24))
258856	27956804	Other clinicopathological parameters including sex, histological differentiation, smoking status and TNM stage were not significantly correlated with FGFR1 amplification.	('amplification', 'Var', (156, 169))	('FGFR1', 'Gene', (150, 155))	('FGFR1', 'Gene', '2260', (150, 155))
258860	27956804	Briefly, FGFR1 amplification in the primary tumor was observed in 11 of 56 cases, and 7 (63.6%) patients also showed FGFR1 amplification in metastatic tumors of the regional lymph nodes.	('FGFR1', 'Gene', '2260', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('amplification', 'Var', (15, 28))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('FGFR1', 'Gene', (117, 122))	('FGFR1', 'Gene', '2260', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (96, 104))	('amplification', 'Var', (123, 136))	('FGFR1', 'Gene', (9, 14))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
258865	27956804	Kaplan-Meier analysis revealed that DFS of ESCC patients with FGFR1 amplification was significantly prolonged compared with those without FGFR1 amplification (P = 0.021; Figure 2A).	('SCC', 'Gene', '6317', (44, 47))	('FGFR1', 'Gene', (138, 143))	('prolonged', 'PosReg', (100, 109))	('FGFR1', 'Gene', (62, 67))	('SCC', 'Gene', (44, 47))	('FGFR1', 'Gene', '2260', (138, 143))	('amplification', 'Var', (68, 81))	('patients', 'Species', '9606', (48, 56))	('FGFR1', 'Gene', '2260', (62, 67))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('DFS', 'MPA', (36, 39))
258866	27956804	OS also tended to be longer in patients with FGFR1 amplification compared with those without FGFR1 amplification (P = 0.081; Figure 2B).	('OS', 'Chemical', '-', (0, 2))	('longer', 'PosReg', (21, 27))	('patients', 'Species', '9606', (31, 39))	('FGFR1', 'Gene', (45, 50))	('FGFR1', 'Gene', (93, 98))	('FGFR1', 'Gene', '2260', (45, 50))	('FGFR1', 'Gene', '2260', (93, 98))	('amplification', 'Var', (51, 64))
258874	27956804	In patients without adjuvant therapy, FGFR1 amplification and MYC expression were significantly associated with prolonged OS (P = 0.024 and 0.031, respectively; Figure 2E and F), but not in patients who received adjuvant chemo- and/or radiotherapy (Figure 2G and H).	('MYC', 'Gene', (62, 65))	('patients', 'Species', '9606', (190, 198))	('associated', 'Reg', (96, 106))	('amplification', 'Var', (44, 57))	('FGFR1', 'Gene', (38, 43))	('MYC', 'Gene', '4609', (62, 65))	('patients', 'Species', '9606', (3, 11))	('FGFR1', 'Gene', '2260', (38, 43))	('OS', 'Chemical', '-', (122, 124))	('prolonged OS', 'Disease', (112, 124))
258876	27956804	In contrast, FGFR1 amplification was found to be an independent favorable prognostic factor in all patients (HR = 0.532 with 95%CI: 0.302-0.937, P = 0.029) and in patients without adjuvant therapy (HR = 0.301 with 95%CI: 0.117-0.774, P = 0.013), but not in patients with adjuvant therapy (Table 4).	('patients', 'Species', '9606', (163, 171))	('amplification', 'Var', (19, 32))	('FGFR1', 'Gene', (13, 18))	('patients', 'Species', '9606', (99, 107))	('favorable', 'PosReg', (64, 73))	('FGFR1', 'Gene', '2260', (13, 18))	('patients', 'Species', '9606', (257, 265))
258878	27956804	ESCC patients (25/173) with both FGFR1 amplification and MYC expression (hereafter referred to as combined positivity) exhibited prolonged DFS (P = 0.023; data not shown) and OS (P = 0.066) in Kaplan-Meier analysis (Figure 2I).	('OS', 'Chemical', '-', (175, 177))	('patients', 'Species', '9606', (5, 13))	('FGFR1', 'Gene', (33, 38))	('FGFR1', 'Gene', '2260', (33, 38))	('amplification', 'Var', (39, 52))	('MYC', 'Gene', '4609', (57, 60))	('SCC', 'Gene', (1, 4))	('prolonged', 'PosReg', (129, 138))	('SCC', 'Phenotype', 'HP:0002860', (1, 4))	('SCC', 'Gene', '6317', (1, 4))	('MYC', 'Gene', (57, 60))	('DFS', 'MPA', (139, 142))
258882	27956804	Several previous studies reported the prognostic implication of FGFR1 amplification in ESCC, but the results were controversial.	('amplification', 'Var', (70, 83))	('FGFR1', 'Gene', (64, 69))	('SCC', 'Gene', (88, 91))	('FGFR1', 'Gene', '2260', (64, 69))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
258883	27956804	FGFR1 amplification was associated with poor prognosis or had no prognostic significance in ESCC; however, the FISH criteria for FGFR1 amplification were not identical.	('FGFR1', 'Gene', (129, 134))	('FGFR1', 'Gene', '2260', (129, 134))	('SCC', 'Gene', (93, 96))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('SCC', 'Gene', '6317', (93, 96))	('amplification', 'Var', (6, 19))
258884	27956804	In the present study, FGFR1 amplification was a favorable prognostic indicator in patients with resected ESCC, which was in conflict with a previous report using the same FISH criteria.	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('FGFR1', 'Gene', '2260', (22, 27))	('SCC', 'Gene', '6317', (106, 109))	('patients', 'Species', '9606', (82, 90))	('amplification', 'Var', (28, 41))	('SCC', 'Gene', (106, 109))	('FGFR1', 'Gene', (22, 27))
258885	27956804	In a study using FISH and different criteria, FGFR1 amplification was not associated with clinical outcomes in patients with ESCC.	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('SCC', 'Gene', '6317', (126, 129))	('SCC', 'Gene', (126, 129))	('FGFR1', 'Gene', (46, 51))	('amplification', 'Var', (52, 65))	('FGFR1', 'Gene', '2260', (46, 51))	('patients', 'Species', '9606', (111, 119))
258887	27956804	One study demonstrated that FGFR1 amplification was an independent favorable prognostic factor in pulmonary SCC and large cell carcinoma, which contrasted with another study showing that FGFR1 amplification was an independent negative prognostic factor in resected pulmonary SCC.	('FGFR1', 'Gene', (187, 192))	('FGFR1', 'Gene', '2260', (187, 192))	('SCC', 'Gene', (275, 278))	('SCC', 'Gene', (108, 111))	('cell carcinoma', 'Disease', (122, 136))	('SCC', 'Phenotype', 'HP:0002860', (275, 278))	('FGFR1', 'Gene', (28, 33))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('SCC', 'Gene', '6317', (275, 278))	('SCC', 'Gene', '6317', (108, 111))	('FGFR1', 'Gene', '2260', (28, 33))	('amplification', 'Var', (34, 47))	('cell carcinoma', 'Disease', 'MESH:C538614', (122, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (116, 136))
258888	27956804	Consequently, a recent meta-analysis concluded that FGFR1 amplification had no influence on the survival of patients with pulmonary SCC.	('patients', 'Species', '9606', (108, 116))	('SCC', 'Gene', (132, 135))	('SCC', 'Phenotype', 'HP:0002860', (132, 135))	('SCC', 'Gene', '6317', (132, 135))	('FGFR1', 'Gene', (52, 57))	('FGFR1', 'Gene', '2260', (52, 57))	('amplification', 'Var', (58, 71))
258889	27956804	Notably, in this study, the association of FGFR1 amplification with clinical outcome of resected ESCC patients was dependent on the status of adjuvant therapy; i.e., FGFR1 amplification was a favorable prognostic factor in patients with ESCC who did not receive adjuvant therapy.	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('amplification', 'Var', (49, 62))	('FGFR1', 'Gene', (43, 48))	('SCC', 'Gene', '6317', (98, 101))	('patients', 'Species', '9606', (102, 110))	('FGFR1', 'Gene', '2260', (43, 48))	('SCC', 'Gene', (238, 241))	('SCC', 'Phenotype', 'HP:0002860', (238, 241))	('FGFR1', 'Gene', '2260', (166, 171))	('FGFR1', 'Gene', (166, 171))	('patients', 'Species', '9606', (223, 231))	('amplification', 'Var', (172, 185))	('SCC', 'Gene', '6317', (238, 241))	('SCC', 'Gene', (98, 101))
258890	27956804	Adjuvant therapy after surgery for patients with stage III-IV or lymph node metastasis prolonged survival compared with surgery alone in ESCC.	('survival', 'MPA', (97, 105))	('SCC', 'Gene', (138, 141))	('prolonged', 'PosReg', (87, 96))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('SCC', 'Gene', '6317', (138, 141))	('lymph node metastasis', 'Var', (65, 86))	('patients', 'Species', '9606', (35, 43))
258894	27956804	Otherwise, it could be possible that ESCC with FGFR1 amplification represents a biologically less aggressive group among ESCCs having variable genetic alterations.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('FGFR1', 'Gene', (47, 52))	('SCC', 'Gene', (38, 41))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('amplification', 'Var', (53, 66))	('SCC', 'Gene', '6317', (122, 125))	('FGFR1', 'Gene', '2260', (47, 52))	('SCC', 'Gene', '6317', (38, 41))
258901	27956804	Thus, the favorable prognosis of patients with ESCC who showed combined FGFR1 amplification and MYC expression in the group without adjuvant therapy might be due to the association of FGFR1 amplification with prognosis.	('FGFR1', 'Gene', '2260', (184, 189))	('MYC', 'Gene', (96, 99))	('patients', 'Species', '9606', (33, 41))	('amplification', 'Var', (78, 91))	('SCC', 'Gene', (48, 51))	('SCC', 'Phenotype', 'HP:0002860', (48, 51))	('association', 'Interaction', (169, 180))	('MYC', 'Gene', '4609', (96, 99))	('FGFR1', 'Gene', '2260', (72, 77))	('SCC', 'Gene', '6317', (48, 51))	('FGFR1', 'Gene', (72, 77))	('FGFR1', 'Gene', (184, 189))
258907	27956804	Thus, another study using large prospective cohorts is required to validate the prognostic role of FGFR1 amplification in ESCC according to adjuvant therapy status.	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('amplification', 'Var', (105, 118))	('SCC', 'Gene', '6317', (123, 126))	('FGFR1', 'Gene', (99, 104))	('FGFR1', 'Gene', '2260', (99, 104))	('SCC', 'Gene', (123, 126))
258914	27956804	Among the all patients with resected ESCC, 12.3% (20/163) exhibited both FGFR1 amplification and MYC expression.	('exhibited', 'Reg', (58, 67))	('FGFR1', 'Gene', '2260', (73, 78))	('SCC', 'Gene', (38, 41))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('MYC', 'Gene', (97, 100))	('SCC', 'Gene', '6317', (38, 41))	('MYC', 'Gene', '4609', (97, 100))	('amplification', 'Var', (79, 92))	('patients', 'Species', '9606', (14, 22))	('FGFR1', 'Gene', (73, 78))
258917	27956804	In conclusion, FGFR1 amplifications were observed in 21.4% of patients and combined FGFR1 amplification and MYC expression was observed in 12.3% of patients with resected ESCC.	('MYC', 'Gene', '4609', (108, 111))	('FGFR1', 'Gene', (84, 89))	('patients', 'Species', '9606', (148, 156))	('SCC', 'Gene', (172, 175))	('FGFR1', 'Gene', '2260', (84, 89))	('FGFR1', 'Gene', '2260', (15, 20))	('SCC', 'Phenotype', 'HP:0002860', (172, 175))	('amplifications', 'Var', (21, 35))	('MYC', 'Gene', (108, 111))	('SCC', 'Gene', '6317', (172, 175))	('observed', 'Reg', (41, 49))	('patients', 'Species', '9606', (62, 70))	('FGFR1', 'Gene', (15, 20))
258918	27956804	FGFR1 amplification had prognostic implications in patients with resected ESCC with respect to adjuvant therapy.	('SCC', 'Gene', '6317', (75, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('patients', 'Species', '9606', (51, 59))	('SCC', 'Gene', (75, 78))	('amplification', 'Var', (6, 19))	('implications', 'Reg', (35, 47))
258926	27956804	In this study, FGFR1 amplifications were observed in 21.4% of patients and combined FGFR1 amplification and MYC expression was observed in 12.3% of patients with resected ESCC.	('MYC', 'Gene', '4609', (108, 111))	('FGFR1', 'Gene', (84, 89))	('patients', 'Species', '9606', (148, 156))	('SCC', 'Gene', (172, 175))	('FGFR1', 'Gene', '2260', (84, 89))	('FGFR1', 'Gene', '2260', (15, 20))	('SCC', 'Phenotype', 'HP:0002860', (172, 175))	('amplifications', 'Var', (21, 35))	('MYC', 'Gene', (108, 111))	('SCC', 'Gene', '6317', (172, 175))	('observed', 'Reg', (41, 49))	('patients', 'Species', '9606', (62, 70))	('FGFR1', 'Gene', (15, 20))
258927	27956804	This study suggests that patients with ESCC harboring combined FGFR1 amplification and MYC expression might benefit from therapies targeting FGFR1 and/or MYC, especially those with advanced disease requiring adjuvant therapies.	('SCC', 'Gene', '6317', (40, 43))	('MYC', 'Gene', (87, 90))	('MYC', 'Gene', '4609', (154, 157))	('benefit', 'PosReg', (108, 115))	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('patients', 'Species', '9606', (25, 33))	('MYC', 'Gene', (154, 157))	('FGFR1', 'Gene', (141, 146))	('SCC', 'Gene', (40, 43))	('SCC', 'Phenotype', 'HP:0002860', (40, 43))	('amplification', 'Var', (69, 82))	('MYC', 'Gene', '4609', (87, 90))	('FGFR1', 'Gene', '2260', (141, 146))
258933	26034601	Though recent studies suggest that changes in dietary composition may alter the distal gut microbiome, little is currently known about the impact of a restricted diet upon microbial communities of the oral and esophageal microenvironments in the context of EoE.	('gut microbiome', 'Species', '749906', (87, 101))	('changes', 'Var', (35, 42))	('distal gut', 'MPA', (80, 90))	('alter', 'Reg', (70, 75))
258947	26034601	A reduction in microbial diversity with increased proportions of E. coli and C. difficile may be associated with a higher risk of eczema and allergic sensitization.	('E. coli', 'Var', (65, 72))	('allergic sensitization', 'Phenotype', 'HP:0012393', (141, 163))	('eczema', 'Disease', 'MESH:D004485', (130, 136))	('allergic', 'Disease', (141, 149))	('eczema', 'Phenotype', 'HP:0000964', (130, 136))	('reduction', 'NegReg', (2, 11))	('eczema', 'Disease', (130, 136))	('microbial diversity', 'MPA', (15, 34))	('C. difficile', 'Var', (77, 89))	('increased', 'PosReg', (40, 49))	('C. difficile', 'Species', '1496', (77, 89))	('E. coli', 'Species', '562', (65, 72))	('allergic', 'Disease', 'MESH:D004342', (141, 149))
258979	26034601	Campylobacter species have been associated with inflammatory states of gastrointestinal tract including periodontal disease, Barrett's esophagus, and IBD.	('gastrointestinal tract', 'Disease', (71, 93))	('Campylobacter species', 'Var', (0, 21))	('inflammatory', 'Disease', (48, 60))	('Campylobacter', 'Species', '197', (0, 13))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (71, 93))	('periodontal disease', 'Disease', (104, 123))	("Barrett's esophagus", 'Disease', (125, 144))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (125, 144))	('associated', 'Reg', (32, 42))	('IBD', 'Disease', (150, 153))	('periodontal disease', 'Phenotype', 'HP:0000704', (104, 123))
258981	26034601	Others found that seropositivity to Campylobacter jejuni had a greater association to the development of atopy.	('atopy', 'Disease', (105, 110))	('Campylobacter jejuni', 'Gene', (36, 56))	('Campylobacter jejuni', 'Species', '197', (36, 56))	('seropositivity', 'Var', (18, 32))
259023	25346912	The incidence of cardiotoxicity after AC treatment in childhood is similarly dose-dependent: 11, 23, 47, and 100% suffered from cardiac complications after being treated with <400, 400-599, 600-799, and >800 mg/m2 of AC-based chemotherapy.	('cardiotoxicity', 'Disease', 'MESH:D066126', (17, 31))	('cardiotoxicity', 'Disease', (17, 31))	('cardiac complications', 'Disease', 'MESH:D005117', (128, 149))	('AC', 'Chemical', 'MESH:D018943', (38, 40))	('AC', 'Chemical', 'MESH:D018943', (217, 219))	('<400', 'Var', (175, 179))	('cardiac complications', 'Disease', (128, 149))	('suffered', 'Reg', (114, 122))
259077	25346912	Moreover, TnI positivity was the strongest independent predictor of cardiotoxicity (HR = 17.6, p < 0.001) and persistent LVEF impairment (HR 2.33, p < 0.001).	('cardiotoxicity', 'Disease', (68, 82))	('positivity', 'Var', (14, 24))	('LVEF impairment', 'Disease', (121, 136))	('LVEF impairment', 'Disease', 'MESH:D009422', (121, 136))	('TnI', 'Gene', (10, 13))	('cardiotoxicity', 'Disease', 'MESH:D066126', (68, 82))
259123	25346912	found significant associations between NT-proBNP and V3Gy (volume receiving at least 3 Gy), and two ratios for the heart: D15cm3/Dmean and D15cm3/D50% (where Dmean is the mean dose, D50% is the median dose, and  is the minimum isodose received by 15 cm3).	('D15cm3/Dmean', 'Var', (122, 134))	('associations', 'Interaction', (18, 30))	('BNP', 'Gene', (45, 48))	('D15cm3/D50%', 'Var', (139, 150))	('BNP', 'Gene', '4879', (45, 48))	('D50%', 'Var', (182, 186))	('V3Gy', 'Disease', (53, 57))
259190	20494003	In summary, based on meta-analyses (with their limitations), it appears that there is an increase in mortality with open TTE for cancer when compared to open THE.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mortality', 'MPA', (101, 110))	('open TTE', 'Var', (116, 124))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('increase', 'PosReg', (89, 97))
259210	20494003	Rindani conducted a meta-analysis of transhiatal versus Ivor Lewis esophagectomy and, as described above, there were no differences in pulmonary or cardiovascular complications.	('cardiovascular complications', 'Phenotype', 'HP:0001626', (148, 176))	('pulmonary or cardiovascular complications', 'Disease', 'MESH:D002318', (135, 176))	('pulmonary or cardiovascular complications', 'Disease', (135, 176))	('transhiatal', 'Var', (37, 48))
259225	20494003	The mean operative time, blood loss, and length of intensive care unit stay were decreased with the minimally invasive approach compared with an open transthoracic esophagectomy or transhiatal esophagectomy.	('decreased', 'NegReg', (81, 90))	('blood loss', 'Disease', 'MESH:D006473', (25, 35))	('blood loss', 'Disease', (25, 35))	('minimally', 'Var', (100, 109))
259307	32875699	An esophageal cancer cell line that exhibited high Girdin expression showed a marked sensitivity to UV-mediated DNA damage compared to a line with low Girdin expression.	('cancer', 'Disease', (14, 20))	('high', 'Var', (46, 50))	('sensitivity to UV-mediated DNA damage', 'MPA', (85, 122))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('expression', 'Var', (58, 68))	('Girdin', 'Protein', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
259332	32875699	We first found that high Girdin expression was associated with an increased sensitivity of cancer cells to UVC-mediated DNA damage.	('increased', 'PosReg', (66, 75))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('sensitivity', 'MPA', (76, 87))	('high', 'Var', (20, 24))	('Girdin', 'Protein', (25, 31))	('associated', 'Reg', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('expression', 'MPA', (32, 42))
259347	32875699	Lentiviruses expressing dCas9-VP64 and MS2-P65-HSF1 were generated by transfection of the packaging plasmids psPAX2 (#12260; Addgene), pMD2.G (#12259; Addgene), and lenti dCAS-VP64_Blast (#61425; Addgene) or lenti MS2-P65-HSF1_Hygro (#61426; Addgene) into HEK293T cells using Lipofectamine 2000 (Thermo Fisher Scientific).	('#12259', 'Var', (143, 149))	('HEK293T', 'CellLine', 'CVCL:0063', (256, 263))	('#12260', 'Var', (117, 123))	('#61426', 'Var', (234, 240))	('MS2', 'Species', '2710868', (214, 217))	('MS2', 'Species', '2710868', (39, 42))
259371	32875699	As a model of radiotherapy, we subjected cancer cells to high-dose UVC irradiation (20-100 J/m2) that produces pyrimidine dimers and double-stranded DNA breaks that contribute to the induction of apoptotic cell death.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('double-stranded DNA breaks', 'MPA', (133, 159))	('apoptotic cell death', 'CPA', (196, 216))	('pyrimidine', 'Var', (111, 121))	('pyrimidine', 'Chemical', 'MESH:C030986', (111, 121))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
259373	32875699	We found that the number of cells that survived after UVC exposure, which was evaluated by colony-forming capacity, was higher in KYSE150 cells than KYSE140 cells (Figure 2B,C).	('higher', 'PosReg', (120, 126))	('KYSE150', 'Var', (130, 137))	('KYSE150', 'CellLine', 'CVCL:1348', (130, 137))
259416	32875699	23  Our present study added a new dimension to Girdin function, ie that high expression of Girdin enhances the vulnerability of cancer cells to DNA damage.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('vulnerability', 'MPA', (111, 124))	('enhances', 'PosReg', (98, 106))	('Girdin', 'Gene', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('high', 'Var', (72, 76))	('cancer', 'Disease', (128, 134))
259451	32922434	The shRNAs for ECGR4 and OGN knockdown were synthesized from GENERALBIOL (Anhui, China) and were annealed and cloned into a pSilencer 2.1-neo vector (Ambion).	('OGN', 'Gene', '4969', (25, 28))	('OGN', 'Gene', (25, 28))	('knockdown', 'Var', (29, 38))	('ECGR4', 'Gene', (15, 20))	('pSilencer', 'Disease', 'None', (124, 133))	('pSilencer', 'Disease', (124, 133))
259462	32922434	For promoter activity analysis, various lengths of human OGN gene promoter regions (-989/++91, -662/+91, and -287/+91 bp) were synthesized by GENEWIZ Biotech (Suzhou, China) and inserted into the KpnI and XhoI sites of pGL3-Basic (Promega).	('pGL3', 'Gene', '6391', (219, 223))	('human', 'Species', '9606', (51, 56))	('OGN', 'Gene', '4969', (57, 60))	('OGN', 'Gene', (57, 60))	('-989/++91', 'Var', (84, 93))	('pGL3', 'Gene', (219, 223))
259485	32922434	The results demonstrate that ECRG4 upregulation leads to a remarkable reduction in cell migration and invasion, whereas ECRG4 knockout enhances the cell migration and invasion ability of J82 and BC-5367 cells (Figures 2F,G).	('enhances', 'PosReg', (135, 143))	('ECRG4', 'Gene', (120, 125))	('reduction', 'NegReg', (70, 79))	('invasion ability', 'CPA', (167, 183))	('cell migration', 'CPA', (83, 97))	('ECRG4', 'Gene', '84417', (120, 125))	('invasion', 'CPA', (102, 110))	('knockout', 'Var', (126, 134))	('cell migration', 'CPA', (148, 162))	('ECRG4', 'Gene', (29, 34))	('upregulation', 'PosReg', (35, 47))	('ECRG4', 'Gene', '84417', (29, 34))
259492	32922434	On the other hand, ECRG4 knockdown reduced the mRNA and protein levels of OGN in BCa cells (Figures 4A-C).	('ECRG4', 'Gene', '84417', (19, 24))	('reduced', 'NegReg', (35, 42))	('OGN', 'Gene', '4969', (74, 77))	('BCa', 'Phenotype', 'HP:0009725', (81, 84))	('OGN', 'Gene', (74, 77))	('ECRG4', 'Gene', (19, 24))	('knockdown', 'Var', (25, 34))
259493	32922434	Additionally, ECRG4 knockdown remarkably increased the cell proliferation, migration, and invasion abilities of BCa cells, whereas OGN overexpression could partly counteract the promoting effect caused by ECRG4 knockdown (Figures 4D-G).	('increased', 'PosReg', (41, 50))	('ECRG4', 'Gene', '84417', (205, 210))	('ECRG4', 'Gene', (14, 19))	('OGN', 'Gene', '4969', (131, 134))	('OGN', 'Gene', (131, 134))	('cell proliferation', 'CPA', (55, 73))	('invasion abilities of BCa cells', 'CPA', (90, 121))	('BCa', 'Phenotype', 'HP:0009725', (112, 115))	('ECRG4', 'Gene', '84417', (14, 19))	('knockdown', 'Var', (20, 29))	('migration', 'CPA', (75, 84))	('ECRG4', 'Gene', (205, 210))
259509	32922434	We observed that ECRG4 overexpression decreased NF-kappaB activity, whereas ECRG4 knockdown increased NF-kappaB activity (Figure 6A).	('decreased', 'NegReg', (38, 47))	('activity', 'MPA', (58, 66))	('NF-kappaB', 'Gene', '4790', (102, 111))	('NF-kappaB', 'Gene', (102, 111))	('NF-kappaB', 'Gene', (48, 57))	('knockdown', 'Var', (82, 91))	('ECRG4', 'Gene', (17, 22))	('NF-kappaB', 'Gene', '4790', (48, 57))	('increased', 'PosReg', (92, 101))	('ECRG4', 'Gene', (76, 81))	('ECRG4', 'Gene', '84417', (17, 22))	('activity', 'MPA', (112, 120))	('ECRG4', 'Gene', '84417', (76, 81))
259510	32922434	Ectopic expression of ECRG4 resulted in the inhibition of the total p65 and p-p65 (S536) subunit, whereas ECRG4 knockdown enhanced the total p65 and active form of p-p65 (S536) (Figures 6B-D).	('ECRG4', 'Gene', (106, 111))	('enhanced', 'PosReg', (122, 130))	('p65', 'Gene', '5970', (141, 144))	('p65', 'Gene', (78, 81))	('ECRG4', 'Gene', '84417', (22, 27))	('ECRG4', 'Gene', '84417', (106, 111))	('p65', 'Gene', (68, 71))	('p65', 'Gene', '5970', (166, 169))	('inhibition', 'NegReg', (44, 54))	('knockdown', 'Var', (112, 121))	('p65', 'Gene', '5970', (78, 81))	('p65', 'Gene', '5970', (68, 71))	('p65', 'Gene', (141, 144))	('ECRG4', 'Gene', (22, 27))	('p65', 'Gene', (166, 169))
259511	32922434	Furthermore, the luciferase assay indicated that OGN knockdown resulted in an increase in NF-kappaB activity, which was repressed by ECRG4 overexpression and has been confirmed by Western blotting (Figures 6E-G).	('ECRG4', 'Gene', (133, 138))	('OGN', 'Gene', '4969', (49, 52))	('OGN', 'Gene', (49, 52))	('ECRG4', 'Gene', '84417', (133, 138))	('knockdown', 'Var', (53, 62))	('increase', 'PosReg', (78, 86))	('NF-kappaB', 'Gene', '4790', (90, 99))	('NF-kappaB', 'Gene', (90, 99))	('activity', 'MPA', (100, 108))
259535	32922434	Herein, downregulation of total p65 by ECGR4 knockdown suggests that ECGR4 inhibits NF-kappaB activity by decreasing p65 expression.	('NF-kappaB', 'Gene', (84, 93))	('p65', 'Gene', '5970', (117, 120))	('p65', 'Gene', (32, 35))	('p65', 'Gene', '5970', (32, 35))	('expression', 'MPA', (121, 131))	('activity', 'MPA', (94, 102))	('decreasing', 'NegReg', (106, 116))	('NF-kappaB', 'Gene', '4790', (84, 93))	('p65', 'Gene', (117, 120))	('downregulation', 'NegReg', (8, 22))	('ECGR4', 'Var', (69, 74))	('inhibits', 'NegReg', (75, 83))
259598	32083000	Dysregulation of certain lncRNAs leads to the hyper- or hypoactivation of cellular pathways that promote and/or sustain tumor initiation and progression.	('cellular pathways', 'Pathway', (74, 91))	('tumor initiation', 'Disease', (120, 136))	('Dysregulation', 'Var', (0, 13))	('progression', 'CPA', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor initiation', 'Disease', 'MESH:D009369', (120, 136))	('promote', 'PosReg', (97, 104))
259607	32083000	Cancer cells show a plethora of chromosomal abnormalities, including translocations, amplifications, and deletions.	('amplifications', 'Var', (85, 99))	('translocations', 'Var', (69, 83))	('deletions', 'Var', (105, 114))	('plethora of chromosomal abnormalities', 'Phenotype', 'HP:0040012', (20, 57))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('plethora', 'Phenotype', 'HP:0001050', (20, 28))	('chromosomal abnormalities', 'Disease', (32, 57))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (32, 57))
259610	32083000	We now know that PVT1 gene fusions occur in additional hematologic malignancies, such as non-Hodgkin lymphoma and advanced multiple myeloma.	('hematologic malignancies', 'Disease', (55, 79))	('multiple myeloma', 'Disease', (123, 139))	('non-Hodgkin lymphoma', 'Disease', (89, 109))	('multiple myeloma', 'Disease', 'MESH:D009101', (123, 139))	('lymphoma', 'Phenotype', 'HP:0002665', (101, 109))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (89, 109))	('PVT1', 'Gene', (17, 21))	('occur', 'Reg', (35, 40))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (89, 109))	('hematologic malignancies', 'Disease', 'MESH:D019337', (55, 79))	('fusions', 'Var', (27, 34))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (93, 109))	('multiple myeloma', 'Phenotype', 'HP:0006775', (123, 139))
259613	32083000	In addition, human PVT1 is a target of genetic gains and amplifications in a large variety of cancers, including those of the digestive tract.	('amplifications', 'Var', (57, 71))	('genetic', 'Var', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('human', 'Species', '9606', (13, 18))	('gains', 'PosReg', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human PVT1', 'Gene', (13, 23))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
259614	32083000	Moreover, genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) in the PVT1 locus (8q24) that are associated with increased colorectal cancer risk.	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('rectal cancer', 'Phenotype', 'HP:0100743', (163, 176))	('associated with', 'Reg', (133, 148))	('increased', 'PosReg', (149, 158))	('PVT1', 'Gene', (106, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Disease', (159, 176))	('single nucleotide polymorphisms', 'Var', (60, 91))
259617	32083000	In this review, we will discuss the current knowledge of PVT1 alteration/dysregulation, as well as its contribution to gastrointestinal cancer.	('alteration/dysregulation', 'Var', (62, 86))	('PVT1', 'Gene', (57, 61))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (119, 142))	('gastrointestinal cancer', 'Disease', (119, 142))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (119, 142))	('rat', 'Species', '10116', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
259630	32083000	Interestingly, the tumorigenic process does not seem to affect the relative abundance of PVT1 isoforms (Figure 1), being PVT1 Sv-217 the isoform also more abundant in tumors.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('PVT1 Sv-217', 'Var', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (19, 24))	('tumors', 'Disease', (167, 173))	('tumor', 'Disease', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
259633	32083000	Precisely, CACO2, SW480, SW620, HT29, and HCT116 cells derived from human colorectal tumors displayed higher levels of total PVT1 compared to NCM460, FHC and HCoEpiC normal colonic epithelial cells.	('HCoEpiC', 'Disease', (158, 165))	('human', 'Species', '9606', (68, 73))	('FHC', 'Gene', (150, 153))	('colon', 'Disease', 'MESH:D015179', (173, 178))	('HCoEpiC', 'Disease', 'None', (158, 165))	('HCT116', 'CellLine', 'CVCL:0291', (42, 48))	('HT29', 'CellLine', 'CVCL:0320', (32, 36))	('colorectal tumors', 'Disease', 'MESH:D015179', (74, 91))	('PVT1', 'MPA', (125, 129))	('higher', 'PosReg', (102, 108))	('SW480', 'CellLine', 'CVCL:0546', (18, 23))	('SW620', 'CellLine', 'CVCL:0547', (25, 30))	('colorectal tumors', 'Disease', (74, 91))	('SW620', 'Var', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('FHC', 'Gene', '3949', (150, 153))	('colon', 'Disease', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
259638	32083000	PVT1 transcript levels changes upon manipulation of FOXM1 protein expression in gastric cancer cells.	('protein', 'Protein', (58, 65))	('FOXM1', 'Gene', (52, 57))	('gastric cancer', 'Disease', (80, 94))	('manipulation', 'Var', (36, 48))	('changes', 'Reg', (23, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('transcript levels', 'MPA', (5, 22))	('PVT1', 'Gene', (0, 4))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('FOXM1', 'Gene', '2305', (52, 57))
259639	32083000	Specifically, PVT1 expression is reduced upon FOXM1 silencing and increases after FOXM1 overexpression.	('expression', 'MPA', (19, 29))	('FOXM1', 'Gene', '2305', (46, 51))	('silencing', 'Var', (52, 61))	('FOXM1', 'Gene', (46, 51))	('increases', 'PosReg', (66, 75))	('FOXM1', 'Gene', (82, 87))	('PVT1', 'Gene', (14, 18))	('FOXM1', 'Gene', '2305', (82, 87))	('reduced', 'NegReg', (33, 40))
259643	32083000	STAT3 overexpression in gastric cancer cell lines leads to increased PVT1 levels, while STAT3 knockdown results in PVT1 transcriptional downregulation.	('knockdown', 'Var', (94, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('STAT3', 'Gene', '6774', (88, 93))	('downregulation', 'NegReg', (136, 150))	('STAT3', 'Gene', (88, 93))	('STAT3', 'Gene', '6774', (0, 5))	('PVT1 levels', 'MPA', (69, 80))	('gastric cancer', 'Disease', (24, 38))	('overexpression', 'PosReg', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('PVT1', 'Gene', (115, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('STAT3', 'Gene', (0, 5))	('increased', 'PosReg', (59, 68))	('transcriptional', 'MPA', (120, 135))
259646	32083000	This tumor suppressor is involved in the cell cycle regulation by transactivating a plethora of protein-coding but also non-protein-coding genes, that ultimately prevent cell division by inducing cell cycle arrest, senescence, or apoptosis.	('cell cycle arrest', 'CPA', (196, 213))	('cell division', 'CPA', (170, 183))	('plethora', 'Phenotype', 'HP:0001050', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('protein-coding', 'Protein', (96, 110))	('senescence', 'CPA', (215, 225))	('apoptosis', 'CPA', (230, 239))	('inducing', 'Reg', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('prevent', 'NegReg', (162, 169))	('transactivating', 'Var', (66, 81))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (196, 213))
259649	32083000	It is important to mention that PVT1 upregulation upon these conditions was only monitored in p53 wild-type colorectal cancer cell lines and thus, it remains unknown the ability of mutant p53 proteins to exert an equivalent role.	('men', 'Species', '9606', (19, 22))	('mutant', 'Var', (181, 187))	('p53', 'Gene', (94, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('p53', 'Gene', '7157', (94, 97))	('upregulation', 'PosReg', (37, 49))	('rectal cancer', 'Phenotype', 'HP:0100743', (112, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('p53', 'Gene', (188, 191))	('colorectal cancer', 'Disease', (108, 125))	('PVT1', 'Gene', (32, 36))	('p53', 'Gene', '7157', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
259650	32083000	Although most p53 mutations result in expression of dominant-negative forms, certain mutations are known to confer oncogenic functions (Figure 2).	('p53', 'Gene', (14, 17))	('oncogenic functions', 'CPA', (115, 134))	('expression', 'MPA', (38, 48))	('p53', 'Gene', '7157', (14, 17))	('result', 'Reg', (28, 34))	('mutations', 'Var', (18, 27))
259667	32083000	It has been demonstrated experimentally that insertions or deletions in the PVT1 promoter lead to Myc overexpression and consequently, enhanced growth in cancer cells.	('Myc', 'Gene', '4609', (98, 101))	('Myc', 'Gene', (98, 101))	('men', 'Species', '9606', (31, 34))	('insertions', 'Var', (45, 55))	('deletions', 'Var', (59, 68))	('cancer', 'Disease', (154, 160))	('overexpression', 'PosReg', (102, 116))	('rat', 'Species', '10116', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('enhanced', 'PosReg', (135, 143))	('PVT1', 'Gene', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
259668	32083000	As a consequence, genomic DNA structural variations, i.e., deletions, duplications, insertions, inversions, and translocations, are able to modify the three-dimensional chromatin topology and promote or suppress promoter-enhancer interactions within the TADs.	('promoter-enhancer', 'Protein', (212, 229))	('men', 'Species', '9606', (159, 162))	('three-dimensional chromatin topology', 'MPA', (151, 187))	('interactions', 'Interaction', (230, 242))	('promote', 'PosReg', (192, 199))	('translocations', 'Var', (112, 126))	('deletions', 'Var', (59, 68))	('modify', 'Reg', (140, 146))	('insertions', 'Var', (84, 94))	('duplications', 'Var', (70, 82))	('inversions', 'Var', (96, 106))	('suppress', 'NegReg', (203, 211))
259670	32083000	However, under the PVT1 promoter mutational rearrangements found in tumor cells, and even epigenetic inactivation, PVT1 intragenic enhancer elements interact preferentially with MYC promoter, thus boosting the transcription of MYC oncogene and its oncogenic activity of tumor cells (Figure 2).	('tumor', 'Disease', (68, 73))	('MYC', 'Gene', (178, 181))	('boosting', 'PosReg', (197, 205))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('oncogenic activity', 'CPA', (248, 266))	('MYC', 'Gene', (227, 230))	('mutational', 'Var', (33, 43))	('transcription', 'MPA', (210, 223))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('MYC', 'Gene', '4609', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('men', 'Species', '9606', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('PVT1', 'Gene', (115, 119))	('preferentially', 'PosReg', (158, 172))	('MYC', 'Gene', '4609', (227, 230))	('men', 'Species', '9606', (143, 146))	('tumor', 'Disease', (270, 275))
259674	32083000	Precisely, PVT1 expression in gastric tumors enhances microvessel formation, both in vitro and in vivo, through a mechanism that involves vascular endothelial growth factor A (VEGFA) expression in a STAT3-dependent manner.	('vascular endothelial growth factor A', 'Gene', '7422', (138, 174))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('gastric tumors', 'Disease', (30, 44))	('expression', 'Var', (16, 26))	('VEGFA', 'Gene', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('vascular endothelial growth factor A', 'Gene', (138, 174))	('gastric tumors', 'Phenotype', 'HP:0006753', (30, 44))	('STAT3', 'Gene', '6774', (199, 204))	('PVT1', 'Gene', (11, 15))	('VEGFA', 'Gene', '7422', (176, 181))	('gastric tumor', 'Phenotype', 'HP:0006753', (30, 43))	('enhances', 'PosReg', (45, 53))	('STAT3', 'Gene', (199, 204))	('microvessel formation', 'CPA', (54, 75))	('gastric tumors', 'Disease', 'MESH:D013274', (30, 44))
259678	32083000	In fact, expression of PVT1 and VEGFA in combination predicts poor survival in gastric cancer, further supporting the use of antiangiogenic drugs in these patients.	('expression', 'Var', (9, 19))	('VEGFA', 'Gene', '7422', (32, 37))	('PVT1', 'Gene', (23, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('VEGFA', 'Gene', (32, 37))	('patients', 'Species', '9606', (155, 163))	('gastric cancer', 'Disease', (79, 93))	('poor', 'NegReg', (62, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
259681	32083000	The only exception is the study of He et al., where they convincingly demonstrated in HCT116 and SW480 colon cancer cell lines, the ability of PVT1 Sv-214 to promote proliferation, stemness, migration and invasion in vitro; as well as in vivo by establishing tumor xenografts and liver metastasis mouse models in immunodeficient nude mice.	('colon cancer', 'Disease', (103, 115))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('proliferation', 'CPA', (166, 179))	('PVT1 Sv-214', 'Var', (143, 154))	('migration', 'CPA', (191, 200))	('rat', 'Species', '10116', (173, 176))	('rat', 'Species', '10116', (77, 80))	('promote', 'PosReg', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('stemness', 'CPA', (181, 189))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('HCT116', 'CellLine', 'CVCL:0291', (86, 92))	('immunodeficient', 'Disease', 'MESH:D007153', (313, 328))	('mouse', 'Species', '10090', (297, 302))	('immunodeficient', 'Disease', (313, 328))	('SW480', 'CellLine', 'CVCL:0546', (97, 102))	('colon cancer', 'Disease', 'MESH:D015179', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('invasion', 'CPA', (205, 213))	('rat', 'Species', '10116', (194, 197))	('nude mice', 'Species', '10090', (329, 338))	('tumor', 'Disease', (259, 264))
259686	32083000	As depicted in Figure 4, most of the miRNAs contained within the PVT1 transcript variants expressed in the colon and stomach are found in intronic regions.	('colon', 'Disease', 'MESH:D015179', (107, 112))	('miR', 'Gene', (37, 40))	('miR', 'Gene', '22877', (37, 40))	('PVT1', 'Gene', (65, 69))	('colon', 'Disease', (107, 112))	('variants', 'Var', (81, 89))
259696	32083000	Aberrant expression of hTERT is associated with the metastatic ability of gastric tumors.	('Aberrant expression', 'Var', (0, 19))	('gastric tumors', 'Disease', (74, 88))	('gastric tumors', 'Disease', 'MESH:D013274', (74, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('hTERT', 'Gene', '7015', (23, 28))	('gastric tumor', 'Phenotype', 'HP:0006753', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('gastric tumors', 'Phenotype', 'HP:0006753', (74, 88))	('associated', 'Reg', (32, 42))	('metastatic ability', 'CPA', (52, 70))	('hTERT', 'Gene', (23, 28))
259705	32083000	In good agreement, PVT1 is negatively correlated with miR-152 expression in tumors from gastric cancer patients, and its genetic manipulation in SGC7901 and BGC823 gastric cell lines influences miR-152 levels and ultimately, CD151 and FGF2 expression.	('miR-152', 'Gene', '406943', (194, 201))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('influences', 'Reg', (183, 193))	('CD151', 'Gene', '977', (225, 230))	('miR-152', 'Gene', (54, 61))	('negatively', 'NegReg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('FGF2', 'Gene', '2247', (235, 239))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('expression', 'MPA', (240, 250))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('miR-152', 'Gene', '406943', (54, 61))	('CD151', 'Gene', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('genetic manipulation', 'Var', (121, 141))	('men', 'Species', '9606', (13, 16))	('levels', 'MPA', (202, 208))	('FGF2', 'Gene', (235, 239))	('miR-152', 'Gene', (194, 201))	('gastric cancer', 'Disease', (88, 102))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('patients', 'Species', '9606', (103, 111))
259713	32083000	Gastric cancer cell lines with PVT1 overexpression show increased HIF-1alpha mRNA and protein levels, that are reduced with a miR-186 mimic.	('Gastric cancer', 'Disease', (0, 14))	('HIF-1alpha', 'Gene', (66, 76))	('increased', 'PosReg', (56, 65))	('Gastric cancer', 'Disease', 'MESH:D013274', (0, 14))	('reduced', 'NegReg', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('HIF-1alpha', 'Gene', '3091', (66, 76))	('PVT1', 'Gene', (31, 35))	('miR-186', 'Gene', '406962', (126, 133))	('miR-186', 'Gene', (126, 133))	('overexpression', 'Var', (36, 50))
259726	32083000	However, the additional contact sites between the lncRNA and the miRNA pointed out by the authors are not always present in these variants or alternatively differ in length from the central motif.	('miR', 'Gene', '22877', (65, 68))	('variants', 'Var', (130, 138))	('miR', 'Gene', (65, 68))
259753	32083000	Consistently, Lin28 protein levels were reduced in vitro and in vivo when PVT1 was knocked down using siRNAs technology, and increased when PVT1 was overexpressed (Figure 5).	('Lin28', 'Gene', (14, 19))	('Lin28', 'Gene', '79727', (14, 19))	('increased', 'PosReg', (125, 134))	('protein levels', 'MPA', (20, 34))	('reduced', 'NegReg', (40, 47))	('knocked', 'Var', (83, 90))	('PVT1', 'Gene', (74, 78))
259755	32083000	Therefore, besides PVT1 Sv-214, only PVT1 Sv-217 could potentially interact with Lin28.	('Lin28', 'Gene', '79727', (81, 86))	('PVT1 Sv-217', 'Var', (37, 48))	('Lin28', 'Gene', (81, 86))	('interact', 'Interaction', (67, 75))
259756	32083000	Altogether, Lin28 is regulated by PVT1 through two independent mechanisms: (1) post-transcriptionally, preventing Lin28 transcript targeting by mir-128, as described above, and; (2) post-translationally, reducing Lin28 protein degradation by the proteasome machinery.	('mir-128', 'Var', (144, 151))	('Lin28', 'Gene', '79727', (213, 218))	('transcript targeting', 'MPA', (120, 140))	('PVT1', 'Gene', (34, 38))	('Lin28', 'Gene', (114, 119))	('Lin28', 'Gene', '79727', (114, 119))	('Lin28', 'Gene', (12, 17))	('Lin28', 'Gene', '79727', (12, 17))	('reducing', 'NegReg', (204, 212))	('Lin28', 'Gene', (213, 218))	('protein degradation', 'MPA', (219, 238))	('preventing', 'NegReg', (103, 113))
259757	32083000	LncRNAs are important epigenetic regulators and in turn, perturbations of epigenetic regulation are thought to be a key feature of many cancers and even driver events.	('epigenetic regulation', 'MPA', (74, 95))	('perturbations', 'Var', (57, 70))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
259759	32083000	PVT1 has been shown to recruit Enhancer of Zeste homolog 2 (EZH2) to epigenetically negatively regulate the expression of p15 and p16 in gastric cancer cell lines.	('EZH2', 'Gene', (60, 64))	('regulate', 'Reg', (95, 103))	('p15', 'Gene', (122, 125))	('p16', 'Gene', (130, 133))	('p15', 'Gene', '1030', (122, 125))	('negatively', 'NegReg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Enhancer of Zeste homolog 2', 'Gene', '2146', (31, 58))	('PVT1', 'Gene', (0, 4))	('gastric cancer', 'Disease', (137, 151))	('Enhancer of Zeste homolog 2', 'Gene', (31, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('expression', 'MPA', (108, 118))	('p16', 'Gene', '1029', (130, 133))	('epigenetically', 'Var', (69, 83))	('EZH2', 'Gene', '2146', (60, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
259766	32083000	PVT1 Sv-203 when amplified with qPCR primers that could co-amplify Sv-202 and Sv-211 (two isoforms that according to genome-wide RNAseq profiling have no detectable expression in colorectal malignancies) correlates with advanced stage (III-IV), lymph node metastasis, venous invasion, and decreased overall survival.	('colorectal malignancies', 'Disease', 'MESH:D015179', (179, 202))	('lymph node metastasis', 'CPA', (245, 266))	('overall survival', 'CPA', (299, 315))	('venous invasion', 'CPA', (268, 283))	('colorectal malignancies', 'Disease', (179, 202))	('PVT1', 'Gene', (0, 4))	('decreased', 'NegReg', (289, 298))	('Sv-211', 'Var', (78, 84))
259768	32083000	Additional studies assessing PVT1 overall levels by means of high-throughput technologies such as microarrays or RNA sequencing, observed that high expression values were associated with shorter patient overall survival.	('patient overall survival', 'CPA', (195, 219))	('patient', 'Species', '9606', (195, 202))	('high', 'Var', (143, 147))	('shorter', 'NegReg', (187, 194))
259790	32083000	Currently, there are no reports associating PVT1 up-regulation with well-established and clinically relevant molecular features of colorectal and gastric tumors such as microsatellite stability (MSI/MSS), CpG island methylator phenotype (CIMP+/CIMP-), consensus molecular subtypes (CMS1, CMS2, CMS3, and CMS4 for colorectal cancer, and MSI, EBV, CIN, GS for gastric cancer) or mutations in key driver genes (APC, CTNNB1, SMAD4, TGFB1, TP53, KRAS, PI3K, CDKN2A, CDH1, ERBB2, or RHOA).	('gastric cancer', 'Disease', (358, 372))	('GS', 'Disease', 'MESH:D011125', (351, 353))	('gastric tumors', 'Phenotype', 'HP:0006753', (146, 160))	('SMAD4', 'Gene', (421, 426))	('CDH1', 'Gene', (461, 465))	('PI3K', 'Gene', (447, 451))	('rectal cancer', 'Phenotype', 'HP:0100743', (317, 330))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('TP53', 'Gene', (435, 439))	('gastric cancer', 'Disease', 'MESH:D013274', (358, 372))	('colorectal and gastric tumors', 'Disease', 'MESH:D015179', (131, 160))	('up-regulation', 'PosReg', (49, 62))	('CTNNB1', 'Gene', '1499', (413, 419))	('CIN', 'Disease', (346, 349))	('colorectal cancer', 'Phenotype', 'HP:0003003', (313, 330))	('CDKN2A', 'Gene', (453, 459))	('EBV', 'Disease', (341, 344))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('APC', 'Disease', 'MESH:D011125', (408, 411))	('gastric cancer', 'Phenotype', 'HP:0012126', (358, 372))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('APC', 'Disease', (408, 411))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CDKN2A', 'Gene', '1029', (453, 459))	('CTNNB1', 'Gene', (413, 419))	('EBV', 'Disease', 'MESH:D020031', (341, 344))	('colorectal cancer', 'Disease', 'MESH:D015179', (313, 330))	('gastric tumor', 'Phenotype', 'HP:0006753', (146, 159))	('CIN', 'Disease', 'MESH:D007674', (346, 349))	('colorectal cancer', 'Disease', (313, 330))	('TGFB1', 'Gene', (428, 433))	('mutations', 'Var', (377, 386))
259819	31226960	Third, several population-based studies have reported a higher re-intervention rate in patients who underwent MIE, while no evident reduction in postoperative complications or overall morbidity was observed.	('MIE', 'Chemical', '-', (110, 113))	('MIE', 'Var', (110, 113))	('postoperative complications', 'Disease', (145, 172))	('postoperative complications', 'Disease', 'MESH:D011183', (145, 172))	('higher', 'PosReg', (56, 62))	('re-intervention', 'MPA', (63, 78))	('patients', 'Species', '9606', (87, 95))
259857	31226960	Quality of life (QOL): QOL is assessed among patients by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ-C30) and EORTC QLQ-OES18 at randomization, and 3 month, 6 month, 9 month and yearly till 3 years after surgery respectively.	('Cancer', 'Disease', (119, 125))	('Cancer', 'Disease', 'MESH:D009369', (119, 125))	('EORTC', 'Chemical', '-', (181, 186))	('EORTC', 'Var', (181, 186))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (45, 53))	('EORTC', 'Chemical', '-', (162, 167))
259889	29721170	DNMT1 ablation suppresses tumorigenesis by inhibiting the self-renewal of esophageal cancer stem cells Cancer stem cells (CSCs) have been isolated from many tumors and considered as the main reason of cancer recurrence and metastasis.	('self-renewal of', 'CPA', (58, 73))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('inhibiting', 'NegReg', (43, 53))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('esophageal cancer', 'Disease', (74, 91))	('DNMT1', 'Gene', '1786', (0, 5))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))	('suppresses', 'NegReg', (15, 25))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (157, 163))	('Cancer', 'Disease', (103, 109))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumorigenesis', 'CPA', (26, 39))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('DNMT1', 'Gene', (0, 5))	('Cancer', 'Disease', 'MESH:D009369', (103, 109))	('ablation', 'Var', (6, 14))
259894	29721170	Our findings also provided the first evidence that 5-aza-dC inhibited the colony and sphere formation of CSCs.	('5-aza-dC', 'Var', (51, 59))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (51, 59))	('inhibited', 'NegReg', (60, 69))
259895	29721170	Thus, our results indicated that DNMT1 was important for the self-renewal maintenance of CSCs in ESCC, and 5-aza-dC could be a potential therapy for the CSCs of ESCC.	('5-aza-dC', 'Var', (107, 115))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (107, 115))	('ESCC', 'Disease', (97, 101))
259909	29721170	Our results demonstrated that DNMT1 played important roles in the self-renewal maintenance of ESCC-CSCs, and 5-aza-dC, a DNMT inhibitor, could be a potential therapy for the CSCs of ESCC.	('5-aza-dC', 'Chemical', 'MESH:D000077209', (109, 117))	('DNMT', 'Gene', '1786', (121, 125))	('self-renewal maintenance', 'CPA', (66, 90))	('DNMT', 'Gene', (121, 125))	('DNMT', 'Gene', '1786', (30, 34))	('ESCC', 'Disease', (182, 186))	('5-aza-dC', 'Var', (109, 117))	('DNMT', 'Gene', (30, 34))
259915	29721170	We detected the expression of DNMT1 in spheroid formation cells which is another method of enriching CSCs from KYSE510, KYSE180 and EC109 cell lines, and we found that the mRNA level of DNMT1 was higher than that of parental populations (Figure 1D-1E).	('mRNA level', 'MPA', (172, 182))	('DNMT1', 'Var', (186, 191))	('DNMT1', 'Gene', (30, 35))	('EC109', 'CellLine', 'CVCL:6898', (132, 137))	('higher', 'PosReg', (196, 202))
259919	29721170	In EC109 cells, the SP fractions of Lenti-sh-DNMT1 group were also significantly lower than Lenti-sh-NC group (2.867 +- 0.418% vs. 1.200 +- 0.513%, P < 0.05).	('lower', 'NegReg', (81, 86))	('SP fractions', 'CPA', (20, 32))	('SP', 'Chemical', '-', (20, 22))	('Lenti-sh-DNMT1', 'Var', (36, 50))	('EC109', 'CellLine', 'CVCL:6898', (3, 8))
259921	29721170	The measurement of tumor sizes showed that the volumes of tumor xenografts from Lenti-sh-DNMT1 group were much smaller than those from Lenti-sh-NC and KYSE150 groups (Figure 2E and 2F).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('volumes', 'CPA', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (19, 24))	('smaller', 'NegReg', (111, 118))	('Lenti-sh-DNMT1 group', 'Var', (80, 100))
259926	29721170	We found that the percentage of SP cells in the 5-aza-dC group was dramatically decreased compared with control group (Figure 4B).	('5-aza-dC', 'Var', (48, 56))	('decreased', 'NegReg', (80, 89))	('SP', 'Chemical', '-', (32, 34))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (48, 56))
259927	29721170	The numbers of tumor spheres formed by 5-aza-dC group were less than control group (Figure 4C).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('less', 'NegReg', (59, 63))	('5-aza-dC', 'Var', (39, 47))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (39, 47))
259928	29721170	The volume and the weight of tumor xenografts from 5-aza-dC group were both smaller than control group in vivo (Figure 4D-4F).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('5-aza-dC group', 'Var', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (51, 59))	('tumor', 'Disease', (29, 34))	('smaller', 'NegReg', (76, 83))
259931	29721170	SP cells treated with 5-aza-dC expressed lower colony formation abilities than control group (Figure 4G).	('SP', 'Chemical', '-', (0, 2))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (22, 30))	('lower', 'NegReg', (41, 46))	('5-aza-dC', 'Var', (22, 30))	('colony formation abilities', 'CPA', (47, 73))
259932	29721170	Treating SP cells with 5-aza-dC also inhibited their sphere formation capabilities (Figure 4H).	('5-aza-dC', 'Chemical', 'MESH:D000077209', (23, 31))	('inhibited', 'NegReg', (37, 46))	('5-aza-dC', 'Var', (23, 31))	('SP', 'Chemical', '-', (9, 11))	('sphere formation capabilities', 'CPA', (53, 82))
259933	29721170	The results indicated that 5-aza-dC could blunt the self-renewal abilities of CSCs in ESCC.	('5-aza-dC', 'Chemical', 'MESH:D000077209', (27, 35))	('5-aza-dC', 'Var', (27, 35))	('self-renewal abilities of CSCs', 'CPA', (52, 82))	('blunt', 'NegReg', (42, 47))
259937	29721170	In both cell lines, colony formation and migration abilities were decreased after 5-aza-dC treatment (Figure 5D and 5E).	('5-aza-dC', 'Chemical', 'MESH:D000077209', (82, 90))	('decreased', 'NegReg', (66, 75))	('colony formation', 'CPA', (20, 36))	('migration abilities', 'CPA', (41, 60))	('5-aza-dC', 'Var', (82, 90))
259938	29721170	Similarly, cells treated with 5-aza-dC showed reduced drug resistance abilities in all DDP concentrations (Figure 5F).	('drug resistance abilities', 'CPA', (54, 79))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (30, 38))	('reduced', 'NegReg', (46, 53))	('drug resistance', 'Phenotype', 'HP:0020174', (54, 69))	('5-aza-dC', 'Var', (30, 38))
259940	29721170	Using immunohistochemistry assay we found a decreased expression of SOX2 in Lenti-sh-DNMT1 or 5-aza-dC treated tumor xenografts (Figure 6C).	('expression', 'MPA', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (94, 102))	('tumor', 'Disease', (111, 116))	('5-aza-dC', 'Var', (94, 102))	('Lenti-sh-DNMT1', 'Var', (76, 90))	('SOX2', 'Gene', (68, 72))	('SOX2', 'Gene', '6657', (68, 72))	('decreased', 'NegReg', (44, 53))
259942	29721170	We found that all of these miRNAs were up-regulated after the treatment of 5-aza-dC.	('5-aza-dC', 'Var', (75, 83))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (75, 83))	('up-regulated', 'PosReg', (39, 51))
259953	29721170	The mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSCs pool.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mice', 'Species', '10090', (51, 55))	('CSCs pool', 'MPA', (99, 108))	('tumor', 'Disease', (69, 74))	('deletion', 'Var', (33, 41))	('limiting', 'NegReg', (86, 94))	('DNMT1', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
259954	29721170	In pancreatic ductal adenocarcinoma, CSCs expressed higher DNMT1 levels than non-CSCs, deletion of DNMT1 in CSCs reduced their self-renewal and tumorigenic potential.	('tumor', 'Disease', (144, 149))	('DNMT1 levels', 'MPA', (59, 71))	('self-renewal', 'CPA', (127, 139))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (3, 35))	('DNMT1', 'Gene', (99, 104))	('pancreatic ductal adenocarcinoma', 'Disease', (3, 35))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('higher', 'PosReg', (52, 58))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 35))	('deletion', 'Var', (87, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('reduced', 'NegReg', (113, 120))
259957	29721170	In our study, as a result of refrained CSCs by ablation of DNMT1, the malignant phenotypes of the bulk cancer cells in KYSE150 and EC109 ESCC cell lines were inhibited, including cell proliferation, colony formation, migration and drug resistance abilities.	('cell proliferation', 'CPA', (179, 197))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('drug resistance abilities', 'CPA', (231, 256))	('malignant phenotypes', 'CPA', (70, 90))	('EC109 ESCC', 'CellLine', 'CVCL:6898', (131, 141))	('inhibited', 'NegReg', (158, 167))	('ablation', 'Var', (47, 55))	('DNMT1', 'Gene', (59, 64))	('drug resistance', 'Phenotype', 'HP:0020174', (231, 246))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('colony formation', 'CPA', (199, 215))	('migration', 'CPA', (217, 226))
259960	29721170	In our study, we found a dramatic decrease of DNMT1 and DNMT3b at protein level after the 5-aza-dC treatment.	('DNMT1', 'Gene', (46, 51))	('DNMT3b', 'Gene', '1789', (56, 62))	('decrease', 'NegReg', (34, 42))	('5-aza-dC', 'Var', (90, 98))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (90, 98))	('DNMT3b', 'Gene', (56, 62))
259964	29721170	Studies showed that treatment of prostate cancer stem cells with 5-aza-dC could reduce the expression of stem cell-associated genes and induced differentiation of the prostate cancer stem cells.	('prostate cancer', 'Phenotype', 'HP:0012125', (167, 182))	('expression', 'MPA', (91, 101))	('stem cell-associated genes', 'Gene', (105, 131))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('induced', 'Reg', (136, 143))	('5-aza-dC', 'Var', (65, 73))	('prostate cancer', 'Disease', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (65, 73))	('prostate cancer', 'Disease', (167, 182))	('prostate cancer', 'Disease', 'MESH:D011471', (33, 48))	('reduce', 'NegReg', (80, 86))	('differentiation', 'CPA', (144, 159))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (167, 182))
259965	29721170	Tsai et al have recently shown that the application of 5-aza-dC has successfully reduced stem cell characteristics of leukemia.	('5-aza-dC', 'Var', (55, 63))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('leukemia', 'Disease', 'MESH:D007938', (118, 126))	('stem cell characteristics of', 'CPA', (89, 117))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (55, 63))	('leukemia', 'Disease', (118, 126))	('reduced', 'NegReg', (81, 88))
259966	29721170	Pancreatic cancer stem cells have been shown to be sensitive to 5-aza-dC, which reduces tumor sphere formation and induces apoptosis of the cancer stem cells.	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('apoptosis', 'CPA', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('reduces', 'NegReg', (80, 87))	('induces', 'Reg', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Disease', (11, 17))	('5-aza-dC', 'Var', (64, 72))	('tumor', 'Disease', (88, 93))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (64, 72))
259967	29721170	5-aza-dC has also been demonstrated induce differentiation of the pancreatic cancer progenitor cell lines.	('5-aza-dC', 'Var', (0, 8))	('pancreatic cancer', 'Disease', (66, 83))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (0, 8))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('differentiation', 'CPA', (43, 58))	('induce', 'PosReg', (36, 42))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))
259968	29721170	Our study also showed that treatment with 5-aza-dC could reduce proliferation, clone formation, migration and drug resistance abilities of ESCC cells.	('migration', 'CPA', (96, 105))	('drug resistance abilities', 'CPA', (110, 135))	('reduce', 'NegReg', (57, 63))	('5-aza-dC', 'Var', (42, 50))	('drug resistance', 'Phenotype', 'HP:0020174', (110, 125))	('proliferation', 'CPA', (64, 77))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (42, 50))	('clone formation', 'CPA', (79, 94))
259969	29721170	Our work shed light on development of novel clinical regimes that 5-aza-dC may be an effective therapy for ESCC patients by targeting CSCs.	('5-aza-dC', 'Var', (66, 74))	('patients', 'Species', '9606', (112, 120))	('CSCs', 'Disease', (134, 138))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (66, 74))	('ESCC', 'Disease', (107, 111))
259970	29721170	However, after DNMT1 inhibition or 5-aza-dC treatment, we observed a downregulation of SOX2, a stemness transcriptional regulator.	('SOX2', 'Gene', '6657', (87, 91))	('5-aza-dC', 'Var', (35, 43))	('SOX2', 'Gene', (87, 91))	('DNMT1', 'Gene', (15, 20))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (35, 43))	('inhibition', 'Var', (21, 31))	('downregulation', 'NegReg', (69, 83))
259972	29721170	In liver CSCs, histone deacetylatase sirtuin 1 (SIRT1) could regulates transcription of the SOX2 gene by way of chromatin-based epigenetic changes.	('sirtuin 1', 'Gene', (37, 46))	('regulates', 'Reg', (61, 70))	('SOX2', 'Gene', (92, 96))	('SIRT1', 'Gene', '23411', (48, 53))	('SOX2', 'Gene', '6657', (92, 96))	('SIRT1', 'Gene', (48, 53))	('epigenetic changes', 'Var', (128, 146))	('transcription', 'MPA', (71, 84))	('sirtuin 1', 'Gene', '23411', (37, 46))
259973	29721170	Yuan et al found that histone demethylases KDM4C, also can epigenetically enhancing SOX2 expression in tumor-initiating cell populations in human esophageal squamous cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('human', 'Species', '9606', (140, 145))	('KDM4C', 'Gene', '23081', (43, 48))	('KDM4C', 'Gene', (43, 48))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (146, 180))	('tumor', 'Disease', (103, 108))	('SOX2', 'Gene', '6657', (84, 88))	('SOX2', 'Gene', (84, 88))	('esophageal squamous cell carcinoma', 'Disease', (146, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('epigenetically', 'Var', (59, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('enhancing', 'PosReg', (74, 83))
259977	29721170	The expressions of these four miRNAs were up-regulated after the treatment of 5-aza-dC.	('5-aza-dC', 'Var', (78, 86))	('up-regulated', 'PosReg', (42, 54))	('expressions', 'MPA', (4, 15))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (78, 86))
259978	29721170	A possible reason was 5-aza-dC could not only promote the degradation of DNMT1, but also other DNMTs such as DNMT3b which may play more important role in the methylation regulation of miRNAs.	('DNMT3b', 'Gene', (109, 115))	('promote', 'PosReg', (46, 53))	('DNMT', 'Gene', (73, 77))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (22, 30))	('DNMT', 'Gene', '1786', (109, 113))	('DNMT', 'Gene', (109, 113))	('DNMT', 'Gene', '1786', (95, 99))	('DNMT3b', 'Gene', '1789', (109, 115))	('DNMT', 'Gene', '1786', (73, 77))	('DNMT', 'Gene', (95, 99))	('5-aza-dC', 'Var', (22, 30))	('degradation', 'MPA', (58, 69))
259979	29721170	Following DNMT1 knock-down or 5-aza-dC treatment, downregulation of SOX2 and reactivation of CSC inhibitory miRNAs might partially contribute to the inhibition of ESCC-CSCs, but the exact mechanism need a further study.	('ESCC-CSCs', 'Disease', (163, 172))	('downregulation', 'NegReg', (50, 64))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (30, 38))	('SOX2', 'Gene', (68, 72))	('reactivation', 'MPA', (77, 89))	('SOX2', 'Gene', '6657', (68, 72))	('DNMT1', 'Gene', (10, 15))	('CSC inhibitory miRNAs', 'MPA', (93, 114))	('knock-down', 'Var', (16, 26))
260026	25851181	Food and water are also potential sources of some of the carcinogens that are possibly involved in the etiology of ESCC, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and nitrates.	('ESCC', 'Disease', (115, 119))	('heterocyclic amines', 'Chemical', '-', (131, 150))	('nitrates', 'Chemical', 'MESH:D009566', (203, 211))	('polycyclic', 'Var', (159, 169))	('HCAs', 'Chemical', '-', (152, 156))	('PAHs', 'Chemical', 'MESH:D011084', (193, 197))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (159, 191))	('heterocyclic amines', 'MPA', (131, 150))	('water', 'Chemical', 'MESH:D014867', (9, 14))
260032	25851181	Several ecological and epidemiological studies have suggested a link between high nitrate content of water and GI cancers, including ESCC.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('GI cancers', 'Disease', 'MESH:D009369', (111, 121))	('GI cancer', 'Phenotype', 'HP:0007378', (111, 120))	('nitrate', 'Chemical', 'MESH:D009566', (82, 89))	('high', 'Var', (77, 81))	('ESCC', 'Disease', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('GI cancers', 'Disease', (111, 121))	('water', 'Chemical', 'MESH:D014867', (101, 106))
260044	25851181	Body mass index (BMI) was calculated by dividing measured weight (kg) by the square of the measured height (m), and categorized using the World Health Organization (WHO) cutoffs: underweight (BMI<18.5 kg/m2), normal (18.5<=BMI<25 kg/m2), overweight (25<=BMI<30kg/m2), and obese (BMI>= 30 kg/m2).	('BMI', 'Var', (192, 195))	('25<=BMI<30kg/m2', 'Var', (250, 265))	('obese', 'Disease', 'MESH:D009765', (272, 277))	('obese', 'Disease', (272, 277))	('overweight', 'Phenotype', 'HP:0025502', (238, 248))
260104	25851181	Measurement error in dietary intake could have affected our findings, and is an integral part of any study relying on dietary assessment tools.	('men', 'Species', '9606', (7, 10))	('affected', 'Reg', (47, 55))	('Measurement', 'Var', (0, 11))	('men', 'Species', '9606', (132, 135))
260229	26335067	The main RFs for RT included: pT4, pT3N1, pT1-2N1 (N1 at levels IV/V), close margins <=2 mm, poor differentiation with tumor depth >=4 mm.	('pT4', 'Var', (30, 33))	('tumor', 'Disease', (119, 124))	('pT1', 'Gene', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('pT1', 'Gene', '58492', (42, 45))	('pT3N1', 'Var', (35, 40))
260284	26335067	Moreover, intermediate-risk patients with a score of 1 had worse 5-year OS rates than low-risk patients who scored 0 (Fig 2d).	('OS', 'Chemical', '-', (72, 74))	('worse', 'NegReg', (59, 64))	('patients', 'Species', '9606', (95, 103))	('score', 'Var', (44, 49))	('OS rates', 'MPA', (72, 80))	('patients', 'Species', '9606', (28, 36))
260338	23691264	The evidence presented in this review shows that pterostilbene reduces oxidative stress (OS) and production of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2) and superoxide anion (O2 -), which are implicated in the initiation and pathogenesis of several disease processes.	('pterostilbene', 'Chemical', 'MESH:C107773', (49, 62))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (111, 134))	('ROS', 'Chemical', 'MESH:D017382', (136, 139))	('oxidative stress', 'Phenotype', 'HP:0025464', (71, 87))	('OS', 'Phenotype', 'HP:0025464', (89, 91))	('O2', 'Chemical', '-', (197, 199))	('OS', 'Phenotype', 'HP:0025464', (137, 139))	('H2O2', 'Chemical', 'MESH:D006861', (169, 173))	('reduces', 'NegReg', (63, 70))	('hydrogen peroxide', 'MPA', (150, 167))	('oxidative stress', 'MPA', (71, 87))	('superoxide anion', 'Chemical', 'MESH:D013481', (179, 195))	('superoxide', 'MPA', (179, 189))	('O2', 'Chemical', '-', (171, 173))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (150, 167))	('production of reactive oxygen species', 'MPA', (97, 134))	('pterostilbene', 'Var', (49, 62))
260339	23691264	In addition, various cell lines treated with pterostilbene have shown increased expression of the antioxidants catalase, total glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD).	('glutathione reductase', 'Gene', (176, 197))	('SOD', 'Gene', (230, 233))	('GR', 'Gene', '116686', (199, 201))	('glutathione', 'Chemical', 'MESH:D005978', (127, 138))	('increased', 'PosReg', (70, 79))	('glutathione reductase', 'Gene', '116686', (176, 197))	('glutathione', 'Chemical', 'MESH:D005978', (146, 157))	('glutathione peroxidase', 'MPA', (146, 168))	('SOD', 'Gene', '6647', (230, 233))	('total glutathione', 'MPA', (121, 138))	('pterostilbene', 'Var', (45, 58))	('glutathione', 'Chemical', 'MESH:D005978', (176, 187))	('expression', 'MPA', (80, 90))	('superoxide dismutase', 'Gene', (208, 228))	('GSH', 'Chemical', 'MESH:D005978', (140, 143))	('pterostilbene', 'Chemical', 'MESH:C107773', (45, 58))
260390	23691264	Blueberry supplementation was also shown to reduce H2O2-induced intracellular ROS production in human microvascular endothelial cells (HMVECs).	('ROS', 'Chemical', 'MESH:D017382', (78, 81))	('intracellular ROS production', 'MPA', (64, 92))	('reduce', 'NegReg', (44, 50))	('human', 'Species', '9606', (96, 101))	('men', 'Species', '9606', (16, 19))	('OS', 'Phenotype', 'HP:0025464', (79, 81))	('H2O2-induced', 'Var', (51, 63))	('H2O2', 'Chemical', 'MESH:D006861', (51, 55))
260393	23691264	In experimental studies, VSMCs treated with pterostilbene exhibited reduction in platelet-derived-growth-factor-(PDGF-) induced proliferation and Akt, a serine-threonine kinase.	('rat', 'Species', '10116', (135, 138))	('Akt', 'Gene', (146, 149))	('pterostilbene', 'Var', (44, 57))	('men', 'Species', '9606', (9, 12))	('growth-factor', 'Gene', (98, 111))	('proliferation', 'CPA', (128, 141))	('VSMCs', 'Chemical', '-', (25, 30))	('pterostilbene', 'Chemical', 'MESH:C107773', (44, 57))	('reduction', 'NegReg', (68, 77))	('growth-factor', 'Gene', '79215', (98, 111))	('Akt', 'Gene', '24185', (146, 149))
260395	23691264	The results may be clinically relevant because abnormal proliferation of VSMCs is a significant component of the pathogenesis of atherosclerosis and a major contributor to the development of vascular stenosis.	('vascular stenosis', 'Disease', (191, 208))	('men', 'Species', '9606', (183, 186))	('atherosclerosis', 'Disease', 'MESH:D050197', (129, 144))	('atherosclerosis', 'Phenotype', 'HP:0002621', (129, 144))	('VSMCs', 'Protein', (73, 78))	('atherosclerosis', 'Disease', (129, 144))	('rat', 'Species', '10116', (63, 66))	('vascular stenosis', 'Phenotype', 'HP:0100545', (191, 208))	('abnormal', 'Var', (47, 55))	('VSMCs', 'Chemical', '-', (73, 78))	('vascular stenosis', 'Disease', 'MESH:D003251', (191, 208))
260397	23691264	In separate studies conducted by Zhang et al., pterostilbene was shown to inhibit apoptosis and induce autophagy in VECs counteracting the proatherosclerosis effect of oxidized low-density lipoprotein (oxLDL).	('atherosclerosis', 'Disease', (142, 157))	('autophagy', 'CPA', (103, 112))	('apoptosis', 'CPA', (82, 91))	('pterostilbene', 'Var', (47, 60))	('induce', 'PosReg', (96, 102))	('inhibit', 'NegReg', (74, 81))	('pterostilbene', 'Chemical', 'MESH:C107773', (47, 60))	('rat', 'Species', '10116', (7, 10))	('atherosclerosis', 'Disease', 'MESH:D050197', (142, 157))	('atherosclerosis', 'Phenotype', 'HP:0002621', (142, 157))
260398	23691264	Zhang and colleagues have demonstrated that pterostilbene treatment induces autophagy in oxLDL-stimulated VECs through activation of AMP-activated protein kinase (AMPK), intracellular calcium (Ca2+), and mammalian target of rapamycin (mTOR) signaling.	('men', 'Species', '9606', (63, 66))	('mammalian target of rapamycin', 'Gene', (204, 233))	('calcium', 'Chemical', 'MESH:D002118', (184, 191))	('autophagy', 'CPA', (76, 85))	('pterostilbene', 'Var', (44, 57))	('mTOR', 'Gene', (235, 239))	('Ca2+', 'Chemical', 'MESH:D000069285', (193, 197))	('mTOR', 'Gene', '2475', (235, 239))	('rat', 'Species', '10116', (33, 36))	('activation', 'PosReg', (119, 129))	('pterostilbene', 'Chemical', 'MESH:C107773', (44, 57))	('mammalian target of rapamycin', 'Gene', '2475', (204, 233))	('AMP-activated', 'MPA', (133, 146))
260419	23691264	Boivin and colleagues demonstrated that juice from velvet leaf blueberry, low-bush blueberry, and high-bush blueberry, all inhibited cell proliferation of gastric adenocarcinoma cells.	('cell proliferation', 'CPA', (133, 151))	('rat', 'Species', '10116', (29, 32))	('high-bush', 'Var', (98, 107))	('inhibited', 'NegReg', (123, 132))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (155, 177))	('gastric adenocarcinoma', 'Disease', (155, 177))	('rat', 'Species', '10116', (145, 148))
260422	23691264	Similarly, in a study performed by Pan and colleagues, pterostilbene treatment inhibited cell proliferation in a dose-dependent manner and induced apoptosis by increasing cytochrome C, Bad, Bax, and caspases 1, 2, 3, 8, and 9 in gastric adenocarcinoma cells in vitro.	('increasing', 'PosReg', (160, 170))	('induced', 'Reg', (139, 146))	('cytochrome C', 'MPA', (171, 183))	('gastric adenocarcinoma', 'Disease', (229, 251))	('cell proliferation', 'CPA', (89, 107))	('Bax', 'Gene', (190, 193))	('pterostilbene', 'Chemical', 'MESH:C107773', (55, 68))	('Bax', 'Gene', '24887', (190, 193))	('rat', 'Species', '10116', (101, 104))	('inhibited', 'NegReg', (79, 88))	('men', 'Species', '9606', (74, 77))	('apoptosis', 'CPA', (147, 156))	('caspases 1, 2, 3, 8, and 9', 'Gene', '25166;64314;25402;64044;58918', (199, 225))	('Bad', 'MPA', (185, 188))	('pterostilbene', 'Var', (55, 68))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (229, 251))
260436	23691264	The transcription factor Nrf2 plays a critical role in regulation of mucosal inflammation and Nrf2 deficient mice have been shown to express increased mucosal inflammation, and OS.	('mucosal inflammation', 'Disease', (69, 89))	('OS', 'Phenotype', 'HP:0025464', (177, 179))	('increased', 'PosReg', (141, 150))	('deficient', 'Var', (99, 108))	('mucosal inflammation', 'Disease', 'MESH:D007249', (151, 171))	('mucosal inflammation', 'Disease', 'MESH:D007249', (69, 89))	('mice', 'Species', '10090', (109, 113))	('Nrf2', 'Gene', (94, 98))	('mucosal inflammation', 'Disease', (151, 171))
260446	23691264	Pterostilbene's modulation of antioxidant activity may also facilitate anti-inflammatory and anticarcinogenic mechanisms that confer clinical benefits in inflammatory bowel disease and colorectal malignancies.	('benefits', 'PosReg', (142, 150))	('antioxidant activity', 'MPA', (30, 50))	('colorectal malignancies', 'Disease', 'MESH:D009369', (185, 208))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (154, 180))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (154, 180))	('carcinogenic', 'Disease', 'MESH:D063646', (97, 109))	('inflammatory bowel disease', 'Disease', (154, 180))	('colorectal malignancies', 'Disease', (185, 208))	('Pterostilbene', 'Chemical', 'MESH:C107773', (0, 13))	('modulation', 'Var', (16, 26))	('facilitate', 'PosReg', (60, 70))	('anti-inflammatory', 'CPA', (71, 88))	('carcinogenic', 'Disease', (97, 109))
260503	23691264	In addition to inhibiting pancreatic cancer, recent research found that pterostilbene ameliorated inflammation and acinar damage in pancreatitis in vitro.	('pancreatitis', 'Disease', 'MESH:D010195', (132, 144))	('pterostilbene', 'Chemical', 'MESH:C107773', (72, 85))	('pancreatitis', 'Phenotype', 'HP:0001733', (132, 144))	('acinar damage', 'Disease', (115, 128))	('inflammation', 'Disease', 'MESH:D007249', (98, 110))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('rat', 'Species', '10116', (92, 95))	('acinar damage', 'Disease', 'MESH:D018267', (115, 128))	('pancreatitis', 'Disease', (132, 144))	('ameliorated', 'PosReg', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('inflammation', 'Disease', (98, 110))	('pterostilbene', 'Var', (72, 85))	('pancreatic cancer', 'Disease', (26, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))
260535	23691264	The exact relationship between antioxidant activity and glucose regulation induced by pterostilbene treatment has not been elucidated; however, it is postulated that pterostilbene increases antioxidant activity leading to improved glucose metabolism.	('pterostilbene', 'Chemical', 'MESH:C107773', (86, 99))	('glucose', 'Chemical', 'MESH:D005947', (56, 63))	('pterostilbene', 'Chemical', 'MESH:C107773', (166, 179))	('increases', 'PosReg', (180, 189))	('glucose', 'Chemical', 'MESH:D005947', (231, 238))	('men', 'Species', '9606', (105, 108))	('glucose metabolism', 'MPA', (231, 249))	('antioxidant activity', 'MPA', (190, 210))	('improved', 'PosReg', (222, 230))	('pterostilbene', 'Var', (166, 179))
260545	23691264	Rimando and colleagues found that hypercholesterolemic hamsters fed 20 ppm oral pterostilbene demonstrated a 29% decrease in plasma low density lipoprotein (LDL) cholesterol, 7% increase in high density lipoprotein (HDL) cholesterol, and 14% decrease in plasma glucose levels compared to controls.	('pterostilbene', 'Chemical', 'MESH:C107773', (80, 93))	('decrease', 'NegReg', (113, 121))	('hypercholesterolemic', 'Disease', 'MESH:D006938', (34, 54))	('rat', 'Species', '10116', (101, 104))	('hypercholesterolemic', 'Disease', (34, 54))	('cholesterol', 'Chemical', 'MESH:D002784', (39, 50))	('decrease', 'NegReg', (242, 250))	('increase', 'PosReg', (178, 186))	('cholesterol', 'Chemical', 'MESH:D002784', (162, 173))	('glucose', 'Chemical', 'MESH:D005947', (261, 268))	('plasma glucose levels', 'MPA', (254, 275))	('cholesterol', 'Chemical', 'MESH:D002784', (221, 232))	('pterostilbene', 'Var', (80, 93))	('plasma low density lipoprotein', 'MPA', (125, 155))
260568	23691264	Furthermore, in experiments performed by Casadesus et al., supplementation with blueberry extract was shown to enhance hippocampal plasticity and increase levels of insulin-like growth factor (IGF-) 1, IGF-2, and ERK resulting in improved spatial memory.	('levels', 'MPA', (155, 161))	('improved', 'PosReg', (230, 238))	('hippocampal', 'MPA', (119, 130))	('IGF-2', 'Gene', (202, 207))	('increase', 'PosReg', (146, 154))	('insulin-like growth factor (IGF-) 1', 'Gene', '24482', (165, 200))	('men', 'Species', '9606', (65, 68))	('increase levels of insulin', 'Phenotype', 'HP:0000842', (146, 172))	('men', 'Species', '9606', (22, 25))	('spatial memory', 'CPA', (239, 253))	('enhance', 'PosReg', (111, 118))	('supplementation', 'Var', (59, 74))	('ERK', 'Gene', (213, 216))	('IGF-2', 'Gene', '24483', (202, 207))	('ERK', 'Gene', '24338', (213, 216))
260574	23691264	To determine whether pterostilbene was involved in neuroprotective outcomes, Joseph and colleagues treated aged rats with low (0.004%) and high (0.016%) dose pterostilbene and evaluated endpoints of cognitive and motor functions.	('pterostilbene', 'Chemical', 'MESH:C107773', (21, 34))	('rats', 'Species', '10116', (112, 116))	('0.016%', 'Var', (145, 151))	('0.004%', 'Var', (127, 133))	('pterostilbene', 'Chemical', 'MESH:C107773', (158, 171))
260576	23691264	Specifically, aged rats treated with pterostilbene had higher level MWM performance, which was similarly shown in a blueberry supplementation study conducted by Andres-Lacueva and colleagues.	('level MWM performance', 'MPA', (62, 83))	('pterostilbene', 'Var', (37, 50))	('pterostilbene', 'Chemical', 'MESH:C107773', (37, 50))	('men', 'Species', '9606', (132, 135))	('rats', 'Species', '10116', (19, 23))	('higher', 'PosReg', (55, 61))
260585	23691264	Pterostilbene was also shown to increase levels of PPAR-alpha, an upstream inducer of MnSOD, and decrease levels of phosphorylated JnK and tau, both of which are associated with OS signaling dysfunction.	('tau', 'MPA', (139, 142))	('PPAR-alpha', 'Protein', (51, 61))	('increase', 'PosReg', (32, 40))	('OS signaling dysfunction', 'Disease', (178, 202))	('OS', 'Phenotype', 'HP:0025464', (178, 180))	('OS signaling dysfunction', 'Disease', 'MESH:C567932', (178, 202))	('Pterostilbene', 'Var', (0, 13))	('Pterostilbene', 'Chemical', 'MESH:C107773', (0, 13))	('decrease', 'NegReg', (97, 105))
260592	23691264	Epidemiological trials have shown an association between poor diets and increased risk of prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('prostate cancer', 'Disease', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('poor diets', 'Var', (57, 67))
260605	23691264	The paradoxical increase in ROS production in pterostilbene treated cells may occur through alteration of specific carcinogenic mutations present in prostate cancer that lead to programmed cell death.	('OS', 'Phenotype', 'HP:0025464', (29, 31))	('pterostilbene', 'Chemical', 'MESH:C107773', (46, 59))	('mutations', 'Var', (128, 137))	('prostate cancer', 'Disease', 'MESH:D011471', (149, 164))	('ROS production', 'MPA', (28, 42))	('prostate cancer', 'Phenotype', 'HP:0012125', (149, 164))	('ROS', 'Chemical', 'MESH:D017382', (28, 31))	('increase', 'PosReg', (16, 24))	('carcinogenic', 'Disease', 'MESH:D063646', (115, 127))	('rat', 'Species', '10116', (96, 99))	('carcinogenic', 'Disease', (115, 127))	('prostate cancer', 'Disease', (149, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('increase in ROS production', 'Phenotype', 'HP:0025464', (16, 42))
260606	23691264	The findings indicate that pterostilbene is capable of inducing apoptosis through ROS-mediated mechanism in prostate cancer cells, despite upregulation of basal antioxidant activity.	('pterostilbene', 'Chemical', 'MESH:C107773', (27, 40))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('inducing', 'PosReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('upregulation', 'PosReg', (139, 151))	('basal antioxidant activity', 'MPA', (155, 181))	('apoptosis', 'CPA', (64, 73))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('pterostilbene', 'Var', (27, 40))	('OS', 'Phenotype', 'HP:0025464', (83, 85))	('prostate cancer', 'Disease', (108, 123))	('ROS-mediated', 'Protein', (82, 94))
260616	23691264	In breast, esophageal, stomach, colon, liver, pancreatic, and prostate cancer studies, pterostilbene exhibits profound anticancer mechanisms which include reduction of proliferation rates, induction of apoptosis, alteration of the cell cycle, and inhibition of metastasis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('pancreatic', 'Disease', (46, 56))	('rat', 'Species', '10116', (182, 185))	('rat', 'Species', '10116', (175, 178))	('reduction', 'NegReg', (155, 164))	('metastasis', 'CPA', (261, 271))	('proliferation rates', 'CPA', (168, 187))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cell cycle', 'CPA', (231, 241))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('colon', 'Disease', 'MESH:D015179', (32, 37))	('prostate cancer', 'Disease', (62, 77))	('apoptosis', 'CPA', (202, 211))	('pterostilbene', 'Var', (87, 100))	('pterostilbene', 'Chemical', 'MESH:C107773', (87, 100))	('colon', 'Disease', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('pancreatic', 'Disease', 'MESH:D010195', (46, 56))	('cancer', 'Disease', (123, 129))	('inhibition', 'NegReg', (247, 257))	('alteration', 'Reg', (213, 223))	('rat', 'Species', '10116', (217, 220))
260617	23691264	The relationship between pterostilbene and oxidation in cancer cell death has not been fully elucidated; however, it has been discovered that generation of ROS plays a significant role in the apoptotic mechanism in pterostilbene treated breast and prostate cancer cells.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('ROS', 'MPA', (156, 159))	('apoptotic mechanism', 'CPA', (192, 211))	('pterostilbene', 'Var', (215, 228))	('rat', 'Species', '10116', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('OS', 'Phenotype', 'HP:0025464', (157, 159))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (237, 263))	('prostate cancer', 'Phenotype', 'HP:0012125', (248, 263))	('pterostilbene', 'Chemical', 'MESH:C107773', (215, 228))	('ROS', 'Chemical', 'MESH:D017382', (156, 159))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', (257, 263))	('pterostilbene', 'Chemical', 'MESH:C107773', (25, 38))
260637	23667687	Inhibition of SLP-2 by SLP-2 siRNA can decrease ESCC cells invasive capability through MMP-2 dependent manner.	('SLP-2', 'Gene', (14, 19))	('decrease', 'NegReg', (39, 47))	('MMP-2', 'Gene', (87, 92))	('SLP-2', 'Gene', '30968', (14, 19))	('decrease ESCC', 'Phenotype', 'HP:0025022', (39, 52))	('SLP-2', 'Gene', (23, 28))	('Inhibition', 'Var', (0, 10))	('ESCC', 'Disease', (48, 52))	('SLP-2', 'Gene', '30968', (23, 28))	('MMP-2', 'Gene', '4313', (87, 92))
260638	23667687	Up-regulation of SLP-2 was effectively abrogated by the ERK1/2 inhibitors either PD98059 or U0126, but no effect was showed by the treatment of AKT inhibitors either LY294002 or MK-2206.	('SLP-2', 'Gene', (17, 22))	('AKT', 'Gene', (144, 147))	('ERK1/2', 'Gene', (56, 62))	('U0126', 'Var', (92, 97))	('PD98059', 'Chemical', 'MESH:C093973', (81, 88))	('ERK1/2', 'Gene', '5595;5594', (56, 62))	('SLP-2', 'Gene', '30968', (17, 22))	('abrogated', 'NegReg', (39, 48))	('Up-regulation', 'PosReg', (0, 13))	('U0126', 'Chemical', 'MESH:C113580', (92, 97))	('AKT', 'Gene', '207', (144, 147))	('MK-2206', 'Chemical', 'MESH:C548887', (178, 185))	('PD98059', 'Var', (81, 88))	('LY294002', 'Chemical', 'MESH:C085911', (166, 174))
260650	23667687	Aberrant expression of SLP-2 has been found in various malignancies.	('Aberrant', 'Var', (0, 8))	('malignancies', 'Disease', 'MESH:D009369', (55, 67))	('expression', 'MPA', (9, 19))	('SLP-2', 'Gene', (23, 28))	('malignancies', 'Disease', (55, 67))	('found', 'Reg', (38, 43))	('SLP-2', 'Gene', '30968', (23, 28))
260664	23667687	Two ERK1/2 inhibitors (PD98059 and U0126) and two AKT inhibitors (LY294002 and MK-2206) all were purchased from Selleck Chemicals LLC (Houston, TX), using at 1 microM.	('ERK1/2', 'Gene', (4, 10))	('MK-2206', 'Chemical', 'MESH:C548887', (79, 86))	('AKT', 'Gene', '207', (50, 53))	('PD98059', 'Chemical', 'MESH:C093973', (23, 30))	('ERK1/2', 'Gene', '5595;5594', (4, 10))	('LY294002', 'Var', (66, 74))	('U0126', 'Chemical', 'MESH:C113580', (35, 40))	('AKT', 'Gene', (50, 53))	('U0126', 'Var', (35, 40))	('LY294002', 'Chemical', 'MESH:C085911', (66, 74))	('PD98059', 'Var', (23, 30))
260702	23667687	To further explore whether SLP-2 overexpression increasing ESCC cell invasive ability was due to the induction of MMPs, we used RT-PCR analysis revealed that the knockdown of SLP-2 in both KYSE510 and EC9706 cells drastically repressed MMP-2 expression at both mRNA level and protein level (P<0.05, Fig.	('expression', 'MPA', (242, 252))	('SLP-2', 'Gene', (27, 32))	('MMPs', 'Gene', '4313', (114, 118))	('SLP-2', 'Gene', '30968', (175, 180))	('MMP-2', 'Gene', '4313', (236, 241))	('SLP-2', 'Gene', '30968', (27, 32))	('knockdown', 'Var', (162, 171))	('EC9706', 'CellLine', 'CVCL:E307', (201, 207))	('repressed', 'NegReg', (226, 235))	('KYSE510', 'CellLine', 'CVCL:1354', (189, 196))	('MMP-2', 'Gene', (236, 241))	('MMPs', 'Gene', (114, 118))	('SLP-2', 'Gene', (175, 180))
260715	23667687	We pretreated KYSE510 cell with ERK1/2 inhibitors (PD98059 and U0126), and AKT inhibitors (LY294002 and MK-2206) respectively for 3 hours and then used PMA for 15 minutes to induce the activation of MAPK/ERK and AKT pathway.	('ERK', 'Gene', (204, 207))	('PD98059', 'Chemical', 'MESH:C093973', (51, 58))	('activation', 'PosReg', (185, 195))	('ERK', 'Gene', '5594', (32, 35))	('AKT', 'Gene', (212, 215))	('MK-2206', 'Chemical', 'MESH:C548887', (104, 111))	('LY294002', 'Chemical', 'MESH:C085911', (91, 99))	('MK-2206', 'Var', (104, 111))	('PD98059', 'Var', (51, 58))	('AKT', 'Gene', (75, 78))	('ERK1/2', 'Gene', (32, 38))	('ERK1/2', 'Gene', '5595;5594', (32, 38))	('KYSE510', 'CellLine', 'CVCL:1354', (14, 21))	('PMA', 'Chemical', '-', (152, 155))	('ERK', 'Gene', (32, 35))	('AKT', 'Gene', '207', (212, 215))	('U0126', 'Chemical', 'MESH:C113580', (63, 68))	('ERK', 'Gene', '5594', (204, 207))	('AKT', 'Gene', '207', (75, 78))	('LY294002', 'Var', (91, 99))	('U0126', 'Var', (63, 68))
260722	23667687	The results showed that after 24 hours inhibitors only targeted MAPK/ERK pathway can down-regulate the SLP-2 expression by either PMA or EGF stimulation (Fig.	('inhibitors', 'Var', (39, 49))	('down-regulate', 'NegReg', (85, 98))	('SLP-2', 'Gene', (103, 108))	('EGF', 'Gene', (137, 140))	('SLP-2', 'Gene', '30968', (103, 108))	('EGF', 'Gene', '1950', (137, 140))	('PMA', 'Chemical', '-', (130, 133))	('ERK', 'Gene', '5594', (69, 72))	('ERK', 'Gene', (69, 72))
260741	23667687	Therefore in this study, down-regulation of SLP-2 protein expression by transfected with SLP-2-specific siRNA in ESCC cell lines, KYSE510 and EC9706, resulted in decreased invasive ability as well as down-regulation of MMP-2 at both RNA and protein level.	('down-regulation', 'NegReg', (200, 215))	('SLP-2', 'Gene', '30968', (44, 49))	('EC9706', 'Var', (142, 148))	('MMP-2', 'Gene', (219, 224))	('expression', 'MPA', (58, 68))	('SLP-2', 'Gene', '30968', (89, 94))	('KYSE510', 'CellLine', 'CVCL:1354', (130, 137))	('decreased', 'NegReg', (162, 171))	('MMP-2', 'Gene', '4313', (219, 224))	('EC9706', 'CellLine', 'CVCL:E307', (142, 148))	('SLP-2', 'Gene', (44, 49))	('down-regulation', 'NegReg', (25, 40))	('SLP-2', 'Gene', (89, 94))	('invasive ability', 'CPA', (172, 188))
260748	23667687	Phosphorylated ERK immunoreactivity has been related to tumour progression in oligodendrogliomas, and to metastasis in breast cancer.	('Phosphorylated', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('metastasis in breast cancer', 'Disease', (105, 132))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (78, 96))	('ERK', 'Gene', '5594', (15, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('ERK', 'Gene', (15, 18))	('oligodendrogliomas', 'Disease', (78, 96))	('metastasis in breast cancer', 'Disease', 'MESH:D009362', (105, 132))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('related', 'Reg', (45, 52))	('tumour', 'Disease', (56, 62))
260763	23667687	In conclusion, data derived from this study have shown that the aberrant expression of SLP-2 might play important roles in the invasion of esophageal squamous cell carcinoma.	('roles', 'Reg', (114, 119))	('SLP-2', 'Gene', (87, 92))	('SLP-2', 'Gene', '30968', (87, 92))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (139, 173))	('play', 'Reg', (99, 103))	('expression', 'MPA', (73, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('aberrant', 'Var', (64, 72))	('esophageal squamous cell carcinoma', 'Disease', (139, 173))
260766	19001876	Cleavage of MCM2 licensing protein fosters senescence in human keratinocytes In eukaryotic cells, MCM, the minichromosome maintenance proteins, form a heterohexamer during G1 phase in a cell cycle and constitute a DNA helicase activity at the onset of replication.	('Cleavage', 'Var', (0, 8))	('MCM2', 'Gene', '4171', (12, 16))	('MCM2', 'Gene', (12, 16))	('senescence', 'MPA', (43, 53))	('human', 'Species', '9606', (57, 62))	('heterohexamer', 'MPA', (151, 164))
260781	19001876	Retrovirus-mediated stable transduction of a catalytic subunit of telomerase (hTERT) in the presenescent EPC2 cells (42 PD) permitted the cells to reenter the cell cycle and resulted in immortalization.	('PD', 'Disease', 'MESH:D010300', (120, 122))	('EPC2', 'Gene', '26122', (105, 109))	('transduction', 'Var', (27, 39))	('resulted in', 'Reg', (174, 185))	('EPC2', 'Gene', (105, 109))	('immortalization', 'CPA', (186, 201))	('hTERT', 'Gene', '7015', (78, 83))	('hTERT', 'Gene', (78, 83))	('reenter', 'CPA', (147, 154))
260803	19001876	By contrast, two fragments (148-441 and 442-676) from the central region were responsible chiefly for the interaction between MCM2 and MCM4.	('interaction', 'Interaction', (106, 117))	('responsible', 'Reg', (78, 89))	('148-441', 'Var', (28, 35))	('MCM4', 'Gene', (135, 139))	('MCM2', 'Gene', (126, 130))	('442-676', 'Var', (40, 47))	('MCM4', 'Gene', '4173', (135, 139))
260813	19001876	The MCM2 mRNA was determined by TaqMan  Gene Expression Assays (Applied Biosystems) using three independent sets of primers and the probes (Hs00170472_m1 for exons 2-3, Hs01091568_g1 for exons 3-4 and Hs01091564_m1 for exons 13-14), targeting different exon boundaries of the MCM2 transcript (MN_004526.2).	('Hs00170472_m1', 'Var', (140, 153))	('MN', 'CellLine', 'CVCL:U508', (293, 295))	('Expression', 'Species', '29278', (45, 55))	('Hs01091568_g1', 'Var', (169, 182))	('Hs01091564_m1', 'Var', (201, 214))
260817	19001876	The membranes were incubated with anti-MCM2 (A300-191A)(amino acid residues 1-50)(Bethyl laboratories, Montgomery, TX), anti-MCM2 (559542)(amino acid residues 131-150)(BD Pharmingen), anti-MCM2 (clone 6A8)(amino acid residues 805-904)(Novus Biologicals, Littleton, CO), anti-MCM3 (BD Pharmingen), anti-MCM4 (BD Pharmingen), anti-MCM5 (BD Pharmingen), anti-MCM6 (BD Pharmingen), anti-MCM7 (BD Pharmingen), anti-FLAG M2 (Sigma), AC-74 against beta-actin (Sigma), and DMA1A + DM1B against tubulin (Neo Markers).	('MCM5', 'Gene', (329, 333))	('beta-actin (Sigma)', 'Gene', '728378', (441, 459))	('MCM4', 'Gene', (302, 306))	('DMA1A + DM1B', 'Var', (465, 477))	('tubulin', 'Protein', (486, 493))	('MCM3', 'Gene', '4172', (275, 279))	('MCM7', 'Gene', '4176', (383, 387))	('MCM6', 'Gene', (356, 360))	('MCM5', 'Gene', '4174', (329, 333))	('MCM7', 'Gene', (383, 387))	('MCM3', 'Gene', (275, 279))	('MCM6', 'Gene', '4175', (356, 360))	('beta-actin (Sigma', 'Gene', (441, 458))	('MCM4', 'Gene', '4173', (302, 306))
260872	31844668	We first defined gastrointestinal tissue-specific chromatin accessibility and gene expression during development, identifying the dynamic epigenetic regulation of SOX family of TFs.	('epigenetic', 'Var', (138, 148))	('SOX', 'Gene', '104009', (163, 166))	('SOX', 'Gene', (163, 166))
260874	31844668	By analyzing mice deleted for both Sox2 and Sox9, we revealed their potentially redundant roles in both gastric development and cancer, highlighting the importance of developmental lineage programs reactivated by gastrointestinal TFs in cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mice', 'Species', '10090', (13, 17))	('Sox9', 'Gene', (44, 48))	('gastrointestinal TFs', 'Disease', 'MESH:D005767', (213, 233))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('gastric development', 'CPA', (104, 123))	('gastrointestinal TFs', 'Disease', (213, 233))	('deleted', 'Var', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', (128, 134))
260887	31844668	In addition, although Sox2 labels gastric stem cells, it is dispensable during adult homeostasis; unexpectedly, its deletion in Wnt signaling-activated gastric cancer promoted gastric tumorigenesis, implying potential redundancy.	('gastric cancer', 'Disease', 'MESH:D013274', (152, 166))	('gastric cancer', 'Disease', (152, 166))	('gastric tumorigenesis', 'Disease', (176, 197))	('promoted', 'PosReg', (167, 175))	('gastric tumorigenesis', 'Disease', 'MESH:D013274', (176, 197))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('deletion', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('gastric cancer', 'Phenotype', 'HP:0012126', (152, 166))
260890	31844668	Moreover, by comparing our GI developmental gene expression data to the human GI cancer data, we have shown that stomach and intestinal lineage programs are enriched in Sox2high/Sox9high and Cdx2high GI cancers, respectively.	('GI cancers', 'Disease', (200, 210))	('stomach', 'CPA', (113, 120))	('GI cancer', 'Phenotype', 'HP:0007378', (200, 209))	('Sox2high/Sox9high', 'Var', (169, 186))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('GI cancers', 'Disease', 'MESH:D009369', (200, 210))	('cancer', 'Disease', (81, 87))	('human', 'Species', '9606', (72, 77))	('GI cancer', 'Phenotype', 'HP:0007378', (78, 87))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('intestinal lineage programs', 'CPA', (125, 152))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
260891	31844668	By analyzing mice deleted for both Sox2 and Sox9 in our gastric development and cancer models, we have revealed their potential redundancy.	('mice', 'Species', '10090', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Sox2', 'Gene', (35, 39))	('deleted', 'Var', (18, 25))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Sox9', 'Gene', (44, 48))	('cancer', 'Disease', (80, 86))
260892	31844668	Together, our study highlights the importance of tissue-specific programs reactivated by GI lineage TFs in cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('GI lineage', 'Var', (89, 99))
260900	31844668	To identify key transcriptional regulators of GI development, we conducted TF motif analysis of E13.5 and E16.5 region-specific ATAC-seq profiles and identified the SOX TFs as one of the most enriched TF families in both E13.5 stomach peaks and E16.5 forestomach/hindstomach common peaks (Fig.	('E13.5', 'Var', (221, 226))	('E16.5', 'Var', (245, 250))	('SOX', 'Gene', '104009', (165, 168))	('SOX', 'Gene', (165, 168))
260904	31844668	Immunohistochemistry analysis of the mutant epithelium demonstrated an absence of transformation-related protein 63 (TP63), a forestomach marker, but properly localized expression of H+ K+ ATPase and PDX1 (i.e., hindstomach markers) (Fig.	('TP63', 'Gene', (117, 121))	('absence', 'NegReg', (71, 78))	('TP63', 'Gene', '22061', (117, 121))	('PDX1', 'Gene', '18609', (200, 204))	('transformation-related protein 63', 'Gene', '22061', (82, 115))	('mutant', 'Var', (37, 43))	('transformation-related protein 63', 'Gene', (82, 115))	('PDX1', 'Gene', (200, 204))
260908	31844668	These Sox2-/GFP+ cells in the mutant intestines were negative for intestinal (i.e., Cdx2 and Tff3) and gastric markers (Tp63 and H+ K+ ATPase), unlike Sox2+/GFP+ cells in the control intestines (fig.	('Tp63', 'Gene', '22061', (120, 124))	('Tff3', 'Gene', (93, 97))	('Tff3', 'Gene', '21786', (93, 97))	('mutant', 'Var', (30, 36))	('negative', 'NegReg', (53, 61))	('Tp63', 'Gene', (120, 124))
260910	31844668	To determine their potential redundancy in gastric development, we generated mice conditionally deleted for both Sox2 and Sox9 [double knockout (DKO)] (Sox2CreERT2/flox;Sox9flox/flox) at E8.5, the onset of gut organogenesis.	('Sox9', 'Gene', (122, 126))	('mice', 'Species', '10090', (77, 81))	('deleted', 'Var', (96, 103))	('D', 'Chemical', 'MESH:D003903', (145, 146))	('Sox2', 'Gene', (113, 117))
260911	31844668	Despite efficient deletion of Sox2, these DKO embryos still maintained gastric specification due to the Cre escapers expressing Sox9 (Fig.	('Sox2', 'Gene', (30, 34))	('D', 'Chemical', 'MESH:D003903', (0, 1))	('D', 'Chemical', 'MESH:D003903', (42, 43))	('Sox9', 'Gene', (128, 132))	('maintained', 'Reg', (60, 70))	('deletion', 'Var', (18, 26))	('gastric specification', 'CPA', (71, 92))
260914	31844668	While we observed a drastic reduction in organ size by H&E staining, we similarly observed the presence of Sox9+ gastric epithelial cells in the DKO mutants, masking the true DKO phenotype (fig.	('D', 'Chemical', 'MESH:D003903', (145, 146))	('H&E', 'Chemical', '-', (55, 58))	('organ size', 'CPA', (41, 51))	('DKO', 'Var', (145, 148))	('D', 'Chemical', 'MESH:D003903', (175, 176))	('the', 'Gene', (141, 144))	('reduction', 'NegReg', (28, 37))
260922	31844668	For instance, the chromatin near the loci of SOX2+ endodermal targets such as Sox21 and Sox4 was still accessible, suggesting that additional co-factors are able to preserve chromatin accessibility despite Sox2 deletion (Fig.	('Sox2', 'Gene', (206, 210))	('deletion', 'Var', (211, 219))	('Sox21', 'Gene', (78, 83))	('chromatin accessibility', 'MPA', (174, 197))	('Sox4', 'Gene', '20677', (88, 92))	('Sox4', 'Gene', (88, 92))	('Sox21', 'Gene', '223227', (78, 83))
260923	31844668	This mutant epithelium ectopically expressed SOX2 and TP63 and acquired a forestomach, squamous cellular morphology.	('forestomach', 'CPA', (74, 85))	('TP63', 'Gene', (54, 58))	('acquired', 'PosReg', (63, 71))	('mutant', 'Var', (5, 11))	('TP63', 'Gene', '22061', (54, 58))	('SOX2', 'Gene', (45, 49))
260930	31844668	Together, our results demonstrate that the ectopic expression of Sox2 is responsible for squamous transformation induced by Cdx2 deletion.	('ectopic expression', 'MPA', (43, 61))	('Sox2', 'Gene', (65, 69))	('squamous transformation', 'Disease', (89, 112))	('Cdx2', 'Gene', (124, 128))	('deletion', 'Var', (129, 137))	('squamous transformation', 'Disease', 'MESH:D002294', (89, 112))	('responsible', 'Reg', (73, 84))
260934	31844668	To examine whether E16.5 organ-specific programs become activated in GI cancers, we used The Cancer Genome Atlas (TCGA) GI cancer database to identify Sox2high-, Sox9high-, and Cdx2high-expressing human gastric [stomach adenocarcinoma (STAD)] and colorectal [colon adenocarcinoma (COAD)] cancers.	('D', 'Chemical', 'MESH:D003903', (239, 240))	('GI cancers', 'Disease', 'MESH:D009369', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('COAD', 'Disease', (281, 285))	('cancers', 'Phenotype', 'HP:0002664', (288, 295))	('Cdx2high-expressing', 'Var', (177, 196))	('cancers', 'Disease', (288, 295))	('cancer', 'Disease', (288, 294))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (259, 279))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('Cancer', 'Disease', (93, 99))	('D', 'Chemical', 'MESH:D003903', (284, 285))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('Sox2high-', 'Var', (151, 160))	('cancer', 'Disease', (72, 78))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (212, 234))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('stomach adenocarcinoma', 'Disease', (212, 234))	('Cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancers', 'Disease', 'MESH:D009369', (288, 295))	('colon adenocarcinoma', 'Disease', (259, 279))	('COAD', 'Disease', 'MESH:D029424', (281, 285))	('GI cancer', 'Phenotype', 'HP:0007378', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('GI cancers', 'Disease', (69, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('human', 'Species', '9606', (197, 202))	('cancer', 'Disease', (123, 129))	('GI cancer', 'Phenotype', 'HP:0007378', (69, 78))
260935	31844668	By performing gene set enrichment analyses, we demonstrated that Sox2high and Cdx2high cancers are enriched for E16.5 stomach and intestinal genes, respectively (Fig.	('cancers', 'Disease', (87, 94))	('stomach', 'Disease', (118, 125))	('intestinal', 'Disease', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('E16.5', 'Var', (112, 117))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('Sox2high', 'Disease', (65, 73))
260941	31844668	To determine its role in gastric cancer in vivo, we conditionally deleted Sox9 in Atp4bCre;R26NICD/+;Sox9flox/flox mice.	('D', 'Chemical', 'MESH:D003903', (97, 98))	('deleted', 'Var', (66, 73))	('gastric cancer', 'Phenotype', 'HP:0012126', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mice', 'Species', '10090', (115, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (25, 39))	('gastric cancer', 'Disease', (25, 39))	('Sox9', 'Gene', (74, 78))
260942	31844668	However, we observed more disorganized glandular epithelia and increased presence of Alcian blue+ mucin cells (i.e., a hallmark of early-stage gastric cancer) in Sox9 KO adenoma mice compared to the controls (Fig.	('adenoma', 'Disease', (170, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('increased', 'PosReg', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mice', 'Species', '10090', (178, 182))	('Alcian', 'Protein', (85, 91))	('disorganized glandular epithelia', 'CPA', (26, 58))	('gastric cancer', 'Disease', (143, 157))	('Alcian blue', 'Chemical', 'MESH:D000423', (85, 96))	('adenoma', 'Disease', 'MESH:D000236', (170, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('Sox9 KO', 'Var', (162, 169))
260945	31844668	Consistent with recently published work addressing the role of Sox2 in Wnt signaling-activated gastric cancer, we observed increased tumor severity upon Sox2 deletion (Fig.	('increased', 'PosReg', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('gastric cancer', 'Disease', (95, 109))	('Sox2', 'Gene', (153, 157))	('tumor', 'Disease', (133, 138))	('deletion', 'Var', (158, 166))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))
260948	31844668	To examine whether Sox2 and Sox9 act in a redundant manner during cancer initiation, we generated Sox2 and Sox9 DKO mice in the adenoma background.	('mice', 'Species', '10090', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('DKO', 'Var', (112, 115))	('Sox9', 'Gene', (107, 111))	('adenoma', 'Disease', 'MESH:D000236', (128, 135))	('D', 'Chemical', 'MESH:D003903', (112, 113))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('adenoma', 'Disease', (128, 135))	('Sox2', 'Gene', (98, 102))	('cancer', 'Disease', (66, 72))
260950	31844668	Histopathology scoring confirmed significant reductions in disease severity and the presence of dysplastic epithelium when comparing DKO adenoma mice to their single-KO counterparts (fig.	('reductions', 'Disease', (45, 55))	('adenoma', 'Disease', 'MESH:D000236', (137, 144))	('DKO', 'Var', (133, 136))	('dysplastic', 'Disease', (96, 106))	('adenoma', 'Disease', (137, 144))	('dysplastic', 'Disease', 'MESH:D004416', (96, 106))	('reductions', 'Disease', 'MESH:D007022', (45, 55))	('mice', 'Species', '10090', (145, 149))	('D', 'Chemical', 'MESH:D003903', (133, 134))
260951	31844668	These data demonstrate that both SOX TFs cooperatively regulate genes that are important during cancer initiation, and single-SOX TF deletions are inadequate in preventing gastric cancer initiation.	('SOX', 'Gene', '104009', (33, 36))	('deletions', 'Var', (133, 142))	('gastric cancer', 'Phenotype', 'HP:0012126', (172, 186))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer initiation', 'Disease', 'MESH:D013274', (172, 197))	('SOX', 'Gene', '104009', (126, 129))	('genes', 'Gene', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('SOX', 'Gene', (33, 36))	('regulate', 'Reg', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('gastric cancer initiation', 'Disease', (172, 197))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (180, 186))	('SOX', 'Gene', (126, 129))
260956	31844668	Sox2 deletion at E8.5 followed by lineage tracing showed that despite the fact that Sox2-deleted gastric progenitors were properly incorporated into the intestine, they failed to express intestinal genes, suggesting a deficiency in responding to niche signals.	('Sox2-deleted', 'Gene', (84, 96))	('Sox2', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('responding to niche signals', 'MPA', (232, 259))	('deficiency', 'Disease', (218, 228))	('deficiency', 'Disease', 'MESH:D007153', (218, 228))
260958	31844668	We found an enrichment of forestomach, hindstomach, and intestinal lineage-specific developmental genes in Sox2high-, Sox9high-, and Cdx2high-expressing gastric and colorectal cancers, respectively.	('intestinal lineage-specific developmental genes', 'Gene', (56, 103))	('colorectal cancers', 'Disease', 'MESH:D015179', (165, 183))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Sox9high-', 'Var', (118, 127))	('gastric', 'Disease', (153, 160))	('colorectal cancers', 'Disease', (165, 183))	('hindstomach', 'Disease', (39, 50))	('Cdx2high-expressing', 'Var', (133, 152))	('forestomach', 'Gene', (26, 37))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('Sox2high-', 'Var', (107, 116))
260969	31844668	On E8.5 and E10.5, 100 mul of tamoxifen (20 mg/ml) and progesterone (10 mg/ml) in sunflower seed oil was administered to the dam on each day.	('progesterone', 'Chemical', 'MESH:D011374', (55, 67))	('sunflower', 'Species', '4232', (82, 91))	('E10.5', 'Var', (12, 17))	('tamoxifen', 'Chemical', 'MESH:D013629', (30, 39))	('E8.5', 'Var', (3, 7))
261105	31308755	Further, UC2288, an inhibitor of p21, was used to decrease the level of p21, and flow cytometry was used to detect cell cycle.	('level', 'MPA', (63, 68))	('UC2288', 'Var', (9, 15))	('UC2288', 'Chemical', 'MESH:C582887', (9, 15))	('p21', 'MPA', (72, 75))	('decrease', 'NegReg', (50, 58))
261109	31308755	Pathway analysis found p53 pathway was downregulated, and upregulation of LincRNA-p21 inhibited the expression of cyclin D. Conclusion: Our study suggests that LincRNA-p21 plays as a tumor inhibitor in ESCC development and LincRNA-p21 might induce G1 arrest through p53 signal pathway.	('p53 signal pathway', 'Pathway', (266, 284))	('cyclin', 'Gene', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('induce', 'PosReg', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('ESCC', 'Disease', (202, 206))	('G1 arrest', 'CPA', (248, 257))	('tumor', 'Disease', (183, 188))	('LincRNA-p21', 'Var', (223, 234))	('cyclin', 'Gene', '5111', (114, 120))
261163	31308755	The result shows that LincRNA-p21 induced G1/S cell-cycle arrest in EC109 cells.	('LincRNA-p21', 'Var', (22, 33))	('EC109', 'CellLine', 'CVCL:6898', (68, 73))	('G1/S cell-cycle arrest', 'CPA', (42, 64))
261168	31308755	To get rid of influence of p21, we used a kind of p21 attenuator, named UC2288, which could decrease p21 mRNA expression and attenuated p21 protein levels as shown in Figure 5A-C. Then, we detected the cell apoptosis and periodic distribution in EC109 cells overexpressing LincRNA-p21.	('decrease', 'NegReg', (92, 100))	('p21 protein levels', 'MPA', (136, 154))	('attenuated', 'NegReg', (125, 135))	('LincRNA-p21', 'Var', (273, 284))	('UC2288', 'Chemical', 'MESH:C582887', (72, 78))	('p21 mRNA expression', 'MPA', (101, 120))	('EC109', 'CellLine', 'CVCL:6898', (246, 251))	('cell apoptosis', 'CPA', (202, 216))	('detected', 'Reg', (189, 197))
261173	31308755	Our result showed that p21 and p53 were significantly decreased in EC109 compared to Het-1A , while the Cyclin D was significantly increased in EC109.	('p53', 'Protein', (31, 34))	('increased', 'PosReg', (131, 140))	('EC109', 'Var', (67, 72))	('Cyclin', 'Gene', '5111', (104, 110))	('EC109', 'CellLine', 'CVCL:6898', (67, 72))	('p21', 'Protein', (23, 26))	('decreased', 'NegReg', (54, 63))	('Cyclin', 'Gene', (104, 110))	('EC109', 'CellLine', 'CVCL:6898', (144, 149))
261194	31308755	In our study, overexpressing LincRNA-p21 increased the level of p21 while had no effect on p53, which implies that LincRNA-p21 could influence EC109 cell proliferation and cycle via enhancing p21 activity in a p53-independent manner.	('EC109', 'CellLine', 'CVCL:6898', (143, 148))	('EC109 cell proliferation', 'CPA', (143, 167))	('LincRNA-p21', 'Var', (115, 126))	('p21', 'MPA', (64, 67))	('influence', 'Reg', (133, 142))	('level', 'MPA', (55, 60))	('enhancing', 'PosReg', (182, 191))	('cycle', 'CPA', (172, 177))	('activity', 'MPA', (196, 204))	('p21', 'Enzyme', (192, 195))
261195	31308755	However, our research was still not perfect, and we did not observe the effect of LincRNA-p21 on EC109 cells after LincRNA-p21 knockdown in LV-EC109 cells.	('EC109', 'CellLine', 'CVCL:6898', (143, 148))	('EC109', 'CellLine', 'CVCL:6898', (97, 102))	('LincRNA-p21', 'Gene', (115, 126))	('LV-EC109', 'CellLine', 'CVCL:6898', (140, 148))	('knockdown', 'Var', (127, 136))
261199	31308755	LincRNA-p21 plays as a tumor inhibitor in ESCC development and LincRNA-p21 might induce G1 arrest through p53 signal pathway.	('induce', 'PosReg', (81, 87))	('G1 arrest', 'CPA', (88, 97))	('ESCC development', 'Disease', (42, 58))	('p53 signal pathway', 'Pathway', (106, 124))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('LincRNA-p21', 'Var', (63, 74))
261414	27918777	Between 2005 and 2015, age-standardized DALY rates for both sexes decreased by 8% (-10.2% to -6.2%) at the global level, with the largest decrease in high-SDI countries of 11% (-13.6% to -9.1%) and the largest (non significant) increase in the low SDI quintile of 9% (-6.0% to 27.8%) (Web Table 3).	('decreased', 'NegReg', (66, 75))	('to -9', 'Species', '1214577', (184, 189))	('SDI', 'Chemical', '-', (155, 158))	('DALY rates', 'MPA', (40, 50))	('decrease', 'NegReg', (138, 146))	('SDI', 'Chemical', '-', (248, 251))	('high-SDI', 'Var', (150, 158))
261545	27918777	Our results show that progress in reducing cervical cancer burden was the slowest in low SDI countries where the decrease in ASIRs and ASDRs was the lowest; a 12% decrease in ASIR occurred for countries at low-SDI compared to a greater than 14% decrease in all other SDI quintiles, and a 14% decrease in ASDR in low SDI compared to the other SDI quintiles, with decreases in ASDR of greater than 16%.	('SDI', 'Chemical', '-', (267, 270))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cervical cancer', 'Disease', 'MESH:D002583', (43, 58))	('SDI', 'Chemical', '-', (342, 345))	('ASIR', 'Chemical', '-', (125, 129))	('SDI', 'Chemical', '-', (89, 92))	('cervical cancer', 'Disease', (43, 58))	('ASDR', 'Chemical', '-', (375, 379))	('low-SDI', 'Var', (206, 213))	('ASDR', 'MPA', (375, 379))	('SDI', 'Chemical', '-', (316, 319))	('ASDR', 'Chemical', '-', (135, 139))	('SDI', 'Chemical', '-', (210, 213))	('ASDR', 'Chemical', '-', (304, 308))	('ASIR', 'MPA', (175, 179))	('decrease', 'NegReg', (163, 171))	('ASIR', 'Chemical', '-', (175, 179))
261558	27918777	Increased physical exercise, avoidance of processed meat, alcohol, and tobacco, as well as aspirin use have all been associated with reduced colorectal cancer incidence.	('tobacco', 'Species', '4097', (71, 78))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('Increased physical exercise', 'Phenotype', 'HP:0003546', (0, 27))	('aspirin', 'Chemical', 'MESH:D001241', (91, 98))	('alcohol', 'Chemical', 'MESH:D000438', (58, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('physical exercise', 'CPA', (10, 27))	('colorectal cancer', 'Disease', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('reduced', 'NegReg', (133, 140))	('avoidance', 'Var', (29, 38))
261616	29749531	MicroRNA-125b inhibits cell proliferation and induces cell apoptosis in esophageal squamous cell carcinoma by targeting BMF MicroRNAs (miRNAs) have been reported to regulate the expression of genes by suppressing translation or facilitating mRNA decay.	('si', 'Chemical', 'MESH:D012825', (184, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('si', 'Chemical', 'MESH:D012825', (208, 210))	('inhibits', 'NegReg', (14, 22))	('cell apoptosis', 'CPA', (54, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (72, 106))	('expression', 'MPA', (178, 188))	('translation', 'MPA', (213, 224))	('BMF', 'Gene', (120, 123))	('regulate', 'Reg', (165, 173))	('mRNA decay', 'MPA', (241, 251))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('esophageal squamous cell carcinoma', 'Disease', (72, 106))	('induces', 'PosReg', (46, 53))	('cell proliferation', 'CPA', (23, 41))	('suppressing', 'NegReg', (201, 212))	('MicroRNA-125b', 'Var', (0, 13))
261624	29749531	Additionally, overexpression of miR-125b significantly inhibited tumor growth in vivo.	('si', 'Chemical', 'MESH:D012825', (24, 26))	('tumor', 'Disease', (65, 70))	('miR-125b', 'Chemical', '-', (32, 40))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('miR-125b', 'Var', (32, 40))	('overexpression', 'PosReg', (14, 28))	('inhibited', 'NegReg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
261625	29749531	Furthermore, BCL-2-modifying factor (BMF) was considered to be a potential candidate target of miR-125b based on miRNA target databases.	('BMF', 'Gene', (37, 40))	('BCL-2-modifying factor', 'Gene', '90427', (13, 35))	('miR-125b', 'Chemical', '-', (95, 103))	('BCL-2-modifying factor', 'Gene', (13, 35))	('BMF', 'Gene', '90427', (37, 40))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('miR-125b', 'Var', (95, 103))
261629	29749531	In conclusion, miR-125b had an antitumor role in ESCC cells mediated by targeting BMF, which can be potentially useful for tumorigenesis in ESCC.	('miR-125b', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('BMF', 'Gene', (82, 85))	('ESCC', 'Disease', (140, 144))	('tumor', 'Disease', (35, 40))	('miR-125b', 'Chemical', '-', (15, 23))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('si', 'Chemical', 'MESH:D012825', (133, 135))	('ESCC', 'Disease', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('BMF', 'Gene', '90427', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
261636	29749531	Aberrantly expressed miRNAs are known to be closely associated with tumor development and progression via the regulation of cell growth, drug resistance and metastasis.	('tumor', 'Disease', (68, 73))	('drug resistance', 'Phenotype', 'HP:0020174', (137, 152))	('Aberrantly expressed', 'Var', (0, 20))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('associated', 'Reg', (52, 62))	('miRNAs', 'Protein', (21, 27))	('si', 'Chemical', 'MESH:D012825', (144, 146))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('metastasis', 'CPA', (157, 167))
261639	29749531	miR-125b, a tumor-suppressor miRNA, suppressed cell proliferation and differentiation by affecting Hedgehog signaling in cerebellar neuronal progenitor and tumor cells.	('suppressed', 'NegReg', (36, 46))	('differentiation', 'CPA', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('affecting', 'Reg', (89, 98))	('miR-125b', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (156, 161))	('miR-125b', 'Chemical', '-', (0, 8))	('tumor', 'Disease', (12, 17))	('Hedgehog signaling', 'MPA', (99, 117))	('si', 'Chemical', 'MESH:D012825', (108, 110))	('cell proliferation', 'CPA', (47, 65))
261641	29749531	Additionally, miR-125b exhibited its antitumor effects in colorectal and breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR-125b', 'Var', (14, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('colorectal and breast cancer', 'Disease', 'MESH:D015179', (58, 86))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('miR-125b', 'Chemical', '-', (14, 22))
261644	29749531	Herein, we analyzed the underlying mechanisms of action of miR-125b, resulting in tumor suppression in ESCC.	('miR-125b', 'Chemical', '-', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('miR-125b', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ESCC', 'Disease', (103, 107))	('tumor', 'Disease', (82, 87))
261680	29749531	The mutant or wild-type 3'-UTR of BMF was amplified and cloned into the vector psiCHECK-2 to construct luciferase reporter plasmids.	('BMF', 'Gene', (34, 37))	('mutant', 'Var', (4, 10))	('BMF', 'Gene', '90427', (34, 37))	('si', 'Chemical', 'MESH:D012825', (80, 82))
261698	29749531	Furthermore, compared to HET-1A, a normal esophageal epithelial cell line, the expression of miR-125b was lower in ESCC cell lines (EC109 and EC9706) (Fig.	('ESCC', 'Disease', (115, 119))	('miR-125b', 'Chemical', '-', (93, 101))	('lower', 'NegReg', (106, 111))	('expression', 'MPA', (79, 89))	('EC109', 'CellLine', 'CVCL:6898', (132, 137))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('miR-125b', 'Var', (93, 101))	('EC9706', 'CellLine', 'CVCL:E307', (142, 148))
261703	29749531	A CCK-8 assay was performed to assess the proliferation rate of EC109 and EC9706 cells transfected with miR-125b mimics or miR-125b inhibitors for 24, 48 and 72 h. Compared with the control, overexpressed miR-125b decreased cell proliferation in EC109 and EC9706 cells, whereas the growth of EC109 and EC9706 cells significantly increased post-transfection with miR-125b inhibitors (Fig.	('miR-125b', 'Chemical', '-', (104, 112))	('EC9706', 'CellLine', 'CVCL:E307', (256, 262))	('EC109', 'CellLine', 'CVCL:6898', (292, 297))	('miR-125b', 'Chemical', '-', (362, 370))	('miR-125b', 'Chemical', '-', (205, 213))	('si', 'Chemical', 'MESH:D012825', (315, 317))	('cell proliferation', 'CPA', (224, 242))	('EC9706', 'CellLine', 'CVCL:E307', (302, 308))	('growth', 'MPA', (282, 288))	('EC109', 'CellLine', 'CVCL:6898', (246, 251))	('miR-125b', 'Chemical', '-', (123, 131))	('decreased', 'NegReg', (214, 223))	('increased', 'PosReg', (329, 338))	('miR-125b', 'Var', (205, 213))	('EC9706', 'CellLine', 'CVCL:E307', (74, 80))	('EC109', 'CellLine', 'CVCL:6898', (64, 69))
261704	29749531	Flow cytometric analysis was performed to detect the effect of miR-125b on the cell cycle in EC109 and EC9706 cells.	('cell cycle', 'CPA', (79, 89))	('EC109', 'CellLine', 'CVCL:6898', (93, 98))	('miR-125b', 'Var', (63, 71))	('EC9706', 'CellLine', 'CVCL:E307', (103, 109))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('miR-125b', 'Chemical', '-', (63, 71))
261706	29749531	Collectively, it was observed that miR-125b could arrest the cell cycle in the G1 phase in ESCC (Fig.	('ESCC', 'Disease', (91, 95))	('arrest', 'NegReg', (50, 56))	('miR-125b', 'Var', (35, 43))	('cell cycle in the G1 phase', 'CPA', (61, 87))	('miR-125b', 'Chemical', '-', (35, 43))
261710	29749531	Similarly, the EC9706 cells after transfection with miR-125b mimics exhibited increased cell apoptosis compared with the control, while inhibition of miR-125b significantly decreased cell apoptosis (Fig.	('si', 'Chemical', 'MESH:D012825', (159, 161))	('mimics', 'Var', (61, 67))	('cell apoptosis', 'CPA', (88, 102))	('miR-125b', 'Chemical', '-', (52, 60))	('miR-125b', 'Gene', (150, 158))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('si', 'Chemical', 'MESH:D012825', (194, 196))	('increased', 'PosReg', (78, 87))	('miR-125b', 'Gene', (52, 60))	('miR-125b', 'Chemical', '-', (150, 158))	('decreased', 'NegReg', (173, 182))	('cell apoptosis', 'CPA', (183, 197))	('EC9706', 'CellLine', 'CVCL:E307', (15, 21))
261712	29749531	Of these proteins, 3 of the pro-apoptotic proteins, namely Bax, caspase-3 and p27, were observed to be upregulated in the EC109 and EC9706 cells transfected with miR-125b mimics in comparison with the cells of the control group.	('p27', 'Gene', '3429', (78, 81))	('p27', 'Gene', (78, 81))	('caspase-3', 'Gene', '836', (64, 73))	('caspase-3', 'Gene', (64, 73))	('miR-125b', 'Chemical', '-', (162, 170))	('Bax', 'Gene', '581', (59, 62))	('EC9706', 'Var', (132, 138))	('EC9706', 'CellLine', 'CVCL:E307', (132, 138))	('EC109', 'CellLine', 'CVCL:6898', (122, 127))	('miR-125b', 'Gene', (162, 170))	('Bax', 'Gene', (59, 62))	('upregulated', 'PosReg', (103, 114))
261722	29749531	Compared with the control, miR-125b mimics markedly inhibited tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('miR-125b', 'Chemical', '-', (27, 35))	('inhibited', 'NegReg', (52, 61))	('mimics', 'Var', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
261728	29749531	Furthermore, we examined whether the expression of BMF was affected by miR-125b in ESCC cells.	('BMF', 'Gene', '90427', (51, 54))	('miR-125b', 'Var', (71, 79))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('affected', 'Reg', (59, 67))	('miR-125b', 'Chemical', '-', (71, 79))	('BMF', 'Gene', (51, 54))
261736	29749531	BMF silencing notably promoted cell apoptosis in EC109 and EC9706 cells.	('EC109', 'CellLine', 'CVCL:6898', (49, 54))	('promoted', 'PosReg', (22, 30))	('BMF', 'Gene', (0, 3))	('EC9706', 'CellLine', 'CVCL:E307', (59, 65))	('BMF', 'Gene', '90427', (0, 3))	('cell apoptosis', 'CPA', (31, 45))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('silencing', 'Var', (4, 13))
261737	29749531	For EC109 cells, the proportion of apoptotic cells (Q2 + Q3) was 8.09+-1.96% in the control group, while the proportion of apoptotic cells (Q2 + Q3) was 30.30+-5.61% in the si-BMF group thus, revealing a significant increase in apoptotic cells.	('si', 'Chemical', 'MESH:D012825', (204, 206))	('EC109', 'CellLine', 'CVCL:6898', (4, 9))	('si', 'Chemical', 'MESH:D012825', (173, 175))	('EC109', 'Var', (4, 9))	('BMF', 'Gene', '90427', (176, 179))	('apoptotic cells', 'CPA', (228, 243))	('increase', 'PosReg', (216, 224))	('BMF', 'Gene', (176, 179))
261738	29749531	Western blot analysis indicated that BMF silencing markedly increased the expression of Bax, caspase-3 and p27, and decreased that of Bcl-2 in ESCC cells (Fig.	('caspase-3', 'Gene', (93, 102))	('expression', 'MPA', (74, 84))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('decreased', 'NegReg', (116, 125))	('silencing', 'Var', (41, 50))	('BMF', 'Gene', (37, 40))	('Bax', 'Gene', (88, 91))	('p27', 'Gene', '3429', (107, 110))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('caspase-3', 'Gene', '836', (93, 102))	('Bax', 'Gene', '581', (88, 91))	('Bcl-2', 'Gene', '596', (134, 139))	('p27', 'Gene', (107, 110))	('BMF', 'Gene', '90427', (37, 40))	('Bcl-2', 'Gene', (134, 139))	('increased', 'PosReg', (60, 69))	('si', 'Chemical', 'MESH:D012825', (80, 82))
261743	29749531	We further observed that the levels of BMF in EC109 and EC9706 were in accordance with the tissues (Fig.	('EC9706', 'Var', (56, 62))	('EC109', 'CellLine', 'CVCL:6898', (46, 51))	('BMF', 'Gene', (39, 42))	('EC9706', 'CellLine', 'CVCL:E307', (56, 62))	('EC109', 'Var', (46, 51))	('BMF', 'Gene', '90427', (39, 42))
261746	29749531	Accumulating evidence has revealed that miRNAs are closely associated with the initiation and progression of ESCC by activating or suppressing multiple malignant processes.	('si', 'Chemical', 'MESH:D012825', (138, 140))	('ESCC', 'Disease', (109, 113))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('activating', 'PosReg', (117, 127))	('miRNAs', 'Var', (40, 46))	('associated', 'Reg', (59, 69))	('suppressing', 'NegReg', (131, 142))
261750	29749531	It was also observed that the level of miR-125b was closely associated with ESCC tumorigenesis.	('miR-125b', 'Var', (39, 47))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('associated', 'Reg', (60, 70))	('miR-125b', 'Chemical', '-', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ESCC', 'Disease', (76, 80))	('tumor', 'Disease', (81, 86))
261753	29749531	Furthermore, we observed that miR-125b directly targeted BMF in ESCC cells.	('targeted', 'Reg', (48, 56))	('miR-125b', 'Var', (30, 38))	('BMF', 'Gene', (57, 60))	('miR-125b', 'Chemical', '-', (30, 38))	('BMF', 'Gene', '90427', (57, 60))
261768	29749531	In the present study, the results revealed that silencing BMF could markedly inhibit cell growth and promote cell apoptosis in EC109 and EC9706 cells.	('promote', 'PosReg', (101, 108))	('silencing', 'Var', (48, 57))	('EC9706', 'CellLine', 'CVCL:E307', (137, 143))	('EC109', 'CellLine', 'CVCL:6898', (127, 132))	('inhibit', 'NegReg', (77, 84))	('cell apoptosis', 'CPA', (109, 123))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('BMF', 'Gene', (58, 61))	('cell growth', 'CPA', (85, 96))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('BMF', 'Gene', '90427', (58, 61))
261769	29749531	In summary, the results indicated that knockdown of miR-125b expression may prevent ESCC tumor initiation and progression by controlling BMF levels.	('miR-125b', 'Chemical', '-', (52, 60))	('BMF', 'Gene', '90427', (137, 140))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('knockdown', 'Var', (39, 48))	('BMF', 'Gene', (137, 140))	('ESCC tumor initiation', 'Disease', 'MESH:D004938', (84, 105))	('miR-125b', 'Gene', (52, 60))	('progression', 'CPA', (110, 121))	('ESCC tumor initiation', 'Disease', (84, 105))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('prevent', 'NegReg', (76, 83))
261777	29358879	Core tip: Competing endogenous RNAs (ceRNAs) may play a critical role in tumourigenesis, and perturbations to ceRNA networks would result in the progression of oesophageal squamous cell carcinoma (ESCC).	('result in', 'Reg', (131, 140))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (160, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('oesophageal squamous cell carcinoma', 'Disease', (160, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('perturbations', 'Var', (93, 106))
261784	29358879	Tumourigenesis and cancer development have been closely associated with the aberrant expression of protein coding mRNAs and non-coding RNAs.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('mRNAs', 'Gene', (114, 119))	('cancer', 'Disease', (19, 25))	('associated', 'Reg', (56, 66))	('aberrant', 'Var', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Tumourigenesis', 'CPA', (0, 14))
261785	29358879	Approximately 98% of the human genome are non-coding RNAs, suggesting their promising effects on physiological and pathological processes.	('effects', 'Reg', (86, 93))	('non-coding RNAs', 'Var', (42, 57))	('human', 'Species', '9606', (25, 30))
261788	29358879	With these information, a synthetic analysis could be performed on the association between molecular alterations and certain cancer type.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('molecular alterations', 'Var', (91, 112))	('association', 'Interaction', (71, 82))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
261790	29358879	The expression data of miRNAs and mRNAs in 101 oesophageal cancer patients were collected from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI) with login numbers of GSE45670 (38 patients, =GSE45670), GSE26886 (28 patients, =GSE26886), GSE17351 (10 samples, =GSE17351), GSE55856 (216 patients, =GSE55856), and GSE66274 (60 patients, =GSE66274).	('oesophageal cancer', 'Disease', 'MESH:D009369', (47, 65))	('GSE45670', 'Var', (198, 206))	('patients', 'Species', '9606', (355, 363))	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (246, 254))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('GSE66274', 'Var', (342, 350))	('patients', 'Species', '9606', (316, 324))	('oesophageal cancer', 'Disease', (47, 65))	('patients', 'Species', '9606', (66, 74))
261804	29358879	However, the expression levels were down-regulated for has-miR-30a-3p, has-miR-150-5p, and has-miR-133a-3p.	('expression levels', 'MPA', (13, 30))	('miR-150', 'Gene', (75, 82))	('miR-150', 'Gene', '406942', (75, 82))	('has-miR-30a-3p', 'Var', (55, 69))	('has-miR-133a-3p', 'Var', (91, 106))	('down-regulated', 'NegReg', (36, 50))
261807	29358879	Among the six significant mRNAs, the overall survival was negatively related to five mRNA transcripts (STC2, SLC6A1, MMP12, EPCAM, and EPB411L4B) (P < 0.05) while positively associated with the remaining mRNA transcript (LAMC2) (P < 0.05) (Figure 7A-F).	('positively', 'PosReg', (163, 173))	('STC2', 'Gene', (103, 107))	('EPCAM', 'Gene', '4072', (124, 129))	('MMP12', 'Gene', (117, 122))	('LAMC2', 'Gene', (221, 226))	('LAMC2', 'Gene', '3918', (221, 226))	('EPB411L4B', 'Var', (135, 144))	('MMP12', 'Gene', '4321', (117, 122))	('SLC6A1', 'Gene', '6529', (109, 115))	('SLC6A1', 'Gene', (109, 115))	('STC2', 'Gene', '8614', (103, 107))	('negatively', 'NegReg', (58, 68))	('EPCAM', 'Gene', (124, 129))
261835	29358879	However, the levels of has-miR-30a-3p, has-miR-150-5p, and has-miR-133a-3p were down-regulated.	('has-miR-133a-3p', 'Var', (59, 74))	('miR-150', 'Gene', (43, 50))	('has-miR-30a-3p', 'Var', (23, 37))	('miR-150', 'Gene', '406942', (43, 50))	('down-regulated', 'NegReg', (80, 94))	('levels', 'MPA', (13, 19))
261848	29196415	Known risk factors include gastro-esophageal reflux disease (GERD), obesity, low fruit/vegetable intake, and smoking for EAC, and alcohol drinking, low fruit/vegetable intake, and smoking for ESCC, but the etiology of these diseases cannot be fully explained by these factors.	('low', 'NegReg', (77, 80))	('GERD', 'Disease', 'MESH:D005764', (61, 65))	('obesity', 'Phenotype', 'HP:0001513', (68, 75))	('alcohol', 'Disease', (130, 137))	('alcohol', 'Chemical', 'MESH:D000438', (130, 137))	('GERD', 'Disease', (61, 65))	('gastro-esophageal reflux disease', 'Disease', (27, 59))	('obesity', 'Disease', 'MESH:D009765', (68, 75))	('alcohol drinking', 'Phenotype', 'HP:0030955', (130, 146))	('low fruit/vegetable intake', 'Var', (148, 174))	('obesity', 'Disease', (68, 75))	('EAC', 'Phenotype', 'HP:0011459', (121, 124))	('gastro-esophageal reflux disease', 'Phenotype', 'HP:0002020', (27, 59))	('gastro-esophageal reflux disease', 'Disease', 'MESH:D005764', (27, 59))	('GERD', 'Phenotype', 'HP:0002020', (61, 65))
261887	29196415	While obesity, low fruit/vegetable intake, and smoking are recognized risk factors for EAC, and alcohol drinking, low fruit/vegetable intake, and smoking are recognized risk factors for ESCC, only alcohol drinking was associated with ESCC (p=0.004).	('low', 'Var', (114, 117))	('low', 'Var', (15, 18))	('EAC', 'Disease', (87, 90))	('obesity', 'Phenotype', 'HP:0001513', (6, 13))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))	('alcohol drinking', 'Phenotype', 'HP:0030955', (96, 112))	('obesity', 'Disease', 'MESH:D009765', (6, 13))	('EAC', 'Phenotype', 'HP:0011459', (87, 90))	('obesity', 'Disease', (6, 13))	('ESCC', 'Disease', (186, 190))	('alcohol', 'Chemical', 'MESH:D000438', (197, 204))	('alcohol drinking', 'Phenotype', 'HP:0030955', (197, 213))
261891	29196415	Increased abundance of species Actinomyces cardiffensis, Selenomonas oral taxon 134, and Veillonella oral taxon 917 was associated with higher EAC risk (all p<0.05).	('Veillonella oral', 'Disease', (89, 105))	('EAC', 'Phenotype', 'HP:0011459', (143, 146))	('Selenomonas oral taxon 134', 'Species', '712530', (57, 83))	('Selenomonas', 'Var', (57, 68))	('Actinomyces cardiffensis', 'Species', '181487', (31, 55))	('EAC', 'Disease', (143, 146))	('Veillonella oral', 'Disease', 'MESH:D020820', (89, 105))
261892	29196415	Conversely, increased abundance of Corynebacterium durum, Prevotella nanceiensis, Streptococcus pneumoniae, Lachnoanaerobaculum umeaense, Oribacterium parvum, Solobacterium moorei, Neisseria sicca, Neisseria flavescens, and Haemophilus oral taxon 908 was associated with lower EAC risk (all p<0.05).	('Haemophilus oral', 'Disease', (224, 240))	('Haemophilus oral', 'Disease', 'MESH:D006192', (224, 240))	('Neisseria sicca', 'Species', '490', (181, 196))	('Neisseria flavescens', 'Species', '484', (198, 218))	('Streptococcus pneumoniae', 'Species', '1313', (82, 106))	('Prevotella nanceiensis', 'Species', '425941', (58, 80))	('Neisseria sicca', 'Phenotype', 'HP:0001097', (181, 196))	('EAC', 'Phenotype', 'HP:0011459', (277, 280))	('lower', 'NegReg', (271, 276))	('EAC', 'Disease', (277, 280))	('Oribacterium parvum', 'Species', '1501329', (138, 157))	('Oribacterium', 'Var', (138, 150))	('Solobacterium moorei', 'Species', '102148', (159, 179))	('Corynebacterium durum', 'Species', '61592', (35, 56))	('Lachnoanaerobaculum umeaense', 'Species', '617123', (108, 136))
261899	29196415	Selenomonas oral taxon 134 was associated with higher EAC risk in the PLCO cohort only (p-interaction=0.02).	('EAC', 'Phenotype', 'HP:0011459', (54, 57))	('Selenomonas', 'Var', (0, 11))	('EAC', 'Disease', (54, 57))	('Selenomonas oral taxon 134', 'Species', '712530', (0, 26))
261901	29196415	When stratifying by smoking status we observed that Lachnoanaerobaculum umeaense was associated with lower EAC risk only in smokers (p-interaction=0.02) (Supplementary Table 5), while other taxon-EAC associations did not differ significantly between ever and never smokers (p-interaction>0.19).	('Lachnoanaerobaculum umeaense', 'Species', '617123', (52, 80))	('EAC', 'Disease', (107, 110))	('Lachnoanaerobaculum umeaense', 'Var', (52, 80))	('EAC', 'Phenotype', 'HP:0011459', (196, 199))	('lower', 'NegReg', (101, 106))	('men', 'Species', '9606', (160, 163))	('EAC', 'Phenotype', 'HP:0011459', (107, 110))
261902	29196415	When stratifying by obesity we observed that Actinomyces cardiffensis was associated with higher EAC risk only in non-obese (p-interaction=0.02), while other taxon-EAC associations did not differ significantly between non-obese and obese (p-interaction>0.11) (Supplementary Table 6).	('obese', 'Disease', (232, 237))	('Actinomyces cardiffensis', 'Species', '181487', (45, 69))	('obesity', 'Disease', (20, 27))	('obese', 'Disease', 'MESH:D009765', (232, 237))	('EAC', 'Disease', (97, 100))	('EAC', 'Phenotype', 'HP:0011459', (164, 167))	('obese', 'Disease', (222, 227))	('non-obese', 'Disease', (218, 227))	('obesity', 'Disease', 'MESH:D009765', (20, 27))	('obese', 'Disease', 'MESH:D009765', (222, 227))	('obese', 'Disease', (118, 123))	('Actinomyces cardiffensis', 'Var', (45, 69))	('non-obese', 'Disease', (114, 123))	('non-obese', 'Disease', 'MESH:D009765', (218, 227))	('higher', 'PosReg', (90, 96))	('obese', 'Disease', 'MESH:D009765', (118, 123))	('obesity', 'Phenotype', 'HP:0001513', (20, 27))	('non-obese', 'Disease', 'MESH:D009765', (114, 123))	('men', 'Species', '9606', (266, 269))	('EAC', 'Phenotype', 'HP:0011459', (97, 100))
261904	29196415	The periodontal pathogen Porphyromonas gingivalis was marginally associated with higher ESCC risk (OR [95% CI]=1.30 [0.96-1.77], p=0.09) (Table 2; Figure 1).	('ESCC', 'Disease', (88, 92))	('Porphyromonas gingivalis', 'Var', (25, 49))	('Porphyromonas gingivalis', 'Species', '837', (25, 49))
261939	29196415	Bacterial siderophore synthesis may upset iron homeostasis, and thus might increase EAC risk.	('upset', 'Reg', (36, 41))	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('Bacterial', 'Var', (0, 9))	('iron', 'Chemical', 'MESH:D007501', (42, 46))	('iron homeostasis', 'MPA', (42, 58))	('upset iron homeostasis', 'Phenotype', 'HP:0011031', (36, 58))	('EAC', 'Disease', (84, 87))	('increase', 'PosReg', (75, 83))
261952	27563815	However, OS (hazard ratio (HR)=1.480, P=0.013) and DFS (HR=1.418, P=0.024) were worse for male patients with high KIF-2C expression compared with male patients with low KIF-2C expression.	('high', 'Var', (109, 113))	('patients', 'Species', '9606', (95, 103))	('KIF-2C', 'Gene', (114, 120))	('KIF-2C', 'Gene', '11004', (169, 175))	('patients', 'Species', '9606', (151, 159))	('KIF-2C', 'Gene', '11004', (114, 120))	('KIF-2C', 'Gene', (169, 175))	('DFS', 'MPA', (51, 54))
261953	27563815	Moreover, the OS and DFS of male patients with high KIF-2C expression were also significantly shorter compared with female patients with low KIF-2C expression (P=0.022, P=0.029) and female patients with high KIF-2C expression (P=0.014, P=0.018).	('KIF-2C', 'Gene', (52, 58))	('KIF-2C', 'Gene', '11004', (141, 147))	('KIF-2C', 'Gene', '11004', (52, 58))	('patients', 'Species', '9606', (33, 41))	('KIF-2C', 'Gene', (141, 147))	('high', 'Var', (47, 51))	('KIF-2C', 'Gene', '11004', (208, 214))	('shorter', 'NegReg', (94, 101))	('patients', 'Species', '9606', (123, 131))	('KIF-2C', 'Gene', (208, 214))	('patients', 'Species', '9606', (189, 197))	('DFS', 'CPA', (21, 24))
261955	27563815	Prognosis was worse for male patients with high KIF-2C expression compared with patients with the same pathologic tumor-node-metastasis (pTNM) stage.	('patients', 'Species', '9606', (29, 37))	('KIF-2C', 'Gene', '11004', (48, 54))	('patients', 'Species', '9606', (80, 88))	('tumor-node-metastasis', 'Disease', (114, 135))	('KIF-2C', 'Gene', (48, 54))	('high', 'Var', (43, 47))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (114, 135))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('expression', 'MPA', (55, 65))
261959	27563815	Most solid tumors are aneuploid and many contain aberrant chromosomes.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('contain', 'Reg', (41, 48))	('solid tumors', 'Disease', 'MESH:D009369', (5, 17))	('aberrant chromosomes', 'Var', (49, 69))	('aneuploid', 'Var', (22, 31))	('solid tumors', 'Disease', (5, 17))
261962	27563815	KIF-2C localizes to the cytoplasm throughout the cell cycle and is particularly enriched at centrosomes, centromeres/kinetochores, and the spindle midzone during mitosis KIF-2C contributes to proper spindle formation, correction of aberrant attachments of microtubules to chromosomes, and chromosome segregation.	('KIF-2C', 'Gene', '11004', (0, 6))	('KIF-2C', 'Gene', (0, 6))	('chromosome segregation', 'CPA', (289, 311))	('mitosis KIF-2C', 'Disease', (162, 176))	('spindle formation', 'CPA', (199, 216))	('mitosis KIF-2C', 'Disease', 'MESH:C564684', (162, 176))	('microtubules', 'Protein', (256, 268))	('KIF-2C', 'Gene', '11004', (170, 176))	('KIF-2C', 'Gene', (170, 176))	('attachments', 'Interaction', (241, 252))	('men', 'Species', '9606', (247, 250))	('aberrant', 'Var', (232, 240))
261963	27563815	The abnormal expression of KIF-2C is associated with abnormal mitosis, chromosomal aberrations, and malignant transformation.	('malignant transformation', 'CPA', (100, 124))	('KIF-2C', 'Gene', (27, 33))	('abnormal', 'Var', (4, 12))	('chromosomal aberrations', 'CPA', (71, 94))	('KIF-2C', 'Gene', '11004', (27, 33))	('abnormal mitosis', 'Disease', (53, 69))	('associated', 'Reg', (37, 47))	('abnormal mitosis', 'Disease', 'MESH:D000014', (53, 69))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (71, 94))
261964	27563815	Therefore, the deregulation of KIF-2C expression likely plays a role in cancer development and progression.	('KIF-2C', 'Gene', '11004', (31, 37))	('men', 'Species', '9606', (86, 89))	('KIF-2C', 'Gene', (31, 37))	('plays', 'Reg', (56, 61))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('deregulation', 'Var', (15, 27))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
261984	27563815	Multivariable regression analysis of male patients indicated that high levels of KIF-2C were independently associated with a significantly increased risk of ESCC-related death (HR=1.480, P=0.013) and tumor recurrence (HR=1.418, P=0.024).	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('high levels', 'Var', (66, 77))	('associated', 'Reg', (107, 117))	('tumor', 'Disease', (200, 205))	('KIF-2C', 'Gene', '11004', (81, 87))	('death', 'Disease', 'MESH:D003643', (170, 175))	('KIF-2C', 'Gene', (81, 87))	('patients', 'Species', '9606', (42, 50))	('death', 'Disease', (170, 175))
261995	27563815	Interestingly, in the subgroup analyses conducted here, the prognoses of male patients with different levels of KIF-2C were significantly different, in contrast to those of female patients.	('levels', 'Var', (102, 108))	('different', 'Reg', (138, 147))	('patients', 'Species', '9606', (78, 86))	('KIF-2C', 'Gene', (112, 118))	('KIF-2C', 'Gene', '11004', (112, 118))	('patients', 'Species', '9606', (180, 188))
261996	27563815	Specifically, after controlling for tumor differentiation, pT and pN status, pTNM stage, and surgical quality, male patients with high levels of KIF-2C expression had significantly worse OS and DFS compared with male patients with low expression.	('worse', 'NegReg', (181, 186))	('KIF-2C', 'Gene', '11004', (145, 151))	('patients', 'Species', '9606', (116, 124))	('KIF-2C', 'Gene', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('DFS', 'CPA', (194, 197))	('high levels', 'Var', (130, 141))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('patients', 'Species', '9606', (217, 225))	('tumor', 'Disease', (36, 41))
261998	27563815	Kaplan-Meier analysis suggested that the OS and DFS of male patients with high KIF-2C expression were significantly shorter compared with those of other patients.	('shorter', 'NegReg', (116, 123))	('DFS', 'CPA', (48, 51))	('patients', 'Species', '9606', (153, 161))	('KIF-2C', 'Gene', (79, 85))	('high', 'Var', (74, 78))	('KIF-2C', 'Gene', '11004', (79, 85))	('patients', 'Species', '9606', (60, 68))
262000	27563815	However, from a relatively large cohort and extended follow-up, the present study suggests that male patients with high KIF-2C expression had a significantly worse prognosis.	('high', 'Var', (115, 119))	('patients', 'Species', '9606', (101, 109))	('expression', 'MPA', (127, 137))	('KIF-2C', 'Gene', (120, 126))	('KIF-2C', 'Gene', '11004', (120, 126))
262002	27563815	However, the accumulating data suggest that reactivation of germline genes might confers essential characteristics to cancer cells.	('essential characteristics', 'CPA', (89, 114))	('cancer', 'Disease', (118, 124))	('reactivation', 'Var', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
262005	27563815	It can be speculated that some meiotic programs are reactivated in cancer cells by the aberrantly expressed germ cell proteins and contribute to genome instability in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('aberrantly', 'Var', (87, 97))	('reactivated', 'PosReg', (52, 63))	('meiotic programs', 'CPA', (31, 47))	('germ', 'Protein', (108, 112))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('genome instability', 'MPA', (145, 163))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('contribute', 'Reg', (131, 141))
262006	27563815	In this study, we found that male patients with high KIF-2C expression suffered the worst prognosis.	('high', 'Var', (48, 52))	('KIF-2C', 'Gene', (53, 59))	('patients', 'Species', '9606', (34, 42))	('KIF-2C', 'Gene', '11004', (53, 59))
262008	27563815	Therefore, the tumorigenic function of highly expressed KIF-2C in ESCC cells may also be facilitated with androgen in male patients.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('KIF-2C', 'Gene', (56, 62))	('KIF-2C', 'Gene', '11004', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('facilitated', 'PosReg', (89, 100))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', (15, 20))	('highly expressed', 'Var', (39, 55))
262015	27563815	For example, the majority of the male patients in our study with high-expression of KIF-2C had shorter OS and DFS, indicating that surgical resection alone was insufficient.	('DFS', 'CPA', (110, 113))	('insufficient', 'Disease', 'MESH:D000309', (160, 172))	('KIF-2C', 'Gene', '11004', (84, 90))	('KIF-2C', 'Gene', (84, 90))	('patients', 'Species', '9606', (38, 46))	('high-expression', 'Var', (65, 80))	('insufficient', 'Disease', (160, 172))	('shorter', 'NegReg', (95, 102))
262019	27563815	In addition, an inhibitor of KIF-2C induced the inhibition of responder T-lymphocyte activation.	('inhibitor', 'Var', (16, 25))	('KIF-2C', 'Gene', '11004', (29, 35))	('KIF-2C', 'Gene', (29, 35))	('responder T-lymphocyte activation', 'CPA', (62, 95))	('inhibition', 'NegReg', (48, 58))
262175	25691110	pT4 tumors had a significant higher lymph node count compared to the pT1-3 tumors.	('higher', 'PosReg', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('pT1', 'Gene', (69, 72))	('pT4', 'Var', (0, 3))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('lymph node count', 'CPA', (36, 52))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('pT1', 'Gene', '58492', (69, 72))	('tumors', 'Disease', (75, 81))
262229	25603875	EBS is usually due to autosomal dominant mutations in keratin 5 or 14 or in plectin and is often of milder severity.	('autosomal', 'Var', (22, 31))	('due', 'Reg', (15, 18))	('EBS', 'Chemical', 'MESH:C004912', (0, 3))	('keratin 5 or 14', 'Protein', (54, 69))	('plectin', 'Gene', (76, 83))	('EBS', 'Disease', (0, 3))	('plectin', 'Gene', '5339', (76, 83))
262230	25603875	JEB can result from mutations in any of six different basement membrane components, is inherited as an autosomal recessive disorder, and can range from mild to fatal early in life.	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (103, 131))	('autosomal recessive disorder', 'Disease', (103, 131))	('JEB', 'Disease', (0, 3))	('mutations', 'Var', (20, 29))	('result from', 'Reg', (8, 19))
262238	25603875	The population of interest comprises patients with pain who have any variant of EB.	('pain', 'Disease', (51, 55))	('variant', 'Var', (69, 76))	('patients', 'Species', '9606', (37, 45))	('pain', 'Phenotype', 'HP:0012531', (51, 55))	('pain', 'Disease', 'MESH:D010146', (51, 55))
262263	25603875	Beyond this, damage of the integrity of the skin can create a portal of entry for systemic infections.	('systemic infections', 'Disease', 'MESH:D034721', (82, 101))	('damage', 'Var', (13, 19))	('systemic infections', 'Disease', (82, 101))
262436	25603875	Further, impaired mobility can add a myofascial component to pain.	('pain', 'Phenotype', 'HP:0012531', (61, 65))	('impaired', 'Var', (9, 17))	('myofascial component to pain', 'Disease', (37, 65))	('myofascial component to pain', 'Disease', 'MESH:D009209', (37, 65))
262476	25603875	Codeine is not recommended, when alternatives are available, as neonates lack the capacity to metabolize the drug into active metabolites, and clinical responses are highly variable at all ages, due to polymorphisms in codeine's metabolic pathway,.	('metabolize', 'MPA', (94, 104))	('metabolic pathway', 'Enzyme', (229, 246))	('lack', 'NegReg', (73, 77))	('polymorphisms', 'Var', (202, 215))	('Codeine', 'Chemical', 'MESH:D003061', (0, 7))	('codeine', 'Gene', (219, 226))	('codeine', 'Chemical', 'MESH:D003061', (219, 226))
262608	21858113	DSBs are primarily repaired by two pathways, i.e., non-homologous end joining and homologous recombination.	('non-homologous', 'Var', (51, 65))	('homologous', 'Var', (82, 92))	('DSBs', 'Chemical', '-', (0, 4))
262667	21858113	While previous studies showed that berberine possesses direct anti-tumor effects by inducing the production of reactive oxygen species in cancer cells, which would presumably confer radiosensitization, our study is the first to show that berberine can confer radiosensitivity by downregulating a key player in the repair of DSBs.	('cancer', 'Disease', (138, 144))	('DSBs', 'Disease', (324, 328))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (111, 134))	('DSBs', 'Chemical', '-', (324, 328))	('repair', 'MPA', (314, 320))	('downregulating', 'NegReg', (279, 293))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('berberine', 'Var', (238, 247))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('radiosensitivity', 'MPA', (259, 275))	('inducing', 'PosReg', (84, 92))	('tumor', 'Disease', (67, 72))	('berberine', 'Chemical', 'MESH:D001599', (35, 44))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('production of reactive oxygen species', 'MPA', (97, 134))	('berberine', 'Chemical', 'MESH:D001599', (238, 247))
262677	21858113	The human esophageal squamous cell carcinoma (ESCC) lines KYSE30, KYSE450, KYSE410, EC109 and TE-1 were obtained from Cancer Institute & Hospital, Chinese Academy of Medical Sciences (Beijing) and cultured in RPMI 1640 supplemented with 10% fetal bovine serum, 100 units/mL penicillin, and 100 microg/mL streptomycin.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (10, 44))	('KYSE410', 'Var', (75, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('human', 'Species', '9606', (4, 9))	('bovine', 'Species', '9913', (247, 253))	('penicillin', 'Chemical', 'MESH:D010406', (274, 284))	('EC109', 'CellLine', 'CVCL:6898', (84, 89))	('esophageal squamous cell carcinoma', 'Disease', (10, 44))	('RPMI', 'Chemical', '-', (209, 213))	('streptomycin', 'Chemical', 'MESH:D013307', (304, 316))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))	('Cancer', 'Phenotype', 'HP:0002664', (118, 124))
262678	21858113	KYSE30, KYSE450 and KYSE410 were originally generated by Dr. Yutaka Shimada, Normal human fibroblast (NHF) cells were obtained from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (Beijing), and were maintained in DMEM supplemented with 10% fetal bovine serum, 100 units/mL penicillin-streptomycin and 4 microg/mL bFGF.	('bFGF', 'Gene', (343, 347))	('streptomycin', 'Chemical', 'MESH:D013307', (314, 326))	('KYSE450', 'Var', (8, 15))	('human', 'Species', '9606', (84, 89))	('bovine', 'Species', '9913', (276, 282))	('KYSE410', 'Var', (20, 27))	('bFGF', 'Gene', '2247', (343, 347))	('DMEM', 'Chemical', '-', (243, 247))	('penicillin', 'Chemical', 'MESH:D010406', (303, 313))
262699	21858113	Antibodies to Ku70, Ku86, and RAD51 were from Santa Cruz Biotechnology (Santa Cruz, CA); and GAPDH was from Chemicon (Temecula, CA).	('Ku70', 'Gene', (14, 18))	('Ku86', 'Gene', (20, 24))	('GAPDH', 'Gene', '2597', (93, 98))	('GAPDH', 'Gene', (93, 98))	('Ku86', 'Gene', '7520', (20, 24))	('Ku70', 'Gene', '2547', (14, 18))	('RAD51', 'Var', (30, 35))
262718	17895998	Effects of Environment, Genetics and Data Analysis Pitfalls in an Esophageal Cancer Genome-Wide Association Study The development of new high-throughput genotyping technologies has allowed fast evaluation of single nucleotide polymorphisms (SNPs) on a genome-wide scale.	('Esophageal Cancer', 'Disease', 'MESH:D004938', (66, 83))	('single nucleotide polymorphisms', 'Var', (208, 239))	('Esophageal Cancer', 'Disease', (66, 83))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))
262775	33350074	We found that high KIF4A expression was associated with poor overall survival in esophageal squamous cell carcinoma.	('poor', 'NegReg', (56, 60))	('esophageal squamous cell carcinoma', 'Disease', (81, 115))	('expression', 'MPA', (25, 35))	('KIF4A', 'Gene', (19, 24))	('KIF4A', 'Gene', '24137', (19, 24))	('high', 'Var', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (81, 115))	('overall', 'MPA', (61, 68))
262785	33350074	10 ,  11  Previous studies have shown that inactivation of LATS1/2, a key kinase in the Hippo signaling pathway, or overexpression of YAP, a target gene downstream of the Hippo signaling pathway, can lead to substantial accumulation of E3 ubiquitin ligase Skp2 in the cytoplasm and decrease of Skp2 level in the nucleus, leading to cell mitosis arrest and polyploid formation.	('accumulation', 'PosReg', (220, 232))	('polyploid formation', 'CPA', (356, 375))	('E3 ubiquitin ligase', 'Protein', (236, 255))	('inactivation', 'Var', (43, 55))	('mitosis arrest', 'Disease', (337, 351))	('mitosis arrest', 'Disease', 'MESH:D006323', (337, 351))	('Skp2', 'Gene', '6502', (294, 298))	('LATS1', 'Gene', (59, 64))	('Skp2', 'Gene', '6502', (256, 260))	('YAP', 'Gene', '10413', (134, 137))	('LATS1', 'Gene', '9113', (59, 64))	('overexpression', 'Var', (116, 130))	('Skp2', 'Gene', (294, 298))	('decrease', 'NegReg', (282, 290))	('Skp2', 'Gene', (256, 260))	('YAP', 'Gene', (134, 137))
262809	33350074	To observe the effect of KIF4A, EX-A3631-Lv105 (OE-KIF4A, GeneCopoeia, Inc.) was transfected into Eca150 cells.	('KIF4A', 'Gene', (25, 30))	('KIF4A', 'Gene', (51, 56))	('KIF4A', 'Gene', '24137', (25, 30))	('KIF4A', 'Gene', '24137', (51, 56))	('EX-A3631-Lv105', 'Var', (32, 46))
262853	33350074	Eca109 cells were infected with either control or KIF4A siRNA and Eca150 cells were infected with negative control or EX-A3631-Lv105.	('infected', 'Disease', (84, 92))	('infected', 'Disease', 'MESH:D007239', (18, 26))	('KIF4A', 'Gene', (50, 55))	('infected', 'Disease', (18, 26))	('EX-A3631-Lv105', 'Var', (118, 132))	('infected', 'Disease', 'MESH:D007239', (84, 92))	('KIF4A', 'Gene', '24137', (50, 55))
262854	33350074	Western blot analyses suggested that siRNA-KIF4A and EX-A3631-Lv105 could significantly inhibit and increase the expression of KIF4A in protein levels, respectively (Fig 4c,d).	('expression', 'MPA', (113, 123))	('KIF4A', 'Gene', '24137', (43, 48))	('KIF4A', 'Gene', '24137', (127, 132))	('inhibit', 'NegReg', (88, 95))	('KIF4A', 'Gene', (43, 48))	('EX-A3631-Lv105', 'Var', (53, 67))	('increase', 'PosReg', (100, 108))	('KIF4A', 'Gene', (127, 132))
262865	33350074	Results are shown in Fig 5e, and after the transfection of KIF4A siRNA in ESCC cells, the phosphorylation levels of LATS1 and YAP in the cells increased significantly, whereas the total LATS1 and YAP protein contents remained unchanged.	('increased', 'PosReg', (143, 152))	('YAP', 'Gene', (126, 129))	('transfection', 'Var', (43, 55))	('KIF4A', 'Gene', '24137', (59, 64))	('LATS1', 'Gene', '9113', (186, 191))	('LATS1', 'Gene', (116, 121))	('LATS1', 'Gene', '9113', (116, 121))	('YAP', 'Gene', '10413', (126, 129))	('phosphorylation levels', 'MPA', (90, 112))	('YAP', 'Gene', '10413', (196, 199))	('KIF4A', 'Gene', (59, 64))	('LATS1', 'Gene', (186, 191))	('YAP', 'Gene', (196, 199))
262878	33350074	In a series of cell function experiments, KIF4A overexpression was found to increase the migratory capability and decrease the apoptotic ability of ESCC cells, suggesting that KIF4A may be an oncogene of ESCC.	('KIF4A', 'Gene', (42, 47))	('men', 'Species', '9606', (35, 38))	('increase', 'PosReg', (76, 84))	('KIF4A', 'Gene', (176, 181))	('overexpression', 'Var', (48, 62))	('KIF4A', 'Gene', '24137', (42, 47))	('apoptotic ability', 'CPA', (127, 144))	('KIF4A', 'Gene', '24137', (176, 181))	('decrease', 'NegReg', (114, 122))	('migratory capability', 'CPA', (89, 109))
262905	27803900	EUS understaged 15.05% T1b superficial esophageal cancer and overstaged 4.30% T1a lesion about the evaluation for submucosal invasion.	('T1b', 'Var', (23, 26))	('understaged', 'NegReg', (4, 15))	('esophageal cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))
262970	19222528	Phase I and II enzyme polymorphisms as risk factors for Barrett's esophagus and esophageal adenocarcinoma: a systematic review and meta-analysis Although several studies have examined the association between phase I/II enzyme polymorphisms and esophageal adenocarcinoma (EAC) and/or Barrett's esophagus (BE), their overall findings remain unclear.	("Barrett's esophagus", 'Disease', (283, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('association', 'Interaction', (188, 199))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (80, 105))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (244, 269))	('polymorphisms', 'Var', (226, 239))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (283, 302))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('esophageal adenocarcinoma', 'Disease', (244, 269))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (244, 269))	("Barrett's esophagus", 'Disease', (56, 75))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (56, 75))	('esophageal adenocarcinoma', 'Disease', (80, 105))
262972	19222528	Meta-analysis suggested the minor allele for GSTP1 Val105 conveys modest excess risk (odds ratio [OR]BE = 1.50, 95% confidence interval [CI] 1.16-1.95; OREAC = 1.20, 95% CI 0.94-1.54).	('GSTP1', 'Gene', '2950', (45, 50))	('GSTP1', 'Gene', (45, 50))	('Val105', 'Var', (51, 57))
263007	19222528	CYP1A1 Ile462Val involves a A   G substitution in exon 7 and leads to a twofold increase in enzymatic expression.	('Ile462Val', 'Var', (7, 16))	('enzymatic expression', 'MPA', (92, 112))	('CYP1A1', 'Gene', '1543', (0, 6))	('increase', 'PosReg', (80, 88))	('Ile462Val', 'Chemical', '-', (7, 16))	('CYP1A1', 'Gene', (0, 6))
263008	19222528	CYP1A1 MspI is in strict linkage disequilibrium with CYP1A1 Ile462Val and involves a T   C (T6235C) substitution in the 3' flanking region.	('Ile462Val', 'Chemical', '-', (60, 69))	('CYP1A1', 'Gene', '1543', (0, 6))	('CYP1A1', 'Gene', (53, 59))	('CYP1A1', 'Gene', '1543', (53, 59))	('T6235C', 'Mutation', 'rs4646903', (92, 98))	('CYP1A1', 'Gene', (0, 6))	('Ile462Val', 'Var', (60, 69))
263009	19222528	The frequency of the rare homozygous genotype for CYP1A1 Ile462Val (Val462/Val462) is 0.6% in Caucasians and 4.9% in Asians, while the frequency of the rare homozygous genotype for CYP1A1 MspI (C6235/C6235) is 1.2% in Caucasians and 14% in Asians.	('C6235/C6235', 'Var', (194, 205))	('CYP1A1', 'Gene', '1543', (181, 187))	('Val462', 'Chemical', '-', (68, 74))	('Ile462Val', 'Chemical', '-', (57, 66))	('CYP1A1', 'Gene', (50, 56))	('is 1', 'Species', '1433131', (207, 211))	('Ile462Val', 'Var', (57, 66))	('CYP1A1', 'Gene', '1543', (50, 56))	('CYP1A1', 'Gene', (181, 187))	('Val462', 'Chemical', '-', (75, 81))
263010	19222528	We identified three studies that examined CYP1A1 Ile462Val and two that examined CYP1A1 MspI as risk factors for EAC (see Fig.	('CYP1A1', 'Gene', '1543', (42, 48))	('Ile462Val', 'Var', (49, 58))	('CYP1A1', 'Gene', (81, 87))	('EAC', 'Disease', (113, 116))	('Ile462Val', 'Chemical', '-', (49, 58))	('CYP1A1', 'Gene', '1543', (81, 87))	('CYP1A1', 'Gene', (42, 48))
263012	19222528	We assumed a dominant model of inheritance in the meta-analysis because there were insufficient reported cases of minor allele homozygote (Val462/Val462) in the three studies.	('Val462/Val462', 'Var', (139, 152))	('insufficient', 'Disease', (83, 95))	('insufficient', 'Disease', 'MESH:D000309', (83, 95))	('Val462', 'Chemical', '-', (139, 145))	('Val462', 'Chemical', '-', (146, 152))
263017	19222528	Two SNPs known to affect enzymatic activity are EPHX1 Tyr113His (EPHX1 exon3) and EPHX1 His139Arg (EPHX1 exon4).	('EPHX1', 'Gene', (82, 87))	('EPHX1', 'Gene', (99, 104))	('N', 'Chemical', 'MESH:D009584', (5, 6))	('enzymatic', 'MPA', (25, 34))	('EPHX1', 'Gene', (65, 70))	('EPHX1', 'Gene', '2052', (48, 53))	('Tyr113His', 'SUBSTITUTION', 'None', (54, 63))	('EPHX1', 'Gene', (48, 53))	('Tyr113His', 'Var', (54, 63))	('EPHX1', 'Gene', '2052', (82, 87))	('His139Arg', 'Var', (88, 97))	('EPHX1', 'Gene', '2052', (99, 104))	('His139Arg', 'SUBSTITUTION', 'None', (88, 97))	('EPHX1', 'Gene', '2052', (65, 70))
263020	19222528	EPHX1 polymorphisms have also been associated with lung, colorectal, and liver cancer.	('lung', 'Disease', (51, 55))	('colorectal', 'Disease', 'MESH:D015179', (57, 67))	('EPHX1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (73, 85))	('associated', 'Reg', (35, 45))	('polymorphisms', 'Var', (6, 19))	('colorectal', 'Disease', (57, 67))	('liver cancer', 'Disease', 'MESH:D006528', (73, 85))	('EPHX1', 'Gene', '2052', (0, 5))	('liver cancer', 'Disease', (73, 85))
263029	19222528	A -C609T substitution leads to a proline to a serine amino acid substitution.	('leads to', 'Reg', (22, 30))	('proline to a serine amino acid substitution', 'MPA', (33, 76))	('A -C609T', 'Var', (0, 8))	('C609T', 'Mutation', 'rs1800566', (3, 8))	('serine amino acid', 'Chemical', '-', (46, 63))	('proline', 'Chemical', 'MESH:D011392', (33, 40))
263031	19222528	We identified three case-control studies that examined NQO1 Ser-609 in EAC (Fig.	('NQO1', 'Gene', '1728', (55, 59))	('Ser', 'Chemical', 'MESH:D012694', (60, 63))	('EAC', 'Disease', (71, 74))	('NQO1', 'Gene', (55, 59))	('Ser-609', 'Var', (60, 67))
263035	19222528	Similar to their results for EAC, a strong decreased risk of BE was observed with NQO1 Ser-609 minor allele (OR = 0.22, 95% CI 0.07-0.76, P = 0.01).	('Ser-609 minor allele', 'Var', (87, 107))	('Ser', 'Chemical', 'MESH:D012694', (87, 90))	('NQO1', 'Gene', (82, 86))	('NQO1', 'Gene', '1728', (82, 86))	('decreased', 'NegReg', (43, 52))
263038	19222528	NAT1 variants have also been associated with lung and breast cancer.	('breast cancer', 'Disease', (54, 67))	('lung', 'Disease', (45, 49))	('NAT1', 'Gene', '9', (0, 4))	('NAT1', 'Gene', (0, 4))	('variants', 'Var', (5, 13))	('associated', 'Reg', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
263040	19222528	Combinations of nucleotide insertions/deletions and substitutions result in more than 24 different allelic variants in humans.	('substitutions', 'Var', (52, 65))	('insertions/deletions', 'Var', (27, 47))	('humans', 'Species', '9606', (119, 125))	('nucleotide insertions/deletions', 'Var', (16, 47))	('result in', 'Reg', (66, 75))
263041	19222528	NAT1*3 (C1095A), NAT1*4 (wild-type referent), NAT1*10 (T1088A, C1095A), and NAT1*11 (Val149Ile, Ser214Ala) are the most commonly examined polymorphisms in the literature.	('NAT1', 'Gene', (17, 21))	('T1088A', 'Mutation', 'c.1088T>A', (55, 61))	('C1095A', 'Var', (8, 14))	('C1095A', 'Mutation', 'c.1095C>A', (63, 69))	('NAT1', 'Gene', '9', (0, 4))	('Ser214Ala', 'Var', (96, 105))	('Ser214Ala', 'SUBSTITUTION', 'None', (96, 105))	('NAT1', 'Gene', '9', (46, 50))	('C1095A', 'Var', (63, 69))	('Val149Ile', 'Mutation', 'rs4987076', (85, 94))	('NAT1', 'Gene', (0, 4))	('NAT1*4', 'Gene', '57106;9;10;51126', (17, 23))	('T1088A', 'Var', (55, 61))	('NAT1*4', 'Gene', (17, 23))	('NAT1', 'Gene', (46, 50))	('Val149Ile', 'Var', (85, 94))	('NAT1', 'Gene', '9', (76, 80))	('NAT1', 'Gene', '9', (17, 21))	('C1095A', 'Mutation', 'c.1095C>A', (8, 14))	('NAT1', 'Gene', (76, 80))
263042	19222528	Because of the variant polyadenylation signal, NAT1*10 is associated with increased N-acetyltransferase activity in the colon, liver, and bladder.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('activity', 'MPA', (104, 112))	('variant', 'Var', (15, 22))	('NAT1', 'Gene', '9', (47, 51))	('NAT1', 'Gene', (47, 51))	('increased', 'PosReg', (74, 83))	('N-acetyltransferase', 'Enzyme', (84, 103))
263044	19222528	We identified only one study that examined NAT1 variants, which only examined cases with EAC (Fig.	('NAT1', 'Gene', (43, 47))	('variants', 'Var', (48, 56))	('NAT1', 'Gene', '9', (43, 47))	('EAC', 'Disease', (89, 92))
263051	19222528	There are two variants of the GSTP1 gene, Ile105Val and Ala114 Val, and both produce decreased levels of enzymatic activity.	('Ala114 Val', 'Var', (56, 66))	('decreased', 'NegReg', (85, 94))	('GSTP1', 'Gene', (30, 35))	('levels of enzymatic activity', 'MPA', (95, 123))	('Ile105Val', 'Chemical', '-', (42, 51))	('Ala114 Val', 'Mutation', 'rs1138272', (56, 66))	('GSTP1', 'Gene', '2950', (30, 35))	('Ile105Val', 'Var', (42, 51))
263053	19222528	GSTT1 and GSTM1 both have homozygous deletion polymorphisms (GSTT1 null and GSTM1 null) that result in loss of enzymatic activity.	('GSTM1', 'Gene', (10, 15))	('enzymatic activity', 'MPA', (111, 129))	('GSTT1', 'Gene', (61, 66))	('GSTM1', 'Gene', (76, 81))	('GSTT1', 'Gene', '2952', (0, 5))	('GSTT1', 'Gene', '2952', (61, 66))	('GSTT1', 'Gene', (0, 5))	('deletion polymorphisms', 'Var', (37, 59))	('GSTM1', 'Gene', '2944', (10, 15))	('loss', 'NegReg', (103, 107))	('GSTM1', 'Gene', '2944', (76, 81))
263054	19222528	GSTM3, which is in tight disequilibrium with GSTM1, has a 3 bp deletion mutation on intron 6 that similarly results in a loss of function.	('GSTM1', 'Gene', (45, 50))	('loss', 'NegReg', (121, 125))	('deletion mutation', 'Var', (63, 80))	('GSTM3', 'Gene', (0, 5))	('GSTM3', 'Gene', '2947', (0, 5))	('GSTM1', 'Gene', '2944', (45, 50))
263061	19222528	The pooled estimator suggested that carriage of the minor or 'high-risk' allele for GSTP1 results in modest excess risk of EAC (OREAC = 1.20, 95% CI 0.94-1.54).	("'high-risk'", 'PosReg', (61, 72))	('GSTP1', 'Gene', '2950', (84, 89))	('EAC', 'Disease', (123, 126))	('GSTP1', 'Gene', (84, 89))	('carriage', 'Var', (36, 44))
263064	19222528	Three studies also examined the GSTM1 null variants in BE cases, which included 245 BE cases compared with 515 controls.	('GSTM1', 'Gene', (32, 37))	('variants', 'Var', (43, 51))	('examined', 'Reg', (19, 27))	('GSTM1', 'Gene', '2944', (32, 37))
263070	19222528	While other review studies have examined genetic variants in esophageal squamous cell carcinoma or in unspecified esophageal cancer, little work has focused in EAC or BE.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('esophageal squamous cell carcinoma', 'Disease', (61, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('unspecified', 'Species', '32644', (102, 113))	('variants', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (61, 95))
263072	19222528	We found that carriage of GSTP1 Val105 allele was associated with a modest increase in the risk of having BE (ORBE = 1.50, 95% CI 1.16-1.95), and was also a suggestive factor in the risk of EAC (OREAC = 1.20, 95% CI 0.94-1.54).	('GSTP1', 'Gene', '2950', (26, 31))	('GSTP1', 'Gene', (26, 31))	('EAC', 'Disease', (190, 193))	('Val105', 'Var', (32, 38))
263076	19222528	While the mechanism by which an amino acid change from isoleucine to valine in the GSTP1 gene affects EAC or BE susceptibility is unknown, the resulting conformational change may affect the enzyme-binding site, thus changing substrate stability.	('BE susceptibility', 'MPA', (109, 126))	('affect', 'Reg', (179, 185))	('valine', 'Chemical', 'MESH:D014633', (69, 75))	('substrate stability', 'MPA', (225, 244))	('isoleucine', 'Chemical', 'MESH:D007532', (55, 65))	('enzyme-binding site', 'MPA', (190, 209))	('GSTP1', 'Gene', (83, 88))	('changing', 'Reg', (216, 224))	('conformational', 'MPA', (153, 167))	('amino acid change', 'Var', (32, 49))	('GSTP1', 'Gene', '2950', (83, 88))	('affects', 'Reg', (94, 101))	('EAC', 'MPA', (102, 105))	('isoleucine', 'Var', (55, 65))
263078	19222528	The second most frequently examined SNPs were the deletion polymorphisms GSTM1 null and GSTT1 null.	('GSTT1', 'Gene', '2952', (88, 93))	('N', 'Chemical', 'MESH:D009584', (37, 38))	('GSTT1', 'Gene', (88, 93))	('GSTM1', 'Gene', (73, 78))	('deletion polymorphisms', 'Var', (50, 72))	('GSTM1', 'Gene', '2944', (73, 78))
263081	19222528	GSTM3 gene is in tight disequilibrium with the GSTM1, and the GSTM3*B variant has been suggested to modify the GSTM1 enzyme expression, thereby effecting susceptibility to some cancers like basal cell carcinoma.	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (190, 210))	('GSTM3', 'Gene', '2947', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('GSTM1', 'Gene', '2944', (111, 116))	('GSTM1', 'Gene', '2944', (47, 52))	('basal cell carcinoma', 'Disease', (190, 210))	('variant', 'Var', (70, 77))	('GSTM3', 'Gene', '2947', (62, 67))	('modify', 'Reg', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('GSTM3', 'Gene', (0, 5))	('enzyme', 'Enzyme', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('GSTM1', 'Gene', (111, 116))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (190, 210))	('effecting susceptibility', 'Reg', (144, 168))	('GSTM1', 'Gene', (47, 52))	('expression', 'MPA', (124, 134))	('GSTM3', 'Gene', (62, 67))
263084	19222528	Sufficient studies also existed to meta-analyze one of the gene variants in the CYP1A in EAC cases.	('CYP', 'Gene', '4051', (80, 83))	('CYP', 'Gene', (80, 83))	('variants', 'Var', (64, 72))	('EAC cases', 'Disease', (89, 98))
263085	19222528	We found that the CYP1A1 Val462 allele effect was neither strong nor significant for EAC (OR = 0.89, 95% CI 0.40-1.97) or BE.	('Val462', 'Var', (25, 31))	('CYP1A1', 'Gene', (18, 24))	('Val462', 'Chemical', '-', (25, 31))	('CYP1A1', 'Gene', '1543', (18, 24))	('EAC', 'Disease', (85, 88))
263087	19222528	suggested a possible relationship between CYP1A1 Ile462/Val462 and esophageal squamous cell carcinoma, citing that seven studies showed an OR > 1.0.	('CYP1A1', 'Gene', '1543', (42, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (67, 101))	('Val462', 'Chemical', '-', (56, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('Ile462/Val462', 'Var', (49, 62))	('esophageal squamous cell carcinoma', 'Disease', (67, 101))	('CYP1A1', 'Gene', (42, 48))
263090	19222528	Other phase I and phase II enzymes investigated in the literature, CYP1A1 MspI, EPHX1 His113Tyr (EH3) or EPHX1 Arg139His (EH4), and NAT1*10, NAT1*11 alleles, were not available in sufficient numbers to meta-analyze, being only identified in one or two studies.	('EPHX1', 'Gene', (105, 110))	('EPHX1', 'Gene', '2052', (80, 85))	('Arg139His', 'Var', (111, 120))	('CYP1A1', 'Gene', (67, 73))	('EH3', 'Gene', '79852', (97, 100))	('His113Tyr', 'Mutation', 'rs1051740', (86, 95))	('His113Tyr', 'Var', (86, 95))	('EPHX1', 'Gene', '2052', (105, 110))	('CYP1A1', 'Gene', '1543', (67, 73))	('EH3', 'Gene', (97, 100))	('EH4', 'Gene', '253152', (122, 125))	('Arg139His', 'SUBSTITUTION', 'None', (111, 120))	('EPHX1', 'Gene', (80, 85))	('EH4', 'Gene', (122, 125))	('NAT1', 'Gene', '9', (141, 145))	('NAT1', 'Gene', '9', (132, 136))	('NAT1', 'Gene', (132, 136))	('NAT1', 'Gene', (141, 145))
263096	19222528	Our meta-analysis identified GSTP1 Val105 as a possible determinant of increased BE risk and may also effect the risk of EAC.	('EAC', 'Disease', (121, 124))	('GSTP1', 'Gene', '2950', (29, 34))	('Val105', 'Var', (35, 41))	('GSTP1', 'Gene', (29, 34))	('effect', 'Reg', (102, 108))
263098	19222528	Future research could also involve more diverse populations, such as women and different racial group, and include more or newly identified variants in the phase I and phase II metabolic pathways.	('women', 'Species', '9606', (69, 74))	('variants', 'Var', (140, 148))	('phase II metabolic pathways', 'Pathway', (168, 195))
263099	19222528	Begg's funnel plot of log odds ratios and pseudo 95% confidence intervals for studies evaluating associations between GSTP1Ile105Val single-nucleotide polymorphism and esophageal adenocarcinoma.	('GSTP1Ile105Val', 'Gene', (118, 132))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (168, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('single-nucleotide polymorphism', 'Var', (133, 163))	('esophageal adenocarcinoma', 'Disease', (168, 193))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (168, 193))
263100	19222528	Begg's funnel plot of unadjusted odds ratios and corresponding 95% confidence intervals for studies evaluating associations between GSTP1Ile105Val SNP and Barrett's esophagus.	('N', 'Chemical', 'MESH:D009584', (148, 149))	("Barrett's esophagus", 'Disease', (155, 174))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (155, 174))	('GSTP1Ile105Val', 'Var', (132, 146))
263101	19222528	Begg's funnel plot of log odds ratios and pseudo 95% confidence intervals for studies evaluating associations between GSTM1null variant and esophageal adenocarcinoma.	('variant', 'Var', (128, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('GSTM1', 'Gene', '2944', (118, 123))	('GSTM1', 'Gene', (118, 123))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (140, 165))	('esophageal adenocarcinoma', 'Disease', (140, 165))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (140, 165))
263102	19222528	Begg's funnel plot of log odds ratios and pseudo 95% confidence intervals for studies evaluating associations between GSTM1null variant and Barrett's esophagus.	('variant', 'Var', (128, 135))	('GSTM1', 'Gene', '2944', (118, 123))	('GSTM1', 'Gene', (118, 123))	("Barrett's esophagus", 'Disease', (140, 159))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (140, 159))
263103	19222528	Begg's funnel plot of log odds ratios and pseudo 95% confidence intervals for studies evaluating associations between GSTT1null variant and esophageal adenocarcinoma.	('GSTT1', 'Gene', '2952', (118, 123))	('variant', 'Var', (128, 135))	('GSTT1', 'Gene', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (140, 165))	('esophageal adenocarcinoma', 'Disease', (140, 165))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (140, 165))
263104	19222528	Begg's funnel plot of log odds ratios and pseudo 95% confidence intervals for studies evaluating associations between GSTT1null variant and Barrett's esophagus.	('GSTT1', 'Gene', '2952', (118, 123))	('variant', 'Var', (128, 135))	('GSTT1', 'Gene', (118, 123))	("Barrett's esophagus", 'Disease', (140, 159))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (140, 159))
263121	23423151	On the other hand, clinical series seem to use additional ablative modalities, like radiofrequency energy or argon plasma coagulation (APC), to ablate residual BE after the initial PDT treatment.	('APC', 'Disease', (135, 138))	('BE', 'Phenotype', 'HP:0100580', (160, 162))	('residual BE', 'MPA', (151, 162))	('argon', 'Chemical', 'MESH:D001128', (109, 114))	('ablate', 'Var', (144, 150))	('APC', 'Disease', 'MESH:D011125', (135, 138))
263216	23423151	Progression to cancer was seen in 1.2% in the RFA group compared to 9.3% in the control group (p<0.05).	('cancer', 'Disease', (15, 21))	('RFA', 'Var', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('to 9', 'Species', '1214577', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
263360	33330609	Blood test analysis showed hemoglobin 12.4 g/dL (n.v. 14-18 g/d/L), albumin 3.6 g/dL (n.v. 3.5-5.2 g/dL), Ca19.9 120 U/mL (n.v. <37 U/mL), CEA 12 ng/mL (n.v. <5 ng/mL).	('CEA', 'MPA', (139, 142))	('Ca19.9 120 U/mL', 'Var', (106, 121))	('Ca19.9', 'CellLine', 'CVCL:X558', (106, 112))	('hemoglobin', 'MPA', (27, 37))
263376	33330609	understood the common genetic signature of rhabdoid tumors: mutations involving the SMARCB1 (INI1) gene or, rarely, the SMARCA4 gene, which encode proteins that are components of the chromatin remodeling complex SWI/SNF.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('SMARCA4', 'Gene', (120, 127))	('rhabdoid tumors', 'Disease', (43, 58))	('SMARCA4', 'Gene', '6597', (120, 127))	('INI1', 'Gene', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('SMARCB1', 'Gene', '6598', (84, 91))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (43, 58))	('SMARCB1', 'Gene', (84, 91))	('mutations', 'Var', (60, 69))	('INI1', 'Gene', '6598', (93, 97))
263439	33298095	T factors classified the following; Tis: high-grade dysplasia, T1: invasion into the lamina propria, muscularis mucosae, or submucosa, T2: invasion into the muscularis propria, T3: invasion into the adventitia, T4a: invades resectable adjacent structures (pleura, pericardium, diaphragm), and T4b: invades unresectable adjacent structures (aorta, vertebral body, trachea).	('dysplasia', 'Disease', (52, 61))	('muscularis propria', 'Phenotype', 'HP:0030936', (157, 175))	('adventitia', 'Disease', (199, 209))	('T4a', 'Var', (211, 214))	('invades', 'Reg', (298, 305))	('invades', 'Reg', (216, 223))	('T4b', 'Var', (293, 296))	('dysplasia', 'Disease', 'MESH:C536170', (52, 61))	('adventitia', 'Disease', 'None', (199, 209))
263481	33298095	In the present study, although we selected only two groups of patients with or without psychological distress at all times for the perioperative period, we were able to describe that patients with psychological distress at all times had a significantly lower and unhealthier level of functioning in almost all the functional scales, and a higher level of symptomatology or problems in almost all the symptom scales than the patients without psychological distress.	('problems', 'Reg', (373, 381))	('patients', 'Species', '9606', (424, 432))	('higher', 'PosReg', (339, 345))	('patients', 'Species', '9606', (62, 70))	('psychological distress', 'Var', (197, 219))	('lower', 'NegReg', (253, 258))	('patients', 'Species', '9606', (183, 191))
263537	31050820	Further datasets included were from colorectal (GSE38832), breast (GSE58812) and lung cancer samples (GSE31210).	('lung cancer', 'Disease', (81, 92))	('colorectal', 'Disease', 'MESH:D015179', (36, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('breast', 'Disease', (59, 65))	('GSE31210', 'Var', (102, 110))	('GSE38832', 'Var', (48, 56))	('GSE58812', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal', 'Disease', (36, 46))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))
263567	31050820	Bearing in mind the heterogeneous nature of genomic alterations in this cancer and the relatively small sample size with WGS available,22 there was no demonstrable difference between the three subtypes with regards to the overall mutational burden and the profile of copy number aberrations and amplifications or deletions (Supporting Information Fig.	('amplifications', 'Var', (295, 309))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('deletions', 'Var', (313, 322))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
263704	30333404	The model including age >=68 years, creatinine level >=0.71 mg/dL and CRP level >=1.30 mg/dL showed the best discriminative ability (highest AUROC and lowest -2LL).	('>=0.71', 'Var', (53, 59))	('creatinine level', 'MPA', (36, 52))	('CRP', 'Gene', '1401', (70, 73))	('lowest', 'NegReg', (151, 157))	('>=1.30', 'Var', (80, 86))	('creatinine', 'Chemical', 'MESH:D003404', (36, 46))	('CRP', 'Gene', (70, 73))
263707	30333404	In Child-Pugh C patients, the 6-week mortality was associated with CRP >=1.30 mg/dL (19% vs. 73%, respectively, for <1.30 and >=1.30 mg/dL, p<0.0001).	('CRP', 'Gene', (67, 70))	('>=1.30 mg/dL', 'Var', (71, 83))	('patients', 'Species', '9606', (16, 24))	('CRP', 'Gene', '1401', (67, 70))	('Child', 'Species', '9606', (3, 8))
263711	30333404	Patients with CRP levels >=1.30 mg/dL also more frequently had HCC (p=0.001) and PVT (p=0.002) than those with a CRP level <1.30 mg/dL.	('CRP', 'Gene', '1401', (14, 17))	('PVT', 'Disease', (81, 84))	('PVT', 'Phenotype', 'HP:0030242', (81, 84))	('HCC', 'Gene', (63, 66))	('HCC', 'Phenotype', 'HP:0001402', (63, 66))	('CRP', 'Gene', (113, 116))	('>=1.30 mg/dL', 'Var', (25, 37))	('Patients', 'Species', '9606', (0, 8))	('CRP', 'Gene', '1401', (113, 116))	('HCC', 'Gene', '619501', (63, 66))	('CRP', 'Gene', (14, 17))
263754	30333404	In Child-Pugh class C patients with CRP levels >=1.30 mg/dL, variceal bleeding should be considered a fatal event.	('CRP', 'Gene', (36, 39))	('bleeding', 'Disease', (70, 78))	('CRP', 'Gene', '1401', (36, 39))	('patients', 'Species', '9606', (22, 30))	('Child', 'Species', '9606', (3, 8))	('>=1.30', 'Var', (47, 53))	('bleeding', 'Disease', 'MESH:D006470', (70, 78))
263759	30333404	However, the TIPS procedure is not commonly performed in Japan due to the disadvantages associated with TIPS, such as an increased incidence of encephalopathy, that may not be outweighed by their advantages.	('encephalopathy', 'Phenotype', 'HP:0001298', (144, 158))	('encephalopathy', 'Disease', (144, 158))	('encephalopathy', 'Disease', 'MESH:D001927', (144, 158))	('TIPS', 'Var', (104, 108))
263791	30049286	The presence of deregulated EGFR-tyrosine kinase (TK) has been confirmed in many types of solid tumors, such as head and neck cancers, colorectal cancers, non-small cell lung cancers, and breast cancers.	('solid tumors', 'Disease', 'MESH:D009369', (90, 102))	('breast cancers', 'Disease', 'MESH:D001943', (188, 202))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('breast cancers', 'Disease', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancers', 'Phenotype', 'HP:0003002', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('non-small cell lung cancers', 'Disease', (155, 182))	('EGFR-tyrosine kinase', 'Gene', '7294', (28, 48))	('head and neck cancers', 'Phenotype', 'HP:0012288', (112, 133))	('lung cancers', 'Phenotype', 'HP:0100526', (170, 182))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (155, 182))	('colorectal cancers', 'Disease', 'MESH:D015179', (135, 153))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('deregulated', 'Var', (16, 27))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('neck cancers', 'Disease', (121, 133))	('EGFR-tyrosine kinase', 'Gene', (28, 48))	('solid tumors', 'Disease', (90, 102))	('neck cancers', 'Disease', 'MESH:D006258', (121, 133))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (159, 182))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('TK', 'Gene', '7294', (50, 52))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (155, 182))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('colorectal cancers', 'Disease', (135, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
263845	30049286	1c, the gefitinib-resistance induced specific morphological changes, including loss of cell polarity causing spindle-like cell morphology, increased intercellular separation signifying loss of intercellular adhesion, and increased formation of pseudopodia.	('loss', 'NegReg', (79, 83))	('gefitinib-resistance', 'Var', (8, 28))	('spindle-like cell morphology', 'CPA', (109, 137))	('increased', 'PosReg', (221, 230))	('increased', 'PosReg', (139, 148))	('cell polarity', 'CPA', (87, 100))	('gefitinib', 'Chemical', 'MESH:D000077156', (8, 17))	('formation', 'CPA', (231, 240))	('intercellular separation', 'CPA', (149, 173))	('loss', 'NegReg', (185, 189))	('intercellular adhesion', 'CPA', (193, 215))
263852	30049286	Experimental validation using RT-qPCR showed that STAT1 expression was upregulated in gefitinib-resistant cells when compared to parental cells at both transcript and protein levels (Fig.	('STAT1', 'Gene', '6772', (50, 55))	('gefitinib', 'Chemical', 'MESH:D000077156', (86, 95))	('expression', 'MPA', (56, 66))	('STAT1', 'Gene', (50, 55))	('gefitinib-resistant', 'Var', (86, 105))	('upregulated', 'PosReg', (71, 82))
263862	30049286	Compared with the response of the control group, silencing lncRNA PART1 promoted the cytotoxicity induced by gefitinib treatment (1 muM) (Fig.	('silencing', 'Var', (49, 58))	('muM', 'Gene', '56925', (132, 135))	('cytotoxicity', 'Disease', (85, 97))	('lncRNA PART1', 'Gene', (59, 71))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('muM', 'Gene', (132, 135))	('gefitinib', 'Chemical', 'MESH:D000077156', (109, 118))	('promoted', 'PosReg', (72, 80))
263863	30049286	Moreover, knockdown of PART1 resulted in a significant decreased IC50 and repressed anchorage-independent growth upon gefitinib treatment (Fig.	('repressed anchorage-independent growth', 'CPA', (74, 112))	('IC50', 'MPA', (65, 69))	('gefitinib', 'Chemical', 'MESH:D000077156', (118, 127))	('decreased', 'NegReg', (55, 64))	('PART1', 'Gene', (23, 28))	('knockdown', 'Var', (10, 19))
263864	30049286	In addition, flow cytometry analysis indicated that PART1 silencing significantly promoted the proportion of apoptotic cells following treatment with gefitinib in both the resistant cell lines (Fig.	('gefitinib', 'Chemical', 'MESH:D000077156', (150, 159))	('PART1', 'Gene', (52, 57))	('promoted', 'PosReg', (82, 90))	('silencing', 'Var', (58, 67))
263890	30049286	By cloning wild or mutant 3'-UTR of Bcl-2 and PART1 downstream into PGL4 luciferase reporters (Fig.	('PGL4', 'Gene', '6390', (68, 72))	('mutant', 'Var', (19, 25))	('PGL4', 'Gene', (68, 72))
263893	30049286	A RIP experiment also revealed that the overexpression of PART1 inhibited the interaction between miR-129 and Bcl-2, and silencing PART1 increased this effect (Fig.	('silencing', 'Var', (121, 130))	('Bcl-2', 'Protein', (110, 115))	('miR', 'Gene', '220972', (98, 101))	('overexpression', 'PosReg', (40, 54))	('inhibited', 'NegReg', (64, 73))	('PART1', 'Gene', (131, 136))	('miR', 'Gene', (98, 101))	('increased', 'PosReg', (137, 146))	('interaction', 'Interaction', (78, 89))
263912	30049286	Based on the cut-offs established by ROC (0.1103), the proportion of patients not responding to gefitinib therapy was significantly higher in the high exosomal PART1 expressing group than in the low expressing group (Fig.	('higher', 'PosReg', (132, 138))	('gefitinib', 'Chemical', 'MESH:D000077156', (96, 105))	('high exosomal', 'Var', (146, 159))	('patients', 'Species', '9606', (69, 77))
263922	30049286	EGFR mutations occur more frequently in Asian patients compared with Caucasian patients.	('patients', 'Species', '9606', (46, 54))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (79, 87))	('Asian', 'Disease', (40, 45))	('EGFR', 'Gene', '1956', (0, 4))
263925	30049286	Therefore, breakthroughs are needed in the understanding and treatment of acquired gefitinib resistance, especially for patients with EGFR mutations and ALK rearrangement-positive sites.	('ALK', 'Gene', (153, 156))	('EGFR', 'Gene', (134, 138))	('gefitinib', 'Chemical', 'MESH:D000077156', (83, 92))	('mutations', 'Var', (139, 148))	('ALK', 'Gene', '238', (153, 156))	('patients', 'Species', '9606', (120, 128))	('EGFR', 'Gene', '1956', (134, 138))
263932	30049286	PART1 is activated by the transcription factor STAT1 and inhibition of PART1 could resensitize resistant cells to gefitinib treatment, indicating that PART1 is essential for the maintenance of a gefitinib-resistant status in ESCC cells.	('STAT1', 'Gene', '6772', (47, 52))	('gefitinib', 'Chemical', 'MESH:D000077156', (195, 204))	('inhibition', 'Var', (57, 67))	('gefitinib', 'Chemical', 'MESH:D000077156', (114, 123))	('PART1', 'Gene', (71, 76))	('STAT1', 'Gene', (47, 52))
263949	27902974	We found that the knockdown of NHE1 in ESCC cells inhibited apoptosis and promoted cell proliferation, migration, and invasion and showed increases in Snail, beta-catenin, and activation of PI3K-AKT signaling, which was consistent with the results obtained from microarrays.	('AKT', 'Gene', (195, 198))	('promoted', 'PosReg', (74, 82))	('knockdown', 'Var', (18, 27))	('beta-catenin', 'Gene', (158, 170))	('beta-catenin', 'Gene', '1499', (158, 170))	('increases', 'PosReg', (138, 147))	('cell proliferation', 'CPA', (83, 101))	('apoptosis', 'CPA', (60, 69))	('NHE1', 'Gene', (31, 35))	('AKT', 'Gene', '207', (195, 198))	('Snail', 'Gene', (151, 156))	('Snail', 'Gene', '6615', (151, 156))	('NHE1', 'Gene', '6548', (31, 35))	('invasion', 'CPA', (118, 126))	('activation', 'PosReg', (176, 186))	('inhibited', 'NegReg', (50, 59))	('migration', 'CPA', (103, 112))
263950	27902974	Microarrays results suggested that the knockdown of NHE1 suppressed Notch signaling pathway.	('Notch', 'Gene', (68, 73))	('knockdown', 'Var', (39, 48))	('NHE1', 'Gene', (52, 56))	('NHE1', 'Gene', '6548', (52, 56))	('Notch', 'Gene', '4851;4854', (68, 73))	('suppressed', 'NegReg', (57, 67))
263961	27902974	showed that epidermal growth factor upregulated the expression of NHE1 and promoted cervical cancer cell invasiveness, and high expression level of NHE1 was associated with poor clinical outcomes in cervical cancer.	('upregulated', 'PosReg', (36, 47))	('associated', 'Reg', (157, 167))	('cervical cancer', 'Disease', 'MESH:D002583', (84, 99))	('promoted', 'PosReg', (75, 83))	('cervical cancer', 'Disease', (84, 99))	('NHE1', 'Gene', (66, 70))	('high', 'Var', (123, 127))	('epidermal growth factor', 'Gene', (12, 35))	('NHE1', 'Gene', (148, 152))	('expression', 'MPA', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('NHE1', 'Gene', '6548', (66, 70))	('cervical cancer', 'Disease', 'MESH:D002583', (199, 214))	('NHE1', 'Gene', '6548', (148, 152))	('epidermal growth factor', 'Gene', '1950', (12, 35))	('cervical cancer', 'Disease', (199, 214))
263976	27902974	These results indicate that suppression of NHE1 expression promote cell proliferation and inhibit apoptosis.	('inhibit', 'NegReg', (90, 97))	('apoptosis', 'CPA', (98, 107))	('NHE1', 'Gene', '6548', (43, 47))	('promote', 'PosReg', (59, 66))	('cell proliferation', 'CPA', (67, 85))	('suppression', 'Var', (28, 39))	('NHE1', 'Gene', (43, 47))
263980	27902974	These results suggest that knockdown of NHE1 activates PI3K-AKT signaling in ESCC cells.	('knockdown', 'Var', (27, 36))	('activates', 'PosReg', (45, 54))	('NHE1', 'Gene', (40, 44))	('AKT', 'Gene', '207', (60, 63))	('AKT', 'Gene', (60, 63))	('NHE1', 'Gene', '6548', (40, 44))
263982	27902974	Knockdown of NHE1 increased expression of p53 in TE5 cells (Figure 1E).Inhibition of apoptosis by knockdown of NHE1 was greater in TE5 cells than in TE2 cells (Figure 1D).	('p53', 'Gene', (42, 45))	('NHE1', 'Gene', '6548', (13, 17))	('p53', 'Gene', '7157', (42, 45))	('knockdown', 'Var', (98, 107))	('apoptosis', 'CPA', (85, 94))	('TE2', 'Gene', '8260', (149, 152))	('NHE1', 'Gene', (111, 115))	('NHE1', 'Gene', '6548', (111, 115))	('.Inhibition', 'NegReg', (70, 81))	('TE2', 'Gene', (149, 152))	('NHE1', 'Gene', (13, 17))
263988	27902974	These results indicated that downregulation of NHE1 promotes cell migration and invasion in ESCC cells by upregulating EMT markers, particularly Snail and beta-catenin.	('beta-catenin', 'Gene', (155, 167))	('NHE1', 'Gene', (47, 51))	('invasion', 'CPA', (80, 88))	('NHE1', 'Gene', '6548', (47, 51))	('upregulating', 'PosReg', (106, 118))	('beta-catenin', 'Gene', '1499', (155, 167))	('promotes', 'PosReg', (52, 60))	('cell migration', 'CPA', (61, 75))	('downregulation', 'Var', (29, 43))	('Snail', 'Gene', '6615', (145, 150))	('Snail', 'Gene', (145, 150))
263990	27902974	The results of the microarray analysis showed that the expression levels of 6219 genes displayed fold changes of > 1.5 in TE2 cells following the depletion of NHE1.	('TE2', 'Gene', '8260', (122, 125))	('expression levels', 'MPA', (55, 72))	('TE2', 'Gene', (122, 125))	('NHE1', 'Gene', (159, 163))	('depletion', 'Var', (146, 155))	('NHE1', 'Gene', '6548', (159, 163))
263993	27902974	An Ingenuity Pathway Analysis (IPA) showed that "Cancer" was the top-ranked disease and that "Cellular Movement", "Cellular Development", and "Cellular Growth and Proliferation" were some of the top-ranked biological functions related to the depletion of NHE1 (Supplementary Table S2).	('depletion', 'Var', (242, 251))	('NHE1', 'Gene', (255, 259))	('Cellular Movement', 'CPA', (94, 111))	('NHE1', 'Gene', '6548', (255, 259))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancer', 'Disease', (49, 55))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('Development', 'CPA', (124, 135))
263994	27902974	Furthermore, "Colorectal Cancer Metastasis Signaling" and "Regulation of the Epithelial-Mesenchymal Transition Pathway" were two of the top-ranked canonical pathways related to the depletion of NHE1 (Supplementary Table S3).	('NHE1', 'Gene', '6548', (194, 198))	('Colorectal Cancer Metastasis Signaling"', 'Disease', 'MESH:D009362', (14, 53))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Colorectal Cancer Metastasis Signaling"', 'Disease', (14, 53))	('depletion', 'Var', (181, 190))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (14, 31))	('NHE1', 'Gene', (194, 198))	('Epithelial-Mesenchymal Transition Pathway', 'Pathway', (77, 118))
263995	27902974	IPA showed that the top-ranked network related to the knockdown of NHE1 was "Hematological Diseases, Hereditary Disorders, Metabolic Diseases" (Figure 4).	('NHE1', 'Gene', '6548', (67, 71))	('knockdown', 'Var', (54, 63))	('Hereditary Disorders', 'Disease', (101, 121))	('Metabolic Diseases"', 'Disease', (123, 142))	('Metabolic Diseases"', 'Disease', 'MESH:D008659', (123, 142))	('Hereditary Disorders', 'Disease', 'MESH:D030342', (101, 121))	('NHE1', 'Gene', (67, 71))
263999	27902974	The results of the microarray analysis also indicated that Notch signaling was down-regulated by the knockdown of NHE1 (Supplementary Figure S2).	('Notch', 'Gene', '4851;4854', (59, 64))	('Notch', 'Gene', (59, 64))	('down-regulated', 'NegReg', (79, 93))	('NHE1', 'Gene', (114, 118))	('NHE1', 'Gene', '6548', (114, 118))	('knockdown', 'Var', (101, 110))
264003	27902974	These results are consistent with the microarray results and suggest that knockdown of NHE1 suppresses Notch signaling in ESCC cells.	('suppresses', 'NegReg', (92, 102))	('Notch', 'Gene', '4851;4854', (103, 108))	('NHE1', 'Gene', (87, 91))	('Notch', 'Gene', (103, 108))	('knockdown', 'Var', (74, 83))	('NHE1', 'Gene', '6548', (87, 91))
264014	27902974	A multivariate analysis with these four factors revealed that the presence of lymphatic invasion, pathological depth of the tumor and weak expression of NHE1 were independent prognostic factors (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('weak expression', 'Var', (134, 149))	('NHE1', 'Gene', (153, 157))	('lymphatic invasion', 'CPA', (78, 96))	('NHE1', 'Gene', '6548', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
264022	27902974	In normal esophageal epithelial cells, an inhibitor of NHE1 was shown to increase cytoprotective ROS generation, cell viability, and AKT phosphorylation under acid loading.	('esophageal epithelia', 'Disease', 'MESH:D004941', (10, 30))	('increase', 'PosReg', (73, 81))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (10, 30))	('esophageal epithelia', 'Disease', (10, 30))	('AKT', 'Gene', '207', (133, 136))	('NHE1', 'Gene', (55, 59))	('inhibitor', 'Var', (42, 51))	('cytoprotective ROS generation', 'MPA', (82, 111))	('NHE1', 'Gene', '6548', (55, 59))	('ROS', 'Chemical', 'MESH:D000077154', (97, 100))	('AKT', 'Gene', (133, 136))	('cell viability', 'CPA', (113, 127))
264023	27902974	In our in vitro study, the knockdown of NHE1 promoted cell proliferation and inhibited apoptosis and also attenuated staurosporine stimulus-induced apoptosis.	('cell proliferation', 'CPA', (54, 72))	('knockdown', 'Var', (27, 36))	('staurosporine stimulus-induced', 'MPA', (117, 147))	('attenuated', 'NegReg', (106, 116))	('inhibited', 'NegReg', (77, 86))	('promoted', 'PosReg', (45, 53))	('apoptosis', 'CPA', (87, 96))	('staurosporine', 'Chemical', 'MESH:D019311', (117, 130))	('NHE1', 'Gene', (40, 44))	('NHE1', 'Gene', '6548', (40, 44))
264030	27902974	In the present study, we found that the knockdown of NHE1 in ESCC cells promoted cell migration and invasion and increased the expression of Snail and beta-catenin.	('NHE1', 'Gene', '6548', (53, 57))	('expression', 'MPA', (127, 137))	('beta-catenin', 'Gene', '1499', (151, 163))	('beta-catenin', 'Gene', (151, 163))	('knockdown', 'Var', (40, 49))	('invasion', 'CPA', (100, 108))	('increased', 'PosReg', (113, 122))	('Snail', 'Gene', (141, 146))	('Snail', 'Gene', '6615', (141, 146))	('NHE1', 'Gene', (53, 57))	('promoted', 'PosReg', (72, 80))	('cell migration', 'CPA', (81, 95))
264031	27902974	The results of the microarray analysis supported the depletion of NHE1 in TE2 cells inducing EMT transformation.	('depletion', 'Var', (53, 62))	('TE2', 'Gene', (74, 77))	('NHE1', 'Gene', (66, 70))	('NHE1', 'Gene', '6548', (66, 70))	('inducing', 'Reg', (84, 92))	('EMT transformation', 'CPA', (93, 111))	('TE2', 'Gene', '8260', (74, 77))
264033	27902974	Taken together, these results suggest that suppression of NHE1 increases cell migration and invasion by promoting EMT transformation in ESCC cells and, thus, the expression of NHE1 in tissue samples may be a useful prognostic factor and predictor for metastasis.	('increases', 'PosReg', (63, 72))	('promoting', 'PosReg', (104, 113))	('invasion', 'CPA', (92, 100))	('NHE1', 'Gene', (58, 62))	('suppression', 'Var', (43, 54))	('cell migration', 'CPA', (73, 87))	('NHE1', 'Gene', '6548', (58, 62))	('NHE1', 'Gene', (176, 180))	('NHE1', 'Gene', '6548', (176, 180))	('EMT transformation', 'CPA', (114, 132))
264035	27902974	p53 status is different between TE2 cells and TE5 cells and p53 is upregulated by NHE1 knockdown in TE5 cells.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('TE2', 'Gene', (32, 35))	('NHE1', 'Gene', '6548', (82, 86))	('p53', 'Gene', (60, 63))	('p53', 'Gene', '7157', (60, 63))	('TE2', 'Gene', '8260', (32, 35))	('upregulated', 'PosReg', (67, 78))	('NHE1', 'Gene', (82, 86))	('knockdown', 'Var', (87, 96))
264037	27902974	Deletion of p53 upregulates expression of Fascin and vimentin via NF-kappaB signaling, and promotes cell invasion and migration in colorectal cancer cells.	('promotes', 'PosReg', (91, 99))	('Fascin', 'Gene', '6624', (42, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('upregulates', 'PosReg', (16, 27))	('Fascin', 'Gene', (42, 48))	('expression', 'MPA', (28, 38))	('vimentin', 'Gene', '7431', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('p53', 'Gene', (12, 15))	('NF-kappaB', 'MPA', (66, 75))	('cell invasion', 'CPA', (100, 113))	('p53', 'Gene', '7157', (12, 15))	('vimentin', 'Gene', (53, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('colorectal cancer', 'Disease', (131, 148))	('Deletion', 'Var', (0, 8))
264038	27902974	Taken together, p53 status in ESCC cells may relieve EMT transformation by knockdown of NHE1.	('relieve', 'PosReg', (45, 52))	('EMT transformation', 'CPA', (53, 71))	('p53', 'Gene', (16, 19))	('knockdown', 'Var', (75, 84))	('p53', 'Gene', '7157', (16, 19))	('NHE1', 'Gene', (88, 92))	('NHE1', 'Gene', '6548', (88, 92))
264042	27902974	reported that EGFR inhibitors upregulated Notch1, Notch3, and critical transcriptional factors in keratinocyte differentiation and suppressed TGF-beta-induced EMT in the cancer stem-like cells of ESCC.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('Notch1', 'Gene', (42, 48))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('cancer', 'Disease', (170, 176))	('upregulated', 'PosReg', (30, 41))	('TGF-beta-induced', 'Gene', (142, 158))	('Notch1', 'Gene', '4851', (42, 48))	('inhibitors', 'Var', (19, 29))	('keratinocyte differentiation', 'CPA', (98, 126))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('suppressed', 'NegReg', (131, 141))	('Notch3', 'Gene', '4854', (50, 56))	('Notch3', 'Gene', (50, 56))
264043	27902974	In the present study, the results of the microarray analysis revealed that the knockdown of NHE1 down-regulated Notch signaling in TE2 cells.	('NHE1', 'Gene', '6548', (92, 96))	('TE2', 'Gene', '8260', (131, 134))	('TE2', 'Gene', (131, 134))	('Notch', 'Gene', '4851;4854', (112, 117))	('knockdown', 'Var', (79, 88))	('NHE1', 'Gene', (92, 96))	('down-regulated', 'NegReg', (97, 111))	('Notch', 'Gene', (112, 117))
264045	27902974	These results indicate that knockdown of NHE1 leads to EMT transformation through up-regulation of Snail, beta-catenin and other EMT markers by suppression of Notch signaling in ESCC cells.	('suppression', 'NegReg', (144, 155))	('beta-catenin', 'Gene', '1499', (106, 118))	('NHE1', 'Gene', (41, 45))	('Snail', 'Gene', '6615', (99, 104))	('Snail', 'Gene', (99, 104))	('Notch', 'Gene', '4851;4854', (159, 164))	('NHE1', 'Gene', '6548', (41, 45))	('Notch', 'Gene', (159, 164))	('up-regulation', 'PosReg', (82, 95))	('knockdown', 'Var', (28, 37))	('leads to', 'Reg', (46, 54))	('EMT transformation', 'CPA', (55, 73))	('beta-catenin', 'Gene', (106, 118))
264051	27902974	However, we herein found that the knockdown of NHE1 in ESCC cells promoted cell growth, invasion, and migration.	('NHE1', 'Gene', (47, 51))	('NHE1', 'Gene', '6548', (47, 51))	('invasion', 'CPA', (88, 96))	('cell growth', 'CPA', (75, 86))	('migration', 'CPA', (102, 111))	('knockdown', 'Var', (34, 43))	('promoted', 'PosReg', (66, 74))
264054	27902974	Furthermore, activation of NHE1 causes intracellular alkalization, which leads to inhibit BAD and caspases.	('activation', 'Var', (13, 23))	('NHE1', 'Gene', (27, 31))	('inhibit', 'NegReg', (82, 89))	('NHE1', 'Gene', '6548', (27, 31))	('caspases', 'CPA', (98, 106))	('intracellular alkalization', 'MPA', (39, 65))
264057	27902974	In normal esophageal epithelial cells, an inhibitor of NHE1 was found to exert protective effects against a low pH stimulation.	('esophageal epithelia', 'Disease', 'MESH:D004941', (10, 30))	('esophageal epithelia', 'Disease', (10, 30))	('protective effects', 'CPA', (79, 97))	('NHE1', 'Gene', (55, 59))	('inhibitor', 'Var', (42, 51))	('NHE1', 'Gene', '6548', (55, 59))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (10, 30))
264059	27902974	found that the inhibition of NHE1 in human colon cancer cells reduced cisplatin-induced apoptosis triggered by the activation of ASMase and increases in membrane fluidity.	('membrane fluidity', 'MPA', (153, 170))	('increases', 'PosReg', (140, 149))	('activation', 'PosReg', (115, 125))	('cisplatin-induced', 'MPA', (70, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colon cancer', 'Disease', 'MESH:D015179', (43, 55))	('ASMase', 'Gene', (129, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (43, 55))	('colon cancer', 'Disease', (43, 55))	('NHE1', 'Gene', '6548', (29, 33))	('NHE1', 'Gene', (29, 33))	('ASMase', 'Gene', '6609', (129, 135))	('human', 'Species', '9606', (37, 42))	('inhibition', 'Var', (15, 25))	('reduced', 'NegReg', (62, 69))
264060	27902974	In the present study, the effects of the knockdown of NHE1 differed slightly between TE2 and TE5 cells.	('TE2', 'Gene', '8260', (85, 88))	('TE2', 'Gene', (85, 88))	('NHE1', 'Gene', (54, 58))	('knockdown', 'Var', (41, 50))	('NHE1', 'Gene', '6548', (54, 58))
264072	27902974	Cells were detached from the flasks with trypsin-EDTA 72 h after siRNA transfection and were counted using a hemocytometer.	('EDTA', 'Chemical', 'MESH:D004492', (49, 53))	('siRNA', 'Gene', (65, 70))	('transfection', 'Var', (71, 83))
264074	27902974	Expression levels were measured for the following genes: NHE1 (Hs 00300047 m1), Snail (Hs 00195591 m1), beta-catenin (Hs 00355049 m1), vimentin (Hs 00185584 m1), Zeb-1 (Hs 00232783 m1), claudin-1 (Hs 00221623 m1), Notch 1 (Hs 01062014 m1), DTX 4 (Hs 00302288 m1), HES 7 (Hs 00261517 m1), and MAML 2 (Hs 00418423 m1) (Applied Biosystems).	('Hs 00195591 m1', 'Var', (87, 101))	('beta-catenin', 'Gene', (104, 116))	('Expression levels', 'MPA', (0, 17))	('beta-catenin', 'Gene', '1499', (104, 116))	('claudin-1', 'Gene', '9076', (186, 195))	('Snail', 'Gene', '6615', (80, 85))	('Hs 00300047 m1', 'Var', (63, 77))	('Notch 1', 'Gene', '4851', (214, 221))	('Zeb-1', 'Gene', (162, 167))	('MAML 2', 'Gene', (292, 298))	('MAML 2', 'Gene', '84441', (292, 298))	('Hs 00221623 m1', 'Var', (197, 211))	('NHE1', 'Gene', '6548', (57, 61))	('vimentin', 'Gene', '7431', (135, 143))	('Hs 00418423 m1', 'Var', (300, 314))	('vimentin', 'Gene', (135, 143))	('Notch 1', 'Gene', (214, 221))	('Snail', 'Gene', (80, 85))	('claudin-1', 'Gene', (186, 195))	('Hs 00261517 m1', 'Var', (271, 285))	('Hs 00232783 m1', 'Var', (169, 183))	('Hs 00185584 m1', 'Var', (145, 159))	('DTX 4', 'Gene', (240, 245))	('Hs 00355049 m1', 'Var', (118, 132))	('DTX 4', 'Gene', '23220', (240, 245))	('Hs 01062014 m1', 'Var', (223, 237))	('Zeb-1', 'Gene', '6935', (162, 167))	('Hs 00302288 m1', 'Var', (247, 261))	('NHE1', 'Gene', (57, 61))
264130	28103879	However, CSA results in end-to-side anastomosis, in which the circulation net of the gastric wall was blocked by the stapler, causing anastomosis failure.	('anastomosis failure', 'Disease', 'MESH:C563598', (134, 153))	('anastomosis failure', 'Disease', (134, 153))	('CSA', 'Chemical', '-', (9, 12))	('CSA', 'Var', (9, 12))	('end-to-side', 'Disease', (24, 35))
264154	27187365	NAFLD has an intertwined relationship with metabolic syndrome and significantly contributes to the risk of hepatocellular carcinoma (HCC), but recent evidence have fuelled concerns that NAFLD may be a new, and added, risk factor for extra-hepatic cancers, particularly in the gastrointestinal tract.	('gastrointestinal tract', 'Disease', (276, 298))	('NAFLD', 'Var', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (107, 131))	('extra-hepatic cancers', 'Disease', 'MESH:D008113', (233, 254))	('hepatocellular carcinoma', 'Disease', (107, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (107, 131))	('extra-hepatic cancers', 'Disease', (233, 254))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (276, 298))	('HCC', 'Phenotype', 'HP:0001402', (133, 136))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('metabolic syndrome', 'Disease', 'MESH:D008659', (43, 61))	('metabolic syndrome', 'Disease', (43, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
264159	27187365	NAFLD is traditionally considered the hepatic manifestation of metabolic syndrome (MetS) and an impressive body of evidence indicates an increased general risk of cancer in subjects with MetS, particularly in the gastrointestinal tract.	('NAFLD', 'Disease', (0, 5))	('metabolic syndrome', 'Disease', 'MESH:D008659', (63, 81))	('metabolic syndrome', 'Disease', (63, 81))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('gastrointestinal tract', 'Disease', (213, 235))	('MetS', 'Var', (187, 191))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (213, 235))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
264164	27187365	Almost all of the studies showed a higher prevalence of colorectal lesions in patients with NAFLD compared to patients without.	('NAFLD', 'Var', (92, 97))	('patients', 'Species', '9606', (78, 86))	('colorectal lesions', 'Disease', 'MESH:D015179', (56, 74))	('colorectal lesions', 'Disease', (56, 74))	('patients', 'Species', '9606', (110, 118))
264167	27187365	The prevalence of NAFLD was 41.5% in the adenomatous polyp group versus 30.2% in the control group; with multivariate analysis, NAFLD was associated with a three-fold increased risk of colorectal adenomas.	('adenomatous polyp', 'Disease', (41, 58))	('NAFLD', 'Var', (128, 133))	('colorectal adenomas', 'Disease', (185, 204))	('adenomatous polyp', 'Disease', 'MESH:D018256', (41, 58))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (41, 58))	('colorectal adenomas', 'Disease', 'MESH:D015179', (185, 204))
264168	27187365	This preliminary finding was confirmed in a large retrospective cohort study of 5.517 Korean women, where a two-fold increase in the occurrence of adenomatous polyps and a three-fold increase in the risk of colorectal cancer was found in patients with NAFLD compared to controls.	('colorectal cancer', 'Disease', 'MESH:D015179', (207, 224))	('increase', 'PosReg', (117, 125))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (147, 164))	('NAFLD', 'Var', (252, 257))	('adenomatous polyps', 'Disease', (147, 165))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (147, 165))	('adenomatous polyps', 'Disease', 'MESH:D018256', (147, 165))	('women', 'Species', '9606', (93, 98))	('colorectal cancer', 'Disease', (207, 224))	('patients', 'Species', '9606', (238, 246))
264169	27187365	However, the presence of NAFLD had no influence on the prognosis of colorectal cancer and, in particular, on the disease recurrence during follow-up.	('colorectal cancer', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('presence', 'Var', (13, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('NAFLD', 'Gene', (25, 30))
264171	27187365	In a cross-sectional study patients with NAFLD, diagnosed by both proton magnetic resonance spectroscopy and liver biopsy, had a significantly higher rate of colorectal adenomas (34.7% vs. 21.5%) and advanced neoplasms (18.6% vs. 5.5%) than healthy controls.	('neoplasms', 'Disease', (209, 218))	('colorectal adenomas', 'Disease', 'MESH:D015179', (158, 177))	('neoplasm', 'Phenotype', 'HP:0002664', (209, 217))	('patients', 'Species', '9606', (27, 35))	('neoplasms', 'Phenotype', 'HP:0002664', (209, 218))	('higher', 'PosReg', (143, 149))	('colorectal adenomas', 'Disease', (158, 177))	('NAFLD', 'Var', (41, 46))	('neoplasms', 'Disease', 'MESH:D009369', (209, 218))
264175	27187365	In the largest study performed so far in Europe, male patients with NAFLD had significantly more colorectal adenomas and early colorectal cancers compared to those without NAFLD.	('more', 'PosReg', (92, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('colorectal cancers', 'Disease', 'MESH:D015179', (127, 145))	('patients', 'Species', '9606', (54, 62))	('colorectal cancers', 'Disease', (127, 145))	('colorectal adenomas', 'Disease', (97, 116))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('NAFLD', 'Var', (68, 73))	('colorectal adenomas', 'Disease', 'MESH:D015179', (97, 116))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))
264176	27187365	Multivariate regression analysis confirmed an independent association of colorectal adenomas with NAFLD (OR 1.47).	('colorectal adenomas', 'Disease', 'MESH:D015179', (73, 92))	('colorectal adenomas', 'Disease', (73, 92))	('NAFLD', 'Var', (98, 103))
264179	27187365	In contrast, only two studies failed to demonstrate an increased incidence of colorectal adenomas in patients with NAFLD compared to healthy controls.	('NAFLD', 'Var', (115, 120))	('patients', 'Species', '9606', (101, 109))	('colorectal adenomas', 'Disease', 'MESH:D015179', (78, 97))	('colorectal adenomas', 'Disease', (78, 97))
264180	27187365	The first one found a higher burden of adenomas in patients with NAFLD, but data did not reach a statistical significance, probably for the smaller sample size and the younger median age.	('patients', 'Species', '9606', (51, 59))	('NAFLD', 'Var', (65, 70))	('adenomas', 'Disease', (39, 47))	('adenomas', 'Disease', 'MESH:D000236', (39, 47))
264190	27187365	What is currently unknown is whether both NAFLD and visceral obesity are just markers of an increased risk of cancers or also active players in this process.	('visceral obesity', 'Disease', 'MESH:D056128', (52, 68))	('cancers', 'Disease', (110, 117))	('visceral obesity', 'Disease', (52, 68))	('visceral obesity', 'Phenotype', 'HP:0012743', (52, 68))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('NAFLD', 'Var', (42, 47))	('obesity', 'Phenotype', 'HP:0001513', (61, 68))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
264197	27187365	In a meta-analysis performed in 2012, MetS has been identified itself as a neoplastic risk factor, with a RR of 1.58 (p < 0.0001) for pancreatic cancer in female gender, possibly mediated by decreased physical activity, consumption of high-calorie dense foods, high dietary fat intake, low fiber intake, and oxidative stress.	('pancreatic cancer', 'Disease', 'MESH:D010190', (134, 151))	('MetS', 'Var', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (134, 151))	('decreased', 'NegReg', (191, 200))	('pancreatic cancer', 'Disease', (134, 151))	('oxidative stress', 'Phenotype', 'HP:0025464', (308, 324))
264210	27187365	In the first one, NAFLD was found to be protective against neoplastic recurrence after radical prostatectomy for prostate cancer in 293 consecutive patients.	('patients', 'Species', '9606', (148, 156))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('prostate cancer', 'Disease', (113, 128))	('neoplastic recurrence', 'CPA', (59, 80))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('NAFLD', 'Var', (18, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
264211	27187365	The NAFLD group showed significantly longer time-to-recurrence compared with patients without NAFLD both in the training and validation set (hazard ratio: 0.33 and 0.22; 95% CI 0.16-0.69, and 95% CI 0.11-0.43, respectively).	('longer', 'PosReg', (37, 43))	('patients', 'Species', '9606', (77, 85))	('NAFLD', 'Var', (4, 9))
264212	27187365	The second one analyzed the development of malignancies and the specific site of disease in 1600 US-defined NAFLD subjects and in 1600 matched hepatitis C virus (HCV)-infected patients: prostate cancer developed in 12.6% of NAFLD compared to 3.5% in HCV patients, and the incidence of prostate cancer in NAFLD was higher than in the general population.	('hepatitis', 'Phenotype', 'HP:0012115', (143, 152))	('NAFLD', 'Var', (224, 229))	('men', 'Species', '9606', (35, 38))	('prostate cancer', 'Disease', (186, 201))	('patients', 'Species', '9606', (176, 184))	('prostate cancer', 'Disease', 'MESH:D011471', (285, 300))	('malignancies', 'Disease', (43, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (285, 300))	('prostate cancer', 'Disease', 'MESH:D011471', (186, 201))	('HCV', 'Species', '11103', (162, 165))	('hepatitis C virus (HCV)-infected', 'Disease', 'MESH:D006526', (143, 175))	('HCV', 'Species', '11103', (250, 253))	('prostate cancer', 'Phenotype', 'HP:0012125', (186, 201))	('prostate cancer', 'Disease', (285, 300))	('patients', 'Species', '9606', (254, 262))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('malignancies', 'Disease', 'MESH:D009369', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
264217	27187365	These alterations favor the translocation of bacterial metabolites and activation of TLRs via the recognition of microorganism-associated molecular patterns (MAMPs) and can promote tumorigenesis through the reduced release of the inflammasome-derived interleukin 18 (IL-18) and the increased IL-6 signaling which, in turn, protects normal and premalignant cells from apoptosis.	('alterations', 'Var', (6, 17))	('IL-6', 'Gene', '3569', (292, 296))	('tumor', 'Disease', (181, 186))	('release', 'MPA', (215, 222))	('interleukin 18', 'Gene', '3606', (251, 265))	('activation', 'PosReg', (71, 81))	('IL-18', 'Gene', '3606', (267, 272))	('translocation', 'MPA', (28, 41))	('IL-18', 'Gene', (267, 272))	('reduced', 'NegReg', (207, 214))	('IL-6', 'Gene', (292, 296))	('increased IL-6', 'Phenotype', 'HP:0030783', (282, 296))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('TLRs', 'Gene', (85, 89))	('promote', 'PosReg', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('favor', 'PosReg', (18, 23))	('interleukin 18', 'Gene', (251, 265))
264220	27187365	Loss-of-function mutation or knockout mice in TLR4 prevents IR induced by obesity underlying the important role of this receptor in the modulation of the innate immune system.	('Loss-of-function', 'NegReg', (0, 16))	('obesity', 'Phenotype', 'HP:0001513', (74, 81))	('mice', 'Species', '10090', (38, 42))	('obesity', 'Disease', 'MESH:D009765', (74, 81))	('mutation', 'Var', (17, 25))	('obesity', 'Disease', (74, 81))	('TLR4', 'Gene', (46, 50))	('IR', 'Phenotype', 'HP:0000855', (60, 62))
264223	27187365	Through its proliferative and anti-apoptotic effects, this pathway can boost mutations favoring carcinogenesis.	('boost', 'PosReg', (71, 76))	('mutations', 'Var', (77, 86))	('carcinogenesis', 'Disease', (96, 110))	('carcinogenesis', 'Disease', 'MESH:D063646', (96, 110))
264234	27187365	In obese subjects the combination of high leptin and low adiponectin levels may also increase the risk of Barrett's esophagus and esophageal adenocarcinoma by enhanced cell proliferation and reduced apoptosis via extracellular signal-regulated kinase (ERK), p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and Janus kinase-2 (JAK2)-dependent activation of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2).	('COX-2', 'Gene', (372, 377))	('extracellular signal-regulated kinase', 'Gene', (213, 250))	('PGE2', 'Chemical', 'MESH:D015232', (401, 405))	('enhanced', 'PosReg', (159, 167))	('low', 'Var', (53, 56))	('adiponectin', 'Gene', (57, 68))	('obese', 'Disease', 'MESH:D009765', (3, 8))	('extracellular signal-regulated kinase', 'Gene', '5594', (213, 250))	('cyclooxygenase-2', 'Gene', '5743', (354, 370))	('Akt', 'Gene', (299, 302))	('COX-2', 'Gene', '5743', (372, 377))	('low adiponectin levels', 'Phenotype', 'HP:0030685', (53, 75))	('cell proliferation', 'CPA', (168, 186))	('reduced', 'NegReg', (191, 198))	('leptin', 'Gene', '3952', (42, 48))	("Barrett's esophagus", 'Disease', (106, 125))	('Akt', 'Gene', '207', (299, 302))	('leptin', 'Gene', (42, 48))	('JAK2', 'Gene', '3717', (324, 328))	('high', 'Var', (37, 41))	('cyclooxygenase-2', 'Gene', (354, 370))	('adiponectin', 'Gene', '9370', (57, 68))	('ERK', 'Gene', '5594', (252, 255))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (130, 155))	('MAPK', 'Gene', (262, 266))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (106, 125))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (383, 399))	('prostaglandin E2', 'MPA', (383, 399))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (130, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('JAK2', 'Gene', (324, 328))	('high leptin', 'Phenotype', 'HP:0031793', (37, 48))	('Janus kinase-2', 'Gene', (308, 322))	('ERK', 'Gene', (252, 255))	('MAPK', 'Gene', '5594', (262, 266))	('esophageal adenocarcinoma', 'Disease', (130, 155))	('apoptosis', 'CPA', (199, 208))	('Janus kinase-2', 'Gene', '3717', (308, 322))	('activation', 'PosReg', (340, 350))	('obese', 'Disease', (3, 8))
264245	27187365	Beyond the risk of HCC, clearly mediated by NASH, substantial evidence is accumulating for a role of NAFLD as independent risk factor for cancers, particularly in the gastrointestinal tract.	('NAFLD', 'Var', (101, 106))	('HCC', 'Disease', (19, 22))	('gastrointestinal tract', 'Disease', (167, 189))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('HCC', 'Phenotype', 'HP:0001402', (19, 22))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (167, 189))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
264266	27037803	About 10 to 15 % of all duplication cysts in the gastrointestinal tract are esophageal.	('esophageal', 'Disease', (76, 86))	('gastrointestinal tract', 'Disease', (49, 71))	('duplication', 'Var', (24, 35))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (49, 71))
264270	27037803	In 1937, Ladd suggested the use of the term "duplications of the alimentary tract" and applied the term to congenital lesions having three characteristics: (1) the presence of a well-developed coat of smooth muscle, (2) an epithelial lining representing some type of intestinal tract mucosa, and (3) intimate anatomic association with some portion of the gastrointestinal tract.	('gastrointestinal tract', 'Disease', (355, 377))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (355, 377))	('duplications', 'Var', (45, 57))	('congenital lesions', 'Disease', (107, 125))
264287	26970127	The pathophysiology of EA is complex and involves diverse factors, including gastroesophageal reflux, gastric acid secretion, dysfunction of the antireflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms.	('gastric acid secretion', 'MPA', (102, 124))	('abnormalities', 'Var', (200, 213))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (77, 100))	('esophageal reflux', 'Phenotype', 'HP:0002020', (83, 100))	('gastric emptying', 'Phenotype', 'HP:0002578', (165, 181))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (77, 100))	('gastroesophageal reflux', 'Disease', (77, 100))	('gastric emptying disturbances', 'Disease', (165, 194))	('dysfunction', 'Disease', (126, 137))
264290	26970127	If changes in the proposed factors alter the stepwise progression (RE-BE-dysplasia- EA), they may represent potential targets for chemoprevention.	('changes', 'Var', (3, 10))	('stepwise progression', 'CPA', (45, 65))	('alter', 'Reg', (35, 40))	('RE-BE-dysplasia- EA', 'Disease', 'MESH:C535499', (67, 86))	('RE-BE-dysplasia- EA', 'Disease', (67, 86))
264303	26970127	Dysbiosis is a term that describes such microbial alterations that disrupt the symbiotic relationship between the host and the microbiome.	('alterations', 'Var', (50, 61))	('disrupt', 'NegReg', (67, 74))	('Dysbiosis', 'Disease', (0, 9))	('Dysbiosis', 'Disease', 'MESH:D064806', (0, 9))	('symbiotic relationship', 'CPA', (79, 101))
264349	26970127	Furthermore, S. bovis has also been associated with hematopoietic malignancy.	('hematopoietic malignancy', 'Disease', (52, 76))	('S. bovis', 'Species', '1335', (13, 21))	('hematopoietic malignancy', 'Disease', 'MESH:D019337', (52, 76))	('associated', 'Reg', (36, 46))	('hematopoietic malignancy', 'Phenotype', 'HP:0004377', (52, 76))	('S. bovis', 'Var', (13, 21))
264355	26970127	Alterations in MAMPs trigger pattern receptors of innate immunity, including Toll-like receptors (TLR) and/or nucleotide-binding-oligomerization-domain (NOD)-like receptors.	('Alterations', 'Var', (0, 11))	('trigger', 'Reg', (21, 28))	('TLR', 'Gene', (98, 101))	('TLR', 'Gene', '7099', (98, 101))	('MAMPs', 'Gene', (15, 20))
264356	26970127	Stimulating the receptors activates the NF-kappaB pathway and causes expression of cytokines and interleukins.	('NF-kappaB', 'Gene', '4790', (40, 49))	('Stimulating', 'Var', (0, 11))	('NF-kappaB', 'Gene', (40, 49))	('causes', 'Reg', (62, 68))	('activates', 'PosReg', (26, 35))	('expression of cytokines', 'MPA', (69, 92))
264362	26970127	nitrosamine and acetaldehyde), activation of dietary phytochemicals, metabolism of hormones, xenobiotics, and modification of tumor promoting bile acids.	('metabolism', 'MPA', (69, 79))	('nitrosamine', 'Chemical', 'MESH:D009602', (0, 11))	('acetaldehyde', 'Chemical', 'MESH:D000079', (16, 28))	('bile acids', 'Chemical', 'MESH:D001647', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('modification', 'Var', (110, 122))	('activation', 'PosReg', (31, 41))	('tumor', 'Disease', (126, 131))
264383	26970127	Other studies suggest that H. pylori may act as a significant protective factor against EA via a mechanism involving ghrelin, a hormone that stimulates appetite and contributes to the development of obesity.	('H. pylori', 'Var', (27, 36))	('ghrelin', 'Chemical', 'MESH:D054439', (117, 124))	('obesity', 'Phenotype', 'HP:0001513', (199, 206))	('appetite', 'MPA', (152, 160))	('obesity', 'Disease', 'MESH:D009765', (199, 206))	('H. pylori', 'Species', '210', (27, 36))	('stimulates appetite', 'Phenotype', 'HP:0002591', (141, 160))	('obesity', 'Disease', (199, 206))	('ghrelin', 'Protein', (117, 124))	('stimulates', 'PosReg', (141, 151))
264384	26970127	Studies suggest that eradication of H. pylori may result in increased serum levels of ghrelin, which may in turn lead to obesity.	('H. pylori', 'Species', '210', (36, 45))	('obesity', 'Disease', (121, 128))	('eradication', 'Var', (21, 32))	('lead to', 'Reg', (113, 120))	('ghrelin', 'Protein', (86, 93))	('obesity', 'Phenotype', 'HP:0001513', (121, 128))	('serum levels of', 'MPA', (70, 85))	('obesity', 'Disease', 'MESH:D009765', (121, 128))	('H. pylori', 'Gene', (36, 45))	('increased', 'PosReg', (60, 69))	('ghrelin', 'Chemical', 'MESH:D054439', (86, 93))
264386	26970127	There is also evidence that suggests that H. pylori stimulates apoptosis in Barrett's derived EA cells via the Fas-caspase cascade, providing yet another potential mechanism that may account for the possible protective effects of H. pylori.	('H. pylori', 'Species', '210', (230, 239))	('H. pylori', 'Species', '210', (42, 51))	('stimulates', 'PosReg', (52, 62))	('apoptosis', 'CPA', (63, 72))	('H. pylori', 'Var', (42, 51))
264393	26970127	Second, in mice, sub-therapeutic antibiotics consistently increase the relative abundance of Firmicutes at the cost of decreasing the abundance of Bacteroidetes.	('increase', 'PosReg', (58, 66))	('mice', 'Species', '10090', (11, 15))	('Bacteroidetes', 'MPA', (147, 160))	('Firmicutes', 'MPA', (93, 103))	('sub-therapeutic', 'Var', (17, 32))
264426	26970127	In a mouse model, LPS caused a dose-dependent fall in the basal tone.	('basal tone', 'MPA', (58, 68))	('LPS', 'Chemical', 'MESH:D008070', (18, 21))	('LPS', 'Var', (18, 21))	('fall', 'NegReg', (46, 50))	('mouse', 'Species', '10090', (5, 10))	('fall', 'Phenotype', 'HP:0002527', (46, 50))
264451	26970127	Detailed analyses suggest that H. pylori eradication increases the risk for development of RE in patients who have existing risks for BE and EA, such as male gender and hiatal hernia.	('development', 'Disease', (76, 87))	('eradication', 'Var', (41, 52))	('hiatal hernia', 'Disease', 'MESH:D006551', (169, 182))	('H. pylori', 'Gene', (31, 40))	('hernia', 'Phenotype', 'HP:0100790', (176, 182))	('hiatal hernia', 'Disease', (169, 182))	('H. pylori', 'Species', '210', (31, 40))	('hiatal hernia', 'Phenotype', 'HP:0002036', (169, 182))	('BE', 'Chemical', 'MESH:D001608', (134, 136))	('patients', 'Species', '9606', (97, 105))
264511	26970127	Nevertheless, erythromycin has been shown to significantly increase the lower esophageal sphincter (LES) pressure, without affecting the postdeglutition relaxation of LES.	('erythromycin', 'Chemical', 'MESH:D004917', (14, 26))	('erythromycin', 'Var', (14, 26))	('esophageal sphincter', 'Disease', (78, 98))	('esophageal sphincter', 'Disease', 'MESH:D009122', (78, 98))	('increase', 'PosReg', (59, 67))
264558	25572431	The longitudinal gross tumor length of GTVGRAD, GTV1.4 and GTV30%max, were recorded as LGRAD, L1.4 and L30%max, respectively.	('GTV', 'Gene', '9334', (59, 62))	('longitudinal gross tumor', 'Disease', (4, 28))	('L30', 'Var', (103, 106))	('GTV', 'Gene', '9334', (48, 51))	('GTV', 'Gene', (39, 42))	('L1.4', 'Gene', (94, 98))	('longitudinal gross tumor', 'Disease', 'MESH:C536704', (4, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('GTV', 'Gene', (59, 62))	('L1.4', 'Gene', '28900', (94, 98))	('GTV', 'Gene', '9334', (39, 42))	('GTV', 'Gene', (48, 51))
264582	25572431	The correlation coefficients of LGRAD, L1.4, L30%max, LCT with LPath were 0.989 (P < 0.05), 0.920 (P < 0.05), 0.920 (P < 0.05), 0.862 (P < 0.05), respetively.	('LPath', 'Chemical', '-', (63, 68))	('LCT', 'Gene', (54, 57))	('L1.4', 'Gene', (39, 43))	('LCT', 'Gene', '3938', (54, 57))	('L1.4', 'Gene', '28900', (39, 43))	('L30', 'Var', (45, 48))
264612	25572431	While conformality and homogeneity of the two groups of PTVs were similar, planGRAD resulted in significantly lower organ at risk doses than planCT.	('organ', 'MPA', (116, 121))	('PTV', 'Chemical', '-', (56, 59))	('lower', 'NegReg', (110, 115))	('planGRAD', 'Var', (75, 83))
264629	25663943	The following dosimetric parameters were generated from the total lung DVH: mean dose, V5, V10, V15, V20, V30, V40, V45 and V50.	('V50', 'Var', (124, 127))	('V15', 'Gene', '28814', (96, 99))	('V20', 'Var', (101, 104))	('V45', 'Var', (116, 119))	('V10', 'Var', (91, 94))	('V15', 'Gene', (96, 99))	('V40', 'Var', (111, 114))	('V30', 'Var', (106, 109))
264632	25663943	Lung V45 was the only variable which was significantly associated with higher incidence of postoperative pulmonary plus non-pulmonary complications (Exp(B): 1.285, 95%CI 1.029-1.606, p=0.027), but not with the postoperative pulmonary complications (Exp(B): 1.249, 95%CI 0.999-1.561, p=0.051).	('postoperative pulmonary plus non-pulmonary complications', 'Disease', 'MESH:D008171', (91, 147))	('pulmonary complications', 'Phenotype', 'HP:0006532', (224, 247))	('Lung V45', 'Var', (0, 8))	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (210, 247))	('postoperative pulmonary complications', 'Disease', (210, 247))	('pulmonary complications', 'Phenotype', 'HP:0006532', (124, 147))
264647	25663943	An older meta-analysis published in 2004 showed that postoperative mortality was higher in patients treated with TMT compared to those treated with surgery alone.	('patients', 'Species', '9606', (91, 99))	('TMT', 'Var', (113, 116))	('higher', 'PosReg', (81, 87))	('TMT', 'Chemical', '-', (113, 116))	('postoperative mortality', 'CPA', (53, 76))
264656	25663943	The following dosimetric parameters were generated from the DVH for total lung (left plus right lung): mean lung dose, V5, V10, V15, V20, V30, V40, V45 and V50.	('V30', 'Var', (138, 141))	('V40', 'Var', (143, 146))	('V50', 'Var', (156, 159))	('left plus right lung', 'Disease', 'MESH:C566610', (80, 100))	('V15', 'Gene', '28814', (128, 131))	('V20', 'Var', (133, 136))	('left plus right lung', 'Disease', (80, 100))	('V10', 'Var', (123, 126))	('V15', 'Gene', (128, 131))	('V45', 'Var', (148, 151))
264704	24348764	Furthermore, FB1 has been demonstrated to induce apoptosis in human proximal tubule-derived cells (IHKE cells) and to cause oxidative stress in the human intestinal cell line Caco-2.	('induce', 'Reg', (42, 48))	('human', 'Species', '9606', (62, 67))	('FB1', 'Var', (13, 16))	('rat', 'Species', '10116', (33, 36))	('human', 'Species', '9606', (148, 153))	('oxidative stress', 'Phenotype', 'HP:0025464', (124, 140))	('Caco-2', 'CellLine', 'CVCL:0025', (175, 181))	('apoptosis', 'CPA', (49, 58))	('oxidative stress', 'MPA', (124, 140))	('cause', 'Reg', (118, 123))
264730	24348764	However, the HEECs treated with FB1 and the control cells were negative for the protein expression of p16 (data not shown).	('FB1', 'Var', (32, 35))	('p16', 'Gene', (102, 105))	('negative', 'NegReg', (63, 71))	('protein expression', 'MPA', (80, 98))	('p16', 'Gene', '1029', (102, 105))
264732	24348764	These results showed that FB1 significantly increased the protein expression level of cyclin D1 and significantly decreased the protein expression levels of cyclin E, p21 and p27 in the HEECs.	('cyclin D1', 'Gene', (86, 95))	('FB1', 'Var', (26, 29))	('p27', 'Gene', (175, 178))	('p27', 'Gene', '3429', (175, 178))	('decreased', 'NegReg', (114, 123))	('cyclin', 'Gene', '5111', (157, 163))	('cyclin', 'Gene', (157, 163))	('cyclin', 'Gene', '5111', (86, 92))	('increased', 'PosReg', (44, 53))	('cyclin', 'Gene', (86, 92))	('p21', 'Gene', '1026', (167, 170))	('protein expression levels', 'MPA', (128, 153))	('p21', 'Gene', (167, 170))	('cyclin D1', 'Gene', '595', (86, 95))	('protein expression level', 'MPA', (58, 82))
264739	24348764	Similarly, lower concentrations of mycotoxins (aflatoxin B1, FB1, deoxynivalenol and nivalenol) have been shown to enhance cellular proliferation, with the effect being more pronounced in human than in porcine lymphocytes.	('human', 'Species', '9606', (188, 193))	('nivalenol', 'Chemical', 'MESH:C038405', (85, 94))	('rat', 'Species', '10116', (139, 142))	('FB1', 'Gene', (61, 64))	('deoxynivalenol', 'Var', (66, 80))	('nivalenol', 'Chemical', 'MESH:C038405', (71, 80))	('cellular proliferation', 'CPA', (123, 145))	('enhance', 'PosReg', (115, 122))	('deoxynivalenol', 'Chemical', 'MESH:C007262', (66, 80))	('rat', 'Species', '10116', (24, 27))	('aflatoxin', 'Chemical', 'MESH:D000348', (47, 56))
264748	24348764	In a different study, the results showed that the number of C6 glioma cells in the S phase decreased significantly compared with the control, from 18.7+-2.5 to 8.1+-1.1% for 9 mumol/l FB1, and the number of cells in the G2/M phase increased significantly compared with the control, from 45.7+-0.4 to 54.8+-1.1% for 9 mumol/l FB1.	('C6 glioma', 'Disease', 'MESH:C567307', (60, 69))	('FB1', 'Var', (184, 187))	('C6 glioma', 'Disease', (60, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('S phase', 'CPA', (83, 90))	('decreased', 'NegReg', (91, 100))
264756	24348764	In the present study, the increased expression of cyclin D1 and decreased expression of CDK inhibitors, including p21 and p27, strongly suggest that FB1 induced the low expression of the members of KIP/CIP family, which sequentially stimulated the activities of the CDK/cyclin complexes.	('cyclin D1', 'Gene', '595', (50, 59))	('cyclin', 'Gene', '5111', (270, 276))	('cyclin', 'Gene', (50, 56))	('expression', 'MPA', (169, 179))	('FB1', 'Var', (149, 152))	('expression', 'MPA', (74, 84))	('p21', 'Gene', '1026', (114, 117))	('cyclin', 'Gene', (270, 276))	('CIP', 'Disease', 'MESH:D010259', (202, 205))	('stimulated', 'PosReg', (233, 243))	('decreased', 'NegReg', (64, 73))	('CIP', 'Disease', (202, 205))	('activities', 'MPA', (248, 258))	('low', 'NegReg', (165, 168))	('increased', 'PosReg', (26, 35))	('cyclin', 'Gene', '5111', (50, 56))	('p27', 'Gene', '3429', (122, 125))	('p21', 'Gene', (114, 117))	('cyclin D1', 'Gene', (50, 59))	('p27', 'Gene', (122, 125))	('expression', 'MPA', (36, 46))
264770	33279803	Because the esophagus and trachea are closely adjacent and P. gingivalis can instantly enter and colonize in cells, we speculate that P. gingivalis may be colonized in lung cancer cells through oral or blood, promoting the malignant progression of lung cancer.	('P. gingivalis', 'Var', (134, 147))	('lung cancer', 'Disease', 'MESH:D008175', (248, 259))	('P. gingivalis', 'Species', '837', (59, 72))	('lung cancer', 'Disease', (168, 179))	('P. gingivalis', 'Species', '837', (134, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('trachea', 'Disease', (26, 33))	('malignant progression', 'CPA', (223, 244))	('lung cancer', 'Disease', (248, 259))	('trachea', 'Disease', 'MESH:C557675', (26, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (248, 259))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('promoting', 'PosReg', (209, 218))
264771	33279803	In this study, we investigated P. gingivalis infection in lung carcinoma tissues and adjacent lung tissues, and found that the colonization rate of P. gingivalis in carcinoma tissues was significantly higher than that in adjacent lung tissues.	('carcinoma', 'Disease', (165, 174))	('gingivalis in carcinoma', 'Phenotype', 'HP:0000169', (151, 174))	('gingivalis infection', 'Disease', (34, 54))	('colonization', 'CPA', (127, 139))	('gingivalis infection', 'Disease', 'MESH:D007239', (34, 54))	('lung carcinoma', 'Disease', 'MESH:D008175', (58, 72))	('carcinoma', 'Disease', (63, 72))	('carcinoma', 'Disease', 'MESH:D009369', (165, 174))	('P. gingivalis', 'Var', (148, 161))	('P. gingivalis', 'Species', '837', (31, 44))	('P. gingivalis', 'Species', '837', (148, 161))	('carcinoma', 'Disease', 'MESH:D009369', (63, 72))	('lung carcinoma', 'Disease', (58, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('higher', 'PosReg', (201, 207))
264783	33279803	The main risk factors include smoking, occupational and environmental exposure, past chronic lung infection, genetic susceptibility and decreased immune function.	('immune function', 'CPA', (146, 161))	('decreased immune function', 'Phenotype', 'HP:0002721', (136, 161))	('chronic lung infection', 'Phenotype', 'HP:0002783', (85, 107))	('genetic susceptibility', 'Var', (109, 131))	('lung infection', 'Phenotype', 'HP:0006532', (93, 107))	('lung infection', 'Disease', 'MESH:D012141', (93, 107))	('lung infection', 'Disease', (93, 107))	('decreased', 'NegReg', (136, 145))
264784	33279803	With the continuous development and progress of medical research, genetic changes and environmental exposure constitute the etiology of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('genetic changes', 'Var', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('lung cancer', 'Disease', (136, 147))
264791	33279803	We had found that the detection rate of P. gingivalis in cancer tissues of patients with esophageal cancer was as high as 42%.	('esophageal cancer', 'Disease', (89, 106))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('P. gingivalis', 'Var', (40, 53))	('P. gingivalis', 'Species', '837', (40, 53))	('cancer', 'Disease', (57, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
264793	33279803	Therefore, P. gingivalis is closely related to the occurrence and development of esophageal cancer.	('related', 'Reg', (36, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('P. gingivalis', 'Species', '837', (11, 24))	('P. gingivalis', 'Var', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', (81, 98))
264794	33279803	Because the esophagus and trachea are closely adjacent to each other, and the process of P. gingivalis entering the cells is instantaneous and can be colonized in the cells for a long time, we speculate that P. gingivalis may be colonized in lung cancer cells through oral or blood, promoting the malignant progression of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('lung cancer', 'Disease', (322, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (322, 333))	('P. gingivalis', 'Species', '837', (89, 102))	('malignant progression', 'CPA', (297, 318))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('P. gingivalis', 'Species', '837', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('trachea', 'Disease', (26, 33))	('trachea', 'Disease', 'MESH:C557675', (26, 33))	('promoting', 'PosReg', (283, 292))	('lung cancer', 'Disease', (242, 253))	('lung cancer', 'Disease', 'MESH:D008175', (322, 333))	('P. gingivalis', 'Var', (208, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))
264823	33279803	Moreover, it was found that the positive rates of P. gingivalis staining in carcinoma tissues of patients with small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma were 35.00%, 26.89% and 39.00%, respectively, which were significantly higher than those in the adjacent lung tissues, as presented in Table 2 and Fig.	('small cell lung cancer', 'Disease', 'MESH:D055752', (111, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinoma', 'Disease', (178, 187))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (159, 187))	('small cell lung cancer', 'Disease', (111, 133))	('carcinoma', 'Disease', (145, 154))	('carcinoma', 'Disease', 'MESH:D009369', (76, 85))	('higher', 'PosReg', (259, 265))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('carcinoma', 'Disease', 'MESH:D009369', (178, 187))	('P. gingivalis', 'Var', (50, 63))	('lung squamous cell carcinoma', 'Disease', (159, 187))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (159, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('carcinoma', 'Disease', 'MESH:D009369', (145, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung adenocarcinoma', 'Disease', (135, 154))	('P. gingivalis', 'Species', '837', (50, 63))	('patients', 'Species', '9606', (97, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (135, 154))	('carcinoma', 'Disease', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))
264824	33279803	P. gingivalis was associated with smoking, alcohol, lymph node metastasis and clinical stages in patients with small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma (P <0.05), but not with sex, age and degree of differentiation, as presented in Table 3.	('small cell lung cancer', 'Disease', 'MESH:D055752', (111, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('P. gingivalis', 'Species', '837', (0, 13))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (159, 187))	('small cell lung cancer', 'Disease', (111, 133))	('lymph', 'Disease', (52, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('alcohol', 'Disease', (43, 50))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (159, 187))	('lung squamous cell carcinoma', 'Disease', (159, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('age', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung adenocarcinoma', 'Disease', (135, 154))	('age', 'Gene', (217, 220))	('associated', 'Interaction', (18, 28))	('patients', 'Species', '9606', (97, 105))	('P. gingivalis', 'Var', (0, 13))	('alcohol', 'Chemical', 'MESH:D000438', (43, 50))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (135, 154))	('age', 'Gene', '5973', (89, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('age', 'Gene', '5973', (217, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))
264831	33279803	In patients with these three types of lung cancer, the 5-year survival rate and median survival time in P. gingivalis positive group were significantly lower than those in P. gingivalis negative group, as presented in Table 4 and Fig.	('lung cancer', 'Disease', (38, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('P. gingivalis', 'Species', '837', (172, 185))	('P. gingivalis', 'Species', '837', (104, 117))	('P. gingivalis', 'Var', (104, 117))	('survival', 'CPA', (87, 95))	('lower', 'NegReg', (152, 157))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))
264846	33279803	Meanwhile, P. gingivalis infection could cause the overexpression of lysine demethylase 5B in esophageal cancer cells, while the overexpression of KDM5B can "hypnotize" T-cells in the tumor by inhibiting the attraction and aggregation of lymphocytes in the tumor bed, thus inhibiting the immune system and assisting tumor cells to evade immune surveillance.	('esophageal cancer', 'Disease', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lysine', 'Chemical', 'MESH:D008239', (69, 75))	('inhibiting', 'NegReg', (273, 283))	('tumor', 'Disease', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('gingivalis infection', 'Disease', 'MESH:D007239', (14, 34))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('assisting', 'PosReg', (306, 315))	('KDM5B', 'Var', (147, 152))	('overexpression', 'PosReg', (51, 65))	('inhibiting', 'NegReg', (193, 203))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('evade immune surveillance', 'CPA', (331, 356))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('immune system', 'CPA', (288, 301))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('gingivalis infection', 'Disease', (14, 34))	('tumor', 'Disease', (316, 321))	('P. gingivalis', 'Species', '837', (11, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
264847	33279803	Therefore, P. gingivalis can indeed promote the occurrence and development of malignant tumors by remodeling the host immune microenvironment.	('malignant tumors', 'Disease', (78, 94))	('promote', 'PosReg', (36, 43))	('malignant tumors', 'Disease', 'MESH:D009369', (78, 94))	('P. gingivalis', 'Species', '837', (11, 24))	('P. gingivalis', 'Var', (11, 24))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
264849	33279803	We found that, the positive rates of P. gingivalis staining in carcinoma tissues of patients with small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma were 35.00%, 26.89% and 39.00%, respectively, and the intensity and frequency of the sections stained with P. gingivalis were significantly enhanced in cancerous tissues of these three types of lung cancer compared to those in adjacent lung tissues, as presented in Table 2 and Fig.	('lung cancer', 'Disease', 'MESH:D008175', (369, 380))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('cancerous', 'Disease', 'MESH:D009369', (327, 336))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (146, 174))	('lung squamous cell carcinoma', 'Disease', (146, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (369, 380))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('carcinoma', 'Disease', 'MESH:D009369', (132, 141))	('patients', 'Species', '9606', (84, 92))	('carcinoma', 'Disease', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('P. gingivalis', 'Var', (282, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('lung adenocarcinoma', 'Disease', (122, 141))	('P. gingivalis', 'Species', '837', (37, 50))	('cancerous', 'Disease', (327, 336))	('carcinoma', 'Disease', (165, 174))	('P. gingivalis', 'Species', '837', (282, 295))	('carcinoma', 'Disease', 'MESH:D009369', (63, 72))	('small cell lung cancer', 'Disease', 'MESH:D055752', (98, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('lung cancer', 'Disease', (369, 380))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (122, 141))	('small cell lung cancer', 'Disease', (98, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('enhanced', 'PosReg', (315, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (146, 174))	('carcinoma', 'Disease', 'MESH:D009369', (165, 174))	('carcinoma', 'Disease', (132, 141))
264855	33279803	Since long term heavy smoking can severely damage the immune function of the body, P. gingivalis may be more likely to sneak in.	('age', 'Gene', '5973', (46, 49))	('P. gingivalis', 'Species', '837', (83, 96))	('immune function of the body', 'CPA', (54, 81))	('P. gingivalis', 'Var', (83, 96))	('age', 'Gene', (46, 49))
264858	33279803	It was suggested that long term smoking and alcohol could lead to worse immune microenvironment, creating a better "hotbed" for P. gingivalis, and P. gingivalis was more likely to be infected and colonized in this environment.	('P. gingivalis', 'Var', (147, 160))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('P. gingivalis', 'Species', '837', (147, 160))	('infected', 'Disease', 'MESH:D007239', (183, 191))	('infected', 'Disease', (183, 191))	('P. gingivalis', 'Species', '837', (128, 141))
264859	33279803	In this case, P. gingivalis may further induce host immunosuppression and assist the immune escape of tumor cells, thus promoting the invasion, proliferation and metastasis of lung cancer cells.	('assist', 'PosReg', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('P. gingivalis', 'Var', (14, 27))	('host immunosuppression', 'CPA', (47, 69))	('P. gingivalis', 'Species', '837', (14, 27))	('metastasis of lung cancer', 'Disease', (162, 187))	('invasion', 'CPA', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (162, 187))	('promoting', 'PosReg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('proliferation', 'CPA', (144, 157))	('induce', 'PosReg', (40, 46))
264860	33279803	In this study we also found that the 5-year survival rate and median survival time of these three types of lung cancer patients in the P. gingivalis positive group were significantly lower than those in the P. gingivalis negative group, as presented in Table 2 and Fig.	('P. gingivalis', 'Species', '837', (135, 148))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('P. gingivalis', 'Var', (135, 148))	('lung cancer', 'Disease', (107, 118))	('P. gingivalis', 'Species', '837', (207, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('lower', 'NegReg', (183, 188))	('positive', 'Var', (149, 157))
264865	33279803	In summary, P. gingivalis could promote the metastasis and malignant progression of lung cancer through long term colonization of lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('metastasis', 'CPA', (44, 54))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('malignant progression', 'CPA', (59, 80))	('promote', 'PosReg', (32, 39))	('P. gingivalis', 'Species', '837', (12, 25))	('P. gingivalis', 'Var', (12, 25))	('lung cancer', 'Disease', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
264867	33061973	Circ_0072088 Promotes Proliferation, Migration, and Invasion of Esophageal Squamous Cell Cancer by Absorbing miR-377 Circular RNA (circRNA) is an endogenous noncoding RNA.	('miR-377 Circular', 'Var', (109, 125))	('Squamous Cell Cancer', 'Disease', 'MESH:D002294', (75, 95))	('miR-377', 'Chemical', '-', (109, 116))	('Squamous Cell Cancer', 'Disease', (75, 95))	('Absorbing', 'NegReg', (99, 108))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Migration', 'CPA', (37, 46))	('Proliferation', 'CPA', (22, 35))	('Invasion', 'CPA', (52, 60))	('Squamous Cell Cancer', 'Phenotype', 'HP:0002860', (75, 95))	('Promotes', 'PosReg', (13, 21))
264869	33061973	Herein, we examined the expression and mechanism of circ_0072088 in esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('esophageal squamous cell carcinoma', 'Disease', (68, 102))	('circ_0072088', 'Var', (52, 64))
264870	33061973	As a result, circ_0072088 was significantly overexpressed in ESCC tissues and cells, which was closely associated with tumor size, invasion depth, clinical stage, and lymph node metastasis of esophageal cancer.	('tumor', 'Disease', (119, 124))	('associated', 'Reg', (103, 113))	('circ_0072088', 'Var', (13, 25))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('overexpressed', 'PosReg', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
264871	33061973	RNase R treatment assay revealed that circ_0072088 was steadier than linear ZFR mRNA.	('ZFR', 'Gene', (76, 79))	('ZFR', 'Gene', '51663', (76, 79))	('circ_0072088', 'Var', (38, 50))
264872	33061973	Mechanistically, circ_0072088 upregulated VEGF gene expression by acting as the sponge of miRNA-377.	('circ_0072088', 'Var', (17, 29))	('upregulated', 'PosReg', (30, 41))	('expression', 'MPA', (52, 62))	('VEGF', 'Gene', '7422', (42, 46))	('VEGF', 'Gene', (42, 46))
264877	33061973	Based on the differential expression of circRNA chip from 10 pairs of ESCC and matched adjacent tissues in our previous study, in this study, the top ten circRNAs with elevated expression were selected and further validated in cancer tissues and matched adjacent tissues of another 25 ESCC patients, revealing circ_0072088 with the most significant differential expression.	('patients', 'Species', '9606', (290, 298))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('elevate', 'Disease', (168, 175))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('circ_0072088', 'Var', (310, 322))	('elevate', 'Disease', 'MESH:D006973', (168, 175))
264882	33061973	Five ESCC cells (TE-13, Kyse150, ECA109, Kyse450, and Kyse510) and normal esophageal epithelial cells HET-1A were commercially obtained from Cell Bank of the Chinese Academy of Sciences (Shanghai, China).	('Kyse150', 'Var', (24, 31))	('Kyse510', 'Var', (54, 61))	('TE-13', 'CellLine', 'CVCL:4463', (17, 22))
264890	33061973	qRT-PCR for determining the mRNA level of circ_0072088 and linear ZFR before and after RNase R treatment.	('ZFR', 'Gene', '51663', (66, 69))	('circ_0072088', 'Var', (42, 54))	('mRNA level', 'MPA', (28, 38))	('ZFR', 'Gene', (66, 69))
264898	33061973	The antibodies used in Western blot were as follows: VEGF (1 : 1000, YEASEN), Tubulin (1 : 1000, Beyotime Biotechnology), and HRP-conjugated secondary antibody (1 : 1000, Beyotime Biotechnology).	('1 : 1000', 'Var', (87, 95))	('HRP-conjugated secondary', 'Protein', (126, 150))	('VEGF', 'Gene', (53, 57))	('VEGF', 'Gene', '7422', (53, 57))	('Tubulin', 'Protein', (78, 85))
264905	33061973	Based on the previous circRNA microarray analysis of ESCC and matched adjacent tissues (N = 10), the top ten circRNAs with elevated expression were validated by qRT-PCR in another 25 cases of ESCC cancer tissues and matched adjacent tissues, which revealed circ_0072088 as the most significantly differentially expressed circRNAs (Figure 1(a)).	('circ_0072088', 'Var', (257, 269))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('elevate', 'Disease', (123, 130))	('cancer', 'Disease', (197, 203))	('ESCC', 'Disease', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('elevate', 'Disease', 'MESH:D006973', (123, 130))
264906	33061973	Afterward, qRT-PCR was adopted to determine the expression of circ_0072088 in cancer tissues and paired adjacent tissues of another 58 ESCC patients, which confirmed the significantly increased circ_0072088 expression in ESCC tissue than in adjacent tissue (Figure 1(b)).	('cancer', 'Disease', (78, 84))	('increased', 'PosReg', (184, 193))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('ESCC', 'Disease', (221, 225))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('expression', 'MPA', (207, 217))	('circ_0072088', 'Var', (194, 206))
264907	33061973	We further analyzed the correlation of circ_0072088 expression with clinicopathological characteristics, demonstrating that the expression of circ_0072088 was significantly correlated with tumor size, invasion depth, TNM stage, and LNM (Table 1).	('tumor', 'Disease', (189, 194))	('TNM', 'Gene', '10178', (217, 220))	('correlated', 'Reg', (173, 183))	('invasion depth', 'CPA', (201, 215))	('LNM', 'Disease', (232, 235))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('circ_0072088', 'Var', (142, 154))	('TNM', 'Gene', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
264912	33061973	circ_0072088 is located on chromosome 5 and is circularized by exons 13-17 on the linear ZFR mRNA, with 693 bases in length (Figure 2(a)).	('circ_0072088', 'Var', (0, 12))	('ZFR', 'Gene', (89, 92))	('ZFR', 'Gene', '51663', (89, 92))
264915	33061973	qRT-PCR further showed that sh-circ_0072088 transfection could significantly decrease circ_0072088 expression in TE-13 cells (Figure 3(a)), which was more obvious in the cytoplasm than in the nucleus (Figures 3(b) and 3(c)).	('expression', 'MPA', (99, 109))	('transfection', 'Var', (44, 56))	('sh-circ_0072088 transfection', 'Var', (28, 56))	('decrease', 'NegReg', (77, 85))	('TE-13', 'CellLine', 'CVCL:4463', (113, 118))	('circ_0072088', 'Gene', (86, 98))
264916	33061973	However, knocking down circ_0072088 did not affect the expression of linear ZFR (Figure 3(d)).	('ZFR', 'Gene', (76, 79))	('ZFR', 'Gene', '51663', (76, 79))	('circ_0072088', 'Gene', (23, 35))	('knocking', 'Var', (9, 17))
264917	33061973	CCK-8 and colony formation assays showed that the proliferation capacity of TE-13 cells was significantly decreased after knocking down circ_0072088 (Figures 3(e) and 3(f)).	('decreased', 'NegReg', (106, 115))	('proliferation capacity', 'CPA', (50, 72))	('TE-13', 'CellLine', 'CVCL:4463', (76, 81))	('circ_0072088', 'Gene', (136, 148))	('CCK-8', 'Chemical', '-', (0, 5))	('knocking down', 'Var', (122, 135))
264919	33061973	Transfection of circ_0072088 overexpression plasmid into ECA109 cells could significantly increase the expression level of circ_0072088, which did not affect the expression of linear ZFR (Figures 3(h) and 3(i)).	('expression level', 'MPA', (103, 119))	('circ_0072088', 'Var', (123, 135))	('ZFR', 'Gene', (183, 186))	('ZFR', 'Gene', '51663', (183, 186))	('increase', 'PosReg', (90, 98))
264920	33061973	By searching and analyzing the circular RNA interactome and starBase databases, we found that nine miRNAs had the binding sites for circ_0072088, including miRNA-223, miRNA-330-3p, miRNA-377, miRNA-532-3p, miRNA-545, miRNA-616, miRNA-1270, miRNA-620, and miRNA-624 (Figure 4(a)).	('miRNA-624', 'Var', (255, 264))	('miRNA-532-3p', 'Var', (192, 204))	('miRNA-620', 'Var', (240, 249))	('miRNA-377', 'Var', (181, 190))	('miRNA-616', 'Var', (217, 226))	('miRNA-223', 'Gene', '407008', (156, 165))	('miRNA-223', 'Gene', (156, 165))	('binding', 'Interaction', (114, 121))	('miRNA-1270', 'Var', (228, 238))	('miRNA-330-3p', 'Var', (167, 179))	('miRNA-545', 'Var', (206, 215))	('circ_0072088', 'Gene', (132, 144))
264921	33061973	The qRT-PCR assay showed that miRNA-377 expression was significantly upregulated after knocking down circ_0072088 in TE-13 cells, while the expression of other miRNAs was not significantly changed (Figure 4(b)).	('expression', 'MPA', (40, 50))	('TE-13', 'CellLine', 'CVCL:4463', (117, 122))	('knocking down', 'Var', (87, 100))	('upregulated', 'PosReg', (69, 80))	('miRNA-377', 'Gene', (30, 39))	('circ_0072088', 'Gene', (101, 113))
264924	33061973	circ_0072088-wt/circ_0072088-mut plasmid and miRNA-377 mimic or miRNA-NC mimic were cotransfected into TE-13 cells, revealing that miRNA-377 could only decrease the luciferase activity of the circ_0072088-wt plasmid, but not circ_0072088-mut plasmid (Figure 4(h)).	('TE-13', 'CellLine', 'CVCL:4463', (103, 108))	('activity', 'MPA', (176, 184))	('miRNA-377', 'Var', (131, 140))	('luciferase', 'Enzyme', (165, 175))	('decrease', 'NegReg', (152, 160))
264927	33061973	Western blot showed that circ_0072088 downregulation could significantly decrease the protein level of VEGF (Figure 5(e)), while circ_0072088 upregulation could significantly increase the protein level of VEGF (Figure 5(f)).	('VEGF', 'Gene', (103, 107))	('upregulation', 'PosReg', (142, 154))	('VEGF', 'Gene', (205, 209))	('circ_0072088', 'Var', (25, 37))	('downregulation', 'NegReg', (38, 52))	('VEGF', 'Gene', '7422', (103, 107))	('VEGF', 'Gene', '7422', (205, 209))	('decrease', 'NegReg', (73, 81))	('increase', 'PosReg', (175, 183))	('circ_0072088', 'Var', (129, 141))
264929	33061973	The above findings indicated that circ_0072088 could promote the migration of ESCC cells through upregulating VEGF by acting as a sponge for miRNA-377.	('migration', 'CPA', (65, 74))	('circ_0072088', 'Var', (34, 46))	('VEGF', 'Gene', '7422', (110, 114))	('upregulating', 'PosReg', (97, 109))	('ESCC cells', 'CPA', (78, 88))	('VEGF', 'Gene', (110, 114))	('promote', 'PosReg', (53, 60))
264930	33061973	To confirm the functions of circ_0072088 on ESCC cell proliferation in vivo, sh-circ_0072088 TE-13 cells and sh-control TE-13 cells were subcutaneously injected into the right axilla of 6-week-old nude mice, respectively (4 x 106/each mouse).	('sh-circ_0072088', 'Var', (77, 92))	('ESCC', 'Disease', (44, 48))	('TE-13', 'CellLine', 'CVCL:4463', (93, 98))	('nude mice', 'Species', '10090', (197, 206))	('mouse', 'Species', '10090', (235, 240))	('TE-13', 'CellLine', 'CVCL:4463', (120, 125))
264932	33061973	As a result, tumor growth was significantly lower in the sh-circ_0072088 group than in the control group.	('lower', 'NegReg', (44, 49))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('sh-circ_0072088', 'Var', (57, 72))
264933	33061973	After 28 days, tumor volume was significantly smaller in the sh-circ_0072088 group than in the control group (Figures 6(a)-6(c)).	('sh-circ_0072088', 'Var', (61, 76))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('smaller', 'NegReg', (46, 53))
264934	33061973	IHC showed significantly lower VEGF expression of tumor tissue in the sh-circ_0072088 group than in the sh-control group (Figure 6(d)).	('VEGF', 'Gene', (31, 35))	('lower', 'NegReg', (25, 30))	('VEGF', 'Gene', '7422', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('sh-circ_0072088', 'Var', (70, 85))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
264935	33061973	qRT-PCR indicated that VEGF expression in tumor tissue was significantly lower in the sh-circ_0072088 group than in the sh-control group (Figure 6(e)).	('tumor', 'Disease', (42, 47))	('expression', 'MPA', (28, 38))	('VEGF', 'Gene', (23, 27))	('sh-circ_0072088', 'Var', (86, 101))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('lower', 'NegReg', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('VEGF', 'Gene', '7422', (23, 27))
264937	33061973	In this study, we further confirmed that the expressions of circ_0072088 and linear ZFR were increased in ESCC tissues and cells.	('increased', 'PosReg', (93, 102))	('expressions', 'MPA', (45, 56))	('ESCC', 'Disease', (106, 110))	('ZFR', 'Gene', (84, 87))	('ZFR', 'Gene', '51663', (84, 87))	('circ_0072088', 'Var', (60, 72))
264938	33061973	si-ZFR transfection in ESCC cells could decrease linear ZFR expression and simultaneously reduce circ_0072088 expression, indicating that the elevated expression circ_0072088 in ESCC tissues and cells was partially due to the increased expression of linear ZFR.	('expression', 'MPA', (60, 70))	('decrease', 'NegReg', (40, 48))	('ZFR', 'Gene', (56, 59))	('elevate', 'Disease', 'MESH:D006973', (142, 149))	('ZFR', 'Gene', '51663', (56, 59))	('expression', 'MPA', (151, 161))	('circ_0072088 expression', 'MPA', (97, 120))	('transfection', 'Var', (7, 19))	('elevate', 'Disease', (142, 149))	('reduce', 'NegReg', (90, 96))	('ZFR', 'Gene', (3, 6))	('ZFR', 'Gene', (257, 260))	('ZFR', 'Gene', '51663', (3, 6))	('ZFR', 'Gene', '51663', (257, 260))
264939	33061973	In addition, the expression of circ_0072088 in ESCC was positively related to tumor size, invasion depth, clinical stage, and LNM.	('related', 'Reg', (67, 74))	('invasion depth', 'CPA', (90, 104))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('circ_0072088', 'Var', (31, 43))	('expression', 'MPA', (17, 27))	('ESCC', 'Disease', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('LNM', 'Disease', (126, 129))	('clinical stage', 'CPA', (106, 120))
264940	33061973	Large tumor size, deep invasion, advanced clinical stage, and LNM in ESCC patients suggest poor prognosis; therefore, circ_0072088 might be adopted as a diagnostic and prognostic predictor of ESCC.	('patients', 'Species', '9606', (74, 82))	('ESCC', 'Disease', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('circ_0072088', 'Var', (118, 130))	('ESCC', 'Disease', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
264941	33061973	In this study, RNase R treatment was performed, which confirmed that circ_0072088 was steadier than linear ZFR mRNA.	('ZFR', 'Gene', (107, 110))	('ZFR', 'Gene', '51663', (107, 110))	('circ_0072088', 'Var', (69, 81))
264944	33061973	circ_0072088 is circularized from linear ZFR and mainly exists in the cytoplasm as an exon circRNA.	('ZFR', 'Gene', '51663', (41, 44))	('circ_0072088', 'Var', (0, 12))	('ZFR', 'Gene', (41, 44))
264952	33061973	VEGF is widely expressed in multiple types of malignancies, including lung cancer, EC, head and neck squamous cell carcinoma, colorectal cancer, breast cancer, and ovarian cancer, and the high expression of VEGF is positively related to LNM and tumor angiogenesis.	('neck squamous cell carcinoma', 'Disease', (96, 124))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (96, 124))	('lung cancer', 'Disease', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ovarian cancer', 'Disease', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (164, 178))	('high', 'Var', (188, 192))	('malignancies', 'Disease', 'MESH:D009369', (46, 58))	('related', 'Reg', (226, 233))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('VEGF', 'Gene', '7422', (207, 211))	('malignancies', 'Disease', (46, 58))	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('VEGF', 'Gene', (207, 211))	('colorectal cancer', 'Disease', (126, 143))	('VEGF', 'Gene', '7422', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('tumor', 'Disease', (245, 250))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('VEGF', 'Gene', (0, 4))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (87, 124))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('ovarian cancer', 'Disease', 'MESH:D010051', (164, 178))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('breast cancer', 'Disease', (145, 158))	('LNM', 'Disease', (237, 240))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
264960	33061973	We demonstrated the elevated expression of circ_0072088 in ESCC tissues and cells, which was positively related to tumor size, invasion depth, clinical stage, and LNM in ESCC patients.	('elevate', 'Disease', 'MESH:D006973', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('elevate', 'Disease', (20, 27))	('patients', 'Species', '9606', (175, 183))	('related', 'Reg', (104, 111))	('expression', 'MPA', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('circ_0072088', 'Var', (43, 55))
265038	32453764	Similarly, the levels of NAB were 7.5- (p < 0.001), 2.7- (p = 0.009), and 8.0-fold (p < 0.0001) higher for Bangladeshi SLT brands than SLT brands from the USA, India and Pakistan, respectively.	('NAB', 'Chemical', 'MESH:C010257', (25, 28))	('higher', 'PosReg', (96, 102))	('Bangladeshi', 'Var', (107, 118))
265132	32462117	The explanatory variables were age (<45, 45-54, 55-64, 65-74, 75-84, 85+), sex (female, male), year of death (2010, 2011, 2012, 2013), income level (5 groups), region of residence (northern, middle, southern, eastern and offshore islands, and not mentioned), and reasons for terminal hospitalization.	('death', 'Disease', 'MESH:D003643', (103, 108))	('<45', 'Var', (36, 39))	('death', 'Disease', (103, 108))	('men', 'Species', '9606', (247, 250))
265165	32462117	Esophageal varices (aRR 1 13 [95% confidence interval 1 08-1 18] in ESLD only group; aRR 1 78 [1 64-1 92] in ESLD plus HCC group), septicemia (aRR 1 12 [1 07-1 16]; 1 36 [1 25-1 48]), pneumonia and respiratory failure (aRR 1 26 [1 21-1 31]; 2 09 [1 94-2 25]), and renal failure (aRR 1 10 [1 05-1 15]; 1 38 [1 25-1 52]) were associated with higher probability of ICU admission in both groups.	('pneumonia', 'Phenotype', 'HP:0002090', (184, 193))	('septicemia', 'Disease', 'MESH:D018805', (131, 141))	('septicemia', 'Disease', (131, 141))	('renal failure', 'Phenotype', 'HP:0000083', (264, 277))	('Esophageal varices', 'Phenotype', 'HP:0002040', (0, 18))	('respiratory failure', 'Phenotype', 'HP:0002878', (198, 217))	('pneumonia', 'Disease', (184, 193))	('pneumonia', 'Disease', 'MESH:D011014', (184, 193))	('Esophageal varices', 'Disease', (0, 18))	('HCC', 'Phenotype', 'HP:0001402', (119, 122))	('renal failure', 'Disease', 'MESH:D051437', (264, 277))	('ESLD plus HCC', 'Disease', 'MESH:D006528', (109, 122))	('aRR', 'Var', (85, 88))	('respiratory failure', 'Disease', (198, 217))	('respiratory failure', 'Disease', 'MESH:D012131', (198, 217))	('renal failure', 'Disease', (264, 277))	('ICU admission', 'Disease', (362, 375))	('ESLD plus HCC', 'Disease', (109, 122))
265220	31693854	The anticancer drugs, flutamide and bicalutamide, inhibited cell viability and [3H]choline uptake in a concentration-dependent manner.	('cell viability', 'CPA', (60, 74))	('cancer', 'Disease', (8, 14))	('bicalutamide', 'Var', (36, 48))	('bicalutamide', 'Chemical', 'MESH:C053541', (36, 48))	('flutamide', 'Chemical', 'MESH:D005485', (22, 31))	('[3H]choline', 'Chemical', '-', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('[3H]choline uptake', 'MPA', (79, 97))	('inhibited', 'NegReg', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
265222	31693854	Caspase-3/7 activity was significantly increased by both flutamide and bicalutamide.	('Caspase-3', 'Gene', (0, 9))	('bicalutamide', 'Var', (71, 83))	('activity', 'MPA', (12, 20))	('flutamide', 'Chemical', 'MESH:D005485', (57, 66))	('increased', 'PosReg', (39, 48))	('bicalutamide', 'Chemical', 'MESH:C053541', (71, 83))	('Caspase-3', 'Gene', '836', (0, 9))
265243	31693854	Our studies have shown that many cancer cells express high levels of CTL1, and inhibition of CTL1 function induces apoptotic cell death.	('apoptotic cell death', 'CPA', (115, 135))	('CTL1', 'Gene', (69, 73))	('cancer', 'Disease', (33, 39))	('CTL1', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('inhibition', 'Var', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('CTL1', 'Gene', '23446', (69, 73))	('CTL1', 'Gene', '23446', (93, 97))
265247	31693854	The human prostate adenocarcinoma cell line, LNCaP (RCB2144), PC-3 (RCB2145) and DU-145 (RCB2143) were provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT (Ibaraki, Japan).	('human', 'Species', '9606', (4, 9))	('RCB2143', 'Var', (89, 96))	('prostate adenocarcinoma', 'Disease', (10, 33))	('PC-3', 'Gene', '3853', (62, 66))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (10, 33))	('PC-3', 'Gene', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))
265336	31693854	Thus, both flutamide and bicalutamide were found to have not only antiandrogenic activity but also apoptosis-inducing activity by inhibiting choline uptake.	('inhibiting', 'NegReg', (130, 140))	('flutamide', 'Chemical', 'MESH:D005485', (11, 20))	('choline uptake', 'MPA', (141, 155))	('choline', 'Chemical', 'MESH:D002794', (141, 148))	('apoptosis-inducing', 'CPA', (99, 117))	('bicalutamide', 'Var', (25, 37))	('bicalutamide', 'Chemical', 'MESH:C053541', (25, 37))	('antiandrogenic activity', 'MPA', (66, 89))
265351	31854042	In our study, NOTCH2 had higher expression in human esophageal carcinoma cell lines compared to normal human esophageal epithelial cell line, and ablation of NOTCH2 suppressed the proliferation and migration of esophageal carcinoma cells.	('ablation', 'Var', (146, 154))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (211, 231))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (211, 231))	('human', 'Species', '9606', (103, 108))	('NOTCH2', 'Gene', '4853', (158, 164))	('esophageal carcinoma', 'Disease', (52, 72))	('NOTCH2', 'Gene', (14, 20))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (52, 72))	('NOTCH2', 'Gene', '4853', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('suppressed', 'NegReg', (165, 175))	('esophageal carcinoma', 'Disease', (211, 231))	('human', 'Species', '9606', (46, 51))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (52, 72))	('higher', 'PosReg', (25, 31))	('expression', 'MPA', (32, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('NOTCH2', 'Gene', (158, 164))
265386	31854042	The membrane was incubated with the appropriate antibodies against NOTCH2 (1:000), DTX1 (1:1000, 18350-1-AP, Proteintech), DTX2 (1:500, 18565-1-AP, Proteintech), DTX3 (1:1000, ab116084, Abcam), DTX3L (1:800, 11963-1-AP, Proteintech), DTX4 (1:100, 25222-1-AP, Proteintech), NICH (1:600, ab8925, Abcam), ubiquitin (1:500, sc-47721, Santa Cruz), Ki-67 (1:1000, ab92742, Abcam), p-AKT (1:500, ab38449, Abcam), Bad (1:800, 10435-1-AP, Proteintech), BAX (1:1500, 60267-1-Ig, Proteintech), MMP-9 (1:1000, 10375-2-AP, Proteintech), LMNB1 (1:5000, 12987-1-AP, Proteintech), beta-Tubulin (1:1000, 10094-1-AP, Proteintech) and GAPDH (1:5000, 60004-1-Ig, Proteintech).	('DTX3L', 'Gene', (194, 199))	('DTX2', 'Gene', (123, 127))	('25222-1-AP', 'Chemical', 'None', (247, 257))	('NICH', 'Disease', (273, 277))	('GAPDH', 'Gene', (616, 621))	('Ki-67', 'Gene', (343, 348))	('DTX1', 'Gene', (83, 87))	('NOTCH2', 'Gene', '4853', (67, 73))	('10094-1-AP', 'Chemical', 'None', (587, 597))	('LMNB1', 'Gene', (524, 529))	('NOTCH2', 'Gene', (67, 73))	('DTX2', 'Gene', '113878', (123, 127))	('DTX3L', 'Gene', '151636', (194, 199))	('BAX', 'Gene', (444, 447))	('1:1000', 'Var', (579, 585))	('BAX', 'Gene', '581', (444, 447))	('10435-1-AP', 'Chemical', 'None', (418, 428))	('12987-1-AP', 'Chemical', 'None', (539, 549))	('18565-1-AP', 'Chemical', 'None', (136, 146))	('1:5000', 'Var', (531, 537))	('DTX4', 'Gene', (234, 238))	('NICH', 'Disease', 'None', (273, 277))	('18350-1-AP', 'Chemical', 'None', (97, 107))	('DTX4', 'Gene', '23220', (234, 238))	('MMP-9', 'Gene', '4318', (483, 488))	('Ki-67', 'Gene', '17345', (343, 348))	('beta-Tubulin', 'Protein', (565, 577))	('MMP-9', 'Gene', (483, 488))	('GAPDH', 'Gene', '2597', (616, 621))	('LMNB1', 'Gene', '4001', (524, 529))	('DTX1', 'Gene', '1840', (83, 87))
265404	31854042	Cell viability were detected by CCK-8 assay at 24, 48 and 72 hours post-culture, and obvious cell growth arrest was observed in NOTCH2 knockdown cell lines compared to control groups, while reintroduction of NOTCH2 led to a reverse of this change (Figure 1B).	('knockdown', 'Var', (135, 144))	('NOTCH2', 'Gene', (128, 134))	('NOTCH2', 'Gene', (208, 214))	('cell growth arrest', 'CPA', (93, 111))	('growth arrest', 'Phenotype', 'HP:0001510', (98, 111))	('NOTCH2', 'Gene', '4853', (208, 214))	('NOTCH2', 'Gene', '4853', (128, 134))
265406	31854042	Significantly decreased colony numbers were found in NOTCH2 knockdown groups compared to control groups both in TE-1 and Eca-109 cell lines, while reintroduction of NOTCH2 could reverse this phenomenon (Figure 1C).	('decreased', 'NegReg', (14, 23))	('colony numbers', 'CPA', (24, 38))	('NOTCH2', 'Gene', (53, 59))	('NOTCH2', 'Gene', '4853', (165, 171))	('knockdown', 'Var', (60, 69))	('NOTCH2', 'Gene', '4853', (53, 59))	('NOTCH2', 'Gene', (165, 171))
265407	31854042	Then, the wound-healing assay indicated that NOTCH2 knockdown cells maintained longer widths 12 hours after scratching as compared to the control groups which exhibited much smaller widths, while reintroduction of NOTCH2 led to a reverse of this change, implying a poorer migration ability of cells with NOTCH2 knockdown (Figure 1D).	('NOTCH2', 'Gene', '4853', (304, 310))	('NOTCH2', 'Gene', (45, 51))	('migration ability', 'CPA', (272, 289))	('NOTCH2', 'Gene', (214, 220))	('NOTCH2', 'Gene', '4853', (45, 51))	('poorer', 'NegReg', (265, 271))	('knockdown', 'Var', (311, 320))	('NOTCH2', 'Gene', (304, 310))	('knockdown', 'Var', (52, 61))	('NOTCH2', 'Gene', '4853', (214, 220))
265408	31854042	These data suggest that ablation of NOTCH2 inhibited the proliferation and migration of human esophageal carcinoma cells.	('NOTCH2', 'Gene', '4853', (36, 42))	('inhibited', 'NegReg', (43, 52))	('esophageal carcinoma', 'Disease', (94, 114))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (94, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (94, 114))	('NOTCH2', 'Gene', (36, 42))	('human', 'Species', '9606', (88, 93))	('ablation', 'Var', (24, 32))
265421	31854042	The ablation of DTX3 by shRNA inhibited the degradation of NOTCH2, while reintroducion of DTX3 could rescue the protein levels of NOTCH2 (Figure 3D).	('NOTCH2', 'Gene', '4853', (130, 136))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('NOTCH2', 'Gene', (59, 65))	('inhibited', 'NegReg', (30, 39))	('protein levels', 'MPA', (112, 126))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('rescue', 'PosReg', (101, 107))	('rad', 'Gene', '6236', (47, 50))	('ablation', 'Var', (4, 12))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('NOTCH2', 'Gene', (130, 136))	('NOTCH2', 'Gene', '4853', (59, 65))	('rad', 'Gene', (47, 50))
265423	31854042	DTX3 could reduce the stability of NOTCH2 protein and its effect on the proliferation of EC cells was detected.	('DTX3', 'Var', (0, 4))	('NOTCH2', 'Gene', (35, 41))	('reduce', 'NegReg', (11, 17))	('NOTCH2', 'Gene', '4853', (35, 41))	('EC', 'Disease', 'MESH:D004938', (89, 91))	('stability', 'MPA', (22, 31))
265424	31854042	Then, the proliferation and apoptosis-related molecular markers were detected in Eca-109 cells that stably expressed Scramble or NOTCH2 shRNA1.	('N', 'Chemical', 'MESH:D009584', (139, 140))	('NOTCH2', 'Gene', '4853', (129, 135))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('Scramble', 'Var', (117, 125))	('NOTCH2', 'Gene', (129, 135))
265432	31854042	The results indicated that proliferation-related molecules Ki-67 and p-AKT and migration-related molecules MMP-9 were obviously downregulated in the PCDH-DTX3 group compared to the pCDH group, while apoptosis-related molecules Bad and BAX were significantly upregulated in the pCDH-DTX3 group compared to the pCDH group (Figure 5D).	('MMP-9', 'Gene', '4318', (107, 112))	('Ki-67', 'Gene', (59, 64))	('BAX', 'Gene', '581', (235, 238))	('MMP-9', 'Gene', (107, 112))	('pCDH-DTX3', 'Gene', (277, 286))	('PCDH-DTX3', 'Var', (149, 158))	('Ki-67', 'Gene', '17345', (59, 64))	('upregulated', 'PosReg', (258, 269))	('apoptosis-related', 'CPA', (199, 216))	('p-AKT', 'Protein', (69, 74))	('downregulated', 'NegReg', (128, 141))	('pCDH-DTX3', 'Gene', '196403', (277, 286))	('PCDH', 'Chemical', 'MESH:C081682', (149, 153))	('BAX', 'Gene', (235, 238))
265438	31854042	The Notch signaling pathway has been extensively studied and is involved in many biology functions, such as cell proliferation, differentiation, apoptosis, adhesion, embryonic development, angiogenesis and tumor formation.19, 20 Mammalian Notch receptors include NOTCH1, NOTCH2, NOTCH3 and NOTCH4.8 NOTCH2 plays an important role in the development of various tumors, it can promote the proliferation of hepatocellular carcinoma and reduce the sensitivity of tumors to 5-fluorouracil.21 study Liu et al (2016) reported that high Notch2 mRNA expression predicted better overall survival in lung adenocarcinoma.22 However, in our study, we found that low expression of NOTCH2 is beneficial to patients with EC.	('patients', 'Species', '9606', (691, 699))	('Notch', 'Gene', '31293', (239, 244))	('Notch2', 'Gene', '4853', (529, 535))	('tumors', 'Disease', 'MESH:D009369', (360, 366))	('Notch', 'Gene', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (404, 428))	('N', 'Chemical', 'MESH:D009584', (4, 5))	('N', 'Chemical', 'MESH:D009584', (529, 530))	('tumors', 'Phenotype', 'HP:0002664', (459, 465))	('N', 'Chemical', 'MESH:D009584', (299, 300))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (589, 608))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('NOTCH2', 'Gene', (299, 305))	('tumor', 'Disease', (360, 365))	('lung adenocarcinoma', 'Disease', (589, 608))	('N', 'Chemical', 'MESH:D009584', (290, 291))	('NOTCH2', 'Gene', '4853', (271, 277))	('NOTCH2', 'Gene', '4853', (667, 673))	('hepatocellular carcinoma', 'Disease', (404, 428))	('Mammalian', 'Species', '9606', (229, 238))	('Notch', 'Gene', '31293', (529, 534))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('tumors', 'Disease', (459, 465))	('carcinoma', 'Phenotype', 'HP:0030731', (419, 428))	('Notch', 'Gene', (239, 244))	('N', 'Chemical', 'MESH:D009584', (263, 264))	('tumors', 'Phenotype', 'HP:0002664', (360, 366))	('Notch', 'Gene', '31293', (4, 9))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (469, 483))	('Notch2', 'Gene', (529, 535))	('N', 'Chemical', 'MESH:D009584', (271, 272))	('tumor', 'Disease', (459, 464))	('N', 'Chemical', 'MESH:D009584', (667, 668))	('NOTCH3', 'Gene', '4854', (279, 285))	('N', 'Chemical', 'MESH:D009584', (279, 280))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('NOTCH2', 'Gene', (667, 673))	('tumors', 'Disease', 'MESH:D009369', (459, 465))	('tumors', 'Disease', (360, 366))	('NOTCH2', 'Gene', (271, 277))	('NOTCH1', 'Gene', (263, 269))	('N', 'Chemical', 'MESH:D009584', (538, 539))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('Notch', 'Gene', (529, 534))	('tumor', 'Disease', (206, 211))	('N', 'Chemical', 'MESH:D009584', (239, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (599, 608))	('low expression', 'Var', (649, 663))	('NOTCH4', 'Gene', (290, 296))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (404, 428))	('NOTCH3', 'Gene', (279, 285))	('NOTCH4', 'Gene', '4855', (290, 296))	('NOTCH2', 'Gene', '4853', (299, 305))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('EC', 'Disease', 'MESH:D004938', (705, 707))	('NOTCH1', 'Gene', '4851', (263, 269))
265441	31854042	The ubiquitin-proteasome pathway plays an important role in biological function.16 DTX3 contains a typical RING-type E3 ubiquitin ligase domain23 and no substrate has been reported before.	('N', 'Chemical', 'MESH:D009584', (109, 110))	('domain23', 'Var', (137, 145))	('E3 ubiquitin ligase', 'Protein', (117, 136))	('DTX3', 'Gene', (83, 87))
265442	31854042	In our study, DTX3 was identified as a novel E3 ligase for NOTCH2, and promoted its degradation.	('rad', 'Gene', '6236', (87, 90))	('rad', 'Gene', (87, 90))	('NOTCH2', 'Gene', (59, 65))	('promoted', 'PosReg', (71, 79))	('DTX3', 'Var', (14, 18))	('NOTCH2', 'Gene', '4853', (59, 65))
265528	31964952	Alcohol drinking, tobacco smoking and betel nut chewing, as well as the ALDH-2 polymorphism might explain these geographic differences.	('nut', 'Gene', '256646', (44, 47))	('polymorphism', 'Var', (79, 91))	('ALDH-2', 'Gene', (72, 78))	('Alcohol', 'Chemical', 'MESH:D000431', (0, 7))	('Alcohol drinking', 'Phenotype', 'HP:0030955', (0, 16))	('nut', 'Gene', (44, 47))	('tobacco', 'Species', '4097', (18, 25))
265583	31529338	Later, it was reported that prostasin is GPI anchored to the cell surface and is released from the cell upon GPI-anchor cleavage by phospholipase C (Fig.	('GPI-anchor', 'Disease', 'MESH:C537277', (109, 119))	('GPI-anchor', 'Disease', (109, 119))	('cleavage', 'Var', (120, 128))
265591	31529338	Furthermore, after exposure to a single topical dose of the chemical carcinogen 7,12-dimethylbenzanthracene (DMBA), nearly all the matriptase transgenic mice developed SCC within 40 weeks.	('SCC', 'Gene', (168, 171))	('transgenic mice', 'Species', '10090', (142, 157))	('7,12-dimethylbenzanthracene', 'Chemical', 'MESH:D015127', (80, 107))	('transgenic', 'Var', (142, 152))	('SCC', 'Gene', '6317', (168, 171))	('matriptase', 'Gene', '19143', (131, 141))	('matriptase', 'Gene', (131, 141))	('developed', 'PosReg', (158, 167))	('DMBA', 'Chemical', 'MESH:D015127', (109, 113))
265592	31529338	Importantly, when the cognate matriptase inhibitor HAI-1 was simultaneously overexpressed with matriptase in the epidermis, development of SCC following DMBA exposure was abrogated, indicating that HAI-1 expression is sufficient to protect mice from matriptase-induced SCC.	('SCC', 'Gene', '6317', (139, 142))	('HAI-1', 'Var', (198, 203))	('SCC', 'Gene', (269, 272))	('matriptase', 'Gene', (95, 105))	('mice', 'Species', '10090', (240, 244))	('matriptase', 'Gene', (250, 260))	('matriptase', 'Gene', (30, 40))	('DMBA', 'Chemical', 'MESH:D015127', (153, 157))	('SCC', 'Gene', '6317', (269, 272))	('matriptase', 'Gene', '19143', (250, 260))	('SCC', 'Gene', (139, 142))	('abrogated', 'NegReg', (171, 180))	('development', 'CPA', (124, 135))	('matriptase', 'Gene', '19143', (30, 40))	('matriptase', 'Gene', '19143', (95, 105))
265595	31529338	This indicates that continued dysregulation of matriptase activity is necessary for SCC progression, and that inhibition of matriptase activity in established tumors may be an avenue for therapeutic intervention.	('SCC', 'Gene', '6317', (84, 87))	('activity', 'MPA', (58, 66))	('dysregulation', 'Var', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('matriptase', 'Gene', (47, 57))	('tumors', 'Disease', (159, 165))	('matriptase', 'Gene', '19143', (124, 134))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('matriptase', 'Gene', '19143', (47, 57))	('SCC', 'Gene', (84, 87))	('matriptase', 'Gene', (124, 134))
265599	31529338	K5-matriptase transgenic mice crossed to PAR-2 null mice were protected against development of epidermal hyperplasia or dysplasia that is normally associated with matriptase overexpression in the epidermis, indicating that pre-malignant transformation into SCC is dependent on PAR-2 expression.	('epidermal hyperplasia or dysplasia', 'Disease', (95, 129))	('mice', 'Species', '10090', (25, 29))	('transgenic', 'Var', (14, 24))	('matriptase', 'Gene', (163, 173))	('matriptase', 'Gene', '19143', (3, 13))	('SCC', 'Gene', '6317', (257, 260))	('transgenic mice', 'Species', '10090', (14, 29))	('PAR-2', 'Gene', (277, 282))	('mice', 'Species', '10090', (52, 56))	('PAR-2', 'Gene', '2150', (277, 282))	('overexpression', 'PosReg', (174, 188))	('matriptase', 'Gene', '19143', (163, 173))	('epidermal hyperplasia or dysplasia', 'Disease', 'MESH:D006965', (95, 129))	('matriptase', 'Gene', (3, 13))	('PAR-2', 'Gene', (41, 46))	('PAR-2', 'Gene', '2150', (41, 46))	('SCC', 'Gene', (257, 260))
265600	31529338	This was further confirmed by the inability of transgenic matriptase to potentiate DMBA-induced tumors in the absence of PAR-2.	('inability', 'Disease', 'MESH:D007319', (34, 43))	('PAR-2', 'Gene', (121, 126))	('matriptase', 'Gene', '19143', (58, 68))	('PAR-2', 'Gene', '2150', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('DMBA-induced', 'Disease', (83, 95))	('DMBA', 'Chemical', 'MESH:D015127', (83, 87))	('transgenic', 'Var', (47, 57))	('potentiate', 'PosReg', (72, 82))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('matriptase', 'Gene', (58, 68))	('inability', 'Disease', (34, 43))
265605	31529338	Loss of c-Met impaired matriptase-induced SCC formation, demonstrating an essential role for c-Met signaling for the pro-oncogenic properties of matriptase.	('SCC', 'Gene', (42, 45))	('matriptase', 'Gene', '19143', (145, 155))	('matriptase', 'Gene', '19143', (23, 33))	('matriptase', 'Gene', (23, 33))	('rat', 'Species', '10116', (64, 67))	('SCC', 'Gene', '6317', (42, 45))	('c-Met', 'Protein', (8, 13))	('Loss', 'Var', (0, 4))	('matriptase', 'Gene', (145, 155))	('impaired', 'NegReg', (14, 22))
265606	31529338	Another study specifically investigating the role of HAI-1 in oral SCC (OSCC) cell lines, including those of the gingiva and tongue, found that silencing of HAI-1 enhanced migration and tumorigenicity.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('SCC', 'Gene', (73, 76))	('tumor', 'Disease', (186, 191))	('SCC', 'Gene', '6317', (67, 70))	('SCC', 'Gene', (67, 70))	('enhanced', 'PosReg', (163, 171))	('rat', 'Species', '10116', (175, 178))	('SCC', 'Gene', '6317', (73, 76))	('silencing', 'Var', (144, 153))	('HAI-1', 'Gene', (157, 162))	('migration', 'CPA', (172, 181))
265611	31529338	It was previously demonstrated that a matriptase-prostasin reciprocal zymogen activation complex exists, which could cause dysregulation of both matriptase and prostasin activity upon HAI-2 KO.	('matriptase', 'Gene', '19143', (38, 48))	('prostasin activity', 'MPA', (160, 178))	('HAI-2', 'Var', (184, 189))	('KO', 'Gene', '3856', (190, 192))	('matriptase', 'Gene', '19143', (145, 155))	('dysregulation', 'MPA', (123, 136))	('matriptase', 'Gene', (38, 48))	('cause', 'Reg', (117, 122))	('rat', 'Species', '10116', (25, 28))	('matriptase', 'Gene', (145, 155))
265614	31529338	HAI-1 silencing in SAS cells further enhanced the migratory CAF phenotype, due to an increase in active matriptase produced by the cancer cells.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('CAF', 'Gene', (60, 63))	('silencing', 'Var', (6, 15))	('CAF', 'Gene', '8850', (60, 63))	('matriptase', 'Gene', '19143', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('rat', 'Species', '10116', (53, 56))	('SAS', 'CellLine', 'CVCL:1675', (19, 22))	('HAI-1', 'Gene', (0, 5))	('enhanced', 'PosReg', (37, 45))	('increase', 'PosReg', (85, 93))	('matriptase', 'Gene', (104, 114))
265619	31529338	In some cases, DESC1 is undetectable in HNSCC, which suggests that loss of the protease may be important for the development of SCC.	('SCC', 'Gene', (128, 131))	('SCC', 'Gene', (42, 45))	('SCC', 'Gene', '6317', (128, 131))	('SCC', 'Gene', '6317', (42, 45))	('loss', 'Var', (67, 71))
265637	31529338	Stable knock-down (KD) of TMPRSS3 in NPC cells reduced the proliferation and invasive phenotype of the cells in vitro by inhibition of the PI3K/Akt oncogenic signaling pathway.	('NPC', 'Gene', '4864', (37, 40))	('TMPRSS3', 'Gene', (26, 33))	('TMPRSS3', 'Gene', '64699', (26, 33))	('knock-down', 'Var', (7, 17))	('rat', 'Species', '10116', (66, 69))	('PI3K/Akt oncogenic signaling pathway', 'Pathway', (139, 175))	('NPC', 'Gene', (37, 40))	('invasive phenotype of the cells in vitro', 'CPA', (77, 117))	('inhibition', 'NegReg', (121, 131))	('reduced', 'NegReg', (47, 54))
265641	31529338	In ESCC tissues and cell lines with low or undetectable expression of prostasin, the CpG island-containing region of the PRSS8 gene promoter was hypermethylated.	('SCC', 'Gene', (4, 7))	('PRSS8', 'Gene', (121, 126))	('PRSS8', 'Gene', '5652', (121, 126))	('SCC', 'Gene', '6317', (4, 7))	('hypermethylated', 'Var', (145, 160))
265642	31529338	This CpG island hypermethylation silenced prostasin expression and could be reversed by treatment of cells with the demethylating agent decitabine.	('prostasin', 'Protein', (42, 51))	('hypermethylation', 'Var', (16, 32))	('expression', 'MPA', (52, 62))	('silenced', 'NegReg', (33, 41))	('decitabine', 'Chemical', 'MESH:D000077209', (136, 146))
265651	31529338	For mechanistic studies, primary mammary carcinoma cells with genetic disruption of the matriptase encoding gene by tamoxifen-inducible Cre-loxP recombination were generated.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('matriptase', 'Gene', (88, 98))	('carcinoma', 'Disease', (41, 50))	('tamoxifen', 'Chemical', 'MESH:D013629', (116, 125))	('matriptase', 'Gene', '19143', (88, 98))	('rat', 'Species', '10116', (168, 171))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (33, 50))	('carcinoma', 'Disease', 'MESH:D009369', (41, 50))	('genetic disruption', 'Var', (62, 80))
265663	31529338	Thirteen single nucleotide polymorphisms (SNPs) in the TMPRSS6 gene were investigated in triple-negative breast cancer and four variants were associated with reduced matriptase-2 expression and poor survival.	('matriptase-2 expression', 'MPA', (166, 189))	('TMPRSS6', 'Gene', '164656', (55, 62))	('single nucleotide polymorphisms', 'Var', (9, 40))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('TMPRSS6', 'Gene', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('reduced', 'NegReg', (158, 165))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
265667	31529338	Hepsin facilitates the invasive potential of breast cancer cells through remodeling of the basement membrane by cleavage of laminin-332, a component of the hemidesmosome at cell-cell junctions.	('cleavage', 'Var', (112, 120))	('Hepsin', 'Protein', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('laminin-332', 'Protein', (124, 135))	('remodeling of the basement membrane', 'CPA', (73, 108))	('facilitates', 'PosReg', (7, 18))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('invasive potential', 'CPA', (23, 41))
265668	31529338	Decreasing hepsin activity with a selective inhibitor or its expression with siRNA-mediated silencing reduced desmosome cleavage and impaired the proliferation and invasiveness of cultured breast cancer cells.	('invasiveness', 'CPA', (164, 176))	('activity', 'MPA', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Decreasing', 'NegReg', (0, 10))	('hepsin', 'Protein', (11, 17))	('proliferation', 'CPA', (146, 159))	('rat', 'Species', '10116', (153, 156))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('desmosome cleavage', 'MPA', (110, 128))	('silencing', 'Var', (92, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('impaired', 'NegReg', (133, 141))	('breast cancer', 'Disease', (189, 202))	('reduced', 'NegReg', (102, 109))	('expression', 'MPA', (61, 71))
265677	31529338	Prostasin expression may be lost in breast cancer cells lines due to methylation of its promoter region, as treatment of breast cancer cell lines with a DNA methyltransferase inhibitor was able to reactivate prostasin expression.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('expression', 'MPA', (10, 20))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('lost', 'NegReg', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('methylation', 'Var', (69, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
265682	31529338	Silencing of matriptase expression with siRNA or inhibition of matriptase activity using small-molecule inhibitors in the CRC cell line DLD-1 led to decreased activation of pro-HGF and decreased cell invasion through an extracellular matrix in vitro.	('activation', 'PosReg', (159, 169))	('decreased', 'NegReg', (185, 194))	('matriptase', 'Gene', '19143', (13, 23))	('matriptase', 'Gene', '19143', (63, 73))	('pro-HGF', 'Protein', (173, 180))	('matriptase', 'Gene', (13, 23))	('decreased', 'NegReg', (149, 158))	('matriptase', 'Gene', (63, 73))	('Silencing', 'Var', (0, 9))	('inhibition', 'NegReg', (49, 59))
265683	31529338	Similarly to matriptase null mice, which have severe epidermal barrier defects, mice with matriptase ablation specifically in the intestinal epithelium (villin-Cre+/0;St14LoxP/-) display intestinal epithelial barrier defects due to decreased tight junction formation.	('matriptase', 'Gene', '19143', (13, 23))	('ablation', 'Var', (101, 109))	('tight junction formation', 'CPA', (242, 266))	('matriptase', 'Gene', '19143', (90, 100))	('matriptase', 'Gene', (13, 23))	('intestinal epithelial barrier defects', 'CPA', (187, 224))	('mice', 'Species', '10090', (80, 84))	('mice', 'Species', '10090', (29, 33))	('decreased', 'NegReg', (232, 241))	('matriptase', 'Gene', (90, 100))
265690	31529338	RNAi-mediated silencing of TMPRSS4 in the CRC cell line HCT116 demonstrated decreased cell proliferation, invasion and migration, as well as a reduction in the cancer stem cell (CSC) markers CD44 and CD133.	('silencing', 'Var', (14, 23))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('rat', 'Species', '10116', (70, 73))	('cancer', 'Disease', (160, 166))	('CD133', 'Gene', (200, 205))	('TMPRSS4', 'Gene', (27, 34))	('CD133', 'Gene', '8842', (200, 205))	('decreased', 'NegReg', (76, 85))	('invasion', 'CPA', (106, 114))	('HCT116', 'CellLine', 'CVCL:0291', (56, 62))	('cell proliferation', 'CPA', (86, 104))	('rat', 'Species', '10116', (98, 101))	('rat', 'Species', '10116', (122, 125))	('reduction', 'NegReg', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CD44', 'Gene', '960', (191, 195))	('TMPRSS4', 'Gene', '56649', (27, 34))	('CD44', 'Gene', (191, 195))
265702	31529338	Since epidermal ablation of either prostasin or matriptase leads to identical epidermal barrier phenotypes, it is plausible that the conditional prostasin KO mice have impaired intestinal barrier function which could promote inflammation and carcinogenesis as a secondary effect.	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('carcinogenesis', 'Disease', (242, 256))	('matriptase', 'Gene', '19143', (48, 58))	('mice', 'Species', '10090', (158, 162))	('KO', 'Gene', '3856', (155, 157))	('promote', 'PosReg', (217, 224))	('inflammation', 'Disease', (225, 237))	('intestinal barrier function', 'CPA', (177, 204))	('ablation', 'Var', (16, 24))	('matriptase', 'Gene', (48, 58))	('impaired', 'NegReg', (168, 176))	('carcinogenesis', 'Disease', 'MESH:D063646', (242, 256))
265717	31529338	In a later study, genome-profiling was performed in epithelial ovarian cancer (EOC) cell lines following treatment with S-adenosyl-l-methionine (SAM, a compound that stimulates DNA methylation).	('epithelial ovarian cancer', 'Disease', (52, 77))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (52, 77))	('S-adenosyl-l-methionine', 'Chemical', 'MESH:D012436', (120, 143))	('SAM', 'Chemical', 'MESH:D012436', (145, 148))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('S-adenosyl-l-methionine', 'Var', (120, 143))	('DNA methylation', 'MPA', (177, 192))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (52, 77))
265721	31529338	TMPRSS3 overexpression in the ovarian cancer cell line A2780 increased proliferation, invasion, and migration of the cells, and conversely, silencing of TMPRSS3 in HO8910 cells had the opposite effect further suggesting a role of TMPRSS3 as a pro-oncogenic protease in ovarian cancer.	('ovarian cancer', 'Disease', (30, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (269, 283))	('increased', 'PosReg', (61, 70))	('proliferation', 'CPA', (71, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))	('rat', 'Species', '10116', (103, 106))	('TMPRSS3', 'Gene', (230, 237))	('rat', 'Species', '10116', (78, 81))	('TMPRSS3', 'Gene', (0, 7))	('HO8910', 'CellLine', 'CVCL:6868', (164, 170))	('silencing', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('TMPRSS3', 'Gene', '64699', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('A2780', 'CellLine', 'CVCL:0134', (55, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (269, 283))	('overexpression', 'PosReg', (8, 22))	('migration of the cells', 'CPA', (100, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('TMPRSS3', 'Gene', '64699', (0, 7))	('TMPRSS3', 'Gene', '64699', (230, 237))	('invasion', 'CPA', (86, 94))	('TMPRSS3', 'Gene', (153, 160))	('ovarian cancer', 'Disease', (269, 283))
265734	31529338	When matriptase expression was reduced in these cells using hammerhead ribozyme transgenes, the cells exhibited slower growth, reduced invasion and migration, and increased cell-cell adhesion.	('slower', 'NegReg', (112, 118))	('reduced', 'NegReg', (31, 38))	('increased', 'PosReg', (163, 172))	('matriptase', 'Gene', (5, 15))	('hammerhead ribozyme', 'Var', (60, 79))	('cell-cell adhesion', 'CPA', (173, 191))	('rat', 'Species', '10116', (151, 154))	('reduced', 'NegReg', (127, 134))	('expression', 'MPA', (16, 26))	('matriptase', 'Gene', '19143', (5, 15))
265740	31529338	This lends credence to the idea that dysregulation of HAI-1 expression, under some conditions, can lead to a more aggressive prostate cancer phenotype.	('dysregulation', 'Var', (37, 50))	('lead to', 'Reg', (99, 106))	('aggressive prostate cancer', 'Disease', 'MESH:D011471', (114, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (125, 140))	('aggressive prostate cancer', 'Disease', (114, 140))	('HAI-1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('more', 'PosReg', (109, 113))
265743	31529338	Furthermore, shRNA-mediated silencing of HAI-2 in CWR22Rv1 prostate cancer cells demonstrated increased levels of active matriptase and increased prostate cancer invasiveness, while overexpression of HAI-2 in N2 cells showed co-localization with matriptase on the cell surface, reduced matriptase activity, and reduced invasive capability.	('levels', 'MPA', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('matriptase', 'Gene', (246, 256))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('increased', 'PosReg', (94, 103))	('rat', 'Species', '10116', (88, 91))	('prostate cancer', 'Disease', 'MESH:D011471', (146, 161))	('invasive capability', 'CPA', (319, 338))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('reduced', 'NegReg', (311, 318))	('prostate cancer', 'Disease', (59, 74))	('matriptase', 'Gene', '19143', (121, 131))	('increased prostate cancer invasiveness', 'Disease', 'MESH:D011471', (136, 174))	('silencing', 'Var', (28, 37))	('reduced', 'NegReg', (278, 285))	('matriptase', 'Gene', '19143', (286, 296))	('CWR22Rv1', 'CellLine', 'CVCL:1045', (50, 58))	('HAI-2', 'Gene', (41, 46))	('increased prostate cancer invasiveness', 'Disease', (136, 174))	('matriptase', 'Gene', '19143', (246, 256))	('matriptase', 'Gene', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('N2', 'CellLine', 'CVCL:H592', (209, 211))	('matriptase', 'Gene', (286, 296))
265744	31529338	Silencing of matriptase reduced the invasive potential induced by HAI-2 silencing in CWR22Rv1 cells.	('matriptase', 'Gene', '19143', (13, 23))	('silencing', 'Var', (72, 81))	('reduced', 'NegReg', (24, 31))	('HAI-2', 'Gene', (66, 71))	('matriptase', 'Gene', (13, 23))	('Silencing', 'Var', (0, 9))	('CWR22Rv1', 'CellLine', 'CVCL:1045', (85, 93))	('invasive potential', 'CPA', (36, 54))
265746	31529338	These results suggest that matriptase activity is primarily controlled by HAI-2 in prostate cancer and that an imbalance between HAI-2 and matriptase expression leads to matriptase-mediated cell migration, invasion, and metastasis.	('leads to', 'Reg', (161, 169))	('matriptase', 'Gene', (139, 149))	('matriptase', 'Gene', '19143', (27, 37))	('imbalance', 'Var', (111, 120))	('activity', 'MPA', (38, 46))	('imbalance', 'Phenotype', 'HP:0002172', (111, 120))	('matriptase', 'Gene', (170, 180))	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('invasion', 'CPA', (206, 214))	('matriptase', 'Gene', '19143', (139, 149))	('rat', 'Species', '10116', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('prostate cancer', 'Disease', (83, 98))	('matriptase', 'Gene', '19143', (170, 180))	('matriptase', 'Gene', (27, 37))	('HAI-2', 'Gene', (129, 134))	('metastasis', 'CPA', (220, 230))
265757	31529338	Dysregulated ErbB-2 signaling is associated with cancer cell proliferation and invasion, and this signaling can be ligand-dependent as well as ligand-independent.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('associated', 'Reg', (33, 43))	('Dysregulated', 'Var', (0, 12))	('ErbB-2', 'Gene', (13, 19))	('rat', 'Species', '10116', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('invasion', 'CPA', (79, 87))	('cancer', 'Disease', (49, 55))
265763	31529338	Matriptase was identified as a TMPRSS2 substrate in prostate cancer cell lines, where TMPRSS2 can proteolytically activate matriptase and enhance its shedding.	('Matriptase', 'Gene', (0, 10))	('Matriptase', 'Gene', '19143', (0, 10))	('enhance', 'PosReg', (138, 145))	('TMPRSS2', 'Var', (86, 93))	('matriptase', 'Gene', (123, 133))	('rat', 'Species', '10116', (44, 47))	('activate', 'PosReg', (114, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('shedding', 'MPA', (150, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('prostate cancer', 'Disease', (52, 67))	('proteolytically', 'MPA', (98, 113))	('matriptase', 'Gene', '19143', (123, 133))
265766	31529338	This matriptase activation mechanism is dependent on activation of Src tyrosine kinase by androgen binding to androgen receptor (AR), and silencing of matriptase with siRNA significantly decreases the AR-dependent invasiveness of the PC-3 cells.	('androgen receptor', 'Gene', '367', (110, 127))	('silencing', 'Var', (138, 147))	('matriptase', 'Gene', '19143', (151, 161))	('androgen receptor', 'Gene', (110, 127))	('AR', 'Gene', '367', (201, 203))	('matriptase', 'Gene', (5, 15))	('Src tyrosine kinase', 'Enzyme', (67, 86))	('AR', 'Gene', '367', (129, 131))	('matriptase', 'Gene', '19143', (5, 15))	('decreases', 'NegReg', (187, 196))	('PC-3', 'CellLine', 'CVCL:0035', (234, 238))	('matriptase', 'Gene', (151, 161))	('binding', 'Interaction', (99, 106))
265768	31529338	COX-2 silencing in PC-3 cells leads to a 90% decrease in levels of activated matriptase.	('PC-3', 'CellLine', 'CVCL:0035', (19, 23))	('matriptase', 'Gene', (77, 87))	('decrease', 'NegReg', (45, 53))	('matriptase', 'Gene', '19143', (77, 87))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))	('silencing', 'Var', (6, 15))
265775	31529338	Furthermore, a major 11-locus haplotype was significantly associated with prostate cancer susceptibility and one of the SNPs correlated with Gleason score.	('associated', 'Reg', (58, 68))	('prostate cancer', 'Disease', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('haplotype', 'Var', (30, 39))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))
265791	31529338	In a different study, a mouse model was generated in which PB-Hepsin transgenic mice were crossed with mice in which adenomatous polyposis coli (APC, a tumor suppressor that inhibits Wnt signaling), was knocked out in the prostate (ApcPBKOHepsin mice).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (117, 143))	('mouse', 'Species', '10090', (24, 29))	('adenomatous polyposis coli', 'Gene', (117, 143))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mice', 'Species', '10090', (103, 107))	('PB', 'Gene', '54192', (59, 61))	('tumor', 'Disease', (152, 157))	('rat', 'Species', '10116', (44, 47))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('PB', 'Gene', '54192', (235, 237))	('mice', 'Species', '10090', (80, 84))	('APC', 'Disease', (145, 148))	('transgenic mice', 'Species', '10090', (69, 84))	('knocked out', 'Var', (203, 214))	('mice', 'Species', '10090', (246, 250))
265796	31529338	Around 50% of prostate cancers harbor a gene rearrangement between TMPRSS2 and estrogen-regulated gene (ERG), a member of the erythroblast transformation specific (ETS) family of transcription factors.	('prostate cancers', 'Disease', 'MESH:D011471', (14, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('ERG', 'Gene', (104, 107))	('prostate cancer', 'Phenotype', 'HP:0012125', (14, 29))	('prostate cancers', 'Phenotype', 'HP:0012125', (14, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('prostate cancers', 'Disease', (14, 30))	('TMPRSS2', 'Gene', (67, 74))	('gene rearrangement', 'Var', (40, 58))
265808	31529338	Thus, the mRNA expression of uPA, uPAR, COX-2, and the inducible nitric oxide synthase (iNOS) was decreased by WT and active-site mutant prostasin in PC-3 cells.	('uPA', 'Gene', (29, 32))	('PC-3', 'CellLine', 'CVCL:0035', (150, 154))	('iNOS', 'Gene', (88, 92))	('uPAR', 'Gene', (34, 38))	('uPA', 'Gene', '5328', (29, 32))	('inducible nitric oxide synthase', 'Gene', (55, 86))	('uPA', 'Gene', (34, 37))	('iNOS', 'Gene', '4843', (88, 92))	('COX-2', 'Gene', (40, 45))	('mRNA expression', 'MPA', (10, 25))	('active-site mutant', 'Var', (118, 136))	('COX-2', 'Gene', '5743', (40, 45))	('inducible nitric oxide synthase', 'Gene', '4843', (55, 86))	('uPA', 'Gene', '5328', (34, 37))	('decreased', 'NegReg', (98, 107))	('uPAR', 'Gene', '5329', (34, 38))
265809	31529338	Mutant prostasin reduced the protein level of EGFR upon treatment of the cells with EGF but did not affect the mRNA expression of EGFR or the expression of activated Erk2, a kinase downstream of EGFR signaling.	('Erk2', 'Gene', (166, 170))	('EGFR', 'Gene', (195, 199))	('EGFR', 'Gene', '1956', (46, 50))	('EGF', 'Gene', '1950', (84, 87))	('EGF', 'Gene', (46, 49))	('EGFR', 'Gene', (130, 134))	('reduced', 'NegReg', (17, 24))	('EGF', 'Gene', '1950', (195, 198))	('protein level', 'MPA', (29, 42))	('prostasin', 'Gene', (7, 16))	('EGF', 'Gene', '1950', (130, 133))	('EGFR', 'Gene', '1956', (195, 199))	('EGF', 'Gene', (84, 87))	('EGF', 'Gene', (195, 198))	('EGFR', 'Gene', (46, 50))	('Mutant', 'Var', (0, 6))	('EGFR', 'Gene', '1956', (130, 134))	('EGF', 'Gene', '1950', (46, 49))	('EGF', 'Gene', (130, 133))	('Erk2', 'Gene', '5594', (166, 170))
265812	31529338	Furthermore, the mutant prostasin significantly upregulated the mRNA and protein expression of matriptase in PC-3 cells, indicating that both proteolytically active and inactive prostasin play a role in matriptase-mediated oncogenic signaling.	('matriptase', 'Gene', '19143', (203, 213))	('matriptase', 'Gene', (95, 105))	('prostasin', 'Gene', (24, 33))	('PC-3', 'CellLine', 'CVCL:0035', (109, 113))	('matriptase', 'Gene', (203, 213))	('upregulated', 'PosReg', (48, 59))	('matriptase', 'Gene', '19143', (95, 105))	('mutant', 'Var', (17, 23))
265815	31529338	Furthermore, high matriptase expression is significantly associated with poor progression-free and overall survival in patients with endometrial cancer.	('progression-free', 'CPA', (78, 94))	('endometrial cancer', 'Phenotype', 'HP:0012114', (133, 151))	('high', 'Var', (13, 17))	('endometrial cancer', 'Disease', 'MESH:D016889', (133, 151))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('matriptase', 'Gene', '19143', (18, 28))	('overall survival', 'CPA', (99, 115))	('endometrial cancer', 'Disease', (133, 151))	('expression', 'MPA', (29, 39))	('poor', 'NegReg', (73, 77))	('matriptase', 'Gene', (18, 28))
265819	31529338	These improved patient outcomes are likely due to HAI-1/HAI-2 inhibition of their oncogenic protease targets, including matriptase.	('patient', 'Species', '9606', (15, 22))	('improved', 'PosReg', (6, 14))	('HAI-1/HAI-2', 'Var', (50, 61))	('matriptase', 'Gene', (120, 130))	('matriptase', 'Gene', '19143', (120, 130))	('inhibition', 'NegReg', (62, 72))
265828	31529338	Hepsin is another target for inhibition by HAI-1 and HAI-2, and overexpression of HAI-1 and HAI-2 in HeLa and SiHa cervical cancer cell lines reduced hepsin protein expression and induced apoptosis.	('induced', 'Reg', (180, 187))	('HeLa', 'CellLine', 'CVCL:0030', (101, 105))	('HAI-1', 'Var', (82, 87))	('reduced', 'NegReg', (142, 149))	('SiHa cervical cancer', 'Disease', (110, 130))	('apoptosis', 'CPA', (188, 197))	('HAI-2', 'Var', (92, 97))	('overexpression', 'PosReg', (64, 78))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('SiHa cervical cancer', 'Disease', 'MESH:D002583', (110, 130))	('hepsin protein', 'Protein', (150, 164))
265837	31529338	Thus, HAI-1 stable knock-down in the SUIT-2 pancreatic cancer cell line caused the cells to adopt an EMT-like phenotype, including reduced levels of the epithelial marker E-cadherin and increased expression of matrix metalloprotease-9 (MMP-9), a protease associated with ECM cleavage.	('SUIT-2 pancreatic cancer', 'Disease', (37, 61))	('SUIT-2 pancreatic cancer', 'Disease', 'MESH:D010190', (37, 61))	('E-cadherin', 'Gene', (171, 181))	('increased', 'PosReg', (186, 195))	('EMT-like', 'CPA', (101, 109))	('expression', 'MPA', (196, 206))	('matrix metalloprotease-9', 'Gene', (210, 234))	('E-cadherin', 'Gene', '999', (171, 181))	('reduced', 'NegReg', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('MMP-9', 'Gene', '4318', (236, 241))	('matrix metalloprotease-9', 'Gene', '4318', (210, 234))	('HAI-1', 'Gene', (6, 11))	('MMP-9', 'Gene', (236, 241))	('knock-down', 'Var', (19, 29))
265838	31529338	Stable knock-down of matriptase in HAI-1 knockdown SUIT-2 cells partially reversed the EMT-like phenotype of the cells, suggesting that matriptase may be acting alongside other HAI-1 targets like TMPRSS4 to enhance invasiveness of pancreatic cancer cells.	('matriptase', 'Gene', '19143', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('TMPRSS4', 'Gene', (196, 203))	('knock-down', 'Var', (7, 17))	('invasiveness of pancreatic cancer', 'Disease', (215, 248))	('matriptase', 'Gene', (136, 146))	('invasiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (215, 248))	('TMPRSS4', 'Gene', '56649', (196, 203))	('enhance', 'PosReg', (207, 214))	('matriptase', 'Gene', (21, 31))	('matriptase', 'Gene', '19143', (136, 146))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (231, 248))
265839	31529338	In vivo models using SUIT-2 and S2-CP8 pancreatic cancer cell xenografts showed that loss of HAI-1 in these cells increased the number of lung metastases, while forced overexpression of HAI-1 in S2-CP8 cells decreased the number of metastatic lesions.	('loss', 'Var', (85, 89))	('lung metastases', 'Disease', (138, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('HAI-1', 'Gene', (93, 98))	('lung metastases', 'Disease', 'MESH:D009362', (138, 153))	('increased', 'PosReg', (114, 123))	('pancreatic cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))
265840	31529338	These studies demonstrate an important role for HAI-1 regulation of metastatic spreading in pancreatic cancer, mediated in part by dysregulation of matriptase expression.	('HAI-1', 'Gene', (48, 53))	('matriptase', 'Gene', (148, 158))	('metastatic spreading', 'CPA', (68, 88))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('expression', 'MPA', (159, 169))	('matriptase', 'Gene', '19143', (148, 158))	('rat', 'Species', '10116', (21, 24))	('pancreatic cancer', 'Disease', (92, 109))	('dysregulation', 'Var', (131, 144))
265847	31529338	It was found that, in cell lines that do not express testisin like the embryonal carcinoma line Tera-2, the promoter CpG rich region of the testisin gene is hypermethylated, leading to silencing of the gene.	('testisin', 'Gene', (140, 148))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (71, 90))	('Tera-2', 'CellLine', 'CVCL:2777', (96, 102))	('hypermethylated', 'Var', (157, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (71, 90))	('embryonal carcinoma', 'Disease', (71, 90))	('silencing', 'MPA', (185, 194))
265848	31529338	Hypermethylation was also observed in primary testicular tumors, while adjacent normal testis tissue harbored mainly unmethylated testisin promoters.	('testicular tumors', 'Disease', 'MESH:D013736', (46, 63))	('testicular tumors', 'Phenotype', 'HP:0010788', (46, 63))	('Hypermethylation', 'Var', (0, 16))	('testicular tumors', 'Disease', (46, 63))	('observed', 'Reg', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))
265851	31529338	Interestingly, the cleavage of PAR-2 induces its internalization and intracellular signaling and may contribute to its degradation.	('induces', 'Reg', (37, 44))	('contribute', 'Reg', (101, 111))	('PAR-2', 'Gene', '2150', (31, 36))	('intracellular signaling', 'MPA', (69, 92))	('internalization', 'MPA', (49, 64))	('cleavage', 'Var', (19, 27))	('degradation', 'MPA', (119, 130))	('PAR-2', 'Gene', (31, 36))
265855	31529338	Silencing of matriptase in B-cell Burkitt's lymphoma Namalwa cells caused a significant reduction in cell invasion through reconstituted basement membrane matrix, but the proliferation of the cells was unaffected.	('matriptase', 'Gene', '19143', (13, 23))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (34, 52))	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (34, 52))	('reduction', 'NegReg', (88, 97))	("Burkitt's lymphoma", 'Disease', (34, 52))	('matriptase', 'Gene', (13, 23))	('rat', 'Species', '10116', (178, 181))	('Silencing', 'Var', (0, 9))
265865	31529338	RNAi-mediated silencing of HATL-4 in the THP-1 AML cell line significantly reduced cell invasion, mediated by reduced activation of MMP-2 and ECM cleavage.	('silencing', 'Var', (14, 23))	('activation', 'PosReg', (118, 128))	('MMP-2', 'Gene', '4313', (132, 137))	('reduced', 'NegReg', (110, 117))	('cell invasion', 'CPA', (83, 96))	('HATL-4', 'Gene', (27, 33))	('THP-1', 'Gene', (41, 46))	('HATL-4', 'Gene', '389208', (27, 33))	('AML', 'Disease', 'MESH:D015470', (47, 50))	('reduced', 'NegReg', (75, 82))	('THP-1', 'Gene', '2736', (41, 46))	('ECM cleavage', 'CPA', (142, 154))	('AML', 'Disease', (47, 50))	('MMP-2', 'Gene', (132, 137))
265881	31529338	A significant reduction in final mean tumor volume was observed in CVS-3983 treated compared to vehicle-treated mice.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('CVS-3983', 'Var', (67, 75))	('reduction', 'NegReg', (14, 23))	('mice', 'Species', '10090', (112, 116))
265882	31529338	Additionally, in a cell culture assay CVS-3983 reduced the invasion of prostate cancer cell lines through reconstituted ECM.	('invasion of prostate cancer', 'Disease', (59, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CVS-3983', 'Var', (38, 46))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('reduced', 'NegReg', (47, 54))	('invasion of prostate cancer', 'Disease', 'MESH:D011471', (59, 86))
265888	31529338	Although CVS-3983 and analogs 8 and 59 are highly selective towards matriptase when compared to the tested secreted serine proteases, it cannot be ruled out that the inhibition of additional proteases including TTSP family members plays a role in the cell culture and in vivo models used.	('matriptase', 'Gene', '19143', (68, 78))	('TTSP', 'Gene', '243084', (211, 215))	('matriptase', 'Gene', (68, 78))	('CVS-3983', 'Var', (9, 17))	('TTSP', 'Gene', (211, 215))
265895	31529338	One scFv was shown to detect denatured matriptase by western blot analysis with no cross reactivity to other family members in HeLa or PC-3 cell lysates.	('scFv', 'Gene', '652070', (4, 8))	('matriptase', 'Gene', (39, 49))	('scFv', 'Gene', (4, 8))	('PC-3', 'CellLine', 'CVCL:0035', (135, 139))	('HeLa', 'CellLine', 'CVCL:0030', (127, 131))	('matriptase', 'Gene', '19143', (39, 49))	('denatured', 'Var', (29, 38))
265907	31529338	MAbs were generated in mice immunized with a mutated variant of human matriptase in which the serine protease domain is locked in the zymogen conformation (R614A).	('human', 'Species', '9606', (64, 69))	('matriptase', 'Gene', '19143', (70, 80))	('R614A', 'Var', (156, 161))	('R614A', 'Mutation', 'p.R614A', (156, 161))	('matriptase', 'Gene', (70, 80))	('rat', 'Species', '10116', (14, 17))	('mutated', 'Var', (45, 52))	('mice', 'Species', '10090', (23, 27))
265915	31529338	M69 has previously been shown to bind active matriptase and matriptase in complex with HAI-1 with no cross-activity with epithin.	('matriptase', 'Gene', (60, 70))	('epithin', 'Gene', (121, 128))	('matriptase', 'Gene', '19143', (45, 55))	('bind', 'Interaction', (33, 37))	('epithin', 'Gene', '19143', (121, 128))	('M69', 'Var', (0, 3))	('matriptase', 'Gene', '19143', (60, 70))	('matriptase', 'Gene', (45, 55))
265916	31529338	M69-MMAE displayed IC50 equivalent values ranging from 30-322 pM in cell lines expressing high levels of matriptase versus 758-838 pM in cell lines with low expression.	('matriptase', 'Gene', '19143', (105, 115))	('matriptase', 'Gene', (105, 115))	('IC50 equivalent', 'MPA', (19, 34))	('M69-MMAE', 'Var', (0, 8))
265921	31529338	Anti-tumor activity of M69-MMAE against TNBC-PDX tumors was also observed.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('M69-MMAE', 'Var', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TNBC-PDX tumors', 'Disease', (40, 55))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('TNBC-PDX tumors', 'Disease', 'MESH:D009369', (40, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))
265922	31529338	Furthermore, the ADC enhanced the anti-tumor response of cisplatin in MDA-MB-468 xenografts, which suggests that targeted therapy against matriptase in combination with conventional chemotherapy may provide treatment benefits for breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('breast cancer', 'Disease', (230, 243))	('enhanced', 'PosReg', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('matriptase', 'Gene', '19143', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ADC', 'Var', (17, 20))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (70, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('tumor', 'Disease', (39, 44))	('patients', 'Species', '9606', (244, 252))	('matriptase', 'Gene', (138, 148))
265927	31529338	In humans with mutations in the matriptase encoding ST14 gene rendering the protease inactive or retaining very low activity, no gastrointestinal symptoms were reported Therefore, it still remains of high priority to assess the safety of matriptase targeting in clinical settings.	('matriptase', 'Gene', (238, 248))	('matriptase', 'Gene', (32, 42))	('ST14', 'Gene', '6768', (52, 56))	('mutations', 'Var', (15, 24))	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (129, 154))	('humans', 'Species', '9606', (3, 9))	('ST14', 'Gene', (52, 56))	('matriptase', 'Gene', '19143', (32, 42))	('activity', 'MPA', (116, 124))	('matriptase', 'Gene', '19143', (238, 248))	('protease', 'Enzyme', (76, 84))	('gastrointestinal symptoms', 'Disease', (129, 154))
265931	31529338	Studies of peptidomimetics/semi-peptidic TTSP inhibitors revealed that removal of the N-terminal amino group (desamino) yielded more biologically stable compounds.	('TTSP', 'Gene', (41, 45))	('removal', 'Var', (71, 78))	('biologically stable compounds', 'MPA', (133, 162))	('desamino', 'Chemical', '-', (110, 118))	('TTSP', 'Gene', '243084', (41, 45))
265934	31529338	It was demonstrated that MCoTI-II is a significantly more potent matriptase inhibitor than SFTI-1 and that all alanine mutants of both peptides, generated using positional scanning mutagenesis, had decreased trypsin affinity, whereas several mutations resulted in enhanced matriptase inhibitory activity - the most potent with a Ki of 290 pM.	('rat', 'Species', '10116', (149, 152))	('decreased trypsin', 'Phenotype', 'HP:0032493', (198, 215))	('matriptase', 'Gene', '19143', (65, 75))	('alanine mutants', 'Var', (111, 126))	('matriptase', 'Gene', (273, 283))	('trypsin affinity', 'MPA', (208, 224))	('SFTI-1', 'Gene', '110928012', (91, 97))	('SFTI-1', 'Gene', (91, 97))	('rat', 'Species', '10116', (14, 17))	('enhanced', 'PosReg', (264, 272))	('alanine', 'Chemical', 'MESH:D000409', (111, 118))	('MCoTI-II', 'Chemical', '-', (25, 33))	('matriptase', 'Gene', '19143', (273, 283))	('decreased', 'NegReg', (198, 207))	('Ki', 'Gene', '21941', (329, 331))	('matriptase', 'Gene', (65, 75))
265941	31529338	Macromolecular matriptase inhibitors include ecotin and variants (described above in 3.1), eglin C, and KD1-KD2/1-Fc (engineered HAI-1).	('variants', 'Var', (56, 64))	('matriptase', 'Gene', (15, 25))	('matriptase', 'Gene', '19143', (15, 25))
265942	31529338	In order to identify potent matriptase inhibitors, a cDNA library expressing variants of the protease inhibitor eglin C was screened.	('variants', 'Var', (77, 85))	('matriptase', 'Gene', '19143', (28, 38))	('matriptase', 'Gene', (28, 38))	('eglin C', 'Gene', (112, 119))
265943	31529338	The most potent of these, R1K4'-eglin, which had the wild-type Pro45 (P1 position) and Tyr49 (P4' position) residues replaced with arginine and lysine, respectively, led to the production of a selective, high affinity (Ki of 4 nM), and proteolytically stable inhibitor of matriptase.	('matriptase', 'Gene', '19143', (272, 282))	('Ki', 'Gene', '21941', (219, 221))	('Tyr49', 'Chemical', '-', (87, 92))	("R1K4'-eglin", 'Var', (26, 37))	('matriptase', 'Gene', (272, 282))	('lysine', 'Chemical', 'MESH:D008239', (144, 150))	('Pro45', 'Chemical', '-', (63, 68))	('Tyr49', 'Var', (87, 92))	('arginine', 'Chemical', 'MESH:D001120', (131, 139))
265953	31529338	Additionally, SRI31215 reduced primary resistance to cetuximab and gefitinib in pro-HGF-producing colon cancer cells, blocked crosstalk between c-MET-amplified non-small cell lung cancer (NSCLC) cells and pro-HGF-secreting fibroblasts, and perturbed fibroblast-mediated resistance to c-Met kinase inhibition in NSCLC cells.	('blocked', 'NegReg', (118, 125))	('perturbed', 'NegReg', (240, 249))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('c-MET', 'Gene', '4233', (144, 149))	('lung cancer', 'Disease', (175, 186))	('c-MET', 'Gene', (144, 149))	('crosstalk', 'MPA', (126, 135))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('cetuximab', 'Chemical', 'MESH:D000068818', (53, 62))	('SRI31215', 'Var', (14, 22))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('primary resistance', 'MPA', (31, 49))	('NSCLC', 'Disease', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('colon cancer', 'Disease', (98, 110))	('gefitinib', 'Chemical', 'MESH:D000077156', (67, 76))	('reduced', 'NegReg', (23, 30))	('NSCLC', 'Disease', 'MESH:D002289', (311, 316))	('SRI31215', 'Chemical', 'MESH:C000625563', (14, 22))	('NSCLC', 'Disease', (311, 316))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))
265961	31529338	It was demonstrated that the dipeptide analog Ac-LR-kbt (15) exhibited strong inhibition of hepsin activity with Ki values of 3.38 nM and 2.91 nM for the (S)-epimer and the (R)-epimer, respectively.	('hepsin activity', 'MPA', (92, 107))	('Ac-LR-kbt', 'Chemical', '-', (46, 55))	('Ac-LR-kbt', 'Var', (46, 55))	('dipeptide', 'Chemical', 'MESH:D004151', (29, 38))	('inhibition', 'NegReg', (78, 88))	('rat', 'Species', '10116', (14, 17))	('Ki', 'Gene', '21941', (113, 115))
265965	31529338	The Leu-Arg dipeptides attached to borondipyrromethene (BODIPY) or SulfoCy7 exhibited strong hepsin binding affinities with Ki values of 21 and 22nM, respectively and high selectivity over matriptase.	('BODIPY', 'Chemical', '-', (56, 62))	('Leu-Arg', 'Chemical', 'MESH:C078789', (4, 11))	('dipeptides', 'Chemical', 'MESH:D004151', (12, 22))	('SulfoCy7', 'Chemical', '-', (67, 75))	('borondipyrromethene', 'Chemical', '-', (35, 54))	('matriptase', 'Gene', '19143', (189, 199))	('Ki', 'Gene', '21941', (124, 126))	('hepsin', 'Protein', (93, 99))	('SulfoCy7', 'Var', (67, 75))	('Leu-Arg dipeptides', 'Var', (4, 22))	('matriptase', 'Gene', (189, 199))	('affinities', 'MPA', (108, 118))
265966	31529338	In cell uptake studies, SulfoCy7-conjugated inhibitor exhibited selective targeting and retention in hepsin-overexpressing prostate cancer cells.	('prostate cancer', 'Phenotype', 'HP:0012125', (123, 138))	('prostate cancer', 'Disease', (123, 138))	('retention', 'MPA', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (123, 138))	('SulfoCy7', 'Chemical', '-', (24, 32))	('SulfoCy7-conjugated', 'Var', (24, 43))
266001	31529338	The native activation sequence of PrAG was mutated to a sequence derived from protein C inhibitor (PCI), that can be cleaved by membrane-anchored serine proteases, to generate the mutant protein PrAg-PCIS.	('PCI', 'Gene', '5104', (99, 102))	('PCI', 'Gene', (200, 203))	('PrAg', 'Chemical', '-', (195, 199))	('PCI', 'Gene', (99, 102))	('PrAG', 'Gene', (34, 38))	('mutant', 'Var', (180, 186))	('protein C inhibitor', 'Gene', '5104', (78, 97))	('rat', 'Species', '10116', (171, 174))	('PCI', 'Gene', '5104', (200, 203))	('protein C inhibitor', 'Gene', (78, 97))
266013	31666923	Epigenetic silencing of HOPX is critically involved in aggressive phenotypes and patient prognosis in papillary thyroid cancer HOPX is involved in multiple organ development and acts as a tumor suppressor in various cancers.	('tumor', 'Disease', (188, 193))	('patient', 'Species', '9606', (81, 88))	('HOPX', 'Gene', (127, 131))	('HOPX', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('HOPX', 'Gene', '84525', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('involved', 'Reg', (135, 143))	('HOPX', 'Gene', '84525', (24, 28))	('papillary thyroid cancer', 'Disease', (102, 126))	('papillary thyroid cancer', 'Disease', 'MESH:C536915', (102, 126))	('Epigenetic silencing', 'Var', (0, 20))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (102, 126))	('thyroid cancer', 'Phenotype', 'HP:0002890', (112, 126))	('involved', 'Reg', (43, 51))
266014	31666923	Epigenetic silencing of HOPX via its promoter methylation has been shown frequent and cancer-specific in human cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('human', 'Species', '9606', (105, 110))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('promoter', 'MPA', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('HOPX', 'Gene', (24, 28))	('Epigenetic silencing', 'Var', (0, 20))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
266015	31666923	The proliferation of thyroid cancer cells and cancer progression are strongly influenced by epigenetic alterations as well as genetic changes.	('cancer', 'Disease', (29, 35))	('genetic changes', 'Var', (126, 141))	('proliferation', 'CPA', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('thyroid cancer', 'Disease', 'MESH:D013964', (21, 35))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('epigenetic alterations', 'Var', (92, 114))	('influenced', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('thyroid cancer', 'Phenotype', 'HP:0002890', (21, 35))	('thyroid cancer', 'Disease', (21, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
266019	31666923	Here, we aimed to seek into the roles and clinical impact of epigenetic silencing of HOPX in PTC.	('epigenetic silencing', 'Var', (61, 81))	('PTC', 'Phenotype', 'HP:0002895', (93, 96))	('HOPX', 'Gene', (85, 89))	('PTC', 'Gene', (93, 96))	('PTC', 'Gene', '5979', (93, 96))
266023	31666923	HOPX promoter methylation independently predicted disease recurrence in PTC patients.	('PTC', 'Gene', '5979', (72, 75))	('patients', 'Species', '9606', (76, 84))	('PTC', 'Phenotype', 'HP:0002895', (72, 75))	('disease recurrence', 'Disease', (50, 68))	('HOPX', 'Gene', (0, 4))	('methylation', 'Var', (14, 25))	('PTC', 'Gene', (72, 75))	('predicted', 'Reg', (40, 49))
266024	31666923	Of note, HOPX promoter methylation was dramatically associated with worse prognosis especially in patients with stage I PTC.	('HOPX', 'Gene', (9, 13))	('methylation', 'Var', (23, 34))	('associated', 'Reg', (52, 62))	('patients', 'Species', '9606', (98, 106))	('PTC', 'Gene', (120, 123))	('PTC', 'Phenotype', 'HP:0002895', (120, 123))	('PTC', 'Gene', '5979', (120, 123))
266026	31666923	Epigenetic silencing of HOPX may be a clue to tackle cancer progression and have clinical impact as a novel biomarker in PTC.	('PTC', 'Phenotype', 'HP:0002895', (121, 124))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('HOPX', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Epigenetic silencing', 'Var', (0, 20))	('PTC', 'Gene', (121, 124))	('PTC', 'Gene', '5979', (121, 124))
266029	31666923	Accumulation of genetic alterations and epigenetic gene modifications are one of the hallmarks of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (85, 104))	('genetic alterations', 'Var', (16, 35))	('hallmarks of cancer', 'Disease', (85, 104))	('epigenetic gene modifications', 'Var', (40, 69))
266030	31666923	Cancer emerges as a result of such epigenetic changes or genetic abnormalities.	('genetic abnormalities', 'Disease', 'MESH:D030342', (57, 78))	('result', 'Reg', (20, 26))	('genetic abnormalities', 'Disease', (57, 78))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('epigenetic changes', 'Var', (35, 53))
266032	31666923	A growing body of evidences have demonstrated that complicated mechanisms of carcinogenesis and cancer progression cannot be solved by genetic alterations alone, but also involve epigenetic modifications such as DNA methylation, histone modifications, and microRNA expression.	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinogenesis', 'Disease', (77, 91))	('microRNA expression', 'MPA', (256, 275))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('histone', 'MPA', (229, 236))	('DNA methylation', 'Var', (212, 227))	('cancer', 'Disease', (96, 102))
266033	31666923	The differentiation and proliferation of thyroid cancer cells are strongly affected by epigenetic alterations, results in cancer progression.	('thyroid cancer', 'Phenotype', 'HP:0002890', (41, 55))	('thyroid cancer', 'Disease', (41, 55))	('results in', 'Reg', (111, 121))	('differentiation', 'CPA', (4, 19))	('proliferation', 'CPA', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (122, 128))	('affected', 'Reg', (75, 83))	('thyroid cancer', 'Disease', 'MESH:D013964', (41, 55))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('epigenetic alterations', 'Var', (87, 109))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (49, 55))
266039	31666923	Moreover, enforced HOPX expression inhibited tumor progression, and knockdown of endogenous HOPX restored the tumor aggressiveness by influencing several mechanism of cancer cell activities.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('HOPX', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Disease', (45, 50))	('cancer', 'Disease', (167, 173))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('aggressiveness', 'Phenotype', 'HP:0000718', (116, 130))	('tumor aggressiveness', 'Disease', (110, 130))	('knockdown', 'Var', (68, 77))	('inhibited', 'NegReg', (35, 44))	('restored', 'PosReg', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('influencing', 'Reg', (134, 145))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (110, 130))	('HOPX', 'Gene', (19, 23))
266042	31666923	Among them, promoter methylation of HOPX is observed very frequently in a cancer-specific manner, and is correlated with worse long-term prognosis in esophageal squamous cell carcinoma, gastric cancer, colorectal cancer, pancreas cancer, and breast cancer.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (150, 184))	('colorectal cancer', 'Disease', (202, 219))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (249, 255))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('promoter methylation', 'Var', (12, 32))	('cancer', 'Disease', (213, 219))	('cancer', 'Disease', (230, 236))	('HOPX', 'Gene', (36, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (242, 255))	('gastric cancer', 'Disease', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('esophageal squamous cell carcinoma', 'Disease', (150, 184))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('pancreas cancer', 'Disease', 'MESH:D010190', (221, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('pancreas cancer', 'Phenotype', 'HP:0002894', (221, 236))	('breast cancer', 'Disease', (242, 255))	('breast cancer', 'Disease', 'MESH:D001943', (242, 255))	('cancer', 'Disease', (194, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('pancreas cancer', 'Disease', (221, 236))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('correlated with', 'Reg', (105, 120))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))
266044	31666923	Despite that epigenetic DNA modifications may be critical events also in thyroid cancer, the clinical importance and the involved mechanisms of HOPX in thyroid cancer has been elusive.	('thyroid cancer', 'Phenotype', 'HP:0002890', (73, 87))	('thyroid cancer', 'Disease', (73, 87))	('epigenetic DNA modifications', 'Var', (13, 41))	('thyroid cancer', 'Disease', (152, 166))	('thyroid cancer', 'Phenotype', 'HP:0002890', (152, 166))	('thyroid cancer', 'Disease', 'MESH:D013964', (73, 87))	('thyroid cancer', 'Disease', 'MESH:D013964', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
266046	31666923	Here, we particularly focused on the clinical impact of epigenetic silencing of HOPX in PTC that comprises the majority of thyroid cancer.	('thyroid cancer', 'Disease', 'MESH:D013964', (123, 137))	('PTC', 'Gene', (88, 91))	('PTC', 'Phenotype', 'HP:0002895', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('PTC', 'Gene', '5979', (88, 91))	('epigenetic silencing', 'Var', (56, 76))	('thyroid cancer', 'Phenotype', 'HP:0002890', (123, 137))	('thyroid cancer', 'Disease', (123, 137))	('HOPX', 'Gene', (80, 84))
266058	31666923	This construct is common to all three transcript variants and is transiently transfected to K1 PTC cells.	('PTC', 'Gene', '5979', (95, 98))	('PTC', 'Gene', (95, 98))	('PTC', 'Phenotype', 'HP:0002895', (95, 98))	('variants', 'Var', (49, 57))
266059	31666923	The mRNA levels in the HOPX transfectants were comparable to those in normal human thyroid tissues (data not shown).	('transfectants', 'Var', (28, 41))	('mRNA levels', 'MPA', (4, 15))	('human', 'Species', '9606', (77, 82))
266065	31666923	Kaplan-Meier curves indicate that patients with high Q-MSP values exhibited dramatically worse RFS (10-year RFS=70.3%) compared with their counterparts (10-year RFS=92.3%) (Figure 4B).	('worse', 'NegReg', (89, 94))	('Q-MSP', 'Gene', (53, 58))	('RFS', 'MPA', (95, 98))	('patients', 'Species', '9606', (34, 42))	('high', 'Var', (48, 52))
266066	31666923	Patients with high Q-MSP values showed marginally poor overall survival (OS) (Supplementary Figure 1A).	('overall survival', 'MPA', (55, 71))	('poor', 'NegReg', (50, 54))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('Q-MSP', 'Gene', (19, 24))
266067	31666923	In univariable analyses, elder age, male gender, tumor size, extrathyroidal extension, pathological lymph node metastasis (pN), higher pStage and high Q-MSP values exhibited significantly poor 10-year RFS among tumor factors (Table 1).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('RFS', 'MPA', (201, 204))	('poor', 'NegReg', (188, 192))	('extrathyroidal extension', 'CPA', (61, 85))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('high', 'Var', (146, 150))
266069	31666923	In the dissociative analyses taking stages into account, patients with high Q-MSP values exhibited significantly poor prognosis in stage I PTC (p < 0.001, Figure 4C).	('PTC', 'Gene', (139, 142))	('high', 'Var', (71, 75))	('PTC', 'Gene', '5979', (139, 142))	('poor', 'NegReg', (113, 117))	('patients', 'Species', '9606', (57, 65))	('PTC', 'Phenotype', 'HP:0002895', (139, 142))	('Q-MSP', 'Gene', (76, 81))
266070	31666923	On the other hand, patients with high Q-MSP values have prognostic association only marginally in stage II PTC (p = 0.100, Figure 4D), and no statistical significance in stage III (Figure 4E).	('PTC', 'Phenotype', 'HP:0002895', (107, 110))	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (19, 27))	('PTC', 'Gene', (107, 110))	('PTC', 'Gene', '5979', (107, 110))
266071	31666923	Similarly, patients with high Q-MSP values showed poor 10-year overall survival in stage I PTC (Supplementary Figure 1).	('overall', 'MPA', (63, 70))	('poor', 'NegReg', (50, 54))	('PTC', 'Gene', '5979', (91, 94))	('PTC', 'Gene', (91, 94))	('PTC', 'Phenotype', 'HP:0002895', (91, 94))	('high', 'Var', (25, 29))	('patients', 'Species', '9606', (11, 19))
266074	31666923	Furthermore, immunohistochemical assay of Ki-67 revealed that Ki-67 expression is significantly higher in patients with HOPX hypermethylation (p = 0.038, Figure 5C and 5D, Table 2).	('expression', 'MPA', (68, 78))	('hypermethylation', 'Var', (125, 141))	('Ki-67', 'Gene', (62, 67))	('HOPX', 'Gene', (120, 124))	('patients', 'Species', '9606', (106, 114))	('higher', 'PosReg', (96, 102))
266075	31666923	These results show that silencing of HOPX by its promoter hypermethylation promotes cancer cell proliferation in PTC.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('PTC', 'Gene', (113, 116))	('cancer', 'Disease', (84, 90))	('promotes', 'PosReg', (75, 83))	('HOPX', 'Gene', (37, 41))	('PTC', 'Gene', '5979', (113, 116))	('PTC', 'Phenotype', 'HP:0002895', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('silencing', 'Var', (24, 33))
266076	31666923	Collectively, epigenetic silencing of HOPX expression caused by the promoter methylation is critically involved in cancer progression and patient prognosis in PTC.	('PTC', 'Phenotype', 'HP:0002895', (159, 162))	('cancer', 'Disease', (115, 121))	('epigenetic silencing', 'Var', (14, 34))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('HOPX', 'Gene', (38, 42))	('promoter methylation', 'Var', (68, 88))	('patient', 'Species', '9606', (138, 145))	('involved', 'Reg', (103, 111))	('PTC', 'Gene', (159, 162))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('PTC', 'Gene', '5979', (159, 162))
266078	31666923	Q-MSP value was associated with male gender, tumor diameter, extrathyroidal extension and lymph node metastasis in univariable analyses.	('lymph node metastasis', 'CPA', (90, 111))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('extrathyroidal extension', 'CPA', (61, 85))	('Q-MSP value', 'Var', (0, 11))	('associated', 'Reg', (16, 26))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
266083	31666923	These previous results prompted us to seek the clinical ramifications of epigenetic silencing of HOPX in papillary thyroid cancer (PTC) which represents the vast majority of thyroid malignancies.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PTC', 'Gene', (131, 134))	('PTC', 'Gene', '5979', (131, 134))	('thyroid cancer', 'Phenotype', 'HP:0002890', (115, 129))	('PTC', 'Phenotype', 'HP:0002895', (131, 134))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (105, 129))	('papillary thyroid cancer', 'Disease', 'MESH:C536915', (105, 129))	('epigenetic silencing', 'Var', (73, 93))	('thyroid malignancies', 'Phenotype', 'HP:0100031', (174, 194))	('thyroid malignancies', 'Disease', 'MESH:D013966', (174, 194))	('thyroid malignancies', 'Disease', (174, 194))	('HOPX', 'Gene', (97, 101))	('papillary thyroid cancer', 'Disease', (105, 129))
266084	31666923	Indeed, epigenetic silencing of HOPX by its promoter methylation was observed with high sensitivity and specificity in PTC as well (Figure 3).	('PTC', 'Gene', (119, 122))	('PTC', 'Gene', '5979', (119, 122))	('epigenetic silencing', 'Var', (8, 28))	('PTC', 'Phenotype', 'HP:0002895', (119, 122))	('promoter', 'MPA', (44, 52))	('HOPX', 'Gene', (32, 36))
266088	31666923	In these cell lines, HOPX-beta and HOPX-core expression were restored by 5-Aza-dC with/without TSA, suggesting that HOPX expression depends on HOPX-beta expression.	('HOPX-beta', 'Gene', (21, 30))	('HOPX-core', 'Gene', (35, 44))	('5-Aza-dC', 'Chemical', 'MESH:C014347', (73, 81))	('5-Aza-dC', 'Var', (73, 81))	('TSA', 'Chemical', 'MESH:C012589', (95, 98))
266092	31666923	Actually, a very recent study reports hypermethylation of HOPX-beta was associated with poor survival in differentiated thyroid cancer.	('hypermethylation', 'Var', (38, 54))	('HOPX-beta', 'Gene', (58, 67))	('poor', 'NegReg', (88, 92))	('associated', 'Reg', (72, 82))	('thyroid cancer', 'Phenotype', 'HP:0002890', (120, 134))	('thyroid cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('thyroid cancer', 'Disease', 'MESH:D013964', (120, 134))
266093	31666923	In our current study, the hypermethylation of HOPX independently correlated with tumor size among the tumor factors in PTC.	('PTC', 'Gene', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PTC', 'Gene', '5979', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('hypermethylation', 'Var', (26, 42))	('PTC', 'Phenotype', 'HP:0002895', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('HOPX', 'Gene', (46, 50))	('tumor', 'Disease', (81, 86))	('correlated', 'Reg', (65, 75))
266094	31666923	Immunohistochemistry of Ki-67 supports that hypermethylation of HOPX leads to more cancer cell proliferation in patients with PTC (Table 2, Figures 5C and 5D).	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('more', 'PosReg', (78, 82))	('HOPX', 'Gene', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (112, 120))	('PTC', 'Gene', (126, 129))	('hypermethylation', 'Var', (44, 60))	('PTC', 'Phenotype', 'HP:0002895', (126, 129))	('PTC', 'Gene', '5979', (126, 129))	('cancer', 'Disease', (83, 89))
266099	31666923	In addition, co-expressed gene profiles indicate that HOPX may suppress dedifferentiation of cancer cell in consistent with our previous study on colorectal cancer in which epigenetic silencing of HOPX was associated with poor differentiation.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('HOPX', 'Gene', (197, 201))	('associated', 'Reg', (206, 216))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('epigenetic silencing', 'Var', (173, 193))	('poor differentiation', 'CPA', (222, 242))	('colorectal cancer', 'Disease', (146, 163))	('cancer', 'Disease', (157, 163))	('suppress', 'NegReg', (63, 71))
266102	31666923	Recent study reported that HOPX suppresses tumor progression by an epigenetic regulation of SNAIL transcription through the enhancement of histone H3K9 deacetylation in the SNAIL promoter.	('SNAIL', 'Gene', '6615', (173, 178))	('SNAIL', 'Gene', (173, 178))	('suppresses', 'NegReg', (32, 42))	('enhancement', 'PosReg', (124, 135))	('SNAIL', 'Gene', '6615', (92, 97))	('SNAIL', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('histone H3K9', 'Protein', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('HOPX', 'Var', (27, 31))	('tumor', 'Disease', (43, 48))	('epigenetic regulation', 'MPA', (67, 88))
266104	31666923	These findings suggest that silencing of HOPX may promote dedifferentiation of epithelial cells and accelerate cancer initiation and progression.	('dedifferentiation of epithelial cells', 'CPA', (58, 95))	('cancer initiation', 'Disease', (111, 128))	('promote', 'PosReg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('accelerate', 'PosReg', (100, 110))	('HOPX', 'Gene', (41, 45))	('silencing', 'Var', (28, 37))	('cancer initiation', 'Disease', 'MESH:D009369', (111, 128))
266137	31666923	HOPX promoter methylation critically predicts disease recurrence particularly in stage I PTC.	('PTC', 'Gene', (89, 92))	('predicts', 'Reg', (37, 45))	('HOPX', 'Gene', (0, 4))	('disease', 'Disease', (46, 53))	('PTC', 'Gene', '5979', (89, 92))	('methylation', 'Var', (14, 25))	('PTC', 'Phenotype', 'HP:0002895', (89, 92))
266139	31666923	Therefore, silencing of HOPX expression may have significant potential as a useful biomarker in patients with PTC.	('silencing', 'Var', (11, 20))	('PTC', 'Gene', '5979', (110, 113))	('PTC', 'Phenotype', 'HP:0002895', (110, 113))	('HOPX', 'Gene', (24, 28))	('patients', 'Species', '9606', (96, 104))	('PTC', 'Gene', (110, 113))
266245	31308688	Inflammatory reactions can cause the release of a large number of free radicals and lead to oxidative stress in tissue cells, and oxidative stress can promote the occurrence of inflammatory reactions through specific signaling pathways.	('free radicals', 'MPA', (66, 79))	('oxidative stress', 'Phenotype', 'HP:0025464', (92, 108))	('lead to', 'Reg', (84, 91))	('oxidative stress', 'Phenotype', 'HP:0025464', (130, 146))	('release', 'MPA', (37, 44))	('cause', 'Reg', (27, 32))	('oxidative stress', 'MPA', (92, 108))	('promote', 'PosReg', (151, 158))	('oxidative', 'Var', (130, 139))	('free radicals', 'Chemical', 'MESH:D005609', (66, 79))	('inflammatory', 'Pathway', (177, 189))
266252	31308688	Aberrations in the COX2 pathway are associated with tumor development in the digestive system.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('Aberrations', 'Var', (0, 11))	('COX2 pathway', 'Pathway', (19, 31))	('rat', 'Species', '10116', (4, 7))	('associated', 'Reg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
266255	31308688	Additionally, in a model of dimethylhydrazine-induced colon cancer in rats, NFkappaB and COX2 expression in the DMH group was significantly upregulated, while NFkappaB and COX2 expression in the DMH-AST group was significantly decreased, suggesting that AST inhibited colon cancer via the NFkappaB-COX2 signaling pathway.	('AST', 'Chemical', 'MESH:C005948', (199, 202))	('upregulated', 'PosReg', (140, 151))	('colon cancer', 'Disease', (54, 66))	('AST', 'Chemical', 'MESH:C005948', (254, 257))	('inhibited', 'NegReg', (258, 267))	('DMH', 'Chemical', 'MESH:D004111', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('colon cancer', 'Disease', (268, 280))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('NFkappaB', 'Gene', (76, 84))	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('NFkappaB-COX2 signaling pathway', 'Pathway', (289, 320))	('expression', 'MPA', (94, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (268, 280))	('DMH', 'Chemical', 'MESH:D004111', (195, 198))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('DMH', 'Var', (112, 115))	('decreased', 'NegReg', (227, 236))	('COX2', 'Gene', (89, 93))	('rats', 'Species', '10116', (70, 74))	('dimethylhydrazine', 'Chemical', 'MESH:D004127', (28, 45))	('colon cancer', 'Disease', 'MESH:D015179', (268, 280))
266325	30890138	Additionally, Swainsonine impeded the abilities of migration and invasion by decreasing MMP-2, MMP-9, Vimentin and E-cadherin.	('MMP-9', 'Gene', (95, 100))	('Vimentin', 'Gene', '7431', (102, 110))	('decreasing', 'NegReg', (77, 87))	('impeded', 'NegReg', (26, 33))	('MMP-2', 'Gene', '4313', (88, 93))	('Swainsonine', 'Var', (14, 25))	('Swainsonine', 'Chemical', 'MESH:D017026', (14, 25))	('Vimentin', 'Gene', (102, 110))	('invasion', 'CPA', (65, 73))	('MMP-9', 'Gene', '4318', (95, 100))	('MMP-2', 'Gene', (88, 93))	('E-cadherin', 'Gene', (115, 125))	('E-cadherin', 'Gene', '999', (115, 125))
266339	30890138	It has been showed that Swainsonine could directly suppress colon cancer cells growth and enhance the immune function.	('suppress', 'NegReg', (51, 59))	('colon cancer', 'Phenotype', 'HP:0003003', (60, 72))	('colon cancer', 'Disease', 'MESH:D015179', (60, 72))	('enhance', 'PosReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colon cancer', 'Disease', (60, 72))	('Swainsonine', 'Var', (24, 35))	('Swainsonine', 'Chemical', 'MESH:D017026', (24, 35))	('immune function', 'CPA', (102, 117))
266379	30890138	After sealing with 5% non-fat milk, the membranes were co-cultivated with the primary antibodies of CyclinD1 (ab134175), Cyclin-dependent kinase 4 (CDK4, ab199728), p16 (ab51243), pro-Caspase-3 (ab32150), cleaved-Caspase-3 (ab2302), pro-Caspase-9 (ab138412), cleaved-Caspase-9 (ab2324), matrix metalloproteinase-2 (MMP-2, ab37150), matrix metalloproteinase-9 (MMP-9, ab38898), Vimentin (ab16700), E-cadherin (ab15148), t-PI3K (ab191606), phosphorylated (p)-PI3K (ab182651), t-AKT (ab227100), p-AKT (ab133458), t-mTOR (ab32028), p-mTOR (ab109268), beta-actin (ab8227, Abcam) and t-phosphorylated and total 70-kDa ribosomal protein S6 kinase (p70S6K, #2708), p-p70S6K (#9204, all from Cell Signal Technology) overnight at 4  C. Afterward, the second antibody (ab205718, 1:2000, Abcam) was co-incubated with above membranes for another 1 h at ambient temperature.	('beta-actin', 'Gene', (547, 557))	('p70S6K', 'Gene', '6198', (641, 647))	('matrix metalloproteinase-2', 'Gene', (287, 313))	('p70S6K', 'Gene', (659, 665))	('MMP-2', 'Gene', '4313', (315, 320))	('ab205718', 'Var', (758, 766))	('PI3', 'Gene', '5266', (421, 424))	('matrix metalloproteinase-9', 'Gene', (332, 358))	('Cyclin-dependent kinase 4', 'Gene', '1019', (121, 146))	('PI3', 'Gene', (457, 460))	('CDK4', 'Gene', '1019', (148, 152))	('Caspase-9', 'Gene', '842', (237, 246))	('Caspase-9', 'Gene', (237, 246))	('Caspase-9', 'Gene', '842', (267, 276))	('Cyclin-dependent kinase 4', 'Gene', (121, 146))	('beta-actin', 'Gene', '728378', (547, 557))	('MMP-9', 'Gene', (360, 365))	('Caspase-9', 'Gene', (267, 276))	('MMP-9', 'Gene', '4318', (360, 365))	('p70S6K', 'Gene', (641, 647))	('MMP-2', 'Gene', (315, 320))	('Vimentin', 'Gene', '7431', (377, 385))	('PI3', 'Gene', (421, 424))	('p70S6K', 'Gene', '6198', (659, 665))	('matrix metalloproteinase-2', 'Gene', '4313', (287, 313))	('matrix metalloproteinase-9', 'Gene', '4318', (332, 358))	('Vimentin', 'Gene', (377, 385))	('CyclinD1', 'Gene', '595', (100, 108))	('E-cadherin', 'Gene', (397, 407))	('E-cadherin', 'Gene', '999', (397, 407))	('p16', 'Gene', (165, 168))	('pro-Caspase-3', 'Gene', (180, 193))	('PI3', 'Gene', '5266', (457, 460))	('CyclinD1', 'Gene', (100, 108))	('p16', 'Gene', '1029', (165, 168))	('CDK4', 'Gene', (148, 152))	('pro-Caspase-3', 'Gene', '836', (180, 193))
266391	30890138	Cell cycle assay results displayed that the percentage of G2/M phase cells were enhanced, but the percentage of G0/G1 phase cells were lowered after disposing with Swainsonine in U251 cells, indicating that Swainsonine could induce cell cycle arrest at G2/M phase (Fig.	('U251', 'CellLine', 'CVCL:0021', (179, 183))	('Swainsonine', 'Chemical', 'MESH:D017026', (207, 218))	('Swainsonine', 'Chemical', 'MESH:D017026', (164, 175))	('enhanced', 'PosReg', (80, 88))	('cell cycle arrest at G2/M phase', 'CPA', (232, 263))	('Swainsonine', 'Var', (207, 218))
266392	30890138	2e and f, we observed that Swainsonine notably down-regulated CyclinD1 and CDK4 protein levels, but increased p16 protein level as compared with control group (p < 0.05).	('p16', 'Gene', '1029', (110, 113))	('CyclinD1', 'Gene', '595', (62, 70))	('increased', 'PosReg', (100, 109))	('Swainsonine', 'Var', (27, 38))	('CDK4', 'Gene', (75, 79))	('Swainsonine', 'Chemical', 'MESH:D017026', (27, 38))	('p16', 'Gene', (110, 113))	('CDK4', 'Gene', '1019', (75, 79))	('CyclinD1', 'Gene', (62, 70))	('down-regulated', 'NegReg', (47, 61))
266399	30890138	Cell migration was evidently repressed by Swainsonine, meanwhile MMP-2 and MMP-9 were also declined in Swainsonine-treated U251 cells (p < 0.05, Fig.	('Cell migration', 'CPA', (0, 14))	('declined', 'NegReg', (91, 99))	('Swainsonine-treated', 'Var', (103, 122))	('MMP-2', 'Gene', (65, 70))	('U251', 'CellLine', 'CVCL:0021', (123, 127))	('Swainsonine', 'Chemical', 'MESH:D017026', (103, 114))	('MMP-2', 'Gene', '4313', (65, 70))	('MMP-9', 'Gene', (75, 80))	('MMP-9', 'Gene', '4318', (75, 80))	('Swainsonine', 'Chemical', 'MESH:D017026', (42, 53))
266401	30890138	3d-f revealed that Swainsonine significantly inhibited the ability of cell invasion, as well as hindered Vimentin and enhanced E-cadherin in U251 cells (p < 0.01).	('Swainsonine', 'Chemical', 'MESH:D017026', (19, 30))	('hindered', 'NegReg', (96, 104))	('enhanced', 'PosReg', (118, 126))	('Vimentin', 'Gene', (105, 113))	('U251', 'CellLine', 'CVCL:0021', (141, 145))	('E-cadherin', 'Gene', (127, 137))	('inhibited', 'NegReg', (45, 54))	('E-cadherin', 'Gene', '999', (127, 137))	('Vimentin', 'Gene', '7431', (105, 113))	('Swainsonine', 'Var', (19, 30))
266433	30890138	It has been demonstrated that Swainsonine induced lung cancer A549 cells apoptosis, and inhibited tumor growth in vivo.	('lung cancer', 'Disease', (50, 61))	('inhibited', 'NegReg', (88, 97))	('Swainsonine', 'Chemical', 'MESH:D017026', (30, 41))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('Swainsonine', 'Var', (30, 41))
266435	30890138	testified that Swainsonine could restrain C6 glioma cells growth in vitro, and decrease the tumor weight in vivo.	('Swainsonine', 'Chemical', 'MESH:D017026', (15, 26))	('Swainsonine', 'Var', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('decrease', 'NegReg', (79, 87))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('restrain', 'NegReg', (33, 41))	('tumor', 'Disease', (92, 97))	('glioma', 'Disease', (45, 51))
266456	30890138	In this study, we found that the repressive effect of Swainsonine on PI3K/AKT/mTOR pathway was reversed by overexpression of miR-92a, indicating that Swainsonine hindered PI3K/AKT/mTOR pathway might be through restraining miR-92a expression in glioma cells.	('PI3', 'Gene', (69, 72))	('glioma', 'Disease', (244, 250))	('Swainsonine', 'Var', (150, 161))	('miR-92', 'Gene', (222, 228))	('PI3', 'Gene', '5266', (171, 174))	('Swainsonine', 'Chemical', 'MESH:D017026', (54, 65))	('miR-92', 'Gene', '407047', (222, 228))	('Swainsonine', 'Chemical', 'MESH:D017026', (150, 161))	('expression', 'MPA', (230, 240))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('restraining', 'NegReg', (210, 221))	('PI3', 'Gene', '5266', (69, 72))	('hindered', 'NegReg', (162, 170))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('PI3', 'Gene', (171, 174))	('miR-92', 'Gene', (125, 131))	('miR-92', 'Gene', '407047', (125, 131))
266462	28531216	Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis Esophageal adenocarcinoma (EAC) develops in an inflammatory microenvironment with reduced microbial diversity, but mechanisms for these influences remain poorly characterized.	('Esophageal adenocarcinoma', 'Disease', (85, 110))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (59, 84))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (85, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (85, 110))	('esophageal carcinogenesis', 'Disease', (59, 84))	('mutations', 'Var', (10, 19))
266463	28531216	We hypothesized that mutations targeting the Toll-like receptor (TLR) pathway could disrupt innate immune signaling and promote a microenvironment that favors tumorigenesis.	('microenvironment', 'MPA', (130, 146))	('innate immune signaling', 'MPA', (92, 115))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('favors', 'PosReg', (152, 158))	('promote', 'PosReg', (120, 127))	('tumor', 'Disease', (159, 164))	('disrupt', 'NegReg', (84, 91))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('TLR', 'Gene', (65, 68))	('mutations', 'Var', (21, 30))
266464	28531216	Through interrogating whole genome sequencing data from 171 EAC patients, we showed that non-synonymous mutations collectively affect the TLR pathway in 25/171 (14.6%, PathScan p = 8.7x10-5) tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('non-synonymous mutations', 'Var', (89, 113))	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('TLR', 'Gene', (138, 141))	('patients', 'Species', '9606', (64, 72))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (138, 141))	('affect', 'Reg', (127, 133))
266465	28531216	TLR mutant cases were associated with more proximal tumors and metastatic disease, indicating possible clinical significance of these mutations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutant', 'Var', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('more', 'PosReg', (38, 42))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (0, 3))	('metastatic disease', 'CPA', (63, 81))	('TLR', 'Gene', (0, 3))
266467	28531216	We validated our findings in an external EAC dataset with non-synonymous TLR pathway mutations in 33/149 (22.1%, PathScan p = 0.05) tumors, and in other solid tumor types exposed to microbiomes in the COSMIC database (10,318 samples), including uterine endometrioid carcinoma (188/320, 58.8%), cutaneous melanoma (377/988, 38.2%), colorectal adenocarcinoma (402/1519, 26.5%), and stomach adenocarcinoma (151/579, 26.1%).	('TLR', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (132, 137))	('stomach adenocarcinoma', 'Disease', (380, 402))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (253, 275))	('cutaneous melanoma', 'Disease', (294, 312))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (294, 312))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (294, 312))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('colorectal adenocarcinoma', 'Disease', (331, 356))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (253, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (347, 356))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (380, 402))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (159, 164))	('mutations', 'Var', (85, 94))	('tumors', 'Disease', (132, 138))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (73, 76))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (331, 356))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('endometrioid carcinoma', 'Disease', (253, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (393, 402))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
266468	28531216	TLR4 was the most frequently mutated gene with eleven mutations in 10/171 (5.8%) of EAC tumors.	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('TLR4', 'Gene', (0, 4))	('mutations', 'Var', (54, 63))	('EAC tumors', 'Disease', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('EAC tumors', 'Disease', 'MESH:C536611', (84, 94))
266469	28531216	The TLR4 mutants E439G, S570I, F703C and R787H were confirmed to have impaired reactivity to bacterial lipopolysaccharide with marked reductions in signaling by luciferase reporter assays.	('R787H', 'Var', (41, 46))	('S570I', 'Var', (24, 29))	('F703C', 'Var', (31, 36))	('S570I', 'Mutation', 'p.S570I', (24, 29))	('TLR4', 'Gene', (4, 8))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (103, 121))	('impaired reactivity to bacterial lipopolysaccharide', 'Phenotype', 'HP:0002848', (70, 121))	('signaling', 'MPA', (148, 157))	('reductions', 'NegReg', (134, 144))	('F703C', 'Mutation', 'rs141844350', (31, 36))	('reactivity to bacterial lipopolysaccharide', 'MPA', (79, 121))	('E439G', 'Var', (17, 22))	('E439G', 'Mutation', 'p.E439G', (17, 22))	('R787H', 'Mutation', 'rs200905500', (41, 46))	('impaired', 'NegReg', (70, 78))
266470	28531216	Overall, our findings show that TLR pathway genes are recurrently mutated in EAC, and TLR4 mutations have decreased responsiveness to bacterial lipopolysaccharide and may play a role in disease pathogenesis in a subset of patients.	('decreased', 'NegReg', (106, 115))	('TLR', 'Gene', (86, 89))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (32, 35))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('patients', 'Species', '9606', (222, 230))	('TLR', 'Gene', (32, 35))	('EAC', 'Disease', (77, 80))	('play', 'Reg', (171, 175))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (144, 162))	('responsiveness to bacterial lipopolysaccharide', 'MPA', (116, 162))	('mutations', 'Var', (91, 100))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (86, 89))	('role', 'Reg', (178, 182))
266473	28531216	The Toll-like receptor (TLR) signalling pathway is critical for host-microbe interaction, and therefore mutations in these pathways could be important in the pathogenesis of EAC.	('TLR', 'Gene', (24, 27))	('mutations', 'Var', (104, 113))	('important', 'Reg', (141, 150))	('EAC', 'Phenotype', 'HP:0011459', (174, 177))	('EAC', 'Disease', (174, 177))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (24, 27))
266474	28531216	Here we show that TLR pathway genes are recurrently mutated in 15% of EAC tumours and other solid tumour types exposed to microbial communities, including uterine endometrioid carcinoma (59%), cutaneous melanoma (38%), colorectal adenocarcinoma (27%), and stomach adenocarcinoma (26%).	('TLR', 'Gene', (18, 21))	('endometrioid carcinoma', 'Disease', (163, 185))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (256, 278))	('EAC tumours', 'Disease', (70, 81))	('EAC tumours', 'Disease', 'MESH:C536611', (70, 81))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('mutated', 'Var', (52, 59))	('colorectal adenocarcinoma', 'Disease', (219, 244))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumour', 'Disease', (98, 104))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (163, 185))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (18, 21))	('cutaneous melanoma', 'Disease', (193, 211))	('stomach adenocarcinoma', 'Disease', (256, 278))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (219, 244))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (193, 211))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (193, 211))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (163, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
266475	28531216	TLR mutant cases were associated with more proximal tumours and metastatic disease, indicating possible clinical significance of these mutations.	('mutant', 'Var', (4, 10))	('tumours', 'Disease', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('metastatic disease', 'CPA', (64, 82))	('more', 'PosReg', (38, 42))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (0, 3))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('TLR', 'Gene', (0, 3))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
266476	28531216	A better understanding of how altered TLR signalling contributes to the inflammatory tumour microenvironment in EAC could help inform cancer prevention strategies.	('TLR', 'Gene', (38, 41))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('EAC', 'Disease', (112, 115))	('inflammatory tumour', 'Disease', 'MESH:D058922', (72, 91))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (38, 41))	('altered', 'Var', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('inflammatory tumour', 'Disease', (72, 91))
266480	28531216	The combination of exposure to noxious substances and defects in DNA damage repair enable cancer cells to accumulate mutations, evidenced by characteristic mutational signatures.	('mutations', 'Var', (117, 126))	('accumulate', 'PosReg', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('defects', 'Var', (54, 61))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
266484	28531216	An example is the SWI/SNF nucleosome remodeling complex (ARID1A, SMARCA4 and ARID2), for which gene members are mutated collectively in 20% of EAC tumors.	('mutated', 'Var', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('EAC tumors', 'Disease', (143, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('EAC', 'Phenotype', 'HP:0011459', (143, 146))	('SMARCA4', 'Gene', (65, 72))	('EAC tumors', 'Disease', 'MESH:C536611', (143, 153))	('ARID2', 'Gene', '196528', (77, 82))	('SMARCA4', 'Gene', '6597', (65, 72))	('ARID2', 'Gene', (77, 82))	('ARID1A', 'Gene', (57, 63))	('ARID1A', 'Gene', '8289', (57, 63))
266491	28531216	Genome-wide association studies and next-generation sequencing studies have identified TLR4 gene mutations in solid tumors including EAC.	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('mutations', 'Var', (97, 106))	('EAC', 'Phenotype', 'HP:0011459', (133, 136))	('TLR4', 'Gene', (87, 91))	('solid tumors', 'Disease', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('EAC', 'Disease', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
266493	28531216	We aimed to interrogate TLR pathway mutations and expression in a cohort of EAC and Barrett's esophagus patients with clinical outcome data.	('TLR', 'Gene', (24, 27))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (84, 103))	("Barrett's esophagus", 'Disease', (84, 103))	('EAC', 'Disease', (76, 79))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (84, 103))	('mutations', 'Var', (36, 45))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (24, 27))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))	('patients', 'Species', '9606', (104, 112))
266494	28531216	Finally, we aimed to determine the broader relevance of TLR pathway mutations in other cancers using TCGA data and the COSMIC database.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (56, 59))	('cancers', 'Disease', (87, 94))	('TLR', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('mutations', 'Var', (68, 77))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
266495	28531216	To determine whether the TLR signaling pathway is dysregulated through somatic mutations in EAC, we interrogated the mutational profiles of 171 EAC tumors and matched germline controls that were sequenced as part of the International Cancer Genome Consortium (ICGC) esophageal study.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('dysregulated', 'Reg', (50, 62))	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('EAC tumors', 'Disease', 'MESH:C536611', (144, 154))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('Cancer', 'Phenotype', 'HP:0002664', (234, 240))	('EAC', 'Gene', (92, 95))	('TLR', 'Gene', (25, 28))	('mutations', 'Var', (79, 88))	('EAC tumors', 'Disease', (144, 154))
266496	28531216	Missense mutations (and two splice variants) were identified in TLR4 (5.8%), TRAF6 (1.8%), TLR7 (1.8%), TLR9 (1.2%), MYD88 (1.2%), IRAK4 (1.2%), LBP (0.6%), TRAF3 (0.6%), TLR5 (0.6%), and TLR2 (0.6%, Fig 1A, S1 Table).	('LBP', 'Gene', '3929', (145, 148))	('TLR5', 'Gene', '7100', (171, 175))	('TLR7', 'Gene', (91, 95))	('TLR7', 'Gene', '51284', (91, 95))	('TLR9', 'Gene', (104, 108))	('TRAF6', 'Gene', (77, 82))	('TRAF3', 'Gene', '7187', (157, 162))	('TLR9', 'Gene', '54106', (104, 108))	('MYD88', 'Gene', '4615', (117, 122))	('LBP', 'Gene', (145, 148))	('MYD88', 'Gene', (117, 122))	('IRAK4', 'Gene', (131, 136))	('TRAF3', 'Gene', (157, 162))	('IRAK4', 'Gene', '51135', (131, 136))	('TLR2', 'Gene', '7097', (188, 192))	('TLR5', 'Gene', (171, 175))	('TLR2', 'Gene', (188, 192))	('TRAF6', 'Gene', '7189', (77, 82))	('Missense mutations', 'Var', (0, 18))
266497	28531216	Applying the PathScan tool showed that genes in the TLR signaling pathway were significantly enriched for mutations (p = 8.7x10-5).	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (52, 55))	('mutations', 'Var', (106, 115))	('TLR', 'Gene', (52, 55))
266498	28531216	Fig 1A presents the mutation and copy number status for known recurrent alterations in EAC in the context of TLR pathway mutated samples, and these events are compared with the remainder of the ICGC cohort in S1 Fig.	('alterations', 'Var', (72, 83))	('EAC', 'Gene', (87, 90))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (109, 112))	('mutated', 'Var', (121, 128))	('TLR', 'Gene', (109, 112))	('EAC', 'Phenotype', 'HP:0011459', (87, 90))
266499	28531216	As expected in EAC, most samples showed mutations in TP53, independent of whether or not they contain TLR pathway mutations.	('EAC', 'Phenotype', 'HP:0011459', (15, 18))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (102, 105))	('mutations', 'Var', (40, 49))	('TP53', 'Gene', '7157', (53, 57))	('TLR', 'Gene', (102, 105))	('TP53', 'Gene', (53, 57))
266500	28531216	There was no significant enrichment of other known driver mutations in the TLR pathway mutated samples (S1 Fig).	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (75, 78))	('mutated', 'Var', (87, 94))	('TLR', 'Gene', (75, 78))
266501	28531216	TLR pathway mutated tumors did not show significant differences in the numbers of total SNVs (Welch's t-test, p = 0.134) or non-synonymous SNVs (p = 0.147) compared to wild-type tumors and did not show significant enrichment of any of the molecular subtypes recently defined on the basis of their dominant molecular signature (Fisher's exact test, p = 0.57, S1 Fig).	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('mutated', 'Var', (12, 19))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TLR', 'Gene', (0, 3))
266502	28531216	To investigate other potential sources of altered function of the TLR pathway genes, we investigated copy number and structural variants potentially affecting the TLR pathway in the ICGC cohort.	('TLR', 'Gene', (66, 69))	('TLR', 'Gene', (163, 166))	('variants', 'Var', (128, 136))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (66, 69))	('affecting', 'Reg', (149, 158))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (163, 166))
266504	28531216	Three samples showed homozygous deletions in TLR pathway genes: MYD88 in ICGC-30, IRAK1 in ICGC-24, and TLR7, TLR8 and IRAK1 in ICGC-10.	('MYD88', 'Gene', (64, 69))	('deletions', 'Var', (32, 41))	('TLR', 'Gene', (45, 48))	('TLR', 'Gene', (104, 107))	('TLR', 'Gene', (110, 113))	('TLR8', 'Gene', (110, 114))	('TLR8', 'Gene', '51311', (110, 114))	('IRAK1', 'Gene', '3654', (82, 87))	('TLR7', 'Gene', (104, 108))	('IRAK1', 'Gene', (82, 87))	('IRAK1', 'Gene', '3654', (119, 124))	('TLR7', 'Gene', '51284', (104, 108))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (45, 48))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (104, 107))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (110, 113))	('MYD88', 'Gene', '4615', (64, 69))	('IRAK1', 'Gene', (119, 124))
266505	28531216	Interestingly, several TLR pathway genes were affected by loss of heterozygosity.	('TLR', 'Gene', (23, 26))	('affected', 'Reg', (46, 54))	('loss of heterozygosity', 'Var', (58, 80))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (23, 26))
266507	28531216	Eleven out of 171 samples showed structural variants whose breakpoints overlap with TLR pathway genes or lead to a potential fusion with a TLR pathway gene (S2 Table).	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (139, 142))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (84, 87))	('lead to', 'Reg', (105, 112))	('TLR', 'Gene', (139, 142))	('TLR', 'Gene', (84, 87))	('fusion', 'Interaction', (125, 131))	('variants', 'Var', (44, 52))
266511	28531216	We verified 11/11 TLR4 mutations and 2/2 TLR9 mutations from the ICGC cohort using PCR and Sanger sequencing (S3 Fig).	('TLR4', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('TLR9', 'Gene', (41, 45))	('TLR9', 'Gene', '54106', (41, 45))
266512	28531216	We also examined the COSMIC database for 20 different cancer types (as defined in S3 Table), comprising a total of 10,318 samples, and found a high proportion of mutations in TLR pathway genes in endometrial carcinoma (188/320, 58.8%), cutaneous melanoma (377/988, 38.2%), colorectal adenocarcinoma (402/1519, 26.5%), stomach adenocarcinoma (151/579, 26.1%), lung adenocarcinoma (81/477, 17%), lung squamous cell carcinoma (81/497, 16.3%), head and neck squamous cell carcinoma (41/330, 12.4%), and esophageal carcinoma (combined adenocarcinoma and squamous cell carcinoma: 99/869, 11.4%, Fig 2A).	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (273, 298))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (454, 477))	('esophageal carcinoma', 'Disease', (499, 519))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('adenocarcinoma', 'Disease', (364, 378))	('adenocarcinoma', 'Disease', 'MESH:D000230', (326, 340))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (196, 217))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (399, 422))	('adenocarcinoma', 'Disease', (530, 544))	('TLR', 'Gene', (175, 178))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (549, 572))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (440, 477))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (196, 217))	('adenocarcinoma', 'Disease', (284, 298))	('lung adenocarcinoma', 'Disease', (359, 378))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (318, 340))	('carcinoma', 'Phenotype', 'HP:0030731', (413, 422))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (454, 477))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('cutaneous melanoma', 'Disease', (236, 254))	('adenocarcinoma', 'Disease', 'MESH:D000230', (364, 378))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (499, 519))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (236, 254))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (236, 254))	('adenocarcinoma', 'Disease', 'MESH:D000230', (530, 544))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (394, 422))	('squamous cell carcinoma', 'Disease', (549, 572))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (359, 378))	('adenocarcinoma', 'Disease', 'MESH:D000230', (284, 298))	('cancer', 'Disease', (54, 60))	('neck squamous cell carcinoma', 'Disease', (449, 477))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (359, 378))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('colorectal adenocarcinoma', 'Disease', (273, 298))	('endometrial carcinoma', 'Disease', (196, 217))	('adenocarcinoma', 'Disease', (326, 340))	('mutations', 'Var', (162, 171))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (394, 422))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (449, 477))	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (399, 422))	('lung squamous cell carcinoma', 'Disease', (394, 422))	('stomach adenocarcinoma', 'Disease', (318, 340))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (175, 178))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (499, 519))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (549, 572))
266513	28531216	The COSMIC database further showed a high proportion of TLR4 non-synonymous mutations in cutaneous melanoma (60/988, 6.1%), lung adenocarcinoma (22/477, 4.6%), stomach adenocarcinoma (26/579, 4.5%) and lung squamous cell carcinoma (17/497, 3.4%, Fig 2A and S4 Table).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (89, 107))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (202, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('lung adenocarcinoma', 'Disease', (124, 143))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (160, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (207, 230))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (202, 230))	('lung squamous cell carcinoma', 'Disease', (202, 230))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('stomach adenocarcinoma', 'Disease', (160, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('TLR4', 'Gene', (56, 60))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('non-synonymous mutations', 'Var', (61, 85))	('cutaneous melanoma', 'Disease', (89, 107))
266515	28531216	There was an increase in the frequency of TLR pathway mutations in cancer types that are highly exposed to microbes (p = 0.019, Wilcoxon rank-sum test, S4 Fig).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('TLR', 'Gene', (42, 45))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('increase', 'PosReg', (13, 21))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (42, 45))
266516	28531216	This trend was also present when looking only at the fraction of TLR4 mutant tumors (p = 0.028).	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('TLR4', 'Gene', (65, 69))	('mutant', 'Var', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
266517	28531216	Next we investigated the clinical relevance of TLR pathway mutations through correlation with clinical outcome data.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (47, 50))	('TLR', 'Gene', (47, 50))	('mutations', 'Var', (59, 68))	('investigated', 'Reg', (8, 20))
266518	28531216	In the ICGC EAC cohort, patients with TLR pathway mutations (n = 25) tended to have more advanced disease with metastases (Fisher's exact test, p = 0.036, Table 1).	('TLR', 'Gene', (38, 41))	('metastases', 'Disease', (111, 121))	('mutations', 'Var', (50, 59))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (38, 41))	('patients', 'Species', '9606', (24, 32))	('EAC', 'Phenotype', 'HP:0011459', (12, 15))
266519	28531216	TLR mutant tumors originated more proximally at the level of the gastro-esophageal junction or above (Siewert Type 1-2 or esophageal, Fisher's exact test, p = 0.012).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('mutant', 'Var', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('gastro-esophageal junction', 'Disease', (65, 91))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('gastro-esophageal junction', 'Disease', 'MESH:D005764', (65, 91))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (0, 3))	('TLR', 'Gene', (0, 3))
266520	28531216	There was a trend towards decreased survival in patients with TLR mutations in comparison to wild-type although this did not reach statistical significance, possibly due to the limited number of TLR mutant cases and length of follow-up (S5 Fig).	('mutations', 'Var', (66, 75))	('survival', 'MPA', (36, 44))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (195, 198))	('patients', 'Species', '9606', (48, 56))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (62, 65))	('decreased', 'NegReg', (26, 35))	('TLR', 'Gene', (195, 198))	('TLR', 'Gene', (62, 65))
266521	28531216	This trend was also seen when comparing patients with TLR pathway mutations to wild-type patients in the EAC cohort from the TCGA database, although again the clinical data is limited.	('mutations', 'Var', (66, 75))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (54, 57))	('patients', 'Species', '9606', (40, 48))	('TLR', 'Gene', (54, 57))	('patients', 'Species', '9606', (89, 97))	('EAC', 'Phenotype', 'HP:0011459', (105, 108))
266523	28531216	To investigate the timing of TLR pathway mutations in disease pathogenesis, we examined samples from patients with Barrett's esophagus adjacent to tumor (n = 24).	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('patients', 'Species', '9606', (101, 109))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (29, 32))	('TLR', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (115, 134))	("Barrett's esophagus", 'Disease', (115, 134))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (115, 134))
266525	28531216	Only 2/24 Barrett's samples showed mutations in the TLR pathway.	('mutations', 'Var', (35, 44))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (52, 55))	('TLR', 'Gene', (52, 55))
266526	28531216	A TRAF6 mutation was present in tumor and adjacent Barrett's, indicating that the mutation had occurred early in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('TRAF6', 'Gene', (2, 7))	('carcinogenesis', 'Disease', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutation', 'Var', (8, 16))	('TRAF6', 'Gene', '7189', (2, 7))	('tumor', 'Disease', (32, 37))
266527	28531216	In another patient, a TLR9 mutation was detected in Barrett's but not the adjacent tumor.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('TLR9', 'Gene', (22, 26))	('detected', 'Reg', (40, 48))	('mutation', 'Var', (27, 35))	('patient', 'Species', '9606', (11, 18))	('TLR9', 'Gene', '54106', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
266529	28531216	Since TLR4 was frequently mutated in both EAC cohorts and other solid tumor types in the COSMIC database, we decided to characterize these mutations in greater detail.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TLR4', 'Gene', (6, 10))	('tumor', 'Disease', (70, 75))	('mutated', 'Var', (26, 33))	('EAC', 'Phenotype', 'HP:0011459', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
266530	28531216	Both EAC cohorts identified missense mutations at amino acid position E439 (substitution to glycine) and F487 (substitution to leucine or valine, Fig 2B).	('valine', 'Chemical', 'MESH:D014633', (138, 144))	('leucine', 'Chemical', 'MESH:D007930', (127, 134))	('EAC', 'Phenotype', 'HP:0011459', (5, 8))	('E439', 'Var', (70, 74))	('missense mutations', 'Var', (28, 46))	('glycine', 'Chemical', 'MESH:D005998', (92, 99))
266531	28531216	The COSMIC database showed additional missense mutations at position E439 (two in stomach adenocarcinoma and one in cutaneous melanoma) and position F487 (two in stomach adenocarcinoma and one in esophageal carcinoma, Fig 2C).	('esophageal carcinoma', 'Disease', (196, 216))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (196, 216))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (196, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (82, 104))	('position F487', 'Var', (140, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('stomach adenocarcinoma', 'Disease', (82, 104))	('cutaneous melanoma', 'Disease', (116, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (162, 184))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('stomach adenocarcinoma', 'Disease', (162, 184))
266532	28531216	Seven tumors with TLR4 mutations had paraffin-embedded tissue available to evaluate mutant TLR4 protein expression using immunohistochemistry for TLR4 monoclonal antibody.	('protein', 'Protein', (96, 103))	('TLR4', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('paraffin', 'Chemical', 'MESH:D010232', (37, 45))	('TLR4', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
266533	28531216	Similar to wild-type tumors, the TLR4 mutant tumors showed combined membranous and cytoplasmic staining of TLR4 protein, with staining intensity ranging from weak to strongly positive (S6 Fig).	('mutant', 'Var', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('TLR4', 'Gene', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('TLR4', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
266534	28531216	None of the mutant tumors showed complete loss of TLR4 expression, which was anticipated since the missense mutations did not cause truncation of the protein.	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('missense mutations', 'Var', (99, 117))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('expression', 'MPA', (55, 65))	('TLR4', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
266535	28531216	We hypothesized that the mutations could have a functional effect on TLR4 signaling, and this was supported by computational modeling using a published crystal structure for dimerized human TLR4 ectodomain with associated MD2 co-receptor (LY96 gene product) with LPS bound (PDB ID 4G8A) and a hypothetical structure for the dimerized TIR domain based on TLR10 (PDB ID 2J67, S7 Fig).	('mutations', 'Var', (25, 34))	('TLR10', 'Gene', (354, 359))	('PDB ID', 'Disease', 'MESH:C537985', (361, 367))	('LY96', 'Gene', '23643', (239, 243))	('PDB ID', 'Disease', (274, 280))	('TLR10', 'Gene', '81793', (354, 359))	('effect', 'Reg', (59, 65))	('LY96', 'Gene', (239, 243))	('LPS', 'Disease', (263, 266))	('PDB ID', 'Disease', 'MESH:C537985', (274, 280))	('TLR4 signaling', 'MPA', (69, 83))	('human', 'Species', '9606', (184, 189))	('MD2', 'Gene', '23643', (222, 225))	('PDB ID', 'Disease', (361, 367))	('LPS', 'Disease', 'MESH:C536528', (263, 266))	('MD2', 'Gene', (222, 225))
266536	28531216	Two structurally significant mutations affected the TIR domain (F703C and R787H), which is involved in downstream signaling and interaction with the adaptor molecule MyD88.	('F703C', 'Mutation', 'rs141844350', (64, 69))	('affected', 'Reg', (39, 47))	('R787H', 'Var', (74, 79))	('R787H', 'Mutation', 'rs200905500', (74, 79))	('MyD88', 'Gene', (166, 171))	('MyD88', 'Gene', '4615', (166, 171))	('F703C', 'Var', (64, 69))
266537	28531216	The E439G mutation is also critically located at the TLR4 dimerization interface and may disrupt hydrogen bonds in the binding site of LPS and MD2 (Fig 2D).	('MD2', 'Gene', (143, 146))	('hydrogen bonds', 'MPA', (97, 111))	('LPS', 'Disease', (135, 138))	('E439G', 'Var', (4, 9))	('E439G', 'Mutation', 'p.E439G', (4, 9))	('LPS', 'Disease', 'MESH:C536528', (135, 138))	('hydrogen', 'Chemical', 'MESH:D006859', (97, 105))	('disrupt', 'NegReg', (89, 96))	('MD2', 'Gene', '23643', (143, 146))	('binding', 'Interaction', (119, 126))
266538	28531216	Further, amino acid sequence alignment against seven non-human species showed that the positions of the TIR domain mutations (F703 and R787) are evolutionarily conserved, along with amino acids L80, L498 and S570, and E439 is semi-conserved (S8 Fig).	('R787', 'Var', (135, 139))	('L498', 'Var', (199, 203))	('F703', 'Var', (126, 130))	('L80', 'Var', (194, 197))	('S570', 'Var', (208, 212))	('human', 'Species', '9606', (57, 62))
266539	28531216	Overall the combination of crystal structure modeling, sequence alignment, and SNP prediction algorithms (SIFT and Polyphen) suggested that six of the verified TLR4 mutations could have a functional consequence: L80M, E439G, L498V, S570I, F703C and R787H (S5 Table).	('R787H', 'Var', (249, 254))	('SIFT', 'Disease', 'None', (106, 110))	('R787H', 'Mutation', 'rs200905500', (249, 254))	('E439G', 'Mutation', 'p.E439G', (218, 223))	('E439G', 'Var', (218, 223))	('F703C', 'Var', (239, 244))	('L80M', 'Mutation', 'p.L80M', (212, 216))	('S570I', 'Var', (232, 237))	('TLR4', 'Gene', (160, 164))	('SIFT', 'Disease', (106, 110))	('L80M', 'Var', (212, 216))	('S570I', 'Mutation', 'p.S570I', (232, 237))	('L498V', 'Mutation', 'rs1481925827', (225, 230))	('F703C', 'Mutation', 'rs141844350', (239, 244))	('L498V', 'Var', (225, 230))
266540	28531216	To test our functional predictions for the TLR4 mutants, we performed site-directed mutagenesis and NF-kappaB luciferase reporter assays in HEK293 cells, a common model for measuring TLR signaling.	('HEK293', 'CellLine', 'CVCL:0045', (140, 146))	('TLR', 'Gene', (183, 186))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (43, 46))	('mutants', 'Var', (48, 55))	('TLR', 'Gene', (43, 46))	('NF-kappaB', 'Gene', '4790', (100, 109))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (183, 186))	('NF-kappaB', 'Gene', (100, 109))
266541	28531216	The TLR4 mutants were stimulated first using the weak agonist synthetic monophosphoryl Lipid A (MPLA).	('TLR4', 'Gene', (4, 8))	('mutants', 'Var', (9, 16))	('MPLA', 'Chemical', 'MESH:C048436', (96, 100))	('monophosphoryl Lipid A', 'Chemical', 'MESH:C048436', (72, 94))
266542	28531216	There was a significant decrease in ligand-dependent signaling for 7/9 of the TLR4 mutations stimulated with synthetic MPLA (S9 Fig).	('mutations', 'Var', (83, 92))	('ligand-dependent signaling', 'MPA', (36, 62))	('decrease', 'NegReg', (24, 32))	('MPLA', 'Chemical', 'MESH:C048436', (119, 123))	('TLR4', 'Gene', (78, 82))
266543	28531216	A double mutation of E439G with F703C, representing a tumor with two TLR4 mutations, showed a further decrease in TLR4 signaling compared to F703C (p = 0.0052) but not E439G (p = 0.099).	('F703C', 'Mutation', 'rs141844350', (32, 37))	('decrease', 'NegReg', (102, 110))	('TLR4', 'Gene', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('F703C', 'Var', (32, 37))	('F703C', 'Mutation', 'rs141844350', (141, 146))	('E439G', 'Mutation', 'p.E439G', (168, 173))	('E439G', 'Var', (21, 26))	('E439G', 'Mutation', 'p.E439G', (21, 26))	('TLR4 signaling', 'MPA', (114, 128))
266544	28531216	Stimulation with stronger TLR4 agonists, synthetic Lipid A and lipopolysaccharide (LPS), showed a significant decrease in signaling for four single mutants (E439G, S570I, F703C and R787H) and the double mutation E439G + F703C (Fig 3A).	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (63, 81))	('signaling', 'MPA', (122, 131))	('LPS', 'Disease', (83, 86))	('S570I', 'Mutation', 'p.S570I', (164, 169))	('F703C', 'Mutation', 'rs141844350', (220, 225))	('E439G', 'Mutation', 'p.E439G', (157, 162))	('F703C', 'Var', (171, 176))	('E439G', 'Var', (157, 162))	('LPS', 'Disease', 'MESH:C536528', (83, 86))	('E439G', 'Mutation', 'p.E439G', (212, 217))	('R787H', 'Var', (181, 186))	('decrease', 'NegReg', (110, 118))	('R787H', 'Mutation', 'rs200905500', (181, 186))	('TLR4', 'Gene', (26, 30))	('E439G + F703C', 'Var', (212, 225))	('S570I', 'Var', (164, 169))	('Lipid A', 'Chemical', 'MESH:D008050', (51, 58))	('F703C', 'Mutation', 'rs141844350', (171, 176))
266545	28531216	We also visualized recombinant TLR4-FLAG protein expression in HEK293 cells using confocal microscopy for mutants E439G and R787H, and there was no difference in expression or localization of TLR4-FLAG for either of the mutants in comparison to wild-type, suggesting that the decreased signaling was due to altered protein function rather than mis-folding and failure to reach the cell surface (Fig 3C).	('R787H', 'Mutation', 'rs200905500', (124, 129))	('E439G', 'Var', (114, 119))	('E439G', 'Mutation', 'p.E439G', (114, 119))	('altered', 'Reg', (307, 314))	('decreased', 'NegReg', (276, 285))	('signaling', 'MPA', (286, 295))	('HEK293', 'CellLine', 'CVCL:0045', (63, 69))	('TLR4-FLAG', 'Gene', (31, 40))	('protein', 'Protein', (315, 322))	('R787H', 'Var', (124, 129))
266546	28531216	Next, TLR4 mutants E439G, R787H and E439G+F703C were transfected into EAC cell lines stimulated with LPS for 24 hours, and secretion of the NF-kappaB dependent cytokine IL-8 was measured.	('IL-8', 'Gene', (169, 173))	('TLR4', 'Gene', (6, 10))	('E439G', 'Var', (19, 24))	('NF-kappaB', 'Gene', '4790', (140, 149))	('F703C', 'Mutation', 'rs141844350', (42, 47))	('E439G+F703C', 'Var', (36, 47))	('LPS', 'Disease', (101, 104))	('secretion', 'MPA', (123, 132))	('NF-kappaB', 'Gene', (140, 149))	('E439G', 'Mutation', 'p.E439G', (19, 24))	('E439G', 'Mutation', 'p.E439G', (36, 41))	('R787H', 'Var', (26, 31))	('R787H', 'Mutation', 'rs200905500', (26, 31))	('LPS', 'Disease', 'MESH:C536528', (101, 104))	('IL-8', 'Gene', '3576', (169, 173))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))
266548	28531216	The fold change of IL-8 secretion was significantly lower for mutants R787H and E439G+F703C in comparison to wild-type TLR4 (Fig 3D).	('IL-8', 'Gene', '3576', (19, 23))	('E439G', 'Mutation', 'p.E439G', (80, 85))	('R787H', 'Var', (70, 75))	('IL-8', 'Gene', (19, 23))	('lower', 'NegReg', (52, 57))	('secretion', 'MPA', (24, 33))	('F703C', 'Mutation', 'rs141844350', (86, 91))	('E439G+F703C', 'Var', (80, 91))	('R787H', 'Mutation', 'rs200905500', (70, 75))
266549	28531216	In contrast to HEK293 cells, no significant decrease in TLR4 signaling was observed for mutant E439G stimulated with LPS in the EAC cell lines, suggesting that the strong agonist LPS was still able to trigger TLR signaling despite mutation of the ligand binding site.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (56, 59))	('HEK293', 'CellLine', 'CVCL:0045', (15, 21))	('LPS', 'Disease', (117, 120))	('LPS', 'Disease', 'MESH:C536528', (179, 182))	('mutant E439G', 'Var', (88, 100))	('TLR', 'Gene', (56, 59))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (209, 212))	('binding', 'Interaction', (254, 261))	('E439G', 'Var', (95, 100))	('LPS', 'Disease', 'MESH:C536528', (117, 120))	('E439G', 'Mutation', 'p.E439G', (95, 100))	('TLR', 'Gene', (209, 212))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('LPS', 'Disease', (179, 182))
266550	28531216	Our experiments in cell lines suggest that TLR4 mutations impair TLR signaling and NF-kappaB activation in HEK293 cells and IL-8 secretion by EAC cell lines.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (43, 46))	('impair', 'NegReg', (58, 64))	('NF-kappaB', 'Gene', '4790', (83, 92))	('TLR', 'Gene', (43, 46))	('IL-8', 'Gene', '3576', (124, 128))	('HEK293', 'CellLine', 'CVCL:0045', (107, 113))	('activation', 'MPA', (93, 103))	('NF-kappaB', 'Gene', (83, 92))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (65, 68))	('mutations', 'Var', (48, 57))	('TLR', 'Gene', (65, 68))	('IL-8', 'Gene', (124, 128))
266552	28531216	Out of 89 samples with RNA-Seq data available, 17 samples had TLR pathway mutations and four had TLR4 mutations.	('TLR', 'Gene', (97, 100))	('TLR', 'Gene', (62, 65))	('mutations', 'Var', (74, 83))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (62, 65))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (97, 100))
266553	28531216	Our analysis using DESeq2 shows that expression of IL-8, NFKB2 and RELB was significantly elevated in the tumors compared to normal samples (n = 10), but no significant difference was observed when comparing tumors with mutations in the TLR pathway and wild-type tumors, possibly related to the small sample size (Fig 4A).	('NFKB2', 'Gene', (57, 62))	('tumors', 'Disease', (106, 112))	('RELB', 'Gene', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('TLR', 'Gene', (237, 240))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('IL-8', 'Gene', '3576', (51, 55))	('mutations', 'Var', (220, 229))	('elevated', 'PosReg', (90, 98))	('RELB', 'Gene', '5971', (67, 71))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('NFKB2', 'Gene', '4791', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('expression', 'MPA', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (237, 240))	('IL-8', 'Gene', (51, 55))	('tumors', 'Disease', (263, 269))
266554	28531216	Similarly, there was no significant difference in gene expression between TLR4 mutant and wild-type tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutant', 'Var', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('TLR4', 'Gene', (74, 78))
266555	28531216	We next searched for alternative genes whose expression could be affected by TLR mutations in vivo.	('expression', 'MPA', (45, 55))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (77, 80))	('TLR', 'Gene', (77, 80))	('mutations', 'Var', (81, 90))
266556	28531216	Tumors with TLR pathway mutations showed significant upregulation of NLRP6, GAST, TTC29 and C19orf69, and down-regulation of SFRP5, MYO18B, NAT8L, SHISA9 and IGFALS (Fig 4B).	('TTC29', 'Gene', (82, 87))	('C19orf69', 'Gene', (92, 100))	('NLRP6', 'Gene', (69, 74))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (24, 33))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (12, 15))	('SHISA9', 'Gene', (147, 153))	('IGFALS', 'Gene', '3483', (158, 164))	('Tumors', 'Disease', (0, 6))	('SHISA9', 'Gene', '729993', (147, 153))	('SFRP5', 'Gene', '6425', (125, 130))	('TLR', 'Gene', (12, 15))	('NAT8L', 'Gene', '339983', (140, 145))	('upregulation', 'PosReg', (53, 65))	('SFRP5', 'Gene', (125, 130))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('MYO18B', 'Gene', (132, 138))	('MYO18B', 'Gene', '84700', (132, 138))	('NAT8L', 'Gene', (140, 145))	('NLRP6', 'Gene', '171389', (69, 74))	('C19orf69', 'Gene', '100170765', (92, 100))	('IGFALS', 'Gene', (158, 164))	('down-regulation', 'NegReg', (106, 121))	('GAST', 'Gene', (76, 80))	('TTC29', 'Gene', '83894', (82, 87))
266557	28531216	We validated our findings using RNA-Seq data from 23 independent tumors of which 2 were mutated in the TLR pathway, and significant upregulation was found only for NLRP6 (p = 0.004).	('NLRP6', 'Gene', '171389', (164, 169))	('NLRP6', 'Gene', (164, 169))	('upregulation', 'PosReg', (132, 144))	('TLR', 'Gene', (103, 106))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutated', 'Var', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (103, 106))
266559	28531216	Additionally, quantitative RT-PCR was performed in 22 tumor samples with available RNA (11 of which contained TLR pathway mutations, including 5 TLR4 mutations).	('TLR', 'Gene', (145, 148))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (145, 148))	('TLR', 'Gene', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (122, 131))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', (54, 59))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (110, 113))
266560	28531216	The results showed a similar trend, with upregulation of NLRP6 in TLR pathway mutated samples in comparison to wild-type tumors; however, this did not reach significance likely due to the small sample size (p = 0.172, S11 Fig).	('TLR', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mutated', 'Var', (78, 85))	('NLRP6', 'Gene', '171389', (57, 62))	('NLRP6', 'Gene', (57, 62))	('upregulation', 'PosReg', (41, 53))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (66, 69))
266561	28531216	Of the samples with TLR4 mutations, R787H (relative expression 6.8) and L80M (relative expression 3.7) showed upregulation of NLRP6 compared to mean expression in wild-type tumors (relative expression 0.87, S6 Table).	('NLRP6', 'Gene', (126, 131))	('upregulation', 'PosReg', (110, 122))	('mutations', 'Var', (25, 34))	('TLR4', 'Gene', (20, 24))	('L80M', 'Var', (72, 76))	('R787H', 'Var', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('R787H', 'Mutation', 'rs200905500', (36, 41))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('L80M', 'Mutation', 'p.L80M', (72, 76))	('NLRP6', 'Gene', '171389', (126, 131))
266565	28531216	TLR4 mutations have been previously reported in high grade dysplasia, which implies that this mutation may be acquired later during disease progression.	('TLR4', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('reported', 'Reg', (36, 44))	('dysplasia', 'Disease', (59, 68))	('dysplasia', 'Disease', 'MESH:D004476', (59, 68))
266568	28531216	In addition to EAC, TLR pathway mutations were frequently observed in solid tumors arising in body sites exposed to microbiota including the oral and gastrointestinal tract (colorectal adenocarcinoma, stomach adenocarcinoma and head and neck squamous cell carcinoma), skin (melanoma), urogenital tract (endometrial carcinoma) and respiratory tract (lung adenocarcinoma and squamous cell carcinoma).	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (349, 368))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (228, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('solid tumors', 'Disease', (70, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (373, 396))	('respiratory tract', 'Disease', 'MESH:D012140', (330, 347))	('EAC', 'Phenotype', 'HP:0011459', (15, 18))	('neck squamous cell carcinoma', 'Disease', (237, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (237, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('endometrial carcinoma', 'Disease', (303, 324))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (32, 41))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (20, 23))	('lung adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (349, 396))	('solid tumors', 'Disease', 'MESH:D009369', (70, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (242, 265))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('gastrointestinal tract', 'Disease', (150, 172))	('melanoma', 'Disease', (274, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (303, 324))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (150, 172))	('colorectal adenocarcinoma, stomach adenocarcinoma', 'Disease', 'MESH:D000230', (174, 223))	('TLR', 'Gene', (20, 23))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (303, 324))	('respiratory tract', 'Disease', (330, 347))	('observed', 'Reg', (58, 66))
266571	28531216	However, only one of the tumors from that study had a TLR4 mutation so it was not possible to further correlate the findings with our current study, and additional research is needed to investigate the link between TLR mutations and the microbiome in EAC.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (215, 218))	('tumors', 'Disease', (25, 31))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('EAC', 'Phenotype', 'HP:0011459', (251, 254))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('TLR', 'Gene', (215, 218))	('TLR', 'Gene', (54, 57))	('mutation', 'Var', (59, 67))	('EAC', 'Disease', (251, 254))	('mutations', 'Var', (219, 228))
266572	28531216	This suggests that the mutations differentially affected signaling with weak versus strong agonists, which may be relevant to the different microbial antigens present in the tumor environment.	('signaling', 'MPA', (57, 66))	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('affected', 'Reg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
266573	28531216	The model system was also a contributing factor; for instance E439G was hyporesponsive to LPS in HEK293 cells but not EAC cell lines.	('E439G', 'Var', (62, 67))	('LPS', 'Disease', (90, 93))	('LPS', 'Disease', 'MESH:C536528', (90, 93))	('E439G', 'Mutation', 'p.E439G', (62, 67))	('EAC', 'Phenotype', 'HP:0011459', (118, 121))	('HEK293', 'CellLine', 'CVCL:0045', (97, 103))
266574	28531216	In EAC cell lines, addition of the second mutation F703C was required to significantly reduce TLR4 signaling activity.	('TLR4 signaling activity', 'MPA', (94, 117))	('F703C', 'Var', (51, 56))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('F703C', 'Mutation', 'rs141844350', (51, 56))	('reduce', 'NegReg', (87, 93))
266575	28531216	Further, loss of heterozygosity events overlapped with four TLR4 mutations, R787H, E603D, T193K, and L498V.	('T193K', 'Mutation', 'rs752866944', (90, 95))	('R787H', 'Var', (76, 81))	('L498V', 'Var', (101, 106))	('R787H', 'Mutation', 'rs200905500', (76, 81))	('E603D', 'Mutation', 'p.E603D', (83, 88))	('T193K', 'Var', (90, 95))	('E603D', 'Var', (83, 88))	('L498V', 'Mutation', 'rs1481925827', (101, 106))	('TLR4', 'Gene', (60, 64))
266576	28531216	Of these, R787H showed decreased signaling in response to strong and weak agonists, L498V showed decreased signaling in response to weak agonist only, and E603D and T193K showed no significant change.	('L498V', 'Var', (84, 89))	('E603D', 'Var', (155, 160))	('T193K', 'Var', (165, 170))	('decreased', 'NegReg', (97, 106))	('signaling', 'MPA', (107, 116))	('T193K', 'Mutation', 'rs752866944', (165, 170))	('E603D', 'Mutation', 'p.E603D', (155, 160))	('R787H', 'Var', (10, 15))	('decreased', 'NegReg', (23, 32))	('signaling', 'MPA', (33, 42))	('L498V', 'Mutation', 'rs1481925827', (84, 89))	('R787H', 'Mutation', 'rs200905500', (10, 15))
266577	28531216	A possible mechanism is that defective TLR4 signaling may negatively impact epithelial cell repair, which is in part dependent on TLR4 stimulation, and potentially enable microbes to breach the epithelial barrier in the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('negatively impact', 'NegReg', (58, 75))	('enable', 'Reg', (164, 170))	('defective', 'Var', (29, 38))	('epithelial cell repair', 'CPA', (76, 98))	('TLR4', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
266578	28531216	found that the single nucleotide polymorphism c.896A>G (p.D299G) was associated with an increased risk of gastric cancer in two patient populations, and cells with this mutation have been shown to be hypo-responsive to lipopolysaccharide.	('c.896A>G', 'Mutation', 'rs4986790', (46, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('c.896A>G', 'Var', (46, 54))	('gastric cancer', 'Disease', (106, 120))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (219, 237))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('patient', 'Species', '9606', (128, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('p.D299G', 'Mutation', 'rs4986790', (56, 63))
266579	28531216	found no significant increased risk for EAC or esophageal squamous cell carcinoma with this germline polymorphism, and the D299G polymorphism was not identified in either of the ICGC or TCGA cohorts.	('EAC', 'Phenotype', 'HP:0011459', (40, 43))	('esophageal squamous cell carcinoma', 'Disease', (47, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('EAC', 'Disease', (40, 43))	('D299G', 'Mutation', 'rs4986790', (123, 128))	('D299G', 'Var', (123, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (47, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))
266580	28531216	The relationship between TLR4 signaling and tumorigenesis is complex and involves both innate and adaptive immunity, with evidence showing that TLR4 signaling can enhance or suppress cancer development, depending on the model system.	('cancer', 'Disease', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('enhance', 'PosReg', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('suppress', 'NegReg', (174, 182))	('tumor', 'Disease', (44, 49))	('TLR4', 'Var', (144, 148))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
266583	28531216	Additionally, analysis of TCGA expression data suggested that NLRP6 is upregulated in TLR mutant tumors, which may reflect cross-talk between the TLR pathway and NOD-like receptor signaling pathway.	('TLR', 'Gene', (86, 89))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (146, 149))	('NLRP6', 'Gene', '171389', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutant', 'Var', (90, 96))	('TLR', 'Gene', (146, 149))	('NLRP6', 'Gene', (62, 67))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (86, 89))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('upregulated', 'PosReg', (71, 82))
266585	28531216	Further understanding of how altered TLR signaling may contribute to the inflammatory tumor microenvironment in Barrett's carcinogenesis could be helpful in cancer prevention strategies.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (37, 40))	("Barrett's carcinogenesis", 'Disease', (112, 136))	('tumor', 'Disease', (86, 91))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (112, 136))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('TLR', 'Gene', (37, 40))	('altered', 'Var', (29, 36))	('cancer', 'Disease', (157, 163))	('contribute', 'Reg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
266594	28531216	PathScan was used to assess whether mutations affecting the TLR pathway were significantly enriched in the ICGC cohort or the Dulak et al.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (60, 63))	('TLR', 'Gene', (60, 63))	('ICGC', 'Disease', (107, 111))	('mutations', 'Var', (36, 45))
266597	28531216	The COSMIC database v78 (http://cancer.sanger.ac.uk/cosmic) was downloaded and interrogated for TLR4 and TLR pathway mutations.	('mutations', 'Var', (117, 126))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('TLR', 'Gene', (105, 108))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('TLR', 'Gene', (96, 99))
266598	28531216	Mutations were counted by cancer type as defined by the filters for tissue type and histology described in S3 Table.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
266599	28531216	The ICGC TLR4 mutations were modeled using mutation functions in COOT (Crystallographic Object-Oriented Toolkit) applied to the crystal structure for dimerized TLR4 ectodomain (PDB ID: 4G8A) bound to MD2 and lipopolysaccharide (LPS) and a hypothetical structure for the Toll/interleukin-1 receptor (TIR) domain based on the TLR10 dimer (PDB ID: 2J67).	('PDB ID', 'Disease', (177, 183))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (208, 226))	('PDB ID', 'Disease', 'MESH:C537985', (177, 183))	('LPS', 'Disease', (228, 231))	('TLR10', 'Gene', '81793', (324, 329))	('MD2', 'Gene', '23643', (200, 203))	('TLR4', 'Gene', (9, 13))	('PDB ID', 'Disease', 'MESH:C537985', (337, 343))	('bound', 'Interaction', (191, 196))	('PDB ID', 'Disease', (337, 343))	('MD2', 'Gene', (200, 203))	('LPS', 'Disease', 'MESH:C536528', (228, 231))	('mutations', 'Var', (14, 23))	('TLR10', 'Gene', (324, 329))
266600	28531216	The starting ectodomain PDB structure 4G8A was the common human variant (D299G and T399I), which was initially mutated back to D299 T399 before modeling the observed ICGC mutations.	('D299 T399', 'Var', (127, 136))	('human variant', 'Species', '9606', (58, 71))	('T399I', 'Mutation', 'rs4986791', (83, 88))	('T399I', 'Var', (83, 88))	('D299G', 'Var', (73, 78))	('D299G', 'Mutation', 'rs4986790', (73, 78))
266632	28531216	RNA-Seq read counts per gene and variant calls for esophageal cancer were downloaded from the TCGA data portal (https://gdc.cancer.gov/).	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancer', 'Disease', (51, 68))	('variant', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
266634	28531216	Differential expression analysis between TLR pathway mutated vs. wild-type, TLR pathway vs. control and wild-type vs. control samples was performed using DESeq2.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (76, 79))	('TLR', 'Gene', (76, 79))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (41, 44))	('mutated', 'Var', (53, 60))	('TLR', 'Gene', (41, 44))
266635	28531216	The Wilcoxon rank-sum test was used to compare the frequency of TLR mutant samples for microbiome exposed versus rarely exposed tumors in the COSMIC database.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (128, 134))	('TLR', 'Gene', (64, 67))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('mutant', 'Var', (68, 74))
266636	24260422	 Hsa-miR-34b/c rs4938723 T>C and hsa-miR-423 rs6505162 C>A Polymorphisms Are Associated with the Risk of Esophageal Cancer in a Chinese Population Esophageal cancer is the eighth most common cancer and sixth leading cause of cancer associated death worldwide.	('Esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('cancer', 'Disease', (225, 231))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (105, 122))	('eighth', 'Disease', 'MESH:D061285', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('Associated', 'Reg', (77, 87))	('rs4938723', 'Mutation', 'rs4938723', (15, 24))	('rs6505162', 'Mutation', 'rs6505162', (45, 54))	('cancer', 'Disease', (191, 197))	('rs4938723 T>C', 'Var', (15, 28))	('death', 'Disease', 'MESH:D003643', (243, 248))	('miR-34b', 'Gene', '407041', (5, 12))	('cancer', 'Disease', (158, 164))	('rs6505162 C>A', 'Var', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('miR-34b', 'Gene', (5, 12))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('Esophageal cancer', 'Disease', (147, 164))	('eighth', 'Disease', (172, 178))	('Esophageal Cancer', 'Disease', (105, 122))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('hsa-miR-423', 'Gene', '494335', (33, 44))	('hsa-miR-423', 'Gene', (33, 44))	('death', 'Disease', (243, 248))
266638	24260422	We conducted a hospital based case-control study to evaluate the genetic susceptibility of functional single nucleotide polymorphisms (SNPs) in the microRNAs on the development of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (180, 197))	('esophageal cancer', 'Disease', (180, 197))	('single nucleotide polymorphisms', 'Var', (102, 133))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
266640	24260422	The hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G, pre-miR-125a rs12975333 G>T and hsa-miR-423 rs6505162 C>A genotypes were determined using Ligation Detection Reaction (LDR) method.	('hsa-miR-423', 'Gene', (93, 104))	('miR-125a', 'Gene', '406910', (65, 73))	('rs6505162', 'Mutation', 'rs6505162', (105, 114))	('rs531564 C>G', 'Var', (47, 59))	('hsa-miR-423', 'Gene', '494335', (93, 104))	('miR-124-1', 'Gene', '406907', (37, 46))	('rs12975333', 'Mutation', 'rs12975333', (74, 84))	('rs4938723', 'Mutation', 'rs4938723', (18, 27))	('miR-124-1', 'Gene', (37, 46))	('rs531564', 'Mutation', 'rs531564', (47, 55))	('rs12975333 G>T', 'Var', (74, 88))	('rs4938723 T>C', 'Var', (18, 31))	('miR-125a', 'Gene', (65, 73))
266641	24260422	Our results demonstrated that hsa-miR-34b/c rs4938723 CC genotype had a decreased risk of ESCC.	('decreased', 'NegReg', (72, 81))	('rs4938723', 'Mutation', 'rs4938723', (44, 53))	('rat', 'Species', '10116', (19, 22))	('ESCC', 'Disease', (90, 94))	('rs4938723 CC', 'Var', (44, 56))	('hsa-miR-34b/c', 'Protein', (30, 43))
266643	24260422	Hsa-miR-423 rs6505162 C>A might associated with a significantly increased risk of ESCC in patients who smoking.	('rs6505162 C>A', 'Var', (12, 25))	('ESCC', 'Disease', (82, 86))	('Hsa-miR-423', 'Gene', (0, 11))	('Hsa-miR-423', 'Gene', '494335', (0, 11))	('rs6505162', 'Mutation', 'rs6505162', (12, 21))	('associated', 'Reg', (32, 42))	('patients', 'Species', '9606', (90, 98))
266644	24260422	These findings indicated that functional polymorphisms hsa-miR-34b/c rs4938723 T>C and hsa-miR-423 rs6505162 C>A might alter individual susceptibility to ESCC.	('hsa-miR-423', 'Gene', '494335', (87, 98))	('hsa-miR-423', 'Gene', (87, 98))	('ESCC', 'Disease', (154, 158))	('alter', 'Reg', (119, 124))	('rs6505162 C>A', 'Var', (99, 112))	('rs4938723', 'Mutation', 'rs4938723', (69, 78))	('rs6505162', 'Mutation', 'rs6505162', (99, 108))	('rs4938723 T>C', 'Var', (69, 82))
266648	24260422	Genetic factors, such as single nucleotide polymorphisms (SNPs), may contribute to carcinogenesis.	('carcinogenesis', 'Disease', (83, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('single nucleotide polymorphisms', 'Var', (25, 56))	('contribute', 'Reg', (69, 79))
266649	24260422	The SNPs in the genomic miRNA sequences could influence miRNA-dependent regulation, affect the final level and function of miRNAs and alter consequently tumor susceptibility.	('influence', 'Reg', (46, 55))	('final level', 'MPA', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('miR', 'Gene', '220972', (123, 126))	('alter', 'Reg', (134, 139))	('miR', 'Gene', (123, 126))	('affect', 'Reg', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('miR', 'Gene', '220972', (24, 27))	('SNPs', 'Var', (4, 8))	('miR', 'Gene', (24, 27))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))
266651	24260422	In previous studies in colorectal cancer, oral cancer and malignant melanoma, down-regulation of mir-34b/c by methylation was found.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('colorectal cancer', 'Disease', (23, 40))	('malignant melanoma', 'Phenotype', 'HP:0002861', (58, 76))	('mir-34b', 'Gene', '407041', (97, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (23, 40))	('malignant melanoma', 'Disease', 'MESH:D008545', (58, 76))	('malignant melanoma', 'Disease', (58, 76))	('oral cancer', 'Disease', 'MESH:D009062', (42, 53))	('down-regulation', 'NegReg', (78, 93))	('methylation', 'Var', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (23, 40))	('oral cancer', 'Disease', (42, 53))	('mir-34b', 'Gene', (97, 104))
266652	24260422	Hsa-miR-34b/c rs4938723 polymorphism is located within the CpG island of pri-miR-34b/c, and might be the predicted binding site for GATA-X transcription factors.	('Hsa-miR-34b/c', 'Gene', (0, 13))	('rs4938723', 'Var', (14, 23))	('pri-miR-34b/c', 'Gene', (73, 86))	('rs4938723', 'Mutation', 'rs4938723', (14, 23))
266653	24260422	Hsa-miR-34b/c rs4938723 T>C polymorphism was associated with the risk of nasopharyngeal carcinoma, hepatocellular carcinoma, colorectal cancer and breast cancer survival.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('nasopharyngeal carcinoma', 'Disease', (73, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (73, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('rs4938723', 'Mutation', 'rs4938723', (14, 23))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (99, 123))	('rs4938723 T>C', 'Var', (14, 27))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('Hsa-miR-34b/c', 'Gene', (0, 13))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('breast cancer', 'Disease', (147, 160))	('associated', 'Reg', (45, 55))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (73, 97))	('hepatocellular carcinoma', 'Disease', (99, 123))	('colorectal cancer', 'Disease', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
266654	24260422	Besides hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G, pre-miR-125a rs12975333 G>T and hsa-miR-423 rs6505162 C>A were also associated with the risk of different types of cancers.	('rs12975333', 'Mutation', 'rs12975333', (78, 88))	('rs6505162', 'Mutation', 'rs6505162', (109, 118))	('miR-124-1', 'Gene', (41, 50))	('rs6505162 C>A', 'Var', (109, 122))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('rs12975333 G>T', 'Var', (78, 92))	('miR-124-1', 'Gene', '406907', (41, 50))	('associated', 'Reg', (133, 143))	('rs4938723', 'Mutation', 'rs4938723', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('rs4938723 T>C', 'Var', (22, 35))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('hsa-miR-423', 'Gene', '494335', (97, 108))	('hsa-miR-423', 'Gene', (97, 108))	('cancers', 'Disease', (180, 187))	('miR-125a', 'Gene', '406910', (69, 77))	('rs531564 C>G', 'Var', (51, 63))	('miR-125a', 'Gene', (69, 77))	('rs531564', 'Mutation', 'rs531564', (51, 59))
266655	24260422	The rs531564 C>G SNP in pri-miR-124-1 was associated with an increased risk of bladder cancer and esophageal cancer in males.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('associated', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('miR-124-1', 'Gene', '406907', (28, 37))	('esophageal cancer', 'Disease', (98, 115))	('rs531564 C>G', 'Var', (4, 16))	('rs531564', 'Mutation', 'rs531564', (4, 12))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('bladder cancer', 'Disease', (79, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))	('miR-124-1', 'Gene', (28, 37))
266656	24260422	The pre-miR-125a rs12975333 G>T polymorphism was a founder mutation specific to the Antwerp area and associated with high risk for breast cancer.	('miR-125a', 'Gene', '406910', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('associated', 'Reg', (101, 111))	('breast cancer', 'Disease', (131, 144))	('rs12975333', 'Mutation', 'rs12975333', (17, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('rs12975333 G>T', 'Var', (17, 31))	('miR-125a', 'Gene', (8, 16))
266657	24260422	Hsa-miR-423 rs6505162 C>A polymorphism was associated with reduced breast cancer risk.	('rs6505162 C>A', 'Var', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('reduced', 'NegReg', (59, 66))	('Hsa-miR-423', 'Gene', (0, 11))	('Hsa-miR-423', 'Gene', '494335', (0, 11))	('rs6505162', 'Mutation', 'rs6505162', (12, 21))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
266658	24260422	Hsa-miR-423 rs6505162 C>A polymorphism was also significantly associated with both the overall survival and the recurrence-free survival of colorectal cancer.	('rs6505162 C>A', 'Var', (12, 25))	('colorectal cancer', 'Disease', (140, 157))	('associated with', 'Reg', (62, 77))	('Hsa-miR-423', 'Gene', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('recurrence-free survival', 'CPA', (112, 136))	('Hsa-miR-423', 'Gene', '494335', (0, 11))	('rs6505162', 'Mutation', 'rs6505162', (12, 21))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))
266659	24260422	We previously investigated miR-196a2 rs11614913 T>C, miR-146a rs2910164 C>G, miR-499 rs3746444 T>C, miR-26a-1 rs7372209 C>T and miR-27a rs895819 T>C SNPs and esophageal squamous cell carcinoma (ESCC) risk in 380 cancer cases and 380 controls.	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (53, 56))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (158, 192))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (100, 103))	('rs2910164 C>G', 'Var', (62, 75))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('rs7372209 C>T', 'Var', (110, 123))	('miR', 'Gene', (53, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('miR', 'Gene', (27, 30))	('rs895819', 'Mutation', 'rs895819', (136, 144))	('miR-26a', 'Gene', (100, 107))	('rs895819 T>C SNPs', 'Var', (136, 153))	('miR', 'Gene', '220972', (128, 131))	('miR-27a', 'Gene', '407018', (128, 135))	('miR-146a', 'Gene', (53, 61))	('miR-26a', 'Gene', '407015', (100, 107))	('miR-146a', 'Gene', '406938', (53, 61))	('esophageal squamous cell carcinoma', 'Disease', (158, 192))	('cancer', 'Disease', (212, 218))	('miR', 'Gene', (128, 131))	('rs7372209', 'Mutation', 'rs7372209', (110, 119))	('rs2910164', 'Mutation', 'rs2910164', (62, 71))	('rs3746444 T>C', 'Var', (85, 98))	('miR-196a2', 'Gene', '406973', (27, 36))	('rs3746444', 'Mutation', 'rs3746444', (85, 94))	('miR', 'Gene', '220972', (77, 80))	('rs11614913', 'Mutation', 'rs11614913', (37, 47))	('rs11614913 T>C', 'Var', (37, 51))	('miR-27a', 'Gene', (128, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('miR', 'Gene', '220972', (100, 103))	('miR-196a2', 'Gene', (27, 36))
266660	24260422	We found miR-196a2 rs11614913 T>C might contribute to decreased ESCC risk among women patients and patients who never smoking or drinking.	('rs11614913 T>C', 'Var', (19, 33))	('women', 'Species', '9606', (80, 85))	('ESCC', 'Disease', (64, 68))	('rs11614913', 'Mutation', 'rs11614913', (19, 29))	('miR-196a2', 'Gene', '406973', (9, 18))	('decreased ESCC', 'Phenotype', 'HP:0025022', (54, 68))	('patients', 'Species', '9606', (99, 107))	('decreased', 'NegReg', (54, 63))	('miR-196a2', 'Gene', (9, 18))	('patients', 'Species', '9606', (86, 94))
266661	24260422	Now, the objective of this investigation was to evaluate the association between hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G, pre-miR-125a rs12975333 G>T and hsa-miR-423 rs6505162 C>A genotypes and ESCC risk.	('miR-124-1', 'Gene', '406907', (114, 123))	('rs4938723', 'Mutation', 'rs4938723', (95, 104))	('hsa-miR-423', 'Gene', '494335', (170, 181))	('hsa-miR-423', 'Gene', (170, 181))	('miR-124-1', 'Gene', (114, 123))	('miR-125a', 'Gene', '406910', (142, 150))	('rs4938723 T>C', 'Var', (95, 108))	('ESCC', 'Disease', (210, 214))	('rs6505162', 'Mutation', 'rs6505162', (182, 191))	('miR-125a', 'Gene', (142, 150))	('rs12975333', 'Mutation', 'rs12975333', (151, 161))	('rs531564 C>G', 'Var', (124, 136))	('rs12975333 G>T', 'Var', (151, 165))	('rs531564', 'Mutation', 'rs531564', (124, 132))	('association', 'Interaction', (61, 72))
266669	24260422	Differences in the distributions of demographic characteristics, selected variables, and genotypes of the hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G, pre-miR-125a rs12975333 G>T and hsa-miR-423 rs6505162 C>A variants between the cases and controls were evaluated using student t test and the chi 2 test.	('rs12975333', 'Mutation', 'rs12975333', (176, 186))	('rs531564 C>G', 'Var', (149, 161))	('rs531564', 'Mutation', 'rs531564', (149, 157))	('miR-124-1', 'Gene', '406907', (139, 148))	('rs4938723', 'Mutation', 'rs4938723', (120, 129))	('miR-125a', 'Gene', '406910', (167, 175))	('miR-124-1', 'Gene', (139, 148))	('rs6505162', 'Mutation', 'rs6505162', (207, 216))	('miR-125a', 'Gene', (167, 175))	('rs4938723 T>C', 'Var', (120, 133))	('hsa-miR-423', 'Gene', '494335', (195, 206))	('hsa-miR-423', 'Gene', (195, 206))
266673	24260422	The observed genotype frequencies for hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G and hsa-miR-423 rs6505162 C>A polymorphisms in the controls were in HWE (p = 0.675, p = 0.400 and p = 0.299) except pre-miR-125a rs12975333 G>T (not available) (Table 2).	('miR-125a', 'Gene', (214, 222))	('miR-124-1', 'Gene', '406907', (71, 80))	('rs6505162', 'Mutation', 'rs6505162', (110, 119))	('rs531564 C>G', 'Var', (81, 93))	('rs12975333 G>T', 'Var', (223, 237))	('rs4938723', 'Mutation', 'rs4938723', (52, 61))	('miR-124-1', 'Gene', (71, 80))	('miR-125a', 'Gene', '406910', (214, 222))	('hsa-miR-423', 'Gene', '494335', (98, 109))	('hsa-miR-423', 'Gene', (98, 109))	('rs12975333', 'Mutation', 'rs12975333', (223, 233))	('rs531564', 'Mutation', 'rs531564', (81, 89))	('rs6505162 C>A', 'Var', (110, 123))	('rs4938723 T>C', 'Var', (52, 65))
266674	24260422	The genotype distributions of hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G, pre-miR-125a rs12975333 G>T and hsa-miR-423 rs6505162 C>A in the cases and the controls are shown in Table 3.	('rs12975333 G>T', 'Var', (100, 114))	('miR-124-1', 'Gene', (63, 72))	('miR-125a', 'Gene', (91, 99))	('rs531564', 'Mutation', 'rs531564', (73, 81))	('rs6505162', 'Mutation', 'rs6505162', (131, 140))	('rs4938723', 'Mutation', 'rs4938723', (44, 53))	('hsa-miR-423', 'Gene', '494335', (119, 130))	('hsa-miR-423', 'Gene', (119, 130))	('miR-125a', 'Gene', '406910', (91, 99))	('rs4938723 T>C', 'Var', (44, 57))	('rs531564 C>G', 'Var', (73, 85))	('miR-124-1', 'Gene', '406907', (63, 72))	('rs12975333', 'Mutation', 'rs12975333', (100, 110))	('rs6505162 C>A', 'Var', (131, 144))
266675	24260422	In the single locus analyses, the genotype frequencies of hsa-miR-34b/c rs4938723 T>C were 46.2% (TT), 46.3% (TC), and 7.5% (CC) in the case patients and 46.1% (TT), 43.1% (TC), and 10.8% (CC) in the control subjects, and the difference was not statistically significant (p = 0.101).	('TC', 'Chemical', 'MESH:D013667', (173, 175))	('hsa-miR-34b/c', 'Gene', (58, 71))	('rs4938723 T>C', 'Var', (72, 85))	('rs4938723', 'Mutation', 'rs4938723', (72, 81))	('TC', 'Chemical', 'MESH:D013667', (110, 112))	('patients', 'Species', '9606', (141, 149))
266676	24260422	In the recessive model, when the hsa-miR-34b/c rs4938723 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with a statistically significantly decreased risk for ESCC (CC vs. TT/TC: adjusted OR = 0.65, 95% CI = 0.44-0.97, p = 0.036).	('rs4938723', 'Mutation', 'rs4938723', (47, 56))	('TC', 'Chemical', 'MESH:D013667', (60, 62))	('ESCC', 'Disease', (203, 207))	('TC', 'Chemical', 'MESH:D013667', (219, 221))	('decreased', 'NegReg', (184, 193))	('rs4938723', 'Var', (47, 56))
266677	24260422	When the hsa-miR-34b/c rs4938723 TT homozygote genotype was used as the reference group, the TC genotype was not associated with the risk for ESCC (TC vs. TT: adjusted OR = 1.11, 95% CI = 0.88-1.40, p = 0.397); the CC genotype was not associated with the risk for ESCC (CC vs. TT: adjusted OR = 0.69, 95% CI = 0.45-1.04, p = 0.076).	('rs4938723', 'Mutation', 'rs4938723', (23, 32))	('rs4938723', 'Var', (23, 32))	('ESCC', 'Disease', (142, 146))	('TC', 'Chemical', 'MESH:D013667', (148, 150))	('TC', 'Chemical', 'MESH:D013667', (93, 95))
266678	24260422	In the dominant model, the hsa-miR-34b/c rs4938723 TC/CC variants were not associated with the risk for ESCC, compared with the hsa-miR-34b/c rs4938723 TT genotype (adjusted OR = 1.02, 95% CI = 0.82-1.28, p = 0.853) (Table 3).	('rs4938723', 'Var', (41, 50))	('rs4938723', 'Mutation', 'rs4938723', (41, 50))	('rs4938723', 'Mutation', 'rs4938723', (142, 151))	('ESCC', 'Disease', (104, 108))	('TC', 'Chemical', 'MESH:D013667', (51, 53))
266679	24260422	No association was observed between pri-miR-124-1 rs531564 C>G and hsa-miR-423 rs6505162 C>A polymorphisms and the risk of ESCC (Table 3).	('rs531564 C>G', 'Var', (50, 62))	('hsa-miR-423', 'Gene', '494335', (67, 78))	('hsa-miR-423', 'Gene', (67, 78))	('ESCC', 'Disease', (123, 127))	('rs531564', 'Mutation', 'rs531564', (50, 58))	('miR-124-1', 'Gene', '406907', (40, 49))	('rs6505162 C>A', 'Var', (79, 92))	('miR-124-1', 'Gene', (40, 49))	('rs6505162', 'Mutation', 'rs6505162', (79, 88))
266680	24260422	For pre-miR-125a rs12975333 G>T, all genotypes are GG homozygotes (Table 3).	('rs12975333', 'Mutation', 'rs12975333', (17, 27))	('miR-125a', 'Gene', '406910', (8, 16))	('rs12975333 G>T', 'Var', (17, 31))	('miR-125a', 'Gene', (8, 16))
266681	24260422	To evaluate the effects of hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G and hsa-miR-423 rs6505162 C>A genotypes on ESCC risk according to different age, sex, smoking and alcohol drinking status; we performed the stratification analyses (Table 4).	('rs531564 C>G', 'Var', (70, 82))	('rs531564', 'Mutation', 'rs531564', (70, 78))	('hsa-miR-423', 'Gene', '494335', (87, 98))	('hsa-miR-423', 'Gene', (87, 98))	('rs6505162 C', 'Var', (99, 110))	('rat', 'Species', '10116', (225, 228))	('alcohol drinking', 'Phenotype', 'HP:0030955', (181, 197))	('miR-124-1', 'Gene', '406907', (60, 69))	('rs4938723', 'Mutation', 'rs4938723', (41, 50))	('alcohol', 'Chemical', 'MESH:D000438', (181, 188))	('ESCC', 'Disease', (126, 130))	('rs4938723 T>C', 'Var', (41, 54))	('rs6505162', 'Mutation', 'rs6505162', (99, 108))	('miR-124-1', 'Gene', (60, 69))
266682	24260422	A significantly decreased risk of ESCC associated with the hsa-miR-34b/c rs4938723 T>C polymorphism was evident among patients who never drinking (CC vs. TT/TC: adjusted OR = 0.57, 95% CI = 0.34-0.94, p = 0.029) (Table 4).	('rs4938723 T>C', 'Var', (73, 86))	('TC', 'Chemical', 'MESH:D013667', (157, 159))	('ESCC', 'Disease', (34, 38))	('rs4938723', 'Mutation', 'rs4938723', (73, 82))	('hsa-miR-34b/c', 'Gene', (59, 72))	('patients', 'Species', '9606', (118, 126))	('decreased', 'NegReg', (16, 25))
266683	24260422	In patients who smoking, hsa-miR-423 rs6505162 C>A might associated with a significantly increased risk of ESCC (AA vs. CC/CA: adjusted OR = 4.94, 95% CI = 1.42-17.21, p = 0.012) (Table 4).	('rs6505162 C>A', 'Var', (37, 50))	('rs6505162', 'Mutation', 'rs6505162', (37, 46))	('patients', 'Species', '9606', (3, 11))	('hsa-miR-423', 'Gene', '494335', (25, 36))	('hsa-miR-423', 'Gene', (25, 36))
266684	24260422	In this hospital-based case-control study of ESCC, we investigated the associations of hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G, pre-miR-125a rs12975333 G>T and hsa-miR-423 rs6505162 C>A with risk of ESCC in a high risk Chinese population.	('ESCC', 'Disease', (215, 219))	('miR-125a', 'Gene', (148, 156))	('rs4938723 T>C', 'Var', (101, 114))	('hsa-miR-423', 'Gene', '494335', (176, 187))	('hsa-miR-423', 'Gene', (176, 187))	('miR-124-1', 'Gene', '406907', (120, 129))	('rs531564 C>G', 'Var', (130, 142))	('miR-125a', 'Gene', '406910', (148, 156))	('rs531564', 'Mutation', 'rs531564', (130, 138))	('rs12975333', 'Mutation', 'rs12975333', (157, 167))	('rs4938723', 'Mutation', 'rs4938723', (101, 110))	('rs12975333 G>T', 'Var', (157, 171))	('associations', 'Interaction', (71, 83))	('miR-124-1', 'Gene', (120, 129))	('rs6505162', 'Mutation', 'rs6505162', (188, 197))
266685	24260422	Our multivariable logistic analysis revealed that hsa-miR-34b/c rs4938723 CC genotype had a decreased risk of ESCC.	('decreased', 'NegReg', (92, 101))	('rs4938723', 'Mutation', 'rs4938723', (64, 73))	('rs4938723 CC', 'Var', (64, 76))	('ESCC', 'Disease', (110, 114))
266687	24260422	A rat model experiment indicated that the alteration of miR-34b/c under an inflammatory microenvironment can be influenced by p53.	('rat', 'Species', '10116', (46, 49))	('miR-34b/c', 'Gene', (56, 65))	('rat', 'Species', '10116', (2, 5))	('influenced', 'Reg', (112, 122))	('p53', 'Var', (126, 129))
266688	24260422	By DNA methylation of its own promoter, miR-34 family has been silenced in numerous cancers.	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('numerous cancers', 'Disease', 'MESH:D009369', (75, 91))	('methylation', 'Var', (7, 18))	('miR-34', 'Gene', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('miR-34', 'Gene', '407040', (40, 46))	('numerous cancers', 'Disease', (75, 91))	('silenced', 'NegReg', (63, 71))
266689	24260422	By triggering Wnt signaling cascades, the loss of miR-34 impairs p53-mediated cell death.	('loss', 'Var', (42, 46))	('impairs', 'NegReg', (57, 64))	('miR-34', 'Gene', (50, 56))	('miR-34', 'Gene', '407040', (50, 56))	('death', 'Disease', 'MESH:D003643', (83, 88))	('death', 'Disease', (83, 88))
266692	24260422	In a previous study, down-regulation of mir-34b/c by methylation was found in colorectal cancer, oral cancer and malignant melanoma.	('malignant melanoma', 'Phenotype', 'HP:0002861', (113, 131))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('malignant melanoma', 'Disease', (113, 131))	('malignant melanoma', 'Disease', 'MESH:D008545', (113, 131))	('mir-34b', 'Gene', '407041', (40, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('methylation', 'Var', (53, 64))	('oral cancer', 'Disease', 'MESH:D009062', (97, 108))	('down-regulation', 'NegReg', (21, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('mir-34b', 'Gene', (40, 47))	('oral cancer', 'Disease', (97, 108))	('colorectal cancer', 'Disease', (78, 95))
266693	24260422	The hsa-miR-34b/c rs4938723 T>C SNP is located within the CpG island of pri-miR-34b/c and may affect a predicted GATA-X transcription factor binding.	('binding', 'Interaction', (141, 148))	('affect', 'Reg', (94, 100))	('rs4938723 T>', 'Var', (18, 30))	('rs4938723', 'Mutation', 'rs4938723', (18, 27))	('GATA-X', 'Protein', (113, 119))	('hsa-miR-34b/c', 'Gene', (4, 17))
266694	24260422	Hsa-miR-423 rs6505162 C>A polymorphism was associated with reduced breast cancer risk and both the overall survival and the recurrence-free survival of colorectal cancer.	('rs6505162 C>A', 'Var', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('reduced', 'NegReg', (59, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('Hsa-miR-423', 'Gene', (0, 11))	('Hsa-miR-423', 'Gene', '494335', (0, 11))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('rs6505162', 'Mutation', 'rs6505162', (12, 21))	('colorectal cancer', 'Disease', (152, 169))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
266695	24260422	In our study, we found hsa-miR-34b/c rs4938723 CC genotype had a decreased risk of ESCC among patients who never drinking, hsa-miR-423 rs6505162 C>A might associated with a significantly increased risk of ESCC in patients who smoking, indicating gene-environment interaction.	('rs4938723', 'Mutation', 'rs4938723', (37, 46))	('patients', 'Species', '9606', (94, 102))	('decreased', 'NegReg', (65, 74))	('rs6505162', 'Mutation', 'rs6505162', (135, 144))	('rs4938723 CC', 'Var', (37, 49))	('patients', 'Species', '9606', (213, 221))	('ESCC', 'Disease', (83, 87))	('hsa-miR-423', 'Gene', (123, 134))	('hsa-miR-423', 'Gene', '494335', (123, 134))	('rs6505162 C>A', 'Var', (135, 148))	('ESCC', 'Disease', (205, 209))
266696	24260422	In the present Chinese study, the allele frequency of hsa-miR-34b/c rs4938723 C was 0.324 among 686 control subjects, which is slightly higher than that of Japanese population (0.261) and similar to that of European population (0.310) and Sub-Saharan African population (0.305).	('rs4938723', 'Mutation', 'rs4938723', (68, 77))	('0.324', 'Var', (84, 89))	('rs4938723 C', 'Var', (68, 79))	('hsa-miR-34b/c', 'Gene', (54, 67))
266697	24260422	The allele frequency of hsa-miR-423 rs6505162 A was 0.188 among 686 control subjects, which is in accordance with that of Chinese population (0.200) and Japanese population (0.178).	('hsa-miR-423', 'Gene', '494335', (24, 35))	('rs6505162 A', 'Var', (36, 47))	('hsa-miR-423', 'Gene', (24, 35))	('rs6505162', 'Mutation', 'rs6505162', (36, 45))
266698	24260422	Using Power and Sample Size Calculation (PS, version 3.0, 2009, http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize), considering hsa-miR-34b/c rs4938723 T>C mutant alleles in the control group, OR, ESCC samples and control samples, the power of our analysis (alpha = 0.05) was 0.929 in 600 ESCC cases and 673 controls with adjusted OR 0.65.	('ESCC', 'Disease', (308, 312))	('rs4938723', 'Mutation', 'rs4938723', (161, 170))	('rs4938723 T>C', 'Var', (161, 174))
266699	24260422	For hsa-miR-423 rs6505162 C>A, the power of our analysis (alpha = 0.05) was 1.000 in 263 ESCC cases and 179 controls with adjusted OR 4.94 in smoking subgroup.	('hsa-miR-423', 'Gene', (4, 15))	('rs6505162 C>A', 'Var', (16, 29))	('ESCC', 'Disease', (89, 93))	('rs6505162', 'Mutation', 'rs6505162', (16, 25))	('hsa-miR-423', 'Gene', '494335', (4, 15))
266704	24260422	In conclusion, our study provides evidence that functional polymorphisms hsa-miR-34b/c rs4938723 T>C and hsa-miR-423 rs6505162 C>A might alter individual susceptibility to ESCC.	('rs4938723 T>C', 'Var', (87, 100))	('hsa-miR-34b/c', 'Gene', (73, 86))	('rs6505162', 'Mutation', 'rs6505162', (117, 126))	('hsa-miR-423', 'Gene', (105, 116))	('rs4938723', 'Mutation', 'rs4938723', (87, 96))	('alter', 'Reg', (137, 142))	('hsa-miR-423', 'Gene', '494335', (105, 116))	('ESCC', 'Disease', (172, 176))	('rs6505162 C>A', 'Var', (117, 130))
266768	23605564	Complete eradication of dysplasia was achieved in 91% of cases with low grade dysplasia while 81% was achieved for those with high grade dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (24, 33))	('low grade', 'Var', (68, 77))	('dysplasia', 'Disease', (78, 87))	('dysplasia', 'Disease', (137, 146))	('dysplasia', 'Disease', 'MESH:D004476', (78, 87))	('dysplasia', 'Disease', 'MESH:D004476', (137, 146))	('dysplasia', 'Disease', (24, 33))
266785	23605564	Another set of biomarkers studied for progression to EAC is aberrant DNA methylation of tumor suppression genes.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('EAC', 'Phenotype', 'HP:0011459', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('DNA', 'MPA', (69, 72))	('tumor', 'Disease', (88, 93))	('aberrant', 'Var', (60, 68))
266786	23605564	In a recent population based study, abnormal DNA ploidy, and Aspergillus oryzae lectin has shown to increase the odds of detecting dysplasia with each factors by 3.7.	('dysplasia', 'Disease', (131, 140))	('abnormal DNA ploidy', 'Var', (36, 55))	('detecting', 'Disease', (121, 130))	('dysplasia', 'Disease', 'MESH:D004476', (131, 140))	('Aspergillus oryzae', 'Species', '5062', (61, 79))	('increase', 'PosReg', (100, 108))
266787	23605564	Mutation in mitochondrial DNA has been previously postulated in carcinogenesis and recently found to be strongly associated with progression of dysplasia in BE.	('dysplasia', 'Disease', 'MESH:D004476', (144, 153))	('associated with', 'Reg', (113, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('Mutation', 'Var', (0, 8))	('carcinogenesis', 'Disease', (64, 78))	('BE', 'Phenotype', 'HP:0100580', (157, 159))	('mitochondrial DNA', 'Gene', (12, 29))	('dysplasia', 'Disease', (144, 153))
266799	19918949	In HPV-positive cases, we evaluated p16INK4a overexpression and HPV E6/E7 seropositivity as evidence of carcinogenic HPV activity.	('HPV', 'Gene', (64, 67))	('HPV', 'Species', '10566', (64, 67))	('carcinogenic HPV', 'Disease', 'MESH:D030361', (104, 120))	('HPV', 'Species', '10566', (117, 120))	('E6/E7', 'Gene', '25479186', (68, 73))	('E6/E7', 'Gene', (68, 73))	('p16INK4a', 'Var', (36, 44))	('carcinogenic HPV', 'Disease', (104, 120))	('overexpression', 'PosReg', (45, 59))	('HPV', 'Species', '10566', (3, 6))
266866	19918949	Cases positive for HPV DNA were evaluated for evidence of HPV-induced carcinogenesis by immunohistochemical analysis of p16INK4a overexpression, a well-established marker for HPV oncogene expression.	('p16INK4a', 'Var', (120, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (70, 84))	('HPV', 'Species', '10566', (19, 22))	('HPV', 'Species', '10566', (175, 178))	('carcinogenesis', 'Disease', (70, 84))	('HPV', 'Species', '10566', (58, 61))
266878	19918949	One male case tested weakly positive for HPV89 (CP6108), a non-cancer causing HPV type.	('HPV', 'Species', '10566', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('HPV89', 'Gene', (41, 46))	('CP6108', 'Var', (48, 54))	('HPV', 'Species', '10566', (78, 81))	('non-cancer', 'Disease', 'MESH:D009369', (59, 69))	('non-cancer', 'Disease', (59, 69))
266879	19918949	No cases were positive by HPV16 or HPV18 E6 or E7-based PCR (100.0% negative, 95% CI: 98.6-100.0%).	('HPV', 'Species', '10566', (35, 38))	('E7-based', 'Var', (47, 55))	('HPV16', 'Gene', (26, 31))	('HPV16', 'Species', '333760', (26, 31))	('HPV', 'Species', '10566', (26, 29))	('HPV18', 'Gene', (35, 40))
266908	33314700	A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death The tumor suppressor gene TP53 is the most frequently mutated gene in cancer.	('thiol', 'Chemical', 'MESH:D013438', (2, 7))	('APR', 'Gene', '5366', (38, 41))	('TP53', 'Gene', (108, 112))	('death', 'Disease', 'MESH:D003643', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', (152, 158))	('tumor', 'Disease', (65, 70))	('APR', 'Gene', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TP53', 'Gene', '7157', (108, 112))	('mutant', 'Var', (54, 60))	('p53', 'Gene', '7157', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('death', 'Disease', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('enhances', 'PosReg', (29, 37))	('tumor', 'Disease', (86, 91))	('p53', 'Gene', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
266909	33314700	The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance.	('mutant', 'Var', (106, 112))	('cellular antioxidant balance', 'MPA', (138, 166))	('PRIMA-1', 'Gene', (22, 29))	('protein', 'Protein', (117, 124))	('methylene quinuclidinone', 'Chemical', '-', (63, 87))	('PRIMA-1', 'Gene', '145270', (22, 29))	('MQ', 'Chemical', '-', (89, 91))	('p53', 'Gene', (113, 116))	('APR-246', 'Chemical', 'MESH:C533410', (13, 20))	('perturbs', 'NegReg', (129, 137))
266911	33314700	By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR-246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells.	('ABCC1', 'Gene', (122, 127))	('APR-246', 'Chemical', 'MESH:C533410', (79, 86))	('inhibitors', 'Var', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('APR-246', 'Gene', (79, 86))	('tumor cell death', 'Disease', 'MESH:D003643', (151, 167))	('ABCC1', 'Gene', '4363', (122, 127))	('TP53', 'Gene', '7157', (197, 201))	('TP53', 'Gene', (197, 201))	('tumor cell death', 'Disease', (151, 167))	('mutant', 'Var', (202, 208))
266913	33314700	Due to the reversibility of MQ conjugation, GS-MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53.	('GS-MQ', 'Chemical', '-', (44, 49))	('MQ', 'Chemical', '-', (28, 30))	('increases', 'PosReg', (93, 102))	('availability', 'MPA', (103, 115))	('MQ', 'Chemical', '-', (47, 49))	('MQ', 'Chemical', '-', (119, 121))	('mutant', 'Var', (136, 142))	('p53', 'Gene', (143, 146))
266914	33314700	Our study shows that redox homeostasis is a critical determinant of the response to mutant p53-targeted cancer therapy.	('p53-targeted', 'Gene', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutant', 'Var', (84, 90))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
266919	33314700	TP53 mutation is associated with poor prognosis and chemoresistance.	('chemoresistance', 'CPA', (52, 67))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
266920	33314700	APR-246 (Eprenetapopt) is the only compound in clinical development that reactivates mutant p53 protein, at Phase III clinical stage in myelodysplastic syndrome (MDS).	('myelodysplastic syndrome', 'Disease', (136, 160))	('APR-246', 'Chemical', 'MESH:C533410', (0, 7))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (136, 160))	('protein', 'Protein', (96, 103))	('MDS', 'Disease', (162, 165))	('MDS', 'Disease', 'MESH:D009190', (162, 165))	('MDS', 'Phenotype', 'HP:0002863', (162, 165))	('p53', 'Gene', (92, 95))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (136, 160))	('mutant', 'Var', (85, 91))
266924	33314700	We have shown that this complex can be exported through the multidrug resistance-associated protein 1 (MRP1) efflux pump and that blocking MRP1 traps MQ inside the cell.	('blocking', 'Var', (130, 138))	('drug resistance', 'Phenotype', 'HP:0020174', (65, 80))	('MRP1', 'Gene', (139, 143))	('multidrug resistance-associated protein 1', 'Gene', '4363', (60, 101))	('MQ', 'Chemical', '-', (150, 152))	('multidrug resistance-associated protein 1', 'Gene', (60, 101))
266925	33314700	This leads to intracellular accumulation of MQ bound to glutathione, forming a reservoir of MQ that can bind mutant p53 and other cellular targets.	('p53', 'Gene', (116, 119))	('glutathione', 'Chemical', 'MESH:D005978', (56, 67))	('MQ', 'Chemical', '-', (92, 94))	('mutant', 'Var', (109, 115))	('leads to', 'Reg', (5, 13))	('MQ', 'Chemical', '-', (44, 46))	('bind', 'Interaction', (104, 108))
266926	33314700	Blocking MRP1 also disrupts antioxidant shields often elevated in cancer cells, thus enhancing cancer cell death in vitro, ex vivo, and in vivo.	('disrupts', 'NegReg', (19, 27))	('enhancing', 'PosReg', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Blocking', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (95, 101))	('death', 'Disease', 'MESH:D003643', (107, 112))	('antioxidant shields', 'MPA', (28, 47))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('death', 'Disease', (107, 112))	('MRP1', 'Gene', (9, 13))	('cancer', 'Disease', (66, 72))
266930	33314700	TP53 is the most frequently mutated gene in cancer (Kandoth et al, 2013), and TP53 mutation is associated with chromosomal instability (Donehower et al, 2019) and poor prognosis according to some studies (Olivier et al, 2006; Bally et al, 2014).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('chromosomal instability', 'MPA', (111, 134))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('mutation', 'Var', (83, 91))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('chromosomal instability', 'Phenotype', 'HP:0040012', (111, 134))	('associated', 'Reg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
266931	33314700	The majority of TP53 mutations are missense mutations which disrupt p53-dependent transcription (Soussi & Wiman, 2015).	('missense', 'Var', (35, 43))	('TP53', 'Gene', (16, 20))	('TP53', 'Gene', '7157', (16, 20))	('disrupt', 'NegReg', (60, 67))	('p53-dependent transcription', 'MPA', (68, 95))	('mutations', 'Var', (21, 30))
266932	33314700	Mutant p53 may also in some settings have gain-of-function (GOF) activities that promote tumor growth (Muller & Vousden, 2014).	('promote', 'PosReg', (81, 88))	('activities', 'MPA', (65, 75))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('gain-of-function', 'PosReg', (42, 58))	('Mutant', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('p53', 'Gene', (7, 10))
266933	33314700	The mutant p53-targeting compounds PRIMA-1 and APR-246 (PRIMA-1Met/Eprenetapopt) are converted to the active product methylene quinuclidinone (MQ), a Michael acceptor that reacts with thiols (Lambert et al, 2009).	('PRIMA-1', 'Gene', (56, 63))	('PRIMA-1', 'Gene', '145270', (35, 42))	('thiols', 'Chemical', 'MESH:D013438', (184, 190))	('mutant', 'Var', (4, 10))	('p53-targeting', 'Disease', (11, 24))	('PRIMA-1', 'Gene', '145270', (56, 63))	('APR-246', 'Chemical', 'MESH:C533410', (47, 54))	('PRIMA-1', 'Gene', (35, 42))	('methylene quinuclidinone', 'Chemical', '-', (117, 141))	('MQ', 'Chemical', '-', (143, 145))
266934	33314700	MQ has been shown to bind preferentially to Cys124 and Cys277 (Wassman et al, 2013; Zhang et al, 2018) of the 10 cysteine (Cys) residues in the DNA-binding core domain of p53 (Meplan et al, 2000).	('MQ', 'Chemical', '-', (0, 2))	('Cys124', 'Chemical', '-', (44, 50))	('Cys', 'Chemical', 'MESH:D003545', (44, 47))	('Cys124', 'Var', (44, 50))	('Cys', 'Chemical', 'MESH:D003545', (123, 126))	('cysteine', 'Chemical', 'MESH:D003545', (113, 121))	('bind', 'Interaction', (21, 25))	('Cys277', 'Chemical', '-', (55, 61))	('Cys', 'Chemical', 'MESH:D003545', (55, 58))	('Cys277', 'Var', (55, 61))
266935	33314700	Treatment of mutant p53-expressing cells with PRIMA-1 or APR-246 results in mutant p53 reactivation and cell death (Bykov et al, 2002b).	('p53', 'Gene', (83, 86))	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('PRIMA-1', 'Gene', (46, 53))	('mutant', 'Var', (76, 82))	('APR-246', 'Chemical', 'MESH:C533410', (57, 64))	('PRIMA-1', 'Gene', '145270', (46, 53))	('reactivation', 'MPA', (87, 99))
266938	33314700	We and others have previously shown that APR-246 (through MQ) exhibits pro-oxidant activities through depletion of glutathione (GSH) and inhibition of the GSH and thioredoxin (TXN) antioxidant systems (Peng et al, 2013; Tessoulin et al, 2014; Mohell et al, 2015; Haffo et al, 2018; Hang et al, 2018; Mlakar et al, 2019).	('TXN', 'Gene', '7295', (176, 179))	('GSH', 'Chemical', '-', (155, 158))	('MQ', 'Chemical', '-', (58, 60))	('APR-246', 'Var', (41, 48))	('GSH', 'Chemical', '-', (128, 131))	('thioredoxin', 'Gene', '7295', (163, 174))	('inhibition', 'NegReg', (137, 147))	('glutathione', 'Chemical', 'MESH:D005978', (115, 126))	('TXN', 'Gene', (176, 179))	('APR-246', 'Chemical', 'MESH:C533410', (41, 48))	('pro-oxidant activities', 'MPA', (71, 93))	('thioredoxin', 'Gene', (163, 174))	('depletion of glutathione', 'MPA', (102, 126))	('GSH', 'Enzyme', (155, 158))
266946	33314700	The association of MRP expression with PRIMA-1 resistance, MRP1's role in redox regulation and export of GSH-conjugated drugs, and the fact that MQ conjugates to GSH led us to hypothesize that inhibition of MRP1 in mutant TP53-carrying tumor cells enhances sensitivity to APR-246.	('MRP', 'Gene', '4363', (207, 210))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('enhances', 'PosReg', (248, 256))	('inhibition', 'Var', (193, 203))	('sensitivity to APR-246', 'MPA', (257, 279))	('PRIMA-1', 'Gene', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('mutant', 'Var', (215, 221))	('TP53', 'Gene', '7157', (222, 226))	('MRP', 'Gene', (59, 62))	('MQ', 'Chemical', '-', (145, 147))	('GSH', 'Chemical', '-', (162, 165))	('GSH', 'Chemical', '-', (105, 108))	('tumor', 'Disease', (236, 241))	('MRP', 'Gene', '4363', (59, 62))	('MRP', 'Gene', (19, 22))	('MRP', 'Gene', '4363', (19, 22))	('MRP', 'Gene', (207, 210))	('PRIMA-1', 'Gene', '145270', (39, 46))	('TP53', 'Gene', (222, 226))	('APR-246', 'Chemical', 'MESH:C533410', (272, 279))
266947	33314700	We show here that inhibition of MRP1 or xCT/SLC7A11 synergizes with APR-246 to induce cancer cell death by increasing intracellular drug availability and by altering cellular redox status.	('cellular redox status', 'MPA', (166, 187))	('death', 'Disease', 'MESH:D003643', (98, 103))	('death', 'Disease', (98, 103))	('altering', 'Reg', (157, 165))	('xCT', 'Gene', '23657', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('intracellular drug availability', 'MPA', (118, 149))	('APR-246', 'Chemical', 'MESH:C533410', (68, 75))	('induce', 'PosReg', (79, 85))	('MRP1', 'Protein', (32, 36))	('increasing', 'PosReg', (107, 117))	('inhibition', 'Var', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('xCT', 'Gene', (40, 43))	('cancer', 'Disease', (86, 92))
266948	33314700	We also demonstrate that GS-MQ adduct formation is reversible, indicating that GS-MQ could serve as an intracellular drug reservoir to promote mutant p53 reactivation.	('promote', 'PosReg', (135, 142))	('mutant', 'Var', (143, 149))	('rat', 'Species', '10116', (15, 18))	('GS-MQ', 'Chemical', '-', (79, 84))	('GS-MQ', 'Chemical', '-', (25, 30))	('p53', 'Gene', (150, 153))	('reactivation', 'MPA', (154, 166))
266950	33314700	Indeed, combination of APR-246 with the MRP1 inhibitor MK-571 resulted in enhanced growth suppression in TP53 mutant TOV-112D and OVCAR-3 ovarian cancer cell lines and HCT116 colorectal cancer cells with WT or R248W mutant TP53 (Fig 1A), as well as several esophageal cancer cell lines (Fig EV1B) and cancer cell lines of other origins and different TP53 status (Appendix Fig S1A).	('cancer', 'Disease', (146, 152))	('growth suppression', 'CPA', (83, 101))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('TP53', 'Gene', '7157', (350, 354))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('TP53', 'Gene', '7157', (223, 227))	('OVCAR-3 ovarian cancer', 'Disease', 'OMIM:614324', (130, 152))	('colorectal cancer', 'Disease', (175, 192))	('HCT116', 'CellLine', 'CVCL:0291', (168, 174))	('cancer', 'Disease', (301, 307))	('APR-246', 'Chemical', 'MESH:C533410', (23, 30))	('TP53', 'Gene', (105, 109))	('APR-246', 'Var', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('MK-571', 'Chemical', 'MESH:C059141', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('R248W', 'Mutation', 'rs121912651', (210, 215))	('mutant', 'Var', (110, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('OVCAR-3 ovarian cancer', 'Disease', (130, 152))	('MK-571', 'Var', (55, 61))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', (268, 274))	('TP53', 'Gene', (350, 354))	('combination', 'Interaction', (8, 19))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('TP53', 'Gene', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('R248W', 'Var', (210, 215))	('TP53', 'Gene', '7157', (105, 109))	('MRP1', 'Gene', (40, 44))	('enhanced', 'PosReg', (74, 82))
266952	33314700	Clustering analysis divided the cell lines into high and low sensitivity to APR-246 groups where most lines in the high sensitivity group carry mutant TP53 (Appendix Fig S1B).	('APR-246', 'Chemical', 'MESH:C533410', (76, 83))	('mutant', 'Var', (144, 150))	('TP53', 'Gene', '7157', (151, 155))	('TP53', 'Gene', (151, 155))
266954	33314700	We observed synergy in essentially all cancer cell lines (Fig 1D and Appendix Fig S1C), but cells with mutant TP53 showed stronger synergy than WT TP53 cells (Fig 1D).	('TP53', 'Gene', (147, 151))	('TP53', 'Gene', '7157', (110, 114))	('cancer', 'Disease', (39, 45))	('TP53', 'Gene', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutant', 'Var', (103, 109))	('stronger', 'PosReg', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('TP53', 'Gene', '7157', (147, 151))	('synergy', 'MPA', (131, 138))
266958	33314700	Synergistic growth suppression by APR-246 and MK-571 combination treatment was also shown in OVCAR-3 cells by flow cytometry (sub-G1 DNA content) (Fig 1E and Appendix Fig S1F) and real-time cell confluence using Incucyte  (Fig 1F and Appendix Fig S7O-Q).	('APR-246', 'Var', (34, 41))	('MK-571', 'Chemical', 'MESH:C059141', (46, 52))	('MK-571', 'Gene', (46, 52))	('suppression', 'NegReg', (19, 30))	('growth', 'CPA', (12, 18))	('APR-246', 'Chemical', 'MESH:C533410', (34, 41))
266959	33314700	Combining APR-246 with Reversan, another MRP1 inhibitor, also led to synergistic growth suppression and cell death in HCT116 TP53 R248W and WT cells (Fig 1G and Appendix Fig S1G).	('APR-246', 'Var', (10, 17))	('growth suppression', 'CPA', (81, 99))	('TP53', 'Gene', '7157', (125, 129))	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('synergistic', 'MPA', (69, 80))	('APR-246', 'Chemical', 'MESH:C533410', (10, 17))	('TP53', 'Gene', (125, 129))	('R248W', 'Mutation', 'rs121912651', (130, 135))	('HCT116', 'CellLine', 'CVCL:0291', (118, 124))	('Reversan', 'Chemical', 'MESH:C543413', (23, 31))	('R248W', 'Var', (130, 135))
266960	33314700	Partial silencing of MRP1 using four different siRNAs separately (Fig 1H, and Appendix Fig S1H and I) increased sensitivity to APR-246 in both HCT116 WT and R248W TP53 cells (Fig 1I, and Appendix Fig S1J and K) whereas overexpression of MRP1 (Fig 1J and Appendix Fig S1L) resulted in resistance to APR-246 (Fig 1K and Appendix Fig S1M).	('R248W', 'Var', (157, 162))	('MRP1', 'Gene', (21, 25))	('resistance to APR-246', 'MPA', (284, 305))	('TP53', 'Gene', '7157', (163, 167))	('APR-246', 'Chemical', 'MESH:C533410', (127, 134))	('HCT116', 'CellLine', 'CVCL:0291', (143, 149))	('sensitivity to APR-246', 'MPA', (112, 134))	('APR-246', 'Chemical', 'MESH:C533410', (298, 305))	('TP53', 'Gene', (163, 167))	('rat', 'Species', '10116', (58, 61))	('increased', 'PosReg', (102, 111))	('R248W', 'Mutation', 'rs121912651', (157, 162))
266964	33314700	However, combination treatment with MK-571 significantly enhanced APR-246 anti-tumor activity (Fig 2A, and Appendix Fig S2A and B) and survival (Fig 2B) in MRP1-expressing Eso26 xenografts (Appendix Fig S2C), consistent with the in vitro data on esophageal cell lines (Fig EV1B).	('MK-571', 'Var', (36, 42))	('APR-246', 'Gene', (66, 73))	('tumor', 'Disease', (79, 84))	('MK-571', 'Chemical', 'MESH:C059141', (36, 42))	('MRP1-expressing', 'Gene', (156, 171))	('APR-246', 'Chemical', 'MESH:C533410', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('survival', 'CPA', (135, 143))	('enhanced', 'PosReg', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
266966	33314700	At late time points (> 22 days after treatment initiation), we observed an increased cleaved caspase 3 staining in both APR-246 and the combination treatment group (Fig 2D and E).	('APR-246', 'Var', (120, 127))	('caspase 3', 'Gene', (93, 102))	('cleaved', 'MPA', (85, 92))	('caspase 3', 'Gene', '836', (93, 102))	('APR-246', 'Chemical', 'MESH:C533410', (120, 127))	('increased', 'PosReg', (75, 84))	('staining', 'MPA', (103, 111))
266969	33314700	For the first time, we demonstrate APR-246 anti-tumor efficacy in PDO cultures derived from TP53 missense mutant colorectal cancer (colo-PDO) (Fig 2F) and esophageal adenocarcinoma (eso-PDO) (Appendix Fig S2D), as assessed by the ATP-based CTG assay.	('CTG', 'Chemical', '-', (240, 243))	('colorectal cancer', 'Disease', (113, 130))	('missense mutant', 'Var', (97, 112))	('TP53', 'Gene', (92, 96))	('adenocarcinoma', 'Disease', 'MESH:D000230', (166, 180))	('rat', 'Species', '10116', (30, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('tumor', 'Disease', (48, 53))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (155, 180))	('colo', 'Species', '307630', (132, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('TP53', 'Gene', '7157', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('APR-246', 'Chemical', 'MESH:C533410', (35, 42))	('APR-246', 'Gene', (35, 42))	('ATP', 'Chemical', 'MESH:D000255', (230, 233))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('adenocarcinoma', 'Disease', (166, 180))	('colo', 'Species', '307630', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
266971	33314700	Combination treatment of APR-246 and MK-571 resulted in synergistic growth suppression in colo-PDOs according to the metabolic CTG assay (Fig 2F).	('APR-246', 'Var', (25, 32))	('MK-571', 'Var', (37, 43))	('MK-571', 'Chemical', 'MESH:C059141', (37, 43))	('colo', 'Species', '307630', (90, 94))	('suppression', 'NegReg', (75, 86))	('CTG', 'Chemical', '-', (127, 130))	('APR-246', 'Chemical', 'MESH:C533410', (25, 32))	('growth', 'CPA', (68, 74))
266975	33314700	However, organoid area decreased and PI intensity increased dramatically upon addition of MK-571 (Fig 2H).	('PI intensity', 'CPA', (37, 49))	('increased', 'PosReg', (50, 59))	('MK-571', 'Var', (90, 96))	('organoid area', 'CPA', (9, 22))	('decreased', 'NegReg', (23, 32))	('MK-571', 'Chemical', 'MESH:C059141', (90, 96))
266978	33314700	In conclusion, MK-571 potentiates APR-246 efficacy in vitro in cultured cancer cell lines, in vivo in mouse xenografts, and ex vivo in patient-derived organoids.	('APR-246', 'Gene', (34, 41))	('patient', 'Species', '9606', (135, 142))	('MK-571', 'Var', (15, 21))	('MK-571', 'Chemical', 'MESH:C059141', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('potentiates', 'PosReg', (22, 33))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('APR-246', 'Chemical', 'MESH:C533410', (34, 41))	('mouse', 'Species', '10090', (102, 107))	('cancer', 'Disease', (72, 78))
266982	33314700	MK-571 blocked MRP1 pump activity already after 6-h treatment according to accumulation of MRP1 substrate doxorubicin (Appendix Fig S3C; Deeley & Cole, 2006; Zhang et al, 2016).	('rat', 'Species', '10116', (101, 104))	('doxorubicin', 'Chemical', 'MESH:D004317', (106, 117))	('MRP1 pump', 'Protein', (15, 24))	('blocked', 'NegReg', (7, 14))	('MK-571', 'Var', (0, 6))	('MK-571', 'Chemical', 'MESH:C059141', (0, 6))	('accumulation', 'PosReg', (75, 87))
266985	33314700	Reversan enhanced 14C accumulation to a similar extent as MK-571 in the isogenic HCT116 cell lines with either WT or R248W mutant TP53 (Fig 3C and Appendix Fig S3D).	('14C accumulation', 'MPA', (18, 34))	('HCT116', 'CellLine', 'CVCL:0291', (81, 87))	('R248W', 'Mutation', 'rs121912651', (117, 122))	('Reversan', 'Chemical', 'MESH:C543413', (0, 8))	('R248W', 'Var', (117, 122))	('MK-571', 'Chemical', 'MESH:C059141', (58, 64))	('14C', 'Chemical', 'MESH:C000615234', (18, 21))	('TP53', 'Gene', '7157', (130, 134))	('enhanced', 'PosReg', (9, 17))	('TP53', 'Gene', (130, 134))
266987	33314700	Our results demonstrate that 14C-APR-246 accumulates inside cells upon MRP1 inhibition or siRNA knockdown, suggesting that either APR-246, MQ, MQ conjugates, or all three are exported via MRP1.	('knockdown', 'Var', (96, 105))	('MRP1', 'Gene', (71, 75))	('inhibition', 'NegReg', (76, 86))	('MQ', 'Chemical', '-', (139, 141))	('APR-246', 'Chemical', 'MESH:C533410', (130, 137))	('APR-246', 'Chemical', 'MESH:C533410', (33, 40))	('rat', 'Species', '10116', (19, 22))	('14C-APR', 'Chemical', '-', (29, 36))	('APR-246', 'Var', (130, 137))	('MQ', 'Chemical', '-', (143, 145))
266992	33314700	However, incubation with equimolar concentrations of NAC resulted in a marked decrease in the amounts of GS-MQ within 30 min and a concomitant increase in NAC-MQ (Fig 4D), indicating that MQ is in rapid flux between a conjugated form and a free form, that becomes apparent in the presence of a suitable donor, e.g., free thiol group(s).	('GS-MQ', 'Chemical', '-', (105, 110))	('GS-MQ', 'MPA', (105, 110))	('MQ', 'Chemical', '-', (188, 190))	('decrease', 'NegReg', (78, 86))	('NAC-MQ', 'Chemical', '-', (155, 161))	('MQ', 'Chemical', '-', (108, 110))	('thiol', 'Chemical', 'MESH:D013438', (321, 326))	('NAC', 'Chemical', 'MESH:D000111', (53, 56))	('MQ', 'Chemical', '-', (159, 161))	('NAC-MQ', 'MPA', (155, 161))	('NAC', 'Var', (53, 56))	('amounts', 'MPA', (94, 101))	('increase', 'PosReg', (143, 151))	('NAC', 'Chemical', 'MESH:D000111', (155, 158))	('rat', 'Species', '10116', (42, 45))
266996	33314700	Cells expressing mutant p53 were more sensitive to APR-246 than cells lacking p53 (Appendix Table S1, Figs 5A and EV5A), in agreement with our previous data (Bykov et al, 2005).	('sensitive', 'MPA', (38, 47))	('APR-246', 'Chemical', 'MESH:C533410', (51, 58))	('mutant', 'Var', (17, 23))	('p53', 'Gene', (24, 27))
266997	33314700	Mutant p53-expressing cells in all three isogenic cell systems tested (HCT116, H1299, and Saos-2) showed a more pronounced synergistic growth suppression compared with p53 null and WT cells (Appendix Table S1).	('synergistic growth suppression', 'CPA', (123, 153))	('Mutant', 'Var', (0, 6))	('p53-expressing', 'Gene', (7, 21))	('H1299', 'CellLine', 'CVCL:0060', (79, 84))	('HCT116', 'CellLine', 'CVCL:0291', (71, 77))
266998	33314700	Liu et al (2017) showed that tumor cells with TP53 mutation can exhibit reduced de novo synthesis of GSH due to mutant p53 gain-of-function (GOF) activities that increase sensitivity to APR-246.	('de novo synthesis', 'MPA', (80, 97))	('reduced', 'NegReg', (72, 79))	('GSH', 'Protein', (101, 104))	('increase', 'PosReg', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('gain-of-function', 'PosReg', (123, 139))	('APR-246', 'Chemical', 'MESH:C533410', (186, 193))	('TP53', 'Gene', '7157', (46, 50))	('GSH', 'Chemical', '-', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('activities', 'MPA', (146, 156))	('tumor', 'Disease', (29, 34))	('mutation', 'Var', (51, 59))	('TP53', 'Gene', (46, 50))	('mutant', 'Var', (112, 118))	('p53', 'Gene', (119, 122))	('sensitivity to APR-246', 'MPA', (171, 193))
267001	33314700	H1299 lung cancer cells with exogenous R175H mutant TP53 had a lower basal concentration of total GSH + GSSG as compared to parental p53 null H1299 cells or doxycycline-treated H1299 tet-off R175H cells (Fig 5C, and Appendix Fig S5A and B).	('H1299', 'CellLine', 'CVCL:0060', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('lung cancer', 'Disease', (6, 17))	('TP53', 'Gene', (52, 56))	('lower', 'NegReg', (63, 68))	('GSSG', 'Chemical', 'MESH:D019803', (104, 108))	('GSH', 'Chemical', '-', (98, 101))	('tet', 'Chemical', 'MESH:C010349', (183, 186))	('basal concentration of total GSH + GSSG', 'MPA', (69, 108))	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('mutant', 'Var', (45, 51))	('TP53', 'Gene', '7157', (52, 56))	('R175H', 'Mutation', 'rs28934578', (39, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('H1299', 'CellLine', 'CVCL:0060', (177, 182))	('R175H', 'Mutation', 'rs28934578', (191, 196))	('rat', 'Species', '10116', (82, 85))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))	('doxycycline', 'Chemical', 'MESH:D004318', (157, 168))
267003	33314700	In Saos-2 cells, there was no detectable difference in total GSH + GSSG levels between parental p53 null and untreated and doxycycline-treated tet-off R273H mutant p53-expressing cells (Appendix Fig S5C).	('tet', 'Chemical', 'MESH:C010349', (143, 146))	('GSH + GSSG levels', 'MPA', (61, 78))	('R273H mutant', 'Var', (151, 163))	('doxycycline', 'Chemical', 'MESH:D004318', (123, 134))	('p53-expressing', 'Gene', (164, 178))	('GSSG', 'Chemical', 'MESH:D019803', (67, 71))	('GSH', 'Chemical', '-', (61, 64))	('R273H', 'Mutation', 'rs28934576', (151, 156))
267007	33314700	Hence, cells that accumulate more APR-246/MQ are also more sensitive, irrespective of TP53 status.	('APR-246/MQ', 'Var', (34, 44))	('MQ', 'Chemical', '-', (42, 44))	('TP53', 'Gene', '7157', (86, 90))	('sensitive', 'MPA', (59, 68))	('TP53', 'Gene', (86, 90))	('APR-246', 'Chemical', 'MESH:C533410', (34, 41))
267008	33314700	Nonetheless, analysis of The Cancer Genome Atlas (TCGA) PanCancer Atlas (Hoadley et al, 2018) from cBioportal (Cerami et al, 2012; Gao et al, 2013) revealed that in some tumors types, ABCC1 (MRP1) mRNA is higher in patients with putative driver TP53 missense mutations compared with wild-type TP53 (Fig 5G).	('ABCC1', 'Gene', '4363', (184, 189))	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('Cancer', 'Disease', 'MESH:D009369', (29, 35))	('higher', 'PosReg', (205, 211))	('TP53', 'Gene', '7157', (293, 297))	('TP53', 'Gene', '7157', (245, 249))	('Cancer', 'Disease', (59, 65))	('ABCC1', 'Gene', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('Cancer', 'Disease', 'MESH:D009369', (59, 65))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (215, 223))	('missense mutations', 'Var', (250, 268))	('TP53', 'Gene', (293, 297))	('mRNA', 'MPA', (197, 201))	('TP53', 'Gene', (245, 249))	('Cancer', 'Disease', (29, 35))	('tumors', 'Disease', (170, 176))
267010	33314700	This suggests that TP53 mutant tumor cells of these cancer types may have a better capacity to export drugs.	('mutant', 'Var', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('export drugs', 'MPA', (95, 107))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
267011	33314700	However, as mentioned above, our data show that mutant p53-expressing cells are more sensitive to APR-246.	('p53-expressing', 'Gene', (55, 69))	('mutant', 'Var', (48, 54))	('APR-246', 'Chemical', 'MESH:C533410', (98, 105))	('sensitive to APR-246', 'MPA', (85, 105))
267012	33314700	To further examine the role of mutant p53 in APR-246 accumulation, mutant p53 expression in tet-off R175H cells was repressed using doxycycline and accumulation of 14C-APR-246/MQ was assessed (Fig 5H and Appendix Fig S5E).	('R175H', 'Mutation', 'rs28934578', (100, 105))	('MQ', 'Chemical', '-', (176, 178))	('doxycycline', 'Chemical', 'MESH:D004318', (132, 143))	('tet', 'Chemical', 'MESH:C010349', (92, 95))	('p53', 'Gene', (74, 77))	('APR-246', 'Chemical', 'MESH:C533410', (168, 175))	('mutant', 'Var', (67, 73))	('14C-APR', 'Chemical', '-', (164, 171))	('APR-246', 'Chemical', 'MESH:C533410', (45, 52))
267013	33314700	Inhibition of mutant p53 expression did not affect 14C-APR-246/MQ accumulation but still decreased APR-246-induced growth suppression (Fig 5I and Appendix Fig S5F).	('14C-APR', 'Chemical', '-', (51, 58))	('APR-246-induced growth suppression', 'MPA', (99, 133))	('MQ', 'Chemical', '-', (63, 65))	('mutant', 'Var', (14, 20))	('APR-246', 'Chemical', 'MESH:C533410', (99, 106))	('p53', 'Gene', (21, 24))	('APR-246', 'Chemical', 'MESH:C533410', (55, 62))	('decreased', 'NegReg', (89, 98))
267014	33314700	Similarly, siRNA knockdown of R248W mutant p53 in HCT116 cells (Appendix Fig S5H) did not affect total GSH + GSSG level (Fig EV5C) or 14C content after treatment with 14C-APR-246 (Fig EV5D and Appendix Table S4), but nonetheless reduced APR-246-induced growth suppression (Fig EV5E).	('HCT116', 'CellLine', 'CVCL:0291', (50, 56))	('14C content', 'MPA', (134, 145))	('GSH', 'Chemical', '-', (103, 106))	('14C', 'Chemical', 'MESH:C000615234', (167, 170))	('14C', 'Chemical', 'MESH:C000615234', (134, 137))	('reduced', 'NegReg', (229, 236))	('APR-246', 'Chemical', 'MESH:C533410', (237, 244))	('growth suppression', 'CPA', (253, 271))	('p53', 'Gene', (43, 46))	('R248W', 'Mutation', 'rs121912651', (30, 35))	('14C-APR', 'Chemical', '-', (167, 174))	('APR-246', 'Chemical', 'MESH:C533410', (171, 178))	('GSH + GSSG level', 'MPA', (103, 119))	('GSSG', 'Chemical', 'MESH:D019803', (109, 113))	('R248W', 'Var', (30, 35))
267015	33314700	Thus, sensitivity to APR-246 treatment is dependent on mutant TP53 status, GSH content, and drug accumulation, but neither of these factors alone can fully explain sensitivity to APR-246.	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('mutant', 'Var', (55, 61))	('GSH', 'Chemical', '-', (75, 78))	('APR-246', 'Chemical', 'MESH:C533410', (21, 28))	('APR-246', 'Chemical', 'MESH:C533410', (179, 186))
267020	33314700	The combination treatment with APR-246 and MK-571 caused a marked decrease in both GSH and GSSG levels (Fig 6B and C).	('MK-571', 'Var', (43, 49))	('APR-246', 'Var', (31, 38))	('GSH', 'Chemical', '-', (83, 86))	('MK-571', 'Chemical', 'MESH:C059141', (43, 49))	('decrease', 'NegReg', (66, 74))	('APR-246', 'Chemical', 'MESH:C533410', (31, 38))	('GSSG', 'Chemical', 'MESH:D019803', (91, 95))
267024	33314700	Similar results were observed in HCT116 WT and R248W cells (Fig 6E and Appendix Fig S6D) as well as other cancer cell lines (Appendix Fig S6E-G).	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('R248W', 'Mutation', 'rs121912651', (47, 52))	('HCT116', 'CellLine', 'CVCL:0291', (33, 39))	('R248W', 'Var', (47, 52))
267028	33314700	Interestingly, H1299 TP53 -/- and HCT116 TP53 -/- cells exhibited higher basal expression of xCT compared with their isogenic counterparts carrying mutant or WT TP53 and did not show an adaptive increase in xCT expression upon MK-571 treatment (Appendix Fig S6G).	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (21, 25))	('TP53', 'Gene', (41, 45))	('TP53', 'Gene', (161, 165))	('xCT', 'Gene', '23657', (207, 210))	('H1299', 'CellLine', 'CVCL:0060', (15, 20))	('HCT116', 'CellLine', 'CVCL:0291', (34, 40))	('xCT', 'Gene', (93, 96))	('basal expression', 'MPA', (73, 89))	('higher', 'PosReg', (66, 72))	('xCT', 'Gene', (207, 210))	('MK-571', 'Chemical', 'MESH:C059141', (227, 233))	('HCT116', 'Var', (34, 40))	('TP53', 'Gene', '7157', (161, 165))	('xCT', 'Gene', '23657', (93, 96))	('TP53', 'Gene', '7157', (21, 25))
267030	33314700	Cells exposed to APR-246 and MK-571 had a higher level of xCT (Fig 6D and E, and Appendix Fig S6E and F) and lower level of intracellular Glu (Appendix Fig S6H), also consistent with increased xCT activity.	('APR-246', 'Var', (17, 24))	('lower', 'NegReg', (109, 114))	('MK-571', 'Chemical', 'MESH:C059141', (29, 35))	('Glu', 'Chemical', 'MESH:D018698', (138, 141))	('xCT', 'Gene', (58, 61))	('xCT', 'Gene', '23657', (58, 61))	('APR-246', 'Chemical', 'MESH:C533410', (17, 24))	('level of intracellular Glu', 'MPA', (115, 141))	('xCT', 'Gene', (193, 196))	('xCT', 'Gene', '23657', (193, 196))	('MK-571', 'Var', (29, 35))
267033	33314700	Hence, MK-571 potentiates the cell death-inducing activity of APR-246 through a dual mechanism: inhibition of drug export and perturbation of intracellular thiol pools.	('potentiates', 'PosReg', (14, 25))	('APR-246', 'Gene', (62, 69))	('intracellular thiol pools', 'MPA', (142, 167))	('thiol', 'Chemical', 'MESH:D013438', (156, 161))	('MK-571', 'Var', (7, 13))	('MK-571', 'Chemical', 'MESH:C059141', (7, 13))	('death', 'Disease', 'MESH:D003643', (35, 40))	('APR-246', 'Chemical', 'MESH:C533410', (62, 69))	('death', 'Disease', (35, 40))	('drug export', 'MPA', (110, 121))	('inhibition', 'NegReg', (96, 106))	('perturbation', 'MPA', (126, 138))
267034	33314700	Partial knockdown of antiporter xCT after 14C-APR-246 treatment led to a roughly twofold increase in 14C accumulation in WT and R248W mutant TP53 HCT116 cells (Fig 7A, Appendix Fig S7A and Appendix Table S4).	('14C', 'Chemical', 'MESH:C000615234', (101, 104))	('xCT', 'Gene', '23657', (32, 35))	('14C-APR', 'Chemical', '-', (42, 49))	('14C accumulation', 'MPA', (101, 117))	('APR-246', 'Chemical', 'MESH:C533410', (46, 53))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('R248W', 'Mutation', 'rs121912651', (128, 133))	('14C', 'Chemical', 'MESH:C000615234', (42, 45))	('HCT116', 'CellLine', 'CVCL:0291', (146, 152))	('xCT', 'Gene', (32, 35))	('R248W', 'Var', (128, 133))	('increase', 'PosReg', (89, 97))
267035	33314700	Simultaneous xCT knockdown and MRP1 inhibition by MK-571 caused a three- and fourfold increase in 14C accumulation (Fig 7A and Appendix Table S4) and increased APR-246-induced growth suppression (Appendix Fig S7B).	('MK-571', 'Var', (50, 56))	('increase', 'PosReg', (86, 94))	('increased APR', 'Phenotype', 'HP:0008151', (150, 163))	('MK-571', 'Chemical', 'MESH:C059141', (50, 56))	('xCT', 'Gene', '23657', (13, 16))	('APR-246', 'Chemical', 'MESH:C533410', (160, 167))	('inhibition', 'NegReg', (36, 46))	('14C', 'Chemical', 'MESH:C000615234', (98, 101))	('MRP1', 'Gene', (31, 35))	('growth suppression', 'CPA', (176, 194))	('14C accumulation', 'MPA', (98, 114))	('knockdown', 'Var', (17, 26))	('increased', 'PosReg', (150, 159))	('xCT', 'Gene', (13, 16))
267036	33314700	Silencing of either xCT or MRP1 resulted in a similar potentiation of APR-246 activity in HCT116 TP53 WT cells (Fig 7B, Appendix Fig S7C, left panel and Appendix Fig S1J).	('potentiation', 'PosReg', (54, 66))	('TP53', 'Gene', '7157', (97, 101))	('xCT', 'Gene', (20, 23))	('MRP1', 'Gene', (27, 31))	('APR-246 activity', 'MPA', (70, 86))	('TP53', 'Gene', (97, 101))	('HCT116', 'CellLine', 'CVCL:0291', (90, 96))	('xCT', 'Gene', '23657', (20, 23))	('Silencing', 'Var', (0, 9))	('APR-246', 'Chemical', 'MESH:C533410', (70, 77))
267037	33314700	Interestingly, xCT silencing had a more potent effect than MRP1 knockdown on APR-246-induced growth suppression in HCT116 cells with mutant TP53 (Fig 7B, Appendix Fig S7C, right panel, and Appendix Fig S1J and K).	('xCT', 'Gene', '23657', (15, 18))	('TP53', 'Gene', (140, 144))	('silencing', 'NegReg', (19, 28))	('APR-246', 'Chemical', 'MESH:C533410', (77, 84))	('APR-246-induced', 'Gene', (77, 92))	('growth suppression', 'CPA', (93, 111))	('xCT', 'Gene', (15, 18))	('HCT116', 'CellLine', 'CVCL:0291', (115, 121))	('mutant', 'Var', (133, 139))	('TP53', 'Gene', '7157', (140, 144))
267038	33314700	This is consistent with results showing that xCT can promote resistance to APR-246 in mutant TP53-harboring tumor cells (Appendix Fig S7D and E) (Liu et al, 2017).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutant', 'Var', (86, 92))	('xCT', 'Gene', (45, 48))	('TP53', 'Gene', '7157', (93, 97))	('APR-246', 'Chemical', 'MESH:C533410', (75, 82))	('TP53', 'Gene', (93, 97))	('resistance', 'MPA', (61, 71))	('tumor', 'Disease', (108, 113))	('xCT', 'Gene', '23657', (45, 48))	('promote', 'PosReg', (53, 60))
267041	33314700	High xCT is also associated with higher APR-246 IC50 values in combination treatment with MK-571 when cell lines are grouped according to xCT levels (Appendix Fig S7J).	('higher', 'PosReg', (33, 39))	('xCT', 'Gene', '23657', (5, 8))	('High', 'Var', (0, 4))	('APR-246', 'Chemical', 'MESH:C533410', (40, 47))	('APR-246 IC50 values', 'MPA', (40, 59))	('xCT', 'Gene', (138, 141))	('xCT', 'Gene', '23657', (138, 141))	('xCT', 'Gene', (5, 8))	('MK-571', 'Chemical', 'MESH:C059141', (90, 96))
267042	33314700	Furthermore, downregulation of xCT sensitized to APR-246 more than downregulation of MRP1 in mutant TP53 cells (Fig 7B right panel), even though the cells accumulated drug to a similar extent (Fig 7A right panel and Appendix Table S4).	('TP53', 'Gene', '7157', (100, 104))	('downregulation', 'NegReg', (67, 81))	('MRP1', 'Gene', (85, 89))	('xCT', 'Gene', (31, 34))	('TP53', 'Gene', (100, 104))	('downregulation', 'NegReg', (13, 27))	('mutant', 'Var', (93, 99))	('xCT', 'Gene', '23657', (31, 34))	('APR-246', 'Chemical', 'MESH:C533410', (49, 56))
267043	33314700	Partial knockdown of MRP1 or xCT at 24 h did not significantly affect the total GSH + GSSG content in cells (Fig 7C and Appendix Fig S7K).	('MRP1', 'Gene', (21, 25))	('knockdown', 'Var', (8, 17))	('GSH + GSSG content', 'MPA', (80, 98))	('xCT', 'Gene', '23657', (29, 32))	('GSH', 'Chemical', '-', (80, 83))	('GSSG', 'Chemical', 'MESH:D019803', (86, 90))	('xCT', 'Gene', (29, 32))
267044	33314700	Thus, the observed increase in 14C accumulation after siRNA knockdown of xCT (Fig 7A) could not be explained by changes in total GSH + GSSG levels (Fig 7C), but may instead be related to other thiols.	('GSH + GSSG levels', 'MPA', (129, 146))	('thiols', 'Chemical', 'MESH:D013438', (193, 199))	('increase', 'PosReg', (19, 27))	('xCT', 'Gene', (73, 76))	('knockdown', 'Var', (60, 69))	('14C', 'Chemical', 'MESH:C000615234', (31, 34))	('GSSG', 'Chemical', 'MESH:D019803', (135, 139))	('14C accumulation', 'MPA', (31, 47))	('xCT', 'Gene', '23657', (73, 76))	('GSH', 'Chemical', '-', (129, 132))
267048	33314700	We observed pronounced growth suppression by combined treatment with APR-246 and SSZ as compared to APR-246 alone in both HCT116 WT and R248W cells, as assessed by total cellular protein in cell culture wells (Fig 7F).	('HCT116', 'CellLine', 'CVCL:0291', (122, 128))	('SSZ', 'Chemical', 'MESH:D012460', (81, 84))	('APR-246', 'Var', (69, 76))	('APR-246', 'Chemical', 'MESH:C533410', (69, 76))	('R248W', 'Mutation', 'rs121912651', (136, 141))	('suppression', 'NegReg', (30, 41))	('growth', 'CPA', (23, 29))	('R248W', 'Var', (136, 141))	('APR-246', 'Chemical', 'MESH:C533410', (100, 107))
267050	33314700	Real-time confluence analysis in OVCAR-3 cells confirmed that both MK-571 and SSZ potentiate APR-246-induced growth suppression (Fig 7G and H and Appendix Fig S7O-Q).	('APR-246', 'Chemical', 'MESH:C533410', (93, 100))	('MK-571', 'Var', (67, 73))	('SSZ', 'Gene', (78, 81))	('potentiate', 'PosReg', (82, 92))	('MK-571', 'Chemical', 'MESH:C059141', (67, 73))	('APR-246-induced', 'Gene', (93, 108))	('SSZ', 'Chemical', 'MESH:D012460', (78, 81))	('growth suppression', 'CPA', (109, 127))
267051	33314700	In summary, MK-571 and SSZ synergize with APR-246 by affecting both GSH/GSSG and Cys/CySS availability, which in turn dictates APR-246/MQ accumulation and APR-246-induced growth suppression.	('growth suppression', 'CPA', (171, 189))	('GSH/GSSG', 'MPA', (68, 76))	('affecting', 'Reg', (53, 62))	('MK-571', 'Var', (12, 18))	('CySS', 'Chemical', '-', (85, 89))	('Cys', 'Chemical', 'MESH:D003545', (81, 84))	('MK-571', 'Chemical', 'MESH:C059141', (12, 18))	('APR-246', 'Chemical', 'MESH:C533410', (127, 134))	('MQ', 'Chemical', '-', (135, 137))	('dictates', 'Reg', (118, 126))	('GSSG', 'Chemical', 'MESH:D019803', (72, 76))	('SSZ', 'Chemical', 'MESH:D012460', (23, 26))	('Cys/CySS availability', 'MPA', (81, 102))	('APR-246/MQ accumulation', 'MPA', (127, 150))	('APR-246', 'Chemical', 'MESH:C533410', (42, 49))	('GSH', 'Chemical', '-', (68, 71))	('APR-246', 'Chemical', 'MESH:C533410', (155, 162))
267053	33314700	Previous studies have indicated that the dependence of APR-246-induced growth suppression and cell death on mutant p53 varies with cellular background (Tessoulin et al, 2014; Grellety et al, 2015; Mohell et al, 2015; Sobhani et al, 2015; Ali et al, 2016; Liu et al, 2017).	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('mutant', 'Var', (108, 114))	('p53', 'Gene', (115, 118))	('growth suppression', 'CPA', (71, 89))	('APR-246', 'Chemical', 'MESH:C533410', (55, 62))
267054	33314700	Two aspects of the mechanism of MQ make it challenging to determine the relative importance of mutant p53 reactivation and induction of oxidative conditions for APR-246-induced cell death; first, mutant p53 restoration may synergize with oxidative injuries in promoting tumor cell death and, second, the thiol-binding properties of MQ underlies both effects.	('death', 'Disease', 'MESH:D003643', (281, 286))	('MQ', 'Chemical', '-', (332, 334))	('death', 'Disease', (281, 286))	('thiol', 'Chemical', 'MESH:D013438', (304, 309))	('tumor cell death', 'Disease', (270, 286))	('death', 'Disease', 'MESH:D003643', (182, 187))	('death', 'Disease', (182, 187))	('rat', 'Species', '10116', (212, 215))	('MQ', 'Chemical', '-', (32, 34))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('p53', 'Gene', (102, 105))	('APR-246', 'Chemical', 'MESH:C533410', (161, 168))	('tumor cell death', 'Disease', 'MESH:D003643', (270, 286))	('promoting', 'PosReg', (260, 269))	('mutant', 'Var', (196, 202))	('p53', 'Gene', (203, 206))
267055	33314700	Therefore, the use of, for example, NAC to prevent oxidative conditions in APR-246-treated cells will also result in the capture of MQ, and as a consequence, less MQ will be available to target mutant p53.	('capture', 'MPA', (121, 128))	('NAC', 'Chemical', 'MESH:D000111', (36, 39))	('p53', 'Gene', (201, 204))	('APR-246', 'Chemical', 'MESH:C533410', (75, 82))	('MQ', 'Chemical', '-', (163, 165))	('mutant', 'Var', (194, 200))	('MQ', 'Chemical', '-', (132, 134))	('result in', 'Reg', (107, 116))
267060	33314700	Thus, our data suggest that the synergy observed upon combination treatment with APR-246 and MRP1 efflux inhibitor or siRNA knockdown is at least in part due to increased intracellular accumulation of GS-MQ and/or other MQ adducts.	('knockdown', 'Var', (124, 133))	('siRNA', 'Gene', (118, 123))	('MQ', 'Chemical', '-', (220, 222))	('MQ', 'Chemical', '-', (204, 206))	('combination', 'Interaction', (54, 65))	('adducts', 'Interaction', (223, 230))	('GS-MQ', 'Protein', (201, 206))	('APR-246', 'Chemical', 'MESH:C533410', (81, 88))	('increased intracellular accumulation', 'Phenotype', 'HP:0003575', (161, 197))	('APR-246', 'Gene', (81, 88))	('MRP1', 'Gene', (93, 97))	('increased', 'PosReg', (161, 170))	('GS-MQ', 'Chemical', '-', (201, 206))
267065	33314700	This indicates that the steady state concentration of free MQ in APR-246-treated cells is very low and that MQ rapidly travels between various cellular thiol targets, including known targets such as mutant p53 (Lambert et al, 2009), thioredoxin reductase (Peng et al, 2013), thioredoxin, glutaredoxin, and ribonucleotide reductase (Haffo et al, 2018).	('p53', 'Gene', (206, 209))	('thioredoxin', 'Gene', '7295', (233, 244))	('thioredoxin', 'Gene', '7295', (275, 286))	('MQ', 'Chemical', '-', (59, 61))	('glutaredoxin', 'Gene', '2745', (288, 300))	('MQ', 'Chemical', '-', (108, 110))	('ribonucleotide reductase', 'Enzyme', (306, 330))	('thioredoxin', 'Gene', (233, 244))	('rat', 'Species', '10116', (44, 47))	('thioredoxin', 'Gene', (275, 286))	('glutaredoxin', 'Gene', (288, 300))	('APR-246', 'Chemical', 'MESH:C533410', (65, 72))	('thiol', 'Chemical', 'MESH:D013438', (152, 157))	('mutant', 'Var', (199, 205))
267066	33314700	We hypothesize that a transient stabilization of mutant p53 by MQ binding is sufficient to induce p53 tetramerization on DNA, driving p53-dependent transcription.	('mutant', 'Var', (49, 55))	('p53', 'Gene', (56, 59))	('tet', 'Chemical', 'MESH:C010349', (102, 105))	('MQ', 'Chemical', '-', (63, 65))	('binding', 'Interaction', (66, 73))	('p53', 'Protein', (98, 101))	('tetramerization', 'MPA', (102, 117))	('p53-dependent', 'MPA', (134, 147))	('driving', 'Reg', (126, 133))	('induce', 'Reg', (91, 97))
267067	33314700	This is consistent with data showing that brief exposure of R175H mutant p53 to Zn2+ is sufficient to induce mutant p53 reactivation and apoptosis (Yu et al, 2018).	('induce', 'Reg', (102, 108))	('apoptosis', 'CPA', (137, 146))	('Zn2+', 'Chemical', '-', (80, 84))	('p53', 'Gene', (73, 76))	('R175H', 'Mutation', 'rs28934578', (60, 65))	('mutant', 'Var', (109, 115))	('reactivation', 'MPA', (120, 132))	('R175H', 'Var', (60, 65))	('p53', 'Gene', (116, 119))
267069	33314700	Thus, our data suggest that the trapping of GS-MQ within tumor cells by inhibiting MRP1-mediated drug efflux can potentiate the effect of APR-246/MQ by forming an intracellular MQ reservoir, from which MQ can be released to target for instance thiols in mutant p53.	('MQ', 'Chemical', '-', (202, 204))	('thiols', 'Chemical', 'MESH:D013438', (244, 250))	('potentiate', 'PosReg', (113, 123))	('MRP1-mediated drug efflux', 'MPA', (83, 108))	('p53', 'Gene', (261, 264))	('GS-MQ within tumor', 'Disease', 'MESH:D011125', (44, 62))	('MQ', 'Chemical', '-', (146, 148))	('inhibiting', 'NegReg', (72, 82))	('MQ', 'Chemical', '-', (47, 49))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('GS-MQ within tumor', 'Disease', (44, 62))	('MQ', 'Chemical', '-', (177, 179))	('APR-246', 'Chemical', 'MESH:C533410', (138, 145))	('mutant', 'Var', (254, 260))
267070	33314700	Treatment with MK-571 caused a decrease in intracellular total GSH + GSSG concentration in a majority of the tested cell lines (Fig 6A-C), in agreement with previous reports (Cullen et al, 2001; Hirrlinger et al, 2002; Minich et al, 2006).	('GSH', 'Chemical', '-', (63, 66))	('MK-571', 'Var', (15, 21))	('rat', 'Species', '10116', (81, 84))	('MK-571', 'Chemical', 'MESH:C059141', (15, 21))	('GSSG', 'Chemical', 'MESH:D019803', (69, 73))	('decrease', 'NegReg', (31, 39))	('intracellular total GSH + GSSG concentration', 'MPA', (43, 87))
267073	33314700	It is conceivable that a higher intracellular concentration of MQ in the context of diminished GSH levels will allow more extensive modification of key mutant p53 cysteines or other protein thiols, and thus more efficient mutant p53 activation and subsequent tumor cell killing.	('cysteines', 'Chemical', 'MESH:D003545', (163, 172))	('cysteines', 'MPA', (163, 172))	('tumor', 'Disease', (259, 264))	('thiols', 'Chemical', 'MESH:D013438', (190, 196))	('p53', 'Gene', (159, 162))	('MQ', 'Chemical', '-', (63, 65))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('p53', 'Gene', (229, 232))	('modification', 'MPA', (132, 144))	('more', 'PosReg', (207, 211))	('GSH', 'Chemical', '-', (95, 98))	('rat', 'Species', '10116', (53, 56))	('mutant', 'Var', (152, 158))	('mutant', 'Var', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('higher', 'PosReg', (25, 31))	('activation', 'PosReg', (233, 243))	('GSH', 'MPA', (95, 98))
267075	33314700	The synergy between APR-246 and MK-571 was more prominent in cells carrying mutant TP53 (Fig 1D), but there was no obvious correlation between 14C accumulation and TP53 status (Fig 5F and H, and EV5D).	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', '7157', (164, 168))	('TP53', 'Gene', (164, 168))	('TP53', 'Gene', (83, 87))	('mutant', 'Var', (76, 82))	('MK-571', 'Chemical', 'MESH:C059141', (32, 38))	('14C', 'Chemical', 'MESH:C000615234', (143, 146))	('APR-246', 'Chemical', 'MESH:C533410', (20, 27))
267076	33314700	Thus, transient downregulation of R175H mutant p53 did not affect 14C accumulation (Fig 5H), nor did it abrogate the synergistic cell death induced by combination treatment with APR-246 and MK-571 (Appendix Fig S5G).	('downregulation', 'NegReg', (16, 30))	('14C accumulation', 'MPA', (66, 82))	('MK-571', 'Chemical', 'MESH:C059141', (190, 196))	('death', 'Disease', 'MESH:D003643', (134, 139))	('R175H mutant', 'Var', (34, 46))	('death', 'Disease', (134, 139))	('14C', 'Chemical', 'MESH:C000615234', (66, 69))	('combination', 'Interaction', (151, 162))	('APR-246', 'Chemical', 'MESH:C533410', (178, 185))	('p53', 'Gene', (47, 50))	('R175H', 'Mutation', 'rs28934578', (34, 39))	('abrogate', 'NegReg', (104, 112))
267079	33314700	Considering that APR-246 can induce lipid peroxidation in tumor cells (Liu et al, 2017), it seems likely that increased intracellular accumulation of toxic byproducts of lipid peroxidation following MRP1 inhibition contributes to the observed synergy.	('APR-246', 'Var', (17, 24))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('inhibition', 'NegReg', (204, 214))	('lipid peroxidation', 'MPA', (36, 54))	('MRP1', 'Gene', (199, 203))	('induce', 'Reg', (29, 35))	('APR-246', 'Chemical', 'MESH:C533410', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('lipid', 'Chemical', 'MESH:D008055', (170, 175))	('increased intracellular accumulation', 'Phenotype', 'HP:0003575', (110, 146))	('lipid', 'Chemical', 'MESH:D008055', (36, 41))
267082	33314700	APR-246 also synergizes with the xCT inhibitor sulfasalazine (SSZ) in vitro (Fig 7G) and in vivo (Liu et al, 2017).	('APR-246', 'Var', (0, 7))	('xCT', 'Gene', '23657', (33, 36))	('sulfasalazine', 'Chemical', 'MESH:D012460', (47, 60))	('SSZ', 'Chemical', 'MESH:D012460', (62, 65))	('APR-246', 'Chemical', 'MESH:C533410', (0, 7))	('xCT', 'Gene', (33, 36))
267083	33314700	In the present study, we found that MK-571 treatment leads to increased xCT protein levels in tumor cells carrying WT or mutant TP53 (Fig 6D and E, and Appendix Fig S6E-G).	('increased', 'PosReg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutant', 'Var', (121, 127))	('MK-571', 'Chemical', 'MESH:C059141', (36, 42))	('TP53', 'Gene', '7157', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('TP53', 'Gene', (128, 132))	('tumor', 'Disease', (94, 99))	('xCT', 'Gene', (72, 75))	('xCT', 'Gene', '23657', (72, 75))
267086	33314700	Increased xCT protein levels after MK-571 treatment could be interpreted as a response to shifts in the intracellular Cys/CySS and GSH/GSSG ratio, which involves induction of SLC7A11 (xCT) via transactivation by ATF4 and NRF2 (Ishii & Mann, 2014; Yu & Long, 2016).	('xCT', 'Gene', '23657', (184, 187))	('Cys', 'Chemical', 'MESH:D003545', (118, 121))	('NRF2', 'Gene', '4780', (221, 225))	('CySS', 'Chemical', '-', (122, 126))	('NRF2', 'Gene', (221, 225))	('xCT', 'Gene', (10, 13))	('xCT', 'Gene', '23657', (10, 13))	('SLC7A11', 'Gene', (175, 182))	('ATF4', 'Gene', (212, 216))	('GSH', 'Chemical', '-', (131, 134))	('xCT', 'Gene', (184, 187))	('GSSG', 'Chemical', 'MESH:D019803', (135, 139))	('rat', 'Species', '10116', (140, 143))	('ATF4', 'Gene', '468', (212, 216))	('MK-571', 'Var', (35, 41))	('transactivation', 'PosReg', (193, 208))	('MK-571', 'Chemical', 'MESH:C059141', (35, 41))
267087	33314700	Interestingly, several studies have shown that APR-246 treatment leads to an increased xCT protein level in tumor cells (Ali et al, 2016; Liu et al, 2017; Lisek et al, 2018; Synnott et al, 2018), possibly due to its inhibition of mutant p53-NRF2 complexing and/or its pro-oxidant activities (Walerych et al, 2016; Eriksson et al, 2019).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('NRF2', 'Gene', '4780', (241, 245))	('mutant', 'Var', (230, 236))	('NRF2', 'Gene', (241, 245))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('xCT', 'Gene', (87, 90))	('APR-246', 'Chemical', 'MESH:C533410', (47, 54))	('increased', 'PosReg', (77, 86))	('APR-246', 'Gene', (47, 54))	('xCT', 'Gene', '23657', (87, 90))	('inhibition', 'NegReg', (216, 226))	('complexing', 'Interaction', (246, 256))
267089	33314700	siRNA knockdown of xCT in HCT116 TP53 WT or R248W cells increased both 14C levels and sensitivity to APR-246, although the total GSH + GSSG level was not altered (Fig 7A-C).	('sensitivity to APR-246', 'MPA', (86, 108))	('HCT116', 'Gene', (26, 32))	('14C levels', 'MPA', (71, 81))	('14C', 'Chemical', 'MESH:C000615234', (71, 74))	('increased', 'PosReg', (56, 65))	('APR-246', 'Chemical', 'MESH:C533410', (101, 108))	('xCT', 'Gene', '23657', (19, 22))	('TP53', 'Gene', '7157', (33, 37))	('GSSG', 'Chemical', 'MESH:D019803', (135, 139))	('TP53', 'Gene', (33, 37))	('R248W', 'Mutation', 'rs121912651', (44, 49))	('knockdown', 'Var', (6, 15))	('GSH', 'Chemical', '-', (129, 132))	('xCT', 'Gene', (19, 22))	('R248W', 'Var', (44, 49))	('HCT116', 'CellLine', 'CVCL:0291', (26, 32))
267092	33314700	This notion is further supported by our data on 14C accumulation upon combination treatment with 14C-APR-246, MK-571, and siRNA against MRP1 or xCT.	('MK-571', 'Var', (110, 116))	('14C-APR-246', 'Var', (97, 108))	('MK-571', 'Chemical', 'MESH:C059141', (110, 116))	('14C', 'MPA', (48, 51))	('APR-246', 'Chemical', 'MESH:C533410', (101, 108))	('14C-APR', 'Chemical', '-', (97, 104))	('xCT', 'Gene', (144, 147))	('accumulation', 'PosReg', (52, 64))	('xCT', 'Gene', '23657', (144, 147))	('combination', 'Interaction', (70, 81))	('14C', 'Chemical', 'MESH:C000615234', (48, 51))	('MRP1', 'Protein', (136, 140))	('14C', 'Chemical', 'MESH:C000615234', (97, 100))
267093	33314700	The robust increase in 14C accumulation in xCT-deficient cells treated with APR-246 plus MK-571 (Fig 7A) suggests that MRP1 and xCT have complementary activities.	('xCT-deficient', 'Disease', 'MESH:D007153', (43, 56))	('increase', 'PosReg', (11, 19))	('xCT', 'Gene', '23657', (43, 46))	('APR-246', 'Chemical', 'MESH:C533410', (76, 83))	('14C', 'Chemical', 'MESH:C000615234', (23, 26))	('xCT', 'Gene', (128, 131))	('APR-246', 'Var', (76, 83))	('xCT-deficient', 'Disease', (43, 56))	('MK-571', 'Var', (89, 95))	('14C accumulation', 'MPA', (23, 39))	('MK-571', 'Chemical', 'MESH:C059141', (89, 95))	('xCT', 'Gene', '23657', (128, 131))	('xCT', 'Gene', (43, 46))
267095	33314700	Furthermore, it has been suggested that MK-571 treatment inhibits secretion of Cys via MRP1 (Olm et al, 2009).	('secretion of Cys via', 'MPA', (66, 86))	('MK-571', 'Var', (40, 46))	('MRP1', 'Protein', (87, 91))	('MK-571', 'Chemical', 'MESH:C059141', (40, 46))	('inhibits', 'NegReg', (57, 65))	('Cys', 'Chemical', 'MESH:D003545', (79, 82))
267098	33314700	In summary, we have demonstrated synergy between APR-246 and MK-571 in in vitro cultured cancer cells, in vivo in mice, and ex vivo in esophageal and colorectal cancer PDOs.	('APR-246', 'Var', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('colorectal cancer PDOs', 'Disease', (150, 172))	('colorectal cancer PDOs', 'Disease', 'MESH:D015179', (150, 172))	('MK-571', 'Chemical', 'MESH:C059141', (61, 67))	('esophageal', 'Disease', (135, 145))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (89, 95))	('rat', 'Species', '10116', (27, 30))	('MK-571', 'Gene', (61, 67))	('mice', 'Species', '10090', (114, 118))	('cancer', 'Disease', (161, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('APR-246', 'Chemical', 'MESH:C533410', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
267101	33314700	Thus, the strong synergistic effect of APR-246 and MK-571 combination treatment is most likely due to the co-targeting of high molecular weight (HMW) thiols such as mutant p53 (leading to p53 core domain refolding), cellular redox homeostasis (depletion of GSH + GSSG, accumulation of lipid peroxides, and Cys/CySS imbalance), and drug export (accumulation of an intracellular MQ pool).	('cellular redox homeostasis', 'MPA', (216, 242))	('GSH', 'MPA', (257, 260))	('accumulation', 'PosReg', (344, 356))	('CySS', 'Chemical', '-', (310, 314))	('Cys', 'Chemical', 'MESH:D003545', (306, 309))	('lipid peroxides', 'MPA', (285, 300))	('APR-246', 'Chemical', 'MESH:C533410', (39, 46))	('GSH', 'Chemical', '-', (257, 260))	('MQ', 'Chemical', '-', (377, 379))	('drug export', 'MPA', (331, 342))	('depletion', 'NegReg', (244, 253))	('accumulation', 'PosReg', (269, 281))	('imbalance', 'Phenotype', 'HP:0002172', (315, 324))	('GSSG', 'Chemical', 'MESH:D019803', (263, 267))	('lipid peroxides', 'Chemical', 'MESH:D008054', (285, 300))	('p53', 'Gene', (172, 175))	('mutant', 'Var', (165, 171))	('thiols', 'Chemical', 'MESH:D013438', (150, 156))	('MK-571', 'Chemical', 'MESH:C059141', (51, 57))
267104	33314700	Saos-2 R273H and H1299 R175H cells carry exogenous tetracycline-regulated mutant p53 (Tet-off) (Bykov et al, 2002b).	('R273H', 'Mutation', 'rs28934576', (7, 12))	('Tet', 'Chemical', 'MESH:C010349', (86, 89))	('tetracycline', 'Chemical', 'MESH:D013752', (51, 63))	('R175H', 'Var', (23, 28))	('p53', 'Gene', (81, 84))	('R175H', 'SUBSTITUTION', 'None', (23, 28))
267105	33314700	H1299 R175H cells were treated with 2 mug/ml doxycycline for 2 days and then continuously with 0.5 mug/ml doxycycline for at least 1 week to turn off expression of mutant p53.	('mutant', 'Var', (164, 170))	('expression', 'MPA', (150, 160))	('R175H', 'SUBSTITUTION', 'None', (6, 11))	('turn off', 'NegReg', (141, 149))	('doxycycline', 'Chemical', 'MESH:D004318', (106, 117))	('p53', 'Gene', (171, 174))	('R175H', 'Var', (6, 11))	('doxycycline', 'Chemical', 'MESH:D004318', (45, 56))
267106	33314700	Saos-2 R273H cells were treated continuously with 5 mug/ml doxycycline for at least 1 week to turn off expression of mutant p53.	('R273H', 'Mutation', 'rs28934576', (7, 12))	('p53', 'Gene', (124, 127))	('mutant', 'Var', (117, 123))	('expression', 'MPA', (103, 113))	('turn off', 'NegReg', (94, 102))	('doxycycline', 'Chemical', 'MESH:D004318', (59, 70))
267108	33314700	HCT116 TP53 null and R248W cells were generated by targeted disruption of endogenous WT TP53 or knockin of R248W-mutant TP53 (Bunz et al, 1998).	('R248W', 'Mutation', 'rs121912651', (21, 26))	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('R248W', 'Mutation', 'rs121912651', (107, 112))	('R248W-mutant', 'Var', (107, 119))	('HCT116', 'CellLine', 'CVCL:0291', (0, 6))	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))	('TP53', 'Gene', '7157', (120, 124))	('rat', 'Species', '10116', (42, 45))	('TP53', 'Gene', (120, 124))
267138	33314700	Sections were blocked in 10% (w/v) bovine serum albumin (BSA) in TBS-Tween-20 0.1% (TBS-T) for 1 h at room temperature and incubated with primary antibodies diluted in 1% (w/v) BSA in TBS-T overnight at 4 C. Sections were then incubated with HRP-conjugated secondary antibody (K4003, Dako EnVision + System-HRP labeled Polymer, Dako) for 45 min at room temperature and stained by DAB (K3468, Dako) for 2 min at room temperature.	('rat', 'Species', '10116', (358, 361))	('TBS-T', 'Disease', 'MESH:D001260', (84, 89))	('TBS-T', 'Disease', 'MESH:D001260', (184, 189))	('TBS-T', 'Disease', (65, 70))	('rat', 'Species', '10116', (421, 424))	('serum albumin', 'Gene', (42, 55))	('Tween-20', 'Chemical', 'MESH:D011136', (69, 77))	('TBS-T', 'Disease', (84, 89))	('TBS-T', 'Disease', (184, 189))	('rat', 'Species', '10116', (112, 115))	('K3468', 'Var', (385, 390))	('TBS-T', 'Disease', 'MESH:D001260', (65, 70))	('serum albumin', 'Gene', '213', (42, 55))
267171	33314700	Cells were treated with APR-246 and/or MK-571 the next day.	('MK-571', 'Chemical', 'MESH:C059141', (39, 45))	('MK-571', 'Var', (39, 45))	('APR-246', 'Var', (24, 31))	('APR-246', 'Chemical', 'MESH:C533410', (24, 31))
267175	33314700	To dissociate PDOs, ice-cold PBS was added to dissolve the Matrigel, cells were then centrifuged at 350 g for 5 min and resuspended in 40% TrypLE Express (12605028, Thermo Fisher Scientific, Waltham, MA, USA) in PBS for 1 h at 37 C. Once dissociated, cells were centrifuged at 350 g for 5 min, resuspended in BCM (see Appendix Table S2), and counted using Countess  II, Thermo Fisher Scientific, USA.	('PBS', 'Chemical', '-', (29, 32))	('cold PBS', 'Disease', (24, 32))	('cold PBS', 'Disease', 'MESH:D011535', (24, 32))	('12605028', 'Var', (155, 163))	('PBS', 'Chemical', '-', (212, 215))
267183	33314700	After adhesion overnight, cells were treated with different concentrations of APR-246 and/or MK-571.	('rat', 'Species', '10116', (67, 70))	('MK-571', 'Chemical', 'MESH:C059141', (93, 99))	('MK-571', 'Gene', (93, 99))	('APR-246', 'Chemical', 'MESH:C533410', (78, 85))	('APR-246', 'Var', (78, 85))
267198	33314700	After allowing the cells to adhere overnight, cells were treated with the indicated concentrations of APR-246 and/or MK-571.	('rat', 'Species', '10116', (91, 94))	('MK-571', 'Var', (117, 123))	('APR-246', 'Chemical', 'MESH:C533410', (102, 109))	('MK-571', 'Chemical', 'MESH:C059141', (117, 123))	('APR-246', 'Var', (102, 109))
267207	33314700	Primary antibody D7O8N against MRP1 diluted 1:200 (14685S, Cell Signaling, USA) was prepared in blocking buffer and incubated at 4 C over night.	('MRP1', 'Gene', (31, 35))	('D7O8N', 'Var', (17, 22))	('D7O8N', 'Chemical', '-', (17, 22))
267211	33314700	Patients were selected for having genetic alternations with putative TP53 mutation (missense or truncating mutations) or no TP53 alteration.	('mutation', 'Var', (74, 82))	('TP53', 'Gene', '7157', (124, 128))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('rat', 'Species', '10116', (133, 136))	('TP53', 'Gene', (124, 128))	('Patients', 'Species', '9606', (0, 8))
267242	31319002	Further, the largest to date prospective study examining the association of individual components of the metabolic syndrome (including BP measurements) and cancer in over half a million participants from Norway, Sweden and Austria: the Metabolic syndrome and Cancer project (Me-Can), reported positive associations of high BP with the risk of cancers in locations other than the kidney in both men (oropharynx, colon, rectum and anus, lung with larynx and trachea, bladder, malignant melanoma, non-melanoma skin cancer) and women (liver, pancreas, corpus uteri, cervix, malignant melanoma).	('men', 'Species', '9606', (526, 529))	('men', 'Species', '9606', (145, 148))	('pancreas', 'Disease', (538, 546))	('malignant melanoma', 'Disease', (570, 588))	('Metabolic syndrome', 'Disease', 'MESH:D024821', (236, 254))	('cancers', 'Phenotype', 'HP:0002664', (343, 350))	('skin cancer', 'Phenotype', 'HP:0008069', (507, 518))	('cancers', 'Disease', (343, 350))	('cancer', 'Disease', (343, 349))	('melanoma', 'Phenotype', 'HP:0002861', (580, 588))	('BP', 'Chemical', 'MESH:C038809', (323, 325))	('cancer', 'Disease', 'MESH:D009369', (512, 518))	('Cancer', 'Disease', 'MESH:D009369', (259, 265))	('metabolic syndrome', 'Disease', 'MESH:D024821', (105, 123))	('melanoma', 'Phenotype', 'HP:0002861', (484, 492))	('participants', 'Species', '9606', (186, 198))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('bladder', 'Disease', (465, 472))	('Metabolic syndrome', 'Disease', (236, 254))	('high BP', 'Var', (318, 325))	('women', 'Species', '9606', (524, 529))	('malignant melanoma', 'Disease', (474, 492))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (494, 518))	('trachea', 'Disease', (456, 463))	('malignant melanoma', 'Phenotype', 'HP:0002861', (570, 588))	('malignant melanoma', 'Disease', 'MESH:D008545', (570, 588))	('melanoma', 'Phenotype', 'HP:0002861', (498, 506))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('cancers', 'Disease', 'MESH:D009369', (343, 350))	('corpus uteri', 'Disease', (548, 560))	('BP', 'Chemical', 'MESH:C038809', (135, 137))	('cancer', 'Disease', (512, 518))	('men', 'Species', '9606', (394, 397))	('Cancer', 'Phenotype', 'HP:0002664', (259, 265))	('lung', 'Disease', (435, 439))	('trachea', 'Disease', 'MESH:C557675', (456, 463))	('non-melanoma skin cancer', 'Disease', (494, 518))	('cancer', 'Disease', (156, 162))	('colon', 'Disease', (411, 416))	('cancer', 'Phenotype', 'HP:0002664', (512, 518))	('malignant melanoma', 'Phenotype', 'HP:0002861', (474, 492))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('malignant melanoma', 'Disease', 'MESH:D008545', (474, 492))	('Cancer', 'Disease', (259, 265))	('metabolic syndrome', 'Disease', (105, 123))	('cervix', 'Disease', (562, 568))
267247	31319002	Studies in mice have also provided preliminary evidence that blockade of the angiotensin II type 1 receptor attenuates the growth and metastatic potential of RCC.	('blockade', 'Var', (61, 69))	('mice', 'Species', '10090', (11, 15))	('attenuates', 'NegReg', (108, 118))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('angiotensin', 'Protein', (77, 88))
267305	31319002	reported, based on 250 cases in the EPIC study, that high SBP and DBP are associated with a higher risk of RCC, both in men and women and found that individuals receiving antihypertensive treatment had higher risk only if hypertension was poorly controlled.	('hypertensive', 'Disease', 'MESH:D006973', (175, 187))	('women', 'Species', '9606', (128, 133))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('high SBP', 'Var', (53, 61))	('hypertension', 'Disease', 'MESH:D006973', (222, 234))	('hypertensive', 'Disease', (175, 187))	('hypertension', 'Phenotype', 'HP:0000822', (222, 234))	('BP', 'Chemical', 'MESH:C038809', (59, 61))	('hypertension', 'Disease', (222, 234))	('men', 'Species', '9606', (193, 196))	('DBP', 'Gene', (66, 69))	('BP', 'Chemical', 'MESH:C038809', (67, 69))	('men', 'Species', '9606', (130, 133))	('men', 'Species', '9606', (120, 123))
267314	31319002	For mouth and oropharynx, the positive associations were statistically significant only in women, in individuals older than 53 years at recruitment and for alcohol intake>12g/day and for head and neck cancers and esophageal SCC only for alcohol intake>12g/day and not below.	('alcohol', 'Chemical', 'MESH:D000438', (156, 163))	('head and neck cancers', 'Disease', 'MESH:D006258', (187, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('age', 'Gene', (218, 221))	('head and neck cancers', 'Phenotype', 'HP:0012288', (187, 208))	('SCC', 'Gene', (224, 227))	('men', 'Species', '9606', (93, 96))	('mouth', 'Disease', (4, 9))	('women', 'Species', '9606', (91, 96))	('alcohol', 'Chemical', 'MESH:D000438', (237, 244))	('mouth', 'Disease', 'MESH:D009059', (4, 9))	('SCC', 'Gene', '6317', (224, 227))	('age', 'Gene', '5973', (218, 221))	('>12g/day', 'Var', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('men', 'Species', '9606', (143, 146))
267334	31319002	We also found a weak positive association of DBP with the risk of cancer of the colon (n=3003) (75% of which had AC (code 8140/3) morphology): HR=1.06 (1.02-1.10) for DBP, similarly for men and women (Supplementary Figure 1B), but not the rectum and rectosigmoid junction (n=1622) (81% AC) (Figure 2).	('men', 'Species', '9606', (196, 199))	('cancer of the colon', 'Disease', 'MESH:D015179', (66, 85))	('BP', 'Chemical', 'MESH:C038809', (168, 170))	('women', 'Species', '9606', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('men', 'Species', '9606', (207, 210))	('cancer of the colon', 'Disease', (66, 85))	('men', 'Species', '9606', (186, 189))	('cancer of the colon', 'Phenotype', 'HP:0100273', (66, 85))	('BP', 'Chemical', 'MESH:C038809', (46, 48))	('DBP', 'Var', (167, 170))
267337	31319002	Our data are broadly compatible with results from previous large studies, which suggest that high BP is associated with the risk of colorectal cancer in men but not in women.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('high BP', 'Var', (93, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('men', 'Species', '9606', (153, 156))	('men', 'Species', '9606', (170, 173))	('colorectal cancer', 'Disease', (132, 149))	('women', 'Species', '9606', (168, 173))	('BP', 'Chemical', 'MESH:C038809', (98, 100))
267354	31319002	Large European case-control and cohort studies (n>700 in each), although not accounting for specific morphologies, have consistently reported, in agreement with our findings, a higher risk of endometrial cancer with high BP, especially in obese women, while a relatively smaller case-control study in the United States (n=469) found a higher risk only in women receiving thiazide diuretics.	('endometrial cancer', 'Disease', (192, 210))	('men', 'Species', '9606', (151, 154))	('obese', 'Disease', 'MESH:D009765', (239, 244))	('endometrial cancer', 'Phenotype', 'HP:0012114', (192, 210))	('obese', 'Disease', (239, 244))	('women', 'Species', '9606', (245, 250))	('endometrial cancer', 'Disease', 'MESH:D016889', (192, 210))	('men', 'Species', '9606', (357, 360))	('BP', 'Chemical', 'MESH:C038809', (221, 223))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('high BP', 'Var', (216, 223))	('thiazide', 'Chemical', 'MESH:D049971', (371, 379))	('men', 'Species', '9606', (247, 250))	('women', 'Species', '9606', (355, 360))
267355	31319002	For cervical SCC (n=145), but not for total cervical cancers (n=223), we found an inverse association (Figure 2), which was especially pronounced in women with BMI>25kg/m2 (n=68): HR=0.81 (0.71-0.93) for SBP and HR=0.74 (0.57-0.95) for DBP (Supplementary Figure 1C,D), whilst we found no evidence for association of BP with cervical AC (n=37) and a positive association for the remaining morphologies (n=41): HR=1.28 (1.10-1.48) for SBP and HR=1.53 (1.17-2.01) for DBP, which would have contributed to absence of an overall association for total cervical cancers, but with a small number of cases, this could be a chance finding.	('men', 'Species', '9606', (247, 250))	('SBP', 'Disease', (433, 436))	('cancers', 'Phenotype', 'HP:0002664', (555, 562))	('DBP', 'Disease', (465, 468))	('cervical cancers', 'Disease', (546, 562))	('cervical cancers', 'Disease', 'MESH:D002583', (546, 562))	('cancer', 'Phenotype', 'HP:0002664', (555, 561))	('men', 'Species', '9606', (151, 154))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('women', 'Species', '9606', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BMI>25kg/m2', 'Var', (160, 171))	('cervical cancers', 'Disease', (44, 60))	('BP', 'Chemical', 'MESH:C038809', (237, 239))	('SCC', 'Gene', '6317', (13, 16))	('cervical cancers', 'Disease', 'MESH:D002583', (44, 60))	('BP', 'Chemical', 'MESH:C038809', (316, 318))	('HR=1.53', 'Var', (441, 448))	('BP', 'Chemical', 'MESH:C038809', (205, 207))	('BP', 'Chemical', 'MESH:C038809', (434, 436))	('BP', 'Chemical', 'MESH:C038809', (466, 468))	('SCC', 'Gene', (13, 16))
267419	31922234	A previous study observed the abnormal activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway in Burkitt's lymphoma cells, and demonstrated that inhibition of PI3K/AKT pathway activation can inhibit the growth of Burkitt's lymphoma cells.	('PI3', 'Gene', (101, 104))	('AKT', 'Gene', '207', (106, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (248, 256))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (122, 140))	('PI3', 'Gene', '5266', (184, 187))	('inhibition', 'Var', (170, 180))	('AKT', 'Gene', (189, 192))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (122, 140))	('protein kinase B', 'Gene', '2185', (83, 99))	("Burkitt's lymphoma", 'Disease', (122, 140))	('protein kinase B', 'Gene', (83, 99))	('activation', 'PosReg', (39, 49))	('PI3', 'Gene', (184, 187))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (238, 256))	('growth', 'CPA', (228, 234))	('AKT', 'Gene', '207', (189, 192))	('PI3', 'Gene', '5266', (101, 104))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (238, 256))	('abnormal activation of the phosphoinositide 3-kinase', 'Phenotype', 'HP:0012175', (30, 82))	('AKT', 'Gene', (106, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	("Burkitt's lymphoma", 'Disease', (238, 256))	('inhibit', 'NegReg', (216, 223))
267421	31922234	As a negative regulatory factor, PTEN exhibits mutations, deletions, methylation and abnormal activity in solid tumors.	('solid tumors', 'Disease', (106, 118))	('methylation', 'MPA', (69, 80))	('PTEN', 'Gene', (33, 37))	('mutations', 'Var', (47, 56))	('PTEN', 'Gene', '5728', (33, 37))	('deletions', 'Var', (58, 67))	('activity', 'MPA', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
267424	31922234	Therefore, it is hypothesized that abnormal expression of PTEN may serve an essential role in the pathogenesis of Burkitt's lymphoma.	('PTEN', 'Gene', '5728', (58, 62))	("Burkitt's lymphoma", 'Disease', (114, 132))	('abnormal', 'Var', (35, 43))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (114, 132))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (114, 132))	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))	('PTEN', 'Gene', (58, 62))
267445	31922234	The catalog numbers of anti-GAPDH, anti-PTEN, anti-AKT, anti-pAKT, anti-Bad, anti-Bax, anti-P53, anti-P21, anti-CDK4 and anti-CDK6 were #5157, #9188, #4685, #4060, #9268, #5023, #2527, #2947, #12790, #13331, respectively.	('AKT', 'Gene', (62, 65))	('GAPDH', 'Gene', (28, 33))	('Bax', 'Gene', (82, 85))	('anti-Bad', 'Var', (67, 75))	('Bax', 'Gene', '581', (82, 85))	('CDK6', 'Gene', '1021', (126, 130))	('AKT', 'Gene', '207', (62, 65))	('#9268', 'Var', (164, 169))	('#2527', 'Var', (178, 183))	('#4060', 'Var', (157, 162))	('P21', 'Gene', '644914', (102, 105))	('P53', 'Gene', (92, 95))	('#4685', 'Var', (150, 155))	('PTEN', 'Gene', (40, 44))	('AKT', 'Gene', (51, 54))	('#13331', 'Var', (200, 206))	('CDK6', 'Gene', (126, 130))	('CDK4', 'Gene', (112, 116))	('#2947', 'Var', (185, 190))	('GAPDH', 'Gene', '2597', (28, 33))	('PTEN', 'Gene', '5728', (40, 44))	('P53', 'Gene', '7157', (92, 95))	('#12790', 'Var', (192, 198))	('#5023', 'Var', (171, 176))	('P21', 'Gene', (102, 105))	('CDK4', 'Gene', '1019', (112, 116))	('#9188', 'Var', (143, 148))	('AKT', 'Gene', '207', (51, 54))
267449	31922234	In addition, the expression level of p-AKT (Ser473) in the Lv-PTEN cell group was lower when compared with the Lv-NC cell group in both the CA46 and RAJI cell lines (Fig.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('Ser', 'Chemical', 'MESH:C530429', (44, 47))	('Ser473', 'Var', (44, 50))	('AKT', 'Gene', '207', (39, 42))	('expression level', 'MPA', (17, 33))	('AKT', 'Gene', (39, 42))	('lower', 'NegReg', (82, 87))
267459	31922234	4A and B, the optical density (OD) values of the cells in each group were 0.506+-0.012 in the CA46-Lv-NC cell group, 0.194+-0.024 in the CA46-Lv-PTEN cell group, and 0.403+-0.015 in the RAJI-Lv-NC cell group.	('PTEN', 'Gene', '5728', (145, 149))	('0.194+-0.024', 'Var', (117, 129))	('0.506+-0.012', 'Var', (74, 86))	('PTEN', 'Gene', (145, 149))
267466	31922234	To further verify the biological function of the silencing of PTEN on CA46 and RAJI cells, PTEN was silenced and cell function assays were performed.	('PTEN', 'Gene', (62, 66))	('silencing', 'Var', (49, 58))	('PTEN', 'Gene', '5728', (62, 66))	('PTEN', 'Gene', (91, 95))	('PTEN', 'Gene', '5728', (91, 95))
267467	31922234	As expected, silencing of PTEN promoted the growth, migration and invasion of the two cell lines.	('migration', 'CPA', (52, 61))	('PTEN', 'Gene', '5728', (26, 30))	('promoted', 'PosReg', (31, 39))	('PTEN', 'Gene', (26, 30))	('growth', 'CPA', (44, 50))	('invasion of the two cell lines', 'CPA', (66, 96))	('silencing', 'Var', (13, 22))
267473	31922234	These results demonstrated that the silencing of PTEN produced opposite results on cell behavior when compared with the overexpression of PTEN.	('PTEN', 'Gene', '5728', (49, 53))	('PTEN', 'Gene', (138, 142))	('PTEN', 'Gene', '5728', (138, 142))	('cell behavior', 'CPA', (83, 96))	('silencing', 'Var', (36, 45))	('PTEN', 'Gene', (49, 53))
267475	31922234	Our previous studies found that inhibition of the PI3K pathway can inhibit the proliferation of Burkitt's lymphoma, and abnormal expression of phosphatase and tensin homolog (PTEN) is common in solid tumors, including breast cancer, kidney cancer, esophageal cancer, endometrial cancer and diffuse large B cell lymphoma.	('B cell lymphoma', 'Disease', 'MESH:D016393', (304, 319))	('proliferation', 'CPA', (79, 92))	('kidney cancer', 'Disease', 'MESH:D007680', (233, 246))	('inhibition', 'NegReg', (32, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('endometrial cancer', 'Phenotype', 'HP:0012114', (267, 285))	('kidney cancer', 'Phenotype', 'HP:0009726', (233, 246))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (304, 319))	('expression', 'MPA', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('esophageal cancer', 'Disease', 'MESH:D004938', (248, 265))	('endometrial cancer', 'Disease', (267, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('PI3', 'Gene', (50, 53))	('kidney cancer', 'Disease', (233, 246))	('lymphoma', 'Phenotype', 'HP:0002665', (311, 319))	('solid tumors', 'Disease', (194, 206))	('endometrial cancer', 'Disease', 'MESH:D016889', (267, 285))	('B cell lymphoma', 'Disease', (304, 319))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('inhibit', 'NegReg', (67, 74))	('common', 'Reg', (184, 190))	('esophageal cancer', 'Disease', (248, 265))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (96, 114))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	("Burkitt's lymphoma", 'Disease', (96, 114))	('PTEN', 'Gene', (175, 179))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('breast cancer', 'Disease', (218, 231))	('solid tumors', 'Disease', 'MESH:D009369', (194, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('PTEN', 'Gene', '5728', (175, 179))	('abnormal', 'Var', (120, 128))	('PI3', 'Gene', '5266', (50, 53))
267478	31922234	Zhao et al used PTEN as a silencing target and performed PTEN knockdown in neuronal cells, which activated the PI3K/AKT signaling pathway and promoted cell growth and proliferation.	('activated', 'PosReg', (97, 106))	('PI3', 'Gene', (111, 114))	('PTEN', 'Gene', (57, 61))	('PTEN', 'Gene', (16, 20))	('PTEN', 'Gene', '5728', (57, 61))	('AKT', 'Gene', '207', (116, 119))	('PTEN', 'Gene', '5728', (16, 20))	('promoted', 'PosReg', (142, 150))	('PI3', 'Gene', '5266', (111, 114))	('cell growth', 'CPA', (151, 162))	('AKT', 'Gene', (116, 119))	('knockdown', 'Var', (62, 71))
267480	31922234	Silencing of PTEN promoted the growth and proliferation of Burkitt's lymphoma cells.	('proliferation', 'CPA', (42, 55))	('growth', 'CPA', (31, 37))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (59, 77))	('promoted', 'PosReg', (18, 26))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (59, 77))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('PTEN', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('PTEN', 'Gene', '5728', (13, 17))	("Burkitt's lymphoma", 'Disease', (59, 77))
267494	31922234	In contrast, silencing of PTEN was revealed to promote the migration and invasion of Burkitt's lymphoma cells.	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (85, 103))	('lymphoma', 'Phenotype', 'HP:0002665', (95, 103))	('promote', 'PosReg', (47, 54))	("Burkitt's lymphoma", 'Disease', (85, 103))	('PTEN', 'Gene', (26, 30))	('invasion', 'CPA', (73, 81))	('PTEN', 'Gene', '5728', (26, 30))	('migration', 'CPA', (59, 68))	('silencing', 'Var', (13, 22))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (85, 103))
267498	31922234	Xu et al demonstrated that treatment with doxorubicin can upregulate the expression of PTEN and inhibit the phosphorylation of AKT in gastric cancer cells, thereby inhibiting the metastasis and invasion of gastric cancer.	('PTEN', 'Gene', '5728', (87, 91))	('inhibiting', 'NegReg', (164, 174))	('gastric cancer', 'Disease', (134, 148))	('gastric cancer', 'Disease', (206, 220))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('invasion', 'CPA', (194, 202))	('doxorubicin', 'Var', (42, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('expression', 'MPA', (73, 83))	('AKT', 'Gene', '207', (127, 130))	('metastasis', 'CPA', (179, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('upregulate', 'PosReg', (58, 68))	('phosphorylation', 'MPA', (108, 123))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('PTEN', 'Gene', (87, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('inhibit', 'NegReg', (96, 103))	('AKT', 'Gene', (127, 130))
267499	31922234	Wang et al demonstrated that knockdown of PTEN can promote the migration of nasopharyngeal carcinoma cells.	('PTEN', 'Gene', (42, 46))	('PTEN', 'Gene', '5728', (42, 46))	('knockdown', 'Var', (29, 38))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (76, 100))	('migration of nasopharyngeal', 'CPA', (63, 90))	('promote', 'PosReg', (51, 58))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Disease', (91, 100))
267506	31922234	Jin et al also indicated that inhibition of the PTEN/PI3K/AKT signaling pathway can enhance the sensitivity of esophageal cancer to radiotherapy and reverse the process of EMT.	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('inhibition', 'Var', (30, 40))	('PI3', 'Gene', '5266', (53, 56))	('sensitivity', 'MPA', (96, 107))	('esophageal cancer', 'Disease', (111, 128))	('PI3', 'Gene', (53, 56))	('AKT', 'Gene', '207', (58, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('enhance', 'PosReg', (84, 91))	('AKT', 'Gene', (58, 61))
267509	31922234	beta-catenin is an important molecule in the Wnt pathway, and abnormal expression of beta-catenin can promote tumor metastasis and infiltration.	('beta-catenin', 'Gene', '1499', (85, 97))	('beta-catenin', 'Gene', '1499', (0, 12))	('abnormal expression', 'Var', (62, 81))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('promote', 'PosReg', (102, 109))	('tumor metastasis', 'Disease', (110, 126))	('tumor metastasis', 'Disease', 'MESH:D009362', (110, 126))	('beta-catenin', 'Gene', (85, 97))	('beta-catenin', 'Gene', (0, 12))
267518	31922234	In the future, tumor cells should be induced to specifically express high PTEN using other methods, without affecting the expression level of PTEN in normal cells; thereby achieving the aim of treating lymphoma.	('PTEN', 'Gene', (142, 146))	('PTEN', 'Gene', '5728', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('lymphoma', 'Disease', (202, 210))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('lymphoma', 'Disease', 'MESH:D008223', (202, 210))	('PTEN', 'Gene', (74, 78))	('tumor', 'Disease', (15, 20))	('PTEN', 'Gene', '5728', (74, 78))	('high', 'Var', (69, 73))	('lymphoma', 'Phenotype', 'HP:0002665', (202, 210))
267524	30200913	Multivariate analyses revealed that tumor length, tumor width and T-staging were predictors of risk of locoregional recurrence, and that differentiation, N-staging, LVSI and PNI were predictors of risk of distant metastasis.	('PNI', 'Var', (174, 177))	('LVSI', 'Var', (165, 169))	('distant metastasis', 'CPA', (205, 223))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('locoregional', 'Disease', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', (50, 55))
267573	30200913	demonstrated that a patient with pN0 or pN1 did not need adjuvant chemotherapy, which leads to complications, such as vomit, diarrhea, granulocytopenia, and reduced quality of life.	('pN1', 'Gene', '5270', (40, 43))	('vomit', 'Disease', (118, 123))	('granulocytopenia', 'Disease', 'MESH:D000380', (135, 151))	('granulocytopenia', 'Phenotype', 'HP:0001913', (135, 151))	('vomit', 'Phenotype', 'HP:0002013', (118, 123))	('pN1', 'Gene', (40, 43))	('patient', 'Species', '9606', (20, 27))	('diarrhea', 'Phenotype', 'HP:0002014', (125, 133))	('diarrhea', 'Disease', 'MESH:D003967', (125, 133))	('vomit', 'Disease', 'MESH:D014839', (118, 123))	('pN0', 'Var', (33, 36))	('diarrhea', 'Disease', (125, 133))	('granulocytopenia', 'Disease', (135, 151))	('quality', 'MPA', (165, 172))	('reduced', 'NegReg', (157, 164))
267581	29168599	Moreover, knockdown of HOXC13 inhibited proliferation and induced apoptosis of ESCC through upregulating CASP3.	('CASP3', 'Gene', (105, 110))	('inhibited', 'NegReg', (30, 39))	('induced', 'Reg', (58, 65))	('HOXC13', 'Gene', '3229', (23, 29))	('HOXC13', 'Gene', (23, 29))	('apoptosis', 'CPA', (66, 75))	('CASP3', 'Gene', '836', (105, 110))	('knockdown', 'Var', (10, 19))	('proliferation', 'CPA', (40, 53))	('upregulating', 'PosReg', (92, 104))
267608	29168599	Transfection of shRNA and miR-503 mimics was performed according to the Lipofectamine 3000 Reagent (Invitrogen, Carlsbad, CA, USA) protocol; nonsense shRNA (sh-nc) and negative control mimic (miR-nc) were used as the respective controls.	('nonsense', 'Var', (141, 149))	('miR', 'Gene', '220972', (26, 29))	('miR-503', 'Gene', (26, 33))	('miR', 'Gene', (26, 29))	('miR', 'Gene', '220972', (192, 195))	('miR', 'Gene', (192, 195))	('miR-503', 'Gene', '574506', (26, 33))	('Lipofectamine', 'Chemical', 'MESH:C086724', (72, 85))
267635	29168599	To further investigate the biological function of HOXC13 in ESCC, we conducted two shRNA (sh1 and sh2) to knockdown HOXC13 in ECA109 and TE13 cells.	('HOXC13', 'Gene', '3229', (50, 56))	('HOXC13', 'Gene', (50, 56))	('HOXC13', 'Gene', '3229', (116, 122))	('HOXC13', 'Gene', (116, 122))	('knockdown', 'Var', (106, 115))	('sh2', 'Gene', '100125854', (98, 101))	('sh2', 'Gene', (98, 101))
267636	29168599	Cell Counting Kit-8 (CCK-8) assay, colony formation test and xCELLigence System assay all revealed that knockdown of HOXC13 inhibited proliferation of ECA109 and TE13 cells (Figure 2C-E).	('inhibited', 'NegReg', (124, 133))	('HOXC13', 'Gene', '3229', (117, 123))	('proliferation', 'CPA', (134, 147))	('HOXC13', 'Gene', (117, 123))	('knockdown', 'Var', (104, 113))
267638	29168599	Results indicated that knockdown of HOXC13 significantly induced apoptosis in ECA109 and TE13 cells (Figure 2F).	('HOXC13', 'Gene', (36, 42))	('knockdown', 'Var', (23, 32))	('HOXC13', 'Gene', '3229', (36, 42))	('induced', 'Reg', (57, 64))	('apoptosis', 'CPA', (65, 74))
267642	29168599	Using qRT-PCR and western blot analysis, we found that expression of CASP3 was significantly upregulated by knockdown of HOXC13 (Figure 3B,C).	('knockdown', 'Var', (108, 117))	('CASP3', 'Gene', '836', (69, 74))	('expression', 'Species', '29278', (55, 65))	('expression', 'MPA', (55, 65))	('CASP3', 'Gene', (69, 74))	('HOXC13', 'Gene', (121, 127))	('upregulated', 'PosReg', (93, 104))	('HOXC13', 'Gene', '3229', (121, 127))
267646	29168599	Moreover, ectopic expression of HOXC13 promotes proliferation of TE3 cells (Figure 4A-C) and inhibits apoptosis (Figure 4D).	('promotes', 'PosReg', (39, 47))	('HOXC13', 'Gene', (32, 38))	('apoptosis', 'CPA', (102, 111))	('proliferation', 'CPA', (48, 61))	('HOXC13', 'Gene', '3229', (32, 38))	('expression', 'Species', '29278', (18, 28))	('inhibits', 'NegReg', (93, 101))	('ectopic expression', 'Var', (10, 28))
267651	29168599	Immunohistochemistry (IHC) analysis revealed that tumors derived from sh-HOXC13 transfected cells showed thicker staining of CASP3 than those in the sh-nc group (Figure 5E).	('HOXC13', 'Gene', '3229', (73, 79))	('HOXC13', 'Gene', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('staining', 'MPA', (113, 121))	('transfected', 'Var', (80, 91))	('thicker', 'PosReg', (105, 112))	('CASP3', 'Gene', '836', (125, 130))	('CASP3', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
267711	29156845	Patients classified as MNLNR 0, MNLNR 0.01-0.2, and MNLNR >0.2, the observed 5-year OS rates were 46.6%, 31.2%, and 7.4%, respectively, and the median survival times of these three groups were 58.0, 42.0, and 33.0 months, respectively (chi2 = 17.375, P = 0.000 by log-rank test).	('MNLNR', 'Var', (23, 28))	('Patients', 'Species', '9606', (0, 8))	('MNLNR 0.01-0.2', 'Var', (32, 46))	('MNLNR >0.2', 'Var', (52, 62))
267721	29156845	It will be necessary to confirm the additional cut-off value especially for patients with MNLNR > 0.2 and to explore the optimal cut-off point.	('MNLNR', 'Gene', (90, 95))	('patients', 'Species', '9606', (76, 84))	('> 0.2', 'Var', (96, 101))
267742	28211613	Unlike with existing anti-CEA antibody therapies, antitumor activity of 15-1-32-vcMMAE was retained in the presence of high concentrations of soluble CEA.	('vcMMAE', 'Chemical', '-', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('15-1-32-vcMMAE', 'Var', (72, 86))
267821	28211613	The reactivity of 15-1-32 with MKN-45 is almost 10 times higher than PR1A3 in this condition.	('MKN-45', 'Var', (31, 37))	('reactivity', 'MPA', (4, 14))	('MKN-45', 'Chemical', '-', (31, 37))	('higher', 'PosReg', (57, 63))
267841	28211613	Cytotoxic activity of 15-1-32-vcMMAE was almost the same as labetuzumab-vcMMAE.	('Cytotoxic', 'Disease', 'MESH:D064420', (0, 9))	('15-1-32-vcMMAE', 'Var', (22, 36))	('labetuzumab-vcMMAE', 'Chemical', '-', (60, 78))	('vcMMAE', 'Chemical', '-', (30, 36))	('Cytotoxic', 'Disease', (0, 9))	('vcMMAE', 'Chemical', '-', (72, 78))
267851	28211613	Although the kinetics analysis of 15-1-32 to membrane-bound CEA was not investigated owing to technical difficulty, we speculate that 15-1-32 would retain the high kass, even to the CEA expressed on the cell surface, and that kdiss may decrease, indicating that it is not easily removed from cells.	('decrease', 'NegReg', (236, 244))	('kdiss', 'Chemical', '-', (226, 231))	('kdiss', 'MPA', (226, 231))	('high kass', 'MPA', (159, 168))	('15-1-32', 'Var', (134, 141))
267857	28211613	The results showed that the cytotoxicity of 15-1-32-vcMMAE was almost the same as the cytotoxicity of labetuzumab-vcMMAE.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('vcMMAE', 'Chemical', '-', (114, 120))	('cytotoxicity', 'Disease', 'MESH:D064420', (86, 98))	('labetuzumab-vcMMAE', 'Chemical', '-', (102, 120))	('15-1-32-vcMMAE', 'Var', (44, 58))	('cytotoxicity', 'Disease', (28, 40))	('cytotoxicity', 'Disease', (86, 98))	('vcMMAE', 'Chemical', '-', (52, 58))
268027	25108624	The endoscopic procedures were carried out using a high-resolution magnifying upper gastrointestinal endoscope (GIF-Q240Z or GIF-FQ260Z; Olympus, Tokyo, Japan) or a high-definition magnifying upper gastrointestinal endoscope (GIF-H260Z; Olympus).	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (78, 110))	('Q240Z', 'Var', (116, 121))	('H260Z', 'Var', (230, 235))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (192, 224))	('H260Z', 'SUBSTITUTION', 'None', (230, 235))	('GIF-FQ260Z', 'Var', (125, 135))	('upper gastrointestinal endoscope', 'Disease', (78, 110))	('Q240Z', 'SUBSTITUTION', 'None', (116, 121))	('upper gastrointestinal endoscope', 'Disease', (192, 224))
268028	25108624	A black soft hood (MB-162 for GIF-Q240Z and MB-46 for FQ260Z and GIF-H260Z; Olympus) was mounted on the tip of the endoscope to maintain an adequate distance between the tip of the endoscope zoom lens and the mucosal surface during magnifying observation.	('H260Z', 'SUBSTITUTION', 'None', (69, 74))	('Q240Z', 'Var', (34, 39))	('Q240Z', 'SUBSTITUTION', 'None', (34, 39))	('H260Z', 'Var', (69, 74))
268189	24651385	Inhibition of the COX-2 enzyme is hypothesised to be one of the mechanisms by which COX inhibitors might exert their antitumour effects.	('Inhibition', 'NegReg', (0, 10))	('antitumour effects', 'CPA', (117, 135))	('COX-2', 'Gene', '4513', (18, 23))	('COX-2', 'Gene', (18, 23))	('inhibitors', 'Var', (88, 98))
268307	31172291	In the H. pylori positive subjects, intragastric acidity was substantially less in all regions of the stomach compared to the H. pylori negatives under fasting conditions.	('intragastric acidity', 'MPA', (36, 56))	('positive', 'Var', (17, 25))	('H. pylori', 'Species', '210', (126, 135))	('H. pylori', 'Species', '210', (7, 16))	('less', 'NegReg', (75, 79))
268308	31172291	Intragastric acidity was also substantially less in the H. pylori positives after the meal and this was most marked in the proximal stomach close to the gastroesophageal junction (Fig.	('positives', 'Var', (66, 75))	('H. pylori', 'Gene', (56, 65))	('less', 'NegReg', (44, 48))	('H. pylori', 'Species', '210', (56, 65))	('gastroesophageal junction', 'Disease', (153, 178))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (153, 178))	('Intragastric acidity', 'MPA', (0, 20))
268311	31172291	These studies demonstrate that the gastric juice of H. pylori infected subjects will be much less damaging to the oesophageal mucosa than that of uninfected subjects.	('esophageal mucosa', 'Disease', (115, 132))	('infected', 'Var', (62, 70))	('esophageal mucosa', 'Disease', 'MESH:D004941', (115, 132))	('H. pylori', 'Species', '210', (52, 61))	('H. pylori', 'Disease', (52, 61))
268355	31056940	Two gastric cancer regimens are preferred by the NCCN: fluoropyrimidine plus cisplatin (category 1) or fluoropyrimidine plus oxaliplatin (FOLFOX, category 2A).	('fluoropyrimidine', 'Chemical', '-', (55, 71))	('fluoropyrimidine', 'Chemical', '-', (103, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (4, 18))	('FOLFOX', 'Chemical', '-', (138, 144))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (125, 136))	('fluoropyrimidine', 'Var', (103, 119))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('gastric cancer', 'Disease', (4, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (4, 18))
268356	31056940	Modified dosing of the DCF (docetaxel, cisplatin, and a fluoropyrimidine) regimen or substitution of cisplatin with oxaliplatin are considered category 2A evidence for GEJ and esophageal cancers (squamous and adenocarcinoma).	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('docetaxel', 'Chemical', 'MESH:D000077143', (28, 37))	('fluoropyrimidine', 'Chemical', '-', (56, 72))	('squamous and adenocarcinoma', 'Disease', 'MESH:D002294', (196, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('esophageal cancers', 'Disease', (176, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('substitution', 'Var', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('esophageal cancers', 'Disease', 'MESH:D004938', (176, 194))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (116, 127))	('DCF', 'Chemical', 'MESH:D015649', (23, 26))
268359	31056940	Pembrolizumab is supported by category 2A evidence for the second-line or subsequent treatment of tumors with high-microsatellite instability (MSI-H) or for deficient mismatch repair tumors and in the third-line or later setting for PD-L1-positive adenocarcinoma.	('tumors', 'Disease', (98, 104))	('deficient mismatch repair', 'Var', (157, 182))	('PD-L1-positive adenocarcinoma', 'Disease', (233, 262))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('PD-L1-positive adenocarcinoma', 'Disease', 'MESH:D010300', (233, 262))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('MSI-H', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('high-microsatellite', 'Var', (110, 129))	('tumors', 'Disease', (183, 189))	('MSI-H', 'Disease', 'MESH:D000848', (143, 148))
268360	31056940	In the REGARD trial, ramucirumab monotherapy reduced all-cause mortality by 22% compared to placebo plus best supportive care (BSC; hazard ratio [HR] for overall survival [OS] = 0.78; 95% confidence interval [CI]: 0.603-0.998; P = .0473) and reduced the risk of disease progression or death by 52% (HR for progression-free survival [PFS] = 0.48; 95% CI: 0.376-0.620; P < .001) in patients with gastric or GEJ adenocarcinoma.	('BSC', 'Chemical', '-', (127, 130))	('OS', 'Chemical', '-', (172, 174))	('reduced', 'NegReg', (45, 52))	('gastric or GEJ adenocarcinoma', 'Disease', (394, 423))	('carcinoma', 'Phenotype', 'HP:0030731', (414, 423))	('ramucirumab', 'Chemical', 'MESH:C543333', (21, 32))	('reduced', 'NegReg', (242, 249))	('patients', 'Species', '9606', (380, 388))	('all-cause mortality', 'MPA', (53, 72))	('death', 'Disease', 'MESH:D003643', (285, 290))	('ramucirumab', 'Var', (21, 32))	('death', 'Disease', (285, 290))	('gastric or GEJ adenocarcinoma', 'Disease', 'MESH:D013274', (394, 423))
268361	31056940	An open-label, randomized study of irinotecan versus BSC in patients with gastric or GEJ adenocarcinoma found that irinotecan improved OS (HR = 0.48; 95% CI: 0.25-0.92, P = .012); PFS was not compared.	('improved', 'PosReg', (126, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('gastric or GEJ adenocarcinoma', 'Disease', 'MESH:D013274', (74, 103))	('patients', 'Species', '9606', (60, 68))	('gastric or GEJ adenocarcinoma', 'Disease', (74, 103))	('OS', 'Chemical', '-', (135, 137))	('BSC', 'Chemical', '-', (53, 56))	('irinotecan', 'Chemical', 'MESH:D000077146', (115, 125))	('irinotecan', 'Var', (115, 125))	('irinotecan', 'Chemical', 'MESH:D000077146', (35, 45))
268419	31056940	While the Flatiron database does not capture tumor genomic profiling given biomarker testing outside HER2 for first-line therapy remains experimental, certain oncogene amplifications such as MET and FGFR2 have been identified in a minority of gastroesophageal cancers and portend poor prognosis.	('HER2', 'Gene', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('gastroesophageal cancers', 'Disease', (243, 267))	('HER2', 'Gene', '2064', (101, 105))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('tumor', 'Disease', (45, 50))	('amplifications', 'Var', (168, 182))	('FGFR2', 'Gene', '2263', (199, 204))	('identified', 'Reg', (215, 225))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (243, 267))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('FGFR2', 'Gene', (199, 204))	('MET', 'Gene', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
268424	31056940	In multivariable analysis, tumor HER2 positivity was associated with higher likelihood of receiving second-line therapy.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('HER2', 'Gene', (33, 37))	('positivity', 'Var', (38, 48))	('tumor', 'Disease', (27, 32))	('HER2', 'Gene', '2064', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
268444	27322149	Anti-PD-1 or anti-PD-L1 antibodies have clinically benefitted patients with some solid cancers in early clinical trials.	('anti-PD-L1', 'Gene', (13, 23))	('solid cancers', 'Disease', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('antibodies', 'Var', (24, 34))	('solid cancers', 'Disease', 'MESH:D009369', (81, 94))	('benefitted', 'PosReg', (51, 61))	('PD-1', 'Gene', (5, 9))	('patients', 'Species', '9606', (62, 70))	('PD-1', 'Gene', '5133', (5, 9))
268449	27322149	Recently, high mutation burdens in tumors were reported to be associated with a clinical benefit of PD-1 blockade.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('PD-1', 'Gene', (100, 104))	('PD-1', 'Gene', '5133', (100, 104))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutation burdens', 'Var', (15, 31))	('benefit', 'PosReg', (89, 96))
268470	27322149	Patients with PD-L1 positive in TIICs had significantly better OS than those with PD-L1 negative in TIICs (P = 0.041).	('OS', 'Chemical', '-', (63, 65))	('positive', 'Var', (20, 28))	('better', 'PosReg', (56, 62))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', (14, 19))
268491	27322149	In addition, marked infiltrations of immune suppressor cells such as regulatory T cells (FOXP3+) and M2 macrophages (CD204+) were also associated with PD-L1 expression in both TCs and TIICs.	('TCs', 'Chemical', '-', (176, 179))	('CD204', 'Gene', (117, 122))	('associated', 'Reg', (135, 145))	('expression', 'Var', (157, 167))	('CD204', 'Gene', '4481', (117, 122))	('PD-L1', 'Gene', (151, 156))
268493	27322149	In contrast, significant associations of positivity for PD-L1 expression with the CD8+/FOXP3+ and CD8+/CD204+ ratios, as well as a trend for an inverse association of PD-L1 expression with the FOXP3+/CD4+ ratio, were observed, suggesting PD- L1 expression to be associated with the balance between infiltrating effector cells and immune suppressor cells.	('associations', 'Interaction', (25, 37))	('CD8', 'Gene', (98, 101))	('CD8', 'Gene', (82, 85))	('positivity', 'Var', (41, 51))	('CD8', 'Gene', '925', (82, 85))	('PD-L1', 'Gene', (167, 172))	('CD8', 'Gene', '925', (98, 101))	('inverse', 'NegReg', (144, 151))	('CD4', 'Gene', (200, 203))	('CD204', 'Gene', '4481', (103, 108))	('CD204', 'Gene', (103, 108))	('CD4', 'Gene', '920', (200, 203))	('PD-L1', 'Gene', (56, 61))
268502	27322149	The number of tumor infiltrating FOXP3+ regulatory T cells, especially as reflected by a decreased CD8+/FOXP3+ ratio, is reportedly associated with a poor prognosis for several cancer types.	('cancer', 'Disease', (177, 183))	('tumor', 'Disease', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('CD8', 'Gene', (99, 102))	('CD8', 'Gene', '925', (99, 102))	('FOXP3+', 'Var', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('decreased', 'NegReg', (89, 98))
268566	28049283	Previous studies showed that the overall survival (OS) of patients with mucosal esophageal SCC treated with PDT was similar to that of patients who underwent esophagectomy.	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (58, 66))	('PDT', 'Var', (108, 111))	('mucosal esophageal SCC', 'Disease', (72, 94))	('mucosal esophageal SCC', 'Disease', 'MESH:D052016', (72, 94))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))
268584	28049283	These trials showed that PDT improved cholestasis and quality of life by diminishing the need for further procedures, such as stent revision and percutaneous biliary drainage.	('cholestasis', 'Disease', 'MESH:D002779', (38, 49))	('PDT', 'Var', (25, 28))	('diminishing', 'NegReg', (73, 84))	('cholestasis', 'Disease', (38, 49))	('quality', 'MPA', (54, 61))	('improved', 'PosReg', (29, 37))	('cholestasis', 'Phenotype', 'HP:0001396', (38, 49))
268585	28049283	This results in a longer stent patency period because PDT may cause tumor "remodeling," which can prolong or enhance the decompression effect.	('tumor', 'Disease', (68, 73))	('stent patency', 'MPA', (25, 38))	('decompression effect', 'CPA', (121, 141))	('cause', 'Reg', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('prolong', 'PosReg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('enhance', 'PosReg', (109, 116))	('PDT', 'Var', (54, 57))
268587	28049283	Thus, PDT seems to be a promising palliative treatment for unresectable CCC and should be considered part of the standard of care for these patients.	('CCC', 'Phenotype', 'HP:0030153', (72, 75))	('PDT', 'Var', (6, 9))	('CCC', 'Disease', (72, 75))	('unresectable', 'Disease', (59, 71))	('patients', 'Species', '9606', (140, 148))
268610	28049283	Talaporfin-mediated PDT also exerts considerable antitumor effects in vivo.	('PDT', 'Var', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('Talaporfin', 'Chemical', 'MESH:C053434', (0, 10))
268637	28049283	In a mouse model of PanCa, PMIL resulted in prolonged tumor reduction and metastasis suppression.	('prolonged tumor', 'Disease', 'MESH:D011273', (44, 59))	('PMIL', 'Var', (27, 31))	('PMIL', 'Chemical', '-', (27, 31))	('metastasis', 'CPA', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mouse', 'Species', '10090', (5, 10))	('PanCa', 'Phenotype', 'HP:0002894', (20, 25))	('prolonged tumor', 'Disease', (44, 59))	('PanCa', 'Disease', (20, 25))
268645	26471010	The highest adherence score to an MD was significantly associated with a lower risk of all-cause cancer mortality (RR: 0.87, 95% CI 0.81-0.93, I 2 = 84%), colorectal cancer (RR: 0.83, 95% CI 0.76-0.89, I 2 = 56%), breast cancer (RR: 0.93, 95% CI 0.87-0.99, I 2=15%), gastric cancer (RR: 0.73, 95% CI 0.55-0.97, I 2 = 66%), prostate cancer (RR: 0.96, 95% CI 0.92-1.00, I 2 = 0%), liver cancer (RR: 0.58, 95% CI 0.46-0.73, I 2 = 0%), head and neck cancer (RR: 0.40, 95% CI 0.24-0.66, I 2 = 90%), pancreatic cancer (RR: 0.48, 95% CI 0.35-0.66), and respiratory cancer (RR: 0.10, 95% CI 0.01-0.70).	('pancreatic cancer', 'Disease', (494, 511))	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('cancer', 'Disease', (558, 564))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('respiratory cancer', 'Disease', 'MESH:D012131', (546, 564))	('RR', 'Phenotype', 'HP:0100606', (174, 176))	('respiratory cancer', 'Phenotype', 'HP:0100606', (546, 564))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('liver cancer', 'Phenotype', 'HP:0002896', (379, 391))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (446, 452))	('liver cancer', 'Disease', (379, 391))	('cancer', 'Disease', 'MESH:D009369', (505, 511))	('breast cancer', 'Disease', (214, 227))	('RR', 'Phenotype', 'HP:0100606', (283, 285))	('RR', 'Phenotype', 'HP:0100606', (229, 231))	('respiratory cancer', 'Disease', (546, 564))	('head and neck cancer', 'Phenotype', 'HP:0012288', (432, 452))	('cancer', 'Disease', (97, 103))	('gastric cancer', 'Disease', (267, 281))	('RR', 'Phenotype', 'HP:0100606', (340, 342))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (494, 511))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (385, 391))	('cancer', 'Disease', 'MESH:D009369', (558, 564))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', (221, 227))	('gastric cancer', 'Phenotype', 'HP:0012126', (267, 281))	('gastric cancer', 'Disease', 'MESH:D013274', (267, 281))	('cancer', 'Disease', (332, 338))	('cancer', 'Disease', 'MESH:D009369', (446, 452))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('lower', 'NegReg', (73, 78))	('head and neck cancer', 'Disease', 'MESH:D006258', (432, 452))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('RR', 'Phenotype', 'HP:0100606', (115, 117))	('cancer', 'Disease', (505, 511))	('cancer', 'Disease', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('pancreatic cancer', 'Disease', 'MESH:D010190', (494, 511))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('prostate cancer', 'Disease', 'MESH:D011471', (323, 338))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('prostate cancer', 'Phenotype', 'HP:0012125', (323, 338))	('colorectal cancer', 'Disease', (155, 172))	('adherence', 'Var', (12, 21))	('liver cancer', 'Disease', 'MESH:D006528', (379, 391))	('neck cancer', 'Phenotype', 'HP:0012288', (441, 452))	('cancer', 'Disease', (385, 391))	('prostate cancer', 'Disease', (323, 338))
268648	26471010	The updated meta-analyses confirm a prominent and consistent inverse association provided by adherence to an MD in relation to cancer mortality and risk of several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('inverse', 'NegReg', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('adherence', 'Var', (93, 102))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', (127, 133))
268651	26471010	Adherence to the highest category of MD was associated with a significant lower risk of overall cancer mortality/incidence as well as the incidence of several cancer types, especially colorectal cancer, aerodigestive cancer (pharyngeal or esophageal cancer), and prostate cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (184, 201))	('Adherence', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('lower', 'NegReg', (74, 79))	('colorectal cancer', 'Disease', (184, 201))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('prostate cancer', 'Disease', 'MESH:D011471', (263, 278))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))	('prostate cancer', 'Phenotype', 'HP:0012125', (263, 278))	('prostate cancer', 'Disease', (263, 278))	('cancer', 'Disease', (195, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (184, 201))	('esophageal cancer', 'Disease', (239, 256))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', (272, 278))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
268667	26471010	Furthermore, subgroup analyses were performed for pre versus postmenopausal status (breast cancer), and breast cancer subtypes (e.g., ER+/PR+ and HER2-, ER+, ER-, HER2+, HER2-).	('HER2', 'Gene', (170, 174))	('HER2', 'Gene', '2064', (146, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('HER2', 'Gene', (163, 167))	('ER-', 'Var', (158, 161))	('HER2', 'Gene', '2064', (170, 174))	('ER+/PR+', 'Var', (134, 141))	('HER2', 'Gene', '2064', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('ER+', 'Var', (153, 156))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('postmenopausal status', 'Phenotype', 'HP:0008209', (61, 82))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('HER2', 'Gene', (146, 150))	('breast cancer', 'Disease', (84, 97))
268679	26471010	There was a trend for high adherence to MD to be associated with a lower risk of breast cancer in postmenopausal women (RR: 0.95, 95% CI 0.88-1.02) (Fig.	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('high', 'Var', (22, 26))	('women', 'Species', '9606', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lower', 'NegReg', (67, 72))	('RR', 'Phenotype', 'HP:0100606', (120, 122))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
268686	26471010	The main results suggest that adherence to the highest category of an MD is associated with a significant lower risk of overall cancer mortality (by approximately 13%) as well as incidence of colorectal cancer (by 15%), breast cancer (by 7%, no significant lower risk could be observed for cohort studies), gastric cancer (by 27%, no significant lower risk could be observed for cohort studies), prostate cancer (by 4%), liver cancer (by 42%), and head and neck cancer (by 60%, no significant lower risk could be observed for cohort studies).	('cancer', 'Disease', (462, 468))	('colorectal cancer', 'Disease', (192, 209))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('cancer', 'Disease', 'MESH:D009369', (427, 433))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('cancer', 'Disease', (405, 411))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('gastric cancer', 'Phenotype', 'HP:0012126', (307, 321))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (405, 411))	('cancer', 'Disease', (128, 134))	('lower', 'NegReg', (106, 111))	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('breast cancer', 'Disease', (220, 233))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('liver cancer', 'Disease', 'MESH:D006528', (421, 433))	('colorectal cancer', 'Phenotype', 'HP:0003003', (192, 209))	('head and neck cancer', 'Phenotype', 'HP:0012288', (448, 468))	('gastric cancer', 'Disease', (307, 321))	('cancer', 'Disease', 'MESH:D009369', (462, 468))	('cancer', 'Disease', (427, 433))	('cancer', 'Disease', 'MESH:D009369', (405, 411))	('prostate cancer', 'Disease', 'MESH:D011471', (396, 411))	('cancer', 'Disease', (315, 321))	('liver cancer', 'Phenotype', 'HP:0002896', (421, 433))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', (227, 233))	('prostate cancer', 'Phenotype', 'HP:0012125', (396, 411))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('liver cancer', 'Disease', (421, 433))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('prostate cancer', 'Disease', (396, 411))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('adherence', 'Var', (30, 39))	('head and neck cancer', 'Disease', 'MESH:D006258', (448, 468))	('gastric cancer', 'Disease', 'MESH:D013274', (307, 321))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('neck cancer', 'Phenotype', 'HP:0012288', (457, 468))	('colorectal cancer', 'Disease', 'MESH:D015179', (192, 209))
268691	26471010	In the original analysis, overall cancer mortality data were synthesized together with overall cancer incidence, whenever no information on the specific site of neoplasm was given (yielding a 10% lower risk following adherence to an MD).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('neoplasm', 'Disease', 'MESH:D009369', (161, 169))	('neoplasm', 'Phenotype', 'HP:0002664', (161, 169))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('adherence', 'Var', (217, 226))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('lower', 'NegReg', (196, 201))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('neoplasm', 'Disease', (161, 169))
268722	26471010	In conclusion, the present systematic review and meta-analysis provided further evidence that adherence to an MD is associated with lower risk of overall cancer mortality as well as incidence of colorectal, breast, gastric, prostate, liver, and head and neck cancer.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('head and neck cancer', 'Disease', 'MESH:D006258', (245, 265))	('colorectal', 'Disease', 'MESH:D015179', (195, 205))	('neck cancer', 'Phenotype', 'HP:0012288', (254, 265))	('cancer', 'Disease', (154, 160))	('liver', 'Disease', (234, 239))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('breast', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('prostate', 'Disease', (224, 232))	('adherence', 'Var', (94, 103))	('head and neck cancer', 'Phenotype', 'HP:0012288', (245, 265))	('colorectal', 'Disease', (195, 205))	('lower', 'NegReg', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('gastric', 'Disease', (215, 222))	('cancer', 'Disease', (259, 265))
268768	24949409	In the patient with the Bacteroides bacteremia, only the 2nd set of blood cultures taken after the flexible sigmoidoscopy and/or radial EUS exam was positive, while in the patient with Gemella bacteremia the final blood culture returned positive.	('Bacteroides', 'Species', '817', (24, 35))	('bacteremia', 'Disease', (193, 203))	('patient', 'Species', '9606', (7, 14))	('Gemella bacteremia', 'Disease', (185, 203))	('Bacteroides', 'Var', (24, 35))	('bacteremia', 'Disease', (36, 46))	('Gemella bacteremia', 'Disease', 'MESH:D016470', (185, 203))	('patient', 'Species', '9606', (172, 179))	('bacteremia', 'Phenotype', 'HP:0031864', (193, 203))	('bacteremia', 'Phenotype', 'HP:0031864', (36, 46))	('bacteremia', 'Disease', 'MESH:D016470', (193, 203))	('bacteremia', 'Disease', 'MESH:D016470', (36, 46))
268830	24949409	Furthermore, when we unintentionally, or intentionally, traverse a blood vessel during EUS-FNA, care is taken to avoid torquing the echoendoscope as this may lacerate the blood vessel wall and increase the risk of bleeding.	('lacerate', 'NegReg', (158, 166))	('bleeding', 'Disease', 'MESH:D006470', (214, 222))	('increase', 'PosReg', (193, 201))	('bleeding', 'Disease', (214, 222))	('traverse', 'Var', (56, 64))
268836	24949409	EUS-FNA of a pancreatic mass carries the risk of pancreatitis [Figure 3] as the needle often traverses normal pancreatic parenchyma and/or ducts to reach the target lesion.	('pancreatitis', 'Phenotype', 'HP:0001733', (49, 61))	('pancreatic', 'Disease', (110, 120))	('pancreatitis', 'Disease', (49, 61))	('pancreatic parenchyma', 'Disease', 'MESH:D010195', (110, 131))	('pancreatic', 'Disease', 'MESH:D010195', (13, 23))	('pancreatic parenchyma', 'Disease', (110, 131))	('pancreatitis', 'Disease', 'MESH:D010195', (49, 61))	('pancreatic', 'Disease', (13, 23))	('EUS-FNA', 'Var', (0, 7))	('pancreatic', 'Disease', 'MESH:D010195', (110, 120))
268839	24949409	The risk of pancreatitis following EUS-FNA is lower than the 3% risk of severe pancreatitis previously reported with percutaneous pancreatic FNA.	('EUS-FNA', 'Var', (35, 42))	('pancreatitis', 'Phenotype', 'HP:0001733', (12, 24))	('pancreatitis', 'Disease', 'MESH:D010195', (12, 24))	('pancreatitis', 'Disease', (79, 91))	('pancreatic', 'Disease', 'MESH:D010195', (130, 140))	('pancreatic', 'Disease', (130, 140))	('pancreatitis', 'Phenotype', 'HP:0001733', (79, 91))	('pancreatitis', 'Disease', (12, 24))	('pancreatitis', 'Disease', 'MESH:D010195', (79, 91))
268864	24949409	Although the analysis was not limited to pancreatitis (pancreatitis N = 6, abdominal pain N = 4, bleeding N = 1), a multivariate analysis concerning the risk factors associated with adverse events following EUS-FNA of solid pancreatic masses was significant for tumor size <=20 mm (odds ratio [OR] 18.48, 95% CI: 3.55-96.17) and PNET (OR: 36.5, 95% CI: 1.73-771.83).	('PNET', 'Phenotype', 'HP:0030405', (329, 333))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('pancreatitis', 'Disease', (41, 53))	('abdominal pain', 'Phenotype', 'HP:0002027', (75, 89))	('bleeding', 'Disease', 'MESH:D006470', (97, 105))	('pancreatitis', 'Disease', 'MESH:D010195', (55, 67))	('pancreatitis', 'Disease', (55, 67))	('pancreatitis N', 'Disease', (55, 69))	('abdominal pain', 'Disease', (75, 89))	('bleeding', 'Disease', (97, 105))	('abdominal pain', 'Disease', 'MESH:D015746', (75, 89))	('solid pancreatic masses', 'Disease', 'MESH:D010195', (218, 241))	('<=20', 'Var', (273, 277))	('tumor', 'Disease', (262, 267))	('solid pancreatic masses', 'Disease', (218, 241))	('PNET', 'Disease', (329, 333))	('pancreatitis N', 'Disease', 'MESH:D010195', (55, 69))	('pancreatitis', 'Phenotype', 'HP:0001733', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('pain', 'Phenotype', 'HP:0012531', (85, 89))	('pancreatitis', 'Phenotype', 'HP:0001733', (55, 67))	('pancreatitis', 'Disease', 'MESH:D010195', (41, 53))
268899	24949409	One patient developed peritoneal carcinomatosis in the EUS-FNA group compared to seven patients in the percutaneous FNA group (2.2% vs. 16.3%; P < 0.025).	('EUS-FNA', 'Var', (55, 62))	('carcinomatosis', 'Disease', (33, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('patient', 'Species', '9606', (4, 11))	('patient', 'Species', '9606', (87, 94))	('patients', 'Species', '9606', (87, 95))	('carcinomatosis', 'Disease', 'MESH:D002277', (33, 47))
268918	23691458	Meta-Analysis of the Association between Mir-196a-2 Polymorphism and Cancer Susceptibility MicroRNA plays a vital role in gene expression, and microRNA dysregulation is involved in carcinogenesis.	('involved', 'Reg', (169, 177))	('Mir-196a-2', 'Gene', '406973', (41, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (181, 195))	('Polymorphism', 'Var', (52, 64))	('microRNA', 'MPA', (143, 151))	('carcinogenesis', 'Disease', (181, 195))	('Mir-196a-2', 'Gene', (41, 51))	('Cancer', 'Disease', (69, 75))	('Association', 'Interaction', (21, 32))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancer', 'Disease', 'MESH:D009369', (69, 75))
268919	23691458	The miR-196a-2 polymorphism rs11614913 is reportedly associated with cancer susceptibility.	('rs11614913', 'Var', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('miR-196a-2', 'Gene', (4, 14))	('miR-196a-2', 'Gene', '406973', (4, 14))	('rs11614913', 'Mutation', 'rs11614913', (28, 38))	('associated', 'Reg', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
268922	23691458	A significant association was found between rs11614913 polymorphism and cancer risk in four genetic models (CT vs. TT, OR=1.15, 95%CI=1.05-1.27; CC vs. TT, OR=1.23, 95%CI=1.08-1.39; Dominant model, OR=1.17, 95%CI=1.06-1.30; Additive model, OR=1.08, 95%CI=1.01-1.14).	('cancer', 'Disease', (72, 78))	('OR=1.17', 'Gene', '81448', (198, 205))	('OR=1.23', 'Gene', '81442', (156, 163))	('rs11614913', 'Mutation', 'rs11614913', (44, 54))	('polymorphism', 'Var', (55, 67))	('rs11614913 polymorphism', 'Var', (44, 67))	('OR=1.15', 'Gene', '10819', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CT', 'Chemical', 'MESH:D002251', (108, 110))	('OR=1.15', 'Gene', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('OR=1.23', 'Gene', (156, 163))	('OR=1.17', 'Gene', (198, 205))
268923	23691458	In the subgroup analysis of different tumor types, the C allele was associated with increased risk of lung, breast, and colorectal cancer, but not with liver, gastric, or esophageal cancer.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('lung', 'Disease', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('colorectal cancer', 'Disease', (120, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast', 'Disease', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('C allele', 'Var', (55, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('esophageal cancer', 'Disease', (171, 188))
268925	23691458	The meta-analysis demonstrated that the miR-196a-2 polymorphism is associated with cancer susceptibility, especially lung cancer, colorectal cancer, and breast cancer among Asian populations.	('colorectal cancer', 'Disease', (130, 147))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('miR-196a-2', 'Gene', (40, 50))	('miR-196a-2', 'Gene', '406973', (40, 50))	('polymorphism', 'Var', (51, 63))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('especially lung cancer', 'Disease', (106, 128))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (141, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('associated', 'Reg', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (122, 128))	('especially lung cancer', 'Disease', 'MESH:D008175', (106, 128))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', (153, 166))
268933	23691458	identified a polymorphism in miR-196a-2 with a T to C change (rs11614913).	('rs11614913', 'Mutation', 'rs11614913', (62, 72))	('miR-196a-2', 'Gene', (29, 39))	('rs11614913', 'Var', (62, 72))	('miR-196a-2', 'Gene', '406973', (29, 39))
268934	23691458	Rs11614913 is located in the 3' passenger (3p) strand mature sequence of miR-196a-2.	('Rs11614913', 'Var', (0, 10))	('miR-196a-2', 'Gene', (73, 83))	('miR-196a-2', 'Gene', '406973', (73, 83))	('Rs11614913', 'Mutation', 'Rs11614913', (0, 10))
268935	23691458	This functional polymorphism is reportedly associated with the susceptibility of various tumors, including lung cancer  and breast cancer , and with lower survival rates of non-small cell lung cancer , gliomas , gastric cancer , gallbladder cancer , head and neck cancer , esophageal cancer , and hepatocellular carcinoma .	('tumors', 'Disease', (89, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (212, 226))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (297, 321))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (173, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('head and neck cancer', 'Phenotype', 'HP:0012288', (250, 270))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gliomas', 'Disease', (202, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (273, 290))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (177, 199))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (297, 321))	('gallbladder cancer', 'Disease', 'MESH:D005706', (229, 247))	('breast cancer', 'Disease', (124, 137))	('gastric cancer', 'Disease', (212, 226))	('gliomas', 'Disease', 'MESH:D005910', (202, 209))	('cell lung cancer', 'Disease', 'MESH:D008175', (183, 199))	('esophageal cancer', 'Disease', (273, 290))	('head and neck cancer', 'Disease', 'MESH:D006258', (250, 270))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('polymorphism', 'Var', (16, 28))	('cell lung cancer', 'Disease', (183, 199))	('hepatocellular carcinoma', 'Disease', (297, 321))	('lung cancer', 'Disease', 'MESH:D008175', (188, 199))	('lung cancer', 'Disease', (107, 118))	('associated', 'Reg', (43, 53))	('gliomas', 'Phenotype', 'HP:0009733', (202, 209))	('gastric cancer', 'Disease', 'MESH:D013274', (212, 226))	('survival', 'MPA', (155, 163))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('gallbladder cancer', 'Disease', (229, 247))	('lower', 'NegReg', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
268937	23691458	Therefore, this meta-analysis was employed to investigate the association of the miR-196a-2 rs11614913 polymorphism with cancer risk.	('miR-196a-2', 'Gene', '406973', (81, 91))	('rs11614913', 'Mutation', 'rs11614913', (92, 102))	('association', 'Interaction', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('rs11614913', 'Var', (92, 102))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('miR-196a-2', 'Gene', (81, 91))
268938	23691458	A meta-analysis was conducted based on all case-control studies that examined the association between miR-196a2 rs11614913 polymorphism and cancer risk.	('rs11614913', 'Mutation', 'rs11614913', (112, 122))	('miR-196a2', 'Gene', (102, 111))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('rs11614913', 'Var', (112, 122))	('miR-196a2', 'Gene', '406973', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
268939	23691458	The terms rs11614913, polymorphism, and cancer were used to search in the PubMed, EMBASE, Cochran library, and Web of Knowledge databases.	('rs11614913', 'Var', (10, 20))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('rs11614913', 'Mutation', 'rs11614913', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
268940	23691458	The inclusion criteria for our meta-analysis were as follows: (1) a case-control study design; (2) an association reported between miR-196a2 rs11614913 polymorphism and cancer risk; (3) number of subjects in each genotype available or sufficient allele frequencies for estimating odds ratio (OR), and 95% confidence interval (CI).	('miR-196a2', 'Gene', '406973', (131, 140))	('association', 'Interaction', (102, 113))	('cancer', 'Disease', (169, 175))	('rs11614913', 'Var', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('rs11614913', 'Mutation', 'rs11614913', (141, 151))	('miR-196a2', 'Gene', (131, 140))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
268942	23691458	The association between miR-196a-2 polymorphism and cancer risk was evaluated by calculating the pooled OR and 95% CI.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('polymorphism', 'Var', (35, 47))	('miR-196a-2', 'Gene', (24, 34))	('miR-196a-2', 'Gene', '406973', (24, 34))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
268947	23691458	Four studies focused on the association of SNPs with lung cancer, 4 with liver cancer, 5 with breast cancer, 4 with colorectal cancer, 2 with gastric cancer, 2 with esophageal cancer, and the remaining 6 studies were associated with other types of cancer.	('esophageal cancer', 'Disease', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('lung cancer', 'Disease', (53, 64))	('cancer', 'Disease', (248, 254))	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('gastric cancer', 'Disease', (142, 156))	('liver cancer', 'Disease', 'MESH:D006528', (73, 85))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (127, 133))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (79, 85))	('breast cancer', 'Disease', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SNPs', 'Var', (43, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (73, 85))	('association', 'Interaction', (28, 39))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))	('liver cancer', 'Disease', (73, 85))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('cancer', 'Disease', (101, 107))	('colorectal cancer', 'Disease', (116, 133))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
268948	23691458	Figure 2 shows the significant difference (C as the minor allele) in MAF distribution of miR-196a-2 rs11614913 T>C polymorphism among the controls of the different races: Asians and Caucasians.	('rs11614913 T>C', 'Var', (100, 114))	('miR-196a-2', 'Gene', (89, 99))	('miR-196a-2', 'Gene', '406973', (89, 99))	('rs11614913', 'Mutation', 'rs11614913', (100, 110))
268950	23691458	The associations of the miR-196a-2 polymorphism with the risk of developing different cancer types among the different racial groups are shown in Table 2.	('polymorphism', 'Var', (35, 47))	('miR-196a-2', 'Gene', (24, 34))	('miR-196a-2', 'Gene', '406973', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('associations', 'Interaction', (4, 16))	('cancer', 'Disease', (86, 92))
268951	23691458	In the meta-analysis of all studies, the rs11614913 polymorphism was significantly associated with the risk of cancer in 4 genetic models (CT vs. TT, OR=1.15, 95%CI=1.05-1.27; CC vs. TT, OR=1.23, 95%CI=1.08-1.39; Dominant model, OR=1.17, 95%CI=1.06-1.30; Additive model, OR=1.08, 95%CI=1.01-1.14).	('rs11614913', 'Var', (41, 51))	('CT', 'Chemical', 'MESH:D002251', (139, 141))	('OR=1.15', 'Gene', '10819', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('rs11614913', 'Mutation', 'rs11614913', (41, 51))	('associated', 'Reg', (83, 93))	('OR=1.23', 'Gene', (187, 194))	('OR=1.15', 'Gene', (150, 157))	('cancer', 'Disease', (111, 117))	('OR=1.17', 'Gene', (229, 236))	('OR=1.23', 'Gene', '81442', (187, 194))	('OR=1.17', 'Gene', '81448', (229, 236))
268954	23691458	In the subgroup analysis of tumor types, the C allele was associated with increased risks for lung cancer, breast cancer, and colorectal cancers, but was not associated with those for liver cancer, gastric cancer, and esophageal cancers.	('gastric cancer', 'Disease', (198, 212))	('tumor', 'Disease', (28, 33))	('colorectal cancers', 'Disease', (126, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('lung cancer', 'Disease', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('esophageal cancers', 'Disease', 'MESH:D004938', (218, 236))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('liver cancer', 'Disease', 'MESH:D006528', (184, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('colorectal cancers', 'Disease', 'MESH:D015179', (126, 144))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('breast cancer', 'Disease', (107, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('liver cancer', 'Phenotype', 'HP:0002896', (184, 196))	('liver cancer', 'Disease', (184, 196))	('C allele', 'Var', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))	('esophageal cancers', 'Disease', (218, 236))
268955	23691458	A significant association with lung cancer was observed in all genetic models (CC vs. TT, OR=1.26, 95%CI=1.07-1.49; CT vs. TT, OR=1.15, 95%CI=1.00-1.33; Dominant model, OR=1.19, 95%CI=1.04-1.36; Additive model, OR=1.12, 95%CI=1.03-1.22) except for the recessive model.	('OR=1.26', 'Gene', (90, 97))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('CT', 'Chemical', 'MESH:D002251', (116, 118))	('OR=1.19', 'Gene', '8586', (169, 176))	('OR=1.26', 'Gene', '121364', (90, 97))	('OR=1.12', 'Gene', '10822', (211, 218))	('OR=1.15', 'Gene', '10819', (127, 134))	('lung cancer', 'Disease', (31, 42))	('CT vs. TT', 'Var', (116, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('OR=1.12', 'Gene', (211, 218))	('OR=1.15', 'Gene', (127, 134))	('OR=1.19', 'Gene', (169, 176))
268966	23691458	The funnel plot for CC vs. TT of miR-196a-2 rs11614913 polymorphism seemed approximately symmetrical (Figure 4).	('miR-196a-2', 'Gene', '406973', (33, 43))	('rs11614913', 'Var', (44, 54))	('rs11614913', 'Mutation', 'rs11614913', (44, 54))	('miR-196a-2', 'Gene', (33, 43))
268970	23691458	Although genetic and epigenetic regulation influence miRNA activity, the mechanism of miRNAs involvement in carcinogenesis remains unclear.	('influence', 'Reg', (43, 52))	('miRNA activity', 'MPA', (53, 67))	('epigenetic regulation', 'Var', (21, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('genetic', 'Var', (9, 16))	('carcinogenesis', 'Disease', (108, 122))
268971	23691458	Considering the extensive regulation of many target genes by miRNA, a single nucleotide polymorphism in the miRNAs gene may affect the expression and activity of various genes or proteins, which further influence the carcinogenic process and tumor progression.	('proteins', 'Protein', (179, 187))	('genes', 'Protein', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('affect', 'Reg', (124, 130))	('carcinogenic', 'Disease', 'MESH:D063646', (217, 229))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('influence', 'Reg', (203, 212))	('single nucleotide polymorphism', 'Var', (70, 100))	('carcinogenic', 'Disease', (217, 229))	('expression', 'MPA', (135, 145))	('tumor', 'Disease', (242, 247))	('miRNAs', 'Gene', (108, 114))	('activity', 'MPA', (150, 158))
268974	23691458	Of these pre-miRNA SNPs, the miR-196a-2 rs11614913 T>C polymorphism is the most studied SNP.	('rs11614913', 'Mutation', 'rs11614913', (40, 50))	('rs11614913 T>C', 'Var', (40, 54))	('miR-196a-2', 'Gene', '406973', (29, 39))	('miR-196a-2', 'Gene', (29, 39))
268975	23691458	This functional polymorphism reportedly has an association with susceptibility to various forms of tumor including lung cancer, breast cancer, glioma, gastric cancer, gallbladder cancer, head and neck cancer, esophageal cancer, hepatocellular carcinoma, as well as shortened survival time in non-small cell lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (292, 318))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (228, 252))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('head and neck cancer', 'Phenotype', 'HP:0012288', (187, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('gastric cancer', 'Disease', (151, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (296, 318))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', (99, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (209, 226))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('hepatocellular carcinoma', 'Disease', (228, 252))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('association', 'Reg', (47, 58))	('gallbladder cancer', 'Disease', (167, 185))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('head and neck cancer', 'Disease', 'MESH:D006258', (187, 207))	('esophageal cancer', 'Disease', (209, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('polymorphism', 'Var', (16, 28))	('shortened', 'NegReg', (265, 274))	('glioma', 'Disease', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('lung cancer', 'Disease', (115, 126))	('cell lung cancer', 'Disease', 'MESH:D008175', (302, 318))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (307, 318))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (228, 252))	('gallbladder cancer', 'Disease', 'MESH:D005706', (167, 185))	('cell lung cancer', 'Disease', (302, 318))	('lung cancer', 'Phenotype', 'HP:0100526', (307, 318))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
268976	23691458	The results of the meta-analysis show that people carrying the variant genotype C have an increased risk of cancer compared to those carrying the wild genotype T. This finding coincides with a previous meta-analysis .	('variant', 'Var', (63, 70))	('people', 'Species', '9606', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
268977	23691458	The miR-196a-2 polymorphism may play a role in carcinogenesis.	('play', 'Reg', (32, 36))	('carcinogenesis', 'Disease', (47, 61))	('miR-196a-2', 'Gene', (4, 14))	('miR-196a-2', 'Gene', '406973', (4, 14))	('polymorphism', 'Var', (15, 27))	('carcinogenesis', 'Disease', 'MESH:D063646', (47, 61))
268978	23691458	Stratification of the analysis in terms of tumor type revealed that the miR-196a-2 polymorphism was related to lung cancer, colorectal cancer, and breast cancer, but no relationship was seen for liver cancer, gastric cancer, or esophageal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('liver cancer', 'Disease', 'MESH:D006528', (195, 207))	('miR-196a-2', 'Gene', (72, 82))	('miR-196a-2', 'Gene', '406973', (72, 82))	('esophageal cancer', 'Disease', (228, 245))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('related', 'Reg', (100, 107))	('lung cancer', 'Disease', (111, 122))	('tumor', 'Disease', (43, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (209, 223))	('liver cancer', 'Phenotype', 'HP:0002896', (195, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('polymorphism', 'Var', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('liver cancer', 'Disease', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Disease', (147, 160))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('colorectal cancer', 'Disease', (124, 141))	('gastric cancer', 'Disease', (209, 223))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (209, 223))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('esophageal cancer', 'Disease', 'MESH:D004938', (228, 245))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
268981	23691458	Previous meta-analyses has found that rs11614913 is associated with colorectal cancer risk , breast cancer risk, and lung cancer risk , consistent with the results of our study.	('rs11614913', 'Var', (38, 48))	('colorectal cancer', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (52, 62))	('lung cancer', 'Disease', (117, 128))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('rs11614913', 'Mutation', 'rs11614913', (38, 48))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
268983	23691458	In the subgroup analysis in terms of the control source, the C allele was associated with cancer susceptibility in studies with population-based controls.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('C allele', 'Var', (61, 69))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('associated', 'Reg', (74, 84))
268984	23691458	Finally, the C allele was associated with cancer risk among studies that used PCR-RFLP for genotyping.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('C allele', 'Var', (13, 21))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('associated with', 'Reg', (26, 41))
268985	23691458	After adjusting for genotyping method, the rs11614913 C genotype was associated with cancer risk.	('rs11614913', 'Mutation', 'rs11614913', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('associated', 'Reg', (69, 79))	('cancer', 'Disease', (85, 91))	('rs11614913 C', 'Var', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
268986	23691458	Currently, two possibilities explain the association of the miR-196a-2 polymorphism with cancer risk.	('miR-196a-2', 'Gene', (60, 70))	('miR-196a-2', 'Gene', '406973', (60, 70))	('association', 'Interaction', (41, 52))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('polymorphism', 'Var', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
268987	23691458	First, the rs11614913 variant may increase mature miR-196a expression and enhance target mRNA binding .	('miR-196a', 'Gene', (50, 58))	('rs11614913', 'Var', (11, 21))	('rs11614913', 'Mutation', 'rs11614913', (11, 21))	('increase', 'PosReg', (34, 42))	('enhance', 'PosReg', (74, 81))
268993	23691458	In conclusion, miR-196a-2 polymorphism is associated with cancer risk, especially lung cancer, colorectal cancer, and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (106, 112))	('miR-196a-2', 'Gene', (15, 25))	('miR-196a-2', 'Gene', '406973', (15, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('especially lung cancer', 'Disease', 'MESH:D008175', (71, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('cancer', 'Disease', (125, 131))	('breast cancer', 'Disease', (118, 131))	('cancer', 'Disease', (87, 93))	('colorectal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('polymorphism', 'Var', (26, 38))	('especially lung cancer', 'Disease', (71, 93))	('associated', 'Reg', (42, 52))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))
268994	23691458	Asians carrying the miR-196a-2 variant genotype are more susceptible to cancer compared with Caucasians.	('susceptible', 'Reg', (57, 68))	('miR-196a-2', 'Gene', (20, 30))	('miR-196a-2', 'Gene', '406973', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('variant', 'Var', (31, 38))	('cancer', 'Disease', (72, 78))
268995	23691458	The SNP in miR-196a-2 may be a key factor in carcinogenesis.	('SNP', 'Var', (4, 7))	('miR-196a-2', 'Gene', (11, 21))	('miR-196a-2', 'Gene', '406973', (11, 21))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('carcinogenesis', 'Disease', (45, 59))
269006	23082154	HER2-expression was significantly elevated under AMD3100 treatment in the primary tumor and particularly in the metastases.	('AMD3100', 'Chemical', 'MESH:C088327', (49, 56))	('AMD3100', 'Var', (49, 56))	('metastases', 'Disease', (112, 122))	('primary tumor', 'Disease', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('elevated', 'PosReg', (34, 42))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('primary tumor', 'Disease', 'MESH:D009369', (74, 87))	('HER2-expression', 'Protein', (0, 15))
269049	23082154	PCR primers (TaqMan Gene Expression Assay Gapdh human Hs99999905_m1, Partnumber 4351370, TaqMan Gene Expression Assay 18S Hs99999901_s1) and TaqMan Universal PCR Mastermix were obtained (Applied Biosystems).	('Hs99999905_m1', 'Var', (54, 67))	('human', 'Species', '9606', (48, 53))	('Gapdh', 'Gene', '2597', (42, 47))	('Gapdh', 'Gene', (42, 47))
269090	23082154	Tumor weights in the AMD3100-treated group were significantly higher than in the trastuzumab-treated (p = 0.04) and trastuzumab/AMD3100-treated (p = 0.02) groups (Figure 2A).	('trastuzumab', 'Chemical', 'MESH:D000068878', (81, 92))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('AMD3100', 'Chemical', 'MESH:C088327', (21, 28))	('trastuzumab', 'Chemical', 'MESH:D000068878', (116, 127))	('AMD3100', 'Chemical', 'MESH:C088327', (128, 135))	('higher', 'PosReg', (62, 68))	('AMD3100-treated', 'Var', (21, 36))	('Tumor weights', 'CPA', (0, 13))
269091	23082154	Although the effect of AMD3100 on the primary tumor weight was not as significant as the effect of trastuzumab, a potent effect was achieved by AMD3100 treatment alone compared to the untreated group.	('AMD3100', 'Chemical', 'MESH:C088327', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('primary tumor', 'Disease', (38, 51))	('AMD3100', 'Var', (144, 151))	('primary tumor', 'Disease', 'MESH:D009369', (38, 51))	('AMD3100', 'Chemical', 'MESH:C088327', (23, 30))	('trastuzumab', 'Chemical', 'MESH:D000068878', (99, 110))
269099	23082154	In particular, a significant reduction of lung metastases could be observed compared to the control group after AMD3100, trastuzumab and combined treatment as well as to the liver after trastuzumab and combined treatment (Figure 2C).	('AMD3100', 'Var', (112, 119))	('trastuzumab', 'Chemical', 'MESH:D000068878', (121, 132))	('reduction of lung metastases', 'Disease', (29, 57))	('reduction of lung metastases', 'Disease', 'MESH:D009362', (29, 57))	('trastuzumab', 'Chemical', 'MESH:D000068878', (186, 197))	('AMD3100', 'Chemical', 'MESH:C088327', (112, 119))
269138	23082154	Inhibition of CXCR4 with AMD3100 on the other hand leads to a significant reduction of primary tumor growth and a relevant reduction of overall metastatic spread and of micrometastatic lung metastases.	('AMD3100', 'Chemical', 'MESH:C088327', (25, 32))	('reduction of primary tumor', 'Disease', 'MESH:D009369', (74, 100))	('micrometastatic lung metastases', 'Disease', 'MESH:D009362', (169, 200))	('reduction of primary tumor', 'Disease', (74, 100))	('AMD3100', 'Var', (25, 32))	('CXCR4', 'Gene', '7852', (14, 19))	('reduction', 'NegReg', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('metastatic spread', 'CPA', (144, 161))	('micrometastatic lung metastases', 'Disease', (169, 200))	('CXCR4', 'Gene', (14, 19))
269157	23082154	Inhibition of the CXCR4 receptor reduces metastases compared to the non-treated group in our experiments and leads to an over-expression of HER2 in the primary tumor and even greater expression in the metastases.	('over-expression', 'PosReg', (121, 136))	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('greater', 'PosReg', (175, 182))	('metastases', 'Disease', (201, 211))	('primary tumor', 'Disease', (152, 165))	('CXCR4', 'Gene', '7852', (18, 23))	('metastases', 'Disease', 'MESH:D009362', (201, 211))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('primary tumor', 'Disease', 'MESH:D009369', (152, 165))	('expression', 'MPA', (183, 193))	('Inhibition', 'Var', (0, 10))	('metastases', 'Disease', (41, 51))	('CXCR4', 'Gene', (18, 23))	('reduces', 'NegReg', (33, 40))	('HER2', 'Protein', (140, 144))
269162	23082154	In an orthotopic model of HER2-positive esophageal carcinoma we have previously shown the significantly positive impact of inhibition of HER2 on primary tumor and on metastases.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (40, 60))	('metastases', 'Disease', (166, 176))	('inhibition', 'Var', (123, 133))	('primary tumor', 'Disease', (145, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('metastases', 'Disease', 'MESH:D009362', (166, 176))	('positive', 'PosReg', (104, 112))	('esophageal carcinoma', 'Disease', (40, 60))	('primary tumor', 'Disease', 'MESH:D009369', (145, 158))	('HER2', 'Protein', (137, 141))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (40, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
269167	23082154	If assuming that HER2 upregulates the expression of CXCR4, this might even suggest that through inhibition of CXCR4, HER2 in rebound is upregulated to again increase CXCR4.	('upregulated', 'PosReg', (136, 147))	('CXCR4', 'Gene', (52, 57))	('CXCR4', 'Gene', (166, 171))	('HER2', 'Gene', (117, 121))	('CXCR4', 'Gene', (110, 115))	('upregulates', 'PosReg', (22, 33))	('CXCR4', 'Gene', '7852', (166, 171))	('CXCR4', 'Gene', '7852', (52, 57))	('inhibition', 'Var', (96, 106))	('increase', 'PosReg', (157, 165))	('CXCR4', 'Gene', '7852', (110, 115))
269173	23082154	Overall we show that inhibition of the CXCR4 receptor leads to significant changes in HER2-expression, indicating that blockage of the CXCR4 pathway activates HER2-overexpression.	('changes', 'Reg', (75, 82))	('CXCR4', 'Gene', '7852', (135, 140))	('CXCR4', 'Gene', (135, 140))	('HER2-overexpression', 'Protein', (159, 178))	('CXCR4', 'Gene', (39, 44))	('activates', 'PosReg', (149, 158))	('blockage', 'Var', (119, 127))	('HER2-expression', 'Protein', (86, 101))	('CXCR4', 'Gene', '7852', (39, 44))
269175	23082154	While the fact that, under inhibition of the HER2 receptor, no metastases occur indicates a reciprocal mechanism, solitary inhibition of CXCR4 still leads to metastases.	('metastases', 'Disease', 'MESH:D009362', (158, 168))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('CXCR4', 'Gene', '7852', (137, 142))	('inhibition', 'Var', (27, 37))	('metastases', 'Disease', (158, 168))	('HER2 receptor', 'Protein', (45, 58))	('leads to', 'Reg', (149, 157))	('CXCR4', 'Gene', (137, 142))	('metastases', 'Disease', (63, 73))
269182	20816834	We used the ED-L2 promoter of Epstein-Barr virus to overexpress the transcriptional regulator Kruppel-like factor 4 (Klf4) in esophageal epithelia of mice; we used mouse primary esophageal keratinocytes to examine the mechanisms by which KLF4 induces cytokine production.	('esophageal epithelia', 'Disease', (126, 146))	('esophageal epithelia', 'Disease', 'MESH:D004941', (126, 146))	('mice', 'Species', '10090', (150, 154))	('mouse', 'Species', '10090', (164, 169))	('cytokine production', 'MPA', (251, 270))	('Kruppel-like factor 4', 'Gene', (94, 115))	('induces', 'Reg', (243, 250))	('rat', 'Species', '10116', (191, 194))	('Kruppel-like factor 4', 'Gene', '16600', (94, 115))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (126, 146))	('KLF4', 'Var', (238, 242))	('Epstein-Barr virus', 'Species', '10376', (30, 48))
269191	20816834	Alterations in a number of genes have been linked to human esophageal squamous cell cancer, but these genetic alterations were identified by examining existing esophageal squamous cell cancers.	('rat', 'Species', '10116', (114, 117))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (59, 90))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Alterations', 'Var', (0, 11))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (70, 90))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (171, 191))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (160, 191))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('esophageal squamous cell cancer', 'Disease', (59, 90))	('linked', 'Reg', (43, 49))	('esophageal squamous cell cancers', 'Disease', (160, 192))	('human', 'Species', '9606', (53, 58))	('rat', 'Species', '10116', (4, 7))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (171, 192))	('esophageal squamous cell cancers', 'Disease', 'MESH:D002294', (160, 192))
269192	20816834	Thus, little direct evidence has linked genetic alterations functionally to the development of esophageal squamous cell cancer.	('squamous cell cancer', 'Phenotype', 'HP:0002860', (106, 126))	('rat', 'Species', '10116', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('esophageal squamous cell cancer', 'Disease', (95, 126))	('genetic alterations', 'Var', (40, 59))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (95, 126))
269217	20816834	However, by 6 months of age, although littermate controls maintained normal esophageal epithelia (Figure 1C, Supplementary Figure 2C), ED-L2/Klf4 mice developed hyperplasia, dysplasia, and a prominent inflammatory infiltrate in the epithelia and lamina propria (Figure 1D, Supplementary Figure 2D).	('esophageal epithelia', 'Phenotype', 'HP:0012859', (76, 96))	('developed', 'PosReg', (151, 160))	('hyperplasia', 'Disease', 'MESH:D006965', (161, 172))	('inflammatory infiltrate', 'CPA', (201, 224))	('esophageal epithelia', 'Disease', (76, 96))	('esophageal epithelia', 'Disease', 'MESH:D004941', (76, 96))	('mice', 'Species', '10090', (146, 150))	('rat', 'Species', '10116', (220, 223))	('hyperplasia', 'Disease', (161, 172))	('dysplasia', 'Disease', (174, 183))	('ED-L2/Klf4', 'Var', (135, 145))	('dysplasia', 'Disease', 'MESH:D004476', (174, 183))
269222	20816834	Although there was no significant difference in proliferation within the esophageal epithelia of control and ED-L2/Klf4 mice at 3 months of age, 6-month-old ED-L2/Klf4 mice showed a 3.8-fold increase in the number of proliferating cells compared with controls (Supplementary Figure 4).	('esophageal epithelia', 'Phenotype', 'HP:0012859', (73, 93))	('mice', 'Species', '10090', (120, 124))	('increase', 'PosReg', (191, 199))	('mice', 'Species', '10090', (168, 172))	('esophageal epithelia', 'Disease', (73, 93))	('ED-L2/Klf4', 'Var', (157, 167))	('esophageal epithelia', 'Disease', 'MESH:D004941', (73, 93))	('rat', 'Species', '10116', (224, 227))	('rat', 'Species', '10116', (55, 58))
269227	20816834	Although the expression domains of keratin 14 and keratin 4 were unchanged in ED-L2/Klf4 mice at 3 months of age (data not shown), compared with control mice (Figure 2C), the area of keratin 14 staining was expanded in 6-month-old ED-L2/Klf4 mice (Figure 2D).	('keratin 14', 'Gene', '16664', (35, 45))	('expression', 'MPA', (13, 23))	('keratin 14', 'Gene', '16664', (183, 193))	('mice', 'Species', '10090', (89, 93))	('keratin 14', 'Gene', (35, 45))	('ED-L2/Klf4', 'Var', (78, 88))	('keratin 4', 'Gene', '16682', (50, 59))	('keratin 4', 'Gene', (50, 59))	('expanded', 'PosReg', (207, 215))	('keratin 14', 'Gene', (183, 193))	('mice', 'Species', '10090', (153, 157))	('mice', 'Species', '10090', (242, 246))
269233	20816834	In contrast, KLF5 was decreased in ED-L2/Klf4 mice at 3 months of age but increased at 6 months of age.	('increased', 'PosReg', (74, 83))	('mice', 'Species', '10090', (46, 50))	('ED-L2/Klf4', 'Var', (35, 45))	('KLF5', 'Gene', '12224', (13, 17))	('KLF5', 'Gene', (13, 17))	('decreased', 'NegReg', (22, 31))
269236	20816834	However, KLF4 is lost in human esophageal squamous cell cancer, and homozygous deletion of Klf4 produces squamous cell dysplasia in mice.	('squamous cell dysplasia', 'Disease', 'MESH:D002294', (105, 128))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (42, 62))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (31, 62))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (105, 128))	('squamous cell dysplasia', 'Disease', (105, 128))	('human', 'Species', '9606', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mice', 'Species', '10090', (132, 136))	('esophageal squamous cell cancer', 'Disease', (31, 62))	('deletion', 'Var', (79, 87))	('Klf4', 'Gene', (91, 95))
269238	20816834	Although KLF4 was localized to esophageal suprabasal cells in littermate controls (Figure 3A), KLF4 was absent from the tumors (Figure 3B), which arose from esophageal epithelia of ED-L2/Klf4 mice, and yet was still present in the suprabasal layers of adjacent epithelia from ED-L2/Klf4 mice (Figure 3C).	('esophageal epithelia', 'Disease', (157, 177))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('mice', 'Species', '10090', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('KLF4', 'Gene', (95, 99))	('absent', 'NegReg', (104, 110))	('ED-L2/Klf4', 'Var', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (157, 177))	('esophageal epithelia', 'Disease', 'MESH:D004941', (157, 177))	('mice', 'Species', '10090', (287, 291))
269249	20816834	However, compared with 6-month-old control mice (Figure 4A and C), ED-L2/Klf4 had a large number of neutrophils throughout the epithelia and lamina propria by staining with anti-7/4 antibody (Figure 4B) and increased numbers of F4/80-positive macrophages (Figure 4D), predominantly in the lamina propria just below the basal layer.	('mice', 'Species', '10090', (43, 47))	('neutrophils', 'CPA', (100, 111))	('increased', 'PosReg', (207, 216))	('ED-L2/Klf4', 'Var', (67, 77))
269254	20816834	At 6 months of age, ED-L2/Klf4 mice had a 100-fold increase in CXCL5 expression (Figure 5A) and a 13-fold increase in TNFalpha expression (Figure 5B), compared with littermate controls.	('increase', 'PosReg', (51, 59))	('CXCL5', 'Gene', (63, 68))	('ED-L2/Klf4', 'Var', (20, 30))	('TNFalpha', 'Gene', (118, 126))	('mice', 'Species', '10090', (31, 35))	('increase', 'PosReg', (106, 114))	('TNFalpha', 'Gene', '21926', (118, 126))	('CXCL5', 'Gene', '20311', (63, 68))
269261	20816834	This up-regulation of G-CSF and IL-1alpha also was confirmed by infecting primary esophageal keratinocytes from wild-type mice with Klf4-expressing retrovirus (Supplementary Figure 7) and in vivo because 6-month-old Klf4 transgenic mice had a 44-fold increase in G-CSF mRNA levels (Figure 5E) and a 2-fold increase in IL-1alpha mRNA (Figure 5F), compared with littermate controls.	('mice', 'Species', '10090', (122, 126))	('G-CSF', 'Gene', (22, 27))	('G-CSF', 'Gene', '12985', (263, 268))	('G-CSF', 'Gene', '12985', (22, 27))	('increase', 'PosReg', (306, 314))	('rat', 'Species', '10116', (95, 98))	('transgenic mice', 'Species', '10090', (221, 236))	('Klf4 transgenic', 'Var', (216, 231))	('IL-1alpha', 'Gene', (318, 327))	('IL-1alpha', 'Gene', (32, 41))	('increase', 'PosReg', (251, 259))	('G-CSF', 'Gene', (263, 268))	('IL-1alpha', 'Gene', '16175', (318, 327))	('IL-1alpha', 'Gene', '16175', (32, 41))	('mice', 'Species', '10090', (232, 236))
269276	20816834	Inhibition of NF-kappaB signaling abolished the up-regulation of CXCL5 (Figure 6B), TNFalpha (Figure 6C), G-CSF (Figure 6D), and IL-1alpha mRNA (Figure 6E) in ED-L2/Klf4 keratinocytes, indicating that NF-kappaB activation was upstream of these proinflammatory cytokines in esophageal keratinocytes.	('NF-kappaB', 'Gene', (201, 210))	('rat', 'Species', '10116', (286, 289))	('NF-kappaB', 'Gene', '18033', (14, 23))	('G-CSF', 'Gene', (106, 111))	('abolished', 'NegReg', (34, 43))	('TNFalpha', 'Gene', '21926', (84, 92))	('NF-kappaB', 'Gene', '18033', (201, 210))	('CXCL5', 'Gene', (65, 70))	('G-CSF', 'Gene', '12985', (106, 111))	('NF-kappaB', 'Gene', (14, 23))	('IL-1alpha', 'Gene', (129, 138))	('TNFalpha', 'Gene', (84, 92))	('Inhibition', 'Var', (0, 10))	('rat', 'Species', '10116', (172, 175))	('IL-1alpha', 'Gene', '16175', (129, 138))	('CXCL5', 'Gene', '20311', (65, 70))	('up-regulation', 'PosReg', (48, 61))
269282	20816834	Without addition of recombinant TNFalpha, TNFalpha neutralization had no effect on NF-kappaB transcriptional activity in control keratinocytes; however, in keratinocytes from ED-L2/Klf4 mice, inhibition of TNFalpha decreased NF-kappaB transcriptional activity (Figure 7A).	('NF-kappaB', 'Gene', '18033', (83, 92))	('rat', 'Species', '10116', (131, 134))	('NF-kappaB', 'Gene', (225, 234))	('TNFalpha', 'Gene', '21926', (32, 40))	('TNFalpha', 'Gene', (42, 50))	('TNFalpha', 'Gene', (206, 214))	('inhibition', 'Var', (192, 202))	('NF-kappaB', 'Gene', '18033', (225, 234))	('TNFalpha', 'Gene', (32, 40))	('TNFalpha', 'Gene', '21926', (206, 214))	('rat', 'Species', '10116', (158, 161))	('mice', 'Species', '10090', (186, 190))	('NF-kappaB', 'Gene', (83, 92))	('TNFalpha', 'Gene', '21926', (42, 50))	('decreased', 'NegReg', (215, 224))
269288	20816834	Recently, we showed that deletion of Klf4 in murine esophagus results in squamous cell dysplasia and delayed differentiation.	('murine', 'Species', '10090', (45, 51))	('deletion', 'Var', (25, 33))	('delayed differentiation', 'CPA', (101, 124))	('squamous cell dysplasia', 'Disease', 'MESH:D002294', (73, 96))	('results in', 'Reg', (62, 72))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (73, 96))	('Klf4', 'Gene', (37, 41))	('squamous cell dysplasia', 'Disease', (73, 96))
269294	20816834	Previously, deletion of p120 catenin was shown to similarly initiate inflammation in skin keratinocytes through indirect activation of NF-kappaB by a complex mechanism, possibly involving induction of RhoA guanosine triphosphatase activity.	('deletion', 'Var', (12, 20))	('NF-kappaB', 'Gene', (135, 144))	('RhoA', 'Gene', (201, 205))	('inflammation in skin', 'Phenotype', 'HP:0011123', (69, 89))	('inflammation', 'Disease', (69, 81))	('NF-kappaB', 'Gene', '18033', (135, 144))	('RhoA', 'Gene', '11848', (201, 205))	('p120 catenin', 'Gene', '12388', (24, 36))	('rat', 'Species', '10116', (92, 95))	('initiate', 'Reg', (60, 68))	('p120 catenin', 'Gene', (24, 36))	('activation', 'PosReg', (121, 131))	('inflammation', 'Disease', 'MESH:D007249', (69, 81))
269300	20816834	The mechanism of KLF4 loss in esophageal cancers is not known but may parallel loss in other gastrointestinal cancers, in which both hypermethylation and hemizygous deletion have been implicated.	('gastrointestinal cancers', 'Disease', (93, 117))	('esophageal cancers', 'Disease', (30, 48))	('loss', 'NegReg', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('KLF4', 'Gene', (17, 21))	('esophageal cancers', 'Disease', 'MESH:D004938', (30, 48))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('hemizygous', 'Var', (154, 164))	('loss', 'NegReg', (22, 26))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (93, 117))
269307	20816834	Disruption of the epithelial barrier can elicit an inflammatory response, and we did observe ultrastructural changes in esophageal epithelia of ED-L2/Klf4 mice, with dilated paracellular spaces or spongiosis.	('esophageal epithelia', 'Disease', (120, 140))	('spongiosis', 'CPA', (197, 207))	('inflammatory response', 'CPA', (51, 72))	('esophageal epithelia', 'Disease', 'MESH:D004941', (120, 140))	('paracellular spaces', 'CPA', (174, 193))	('elicit', 'Reg', (41, 47))	('mice', 'Species', '10090', (155, 159))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (120, 140))	('Disruption', 'Var', (0, 10))
269309	20816834	Because KLF4 induces a proinflammatory response in a sterile environment in vitro, we believe that activation of the NF-kappaB pathway is the initial event after Klf4 overexpression in vivo, which subsequently induces dilatation of paracellular spaces.	('NF-kappaB', 'Gene', '18033', (117, 126))	('induces', 'Reg', (13, 20))	('induces', 'Reg', (210, 217))	('dilatation', 'MPA', (218, 228))	('KLF4', 'Var', (8, 12))	('proinflammatory response', 'MPA', (23, 47))	('NF-kappaB', 'Gene', (117, 126))	('dilatation', 'Phenotype', 'HP:0002617', (218, 228))
269329	33603170	We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients.	('CHRNA7 expression', 'Protein', (23, 40))	('ESCC patients', 'Disease', (91, 104))	('patients', 'Species', '9606', (96, 104))	('aberrant', 'Var', (14, 22))
269334	33603170	Apart from potentially causing immediate harm to adolescent health, nicotine consumption also sows the seeds for future problems by predisposing consumers to substance abuse.	('nicotine', 'Chemical', 'MESH:D009538', (68, 76))	('substance abuse', 'Disease', (158, 173))	('nicotine consumption', 'Var', (68, 88))
269335	33603170	More recent evidence suggests that nicotine as well as its metabolites such as nitrosamine ketone can induce DNA damage and hinder DNA damage repair.	('DNA', 'MPA', (109, 112))	('nicotine', 'Var', (35, 43))	('induce', 'PosReg', (102, 108))	('hinder', 'NegReg', (124, 130))	('nicotine', 'Chemical', 'MESH:D009538', (35, 43))	('nitrosamine ketone', 'Chemical', '-', (79, 97))	('DNA', 'MPA', (131, 134))
269338	33603170	The functional nAChRs comprise homopentamers of alpha-subunits or heteropentamers with at least one alpha- and one beta-subunit.	('homopentamers', 'Var', (31, 44))	('nAChR', 'Gene', '1137', (15, 20))	('heteropentamers', 'Protein', (66, 81))	('nAChR', 'Gene', (15, 20))
269341	33603170	Among them, CHRNA7 and CHRNA9 have been reported to be capable of inducing cancer stem cell-like cells (CSC) or cancer-initiating cells (CIC).	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('inducing', 'PosReg', (66, 74))	('cancer', 'Disease', (75, 81))	('CHRNA7', 'Var', (12, 18))	('CHRNA9', 'Gene', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CHRNA9', 'Gene', '55584', (23, 29))
269349	33603170	In addition, we found that nicotine is also capable of increasing both the number and the size of ESCC tumorspheres in 3D culture (Fig.	('tumorspheres', 'Disease', (103, 115))	('nicotine', 'Var', (27, 35))	('ESCC tumor', 'Disease', (98, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumorspheres', 'Disease', 'None', (103, 115))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('ESCC tumor', 'Disease', 'MESH:D004938', (98, 108))	('nicotine', 'Chemical', 'MESH:D009538', (27, 35))	('increasing', 'PosReg', (55, 65))
269355	33603170	These observations collectively indicate that nicotine can enhance tumor-initiating properties in human ESCC cells likely through one or more nAChR.	('nicotine', 'Chemical', 'MESH:D009538', (46, 54))	('enhance', 'PosReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('nicotine', 'Var', (46, 54))	('nAChR', 'Gene', '1137', (142, 147))	('ESCC', 'Disease', (104, 108))	('nAChR', 'Gene', (142, 147))	('tumor', 'Disease', (67, 72))	('human', 'Species', '9606', (98, 103))
269357	33603170	Although the levels of CHRNA1, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB3, and CHRNB4 in ESCC were all significantly higher than that of the normal esophageal tissues (Fig.	('CHRNA5', 'Gene', (31, 37))	('CHRNB3', 'Gene', (71, 77))	('CHRNA7', 'Var', (47, 53))	('CHRNA9', 'Gene', (55, 61))	('CHRNB3', 'Gene', '1142', (71, 77))	('CHRNA5', 'Gene', '1138', (31, 37))	('CHRNA9', 'Gene', '55584', (55, 61))	('CHRNB1', 'Gene', (63, 69))	('CHRNA1', 'Gene', (23, 29))	('CHRNB4', 'Gene', '1143', (83, 89))	('CHRNA1', 'Gene', '1134', (23, 29))	('levels', 'MPA', (13, 19))	('CHRNB4', 'Gene', (83, 89))	('higher', 'PosReg', (121, 127))	('CHRNB1', 'Gene', '1140', (63, 69))	('CHRNA6', 'Gene', '8973', (39, 45))	('CHRNA6', 'Gene', (39, 45))
269363	33603170	We found that high expression of CHRNA7 is highly correlated with lymph node metastasis (P = 0.010), tumor stage (P = 0.019), and smoking history (P = 0.048).	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('correlated', 'Reg', (50, 60))	('high', 'Var', (14, 18))	('CHRNA7', 'Protein', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('lymph node metastasis', 'CPA', (66, 87))
269365	33603170	Kaplan-Meier analysis revealed that patients with high CHRNA7 expression were associated with a significantly shorter overall survival (median: 34.9 months) than those with low CHRNA7 expression (median: 46.4 months) (log-rank test; P = 0.008, Fig.	('high CHRNA7 expression', 'Var', (50, 72))	('shorter', 'NegReg', (110, 117))	('overall survival', 'MPA', (118, 134))	('patients', 'Species', '9606', (36, 44))
269370	33603170	2c), we conducted flow cytometry assays and demonstrated that knocking down CHRNA7 attenuated the nicotine-induced subpopulation of both ALDH+ (Fig.	('ALDH', 'Gene', '11670', (137, 141))	('knocking down', 'Var', (62, 75))	('ALDH', 'Gene', (137, 141))	('nicotine', 'Chemical', 'MESH:D009538', (98, 106))	('attenuated', 'NegReg', (83, 93))	('CHRNA7', 'Gene', (76, 82))	('nicotine-induced subpopulation', 'MPA', (98, 128))
269374	33603170	2d), we test the hypothesis that nicotine enhances tumor-initiating capacity by activating CHRNA7 and subsequently the JAK2/STAT3 pathway.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('nicotine', 'Chemical', 'MESH:D009538', (33, 41))	('JAK2/STAT3 pathway', 'Pathway', (119, 137))	('activating', 'PosReg', (80, 90))	('enhances', 'PosReg', (42, 50))	('nicotine', 'Var', (33, 41))	('CHRNA7', 'Protein', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
269376	33603170	Given the well-established role of SOX2 in tumor-initiating cells, we experimentally demonstrated the parallel relationship between CHRNA7 and SOX2 when CHRNA7 is either knocked down or overexpressed (Supplementary Fig.	('knocked', 'Var', (170, 177))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('overexpressed', 'PosReg', (186, 199))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('CHRNA7', 'Gene', (153, 159))
269383	33603170	4e) showed that overexpressed CHRNA7 not only activated the JAK2/STAT3 pathway but also increased CIC properties evidenced by increased CD44 and SOX2.	('activated', 'PosReg', (46, 55))	('JAK2/STAT3 pathway', 'Pathway', (60, 78))	('CD44', 'Gene', '960', (136, 140))	('CD44', 'Gene', (136, 140))	('CIC properties', 'MPA', (98, 112))	('increased', 'PosReg', (88, 97))	('increased', 'PosReg', (126, 135))	('CHRNA7', 'Var', (30, 36))
269384	33603170	Consistent with the results from the patients (Supplementary Table 1), CHRNA7 overexpression led to an increase of metastatic lesions in the lymph node (Supplementary Fig.	('increase', 'PosReg', (103, 111))	('patients', 'Species', '9606', (37, 45))	('metastatic lesions in the lymph node', 'CPA', (115, 151))	('overexpression', 'PosReg', (78, 92))	('CHRNA7', 'Var', (71, 77))
269387	33603170	To explore whether inhibiting CHRNA7 expression or repressing its activity could be an efficacious therapeutic strategy, we first conducted bioinformatics analyses of the publicly available dataset with 95 human ESCC samples in cBio Cancer Genomics Portal (http://cbioportal.org) but failed to identify any mutation, deletion, fusion or two cases of amplification of CHRNA7 in this dataset (Supplementary Fig.	('inhibiting', 'NegReg', (19, 29))	('human', 'Species', '9606', (206, 211))	('activity', 'MPA', (66, 74))	('Cancer', 'Disease', 'MESH:D009369', (233, 239))	('Cancer', 'Disease', (233, 239))	('Cancer', 'Phenotype', 'HP:0002664', (233, 239))	('CHRNA7', 'Protein', (30, 36))	('deletion', 'Var', (317, 325))
269401	33603170	But as a non-competitive antagonist of CHRNA7, dextromethorphan can attenuate nicotine's antinociceptive and reinforcing effects at a relatively low dosage.	('dextromethorphan', 'Var', (47, 63))	('nicotine', 'Protein', (78, 86))	('attenuate', 'NegReg', (68, 77))	('nicotine', 'Chemical', 'MESH:D009538', (78, 86))	('antinociceptive', 'MPA', (89, 104))	('dextromethorphan', 'Chemical', 'MESH:D003915', (47, 63))
269403	33603170	Two ESCC cell lines were treated with either 10 muM nicotine alone or in combination with different concentrations (10, 20, 30, or 40 muM) of dextromethorphan and found that dextromethorphan at a concentration of 30 or 40 muM is capable of counteracting nicotine-enhanced CIC properties (Fig.	('dextromethorphan', 'Var', (174, 190))	('dextromethorphan', 'Chemical', 'MESH:D003915', (142, 158))	('dextromethorphan', 'Chemical', 'MESH:D003915', (174, 190))	('CIC', 'MPA', (272, 275))	('nicotine', 'Chemical', 'MESH:D009538', (254, 262))	('nicotine', 'Chemical', 'MESH:D009538', (52, 60))
269409	33603170	Notably, a combination of these drugs appeared to synergistically counteract nicotine-induced expression of CHRNA7, as well as downstream signaling in terms of p-JAK2, p-STAT3, and SOX2 (Supplementary Fig.	('p-STAT3', 'MPA', (168, 175))	('nicotine', 'Chemical', 'MESH:D009538', (77, 85))	('CHRNA7', 'Gene', (108, 114))	('p-JAK2', 'Var', (160, 166))
269422	33603170	Our studies reveal that CHRNA7, a nicotine-enhanced receptor, confers high oncogenic potential by inducing CIC properties and serves as a predictor of poor prognostic in ESCC.	('CHRNA7', 'Var', (24, 30))	('CIC', 'MPA', (107, 110))	('inducing', 'PosReg', (98, 106))	('nicotine', 'Chemical', 'MESH:D009538', (34, 42))	('oncogenic potential', 'CPA', (75, 94))	('ESCC', 'Disease', (170, 174))
269424	33603170	Our results derived from bioinformatics analyses, in vivo and in vitro studies and clinical data indicate that CHRNA7 mediates nicotine-induced ESCC tumor-initiating capacity at least in part via activating the JAK2/STAT3/SOX2 signaling pathway, which has been proven to be frequently dysregulated in human ESCC.	('ESCC tumor', 'Disease', (144, 154))	('CHRNA7', 'Var', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('activating', 'PosReg', (196, 206))	('nicotine', 'Chemical', 'MESH:D009538', (127, 135))	('ESCC tumor', 'Disease', 'MESH:D004938', (144, 154))	('human', 'Species', '9606', (301, 306))	('JAK2/STAT3/SOX2 signaling pathway', 'Pathway', (211, 244))
269437	33603170	The human ESCC cells KYSE140, KYSE150, KYSE510, KYSE270, and KYSE520 cells were obtained from the tumor cell bank of the Chinese Academy of Medical Science.	('human', 'Species', '9606', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('KYSE150', 'Var', (30, 37))	('KYSE510', 'CellLine', 'CVCL:1354', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('KYSE520', 'CellLine', 'CVCL:1355', (61, 68))	('tumor', 'Disease', (98, 103))
269558	31754346	MTHFR C677T genetic polymorphism in combination with serum vitamin B2, B12 and aberrant DNA methylation of P16 and P53 genes in esophageal squamous cell carcinoma and esophageal precancerous lesions: a case-control study The study aimed to explore the associations between the interactions of serum vitamin B2 or B12 levels, aberrant DNA methylation of p16 or p53 and MTHFR C677T polymorphism and the risks of esophageal squamous cell carcinoma (ESCC) and esophageal precancerous lesion (EPL).	('ESCC', 'Disease', 'MESH:C562729', (446, 450))	('p53', 'Gene', '7157', (360, 363))	('P53', 'Gene', '7157', (115, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (421, 444))	('p16', 'Gene', (353, 356))	('C677T', 'Mutation', 'rs1801133', (374, 379))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('methyl', 'Chemical', 'MESH:C031105', (92, 98))	('EPL', 'Disease', (488, 491))	('MTHFR', 'Gene', (0, 5))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (167, 198))	('p16', 'Gene', '1029', (353, 356))	('aberrant', 'Var', (325, 333))	('p53', 'Gene', (360, 363))	('EPL', 'Disease', 'MESH:D011230', (488, 491))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (410, 444))	('esophageal precancerous lesions', 'Disease', (167, 198))	('B12', 'Gene', '4709', (71, 74))	('methyl', 'Chemical', 'MESH:C031105', (338, 344))	('MTHFR', 'Gene', '4524', (368, 373))	('C677T', 'Mutation', 'rs1801133', (6, 11))	('vitamin B2', 'Chemical', 'MESH:D025101', (299, 309))	('cancer', 'Phenotype', 'HP:0002664', (470, 476))	('ESCC', 'Disease', (446, 450))	('esophageal precancerous lesion', 'Disease', 'MESH:D011230', (456, 486))	('B12', 'Gene', (313, 316))	('esophageal squamous cell carcinoma', 'Disease', (128, 162))	('esophageal precancerous lesion', 'Disease', 'MESH:D011230', (167, 197))	('vitamin B2', 'Chemical', 'MESH:D025101', (59, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('esophageal precancerous lesion', 'Disease', (456, 486))	('carcinoma', 'Phenotype', 'HP:0030731', (435, 444))	('MTHFR', 'Gene', (368, 373))	('P53', 'Gene', (115, 118))	('P16', 'Gene', '1029', (107, 110))	('esophageal squamous cell carcinoma', 'Disease', (410, 444))	('B12', 'Gene', (71, 74))	('MTHFR', 'Gene', '4524', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('P16', 'Gene', (107, 110))	('B12', 'Gene', '4709', (313, 316))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (128, 162))
269561	31754346	The lowest quartile of both serum vitamin B2 and B12 with TT genotype showed significant increased EPL risk (OR = 4.91, 95% CI 1.31-18.35; OR = 6.88, 95% CI 1.10-42.80).	('genotype', 'Var', (61, 69))	('EPL', 'Disease', 'MESH:D011230', (99, 102))	('B12', 'Gene', (49, 52))	('B12', 'Gene', '4709', (49, 52))	('TT genotype', 'Var', (58, 69))	('vitamin B2', 'Chemical', 'MESH:D025101', (34, 44))	('EPL', 'Disease', (99, 102))
269563	31754346	The ORs of p16 methylation for genotype CT and TT were 1.98 (95% CI 1.01-3.89) and 17.79 (95% CI 2.26-140.22) in EPL, 4.86 (95% CI 2.48-9.50) and 20.40 (95% CI 2.53-164.81) in ESCC, respectively.	('ESCC', 'Disease', (176, 180))	('methylation', 'Var', (15, 26))	('p16', 'Gene', (11, 14))	('ESCC', 'Disease', 'MESH:C562729', (176, 180))	('methyl', 'Chemical', 'MESH:C031105', (15, 21))	('EPL', 'Disease', 'MESH:D011230', (113, 116))	('p16', 'Gene', '1029', (11, 14))	('EPL', 'Disease', (113, 116))
269564	31754346	Similarly, p53 methylation with genotype TT was associated with increased EPL and ESCC risks (OR = 13.28, 95% CI 1.67-105.70; OR = 15.24, 95% CI 1.90-122.62).	('p53', 'Gene', (11, 14))	('methylation', 'Var', (15, 26))	('p53', 'Gene', '7157', (11, 14))	('ESCC', 'Disease', (82, 86))	('EPL', 'Disease', 'MESH:D011230', (74, 77))	('methyl', 'Chemical', 'MESH:C031105', (15, 21))	('increased', 'PosReg', (64, 73))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))	('EPL', 'Disease', (74, 77))
269565	31754346	The MTHFR C677T genotype and serum vitamin B2 or B12 levels may interact in ways which associated with the EPL and ESCC risks.	('ESCC', 'Disease', (115, 119))	('EPL', 'Disease', 'MESH:D011230', (107, 110))	('vitamin B2', 'Chemical', 'MESH:D025101', (35, 45))	('MTHFR', 'Gene', (4, 9))	('C677T', 'Mutation', 'rs1801133', (10, 15))	('ESCC', 'Disease', 'MESH:C562729', (115, 119))	('associated', 'Reg', (87, 97))	('C677T', 'Var', (10, 15))	('EPL', 'Disease', (107, 110))	('B12', 'Gene', (49, 52))	('B12', 'Gene', '4709', (49, 52))	('MTHFR', 'Gene', '4524', (4, 9))
269566	31754346	The gene-gene interaction suggested that aberrant DNA methyaltion of either p16 or p53 combined with T alleles of MTHFR was associated with increased risks of both EPL and ESCC.	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('EPL', 'Disease', (164, 167))	('p16', 'Gene', '1029', (76, 79))	('ESCC', 'Disease', 'MESH:C562729', (172, 176))	('MTHFR', 'Gene', '4524', (114, 119))	('associated', 'Reg', (124, 134))	('aberrant DNA', 'Var', (41, 53))	('EPL', 'Disease', 'MESH:D011230', (164, 167))	('ESCC', 'Disease', (172, 176))	('p16', 'Gene', (76, 79))	('MTHFR', 'Gene', (114, 119))
269573	31754346	Deficiencies of some certain micronutrients, such as folate and vitamin B6 which are the key methyl donor and cofactor for the enzyme serine hydroxymethyltransferase respectively, have been recognized as the risk factors for cancers including ESCC.	('Deficiencies', 'Var', (0, 12))	('risk factors', 'Reg', (208, 220))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('ESCC', 'Disease', (243, 247))	('methyl', 'Chemical', 'MESH:C031105', (148, 154))	('methyl', 'Chemical', 'MESH:C031105', (93, 99))	('serine', 'Chemical', 'MESH:C047902', (134, 140))	('cancers', 'Disease', (225, 232))	('vitamin B6', 'Chemical', 'MESH:D025101', (64, 74))	('donor', 'Species', '9606', (100, 105))	('folate', 'Chemical', 'MESH:D005492', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('ESCC', 'Disease', 'MESH:C562729', (243, 247))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
269579	31754346	Several studies illustrated that high intake or plasma concentration of vitamin B12 were associated with increased risk of cancers including EC, but the mechanism remains unclear and epidemiological studies have always showed inconsistent findings.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('EC', 'Disease', 'MESH:D004938', (141, 143))	('B12', 'Gene', (80, 83))	('B12', 'Gene', '4709', (80, 83))	('vitamin B', 'Chemical', 'MESH:D025101', (72, 81))	('high intake', 'Var', (33, 44))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))
269580	31754346	Additionally, nucleotide substitution of C to T at nucleotide 677, the commonest polymorphism for MTHFR gene, results in an alanine to valine replacement so that the activity of MTHFR is reduced.	('MTHFR', 'Gene', '4524', (178, 183))	('valine', 'Chemical', 'MESH:C521924', (135, 141))	('nucleotide substitution', 'Var', (14, 37))	('activity', 'MPA', (166, 174))	('C to T', 'Gene', (41, 47))	('MTHFR', 'Gene', (98, 103))	('alanine', 'Chemical', 'MESH:D000409', (124, 131))	('alanine to valine replacement', 'MPA', (124, 153))	('C to T at nucleotide 677', 'Mutation', 'rs1801133', (41, 65))	('MTHFR', 'Gene', (178, 183))	('reduced', 'NegReg', (187, 194))	('MTHFR', 'Gene', '4524', (98, 103))	('results in', 'Reg', (110, 120))
269581	31754346	Over the past decade, relations between MTHFR C677T polymorphism and aberrant DNA methylation with the risk of ESCC called for more concern, but the available data remains incomplete and the results are limited.	('ESCC', 'Disease', 'MESH:C562729', (111, 115))	('MTHFR', 'Gene', (40, 45))	('aberrant', 'Var', (69, 77))	('methyl', 'Chemical', 'MESH:C031105', (82, 88))	('C677T', 'Mutation', 'rs1801133', (46, 51))	('C677T', 'Var', (46, 51))	('ESCC', 'Disease', (111, 115))	('MTHFR', 'Gene', '4524', (40, 45))
269585	31754346	Studies have indicated that p16 methylation and p53 mutations are frequently found in ESCC, suggesting that genetic and epigenetic alterations in p16 and p53 are involved in the pathogenesis of ESCC.	('mutations', 'Var', (52, 61))	('p53', 'Gene', (48, 51))	('p16', 'Gene', '1029', (28, 31))	('ESCC', 'Disease', (194, 198))	('p53', 'Gene', '7157', (48, 51))	('p16', 'Gene', '1029', (146, 149))	('ESCC', 'Disease', 'MESH:C562729', (86, 90))	('found', 'Reg', (77, 82))	('methyl', 'Chemical', 'MESH:C031105', (32, 38))	('p16', 'Gene', (28, 31))	('p53', 'Gene', (154, 157))	('involved', 'Reg', (162, 170))	('ESCC', 'Disease', 'MESH:C562729', (194, 198))	('p53', 'Gene', '7157', (154, 157))	('p16', 'Gene', (146, 149))	('ESCC', 'Disease', (86, 90))
269586	31754346	Aberrant DNA promoter hypermethylation in the normal p16 gene was reported to be responsible for the inactivation of p16 gene and the silence of the corresponding gene which is involved in carcinogenesis of esophagus.	('p16', 'Gene', (53, 56))	('inactivation', 'MPA', (101, 113))	('Aberrant', 'Var', (0, 8))	('p16', 'Gene', '1029', (117, 120))	('carcinogenesis', 'Disease', 'MESH:D063646', (189, 203))	('carcinogenesis', 'Disease', (189, 203))	('DNA promoter', 'MPA', (9, 21))	('p16', 'Gene', '1029', (53, 56))	('p16', 'Gene', (117, 120))	('methyl', 'Chemical', 'MESH:C031105', (27, 33))	('silence', 'NegReg', (134, 141))
269587	31754346	Meanwhile, it was reported that both p53 mutations and single-nucleotide polymorphism in codon 72 of p53 gene are associated with esophageal carcinogenesis.	('mutations', 'Var', (41, 50))	('esophageal carcinogenesis', 'Disease', (130, 155))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('single-nucleotide polymorphism in', 'Var', (55, 88))	('p53', 'Gene', (37, 40))	('associated', 'Reg', (114, 124))	('p53', 'Gene', '7157', (37, 40))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (130, 155))
269589	31754346	Our previous study indicated that MTHFR C677T polymorphism may further modify associations between serum concentration of folate and risk of ESCC, but no statistically significant results were found with the risk of EPL.	('MTHFR', 'Gene', '4524', (34, 39))	('C677T', 'Mutation', 'rs1801133', (40, 45))	('C677T', 'Var', (40, 45))	('modify', 'Reg', (71, 77))	('EPL', 'Disease', (216, 219))	('ESCC', 'Disease', 'MESH:C562729', (141, 145))	('MTHFR', 'Gene', (34, 39))	('folate', 'Chemical', 'MESH:D005492', (122, 128))	('associations', 'Interaction', (78, 90))	('EPL', 'Disease', 'MESH:D011230', (216, 219))	('serum concentration of folate', 'MPA', (99, 128))	('ESCC', 'Disease', (141, 145))
269639	31754346	Compared with control group, EPL group had a higher proportion of variant genotype TT and the difference was statistically significant (chi2 = 5.79, p < 0.05).	('EPL', 'Disease', 'MESH:D011230', (29, 32))	('variant', 'Var', (66, 73))	('EPL', 'Disease', (29, 32))
269642	31754346	Additionally, our finding of Chi square test showed that p16 methylation was associated with 58% and 216% increases in the risk of EPL and ESCC, respectively (p < 0.05).	('methylation', 'Var', (61, 72))	('p16', 'Gene', (57, 60))	('EPL', 'Disease', 'MESH:D011230', (131, 134))	('ESCC', 'Disease', 'MESH:C562729', (139, 143))	('methyl', 'Chemical', 'MESH:C031105', (61, 67))	('p16', 'Gene', '1029', (57, 60))	('increases', 'PosReg', (106, 115))	('EPL', 'Disease', (131, 134))	('ESCC', 'Disease', (139, 143))
269644	31754346	Based on the significant results of the comparison of MTHFR C677T genotype and allele frequencies between EPL and controls provided by Tables 4 and 5 further illustrated the internal comparison of genotype and allele frequencies for the MTHFR C677T polymorphism among mild, moderate and severe EPL cases by Chi square test.	('mild', 'Disease', (268, 272))	('C677T', 'Mutation', 'rs1801133', (60, 65))	('EPL', 'Disease', (294, 297))	('EPL', 'Disease', (106, 109))	('MTHFR', 'Gene', '4524', (237, 242))	('C677T', 'Mutation', 'rs1801133', (243, 248))	('MTHFR', 'Gene', (54, 59))	('C677T', 'Var', (243, 248))	('EPL', 'Disease', 'MESH:D011230', (294, 297))	('EPL', 'Disease', 'MESH:D011230', (106, 109))	('MTHFR', 'Gene', (237, 242))	('moderate', 'Disease', (274, 282))	('MTHFR', 'Gene', '4524', (54, 59))
269646	31754346	The interaction between serum vitamin B2, B12 and MTHFR C677T genotype was determined by logistic regression analysis using controls, EPL and ESCC cases.	('MTHFR', 'Gene', (50, 55))	('EPL', 'Disease', (134, 137))	('ESCC', 'Disease', 'MESH:C562729', (142, 146))	('B12', 'Gene', '4709', (42, 45))	('EPL', 'Disease', 'MESH:D011230', (134, 137))	('vitamin B2', 'Chemical', 'MESH:D025101', (30, 40))	('C677T', 'Mutation', 'rs1801133', (56, 61))	('B12', 'Gene', (42, 45))	('ESCC', 'Disease', (142, 146))	('C677T', 'Var', (56, 61))	('MTHFR', 'Gene', '4524', (50, 55))
269647	31754346	As shown in Table 6, after adjustment for gender, age, tobacco smoking and alcoholic drinking, the interaction of the lowest quartile of both serum vitamin B2 and B12 with MTHFR C677T genotypes in EPL showed significant increased risk for variant genotype TT (OR = 4.91, 95% CI 1.31-18.35; OR = 6.88, 95% CI 1.10-42.80).	('MTHFR', 'Gene', '4524', (172, 177))	('alcoholic drinking', 'Phenotype', 'HP:0030955', (75, 93))	('EPL', 'Disease', 'MESH:D011230', (197, 200))	('variant', 'Var', (239, 246))	('C677T', 'Mutation', 'rs1801133', (178, 183))	('vitamin B2', 'Chemical', 'MESH:D025101', (148, 158))	('C677T', 'Var', (178, 183))	('alcoholic', 'Chemical', 'MESH:D012835', (75, 84))	('EPL', 'Disease', (197, 200))	('MTHFR', 'Gene', (172, 177))	('tobacco', 'Species', '4097', (55, 62))	('interaction', 'Interaction', (99, 110))	('B12', 'Gene', (163, 166))	('B12', 'Gene', '4709', (163, 166))
269648	31754346	The interaction of the highest quartile of both serum vitamin B2 and B12 with MTHFR C677T genotypes in ESCC showed significant decreased risk for wild genotype CC (OR = 0.16, 95% CI 0.04-0.60; OR = 0.10, 95% CI 0.02-0.46), as well as for heterozygote CT (OR = 0.23, 95% CI 0.07-0.77; OR = 0.18, 95% CI 0.05-0.62).	('C677T', 'Var', (84, 89))	('decreased', 'NegReg', (127, 136))	('interaction', 'Interaction', (4, 15))	('ESCC', 'Disease', 'MESH:C562729', (103, 107))	('MTHFR', 'Gene', (78, 83))	('B12', 'Gene', (69, 72))	('MTHFR', 'Gene', '4524', (78, 83))	('B12', 'Gene', '4709', (69, 72))	('ESCC', 'Disease', (103, 107))	('vitamin B2', 'Chemical', 'MESH:D025101', (54, 64))	('C677T', 'Mutation', 'rs1801133', (84, 89))
269650	31754346	However, the variant genotype TT along with the highest quartile of serum vitamin B12 conferred a tenfold increased EPL risk (OR = 10.08, 95% CI 2.22-45.71).	('B12', 'Gene', (82, 85))	('EPL', 'Disease', (116, 119))	('B12', 'Gene', '4709', (82, 85))	('vitamin B', 'Chemical', 'MESH:D025101', (74, 83))	('variant', 'Var', (13, 20))	('EPL', 'Disease', 'MESH:D011230', (116, 119))
269652	31754346	The methylation statuses of p16 and p53 in EPL and ESCC cases were significantly associated with MTHFR C677T genotypes.	('p16', 'Gene', '1029', (28, 31))	('ESCC', 'Disease', 'MESH:C562729', (51, 55))	('methyl', 'Chemical', 'MESH:C031105', (4, 10))	('EPL', 'Disease', (43, 46))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('methylation statuses', 'MPA', (4, 24))	('EPL', 'Disease', 'MESH:D011230', (43, 46))	('p16', 'Gene', (28, 31))	('C677T', 'Var', (103, 108))	('MTHFR', 'Gene', '4524', (97, 102))	('ESCC', 'Disease', (51, 55))	('C677T', 'Mutation', 'rs1801133', (103, 108))	('associated', 'Reg', (81, 91))	('MTHFR', 'Gene', (97, 102))
269655	31754346	Similarly, p53 methylation with variant genotype TT was associated with increased risks of EPL and ESCC (OR = 13.28, 95% CI 1.67-105.70; OR = 15.24, 95% CI 1.90-122.62).	('EPL', 'Disease', (91, 94))	('methylation', 'Var', (15, 26))	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('variant', 'Var', (32, 39))	('EPL', 'Disease', 'MESH:D011230', (91, 94))	('ESCC', 'Disease', (99, 103))	('methyl', 'Chemical', 'MESH:C031105', (15, 21))	('ESCC', 'Disease', 'MESH:C562729', (99, 103))
269657	31754346	Our study suggested that: firstly, healthy controls were more likely to have higher levels of vitamin B2 and B12 than ESCC cases; secondly, variant genotype TT and the T allele were associated with significantly increased risk of EPL; thirdly, the MTHFR C677T genotype may modify association between serum vitamin B2 or B12 levels and the risks of EPL and ESCC; fourthly, gene-gene interaction was observed as there were strong association between the interaction of p16 and p53 methylations and MTHFR C677T polymorphism and the risks of EPL and ESCC.	('ESCC', 'Disease', (118, 122))	('B12', 'Gene', (109, 112))	('methylations', 'Var', (479, 491))	('vitamin B2', 'Chemical', 'MESH:D025101', (94, 104))	('C677T', 'Mutation', 'rs1801133', (254, 259))	('interaction', 'Interaction', (452, 463))	('p53', 'Gene', '7157', (475, 478))	('vitamin B2', 'Chemical', 'MESH:D025101', (306, 316))	('B12', 'Gene', (320, 323))	('variant', 'Var', (140, 147))	('MTHFR', 'Gene', '4524', (496, 501))	('C677T', 'Mutation', 'rs1801133', (502, 507))	('p53', 'Gene', (475, 478))	('modify', 'Reg', (273, 279))	('ESCC', 'Disease', 'MESH:C562729', (356, 360))	('p16', 'Gene', (467, 470))	('MTHFR', 'Gene', '4524', (248, 253))	('EPL', 'Disease', (230, 233))	('B12', 'Gene', '4709', (109, 112))	('ESCC', 'Disease', 'MESH:C562729', (546, 550))	('methyl', 'Chemical', 'MESH:C031105', (479, 485))	('EPL', 'Disease', (348, 351))	('ESCC', 'Disease', 'MESH:C562729', (118, 122))	('EPL', 'Disease', 'MESH:D011230', (230, 233))	('p16', 'Gene', '1029', (467, 470))	('EPL', 'Disease', (538, 541))	('EPL', 'Disease', 'MESH:D011230', (348, 351))	('MTHFR', 'Gene', (496, 501))	('EPL', 'Disease', 'MESH:D011230', (538, 541))	('ESCC', 'Disease', (356, 360))	('MTHFR', 'Gene', (248, 253))	('B12', 'Gene', '4709', (320, 323))	('ESCC', 'Disease', (546, 550))
269658	31754346	To the best of our knowledge, the MTHFR C677T variant is a C to T transition in exon 4 at nucleotide 677 and results in an alanine to valine replacement at position 222 of the MTHFR amino acid sequence.	('MTHFR', 'Gene', '4524', (34, 39))	('C677T', 'Mutation', 'rs1801133', (40, 45))	('C677T', 'Var', (40, 45))	('MTHFR', 'Gene', '4524', (176, 181))	('alanine', 'Var', (123, 130))	('results in', 'Reg', (109, 119))	('MTHFR', 'Gene', (34, 39))	('MTHFR', 'Gene', (176, 181))	('alanine to valine replacement at position 222', 'Mutation', 'rs1801133', (123, 168))
269659	31754346	Compared with homozygous wild genotype CC, the activity of MTHFR was observed to reduce by 35% and 70% for heterozygote CT and variant genotype TT, respectively.	('MTHFR', 'Gene', '4524', (59, 64))	('reduce', 'NegReg', (81, 87))	('MTHFR', 'Gene', (59, 64))	('variant', 'Var', (127, 134))	('activity', 'MPA', (47, 55))
269661	31754346	Individually, both the serum levels of vitamin B2 and B12 and the MTHFR C677T genotypes may be associated with the risks of EPL and ESCC.	('B12', 'Gene', (54, 57))	('B12', 'Gene', '4709', (54, 57))	('MTHFR', 'Gene', '4524', (66, 71))	('ESCC', 'Disease', 'MESH:C562729', (132, 136))	('MTHFR', 'Gene', (66, 71))	('vitamin B2', 'Chemical', 'MESH:D025101', (39, 49))	('EPL', 'Disease', (124, 127))	('C677T', 'Mutation', 'rs1801133', (72, 77))	('C677T', 'Var', (72, 77))	('associated', 'Reg', (95, 105))	('EPL', 'Disease', 'MESH:D011230', (124, 127))	('ESCC', 'Disease', (132, 136))
269662	31754346	However, the serum levels of vitamin B2 and B12 and the MTHFR C677T genotypes interact in ways which has a different effect on the EPL and ESCC risks.	('effect', 'Reg', (117, 123))	('B12', 'Gene', (44, 47))	('interact', 'Reg', (78, 86))	('EPL', 'Disease', 'MESH:D011230', (131, 134))	('B12', 'Gene', '4709', (44, 47))	('MTHFR', 'Gene', '4524', (56, 61))	('vitamin B2', 'Chemical', 'MESH:D025101', (29, 39))	('C677T', 'Mutation', 'rs1801133', (62, 67))	('ESCC', 'Disease', 'MESH:C562729', (139, 143))	('C677T', 'Var', (62, 67))	('MTHFR', 'Gene', (56, 61))	('EPL', 'Disease', (131, 134))	('ESCC', 'Disease', (139, 143))
269675	31754346	The variant homozygotes TT for the C677T variant only has 30% MTHFR enzyme activity of the homozygous wild genotype CC, consequently the utilization rate of cofactors such as vitamin B2 and B12 is reduced in the folate cycle.	('utilization rate of', 'MPA', (137, 156))	('folate', 'Chemical', 'MESH:D005492', (212, 218))	('B12', 'Gene', (190, 193))	('B12', 'Gene', '4709', (190, 193))	('MTHFR', 'Gene', '4524', (62, 67))	('reduced', 'NegReg', (197, 204))	('C677T', 'Mutation', 'rs1801133', (35, 40))	('vitamin B2', 'Chemical', 'MESH:D025101', (175, 185))	('C677T', 'Var', (35, 40))	('MTHFR', 'Gene', (62, 67))	('activity', 'MPA', (75, 83))
269677	31754346	In individuals with the homozygous wild genotype CC who had the lowest quartile of serum vitamin B12 level as reference, those with the homozygous mutation TT who had the highest quartile of serum vitamin B12 level had an tenfold increase in EPL risk (p < 0.05).	('B12', 'Gene', (205, 208))	('B12', 'Gene', '4709', (205, 208))	('EPL', 'Disease', 'MESH:D011230', (242, 245))	('mutation', 'Var', (147, 155))	('vitamin B', 'Chemical', 'MESH:D025101', (197, 206))	('vitamin B', 'Chemical', 'MESH:D025101', (89, 98))	('EPL', 'Disease', (242, 245))	('B12', 'Gene', (97, 100))	('B12', 'Gene', '4709', (97, 100))
269687	31754346	Here, the hypermethylation of p53 promoter was associated with silencing of protein expression of the gene.	('hypermethylation', 'Var', (10, 26))	('protein expression', 'MPA', (76, 94))	('methyl', 'Chemical', 'MESH:C031105', (15, 21))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('associated', 'Reg', (47, 57))	('silencing', 'NegReg', (63, 72))
269688	31754346	Because as an important tumor suppressor gene, p53 is essential for regulating cell division and preventing tumor formation, the silencing of it may be associated with the development of tumor and a higher risk of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('ESCC', 'Disease', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('ESCC', 'Disease', 'MESH:C562729', (214, 218))	('tumor', 'Disease', (108, 113))	('silencing', 'Var', (129, 138))	('tumor', 'Disease', (187, 192))	('associated', 'Reg', (152, 162))	('p53', 'Gene', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('p53', 'Gene', '7157', (47, 50))
269690	31754346	Similarly, p16 silencing was also associated with the DNA methylation in the p16 promoter, which suggests that p16 silencing in ESCC may be a frequent event in the endemic region.	('p16', 'Gene', (77, 80))	('p16', 'Gene', (11, 14))	('ESCC', 'Disease', 'MESH:C562729', (128, 132))	('p16', 'Gene', '1029', (111, 114))	('DNA', 'Var', (54, 57))	('silencing', 'Var', (15, 24))	('p16', 'Gene', '1029', (77, 80))	('ESCC', 'Disease', (128, 132))	('p16', 'Gene', '1029', (11, 14))	('p16', 'Gene', (111, 114))	('methyl', 'Chemical', 'MESH:C031105', (58, 64))
269692	31754346	However, the epigenetic silencing of p16 was frequent in EAC, whereas relatively rare in ESCC.	('epigenetic silencing', 'Var', (13, 33))	('ESCC', 'Disease', 'MESH:C562729', (89, 93))	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('ESCC', 'Disease', (89, 93))	('EAC', 'Disease', (57, 60))	('p16', 'Gene', '1029', (37, 40))	('frequent', 'Reg', (45, 53))	('EAC', 'Disease', 'MESH:D004941', (57, 60))	('p16', 'Gene', (37, 40))
269695	31754346	During the development of carcinogenesis, it has been found that epigenetic silencing of tumor suppressor genes by aberrant DNA methylation is an early major event, but the interaction between aberrant DNA methylation and the MTHFR 677T allele cannot be ruled out.	('methyl', 'Chemical', 'MESH:C031105', (206, 212))	('carcinogenesis', 'Disease', 'MESH:D063646', (26, 40))	('methyl', 'Chemical', 'MESH:C031105', (128, 134))	('carcinogenesis', 'Disease', (26, 40))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('MTHFR', 'Gene', (226, 231))	('MTHFR', 'Gene', '4524', (226, 231))	('aberrant', 'Var', (115, 123))	('epigenetic', 'MPA', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
269696	31754346	Our study demonstrated the gene-gene interaction between p16 and p53 methylations and MTHFR C677T polymorphism, suggesting that they may have an even greater role to play in cancer development than the single effect seen to date.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('C677T', 'Mutation', 'rs1801133', (92, 97))	('play', 'Reg', (166, 170))	('methyl', 'Chemical', 'MESH:C031105', (69, 75))	('p16', 'Gene', (57, 60))	('MTHFR', 'Gene', '4524', (86, 91))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('C677T polymorphism', 'Var', (92, 110))	('polymorphism', 'Var', (98, 110))	('p16', 'Gene', '1029', (57, 60))	('methylations', 'Var', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('MTHFR', 'Gene', (86, 91))
269698	31754346	As reported previously, the activity of MTHFR is involved in the DNA methylation process, and MTHFR C677T polymorphism and folate status can interact in ways which affect DNA methylation status as well.	('folate', 'Chemical', 'MESH:D005492', (123, 129))	('methyl', 'Chemical', 'MESH:C031105', (69, 75))	('DNA methylation status', 'MPA', (171, 193))	('C677T polymorphism', 'Var', (100, 118))	('MTHFR', 'Gene', (40, 45))	('involved', 'Reg', (49, 57))	('MTHFR', 'Gene', '4524', (94, 99))	('methyl', 'Chemical', 'MESH:C031105', (175, 181))	('MTHFR', 'Gene', '4524', (40, 45))	('C677T', 'Mutation', 'rs1801133', (100, 105))	('MTHFR', 'Gene', (94, 99))	('interact', 'Reg', (141, 149))	('affect', 'Reg', (164, 170))
269700	31754346	However, so far it is still controversial about the role of MTHFR genetic polymorphisms because it may also have a dual role in the cancer development depending on different conditions including folate status, and the interaction between MTHFR C677T polymorphism and aberrant DNA methylation may vary from gene to another.	('MTHFR', 'Gene', '4524', (60, 65))	('cancer', 'Disease', (132, 138))	('folate', 'Chemical', 'MESH:D005492', (195, 201))	('MTHFR', 'Gene', (238, 243))	('C677T', 'Mutation', 'rs1801133', (244, 249))	('MTHFR', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('C677T', 'Var', (244, 249))	('methyl', 'Chemical', 'MESH:C031105', (280, 286))	('MTHFR', 'Gene', '4524', (238, 243))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
269703	31754346	An exciting clue was obtained by the results that combining the detection of MTHFR C677T polymorphism and aberrant DNA methylation of p16 and p53 can find the individual who has extremely high risk of ESCC or EPL.	('EPL', 'Disease', (209, 212))	('p53', 'Gene', (142, 145))	('MTHFR', 'Gene', (77, 82))	('p53', 'Gene', '7157', (142, 145))	('aberrant', 'Var', (106, 114))	('p16', 'Gene', (134, 137))	('ESCC', 'Disease', 'MESH:C562729', (201, 205))	('C677T', 'Var', (83, 88))	('C677T', 'Mutation', 'rs1801133', (83, 88))	('EPL', 'Disease', 'MESH:D011230', (209, 212))	('MTHFR', 'Gene', '4524', (77, 82))	('methyl', 'Chemical', 'MESH:C031105', (119, 125))	('ESCC', 'Disease', (201, 205))	('p16', 'Gene', '1029', (134, 137))
269705	31754346	Healthy controls were more likely to have higher levels of vitamin B2 and B12 than ESCC cases, and the MTHFR C677T genotype may modify the association between serum concentrations of vitamin B2 and B12 and the risks of EPL and ESCC.	('levels', 'MPA', (49, 55))	('B12', 'Gene', (198, 201))	('B12', 'Gene', '4709', (74, 77))	('EPL', 'Disease', (219, 222))	('C677T', 'Var', (109, 114))	('MTHFR', 'Gene', (103, 108))	('ESCC', 'Disease', (83, 87))	('ESCC', 'Disease', (227, 231))	('EPL', 'Disease', 'MESH:D011230', (219, 222))	('serum concentrations', 'MPA', (159, 179))	('vitamin B2', 'Chemical', 'MESH:D025101', (59, 69))	('B12', 'Gene', (74, 77))	('C677T', 'Mutation', 'rs1801133', (109, 114))	('B12', 'Gene', '4709', (198, 201))	('higher', 'PosReg', (42, 48))	('association', 'Interaction', (139, 150))	('ESCC', 'Disease', 'MESH:C562729', (83, 87))	('ESCC', 'Disease', 'MESH:C562729', (227, 231))	('MTHFR', 'Gene', '4524', (103, 108))	('vitamin B2', 'Chemical', 'MESH:D025101', (183, 193))	('modify', 'Reg', (128, 134))
269706	31754346	The gene-gene interaction suggested the possible crosstalk between the aberrant DNA methyaltion of either p16 or p53 and T alleles of MTHFR.	('MTHFR', 'Gene', (134, 139))	('p16', 'Gene', (106, 109))	('p53', 'Gene', '7157', (113, 116))	('crosstalk', 'Reg', (49, 58))	('p53', 'Gene', (113, 116))	('p16', 'Gene', '1029', (106, 109))	('MTHFR', 'Gene', '4524', (134, 139))	('aberrant', 'Var', (71, 79))
269763	31533862	Before matching, there were significant differences in the distribution of age and the pathological T stage between patients with high preoperative CRP levels (> 5.0 mg/mL) and those with low preoperative CRP levels (<= 5.0 mg/mL).	('differences', 'Reg', (40, 51))	('CRP', 'Gene', '1401', (148, 151))	('CRP', 'Gene', (148, 151))	('CRP', 'Gene', (205, 208))	('CRP', 'Gene', '1401', (205, 208))	('patients', 'Species', '9606', (116, 124))	('> 5.0', 'Var', (160, 165))
269767	31533862	In the matched cohort, the differences in survival between the low- and high-CRP group remained significant (p = 0.044, Fig.	('CRP', 'Gene', (77, 80))	('low-', 'Var', (63, 67))	('CRP', 'Gene', '1401', (77, 80))
269776	31533862	It has been reported that some factors may affect the prognosis of patients with EC, such as patient status; tumor biological behavior, including the number of cancer-positive lymph nodes; histopathological cell type; histological grade; cancer location, including the esophagogastric junction; genetic mutations; and surgery type.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('patient', 'Species', '9606', (67, 74))	('patients', 'Species', '9606', (67, 75))	('cancer', 'Disease', (160, 166))	('genetic mutations', 'Var', (295, 312))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('affect', 'Reg', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('EC', 'Disease', 'MESH:D004938', (81, 83))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
269793	31533862	showed significantly better survival in patients with normal CRP compared to that in patients with raised CRP levels among those who received neoadjuvant therapy that comprised 2 cycles of 5-fluorouracil (5-FU) and cisplatin in combination with 45-54 Gy of radiotherapy.	('normal', 'Var', (54, 60))	('patients', 'Species', '9606', (40, 48))	('better', 'PosReg', (21, 27))	('CRP', 'Gene', (61, 64))	('patients', 'Species', '9606', (85, 93))	('raised CRP', 'Phenotype', 'HP:0011227', (99, 109))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (189, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (215, 224))	('CRP', 'Gene', '1401', (106, 109))	('5-FU', 'Chemical', 'MESH:D005472', (205, 209))	('CRP', 'Gene', '1401', (61, 64))	('CRP', 'Gene', (106, 109))
269819	31070019	The influence of ACYP2 polymorphisms on gastrointestinal cancer susceptibility in the Chinese Han population Gastrointestinal cancer (GI cancer) is a type of cancer that has a high death rate.	('polymorphisms', 'Var', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('GI cancer', 'Disease', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gastrointestinal cancer', 'Disease', (40, 63))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (40, 63))	('ACYP2', 'Gene', '98', (17, 22))	('Gastrointestinal cancer', 'Disease', 'MESH:D004067', (109, 132))	('GI cancer', 'Disease', 'MESH:D009369', (134, 143))	('Gastrointestinal cancer', 'Disease', (109, 132))	('type of cancer', 'Disease', 'MESH:D009369', (150, 164))	('GI cancer', 'Phenotype', 'HP:0007378', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (40, 63))	('Gastrointestinal cancer', 'Phenotype', 'HP:0007378', (109, 132))	('ACYP2', 'Gene', (17, 22))	('type of cancer', 'Disease', (150, 164))
269821	31070019	This study aimed to investigate the association between polymorphisms of ACYP2 and GI cancer in the Chinese Han population.	('ACYP2', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('GI cancer', 'Disease', (83, 92))	('ACYP2', 'Gene', '98', (73, 78))	('polymorphisms', 'Var', (56, 69))	('GI cancer', 'Disease', 'MESH:D009369', (83, 92))	('GI cancer', 'Phenotype', 'HP:0007378', (83, 92))
269823	31070019	The correlation between ACYP2 variants and GI cancer risk was examined by logistic regression analysis.	('variants', 'Var', (30, 38))	('GI cancer', 'Disease', 'MESH:D009369', (43, 52))	('ACYP2', 'Gene', '98', (24, 29))	('GI cancer', 'Phenotype', 'HP:0007378', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('ACYP2', 'Gene', (24, 29))	('GI cancer', 'Disease', (43, 52))
269824	31070019	We identified that rs6713088 (OR = 1.17, 95% CI: 1.00-1.36, p = 0.047), rs843711 (OR = 1.17, 95 CI: 1.01-1.36, p = 0.035), and rs11896604 (OR = 1.20, 95% CI: 1.00-1.45, p = 0.048) were correlated with an increased risk of GI cancer under allele model.	('GI cancer', 'Disease', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('rs6713088', 'Mutation', 'rs6713088', (19, 28))	('GI cancer', 'Disease', 'MESH:D009369', (222, 231))	('rs843711', 'Var', (72, 80))	('rs11896604', 'Mutation', 'rs11896604', (127, 137))	('GI cancer', 'Phenotype', 'HP:0007378', (222, 231))	('rs6713088', 'Var', (19, 28))	('rs843711', 'Mutation', 'rs843711', (72, 80))	('rs11896604', 'Var', (127, 137))
269825	31070019	Rs11125529 under the recessive model (OR = 2.05, 95% CI: 1.00-4.23, p = 0.038), rs843711 in recessive model (OR = 1.37, 95% CI: 1.04-1.82, p = 0.026), and rs11896604 under log-additive model (OR = 1.23, 95% CI: 1.01-1.51, p = 0.042) were associated with an increased risk of GI cancer.	('GI cancer', 'Phenotype', 'HP:0007378', (275, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('Rs11125529', 'Mutation', 'Rs11125529', (0, 10))	('GI cancer', 'Disease', (275, 284))	('Rs11125529', 'Var', (0, 10))	('rs843711', 'Var', (80, 88))	('GI cancer', 'Disease', 'MESH:D009369', (275, 284))	('rs11896604', 'Mutation', 'rs11896604', (155, 165))	('rs843711', 'Mutation', 'rs843711', (80, 88))	('rs11896604', 'Var', (155, 165))
269826	31070019	Our study suggested that polymorphisms of ACYP2 gene might be associated with susceptibility to GI cancer.	('associated', 'Reg', (62, 72))	('ACYP2', 'Gene', '98', (42, 47))	('GI cancer', 'Disease', (96, 105))	('polymorphisms', 'Var', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('GI cancer', 'Disease', 'MESH:D009369', (96, 105))	('GI cancer', 'Phenotype', 'HP:0007378', (96, 105))	('ACYP2', 'Gene', (42, 47))
269833	31070019	However, the pathogenesis of digestive tract tumor is not clear, but a large number of studies have shown that it is caused by the combination of environmental (drinking, smoking, dietary habits, etc.)	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tract tumor', 'Disease', 'MESH:D009369', (39, 50))	('digestive tract tumor', 'Phenotype', 'HP:0007378', (29, 50))	('tract tumor', 'Disease', (39, 50))	('caused by', 'Reg', (117, 126))	('drinking', 'Var', (161, 169))
269837	31070019	But the relationship between ACYP2 gene polymorphism and the risk of GI tumors has not been reported.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('GI tumors', 'Disease', (69, 78))	('ACYP2', 'Gene', (29, 34))	('GI tumors', 'Disease', 'MESH:D009369', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('polymorphism', 'Var', (40, 52))	('ACYP2', 'Gene', '98', (29, 34))	('GI tumors', 'Phenotype', 'HP:0007378', (69, 78))
269840	31070019	A recent paper has indicated a significant association between ACYP2 single nucleotide polymorphisms (SNPs) and testicular cancer (Drogemoller et al., 2018).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('testicular cancer', 'Phenotype', 'HP:0010788', (112, 129))	('ACYP2', 'Gene', '98', (63, 68))	('single nucleotide polymorphisms', 'Var', (69, 100))	('testicular cancer', 'Disease', 'MESH:D013736', (112, 129))	('testicular cancer', 'Disease', (112, 129))	('ACYP2', 'Gene', (63, 68))
269841	31070019	(2017) found that ACYP2 polymorphism was associated with ototoxicity risk in children with cancer.	('ACYP2', 'Gene', (18, 23))	('associated', 'Reg', (41, 51))	('polymorphism', 'Var', (24, 36))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('ACYP2', 'Gene', '98', (18, 23))	('ototoxicity', 'Disease', 'MESH:D006311', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('children', 'Species', '9606', (77, 85))	('ototoxicity', 'Disease', (57, 68))
269842	31070019	(2012) determined that the polymorphism of ACYP2 gene was related to the risk of colorectal cancer.	('polymorphism', 'Var', (27, 39))	('ACYP2', 'Gene', '98', (43, 48))	('colorectal cancer', 'Disease', (81, 98))	('related', 'Reg', (58, 65))	('ACYP2', 'Gene', (43, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))
269843	31070019	Therefore, we hypothesized that the polymorphism of ACYP2 might be associated with the risk of GI cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ACYP2', 'Gene', (52, 57))	('GI cancer', 'Disease', (95, 104))	('ACYP2', 'Gene', '98', (52, 57))	('GI cancer', 'Disease', 'MESH:D009369', (95, 104))	('associated', 'Reg', (67, 77))	('polymorphism', 'Var', (36, 48))	('GI cancer', 'Phenotype', 'HP:0007378', (95, 104))
269861	31070019	The analyses showed that three variants were observed to associated with GI cancer risk under allele model (rs6713088, OR = 1.17, 95% CI: 1.00-1.36, p = 0.047; rs843711, OR = 1.17, 95% CI: 1.01-1.36, p = 0.035; rs11896604, OR = 1.20, 95% CI: 1.00-1.45, p = 0.048), and there was no statistical significance found in other eight variants.	('rs11896604', 'Mutation', 'rs11896604', (211, 221))	('rs11896604', 'Var', (211, 221))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('GI cancer', 'Disease', (73, 82))	('rs6713088', 'Var', (108, 117))	('rs6713088', 'Mutation', 'rs6713088', (108, 117))	('rs843711', 'Var', (160, 168))	('GI cancer', 'Phenotype', 'HP:0007378', (73, 82))	('rs843711', 'Mutation', 'rs843711', (160, 168))	('GI cancer', 'Disease', 'MESH:D009369', (73, 82))	('associated', 'Reg', (57, 67))
269862	31070019	Furthermore, HaploReg annotation revealed that SNPs associated with GI cancer risk were successfully predicted to have biological functions, and rs6713088, rs843711, and rs11896604 were associated with motifs changed and selected eQTL hits.	('rs11896604', 'Mutation', 'rs11896604', (170, 180))	('GI cancer', 'Disease', (68, 77))	('rs11896604', 'Var', (170, 180))	('rs843711', 'Mutation', 'rs843711', (156, 164))	('GI cancer', 'Disease', 'MESH:D009369', (68, 77))	('rs843711', 'Var', (156, 164))	('rs6713088', 'Mutation', 'rs6713088', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('GI cancer', 'Phenotype', 'HP:0007378', (68, 77))	('rs6713088', 'Var', (145, 154))
269864	31070019	The results with adjusted for age and gender showed that the risk of GI cancer would significantly increasing with rs11125529 under the recessive model (adjusted OR = 2.05, 95% CI: 1.00-4.23, p = 0.038), rs843711 under the recessive model (adjusted OR = 1.37, 95% CI: 1.04-.82, p = 0.026), and rs11896604 under the log-additive model (adjusted OR = 1.23, 95% CI: 1.01-1.51, p = 0.042).	('rs843711', 'Mutation', 'rs843711', (204, 212))	('rs11125529', 'Var', (115, 125))	('increasing', 'PosReg', (99, 109))	('rs11896604', 'Mutation', 'rs11896604', (294, 304))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('GI cancer', 'Disease', (69, 78))	('rs11896604', 'Var', (294, 304))	('rs11125529', 'Mutation', 'rs11125529', (115, 125))	('GI cancer', 'Disease', 'MESH:D009369', (69, 78))	('rs843711', 'Var', (204, 212))	('GI cancer', 'Phenotype', 'HP:0007378', (69, 78))
269866	31070019	One block of ACYP2 SNPs (Figure 1) comprising rs1682111, rs843752, rs10439478, rs843645, rs11125529, rs12615793, rs843711, and rs11896604 was found in studies by haplotype analysis.	('rs10439478', 'Var', (67, 77))	('rs12615793', 'Var', (101, 111))	('rs843711', 'Mutation', 'rs843711', (113, 121))	('rs843752', 'Mutation', 'rs843752', (57, 65))	('rs843752', 'Var', (57, 65))	('rs11125529', 'Mutation', 'rs11125529', (89, 99))	('rs1682111', 'Mutation', 'rs1682111', (46, 55))	('rs1682111', 'Var', (46, 55))	('ACYP2', 'Gene', '98', (13, 18))	('rs12615793', 'Mutation', 'rs12615793', (101, 111))	('rs10439478', 'Mutation', 'rs10439478', (67, 77))	('rs11896604', 'Mutation', 'rs11896604', (127, 137))	('rs843645', 'Mutation', 'rs843645', (79, 87))	('rs843645', 'Var', (79, 87))	('rs11125529', 'Var', (89, 99))	('rs11896604', 'Var', (127, 137))	('ACYP2', 'Gene', (13, 18))	('rs843711', 'Var', (113, 121))
269867	31070019	The results of the association between the ACYP2 haplotype and the risk of GI cancer are listed in Table 3.	('ACYP2', 'Gene', '98', (43, 48))	('GI cancer', 'Disease', (75, 84))	('haplotype', 'Var', (49, 58))	('GI cancer', 'Disease', 'MESH:D009369', (75, 84))	('ACYP2', 'Gene', (43, 48))	('GI cancer', 'Phenotype', 'HP:0007378', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('association', 'Interaction', (19, 30))
269870	31070019	We found that five SNPs (rs6713088, rs1682111, rs843752, rs843645, and rs843711) of ACYP2 were significantly expressed in the relevant tissues of the digestive (Table 4), hinted that these SNPs may affect the expression of ACYP2 in GI cancer.	('expression', 'MPA', (209, 219))	('rs843752', 'Mutation', 'rs843752', (47, 55))	('rs843645', 'Var', (57, 65))	('ACYP2', 'Gene', '98', (223, 228))	('rs6713088', 'Var', (25, 34))	('rs843711', 'Mutation', 'rs843711', (71, 79))	('rs1682111', 'Var', (36, 45))	('GI cancer', 'Disease', (232, 241))	('ACYP2', 'Gene', (84, 89))	('rs6713088', 'Mutation', 'rs6713088', (25, 34))	('rs1682111', 'Mutation', 'rs1682111', (36, 45))	('ACYP2', 'Gene', '98', (84, 89))	('rs843711', 'Var', (71, 79))	('rs843645', 'Mutation', 'rs843645', (57, 65))	('GI cancer', 'Disease', 'MESH:D009369', (232, 241))	('GI cancer', 'Phenotype', 'HP:0007378', (232, 241))	('affect', 'Reg', (198, 204))	('rs843752', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('ACYP2', 'Gene', (223, 228))
269871	31070019	Especially the two SNPs (rs6713088 and rs843711) correlated with GI cancer risk as Figure 2 displayed, rs6713088 loci were significantly expressed in esophagus-mucosa (p = 3.10 x 10-30), colon-transverse (p = 1.10 x 10-17), stomach (p = 3.80 x 10-7), and whole blood (p = 5.90 x 10-8); rs843711 was significantly expressed in esophagus-mucosa (p = 2.10 x 10-7) and esophagus-muscularis (p = 5.20 x 10-5).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs843711', 'Mutation', 'rs843711', (39, 47))	('GI cancer', 'Disease', (65, 74))	('rs6713088', 'Var', (103, 112))	('rs6713088', 'Mutation', 'rs6713088', (103, 112))	('GI cancer', 'Disease', 'MESH:D009369', (65, 74))	('rs6713088', 'Mutation', 'rs6713088', (25, 34))	('rs843711', 'Var', (286, 294))	('rs843711', 'Mutation', 'rs843711', (286, 294))	('GI cancer', 'Phenotype', 'HP:0007378', (65, 74))
269873	31070019	We identified that rs6713088, rs843711, and rs11896604 in the ACYP2 gene associated with an increased risk of GI cancer, suggesting an association between genetic polymorphism of ACYP2 and the susceptibility of GI cancer.	('GI cancer', 'Disease', (211, 220))	('GI cancer', 'Phenotype', 'HP:0007378', (110, 119))	('rs11896604', 'Mutation', 'rs11896604', (44, 54))	('associated', 'Reg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ACYP2', 'Gene', (62, 67))	('GI cancer', 'Disease', 'MESH:D009369', (211, 220))	('rs843711', 'Mutation', 'rs843711', (30, 38))	('GI cancer', 'Phenotype', 'HP:0007378', (211, 220))	('rs11896604', 'Var', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('ACYP2', 'Gene', '98', (62, 67))	('ACYP2', 'Gene', (179, 184))	('ACYP2', 'Gene', '98', (179, 184))	('rs6713088', 'Var', (19, 28))	('GI cancer', 'Disease', (110, 119))	('rs843711', 'Var', (30, 38))	('rs6713088', 'Mutation', 'rs6713088', (19, 28))	('GI cancer', 'Disease', 'MESH:D009369', (110, 119))
269875	31070019	In liver cancer (Chen et al., 2017), rs6713088 G allele increased the risk of liver cancer compared with the C allele carriers (OR = 1.27).	('liver cancer', 'Disease', (78, 90))	('liver cancer', 'Phenotype', 'HP:0002896', (3, 15))	('liver cancer', 'Disease', 'MESH:D006528', (3, 15))	('rs6713088 G', 'Var', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('liver cancer', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rs6713088', 'Mutation', 'rs6713088', (37, 46))	('liver cancer', 'Disease', 'MESH:D006528', (78, 90))	('liver cancer', 'Phenotype', 'HP:0002896', (78, 90))
269876	31070019	Meanwhile, rs6713088 G allele also promoted the risk of gastric cancer (OR = 1.30) (Li et al., 2017).	('gastric cancer', 'Disease', (56, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('rs6713088', 'Mutation', 'rs6713088', (11, 20))	('promoted', 'PosReg', (35, 43))	('rs6713088 G', 'Var', (11, 22))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
269877	31070019	In colorectal cancer, G allele is also a risk factor for colorectal cancer (Liu, Zhang, et al., 2017).	('colorectal cancer', 'Disease', (57, 74))	('risk factor', 'Reg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (57, 74))	('colorectal cancer', 'Disease', (3, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('G allele', 'Var', (22, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
269879	31070019	(2017) found that the mutation of rs843711 was associated with colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('rs843711', 'Var', (34, 42))	('rs843711', 'Mutation', 'rs843711', (34, 42))	('colorectal cancer', 'Disease', (63, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('associated', 'Reg', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
269880	31070019	Rs843711 risk allele "T" frequency in case and control had a significant difference and the variant increased the gastric cancer risk (Li et al., 2017).	('gastric cancer', 'Disease', (114, 128))	('increased', 'PosReg', (100, 109))	('Rs843711', 'Var', (0, 8))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('variant', 'Var', (92, 99))	('Rs843711', 'Mutation', 'Rs843711', (0, 8))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
269883	31070019	Therefore, the mutation of ACYP2 may be involved in the occurrence of tumorigenesis (Calamai et al., 2005).	('mutation', 'Var', (15, 23))	('ACYP2', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('ACYP2', 'Gene', '98', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('involved', 'Reg', (40, 48))
269886	31070019	Furthermore, results of the GTEx database revealed an eQTL of rs6713088 and rs843711 that affect the expression of ACYP2 gene.	('affect', 'Reg', (90, 96))	('ACYP2', 'Gene', (115, 120))	('rs6713088', 'Mutation', 'rs6713088', (62, 71))	('rs6713088', 'Var', (62, 71))	('ACYP2', 'Gene', '98', (115, 120))	('rs843711', 'Var', (76, 84))	('expression', 'MPA', (101, 111))	('rs843711', 'Mutation', 'rs843711', (76, 84))
269889	31070019	Our results show an association between ACYP2 gene polymorphism and GI cancer in Chinese Han population.	('polymorphism', 'Var', (51, 63))	('GI cancer', 'Disease', (68, 77))	('association', 'Interaction', (20, 31))	('GI cancer', 'Disease', 'MESH:D009369', (68, 77))	('ACYP2', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('GI cancer', 'Phenotype', 'HP:0007378', (68, 77))	('ACYP2', 'Gene', '98', (40, 45))
269950	29611027	In the univariable analysis (Table 2), independent prognostic factors associated with DFS were gender, pT3 stage, pN1-3, positive CRM and EMVI/N (nodal status).	('positive CRM', 'CPA', (121, 133))	('pT3', 'Gene', '7694', (103, 106))	('DFS', 'Disease', (86, 89))	('pT3', 'Gene', (103, 106))	('pN1-3', 'Var', (114, 119))
269983	29682174	A new transcriptome analysis performed with ESCC cell lineage TE-1 showed that the modulation of FOXM1 expression resulted in PIK3R3 expression changes, whereas chromatin immunoprecipitation assay revealed that FOXM1 was capable of binding onto PIK3R3 promoter, thus demonstrating that PIK3R3 is a new FOXM1 target.	('FOXM1', 'Gene', '2305', (97, 102))	('PIK3R3', 'Gene', '8503', (126, 132))	('changes', 'Reg', (144, 151))	('PIK3R3', 'Gene', (286, 292))	('expression', 'Species', '29278', (133, 143))	('PIK3R3', 'Gene', '8503', (245, 251))	('FOXM1', 'Gene', '2305', (302, 307))	('PIK3R3', 'Gene', (126, 132))	('FOXM1', 'Gene', (211, 216))	('modulation', 'Var', (83, 93))	('binding', 'Interaction', (232, 239))	('FOXM1', 'Gene', (97, 102))	('PIK3R3', 'Gene', (245, 251))	('TE-1', 'CellLine', 'CVCL:1759', (62, 66))	('FOXM1', 'Gene', (302, 307))	('expression', 'MPA', (133, 143))	('expression', 'Species', '29278', (103, 113))	('FOXM1', 'Gene', '2305', (211, 216))	('PIK3R3', 'Gene', '8503', (286, 292))
269996	29682174	Furthermore, modulation of FOXM1 expression in the ESCC cell line, TE-1, resulted in activation of the PI3K/AKT pathway through PIK3R3 overexpression.	('FOXM1', 'Gene', '2305', (27, 32))	('AKT', 'Gene', '207', (108, 111))	('modulation', 'Var', (13, 23))	('AKT', 'Gene', (108, 111))	('expression', 'Species', '29278', (33, 43))	('activation', 'PosReg', (85, 95))	('TE-1', 'CellLine', 'CVCL:1759', (67, 71))	('expression', 'Species', '29278', (139, 149))	('PIK3R3', 'Gene', '8503', (128, 134))	('PIK3R3', 'Gene', (128, 134))	('FOXM1', 'Gene', (27, 32))	('overexpression', 'PosReg', (135, 149))
270029	29682174	FOXM1 overexpression in TE-1 cells was found capable of increasing PIK3R3 expression and the levels of phospho-AKT, the key effector of the PI3K/AKT pathway activity (Figure 6A).	('AKT', 'Gene', '207', (111, 114))	('expression', 'MPA', (74, 84))	('PIK3R3', 'Gene', (67, 73))	('AKT', 'Gene', '207', (145, 148))	('AKT', 'Gene', (145, 148))	('overexpression', 'Var', (6, 20))	('TE-1', 'CellLine', 'CVCL:1759', (24, 28))	('expression', 'Species', '29278', (10, 20))	('AKT', 'Gene', (111, 114))	('increasing', 'PosReg', (56, 66))	('FOXM1', 'Gene', '2305', (0, 5))	('FOXM1', 'Gene', (0, 5))	('PIK3R3', 'Gene', '8503', (67, 73))	('expression', 'Species', '29278', (74, 84))
270031	29682174	Consistently, PIK3R3 silencing in TE-1 cells reduced PIK3R3 and, slightly, phospho-AKT levels.	('AKT', 'Gene', '207', (83, 86))	('PIK3R3', 'Gene', (53, 59))	('reduced', 'NegReg', (45, 52))	('TE-1', 'CellLine', 'CVCL:1759', (34, 38))	('AKT', 'Gene', (83, 86))	('PIK3R3', 'Gene', '8503', (14, 20))	('PIK3R3', 'Gene', '8503', (53, 59))	('PIK3R3', 'Gene', (14, 20))	('silencing', 'Var', (21, 30))
270032	29682174	Moreover, PIK3R3 silencing in TE-1 cells followed by induced FOXM1 overexpression was capable of partially restoring both PIK3R3 and phospho-AKT levels, similarly to SCRsi controls (Figure 6C).	('restoring', 'PosReg', (107, 116))	('PIK3R3', 'Gene', (122, 128))	('TE-1', 'CellLine', 'CVCL:1759', (30, 34))	('overexpression', 'PosReg', (67, 81))	('AKT', 'Gene', (141, 144))	('FOXM1', 'Gene', (61, 66))	('PIK3R3', 'Gene', '8503', (10, 16))	('FOXM1', 'Gene', '2305', (61, 66))	('AKT', 'Gene', '207', (141, 144))	('PIK3R3', 'Gene', (10, 16))	('silencing', 'Var', (17, 26))	('expression', 'Species', '29278', (71, 81))	('PIK3R3', 'Gene', '8503', (122, 128))
270034	29682174	Survival analysis, with respect to gene expression, after age and tumor stage adjustments, revealed that high FOXM1 expression was associated with a poor ESCC patients prognosis, presenting a 2.73-fold increase of the risk of death (p = 0.03; 95% CI 1.11-5.93).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('expression', 'MPA', (116, 126))	('high', 'Var', (105, 109))	('FOXM1', 'Gene', '2305', (110, 115))	('expression', 'Species', '29278', (40, 50))	('FOXM1', 'Gene', (110, 115))	('tumor', 'Disease', (66, 71))	('ESCC patients', 'Disease', (154, 167))	('death', 'Disease', (226, 231))	('death', 'Disease', 'MESH:D003643', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('expression', 'Species', '29278', (116, 126))	('patients', 'Species', '9606', (159, 167))
270035	29682174	In a similar way, PIK3R3 expression was also related to worse prognosis, with a 2.69-fold increase of the risk of death (p = 0.026, 95% CI 1.20-7.27).	('expression', 'Species', '29278', (25, 35))	('PIK3R3', 'Gene', '8503', (18, 24))	('PIK3R3', 'Gene', (18, 24))	('death', 'Disease', 'MESH:D003643', (114, 119))	('expression', 'Var', (25, 35))	('death', 'Disease', (114, 119))
270036	29682174	Finally, the Cox's Regression Models including both genes showed that survival was associated only to PIK3R3 expression (p = 0.031, 95% CI 1.09-6.79), patients with high PIK3R3 expression showed a 2-fold lower survival time than those with low PIK3R3 expression (9.13 months versus 18.5 months) (Figure 7).	('PIK3R3', 'Gene', (170, 176))	('expression', 'Species', '29278', (251, 261))	('Cox', 'Gene', (13, 16))	('PIK3R3', 'Gene', '8503', (102, 108))	('PIK3R3', 'Gene', (102, 108))	('high', 'Var', (165, 169))	('patients', 'Species', '9606', (151, 159))	('PIK3R3', 'Gene', '8503', (244, 250))	('survival time', 'CPA', (210, 223))	('expression', 'Species', '29278', (177, 187))	('lower', 'NegReg', (204, 209))	('PIK3R3', 'Gene', (244, 250))	('PIK3R3', 'Gene', '8503', (170, 176))	('expression', 'Species', '29278', (109, 119))	('Cox', 'Gene', '1351', (13, 16))
270037	29682174	On the other hand, expression levels of PLK1 (p = 0.99), ETV5 (p = 0.83), CDK1 (p = 0.36), MMP9 (p = 0.92), MMP12 (p = 0.39), and CCNB1 (p = 0.11) were found to be unrelated to outcome.	('PLK1', 'Gene', (40, 44))	('CDK1', 'Gene', (74, 78))	('CCNB1', 'Gene', (130, 135))	('MMP9', 'Var', (91, 95))	('expression', 'Species', '29278', (19, 29))	('MMP12', 'Var', (108, 113))
270045	29682174	Furthermore, increased FOXM1 expression through deregulation of miR204 has been shown to contribute to the epithelial-mesenchymal transition of ESCC cells and to be associated with ESCC invasion.	('FOXM1', 'Gene', '2305', (23, 28))	('associated', 'Reg', (165, 175))	('miR204', 'Gene', (64, 70))	('FOXM1', 'Gene', (23, 28))	('contribute', 'Reg', (89, 99))	('deregulation', 'Var', (48, 60))	('ESCC', 'Disease', (181, 185))	('expression', 'Species', '29278', (29, 39))	('epithelial-mesenchymal transition', 'CPA', (107, 140))	('expression', 'MPA', (29, 39))	('increased', 'PosReg', (13, 22))
270050	29682174	One of these DEG, a novel potential FOXM1 target, PIK3R3 was underexpressed following FOXM1 abrogation in TE-1 cells, while PIK3R3 was found to be overexpressed and positively correlated with FOXM1 expression in ESCC samples.	('PIK3R3', 'Gene', (50, 56))	('TE-1', 'CellLine', 'CVCL:1759', (106, 110))	('FOXM1', 'Gene', (86, 91))	('abrogation', 'Var', (92, 102))	('underexpressed', 'NegReg', (61, 75))	('ESCC', 'Disease', (212, 216))	('FOXM1', 'Gene', '2305', (86, 91))	('FOXM1', 'Gene', (36, 41))	('expression', 'Species', '29278', (198, 208))	('FOXM1', 'Gene', '2305', (36, 41))	('FOXM1', 'Gene', (192, 197))	('PIK3R3', 'Gene', '8503', (124, 130))	('expression', 'MPA', (198, 208))	('FOXM1', 'Gene', '2305', (192, 197))	('PIK3R3', 'Gene', '8503', (50, 56))	('overexpressed', 'PosReg', (147, 160))	('PIK3R3', 'Gene', (124, 130))	('correlated', 'Reg', (176, 186))
270057	29682174	PIK3R3 overexpression has been shown to play a role in colon, liver, and pancreatic tumors by promoting proliferation, migration and invasion across the epithelial-mesenchymal transition.	('expression', 'Species', '29278', (11, 21))	('overexpression', 'Var', (7, 21))	('pancreatic tumors', 'Disease', 'MESH:D010190', (73, 90))	('proliferation', 'CPA', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('promoting', 'PosReg', (94, 103))	('pancreatic tumors', 'Disease', (73, 90))	('PIK3R3', 'Gene', '8503', (0, 6))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (73, 90))	('colon', 'Disease', (55, 60))	('PIK3R3', 'Gene', (0, 6))	('liver', 'Disease', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('migration', 'CPA', (119, 128))
270058	29682174	Induced FOXM1 overexpression in TE-1 cells led to increased levels of both PIK3R3 and phospho-AKT, while increased phospho-AKT levels were also detected with PIK3R3 overexpression.	('AKT', 'Gene', '207', (94, 97))	('PIK3R3', 'Gene', '8503', (158, 164))	('PIK3R3', 'Gene', (75, 81))	('overexpression', 'Var', (14, 28))	('FOXM1', 'Gene', (8, 13))	('AKT', 'Gene', (94, 97))	('increased', 'PosReg', (50, 59))	('PIK3R3', 'Gene', (158, 164))	('expression', 'Species', '29278', (18, 28))	('expression', 'Species', '29278', (169, 179))	('AKT', 'Gene', '207', (123, 126))	('FOXM1', 'Gene', '2305', (8, 13))	('levels', 'MPA', (60, 66))	('TE-1', 'CellLine', 'CVCL:1759', (32, 36))	('AKT', 'Gene', (123, 126))	('PIK3R3', 'Gene', '8503', (75, 81))
270061	29682174	PI3K signaling is activated in human cancers by several different mechanisms, including mutations or amplification of genes that encode key components of the PI3K pathway, like PIK3CA and AKT1, or loss of PTEN.	('genes', 'Gene', (118, 123))	('AKT1', 'Gene', (188, 192))	('PTEN', 'Gene', (205, 209))	('PIK3CA', 'Gene', '5290', (177, 183))	('amplification', 'Var', (101, 114))	('PTEN', 'Gene', '5728', (205, 209))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('mutations', 'Var', (88, 97))	('cancers', 'Disease', (37, 44))	('human', 'Species', '9606', (31, 36))	('loss', 'NegReg', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('AKT1', 'Gene', '207', (188, 192))	('PIK3CA', 'Gene', (177, 183))	('activated', 'PosReg', (18, 27))
270062	29682174	PIK3CA and PTEN non-concurrent mutations have been shown to occur in 13% and 9% of ESCC, respectively, while PIK3CA amplification has not been observed in ESCC.	('PTEN', 'Gene', (11, 15))	('PIK3CA', 'Gene', (109, 115))	('mutations', 'Var', (31, 40))	('PTEN', 'Gene', '5728', (11, 15))	('PIK3CA', 'Gene', '5290', (109, 115))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('ESCC', 'Disease', (83, 87))	('occur', 'Reg', (60, 65))
270063	29682174	Other studies have reported the presence of PIK3CA mutations in 2 -17% of the ESCC samples.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('ESCC', 'Disease', (78, 82))	('PIK3CA', 'Gene', '5290', (44, 50))	('presence', 'Reg', (32, 40))
270067	29682174	FOXO3 is a transcriptional antagonist of FOXM1, acting in three different ways: (i) displacing FOXM1 from the FKHDs of target genes, (ii) transcriptionally silencing FOXM1 and (iii) recruiting chromatin-remodeling proteins, which promote chromatin condensation and limit the access of transcription factors, such as FOXM1.	('FOXM1', 'Gene', (316, 321))	('FOXM1', 'Gene', (166, 171))	('FOXM1', 'Gene', (41, 46))	('silencing', 'NegReg', (156, 165))	('FOXM1', 'Gene', '2305', (316, 321))	('FOXM1', 'Gene', '2305', (166, 171))	('FKHD', 'Disease', (110, 114))	('chromatin condensation', 'MPA', (238, 260))	('recruiting', 'PosReg', (182, 192))	('promote', 'PosReg', (230, 237))	('limit', 'NegReg', (265, 270))	('transcriptionally', 'Var', (138, 155))	('access', 'MPA', (275, 281))	('FOXM1', 'Gene', (95, 100))	('displacing', 'NegReg', (84, 94))	('FOXM1', 'Gene', '2305', (95, 100))	('FKHD', 'Disease', 'None', (110, 114))	('FOXM1', 'Gene', '2305', (41, 46))
270070	29682174	The high expression of FOXM1 and PIK3R3 was associated with a poor overall survival rate, although multivariate analysis showed that PIK3R3 expression was classified an independent prognostic variable.	('PIK3R3', 'Gene', (33, 39))	('expression', 'Species', '29278', (140, 150))	('PIK3R3', 'Gene', '8503', (133, 139))	('FOXM1', 'Gene', '2305', (23, 28))	('FOXM1', 'Gene', (23, 28))	('PIK3R3', 'Gene', (133, 139))	('expression', 'Species', '29278', (9, 19))	('high', 'Var', (4, 8))	('overall', 'MPA', (67, 74))	('PIK3R3', 'Gene', '8503', (33, 39))	('poor', 'NegReg', (62, 66))
270071	29682174	This observation might indicate that previous results associating FOXM1 expression with a worse prognosis of ESCC patients may do so through the induction of PIK3R3.	('FOXM1', 'Gene', (66, 71))	('PIK3R3', 'Gene', '8503', (158, 164))	('ESCC', 'Disease', (109, 113))	('expression', 'Species', '29278', (72, 82))	('PIK3R3', 'Gene', (158, 164))	('expression', 'Var', (72, 82))	('FOXM1', 'Gene', '2305', (66, 71))	('patients', 'Species', '9606', (114, 122))
270096	29682174	Following PIK3R3 silencing, cells were transfected for FOXM1 overexpression, using a transfection with the empty vector as control, 6 hours after the second PIK3R3 silencing transfection.	('FOXM1', 'Gene', (55, 60))	('FOXM1', 'Gene', '2305', (55, 60))	('overexpression', 'PosReg', (61, 75))	('PIK3R3', 'Gene', '8503', (157, 163))	('expression', 'Species', '29278', (65, 75))	('PIK3R3', 'Gene', (157, 163))	('PIK3R3', 'Gene', '8503', (10, 16))	('PIK3R3', 'Gene', (10, 16))	('silencing', 'Var', (17, 26))
270097	29682174	DNA microarray analysis was carried out with the ESCC-derived cell line, TE-1, with and without FOXM1 silencing, each with two replicates.	('FOXM1', 'Gene', (96, 101))	('silencing', 'Var', (102, 111))	('FOXM1', 'Gene', '2305', (96, 101))	('TE-1', 'CellLine', 'CVCL:1759', (73, 77))
270098	29682174	A 1.5-fold, change-in-expression cutoff was used for identifying differentially expressed genes following FOXM1 silencing.	('FOXM1', 'Gene', (106, 111))	('FOXM1', 'Gene', '2305', (106, 111))	('silencing', 'Var', (112, 121))	('expression', 'Species', '29278', (22, 32))
270158	25852538	The 155 and 140-kDa proteins recognized by anti-155/140 antibodies are TIF-1gamma and TIF-1alpha, respectively.	('TIF-1alpha', 'Gene', '8805', (86, 96))	('anti-155/140', 'Var', (43, 55))	('TIF-1gamma', 'Gene', (71, 81))	('TIF-1alpha', 'Gene', (86, 96))	('TIF-1gamma', 'Gene', '51592', (71, 81))
270159	25852538	Anti-155/140 antibodies react with both TIF-1alpha and TIF-1gamma or only TIF-1gamma but not with TIF-1alpha alone.	('TIF-1gamma', 'Gene', '51592', (74, 84))	('TIF-1alpha', 'Gene', (98, 108))	('react', 'Reg', (24, 29))	('TIF-1alpha', 'Gene', (40, 50))	('TIF-1alpha', 'Gene', '8805', (98, 108))	('TIF-1alpha', 'Gene', '8805', (40, 50))	('TIF-1gamma', 'Gene', (74, 84))	('TIF-1gamma', 'Gene', '51592', (55, 65))	('Anti-155/140', 'Var', (0, 12))	('TIF-1gamma', 'Gene', (55, 65))
270162	25852538	However, there are few reports that evaluate the cutaneous features of DM associated with the presence of anti-TIF-1 antibodies.	('TIF-1', 'Gene', (111, 116))	('TIF-1', 'Gene', '8805', (111, 116))	('antibodies', 'Var', (117, 127))	('DM', 'Disease', 'MESH:D009223', (71, 73))	('associated', 'Reg', (74, 84))
270166	25852538	In another report, heliotrope rash, Gottron's sign and flagellate erythema were said to be significantly more frequent in anti-TIF-1 antibody-positive DM patients compared with anti-TIF-1 antibody-negative DM patients.	('TIF-1', 'Gene', (182, 187))	("Gottron's sign", 'Phenotype', 'HP:0025508', (36, 50))	('erythema', 'Phenotype', 'HP:0010783', (66, 74))	('flagellate erythema', 'Disease', (55, 74))	('heliotrope rash', 'Phenotype', 'HP:0040324', (19, 34))	('DM', 'Disease', 'MESH:D009223', (206, 208))	('patients', 'Species', '9606', (154, 162))	('heliotrope rash', 'Disease', 'MESH:D005076', (19, 34))	('heliotrope rash', 'Disease', (19, 34))	('DM', 'Disease', 'MESH:D009223', (151, 153))	('antibody-positive', 'Var', (133, 150))	('patients', 'Species', '9606', (209, 217))	('TIF-1', 'Gene', '8805', (182, 187))	("Gottron's sign", 'Disease', (36, 50))	('TIF-1', 'Gene', '8805', (127, 132))	('flagellate erythema', 'Disease', 'MESH:D004890', (55, 74))	('rash', 'Phenotype', 'HP:0000988', (30, 34))	('TIF-1', 'Gene', (127, 132))
270178	19826048	Polymorphisms of several genes have been associated with susceptibility to esophageal cancer in various populations, but these have not been studied in Iran.	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Polymorphisms', 'Var', (0, 13))	('esophageal cancer', 'Disease', (75, 92))
270180	19826048	The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC under a recessive model (OR = 0.41, 95%, CI = 0.19 to 0.49; P = 4x10-4).	('histidine allele at codon', 'Var', (4, 29))	('ADH1B', 'Gene', (36, 41))	('decreased', 'NegReg', (83, 92))	('ADH1B', 'Gene', '125', (36, 41))	('histidine', 'Chemical', 'MESH:D006639', (4, 13))	('ESCC', 'Disease', (101, 105))
270181	19826048	For four additional variants, an association was present in the Turkmen subgroup, but the statistical significance of these was less compelling than for ADH1B.	('ADH1B', 'Gene', '125', (153, 158))	('ADH1B', 'Gene', (153, 158))	('variants', 'Var', (20, 28))
270182	19826048	The G allele of the c.870A>G variant of CCND1 gene was associated with a 1.5-fold increased risk of ESCC under the recessive model (OR = 1.50, 95% CI = 1.14 to 2.16, P = 0.02) and the A allele of the rs1625895 variant of TP53 gene was associated with a 1.5-fold increased risk of ESCC under a dominant model (OR = 1.54, 95% CI = 1.21 to 4.07, P = 0.005).	('ESCC', 'Disease', (280, 284))	('rs1625895', 'Mutation', 'rs1625895', (200, 209))	('TP53', 'Gene', '7157', (221, 225))	('CCND1', 'Gene', (40, 45))	('rs1625895', 'Var', (200, 209))	('ESCC', 'Disease', (100, 104))	('TP53', 'Gene', (221, 225))	('c.870A>G', 'Var', (20, 28))	('CCND1', 'Gene', '595', (40, 45))	('c.870A>G', 'Mutation', 'rs9344', (20, 28))
270183	19826048	The C allele of the rs886205 variant of ALDH2 was associated with a decreased risk of ESCC under a recessive model (OR = 0.58, 95% CI = 0.34 to 0.87, P = 0.02) and the A allele of the rs7087131 variant of MGMT was associated with a decreased risk of ESCC under the recessive model (OR = 0.26, 95% CI = 0.05 to 0.49, P=0.01).	('decreased', 'NegReg', (68, 77))	('ALDH2', 'Gene', '217', (40, 45))	('MGMT', 'Gene', '4255', (205, 209))	('ALDH2', 'Gene', (40, 45))	('MGMT', 'Gene', (205, 209))	('ESCC', 'Disease', (250, 254))	('rs886205', 'Var', (20, 28))	('rs7087131', 'Mutation', 'rs7087131', (184, 193))	('rs7087131', 'Var', (184, 193))	('decreased', 'NegReg', (232, 241))	('ESCC', 'Disease', (86, 90))	('rs886205', 'Mutation', 'rs886205', (20, 28))
270192	19826048	Protein-truncating mutations in BRCA2 are associated with an increased risk of esophageal cancer among Turkmen.	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (42, 52))	('BRCA2', 'Gene', (32, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('BRCA2', 'Gene', '675', (32, 37))	('Protein-truncating mutations', 'Var', (0, 28))
270193	19826048	However, because only 8% of the cases in the region carry a deleterious BRCA2 mutation it is likely that other genes are involved.	('BRCA2', 'Gene', (72, 77))	('BRCA2', 'Gene', '675', (72, 77))	('mutation', 'Var', (78, 86))
270204	19826048	The role of these genes and their variants in esophageal cancer has been reviewed.	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('variants', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
270205	19826048	These variants include Asp312Asn (rs1799793) and Lys751Gln (rs13181) from ERCC2 gene, Arg399Gln (rs25487) from XRCC1 gene; Ser326Cys (rs1052133) from hOGG1 gene; Leu74Phe (rs12917) and Lys178Arg (rs2308327) from MGMT gene; c.870A>G (rs9344) from CCND1 gene; Ala148Thr (rs3731249) from CDKN2A gene; Arg72Pro (rs1042522) from TP53 gene; Arg293Gln (rs353163) from TMPRSS11A (ECRG1) gene; Ile462Val (rs1048943) from CYP1A1 gene; c.-1019C>T (rs2031920) from CYP2E1; Ile105Val (rs1695) from GSTP1 gene; Tyr94Tyr (rs1041983), Ile114Thr (rs1801280), Leu161Leu (rs1799929), Arg197Gln (rs1799930) and Gly286Glu (rs1799931) from NAT2 gene; Arg48His (rs1229984) from ADH1B gene; Glu487Lys (rs671) from ALDH2 gene; and Ala222Val (rs1801133) and Glu429Ala (rs1801131) from MTHFR gene.	('rs1229984', 'Var', (639, 648))	('MTHFR', 'Gene', '4524', (759, 764))	('Arg48His', 'Var', (629, 637))	('ALDH2', 'Gene', '217', (690, 695))	('Ile105Val', 'Mutation', 'rs1695', (461, 470))	('TP53', 'Gene', (324, 328))	('c.-1019C>T', 'Mutation', 'rs2031920', (425, 435))	('rs1799931', 'Var', (602, 611))	('XRCC1', 'Gene', '7515', (111, 116))	('TMPRSS11A', 'Gene', '339967', (361, 370))	('CCND1', 'Gene', '595', (246, 251))	('MGMT', 'Gene', '4255', (212, 216))	('Glu487Lys', 'Var', (667, 676))	('rs1799929', 'Var', (553, 562))	('c.870A>G', 'Mutation', 'rs9344', (223, 231))	('CYP1A1', 'Gene', '1543', (412, 418))	('Ile114Thr', 'SUBSTITUTION', 'None', (519, 528))	('rs1801133', 'Var', (717, 726))	('CCND1', 'Gene', (246, 251))	('rs9344', 'Mutation', 'rs9344', (233, 239))	('Arg197Gln', 'Var', (565, 574))	('rs671', 'Mutation', 'rs671', (678, 683))	('CYP2E1', 'Gene', (453, 459))	('Ile114Thr', 'Var', (519, 528))	('Asp312Asn', 'Mutation', 'rs1799793', (23, 32))	('hOGG1', 'Gene', '4968', (150, 155))	('Lys178Arg', 'Mutation', 'rs2308327', (185, 194))	('rs1801280', 'Var', (530, 539))	('rs1041983', 'Mutation', 'rs1041983', (507, 516))	('rs1041983', 'Var', (507, 516))	('Glu429Ala (rs1801131', 'Var', (732, 752))	('hOGG1', 'Gene', (150, 155))	('ERCC2', 'Gene', '2068', (74, 79))	('Ile462Val', 'Mutation', 'rs1048943', (385, 394))	('Ala222Val', 'Mutation', 'rs1801133', (706, 715))	('Gly286Glu', 'SUBSTITUTION', 'None', (591, 600))	('rs3731249', 'Mutation', 'rs3731249', (269, 278))	('TP53', 'Gene', '7157', (324, 328))	('CDKN2A', 'Gene', (285, 291))	('NAT2', 'Gene', '10', (618, 622))	('Glu429Ala', 'Mutation', 'rs1801131', (732, 741))	('Arg72Pro', 'Mutation', 'rs1042522', (298, 306))	('rs13181', 'Mutation', 'rs13181', (60, 67))	('MGMT', 'Gene', (212, 216))	('rs353163', 'Mutation', 'rs353163', (346, 354))	('CDKN2A', 'Gene', '1029', (285, 291))	('ECRG1', 'Gene', (372, 377))	('rs1801131', 'Mutation', 'rs1801131', (743, 752))	('rs1801133', 'Mutation', 'rs1801133', (717, 726))	('rs1801280', 'Mutation', 'rs1801280', (530, 539))	('Leu74Phe', 'Mutation', 'rs12917', (162, 170))	('rs2308327', 'Mutation', 'rs2308327', (196, 205))	('Arg197Gln', 'SUBSTITUTION', 'None', (565, 574))	('CYP2E1', 'Gene', '1571', (453, 459))	('rs1229984', 'Mutation', 'rs1229984', (639, 648))	('rs1695', 'Mutation', 'rs1695', (472, 478))	('Ser326Cys', 'Mutation', 'rs1052133', (123, 132))	('ADH1B', 'Gene', '125', (655, 660))	('rs1052133', 'Mutation', 'rs1052133', (134, 143))	('rs1799931', 'Mutation', 'rs1799931', (602, 611))	('TMPRSS11A', 'Gene', (361, 370))	('rs1042522', 'Mutation', 'rs1042522', (308, 317))	('ADH1B', 'Gene', (655, 660))	('Lys751Gln', 'Mutation', 'rs13181', (49, 58))	('NAT2', 'Gene', (618, 622))	('rs1801131', 'Var', (743, 752))	('rs25487', 'Mutation', 'rs25487', (97, 104))	('Glu487Lys', 'SUBSTITUTION', 'None', (667, 676))	('Gly286Glu', 'Var', (591, 600))	('rs1799930', 'Var', (576, 585))	('Arg48His', 'SUBSTITUTION', 'None', (629, 637))	('CYP1A1', 'Gene', (412, 418))	('Ala148Thr', 'Mutation', 'rs3731249', (258, 267))	('rs1799793', 'Mutation', 'rs1799793', (34, 43))	('Arg399Gln', 'Mutation', 'rs25487', (86, 95))	('MTHFR', 'Gene', (759, 764))	('GSTP1', 'Gene', '2950', (485, 490))	('rs1799929', 'Mutation', 'rs1799929', (553, 562))	('rs12917', 'Mutation', 'rs12917', (172, 179))	('rs1799930', 'Mutation', 'rs1799930', (576, 585))	('ECRG1', 'Gene', '339967', (372, 377))	('GSTP1', 'Gene', (485, 490))	('rs2031920', 'Mutation', 'rs2031920', (437, 446))	('ALDH2', 'Gene', (690, 695))	('XRCC1', 'Gene', (111, 116))	('ERCC2', 'Gene', (74, 79))	('rs1048943', 'Mutation', 'rs1048943', (396, 405))	('Arg293Gln', 'Mutation', 'rs353163', (335, 344))
270207	19826048	Variants Ile114Thr and Leu161Leu constitute allele M1; variants Arg197Gln and Tyr94Tyr constitute allele M2; and variant Gly286Glu is named allele M3.	('Arg197Gln', 'SUBSTITUTION', 'None', (64, 73))	('Tyr94Tyr', 'Var', (78, 86))	('Arg197Gln', 'Var', (64, 73))	('Gly286Glu', 'SUBSTITUTION', 'None', (121, 130))	('Ile114Thr', 'SUBSTITUTION', 'None', (9, 18))	('Ile114Thr', 'Var', (9, 18))	('Gly286Glu', 'Var', (121, 130))	('Leu161Leu', 'Var', (23, 32))
270211	19826048	The results of the 17 dysfunctional variants and three slow metabolizing alleles of NAT2 gene in the primary set of 451 samples are shown in table 3.	('NAT2', 'Gene', (84, 88))	('NAT2', 'Gene', '10', (84, 88))	('variants', 'Var', (36, 44))
270212	19826048	The frequencies of the minor alleles of all variants except one (ALDH2 Glu487Lys) were greater than 1%.	('ALDH2', 'Gene', '217', (65, 70))	('Glu487Lys', 'Var', (71, 80))	('ALDH2', 'Gene', (65, 70))	('Glu487Lys', 'SUBSTITUTION', 'None', (71, 80))
270213	19826048	Two functional variants showed associations with ESCC in the primary sample set with p-values less than 0.05 (the Arg48His variant from ADH1B gene and c.870A>G from CCND1).	('CCND1', 'Gene', '595', (165, 170))	('Arg48His', 'SUBSTITUTION', 'None', (114, 122))	('associations', 'Reg', (31, 43))	('ADH1B', 'Gene', (136, 141))	('c.870A>G', 'Var', (151, 159))	('Arg48His', 'Var', (114, 122))	('ADH1B', 'Gene', '125', (136, 141))	('CCND1', 'Gene', (165, 170))	('ESCC', 'Disease', (49, 53))	('c.870A>G', 'Mutation', 'rs9344', (151, 159))
270214	19826048	The strongest association was observed with the His allele of the Arg48His variant of ADH1B gene.	('Arg48His', 'SUBSTITUTION', 'None', (66, 74))	('ADH1B', 'Gene', '125', (86, 91))	('His', 'Chemical', 'MESH:D006639', (48, 51))	('Arg48His', 'Var', (66, 74))	('ADH1B', 'Gene', (86, 91))	('His', 'Chemical', 'MESH:D006639', (71, 74))
270216	19826048	The G allele of the c.870A>G variant of CCND1 gene was associated with an increased risk of ESCC under both additive and recessive models.	('ESCC', 'Disease', (92, 96))	('CCND1', 'Gene', (40, 45))	('c.870A>G', 'Var', (20, 28))	('CCND1', 'Gene', '595', (40, 45))	('c.870A>G', 'Mutation', 'rs9344', (20, 28))
270217	19826048	Three tagSNPs from ALDH2 (rs886205), MGMT (rs7087131) and TP53 (rs1625895) genes were associated with increased risks of ESCC in Turkmen only [table 6].	('rs7087131', 'Var', (43, 52))	('ALDH2', 'Gene', (19, 24))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('rs886205', 'Var', (26, 34))	('rs1625895', 'Mutation', 'rs1625895', (64, 73))	('MGMT', 'Gene', '4255', (37, 41))	('MGMT', 'Gene', (37, 41))	('ALDH2', 'Gene', '217', (19, 24))	('rs886205', 'Mutation', 'rs886205', (26, 34))	('ESCC', 'Disease', (121, 125))	('rs7087131', 'Mutation', 'rs7087131', (43, 52))	('rs1625895', 'Var', (64, 73))
270218	19826048	However, of the 22 variants tested, only two polymorphisms (ADH1B Arg48His and CCND1 c.870A>G) showed significant associations at the p = 0.05 level in the entire data set and for only one of these (ADH1B Arg48His) was the association compelling.	('CCND1', 'Gene', '595', (79, 84))	('Arg48His', 'SUBSTITUTION', 'None', (66, 74))	('Arg48His', 'SUBSTITUTION', 'None', (205, 213))	('associations', 'Interaction', (114, 126))	('ADH1B', 'Gene', (60, 65))	('Arg48His', 'Var', (66, 74))	('c.870A>G', 'Var', (85, 93))	('ADH1B', 'Gene', (199, 204))	('ADH1B', 'Gene', '125', (60, 65))	('Arg48His', 'Var', (205, 213))	('CCND1', 'Gene', (79, 84))	('c.870A>G', 'Mutation', 'rs9344', (85, 93))	('ADH1B', 'Gene', '125', (199, 204))
270219	19826048	The His allele of the Arg48His variant of ADH1B gene was associated with a decreased risk of ESCC in both Turkmen and non-Turkmen under a recessive model [table 5].	('His', 'Chemical', 'MESH:D006639', (4, 7))	('His', 'Chemical', 'MESH:D006639', (27, 30))	('Arg48His', 'SUBSTITUTION', 'None', (22, 30))	('ADH1B', 'Gene', (42, 47))	('ADH1B', 'Gene', '125', (42, 47))	('ESCC', 'Disease', (93, 97))	('Arg48His', 'Var', (22, 30))	('decreased', 'NegReg', (75, 84))
270225	19826048	When the arginine is replaced by histidine at this codon, the enzyme activity increases by 70-80 fold.	('activity', 'MPA', (69, 77))	('histidine', 'Chemical', 'MESH:D006639', (33, 42))	('arginine', 'Var', (9, 17))	('increases', 'PosReg', (78, 87))	('arginine', 'Chemical', 'MESH:D001120', (9, 17))
270227	19826048	In previous studies, the Arg allele of ADH1B has been consistently reported to increase the risk of ESCC by 1.6- to 4-fold among alcohol drinkers, compared to individuals with two His alleles.	('increase', 'PosReg', (79, 87))	('ADH1B', 'Gene', (39, 44))	('alcohol', 'Chemical', 'MESH:D000438', (129, 136))	('ADH1B', 'Gene', '125', (39, 44))	('ESCC', 'Disease', (100, 104))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (129, 145))	('His', 'Chemical', 'MESH:D006639', (180, 183))	('Arg', 'Chemical', 'MESH:D001120', (25, 28))	('Arg', 'Var', (25, 28))
270230	19826048	We confirmed that the presence of the Arg allele at codon 48 of the ADH1B protein increases the risk of ESCC by 2.4 fold in comparison to two His alleles (p = 4 x 10-4).	('Arg', 'Var', (38, 41))	('Arg', 'Chemical', 'MESH:D001120', (38, 41))	('ADH1B', 'Gene', (68, 73))	('ADH1B', 'Gene', '125', (68, 73))	('His', 'Chemical', 'MESH:D006639', (142, 145))	('ESCC', 'Disease', (104, 108))	('presence', 'Var', (22, 30))
270232	19826048	Our observation is contrary to other studies which report no association between Arg48His variant of the ADH1B gene and the risk of ESCC among non-drinkers [, and ].	('Arg48His', 'Var', (81, 89))	('ADH1B', 'Gene', (105, 110))	('ADH1B', 'Gene', '125', (105, 110))	('Arg48His', 'SUBSTITUTION', 'None', (81, 89))	('ESCC', 'Disease', (132, 136))
270233	19826048	Most studies which showed the association of Arg48His variant of ADH1B with ESCC in alcohol drinkers also report an association between the Glu487Lys variant of ALDH2 and esophageal cancer.	('alcohol', 'Chemical', 'MESH:D000438', (84, 91))	('Arg48His', 'SUBSTITUTION', 'None', (45, 53))	('Glu487Lys', 'SUBSTITUTION', 'None', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('ALDH2', 'Gene', (161, 166))	('Arg48His', 'Var', (45, 53))	('ADH1B', 'Gene', (65, 70))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (84, 100))	('ADH1B', 'Gene', '125', (65, 70))	('Glu487Lys', 'Var', (140, 149))	('ESCC', 'Disease', (76, 80))	('esophageal cancer', 'Disease', (171, 188))	('ALDH2', 'Gene', '217', (161, 166))
270234	19826048	The ALDH2 protein with lysine residue at codon 487 is catalytically inactive and can not metabolize acetaldehyde, a known carcinogen.	('ALDH2', 'Gene', '217', (4, 9))	('protein', 'Protein', (10, 17))	('acetaldehyde', 'Chemical', 'MESH:D000079', (100, 112))	('ALDH2', 'Gene', (4, 9))	('metabolize', 'MPA', (89, 99))	('lysine residue at codon 487', 'Var', (23, 50))	('lysine', 'Chemical', 'MESH:D008239', (23, 29))	('catalytically', 'MPA', (54, 67))
270239	19826048	Polycyclic aromatic hydrocarbons (PAH) have been shown to be esophageal carcinogens in both animal and human studies.	('PAH', 'Chemical', 'MESH:D011084', (34, 37))	('esophageal carcinogens', 'Disease', (61, 83))	('human', 'Species', '9606', (103, 108))	('Polycyclic', 'Var', (0, 10))	('esophageal carcinogens', 'Disease', 'MESH:D004941', (61, 83))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (0, 32))
270264	19826048	The second functional variant associated with ESCC in this study was c.870A>G of the Cyclin D1 (CCND1) gene.	('ESCC', 'Disease', (46, 50))	('CCND1', 'Gene', '595', (96, 101))	('Cyclin D1', 'Gene', '595', (85, 94))	('Cyclin D1', 'Gene', (85, 94))	('c.870A>G', 'Var', (69, 77))	('CCND1', 'Gene', (96, 101))	('c.870A>G', 'Mutation', 'rs9344', (69, 77))
270267	19826048	Alternative splicing of CCND1 at the exon 4 and intron 4 boundaries results in the formation of two different transcripts, CCND1a and CCND1b.	('CCND1', 'Gene', '595', (24, 29))	('CCND1', 'Gene', '595', (123, 128))	('CCND1', 'Gene', (134, 139))	('Alternative splicing', 'Var', (0, 20))	('results in', 'Reg', (68, 78))	('CCND1', 'Gene', (123, 128))	('CCND1', 'Gene', (24, 29))	('CCND1', 'Gene', '595', (134, 139))
270269	19826048	The c.870A>G variant, which is located at the end of exon 4, is believed to be associated with alternative splicing of CCND1 between transcripts a and b.	('CCND1', 'Gene', (119, 124))	('CCND1', 'Gene', '595', (119, 124))	('c.870A>G', 'Mutation', 'rs9344', (4, 12))	('c.870A>G', 'Var', (4, 12))
270270	19826048	The association of c.870A>G variant and different cancer types is also controversial.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('c.870A>G', 'Var', (19, 27))	('c.870A>G', 'Mutation', 'rs9344', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
270272	19826048	These discrepancies suggest that there are cis- or trans-acting modifiers which, in combination with the c.870A>G variant, determine the splicing of CCND1.	('CCND1', 'Gene', (149, 154))	('c.870A>G', 'Var', (105, 113))	('determine', 'Reg', (123, 132))	('splicing', 'MPA', (137, 145))	('c.870A>G', 'Mutation', 'rs9344', (105, 113))	('CCND1', 'Gene', '595', (149, 154))
270273	19826048	In addition to these two functional variants, tagSNPs from ALDH2 (rs886205), MGMT (rs7087131) and TP53 (rs1625895) were also associated with ESCC in Turkmen.	('rs7087131', 'Mutation', 'rs7087131', (83, 92))	('ALDH2', 'Gene', '217', (59, 64))	('rs886205', 'Mutation', 'rs886205', (66, 74))	('rs1625895', 'Var', (104, 113))	('rs1625895', 'Mutation', 'rs1625895', (104, 113))	('rs7087131', 'Var', (83, 92))	('associated with', 'Reg', (125, 140))	('ALDH2', 'Gene', (59, 64))	('TP53', 'Gene', (98, 102))	('TP53', 'Gene', '7157', (98, 102))	('MGMT', 'Gene', (77, 81))	('MGMT', 'Gene', '4255', (77, 81))	('ESCC', 'Disease', (141, 145))	('rs886205', 'Var', (66, 74))
270276	19826048	The rs886205 variant is the substitution of T by C nucleotide at the 5' untranslated region of Exon 1 at the promoter region of ALDH2.	('rs886205', 'Mutation', 'rs886205', (4, 12))	('rs886205', 'Var', (4, 12))	('ALDH2', 'Gene', '217', (128, 133))	('ALDH2', 'Gene', (128, 133))
270278	19826048	These reports are consistent with our finding that the C allele (minor allele) of this variant decreases the risk of ESCC under a recessive model (OR = 0.58, p = 0.02); possibly by increasing the expression of ALDH2, which metabolizes the aldehyde group of carcinogens like acetaldehyde.	('acetaldehyde', 'Chemical', 'MESH:D000079', (274, 286))	('increasing', 'PosReg', (181, 191))	('expression', 'MPA', (196, 206))	('aldehyde', 'Chemical', 'MESH:D000447', (278, 286))	('ALDH2', 'Gene', '217', (210, 215))	('aldehyde', 'Chemical', 'MESH:D000447', (239, 247))	('decreases', 'NegReg', (95, 104))	('ESCC', 'Disease', (117, 121))	('ALDH2', 'Gene', (210, 215))	('variant', 'Var', (87, 94))
270279	19826048	The rs7087131 variant of MGMT was also found to be associated with ESCC.	('rs7087131', 'Mutation', 'rs7087131', (4, 13))	('ESCC', 'Disease', (67, 71))	('rs7087131', 'Var', (4, 13))	('associated', 'Reg', (51, 61))	('MGMT', 'Gene', (25, 29))	('MGMT', 'Gene', '4255', (25, 29))
270283	19826048	O6-methylguanine-DNA methytransferase (MGMT) repairs O6-methylguanine by transferring the methyl group to a cysteine residue at codon 145 of the enzyme.	('O6-methylguanine-DNA methytransferase', 'Gene', (0, 37))	('cysteine', 'Chemical', 'MESH:D003545', (108, 116))	('O6-methylguanine', 'Var', (53, 69))	('O6-methylguanine-DNA methytransferase', 'Gene', '4255', (0, 37))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (53, 69))	('MGMT', 'Gene', (39, 43))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (0, 16))	('MGMT', 'Gene', '4255', (39, 43))	('methyl group', 'MPA', (90, 102))
270288	19826048	The rs7087131 variant is also located at the 5' half of the MGMT gene in the intronic region between exons 2 and 3 and directly or indirectly might affect expression level of the gene and contribute to the risk of ESCC in Turkmens.	('expression level', 'MPA', (155, 171))	('ESCC', 'Disease', (214, 218))	('rs7087131', 'Mutation', 'rs7087131', (4, 13))	('affect', 'Reg', (148, 154))	('rs7087131', 'Var', (4, 13))	('contribute', 'Reg', (188, 198))	('MGMT', 'Gene', (60, 64))	('risk', 'Reg', (206, 210))	('MGMT', 'Gene', '4255', (60, 64))
270289	19826048	The last tagSNP identified in this study to be associated with ESCC in Turkmen was the rs1625895 variant of TP53.	('rs1625895', 'Var', (87, 96))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('ESCC', 'Disease', (63, 67))	('rs1625895', 'Mutation', 'rs1625895', (87, 96))	('associated', 'Reg', (47, 57))
270292	19826048	This variant has been described in association with colorectal and nasopharyngeal cancer.	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (67, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colorectal and nasopharyngeal cancer', 'Disease', 'MESH:D015179', (52, 88))	('variant', 'Var', (5, 12))	('association', 'Reg', (35, 46))
270293	19826048	Recently, one study reported that the rs1625895 variant is associated with a higher level of micronuclei in the blood cells of individuals exposed to vinyl chloride.	('micronuclei', 'CPA', (93, 104))	('rs1625895', 'Var', (38, 47))	('rs1625895', 'Mutation', 'rs1625895', (38, 47))	('vinyl chloride', 'Chemical', 'MESH:D014752', (150, 164))
270295	19826048	Third, genetic modifier variants may be required to increase cancer risk and the relevant genetic modifier alleles may be prevalent in Turkmen, but not in non-Turkmen.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('variants', 'Var', (24, 32))	('increase', 'PosReg', (52, 60))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
270297	19826048	A strong and significant association was seen with the Arg48His allele of ADH1B gene.	('Arg48His', 'Var', (55, 63))	('Arg48His', 'SUBSTITUTION', 'None', (55, 63))	('ADH1B', 'Gene', '125', (74, 79))	('ADH1B', 'Gene', (74, 79))
270298	19826048	Interestingly, the variant is related to the risk of ESCC in alcohol non-drinkers, suggesting that other carcinogens might be causative.	('alcohol', 'Chemical', 'MESH:D000438', (61, 68))	('ESCC', 'Disease', (53, 57))	('variant', 'Var', (19, 26))
270311	32161513	Clinically, linc02042 was identified as an effective diagnostic and prognostic biomarker for ESCC patients, and its expression was strongly positively correlated with c-Myc expression in ESCC tissues.	('ESCC', 'Disease', (187, 191))	('expression', 'MPA', (116, 126))	('ESCC', 'Disease', 'MESH:D000077277', (93, 97))	('patients', 'Species', '9606', (98, 106))	('linc02042', 'Var', (12, 21))	('c-Myc', 'Gene', (167, 172))	('c-Myc', 'Gene', '4609', (167, 172))	('positively', 'PosReg', (140, 150))	('ESCC', 'Disease', 'MESH:D000077277', (187, 191))	('ESCC', 'Disease', (93, 97))	('correlated', 'Reg', (151, 161))
270312	32161513	Our data suggest that linc02042 plays an important tumor-promoting role in ESCC, which lays a foundation for considering it as a potential target for ESCC patients.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ESCC', 'Disease', (75, 79))	('tumor', 'Disease', (51, 56))	('ESCC', 'Disease', 'MESH:D000077277', (75, 79))	('ESCC', 'Disease', (150, 154))	('ESCC', 'Disease', 'MESH:D000077277', (150, 154))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('linc02042', 'Var', (22, 31))
270339	32161513	The member was incubated with anti-c-Myc (#9402, CST, 1:1000 dilution) and anti-YBX1 (#9744, CST, 1:2000 dilution) primary antibodies at 4 C overnight.	('#9744', 'Var', (86, 91))	('#9402', 'Var', (42, 47))	('CST', 'Gene', '106478911', (93, 96))	('c-Myc', 'Gene', '4609', (35, 40))	('YBX1', 'Gene', (80, 84))	('CST', 'Gene', (49, 52))	('c-Myc', 'Gene', (35, 40))	('CST', 'Gene', (93, 96))	('YBX1', 'Gene', '4904', (80, 84))	('CST', 'Gene', '106478911', (49, 52))
270345	32161513	The sample was incubated with anti-c-Myc (#9402, CST, 1:50) at 4 C overnight, followed by incubation with ChIP-Grade Protein G Agarose Beads (#9007, CST) at 4 C for 1 h, and the complex was washed and eluted by Elution buffer (1% SDS, 0.1 M NaHCO3).	('#9402', 'Var', (42, 47))	('c-Myc', 'Gene', '4609', (35, 40))	('CST', 'Gene', '106478911', (149, 152))	('NaHCO3', 'Chemical', 'MESH:D017693', (241, 247))	('CST', 'Gene', (49, 52))	('c-Myc', 'Gene', (35, 40))	('CST', 'Gene', (149, 152))	('SDS', 'Chemical', 'MESH:D012967', (230, 233))	('Agarose', 'Chemical', 'MESH:D012685', (127, 134))	('CST', 'Gene', '106478911', (49, 52))
270349	32161513	We then evaluated the relationship between linc02042 expression and clinicopathological features of ESCC patients, the results showed that high linc02042 was positively correlated with malignant features, including larger tumor size, poor differentiation, advanced TNM stage and lymph node metastasis (Table 1).	('linc02042', 'Gene', (144, 153))	('patients', 'Species', '9606', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('correlated', 'Reg', (169, 179))	('TNM', 'Gene', '10178', (265, 268))	('ESCC', 'Disease', (100, 104))	('ESCC', 'Disease', 'MESH:D000077277', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('TNM', 'Gene', (265, 268))	('poor differentiation', 'CPA', (234, 254))	('lymph node metastasis', 'CPA', (279, 300))	('high', 'Var', (139, 143))
270351	32161513	1d), implying that plasma linc02042 has an excellent diagnostic efficacy for ESCC.	('ESCC', 'Disease', 'MESH:D000077277', (77, 81))	('ESCC', 'Disease', (77, 81))	('plasma linc02042', 'Var', (19, 35))
270352	32161513	Kaplan-Meier plotter displayed that patients with high linc02042 had shorter overall survival time than those with low linc02042 (Fig.	('high linc02042', 'Var', (50, 64))	('overall survival', 'MPA', (77, 93))	('shorter', 'NegReg', (69, 76))	('patients', 'Species', '9606', (36, 44))
270353	32161513	These above data suggest that linc02042 is frequently overexpressed in ESCC and may play an essential role in the pathogenesis of ESCC.	('linc02042', 'Var', (30, 39))	('ESCC', 'Disease', (71, 75))	('ESCC', 'Disease', (130, 134))	('ESCC', 'Disease', 'MESH:D000077277', (130, 134))	('ESCC', 'Disease', 'MESH:D000077277', (71, 75))	('overexpressed', 'PosReg', (54, 67))
270356	32161513	The results showed that the tumor volume/weight and lung metastasis nodules in sh-linc02042 group were less than those in control group (Fig.	('sh-linc02042', 'Var', (79, 91))	('tumor', 'Disease', (28, 33))	('lung metastasis nodules', 'CPA', (52, 75))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('less', 'NegReg', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
270357	32161513	These findings indicate that linc02042 enhances ESCC cell aggressive phenotype.	('ESCC', 'Disease', (48, 52))	('enhances', 'PosReg', (39, 47))	('linc02042', 'Var', (29, 38))	('ESCC', 'Disease', 'MESH:D000077277', (48, 52))
270359	32161513	Consistently, c-Myc mRNA as well as protein levels were significantly decreased in linc02042 knockdown ESCC cells in comparison with control cells (Fig.	('knockdown', 'Var', (93, 102))	('ESCC', 'Disease', 'MESH:D000077277', (103, 107))	('c-Myc', 'Gene', (14, 19))	('linc02042', 'Gene', (83, 92))	('protein levels', 'MPA', (36, 50))	('decreased', 'NegReg', (70, 79))	('ESCC', 'Disease', (103, 107))	('c-Myc', 'Gene', '4609', (14, 19))
270364	32161513	Surprisingly, knockdown of linc02042 shortened the half-life of c-Myc mRNA from more than 60 min to about 35 min (Fig.	('half-life', 'MPA', (51, 60))	('linc02042', 'Gene', (27, 36))	('knockdown', 'Var', (14, 23))	('c-Myc', 'Gene', '4609', (64, 69))	('shortened', 'NegReg', (37, 46))	('c-Myc', 'Gene', (64, 69))
270368	32161513	Given that YBX1 acts as an important regulator of c-Myc mRNA stability via binding to its 3'-UTR and that numerous lncRNAs have been found to be bound by YBX1, we thus inferred that linc02042 might increase c-Myc mRNA stability via YBX1.	('YBX1', 'Gene', '4904', (232, 236))	('YBX1', 'Gene', (11, 15))	('YBX1', 'Gene', '4904', (154, 158))	('increase', 'PosReg', (198, 206))	('YBX1', 'Gene', (154, 158))	('c-Myc', 'Gene', '4609', (207, 212))	('linc02042', 'Var', (182, 191))	('c-Myc', 'Gene', '4609', (50, 55))	('YBX1', 'Gene', '4904', (11, 15))	('YBX1', 'Gene', (232, 236))	('c-Myc', 'Gene', (50, 55))	('binding', 'Interaction', (75, 82))	('c-Myc', 'Gene', (207, 212))
270369	32161513	To confirm this inference, we first test the possibility of binding between linc02042 and YBX1 by using RPISeq database, the results showed that linc02042 has a strong possibility of direct interaction with YBX1 (RF classifier = 0.88, SVM classifier = 0.9) (Fig.	('YBX1', 'Gene', (90, 94))	('YBX1', 'Gene', (207, 211))	('RF', 'Chemical', 'MESH:C067582', (213, 215))	('YBX1', 'Gene', '4904', (90, 94))	('interaction', 'Interaction', (190, 201))	('YBX1', 'Gene', '4904', (207, 211))	('linc02042', 'Var', (145, 154))
270376	32161513	4f), and the enhanced aggressive phenotype caused by linc02042 overexpression was substantially blocked by YBX1 knockdown (Fig.	('enhanced', 'PosReg', (13, 21))	('overexpression', 'PosReg', (63, 77))	('YBX1', 'Gene', (107, 111))	('knockdown', 'Var', (112, 121))	('blocked', 'NegReg', (96, 103))	('aggressive phenotype', 'CPA', (22, 42))	('YBX1', 'Gene', '4904', (107, 111))	('linc02042', 'Gene', (53, 62))
270377	32161513	These results indicate that linc02042 and YBX1 form a dimer complex that regulates c-Myc expression.	('YBX1', 'Gene', (42, 46))	('c-Myc', 'Gene', (83, 88))	('YBX1', 'Gene', '4904', (42, 46))	('linc02042', 'Var', (28, 37))	('regulates', 'Reg', (73, 82))	('c-Myc', 'Gene', '4609', (83, 88))
270380	32161513	The results showed that silencing of c-Myc significantly reduced the promoter activity of wild-type vector in both KYSE30 and KYSE150 cells, whereas this phenomenon was eliminated after mutation of E-box#3 rather than E-box#1 or E-box#2 (Fig.	('E-box#3', 'Var', (198, 205))	('c-Myc', 'Gene', '4609', (37, 42))	('c-Myc', 'Gene', (37, 42))	('reduced', 'NegReg', (57, 64))	('promoter activity', 'MPA', (69, 86))	('mutation', 'Var', (186, 194))	('silencing', 'Var', (24, 33))
270381	32161513	Further, the ChIP assay results revealed that c-Myc directly bound to E-box#3, but not E-box#1 or E-box#2 (Fig.	('c-Myc', 'Gene', '4609', (46, 51))	('E-box#3', 'Var', (70, 77))	('c-Myc', 'Gene', (46, 51))	('bound', 'Interaction', (61, 66))
270386	32161513	Gain and loss functional assays showed that linc02042 promoted ESCC cell proliferation and invasion both in vitro and in vivo.	('promoted', 'PosReg', (54, 62))	('linc02042', 'Var', (44, 53))	('invasion', 'CPA', (91, 99))	('ESCC', 'Disease', 'MESH:D000077277', (63, 67))	('ESCC', 'Disease', (63, 67))
270387	32161513	Stepwise mechanism studies revealed that linc02042 directly interacted with YBX1 and increased the binding of YBX1 to c-Myc 3'-UTR, resulting in potentiating c-Myc mRNA stability, thereby facilitating ESCC malignant progression.	('YBX1', 'Gene', (110, 114))	('c-Myc', 'Gene', (158, 163))	('potentiating', 'PosReg', (145, 157))	('YBX1', 'Gene', (76, 80))	('ESCC', 'Disease', 'MESH:D000077277', (201, 205))	('c-Myc', 'Gene', '4609', (118, 123))	('YBX1', 'Gene', '4904', (110, 114))	('linc02042', 'Var', (41, 50))	('facilitating', 'PosReg', (188, 200))	('c-Myc', 'Gene', (118, 123))	('increased', 'PosReg', (85, 94))	('c-Myc', 'Gene', '4609', (158, 163))	('interacted', 'Interaction', (60, 70))	('ESCC', 'Disease', (201, 205))	('YBX1', 'Gene', '4904', (76, 80))	('binding', 'Interaction', (99, 106))
270389	32161513	A large number of studies have reported that non-coding RNA is an effective cancer biomarker, especially lncRNA with length over 200 nt.	('lncRNA', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('non-coding RNA', 'Var', (45, 59))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
270391	32161513	Herein, ESCC patients with high linc02042 expression displayed shorter survival time than those with low linc02042 expression, implicating the prognostic value of linc02042 in ESCC.	('ESCC', 'Disease', (176, 180))	('ESCC', 'Disease', (8, 12))	('ESCC', 'Disease', 'MESH:D000077277', (8, 12))	('high linc02042 expression', 'Var', (27, 52))	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (63, 70))	('ESCC', 'Disease', 'MESH:D000077277', (176, 180))	('survival time', 'CPA', (71, 84))
270394	32161513	Herein, we found that linc02042 could directly bind to YBX1 by performing RNA pull-down and RIP assays.	('YBX1', 'Gene', '4904', (55, 59))	('bind', 'Interaction', (47, 51))	('YBX1', 'Gene', (55, 59))	('linc02042', 'Var', (22, 31))
270397	32161513	However, in this study, the interaction between linc02042 and YBX1 did not increase YBX1 protein level, but rather recruited YBX1 to the 3'-UTR of c-Myc mRNA to stabilize c-Myc.	('YBX1', 'Gene', (62, 66))	('YBX1', 'Gene', '4904', (84, 88))	('c-Myc', 'Gene', (147, 152))	('YBX1', 'Gene', (125, 129))	('recruited', 'Reg', (115, 124))	('linc02042', 'Var', (48, 57))	('interaction', 'Interaction', (28, 39))	('YBX1', 'Gene', '4904', (62, 66))	('YBX1', 'Gene', '4904', (125, 129))	('YBX1', 'Gene', (84, 88))	('c-Myc', 'Gene', '4609', (171, 176))	('c-Myc', 'Gene', (171, 176))	('c-Myc', 'Gene', '4609', (147, 152))
270398	32161513	This notion was confirmed by the RIP assay in which linc02042 knockdown substantially decreased the binding of YBX1 to c-Myc 3'-UTR.	('YBX1', 'Gene', (111, 115))	('binding', 'Interaction', (100, 107))	('linc02042', 'Gene', (52, 61))	('decreased', 'NegReg', (86, 95))	('YBX1', 'Gene', '4904', (111, 115))	('c-Myc', 'Gene', '4609', (119, 124))	('c-Myc', 'Gene', (119, 124))	('knockdown', 'Var', (62, 71))
270402	32161513	Here, we found that linc02042 increased c-Myc mRNA stability, and the pro-tumor effect of linc02042 was practically disappeared in the absence of c-Myc, suggesting that c-Myc is required for the function of linc02042 in ESCC.	('c-Myc', 'Gene', '4609', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('linc02042', 'Var', (20, 29))	('c-Myc', 'Gene', '4609', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('c-Myc', 'Gene', (146, 151))	('c-Myc', 'Gene', (169, 174))	('ESCC', 'Disease', (220, 224))	('ESCC', 'Disease', 'MESH:D000077277', (220, 224))	('tumor', 'Disease', (74, 79))	('c-Myc', 'Gene', '4609', (40, 45))	('increased', 'PosReg', (30, 39))	('c-Myc', 'Gene', (40, 45))
270403	32161513	Besides, silencing of YBX1 evidently blocked the increased c-Myc level caused by linc02042 overexpression, indicating that linc02042 regulates c-Myc mRNA stability in an YBX1-dependent mechanism.	('c-Myc', 'Gene', (59, 64))	('c-Myc', 'Gene', '4609', (59, 64))	('regulates', 'Reg', (133, 142))	('YBX1', 'Gene', '4904', (22, 26))	('c-Myc', 'Gene', (143, 148))	('silencing', 'Var', (9, 18))	('increased', 'PosReg', (49, 58))	('blocked', 'NegReg', (37, 44))	('YBX1', 'Gene', (170, 174))	('YBX1', 'Gene', (22, 26))	('c-Myc', 'Gene', '4609', (143, 148))	('YBX1', 'Gene', '4904', (170, 174))	('linc02042', 'Gene', (81, 90))
270408	32161513	This positive feedback loop between linc02042 and c-Myc magnifies the pro-tumor effect of linc02042 in ESCC.	('ESCC', 'Disease', 'MESH:D000077277', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('c-Myc', 'Gene', '4609', (50, 55))	('tumor', 'Disease', (74, 79))	('linc02042', 'Var', (90, 99))	('c-Myc', 'Gene', (50, 55))	('ESCC', 'Disease', (103, 107))	('magnifies', 'PosReg', (56, 65))
270410	32161513	Whether linc02042 also plays the fundamental role in other malignancies is worth further investigation.	('linc02042', 'Var', (8, 17))	('malignancies', 'Disease', (59, 71))	('malignancies', 'Disease', 'MESH:D009369', (59, 71))
270442	29871822	Multiple pathways have been shown to play an important role in regulating these early Sox2 proximal progenitors, including epigenetic factors.	('Sox2', 'Gene', '20674', (86, 90))	('epigenetic', 'Var', (123, 133))	('Sox2', 'Gene', (86, 90))
270443	29871822	Histone deacetylases 1/2 (HDAC1/2) are required for the early development of Sox2+ proximal progenitors in the mouse lung and lung endoderm-specific loss of these two factors results in an organ comprising solely Sox9+ distal lung endoderm progenitors.	('Sox9', 'Gene', '20682', (213, 217))	('HDAC1/2', 'Gene', (26, 33))	('Histone deacetylases 1/2', 'Gene', '433759;15182', (0, 24))	('mouse', 'Species', '10090', (111, 116))	('Sox9', 'Gene', (213, 217))	('loss', 'Var', (149, 153))	('Sox2', 'Gene', '20674', (77, 81))	('results in', 'Reg', (175, 185))	('Histone deacetylases 1/2', 'Gene', (0, 24))	('organ comprising', 'MPA', (189, 205))	('Sox2', 'Gene', (77, 81))	('HDAC1/2', 'Gene', '433759;15182', (26, 33))
270444	29871822	This phenotype correlates with derepression of Bmp4, which is known to promote the distal endoderm progenitor fate during lung development.	('Bmp4', 'Gene', '12159', (47, 51))	('promote', 'PosReg', (71, 78))	('Bmp4', 'Gene', (47, 51))	('distal endoderm progenitor fate', 'CPA', (83, 114))	('derepression', 'Var', (31, 43))
270455	29871822	While not much is known about the Trp63 isoforms in esophageal development, conditional deletion of the DeltaNTrp63 isoform results in defects in differentiation and stratification in the esophageal epithelium.	('DeltaNTrp63', 'Gene', (104, 115))	('defects', 'NegReg', (135, 142))	('deletion', 'Var', (88, 96))	('stratification', 'CPA', (166, 180))	('rat', 'Species', '10116', (168, 171))
270458	29871822	Deletion of the Barx1 gene results in expansion of canonical Wnt signaling and mutants demonstrate EA/TEF.	('rat', 'Species', '10116', (94, 97))	('Barx1', 'Gene', (16, 21))	('mutants', 'Var', (79, 86))	('Barx1', 'Gene', '12022', (16, 21))	('canonical Wnt signaling', 'MPA', (51, 74))	('TEF', 'Gene', (102, 105))	('expansion', 'PosReg', (38, 47))	('TEF', 'Gene', '21685', (102, 105))	('Deletion', 'Var', (0, 8))
270486	29871822	Surprisingly, recent evidence has revealed that these secretory cells can also dedifferentiate into basal cells in the large airways of the mouse lung after genetic depletion of the Trp63+ basal cells.	('dedifferentiate', 'CPA', (79, 94))	('genetic depletion', 'Var', (157, 174))	('mouse', 'Species', '10090', (140, 145))
270491	29871822	Disruption or activation of these pathways could provide possible therapeutic approaches for cancer and tissue regeneration, respectively.	('cancer', 'Disease', (93, 99))	('rat', 'Species', '10116', (117, 120))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tissue regeneration', 'CPA', (104, 123))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Disruption', 'Var', (0, 10))
270497	29871822	However, this plasticity could also engender increased oncogenic risk, which is consistent with the high frequency of lung and esophageal cancers.	('oncogenic', 'CPA', (55, 64))	('plasticity', 'Var', (14, 24))	('engender', 'Reg', (36, 44))	('lung and esophageal cancers', 'Disease', 'MESH:D004938', (118, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))
270515	29871822	Loss of Notch3 prevents esophageal basal cells from undergoing terminal differentiation, with concurrent suppression of the transcription factor KLF4, and loss of Notch 3 facilitates epithelial-mesenchymal transition, a feature of tumorigenesis, via transcription factors ZEB1 and ZEB2.	('KLF4', 'Gene', '16600', (145, 149))	('facilitates', 'PosReg', (171, 182))	('KLF4', 'Gene', (145, 149))	('ZEB1', 'Gene', '21417', (272, 276))	('loss', 'Var', (155, 159))	('ZEB2', 'Gene', '24136', (281, 285))	('ZEB2', 'Gene', (281, 285))	('epithelial-mesenchymal transition', 'CPA', (183, 216))	('suppression', 'NegReg', (105, 116))	('Notch 3', 'Gene', (163, 170))	('Notch3', 'Gene', '18131', (8, 14))	('ZEB1', 'Gene', (272, 276))	('Loss', 'Var', (0, 4))	('Notch3', 'Gene', (8, 14))	('Notch 3', 'Gene', '18131', (163, 170))
270517	29871822	Interestingly, Notch inhibition plays a role in the development of intestinal metaplasia in the esophageal squamous epithelium, one feature of which is goblet cell hyperplasia.	('Notch inhibition', 'Var', (15, 31))	('hyperplasia', 'Disease', 'MESH:D006965', (164, 175))	('esophageal squamous', 'Disease', 'MESH:D000077277', (96, 115))	('esophageal squamous', 'Disease', (96, 115))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (67, 88))	('hyperplasia', 'Disease', (164, 175))	('intestinal metaplasia', 'Disease', (67, 88))
270528	29871822	Foxp1/2/4 triple mutants exhibit ectopic activation of an entire non-pulmonary gene expression program, including genes highly expressed in esophageal epithelium such as Pax9.	('Foxp1/2/4', 'Gene', '108655;114142;74123', (0, 9))	('Foxp1/2/4', 'Gene', (0, 9))	('Pax9', 'Gene', '18511', (170, 174))	('activation', 'PosReg', (41, 51))	('Pax9', 'Gene', (170, 174))	('non-pulmonary', 'Pathway', (65, 78))	('triple mutants', 'Var', (10, 24))
270572	29916308	The mTOR is phosphorylated by Akt1 at Ser2448 to yield phospho-mTOR (p-mTOR), which regulates ribosome biogenesis and protein synthesis, and is also present in the cytoplasm and nucleus, with high p-mTOR expression indicating reduced response to tumor treatment.	('Akt1', 'Gene', (30, 34))	('regulates ribosome biogenesis', 'MPA', (84, 113))	('protein synthesis', 'MPA', (118, 135))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('expression', 'MPA', (204, 214))	('Akt1', 'Gene', '207', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('Ser2448', 'Var', (38, 45))	('Ser2448', 'Chemical', '-', (38, 45))	('tumor', 'Disease', (246, 251))
270575	29916308	The loss or mutation of these genes leads to a wide variety of human sporadic and inherited cancer.	('human', 'Species', '9606', (63, 68))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('leads to', 'Reg', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutation', 'Var', (12, 20))	('loss', 'NegReg', (4, 8))
270576	29916308	We have observed increased activity of the mTOR pathway after silencing PTEN.	('increased', 'PosReg', (17, 26))	('silencing', 'Var', (62, 71))	('mTOR pathway', 'Pathway', (43, 55))	('PTEN', 'Gene', (72, 76))	('PTEN', 'Gene', '5728', (72, 76))	('activity', 'MPA', (27, 35))
270577	29916308	In the present study, we knocked down PTEN to activate the mTOR pathway.	('PTEN', 'Gene', '5728', (38, 42))	('knocked down', 'Var', (25, 37))	('mTOR pathway', 'Pathway', (59, 71))	('activate', 'PosReg', (46, 54))	('PTEN', 'Gene', (38, 42))
270580	29916308	These alterations increase tumor cell proliferation (Warburg effect).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('alterations', 'Var', (6, 17))	('increase', 'PosReg', (18, 26))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
270581	29916308	Moreover, knocking down HIF-1alpha inhibits lactate production and pyruvate kinase M2 isoform (PKM2) expression in pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('knocking down', 'Var', (10, 23))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('lactate', 'Chemical', 'MESH:D019344', (44, 51))	('inhibits', 'NegReg', (35, 43))	('pancreatic cancer', 'Disease', (115, 132))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('lactate production', 'MPA', (44, 62))	('pyruvate kinase M2 isoform', 'Gene', (67, 93))	('expression', 'MPA', (101, 111))	('HIF-1alpha', 'Gene', (24, 34))	('pyruvate kinase M2 isoform', 'Gene', '5315', (67, 93))
270587	29916308	We hypothesized that knocking down PTEN will affect mTOR and thus regulate PKM2, inducing cancer cells to convert glucose into lactic acid to produce energy, which may be the major pathway for cellular energy metabolism in ESCC.	('affect', 'Reg', (45, 51))	('convert glucose into lactic acid to produce energy', 'MPA', (106, 156))	('knocking down', 'Var', (21, 34))	('PKM2', 'Enzyme', (75, 79))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('PTEN', 'Gene', (35, 39))	('mTOR', 'MPA', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lactic acid', 'Chemical', 'MESH:D019344', (127, 138))	('PTEN', 'Gene', '5728', (35, 39))	('regulate', 'Reg', (66, 74))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('inducing', 'Reg', (81, 89))
270611	29916308	Immunoblot analysis was performed using secondary antibodies conjugated to horseradish peroxidase, and the primary antibodies included anti-mTOR, anti-p-mTOR, anti-PKM2, and anti-GAPDH (Sangon Biotech, D110016, China).	('GAPDH', 'Gene', (179, 184))	('anti-p-mTOR', 'Var', (146, 157))	('horseradish', 'Species', '3704', (75, 86))	('GAPDH', 'Gene', '2597', (179, 184))	('anti-mTOR', 'Var', (135, 144))	('anti-PKM2', 'Var', (159, 168))
270619	29916308	The remaining glucose in the medium showed that the PKM2-up and PKM2-down groups consumed more and less glucose, respectively, than the control group (Figure 2B).	('less', 'NegReg', (99, 103))	('PKM2-up', 'Var', (52, 59))	('glucose', 'MPA', (104, 111))	('PKM2-down', 'Var', (64, 73))	('glucose', 'Chemical', 'MESH:D005947', (14, 21))	('glucose', 'Chemical', 'MESH:D005947', (104, 111))
270620	29916308	Lactate assays showed that modifying PKM2 expression also affected lactate production.	('lactate', 'Chemical', 'MESH:D019344', (67, 74))	('Lactate', 'Chemical', 'MESH:D019344', (0, 7))	('lactate production', 'MPA', (67, 85))	('affected', 'Reg', (58, 66))	('modifying', 'Var', (27, 36))	('PKM2', 'Gene', (37, 41))
270621	29916308	The PKM2-up group produced more lactate and the PKM2-down group produced less lactate than the control group (Figure 2C).	('lactate', 'Chemical', 'MESH:D019344', (32, 39))	('lactate', 'Chemical', 'MESH:D019344', (78, 85))	('lactate', 'MPA', (32, 39))	('PKM2-up', 'Var', (4, 11))	('more', 'PosReg', (27, 31))
270626	29916308	Measurement of the remaining glucose in the medium showed that the rapamycin group consumed less glucose than did the control group (Figure 3C).	('glucose', 'Chemical', 'MESH:D005947', (97, 104))	('less', 'NegReg', (92, 96))	('rapamycin', 'Chemical', 'MESH:D020123', (67, 76))	('glucose', 'Chemical', 'MESH:D005947', (29, 36))	('glucose', 'MPA', (97, 104))	('rapamycin', 'Var', (67, 76))
270627	29916308	Furthermore, in the lactate assay, the rapamycin group produced less lactate than did the control group (Figure 3D).	('lactate', 'MPA', (69, 76))	('less', 'NegReg', (64, 68))	('rapamycin', 'Chemical', 'MESH:D020123', (39, 48))	('lactate assay', 'MPA', (20, 33))	('lactate', 'Chemical', 'MESH:D019344', (20, 27))	('lactate', 'Chemical', 'MESH:D019344', (69, 76))	('rapamycin', 'Var', (39, 48))
270630	29916308	However, the PTEN gene is a key suppressor gene in the mTOR pathway, as mentioned earlier; therefore, we knocked down PTEN to activate mTOR.	('activate', 'PosReg', (126, 134))	('PTEN', 'Gene', '5728', (118, 122))	('PTEN', 'Gene', (118, 122))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('knocked down', 'Var', (105, 117))
270632	29916308	Western blotting showed that knocking down PTEN was associated with increased p-mTOR expression (Figure 3B).	('knocking down', 'Var', (29, 42))	('PTEN', 'Gene', (43, 47))	('p-mTOR expression', 'MPA', (78, 95))	('PTEN', 'Gene', '5728', (43, 47))	('increased', 'PosReg', (68, 77))
270637	29916308	We knocked down both PTEN and PKM2 in the same group (PTEN-down + PKM2-down group) to activate mTOR and inhibit PKM2.	('mTOR', 'MPA', (95, 99))	('PKM2', 'Enzyme', (112, 116))	('activate', 'PosReg', (86, 94))	('PTEN', 'Gene', (54, 58))	('knocked', 'Var', (3, 10))	('PTEN', 'Gene', '5728', (54, 58))	('PTEN', 'Gene', (21, 25))	('inhibit', 'NegReg', (104, 111))	('PTEN', 'Gene', '5728', (21, 25))
270640	29916308	Inhibitors of mTOR (including rapamycin derivatives) and PKM2 are thus potential drugs that could serve as new therapeutic options for cancer treatment (Figure 4B).	('cancer', 'Disease', (135, 141))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rapamycin', 'Chemical', 'MESH:D020123', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('mTOR', 'Gene', (14, 18))	('PKM2', 'Gene', (57, 61))
270645	29916308	mTOR is phosphorylated by Akt1 at Ser2448, leading to downstream signaling by p-mTOR.	('leading to', 'Reg', (43, 53))	('Akt1', 'Gene', '207', (26, 30))	('Ser2448', 'Var', (34, 41))	('Ser2448', 'Chemical', '-', (34, 41))	('downstream signaling', 'MPA', (54, 74))	('Akt1', 'Gene', (26, 30))
270649	29916308	The consumption of glucose and the production of lactic acid by ESCC cells changed following the modification of PKM2 expression.	('production of lactic acid', 'MPA', (35, 60))	('glucose', 'Chemical', 'MESH:D005947', (19, 26))	('changed', 'Reg', (75, 82))	('consumption of glucose', 'MPA', (4, 26))	('lactic acid', 'Chemical', 'MESH:D019344', (49, 60))	('PKM2', 'Gene', (113, 117))	('modification', 'Var', (97, 109))
270654	29916308	We thus knocked down PTEN to activate mTOR and inhibited mTOR with rapamycin.	('inhibited', 'NegReg', (47, 56))	('mTOR', 'MPA', (38, 42))	('PTEN', 'Gene', '5728', (21, 25))	('rapamycin', 'Chemical', 'MESH:D020123', (67, 76))	('PTEN', 'Gene', (21, 25))	('activate', 'PosReg', (29, 37))	('knocked down', 'Var', (8, 20))
270663	29720856	Many less invasive methods for screening of varices have been investigated and the most recent Baveno VI guidelines suggest that endoscopy is not necessary in patients with liver stiffness <20 kPa and platelets >150,000/muL.	('muL', 'Gene', '4591', (220, 223))	('muL', 'Gene', (220, 223))	('liver stiffness', 'Disease', (173, 188))	('liver stiffness', 'Disease', 'MESH:D017093', (173, 188))	('<20 kPa', 'Var', (189, 196))	('patients', 'Species', '9606', (159, 167))
270796	28690767	Stage II disease with locally advanced cancer (T3-T4 N0 M0), or stage III with lymph node metastasis (T1-4 N1-2 M0) will benefit maximally and improve recurrence-free survival when neoadjuvant radio-chemotherapy is given.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('improve', 'PosReg', (143, 150))	('benefit', 'PosReg', (121, 128))	('recurrence-free survival', 'CPA', (151, 175))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('T3-T4 N0 M0', 'Var', (47, 58))
270804	28690767	Over- or under-staging leads to changes in a patient's treatment.	('changes', 'Reg', (32, 39))	('patient', 'Species', '9606', (45, 52))	('under-staging', 'Var', (9, 22))
270923	28293396	Then we generated mutations by deletion of 4 bp from the perfectly complementary site of the LDHA 3'-UTR using the QIAGEN XL-site directed Mutagenesis Kit (QIAGEN, CA).	('LDHA', 'Gene', '3939', (93, 97))	('deletion of', 'Var', (31, 42))	('LDHA', 'Gene', (93, 97))
270929	28293396	The membranes were incubated with 5% skim milk powder for 1 hr at room temperature to block nonspecific binding, followed by antibody against LDHA (Affinity, USA) at 4  C overnight.	('nonspecific binding', 'MPA', (92, 111))	('LDHA', 'Gene', (142, 146))	('antibody', 'Var', (125, 133))	('LDHA', 'Gene', '3939', (142, 146))
270936	28293396	MTT assay was performed to further confirm the inhibition of cell proliferation after miR-383 transfection.	('miR-383', 'Gene', (86, 93))	('inhibition', 'NegReg', (47, 57))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('transfection', 'Var', (94, 106))	('miR-383', 'Gene', '494332', (86, 93))	('cell proliferation', 'CPA', (61, 79))
270937	28293396	The results showed that transfection of miR-383 indeed inhibited cell proliferation (Figure 1C).	('miR-383', 'Gene', '494332', (40, 47))	('transfection', 'Var', (24, 36))	('cell proliferation', 'CPA', (65, 83))	('miR-383', 'Gene', (40, 47))	('inhibited', 'NegReg', (55, 64))
270949	28293396	Furthermore, mutation of the miR-383 binding sites in LDHA 3'UTR abrogated the luciferase response to miR-383 (Figure 3B).	('miR-383', 'Gene', (102, 109))	('mutation', 'Var', (13, 21))	('miR-383', 'Gene', '494332', (29, 36))	('luciferase', 'Enzyme', (79, 89))	('LDHA', 'Gene', '3939', (54, 58))	('miR-383', 'Gene', '494332', (102, 109))	('LDHA', 'Gene', (54, 58))	('miR-383', 'Gene', (29, 36))	('abrogated', 'NegReg', (65, 74))
270974	28293396	Aberrant metabolism has been proved to help the progression and metastasis of cancers.	('metastasis of cancers', 'Disease', 'MESH:D009362', (64, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('help', 'PosReg', (39, 43))	('Aberrant metabolism', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('progression', 'CPA', (48, 59))	('metastasis of cancers', 'Disease', (64, 85))
270992	27462867	However, previous studies on the association of mTOR polymorphisms with predisposition to different cancer types are somewhat contradictory.	('mTOR', 'Gene', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('association', 'Interaction', (33, 44))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('polymorphisms', 'Var', (53, 66))
270993	27462867	Therefore, we performed a systematic review and updated meta-analysis of the available evidence regarding the relationship between mTOR single nucleotide polymorphisms (SNPs) and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mTOR', 'Gene', (131, 135))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('single nucleotide polymorphisms', 'Var', (136, 167))	('cancer', 'Disease', (179, 185))
270994	27462867	Up to November 2015, 23 original publications were identified covering 20 mTOR SNPs, of which seven SNPs (rs2536, rs2295080, rs1883965, rs1034528, rs17036508, rs3806317 and rs1064261) were included in the final meta-analysis.	('rs3806317', 'Mutation', 'rs3806317', (159, 168))	('rs2295080', 'Var', (114, 123))	('rs1034528', 'Mutation', 'rs1034528', (136, 145))	('rs1064261', 'Var', (173, 182))	('rs17036508', 'Var', (147, 157))	('rs1064261', 'Mutation', 'rs1064261', (173, 182))	('rs3806317', 'Var', (159, 168))	('rs1883965', 'Var', (125, 134))	('rs1883965', 'Mutation', 'rs1883965', (125, 134))	('rs1034528', 'Var', (136, 145))	('rs2295080', 'Mutation', 'rs2295080', (114, 123))	('rs2536', 'Mutation', 'rs2536', (106, 112))	('rs2536', 'Var', (106, 112))	('rs17036508', 'Mutation', 'rs17036508', (147, 157))
270995	27462867	We estimated the summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for mTOR polymorphisms and cancer risk, and used the model-free approach to investigate the biological effect of each polymorphism.	('mTOR', 'Gene', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('polymorphisms', 'Var', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
270996	27462867	Our meta-analysis found that rs1883965, rs1034528, and rs17036508 were correlated with increased cancer risk in the complete over-dominant model (rs1883965 GA versus GG/AA: fixed-effects OR=1.15, 95% CI 1.02-1.29; rs1034528 GC versus GG/CC: fixed-effects OR=1.30, 95% CI 1.13-1.48; rs17036508 TC versus CC/TT: fixed-effects OR=1.23, 95% CI 1.06-1.43).	('rs17036508', 'Mutation', 'rs17036508', (282, 292))	('rs17036508', 'Mutation', 'rs17036508', (55, 65))	('cancer', 'Disease', (97, 103))	('rs1883965', 'Var', (146, 155))	('rs1034528', 'Var', (214, 223))	('rs17036508', 'Var', (55, 65))	('rs1034528', 'Var', (40, 49))	('rs1883965', 'Mutation', 'rs1883965', (146, 155))	('rs1883965', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rs17036508 TC', 'Var', (282, 295))	('rs1883965', 'Mutation', 'rs1883965', (29, 38))	('TC', 'Chemical', 'MESH:D013667', (293, 295))	('rs1034528', 'Mutation', 'rs1034528', (214, 223))	('rs1034528', 'Mutation', 'rs1034528', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
270997	27462867	Stratifying analyses by cancer type, we found that the rs2295080 G allele was associated with a significantly higher risk of acute leukemia in the recessive model (GG versus GT/TT: fixed-effects OR=2.08, 95% CI 1.34-3.22) and a lower risk of genitourinary cancers in the dominant model (TG/GG versus TT: fixed-effects OR=0.77, 95% CI 0.68-0.86).	('genitourinary cancers', 'Disease', 'MESH:D014565', (242, 263))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('rs2295080 G', 'Var', (55, 66))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('acute leukemia', 'Disease', (125, 139))	('acute leukemia', 'Phenotype', 'HP:0002488', (125, 139))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('cancer', 'Disease', (256, 262))	('genitourinary cancers', 'Disease', (242, 263))	('rs2295080', 'Mutation', 'rs2295080', (55, 64))	('TG', 'Chemical', '-', (287, 289))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('acute leukemia', 'Disease', 'MESH:D015470', (125, 139))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))
270998	27462867	Interestingly, further expression analysis showed that homozygous variant genotype carriers of rs1883965, rs1034528 and rs17036508 had lower mTOR transcript levels, based on HapMap data.	('rs17036508', 'Var', (120, 130))	('rs1034528', 'Mutation', 'rs1034528', (106, 115))	('mTOR transcript levels', 'MPA', (141, 163))	('rs1034528', 'Var', (106, 115))	('lower', 'NegReg', (135, 140))	('rs17036508', 'Mutation', 'rs17036508', (120, 130))	('rs1883965', 'Var', (95, 104))	('rs1883965', 'Mutation', 'rs1883965', (95, 104))
271000	27462867	Deregulation of the PI3K pathway is one of the most frequent alterations occurring in human cancer.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('Deregulation', 'Var', (0, 12))	('human', 'Species', '9606', (86, 91))	('PI3K pathway', 'Pathway', (20, 32))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
271002	27462867	These changes may be caused by genetic alterations, and single nucleotide polymorphisms (SNPs) widespread in the human genome, have been extensively studied in mTOR to identify susceptibility loci for cancer.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('single nucleotide polymorphisms', 'Var', (56, 87))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('human', 'Species', '9606', (113, 118))
271004	27462867	first reported a positive association between mTOR rs1057079 and colon cancer risk in 2010, clinical evidence has accumulated regarding the relationship between mTOR SNPs and the risk of various cancers, such as gastric cancer, esophageal carcinoma, endometrial cancer, renal cell cancer, acute leukemia, and colorectal cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (212, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('acute leukemia', 'Disease', (289, 303))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (309, 326))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (228, 248))	('colorectal cancer', 'Disease', (309, 326))	('acute leukemia', 'Disease', 'MESH:D015470', (289, 303))	('rs1057079', 'Var', (51, 60))	('renal cell cancer', 'Disease', (270, 287))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('gastric cancer', 'Disease', (212, 226))	('renal cell cancer', 'Disease', 'MESH:C538614', (270, 287))	('esophageal carcinoma', 'Disease', (228, 248))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('endometrial cancer', 'Phenotype', 'HP:0012114', (250, 268))	('renal cell cancer', 'Phenotype', 'HP:0005584', (270, 287))	('rs1057079', 'Mutation', 'rs1057079', (51, 60))	('acute leukemia', 'Phenotype', 'HP:0002488', (289, 303))	('mTOR', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('endometrial cancer', 'Disease', (250, 268))	('gastric cancer', 'Disease', 'MESH:D013274', (212, 226))	('endometrial cancer', 'Disease', 'MESH:D016889', (250, 268))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('colon cancer', 'Disease', (65, 77))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (228, 248))	('colorectal cancer', 'Phenotype', 'HP:0003003', (309, 326))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancers', 'Disease', (195, 202))	('leukemia', 'Phenotype', 'HP:0001909', (295, 303))
271005	27462867	performed a meta-analysis pooling the data from six case-control studies and indicated an association between rs2295080 in the promoter region of mTOR and cancer risk.	('mTOR', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('rs2295080', 'Mutation', 'rs2295080', (110, 119))	('rs2295080', 'Var', (110, 119))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
271007	27462867	A total of 23 case-control studies matched the inclusion criteria, including one that discussed the relationship between mTOR polymorphisms and meningioma, which is generally considered to be benign.	('mTOR', 'Gene', (121, 125))	('polymorphisms', 'Var', (126, 139))	('meningioma', 'Disease', (144, 154))	('meningioma', 'Phenotype', 'HP:0002858', (144, 154))	('meningioma', 'Disease', 'MESH:D008577', (144, 154))
271009	27462867	Seven SNPs (rs2536, rs2295080, rs1883965, rs1034528, rs17036508, rs3806317, and rs1064261) included in the final meta-analysis were analyzed in at least two series and were described in 14 studies (one article examined the association in independent populations of childhood acute lymphoblastic leukemia and acute myeloid leukemia, so this was treated as two separate studies).	('acute myeloid leukemia', 'Disease', (308, 330))	('rs1064261', 'Mutation', 'rs1064261', (80, 89))	('acute lymphoblastic leukemia', 'Disease', (275, 303))	('rs1883965', 'Mutation', 'rs1883965', (31, 40))	('rs2536', 'Var', (12, 18))	('rs1034528', 'Mutation', 'rs1034528', (42, 51))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (275, 303))	('rs3806317', 'Mutation', 'rs3806317', (65, 74))	('rs3806317', 'Var', (65, 74))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (275, 303))	('rs17036508', 'Mutation', 'rs17036508', (53, 63))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (308, 330))	('leukemia', 'Phenotype', 'HP:0001909', (322, 330))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (308, 330))	('rs2295080', 'Mutation', 'rs2295080', (20, 29))	('rs1883965', 'Var', (31, 40))	('rs2536', 'Mutation', 'rs2536', (12, 18))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (281, 303))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (314, 330))	('rs17036508', 'Var', (53, 63))	('rs2295080', 'Var', (20, 29))	('rs1034528', 'Var', (42, 51))	('rs1064261', 'Var', (80, 89))	('leukemia', 'Phenotype', 'HP:0001909', (295, 303))
271012	27462867	We carried out a meta-analysis of rs2536 overall and in different cancer types under various genetic models.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('rs2536', 'Mutation', 'rs2536', (34, 40))	('rs2536', 'Var', (34, 40))	('cancer', 'Disease', (66, 72))
271013	27462867	rs2536 OR1, OR2, and OR3 were 1.61 (P = 0.501), 0.97 (P = 0.504), and 1.20 (P = 0.422), respectively, suggesting a recessive effect of allele C. Therefore, the TC and TT genotypes were combined and compared with the CC genotype.	('rs2536 OR1', 'Var', (0, 10))	('OR3', 'Var', (21, 24))	('TC', 'Chemical', 'MESH:D013667', (160, 162))	('OR2', 'Var', (12, 15))	('rs2536', 'Mutation', 'rs2536', (0, 6))
271017	27462867	Accordingly, it appeared that rs2536 had no significant effect on susceptibility to cancer (Table 2).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('rs2536', 'Mutation', 'rs2536', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rs2536', 'Var', (30, 36))
271018	27462867	Ten studies, consisting of 6585 cases and 7120 controls, investigated the association between SNP rs2295080 and cancer risk.	('investigated', 'Reg', (57, 69))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('rs2295080', 'Var', (98, 107))	('SNP', 'Gene', (94, 97))	('rs2295080', 'Mutation', 'rs2295080', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
271024	27462867	Four studies, consisting of 4300 cases and 4420 controls, investigated the association between SNP rs1883965 and cancer risk.	('rs1883965', 'Mutation', 'rs1883965', (99, 108))	('investigated', 'Reg', (58, 70))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('SNP', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('rs1883965', 'Var', (99, 108))
271025	27462867	The summary estimate under the heterozygous model (GA versus GG) was statistically significant, implying that carriers of the rs1883965 GA heterozygote were more susceptible to cancer development.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('rs1883965', 'Var', (126, 135))	('rs1883965', 'Mutation', 'rs1883965', (126, 135))	('men', 'Species', '9606', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('susceptible', 'Reg', (162, 173))
271028	27462867	Two studies determined the association between SNPs rs1034528, rs17036508, and rs3806317 and cancer risk, with 2,006 cancer patients and 2,054 controls enrolled.	('rs3806317', 'Var', (79, 88))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('rs17036508', 'Mutation', 'rs17036508', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('SNPs', 'Gene', (47, 51))	('rs17036508', 'Var', (63, 73))	('rs1034528', 'Mutation', 'rs1034528', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('rs3806317', 'Mutation', 'rs3806317', (79, 88))	('cancer', 'Disease', (117, 123))	('rs1034528', 'Var', (52, 61))	('patients', 'Species', '9606', (124, 132))
271029	27462867	For rs1034528, studies were homogenous for OR1, OR2, and OR3, with values of 0.95 (P = 0.791), 1.30 (P < 0.001), and 0.73 (P = 0.109), respectively, suggesting a complete over-dominant model (GC versus GG/CC: fixed-effect OR = 1.30, 95% CI 1.13-1.48, P < 0.001).	('over-dominant', 'PosReg', (171, 184))	('rs1034528', 'Var', (4, 13))	('rs1034528', 'Mutation', 'rs1034528', (4, 13))
271030	27462867	For rs17036508, heterogeneity tests were also negative for OR1, OR2, and OR3, at 0.99 (P = 0.975), 1.23 (P = 0.006), and 0.81 (P = 0.36), respectively, again suggesting a complete over-dominant model (GC versus GG/CC: fixed-effect OR = 1.23, 95% CI 1.06-1.43, P = 0.006) (Table 3).	('rs17036508', 'Var', (4, 14))	('rs17036508', 'Mutation', 'rs17036508', (4, 14))	('over-dominant', 'PosReg', (180, 193))
271032	27462867	Two studies reporting rs1064261 genotype data from 1599 cancer patients and 1790 controls were homogenous for OR1, OR2, and OR3, with values of 0.90 (P = 0.82), 1.14 (P = 0.171), and 0.82 (P = 0.665), respectively.	('rs1064261', 'Var', (22, 31))	('rs1064261', 'Mutation', 'rs1064261', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (63, 71))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
271035	27462867	Among the mTOR SNPs analyzed, data from the SNPinfo database suggested that six (rs3806317, rs1034528, rs12125777, rs1883965, rs2295080, and rs1074078) are located in transcription factor binding sites (TFBS), four (rs11121691, rs1057079, rs17036508, and rs1064261) may affect exonic splicing enhancer or exonic splicing silencer binding site activity or even abolish a protein domain, and two (rs2536 and rs17036508) are within microRNA (miRNA) binding sites.	('enhancer', 'PosReg', (293, 301))	('rs17036508', 'Mutation', 'rs17036508', (406, 416))	('rs1057079', 'Mutation', 'rs1057079', (228, 237))	('exonic splicing silencer', 'MPA', (305, 329))	('rs17036508', 'Mutation', 'rs17036508', (239, 249))	('rs1074078', 'Var', (141, 150))	('rs2295080', 'Mutation', 'rs2295080', (126, 135))	('rs3806317', 'Mutation', 'rs3806317', (81, 90))	('exonic splicing', 'MPA', (277, 292))	('rs1883965', 'Mutation', 'rs1883965', (115, 124))	('rs12125777', 'Mutation', 'rs12125777', (103, 113))	('rs11121691', 'Mutation', 'rs11121691', (216, 226))	('rs3806317', 'Var', (81, 90))	('rs12125777', 'Var', (103, 113))	('rs2536', 'Mutation', 'rs2536', (395, 401))	('rs11121691', 'Var', (216, 226))	('rs1074078', 'Mutation', 'rs1074078', (141, 150))	('rs1034528', 'Var', (92, 101))	('rs2295080', 'Var', (126, 135))	('rs17036508', 'Var', (406, 416))	('rs1034528', 'Mutation', 'rs1034528', (92, 101))	('rs17036508', 'Var', (239, 249))	('abolish', 'NegReg', (360, 367))	('protein', 'Protein', (370, 377))	('rs1883965', 'Var', (115, 124))	('affect', 'Reg', (270, 276))	('activity', 'MPA', (343, 351))	('rs1064261', 'Var', (255, 264))	('rs1057079', 'Var', (228, 237))	('rs1064261', 'Mutation', 'rs1064261', (255, 264))	('rs2536', 'Var', (395, 401))
271037	27462867	Intronic polymorphisms rs3806317, rs17036508, and rs1883965 had an FS score of 0.101, while that of rs1034528 was 0.398, probably reflecting the frameshift coding changes it may cause.	('rs17036508', 'Var', (34, 44))	('rs3806317', 'Mutation', 'rs3806317', (23, 32))	('rs1883965', 'Var', (50, 59))	('rs3806317', 'Var', (23, 32))	('rs1883965', 'Mutation', 'rs1883965', (50, 59))	('rs1034528', 'Mutation', 'rs1034528', (100, 109))	('rs17036508', 'Mutation', 'rs17036508', (34, 44))
271040	27462867	Given that rs2295080, rs1883965, rs1034528 and rs17036508 showed a potential association with cancer susceptibility, we further explored their relationship with mTOR transcript expression levels using the SNPexp web tool (Table 6-7).	('rs2295080', 'Mutation', 'rs2295080', (11, 20))	('rs1034528', 'Var', (33, 42))	('rs1883965', 'Var', (22, 31))	('association', 'Reg', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rs17036508', 'Mutation', 'rs17036508', (47, 57))	('rs1034528', 'Mutation', 'rs1034528', (33, 42))	('rs17036508', 'Var', (47, 57))	('rs2295080', 'Var', (11, 20))	('rs1883965', 'Mutation', 'rs1883965', (22, 31))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
271042	27462867	In the YRI population, the expression level of the rs1883965 heterozygote was lower than that of homozygotes (complete over-dominant: P = 0.043) (Table 6).	('rs1883965', 'Var', (51, 60))	('rs1883965', 'Mutation', 'rs1883965', (51, 60))	('expression level', 'MPA', (27, 43))	('lower', 'NegReg', (78, 83))
271043	27462867	For rs1034528, the C allele was correlated with significantly decreased levels of mTOR transcript expression compared with the G allele in both the European population (heterozygous: P = 0.023; dominant: P = 0.035; complete over-dominant: P = 0.019) and all populations (heterozygous: P = 0.002; dominant: P = 0.001; complete over-dominant: P = 0.003).	('levels', 'MPA', (72, 78))	('decreased', 'NegReg', (62, 71))	('rs1034528', 'Mutation', 'rs1034528', (4, 13))	('rs1034528', 'Var', (4, 13))	('mTOR transcript expression', 'MPA', (82, 108))
271050	27462867	As the mTOR pathway is a central controller of cellular growth, excessive activation caused by mutations or other changes in upstream pathways confers a growth advantage to cancer cells.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('growth advantage', 'CPA', (153, 169))	('activation', 'PosReg', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (95, 104))	('changes', 'Reg', (114, 121))
271051	27462867	Mutant mTOR proteins caused by point mutations around the kinase domain of mTOR demonstrate constitutive activation, and have been shown to affect cell cycle progression and cell size in human cancers.	('mTOR', 'Gene', (7, 11))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cell cycle progression', 'CPA', (147, 169))	('caused', 'Reg', (21, 27))	('cell size', 'CPA', (174, 183))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('cancers', 'Disease', (193, 200))	('activation', 'PosReg', (105, 115))	('proteins', 'Protein', (12, 20))	('point mutations', 'Var', (31, 46))	('affect', 'Reg', (140, 146))	('human', 'Species', '9606', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('mTOR', 'Gene', (75, 79))	('Mutant', 'Var', (0, 6))
271052	27462867	The present systematic review evaluated the overall effect of mTOR polymorphisms on cancer risk, and the updated meta-analysis evaluated the most commonly investigated mTOR polymorphisms: rs2536, rs2295080, rs1883965, rs1034528, rs17036508, rs3806317 and rs1064261.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('rs3806317', 'Var', (241, 250))	('rs2295080', 'Mutation', 'rs2295080', (196, 205))	('rs2536', 'Mutation', 'rs2536', (188, 194))	('cancer', 'Disease', (84, 90))	('rs1034528', 'Var', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rs17036508', 'Mutation', 'rs17036508', (229, 239))	('rs1883965', 'Var', (207, 216))	('rs2295080', 'Var', (196, 205))	('rs1883965', 'Mutation', 'rs1883965', (207, 216))	('rs3806317', 'Mutation', 'rs3806317', (241, 250))	('rs1064261', 'Var', (255, 264))	('rs1064261', 'Mutation', 'rs1064261', (255, 264))	('rs17036508', 'Var', (229, 239))	('rs2536', 'Var', (188, 194))	('rs1034528', 'Mutation', 'rs1034528', (218, 227))
271053	27462867	We identified a significant correlation between heterozygotes of SNPs rs1883965, rs1034528 and rs17036508 and increased cancer risk compared with homozygotes.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs1034528', 'Mutation', 'rs1034528', (81, 90))	('increased', 'PosReg', (110, 119))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('rs1883965', 'Var', (70, 79))	('rs1883965', 'Mutation', 'rs1883965', (70, 79))	('rs1034528', 'Var', (81, 90))	('rs17036508', 'Mutation', 'rs17036508', (95, 105))	('SNPs', 'Gene', (65, 69))	('rs17036508', 'Var', (95, 105))
271054	27462867	Significant results were also identified for SNP rs2295080 in the subgroup of genitourinary cancers and acute leukemia.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('genitourinary cancers', 'Disease', 'MESH:D014565', (78, 99))	('acute leukemia', 'Disease', 'MESH:D015470', (104, 118))	('acute leukemia', 'Disease', (104, 118))	('acute leukemia', 'Phenotype', 'HP:0002488', (104, 118))	('rs2295080', 'Mutation', 'rs2295080', (49, 58))	('genitourinary cancers', 'Disease', (78, 99))	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('SNP rs2295080', 'Var', (45, 58))
271056	27462867	The rs2536 (T > C) polymorphism in the mTOR 3'-UTR was predicted to affect miRNA-binding site activity based on the SNPinfo database.	('rs2536', 'Mutation', 'rs2536', (4, 10))	('miRNA-binding site activity', 'MPA', (75, 102))	('affect', 'Reg', (68, 74))	('rs2536 (T > C', 'Var', (4, 17))
271057	27462867	previously reported that co-transfection of the rs2536 G allele and A allele with miR-767-3p exhibited different promoter activities.	('rs2536', 'Mutation', 'rs2536', (48, 54))	('rs2536 G', 'Var', (48, 56))	('promoter activities', 'MPA', (113, 132))
271058	27462867	However, previous studies regarding the relationship between rs2536 and cancer risk are inconsistent.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rs2536', 'Mutation', 'rs2536', (61, 67))	('rs2536', 'Var', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
271059	27462867	In a study by Li et al., rs2536 was correlated with an increased risk of prostate cancer, while an earlier Chinese case-control study focusing on the risk of childhood acute lymphoblastic leukemia reported the opposite effect.	('rs2536', 'Var', (25, 31))	('prostate cancer', 'Disease', (73, 88))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (168, 196))	('leukemia', 'Phenotype', 'HP:0001909', (188, 196))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('acute lymphoblastic leukemia', 'Disease', (168, 196))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (168, 196))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (174, 196))	('rs2536', 'Mutation', 'rs2536', (25, 31))
271061	27462867	The present pooled analysis also found no significant association between rs2536 and cancer risk, after removing the main source of heterogeneity and performing stratified analyses by cancer type.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (85, 91))	('rs2536', 'Mutation', 'rs2536', (74, 80))	('rs2536', 'Var', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
271062	27462867	However, several studies indicated that although the main effect was not obvious, rs2536 was included in the best model to predict the risk of esophageal carcinoma and prostate cancer, together with polymorphisms known to be associated with cancer susceptibility and environmental factors such as body mass index (BMI).	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (143, 163))	('esophageal carcinoma and prostate cancer', 'Disease', 'MESH:D011471', (143, 183))	('men', 'Species', '9606', (274, 277))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('rs2536', 'Mutation', 'rs2536', (82, 88))	('rs2536', 'Var', (82, 88))
271063	27462867	This means that rs2536 should not be simply categorized as "not important", because it may interact with environmental factors or other genetic variations and is linked to cancer development through joint effects.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('men', 'Species', '9606', (186, 189))	('rs2536', 'Mutation', 'rs2536', (16, 22))	('rs2536', 'Var', (16, 22))	('linked', 'Reg', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('men', 'Species', '9606', (112, 115))	('interact', 'Reg', (91, 99))
271065	27462867	Moreover, patients with gastric cancer and renal cell cancer carrying the rs2295080 G allele showed decreased mTOR mRNA levels compared with those with the wild-type T allele.	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('renal cell cancer', 'Phenotype', 'HP:0005584', (43, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('decreased', 'NegReg', (100, 109))	('mTOR mRNA levels', 'MPA', (110, 126))	('gastric cancer', 'Disease', (24, 38))	('rs2295080', 'Mutation', 'rs2295080', (74, 83))	('rs2295080 G', 'Var', (74, 85))	('renal cell cancer', 'Disease', 'MESH:C538614', (43, 60))	('renal cell cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('patients', 'Species', '9606', (10, 18))
271066	27462867	Additionally, rs2295080 has been linked to decreased mTOR promoter activity in several cell lines.	('mTOR promoter activity', 'MPA', (53, 75))	('rs2295080', 'Mutation', 'rs2295080', (14, 23))	('decreased', 'NegReg', (43, 52))	('rs2295080', 'Var', (14, 23))
271067	27462867	Many previous studies have shown that the rs2295080 G allele is associated with a decreased risk of gastric cancer, colon cancer, prostate cancer, and renal cell cancer, and this was supported by a previously published meta-analysis.	('rs2295080 G', 'Var', (42, 53))	('prostate cancer', 'Disease', (130, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('renal cell cancer', 'Disease', 'MESH:C538614', (151, 168))	('renal cell cancer', 'Disease', (151, 168))	('renal cell cancer', 'Phenotype', 'HP:0005584', (151, 168))	('colon cancer', 'Disease', (116, 128))	('gastric cancer', 'Disease', (100, 114))	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('rs2295080', 'Mutation', 'rs2295080', (42, 51))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('prostate cancer', 'Disease', 'MESH:D011471', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (130, 145))	('decreased', 'NegReg', (82, 91))
271069	27462867	We found that the rs2295080 G allele was associated with a significantly lower risk of genitourinary cancers in the dominant model, and a higher risk of acute leukemia in the recessive model.	('genitourinary cancers', 'Disease', (87, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('rs2295080', 'Mutation', 'rs2295080', (18, 27))	('rs2295080 G', 'Var', (18, 29))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('acute leukemia', 'Disease', (153, 167))	('acute leukemia', 'Phenotype', 'HP:0002488', (153, 167))	('acute leukemia', 'Disease', 'MESH:D015470', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('genitourinary cancers', 'Disease', 'MESH:D014565', (87, 108))	('lower', 'NegReg', (73, 78))
271070	27462867	Therefore, the biological effect of rs2295080 might be cancer-specific.	('rs2295080', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('rs2295080', 'Mutation', 'rs2295080', (36, 45))	('cancer', 'Disease', (55, 61))
271071	27462867	Notably, an obvious divergence of rs2295080 effects was observed in cancers of the digestive system, which might be partially explained by a high degree of heterogeneity, especially for gastric cancer.	('gastric cancer', 'Disease', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs2295080', 'Mutation', 'rs2295080', (34, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('rs2295080', 'Var', (34, 43))
271072	27462867	A more detailed classification based on clinical, histologic, and molecular features will help to elucidate the relationship between rs2295080 and gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('rs2295080', 'Var', (133, 142))	('gastrointestinal cancers', 'Disease', (147, 171))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (147, 171))	('rs2295080', 'Mutation', 'rs2295080', (133, 142))
271073	27462867	The SNP rs1883965 (G > A) is located within the first intron of mTOR, so is more likely to be involved in the regulation of transcription and be associated with disease compared with SNPs in other introns.	('SNP', 'Var', (4, 7))	('regulation of transcription', 'MPA', (110, 137))	('rs1883965 (G > A', 'Var', (8, 24))	('mTOR', 'Gene', (64, 68))	('associated with', 'Reg', (145, 160))	('rs1883965', 'Mutation', 'rs1883965', (8, 17))	('involved', 'Reg', (94, 102))	('disease', 'Disease', (161, 168))
271074	27462867	The SNPinfo database indicated that rs1883965 is located in a TFBS, which may affect the level or timing of gene expression.	('rs1883965', 'Var', (36, 45))	('level', 'MPA', (89, 94))	('rs1883965', 'Mutation', 'rs1883965', (36, 45))	('affect', 'Reg', (78, 84))
271075	27462867	Two previous studies indicated increased associations between the rs1883965 A allele and the risks of esophageal carcinoma and gastric cancer, and our present meta-analysis found the heterozygote GA to be significantly associated with increased cancer risk compared with homozygotes GG and AA.	('associations', 'Interaction', (41, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (102, 122))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (102, 122))	('rs1883965 A', 'Var', (66, 77))	('cancer', 'Disease', (245, 251))	('rs1883965', 'Mutation', 'rs1883965', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('gastric cancer', 'Disease', (127, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('esophageal carcinoma', 'Disease', (102, 122))
271076	27462867	Interestingly, we observed slightly decreased mTOR mRNA expression in YRI individuals carrying the rs1883965 heterozygote GA (P = 0.043).	('mTOR mRNA expression', 'MPA', (46, 66))	('rs1883965', 'Mutation', 'rs1883965', (99, 108))	('rs1883965', 'Var', (99, 108))	('decreased', 'NegReg', (36, 45))
271077	27462867	Therefore, more studies are essential to obtain a more reliable conclusion regarding the association between rs1883965 and mTOR transcription.	('mTOR', 'Gene', (123, 127))	('rs1883965', 'Var', (109, 118))	('rs1883965', 'Mutation', 'rs1883965', (109, 118))	('association', 'Interaction', (89, 100))
271079	27462867	Bioinformatics analysis revealed that rs1034528 is located within a TFBS and causes a frameshift coding change.	('frameshift coding change', 'MPA', (86, 110))	('causes', 'Reg', (77, 83))	('rs1034528', 'Var', (38, 47))	('rs1034528', 'Mutation', 'rs1034528', (38, 47))
271080	27462867	SNP rs17036508 was predicted to be located within a miRNA binding site and an exonic splicing enhancer or silencer motif, affecting the splicing of pre-RNA.	('rs17036508', 'Mutation', 'rs17036508', (4, 14))	('silencer motif', 'Disease', 'None', (106, 120))	('affecting', 'Reg', (122, 131))	('silencer motif', 'Disease', (106, 120))	('splicing', 'MPA', (136, 144))	('SNP rs17036508', 'Var', (0, 14))
271081	27462867	Previously, the associations between rs1034528 and rs17036508 and gastric and prostate cancer were investigated and the rs1034528 C allele was shown to be a risk factor in two independent studies.	('rs17036508', 'Mutation', 'rs17036508', (51, 61))	('gastric and prostate cancer', 'Disease', 'MESH:D013274', (66, 93))	('rs1034528', 'Mutation', 'rs1034528', (120, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (78, 93))	('rs1034528', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rs17036508', 'Var', (51, 61))	('rs1034528', 'Var', (120, 129))	('rs1034528', 'Mutation', 'rs1034528', (37, 46))
271082	27462867	In the present study, we found that heterozygote carriers of rs1034528 and rs17036508 were more likely to develop cancer compared with homozygotes.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('rs1034528', 'Mutation', 'rs1034528', (61, 70))	('develop', 'PosReg', (106, 113))	('rs1034528', 'Var', (61, 70))	('rs17036508', 'Mutation', 'rs17036508', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rs17036508', 'Var', (75, 85))	('cancer', 'Disease', (114, 120))
271083	27462867	Because the mTOR signaling pathway usually promotes oncogenesis, this finding is unexpected but could be explained by the fact that mTOR mutants caused by different amino acid substitutions have different abilities to phosphorylate substrates S6K1 and 4E-BP1, even though they are expressed at similar levels after nutrient starvation.	('phosphorylate', 'MPA', (218, 231))	('caused by', 'Reg', (145, 154))	('promotes', 'PosReg', (43, 51))	('substitutions', 'Var', (176, 189))	('mTOR', 'Gene', (132, 136))	('S6K1 and 4E-BP1', 'Gene', '6198;1978', (243, 258))	('oncogenesis', 'CPA', (52, 63))	('abilities', 'MPA', (205, 214))	('mutants', 'Var', (137, 144))
271084	27462867	Thus, it is conceivable that a frameshift within the coding region (rs1034528) or splicing variants (rs17036508) confers hyperactivation to the mTOR protein, which promotes the development of cancer regardless of the expression level.	('development', 'CPA', (177, 188))	('hyperactivation', 'PosReg', (121, 136))	('rs1034528', 'Mutation', 'rs1034528', (68, 77))	('mTOR protein', 'Protein', (144, 156))	('rs17036508', 'Mutation', 'rs17036508', (101, 111))	('promotes', 'PosReg', (164, 172))	('cancer', 'Disease', (192, 198))	('men', 'Species', '9606', (184, 187))	('rs1034528', 'Var', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('rs17036508', 'Var', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
271085	27462867	Alternatively, rs1034528 and rs17036508 are respectively located in 5' upstream region and 3'-UTR of the angiopoietin-like 7 gene (ANGPTL7), itself within intron 28 of mTOR.	('rs1034528', 'Var', (15, 24))	('angiopoietin-like 7', 'Gene', '10218', (105, 124))	('rs17036508', 'Mutation', 'rs17036508', (29, 39))	('rs17036508', 'Var', (29, 39))	('rs1034528', 'Mutation', 'rs1034528', (15, 24))	('ANGPTL7', 'Gene', (131, 138))	('ANGPTL7', 'Gene', '10218', (131, 138))	('angiopoietin-like 7', 'Gene', (105, 124))
271090	27462867	Positive correlations of the rs1064261 C allele with an increased risk of neuroendocrine tumors and gastric cancer in men have been reported, while its interaction with rs2295080 was also identified in esophageal squamous cell carcinoma.	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (202, 236))	('neuroendocrine tumors', 'Disease', (74, 95))	('rs1064261', 'Mutation', 'rs1064261', (29, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (74, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('rs2295080', 'Mutation', 'rs2295080', (169, 178))	('men', 'Species', '9606', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('esophageal squamous cell carcinoma', 'Disease', (202, 236))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (74, 95))	('gastric cancer', 'Disease', (100, 114))	('rs1064261 C', 'Var', (29, 40))
271091	27462867	However, our previous work found no association between rs1064261 and total or phosphorylated mTOR protein in gastric cancer mucosa.	('gastric cancer', 'Disease', (110, 124))	('phosphorylated', 'MPA', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs1064261', 'Var', (56, 65))	('rs1064261', 'Mutation', 'rs1064261', (56, 65))
271092	27462867	The present meta-analysis also revealed no association between rs1064261 and overall cancer risk.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('rs1064261', 'Var', (63, 72))	('rs1064261', 'Mutation', 'rs1064261', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
271093	27462867	As for SNP rs1057079, carriers of the G allele were at higher risk of developing colon cancer and breast cancer and ethnic differences might exist for the effect of rs1057079 on cancer risk.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('cancer', 'Disease', (87, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (98, 111))	('rs1057079', 'Mutation', 'rs1057079', (165, 174))	('colon cancer', 'Phenotype', 'HP:0003003', (81, 93))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colon cancer', 'Disease', 'MESH:D015179', (81, 93))	('SNP rs1057079', 'Var', (7, 20))	('rs1057079', 'Mutation', 'rs1057079', (11, 20))	('colon cancer', 'Disease', (81, 93))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
271096	27462867	While no functional information currently exists for SNPs rs2024627 (C > T) and rs718206 (A > T), they were shown to be significantly associated with increased colon cancer risk by a case-control study.	('associated', 'Reg', (134, 144))	('rs2024627', 'Mutation', 'rs2024627', (58, 67))	('colon cancer', 'Disease', 'MESH:D015179', (160, 172))	('rs718206 (A > T', 'Var', (80, 95))	('colon cancer', 'Disease', (160, 172))	('rs718206', 'Mutation', 'rs718206', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('increased', 'PosReg', (150, 159))	('colon cancer', 'Phenotype', 'HP:0003003', (160, 172))
271100	27462867	found that individuals carrying four adverse genotypes from six mTOR polymorphisms (rs2536, rs1883965, rs1034528, rs17036508, rs3806317, and rs2295080) exhibited a higher susceptibility of developing prostate cancer (adjusted OR = 1.74, 95% CI 1.20-2.51) compared with those with one or zero adverse genotypes.	('rs17036508', 'Mutation', 'rs17036508', (114, 124))	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('rs2295080', 'Mutation', 'rs2295080', (141, 150))	('rs2536', 'Var', (84, 90))	('rs1034528', 'Mutation', 'rs1034528', (103, 112))	('rs3806317', 'Mutation', 'rs3806317', (126, 135))	('rs2536', 'Mutation', 'rs2536', (84, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('rs1883965', 'Var', (92, 101))	('rs17036508', 'Var', (114, 124))	('rs1883965', 'Mutation', 'rs1883965', (92, 101))	('rs3806317', 'Var', (126, 135))	('prostate cancer', 'Disease', (200, 215))	('rs1034528', 'Var', (103, 112))	('rs2295080', 'Var', (141, 150))
271101	27462867	Such cumulative effects were also observed across SNPs in mTOR and mTOR pathway-related genes (PIK3R1, AKT2, and PTEN), or in genes encoding components of mTOR complex 1 (mLST8 and RPTOR).	('AKT2', 'Gene', (103, 107))	('PIK3R1', 'Gene', (95, 101))	('AKT2', 'Gene', '208', (103, 107))	('mTOR', 'Gene', (58, 62))	('mLST8', 'Gene', (171, 176))	('SNPs', 'Var', (50, 54))	('RPTOR', 'Gene', (181, 186))	('RPTOR', 'Gene', '57521', (181, 186))	('mLST8', 'Gene', '56716', (171, 176))	('PTEN', 'Gene', (113, 117))	('PTEN', 'Gene', '5728', (113, 117))	('PIK3R1', 'Gene', '5295', (95, 101))
271102	27462867	Several studies assessed mTOR haplotype effects on cancer risk.	('haplotype', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('effects', 'Reg', (40, 47))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mTOR', 'Gene', (25, 29))
271103	27462867	explored the relationships between haplotypes of rs2295080, rs1064261 and rs1057079 and the risk of esophageal squamous cell carcinoma.	('rs1057079', 'Var', (74, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (100, 134))	('rs1064261', 'Var', (60, 69))	('rs2295080', 'Mutation', 'rs2295080', (49, 58))	('rs1064261', 'Mutation', 'rs1064261', (60, 69))	('esophageal squamous cell carcinoma', 'Disease', (100, 134))	('rs1057079', 'Mutation', 'rs1057079', (74, 83))	('rs2295080', 'Var', (49, 58))
271104	27462867	Although no significant association was observed when SNPs were analyzed individually, there were clear associations between three of the seven identified haplotypes and increased cancer risk compared with the most frequent haplotype.	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (180, 186))	('haplotypes', 'Var', (155, 165))
271105	27462867	Interactions of rs2295080 with either rs1057079 or rs1064261 were also found.	('rs1064261', 'Mutation', 'rs1064261', (51, 60))	('rs1057079', 'Var', (38, 47))	('rs2295080', 'Var', (16, 25))	('rs1057079', 'Mutation', 'rs1057079', (38, 47))	('Interactions', 'Interaction', (0, 12))	('rs1064261', 'Var', (51, 60))	('rs2295080', 'Mutation', 'rs2295080', (16, 25))
271106	27462867	Possible interactions between mTOR polymorphisms and environmental factors such as smoking status, drinking status, age, sex and BMI have also been reported.	('men', 'Species', '9606', (60, 63))	('interactions', 'Interaction', (9, 21))	('mTOR', 'Gene', (30, 34))	('polymorphisms', 'Var', (35, 48))
271109	27462867	It has been reported in mouse heart tissue that phosphorylated S6, which reflects the activity of mTOR, is positively related to body weight.	('related', 'Reg', (118, 125))	('phosphorylated', 'Var', (48, 62))	('mouse', 'Species', '10090', (24, 29))
271110	27462867	Because the mTOR pathway regulates energy metabolism and as cancer can be regarded as a metabolic disorder, it is not surprising that BMI might be a mediator between mTOR variants and cancer susceptibility.	('cancer', 'Disease', (184, 190))	('metabolic disorder', 'Disease', (88, 106))	('mTOR', 'Gene', (166, 170))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('regulates', 'Reg', (25, 34))	('metabolic disorder', 'Phenotype', 'HP:0001939', (88, 106))	('mTOR pathway', 'Pathway', (12, 24))	('metabolic disorder', 'Disease', 'MESH:D008659', (88, 106))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('energy metabolism', 'MPA', (35, 52))	('variants', 'Var', (171, 179))
271112	27462867	First, although we collected all published clinical evidence investigating mTOR SNPs and cancer risk, the pooled sample size of this meta-analysis was still relatively small, especially for rs1034528, rs17036508, rs1064261, and rs3806317.	('rs3806317', 'Mutation', 'rs3806317', (228, 237))	('rs1034528', 'Var', (190, 199))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('rs17036508', 'Mutation', 'rs17036508', (201, 211))	('rs3806317', 'Var', (228, 237))	('cancer', 'Disease', (89, 95))	('rs1064261', 'Var', (213, 222))	('rs17036508', 'Var', (201, 211))	('rs1064261', 'Mutation', 'rs1064261', (213, 222))	('rs1034528', 'Mutation', 'rs1034528', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
271118	27462867	Several polymorphisms, such as rs2295080, rs11121704, and rs12139042, have been shown to be significantly associated with lung and esophageal cancer, but more attention should be given to the association of mTOR polymorphisms with treatment response to inhibitors of the mTOR pathway.	('rs11121704', 'Var', (42, 52))	('associated', 'Reg', (106, 116))	('rs2295080', 'Mutation', 'rs2295080', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('esophageal cancer', 'Disease', (131, 148))	('rs11121704', 'Mutation', 'rs11121704', (42, 52))	('men', 'Species', '9606', (236, 239))	('rs12139042', 'Var', (58, 68))	('rs12139042', 'Mutation', 'rs12139042', (58, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('lung', 'Disease', (122, 126))	('rs2295080', 'Var', (31, 40))
271120	27462867	This means that mTOR polymorphisms may also play roles in other age-related diseases, such as cardiovascular and neurodegenerative disorders, and further investigation is required.	('play roles', 'Reg', (44, 54))	('polymorphisms', 'Var', (21, 34))	('mTOR', 'Gene', (16, 20))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (113, 140))	('cardiovascular and neurodegenerative disorders', 'Disease', 'MESH:D002318', (94, 140))
271122	27462867	The following keywords were used jointly as search terms: "mTOR" or "FRAP" or "RAFT1" or "RAPT1", "polymorphism" or "variant" or "mutation" and "cancer" or "tumor" or "carcinoma" or "carcinoma" or "malignancy".	('cancer', 'Disease', (145, 151))	('tumor', 'Disease', (157, 162))	('"carcinoma" or "carcinoma" or "malignancy', 'Disease', 'MESH:D009369', (167, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('polymorphism" or "variant" or "mutation', 'Var', (99, 138))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('"carcinoma" or "carcinoma" or "malignancy', 'Disease', (167, 208))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
271123	27462867	Studies were eligible if they met the following criteria: (1) evaluated the association between mTOR polymorphisms and cancer risk; (2) written in English or Chinese; and (3) case-control studies.	('mTOR', 'Gene', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('association', 'Interaction', (76, 87))	('cancer', 'Disease', (119, 125))	('polymorphisms', 'Var', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
271128	27462867	To identify the best matching genetic model for mTOR polymorphisms in the occurrence of malignancies, we used the methods recommended by Thakkinstian.	('mTOR', 'Gene', (48, 52))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))	('malignancies', 'Disease', (88, 100))	('men', 'Species', '9606', (127, 130))	('polymorphisms', 'Var', (53, 66))
271131	27462867	(2) If a recessive model was indicated, VV versus W carriers (WV plus WW).	('WV plus WW', 'Disease', (62, 72))	('VV versus W carriers', 'Var', (40, 60))	('WV plus WW', 'Disease', 'MESH:D007625', (62, 72))
271162	27957288	A study that was conducted in China concluded that findings did not support a major role for HPV16, HPV18, and HPV73 in the etiology of EC.	('HPV16', 'Gene', (93, 98))	('HPV73', 'Var', (111, 116))	('HPV16', 'Species', '333760', (93, 98))
271175	27957288	Some of tumor suppressor genes that have been studied in ESCC include:   Over 100 ESCC mutations have been gathered in the IARC TP53 mutation database.	('P53', 'Gene', (129, 132))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('P53', 'Gene', '7157', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ESCC', 'Gene', (82, 86))	('mutations', 'Var', (87, 96))
271177	27957288	In Japan, Kihara and colleagues found that the prognosis of patients with p53 mutated EC was significantly poorer (chemotherapy resistant) than patients whose tumors had no p53 mutations (p=0.006).	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('poorer', 'NegReg', (107, 113))	('tumors', 'Disease', (159, 165))	('p53', 'Gene', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('mutated', 'Var', (78, 85))
271179	27957288	The preliminary data suggested that p21 polymorphisms were not associated with development of ESCC in northeastern Iran, and gene-environment interaction analysis showed that cigarette smoking might have synergistic interactions with P21 C/A and p21 C/T genotype in ESCC carcinogenesis in this region.	('P21 C', 'Mutation', 'p.P21C', (234, 239))	('ESCC carcinogenesis', 'Disease', (266, 285))	('P21 C/A', 'Var', (234, 241))	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (266, 285))	('p21 C/T', 'Var', (246, 253))
271181	27957288	P16 gene silencing caused by hypermethylation of CpG islands may be a major mechanism in the ESCC development and is associated with overexpression of p53 protein.	('silencing', 'NegReg', (9, 18))	('P16', 'Gene', (0, 3))	('hypermethylation', 'Var', (29, 45))	('P16', 'Gene', '1029', (0, 3))	('ESCC', 'Disease', (93, 97))
271183	27957288	Genetic polymorphisms may affect the activity of enzymes that metabolize carcinogens and make individuals more or less susceptible to the carcinogenic effects of the carcinogenic exposure.	('metabolize', 'Enzyme', (62, 72))	('less', 'NegReg', (114, 118))	('enzymes', 'Enzyme', (49, 56))	('affect', 'Reg', (26, 32))	('carcinogenic effects of the carcinogenic', 'Disease', (138, 178))	('activity', 'MPA', (37, 45))	('Genetic polymorphisms', 'Var', (0, 21))	('carcinogenic effects of the carcinogenic', 'Disease', 'MESH:D063646', (138, 178))
271187	27957288	Acetaldehyde has been demonstrated to be carcinogenic and therefore genetic variations resulting in functional differences in ADH and ALDH activity, which lead to increased levels of acetaldehyde in drinkers may be important.	('increased levels of acetaldehyde', 'Phenotype', 'HP:0003533', (163, 195))	('increased', 'PosReg', (163, 172))	('ALDH', 'Protein', (134, 138))	('levels of acetaldehyde', 'MPA', (173, 195))	('variations', 'Var', (76, 86))	('activity', 'MPA', (139, 147))	('ADH', 'Gene', (126, 129))	('Acetaldehyde', 'Chemical', 'MESH:D000079', (0, 12))
271188	27957288	An association was shown between inactive polymorphism of the GSTM1 gene and the presence of esophageal squamous dysplasia, in a PAH-exposed population in China.	('polymorphism', 'Var', (42, 54))	('GSTM1', 'Gene', (62, 67))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (104, 122))	('esophageal squamous dysplasia', 'Disease', (93, 122))	('esophageal squamous dysplasia', 'Disease', 'MESH:D000077277', (93, 122))
271191	27957288	The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC in the joint data set under a recessive model (OR=0.41, 95% CI: 0.29-0.76, p=0.0004).	('histidine allele at codon 48', 'Var', (4, 32))	('ADH1B', 'Gene', (36, 41))	('decreased', 'NegReg', (83, 92))	('ADH1B', 'Gene', '125', (36, 41))	('histidine', 'Chemical', 'MESH:D006639', (4, 13))	('ESCC', 'Disease', (101, 105))
271192	27957288	The allele of the rs7087131 variant of MGMT (methyl guanine DNA methyltransferase) gene was associated with a decreased risk of ESCC under a dominant model (OR=0.79, 95% CI: 0.64-0.96, p=0.02).	('rs7087131', 'Mutation', 'rs7087131', (18, 27))	('methyl guanine DNA methyltransferase', 'Gene', '4255', (45, 81))	('decreased', 'NegReg', (110, 119))	('methyl guanine DNA methyltransferase', 'Gene', (45, 81))	('MGMT', 'Gene', (39, 43))	('rs7087131', 'Var', (18, 27))	('MGMT', 'Gene', '4255', (39, 43))	('ESCC', 'Disease', (128, 132))
271195	27957288	In a meta-analysis it was shown that NQO1 C609T polymorphism increased the risk of ESCC (OR=2.03, 95% CI=1.29-3.19).	('NQO1', 'Gene', (37, 41))	('C609T', 'Var', (42, 47))	('C609T', 'Mutation', 'rs1800566', (42, 47))	('ESCC', 'Disease', (83, 87))
271205	27957288	Some of miRNAs, which were associated with poor prognosis of ESCC are miR-103/107, miR-21, and MiR-27a.	('MiR-27a', 'Gene', '407018', (95, 102))	('ESCC', 'Disease', (61, 65))	('MiR-27a', 'Gene', (95, 102))	('miR-21', 'Gene', (83, 89))	('miR-103/107', 'Var', (70, 81))	('miR-21', 'Gene', '406991', (83, 89))
271214	25927305	Our findings suggest that the CYP2C19*2 polymorphism plays an important role in the development of ESCC in the Chinese population, modified by tea drinking and consumption of pickled vegetables or hot beverages/food.	('hot beverage', 'Phenotype', 'HP:0031217', (197, 209))	('CYP2C19', 'Gene', (30, 37))	('hot', 'Gene', (197, 200))	('ESCC', 'Disease', (99, 103))	('polymorphism', 'Var', (40, 52))	('CYP2C19', 'Gene', '1557', (30, 37))	('hot', 'Gene', '137872', (197, 200))
271216	25927305	Although smoking, alcohol drinking and prolonged use of wood or charcoal as sources of fuel for cooking and heating (resulting in excessive smoke inhalation) have been demonstrated as lifestyle factors that contribute to the development of the disease, the DNA sequence variations that confer an additional risk remain largely unknown.	('variations', 'Var', (270, 280))	('smoke inhalation', 'MPA', (140, 156))	('alcohol', 'Chemical', 'MESH:D000438', (18, 25))	('alcohol drinking', 'Phenotype', 'HP:0030955', (18, 34))
271220	25927305	Therefore, it is conceivable that CYP2C19 gene polymorphisms may play a major role in inter-individual variability in drug response, drug-drug and drug-xenobiotic interactions and susceptibility to chemical-induced diseases.	('CYP2C19', 'Gene', '1557', (34, 41))	('polymorphisms', 'Var', (47, 60))	('role', 'Reg', (78, 82))	('CYP2C19', 'Gene', (34, 41))	('drug-xenobiotic', 'Disease', 'MESH:D019966', (147, 162))	('chemical-induced diseases', 'Disease', (198, 223))	('drug-xenobiotic', 'Disease', (147, 162))	('play', 'Reg', (65, 69))
271221	25927305	Several polymorphisms of CYP2C19 are known to be associated with reduced enzyme activity; however, most cases are due to either CYP2C19*2, which is characterized by a point mutation in exon 5 (681G   A, rs4244285), or CYP2C19*3, which has a mutation in exon 4 (636G   A, rs4986893).	('CYP2C19', 'Gene', '1557', (218, 225))	('636G   A', 'Var', (261, 269))	('CYP2C19', 'Gene', '1557', (25, 32))	('reduced', 'NegReg', (65, 72))	('CYP2C19', 'Gene', (218, 225))	('rs4986893', 'Var', (271, 280))	('enzyme activity', 'MPA', (73, 88))	('CYP2C19', 'Gene', '1557', (128, 135))	('rs4986893', 'Mutation', 'rs4986893', (271, 280))	('CYP2C19', 'Gene', (25, 32))	('rs4244285', 'Mutation', 'rs4244285', (203, 212))	('681G   A', 'Var', (193, 201))	('CYP2C19', 'Gene', (128, 135))	('rs4244285', 'Var', (203, 212))	('due', 'Reg', (114, 117))
271234	25927305	DNA was extracted from the blood cell pellet using a Blood Genome DNA Extraction Kit (Takara Bio Inc., Otsu, Japan) and stored at -20 C. CYP2C19*2 (681G   A, rs4244285) and CYP2C19*3 (636G   A, rs4986893) genotypes were determined using polymerase chain reaction (PCR)-based restriction fragment length polymorphism.	('rs4986893', 'Mutation', 'rs4986893', (194, 203))	('CYP2C19', 'Gene', '1557', (173, 180))	('636G   A', 'Var', (184, 192))	('rs4244285', 'Mutation', 'rs4244285', (158, 167))	('CYP2C19', 'Gene', (137, 144))	('681G   A', 'Var', (148, 156))	('CYP2C19', 'Gene', '1557', (137, 144))	('CYP2C19', 'Gene', (173, 180))	('rs4244285', 'Var', (158, 167))
271239	25927305	Individuals who inherit two mutant CYP2C19 alleles, whether of the same type (*2/*2, *3/*3) or one of each (*2/*3) have a reduced capacity to metabolize CYP2C19 substrates and are considered to be PMs.	('*2/*2', 'Var', (78, 83))	('CYP2C19', 'Gene', '1557', (153, 160))	('*3/*3', 'Var', (85, 90))	('CYP2C19', 'Gene', (35, 42))	('CYP2C19', 'Gene', (153, 160))	('PMs', 'Chemical', '-', (197, 200))	('capacity', 'MPA', (130, 138))	('reduced', 'NegReg', (122, 129))	('CYP2C19', 'Gene', '1557', (35, 42))
271240	25927305	Individuals who are homozygous (*1/*1) or heterozygous (*1/*2, *1/*3) for the WT CYP2C19*1 allele have an effective enzyme for metabolizing CYP2C19 substrates and are EMs.	('CYP2C19', 'Gene', (81, 88))	('*1/*1', 'Var', (32, 37))	('CYP2C19', 'Gene', (140, 147))	('CYP2C19', 'Gene', '1557', (81, 88))	('CYP2C19', 'Gene', '1557', (140, 147))
271244	25927305	A goodness of fit chi-square test was used to assess whether the genotype distribution of CYP2C19 polymorphisms was in Hardy-Weinberg equilibrium among the control subjects.	('CYP2C19', 'Gene', '1557', (90, 97))	('polymorphisms', 'Var', (98, 111))	('goodness', 'Disease', (2, 10))	('CYP2C19', 'Gene', (90, 97))	('goodness', 'Disease', 'None', (2, 10))
271268	25927305	Generally in case control studies, a potential gene-environment interaction is assessed; our results show that the association between the CYP2C19*2 A variant and ESCC was modified by tea drinking and consumption of pickled vegetables or hot beverages/food.	('ESCC', 'Disease', (163, 167))	('hot', 'Gene', (238, 241))	('CYP2C19', 'Gene', (139, 146))	('hot beverage', 'Phenotype', 'HP:0031217', (238, 250))	('CYP2C19', 'Gene', '1557', (139, 146))	('hot', 'Gene', '137872', (238, 241))	('variant', 'Var', (151, 158))	('association', 'Interaction', (115, 126))	('modified', 'Reg', (172, 180))
271270	25927305	To our knowledge, this is the first study to report this gene-environment interaction between environmental factors and the CYP2C19*2 polymorphism with respect to the risk of ESCC in a Chinese population.	('polymorphism', 'Var', (134, 146))	('ESCC', 'Disease', (175, 179))	('CYP2C19', 'Gene', (124, 131))	('CYP2C19', 'Gene', '1557', (124, 131))
271273	25927305	The human CYP2C19 gene is highly polymorphic; the most important alleles are CYP2C19*2 (681G   A, rs4244285) and CYP2C19*3 (636G   A, rs4986893).	('636G   A', 'Var', (124, 132))	('rs4244285', 'Mutation', 'rs4244285', (98, 107))	('CYP2C19', 'Gene', (77, 84))	('rs4986893', 'Mutation', 'rs4986893', (134, 143))	('human', 'Species', '9606', (4, 9))	('CYP2C19', 'Gene', '1557', (10, 17))	('CYP2C19', 'Gene', (113, 120))	('rs4244285', 'Var', (98, 107))	('CYP2C19', 'Gene', '1557', (113, 120))	('CYP2C19', 'Gene', '1557', (77, 84))	('CYP2C19', 'Gene', (10, 17))	('rs4986893', 'Var', (134, 143))
271274	25927305	The nucleotide changes in CYP2C19*2 and *3 lead to a splicing defect and a stop codon, respectively, and thereby to nonfunctional proteins and the PM phenotype.	('CYP2C19', 'Gene', (26, 33))	('nonfunctional proteins', 'MPA', (116, 138))	('lead', 'Reg', (43, 47))	('defect', 'NegReg', (62, 68))	('splicing', 'MPA', (53, 61))	('CYP2C19', 'Gene', '1557', (26, 33))	('nucleotide changes', 'Var', (4, 22))
271285	25927305	CYP2C19 polymorphism is considered to be one of the factors that determine an individual's susceptibility cancer through variations in ability to detoxify carcinogens and/or activate procarcinogens.	('activate', 'PosReg', (174, 182))	('ability', 'MPA', (135, 142))	('variations', 'Var', (121, 131))	('detoxify carcinogens', 'MPA', (146, 166))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('CYP2C19', 'Gene', (0, 7))	('cancer', 'Disease', (106, 112))	('CYP2C19', 'Gene', '1557', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
271288	25927305	Our findings suggest that the CYP2C19*2 polymorphism has a multiplicative joint effect with tea drinking and hot beverage/food consumption and an additive joint effect with pickled vegetable consumption.	('hot beverage', 'Phenotype', 'HP:0031217', (109, 121))	('CYP2C19', 'Gene', (30, 37))	('hot', 'Gene', '137872', (109, 112))	('hot', 'Gene', (109, 112))	('polymorphism', 'Var', (40, 52))	('CYP2C19', 'Gene', '1557', (30, 37))
271291	25927305	Consistent with this, our data show that pickled food consumption was associated with a 1.76-fold increased risk of ESCC compared with subjects who did not consume pickled food, and this association was modified by the presence of CYP2C19*2.	('pickled food', 'Var', (41, 53))	('ESCC', 'Disease', (116, 120))	('CYP2C19', 'Gene', (231, 238))	('CYP2C19', 'Gene', '1557', (231, 238))
271294	25927305	Furthermore, polymorphisms in CYP2C19 largely account for PM status and influence metabolism, particularly detoxification of carcinogens.	('CYP2C19', 'Gene', (30, 37))	('detoxification of carcinogens', 'MPA', (107, 136))	('polymorphisms', 'Var', (13, 26))	('CYP2C19', 'Gene', '1557', (30, 37))	('influence', 'Reg', (72, 81))	('metabolism', 'MPA', (82, 92))	('account for', 'Reg', (46, 57))	('PM status', 'MPA', (58, 67))
271295	25927305	Therefore, synergism between the CYP2C19*2 polymorphism and pickled vegetable consumption may be expected.	('polymorphism', 'Var', (43, 55))	('CYP2C19', 'Gene', (33, 40))	('CYP2C19', 'Gene', '1557', (33, 40))
271298	25927305	Notably, we found significant synergism between consumption of hot beverages/food and the CYP2C19*2 polymorphism.	('polymorphism', 'Var', (100, 112))	('synergism', 'Reg', (30, 39))	('CYP2C19', 'Gene', '1557', (90, 97))	('hot', 'Gene', '137872', (63, 66))	('hot beverage', 'Phenotype', 'HP:0031217', (63, 75))	('CYP2C19', 'Gene', (90, 97))	('hot', 'Gene', (63, 66))
271300	25927305	The results of the present study also suggest possible interactions between tea drinking and the CYP2C19*2 polymorphism.	('interactions', 'Interaction', (55, 67))	('polymorphism', 'Var', (107, 119))	('CYP2C19', 'Gene', (97, 104))	('CYP2C19', 'Gene', '1557', (97, 104))
271306	25927305	Finally, the selected CYP2C19 polymorphism is a single example that was previously reported to have potential functional significance.	('polymorphism', 'Var', (30, 42))	('CYP2C19', 'Gene', (22, 29))	('CYP2C19', 'Gene', '1557', (22, 29))
271307	25927305	Further studies of additional SNPs of functional significance are warranted to identify the role of CYP2C19 polymorphism and gene-environment interactions in esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (158, 183))	('CYP2C19', 'Gene', '1557', (100, 107))	('esophageal carcinogenesis', 'Disease', (158, 183))	('polymorphism', 'Var', (108, 120))	('CYP2C19', 'Gene', (100, 107))
271310	22867894	Propensity score based comparison of long term outcomes with 3D conformal radiotherapy (3DCRT) versus Intensity Modulated Radiation Therapy (IMRT) in the treatment of esophageal cancer Although 3DCRT is the worldwide standard for the treatment of esophageal cancers, IMRT improves dose conformality and reduces radiation exposure to normal tissues.	('radiation exposure to normal tissues', 'MPA', (311, 347))	('esophageal cancer', 'Disease', 'MESH:D004938', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('IMRT', 'Var', (267, 271))	('esophageal cancers', 'Disease', (247, 265))	('dose conformality', 'MPA', (281, 298))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('esophageal cancers', 'Disease', 'MESH:D004938', (247, 265))	('reduces', 'NegReg', (303, 310))	('esophageal cancer', 'Disease', 'MESH:D004938', (247, 264))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('improves', 'PosReg', (272, 280))	('esophageal cancer', 'Disease', (167, 184))
271316	22867894	An increased cumulative incidence of cardiac deaths was seen in the 3DCRT group (p=0.049), but most deaths were undocumented (5 year estimate: 11.7% in 3DCRT vs 5.4% in IMRT, Gray's test, p=0.0029).	('cardiac deaths', 'Disease', (37, 51))	('cardiac deaths', 'Phenotype', 'HP:0001645', (37, 51))	('cardiac deaths', 'Disease', 'MESH:D003643', (37, 51))	('3DCRT', 'Var', (68, 73))	('death', 'Disease', 'MESH:D003643', (100, 105))	('death', 'Disease', (100, 105))	('3DCRT', 'Var', (152, 157))	('death', 'Disease', (45, 50))	('death', 'Disease', 'MESH:D003643', (45, 50))
271317	22867894	Overall survival, locoregional control, and non-cancer related deaths were significantly better for IMRT compared to 3DCRT.	('better', 'PosReg', (89, 95))	('locoregional control', 'CPA', (18, 38))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('death', 'Disease', 'MESH:D003643', (63, 68))	('death', 'Disease', (63, 68))	('non-cancer', 'Disease', (44, 54))	('IMRT', 'Var', (100, 104))	('non-cancer', 'Disease', 'MESH:D009369', (44, 54))	('Overall survival', 'CPA', (0, 16))
271336	22867894	A minority of patients also received transhiatal, left thoracotomy, radical (en block) resection, or minimally invasive esophagectomy.	('patients', 'Species', '9606', (14, 22))	('left thoracotomy', 'Disease', (50, 66))	('transhiatal', 'Var', (37, 48))
271368	22867894	Excess deaths due to indeterminate causes were also significantly higher for 3DCRT compared to IMRT (5 year estimate: 11.7% 3DCRT vs. 5.4% IMRT, p=0.0029, Gray's test).	('Excess deaths', 'Disease', (0, 13))	('3DCRT', 'Var', (77, 82))	('higher', 'PosReg', (66, 72))	('Excess deaths', 'Disease', 'MESH:D003643', (0, 13))
271375	22867894	We also observed a higher incidence of documented cardiac-related deaths with 3DCRT, but more patients were lost to follow up in the 3DCRT patients without clear documentation of the cause of death.	('3DCRT', 'Var', (78, 83))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (139, 147))	('death', 'Disease', 'MESH:D003643', (192, 197))	('death', 'Disease', (192, 197))	('death', 'Disease', 'MESH:D003643', (66, 71))	('death', 'Disease', (66, 71))
271422	22410812	The diagnosis of DM was based on the updated criteria of the American Diabetes Association, including a past history of DM, a fasting plasma glucose >=126 mg/dL, or glycated hemoglobin (HbA1c) >=6.5%.	('HbA1', 'Gene', (186, 190))	('DM', 'Disease', 'MESH:D009223', (120, 122))	('glucose', 'Chemical', 'MESH:D005947', (141, 148))	('DM', 'Disease', 'MESH:D009223', (17, 19))	('Diabetes', 'Disease', (70, 78))	('glycated hemoglobin', 'Phenotype', 'HP:0040217', (165, 184))	('>=126', 'Var', (149, 154))	('HbA1', 'Gene', '3039', (186, 190))	('Diabetes', 'Disease', 'MESH:D003920', (70, 78))	('glycated', 'MPA', (165, 173))
271446	22410812	Second, to explore the association between glycemic control and various GI manifestations, we further stratified the total study population into three groups based on the HbA1c levels: HbA1c <5.5, 5.5<= HbA1c <6.0, and HbA1c >=6.0.	('HbA1', 'Gene', '3039', (171, 175))	('HbA1', 'Gene', '3039', (203, 207))	('HbA1', 'Gene', '3039', (185, 189))	('HbA1', 'Gene', '3039', (219, 223))	('HbA1', 'Gene', (171, 175))	('HbA1', 'Gene', (203, 207))	('5.5<=', 'Var', (197, 202))	('HbA1', 'Gene', (185, 189))	('HbA1', 'Gene', (219, 223))
271539	18940008	Many in vitro and in vivo studies demonstrated that polyphenols from green tea were anti-carcinogenic by inducing apoptosis and inhibiting cell-growth, cyclin-dependent kinase inhibitor and urokinase (an enzyme crucial for cancer growth).	('urokinase', 'MPA', (190, 199))	('cell-growth', 'CPA', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cyclin-dependent kinase inhibitor', 'MPA', (152, 185))	('inducing', 'PosReg', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('polyphenols', 'Chemical', 'MESH:D059808', (52, 63))	('inhibiting', 'NegReg', (128, 138))	('cancer', 'Disease', (223, 229))	('apoptosis', 'CPA', (114, 123))	('polyphenols', 'Var', (52, 63))
271566	18940008	The tea polyphenol epigallocatechin in urine was inversely associated with cancer risk when the data of gastric and esophageal cancer sub-sites were combined, indicating protective effect of green tea.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('epigallocatechin', 'Var', (19, 35))	('polyphenol epigallocatechin', 'Chemical', '-', (8, 35))	('cancer', 'Disease', (75, 81))	('associated', 'Reg', (59, 69))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('gastric and esophageal cancer', 'Disease', 'MESH:D013274', (104, 133))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('inversely', 'NegReg', (49, 58))
271618	30854115	Association between TNF-alpha-308G/A polymorphism and esophageal cancer risk: An updated meta-analysis and trial sequential analysis Background: TNF-alpha-308G/A (rs1800629) polymorphism has been previously implicated in the susceptibility to esophageal cancer, but results of these studies remained controversial or ambiguous.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('TNF-alpha', 'Gene', (20, 29))	('rs1800629', 'Mutation', 'rs1800629', (163, 172))	('implicated', 'Reg', (207, 217))	('rs1800629', 'Var', (163, 172))	('TNF-alpha', 'Gene', '7124', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('TNF-alpha', 'Gene', '7124', (20, 29))	('-308G/A', 'Mutation', 'rs1800629', (29, 36))	('TNF-alpha', 'Gene', (145, 154))	('esophageal cancer', 'Disease', (243, 260))	('polymorphism', 'Var', (174, 186))	('Association', 'Interaction', (0, 11))	('-308G/A', 'Mutation', 'rs1800629', (154, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (243, 260))
271619	30854115	A meta-analysis was conducted to provide a more reliable conclusion about the association between TNF-alpha-308G/A polymorphism and risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('polymorphism', 'Var', (115, 127))	('esophageal cancer', 'Disease', (140, 157))	('TNF-alpha-308G/A', 'Gene', (98, 114))	('association', 'Interaction', (78, 89))
271622	30854115	Overall, our results indicated no significant correlation between TNF-alpha-308G/A polymorphism and increased risk of esophageal cancer in the fixed-effects model (allele model: pooled OR=1.11, 95% CI: 0.96-1.27, homozygote model: pooled OR=1.23, 95% CI: 0.77-1.95, heterozygote model: pooled OR=1.14, 95% CI: 0.97-1.35, dominant model: pooled OR=1.14, 95% CI: 0.97-1.34 and recessive model: pooled OR=1.00, 95% CI: 0.64-1.56).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('polymorphism', 'Var', (83, 95))	('TNF-alpha-308G/A', 'Gene', (66, 82))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))
271625	30854115	Conclusions: This meta-analysis study suggested no significant association between TNF-alpha-308G/A polymorphism and the risk of esophageal cancer.	('polymorphism', 'Var', (100, 112))	('TNF-alpha-308G/A', 'Gene', (83, 99))	('esophageal cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
271629	30854115	Recent studies have shown that several single-nucleotide genetic polymorphisms (SNPs) were associated with the susceptibility to esophageal cancer.	('single-nucleotide genetic polymorphisms', 'Var', (39, 78))	('associated', 'Reg', (91, 101))	('esophageal cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
271632	30854115	Dysregulated expression of TNF-alpha was reported to be associated with various disorders, including inflammatory diseases (such as Rheumatoid arthritis, Crohn's disease), central nervous system diseases (Alzheimer's disease) and a variety of other tumors.	('arthritis', 'Phenotype', 'HP:0001369', (143, 152))	('central nervous system diseases', 'Disease', (172, 203))	('Rheumatoid arthritis', 'Disease', 'MESH:D001172', (132, 152))	('associated', 'Reg', (56, 66))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (205, 224))	("Alzheimer's disease", 'Disease', (205, 224))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('central nervous system diseases', 'Disease', 'MESH:D002493', (172, 203))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (205, 224))	('Dysregulated', 'Var', (0, 12))	('central nervous system diseases', 'Phenotype', 'HP:0002011', (172, 203))	('inflammatory diseases', 'Disease', (101, 122))	('Rheumatoid arthritis', 'Phenotype', 'HP:0001370', (132, 152))	('TNF-alpha', 'Gene', '7124', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('TNF-alpha', 'Gene', (27, 36))	("Crohn's disease", 'Phenotype', 'HP:0100280', (154, 169))	("Crohn's disease", 'Disease', 'MESH:D003424', (154, 169))	('Rheumatoid arthritis', 'Disease', (132, 152))	("Crohn's disease", 'Disease', (154, 169))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('expression', 'MPA', (13, 23))	('inflammatory diseases', 'Disease', 'MESH:D007249', (101, 122))	('tumors', 'Disease', (249, 255))
271634	30854115	A number of SNPs of TNF-alpha gene have been found, which include TNF-alpha-238 G/A (rs361525), TNF-alpha-308G/A (rs1800629), TNF-alpha-857C/T (rs179972), TNF-alpha-863C/A (rs1800630), TNF-alpha-509C/T (rs1800469) and TNF-alpha-1031T/C (rs1799964).	('rs179972', 'Var', (144, 152))	('TNF-alpha', 'Gene', (126, 135))	('rs1800469', 'Var', (203, 212))	('rs179972', 'Mutation', 'rs179972', (144, 152))	('rs361525', 'Mutation', 'rs361525', (85, 93))	('rs1799964', 'Mutation', 'rs1799964', (237, 246))	('TNF-alpha', 'Gene', '7124', (20, 29))	('rs361525', 'Var', (85, 93))	('TNF-alpha', 'Gene', (20, 29))	('rs1800629', 'Var', (114, 123))	('TNF-alpha', 'Gene', '7124', (155, 164))	('rs1800469', 'Mutation', 'rs1800469', (203, 212))	('TNF-alpha', 'Gene', (155, 164))	('TNF-alpha', 'Gene', '7124', (218, 227))	('rs1800630', 'Var', (173, 182))	('TNF-alpha', 'Gene', (218, 227))	('TNF-alpha', 'Gene', '7124', (185, 194))	('TNF-alpha', 'Gene', (185, 194))	('rs1799964', 'Var', (237, 246))	('rs1800629', 'Mutation', 'rs1800629', (114, 123))	('TNF-alpha', 'Gene', '7124', (66, 75))	('TNF-alpha', 'Gene', (66, 75))	('TNF-alpha', 'Gene', '7124', (96, 105))	('TNF-alpha', 'Gene', (96, 105))	('rs1800630', 'Mutation', 'rs1800630', (173, 182))	('TNF-alpha', 'Gene', '7124', (126, 135))
271635	30854115	Among these, the most common TNF-alpha polymorphisms is present in the promoter region at position -308 and it has been studied most extensively.	('TNF-alpha', 'Gene', (29, 38))	('TNF-alpha', 'Gene', '7124', (29, 38))	('polymorphisms', 'Var', (39, 52))
271638	30854115	Therefore, the results of this meta-analysis demonstrated that no evidence supporting the relationship between TNF-alpha-308G/A polymorphism and esophageal cancer risk was detected.	('esophageal cancer', 'Disease', (145, 162))	('polymorphism', 'Var', (128, 140))	('TNF-alpha-308G/A', 'Gene', (111, 127))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))
271639	30854115	The following index terms and Mesh terms were used for the search: "tumor necrosis factor alpha" or "TNF-alpha", "polymorphism" or "variants" and "esophageal cancer" or "esophageal tumor" or "ECa".	('esophageal cancer', 'Disease', (147, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('esophageal tumor', 'Phenotype', 'HP:0100751', (170, 186))	('TNF-alpha', 'Gene', '7124', (101, 110))	('tumor necrosis factor alpha', 'Gene', '7124', (68, 95))	('TNF-alpha', 'Gene', (101, 110))	('polymorphism" or "variants', 'Var', (114, 140))	('tumor necrosis factor alpha', 'Gene', (68, 95))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('esophageal tumor', 'Disease', 'MESH:D004938', (170, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('esophageal tumor', 'Disease', (170, 186))
271640	30854115	Inclusion criteria were as follows: (1) An independent case-control study; (2) Association between TNF-alpha-308G/A gene polymorphism and susceptibility to esophageal cancer; (3) The study should also contain abundant data of regarding the genotype frequency to evaluate whether such association was available.	('polymorphism', 'Var', (121, 133))	('esophageal cancer', 'Disease', (156, 173))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('TNF-alpha-308G/A', 'Gene', (99, 115))	('Association', 'Interaction', (79, 90))
271649	30854115	The strength of association between TNF-alpha-308G/A polymorphism and esophageal cancer risk was evaluated by the pooled ORs with 95% CIs based on five genetic comparison models.	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('TNF-alpha-308G/A', 'Gene', (36, 52))	('polymorphism', 'Var', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
271650	30854115	Summary of all results regarding the relationship between TNF-alpha-308G/A polymorphisms and esophageal cancer risk in the 9 studies was provided in Table 2.	('polymorphisms', 'Var', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('TNF-alpha-308G/A', 'Gene', (58, 74))	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))
271657	30854115	Previous studies have suggested that dysregulated expression of TNF-alpha might promote the occurrence and development of tumors.	('tumors', 'Disease', (122, 128))	('TNF-alpha', 'Gene', (64, 73))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('promote', 'PosReg', (80, 87))	('occurrence', 'CPA', (92, 102))	('dysregulated', 'Var', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('TNF-alpha', 'Gene', '7124', (64, 73))	('expression', 'MPA', (50, 60))
271658	30854115	Notably, TNF-alpha production is regulated by SNP in the promoter region.	('TNF-alpha', 'Gene', '7124', (9, 18))	('SNP', 'Var', (46, 49))	('regulated', 'Reg', (33, 42))	('TNF-alpha', 'Gene', (9, 18))
271659	30854115	At least 12 SNPs have been identified in the TNF-alpha gene, and the most studied SNP is TNF-alpha-308G/A (rs1800629).	('rs1800629', 'Var', (107, 116))	('TNF-alpha', 'Gene', (89, 98))	('TNF-alpha', 'Gene', '7124', (45, 54))	('TNF-alpha', 'Gene', (45, 54))	('TNF-alpha', 'Gene', '7124', (89, 98))	('rs1800629', 'Mutation', 'rs1800629', (107, 116))
271661	30854115	To date, some studies have investigated whether TNF-alpha-308G/A polymorphism was associated with the risk of esophageal cancer.	('associated', 'Reg', (82, 92))	('polymorphism', 'Var', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TNF-alpha-308G/A', 'Gene', (48, 64))	('esophageal cancer', 'Disease', (110, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))
271662	30854115	In a word, there is no definitive conclusion about the role of rs1800629 in esophageal cancer risk.	('esophageal cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('rs1800629', 'Mutation', 'rs1800629', (63, 72))	('rs1800629', 'Var', (63, 72))
271663	30854115	study suggested that TNF-alpha-308 G>A polymorphism enhanced the risk of esophageal cancer, especially in females and in patients with regional lymph node involvement.	('esophageal cancer', 'Disease', (73, 90))	('TNF-alpha-308', 'Gene', (21, 34))	('enhanced', 'PosReg', (52, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('polymorphism', 'Var', (39, 51))	('patients', 'Species', '9606', (121, 129))
271669	30854115	With the development of the current meta-analysis study, a more comprehensive understanding of the relationship between rs1800629 and the risk of esophageal cancer by different subgroup analysis was performed.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('esophageal cancer', 'Disease', (146, 163))	('rs1800629', 'Mutation', 'rs1800629', (120, 129))	('rs1800629', 'Var', (120, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))
271670	30854115	Our study results revealed no significant relationship between TNF-alpha-308G/A polymorphism and increased risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TNF-alpha-308G/A', 'Gene', (63, 79))	('polymorphism', 'Var', (80, 92))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))
271677	30854115	In conclusion, our meta-analysis study demonstrated no evidence supporting the relationship between TNF-alpha-308G/A polymorphism and esophageal cancer risk.	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('polymorphism', 'Var', (117, 129))	('TNF-alpha-308G/A', 'Gene', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('esophageal cancer', 'Disease', (134, 151))
271692	27866035	Common presentations of ectopic thyroid include incidental, asymptomatic, functional hypo- or hyperthyroidism, and mass effect.	('functional hypo- or hyperthyroidism', 'Phenotype', 'HP:0008223', (74, 109))	('asymptomatic', 'Disease', (60, 72))	('hyperthyroidism', 'Phenotype', 'HP:0000836', (94, 109))	('ectopic', 'Var', (24, 31))	('ectopic thyroid', 'Phenotype', 'HP:0100028', (24, 39))	('hyperthyroidism', 'Disease', (94, 109))	('incidental', 'Disease', (48, 58))	('mass effect', 'Disease', (115, 126))	('hyperthyroidism', 'Disease', 'MESH:D006980', (94, 109))
271722	27866035	Ectopic thyroid has been reported to cause mass effect, and depending on location and malignant potential, dysphagia, but not to the extent of creating point tenderness.	('Ectopic thyroid', 'Phenotype', 'HP:0100028', (0, 15))	('dysphagia', 'Disease', (107, 116))	('point tenderness', 'Disease', (152, 168))	('dysphagia', 'Phenotype', 'HP:0002015', (107, 116))	('point tenderness', 'Disease', 'MESH:D016171', (152, 168))	('Ectopic', 'Var', (0, 7))	('dysphagia', 'Disease', 'MESH:D003680', (107, 116))	('cause', 'Reg', (37, 42))	('mass effect', 'Disease', (43, 54))
271771	23829638	When the diffusion-sensitive gradient b-value was 400, 600, and 800 s/mm2, the differences between the GTV length using DWI and pathology were 0.73 +- 6.09 mm, -0.54 +- 6.03 mm and -1.58 +- 5.71 mm, respectively.	('mm2', 'Gene', '10687', (70, 73))	('mm2', 'Gene', (70, 73))	('400', 'Var', (50, 53))	('GTV', 'Chemical', '-', (103, 106))
271839	23829638	When the diffusion-sensitive gradient b-value was 400, 600, and 800 s/mm2, the difference between the pathologic lesion length and the GTV length on the DWI scans was 0.73 +- 6.09 mm, -0.54 +- 6.03 mm and -1.58 +- 5.71 mm, respectively.	('mm2', 'Gene', '10687', (70, 73))	('mm2', 'Gene', (70, 73))	('400', 'Var', (50, 53))	('GTV', 'Chemical', '-', (135, 138))
271888	21913019	Overexpression of BMP7 mRNA in colorectal cancer patients was significantly associated with poor prognosis and low overall survival.	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('BMP7', 'Gene', (18, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('colorectal cancer', 'Disease', (31, 48))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (49, 57))	('low', 'NegReg', (111, 114))	('BMP7', 'Gene', '655', (18, 22))
271935	21913019	Those who had BMP7 expression tended to occur local lymph node relapse.	('BMP7', 'Gene', '655', (14, 18))	('expression', 'Var', (19, 29))	('BMP7', 'Gene', (14, 18))	('local lymph node relapse', 'CPA', (46, 70))
271952	21913019	In this study, the 5-year overall survival rate for the patients with BMP7 positive expression was significantly worse than those with negative expression even in the patients without lymph node metastasis.	('patients', 'Species', '9606', (56, 64))	('BMP7', 'Gene', '655', (70, 74))	('positive expression', 'Var', (75, 94))	('patients', 'Species', '9606', (167, 175))	('BMP7', 'Gene', (70, 74))	('overall survival', 'CPA', (26, 42))	('worse', 'NegReg', (113, 118))
271967	20846397	Patients with higher HDGF expression showed a significantly shorter overall survival time than did patients with low HDGF expression.	('expression', 'Var', (26, 36))	('overall survival time', 'CPA', (68, 89))	('patients', 'Species', '9606', (99, 107))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (60, 67))	('HDGF', 'Protein', (21, 25))
271970	20846397	Compared to the parental and control shRNA-transfected (shCtrl) HepG2 cells, the shHDGF cells exhibited significantly reduced in vitro cell growth, anchorage-independent growth, cell migration and invasion (p < 0.05).	('invasion', 'CPA', (197, 205))	('cell migration', 'CPA', (178, 192))	('reduced', 'NegReg', (118, 125))	('shHDGF', 'Var', (81, 87))	('HepG2', 'CellLine', 'CVCL:0027', (64, 69))	('anchorage-independent growth', 'CPA', (148, 176))
271971	20846397	In vivo, the xenograft transplants from shHDGF cells gave rise to much smaller tumors as compared to those from shCtrl cells.	('shHDGF', 'Var', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('smaller', 'NegReg', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
271972	20846397	High HDGF expression is associated with poor overall survival in patients with HCC.	('High', 'Var', (0, 4))	('HDGF', 'Protein', (5, 9))	('patients', 'Species', '9606', (65, 73))	('HCC', 'Disease', (79, 82))	('HCC', 'Phenotype', 'HP:0001402', (79, 82))
271977	20846397	Similar to most other types of cancer, hepatocarcinogenesis is a multi-step process involving multiple genetic alterations, such as activation of oncogenes and inactivation of tumor suppressor genes, which ultimately lead to malignant transformation of hepatocytes.	('activation', 'PosReg', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (176, 181))	('malignant transformation', 'CPA', (225, 249))	('lead to', 'Reg', (217, 224))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (39, 59))	('inactivation', 'Var', (160, 172))	('cancer', 'Disease', (31, 37))	('oncogenes', 'Gene', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('hepatocarcinogenesis', 'Disease', (39, 59))
272035	20846397	When testing the abilities of HepG2 cells to migrate/invade through 8-mumum pores on the polycarbonate membrane either without or with pre-coated matrigel, we found the knocking down endogenous HDGF significantly reduced the potentials of HepG2 cells to both migrate and invade (p < 0.05), as compared to the parental or shCtrl cells (Figure 5).	('reduced', 'NegReg', (213, 220))	('HDGF', 'Gene', (194, 198))	('invade', 'CPA', (271, 277))	('HepG2', 'CellLine', 'CVCL:0027', (239, 244))	('HepG2', 'CellLine', 'CVCL:0027', (30, 35))	('knocking down', 'Var', (169, 182))	('migrate', 'CPA', (259, 266))
272037	20846397	As shown in Figure 6, by measuring the tumor weights, we found that shHDGF cells gave rise to significantly smaller tumors than shCtrl cells (p < 0.05).	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('shHDGF cells', 'Var', (68, 80))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('smaller', 'NegReg', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))
272038	20846397	Real-time qPCR showed that HDGF expression was obviously reduced in implanted nude mice of shHDGF cell groups compared with control cell groups(Figure 6C).	('nude mice', 'Species', '10090', (78, 87))	('shHDGF', 'Var', (91, 97))	('HDGF', 'Gene', (27, 31))	('reduced', 'NegReg', (57, 64))	('expression', 'MPA', (32, 42))
272041	20846397	On the molecular level, a number of epigenetic and genetic events have been associated with the development of HCC, including inactivation of tumor suppressor p53 and epigenetic targeting of cancer-related genes such as HIA-2, CDKN2A, p16-INK4a, E-cadherin and T-cadherin, activation of JNK1, ErbB-2, Wnt signaling and multiple receptor tyrosine kinases.	('p16', 'Gene', (235, 238))	('ErbB-2', 'Gene', '2064', (293, 299))	('inactivation', 'Var', (126, 138))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('p53', 'Gene', '7157', (159, 162))	('activation', 'PosReg', (273, 283))	('p16', 'Gene', '1029', (235, 238))	('receptor tyrosine kinases', 'Enzyme', (328, 353))	('CDKN2A', 'Gene', '1029', (227, 233))	('HCC', 'Disease', (111, 114))	('cancer', 'Disease', (191, 197))	('HCC', 'Phenotype', 'HP:0001402', (111, 114))	('ErbB-2', 'Gene', (293, 299))	('p53', 'Gene', (159, 162))	('epigenetic targeting', 'Var', (167, 187))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('T-cadherin', 'Gene', '1012', (261, 271))	('Wnt signaling', 'Pathway', (301, 314))	('tumor', 'Disease', (142, 147))	('JNK1', 'Gene', '5599', (287, 291))	('HIA-2', 'Gene', (220, 225))	('INK4a', 'Gene', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('E-cadherin', 'Gene', (246, 256))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('JNK1', 'Gene', (287, 291))	('E-cadherin', 'Gene', '999', (246, 256))	('T-cadherin', 'Gene', (261, 271))	('CDKN2A', 'Gene', (227, 233))	('INK4a', 'Gene', '1029', (239, 244))
272042	20846397	All these genetic and epigenetic alterations are not unique for HCC, but also present in many other human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('malignancies', 'Disease', (106, 118))	('epigenetic alterations', 'Var', (22, 44))	('HCC', 'Disease', (64, 67))	('human', 'Species', '9606', (100, 105))	('HCC', 'Phenotype', 'HP:0001402', (64, 67))	('present', 'Reg', (78, 85))
272048	20846397	Similar to our result, Yoshida et al also reported that HCC patients from Japan with a positive HDGF index had significantly poorer disease-free and overall survivals compared with patients with a negative index.	('HCC', 'Disease', (56, 59))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('poorer', 'NegReg', (125, 131))	('patients', 'Species', '9606', (60, 68))	('overall survivals', 'CPA', (149, 166))	('index', 'Var', (101, 106))	('patients', 'Species', '9606', (181, 189))	('positive', 'Var', (87, 95))	('HDGF', 'Gene', (96, 100))
272050	20846397	By transfecting the cells with shRNA-expressing lentiviral vector followed by selection with Blasticidin, we successfully established stable cells expressing either control or HDGF-specific shRNA, with the latter showing dramatically reduced HDGF level as compared to the former.	('reduced', 'NegReg', (234, 241))	('Blasticidin', 'Chemical', 'MESH:C004500', (93, 104))	('shRNA', 'Gene', (190, 195))	('HDGF-specific', 'Var', (176, 189))	('HDGF level', 'MPA', (242, 252))	('reduced HDGF level', 'Phenotype', 'HP:0004315', (234, 252))
272051	20846397	The subsequent functional studies demonstrated that knocking down the endogenous expression of HDGF led to significant reduced in vitro cell growth, transformation, migration, invasion, as well as in vivo xenograft tumor formation.	('migration', 'CPA', (165, 174))	('knocking down', 'Var', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('endogenous', 'MPA', (70, 80))	('transformation', 'CPA', (149, 163))	('HDGF', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('reduced', 'NegReg', (119, 126))	('invasion', 'CPA', (176, 184))
272061	33667223	Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed.	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Disease', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('variants', 'Var', (22, 30))
272062	33667223	To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('oro/pharyngeal SqCC', 'Disease', (118, 137))	('laryngeal SqCC', 'Disease', (147, 161))	('lung SqCC', 'Disease', (98, 107))	('esophageal SqCC', 'Disease', (175, 190))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('variants', 'Var', (43, 51))	('cancers', 'Disease', (199, 206))	('LuSqCC', 'Chemical', '-', (109, 115))
272063	33667223	We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273).	('rs56321285', 'Var', (124, 134))	('rs56321285', 'Mutation', 'rs56321285', (124, 134))	('aerodigestive SqCC', 'Disease', (63, 81))	('TMEM273', 'Gene', (136, 143))	('TMEM273', 'Gene', '170371', (136, 143))
272064	33667223	Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8).	('rs12133735', 'Mutation', 'rs12133735', (100, 110))	('ABHD8', 'Gene', '79575', (179, 184))	('MDM4', 'Gene', '4194', (117, 121))	('ABHD8', 'Gene', (179, 184))	('rs12133735', 'Var', (100, 110))	('TMEM173', 'Gene', (144, 151))	('MDM4', 'Gene', (117, 121))	('TMEM173', 'Gene', '340061', (144, 151))	('rs61494113', 'Var', (167, 177))	('rs13181561', 'Var', (132, 142))	('rs61494113', 'Mutation', 'rs61494113', (167, 177))	('rs13181561', 'Mutation', 'rs13181561', (132, 142))
272065	33667223	Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2).	('CDKN2B-AS1', 'Gene', (200, 210))	('STK19', 'Gene', (163, 168))	('CDKN2B-AS1', 'Gene', '100048912', (200, 210))	('9p21.33', 'Var', (191, 198))	('HLA-DQB1', 'Gene', (180, 188))	('BRCA2', 'Gene', '675', (224, 229))	('BRCA2', 'Gene', (224, 229))	('6p21.33', 'Var', (154, 161))	('STK19', 'Gene', '8859', (163, 168))	('ADH1B', 'Gene', (146, 151))	('HLA-DQB1', 'Gene', '3119', (180, 188))	('6p21.32', 'Var', (171, 178))	('4q23', 'Var', (140, 144))	('ADH1B', 'Gene', '125', (146, 151))
272072	33667223	Similarly, recent molecular characterization studies across anatomically distinct SqCCs have shown that histology is more important than tissue of origin in defining tumor molecular profiles determined by shared features including somatic mutations, copy number alternations, deregulation of DNA methylation and/or gene expression.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('DNA methylation', 'Protein', (292, 307))	('deregulation', 'Var', (276, 288))	('gene', 'MPA', (315, 319))	('copy number alternations', 'Var', (250, 274))
272073	33667223	Previous genome-wide association studies (GWAS) have identified multiple genetic risk variants for individual aerodigestive SqCC types; notably variants in smoking-related genes at 15q25.1 for LuSqCC and 4q23 variants in alcohol-related genes for upper aerodigestive tract (UADT) cancers.	('upper aerodigestive tract', 'Disease', (247, 272))	('variants', 'Var', (144, 152))	('alcohol', 'Chemical', 'MESH:D000438', (221, 228))	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('LuSqCC', 'Disease', (193, 199))	('cancers', 'Disease', (280, 287))	('cancers', 'Disease', 'MESH:D009369', (280, 287))	('aerodigestive SqCC', 'Disease', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('alcohol-related genes', 'Gene', (221, 242))	('LuSqCC', 'Chemical', '-', (193, 199))	('4q23', 'Gene', (204, 208))
272074	33667223	Importantly, candidate-gene and GWAS studies have previously described rare genetic variants linked to aerodigestive SqCC risk; including variants near BRCA2 (13q13.1), first identified as a risk factor for ESqCC in Middle Eastern populations and later described to increase risk of LuSqCC and UADT SqCC in Europeans.	('ESqCC', 'Disease', (207, 212))	('UADT SqCC', 'Disease', (294, 303))	('aerodigestive SqCC', 'Disease', (103, 121))	('BRCA2', 'Gene', '675', (152, 157))	('LuSqCC', 'Disease', (283, 289))	('linked', 'Reg', (93, 99))	('risk factor', 'Reg', (191, 202))	('variants', 'Var', (138, 146))	('LuSqCC', 'Chemical', '-', (283, 289))	('BRCA2', 'Gene', (152, 157))
272075	33667223	Similarly, at 22q12.1 another rare missense variant within CHEK2 (rs17879961, p.Ile157Thr) has been linked to reduced risk of lung and UADT SqCCs.	('CHEK2', 'Gene', '11200', (59, 64))	('rs17879961', 'Var', (66, 76))	('reduced', 'NegReg', (110, 117))	('CHEK2', 'Gene', (59, 64))	('rs17879961', 'Mutation', 'rs17879961', (66, 76))	('p.Ile157Thr', 'Mutation', 'rs17879961', (78, 89))	('p.Ile157Thr', 'Var', (78, 89))
272076	33667223	Such studies provide evidence of genetic pleiotropy across aerodigestive SqCCs, as these variants exert cross-cancer effects possibly related to similar underlying mechanisms (i.e.	('variants', 'Var', (89, 97))	('exert', 'Reg', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cross-cancer', 'Disease', (104, 116))	('cross-cancer', 'Disease', 'MESH:D009369', (104, 116))	('aerodigestive', 'Disease', (59, 72))
272088	33667223	In contrast, other known cancer regions that reached the GWAS threshold (12p13.33, 15q25, 19q13.2) or Pmeta < 5x10-7 (4p14, 9q34.1, 10q24.31, 11q21, 15q15.3) in the SqCC meta-analysis were not pleiotropic (Fig 1).	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('12p13.33', 'Var', (73, 81))
272090	33667223	At 2q33.1, the intronic variant rs56321285[A] within the transmembrane protein 237 (TMEM237) gene was associated with reduced risk of aerodigestive SqCC (OR = 0.90, Pmeta = 6.99x10-9).	('aerodigestive SqCC', 'Disease', (134, 152))	('transmembrane protein 237', 'Gene', (57, 82))	('transmembrane protein 237', 'Gene', '65062', (57, 82))	('TMEM237', 'Gene', '65062', (84, 91))	('reduced', 'NegReg', (118, 125))	('rs56321285', 'Mutation', 'rs56321285', (32, 42))	('rs56321285[', 'Var', (32, 43))	('TMEM237', 'Gene', (84, 91))
272092	33667223	rs56321285 is in low linkage disequilibrium (LD) with other variants in the region (S2 Fig) including rs10931936 (r2 = 0.02, 1000 Genomes (1KG), Europeans), the lead SNP of a weaker 2q33.1 association (SqCC ORmeta = 1.08, Pmeta = 1.83x10-6).	('2q33.1', 'Gene', (182, 188))	('rs10931936', 'Mutation', 'rs10931936', (102, 112))	('rs56321285', 'Mutation', 'rs56321285', (0, 10))	('rs10931936', 'Var', (102, 112))	('rs56321285', 'Var', (0, 10))
272093	33667223	rs10931936 is in LD with nearby CASP8-ALS2CR12 variants which have been previously linked with risk of multiple cancers in Europeans, as well as esophageal and lung cancer in Chinese populations.	('multiple cancers', 'Disease', (103, 119))	('CASP8', 'Gene', (32, 37))	('variants', 'Var', (47, 55))	('rs10931936', 'Mutation', 'rs10931936', (0, 10))	('ALS2CR12', 'Gene', (38, 46))	('ALS2CR12', 'Gene', '130540', (38, 46))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('multiple cancers', 'Disease', 'MESH:D009369', (103, 119))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('rs10931936', 'Var', (0, 10))	('esophageal', 'Disease', (145, 155))	('CASP8', 'Gene', '841', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('linked with', 'Reg', (83, 94))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
272094	33667223	CASP8 plays an important role in apoptosis; mutations in this gene have been described in 2% of LuSqCC and 6% of UADT SqCC tumors (S7 Table).	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('CASP8', 'Gene', (0, 5))	('CASP8', 'Gene', '841', (0, 5))	('LuSqCC', 'Chemical', '-', (96, 102))	('UADT SqCC tumors', 'Disease', 'MESH:D006258', (113, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mutations', 'Var', (44, 53))	('described', 'Reg', (77, 86))	('UADT SqCC tumors', 'Disease', (113, 129))	('LuSqCC', 'Disease', (96, 102))
272095	33667223	However, the 2q33.1 genome-wide significant SNP (rs56321285) associated with aerodigestive SqCC risk, seems independent from CASP8-ALS2CR12 variants.	('associated with', 'Reg', (61, 76))	('rs56321285', 'Var', (49, 59))	('rs56321285', 'Mutation', 'rs56321285', (49, 59))	('ALS2CR12', 'Gene', '130540', (131, 139))	('CASP8', 'Gene', '841', (125, 130))	('ALS2CR12', 'Gene', (131, 139))	('CASP8', 'Gene', (125, 130))	('aerodigestive SqCC', 'Disease', (77, 95))
272096	33667223	In eQTL analyses using lung tissues Lung Microarray Study (S3 Table), rs56321285 is a nominally significant cis-eQTL for AOX2P (Laval and Groningen datasets) and CDK15 (Laval and UBC datasets).	('rs56321285', 'Var', (70, 80))	('rs56321285', 'Mutation', 'rs56321285', (70, 80))	('CDK15', 'Gene', (162, 167))	('AOX2P', 'Gene', '344454', (121, 126))	('AOX2P', 'Gene', (121, 126))	('CDK15', 'Gene', '65061', (162, 167))
272099	33667223	The lead SNP (rs12133735) at 1q32.1; the G allele was associated with increased risk of aerodigestive SqCC (ORmeta = 1.08, Pmeta = 2.16x10-7, Table 2 and Fig 2B), predominantly driven by the LuSqCC (OR = 1.07, P = 4.63x10-4) and OSqCC (OR = 1.14, P = 9.82x10-6) results.	('aerodigestive SqCC', 'Disease', (88, 106))	('LuSqCC', 'Chemical', '-', (191, 197))	('rs12133735', 'Var', (14, 24))	('rs12133735', 'Mutation', 'rs12133735', (14, 24))
272100	33667223	rs12133735 is located 3' of MDM4 (S3 Fig) and is a MDM4 eQTL in all datasets from the lung eQTL study (S3 Table and S4 Fig), and in lung and esophageal GTEx tissues (S4 Table).	('MDM4', 'Gene', '4194', (51, 55))	('rs12133735', 'Var', (0, 10))	('MDM4', 'Gene', '4194', (28, 32))	('MDM4', 'Gene', (51, 55))	('MDM4', 'Gene', (28, 32))	('rs12133735', 'Mutation', 'rs12133735', (0, 10))
272102	33667223	In contrast, in our analyses rs12133735-G is associated with lower MDM4 expression in lung tissues and increased SqCC risk.	('lower', 'NegReg', (61, 66))	('increased', 'PosReg', (103, 112))	('SqCC', 'Disease', (113, 117))	('rs12133735-G', 'Var', (29, 41))	('rs12133735', 'Mutation', 'rs12133735', (29, 39))	('expression', 'MPA', (72, 82))	('MDM4', 'Gene', '4194', (67, 71))	('MDM4', 'Gene', (67, 71))
272104	33667223	In Europeans, rs12133735[G] is in moderate LD (r2 = 0.61, 1KG) with rs4245739 [C] (SqCC OR meta = 1.07, P = 7.62x10-6) which has been associated with increased risk of triple negative breast cancer and ovarian cancer (S6 Table).	('rs12133735', 'Mutation', 'rs12133735', (14, 24))	('breast cancer', 'Disease', (184, 197))	('rs4245739 [C]', 'Var', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('ovarian cancer', 'Phenotype', 'HP:0100615', (202, 216))	('ovarian cancer', 'Disease', 'MESH:D010051', (202, 216))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('rs4245739', 'Mutation', 'rs4245739', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ovarian cancer', 'Disease', (202, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('rs12133735[', 'Var', (14, 25))
272105	33667223	Intriguingly, rs4245739 [C] has also been associated with reduced prostate cancer risk (Europeans) and lower risk of all cancers in Asians.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('reduced prostate cancer', 'Disease', (58, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('reduced prostate', 'Phenotype', 'HP:0008687', (58, 74))	('rs4245739 [C]', 'Var', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs4245739', 'Mutation', 'rs4245739', (14, 23))	('reduced prostate cancer', 'Disease', 'MESH:D011471', (58, 81))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
272106	33667223	A candidate-gene study also described associations between risk of HPV16-associated OSqCC and 1q32.1 MDM4 SNPs including rs11801299 (r2 = 0.12, with rs12133735, 1KG, Europeans), which was marginally associated with SqCC risk in our analysis (ORmeta = 0.91, Pmeta = 1.34x10-5).	('HPV16', 'Species', '333760', (67, 72))	('OSqCC', 'Disease', (84, 89))	('associated', 'Reg', (199, 209))	('associations', 'Interaction', (38, 50))	('SqCC', 'Disease', (215, 219))	('rs12133735', 'Mutation', 'rs12133735', (149, 159))	('MDM4 SNPs', 'Disease', 'None', (101, 110))	('rs12133735', 'Var', (149, 159))	('rs11801299', 'Var', (121, 131))	('MDM4 SNPs', 'Disease', (101, 110))	('rs11801299', 'Mutation', 'rs11801299', (121, 131))	('HPV16-associated', 'Gene', (67, 83))
272107	33667223	The lead variant at 5q31.2 rs13181561[G] (ORmeta = 1.09, P meta = 1.74x10-7, Fig 3A) near TMEM173 (S5 Fig) showed homogenous associations across tumor sites but only significant in LuSqCC and OSqCC.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('OSqCC', 'Disease', (192, 197))	('LuSqCC', 'Chemical', '-', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TMEM173', 'Gene', (90, 97))	('tumor', 'Disease', (145, 150))	('TMEM173', 'Gene', '340061', (90, 97))	('rs13181561', 'Mutation', 'rs13181561', (27, 37))	('rs13181561[', 'Var', (27, 38))	('LuSqCC', 'Disease', (181, 187))
272108	33667223	rs13181561 is associated with DNAJC18 and SPATA24 gene expression in lung tissues (Laval, Groningen and UBC; S3 Table), and of DNAJC18 in esophagus (GTEx, S4 Table).	('rs13181561', 'Var', (0, 10))	('DNAJC18', 'Gene', '202052', (127, 134))	('DNAJC18', 'Gene', (30, 37))	('DNAJC18', 'Gene', (127, 134))	('SPATA24', 'Gene', '202051', (42, 49))	('associated', 'Reg', (14, 24))	('expression', 'MPA', (55, 65))	('SPATA24', 'Gene', (42, 49))	('rs13181561', 'Mutation', 'rs13181561', (0, 10))	('DNAJC18', 'Gene', '202052', (30, 37))
272109	33667223	rs13181561 overlaps with an enhancer in esophageal and lung tissues (S5 Table).	('enhancer', 'PosReg', (28, 36))	('rs13181561', 'Var', (0, 10))	('rs13181561', 'Mutation', 'rs13181561', (0, 10))
272110	33667223	Additionally, rs13181561[G] is highly correlated with rs7447927[C] (r2 = 0.94, 1KG, Europeans), the latter (ORmeta = 1.08, P = 5.45x10-7) has been previously linked to increased ESqCC risk in Chinese populations (S6 Table).	('ESqCC', 'Disease', (178, 183))	('rs7447927[C', 'Var', (54, 65))	('rs7447927', 'Mutation', 'rs7447927', (54, 63))	('rs13181561[', 'Var', (14, 25))	('rs13181561', 'Mutation', 'rs13181561', (14, 24))
272112	33667223	Lung eQTL analysis showed rs61494113 as a significant eQTL for OCEL1 (Laval and Groening, S3 Table).	('OCEL1', 'Gene', (63, 68))	('OCEL1', 'Gene', '79629', (63, 68))	('rs61494113', 'Var', (26, 36))	('rs61494113', 'Mutation', 'rs61494113', (26, 36))
272113	33667223	However, the GTEx catalog shows rs61494113 as an esophageal ABHD8 eQTL and a BABAM1 splice-QTL (lung and esophagus) but not for OCEL1 (S4 Table).	('rs61494113', 'Var', (32, 42))	('rs61494113', 'Mutation', 'rs61494113', (32, 42))	('ABHD8', 'Gene', (60, 65))	('BABAM1', 'Gene', (77, 83))	('BABAM1', 'Gene', '29086', (77, 83))	('OCEL1', 'Gene', (128, 133))	('OCEL1', 'Gene', '79629', (128, 133))	('ABHD8', 'Gene', '79575', (60, 65))
272114	33667223	rs61494113 maps within H3K4me1 histone and DNase marks in normal lung tissues and in lung carcinoma cells (S5 Table).	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('rs61494113', 'Mutation', 'rs61494113', (0, 10))	('lung carcinoma', 'Disease', (85, 99))	('DNase', 'Protein', (43, 48))	('lung carcinoma', 'Disease', 'MESH:D008175', (85, 99))	('rs61494113', 'Var', (0, 10))	('H3K4me1 histone', 'Protein', (23, 38))
272115	33667223	rs61494113[A] is in complete LD with rs56069439[A] (r2 = 1, 1KG, Europeans), also associated with a SqCC risk (S1 Table and S6 Fig) and previously linked with increased risk of ER-negative breast and ovarian cancers (S6 Table).	('rs61494113[', 'Var', (0, 11))	('rs56069439', 'Mutation', 'rs56069439', (37, 47))	('associated with', 'Reg', (82, 97))	('ER', 'Gene', '2069', (177, 179))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('rs61494113', 'Mutation', 'rs61494113', (0, 10))	('rs56069439[', 'Var', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('SqCC', 'Disease', (100, 104))	('ovarian cancers', 'Phenotype', 'HP:0100615', (200, 215))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (189, 215))
272118	33667223	rs389884 near STK19 was the top pleotropic SNP at 6p21.33 (SqCC ORmeta = 1.26; P = 2.4x10-19, Table 3 and S2 Table).	('rs389884', 'Mutation', 'rs389884', (0, 8))	('rs389884', 'Var', (0, 8))	('STK19', 'Gene', '8859', (14, 19))	('STK19', 'Gene', (14, 19))
272119	33667223	6p21.33 SNPs are in moderate LD (rs389884 and rs115785414, r2>0.4, 1KG, Europeans) with variants at 6p22.1, suggesting a common haplotype.	('rs115785414', 'Mutation', 'rs115785414', (46, 57))	('rs115785414', 'Var', (46, 57))	('rs389884', 'Var', (33, 41))	('rs389884', 'Mutation', 'rs389884', (33, 41))
272120	33667223	We also detected associations at 6p21.32; rs9271611 near HLA-DQA1 (class II) is not correlated (S7 Fig) with 6p21.33 SNPs, pairwise LD between rs9267123 and rs9271611 r2 = 0.09 (1 KG, Europeans).	('rs9271611', 'Var', (42, 51))	('rs9271611', 'Mutation', 'rs9271611', (42, 51))	('HLA-DQA1', 'Gene', '3117', (57, 65))	('rs9271611', 'Var', (157, 166))	('rs9267123', 'Var', (143, 152))	('HLA-DQA1', 'Gene', (57, 65))	('rs9267123', 'Mutation', 'rs9267123', (143, 152))	('rs9271611', 'Mutation', 'rs9271611', (157, 166))
272124	33667223	rs7857345 (9p21.33 lead SNP mapped to CDKN2B-AS1, S8 Fig) was associated with a slight increase in SqCC risk (ORmeta = 1.11, Pmeta = 5.55x10-10, Table 3).	('CDKN2B-AS1', 'Gene', '100048912', (38, 48))	('SqCC', 'Disease', (99, 103))	('rs7857345', 'Mutation', 'rs7857345', (0, 9))	('rs7857345', 'Var', (0, 9))	('CDKN2B-AS1', 'Gene', (38, 48))
272125	33667223	rs7857345 is in LD with rs61271866 (r2 = 0.51) previously associated with ESqCC in Chinese populations.	('associated', 'Reg', (58, 68))	('rs7857345', 'Mutation', 'rs7857345', (0, 9))	('rs61271866', 'Var', (24, 34))	('rs61271866', 'Mutation', 'rs61271866', (24, 34))	('ESqCC', 'Disease', (74, 79))	('rs7857345', 'Var', (0, 9))
272126	33667223	However, rs7857345 is not in LD with rs885518 (r2 = 0.006, 1KG, Europeans), suggesting that this is a different signal to that previously reported for lung adenocarcinoma risk in Europeans.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (151, 170))	('rs7857345', 'Mutation', 'rs7857345', (9, 18))	('rs7857345', 'Var', (9, 18))	('lung adenocarcinoma', 'Disease', (151, 170))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (151, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('rs885518', 'Mutation', 'rs885518', (37, 45))
272127	33667223	Expectedly, two other previously reported rare variants at 4q23 (rs1229984, ADH1B) and 13q13.1 (rs11571815, BRCA2) also displayed pleiotropy in this analyses (Fig 1, Table 3).	('BRCA2', 'Gene', (108, 113))	('rs11571815', 'Var', (96, 106))	('ADH1B', 'Gene', '125', (76, 81))	('rs1229984', 'Var', (65, 74))	('rs1229984', 'Mutation', 'rs1229984', (65, 74))	('rs11571815', 'Mutation', 'rs11571815', (96, 106))	('BRCA2', 'Gene', '675', (108, 113))	('pleiotropy', 'Var', (130, 140))	('ADH1B', 'Gene', (76, 81))
272128	33667223	Of note, we did not observe pleiotropy for variants at 15q25.1, a known locus related to lung cancer and smoking behavior.	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('variants', 'Var', (43, 51))
272129	33667223	The lead SNP in this region rs55781567 (CHRNA5) was prominent for SqCC (ORmeta = 1.19; Pmeta = 1.74x10-29), but this result was primarily driven by the LuSqCC (OR = 1.3; P = 4.6x10-41) with no effect in any other SqCC site (OSqCC P = 0.26; LaSqCC P = 0.68 and ESqCC P = 0.7, S1 Table and S9 Fig).	('rs55781567', 'Mutation', 'rs55781567', (28, 38))	('CHRNA5', 'Gene', (40, 46))	('LuSqCC', 'Chemical', '-', (152, 158))	('SqCC', 'Disease', (66, 70))	('rs55781567', 'Var', (28, 38))	('CHRNA5', 'Gene', '1138', (40, 46))
272132	33667223	To gain further functional insight into aerodigestive SqCC genetic susceptibility, we used the results of the F-E meta-analyses to map risk variants to genes (FUMA) and to perform a genome-wide gene-based association analysis (GWGAS) using MAGMA.	('E meta', 'Species', '596559', (112, 118))	('FUMA', 'Gene', (159, 163))	('variants', 'Var', (140, 148))
272143	33667223	In contrast, most of the known loci that exhibited pleiotropy in our analysis have larger effects sizes, particularly true for the less common variants within BRCA2 and CHEK2.	('BRCA2', 'Gene', (159, 164))	('BRCA2', 'Gene', '675', (159, 164))	('CHEK2', 'Gene', '11200', (169, 174))	('CHEK2', 'Gene', (169, 174))	('variants', 'Var', (143, 151))
272155	33667223	The oral and pharyngeal GWAS summary statistics by cancer site and world region have been deposited in the IEU Open GWAS platform (https://gwas.mrcieu.ac.uk/) under the GWAs IDs: ieu-b-89, ieu-b-90, ieu-b-94, ieu-b-96, ieu-b-93, ieu-b-97, ieu-b-91, ieu-b-95 and 98.	('ieu-b-91', 'Var', (239, 247))	('ieu-b-90', 'Var', (189, 197))	('ieu-b-94', 'Var', (199, 207))	('ieu-b-97', 'Var', (229, 237))	('ieu-b-95', 'Var', (249, 257))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('ieu-b-89', 'Var', (179, 187))	('GWAs IDs', 'Disease', (169, 177))	('GWAs IDs', 'Disease', 'MESH:C535742', (169, 177))	('ieu-b-93', 'Var', (219, 227))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('ieu-b-96', 'Var', (209, 217))
272261	33658850	Our results could be explained from the following points: First, the longer the operation time, which means that the surgical trauma is greater, and it is more likely that it will take longer to clean the recurrent laryngeal nerve chain lymph nodes, resulting in a higher probability of RLNI; Second, the RLNI can cause temporary or permanent injury of vocal cord, which could cause serious persistent hoarseness, weak cough and expectoration leading to postoperative pneumonia, tracheal intubation or tracheotomy is needed in severe cases, and it will affect patients' postoperative rehabilitation and quality of life, and is even life-threatening.	('expectoration', 'Disease', (429, 442))	('cough', 'Disease', (419, 424))	('patients', 'Species', '9606', (560, 568))	('hoarseness', 'Disease', (402, 412))	('affect', 'Reg', (553, 559))	('hoarseness', 'Phenotype', 'HP:0001609', (402, 412))	('leading to', 'Reg', (443, 453))	('pneumonia', 'Phenotype', 'HP:0002090', (468, 477))	('cough', 'Phenotype', 'HP:0012735', (419, 424))	('postoperative rehabilitation', 'CPA', (570, 598))	('laryngeal nerve chain', 'Phenotype', 'HP:0005950', (215, 236))	('cause temporary or permanent injury of vocal cord', 'Phenotype', 'HP:0001604', (314, 363))	('quality of life', 'CPA', (603, 618))	('permanent injury', 'Disease', 'MESH:D003638', (333, 349))	('postoperative pneumonia', 'Disease', (454, 477))	('cause', 'Reg', (314, 319))	('trauma', 'Disease', (126, 132))	('permanent injury', 'Disease', (333, 349))	('RLNI', 'Disease', (287, 291))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (454, 477))	('RLNI', 'Var', (305, 309))	('cause', 'Reg', (377, 382))	('trauma', 'Disease', 'MESH:D014947', (126, 132))	('cough', 'Disease', 'MESH:D003371', (419, 424))
272272	32426284	A body of preclinical and clinical evidence indicates that dysregulation of metal homeostasis, both at intracellular and tissue level, contributes to the pathogenesis of many different types of cancer.	('cancer', 'Disease', (194, 200))	('metal homeostasis', 'MPA', (76, 93))	('dysregulation', 'Var', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('metal', 'Chemical', 'MESH:D008670', (76, 81))	('contributes', 'Reg', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
272283	32426284	A large body of preclinical and clinical studies related to dietary deficiencies, indicates that this metal dysregulation triggers neoplastic transformation of cells and/or reduces anti-tumorigenic functions of immune cells by controlling a plethora of chemical and biological reactions.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('dietary deficiencies', 'Disease', (60, 80))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('reduces', 'NegReg', (173, 180))	('triggers', 'Reg', (122, 130))	('neoplastic transformation of', 'CPA', (131, 159))	('plethora', 'Phenotype', 'HP:0001050', (241, 249))	('dysregulation', 'Var', (108, 121))	('dietary deficiencies', 'Disease', 'MESH:D018798', (60, 80))	('metal', 'Chemical', 'MESH:D008670', (102, 107))
272319	32426284	On the one hand, Zn depletion increases monocytes maturation into macrophages, on the other hand, it induces apoptosis in macrophages by p53-dependent mechanisms.	('monocytes maturation into macrophages', 'CPA', (40, 77))	('Zn', 'Chemical', 'MESH:D015032', (17, 19))	('apoptosis', 'CPA', (109, 118))	('depletion', 'Var', (20, 29))	('Zn depletion', 'Var', (17, 29))	('induces', 'Reg', (101, 108))	('increases', 'PosReg', (30, 39))
272348	32426284	Yu and co-workers have demonstrated in a murine model of pancreatic cancer that its supplementation via zinc metallochaperones (ZMCs) is able to reactivate quickly and effectively zinc deficient mutants p53 and to recover their wild type transcriptional activities and pro-apoptotic mechanisms.	('pro-apoptotic mechanisms', 'CPA', (269, 293))	('mutants', 'Var', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('transcriptional', 'MPA', (238, 253))	('zinc metallochaperones', 'Chemical', '-', (104, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('recover', 'PosReg', (214, 221))	('reactivate', 'Var', (145, 155))	('murine', 'Species', '10090', (41, 47))	('pancreatic cancer', 'Disease', (57, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (57, 74))	('p53', 'Gene', (203, 206))
272380	32426284	The FThigh and FPN1low pro-inflammatory macrophages display an iron sequestering phenotype characterized by iron withdrawal, restriction and storage.	('iron withdrawal', 'MPA', (108, 123))	('FThigh', 'Var', (4, 10))	('iron', 'Chemical', 'MESH:D007501', (63, 67))	('FPN1', 'Gene', '30061', (15, 19))	('iron', 'Chemical', 'MESH:D007501', (108, 112))	('restriction', 'MPA', (125, 136))	('FPN1', 'Gene', (15, 19))	('iron sequestering', 'MPA', (63, 80))
272439	32426284	Indeed its deficiency leads to a defective respiratory burst, impaired phagocytosis, and killing ability, with consequent susceptibility to recurrent pulmonary and urinary infections as well as septicaemia.	('impaired', 'NegReg', (62, 70))	('septicaemia', 'Disease', (194, 205))	('urinary infections', 'Phenotype', 'HP:0000010', (164, 182))	('defective', 'NegReg', (33, 42))	('susceptibility', 'Reg', (122, 136))	('septicaemia', 'Disease', 'MESH:D018805', (194, 205))	('deficiency', 'Var', (11, 21))	('respiratory burst', 'CPA', (43, 60))	('pulmonary and urinary infections', 'Disease', 'MESH:D014552', (150, 182))	('phagocytosis', 'CPA', (71, 83))	('killing ability', 'CPA', (89, 104))
272460	32426284	Selenium is generally transported by selenoprotein P (SEPP1) and its mutations and/or haplo insufficiency increases genomic instability and risk of cancer.	('cancer', 'Disease', (148, 154))	('mutations', 'Var', (69, 78))	('Selenium', 'Chemical', 'MESH:D012643', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('insufficiency', 'Disease', 'MESH:D000309', (92, 105))	('insufficiency', 'Disease', (92, 105))	('selenoprotein P', 'Gene', '6414', (37, 52))	('genomic instability', 'CPA', (116, 135))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('selenoprotein P', 'Gene', (37, 52))	('increases', 'PosReg', (106, 115))	('SEPP1', 'Gene', (54, 59))
272461	32426284	Indeed, populations with low Se intake are exposed to higher risk of cancer development and its supplementation in suboptimal doses enhances immune responses to prevent cancer growth, reduce relapse, and cancer-specific mortality.	('enhances', 'PosReg', (132, 140))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', (169, 175))	('relapse', 'CPA', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mortality', 'Disease', 'MESH:D003643', (220, 229))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('immune responses', 'MPA', (141, 157))	('Se', 'Chemical', 'MESH:D012643', (29, 31))	('supplementation', 'Var', (96, 111))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mortality', 'Disease', (220, 229))	('reduce', 'NegReg', (184, 190))	('cancer', 'Disease', (69, 75))
272463	32426284	A recent study on SELENOP (SEPP1) has led to the identification of several single nucleotide polymorphisms (SNPs) which decrease the expression or function of this metal in various tumor types, including hepatocellular carcinomas, gastric adenocarcinomas, colorectal cancer, and prostate cancer.	('gastric adenocarcinomas', 'Disease', (231, 254))	('colorectal cancer', 'Disease', 'MESH:D015179', (256, 273))	('single nucleotide polymorphisms', 'Var', (75, 106))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (231, 254))	('colorectal cancer', 'Disease', (256, 273))	('prostate cancer', 'Disease', 'MESH:D011471', (279, 294))	('prostate cancer', 'Phenotype', 'HP:0012125', (279, 294))	('SELENOP', 'Gene', (18, 25))	('SELENOP', 'Gene', '6414', (18, 25))	('prostate cancer', 'Disease', (279, 294))	('metal', 'Chemical', 'MESH:D008670', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (204, 229))	('colorectal cancer', 'Phenotype', 'HP:0003003', (256, 273))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))	('expression', 'MPA', (133, 143))	('function', 'MPA', (147, 155))	('tumor', 'Disease', (181, 186))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (204, 229))	('carcinomas', 'Phenotype', 'HP:0030731', (244, 254))	('decrease', 'NegReg', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('hepatocellular carcinomas', 'Disease', (204, 229))
272473	32426284	On the other hand, GPx1 expression has been linked to higher tumor number and growth rate, as well as to chemo/radio resistance.	('growth rate', 'CPA', (78, 89))	('higher', 'PosReg', (54, 60))	('chemo/radio resistance', 'CPA', (105, 127))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('GPx1', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('expression', 'Var', (24, 34))	('GPx1', 'Gene', '2876', (19, 23))	('tumor', 'Disease', (61, 66))
272475	32426284	Indeed, its deficiency has been linked to colitis-associated tumorigenesis.	('colitis', 'Disease', 'MESH:D003092', (42, 49))	('colitis', 'Disease', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('colitis', 'Phenotype', 'HP:0002583', (42, 49))	('linked', 'Reg', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('deficiency', 'Var', (12, 22))	('tumor', 'Disease', (61, 66))
272477	32426284	In tumor cells, GPx3 is often a target of hypermethylation and its downregulation is associated with bad prognosis and chemoresistance in several types of tumor.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('hypermethylation', 'Var', (42, 58))	('tumor', 'Disease', (3, 8))	('downregulation', 'NegReg', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('GPx3', 'Gene', '2878', (16, 20))	('chemoresistance', 'CPA', (119, 134))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('GPx3', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
272480	32426284	Several in vitro and in vivo studies agree that TrxRs can inhibit tumor growth by extinguishing oxidative damage and DNA alterations, especially in the context of inflammatory-driven cancers.	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('oxidative damage', 'MPA', (96, 112))	('cancers', 'Disease', (183, 190))	('tumor', 'Disease', (66, 71))	('TrxRs', 'Var', (48, 53))	('Se', 'Chemical', 'MESH:D012643', (0, 2))	('extinguishing', 'NegReg', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('inhibit', 'NegReg', (58, 65))	('DNA alterations', 'MPA', (117, 132))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
272487	32426284	In particular, loss of Trsp leads to a decrease in M2 macrophage markers, a corresponding increase in M1 macrophage markers, an altered regulation in extracellular matrix-related gene expression and a diminished migration of macrophages in a protein gel matrix.	('migration of macrophages in a protein gel matrix', 'CPA', (212, 260))	('decrease', 'NegReg', (39, 47))	('increase', 'PosReg', (90, 98))	('M2 macrophage markers', 'MPA', (51, 72))	('altered', 'Reg', (128, 135))	('loss', 'Var', (15, 19))	('regulation', 'MPA', (136, 146))	('Trsp', 'Gene', (23, 27))	('Trsp', 'Gene', '7234', (23, 27))	('extracellular matrix-related gene expression', 'MPA', (150, 194))	('M1 macrophage markers', 'MPA', (102, 123))	('diminished', 'NegReg', (201, 211))
272491	32426284	Vunta et al., demonstrated that selenium deficiency in mice exacerbates the LPS-mediated infiltration of macrophages into the lungs and also that selenium reintegration in macrophages leads to a significant decrease in LPS-induced expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor-a (TNF-a).	('tumor necrosis factor-a', 'Gene', (274, 297))	('selenium', 'Chemical', 'MESH:D012643', (146, 154))	('selenium', 'Chemical', 'MESH:D012643', (32, 40))	('tumor necrosis factor-a', 'Gene', '21926', (274, 297))	('COX-2', 'Gene', '19225', (263, 268))	('selenium', 'Var', (32, 40))	('cyclooxygenase-2', 'Gene', '19225', (245, 261))	('cyclooxygenase-2', 'Gene', (245, 261))	('TNF-a', 'Gene', (299, 304))	('COX-2', 'Gene', (263, 268))	('mice', 'Species', '10090', (55, 59))	('deficiency', 'Var', (41, 51))	('exacerbates', 'PosReg', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('TNF-a', 'Gene', '21926', (299, 304))	('decrease', 'NegReg', (207, 215))	('LPS-induced expression', 'MPA', (219, 241))
272503	32426284	Following Se-supplementation, selenoproteins affect the production of Delta12-PGJ2 in the M2 macrophage.	('affect', 'Reg', (45, 51))	('Delta12-PGJ2', 'Var', (70, 82))	('Delta12', 'Mutation', 'c.del12', (70, 77))	('Se', 'Chemical', 'MESH:D012643', (10, 12))	('selenoprotein', 'Gene', '93684', (30, 43))	('selenoprotein', 'Gene', (30, 43))	('production', 'MPA', (56, 66))
272504	32426284	Delta12-PGJ2 released by macrophages activates in cancer stem cells the tumor suppressor protein p53, which in turn upregulates the TCA cycle, oxidative phosphorylation, and lowers glucose uptake.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('p53', 'Gene', (97, 100))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('TCA', 'Chemical', 'MESH:D014238', (132, 135))	('tumor', 'Disease', (72, 77))	('Delta12', 'Mutation', 'c.del12', (0, 7))	('glucose uptake', 'MPA', (181, 195))	('upregulates', 'PosReg', (116, 127))	('activates', 'PosReg', (37, 46))	('oxidative phosphorylation', 'MPA', (143, 168))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('TCA', 'Enzyme', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Delta12-PGJ2', 'Var', (0, 12))	('glucose', 'Chemical', 'MESH:D005947', (181, 188))	('lowers', 'NegReg', (174, 180))
272518	32426284	To sum up: heme iron intake and high serum levels of iron are associated with increased risk of breast and liver cancer; copper overload causes liver, lung, urinary, stomach, and cervical cancer; zinc poisoning or deficiency are associated with breast, lung, gastric, colon, and prostatic cancer; lower selenium intake increases liver, gastric, colon, and prostatic cancer incidence.	('selenium', 'Chemical', 'MESH:D012643', (303, 311))	('heme', 'Chemical', 'MESH:D006418', (11, 15))	('causes', 'Reg', (137, 143))	('colon', 'Disease', 'MESH:D003110', (268, 273))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('breast and liver cancer', 'Disease', 'MESH:D001943', (96, 119))	('prostatic cancer', 'Disease', (279, 295))	('cancer', 'Disease', (366, 372))	('cancer', 'Disease', (113, 119))	('prostatic cancer', 'Disease', 'MESH:D011471', (356, 372))	('urinary', 'Disease', (157, 164))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('prostatic cancer', 'Phenotype', 'HP:0012125', (356, 372))	('breast', 'Disease', (245, 251))	('colon', 'Disease', (345, 350))	('iron', 'Chemical', 'MESH:D007501', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lung', 'Disease', (151, 155))	('gastric', 'Disease', (336, 343))	('liver cancer', 'Phenotype', 'HP:0002896', (107, 119))	('colon', 'Disease', 'MESH:D003110', (345, 350))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('iron', 'Chemical', 'MESH:D007501', (53, 57))	('lung', 'Disease', (253, 257))	('increases', 'PosReg', (319, 328))	('lower', 'Var', (297, 302))	('prostatic cancer', 'Disease', (356, 372))	('liver', 'Disease', (329, 334))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('poisoning or deficiency', 'Disease', (201, 224))	('prostatic cancer', 'Disease', 'MESH:D011471', (279, 295))	('cancer', 'Disease', (188, 194))	('prostatic cancer', 'Phenotype', 'HP:0012125', (279, 295))	('copper', 'Chemical', 'MESH:D003300', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('stomach', 'Disease', (166, 173))	('liver', 'Disease', (144, 149))	('poisoning or deficiency', 'Disease', 'MESH:D011041', (201, 224))	('colon', 'Disease', (268, 273))	('gastric', 'Disease', (259, 266))	('cancer', 'Disease', (289, 295))
272549	30116873	For patients being considered for a curative pathway, endoscopic ultrasound (EUS) and 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) are performed due to the high sensitivity and specificity of EUS for local tumor and nodal staging; and 18F-FDG PET for distant metastases.	('metastases', 'Disease', (286, 296))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('metastases', 'Disease', 'MESH:D009362', (286, 296))	('tumor', 'Disease', (233, 238))	('18F-FDG', 'Var', (262, 269))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (86, 108))	('18F-FDG', 'Chemical', 'MESH:D019788', (262, 269))	('patients', 'Species', '9606', (4, 12))	('18F-FDG', 'Chemical', 'MESH:D019788', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
272551	30116873	If curative treatment is being considered, the use of endoscopic ultrasound (EUS) is helpful in determining the proximal and distal extent of the tumor, whereas 18F-FDG PET/CT has been shown to improve staging by detecting involved lymph nodes and metastatic disease, although it can be less accurate in mucinous and diffuse tumors.	('improve', 'PosReg', (194, 201))	('18F-FDG', 'Var', (161, 168))	('tumors', 'Disease', (325, 331))	('tumors', 'Disease', 'MESH:D009369', (325, 331))	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('staging', 'MPA', (202, 209))	('18F-FDG', 'Chemical', 'MESH:D019788', (161, 168))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('metastatic disease', 'CPA', (248, 266))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Disease', (325, 330))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
272583	30116873	showed in 56 patients, that first-order energy, entropy, and skewness were significantly associated with a negative prognosis.	('skewness', 'Var', (61, 69))	('first-order energy', 'MPA', (28, 46))	('patients', 'Species', '9606', (13, 21))	('entropy', 'MPA', (48, 55))
272605	30390154	After stratification analysis for Siewert type II, the C-index for TNM-GC scheme was still larger than that of TNM-EC in both training (0.724 vs. 0.694, P = 0.005) and validation (0.723 vs. 0.699, P < 0.001) cohorts.	('TNM-GC', 'Var', (67, 73))	('GC', 'Chemical', 'MESH:C057580', (71, 73))	('C-index', 'MPA', (55, 62))	('TNM', 'Chemical', '-', (111, 114))	('TNM', 'Chemical', '-', (67, 70))	('TNM-EC', 'Chemical', '-', (111, 117))
272641	30390154	However, the TNM-GC and TNM-EC had different definition for T3/4 stage, for instance, pT4a means tumor invaded serosa in TNM-GC, whereas pT4 means tumor invaded pleura, pericardium, azygos vein, diaphragm, or adjacent peritoneum in TNM-EC.	('TNM-EC', 'Chemical', '-', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('pT4', 'Var', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TNM', 'Chemical', '-', (24, 27))	('pT4a', 'Var', (86, 90))	('TNM-EC', 'Chemical', '-', (24, 30))	('tumor', 'Disease', (97, 102))	('TNM', 'Chemical', '-', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('GC', 'Chemical', 'MESH:C057580', (17, 19))	('TNM', 'Chemical', '-', (232, 235))	('GC', 'Chemical', 'MESH:C057580', (125, 127))	('TNM', 'Chemical', '-', (13, 16))
272663	30390154	When compared with TNM-EC, TNM-GC demonstrated a smaller AIC (3174.5 vs. 3231.7), (3410.4 vs. 3458.2) and larger C-index (0.721 vs. 0.690, P < 0.001) (0.721 vs. 0.696, P < 0.001) in both training and the validation cohorts.	('C-index', 'MPA', (113, 120))	('TNM-EC', 'Chemical', '-', (19, 25))	('TNM', 'Chemical', '-', (27, 30))	('smaller', 'NegReg', (49, 56))	('larger', 'PosReg', (106, 112))	('TNM', 'Chemical', '-', (19, 22))	('3410.4', 'Var', (83, 89))	('GC', 'Chemical', 'MESH:C057580', (31, 33))
272701	30390154	The former research had found more proportion of undifferentiated type in gastric cardia cancer leads to worse prognosis.	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('gastric cardia cancer', 'Disease', (74, 95))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (74, 95))	('undifferentiated type', 'Var', (49, 70))
272704	30390154	The groups with G1/2 differentiated adenocarcinoma indicated better survival than those with G3 in training cohort.	('better', 'PosReg', (61, 67))	('adenocarcinoma', 'Disease', 'MESH:D000230', (36, 50))	('survival', 'MPA', (68, 76))	('G1/2', 'Var', (16, 20))	('adenocarcinoma', 'Disease', (36, 50))
272732	30328537	Autophagy Inhibitor (LY294002) and 5-fluorouracil (5-FU) Combination-Based Nanoliposome for Enhanced Efficacy Against Esophageal Squamous Cell Carcinoma In this study, 5-fluorouracil (5-FU) and LY294002 (LY)-loaded PEGylated nanoliposome was prepared to target esophageal squamous cell carcinoma (ESCC).	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (118, 152))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (261, 295))	('5-FU', 'Chemical', 'MESH:D005472', (51, 55))	('PEG', 'Chemical', 'MESH:D011092', (215, 218))	('LY', 'Chemical', 'MESH:C085911', (21, 23))	('Carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('LY294002', 'Var', (194, 202))	('LY294002', 'Chemical', 'MESH:C085911', (21, 29))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (35, 49))	('Esophageal Squamous Cell Carcinoma', 'Disease', (118, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (168, 182))	('5-FU', 'Chemical', 'MESH:D005472', (184, 188))	('LY294002', 'Chemical', 'MESH:C085911', (194, 202))	('LY', 'Chemical', 'MESH:C085911', (194, 196))	('esophageal squamous cell carcinoma', 'Disease', (261, 295))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (272, 295))	('LY', 'Chemical', 'MESH:C085911', (204, 206))
272736	30328537	The combination of 5-FU and LY resulted in higher cytotoxic effect compared to that of individual drugs.	('higher', 'PosReg', (43, 49))	('5-FU', 'Var', (19, 23))	('LY', 'Chemical', 'MESH:C085911', (28, 30))	('cytotoxic effect', 'CPA', (50, 66))	('5-FU', 'Chemical', 'MESH:D005472', (19, 23))
272737	30328537	Most importantly, FLNP exhibited a significantly higher anticancer effect in cancer cells compared to that of free cocktail combinations.	('FLNP', 'Chemical', '-', (18, 22))	('FLNP', 'Var', (18, 22))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('higher', 'PosReg', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
272826	30328537	The 5-FU exhibited a relatively higher anticancer effect compared to that of LY in the cancer cells.	('cancer', 'Disease', (87, 93))	('LY', 'Chemical', 'MESH:C085911', (77, 79))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('5-FU', 'Var', (4, 8))	('higher', 'PosReg', (32, 38))	('5-FU', 'Chemical', 'MESH:D005472', (4, 8))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
272829	30328537	It should be noted that FLNP was more effective than free cocktail combinations due to a more programmed release of drugs in a controlled manner.	('more', 'PosReg', (89, 93))	('FLNP', 'Var', (24, 28))	('programmed release of drugs', 'MPA', (94, 121))	('FLNP', 'Chemical', '-', (24, 28))
272835	30328537	Consistent with the MTT assay, 5-FU (~ 20%) resulted in greater apoptosis of cancer cells compared to that of LY (~ 12%), while 5-FU + LY combination induced greater apoptotic cell death (~ 30%).	('LY', 'Chemical', 'MESH:C085911', (135, 137))	('5-FU', 'Var', (31, 35))	('cancer', 'Disease', (77, 83))	('apoptosis', 'CPA', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('MTT', 'Chemical', 'MESH:C070243', (20, 23))	('5-FU', 'Chemical', 'MESH:D005472', (128, 132))	('5-FU', 'Chemical', 'MESH:D005472', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('LY', 'Chemical', 'MESH:C085911', (110, 112))
272836	30328537	Compared to any other group, FLNP induced a greater apoptosis (~ 48%) of cancer cells suggesting that receptor-mediated cellular uptake greatly increased the intracellular concentration of anticancer drugs that resulted in higher therapeutic effect.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('therapeutic effect', 'MPA', (230, 248))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('FLNP', 'Chemical', '-', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('FLNP', 'Var', (29, 33))	('higher', 'PosReg', (223, 229))	('increased', 'PosReg', (144, 153))
272850	30328537	Importantly, FLNP showed significantly (p < 0.05; p < 0.0001) higher antitumor efficacy compared to any other group.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('higher', 'PosReg', (62, 68))	('FLNP', 'Chemical', '-', (13, 17))	('FLNP', 'Var', (13, 17))
272852	30328537	The significantly higher antitumor effect in tumor model was attributed to the nanosized of particle which might be accumulated in the tumor tissues owing to enhanced permeation and retention effect.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('permeation', 'MPA', (167, 177))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('enhanced', 'PosReg', (158, 166))	('tumor', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('nanosized', 'Var', (79, 88))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', (29, 34))	('higher', 'PosReg', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
272854	30328537	In conclusion, 5-fluorouracil (5-FU) and LY294002 (LY)-loaded PEGylated nanoliposome was successfully prepared to target esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (15, 29))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (121, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('LY', 'Chemical', 'MESH:C085911', (51, 53))	('esophageal squamous cell carcinoma', 'Disease', (121, 155))	('LY294002', 'Chemical', 'MESH:C085911', (41, 49))	('5-FU', 'Chemical', 'MESH:D005472', (31, 35))	('LY', 'Chemical', 'MESH:C085911', (41, 43))	('PEG', 'Chemical', 'MESH:D011092', (62, 65))	('LY294002', 'Var', (41, 49))
272935	15563371	As the deletion of a tumor suppressor gene can lead to tumor development, one objective of these studies is to determine which, if any, chromosome arms harbor tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('lead to', 'Reg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('deletion', 'Var', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
272937	15563371	When no tumor suppressor genes are present and background allelic-loss varies, the Bayes factors are often inconclusive, although this results in a markedly reduced false-positive rate compared to that of standard frequentist approaches.	('false-positive', 'MPA', (165, 179))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('varies', 'Var', (71, 77))	('allelic-loss varies', 'Var', (58, 77))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('reduced', 'NegReg', (157, 164))
272939	15563371	The goal of studies of allelic loss is to determine those loci in tumor tissue where genetic material has been lost.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('allelic', 'Var', (23, 30))
272951	15563371	We examine three data sets of allelic-loss on esophageal adenocarcinomas that attempt to identify the tumor suppressor genes (TSGs) involved in the development of this disease.	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (46, 72))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (46, 71))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('esophageal adenocarcinomas', 'Disease', (46, 72))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('allelic-loss', 'Var', (30, 42))
272954	15563371	For example, deletion of a particular TSG may be in the causal pathway for 60% of tumors of a particular type while another TSG (or other TSGs) may account for the remaining 40% of the cases.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('deletion', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('TSG', 'Gene', (38, 41))
272956	15563371	Let Xi be the number of tumors with allelic-loss for the ith chromosome arm, and let ni be the number of informative tumors for the ith chromosome arm, for i = 1, 2,...,N, where N is the number of chromosome arms in the study.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('allelic-loss', 'Var', (36, 48))
272957	15563371	The density function for Xi is written as follows: where theta   (eta, pi1, omega1, pi0, omega0) is a vector of unknown parameters, eta is the mixing probability, pij is the average loss rate, and omegaj is the dispersion parameter for j = 0,1.	('loss', 'NegReg', (182, 186))	('eta', 'Gene', '1909', (59, 62))	('eta', 'Gene', '1909', (66, 69))	('eta', 'Gene', (66, 69))	('eta', 'Gene', (59, 62))	('pi1, omega1, pi0, omega0', 'Gene', '5265', (71, 95))	('eta', 'Gene', '1909', (132, 135))	('eta', 'Gene', (132, 135))	('pij', 'Var', (163, 166))
272958	15563371	If only one of the dispersion parameters goes to 0 (omega0   0 or omega1   0), the distribution reduces to a mixture of a beta-binomial and a binomial distribution.	('reduces', 'NegReg', (96, 103))	('a beta', 'Gene', '351', (120, 126))	('a beta', 'Gene', (120, 126))	('mixture', 'MPA', (109, 116))	('omega1   0', 'Var', (66, 76))
272987	15563371	The Barrett data set records allelic loss on 20 esophageal adenocarcinomas and two high-grade dysplasias.	('allelic loss', 'Var', (29, 41))	('esophageal adenocarcinomas', 'Disease', (48, 74))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (48, 73))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (48, 74))	('dysplasias', 'Disease', 'MESH:D004476', (94, 104))	('dysplasias', 'Disease', (94, 104))
272988	15563371	Figure 1 presents a histogram of the proportion of tumors with allelic loss for each of the forty chromosome arms studied (markers were not placed on the short arms of chromosomes 13, 14, 15 and 22 as these are too small to study).	('short arms', 'Phenotype', 'HP:0009824', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('allelic loss', 'Var', (63, 75))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))
272989	15563371	Two of the chromosome arms examined do not exhibit allelic loss (arms 20q and 21p) for any of the tumors observed.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('arms 20q', 'Var', (65, 73))
273004	15563371	Classification using both the two-component beta-binomial/binomlal model and the two-component binomial model places chromosome arms 4q and 17p in the TSG group.	('TSG', 'Disease', (151, 154))	('chromosome arms', 'Var', (117, 132))	('eta', 'Gene', '1909', (45, 48))	('eta', 'Gene', (45, 48))
273031	26369701	While a loss-of-function allele of purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) failed to affect cancer-specific survival, its presence did correlate with an increase in Treg infiltration.	('Treg infiltration', 'CPA', (186, 203))	('purinergic receptor P2X, ligand-gated ion channel, 7', 'Gene', '5027', (35, 87))	('P2RX7', 'Gene', (89, 94))	('P2RX7', 'Gene', '5027', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('loss-of-function', 'NegReg', (8, 24))	('presence', 'Var', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Treg', 'Chemical', '-', (186, 190))
273040	26369701	While loss-of-function mutations affecting TLR4 or P2RX7 have a negative impact on the survival of breast cancer patients, local expression of MX1 constitutes a positive prognostic marker.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('patients', 'Species', '9606', (113, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('P2RX7', 'Gene', (51, 56))	('MX1', 'Gene', (143, 146))	('loss-of-function', 'NegReg', (6, 22))	('survival', 'CPA', (87, 95))	('mutations', 'Var', (23, 32))	('MX1', 'Gene', '4599', (143, 146))	('TLR4', 'Gene', '7099', (43, 47))	('P2RX7', 'Gene', '5027', (51, 56))	('TLR4', 'Gene', (43, 47))	('negative', 'NegReg', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
273042	26369701	For example, we found that loss-of-function alleles of TLR4 and P2RX7 have no significant impact on the survival of patients with non-small cell lung cancer.	('TLR4', 'Gene', '7099', (55, 59))	('P2RX7', 'Gene', (64, 69))	('P2RX7', 'Gene', '5027', (64, 69))	('TLR4', 'Gene', (55, 59))	('loss-of-function', 'NegReg', (27, 43))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (130, 156))	('patients', 'Species', '9606', (116, 124))	('non-small cell lung cancer', 'Disease', (130, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (134, 156))	('alleles', 'Var', (44, 51))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (130, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
273045	26369701	As mentioned in the introduction, loss-of-function alleles of TLR4 (rs4986790, Asp299Gly) and P2RX7 (rs3751143, Glu496Ala) may negatively affect the therapeutic response of breast cancer patients to adjuvant chemotherapy.	('rs3751143', 'Mutation', 'rs3751143', (101, 110))	('patients', 'Species', '9606', (187, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('Glu496Ala', 'SUBSTITUTION', 'None', (112, 121))	('Asp299Gly', 'SUBSTITUTION', 'None', (79, 88))	('loss-of-function', 'NegReg', (34, 50))	('P2RX7', 'Gene', (94, 99))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('TLR4', 'Gene', '7099', (62, 66))	('breast cancer', 'Disease', (173, 186))	('Glu496Ala', 'Var', (112, 121))	('rs4986790', 'Mutation', 'rs4986790', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Asp299Gly', 'Var', (79, 88))	('TLR4', 'Gene', (62, 66))	('therapeutic response', 'CPA', (149, 169))	('rs4986790', 'Var', (68, 77))	('negatively', 'NegReg', (127, 137))	('rs3751143', 'Var', (101, 110))	('P2RX7', 'Gene', '5027', (94, 99))
273046	26369701	Moreover, the most common loss-of-function allele of TLR4 (Asp299Gly) also is a poor prognostic feature for colorectal cancer patients treated with adjuvant chemotherapy.	('Asp299Gly', 'Var', (59, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('Asp299Gly', 'SUBSTITUTION', 'None', (59, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('TLR4', 'Gene', '7099', (53, 57))	('patients', 'Species', '9606', (126, 134))	('colorectal cancer', 'Disease', (108, 125))	('TLR4', 'Gene', (53, 57))	('loss-of-function', 'NegReg', (26, 42))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
273048	26369701	To our surprise, we found that patients harboring one copy of the mutated allele of TLR4 exhibited an improved cancer-specific survival as compared to the majority of patients bearing two copies of the most frequent, functional TLR4 allele (Figure 1A).	('mutated', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (167, 175))	('TLR4', 'Gene', '7099', (228, 232))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('TLR4', 'Gene', '7099', (84, 88))	('patients', 'Species', '9606', (31, 39))	('TLR4', 'Gene', (228, 232))	('cancer', 'Disease', (111, 117))	('TLR4', 'Gene', (84, 88))	('improved', 'PosReg', (102, 110))
273049	26369701	In contrast, loss-of-function alleles affecting P2RX7 (Glu496Ala, Figure 1B), the autophagy-relevant gene autophagy related 16-like 1 (S. cerevisiae) (ATG16L1, rs2241880, Thr300Ala) (Supplemental Figure 2A) and the autoimmune disease-related gene protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22, rs2476601, Arg620Trp) (Supplemental Figure 2B) had no impact on patients survival.	('ATG16L1', 'Gene', (151, 158))	('Thr300Ala', 'Mutation', 'rs2241880', (171, 180))	('P2RX7', 'Gene', (48, 53))	('PTPN22', 'Gene', (310, 316))	('rs2241880', 'Var', (160, 169))	('Arg620Trp', 'Var', (329, 338))	('autoimmune disease', 'Phenotype', 'HP:0002960', (215, 233))	('rs2476601', 'Mutation', 'rs2476601', (318, 327))	('Arg620Trp', 'Mutation', 'rs2476601', (329, 338))	('S. cerevisiae', 'Species', '4932', (135, 148))	('P2RX7', 'Gene', '5027', (48, 53))	('Glu496Ala', 'SUBSTITUTION', 'None', (55, 64))	('Thr300Ala', 'Var', (171, 180))	('patients', 'Species', '9606', (382, 390))	('loss-of-function', 'NegReg', (13, 29))	('rs2241880', 'Mutation', 'rs2241880', (160, 169))	('PTPN22', 'Gene', '26191', (310, 316))	('Glu496Ala', 'Var', (55, 64))	('ATG16L1', 'Gene', '55054', (151, 158))	('rs2476601', 'Var', (318, 327))
273050	26369701	These findings are reminiscent of those previously obtained on patients with non-small cell lung cancer, in which loss-of-function mutation of TLR4 had positive effects while that affecting P2RX7 had no impact.	('TLR4', 'Gene', (143, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (77, 103))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (81, 103))	('TLR4', 'Gene', '7099', (143, 147))	('non-small cell lung cancer', 'Disease', (77, 103))	('P2RX7', 'Gene', (190, 195))	('loss-of-function', 'NegReg', (114, 130))	('P2RX7', 'Gene', '5027', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('patients', 'Species', '9606', (63, 71))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (77, 103))	('mutation', 'Var', (131, 139))
273066	26369701	While there was no difference in the frequency of tumor-infiltrating Tregs among patients with normal or loss-of-function alleles of TLR4 (Figure 6A), patients bearing the mutated alleles of P2RX7 exhibited an increased Treg infiltration (Figure 6B).	('alleles', 'Var', (122, 129))	('increased', 'PosReg', (210, 219))	('P2RX7', 'Gene', (191, 196))	('P2RX7', 'Gene', '5027', (191, 196))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (151, 159))	('Treg infiltration', 'CPA', (220, 237))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('TLR4', 'Gene', '7099', (133, 137))	('Treg', 'Chemical', '-', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('Treg', 'Chemical', '-', (69, 73))	('mutated', 'Var', (172, 179))	('TLR4', 'Gene', (133, 137))	('loss-of-function', 'NegReg', (105, 121))
273084	26369701	Gene-specific Taqman  primers and genotype-specific probes (Applied Biosystems-Life Technologies Inc.) were used to amplify (i) a TLR4 fragment containing the Asp299Gly single nucleotide polymorphism (SNP) (rs4986790), (ii) a P2RX7 fragment containing the Glu496Ala SNP (rs3751143), (iii) an ATG16L1 fragment containing the Thr300Ala SNP (rs2241880) and a PTPN22 fragment containing the Arg620Trp SNP (rs2476601).	('ATG16L1', 'Gene', (292, 299))	('PTPN22', 'Gene', '26191', (356, 362))	('P2RX7', 'Gene', '5027', (226, 231))	('rs4986790', 'Var', (207, 216))	('PTPN22', 'Gene', (356, 362))	('Glu496Ala', 'SUBSTITUTION', 'None', (256, 265))	('Asp299Gly', 'SUBSTITUTION', 'None', (159, 168))	('rs2241880', 'Mutation', 'rs2241880', (339, 348))	('rs3751143', 'Var', (271, 280))	('Glu496Ala', 'Var', (256, 265))	('P2RX7', 'Gene', (226, 231))	('rs2476601', 'Var', (402, 411))	('Arg620Trp', 'Mutation', 'rs2476601', (387, 396))	('Asp299Gly', 'Var', (159, 168))	('rs3751143', 'Mutation', 'rs3751143', (271, 280))	('rs2241880', 'Var', (339, 348))	('TLR4', 'Gene', '7099', (130, 134))	('ATG16L1', 'Gene', '55054', (292, 299))	('Thr300Ala', 'Mutation', 'rs2241880', (324, 333))	('TLR4', 'Gene', (130, 134))	('rs2476601', 'Mutation', 'rs2476601', (402, 411))	('rs4986790', 'Mutation', 'rs4986790', (207, 216))
273156	20700119	Tooth loss has been reported to be associated with an increased risk of esophageal cancer Changes in chewing may expose the esophagus to more frequent injury and may also result in increased risk of oral bacterial infection and production of carcinogens, such as nitrosamines.	('Tooth loss', 'Disease', (0, 10))	('bacterial infection', 'Phenotype', 'HP:0002718', (204, 223))	('oral bacterial infection', 'Disease', 'MESH:D001424', (199, 223))	('nitrosamines', 'Chemical', 'MESH:D009602', (263, 275))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('injury', 'Disease', (151, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('injury', 'Disease', 'MESH:D058186', (151, 157))	('oral bacterial infection', 'Disease', (199, 223))	('Tooth loss', 'Disease', 'MESH:D016388', (0, 10))	('Changes', 'Var', (90, 97))
273172	31899792	Gastric atrophy caused by chronic Helicobacter pylori infection is already known to be involved in the development of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gastric cancer', 'Disease', (118, 132))	('men', 'Species', '9606', (110, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('infection', 'Disease', (54, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('Helicobacter pylori', 'Var', (34, 53))	('infection', 'Disease', 'MESH:D007239', (54, 63))	('Gastric atrophy', 'Disease', 'MESH:D013274', (0, 15))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (34, 63))	('Gastric atrophy', 'Disease', (0, 15))	('Helicobacter pylori', 'Species', '210', (34, 53))
273201	31899792	For the "almost fully adjusting" model, we also adjusted for education (illiteracy, primary school, middle school, high school and above), marital status (unmarried, married, divorced or widowed), occupation (farmer, worker, service/clerk/professional/administrator), family wealth score (quartiles 1-5), body mass index 10 years before (<18.5, 18.5-23.9, 24.0-27.9, >=28.0), tea drinking (never/ever), history of esophageal cancer among first-degree relatives (no/yes), cigarette smoking (in pack years: never-smoker, former-smoker, current light smoker (<=18), current medium smoker (19-40), current heavy smoker (>41)), alcohol consumption in g/day (never drinker, former drinker, current low consumption (<=40), current medium consumption (41-135), current high consumption (>135)), and H. pylori serostatus (negative/positive).	('cancer', 'Phenotype', 'HP:0002664', (425, 431))	('alcohol', 'Chemical', 'MESH:D000438', (623, 630))	('cancer', 'Disease', (425, 431))	('cancer', 'Disease', 'MESH:D009369', (425, 431))	('<=40', 'Var', (709, 713))	('H. pylori', 'Species', '210', (791, 800))
273226	31899792	However, with a similar cutoff value of <=50 mug/L for PGI, the point estimate of 1.64 (hazard ratio) in that earlier investigation (although only borderline statistically significant due to the small sample size) is very close to our estimate here.	('PGI', 'Gene', '633', (55, 58))	('<=50 mug/L', 'Var', (40, 50))	('PGI', 'Gene', (55, 58))
273253	32344898	In addition, we demonstrate that cells expressing PAI1 protein are more sensitive to the PIM inhibitor AZD1208, suggesting that PAI1 could be used to predict response to treatment with PIM inhibitors and to complement radiotherapy in rectal tumors.	('rectal tumors', 'Disease', 'MESH:D012004', (234, 247))	('PIM', 'Gene', (89, 92))	('PIM', 'Gene', '5292', (89, 92))	('PAI1', 'Gene', (128, 132))	('rectal tumors', 'Disease', (234, 247))	('rectal tumors', 'Phenotype', 'HP:0100743', (234, 247))	('PIM', 'Gene', (185, 188))	('PAI1', 'Gene', (50, 54))	('PIM', 'Gene', '5292', (185, 188))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('PAI1', 'Gene', '5054', (128, 132))	('protein', 'Var', (55, 62))	('PAI1', 'Gene', '5054', (50, 54))	('sensitive', 'MPA', (72, 81))	('rectal tumor', 'Phenotype', 'HP:0100743', (234, 246))	('AZD1208', 'Chemical', 'MESH:C587575', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
273266	32344898	Moreover, deregulation of PAI1 expression has been involved in cardiovascular diseases, obesity, metabolic syndrome and various types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('deregulation', 'Var', (10, 22))	('obesity', 'Disease', 'MESH:D009765', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cardiovascular diseases', 'Disease', (63, 86))	('involved', 'Reg', (51, 59))	('expression', 'MPA', (31, 41))	('metabolic syndrome', 'Disease', (97, 115))	('cancer', 'Disease', (137, 143))	('PAI1', 'Gene', (26, 30))	('obesity', 'Disease', (88, 95))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (63, 86))	('metabolic syndrome', 'Disease', 'MESH:D024821', (97, 115))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (63, 86))	('obesity', 'Phenotype', 'HP:0001513', (88, 95))	('PAI1', 'Gene', '5054', (26, 30))
273270	32344898	Moreover, PAI1 expression is also correlated with poor outcome in several other cancer subtypes, such as node-negative breast cancer and ovarian serous carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('expression', 'Var', (15, 25))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (137, 161))	('PAI1', 'Gene', '5054', (10, 14))	('breast cancer', 'Disease', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('ovarian serous carcinoma', 'Disease', (137, 161))	('correlated', 'Reg', (34, 44))	('PAI1', 'Gene', (10, 14))	('cancer', 'Disease', (80, 86))
273286	32344898	Eligible patients were those with locally advanced rectal cancer T3-4 N+ M0 (stages II-III) that had completed the neoadjuvant chemoradiotherapy plan before resection with curative intention.	('rectal cancer', 'Phenotype', 'HP:0100743', (51, 64))	('patients', 'Species', '9606', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('T3-4 N+ M0', 'Var', (65, 75))
273297	32344898	Briefly, SW48, SW480, T84, LS180, LOVO, HT29 HCT116 and COLO205 were cultured in the corresponding medium and incubated at 37  C in 5% CO2 in a humidified atmosphere.	('T84', 'Var', (22, 25))	('SW48', 'CellLine', 'CVCL:1724', (9, 13))	('SW48', 'CellLine', 'CVCL:1724', (15, 19))	('SW480', 'Var', (15, 20))	('HT29 HCT116', 'CellLine', 'CVCL:0291', (40, 51))	('SW480', 'CellLine', 'CVCL:0546', (15, 20))	('CO2', 'Chemical', 'MESH:D002245', (135, 138))	('SW48', 'Var', (9, 13))
273308	32344898	To study the potential of PAI1 as a marker in rectal cancer, we first analyzed PAI1 expression levels in four public rectal cancer databases: GSE35452, GSE8671 and GSE2109 (Table S3).	('GSE35452', 'Var', (142, 150))	('PAI1', 'Gene', (79, 83))	('cancer', 'Disease', (124, 130))	('rectal cancer', 'Phenotype', 'HP:0100743', (46, 59))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('GSE8671', 'Var', (152, 159))	('PAI1', 'Gene', '5054', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PAI1', 'Gene', (26, 30))	('rectal cancer', 'Phenotype', 'HP:0100743', (117, 130))	('GSE2109', 'Var', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('PAI1', 'Gene', '5054', (26, 30))
273311	32344898	We extended this analysis to colorectal cancer patients in GSE8671 and four additional databases with paired non-tumor and tumor samples (GSE21510, GSE4183, GSE201916 and GSE33114).	('tumor', 'Disease', (113, 118))	('GSE201916', 'Var', (157, 166))	('GSE4183', 'Var', (148, 155))	('GSE8671', 'Var', (59, 66))	('GSE21510', 'Var', (138, 146))	('tumor', 'Disease', (123, 128))	('GSE4183', 'Chemical', '-', (148, 155))	('rectal cancer', 'Phenotype', 'HP:0100743', (33, 46))	('colorectal cancer', 'Disease', 'MESH:D015179', (29, 46))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('colorectal cancer', 'Disease', (29, 46))	('GSE33114', 'Var', (171, 179))
273317	32344898	We found that patients in our cohort with higher PAI1 expression showed a decrease in disease-free survival (DFS) compared to that in patients with lower PAI1 expression, although it did not reach statistical significance (Figure 1G; p = 0.076).	('decrease', 'NegReg', (74, 82))	('PAI1', 'Gene', (49, 53))	('PAI1', 'Gene', '5054', (154, 158))	('PAI1', 'Gene', '5054', (49, 53))	('expression', 'Var', (54, 64))	('higher', 'Var', (42, 48))	('patients', 'Species', '9606', (134, 142))	('disease-free survival', 'CPA', (86, 107))	('patients', 'Species', '9606', (14, 22))	('PAI1', 'Gene', (154, 158))
273327	32344898	To explore this possibility, we visualized in a heatmap the expression levels of EMT-associated genes that significantly correlated with PAI1 expression in two representative patient databases with available microarray expression data: GSE35452 and TCGA (Figure 2B) (Note that microarray data are not available for the HUVR-IBIS cohort).	('correlated', 'Reg', (121, 131))	('patient', 'Species', '9606', (175, 182))	('GSE35452', 'Var', (236, 244))	('PAI1', 'Gene', (137, 141))	('expression levels', 'MPA', (60, 77))	('expression', 'MPA', (142, 152))	('B) (Note', 'Species', '1054174', (263, 271))	('PAI1', 'Gene', '5054', (137, 141))
273343	32344898	FGFR1 (R = 0.61, p < 0.0001; Figure 4C) is a member of the Fibroblast Growth Factor family whose alterations have been recently identified as likely mechanisms of primary and secondary resistance to therapy using anti-EGFR antibody in CRC.	('alterations', 'Var', (97, 108))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('EGFR', 'Gene', '1956', (218, 222))	('EGFR', 'Gene', (218, 222))
273346	32344898	Finally, the BRAF gene (R = 0.38, p < 0.0001; Figure 4C) encodes a serine/threonine kinase and BRAF mutations have been associated with poor prognosis and less response to treatment in metastatic CRC.	('mutations', 'Var', (100, 109))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', '673', (95, 99))	('BRAF', 'Gene', (13, 17))	('BRAF', 'Gene', (95, 99))	('metastatic CRC', 'Disease', (185, 199))	('serine', 'Chemical', 'MESH:D012694', (67, 73))
273353	32344898	Vemurafenib is the first BRAF serine-threonine kinase protein inhibitor authorized for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E positive mutation.	('V600E positive', 'Var', (172, 186))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('serine', 'Chemical', 'MESH:D012694', (30, 36))	('BRAF', 'Gene', '673', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('BRAF', 'Gene', (25, 29))	('V600E', 'Mutation', 'rs113488022', (172, 177))	('patients', 'Species', '9606', (110, 118))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))
273354	32344898	Mutations in the BRAF gene substitute the amino acid valine for glutamic acid at position 600 and lead to the oncogenic activation of BRAF proteins.	('amino acid valine', 'MPA', (42, 59))	('oncogenic activation', 'MPA', (110, 130))	('lead to', 'Reg', (98, 105))	('glutamic acid', 'MPA', (64, 77))	('BRAF', 'Gene', '673', (17, 21))	('BRAF', 'Gene', '673', (134, 138))	('proteins', 'Protein', (139, 147))	('BRAF', 'Gene', (134, 138))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (17, 21))	('valine for glutamic acid at position 600', 'Mutation', 'rs113488022', (53, 93))
273355	32344898	AZD1208 is a potent and selective inhibitor that affects all three isoforms of serine-threonine Pim kinases.	('Pim', 'Gene', (96, 99))	('serine', 'Chemical', 'MESH:D012694', (79, 85))	('affects', 'Reg', (49, 56))	('AZD1208', 'Chemical', 'MESH:C587575', (0, 7))	('Pim', 'Gene', '5292', (96, 99))	('AZD1208', 'Var', (0, 7))
273361	32344898	Interestingly, the analysis with the Pim inhibitor AZD1208 showed that, although the IC50 was negatively correlated with PAI1 protein levels, most of the cell lines expressing PAI1 were similarly affected by AZD1208 treatment, in contrast to cell lines expressing undetectable levels (Figure 5C; Table S4), indicating that PAI1 expression determines sensitivity to AZD1208-mediated PIM inhibition.	('PAI1', 'Gene', (121, 125))	('AZD1208', 'Chemical', 'MESH:C587575', (365, 372))	('PAI1', 'Gene', (323, 327))	('affected', 'Reg', (196, 204))	('PAI1', 'Gene', (176, 180))	('Pim', 'Gene', (37, 40))	('AZD1208', 'Chemical', 'MESH:C587575', (208, 215))	('PAI1', 'Gene', '5054', (121, 125))	('PIM', 'Gene', '5292', (382, 385))	('PAI1', 'Gene', '5054', (323, 327))	('PAI1', 'Gene', '5054', (176, 180))	('Pim', 'Gene', '5292', (37, 40))	('AZD1208', 'Var', (208, 215))	('PIM', 'Gene', (382, 385))	('AZD1208', 'Chemical', 'MESH:C587575', (51, 58))
273362	32344898	The mutation status of KRAS, BRAF and PI3KCA did not seem to be related to the degree of sensitivity of these cell lines to AZD1208.	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('KRAS', 'Gene', (23, 27))	('PI3KCA', 'Var', (38, 44))	('AZD1208', 'Chemical', 'MESH:C587575', (124, 131))	('KRAS', 'Gene', '3845', (23, 27))
273371	32344898	PAI1 deregulation has been associated with cardiovascular diseases, obesity, metabolic syndrome and various types of cancer.	('obesity', 'Phenotype', 'HP:0001513', (68, 75))	('cardiovascular diseases', 'Disease', (43, 66))	('PAI1', 'Gene', '5054', (0, 4))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (43, 66))	('metabolic syndrome', 'Disease', 'MESH:D024821', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (43, 66))	('PAI1', 'Gene', (0, 4))	('obesity', 'Disease', 'MESH:D009765', (68, 75))	('associated', 'Reg', (27, 37))	('obesity', 'Disease', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('deregulation', 'Var', (5, 17))	('metabolic syndrome', 'Disease', (77, 95))	('cancer', 'Disease', (117, 123))
273373	32344898	Patients with higher PAI1 expression show a decrease in the survival probability in our patient database, as compared to patients with lower PAI1 expression.	('patient', 'Species', '9606', (88, 95))	('PAI1', 'Gene', (141, 145))	('decrease', 'NegReg', (44, 52))	('PAI1', 'Gene', '5054', (21, 25))	('expression', 'Var', (26, 36))	('PAI1', 'Gene', '5054', (141, 145))	('survival', 'MPA', (60, 68))	('Patients', 'Species', '9606', (0, 8))	('patient', 'Species', '9606', (121, 128))	('patients', 'Species', '9606', (121, 129))	('PAI1', 'Gene', (21, 25))
273376	32344898	Moreover, PAI1 expression is also correlated with poor outcome in several other cancer subtypes, particularly in ovarian serous carcinoma and node-negative breast cancer.	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (113, 137))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('expression', 'Var', (15, 25))	('PAI1', 'Gene', '5054', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('breast cancer', 'Disease', (156, 169))	('ovarian serous carcinoma', 'Disease', (113, 137))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('correlated', 'Reg', (34, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('cancer', 'Disease', (163, 169))	('PAI1', 'Gene', (10, 14))	('cancer', 'Disease', (80, 86))
273396	32344898	Overexpression of PIM kinases is common in many types of tumors, including CRCs.	('PIM', 'Gene', '5292', (18, 21))	('common', 'Reg', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('PIM', 'Gene', (18, 21))	('Overexpression', 'Var', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('CRCs', 'Disease', (75, 79))
273399	32344898	The pan-PIM kinase inhibitor AZD1208 acts over the serine/threonine kinases PIM1, 2 and 3, which may result in cell cycle arrest and apoptosis when those kinases are overexpressed.	('PIM1', 'Gene', (76, 80))	('PIM1', 'Gene', '5292', (76, 80))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('AZD1208', 'Chemical', 'MESH:C587575', (29, 36))	('apoptosis', 'CPA', (133, 142))	('serine', 'Chemical', 'MESH:D012694', (51, 57))	('arrest', 'Disease', 'MESH:D006323', (122, 128))	('PIM', 'Gene', '5292', (76, 79))	('AZD1208', 'Var', (29, 36))	('serine/threonine', 'MPA', (51, 67))	('PIM', 'Gene', (8, 11))	('PIM', 'Gene', '5292', (8, 11))	('PIM', 'Gene', (76, 79))	('result in', 'Reg', (101, 110))	('arrest', 'Disease', (122, 128))
273424	32063692	Premedication with simethicone or simethicone and N-acetylcysteine improved visualization in the esophagus and stomach significantly compared to pre-medication with water alone in the esophagus and stomach.	('simethicone', 'Chemical', 'MESH:D012841', (19, 30))	('N-acetylcysteine', 'Var', (50, 66))	('simethicone', 'Chemical', 'MESH:D012841', (34, 45))	('visualization', 'MPA', (76, 89))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (50, 66))	('improved', 'PosReg', (67, 75))	('simethicone', 'Var', (34, 45))
273459	32063692	In a prospective, propensity matched study, non-magnifying NBI was found to have similar sensitivity with superior accuracy and specificity compared to chromo-endoscopy with iodine staining for early squamous cell carcinoma.	('iodine', 'Chemical', 'MESH:D007455', (174, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('squamous cell carcinoma', 'Disease', (200, 223))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 223))	('non-magnifying', 'Var', (44, 58))
273465	32063692	Comparing the use newer generation NBI which is twice as bright as the previous version to high definition white light endoscopy, the use of NBI resulted in higher pick up rate of focal gastric lesions (40.6% vs 29%, P = 0.003) and intestinal metaplasia (17.7% vs 7.7%, P < 0.001) with no difference in the detection of gastric cancers (1% vs 2.4%, P = 0.189).	('NBI', 'Var', (141, 144))	('gastric lesions', 'Disease', 'MESH:D013272', (186, 201))	('gastric cancer', 'Phenotype', 'HP:0012126', (320, 334))	('cancers', 'Phenotype', 'HP:0002664', (328, 335))	('gastric lesions', 'Disease', (186, 201))	('higher', 'PosReg', (157, 163))	('gastric cancers', 'Disease', 'MESH:D013274', (320, 335))	('intestinal metaplasia', 'CPA', (232, 253))	('pick up', 'CPA', (164, 171))	('gastric cancers', 'Disease', (320, 335))	('gastric cancers', 'Phenotype', 'HP:0012126', (320, 335))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))
273467	32063692	In the presence of a demarcation line as well as irregular micro surface and/or irregular microvascular pattern, a diagnosis of early gastric cancer can be confidently made.	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('irregular', 'Var', (49, 58))
273487	32063692	Endocytoscopy findings in the antrum correlates with Helicobacter pylori positivity with high sensitivity and specificity for intestinal metaplasia and atrophic gastritis as well as gastric cancer diagnosis.	('intestinal metaplasia', 'Disease', (126, 147))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (152, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('gastritis', 'Phenotype', 'HP:0005263', (161, 170))	('Helicobacter pylori positivity', 'Phenotype', 'HP:0005202', (53, 83))	('Helicobacter pylori', 'Species', '210', (53, 72))	('positivity', 'Var', (73, 83))	('atrophic gastritis', 'Disease', 'MESH:D005757', (152, 170))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('atrophic gastritis', 'Disease', (152, 170))	('gastric cancer', 'Disease', (182, 196))	('Helicobacter pylori', 'Disease', (53, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))
273505	31516566	Association between SFRP promoter hypermethylation and different types of cancer: A systematic review and meta-analysis Abnormal methylation of secreted frizzled-related proteins (SFRPs) has been observed in various human cancer types.	('SFRPs', 'Gene', (180, 185))	('human', 'Species', '9606', (216, 221))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('methylation', 'Var', (129, 140))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (222, 228))	('cancer', 'Disease', (74, 80))	('observed', 'Reg', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('Association', 'Interaction', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('SFRP', 'Gene', (20, 24))
273507	31516566	The aim of the present systematic review was to assess the association between SFRP methylation and cancer risk.	('methylation', 'Var', (84, 95))	('association', 'Interaction', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('SFRP', 'Gene', (79, 83))
273508	31516566	A meta-analysis was systematically conducted to assess the clinicopathological significance of SFRP methylation in cancer risk.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('methylation', 'Var', (100, 111))	('SFRP', 'Gene', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
273510	31516566	SFRP1, SFRP2, SFRP4 and SFRP5 hypermethylation was significantly associated with cancer risk, with ORs of 8.48 (95% CI, 6.26-11.49), 8.21 (95% CI, 6.20-10.88), 11.41 (95% CI, 6.42-20.30) and 6.34 (95% CI, 3.86-10.42), respectively.	('SFRP5', 'Gene', (24, 29))	('SFRP4', 'Gene', (14, 19))	('SFRP1', 'Gene', (0, 5))	('SFRP4', 'Gene', '6424', (14, 19))	('SFRP2', 'Gene', '6423', (7, 12))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('SFRP2', 'Gene', (7, 12))	('associated', 'Reg', (65, 75))	('SFRP5', 'Gene', '6425', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('SFRP1', 'Gene', '6422', (0, 5))	('hypermethylation', 'Var', (30, 46))
273511	31516566	SFRP2 methylation was significantly associated with differentiation in colorectal cancer (OR, 2.16; 95% CI, 1.02-4.56).	('colorectal cancer', 'Disease', (71, 88))	('SFRP2', 'Gene', '6423', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('SFRP2', 'Gene', (0, 5))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('methylation', 'Var', (6, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('associated with', 'Reg', (36, 51))
273512	31516566	The results of the present study demonstrated that SFRP methylation may contribute to carcinogenesis, especially in certain cancer types, including hepatocellular carcinoma and colorectal cancer.	('carcinogenesis', 'Disease', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (124, 130))	('colorectal cancer', 'Disease', (177, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (148, 172))	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('hepatocellular carcinoma', 'Disease', (148, 172))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('SFRP', 'Protein', (51, 55))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (148, 172))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('cancer', 'Disease', (188, 194))	('contribute', 'Reg', (72, 82))	('methylation', 'Var', (56, 67))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
273513	31516566	In cancer, epigenetic modifications involve DNA methylation of tumor suppressor gene (TSG) promoters, which inhibits gene transcription.	('tumor', 'Disease', (63, 68))	('gene transcription', 'MPA', (117, 135))	('inhibits', 'NegReg', (108, 116))	('epigenetic modifications', 'Var', (11, 35))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('TSG', 'Gene', '57045', (86, 89))	('DNA methylation', 'Var', (44, 59))	('cancer', 'Disease', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TSG', 'Gene', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
273514	31516566	Aberrant DNA methylation often occurs early in carcinogenesis in a number of cancer types, including breast cancer, colorectal cancer and gastric cancer.	('cancer', 'Disease', (146, 152))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('DNA', 'Protein', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('Aberrant', 'Var', (0, 8))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('cancer', 'Disease', (127, 133))	('breast cancer', 'Disease', (101, 114))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (77, 83))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (108, 114))	('gastric cancer', 'Disease', (138, 152))	('colorectal cancer', 'Disease', (116, 133))	('carcinogenesis', 'Disease', (47, 61))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('carcinogenesis', 'Disease', 'MESH:D063646', (47, 61))
273522	31516566	The downregulation of SFRP genes by promoter methylation has been demonstrated in various cancer types, including cervical cancer, leukemia and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (149, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('promoter methylation', 'Var', (36, 56))	('SFRP genes', 'Gene', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('downregulation', 'NegReg', (4, 18))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('leukemia and lung cancer', 'Disease', 'MESH:D008175', (131, 155))
273524	31516566	In another meta-analysis, SFRP2 methylation was identified as a new biomarker for screening early CRC by detecting stool-based DNA methylation.	('methylation', 'Var', (32, 43))	('SFRP2', 'Gene', (26, 31))	('stool-based DNA methylation', 'MPA', (115, 142))	('early CRC', 'Disease', (92, 101))	('SFRP2', 'Gene', '6423', (26, 31))
273525	31516566	In addition, aberrant methylation of the SFRP1 promoter has been demonstrated to contribute to colorectal carcinogenesis.	('SFRP1', 'Gene', '6422', (41, 46))	('contribute', 'Reg', (81, 91))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (95, 120))	('colorectal carcinogenesis', 'Disease', (95, 120))	('SFRP1', 'Gene', (41, 46))	('methylation', 'MPA', (22, 33))	('aberrant', 'Var', (13, 21))
273526	31516566	Despite numerous investigations, the association between SFRP methylation in CRC and clinicopathological significance still needs to be clarified, and the association between SFRP promoter methylation and multiple tumors remains controversial.	('CRC', 'Disease', (77, 80))	('methylation', 'Var', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('SFRP', 'Gene', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('multiple tumors', 'Disease', (205, 220))	('multiple tumors', 'Disease', 'MESH:D009369', (205, 220))
273527	31516566	For example, Kloten et al reported that SFRP1 and SFRP2 methylation had no association with breast cancer, whereas Suzuki et al reported that SFRP1 and SFRP2 methylation was associated with breast cancer.	('methylation', 'Var', (158, 169))	('SFRP1', 'Gene', (142, 147))	('methylation', 'Var', (56, 67))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('SFRP1', 'Gene', (40, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('associated', 'Reg', (174, 184))	('SFRP2', 'Gene', '6423', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('SFRP2', 'Gene', '6423', (50, 55))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('breast cancer', 'Disease', (92, 105))	('SFRP1', 'Gene', '6422', (142, 147))	('SFRP1', 'Gene', '6422', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('SFRP2', 'Gene', (152, 157))	('SFRP2', 'Gene', (50, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
273529	31516566	Therefore, the aim of the present study was to conduct a meta-analysis to further analyze the association between different types of cancer and SFRP methylation.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('association', 'Interaction', (94, 105))	('methylation', 'Var', (149, 160))	('SFRP', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
273543	31516566	The results of the meta-analysis demonstrated that the frequency of SFRP1 methylation was significantly higher in patients with cancer compared with that in control samples.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('methylation', 'Var', (74, 85))	('patients', 'Species', '9606', (114, 122))	('SFRP1', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('higher', 'PosReg', (104, 110))	('SFRP1', 'Gene', '6422', (68, 73))	('cancer', 'Disease', (128, 134))
273545	31516566	In the analysis by cancer type, SFRP1 methylation was associated with HCC (OR, 5.00; 95% CI, 2.74-9.11; P<0.001), GC (OR, 10.27; 95% CI, 5.14-20.50; P<0.001), CRC (OR, 7.86; 95% CI, 4.87-12.68; P<0.001), EC (OR, 16.18; 95% CI, 3.77-69.47; P<0.001), RCC (OR, 12.18; 95% CI, 5.66-6.21; P<0.001), CC (OR, 60.61; 95% CI, 7.10-517.42; P<0.001), leukemia (OR, 12.85; 95% CI, 3.64-45.31; P<0.001), lung cancer (OR, 10.68; 95% CI, 5.94-19.20; P<0.001), bladder cancer (OR, 8.20; 95% CI; 3.23-20.76; P<0.001), ovarian cancer (OR, 22.19; 95% CI, 10.54-46.72; P<0.001) and endometrial carcinoma (OR, 3.07; 95% CI, 1.03-9.12; P=0.04), but not BC (OR, 10.70; 95% CI, 0.82-140.26; P=0.07).	('cancer', 'Disease', 'MESH:D009369', (396, 402))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (562, 583))	('methylation', 'Var', (38, 49))	('cancer', 'Disease', (19, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (574, 583))	('cancer', 'Disease', (453, 459))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (562, 583))	('SFRP1', 'Gene', (32, 37))	('lung cancer', 'Disease', 'MESH:D008175', (391, 402))	('cancer', 'Disease', (509, 515))	('cancer', 'Phenotype', 'HP:0002664', (453, 459))	('leukemia', 'Phenotype', 'HP:0001909', (340, 348))	('cancer', 'Phenotype', 'HP:0002664', (509, 515))	('lung cancer', 'Phenotype', 'HP:0100526', (391, 402))	('bladder cancer', 'Disease', 'MESH:D001749', (445, 459))	('bladder cancer', 'Disease', (445, 459))	('RCC', 'Disease', (249, 252))	('ovarian cancer', 'Disease', 'MESH:D010051', (501, 515))	('associated', 'Reg', (54, 64))	('bladder cancer', 'Phenotype', 'HP:0009725', (445, 459))	('CRC', 'Disease', (159, 162))	('HCC', 'Gene', '619501', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (396, 402))	('leukemia', 'Disease', (340, 348))	('leukemia', 'Disease', 'MESH:D007938', (340, 348))	('SFRP1', 'Gene', '6422', (32, 37))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('HCC', 'Gene', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (509, 515))	('cancer', 'Disease', 'MESH:D009369', (453, 459))	('ovarian cancer', 'Disease', (501, 515))	('endometrial carcinoma', 'Disease', (562, 583))	('lung cancer', 'Disease', (391, 402))	('ovarian cancer', 'Phenotype', 'HP:0100615', (501, 515))
273546	31516566	In the analysis based on method, significantly increased cancer risk was associated with SFRP1 methylation according to the MSP method (OR, 9.95; 95% CI, 7.26-13.64; P<0.001), COBRA method (OR, 5.48; 95% CI, 1.89-15.85; P=0.002), MethyLight (OR, 8.92; 95% CI, 1.10-72.12; P=0.04) and methylation-sensitive restriction endonuclease digestion and quantitative PCR (OR, 3.26; 95% CI, 1.33-7.95; P=0.01), but not by QMSP (OR, 5.01; 95% CI, 0.62-40.67; P=0.13).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('SFRP1', 'Gene', (89, 94))	('methylation', 'Var', (95, 106))	('cancer', 'Disease', (57, 63))	('increased', 'PosReg', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('MethyLight', 'Var', (230, 240))	('SFRP1', 'Gene', '6422', (89, 94))
273547	31516566	Stratified analysis by sample material revealed that significantly increased cancer risk was associated with SFRP1 methylation in tissue (OR, 9.46; 95% CI, 6.93-12.92; P<0.001), stool (OR, 9.33; 95% CI, 3.09-28.15; P<0.001) and blood (OR, 9.30; 95% CI, 3.60-24.03; P<0.001) samples, but not in bone marrow samples (OR, 2.01; 95% CI, 0.35-11.69; P=0.44).	('methylation', 'Var', (115, 126))	('SFRP1', 'Gene', (109, 114))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('SFRP1', 'Gene', '6422', (109, 114))
273548	31516566	Moreover, subgroup analysis based on region demonstrated that SFRP1 methylation was associated with cancer in patients from Asia (OR, 7.83; 95% CI, 5.70-10.76; P<0.001), Europe (OR, 7.58; 95% CI, 2.74-20.98; P<0.001) and North America (OR, 18.21; 95% CI, 9.28-35.71; P<0.001; Table I).	('associated with', 'Reg', (84, 99))	('SFRP1', 'Gene', '6422', (62, 67))	('methylation', 'Var', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('SFRP1', 'Gene', (62, 67))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patients', 'Species', '9606', (110, 118))
273550	31516566	In total, 54 studies with 8,577 samples were included in the meta-analysis to assess the association between SFRP2 methylation status and cancer risk.	('methylation', 'Var', (115, 126))	('cancer', 'Disease', (138, 144))	('SFRP2', 'Gene', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('SFRP2', 'Gene', '6423', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('association', 'Interaction', (89, 100))
273551	31516566	A significant association was identified between SFRP2 promoter hypermethylation and increased cancer risk, with an OR of 8.21 (95% CI, 6.20-10.88; P<0.001) (Table I; Fig.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('SFRP2', 'Gene', '6423', (49, 54))	('cancer', 'Disease', (95, 101))	('SFRP2', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('promoter hypermethylation', 'Var', (55, 80))
273552	31516566	Analysis by cancer type revealed that significantly increased cancer risk was associated with SFRP2 methylation in HCC (OR, 1.91; 95% CI, 1.20-3.03; P=0.006), CRC (OR, 8.32; 95% CI, 5.88-11.78; P<0.001), GC (OR, 6.97; 95% CI, 2.66-18.25; P<0.001), EC (OR, 7.28; 95% CI, 1.72-30.79; P=0.007), leukemia (OR, 14.07; 95% CI, 1.84-107.61; P=0.01), CC (OR, 93.72; 95% CI, 29.05-302.32; P<0.001), ovarian cancer (OR, 19.00; 95% CI, 6.54-55.16; P<0.001), endometrial carcinoma (OR, 5.97; 95% CI, 2.06-17.33; P=0.001) and RCC (OR, 13.48; 95% CI, 5.37-33.79; P=0.001), but not BC (OR, 30.81; 95% CI, 0.52-1,837.06; P=0.10).	('RCC', 'Disease', (513, 516))	('cancer', 'Disease', (398, 404))	('SFRP2', 'Gene', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('RCC', 'Disease', 'MESH:C538614', (513, 516))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('endometrial carcinoma', 'Disease', (447, 468))	('carcinoma', 'Phenotype', 'HP:0030731', (459, 468))	('leukemia', 'Phenotype', 'HP:0001909', (292, 300))	('methylation', 'Var', (100, 111))	('cancer', 'Disease', (62, 68))	('ovarian cancer', 'Disease', 'MESH:D010051', (390, 404))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('leukemia', 'Disease', 'MESH:D007938', (292, 300))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (447, 468))	('leukemia', 'Disease', (292, 300))	('cancer', 'Disease', 'MESH:D009369', (398, 404))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (447, 468))	('HCC', 'Gene', '619501', (115, 118))	('cancer', 'Disease', (12, 18))	('SFRP2', 'Gene', '6423', (94, 99))	('ovarian cancer', 'Disease', (390, 404))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('HCC', 'Gene', (115, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (390, 404))
273553	31516566	In the subgroup analysis based on method, significantly increased cancer risk was associated with SFRP2 methylation as determined by the MSP method (OR, 8.82; 95% CI, 6.21-12.54; P<0.001), COBRA method (OR, 9.74; 95% CI, 5.59-16.98, P<0.001) and MethyLight (OR, 12.19; 95% CI, 6.92-21.48; P<0.001), but not according to the QMSP (OR, 5.00; 95% CI, 0.60-41.83; P=0.14) or reverse hybridization (OR, 2.46; 95% CI, 0.45-13.58; P=0.30) methods.	('SFRP2', 'Gene', (98, 103))	('MethyLight', 'Var', (246, 256))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('methylation', 'Var', (104, 115))	('SFRP2', 'Gene', '6423', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
273554	31516566	In addition, subgroup analysis based on region reported that SFRP2 methylation was associated with cancer in patients from Asia (OR 8.69; 95% CI, 6.40-11.81; P<0.001), Europe (OR, 5.73; 95% CI, 1.76-18.72; P=0.004) and North America (OR, 6.99; 95% CI, 2.53-19.33; P<0.001).	('patients', 'Species', '9606', (109, 117))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('methylation', 'Var', (67, 78))	('cancer', 'Disease', (99, 105))	('associated with', 'Reg', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('SFRP2', 'Gene', '6423', (61, 66))	('SFRP2', 'Gene', (61, 66))
273555	31516566	Stratified analysis by sample material revealed that significantly increased cancer risk was associated with SFRP2 methylation in tissue (OR, 8.29; 95% CI, 5.79-11.87; P<0.001), stool (OR, 9.20; 95% CI, 7.06-11.99; P<0.001) and blood sample (OR, 7.50; 95% CI, 2.30-24.42; P<0.001; Table I).	('methylation', 'Var', (115, 126))	('SFRP2', 'Gene', (109, 114))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('SFRP2', 'Gene', '6423', (109, 114))
273557	31516566	A significant association was identified between SFRP4 promoter hypermethylation and increased cancer risk with an OR of 11.41 (95% CI, 6.42-20.30; P<0.001) (Table I; Fig.	('SFRP4', 'Gene', (49, 54))	('SFRP4', 'Gene', '6424', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('promoter hypermethylation', 'Var', (55, 80))
273558	31516566	Analysis by cancer type revealed that significantly increased cancer risk was associated with SFRP4 methylation in CRC (OR, 11.04; 95% CI, 2.50-48.76; P=0.002), ovarian cancer (OR, 22.01, 95% CI, 10.49-46.19; P<0.001), CC (OR, 215.02; 95% CI, 40.42-1143.79; P<0.001 and RCC (OR, 7.39; 95% CI, 3.22-16.98; P<0.001), but not endometrial carcinoma (OR, 0.71; 95% CI, 0.16-3.19; P=0.66) or GC (OR, 7.66; 95% CI, 0.87-67.08; P=0.07).	('cancer', 'Disease', (169, 175))	('SFRP4', 'Gene', '6424', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (323, 344))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (323, 344))	('SFRP4', 'Gene', (94, 99))	('methylation', 'Var', (100, 111))	('ovarian cancer', 'Disease', 'MESH:D010051', (161, 175))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('RCC', 'Disease', (270, 273))	('ovarian cancer', 'Disease', (161, 175))	('cancer', 'Disease', (12, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('RCC', 'Disease', 'MESH:C538614', (270, 273))	('endometrial carcinoma', 'Disease', (323, 344))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
273559	31516566	In the subgroup analysis based on method, significantly increased cancer risk was associated with SFRP1 methylation as assessed by the MSP method (OR, 11.25; 95% CI, 6.63-19.11; P<0.001), but not by QMSP (OR, 25.86; 95% CI, 0.18-3638.77; P=0.20).	('increased', 'PosReg', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('methylation', 'Var', (104, 115))	('SFRP1', 'Gene', '6422', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))	('SFRP1', 'Gene', (98, 103))
273560	31516566	In addition, subgroup analysis based on region exhibited that SFRP4 methylation was associated with cancer in patients from Asia (OR, 11.69; 95% CI, 5.86-23.32; P<0.001), and North America (OR, 9.39; 95% CI, 5.25-16.79; P<0.001).	('associated with', 'Reg', (84, 99))	('SFRP4', 'Gene', (62, 67))	('SFRP4', 'Gene', '6424', (62, 67))	('methylation', 'Var', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patients', 'Species', '9606', (110, 118))
273561	31516566	Stratified analysis by sample material revealed that significantly increased cancer risk was associated with SFRP4 methylation in tissue (OR, 12.12; 95% CI, 6.50-22.59; P<0.001) and blood sample (OR, 9.15; 95% CI, 1.18-70.81; P<0.001; Table I).	('methylation', 'Var', (115, 126))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('SFRP4', 'Gene', (109, 114))	('SFRP4', 'Gene', '6424', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
273562	31516566	In total, 28 studies including 3,606 samples were analyzed to evaluate the association of SFRP5 methylation status with various cancer types.	('SFRP5', 'Gene', '6425', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('SFRP5', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('methylation', 'Var', (96, 107))	('association', 'Interaction', (75, 86))	('cancer', 'Disease', (128, 134))
273563	31516566	The pooled OR of SFRP5 hypermethylation was 6.34 (95% CI, 3.86-10.42; P<0.001) (Table I; Fig.	('hypermethylation', 'Var', (23, 39))	('SFRP5', 'Gene', '6425', (17, 22))	('SFRP5', 'Gene', (17, 22))
273564	31516566	Analysis by cancer type revealed that significantly increased cancer risk was associated with SFRP5 methylation in HCC (OR, 4.11; 95% CI, 1.95-8.67; P<0.001), CRC (OR, 6.37; 95% CI, 2.18-18.62; P<0.001), ovarian cancer (OR, 59.70; 95% CI, 23.59-151.07; P<0.001) and RCC (OR, 9.75; 95% CI, 4.29-22.12; P<0.001), but not endometrial carcinoma (OR, 2.09; 95% CI, 0.44-10.04; P=0.36), GC (OR, 3.36; 95% CI, 0.47-23.83; P=0.22) and CC (OR, 11.89; 95% CI, 0.50-282.90; P=0.13).	('ovarian cancer', 'Disease', (204, 218))	('RCC', 'Disease', (266, 269))	('ovarian cancer', 'Phenotype', 'HP:0100615', (204, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('methylation', 'Var', (100, 111))	('cancer', 'Disease', (62, 68))	('endometrial carcinoma', 'Disease', (319, 340))	('SFRP5', 'Gene', '6425', (94, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SFRP5', 'Gene', (94, 99))	('cancer', 'Disease', (212, 218))	('ovarian cancer', 'Disease', 'MESH:D010051', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('HCC', 'Gene', '619501', (115, 118))	('cancer', 'Disease', (12, 18))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (319, 340))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('HCC', 'Gene', (115, 118))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (319, 340))
273565	31516566	In the stratified analysis based on method, significantly increased cancer risk was associated with SFRP5 methylation as determined by the MSP method (OR, 7.21; 95% CI, 4.32-12.03; P<0.001).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('increased', 'PosReg', (58, 67))	('SFRP5', 'Gene', (100, 105))	('methylation', 'Var', (106, 117))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('SFRP5', 'Gene', '6425', (100, 105))
273566	31516566	Additionally, subgroup analysis based on region demonstrated that SFRP5 methylation was associated with cancer in patients from Asia (OR, 6.54; 95% CI, 3.51-12.21; P<0.001), Europe (OR, 8.69; 95% CI, 6.40-11.81; P<0.001) and North America (OR, 2.08; 95% CI, 1.22-3.55; P<0.007).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('SFRP5', 'Gene', (66, 71))	('methylation', 'Var', (72, 83))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Disease', (104, 110))	('SFRP5', 'Gene', '6425', (66, 71))	('associated with', 'Reg', (88, 103))
273567	31516566	Stratified analysis by sample material revealed that significantly increased cancer risk was associated with SFRP5 methylation in tissue (OR, 6.63; 95% CI, 3.85-11.42; P<0.001) and blood sample (OR, 17.36; 95% CI, 2.29-131.85; P<0.006; Table I).	('methylation', 'Var', (115, 126))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('SFRP5', 'Gene', '6425', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('SFRP5', 'Gene', (109, 114))
273569	31516566	No associations were observed between SFRP1 methylation and certain factors, including sex, smoking habit or pathological type in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('methylation', 'Var', (44, 55))	('SFRP1', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('lung cancer', 'Disease', (130, 141))	('SFRP1', 'Gene', '6422', (38, 43))
273570	31516566	SFRP2 methylation was not associated with any reported clinicopathological features in BC and GC.	('SFRP2', 'Gene', '6423', (0, 5))	('methylation', 'Var', (6, 17))	('SFRP2', 'Gene', (0, 5))
273572	31516566	To analyze the association between SFRP2 methylation and tumor differentiation in CRC, deletion of the study by Takeda et al increased the pooled OR from 2.16 (95% CI, 1.02-4.56) to 2.70 (95% CI, 1.39-5.25), whereas the heterogeneity was reduced from 59% (P=0.02) to 39% (P=0.30).	('increased', 'PosReg', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('SFRP2', 'Gene', '6423', (35, 40))	('CRC', 'Disease', (82, 85))	('SFRP2', 'Gene', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('deletion', 'Var', (87, 95))	('tumor', 'Disease', (57, 62))	('association', 'Interaction', (15, 26))
273578	31516566	The OR remained significant for the association between SFRP1 methylation and risk of various cancer types (OR, 1.872; 95% CI, 1.568-2.176).	('SFRP1', 'Gene', '6422', (56, 61))	('methylation', 'Var', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('SFRP1', 'Gene', (56, 61))	('association', 'Interaction', (36, 47))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
273580	31516566	Hypermethylation of SFRP gene promoter is an important mechanism of Wnt signaling pathway activation, and it is also key to tumor formation and development.	('Wnt signaling pathway', 'Pathway', (68, 89))	('activation', 'PosReg', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', (124, 129))	('SFRP gene', 'Gene', (20, 29))	('key', 'Reg', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
273582	31516566	The results demonstrated that the frequency of SFRP1, SFRP2, SFRP4 and SFRP5 promoter methylation was 8.48-, 8.21-, 11.41- and 6.34-fold higher, respectively, in patients with cancer compared with that in healthy controls.	('patients', 'Species', '9606', (162, 170))	('SFRP2', 'Gene', (54, 59))	('SFRP1', 'Gene', (47, 52))	('SFRP5', 'Gene', '6425', (71, 76))	('higher', 'PosReg', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('methylation', 'Var', (86, 97))	('SFRP1', 'Gene', '6422', (47, 52))	('SFRP4', 'Gene', (61, 66))	('SFRP4', 'Gene', '6424', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('SFRP5', 'Gene', (71, 76))	('SFRP2', 'Gene', '6423', (54, 59))
273583	31516566	Additionally, SFRP2 promoter methylation was significantly associated with poor differentiation in CRC.	('methylation', 'Var', (29, 40))	('SFRP2', 'Gene', '6423', (14, 19))	('SFRP2', 'Gene', (14, 19))	('associated', 'Reg', (59, 69))	('CRC', 'Disease', (99, 102))
273585	31516566	The results demonstrated that SFRP1 promoter methylation was significantly associated with HCC, GC, CRC, EC, RCC, CC, ovarian cancer, endometrial carcinoma, bladder cancer, lung cancer and leukemia.	('ovarian cancer', 'Disease', (118, 132))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (134, 155))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('lung cancer', 'Disease', (173, 184))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (134, 155))	('leukemia', 'Phenotype', 'HP:0001909', (189, 197))	('methylation', 'Var', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SFRP1', 'Gene', (30, 35))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('HCC', 'Gene', '619501', (91, 94))	('leukemia', 'Disease', (189, 197))	('leukemia', 'Disease', 'MESH:D007938', (189, 197))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('bladder cancer', 'Disease', (157, 171))	('associated', 'Reg', (75, 85))	('ovarian cancer', 'Disease', 'MESH:D010051', (118, 132))	('endometrial carcinoma', 'Disease', (134, 155))	('HCC', 'Gene', (91, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('RCC', 'Disease', (109, 112))	('CRC', 'Disease', (100, 103))	('SFRP1', 'Gene', '6422', (30, 35))
273586	31516566	SFRP2 promoter methylation was associated with HCC, GC, CRC, EC, RCC, CC, ovarian cancer and endometrial carcinoma.	('methylation', 'Var', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('SFRP2', 'Gene', '6423', (0, 5))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (93, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('CRC', 'Disease', (56, 59))	('HCC', 'Gene', (47, 50))	('SFRP2', 'Gene', (0, 5))	('ovarian cancer', 'Disease', 'MESH:D010051', (74, 88))	('endometrial carcinoma', 'Disease', (93, 114))	('associated', 'Reg', (31, 41))	('HCC', 'Gene', '619501', (47, 50))	('ovarian cancer', 'Disease', (74, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (93, 114))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
273588	31516566	SFRP1 and SFRP2 methylation were not associated with BC.	('SFRP1', 'Gene', (0, 5))	('SFRP2', 'Gene', '6423', (10, 15))	('SFRP2', 'Gene', (10, 15))	('associated', 'Reg', (37, 47))	('SFRP1', 'Gene', '6422', (0, 5))	('methylation', 'Var', (16, 27))
273589	31516566	SFRP4 and SFRP5 promoter methylation was not associated with endometrial carcinoma and GC, and SFRP5 promoter methylation was not associated with CC.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (61, 82))	('SFRP5', 'Gene', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('SFRP4', 'Gene', '6424', (0, 5))	('methylation', 'Var', (25, 36))	('SFRP5', 'Gene', '6425', (95, 100))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (61, 82))	('SFRP5', 'Gene', '6425', (10, 15))	('SFRP4', 'Gene', (0, 5))	('endometrial carcinoma', 'Disease', (61, 82))	('SFRP5', 'Gene', (95, 100))
273590	31516566	Therefore, despite the limited number of studies that described other specific types of cancer, SFRPs gene hypermethylation was associated with the majority of cancer types.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('hypermethylation', 'Var', (107, 123))	('associated', 'Reg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('SFRPs', 'Gene', (96, 101))
273591	31516566	In the present study, SFRP methylation was significantly associated with cancer risk in tissue, blood and stool samples.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SFRP', 'Gene', (22, 26))	('methylation', 'Var', (27, 38))	('associated with', 'Reg', (57, 72))
273598	31516566	Subgroup analysis based on methylation detection method revealed significant associations between SFRP methylation and cancer using MSP, COBRA and MethyLight, but not QMSP.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('SFRP', 'Gene', (98, 102))	('cancer', 'Disease', (119, 125))	('methylation', 'Var', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
273599	31516566	Subgroup analysis based on different regions revealed that SFRP methylation was associated with cancer in patients from all covered regions.	('methylation', 'Var', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('associated with', 'Reg', (80, 95))	('patients', 'Species', '9606', (106, 114))	('SFRP', 'Gene', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
273602	31516566	Meta-regression was performed to explain the sources of heterogeneity; the results demonstrated that the sample material contributed to the bias among studies that investigated the association between SFRP1 methylation and multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('association', 'Interaction', (181, 192))	('cancer', 'Disease', (232, 238))	('SFRP1', 'Gene', '6422', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('methylation', 'Var', (207, 218))	('SFRP1', 'Gene', (201, 206))
273607	31516566	A trim and fill analysis was performed to amend the bias, and SFRP1 methylation still exhibited a significant association with cancer risk.	('SFRP1', 'Gene', '6422', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('methylation', 'Var', (68, 79))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('SFRP1', 'Gene', (62, 67))	('cancer', 'Disease', (127, 133))
273609	31516566	In addition, SFRP2 methylation was associated with CRC differentiation.	('SFRP2', 'Gene', '6423', (13, 18))	('methylation', 'Var', (19, 30))	('SFRP2', 'Gene', (13, 18))	('associated', 'Reg', (35, 45))	('CRC differentiation', 'Disease', (51, 70))
273615	31354296	This study aimed to determine the associations between single nucleotide polymorphisms (SNPs) of chemokine family members and the prognosis of esophageal cancer (EC).	('associations', 'Interaction', (34, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('single nucleotide polymorphisms', 'Var', (55, 86))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('esophageal cancer', 'Disease', (143, 160))
273616	31354296	Methods: The Cox risk proportional model and log-rank test were used to analyze the associations of 16 potentially functional SNPs in 13 genes from the chemokine family with the survival of 729 Chinese patients with EC.	('Cox', 'Gene', (13, 16))	('associations', 'Interaction', (84, 96))	('patients', 'Species', '9606', (202, 210))	('SNPs', 'Var', (126, 130))	('Cox', 'Gene', '1351', (13, 16))
273618	31354296	Multivariate Cox regression analysis showed that the risk of death was higher in CCL26rs2302009 genotype A/C carriers than in A/A carriers and it was also higher in CX3CL1rs2239352 genotype T/T carriers than in C/C carriers.	('higher', 'PosReg', (71, 77))	('CCL26rs2302009', 'Chemical', '-', (81, 95))	('CX3CL1', 'Gene', (165, 171))	('Cox', 'Gene', (13, 16))	('death', 'Disease', (61, 66))	('death', 'Disease', 'MESH:D003643', (61, 66))	('Cox', 'Gene', '1351', (13, 16))	('genotype', 'Var', (96, 104))	('CCL26rs2302009', 'Gene', (81, 95))	('higher', 'PosReg', (155, 161))	('CX3CL1', 'Gene', '6376', (165, 171))
273619	31354296	Stepwise Cox regression analysis showed that CCL26rs2302009 genotype A/C was an independent prognostic factor of EC, and its association with increased risk of death was stronger in patients who were <=60 years old, female, with tumors located in the middle part of esophagus, with undifferentiated or poorly differentiated tumors, with early-stage pathologic type disease, with the longest diameter of tumor <=5cm than in their counterparts.	('CCL26rs2302009', 'Var', (45, 59))	('tumor', 'Disease', 'MESH:D009369', (403, 408))	('CCL26rs2302009', 'Chemical', '-', (45, 59))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('patients', 'Species', '9606', (182, 190))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('death', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Phenotype', 'HP:0002664', (403, 408))	('tumors', 'Disease', (324, 330))	('tumors', 'Disease', (229, 235))	('tumor', 'Disease', (229, 234))	('Cox', 'Gene', '1351', (9, 12))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('Cox', 'Gene', (9, 12))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('death', 'Disease', 'MESH:D003643', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (324, 329))	('tumor', 'Disease', (403, 408))	('stronger', 'PosReg', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
273620	31354296	Conclusion: These findings suggest that CCL26rs2302009 may be a candidate biomarker for EC and its effect on death risk are associated with the histological grade, pathologic type, and the longest diameter of tumor.	('tumor', 'Disease', (209, 214))	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('CCL26rs2302009', 'Chemical', '-', (40, 54))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('CCL26rs2302009', 'Var', (40, 54))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
273626	31354296	Dysregulated inflammatory response is known to be associated with increased risk of some chronic diseases, including cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('chronic diseases', 'Disease', 'MESH:D002908', (89, 105))	('Dysregulated', 'Var', (0, 12))	('chronic diseases', 'Disease', (89, 105))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('associated', 'Reg', (50, 60))	('cancers', 'Disease', (117, 124))
273633	31354296	The associations between the polymorphisms of a few genes in the chemokine family and the progression and prognosis of tumors have been studied.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('polymorphisms', 'Var', (29, 42))
273636	31354296	The C>A mutation of CCL22rs4359426 may aggravate H. pylori infections, increasing the risk of gastric cancer.	('CCL22rs4359426', 'Chemical', '-', (20, 34))	('gastric cancer', 'Disease', (94, 108))	('increasing', 'PosReg', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CCL22rs4359426', 'Gene', (20, 34))	('aggravate H. pylori infections', 'Phenotype', 'HP:0005202', (39, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('C>A', 'Var', (4, 7))	('pylori infections', 'Disease', (52, 69))	('aggravate', 'PosReg', (39, 48))	('increasing the risk of gastric cancer', 'Phenotype', 'HP:0006753', (71, 108))	('pylori infections', 'Disease', 'MESH:D016481', (52, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))
273638	31354296	Although these studies have shown the associations between polymorphisms of some genes in the chemokine family and the prognosis of some tumors, most studies have only focused on a few genes/polymorphisms, and thus could not reveal associations between functional polymorphisms of chemokine family members and tumor progression.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', (137, 142))	('associations', 'Interaction', (38, 50))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('polymorphisms', 'Var', (59, 72))	('tumor', 'Disease', (310, 315))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
273639	31354296	In the present study, we used the improved multiple ligase detection reaction (iMLDR) genotyping to detect potentially functional SNPs of chemokine family members and to determine their associations with the prognosis of Chinese patients with EC.	('patients', 'Species', '9606', (229, 237))	('associations', 'Interaction', (186, 198))	('SNPs', 'Var', (130, 134))
273650	31354296	The associations between CCL26 rs2302009 genotypes and EC survival were evaluated by stratified analysis of age, gender, histological types, anatomical site, pathologic grade, pathologic type, TNM stage, and longest diameter of tumor.	('CCL26', 'Gene', '10344', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('rs2302009', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('rs2302009', 'Mutation', 'rs2302009', (31, 40))	('TNM', 'Gene', '10178', (193, 196))	('CCL26', 'Gene', (25, 30))	('tumor', 'Disease', (228, 233))	('associations', 'Interaction', (4, 16))	('TNM', 'Gene', (193, 196))
273658	31354296	Multivariate Cox regression analysis on the prognostic values of the 5 SNPs showed that CCL26rs2302009 and CX3CL1rs2239352 were associated with the prognosis of EC patients (Table 3).	('CX3CL1', 'Gene', (107, 113))	('Cox', 'Gene', (13, 16))	('CX3CL1', 'Gene', '6376', (107, 113))	('associated', 'Reg', (128, 138))	('CCL26rs2302009', 'Var', (88, 102))	('patients', 'Species', '9606', (164, 172))	('CCL26rs2302009', 'Chemical', '-', (88, 102))	('Cox', 'Gene', '1351', (13, 16))
273659	31354296	After adjustment of age, gender, histological type, tumor location, histological grade, pathologic type, TNM stage, and the longest diameter of tumor, the heterozygous mutation genotype A/C of CCL26rs2302009 and the homozygous mutation genotype T/T of CX3CL1rs2239352 were associated with increased risk of death.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TNM', 'Gene', (105, 108))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('death', 'Disease', 'MESH:D003643', (307, 312))	('T/T', 'Var', (245, 248))	('A/C', 'Var', (186, 189))	('CCL26rs2302009', 'Chemical', '-', (193, 207))	('TNM', 'Gene', '10178', (105, 108))	('CX3CL1', 'Gene', '6376', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CX3CL1', 'Gene', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('death', 'Disease', (307, 312))	('associated', 'Reg', (273, 283))
273661	31354296	To identify independent prognostic factors, age, gender, histological type, tumor location, histological grade, pathologic type, TNM stage, the longest diameter of tumor, CCL26rs2302009 genotypes, and CX3CL1rs2239352 genotypes were included in stepwise Cox regression analysis.	('Cox', 'Gene', (253, 256))	('tumor', 'Disease', (164, 169))	('CX3CL1', 'Gene', '6376', (201, 207))	('tumor', 'Disease', (76, 81))	('TNM', 'Gene', (129, 132))	('CCL26rs2302009', 'Chemical', '-', (171, 185))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CX3CL1', 'Gene', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('TNM', 'Gene', '10178', (129, 132))	('Cox', 'Gene', '1351', (253, 256))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('CCL26rs2302009', 'Var', (171, 185))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
273663	31354296	Stratified analysis showed that the association between CCL26rs2302009 genotype A/C and the increased risk of death was stronger in patients who were <=60 years old, female, with tumors located in the middle part of esophagus, with undifferentiated or poorly differentiated tumors, with early-stage pathologic type disease, with the longest diameter of tumor <=5cm than in their counterparts (Table 5).	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Disease', (274, 279))	('patients', 'Species', '9606', (132, 140))	('tumor', 'Disease', (353, 358))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('death', 'Disease', (110, 115))	('association', 'Interaction', (36, 47))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('CCL26rs2302009', 'Var', (56, 70))	('CCL26rs2302009', 'Chemical', '-', (56, 70))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('tumors', 'Disease', (274, 280))	('tumors', 'Disease', (179, 185))	('death', 'Disease', 'MESH:D003643', (110, 115))	('tumor', 'Disease', (179, 184))
273665	31354296	In the present study, we analyzed the associations between potentially functional SNPs of genes from the chemokine family and prognosis of EC patients after surgery.	('patients', 'Species', '9606', (142, 150))	('SNPs', 'Var', (82, 86))	('associations', 'Interaction', (38, 50))
273666	31354296	Multivariate Cox regression analysis showed that CCL26rs2302009 and CX3CL1rs2239352 genotypes were associated with the prognosis.	('CX3CL1', 'Gene', (68, 74))	('Cox', 'Gene', (13, 16))	('CCL26rs2302009', 'Var', (49, 63))	('CCL26rs2302009', 'Chemical', '-', (49, 63))	('CX3CL1', 'Gene', '6376', (68, 74))	('associated', 'Reg', (99, 109))	('Cox', 'Gene', '1351', (13, 16))
273667	31354296	Stepwise Cox regression analysis showed that histological grade, pathologic type, the longest diameter of tumor, and CCL26rs2302009 genotype A/C were the independent prognostic factors.	('CCL26rs2302009', 'Var', (117, 131))	('CCL26rs2302009', 'Chemical', '-', (117, 131))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (106, 111))	('Cox', 'Gene', '1351', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('Cox', 'Gene', (9, 12))
273668	31354296	These findings suggest that, in addition to pathologic stage, pathologic type, and the longest diameter of tumor, CCL26 rs2302009 may be a candidate biomarker for the prediction of the survival of EC patients and may affect the risk of death.	('rs2302009', 'Mutation', 'rs2302009', (120, 129))	('patients', 'Species', '9606', (200, 208))	('tumor', 'Disease', (107, 112))	('death', 'Disease', (236, 241))	('death', 'Disease', 'MESH:D003643', (236, 241))	('CCL26', 'Gene', '10344', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('affect', 'Reg', (217, 223))	('CCL26', 'Gene', (114, 119))	('rs2302009', 'Var', (120, 129))
273679	31354296	Blanchard et al reported that external stimulation or damage may induce the activation of CCL26.	('damage', 'Var', (54, 60))	('CCL26', 'Gene', '10344', (90, 95))	('CCL26', 'Gene', (90, 95))	('activation', 'MPA', (76, 86))
273682	31354296	This may explain, in part, the role of CCL26rs2302009 mutation in facilitating tumor metastasis and causing poor prognosis.	('tumor metastasis', 'Disease', 'MESH:D009362', (79, 95))	('tumor metastasis', 'Disease', (79, 95))	('CCL26rs2302009', 'Var', (39, 53))	('CCL26rs2302009', 'Chemical', '-', (39, 53))	('poor prognosis', 'MPA', (108, 122))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('facilitating', 'PosReg', (66, 78))
273686	31354296	In the present study, we found that CCL26 mutations were associated with poor prognosis of EC patients after surgery.	('patients', 'Species', '9606', (94, 102))	('CCL26', 'Gene', (36, 41))	('CCL26', 'Gene', '10344', (36, 41))	('mutations', 'Var', (42, 51))	('associated', 'Reg', (57, 67))
273737	30834211	Weight loss of over 4.5 kg was more common in patients who received nCRT (53% in the >35d cohort and 68% in the <=35d cohort) than in those in the no nCRT group (33%, p<0.001).	('patients', 'Species', '9606', (46, 54))	('Weight loss', 'Phenotype', 'HP:0001824', (0, 11))	('Weight loss', 'Disease', (0, 11))	('Weight loss', 'Disease', 'MESH:D015431', (0, 11))	('nCRT', 'Var', (68, 72))
273741	30834211	Anastomotic leaks were observed in 10.3% of patients (24 of 232) who received nCRT, but in 14.7% (17 of 116) of no nCRT group (p=0.247).	('Anastomotic leaks', 'Disease', 'MESH:D057868', (0, 17))	('patients', 'Species', '9606', (44, 52))	('nCRT', 'Var', (78, 82))	('Anastomotic leaks', 'Disease', (0, 17))
273758	30834211	However, differences in the occurrence of anastomotic leaks due to nCRT did not affect overall survival; no difference in the survival rate was observed between patients who received nCRT and those who did not (Fig.	('anastomotic leaks', 'Disease', 'MESH:D057868', (42, 59))	('patients', 'Species', '9606', (161, 169))	('anastomotic leaks', 'Disease', (42, 59))	('nCRT', 'Var', (183, 187))
273820	30347938	We considered subjects showing moderate-to-severe state or trait anxiety by using a cut-off value of STAI-X1 >=57 or STAI-X2 >=59, respectively.	('anxiety', 'Disease', (65, 72))	('STAI-X1', 'Gene', (101, 108))	('anxiety', 'Phenotype', 'HP:0000739', (65, 72))	('STAI-X2', 'Var', (117, 124))	('anxiety', 'Disease', 'MESH:D001008', (65, 72))
273828	30347938	The percentage of women was lower in the ERD and AEE groups than in the control group (14.2% and 11.5% vs 37.3%, P < 0.001, respectively), but higher in the NERD group than in the control group (42.4% vs 37.3%, P < 0.001).	('lower', 'NegReg', (28, 33))	('women', 'Species', '9606', (18, 23))	('higher', 'PosReg', (143, 149))	('ERD', 'Var', (41, 44))	('AEE', 'Chemical', '-', (49, 52))
273829	30347938	BMI was significantly higher in the ERD and AEE groups than in the control group (25.5 +- 3.2 and 25.1 +- 3.0 vs 23.6 +- 3.0, P < 0.001, respectively).	('higher', 'PosReg', (22, 28))	('AEE', 'Var', (44, 47))	('AEE', 'Chemical', '-', (44, 47))	('ERD', 'Var', (36, 39))	('BMI', 'MPA', (0, 3))
273831	30347938	The percentage of current smokers and alcohol user was significantly higher in the ERD group and the NERD group than in the control group (P < 0.001, all).	('higher', 'PosReg', (69, 75))	('alcohol', 'Chemical', 'MESH:D000438', (38, 45))	('alcohol user', 'Phenotype', 'HP:0030955', (38, 50))	('ERD', 'Var', (83, 86))
273846	30347938	After adjusting for various clinical factors, subjects in the ERD group showed higher state anxiety and depression levels than those in the control group.	('anxiety and depression', 'Disease', 'MESH:D001008', (92, 114))	('depression', 'Phenotype', 'HP:0000716', (104, 114))	('higher', 'PosReg', (79, 85))	('anxiety', 'Phenotype', 'HP:0000739', (92, 99))	('ERD', 'Var', (62, 65))
273849	30347938	Thus, anxiety and depression levels were significantly higher in subjects with GERD, most notably in the NERD group.	('anxiety', 'Phenotype', 'HP:0000739', (6, 13))	('depression', 'Phenotype', 'HP:0000716', (18, 28))	('anxiety and depression', 'Disease', 'MESH:D001008', (6, 28))	('GERD', 'Var', (79, 83))	('higher', 'PosReg', (55, 61))
273883	28852266	This study was designed to elucidate whether autoantibodies against STIP1 could be a diagnostic biomarker in ESCC.	('STIP1', 'Gene', '10963', (68, 73))	('autoantibodies', 'Var', (45, 59))	('ESCC', 'Disease', (109, 113))	('STIP1', 'Gene', (68, 73))
273887	28852266	Moreover, detection of autoantibodies against STIP1 could discriminate early-stage ESCC patients from controls, with sensitivity, specificity, and AUC of 35.7%, 90.1%, and 0.684 in the training cohort and 38.5%, 92.5%, and 0.756 in the validation cohort, respectively.	('early-stage ESCC', 'Disease', (71, 87))	('discriminate', 'Reg', (58, 70))	('patients', 'Species', '9606', (88, 96))	('autoantibodies', 'Var', (23, 37))	('STIP1', 'Gene', (46, 51))	('STIP1', 'Gene', '10963', (46, 51))
273888	28852266	Our findings indicated that autoantibodies against STIP1 might be a useful biomarker for early-stage ESCC detection.	('ESCC', 'Disease', (101, 105))	('STIP1', 'Gene', (51, 56))	('STIP1', 'Gene', '10963', (51, 56))	('autoantibodies', 'Var', (28, 42))
273933	28852266	For all ESCC patients in the training cohort, autoantibodies against STIP1 had an AUC of 0.682 (95% CI: 0.619-0.746) to distinguish individuals with ESCC from normal controls with a sensitivity/specificity of 41.9% (95% CI: 33.9%-50.3%)/90.1% (95% CI: 82.6%-94.7%) (Figure 2, Table 3).	('ESCC', 'Disease', (149, 153))	('ESCC', 'Disease', (8, 12))	('patients', 'Species', '9606', (13, 21))	('STIP1', 'Gene', (69, 74))	('autoantibodies', 'Var', (46, 60))	('STIP1', 'Gene', '10963', (69, 74))
273934	28852266	Autoantibodies against STIP1 also identified early-stage ESCC with a similar AUC value of 0.684 (95% CI: 0.586-0.782), a sensitivity of 35.7% (95% CI: 22.0-52.0%), and a specificity of 90.1% (95% CI: 82.6%-94.7%).	('STIP1', 'Gene', (23, 28))	('STIP1', 'Gene', '10963', (23, 28))	('ESCC', 'Disease', (57, 61))	('early-stage ESCC', 'Disease', (45, 61))	('Autoantibodies', 'Var', (0, 14))
273935	28852266	To improve clinical interpretation, we also presented false positive rate, false negative rate, predictive values, and likelihood ratios for autoantibodies against STIP1 in ESCC diagnosis in Table 3.	('autoantibodies', 'Var', (141, 155))	('STIP1', 'Gene', (164, 169))	('STIP1', 'Gene', '10963', (164, 169))	('ESCC', 'Disease', (173, 177))
273942	28852266	In addition, autoantibodies against STIP1 could detect early-stage ESCC (AJCC 0 + I + IIA).	('detect', 'Reg', (48, 54))	('STIP1', 'Gene', (36, 41))	('STIP1', 'Gene', '10963', (36, 41))	('early-stage ESCC', 'Disease', (55, 71))	('autoantibodies', 'Var', (13, 27))
273943	28852266	Our findings indicated autoantibodies against STIP1 as a potential noninvasive biomarker for early ESCC detection.	('STIP1', 'Gene', (46, 51))	('autoantibodies', 'Var', (23, 37))	('STIP1', 'Gene', '10963', (46, 51))	('ESCC', 'Disease', (99, 103))
273944	28852266	In recent years, there is no doubt that autoantibodies against TAAs have been a hot topic of research in early cancer diagnosis.	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('autoantibodies', 'Var', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))
273948	28852266	also reported that autoantibodies against a panel of four TAAs (i.e., c-Myc, HCCR, p53, and p62) provided a high diagnostic efficiency for early-stage ESCC detection.	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('autoantibodies', 'Var', (19, 33))	('c-Myc', 'Gene', (70, 75))	('ESCC', 'Disease', (151, 155))	('p62', 'Gene', '23636', (92, 95))	('HCCR', 'Protein', (77, 81))	('p62', 'Gene', (92, 95))	('c-Myc', 'Gene', '4609', (70, 75))
273950	28852266	This study shows that autoantibodies against STIP1 have sensitivities of 35.7% (95% CI: 22.0-52.0%) in the training cohort and 38.5% (95% CI: 15.1%-67.7%) in the validation cohort to diagnose early-stage ESCC.	('autoantibodies', 'Var', (22, 36))	('early-stage ESCC', 'Disease', (192, 208))	('STIP1', 'Gene', '10963', (45, 50))	('STIP1', 'Gene', (45, 50))
273951	28852266	Such sensitivity is better than the recently identified autoantibody biomarkers in early-stage ESCC reported by our team, including autoantibodies against ezrin, fascin, and L1CAM, which indicates that autoantibodies against STIP1 might be an encouraging candidate for establishment of an optimized autoantibody signature required to gain high sensitivity necessary for ESCC screening.	('L1CAM', 'Gene', '3897', (174, 179))	('autoantibodies', 'Var', (202, 216))	('STIP1', 'Gene', '10963', (225, 230))	('fascin', 'Gene', (162, 168))	('ESCC', 'Disease', (95, 99))	('L1CAM', 'Gene', (174, 179))	('ezrin', 'Gene', '7430', (155, 160))	('ezrin', 'Gene', (155, 160))	('fascin', 'Gene', '6624', (162, 168))	('STIP1', 'Gene', (225, 230))
273960	28852266	Our data demonstrated that autoantibodies against STIP1 might be a potential biomarker significantly associated with ESCC.	('autoantibodies', 'Var', (27, 41))	('STIP1', 'Gene', (50, 55))	('STIP1', 'Gene', '10963', (50, 55))	('associated', 'Reg', (101, 111))	('ESCC', 'Disease', (117, 121))
273999	27785316	Iatrogenic lesion or pathological lesion of these nerves can result in muscular function loss, hoarseness and dysphonia.	('hoarseness', 'Phenotype', 'HP:0001609', (95, 105))	('result', 'Reg', (61, 67))	('Iatrogenic lesion', 'Disease', 'MESH:D007049', (0, 17))	('dysphonia', 'Disease', 'MESH:D055154', (110, 119))	('dysphonia', 'Phenotype', 'HP:0001618', (110, 119))	('dysphonia', 'Disease', (110, 119))	('Iatrogenic lesion', 'Disease', (0, 17))	('hoarseness', 'Disease', (95, 105))	('pathological lesion', 'Var', (21, 40))	('muscular function', 'CPA', (71, 88))	('loss', 'NegReg', (89, 93))
274427	24672362	The most significant sequelae of chronic erosive vulvar LP are scarring, which can result in resorption of the labia minora (agglutination) and clitoral hood, with subsequent clitoral burying (synechiae, 68%), stenosis of the introitus (59%), and potentially total obliteration of the vagina.	('clitoral burying', 'CPA', (175, 191))	('stenosis of the introitus', 'Disease', 'MESH:D003251', (210, 235))	('scarring', 'Disease', (63, 71))	('labia minora', 'Disease', 'MESH:C537290', (111, 123))	('erosive', 'Var', (41, 48))	('scarring', 'Phenotype', 'HP:0100699', (63, 71))	('stenosis of the introitus', 'Disease', (210, 235))	('resorption', 'CPA', (93, 103))	('result in', 'Reg', (83, 92))	('labia minora', 'Disease', (111, 123))
274431	24672362	In addition to dyspareunia, vulvar LP can lead to symptoms of intense pruritus with chronic vaginal discharge, burning, and postcoital bleeding.	('burning', 'Disease', (111, 118))	('dyspareunia', 'Disease', (15, 26))	('postcoital bleeding', 'Disease', (124, 143))	('postcoital bleeding', 'Disease', 'MESH:D006470', (124, 143))	('vulvar', 'Var', (28, 34))	('dyspareunia', 'Phenotype', 'HP:0030016', (15, 26))	('pruritus', 'Phenotype', 'HP:0000989', (70, 78))	('dyspareunia', 'Disease', 'MESH:D004414', (15, 26))	('pruritus', 'Disease', (70, 78))	('lead to', 'Reg', (42, 49))	('pruritus', 'Disease', 'MESH:D011537', (70, 78))
274517	24672362	TLR2 activation is known to induce TH1 activation.	('activation', 'Var', (5, 15))	('TLR2', 'Gene', (0, 4))	('TH1 activation', 'MPA', (35, 49))	('TLR2', 'Gene', '7097', (0, 4))
274525	24672362	Gene polymorphisms of different HLA markers as well as the inflammatory cytokines and chemokines have been associated with the presence of LP (Table 6).	('associated', 'Reg', (107, 117))	('polymorphisms', 'Var', (5, 18))	('HLA', 'Gene', (32, 35))	('HLA', 'Gene', '3119', (32, 35))
274537	24672362	This group hypothesized that genogroup 1 TTV is correlated with the immuno-inflammatory response in OLP patients.	('correlated', 'Reg', (48, 58))	('genogroup', 'Var', (29, 38))	('OLP', 'Disease', (100, 103))	('patients', 'Species', '9606', (104, 112))
274560	24672362	suggested the co-expression of podoplanin and ATP-binding cassette transporter G2 (ABCG2) as a higher prognostic marker with a significant odds ratio (25.24, 95% CI: 4.48-142.27, P < 0.001).	('ABCG2', 'Gene', (83, 88))	('ABCG2', 'Gene', '9429', (83, 88))	('co-expression', 'Var', (14, 27))	('podoplanin', 'Gene', '10630', (31, 41))	('ATP-binding cassette transporter G2', 'Gene', (46, 81))	('ATP-binding cassette transporter G2', 'Gene', '9429', (46, 81))	('podoplanin', 'Gene', (31, 41))
274627	24348287	Complications in the form of chest infection and post-operative nausea and vomiting were significantly lower in the Doppler fluid guided group; this was accompanied with a significant reduction in the hospital stay.	('nausea', 'Disease', (64, 70))	('reduction', 'NegReg', (184, 193))	('nausea', 'Disease', 'MESH:D009325', (64, 70))	('vomiting', 'Phenotype', 'HP:0002013', (75, 83))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (64, 83))	('hospital stay', 'MPA', (201, 214))	('vomiting', 'Disease', (75, 83))	('vomiting', 'Disease', 'MESH:D014839', (75, 83))	('Doppler fluid guided', 'Var', (116, 136))	('lower', 'NegReg', (103, 108))	('chest infection', 'Disease', (29, 44))	('chest infection', 'Disease', 'MESH:D002637', (29, 44))	('nausea', 'Phenotype', 'HP:0002018', (64, 70))
274709	23614130	The possible mechanism underlying how locally recurrent SMT-like cancer occurred after incomplete ESD was suggested as follows: after incomplete ESD, the remnant cancer might have been buried under the normal surrounding squamous EP during the healing process.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('incomplete', 'Var', (134, 144))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
274719	21369488	Although there were only limited studies, the prevalence of extra-esophageal syndromes in Asia was higher in GERD group than in controls.	('higher', 'PosReg', (99, 105))	('extra-esophageal syndrome', 'Disease', (60, 85))	('extra-esophageal syndrome', 'Disease', 'MESH:D004941', (60, 85))	('GERD group', 'Var', (109, 119))	('Asia', 'Disease', (90, 94))
274762	21369488	The proportion of sleep dysfunction was 52.5%-56.6% among the patients with GERD, and GERD increased the OR of sleep disturbance to about twice than controls.	('GERD', 'Var', (86, 90))	('sleep dysfunction', 'Disease', 'MESH:D012893', (18, 35))	('sleep disturbance', 'Phenotype', 'HP:0002360', (111, 128))	('sleep dysfunction', 'Phenotype', 'HP:0002360', (18, 35))	('increased', 'PosReg', (91, 100))	('GERD', 'Disease', (76, 80))	('sleep dysfunction', 'Disease', (18, 35))	('sleep disturbance', 'Disease', (111, 128))	('patients', 'Species', '9606', (62, 70))	('sleep disturbance', 'Disease', 'MESH:D012893', (111, 128))
274776	30921184	Effect of ALDH2 polymorphism on cancer risk in Asians Numerous studies have investigated the association between ALDH2 gene rs671G>A polymorphism and various cancer type in Asians.	('rs671G>A', 'Var', (124, 132))	('ALDH2', 'Gene', '217', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('rs671G>A', 'DBSNP_MENTION', 'None', (124, 132))	('cancer', 'Disease', (32, 38))	('ALDH2', 'Gene', '217', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('ALDH2', 'Gene', (113, 118))	('cancer', 'Disease', (158, 164))	('ALDH2', 'Gene', (10, 15))	('association', 'Interaction', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
274777	30921184	Pooled results indicated that ALDH2 gene rs671 polymorphism was significantly associated with the overall cancer risk in Asians (homozygous model: odds ratio [OR] = 0.85, 95% confidence interval [CI] = 0.72-0.99, P = .042; heterozygous model: OR = 1.32, 95% CI = 1.14-1.52, P  < .001; recessive model: OR = 0.73, 95% CI = 0.60-0.88, P = .001; dominant model: OR = 1.32, 95% CI = 1.16-1.51, P < .001; and allele comparison model: OR = 1.11, 95% CI = 1.03-1.19, P = .004), especially in esophageal cancer and among the Chinese and the Japanese.	('associated', 'Reg', (78, 88))	('cancer', 'Disease', (496, 502))	('cancer', 'Disease', 'MESH:D009369', (496, 502))	('esophageal cancer', 'Disease', (485, 502))	('ALDH2', 'Gene', (30, 35))	('rs671 polymorphism', 'Var', (41, 59))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (485, 502))	('cancer', 'Disease', (106, 112))	('rs671', 'Mutation', 'rs671', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (496, 502))	('polymorphism', 'Var', (47, 59))	('ALDH2', 'Gene', '217', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
274778	30921184	Our results suggest that ALDH2 rs671 polymorphism is associated with the overall cancer risk in Asians.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ALDH2', 'Gene', '217', (25, 30))	('cancer', 'Disease', (81, 87))	('rs671 polymorphism', 'Var', (31, 49))	('associated', 'Reg', (53, 63))	('rs671', 'Mutation', 'rs671', (31, 36))	('ALDH2', 'Gene', (25, 30))
274791	30921184	The ALDH2 gene, located at chromosome 12q24, is composed of 13 exons with 46,031 base pairs, and its polymorphisms affect the blood acetaldehyde concentrations after alcohol consumption.	('ALDH2', 'Gene', '217', (4, 9))	('affect', 'Reg', (115, 121))	('blood acetaldehyde concentrations', 'MPA', (126, 159))	('blood acetaldehyde', 'Phenotype', 'HP:0003533', (126, 144))	('ALDH2', 'Gene', (4, 9))	('blood acetaldehyde concentrations', 'Phenotype', 'HP:0003533', (126, 159))	('acetaldehyde', 'Chemical', 'MESH:D000079', (132, 144))	('polymorphisms', 'Var', (101, 114))	('alcohol', 'Chemical', 'MESH:D000438', (166, 173))
274792	30921184	Rs671G>A, the most commonly studied polymorphism, is reported to an amino acid substitution from glutamine to lysine (Glu487Lys).	('glutamine', 'Chemical', 'MESH:D005973', (97, 106))	('Glu487Lys', 'Var', (118, 127))	('lysine', 'Chemical', 'MESH:D008239', (110, 116))	('Glu487Lys', 'SUBSTITUTION', 'None', (118, 127))	('Rs671G>A', 'Var', (0, 8))
274793	30921184	The 487Lys allele encodes a catalytically inactive subunit and finally affects the status of the ALDH2 enzyme, with only 6.25% of normal 487Glu activity.	('affects', 'Reg', (71, 78))	('The 487Lys', 'Mutation', 'p.THE487K', (0, 10))	('487Lys', 'Var', (4, 10))	('catalytically', 'MPA', (28, 41))	('status', 'MPA', (83, 89))	('ALDH2', 'Gene', '217', (97, 102))	('ALDH2', 'Gene', (97, 102))
274794	30921184	Such a polymorphism inactivates ALDH2 and leads a high concentration of blood acetaldehyde after drinking alcohol, which could contribute to susceptibility to carcinogenesis.	('carcinogenesis', 'Disease', (159, 173))	('ALDH2', 'Gene', (32, 37))	('polymorphism', 'Var', (7, 19))	('acetaldehyde', 'Chemical', 'MESH:D000079', (78, 90))	('high concentration of blood acetaldehyde', 'MPA', (50, 90))	('leads', 'Reg', (42, 47))	('alcohol', 'Chemical', 'MESH:D000438', (106, 113))	('contribute', 'Reg', (127, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))	('inactivates', 'NegReg', (20, 31))	('ALDH2', 'Gene', '217', (32, 37))	('blood acetaldehyde', 'Phenotype', 'HP:0003533', (72, 90))
274795	30921184	Increasing evidence suggests that the rs671 polymorphism may be associated with many types of cancer, such as head and neck cancer, esophageal cancer, liver cancer, breast cancer, colorectal cancer and gastric cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('esophageal cancer', 'Disease', (132, 149))	('colorectal cancer', 'Phenotype', 'HP:0003003', (180, 197))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('head and neck cancer', 'Disease', 'MESH:D006258', (110, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('associated', 'Reg', (64, 74))	('cancer', 'Disease', (191, 197))	('rs671', 'Var', (38, 43))	('breast cancer', 'Disease', (165, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (202, 216))	('rs671', 'Mutation', 'rs671', (38, 43))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('liver cancer', 'Disease', 'MESH:D006528', (151, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (157, 163))	('colorectal cancer', 'Disease', (180, 197))	('cancer', 'Disease', (172, 178))	('gastric cancer', 'Disease', (202, 216))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('liver cancer', 'Phenotype', 'HP:0002896', (151, 163))	('head and neck cancer', 'Phenotype', 'HP:0012288', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('liver cancer', 'Disease', (151, 163))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', (210, 216))	('gastric cancer', 'Disease', 'MESH:D013274', (202, 216))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
274796	30921184	Hence, we conducted a comprehensive meta-analysis to assess the association of ALDH2 rs671 polymorphism and the overall cancer risk in Asians.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs671', 'Mutation', 'rs671', (85, 90))	('ALDH2', 'Gene', '217', (79, 84))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('polymorphism', 'Var', (91, 103))	('ALDH2', 'Gene', (79, 84))	('rs671 polymorphism', 'Var', (85, 103))	('association', 'Interaction', (64, 75))
274797	30921184	The following search terms were used: "alcohol dehydrogenase 2 or ALDH2" or "polymorphism or variant or variation" or "cancer or tumor or neoplasm or carcinoma."	('"cancer', 'Disease', (118, 125))	('neoplasm or carcinoma', 'Disease', 'MESH:D009369', (138, 159))	('alcohol dehydrogenase', 'Gene', '10327', (39, 60))	('tumor', 'Disease', (129, 134))	('neoplasm or carcinoma', 'Disease', (138, 159))	('"cancer', 'Disease', 'MESH:D009369', (118, 125))	('ALDH2', 'Gene', '217', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('polymorphism', 'Var', (77, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('variation', 'Var', (104, 113))	('ALDH2', 'Gene', (66, 71))	('variant or variation', 'Var', (93, 113))	('alcohol dehydrogenase', 'Gene', (39, 60))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
274799	30921184	The studies included in our meta-analysis must meet the following criteria: evaluating the association between the ALDH2 rs671 polymorphism and cancer risk in Asians; case-control design; written in English and Chinese; and sufficient information for estimation of odds ratios (ORs) and their 95% confidence intervals (CIs).	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('rs671', 'Var', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('ALDH2', 'Gene', '217', (115, 120))	('cancer', 'Disease', (144, 150))	('rs671', 'Mutation', 'rs671', (121, 126))	('ALDH2', 'Gene', (115, 120))	('association', 'Interaction', (91, 102))
274801	30921184	Crude ORs and their corresponding 95% CIs were applied to assess the strength of association between the ALDH2 rs671 polymorphism and the overall cancer risk in Asians under the five genetic models: homozygous model (AA vs GG), heterozygous model (GA vs GG), recessive model (AA vs GA + GG), dominant model (GA + AA vs GG), and allele comparison model (A vs G).	('association', 'Interaction', (81, 92))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('polymorphism', 'Var', (117, 129))	('ALDH2', 'Gene', (105, 110))	('rs671', 'Gene', (111, 116))	('rs671', 'Mutation', 'rs671', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ALDH2', 'Gene', '217', (105, 110))
274803	30921184	After title and abstract screening, 286 articles were excluded for not dealing with the association between the ALDH2 rs671 polymorphism and any cancer risk in Asians.	('cancer', 'Disease', (145, 151))	('polymorphism', 'Var', (124, 136))	('ALDH2', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('rs671 polymorphism', 'Var', (118, 136))	('ALDH2', 'Gene', '217', (112, 117))	('association', 'Interaction', (88, 99))	('rs671', 'Mutation', 'rs671', (118, 123))
274805	30921184	A significant association between ALDH2 rs671 polymorphism and overall cancer risk in Asians was observed under all the 5 genetic models (Table 2): homozygous model (AA vs GG): OR = 0.85, 95% CI = 0.72 to 0.99, P = .042; heterozygous model (GA vs GG): OR = 1.32, 95% CI = 1.14 to 1.52, P < .001; recessive model (AA vs GA + GG): OR = 0.73, 95% CI = 0.60 to 0.88, P = .001 (Fig.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('rs671', 'Mutation', 'rs671', (40, 45))	('ALDH2', 'Gene', '217', (34, 39))	('cancer', 'Disease', (71, 77))	('polymorphism', 'Var', (46, 58))	('ALDH2', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs671 polymorphism', 'Var', (40, 58))
274806	30921184	However, ALDH2 rs671 polymorphism was associated with the increased cancer risk in Chinese: heterozygous model (GA vs GG): OR = 1.21, 95% CI = 1.02 to 1.44, P = .029; dominant model (GA + AA vs GG): OR = 1.35, 95% CI = 1.11 to 1.64, P = .003; and allele comparison model (A vs G): OR = 1.12, 95% CI = 1.01 to 1.25, P = .030; and with the decreased cancer risk in Korean: homozygous model (AA vs GG): OR = 0.57, 95% CI = 0.35 to 0.91, P = .018; recessive model (AA vs GA + GG): OR = 0.55, 95% CI = 0.34 to 0.88, P = .013.	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('ALDH2', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('ALDH2', 'Gene', '217', (9, 14))	('rs671', 'Mutation', 'rs671', (15, 20))	('cancer', 'Disease', (68, 74))	('polymorphism', 'Var', (21, 33))	('rs671 polymorphism', 'Var', (15, 33))	('cancer', 'Disease', (348, 354))
274808	30921184	Heterogeneities were detected among all the studies investigating the association between ALDH2 rs671 polymorphism and the overall cancer risk in Asians (homozygous model, P < .001; heterozygous model, P < .001; recessive model, P < .001; dominant model, P < .001; and allele comparison model, P < 0.001).	('polymorphism', 'Var', (102, 114))	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('ALDH2', 'Gene', '217', (90, 95))	('rs671 polymorphism', 'Var', (96, 114))	('rs671', 'Mutation', 'rs671', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('ALDH2', 'Gene', (90, 95))
274813	30921184	However, acetaldehyde could interfere DNA synthesis and repair and consequently results in more than 200 diseases, including alcohol-related cancer.	('results in', 'Reg', (80, 90))	('acetaldehyde', 'Var', (9, 21))	('diseases', 'Disease', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('repair', 'CPA', (56, 62))	('interfere', 'NegReg', (28, 37))	('DNA synthesis', 'MPA', (38, 51))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('acetaldehyde', 'Chemical', 'MESH:D000079', (9, 21))	('cancer', 'Disease', (141, 147))	('alcohol', 'Chemical', 'MESH:D000438', (125, 132))
274814	30921184	Many studies have investigated the role of ALDH2 gene polymorphisms and their relationship with acetaldehyde elimination.	('polymorphisms', 'Var', (54, 67))	('acetaldehyde elimination', 'MPA', (96, 120))	('ALDH2', 'Gene', (43, 48))	('acetaldehyde', 'Chemical', 'MESH:D000079', (96, 108))	('ALDH2', 'Gene', '217', (43, 48))
274815	30921184	Among them, ALDH2 rs671G>A polymorphism was found dramatically reducing the activity of ALDH2 enzyme and maintaining the high blood acetaldehyde concentrations after alcohol consumption.	('ALDH2', 'Gene', (12, 17))	('rs671G>A', 'Var', (18, 26))	('ALDH2', 'Gene', (88, 93))	('activity', 'MPA', (76, 84))	('maintaining', 'Reg', (105, 116))	('rs671G>A', 'DBSNP_MENTION', 'None', (18, 26))	('high blood acetaldehyde', 'Phenotype', 'HP:0003533', (121, 144))	('reducing', 'NegReg', (63, 71))	('blood acetaldehyde', 'Phenotype', 'HP:0003533', (126, 144))	('alcohol', 'Chemical', 'MESH:D000438', (166, 173))	('blood acetaldehyde concentrations', 'Phenotype', 'HP:0003533', (126, 159))	('high blood acetaldehyde concentrations', 'MPA', (121, 159))	('acetaldehyde', 'Chemical', 'MESH:D000079', (132, 144))	('ALDH2', 'Gene', '217', (12, 17))	('ALDH2', 'Gene', '217', (88, 93))
274818	30921184	To the best of our knowledge, this is the 1st meta-analysis to investigate the association between ALDH2 rs671 polymorphism and the overall cancer risk in Asians.	('rs671 polymorphism', 'Var', (105, 123))	('rs671', 'Mutation', 'rs671', (105, 110))	('ALDH2', 'Gene', '217', (99, 104))	('polymorphism', 'Var', (111, 123))	('cancer', 'Disease', (140, 146))	('ALDH2', 'Gene', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
274819	30921184	A significant association between ALDH2 rs671 polymorphism and the overall cancer risk in Asians was observed.	('rs671', 'Mutation', 'rs671', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('ALDH2', 'Gene', '217', (34, 39))	('Asians', 'Disease', (90, 96))	('cancer', 'Disease', (75, 81))	('polymorphism', 'Var', (46, 58))	('ALDH2', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs671 polymorphism', 'Var', (40, 58))
274822	30921184	In a latest meta-analysis, Cai et al explored whether the polymorphism was associated with the overall cancer risk in all the ethnicity, and retrieved only 51 studies (49 studies in Asians) with a total of 16,774 cases and 32,060 controls before 2014.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('polymorphism', 'Var', (58, 70))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (103, 109))	('associated', 'Reg', (75, 85))
274823	30921184	In turn, in our meta-analysis, at least 15 studies were published evaluating the association between ALDH2 rs671 polymorphism and cancer risk in Asians.	('association', 'Interaction', (81, 92))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('ALDH2', 'Gene', '217', (101, 106))	('rs671 polymorphism', 'Var', (107, 125))	('rs671', 'Mutation', 'rs671', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('polymorphism', 'Var', (113, 125))	('ALDH2', 'Gene', (101, 106))
274824	30921184	Moreover, Cai et al evaluated the association only under 2 genetic models, the dominant model (GA + AA vs GG) and the allele comparison model (A vs G), and ALDH2 rs671 polymorphism was observed to be associated with the increased overall cancer risk under the dominant model instead of the allele comparison model.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('polymorphism', 'Var', (168, 180))	('ALDH2', 'Gene', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('rs671 polymorphism', 'Var', (162, 180))	('associated', 'Reg', (200, 210))	('rs671', 'Mutation', 'rs671', (162, 167))	('ALDH2', 'Gene', '217', (156, 161))
274825	30921184	In the stratification analyses by country, Cai et al also found that ALDH2 rs671 polymorphism was associated with the increased cancer risk in Japanese under the dominant model rather than the allele comparison model.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('associated with', 'Reg', (98, 113))	('rs671 polymorphism', 'Var', (75, 93))	('rs671', 'Mutation', 'rs671', (75, 80))	('ALDH2', 'Gene', '217', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ALDH2', 'Gene', (69, 74))	('polymorphism', 'Var', (81, 93))	('cancer', 'Disease', (128, 134))
274826	30921184	In our meta-analysis, ALDH2 rs671 polymorphism was associated with the increased overall cancer risk in Asians, especially in Japanese and Chinese, not only under the dominant model but also the allele comparison model.	('ALDH2', 'Gene', (22, 27))	('rs671', 'Var', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('rs671', 'Mutation', 'rs671', (28, 33))	('cancer', 'Disease', (89, 95))	('ALDH2', 'Gene', '217', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
274827	30921184	In our meta-analysis, we found that ALDH2 rs671 polymorphism was associated with an increased overall cancer risk in Asians, especially with esophageal cancer and among the Chinese and the Japanese.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs671', 'Var', (42, 47))	('esophageal cancer', 'Disease', (141, 158))	('ALDH2', 'Gene', (36, 41))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('rs671', 'Mutation', 'rs671', (42, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ALDH2', 'Gene', '217', (36, 41))
274828	30921184	Interestingly, individuals with ALDH2 rs671 AA genotype were associated with a reduced risk of esophageal cancer and among the Japanese (Table 2).	('ALDH2', 'Gene', (32, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('reduced', 'NegReg', (79, 86))	('rs671 AA', 'Var', (38, 46))	('rs671', 'Mutation', 'rs671', (38, 43))	('esophageal cancer', 'Disease', (95, 112))	('ALDH2', 'Gene', '217', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
274834	30921184	In conclusion, our meta-analysis indicated that ALDH2 rs671G>A polymorphism may be associated with the overall cancer risk in Asians, especially in esophageal cancer and among the Chinese and the Japanese.	('cancer', 'Disease', (159, 165))	('ALDH2', 'Gene', '217', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('rs671G>A', 'Var', (54, 62))	('esophageal cancer', 'Disease', (148, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('associated', 'Reg', (83, 93))	('ALDH2', 'Gene', (48, 53))	('rs671G>A', 'DBSNP_MENTION', 'None', (54, 62))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
274837	30568465	High expression of uPA related to p38MAPK in esophageal cancer indicates poor prognosis The aim of the study was to investigate the relationship between urokinase-type plasminogen activator (uPA) and mitogen-activated protein kinase 38 (p38MAPK), and preliminarily analyze their relationship with clinical characteristics of esophageal cancer.	('uPA', 'Gene', (191, 194))	('esophageal cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('uPA', 'Gene', '5328', (191, 194))	('uPA', 'Gene', (19, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (325, 342))	('p38MAPK', 'Var', (34, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('uPA', 'Gene', '5328', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('urokinase-type plasminogen activator', 'Gene', '5328', (153, 189))	('urokinase-type plasminogen activator', 'Gene', (153, 189))	('esophageal cancer', 'Disease', (325, 342))
274838	30568465	Immunohistochemistry and Western blot were used to detect the expressions of uPA and p38MAPK in patients with esophageal cancer.	('p38MAPK', 'Var', (85, 92))	('uPA', 'Gene', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('uPA', 'Gene', '5328', (77, 80))	('esophageal cancer', 'Disease', (110, 127))	('patients', 'Species', '9606', (96, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))
274840	30568465	The expressions of uPA and p38MAPK proteins were significantly higher in esophageal squamous cell carcinoma or adenocarcinoma than in normal esophageal mucosa tissue (both P<0.0001).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (73, 107))	('p38MAPK', 'Var', (27, 34))	('uPA', 'Gene', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('expressions', 'MPA', (4, 15))	('uPA', 'Gene', '5328', (19, 22))	('adenocarcinoma', 'Disease', (111, 125))	('esophageal squamous cell carcinoma', 'Disease', (73, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('higher', 'PosReg', (63, 69))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))
274841	30568465	The expression of uPA was significantly correlated with the depth of invasion of esophageal cancer (P=0.0067), tumor size (P=0.0364), and pathological stage (P<0.0001); p38MAPK expression vs esophageal cancer tissue type (P=0.0043), esophageal cancer infiltration depth (P=0.0097), tumor size (P=0.0015), and pathological stage (P<0.0001).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('esophageal cancer', 'Disease', 'MESH:D004938', (233, 250))	('p38MAPK', 'Var', (169, 176))	('esophageal cancer infiltration depth', 'Disease', (233, 269))	('uPA', 'Gene', (18, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Disease', (111, 116))	('correlated', 'Reg', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', (81, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('esophageal cancer', 'Disease', (191, 208))	('esophageal cancer infiltration depth', 'Disease', 'MESH:D017254', (233, 269))	('uPA', 'Gene', '5328', (18, 21))
274843	30568465	There was a positive correlation between uPA and p38MAPK expressions (r=0.7301, P=0.0104).	('uPA', 'Gene', '5328', (41, 44))	('uPA', 'Gene', (41, 44))	('p38MAPK expressions', 'Var', (49, 68))
274844	30568465	Kaplan-Meier analysis showed that the overall survival time of patients with positive expression of uPA or p38MAPK protein was significantly shorter, and the time of recurrence or metastasis of esophageal cancer was significantly earlier in patients with uPA-positive expression.	('metastasis of esophageal cancer', 'Disease', (180, 211))	('earlier', 'PosReg', (230, 237))	('shorter', 'NegReg', (141, 148))	('p38MAPK', 'Var', (107, 114))	('uPA', 'Gene', (255, 258))	('uPA', 'Gene', (100, 103))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (180, 211))	('patients', 'Species', '9606', (63, 71))	('uPA', 'Gene', '5328', (255, 258))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('uPA', 'Gene', '5328', (100, 103))	('patients', 'Species', '9606', (241, 249))
274845	30568465	Multivariate analysis of Cox model showed that uPA, p38MAPK, and pathological staging were independent factors influencing survival.	('Cox', 'Gene', '1351', (25, 28))	('Cox', 'Gene', (25, 28))	('p38MAPK', 'Var', (52, 59))	('uPA', 'Gene', (47, 50))	('uPA', 'Gene', '5328', (47, 50))
274846	30568465	The expressions of uPA and p38MAPK may play an important role in the progression of esophageal cancer, and there is a close relationship between the two proteins, which may be one of the prognostic indicators.	('relationship', 'Interaction', (124, 136))	('p38MAPK', 'Var', (27, 34))	('uPA', 'Gene', (19, 22))	('uPA', 'Gene', '5328', (19, 22))	('play', 'Reg', (39, 43))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
274858	30568465	Although some progress has been made on this research, there are few more detailed studies on them, such as whether p38MAPK participates in the formation of uPA/uPAR/PAI-1 and affects the degradation of the outer matrix (ECM), or their relationship in the esophagus carcinoma progression.	('p38MAPK', 'Var', (116, 123))	('uPA', 'Gene', '5328', (157, 160))	('uPAR', 'Gene', (161, 165))	('esophagus carcinoma', 'Phenotype', 'HP:0011459', (256, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('uPA', 'Gene', (161, 164))	('uPA', 'Gene', (157, 160))	('uPA', 'Gene', '5328', (161, 164))	('esophagus carcinoma', 'Disease', 'MESH:D004938', (256, 275))	('degradation', 'MPA', (188, 199))	('PAI-1', 'Gene', (166, 171))	('PAI-1', 'Gene', '5054', (166, 171))	('uPAR', 'Gene', '5329', (161, 165))	('participates', 'Reg', (124, 136))	('affects', 'Reg', (176, 183))	('esophagus carcinoma', 'Disease', (256, 275))
274861	30568465	p38MAPK is known to be involved in a variety of different biological processes, including promoting apoptosis, participating in inflammatory reactions, malignant tumor development, and regulating transcription and translation of many different proteins, but its research in esophageal cancer is relatively rare.	('p38MAPK', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('transcription', 'MPA', (196, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (274, 291))	('regulating', 'Reg', (185, 195))	('malignant tumor', 'Disease', (152, 167))	('promoting', 'PosReg', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('esophageal cancer', 'Disease', (274, 291))	('participating', 'Reg', (111, 124))	('malignant tumor', 'Disease', 'MESH:D018198', (152, 167))	('apoptosis', 'CPA', (100, 109))
274862	30568465	In our previous study, we found that uPA and p38MAPK may be closely related to esophageal cancer.	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('uPA', 'Gene', '5328', (37, 40))	('p38MAPK', 'Var', (45, 52))	('uPA', 'Gene', (37, 40))	('related', 'Reg', (68, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))
274881	30568465	After blocking with 5% nonfat dry milk for 2 hours, added anti-uPA (1:600), anti-p38MAPK (1:500), and mouse anti-beta-actin (clone AC-15; 1:10,000, Sigma-Aldrich).	('uPA', 'Gene', '5328', (63, 66))	('uPA', 'Gene', (63, 66))	('mouse', 'Species', '10090', (102, 107))	('anti-p38MAPK', 'Var', (76, 88))
274884	30568465	After immunohistochemistry test, according to the above methods, the expressions of uPA and p38MAPK in esophageal squamous cell carcinoma and adenocarcinoma were found to be higher than those in normal esophageal tissues (both P<0.0001): uPA (squamous cell carcinoma: 89/112, adenocarcinoma: 61/72, and normal tissue: 15/62) and p38MAPK (squamous cell carcinoma: 92/112, adenocarcinoma: 61/72, normal tissue: 20/62).	('uPA', 'Gene', '5328', (238, 241))	('higher', 'PosReg', (174, 180))	('squamous cell carcinoma', 'Disease', (338, 361))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('adenocarcinoma', 'Disease', (142, 156))	('squamous cell carcinoma', 'Disease', (243, 266))	('p38MAPK', 'Var', (329, 336))	('adenocarcinoma', 'Disease', (276, 290))	('adenocarcinoma', 'Disease', (371, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal squamous cell carcinoma', 'Disease', (103, 137))	('adenocarcinoma', 'Disease', 'MESH:D000230', (142, 156))	('uPA', 'Gene', (84, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (338, 361))	('adenocarcinoma', 'Disease', 'MESH:D000230', (276, 290))	('uPA', 'Gene', '5328', (84, 87))	('adenocarcinoma', 'Disease', 'MESH:D000230', (371, 385))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (103, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (338, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (243, 266))	('uPA', 'Gene', (238, 241))
274885	30568465	Further detection by Western blot found similar results, compared with normal esophageal tissue; the expression of uPA or p38MAPK protein in esophageal squamous cell carcinoma or adenocarcinoma was higher than that of normal esophageal tissue, and all P-value < 0.0001 (Table 1 and Figure 1).	('p38MAPK', 'Var', (122, 129))	('uPA', 'Gene', '5328', (115, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (141, 175))	('adenocarcinoma', 'Disease', (179, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('adenocarcinoma', 'Disease', 'MESH:D000230', (179, 193))	('expression', 'MPA', (101, 111))	('higher', 'PosReg', (198, 204))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))	('uPA', 'Gene', (115, 118))
274886	30568465	After further analysis, it was found that there was a close correlation between the expressions of uPA and p38MAPK in esophageal cancer tissues (r=0.7301, P=0.0104, Table 1).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('uPA', 'Gene', '5328', (99, 102))	('uPA', 'Gene', (99, 102))	('p38MAPK', 'Var', (107, 114))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))
274888	30568465	p38MAPK expression was correlated with esophageal cancer infiltration depth (T stage, P=0.0097), tumor length (P=0.0015), pTNM stage (P<0.0001), and tissue type (P=0.0043), but it was also not significantly associated with morphologic type, age, gender, and lymph node staging (Table 2).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('p38MAPK', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TNM', 'Gene', (123, 126))	('esophageal cancer infiltration depth', 'Disease', 'MESH:D017254', (39, 75))	('esophageal cancer infiltration depth', 'Disease', (39, 75))	('tumor', 'Disease', (97, 102))	('correlated', 'Reg', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('TNM', 'Gene', '10178', (123, 126))
274889	30568465	After Kaplan-Meier analysis, the survival time of uPA- and p38MAPK-positive expression patients was found to be significantly shorter than that of negative patients (former, median survival: 42 vs 96 months, P<0.0001; latter, median survival: 45 vs 78 months, P=0.0121).	('patients', 'Species', '9606', (156, 164))	('survival time', 'CPA', (33, 46))	('shorter', 'NegReg', (126, 133))	('uPA', 'Gene', '5328', (50, 53))	('uPA', 'Gene', (50, 53))	('patients', 'Species', '9606', (87, 95))	('p38MAPK-positive expression', 'Var', (59, 86))
274891	30568465	Cox multivariate regression analysis was performed based on patient age, gender, depth of tumor invasion, lymph node metastasis, lesion length, pTNM, uPA, and p38MAPK protein expressions.	('patient', 'Species', '9606', (60, 67))	('uPA', 'Gene', (150, 153))	('Cox', 'Gene', (0, 3))	('TNM', 'Gene', '10178', (145, 148))	('Cox', 'Gene', '1351', (0, 3))	('tumor', 'Disease', (90, 95))	('uPA', 'Gene', '5328', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('p38MAPK', 'Var', (159, 166))	('TNM', 'Gene', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
274892	30568465	The results showed that uPA, p38MAPK protein expressions, and pTNM staging were independent prognostic factors (Table 3).	('TNM', 'Gene', '10178', (63, 66))	('TNM', 'Gene', (63, 66))	('p38MAPK', 'Var', (29, 36))	('uPA', 'Gene', (24, 27))	('uPA', 'Gene', '5328', (24, 27))
274895	30568465	This study explored the relationship between uPA, p38MAPK, and esophageal cancer, explored its possible mechanism, and provided a preliminary scientific basis for expanding the new diagnosis and treatment of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('esophageal cancer', 'Disease', (208, 225))	('uPA', 'Gene', (45, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('uPA', 'Gene', '5328', (45, 48))	('p38MAPK', 'Var', (50, 57))
274904	30568465	Kim et al found that inhibition of p38MAPK activity can reduce the ability of cancer cells to exercise and reduce invasion and metastasis.	('ability', 'CPA', (67, 74))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('inhibition', 'Var', (21, 31))	('reduce', 'NegReg', (56, 62))	('reduce', 'NegReg', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('p38MAPK activity', 'Protein', (35, 51))
274905	30568465	Studies on human choriocarcinoma have shown that activated p38 enhances the invasive behavior of human trophoblast cells and plays an important role in the formation of choriocarcinoma.	('p38', 'Gene', (59, 62))	('choriocarcinoma', 'Disease', 'MESH:D002822', (169, 184))	('choriocarcinoma', 'Disease', (17, 32))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (17, 32))	('human', 'Species', '9606', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('human', 'Species', '9606', (97, 102))	('choriocarcinoma', 'Disease', (169, 184))	('p38', 'Gene', '5594', (59, 62))	('activated', 'Var', (49, 58))	('choriocarcinoma', 'Disease', 'MESH:D002822', (17, 32))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (169, 184))	('enhances', 'PosReg', (63, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('invasive behavior of human trophoblast cells', 'CPA', (76, 120))
274906	30568465	This study showed that the expressions of uPA and p38MAPK in esophageal cancer tissues were much higher than those in adjacent normal esophageal tissues, suggesting that both proteins may play an important role in the progression of esophageal cancer.	('higher', 'PosReg', (97, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('esophageal cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('play', 'Reg', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (233, 250))	('expressions', 'MPA', (27, 38))	('uPA', 'Gene', (42, 45))	('esophageal cancer', 'Disease', (61, 78))	('uPA', 'Gene', '5328', (42, 45))	('p38MAPK', 'Var', (50, 57))
274907	30568465	These data suggest an important possibility: do not rule out the role of uPA and p38MAPK in promoting the progression of esophageal cancer in the same pathway.	('uPA', 'Gene', '5328', (73, 76))	('p38MAPK', 'Var', (81, 88))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('uPA', 'Gene', (73, 76))
274911	30568465	We found that the positive expressions of uPA and p38MAPK are closely related to the cancer size, depth of invasion, and pathological stage of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (154, 160))	('p38MAPK', 'Var', (50, 57))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('positive', 'PosReg', (18, 26))	('uPA', 'Gene', (42, 45))	('related', 'Reg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('uPA', 'Gene', '5328', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal cancer', 'Disease', (143, 160))
274913	30568465	In these studies, uPA or p38MAPK was also observed to be closely related to esophageal cancer size and pTNM staging.	('esophageal cancer', 'Disease', (76, 93))	('p38MAPK', 'Var', (25, 32))	('TNM', 'Gene', '10178', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('TNM', 'Gene', (104, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('related', 'Reg', (65, 72))	('uPA', 'Gene', (18, 21))	('uPA', 'Gene', '5328', (18, 21))
274914	30568465	In this study, we also found that uPA has no significant relationship with esophageal cancer tissue type, and p38MAPK is relatively high in adenocarcinoma.	('high', 'Reg', (132, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('adenocarcinoma', 'Disease', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('p38MAPK', 'Var', (110, 117))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('uPA', 'Gene', (34, 37))	('uPA', 'Gene', '5328', (34, 37))	('esophageal cancer', 'Disease', (75, 92))
274918	30568465	We found that the median survival time of patients with positive protein expression was significantly shortened, which is consistent with the above data and also with most of research on their relationship between single uPA or p38MAPK and esophageal cancer.	('esophageal cancer', 'Disease', (240, 257))	('uPA', 'Gene', '5328', (221, 224))	('shortened', 'NegReg', (102, 111))	('uPA', 'Gene', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('protein', 'Protein', (65, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (240, 257))	('positive', 'Var', (56, 64))	('p38MAPK', 'Var', (228, 235))	('patients', 'Species', '9606', (42, 50))
274921	30568465	In this study, we found that uPA and p38MAPK proteins may play important roles in the progression of esophageal cancer, and there may be synergistic effects in this process, which provide a new perspective for us to further explore the mechanism of esophageal cancer progression.	('uPA', 'Gene', (29, 32))	('proteins', 'Protein', (45, 53))	('uPA', 'Gene', '5328', (29, 32))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', (249, 266))	('esophageal cancer', 'Disease', 'MESH:D004938', (249, 266))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('p38MAPK', 'Var', (37, 44))
274923	30568465	The role of uPA and p38MAPK in the progression of esophageal cancer may provide a scientific basis for exploring the feasibility of biologically targeted therapy for esophageal cancer.	('uPA', 'Gene', '5328', (12, 15))	('esophageal cancer', 'Disease', (166, 183))	('p38MAPK', 'Var', (20, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('esophageal cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))	('uPA', 'Gene', (12, 15))
274933	29909422	Overexpression of TCF21 greatly inhibited the proliferation, migration, and invasion in both TE10 and KYSE510 cell lines.	('TCF21', 'Gene', '6943', (18, 23))	('inhibited', 'NegReg', (32, 41))	('TCF21', 'Gene', (18, 23))	('proliferation', 'CPA', (46, 59))	('migration', 'CPA', (61, 70))	('Overexpression', 'Var', (0, 14))	('invasion', 'CPA', (76, 84))
274943	29909422	Transcription factor 21 (TCF21, also known as capsulin, epicardin, and Pod1), locates at chromosome 6q23-q24 and belongs to the basic helix-loop-helix (bHLH) family, and it has been verified as a tumor suppressor gene, and the hypermethylation of aberrant promoter induces its low expression in tumor tissues.	('TCF21', 'Gene', '6943', (25, 30))	('hypermethylation', 'Var', (227, 243))	('tumor', 'Disease', (196, 201))	('Transcription factor 21', 'Gene', (0, 23))	('Transcription factor 21', 'Gene', '6943', (0, 23))	('TCF21', 'Gene', (25, 30))	('epicardin', 'Gene', '6943', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('epicardin', 'Gene', (56, 65))	('low expression', 'MPA', (277, 291))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('capsulin', 'Gene', '6943', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('capsulin', 'Gene', (46, 54))	('tumor', 'Disease', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
274995	29909422	After the expressions of TCF21 in TE10 and KYSE510 were proven to increase, we performed the colony formation assay and CCK-8 cell proliferation assay to investigate the status of cell proliferation.	('increase', 'PosReg', (66, 74))	('KYSE510', 'Var', (43, 50))	('TCF21', 'Gene', '6943', (25, 30))	('TCF21', 'Gene', (25, 30))	('expressions', 'MPA', (10, 21))	('colony formation assay', 'CPA', (93, 115))
275009	29909422	Recent studies suggest that aberrant promoter methylation of TCF21 causes it to be frequently lost in human malignancies.	('TCF21', 'Gene', (61, 66))	('malignancies', 'Disease', (108, 120))	('malignancies', 'Disease', 'MESH:D009369', (108, 120))	('aberrant', 'Var', (28, 36))	('TCF21', 'Gene', '6943', (61, 66))	('promoter', 'MPA', (37, 45))	('human', 'Species', '9606', (102, 107))
275010	29909422	Aberrant promoter methylation of cancer-associated genes has now been confirmed as an alternative mechanism to heritably silence gene transcription, which is a significant epigenetic process that fundamental biological events are involved in, such as development and cell differentiation.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('silence', 'NegReg', (121, 128))	('gene transcription', 'MPA', (129, 147))
275030	29909422	Loss of the TCF21 will result in the failure of mesenchymal-to-epithelial transition, a reverse process of EMT which has been described as an absolute requirement for cell migration and invasion in many malignancies.	('mesenchymal-to-epithelial transition', 'CPA', (48, 84))	('TCF21', 'Gene', '6943', (12, 17))	('malignancies', 'Disease', 'MESH:D009369', (203, 215))	('failure', 'NegReg', (37, 44))	('malignancies', 'Disease', (203, 215))	('Loss', 'Var', (0, 4))	('TCF21', 'Gene', (12, 17))
275035	29909422	KP-54, the largest of the 3 KPs, inhibits tumor metastasis through the receptor GPR54.	('GPR54', 'Gene', (80, 85))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('inhibits', 'NegReg', (33, 41))	('KP-54', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('GPR54', 'Gene', '84634', (80, 85))
275036	29909422	found that KP-54 can result in the PKD1 phosphorylation-dependent decrease of Slug but the concomitant increase of E-cadherin, which has been supposed to influence cell invasion and metastasis.	('Slug', 'Gene', (78, 82))	('Slug', 'Gene', '6591', (78, 82))	('PKD1', 'Gene', '5310', (35, 39))	('increase', 'PosReg', (103, 111))	('influence', 'Reg', (154, 163))	('PKD1', 'Gene', (35, 39))	('decrease', 'NegReg', (66, 74))	('E-cadherin', 'Gene', (115, 125))	('E-cadherin', 'Gene', '999', (115, 125))	('KP-54', 'Var', (11, 16))
275046	27583562	Although previously implicated in other malignancies and in epithelial-to-mesenchymal transition phenotypes, our experimental validation shows for the first time that CYR61 and TAZ have the potential to be predictive biomarkers for cancer progression.	('malignancies', 'Disease', (40, 52))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (232, 238))	('CYR61', 'Var', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('malignancies', 'Disease', 'MESH:D009369', (40, 52))	('TAZ', 'Gene', (177, 180))
275048	27583562	In our cohort CYR61 and TAZ up-regulation ranged from one to ten years prior to progression to adenocarcinoma in Barrett's esophagus index samples.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('adenocarcinoma', 'Disease', (95, 109))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (113, 132))	('adenocarcinoma', 'Disease', 'MESH:D000230', (95, 109))	('TAZ', 'Gene', (24, 27))	('CYR61', 'Var', (14, 19))	('up-regulation', 'PosReg', (28, 41))
275091	27583562	Thus, to indirectly check the amount of each isolated total RNA FFPE sample and its quantitative real-time PCR (qRT-PCR) downstream performance, we prepared two standards dilution series using cDNA from the two control cell lines, corresponding to 100, 10 1, 0.1, 0.01, 0.001 and 0.0001 ng of the original total RNA.	('P', 'Chemical', 'MESH:D010758', (107, 108))	('0.1', 'Var', (259, 262))	('P', 'Chemical', 'MESH:D010758', (66, 67))	('0.001', 'Var', (270, 275))	('0.01', 'Var', (264, 268))	('P', 'Chemical', 'MESH:D010758', (116, 117))	('0.0001 ng', 'Var', (280, 289))
275121	27583562	Blinded analysis showed that despite the somewhat heterogeneous cytoplasmatic staining of CYR61 protein, its levels were mainly intermediate to high in the P-BE group and mostly varied from low to intermediate in the nonP-BE group (Fig 2B).	('CYR61', 'Gene', (90, 95))	('P', 'Chemical', 'MESH:D010758', (220, 221))	('BE', 'Phenotype', 'HP:0100580', (222, 224))	('P-BE', 'Var', (156, 160))	('levels', 'MPA', (109, 115))	('BE', 'Phenotype', 'HP:0100580', (158, 160))	('P', 'Chemical', 'MESH:D010758', (156, 157))
275122	27583562	As for CYR61, despite some heterogeneity of TAZ IHC pattern (Fig 2C, Table 2), TAZ protein levels were increased in the P-BE as compared to nonP-BE group, with P-BE samples from t0 displaying a more distinct TAZ over-expression.	('BE', 'Phenotype', 'HP:0100580', (145, 147))	('P', 'Chemical', 'MESH:D010758', (160, 161))	('increased', 'PosReg', (103, 112))	('P', 'Chemical', 'MESH:D010758', (120, 121))	('BE', 'Phenotype', 'HP:0100580', (162, 164))	('P', 'Chemical', 'MESH:D010758', (143, 144))	('TAZ protein levels', 'MPA', (79, 97))	('BE', 'Phenotype', 'HP:0100580', (122, 124))	('P-BE', 'Var', (120, 124))
275135	27583562	Validation with qRT-PCR and IHC emphasized CYR61 and TAZ over-expression as early markers of at risk BE index samples, years before HGD/EA emergence.	('P', 'Chemical', 'MESH:D010758', (20, 21))	('TAZ', 'Gene', (53, 56))	('BE', 'Phenotype', 'HP:0100580', (101, 103))	('over-expression', 'PosReg', (57, 72))	('CYR61', 'Var', (43, 48))	('EA', 'Phenotype', 'HP:0011459', (136, 138))
275140	27583562	Several studies have implicated CYR61 and TAZ in the biology of major cancers (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CYR61', 'Var', (32, 37))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Disease', (70, 77))
275143	27583562	CYR61 is an important factor in acid-induced esophageal epithelial transformation and its up-regulation is an early response of esophageal cells exposed to low pH.	('esophageal epithelial transformation', 'Disease', (45, 81))	('CYR61', 'Var', (0, 5))	('up-regulation', 'PosReg', (90, 103))	('esophageal epithelial transformation', 'Disease', 'MESH:D017573', (45, 81))
275144	27583562	In a non-esophageal context, CYR61 plays a role in inflammation, it is notably expressed at wounded tissues and also up regulated upon mechanical stress (reviewed in).	('up regulated', 'PosReg', (117, 129))	('CYR61', 'Var', (29, 34))	('inflammation', 'Disease', 'MESH:D007249', (51, 63))	('inflammation', 'Disease', (51, 63))
275145	27583562	CYR61 has also an independent prognostic value in esophageal squamous cell carcinoma and is a negative predictor in early onset sporadic colorectal and ovarian cancers.	('sporadic colorectal and ovarian cancers', 'Disease', 'MESH:D015179', (128, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('CYR61', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))	('ovarian cancers', 'Phenotype', 'HP:0100615', (152, 167))
275146	27583562	Functionally, CYR61 is a ligand for several integrins which in turn can trigger cancer cells motility (reviewed in) as it was recently demonstrated in pancreatic cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('cancer', 'Disease', (162, 168))	('trigger', 'PosReg', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('CYR61', 'Var', (14, 19))	('cancer', 'Disease', (80, 86))	('pancreatic cancer', 'Disease', (151, 168))
275149	27583562	This type of cancer-associated molecular alterations in non-cancer tissues (e.g.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', (60, 66))	('non-cancer', 'Disease', (56, 66))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('non-cancer', 'Disease', 'MESH:D009369', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('alterations', 'Var', (41, 52))
275151	27583562	We analyzed CYR61 and TAZ levels in non-dysplastic/EA-free BE index biopsies of P-BE and nonP-BE patients by qRT-PCR to distinguish whether CYR61 and TAZ up-regulation were a cancer field effect or an early property of P-BE samples.	('TAZ', 'MPA', (150, 153))	('P', 'Chemical', 'MESH:D010758', (92, 93))	('BE', 'Phenotype', 'HP:0100580', (94, 96))	('P', 'Chemical', 'MESH:D010758', (113, 114))	('P', 'Chemical', 'MESH:D010758', (219, 220))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('EA', 'Phenotype', 'HP:0011459', (51, 53))	('BE', 'Phenotype', 'HP:0100580', (221, 223))	('non-dysplastic', 'Disease', (36, 50))	('CYR61', 'Var', (140, 145))	('non-dysplastic', 'Disease', 'MESH:D004416', (36, 50))	('P', 'Chemical', 'MESH:D010758', (80, 81))	('BE', 'Phenotype', 'HP:0100580', (82, 84))	('up-regulation', 'PosReg', (154, 167))	('BE', 'Phenotype', 'HP:0100580', (59, 61))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('patients', 'Species', '9606', (97, 105))
275154	27583562	This phenomenon of increased expression on localized benign disease and a decreased expression upon progression to metastasis is known to occur in several contexts such as for CYR61 in prostate cancer (reviewed in).	('CYR61', 'Var', (176, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('localized benign disease', 'Disease', (43, 67))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('increased', 'PosReg', (19, 28))	('prostate cancer', 'Disease', (185, 200))	('decreased', 'NegReg', (74, 83))	('expression', 'MPA', (84, 94))	('expression', 'MPA', (29, 39))
275155	27583562	Although CYR61 up-regulation was previously described in BE samples where dysplasia/EA is already present, our work is the first to describe that such up-regulation is in fact a very early event in Barrett's tumorigenic process, being an indicator for a later establishment of dysplasia/EA, since it is detected in BE index biopsies.	('CYR61', 'Var', (9, 14))	('EA', 'Phenotype', 'HP:0011459', (84, 86))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('up-regulation', 'PosReg', (15, 28))	('dysplasia', 'Disease', (277, 286))	('dysplasia', 'Disease', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('BE', 'Phenotype', 'HP:0100580', (315, 317))	('dysplasia', 'Disease', 'MESH:D004476', (74, 83))	('tumor', 'Disease', (208, 213))	('EA', 'Phenotype', 'HP:0011459', (287, 289))	('dysplasia', 'Disease', 'MESH:D004476', (277, 286))	('up-regulation', 'PosReg', (151, 164))
275156	27583562	CYR61 belongs to the CCN family of six structurally related proteins, a multi-tasking group of secreted proteins which primarily function in adhesion, migration, proliferation, ECM synthesis, inflammation and mechanical stress regulation (reviewed in).	('migration', 'CPA', (151, 160))	('inflammation', 'Disease', 'MESH:D007249', (192, 204))	('inflammation', 'Disease', (192, 204))	('CYR61', 'Var', (0, 5))	('function', 'Reg', (129, 137))
275165	27583562	Moreover, it was recently reported that TAZ and CYR61 were implicated in lung cancer progression and EMT via angiomotin.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('EMT', 'CPA', (101, 104))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('implicated', 'Reg', (59, 69))	('CYR61', 'Var', (48, 53))
275166	27583562	Our observations indicate that in particular, being CYR61 an extracellular matrix secreted protein it harbors the potential to become a serum biomarker to stratify the risk of progression to malignancy in BE allowing for less invasive follow-up exams.	('CYR61', 'Var', (52, 57))	('malignancy', 'Disease', (191, 201))	('BE', 'Phenotype', 'HP:0100580', (205, 207))	('malignancy', 'Disease', 'MESH:D009369', (191, 201))
275168	27583562	Despite the very low BE progression frequency, we had access to a small, yet precious and very rare, cohort of FFPE follow-up samples for validation and more importantly to implement CYR61 and TAZ detection by IHC, a method directly translatable to all pathology labs.	('BE', 'Phenotype', 'HP:0100580', (21, 23))	('P', 'Chemical', 'MESH:D010758', (113, 114))	('TAZ', 'MPA', (193, 196))	('CYR61', 'Var', (183, 188))
275178	27583562	Our results support the use of CYR61 and TAZ as early biomarkers to discriminate which BE patients have an increased risk to progress to dysplasia and cancer and further suggest that proteins/genes involved in EMT are critical to trigger the BE lesions that evolve to more aggressive lesions.	('CYR61', 'Var', (31, 36))	('BE', 'Phenotype', 'HP:0100580', (87, 89))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('BE', 'Phenotype', 'HP:0100580', (242, 244))	('dysplasia and cancer', 'Disease', 'MESH:D009369', (137, 157))	('progress', 'PosReg', (125, 133))	('patients', 'Species', '9606', (90, 98))
275333	26800661	Although various studies have described, intraluminal radioactive stent got a better long-term clinical effect of dysphagia and went with fewer complications.	('dysphagia', 'Disease', (114, 123))	('intraluminal', 'Var', (41, 53))	('dysphagia', 'Phenotype', 'HP:0002015', (114, 123))	('dysphagia', 'Disease', 'MESH:D003680', (114, 123))
275334	26800661	Moreover, the median survival time was also longer in intraluminal radioactive stent than self-expanding metal stent alone.	('metal stent', 'Chemical', '-', (105, 116))	('intraluminal radioactive stent', 'Var', (54, 84))	('longer', 'PosReg', (44, 50))
275357	26800661	Although various studies have described a longer survival time of intraluminal radioactive stent than that of self-expanding metal stent, our results showed no evidence of significance supporting this fact in inoperable esophageal squamous cell cancer.	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (220, 251))	('metal stent', 'Chemical', '-', (125, 136))	('longer', 'PosReg', (42, 48))	('intraluminal radioactive', 'Var', (66, 90))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (231, 251))	('esophageal squamous cell cancer', 'Disease', (220, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('survival', 'MPA', (49, 57))
275371	23785299	Cancer is a disease that develops over decades as result of accumulation of abnormalities in the genomes of otherwise normal cells.	('Cancer', 'Disease', (0, 6))	('abnormalities', 'Var', (76, 89))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
275380	23785299	Somatic genomic abnormalities (SGA), such as copy number alterations and loss of heterozygosity (LOH), can be used as polymorphic DNA markers for identifying evolving clones.	('Somatic genomic abnormalities', 'Disease', 'MESH:D013001', (0, 29))	('Somatic genomic abnormalities', 'Disease', (0, 29))	('copy number alterations', 'Var', (45, 68))	('loss of heterozygosity', 'Var', (73, 95))
275389	23785299	evaluated 3131 cancer specimens from 26 histologic types and 1480 normal tissue specimens and found that copy number gains and losses affected 17% and 16% of the genome in a typical cancer specimen and only 0.35% and 0.1% of the genome in a typical normal tissue specimen.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', (15, 21))	('copy number', 'Var', (105, 116))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('men', 'Species', '9606', (268, 271))	('men', 'Species', '9606', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('men', 'Species', '9606', (85, 88))	('losses', 'NegReg', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('men', 'Species', '9606', (27, 30))	('gains', 'PosReg', (117, 122))
275393	23785299	showed that NSAID use reduced the 10-year cumulative incidence of esophageal adenocarcinoma from 79% to 30% in individuals with BE who had one or more somatic genomic abnormalities detected at baseline endoscopy, which included DNA content tetraploidy and/or aneuploidy, assayed by DNA content flow cytometry, or genetic abnormalities, such as loss of heterozygosity (LOH) on chromosomes 9p and 17p, assayed by PCR of small tandem repeat (STR) loci.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (66, 91))	('aneuploidy', 'Disease', (259, 269))	('genetic abnormalities', 'Disease', 'MESH:D030342', (313, 334))	('loss', 'Var', (344, 348))	('reduced', 'NegReg', (22, 29))	('genetic abnormalities', 'Disease', (313, 334))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (66, 91))	('aneuploidy', 'Disease', 'MESH:D000782', (259, 269))	('esophageal adenocarcinoma', 'Disease', (66, 91))
275408	23785299	Models of this stasis are based on an evolving population diffusing across a fitness plateau due to evolutionarily neutral mutations, until they find an adaptive genotype.	('mutations', 'Var', (123, 132))	('fitness plateau', 'Disease', (77, 92))	('fitness plateau', 'Disease', 'MESH:D012640', (77, 92))
275438	23785299	For every new segment, we used thresholds to call allelic imbalance based on the smoothed mBAF profile, and to call single or double copy gain or loss, based on the homozygous and heterozygous log2R profiles.	('gain', 'PosReg', (138, 142))	('BAF', 'Gene', '8815', (91, 94))	('imbalance', 'Phenotype', 'HP:0002172', (58, 67))	('BAF', 'Gene', (91, 94))	('single', 'Var', (116, 122))	('men', 'Species', '9606', (17, 20))
275451	23785299	We also performed additional analyses of SGA lesions new appearances and regressions during on- and off- NSAID periods that do not use phylogenies (Text S3, Figures S12, S13 and Text S4, Figure S14).	('SGA', 'Disease', (41, 44))	('S14', 'Gene', (194, 197))	('S14', 'Gene', '6208', (194, 197))	('S12', 'Gene', (165, 168))	('S12', 'Gene', '6268', (165, 168))	('Text S4', 'Var', (178, 185))
275457	21791690	Germline Mutations in MSR1, ASCC1, and CTHRC1 in Patients With Barrett Esophagus and Esophageal Adenocarcinoma Barrett esophagus (BE) occurs in 1% to 10% of the general population and is believed to be the precursor of esophageal adenocarcinoma (EAC).	('ASCC1', 'Gene', (28, 33))	('BE', 'Phenotype', 'HP:0100580', (130, 132))	('Germline', 'Var', (0, 8))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (85, 110))	('Patients', 'Species', '9606', (49, 57))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (85, 110))	('EAC', 'Gene', '1540', (246, 249))	('CTHRC1', 'Gene', '115908', (39, 45))	('EAC', 'Gene', (246, 249))	('Esophageal Adenocarcinoma', 'Disease', (85, 110))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (219, 244))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (111, 128))	('MSR1', 'Gene', (22, 26))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (219, 244))	('MSR1', 'Gene', '4481', (22, 26))	('CTHRC1', 'Gene', (39, 45))	('esophageal adenocarcinoma', 'Disease', (219, 244))	('ASCC1', 'Gene', '51008', (28, 33))	('Barrett esophagus', 'Disease', (111, 128))	('Barrett Esophagus', 'Phenotype', 'HP:0100580', (63, 80))	('EAC', 'Phenotype', 'HP:0011459', (246, 249))
275468	21791690	MSR1 was the most frequently mutated, with 8 of 116 (proportion, 0.069; 95% confidence interval [CI], 0.030-0.130; P<.001) cases with c.877C>T (p.R293X).	('MSR1', 'Gene', (0, 4))	('c.877C>T', 'Var', (134, 142))	('c.877C>T', 'Mutation', 'rs41341748', (134, 142))	('MSR1', 'Gene', '4481', (0, 4))	('p.R293X', 'Mutation', 'rs41341748', (144, 151))
275469	21791690	An independent validation series confirmed germline MSR1 mutations in 2 of 58 cases (proportion, 0.035; 95% CI, 0.004-0.120; P=.09).	('MSR1', 'Gene', '4481', (52, 56))	('mutations', 'Var', (57, 66))	('MSR1', 'Gene', (52, 56))
275470	21791690	MSR1 mutation resulted in CCND1 up-regulation in peripheral-protein lysate.	('MSR1', 'Gene', (0, 4))	('MSR1', 'Gene', '4481', (0, 4))	('CCND1', 'Gene', (26, 31))	('up-regulation', 'PosReg', (32, 45))	('CCND1', 'Gene', '595', (26, 31))	('mutation', 'Var', (5, 13))
275472	21791690	MSR1 was significantly associated with the presence of BE/EAC in derivation and validation samples, although it was only present in a small percentage of the cases.	('MSR1', 'Gene', (0, 4))	('BE', 'Phenotype', 'HP:0100580', (55, 57))	('BE/EAC', 'Gene', '1540', (55, 61))	('BE/EAC', 'Gene', (55, 61))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('MSR1', 'Gene', '4481', (0, 4))	('presence', 'Var', (43, 51))	('associated', 'Reg', (23, 33))
275483	21791690	The discovery of germline mutations in a gene or genes that predispose to BE/EAC may have ramifications regarding cancer risk assessment, genetic counseling, premorbid diagnosis, and targeted surveillance and management, and also add to the fundamental understanding of the pathophysiology of sporadic BE and EAC.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('EAC', 'Gene', '1540', (77, 80))	('men', 'Species', '9606', (246, 249))	('men', 'Species', '9606', (132, 135))	('EAC', 'Gene', (77, 80))	('germline mutations', 'Var', (17, 35))	('BE/EAC', 'Gene', '1540', (74, 80))	('men', 'Species', '9606', (215, 218))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('EAC', 'Phenotype', 'HP:0011459', (309, 312))	('BE', 'Phenotype', 'HP:0100580', (74, 76))	('EAC', 'Gene', '1540', (309, 312))	('BE/EAC', 'Gene', (74, 80))	('EAC', 'Gene', (309, 312))	('BE', 'Phenotype', 'HP:0100580', (302, 304))	('cancer', 'Disease', (114, 120))
275493	21791690	To narrow in on one or a subset of genes within and in proximity to the significant SNPs/haplotypes germane to BE/EAC (by tissue-specific expression in oncologic pathways and for functional-genomic validation), we integrated our significant regions with publicly available somatic gene expression data derived from 19 patients with BE/EAC (GDS3472 or GSE13083), followed up by unsupervised hierarchical clustering of genes within 250 kb flanking the significant SNPs and haplotypes across BE/EAC and unaffected individuals (eFigure 1, Table 1, and Table 2).	('BE/EAC', 'Gene', '1540', (111, 117))	('BE/EAC', 'Gene', '1540', (489, 495))	('BE', 'Phenotype', 'HP:0100580', (489, 491))	('patients', 'Species', '9606', (318, 326))	('EAC', 'Phenotype', 'HP:0011459', (335, 338))	('BE/EAC', 'Gene', (111, 117))	('GDS3472', 'Var', (340, 347))	('GSE13083', 'Var', (351, 359))	('BE', 'Phenotype', 'HP:0100580', (111, 113))	('BE/EAC', 'Gene', (489, 495))	('BE/EAC', 'Gene', '1540', (332, 338))	('EAC', 'Phenotype', 'HP:0011459', (492, 495))	('BE', 'Phenotype', 'HP:0100580', (332, 334))	('EAC', 'Phenotype', 'HP:0011459', (114, 117))	('BE/EAC', 'Gene', (332, 338))
275504	21791690	Mutational analyses of these 12 priority candidate genes in BE/EAC cases and controls revealed germline mutations in 3 genes (MSR1 [macrophage scavenger receptor 1] [MIM153622], ASCC1 [activating signal co-integrator 1 complex subunit 1] [NC_000010.10], or CTHRC1 [collagen triple-helix repeat-containing 1] [MIM610635]) in 13 of 116 patients (11.2%) with BE/EAC (Table 3 and eTable 1).	('collagen triple-helix repeat-containing 1', 'Gene', '115908', (265, 306))	('EAC', 'Phenotype', 'HP:0011459', (63, 66))	('BE', 'Phenotype', 'HP:0100580', (60, 62))	('BE/EAC', 'Gene', '1540', (356, 362))	('BE/EAC', 'Gene', (356, 362))	('macrophage scavenger receptor 1', 'Gene', '4481', (132, 163))	('MSR1', 'Gene', (126, 130))	('CTHRC1', 'Gene', (257, 263))	('mutations', 'Var', (104, 113))	('ASCC1', 'Gene', (178, 183))	('MSR1', 'Gene', '4481', (126, 130))	('[MIM153622]', 'Var', (165, 176))	('collagen triple-helix repeat-containing 1', 'Gene', (265, 306))	('BE/EAC', 'Gene', '1540', (60, 66))	('BE', 'Phenotype', 'HP:0100580', (356, 358))	('patients', 'Species', '9606', (334, 342))	('BE/EAC', 'Gene', (60, 66))	('macrophage scavenger receptor 1', 'Gene', (132, 163))	('EAC', 'Phenotype', 'HP:0011459', (359, 362))	('ASCC1', 'Gene', '51008', (178, 183))	('CTHRC1', 'Gene', '115908', (257, 263))
275505	21791690	Among the 116 patients with BE/EAC, 8 patients (proportion, 0.069; 95% confidence interval [CI], 0.030-0.130; P < .001) had a germline truncating mutation in MSR1 c.877C>T, resulting in p.R293X (Figure 2 and Table 3), and 2 additional patients (proportion, 0.017; 95% CI, 0.021-0.061; P= .19) with BE/EAC carried germline MSR1 p.L254V (c.760C>G) in exon 5 (Table 3 and eFigure 3A).	('c.760C>G', 'Mutation', 'rs387906645', (336, 344))	('EAC', 'Phenotype', 'HP:0011459', (301, 304))	('p.R293X', 'Mutation', 'rs41341748', (186, 193))	('EAC', 'Phenotype', 'HP:0011459', (31, 34))	('BE', 'Phenotype', 'HP:0100580', (298, 300))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (14, 22))	('MSR1', 'Gene', (158, 162))	('BE', 'Phenotype', 'HP:0100580', (28, 30))	('c.877C>T', 'Mutation', 'rs41341748', (163, 171))	('patients', 'Species', '9606', (235, 243))	('p.L254V (c.760C>G', 'Var', (327, 344))	('MSR1', 'Gene', '4481', (158, 162))	('MSR1', 'Gene', (322, 326))	('BE/EAC', 'Gene', '1540', (28, 34))	('p.L254V', 'Mutation', 'rs387906645', (327, 334))	('BE/EAC', 'Gene', (28, 34))	('MSR1', 'Gene', '4481', (322, 326))	('BE/EAC', 'Gene', '1540', (298, 304))	('BE/EAC', 'Gene', (298, 304))	('p.R293X', 'Var', (186, 193))	('c.877C>T', 'Var', (163, 171))
275506	21791690	Additionally, we identified 2 germline missense mutations:c.869A>G in exon 8 of ASCC1, resulting in p.N290S in 2 patients (proportion, 0.021; 95% CI, 0.003-0.074; P = .18 ); and c.131A>C in exon 1 of CTHRC1, resulting in p.Q44P in 1 patient (proportion, 0.011; 95% CI, 0.0003-0.061; P= .42), neither of which were found among 125 controls (Table 3, eFigure 3B, and eFigure 3C).	('CTHRC1', 'Gene', '115908', (200, 206))	('patient', 'Species', '9606', (113, 120))	('c.131A>C', 'Mutation', 'rs387907029', (178, 186))	('p.Q44P', 'Var', (221, 227))	('CTHRC1', 'Gene', (200, 206))	('patient', 'Species', '9606', (233, 240))	('ASCC1', 'Gene', '51008', (80, 85))	('patients', 'Species', '9606', (113, 121))	('mutations:c.869A>G', 'Var', (48, 66))	('p.N290S', 'Var', (100, 107))	('p.Q44P', 'Mutation', 'rs387907029', (221, 227))	('mutations:c.869A>G', 'SUBSTITUTION', 'None', (48, 66))	('ASCC1', 'Gene', (80, 85))	('c.131A>C', 'Var', (178, 186))	('p.N290S', 'Mutation', 'rs146370051', (100, 107))
275508	21791690	These samples confirmed the presence of germline MSR1 c.877C>T, p.R293X mutation in 2 of 58 cases (proportion, 0.034; 95% CI, 0.004-0.120; P = .09) and CTHRC1 c.131A>C, p.Q44P mutation in 1 of 58 cases (1.7%).	('c.877C>T', 'Var', (54, 62))	('MSR1', 'Gene', (49, 53))	('p.Q44P', 'Var', (169, 175))	('c.131A>C', 'Mutation', 'rs387907029', (159, 167))	('c.877C>T', 'Mutation', 'rs41341748', (54, 62))	('CTHRC1', 'Gene', (152, 158))	('CTHRC1', 'Gene', '115908', (152, 158))	('p.R293X', 'Mutation', 'rs41341748', (64, 71))	('MSR1', 'Gene', '4481', (49, 53))	('p.Q44P', 'Mutation', 'rs387907029', (169, 175))	('p.R293X', 'Var', (64, 71))	('c.131A>C', 'Var', (159, 167))
275509	21791690	After pooling the original 116 cases with the validation series of 58, a total of 10 cases with BE/EAC carried p.R293X (proportion, 0.054; 95% CI, 0.026-0.098; P= .006) (Table 3).	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('BE', 'Phenotype', 'HP:0100580', (96, 98))	('BE/EAC', 'Gene', (96, 102))	('p.R293X', 'Var', (111, 118))	('p.R293X', 'Mutation', 'rs41341748', (111, 118))	('BE/EAC', 'Gene', '1540', (96, 102))
275512	21791690	Barrett esophagus tissues from patients who were mutation-positive showed increased nuclear expression of CCND1 by immunohistochemistry compared with control esophageal specimens (Figure 4).	('Barrett esophagus', 'Phenotype', 'HP:0100580', (0, 17))	('nuclear expression', 'MPA', (84, 102))	('increased', 'PosReg', (74, 83))	('patients', 'Species', '9606', (31, 39))	('mutation-positive', 'Var', (49, 66))	('CCND1', 'Gene', (106, 111))	('men', 'Species', '9606', (174, 177))	('CCND1', 'Gene', '595', (106, 111))
275516	21791690	Herein, we have identified germline mutations in 3 candidate genes in approximately 11% of our series of patients with BE/EAC, with the most commonly affected being MSR1 (approximately 7%), followed by ASCC1 and CTHRC1.	('ASCC1', 'Gene', '51008', (202, 207))	('MSR1', 'Gene', (165, 169))	('patients', 'Species', '9606', (105, 113))	('MSR1', 'Gene', '4481', (165, 169))	('affected', 'Reg', (150, 158))	('germline mutations', 'Var', (27, 45))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('ASCC1', 'Gene', (202, 207))	('BE', 'Phenotype', 'HP:0100580', (119, 121))	('CTHRC1', 'Gene', '115908', (212, 218))	('BE/EAC', 'Gene', '1540', (119, 125))	('BE/EAC', 'Gene', (119, 125))	('CTHRC1', 'Gene', (212, 218))
275517	21791690	Findings of germline MSR1 and CTHRC1 mutations were replicated in an independent validation series.	('MSR1', 'Gene', '4481', (21, 25))	('mutations', 'Var', (37, 46))	('CTHRC1', 'Gene', (30, 36))	('CTHRC1', 'Gene', '115908', (30, 36))	('MSR1', 'Gene', (21, 25))
275519	21791690	The MSR1 c.877C>T sequence variant, resulting in p.R293X, located within a highly conserved collagen-like domain of the MSR1 protein, would be expected to disrupt function.	('c.877C>T', 'Mutation', 'rs41341748', (9, 17))	('MSR1', 'Gene', (4, 8))	('disrupt', 'NegReg', (155, 162))	('MSR1', 'Gene', '4481', (120, 124))	('MSR1', 'Gene', '4481', (4, 8))	('function', 'MPA', (163, 171))	('MSR1', 'Gene', (120, 124))	('p.R293X', 'Mutation', 'rs41341748', (49, 56))	('p.R293X', 'Var', (49, 56))
275520	21791690	The MSR1 p.R293X was previously shown to associate with prostate cancer in specific ancestries, although this association is controversial.	('MSR1', 'Gene', (4, 8))	('associate', 'Reg', (41, 50))	('p.R293X', 'Var', (9, 16))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('p.R293X', 'Mutation', 'rs41341748', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('MSR1', 'Gene', '4481', (4, 8))	('prostate cancer', 'Disease', (56, 71))
275522	21791690	In many inherited neoplasia syndromes, single gene mutations predispose to cancers in more than 1 organ.	('neoplasia syndromes', 'Disease', 'MESH:D009369', (18, 37))	('single gene mutations', 'Var', (39, 60))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('neoplasia', 'Phenotype', 'HP:0002664', (18, 27))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('predispose', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('neoplasia syndromes', 'Disease', (18, 37))
275523	21791690	We found both p.R293X and p.L254V (also within the conserved coiled-coil domain and near the glycosylation site at the 249th amino acid) in the germline of our BE/EAC cases, but not in the ancestry-matched population controls, which strongly suggest that these mutations contribute to BE/EAC risk, or at least are necessary for BE/EAC predisposition.	('BE/EAC', 'Gene', (328, 334))	('p.R293X', 'Var', (14, 21))	('BE/EAC', 'Gene', '1540', (285, 291))	('EAC', 'Phenotype', 'HP:0011459', (288, 291))	('BE', 'Phenotype', 'HP:0100580', (285, 287))	('p.L254V', 'Mutation', 'rs387906645', (26, 33))	('BE/EAC', 'Gene', '1540', (160, 166))	('BE/EAC', 'Gene', (285, 291))	('BE', 'Phenotype', 'HP:0100580', (160, 162))	('p.L254V', 'Var', (26, 33))	('BE/EAC', 'Gene', (160, 166))	('contribute', 'Reg', (271, 281))	('BE', 'Phenotype', 'HP:0100580', (328, 330))	('EAC', 'Phenotype', 'HP:0011459', (163, 166))	('BE/EAC', 'Gene', '1540', (328, 334))	('p.R293X', 'Mutation', 'rs41341748', (14, 21))	('EAC', 'Phenotype', 'HP:0011459', (331, 334))
275528	21791690	Beyond genetic evidence, we have additionally shown up-regulation of key cell cycle molecule CCND1 by both Western blotting of germline proteins and immunohistochemistry of MSR1 mutation-related BE tissue, in which CCND1 is overexpressed in the nucleus.	('up-regulation', 'PosReg', (52, 65))	('MSR1', 'Gene', '4481', (173, 177))	('CCND1', 'Gene', '595', (93, 98))	('CCND1', 'Gene', (215, 220))	('mutation-related', 'Var', (178, 194))	('MSR1', 'Gene', (173, 177))	('BE', 'Phenotype', 'HP:0100580', (195, 197))	('CCND1', 'Gene', '595', (215, 220))	('CCND1', 'Gene', (93, 98))
275529	21791690	MSR1 p.R293X results in a truncated protein (affecting cytoplasmic topology, the transmembrane and parts of the collagen-like motifs), which still expresses, but variably.	('MSR1', 'Gene', (0, 4))	('cytoplasmic topology', 'MPA', (55, 75))	('truncated', 'MPA', (26, 35))	('p.R293X', 'Var', (5, 12))	('MSR1', 'Gene', '4481', (0, 4))	('p.R293X', 'Mutation', 'rs41341748', (5, 12))	('affecting', 'Reg', (45, 54))
275530	21791690	We observed germline MSR1 mutation, with variably decreased MSR1 protein levels, was associated with overexpression of nuclear CCND1 in BE tissues in MSR1-mutation carriers (but not in control normal epithelium).	('CCND1', 'Gene', '595', (127, 132))	('overexpression', 'PosReg', (101, 115))	('MSR1', 'Gene', '4481', (60, 64))	('mutation', 'Var', (26, 34))	('MSR1', 'Gene', '4481', (21, 25))	('MSR1', 'Gene', '4481', (150, 154))	('BE', 'Phenotype', 'HP:0100580', (136, 138))	('decreased', 'NegReg', (50, 59))	('MSR1', 'Gene', (60, 64))	('CCND1', 'Gene', (127, 132))	('MSR1', 'Gene', (21, 25))	('MSR1', 'Gene', (150, 154))
275533	21791690	It remains to be determined whether increased expression of CCND1 in the setting of germline MSR1 mutation can by itself, or in combination with other oncogenic events, lead to neoplastic transformation in BE.	('mutation', 'Var', (98, 106))	('MSR1', 'Gene', (93, 97))	('BE', 'Phenotype', 'HP:0100580', (206, 208))	('neoplastic transformation', 'CPA', (177, 202))	('CCND1', 'Gene', (60, 65))	('increased', 'PosReg', (36, 45))	('CCND1', 'Gene', '595', (60, 65))	('MSR1', 'Gene', '4481', (93, 97))	('expression', 'MPA', (46, 56))	('lead to', 'Reg', (169, 176))
275534	21791690	We also found that ASCC1 germline p.N290S, affecting a region conserved across species, occurred in 2.1% of BE/EAC cases, but not in ancestral-matched population controls.	('affecting', 'Reg', (43, 52))	('BE', 'Phenotype', 'HP:0100580', (108, 110))	('BE/EAC', 'Gene', '1540', (108, 114))	('BE/EAC', 'Gene', (108, 114))	('ASCC1', 'Gene', '51008', (19, 24))	('p.N290S', 'Var', (34, 41))	('p.N290S', 'Mutation', 'rs146370051', (34, 41))	('ASCC1', 'Gene', (19, 24))	('EAC', 'Phenotype', 'HP:0011459', (111, 114))
275540	21791690	Although this sequence alteration is a rare variant, and this study may not be powered to differentiate between 1 of 89 and 0 of 125, a change from glutamine to proline results in an alteration from a single-branch polar (negative) amino acid to a small hydrophobic cyclic amino acid.	('glutamine', 'Chemical', 'MESH:D005973', (148, 157))	('change', 'Var', (136, 142))	('alteration', 'Reg', (183, 193))	('proline', 'Chemical', 'MESH:D011392', (161, 168))	('cyclic amino acid', 'Chemical', 'MESH:D000598', (266, 283))
275541	21791690	This change is predicted to disrupt the protein's ability to form secondary structure and the helix-loop-helix structure necessary for collagen deposition, fibrosis, and involvement in the WNT and APC pathways.	('ability', 'MPA', (50, 57))	('APC', 'Disease', (197, 200))	('involvement', 'Reg', (170, 181))	('disrupt', 'NegReg', (28, 35))	('men', 'Species', '9606', (177, 180))	('fibrosis', 'Disease', 'MESH:D005355', (156, 164))	('fibrosis', 'Disease', (156, 164))	('helix-loop-helix structure', 'MPA', (94, 120))	('collagen deposition', 'CPA', (135, 154))	('form secondary structure', 'MPA', (61, 85))	('APC', 'Disease', 'MESH:D011125', (197, 200))	('change', 'Var', (5, 11))
275543	21791690	Given its role in collagen matrix deposition and its expression in myofibroblasts, an alteration of CTHRC1 might predispose to decreased lower esophageal sphincter tone and consequent tendency toward GERD and BE.	('CTHRC1', 'Gene', '115908', (100, 106))	('decreased', 'NegReg', (127, 136))	('esophageal sphincter', 'Disease', 'MESH:D009122', (143, 163))	('CTHRC1', 'Gene', (100, 106))	('sphincter tone', 'Phenotype', 'HP:0002839', (154, 168))	('alteration', 'Var', (86, 96))	('GERD', 'Disease', 'MESH:D005764', (200, 204))	('BE', 'Phenotype', 'HP:0100580', (209, 211))	('GERD', 'Disease', (200, 204))	('esophageal sphincter', 'Disease', (143, 163))
275545	21791690	In addition, rather than performing brute-force sequencing of at least 38 genes in just our 9 top priority regions (which would have increased the likelihood of finding "noise"), we used a systems-biology approach of statistically prioritizing regions of interest by integrating multiple platforms to finally come up with 12 top priority genes, which eventually yielded germline mutations in MSR1, ASCC1, and CTHRC1 in patients with BE/EAC but not in population controls.	('BE/EAC', 'Gene', (433, 439))	('CTHRC1', 'Gene', (409, 415))	('MSR1', 'Gene', '4481', (392, 396))	('yielded', 'Reg', (362, 369))	('ASCC1', 'Gene', (398, 403))	('germline', 'Var', (370, 378))	('MSR1', 'Gene', (392, 396))	('EAC', 'Phenotype', 'HP:0011459', (436, 439))	('BE', 'Phenotype', 'HP:0100580', (433, 435))	('patients', 'Species', '9606', (419, 427))	('BE/EAC', 'Gene', '1540', (433, 439))	('CTHRC1', 'Gene', '115908', (409, 415))	('ASCC1', 'Gene', '51008', (398, 403))
275546	21791690	The functional interrogation and immunohistochemistry results support the pathogenicity of these germline MSR1 mutations.	('mutations', 'Var', (111, 120))	('MSR1', 'Gene', (106, 110))	('MSR1', 'Gene', '4481', (106, 110))
275548	21791690	In summary, germline mutations in MSR1, ASCC1, and CTHRC1 in patients with BE/EAC appear physiologically relevant to BE, encoding proteins involved in apoptosis, innate immunity, polarity, and mobility that affect inflammatory and TGFB/WNT signaling pathways.	('ASCC1', 'Gene', (40, 45))	('MSR1', 'Gene', (34, 38))	('TGFB', 'Gene', (231, 235))	('CTHRC1', 'Gene', (51, 57))	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('TGFB', 'Gene', '7040', (231, 235))	('patients', 'Species', '9606', (61, 69))	('affect', 'Reg', (207, 213))	('BE/EAC', 'Gene', '1540', (75, 81))	('MSR1', 'Gene', '4481', (34, 38))	('BE', 'Phenotype', 'HP:0100580', (75, 77))	('ASCC1', 'Gene', '51008', (40, 45))	('encoding', 'Reg', (121, 129))	('BE/EAC', 'Gene', (75, 81))	('germline', 'Var', (12, 20))	('CTHRC1', 'Gene', '115908', (51, 57))	('BE', 'Phenotype', 'HP:0100580', (117, 119))
275610	31238878	Postoperative BW (kg) was not different between the two groups, but the rate of BW decrease, from the preoperative BW, was greater in the BOFJ than Non-BOFJ group over the first month after surgery (Fig.	('BOFJ', 'Var', (138, 142))	('decrease', 'NegReg', (83, 91))	('BOFJ', 'Chemical', '-', (152, 156))	('BOFJ', 'Chemical', '-', (138, 142))
275612	31238878	In the patient's stature, the BOFJ patients had significantly shorter distance between the site of jejunostomy and midline (40 mm versus 48 mm, P = 0.011), and shorter distance between the site of jejunostomy and xiphoid process line (100 mm versus 110 mm, P = 0.051), compared to those in the non-BOFJ group.	('shorter', 'NegReg', (62, 69))	('patient', 'Species', '9606', (7, 14))	('patient', 'Species', '9606', (35, 42))	('BOFJ', 'Chemical', '-', (298, 302))	('shorter', 'NegReg', (160, 167))	('patients', 'Species', '9606', (35, 43))	('BOFJ', 'Chemical', '-', (30, 34))	('BOFJ', 'Var', (30, 34))
275616	31238878	Of note, the rate of postoperative body weight loss was greater in the BOFJ than the Non-BOFJ group.	('BOFJ', 'Chemical', '-', (89, 93))	('weight loss', 'Phenotype', 'HP:0001824', (40, 51))	('weight loss', 'Disease', 'MESH:D015431', (40, 51))	('BOFJ', 'Chemical', '-', (71, 75))	('weight loss', 'Disease', (40, 51))	('BOFJ', 'Var', (71, 75))
275617	31238878	In addition, our study demonstrated that shorter distance between the jejunostomy and midline or xiphoid process line might be a risk of BOFJ.	('midline or xiphoid process', 'Disease', (86, 112))	('BOFJ', 'Disease', (137, 141))	('shorter distance', 'Var', (41, 57))	('midline or xiphoid process', 'Disease', 'MESH:D009436', (86, 112))	('BOFJ', 'Chemical', '-', (137, 141))
275632	31238878	The higher preoperative BMI is likely indicative of fewer symptoms of esophageal cancer, including dysphagia and pain during swallowing, and, thus, patients with a higher preoperative BMI are likely to have maintained a better oral caloric prior to surgery and, thus, to have insufficient oral intake after esophagectomy.	('patients', 'Species', '9606', (148, 156))	('insufficient oral', 'Phenotype', 'HP:0000160', (276, 293))	('esophageal cancer', 'Disease', (70, 87))	('dysphagia', 'Disease', 'MESH:D003680', (99, 108))	('higher', 'Var', (164, 170))	('pain', 'Phenotype', 'HP:0012531', (113, 117))	('better', 'PosReg', (220, 226))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('insufficient oral intake', 'Disease', (276, 300))	('pain', 'Disease', 'MESH:D010146', (113, 117))	('pain', 'Disease', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('dysphagia', 'Disease', (99, 108))	('insufficient oral intake', 'Disease', 'MESH:D000309', (276, 300))	('dysphagia', 'Phenotype', 'HP:0002015', (99, 108))
275654	29905303	Cryotherapy induces cell necrosis for therapeutic purposes through cycles of controlled local freezing and thawing of the tissue.	('necrosis', 'Disease', (25, 33))	('necrosis', 'Disease', 'MESH:D009336', (25, 33))	('Cryotherapy', 'Var', (0, 11))
275711	29905303	The best response to cryotherapy was seen in patients with AVMs and GAVE, with cessation of bleeding in 6 out of 7 patients and 5 out of 7 patients, respectively.	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (139, 147))	('bleeding', 'Disease', 'MESH:D006470', (92, 100))	('bleeding', 'Disease', (92, 100))	('patients', 'Species', '9606', (45, 53))	('AVMs', 'Phenotype', 'HP:0100026', (59, 63))	('AVMs', 'Var', (59, 63))
275733	29905303	As an alternative, endoscopists may consider reporting an unlisted service code, (ie, unlisted procedure, esophagus - 43499; in stomach - 43999; in rectum - 45999; in colon 45399).	('ice', 'Chemical', 'MESH:D007053', (71, 74))	('esophagus - 43499', 'Var', (106, 123))	('colon', 'Disease', (167, 172))
275744	29805899	Transcriptome sequencing has become a powerful method for detecting driver mutations in cancer, since somatic point mutations as well as aberrant RNA variants, such as fusion genes and alternative splicing, can be identified.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('fusion genes', 'Var', (168, 180))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('alternative splicing', 'Var', (185, 205))
275761	27577754	Moreover, by knocking down AFAP1-AS1 expression in ESCC cells, the proliferation and colony-forming ability were inhibited and cell apoptosis was induced.	('AFAP1-AS1', 'Gene', (27, 36))	('knocking down', 'Var', (13, 26))	('inhibited', 'NegReg', (113, 122))	('cell apoptosis', 'CPA', (127, 141))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (27, 36))	('expression', 'MPA', (37, 47))	('induced', 'Reg', (146, 153))
275778	27577754	After verification, two siRNAs were thought to be appropriate for AFAP1-AS1 knockdown (Fig.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (66, 75))	('AFAP1-AS1', 'Gene', (66, 75))	('knockdown', 'Var', (76, 85))
275780	27577754	Cells were seeded at 6-well plates for 24 h and then transfected with designed siRNA (100 nmol/L) and si-NC (100 nmol/L), respectively, by Lipofectamine RNAi MAX in serum-free medium, according to the manufacturer's protocols (Invitrogen, Grand Island, NY, USA).	('100 nmol/L', 'Var', (86, 96))	('si-NC', 'Chemical', 'MESH:C052464', (102, 107))	('100', 'Var', (109, 112))	('Lipofectamine', 'Chemical', 'MESH:C086724', (139, 152))
275790	27577754	Importantly, high expression of AFAP1-AS1 in ESCC was associated with tumor size (P = 0.040) and advanced TNM stage (P = 0.004).	('AFAP1-AS1', 'Gene', '84740;60312;5729', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TNM', 'Gene', '10178', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('high', 'Var', (13, 17))	('tumor', 'Disease', (70, 75))	('TNM', 'Gene', (106, 109))	('AFAP1-AS1', 'Gene', (32, 41))	('associated', 'Reg', (54, 64))
275795	27577754	MTT assay was used to measure cell proliferative activity, which showed that the growth and proliferation of ESCC cells transiently transfected with siRNA1#, and siRNA2# were significantly inhibited compared with negative control groups (Fig.	('siRNA1', 'Gene', (149, 155))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('inhibited', 'NegReg', (189, 198))	('proliferation', 'CPA', (92, 105))	('growth', 'CPA', (81, 87))	('siRNA2#', 'Var', (162, 169))
275796	27577754	Colony formation assay also demonstrated that the clonogenic survival rate of ECA109 and TE1 cells with AFAP1-AS1 knockdown was significantly decreased (Fig.	('AFAP1-AS1', 'Gene', (104, 113))	('knockdown', 'Var', (114, 123))	('decreased', 'NegReg', (142, 151))	('clonogenic survival rate', 'CPA', (50, 74))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (104, 113))
275807	27577754	Previous studies have demonstrated that AFAP1-AS1 was dysregulated in a variety of cancers and associated with tumor progression, including EAC 6, hepatocellular carcinoma (HCC) 19, colorectal cancer 20, pancreatic ductal adenocarcinoma 21, lung cancer 22, and nasopharyngeal carcinoma 23.	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('pancreatic ductal adenocarcinoma', 'Disease', (204, 236))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (241, 252))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('associated', 'Reg', (95, 105))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (147, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('nasopharyngeal carcinoma', 'Disease', (261, 285))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (204, 236))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (147, 171))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (261, 285))	('lung cancer', 'Disease', (241, 252))	('colorectal cancer', 'Disease', (182, 199))	('tumor', 'Disease', (111, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('hepatocellular carcinoma', 'Disease', (147, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('EAC 6', 'Disease', (140, 145))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (204, 236))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (261, 285))	('dysregulated', 'Var', (54, 66))	('AFAP1-AS1', 'Gene', (40, 49))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('lung cancer', 'Disease', 'MESH:D008175', (241, 252))	('cancers', 'Disease', (83, 90))
275814	27577754	The results showed that there was a significant relationship between high AFAP1-AS1 expression and tumor size, as well as advanced TNM stage.	('tumor', 'Disease', (99, 104))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (74, 83))	('AFAP1-AS1', 'Gene', (74, 83))	('TNM', 'Gene', '10178', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('high', 'Var', (69, 73))	('expression', 'MPA', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('TNM', 'Gene', (131, 134))
275817	27577754	It was previously reported in human non-small-cell lung cancer that AFAP1-AS1 can affect cell proliferation partly through epigenetically regulating the expression of homeobox B7 (HOXB7).	('human', 'Species', '9606', (30, 35))	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('HOXB7', 'Gene', '3217', (180, 185))	('AFAP1-AS1', 'Gene', (68, 77))	('cell proliferation', 'CPA', (89, 107))	('homeobox B7', 'Gene', (167, 178))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('HOXB7', 'Gene', (180, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('homeobox B7', 'Gene', '3217', (167, 178))	('expression', 'MPA', (153, 163))	('epigenetically regulating', 'Var', (123, 148))	('affect', 'Reg', (82, 88))
275831	27818681	miR-219-1 rs107822G > A polymorphism might significantly decrease ESCC risk through changing individual susceptibility to Chinese Kazakhs.	('decrease', 'NegReg', (57, 65))	('miR-219-1', 'Gene', (0, 9))	('changing', 'Reg', (84, 92))	('miR-219-1', 'Gene', '407002', (0, 9))	('decrease ESCC', 'Phenotype', 'HP:0025022', (57, 70))	('ESCC', 'Disease', (66, 70))	('rs107822G > A', 'DBSNP_MENTION', 'None', (10, 23))	('rs107822G > A', 'Var', (10, 23))
275834	27818681	DACT2 is frequently methylated in human esophageal cancer; methylated DATC2 accelerates esophageal cancer development by activating Wnt signaling.	('Wnt', 'Gene', (132, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('human', 'Species', '9606', (34, 39))	('DACT2', 'Gene', '168002', (0, 5))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('activating', 'PosReg', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('methylated', 'Var', (59, 69))	('Wnt', 'Gene', '80326', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('accelerates', 'PosReg', (76, 87))	('DACT2', 'Gene', (0, 5))	('esophageal cancer', 'Disease', (88, 105))	('DATC2', 'Gene', (70, 75))	('esophageal cancer', 'Disease', (40, 57))
275835	27818681	RUNX3 methylation is associated with an increased risk, progression, and poor survival in EC.	('methylation', 'Var', (6, 17))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))	('EC', 'Phenotype', 'HP:0011459', (90, 92))
275837	27818681	Total of 5 mRNA expression datasets of EC tissues/cell lines comprising GSE53625, GSE33810, GSE17351, GSE9982, and GSE12737 were included in our study.	('GSE9982', 'Chemical', '-', (102, 109))	('EC', 'Phenotype', 'HP:0011459', (39, 41))	('GSE17351', 'Var', (92, 100))	('GSE33810', 'Var', (82, 90))	('GSE12737', 'Var', (115, 123))	('GSE53625', 'Var', (72, 80))
275841	27818681	The pathways enriched by 919 upregulated DEGs were mainly related to cell cycle, RNA transport, and p53 signaling pathway (Table 5).	('upregulated', 'PosReg', (29, 40))	('cell cycle', 'CPA', (69, 79))	('RNA', 'MPA', (81, 84))	('p53', 'Gene', '7157', (100, 103))	('DEGs', 'Var', (41, 45))	('p53', 'Gene', (100, 103))
275854	27818681	The methylated status of THSD4 shows positive correlation with short survival in glioblastoma patients and hypermethylation of THSD4 indicates poor survival.	('glioblastoma', 'Disease', (81, 93))	('THSD4', 'Gene', (127, 132))	('hypermethylation', 'Var', (107, 123))	('glioblastoma', 'Disease', 'MESH:D005909', (81, 93))	('methylated status', 'Var', (4, 21))	('THSD4', 'Gene', (25, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))
275872	27559738	Overexpression of the hepatocyte growth factor receptor (CMET) has also been correlated with poor prognosis in esophageal adenocarcinoma, and inhibition of CMET-dependent signaling regulates the activity of HER1 and HER3.	('esophageal adenocarcinoma', 'Disease', (111, 136))	('receptor (CMET', 'Gene', (47, 61))	('CMET', 'Gene', '4233', (156, 160))	('HER1', 'Gene', (207, 211))	('HER3', 'Gene', '2065', (216, 220))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (111, 136))	('CMET', 'Gene', (156, 160))	('CMET', 'Gene', '4233', (57, 61))	('regulates', 'Reg', (181, 190))	('CMET', 'Gene', (57, 61))	('HER1', 'Gene', '1956', (207, 211))	('receptor (CMET)', 'Gene', '4233', (47, 62))	('inhibition', 'Var', (142, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (111, 136))	('HER3', 'Gene', (216, 220))	('activity', 'MPA', (195, 203))
275888	27559738	A total of 73 patients with Barrett's esophagus with low-grade dysplasia (n = 32) or high-grade dysplasia (n = 59) were identified.	('dysplasia', 'Disease', (96, 105))	('low-grade dysplasia', 'Disease', 'MESH:D008228', (53, 72))	('dysplasia', 'Disease', 'MESH:D004476', (96, 105))	('dysplasia', 'Disease', 'MESH:D004476', (63, 72))	('low-grade dysplasia', 'Disease', (53, 72))	('high-grade', 'Var', (85, 95))	("Barrett's esophagus", 'Disease', (28, 47))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (28, 47))	('patients', 'Species', '9606', (14, 22))	('dysplasia', 'Disease', (63, 72))
275948	24584782	Effects of MG132 on the enhancment of the anticancer functions of cisplatin were then investigated in human esophageal cancer EC9706 cells in relation to apoptosis and cell signaling events.	('EC9706', 'CellLine', 'CVCL:E307', (126, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('MG132', 'Var', (11, 16))	('cancer', 'Disease', (46, 52))	('MG132', 'Chemical', 'MESH:C072553', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('esophageal cancer', 'Disease', (108, 125))	('cancer', 'Disease', (119, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('enhancment', 'PosReg', (24, 34))	('human', 'Species', '9606', (102, 107))
275949	24584782	Exposure of cells to MG132 resulted in a marked decrease in cell viability in a dose- and time-dependent manner.	('cell viability', 'CPA', (60, 74))	('MG132', 'Var', (21, 26))	('decrease', 'NegReg', (48, 56))	('MG132', 'Chemical', 'MESH:C072553', (21, 26))
275951	24584782	MG132 significantly enhanced cisplatin-induced apoptosis in association with the activation of caspase-3 and -8.	('MG132', 'Var', (0, 5))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('enhanced', 'PosReg', (20, 28))	('cisplatin-induced', 'MPA', (29, 46))	('activation', 'PosReg', (81, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('caspase-3 and -8', 'Gene', '836;841', (95, 111))
275953	24584782	Taken together, these findings demonstrate a novel mechanism by which proteasome inhibitor MG132 potentiates cisplatin-induced apoptosis in human ESCC and inhibitory activity of tumor growth of the EC9706 xenograft model.	('tumor', 'Disease', (178, 183))	('human', 'Species', '9606', (140, 145))	('potentiates', 'PosReg', (97, 108))	('inhibitory activity', 'MPA', (155, 174))	('MG132', 'Chemical', 'MESH:C072553', (91, 96))	('EC9706', 'CellLine', 'CVCL:E307', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('ESCC', 'Disease', (146, 150))	('cisplatin-induced apoptosis', 'MPA', (109, 136))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('MG132', 'Var', (91, 96))
275959	24584782	MG132, which acts as a blocker in ubiquitin-proteasome pathway, is involved in >80% of intracellular protein degradation.	('MG132', 'Var', (0, 5))	('involved', 'Reg', (67, 75))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('ubiquitin', 'Gene', '850620', (34, 43))	('intracellular protein degradation', 'MPA', (87, 120))	('ubiquitin', 'Gene', (34, 43))
275962	24584782	Findings of previous studies have indicated that MG132 enhances cisplatin-induced apoptosis in various types of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('MG132', 'Var', (49, 54))	('MG132', 'Chemical', 'MESH:C072553', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cisplatin-induced', 'MPA', (64, 81))	('tumor', 'Disease', (112, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('enhances', 'PosReg', (55, 63))
275980	24584782	A time-course study of cells exposed to MG132 revealed a significant increase in cell viability as early as 24 h, and reached near-maximal levels after 60 h (Fig.	('MG132', 'Chemical', 'MESH:C072553', (40, 45))	('increase', 'PosReg', (69, 77))	('MG132', 'Var', (40, 45))	('cell viability', 'CPA', (81, 95))
275982	24584782	2, treatment with MG132 resulted in a marked decrease in cell viability in the four cell lines.	('cell viability in the', 'CPA', (57, 78))	('MG132', 'Var', (18, 23))	('decrease', 'NegReg', (45, 53))	('MG132', 'Chemical', 'MESH:C072553', (18, 23))
275985	24584782	3a, treatment with MG132 resulted in a modest, but significant suppression of tumor growth 10 days following drug exposure (P<0.05 vs. vehicle control).	('suppression', 'NegReg', (63, 74))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MG132', 'Chemical', 'MESH:C072553', (19, 24))	('tumor', 'Disease', (78, 83))	('MG132', 'Var', (19, 24))
275988	24584782	Moreover, the mice of MG132 group did not exhibit any other signs of toxicity such as agitation, impaired movement, posture, indigestion, diarrhea or areas of redness.	('agitation', 'Disease', 'MESH:D011595', (86, 95))	('agitation', 'Phenotype', 'HP:0000713', (86, 95))	('agitation', 'Disease', (86, 95))	('mice', 'Species', '10090', (14, 18))	('diarrhea', 'Phenotype', 'HP:0002014', (138, 146))	('impaired movement', 'Phenotype', 'HP:0100022', (97, 114))	('toxicity', 'Disease', 'MESH:D064420', (69, 77))	('impaired movement', 'Disease', 'MESH:D009069', (97, 114))	('toxicity', 'Disease', (69, 77))	('diarrhea', 'Disease', (138, 146))	('diarrhea', 'Disease', 'MESH:D003967', (138, 146))	('indigestion', 'Phenotype', 'HP:0410281', (125, 136))	('MG132', 'Var', (22, 27))	('MG132', 'Chemical', 'MESH:C072553', (22, 27))	('impaired movement', 'Disease', (97, 114))
275989	24584782	These results indicated that MG132 administration significantly inhibited tumor growth of the EC9706 xenograft without causing toxicity to the mice.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('toxicity', 'Disease', 'MESH:D064420', (127, 135))	('toxicity', 'Disease', (127, 135))	('inhibited', 'NegReg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('EC9706', 'CellLine', 'CVCL:E307', (94, 100))	('tumor', 'Disease', (74, 79))	('MG132', 'Var', (29, 34))	('MG132', 'Chemical', 'MESH:C072553', (29, 34))	('mice', 'Species', '10090', (143, 147))
275995	24584782	Addition of 5 muM MG132 for 24 h resulted in a marked decrease in cell viability in the combined group as compared with the individual agents (P<0.01) (Fig.	('decrease', 'NegReg', (54, 62))	('muM', 'Gene', '56925', (14, 17))	('MG132', 'Chemical', 'MESH:C072553', (18, 23))	('cell viability', 'CPA', (66, 80))	('MG132', 'Var', (18, 23))	('muM', 'Gene', (14, 17))
276001	24584782	The addition of MG132, increased the cisplatin-induced apoptosis rate from 23 to 68%.	('cisplatin-induced', 'MPA', (37, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('increased', 'PosReg', (23, 32))	('MG132', 'Var', (16, 21))	('MG132', 'Chemical', 'MESH:C072553', (16, 21))
276004	24584782	Annexin V-FITC+ cells were rarely observed in the control group, while many positive cells were visible in the MG132 group, DDP group and, particularly the DDP + MG132 group (Fig.	('Annexin V', 'Gene', '308', (0, 9))	('DDP', 'Gene', '1678', (124, 127))	('Annexin V', 'Gene', (0, 9))	('DDP', 'Gene', '1678', (156, 159))	('MG132', 'Chemical', 'MESH:C072553', (162, 167))	('MG132', 'Var', (111, 116))	('MG132', 'Chemical', 'MESH:C072553', (111, 116))	('DDP', 'Gene', (124, 127))	('DDP', 'Gene', (156, 159))
276005	24584782	The results obtained suggested that MG132 is able to enhance cisplatin-induced apoptosis in esophageal cancer cells.	('MG132', 'Chemical', 'MESH:C072553', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('esophageal cancer', 'Disease', (92, 109))	('enhance', 'PosReg', (53, 60))	('cisplatin-induced', 'MPA', (61, 78))	('MG132', 'Var', (36, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
276009	24584782	Conversely, MG132 partially counteracted the upregulation of NF-kappaB in the combined group compared with the DDP group (P<0.01).	('DDP', 'Gene', '1678', (111, 114))	('NF-kappaB', 'Gene', (61, 70))	('DDP', 'Gene', (111, 114))	('MG132', 'Var', (12, 17))	('upregulation', 'PosReg', (45, 57))	('MG132', 'Chemical', 'MESH:C072553', (12, 17))	('NF-kappaB', 'Gene', '4790', (61, 70))
276012	24584782	In the present study, we have shown that MG132 suppressed the growth of esophageal cancer cells in culture as well as in the animal model.	('suppressed', 'NegReg', (47, 57))	('growth', 'CPA', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MG132', 'Var', (41, 46))	('esophageal cancer', 'Disease', (72, 89))	('MG132', 'Chemical', 'MESH:C072553', (41, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))
276013	24584782	The experimental results in vitro demonstrated that MG132 inhibited the proliferation in EC9706 cells in a dose- and time-dependent manner, with the concentration increasing from 0 to 10 muM and the survival rate decreasing from 100 to 18.43% after 36 h (Fig.	('survival rate', 'CPA', (199, 212))	('EC9706', 'CellLine', 'CVCL:E307', (89, 95))	('proliferation', 'CPA', (72, 85))	('MG132', 'Var', (52, 57))	('muM', 'Gene', '56925', (187, 190))	('MG132', 'Chemical', 'MESH:C072553', (52, 57))	('decreasing', 'NegReg', (213, 223))	('inhibited', 'NegReg', (58, 67))	('muM', 'Gene', (187, 190))
276014	24584782	MG132 also markedly induced cell death in multiple human esophageal cancer cell types, including EC9706, EC109, EC1 and TE-1 cell lines.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('MG132', 'Var', (0, 5))	('TE-1', 'CellLine', 'CVCL:1759', (120, 124))	('EC1', 'Gene', '4819', (112, 115))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cell death', 'CPA', (28, 38))	('human', 'Species', '9606', (51, 56))	('esophageal cancer', 'Disease', (57, 74))	('induced', 'Reg', (20, 27))	('EC1', 'Gene', (105, 108))	('EC9706', 'CellLine', 'CVCL:E307', (97, 103))	('EC1', 'Gene', (112, 115))	('EC1', 'Gene', '4819', (105, 108))
276015	24584782	The results from in vivo studies about xenograft model showed that MG132 exhibited significant inhibitory effects on the growth of esophageal cancer xenograft.	('growth', 'CPA', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('esophageal cancer', 'Disease', (131, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('MG132', 'Var', (67, 72))	('inhibitory effects', 'NegReg', (95, 113))	('MG132', 'Chemical', 'MESH:C072553', (67, 72))
276016	24584782	In order to justify whether or not the application of MG132 could improve the sensitivity to chemotherapy drugs in esophageal cancer cells, the cells were divided into the blank control, 100 mug/ml DDP, 5 muM MG132, 100 mug/ml DDP and 5 muM MG132 groups.	('muM', 'Gene', '56925', (237, 240))	('MG132', 'Chemical', 'MESH:C072553', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('DDP', 'Gene', (198, 201))	('DDP', 'Gene', '1678', (227, 230))	('MG132', 'Chemical', 'MESH:C072553', (209, 214))	('MG132', 'Chemical', 'MESH:C072553', (241, 246))	('muM', 'Gene', (237, 240))	('sensitivity to chemotherapy drugs', 'MPA', (78, 111))	('improve', 'PosReg', (66, 73))	('esophageal cancer', 'Disease', (115, 132))	('muM', 'Gene', '56925', (205, 208))	('DDP', 'Gene', (227, 230))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('DDP', 'Gene', '1678', (198, 201))	('muM', 'Gene', (205, 208))	('MG132', 'Var', (54, 59))
276025	24584782	To identify the mechanism by which proteasome inhibitor MG132 potentiates cisplatin-induced apoptosis in human esophageal squamous cancer cells, we investigated changes of the expression levels of caspase-8, -3 and NF-kappaB after treatment with DDP and MG132 individually or in combination.	('NF-kappaB', 'Gene', '4790', (215, 224))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (111, 137))	('esophageal squamous cancer', 'Disease', (111, 137))	('MG132', 'Chemical', 'MESH:C072553', (254, 259))	('caspase-8, -3', 'Gene', '841;836', (197, 210))	('DDP', 'Gene', '1678', (246, 249))	('MG132', 'Chemical', 'MESH:C072553', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('NF-kappaB', 'Gene', (215, 224))	('cisplatin-induced', 'MPA', (74, 91))	('MG132', 'Var', (56, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('squamous cancer', 'Phenotype', 'HP:0002860', (122, 137))	('DDP', 'Gene', (246, 249))	('human', 'Species', '9606', (105, 110))	('potentiates', 'PosReg', (62, 73))
276026	24584782	The results of our study suggest that MG132 significantly enhanced cisplatin-induced apoptosis in association with the activation of caspase-3 and -8.	('MG132', 'Var', (38, 43))	('MG132', 'Chemical', 'MESH:C072553', (38, 43))	('enhanced', 'PosReg', (58, 66))	('cisplatin-induced', 'MPA', (67, 84))	('activation', 'PosReg', (119, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('caspase-3 and -8', 'Gene', '836;841', (133, 149))
276029	24584782	MG132 can significantly enhance the sensitivity of esophageal cancer cells to cisplatin and effectively improve the rate of cell apoptosis by inhibiting the activation of NF-kappaB, potentiating the expression levels of apoptosis-related protein caspase-8 and -3.	('expression levels', 'MPA', (199, 216))	('MG132', 'Var', (0, 5))	('NF-kappaB', 'Gene', '4790', (171, 180))	('apoptosis-related', 'MPA', (220, 237))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('caspase-8 and -3', 'Gene', '841;836', (246, 262))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('activation', 'MPA', (157, 167))	('esophageal cancer', 'Disease', (51, 68))	('enhance', 'PosReg', (24, 31))	('NF-kappaB', 'Gene', (171, 180))	('improve', 'PosReg', (104, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('potentiating', 'PosReg', (182, 194))	('sensitivity', 'MPA', (36, 47))	('cell apoptosis', 'CPA', (124, 138))	('inhibiting', 'NegReg', (142, 152))
276030	24584782	In summary, these findings indicate that proteasome inhibitor MG132 may promote cisplatin-induced apoptosis by inhibiting the activation of NF-kappaB and upregulating the expression levels of caspase-3 and -8.	('activation', 'MPA', (126, 136))	('cisplatin-induced apoptosis', 'CPA', (80, 107))	('upregulating', 'PosReg', (154, 166))	('NF-kappaB', 'Gene', '4790', (140, 149))	('MG132', 'Var', (62, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('MG132', 'Chemical', 'MESH:C072553', (62, 67))	('NF-kappaB', 'Gene', (140, 149))	('promote', 'PosReg', (72, 79))	('inhibiting', 'NegReg', (111, 121))	('caspase-3 and -8', 'Gene', '836;841', (192, 208))	('expression levels', 'MPA', (171, 188))
276031	24584782	MG132 may be used alone or in combination with other therapeutic agents to treat ESCC.	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('MG132', 'Var', (0, 5))	('ESCC', 'Disease', (81, 85))
276046	21498395	In this manuscript, we will explore an overarching evolutionary theory of the development of Barrett's esophagus and its progression to esophageal adenocarcinoma that incorporates inherited changes in the constitutive genome and clonal somatic genomic instability in Barrett's epithelium that predispose to esophageal adenocarcinoma.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (93, 112))	('changes', 'Var', (190, 197))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (307, 332))	('predispose', 'Reg', (293, 303))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (136, 161))	('esophageal adenocarcinoma', 'Disease', (136, 161))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (136, 161))	('esophageal adenocarcinoma', 'Disease', (307, 332))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (307, 332))
276057	21498395	In 1976, Nowell described another level of evolution when he hypothesized that "Acquired genetic lability permits stepwise selection of variant sublines and underlies tumor progression".	('underlies', 'Reg', (157, 166))	('variant', 'Var', (136, 143))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
276061	21498395	Most esophageal adenocarcinomas, on the order of 90-95%, arise in association with chromosome instability that leads to gains, losses or loss of heterozygosity (LOH) of large regions of chromosomes.	('chromosome', 'Var', (83, 93))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (5, 31))	('arise', 'Reg', (57, 62))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (5, 30))	('chromosome instability', 'Phenotype', 'HP:0040012', (83, 105))	('gains', 'PosReg', (120, 125))	('association', 'Reg', (66, 77))	('loss of', 'NegReg', (137, 144))	('esophageal adenocarcinomas', 'Disease', (5, 31))	('losses', 'NegReg', (127, 133))
276064	21498395	9p and 17p LOH, CDKN2A mutations and methylation and TP53 mutations have been found to be highly associated with clonal expansions, suggesting that these alterations provide a selective advantage to a Barrett's clone.	('mutations', 'Var', (58, 67))	('methylation', 'Var', (37, 48))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('mutations', 'Var', (23, 32))	('TP53', 'Gene', '7157', (53, 57))	('clonal expansions', 'CPA', (113, 130))	('associated', 'Reg', (97, 107))	('TP53', 'Gene', (53, 57))
276065	21498395	However, 9q LOH and 17q LOH as well as microsatellite shifts behave as neutral genetic abnormalities.	('genetic abnormalities', 'Disease', (79, 100))	('genetic abnormalities', 'Disease', 'MESH:D030342', (79, 100))	('microsatellite shifts', 'Var', (39, 60))
276067	21498395	This result supports the hypothesis that expansion of a genetically unstable clone increases risk of progression to esophageal adenocarcinoma.	('expansion', 'Var', (41, 50))	('esophageal adenocarcinoma', 'Disease', (116, 141))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (116, 141))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (116, 141))
276068	21498395	One prediction of this hypothesis is that the genetically unstable clone produces viable variants during an expansion that increase the probability of evolving to cancer.	('variants', 'Var', (89, 97))	('evolving', 'Disease', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
276079	21498395	The second manuscript reported that biopsies of individuals with Barrett's esophagus who had flow cytometric DNA content abnormalities (tetraploidy or aneuploidy), including some who progressed to esophageal adenocarcinoma, had reduced mucous content as well striking ultrastructural abnormalities that included distended rough endoplasmic reticulum, increased cytoplasmic glycogen aggregates, small or dysmorphic Golgi apparatus, atypical mucous granules and a "simplified cytoplasm" with fewer organelles and mucous granules.	('dysmorphic', 'Disease', 'None', (403, 413))	('abnormalities', 'Var', (121, 134))	('cytoplasmic glycogen aggregates', 'CPA', (361, 392))	('increased', 'PosReg', (351, 360))	('tetraploidy or aneuploidy', 'Disease', 'MESH:D057891', (136, 161))	('mucous', 'MPA', (236, 242))	('tetraploidy or aneuploidy', 'Disease', (136, 161))	('esophageal adenocarcinoma', 'Disease', (197, 222))	('increased cytoplasmic glycogen', 'Phenotype', 'HP:0030232', (351, 381))	('reduced', 'NegReg', (228, 235))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (197, 222))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (197, 222))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (65, 84))	('dysmorphic', 'Disease', (403, 413))	('progressed', 'PosReg', (183, 193))	('glycogen', 'Chemical', 'MESH:D006003', (373, 381))	('atypical mucous granules', 'CPA', (431, 455))
276080	21498395	Currently available data are not sufficient to determine whether genomic instability develops as a consequence of loss of the barrier function with genotoxic injury to stem cells at the base of the crypts, whether chromosome instability leads to disruption of the barrier function of Barrett's metaplasia, whether they are independent of each other or whether both interact in a vicious cycle that leads to selfish cell proliferation and evolution to esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (451, 476))	('chromosome instability', 'Phenotype', 'HP:0040012', (214, 236))	('esophageal adenocarcinoma', 'Disease', (451, 476))	('selfish cell proliferation', 'CPA', (407, 433))	('chromosome', 'Var', (214, 224))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (451, 476))	('genotoxic injury', 'Disease', (148, 164))	('genotoxic injury', 'Disease', 'MESH:D058186', (148, 164))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (284, 304))	('barrier', 'MPA', (264, 271))	("Barrett's metaplasia", 'Disease', (284, 304))
276085	21498395	A ten year prospective cohort study reported that a panel of 9p LOH, 17p LOH and DNA content abnormalities (tetraploidy and/or aneuploidy) was a strong predictor of progression from Barrett's esophagus to esophageal adenocarcinoma (relative risk = 38.7; 95% CI = 10.8-138.5; p<0.001).	('abnormalities', 'Var', (93, 106))	('tetraploidy', 'Disease', (108, 119))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (205, 230))	('aneuploidy', 'Disease', 'MESH:D000782', (127, 137))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (182, 201))	("Barrett's esophagus to esophageal adenocarcinoma", 'Disease', (182, 230))	("Barrett's esophagus to esophageal adenocarcinoma", 'Disease', 'MESH:D001471', (182, 230))	('aneuploidy', 'Disease', (127, 137))	('tetraploidy', 'Disease', 'MESH:D057891', (108, 119))
276086	21498395	Individuals with all three manifestations of chromosome instability at baseline had a 79.1% five-year cumulative incidence of cancer compared to a zero percent cumulative incidence of cancer to nearly eight years in individuals who had none of the markers.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('chromosome instability', 'Phenotype', 'HP:0040012', (45, 67))	('chromosome instability', 'Var', (45, 67))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
276087	21498395	Single nucleotide polymorphism (SNP) arrays provide flexible platforms for a variety of approaches to investigate cancer, including GWAS, customized platforms to assess specific regions of the genome and a uniform platform for genome-wide assessment of somatic LOH, copy change and aneuploidy.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('aneuploidy', 'Disease', (282, 292))	('aneuploidy', 'Disease', 'MESH:D000782', (282, 292))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('copy change', 'Var', (266, 277))	('cancer', 'Disease', (114, 120))
276093	21498395	This can be the prototype for large, well designed studies using a uniform platform to determine the extent to which chromosome instability, clonal expansions, and clonal diversity predict progression to esophageal adenocarcinoma as well as identifying benign subsets of individuals who require no clinical intervention because of their low risk.	('predict', 'Reg', (181, 188))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (204, 229))	('esophageal adenocarcinoma', 'Disease', (204, 229))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (204, 229))	('chromosome instability', 'Phenotype', 'HP:0040012', (117, 139))	('clonal expansions', 'Var', (141, 158))	('chromosome instability', 'Var', (117, 139))
276094	21498395	While genomic biomarkers characterize somatic alterations at snapshots of time during patient evaluation, clonal evolutionary biomarkers have the potential to summarize changes of genomic state temporally that may be widely applicable to a broad range of neoplasms because genomic instability, selection of variants, and clonal expansions are believed to occur during progression in most, if not all, cancers.	('neoplasms', 'Disease', 'MESH:D009369', (255, 264))	('neoplasms', 'Disease', (255, 264))	('variants', 'Var', (307, 315))	('cancers', 'Phenotype', 'HP:0002664', (401, 408))	('patient', 'Species', '9606', (86, 93))	('cancers', 'Disease', (401, 408))	('cancers', 'Disease', 'MESH:D009369', (401, 408))	('cancer', 'Phenotype', 'HP:0002664', (401, 407))	('neoplasms', 'Phenotype', 'HP:0002664', (255, 264))
276104	21498395	Advances in esophageal genomics, and detection of individuals with inherited mutations placing them at risk for esophageal adenocarcinoma will inform increasingly sophisticated risk models to improve identification of patients at risk for esophageal adenocarcinoma, provide opportunity for advances in prevention and guide selection of interventions appropriate to risk.	('patients', 'Species', '9606', (218, 226))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (239, 264))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (112, 137))	('esophageal adenocarcinoma', 'Disease', (239, 264))	('esophageal adenocarcinoma', 'Disease', (112, 137))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (239, 264))	('mutations', 'Var', (77, 86))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (112, 137))
276105	19147583	Unlike Esophageal Squamous Cells, Barrett's Epithelial Cells Resist Apoptosis by Activating the Nuclear Factor-kappaB Pathway Apoptosis is an important mechanism for maintaining tissue homeostasis and for preventing the proliferation of cells with mutations that could result in malignancy.	('proliferation', 'CPA', (220, 233))	('rat', 'Species', '10116', (227, 230))	('mutations', 'Var', (248, 257))	('malignancy', 'Disease', 'MESH:D009369', (279, 289))	('Nuclear Factor-kappaB', 'Gene', '4790', (96, 117))	('preventing', 'NegReg', (205, 215))	('malignancy', 'Disease', (279, 289))	('Activating', 'PosReg', (81, 91))	('Nuclear Factor-kappaB', 'Gene', (96, 117))
276116	19147583	This condition is called Barrett's esophagus and, for reasons that are not clear, metaplastic Barrett's epithelium is predisposed to develop neoplasia.	('metaplastic', 'Var', (82, 93))	('Barrett', 'Disease', (25, 32))	('neoplasia', 'Phenotype', 'HP:0002664', (141, 150))	('neoplasia', 'Disease', 'MESH:D009369', (141, 150))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (25, 44))	('neoplasia', 'Disease', (141, 150))
276118	19147583	Apoptosis is an important mechanism for maintaining tissue homeostasis and for preventing the proliferation of cells with mutations that could result in malignancy.	('rat', 'Species', '10116', (101, 104))	('malignancy', 'Disease', 'MESH:D009369', (153, 163))	('proliferation', 'CPA', (94, 107))	('mutations', 'Var', (122, 131))	('malignancy', 'Disease', (153, 163))	('preventing', 'NegReg', (79, 89))
276121	19147583	Failure to undergo apoptosis in the setting of severe DNA injury allows dangerous mutations to persist and contribute to cancer formation.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('injury', 'Disease', (58, 64))	('mutations', 'Var', (82, 91))	('injury', 'Disease', 'MESH:D058186', (58, 64))	('contribute', 'Reg', (107, 117))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
276126	19147583	For example, chronic gastritis due to Helicobacter pylori results in intestinal metaplasia, which is far less susceptible to H. pylori infection than the normal gastric epithelium.	('Helicobacter pylori', 'Species', '210', (38, 57))	('gastritis due to Helicobacter pylori', 'Phenotype', 'HP:0005202', (21, 57))	('intestinal metaplasia', 'Disease', (69, 90))	('gastritis', 'Phenotype', 'HP:0005263', (21, 30))	('chronic gastritis', 'Disease', (13, 30))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (69, 90))	('H. pylori', 'Species', '210', (125, 134))	('results in', 'Reg', (58, 68))	('infection', 'Disease', (135, 144))	('H. pylori infection', 'Phenotype', 'HP:0005202', (125, 144))	('infection', 'Disease', 'MESH:D007239', (135, 144))	('Helicobacter pylori', 'Var', (38, 57))	('chronic gastritis', 'Phenotype', 'HP:0005231', (13, 30))	('chronic gastritis', 'Disease', 'MESH:D005756', (13, 30))
276129	19147583	Clinical data suggest that alterations in the susceptibility to apoptosis underlie the neoplastic progression of Barrett's esophagus.	("Barrett's esophagus", 'Disease', (113, 132))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (113, 132))	('underlie', 'Reg', (74, 82))	('susceptibility', 'MPA', (46, 60))	('rat', 'Species', '10116', (31, 34))	('alterations', 'Var', (27, 38))
276137	19147583	We used two telomerase-immortalized, esophageal squamous cell lines created from endoscopic biopsy specimens of normal esophageal squamous mucosa taken from the distal esophagus of patients who had GERD with (NES-B3T) and without (NES-G2T) Barrett's esophagus.	('esophageal squamous mucosa', 'Disease', (119, 145))	('G2T', 'Mutation', 'rs764211596', (235, 238))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (240, 259))	('patients', 'Species', '9606', (181, 189))	('esophageal squamous mucosa', 'Disease', 'MESH:D000077277', (119, 145))	('NES-B3T', 'Var', (209, 216))	('GERD', 'Disease', (198, 202))	('GERD', 'Disease', 'MESH:D005764', (198, 202))
276151	19147583	Bay11-7085 (Sigma), is a pharmacologic inhibitor which blocks IkappaBalpha phosphorylation.	('IkappaBalpha', 'Gene', (62, 74))	('Bay11-7085', 'Chemical', 'MESH:C416282', (0, 10))	('Bay11-7085', 'Var', (0, 10))	('blocks', 'NegReg', (55, 61))	('IkappaBalpha', 'Gene', '4792', (62, 74))
276163	19147583	Similar to the BAR-T cells, the level of apoptosis induced induced by just 100 J/m2 in our NES cell lines (NES-G2T 57.8 +- 2.5%; NES-B3T 59.5 +- .50%) was significantly higher than that induced by 400 J/m2 in the BAR-T cell lines (BAR-T9 38.3 +- .30 % SEM; BAR-T10 39.4 +- .21 % SEM; p<0.05 for BAR-T9 and BAR-T10) cells.	('G2T', 'Mutation', 'rs764211596', (111, 114))	('higher', 'PosReg', (169, 175))	('J/m2', 'Var', (79, 83))	('apoptosis', 'MPA', (41, 50))
276171	19147583	These data suggest that the NF-kappaB pathway is activated by low dose UV-B irradiation in BAR-T, but not in NES cells.	('NF-kappaB', 'Gene', (28, 37))	('UV-B irradiation', 'Var', (71, 87))	('activated', 'PosReg', (49, 58))	('NF-kappaB', 'Gene', '4790', (28, 37))
276176	19147583	In BAR-T cells, the resistance to apoptosis in response to low dose UV-B irradiation was abolished by treatment with Bay 11-7085 in a dose-dependent fashion; Bay 11-7085 also induced a dose-dependent increase in the rates of apoptosis following 200 and 400 J/m2 of UV-B, with the maximal rate of apoptosis found to plateau with 5 muM of Bay 11-7085 (Figure 5A).	('muM', 'Gene', '56925', (330, 333))	('apoptosis', 'CPA', (225, 234))	('Bay 11-7085', 'Chemical', 'MESH:C416282', (158, 169))	('increase', 'PosReg', (200, 208))	('Bay 11-7085', 'Var', (158, 169))	('rat', 'Species', '10116', (288, 291))	('muM', 'Gene', (330, 333))	('Bay 11-7085', 'Chemical', 'MESH:C416282', (117, 128))	('Bay 11-7085', 'Chemical', 'MESH:C416282', (337, 348))	('rat', 'Species', '10116', (216, 219))
276181	19147583	In contrast, low-dose UV-B irradiation did not cause apoptosis in control cells that were transfected with a siRNA targeted against lamin A/C, suggesting that the apoptosis induced by low dose UV-B was indeed due to inhibition of NF-kappaB and not due to a non-specific effect of the siRNA (Figure 5B).	('apoptosis', 'CPA', (163, 172))	('UV-B', 'Var', (193, 197))	('NF-kappaB', 'Gene', '4790', (230, 239))	('lamin A/C', 'Gene', (132, 141))	('NF-kappaB', 'Gene', (230, 239))	('lamin A/C', 'Gene', '4000', (132, 141))	('inhibition', 'NegReg', (216, 226))
276185	19147583	We noted complete loss of Bcl-2 expression following transfection with the siRNA both at baseline and following UV-B irradiation (Figure 6A).	('loss', 'NegReg', (18, 22))	('transfection', 'Var', (53, 65))	('Bcl-2', 'Gene', (26, 31))	('Bcl-2', 'Gene', '596', (26, 31))	('expression', 'MPA', (32, 42))
276225	33320959	2  Established and strongly suggested risk factors for ESCC (in any setting) include tobacco, alcohol, low fruit and vegetable intake, opium use, polycyclic aromatic hydrocarbons, micronutrient deficiencies, hot beverages and poor oral health, although the role of mycotoxins and infections including HIV is uncertain.	('polycyclic aromatic', 'Var', (146, 165))	('hot beverage', 'Phenotype', 'HP:0031217', (208, 220))	('tobacco', 'Species', '4097', (85, 92))	('infections', 'Disease', 'MESH:D007239', (280, 290))	('infections', 'Disease', (280, 290))	('poor oral', 'Phenotype', 'HP:0000160', (226, 235))	('age', 'Gene', (217, 220))	('low', 'NegReg', (103, 106))	('ESCC', 'Disease', (55, 59))	('alcohol', 'Chemical', 'MESH:D000438', (94, 101))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (146, 178))	('age', 'Gene', '5973', (217, 220))
276302	33320959	In participants that the nondental observed rated as TFI 0 (no fluorosis), the majority (87% = 13/15) were also considered as "no fluorosis" by the dentist.	('TFI', 'Var', (53, 56))	('participants', 'Species', '9606', (3, 15))	('fluorosis', 'MPA', (63, 72))
276318	33320959	The effects of missing, decayed or DMFT with ESCC risk were marginally stronger in never tobacco users (OR2a); however, they were strongly attenuated after adjusting for nondental observer assessed TFI to an OR3 of 1.4 (0.7, 3.0) for DMFT of 10+ compared to people with a DMFT of 0.	('tobacco', 'Species', '4097', (89, 96))	('attenuated', 'NegReg', (139, 149))	('ESCC', 'Disease', (45, 49))	('DMFT', 'Chemical', '-', (234, 238))	('DMFT of 10+', 'Var', (234, 245))	('DMFT', 'Chemical', '-', (272, 276))	('DMFT', 'Chemical', '-', (35, 39))	('people', 'Species', '9606', (258, 264))
276319	33320959	For TFI 1 to 4 compared to no fluorosis (0), stepwise increases in ESCC risk were present (OR1) in crude analyses, which halved in magnitude upon adjustment for tobacco and alcohol use to an OR2 of 3.5 (1.7-7.1) for TFI 4 vs 0.	('ESCC', 'Disease', (67, 71))	('men', 'Species', '9606', (152, 155))	('tobacco', 'Species', '4097', (161, 168))	('alcohol use', 'Phenotype', 'HP:0030955', (173, 184))	('TFI 1 to 4', 'Var', (4, 14))	('alcohol', 'Chemical', 'MESH:D000438', (173, 180))
276321	33320959	However, as shown in Figure 3 (Supplementary Table 1), when restricted to non-Moshi residents, never oral charcoal users or DMFT<4, ESCC risks differed between those with TFI index 1 compared to 0 (OR3b/d/e of 2.6-2.9) and therafter plateaued for TFI 1 to 4.	('differed', 'Reg', (143, 151))	('men', 'Species', '9606', (37, 40))	('TFI index 1', 'Var', (171, 182))	('DMFT', 'Chemical', '-', (124, 128))	('oral charcoal', 'Chemical', '-', (101, 114))	('ESCC', 'Disease', (132, 136))
276391	32738923	We detected 7475 ctDNA mutations in 238 (76%) patients and 6196 (96.0%) of the mutations are detected in only one test.	('mutations', 'Var', (23, 32))	('ctDNA', 'Gene', (17, 22))	('patients', 'Species', '9606', (46, 54))
276405	32738923	Currently, the most prevalent way to analyze ctDNA employs next-generation sequencing (NGS) in combination with multiplex PCR to check a panel of hotspot mutations, which can be either generic to all tumors or specific to a certain cancer type.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Disease', (232, 238))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('mutations', 'Var', (154, 163))
276406	32738923	Although low cost and easy to design, ctDNA panels generated these ways can potentially miss important mutational clones in some patients if the mutations are not included in the panel targets, therefore result in inaccurate evaluation of disease status and treatment response.	('mutational', 'Var', (103, 113))	('patients', 'Species', '9606', (129, 137))	('miss', 'NegReg', (88, 92))
276410	32738923	The authors found that the tumor volume correlated with the variant allele frequency (VAF) and ctDNA monitoring could detect tumor recurrence earlier than clinical CT imaging.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('variant', 'Var', (60, 67))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
276415	32738923	We also took the advantage of ctDNA monitoring to detect acquired drug-related mutations during tumor evolution with a pre-designed panel consisted of eight hotspot tumor genes.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mutations', 'Var', (79, 88))	('tumor', 'Disease', (165, 170))
276426	32738923	Only the samples with tumor content > 20% were used to ensure the sequencing and variant calling quality.	('variant', 'Var', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (22, 27))
276434	32738923	First, clonal clusters were measured using SciClone tools with the following parameters: tumor purity as determined by pathologists, and tumor copy number alterations (CNA), loss of heterozygosity (LOH) ratio in somatic mutation regions, and somatic variant allele frequency (VAF).	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('loss', 'Var', (174, 178))
276443	32738923	The clinical interpretation of genes and mutations was made using the Clinical Interpretation of Variants in Cancer (CIViC) knowledge base, an open source, community-driven web resource.	('Cancer', 'Disease', 'MESH:D009369', (109, 115))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Cancer', 'Disease', (109, 115))	('Variants', 'Var', (97, 105))
276444	32738923	414 genes and 3331 mutations were selected as reference objects because they have predictive, diagnostic, prognostic, and predisposing values and are predicted to be functional in cancers (Additional file 2: Table S2).	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('mutations', 'Var', (19, 28))	('functional', 'Reg', (166, 176))
276452	32738923	Out of the 313 patients and eight tumor types, we detected one potential acquired drug-related mutations in eight patients and three mutations in one patient (Additional file 3: Table S3).	('patient', 'Species', '9606', (15, 22))	('patients', 'Species', '9606', (15, 23))	('patient', 'Species', '9606', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('mutations', 'Var', (95, 104))	('patient', 'Species', '9606', (114, 121))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
276453	32738923	Six CRC patients acquired KRAS mutations with an allelic frequency > 0.05%.	('mutations', 'Var', (31, 40))	('CRC', 'Phenotype', 'HP:0003003', (4, 7))	('CRC', 'Disease', 'MESH:D015179', (4, 7))	('KRAS', 'Gene', (26, 30))	('CRC', 'Disease', (4, 7))	('KRAS', 'Gene', '3845', (26, 30))	('patients', 'Species', '9606', (8, 16))
276454	32738923	One lung adenocarcinoma patient acquired an EGFR p.T790M mutation, which was found 2 months before the imaging confirmed PD.	('lung adenocarcinoma', 'Disease', (4, 23))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('p.T790M', 'Mutation', 'rs121434569', (49, 56))	('patient', 'Species', '9606', (24, 31))	('PD', 'Disease', 'MESH:D010300', (121, 123))	('p.T790M', 'Var', (49, 56))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
276456	32738923	PIK3CA mutations were detected in a cholangiocarcinoma patient and a breast cancer patient.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (36, 54))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (36, 54))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PIK3CA', 'Gene', (0, 6))	('breast cancer', 'Disease', (69, 82))	('PIK3CA', 'Gene', '5290', (0, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('cholangiocarcinoma', 'Disease', (36, 54))	('patient', 'Species', '9606', (83, 90))	('patient', 'Species', '9606', (55, 62))	('detected', 'Reg', (22, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('mutations', 'Var', (7, 16))
276461	32738923	Most cancer-related genes and variants had a low incidence, with only 27 out of the 414 CIViC genes and 3 out of the 3331 variants occurred ten or more times in our cohort.	('variants', 'Var', (30, 38))	('cancer', 'Disease', (5, 11))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
276508	32738923	In a breast cancer patient whose status changed from SD to PD, the ctDNA content of most mutations increased, but the level of ZFYVE21, a known breast cancer marker, continued to decrease.	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('patient', 'Species', '9606', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ZFYVE21', 'Gene', (127, 134))	('breast cancer', 'Disease', (144, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('breast cancer', 'Disease', 'MESH:D001943', (5, 18))	('PD', 'Disease', 'MESH:D010300', (59, 61))	('ctDNA content', 'MPA', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (89, 98))	('increased', 'PosReg', (99, 108))	('ZFYVE21', 'Gene', '79038', (127, 134))	('breast cancer', 'Disease', (5, 18))
276513	32738923	This is one of the major motivations for us to use paired WES data from patient tumors and blood to screen the variants specific to the tumor and free from the interference from the clonal hematopoietic cells.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (80, 85))	('variants', 'Var', (111, 119))	('patient', 'Species', '9606', (72, 79))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
276521	32738923	Those includes EGFR c.2369C > T p.T790M, an important biomarker for patients with lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patients', 'Species', '9606', (68, 76))	('p.T790M', 'Mutation', 'rs121434569', (32, 39))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('c.2369C > T p.T790M', 'Var', (20, 39))	('c.2369C > T', 'Mutation', 'rs121434569', (20, 31))
276522	32738923	It generally appears after patients develop resistance to first-line EGFR inhibitors, and those patients with EGFR p.T790M mutation can obtain clinical benefits by treatment with osimertinib.	('EGFR', 'Gene', '1956', (69, 73))	('benefits', 'PosReg', (152, 160))	('osimertinib', 'Chemical', '-', (179, 190))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('EGFR', 'Gene', (69, 73))	('resistance', 'MPA', (44, 54))	('p.T790M', 'Mutation', 'rs121434569', (115, 122))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (96, 104))	('p.T790M', 'Var', (115, 122))
276524	32738923	Furthermore, this assay only targets SNVs because short sequencing length is used, therefore changes of indels and longer range variants cannot be detected, including gene fusions/chromosomal rearrangements and copy number variations (CNVs), which are highly valuable diagnostic tools for some tumors.	('tumors', 'Phenotype', 'HP:0002664', (294, 300))	('copy number variations', 'Var', (211, 233))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumors', 'Disease', (294, 300))	('tumors', 'Disease', 'MESH:D009369', (294, 300))
276717	31620943	The odynophagia, fatigue, and weight loss scores even improved after nCRT compared with baseline levels at 6, 16, and 12 weeks, respectively.	('weight loss', 'Disease', (30, 41))	('nCRT', 'Var', (69, 73))	('weight loss', 'Phenotype', 'HP:0001824', (30, 41))	('fatigue', 'Phenotype', 'HP:0012378', (17, 24))	('odynophagia', 'Phenotype', 'HP:0032043', (4, 15))	('improved', 'PosReg', (54, 62))	('weight loss', 'Disease', 'MESH:D015431', (30, 41))	('fatigue', 'Disease', 'MESH:D005221', (17, 24))	('fatigue', 'Disease', (17, 24))	('odynophagia', 'Disease', (4, 15))
276871	29085570	Tumor cells did not show any expression for P40, a marker for squamous cell carcinoma (Figure 3D).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('squamous cell carcinoma', 'Disease', (62, 85))	('P40', 'Var', (44, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
276963	28819564	Furthermore, there is increasing evidence that not only does NAFLD increase the risk of HCC, it may also increase the risk for tumor recurrence after treatment with locoregional therapy when compared to other etiologies of cirrhosis and HCC.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cirrhosis', 'Disease', (223, 232))	('men', 'Species', '9606', (155, 158))	('tumor', 'Disease', (127, 132))	('CC', 'Phenotype', 'HP:0030153', (238, 240))	('NAFLD', 'Var', (61, 66))	('HCC', 'Disease', (88, 91))	('cirrhosis', 'Phenotype', 'HP:0001394', (223, 232))	('increase', 'PosReg', (105, 113))	('HCC', 'Phenotype', 'HP:0001402', (88, 91))	('increase', 'PosReg', (67, 75))	('CC', 'Phenotype', 'HP:0030153', (89, 91))	('cirrhosis', 'Disease', 'MESH:D005355', (223, 232))	('HCC', 'Phenotype', 'HP:0001402', (237, 240))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
277001	27143920	Dysregulation of CSC signaling such as the Hippo/Yes-associated protein 1 (YAP-1), Wnt/beta-catenin, and Hh has been implicated in tumor maintenance and in conferring therapy resistance.	('CSC signaling', 'MPA', (17, 30))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('beta-catenin', 'Gene', (87, 99))	('YAP-1', 'Gene', (75, 80))	('YAP-1', 'Gene', '10413', (75, 80))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('beta-catenin', 'Gene', '1499', (87, 99))	('tumor', 'Disease', (131, 136))	('therapy resistance', 'CPA', (167, 185))	('Hippo/Yes-associated protein 1', 'Gene', (43, 73))	('implicated', 'Reg', (117, 127))	('Hippo/Yes-associated protein 1', 'Gene', '10413', (43, 73))
277027	27143920	In addition, ABCG2/V-ATPase expression may result in cell invasion, metastasis, and drug tolerance of EC.	('ATPase', 'Gene', '1769', (21, 27))	('ABCG2', 'Gene', '9429', (13, 18))	('ATPase', 'Gene', (21, 27))	('result in', 'Reg', (43, 52))	('expression', 'Var', (28, 38))	('metastasis', 'CPA', (68, 78))	('cell invasion', 'CPA', (53, 66))	('ABCG2', 'Gene', (13, 18))	('drug tolerance', 'CPA', (84, 98))
277050	27143920	Any dysregulation of such signaling drives CSC activity in diverse cancer types.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('CSC activity', 'Disease', (43, 55))	('cancer', 'Disease', (67, 73))	('drives', 'Reg', (36, 42))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
277055	27143920	The aberrant beta-catenin expression could be an adverse underlying factor of ESCC in cancer progression, metastasis, and invasion.	('expression', 'MPA', (26, 36))	('ESCC', 'Disease', (78, 82))	('beta-catenin', 'Gene', '1499', (13, 25))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('aberrant', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('metastasis', 'CPA', (106, 116))	('beta-catenin', 'Gene', (13, 25))	('cancer', 'Disease', (86, 92))
277065	27143920	Their results elucidated that HEY1 and HEY2 were significantly overexpressed in association with the clinicopathological features of ESCC patients, confirming that deregulated activation of the Notch signaling pathway plays a role in the development and progression of the malignancy and may be considered in therapeutic modalities to restrict ESCC progression.	('HEY1', 'Gene', (30, 34))	('HEY1', 'Gene', '23462', (30, 34))	('ESCC', 'Disease', (344, 348))	('HEY2', 'Gene', (39, 43))	('overexpressed', 'PosReg', (63, 76))	('patients', 'Species', '9606', (138, 146))	('Notch signaling pathway', 'Pathway', (194, 217))	('HEY2', 'Gene', '23493', (39, 43))	('ESCC', 'Disease', (133, 137))	('deregulated', 'Var', (164, 175))	('malignancy', 'Disease', 'MESH:D009369', (273, 283))	('activation', 'PosReg', (176, 186))	('malignancy', 'Disease', (273, 283))
277074	27143920	The Hippo signaling pathway is regarded as an important player not only in organ size control but also in tumorigenesis, because the disruption of any important components (mammalian ste20-like kinase [Mst] 1/2, salvador homolog 1 [Sav1] and large tumor suppressor [Lats] 1/2, and YAP-1) in this pathway can lead to tumorigenesis.	('YAP-1', 'Gene', '10413', (281, 286))	('lead to', 'Reg', (308, 315))	('ste20-like kinase [Mst] 1/2', 'Gene', '6789;6788', (183, 210))	('ste20-like kinase [Mst] 1/2', 'Gene', (183, 210))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', (248, 253))	('YAP-1', 'Gene', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('Sav1', 'Gene', (232, 236))	('disruption', 'Var', (133, 143))	('mammalian', 'Species', '9606', (173, 182))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('Sav1', 'Gene', '60485', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('salvador homolog 1', 'Gene', '60485', (212, 230))	('tumor', 'Disease', (316, 321))	('salvador homolog 1', 'Gene', (212, 230))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
277076	27143920	Emerging evidence indicates the importance of YAP-1 and deregulation of the Hippo pathway during cancer development and progression.	('cancer', 'Disease', (97, 103))	('deregulation', 'Var', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('YAP-1', 'Gene', '10413', (46, 51))	('Hippo pathway', 'Pathway', (76, 89))	('YAP-1', 'Gene', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
277084	27143920	All-trans retinoic acid can also induce ESCC differentiation and dramatically downregulate the expression of CD44 mRNA and protein levels, which is a platform that integrates cellular microenvironmental cues with growth factor and cytokine signals, suggesting a potential application of all-trans retinoic acid differentiation therapy for CD44.	('CD44', 'Gene', '960', (109, 113))	('retinoic acid', 'Chemical', 'MESH:D014212', (297, 310))	('trans', 'Chemical', 'MESH:C057348', (291, 296))	('CD44', 'Gene', (109, 113))	('downregulate', 'NegReg', (78, 90))	('trans', 'Chemical', 'MESH:C057348', (4, 9))	('ESCC differentiation', 'CPA', (40, 60))	('CD44', 'Gene', '960', (339, 343))	('retinoic acid', 'Chemical', 'MESH:D014212', (10, 23))	('All-trans retinoic acid', 'Chemical', 'MESH:D014212', (0, 23))	('CD44', 'Gene', (339, 343))	('induce', 'PosReg', (33, 39))	('expression', 'MPA', (95, 105))	('All-trans', 'Var', (0, 9))
277085	27143920	CXCR4 silenced by small interfering RNA can suppress the proliferation, invasion, and metastasis of EC cell lines KYSE-150 and TE-13 in vitro and in vivo.	('CXCR4', 'Gene', '7852', (0, 5))	('suppress', 'NegReg', (44, 52))	('small interfering', 'Var', (18, 35))	('proliferation', 'CPA', (57, 70))	('CXCR4', 'Gene', (0, 5))	('invasion', 'CPA', (72, 80))	('metastasis', 'CPA', (86, 96))
277089	27143920	The synergy between metformin and 5-FU can potentially treat CSCs and simultaneously increase the sensitivity of chemoradiation in EAC patients through ribosomal S6 kinase (S6K) phosphorylation, and the crosstalk between mTOR and Hh signaling confers tumor cell growth advantage and resistance to therapy.	('sensitivity', 'MPA', (98, 109))	('patients', 'Species', '9606', (135, 143))	('tumor', 'Disease', (251, 256))	('mTOR', 'Gene', (221, 225))	('mTOR', 'Gene', '2475', (221, 225))	('crosstalk', 'Reg', (203, 212))	('5-FU', 'Chemical', 'MESH:D005472', (34, 38))	('metformin', 'Chemical', 'MESH:D008687', (20, 29))	('synergy', 'Var', (4, 11))	('CSCs', 'Disease', (61, 65))	('treat', 'Reg', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('increase', 'PosReg', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
277091	27143920	These results were consistent with the recent finding of Huang et al, who reported that YAP-1 knockdown sensitized ovarian cancer cells to cisplatin and survivin inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('knockdown', 'Var', (94, 103))	('YAP-1', 'Gene', (88, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('sensitized', 'Reg', (104, 114))	('ovarian cancer', 'Disease', 'MESH:D010051', (115, 129))	('YAP-1', 'Gene', '10413', (88, 93))	('ovarian cancer', 'Disease', (115, 129))
277188	25586902	The WCRF/AICR panel found no statistically significantly decreased risk of colorectal cancer with highest garlic intake in two prospective cohorts, while three case-control studies showed significantly decreased risk of colorectal cancer for those with the highest garlic intake and three other case-control studies did not.	('colorectal cancer', 'Phenotype', 'HP:0003003', (220, 237))	('colorectal cancer', 'Disease', (75, 92))	('garlic', 'Species', '4682', (265, 271))	('decreased', 'NegReg', (202, 211))	('garlic', 'Var', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', (220, 237))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('garlic', 'Species', '4682', (106, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('decreased', 'NegReg', (57, 66))
277193	25586902	Intermediate and high garlic use were associated with decreased risk of colorectal cancer with ORs of 0.88 (95% CI 0.78-0.98) and 0.74 (95%CI 0.63-8.86), respectively, compared to low or no use (p-trend <0.001).	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('high', 'Var', (17, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('garlic', 'Species', '4682', (22, 28))	('decreased', 'NegReg', (54, 63))	('colorectal cancer', 'Disease', (72, 89))
277210	25586902	High garlic intake was also associated with decreased odds of oral cavity/pharyngeal cancer (OR = 0.43; 95% CI 0.28-0.67; p-trend = 0.002), laryngeal cancer (OR = 0.56; 95% CI 0.38-0.82; p-trend = 0.005), ovarian cancer (OR = 0.78; 95% CI 0.62-0.98; p-trend = 0.10), renal cell carcinoma (OR = 0.69; 95% CI 0.53-0.92; p-trend = 0.003), and endometrial cancer (OR = 0.62; 95% CI 0.42-0.92; p-trend = 0.02) compared to low or no garlic intake.	('endometrial cancer', 'Phenotype', 'HP:0012114', (340, 358))	('ovarian cancer', 'Disease', (205, 219))	('renal cell carcinoma', 'Disease', (267, 287))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (267, 287))	('laryngeal cancer', 'Disease', 'MESH:D007822', (140, 156))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('ovarian cancer', 'Phenotype', 'HP:0100615', (205, 219))	('endometrial cancer', 'Disease', (340, 358))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('laryngeal cancer', 'Disease', (140, 156))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (140, 156))	('endometrial cancer', 'Disease', 'MESH:D016889', (340, 358))	('pharyngeal cancer', 'Disease', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('pharyngeal cancer', 'Disease', 'MESH:D010610', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (74, 91))	('garlic', 'Species', '4682', (427, 433))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (267, 287))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (205, 219))	('High garlic', 'Var', (0, 11))	('garlic', 'Species', '4682', (5, 11))	('decreased', 'NegReg', (44, 53))
277214	25586902	The association with squamous cell carcinoma was modified by CYP1A1 genotype, as onions were more protective in those with the homozygous wild-type *1/*1 genotype compared to those with *1/*2 or *2/*2 genotypes.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('squamous cell carcinoma', 'Disease', (21, 44))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (21, 44))	('CYP1A1', 'Var', (61, 67))	('protective', 'NegReg', (98, 108))	('onions', 'Disease', (81, 87))	('onions', 'Species', '4679', (81, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))
277220	25586902	In addition, other factors including epigenetic modifications and variability in the gut microbiome, currently largely unexplored in studies on associations between Allium intake and cancer risk, may also influence responses.	('influence', 'Reg', (205, 214))	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('gut microbiome', 'Species', '749906', (85, 99))	('responses', 'MPA', (215, 224))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('epigenetic modifications', 'Var', (37, 61))
277273	25586902	Garlic and onion constituents, including DADS, DATS, S-allylmercaptocysteine, and ajoene, have the ability to suppress proliferation of a wide variety of cancer cells by retarding cell cycle progression and/or inducing apoptosis.	('suppress', 'NegReg', (110, 118))	('DADS', 'Chemical', 'MESH:C028009', (41, 45))	('S-allylmercaptocysteine', 'Chemical', 'MESH:C086300', (53, 76))	('inducing', 'Reg', (210, 218))	('ajoene', 'Chemical', 'MESH:C048980', (82, 88))	('cell cycle progression', 'CPA', (180, 202))	('Garlic', 'Species', '4682', (0, 6))	('cancer', 'Disease', (154, 160))	('S-allylmercaptocysteine', 'Var', (53, 76))	('onion', 'Species', '4679', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('DATS', 'Chemical', 'MESH:C042577', (47, 51))	('apoptosis', 'CPA', (219, 228))	('retarding', 'NegReg', (170, 179))	('rat', 'Species', '10116', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('proliferation', 'CPA', (119, 132))
277275	25586902	For example, DADS suppressed Cdk1 activity during cell cycle arrest in G2/M that was associated with a temporal and dose-dependent increase in cyclin B1 protein level, a reduction in the level of Cdk1-cyclin B1 complex formation, an inactivation of Cdk1 by hyperphosphorylation, and a decrease in Cdc25C protein level.	('activity', 'MPA', (34, 42))	('reduction', 'NegReg', (170, 179))	('DADS', 'Var', (13, 17))	('cyclin B1 protein level', 'MPA', (143, 166))	('Cdk1', 'Enzyme', (29, 33))	('inactivation', 'NegReg', (233, 245))	('increase', 'PosReg', (131, 139))	('Cdc25C protein level', 'MPA', (297, 317))	('Cdk1', 'Gene', (249, 253))	('decrease', 'NegReg', (285, 293))	('cell cycle arrest', 'CPA', (50, 67))	('level', 'MPA', (187, 192))	('suppressed', 'NegReg', (18, 28))	('DADS', 'Chemical', 'MESH:C028009', (13, 17))	('Cdk1-cyclin B1 complex formation', 'MPA', (196, 228))
277287	25586902	While an epidemiological study suggested an association between increased garlic consumption and reduced H. pylori infection, two clinical studies that tested different garlic preparations in H. pylori infected subjects did not show efficacy.	('H. pylori', 'Species', '210', (105, 114))	('garlic', 'Var', (74, 80))	('garlic', 'Species', '4682', (169, 175))	('H. pylori', 'Species', '210', (192, 201))	('pylori infection', 'Phenotype', 'HP:0005202', (108, 124))	('reduced', 'NegReg', (97, 104))	('infection', 'Disease', (115, 124))	('rat', 'Species', '10116', (181, 184))	('garlic', 'Species', '4682', (74, 80))	('infection', 'Disease', 'MESH:D007239', (115, 124))
277296	25586902	The presence of both the allyl and sulfur groups appears to magnify the antioxidant capabilities of the molecule.	('presence', 'Var', (4, 12))	('magnify', 'PosReg', (60, 67))	('sulfur', 'Chemical', 'MESH:D013455', (35, 41))	('antioxidant capabilities of the molecule', 'MPA', (72, 112))
277397	21818286	Location-Specific Epigenetic Regulation of the Metallothionein 3 Gene in Esophageal Adenocarcinomas Metallothionein 3 (MT3) maintains intracellular metal homeostasis and protects against reactive oxygen species (ROS)-induced DNA damage.	('Epigenetic Regulation', 'Var', (18, 39))	('MT3', 'Gene', (119, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('maintains', 'PosReg', (124, 133))	('ROS', 'Chemical', 'MESH:D017382', (212, 215))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (187, 210))	('Esophageal Adenocarcinomas', 'Disease', (73, 99))	('Esophageal Adenocarcinomas', 'Disease', 'MESH:D004938', (73, 99))	('Metallothionein 3', 'Gene', (100, 117))	('Metallothionein 3', 'Gene', '4504', (47, 64))	('metal', 'Chemical', 'MESH:D008670', (148, 153))	('intracellular metal homeostasis', 'MPA', (134, 165))	('MT3', 'Gene', '4504', (119, 122))	('Metallothionein 3', 'Gene', (47, 64))	('Metallothionein 3', 'Gene', '4504', (100, 117))
277402	21818286	Moreover, the DNA hypermethylation from -127 to -8 CpG sites significantly correlated with advanced tumor stages and lymph node metastasis (P = 0.005 and P = 0.0313, respectively).	('lymph node metastasis', 'CPA', (117, 138))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('hypermethylation', 'Var', (18, 34))	('tumor', 'Disease', (100, 105))	('correlated', 'Reg', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
277403	21818286	The ChIP analysis demonstrated a more repressive histone modification (H3K9me2) and less active histone modifications (H3K4me2, H3K9ace) in OE33 cells than in FLO-1 cells; concordant with the presence of higher DNA methylation levels and silencing of MT3 expression in OE33 as compared to FLO-1 cells.	('MT3', 'Gene', '4504', (251, 254))	('active histone modifications', 'MPA', (89, 117))	('silencing', 'NegReg', (238, 247))	('less', 'NegReg', (84, 88))	('MT3', 'Gene', (251, 254))	('H3K4me2', 'Var', (119, 126))	('repressive histone modification', 'MPA', (38, 69))	('OE33', 'Chemical', '-', (140, 144))	('DNA methylation levels', 'MPA', (211, 233))	('H3K9ace', 'Var', (128, 135))	('OE33', 'Chemical', '-', (269, 273))	('H3K9me2', 'Var', (71, 78))	('higher', 'PosReg', (204, 210))
277405	21818286	In summary, EACs are characterized by frequent epigenetic silencing of MT3.	('epigenetic silencing', 'Var', (47, 67))	('EACs', 'Disease', (12, 16))	('MT3', 'Gene', (71, 74))	('MT3', 'Gene', '4504', (71, 74))
277410	21818286	Hypermethylation of the gene promoter CpG islands is one of the major mechanisms to silence tumor suppressor genes and other tumor related genes.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (92, 97))	('silence', 'NegReg', (84, 91))
277416	21818286	Conversely, DNA methylation of the MT3 promoter has been associated with the down-regulation of the MT3 gene in gastric carcinoma and esophageal squamous cell carcinoma.	('MT3', 'Gene', '4504', (35, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('DNA methylation', 'Var', (12, 27))	('gastric carcinoma', 'Disease', (112, 129))	('down-regulation', 'NegReg', (77, 92))	('esophageal squamous cell carcinoma', 'Disease', (134, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('MT3', 'Gene', (35, 38))	('MT3', 'Gene', (100, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (134, 168))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (112, 129))	('MT3', 'Gene', '4504', (100, 103))	('gastric carcinoma', 'Disease', 'MESH:D013274', (112, 129))
277418	21818286	MT3 prevents the gamma-radiation-induced 8-oxoG accumulation and mutation in normal and hOGG1-depleted cells.	('hOGG1', 'Gene', (88, 93))	('MT3', 'Gene', (0, 3))	('8-oxoG accumulation', 'MPA', (41, 60))	('mutation', 'Var', (65, 73))	('hOGG1', 'Gene', '4968', (88, 93))	('MT3', 'Gene', '4504', (0, 3))
277420	21818286	Our results demonstrated epigenetic silencing of MT3 through promoter DNA hypermethylation and repressive histone modification mechanisms.	('epigenetic silencing', 'Var', (25, 45))	('MT3', 'Gene', '4504', (49, 52))	('promoter DNA', 'Var', (61, 73))	('MT3', 'Gene', (49, 52))
277431	21818286	Taken together, our results indicate that Region 2 (from -127 to -8) is the most suitable region for functional analysis of the MT3 promoter methylation; since it was frequently hypermethylated in EACs, had the strongest inverse correlation between DNA methylation and gene expression (Figure 3C), and was the best discriminating region between tumor and normal samples (Figure 1B).	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('MT3', 'Gene', '4504', (128, 131))	('inverse correlation', 'NegReg', (221, 240))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('hypermethylated', 'Var', (178, 193))	('tumor', 'Disease', (345, 350))	('MT3', 'Gene', (128, 131))	('gene expression', 'MPA', (269, 284))
277439	21818286	In contrast, the OE33 cells displayed a significant level of H3K9me2 as compared to the other two histones (Figure 5C).	('H3K9me2', 'Protein', (61, 68))	('OE33', 'Var', (17, 21))	('OE33', 'Chemical', '-', (17, 21))
277443	21818286	As shown in Figure 6, DNA methylation of R2 (from -127 to -8 CpG sites) was significantly associated with advanced tumor stages (P = 0.005) and lymph node metastasis (P = 0.031).	('methylation', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('associated', 'Reg', (90, 100))	('lymph node metastasis', 'CPA', (144, 165))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
277444	21818286	However, DNA methylation R3 (from +28 to +344 sites) was only associated with tumor stage (P = 0.033) but not with lymph node metastasis (P = 0.45).	('from +28 to +344 sites', 'Var', (29, 51))	('associated', 'Reg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
277448	21818286	Although the mechanisms explaining progressive methylation patterns remain unclear, recent studies suggested that dimethylation of lysine 4 of histone 3 (H3K4me2) may protect against DNA methylation.	('dimethylation', 'Var', (114, 127))	('DNA methylation', 'MPA', (183, 198))	('lysine', 'Chemical', 'MESH:D008239', (131, 137))
277449	21818286	Our ChIP results also support this hypothesis by showing a high level of H3K4me2 in an active MT3 promoter (in particular, in ChIP 2) in the FLO-1 cell line and a significantly decreased level of H3K4me2 in a suppressive promoter in OE33.	('MT3', 'Gene', '4504', (94, 97))	('OE33', 'Chemical', '-', (233, 237))	('MT3', 'Gene', (94, 97))	('decreased', 'NegReg', (177, 186))	('H3K4me2', 'Var', (73, 80))
277458	21818286	In a cell model of OE33, the treatment with 5-Aza demethylated the promoter region and restored MT3 gene expression, concordant with many other reports.	('MT3', 'Gene', '4504', (96, 99))	('OE33', 'Chemical', '-', (19, 23))	('MT3', 'Gene', (96, 99))	('promoter region', 'MPA', (67, 82))	('restored', 'PosReg', (87, 95))	('5-Aza', 'Chemical', 'MESH:D001374', (44, 49))	('demethylated', 'Var', (50, 62))
277460	21818286	Analysis of three different regions of the MT3 promoter demonstrated significantly high levels of H3K4me2 and H3K9ace, and low levels of H3K9me2 in all three regions in FLO-1 cells.	('MT3', 'Gene', (43, 46))	('MT3', 'Gene', '4504', (43, 46))	('H3K4me2', 'Protein', (98, 105))	('H3K9ace', 'Var', (110, 117))
277462	21818286	The 5-Aza administration in the methylated OE33 cells reversed the ratio of repressive to active histone H3K9, showing higher levels of H3K9ace than H3K9me2.	('OE33', 'Chemical', '-', (43, 47))	('repressive to active', 'MPA', (76, 96))	('higher', 'PosReg', (119, 125))	('levels', 'MPA', (126, 132))	('5-Aza', 'Chemical', 'MESH:D001374', (4, 9))	('ratio', 'MPA', (67, 72))	('H3K9ace', 'Var', (136, 143))
277463	21818286	These results indicate that DNA methylation of the MT3 gene is linked with unique histone modifications in regulating gene expression.	('DNA', 'Var', (28, 31))	('MT3', 'Gene', '4504', (51, 54))	('MT3', 'Gene', (51, 54))	('histone modifications', 'MPA', (82, 103))	('regulating gene expression', 'MPA', (107, 133))
277465	21818286	After 5-Aza treatment of OE33 cells, H3K4me2 showed a significant increase only in the ChIP3 region not in the ChIP2 region where the strongest correlation between DNA methylation and MT3 expression was observed.	('5-Aza', 'Chemical', 'MESH:D001374', (6, 11))	('increase', 'PosReg', (66, 74))	('MT3', 'Gene', '4504', (184, 187))	('H3K4me2', 'Var', (37, 44))	('OE33', 'Chemical', '-', (25, 29))	('MT3', 'Gene', (184, 187))
277467	21818286	Interestingly, we found that DNA methylation of the MT3 promoter region (R2, from -127 to -8 sites) was significantly associated with advanced tumor stages and lymph node metastasis (Figure 6), indicating that dysfunction of MT3 through DNA methylation of the core promoter region may be associated with tumor progression.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (143, 148))	('lymph node metastasis', 'CPA', (160, 181))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('dysfunction', 'Var', (210, 221))	('MT3', 'Gene', '4504', (225, 228))	('MT3', 'Gene', '4504', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('MT3', 'Gene', (52, 55))	('associated', 'Reg', (118, 128))	('tumor', 'Disease', (304, 309))	('MT3', 'Gene', (225, 228))	('associated', 'Reg', (288, 298))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
277500	21818286	Fold enrichment in the binding of histones (H3K4me2, H3K9ace, and H3K9me2) to MT3 promoter regions in each immunoprecipitation was normalized to the indicated histone binding level in its corresponding input and H3 levels in input DNA.	('H3K9ace', 'Var', (53, 60))	('MT3', 'Gene', (78, 81))	('H3K9me2', 'Var', (66, 73))	('H3K4me2', 'Var', (44, 51))	('MT3', 'Gene', '4504', (78, 81))	('binding', 'Interaction', (23, 30))
277502	20128888	A functional polymorphism in the DNA methyltransferase-3A promoter modifies the susceptibility in gastric cancer but not in esophageal carcinoma DNA-methyltransferase (DNMT)-3A plays an important role in the development of embryogenesis and the generation of aberrant methylation in carcinogenesis.	('polymorphism', 'Var', (13, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('esophageal carcinoma', 'Disease', (124, 144))	('gastric cancer', 'Disease', (98, 112))	('carcinogenesis', 'Disease', (283, 297))	('modifies', 'Reg', (67, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (124, 144))	('DNA-methyltransferase (DNMT)-3A', 'Gene', '1788', (145, 176))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (124, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('carcinogenesis', 'Disease', 'MESH:D063646', (283, 297))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
277503	20128888	The aim of this study was to investigate the role of a DNMT3A promoter genetic variant on its transcriptional activity and to evaluate the association between DNMT3A gene polymorphism and the susceptibility to gastric cancer (GC) and oesophagus carcinoma (EC) in the Chinese population.	('GC', 'Phenotype', 'HP:0012126', (226, 228))	('Chinese', 'Species', '10029', (267, 274))	('gastric cancer', 'Disease', 'MESH:D013274', (210, 224))	('susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (192, 224))	('gastric cancer', 'Phenotype', 'HP:0012126', (210, 224))	('EC', 'Phenotype', 'HP:0011459', (256, 258))	('oesophagus carcinoma', 'Phenotype', 'HP:0011459', (234, 254))	('polymorphism', 'Var', (171, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('oesophagus carcinoma', 'Disease', 'MESH:D002277', (234, 254))	('transcriptional activity', 'MPA', (94, 118))	('oesophagus carcinoma', 'Disease', (234, 254))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('association', 'Interaction', (139, 150))	('gastric cancer', 'Disease', (210, 224))	('DNMT3A', 'Gene', (159, 165))	('DNMT3A', 'Gene', (55, 61))	('variant', 'Var', (79, 86))
277515	20128888	DNMT3A and DNMT3B are considered to be de novo DNA methyltranferase, which are critical in the dynamic DNA methylation process during embryogenesis and pathogenesis.	('DNMT3B', 'Gene', (11, 17))	('DNMT3B', 'Gene', '1789', (11, 17))	('DNMT3A', 'Var', (0, 6))
277516	20128888	Aberrant promoter methylation in various tumour suppressor genes is also involved in human gastric cancer and oesophagus carcinoma and the epigenetic silencing linked this aberrant de novo methylation of CpG islands to the overexpression of the DNMT-3 family (DNMT3A and DNMT3B).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('DNMT', 'Gene', '1786', (260, 264))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('involved', 'Reg', (73, 81))	('DNMT', 'Gene', (260, 264))	('DNMT3B', 'Gene', '1789', (271, 277))	('DNMT3B', 'Gene', (271, 277))	('Aberrant', 'Var', (0, 8))	('methylation', 'Var', (189, 200))	('DNMT', 'Gene', '1786', (271, 275))	('oesophagus carcinoma', 'Disease', 'MESH:D002277', (110, 130))	('DNMT', 'Gene', (271, 275))	('gastric cancer', 'Disease', (91, 105))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('epigenetic silencing', 'Var', (139, 159))	('overexpression', 'PosReg', (223, 237))	('oesophagus carcinoma', 'Disease', (110, 130))	('tumour', 'Disease', (41, 47))	('human', 'Species', '9606', (85, 90))	('DNMT', 'Gene', '1786', (245, 249))	('gastric cancer', 'Disease', 'MESH:D013274', (91, 105))	('DNMT', 'Gene', (245, 249))	('oesophagus carcinoma', 'Phenotype', 'HP:0011459', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
277517	20128888	Studies showed that DNMT3A and DNMT3B, like DNMT1, repress transcription in a methylation-dependent manner.	('DNMT3A', 'Var', (20, 26))	('repress', 'NegReg', (51, 58))	('DNMT3B', 'Gene', '1789', (31, 37))	('transcription', 'MPA', (59, 72))	('DNMT1', 'Gene', (44, 49))	('methylation-dependent', 'MPA', (78, 99))	('DNMT1', 'Gene', '1786', (44, 49))	('DNMT3B', 'Gene', (31, 37))
277518	20128888	showed that DNMT3A and DNMT3B repress the transcription independence of their methylating activities and that this repression is partially dependent upon histone deacetylase activity.	('methylating activities', 'MPA', (78, 100))	('DNMT3B', 'Gene', '1789', (23, 29))	('transcription independence', 'MPA', (42, 68))	('DNMT3B', 'Gene', (23, 29))	('DNMT3A', 'Var', (12, 18))	('repress', 'NegReg', (30, 37))
277528	20128888	Many gene polymorphisms, including some epigenetic marker genes, have been reported to be closely associated with a susceptibility to tumours.	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('tumours', 'Disease', 'MESH:D009369', (134, 141))	('polymorphisms', 'Var', (10, 23))	('tumours', 'Disease', (134, 141))	('associated', 'Reg', (98, 108))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
277529	20128888	The polymorphism in the DNMT3B promoter that plays a role in de novo methylation has also been reported to be associated with several tumour susceptibilities, including gastric cancer.	('gastric cancer', 'Disease', (169, 183))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('tumour', 'Disease', (134, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('associated', 'Reg', (110, 120))	('DNMT3B', 'Gene', (24, 30))	('DNMT3B', 'Gene', '1789', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('polymorphism', 'Var', (4, 16))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
277531	20128888	To our knowledge, the association between DNMT3A polymorphisms and clinical implication of GC and esophageal carcinoma (EC) has not been previously been reported.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (98, 118))	('EC', 'Phenotype', 'HP:0011459', (120, 122))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (98, 118))	('DNMT3A', 'Gene', (42, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('polymorphisms', 'Var', (49, 62))	('association', 'Interaction', (22, 33))	('GC', 'Phenotype', 'HP:0012126', (91, 93))	('esophageal carcinoma', 'Disease', (98, 118))
277532	20128888	In the present work, we want to determine whether a single nucleotide polymorphism (SNP) in DNMT3A promoters contributes to its increased expression and whether functional SNP is substantially associated with cancer susceptibility.	('DNMT3A', 'Gene', (92, 98))	('increased', 'PosReg', (128, 137))	('single nucleotide polymorphism', 'Var', (52, 82))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (209, 215))	('expression', 'MPA', (138, 148))	('associated', 'Reg', (193, 203))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
277533	20128888	We now show that, as with some SNPs in the DNMT3B promoter, a SNP in DNMT3A promoter could activate its expression at the transcription level.	('SNP', 'Var', (62, 65))	('DNMT3B', 'Gene', (43, 49))	('DNMT3B', 'Gene', '1789', (43, 49))	('expression', 'MPA', (104, 114))	('DNMT3A', 'Gene', (69, 75))	('activate', 'PosReg', (91, 99))
277535	20128888	We hypothesized that the genetic variants of DNMT3A that are responsible for regulating the methylation status of other genes are associated with an increased risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('DNMT3A', 'Gene', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('variants', 'Var', (33, 41))	('associated with', 'Reg', (130, 145))
277536	20128888	In this hospital-based case-control study, we genotyped a functional DNMT3A polymorphism and investigated the association between this genetic variant and the risk of gastric cancer and oesophagus carcinoma.	('gastric cancer', 'Disease', (167, 181))	('investigated', 'Reg', (93, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('association', 'Interaction', (110, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('polymorphism', 'Var', (76, 88))	('oesophagus carcinoma', 'Phenotype', 'HP:0011459', (186, 206))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	('oesophagus carcinoma', 'Disease', 'MESH:D002277', (186, 206))	('DNMT3A', 'Gene', (69, 75))	('oesophagus carcinoma', 'Disease', (186, 206))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
277549	20128888	The transition of A>G of DNMT3A SNP creates a TaaI restriction site, PCR-restriction fragment length polymorphism (RFLP) was used to detect this A-G transition in the promoter of DNMT3A at -448A>G (GenBank accession No.	('TaaI restriction site', 'MPA', (46, 67))	('-448A>G', 'Mutation', 'rs1550117', (189, 196))	('transition', 'Var', (4, 14))
277564	20128888	All patients and controls were successfully genotyped for the DNMT3A polymorphism.	('polymorphism', 'Var', (69, 81))	('patients', 'Species', '9606', (4, 12))	('DNMT3A', 'Gene', (62, 68))
277566	20128888	The gastric cancer risks related to the DNMT3A -448A>G genotype are shown in Tables 4 and 5.	('DNMT3A -448A>G', 'Var', (40, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('-448A>G', 'Mutation', 'rs1550117', (47, 54))	('gastric cancer', 'Disease', (4, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (4, 18))
277570	20128888	The oesophagus cancer risk related to the DNMT3A -448A>G genotype are shown in Tables 6 and 7.	('oesophagus cancer', 'Disease', 'MESH:D009369', (4, 21))	('DNMT3A -448A>G', 'Var', (42, 56))	('oesophagus cancer', 'Disease', (4, 21))	('-448A>G', 'Mutation', 'rs1550117', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
277574	20128888	Thus, our data reveal important evidence that the presence of -448A shows that there is a significance likelihood of carcinogenesis occurring in GC patients but not in EC patients, at least in this Chinese population.	('patients', 'Species', '9606', (148, 156))	('Chinese', 'Species', '10029', (198, 205))	('carcinogenesis', 'Disease', 'MESH:D063646', (117, 131))	('patients', 'Species', '9606', (171, 179))	('presence', 'Var', (50, 58))	('GC', 'Phenotype', 'HP:0012126', (145, 147))	('EC', 'Phenotype', 'HP:0011459', (168, 170))	('carcinogenesis', 'Disease', (117, 131))
277578	20128888	In gastric cancers, tumour-suppressor genes (TSGs) are more frequently inactivated by aberrant DNA methylation than by mutations.	('aberrant DNA methylation', 'Var', (86, 110))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('gastric cancers', 'Disease', 'MESH:D013274', (3, 18))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('gastric cancers', 'Disease', (3, 18))	('tumour', 'Disease', (20, 26))	('gastric cancers', 'Phenotype', 'HP:0012126', (3, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('inactivated', 'NegReg', (71, 82))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
277579	20128888	CpG island hepermethylation of TSGs is associated with a recurrence of early stage oesophageal carcinoma.	('associated with', 'Reg', (39, 54))	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 104))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (84, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('TSGs', 'Gene', (31, 35))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (83, 104))	('oesophageal carcinoma', 'Disease', (83, 104))	('hepermethylation', 'Var', (11, 27))
277580	20128888	Increased expression of DNMT3A and DNMT3B as de novo DNA methyltransferase are common in many tumours which implies the that aberrant DNMT3A and DNMT3B expression are involved in carcinogenesis.	('tumours', 'Disease', (94, 101))	('DNMT3A', 'Gene', (134, 140))	('involved', 'Reg', (167, 175))	('carcinogenesis', 'Disease', 'MESH:D063646', (179, 193))	('DNMT3A', 'Gene', (24, 30))	('DNMT3B', 'Gene', '1789', (35, 41))	('expression', 'MPA', (10, 20))	('carcinogenesis', 'Disease', (179, 193))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('Increased', 'PosReg', (0, 9))	('DNMT3B', 'Gene', '1789', (145, 151))	('aberrant', 'Var', (125, 133))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('DNMT3B', 'Gene', (35, 41))	('tumours', 'Disease', 'MESH:D009369', (94, 101))	('DNMT3B', 'Gene', (145, 151))
277581	20128888	Our immunohistochemical data showed that the positive rates of DNMT3A expression in GC tissues were significantly higher than those of para-cancerous tissues (which agrees with a previous study of GC paraffin sections) and therefore shows that SNP of a promoter of a gene may increase the enzyme activity and play a role in the biological process.	('para-cancerous', 'Disease', 'MESH:D009369', (135, 149))	('enzyme activity', 'MPA', (289, 304))	('SNP', 'Var', (244, 247))	('increase', 'PosReg', (276, 284))	('paraffin', 'Chemical', 'MESH:D010232', (200, 208))	('para-cancerous', 'Disease', (135, 149))	('expression', 'MPA', (70, 80))	('GC', 'Phenotype', 'HP:0012126', (197, 199))	('GC', 'Phenotype', 'HP:0012126', (84, 86))	('DNMT3A', 'Gene', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('play', 'Reg', (309, 313))	('higher', 'PosReg', (114, 120))
277582	20128888	Our previous results suggested that a polymorphism at position -579 of the DNMT3B promoter was associated with a susceptibility to GC but not EC.	('susceptibility', 'Reg', (113, 127))	('GC', 'Phenotype', 'HP:0012126', (131, 133))	('DNMT3B', 'Gene', '1789', (75, 81))	('DNMT3B', 'Gene', (75, 81))	('EC', 'Phenotype', 'HP:0011459', (142, 144))	('associated', 'Reg', (95, 105))	('polymorphism at position -579', 'Var', (38, 67))
277583	20128888	We hypothesized that polymorphisms of DNMT3A promoter are associated with the risk of cancer.	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('DNMT3A', 'Gene', (38, 44))	('polymorphisms', 'Var', (21, 34))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
277587	20128888	The relationship between more than twofold overexpression of DNMT3A and an expression of tumour suppressor genes was not confirmed but elevated DNMT3A expression does coincide with some tumour-related genes and includes SFRP5 hypermethylation and transcriptional repression in paired patient biopsies.	('tumour', 'Disease', (186, 192))	('elevated', 'PosReg', (135, 143))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('SFRP5', 'Gene', (220, 225))	('DNMT3A', 'Gene', (144, 150))	('expression', 'MPA', (151, 161))	('tumour', 'Disease', (89, 95))	('patient', 'Species', '9606', (284, 291))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('transcriptional', 'MPA', (247, 262))	('hypermethylation', 'Var', (226, 242))
277591	20128888	Further studies are needed in order to elucidate the role of DNMT3A variants in the expression level of DNMT3A in GC patients and the function of the DNA methylaton.	('variants', 'Var', (68, 76))	('DNMT3A', 'Gene', (61, 67))	('GC', 'Phenotype', 'HP:0012126', (114, 116))	('expression', 'MPA', (84, 94))	('patients', 'Species', '9606', (117, 125))
277593	20128888	The present study provides evidence that a SNP in the DNMT3A promoter region may modify the risk of GC but not of oesophagus carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('GC', 'Phenotype', 'HP:0012126', (100, 102))	('DNMT3A', 'Gene', (54, 60))	('modify', 'Reg', (81, 87))	('oesophagus carcinoma', 'Phenotype', 'HP:0011459', (114, 134))	('oesophagus carcinoma', 'Disease', 'MESH:D002277', (114, 134))	('oesophagus carcinoma', 'Disease', (114, 134))	('SNP', 'Var', (43, 46))
277595	20128888	Different genetics factors, including tumour suppressor genes and silencing catalyzed by de novo methylatransferases, were involved in the tumourigenesis of different types of tumours.	('tumour', 'Disease', (139, 145))	('tumours', 'Disease', 'MESH:D009369', (176, 183))	('tumours', 'Disease', (176, 183))	('involved', 'Reg', (123, 131))	('silencing', 'Var', (66, 75))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('tumour', 'Disease', (38, 44))	('tumour', 'Disease', (176, 182))	('tumour', 'Disease', 'MESH:D009369', (139, 145))
277599	20128888	Future studies of other DNMT3A sequence variants and their biologic function are also needed in order to understand the role of DNMT3A polymorphisms in determining the risk of cancer.	('DNMT3A', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('variants', 'Var', (40, 48))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
277602	20128888	CHO: Chinese hamster ovary; DNMT: DNA-methyltransferase; EB: ethidium bromide; EC: oesophagus carcinoma; EDTA: ethylenediaminetetra-acetic acid; GC: gastric cancer; PCR: polymerase chain reaction; RFLP: restriction fragment length polymorphism; SNP: single nucleotide polymorphism; TSG: tumour-suppressor gene.	('single nucleotide polymorphism', 'Var', (250, 280))	('oesophagus carcinoma', 'Disease', (83, 103))	('ethylenediaminetetra-acetic acid', 'Chemical', 'MESH:D004492', (111, 143))	('DNMT', 'Gene', '1786', (28, 32))	('gastric cancer', 'Disease', (149, 163))	('DNMT', 'Gene', (28, 32))	('EB', 'Chemical', 'MESH:D004996', (57, 59))	('ethidium bromide', 'Chemical', 'MESH:D004996', (61, 77))	('oesophagus carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('tumour', 'Disease', 'MESH:D009369', (287, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('tumour', 'Disease', (287, 293))	('EDTA', 'Chemical', 'MESH:D004492', (105, 109))	('Chinese hamster', 'Species', '10029', (5, 20))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CHO', 'CellLine', 'CVCL:0213', (0, 3))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('GC', 'Phenotype', 'HP:0012126', (145, 147))	('oesophagus carcinoma', 'Disease', 'MESH:D002277', (83, 103))	('EC', 'Phenotype', 'HP:0011459', (79, 81))
277656	33193745	Common classification algorithms include Support Vector Machine (SVM) (Hou et al.,), Classification And Regression Tree (CART), K-Nearest Neighbor (KNN), Ensemble algorithm, Extreme Learning Machine (ELM), etc.	('CART', 'Gene', '9607', (121, 125))	('CART', 'Gene', (121, 125))	('K-Nearest', 'Var', (128, 137))
277674	33193745	X11 represents the red blood cell count and X12 represents the PT.	('X11', 'Gene', (0, 3))	('X12', 'Var', (44, 47))	('X11', 'Gene', '320', (0, 3))
277735	30700935	For example, studies have documented amplification of the c-Myc gene in cancer cells, which may act as the "driver mutation" and determine the metabolic profile of cancer cells.	('c-Myc', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('amplification', 'Var', (37, 50))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('determine', 'Reg', (129, 138))	('c-Myc', 'Gene', '4609', (58, 63))	('cancer', 'Disease', (72, 78))
277754	30700935	PKM2 knockdown partially affected the stability of the NF-kB subunit p65, indicating that post-translational regulation of p65 is one of the mechanisms used by PKM2 to drive tumor growth.	('tumor', 'Disease', (174, 179))	('stability', 'MPA', (38, 47))	('PKM2', 'Gene', (0, 4))	('p65', 'Gene', (123, 126))	('affected', 'Reg', (25, 33))	('knockdown', 'Var', (5, 14))	('drive', 'PosReg', (168, 173))	('PKM2', 'Gene', '5315', (0, 4))	('PKM2', 'Gene', (160, 164))	('p65', 'Gene', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('p65', 'Gene', '5970', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('PKM2', 'Gene', '5315', (160, 164))	('p65', 'Gene', '5970', (69, 72))
277759	30700935	In addition to stimulating cell proliferation, PKM2 translocation also promotes apoptosis via a caspase and Bcl-2 independent manner in response to stimuli like DNA damage or oxidative stress.	('promotes', 'PosReg', (71, 79))	('PKM2', 'Gene', '5315', (47, 51))	('cell proliferation', 'CPA', (27, 45))	('Bcl-2', 'Gene', (108, 113))	('translocation', 'Var', (52, 65))	('Bcl-2', 'Gene', '596', (108, 113))	('oxidative stress', 'Phenotype', 'HP:0025464', (175, 191))	('PKM2', 'Gene', (47, 51))	('apoptosis', 'CPA', (80, 89))
277760	30700935	Furthermore, PKM2 knockout in Eca109 and EC9706 cells activated caspase 3, down-regulated caspase 9, and increased expression of Bim.	('PKM2', 'Gene', (13, 17))	('activated', 'PosReg', (54, 63))	('Bim', 'Gene', (129, 132))	('Bim', 'Gene', '10018', (129, 132))	('PKM2', 'Gene', '5315', (13, 17))	('EC9706', 'CellLine', 'CVCL:E307', (41, 47))	('caspase 9', 'Gene', '842', (90, 99))	('caspase 9', 'Gene', (90, 99))	('expression', 'MPA', (115, 125))	('increased', 'PosReg', (105, 114))	('knockout', 'Var', (18, 26))	('down-regulated', 'NegReg', (75, 89))	('caspase 3', 'Gene', (64, 73))	('caspase 3', 'Gene', '836', (64, 73))
277773	30700935	In addition, knockdown of both PKM2 and GLS1 significantly reversed oxaliplatin-resistance in CRC cells.	('GLS1', 'Gene', (40, 44))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (68, 79))	('GLS1', 'Gene', '2744', (40, 44))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('PKM2', 'Gene', (31, 35))	('reversed', 'Reg', (59, 67))	('oxaliplatin-resistance', 'MPA', (68, 90))	('PKM2', 'Gene', '5315', (31, 35))	('knockdown', 'Var', (13, 22))
277779	30700935	A meta-analysis showed that high expression of PKM2 was associated with poor prognosis in esophageal squamous carcinoma, and highlighted its prognostic significance.	('squamous carcinoma', 'Phenotype', 'HP:0002860', (101, 119))	('PKM2', 'Gene', '5315', (47, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (90, 119))	('esophageal squamous carcinoma', 'Disease', (90, 119))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (90, 119))	('high', 'Var', (28, 32))	('PKM2', 'Gene', (47, 51))
277780	30700935	In addition, high PKM2 expression was associated with the clinical stage, tumor stage, nodal metastasis and differentiation, indicating its potential as a prognostic biomarker in esophageal cancer.	('clinical stage', 'CPA', (58, 72))	('esophageal cancer', 'Disease', (179, 196))	('nodal metastasis', 'CPA', (87, 103))	('associated', 'Reg', (38, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('high', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('PKM2', 'Gene', (18, 22))	('differentiation', 'CPA', (108, 123))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PKM2', 'Gene', '5315', (18, 22))	('tumor', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('expression', 'MPA', (23, 33))
277796	30700935	As mentioned above, nuclear PKM2 modulated the sensitivity of CRC cells to gefitinib and indicated that small molecule pharmacological disruption of nuclear PKM2 association with STAT3 is a potential avenue for overcoming EGFR-TKI resistance in CRC patients.	('sensitivity', 'MPA', (47, 58))	('PKM2', 'Gene', (157, 161))	('modulated', 'Reg', (33, 42))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('PKM2', 'Gene', (28, 32))	('patients', 'Species', '9606', (249, 257))	('PKM2', 'Gene', '5315', (157, 161))	('association', 'Interaction', (162, 173))	('EGFR', 'Gene', '1956', (222, 226))	('PKM2', 'Gene', '5315', (28, 32))	('STAT3', 'Gene', '6774', (179, 184))	('CRC', 'Phenotype', 'HP:0003003', (245, 248))	('gefitinib', 'Chemical', 'MESH:D000077156', (75, 84))	('STAT3', 'Gene', (179, 184))	('EGFR', 'Gene', (222, 226))	('disruption', 'Var', (135, 145))
277803	30700935	In addition, high levels of PKM2 in solid tumors are associated with poor prognosis.	('high levels', 'Var', (13, 24))	('PKM2', 'Gene', (28, 32))	('solid tumors', 'Disease', 'MESH:D009369', (36, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('PKM2', 'Gene', '5315', (28, 32))	('solid tumors', 'Disease', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
277843	26529033	A single HPV16 DNA+ tumor additionally harbored HPV16 E6*I mRNA but was p16INK4a negative (HPV16 E1 seropositive patient).	('tumor', 'Disease', (20, 25))	('patient', 'Species', '9606', (113, 120))	('HPV16', 'Species', '333760', (91, 96))	('p16INK4a', 'Gene', '1029', (72, 80))	('HPV16 E6*I', 'Var', (48, 58))	('HPV16', 'Species', '333760', (9, 14))	('E6*I', 'Var', (54, 58))	('HPV16', 'Species', '333760', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('sero', 'Chemical', '-', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('HPV16', 'Gene', (9, 14))	('p16INK4a', 'Gene', (72, 80))
277864	26529033	In addition to HPV functional markers that can be assessed in tumor tissues, antibodies to HPV early proteins, especially E6 and E7, have been demonstrated to be markers for HPV-driven SCC of the cervix, penis, and oropharynx.	('antibodies', 'Var', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('SCC of', 'Disease', (185, 191))	('tumor', 'Disease', (62, 67))	('HPV early', 'Gene', (91, 100))	('HPV', 'Species', '10566', (15, 18))	('markers', 'Reg', (162, 169))	('HPV', 'Species', '10566', (91, 94))	('HPV', 'Species', '10566', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
277871	26529033	Of these 1,561 ESCC patients, 357 were seropositive to at least one of the sixteen HPV early proteins from the eight most prevalent HR-HPV types: HPV16 (E1, E2, E6, E7); HPV18 (E6, E7); HPV31, 33, 35, 45, 52, and 58 (E6); or LR-HPV types 6 and 11 (E6, E7).	('ESCC', 'Disease', (15, 19))	('HR-HPV', 'Disease', (132, 138))	('sero', 'Chemical', '-', (39, 43))	('HPV', 'Species', '10566', (83, 86))	('HPV', 'Species', '10566', (146, 149))	('HPV', 'Species', '10566', (228, 231))	('HPV', 'Species', '10566', (170, 173))	('HPV', 'Species', '10566', (135, 138))	('patients', 'Species', '9606', (20, 28))	('HPV', 'Species', '10566', (186, 189))	('HPV31', 'Var', (186, 191))	('HPV16', 'Species', '333760', (146, 151))	('HR-HPV', 'Disease', 'MESH:D030361', (132, 138))
277900	26529033	All 133 ESCC patients' tissues were analyzed for the presence of: (i) HPV16 E6*I mRNA, (ii) ubC mRNA as a cellular mRNA positive control, and (iii) mRNA of the non-HPV16 types determined by genotyping and/or serological assays.	('E6*I', 'Var', (76, 80))	('ESCC', 'Disease', (8, 12))	('ubC', 'Chemical', '-', (92, 95))	('patients', 'Species', '9606', (13, 21))	('HPV16', 'Species', '333760', (164, 169))	('HPV16', 'Gene', (70, 75))	('HPV16', 'Species', '333760', (70, 75))	('sero', 'Chemical', '-', (208, 212))
277905	26529033	Each staining batch included tissue sections for HPV16 DNA+/RNA+ cervical cancer, and HPV DNA-negative (HPV DNA-) normal oral epithelium, which served to control for intra- and inter-day staining reproducibility and protocol performance.	('HPV', 'Species', '10566', (86, 89))	('HPV', 'Species', '10566', (104, 107))	('HPV', 'Species', '10566', (49, 52))	('cervical cancer', 'Disease', (65, 80))	('HPV16 DNA+/RNA+', 'Var', (49, 64))	('cervical cancer', 'Disease', 'MESH:D002583', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('HPV16', 'Species', '333760', (49, 54))
277924	26529033	HPV types identified were: HPV16 (four tumors); HPV33, 35, 45 (one tumor each), HPV11 (two tumors); and HPV16, 70 double infection (one tumor) (Table 2).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('HPV11', 'Species', '10580', (80, 85))	('infection', 'Disease', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('infection', 'Disease', 'MESH:D007239', (121, 130))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (91, 96))	('tumors', 'Disease', (39, 45))	('HPV16', 'Var', (104, 109))	('HPV', 'Species', '10566', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('HPV16', 'Species', '333760', (27, 32))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('HPV', 'Species', '10566', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (39, 44))	('HPV16', 'Species', '333760', (104, 109))	('HPV11', 'Var', (80, 85))	('tumors', 'Disease', (91, 97))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (48, 51))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('HPV', 'Species', '10566', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('HPV16', 'Var', (27, 32))	('HPV33', 'Var', (48, 53))
277925	26529033	Of the 118 tissues analyzed in a total of 170 RNA reactions (118 reactions for HPV16 and ubC and 52 additional reactions performed for a non-HPV16 type determined by genotyping or serological assays), a single tissue positive for HPV16 DNA exclusively by TS-E7-PCR/MPG also expressed HPV16 E6*I mRNA (Table 2).	('MPG', 'Gene', '4350', (265, 268))	('E6*I mRNA', 'Var', (290, 299))	('HPV16', 'Gene', (284, 289))	('HPV16', 'Species', '333760', (284, 289))	('ubC', 'Chemical', '-', (89, 92))	('MPG', 'Gene', (265, 268))	('HPV16', 'Gene', (230, 235))	('HPV16', 'Species', '333760', (230, 235))	('HPV16', 'Species', '333760', (79, 84))	('sero', 'Chemical', '-', (180, 184))	('HPV16', 'Species', '333760', (141, 146))
277935	26529033	Interestingly, only 33% of patients with HPV DNA- tumors were female, in contrast to the 70% females among patients with HPV DNA+ tumors (p=0.019).	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('HPV', 'Species', '10566', (41, 44))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('HPV', 'Var', (41, 44))	('HPV', 'Species', '10566', (121, 124))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('patients', 'Species', '9606', (107, 115))
277944	26529033	None of the tumors that were positive for other HPV DNA types (HPV33, 35, 45, 70, or 11) showed type-concordant E6*I or E6 fl mRNA.	('HPV', 'Species', '10566', (48, 51))	('HPV', 'Species', '10566', (63, 66))	('E6 fl mRNA', 'Var', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('E6*I', 'Var', (112, 116))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
277947	26529033	(i) viral load 1 copy per cell, (ii) presence of HPV type-concordant E6*I mRNA, and (iii) up-regulation of the cellular surrogate marker p16INK4a), none was positive for all three or even two functional markers.	('E6*I', 'Var', (69, 73))	('up-regulation', 'PosReg', (90, 103))	('p16INK4a', 'Gene', (137, 145))	('HPV', 'Species', '10566', (49, 52))	('viral load', 'MPA', (4, 14))	('p16INK4a', 'Gene', '1029', (137, 145))	('presence', 'Reg', (37, 45))
277948	26529033	Of the two HPV16 DNA+ tissues that displayed at least one functional marker, one harbored HPV16 mRNA but without p16INK4a up-regulation and the other showed up-regulated p16INK4a in the absence of HPV16 transcription.	('p16INK4a', 'Gene', '1029', (170, 178))	('p16INK4a', 'Gene', (113, 121))	('HPV16', 'Species', '333760', (197, 202))	('p16INK4a', 'Gene', (170, 178))	('p16INK4a', 'Gene', '1029', (113, 121))	('mRNA', 'Var', (96, 100))	('HPV16', 'Species', '333760', (11, 16))	('up-regulated', 'PosReg', (157, 169))	('HPV16', 'Species', '333760', (90, 95))	('HPV16', 'Gene', (90, 95))
277972	26529033	We found a single HPV16 DNA+ ESCC tumor that expressed HPV16 mRNA, however, without p16INK4a up-regulation.	('tumor', 'Disease', (34, 39))	('p16INK4a', 'Gene', (84, 92))	('p16INK4a', 'Gene', '1029', (84, 92))	('HPV16', 'Species', '333760', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('HPV16', 'Species', '333760', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('HPV16 mRNA', 'Var', (55, 65))
277973	26529033	HPV16 E6*I transcripts can be abundantly expressed in the cervix in the absence of malignant transformation, as well as in some non-HPV-driven oropharyngeal and laryngeal cancers.	('HPV', 'Species', '10566', (0, 3))	('HPV16', 'Species', '333760', (0, 5))	('HPV', 'Species', '10566', (132, 135))	('laryngeal cancers', 'Disease', 'MESH:D007822', (161, 178))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (161, 178))	('HPV16', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('laryngeal cancers', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('E6*I', 'Var', (6, 10))
277974	26529033	The E6*I transcripts are, therefore, markers of active viral infection but are not transformation-specific; thus we did not consider this single low viral load HPV DNA+/RNA+ ESCC an HPV-driven tumor.	('HPV', 'Species', '10566', (182, 185))	('active viral infection', 'Disease', (48, 70))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('active viral infection', 'Disease', 'MESH:D001102', (48, 70))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('HPV', 'Species', '10566', (160, 163))	('tumor', 'Disease', (193, 198))	('E6*I', 'Var', (4, 8))
277983	26529033	Lack of CDKN2a mutations in combination with p16INK4a up-regulation was demonstrated for HPV RNA+ cervical cancers and cervical cancer cell lines, as well as for the HPV RNA+ tumors of the head-and-neck including oral, oropharyngeal and laryngeal tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Disease', (175, 181))	('cervical cancers', 'Disease', (98, 114))	('tumors', 'Disease', (247, 253))	('cervical cancer', 'Disease', 'MESH:D002583', (119, 134))	('laryngeal tumors', 'Disease', 'MESH:D007822', (237, 253))	('oropharyngeal and laryngeal tumors', 'Phenotype', 'HP:0100638', (219, 253))	('cervical cancers', 'Disease', 'MESH:D002583', (98, 114))	('cervical cancer', 'Disease', (119, 134))	('p16INK4a', 'Gene', (45, 53))	('oral', 'Disease', (213, 217))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('laryngeal tumors', 'Disease', (237, 253))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (237, 253))	('mutations', 'Var', (15, 24))	('up-regulation', 'PosReg', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HPV', 'Species', '10566', (89, 92))	('p16INK4a', 'Gene', '1029', (45, 53))	('CDKN2a', 'Gene', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumors of the head-and-neck', 'Phenotype', 'HP:0012288', (175, 202))	('cervical cancer', 'Disease', 'MESH:D002583', (98, 113))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('HPV', 'Species', '10566', (166, 169))	('oropharyngeal', 'Disease', (219, 232))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
277987	26529033	For the one case with HPV16 DNA+ ESCC with p16INK4a up-regulation in our study, the low viral load and absence of HPV16 E6*I mRNA do not support classification of this case as HPV16-driven.	('up-regulation', 'PosReg', (52, 65))	('HPV16', 'Species', '333760', (22, 27))	('HPV16', 'Gene', (114, 119))	('p16INK4a', 'Gene', (43, 51))	('p16INK4a', 'Gene', '1029', (43, 51))	('E6*I', 'Var', (120, 124))	('HPV16', 'Species', '333760', (176, 181))	('HPV16', 'Species', '333760', (114, 119))	('viral load', 'MPA', (88, 98))
277989	26529033	Two studies found p16INK4a positivity statistically significantly associated with HPV DNA+ ESCC.	('p16INK4a', 'Gene', '1029', (18, 26))	('positivity', 'Var', (27, 37))	('associated', 'Reg', (66, 76))	('p16INK4a', 'Gene', (18, 26))	('HPV DNA+ ESCC', 'Disease', (82, 95))	('HPV', 'Species', '10566', (82, 85))
277991	26529033	Castillo and colleagues used 10% as a cut-off to define p16INK4a positivity and reported high p16INK4a positivity in both HPV DNA+ (56%) and HPV DNA- tissues (33%).	('positivity', 'MPA', (103, 113))	('HPV', 'Species', '10566', (122, 125))	('HPV', 'Species', '10566', (141, 144))	('p16INK4a', 'Gene', '1029', (56, 64))	('positivity', 'Var', (65, 75))	('p16INK4a', 'Gene', '1029', (94, 102))	('p16INK4a', 'Gene', (56, 64))	('p16INK4a', 'Gene', (94, 102))
278003	26529033	More precisely, HPV16 E6 seropositivity was present in prediagnostic samples of 35% of OPSCC patients and 0.6% controls (OR, 274; 95% CI 110 to 681) but was not associated with cancer at other sites including esophagus.	('esophagus', 'Disease', (209, 218))	('HPV16', 'Species', '333760', (16, 21))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('E6 seropositivity', 'Var', (22, 39))	('associated', 'Reg', (161, 171))	('OPSCC', 'Phenotype', 'HP:0012182', (87, 92))	('HPV16', 'Gene', (16, 21))	('OPSCC', 'Disease', (87, 92))	('sero', 'Chemical', '-', (25, 29))	('seropositivity', 'Var', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('patients', 'Species', '9606', (93, 101))
278012	28123547	CEP55 overexpression predicts poor prognosis in patients with locally advanced esophageal squamous cell carcinoma Development of esophageal squamous cell carcinoma (ESCC) involves alterations in multiple genes with corresponding proteins.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('men', 'Species', '9606', (121, 124))	('alterations', 'Var', (180, 191))	('CEP55', 'Gene', '55165', (0, 5))	('CEP55', 'Gene', (0, 5))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (129, 163))	('proteins', 'Protein', (229, 237))	('overexpression', 'PosReg', (6, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))	('patients', 'Species', '9606', (48, 56))	('esophageal squamous cell carcinoma', 'Disease', (129, 163))
278019	28123547	Overexpression of CEP55 was significantly associated with differentiation degree (P=0.022), T stage (P=0.019), lymph node metastasis (P=0.033), clinicopathological staging (P=0.002) and tumor recurrence (P=0.021) in locally advanced ESCC patients.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('T stage', 'CPA', (92, 99))	('lymph node metastasis', 'CPA', (111, 132))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('associated', 'Reg', (42, 52))	('tumor', 'Disease', (186, 191))	('locally advanced ESCC', 'Disease', (216, 237))	('CEP55', 'Gene', '55165', (18, 23))	('Overexpression', 'Var', (0, 14))	('ESCC', 'Disease', (233, 237))	('CEP55', 'Gene', (18, 23))	('differentiation degree', 'CPA', (58, 80))	('patients', 'Species', '9606', (238, 246))
278029	28123547	In our previous study, some molecular indicators (including C-C chemokine receptor type 7 and vascular endothelial growth factor-C) were identified that may be useful to predict lymphatic metastatic recurrence in pN0 esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (217, 251))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (228, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('lymphatic metastatic recurrence', 'CPA', (178, 209))	('esophageal squamous cell carcinoma', 'Disease', (217, 251))	('C-C chemokine receptor type 7 and vascular endothelial growth factor-C', 'Gene', '1236;7424', (60, 130))	('pN0', 'Var', (213, 216))
278033	28123547	Overexpression of CEP55 leads to cytokinesis defects and multinucleated cells increase, which may cause tumorigenesis.	('cause', 'Reg', (98, 103))	('cytokinesis defects', 'CPA', (33, 52))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('increase', 'PosReg', (78, 86))	('CEP55', 'Gene', '55165', (18, 23))	('Overexpression', 'Var', (0, 14))	('multinucleated cells', 'CPA', (57, 77))	('CEP55', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
278035	28123547	Overexpression of CEP55 in mammalian cells correlates with increased cell migration and invasion.	('mammalian', 'Species', '9606', (27, 36))	('invasion', 'CPA', (88, 96))	('cell migration', 'CPA', (69, 83))	('CEP55', 'Gene', '55165', (18, 23))	('Overexpression', 'Var', (0, 14))	('CEP55', 'Gene', (18, 23))	('increased', 'PosReg', (59, 68))
278076	28123547	Typically, patients with pT3-4 are advised to receive radiotherapy and those with pN1 should receive chemotherapy as a minimum.	('patients', 'Species', '9606', (11, 19))	('pN1', 'Gene', (82, 85))	('pN1', 'Gene', '5270', (82, 85))	('pT3-4', 'Var', (25, 30))
278123	28123547	Failure of cytokinesis results in tetraploid cells, which are chromosomally unstable and hence more prone to tumorigenesis.	('prone', 'Reg', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('results in', 'Reg', (23, 33))	('tetraploid cells', 'Var', (34, 50))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
278124	28123547	Overexpression of CEP55 causes cytokinesis defects via an increase of chromosomally unstable binucleated cells, suggesting CEP55 overexpression is associated with tumorigenesis.	('increase', 'PosReg', (58, 66))	('associated', 'Reg', (147, 157))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('overexpression', 'PosReg', (129, 143))	('chromosomally unstable binucleated cells', 'CPA', (70, 110))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cytokinesis defects', 'CPA', (31, 50))	('CEP55', 'Gene', '55165', (123, 128))	('tumor', 'Disease', (163, 168))	('Overexpression', 'Var', (0, 14))	('CEP55', 'Gene', (18, 23))	('CEP55', 'Gene', (123, 128))	('CEP55', 'Gene', '55165', (18, 23))
278134	28123547	Further research should be performed to identify whether knockdown of the CEP55 gene can retard the invasiveness of ESCC cells.	('CEP55', 'Gene', '55165', (74, 79))	('CEP55', 'Gene', (74, 79))	('retard', 'NegReg', (89, 95))	('invasiveness of ESCC cells', 'CPA', (100, 126))	('knockdown', 'Var', (57, 66))
278139	25097879	Pooled hazard ratios of miR-21and miR-375 for OS in ESCC were calculated.	('miR-375', 'Var', (34, 41))	('miR-21', 'Gene', (24, 30))	('ESCC', 'Disease', (52, 56))	('miR-21', 'Gene', '406991', (24, 30))
278145	25097879	demonstrated that more than 50% of miRNA genes are located in fragile sites and cancer-associated genomic regions, suggesting that miRNAs may play a vital role in the pathogenesis of human cancers and are able to dramatically change the biological function of organisms.	('fragile', 'Disease', (62, 69))	('play', 'Reg', (142, 146))	('change', 'Reg', (226, 232))	('fragile', 'Disease', 'MESH:D005600', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('cancers', 'Disease', (189, 196))	('biological function', 'CPA', (237, 256))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('miRNA genes', 'Gene', (35, 46))	('miRNAs', 'Var', (131, 137))
278146	25097879	Growing evidence has indicated that aberrant expression of miRNAs has been linked to development and progression of cancer and has been shown to have prognostic significance in several tumor types, including colon, lung, breast, and ovarian cancer.	('tumor', 'Disease', (185, 190))	('development', 'CPA', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('ovarian cancer', 'Phenotype', 'HP:0100615', (233, 247))	('ovarian cancer', 'Disease', 'MESH:D010051', (233, 247))	('breast', 'Disease', (221, 227))	('miRNAs', 'Protein', (59, 65))	('expression', 'MPA', (45, 55))	('aberrant', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('linked', 'Reg', (75, 81))	('lung', 'Disease', (215, 219))	('ovarian cancer', 'Disease', (233, 247))	('colon', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('significance', 'Reg', (161, 173))
278154	25097879	The promoter of miR-375 was frequently hypermethylated in EC and miR-375 is a negative regulator of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in EC.	('negative', 'NegReg', (78, 86))	('miR-375', 'Gene', (65, 72))	('PDK1', 'Gene', '5170', (147, 151))	('PDK1', 'Gene', (147, 151))	('miR-375', 'Gene', (16, 23))	('3-phosphoinositide-dependent protein kinase-1', 'Gene', (100, 145))	('hypermethylated', 'Var', (39, 54))	('3-phosphoinositide-dependent protein kinase-1', 'Gene', '5170', (100, 145))
278156	25097879	Functional assays demonstrated that miR-375 could inhibit clonogenicity, cell motility, cell proliferation, tumor formation, and metastasis in mice.	('tumor formation', 'CPA', (108, 123))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('miR-375', 'Var', (36, 43))	('inhibit', 'NegReg', (50, 57))	('clonogenicity', 'CPA', (58, 71))	('cell motility', 'CPA', (73, 86))	('metastasis', 'CPA', (129, 139))	('cell proliferation', 'CPA', (88, 106))	('mice', 'Species', '10090', (143, 147))
278163	25097879	suggest that expression patterns of miR-21, miR-181b, and miR-146b, alone or in combination with inflammatory risk score can be used as prognostic classifiers for patients with ESCC.	('miR-146b', 'Gene', (58, 66))	('miR-181b', 'Var', (44, 52))	('ESCC', 'Disease', (177, 181))	('miR-146b', 'Gene', '574447', (58, 66))	('miR-21', 'Gene', (36, 42))
278186	23833663	Such inflammatory processes are often associated with hypermethylation of promoter regions in tumor-suppressor and/or pro-apoptotic genes.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('associated', 'Reg', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('hypermethylation', 'Var', (54, 70))
278216	23833663	Before adding TNF-alpha, the SK-GT-4 and OE19 cells were treated with AA at 5, 10, 20 and 40 muM, respectively, for 12 h. The CellTiter-Glo assay was performed according to the manufacturer's instructions (G7570, Promega, Madison, WI, USA).	('TNF-alpha', 'Gene', '7124', (14, 23))	('TNF-alpha', 'Gene', (14, 23))	('muM', 'Gene', '56925', (93, 96))	('G7570', 'Var', (206, 211))	('muM', 'Gene', (93, 96))	('SK-GT-4', 'CellLine', 'CVCL:2195', (29, 36))
278240	23833663	Furthermore, the cell death percentage of OE19 cells was higher than SK-GT-4 cells.	('OE19', 'Var', (42, 46))	('cell death percentage', 'CPA', (17, 38))	('SK-GT-4', 'CellLine', 'CVCL:2195', (69, 76))	('higher', 'PosReg', (57, 63))
278300	23833663	During carcinogenesis, there is a drive in the cancer cells to acquire mutations that render them resistant to apoptosis.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (7, 21))	('mutations', 'Var', (71, 80))	('carcinogenesis', 'Disease', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
278309	23123827	This review has a threefold purpose: 1) describe S100A9 structural elements important for its biological activity, 2) describe S100A9 biology in the context of the immune system, and 3) illustrate the role of S100A9 in the development of malignancy via interactions with the immune system and other cellular processes.	('S100A9', 'Var', (209, 215))	('S100A9', 'Gene', (127, 133))	('rat', 'Species', '10116', (192, 195))	('S100A9', 'Gene', (49, 55))	('malignancy', 'Disease', 'MESH:D009369', (238, 248))	('malignancy', 'Disease', (238, 248))	('interactions', 'Interaction', (253, 265))
278338	23123827	In the context of normal human gastrointestinal physiology, S100A9 is located in the cytoplasm and plasma membrane of pancreatic cell lines, whereas in the esophageal mucosa, S100A9 is located within the nuclei.	('human', 'Species', '9606', (25, 30))	('pancreatic', 'Disease', 'MESH:D010195', (118, 128))	('pancreatic', 'Disease', (118, 128))	('S100A9', 'Var', (60, 66))
278339	23123827	S100A8 and S100A9 are minimally expressed in normal esophageal epithelium, but S100A9 is expressed across the spectrum of Barrett's esophagus through adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('adenocarcinoma', 'Disease', (150, 164))	('S100A9', 'Var', (79, 85))	('adenocarcinoma', 'Disease', 'MESH:D000230', (150, 164))	("Barrett's esophagus", 'Disease', (122, 141))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (122, 141))
278342	23123827	It has become clear that S100A9 localizes with its partner S100A8 in many biological processes but may act as a sole player in other cancers.	('localizes', 'Reg', (32, 41))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('S100A9', 'Var', (25, 31))
278343	23123827	One study in particular examined a variety of cell lines and found S100A9, S100A8, or S100A8/A9 located within multiple cancer cell types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('S100A9', 'Var', (67, 73))	('S100A8/A9', 'Var', (86, 95))	('S100A8', 'Var', (75, 81))
278347	23123827	S100A9 transfers arachidonic acid to gp91phox of the NADPH complex while S100A8 binds to p67phox and rac-2 of the NADPH oxidase complex leading to the oxidative burst important in inflammatory cells (Figure 2).	('arachidonic acid', 'MPA', (17, 33))	('p67phox', 'Gene', (89, 96))	('oxidative burst', 'Phenotype', 'HP:0003203', (151, 166))	('S100A9', 'Var', (0, 6))	('oxidative burst', 'MPA', (151, 166))	('rac-2', 'Gene', (101, 106))	('rac-2', 'Gene', '5880', (101, 106))	('leading to', 'Reg', (136, 146))	('NADPH', 'Chemical', 'MESH:D009249', (114, 119))	('S100A8', 'Var', (73, 79))	('p67phox', 'Gene', '4688', (89, 96))	('gp91phox', 'Gene', '1536', (37, 45))	('arachidonic acid', 'Chemical', 'MESH:D016718', (17, 33))	('NADPH', 'Chemical', 'MESH:D009249', (53, 58))	('gp91phox', 'Gene', (37, 45))
278349	23123827	The C-terminus of S100A9 (residues 103-105) in either the homodimeric or heterodimeric state with S100A8 facilitates arachidonic acid transport.	('arachidonic acid', 'Chemical', 'MESH:D016718', (117, 133))	('S100A8', 'Var', (98, 104))	('arachidonic acid transport', 'MPA', (117, 143))	('S100A9', 'Gene', (18, 24))	('facilitates', 'PosReg', (105, 116))
278351	23123827	The NADPH oxidative burst is decreased in neutrophils from S100A9 knockout mice.	('NADPH', 'Chemical', 'MESH:D009249', (4, 9))	('knockout', 'Var', (66, 74))	('mice', 'Species', '10090', (75, 79))	('oxidative burst', 'Phenotype', 'HP:0003203', (10, 25))	('S100A9', 'Gene', (59, 65))	('decreased', 'NegReg', (29, 38))	('NADPH oxidative burst', 'MPA', (4, 25))
278352	23123827	Two mutations, (H103A,H104A,H105A,K106A) S100A9 mutant and truncation of S100A9 to residues 1-100 eliminated the ability of S100A9 to activate the NADPH oxidase complex presumably due to lack of arachidonic acid migration to the plasma membrane.	('activate', 'PosReg', (134, 142))	('H103A', 'Var', (16, 21))	('NADPH', 'Chemical', 'MESH:D009249', (147, 152))	('rat', 'Species', '10116', (215, 218))	('H104A', 'SUBSTITUTION', 'None', (22, 27))	('H105A', 'SUBSTITUTION', 'None', (28, 33))	('NADPH oxidase complex', 'Enzyme', (147, 168))	('lack of arachidonic acid', 'Phenotype', 'HP:0020197', (187, 211))	('K106A', 'Mutation', 'p.K106A', (34, 39))	('arachidonic acid', 'Chemical', 'MESH:D016718', (195, 211))	('eliminated', 'NegReg', (98, 108))	('ability', 'MPA', (113, 120))	('S100A9', 'Var', (124, 130))	('H105A', 'Var', (28, 33))	('H103A', 'SUBSTITUTION', 'None', (16, 21))	('S100A9', 'Gene', (41, 47))	('K106A', 'Var', (34, 39))	('arachidonic acid migration to the plasma membrane', 'MPA', (195, 244))	('H104A', 'Var', (22, 27))	('truncation', 'Var', (59, 69))	('lack', 'NegReg', (187, 191))
278353	23123827	Studies in HaCaT keratinocytes that over-express S100A9 demonstrate increased NADPH oxidase and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity whereas HeLa cells bearing the (H103A,H104A,H105A,K106A) S100A9 mutation are unable to bind arachidonic acid and fail to promote PMA (phorbol myristate acetate)-induced NADPH oxidase activity.	('H103A', 'Var', (212, 217))	('HaCaT', 'CellLine', 'CVCL:0038', (11, 16))	('rat', 'Species', '10116', (63, 66))	('H104A', 'SUBSTITUTION', 'None', (218, 223))	('nuclear factor kappa-light-chain-enhancer', 'MPA', (96, 137))	('K106A', 'Mutation', 'p.K106A', (230, 235))	('increased', 'PosReg', (68, 77))	('over-express', 'PosReg', (36, 48))	('NADPH', 'Chemical', 'MESH:D009249', (78, 83))	('NADPH', 'Chemical', 'MESH:D009249', (349, 354))	('H103A', 'SUBSTITUTION', 'None', (212, 217))	('arachidonic acid', 'Chemical', 'MESH:D016718', (272, 288))	('NADPH', 'MPA', (78, 83))	('arachidonic acid', 'MPA', (272, 288))	('HeLa', 'CellLine', 'CVCL:0030', (188, 192))	('S100A9', 'Gene', (49, 55))	('PMA', 'Chemical', 'MESH:D013755', (309, 312))	('H105A', 'SUBSTITUTION', 'None', (224, 229))	('activity', 'MPA', (171, 179))	('unable', 'NegReg', (257, 263))	('K106A', 'Var', (230, 235))	('phorbol myristate acetate', 'Chemical', 'MESH:D013755', (314, 339))	('S100A9', 'Gene', (237, 243))	('bind', 'Interaction', (267, 271))	('rat', 'Species', '10116', (19, 22))	('H104A', 'Var', (218, 223))	('H105A', 'Var', (224, 229))
278354	23123827	In general, S100A9 appears to contribute to the control of the oxidative potential of the NADPH complex.	('oxidative potential of the', 'MPA', (63, 89))	('NADPH', 'Chemical', 'MESH:D009249', (90, 95))	('S100A9', 'Var', (12, 18))	('control', 'MPA', (48, 55))
278355	23123827	Both S100A8 and S100A9 have the capability of being nitrosylated (R-NO) which in general results in decreased inflammatory activity.	('R-NO', 'Chemical', '-', (66, 70))	('inflammatory activity', 'CPA', (110, 131))	('S100A9', 'Var', (16, 22))	('decreased', 'NegReg', (100, 109))	('S100A8', 'Var', (5, 11))
278357	23123827	Translocation of cytosolic NADPH oxidase components such as p47phox and p67phox to the plasma membrane, and subsequent superoxide generation are inhibited by nitrosylated residues on the S100A8 subunit of the S100A8/A9 complex.	('p47phox', 'Gene', (60, 67))	('p67phox', 'Gene', (72, 79))	('nitrosylated residues', 'Var', (158, 179))	('NADPH', 'Chemical', 'MESH:D009249', (27, 32))	('superoxide', 'Chemical', 'MESH:D013481', (119, 129))	('rat', 'Species', '10116', (134, 137))	('superoxide generation', 'MPA', (119, 140))	('p47phox', 'Gene', '653361', (60, 67))	('p67phox', 'Gene', '4688', (72, 79))	('Translocation', 'MPA', (0, 13))	('inhibited', 'NegReg', (145, 154))
278361	23123827	Current evidence supports myeloid secretion of S100A8/A9 which in turn binds to carboxylated glycans on RAGE or RAGE itself in vitro and in many cell types.	('glycans', 'Chemical', 'MESH:D011134', (93, 100))	('S100A8/A9', 'Var', (47, 56))	('carboxylated', 'Protein', (80, 92))	('myeloid secretion', 'MPA', (26, 43))	('binds', 'Interaction', (71, 76))
278362	23123827	The S100A8/A9-RAGE complex can activate signaling pathways including mitogen-activated protein kinase (MAPK) and NF-kappaB in colon tumor cells and NFkappaB in tissues from a murine model of skin carcinogenesis induced by DMBA/TPA.	('signaling pathways', 'Pathway', (40, 58))	('colon tumor', 'Disease', (126, 137))	('S100A8/A9-RAGE', 'Var', (4, 18))	('activate', 'PosReg', (31, 39))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (191, 210))	('MAPK', 'Gene', '5595;5594;5595', (103, 107))	('murine', 'Species', '10090', (175, 181))	('DMBA/TPA', 'Chemical', '-', (222, 230))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('NF-kappaB', 'Gene', (113, 122))	('MAPK', 'Gene', (103, 107))	('colon tumor', 'Disease', 'MESH:D015179', (126, 137))	('skin carcinogenesis', 'Disease', (191, 210))	('NFkappaB', 'Gene', (148, 156))	('colon tumor', 'Phenotype', 'HP:0100273', (126, 137))
278363	23123827	For example, in a S100A9 null murine system, it was determined that TLR4-MD2 and not RAGE was responsible for S100A8/A9 mediated effects.	('TLR4-MD2', 'Gene', (68, 76))	('murine', 'Species', '10090', (30, 36))	('S100A8/A9', 'Var', (110, 119))
278365	23123827	Calcium dependent tetramer formation of S100A8/A9 is essential for the formation of microtubules and has been measured in vitro.	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	('S100A8/A9', 'Var', (40, 49))	('formation of microtubules', 'MPA', (71, 96))
278366	23123827	In epithelial cells, calcium serves as a secondary messenger and binds to S100A8 and S100A9 and induces their translocation to keratin intermediate filaments thought to mediate cellular migration.	('translocation to keratin intermediate filaments', 'MPA', (110, 157))	('binds', 'Interaction', (65, 70))	('S100A8', 'Gene', (74, 80))	('rat', 'Species', '10116', (129, 132))	('induces', 'Reg', (96, 103))	('S100A9', 'Var', (85, 91))	('calcium', 'Chemical', 'MESH:D002118', (21, 28))	('rat', 'Species', '10116', (189, 192))
278370	23123827	In the extra-cellular space, S100A8/A9 not only binds to arachidonic acid in a calcium dependent manner, but has interactions with the major fatty acid transporter of endothelial cells (CD36) to promote fatty acid uptake and heparin sulfate proteoglycans via the S100A9 subunit thereby promoting myeloid cell migration.	('myeloid cell migration', 'CPA', (296, 318))	('S100A8/A9', 'Var', (29, 38))	('fatty acid uptake', 'MPA', (203, 220))	('fatty acid', 'Chemical', 'MESH:D005227', (203, 213))	('fatty acid', 'Chemical', 'MESH:D005227', (141, 151))	('promoting', 'PosReg', (286, 295))	('calcium', 'Chemical', 'MESH:D002118', (79, 86))	('heparin sulfate proteoglycans', 'Protein', (225, 254))	('rat', 'Species', '10116', (312, 315))	('promote', 'PosReg', (195, 202))	('arachidonic acid', 'Chemical', 'MESH:D016718', (57, 73))	('CD36', 'Species', '42374', (186, 190))	('glycans', 'Chemical', 'MESH:D011134', (247, 254))	('interactions', 'Interaction', (113, 125))
278372	23123827	S100A8/A9 is itself able to block the metalloproteinase (MMP) degradation of the extra-cellular matrix by sequestration of zinc, thus forming a negative feedback loop.	('block', 'NegReg', (28, 33))	('MMP', 'Gene', (57, 60))	('MMP', 'Gene', '4313;4318', (57, 60))	('rat', 'Species', '10116', (113, 116))	('S100A8/A9', 'Var', (0, 9))	('sequestration', 'MPA', (106, 119))
278373	23123827	The zinc binding motif on S100A9 (H92-E97) is responsible for inhibiting the spread and phagocytic activity of adherent peritoneal cells presumable by this mechanism.	('inhibiting', 'NegReg', (62, 72))	('H92-E97', 'CellLine', 'CVCL:8607', (34, 41))	('H92-E97', 'Var', (34, 41))
278374	23123827	By its interaction with cytoskeletal components and extracellular matrix factors, S100A8/A9 can promote inflammation and also create the molecular environment responsible for termination of biological activity in the presence of divalent ions such as calcium and zinc.	('inflammation', 'Disease', (104, 116))	('interaction', 'Interaction', (7, 18))	('S100A8/A9', 'Var', (82, 91))	('promote', 'PosReg', (96, 103))	('calcium', 'Chemical', 'MESH:D002118', (251, 258))	('inflammation', 'Disease', 'MESH:D007249', (104, 116))
278379	23123827	In a rheumatoid arthritis model, S100A8 and S100A9 induced the expression and secretion of pro-inflammatory cytokines by monocytes such as IL-6, CXCL8, IL-1beta, and TNF-alpha.	('induced', 'Reg', (51, 58))	('IL-1beta', 'Gene', '3553', (152, 160))	('arthritis', 'Phenotype', 'HP:0001369', (16, 25))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (5, 25))	('secretion of pro-inflammatory cytokines', 'MPA', (78, 117))	('CXCL8', 'Gene', '3576', (145, 150))	('expression', 'MPA', (63, 73))	('CXCL8', 'Gene', (145, 150))	('S100A8', 'Var', (33, 39))	('rheumatoid arthritis', 'Disease', (5, 25))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (5, 25))	('S100A9', 'Var', (44, 50))	('IL-1beta', 'Gene', (152, 160))
278381	23123827	S100A9 null mice and S100A9 null granulocytes in vitro also demonstrate reduced recruitment of granulocytes.	('recruitment', 'MPA', (80, 91))	('reduced', 'NegReg', (72, 79))	('S100A9', 'Var', (21, 27))	('rat', 'Species', '10116', (67, 70))	('S100A9', 'Gene', (0, 6))	('mice', 'Species', '10090', (12, 16))
278387	23123827	Even though S100A9 is not important until later in the development of different cell types, knock-out of its binding partner S100A8 in mice causes early resorption of the embryo.	('early resorption of the embryo', 'CPA', (147, 177))	('causes', 'Reg', (140, 146))	('knock-out', 'Var', (92, 101))	('mice', 'Species', '10090', (135, 139))	('early resorption', 'Phenotype', 'HP:0002797', (147, 163))	('S100A8', 'Gene', (125, 131))
278391	23123827	However, differentiation of HL-60 cells in response to ATRA was reduced by 40% when treated with S100A9-siRNA so elements other than S100A9 may be important for maturation.	('rat', 'Species', '10116', (165, 168))	('differentiation', 'CPA', (9, 24))	('S100A9-siRNA', 'Var', (97, 109))	('ATRA', 'Chemical', 'MESH:D014212', (55, 59))	('reduced', 'NegReg', (64, 71))	('HL-60', 'CellLine', 'CVCL:0002', (28, 33))
278393	23123827	The role of S100A9 in the maturation of myeloid cells is not completely known, but it is interesting to note that early myeloid cells called myeloid derived suppressor cells (MDSC) may be induced by S100A9 and are able to suppress the immune response to cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('rat', 'Species', '10116', (30, 33))	('suppress', 'NegReg', (222, 230))	('cancer', 'Disease', (254, 260))	('S100A9', 'Var', (199, 205))	('induced', 'PosReg', (188, 195))
278395	23123827	Human MDSCs are a heterogeneous population of early myeloid cells that exhibit a multitude of cell surface markers including: CD11b, HLADRlow/-, CD33, CD15, CD14, and IL4Ralpha.	('Human', 'Species', '9606', (0, 5))	('CD14', 'Gene', (157, 161))	('IL4Ralpha', 'Gene', '3566', (167, 176))	('CD14', 'Gene', '929', (157, 161))	('IL4Ralpha', 'Gene', (167, 176))	('CD33', 'Gene', '945', (145, 149))	('CD15', 'Gene', (151, 155))	('CD33', 'Gene', (145, 149))	('CD15', 'Gene', '2526', (151, 155))	('CD11b', 'Var', (126, 131))
278401	23123827	On the biochemical level, it may be possible that S100A8/A9 on MDSCs binds to carboxylated glycans on endothelial surfaces or RAGE on the tumor cell to promote migration of MDSCs.	('rat', 'Species', '10116', (163, 166))	('S100A8/A9', 'Var', (50, 59))	('tumor', 'Disease', (138, 143))	('binds', 'Interaction', (69, 74))	('migration', 'CPA', (160, 169))	('glycans', 'Chemical', 'MESH:D011134', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('carboxylated glycans', 'Protein', (78, 98))	('promote', 'PosReg', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
278402	23123827	S100A8/A9 is also expressed by tumor cells and may provide a mechanism for recruiting additional MDSC into the tumor microenvironment by binding to RAGE on MDSCs and promoting NFkappaB inflammatory pathway signal transduction.	('binding', 'Interaction', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('promoting', 'PosReg', (166, 175))	('tumor', 'Disease', (31, 36))	('NFkappaB inflammatory pathway signal transduction', 'Pathway', (176, 225))	('S100A8/A9', 'Var', (0, 9))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
278405	23123827	S100A9 levels are also increased in the stroma of nasopharyngeal carcinoma, and in transitional cell carcinomas of the bladder.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('S100A9', 'Var', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('carcinomas of the bladder', 'Disease', 'MESH:D001749', (101, 126))	('carcinomas of the bladder', 'Disease', (101, 126))	('stroma of nasopharyngeal carcinoma', 'Disease', (40, 74))	('stroma of nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (40, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('increased', 'PosReg', (23, 32))	('transitional cell carcinomas of the bladder', 'Phenotype', 'HP:0006740', (83, 126))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (50, 74))
278407	23123827	In non-small cell lung adenocarcinoma, S100A9 is associated with a poor prognosis.	('small cell lung adenocarcinoma', 'Phenotype', 'HP:0030357', (7, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('non-small cell lung adenocarcinoma', 'Phenotype', 'HP:0030358', (3, 37))	('cell lung adenocarcinoma', 'Disease', (13, 37))	('S100A9', 'Var', (39, 45))	('cell lung adenocarcinoma', 'Disease', 'MESH:D000077192', (13, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (18, 37))
278410	23123827	S100A8/A9 levels were increased in the poor survival group in the non-macrophage component of the stroma, but in the extended survival group S100A8/A9 was increased in the non-macrophage component of tumor cell islets.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('S100A8/A9', 'MPA', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('increased', 'PosReg', (22, 31))	('S100A8/A9', 'Var', (141, 150))
278412	23123827	S100A8/A9 may also function in M1 macrophages in conjunction with reactive oxygen species to suppress cancer.	('suppress', 'NegReg', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('S100A8/A9', 'Var', (0, 9))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (66, 89))
278415	23123827	S100A8/A9 may function within M1 macrophages to suppress cancer, but may function with TGF-beta, VEGF-A and TNF-alpha to promote cancer.	('suppress', 'NegReg', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('S100A8/A9', 'Var', (0, 9))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('promote', 'PosReg', (121, 128))
278416	23123827	Depending on the molecular environment S100A9 can promote or inhibit tumor growth in lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('lung cancer', 'Disease', (85, 96))	('promote', 'PosReg', (50, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', (69, 74))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('inhibit', 'NegReg', (61, 68))	('S100A9', 'Var', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
278418	23123827	In pancreatic cancer S100A9 may interact with the TGF-beta signaling pathway to influence cell growth and migration.	('S100A9', 'Var', (21, 27))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('interact', 'Reg', (32, 40))	('rat', 'Species', '10116', (109, 112))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('influence', 'Reg', (80, 89))	('TGF-beta signaling pathway', 'Pathway', (50, 76))
278419	23123827	Over half of pancreatic cancers are proposed to have a mutated component of the Smad4-mediated TGF-beta signaling pathway.	('pancreatic cancers', 'Phenotype', 'HP:0002894', (13, 31))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutated', 'Var', (55, 62))	('Smad4', 'Gene', (80, 85))	('Smad4', 'Gene', '4089', (80, 85))	('pancreatic cancers', 'Disease', 'MESH:D010190', (13, 31))	('pancreatic cancers', 'Disease', (13, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (13, 30))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))
278420	23123827	With the lack of Smad4, S100A9 may be preferentially expressed compared to S100A8 in pancreatic adenocarcinoma.	('Smad4', 'Gene', (17, 22))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (85, 110))	('Smad4', 'Gene', '4089', (17, 22))	('pancreatic adenocarcinoma', 'Disease', (85, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (85, 110))	('S100A9', 'Var', (24, 30))	('preferentially', 'PosReg', (38, 52))
278421	23123827	Over 50% of pancreatic cancers lose expression of Smad4 late in the disease course and knockdown of Smad4 in pancreatic cancer cells abolishes TGF-beta-mediated cell cycle arrest.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (12, 29))	('abolishes', 'NegReg', (133, 142))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (161, 178))	('pancreatic cancer', 'Disease', (109, 126))	('Smad4', 'Gene', '4089', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Smad4', 'Gene', (100, 105))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (12, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (12, 29))	('pancreatic cancers', 'Disease', (12, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('Smad4', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('knockdown', 'Var', (87, 96))	('lose', 'NegReg', (31, 35))	('TGF-beta-mediated cell cycle arrest', 'CPA', (143, 178))	('Smad4', 'Gene', '4089', (100, 105))	('pancreatic cancers', 'Disease', 'MESH:D010190', (12, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('expression', 'MPA', (36, 46))
278425	23123827	One possibility is that Smad4 mutations may accentuate the S100A9-TGF-beta pathway in pancreatic adenocarcinoma.	('S100A9-TGF-beta', 'Gene', '6280;7040', (59, 74))	('S100A9-TGF-beta', 'Gene', (59, 74))	('accentuate', 'PosReg', (44, 54))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (86, 111))	('mutations', 'Var', (30, 39))	('pancreatic adenocarcinoma', 'Disease', (86, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (86, 111))	('Smad4', 'Gene', (24, 29))	('Smad4', 'Gene', '4089', (24, 29))
278426	23123827	Therefore, in lung, pancreas and other cancers, S100A9 likely contributes to tumor cell migration through the activity of TGF-beta, and S100A9 also leads to the recruitment of myeloid cells such as inhibitory MDSCs.	('S100A9', 'Var', (48, 54))	('TGF-beta', 'Protein', (122, 130))	('contributes', 'Reg', (62, 73))	('activity', 'MPA', (110, 118))	('rat', 'Species', '10116', (91, 94))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('pancreas', 'Disease', (20, 28))	('cancers', 'Disease', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('leads to', 'Reg', (148, 156))	('pancreas', 'Disease', 'MESH:D010190', (20, 28))	('S100A9', 'Var', (136, 142))	('recruitment', 'MPA', (161, 172))	('tumor', 'Disease', (77, 82))
278429	23123827	were able to validate increased S100A8 and S100A9 levels in hepatocellular carcinoma in murine and human tissue.	('murine', 'Species', '10090', (88, 94))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (60, 84))	('S100A9', 'Var', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('increased', 'PosReg', (22, 31))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('hepatocellular carcinoma', 'Disease', (60, 84))	('S100A8', 'Var', (32, 38))	('human', 'Species', '9606', (99, 104))
278432	23123827	Both S100A8 and S100A9 exhibit increased expression in the resultant tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('increased', 'PosReg', (31, 40))	('expression', 'MPA', (41, 51))	('tumor', 'Disease', (69, 74))	('S100A9', 'Var', (16, 22))	('S100A8', 'Var', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
278439	23123827	S100A9 is associated with high grade, negative ER and PR status, high Ki67 and p53 expression, and ERBB2 and EGFR expression.	('Ki67', 'Gene', (70, 74))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('S100A9', 'Var', (0, 6))	('ERBB2', 'Gene', (99, 104))	('high grade', 'CPA', (26, 36))	('ERBB2', 'Gene', '2064', (99, 104))	('negative', 'NegReg', (38, 46))	('EGFR', 'Gene', '1956', (109, 113))	('expression', 'MPA', (83, 93))	('EGFR', 'Gene', (109, 113))
278441	23123827	The presence of S100A9 in node negative breast cancer patients has prognostic value.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('patients', 'Species', '9606', (54, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('presence', 'Var', (4, 12))	('S100A9', 'Gene', (16, 22))
278443	23123827	An increase in S100A8/A9 protein levels may also result in S100A9 zinc mediated sequestration, inability of MMP9 to cleave S100A9, and activation of RAGE signal transduction pathways all of which are known to be pro-tumorigenic.	('tumor', 'Disease', (216, 221))	('S100A8/A9', 'Gene', (15, 24))	('activation', 'PosReg', (135, 145))	('S100A9', 'Var', (59, 65))	('MMP9', 'Gene', (108, 112))	('protein', 'Protein', (25, 32))	('RAGE signal transduction pathways', 'Pathway', (149, 182))	('sequestration', 'MPA', (80, 93))	('MMP9', 'Gene', '4318', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('rat', 'Species', '10116', (87, 90))	('increase', 'PosReg', (3, 11))
278444	23123827	In contrast, S100A9 induced growth repression in infiltrating ductal carcinoma of the breast in MCF-7 cells.	('ductal carcinoma of the breast', 'Disease', (62, 92))	('growth repression', 'MPA', (28, 45))	('MCF-7', 'CellLine', 'CVCL:0031', (96, 101))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (62, 78))	('rat', 'Species', '10116', (55, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('S100A9', 'Var', (13, 19))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (69, 92))	('ductal carcinoma of the breast', 'Disease', 'MESH:D018270', (62, 92))
278449	23123827	Other evidence suggests that S100A9 appears to promote growth at low concentrations and inhibit growth at high concentrations.	('rat', 'Species', '10116', (76, 79))	('rat', 'Species', '10116', (118, 121))	('promote', 'PosReg', (47, 54))	('inhibit', 'NegReg', (88, 95))	('S100A9', 'Var', (29, 35))	('growth', 'MPA', (96, 102))	('growth', 'MPA', (55, 61))
278450	23123827	In a murine model, exogenous administration of S100A8/A9 was found to inhibit MM46 mammary carcinoma cells with a minimum inhibitory concentration between 50-100 g/mL.	('S100A8/A9', 'Var', (47, 56))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (83, 100))	('rat', 'Species', '10116', (140, 143))	('murine', 'Species', '10090', (5, 11))	('rat', 'Species', '10116', (37, 40))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('inhibit', 'NegReg', (70, 77))	('carcinoma', 'Disease', (91, 100))
278451	23123827	When zinc was added to this same system, it abrogated the ability of S100A8/A9 to inhibit MM46 apoptosis by at least 80% but was unaffected even by millimolar concentrations of either exogenous calcium or magnesium.	('MM46 apoptosis', 'CPA', (90, 104))	('rat', 'Species', '10116', (166, 169))	('calcium', 'Chemical', 'MESH:D002118', (194, 201))	('magnesium', 'Chemical', 'MESH:D008274', (205, 214))	('inhibit', 'NegReg', (82, 89))	('S100A8/A9', 'Var', (69, 78))	('abrogated', 'NegReg', (44, 53))
278453	23123827	Also, increasing levels of S100A9 promotes apoptosis via p53-dependent and p53-independent pathways.	('S100A9', 'Var', (27, 33))	('apoptosis', 'CPA', (43, 52))	('promotes', 'PosReg', (34, 42))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('p53', 'Gene', (57, 60))	('p53', 'Gene', '7157', (57, 60))
278455	23123827	Thus, S100A9 appears to be inhibitory to breast cancers at higher concentrations and may be promoting tumor growth at lower concentrations, but additional research is needed to distinguish between dosage effects and model differences.	('rat', 'Species', '10116', (131, 134))	('S100A9', 'Var', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancers', 'Phenotype', 'HP:0003002', (41, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('inhibitory', 'NegReg', (27, 37))	('breast cancers', 'Disease', 'MESH:D001943', (41, 55))	('breast cancers', 'Disease', (41, 55))	('promoting', 'PosReg', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('rat', 'Species', '10116', (73, 76))
278463	23123827	In prostate cancer cell lines, S100A8/A9 co-localizes with RAGE and likely activates inflammatory signaling pathways such as NF-kappaB.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('co-localizes', 'Interaction', (41, 53))	('inflammatory signaling pathways', 'Pathway', (85, 116))	('prostate cancer', 'Disease', (3, 18))	('activates', 'PosReg', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('S100A8/A9', 'Var', (31, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
278464	23123827	However, circulating S100A8/A9 in blood is not associated with prostate cancer risk.	('prostate cancer', 'Disease', 'MESH:D011471', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('prostate cancer', 'Phenotype', 'HP:0012125', (63, 78))	('prostate cancer', 'Disease', (63, 78))	('S100A8/A9', 'Var', (21, 30))	('associated', 'Reg', (47, 57))
278471	23123827	In the cardiovascular system, the S100A8/A9 heterodimer enhanced secretion of the pro-inflammatory factors IL-6, ICAM-1, VCAM-1 and MCP1 in HUVEC cells in a dose dependent manner.	('ICAM-1', 'Gene', (113, 119))	('VCAM-1', 'Gene', (121, 127))	('ICAM-1', 'Gene', '15894', (113, 119))	('S100A8/A9', 'Var', (34, 43))	('secretion of the pro-inflammatory factors IL-6', 'MPA', (65, 111))	('MCP1', 'Gene', '17224', (132, 136))	('enhanced', 'PosReg', (56, 64))	('VCAM-1', 'Gene', '22329', (121, 127))	('HUVEC', 'CellLine', 'CVCL:2959', (140, 145))	('MCP1', 'Gene', (132, 136))
278472	23123827	The effects of S100A8/A9 were reduced by inhibition of ERK1/2 and p38 in the MAP kinase pathways.	('S100A8/A9', 'Var', (15, 24))	('ERK1/2', 'Gene', (55, 61))	('ERK1/2', 'Gene', '5595;5594', (55, 61))	('p38', 'Gene', '1432', (66, 69))	('inhibition', 'NegReg', (41, 51))	('MAP kinase pathways', 'Pathway', (77, 96))	('p38', 'Gene', (66, 69))
278473	23123827	It has been postulated that blocking S100A8/A9 may represent a modality to treat atherosclerosis via the down-regulation of inflammatory pathways.	('atherosclerosis', 'Disease', 'MESH:D050197', (81, 96))	('atherosclerosis', 'Phenotype', 'HP:0002621', (81, 96))	('inflammatory pathways', 'Pathway', (124, 145))	('down-regulation', 'NegReg', (105, 120))	('S100A8/A9', 'Protein', (37, 46))	('atherosclerosis', 'Disease', (81, 96))	('blocking', 'Var', (28, 36))
278474	23123827	found that arteries lacking atherosclerosis lacked expression of S100A8 or S100A9.	('lacked', 'NegReg', (44, 50))	('S100A8', 'Var', (65, 71))	('expression', 'MPA', (51, 61))	('atherosclerosis', 'Disease', 'MESH:D050197', (28, 43))	('atherosclerosis', 'Phenotype', 'HP:0002621', (28, 43))	('S100A9', 'Var', (75, 81))	('atherosclerosis', 'Disease', (28, 43))
278475	23123827	S100A9 may associate with lipid structures and may promote dystrophic calcification by altering the ability of phospholipid to bind calcium.	('lipid', 'Chemical', 'MESH:D008055', (26, 31))	('calcium', 'Chemical', 'MESH:D002118', (132, 139))	('dystrophic calcification', 'Disease', 'MESH:D061205', (59, 83))	('S100A9', 'Var', (0, 6))	('altering', 'Reg', (87, 95))	('dystrophic calcification', 'Disease', (59, 83))	('bind', 'Interaction', (127, 131))	('associate', 'Interaction', (11, 20))	('lipid', 'Protein', (26, 31))	('promote', 'PosReg', (51, 58))	('phospholipid', 'Chemical', 'MESH:D010743', (111, 123))	('lipid', 'Chemical', 'MESH:D008055', (118, 123))	('ability of phospholipid', 'MPA', (100, 123))
278576	19139022	Tissues stained for Ki-67, COX-2, NF-kappaB p50, CD45, CD34, and for apoptotic cells by TUNEL were viewed and photographed at x200 with a bright-field microscope mounted with a high-resolution spot camera (see Supplementary Fig.	('CD45', 'Gene', (49, 53))	('Ki-67', 'Var', (20, 25))	('CD45', 'Gene', '24699', (49, 53))	('p50', 'Var', (44, 47))	('COX-2', 'Gene', '29527', (27, 32))	('CD34', 'Gene', (55, 59))	('COX-2', 'Gene', (27, 32))	('CD34', 'Gene', '305081', (55, 59))
278602	19139022	In rats treated with NMBA only, Ki-67, TUNEL, COX-2, NF-kappaB p50, CD45, and CD34 staining was higher in papillomas than in whole esophagus.	('COX-2', 'Gene', '29527', (46, 51))	('papillomas', 'Disease', 'MESH:D010212', (106, 116))	('COX-2', 'Gene', (46, 51))	('CD34', 'Gene', (78, 82))	('CD45', 'Gene', '24699', (68, 72))	('CD34', 'Gene', '305081', (78, 82))	('papillomas', 'Phenotype', 'HP:0012740', (106, 116))	('rats', 'Species', '10116', (3, 7))	('CD45', 'Gene', (68, 72))	('NMBA', 'Chemical', 'MESH:C014707', (21, 25))	('papilloma', 'Phenotype', 'HP:0012740', (106, 115))	('p50', 'Var', (63, 66))	('Ki-67', 'Var', (32, 37))	('higher', 'PosReg', (96, 102))	('papillomas', 'Disease', (106, 116))
278607	19139022	These proteins included p42/44 as a measure of cell proliferation, Bcl-2, and Bax for apoptosis; COX-2 for inflammation; and both VEGF and HIF-1alpha for angiogenesis.	('inflammation', 'Disease', (107, 119))	('COX-2', 'Gene', (97, 102))	('Bcl-2', 'Gene', '24224', (67, 72))	('HIF-1alpha', 'Gene', '29560', (139, 149))	('COX-2', 'Gene', '29527', (97, 102))	('VEGF', 'Gene', '83785', (130, 134))	('p42/44', 'Var', (24, 30))	('HIF-1alpha', 'Gene', (139, 149))	('Bax', 'Gene', (78, 81))	('Bax', 'Gene', '24887', (78, 81))	('VEGF', 'Gene', (130, 134))	('Bcl-2', 'Gene', (67, 72))	('rat', 'Species', '10116', (59, 62))	('angiogenesis', 'CPA', (154, 166))	('inflammation', 'Disease', 'MESH:D007249', (107, 119))
278643	19139022	The O6-methylguanine adduct is particularly important for carcinogenesis because it is poorly repaired and leads to single base mispairing in DNA.	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('single base mispairing', 'MPA', (116, 138))	('leads to', 'Reg', (107, 115))	('carcinogenesis', 'Disease', (58, 72))	('O6-methylguanine', 'Var', (4, 20))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (4, 20))
278645	19139022	Inhibition of DNA adduct formation might be expected to inhibit tumor initiation, in part, because one of the principal initiation events in rat esophageal carcinogenesis is mutational activation of the H-ras oncogene.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (145, 170))	('esophageal carcinogenesis', 'Disease', (145, 170))	('H-ras', 'Gene', (203, 208))	('activation', 'PosReg', (185, 195))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('rat', 'Species', '10116', (141, 144))	('H-ras', 'Gene', '293621', (203, 208))	('mutational', 'Var', (174, 184))	('inhibit', 'NegReg', (56, 63))
278646	19139022	Activation of this gene by NMBA is associated with GC AT transition mutations in the second base of codon 12; these mutations are consistent with the formation of O6-methylguanine adducts in DNA.	('O6-methylguanine', 'Chemical', 'MESH:C008449', (163, 179))	('NMBA', 'Chemical', 'MESH:C014707', (27, 31))	('Activation', 'PosReg', (0, 10))	('mutations', 'Var', (68, 77))	('NMBA', 'Gene', (27, 31))
278653	33622273	At present, the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) gene mutation has been observed in esophageal cancer and is associated with poor prognosis.	('v-Raf murine sarcoma viral oncogene homolog B1', 'Gene', (16, 62))	('cancer', 'Disease', (116, 122))	('BRAF', 'Gene', (64, 68))	('mutation', 'Var', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('v-Raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (16, 62))	('observed', 'Reg', (93, 101))
278661	33622273	Transwell assay analysis showed that the migration and invasion of cells in the experimental group were significantly inhibited relative to the control group, and the inhibition rates of the small interfering RNA group were 67% and 60%, respectively.	('small interfering', 'Var', (191, 208))	('inhibited', 'NegReg', (118, 127))	('men', 'Species', '9606', (86, 89))
278669	33622273	Mutations in the Kirsten ras 1 (KRAS) and BRAF genes may be predictive of drug responses that are directly linked to the EGFR pathway.	('KRAS', 'Gene', (32, 36))	('EGFR', 'Gene', (121, 125))	('drug responses', 'CPA', (74, 88))	('Kirsten ras 1', 'Gene', (17, 30))	('KRAS', 'Gene', '3845', (32, 36))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '13649', (121, 125))	('Kirsten ras 1', 'Gene', '3845', (17, 30))	('BRAF', 'Gene', (42, 46))
278722	33622273	At present, the most novel process of cancer treatment is to detect the gene expression levels and mutations of patients, develop targeted drugs for different gene mutations, and create individualized treatments.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('mutations', 'Var', (99, 108))	('men', 'Species', '9606', (50, 53))	('detect', 'Reg', (61, 67))	('cancer', 'Disease', (38, 44))	('gene expression levels', 'MPA', (72, 94))	('men', 'Species', '9606', (206, 209))
278724	33622273	BRAF gene mutations exist in papillary thyroid cancer, malignant melanoma and colorectal cancer.	('papillary thyroid cancer', 'Disease', (29, 53))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (29, 53))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('thyroid cancer', 'Phenotype', 'HP:0002890', (39, 53))	('malignant melanoma', 'Phenotype', 'HP:0002861', (55, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (29, 53))	('BRAF gene', 'Gene', (0, 9))	('malignant melanoma', 'Disease', (55, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('malignant melanoma', 'Disease', 'MESH:D008545', (55, 73))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (10, 19))	('colorectal cancer', 'Disease', (78, 95))
278725	33622273	Approximately 92% of BRAF gene mutations are located in nucleotide 1799 (t   a), resulting in the substitution of valine with glutamic acid (V600E).	('mutations', 'Var', (31, 40))	('V600E', 'Var', (141, 146))	('valine', 'Chemical', 'MESH:D014633', (114, 120))	('substitution', 'Var', (98, 110))	('glutamic acid', 'Chemical', 'MESH:D018698', (126, 139))	('BRAF gene', 'Gene', (21, 30))	('V600E', 'Mutation', 'rs113488022', (141, 146))	('valine', 'MPA', (114, 120))
278726	33622273	BRAF gene mutations significantly increase its kinase activity and continuously activates the mitogen-activated protein kinase (MAPK) pathway, which leads to the phosphorylation of nuclear transcription factors and various proteins and ultimately results in the abnormal proliferation, differentiation, and apoptosis of cells, thereby forming tumors.	('abnormal proliferation', 'CPA', (262, 284))	('tumors', 'Disease', (343, 349))	('forming', 'Reg', (335, 342))	('proteins', 'Protein', (223, 231))	('activates', 'PosReg', (80, 89))	('tumors', 'Disease', 'MESH:D009369', (343, 349))	('tumors', 'Phenotype', 'HP:0002664', (343, 349))	('phosphorylation', 'MPA', (162, 177))	('differentiation', 'CPA', (286, 301))	('BRAF gene', 'Gene', (0, 9))	('increase', 'PosReg', (34, 42))	('results in', 'Reg', (247, 257))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('nuclear', 'Protein', (181, 188))	('kinase activity', 'MPA', (47, 62))	('apoptosis', 'CPA', (307, 316))	('leads to', 'Reg', (149, 157))
278733	33622273	showed that the Ki67 expression is related to the survival and prognosis of patients with EC and that patients with high expression of Ki67 have a shorter survival period and poor prognosis.	('survival period', 'CPA', (155, 170))	('shorter', 'NegReg', (147, 154))	('patients', 'Species', '9606', (76, 84))	('Ki67', 'Gene', (16, 20))	('patients', 'Species', '9606', (102, 110))	('related', 'Reg', (35, 42))	('Ki67', 'Chemical', '-', (135, 139))	('Ki67', 'Var', (135, 139))	('Ki67', 'Chemical', '-', (16, 20))
278736	33622273	In vitro experiments showed that after BRAF knockdown, significantly reduced the cell clone formation rate compared to the control group.	('reduced', 'NegReg', (69, 76))	('BRAF', 'Gene', (39, 43))	('men', 'Species', '9606', (15, 18))	('cell clone formation rate', 'CPA', (81, 106))	('knockdown', 'Var', (44, 53))
278739	33622273	In the nude mice tumor-bearing model, inhibition of BRAF activity decreases tumor growth, which indicated that BRAF played a key role in tumor proliferation.	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('inhibition', 'Var', (38, 48))	('decreases tumor', 'Disease', (66, 81))	('activity', 'MPA', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('nude mice', 'Species', '10090', (7, 16))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('decreases tumor', 'Disease', 'MESH:D002303', (66, 81))
278741	33622273	The best-studied BRAF mutations occur at position V600 (V600E and V600K), resulting in constitutive activation of BRAF and downstream activation of MAPK kinase (MEK) and extracellular signal-regulated kinase.	('V600K', 'Var', (66, 71))	('MEK', 'Gene', (161, 164))	('MEK', 'Gene', '5609', (161, 164))	('V600K', 'Mutation', 'rs121913227', (66, 71))	('died', 'Disease', (12, 16))	('activation', 'PosReg', (134, 144))	('extracellular signal-regulated kinase', 'Pathway', (170, 207))	('BRAF', 'Gene', (17, 21))	('died', 'Disease', 'MESH:D003643', (12, 16))	('activation', 'PosReg', (100, 110))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('BRAF', 'MPA', (114, 118))
278742	33622273	The overall mutation rate of BRAF in malignant tumors is 7% but varies with tumor type, and mutations are observed in approximately 50% of patients with melanoma, approximately 25% of patients with anaplastic thyroid cancer, and 2-8% of patients with non-small cell lung cancer.	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('tumor', 'Disease', (76, 81))	('anaplastic thyroid cancer', 'Disease', (198, 223))	('melanoma', 'Disease', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('patients', 'Species', '9606', (237, 245))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('malignant tumors', 'Disease', (37, 53))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (251, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('malignant tumors', 'Disease', 'MESH:D009369', (37, 53))	('lung cancer', 'Disease', (266, 277))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (255, 277))	('patients', 'Species', '9606', (139, 147))	('BRAF', 'Gene', (29, 33))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (198, 223))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (92, 101))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('thyroid cancer', 'Phenotype', 'HP:0002890', (209, 223))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (198, 223))	('tumor', 'Disease', (47, 52))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('lung cancer', 'Disease', 'MESH:D008175', (266, 277))	('observed', 'Reg', (106, 114))	('mutation', 'Var', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (266, 277))
278743	33622273	BRAF kinase inhibitor can significantly inhibit the proliferation of melanoma cells with BRAF gene V600E mutations in the G1 phase but has no inhibitory effect on wild-type BRAF.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('proliferation', 'CPA', (52, 65))	('inhibit', 'NegReg', (40, 47))	('BRAF gene', 'Gene', (89, 98))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('V600E', 'Var', (99, 104))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
278749	33622273	By applying BRAF kinase inhibitors to EC cell lines with BRAF gene mutation, we can detect whether the expression of differentiation markers is decreased, whether the tumor cells have proliferation arrest, whether the activity of BRAF protein kinase is down regulated, and whether the relative expression of nuclear related genes is decreased, To determine whether the invasion and metastasis of the cells are reduced, so as to obtain a more accurate relationship between BRAF mutation and the occurrence and development of EC.	('decreased', 'NegReg', (144, 153))	('mutation', 'Var', (67, 75))	('invasion', 'CPA', (369, 377))	('expression', 'MPA', (103, 113))	('arrest', 'Disease', 'MESH:D006323', (198, 204))	('men', 'Species', '9606', (516, 519))	('BRAF', 'Gene', (472, 476))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('mutation', 'Var', (477, 485))	('activity', 'MPA', (218, 226))	('arrest', 'Disease', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('down regulated', 'NegReg', (253, 267))
278779	33323552	demonstrated that high FGL2 expression was an independent poor prognostic factor in renal carcinoma patients, while silencing FGL2 significantly reduced renal cancer cell viability and increased cancer cell apoptosis.	('renal cancer', 'Disease', 'MESH:D007680', (153, 165))	('reduced', 'NegReg', (145, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('patients', 'Species', '9606', (100, 108))	('renal carcinoma', 'Disease', 'MESH:C538614', (84, 99))	('cancer', 'Disease', (159, 165))	('renal carcinoma', 'Disease', (84, 99))	('renal carcinoma', 'Phenotype', 'HP:0005584', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('FGL2', 'Gene', (23, 27))	('silencing', 'Var', (116, 125))	('increased', 'PosReg', (185, 194))	('FGL2', 'Gene', (126, 130))	('cancer', 'Disease', (195, 201))	('renal cancer', 'Disease', (153, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('renal cancer', 'Phenotype', 'HP:0009726', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('FGL2', 'Gene', '10875', (23, 27))	('FGL2', 'Gene', '10875', (126, 130))
278786	33323552	As shown in the Venn diagram in Figure 2A, we identified 25 consistently DEGs between M0 macrophages and M2 macrophages in three datasets (GSE57614, GSE36537 and GSE5099).	('GSE5099', 'Chemical', '-', (162, 169))	('GSE36537', 'Var', (149, 157))	('GSE5099', 'Var', (162, 169))	('GSE57614', 'Var', (139, 147))
278787	33323552	In addition, we identified 91 consistently DEGs between M1 and M2 macrophages in four datasets (GSE57614, GSE36537, GSE5099 and GSE95405) (Figure 2C).	('GSE57614', 'Var', (96, 104))	('GSE5099', 'Chemical', '-', (116, 123))	('DEGs', 'NegReg', (43, 47))	('GSE36537', 'Var', (106, 114))	('GSE95405', 'Var', (128, 136))	('GSE5099', 'Var', (116, 123))
278821	33323552	The levels of interleukin (IL)-10, matrix metalloproteinase 9 (MMP9), C-C motif chemokine ligand 5 (CCL5), TIM-3, IL-13, vascular cell adhesion molecule 1 (VCAM1), macrophage colony-stimulating factor (M-CSF) and fibroblast growth factor 7 (FGF-7) were significantly greater in EC109/9706 cells co-cultured with M2 macrophages than in EC109/9706 cells cultured alone or co-cultured with M0 macrophages (Figure 7B-7E).	('VCAM1', 'Gene', '7412', (156, 161))	('MMP9', 'Gene', '4318', (63, 67))	('MMP9', 'Gene', (63, 67))	('IL-13', 'Gene', '3596', (114, 119))	('matrix metalloproteinase 9', 'Gene', (35, 61))	('M-CSF', 'Gene', (202, 207))	('interleukin (IL)-10', 'Gene', (14, 33))	('C-C motif chemokine ligand 5', 'Gene', '6352', (70, 98))	('TIM-3', 'Gene', '84868', (107, 112))	('fibroblast growth factor 7', 'Gene', '2252', (213, 239))	('matrix metalloproteinase 9', 'Gene', '4318', (35, 61))	('macrophage colony-stimulating factor', 'Gene', (164, 200))	('FGF-7', 'Gene', (241, 246))	('greater', 'PosReg', (267, 274))	('TIM-3', 'Gene', (107, 112))	('M-CSF', 'Gene', '1435', (202, 207))	('macrophage colony-stimulating factor', 'Gene', '1435', (164, 200))	('IL-13', 'Gene', (114, 119))	('FGF-7', 'Gene', '2252', (241, 246))	('CCL5', 'Gene', '6352', (100, 104))	('vascular cell adhesion molecule 1', 'Gene', '7412', (121, 154))	('VCAM1', 'Gene', (156, 161))	('fibroblast growth factor 7', 'Gene', (213, 239))	('levels', 'MPA', (4, 10))	('EC109/9706', 'CellLine', 'CVCL:E307', (335, 345))	('EC109/9706', 'Var', (278, 288))	('EC109/9706', 'CellLine', 'CVCL:E307', (278, 288))	('vascular cell adhesion molecule 1', 'Gene', (121, 154))	('C-C motif chemokine ligand 5', 'Gene', (70, 98))	('interleukin (IL)-10', 'Gene', '3586', (14, 33))	('CCL5', 'Gene', (100, 104))
278840	33323552	Our results indicated that inhibiting FGL2 could potentially weaken the immunosuppressive activity of ESCA tumors to prevent their progression.	('FGL2', 'Gene', (38, 42))	('inhibiting', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('weaken', 'NegReg', (61, 67))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('ESCA tumor', 'Disease', (102, 112))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('immunosuppressive activity', 'MPA', (72, 98))	('ESCA tumor', 'Disease', 'MESH:D009369', (102, 112))	('ESCA', 'Phenotype', 'HP:0011459', (102, 106))	('FGL2', 'Gene', '10875', (38, 42))
278848	33323552	To our knowledge, the present study is the first to demonstrate the association between high FGL2 expression in M2 macrophages and a poor prognosis (OS and RFS) in esophageal cancer patients.	('high', 'Var', (88, 92))	('FGL2', 'Gene', '10875', (93, 97))	('cancer', 'Disease', (175, 181))	('FGL2', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('patients', 'Species', '9606', (182, 190))	('RFS', 'Disease', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('expression', 'MPA', (98, 108))
278857	33323552	A previous study indicated that MMP9 activity and expression were reduced by a CYSLTR1 antagonist (montelukast), and that M2 macrophages enriched in leukotriene D4 promoted the migration and invasion of colon cancer cells by inducing MMP9 expression.	('reduced', 'NegReg', (66, 73))	('inducing', 'PosReg', (225, 233))	('colon cancer', 'Disease', 'MESH:D015179', (203, 215))	('expression', 'MPA', (50, 60))	('leukotriene D4', 'Chemical', 'MESH:D017998', (149, 163))	('leukotriene', 'Var', (149, 160))	('colon cancer', 'Disease', (203, 215))	('invasion', 'CPA', (191, 199))	('CYSLTR1', 'Gene', '10800', (79, 86))	('MMP9', 'Gene', (234, 238))	('expression', 'MPA', (239, 249))	('MMP9', 'Gene', '4318', (234, 238))	('promoted', 'PosReg', (164, 172))	('activity', 'MPA', (37, 45))	('migration', 'CPA', (177, 186))	('MMP9', 'Gene', '4318', (32, 36))	('MMP9', 'Gene', (32, 36))	('colon cancer', 'Phenotype', 'HP:0003003', (203, 215))	('montelukast', 'Chemical', 'MESH:C093875', (99, 110))	('CYSLTR1', 'Gene', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
278872	33323552	Thus, inhibiting FGL2 may reduce the polarization of M2 macrophages, weaken immunosuppression and prevent the progression of ESCA.	('reduce', 'NegReg', (26, 32))	('prevent', 'NegReg', (98, 105))	('inhibiting', 'Var', (6, 16))	('weaken', 'NegReg', (69, 75))	('ESCA', 'Phenotype', 'HP:0011459', (125, 129))	('ESCA', 'Disease', (125, 129))	('FGL2', 'Gene', '10875', (17, 21))	('polarization', 'MPA', (37, 49))	('immunosuppression', 'MPA', (76, 93))	('FGL2', 'Gene', (17, 21))
278881	33323552	Thus, inhibiting these genes may reduce the polarization of TAMs into M2 macrophages and weaken their immunosuppressive effects.	('inhibiting', 'Var', (6, 16))	('weaken', 'NegReg', (89, 95))	('polarization', 'MPA', (44, 56))	('TAMs', 'Chemical', '-', (60, 64))	('immunosuppressive effects', 'CPA', (102, 127))	('reduce', 'NegReg', (33, 39))
278884	33323552	In our PPI analysis, the majority of the genes in the most closely connected module were significantly upregulated in M1 macrophages, including STAT1, OAS1, OAS2 and DDX5; thus, developing small molecule agonists for these proteins may enhance anti-tumor immunity.	('STAT1', 'Gene', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('STAT1', 'Gene', '6772', (144, 149))	('DDX5', 'Gene', (166, 170))	('OAS2', 'Gene', '4939', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('DDX5', 'Gene', '1655', (166, 170))	('small molecule', 'Var', (189, 203))	('tumor', 'Disease', (249, 254))	('OAS2', 'Gene', (157, 161))	('OAS1', 'Gene', (151, 155))	('OAS1', 'Gene', '4938', (151, 155))	('enhance', 'PosReg', (236, 243))	('upregulated', 'PosReg', (103, 114))
278905	33323552	We used GSEA software (version: 4.0.0) to identify functions or pathways that differed between ESCA samples with low and high FGL2 mRNA levels.	('ESCA', 'Phenotype', 'HP:0011459', (95, 99))	('ESCA', 'Disease', (95, 99))	('GSEA', 'Chemical', '-', (8, 12))	('high', 'Var', (121, 125))	('FGL2', 'Gene', '10875', (126, 130))	('FGL2', 'Gene', (126, 130))
278920	32391623	The combination of ypT, ypN, and ypG categories yielded significantly higher C-index (0.591; 95%CI, 0.573-0.609) than that of the seventh edition TNM staging (P = .024).	('TNM', 'Gene', (146, 149))	('TNM', 'Gene', '10178', (146, 149))	('ypG categories', 'Var', (33, 47))	('higher', 'PosReg', (70, 76))	('C-index', 'MPA', (77, 84))
278982	30854807	Polymorphism rs2395655 affects LEDGF/p75 binding activity and p21WAF1/CIP1 gene expression in esophageal squamous cell carcinoma p21WAF1/CIP1 (p21) plays critical roles in cell-cycle regulation and DNA repair and is transcriptionally regulated through p53-dependent or -independent pathways.	('CIP1', 'Gene', '1026', (137, 141))	('LEDGF', 'Gene', (31, 36))	('p75', 'Gene', (37, 40))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (94, 128))	('p21WAF1/CIP1', 'Gene', '1026', (62, 74))	('CIP1', 'Gene', (137, 141))	('p21WAF1/CIP1', 'Gene', (62, 74))	('p21', 'Gene', (62, 65))	('p21', 'Gene', (143, 146))	('p53', 'Gene', '7157', (252, 255))	('cell-cycle', 'CPA', (172, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('expression', 'MPA', (80, 90))	('p21', 'Gene', '1026', (129, 132))	('p21WAF1/CIP1', 'Gene', '1026', (129, 141))	('rs2395655', 'Mutation', 'rs2395655', (13, 22))	('p21WAF1/CIP1', 'Gene', (129, 141))	('binding', 'Interaction', (41, 48))	('p53', 'Gene', (252, 255))	('p21', 'Gene', '1026', (143, 146))	('CIP1', 'Gene', '1026', (70, 74))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))	('p21', 'Gene', '1026', (62, 65))	('p75', 'Gene', '11168', (37, 40))	('rs2395655', 'Var', (13, 22))	('CIP1', 'Gene', (70, 74))	('expression', 'Species', '29278', (80, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('LEDGF', 'Gene', '11168', (31, 36))	('p21', 'Gene', (129, 132))
278983	30854807	Bioinformatic analysis predicated one stress-response element (STRE) implicated in single nucleotide polymorphism (SNP) rs2395655 of the p21 promoter.	('S', 'Chemical', 'MESH:D013455', (63, 64))	('rs2395655', 'Var', (120, 129))	('single nucleotide', 'Var', (83, 100))	('S', 'Chemical', 'MESH:D013455', (115, 116))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('p21', 'Gene', '1026', (137, 140))	('rs2395655', 'Mutation', 'rs2395655', (120, 129))	('men', 'Species', '9606', (57, 60))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('p21', 'Gene', (137, 140))
278984	30854807	Here, we investigated the transcriptional regulatory function of rs2395655 variant genotype and analyzed its associations with the p21 expression and clinical outcomes in esophageal squamous cell carcinoma (ESCC) patients.	('esophageal squamous cell carcinoma', 'Disease', (171, 205))	('p21', 'Gene', '1026', (131, 134))	('rs2395655', 'Mutation', 'rs2395655', (65, 74))	('rs2395655', 'Var', (65, 74))	('expression', 'Species', '29278', (135, 145))	('S', 'Chemical', 'MESH:D013455', (208, 209))	('p21', 'Gene', (131, 134))	('associations', 'Interaction', (109, 121))	('patients', 'Species', '9606', (213, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (171, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))
278985	30854807	Luciferase assay results showed significantly increased transcriptional activity of the rs2395655 G allele-containing p21 promoter compared with rs2395655 A allele-containing counterpart, especially in ESCC cells with ectopic LEDGF/p75 expression.	('si', 'Chemical', 'MESH:D012825', (242, 244))	('LEDGF/p75', 'Gene', '11168', (226, 235))	('rs2395655 G', 'Var', (88, 99))	('increased', 'PosReg', (46, 55))	('p21', 'Gene', '1026', (118, 121))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('p21', 'Gene', (118, 121))	('LEDGF/p75', 'Gene', (226, 235))	('transcriptional activity', 'MPA', (56, 80))	('rs2395655', 'Mutation', 'rs2395655', (145, 154))	('rs2395655', 'Mutation', 'rs2395655', (88, 97))	('expression', 'Species', '29278', (236, 246))	('S', 'Chemical', 'MESH:D013455', (203, 204))
278986	30854807	Furthermore electrophoretic mobility shift assay using the rs2395655 G or A allele-containing probe and chromatin immunoprecipitation assay with specific anti-LEDGF/p75 antibody indicated the potential binding activity of LEDGF/p75 with the STRE element implicated in rs2395655 G allele of the p21 promoter.	('LEDGF/p75', 'Gene', (159, 168))	('S', 'Chemical', 'MESH:D013455', (241, 242))	('LEDGF/p75', 'Gene', (222, 231))	('binding', 'Interaction', (202, 209))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('rs2395655', 'Mutation', 'rs2395655', (268, 277))	('p21', 'Gene', '1026', (294, 297))	('men', 'Species', '9606', (249, 252))	('rs2395655 G', 'Var', (59, 70))	('LEDGF/p75', 'Gene', '11168', (159, 168))	('p21', 'Gene', (294, 297))	('LEDGF/p75', 'Gene', '11168', (222, 231))	('rs2395655', 'Mutation', 'rs2395655', (59, 68))	('rs2395655 G', 'Var', (268, 279))
278987	30854807	Subsequent specific RNA interference-mediated depletion or ectopic expression of LEDGF/p75 caused obviously down- or up-regulated expression of p21 mRNA in ESCC cells harboring rs2395655 GG genotype but not cells with rs2395655 AA genotype.	('expression', 'MPA', (130, 140))	('LEDGF/p75', 'Gene', '11168', (81, 90))	('up-regulated', 'PosReg', (117, 129))	('p21', 'Gene', (144, 147))	('LEDGF/p75', 'Gene', (81, 90))	('expression', 'Species', '29278', (67, 77))	('rs2395655', 'Mutation', 'rs2395655', (218, 227))	('S', 'Chemical', 'MESH:D013455', (157, 158))	('rs2395655', 'Mutation', 'rs2395655', (177, 186))	('down-', 'NegReg', (108, 113))	('rs2395655 GG', 'Var', (177, 189))	('expression', 'Species', '29278', (130, 140))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('p21', 'Gene', '1026', (144, 147))
278988	30854807	Furthermore, rs2395655 GG genotype carriers showed significantly elevated p21 protein expression and conferred survival advantage in both univariate and multivariate analyses in total 218 ESCC patients.	('rs2395655', 'Mutation', 'rs2395655', (13, 22))	('patients', 'Species', '9606', (193, 201))	('ESCC', 'Disease', (188, 192))	('survival advantage', 'CPA', (111, 129))	('expression', 'Species', '29278', (86, 96))	('p21', 'Gene', '1026', (74, 77))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('p21', 'Gene', (74, 77))	('elevated', 'PosReg', (65, 73))	('rs2395655 GG', 'Var', (13, 25))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('S', 'Chemical', 'MESH:D013455', (189, 190))
278989	30854807	Our findings suggest that LEDGF/p75 regulates the p21 expression in ESCC cells through interacting with STRE element implicated in polymorphism rs2395655 and the elevated p21 protein expression and rs2395655 GG genotype may serve as positive prognostic factors for ESCC patients.	('LEDGF/p75', 'Gene', '11168', (26, 35))	('rs2395655', 'Mutation', 'rs2395655', (144, 153))	('p21', 'Gene', '1026', (171, 174))	('rs2395655', 'Mutation', 'rs2395655', (198, 207))	('expression', 'Species', '29278', (54, 64))	('elevated', 'PosReg', (162, 170))	('regulates', 'Reg', (36, 45))	('rs2395655', 'Var', (144, 153))	('S', 'Chemical', 'MESH:D013455', (69, 70))	('p21', 'Gene', '1026', (50, 53))	('S', 'Chemical', 'MESH:D013455', (266, 267))	('men', 'Species', '9606', (112, 115))	('rs2395655', 'Var', (198, 207))	('ESCC', 'Disease', (265, 269))	('interacting', 'Interaction', (87, 98))	('LEDGF/p75', 'Gene', (26, 35))	('si', 'Chemical', 'MESH:D012825', (189, 191))	('expression', 'MPA', (54, 64))	('p21', 'Gene', (171, 174))	('patients', 'Species', '9606', (270, 278))	('S', 'Chemical', 'MESH:D013455', (104, 105))	('expression', 'Species', '29278', (183, 193))	('si', 'Chemical', 'MESH:D012825', (235, 237))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('p21', 'Gene', (50, 53))
278995	30854807	We further examined the effects of rs2395655 (-809G/A) and another common polymorphism rs3829963 (-2119C/A) on expression regulation of the p21 gene.	('rs3829963 (-2119C/A', 'Var', (87, 106))	('-809G/A', 'Mutation', 'rs2395655', (46, 53))	('rs2395655', 'Mutation', 'rs2395655', (35, 44))	('expression', 'Species', '29278', (111, 121))	('-2119C/A', 'Var', (98, 106))	('rs3829963', 'Mutation', 'rs3829963', (87, 96))	('expression', 'MPA', (111, 121))	('-2119C/A', 'Mutation', 'rs3829963', (98, 106))	('p21', 'Gene', '1026', (140, 143))	('rs2395655 (-809G/A', 'Var', (35, 53))	('p21', 'Gene', (140, 143))
278996	30854807	The results of luciferase assay demonstrated that the p21 promoter harboring rs2395655 G allele exhibited significantly higher transcriptional activity than rs2395655 A allele-containing counterpart.	('transcriptional activity', 'MPA', (127, 151))	('rs2395655 G', 'Var', (77, 88))	('higher', 'PosReg', (120, 126))	('p21', 'Gene', '1026', (54, 57))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('rs2395655', 'Mutation', 'rs2395655', (157, 166))	('p21', 'Gene', (54, 57))	('rs2395655', 'Mutation', 'rs2395655', (77, 86))
278997	30854807	This prediction was proved by the use of electrophoresis mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay which both showed the capability of the p21 promoter with rs2395655 G but not A allele for binding to lens epithelium-derived growth factor/p75 (LEDGF/p75, also known as PSIP1 and DFS70 autoantigen), a potent survival oncoprotein involved in stress response, autoimmune disease, HIV replication, and cancer progression.24, 25, 26, 27 The regulatory effect of LEDGF/p75 on the p21 expression was further examined in ESCC cells with rs2395655 GG or AA genotype.	('cancer', 'Phenotype', 'HP:0002664', (432, 438))	('p75', 'Gene', (283, 286))	('si', 'Chemical', 'MESH:D012825', (518, 520))	('p75', 'Gene', (497, 500))	('p75', 'Gene', '11168', (272, 275))	('rs2395655', 'Mutation', 'rs2395655', (190, 199))	('si', 'Chemical', 'MESH:D012825', (446, 448))	('autoimmune disease', 'Phenotype', 'HP:0002960', (391, 409))	('HIV', 'Disease', 'MESH:D015658', (411, 414))	('rs2395655', 'Mutation', 'rs2395655', (563, 572))	('LEDGF/p75', 'Gene', '11168', (277, 286))	('p21', 'Gene', (508, 511))	('lens epithelium-derived growth factor', 'Gene', (234, 271))	('S', 'Chemical', 'MESH:D013455', (314, 315))	('expression', 'Species', '29278', (512, 522))	('LEDGF/p75', 'Gene', '11168', (491, 500))	('cancer', 'Disease', 'MESH:D009369', (432, 438))	('lens epithelium-derived growth factor', 'Gene', '11168', (234, 271))	('HIV', 'Disease', (411, 414))	('p75', 'Gene', (272, 275))	('p21', 'Gene', (172, 175))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('PSIP1', 'Gene', (302, 307))	('PSIP1', 'Gene', '11168', (302, 307))	('S', 'Chemical', 'MESH:D013455', (81, 82))	('p75', 'Gene', '11168', (497, 500))	('p75', 'Gene', '11168', (283, 286))	('p21', 'Gene', '1026', (508, 511))	('S', 'Chemical', 'MESH:D013455', (303, 304))	('LEDGF/p75', 'Gene', (277, 286))	('autoimmune disease', 'Disease', (391, 409))	('LEDGF/p75', 'Gene', (491, 500))	('rs2395655 GG', 'Var', (563, 575))	('autoimmune disease', 'Disease', 'MESH:D001327', (391, 409))	('p21', 'Gene', '1026', (172, 175))	('cancer', 'Disease', (432, 438))	('S', 'Chemical', 'MESH:D013455', (548, 549))
278998	30854807	Moreover, the association of rs2395655 variant genotype with the p21 protein expression and their prognostic values in ESCC patients were investigated.	('p21', 'Gene', '1026', (65, 68))	('p21', 'Gene', (65, 68))	('ESCC', 'Disease', (119, 123))	('rs2395655', 'Mutation', 'rs2395655', (29, 38))	('S', 'Chemical', 'MESH:D013455', (120, 121))	('rs2395655', 'Var', (29, 38))	('expression', 'Species', '29278', (77, 87))	('patients', 'Species', '9606', (124, 132))
279000	30854807	The polymerase chain reaction (PCR) product was ligated into pGL3-Basic vector (Promega, Madison, WI) and the resultant reporter construct was used as template to generate three other constructs containing -2119A/-809G, -2119C/-809A, and -2119A/-809A haplotypes, respectively, by using site-specific mutagenesis.	('pGL3', 'Gene', '6391', (61, 65))	('si', 'Chemical', 'MESH:D012825', (281, 283))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('si', 'Chemical', 'MESH:D012825', (308, 310))	('-2119A/-809G', 'Var', (206, 218))	('pGL3', 'Gene', (61, 65))	('si', 'Chemical', 'MESH:D012825', (286, 288))
279025	30854807	The membranes were then blocked with 5% nonfat milk and probed with specific primary antibodies: anti-LEDGF/p75 (BD Biosciences, Heidelberg, Germany) or anti-Actin (Santa Cruz) (1:1000 to 1:5000 dilution), respectively.	('anti-Actin', 'Var', (153, 163))	('LEDGF/p75', 'Gene', '11168', (102, 111))	('LEDGF/p75', 'Gene', (102, 111))	('S', 'Chemical', 'MESH:D013455', (165, 166))
279041	30854807	The rs2395655 variant genotype of the p21 promoter was determined by PCR direct sequencing and the primer sets are listed in Table 1.	('p21', 'Gene', (38, 41))	('rs2395655', 'Mutation', 'rs2395655', (4, 13))	('p21', 'Gene', '1026', (38, 41))	('rs2395655', 'Var', (4, 13))
279060	30854807	The variables in the multivariate analysis were age, sex, tumor location, tumor cell differentiation, TNM stage, p21 expression, and rs2395655 variant genotype.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('rs2395655', 'Var', (133, 142))	('expression', 'Species', '29278', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('p21', 'Gene', '1026', (113, 116))	('TNM stage', 'CPA', (102, 111))	('tumor', 'Disease', (74, 79))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('p21', 'Gene', (113, 116))	('rs2395655', 'Mutation', 'rs2395655', (133, 142))
279062	30854807	To evaluate the effects of polymorphisms rs3829963 (-2119C/A) and rs2395655 (-809G/A) on transcriptional activity of the p21 promoter, reporter constructs were created with each combination of the two SNPs (Figure 1A).	('rs3829963 (-2119C/A', 'Var', (41, 60))	('p21', 'Gene', '1026', (121, 124))	('-809G/A', 'Mutation', 'rs2395655', (77, 84))	('rs2395655', 'Mutation', 'rs2395655', (66, 75))	('S', 'Chemical', 'MESH:D013455', (201, 202))	('p21', 'Gene', (121, 124))	('-2119C/A', 'Mutation', 'rs3829963', (52, 60))	('rs3829963', 'Mutation', 'rs3829963', (41, 50))	('-2119C/A', 'Var', (52, 60))
279063	30854807	The results of luciferase assay showed that reporter gene expression driven by rs2395655 G allele-containing promoters were about two and fourfold greater than A allele-containing counterparts in EC-109 (Figure 1B) and KYSE150 cells (Figure 1C), respectively.	('greater', 'PosReg', (147, 154))	('KYSE150', 'CellLine', 'CVCL:1348', (219, 226))	('reporter gene expression', 'MPA', (44, 68))	('expression', 'Species', '29278', (58, 68))	('rs2395655', 'Mutation', 'rs2395655', (79, 88))	('rs2395655 G', 'Var', (79, 90))
279064	30854807	Ectopic LEDGF/p75 expression further increased the transcriptional activity of rs2395655 G allele-containing p21 promoters by about two and three times in EC-109 and KYSE150 cells, respectively.	('rs2395655', 'Mutation', 'rs2395655', (79, 88))	('transcriptional activity', 'MPA', (51, 75))	('expression', 'Species', '29278', (18, 28))	('KYSE150', 'CellLine', 'CVCL:1348', (166, 173))	('increased', 'PosReg', (37, 46))	('p21', 'Gene', '1026', (109, 112))	('LEDGF/p75', 'Gene', '11168', (8, 17))	('p21', 'Gene', (109, 112))	('rs2395655 G', 'Var', (79, 90))	('LEDGF/p75', 'Gene', (8, 17))
279065	30854807	However, no significant difference between effects of rs3829963 C or A allele-containing haplotypes on the p21 promoter activity was observed.	('p21', 'Gene', '1026', (107, 110))	('rs3829963 C', 'Var', (54, 65))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('p21', 'Gene', (107, 110))	('rs3829963', 'Mutation', 'rs3829963', (54, 63))
279066	30854807	Notably, ectopic LEDGF/p75 expression did not increase the transcriptional activity of rs2395655 A allele-containing p21 promoters in both EC-109 and KYSE150 cells.	('rs2395655', 'Mutation', 'rs2395655', (87, 96))	('p21', 'Gene', '1026', (117, 120))	('expression', 'Species', '29278', (27, 37))	('p21', 'Gene', (117, 120))	('rs2395655', 'Var', (87, 96))	('LEDGF/p75', 'Gene', '11168', (17, 26))	('LEDGF/p75', 'Gene', (17, 26))	('KYSE150', 'CellLine', 'CVCL:1348', (150, 157))	('transcriptional', 'MPA', (59, 74))
279067	30854807	These results indicated that the p21 promoter with rs2395655 G allele displayed significantly higher transcriptional activity than rs2395655 A allele-containing counterpart and LEDGF/p75 showed the ability of increasing transcriptional activity of the rs2395655 G allele-containing p21 promoter in ESCC cells.	('LEDGF/p75', 'Gene', (177, 186))	('S', 'Chemical', 'MESH:D013455', (299, 300))	('rs2395655 G', 'Var', (252, 263))	('transcriptional activity', 'MPA', (220, 244))	('p21', 'Gene', '1026', (282, 285))	('rs2395655', 'Mutation', 'rs2395655', (131, 140))	('increasing', 'PosReg', (209, 219))	('p21', 'Gene', (282, 285))	('rs2395655', 'Mutation', 'rs2395655', (51, 60))	('si', 'Chemical', 'MESH:D012825', (215, 217))	('transcriptional activity', 'MPA', (101, 125))	('p21', 'Gene', '1026', (33, 36))	('p21', 'Gene', (33, 36))	('LEDGF/p75', 'Gene', '11168', (177, 186))	('rs2395655 G', 'Var', (51, 62))	('rs2395655', 'Mutation', 'rs2395655', (252, 261))	('higher', 'PosReg', (94, 100))	('si', 'Chemical', 'MESH:D012825', (80, 82))
279068	30854807	Bioinformatic analysis using the TFSEARCH program predicted that polymorphism rs2395655 A>G transition created one cis-regulatory element, that is STRE element (AGGGGT), comprising nucleotides -810 to -805 of the p21 promoter (Figure 2A).	('men', 'Species', '9606', (155, 158))	('S', 'Chemical', 'MESH:D013455', (147, 148))	('polymorphism', 'Var', (65, 77))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('rs2395655 A>', 'Var', (78, 90))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('p21', 'Gene', '1026', (213, 216))	('men', 'Species', '9606', (133, 136))	('rs2395655', 'Mutation', 'rs2395655', (78, 87))	('p21', 'Gene', (213, 216))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('si', 'Chemical', 'MESH:D012825', (176, 178))
279069	30854807	EMSA was performed to determine whether the different transcriptional activity of the rs2395655 G or A allele-containing promoter is attributable to its binding capability to specific transcription factor(s).	('rs2395655', 'Mutation', 'rs2395655', (86, 95))	('S', 'Chemical', 'MESH:D013455', (2, 3))	('binding', 'Interaction', (153, 160))	('rs2395655 G', 'Var', (86, 97))	('transcriptional activity', 'MPA', (54, 78))
279070	30854807	As shown in Figure 2B, a clear shift band was detected with the rs2395655 G probe (lane 2), which could be supershifted by specific anti-LEDGF/p75 antibody (C-16) (lane 3) but not by anti-IgG antibody (lane 4).	('LEDGF/p75', 'Gene', '11168', (137, 146))	('LEDGF/p75', 'Gene', (137, 146))	('rs2395655 G', 'Var', (64, 75))	('IgG antibody', 'Phenotype', 'HP:0003237', (188, 200))	('rs2395655', 'Mutation', 'rs2395655', (64, 73))
279071	30854807	Further competition experiment with a 400-fold molar excess of unlabeled rs2395655 G probe (lane 5) showed marked reduction in shift signal.	('-fold molar', 'Phenotype', 'HP:0011093', (41, 52))	('rs2395655', 'Mutation', 'rs2395655', (73, 82))	('reduction', 'NegReg', (114, 123))	('si', 'Chemical', 'MESH:D012825', (133, 135))	('men', 'Species', '9606', (26, 29))	('rs2395655 G', 'Var', (73, 84))	('shift signal', 'MPA', (127, 139))
279073	30854807	To further examine the allele specific binding ability of LEDGF/p75, we used the genomic DNA mixture obtained from EC-109 and KYSE410 cells (carrying rs2395655 GG and AA genotype, respectively) and performed ChIP assay.	('LEDGF/p75', 'Gene', '11168', (58, 67))	('S', 'Chemical', 'MESH:D013455', (128, 129))	('LEDGF/p75', 'Gene', (58, 67))	('rs2395655 GG', 'Var', (150, 162))	('rs2395655', 'Mutation', 'rs2395655', (150, 159))
279074	30854807	The PCR amplification of input and IP products and subsequent sequencing results confirmed that LEDGF/p75 interacted with the p21 promoter region containing rs2395655 G allele (Figure 2C).	('interacted', 'Interaction', (106, 116))	('LEDGF/p75', 'Gene', '11168', (96, 105))	('rs2395655 G', 'Var', (157, 168))	('LEDGF/p75', 'Gene', (96, 105))	('rs2395655', 'Mutation', 'rs2395655', (157, 166))	('p21', 'Gene', '1026', (126, 129))	('p21', 'Gene', (126, 129))
279075	30854807	These results suggested the potential binding capability of LEDGF/p75 with the STRE element implicated in rs2395655 G allele of the p21 promoter.	('S', 'Chemical', 'MESH:D013455', (79, 80))	('LEDGF/p75', 'Gene', '11168', (60, 69))	('men', 'Species', '9606', (87, 90))	('LEDGF/p75', 'Gene', (60, 69))	('binding', 'Interaction', (38, 45))	('p21', 'Gene', '1026', (132, 135))	('p21', 'Gene', (132, 135))	('rs2395655 G', 'Var', (106, 117))	('rs2395655', 'Mutation', 'rs2395655', (106, 115))
279076	30854807	Four kinds of human ESCC cells carrying rs2395655 GG or AA genotype were used to examine the effect of RNA interference-mediated depletion or ectopic expression of LEDGF/p75 on expression regulation of the p21 gene.	('rs2395655', 'Var', (40, 49))	('S', 'Chemical', 'MESH:D013455', (21, 22))	('p21', 'Gene', (206, 209))	('p21', 'Gene', '1026', (206, 209))	('human', 'Species', '9606', (14, 19))	('LEDGF/p75', 'Gene', '11168', (164, 173))	('LEDGF/p75', 'Gene', (164, 173))	('expression', 'Species', '29278', (177, 187))	('rs2395655', 'Mutation', 'rs2395655', (40, 49))	('RNA interference-mediated', 'MPA', (103, 128))	('expression regulation', 'MPA', (177, 198))	('expression', 'Species', '29278', (150, 160))
279079	30854807	Obviously down-regulated expression level of p21 mRNA was also observed in EC-109 and KYSE150 cells with rs2395655 GG genotype, but not in KYSE410 and KYSE450 cells with rs2395655 AA genotype.	('p21', 'Gene', '1026', (45, 48))	('KYSE150', 'CellLine', 'CVCL:1348', (86, 93))	('p21', 'Gene', (45, 48))	('expression', 'Species', '29278', (25, 35))	('S', 'Chemical', 'MESH:D013455', (141, 142))	('S', 'Chemical', 'MESH:D013455', (88, 89))	('S', 'Chemical', 'MESH:D013455', (153, 154))	('rs2395655', 'Mutation', 'rs2395655', (170, 179))	('rs2395655 GG', 'Var', (105, 117))	('down-regulated', 'NegReg', (10, 24))	('rs2395655', 'Mutation', 'rs2395655', (105, 114))	('expression level', 'MPA', (25, 41))
279081	30854807	These results supported our speculation that the interaction between LEDGF/p75 and the STRE element implicated in rs2395655 G allele played an important role in regulation of transcriptional activity of the p21 promoter.	('S', 'Chemical', 'MESH:D013455', (87, 88))	('transcriptional activity', 'MPA', (175, 199))	('p21', 'Gene', '1026', (207, 210))	('LEDGF/p75', 'Gene', '11168', (69, 78))	('interaction', 'Interaction', (49, 60))	('rs2395655', 'Mutation', 'rs2395655', (114, 123))	('LEDGF/p75', 'Gene', (69, 78))	('p21', 'Gene', (207, 210))	('men', 'Species', '9606', (95, 98))	('regulation', 'MPA', (161, 171))	('rs2395655 G', 'Var', (114, 125))
279086	30854807	The correlation between rs2395655 variant genotype and the p21 protein expression was further analyzed.	('rs2395655', 'Mutation', 'rs2395655', (24, 33))	('p21', 'Gene', '1026', (59, 62))	('p21', 'Gene', (59, 62))	('rs2395655', 'Var', (24, 33))	('expression', 'Species', '29278', (71, 81))
279090	30854807	Statistical analysis revealed that rs2395655 GG genotype was significantly associated with up-regulated p21 protein expression compared with rs2395655 AA or AG genotype (P = 0.008).	('p21', 'Gene', '1026', (104, 107))	('rs2395655 GG', 'Var', (35, 47))	('rs2395655', 'Mutation', 'rs2395655', (35, 44))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('p21', 'Gene', (104, 107))	('rs2395655', 'Mutation', 'rs2395655', (141, 150))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('up-regulated', 'PosReg', (91, 103))	('expression', 'Species', '29278', (116, 126))	('S', 'Chemical', 'MESH:D013455', (0, 1))
279091	30854807	Univariate analysis using the log-rank test revealed that the p21 protein expression and rs2395655 variant genotype were significantly associated with disease-free survival time of ESCC patients.	('S', 'Chemical', 'MESH:D013455', (182, 183))	('rs2395655', 'Var', (89, 98))	('disease-free survival time', 'CPA', (151, 177))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('associated', 'Reg', (135, 145))	('ESCC', 'Disease', (181, 185))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('p21', 'Gene', '1026', (62, 65))	('expression', 'Species', '29278', (74, 84))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('rs2395655', 'Mutation', 'rs2395655', (89, 98))	('patients', 'Species', '9606', (186, 194))	('p21', 'Gene', (62, 65))
279093	30854807	Notably, ESCC patients carrying rs2395655 GG genotype showed better postoperative outcome than patients with rs2395655 AA or AG genotype (30.0 +- 3.9 vs 20.0 +- 1.8 months, P = 0.003) (Figure 5B).	('better', 'PosReg', (61, 67))	('patients', 'Species', '9606', (95, 103))	('rs2395655 GG', 'Var', (32, 44))	('rs2395655', 'Mutation', 'rs2395655', (32, 41))	('postoperative outcome', 'CPA', (68, 89))	('S', 'Chemical', 'MESH:D013455', (10, 11))	('rs2395655', 'Mutation', 'rs2395655', (109, 118))	('patients', 'Species', '9606', (14, 22))
279094	30854807	Furthermore Cox multivariate analysis supported the positive prognostic roles of up-regulated p21 protein expression and rs2395655 GG genotype in this series of 218 ESCC patients (P = 0.008 and 0.025, respectively), as shown in Table 3. p21 is a principal mediator of cell cycle arrest in response to DNA damage and its expression is regulated by a complex cellular signaling pathway in which many nuclear proteins, including p53, E2F, Ap-1, Ap-2, c-Jun, et al., interact with cis-acting elements in the p21 promoter region and regulate p21 gene transcription.3, 4, 14, 15, 16, 17, 18, 19, 20, 21 Naturally occurring SNPs in the p21 promoter may therefore have impact on gene transcription by altering the binding capability of the promoter with certain nuclear proteins.	('p21', 'Gene', (629, 632))	('p21', 'Gene', '1026', (537, 540))	('SNPs', 'Var', (617, 621))	('p21', 'Gene', '1026', (504, 507))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('si', 'Chemical', 'MESH:D012825', (366, 368))	('p21', 'Gene', (237, 240))	('impact', 'Reg', (661, 667))	('p21', 'Gene', (94, 97))	('nuclear proteins', 'Protein', (754, 770))	('si', 'Chemical', 'MESH:D012825', (326, 328))	('altering', 'Reg', (693, 701))	('gene transcription', 'MPA', (671, 689))	('p21', 'Gene', '1026', (629, 632))	('men', 'Species', '9606', (491, 494))	('patients', 'Species', '9606', (170, 178))	('p53', 'Gene', '7157', (426, 429))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('p21', 'Gene', (537, 540))	('expression', 'Species', '29278', (320, 330))	('binding', 'Interaction', (706, 713))	('p21', 'Gene', (504, 507))	('p21', 'Gene', '1026', (237, 240))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (268, 285))	('p53', 'Gene', (426, 429))	('expression', 'Species', '29278', (106, 116))	('p21', 'Gene', '1026', (94, 97))	('S', 'Chemical', 'MESH:D013455', (166, 167))	('rs2395655', 'Mutation', 'rs2395655', (121, 130))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('S', 'Chemical', 'MESH:D013455', (617, 618))
279096	30854807	LEDGF/p75 was identified to be overexpressed in several human tumor types, including prostate, colon, thyroid, liver, uterine, and breast cancers.32 It was revealed that alphaB-crystallin, a target of LEDGF/p75, was expressed in basal-like tumors and predicted poor survival in breast cancer patients.33 Increased expression of LEDGF/p75 was identified in blasts from chemotherapy resistant human acute myelogenic leukemia patients and demonstrated to protect leukemia cells from apoptosis.34 LEDGF/p75 was reported to tether the mixed-lineage leukemia (MLL1) protein complex to chromatin and promote development of MLL leukemia.35 LEDGF/p75 was also found to bind to a regulatory region of FBXO10 and increase expression during conditions favoring carcinogenesis.36 LEDGF/p75:JPO2 protein complex was identified to be critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma.27 It was recently demonstrated that LEDGF/p75 played an important role in breast cancer tumorigenicity by promoting the expression of genes controlling the cell cycle and tumor metastasis.37  In this study, two SNPs, that is rs3829963 (-2119C/A) and rs2395655 (-809G/A), were evaluated for their effects on the p21 transcriptional activity in ESCC cells.	('men', 'Species', '9606', (608, 611))	('si', 'Chemical', 'MESH:D012825', (383, 385))	('si', 'Chemical', 'MESH:D012825', (486, 488))	('breast cancer', 'Disease', 'MESH:D001943', (278, 291))	('p21', 'Gene', (1207, 1210))	('si', 'Chemical', 'MESH:D012825', (717, 719))	('tumors', 'Disease', (240, 246))	('leukemia', 'Phenotype', 'HP:0001909', (414, 422))	('tumor', 'Disease', (1067, 1072))	('si', 'Chemical', 'MESH:D012825', (1080, 1082))	('tumor', 'Disease', 'MESH:D009369', (1067, 1072))	('myelogenic leukemia', 'Phenotype', 'HP:0012324', (403, 422))	('si', 'Chemical', 'MESH:D012825', (760, 762))	('p21', 'Gene', '1026', (1207, 1210))	('LEDGF/p75', 'Gene', (493, 502))	('LEDGF/p75', 'Gene', '11168', (632, 641))	('myelogenic leukemia', 'Disease', (403, 422))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('LEDGF/p75', 'Gene', '11168', (201, 210))	('JPO2', 'Gene', (777, 781))	('rs2395655', 'Mutation', 'rs2395655', (1146, 1155))	('basal-like tumors', 'Phenotype', 'HP:0002671', (229, 246))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('breast cancer', 'Phenotype', 'HP:0003002', (970, 983))	('leukemia', 'Disease', (544, 552))	('breast cancer', 'Disease', (970, 983))	('leukemia', 'Phenotype', 'HP:0001909', (460, 468))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('-809G/A', 'Mutation', 'rs2395655', (1157, 1164))	('cancer', 'Phenotype', 'HP:0002664', (977, 983))	('patients', 'Species', '9606', (292, 300))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('LEDGF/p75', 'Gene', (932, 941))	('LEDGF/p75', 'Gene', (328, 337))	('LEDGF/p75', 'Gene', '11168', (767, 776))	('tumor metastasis', 'Disease', (1067, 1083))	('expression', 'Species', '29278', (314, 324))	('human', 'Species', '9606', (56, 61))	('carcinogenesis', 'Disease', (749, 763))	('FBXO10', 'Gene', '26267', (691, 697))	('MLL1', 'Gene', (554, 558))	('S', 'Chemical', 'MESH:D013455', (1240, 1241))	('LEDGF/p75', 'Gene', (0, 9))	('leukemia', 'Phenotype', 'HP:0001909', (544, 552))	('carcinogenesis', 'Disease', 'MESH:D063646', (749, 763))	('MLL leukemia', 'Disease', 'MESH:D007938', (616, 628))	('MLL leukemia', 'Disease', (616, 628))	('-2119C/A', 'Mutation', 'rs3829963', (1132, 1140))	('LEDGF/p75', 'Gene', '11168', (493, 502))	('breast cancer', 'Disease', 'MESH:D001943', (970, 983))	('si', 'Chemical', 'MESH:D012825', (320, 322))	('human', 'Species', '9606', (391, 396))	('tumor metastasis', 'Disease', 'MESH:D009362', (1067, 1083))	('rs3829963 (-2119C/A', 'Var', (1121, 1140))	('leukemia', 'Disease', (414, 422))	('tumor', 'Phenotype', 'HP:0002664', (984, 989))	('leukemia', 'Disease', 'MESH:D007938', (414, 422))	('leukemia', 'Disease', 'MESH:D007938', (620, 628))	('tumor', 'Disease', (240, 245))	('expression', 'Species', '29278', (711, 721))	('medulloblastoma', 'Disease', 'MESH:D008527', (879, 894))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('si', 'Chemical', 'MESH:D012825', (872, 874))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('patients', 'Species', '9606', (423, 431))	('LEDGF/p75', 'Gene', '11168', (932, 941))	('rs3829963', 'Mutation', 'rs3829963', (1121, 1130))	('LEDGF/p75', 'Gene', '11168', (328, 337))	('tumor', 'Phenotype', 'HP:0002664', (1067, 1072))	('tumor', 'Disease', (62, 67))	('JPO2', 'Gene', '55536', (777, 781))	('breast cancer', 'Phenotype', 'HP:0003002', (278, 291))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('expression', 'Species', '29278', (1016, 1026))	('LEDGF/p75', 'Gene', '11168', (0, 9))	('breast cancer', 'Disease', (278, 291))	('breast cancers', 'Disease', 'MESH:D001943', (131, 145))	('breast cancers', 'Disease', (131, 145))	('LEDGF/p75', 'Gene', (632, 641))	('leukemia', 'Phenotype', 'HP:0001909', (620, 628))	('si', 'Chemical', 'MESH:D012825', (851, 853))	('LEDGF/p75', 'Gene', (201, 210))	('FBXO10', 'Gene', (691, 697))	('leukemia', 'Disease', (620, 628))	('leukemia', 'Disease', (460, 468))	('leukemia', 'Disease', 'MESH:D007938', (460, 468))	('myelogenic leukemia', 'Disease', 'MESH:D007951', (403, 422))	('S', 'Chemical', 'MESH:D013455', (1107, 1108))	('acute myelogenic leukemia', 'Phenotype', 'HP:0004808', (397, 422))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('MLL1', 'Gene', '4297', (554, 558))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('medulloblastoma', 'Disease', (879, 894))	('si', 'Chemical', 'MESH:D012825', (1022, 1024))	('tumor', 'Disease', (984, 989))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', 'MESH:D009369', (984, 989))	('LEDGF/p75', 'Gene', (767, 776))	('leukemia', 'Disease', 'MESH:D007938', (544, 552))
279097	30854807	Bioinformatic analysis showed that rs2395655 A>G transition introduced one cis-regulatory element, that is STRE element, into the p21 promoter region.	('introduced', 'Reg', (60, 70))	('p21', 'Gene', (130, 133))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('men', 'Species', '9606', (93, 96))	('S', 'Chemical', 'MESH:D013455', (107, 108))	('rs2395655', 'Mutation', 'rs2395655', (35, 44))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('men', 'Species', '9606', (115, 118))	('p21', 'Gene', '1026', (130, 133))	('rs2395655 A>G', 'Var', (35, 48))
279098	30854807	Reporter constructs encompassing nucleotides -2308 to +204 of the p21 promoter with each combination of the above two SNPs were established for luciferase assay and the results showed that polymorphism rs2395655 but not rs3829963 influenced the p21 promoter activity in the context of the 2-site haplotypes.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('p21', 'Gene', (66, 69))	('rs2395655', 'Mutation', 'rs2395655', (202, 211))	('si', 'Chemical', 'MESH:D012825', (291, 293))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('rs3829963', 'Mutation', 'rs3829963', (220, 229))	('rs2395655', 'Var', (202, 211))	('p21', 'Gene', '1026', (245, 248))	('p21', 'Gene', (245, 248))	('p21', 'Gene', '1026', (66, 69))
279099	30854807	Moreover, the p21 promoter containing rs2395655 G allele displayed significantly higher transcriptional activity than A allele-containing counterpart, especially with ectopic LEDGF/p75 expression in ESCC cells.	('transcriptional activity', 'MPA', (88, 112))	('p21', 'Gene', '1026', (14, 17))	('rs2395655', 'Mutation', 'rs2395655', (38, 47))	('expression', 'Species', '29278', (185, 195))	('LEDGF/p75', 'Gene', '11168', (175, 184))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('S', 'Chemical', 'MESH:D013455', (200, 201))	('si', 'Chemical', 'MESH:D012825', (191, 193))	('higher', 'PosReg', (81, 87))	('p21', 'Gene', (14, 17))	('LEDGF/p75', 'Gene', (175, 184))	('rs2395655 G', 'Var', (38, 49))
279100	30854807	Furthermore, gel shift assay using the rs2395655 G or A allele-containing probe and chromatin immunoprecipitation assay with specific anti-LEDGF/p75 antibody indicated the potential binding activity of LEDGF/p75 with the STRE element implicated in rs2395655 G allele of the p21 promoter.	('LEDGF/p75', 'Gene', (139, 148))	('binding', 'Interaction', (182, 189))	('rs2395655 G', 'Var', (39, 50))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('rs2395655', 'Mutation', 'rs2395655', (248, 257))	('S', 'Chemical', 'MESH:D013455', (221, 222))	('LEDGF/p75', 'Gene', '11168', (202, 211))	('p21', 'Gene', '1026', (274, 277))	('men', 'Species', '9606', (229, 232))	('rs2395655', 'Mutation', 'rs2395655', (39, 48))	('LEDGF/p75', 'Gene', (202, 211))	('LEDGF/p75', 'Gene', '11168', (139, 148))	('p21', 'Gene', (274, 277))	('rs2395655 G', 'Var', (248, 259))
279101	30854807	Next, four human ESCC cells with rs2395655 GG or AA genotype were used to examine the potential role of LEDGF/p75 and polymorphism rs2395655 in regulation of transcriptional activity of the p21 promoter.	('transcriptional activity', 'MPA', (158, 182))	('S', 'Chemical', 'MESH:D013455', (18, 19))	('human', 'Species', '9606', (11, 16))	('rs2395655', 'Mutation', 'rs2395655', (131, 140))	('p21', 'Gene', '1026', (190, 193))	('rs2395655', 'Var', (131, 140))	('p21', 'Gene', (190, 193))	('LEDGF/p75', 'Gene', '11168', (104, 113))	('rs2395655', 'Mutation', 'rs2395655', (33, 42))	('LEDGF/p75', 'Gene', (104, 113))	('rs2395655', 'Var', (33, 42))
279102	30854807	Specific RNA interference-mediated depletion or ectopic expression of LEDGF/p75 caused obviously down- or up-regulated expression level of the p21 mRNA in cells harboring rs2395655 GG genotype (EC-109 and KYSE150) but not cells with rs2395655 AA genotype (KYSE410 and KYSE450).	('p21', 'Gene', (143, 146))	('rs2395655', 'Mutation', 'rs2395655', (171, 180))	('S', 'Chemical', 'MESH:D013455', (258, 259))	('rs2395655', 'Mutation', 'rs2395655', (233, 242))	('S', 'Chemical', 'MESH:D013455', (270, 271))	('expression', 'Species', '29278', (56, 66))	('S', 'Chemical', 'MESH:D013455', (207, 208))	('expression', 'Species', '29278', (119, 129))	('LEDGF/p75', 'Gene', '11168', (70, 79))	('expression level', 'MPA', (119, 135))	('KYSE150', 'CellLine', 'CVCL:1348', (205, 212))	('down-', 'NegReg', (97, 102))	('p21', 'Gene', '1026', (143, 146))	('LEDGF/p75', 'Gene', (70, 79))	('up-regulated', 'PosReg', (106, 118))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('rs2395655 GG', 'Var', (171, 183))
279104	30854807	These results were consistent with Singh DK's findings that p21 expression was obviously down-regulated in LEDGF/p75-depleted breast cancer cells.37 Our findings strongly supported the idea that LEDGF/p75 regulated p21 expression in ESCC cells through interacting with STRE element implicated in rs2395655 G allele.	('S', 'Chemical', 'MESH:D013455', (269, 270))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('si', 'Chemical', 'MESH:D012825', (225, 227))	('rs2395655', 'Var', (296, 305))	('LEDGF/p75', 'Gene', (195, 204))	('p21', 'Gene', '1026', (60, 63))	('p21', 'Gene', (215, 218))	('LEDGF/p75', 'Gene', (107, 116))	('S', 'Chemical', 'MESH:D013455', (234, 235))	('expression', 'Species', '29278', (219, 229))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Disease', (126, 139))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('LEDGF/p75', 'Gene', '11168', (195, 204))	('interacting', 'Interaction', (252, 263))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('p21', 'Gene', '1026', (215, 218))	('LEDGF/p75', 'Gene', '11168', (107, 116))	('p21', 'Gene', (60, 63))	('men', 'Species', '9606', (277, 280))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('rs2395655', 'Mutation', 'rs2395655', (296, 305))	('expression', 'MPA', (219, 229))	('expression', 'Species', '29278', (64, 74))
279105	30854807	Due to the regulatory effect of polymorphism rs2395655 on the p21 promoter activity in ESCC cells, we further performed immunohistochemical evaluation of the p21 protein expression in total 218 ESCC tissues and investigated the association of rs2395655 variant genotype with the p21 protein expression.	('rs2395655', 'Var', (243, 252))	('p21', 'Gene', '1026', (279, 282))	('p21', 'Gene', (279, 282))	('rs2395655', 'Mutation', 'rs2395655', (45, 54))	('S', 'Chemical', 'MESH:D013455', (88, 89))	('rs2395655', 'Var', (45, 54))	('p21', 'Gene', '1026', (62, 65))	('rs2395655', 'Mutation', 'rs2395655', (243, 252))	('expression', 'Species', '29278', (170, 180))	('p21', 'Gene', '1026', (158, 161))	('expression', 'Species', '29278', (291, 301))	('p21', 'Gene', (158, 161))	('S', 'Chemical', 'MESH:D013455', (195, 196))	('p21', 'Gene', (62, 65))
279106	30854807	Chi-squared test showed significantly elevated p21 protein expression in ESCC tissues with rs2395655 GG genotype than tissues with rs2395655 AA or AG genotype (P = 0.008).	('si', 'Chemical', 'MESH:D012825', (24, 26))	('rs2395655', 'Mutation', 'rs2395655', (91, 100))	('rs2395655', 'Mutation', 'rs2395655', (131, 140))	('expression', 'Species', '29278', (59, 69))	('S', 'Chemical', 'MESH:D013455', (74, 75))	('rs2395655 GG', 'Var', (91, 103))	('p21', 'Gene', '1026', (47, 50))	('elevated', 'PosReg', (38, 46))	('ESCC', 'Disease', (73, 77))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('p21', 'Gene', (47, 50))
279107	30854807	Moreover, the associations of the p21 protein expression and rs2395655 variant genotype with disease-free survival time were evaluated in this ESCC population.	('associations', 'Interaction', (14, 26))	('p21', 'Gene', (34, 37))	('expression', 'Species', '29278', (46, 56))	('rs2395655', 'Mutation', 'rs2395655', (61, 70))	('p21', 'Gene', '1026', (34, 37))	('S', 'Chemical', 'MESH:D013455', (144, 145))	('rs2395655', 'Var', (61, 70))
279110	30854807	Notably, univariate analysis revealed that the median survival time of ESCC patients with rs2395655 GG genotype was much longer than patients carrying rs2395655 AA or AG genotype (30.0 vs 20.0 months, P = 0.003).	('patients', 'Species', '9606', (76, 84))	('S', 'Chemical', 'MESH:D013455', (72, 73))	('rs2395655', 'Mutation', 'rs2395655', (151, 160))	('ESCC', 'Disease', (71, 75))	('patients', 'Species', '9606', (133, 141))	('rs2395655', 'Mutation', 'rs2395655', (90, 99))	('rs2395655 GG', 'Var', (90, 102))	('longer', 'PosReg', (121, 127))	('si', 'Chemical', 'MESH:D012825', (25, 27))
279111	30854807	Cox multivariate analysis further indicated a positive role of rs2395655 GG genotype in predicting the postoperative outcome of ESCC patients (P = 0.025).	('rs2395655', 'Mutation', 'rs2395655', (63, 72))	('patients', 'Species', '9606', (133, 141))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('rs2395655', 'Var', (63, 72))	('ESCC', 'Disease', (128, 132))	('S', 'Chemical', 'MESH:D013455', (129, 130))	('si', 'Chemical', 'MESH:D012825', (48, 50))
279112	30854807	These results of survival analysis were supported by the research findings of Ma H and his colleagues that p21 rs2395655 AA genotype was significantly associated with the increased risk of cancer death of non-small cell lung cancer (adjusted HR = 1.38, 95% CI = 1.07-1.78).38  Taken together, we demonstrated for the first time that LEDGF/p75 binds to STRE element implicated in polymorphism rs2395655 and regulates the p21 gene expression in ESCC cells and tissues.	('rs2395655', 'Mutation', 'rs2395655', (111, 120))	('polymorphism', 'Var', (379, 391))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('men', 'Species', '9606', (360, 363))	('p21', 'Gene', '1026', (107, 110))	('expression', 'MPA', (429, 439))	('cancer death of non-small cell lung cancer', 'Disease', 'MESH:D002289', (189, 231))	('LEDGF/p75', 'Gene', '11168', (333, 342))	('p21', 'Gene', (420, 423))	('regulates', 'Reg', (406, 415))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('binds', 'Interaction', (343, 348))	('rs2395655', 'Mutation', 'rs2395655', (392, 401))	('S', 'Chemical', 'MESH:D013455', (352, 353))	('si', 'Chemical', 'MESH:D012825', (435, 437))	('expression', 'Species', '29278', (429, 439))	('cancer death of non-small cell lung cancer', 'Disease', (189, 231))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('p21', 'Gene', '1026', (420, 423))	('p21', 'Gene', (107, 110))	('S', 'Chemical', 'MESH:D013455', (444, 445))	('rs2395655', 'Var', (392, 401))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('LEDGF/p75', 'Gene', (333, 342))
279113	30854807	Our results suggested that the elevated p21 protein expression and rs2395655 GG genotype may serve as positive prognostic factors for ESCC patients.	('patients', 'Species', '9606', (139, 147))	('S', 'Chemical', 'MESH:D013455', (135, 136))	('expression', 'Species', '29278', (52, 62))	('ESCC', 'Disease', (134, 138))	('p21', 'Gene', '1026', (40, 43))	('elevated', 'PosReg', (31, 39))	('rs2395655', 'Mutation', 'rs2395655', (67, 76))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('p21', 'Gene', (40, 43))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('rs2395655', 'Var', (67, 76))
279116	30613367	TP53 (87%) and CDKN2A (20%) hot spot mutations were frequently found in early lesions.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('CDKN2A', 'Gene', (15, 21))	('CDKN2A', 'Gene', '1029', (15, 21))	('mutations', 'Var', (37, 46))	('found', 'Reg', (63, 68))
279118	30613367	Copy number variation analysis revealed copy number aberrations in multiple genes, including PIK3CA amplification (48%).	('PIK3CA', 'Gene', (93, 99))	('revealed', 'Reg', (31, 39))	('copy number aberrations', 'Var', (40, 63))	('PIK3CA', 'Gene', '5290', (93, 99))
279119	30613367	NGS was superior to p53 immunostaining for detecting TP53 mutations (74% vs. 87%); in combination, the two tests improved detectability to 94%.	('p53', 'Gene', (20, 23))	('mutations', 'Var', (58, 67))	('p53', 'Gene', '7157', (20, 23))	('TP53', 'Gene', '7157', (53, 57))	('improved', 'PosReg', (113, 121))	('TP53', 'Gene', (53, 57))
279120	30613367	Clinically, smoking was associated with the occurrence of TP53 mutations in these early lesions (p = 0.049).	('mutations', 'Var', (63, 72))	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))
279123	30613367	Mutations of TP53 and CDKN2A, and PIK3CA amplification were common in early esophageal squamous neoplasia, while other mutations accumulated with disease progression.	('TP53', 'Gene', (13, 17))	('PIK3CA', 'Gene', (34, 40))	('esophageal squamous neoplasia', 'Disease', 'MESH:D000077277', (76, 105))	('neoplasia', 'Phenotype', 'HP:0002664', (96, 105))	('CDKN2A', 'Gene', (22, 28))	('esophageal squamous neoplasia', 'Disease', (76, 105))	('CDKN2A', 'Gene', '1029', (22, 28))	('squamous neoplasia', 'Phenotype', 'HP:0002860', (87, 105))	('PIK3CA', 'Gene', '5290', (34, 40))	('Mutations', 'Var', (0, 9))	('common', 'Reg', (60, 66))	('TP53', 'Gene', '7157', (13, 17))
279134	30613367	A total of 93 neoplasia-specific hotspot mutations were found in 54 neoplastic lesions with a cutoff value of 5%.	('mutations', 'Var', (41, 50))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (68, 86))	('neoplasia', 'Disease', 'MESH:D009369', (14, 23))	('neoplasia', 'Phenotype', 'HP:0002664', (14, 23))	('neoplastic lesions', 'Disease', (68, 86))	('neoplastic lesions', 'Disease', 'MESH:D051437', (68, 86))	('neoplasia', 'Disease', (14, 23))
279135	30613367	TP53 mutations were most common (n = 47, 51%), followed by CDKN2A (n = 12, 13%), APC (n = 4, 4%), VHL (n = 3, 3%), KDR (n = 3, 3%), PTEN (n = 3, 3%), CSF1R (n = 3, 3%), STK11 (n = 2, 2%), CTNNB1 (n = 2, 2%), RB1 (n = 2, 2%) and KIT (n = 2, 2%) mutations.	('PTEN', 'Gene', (132, 136))	('CTNNB1', 'Gene', (188, 194))	('RB1', 'Gene', '5925', (208, 211))	('CDKN2A', 'Gene', (59, 65))	('TP53', 'Gene', '7157', (0, 4))	('PTEN', 'Gene', '5728', (132, 136))	('VHL', 'Disease', (98, 101))	('KDR', 'Gene', (115, 118))	('STK11', 'Gene', (169, 174))	('CDKN2A', 'Gene', '1029', (59, 65))	('mutations', 'Var', (5, 14))	('CTNNB1', 'Gene', '1499', (188, 194))	('APC', 'Disease', 'MESH:D011125', (81, 84))	('KDR', 'Gene', '3791', (115, 118))	('VHL', 'Disease', 'MESH:D006623', (98, 101))	('TP53', 'Gene', (0, 4))	('CSF1R', 'Gene', '1436', (150, 155))	('STK11', 'Gene', '6794', (169, 174))	('APC', 'Disease', (81, 84))	('CSF1R', 'Gene', (150, 155))	('KIT', 'Gene', (228, 231))	('RB1', 'Gene', (208, 211))
279136	30613367	When the mutations were demonstrated from the viewpoint of individual neoplasia, TP53 mutations, which were detected in 47 (87%) of 54 lesions were most common.	('mutations', 'Var', (86, 95))	('neoplasia', 'Disease', (70, 79))	('neoplasia', 'Disease', 'MESH:D009369', (70, 79))	('neoplasia', 'Phenotype', 'HP:0002664', (70, 79))	('common', 'Reg', (153, 159))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
279137	30613367	TP53 mutations were frequently found, irrespective of the tumor depth, even in lesions as early as LGIN or HGIN (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('TP53', 'Gene', '7157', (0, 4))	('HGIN', 'Disease', (107, 111))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('LGIN', 'Disease', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('found', 'Reg', (31, 36))
279147	30613367	Copy number gains or losses were frequently observed in various genes, even in early-stage esophageal lesions, including LGIN/HGIN; the amplification of CNV of PIK3CA was most frequently observed (48%, 26/54).	('Copy number gains', 'Disease', (0, 17))	('CNV', 'Var', (153, 156))	('esophageal lesions', 'Disease', 'MESH:D004935', (91, 109))	('PIK3CA', 'Gene', '5290', (160, 166))	('esophageal lesions', 'Disease', (91, 109))	('Copy number gains', 'Disease', 'MESH:D015430', (0, 17))	('observed', 'Reg', (44, 52))	('LGIN/HGIN', 'Disease', (121, 130))	('amplification', 'Var', (136, 149))	('losses', 'NegReg', (21, 27))	('PIK3CA', 'Gene', (160, 166))
279149	30613367	TP53 mutations were identified in 36 of these 40 p53-antibody-positive lesions (90%).	('TP53', 'Gene', '7157', (0, 4))	('p53', 'Gene', '7157', (49, 52))	('TP53', 'Gene', (0, 4))	('p53', 'Gene', (49, 52))	('mutations', 'Var', (5, 14))
279150	30613367	On the other hand, 47 of 54 lesions (87%) were judged as having TP53 mutations by NGS, and 11 of 47 lesions with TP53 mutations were p53-negative.	('mutations', 'Var', (69, 78))	('p53', 'Gene', '7157', (133, 136))	('TP53', 'Gene', '7157', (113, 117))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('p53', 'Gene', (133, 136))	('TP53', 'Gene', (113, 117))
279151	30613367	With regard to the reasons for immunostaining-negativity in these 11 lesions, the TP53 mutations in the 11 lesions were as follows: stop codon mutations, n = 6; frameshift mutations, n = 2; start codon mutations, n = 1; and intron mutations, n = 2.	('frameshift mutations', 'Var', (161, 181))	('TP53', 'Gene', (82, 86))	('intron mutations', 'Var', (224, 240))	('start', 'MPA', (190, 195))	('stop', 'MPA', (132, 136))	('TP53', 'Gene', '7157', (82, 86))	('mutations', 'Var', (87, 96))
279152	30613367	The samples were divided into two groups based on the presence or absence of TP53 mutations (Table 2).	('TP53', 'Gene', '7157', (77, 81))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', (77, 81))
279153	30613367	TP53 mutations were identified in 47 of 54 lesions and were not identified in seven lesions.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
279156	30613367	TP53 mutations tended to be associated with a heavy alcohol intake (p = 0.052).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (28, 38))	('heavy alcohol intake', 'Phenotype', 'HP:0030955', (46, 66))	('mutations', 'Var', (5, 14))	('heavy alcohol intake', 'MPA', (46, 66))	('alcohol', 'Chemical', 'MESH:D000438', (52, 59))
279158	30613367	We additionally investigated whether CYP2A6 polymorphism, which affects smoking-produced nicotine metabolism, alters the association between TP53 mutational status and smoking.	('CYP2A6', 'Gene', '1548', (37, 43))	('association', 'Interaction', (121, 132))	('CYP2A6', 'Gene', (37, 43))	('affects', 'Reg', (64, 71))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('polymorphism', 'Var', (44, 56))	('nicotine', 'Chemical', 'MESH:D009538', (89, 97))	('alters', 'Reg', (110, 116))
279160	30613367	In cases with multiple lesions, the relationship of the patterns of somatic mutations among these lesions were investigated by focusing the analysis on TP53 mutation.	('TP53', 'Gene', '7157', (152, 156))	('TP53', 'Gene', (152, 156))	('mutation', 'Var', (157, 165))
279161	30613367	As shown in Table 3, the mutational patterns of TP53 were different in six of the seven cases involving patients with multiple esophageal lesions, the only exception was case 2 (p.V217G).	('TP53', 'Gene', '7157', (48, 52))	('multiple esophageal lesions', 'Disease', (118, 145))	('different', 'Reg', (58, 67))	('TP53', 'Gene', (48, 52))	('multiple esophageal lesions', 'Disease', 'MESH:D004935', (118, 145))	('p.V217G', 'Var', (178, 185))	('patients', 'Species', '9606', (104, 112))	('p.V217G', 'Mutation', 'p.V217G', (178, 185))
279163	30613367	We found that TP53 mutations already exist in most early lesions, including IEN.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('IEN', 'Disease', (76, 79))
279164	30613367	CNVs were also already frequent in these early lesions, and the amplification of PIK3CA was the most frequent of these CNVs.	('amplification', 'Var', (64, 77))	('PIK3CA', 'Gene', (81, 87))	('frequent', 'Reg', (101, 109))	('PIK3CA', 'Gene', '5290', (81, 87))
279165	30613367	Smoking was associated with TP53 mutations in these early lesions.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('associated', 'Reg', (12, 22))	('mutations', 'Var', (33, 42))
279167	30613367	Namely, considering that cancers develop after the accumulation of cancer-related gene alterations, the active treatment of IENs as HGIN or LGIN, which had been classified as premalignant, and treatment had not been actively recommended when their malignant potential was unknown might be recommended based on the information about somatic aberrations.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('HGIN', 'Disease', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', (67, 73))	('alterations', 'Var', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('LGIN', 'Disease', (140, 144))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('cancer', 'Disease', (25, 31))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('IENs', 'Phenotype', 'HP:0032187', (124, 128))
279168	30613367	The high frequency of TP53 mutations and the resultant high p53 protein expression in ESCC (including early ESCC) has been reported since the 1990s.	('mutations', 'Var', (27, 36))	('p53', 'Gene', (60, 63))	('TP53', 'Gene', '7157', (22, 26))	('p53', 'Gene', '7157', (60, 63))	('high', 'PosReg', (55, 59))	('TP53', 'Gene', (22, 26))	('ESCC', 'Disease', (86, 90))
279170	30613367	In this background, the results of the two most recent NGS studies from China showed the frequent existence of somatic aberrations, including TP53 gene mutations, even in early dysplastic lesions.	('dysplastic lesions', 'Disease', (177, 195))	('mutations', 'Var', (152, 161))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('dysplastic lesions', 'Disease', 'MESH:D021782', (177, 195))
279172	30613367	The TP53 mutation rate was found to be significantly high, and almost comparable to the mutation frequency reported in advanced ESCC, even in LGIN- and HGIN-stage lesions.	('mutation', 'Var', (9, 17))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
279175	30613367	The high frequency of CDKN2A mutations was also reported in previous studies, including studies in which NGS was performed.	('CDKN2A', 'Gene', (22, 28))	('mutations', 'Var', (29, 38))	('CDKN2A', 'Gene', '1029', (22, 28))
279176	30613367	Since TP53 and CDKN2A gene products both work as central players to protect cells against uncontrolled proliferation by maintaining surveillance against the induction of DNA damage, it is plausible that CDKN2A mutations enhance the proliferation of esophageal neoplasia.	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (249, 269))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('CDKN2A', 'Gene', (15, 21))	('mutations', 'Var', (210, 219))	('enhance', 'PosReg', (220, 227))	('esophageal neoplasia', 'Disease', (249, 269))	('CDKN2A', 'Gene', '1029', (15, 21))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (249, 269))	('CDKN2A', 'Gene', (203, 209))	('surveillance', 'MPA', (132, 144))	('proliferation', 'CPA', (232, 245))	('CDKN2A', 'Gene', '1029', (203, 209))	('neoplasia', 'Phenotype', 'HP:0002664', (260, 269))
279179	30613367	Although PIK3CA amplification was also reported in other studies, our study:which used the most accurate LCM system:confirmed that the incidence of PIK3CA amplification was high.	('amplification', 'Var', (155, 168))	('PIK3CA', 'Gene', '5290', (148, 154))	('PIK3CA', 'Gene', (148, 154))	('PIK3CA', 'Gene', (9, 15))	('PIK3CA', 'Gene', '5290', (9, 15))
279183	30613367	Immunohistochemical (IHC) staining of p53 is a commercially available method that can be used to detect p53 abnormalities in the clinical setting.	('p53', 'Gene', (104, 107))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('p53', 'Gene', '7157', (104, 107))	('abnormalities', 'Var', (108, 121))
279188	30613367	When we investigated the TP53 mutation profiles in the 11 neoplasia samples that were mutation-positive but IHC-negative, most samples had genetic aberrations (stop codon mutations, frameshifts, start codon and intron mutations) that could abrogate the expression of p53 protein.	('expression', 'MPA', (253, 263))	('TP53', 'Gene', (25, 29))	('neoplasia', 'Phenotype', 'HP:0002664', (58, 67))	('neoplasia', 'Disease', 'MESH:D009369', (58, 67))	('intron mutations', 'Var', (211, 227))	('p53', 'Gene', (267, 270))	('p53', 'Gene', '7157', (267, 270))	('abrogate', 'NegReg', (240, 248))	('start', 'MPA', (195, 200))	('neoplasia', 'Disease', (58, 67))	('TP53', 'Gene', '7157', (25, 29))	('frameshifts', 'Var', (182, 193))
279194	30613367	On the other hand, the possible existence of genomic aberrations in the background tissues at low frequencies cannot be denied, as some variants were repeatedly observed across different background mucosa specimens (Pro72Ala of TP53, and Val578del of Notch1); further studies are needed will be needed to confirm this.	('Pro72Ala', 'Mutation', 'rs587782769', (216, 224))	('Notch1', 'Gene', (251, 257))	('Val578del', 'Mutation', 'p.578delV', (238, 247))	('Notch1', 'Gene', '4851', (251, 257))	('Val578del', 'Var', (238, 247))	('Pro72Ala', 'Var', (216, 224))	('TP53', 'Gene', '7157', (228, 232))	('TP53', 'Gene', (228, 232))
279195	30613367	With regard to the cause of cancer-related gene aberrations, we focused our analysis on TP53 mutations.	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('TP53', 'Gene', '7157', (88, 92))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('TP53', 'Gene', (88, 92))
279196	30613367	As shown in Table 2, smoking was extracted as risk factors for TP53 mutations in early esophageal neoplasia, which is compatible with previous studies.	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('esophageal neoplasia', 'Disease', (87, 107))	('mutations', 'Var', (68, 77))	('neoplasia', 'Phenotype', 'HP:0002664', (98, 107))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (87, 107))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (87, 107))
279198	30613367	Nucleotide substitution analysis revealed the high frequency of C>A transversion, which is known to be highly associated with benzo(a)pyrene-induced carcinogenesis.	('carcinogenesis', 'Disease', (149, 163))	('C>A transversion', 'Var', (64, 80))	('associated', 'Reg', (110, 120))	('benzo(a)pyrene', 'Chemical', 'MESH:D001564', (126, 140))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))
279200	30613367	On the other hand, the role of chronic inflammation and/or the APOBEC family proteins in ESCC carcinogenesis and their potential correlation with smoking, drinking and other causes, such as human papilloma virus infection, are not well understood, and further studies are needed to confirm the fundamental molecular mechanisms that induce TP53 mutations.	('TP53', 'Gene', '7157', (339, 343))	('TP53', 'Gene', (339, 343))	('papilloma virus infection', 'Disease', (196, 221))	('mutations', 'Var', (344, 353))	('inflammation', 'Disease', 'MESH:D007249', (39, 51))	('papilloma virus infection', 'Disease', 'MESH:D010212', (196, 221))	('ESCC', 'Disease', (89, 93))	('inflammation', 'Disease', (39, 51))	('papilloma', 'Phenotype', 'HP:0012740', (196, 205))	('carcinogenesis', 'Disease', 'MESH:D063646', (94, 108))	('carcinogenesis', 'Disease', (94, 108))
279202	30613367	On the other hand, the frequent presence of hotspot mutations and CNVs in cancer-related genes were successfully reproduced using the panel in the early esophageal neoplasm specimens in this study.	('mutations', 'Var', (52, 61))	('esophageal neoplasm', 'Phenotype', 'HP:0100751', (153, 172))	('esophageal neoplasm', 'Disease', (153, 172))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('neoplasm', 'Phenotype', 'HP:0002664', (164, 172))	('cancer', 'Disease', (74, 80))	('esophageal neoplasm', 'Disease', 'MESH:D004938', (153, 172))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
279205	30613367	We revealed the high frequency of TP53/CDKN2A hotspot mutations and PIK3CA copy number amplification, which was comparable to the frequency observed in advanced ESCC.	('CDKN2A', 'Gene', (39, 45))	('PIK3CA', 'Gene', (68, 74))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (54, 63))	('CDKN2A', 'Gene', '1029', (39, 45))	('PIK3CA', 'Gene', '5290', (68, 74))	('copy number amplification', 'Var', (75, 100))	('TP53', 'Gene', '7157', (34, 38))
279218	30613367	A total of 2,790 hotspot mutations of the 50 cancer-related genes were reported in the Catalogue of Somatic Mutations in Cancer (COSMIC; hotspot mutations) database 8.	('mutations', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
279219	30613367	Variants were regarded as neoplasia-specific if they were only detected in neoplasia (not in the adjacent background mucosa) and if the variant frequency was over the cut-off value of 5%.	('Variants', 'Var', (0, 8))	('neoplasia', 'Phenotype', 'HP:0002664', (26, 35))	('neoplasia', 'Disease', (75, 84))	('neoplasia', 'Disease', (26, 35))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('neoplasia', 'Disease', 'MESH:D009369', (26, 35))	('neoplasia', 'Disease', 'MESH:D009369', (75, 84))
279227	28573929	Interfraction shifts between the internal target volume and esophagus can lead to unanticipated increases in the volume of esophagus receiving high doses when treating central lung tumors with stereotactic body radiation therapy.	('central lung tumors', 'Disease', (168, 187))	('lung tumors', 'Phenotype', 'HP:0100526', (176, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('central lung tumors', 'Disease', 'MESH:D008175', (168, 187))	('increases', 'PosReg', (96, 105))	('lung tumor', 'Phenotype', 'HP:0100526', (176, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('volume', 'MPA', (113, 119))	('stereotactic body', 'Phenotype', 'HP:0000733', (193, 210))	('shifts', 'Var', (14, 20))
279273	28573929	DVH end points evaluated included D5cc (minimum dose in Gy to the 5 cm3 of the esophagus receiving the highest dose), mean dose (Dmean), dose to 3.5 cm3 (D3.5cc), D1cc, and maximum point dose (Dmax), which have been previously identified in prior studies to impact the risk of esophageal toxicity.	('Dmean', 'Chemical', '-', (129, 134))	('D1cc', 'Var', (163, 167))	('D5cc', 'Var', (34, 38))	('esophageal toxicity', 'Disease', 'MESH:D004935', (277, 296))	('D5cc', 'Chemical', '-', (34, 38))	('DVH', 'Chemical', '-', (0, 3))	('esophageal toxicity', 'Disease', (277, 296))
279279	28573929	Over all patients, the median planned values for the full treatment course of the esophagus Dmax, D1cc, D3.5cc, D5cc, and Dmean were 29.2, 23.3, 20.1, 18.4, and 13.3 Gy, respectively.	('patients', 'Species', '9606', (9, 17))	('D5cc', 'Var', (112, 116))	('D5cc', 'Chemical', '-', (112, 116))	('Dmean', 'Chemical', '-', (122, 127))	('D3.5cc', 'Var', (104, 110))
279280	28573929	Distribution of the relative change in dose to D1cc, D3.5cc, D5cc, and Dmean between the planned dose and that predicted from the CBCT for each fraction are shown in Figure 2, whereas the absolute change in BED10 is shown in Figure 3.	('Dmean', 'Chemical', '-', (71, 76))	('D5cc', 'Var', (61, 65))	('D3.5cc', 'Var', (53, 59))	('D5cc', 'Chemical', '-', (61, 65))
279282	28573929	Eight patients received at least 1 fraction, where the D5cc, D3.5cc, and D1cc were greater than calculated from the plan, while 7 patients received at least 1 fraction, where Dmax and Dmean were greater than planned.	('D3.5cc', 'Var', (61, 67))	('D1cc', 'Var', (73, 77))	('D5cc', 'Var', (55, 59))	('patients', 'Species', '9606', (130, 138))	('D5cc', 'Chemical', '-', (55, 59))	('patients', 'Species', '9606', (6, 14))	('Dmean', 'Chemical', '-', (184, 189))
279306	28573929	There is a dose-response relationship, with mean esophagus dose higher than 34 Gy, V35 greater than 50%, V50 greater 40%, and V70 greater than 20% predicting for increased risk for esophageal toxicity.	('esophageal toxicity', 'Disease', (181, 200))	('V50 greater 40%', 'Var', (105, 120))	('V70 greater than', 'Var', (126, 142))	('V35', 'Gene', '28474', (83, 86))	('esophageal toxicity', 'Disease', 'MESH:D004935', (181, 200))	('V35', 'Gene', (83, 86))
279308	28573929	A recent study by Stephans et al found that in SBRT for central NSCLC tumors, no significant late esophageal toxicity occurred when the Dmax was less than 50 Gy and the D1cc was less than 45 Gy.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('SBRT', 'Chemical', '-', (47, 51))	('NSCLC tumors', 'Disease', 'MESH:D009369', (64, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('NSCLC tumors', 'Disease', (64, 76))	('late esophageal toxicity', 'Disease', 'MESH:D004941', (93, 117))	('less', 'Var', (145, 149))	('late esophageal toxicity', 'Disease', (93, 117))
279312	28573929	In a previously published study by our group of 125 patients with central lung tumors treated with SBRT which included the cohort in this analysis, we found that D5cc and Dmax best predicted for increased esophageal toxicity.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('central lung tumors', 'Disease', (66, 85))	('Dmax', 'MPA', (171, 175))	('lung tumors', 'Phenotype', 'HP:0100526', (74, 85))	('central lung tumors', 'Disease', 'MESH:D008175', (66, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('D5cc', 'Var', (162, 166))	('D5cc', 'Chemical', '-', (162, 166))	('increased esophageal toxicity', 'Disease', 'MESH:D004935', (195, 224))	('increased esophageal toxicity', 'Disease', (195, 224))	('lung tumor', 'Phenotype', 'HP:0100526', (74, 84))	('patients', 'Species', '9606', (52, 60))	('SBRT', 'Chemical', '-', (99, 103))
279313	28573929	The probability of complications at 2 years for those with D5cc >14.4 BED10 was 24% and for those with Dmax >29.6 BED10 was 21% compared to 2% and 7%, respectively, if the dose was less than or equal to those values.	('complications', 'Disease', (19, 32))	('D5cc >14.4 BED10', 'Var', (59, 75))	('D5cc', 'Chemical', '-', (59, 63))
279315	28573929	For 5 fraction treatments, they found that D1cc at a dose of 32.9 Gy and Dmax dose of 43.4 Gy corresponded to a complication probability of 50% for grade 2 toxicity.	('toxicity', 'Disease', (156, 164))	('D1cc', 'Var', (43, 47))	('toxicity', 'Disease', 'MESH:D064420', (156, 164))
279320	28573929	Evaluating both cases of high-grade toxicity, movement of the esophagus relative to the PTV resulted in cumulative doses that theoretically would have exceeded the constraints for D5cc (30.5 and 30.5 Gy, respectively).	('toxicity', 'Disease', 'MESH:D064420', (36, 44))	('toxicity', 'Disease', (36, 44))	('D5cc', 'Chemical', '-', (180, 184))	('PTV', 'Chemical', '-', (88, 91))	('movement', 'Var', (46, 54))
279328	28573929	Interfraction variations in the tumor position may also affect the relationship between the tumor and esophagus, independent of esophageal motion.	('affect', 'Reg', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('variations', 'Var', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (32, 37))	('relationship', 'Interaction', (67, 79))
279347	28573929	Although prior studies have identified small dose-volume constraints such at D5cc that are correlated with increased esophageal toxicity, this is not the purpose of this study.	('increased esophageal toxicity', 'Disease', 'MESH:D004935', (107, 136))	('D5cc', 'Var', (77, 81))	('increased esophageal toxicity', 'Disease', (107, 136))	('D5cc', 'Chemical', '-', (77, 81))
279348	28573929	However, it is highly suggestive that in our 2 cases of significant late esophageal toxicity observed, variance in esophageal position relative to the PTV resulted in significantly higher small volume doses than anticipated, which we hypothesize may have enhanced their risk of toxicity.	('PTV', 'Chemical', '-', (151, 154))	('variance', 'Var', (103, 111))	('late esophageal toxicity', 'Disease', (68, 92))	('toxicity', 'Disease', 'MESH:D064420', (278, 286))	('late esophageal toxicity', 'Disease', 'MESH:D004941', (68, 92))	('higher', 'PosReg', (181, 187))	('toxicity', 'Disease', (278, 286))	('small volume doses', 'MPA', (188, 206))	('toxicity', 'Disease', 'MESH:D064420', (84, 92))	('toxicity', 'Disease', (84, 92))
279350	28573929	Interfraction shifts between the PTV and esophagus can lead to unanticipated increases in the volume of esophagus receiving high doses when treating central lung tumors with SBRT.	('lung tumor', 'Phenotype', 'HP:0100526', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('SBRT', 'Chemical', '-', (174, 178))	('PTV', 'Chemical', '-', (33, 36))	('central lung tumors', 'Disease', (149, 168))	('central lung tumors', 'Disease', 'MESH:D008175', (149, 168))	('increases', 'PosReg', (77, 86))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('lung tumors', 'Phenotype', 'HP:0100526', (157, 168))	('shifts', 'Var', (14, 20))	('volume', 'MPA', (94, 100))
279383	27061001	Eligibility criteria for inclusion in this study included patient age of at least 18 years at the time of enrolment and the presence of histologically or cytologically confirmed SCC, which was locally advanced to clinical stage IB/II/III (International Union Against Cancer TNM classification system, 7th edition).22 Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, a life expectancy of >12 weeks, and adequate liver, bone marrow, renal, and cardiovascular function based on the following values: serum bilirubin <=1.5 mg/dL, neutrophil count >=1500/mm3, serum aspartate aminotransferase and alanine aminotransferase <=twice the upper limit of normal range, platelet count >=10 x 104/mm3, hemoglobin >=8.0 g/dL, and creatinine <=1.2 mg/dL (or creatinine clearance >60 mL/min).	('SCC', 'Gene', '6317', (178, 181))	('TNM', 'Gene', '10178', (274, 277))	('SCC', 'Gene', (178, 181))	('Cancer', 'Disease', 'MESH:D009369', (267, 273))	('TNM', 'Gene', (274, 277))	('Oncology', 'Phenotype', 'HP:0002664', (371, 379))	('creatinine', 'Chemical', 'MESH:D003404', (797, 807))	('alanine aminotransferase', 'Gene', (646, 670))	('alanine aminotransferase', 'Gene', '2875', (646, 670))	('Patients', 'Species', '9606', (317, 325))	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (609, 641))	('creatinine', 'MPA', (770, 780))	('creatinine clearance', 'MPA', (797, 817))	('>=10', 'Var', (727, 731))	('Cancer', 'Phenotype', 'HP:0002664', (267, 273))	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('bilirubin', 'Chemical', 'MESH:D001663', (557, 566))	('patient', 'Species', '9606', (58, 65))	('creatinine', 'Chemical', 'MESH:D003404', (770, 780))	('Cancer', 'Disease', (267, 273))
279535	26814381	Accordingly, pretreatment lymphocyte count was considered to be <1 x 109/L (defined as lymphopenia) or >=1 x 109/L (Fig.	('>=1 x 109/L', 'Var', (103, 114))	('lymphopenia', 'Phenotype', 'HP:0001888', (87, 98))	('lymphopenia', 'Disease', (87, 98))	('lymphopenia', 'Disease', 'MESH:D008231', (87, 98))
279626	26722230	Double-strand DNA breaks (DSB) activate the catalytic subunit of the DNA-dependent protein kinase and trigger NHEJ repair activities.	('activate', 'PosReg', (31, 39))	('DNA-dependent protein kinase', 'Gene', '5591', (69, 97))	('trigger', 'Reg', (102, 109))	('catalytic subunit', 'MPA', (44, 61))	('NHEJ repair activities', 'CPA', (110, 132))	('DNA-dependent protein kinase', 'Gene', (69, 97))	('Double-strand', 'Var', (0, 13))
279627	26722230	It has been demonstrated that the silencing of Ku80 proteins prevents DSB repair and telomere maintenance, and results in cell cycle arrest, apoptosis, chemosensitivity and radiosensitivity.	('results in', 'Reg', (111, 121))	('cell cycle arrest', 'CPA', (122, 139))	('telomere maintenance', 'CPA', (85, 105))	('silencing', 'Var', (34, 43))	('DSB repair', 'CPA', (70, 80))	('proteins', 'Protein', (52, 60))	('prevents', 'NegReg', (61, 69))	('radiosensitivity', 'CPA', (173, 189))	('chemosensitivity', 'CPA', (152, 168))	('Ku80', 'Gene', '7520', (47, 51))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('Ku80', 'Gene', (47, 51))	('apoptosis', 'CPA', (141, 150))
279693	26722230	A previous study indicated that genome instability through severe DNA damage is associated with the carcinogenesis and development of ESCC.	('carcinogenesis', 'Disease', (100, 114))	('severe', 'Var', (59, 65))	('ESCC', 'Disease', (134, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (100, 114))	('associated', 'Reg', (80, 90))	('genome instability', 'MPA', (32, 50))
279769	26250827	Dose constraints for normal tissues were defined as: spinal cord, <48 Gy; mean heart dose, <40 Gy; and lung, V10 < 50%, V15 < 40%, V20 < 25%.	('V15', 'Gene', (120, 123))	('V10 < 50%', 'Var', (109, 118))	('V15', 'Gene', '28814', (120, 123))
279788	26250827	Reduction in dose levels depended on creatinine clearance values: >=60 mL/min, no dose modification; <60, >=50 mL/min, reduction in both S-1 and CDDP by one dose level; <50, >=40 mL/min, reduction of both S-1 and CDDP by two dose levels; and <40 mL/min, cessation of both S-1 and CDDP.	('S-1', 'Gene', '5707', (137, 140))	('S-1', 'Gene', (205, 208))	('<60', 'Var', (101, 104))	('CDDP', 'MPA', (145, 149))	('cessation', 'NegReg', (254, 263))	('<50', 'Var', (169, 172))	('CDDP', 'Chemical', 'MESH:D002945', (213, 217))	('reduction', 'NegReg', (187, 196))	('S-1', 'Gene', '5707', (272, 275))	('CDDP', 'Chemical', 'MESH:D002945', (145, 149))	('S-1', 'Gene', '5707', (205, 208))	('CDDP', 'Chemical', 'MESH:D002945', (280, 284))	('S-1', 'Gene', (137, 140))	('creatinine', 'Chemical', 'MESH:D003404', (37, 47))	('reduction', 'NegReg', (119, 128))	('S-1', 'Gene', (272, 275))
279908	26316888	Figure 1CD shows the representative histopathological findings of low or high CA XII expression samples.	('high', 'Var', (73, 77))	('low', 'Var', (66, 69))	('CA XII', 'Gene', '771', (78, 84))	('CA XII', 'Gene', (78, 84))
279913	26316888	On the other hand, the minimum CA XII score in patients with pT2-3 ESCC (n=37) was 0, while the maximum was 2.4 (median= 0.20; mean+-SD= 0.51+-0.60), and no correlation was found between the expression of CA XII and any other clinicopathological parameter (Table III).	('pT2-3', 'Var', (61, 66))	('CA XII', 'Gene', '771', (31, 37))	('CA XII', 'Gene', (205, 211))	('patients', 'Species', '9606', (47, 55))	('CA XII', 'Gene', '771', (205, 211))	('CA XII', 'Gene', (31, 37))
279925	26316888	On the other hand, in patients with pT2-3 ESCC, the 3-year survival rate of patients with the high grade expression of CA XII (29.1 %) was significantly lower than that of patients with the low grade expression of CA XII (70.3 %) (p = 0.011) (Fig.	('pT2-3', 'Var', (36, 41))	('patients', 'Species', '9606', (76, 84))	('CA XII', 'Gene', (214, 220))	('patients', 'Species', '9606', (22, 30))	('CA XII', 'Gene', '771', (214, 220))	('survival', 'CPA', (59, 67))	('CA XII', 'Gene', (119, 125))	('lower', 'NegReg', (153, 158))	('patients', 'Species', '9606', (172, 180))	('CA XII', 'Gene', '771', (119, 125))
279926	26316888	We then assessed which of the 10 variables examined (age, gender, location of the primary tumor, histological type, tumor size, lymphatic invasion, venous invasion, pN category, pStage, and CA XII expression) influenced survival in patients with pT2-3 ESCC following curative resection of esophageal cancer.	('CA XII', 'Gene', (190, 196))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('CA XII', 'Gene', '771', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('influenced', 'Reg', (209, 219))	('esophageal cancer', 'Disease', (289, 306))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (289, 306))	('tumor', 'Disease', (116, 121))	('pT2-3', 'Var', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
279957	26316888	pH regulators, such as anion exchangers, sodium-hydrogen exchangers, vacuolar H+-ATPases, and CAs, have the potential to be key therapeutic targets and the silencing of their expression could provide a new therapeutic strategy in future.	('expression', 'MPA', (175, 185))	('anion exchangers', 'MPA', (23, 39))	('silencing', 'Var', (156, 165))	('sodium-hydrogen exchangers', 'MPA', (41, 67))	('CAs', 'Disease', (94, 97))	('CAs', 'Chemical', 'MESH:D002118', (94, 97))
279985	25324996	Botox and PD can cause tissue injury at the LES and resultant submucosal fibrosis, which to varying degrees obliterates the dissection plane, making POEM more challenging but still feasible.	('cause', 'Reg', (17, 22))	('submucosal fibrosis', 'Disease', 'MESH:D005355', (62, 81))	('submucosal fibrosis', 'Disease', (62, 81))	('tissue injury', 'CPA', (23, 36))	('Botox', 'Var', (0, 5))
280092	23556484	Does the imbalanced inactivation of X chromosomes in female somatic cells, as usually demonstrated using peripheral blood sample, indicate an increased risk of malignant solid tumours development?	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('malignant solid tumours', 'Disease', 'MESH:D009369', (160, 183))	('imbalanced inactivation', 'Var', (9, 32))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('malignant solid tumours', 'Disease', (160, 183))
280104	23556484	The analysis is based on differential inactivation of X chromosomes of female somatic tissues and the CAG short-tandem repeat (STR) polymorphism at the AR gene exon 1.	('polymorphism', 'Var', (132, 144))	('AR', 'Gene', '367', (152, 154))	('STR', 'Gene', (127, 130))	('inactivation', 'NegReg', (38, 50))
280125	23556484	Among the 143 patients with esophageal carcinoma, 134 were shown to be polymorphic at the CAG STR, and thereby informative for X-chromosomal inactivation analysis.	('esophageal carcinoma', 'Disease', (28, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (28, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (28, 48))	('polymorphic', 'Var', (71, 82))	('patients', 'Species', '9606', (14, 22))
280141	23556484	When considering its pathogenic pathways, the skewing that is putatively associated with the unbalanced X-chromosome inactivation of precursor cells in early embryogenesis, is considered to be inborn SXCI, whereas the skewing that occurs during adulthood and is prevalent with age, is designated as acquired SXCI.	('inborn SXCI', 'Disease', 'MESH:D030342', (193, 204))	('associated', 'Reg', (73, 83))	('inborn SXCI', 'Disease', (193, 204))	('skewing', 'Disease', (46, 53))	('unbalanced', 'Var', (93, 103))
280171	33354570	Our result shows that high-risk-type HPV-16 was associated with both cervical cancer and esophageal cancer, which play a role in the high-incidence area in Xinjiang.	('esophageal cancer', 'Disease', (89, 106))	('HPV-16', 'Species', '333760', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('associated', 'Reg', (48, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('HPV-16', 'Gene', (37, 43))	('high-risk-type', 'Var', (22, 36))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
280212	33354570	HPV genotypes were analyzed by commercial HPV GenoArray kit (Yaneng Bioscience (Shenzhen) Co. Ltd.) for detection and genotyping of 23 HPV types (HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73, HPV-82, HPV-6, HPV-11, HPV-42, HPV-43, HPV-82, HPV-53, HPV-66, HPV-83), including all the 13 high-risk HPV genotypes.	('HPV', 'Species', '10566', (297, 300))	('HPV', 'Species', '10566', (242, 245))	('HPV', 'Species', '10566', (321, 324))	('HPV', 'Species', '10566', (305, 308))	('HPV', 'Species', '10566', (266, 269))	('HPV', 'Species', '10566', (250, 253))	('HPV', 'Species', '10566', (154, 157))	('HPV', 'Species', '10566', (178, 181))	('HPV', 'Species', '10566', (226, 229))	('HPV', 'Species', '10566', (210, 213))	('HPV', 'Species', '10566', (202, 205))	('HPV-16', 'Species', '333760', (146, 152))	('HPV', 'Species', '10566', (234, 237))	('HPV', 'Species', '10566', (313, 316))	('HPV', 'Species', '10566', (258, 261))	('HPV', 'Species', '10566', (289, 292))	('HPV', 'Species', '10566', (162, 165))	('HPV', 'Species', '10566', (146, 149))	('HPV', 'Species', '10566', (361, 364))	('HPV', 'Species', '10566', (170, 173))	('HPV', 'Species', '10566', (194, 197))	('HPV', 'Species', '10566', (186, 189))	('HPV', 'Species', '10566', (273, 276))	('HPV', 'Species', '10566', (218, 221))	('HPV', 'Species', '10566', (281, 284))	('HPV', 'Species', '10566', (42, 45))	('HPV-43', 'Var', (289, 295))	('HPV-82', 'Var', (297, 303))	('HPV-53', 'Var', (305, 311))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (135, 138))	('HPV-11', 'Species', '10580', (273, 279))
280239	33354570	Four high-risk HPV genotypes were detected, with the sequence as HPV-16 (30), HPV-18 (7), HPV-59 (1), and HPV-45 (1).	('HPV', 'Species', '10566', (65, 68))	('HPV', 'Species', '10566', (90, 93))	('HPV-18', 'Var', (78, 84))	('HPV-59', 'Var', (90, 96))	('HPV-16', 'Gene', (65, 71))	('HPV', 'Species', '10566', (15, 18))	('HPV-45', 'Var', (106, 112))	('HPV', 'Species', '10566', (78, 81))	('HPV-16', 'Species', '333760', (65, 71))	('HPV', 'Species', '10566', (106, 109))
280256	33354570	We detected 152 paraffin-embedded cervical tissues (CNOR40, CIN53, CSCC59) and 120 esophageal tissues (ENOR40, DYS26, ESCC54).	('CC', 'Phenotype', 'HP:0002664', (120, 122))	('CIN', 'Disease', 'MESH:D007674', (60, 63))	('DYS26', 'Chemical', '-', (111, 116))	('CNOR40', 'Var', (52, 58))	('CC', 'Phenotype', 'HP:0002664', (69, 71))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('CIN', 'Disease', (60, 63))
280267	33354570	A global study shows that HPV-16, HPV-31, and HPV-18 were the main types among the women with normal thinprep cytologic test (TCT) diagnosed in Europe; HPV-16, HPV-18, and HPV-33 in Asia; and HPV-16, HPV-58, and HPV-18 in South America.	('HPV', 'Species', '10566', (172, 175))	('HPV-16', 'Species', '333760', (152, 158))	('HPV-16', 'Species', '333760', (26, 32))	('HPV', 'Species', '10566', (46, 49))	('HPV-33', 'Var', (172, 178))	('HPV', 'Species', '10566', (200, 203))	('HPV', 'Species', '10566', (34, 37))	('HPV', 'Species', '10566', (152, 155))	('HPV', 'Species', '10566', (26, 29))	('HPV', 'Species', '10566', (160, 163))	('HPV-16', 'Species', '333760', (192, 198))	('HPV-16', 'Var', (152, 158))	('women', 'Species', '9606', (83, 88))	('HPV', 'Species', '10566', (192, 195))	('HPV', 'Species', '10566', (212, 215))
280269	33354570	Previous studies also reported the five most prevalent HR-HPV genotypes in cervical cancer in Yunnan Province, Southwest China, were HPV-16 (3.4%), HPV-56 (1.7%), HPV-58 (1.4%), HPV-33 (1.2%), and HPV-52 (0.88%).	('HPV-16', 'Var', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('HPV', 'Species', '10566', (148, 151))	('HR-HPV', 'Gene', (55, 61))	('HPV-58', 'Var', (163, 169))	('HPV-33', 'Var', (178, 184))	('HPV', 'Species', '10566', (197, 200))	('HPV-52', 'Var', (197, 203))	('HPV-16', 'Species', '333760', (133, 139))	('HPV', 'Species', '10566', (58, 61))	('HPV-56', 'Var', (148, 154))	('HPV', 'Species', '10566', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('HPV', 'Species', '10566', (133, 136))	('HPV', 'Species', '10566', (178, 181))
280270	33354570	Data from ICO/IARC HPV Information Centre shows that the five most common HR-HPV genotypes in cervical cancer in China were HPV-16 (59.5%), HPV-18 (9.6%), HPV-58 (8.2), HPV-52 (6.5), and HPV-33 (3.5%).	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('HPV', 'Species', '10566', (124, 127))	('HPV', 'Species', '10566', (155, 158))	('HPV-52', 'Var', (169, 175))	('HPV-18', 'Var', (140, 146))	('HPV', 'Species', '10566', (187, 190))	('HPV-58', 'Var', (155, 161))	('HPV', 'Species', '10566', (169, 172))	('HPV-16', 'Var', (124, 130))	('HPV', 'Species', '10566', (77, 80))	('HPV', 'Species', '10566', (19, 22))	('HR-HPV', 'Gene', (74, 80))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('HPV-33', 'Var', (187, 193))	('HPV-16', 'Species', '333760', (124, 130))	('HPV', 'Species', '10566', (140, 143))
280281	33354570	High-risk-type HPV-16 was associated with both cervical cancer and esophageal cancer, which play a role in the high-incidence area in Xinjiang.	('HPV-16', 'Gene', (15, 21))	('High-risk-type', 'Var', (0, 14))	('HPV-16', 'Species', '333760', (15, 21))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('esophageal cancer', 'Disease', (67, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('associated', 'Reg', (26, 36))
280328	31369887	The significant interaction term revealed that the influence of an increased PTV on increasing the G4 lymphopenia risk was greater in patients with lower BMI compared to higher BMI (Figure 1).	('lymphopenia', 'Phenotype', 'HP:0001888', (102, 113))	('lower BMI', 'Phenotype', 'HP:0045082', (148, 157))	('patients', 'Species', '9606', (134, 142))	('lymphopenia', 'Disease', (102, 113))	('lower BMI', 'Var', (148, 157))	('increased PTV', 'Phenotype', 'HP:0008151', (67, 80))	('PTV', 'Chemical', '-', (77, 80))	('lymphopenia', 'Disease', 'MESH:D008231', (102, 113))
280337	31369887	nomogram sum score 13-15 and >15, respectively) had a significantly worse PFS and OS compared to patients at low risk (i.e.	('PFS', 'Disease', (74, 77))	('>15', 'Var', (29, 32))	('worse', 'NegReg', (68, 73))	('patients', 'Species', '9606', (97, 105))
280349	31369887	In line with our finding that PTV is predictive for the risk of lymphopenia risk, previous studies in breast and pancreatic cancer suggested that shrinkage of radiation fields preserve lymphocytes through reducing exposure of circulating blood.	('breast and pancreatic cancer', 'Disease', 'MESH:D001943', (102, 130))	('exposure', 'MPA', (214, 222))	('shrinkage', 'Var', (146, 155))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('lymphopenia', 'Disease', (64, 75))	('lymphopenia', 'Phenotype', 'HP:0001888', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('reducing', 'NegReg', (205, 213))	('lymphopenia', 'Disease', 'MESH:D008231', (64, 75))	('PTV', 'Chemical', '-', (30, 33))
280383	31803756	Mitochondrial dysfunction is associated with specific mitochondrial DNA (mtDNA) variations (haplogroups), and these variations can contribute to human disease.	('Mitochondrial dysfunction', 'Disease', (0, 25))	('Mitochondrial dysfunction', 'Disease', 'MESH:D028361', (0, 25))	('human', 'Species', '9606', (145, 150))	('mitochondrial DNA', 'Disease', (54, 71))	('Mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (0, 25))	('variations', 'Var', (80, 90))	('associated', 'Reg', (29, 39))	('contribute', 'Reg', (131, 141))
280394	31803756	Pathogenic mtDNA mutations include rearrangement mutations (Holt et al.,), polypeptide gene missense mutations (Wallace et al.,), and gene mutations (rRNA and tRNA) related to protein synthesis (Wallace et al.,; Shoffner et al.,).	('Pathogenic', 'Reg', (0, 10))	('missense mutations', 'Var', (92, 110))	('men', 'Species', '9606', (44, 47))	('mutations', 'Var', (17, 26))	('rearrangement mutations', 'Var', (35, 58))	('mtDNA', 'Gene', (11, 16))
280395	31803756	These mismatches, designated single nucleotide polymorphisms (SNPs) by the Cambridge reference sequence for human mtDNA, determine mitochondrial haplogroups.	('human', 'Species', '9606', (108, 113))	('determine', 'Reg', (121, 130))	('mismatches', 'Var', (6, 16))
280396	31803756	Numerous pathogenic variations in mtDNA or in nuclear DNA (nDNA) encoding mitochondrial proteins may lead to clinically and genetically heterogeneous disorders due to mitochondrial ETC dysfunction (Fang H. et al.,; van Rahden et al.,; Piekutowska-Abramczuk et al.,).	('variations', 'Var', (20, 30))	('mitochondrial ETC dysfunction', 'Disease', (167, 196))	('mtDNA', 'Gene', (34, 39))	('mitochondrial ETC dysfunction', 'Disease', 'MESH:D028361', (167, 196))	('lead to', 'Reg', (101, 108))
280403	31803756	mtDNA mutation can lead to mitophagy (Dombi et al.,) and mitochondrial dysfunction (Dolle et al.,; Pera et al.,; Ehrnhoefer et al.,; Lindqvist et al.,; Pereira et al.,; Puthumana and Regenold,) have long been reported as pathogenic in psychiatric and neurodegenerative diseases.	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (251, 277))	('lead to', 'Reg', (19, 26))	('mutation', 'Var', (6, 14))	('human', 'Species', '9606', (172, 177))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (251, 277))	('mitophagy', 'CPA', (27, 36))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (57, 82))	('psychiatric', 'Disease', 'MESH:D001523', (235, 246))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (57, 82))	('psychiatric', 'Disease', (235, 246))	('mtDNA', 'Gene', (0, 5))	('mitochondrial dysfunction', 'Disease', (57, 82))	('neurodegenerative diseases', 'Disease', (251, 277))
280405	31803756	Studies found increased tricarboxylic acid (TCA) cycle metabolism in AD patients due to an increased levels of ROS from deficiencies in OXPHOS (Bubber et al.,; Carvalho et al.,).	('increased', 'PosReg', (14, 23))	('AD', 'Disease', (69, 71))	('deficiencies', 'Var', (120, 132))	('ROS', 'MPA', (111, 114))	('increased levels of ROS', 'Phenotype', 'HP:0025464', (91, 114))	('levels', 'MPA', (101, 107))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (24, 42))	('increased', 'PosReg', (91, 100))	('OXPHOS', 'MPA', (136, 142))	('TCA', 'Chemical', 'MESH:C000589078', (44, 47))	('AD', 'Disease', 'MESH:D000544', (69, 71))	('AD', 'Phenotype', 'HP:0002511', (69, 71))	('patients', 'Species', '9606', (72, 80))
280410	31803756	Comprehensive epidemiological analyses of mtDNA variations in Japanese patients with AD (n = 96) or PD (n = 96) showed that AD is uniquely associated with haplogroups G2a, B4c1, and N9b1, and PD with haplogroups M7a, M7b2, B4e, and B5b (Takasaki,).	('AD', 'Disease', (124, 126))	('B4c1', 'Var', (172, 176))	('N9b1', 'Var', (182, 186))	('haplogroups', 'Var', (155, 166))	('B4e', 'Var', (223, 226))	('M7b2', 'Var', (217, 221))	('patients', 'Species', '9606', (71, 79))	('AD', 'Disease', 'MESH:D000544', (85, 87))	('AD', 'Disease', (85, 87))	('PD', 'Disease', 'MESH:D010300', (192, 194))	('AD', 'Phenotype', 'HP:0002511', (85, 87))	('PD', 'Disease', 'MESH:D010300', (100, 102))	('associated', 'Reg', (139, 149))	('AD', 'Phenotype', 'HP:0002511', (124, 126))	('G2a', 'Var', (167, 170))	('AD', 'Disease', 'MESH:D000544', (124, 126))
280411	31803756	In Han Chinese populations, haplogroup B5 is significantly associated with AD (n = 341) in patients from Southwest China (Bi et al.,).	('patients', 'Species', '9606', (91, 99))	('AD', 'Disease', 'MESH:D000544', (75, 77))	('AD', 'Disease', (75, 77))	('haplogroup B5', 'Var', (28, 41))	('Bi', 'Chemical', 'MESH:D001729', (122, 124))	('AD', 'Phenotype', 'HP:0002511', (75, 77))	('associated', 'Reg', (59, 69))
280413	31803756	A study of the distribution of mtDNA haplogroups of the Han population with sporadic PD (n = 279) indicated that haplogroup B may confer a lower risk for PD, while haplogroup D may lead to a higher risk of PD in people younger than 50 years of age (Chen et al.,).	('people', 'Species', '9606', (212, 218))	('PD', 'Disease', 'MESH:D010300', (85, 87))	('PD', 'Disease', 'MESH:D010300', (154, 156))	('PD', 'Disease', 'MESH:D010300', (206, 208))	('lower', 'NegReg', (139, 144))	('haplogroup B', 'Var', (113, 125))
280418	31803756	A recent study of 11 families with schizophrenia demonstrated that mtDNA A15395G and A8536G were deleterious (Bi et al.,).	('schizophrenia', 'Disease', 'MESH:D012559', (35, 48))	('schizophrenia', 'Disease', (35, 48))	('A8536G', 'Mutation', 'rs1026645721', (85, 91))	('schizophrenia', 'Phenotype', 'HP:0100753', (35, 48))	('A15395G', 'Mutation', 'g.15395A>G', (73, 80))	('A15395G', 'Var', (73, 80))	('mtDNA', 'Gene', (67, 72))	('Bi', 'Chemical', 'MESH:D001729', (110, 112))	('A8536G', 'Var', (85, 91))
280420	31803756	The T3644C mutation was found in Japanese patients with bipolar disorder (n = 199) but not in healthy controls.	('bipolar disorder', 'Phenotype', 'HP:0007302', (56, 72))	('bipolar disorder', 'Disease', (56, 72))	('T3644C', 'Mutation', 'rs770510347', (4, 10))	('patients', 'Species', '9606', (42, 50))	('T3644C', 'Var', (4, 10))	('bipolar disorder', 'Disease', 'MESH:D001714', (56, 72))
280421	31803756	This mutation converts a well-conserved valine, to alanine in the complex I ND1 subunit, and may impair assembly of complex I.	('converts', 'Reg', (14, 22))	('ND1', 'Gene', '4535', (76, 79))	('alanine', 'Chemical', 'MESH:D000409', (51, 58))	('ND1', 'Gene', (76, 79))	('valine', 'Chemical', 'MESH:C521924', (40, 46))	('assembly', 'MPA', (104, 112))	('impair', 'NegReg', (97, 103))	('alanine', 'MPA', (51, 58))	('mutation', 'Var', (5, 13))
280422	31803756	The m.3644T>C (MT-ND1) variant alters mitochondrial function by decreasing mitochondrial membrane potential (MMP) and complex I activity in 3644C cybrids compared with 3644T cybrids (Munakata et al.,).	('activity', 'MPA', (128, 136))	('decreasing mitochondrial membrane', 'Phenotype', 'HP:0040013', (64, 97))	('complex I', 'Enzyme', (118, 127))	('m.3644T>C', 'Var', (4, 13))	('decreasing', 'NegReg', (64, 74))	('m.3644T>C', 'Mutation', 'rs878991470', (4, 13))	('mitochondrial function', 'MPA', (38, 60))	('3644C', 'Var', (140, 145))	('MT-ND1', 'Gene', '4535', (15, 21))	('alters', 'Reg', (31, 37))	('MT-ND1', 'Gene', (15, 21))
280423	31803756	An epidemiologic study of Korean ADHD children (n = 150) revealed that haplogroup B4 increases the occurrence of ADHD, and haplogroup B5 and D4b are significantly associated with ADHD boys and girls, respectively.	('haplogroup B5', 'Var', (123, 136))	('ADHD', 'Disease', 'MESH:D001289', (33, 37))	('AD', 'Phenotype', 'HP:0002511', (33, 35))	('ADHD', 'Disease', (113, 117))	('ADHD', 'Disease', 'MESH:D001289', (113, 117))	('ADHD boys', 'Disease', (179, 188))	('ADHD', 'Disease', (33, 37))	('ADHD boys', 'Disease', 'MESH:D001289', (179, 188))	('associated', 'Reg', (163, 173))	('D4b', 'Var', (141, 144))	('ADHD', 'Disease', (179, 183))	('ADHD', 'Disease', 'MESH:D001289', (179, 183))	('AD', 'Phenotype', 'HP:0002511', (113, 115))	('haplogroup B4', 'Var', (71, 84))	('AD', 'Phenotype', 'HP:0002511', (179, 181))	('increases', 'PosReg', (85, 94))	('girls', 'Species', '9606', (193, 198))	('children', 'Species', '9606', (38, 46))
280427	31803756	The relationship between several mtDNA variants (G11778A, G3460A, T14484C, G11696A, G13708A, G10680A, and T12338C) and Leber's hereditary optic neuropathy (LHON) have been reported (Yoneda et al.,; Hotta et al.,; Brown et al.,; Ji et al.,).	('G3460A', 'Mutation', 'rs914060942', (58, 64))	('neuropathy', 'Phenotype', 'HP:0009830', (144, 154))	('optic neuropathy', 'Phenotype', 'HP:0001138', (138, 154))	('G10680A', 'Mutation', 'g.10680G>A', (93, 100))	('T12338C', 'Var', (106, 113))	('T14484C', 'Var', (66, 73))	('G10680A', 'Var', (93, 100))	('G11778A', 'SUBSTITUTION', 'None', (49, 56))	('T14484C', 'SUBSTITUTION', 'None', (66, 73))	("Leber's hereditary optic neuropathy", 'Disease', 'MESH:D029242', (119, 154))	('G11778A', 'Var', (49, 56))	('mtDNA', 'Gene', (33, 38))	("Leber's hereditary optic neuropathy", 'Disease', (119, 154))	('G11696A', 'Var', (75, 82))	('G13708A', 'Mutation', 'rs28359178', (84, 91))	('G11696A', 'Mutation', 'g.11696G>A', (75, 82))	('G13708A', 'Var', (84, 91))	('G3460A', 'Var', (58, 64))	('T12338C', 'SUBSTITUTION', 'None', (106, 113))
280428	31803756	The typical LHON-related G11778A mutation in different families belongs to the Chinese haplogroups B5b, G2a, C4a1, M7b102, and M8a; the Thai urban population haplogroups M and B; and European haplogroups J, K, and H, respectively.	('LHON-related', 'Disease', (12, 24))	('G11778A', 'SUBSTITUTION', 'None', (25, 32))	('G11778A', 'Var', (25, 32))
280429	31803756	Several groups constructed cybrids of LHON probands carrying the G3460A, G11778A, and T14484C LHON primary mutations to confirm that mitochondrial dysfunction is caused by these mtDNA variants.	('G11778A', 'Var', (73, 80))	('G3460A', 'Mutation', 'rs914060942', (65, 71))	('T14484C', 'SUBSTITUTION', 'None', (86, 93))	('G11778A', 'SUBSTITUTION', 'None', (73, 80))	('T14484C', 'Var', (86, 93))	('caused', 'Reg', (162, 168))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (133, 158))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (133, 158))	('G3460A', 'Var', (65, 71))	('mitochondrial dysfunction', 'Disease', (133, 158))
280431	31803756	The mtDNA G13051A leaded to variable neurology and activated mitophagy in LHON patients (Dombi et al.,).	('mitophagy', 'CPA', (61, 70))	('neurology', 'MPA', (37, 46))	('patients', 'Species', '9606', (79, 87))	('G13051A', 'Mutation', 'g.13051G>A', (10, 17))	('activated', 'PosReg', (51, 60))	('mtDNA G13051A', 'Var', (4, 17))
280439	31803756	Mitochondria are essential for providing energy to maintain insulin metabolism; mtDNA mutations of OXPHOS complexes can lead to pancreatic islet dysfunction.	('mutations', 'Var', (86, 95))	('insulin', 'Gene', (60, 67))	('pancreatic islet dysfunction', 'Disease', 'MESH:C535838', (128, 156))	('insulin', 'Gene', '3630', (60, 67))	('lead to', 'Reg', (120, 127))	('pancreatic islet dysfunction', 'Disease', (128, 156))
280442	31803756	Some studies found diabetes susceptibility genes located in mitochondria-encoded genomes, such as G3316A and C3310T in a Japanese family (Nakano et al.,; Hattori et al.,), and G3316A, C3310T, A3243G T3394C, G4491A, T16189C, and T16519C in a Chinese population (n = 826) (Liao et al.,; Li M. Z. et al.,; Wang et al.,; Zhong et al.,).	('T16519C', 'SUBSTITUTION', 'None', (228, 235))	('C3310T', 'Mutation', 'rs1045249024', (184, 190))	('T16189C', 'Var', (215, 222))	('G4491A', 'Var', (207, 213))	('C3310T', 'Var', (109, 115))	('A3243G', 'SUBSTITUTION', 'None', (192, 198))	('diabetes', 'Disease', 'MESH:D003920', (19, 27))	('G3316A', 'Var', (176, 182))	('T16189C', 'SUBSTITUTION', 'None', (215, 222))	('A3243G', 'Var', (192, 198))	('G3316A', 'Var', (98, 104))	('C3310T', 'Var', (184, 190))	('C3310T', 'Mutation', 'rs1045249024', (109, 115))	('T3394C', 'Var', (199, 205))	('T16519C', 'Var', (228, 235))	('G3316A', 'Mutation', 'g.3316G>A', (176, 182))	('T3394C', 'SUBSTITUTION', 'None', (199, 205))	('diabetes', 'Disease', (19, 27))	('G3316A', 'Mutation', 'g.3316G>A', (98, 104))	('G4491A', 'Mutation', 'rs1017192374', (207, 213))
280443	31803756	A cybrid with a C3310T mutation showed that mitochondrial complex I activity, ATP generation, oxygen consumption were significantly decreased (Chen et al.,).	('oxygen consumption', 'MPA', (94, 112))	('C3310T', 'Var', (16, 22))	('mitochondrial complex I', 'Enzyme', (44, 67))	('ATP', 'Chemical', 'MESH:D000255', (78, 81))	('oxygen', 'Chemical', 'MESH:D010100', (94, 100))	('decreased', 'NegReg', (132, 141))	('activity', 'MPA', (68, 76))	('C3310T', 'Mutation', 'rs1045249024', (16, 22))	('ATP generation', 'MPA', (78, 92))
280444	31803756	found that N9a was a risk factor for diabetic nephropathy (n = 235) (Niu et al.,).	('N9a', 'Var', (11, 14))	('nephropathy', 'Phenotype', 'HP:0000112', (46, 57))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (37, 57))	('diabetic nephropathy', 'Disease', (37, 57))
280445	31803756	The N9a haplogroup cybrids exhibited lower respiratory chain complex activity, ATP, MMP and oxygen consumption; however, they contained more ROS and fragmented mitochondria than non-N9a haplogroup cybrids.	('respiratory chain complex activity', 'MPA', (43, 77))	('MMP and', 'MPA', (84, 91))	('oxygen', 'CPA', (92, 98))	('more', 'PosReg', (136, 140))	('contained', 'Reg', (126, 135))	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('men', 'Species', '9606', (153, 156))	('ATP', 'MPA', (79, 82))	('lower', 'NegReg', (37, 42))	('N9a', 'Var', (4, 7))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('ROS', 'MPA', (141, 144))
280452	31803756	The accumulation of damaged mtDNA, fragmented mitochondria, activated apoptosis, loss of MMP, and perturbations in glycolysis and TCA cycle were detected in tubules and PBMCs from the patients.	('TCA cycle', 'Enzyme', (130, 139))	('fragmented', 'Var', (35, 45))	('TCA', 'Chemical', 'MESH:C000589078', (130, 133))	('accumulation', 'PosReg', (4, 16))	('MMP', 'MPA', (89, 92))	('patients', 'Species', '9606', (184, 192))	('activated', 'PosReg', (60, 69))	('men', 'Species', '9606', (39, 42))	('apoptosis', 'CPA', (70, 79))	('loss', 'NegReg', (81, 85))	('glycolysis', 'MPA', (115, 125))
280460	31803756	found that the C8684T transition of haplogroup M8a, and the C3497T and T1119C transitions of haplogroup B4c caused increased susceptibility to DM.	('C3497T', 'Var', (60, 66))	('DM', 'Phenotype', 'HP:0000819', (143, 145))	('susceptibility', 'MPA', (125, 139))	('C8684T', 'Mutation', 'rs769651042', (15, 21))	('C3497T', 'Mutation', 'rs1220484240', (60, 66))	('C8684T', 'Var', (15, 21))	('T1119C', 'Var', (71, 77))	('T1119C', 'Mutation', 'rs201394320', (71, 77))
280464	31803756	In the Han population, men with haplogroup R exhibited decreased frequency of asthenozoospermia (n = 312) (Feng et al.,).	('haplogroup R', 'Var', (32, 44))	('decreased', 'NegReg', (55, 64))	('men', 'Species', '9606', (23, 26))	('asthenozoospermia', 'Disease', 'MESH:D053627', (78, 95))	('asthenozoospermia', 'Disease', (78, 95))
280465	31803756	Recently, Wang's group reported that haplogroup M8a played a critical role in the penetrance of variant C8684T in the pathogenesis of non-obstructive azoospermia due to increased mtDNA damage and impaired normal spermatogenesis (Ji et al.,).	('C8684T', 'Var', (104, 110))	('non-obstructive azoospermia', 'Disease', (134, 161))	('azoospermia', 'Phenotype', 'HP:0000027', (150, 161))	('increased', 'PosReg', (169, 178))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (134, 161))	('impaired normal spermatogenesis', 'Phenotype', 'HP:0008669', (196, 227))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (138, 161))	('variant C8684T', 'Var', (96, 110))	('impaired', 'NegReg', (196, 204))	('mtDNA damage', 'CPA', (179, 191))	('C8684T', 'Mutation', 'rs769651042', (104, 110))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (134, 161))
280472	31803756	Therefore, mtDNA mutations profoundly affect the human immune system.	('human', 'Species', '9606', (49, 54))	('mutations', 'Var', (17, 26))	('affect', 'Reg', (38, 44))	('human immune system', 'CPA', (49, 68))	('mtDNA', 'Gene', (11, 16))
280475	31803756	The balance of mitochondrial metabolism plays a crucial role in the pathogenesis and progression of human malignancies, and mtDNA mutations play bidirectional roles in tumorigenesis; some are protective factors, while others are risk factors (Xu et al.,; Li et al.,; Ma L. et al.,).	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('Ma L', 'Gene', (267, 271))	('mtDNA', 'Gene', (124, 129))	('Ma L', 'Gene', '4118', (267, 271))	('malignancies', 'Disease', (106, 118))	('human', 'Species', '9606', (100, 105))	('mutations', 'Var', (130, 139))	('tumorigenesis', 'CPA', (168, 181))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
280479	31803756	Haplogroup M may be a risk factor for breast cancer.	('Haplogroup M', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('risk factor', 'Reg', (22, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))
280480	31803756	Mutations in the D-loop region are more likely to be detected in benign breast tumors (n = 104) (Fang et al.,).	('breast tumors', 'Disease', 'MESH:D061325', (72, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Mutations', 'Var', (0, 9))	('breast tumors', 'Phenotype', 'HP:0100013', (72, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('breast tumors', 'Disease', (72, 85))
280481	31803756	The frequency of haplogroup D5 is significantly increased in patients with breast cancer.	('increased', 'PosReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('patients', 'Species', '9606', (61, 69))	('haplogroup D5', 'Var', (17, 30))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
280482	31803756	It was found that mitochondrial respiration, ATP content, and MMP levels were decreased in D5 haplogroup cybrids compared to those with non-D5 haplogroups.	('MMP levels', 'MPA', (62, 72))	('ATP content', 'MPA', (45, 56))	('mitochondrial respiration', 'MPA', (18, 43))	('ATP', 'Chemical', 'MESH:D000255', (45, 48))	('decreased', 'NegReg', (78, 87))	('D5 haplogroup cybrids', 'Var', (91, 112))
280485	31803756	mtDNA variations located in the D-loop, coding region, and tRNA and rRNA genes are potential biomarkers in cervical carcinogenesis (Kabekkodu et al.,).	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('rRNA genes', 'Gene', (68, 78))	('variations', 'Var', (6, 16))	('carcinogenesis', 'Disease', (116, 130))	('tRNA', 'Gene', (59, 63))	('mtDNA', 'Gene', (0, 5))
280486	31803756	Two groups investigated mtDNA mutations in cervical cancers of Chinese women.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('women', 'Species', '9606', (71, 76))	('mutations', 'Var', (30, 39))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('mtDNA', 'Gene', (24, 29))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
280488	31803756	Li's group found that mitochondrial haplogroup D4b1 enhanced the risk of cervical cancer initiation in Chinese women (n = 150) (Li et al.,).	('women', 'Species', '9606', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cervical cancer initiation', 'Disease', (73, 99))	('enhanced', 'PosReg', (52, 60))	('cervical cancer initiation', 'Disease', 'MESH:D002583', (73, 99))	('mitochondrial haplogroup D4b1', 'Var', (22, 51))
280492	31803756	This study revealed that haplogroup N contributed to overall prostate cancer, however, the mtDNA-encoded OXPHOS genes were not associated with prostate cancer risk in this cohort (Giorgi et al.,).	('prostate cancer', 'Disease', 'MESH:D011471', (143, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (143, 158))	('associated', 'Reg', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('prostate cancer', 'Disease', (61, 76))	('haplogroup', 'Var', (25, 35))	('prostate cancer', 'Disease', (143, 158))	('contributed', 'Reg', (38, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))
280497	31803756	Two case-control cohort studies found an association between mtDNA variation and lung cancer risk in a Han Chinese population from southwestern China (n = 422).	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mtDNA', 'Gene', (61, 66))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('variation', 'Var', (67, 76))
280498	31803756	revealed that haplogroups D and F were protective factors for lung cancer, while haplogroups G and M7 increased susceptibility (Zheng et al.,).	('haplogroups', 'Var', (14, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('haplogroups', 'Var', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('increased', 'PosReg', (102, 111))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))
280499	31803756	However, Fang's group demonstrated that haplogroups F and G predisposed people to lung cancer (n = 237).	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('people', 'Species', '9606', (72, 78))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('predisposed', 'Reg', (60, 71))	('haplogroups F', 'Var', (40, 53))
280500	31803756	Although the results varied, both studies suggest that haplogroup G is a risk factor for lung cancer due to excess ROS generated by the impaired mitochondrial respiration chain (Fang Y. et al.,).	('haplogroup G', 'Var', (55, 67))	('ROS generated', 'MPA', (115, 128))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('impaired', 'NegReg', (136, 144))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('impaired mitochondrial respiration chain', 'Phenotype', 'HP:0200125', (136, 176))	('excess', 'PosReg', (108, 114))	('mitochondrial respiration chain', 'Enzyme', (145, 176))
280502	31803756	Therefore, altering mitochondrial dynamics may be a therapeutic strategy, for example, inhibiting mitochondrial fission can prevent cell cycle progression in lung cancer (Rehman et al.,; Lennon and Salgia,).	('mitochondrial fission', 'MPA', (98, 119))	('lung cancer', 'Disease', (158, 169))	('Lennon and Salgia', 'Disease', 'None', (187, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('inhibiting', 'Var', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('prevent', 'NegReg', (124, 131))	('cell cycle progression', 'CPA', (132, 154))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('mitochondrial', 'MPA', (20, 33))
280503	31803756	Mutations in the mitochondrial D-loop region have been reported in hepatocellular carcinoma (HCC), which may partly contribute to cancer development (Zhang et al.,).	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('men', 'Species', '9606', (144, 147))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('reported', 'Reg', (55, 63))	('contribute', 'Reg', (116, 126))	('cancer', 'Disease', (130, 136))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('hepatocellular carcinoma', 'Disease', (67, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mitochondrial', 'Gene', (17, 30))
280505	31803756	Mitochondrial fission significantly promoted the reprogramming of focal-adhesion dynamics and lamellipodia formation in HCC cells, mainly by activating Ca2+/CaMKII/ERK/FAK pathway (Sun et al.,).	('HCC', 'Phenotype', 'HP:0001402', (120, 123))	('FAK', 'Gene', (168, 171))	('lamellipodia formation', 'CPA', (94, 116))	('activating', 'PosReg', (141, 151))	('ERK', 'Gene', '5594', (164, 167))	('FAK', 'Gene', '5747', (168, 171))	('CaMKII', 'Gene', (157, 163))	('Ca2+', 'Chemical', 'MESH:D002118', (152, 156))	('ERK', 'Gene', (164, 167))	('reprogramming of focal-adhesion dynamics', 'CPA', (49, 89))	('CaMKII', 'Gene', '818', (157, 163))	('promoted', 'PosReg', (36, 44))	('Mitochondrial', 'Var', (0, 13))
280510	31803756	A study of mitochondrial haplogroups and esophageal cancer (n = 30) in the Taihang Mountain and Chaoshan areas of China has shown that haplogroups D4a and D5 in Taihang Mountain, and haplogroups D and D5 in Chaoshan areas, were related to higher susceptibility to esophageal cancer (Li et al.,).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', (264, 281))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('haplogroups', 'Var', (135, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (264, 281))	('D4a', 'Var', (147, 150))	('esophageal cancer', 'Disease', (41, 58))
280511	31803756	Overall, haplogroup D, specifically sub-haplogroups D4a and D5a, can serve as potential biomarkers for esophageal cancer, at least in these two areas.	('D4a', 'Var', (52, 55))	('esophageal cancer', 'Disease', (103, 120))	('D5a', 'Var', (60, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))
280512	31803756	Other papers showed that haplogroup D4a was associated with an increased risk of thyroid cancer (n = 100) in China (Fang et al.,).	('thyroid cancer', 'Disease', (81, 95))	('thyroid cancer', 'Phenotype', 'HP:0002890', (81, 95))	('haplogroup D4a', 'Var', (25, 39))	('thyroid cancer', 'Disease', 'MESH:D013964', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
280513	31803756	As previously mentioned, haplogroup D5 was also a risk factor of breast cancer.	('men', 'Species', '9606', (14, 17))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('risk factor', 'Reg', (50, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('haplogroup D5', 'Var', (25, 38))
280518	31803756	Mutations in the mitochondrial genome are associated with essential hypertension; several mtDNA mutations associated with hypertension are found in haplogroup D4j (A4295G) (Li Z. et al.,), haplogroup G2a1 (A4435G) (Lu et al.,), and haplogroup B5b1 (T16189C) (Zhu et al.,).	('hypertension', 'Disease', 'MESH:D006973', (68, 80))	('hypertension', 'Disease', 'MESH:D006973', (122, 134))	('T16189C', 'Var', (249, 256))	('associated', 'Reg', (106, 116))	('mtDNA', 'Gene', (90, 95))	('hypertension', 'Disease', (68, 80))	('hypertension', 'Disease', (122, 134))	('A4295G', 'Mutation', 'rs1022870249', (164, 170))	('hypertension', 'Phenotype', 'HP:0000822', (68, 80))	('hypertension', 'Phenotype', 'HP:0000822', (122, 134))	('A4435G', 'Mutation', 'g.4435A>G', (206, 212))	('T16189C', 'SUBSTITUTION', 'None', (249, 256))	('B5b1', 'Species', '472953', (243, 247))	('A4295G', 'Var', (164, 170))	('A4435G', 'Var', (206, 212))	('mutations', 'Var', (96, 105))
280523	31803756	Therefore, it is important to determine the variants of mtDNA associated with myocardial and cerebral infarction.	('mtDNA', 'Gene', (56, 61))	('myocardial', 'Disease', (78, 88))	('associated', 'Reg', (62, 72))	('cerebral infarction', 'Disease', (93, 112))	('cerebral infarction', 'Disease', 'MESH:D002544', (93, 112))	('variants', 'Var', (44, 52))
280524	31803756	In the Japanese population, mtDNA C5178A transversion causes leucine to methionine substitution in ND2, resulting in anti-atherosclerotic effects in diabetic subjects and a lower prevalence of myocardial infarction (Takagi et al.,).	('atherosclerotic', 'Disease', (122, 137))	('mtDNA', 'Var', (28, 33))	('C5178A', 'SUBSTITUTION', 'None', (34, 40))	('ND2', 'Gene', (99, 102))	('diabetic', 'Disease', (149, 157))	('ND2', 'Gene', '4536', (99, 102))	('atherosclerotic', 'Disease', 'MESH:D050197', (122, 137))	('myocardial infarction', 'Phenotype', 'HP:0001658', (193, 214))	('myocardial infarction', 'Disease', 'MESH:D009203', (193, 214))	('leucine to', 'Var', (61, 71))	('diabetic', 'Disease', 'MESH:D003920', (149, 157))	('methionine', 'Chemical', 'MESH:D008715', (72, 82))	('myocardial infarction', 'Disease', (193, 214))	('C5178A', 'Var', (34, 40))	('leucine', 'Chemical', 'MESH:C038361', (61, 68))
280526	31803756	Haplogroup N9b protects against myocardial infarction; however, haplogroup G1 is a risk factor for this disease in Japanese males (Nishigaki et al.,).	('myocardial infarction', 'Phenotype', 'HP:0001658', (32, 53))	('risk factor', 'Reg', (83, 94))	('haplogroup G1', 'Var', (64, 77))	('myocardial infarction', 'Disease', (32, 53))	('myocardial infarction', 'Disease', 'MESH:D009203', (32, 53))
280527	31803756	Mitochondrial haplogroups A and M7a increase the risk for coronary atherosclerosis in a Japanese population (n = 1,536).	('coronary atherosclerosis', 'Phenotype', 'HP:0001677', (58, 82))	('coronary atherosclerosis', 'Disease', (58, 82))	('coronary atherosclerosis', 'Disease', 'MESH:D003324', (58, 82))	('atherosclerosis', 'Phenotype', 'HP:0002621', (67, 82))	('M7a', 'Var', (32, 35))
280528	31803756	Surprisingly, a haplogroup associated with extreme longevity, D4a, conferred a risk of myocardial infarction (Alexe et al.,; Cai et al.,; Sawabe et al.,).	('myocardial infarction', 'Phenotype', 'HP:0001658', (87, 108))	('D4a', 'Var', (62, 65))	('myocardial infarction', 'Disease', (87, 108))	('myocardial infarction', 'Disease', 'MESH:D009203', (87, 108))
280529	31803756	Inhibition of mitochondrial permeability transition improved functional recovery and reduced mortality following acute myocardial infarction in mice (Gomez et al.,).	('mitochondrial permeability transition', 'Pathway', (14, 51))	('mortality', 'CPA', (93, 102))	('mice', 'Species', '10090', (144, 148))	('myocardial infarction', 'Phenotype', 'HP:0001658', (119, 140))	('improved', 'PosReg', (52, 60))	('Inhibition', 'Var', (0, 10))	('myocardial infarction', 'Disease', (119, 140))	('myocardial infarction', 'Disease', 'MESH:D009203', (119, 140))	('reduced', 'NegReg', (85, 92))	('functional', 'MPA', (61, 71))
280532	31803756	Mitochondrial haplogroup M10 may be a risk factor for HCM, specifically, three mutations - G7967A in the COX II of complex IV, and T12477C and G13135A in the ND5 of complex I. Mitochondrial complex I activity was markedly decreased in the HCM individuals, resulting in disrupted mitochondrial respiratory function (Wei et al.,).	('G7967A', 'Mutation', 'g.7967G>A', (91, 97))	('ND5', 'Gene', (158, 161))	('ND5', 'Gene', '4540', (158, 161))	('T12477C', 'SUBSTITUTION', 'None', (131, 138))	('activity', 'MPA', (200, 208))	('G13135A', 'Var', (143, 150))	('G13135A', 'Mutation', 'g.13135G>A', (143, 150))	('mitochondrial respiratory function', 'MPA', (279, 313))	('Mitochondrial complex I', 'Enzyme', (176, 199))	('HCM', 'Phenotype', 'HP:0001639', (54, 57))	('disrupted', 'NegReg', (269, 278))	('HCM', 'Phenotype', 'HP:0001639', (239, 242))	('decreased', 'NegReg', (222, 231))	('T12477C', 'Var', (131, 138))
280533	31803756	The mitochondrial ND5 T12338C variant which belongs to haplogroup F2a was associated with hypertrophic cardiomyopathy in a Chinese pedigree (Liu et al.,).	('hypertrophic cardiomyopathy', 'Phenotype', 'HP:0001639', (90, 117))	('ND5', 'Gene', '4540', (18, 21))	('hypertrophic cardiomyopathy', 'Disease', (90, 117))	('ND5', 'Gene', (18, 21))	('T12338C', 'Var', (22, 29))	('T12338C', 'SUBSTITUTION', 'None', (22, 29))	('hypertrophic cardiomyopathy', 'Disease', 'MESH:D002312', (90, 117))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (103, 117))	('associated with', 'Reg', (74, 89))
280534	31803756	A characteristic T2336C homoplasmic mutation in the mitochondrial 16S rRNA gene of HCM has also been found in a Chinese family.	('HCM', 'Gene', (83, 86))	('T2336C', 'Mutation', 'rs369716580', (17, 23))	('HCM', 'Phenotype', 'HP:0001639', (83, 86))	('T2336C', 'Var', (17, 23))
280535	31803756	Reduced ATP and MMP levels, and increased ROS generation in the mutant 2336C cybrids may lead to deterioration of mitochondrial function (Li et al.,).	('mutant 2336C', 'Var', (64, 76))	('Reduced', 'NegReg', (0, 7))	('increased ROS generation', 'Phenotype', 'HP:0025464', (32, 56))	('ROS generation', 'MPA', (42, 56))	('deterioration', 'NegReg', (97, 110))	('increased', 'PosReg', (32, 41))	('ATP', 'Chemical', 'MESH:D000255', (8, 11))	('mitochondrial function', 'MPA', (114, 136))
280537	31803756	found that mtDNA A3397G and T3398C of the complex I ND1 subunit may disrupt mitochondrial function to initiate LVNC (Tang et al.,).	('ND1', 'Gene', '4535', (52, 55))	('T3398C', 'Var', (28, 34))	('A3397G', 'Mutation', 'g.3397A>G', (17, 23))	('mtDNA A3397G', 'Var', (11, 23))	('LVNC', 'MPA', (111, 115))	('ND1', 'Gene', (52, 55))	('T3398C', 'Mutation', 'g.3398T>C', (28, 34))	('mitochondrial function', 'MPA', (76, 98))	('disrupt', 'NegReg', (68, 75))
280540	31803756	Other studies reported that m.5178C, but not m.5178A, is a risk factor for several diseases including myocardial infarction (n = 517), cerebrovascular diseases (n = 127), and diabetes (n = 270) (Wang et al.,; Ohkubo et al.,; Takagi et al.,).	('cerebrovascular diseases', 'Disease', (135, 159))	('diabetes', 'Disease', 'MESH:D003920', (175, 183))	('cerebrovascular diseases', 'Disease', 'MESH:D002561', (135, 159))	('m.5178C', 'Var', (28, 35))	('risk', 'Reg', (59, 63))	('myocardial infarction', 'Phenotype', 'HP:0001658', (102, 123))	('myocardial infarction', 'Disease', (102, 123))	('myocardial infarction', 'Disease', 'MESH:D009203', (102, 123))	('diabetes', 'Disease', (175, 183))
280560	29995799	Several studies have shown MIE has an advantage in perioperative complications and quality of life, with seemingly comparable oncologic outcomes.	('perioperative complications', 'CPA', (51, 78))	('advantage', 'PosReg', (38, 47))	('MIE', 'Var', (27, 30))	('quality of life', 'CPA', (83, 98))	('MIE', 'Chemical', '-', (27, 30))
280574	29995799	There is growing evidence in literature that MIE may decrease morbidity.	('decrease', 'NegReg', (53, 61))	('MIE', 'Chemical', '-', (45, 48))	('morbidity', 'MPA', (62, 71))	('MIE', 'Var', (45, 48))
280659	29637920	The changes of intra-esophageal pressure and long-term food stasis may lead to chronic inflammation of the esophageal mucosa, which explained patients graded d having significantly longer disease duration than the former three grades in the EMIA classification.	('lead to', 'Reg', (71, 78))	('inflammation of the esophageal mucosa', 'Disease', 'MESH:D007249', (87, 124))	('inflammation of the esophageal mucosa', 'Disease', (87, 124))	('inflammation of the esophageal mucosa', 'Phenotype', 'HP:0100633', (87, 124))	('intra-esophageal', 'Disease', (15, 31))	('intra-esophageal', 'Disease', 'MESH:D004941', (15, 31))	('changes', 'Var', (4, 11))	('patients', 'Species', '9606', (142, 150))
280682	27286451	Low DNA copy number entropy was associated with improved survival in the CS group (p=0.011) but not in the S group (p=0.396).	('Low DNA copy number entropy', 'Var', (0, 27))	('CS', 'Chemical', 'MESH:D002586', (73, 75))	('S', 'Chemical', 'MESH:D013455', (107, 108))	('improved', 'PosReg', (48, 56))	('S', 'Chemical', 'MESH:D013455', (74, 75))	('survival', 'CPA', (57, 65))
280709	27286451	Low DNA copy number entropy was significantly associated with longer cancer specific survival in the whole patient group (HR: 1.382, 95%CI: 1.014-1.884, p=0.041).	('Low DNA copy number entropy', 'Var', (0, 27))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('longer', 'PosReg', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('patient', 'Species', '9606', (107, 114))	('cancer', 'Disease', (69, 75))
280713	27286451	with DNA copy number aberrations at similar genomic locations, survived significantly longer than patients with high DNA copy number entropy, e.g.	('longer', 'PosReg', (86, 92))	('survived', 'CPA', (63, 71))	('copy number aberrations', 'Var', (9, 32))	('patients', 'Species', '9606', (98, 106))
280715	27286451	Cox regression analysis using continuous DNA copy number entropy values showed that DNA copy number entropy was significantly associated with cancer specific survival in the CS group (HR: 1.775, 95% CI: 1.047-3.009, p=0.033) but not in the S group (HR: 1.144, 95%CI: 0.699-1.871, p=0.593).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('S', 'Chemical', 'MESH:D013455', (240, 241))	('associated with', 'Reg', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('CS', 'Chemical', 'MESH:D002586', (174, 176))	('S', 'Chemical', 'MESH:D013455', (175, 176))	('DNA copy number entropy', 'Var', (84, 107))	('cancer', 'Disease', (142, 148))
280717	27286451	CS group patients with low DNA copy number entropy had a significantly better survival (median (range) survival time: 6.9 years (0 to 15.6 years)) compared to CS group patients with high DNA copy number entropy (0.9 years (0.7 to 0.97 years), p=0.011, Figure 5B).	('patients', 'Species', '9606', (9, 17))	('CS', 'Chemical', 'MESH:D002586', (159, 161))	('low DNA copy number entropy', 'Var', (23, 50))	('survival', 'MPA', (78, 86))	('patients', 'Species', '9606', (168, 176))	('CS', 'Chemical', 'MESH:D002586', (0, 2))	('better', 'PosReg', (71, 77))
280729	27286451	Importantly, there was also no statistically significant association between DNA copy number entropy and Mandard tumor regression grade of the primary tumor (only investigated in the CS group) or percentage of tumor/area (investigated in both groups).	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (210, 215))	('Mandard tumor', 'Disease', 'MESH:D009369', (105, 118))	('DNA', 'Var', (77, 80))	('CS', 'Chemical', 'MESH:D002586', (183, 185))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('Mandard tumor', 'Disease', (105, 118))
280736	27286451	Low DNA copy number entropy was only related to better outcome in EAC patients who had received chemotherapy prior to surgery.	('Low DNA copy number entropy', 'Var', (0, 27))	('patients', 'Species', '9606', (70, 78))	('EAC', 'Disease', (66, 69))	('EAC', 'Phenotype', 'HP:0011459', (66, 69))
280835	26779631	In our study, 41 (8.8 %) patients were with thrombocytosis (PLT > 300 x 109 L-1) and 9 (1.9 %) patients were with abnormal high MPV (>13.0 fL), which had hardly statistically significance on overall survival.	('patients', 'Species', '9606', (95, 103))	('L-1', 'Gene', '23961', (76, 79))	('thrombocytosis', 'Phenotype', 'HP:0001894', (44, 58))	('thrombocytosis', 'Disease', 'MESH:D013922', (44, 58))	('PLT > 300 x', 'Var', (60, 71))	('L-1', 'Gene', (76, 79))	('patients', 'Species', '9606', (25, 33))	('thrombocytosis', 'Disease', (44, 58))
280909	21895028	While fluorescence intensity associated with 2-NBDG uptake is minimal in the sample diagnosed with IM/LGD with zero to mild levels inflammation (Figure 4A), the 2-NBDG uptake within the gland enhances the visibility of mucin within goblet cells, making them appear dark in contrast.	('inflammation', 'Disease', 'MESH:D007249', (131, 143))	('inflammation', 'Disease', (131, 143))	('visibility', 'MPA', (205, 215))	('enhances', 'PosReg', (192, 200))	('2-NBDG', 'Chemical', 'MESH:C098340', (161, 167))	('2-NBDG', 'Chemical', 'MESH:C098340', (45, 51))	('2-NBDG uptake', 'Var', (161, 174))
280911	21895028	The pattern of glandular uptake is similar to that of IM/LGD with mild inflammation; the image shows characteristic crypts with dark goblet cells associated with IM/LGD.	('inflammation', 'Disease', 'MESH:D007249', (71, 83))	('IM/LGD', 'Var', (162, 168))	('inflammation', 'Disease', (71, 83))
280914	21895028	Glandular uptake of 2-NBDG is significantly higher than is found with IM/LGD, resulting in increasingly bright glands.	('Glandular uptake', 'CPA', (0, 16))	('higher', 'PosReg', (44, 50))	('2-NBDG', 'Chemical', 'MESH:C098340', (20, 26))	('2-NBDG', 'Var', (20, 26))	('bright glands', 'MPA', (104, 117))
280929	21895028	Indeed, the ability to delineate glandular uptake of 2-NBDG from the surrounding lamina propria provides the critical advantage of differentiating neoplasia from inflammation, a significant confounder with other imaging technologies.	('inflammation', 'Disease', 'MESH:D007249', (162, 174))	('2-NBDG', 'Chemical', 'MESH:C098340', (53, 59))	('neoplasia', 'Phenotype', 'HP:0002664', (147, 156))	('inflammation', 'Disease', (162, 174))	('neoplasia', 'Disease', 'MESH:D009369', (147, 156))	('2-NBDG', 'Var', (53, 59))	('neoplasia', 'Disease', (147, 156))
280965	26221490	In the USA and other western countries, tobacco, too much drinking alcohol, diets poor in fresh fruits and vegetables, and low socioeconomic group have been associated with esophageal SCC.	('alcohol', 'Chemical', 'MESH:D000438', (67, 74))	('tobacco', 'Species', '4097', (40, 47))	('associated', 'Reg', (157, 167))	('esophageal SCC', 'Disease', (173, 187))	('esophageal SCC', 'Disease', 'MESH:D004941', (173, 187))	('too much', 'Var', (49, 57))
280984	26221490	The primers used in this study were general primers from MY09 and MY011 pairs (MY09: 5'-CGT CCM AAR GGA WAC TGA TC-3' and MY011: 5'-GCM CAG GGW CAT AAY AAT GG-3').	('AAT', 'Gene', '5265', (152, 155))	('TGA', 'Gene', '6899', (108, 111))	('AAT', 'Gene', (152, 155))	('MY011', 'Var', (122, 127))	('TGA', 'Gene', (108, 111))
280989	26221490	As seen in table 2, we detected HPVs-11 (in 4 cases), 33 (in one case), 56 (in 2 cases) and HPV-56 (in one case) of patient with inflammation.	('patient', 'Species', '9606', (116, 123))	('inflammation', 'Disease', 'MESH:D007249', (129, 141))	('inflammation', 'Disease', (129, 141))	('HPVs-11', 'Var', (32, 39))	('HPV', 'Species', '10566', (32, 35))	('HPV', 'Species', '10566', (92, 95))	('HPV-56', 'Var', (92, 98))
280991	26221490	The most prevalent genotype was HPV11 (17.2%; 5.29) of the HPV positive cases (36.25%; 29.80) and the second more prevalent genotype was HPV 56 with 6.9% (2.29).	('HPV', 'Species', '10566', (59, 62))	('prevalent', 'Reg', (9, 18))	('HPV', 'Gene', (59, 62))	('HPV11', 'Species', '10580', (32, 37))	('HPV', 'Species', '10566', (32, 35))	('HPV11', 'Var', (32, 37))	('HPV', 'Species', '10566', (137, 140))
281012	26221490	In our study, we did not find HPV 16 & 18 genotypes but Tornesello in Italian patients with esophagitis detected HPV-16, 19, 20 and 25.	('detected', 'Var', (104, 112))	('patients', 'Species', '9606', (78, 86))	('HPV 16', 'Species', '333760', (30, 36))	('HPV-16', 'Species', '333760', (113, 119))	('esophagitis', 'Phenotype', 'HP:0100633', (92, 103))	('esophagitis', 'Disease', (92, 103))	('esophagitis', 'Disease', 'MESH:D004941', (92, 103))
281029	25568334	Inactivation of GSK3beta and activation of NF-kappaB pathway via Axl represents an important mediator of tumorigenesis in esophageal squamous cell carcinoma Deregulation of Axl in esophageal squamous cell carcinoma (OSCC) with potential therapeutic implications is described for the first time.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (180, 214))	('esophageal squamous cell carcinoma', 'Disease', (122, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (191, 214))	('Axl', 'Gene', '558', (173, 176))	('GSK3beta', 'Gene', '2932', (16, 24))	('Axl', 'Gene', (173, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (122, 156))	('Inactivation', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('GSK3beta', 'Gene', (16, 24))	('esophageal squamous cell carcinoma', 'Disease', (180, 214))	('activation', 'PosReg', (29, 39))	('NF-kappaB', 'Gene', (43, 52))	('Axl', 'Gene', '558', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('NF-kappaB', 'Gene', '4790', (43, 52))	('Axl', 'Gene', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
281035	25568334	Blockage of Axl gene expression by small interfering RNA inhibits cell survival, proliferation, migration, and invasion in vitro and esophageal tumor growth in vivo.	('migration', 'CPA', (96, 105))	('esophageal tumor', 'Disease', 'MESH:D004938', (133, 149))	('esophageal tumor', 'Disease', (133, 149))	('cell survival', 'CPA', (66, 79))	('Axl gene', 'Gene', (12, 20))	('esophageal tumor', 'Phenotype', 'HP:0100751', (133, 149))	('small interfering', 'Var', (35, 52))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('invasion', 'CPA', (111, 119))	('inhibits', 'NegReg', (57, 65))	('Blockage', 'NegReg', (0, 8))
281049	25568334	Axl phosphorylation and consequent activation have been linked to signaling pathways such as the phosphatidylinositol 3-OH kinase (PI3K) pathway, including its downstream targets S6K and Akt; the mitogen-activated protein kinases (MAPK) pathway; and the Jak/Stat and NF-kappaB signal transduction pathway cascades, which are closely related to progression and development of tumors and inhibition of apoptosis.	('phosphatidylinositol 3-OH kinase', 'Gene', (97, 129))	('NF-kappaB', 'Gene', (267, 276))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('S6K', 'Gene', (179, 182))	('Akt', 'Gene', (187, 190))	('PI3', 'Gene', (131, 134))	('S6K', 'Gene', '6198', (179, 182))	('phosphatidylinositol 3-OH kinase', 'Gene', '5294', (97, 129))	('tumors', 'Disease', (375, 381))	('tumors', 'Disease', 'MESH:D009369', (375, 381))	('tumors', 'Phenotype', 'HP:0002664', (375, 381))	('Akt', 'Gene', '207', (187, 190))	('PI3', 'Gene', '5266', (131, 134))	('phosphorylation', 'Var', (4, 19))	('men', 'Species', '9606', (367, 370))	('activation', 'PosReg', (35, 45))	('NF-kappaB', 'Gene', '4790', (267, 276))
281057	25568334	Furthermore, we reveal that blockage of Axl protein expression inhibits proliferation, invasion, and migration of OSCC cells and tumor formation in vivo.	('blockage', 'Var', (28, 36))	('migration of OSCC cells', 'CPA', (101, 124))	('inhibits', 'NegReg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('proliferation', 'CPA', (72, 85))	('OSCC cells', 'CellLine', 'CVCL:L894', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('invasion', 'CPA', (87, 95))	('tumor', 'Disease', (129, 134))	('Axl protein expression', 'Protein', (40, 62))
281058	25568334	Interestingly, inhibition of Axl expression strikingly leads to reduction of Akt activation, leading to inhibition of IkappaBalpha phosphorylation and consequent blockage of NF-kappaB transcriptional activity.	('inhibition', 'NegReg', (104, 114))	('Akt', 'Gene', '207', (77, 80))	('IkappaBalpha', 'Gene', '4792', (118, 130))	('blockage', 'NegReg', (162, 170))	('IkappaBalpha', 'Gene', (118, 130))	('NF-kappaB', 'Gene', '4790', (174, 183))	('Akt', 'Gene', (77, 80))	('activation', 'PosReg', (81, 91))	('NF-kappaB', 'Gene', (174, 183))	('Axl', 'Protein', (29, 32))	('reduction', 'NegReg', (64, 73))	('transcriptional activity', 'MPA', (184, 208))	('inhibition', 'Var', (15, 25))
281075	25568334	For determining the effect of Axl blockage on tumor formation in vivo, Kyse450 cells infected either with LV-siRNA GFP (control) or LV-siRNA Axl were subcutaneously injected into MF-1 nude mice.	('nude mice', 'Species', '10090', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('LV-siRNA', 'Var', (132, 140))	('tumor', 'Disease', (46, 51))	('LV-siRNA', 'Var', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
281077	25568334	Mice implanted with Kyse450 siSRNA Axl cells developed tumors 60% lower in mass when compared with mice implanted with Kyse450 siRNA GFP control cells (Figure 3).	('mice', 'Species', '10090', (99, 103))	('mass', 'MPA', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Kyse450 siSRNA', 'Var', (20, 34))	('lower', 'NegReg', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('Mice', 'Species', '10090', (0, 4))
281078	25568334	Additionally, we observed lymph node metastasis only in mice implanted with Kyse450 siRNA GFP cells, while no metastases were observed in mice implanted with Kyse450 siRNA Axl (unpublished data), indicating that Axl expression plays an important role for tumor growth in vivo.	('metastases', 'Disease', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('mice', 'Species', '10090', (138, 142))	('lymph node metastasis', 'CPA', (26, 47))	('Kyse450 siRNA GFP', 'Var', (76, 93))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (255, 260))
281085	25568334	Western blot analysis of whole-cell extracts comparing Kyse450 and WHCO5 cells with Axl knockdown to the GFP knockdown cells revealed that inhibition of Axl leads to reduction of both Akt and IKKalpha phosphorylation and activity, which should result in inhibition of NF-kappaB (Figure 4A).	('inhibition', 'Var', (139, 149))	('reduction', 'NegReg', (166, 175))	('activity', 'MPA', (221, 229))	('Akt', 'Gene', (184, 187))	('Axl', 'Protein', (153, 156))	('IKKalpha', 'Gene', (192, 200))	('NF-kappaB', 'Gene', '4790', (268, 277))	('IKKalpha', 'Gene', '1147', (192, 200))	('NF-kappaB', 'Gene', (268, 277))	('inhibition', 'NegReg', (254, 264))	('Akt', 'Gene', '207', (184, 187))
281091	25568334	GSK3beta activity is regulated by site-specific phosphorylation of the Ser-9 residue, and deregulated phosphorylation has been linked to pathological conditions such as cancer.	('linked', 'Reg', (127, 133))	('cancer', 'Disease', (169, 175))	('phosphorylation', 'MPA', (102, 117))	('activity', 'MPA', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('phosphorylation', 'MPA', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('deregulated', 'Var', (90, 101))	('Ser', 'Chemical', 'MESH:D012694', (71, 74))	('GSK3beta', 'Gene', (0, 8))	('GSK3beta', 'Gene', '2932', (0, 8))
281093	25568334	Indeed, Akt phosphorylates the Ser-9 residue in GSK3beta, leading to its inactivation.	('GSK3beta', 'Gene', (48, 56))	('GSK3beta', 'Gene', '2932', (48, 56))	('inactivation', 'MPA', (73, 85))	('Akt', 'Gene', (8, 11))	('Ser', 'Chemical', 'MESH:D012694', (31, 34))	('Ser-9', 'Var', (31, 36))	('Akt', 'Gene', '207', (8, 11))
281096	25568334	As observed in Figure 5A, knockdown of Axl in both Kyse450 and WHCO5 cells inhibits the GSK3beta Ser-9 phosphorylation, indicating that Axl leads to inactivation of GSK3beta in OSSC.	('GSK3beta', 'Gene', '2932', (165, 173))	('GSK3beta', 'Gene', (88, 96))	('Ser', 'Chemical', 'MESH:D012694', (97, 100))	('inactivation', 'NegReg', (149, 161))	('knockdown', 'Var', (26, 35))	('GSK3beta', 'Gene', '2932', (88, 96))	('GSK3beta', 'Gene', (165, 173))	('inhibits', 'NegReg', (75, 83))
281100	25568334	Figure 5B demonstrates that GSK3beta is activated after treatment of esophageal cancer cells with wortmannin, because wortmannin reduces its phosphorylation.	('wortmannin', 'Chemical', 'MESH:D000077191', (98, 108))	('GSK3beta', 'Gene', '2932', (28, 36))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('phosphorylation', 'MPA', (141, 156))	('men', 'Species', '9606', (61, 64))	('GSK3beta', 'Gene', (28, 36))	('wortmannin', 'Var', (118, 128))	('wortmannin', 'Chemical', 'MESH:D000077191', (118, 128))	('reduces', 'NegReg', (129, 136))
281107	25568334	As shown in Supplemental Figure 1, inactivation of GSK3beta is more pronounced in Kyse450 siRNA Axl transfected with pcDNA Flag-Axl vector and treated with GSK3beta inhibitor II.	('inactivation', 'NegReg', (35, 47))	('Kyse450 siRNA Axl', 'Enzyme', (82, 99))	('transfected', 'Var', (100, 111))	('GSK3beta', 'Gene', (156, 164))	('GSK3beta', 'Gene', '2932', (51, 59))	('men', 'Species', '9606', (18, 21))	('GSK3beta', 'Gene', '2932', (156, 164))	('GSK3beta', 'Gene', (51, 59))
281110	25568334	Treatment of cells with wortmannin or GSK3beta inhibitor II reveals that wortmannin reduces proliferation of OSCC cells and knockdown cells transfected with pcDNA Flag-Axl vector, but it does not significantly affect proliferation of cells lacking Axl (Figure 5D).	('men', 'Species', '9606', (5, 8))	('GSK3beta', 'Gene', '2932', (38, 46))	('wortmannin', 'Chemical', 'MESH:D000077191', (24, 34))	('wortmannin', 'Var', (73, 83))	('reduces', 'NegReg', (84, 91))	('OSCC cells', 'CellLine', 'CVCL:L894', (109, 119))	('proliferation', 'CPA', (92, 105))	('wortmannin', 'Chemical', 'MESH:D000077191', (73, 83))	('GSK3beta', 'Gene', (38, 46))
281111	25568334	On the other hand, the GSK3beta inhibitor II induces proliferation in Axl knockdown cells but not in parental cells (Kyse450) or Axl knockdown cells transfected with pcDNA Flag-Axl.	('induces', 'Reg', (45, 52))	('knockdown', 'Var', (74, 83))	('GSK3beta', 'Gene', (23, 31))	('proliferation', 'CPA', (53, 66))	('GSK3beta', 'Gene', '2932', (23, 31))
281119	25568334	In addition, analysis of E-cadherin mRNA levels, an epithelial marker, demonstrates that cells lacking Axl and, consequently, expressing lower levels of Snail, have higher levels of E-cadherin mRNA when compared with control, and transfection of Axl knockdown cells with pcDNA Flag-Axl reduces E-cadherin expression (Figure 6B).	('lower', 'NegReg', (137, 142))	('reduces', 'NegReg', (286, 293))	('transfection', 'Var', (230, 242))	('E-cadherin', 'Gene', (182, 192))	('higher', 'PosReg', (165, 171))	('E-cadherin', 'Gene', (294, 304))	('E-cadherin', 'Gene', (25, 35))	('E-cadherin', 'Gene', '999', (294, 304))	('E-cadherin', 'Gene', '999', (182, 192))	('Snail', 'Gene', (153, 158))	('E-cadherin', 'Gene', '999', (25, 35))	('levels', 'MPA', (172, 178))	('Snail', 'Gene', '6615', (153, 158))
281129	25568334	In fact, Axl has been linked to poor prognosis and resistance to cancer therapy in several tumor types.	('Axl', 'Var', (9, 12))	('cancer', 'Disease', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
281134	25568334	Our findings demonstrate that blockage of Axl expression significantly reduces migration, invasion, and proliferation of OSCC cells and inhibits tumor growth.	('migration', 'CPA', (79, 88))	('reduces', 'NegReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('OSCC cells', 'CellLine', 'CVCL:L894', (121, 131))	('proliferation', 'CPA', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('inhibits', 'NegReg', (136, 144))	('tumor', 'Disease', (145, 150))	('blockage', 'Var', (30, 38))	('invasion', 'CPA', (90, 98))	('Axl expression', 'Protein', (42, 56))
281138	25568334	Furthermore, inhibition of NF-kappaB induces apoptosis and blocks tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('blocks tumor', 'Disease', 'MESH:D006327', (59, 71))	('inhibition', 'Var', (13, 23))	('NF-kappaB', 'Gene', '4790', (27, 36))	('NF-kappaB', 'Gene', (27, 36))	('apoptosis', 'CPA', (45, 54))	('blocks tumor', 'Disease', (59, 71))
281139	25568334	Here we demonstrate that knockdown of Axl expression leads to the inactivation of NF-kappaB by inhibition of Akt and IKKalpha activity.	('Akt', 'Gene', '207', (109, 112))	('NF-kappaB', 'Gene', (82, 91))	('inhibition', 'NegReg', (95, 105))	('inactivation', 'NegReg', (66, 78))	('Akt', 'Gene', (109, 112))	('Axl', 'Gene', (38, 41))	('IKKalpha', 'Gene', '1147', (117, 125))	('NF-kappaB', 'Gene', '4790', (82, 91))	('knockdown', 'Var', (25, 34))	('IKKalpha', 'Gene', (117, 125))
281150	25568334	We demonstrate now that inhibition of Axl expression has a pivotal effect on GSK3beta activation.	('Axl expression', 'Protein', (38, 52))	('GSK3beta', 'Gene', (77, 85))	('inhibition', 'Var', (24, 34))	('activation', 'PosReg', (86, 96))	('GSK3beta', 'Gene', '2932', (77, 85))
281154	25568334	In OSCC cells, expression of Axl activates Akt and leads to GSK3beta inactivation via phosphorylation of its Ser-9.	('expression', 'Var', (15, 25))	('OSCC cells', 'CellLine', 'CVCL:L894', (3, 13))	('Akt', 'Gene', '207', (43, 46))	('inactivation', 'NegReg', (69, 81))	('GSK3beta', 'Gene', (60, 68))	('activates', 'PosReg', (33, 42))	('phosphorylation', 'MPA', (86, 101))	('Akt', 'Gene', (43, 46))	('GSK3beta', 'Gene', '2932', (60, 68))	('Ser', 'Chemical', 'MESH:D012694', (109, 112))
281157	25568334	Accordingly, the treatment of Axl knockdown cells with an inhibitor of GSK3beta leads to increased cell proliferation.	('cell proliferation', 'CPA', (99, 117))	('inhibitor', 'Var', (58, 67))	('GSK3beta', 'Gene', (71, 79))	('men', 'Species', '9606', (22, 25))	('increased', 'PosReg', (89, 98))	('GSK3beta', 'Gene', '2932', (71, 79))
281160	25568334	These observations strongly support the notion that Axl may represent an underexplored therapeutic target for OSCC and may induce EMT in OSCC via GSK3beta inactivation.	('GSK3beta', 'Gene', (146, 154))	('induce', 'PosReg', (123, 129))	('inactivation', 'Var', (155, 167))	('OSCC', 'Disease', (137, 141))	('GSK3beta', 'Gene', '2932', (146, 154))	('OSCC', 'Disease', (110, 114))	('EMT', 'CPA', (130, 133))
281234	25438287	From the results of multiple meta-analysis, insertion of TIPS showed similar improvement of ascites, though survival benefit seemed to be inconclusive as 3 or the 5 meta-analysis did not show improved survival.	('ascites', 'Disease', 'MESH:D001201', (92, 99))	('ascites', 'Phenotype', 'HP:0001541', (92, 99))	('ascites', 'Disease', (92, 99))	('insertion', 'Var', (44, 53))	('improvement', 'PosReg', (77, 88))
281243	25438287	In these studies, TIPS insertion was found to improve renal function through enhanced glomerular filtration rates and renal plasma flow as well as via reductions in serum creatinine and plasma aldosterone levels.	('insertion', 'Var', (23, 32))	('aldosterone', 'Chemical', 'MESH:D000450', (193, 204))	('enhanced', 'PosReg', (77, 85))	('glomerular filtration rates', 'MPA', (86, 113))	('plasma aldosterone levels', 'MPA', (186, 211))	('plasma aldosterone levels', 'Phenotype', 'HP:0000859', (186, 211))	('enhanced glomerular filtration rates', 'Phenotype', 'HP:0012214', (77, 113))	('renal', 'MPA', (54, 59))	('serum creatinine', 'MPA', (165, 181))	('reductions', 'NegReg', (151, 161))	('creatinine', 'Chemical', 'MESH:D003404', (171, 181))	('renal plasma flow', 'MPA', (118, 135))	('improve', 'PosReg', (46, 53))
281290	25438287	Frequency of new or worsening HE ranges from 10-44%, and factors associated with post-TIPS HE development include prior history of HE, increasing age, shunt caliber, high creatinine levels, low serum sodium concentration and liver dysfunction.	('HE', 'Phenotype', 'HP:0002480', (30, 32))	('liver dysfunction', 'Disease', 'MESH:D017093', (225, 242))	('low', 'Var', (190, 193))	('creatinine', 'Chemical', 'MESH:D003404', (171, 181))	('high creatinine', 'Phenotype', 'HP:0003259', (166, 181))	('sodium', 'Chemical', 'MESH:D012964', (200, 206))	('low serum sodium concentration', 'Phenotype', 'HP:0002902', (190, 220))	('HE', 'Phenotype', 'HP:0002480', (131, 133))	('shunt', 'Disease', (151, 156))	('liver dysfunction', 'Phenotype', 'HP:0001410', (225, 242))	('liver dysfunction', 'Disease', (225, 242))	('HE', 'Phenotype', 'HP:0002480', (91, 93))	('high creatinine levels', 'MPA', (166, 188))
281465	23155139	It is also possible that predisposing genetic factors, such as ADH or ALDH polymorphisms, among closed tribal communities may have an additional role in the high incidence of esophageal cancer.	('esophageal cancer', 'Disease', (175, 192))	('ADH', 'Disease', (63, 66))	('polymorphisms', 'Var', (75, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('ADH', 'Disease', 'MESH:D007177', (63, 66))	('ALDH', 'Gene', (70, 74))
281733	32426268	Quantitative analysis of the global proteome revealed ubiquitin-dependent protein catabolism to be more active in A549/DDP cells than in A549 cells.	('A549/DDP', 'Var', (114, 122))	('DDP', 'Chemical', '-', (119, 122))	('active', 'MPA', (104, 110))	('more', 'PosReg', (99, 103))	('ubiquitin-dependent protein catabolism', 'MPA', (54, 92))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('A549', 'CellLine', 'CVCL:0023', (137, 141))
281734	32426268	WDHD1 expression was higher in A549/DDP cells than in A549 cells, and knocking out WDHD1 increased the sensitivity of A549/DDP cells to cisplatin.	('knocking out', 'Var', (70, 82))	('WDHD1', 'Gene', (0, 5))	('expression', 'MPA', (6, 16))	('A549', 'CellLine', 'CVCL:0023', (31, 35))	('WDHD1', 'Gene', (83, 88))	('higher', 'PosReg', (21, 27))	('sensitivity', 'MPA', (103, 114))	('A549', 'CellLine', 'CVCL:0023', (54, 58))	('DDP', 'Chemical', '-', (36, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('increased', 'PosReg', (89, 98))	('A549', 'CellLine', 'CVCL:0023', (118, 122))	('DDP', 'Chemical', '-', (123, 126))
281736	32426268	We observed that MAPRE2 was upregulated when WDHD1 was knocked out.	('knocked out', 'Var', (55, 66))	('MAPRE2', 'Gene', (17, 23))	('WDHD1', 'Gene', (45, 50))	('MAPRE2', 'Gene', '10982', (17, 23))	('upregulated', 'PosReg', (28, 39))
281737	32426268	A MAPRE2 knockout in A549 cells resulted in increased cell viability while decreasing apoptosis when the A549 cells exposed to cisplatin.	('A549', 'CellLine', 'CVCL:0023', (21, 25))	('knockout', 'Var', (9, 17))	('MAPRE2', 'Gene', (2, 8))	('MAPRE2', 'Gene', '10982', (2, 8))	('decreasing', 'NegReg', (75, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('A549', 'CellLine', 'CVCL:0023', (105, 109))	('increased', 'PosReg', (44, 53))	('cell viability', 'CPA', (54, 68))	('apoptosis', 'CPA', (86, 95))
281740	32426268	Immunohistochemistry showed that Ki67 levels increased, and levels of apoptotic indicators significantly decreased in the WDHD1 and MAPRE2 knockout groups.	('WDHD1', 'Gene', (122, 127))	('MAPRE2', 'Gene', '10982', (132, 138))	('increased', 'PosReg', (45, 54))	('knockout', 'Var', (139, 147))	('Ki67 levels', 'MPA', (33, 44))	('levels of apoptotic indicators', 'MPA', (60, 90))	('Ki67', 'Chemical', '-', (33, 37))	('MAPRE2', 'Gene', (132, 138))	('decreased', 'NegReg', (105, 114))
281758	32426268	Overexpression of the ubiquitin ligase MDM2 in malignant pleural mesothelioma is negatively correlated with patient prognosis and leads to p53 degradation and decreased cisplatin sensitivity.	('malignant pleural mesothelioma', 'Disease', (47, 77))	('MDM2', 'Gene', '4193', (39, 43))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (57, 77))	('MDM2', 'Gene', (39, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('p53', 'Gene', (139, 142))	('decreased', 'NegReg', (159, 168))	('degradation', 'MPA', (143, 154))	('Overexpression', 'Var', (0, 14))	('p53', 'Gene', '7157', (139, 142))	('cisplatin sensitivity', 'MPA', (169, 190))	('negatively', 'NegReg', (81, 91))	('patient', 'Species', '9606', (108, 115))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (47, 77))
281765	32426268	The protein chip results demonstrated that ubiquitin-dependent protein catabolism was more active in A549/DDP cells than that in A549 cells.	('DDP', 'Chemical', '-', (106, 109))	('A549/DDP', 'Var', (101, 109))	('A549', 'CellLine', 'CVCL:0023', (101, 105))	('active', 'MPA', (91, 97))	('ubiquitin-dependent protein catabolism', 'MPA', (43, 81))	('A549', 'CellLine', 'CVCL:0023', (129, 133))	('more', 'PosReg', (86, 90))
281792	32426268	The cells were incubated with the primary antibodies anti-WDHD1 (1:100, ab72436; Abcam) and anti-MAPRE2 (1:100, ab45767; Abcam) antibodies at 4 C overnight and then washed with PBS.	('PBS', 'Chemical', '-', (177, 180))	('MAPRE2', 'Gene', '10982', (97, 103))	('1:100', 'Var', (105, 110))	('anti-WDHD1', 'Var', (53, 63))	('1:100', 'Var', (65, 70))	('MAPRE2', 'Gene', (97, 103))
281822	32426268	The primary antibodies anti-WDHD1 (1:100, ab72436; Abcam) and anti-Ki67 (1:100, GTX16667; Genetex) were added to the sections and incubated overnight at 4 C. Each section, after washing, was incubated at room temperature for 30 min with a drop of biotin-labeled secondary antibody.	('1:100', 'Var', (35, 40))	('Ki67', 'Chemical', '-', (67, 71))	('anti-Ki67', 'Var', (62, 71))	('biotin', 'Chemical', 'MESH:D001710', (247, 253))	('anti-WDHD1', 'Var', (23, 33))
281831	32426268	We found that ubiquitin-dependent protein catabolism was more active in A549/DDP cells as compared to that in A549 cells, with statistically significant differences (p < 0.05) (Figure 1C).	('active', 'MPA', (62, 68))	('ubiquitin-dependent protein catabolism', 'MPA', (14, 52))	('more', 'PosReg', (57, 61))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('DDP', 'Chemical', '-', (77, 80))	('A549/DDP', 'Var', (72, 80))
281841	32426268	To further explore the effect of WDHD1 on the sensitivity of A549/DDP cells to cisplatin, we constructed siRNA to knock out WDHD1 in A549/DDP cells.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('DDP', 'Chemical', '-', (66, 69))	('DDP', 'Chemical', '-', (138, 141))	('WDHD1', 'Gene', (124, 129))	('knock out', 'Var', (114, 123))	('A549', 'CellLine', 'CVCL:0023', (133, 137))	('A549', 'CellLine', 'CVCL:0023', (61, 65))
281843	32426268	It was found that the viability of A549/DDP cells significantly decreased after WDHD1 knockout (Figure 2D), and the IC50 decreased significantly (Supplementary Table 1).	('knockout', 'Var', (86, 94))	('decreased', 'NegReg', (121, 130))	('A549', 'CellLine', 'CVCL:0023', (35, 39))	('WDHD1', 'Gene', (80, 85))	('viability', 'CPA', (22, 31))	('IC50', 'MPA', (116, 120))	('DDP', 'Chemical', '-', (40, 43))	('decreased', 'NegReg', (64, 73))
281849	32426268	To determine whether WDHD1 can regulate the expression of MAPRE2 and DSTN, the expression of MAPRE2 and DSTN in A549/DDP cells was detected by Western blotting (WB) after knocking out WDHD1 with si-WDHD1.	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('MAPRE2', 'Gene', '10982', (93, 99))	('DSTN', 'Gene', (104, 108))	('si-WDHD1', 'Var', (195, 203))	('DSTN', 'Gene', (69, 73))	('DDP', 'Chemical', '-', (117, 120))	('MAPRE2', 'Gene', (58, 64))	('MAPRE2', 'Gene', '10982', (58, 64))	('DSTN', 'Gene', '11034', (104, 108))	('DSTN', 'Gene', '11034', (69, 73))	('MAPRE2', 'Gene', (93, 99))
281850	32426268	The results showed that the knocking out of WDHD1 could increase the expression of MAPRE2 but had no significant effect on DSTN (Figure 3A and Supplementary Figure 2B).	('MAPRE2', 'Gene', '10982', (83, 89))	('WDHD1', 'Gene', (44, 49))	('increase', 'PosReg', (56, 64))	('DSTN', 'Gene', '11034', (123, 127))	('expression', 'MPA', (69, 79))	('MAPRE2', 'Gene', (83, 89))	('knocking out', 'Var', (28, 40))	('DSTN', 'Gene', (123, 127))
281851	32426268	The WB results showed that WDHD1 expression in A549/DDP cells was higher than that in A549 cells (Figure 3A).	('WDHD1', 'Gene', (27, 32))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('A549/DDP', 'Var', (47, 55))	('DDP', 'Chemical', '-', (52, 55))	('higher', 'PosReg', (66, 72))	('expression', 'MPA', (33, 43))	('A549', 'CellLine', 'CVCL:0023', (47, 51))
281854	32426268	A WB confirmed that MAPRE2 was successfully knocked out, and after MAPRE2 knocked out, A549 cell viability increased (Figure 3B).	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('MAPRE2', 'Gene', '10982', (67, 73))	('increased', 'PosReg', (107, 116))	('MAPRE2', 'Gene', (20, 26))	('knocked out', 'Var', (74, 85))	('MAPRE2', 'Gene', '10982', (20, 26))	('MAPRE2', 'Gene', (67, 73))
281855	32426268	Flow cytometry results indicated that apoptosis was decreased under the action of cisplatin after MAPRE2 was knocked out in A549 and A549/DDP cells (Figure 3C).	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('decreased', 'NegReg', (52, 61))	('DDP', 'Chemical', '-', (138, 141))	('MAPRE2', 'Gene', (98, 104))	('apoptosis', 'CPA', (38, 47))	('knocked out', 'Var', (109, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('MAPRE2', 'Gene', '10982', (98, 104))	('A549', 'CellLine', 'CVCL:0023', (133, 137))
281859	32426268	A549/DDP cells transfected with either si-con or si-WDHD1 were established as groups A and B, respectively.	('DDP', 'Chemical', '-', (5, 8))	('si-WDHD1', 'Var', (49, 57))	('si-con', 'Var', (39, 45))	('A549', 'CellLine', 'CVCL:0023', (0, 4))
281863	32426268	The results showed that the rate of MAPRE2 degradation was significantly reduced when WDHD1 was knocked out (Figure 3F).	('knocked out', 'Var', (96, 107))	('MAPRE2', 'Gene', (36, 42))	('MAPRE2', 'Gene', '10982', (36, 42))	('reduced', 'NegReg', (73, 80))	('WDHD1', 'Gene', (86, 91))
281865	32426268	A functional recovery experiment was conducted to explore the effect of WDHD1 on cisplatin resistance by regulating MAPRE2, by establishing five groups designated A to E. Groups A was transfected with si-control; groups B and C were transfected with si-WDHD1; group D was transfected with both si-WDHD1 and si-MAPRE2; and group E was transfected with si-MAPRE2.	('MAPRE2', 'Gene', (116, 122))	('MAPRE2', 'Gene', '10982', (354, 360))	('MAPRE2', 'Gene', '10982', (310, 316))	('MAPRE2', 'Gene', '10982', (116, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('MAPRE2', 'Gene', (354, 360))	('si-WDHD1', 'Var', (294, 302))	('si-WDHD1', 'Var', (250, 258))	('MAPRE2', 'Gene', (310, 316))
281868	32426268	The results showed that the cellular viability decreased, and apoptosis increased significantly after knocking out WDHD1 in A549/DDP cells.	('increased', 'PosReg', (72, 81))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('cellular viability', 'CPA', (28, 46))	('WDHD1', 'Gene', (115, 120))	('apoptosis', 'CPA', (62, 71))	('knocking out', 'Var', (102, 114))	('DDP', 'Chemical', '-', (129, 132))	('decreased', 'NegReg', (47, 56))
281869	32426268	When both WDHD1 and MAPRE2 were knocked out, cellular viability increased, and apoptosis decreased.	('MAPRE2', 'Gene', (20, 26))	('cellular viability', 'CPA', (45, 63))	('WDHD1', 'Gene', (10, 15))	('knocked out', 'Var', (32, 43))	('MAPRE2', 'Gene', '10982', (20, 26))	('apoptosis', 'CPA', (79, 88))	('increased', 'PosReg', (64, 73))	('decreased', 'NegReg', (89, 98))
281871	32426268	In groups A and B, A549/DDP cells were transfected with si-control and si-WDHD1, respectively.	('si-control', 'Var', (56, 66))	('DDP', 'Chemical', '-', (24, 27))	('si-WDHD1', 'Var', (71, 79))	('A549', 'CellLine', 'CVCL:0023', (19, 23))
281872	32426268	Group C was transfected with both si-WDHD1 and si-MAPRE2.	('si-WDHD1', 'Var', (34, 42))	('MAPRE2', 'Gene', (50, 56))	('MAPRE2', 'Gene', '10982', (50, 56))
281877	32426268	The expression of Ki67 in the WDHD1 knockout group was significantly lower than that in the control group (Figure 5C).	('WDHD1', 'Gene', (30, 35))	('knockout', 'Var', (36, 44))	('expression', 'MPA', (4, 14))	('lower', 'NegReg', (69, 74))	('Ki67', 'Chemical', '-', (18, 22))	('Ki67', 'Gene', (18, 22))
281879	32426268	The in vivo experiments further demonstrated that WDHD1 knockout increased the sensitivity of LUAD to cisplatin, decreased the proliferation of LUAD cells, and increased apoptosis.	('WDHD1', 'Gene', (50, 55))	('increased', 'PosReg', (65, 74))	('proliferation', 'CPA', (127, 140))	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('increased', 'PosReg', (160, 169))	('sensitivity', 'MPA', (79, 90))	('LUAD', 'Phenotype', 'HP:0030078', (94, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('knockout', 'Var', (56, 64))	('decreased', 'NegReg', (113, 122))	('apoptosis', 'CPA', (170, 179))
281884	32426268	Therefore, we hypothesized that abnormal protein ubiquitination may be the cause of cisplatin resistance in LUAD.	('cause', 'Reg', (75, 80))	('protein', 'Protein', (41, 48))	('LUAD', 'Disease', (108, 112))	('LUAD', 'Phenotype', 'HP:0030078', (108, 112))	('abnormal', 'Var', (32, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('cisplatin resistance', 'MPA', (84, 104))
281898	32426268	For example, studies have confirmed that WDHD1 is upregulated in cervical cancer cells, and knocking out WDHD1 in these cells leads to G1 stagnation, which affects the cell cycle and cellular replication.	('WDHD1', 'Gene', (105, 110))	('upregulated', 'PosReg', (50, 61))	('leads to', 'Reg', (126, 134))	('affects', 'Reg', (156, 163))	('cell cycle', 'CPA', (168, 178))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('knocking out', 'Var', (92, 104))	('cancer', 'Disease', (74, 80))	('WDHD1', 'Gene', (41, 46))	('stagnation', 'NegReg', (138, 148))	('cellular replication', 'CPA', (183, 203))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
281899	32426268	Similarly, high WDHD1 expression was found to be negatively correlated with non-small cell lung cancer and esophageal squamous cell carcinoma, and the knockout of WDHD1 could effectively inhibit the growth of both lung and esophageal cancer cells; however, no studies have reported the association between WDHD1 and cisplatin sensitivity in LUAD.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('WDHD1', 'Gene', (16, 21))	('cancer', 'Disease', (96, 102))	('growth', 'CPA', (199, 205))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('LUAD', 'Phenotype', 'HP:0030078', (341, 345))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('lung cancer', 'Disease', (91, 102))	('inhibit', 'NegReg', (187, 194))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('negatively', 'NegReg', (49, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (316, 325))	('knockout', 'Var', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('WDHD1', 'Gene', (163, 168))	('expression', 'MPA', (22, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))	('high', 'Var', (11, 15))	('cancer', 'Disease', (234, 240))
281902	32426268	Moreover, the MTT assay revealed that the MAPRE2 knockout was associated with increased cell viability and decreased apoptosis in A549 cells, suggesting that decreased MAPRE2 may be the cause of cisplatin resistance in LUAD.	('MTT', 'Chemical', '-', (14, 17))	('decreased', 'NegReg', (158, 167))	('LUAD', 'Phenotype', 'HP:0030078', (219, 223))	('MAPRE2', 'Gene', (168, 174))	('decreased', 'NegReg', (107, 116))	('MAPRE2', 'Gene', (42, 48))	('increased', 'PosReg', (78, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))	('cell viability', 'CPA', (88, 102))	('MAPRE2', 'Gene', '10982', (168, 174))	('apoptosis', 'CPA', (117, 126))	('MAPRE2', 'Gene', '10982', (42, 48))	('knockout', 'Var', (49, 57))	('A549', 'CellLine', 'CVCL:0023', (130, 134))
281925	32426268	RAE1 was highly expressed in A549/DDP, and its high expression was negatively related to the prognosis of LUAD patients (Supplementary Figure 3D).	('LUAD', 'Phenotype', 'HP:0030078', (106, 110))	('RAE1', 'Gene', (0, 4))	('A549/DDP', 'Var', (29, 37))	('DDP', 'Chemical', '-', (34, 37))	('RAE1', 'Gene', '8480', (0, 4))	('high expression', 'MPA', (47, 62))	('negatively', 'NegReg', (67, 77))	('A549', 'CellLine', 'CVCL:0023', (29, 33))	('LUAD', 'Disease', (106, 110))	('patients', 'Species', '9606', (111, 119))
281940	31850292	In esophageal atresia there is almost always a disruption in the continuity of the esophagus resulting in a proximal and distal esophageal pouch and depending on whether there is a communication (tracheoesophageal fistula) between the proximal or distal esophageal pouches and the trachea, the EA is classified into Types A to E (Figure 1).	('esophageal pouch', 'Phenotype', 'HP:0100628', (254, 270))	('disruption', 'Var', (47, 57))	('esophageal atresia', 'Disease', 'MESH:D004933', (3, 21))	('esophageal atresia', 'Disease', (3, 21))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (196, 221))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (196, 221))	('esophageal pouch', 'Phenotype', 'HP:0100628', (128, 144))	('esophageal pouches', 'Phenotype', 'HP:0100628', (254, 272))	('esophageal atresia', 'Phenotype', 'HP:0002032', (3, 21))	('tracheoesophageal fistula', 'Disease', (196, 221))
281944	31850292	The symptoms in EoE are related to eosphageal dysfunction secondary to eosinophilic infiltration in the esophagus resulting in dysmotility and strictures.	('eosinophilic infiltration in the esophagus', 'Phenotype', 'HP:0410151', (71, 113))	('dysmotility', 'Disease', 'MESH:D015154', (127, 138))	('eosinophilic infiltration', 'Var', (71, 96))	('eosphageal dysfunction', 'Disease', (35, 57))	('EoE', 'Phenotype', 'HP:0410151', (16, 19))	('strictures', 'Disease', (143, 153))	('EoE', 'Disease', (16, 19))	('dysmotility', 'Disease', (127, 138))
281965	31850292	This hypothesis has also been recently supported in mouse models where PPI use can cause the formation of food-specific immunoglobulin (Ig) E antibodies and trigger food allergy.	('PPI use', 'Var', (71, 78))	('allergy', 'Phenotype', 'HP:0012393', (170, 177))	('food allergy', 'Phenotype', 'HP:0500093', (165, 177))	('mouse', 'Species', '10090', (52, 57))	('trigger', 'Reg', (157, 164))	('cause', 'Reg', (83, 88))	('food allergy', 'Disease', 'MESH:D004342', (165, 177))	('food allergy', 'Disease', (165, 177))
281966	31850292	have also described other possible mechanisms by which PPI exposure might potentially lead to an increased risk of development of EoE in patients, due to their adverse influence on mucosal barrier function, interference with pH-related protein digestion by pepsin, and antigen processing by immune cells.	('pH-related', 'MPA', (225, 235))	('patients', 'Species', '9606', (137, 145))	('EoE', 'Disease', (130, 133))	('EoE', 'Phenotype', 'HP:0410151', (130, 133))	('antigen processing', 'MPA', (269, 287))	('lead to', 'Reg', (86, 93))	('PPI', 'Var', (55, 58))	('interference', 'NegReg', (207, 219))
281978	31850292	Large prospective longitudinal studies would also be helpful in determining whether prolonging breast feeding and reducing duration and cumulative dosage of exposure to proton pump inhibitor (PPI) therapy in EA patients with EoE susceptible genes would reduce their relative risk of developing EoE in the future.	('EoE', 'Disease', (225, 228))	('patients', 'Species', '9606', (211, 219))	('EoE', 'Disease', (294, 297))	('EoE', 'Phenotype', 'HP:0410151', (294, 297))	('reduce', 'NegReg', (253, 259))	('proton pump', 'Gene', (169, 180))	('genes', 'Var', (241, 246))	('proton pump', 'Gene', '495', (169, 180))	('EoE', 'Phenotype', 'HP:0410151', (225, 228))
281983	31850292	Also EA patients with EoE had a more-severe clinical phenotype, with higher incidence of dysphagia, episodes of food bolus impaction and strictures requiring dilation than in those with EoE alone without EA and EA patients without EoE, highlighting the importance of timely diagnosis and treatment of EoE in EA patients.	('dysphagia', 'Phenotype', 'HP:0002015', (89, 98))	('EoE', 'Phenotype', 'HP:0410151', (186, 189))	('patients', 'Species', '9606', (214, 222))	('food bolus impaction', 'Phenotype', 'HP:0031984', (112, 132))	('EoE', 'Var', (22, 25))	('dysphagia', 'Disease', 'MESH:D003680', (89, 98))	('patients', 'Species', '9606', (311, 319))	('EoE', 'Phenotype', 'HP:0410151', (22, 25))	('EoE', 'Phenotype', 'HP:0410151', (231, 234))	('strictures', 'Disease', (137, 147))	('dysphagia', 'Disease', (89, 98))	('EoE', 'Phenotype', 'HP:0410151', (301, 304))	('patients', 'Species', '9606', (8, 16))
281991	31850292	Acid peptic mucosal injury due to severe GERD may impair the mucosal barrier function in EA patients and thereby increase the risk of sensitization to food and aero-allergens thereby increasing the risk of developing EoE.	('EoE', 'Phenotype', 'HP:0410151', (217, 220))	('mucosal barrier function', 'CPA', (61, 85))	('mucosal injury', 'Disease', (12, 26))	('mucosal injury', 'Disease', 'MESH:D052016', (12, 26))	('patients', 'Species', '9606', (92, 100))	('sensitization to food', 'Phenotype', 'HP:0500093', (134, 155))	('GERD', 'Var', (41, 45))	('sensitization', 'MPA', (134, 147))	('increase', 'PosReg', (113, 121))	('EoE', 'Disease', (217, 220))	('impair', 'NegReg', (50, 56))	('severe GERD', 'Var', (34, 45))
282012	31850292	The finding of vomiting in the EoE group could be explained by the considerable overlap between EoE and GERD symptoms in the EA cohort, and also because the esophageal dysmotility due to EoE can potentially exacerbate GERD.	('vomiting', 'Disease', (15, 23))	('vomiting', 'Disease', 'MESH:D014839', (15, 23))	('EoE', 'Var', (187, 190))	('esophageal dysmotility', 'Disease', (157, 179))	('EoE', 'Phenotype', 'HP:0410151', (31, 34))	('EoE', 'Disease', (96, 99))	('exacerbate', 'PosReg', (207, 217))	('EoE', 'Phenotype', 'HP:0410151', (96, 99))	('esophageal dysmotility', 'Disease', 'MESH:D015154', (157, 179))	('EoE', 'Phenotype', 'HP:0410151', (187, 190))	('vomiting', 'Phenotype', 'HP:0002013', (15, 23))	('GERD', 'Disease', (218, 222))
282016	31850292	chest pain was the only symptom to occur significantly more in EA patients with EoE compared to EA patients without EoE.	('pain', 'Phenotype', 'HP:0012531', (6, 10))	('chest pain', 'Phenotype', 'HP:0100749', (0, 10))	('EoE', 'Var', (80, 83))	('EoE', 'Phenotype', 'HP:0410151', (116, 119))	('patients', 'Species', '9606', (99, 107))	('chest pain', 'Disease', 'MESH:D002637', (0, 10))	('EoE', 'Phenotype', 'HP:0410151', (80, 83))	('chest pain', 'Disease', (0, 10))	('patients', 'Species', '9606', (66, 74))
282040	31850292	The authors' own data from a EA multidisciplinary clinic showed that EA patients with EoE scored lower total scores in in a generic, pediatric QOL questionnaire (PedsQL-EoE module) compared to EA or EoE only groups (Poster at EA conference Rotterdam 2014).	('EA conference Rotterdam', 'Disease', (226, 249))	('EA conference Rotterdam', 'Disease', 'MESH:C563691', (226, 249))	('EoE', 'Phenotype', 'HP:0410151', (86, 89))	('EoE', 'Phenotype', 'HP:0410151', (199, 202))	('lower', 'NegReg', (97, 102))	('EoE', 'Phenotype', 'HP:0410151', (169, 172))	('EoE', 'Var', (86, 89))	('patients', 'Species', '9606', (72, 80))
282060	31850292	Second, PPIs inhibit IL-4-stimulated eotaxin-3 expression by reducing the binding of STAT6 to the exotaxin-3 promoter in esophageal cells thereby potentially reducing eosinophil recruitment.	('reducing', 'NegReg', (61, 69))	('STAT6', 'Gene', '6778', (85, 90))	('eotaxin-3', 'Gene', (37, 46))	('IL-4', 'Gene', (21, 25))	('PPIs', 'Var', (8, 12))	('reducing', 'NegReg', (158, 166))	('expression', 'MPA', (47, 57))	('eosinophil recruitment', 'MPA', (167, 189))	('inhibit', 'NegReg', (13, 20))	('eotaxin-3', 'Gene', '10344', (37, 46))	('IL-4', 'Gene', '3565', (21, 25))	('STAT6', 'Gene', (85, 90))	('binding', 'Interaction', (74, 81))
282061	31850292	Looking at the effect of PPIs on EoE in the EA cohort, in the study by Yamada et al., two (33%) patients treated with esophageal dilatation followed by PPI showed both a symptomatic improvement and a reduction in the eosinophil count in the biopsy.	('dilatation', 'Phenotype', 'HP:0002617', (129, 139))	('EoE', 'Phenotype', 'HP:0410151', (33, 36))	('reduction', 'NegReg', (200, 209))	('patients', 'Species', '9606', (96, 104))	('eosinophil count', 'MPA', (217, 233))	('PPI', 'Var', (152, 155))
282118	30305678	Meanwhile, 13 patients (3%) had N0 status, 178 patients (44%) had N1 status, 116 patients (29%) had N2 status, and 97 patients (24%) had N3 status.	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (81, 89))	('N1 status', 'Var', (66, 75))	('N0 status', 'Var', (32, 41))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (118, 126))
282123	30305678	Significantly better PFS (11.0 months versus 8.4 months, P = 0.019) was found in the 178 patients who had T1-3 status than in the 226 patients who had T4 status, and superior PFS (11.9 months versus 7.9 months, P = 0.001) was also found in the 192 patients with N0-1 status compared to the other 212 patients with N2-3 status.	('T1-3 status', 'Var', (106, 117))	('PFS', 'MPA', (21, 24))	('patients', 'Species', '9606', (134, 142))	('N0-1 status', 'Var', (262, 273))	('better', 'PosReg', (14, 20))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (248, 256))	('patients', 'Species', '9606', (300, 308))
282126	30305678	Significantly better OS (21.2 months versus 14.8 months, P = 0.030) was found in the 178 patients who had T1-3 status than in the 226 patients who had T4 status, and superior OS (23.3 months versus 13.6 months, P = 0.020) was also found in the 192 patients with N0-1 status in comparison to the 212 patients with N2-3 status.	('T1-3 status', 'Var', (106, 117))	('patients', 'Species', '9606', (134, 142))	('N0-1 status', 'Var', (262, 273))	('better', 'PosReg', (14, 20))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (299, 307))	('patients', 'Species', '9606', (248, 256))
282222	27244882	Median DFS and OS of down-staged patients were significantly longer than those of non-downstaged patients.	('longer', 'PosReg', (61, 67))	('patients', 'Species', '9606', (33, 41))	('down-staged', 'Var', (21, 32))	('OS', 'Chemical', '-', (15, 17))	('patients', 'Species', '9606', (97, 105))
282227	27244882	NCT01258192 Esophageal cancer is a malignant tumor with a poor prognosis that is common in China.	('NCT01258192', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('malignant tumor', 'Disease', (35, 50))	('Esophageal cancer', 'Disease', (12, 29))	('malignant tumor', 'Disease', 'MESH:D018198', (35, 50))	('Esophageal cancer', 'Disease', 'MESH:D004938', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
282229	27244882	With surgery alone, the 5-year survival rate for T2-T3N0 disease is < 30-40%, and it declines to < 25% with nodal involvement.	('nodal', 'Gene', '4838', (108, 113))	('T2-T3N0', 'Var', (49, 56))	('declines', 'NegReg', (85, 93))	('nodal', 'Gene', (108, 113))
282265	27244882	Median OS and DFS of down-staged (descent stage) patients were significantly longer than of non-downstaged (no descent stage) patients (HR: 0.26, 95% CI: 0.06- 0.61; P = 0.005 and HR: 0.25, 95% CI: 0.08-0.75; P = 0.01, respectively) (Figure 3C-3D).	('OS', 'Chemical', '-', (7, 9))	('longer', 'PosReg', (77, 83))	('down-staged', 'Var', (21, 32))	('DFS', 'MPA', (14, 17))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (49, 57))
282275	27244882	Enrollment was performed by the clinicians and all eligible patients received nab-PC (100 mg/m2, d1, d8, d22 and d29) and cisplatin (75 mg/m2, d1 and d22) as neoadjuvant chemotherapy (Figure 1), followed by esophagectomy and adjuvant chemotherapy with or without radiotherapy.	('75 mg/m2', 'Var', (133, 141))	('d22', 'Var', (150, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('nab-PC', 'Var', (78, 84))	('patients', 'Species', '9606', (60, 68))	('nab', 'Chemical', '-', (78, 81))	('d29', 'Var', (113, 116))	('d22 and d29', 'Var', (105, 116))
282390	26891324	The present meta-analysis supports a significant association of dietary flavonols intake with a reduced risk of GC, as well as EC and GC combined, especially in smokers.	('flavonols', 'Chemical', 'MESH:D044948', (72, 81))	('GC', 'Phenotype', 'HP:0012126', (112, 114))	('dietary', 'Var', (64, 71))	('GC', 'Phenotype', 'HP:0012126', (134, 136))	('reduced', 'NegReg', (96, 103))
282396	26891324	In our study, a significant inverse association of high dietary flavonols intake with a reduced risk of EC and GC was observed in smokers (OR = 0.81, 95% CI: 0.71-0.91) but not in nonsmokers (OR = 1.07, 95% CI: 0.91-1.25).	('flavonols', 'Chemical', 'MESH:D044948', (64, 73))	('inverse', 'NegReg', (28, 35))	('GC', 'Phenotype', 'HP:0012126', (111, 113))	('reduced', 'NegReg', (88, 95))	('high dietary flavonols', 'Var', (51, 73))
282409	26891324	In conclusion, the present study indicated a significant association of dietary flavonols intake with a decreased risk of GC, as well as EC and GC combined, especially in smokers.	('GC', 'Phenotype', 'HP:0012126', (144, 146))	('flavonols', 'Chemical', 'MESH:D044948', (80, 89))	('decreased', 'NegReg', (104, 113))	('GC', 'Phenotype', 'HP:0012126', (122, 124))	('dietary', 'Var', (72, 79))
282443	26675063	The first method corrects transient effects on the plan image by deforming the exhale phase to all phases of the planning image and then computing an axial-Jacobian-averaged from all the phase deformations, which yields the "plan normalization correction factor":  The mean axial-averaged Jacobian from the exhale phase to the planning phase deformations is the plan normalization correction factor, denoted Phi.	('deforming', 'Var', (65, 74))	('Phi', 'Gene', '2821', (408, 411))	('Phi', 'Gene', (408, 411))
282458	26675063	For most metrics, a gap was evident between the highest value for grade0 and the lowest value for grade3 esophagitis.	('esophagitis', 'Disease', (105, 116))	('grade0', 'Var', (66, 72))	('esophagitis', 'Disease', 'MESH:D004941', (105, 116))	('esophagitis', 'Phenotype', 'HP:0100633', (105, 116))
282461	26675063	While area under the curve (AUC) values from ROC analysis indicated metric performance varied slightly around the binary cutoff for grade2 or grade3, all MaxExp, PerExp95, LenExp30%, and LenExp40% metrics performed strong with AUC>0.88 for both esophagitis endpoints, indicating these metrics' ability to classify esophagitis (Table 1).	('LenExp40%', 'Var', (187, 196))	('LenExp30%', 'Var', (172, 181))	('grade3', 'Var', (142, 148))	('esophagitis', 'Disease', 'MESH:D004941', (314, 325))	('esophagitis', 'Disease', (245, 256))	('esophagitis', 'Phenotype', 'HP:0100633', (314, 325))	('esophagitis', 'Phenotype', 'HP:0100633', (245, 256))	('esophagitis', 'Disease', (314, 325))	('grade2', 'Var', (132, 138))	('esophagitis', 'Disease', 'MESH:D004941', (245, 256))
282480	26675063	Whether expansion precedes grade3 symptoms is not currently discernible as expansion and esophagitis scores are quantified weekly.	('esophagitis', 'Phenotype', 'HP:0100633', (89, 100))	('esophagitis', 'Disease', (89, 100))	('esophagitis', 'Disease', 'MESH:D004941', (89, 100))	('grade3 symptoms', 'Disease', (27, 42))	('expansion', 'Var', (8, 17))
282484	26675063	Although dose-response may be considered a paradigm of radiation therapy, the goal of the current work was to show that esophageal expansion can quantify esophagitis, and dose was not a focus in our study.	('esophagitis', 'Disease', 'MESH:D004941', (154, 165))	('esophagitis', 'Phenotype', 'HP:0100633', (154, 165))	('esophagitis', 'Disease', (154, 165))	('esophageal', 'Var', (120, 130))
282633	25048826	showed that matrix mechanical properties might regulate DKK1 expression in epithelial ovarian cancer cells in vitro and that siRNA silencing of DKK1 expression significantly enhanced invasion.	('enhanced', 'PosReg', (174, 182))	('silencing', 'Var', (131, 140))	('regulate', 'Reg', (47, 55))	('DKK1', 'Gene', (144, 148))	('epithelial ovarian cancer', 'Disease', (75, 100))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (75, 100))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (75, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('DKK1', 'Gene', (56, 60))	('invasion', 'CPA', (183, 191))	('expression', 'MPA', (61, 71))
282634	25048826	showed that Wnt-pathway inactivation in glioma via Dkk1 resulted in a higher vascular density and disrupted barrier function.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('barrier function', 'CPA', (108, 124))	('disrupted', 'NegReg', (98, 107))	('Dkk1', 'Gene', '22943', (51, 55))	('inactivation', 'Var', (24, 36))	('vascular density', 'CPA', (77, 93))	('Dkk1', 'Gene', (51, 55))	('glioma', 'Disease', (40, 46))	('higher', 'PosReg', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
282639	25048826	Because DKK1 can inhibit the WNT/beta-catenin pathway whereas its own expression is induced by the beta-catenin/TCF complex, DKK1 imposes a negative force-feedback loop on itself and can suppress expression of beta-catenin target molecules such as CCND1.	('DKK1', 'Gene', (8, 12))	('negative force-feedback loop', 'MPA', (140, 168))	('CCND1', 'Gene', '595', (248, 253))	('beta-catenin', 'Gene', '1499', (99, 111))	('suppress', 'NegReg', (187, 195))	('beta-catenin', 'Gene', '1499', (210, 222))	('expression', 'MPA', (196, 206))	('CCND1', 'Gene', (248, 253))	('inhibit', 'NegReg', (17, 24))	('beta-catenin', 'Gene', (99, 111))	('beta-catenin', 'Gene', (33, 45))	('beta-catenin', 'Gene', '1499', (33, 45))	('DKK1', 'Var', (125, 129))	('TCF', 'Gene', (112, 115))	('TCF', 'Gene', '3172', (112, 115))	('beta-catenin', 'Gene', (210, 222))
282640	25048826	In breast cancer and colon cancer cells it has been found that inhibition of beta-catenin might enhance invasive potential via upregulation of uPA/uPAR at mRNA and protein level.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('uPA', 'Gene', (143, 146))	('upregulation', 'PosReg', (127, 139))	('uPA', 'Gene', '5328', (143, 146))	('colon cancer', 'Disease', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('uPAR', 'Gene', (147, 151))	('colon cancer', 'Phenotype', 'HP:0003003', (21, 33))	('invasive potential', 'CPA', (104, 122))	('uPA', 'Gene', (147, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('uPA', 'Gene', '5328', (147, 150))	('inhibition', 'Var', (63, 73))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', '1499', (77, 89))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('enhance', 'PosReg', (96, 103))	('breast cancer', 'Disease', (3, 16))	('colon cancer', 'Disease', 'MESH:D015179', (21, 33))	('uPAR', 'Gene', '5329', (147, 151))
282644	25048826	On diagnostic level DKK1 is reported as good serologic and prognostic biomarker for patients suffering from lung and esophageal carcinoma, as well as for patients with cervical cancer.	('patients', 'Species', '9606', (84, 92))	('lung', 'Disease', (108, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal carcinoma', 'Disease', (117, 137))	('patients', 'Species', '9606', (154, 162))	('cervical cancer', 'Disease', 'MESH:D002583', (168, 183))	('DKK1', 'Var', (20, 24))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (117, 137))	('cervical cancer', 'Disease', (168, 183))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (117, 137))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
282747	22194748	Acid contact on the mucosa in the distal esophagus (near the gastroesophageal junction) during the waking state induces increased salivary flow and swallowing mechanisms (primary peristalsis), and localized esophageal peristalsis (secondary peristalsis) to buffer the acid and facilitate volumetric clearance.	('gastroesophageal junction', 'Disease', (61, 86))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (61, 86))	('localized esophageal peristalsis', 'CPA', (197, 229))	('Acid contact', 'Var', (0, 12))	('volumetric clearance', 'CPA', (288, 308))	('buffer', 'MPA', (257, 263))	('acid', 'MPA', (268, 272))	('facilitate', 'PosReg', (277, 287))	('salivary flow', 'MPA', (130, 143))	('increased', 'PosReg', (120, 129))	('swallowing', 'CPA', (148, 158))
282749	22194748	An experimental study on healthy individuals has shown that acid infusion into the esophagus during sleep resulted in a brief period of arousal with a swallowing reflex, which was also believed to promote saliva flow.	('swallowing reflex', 'MPA', (151, 168))	('saliva flow', 'MPA', (205, 216))	('men', 'Species', '9606', (9, 12))	('swallowing reflex', 'Phenotype', 'HP:0002015', (151, 168))	('arousal', 'MPA', (136, 143))	('promote', 'PosReg', (197, 204))	('acid infusion', 'Var', (60, 73))
282835	22194748	In this double-blinded study, there was significantly less enamel thickness lost in the 14 available adult subjects taking esomeprazole (mean = 7.20 mum) than in the 15 adult subjects taking a placebo (mean = 15.25 mum).	('esomeprazole', 'Var', (123, 135))	('less', 'NegReg', (54, 58))	('esomeprazole', 'Chemical', 'MESH:D064098', (123, 135))	('lost', 'NegReg', (76, 80))	('enamel thickness', 'CPA', (59, 75))	('less enamel thickness', 'Phenotype', 'HP:0006297', (54, 75))
282903	21547702	Patients with high preoperative NLR had significantly worse disease-free and overall survival compared with those with low NLR (DFS, P = 0.0002; OS, P < 0.0001) (Fig.	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'CPA', (77, 93))	('NLR', 'Gene', (32, 35))	('worse', 'NegReg', (54, 59))
282908	21547702	In multivariable analyses stratified by receipt of neoadjuvant therapy, high NLR was associated with significantly increased risk of disease recurrence among patients who received neoadjuvant treatment (HR 2.83, 95% CI 1.52-5.25), but not among those who did not receive neoadjuvant therapy (HR 1.44, 95% CI 0.65- 3.16).	('patients', 'Species', '9606', (158, 166))	('disease recurrence', 'CPA', (133, 151))	('NLR', 'Gene', (77, 80))	('high', 'Var', (72, 76))
282911	21547702	For adenocarcinoma, high NLR was associated with significantly increased risk of disease recurrence (HR 2.47, 95% CI 1.44-4.28; P = 0.001) and overall survival (HR 2.29, 95% CI 1.41-3.73; P = 0.001).	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('adenocarcinoma', 'Disease', (4, 18))	('overall survival', 'CPA', (143, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))	('high NLR', 'Var', (20, 28))	('disease recurrence', 'CPA', (81, 99))
282912	21547702	For squamous cell carcinoma, NLR was independently associated with increased risk of overall survival (HR 3.66, 95% CI 1.32-10.10; P = 0.01), and a nonsignificant increased risk of DFS (HR 2.35, 95% CI 0.83-6.64; P = 0.12).	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (4, 27))	('squamous cell carcinoma', 'Disease', (4, 27))	('DFS', 'Disease', (181, 184))	('increased', 'PosReg', (67, 76))	('NLR', 'Var', (29, 32))	('overall survival', 'CPA', (85, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (4, 27))
282969	31559513	Statement: POEM may induce GERD, but incidence depends on measurement.	('induce', 'Reg', (20, 26))	('POEM', 'Var', (11, 15))	('GERD', 'Disease', (27, 31))	('GERD', 'Disease', 'MESH:D005764', (27, 31))
282997	31559513	Statement: excessive gastric myotomy and incision of the collar sling fibers may increase the frequency of GERD after POEM.	('incision', 'Var', (41, 49))	('gastric myotomy', 'Disease', (21, 36))	('GERD', 'Disease', 'MESH:D005764', (107, 111))	('GERD', 'Disease', (107, 111))	('increase', 'PosReg', (81, 89))	('gastric myotomy', 'Disease', 'MESH:D013274', (21, 36))
283006	31559513	Moreover, according to a single-center report by Fukuoka University, incision of the sling fibers (oblique muscle) at the gastric cardia may be the cause of significant GERD, leading to erosive esophagitis above Grade C (Unpublished data.	('gastric cardia', 'Disease', 'MESH:D004938', (122, 136))	('esophagitis', 'Phenotype', 'HP:0100633', (194, 205))	('leading to', 'Reg', (175, 185))	('gastric cardia', 'Disease', (122, 136))	('incision', 'Var', (69, 77))	('F', 'Chemical', 'MESH:D005461', (49, 50))	('GERD', 'Disease', (169, 173))	('esophagitis', 'Disease', (194, 205))	('GERD', 'Disease', 'MESH:D005764', (169, 173))	('esophagitis', 'Disease', 'MESH:D004941', (194, 205))
283020	31559513	Antireflux surgery achieves control of gastroesophageal reflux through correction of local anatomical defects, including the damaged antireflux mechanisms such as the defective lower esophageal sphincter, oblique muscle and phrenoesophageal ligament.	('defective', 'Var', (167, 176))	('antireflux mechanisms', 'MPA', (133, 154))	('esophageal sphincter', 'Disease', (183, 203))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (39, 62))	('gastroesophageal reflux', 'Disease', (39, 62))	('esophageal sphincter', 'Disease', 'MESH:D046628', (183, 203))
283080	31571402	Given that body composition alterations could be associated with early mortality, we performed sensitivity analyses to evaluate the possibility of reversed causality.	('alterations', 'Var', (28, 39))	('associated', 'Reg', (49, 59))	('mortality', 'Disease', 'MESH:D003643', (71, 80))	('mortality', 'Disease', (71, 80))
283089	31571402	Among patients with myosteatosis, characteristics were similar between systemic inflammation-categorized subgroups, except that patients with NLR < 2.8 tended to be ECOG 0, while patients with NLR > 2.8 tended to be ECOG 1 (P = .001; Table S3).	('inflammation', 'Disease', 'MESH:D007249', (80, 92))	('NLR', 'Var', (142, 145))	('inflammation', 'Disease', (80, 92))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (128, 136))	('myosteatosis', 'Disease', (20, 32))	('myosteatosis', 'Disease', 'None', (20, 32))
283114	31571402	Otherwise, we did not observe that a low muscle index, analyzed as a continuous variable, was associated with poor prognosis in contrast to the previous report of Jarvinen et al.50  Strengths of our study comprise its large sample of subjects submitted to dCRT in a tertiary hospital.	('muscle index', 'MPA', (41, 53))	('dCRT', 'Gene', (256, 260))	('dCRT', 'Gene', '45841', (256, 260))	('low', 'Var', (37, 40))
283138	30799355	We diagnosed the patient with SCC, cT1bN0M0 according to the Union for International Cancer Control tumor/node/metastases classification for esophageal carcinoma and recommended surgical resection.	('SCC', 'Gene', '6317', (30, 33))	('metastases', 'Disease', (111, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (141, 161))	('tumor', 'Disease', (100, 105))	('patient', 'Species', '9606', (17, 24))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('esophageal carcinoma', 'Disease', (141, 161))	('SCC', 'Gene', (30, 33))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (141, 161))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cT1bN0M0', 'Var', (35, 43))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))
251812	30324431	We extracted the data for patients diagnosed with thoracic esophageal cancer (C151, C153-155) and treated surgically at a registered hospital for thoracic esophageal cancer, and for patients diagnosed at another hospital but treated surgically at a registered hospital for thoracic esophageal cancer.	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (273, 299))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('thoracic esophageal cancer', 'Disease', (50, 76))	('C153-155', 'Var', (84, 92))	('thoracic esophageal cancer', 'Disease', (273, 299))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (146, 172))	('patients', 'Species', '9606', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('patients', 'Species', '9606', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('thoracic esophageal cancer', 'Disease', (146, 172))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (50, 76))
283255	30889805	We found that Gyp-L increased the SA-beta-galactosidase activity, promoted the production of senescence-associated secretory cytokines, and inhibited cell proliferation of human liver and esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (188, 205))	('SA-beta', 'Gene', (34, 41))	('increased', 'PosReg', (20, 29))	('beta-galactosidase', 'Gene', '2720', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('SA-beta', 'Gene', '9467', (34, 41))	('activity', 'MPA', (56, 64))	('beta-galactosidase', 'Gene', (37, 55))	('inhibited', 'NegReg', (140, 149))	('human', 'Species', '9606', (172, 177))	('Gyp-L', 'Chemical', '-', (14, 19))	('esophageal cancer', 'Disease', (188, 205))	('promoted', 'PosReg', (66, 74))	('Gyp-L', 'Var', (14, 19))
283256	30889805	Moreover, Gyp-L caused cell cycle arrest at S phase, and activated senescence-related cell cycle inhibitor proteins (p21 and p27) and their upstream regulators.	('activated', 'PosReg', (57, 66))	('p21', 'Gene', (117, 120))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (23, 40))	('p21', 'Gene', '644914', (117, 120))	('cell cycle arrest at S phase', 'CPA', (23, 51))	('p27', 'Gene', '3429', (125, 128))	('Gyp-L', 'Chemical', '-', (10, 15))	('p27', 'Gene', (125, 128))	('Gyp-L', 'Var', (10, 15))
283257	30889805	In addition, Gyp-L activated p38 and ERK MAPK pathways and NF-kappaB pathway to induce senescence.	('senescence', 'CPA', (87, 97))	('p38', 'Gene', '1432', (29, 32))	('activated', 'PosReg', (19, 28))	('NF-kappaB', 'Gene', '4790', (59, 68))	('ERK', 'Gene', '5594', (37, 40))	('ERK', 'Gene', (37, 40))	('p38', 'Gene', (29, 32))	('Gyp-L', 'Chemical', '-', (13, 18))	('NF-kappaB', 'Gene', (59, 68))	('induce', 'PosReg', (80, 86))	('Gyp-L', 'Var', (13, 18))
283259	30889805	Furthermore, treatment with Gyp-L, enhanced the cytotoxicity of clinic therapeutic drugs, including 5-fluorouracil and cisplatin, on cancer cells.	('5-fluorouracil', 'Chemical', 'MESH:D005472', (100, 114))	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('enhanced', 'PosReg', (35, 43))	('cancer', 'Disease', (133, 139))	('cytotoxicity', 'Disease', (48, 60))	('Gyp-L', 'Chemical', '-', (28, 33))	('5-fluorouracil', 'MPA', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Gyp-L', 'Var', (28, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
283260	30889805	Overall, these results indicate that Gyp-L inhibits proliferation of cancer cells by inducing senescence and renders cancer cells more sensitive to chemotherapy.	('renders', 'Reg', (109, 116))	('proliferation', 'CPA', (52, 65))	('senescence', 'CPA', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('inducing', 'Reg', (85, 93))	('more', 'PosReg', (130, 134))	('Gyp-L', 'Chemical', '-', (37, 42))	('Gyp-L', 'Var', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (117, 123))	('inhibits', 'NegReg', (43, 51))	('sensitive', 'MPA', (135, 144))	('cancer', 'Disease', (69, 75))
283276	30889805	In the present study, we further revealed that Gyp-L induces senescence to inhibit the growth of human liver and esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('inhibit', 'NegReg', (75, 82))	('human', 'Species', '9606', (97, 102))	('Gyp-L', 'Chemical', '-', (47, 52))	('growth', 'CPA', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Gyp-L', 'Var', (47, 52))	('esophageal cancer', 'Disease', (113, 130))	('senescence', 'MPA', (61, 71))	('induces', 'Reg', (53, 60))
283281	30889805	As shown in Figure 1B, the proportion of EdU-positive cells was higher in the control group, which was remarkably reduced in a concentration-dependent manner in the presence of Gyp-L, indicating that Gyp-L inhibited the proliferative activity of cancer cells.	('Gyp-L', 'Chemical', '-', (200, 205))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('Gyp-L', 'Var', (200, 205))	('cancer', 'Disease', (246, 252))	('Gyp-L', 'Chemical', '-', (177, 182))	('EdU', 'Chemical', 'MESH:C031086', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('inhibited', 'NegReg', (206, 215))
283283	30889805	As expected, the mRNA expression levels of all cytokines were increased by Gyp-L.	('mRNA expression levels of all cytokines', 'MPA', (17, 56))	('Gyp-L', 'Chemical', '-', (75, 80))	('increased', 'PosReg', (62, 71))	('Gyp-L', 'Var', (75, 80))
283284	30889805	Together, these results indicate that Gyp-L induces senescence in human cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('human', 'Species', '9606', (66, 71))	('senescence', 'MPA', (52, 62))	('Gyp-L', 'Chemical', '-', (38, 43))	('Gyp-L', 'Var', (38, 43))	('induces', 'Reg', (44, 51))	('cancer', 'Disease', (72, 78))
283288	30889805	Gyp-L significantly reduced the expression of all cell cycle regulators, such as CDK2, CDK4, CDK6, and cyclin D1, which was consistent with the arrested cell cycle (Figure 2B).	('CDK2', 'Gene', (81, 85))	('reduced', 'NegReg', (20, 27))	('CDK2', 'Gene', '1017', (81, 85))	('Gyp-L', 'Chemical', '-', (0, 5))	('Gyp-L', 'Var', (0, 5))	('CDK6', 'Gene', (93, 97))	('cyclin D1', 'Gene', '595', (103, 112))	('CDK6', 'Gene', '1021', (93, 97))	('expression', 'MPA', (32, 42))	('CDK4', 'Gene', '1019', (87, 91))	('CDK4', 'Gene', (87, 91))	('cyclin D1', 'Gene', (103, 112))
283291	30889805	We found that several CKIs, including p21, p18, and p27 were largely upregulated by Gyp-L (Figure 2C).	('Gyp-L', 'Chemical', '-', (84, 89))	('p21', 'Gene', (38, 41))	('Gyp-L', 'Var', (84, 89))	('p21', 'Gene', '644914', (38, 41))	('p18', 'Gene', '100689229', (43, 46))	('p27', 'Gene', '3429', (52, 55))	('upregulated', 'PosReg', (69, 80))	('p27', 'Gene', (52, 55))	('p18', 'Gene', (43, 46))	('CKIs', 'CPA', (22, 26))
283292	30889805	Besides, we showed that Gyp-L activated cell check kinase CHK2, instead of CHK1, to inhibit cell cycle kinases and cause cell cycle arrest.	('CHK2', 'Gene', '11200', (58, 62))	('CHK1', 'Gene', (75, 79))	('inhibit', 'NegReg', (84, 91))	('cell cycle arrest', 'CPA', (121, 138))	('CHK1', 'Gene', '1111', (75, 79))	('Gyp-L', 'Chemical', '-', (24, 29))	('CHK2', 'Gene', (58, 62))	('cause', 'Reg', (115, 120))	('cell cycle kinases', 'MPA', (92, 110))	('Gyp-L', 'Var', (24, 29))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))
283297	30889805	Firstly, we found that Gyp-L activated MAPK signals, mainly through p38 and ERK signaling pathways, in a dose-dependent manner in esophageal cancer (Figure 3A).	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('activated', 'PosReg', (29, 38))	('ERK', 'Gene', (76, 79))	('ERK', 'Gene', '5594', (76, 79))	('Gyp-L', 'Chemical', '-', (23, 28))	('Gyp-L', 'Var', (23, 28))	('p38', 'Gene', '1432', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('MAPK', 'Pathway', (39, 43))	('p38', 'Gene', (68, 71))	('esophageal cancer', 'Disease', (130, 147))
283299	30889805	SA-beta-gal staining and EdU staining assay clearly demonstrated that single administration of SB203580 or PD98059 had no effect on SA-beta-gal activity and cell proliferation.	('SA-beta', 'Gene', (0, 7))	('SB203580', 'Chemical', 'MESH:C093642', (95, 103))	('SA-beta', 'Gene', '9467', (0, 7))	('beta-gal', 'Chemical', '-', (3, 11))	('cell proliferation', 'CPA', (157, 175))	('SA-beta', 'Gene', (132, 139))	('PD98059', 'Chemical', 'MESH:C093973', (107, 114))	('SA-beta', 'Gene', '9467', (132, 139))	('EdU', 'Chemical', 'MESH:C031086', (25, 28))	('PD98059', 'Var', (107, 114))	('beta-gal', 'Chemical', '-', (135, 143))	('activity', 'MPA', (144, 152))	('SB203580', 'Var', (95, 103))
283300	30889805	However, combinatory treatment with Gyp-L and SB203580 or PD98059 significantly recovered Gyp-L-induced cellular senescence, and cell proliferation, respectively (Figure 3C,D).	('cell proliferation', 'CPA', (129, 147))	('PD98059', 'Var', (58, 65))	('Gyp-L', 'Chemical', '-', (90, 95))	('recovered', 'PosReg', (80, 89))	('PD98059', 'Chemical', 'MESH:C093973', (58, 65))	('Gyp-L-induced', 'MPA', (90, 103))	('Gyp-L', 'Chemical', '-', (36, 41))	('SB203580', 'Chemical', 'MESH:C093642', (46, 54))	('SB203580', 'Var', (46, 54))
283303	30889805	As shown in Figure 4A,B, Gyp-L also activated p38 and ERK in a dose-dependent manner in HepG2 cells.	('Gyp-L', 'Var', (25, 30))	('ERK', 'Gene', '5594', (54, 57))	('p38', 'Gene', (46, 49))	('activated', 'PosReg', (36, 45))	('HepG2', 'CellLine', 'CVCL:0027', (88, 93))	('ERK', 'Gene', (54, 57))	('Gyp-L', 'Chemical', '-', (25, 30))	('p38', 'Gene', '1432', (46, 49))
283304	30889805	Consistently, their inhibition by SB203580 and PD98059 resumed the cell proliferation, impaired by Gyp-L.	('PD98059', 'Var', (47, 54))	('SB203580', 'Var', (34, 42))	('PD98059', 'Chemical', 'MESH:C093973', (47, 54))	('SB203580', 'Chemical', 'MESH:C093642', (34, 42))	('Gyp-L', 'Chemical', '-', (99, 104))	('inhibition', 'NegReg', (20, 30))	('resumed', 'PosReg', (55, 62))	('cell proliferation', 'CPA', (67, 85))
283305	30889805	In addition, treatment of SB203580 or PD98059 alone did not affect cellular senescence, whereas combinatory treatment of SB203580 and PD98059 reduced the ratio of SA-beta-gal-positive cells, and increased the ratio of Edu-positive cells, respectively (Figure 4C,D).	('Edu-positive cells', 'MPA', (218, 236))	('PD98059', 'Chemical', 'MESH:C093973', (134, 141))	('reduced', 'NegReg', (142, 149))	('SA-beta', 'Gene', (163, 170))	('SB203580', 'Chemical', 'MESH:C093642', (26, 34))	('SA-beta', 'Gene', '9467', (163, 170))	('beta-gal', 'Chemical', '-', (166, 174))	('SB203580', 'Var', (121, 129))	('SB203580', 'Chemical', 'MESH:C093642', (121, 129))	('PD98059', 'Chemical', 'MESH:C093973', (38, 45))	('increased', 'PosReg', (195, 204))	('PD98059', 'Var', (134, 141))
283306	30889805	Finally, the protein levels of p21, p18, and p27 were largely reduced in the simultaneous presence of Gyp-L and inhibitors in HepG2 cells (Figure 4E).	('p21', 'Gene', (31, 34))	('p18', 'Gene', '100689229', (36, 39))	('p27', 'Gene', '3429', (45, 48))	('p27', 'Gene', (45, 48))	('p18', 'Gene', (36, 39))	('HepG2', 'CellLine', 'CVCL:0027', (126, 131))	('p21', 'Gene', '644914', (31, 34))	('Gyp-L', 'Chemical', '-', (102, 107))	('Gyp-L', 'Var', (102, 107))	('protein levels', 'MPA', (13, 27))	('reduced', 'NegReg', (62, 69))
283309	30889805	To explore its potential regulation in Gyp-L-induced senescence, a western blotting experiment was performed, which showed that the phosphorylation and activation of NF-kappaB was markedly up-regulated by Gyp-L in ECA-109 cells (Figure 5A).	('up-regulated', 'PosReg', (189, 201))	('Gyp-L', 'Chemical', '-', (39, 44))	('Gyp-L', 'Chemical', '-', (205, 210))	('Gyp-L', 'Var', (205, 210))	('activation', 'MPA', (152, 162))	('phosphorylation', 'MPA', (132, 147))	('NF-kappaB', 'Gene', (166, 175))	('NF-kappaB', 'Gene', '4790', (166, 175))
283310	30889805	Treatment with NF-kappaB inhibitor Bay11-7082 significantly decreased the inhibitory effect of Gyp-L on cancer cell growth (Figure 5B), as well as the percentage of SA-beta-gal positive cell population (Figure 5D).	('Bay11-7082', 'Var', (35, 45))	('NF-kappaB', 'Gene', (15, 24))	('SA-beta', 'Gene', (165, 172))	('decreased', 'NegReg', (60, 69))	('SA-beta', 'Gene', '9467', (165, 172))	('NF-kappaB', 'Gene', '4790', (15, 24))	('beta-gal', 'Chemical', '-', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('inhibitory effect', 'MPA', (74, 91))	('Gyp-L', 'Chemical', '-', (95, 100))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('Bay11-7082', 'Chemical', 'MESH:C434003', (35, 45))
283311	30889805	Consistent with the SA-beta-gal staining, EdU staining of the combinatory treatment of Gyp-L and Bay11-7082 exhibited a remarkable increment of the percentage of proliferating cells (Figure 5D), while single treatment with Bay had no effect.	('SA-beta', 'Gene', (20, 27))	('SA-beta', 'Gene', '9467', (20, 27))	('Bay11-7082', 'Chemical', 'MESH:C434003', (97, 107))	('Gyp-L', 'Gene', (87, 92))	('Bay11-7082', 'Var', (97, 107))	('increment', 'PosReg', (131, 140))	('EdU', 'Chemical', 'MESH:C031086', (42, 45))	('beta-gal', 'Chemical', '-', (23, 31))	('Gyp-L', 'Chemical', '-', (87, 92))
283312	30889805	Finally, the majority of cell cycle regulators, such as p21, p27, and p18, were critically reduced by Bay11-7082 (Figure 5C).	('p27', 'Gene', (61, 64))	('p18', 'Gene', '100689229', (70, 73))	('p21', 'Gene', (56, 59))	('p18', 'Gene', (70, 73))	('cell', 'MPA', (25, 29))	('reduced', 'NegReg', (91, 98))	('p21', 'Gene', '644914', (56, 59))	('Bay11-7082', 'Chemical', 'MESH:C434003', (102, 112))	('Bay11-7082', 'Var', (102, 112))	('p27', 'Gene', '3429', (61, 64))
283315	30889805	Similar to esophageal cancer, Gyp-L activated NF-kappaB in a concentration-dependent manner (Figure 6A).	('NF-kappaB', 'Gene', (46, 55))	('esophageal cancer', 'Disease', (11, 28))	('activated', 'PosReg', (36, 45))	('Gyp-L', 'Chemical', '-', (30, 35))	('esophageal cancer', 'Disease', 'MESH:D004938', (11, 28))	('Gyp-L', 'Var', (30, 35))	('NF-kappaB', 'Gene', '4790', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
283316	30889805	The combination treatment of Gyp-L and Bay11-7082 significantly decreased the percentage of SA-beta-gal positive cells and the expression of cell cycle regulators (Figure 6B,C).	('Gyp-L', 'Chemical', '-', (29, 34))	('expression', 'MPA', (127, 137))	('Bay11-7082', 'Var', (39, 49))	('Bay11-7082', 'Chemical', 'MESH:C434003', (39, 49))	('SA-beta', 'Gene', '9467', (92, 99))	('beta-gal', 'Chemical', '-', (95, 103))	('SA-beta', 'Gene', (92, 99))	('decreased', 'NegReg', (64, 73))
283317	30889805	Bay11-7082 also increased the EdU-positive cells (Figure 6C).	('EdU-positive cells', 'CPA', (30, 48))	('EdU', 'Chemical', 'MESH:C031086', (30, 33))	('increased', 'PosReg', (16, 25))	('Bay11-7082', 'Chemical', 'MESH:C434003', (0, 10))	('Bay11-7082', 'Var', (0, 10))
283318	30889805	Therefore, NF-kappaB signal participated in cellular senescence, caused by Gyp-L. To verify whether the combined usage of Gyp-L and the first-line clinical medication, such as cisplatin (CDDP) or 5-fluorouracil (5-Fu), exerted a superior cytotoxic effect on liver and esophageal cancer cells, we treated HepG2 and ECA-109 cells, with cisplatin (10 muM) or 5-fluorouracil (30 muM), for 48 h in the presence or absence of Gyp-L. CCK8 assay revealed that Gyp-L rendered cancer cells more sensitive toward CDDP and 5-Fu (Figure 7A,B).	('more', 'PosReg', (480, 484))	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('esophageal cancer', 'Disease', (268, 285))	('muM', 'Gene', '56925', (375, 378))	('NF-kappaB', 'Gene', '4790', (11, 20))	('Gyp-L', 'Chemical', '-', (122, 127))	('Gyp-L', 'Chemical', '-', (75, 80))	('muM', 'Gene', (375, 378))	('cancer', 'Disease', (279, 285))	('5-Fu', 'Chemical', 'MESH:D005472', (511, 515))	('cisplatin', 'Chemical', 'MESH:D002945', (334, 343))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('cancer', 'Disease', (467, 473))	('cancer', 'Phenotype', 'HP:0002664', (467, 473))	('Gyp-L', 'Chemical', '-', (420, 425))	('muM', 'Gene', '56925', (348, 351))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (356, 370))	('Gyp-L', 'Chemical', '-', (452, 457))	('Gyp-L', 'Var', (452, 457))	('muM', 'Gene', (348, 351))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('5-Fu', 'Chemical', 'MESH:D005472', (212, 216))	('HepG2', 'CellLine', 'CVCL:0027', (304, 309))	('cancer', 'Disease', 'MESH:D009369', (467, 473))	('esophageal cancer', 'Disease', 'MESH:D004938', (268, 285))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (196, 210))	('NF-kappaB', 'Gene', (11, 20))
283326	30889805	Gyp-L increased SA-beta-gal activity, caused cell cycle arrest at S phase and promoted the secretion of SASP.	('increased', 'PosReg', (6, 15))	('SASP', 'Gene', (104, 108))	('SASP', 'Gene', '7295', (104, 108))	('activity', 'MPA', (28, 36))	('SA-beta', 'Gene', (16, 23))	('promoted', 'PosReg', (78, 86))	('SA-beta', 'Gene', '9467', (16, 23))	('Gyp-L', 'Chemical', '-', (0, 5))	('Gyp-L', 'Var', (0, 5))	('beta-gal', 'Chemical', '-', (19, 27))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (45, 62))	('cell cycle arrest at S phase', 'CPA', (45, 73))
283328	30889805	Moreover, we demonstrated that Gyp-L induced cellular senescence via the activation of MAPK and NF-kappaB pathways.	('Gyp-L', 'Var', (31, 36))	('NF-kappaB', 'Gene', '4790', (96, 105))	('cellular senescence', 'CPA', (45, 64))	('NF-kappaB', 'Gene', (96, 105))	('Gyp-L', 'Chemical', '-', (31, 36))
283331	30889805	Indeed, our previous works also clearly demonstrated that Gyp-L was able to trigger ROS.	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('Gyp-L', 'Chemical', '-', (58, 63))	('Gyp-L', 'Var', (58, 63))	('ROS', 'MPA', (84, 87))
283334	30889805	Furthermore, we showed that Gyp-L enhanced the cytotoxicity of chemotherapeutic agent cisplatin and 5-Fu.	('5-Fu', 'Chemical', 'MESH:D005472', (100, 104))	('enhanced', 'PosReg', (34, 42))	('cytotoxicity', 'Disease', (47, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('Gyp-L', 'Chemical', '-', (28, 33))	('cytotoxicity', 'Disease', 'MESH:D064420', (47, 59))	('Gyp-L', 'Var', (28, 33))
283337	30889805	Considering that Gyp-L possessed the ability to inhibit autophagy, it is reasonable to infer that Gyp-L might render cancer cells more sensitive to cisplatin and 5-Fu by impairing the essential function of autophagy.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('autophagy', 'CPA', (206, 215))	('autophagy', 'CPA', (56, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('impairing', 'NegReg', (170, 179))	('more', 'PosReg', (130, 134))	('essential function', 'CPA', (184, 202))	('Gyp-L', 'Chemical', '-', (98, 103))	('5-Fu', 'Chemical', 'MESH:D005472', (162, 166))	('Gyp-L', 'Var', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Gyp-L', 'Chemical', '-', (17, 22))	('cancer', 'Disease', (117, 123))	('inhibit', 'NegReg', (48, 55))
283338	30889805	In our current works, we provided another possibility that Gyp-L activated senescence, especially long-term cell cycle arrest, to enhance the cytotoxicity of 5-Fu and cisplatin.	('5-Fu', 'Chemical', 'MESH:D005472', (158, 162))	('cytotoxicity', 'Disease', 'MESH:D064420', (142, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (108, 125))	('cytotoxicity', 'Disease', (142, 154))	('senescence', 'CPA', (75, 85))	('cell cycle arrest', 'CPA', (108, 125))	('Gyp-L', 'Chemical', '-', (59, 64))	('enhance', 'PosReg', (130, 137))	('Gyp-L', 'Var', (59, 64))
283344	30889805	Chemical inhibitors SB203580 (S1076), PD98059 (S1177), Bay11-7082 (S2913) were from Selleck (Shanghai, China).	('Bay11-7082', 'Chemical', 'MESH:C434003', (55, 65))	('PD98059', 'Chemical', 'MESH:C093973', (38, 45))	('S2913', 'Var', (67, 72))	('S1076', 'Var', (30, 35))	('SB203580', 'Chemical', 'MESH:C093642', (20, 28))	('PD98059 (S1177', 'Var', (38, 52))	('S1177', 'Var', (47, 52))	('S2913', 'CellLine', 'CVCL:9L55', (67, 72))
283345	30889805	Chemotherapeutic agents 5-Fu (S1209) and cisplatin (s1166) were from Selleck.	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('5-Fu', 'Chemical', 'MESH:D005472', (24, 28))	('S1209', 'Var', (30, 35))	('s1166', 'Var', (52, 57))
283352	30889805	The detection of SA-beta-gal Activity at pH 6.0 was performed according to the manufacturer's instructions (C0602, Beyotime, Shanghai, China).	('SA-beta', 'Gene', (17, 24))	('C0602', 'Var', (108, 113))	('SA-beta', 'Gene', '9467', (17, 24))	('beta-gal', 'Chemical', '-', (20, 28))
283364	30889805	In summary, the present study demonstrated that Gyp-L induces cellular senescence in human hepatocarcinoma and esophageal cancer cells, which may correlate with the activation of MAPK and NF-kappaB pathways.	('NF-kappaB', 'Gene', '4790', (188, 197))	('hepatocarcinoma', 'Disease', (91, 106))	('hepatocarcinoma', 'Disease', 'None', (91, 106))	('esophageal cancer', 'Disease', (111, 128))	('NF-kappaB', 'Gene', (188, 197))	('cellular senescence', 'MPA', (62, 81))	('human', 'Species', '9606', (85, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('Gyp-L', 'Chemical', '-', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('activation', 'PosReg', (165, 175))	('Gyp-L', 'Var', (48, 53))
283367	19657639	A phase I dose escalation study of a pharmacobiologically based scheduling of capecitabine and mitomycin C in patients with gastrointestinal malignancies Mitomycin C (MMC) produces significant upregulation of thymidine phosphorylase, a principal determinant of the therapeutic index of capecitabine-based treatment, starting 4-6 days after treatment.	('mitomycin C', 'Chemical', 'MESH:D016685', (95, 106))	('thymidine phosphorylase', 'Gene', '1890', (209, 232))	('upregulation', 'PosReg', (193, 205))	('MMC', 'Chemical', 'MESH:D016685', (167, 170))	('Mitomycin', 'Var', (154, 163))	('men', 'Species', '9606', (310, 313))	('capecitabine', 'Chemical', 'MESH:D000069287', (286, 298))	('men', 'Species', '9606', (345, 348))	('Mitomycin C', 'Chemical', 'MESH:D016685', (154, 165))	('thymidine phosphorylase', 'Gene', (209, 232))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (124, 153))	('gastrointestinal malignancies', 'Disease', (124, 153))	('capecitabine', 'Chemical', 'MESH:D000069287', (78, 90))	('patients', 'Species', '9606', (110, 118))
283394	19657639	Indeed, transfection of the TP gene into the DLD-1 human colon cancer cell line, which is TP-deficient and highly resistant to 5'-deoxyfluorouracil (5'-DFUR), has been shown to increase TP activity by 1,068-fold and sensitivity to 5'-DFUR by 1,070-fold.	("5'-deoxyfluorouracil", 'Chemical', '-', (127, 147))	('sensitivity', 'MPA', (216, 227))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	("5'-DFUR", 'Chemical', '-', (231, 238))	('increase', 'PosReg', (177, 185))	('human', 'Species', '9606', (51, 56))	('TP', 'Gene', '1890', (90, 92))	("5'-DFUR", 'Chemical', '-', (149, 156))	('colon cancer', 'Disease', (57, 69))	('TP', 'Gene', '1890', (28, 30))	('transfection', 'Var', (8, 20))	('activity', 'MPA', (189, 197))	('TP', 'Gene', '1890', (186, 188))
283398	19657639	TP was shown to be upregulated in the group of patients with operations over 6 days after MMC, in contrast to patients with operations less than 6 days after MMC.	('upregulated', 'PosReg', (19, 30))	('operations over', 'Var', (61, 76))	('MMC', 'Chemical', 'MESH:D016685', (158, 161))	('patients', 'Species', '9606', (47, 55))	('TP', 'Gene', '1890', (0, 2))	('MMC', 'Disease', (90, 93))	('MMC', 'Chemical', 'MESH:D016685', (90, 93))	('patients', 'Species', '9606', (110, 118))
283485	19657639	Future studies utilizing this regimen should be developed in various gastrointestinal malignancies, particularly in MCRC, where recent evidence suggests that patients with a KRAS mutation in their tumors will not benefit from anti-epidermal growth factor receptor inhibitors, leaving around 45% of them with no options beyond the second line.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('MCRC', 'Chemical', '-', (116, 120))	('KRAS', 'Gene', '3845', (174, 178))	('MCRC', 'Disease', (116, 120))	('mutation', 'Var', (179, 187))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('gastrointestinal malignancies', 'Disease', (69, 98))	('patients', 'Species', '9606', (158, 166))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (69, 98))	('tumors', 'Disease', (197, 203))	('KRAS', 'Gene', (174, 178))	('men', 'Species', '9606', (34, 37))
283496	24963396	High expression of RBM3 may signify a subset of upper gastrointestinal cancers arising in a background of intestinal metaplasia and independently predicts a reduced risk of recurrence and death in patients with these cancer forms.	('intestinal metaplasia', 'Disease', (106, 127))	('High expression', 'Var', (0, 15))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (48, 78))	('patients', 'Species', '9606', (197, 205))	('upper gastrointestinal cancers', 'Disease', (48, 78))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (106, 127))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('death', 'Disease', 'MESH:D003643', (188, 193))	('death', 'Disease', (188, 193))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('RBM3', 'Gene', '5935', (19, 23))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('RBM3', 'Gene', (19, 23))	('reduced', 'NegReg', (157, 164))
283507	24963396	While the mechanistic basis for the association between high RBM3 expression and good prognosis needs to be further elucidated, some directions may be provided by the observed association between RBM3 expression and DNA integrity and repair, and the ability of RBM3 to attenuate stem-cell like properties of prostate cancer cells.	('RBM3', 'Gene', (196, 200))	('RBM3', 'Gene', (61, 65))	('RBM3', 'Gene', '5935', (261, 265))	('prostate cancer', 'Disease', (308, 323))	('RBM3', 'Gene', (261, 265))	('expression', 'MPA', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('association', 'Interaction', (176, 187))	('attenuate', 'NegReg', (269, 278))	('RBM3', 'Gene', '5935', (61, 65))	('RBM3', 'Gene', '5935', (196, 200))	('prostate cancer', 'Disease', 'MESH:D011471', (308, 323))	('prostate cancer', 'Phenotype', 'HP:0012125', (308, 323))	('high', 'Var', (56, 60))
283525	24963396	Kaplan-Meier analysis and the log rank test was applied to estimate differences in overall survival (OS) and recurrence free survival (RFS) in strata according to high and low RBM3 expression.	('high', 'Var', (163, 167))	('overall survival', 'MPA', (83, 99))	('RBM3', 'Gene', '5935', (176, 180))	('low', 'NegReg', (172, 175))	('recurrence free survival', 'CPA', (109, 133))	('OS', 'Chemical', '-', (101, 103))	('RBM3', 'Gene', (176, 180))	('RFS', 'Chemical', '-', (135, 138))
283539	24963396	In metastases, however, there was as positive correlation between high RBM3 expression and an increased proliferation (Figure 3B).	('metastases', 'Disease', 'MESH:D009362', (3, 13))	('RBM3', 'Gene', (71, 75))	('proliferation', 'CPA', (104, 117))	('increased', 'PosReg', (94, 103))	('RBM3', 'Gene', '5935', (71, 75))	('expression', 'MPA', (76, 86))	('high', 'Var', (66, 70))	('metastases', 'Disease', (3, 13))
283540	24963396	According to the results of the CRT analysis a prognostic cut off at 0.452 was adopted for OS (low RBM3 expression < =0.452, high RBM3 expression >0.452) and at 0.440 for RFS (low RBM3 expression < =0.440, high RBM3 expression >0.440) (see Additional file 2).	('RBM3', 'Gene', (99, 103))	('RBM3', 'Gene', (130, 134))	('low', 'Var', (95, 98))	('RFS', 'Chemical', '-', (171, 174))	('RBM3', 'Gene', '5935', (180, 184))	('RBM3', 'Gene', '5935', (211, 215))	('OS', 'Chemical', '-', (91, 93))	('RBM3', 'Gene', (180, 184))	('RBM3', 'Gene', (211, 215))	('RBM3', 'Gene', '5935', (99, 103))	('RBM3', 'Gene', '5935', (130, 134))
283558	24963396	Given that high RBM3 expression was demonstrated to be an independent favourable prognostic factor, its association with intestinal-type epithelium is also in line with findings from a previous comprehensive analysis of adenocarcinoma of the distal esophagus and esophagogastric junction, in which cases with associated intestinal-type mucosa were demonstrated to exhibit more favourable histopathological characteristics and a significantly prolonged survival compared to cases with associated cardiac-type mucosa.	('cardiac-type mucosa', 'Disease', 'MESH:D006331', (495, 514))	('survival', 'CPA', (452, 460))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('expression', 'MPA', (21, 31))	('adenocarcinoma', 'Disease', (220, 234))	('RBM3', 'Gene', '5935', (16, 20))	('high', 'Var', (11, 15))	('adenocarcinoma', 'Disease', 'MESH:D000230', (220, 234))	('RBM3', 'Gene', (16, 20))	('cardiac-type mucosa', 'Disease', (495, 514))	('intestinal-type mucosa', 'Disease', (320, 342))	('prolonged', 'PosReg', (442, 451))
283560	24963396	Apart from indicating that loss of RBM3 is an early event in adenocarcinoma of the upper gastrointestinal tract, these findings also support that analysis of RBM3 in the primary tumour is sufficient for prognostic and, potentially, treatment predictive purposes.	('loss', 'Var', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('RBM3', 'Gene', (158, 162))	('RBM3', 'Gene', '5935', (158, 162))	('RBM3', 'Gene', '5935', (35, 39))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('tumour', 'Disease', (178, 184))	('RBM3', 'Gene', (35, 39))	('adenocarcinoma of the upper gastrointestinal tract', 'Disease', (61, 111))	('adenocarcinoma of the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (61, 111))
283565	24963396	Moreover, in that study, Ki67 expression was found to be prognostic, however not independent of other factors, while MCM3 was an independent factor of poor prognosis.	('MCM3', 'Gene', (117, 121))	('Ki67', 'Chemical', '-', (25, 29))	('MCM3', 'Gene', '4172', (117, 121))	('Ki67 expression', 'Var', (25, 40))
283585	23170950	When stratified analyses according to study design (case-control and cohort studies), country (China and Japan), participates source (population-based and hospital-based case-control), and gender (female and male), there were significant association between high/medium/low green tea consumption and non-drinking risk of esophageal cancer among female (High: RR/OR = 0.32, 95% CI: 0.10 to 0.54.	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('tea', 'Gene', (280, 283))	('tea', 'Gene', '11988', (280, 283))	('high/medium/low green', 'Var', (258, 279))	('esophageal cancer', 'Disease', (321, 338))	('esophageal cancer', 'Disease', 'MESH:D004938', (321, 338))
283621	23170950	The results of meta-analysis showed that there were significant association between high/medium/low green tea consumption and non-drinking risk of esophageal cancer among female (High: RR/OR = 0.32, 95% CI: 0.10 to 0.54, P = 0.75 for heterogeneity, Table  2.	('esophageal cancer', 'Disease', (147, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('high/medium/low green', 'Var', (84, 105))	('tea', 'Gene', (106, 109))	('tea', 'Gene', '11988', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
283714	30881031	High Trop-2 expression correlates with poor prognosis in pancreatic, hilar cholangiocarcinoma, cervical cancer, gastric cancer, and others.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 93))	('cervical cancer', 'Disease', 'MESH:D002583', (95, 110))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('pancreatic', 'Disease', 'MESH:D010195', (57, 67))	('cervical cancer', 'Disease', (95, 110))	('gastric cancer', 'Disease', (112, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('Trop-2', 'Gene', (5, 11))	('pancreatic', 'Disease', (57, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('expression', 'MPA', (12, 22))	('cholangiocarcinoma', 'Disease', (75, 93))
283727	30881031	This group has demonstrated that Trop-2 upregulation quantitatively stimulates tumor growth, while Trop-2 knockdown inhibits tumor cell growth.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (79, 84))	('Trop-2', 'Gene', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('stimulates', 'PosReg', (68, 78))	('Trop-2', 'Gene', (99, 105))	('upregulation', 'PosReg', (40, 52))	('tumor', 'Disease', (125, 130))	('knockdown', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('inhibits', 'NegReg', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
283743	30881031	Consistent with this, several groups have demonstrated that knockdown of Trop-2 decreases cancer cell invasion.	('decreases cancer', 'Disease', 'MESH:D009369', (80, 96))	('decreases cancer', 'Disease', (80, 96))	('al', 'Chemical', 'MESH:D000535', (27, 29))	('Trop-2', 'Gene', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('knockdown', 'Var', (60, 69))
283757	30881031	Fong et al demonstrated that Trop-2 expression is associated with poor survival outcomes and increased lymph node metastasis in pancreatic cancer.	('lymph node metastasis', 'CPA', (103, 124))	('Fong', 'Gene', '348751', (0, 4))	('Trop-2', 'Gene', (29, 35))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('increased', 'PosReg', (93, 102))	('pancreatic cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'Var', (36, 46))	('Fong', 'Gene', (0, 4))	('survival outcomes', 'CPA', (71, 88))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('al', 'Chemical', 'MESH:D000535', (77, 79))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))
283758	30881031	Wang et al first identified Trop-2 as an oncogene and demonstrated that knockdown of Trop-2 expression inhibits both tumorigenesis and invasion of colon cancer cells and that ectopic expression of Trop-2 can promote cancer cell growth.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('promote', 'PosReg', (208, 215))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', (117, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (147, 159))	('Trop-2', 'Gene', (85, 91))	('inhibits', 'NegReg', (103, 111))	('colon cancer', 'Disease', 'MESH:D015179', (147, 159))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('ectopic expression', 'Var', (175, 193))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (216, 222))	('colon cancer', 'Disease', (147, 159))	('knockdown', 'Var', (72, 81))
283762	30881031	Kong et al correlated Trop-2 IHC to the presence of BRAF mutations, which are the most common genetic alteration in papillary thyroid cancer.	('al', 'Chemical', 'MESH:D000535', (102, 104))	('papillary thyroid cancer', 'Disease', (116, 140))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (116, 140))	('thyroid cancer', 'Phenotype', 'HP:0002890', (126, 140))	('mutations', 'Var', (57, 66))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('BRAF', 'Gene', '673', (52, 56))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (116, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('BRAF', 'Gene', (52, 56))
283763	30881031	The group concluded that Trop-2 expression is associated with BRAF mutations and that Trop-2 IHC could be used to predict BRAF mutations and alternatively diagnosing papillary thyroid cancer.	('BRAF', 'Gene', '673', (62, 66))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (166, 190))	('thyroid cancer', 'Phenotype', 'HP:0002890', (176, 190))	('BRAF', 'Gene', (62, 66))	('al', 'Chemical', 'MESH:D000535', (141, 143))	('BRAF', 'Gene', '673', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (67, 76))	('BRAF', 'Gene', (122, 126))	('associated', 'Reg', (46, 56))	('mutations', 'Var', (127, 136))	('expression', 'MPA', (32, 42))	('papillary thyroid cancer', 'Disease', (166, 190))	('Trop-2', 'Gene', (25, 31))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (166, 190))
283766	30881031	Gu et al have demonstrated that Trop-2 expression promotes proliferation and migration of osteosarcoma cell lines through the PI3K/AKT pathway.	('proliferation', 'CPA', (59, 72))	('AKT', 'Gene', '207', (131, 134))	('expression', 'Var', (39, 49))	('al', 'Chemical', 'MESH:D000535', (6, 8))	('Trop-2', 'Gene', (32, 38))	('AKT', 'Gene', (131, 134))	('osteosarcoma', 'Disease', (90, 102))	('migration', 'CPA', (77, 86))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('osteosarcoma', 'Disease', 'MESH:D012516', (90, 102))	('promotes', 'PosReg', (50, 58))
283767	30881031	Interestingly, the group also demonstrated that Trop-2 knockdown decreases cell migration and proliferation, hinting toward therapeutic benefit of Trop-2 inhibition.	('knockdown', 'Var', (55, 64))	('decreases', 'NegReg', (65, 74))	('al', 'Chemical', 'MESH:D000535', (25, 27))	('cell migration', 'CPA', (75, 89))	('Trop-2', 'Gene', (48, 54))
283778	30881031	For example, anti-Trop-2 antibodies conjugated to doxorubicin-loaded nanoparticles demonstrated higher toxicity toward MDA-MB-231 triple-negative breast cancer cells when compared to doxorubicin-loaded control nanoparticles without the anti-Trop-2 antibody conjugate.	('doxorubicin', 'Chemical', 'MESH:D004317', (183, 194))	('doxorubicin', 'Chemical', 'MESH:D004317', (50, 61))	('higher', 'PosReg', (96, 102))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('toxicity', 'Disease', 'MESH:D064420', (103, 111))	('antibodies', 'Var', (25, 35))	('toxicity', 'Disease', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('anti-Trop-2', 'Gene', (13, 24))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (119, 129))
283783	30881031	These studies demonstrated superior SN-38 delivery by IMMU-132.	('IMMU-132', 'Var', (54, 62))	('SN-38', 'Chemical', 'MESH:D000077146', (36, 41))	('SN-38 delivery', 'MPA', (36, 50))	('superior', 'PosReg', (27, 35))	('IMMU-132', 'Chemical', 'MESH:C000608132', (54, 62))
283785	30881031	Goldenberg et al have demonstrated that there are increased DNA double-strand breaks in vitro when Trop-2-expressing cells are treated with IMMU-132, when compared to another SN-38 ADC, hA20-SN-38, which is targeted to CD20.	('IMMU-132', 'Chemical', 'MESH:C000608132', (140, 148))	('DNA double-strand breaks', 'MPA', (60, 84))	('CD20', 'Gene', '931', (219, 223))	('increased', 'PosReg', (50, 59))	('al', 'Chemical', 'MESH:D000535', (14, 16))	('SN-38', 'Chemical', 'MESH:D000077146', (191, 196))	('CD20', 'Gene', (219, 223))	('hA20', 'Gene', (186, 190))	('SN-38', 'Chemical', 'MESH:D000077146', (175, 180))	('hA20', 'Gene', '7128', (186, 190))	('IMMU-132', 'Var', (140, 148))
283807	30881031	Cardillo et al evaluated the efficacy of an SN-38-anti-Trop-2 ADC against human tumor types in cynomolgus monkeys, which express Trop-2 across several different normal tissue types similar to humans.	('al', 'Chemical', 'MESH:D000535', (17, 19))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('SN-38-anti-Trop-2', 'Var', (44, 61))	('human', 'Species', '9606', (192, 197))	('al', 'Chemical', 'MESH:D000535', (165, 167))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cynomolgus monkeys', 'Species', '9541', (95, 113))	('tumor', 'Disease', (80, 85))	('SN-38', 'Chemical', 'MESH:D000077146', (44, 49))	('humans', 'Species', '9606', (192, 198))	('al', 'Chemical', 'MESH:D000535', (148, 150))	('al', 'Chemical', 'MESH:D000535', (12, 14))	('human', 'Species', '9606', (74, 79))
283811	30881031	A Phase I study was conducted on PF-06664178, an ADC targeting Trop-2 and delivering Aur0101, an auristatin micro-tubule inhibitor.	('Trop-2', 'Gene', (63, 69))	('PF-06664178', 'Chemical', '-', (33, 44))	('auristatin', 'Chemical', 'MESH:C543533', (97, 107))	('Aur0101', 'Gene', (85, 92))	('PF-06664178', 'Var', (33, 44))	('Aur0101', 'Chemical', '-', (85, 92))
283813	30881031	Thirty-one patients with metastatic solid tumors were treated with escalating doses of PF-0664178.	('PF-0664178', 'Var', (87, 97))	('solid tumors', 'Disease', 'MESH:D009369', (36, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('solid tumors', 'Disease', (36, 48))	('al', 'Chemical', 'MESH:D000535', (70, 72))	('patients', 'Species', '9606', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
283816	30881031	In this study, 31 patients with advanced or metastatic solid tumors were treated with PF-06664178 in escalating doses between 0.15 and 4.8 mg/kg.	('PF-06664178', 'Chemical', '-', (86, 97))	('al', 'Chemical', 'MESH:D000535', (104, 106))	('solid tumors', 'Disease', (55, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('patients', 'Species', '9606', (18, 26))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('solid tumors', 'Disease', 'MESH:D009369', (55, 67))	('PF-06664178', 'Var', (86, 97))
283857	30881031	DS-1062a is an ADC targeting Trop-2 and delivering DXd, a topoisomerase I inhibitor and derivative of exatecan.	('DS', 'Chemical', 'MESH:D003903', (0, 2))	('DS-1062a', 'Var', (0, 8))	('Trop-2', 'Gene', (29, 35))
283860	30881031	Prior to this clinical trial, one group demonstrated that DS-1062 markedly reduced in vitro cancer cell growth with IC50 dosing in the nanomolar range in Trop-2+ cell lines (CFPAC1, BxPC-3); to contrast the group also demonstrated that in Trop-2-negative tumor cells (Calu-6), 100-fold greater dosing was needed to achieve IC50.	('al', 'Chemical', 'MESH:D000535', (20, 22))	('al', 'Chemical', 'MESH:D000535', (213, 215))	('cancer', 'Disease', (92, 98))	('tumor', 'Disease', (255, 260))	('DS-1062', 'Var', (58, 65))	('BxPC-3', 'CellLine', 'CVCL:0186', (182, 188))	('al', 'Chemical', 'MESH:D000535', (269, 271))	('DS', 'Chemical', 'MESH:D003903', (58, 60))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('CFPAC1', 'CellLine', 'CVCL:1119', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('reduced', 'NegReg', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('al', 'Chemical', 'MESH:D000535', (26, 28))
283871	30881031	Given the benefit of IMMU-132 (sacituzumab govitecan) therapy, which provides additional benefit at lower dosages than using irinotecan, this study demonstrates additional potential benefits of combining Trop-2-targeted therapeutics and traditional DNA-damaging chemotherapy, as we theorize Trop-2 inhibition may sensitize cells to DNA-damaging chemotherapy.	('IMMU-132', 'Chemical', 'MESH:C000608132', (21, 29))	('al', 'Chemical', 'MESH:D000535', (179, 181))	('Trop-2', 'Gene', (291, 297))	('al', 'Chemical', 'MESH:D000535', (86, 88))	('inhibition', 'Var', (298, 308))	('al', 'Chemical', 'MESH:D000535', (169, 171))	('al', 'Chemical', 'MESH:D000535', (246, 248))	('irinotecan', 'Chemical', 'MESH:D000077146', (125, 135))	('sacituzumab govitecan', 'Chemical', 'MESH:C000608132', (31, 52))	('sensitize', 'Reg', (313, 322))
283880	30881031	However, milatuzumab-SN-38 was more effective in lymphoma, melanoma, and pancreatic cancer models.	('pancreatic cancer', 'Disease', (73, 90))	('milatuzumab-SN-38', 'Var', (9, 26))	('milatuzumab-SN-38', 'Chemical', '-', (9, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('lymphoma', 'Disease', (49, 57))	('lymphoma', 'Disease', 'MESH:D008223', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
283885	30803483	Aberrant cellular motion can be caused by deregulation of key signalling pathways in pathological conditions, including cancer, and may be critical for disease development and progression, for example leading to invasion and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Aberrant', 'Var', (0, 8))	('key signalling pathways', 'Pathway', (58, 81))	('leading', 'Reg', (201, 208))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('invasion', 'CPA', (212, 220))	('caused', 'Reg', (32, 38))	('cellular motion', 'CPA', (9, 24))	('deregulation', 'MPA', (42, 54))
283887	30803483	For example, disruption of the esophageal squamous columnar epithelial boundary is a feature of Barrett's Esophagus (BE), a condition that confers a 30-50 fold increased risk of esophageal adenocarcinoma (EAC).	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (96, 115))	('esophageal squamous columnar epithelial', 'Disease', (31, 70))	('esophageal squamous columnar epithelial', 'Disease', 'MESH:D000077277', (31, 70))	('disruption', 'Var', (13, 23))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (178, 203))	('esophageal adenocarcinoma', 'Disease', (178, 203))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (178, 203))
283902	30803483	Thirdly, in the squamous-cancer EPC2:OE33 combination, the cancer cell line OE33 expanded continuously, resulting in the disappearance of EPC2 from the field of view (Video 2, Figure 1E) as assessed by the motion field and confocal images (Figure 1:figure supplement 3).	('squamous-cancer', 'Disease', (16, 31))	('OE33', 'Chemical', '-', (76, 80))	('EPC2', 'Gene', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('squamous-cancer', 'Disease', 'MESH:D002294', (16, 31))	('OE33', 'Chemical', '-', (37, 41))	('EPC2', 'Gene', '26122', (138, 142))	('EPC2', 'Gene', '26122', (32, 36))	('EPC2', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('squamous-cancer', 'Phenotype', 'HP:0002860', (16, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('disappearance', 'NegReg', (121, 134))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('OE33', 'Var', (76, 80))
283917	30803483	Interestingly, CP-A:OE33 (Barrett's:cancer, n = 6) also exhibited a substantial increase in VCC following gap closure (0.03 to 0.17) (Figure 3:figure supplement 8D,E) but no substantial increase was observed for CP-A:CP-A (0.01 to 0.06) (Figure 3:figure supplement 8D,E), confirming this observation was not simply CP-A cell line-specific.	('CP-A', 'Gene', '1357', (212, 216))	('CP-A', 'Gene', '1357', (315, 319))	('CP-A', 'Gene', (315, 319))	('CP-A', 'Gene', (212, 216))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('CP-A', 'Gene', '1357', (217, 221))	('increase', 'PosReg', (80, 88))	('CP-A', 'Gene', (217, 221))	('cancer', 'Disease', (36, 42))	('VCC', 'MPA', (92, 95))	('OE33', 'Chemical', '-', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('CP-A', 'Gene', '1357', (15, 19))	('gap closure', 'Var', (106, 117))	('CP-A', 'Gene', (15, 19))
283923	30803483	The epidermal growth factor receptor (EGFR) is frequently mutated in EAC, sometimes overexpressed in BE and is activated by bile acid reflux, the main observed cause of BE clinically.	('EGFR', 'Gene', '1956', (38, 42))	('EAC', 'Disease', (69, 72))	('acid reflux', 'Phenotype', 'HP:0002020', (129, 140))	('epidermal growth factor receptor', 'Gene', (4, 36))	('EGFR', 'Gene', (38, 42))	('bile acid', 'Chemical', 'MESH:D001647', (124, 133))	('epidermal growth factor receptor', 'Gene', '1956', (4, 36))	('mutated', 'Var', (58, 65))	('bile', 'MPA', (124, 128))	('activated', 'PosReg', (111, 120))
283961	30803483	Samples were blocked with image-iT Fx signal enhancer for 1 h before incubation with E-cadherin (610181 Becton Dickinson U.K. Limited) overnight at a 1:400 dilution in Agilent Dako Antibody Diluent with Background Reducing Components (S3022, Agilent Dako) at 4 C. Following 3 washes of 10 min in PBS, samples were incubated for 2 h in the dark with Alexa 488 goat anti-mouse (A11001, Thermo Fisher) secondary antibody and Alexa Fluor 647 Phalloidin (A22287, ThermoFisher), both at a 1:400 dilution and DAPI (1 mg/mL) at 1:1000 dilution (62248, Thermo Fisher) in Agilent Dako Antibody dilutent (S0809, Agilent Dako).	('goat', 'Species', '9925', (359, 363))	('S0809', 'Var', (594, 599))	('PBS', 'Chemical', 'MESH:D007854', (296, 299))	('DAPI', 'Chemical', 'MESH:C007293', (502, 506))	('E-cadherin', 'Gene', (85, 95))	('E-cadherin', 'Gene', '999', (85, 95))	('mouse', 'Species', '10090', (369, 374))
283986	30803483	We report the maximum absolute value for all red-green pairings and the average over all pairings as evidence of interaction between two epithelial sheets.	('epithelia', 'Disease', 'None', (137, 146))	('epithelia', 'Disease', (137, 146))	('red-green', 'Var', (45, 54))	('interaction', 'Interaction', (113, 124))
284008	30803483	These interactions (Video 2) lead to formation of a stable boundary with highly dynamic motion of the two cell populations after collision (in squamous-squamous interactions), a stable boundary with less dynamic motion of cell populations after collision and having squamous monolayer pushed by columnar monolayer (squamous-columnar), and no boundary formation with retraction of squamous cell population after collision (squamous-cancer).	('squamous-cancer', 'Disease', (422, 437))	('interactions', 'Var', (6, 18))	('squamous-cancer', 'Disease', 'MESH:D002294', (422, 437))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('squamous-cancer', 'Phenotype', 'HP:0002860', (422, 437))
284029	30803483	Depletion of Ca2+ is very well known to disrupt the cell-cell contacts in epithelial cells and addition of Ca+ can also induce the re-establishment of the cell/cell contacts.	('induce', 'Reg', (120, 126))	('epithelia', 'Disease', 'None', (74, 83))	('epithelia', 'Disease', (74, 83))	('re-establishment of the cell/cell contacts', 'CPA', (131, 173))	('cell-cell contacts in', 'CPA', (52, 73))	('addition', 'Var', (95, 103))	('disrupt', 'NegReg', (40, 47))	('Depletion', 'MPA', (0, 9))	('Ca2+', 'Chemical', 'MESH:D000069285', (13, 17))
284058	30803483	In the main we now state "in the squamous-cancer EPC2:OE33 combination, the cancer cell line OE33 expanded continuously, resulting in the disappearance of EPC2 from the field of view (Video 2, Figure 1E) as assessed by the motion field and confocal images (Figure 1:figure supplement 3).	('squamous-cancer', 'Disease', (33, 48))	('EPC2', 'Gene', '26122', (155, 159))	('EPC2', 'Gene', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('OE33', 'Chemical', '-', (54, 58))	('squamous-cancer', 'Disease', 'MESH:D002294', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('EPC2', 'Gene', '26122', (49, 53))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('disappearance', 'NegReg', (138, 151))	('squamous-cancer', 'Phenotype', 'HP:0002860', (33, 48))	('OE33', 'Var', (93, 97))	('OE33', 'Chemical', '-', (93, 97))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('EPC2', 'Gene', (49, 53))
284094	29382033	Subgroup analysis based on the treatment procedure showed that, patients treated with preoperative CRT had a significantly higher pCR rate than those treated with CT (RR = 4.63, 95% CI: 2.39, 8.95; P < 0.05), whereas patients treated with definitive CRT had a similar pCR rate with those treated with CT (RR = 1.03, 95% CI: 0.86, 1.23; P = .764) (Fig.	('pCR rate', 'CPA', (130, 138))	('patients', 'Species', '9606', (64, 72))	('higher', 'PosReg', (123, 129))	('CRT', 'Var', (99, 102))	('patients', 'Species', '9606', (217, 225))
284101	29382033	Results from that study suggested that compared with induction CT, induction CRT significantly prolonged OS and disease-free survival (DFS), and it also increased the complication rate.	('disease-free survival', 'CPA', (112, 133))	('increased', 'PosReg', (153, 162))	('induction CRT', 'Var', (67, 80))	('OS', 'Chemical', '-', (105, 107))	('complication', 'CPA', (167, 179))	('prolonged', 'PosReg', (95, 104))
284268	27698691	The mRNA expression levels of LRIG1 were examined by RT-qPCR at 48 h following transfection, and demonstrated a significant increase (magnitude, >212) in the expression levels of LRIG1 mRNA in the transfected cells, as compared with the negative controls (Fig.	('mRNA', 'MPA', (185, 189))	('increase', 'PosReg', (124, 132))	('expression levels', 'MPA', (158, 175))	('transfected', 'Var', (197, 208))	('LRIG1', 'Gene', '26018', (30, 35))	('LRIG1', 'Gene', (30, 35))	('LRIG1', 'Gene', (179, 184))	('LRIG1', 'Gene', '26018', (179, 184))
284300	27698691	Notably, a number of perinuclear LRIG1 were observed following transfection with LRIG1 plasmid.	('LRIG1', 'Gene', (33, 38))	('transfection', 'Var', (63, 75))	('LRIG1', 'Gene', '26018', (33, 38))	('LRIG1', 'Gene', '26018', (81, 86))	('LRIG1', 'Gene', (81, 86))
284302	27698691	The absence of PTEN in cancer cells has typically been associated with the increased activation of the PI3K/Akt signaling pathway, leading to malignant cancer transformation and progression.	('leading to', 'Reg', (131, 141))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Akt', 'Gene', (108, 111))	('progression', 'CPA', (178, 189))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('PTEN', 'Gene', (15, 19))	('activation', 'PosReg', (85, 95))	('malignant cancer', 'Disease', 'MESH:D009369', (142, 158))	('PTEN', 'Gene', '5728', (15, 19))	('Akt', 'Gene', '207', (108, 111))	('malignant cancer', 'Disease', (142, 158))	('absence', 'Var', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
284303	27698691	In the present study, LRIG1-mediated downregulation of PTEN mRNA expression was diminished by pretreatment of ESCC cell lines with bisindolylmaleimide I (PKC inhibitor), PD98059 (ERK 1/2 inhibitor) and U0126 (MEK 1/2 inhibitor).	('downregulation', 'NegReg', (37, 51))	('PD98059', 'Chemical', 'MESH:C093973', (170, 177))	('PTEN', 'Gene', '5728', (55, 59))	('ERK 1/2', 'Gene', (179, 186))	('U0126', 'Chemical', 'MESH:C113580', (202, 207))	('bisindolylmaleimide I', 'Chemical', '-', (131, 152))	('ERK 1/2', 'Gene', '5595;5594', (179, 186))	('LRIG1', 'Gene', '26018', (22, 27))	('LRIG1', 'Gene', (22, 27))	('MEK 1/2', 'Gene', (209, 216))	('PD98059', 'Var', (170, 177))	('U0126', 'Var', (202, 207))	('diminished', 'NegReg', (80, 90))	('MEK 1/2', 'Gene', '5604;5605', (209, 216))	('PTEN', 'Gene', (55, 59))
284305	27698691	The apoptosis of Eca-109 and KYSE-450 cells was significantly inhibited following transfection of the cells with the pLRIG1-EGF plasmid, compared with the control cells.	('transfection', 'Var', (82, 94))	('LRIG1', 'Gene', '26018', (118, 123))	('apoptosis', 'CPA', (4, 13))	('LRIG1', 'Gene', (118, 123))	('inhibited', 'NegReg', (62, 71))	('KYSE-450', 'CellLine', 'CVCL:1353', (29, 37))
284317	27527552	By241 concentration-dependently induced apoptosis of MGC-803 and EC9706 cells, accompanied with the mitochondrial dysfunction and increased ROS levels.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (100, 125))	('mitochondrial dysfunction', 'Disease', (100, 125))	('ROS', 'Chemical', 'MESH:D017382', (140, 143))	('By241', 'Chemical', '-', (0, 5))	('EC9706', 'CellLine', 'CVCL:E307', (65, 71))	('MGC-803', 'CellLine', 'CVCL:5334', (53, 60))	('By241', 'Var', (0, 5))	('increased', 'PosReg', (130, 139))	('ROS levels', 'MPA', (140, 150))	('increased ROS levels', 'Phenotype', 'HP:0025464', (130, 150))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (100, 125))
284318	27527552	NAC can completely restore the decreased cell viability of MGC-803 cells caused by by241, suggesting ROS-mediated mechanisms.	('NAC', 'Gene', (0, 3))	('cell viability', 'CPA', (41, 55))	('decreased', 'NegReg', (31, 40))	('by241', 'Var', (83, 88))	('NAC', 'Gene', '7504', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('by241', 'Chemical', '-', (83, 88))	('MGC-803', 'CellLine', 'CVCL:5334', (59, 66))
284321	27527552	Additionally, by241 inhibited mTOR, activated p53 and its downstream proteins, cleaved MDM2 and PI3K/AKT as well as NF-kappaB signaling pathway.	('AKT', 'Gene', '207', (101, 104))	('NF-kappaB', 'Gene', '4790', (116, 125))	('p53', 'Gene', (46, 49))	('by241', 'Var', (14, 19))	('NF-kappaB', 'Gene', (116, 125))	('activated', 'PosReg', (36, 45))	('AKT', 'Gene', (101, 104))	('p53', 'Gene', '7157', (46, 49))	('inhibited', 'NegReg', (20, 29))	('MDM2', 'Gene', '4193', (87, 91))	('MDM2', 'Gene', (87, 91))	('by241', 'Chemical', '-', (14, 19))	('mTOR', 'Gene', '2475', (30, 34))	('cleaved', 'NegReg', (79, 86))	('mTOR', 'Gene', (30, 34))
284322	27527552	In vivo experiments showed that by241 did not have significant acute oral toxicity and exerted good anticancer efficacy against MGC-803 bearing mice models.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mice', 'Species', '10090', (144, 148))	('MGC-803', 'CellLine', 'CVCL:5334', (128, 135))	('by241', 'Chemical', '-', (32, 37))	('acute oral toxicity', 'Disease', 'MESH:D000208', (63, 82))	('by241', 'Var', (32, 37))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('acute oral toxicity', 'Disease', (63, 82))
284323	27527552	Therefore, by241 may serve as a lead for further development for cancer therapy.	('by241', 'Chemical', '-', (11, 16))	('by241', 'Var', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
284359	27527552	Generally, by241 had broad-spectrum anticancer activity, showing favorable inhibition against the tested cancer cell lines (IC50 < 6.5 muM).	('C', 'Chemical', 'MESH:D002244', (125, 126))	('by241', 'Var', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('muM', 'Gene', '56925', (135, 138))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('muM', 'Gene', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('by241', 'Chemical', '-', (11, 16))
284360	27527552	Also, by241 was more potent than 5-FU and less toxic to human normal cells (IC50 > 20 muM), indicating good selectivity.	('by241', 'Var', (6, 11))	('muM', 'Gene', '56925', (86, 89))	('potent', 'MPA', (21, 27))	('human', 'Species', '9606', (56, 61))	('muM', 'Gene', (86, 89))	('by241', 'Chemical', '-', (6, 11))	('C', 'Chemical', 'MESH:D002244', (77, 78))	('5-FU', 'Chemical', 'MESH:D005472', (33, 37))
284361	27527552	Specifically, by241 exhibited excellent inhibition against human gastric cancer cells (MGC-803 and BGC-803) with the IC50 values of 2.77, 1.18 muM respectively.	('muM', 'Gene', '56925', (143, 146))	('human', 'Species', '9606', (59, 64))	('MGC-803', 'CellLine', 'CVCL:5334', (87, 94))	('muM', 'Gene', (143, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('by241', 'Var', (14, 19))	('C', 'Chemical', 'MESH:D002244', (118, 119))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('inhibition', 'NegReg', (40, 50))	('by241', 'Chemical', '-', (14, 19))	('gastric cancer', 'Disease', (65, 79))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))
284362	27527552	By241 inhibited growth of L-02 with an IC50 value of 21.80 muM, showing around 5- and 8-fold selectivity toward SMMC-7721 (IC50 = 4.83 muM) and ZIP77 (IC50 = 2.71 muM), respectively.	('SMMC-7721', 'CellLine', 'CVCL:0534', (112, 121))	('muM', 'Gene', '56925', (59, 62))	('C', 'Chemical', 'MESH:D002244', (115, 116))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('muM', 'Gene', '56925', (163, 166))	('By241', 'Chemical', '-', (0, 5))	('muM', 'Gene', '56925', (135, 138))	('C', 'Chemical', 'MESH:D002244', (152, 153))	('muM', 'Gene', (59, 62))	('growth', 'CPA', (16, 22))	('inhibited', 'NegReg', (6, 15))	('muM', 'Gene', (163, 166))	('By241', 'Var', (0, 5))	('C', 'Chemical', 'MESH:D002244', (40, 41))	('muM', 'Gene', (135, 138))
284366	27527552	After exposure to by241 at different concentrations for 72 h, the cell viability of cancerous cells and normal cells was decreased gradually with the concentration increase of by241, as demonstrated in Fig.	('cancerous', 'Disease', (84, 93))	('decreased', 'NegReg', (121, 130))	('by241', 'Var', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancerous', 'Disease', 'MESH:D009369', (84, 93))	('by241', 'Chemical', '-', (18, 23))	('by241', 'Chemical', '-', (176, 181))
284374	27527552	Above studies showed that by241 potently inhibited growth of cancer cells and induced morphological changes of MGC-803 and EC9706 cells in a concentration-dependent manner.	('EC9706', 'CellLine', 'CVCL:E307', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('MGC-803', 'CellLine', 'CVCL:5334', (111, 118))	('by241', 'Chemical', '-', (26, 31))	('cancer', 'Disease', (61, 67))	('inhibited', 'NegReg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('morphological changes', 'CPA', (86, 107))	('by241', 'Var', (26, 31))
284375	27527552	These studies suggest that by241 should be capable of inducing apoptosis of cancer cells.	('by241', 'Var', (27, 32))	('inducing', 'PosReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('apoptosis', 'CPA', (63, 72))	('by241', 'Chemical', '-', (27, 32))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
284377	27527552	3A-D, by241 markedly induced apoptosis of MGC-803 cells in a concentration-/time-dependent manner, the late apoptosis in particular.	('apoptosis', 'CPA', (29, 38))	('by241', 'Chemical', '-', (6, 11))	('by241', 'Var', (6, 11))	('MGC-803', 'CellLine', 'CVCL:5334', (42, 49))
284380	27527552	Besides, by241 also induced apoptosis of EC9706 cells in a concentration-/time-dependent manner (Fig.	('by241', 'Var', (9, 14))	('apoptosis', 'CPA', (28, 37))	('EC9706', 'CellLine', 'CVCL:E307', (41, 47))	('by241', 'Chemical', '-', (9, 14))
284381	27527552	After treatment of EC9706 cells for 12 h at 10 muM, the percentage of apoptotic cells was 40.1%, significantly higher than the control group, but slightly lower than that of the group treated for 24 h at the same concentration (Fig.	('EC9706', 'CellLine', 'CVCL:E307', (19, 25))	('muM', 'Gene', (47, 50))	('apoptotic cells', 'CPA', (70, 85))	('lower', 'NegReg', (155, 160))	('EC9706', 'Var', (19, 25))	('higher', 'PosReg', (111, 117))	('muM', 'Gene', '56925', (47, 50))
284388	27527552	From the structural point of view, we speculate that our target molecule by241 incorporating oxindole and steroid nucleus potentially induced cell death through ROS-mediated mechanisms.	('by241', 'Chemical', '-', (73, 78))	('ROS', 'Chemical', 'MESH:D017382', (161, 164))	('steroid', 'Chemical', 'MESH:D013256', (106, 113))	('oxindole', 'Chemical', 'MESH:C022960', (93, 101))	('by241', 'Var', (73, 78))	('cell death', 'CPA', (142, 152))
284389	27527552	2E-H, by241 induced remarkable morphological changes of MGC-803 and EC9706 cells, especially at high concentrations.	('by241', 'Var', (6, 11))	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('MGC-803', 'CellLine', 'CVCL:5334', (56, 63))	('by241', 'Chemical', '-', (6, 11))	('morphological changes', 'CPA', (31, 52))
284391	27527552	4A), suggesting that by241 probably induced cell death through elevating cellular ROS levels.	('elevating', 'PosReg', (63, 72))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('by241', 'Var', (21, 26))	('cellular ROS levels', 'MPA', (73, 92))	('by241', 'Chemical', '-', (21, 26))
284394	27527552	4C), and NAC can decrease the green fluorescence intensity in MGC-803 cells induced by by241, the percentage of cells with green fluorescence was only 14.0% when treated with by241 (10 muM) and NAC (5 mM), slightly higher than that of the control group (8.8%).	('NAC', 'Gene', (194, 197))	('NAC', 'Gene', '7504', (194, 197))	('muM', 'Gene', '56925', (185, 188))	('green fluorescence intensity', 'MPA', (30, 58))	('by241', 'Var', (87, 92))	('muM', 'Gene', (185, 188))	('decrease', 'NegReg', (17, 25))	('C', 'Chemical', 'MESH:D002244', (1, 2))	('by241', 'Chemical', '-', (87, 92))	('by241', 'Chemical', '-', (175, 180))	('C', 'Chemical', 'MESH:D002244', (11, 12))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('C', 'Chemical', 'MESH:D002244', (196, 197))	('NAC', 'Gene', (9, 12))	('NAC', 'Gene', '7504', (9, 12))	('MGC-803', 'CellLine', 'CVCL:5334', (62, 69))
284395	27527552	For EC9706 cells, the percentage of cells with green fluorescence intensity amounted to 35% (around 9-fold increase relative to the control) when treated with by241 at 10 muM, which then decreased to 9.2% when treated with by241 (10 muM) and NAC (5 mM) (Fig.	('muM', 'Gene', '56925', (171, 174))	('by241', 'Chemical', '-', (159, 164))	('muM', 'Gene', (171, 174))	('increase', 'PosReg', (107, 115))	('muM', 'Gene', (233, 236))	('green fluorescence intensity', 'MPA', (47, 75))	('to 9', 'Species', '1214577', (197, 201))	('EC9706', 'CellLine', 'CVCL:E307', (4, 10))	('muM', 'Gene', '56925', (233, 236))	('by241', 'Chemical', '-', (223, 228))	('NAC', 'Gene', (242, 245))	('NAC', 'Gene', '7504', (242, 245))	('EC9706', 'Var', (4, 10))
284398	27527552	4G, NAC alone had no effect on the cell viability of MGC-803 cells even at the concentration of 5 mM, while NAC was found to be able to completely restore the decreased cell viability of MGC-803 cells caused by by241 at 6.25 muM.	('by241', 'Chemical', '-', (211, 216))	('NAC', 'Gene', (4, 7))	('MGC-803', 'CellLine', 'CVCL:5334', (187, 194))	('NAC', 'Gene', '7504', (4, 7))	('cell viability', 'CPA', (169, 183))	('muM', 'Gene', '56925', (225, 228))	('MGC-803', 'CellLine', 'CVCL:5334', (53, 60))	('decreased', 'NegReg', (159, 168))	('NAC', 'Gene', (108, 111))	('NAC', 'Gene', '7504', (108, 111))	('cell', 'CPA', (35, 39))	('by241', 'Var', (211, 216))	('muM', 'Gene', (225, 228))
284400	27527552	This result supported the hypothesis that by241 induced cell death mainly through ROS-mediated mechanisms.	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('by241', 'Var', (42, 47))	('by241', 'Chemical', '-', (42, 47))	('cell', 'CPA', (56, 60))	('ROS-mediated', 'Protein', (82, 94))
284403	27527552	Hence, in this study, the DeltaPsim was measured using the JC-1 dye to evaluate the by241-induced mitochondrial dysfunction (Fig.	('mitochondrial dysfunction', 'Disease', (98, 123))	('by241', 'Chemical', '-', (84, 89))	('DeltaPsim', 'MPA', (26, 35))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (98, 123))	('by241-induced', 'Var', (84, 97))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (98, 123))
284404	27527552	5A,B, by241 concentration-dependently increased the green fluorescence intensity in MGC-803 cells and EC9706 cells, indicating the by241-induced translocation of JC-1 dye from the mitochondria to the cytoplasm.	('by241', 'Var', (6, 11))	('by241', 'Chemical', '-', (131, 136))	('EC9706', 'CellLine', 'CVCL:E307', (102, 108))	('C', 'Chemical', 'MESH:D002244', (103, 104))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('JC-1 dye', 'MPA', (162, 170))	('by241', 'Chemical', '-', (6, 11))	('MGC-803', 'CellLine', 'CVCL:5334', (84, 91))	('green fluorescence intensity', 'MPA', (52, 80))	('translocation', 'MPA', (145, 158))	('by241-induced', 'Var', (131, 144))	('increased', 'PosReg', (38, 47))
284409	27527552	Furthermore, the decreased MMP caused by by241 in MGC-803 could mostly reversed by NAC (Fig.	('MGC-803', 'Gene', (50, 57))	('decreased', 'NegReg', (17, 26))	('by241', 'Var', (41, 46))	('MGC-803', 'CellLine', 'CVCL:5334', (50, 57))	('NAC', 'Gene', (83, 86))	('NAC', 'Gene', '7504', (83, 86))	('by241', 'Chemical', '-', (41, 46))	('MMP', 'MPA', (27, 30))
284417	27527552	Above studies have shown that by241 markedly increased expression of pro-apoptotic proteins Bid, Bax, and Bak, which have been proved to be able to activate expressions of downstream caspases.	('by241', 'Var', (30, 35))	('caspases', 'Gene', '841;842', (183, 191))	('expressions', 'MPA', (157, 168))	('increased', 'PosReg', (45, 54))	('Bid', 'Gene', (92, 95))	('Bid', 'Gene', '637', (92, 95))	('by241', 'Chemical', '-', (30, 35))	('expression', 'MPA', (55, 65))	('Bax', 'Gene', '581', (97, 100))	('activate', 'PosReg', (148, 156))	('Bak', 'Gene', (106, 109))	('Bak', 'Gene', '578', (106, 109))	('caspases', 'Gene', (183, 191))	('Bax', 'Gene', (97, 100))
284419	27527552	6H, by241 concentration-dependently resulted in activation of pro-caspases-9 and -3, leading to increased expression of cleaved caspase-9 and caspase-3.	('increased', 'PosReg', (96, 105))	('caspase-9', 'Gene', (128, 137))	('by241', 'Var', (4, 9))	('expression', 'MPA', (106, 116))	('caspase-3', 'Gene', '836', (142, 151))	('cleaved', 'MPA', (120, 127))	('by241', 'Chemical', '-', (4, 9))	('activation', 'PosReg', (48, 58))	('caspase-9', 'Gene', '842', (128, 137))	('pro-caspases-9 and -3', 'Gene', '836', (62, 83))	('caspase-3', 'Gene', (142, 151))
284423	27527552	6M), we reason that by241 induced apoptosis of MGC-803 cells in part through the mitochondria-related caspase-9/caspase-3 intrinsic pathways, not the membrane death receptor-mediated extrinsic pathways or the caspase-8/Bid/Bax pathway.	('by241', 'Var', (20, 25))	('mitochondria-related', 'MPA', (81, 101))	('caspase-9', 'Gene', '842', (102, 111))	('caspase-8', 'Gene', '841', (209, 218))	('Bax', 'Gene', '581', (223, 226))	('caspase-9', 'Gene', (102, 111))	('by241', 'Chemical', '-', (20, 25))	('apoptosis', 'CPA', (34, 43))	('caspase-3', 'Gene', (112, 121))	('Bid', 'Gene', (219, 222))	('MGC-803', 'CellLine', 'CVCL:5334', (47, 54))	('Bid', 'Gene', '637', (219, 222))	('Bax', 'Gene', (223, 226))	('caspase-3', 'Gene', '836', (112, 121))	('caspase-8', 'Gene', (209, 218))
284425	27527552	Specifically, the apoptotic cells for the by241-treated group accounted for about 22%, while the percentage of apoptotic cells after treatment with by241 and Z-VAD-FMK decreased to around 7%, but still slightly higher than that of cells treated with Z-VAD-FMK alone (about 5%, Fig.	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (158, 167))	('by241-treated', 'Var', (42, 55))	('by241', 'Chemical', '-', (148, 153))	('by241', 'Var', (148, 153))	('by241', 'Chemical', '-', (42, 47))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (250, 259))
284426	27527552	These results revealed that pan caspase inhibitor Z-VAD-FMK cannot prevent by241-induced apoptosis completely, suggesting that apart from the mitochondria-mediated apoptotic pathways, simulation of other signaling pathways and/or key proteins involved in the ROS-mediated pathways by by241 also contributed to MGC-803 cell death.	('MGC-803', 'CellLine', 'CVCL:5334', (310, 317))	('by241', 'Chemical', '-', (75, 80))	('by241', 'Chemical', '-', (284, 289))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (50, 59))	('contributed', 'Reg', (295, 306))	('ROS', 'Chemical', 'MESH:D017382', (259, 262))	('by241', 'Var', (284, 289))	('MGC-803 cell death', 'CPA', (310, 328))
284428	27527552	Activated p53 then induces expression of downstream transcriptional proapoptotic proteins such as Bax and PUMA, ultimately leading to apoptosis of cancer cells.	('induces', 'Reg', (19, 26))	('Bax', 'Gene', '581', (98, 101))	('PUMA', 'Gene', '27113', (106, 110))	('p53', 'Gene', '7157', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('apoptosis', 'CPA', (134, 143))	('Bax', 'Gene', (98, 101))	('expression', 'MPA', (27, 37))	('Activated', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('PUMA', 'Gene', (106, 110))	('leading to', 'Reg', (123, 133))	('cancer', 'Disease', (147, 153))	('p53', 'Gene', (10, 13))
284430	27527552	7, treatment with by241 increased expression of p53, which then transcriptionally activated its downstream proapoptotic proteins such as Bax (Fig.	('Bax', 'Gene', '581', (137, 140))	('p53', 'Gene', (48, 51))	('expression', 'MPA', (34, 44))	('p53', 'Gene', '7157', (48, 51))	('activated', 'PosReg', (82, 91))	('by241', 'Var', (18, 23))	('Bax', 'Gene', (137, 140))	('by241', 'Chemical', '-', (18, 23))	('increased', 'PosReg', (24, 33))
284434	27527552	Also, by241 concentration-dependently cleaved MDM2, generating a 60KD MDM2 fragment (Fig.	('by241', 'Var', (6, 11))	('by241', 'Chemical', '-', (6, 11))	('MDM2', 'Gene', '4193', (70, 74))	('MDM2', 'Gene', '4193', (46, 50))	('MDM2', 'Gene', (70, 74))	('MDM2', 'Gene', (46, 50))
284442	27527552	described that inhibition of NF-kappaB in wild-type p53 retaining tumors may cause a diminished therapeutical response.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('NF-kappaB', 'Gene', (29, 38))	('p53', 'Gene', (52, 55))	('diminished', 'NegReg', (85, 95))	('tumors', 'Disease', (66, 72))	('p53', 'Gene', '7157', (52, 55))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('therapeutical response', 'CPA', (96, 118))	('NF-kappaB', 'Gene', '4790', (29, 38))	('inhibition', 'Var', (15, 25))
284443	27527552	Besides, ROS also activated the PI3K/AKT pathways, leading to increased expression of key proteins such as PI3K and AKT (Fig.	('increased', 'PosReg', (62, 71))	('AKT', 'Gene', '207', (37, 40))	('expression', 'MPA', (72, 82))	('AKT', 'Gene', '207', (116, 119))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('AKT', 'Gene', (37, 40))	('ROS', 'Var', (9, 12))	('PI3K', 'Gene', (107, 111))	('activated', 'PosReg', (18, 27))	('AKT', 'Gene', (116, 119))
284449	27527552	The favorable in vitro potency and low toxicity of by241 observed promoted us to investigate the in vivo anti-tumor potency.	('toxicity', 'Disease', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('by241', 'Var', (51, 56))	('toxicity', 'Disease', 'MESH:D064420', (39, 47))	('by241', 'Chemical', '-', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
284464	27527552	Structurally, by241 shared the same steroid nucleus with anticancer drugs abiraterone and galeterone and also featured a biologically important spirooxindole scaffold.	('abiraterone', 'Chemical', 'MESH:C089740', (74, 85))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('galeterone', 'Chemical', 'MESH:C500627', (90, 100))	('by241', 'Var', (14, 19))	('cancer', 'Disease', (61, 67))	('spirooxindole', 'Chemical', '-', (144, 157))	('by241', 'Chemical', '-', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('steroid', 'Chemical', 'MESH:D013256', (36, 43))
284465	27527552	Compared to 5-FU, by241 exhibited more potent inhibition against the tested cancer cells (EC109, EC9706, KYSE450, MGC-803, BGC-803, SMMC-7721, ZIP77, MCF-7 and PC-3) and was less toxic to human normal cells (Het-1A and L-02), indicating a good selectivity toward cancer cells and normal cells.	('cancer', 'Disease', (263, 269))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('C', 'Chemical', 'MESH:D002244', (91, 92))	('C', 'Chemical', 'MESH:D002244', (161, 162))	('5-FU', 'Chemical', 'MESH:D005472', (12, 16))	('EC9706', 'CellLine', 'CVCL:E307', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('MCF-7', 'CellLine', 'CVCL:0031', (150, 155))	('inhibition', 'NegReg', (46, 56))	('PC-3', 'CellLine', 'CVCL:0035', (160, 164))	('by241', 'Var', (18, 23))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('EC9706', 'Var', (97, 103))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('cancer', 'Disease', (76, 82))	('C', 'Chemical', 'MESH:D002244', (151, 152))	('human', 'Species', '9606', (188, 193))	('C', 'Chemical', 'MESH:D002244', (125, 126))	('MGC-803', 'CellLine', 'CVCL:5334', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('KYSE450', 'Enzyme', (105, 112))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('SMMC-7721', 'CellLine', 'CVCL:0534', (132, 141))	('by241', 'Chemical', '-', (18, 23))
284466	27527552	By241 concentration-dependently inhibited the colony formation, induced typical morphological changes and remarkable apoptosis of MGC-803 cells.	('inhibited', 'NegReg', (32, 41))	('colony formation', 'CPA', (46, 62))	('By241', 'Chemical', '-', (0, 5))	('By241', 'Var', (0, 5))	('MGC-803', 'CellLine', 'CVCL:5334', (130, 137))	('apoptosis', 'CPA', (117, 126))	('morphological changes', 'CPA', (80, 101))
284468	27527552	Interestingly, ROS scavenger NAC was found to be able to completely restore the decreased cell viability, the increased ROS and the decrease of MMP of MGC-803 cells caused by by241, suggesting the ROS-mediated mechanisms for observed cell death.	('by241', 'Var', (175, 180))	('MMP', 'MPA', (144, 147))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('NAC', 'Gene', '7504', (29, 32))	('increased', 'PosReg', (110, 119))	('cell viability', 'CPA', (90, 104))	('decreased', 'NegReg', (80, 89))	('by241', 'Chemical', '-', (175, 180))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('ROS', 'Chemical', 'MESH:D017382', (197, 200))	('ROS', 'MPA', (120, 123))	('decrease', 'NegReg', (132, 140))	('NAC', 'Gene', (29, 32))	('MGC-803', 'CellLine', 'CVCL:5334', (151, 158))
284470	27527552	However, by241 did not affect expression of caspase-8, DR5 and TLR.	('TLR', 'Gene', (63, 66))	('DR5', 'Gene', (55, 58))	('by241', 'Chemical', '-', (9, 14))	('caspase-8', 'Gene', '841', (44, 53))	('DR5', 'Gene', '8795', (55, 58))	('by241', 'Var', (9, 14))	('caspase-8', 'Gene', (44, 53))
284471	27527552	All these data suggest that by241 induced apoptosis of MGC-803 cells through the mitochondria-mediated caspase-9/caspase-3 intrinsic pathways, not the caspase-8 involved pathways such as the membrane death receptor-mediated extrinsic pathway and the caspase-8/Bid/Bax pathway.	('caspase-8', 'Gene', '841', (250, 259))	('Bax', 'Gene', (264, 267))	('caspase-8', 'Gene', (151, 160))	('Bid', 'Gene', (260, 263))	('by241', 'Var', (28, 33))	('Bax', 'Gene', '581', (264, 267))	('MGC-803', 'CellLine', 'CVCL:5334', (55, 62))	('Bid', 'Gene', '637', (260, 263))	('caspase-9', 'Gene', '842', (103, 112))	('caspase-3', 'Gene', '836', (113, 122))	('apoptosis', 'CPA', (42, 51))	('caspase-8', 'Gene', '841', (151, 160))	('membrane death receptor-mediated extrinsic pathway', 'Pathway', (191, 241))	('caspase-3', 'Gene', (113, 122))	('caspase-8', 'Gene', (250, 259))	('by241', 'Chemical', '-', (28, 33))	('caspase-9', 'Gene', (103, 112))
284472	27527552	More interestingly, pretreatment of MGC-803 cells with pan caspase inhibitor Z-VAD-FMK decreased the percentage of apoptotic cells induced by by241, which implies that by241 induced apoptosis of MGC-803 cells through multiple mechanisms, not limited to the intrinsic apoptotic pathway.	('by241', 'Var', (168, 173))	('decreased', 'NegReg', (87, 96))	('by241', 'Var', (142, 147))	('MGC-803', 'CellLine', 'CVCL:5334', (36, 43))	('apoptosis', 'CPA', (182, 191))	('by241', 'Chemical', '-', (142, 147))	('by241', 'Chemical', '-', (168, 173))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (77, 86))	('MGC-803', 'CellLine', 'CVCL:5334', (195, 202))
284473	27527552	Further mechanistic studies were carried out focusing on other ROS-related pathways, showing that by241 also activated p53 and its downstream proteins such as PUMA and p21, inhibited NF-kappaB and mTOR, cleaved MDM2, and activated PI3K/AKT signaling pathway.	('MDM2', 'Gene', (211, 215))	('p21', 'Gene', (168, 171))	('p21', 'Gene', '644914', (168, 171))	('inhibited', 'NegReg', (173, 182))	('activated', 'PosReg', (109, 118))	('mTOR', 'Gene', '2475', (197, 201))	('AKT', 'Gene', (236, 239))	('PUMA', 'Gene', '27113', (159, 163))	('p53', 'Gene', '7157', (119, 122))	('MDM2', 'Gene', '4193', (211, 215))	('by241', 'Var', (98, 103))	('NF-kappaB', 'Gene', (183, 192))	('cleaved', 'Reg', (203, 210))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('NF-kappaB', 'Gene', '4790', (183, 192))	('p53', 'Gene', (119, 122))	('AKT', 'Gene', '207', (236, 239))	('PUMA', 'Gene', (159, 163))	('activated', 'PosReg', (221, 230))	('by241', 'Chemical', '-', (98, 103))	('mTOR', 'Gene', (197, 201))
284475	27527552	Taken together, by241 induced cell death through ROS-mediated multiple mechanisms.	('cell death', 'CPA', (30, 40))	('by241', 'Chemical', '-', (16, 21))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('ROS-mediated', 'Protein', (49, 61))	('by241', 'Var', (16, 21))
284476	27527552	Further in vivo experiments showed that by241 did not have significant acute oral toxicity on mice even at high dose and exerted good in vivo anticancer efficacy.	('acute oral toxicity', 'Disease', 'MESH:D000208', (71, 90))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('acute oral toxicity', 'Disease', (71, 90))	('by241', 'Chemical', '-', (40, 45))	('mice', 'Species', '10090', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('by241', 'Var', (40, 45))
284477	27527552	Therefore, by241 may serve as a lead for developing potent steroid-based anticancer drugs.	('by241', 'Var', (11, 16))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('steroid', 'Chemical', 'MESH:D013256', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('by241', 'Chemical', '-', (11, 16))
284564	26609527	There are significant differences among Northwest China and three other regions (II, V, or VI) for esophageal cancer (p < 0.05); intake of dietary fiber is associated with a reduced risk of esophageal cancer for adults, whereas the risk is increased with red meat.	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('esophageal cancer', 'Disease', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('esophageal cancer', 'Disease', 'MESH:D004938', (190, 207))	('reduced', 'NegReg', (174, 181))	('dietary fiber', 'Var', (139, 152))	('esophageal cancer', 'Disease', (99, 116))
284568	26609527	There is a significant inverse association between high tea consumption and leukemia risk.	('inverse', 'NegReg', (23, 30))	('leukemia', 'Disease', (76, 84))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('high tea', 'Var', (51, 59))	('leukemia', 'Disease', 'MESH:D007938', (76, 84))
284583	26609527	MGN-3 from rice bran may represent a novel adjuvant for the treatment of metastatic breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('men', 'Species', '9606', (65, 68))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('MGN-3', 'Var', (0, 5))	('rice', 'Species', '4530', (11, 15))	('breast cancer', 'Disease', (84, 97))
284621	26609527	The tumor size in mice having walnut in their diet was one-fourth than that of the control diet.	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (18, 22))	('walnut', 'Var', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
284648	26609527	Himalaya 292 for barley mutant has high contents of beta-glucan (9.7%) and protein (16.4%), as well as amylose starch (81.6%).	('mutant', 'Var', (24, 30))	('protein', 'MPA', (75, 82))	('barley', 'Species', '4513', (17, 23))	('beta-glucan', 'Protein', (52, 63))	('amylose starch', 'MPA', (103, 117))	('amylose starch', 'Chemical', '-', (103, 117))	('contents', 'MPA', (40, 48))	('beta-glucan', 'Chemical', 'MESH:D047071', (52, 63))
284661	26609527	The lipid-transfer protein from barley grain has an affinity to bind Co2+ and Pb2+ but has no affinity towards Cd2+, Cu2+, Zn2+, and Cr3+.	('Pb2+', 'Var', (78, 82))	('lipid', 'Chemical', 'MESH:D008055', (4, 9))	('Cd', 'Chemical', 'MESH:D002104', (111, 113))	('bind', 'Interaction', (64, 68))	('Cr', 'Chemical', 'MESH:D002857', (133, 135))	('Cu2+', 'Chemical', '-', (117, 121))	('Co2+', 'Var', (69, 73))	('Pb2+', 'Chemical', 'MESH:D007854', (78, 82))	('Zn2+', 'Chemical', 'MESH:D015032', (123, 127))	('Co2+', 'Chemical', '-', (69, 73))	('barley', 'Species', '4513', (32, 38))
284663	26609527	Barley with polyphenols possesses many other anticarcinogenic activities, and high epicatechin may be related to a reduced risk of breast cancer and colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (149, 161))	('high epicatechin', 'Var', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('reduced', 'NegReg', (115, 122))	('colon cancer', 'Disease', (149, 161))	('epicatechin', 'Chemical', 'MESH:D002392', (83, 94))	('Barley', 'Species', '4513', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('breast cancer', 'Disease', (131, 144))	('polyphenols', 'Chemical', 'MESH:D059808', (12, 23))	('anticarcinogenic activities', 'MPA', (45, 72))	('colon cancer', 'Phenotype', 'HP:0003003', (149, 161))
284814	23188185	Blots were blocked and then probed with Rad51 (1:500, Santa Cruz), Ku70 (1:500, Santa Cruz) and beta-actin (1:5000, Abcam).	('Ku70', 'Gene', '2547', (67, 71))	('Rad51', 'Gene', '5888', (40, 45))	('Rad51', 'Gene', (40, 45))	('1:500', 'Var', (73, 78))	('Ku70', 'Gene', (67, 71))
284818	23188185	Anti-miRTM miRNA-22 inhibitor (ABI PRISM, Carisbad, CA) was used to knockdown miRNA-22 expression.	('miRNA-22', 'Chemical', '-', (78, 86))	('miRNA-22', 'Gene', (78, 86))	('knockdown', 'Var', (68, 77))	('miRNA-22', 'Chemical', '-', (11, 19))
284838	23188185	In contrast, in patients who received concurrent chemotherapy with radiation therapy (58 out of 100), the survival rate of miRNA-22 high-expression patients was higher than that of miRNA-22 low-expression patients (P = 0.042, Fig.	('patients', 'Species', '9606', (148, 156))	('miRNA-22', 'Chemical', '-', (123, 131))	('patients', 'Species', '9606', (205, 213))	('rat', 'Species', '10116', (115, 118))	('high-expression', 'Var', (132, 147))	('patients', 'Species', '9606', (16, 24))	('miRNA-22', 'Chemical', '-', (181, 189))	('miRNA-22', 'Gene', (123, 131))	('higher', 'PosReg', (161, 167))	('survival rate', 'CPA', (106, 119))
284841	23188185	3, the sequence of miRNA-22 level was EC9706 > KYSE510 > KYSE450 >KYSE150.	('KYSE510', 'Var', (47, 54))	('EC9706', 'CellLine', 'CVCL:E307', (38, 44))	('miRNA-22', 'MPA', (19, 27))	('EC9706 > KYSE510', 'Var', (38, 54))	('miRNA-22', 'Chemical', '-', (19, 27))
284844	23188185	The survival fraction of KYSE150 cells with forced miRNA-22 expression was lower than that of control groups (Fig.	('miRNA-22', 'Gene', (51, 59))	('lower', 'NegReg', (75, 80))	('survival fraction', 'CPA', (4, 21))	('miRNA-22', 'Chemical', '-', (51, 59))	('forced', 'Var', (44, 50))
284845	23188185	Conversely, the survival fraction of miRNA-22 knockdown EC9706 cells was significantly higher than that of control groups (Fig.	('survival fraction', 'CPA', (16, 33))	('miRNA-22', 'Chemical', '-', (37, 45))	('knockdown', 'Var', (46, 55))	('EC9706', 'CellLine', 'CVCL:E307', (56, 62))	('miRNA-22', 'Gene', (37, 45))	('higher', 'PosReg', (87, 93))
284850	23188185	The number of gamma-H2X foci in miRNA-22 knockdown cells was significantly lower than in control cells after irradiation (P < 0.01) (Fig.	('lower', 'NegReg', (75, 80))	('miRNA-22', 'Gene', (32, 40))	('gamma-H2X', 'Chemical', '-', (14, 23))	('miRNA-22', 'Chemical', '-', (32, 40))	('knockdown', 'Var', (41, 50))
284856	23188185	7A, Rad51 expression increased after miRNA-22 knockdown after irradiation, but the Ku70 level did not change.	('miRNA-22', 'Chemical', '-', (37, 45))	('increased', 'PosReg', (21, 30))	('knockdown', 'Var', (46, 55))	('Ku70', 'Gene', (83, 87))	('expression', 'MPA', (10, 20))	('miRNA-22', 'Gene', (37, 45))	('Rad51', 'Gene', '5888', (4, 9))	('Rad51', 'Gene', (4, 9))	('Ku70', 'Gene', '2547', (83, 87))
284865	23188185	Other miRNA, such as miRNA-223, miR-142-3p and let-7 were all found to have effects on ESCC progress.	('miRNA-223', 'Gene', (21, 30))	('miRNA-223', 'Gene', '407008', (21, 30))	('let-7', 'Gene', (47, 52))	('miR-142-3p', 'Var', (32, 42))	('effects', 'Reg', (76, 83))	('ESCC', 'Disease', (87, 91))
284875	23188185	Our results showed that the survival time of patients with high miRNA-22 expression was longer than that of patients with low miRNA-22 expression following radiotherapy, but miRNA-22 had no effect on survival time in patients who did not receive radiotherapy.	('miRNA-22', 'Chemical', '-', (64, 72))	('miRNA-22', 'Chemical', '-', (174, 182))	('miRNA-22', 'Chemical', '-', (126, 134))	('survival time', 'CPA', (28, 41))	('miRNA-22', 'Gene', (64, 72))	('high', 'Var', (59, 63))	('expression', 'MPA', (73, 83))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (217, 225))	('longer', 'PosReg', (88, 94))
284885	23188185	Overexpression of the Rad51 protein has been reported to stimulate homologous recombination and increase resistance of mammalian cells to ionizing radiation.	('stimulate', 'PosReg', (57, 66))	('protein', 'Protein', (28, 35))	('resistance', 'MPA', (105, 115))	('homologous recombination', 'CPA', (67, 91))	('Rad51', 'Gene', (22, 27))	('Rad51', 'Gene', '5888', (22, 27))	('Overexpression', 'Var', (0, 14))	('increase', 'PosReg', (96, 104))	('mammalian', 'Species', '9606', (119, 128))
284904	16202147	As a prognostic factor, survivin expression is significantly associated with poor clinical outcome in cancers, such as neuroblastoma, colorectal cancer, breast cancer, lung cancer and esophageal cancer.	('survivin', 'Protein', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('neuroblastoma', 'Disease', (119, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('associated', 'Reg', (61, 71))	('neuroblastoma', 'Phenotype', 'HP:0003006', (119, 132))	('expression', 'Var', (33, 43))	('colorectal cancer', 'Disease', (134, 151))	('esophageal cancer', 'Disease', (184, 201))	('neuroblastoma', 'Disease', 'MESH:D009447', (119, 132))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Disease', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung cancer', 'Disease', (168, 179))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('breast cancer', 'Disease', (153, 166))
284940	16202147	Venous invasion in pancreatic cancer can be a risk factor for liver metastasis.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (19, 36))	('liver metastasis', 'Disease', 'MESH:D009362', (62, 78))	('liver metastasis', 'Disease', (62, 78))	('Venous', 'Var', (0, 6))	('pancreatic cancer', 'Disease', (19, 36))	('pancreatic cancer', 'Disease', 'MESH:D010190', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
284979	32627975	In this study, we hypothesized that changing the position of head and body might affect the swallowing parameters and improve swallowing abnormalities in patients after esophagectomy, which we called it as the Chin-down-plus-larynx-tightening maneuver.	('swallowing abnormalities', 'MPA', (126, 150))	('changing', 'Var', (36, 44))	('patients', 'Species', '9606', (154, 162))	('swallowing parameters', 'MPA', (92, 113))	('affect', 'Reg', (81, 87))	('improve swallowing', 'Phenotype', 'HP:0002015', (118, 136))	('improve', 'PosReg', (118, 125))
285066	32627975	24 ,  25  However, resection of RLN lymph node may cause RLN injuries and paralysis in 9%-50% of cases, which can affect the glottal closing function while eating, causing water or food enter to trachea, and irritating cough and aspiration occurred.	('glottal closing', 'MPA', (125, 140))	('aspiration', 'CPA', (229, 239))	('paralysis', 'Phenotype', 'HP:0003470', (74, 83))	('affect', 'Reg', (114, 120))	('water or food enter', 'MPA', (172, 191))	('irritating cough', 'Disease', 'MESH:D003371', (208, 224))	('aspiration', 'Phenotype', 'HP:0002835', (229, 239))	('resection', 'Var', (19, 28))	('cough', 'Phenotype', 'HP:0012735', (219, 224))	('water', 'Chemical', 'MESH:D014867', (172, 177))	('cause', 'Reg', (51, 56))	('RLN injuries and paralysis', 'Disease', 'MESH:D010243', (57, 83))	('irritating cough', 'Phenotype', 'HP:0000737', (208, 224))	('irritating cough', 'Disease', (208, 224))
285071	32627975	One point needs special explanation, although for patients with swallowing disorders, drinking water is more likely to cause cough and aspiration.	('cough', 'Disease', (125, 130))	('patients', 'Species', '9606', (50, 58))	('aspiration', 'Phenotype', 'HP:0002835', (135, 145))	('aspiration', 'Disease', (135, 145))	('water', 'Chemical', 'MESH:D014867', (95, 100))	('cause', 'Reg', (119, 124))	('swallowing disorders', 'Phenotype', 'HP:0002015', (64, 84))	('cough', 'Disease', 'MESH:D003371', (125, 130))	('cough', 'Phenotype', 'HP:0012735', (125, 130))	('drinking water', 'Var', (86, 100))
285109	31115568	Analysis of luciferase activity demonstrated that miR-30a-3p interacted with the 3'-UTR of IGF-1R, and knockdown of IGF-1R induced similar effects on the migration, invasion, EMT and radiosensitivity of EC cells.	('miR-30a', 'Gene', (50, 57))	('radiosensitivity', 'CPA', (183, 199))	('IGF-1R', 'Gene', (116, 122))	('IGF-1R', 'Gene', (91, 97))	('EC', 'Phenotype', 'HP:0011459', (203, 205))	('miR-30a', 'Gene', '407029', (50, 57))	('rat', 'Species', '10116', (39, 42))	('invasion', 'CPA', (165, 173))	('rat', 'Species', '10116', (157, 160))	('effects', 'Reg', (139, 146))	('migration', 'CPA', (154, 163))	('knockdown', 'Var', (103, 112))	('EMT', 'CPA', (175, 178))
285119	31115568	For example, miRNA-377 inhibits the initiation and progression of esophageal cancer via suppression of cluster of differentiation 133 and vascular endothelial growth factor.	('inhibits', 'NegReg', (23, 31))	('miRNA-377', 'Chemical', '-', (13, 22))	('esophageal cancer', 'Disease', (66, 83))	('vascular endothelial growth factor', 'Gene', (138, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('miRNA-377', 'Var', (13, 22))	('progression', 'CPA', (51, 62))	('suppression', 'NegReg', (88, 99))	('vascular endothelial growth factor', 'Gene', '7422', (138, 172))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cluster of', 'Protein', (103, 113))	('initiation', 'CPA', (36, 46))
285168	31115568	The following antibodies were purchased from Abcam: IGF-1R (ab39675; 1:1,000 dilution); matrix metalloproteinase-2 (MMP-2; ab37150; 1:1,000 dilution); MMP-9 (ab73734; 1:1,000 dilution); E-cadherin (ab1416; 1:1,000 dilution); vimentin (ab8978; 1:1,000 dilution); N-cadherin (ab18203; 1:1,000 dilution) and GAPDH (ab8245; 1:1,000 dilution).	('E-cadherin', 'Gene', (186, 196))	('E-cadherin', 'Gene', '999', (186, 196))	('MMP-2', 'Gene', (116, 121))	('MMP-9', 'Gene', (151, 156))	('MMP-9', 'Gene', '4318', (151, 156))	('ab73734;', 'Var', (158, 166))	('matrix metalloproteinase-2', 'Gene', (88, 114))	('N-cadherin', 'Gene', (262, 272))	('matrix metalloproteinase-2', 'Gene', '4313', (88, 114))	('vimentin', 'Gene', '7431', (225, 233))	('vimentin', 'Gene', (225, 233))	('N-cadherin', 'Gene', '1000', (262, 272))	('ab8245;', 'Var', (312, 319))	('MMP-2', 'Gene', '4313', (116, 121))	('GAPDH', 'Gene', '2597', (305, 310))	('ab18203;', 'Var', (274, 282))	('GAPDH', 'Gene', (305, 310))
285182	31115568	Cells were plated in 48-well plates for 24 h, psiCheck-2 with the wild-type (WT) or mutant (MUT) 3'-UTR of IGF-1R was cotransfected with miR-30a-3p mimics or miR-NC using Lipofectamine  3000 (Invitrogen; Thermo Fisher Scientific, Inc.).	('miR', 'Gene', '220972', (158, 161))	('miR', 'Gene', (158, 161))	('miR-30a', 'Gene', (137, 144))	('miR', 'Gene', '220972', (137, 140))	('miR', 'Gene', (137, 140))	('Lipofectamine', 'Chemical', 'MESH:C086724', (171, 184))	('mutant', 'Var', (84, 90))	('miR-30a', 'Gene', '407029', (137, 144))	('IGF-1R', 'Gene', (107, 113))
285188	31115568	Furthermore, it was demonstrated that the levels of miR-30a-3p expression in the EC cell lines, EC9706 and EC109, were significantly decreased compared with in a human esophageal epithelial cell line, HET-1A (Fig.	('levels', 'MPA', (42, 48))	('miR-30a', 'Gene', '407029', (52, 59))	('EC109', 'CellLine', 'CVCL:6898', (107, 112))	('EC', 'Phenotype', 'HP:0011459', (81, 83))	('human', 'Species', '9606', (162, 167))	('EC9706', 'CellLine', 'CVCL:E307', (96, 102))	('EC', 'Phenotype', 'HP:0011459', (96, 98))	('rat', 'Species', '10116', (27, 30))	('EC109', 'Var', (107, 112))	('EC', 'Phenotype', 'HP:0011459', (107, 109))	('miR-30a', 'Gene', (52, 59))	('EC9706', 'Var', (96, 102))	('decreased', 'NegReg', (133, 142))
285202	31115568	Additionally, it was revealed that the number of apoptotic cells was markedly decreased following transfection with miR-30a-3p inhibitors, whereas, overexpression of miR-30a-3p notably increased the number of apoptotic cells compared with the control group (Fig.	('miR-30a', 'Gene', '407029', (166, 173))	('miR-30a', 'Gene', (116, 123))	('inhibitors', 'Var', (127, 137))	('miR-30a', 'Gene', (166, 173))	('decreased', 'NegReg', (78, 87))	('miR-30a', 'Gene', '407029', (116, 123))	('increased', 'PosReg', (185, 194))
285220	31115568	7C and D, the levels of IGF-1R mRNA and protein expression were significantly downregulated in EC9706 and EC109 cells transfected with miR-30a-3p mimics compared with the control, whereas miR-30a-3p inhibitors promoted IGF-1R expression (Fig.	('EC9706', 'CellLine', 'CVCL:E307', (95, 101))	('miR-30a', 'Gene', (188, 195))	('EC109', 'CellLine', 'CVCL:6898', (106, 111))	('levels', 'MPA', (14, 20))	('EC', 'Phenotype', 'HP:0011459', (95, 97))	('expression', 'MPA', (226, 236))	('miR-30a', 'Gene', '407029', (135, 142))	('EC', 'Phenotype', 'HP:0011459', (106, 108))	('IGF-1R', 'Gene', (24, 30))	('miR-30a', 'Gene', '407029', (188, 195))	('promoted', 'PosReg', (210, 218))	('EC9706', 'Var', (95, 101))	('IGF-1R', 'Gene', (219, 225))	('miR-30a', 'Gene', (135, 142))	('downregulated', 'NegReg', (78, 91))
285223	31115568	To investigate the effects of IGF-1R on the migration, invasion, EMT and radiosensitivity of EC cells, EC9706 and EC109 cells were transfected with si-IGF-1R, and RT-qPCR analysis was performed to determine the transfection efficiency.	('EMT', 'CPA', (65, 68))	('EC109', 'CellLine', 'CVCL:6898', (114, 119))	('EC9706', 'CellLine', 'CVCL:E307', (103, 109))	('rat', 'Species', '10116', (47, 50))	('EC', 'Phenotype', 'HP:0011459', (103, 105))	('si-IGF-1R', 'Var', (148, 157))	('EC', 'Phenotype', 'HP:0011459', (114, 116))	('EC', 'Phenotype', 'HP:0011459', (93, 95))
285224	31115568	9A, the levels of IGF-1R mRNA expression were significantly reduced in EC9706 and EC109 cells following transfection with si-IGF-1R.	('EC', 'Phenotype', 'HP:0011459', (71, 73))	('si-IGF-1R', 'Var', (122, 131))	('levels', 'MPA', (8, 14))	('EC', 'Phenotype', 'HP:0011459', (82, 84))	('reduced', 'NegReg', (60, 67))	('EC109', 'CellLine', 'CVCL:6898', (82, 87))	('EC9706', 'CellLine', 'CVCL:E307', (71, 77))	('IGF-1R mRNA expression', 'MPA', (18, 40))
285227	31115568	It was demonstrated that, compared with the control, E-cadherin protein was significantly upregulated, and vimentin and N-cadherin proteins were significantly downregulated following transfection with si-IGF-1R (Fig.	('vimentin', 'Gene', '7431', (107, 115))	('E-cadherin', 'Gene', (53, 63))	('vimentin', 'Gene', (107, 115))	('E-cadherin', 'Gene', '999', (53, 63))	('N-cadherin', 'Gene', '1000', (120, 130))	('upregulated', 'PosReg', (90, 101))	('downregulated', 'NegReg', (159, 172))	('si-IGF-1R', 'Var', (201, 210))	('rat', 'Species', '10116', (14, 17))	('N-cadherin', 'Gene', (120, 130))
285229	31115568	It was demonstrated that si-IGF-1R significantly suppressed the migration and invasion of EC9706 and EC109 cells compared with the control (Fig.	('rat', 'Species', '10116', (67, 70))	('EC', 'Phenotype', 'HP:0011459', (101, 103))	('EC109', 'CellLine', 'CVCL:6898', (101, 106))	('invasion', 'CPA', (78, 86))	('migration', 'CPA', (64, 73))	('EC9706', 'CellLine', 'CVCL:E307', (90, 96))	('suppressed', 'NegReg', (49, 59))	('EC', 'Phenotype', 'HP:0011459', (90, 92))	('si-IGF-1R', 'Var', (25, 34))	('rat', 'Species', '10116', (14, 17))
285252	31115568	Kim et al reported that bronchial epithelial cells lacking p53 or expressing mutations in v-Ki-Ras2 Kirsten rat sarcoma viral oncogene homolog exhibited upregulation of IGF-1 and IGF-2; the transformed characteristics of these cells could be suppressed by IGF-1R inactivation, or enhanced by overexpression of IGF-1R.	('p53', 'Gene', (59, 62))	('upregulation', 'PosReg', (153, 165))	('IGF-1', 'Gene', '24482', (310, 315))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('v-Ki-Ras2', 'Gene', (90, 99))	('lacking', 'NegReg', (51, 58))	('transformed characteristics of', 'CPA', (190, 220))	('sarcoma viral', 'Disease', 'MESH:D001102', (112, 125))	('IGF-2', 'Gene', (179, 184))	('rat', 'Species', '10116', (108, 111))	('sarcoma viral', 'Disease', (112, 125))	('IGF-1', 'Gene', (169, 174))	('IGF-1', 'Gene', (256, 261))	('mutations', 'Var', (77, 86))	('suppressed', 'NegReg', (242, 252))	('inactivation', 'Var', (263, 275))	('IGF-1', 'Gene', (310, 315))	('IGF-1', 'Gene', '24482', (169, 174))	('p53', 'Gene', '301300', (59, 62))	('IGF-1', 'Gene', '24482', (256, 261))	('enhanced', 'PosReg', (280, 288))
285256	31115568	Furthermore, silencing of IGF-1R affected the migration, invasion and radiosensitivity of EC cells; however, whether miR-30a-3p exerts its effects on EC via targeting IGF-1R requires further investigation.	('miR-30a', 'Gene', '407029', (117, 124))	('affected', 'Reg', (33, 41))	('invasion', 'CPA', (57, 65))	('EC', 'Phenotype', 'HP:0011459', (150, 152))	('migration', 'CPA', (46, 55))	('IGF-1R', 'Gene', (26, 32))	('radiosensitivity', 'CPA', (70, 86))	('IGF-1R', 'Gene', (167, 173))	('miR-30a', 'Gene', (117, 124))	('EC', 'Phenotype', 'HP:0011459', (90, 92))	('rat', 'Species', '10116', (49, 52))	('silencing', 'Var', (13, 22))
285285	30333403	Given these findings, the patient was diagnosed preoperatively with cT1 N0 M0 cStageI [Union for International Cancer Control (UICC) 8th edition] oropharyngeal cancer (p16-negative), and cT1a N0 M0 cStageIA (UICC 7th edition) esophageal cancer.	('patient', 'Species', '9606', (26, 33))	('cT1', 'Disease', (68, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (226, 243))	('cT1a N0 M0 cStageIA', 'Var', (187, 206))	('p16', 'Gene', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (146, 166))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('oropharyngeal cancer', 'Disease', (146, 166))	('esophageal cancer', 'Disease', (226, 243))	('p16', 'Gene', '1029', (168, 171))
285291	30333403	Based on these findings, the patient was diagnosed postoperatively with T1N1M0 pStageIII oropharyngeal cancer (p16-negative) and LPM ly-v-HM-VM-esophageal cancer, and curative resection of the esophageal cancer was achieved by ESD.	('patient', 'Species', '9606', (29, 36))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('oropharyngeal cancer', 'Disease', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('p16', 'Gene', '1029', (111, 114))	('HM-VM-esophageal cancer', 'Disease', 'MESH:D004938', (138, 161))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('T1N1M0', 'Var', (72, 78))	('esophageal cancer', 'Disease', (193, 210))	('p16', 'Gene', (111, 114))	('HM-VM-esophageal cancer', 'Disease', (138, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))
285299	30333403	In general, cancer occurrence following hematopoietic stem cell transplantation is associated with chronic GVHD and is thought to be caused by radiation therapy and immunosuppression prior to and after hematopoietic stem cell transplantation, tumor-associated viruses, and mutations in p35 gene.	('GVHD', 'Disease', (107, 111))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('p35', 'Gene', '3592', (286, 289))	('cancer', 'Disease', (12, 18))	('p35', 'Gene', (286, 289))	('caused by', 'Reg', (133, 142))	('mutations', 'Var', (273, 282))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('associated', 'Reg', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('GVHD', 'Disease', 'MESH:D006086', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
285325	29200867	The relationship between IGF2BP2 and PPARG polymorphisms and susceptibility to esophageal squamous-cell carcinomas in the eastern Chinese Han population The aim of this case-control study was to assess whether PPARG and IGF2BP2 polymorphisms confer susceptibility to esophageal squamous-cell carcinoma (ESCC).	('esophageal squamous-cell carcinomas', 'Disease', 'MESH:D000077277', (79, 114))	('IGF2BP2', 'Gene', '10644', (25, 32))	('IGF2BP2', 'Gene', (220, 227))	('PPARG', 'Gene', '5468', (210, 215))	('esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (267, 301))	('susceptibility', 'Reg', (249, 263))	('squamous-cell carcinomas', 'Phenotype', 'HP:0002860', (90, 114))	('PPARG', 'Gene', (210, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('esophageal squamous-cell carcinoma', 'Disease', (267, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('IGF2BP2', 'Gene', '10644', (220, 227))	('esophageal squamous-cell carcinomas', 'Disease', (79, 114))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('IGF2BP2', 'Gene', (25, 32))	('polymorphisms', 'Var', (228, 241))	('PPARG', 'Gene', '5468', (37, 42))	('PPARG', 'Gene', (37, 42))	('esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (278, 301))
285327	29200867	The PPARG rs1801282 C>G and rs3856806 C>T and IGF2BP2 rs1470579 A>C and rs4402960 G>T polymorphisms were selected and genotyped by SNPscan genotyping assays.	('IGF2BP2', 'Gene', '10644', (46, 53))	('rs4402960', 'Mutation', 'rs4402960', (72, 81))	('rs1470579', 'Mutation', 'rs1470579', (54, 63))	('rs4402960 G>T', 'Var', (72, 85))	('IGF2BP2', 'Gene', (46, 53))	('rs1801282', 'Mutation', 'rs1801282', (10, 19))	('rs1801282 C>G', 'Var', (10, 23))	('PPARG', 'Gene', (4, 9))	('rs3856806', 'Mutation', 'rs3856806', (28, 37))	('PPARG', 'Gene', '5468', (4, 9))	('rs3856806 C>T', 'Var', (28, 41))	('rs1470579 A>C', 'Var', (54, 67))
285328	29200867	Multivariable logistic analysis suggested that the PPARG rs3856806 C>T polymorphism might increase the risk of ESCC.	('PPARG', 'Gene', '5468', (51, 56))	('PPARG', 'Gene', (51, 56))	('increase', 'PosReg', (90, 98))	('rs3856806', 'Mutation', 'rs3856806', (57, 66))	('rs3856806 C>T', 'Var', (57, 70))	('ESCC', 'Disease', (111, 115))
285329	29200867	In different stratified analyses, there were significant associations between PPARG rs3856806 C>T and risk of ESCC in female, never-smoking, drinking, and never-drinking subgroups.	('rs3856806', 'Mutation', 'rs3856806', (84, 93))	('rs3856806 C>T', 'Var', (84, 97))	('PPARG', 'Gene', '5468', (78, 83))	('PPARG', 'Gene', (78, 83))	('ESCC', 'Disease', (110, 114))
285330	29200867	In addition, we also found that PPARG rs1801282 C>G increased ESCC risk in the never-smoking subgroup.	('increased', 'PosReg', (52, 61))	('increased ESCC', 'Phenotype', 'HP:0003565', (52, 66))	('PPARG', 'Gene', '5468', (32, 37))	('PPARG', 'Gene', (32, 37))	('rs1801282', 'Mutation', 'rs1801282', (38, 47))	('rs1801282 C>G', 'Var', (38, 51))	('ESCC', 'Disease', (62, 66))
285331	29200867	There was significant difference in Crs1470579Grs4402960Crs1801282Crs3856806-haplotype distribution among ESCC cases and control subjects.	('ESCC', 'Disease', (106, 110))	('Crs1470579Grs4402960Crs1801282Crs3856806', 'Chemical', '-', (36, 76))	('Crs1470579Grs4402960Crs1801282Crs3856806-haplotype', 'Var', (36, 86))
285332	29200867	In conclusion, our findings highlight that PPARG rs1801282 C>G and rs3856806 C>T polymorphisms are candidates for susceptibility to ESCC in the eastern Chinese Han population.	('rs1801282', 'Mutation', 'rs1801282', (49, 58))	('rs3856806', 'Mutation', 'rs3856806', (67, 76))	('rs3856806 C>T', 'Var', (67, 80))	('PPARG', 'Gene', '5468', (43, 48))	('PPARG', 'Gene', (43, 48))	('susceptibility', 'Reg', (114, 128))	('rs1801282 C>G', 'Var', (49, 62))	('ESCC', 'Disease', (132, 136))
285333	29200867	The Crs1470579Grs4402960Crs1801282Crs3856806 haplotype is associated with susceptibility to ESCC.	('Crs1470579Grs4402960Crs1801282Crs3856806', 'Var', (4, 44))	('susceptibility', 'Reg', (74, 88))	('ESCC', 'Disease', (92, 96))	('associated', 'Reg', (58, 68))	('Crs1470579Grs4402960Crs1801282Crs3856806', 'Chemical', '-', (4, 44))
285341	29200867	Polymorphisms in the PPARG gene are assumed to influence the development of malignancies and metabolism-related diseases.	('malignancies', 'Disease', (76, 88))	('influence', 'Reg', (47, 56))	('Polymorphisms', 'Var', (0, 13))	('malignancies', 'Disease', 'MESH:D009369', (76, 88))	('PPARG', 'Gene', '5468', (21, 26))	('metabolism-related diseases', 'CPA', (93, 120))	('PPARG', 'Gene', (21, 26))
285342	29200867	Pro12Ala (rs1801282 C>G) and His449His (rs3856806 C>T) polymorphisms are the two most common single-nucleotide polymorphism (SNPs) in the PPARG gene.	('rs1801282', 'Mutation', 'rs1801282', (10, 19))	('rs1801282 C>G', 'Var', (10, 23))	('His449His (rs3856806 C>T', 'Var', (29, 53))	('rs3856806', 'Mutation', 'rs3856806', (40, 49))	('PPARG', 'Gene', '5468', (138, 143))	('Pro12Ala', 'Chemical', '-', (0, 8))	('PPARG', 'Gene', (138, 143))
285343	29200867	Recently, a case-control study was conducted to assess the relationship of PPARG rs3856806 C>T with susceptibility to EC.	('rs3856806 C>T', 'Var', (81, 94))	('PPARG', 'Gene', '5468', (75, 80))	('PPARG', 'Gene', (75, 80))	('rs3856806', 'Mutation', 'rs3856806', (81, 90))
285344	29200867	The results indicated that PPARG rs3856806 C>T might be associated with the risk of EC.	('PPARG', 'Gene', (27, 32))	('rs3856806', 'Mutation', 'rs3856806', (33, 42))	('rs3856806 C>T', 'Var', (33, 46))	('associated', 'Reg', (56, 66))	('PPARG', 'Gene', '5468', (27, 32))
285345	29200867	In addition, the association between PPARG rs1801282 C>G polymorphism and EC risk was unknown.	('rs1801282 C>G', 'Var', (43, 56))	('PPARG', 'Gene', (37, 42))	('PPARG', 'Gene', '5468', (37, 42))	('rs1801282', 'Mutation', 'rs1801282', (43, 52))
285348	29200867	Case-control studies have indicated that IGF2BP2 rs4402960 G>T might be associated with the risk of breast cancer and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('rs4402960', 'Mutation', 'rs4402960', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('associated', 'Reg', (72, 82))	('IGF2BP2', 'Gene', '10644', (41, 48))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('IGF2BP2', 'Gene', (41, 48))	('colorectal cancer', 'Disease', (118, 135))	('rs4402960 G>T', 'Var', (49, 62))
285349	29200867	In addition, it has been reported that IGF2BP2 rs1470579 A>C was associated with the risk of type 2 diabetes.	('type 2 diabetes', 'Disease', 'MESH:D003924', (93, 108))	('IGF2BP2', 'Gene', '10644', (39, 46))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (93, 108))	('rs1470579 A>C', 'Var', (47, 60))	('rs1470579', 'Mutation', 'rs1470579', (47, 56))	('IGF2BP2', 'Gene', (39, 46))	('associated', 'Reg', (65, 75))	('type 2 diabetes', 'Disease', (93, 108))
285350	29200867	However, the association between IGF2BP2 polymorphisms and EC risk was unclear.	('polymorphisms', 'Var', (41, 54))	('IGF2BP2', 'Gene', '10644', (33, 40))	('IGF2BP2', 'Gene', (33, 40))
285351	29200867	The aim of this case-control study was to explore the potential relationship of genetic variations in PPARG and IGF2BP2 with risk of ESCC in the eastern Chinese Han population.	('genetic variations', 'Var', (80, 98))	('IGF2BP2', 'Gene', '10644', (112, 119))	('ESCC', 'Disease', (133, 137))	('IGF2BP2', 'Gene', (112, 119))	('PPARG', 'Gene', '5468', (102, 107))	('PPARG', 'Gene', (102, 107))
285352	29200867	PPARG rs1801282 C>G and rs3856806 C>T and IGF2BP2 rs1470579 A>C and rs4402960 G>T polymorphisms were selected and genotyped by SNPscan genotyping assays in 507 patients with ESCC and 1,496 controls.	('patients', 'Species', '9606', (160, 168))	('rs1801282', 'Mutation', 'rs1801282', (6, 15))	('rs1801282 C>G', 'Var', (6, 19))	('ESCC', 'Disease', (174, 178))	('rs4402960 G>T', 'Var', (68, 81))	('IGF2BP2', 'Gene', '10644', (42, 49))	('PPARG', 'Gene', '5468', (0, 5))	('PPARG', 'Gene', (0, 5))	('rs3856806 C>T', 'Var', (24, 37))	('rs4402960', 'Mutation', 'rs4402960', (68, 77))	('rs3856806', 'Mutation', 'rs3856806', (24, 33))	('rs1470579 A>C', 'Var', (50, 63))	('IGF2BP2', 'Gene', (42, 49))	('rs1470579', 'Mutation', 'rs1470579', (50, 59))
285359	29200867	PPARG rs1801282 C>G and rs3856806 C>T and IGF2BP2 rs1470579 A>C and rs4402960 G>T genotypes were determined by double ligation and multiplex-fluorescence polymerase chain reaction (SNPscan; Genesky Biotechnologies, Shanghai, China).	('rs1801282', 'Mutation', 'rs1801282', (6, 15))	('rs1801282 C>G', 'Var', (6, 19))	('rs4402960 G>T', 'Var', (68, 81))	('IGF2BP2', 'Gene', '10644', (42, 49))	('PPARG', 'Gene', '5468', (0, 5))	('PPARG', 'Gene', (0, 5))	('rs3856806 C>T', 'Var', (24, 37))	('rs4402960', 'Mutation', 'rs4402960', (68, 77))	('rs3856806', 'Mutation', 'rs3856806', (24, 33))	('rs1470579 A>C', 'Var', (50, 63))	('IGF2BP2', 'Gene', (42, 49))	('rs1470579', 'Mutation', 'rs1470579', (50, 59))
285360	29200867	Genotypes of PPARG rs1801282 C>G and rs3856806 C>T and IGF2BP2 rs1470579 A>C and rs4402960 G>T polymorphisms were confirmed.	('IGF2BP2', 'Gene', (55, 62))	('rs1801282 C>G', 'Var', (19, 32))	('rs4402960 G>T', 'Var', (81, 94))	('rs3856806', 'Mutation', 'rs3856806', (37, 46))	('rs3856806 C>T', 'Var', (37, 50))	('rs1470579 A>C', 'Var', (63, 76))	('PPARG', 'Gene', '5468', (13, 18))	('IGF2BP2', 'Gene', '10644', (55, 62))	('rs4402960', 'Mutation', 'rs4402960', (81, 90))	('rs1470579', 'Mutation', 'rs1470579', (63, 72))	('PPARG', 'Gene', (13, 18))	('rs1801282', 'Mutation', 'rs1801282', (19, 28))
285362	29200867	The relationships of PPARG rs1801282 C>G and rs3856806 C>T and IGF2BP2 rs1470579 A>C and rs4402960 G>T polymorphisms with ESCC susceptibility were determined by crude odds ratios (ORs) and 95% CIs.	('rs3856806', 'Mutation', 'rs3856806', (45, 54))	('rs1470579 A>C', 'Var', (71, 84))	('IGF2BP2', 'Gene', (63, 70))	('rs1470579', 'Mutation', 'rs1470579', (71, 80))	('ESCC', 'Disease', (122, 126))	('rs4402960 G>T', 'Var', (89, 102))	('rs1801282', 'Mutation', 'rs1801282', (27, 36))	('IGF2BP2', 'Gene', '10644', (63, 70))	('rs1801282 C>G', 'Var', (27, 40))	('PPARG', 'Gene', '5468', (21, 26))	('rs3856806 C>T', 'Var', (45, 58))	('rs4402960', 'Mutation', 'rs4402960', (89, 98))	('PPARG', 'Gene', (21, 26))
285365	29200867	The primary information for PPARG rs1801282 C>G and rs3856806 C>T and IGF2BP2 rs1470579 A>C and rs4402960 G>T SNPs is shown in Table 2.	('rs3856806', 'Mutation', 'rs3856806', (52, 61))	('rs1470579 A>C', 'Var', (78, 91))	('rs4402960', 'Mutation', 'rs4402960', (96, 105))	('rs1470579', 'Mutation', 'rs1470579', (78, 87))	('rs1801282', 'Mutation', 'rs1801282', (34, 43))	('rs1801282 C>G', 'Var', (34, 47))	('PPARG', 'Gene', (28, 33))	('IGF2BP2', 'Gene', '10644', (70, 77))	('rs4402960 G>T', 'Var', (96, 109))	('rs3856806 C>T', 'Var', (52, 65))	('PPARG', 'Gene', '5468', (28, 33))	('IGF2BP2', 'Gene', (70, 77))
285366	29200867	Minor allele frequency of PPARG rs1801282 C>G and rs3856806 C>T and IGF2BP2 rs1470579 A>C and rs4402960 G>T SNPs in controls was close to the minor allele-frequency data for Chinese (Table 2).	('rs1470579', 'Mutation', 'rs1470579', (76, 85))	('rs3856806 C>T', 'Var', (50, 63))	('IGF2BP2', 'Gene', '10644', (68, 75))	('rs1801282 C>G', 'Var', (32, 45))	('rs4402960', 'Mutation', 'rs4402960', (94, 103))	('rs3856806', 'Mutation', 'rs3856806', (50, 59))	('rs1801282', 'Mutation', 'rs1801282', (32, 41))	('PPARG', 'Gene', '5468', (26, 31))	('IGF2BP2', 'Gene', (68, 75))	('PPARG', 'Gene', (26, 31))	('rs1470579 A>C', 'Var', (76, 89))	('rs4402960 G>T', 'Var', (94, 107))
285367	29200867	In controls, the genotype frequencies for PPARG rs1801282 C>G and rs3856806 C>T polymorphisms were in Hardy-Weinberg equilibrium (Table 2).	('rs3856806', 'Mutation', 'rs3856806', (66, 75))	('rs3856806 C>T', 'Var', (66, 79))	('rs1801282', 'Mutation', 'rs1801282', (48, 57))	('rs1801282 C>G', 'Var', (48, 61))	('Hardy-Weinberg equilibrium', 'Disease', (102, 128))	('PPARG', 'Gene', '5468', (42, 47))	('PPARG', 'Gene', (42, 47))
285368	29200867	The genotypes of PPARG rs1801282 C>G and rs3856806 C>T and IGF2BP2 rs1470579 A>C and rs4402960 G>T polymorphisms are summarized in Table 3.	('rs3856806', 'Mutation', 'rs3856806', (41, 50))	('rs1470579 A>C', 'Var', (67, 80))	('rs1801282 C>G', 'Var', (23, 36))	('PPARG', 'Gene', (17, 22))	('rs1470579', 'Mutation', 'rs1470579', (67, 76))	('rs4402960 G>T', 'Var', (85, 98))	('IGF2BP2', 'Gene', '10644', (59, 66))	('rs3856806 C>T', 'Var', (41, 54))	('rs4402960', 'Mutation', 'rs4402960', (85, 94))	('PPARG', 'Gene', '5468', (17, 22))	('IGF2BP2', 'Gene', (59, 66))	('rs1801282', 'Mutation', 'rs1801282', (23, 32))
285369	29200867	In single-locus analyses, the genotype frequencies of PPARG rs3856806 C>T were 54.56% (CC), 39.09% (CT), and 6.35% (TT) in ESCC patients and 59.7% (CC), 36.13% (CT), and 4.16% (TT) in controls.	('rs3856806 C>T', 'Var', (60, 73))	('ESCC', 'Disease', (123, 127))	('PPARG', 'Gene', '5468', (54, 59))	('PPARG', 'Gene', (54, 59))	('rs3856806', 'Mutation', 'rs3856806', (60, 69))	('patients', 'Species', '9606', (128, 136))
285370	29200867	When the PPARG rs3856806 CC homozygote genotype was used as the reference group, the PPARG rs3856806 CT genotype was correlated with a significantly increased risk of ESCC (CT vs CC, adjusted OR 1.28, 95% CI=1.02-1.6; P=0.033).	('PPARG', 'Gene', '5468', (9, 14))	('rs3856806', 'Var', (91, 100))	('rs3856806', 'Mutation', 'rs3856806', (15, 24))	('PPARG', 'Gene', (9, 14))	('PPARG', 'Gene', '5468', (85, 90))	('rs3856806', 'Mutation', 'rs3856806', (91, 100))	('PPARG', 'Gene', (85, 90))
285371	29200867	When the PPARG rs3856806 CC homozygote genotype was used as the reference group, the PPARG rs3856806 TT genotype was correlated with a borderline significantly increased risk of ESCC (TT vs CC, adjusted OR 1.55, 95% CI=0.96-2.50; P=0.074).	('PPARG', 'Gene', '5468', (9, 14))	('rs3856806', 'Var', (91, 100))	('rs3856806', 'Mutation', 'rs3856806', (15, 24))	('PPARG', 'Gene', (9, 14))	('PPARG', 'Gene', '5468', (85, 90))	('rs3856806', 'Mutation', 'rs3856806', (91, 100))	('ESCC', 'Disease', (178, 182))	('PPARG', 'Gene', (85, 90))
285372	29200867	In the recessive model, when the PPARG rs3856806 CC/CT genotypes were used as the reference group, the PPARG rs3856806 TT homozygote genotype was not associated with susceptibility for ESCC (adjusted OR 1.41, 95% CI=0.88-2.26; P=0.153).	('PPARG', 'Gene', (103, 108))	('PPARG', 'Gene', '5468', (33, 38))	('PPARG', 'Gene', (33, 38))	('rs3856806 TT', 'Var', (109, 121))	('rs3856806', 'Mutation', 'rs3856806', (109, 118))	('rs3856806', 'Mutation', 'rs3856806', (39, 48))	('ESCC', 'Disease', (185, 189))	('PPARG', 'Gene', '5468', (103, 108))	('rs3856806', 'Var', (39, 48))
285373	29200867	In the dominant model, PPARG rs3856806 CT/TT genotypes were associated with an increased risk of ESCC compared with the PPARG rs3856806 CC genotype (adjusted OR 1.31, 95% CI=1.06-1.63; P=0.014) (Table 3).	('rs3856806', 'Mutation', 'rs3856806', (29, 38))	('PPARG', 'Gene', '5468', (23, 28))	('PPARG', 'Gene', '5468', (120, 125))	('PPARG', 'Gene', (23, 28))	('PPARG', 'Gene', (120, 125))	('rs3856806', 'Mutation', 'rs3856806', (126, 135))	('rs3856806', 'Var', (29, 38))	('ESCC', 'Disease', (97, 101))
285374	29200867	Logistic regression analyses showed that PPARG rs1801282 C>G and IGF2BP2 rs1470579 A>C, rs4402960 G>T polymorphisms were not correlated with the susceptibility for ESCC (Table 3).	('PPARG', 'Gene', (41, 46))	('rs1801282', 'Mutation', 'rs1801282', (47, 56))	('rs4402960 G>T', 'Var', (88, 101))	('rs1801282 C>G', 'Var', (47, 60))	('ESCC', 'Disease', (164, 168))	('IGF2BP2', 'Gene', '10644', (65, 72))	('rs4402960', 'Mutation', 'rs4402960', (88, 97))	('rs1470579 A>C', 'Var', (73, 86))	('rs1470579', 'Mutation', 'rs1470579', (73, 82))	('IGF2BP2', 'Gene', (65, 72))	('PPARG', 'Gene', '5468', (41, 46))
285375	29200867	To determine the potential effects of PPARG rs1801282 C>G genotypes on ESCC risk in different subgroups according to BMI, age, sex, and smoking and drinking status, we carried out stratified analyses (Table 4).	('rs1801282', 'Mutation', 'rs1801282', (44, 53))	('ESCC', 'Disease', (71, 75))	('rs1801282 C>G', 'Var', (44, 57))	('PPARG', 'Gene', '5468', (38, 43))	('PPARG', 'Gene', (38, 43))
285376	29200867	In the never-smoking subgroup, after adjustment for sex, age, BMI, and alcohol use, we found that the PPARG rs1801282 C>G polymorphism increased ESCC risk in two genetic models (CG vs CC, adjusted OR 1.54, 95% CI 1.01-2.35, P=0.047; CG/GG vs CC, adjusted OR 1.54, 95% CI 1.01-2.34, P=0.044 [Table 4]).	('CG', 'Chemical', 'MESH:C028505', (178, 180))	('alcohol', 'Chemical', 'MESH:D000438', (71, 78))	('CG', 'Chemical', 'MESH:C028505', (233, 235))	('increased ESCC', 'Phenotype', 'HP:0003565', (135, 149))	('PPARG', 'Gene', '5468', (102, 107))	('PPARG', 'Gene', (102, 107))	('rs1801282', 'Mutation', 'rs1801282', (108, 117))	('alcohol use', 'Phenotype', 'HP:0030955', (71, 82))	('rs1801282 C>G', 'Var', (108, 121))	('ESCC', 'Disease', (145, 149))
285377	29200867	Table 5 shows genotype frequencies of PPARG rs3856806 C>T in different subgroups.	('rs3856806 C>T', 'Var', (44, 57))	('PPARG', 'Gene', (38, 43))	('rs3856806', 'Mutation', 'rs3856806', (44, 53))	('PPARG', 'Gene', '5468', (38, 43))
285378	29200867	Significantly increased susceptibility to ESCC associated with the PPARG rs3856806 C>T polymorphism was found among several subgroups (Table 5).	('rs3856806 C>T', 'Var', (73, 86))	('PPARG', 'Gene', '5468', (67, 72))	('PPARG', 'Gene', (67, 72))	('ESCC', 'Disease', (42, 46))	('rs3856806', 'Mutation', 'rs3856806', (73, 82))
285379	29200867	In the female subgroup after adjustment for BMI, age, and smoking and drinking status, the PPARG rs3856806 CT/TT genotypes were associated with increased ESCC risk compared with the PPARG rs3856806 CC genotype (CT/TT vs CC, adjusted OR 1.55, 95% CI 1.02-2.35; P=0.041 [Table 5]).	('rs3856806', 'Mutation', 'rs3856806', (97, 106))	('increased ESCC', 'Phenotype', 'HP:0003565', (144, 158))	('PPARG', 'Gene', '5468', (91, 96))	('ESCC', 'Disease', (154, 158))	('rs3856806', 'Var', (97, 106))	('PPARG', 'Gene', (91, 96))	('rs3856806', 'Mutation', 'rs3856806', (188, 197))	('PPARG', 'Gene', '5468', (182, 187))	('PPARG', 'Gene', (182, 187))
285380	29200867	In the never-smoking subgroup after adjustment for BMI, age, sex, and drinking status, we found that PPARG rs3856806 CT/TT genotypes increased ESCC risk compared with the PPARG rs3856806 CC genotype (CT/TT vs CC, adjusted OR 1.37, 95% CI 1.03-1.82; P=0.032 [Table 5]).	('PPARG', 'Gene', '5468', (101, 106))	('increased ESCC', 'Phenotype', 'HP:0003565', (133, 147))	('PPARG', 'Gene', (101, 106))	('rs3856806', 'Mutation', 'rs3856806', (177, 186))	('ESCC', 'Disease', (143, 147))	('PPARG', 'Gene', '5468', (171, 176))	('PPARG', 'Gene', (171, 176))	('rs3856806', 'Var', (107, 116))	('increased', 'PosReg', (133, 142))	('rs3856806', 'Mutation', 'rs3856806', (107, 116))
285381	29200867	In the drinking subgroup after adjustment for BMI, age, sex, and smoking status, significantly increased risk of ESCC associated with the PPARG rs3856806 C>T polymorphism was also found (TT vs CC, adjusted OR 3.36, 95% CI 1.05-12.74, P=0.041; TT vs CT/CC, adjusted OR 3.58, 95% CI 1.04-12.29, P=0.043 [Table 5]).	('ESCC', 'Disease', (113, 117))	('rs3856806', 'Mutation', 'rs3856806', (144, 153))	('PPARG', 'Gene', '5468', (138, 143))	('rs3856806 C>T', 'Var', (144, 157))	('PPARG', 'Gene', (138, 143))
285382	29200867	In the never-drinking subgroup after adjustment for BMI, age, sex, and smoking status, significantly increased risk of ESCC associated with the PPARG rs3856806 C>T polymorphism was also found (CT vs CC, adjusted OR 1.37, 95% CI 1.06-1.77, P=0.015; CT/TT vs CC, adjusted OR 1.37, 95% CI 1.07-1.75, P=0.013 [Table 5]).	('ESCC', 'Disease', (119, 123))	('rs3856806', 'Mutation', 'rs3856806', (150, 159))	('rs3856806 C>T', 'Var', (150, 163))	('PPARG', 'Gene', '5468', (144, 149))	('PPARG', 'Gene', (144, 149))
285383	29200867	In addition, there was no significant risk of ESCC correlated with the IGF2BP2 rs1470579 A>C and rs4402960 G>T polymorphisms evident among any subgroup (data not shown).	('IGF2BP2', 'Gene', '10644', (71, 78))	('ESCC', 'Disease', (46, 50))	('IGF2BP2', 'Gene', (71, 78))	('rs4402960', 'Mutation', 'rs4402960', (97, 106))	('rs1470579 A>C', 'Var', (79, 92))	('rs1470579', 'Mutation', 'rs1470579', (79, 88))	('rs4402960 G>T', 'Var', (97, 110))
285384	29200867	There were significant differences in the CGCC haplotype of the order rs1470579 A>C, rs4402960 G>T, rs1801282 C>G and rs3856806 C>T polymorphism distribution among ESCC cases and the control subjects (OR 2.23, 95% CI=1.09-4.59; P=0.025 [Table 6]).	('rs1470579', 'Mutation', 'rs1470579', (70, 79))	('rs3856806', 'Mutation', 'rs3856806', (118, 127))	('CGCC', 'Gene', (42, 46))	('differences', 'Reg', (23, 34))	('rs4402960 G>T', 'Var', (85, 98))	('CG', 'Chemical', 'MESH:C028505', (42, 44))	('ESCC', 'Disease', (164, 168))	('rs1801282', 'Mutation', 'rs1801282', (100, 109))	('rs1470579 A>C', 'Var', (70, 83))	('rs1801282 C>G', 'Var', (100, 113))	('rs4402960', 'Mutation', 'rs4402960', (85, 94))	('rs3856806', 'Var', (118, 127))
285385	29200867	In this case-control study, we explored the associations between the PPARG rs1801282 C>G and rs3856806 C>T and IGF2BP2 rs1470579 A>C and rs4402960 G>T SNPs and risk of ESCC in the eastern Chinese Han population.	('rs3856806 C>T', 'Var', (93, 106))	('PPARG', 'Gene', (69, 74))	('rs1801282', 'Mutation', 'rs1801282', (75, 84))	('IGF2BP2', 'Gene', (111, 118))	('rs4402960 G>T', 'Var', (137, 150))	('rs1801282 C>G', 'Var', (75, 88))	('rs1470579 A>C', 'Var', (119, 132))	('rs1470579', 'Mutation', 'rs1470579', (119, 128))	('ESCC', 'Disease', (168, 172))	('rs4402960', 'Mutation', 'rs4402960', (137, 146))	('PPARG', 'Gene', '5468', (69, 74))	('IGF2BP2', 'Gene', '10644', (111, 118))	('rs3856806', 'Mutation', 'rs3856806', (93, 102))
285386	29200867	Multivariable logistic analysis suggested that PPARG rs3856806 C>T might be associated with an increased risk of ESCC.	('ESCC', 'Disease', (113, 117))	('rs3856806 C>T', 'Var', (53, 66))	('PPARG', 'Gene', '5468', (47, 52))	('rs3856806', 'Mutation', 'rs3856806', (53, 62))	('PPARG', 'Gene', (47, 52))
285387	29200867	To the best of our knowledge, this is the first study to identify a potential association between PPARG rs1801282 C>G and rs3856806 C>T polymorphisms and increased risk of ESCC in Asians.	('rs1801282', 'Mutation', 'rs1801282', (104, 113))	('PPARG', 'Gene', '5468', (98, 103))	('rs3856806 C>T', 'Var', (122, 135))	('PPARG', 'Gene', (98, 103))	('rs3856806', 'Mutation', 'rs3856806', (122, 131))	('ESCC', 'Disease', (172, 176))	('rs1801282 C>G', 'Var', (104, 117))
285390	29200867	The PPARG rs1801282 C>G polymorphism is located in the exon B region of the PPARG gene.	('PPARG', 'Gene', '5468', (76, 81))	('PPARG', 'Gene', (76, 81))	('rs1801282', 'Mutation', 'rs1801282', (10, 19))	('rs1801282 C>G', 'Var', (10, 23))	('PPARG', 'Gene', '5468', (4, 9))	('PPARG', 'Gene', (4, 9))
285392	29200867	A recent meta-analysis suggested that PPARG rs1801282 C>G polymorphism is a candidate for susceptibility to Asians.	('rs1801282', 'Mutation', 'rs1801282', (44, 53))	('rs1801282 C>G', 'Var', (44, 57))	('Asians', 'Disease', (108, 114))	('susceptibility', 'Reg', (90, 104))	('PPARG', 'Gene', '5468', (38, 43))	('PPARG', 'Gene', (38, 43))
285393	29200867	The association between PPARG rs1801282 C>G and risk of ESCC has not been studied before.	('ESCC', 'Disease', (56, 60))	('rs1801282', 'Mutation', 'rs1801282', (30, 39))	('rs1801282 C>G', 'Var', (30, 43))	('PPARG', 'Gene', '5468', (24, 29))	('PPARG', 'Gene', (24, 29))
285394	29200867	In this study, we found that the PPARG rs1801282 CG genotype was more frequent in ESCC patients in the never-smoking subgroup, which was in accordance with the results of the meta-analysis just mentioned.	('rs1801282', 'Mutation', 'rs1801282', (39, 48))	('PPARG', 'Gene', '5468', (33, 38))	('ESCC', 'Disease', (82, 86))	('PPARG', 'Gene', (33, 38))	('CG', 'Chemical', 'MESH:C028505', (49, 51))	('patients', 'Species', '9606', (87, 95))	('rs1801282', 'Var', (39, 48))
285395	29200867	The function of the PPARG rs1801282 C>G SNP remains to be investigated in ESCC patients.	('rs1801282', 'Mutation', 'rs1801282', (26, 35))	('rs1801282 C>G', 'Var', (26, 39))	('ESCC', 'Disease', (74, 78))	('PPARG', 'Gene', '5468', (20, 25))	('patients', 'Species', '9606', (79, 87))	('PPARG', 'Gene', (20, 25))
285396	29200867	There was a difference in genotype distribution of the PPARG rs3856806 C>T polymorphism between ESCC patients and controls.	('patients', 'Species', '9606', (101, 109))	('PPARG', 'Gene', (55, 60))	('rs3856806', 'Mutation', 'rs3856806', (61, 70))	('rs3856806 C>T', 'Var', (61, 74))	('ESCC', 'Disease', (96, 100))	('PPARG', 'Gene', '5468', (55, 60))
285397	29200867	The PPARG rs3856806 CT and TT/CT genotypes were more frequent in ESCC patients compared with healthy controls, suggesting that the PPARG rs3856806 TT/CT and CT genotypes might contribute to the development of ESCC.	('PPARG', 'Gene', '5468', (131, 136))	('patients', 'Species', '9606', (70, 78))	('rs3856806', 'Var', (10, 19))	('PPARG', 'Gene', (131, 136))	('rs3856806', 'Mutation', 'rs3856806', (137, 146))	('ESCC', 'Disease', (209, 213))	('ESCC', 'Disease', (65, 69))	('PPARG', 'Gene', '5468', (4, 9))	('PPARG', 'Gene', (4, 9))	('rs3856806', 'Mutation', 'rs3856806', (10, 19))	('contribute', 'Reg', (176, 186))	('rs3856806', 'Var', (137, 146))
285398	29200867	The PPARG rs3856806 C>T polymorphism is located in the exon of the PPARG gene.	('PPARG', 'Gene', '5468', (67, 72))	('PPARG', 'Gene', (67, 72))	('rs3856806 C>T', 'Var', (10, 23))	('PPARG', 'Gene', '5468', (4, 9))	('PPARG', 'Gene', (4, 9))	('rs3856806', 'Mutation', 'rs3856806', (10, 19))
285399	29200867	It is proposed that PPARG rs3856806 C T substitution may disrupt the splice site, and then affect the expression of PPARG.	('rs3856806 C T', 'Var', (26, 39))	('expression', 'MPA', (102, 112))	('affect', 'Reg', (91, 97))	('splice site', 'MPA', (69, 80))	('rs3856806', 'Mutation', 'rs3856806', (26, 35))	('PPARG', 'Gene', (116, 121))	('PPARG', 'Gene', '5468', (20, 25))	('PPARG', 'Gene', '5468', (116, 121))	('PPARG', 'Gene', (20, 25))	('disrupt', 'NegReg', (57, 64))
285400	29200867	A meta-analysis suggested that PPARG rs3856806 C>T is marginally associated with cancer susceptibility, and our results were similar.	('PPARG', 'Gene', '5468', (31, 36))	('PPARG', 'Gene', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('rs3856806', 'Mutation', 'rs3856806', (37, 46))	('cancer', 'Disease', (81, 87))	('rs3856806 C>T', 'Var', (37, 50))	('associated', 'Reg', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
285401	29200867	We found that the Crs1470579Grs4402960Crs1801282Crs3856806 haplotype was associated with susceptibility for ESCC.	('Crs1470579Grs4402960Crs1801282Crs3856806', 'Chemical', '-', (18, 58))	('associated', 'Reg', (73, 83))	('Crs1470579Grs4402960Crs1801282Crs3856806', 'Var', (18, 58))	('ESCC', 'Disease', (108, 112))
285402	29200867	Comparing the CGCC with the AGCC haplotype in the order of rs1470579 A>C, rs4402960 G>T, rs1801282 C>G, and rs3856806 C>T polymorphisms, we found that A C variation in the rs1470579 A>C locus led to susceptibility of the haplotype to ESCC.	('rs3856806', 'Mutation', 'rs3856806', (108, 117))	('rs3856806 C>T', 'Var', (108, 121))	('rs4402960 G>T', 'Var', (74, 87))	('rs1801282', 'Mutation', 'rs1801282', (89, 98))	('susceptibility', 'Reg', (199, 213))	('rs1801282 C>G', 'Var', (89, 102))	('rs1470579 A>C', 'Var', (59, 72))	('CG', 'Chemical', 'MESH:C028505', (14, 16))	('ESCC', 'Disease', (234, 238))	('rs1470579 A>C', 'Var', (172, 185))	('rs1470579', 'Mutation', 'rs1470579', (59, 68))	('rs4402960', 'Mutation', 'rs4402960', (74, 83))	('rs1470579', 'Mutation', 'rs1470579', (172, 181))
285403	29200867	Several case-control studies have reported that IGF2BP2 rs1470579 A>C was associated with type 2 diabetes mellitus.	('IGF2BP2', 'Gene', (48, 55))	('diabetes mellitus', 'Disease', (97, 114))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (90, 105))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (97, 114))	('type 2 diabetes', 'Disease', (90, 105))	('diabetes mellitus', 'Disease', 'MESH:D003920', (97, 114))	('rs1470579 A>C', 'Var', (56, 69))	('IGF2BP2', 'Gene', '10644', (48, 55))	('rs1470579', 'Mutation', 'rs1470579', (56, 65))	('type 2 diabetes', 'Disease', 'MESH:D003924', (90, 105))	('associated', 'Reg', (74, 84))
285404	29200867	However, a potential association between IGF2BP2 rs1470579 A>C polymorphism and ESCC risk was not found in our case-control study.	('ESCC', 'Disease', (80, 84))	('IGF2BP2', 'Gene', '10644', (41, 48))	('rs1470579 A>C', 'Var', (49, 62))	('IGF2BP2', 'Gene', (41, 48))	('rs1470579', 'Mutation', 'rs1470579', (49, 58))
285407	29200867	The relationship of PPARG and IGF2BP2 variants was not fully explored.	('IGF2BP2', 'Gene', '10644', (30, 37))	('variants', 'Var', (38, 46))	('IGF2BP2', 'Gene', (30, 37))	('PPARG', 'Gene', '5468', (20, 25))	('PPARG', 'Gene', (20, 25))
285408	29200867	Fourthly, detailed information on metastasis and survival of ESCC was not available at the time of research, which restricted further analysis on the potential role of PPARG and IGF2BP2 variants in ESCC progression and prognosis.	('ESCC', 'Disease', (198, 202))	('IGF2BP2', 'Gene', '10644', (178, 185))	('IGF2BP2', 'Gene', (178, 185))	('PPARG', 'Gene', '5468', (168, 173))	('variants', 'Var', (186, 194))	('PPARG', 'Gene', (168, 173))
285409	29200867	Our findings highlight that PPARG rs1801282 C>G and rs3856806 C>T polymorphisms are candidates for susceptibility to ESCC in the eastern Chinese Han population.	('rs3856806', 'Mutation', 'rs3856806', (52, 61))	('susceptibility', 'Reg', (99, 113))	('rs1801282', 'Mutation', 'rs1801282', (34, 43))	('rs1801282 C>G', 'Var', (34, 47))	('rs3856806 C>T', 'Var', (52, 65))	('ESCC', 'Disease', (117, 121))	('PPARG', 'Gene', '5468', (28, 33))	('PPARG', 'Gene', (28, 33))
285422	27250034	The dysregulation of autophagy has been implicated in many diseases including neurodegenerative diseases.	('autophagy', 'CPA', (21, 30))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (78, 104))	('dysregulation', 'Var', (4, 17))	('implicated', 'Reg', (40, 50))	('neurodegenerative diseases', 'Disease', (78, 104))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (78, 104))
285460	27250034	In contrast, low p62 nuclear staining correlated with lymph node metastases (p = 0.015), as well as with higher grade (p = 0.042; Table 4).	('p62', 'Gene', '8878', (17, 20))	('lymph node metastases', 'Disease', 'MESH:D009362', (54, 75))	('p62', 'Gene', (17, 20))	('lymph node metastases', 'Disease', (54, 75))	('higher grade', 'CPA', (105, 117))	('low', 'Var', (13, 16))
285464	27250034	Taken together these results indicated that low levels of p62 correlate with a more aggressive phenotype (Table 4; Table 5).	('low levels', 'Var', (44, 54))	('p62', 'Gene', (58, 61))	('p62', 'Gene', '8878', (58, 61))
285466	27250034	Low LC3B was associated with worse outcome as well, but this was not statistically significant (p = 0.335; see Supplementary Figure 1 for LC3B survival curve).	('LC3B', 'Gene', (4, 8))	('LC3B', 'Gene', (138, 142))	('LC3B', 'Gene', '81631', (4, 8))	('LC3B', 'Gene', '81631', (138, 142))	('Low', 'Var', (0, 3))
285476	27250034	Low p62 staining patterns, regardless of type, subcellular localization or combination with LC3B, correlated with a worse prognosis.	('p62', 'Gene', '8878', (4, 7))	('p62', 'Gene', (4, 7))	('LC3B', 'Gene', '81631', (92, 96))	('LC3B', 'Gene', (92, 96))	('Low', 'Var', (0, 3))
285477	27250034	Of note, low p62 nuclear staining was associated with lymph node metastases, a higher grade and with higher stage tumors.	('low', 'Var', (9, 12))	('p62', 'Gene', (13, 16))	('lymph node metastases', 'Disease', 'MESH:D009362', (54, 75))	('associated', 'Reg', (38, 48))	('lymph node metastases', 'Disease', (54, 75))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('p62', 'Gene', '8878', (13, 16))
285500	27250034	This includes the nuclear factor erytheriod-derived-2-like 2 -Kelch-like ECH-associated protein 1-antioxidant response element (Nrf2-Keap1-ARE) pathway, where dysregulated p62 may contribute to oncogenesis.	('oncogenesis', 'CPA', (194, 205))	('dysregulated', 'Var', (159, 171))	('p62', 'Gene', '8878', (172, 175))	('p62', 'Gene', (172, 175))	('Keap1', 'Gene', '9817', (133, 138))	('Nrf2', 'Gene', '4780', (128, 132))	('Nrf2', 'Gene', (128, 132))	('Keap1', 'Gene', (133, 138))	('contribute', 'Reg', (180, 190))
285551	26527528	The K167I variant of DNA polymerase beta that is found in Esophageal Carcinoma patients impairs polymerase activity and BER DNA polymerase beta (pol beta) is a key enzyme in DNA base excision repair, and an important factor for maintaining genomic integrity and stability.	('impairs', 'NegReg', (88, 95))	('Esophageal Carcinoma', 'Disease', (58, 78))	('pol beta', 'Gene', '5423', (145, 153))	('DNA polymerase beta', 'Gene', (124, 143))	('K167I', 'Var', (4, 9))	('Esophageal Carcinoma', 'Disease', 'MESH:D004938', (58, 78))	('K167I', 'Mutation', 'p.K167I', (4, 9))	('DNA polymerase beta', 'Gene', '5423', (21, 40))	('polymerase', 'Enzyme', (96, 106))	('Carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (58, 78))	('patients', 'Species', '9606', (79, 87))	('DNA polymerase beta', 'Gene', '5423', (124, 143))	('DNA polymerase beta', 'Gene', (21, 40))	('pol beta', 'Gene', (145, 153))
285552	26527528	Esophageal carcinoma (EC) patients who have been identified as carrying the K167I variant of pol beta have been shown to have decreased life expectancy.	('decreased', 'NegReg', (126, 135))	('Esophageal carcinoma', 'Disease', (0, 20))	('pol beta', 'Gene', '5423', (93, 101))	('EC', 'Phenotype', 'HP:0011459', (22, 24))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (0, 20))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (0, 20))	('patients', 'Species', '9606', (26, 34))	('K167I', 'Var', (76, 81))	('K167I', 'Mutation', 'p.K167I', (76, 81))	('pol beta', 'Gene', (93, 101))	('life expectancy', 'CPA', (136, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
285553	26527528	However, it is unknown if the variant affects pol beta's functions and/or how it contributes to the initiation and progression of cancer.	('contributes', 'Reg', (81, 92))	('pol beta', 'Gene', '5423', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('variant', 'Var', (30, 37))	('affects', 'Reg', (38, 45))	('functions', 'MPA', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('pol beta', 'Gene', (46, 54))
285555	26527528	Moreover, we found that K167I significantly reduced polymerase activity.	('polymerase', 'Enzyme', (52, 62))	('K167I', 'Mutation', 'p.K167I', (24, 29))	('reduced', 'NegReg', (44, 51))	('K167I', 'Var', (24, 29))
285556	26527528	As a result, the K167I substitution reduced base excision repair (BER) efficiency when assayed in a reconstitution assay or when using cellular extracts.	('K167I', 'Mutation', 'p.K167I', (17, 22))	('K167I', 'Var', (17, 22))	('reduced', 'NegReg', (36, 43))	('base excision repair', 'MPA', (44, 64))
285557	26527528	Finally, we observed EC cells expressing the K167I variant to be sensitive to DNA damaging agents.	('K167I', 'Var', (45, 50))	('K167I', 'Mutation', 'p.K167I', (45, 50))	('sensitive to DNA damaging agents', 'MPA', (65, 97))	('EC', 'Phenotype', 'HP:0011459', (21, 23))
285558	26527528	These results suggest the K167I variant affected pol beta biochemical activity resulting in impaired BER function, which might subsequently contribute to genomic instability and cancer development.	('K167I', 'Var', (26, 31))	('K167I', 'Mutation', 'p.K167I', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('biochemical activity', 'MPA', (58, 78))	('contribute', 'Reg', (140, 150))	('pol beta', 'Gene', (49, 57))	('impaired', 'NegReg', (92, 100))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('BER', 'Protein', (101, 104))	('genomic instability', 'CPA', (154, 173))	('pol beta', 'Gene', '5423', (49, 57))
285559	26527528	Genomic instability, a common feature in cancer cells, fuels the accumulation of oncogenic mutations, while radiation and diverse genotoxic agents remain important, and is found to exist in most tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('accumulation', 'PosReg', (65, 77))	('oncogenic', 'MPA', (81, 90))	('mutations', 'Var', (91, 100))	('Genomic instability', 'MPA', (0, 19))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
285566	26527528	Mutations that affect the dRP lyase or polymerase activity of pol beta have been reported to impair BER efficiency and induce hypersensitive to alkylating or oxidative agents, including methyl methanesulfonate (MMS), in cells.	('polymerase', 'Enzyme', (39, 49))	('methyl methanesulfonate', 'Chemical', 'MESH:D008741', (186, 209))	('hypersensitive', 'Disease', 'MESH:D004342', (126, 140))	('activity', 'MPA', (50, 58))	('Mutations', 'Var', (0, 9))	('dRP lyase', 'Enzyme', (26, 35))	('BER efficiency', 'CPA', (100, 114))	('pol beta', 'Gene', (62, 70))	('hypersensitive', 'Disease', (126, 140))	('impair', 'NegReg', (93, 99))	('pol beta', 'Gene', '5423', (62, 70))	('MMS', 'Chemical', 'MESH:D008741', (211, 214))	('induce', 'Reg', (119, 125))
285567	26527528	Polymorphisms can result in biochemical alternations, BER deficiency, and predisposition to cancers, therefore it is of interest to determine if and how a given polymorphism increases the likelihood of cancer occurrences.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('Polymorphisms', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancers', 'Disease', (92, 99))	('biochemical alternations', 'MPA', (28, 52))	('BER', 'MPA', (54, 57))	('cancer', 'Disease', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('result in', 'Reg', (18, 27))
285569	26527528	The EC patients who were identified as having the K167I variant also had reduced life expectancy.	('K167I', 'Mutation', 'p.K167I', (50, 55))	('K167I', 'Var', (50, 55))	('reduced', 'NegReg', (73, 80))	('life expectancy', 'CPA', (81, 96))	('EC', 'Phenotype', 'HP:0011459', (4, 6))	('patients', 'Species', '9606', (7, 15))
285570	26527528	However, it is unknown if the variant affects pol beta functions and/or how it contributes to the development and progression of cancer.	('pol beta', 'Gene', '5423', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('variant', 'Var', (30, 37))	('cancer', 'Disease', (129, 135))	('contributes', 'Reg', (79, 90))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('affects', 'Reg', (38, 45))	('pol beta', 'Gene', (46, 54))
285571	26527528	In this current study, we expressed and purified the K167I variant and found it to significantly reduced polymerase activity.	('K167I', 'Mutation', 'p.K167I', (53, 58))	('polymerase activity', 'MPA', (105, 124))	('K167I', 'Var', (53, 58))	('reduced', 'NegReg', (97, 104))
285572	26527528	Here, the K167I substitution reduced BER efficiency when assayed in a reconstitution assay and in cellular extracts.	('reduced', 'NegReg', (29, 36))	('BER', 'CPA', (37, 40))	('K167I', 'Mutation', 'p.K167I', (10, 15))	('K167I', 'Var', (10, 15))
285573	26527528	Furthermore, EC cells expressing the K167I variant were sensitive to DNA damaging agents.	('K167I', 'Var', (37, 42))	('sensitive to DNA damaging agents', 'MPA', (56, 88))	('K167I', 'Mutation', 'p.K167I', (37, 42))	('EC', 'Phenotype', 'HP:0011459', (13, 15))
285574	26527528	These results suggest that the K167I variant affected pol beta biochemical activity that resulted in defective BER, which may ultimately contribute to cancer development.	('BER', 'CPA', (111, 114))	('pol beta', 'Gene', (54, 62))	('pol beta', 'Gene', '5423', (54, 62))	('biochemical activity', 'MPA', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('contribute to', 'Reg', (137, 150))	('K167I', 'Var', (31, 36))	('affected', 'Reg', (45, 53))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('K167I', 'Mutation', 'p.K167I', (31, 36))	('defective', 'NegReg', (101, 110))
285575	26527528	To determine the effects of the K167I variant on pol beta biochemical activities and biological functions, we first expressed and purified WT and K167I human pol beta, then conducted primer extension experiments, and finally performed dRP lyase and DNA-binding activity assays.	('K167I', 'Var', (32, 37))	('DNA-binding', 'Interaction', (249, 260))	('pol beta', 'Gene', (49, 57))	('pol beta', 'Gene', (158, 166))	('K167I', 'Var', (146, 151))	('human', 'Species', '9606', (152, 157))	('pol beta', 'Gene', '5423', (158, 166))	('K167I', 'Mutation', 'p.K167I', (146, 151))	('pol beta', 'Gene', '5423', (49, 57))	('K167I', 'Mutation', 'p.K167I', (32, 37))
285576	26527528	In the primer extension assay, we found the K167I variant had approximately 70% reduction in primer extension activity compared to the WT enzyme (Fig.	('primer extension activity', 'MPA', (93, 118))	('K167I', 'Mutation', 'p.K167I', (44, 49))	('K167I', 'Var', (44, 49))	('reduction', 'NegReg', (80, 89))
285577	26527528	However, there were no differences between the K167I variant and the WT enzyme in DNA-binding activity or dRP lyase activity (Fig.	('K167I', 'Var', (47, 52))	('K167I', 'Mutation', 'p.K167I', (47, 52))	('dRP lyase', 'Enzyme', (106, 115))	('activity', 'MPA', (116, 124))	('DNA-binding', 'Interaction', (82, 93))
285579	26527528	The impaired polymerase activity of the K167I variant suggested that K167I likely affected BER function.	('K167I', 'Var', (40, 45))	('polymerase', 'Enzyme', (13, 23))	('activity', 'MPA', (24, 32))	('K167I', 'Mutation', 'p.K167I', (40, 45))	('affected', 'Reg', (82, 90))	('K167I', 'Var', (69, 74))	('K167I', 'Mutation', 'p.K167I', (69, 74))	('impaired', 'NegReg', (4, 12))	('BER function', 'CPA', (91, 103))
285583	26527528	To validate the K167I variant impacts BER efficiency, we expressed human WT and K167I pol beta in pol beta knockout EC9706 cells.	('EC', 'Phenotype', 'HP:0011459', (116, 118))	('pol beta', 'Gene', (98, 106))	('BER', 'MPA', (38, 41))	('pol beta', 'Gene', '5423', (98, 106))	('EC9706', 'CellLine', 'CVCL:E307', (116, 122))	('K167I', 'Var', (80, 85))	('K167I', 'Mutation', 'p.K167I', (80, 85))	('pol beta', 'Gene', (86, 94))	('human', 'Species', '9606', (67, 72))	('K167I', 'Var', (16, 21))	('pol beta', 'Gene', '5423', (86, 94))	('K167I', 'Mutation', 'p.K167I', (16, 21))
285584	26527528	The results from these experiments showed the NE of cells expressing WT pol beta efficiently repaired the uracil lesion, and generated a fully repaired product of 40 nt, whereas the repair efficiency of the NE from cells expressing K167I pol beta had approximately 80% reduction in efficient compared to the WT pol beta efficiency (Fig.	('K167I', 'Var', (232, 237))	('uracil', 'Chemical', 'MESH:D014498', (106, 112))	('pol beta', 'Gene', '5423', (238, 246))	('reduction', 'NegReg', (269, 278))	('pol beta', 'Gene', (311, 319))	('pol beta', 'Gene', '5423', (311, 319))	('uracil lesion', 'MPA', (106, 119))	('pol beta', 'Gene', (238, 246))	('uracil lesion', 'Phenotype', 'HP:0012127', (106, 119))	('pol beta', 'Gene', (72, 80))	('K167I', 'Mutation', 'p.K167I', (232, 237))	('pol beta', 'Gene', '5423', (72, 80))
285585	26527528	First, we conducted colony formation assays to determine the effect of K167I on the anchorage-independent growth capacity of EC9706 cells.	('K167I', 'Var', (71, 76))	('K167I', 'Mutation', 'p.K167I', (71, 76))	('anchorage-independent growth capacity', 'CPA', (84, 121))	('EC9706', 'CellLine', 'CVCL:E307', (125, 131))	('EC', 'Phenotype', 'HP:0011459', (125, 127))
285586	26527528	The EC9706 cells, WT (WT), pol beta knockout cells (pol beta-/-), and pol beta-/- cells expressing human WT or K167I pol beta (pol beta-/-/WT, and pol beta-/-/K167I, respectively), were assayed.	('EC9706', 'CellLine', 'CVCL:E307', (4, 10))	('pol beta', 'Gene', (27, 35))	('pol beta', 'Gene', (147, 155))	('pol beta', 'Gene', (127, 135))	('pol beta', 'Gene', '5423', (127, 135))	('pol beta', 'Gene', '5423', (147, 155))	('pol beta', 'Gene', '5423', (52, 60))	('human', 'Species', '9606', (99, 104))	('K167I', 'Mutation', 'p.K167I', (111, 116))	('pol beta', 'Gene', (117, 125))	('K167I', 'Mutation', 'p.K167I', (159, 164))	('pol beta', 'Gene', '5423', (27, 35))	('K167I', 'Var', (111, 116))	('EC', 'Phenotype', 'HP:0011459', (4, 6))	('pol beta', 'Gene', (52, 60))	('pol beta', 'Gene', (70, 78))	('pol beta', 'Gene', '5423', (117, 125))	('pol beta', 'Gene', '5423', (70, 78))
285588	26527528	Given our observation that K167I pol beta caused impaired BER we proposed the cells expressing the K167I variant would be sensitive to DNA base damaging agents.	('pol beta', 'Gene', (33, 41))	('K167I', 'Var', (99, 104))	('pol beta', 'Gene', '5423', (33, 41))	('K167I', 'Mutation', 'p.K167I', (99, 104))	('K167I', 'Var', (27, 32))	('K167I', 'Mutation', 'p.K167I', (27, 32))	('impaired', 'NegReg', (49, 57))	('BER', 'MPA', (58, 61))
285590	26527528	These results showed a deletion of pol beta caused cells to accumulate DNA damage at MMS concentrations >1 mM (Fig.	('deletion', 'Var', (23, 31))	('pol beta', 'Gene', (35, 43))	('MMS', 'Chemical', 'MESH:D008741', (85, 88))	('caused', 'Reg', (44, 50))	('accumulate', 'PosReg', (60, 70))	('pol beta', 'Gene', '5423', (35, 43))
285592	26527528	Additionally, there was a 6-fold increase in MMS induced apoptosis in K167I cells compared to WT cells (4.6% versus 0.8%) (Fig.	('MMS', 'Chemical', 'MESH:D008741', (45, 48))	('apoptosis', 'CPA', (57, 66))	('increase', 'PosReg', (33, 41))	('MMS', 'Var', (45, 48))	('K167I', 'Mutation', 'p.K167I', (70, 75))
285593	26527528	Data from growth inhibition assays showed MMS consistently had a stronger inhibitory effect on pol beta-/-/K167I cell growth compared to WT or pol beta-/-/WT cells.	('pol beta', 'Gene', (95, 103))	('pol beta', 'Gene', '5423', (95, 103))	('MMS', 'Chemical', 'MESH:D008741', (42, 45))	('pol beta', 'Gene', (143, 151))	('MMS', 'Var', (42, 45))	('K167I', 'Mutation', 'p.K167I', (107, 112))	('pol beta', 'Gene', '5423', (143, 151))	('inhibitory effect', 'NegReg', (74, 91))
285597	26527528	Approximately 30% of human tumors examined for mutations in pol beta appear to express pol beta variants.	('pol beta', 'Gene', '5423', (87, 95))	('pol beta', 'Gene', (60, 68))	('variants', 'Var', (96, 104))	('pol beta', 'Gene', '5423', (60, 68))	('human', 'Species', '9606', (21, 26))	('tumors', 'Disease', (27, 33))	('mutations', 'Var', (47, 56))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('express', 'Reg', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('pol beta', 'Gene', (87, 95))
285598	26527528	In this study, we expressed and purified the K167I pol beta variant.	('pol beta', 'Gene', (51, 59))	('K167I', 'Var', (45, 50))	('pol beta', 'Gene', '5423', (51, 59))	('K167I', 'Mutation', 'p.K167I', (45, 50))
285599	26527528	Studies performed using this variant found the K167I variant was unable to catalyze DNA synthesis, but was still able to bind DNA and possessed dRP lyase activity at a level similar to that of WT pol beta.	('K167I', 'Var', (47, 52))	('bind', 'Interaction', (121, 125))	('K167I', 'Mutation', 'p.K167I', (47, 52))	('pol beta', 'Gene', (196, 204))	('pol beta', 'Gene', '5423', (196, 204))	('dRP lyase', 'Enzyme', (144, 153))	('activity', 'MPA', (154, 162))	('DNA', 'Protein', (126, 129))
285600	26527528	We also discovered the K167I mutation significantly reduced polymerase activity, decreased BER efficiency, and overall DNA base damage repair capacity, both in vitro and in vivo.	('decreased', 'NegReg', (81, 90))	('polymerase', 'Enzyme', (60, 70))	('K167I', 'Var', (23, 28))	('DNA base damage repair capacity', 'MPA', (119, 150))	('reduced', 'NegReg', (52, 59))	('activity', 'MPA', (71, 79))	('BER', 'MPA', (91, 94))	('K167I', 'Mutation', 'p.K167I', (23, 28))
285601	26527528	Consistent with our previous finding of EC patients who carry the K167I have reduced life expectancies, the results of anchorage-independent growth assays showed the colony number of pol beta-/-/K167I was higher than that of pol beta-/-/WT.	('pol beta', 'Gene', (225, 233))	('pol beta', 'Gene', '5423', (225, 233))	('EC', 'Phenotype', 'HP:0011459', (40, 42))	('K167I', 'Mutation', 'p.K167I', (195, 200))	('higher', 'PosReg', (205, 211))	('patients', 'Species', '9606', (43, 51))	('K167I', 'Var', (66, 71))	('colony number', 'CPA', (166, 179))	('K167I', 'Mutation', 'p.K167I', (66, 71))	('reduced', 'NegReg', (77, 84))	('pol beta', 'Gene', (183, 191))	('life expectancies', 'CPA', (85, 102))	('pol beta', 'Gene', '5423', (183, 191))
285602	26527528	These results suggest that an individual with the K167I variant may be sensitive to endogenous and exogenous DNA damaging agents due to impaired polymerase activity and cellular base excision repair capacity.	('K167I', 'Mutation', 'p.K167I', (50, 55))	('K167I', 'Var', (50, 55))	('activity', 'MPA', (156, 164))	('polymerase', 'Enzyme', (145, 155))	('cellular base excision repair capacity', 'MPA', (169, 207))	('impaired', 'NegReg', (136, 144))	('sensitive to', 'MPA', (71, 83))
285603	26527528	The amino acid residue Lys167 is critical to pol beta functions.	('Lys167', 'Var', (23, 29))	('pol beta', 'Gene', '5423', (45, 53))	('Lys167', 'Chemical', '-', (23, 29))	('pol beta', 'Gene', (45, 53))
285604	26527528	According to the crystal structure, K167I maps to the polymerase catalytic domain of pol beta.	('pol beta', 'Gene', (85, 93))	('K167I', 'Var', (36, 41))	('pol beta', 'Gene', '5423', (85, 93))	('K167I', 'Mutation', 'p.K167I', (36, 41))
285605	26527528	The substitution of K167I might disrupt the formation of hydrogen bonds and thus impair polymerase activity.	('hydrogen', 'Chemical', 'MESH:D006859', (57, 65))	('formation of hydrogen bonds', 'MPA', (44, 71))	('K167I', 'Var', (20, 25))	('K167I', 'Mutation', 'p.K167I', (20, 25))	('disrupt', 'NegReg', (32, 39))	('polymerase', 'Enzyme', (88, 98))	('activity', 'MPA', (99, 107))	('impair', 'NegReg', (81, 87))
285606	26527528	Consistent with this hypothesis, in these experiments, K167I had approximately 30% of the DNA polymerase activity of WT pol beta (Fig.	('DNA polymerase', 'Enzyme', (90, 104))	('pol beta', 'Gene', (120, 128))	('activity', 'MPA', (105, 113))	('pol beta', 'Gene', '5423', (120, 128))	('K167I', 'Var', (55, 60))	('K167I', 'Mutation', 'p.K167I', (55, 60))
285607	26527528	Here, we demonstrated that K167I was unable to catalyze DNA synthesis mediated by pol beta.	('pol beta', 'Gene', (82, 90))	('pol beta', 'Gene', '5423', (82, 90))	('K167I', 'Var', (27, 32))	('K167I', 'Mutation', 'p.K167I', (27, 32))	('unable', 'NegReg', (37, 43))	('DNA synthesis', 'MPA', (56, 69))
285609	26527528	If K167I binds to DNA, it is unable to fill in the single nucleotide gap.	('binds', 'Interaction', (9, 14))	('K167I', 'Var', (3, 8))	('DNA', 'Protein', (18, 21))	('K167I', 'Mutation', 'p.K167I', (3, 8))
285610	26527528	Some of the unfilled gaps could lead to cell death, this is consistent with our demonstration that expression of K167I in the non-presence of WT pol beta in cells sensitizes them to MMS.	('lead to', 'Reg', (32, 39))	('sensitizes', 'Reg', (163, 173))	('K167I', 'Mutation', 'p.K167I', (113, 118))	('pol beta', 'Gene', '5423', (145, 153))	('K167I', 'Var', (113, 118))	('expression', 'Var', (99, 109))	('pol beta', 'Gene', (145, 153))	('MMS', 'Chemical', 'MESH:D008741', (182, 185))
285611	26527528	Exposure to MMS induced cell death in cells expressing K167I.	('cell death', 'CPA', (24, 34))	('MMS', 'Chemical', 'MESH:D008741', (12, 15))	('K167I', 'Var', (55, 60))	('K167I', 'Mutation', 'p.K167I', (55, 60))
285615	26527528	In this case, the K167I pol beta variant may significantly contribute to the development of human cancers through impaired polymerase activity.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('K167I', 'Var', (18, 23))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('contribute', 'Reg', (59, 69))	('K167I', 'Mutation', 'p.K167I', (18, 23))	('pol beta', 'Gene', (24, 32))	('cancers', 'Disease', (98, 105))	('activity', 'MPA', (134, 142))	('polymerase', 'Enzyme', (123, 133))	('human', 'Species', '9606', (92, 97))	('pol beta', 'Gene', '5423', (24, 32))	('impaired', 'NegReg', (114, 122))
285616	26527528	The wild type (WT) and K167I variant human pol beta were obtained in our previous research.	('K167I', 'Var', (23, 28))	('pol beta', 'Gene', (43, 51))	('pol beta', 'Gene', '5423', (43, 51))	('human', 'Species', '9606', (37, 42))	('K167I', 'Mutation', 'p.K167I', (23, 28))
285617	26527528	WT pol beta and K167I genes were inserted into the pET28a and pcDNA3.1 vectors.	('pol beta', 'Gene', '5423', (3, 11))	('K167I', 'Var', (16, 21))	('pol beta', 'Gene', (3, 11))	('K167I', 'Mutation', 'p.K167I', (16, 21))
285618	26527528	WT or K167I pol beta fusion proteins were expressed in BL21 DE3 cells.	('pol beta', 'Gene', '5423', (12, 20))	('K167I', 'Var', (6, 11))	('K167I', 'Mutation', 'p.K167I', (6, 11))	('BL21 DE3', 'CellLine', 'CVCL:M639', (55, 63))	('pol beta', 'Gene', (12, 20))
285620	26527528	The enzymes (WT and K167I pol beta) were purified using HisTrap FF crude Kit (GE Healthcare, Piscataway, NJ) according to the manufacturer instructions.	('K167I', 'Mutation', 'p.K167I', (20, 25))	('pol beta', 'Gene', (26, 34))	('pol beta', 'Gene', '5423', (26, 34))	('K167I', 'Var', (20, 25))
285626	26527528	This was followed by the addition of 0-0.8 mg WT or K167I pol beta, and samples were then incubated overnight at 4  C. Next, samples were incubated with a mouse anti-pol beta antibody (Santa Cruz Biotech) and a goat anti-mouse IgG/HRP antibody (Santa Cruz Biotech).	('pol beta', 'Gene', '5423', (166, 174))	('mouse', 'Species', '10090', (221, 226))	('mouse', 'Species', '10090', (155, 160))	('K167I', 'Var', (52, 57))	('K167I', 'Mutation', 'p.K167I', (52, 57))	('pol beta', 'Gene', (58, 66))	('pol beta', 'Gene', (166, 174))	('pol beta', 'Gene', '5423', (58, 66))	('goat', 'Species', '9925', (211, 215))
285629	26527528	The incised APsite- containing DNA was then incubated (20 min, 37  C) with WT or K167I pol beta (0-10 ng) in buffer.	('pol beta', 'Gene', '5423', (87, 95))	('K167I', 'Mutation', 'p.K167I', (81, 86))	('K167I', 'Var', (81, 86))	('pol beta', 'Gene', (87, 95))
285646	26527528	The K167I variant of DNA polymerase beta that is found in Esophageal Carcinoma patients impairs polymerase activity and BER.	('impairs', 'NegReg', (88, 95))	('Esophageal Carcinoma', 'Disease', (58, 78))	('K167I', 'Var', (4, 9))	('activity', 'MPA', (107, 115))	('Esophageal Carcinoma', 'Disease', 'MESH:D004938', (58, 78))	('K167I', 'Mutation', 'p.K167I', (4, 9))	('DNA polymerase beta', 'Gene', '5423', (21, 40))	('polymerase', 'Enzyme', (96, 106))	('BER', 'CPA', (120, 123))	('Carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (58, 78))	('patients', 'Species', '9606', (79, 87))	('DNA polymerase beta', 'Gene', (21, 40))
285649	25988972	Here, we show that inducible overexpression of NANOG in mouse skin epithelia favours the malignant conversion of skin papillomas induced by chemical carcinogenesis, leading to increased SCC formation.	('SCC', 'Gene', '6317', (186, 189))	('overexpression', 'PosReg', (29, 43))	('papilloma', 'Phenotype', 'HP:0012740', (118, 127))	('skin epithelia', 'Disease', 'MESH:D012871', (62, 76))	('increased', 'PosReg', (176, 185))	('skin papillomas', 'Disease', 'MESH:D010212', (113, 128))	('mouse', 'Species', '10090', (56, 61))	('malignant conversion', 'CPA', (89, 109))	('skin papillomas', 'Disease', (113, 128))	('SCC', 'Gene', (186, 189))	('NANOG', 'Var', (47, 52))	('papillomas', 'Phenotype', 'HP:0012740', (118, 128))	('skin epithelia', 'Disease', (62, 76))	('favours', 'PosReg', (77, 84))
285650	25988972	Some of these genes are directly activated by NANOG, including EMT-associated genes Zeb1, Zeb2, Twist1, Prrx1 and miR-21.	('Prrx1', 'Gene', (104, 109))	('miR-21', 'Gene', '387140', (114, 120))	('activated', 'PosReg', (33, 42))	('Twist1', 'Gene', (96, 102))	('Zeb2', 'Gene', '24136', (90, 94))	('Zeb1', 'Gene', '21417', (84, 88))	('NANOG', 'Var', (46, 51))	('miR-21', 'Gene', (114, 120))	('Prrx1', 'Gene', '18933', (104, 109))	('Twist1', 'Gene', '22160', (96, 102))	('Zeb1', 'Gene', (84, 88))	('Zeb2', 'Gene', (90, 94))
285651	25988972	Finally, endogenous NANOG binds to the promoters of theses genes in human SCC cells and, moreover, NANOG induces EMT features in primary keratinocytes.	('human', 'Species', '9606', (68, 73))	('SCC', 'Gene', (74, 77))	('induces', 'PosReg', (105, 112))	('EMT features in primary keratinocytes', 'CPA', (113, 150))	('NANOG', 'Var', (99, 104))	('SCC', 'Gene', '6317', (74, 77))
285652	25988972	These results provide in vivo evidence for the oncogenic role of NANOG in squamous cell carcinomas.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (74, 98))	('NANOG', 'Var', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (74, 98))	('squamous cell carcinomas', 'Disease', (74, 98))
285657	25988972	Also, transgenic overexpression of Nanog in MMTV-Wnt-1 mice accelerates mammary tumorigenesis and metastasis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('accelerates', 'PosReg', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('mice', 'Species', '10090', (55, 59))	('MMTV', 'Species', '11757', (44, 48))	('overexpression', 'PosReg', (17, 31))	('Nanog', 'Var', (35, 40))
285687	25988972	We also noticed that the endogenous Nanog gene was upregulated in TG papillomas and carcinomas (Supplementary Figure S2D), suggesting that transgenic Nanog may upregulate the expression of the endogenous Nanog allele.	('expression', 'MPA', (175, 185))	('TG papillomas and carcinomas', 'Disease', 'MESH:D010212', (66, 94))	('transgenic', 'Var', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('endogenous Nanog gene', 'Gene', (25, 46))	('upregulate', 'PosReg', (160, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('papillomas', 'Phenotype', 'HP:0012740', (69, 79))	('papilloma', 'Phenotype', 'HP:0012740', (69, 78))	('upregulated', 'PosReg', (51, 62))
285689	25988972	The protein and mRNA levels of NANOG were similarly high in the metastasis and the SCC from the same animal (Supplementary Figure S2F and G).	('SCC', 'Gene', (83, 86))	('mRNA levels', 'MPA', (16, 27))	('NANOG', 'Var', (31, 36))	('SCC', 'Gene', '6317', (83, 86))	('protein', 'MPA', (4, 11))	('metastasis', 'CPA', (64, 74))
285692	25988972	Together, these results demonstrate that NANOG can promote malignant progression to skin squamous cell carcinoma.	('skin squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 112))	('NANOG', 'Var', (41, 46))	('promote', 'PosReg', (51, 58))	('malignant progression', 'CPA', (59, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('skin squamous cell carcinoma', 'Disease', (84, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
285695	25988972	Of note, downregulation of E-cadherin was also observed by qRT-PCR and IHC (Fig.	('downregulation', 'NegReg', (9, 23))	('E-cadherin', 'Gene', '12550', (27, 37))	('qRT-PCR', 'Disease', (59, 66))	('IHC', 'Var', (71, 74))	('E-cadherin', 'Gene', (27, 37))
285700	25988972	Interestingly, by qRT-PCR and in situ hybridization (ISH), we found that miR-21 was significantly upregulated in the back skin, papillomas and SCCs after induction of Nanog for 30 weeks (Fig.	('SCC', 'Gene', (143, 146))	('papilloma', 'Phenotype', 'HP:0012740', (128, 137))	('back skin', 'Disease', 'MESH:D012871', (117, 126))	('miR-21', 'Gene', '387140', (73, 79))	('papillomas', 'Disease', 'MESH:D010212', (128, 138))	('papillomas', 'Disease', (128, 138))	('upregulated', 'PosReg', (98, 109))	('SCC', 'Gene', '6317', (143, 146))	('Nanog', 'Var', (167, 172))	('miR-21', 'Gene', (73, 79))	('back skin', 'Disease', (117, 126))	('papillomas', 'Phenotype', 'HP:0012740', (128, 138))
285708	25988972	Together, these observations indicate that NANOG drives SCC tumorigenesis in association with the upregulation of EMT drivers, notably including Zeb1, Zeb2, Twist, Prrx1 and miR-21.	('miR-21', 'Gene', (174, 180))	('SCC', 'Gene', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Zeb1', 'Gene', '21417', (145, 149))	('Prrx1', 'Gene', '18933', (164, 169))	('upregulation', 'PosReg', (98, 110))	('Zeb1', 'Gene', (145, 149))	('Prrx1', 'Gene', (164, 169))	('Zeb2', 'Gene', (151, 155))	('SCC', 'Gene', '6317', (56, 59))	('miR-21', 'Gene', '387140', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('Zeb2', 'Gene', '24136', (151, 155))	('NANOG', 'Var', (43, 48))
285715	25988972	To test this, we performed ChIP in the human esophageal SCC (ESCC) cell line TE2, which is known to have high endogenous levels of NANOG.	('TE2', 'Gene', '8260', (77, 80))	('SCC', 'Gene', '6317', (62, 65))	('TE2', 'Gene', (77, 80))	('SCC', 'Gene', (56, 59))	('NANOG', 'Var', (131, 136))	('SCC', 'Gene', '6317', (56, 59))	('human', 'Species', '9606', (39, 44))	('SCC', 'Gene', (62, 65))
285721	25988972	Interestingly, overexpression of NANOG in HaCat cells increased their migration capacity (Fig.	('overexpression', 'PosReg', (15, 29))	('migration capacity', 'CPA', (70, 88))	('increased', 'PosReg', (54, 63))	('HaCat', 'CellLine', 'CVCL:6758', (42, 47))	('NANOG', 'Var', (33, 38))
285727	25988972	Here, we show that transgenic Nanog expression in the skin epidermis promotes the conversion of skin papillomas into skin SCCs.	('skin papillomas', 'Disease', (96, 111))	('SCC', 'Gene', (122, 125))	('skin', 'Disease', (117, 121))	('SCC', 'Gene', '6317', (122, 125))	('promotes', 'PosReg', (69, 77))	('transgenic', 'Var', (19, 29))	('skin papillomas', 'Disease', 'MESH:D010212', (96, 111))	('Nanog', 'Gene', (30, 35))	('papillomas', 'Phenotype', 'HP:0012740', (101, 111))	('papilloma', 'Phenotype', 'HP:0012740', (101, 110))
285728	25988972	In particular, overexpression of Nanog greatly increased the rate of malignant conversion of papillomas into skin SCCs.	('overexpression', 'PosReg', (15, 29))	('Nanog', 'Var', (33, 38))	('papillomas', 'Disease', 'MESH:D010212', (93, 103))	('papillomas', 'Disease', (93, 103))	('SCC', 'Gene', (114, 117))	('increased', 'PosReg', (47, 56))	('papillomas', 'Phenotype', 'HP:0012740', (93, 103))	('SCC', 'Gene', '6317', (114, 117))	('malignant conversion', 'CPA', (69, 89))	('papilloma', 'Phenotype', 'HP:0012740', (93, 102))
285729	25988972	Analysis of the global transcriptional profiles of papillomas by RNA-seq indicated that, at this early stage of tumorigenesis, transgenic NANOG is already upregulating key transcriptional regulators of EMT.	('papillomas', 'Disease', 'MESH:D010212', (51, 61))	('papillomas', 'Disease', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('upregulating', 'PosReg', (155, 167))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('papillomas', 'Phenotype', 'HP:0012740', (51, 61))	('tumor', 'Disease', (112, 117))	('transgenic', 'Var', (127, 137))	('papilloma', 'Phenotype', 'HP:0012740', (51, 60))
285732	25988972	In particular, Nanog-overexpressing papillomas show upregulation of several EMT mediators (Zeb1, Zeb2, Twist) and the master EMT inducer Prrx1, but not of the classical EMT inducers Snail/Slug.	('upregulation', 'PosReg', (52, 64))	('Zeb2', 'Gene', (97, 101))	('Zeb1', 'Gene', (91, 95))	('Slug', 'Gene', (188, 192))	('Zeb2', 'Gene', '24136', (97, 101))	('papilloma', 'Phenotype', 'HP:0012740', (36, 45))	('papillomas', 'Disease', 'MESH:D010212', (36, 46))	('Snail', 'Gene', (182, 187))	('Snail', 'Gene', '20613', (182, 187))	('Slug', 'Gene', '20583', (188, 192))	('Nanog-overexpressing', 'Var', (15, 35))	('Prrx1', 'Gene', (137, 142))	('papillomas', 'Disease', (36, 46))	('Prrx1', 'Gene', '18933', (137, 142))	('Zeb1', 'Gene', '21417', (91, 95))	('papillomas', 'Phenotype', 'HP:0012740', (36, 46))
285735	25988972	Other miRNAs involved in the inhibition of EMT, such as miR-200 and miR-34, were not found altered in Nanog-overexpressing papillomas.	('papillomas', 'Phenotype', 'HP:0012740', (123, 133))	('papilloma', 'Phenotype', 'HP:0012740', (123, 132))	('papillomas', 'Disease', 'MESH:D010212', (123, 133))	('miR-34', 'Var', (68, 74))	('papillomas', 'Disease', (123, 133))
285736	25988972	To further extend these findings, we show that NANOG regulates the expression of EMT mediators in primary mouse keratinocytes, in immortalized human keratinocytes (HaCat), and in human esophageal SCC cells (TE2).	('SCC', 'Gene', (196, 199))	('regulates', 'Reg', (53, 62))	('TE2', 'Gene', (207, 210))	('human', 'Species', '9606', (179, 184))	('human', 'Species', '9606', (143, 148))	('SCC', 'Gene', '6317', (196, 199))	('HaCat', 'CellLine', 'CVCL:6758', (164, 169))	('expression', 'MPA', (67, 77))	('NANOG', 'Var', (47, 52))	('TE2', 'Gene', '8260', (207, 210))	('mouse', 'Species', '10090', (106, 111))
285741	25988972	In summary, we demonstrate in vivo that NANOG has oncogenic potential to induce skin SCCs and this occurs in association with NANOG-dependent induction of an EMT program and cancer stem features.	('skin', 'Disease', (80, 84))	('SCC', 'Gene', '6317', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('EMT program', 'CPA', (158, 169))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('induce', 'PosReg', (73, 79))	('SCC', 'Gene', (85, 88))	('NANOG', 'Var', (40, 45))
285797	24743895	Silencing DACH1 Promotes Esophageal Cancer Growth by Inhibiting TGF-beta Signaling Human Dachshund homologue 1 (DACH1) is a major component of the Retinal Determination Gene Network.	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('DACH1', 'Gene', (112, 117))	('DACH1', 'Gene', '1602', (112, 117))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (25, 42))	('DACH1', 'Gene', (10, 15))	('Human', 'Species', '9606', (83, 88))	('TGF-beta', 'Gene', '7040', (64, 72))	('Esophageal Cancer', 'Disease', (25, 42))	('TGF-beta', 'Gene', (64, 72))	('DACH1', 'Gene', '1602', (10, 15))	('Silencing', 'Var', (0, 9))	('Inhibiting', 'NegReg', (53, 63))	('Promotes', 'PosReg', (16, 24))
285802	24743895	18.8% (6 of 32) of grade 1, 42.1% (8 of 19) of grade 2 and grade 3 dysplasia (ED2,3), and 61.5% (64 of 104) of esophageal cancer were methylated, but no methylation was found in 10 cases of normal esophageal mucosa.	('methylated', 'Var', (134, 144))	('esophageal cancer', 'Disease', (111, 128))	('dysplasia', 'Disease', (67, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('dysplasia', 'Disease', 'MESH:D004476', (67, 76))	('ED2', 'Gene', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('ED2', 'Gene', '10804', (78, 81))
285804	24743895	DACH1 methylation was associated with poor differentiation (P<0.05) and late tumor stage (P<0.05).	('DACH1', 'Gene', (0, 5))	('late tumor', 'Disease', (72, 82))	('late tumor', 'Disease', 'MESH:D009369', (72, 82))	('methylation', 'Var', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('associated', 'Reg', (22, 32))	('poor differentiation', 'CPA', (38, 58))
285807	24743895	In conclusion, DACH1 is frequently methylated in human esophageal cancer and methylation of DACH1 is involved in the early stage of esophageal carcinogenesis.	('DACH1', 'Gene', (92, 97))	('methylation', 'Var', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (132, 157))	('esophageal cancer', 'Disease', (55, 72))	('human', 'Species', '9606', (49, 54))	('esophageal carcinogenesis', 'Disease', (132, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('involved', 'Reg', (101, 109))
285812	24743895	Multiple genetic and epigenetic alterations were regarded as important factors for developing esophageal cancer.	('epigenetic alterations', 'Var', (21, 43))	('esophageal cancer', 'Disease', (94, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
285815	24743895	The expression of DACH1 was regulated by promoter region hypermethylation in endometrial, colorectal and hepatocellular cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('hypermethylation', 'Var', (57, 73))	('colorectal and hepatocellular cancer', 'Disease', 'MESH:D015179', (90, 126))	('expression', 'MPA', (4, 14))	('endometrial', 'Disease', (77, 88))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (105, 126))	('DACH1', 'Gene', (18, 23))	('regulated', 'Reg', (28, 37))
285823	24743895	Eleven human ESCC cell lines (KYSE30, KYSE70, KYSE140, KYSE150, KYSE180, KYSE410, KYSE450, KYSE510, TE1, TE3 and TE8) were included in this study.	('KYSE150', 'Var', (55, 62))	('KYSE30', 'Var', (30, 36))	('KYSE150', 'CellLine', 'CVCL:1348', (55, 62))	('human', 'Species', '9606', (7, 12))	('KYSE450', 'Var', (82, 89))	('KYSE410', 'Var', (73, 80))	('KYSE70', 'Var', (38, 44))	('KYSE180', 'Var', (64, 71))	('KYSE140', 'Var', (46, 53))	('KYSE510', 'Var', (91, 98))
285838	24743895	DACH1 stably expressed KYSE510 cells and unexpressed control (4x106 cells in 0.2 ml phosphate-buffered saline) was subcutaneously injected into the dorsal flank of 5-week-old female BABL/c nude mice respectively; each group included 5 mice.	('BABL', 'Gene', (182, 186))	('KYSE510', 'Var', (23, 30))	('DACH1', 'Gene', (0, 5))	('BABL', 'Gene', '8091', (182, 186))	('nude mice', 'Species', '10090', (189, 198))	('phosphate-buffered saline', 'Chemical', '-', (84, 109))	('mice', 'Species', '10090', (235, 239))	('mice', 'Species', '10090', (194, 198))
285841	24743895	DACH1 expression was regulated by promoter region hypermethylation in human colorectal and hepatocellular carcinoma.	('DACH1', 'Gene', (0, 5))	('expression', 'MPA', (6, 16))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (91, 115))	('human', 'Species', '9606', (70, 75))	('hypermethylation', 'Var', (50, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('colorectal and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (76, 115))
285843	24743895	As shown in figure 1A, Loss of DACH1 expression was found in KYSE150, KYSE510, TE1 and TE3 cells, reduced DACH1 expression was appeared in TE8 cells, and expression of DACH1 was detected in KYSE30, KYSE70, KYSE140, KYSE180, KYSE450 and KYSE410 cells.	('DACH1', 'Gene', (106, 111))	('Loss', 'NegReg', (23, 27))	('KYSE510', 'Var', (70, 77))	('KYSE150', 'Var', (61, 68))	('DACH1', 'Gene', (31, 36))	('reduced', 'NegReg', (98, 105))	('expression', 'MPA', (37, 47))	('KYSE150', 'CellLine', 'CVCL:1348', (61, 68))	('expression', 'MPA', (112, 122))
285844	24743895	DACH1 was completely methylated in KYSE150, KYSE510, TE1 and TE3 cells, partially in TE8, and unmethylated in KYSE30, KYSE70, KYSE140, KYSE180, KYSE450 and KYSE410 cells.	('DACH1', 'Gene', (0, 5))	('KYSE150', 'Var', (35, 42))	('KYSE150', 'CellLine', 'CVCL:1348', (35, 42))	('KYSE510', 'Var', (44, 51))
285848	24743895	As shown in figure 2A and 2B, 18.8% (6 of 32) of esophageal grade 1 dysplasia (ED1), 42.1% (8 of 19) of grade 2 and grade 3 dysplasia (ED2,3), and 61.5% (64 of 104) of invasive esophageal cancer (EC) were methylated, but none of the 10 cases of normal esophageal mucosa was methylated.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('dysplasia', 'Disease', (124, 133))	('esophageal grade 1 dysplasia (ED1', 'Gene', '1896', (49, 82))	('invasive esophageal cancer', 'Disease', 'MESH:D004938', (168, 194))	('dysplasia', 'Disease', 'MESH:D004476', (124, 133))	('ED2', 'Gene', (135, 138))	('ED2', 'Gene', '10804', (135, 138))	('dysplasia', 'Disease', 'MESH:D004476', (68, 77))	('dysplasia', 'Disease', (68, 77))	('invasive esophageal cancer', 'Disease', (168, 194))	('methylated', 'Var', (205, 215))
285849	24743895	The frequency of DACH1 methylation was increased in progression tendency during esophageal carcinogenesis (P<0.01).	('methylation', 'Var', (23, 34))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (80, 105))	('DACH1', 'Gene', (17, 22))	('esophageal carcinogenesis', 'Disease', (80, 105))	('increased', 'PosReg', (39, 48))
285850	24743895	DACH1 methylation was associated with poor differentiation (P<0.05) and late tumor stage (P<0.05) significantly.	('DACH1', 'Gene', (0, 5))	('late tumor', 'Disease', (72, 82))	('late tumor', 'Disease', 'MESH:D009369', (72, 82))	('methylation', 'Var', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('associated', 'Reg', (22, 32))	('poor differentiation', 'CPA', (38, 58))
285851	24743895	No association was found between DACH1 methylation and age, gender, metastasis or tumor size (P>0.05, Table 1).	('DACH1', 'Gene', (33, 38))	('methylation', 'Var', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
285852	24743895	Above results indicate that DACH1 methylation is an early event of esophageal carcinogenesis and methylation of DACH1 is accumulated during progression of esophageal cancer.	('accumulated', 'PosReg', (121, 132))	('esophageal carcinogenesis', 'Disease', (67, 92))	('DACH1', 'Gene', (112, 117))	('methylation', 'Var', (34, 45))	('esophageal cancer', 'Disease', (155, 172))	('DACH1', 'Gene', (28, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (155, 172))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (67, 92))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('methylation', 'Var', (97, 108))
285862	24743895	3D), and the tumor weight was less in DACH1 expressed KYSE510 cells than in control group (78+-28 mg vs 182+-37 mg, P<0.01, Fig.	('tumor', 'Disease', (13, 18))	('DACH1', 'Gene', (38, 43))	('less', 'NegReg', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('KYSE510', 'Var', (54, 61))
285869	24743895	As shown in figure 4B, the expression of CDK2, CDK 4, cyclinD1 and cyclinE1 were reduced apparently in DACH1 expressed KYSE510 and KYSE150 cells compared with unexpressed cells.	('KYSE510', 'Var', (119, 126))	('CDK2', 'Gene', (41, 45))	('KYSE150', 'Var', (131, 138))	('CDK 4', 'Gene', '1019', (47, 52))	('cyclinD1', 'Gene', '595', (54, 62))	('cyclinD1', 'Gene', (54, 62))	('expression', 'MPA', (27, 37))	('CDK2', 'Gene', '1017', (41, 45))	('CDK 4', 'Gene', (47, 52))	('KYSE150', 'CellLine', 'CVCL:1348', (131, 138))	('DACH1', 'Gene', (103, 108))	('reduced', 'NegReg', (81, 88))	('cyclinE1', 'Gene', (67, 75))	('cyclinE1', 'Gene', '898', (67, 75))
285871	24743895	The effect of DACH1 on cell apoptosis was also analyzed by flow cytometry in KYSE510 and KYSE150 cell lines, but no apoptosis change was found before and after restoration of DACH1 expression in these two cell lines (data not shown).	('restoration', 'Var', (160, 171))	('KYSE150', 'CellLine', 'CVCL:1348', (89, 96))	('DACH1', 'Gene', (175, 180))
285874	24743895	As shown in figure 5A, SBE4 promoter activity was increased more than 3 fold in KYSE510 and 2.6 fold in KYSE150 cells after restoration of DACH1 expression, and the activity was increased in a dose-dependent manner by restoration of DACH1 expression combined with TGF-beta1 treatment.	('KYSE150', 'Var', (104, 111))	('TGF-beta1', 'Gene', '7040', (264, 273))	('TGF-beta1', 'Gene', (264, 273))	('increased', 'PosReg', (50, 59))	('KYSE150', 'CellLine', 'CVCL:1348', (104, 111))	('expression', 'MPA', (145, 155))	('SBE4', 'Gene', (23, 27))	('DACH1', 'Gene', (233, 238))	('activity', 'MPA', (37, 45))	('DACH1', 'Gene', (139, 144))	('increased', 'PosReg', (178, 187))
285879	24743895	p21 was up-regulated and c-Myc was down-regulated after re-expression of DACH1 (Fig.	('re-expression', 'Var', (56, 69))	('p21', 'Gene', (0, 3))	('c-Myc', 'Gene', (25, 30))	('up-regulated', 'PosReg', (8, 20))	('down-regulated', 'NegReg', (35, 49))	('p21', 'Gene', '1026', (0, 3))	('DACH1', 'Gene', (73, 78))	('c-Myc', 'Gene', '4609', (25, 30))
285882	24743895	The level of p-Smad2 didn't change after knocking down DACH1 in DACH1 expressed KYSE140 cells, but the level of p-Smad3 was reduced when knocking down DACH1.	('Smad3', 'Gene', (114, 119))	('Smad2', 'Gene', (15, 20))	('Smad3', 'Gene', '4088', (114, 119))	('DACH1', 'Gene', (55, 60))	('knocking down', 'Var', (41, 54))	('Smad2', 'Gene', '4087', (15, 20))
285885	24743895	Reduced p21 and increased c-Myc expression were found after knocking down DACH1 in KYSE140 cells (Fig.	('p21', 'Gene', '1026', (8, 11))	('Reduced', 'NegReg', (0, 7))	('p21', 'Gene', (8, 11))	('increased', 'PosReg', (16, 25))	('c-Myc', 'Gene', '4609', (26, 31))	('knocking down', 'Var', (60, 73))	('c-Myc', 'Gene', (26, 31))	('DACH1', 'Gene', (74, 79))
285888	24743895	DACH1 expression was regulated by promoter region hypermethylation in endometrial, colorectal and hepatocellular carcinoma.	('DACH1', 'Gene', (0, 5))	('expression', 'MPA', (6, 16))	('hypermethylation', 'Var', (50, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('colorectal and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (83, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('endometrial', 'Disease', (70, 81))
285889	24743895	In the present study, we demonstrated that DACH1 expression was reduced and the expression of DACH1 was regulated by promoter region hypermethylation in human esophageal cancer.	('regulated', 'Reg', (104, 113))	('DACH1', 'Gene', (43, 48))	('esophageal cancer', 'Disease', (159, 176))	('expression', 'MPA', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('human', 'Species', '9606', (153, 158))	('reduced', 'NegReg', (64, 71))	('expression', 'MPA', (80, 90))	('DACH1', 'Gene', (94, 99))	('hypermethylation', 'Var', (133, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))
285890	24743895	We had reported that many tumor suppressors were methylated with a progression tendency during esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (95, 120))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('methylated', 'Var', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (95, 120))
285892	24743895	DACH1 was frequently methylated in esophageal cancer and the frequency was increased with the progression of esophageal carcinogenesis from normal esophageal mucosa to invasive cancer.	('DACH1', 'Gene', (0, 5))	('methylated', 'Var', (21, 31))	('esophageal cancer', 'Disease', (35, 52))	('invasive cancer', 'Disease', (168, 183))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('invasive cancer', 'Disease', 'MESH:D009362', (168, 183))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (109, 134))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('increased', 'PosReg', (75, 84))	('esophageal carcinogenesis', 'Disease', (109, 134))
285894	24743895	The association of poor differentiation and late tumor stage with DACH1 methylation suggests that DACH1 methylation may serve as esophageal cancer prognostic marker.	('late tumor', 'Disease', 'MESH:D009369', (44, 54))	('late tumor', 'Disease', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('methylation', 'Var', (72, 83))	('DACH1', 'Gene', (66, 71))	('esophageal cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
285906	24743895	Moreover, DACH1 synergized with TGF-beta to enhance induction of p21 and repression of c-Myc; correspondingly, knocking down DACH1 suppressed TGF-beta signaling in KYSE140 cells.	('c-Myc', 'Gene', '4609', (87, 92))	('TGF-beta', 'Gene', '7040', (142, 150))	('p21', 'Gene', '1026', (65, 68))	('TGF-beta', 'Gene', '7040', (32, 40))	('TGF-beta', 'Gene', (142, 150))	('p21', 'Gene', (65, 68))	('c-Myc', 'Gene', (87, 92))	('repression', 'MPA', (73, 83))	('knocking down', 'Var', (111, 124))	('TGF-beta', 'Gene', (32, 40))	('DACH1', 'Gene', (125, 130))	('induction', 'MPA', (52, 61))	('suppressed', 'NegReg', (131, 141))	('enhance', 'PosReg', (44, 51))
285971	22934214	It is possible that inflammation provoked cell proliferation, followed by genetic mutations, and the development of cancer.	('genetic mutations', 'Var', (74, 91))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cell proliferation', 'CPA', (42, 60))	('inflammation', 'Disease', 'MESH:D007249', (20, 32))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('inflammation', 'Disease', (20, 32))
286057	33257699	Somatic single nucleotide variations (SNVs) and small insertions and deletions (indels) significantly recur in TP53 and genome-wide single base substitutions (SBSs) typically form a pattern known as Signature 17 in the Catalogue of Somatic Mutations in Cancer (COSMIC).	('single base substitutions', 'Var', (132, 157))	('TP53', 'Gene', '7157', (111, 115))	('Cancer', 'Disease', (253, 259))	('Cancer', 'Disease', 'MESH:D009369', (253, 259))	('Cancer', 'Phenotype', 'HP:0002664', (253, 259))	('deletions', 'Var', (69, 78))	('TP53', 'Gene', (111, 115))	('single nucleotide variations', 'Var', (8, 36))
286058	33257699	Signature 17 may be the footprint of an early mutational mechanism initiating esophageal and gastric adenocarcinoma, and its characteristic SBS, 5'-C[T > G]T-3', has been associated with poor survival of esophageal adenocarcinoma.	('adenocarcinoma', 'Disease', (215, 229))	('adenocarcinoma', 'Disease', 'MESH:D000230', (101, 115))	('esophageal', 'Disease', (78, 88))	('adenocarcinoma', 'Disease', 'MESH:D000230', (215, 229))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (204, 229))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (93, 115))	('gastric adenocarcinoma', 'Disease', (93, 115))	('adenocarcinoma', 'Disease', (101, 115))	("5'-C[T > G]T-3'", 'Var', (145, 160))
286069	33257699	To increase the detection power, we combined the reported coding-region mutations data of 151 ACGEJ samples with our data and found that TP53 was the only gene recurrently mutated in >=10% of samples (Supplementary Table 1).	('mutations', 'Var', (72, 81))	('ACGEJ', 'Chemical', '-', (94, 99))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', (137, 141))
286078	33257699	The median ploidy of WGD genomes was 3.1 and they had a significantly larger proportion of autosomal genome losing heterozygosity than non-WGD genomes (39% versus 25%, P = 2.43e-6), indicating frequent single-copy losses after WGD.	('ploidy', 'Disease', (11, 17))	('ploidy', 'Disease', 'None', (11, 17))	('WGD', 'Var', (21, 24))	('autosomal genome', 'Protein', (91, 107))	('losing', 'NegReg', (108, 114))
286079	33257699	Together, these results suggest the abundant CNVs observed in our ACGEJ genomes were associated with CIN.	('CIN', 'Disease', 'MESH:D007674', (101, 104))	('ACGEJ', 'Gene', (66, 71))	('ACGEJ', 'Chemical', '-', (66, 71))	('CIN', 'Phenotype', 'HP:0040012', (101, 104))	('CIN', 'Disease', (101, 104))	('CNVs', 'Var', (45, 49))	('associated', 'Reg', (85, 95))
286082	33257699	CNVs of these 13 genes are potential ACGEJ drivers, of which CCNE1 and ERBB2 amplifications occurred most frequently (n = 35 and 24; 28.2% and 19.4%, respectively) and significantly co-existed (n = 13, 10.5%; P = 0.004).	('amplifications', 'Var', (77, 91))	('ERBB2', 'Gene', '2064', (71, 76))	('CCNE1', 'Gene', '898', (61, 66))	('CCNE1', 'Gene', (61, 66))	('ERBB2', 'Gene', (71, 76))	('ACGEJ', 'Chemical', '-', (37, 42))	('CNVs', 'Var', (0, 4))
286083	33257699	We found genomic and transcriptomic evidence suggesting an association between the dysfunction of CCNE1 and CIN.	('CCNE1', 'Gene', '898', (98, 103))	('CCNE1', 'Gene', (98, 103))	('CIN', 'Phenotype', 'HP:0040012', (108, 111))	('dysfunction', 'Var', (83, 94))	('CIN', 'Disease', (108, 111))	('CIN', 'Disease', 'MESH:D007674', (108, 111))
286084	33257699	ACGEJ with CCNE1 copy number gains (n = 67, 54.0%) had more CNVs at both chromosomal arm level (median 21 versus 14, P = 3.20e-5) and gene level (median 618 versus 251, P = 8.88e-5), and were more likely to undergo WGD (P = 4.28e-4) than ACGEJ without CCNE1 gains (n = 57, 46.0%) (Fig.	('WGD', 'Disease', (215, 218))	('CCNE1', 'Gene', '898', (252, 257))	('ACGEJ', 'Chemical', '-', (238, 243))	('CCNE1', 'Gene', (252, 257))	('copy number', 'Var', (17, 28))	('gains', 'PosReg', (29, 34))	('ACGEJ', 'Chemical', '-', (0, 5))	('CCNE1', 'Gene', '898', (11, 16))	('CCNE1', 'Gene', (11, 16))	('CNVs', 'MPA', (60, 64))
286087	33257699	Consistently, CCNE1 amplification has been associated with WGD in TCGA pan-cancer analyses and CCNE1 overexpression has been shown to induce CIN phenotypes in various cancer cells.	('overexpression', 'PosReg', (101, 115))	('induce', 'PosReg', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('CCNE1', 'Gene', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('CCNE1', 'Gene', '898', (95, 100))	('CIN', 'Phenotype', 'HP:0040012', (141, 144))	('cancer', 'Disease', (167, 173))	('WGD', 'Disease', (59, 62))	('cancer', 'Disease', (75, 81))	('CCNE1', 'Gene', '898', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CIN', 'Disease', (141, 144))	('CCNE1', 'Gene', (14, 19))	('associated', 'Reg', (43, 53))	('amplification', 'Var', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('CIN', 'Disease', 'MESH:D007674', (141, 144))
286090	33257699	We searched for potential cancer-driving regulatory elements in these regions and found Signature 17 SNVs in 75.3% (314/417) of significantly mutated CTCF binding sites (Supplementary Data 3).	('CTCF', 'Gene', (150, 154))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('mutated', 'Var', (142, 149))	('binding', 'Interaction', (155, 162))	('CTCF', 'Gene', '10664', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
286108	33257699	Five TCGA ACGEJ samples were likely microsatellite instable, while no such samples were identified in our cohort.	('TCGA', 'Gene', (5, 9))	('ACGEJ', 'Chemical', '-', (10, 15))	('microsatellite', 'Var', (36, 50))
286110	33257699	The recurrence rates of functional mutations (annotated as oncogenic or likely oncogenic by OncoKB) in TP53, PTEN, ARID1A, CDKN2A, and KRAS appeared to be significantly higher in TCGA patient cohort than in our patient cohort.	('TP53', 'Gene', '7157', (103, 107))	('higher', 'PosReg', (169, 175))	('TP53', 'Gene', (103, 107))	('KRAS', 'Gene', (135, 139))	('TCGA', 'Disease', (179, 183))	('PTEN', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (135, 139))	('PTEN', 'Gene', '5728', (109, 113))	('CDKN2A', 'Gene', (123, 129))	('ARID1A', 'Gene', '8289', (115, 121))	('ARID1A', 'Gene', (115, 121))	('CDKN2A', 'Gene', '1029', (123, 129))	('patient', 'Species', '9606', (211, 218))	('patient', 'Species', '9606', (184, 191))	('mutations', 'Var', (35, 44))
286111	33257699	We did not find CDKN2A and KRAS mutations in our samples but detected 4.0% of LIPF mutations absent in TCGA samples (Supplementary Table 2).	('mutations', 'Var', (83, 92))	('LIPF', 'Gene', (78, 82))	('KRAS', 'Gene', '3845', (27, 31))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('LIPF', 'Gene', '8513', (78, 82))	('KRAS', 'Gene', (27, 31))
286112	33257699	Homologous deletions or amplifications of these genes, which might drive ACGEJ, occurred mostly at comparable frequencies between two cohorts (Fig.	('drive', 'Reg', (67, 72))	('ACGEJ', 'Disease', (73, 78))	('ACGEJ', 'Chemical', '-', (73, 78))	('amplifications', 'Var', (24, 38))
286113	33257699	3d), except for more frequent CCNE1 and BCL2L1 amplifications in our samples (P = 0.016 and P = 0.007, respectively).	('CCNE1', 'Gene', '898', (30, 35))	('CCNE1', 'Gene', (30, 35))	('BCL2L1', 'Gene', (40, 46))	('BCL2L1', 'Gene', '598', (40, 46))	('amplifications', 'Var', (47, 61))
286114	33257699	We then compared the impacts of potentially functional alterations (i.e., oncogene amplification, TSG homologous deletion, and functional mutations in both) at the pathway level.	('oncogene', 'Gene', (74, 82))	('TSG', 'Gene', (98, 101))	('amplification', 'Var', (83, 96))	('TSG', 'Gene', '57045', (98, 101))
286124	33257699	The vulnerabilities of our patients to the three drugs were predicted mainly based on coding mutations in TP53.	('patients', 'Species', '9606', (27, 35))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))	('coding mutations', 'Var', (86, 102))
286126	33257699	We found significantly more frequent CIN-related genomic alterations (i.e., WGD, chromothripsis, and kataegis) in patients predictively responsive to any of the three drugs (n = 91) than in other patients (P = 2.00e-5, 0.035, and 2.00e-5, respectively) (Fig.	('chromothripsis', 'Disease', 'MESH:D000072837', (81, 95))	('CIN', 'Disease', 'MESH:D007674', (37, 40))	('genomic', 'Var', (49, 56))	('patients', 'Species', '9606', (196, 204))	('CIN', 'Phenotype', 'HP:0040012', (37, 40))	('chromothripsis', 'Disease', (81, 95))	('patients', 'Species', '9606', (114, 122))	('WGD', 'Disease', (76, 79))	('CIN', 'Disease', (37, 40))
286129	33257699	Of the 100 patients without ERBB2 amplifications, 89 had other genomic alterations likely druggable by 59 classes of agents.	('patients', 'Species', '9606', (11, 19))	('ERBB2', 'Gene', (28, 33))	('amplifications', 'Var', (34, 48))	('ERBB2', 'Gene', '2064', (28, 33))
286132	33257699	4c), the TP53 mutations in 88 patients were the major contributors to the predicted efficacy of WEE1 inhibitors.	('WEE1', 'Gene', (96, 100))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('patients', 'Species', '9606', (30, 38))	('WEE1', 'Gene', '7465', (96, 100))	('mutations', 'Var', (14, 23))
286133	33257699	While only 19 patients had CDK4/CDK6 alterations, other alterations such as CDKN2A/CDKN2B deletions or CCND1 amplifications in another 29 patients might also render them vulnerable to CDK4/6 inhibitors.	('CDK6', 'Gene', '1021', (32, 36))	('CDKN2B', 'Gene', '1030', (83, 89))	('CDK4/6', 'Gene', '1019;1021', (184, 190))	('CDK4', 'Gene', (27, 31))	('alterations', 'Var', (37, 48))	('patients', 'Species', '9606', (14, 22))	('CDK6', 'Gene', (32, 36))	('CDKN2A', 'Gene', '1029', (76, 82))	('render', 'Reg', (158, 164))	('CCND1', 'Gene', '595', (103, 108))	('CDK4', 'Gene', '1019', (27, 31))	('deletions', 'Var', (90, 99))	('CCND1', 'Gene', (103, 108))	('patients', 'Species', '9606', (138, 146))	('CDK4', 'Gene', (184, 188))	('amplifications', 'Var', (109, 123))	('CDKN2B', 'Gene', (83, 89))	('CDK4/6', 'Gene', (184, 190))	('CDK4', 'Gene', '1019', (184, 188))	('CDKN2A', 'Gene', (76, 82))
286134	33257699	Using the RNA sequencing data of paired ACGEJ and adjacent normal tissue samples of each patient, we found that 85.2% (404/474) of the predictively targetable gene alterations had corresponding expression changes (Supplementary Data 6).	('alterations', 'Var', (164, 175))	('ACGEJ', 'Chemical', '-', (40, 45))	('patient', 'Species', '9606', (89, 96))	('expression', 'MPA', (194, 204))
286135	33257699	Recurrent inconsistency (>10 samples) was only found for FGF3 and FGF4 amplifications (in 13 and 14 samples, respectively), potentially affecting the predicted response rates of two FGFR inhibitors Lucitanib and Dovitinib.	('amplifications', 'Var', (71, 85))	('Dovitinib', 'Chemical', 'MESH:C500007', (212, 221))	('FGF4', 'Gene', '2249', (66, 70))	('affecting', 'Reg', (136, 145))	('response', 'MPA', (160, 168))	('FGF3', 'Gene', (57, 61))	('FGF4', 'Gene', (66, 70))	('Lucitanib', 'Chemical', 'MESH:C000595232', (198, 207))	('FGF3', 'Gene', '2248', (57, 61))
286144	33257699	For chemotherapeutic agents, cells with oncogenic mutation in NF1 were significantly more sensitive to Vinblastine and cells with oncogenic mutations in ATM and ERCC4 were slightly more sensitive to Cisplatin than those without corresponding mutations.	('ATM', 'Gene', (153, 156))	('ERCC4', 'Gene', '2072', (161, 166))	('more', 'PosReg', (85, 89))	('ERCC4', 'Gene', (161, 166))	('NF1', 'Gene', (62, 65))	('ATM', 'Gene', '472', (153, 156))	('NF1', 'Gene', '4763', (62, 65))	('Cisplatin', 'Chemical', 'MESH:D002945', (199, 208))	('sensitive to Vinblastine', 'MPA', (90, 114))	('Vinblastine', 'Chemical', 'MESH:D014747', (103, 114))	('mutation', 'Var', (50, 58))	('sensitive', 'MPA', (186, 195))
286145	33257699	For targeted therapeutic agents, cells with CCNE1 amplifications were highly responsive to CDK2 inhibitor Roniciclib.	('CDK2', 'Gene', (91, 95))	('CCNE1', 'Gene', '898', (44, 49))	('CCNE1', 'Gene', (44, 49))	('Roniciclib', 'Chemical', 'MESH:C578610', (106, 116))	('CDK2', 'Gene', '1017', (91, 95))	('responsive to', 'MPA', (77, 90))	('amplifications', 'Var', (50, 64))
286146	33257699	Cells with oncogenic mutations in DNA repair genes BRCA2, ATM, ATR, CHEK2, and FANCA were more sensitive to PARP inhibitor Olaparib and cells with oncogenic mutations in TP53 or BRCA1 were more sensitive to WEE1 inhibitor MK-1775 than those without corresponding mutations.	('BRCA2', 'Gene', (51, 56))	('WEE1', 'Gene', '7465', (207, 211))	('FANCA', 'Gene', '2175', (79, 84))	('ATR', 'Gene', (63, 66))	('PARP', 'Gene', (108, 112))	('BRCA1', 'Gene', '672', (178, 183))	('CHEK2', 'Gene', (68, 73))	('BRCA1', 'Gene', (178, 183))	('sensitive', 'MPA', (95, 104))	('BRCA2', 'Gene', '675', (51, 56))	('mutations', 'Var', (157, 166))	('TP53', 'Gene', (170, 174))	('MK-1775', 'Chemical', 'MESH:C549567', (222, 229))	('CHEK2', 'Gene', '11200', (68, 73))	('FANCA', 'Gene', (79, 84))	('ATM', 'Gene', '472', (58, 61))	('WEE1', 'Gene', (207, 211))	('Olaparib', 'Chemical', 'MESH:C531550', (123, 131))	('ATR', 'Gene', '545', (63, 66))	('mutations', 'Var', (21, 30))	('sensitive', 'MPA', (194, 203))	('PARP', 'Gene', '1302', (108, 112))	('TP53', 'Gene', '7157', (170, 174))	('ATM', 'Gene', (58, 61))
286147	33257699	Cells with CDK4/6 or FGF3/4 amplifications showed only slightly but significantly higher sensitivity to CDK4/6 inhibitor LEE011 or FGFR inhibitor Dovitinib, respectively, than those without corresponding gene amplifications (Fig.	('sensitivity', 'MPA', (89, 100))	('FGF3/4', 'Gene', (21, 27))	('amplifications', 'Var', (28, 42))	('higher', 'PosReg', (82, 88))	('CDK4/6', 'Gene', '1019;1021', (11, 17))	('CDK4/6', 'Gene', '1019;1021', (104, 110))	('Dovitinib', 'Chemical', 'MESH:C500007', (146, 155))	('FGF3/4', 'Gene', '2248;2249', (21, 27))	('CDK4/6', 'Gene', (11, 17))	('CDK4/6', 'Gene', (104, 110))
286149	33257699	Regarding genomic changes, both TMB and gene level CNVs were significantly correlated with survival time: patients with low TMB (< 3.45 per Mb) or more gene level CNVs (>=382) in ACGEJ had short survival time (both log-rank P = 0.030) compared with patients with high TMB (>=3.45 per Mb) or less gene level CNVs (<382) in ACGEJ, and the hazard ratios (HRs) of low TMB and more gene level CNVs for death adjusted for age, sex, and tumor stage were 7.70 (95% confidence interval (CI) = 1.02-58.26) and 2.79 (95% CI = 1.05-7.42), respectively (Fig.	('tumor', 'Disease', (430, 435))	('TMB', 'Chemical', '-', (364, 367))	('CNVs', 'Var', (163, 167))	('patients', 'Species', '9606', (249, 257))	('TMB', 'Chemical', '-', (124, 127))	('ACGEJ', 'Chemical', '-', (322, 327))	('TMB', 'Chemical', '-', (268, 271))	('ACGEJ', 'Chemical', '-', (179, 184))	('patients', 'Species', '9606', (106, 114))	('low', 'Var', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (430, 435))	('TMB', 'Chemical', '-', (32, 35))	('death', 'Disease', 'MESH:D003643', (397, 402))	('tumor', 'Phenotype', 'HP:0002664', (430, 435))	('death', 'Disease', (397, 402))
286150	33257699	Given that the TMB and gene level CNVs were moderately correlated in our patients (Spearman's rho = 0.32, P = 2.50e-4), we further classified patients into two groups, the low-TMB high-CNV group (n = 31) versus others (n = 52), and the first group showed significantly shorter survival time than the second group (log-rank P = 0.001), with an adjusted HR of 4.61 (95% CI = 1.80-11.80) (Fig.	('survival time', 'CPA', (277, 290))	('shorter', 'NegReg', (269, 276))	('TMB', 'Chemical', '-', (176, 179))	('low-TMB', 'Var', (172, 179))	('TMB', 'Chemical', '-', (15, 18))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (73, 81))
286154	33257699	Figure 5e shows a multivariate Cox model comparing the relative impacts of featured genomic alterations and other non-genomic factors such as for age, sex, and tumor stage.	('tumor', 'Disease', (160, 165))	('alterations', 'Var', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))
286161	33257699	The results showed that TCGA patients with low TMB (<1.73 per Mb) or high Signature 17 activities (>=48.5%) had significantly shorter survival time (log-rank P = 0.039 and 0.034, respectively) than those with high TMB (>=1.73 per Mb) or low Signature 17 activities (<48.5%); the HRs of low TMB and high Signature 17 activity being 1.78 (95% CI = 0.98-3.22) and 2.61 (95% CI = 1.26-5.38), respectively (Supplementary Fig.	('TMB', 'Chemical', '-', (47, 50))	('patients', 'Species', '9606', (29, 37))	('shorter', 'NegReg', (126, 133))	('survival time', 'CPA', (134, 147))	('activities', 'Var', (87, 97))	('high', 'Var', (69, 73))	('TMB', 'Chemical', '-', (214, 217))	('TMB', 'Chemical', '-', (290, 293))
286162	33257699	Patients with high IFN-alpha response (>= -0.4892) or high IFI30 expression (>=10.80 TPM) in tumors had significantly long survival time (log-rank P = 0.019 and 0.020, respectively), with the HRs of 0.46 (95% CI = 0.27-0.79) and 0.51 (95% CI = 0.28-0.93), respectively (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('high', 'Var', (54, 58))	('long', 'PosReg', (118, 122))	('IFN-alpha', 'Gene', (19, 28))	('survival time', 'CPA', (123, 136))	('IFN-alpha', 'Gene', '3439', (19, 28))	('IFI30', 'Gene', '10437', (59, 64))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('IFI30', 'Gene', (59, 64))	('tumors', 'Disease', (93, 99))
286172	33257699	Both TMB and gene level CNVs of the ACGEJ genome indicate the prognosis of Chinese patients.	('ACGEJ', 'Chemical', '-', (36, 41))	('indicate', 'Reg', (49, 57))	('patients', 'Species', '9606', (83, 91))	('TMB', 'Chemical', '-', (5, 8))	('ACGEJ', 'Gene', (36, 41))	('CNVs', 'Var', (24, 28))
286178	33257699	It has been shown that oxidative stress may generate more mutations in introns and intergenic regions than in exons and promoters, and improperly handled oxidative DNA damages can lead to CIN phenotypes in model systems and in human cells.	('lead to', 'Reg', (180, 187))	('mutations', 'Var', (58, 67))	('oxidative stress', 'Phenotype', 'HP:0025464', (23, 39))	('CIN', 'Disease', (188, 191))	('human', 'Species', '9606', (227, 232))	('CIN', 'Disease', 'MESH:D007674', (188, 191))	('CIN', 'Phenotype', 'HP:0040012', (188, 191))
286184	33257699	However, tumor samples of our patients seem to have fewer functional mutations than TCGA samples, which might reflect different genetic and environmental backgrounds between Chinese patients and Caucasian patients or might be simply due to different coverage of our WGS data and TCGA whole-exome sequencing data.	('mutations', 'Var', (69, 78))	('fewer', 'NegReg', (52, 57))	('patients', 'Species', '9606', (205, 213))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('functional', 'MPA', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (182, 190))
286189	33257699	Since DNA repair deficiency caused by TP53 inactivation and other events is the major mechanism associated with the efficacy of cytotoxic anticancer drugs, we have predicted that more frequent TP53 inactivating mutations may lead to generally higher response rates to cytotoxic anticancer agents in Chinese patients than in Caucasian patients, suggesting that these chemotherapeutic agents may generally benefit Chinese patients with ACGEJ.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('patients', 'Species', '9606', (420, 428))	('TP53', 'Gene', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('patients', 'Species', '9606', (307, 315))	('ACGEJ', 'Chemical', '-', (434, 439))	('deficiency', 'Disease', 'MESH:D007153', (17, 27))	('TP53', 'Gene', (193, 197))	('TP53', 'Gene', '7157', (38, 42))	('deficiency', 'Disease', (17, 27))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('higher', 'PosReg', (243, 249))	('inactivating mutations', 'Var', (198, 220))	('patients', 'Species', '9606', (334, 342))	('cancer', 'Disease', (282, 288))	('response rates', 'MPA', (250, 264))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('TP53', 'Gene', '7157', (193, 197))
286192	33257699	Specifically, we have shown that CCNE1 amplification is a CIN-associated oncogenic event prevalent in Chinese patients and often coexisting with ERBB2 amplifications.	('CIN', 'Disease', (58, 61))	('amplification', 'Var', (39, 52))	('CIN', 'Disease', 'MESH:D007674', (58, 61))	('ERBB2', 'Gene', (145, 150))	('CIN', 'Phenotype', 'HP:0040012', (58, 61))	('ERBB2', 'Gene', '2064', (145, 150))	('patients', 'Species', '9606', (110, 118))	('CCNE1', 'Gene', '898', (33, 38))	('CCNE1', 'Gene', (33, 38))
286194	33257699	We have validated the reliability of gene-alteration-based drug vulnerability prediction by in vitro assays in a panel of cancer cell lines.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('gene-alteration-based', 'Var', (37, 58))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('drug vulnerability', 'Phenotype', 'HP:0020174', (59, 77))
286198	33257699	In addition, we have identified Signature 17 activity as another independent marker for ACGEJ survival time, which one may expect because in our patient set Signature 17 is correlated with CIN-related genomic changes such as WGD and chromothripsis, both confer terrible malignant cancer phenotypes.	('chromothripsis', 'Disease', (233, 247))	('Signature 17', 'Var', (157, 169))	('CIN', 'Phenotype', 'HP:0040012', (189, 192))	('chromothripsis', 'Disease', 'MESH:D000072837', (233, 247))	('correlated', 'Reg', (173, 183))	('ACGEJ', 'Disease', (88, 93))	('CIN', 'Disease', (189, 192))	('ACGEJ', 'Chemical', '-', (88, 93))	('patient', 'Species', '9606', (145, 152))	('CIN', 'Disease', 'MESH:D007674', (189, 192))	('malignant cancer', 'Disease', 'MESH:D009369', (270, 286))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('WGD', 'Disease', (225, 228))	('malignant cancer', 'Disease', (270, 286))
286201	33257699	Moreover, transcriptome analysis has shown that tumors with high Signature 17 activities had repressed activities of IFN-producing cytotoxic cells.	('activities', 'MPA', (78, 88))	('high', 'Var', (60, 64))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('IFN', 'Gene', '3439', (117, 120))	('Signature 17', 'Gene', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('IFN', 'Gene', (117, 120))
286205	33257699	For IFI44, the GEO data agreed with our finding, whereas the TCGA data showed a significantly negative correlation between high IFI44 expression and patient survival.	('IFI44', 'Gene', '10561', (4, 9))	('expression', 'MPA', (134, 144))	('IFI44', 'Gene', (4, 9))	('high', 'Var', (123, 127))	('IFI44', 'Gene', '10561', (128, 133))	('patient', 'Species', '9606', (149, 156))	('patient survival', 'CPA', (149, 165))	('negative', 'NegReg', (94, 102))	('IFI44', 'Gene', (128, 133))
286236	33257699	In a tumor genome, we considered a gene undergoing homozygous deletion, copy-number loss, copy-number gain, or amplification if the corresponding GISTIC score = -2, <= -1, >= 1, or = 2, respectively.	('amplification', 'Var', (111, 124))	('copy-number', 'Var', (72, 83))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('copy-number', 'Var', (90, 101))	('loss', 'NegReg', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('gain', 'PosReg', (102, 106))
286255	33257699	The same approach was applied to divide TCGA patients into good or poor survival groups, with the specific cutoffs of 1.73 per Mb for TMB, 42 for gene level CNVs, 48.5% for Signature 17 activity, -0.4892 for IFN-alpha response, 12.09 for IFI44 expressions, and 10.80 for IFI33 expressions.	('TMB', 'Chemical', '-', (134, 137))	('IFN-alpha', 'Gene', '3439', (208, 217))	('IFN-alpha', 'Gene', (208, 217))	('activity', 'MPA', (186, 194))	('patients', 'Species', '9606', (45, 53))	('CNVs', 'Var', (157, 161))	('IFI44', 'Gene', '10561', (238, 243))	('TMB', 'Gene', (134, 137))	('IFI44', 'Gene', (238, 243))
286262	32369495	Research of the mechanism on miRNA193 in exosomes promotes cisplatin resistance in esophageal cancer cells Chemotherapy resistance of esophageal cancer is a key factor affecting the postoperative treatment of esophageal cancer.	('cancer', 'Disease', (145, 151))	('nt', 'Chemical', 'MESH:D009711', (203, 205))	('miRNA193', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('esophageal cancer', 'Disease', (83, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (209, 226))	('miRNA193', 'Chemical', '-', (29, 37))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('promotes', 'PosReg', (50, 58))	('cancer', 'Disease', (94, 100))	('esophageal cancer', 'Disease', (209, 226))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (220, 226))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cisplatin resistance', 'MPA', (59, 79))	('esophageal cancer', 'Disease', (134, 151))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
286266	32369495	Through high-throughput sequencing analysis of the exosome and of cells after stimulation by exosomes, we determined that the miRNA193 in exosomes conferring cellular resistance played a key role in sensitive cells acquiring resistance to cisplatin.	('resistance to cisplatin', 'MPA', (225, 248))	('cisplatin', 'Chemical', 'MESH:D002945', (239, 248))	('cellular resistance', 'MPA', (158, 177))	('miRNA193', 'Chemical', '-', (126, 134))	('miRNA193', 'Var', (126, 134))
286267	32369495	In vitro experiments showed that miRNA193 can regulate the cell cycle of esophageal cancer cells and inhibit apoptosis, so that sensitive cells can acquire resistance to cisplatin.	('regulate', 'Reg', (46, 54))	('acquire', 'PosReg', (148, 155))	('inhibit', 'NegReg', (101, 108))	('resistance', 'MPA', (156, 166))	('esophageal cancer', 'Disease', (73, 90))	('nt', 'Chemical', 'MESH:D009711', (17, 19))	('apoptosis', 'CPA', (109, 118))	('cell cycle', 'CPA', (59, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (170, 179))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('miRNA193', 'Chemical', '-', (33, 41))	('miRNA193', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
286268	32369495	An in vivo experiment proved that miRNA193 can promote tumor proliferation through the exosomes, and provide sensitive cells with slight resistance to cisplatin.	('nt', 'Chemical', 'MESH:D009711', (19, 21))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miRNA193', 'Chemical', '-', (34, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('promote', 'PosReg', (47, 54))	('tumor', 'Disease', (55, 60))	('miRNA193', 'Var', (34, 42))
286269	32369495	Small RNA sequencing of exosomes showed that exosomes in drug-resistant cells have 189 up-regulated and 304 down-regulated miRNAs; transcriptome results showed that drug-sensitive cells treated with drug-resistant cellular exosomes have 3446 high-expression and 1709 low-expression genes; correlation analysis showed that drug-resistant cellular exosomes mainly affect the drug resistance of sensitive cells through paths such as cytokine-cytokine receptor interaction, and the VEGF and Jak-STAT signaling pathways; miRNA193, one of the high-expression miRNAs in drug-resistant cellular exosomes, can promote drug resistance by removing cisplatin's inhibition of the cell cycle of sensitive cells.	('VEGF', 'Gene', (478, 482))	('drug resistance', 'MPA', (609, 624))	('drug resistance', 'Phenotype', 'HP:0020174', (373, 388))	('cell cycle', 'CPA', (667, 677))	('cisplatin', 'MPA', (637, 646))	('promote', 'PosReg', (601, 608))	('inhibition', 'MPA', (649, 659))	('miRNA193', 'Var', (516, 524))	('miRNA193', 'Chemical', '-', (516, 524))	('VEGF', 'Gene', '7422', (478, 482))	('nt', 'Chemical', 'MESH:D009711', (334, 336))	('cisplatin', 'Chemical', 'MESH:D002945', (637, 646))	('drug resistance', 'Phenotype', 'HP:0020174', (609, 624))	('nt', 'Chemical', 'MESH:D009711', (69, 71))	('nt', 'Chemical', 'MESH:D009711', (458, 460))	('nt', 'Chemical', 'MESH:D009711', (211, 213))	('removing', 'NegReg', (628, 636))	('nt', 'Chemical', 'MESH:D009711', (575, 577))
286270	32369495	Sensitive cells can become resistant to cisplatin through acquired drug-resistant cellular exosomes, and miRNA193 can make tumor cells acquire cisplatin resistance by regulating the cell cycle.	('cell cycle', 'CPA', (182, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('acquire', 'PosReg', (135, 142))	('tumor', 'Disease', (123, 128))	('regulating', 'Reg', (167, 177))	('cisplatin resistance', 'MPA', (143, 163))	('nt', 'Chemical', 'MESH:D009711', (34, 36))	('miRNA193', 'Var', (105, 113))	('nt', 'Chemical', 'MESH:D009711', (79, 81))	('miRNA193', 'Chemical', '-', (105, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
286275	32369495	As a broad-spectrum antitumor drug, cisplatin mainly causes DNA damage in tumor cells, and is a common chemotherapeutic drug used to treat esophageal cancer.	('causes', 'Reg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (24, 29))	('nt', 'Chemical', 'MESH:D009711', (21, 23))	('cisplatin', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('DNA damage', 'MPA', (60, 70))	('tumor', 'Disease', (74, 79))	('esophageal cancer', 'Disease', (139, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
286329	32369495	The 3' untranslated region in the TFAP2C of the miR-193a target gene and its mutant were cloned into the pEZX-MT01 carrier (Genecopeia, Rockville, MD, USA).	('miR-193a', 'Gene', '406968', (48, 56))	('nt', 'Chemical', 'MESH:D009711', (81, 83))	('TFAP2C', 'Gene', (34, 40))	('TFAP2C', 'Gene', '7022', (34, 40))	('mutant', 'Var', (77, 83))	('nt', 'Chemical', 'MESH:D009711', (8, 10))	('miR-193a', 'Gene', (48, 56))	('nt', 'Chemical', 'MESH:D009711', (97, 99))
286355	32369495	After removing low-quality reads, the adapter sequences and reads shorter than 18 nt, clean reads of in total 7879335 and 12960223 were obtained.	('12960223', 'Var', (122, 130))	('7879335', 'Var', (110, 117))	('nt', 'Chemical', 'MESH:D009711', (82, 84))
286372	32369495	The small RNA-seq results showed that miRNA-193 is a high-expression miRNA in TE-1/DDP/exo.	('DDP', 'Gene', '1678', (83, 86))	('TE-1', 'Gene', '57816', (78, 82))	('DDP', 'Gene', (83, 86))	('TE-1', 'Gene', (78, 82))	('miRNA-193', 'Var', (38, 47))
286374	32369495	A fluorescent quantitative PCR experiment was conducted to measure the miRNA193 and TFAP2C in different samples, which showed similar differences (Fig 3A).	('nt', 'Chemical', 'MESH:D009711', (17, 19))	('nt', 'Chemical', 'MESH:D009711', (11, 13))	('nt', 'Chemical', 'MESH:D009711', (101, 103))	('miRNA193', 'Chemical', '-', (71, 79))	('miRNA193', 'Var', (71, 79))	('TFAP2C', 'Gene', (84, 90))	('nt', 'Chemical', 'MESH:D009711', (39, 41))	('TFAP2C', 'Gene', '7022', (84, 90))
286375	32369495	TargentScan-Human V7.0 (http://www.targetscan.org) was used to predict that miRNA-193 and TFAP2C had a targeting sequence relation (Fig 3B).	('nt', 'Chemical', 'MESH:D009711', (5, 7))	('miRNA-193', 'Var', (76, 85))	('TFAP2C', 'Gene', (90, 96))	('TFAP2C', 'Gene', '7022', (90, 96))	('Human', 'Species', '9606', (12, 17))
286381	32369495	In TE-1 and ECA-109 cells, the overexpressed miRNA193 or down-regulated TFAP2C enabled the cells to acquire tolerance to cisplatin (Fig 3D).	('down-regulated', 'NegReg', (57, 71))	('tolerance to cisplatin', 'MPA', (108, 130))	('miRNA193', 'Chemical', '-', (45, 53))	('miRNA193', 'Var', (45, 53))	('TE-1', 'Gene', (3, 7))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('overexpressed', 'PosReg', (31, 44))	('TFAP2C', 'Gene', (72, 78))	('TFAP2C', 'Gene', '7022', (72, 78))	('TE-1', 'Gene', '57816', (3, 7))
286382	32369495	We wished to prove the hypothesis that exosomes or miRNA193 could cause drug resistance by an experiment with nude mice bearing tumors.	('miRNA193', 'Chemical', '-', (51, 59))	('miRNA193', 'Var', (51, 59))	('nt', 'Chemical', 'MESH:D009711', (102, 104))	('drug resistance', 'Phenotype', 'HP:0020174', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cause', 'Reg', (66, 71))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('drug resistance', 'MPA', (72, 87))	('nude mice', 'Species', '10090', (110, 119))
286399	32369495	In the medium containing 0.25 muM cisplatin, the proportion of G0/G1-stage cells of TE-1 cells was higher than the proportion of normally cultured TE-1 cells (Fig 5A).	('G0/G1-stage cells', 'CPA', (63, 80))	('TE-1', 'Gene', '57816', (147, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('higher', 'PosReg', (99, 105))	('TE-1', 'Gene', '57816', (84, 88))	('TE-1', 'Gene', (84, 88))	('cisplatin', 'Var', (34, 43))	('nt', 'Chemical', 'MESH:D009711', (16, 18))	('TE-1', 'Gene', (147, 151))
286414	32369495	Overexpressed miRNA193 can inhibit TFAP2C, which generated the opposite result.	('miRNA193', 'Var', (14, 22))	('miRNA193', 'Chemical', '-', (14, 22))	('TFAP2C', 'Gene', (35, 41))	('TFAP2C', 'Gene', '7022', (35, 41))	('inhibit', 'NegReg', (27, 34))
286428	32369495	In the highly metastatic A375SM melanoma cells, re-expression of TFAP2 can reduce their oncogenicity and inhibit their metastasis potential in nude mice.	('nt', 'Chemical', 'MESH:D009711', (134, 136))	('A375', 'CellLine', 'CVCL:0132', (25, 29))	('reduce', 'NegReg', (75, 81))	('TFAP2', 'Gene', '7020', (65, 70))	('inhibit', 'NegReg', (105, 112))	('melanoma', 'Disease', (32, 40))	('nude mice', 'Species', '10090', (143, 152))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('oncogenicity', 'CPA', (88, 100))	('metastasis potential', 'CPA', (119, 139))	('re-expression', 'Var', (48, 61))	('TFAP2', 'Gene', (65, 70))
286435	32369495	We found that when TE-1/DDP/exo worked on TE-1 or there was overexpression of miRNA193, it caused silence of TFAP2C and reduced TE-1's sensitivity to cisplatin.	('TFAP2C', 'Gene', (109, 115))	('TE-1', 'Gene', '57816', (128, 132))	('TE-1', 'Gene', '57816', (42, 46))	('TFAP2C', 'Gene', '7022', (109, 115))	('TE-1', 'Gene', (42, 46))	('silence', 'NegReg', (98, 105))	('DDP', 'Gene', '1678', (24, 27))	('TE-1', 'Gene', (128, 132))	('DDP', 'Gene', (24, 27))	('TE-1', 'Gene', '57816', (19, 23))	('sensitivity to cisplatin', 'MPA', (135, 159))	('TE-1', 'Gene', (19, 23))	('miRNA193', 'Var', (78, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('miRNA193', 'Chemical', '-', (78, 86))	('reduced', 'NegReg', (120, 127))
286440	32369495	Based on our research, we believe that the main cause is due to the effects of exosome or overexpressed miRNA193 and the target gene TFAP2C.	('miRNA193', 'Var', (104, 112))	('TFAP2C', 'Gene', (133, 139))	('TFAP2C', 'Gene', '7022', (133, 139))	('miRNA193', 'Chemical', '-', (104, 112))	('effects', 'Reg', (68, 75))
286450	29523759	TML-high was strongly associated with MSI-H (P < 0.0001).	('associated', 'Reg', (22, 32))	('MSI', 'Disease', 'MESH:D053842', (38, 41))	('MSI', 'Disease', (38, 41))	('TML-high', 'Var', (0, 8))
286451	29523759	However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS).	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TML-high', 'Var', (13, 21))	('anal cancer', 'Phenotype', 'HP:0032186', (22, 33))	('anal cancers', 'Disease', (22, 34))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('microsatellite', 'Var', (47, 61))	('anal cancers', 'Disease', 'MESH:D001005', (22, 34))
286461	29523759	Proteins resulting from some of these mutated genes are immunogenic and provoke an antitumor immune response by increasing immune cell infiltration and thereby improving sensitivity to ICIs.	('provoke', 'PosReg', (72, 79))	('mutated', 'Var', (38, 45))	('improving', 'PosReg', (160, 169))	('sensitivity to ICIs', 'MPA', (170, 189))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('increasing', 'PosReg', (112, 122))	('tumor', 'Disease', (87, 92))	('immune cell infiltration', 'CPA', (123, 147))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('genes', 'Gene', (46, 51))
286463	29523759	Furthermore, current evidence suggests that tumors with a TML-high status are associated with improved sensitivity to ICIs.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('improved', 'PosReg', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('TML-high status', 'Var', (58, 73))	('sensitivity to ICIs', 'MPA', (103, 122))
286468	29523759	The Cancer Genome Atlas (TCGA) showed that three quarters of hypermutated colorectal cancers (defined as tumors harboring a mutation rate of >12 x 106) were MSI-H, whereas the rest had somatic MMR gene and polymerase epsilon (POLE) mutations, indicating the strong association between MSI-H and TML-high.	('tumors', 'Disease', (105, 111))	('colorectal cancers', 'Disease', 'MESH:D015179', (74, 92))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('colorectal cancers', 'Disease', (74, 92))	('MSI', 'Disease', 'MESH:D053842', (157, 160))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('MSI', 'Disease', (157, 160))	('MSI', 'Disease', 'MESH:D053842', (285, 288))	('mutations', 'Var', (232, 241))	('MSI', 'Disease', (285, 288))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('MMR gene', 'Gene', (193, 201))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
286470	29523759	Defects in DNA polymerase delta and epsilon, which usually have proofreading capabilities, and the DNA MMR system have been shown to cause hypermutation in tumors.	('hypermutation', 'MPA', (139, 152))	('epsilon', 'Enzyme', (36, 43))	('Defects', 'Var', (0, 7))	('DNA polymerase delta', 'Gene', '5424', (11, 31))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('DNA polymerase delta', 'Gene', (11, 31))	('tumors', 'Disease', (156, 162))	('cause', 'Reg', (133, 138))
286480	29523759	TML was measured by counting all nonsynonymous missense mutations found per tumor that had not been previously described as germline alterations (592 genes and 1.4 MB sequenced/tumor).	('nonsynonymous missense mutations', 'Var', (33, 65))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
286484	29523759	The threshold to determine MSI by NGS was determined to be 46 or more loci with insertions or deletions to generate a sensitivity of >95% and specificity of >99%.	('MSI', 'Disease', 'MESH:D053842', (27, 30))	('deletions', 'Var', (94, 103))	('MSI', 'Disease', (27, 30))	('insertions', 'Var', (80, 90))
286495	29523759	In addition, a considerable difference in the prevalence of TML-high between gastric cancers and GEJ adenocarcinomas was observed (8.3% vs. 3.1%, respectively).	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('gastric cancers', 'Disease', (77, 92))	('TML-high', 'Var', (60, 68))	('gastric cancers', 'Phenotype', 'HP:0012126', (77, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('adenocarcinomas', 'Disease', 'MESH:D000230', (101, 116))	('adenocarcinomas', 'Disease', (101, 116))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gastric cancers', 'Disease', 'MESH:D013274', (77, 92))
286498	29523759	The lower frequency of TML-high in metastatic tumors may be related to the finding that primary tumors with TML-high are less likely to develop metastatic disease than TML-low primary tumors.	('primary tumors', 'Disease', 'MESH:D001932', (88, 102))	('less', 'NegReg', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('metastatic tumors', 'Disease', 'MESH:D018223', (35, 52))	('metastatic disease', 'CPA', (144, 162))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('primary tumors', 'Disease', (176, 190))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('metastatic tumors', 'Disease', (35, 52))	('TML-high', 'Var', (108, 116))	('primary tumors', 'Disease', (88, 102))	('primary tumors', 'Disease', 'MESH:D001932', (176, 190))	('develop', 'PosReg', (136, 143))
286503	29523759	In addition, MSI-H was not seen in anal cancers, esophageal squamous cancers, pancreatic NETs, and GISTs; however, in these tumors, TML-high frequencies of 8.3%, 3.5%, 1.3%, and 0%, respectively, were observed, indicating that additional causes exist for TML-high that could result in increased neoantigen production.	('MSI', 'Disease', 'MESH:D053842', (13, 16))	('MSI', 'Disease', (13, 16))	('increased', 'PosReg', (285, 294))	('anal cancers', 'Disease', (35, 47))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('esophageal squamous cancers', 'Disease', (49, 76))	('anal cancers', 'Disease', 'MESH:D001005', (35, 47))	('TML-high', 'Var', (255, 263))	('pancreatic NETs', 'Disease', 'MESH:D010195', (78, 93))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal squamous cancers', 'Disease', 'MESH:D004938', (49, 76))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('GIST', 'Disease', (99, 103))	('neoantigen production', 'MPA', (295, 316))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('squamous cancer', 'Phenotype', 'HP:0002860', (60, 75))	('GIST', 'Phenotype', 'HP:0100723', (99, 103))	('tumors', 'Disease', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('GIST', 'Disease', 'MESH:D046152', (99, 103))	('anal cancer', 'Phenotype', 'HP:0032186', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('pancreatic NETs', 'Disease', (78, 93))	('tumors', 'Disease', 'MESH:D009369', (124, 130))
286522	29523759	Higher levels of mutations are believed to induce the expression of immunogenic and cancer-specific neoantigens, leading to a robust antitumor immune response.	('expression', 'MPA', (54, 64))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Disease', (137, 142))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('induce', 'PosReg', (43, 49))	('mutations', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
286529	29523759	Here, we showed that TML-high is strongly associated with MSI-H status in most gastrointestinal cancers, except for anal cancers, esophageal squamous cell cancers, and pancreatic NETs.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal squamous cell cancers', 'Disease', 'MESH:D018307', (130, 162))	('anal cancers', 'Disease', (116, 128))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('anal cancers', 'Disease', 'MESH:D001005', (116, 128))	('MSI', 'Disease', 'MESH:D053842', (58, 61))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (141, 162))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MSI', 'Disease', (58, 61))	('pancreatic NETs', 'Disease', (168, 183))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (79, 102))	('gastrointestinal cancers', 'Disease', 'MESH:D005770', (79, 103))	('esophageal squamous cell cancers', 'Disease', (130, 162))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('gastrointestinal cancers', 'Disease', (79, 103))	('anal cancer', 'Phenotype', 'HP:0032186', (116, 127))	('associated', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('TML-high', 'Var', (21, 29))	('pancreatic NETs', 'Disease', 'MESH:D010195', (168, 183))
286535	29523759	It has been demonstrated that HPV-induced master regulators play crucial roles with regard to mutation and neoantigen load in cervical cancer.	('cancer', 'Disease', (135, 141))	('mutation', 'Var', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('HPV', 'Species', '10566', (30, 33))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
286553	29523759	Although further analysis among patients with different PD-L1 expression levels is not yet available, it is not unreasonable to speculate that high PD-L1 expressers may have an increased likelihood to respond to the agent based on previously published studies.	('respond', 'MPA', (201, 208))	('patients', 'Species', '9606', (32, 40))	('high', 'Var', (143, 147))	('PD-L1', 'Gene', (148, 153))
286560	29523759	GISTs are rare tumors, not strictly considered typical gastrointestinal tract tumors, characterized by a gain-of-function mutation of c-KIT in approximately 95% of cases.	('gastrointestinal tract tumors', 'Disease', (55, 84))	('GIST', 'Disease', 'MESH:D046152', (0, 4))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('GIST', 'Disease', (0, 4))	('gain-of-function', 'PosReg', (105, 121))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('c-KIT', 'Gene', '3815', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutation', 'Var', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('gastrointestinal tract tumors', 'Phenotype', 'HP:0007378', (55, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('gastrointestinal tract tumors', 'Disease', 'MESH:D005770', (55, 84))	('c-KIT', 'Gene', (134, 139))	('tumors', 'Disease', (15, 21))
286561	29523759	However, we recently demonstrated that mutations in oncogenic driver genes are associated with lower TML-high, which may explain why in our cohort, no GISTs were TML-high.	('GIST', 'Disease', 'MESH:D046152', (151, 155))	('lower', 'NegReg', (95, 100))	('GIST', 'Disease', (151, 155))	('mutations', 'Var', (39, 48))	('GIST', 'Phenotype', 'HP:0100723', (151, 155))	('TML-high', 'Disease', (101, 109))
286564	29523759	More importantly, PD-1 and PD-L1 blockade in vivo enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.	('blockade', 'Var', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('imatinib', 'Chemical', 'MESH:C097613', (84, 92))	('IDO', 'Gene', (159, 162))	('IDO', 'Gene', '3620', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PD-1', 'Gene', (18, 22))	('KIT', 'Gene', '3815', (151, 154))	('increasing', 'PosReg', (96, 106))	('tumor', 'Disease', (67, 72))	('enhanced', 'PosReg', (50, 58))	('PD-L1', 'Gene', (27, 32))	('KIT', 'Gene', (151, 154))	('T-cell effector function', 'CPA', (107, 131))
286569	29523759	For instance, based on our data, small-bowel adenocarcinomas and GISTs may benefit from immunotherapy: the former due to the high rate of TML-high that is correlated to MSI-H status, and the latter due to the high rate of PD-L1 expression.	('GIST', 'Disease', 'MESH:D046152', (65, 69))	('GIST', 'Disease', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('MSI', 'Disease', 'MESH:D053842', (169, 172))	('small-bowel adenocarcinomas', 'Disease', (33, 60))	('GIST', 'Phenotype', 'HP:0100723', (65, 69))	('small-bowel adenocarcinomas', 'Disease', 'MESH:D000230', (33, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('TML-high', 'Var', (138, 146))	('MSI', 'Disease', (169, 172))
286674	31339548	Thus, this panel of serum biomarkers may be alternative indicators of MDM2/MDM4 amplification in tumor cells, which may be a predictive biomarker for HPD.	('MDM4', 'Gene', (75, 79))	('amplification', 'Var', (80, 93))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('HPD', 'Disease', 'MESH:D004421', (150, 153))	('HPD', 'Disease', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('MDM4', 'Gene', '4194', (75, 79))	('MDM2', 'Gene', '4193', (70, 74))	('MDM2', 'Gene', (70, 74))
286676	31339548	Previous studies have shown that higher CD152 and TIM-3 levels indicate a lymphocyte-inflamed tumor microenvironment, and SDF-1alpha may induce migration of monocytes, which may be correlated with the response to ICB.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('higher', 'PosReg', (33, 39))	('induce', 'PosReg', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('SDF-1alpha', 'Var', (122, 132))	('CD152', 'MPA', (40, 45))	('ICB', 'Chemical', '-', (213, 216))	('TIM-3', 'Gene', (50, 55))	('TIM-3', 'Gene', '84868', (50, 55))	('migration', 'CPA', (144, 153))
286713	31346579	Thus, tumor cells infected with telomelysin could be rendered sensitive to ionizing radiation.	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('telomelysin', 'Var', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
286714	31346579	Recently, we assessed the safety and efficacy of intratumoral injection of telomelysin with radiotherapy in esophageal cancer patients not suited for standard treatments.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('esophageal cancer', 'Disease', (108, 125))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('patients', 'Species', '9606', (126, 134))	('telomelysin', 'Var', (75, 86))	('tumor', 'Disease', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('men', 'Species', '9606', (164, 167))
286743	31346579	All patients received telomelysin without dose-limiting toxicity.	('telomelysin', 'Var', (22, 33))	('toxicity', 'Disease', (56, 64))	('toxicity', 'Disease', 'MESH:D064420', (56, 64))	('patients', 'Species', '9606', (4, 12))
286750	31346579	These clinical data suggest that telomelysin is well-tolerated and warrants further clinical studies of its use in treating solid cancers.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('solid cancers', 'Disease', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('telomelysin', 'Var', (33, 44))	('solid cancers', 'Disease', 'MESH:D009369', (124, 137))
286752	31346579	We previously demonstrated that intratumorally injected telomelysin expressing the GFP gene effectively traffics to the regional lymph nodes, as viral replication produced green fluorescent protein-associated fluorescence signals in metastatic lymph nodes in orthotopic human colorectal and oral cancer xenograft models.46, 47 Therefore, we hypothesize that intratumoral administration of telomelysin would radiosensitize both primary tumors and regional lymph nodes.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('telomelysin', 'Var', (389, 400))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('colorectal and oral cancer', 'Disease', 'MESH:D015179', (276, 302))	('tumor', 'Disease', 'MESH:D009369', (435, 440))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('primary tumors', 'Disease', (427, 441))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('tumor', 'Phenotype', 'HP:0002664', (435, 440))	('radiosensitize', 'NegReg', (407, 421))	('tumor', 'Disease', (363, 368))	('human', 'Species', '9606', (270, 275))	('primary tumors', 'Disease', 'MESH:D009369', (427, 441))	('tumors', 'Phenotype', 'HP:0002664', (435, 441))	('tumor', 'Disease', (435, 440))
286770	31346579	Adenovirus E1A-mediated miR-93/106b upregulation induced p21 suppression followed by MDM2 downregulation, leading to p53-mediated apoptosis in OBP-702-infected cells.	('OBP', 'Gene', (143, 146))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('upregulation', 'PosReg', (36, 48))	('MDM2', 'Gene', (85, 89))	('Adenovirus', 'Species', '45659', (0, 10))	('OBP', 'Gene', '29991', (143, 146))	('suppression', 'NegReg', (61, 72))	('p21', 'Protein', (57, 60))	('miR-93/106b', 'Var', (24, 35))	('downregulation', 'NegReg', (90, 104))
286771	31346579	p53 overexpression enhanced adenovirus-mediated autophagy via activation of the damage-regulated autophagy modulator (DRAM).	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('DRAM', 'Gene', '55332', (118, 122))	('overexpression', 'Var', (4, 18))	('adenovirus', 'Species', '45659', (28, 38))	('adenovirus-mediated autophagy', 'CPA', (28, 57))	('DRAM', 'Gene', (118, 122))	('activation', 'PosReg', (62, 72))	('enhanced', 'PosReg', (19, 27))
286773	31346579	These findings suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy for inducing both apoptotic and autophagic cell death pathways via regulation of microRNA and DRAM in human cancers.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('OBP', 'Gene', (28, 31))	('apoptotic', 'CPA', (117, 126))	('human', 'Species', '9606', (201, 206))	('DRAM', 'Gene', '55332', (193, 197))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('transactivation', 'Var', (49, 64))	('autophagic cell death', 'CPA', (131, 152))	('microRNA', 'Protein', (180, 188))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('OBP', 'Gene', '29991', (28, 31))	('p53', 'Gene', '7157', (45, 48))	('inducing', 'PosReg', (103, 111))	('DRAM', 'Gene', (193, 197))	('p53', 'Gene', (45, 48))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('tumor', 'Disease', (84, 89))
286785	29954131	Moreover, an imbalance in this pathway has been linked to certain types of cancers.	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('imbalance', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('imbalance', 'Phenotype', 'HP:0002172', (13, 22))	('linked', 'Reg', (48, 54))
286822	29954131	The OR (95% CI) of EC was 0.96 (0.97-1.00), 0.93 (0.88-0.99), 0.82 (0.76-0.88), 0.67(0.59-0.75), and 0.55 (0.44-0.67) for 1.2, 1.4, 2.0, 2.5, and 3.0 mg/day of dietary vitamin B6 intake, respectively (Figure 3b).	('0.55', 'Var', (101, 105))	('vitamin B6', 'Chemical', 'MESH:D025101', (168, 178))	('0.67', 'Var', (80, 84))
286845	29954131	Moreover, observational studies reported that suboptimal levels of these B vitamins are associated with various types of cancers, including breast, colorectal, and lung cancer.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('lung cancer', 'Disease', (164, 175))	('suboptimal levels', 'Var', (46, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('colorectal', 'Disease', (148, 158))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('associated', 'Reg', (88, 98))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('breast', 'Disease', (140, 146))
286848	29954131	Thus, folate deficiency may lead to the incorporation of uracil instead of thymine into the DNA and may alter DNA repair mechanisms, leading to chromosomal breakage.	('thymine', 'MPA', (75, 82))	('uracil', 'MPA', (57, 63))	('thymine', 'Chemical', 'MESH:D013941', (75, 82))	('chromosomal breakage', 'Phenotype', 'HP:0040012', (144, 164))	('deficiency', 'Var', (13, 23))	('folate', 'Chemical', 'MESH:D005492', (6, 12))	('chromosomal breakage', 'CPA', (144, 164))	('leading to', 'Reg', (133, 143))	('folate', 'Gene', (6, 12))	('uracil', 'Chemical', 'MESH:D014498', (57, 63))	('lead to', 'Reg', (28, 35))	('alter', 'Reg', (104, 109))	('folate deficiency', 'Phenotype', 'HP:0100507', (6, 23))	('DNA repair mechanisms', 'MPA', (110, 131))	('incorporation', 'MPA', (40, 53))
286852	29954131	However, it is worth noting that high intake of vitamin B12 may also cause higher levels of SAM, which could result in the increased activity of DNA methyltransferase (DNMT) enzymes.	('increased', 'PosReg', (123, 132))	('vitamin B', 'Chemical', 'MESH:D012256', (48, 57))	('higher', 'PosReg', (75, 81))	('high intake', 'Var', (33, 44))	('B12', 'Gene', '7126', (56, 59))	('B12', 'Gene', (56, 59))	('DNA methyltransferase', 'Gene', (145, 166))	('activity', 'MPA', (133, 141))	('DNMT', 'Gene', '1786', (168, 172))	('SAM', 'Chemical', 'MESH:D012436', (92, 95))	('DNA methyltransferase', 'Gene', '1786', (145, 166))	('DNMT', 'Gene', (168, 172))	('levels of SAM', 'MPA', (82, 95))
286854	29954131	In addition, hypermethylation of the enzyme O6-methylguanine-DNA methyltransferase (MGMT) also has been correlated with mutations in the tumor suppressor protein p53.	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (44, 82))	('tumor', 'Disease', (137, 142))	('correlated', 'Reg', (104, 114))	('p53', 'Gene', (162, 165))	('p53', 'Gene', '7157', (162, 165))	('hypermethylation', 'MPA', (13, 29))	('MGMT', 'Gene', '4255', (84, 88))	('MGMT', 'Gene', (84, 88))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('O6-methylguanine-DNA methyltransferase', 'Gene', (44, 82))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
286877	29954131	Consistent with our results, an epidemiological intervention study found that supplementation with vitamin B12 was related to the risk of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('B12', 'Gene', '7126', (107, 110))	('lung cancer', 'Disease', (138, 149))	('supplementation', 'Var', (78, 93))	('men', 'Species', '9606', (84, 87))	('vitamin B', 'Chemical', 'MESH:D012256', (99, 108))	('B12', 'Gene', (107, 110))
287014	24487417	Those with macroscopic residual disease in the primary esophageal specimen had a statistically significant benefit with additional chemotherapy after surgery with a benefit in both 5-year OS 38.7% versus 13.9% (P= 0.016) and a 5-year CSS 42.8% versus 18.8%, (P= 0.048) (Fig.	('macroscopic', 'Var', (11, 22))	('benefit', 'PosReg', (107, 114))	('CSS', 'Gene', '55907', (234, 237))	('OS', 'Chemical', '-', (188, 190))	('CSS', 'Gene', (234, 237))
287048	24487417	Our results showed that trimodality patients with gross residual disease in the esophageal surgical specimen had an overall and CSS benefit from postoperative chemotherapy.	('patients', 'Species', '9606', (36, 44))	('CSS', 'Gene', (128, 131))	('benefit', 'PosReg', (132, 139))	('gross residual disease', 'Var', (50, 72))	('CSS', 'Gene', '55907', (128, 131))
287058	28293090	Development and progression of esophageal cancer result from interactions of genetic changes (accumulation or superposition).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('esophageal cancer', 'Disease', (31, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('result from', 'Reg', (49, 60))	('genetic changes', 'Var', (77, 92))	('men', 'Species', '9606', (7, 10))	('interactions', 'Interaction', (61, 73))
287170	23711283	Compared with patients with low tumoral Cystatin SN expression, ESCC patients with tumors high-expression Cystatin SN exhibited increased disease-free survival (DFS) and overall survival (OS) (P < 0.001 and P < 0.001, respectively).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Cystatin SN', 'Gene', '1469', (106, 117))	('low tumoral', 'Disease', (28, 39))	('Cystatin SN', 'Gene', (106, 117))	('overall survival', 'CPA', (170, 186))	('increased', 'PosReg', (128, 137))	('tumors', 'Disease', (83, 89))	('low tumoral', 'Disease', 'MESH:D009800', (28, 39))	('Cystatin SN', 'Gene', '1469', (40, 51))	('patients', 'Species', '9606', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('disease-free survival', 'CPA', (138, 159))	('high-expression', 'Var', (90, 105))	('patients', 'Species', '9606', (14, 22))	('Cystatin SN', 'Gene', (40, 51))
287227	23711283	For the whole cohort, the median DFS and OS were significantly longer for patients with high tumoral expression levels of Cystatin SN than in patients with low tumoural expression levels (both P < 0.001, Figure 2, Table 3).	('high', 'Var', (88, 92))	('Cystatin SN', 'Gene', '1469', (122, 133))	('Cystatin SN', 'Gene', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('low tumoural', 'Disease', 'MESH:D009800', (156, 168))	('patients', 'Species', '9606', (74, 82))	('low tumoural', 'Disease', (156, 168))	('tumor', 'Disease', (93, 98))	('longer', 'PosReg', (63, 69))	('patients', 'Species', '9606', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
287245	23711283	Howere, in our study, we found that ESCC patients with positive expression of Cystatin SN had significantly longer DFS and OS than those with negative Cystatin SN expression.	('positive expression', 'Var', (55, 74))	('Cystatin SN', 'Gene', '1469', (151, 162))	('Cystatin SN', 'Gene', (151, 162))	('patients', 'Species', '9606', (41, 49))	('longer', 'PosReg', (108, 114))	('DFS', 'MPA', (115, 118))	('Cystatin SN', 'Gene', '1469', (78, 89))	('ESCC', 'Disease', (36, 40))	('Cystatin SN', 'Gene', (78, 89))
287250	23711283	Alterations in secretion may result in higher extracellular and lower intracellular levels of Cystatin C and, therefore, the reverse correlation of Cystatin C with patients' survival is to be expected.	('secretion', 'MPA', (15, 24))	('Cystatin C', 'Gene', (94, 104))	('higher', 'PosReg', (39, 45))	('Cystatin C', 'Gene', (148, 158))	('lower', 'NegReg', (64, 69))	('Alterations', 'Var', (0, 11))	('extracellular', 'MPA', (46, 59))	('Cystatin C', 'Gene', '1471', (94, 104))	('patients', 'Species', '9606', (164, 172))	('Cystatin C', 'Gene', '1471', (148, 158))
287266	23711283	Compared with the patients with low expressive level of Cystatin SN, high expression patients have more favourable survivals.	('patients', 'Species', '9606', (85, 93))	('Cystatin SN', 'Gene', '1469', (56, 67))	('Cystatin SN', 'Gene', (56, 67))	('high expression', 'Var', (69, 84))	('patients', 'Species', '9606', (18, 26))
287294	22273456	However as the gastric conduit is blindly elevated intrathoracically, twists in the gastric tube and damage such as vascular damage to other organs is a risk.	('vascular damage', 'Disease', 'MESH:D000783', (116, 131))	('vascular damage', 'Disease', (116, 131))	('gastric tube', 'Disease', 'MESH:D013274', (84, 96))	('gastric tube', 'Disease', (84, 96))	('twists', 'Var', (70, 76))
287359	19515183	Cryotherapy resulted in a complete response in 24 patients with HGD or greater during the study period (Table 4).	('Cryotherapy', 'Var', (0, 11))	('HGD', 'Gene', '3081', (64, 67))	('patients', 'Species', '9606', (50, 58))	('HGD', 'Gene', (64, 67))
287430	18778470	As an acidic drug, doxycycline accumulation in the epithelial cells can also cause a focal contact esophagitis.	('cause', 'Reg', (77, 82))	('doxycycline accumulation', 'Var', (19, 43))	('doxycycline', 'Chemical', 'MESH:D004318', (19, 30))	('esophagitis', 'Phenotype', 'HP:0100633', (99, 110))	('esophagitis', 'Disease', (99, 110))	('esophagitis', 'Disease', 'MESH:D004941', (99, 110))
287431	18778470	With its subsequent local cytochemical effects, doxycycline can cause ulceration and friability of the adjacent esophageal mucosa.	('doxycycline', 'Chemical', 'MESH:D004318', (48, 59))	('cause', 'Reg', (64, 69))	('ulcer', 'Disease', 'MESH:D014456', (70, 75))	('ulcer', 'Disease', (70, 75))	('friability', 'CPA', (85, 95))	('doxycycline', 'Var', (48, 59))
287432	18778470	In addition, doxycycline can also inhibit protein synthesis functions in the esophagus.	('inhibit', 'NegReg', (34, 41))	('doxycycline', 'Chemical', 'MESH:D004318', (13, 24))	('protein synthesis functions', 'MPA', (42, 69))	('doxycycline', 'Var', (13, 24))
287434	18778470	revealed that tetracycline tends to cause distal esophagitis and doxycycline is more frequently associated with mid-esophageal ulceration.	('doxycycline', 'Chemical', 'MESH:D004318', (65, 76))	('tetracycline', 'Chemical', 'MESH:D013752', (14, 26))	('esophageal ulceration', 'Phenotype', 'HP:0004791', (116, 137))	('cause', 'Reg', (36, 41))	('associated', 'Reg', (96, 106))	('doxycycline', 'Var', (65, 76))	('esophagitis', 'Disease', (49, 60))	('esophagitis', 'Phenotype', 'HP:0100633', (49, 60))	('esophagitis', 'Disease', 'MESH:D004941', (49, 60))	('tetracycline', 'Var', (14, 26))	('esophageal ulcer', 'Disease', 'MESH:D014456', (116, 132))	('esophageal ulcer', 'Disease', (116, 132))	('esophageal ulcer', 'Phenotype', 'HP:0004791', (116, 132))
287456	33513939	Evidence has shown that adiposity in adults is a convincing risk factor for many types of cancer, including cancers of the esophagus, pancreas, liver, colorectum, breast (postmenopausal), endometrium, and kidney.	('pancreas', 'Disease', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (108, 132))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('types', 'Disease', (81, 86))	('colorectum', 'Disease', (151, 161))	('breast', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('men', 'Species', '9606', (175, 178))	('kidney', 'Disease', (205, 211))	('endometrium', 'Disease', (188, 199))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancers', 'Disease', (108, 115))	('cancer', 'Disease', (108, 114))	('adiposity', 'Var', (24, 33))	('liver', 'Disease', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('risk factor', 'Reg', (60, 71))	('cancer', 'Disease', (90, 96))
287457	33513939	Fat tissue, in association with immune cells, drives chronic and systemic inflammation, which causes genetic mutation that promotes abnormal cell proliferation, a key component of carcinogenesis.	('Fat', 'Gene', (0, 3))	('promotes', 'PosReg', (123, 131))	('genetic mutation', 'Var', (101, 117))	('Fat', 'Gene', '2195', (0, 3))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('inflammation', 'Disease', (74, 86))	('abnormal cell proliferation', 'CPA', (132, 159))	('carcinogenesis', 'Disease', 'MESH:D063646', (180, 194))	('carcinogenesis', 'Disease', (180, 194))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (132, 159))
287484	33513939	Studies have found that female animals show higher ER-alpha expression in many regions of the brain than their male counterparts and that genetic deletion of ER-alpha affects female animals more than male animals.	('expression', 'MPA', (60, 70))	('ER-alpha', 'Gene', '2099', (158, 166))	('ER-alpha', 'Gene', '2099', (51, 59))	('higher', 'PosReg', (44, 50))	('ar', 'Gene', '100005148', (124, 126))	('genetic deletion', 'Var', (138, 154))	('affects', 'Reg', (167, 174))	('ER-alpha', 'Gene', (51, 59))	('ER-alpha', 'Gene', (158, 166))
287486	33513939	Estrogen depletion leads to an increase in fat accumulation in the abdominal area, and estrogen repletion reverses this effect in female animals.	('fat accumulation', 'MPA', (43, 59))	('depletion', 'Var', (9, 18))	('Estrogen depletion', 'Phenotype', 'HP:0008226', (0, 18))	('ar', 'Gene', '100005148', (77, 79))	('increase', 'PosReg', (31, 39))
287513	33513939	The results indicated that obesity-associated phenotypes were positively associated with two X chromosome mice.	('two X chromosome mice', 'Var', (89, 110))	('mice', 'Species', '10090', (106, 110))	('obesity', 'Phenotype', 'HP:0001513', (27, 34))	('obesity', 'Disease', 'MESH:D009765', (27, 34))	('obesity', 'Disease', (27, 34))	('associated', 'Interaction', (73, 83))
287523	33513939	Deletion of the gene expressing lecithin cholesteric acyl transferase protects female mice from diet-induced obesity.	('obesity', 'Disease', 'MESH:D009765', (109, 116))	('obesity', 'Disease', (109, 116))	('mice', 'Species', '10090', (86, 90))	('obesity', 'Phenotype', 'HP:0001513', (109, 116))	('diet-induced obesity', 'Phenotype', 'HP:0012743', (96, 116))	('Deletion', 'Var', (0, 8))
287549	33513939	In addition, estrogen has anti-inflammatory functions, thus improving esophageal tissue damage, presumably by suppressing cytokine production via mast cell inactivation.. A previous study showed that estrogen downregulates inflammation by inhibiting the expression of macrophage migration inhibitory factor (MIF), which is involved in innate and acquired immunity and cell growth.	('inflammation', 'Disease', (223, 235))	('inhibiting', 'NegReg', (239, 249))	('MIF', 'Gene', '4282', (308, 311))	('estrogen', 'Var', (200, 208))	('expression', 'MPA', (254, 264))	('downregulates', 'NegReg', (209, 222))	('suppressing cytokine production', 'Phenotype', 'HP:0031407', (110, 141))	('macrophage migration inhibitory factor', 'Gene', (268, 306))	('macrophage migration inhibitory factor', 'Gene', '4282', (268, 306))	('MIF', 'Gene', (308, 311))	('inflammation', 'Disease', 'MESH:D007249', (223, 235))
287589	33513939	In another zebrafish model, liver-specific ar knockout also inhibited early HCC development, and androgen treatment stimulated HCC growth only in fish not lacking liver-specific ar, indicating that androgen-AR signaling plays a crucial role in HCC development.	('knockout', 'Var', (46, 54))	('men', 'Species', '9606', (87, 90))	('HCC', 'Phenotype', 'HP:0001402', (76, 79))	('lacking liver', 'Phenotype', 'HP:0100839', (155, 168))	('men', 'Species', '9606', (111, 114))	('zebrafish', 'Species', '7955', (11, 20))	('stimulated', 'PosReg', (116, 126))	('inhibited', 'NegReg', (60, 69))	('HCC growth', 'CPA', (127, 137))	('ar', 'Gene', '100005148', (43, 45))	('ar', 'Gene', '100005148', (71, 73))	('HCC', 'Phenotype', 'HP:0001402', (127, 130))	('men', 'Species', '9606', (255, 258))	('HCC', 'Phenotype', 'HP:0001402', (244, 247))	('ar', 'Gene', '100005148', (178, 180))
287618	33513939	It has been noted that estrogen affects the risk of CRC depending on the stage of CRC development; estrogen enhances ER-beta expression to inhibit colon tumorigenesis in the early disease stages, whereas in the late disease stages, it stimulates ER-alpha expression, resulting in tumor progression.	('ER-alpha', 'Gene', (246, 254))	('stimulates', 'PosReg', (235, 245))	('ER-beta', 'Gene', '2099', (117, 124))	('ER-alpha', 'Gene', '2099', (246, 254))	('estrogen', 'Var', (99, 107))	('colon tumorigenesis', 'Disease', 'MESH:D063646', (147, 166))	('colon tumorigenesis', 'Disease', (147, 166))	('CRC', 'Phenotype', 'HP:0003003', (52, 55))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', (280, 285))	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('ar', 'Gene', '100005148', (175, 177))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('enhances', 'PosReg', (108, 116))	('men', 'Species', '9606', (93, 96))	('inhibit', 'NegReg', (139, 146))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('ER-beta', 'Gene', (117, 124))
287625	33513939	Proximal (right-sided) colon cancer, which is more common among women, is characterized by microsatellite instability, CpG island methylator phenotype+, BRAF mutations, and hereditary non-polyposis colorectal cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (23, 35))	('BRAF', 'Gene', (153, 157))	('hereditary non-polyposis colorectal cancer', 'Disease', (173, 215))	('ar', 'Gene', '100005148', (76, 78))	('colon cancer', 'Disease', 'MESH:D015179', (23, 35))	('ar', 'Gene', '100005148', (180, 182))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (173, 215))	('colon cancer', 'Disease', (23, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('women', 'Species', '9606', (64, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (198, 215))	('mutations', 'Var', (158, 167))	('microsatellite', 'MPA', (91, 105))	('hereditary non-polyposis colorectal cancer', 'Disease', 'MESH:D003123', (173, 215))	('BRAF', 'Gene', '673', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
287626	33513939	Meanwhile, distal (left-sided) colon cancer, which is more prevalent in men, is linked to chromosomal instability, p53 mutations, EGFR/Wnt signaling, and familial adenomatous polyposis.	('colon cancer', 'Disease', (31, 43))	('familial adenomatous polyposis', 'Disease', (154, 184))	('EGFR', 'Gene', '1956', (130, 134))	('linked', 'Reg', (80, 86))	('men', 'Species', '9606', (72, 75))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (163, 184))	('p53', 'Gene', (115, 118))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (154, 184))	('chromosomal instability', 'Phenotype', 'HP:0040012', (90, 113))	('colon cancer', 'Phenotype', 'HP:0003003', (31, 43))	('colon cancer', 'Disease', 'MESH:D015179', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (119, 128))	('EGFR', 'Gene', (130, 134))
287628	33513939	Furthermore, the polymorphisms of vascular endothelial growth factor and lncRNA prostate cancer non-coding RNA were positively associated with CRC risk only in women.	('associated with', 'Reg', (127, 142))	('vascular endothelial growth factor', 'Gene', (34, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('polymorphisms', 'Var', (17, 30))	('women', 'Species', '9606', (160, 165))	('vascular endothelial growth factor', 'Gene', '7422', (34, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('non-coding RNA', 'Gene', (96, 110))	('CRC', 'Disease', (143, 146))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))	('prostate cancer', 'Disease', (80, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
287652	32231423	Publicly available data from genomic studies of esophageal, gastric, pancreatic, cholangiocarcinomas and colorectal cancers were interrogated to unveil the role of BRIP1 in these carcinomas and to discover associations of lesions in BRIP1 with other more common molecular defects in these cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('carcinomas', 'Disease', 'MESH:D002277', (90, 100))	('colorectal cancers', 'Disease', 'MESH:D015179', (105, 123))	('BRIP1', 'Gene', (233, 238))	('pancreatic', 'Disease', (69, 79))	('carcinomas', 'Disease', (179, 189))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (81, 99))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('cancers', 'Disease', 'MESH:D009369', (289, 296))	('BRIP1', 'Gene', '83990', (164, 169))	('pancreatic', 'Disease', 'MESH:D010195', (69, 79))	('carcinomas', 'Disease', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('carcinomas', 'Disease', 'MESH:D002277', (179, 189))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (81, 100))	('colorectal cancers', 'Disease', (105, 123))	('lesions', 'Var', (222, 229))	('associations', 'Reg', (206, 218))	('esophageal', 'Disease', (48, 58))	('BRIP1', 'Gene', '83990', (233, 238))	('cholangiocarcinomas', 'Disease', (81, 100))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', (116, 123))	('gastric', 'Disease', (60, 67))	('BRIP1', 'Gene', (164, 169))	('cancers', 'Disease', (289, 296))
287653	32231423	Molecular lesions in BRIP1 were rare (3.6% of all samples) in GI cancers and consisted almost exclusively of mutations and amplifications.	('BRIP1', 'Gene', '83990', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('GI cancers', 'Disease', (62, 72))	('mutations', 'Var', (109, 118))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('amplifications', 'MPA', (123, 137))	('BRIP1', 'Gene', (21, 26))	('GI cancers', 'Disease', 'MESH:D009369', (62, 72))
287654	32231423	A majority of BRIP1 mutated GI cancers were hyper-mutated due to concomitant mutations in mismatch repair or polymerase epsilon and delta1 genes.	('mismatch repair', 'Gene', (90, 105))	('GI cancers', 'Disease', 'MESH:D009369', (28, 38))	('BRIP1', 'Gene', '83990', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('mutations', 'Var', (77, 86))	('GI cancers', 'Disease', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('polymerase epsilon', 'Gene', (109, 127))	('BRIP1', 'Gene', (14, 19))	('delta1', 'Gene', (132, 138))
287655	32231423	No associations were discovered between amplifications of BRIP1 and any mutated genes.	('amplifications', 'Var', (40, 54))	('BRIP1', 'Gene', '83990', (58, 63))	('BRIP1', 'Gene', (58, 63))
287657	32231423	Overall BRIP1 molecular defects do not seem to play a major role in GI cancers whereas mutations frequently occur in hypermutated carcinomas and co-occur with other HR genes mutations.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('BRIP1', 'Gene', (8, 13))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('GI cancers', 'Disease', (68, 78))	('GI cancers', 'Disease', 'MESH:D009369', (68, 78))	('occur', 'Reg', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('BRIP1', 'Gene', '83990', (8, 13))	('carcinomas', 'Disease', (130, 140))	('carcinomas', 'Disease', 'MESH:D002277', (130, 140))	('mutations', 'Var', (87, 96))
287658	32231423	Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other HR defects.	('defects', 'Var', (28, 35))	('HR defects', 'Disease', 'MESH:D005128', (110, 120))	('BRIP1', 'Gene', (22, 27))	('BRIP1', 'Gene', '83990', (22, 27))	('HR defects', 'Disease', (110, 120))
287659	32231423	Core tip:  BRIP1 gene alterations are uncommon in gastrointestinal cancers.	('BRIP1', 'Gene', (11, 16))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('BRIP1', 'Gene', '83990', (11, 16))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (50, 74))	('gastrointestinal cancers', 'Disease', (50, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('alterations', 'Var', (22, 33))
287660	32231423	Mutations frequently occur in hypermutated carcinomas and co-occur with other homologous recombination genes mutations.	('occur', 'Reg', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('Mutations', 'Var', (0, 9))	('carcinomas', 'Disease', 'MESH:D002277', (43, 53))	('carcinomas', 'Disease', (43, 53))
287661	32231423	Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other homologous recombination defects.	('defects', 'Var', (28, 35))	('BRIP1', 'Gene', (22, 27))	('BRIP1', 'Gene', '83990', (22, 27))
287666	32231423	Besides BRCA1, BRIP1 interacts with mismatch repair (MMR) protein MLH1 and promotes signaling for apoptosis at sites with O6-methylated guanine adducts.	('promotes', 'PosReg', (75, 83))	('BRIP1', 'Gene', (15, 20))	('adducts', 'Var', (144, 151))	('MLH1', 'Gene', '4292', (66, 70))	('BRCA1', 'Gene', '672', (8, 13))	('MLH1', 'Gene', (66, 70))	('interacts', 'Interaction', (21, 30))	('guanine', 'Chemical', 'MESH:D006147', (136, 143))	('BRIP1', 'Gene', '83990', (15, 20))	('O6-methylated', 'Var', (122, 135))	('BRCA1', 'Gene', (8, 13))	('signaling for apoptosis', 'MPA', (84, 107))
287667	32231423	BRIP1 mutant cells that lose the ability for MLH1 interaction survive better when methyl-guanine methyltransferase MGMT is functional as MGMT has more time to process the defective site.	('mutant', 'Var', (6, 12))	('MGMT', 'Gene', '4255', (115, 119))	('MLH1', 'Gene', '4292', (45, 49))	('MGMT', 'Gene', (115, 119))	('MLH1', 'Gene', (45, 49))	('MGMT', 'Gene', (137, 141))	('guanine', 'Chemical', 'MESH:D006147', (89, 96))	('MGMT', 'Gene', '4255', (137, 141))	('BRIP1', 'Gene', (0, 5))	('BRIP1', 'Gene', '83990', (0, 5))
287670	32231423	BRIP1 has been implicated in hereditary ovarian cancers that lack BRCA1 or BRCA2 mutations.	('implicated', 'Reg', (15, 25))	('ovarian cancers', 'Phenotype', 'HP:0100615', (40, 55))	('BRCA1', 'Gene', '672', (66, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (40, 54))	('hereditary ovarian cancers', 'Disease', 'MESH:D061325', (29, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('BRCA2', 'Gene', (75, 80))	('hereditary ovarian cancers', 'Disease', (29, 55))	('BRCA1', 'Gene', (66, 71))	('mutations', 'Var', (81, 90))	('BRCA2', 'Gene', '675', (75, 80))	('BRIP1', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('BRIP1', 'Gene', '83990', (0, 5))
287671	32231423	Up to 0.6%-0.9% of ovarian cancers may carry pathogenic variants in BRIP1, although the percentage may vary in different populations.	('pathogenic', 'Reg', (45, 55))	('BRIP1', 'Gene', '83990', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('ovarian cancers', 'Phenotype', 'HP:0100615', (19, 34))	('ovarian cancers', 'Disease', (19, 34))	('ovarian cancers', 'Disease', 'MESH:D010051', (19, 34))	('variants', 'Var', (56, 64))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('BRIP1', 'Gene', (68, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (19, 33))
287673	32231423	Similarly, rare cases of prostate cancer with BRIP1 mutations reminiscent of prostate cancer in BRCA2 families have been reported.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('BRIP1', 'Gene', (46, 51))	('prostate cancer', 'Disease', 'MESH:D011471', (25, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('prostate cancer', 'Disease', (77, 92))	('BRCA2', 'Gene', '675', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('BRIP1', 'Gene', '83990', (46, 51))	('prostate cancer', 'Disease', (25, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('BRCA2', 'Gene', (96, 101))
287674	32231423	Leukemia predisposition is part of FA and has been described with BRIP1 hereditary mutations, in common with other FA complementation group gene mutations.	('mutations', 'Var', (83, 92))	('Leukemia', 'Disease', 'MESH:D007938', (0, 8))	('BRIP1', 'Gene', (66, 71))	('BRIP1', 'Gene', '83990', (66, 71))	('FA', 'Phenotype', 'HP:0001994', (35, 37))	('Leukemia', 'Disease', (0, 8))	('Leukemia', 'Phenotype', 'HP:0001909', (0, 8))	('FA', 'Phenotype', 'HP:0001994', (115, 117))
287680	32231423	Data from the mutation assessor as reported in cBioportal were used for evaluation of putative functional repercussions of BRIP1 mutations and other mutations of interest.	('mutations', 'Var', (129, 138))	('BRIP1', 'Gene', (123, 128))	('BRIP1', 'Gene', '83990', (123, 128))
287681	32231423	Data from the OncoKB database, a precision oncology database annotating the biologic and oncogenic significance of somatic cancer mutations were incorporated in the functional assessment of discussed mutations.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('oncology', 'Phenotype', 'HP:0002664', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutations', 'Var', (130, 139))	('cancer', 'Disease', (123, 129))
287685	32231423	The frequency of BRIP1 mutations was low in the GI cancers examined.	('BRIP1', 'Gene', '83990', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (23, 32))	('GI cancers', 'Disease', (48, 58))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('BRIP1', 'Gene', (17, 22))	('GI cancers', 'Disease', 'MESH:D009369', (48, 58))
287686	32231423	Among the 1436 samples included in the 5 interrogated studies, 30 samples (2.1%) had one or more BRIP1 mutations.	('BRIP1', 'Gene', '83990', (97, 102))	('mutations', 'Var', (103, 112))	('BRIP1', 'Gene', (97, 102))
287687	32231423	There was a total of 38 BRIP1 mutations in these 30 samples.	('BRIP1', 'Gene', '83990', (24, 29))	('mutations', 'Var', (30, 39))	('BRIP1', 'Gene', (24, 29))
287688	32231423	The distribution of mutations in the exons of BRIP1 is shown in Figure 1.	('BRIP1', 'Gene', (46, 51))	('mutations', 'Var', (20, 29))	('BRIP1', 'Gene', '83990', (46, 51))
287689	32231423	The remaining four likely oncogenic BRIP1 mutations are nonsense mutations.	('oncogenic', 'Reg', (26, 35))	('BRIP1', 'Gene', (36, 41))	('mutations', 'Var', (42, 51))	('BRIP1', 'Gene', '83990', (36, 41))
287690	32231423	The incidence of mutated BRIP1 samples in each of the 5 studies was as follows: esophageal cancer 2.2% (4 of 182 cases), gastric cancer 1.6% (7 of 440 cases), pancreatic cancer 0.5% (1 of 184 cases), no mutations observed in the 36 samples of the cholangiocarcinoma study, colorectal cancer 3% (18 of 594 cases) (Figure 2).	('colorectal cancer', 'Disease', (273, 290))	('pancreatic cancer', 'Disease', (159, 176))	('BRIP1', 'Gene', '83990', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (247, 265))	('colorectal cancer', 'Phenotype', 'HP:0003003', (273, 290))	('BRIP1', 'Gene', (25, 30))	('cholangiocarcinoma', 'Disease', (247, 265))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (159, 176))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (247, 265))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('gastric cancer', 'Disease', (121, 135))	('mutated', 'Var', (17, 24))	('esophageal cancer', 'Disease', (80, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (273, 290))	('pancreatic cancer', 'Disease', 'MESH:D010190', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
287691	32231423	The total number of mutations in BRIP1 mutant samples varied widely ranging between 78 and 11438.	('BRIP1', 'Gene', (33, 38))	('mutant', 'Var', (39, 45))	('BRIP1', 'Gene', '83990', (33, 38))
287692	32231423	The mean and median number of mutations were high (2993.2 and 1747.5 respectively) and 17 of 30 samples with BRIP1 mutations (56.7%) had more than 1000 mutations each.	('mutations', 'Var', (115, 124))	('BRIP1', 'Gene', (109, 114))	('BRIP1', 'Gene', '83990', (109, 114))
287693	32231423	Such a heavy mutation burden is usually observed in cancers with microsatellite instability (MSI) due to mutations in genes that encode for MMR proteins that include MSH2, MSH6, MLH1 and PMS2 or alternatively in cancers with mutations in polymerases epsilon and delta1 (POLE and POLD1 respectively).	('cancers', 'Disease', (52, 59))	('PMS2', 'Gene', (187, 191))	('mutations', 'Var', (105, 114))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('MSH2', 'Gene', (166, 170))	('MSH2', 'Gene', '4436', (166, 170))	('POLD1', 'Gene', '5424', (279, 284))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('MSH6', 'Gene', (172, 176))	('POLD1', 'Gene', (279, 284))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('MSH6', 'Gene', '2956', (172, 176))	('polymerases epsilon', 'Enzyme', (238, 257))	('MLH1', 'Gene', (178, 182))	('PMS2', 'Gene', '5395', (187, 191))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (225, 234))	('MLH1', 'Gene', '4292', (178, 182))	('microsatellite instability', 'MPA', (65, 91))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
287694	32231423	Indeed, 18 of the 30 BRIP1 mutated samples (60%) contained one or more co-occurring mutations in one of these six genes.	('contained', 'Reg', (49, 58))	('mutated', 'Var', (27, 34))	('BRIP1', 'Gene', (21, 26))	('BRIP1', 'Gene', '83990', (21, 26))
287695	32231423	The mean number of mutations in the 18 samples with at least one co-occurring MSI/POLE/POLD1 mutations was 4813 while the mean number of mutations in the 12 samples without any co-occurring MSI/POLE/POLD1 mutations was 262.7.	('POLD1', 'Gene', '5424', (87, 92))	('mutations', 'Var', (93, 102))	('mutations', 'Var', (19, 28))	('POLD1', 'Gene', '5424', (199, 204))	('POLD1', 'Gene', (199, 204))	('POLD1', 'Gene', (87, 92))
287696	32231423	Seventeen of the 18 samples with at least one MSI/ POLE/POLD1 mutation had over 1000 total mutations, while none of the 12 samples with BRIP1 mutations but no MSI/POLE/POLD1 mutation had over 1000 total mutations.	('POLD1', 'Gene', (168, 173))	('mutation', 'Var', (62, 70))	('BRIP1', 'Gene', (136, 141))	('POLD1', 'Gene', '5424', (168, 173))	('BRIP1', 'Gene', '83990', (136, 141))	('POLD1', 'Gene', (56, 61))	('POLD1', 'Gene', '5424', (56, 61))
287697	32231423	Two samples, including the single sample with a BRIP1 mutation in the pancreatic cancer study that contained the higher number of total mutations, an extraordinary 11438, contained mutations in all six MSI/POLE/POLD1 genes.	('mutation', 'Var', (54, 62))	('contained mutations', 'Reg', (171, 190))	('BRIP1', 'Gene', '83990', (48, 53))	('pancreatic cancer', 'Disease', (70, 87))	('POLD1', 'Gene', (211, 216))	('POLD1', 'Gene', '5424', (211, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))	('BRIP1', 'Gene', (48, 53))
287698	32231423	The percentage of mutations in each of the six genes in BRIP1-mutated samples was significantly higher than this percentage in the samples of the 5 studies without BRIP1 mutations (Figure 3).	('BRIP1', 'Gene', (56, 61))	('BRIP1', 'Gene', '83990', (164, 169))	('BRIP1', 'Gene', '83990', (56, 61))	('BRIP1', 'Gene', (164, 169))	('higher', 'PosReg', (96, 102))	('mutations', 'Var', (18, 27))
287699	32231423	POLE mutations were observed in 14 of the 30 BRIP1 mutant samples (46.7%).	('BRIP1', 'Gene', (45, 50))	('mutant', 'Var', (51, 57))	('BRIP1', 'Gene', '83990', (45, 50))	('observed', 'Reg', (20, 28))
287700	32231423	Nine of these POLE mutations were deemed likely oncogenic by the OncoKB database, including 4 samples with the known POLE hotspot mutations V411L and 2 samples with P286R/L hotspot mutations.	('P286R', 'Var', (165, 170))	('V411L', 'SUBSTITUTION', 'None', (140, 145))	('mutations', 'Var', (19, 28))	('V411L', 'Var', (140, 145))	('P286R', 'SUBSTITUTION', 'None', (165, 170))
287701	32231423	The 5 studies contained 74 samples (5.1%) with mutations in POLE and among those 5 and 4 were the hotspot mutations V411L and P286R/L.	('P286R', 'Var', (126, 131))	('V411L', 'SUBSTITUTION', 'None', (116, 121))	('mutations', 'Var', (47, 56))	('V411L', 'Var', (116, 121))	('P286R', 'SUBSTITUTION', 'None', (126, 131))
287702	32231423	Thus, a significant proportion of these characterized deleterious mutations co-occur with BRIP1 mutations.	('mutations', 'Var', (66, 75))	('BRIP1', 'Gene', (90, 95))	('BRIP1', 'Gene', '83990', (90, 95))	('mutations', 'Var', (96, 105))
287703	32231423	Overall these data suggest that BRIP1 mutations do not cause increased tumor burden but are commonly observed in samples with underlying MSI/POLE/POLD1 mutations and thus a substantial subset of GI cancers with somatically mutated BRIP1 have a high tumor mutation burden.	('POLD1', 'Gene', (146, 151))	('POLD1', 'Gene', '5424', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('BRIP1', 'Gene', (231, 236))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('GI cancers', 'Disease', (195, 205))	('BRIP1', 'Gene', (32, 37))	('BRIP1', 'Gene', '83990', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (249, 254))	('BRIP1', 'Gene', '83990', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('GI cancers', 'Disease', 'MESH:D009369', (195, 205))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', (71, 76))
287704	32231423	Among the six samples with likely oncogenic BRIP1 mutations four samples had lower total mutation number (between 81 and 267, Table 1) and three of them had no concomitant MSI/POLE/POLD1 mutations while the fourth, a colorectal cancer sample with a BRIP1 frameshift mutation at I507 had a mutation in MLH1 at L697.	('lower', 'NegReg', (77, 82))	('mutation number', 'MPA', (89, 104))	('MLH1', 'Gene', (301, 305))	('MLH1', 'Gene', '4292', (301, 305))	('mutations', 'Var', (50, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('frameshift mutation at I507', 'Var', (255, 282))	('BRIP1', 'Gene', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('colorectal cancer', 'Disease', (217, 234))	('BRIP1', 'Gene', (44, 49))	('BRIP1', 'Gene', '83990', (249, 254))	('POLD1', 'Gene', (181, 186))	('POLD1', 'Gene', '5424', (181, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('BRIP1', 'Gene', '83990', (44, 49))
287705	32231423	These data suggest that likely oncogenic BRIP1 mutations could contribute to cancer pathogenesis without producing hypermutability.	('BRIP1', 'Gene', (41, 46))	('BRIP1', 'Gene', '83990', (41, 46))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (47, 56))	('contribute', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
287706	32231423	Other BRIP1 mutations with unknown significance may be passengers in hyper-mutated cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('BRIP1', 'Gene', (6, 11))	('cancers', 'Disease', (83, 90))	('BRIP1', 'Gene', '83990', (6, 11))
287707	32231423	In colorectal cancer two thirds of BRIP1-mutated samples (12 of 18) contained also mutations in one or more of the commonly mutated genes of the KRAS/BRAF pathway (KRAS/NRAS/BRAF/PTEN/PIK3CA).	('KRAS', 'Gene', '3845', (164, 168))	('contained', 'Reg', (68, 77))	('colorectal cancer', 'Disease', (3, 20))	('KRAS', 'Gene', (164, 168))	('PTEN', 'Gene', (179, 183))	('BRIP1', 'Gene', (35, 40))	('NRAS', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (174, 178))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('KRAS', 'Gene', '3845', (145, 149))	('BRAF', 'Gene', (174, 178))	('PIK3CA', 'Gene', (184, 190))	('PTEN', 'Gene', '5728', (179, 183))	('KRAS', 'Gene', (145, 149))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('NRAS', 'Gene', '4893', (169, 173))	('BRIP1', 'Gene', '83990', (35, 40))	('PIK3CA', 'Gene', '5290', (184, 190))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
287708	32231423	There was a significant co-occurrence of BRIP1 mutations with mutations in BRAF and PTEN.	('BRIP1', 'Gene', (41, 46))	('BRIP1', 'Gene', '83990', (41, 46))	('BRAF', 'Gene', '673', (75, 79))	('mutations', 'Var', (47, 56))	('PTEN', 'Gene', (84, 88))	('BRAF', 'Gene', (75, 79))	('PTEN', 'Gene', '5728', (84, 88))	('mutations', 'Var', (62, 71))
287709	32231423	However, all 12 samples with BRIP1 mutations co-occurring with the five genes of the KRAS/BRAF pathway were hypermutated and contained mutations in either POLE or POLD1 or both.	('BRAF', 'Gene', (90, 94))	('POLD1', 'Gene', (163, 168))	('POLD1', 'Gene', '5424', (163, 168))	('BRIP1', 'Gene', (29, 34))	('POLE', 'Gene', (155, 159))	('mutations', 'Var', (135, 144))	('BRIP1', 'Gene', '83990', (29, 34))	('contained', 'Reg', (125, 134))	('KRAS', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (90, 94))	('KRAS', 'Gene', '3845', (85, 89))	('mutations', 'Var', (35, 44))
287710	32231423	Thus, the presence of BRIP1 mutations in samples with mutations in genes of the KRAS/BRAF pathway may be co-incidental due to the high mutations burden of hypermutated cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('KRAS', 'Gene', (80, 84))	('mutations', 'Var', (54, 63))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('KRAS', 'Gene', '3845', (80, 84))	('BRIP1', 'Gene', (22, 27))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('mutations', 'Var', (28, 37))	('BRIP1', 'Gene', '83990', (22, 27))
287712	32231423	Thus, mutations of these proteins, especially in their BRIP1-interacting domains, or deletions of BRCA1 and MLH1 even in the absence of BRIP1 lesions per se may result in interference with normal function of BRIP1.	('normal function', 'MPA', (189, 204))	('BRIP1', 'Gene', (55, 60))	('BRIP1', 'Gene', '83990', (136, 141))	('deletions', 'Var', (85, 94))	('BRIP1', 'Gene', (208, 213))	('result', 'Reg', (161, 167))	('interference', 'NegReg', (171, 183))	('BRIP1', 'Gene', '83990', (55, 60))	('BRCA1', 'Gene', '672', (98, 103))	('MLH1', 'Gene', (108, 112))	('BRIP1', 'Gene', '83990', (208, 213))	('MLH1', 'Gene', '4292', (108, 112))	('BRIP1', 'Gene', (136, 141))	('mutations', 'Var', (6, 15))	('BRCA1', 'Gene', (98, 103))
287713	32231423	BRCA1 interacts with BRIP1 through its BRCT domain (aminoacids 1662-1723 and 1757-1842).	('BRCA1', 'Gene', (0, 5))	('aminoacids', 'Var', (52, 62))	('BRCT domain', 'MPA', (39, 50))	('BRIP1', 'Gene', '83990', (21, 26))	('BRCA1', 'Gene', '672', (0, 5))	('BRIP1', 'Gene', (21, 26))
287714	32231423	Mutations in BRCT domain of BRCA1 were observed in only one sample of the total 1436 samples in the 5 studies of GI cancers.	('BRCA1', 'Gene', '672', (28, 33))	('observed', 'Reg', (39, 47))	('BRCA1', 'Gene', (28, 33))	('GI cancers', 'Disease', (113, 123))	('Mutations', 'Var', (0, 9))	('GI cancers', 'Disease', 'MESH:D009369', (113, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
287715	32231423	Deletions of BRCA1 were also rare, observed in 3 samples.	('BRCA1', 'Gene', '672', (13, 18))	('Deletions', 'Var', (0, 9))	('BRCA1', 'Gene', (13, 18))
287717	32231423	Mutations in this part of MLH1 are rare, occurring in 10 samples among the 1436 total samples of the 5 GI cancers studies.	('MLH1', 'Gene', '4292', (26, 30))	('MLH1', 'Gene', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('Mutations', 'Var', (0, 9))	('GI cancers', 'Disease', (103, 113))	('occurring', 'Reg', (41, 50))	('GI cancers', 'Disease', 'MESH:D009369', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
287718	32231423	Deletion of MLH1 occurred in a single sample.	('MLH1', 'Gene', '4292', (12, 16))	('MLH1', 'Gene', (12, 16))	('Deletion', 'Var', (0, 8))
287720	32231423	Despite low mutation frequencies, mutations in several of these genes such as BRCA1, BRCA2, FANCI, FANCD2, PALB2, FANCC and RAD51C were all observed to statistically significantly co-occur with BRIP1 mutations (P < 0.001, Q < 0.001).	('FA', 'Phenotype', 'HP:0001994', (92, 94))	('FANCC', 'Gene', (114, 119))	('mutations', 'Var', (200, 209))	('BRIP1', 'Gene', (194, 199))	('FA', 'Phenotype', 'HP:0001994', (114, 116))	('FANCD2', 'Gene', (99, 105))	('FANCD2', 'Gene', '2177', (99, 105))	('mutations', 'Var', (34, 43))	('PALB2', 'Gene', (107, 112))	('RAD51C', 'Gene', '5889', (124, 130))	('FA', 'Phenotype', 'HP:0001994', (99, 101))	('FANCI', 'Gene', (92, 97))	('BRIP1', 'Gene', '83990', (194, 199))	('BRCA2', 'Gene', (85, 90))	('BRCA1', 'Gene', '672', (78, 83))	('co-occur', 'Reg', (180, 188))	('PALB2', 'Gene', '79728', (107, 112))	('FANCC', 'Gene', '2176', (114, 119))	('BRCA1', 'Gene', (78, 83))	('FANCI', 'Gene', '55215', (92, 97))	('RAD51C', 'Gene', (124, 130))	('BRCA2', 'Gene', '675', (85, 90))
287721	32231423	Comparison of BRIP1 mutations in GI cancers with BRIP1 mutations in breast and ovarian cancer disclosed that in breast cancers BRIP1 mutations are uncommon (10 of 996 samples in the TCGA study of breast cancer, 1%) and contained concomitant MSI/POLE/POLD1 mutations in 3 samples.	('GI cancers', 'Disease', (33, 43))	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('POLD1', 'Gene', (250, 255))	('BRIP1', 'Gene', '83990', (49, 54))	('BRIP1', 'Gene', '83990', (127, 132))	('BRIP1', 'Gene', '83990', (14, 19))	('GI cancers', 'Disease', 'MESH:D009369', (33, 43))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('mutations', 'Var', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancers', 'Disease', 'MESH:D001943', (112, 126))	('breast cancers', 'Disease', (112, 126))	('BRIP1', 'Gene', (49, 54))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (196, 209))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('POLD1', 'Gene', '5424', (250, 255))	('breast cancers', 'Phenotype', 'HP:0003002', (112, 126))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (68, 93))	('BRIP1', 'Gene', (14, 19))	('BRIP1', 'Gene', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
287722	32231423	Similar with GI cancers, mutations of BRIP1 in breast cancers are widely spread in different exons.	('mutations', 'Var', (25, 34))	('BRIP1', 'Gene', '83990', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('GI cancers', 'Disease', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancers', 'Phenotype', 'HP:0003002', (47, 61))	('GI cancers', 'Disease', 'MESH:D009369', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancers', 'Disease', 'MESH:D001943', (47, 61))	('breast cancers', 'Disease', (47, 61))	('BRIP1', 'Gene', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
287723	32231423	In the TCGA study of ovarian cancer the 4 of 5 BRIP1 mutated samples were observed in the absence of MSI or POLE/POLD1 mutations and 3 of the 4 samples were concentrated in the DEAD-2 domain (aminoacids 248 to 415).	('MSI', 'Gene', (101, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mutated', 'Var', (53, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (21, 35))	('BRIP1', 'Gene', (47, 52))	('POLD1', 'Gene', (113, 118))	('POLD1', 'Gene', '5424', (113, 118))	('ovarian cancer', 'Disease', (21, 35))	('mutations', 'Var', (119, 128))	('BRIP1', 'Gene', '83990', (47, 52))
287724	32231423	Copy number alterations of BRIP1 were also uncommon in the studies of the GI cancers examined in this analysis and included 23 BRIP1 amplified samples (1.6%) and a single deleted sample which occurred in an esophageal cancer.	('BRIP1', 'Gene', (127, 132))	('BRIP1', 'Gene', '83990', (127, 132))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('BRIP1', 'Gene', '83990', (27, 32))	('GI cancers', 'Disease', (74, 84))	('Copy number alterations', 'Var', (0, 23))	('esophageal cancer', 'Disease', (207, 224))	('GI cancers', 'Disease', 'MESH:D009369', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (207, 224))	('BRIP1', 'Gene', (27, 32))
287726	32231423	One thousand four hundred twenty-eight genes were co-amplified significantly more often in BRIP1 amplified samples than in BRIP1 non-amplified.	('BRIP1', 'Gene', '83990', (123, 128))	('amplified', 'Var', (97, 106))	('BRIP1', 'Gene', (91, 96))	('BRIP1', 'Gene', (123, 128))	('BRIP1', 'Gene', '83990', (91, 96))
287728	32231423	Co-amplification of ERBB2 was observed in 10 of 14 (71.4%) of BRIP1 amplified gastroesophageal cancer cases (P < 0.001), suggesting that the two genes may be parts of the same amplicon in these cases.	('BRIP1', 'Gene', (62, 67))	('BRIP1', 'Gene', '83990', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ERBB2', 'Gene', '2064', (20, 25))	('ERBB2', 'Gene', (20, 25))	('gastroesophageal cancer', 'Disease', (78, 101))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (78, 101))	('amplified', 'Var', (68, 77))
287729	32231423	As a comparison in breast cancer, where ERBB2 is also commonly amplified, amplification of the two genes co-occurs with statistical significance (P < 0.001) and 36 of the 82 cases (43.9%) with BRIP1 amplifications contained concomitant amplification of ERBB2.	('ERBB2', 'Gene', '2064', (253, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('contained', 'Reg', (214, 223))	('ERBB2', 'Gene', '2064', (40, 45))	('ERBB2', 'Gene', (253, 258))	('amplifications', 'Var', (199, 213))	('ERBB2', 'Gene', (40, 45))	('amplification', 'Var', (236, 249))	('BRIP1', 'Gene', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('BRIP1', 'Gene', '83990', (193, 198))	('breast cancer', 'Disease', (19, 32))
287730	32231423	No significant correlations of BRIP1 amplification with mutations in any gene were found in the GI cancers.	('BRIP1', 'Gene', (31, 36))	('mutations', 'Var', (56, 65))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('BRIP1', 'Gene', '83990', (31, 36))	('GI cancers', 'Disease', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('GI cancers', 'Disease', 'MESH:D009369', (96, 106))
287731	32231423	For example, co-occurrence of BRIP1 amplification with the most commonly mutated tumor suppressor TP53 was observed in 45.8% of BRIP1 amplified samples while 55.6% of BRIP1 non-amplified samples had TP53 mutations (P = 0.22).	('BRIP1', 'Gene', '83990', (167, 172))	('TP53', 'Gene', (199, 203))	('mutations', 'Var', (204, 213))	('BRIP1', 'Gene', (128, 133))	('amplification', 'Var', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('BRIP1', 'Gene', (30, 35))	('BRIP1', 'Gene', (167, 172))	('BRIP1', 'Gene', '83990', (128, 133))	('TP53', 'Gene', '7157', (98, 102))	('amplified', 'Var', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('TP53', 'Gene', '7157', (199, 203))	('BRIP1', 'Gene', '83990', (30, 35))	('tumor', 'Disease', (81, 86))	('TP53', 'Gene', (98, 102))
287732	32231423	Similarly, co-occurrence of BRIP1 amplification with the most commonly mutated oncogene KRAS was seen in 16.7% of BRIP1 amplified samples, while 26.6% of BRIP1 non-amplified samples had KRAS mutations (P = 0.19).	('BRIP1', 'Gene', '83990', (154, 159))	('BRIP1', 'Gene', '83990', (28, 33))	('BRIP1', 'Gene', (114, 119))	('KRAS', 'Gene', (186, 190))	('KRAS', 'Gene', '3845', (186, 190))	('KRAS', 'Gene', (88, 92))	('BRIP1', 'Gene', '83990', (114, 119))	('BRIP1', 'Gene', (154, 159))	('KRAS', 'Gene', '3845', (88, 92))	('amplified', 'Var', (120, 129))	('amplification', 'Var', (34, 47))	('BRIP1', 'Gene', (28, 33))
287750	32231423	Main findings include the low frequency of BRIP1 defects in GI cancers and a significant association of BRIP1 mutations with defects of MSI/polymerase epsilon and delta1 genes and the mutator phenotype.	('BRIP1 defects in GI cancers', 'Disease', (43, 70))	('defects', 'NegReg', (125, 132))	('mutations', 'Var', (110, 119))	('BRIP1', 'Gene', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('BRIP1', 'Gene', '83990', (104, 109))	('MSI/polymerase', 'Gene', (136, 150))	('BRIP1', 'Gene', (43, 48))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('BRIP1', 'Gene', '83990', (43, 48))	('BRIP1 defects in GI cancers', 'Disease', 'MESH:D009369', (43, 70))
287752	32231423	Consistent with this hypothesis, samples with BRIP1 mutations in the five studies had a mean of 4813 mutations while the mean number of mutations in the 83 samples of the colorectal TCGA study, for example, with one or more MSI/POLE/POLD1 mutations was 1734.	('mutations', 'Var', (52, 61))	('BRIP1', 'Gene', (46, 51))	('mutations', 'Var', (101, 110))	('BRIP1', 'Gene', '83990', (46, 51))	('POLD1', 'Gene', (233, 238))	('POLD1', 'Gene', '5424', (233, 238))
287753	32231423	An alternative hypothesis is that samples with more functionally robust MSI/POLE/POLD1 mutations, producing higher total mutation burden, would contain more commonly passenger BRIP1 mutations.	('BRIP1', 'Gene', (176, 181))	('BRIP1', 'Gene', '83990', (176, 181))	('POLD1', 'Gene', (81, 86))	('POLD1', 'Gene', '5424', (81, 86))	('mutations', 'Var', (87, 96))	('mutations', 'Var', (182, 191))
287756	32231423	Another more extensive genomic study that included 359 pancreatic adenocarcinoma samples found no BRIP1 mutations in any of them.	('mutations', 'Var', (104, 113))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (55, 80))	('pancreatic adenocarcinoma', 'Disease', (55, 80))	('BRIP1', 'Gene', (98, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (55, 80))	('BRIP1', 'Gene', '83990', (98, 103))
287760	32231423	Activating mutations in KRAS or other proteins of the pathway are common in GI cancers and thus may affect DNA repair through impairment of the BRCA1/BRIP1 function.	('KRAS', 'Gene', '3845', (24, 28))	('affect', 'Reg', (100, 106))	('GI cancers', 'Disease', 'MESH:D009369', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRCA1', 'Gene', (144, 149))	('Activating mutations', 'Var', (0, 20))	('BRIP1', 'Gene', (150, 155))	('GI cancers', 'Disease', (76, 86))	('impairment', 'NegReg', (126, 136))	('function', 'MPA', (156, 164))	('DNA repair', 'MPA', (107, 117))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('BRIP1', 'Gene', '83990', (150, 155))	('BRCA1', 'Gene', '672', (144, 149))	('KRAS', 'Gene', (24, 28))
287762	32231423	In this study no such mutual exclusivity between BRIP1 mutations and KRAS mutations was observed and in fact a co-occurrence of BRIP1 mutations with mutations of other genes of KRAS pathways was present instead.	('KRAS', 'Gene', (69, 73))	('BRIP1', 'Gene', (49, 54))	('KRAS', 'Gene', '3845', (69, 73))	('mutations', 'Var', (55, 64))	('BRIP1', 'Gene', (128, 133))	('BRIP1', 'Gene', '83990', (49, 54))	('BRIP1', 'Gene', '83990', (128, 133))	('KRAS', 'Gene', (177, 181))	('mutations', 'Var', (134, 143))	('KRAS', 'Gene', '3845', (177, 181))
287763	32231423	This may be due to the common association of both BRIP1 and KRAS pathway mutations with MSI/hypermutable cancers or alternatively due to lack of functional repercussions for some of these BRIP1 mutations.	('BRIP1', 'Gene', '83990', (188, 193))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('mutations', 'Var', (73, 82))	('KRAS', 'Gene', (60, 64))	('BRIP1', 'Gene', (50, 55))	('KRAS', 'Gene', '3845', (60, 64))	('BRIP1', 'Gene', '83990', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('BRIP1', 'Gene', (188, 193))	('association', 'Interaction', (30, 41))
287767	32231423	This may imply, among other plausible explanations, that other transcription factors are involved in the regulation of BRIP1 obscuring the effect of E2F factors or that increased mRNA expression of E2F does not translate into increased expression of the proteins or increased transcription function.	('BRIP1', 'Gene', '83990', (119, 124))	('E2F', 'Var', (198, 201))	('mRNA expression', 'MPA', (179, 194))	('increased', 'PosReg', (266, 275))	('BRIP1', 'Gene', (119, 124))	('increased', 'PosReg', (226, 235))	('expression', 'MPA', (236, 246))	('transcription function', 'MPA', (276, 298))
287769	32231423	Overall this study suggests that neutralization of BRIP1 as a tumor suppressor seems to play a minor role in GI cancers pathogenesis.	('BRIP1', 'Gene', (51, 56))	('neutralization', 'Var', (33, 47))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('GI cancers', 'Disease', (109, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('tumor', 'Disease', (62, 67))	('BRIP1', 'Gene', '83990', (51, 56))	('GI cancers', 'Disease', 'MESH:D009369', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
287770	32231423	However, a contribution as a defect with cumulative influence in cancers with the mutator phenotype is plausible and may be selected by promoting survival in cells with MMR or polymerase mutations, for example if it would contribute to defects in antigen presentation machinery in hypermutated cancers.	('MMR', 'Gene', (169, 172))	('defects', 'NegReg', (236, 243))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (187, 196))	('cancers', 'Disease', (294, 301))	('antigen presentation machinery', 'MPA', (247, 277))	('promoting', 'PosReg', (136, 145))	('polymerase', 'Gene', (176, 186))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
287772	32231423	If a contribution of BRIP1 to an expansion of instability in hypermutated cancers is confirmed, mutations in the gene may become an additional potential predictive marker of response to immunotherapies.	('BRIP1', 'Gene', '83990', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('BRIP1', 'Gene', (21, 26))	('mutations', 'Var', (96, 105))
287780	32231423	TCGA studies were interrogated for BRIP1 mutations and copy number alterations.	('copy number alterations', 'Var', (55, 78))	('BRIP1', 'Gene', (35, 40))	('mutations', 'Var', (41, 50))	('BRIP1', 'Gene', '83990', (35, 40))
287782	32231423	Molecular lesions in BRIP1 are observed in 3.6% of GI cancers and consisted almost exclusively of mutations and amplifications.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('GI cancers', 'Disease', 'MESH:D009369', (51, 61))	('BRIP1', 'Gene', '83990', (21, 26))	('mutations', 'Var', (98, 107))	('BRIP1', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('observed', 'Reg', (31, 39))	('Molecular lesions', 'Var', (0, 17))	('GI cancers', 'Disease', (51, 61))	('amplifications', 'Var', (112, 126))
287783	32231423	Two fifths of all BRIP1 mutations are considered possibly pathogenic.	('BRIP1', 'Gene', '83990', (18, 23))	('mutations', 'Var', (24, 33))	('BRIP1', 'Gene', (18, 23))
287784	32231423	Most BRIP1 mutated GI cancers have concomitant mutations in MMR genes or one of the replication polymerases, polymerase epsilon and delta1 genes.	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('MMR genes', 'Gene', (60, 69))	('BRIP1', 'Gene', (5, 10))	('mutations', 'Var', (47, 56))	('GI cancers', 'Disease', (19, 29))	('GI cancers', 'Disease', 'MESH:D009369', (19, 29))	('BRIP1', 'Gene', '83990', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('mutated', 'Var', (11, 18))
287785	32231423	BRIP1 amplification commonly co-occurs with ERBB2 amplification, a comparatively common amplification in gastroesophageal cancers.	('co-occurs', 'Reg', (29, 38))	('gastroesophageal cancers', 'Disease', (105, 129))	('ERBB2', 'Gene', '2064', (44, 49))	('ERBB2', 'Gene', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (105, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('amplification', 'Var', (6, 19))	('BRIP1', 'Gene', (0, 5))	('BRIP1', 'Gene', '83990', (0, 5))
287786	32231423	BRIP1 gene lesions are not major pathogenic players in GI cancers.	('GI cancers', 'Disease', 'MESH:D009369', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('lesions', 'Var', (11, 18))	('GI cancers', 'Disease', (55, 65))	('BRIP1', 'Gene', (0, 5))	('BRIP1', 'Gene', '83990', (0, 5))
287787	32231423	Association with microsatellite unstable cancers and ERBB2 amplifications in gastroesophageal cancers is worth noting.	('ERBB2', 'Gene', '2064', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('microsatellite unstable cancers', 'Disease', 'MESH:D053842', (17, 48))	('amplifications', 'Var', (59, 73))	('microsatellite unstable cancers', 'Disease', (17, 48))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (77, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('gastroesophageal cancers', 'Disease', (77, 101))	('ERBB2', 'Gene', (53, 58))
287788	32231423	Molecular defects in helicase BRIP1, albeit rare, may provide opportunities for novel therapies in GI cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancers', 'Disease', (99, 109))	('BRIP1', 'Gene', (30, 35))	('GI cancers', 'Disease', 'MESH:D009369', (99, 109))	('helicase', 'Gene', '164045', (21, 29))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('BRIP1', 'Gene', '83990', (30, 35))	('Molecular defects', 'Var', (0, 17))	('helicase', 'Gene', (21, 29))
287790	32231423	BRIP1 defects may contribute to an expansion of instability in hypermutated cancers.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('BRIP1', 'Gene', (0, 5))	('defects', 'Var', (6, 13))	('BRIP1', 'Gene', '83990', (0, 5))
287791	32231423	Thus, BRIP1 mutations could be an additional potential predictive marker of response to immunotherapies.	('mutations', 'Var', (12, 21))	('BRIP1', 'Gene', (6, 11))	('BRIP1', 'Gene', '83990', (6, 11))
287852	31497542	The maximum frequencies of HPV genotypes were HPV-16 and HPV-18 in the ESCC cases, 117 and 37, respectively.	('HPV', 'Species', '10566', (27, 30))	('HPV-16', 'Species', '333760', (46, 52))	('HPV-18', 'Var', (57, 63))	('ESCC', 'Disease', (71, 75))	('HPV', 'Species', '10566', (46, 49))	('HPV-16', 'Var', (46, 52))	('HPV', 'Species', '10566', (57, 60))
287878	31497542	HPV-16 infection may be a risk factor for the EC among Chinese population.	('HPV-16', 'Species', '333760', (0, 6))	('infection', 'Var', (7, 16))	('HPV-16', 'Gene', (0, 6))
287882	31497542	The estimated prevalence of HPV in ESCC cases was 0.277 (95% CI: 0.234, 0.320) by PCR; 0.243 (0.159, 0.326) by ISH; 0.304 (0.185, 0.423) by IHC; 0.322 (0.154, 0.490) by L1 serology; and 0.176 (0.061, 0.292) by Southern blot assay.	('0.243', 'Var', (87, 92))	('HPV', 'Species', '10566', (28, 31))	('ESCC', 'Disease', (35, 39))	('0.304', 'Var', (116, 121))
287895	31497542	The risk of ESCC associated with HPV-16 infection was high (OR: 2.35, 95% CI 1.73-3.19).	('HPV-16', 'Species', '333760', (33, 39))	('HPV-16', 'Gene', (33, 39))	('infection', 'Var', (40, 49))	('ESCC', 'Disease', (12, 16))
287897	31497542	In a meta-analysis including 5755 ESCC cases from 68 studies, 11.67% (95% CI, 7.74%-16.21%) of ESCC cases had HPV-16 and 1.82% (95% CI, 0.90%-2.95%) had HPV-18.	('HPV', 'Species', '10566', (110, 113))	('ESCC', 'Disease', (95, 99))	('HPV-16', 'Var', (110, 116))	('HPV', 'Species', '10566', (153, 156))	('HPV-16', 'Species', '333760', (110, 116))
287909	31497542	Serum samples were tested in 1561 ESCC cases and 2502 controls from 6 case-control studies for antibodies to the HPV major capsid protein (L1) and/or the HPV early proteins (E6 and/or E7).	('E7', 'Var', (184, 186))	('L1', 'Gene', (139, 141))	('ESCC', 'Disease', (34, 38))	('HPV', 'Species', '10566', (154, 157))	('HPV', 'Species', '10566', (113, 116))
287910	31497542	Statistically significant associations were observed between ESCC and antibodies to E6 of HPV-16 (OR 1.89, 95% CI 1.09 to 3.29, P=0.023) and HPV-6 (OR 2.53, 95% CI 1.51 to 4.25, P<0.001).	('HPV', 'Species', '10566', (90, 93))	('HPV-6', 'Gene', (141, 146))	('HPV', 'Species', '10566', (141, 144))	('ESCC', 'Disease', (61, 65))	('HPV-16', 'Gene', (90, 96))	('antibodies', 'Var', (70, 80))	('significant associations', 'Reg', (14, 38))	('HPV-16', 'Species', '333760', (90, 96))
287911	31497542	No significant associations were observed between ESCC and antibodies to E7 of the HPV types.	('HPV', 'Species', '10566', (83, 86))	('antibodies', 'Var', (59, 69))	('ESCC', 'Disease', (50, 54))
287912	31497542	In addition, significant associations was between ESCC and antibodies to L1 capsid protein of HPV-33 (OR 1.30, 95% CI 1.00 to 1.69; P=0.047), HPV-6 (OR 1.22, 95% CI 1.05 to 1.42, P=0.010) and HPV-11 (OR=1.30, 95% CI=1.09 to 1.56, P=0.0036).	('HPV-33', 'Gene', (94, 100))	('HPV-11', 'Species', '10580', (192, 198))	('HPV', 'Species', '10566', (94, 97))	('HPV', 'Species', '10566', (142, 145))	('antibodies', 'Var', (59, 69))	('L1 capsid protein', 'Protein', (73, 90))	('HPV', 'Species', '10566', (192, 195))	('ESCC', 'Disease', (50, 54))
287929	31293986	We found that CEH improved the therapeutic effect of CDDP by manipulating the gut microbiota.	('therapeutic', 'MPA', (31, 42))	('improved', 'PosReg', (18, 26))	('CDDP', 'Disease', (53, 57))	('CEH', 'Var', (14, 17))	('CDDP', 'Chemical', '-', (53, 57))	('CEH', 'Chemical', '-', (14, 17))
287932	31293986	Mechanically, CEH activated TLR4 and MYD88 innate immune signaling, which is advantageous for the activation of the host's innate immunity to exert a balanced intestinal environment as well as to trigger a better chemotherapeutic response to esophageal cancer.	('innate immune', 'MPA', (43, 56))	('TLR4', 'Gene', '21898', (28, 32))	('TLR4', 'Gene', (28, 32))	('men', 'Species', '9606', (177, 180))	('MYD88', 'Gene', '17874', (37, 42))	('esophageal cancer', 'Disease', (242, 259))	('MYD88', 'Gene', (37, 42))	('CEH', 'Var', (14, 17))	('CEH', 'Chemical', '-', (14, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (242, 259))	('activated', 'PosReg', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
287946	31293986	The imbalance of distribution and function in the intestinal microbes caused by CDDP leads to severe intestinal mucosal damage and contributes to adverse events, including similar negative behavioral changes and concurrent gastrointestinal symptoms.	('function', 'MPA', (34, 42))	('CDDP', 'Gene', (80, 84))	('intestinal mucosal damage', 'Disease', (101, 126))	('gastrointestinal symptoms', 'Disease', (223, 248))	('CDDP', 'Chemical', '-', (80, 84))	('imbalance', 'Var', (4, 13))	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (223, 248))	('contributes', 'Reg', (131, 142))	('intestinal mucosal damage', 'Disease', 'MESH:D007410', (101, 126))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))	('behavioral changes', 'Phenotype', 'HP:0000708', (189, 207))
287971	31293986	Antibodies for PARP (9532), Caspase-8 (9746), Caspase-9 (9502), Caspase-3 (9662), TNFR1 (3736), CYLD (8462), JNK (9252), p-JNK (4668), Apaf-1 (8969), Bax (5023), Bcl-2 (15071), Cytochrome c (4280), NF-kappaB (8242), and Myd88 (4283) were purchased from Cell Signaling.	('Caspase-9', 'Gene', '12371', (46, 55))	('CYLD', 'Gene', (96, 100))	('8462', 'Var', (102, 106))	('Myd88', 'Gene', '17874', (220, 225))	('Caspase-9', 'Gene', (46, 55))	('TNFR1', 'Gene', (82, 87))	('Caspase-8', 'Gene', (28, 37))	('TNFR1', 'Gene', '21937', (82, 87))	('NF-kappaB', 'Gene', (198, 207))	('Bcl-2', 'Gene', (162, 167))	('Bax', 'Gene', (150, 153))	('JNK', 'Gene', (109, 112))	('Caspase-8', 'Gene', '12370', (28, 37))	('Caspase-3', 'Gene', (64, 73))	('JNK', 'Gene', '26419', (109, 112))	('Apaf-1', 'Gene', '11783', (135, 141))	('Bcl-2', 'Gene', '12043', (162, 167))	('Caspase-3', 'Gene', '12367', (64, 73))	('JNK', 'Gene', (123, 126))	('NF-kappaB', 'Gene', '18033', (198, 207))	('8969', 'Var', (143, 147))	('PARP', 'Gene', '11545', (15, 19))	('JNK', 'Gene', '26419', (123, 126))	('Myd88', 'Gene', (220, 225))	('Apaf-1', 'Gene', (135, 141))	('Bax', 'Gene', '12028', (150, 153))	('PARP', 'Gene', (15, 19))	('CYLD', 'Gene', '74256', (96, 100))
287977	31293986	16S rRNA genes of V4 region were amplified used the specific primer: 515F, 5'-GTGCCAGCMGCCGCGGTAA-3'; 806R, 5'-GGACTACHVGGGTWTCTAAT-3'.	('16S', 'Gene', '27471', (0, 3))	('515F', 'Var', (69, 73))	('16S', 'Gene', (0, 3))
287990	31293986	Sera were collected from the peripheral blood by centrifugation at 1,000 g. The concentrations of TNF-alpha, TGF-beta, IL-2, IL-10, IFN-beta, and IL-6 in peripheral blood were measured using ELISA kits according to the manufacturers' instructions [EMC102a, EMC002, EMC005, EMC107b, EMC004, EMC016 (NeoBioscience)].	('TGF-beta', 'Gene', '21803', (109, 117))	('TNF-alpha', 'Gene', '21926', (98, 107))	('NeoBioscience', 'Disease', (298, 311))	('EMC005', 'Var', (265, 271))	('IL-10', 'Gene', '16153', (125, 130))	('IFN-beta', 'Gene', '15977', (132, 140))	('NeoBioscience', 'Disease', 'None', (298, 311))	('TGF-beta', 'Gene', (109, 117))	('EMC107b', 'Var', (273, 280))	('IL-2', 'Gene', '16183', (119, 123))	('IL-6', 'Gene', '16193', (146, 150))	('EMC004', 'Var', (282, 288))	('IL-10', 'Gene', (125, 130))	('IL-6', 'Gene', (146, 150))	('IL-2', 'Gene', (119, 123))	('TNF-alpha', 'Gene', (98, 107))	('IFN-beta', 'Gene', (132, 140))
288013	31293986	CEH increased the amount of Parasutterella and Parabacteroides (Figure S2H) relative to the model control group.	('Parasutterella', 'MPA', (28, 42))	('CEH', 'Chemical', '-', (0, 3))	('increased', 'PosReg', (4, 13))	('CEH', 'Var', (0, 3))
288018	31293986	Conversely, CEH significantly increased the amount of Bacteroides, which play a fundamental role in the processing of complex molecules to simpler ones in the host intestine (Wexler,) (Figure S2E).	('CEH', 'Chemical', '-', (12, 15))	('Bacteroides', 'MPA', (54, 65))	('men', 'Species', '9606', (85, 88))	('Bacteroides', 'Species', '817', (54, 65))	('increased', 'PosReg', (30, 39))	('CEH', 'Var', (12, 15))
288041	31293986	Mechanically, CEH activated TLR4 and MYD88 innate immune signaling, which is advantageous for the activation of the host's innate immunity, for a balanced intestinal environment as well as to exert a chemotherapeutic response to esophageal cancer.	('innate immune signaling', 'MPA', (43, 66))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('TLR4', 'Gene', '21898', (28, 32))	('TLR4', 'Gene', (28, 32))	('men', 'Species', '9606', (173, 176))	('MYD88', 'Gene', '17874', (37, 42))	('MYD88', 'Gene', (37, 42))	('CEH', 'Var', (14, 17))	('esophageal cancer', 'Disease', (229, 246))	('esophageal cancer', 'Disease', 'MESH:D004938', (229, 246))	('CEH', 'Chemical', '-', (14, 17))	('activated', 'PosReg', (18, 27))
288047	31293986	CDDP loosed the tight junctions of the cells, destroyed intestinal mucosal integrity, and shallowed the crypts in the small intestine (Figure 6H).	('destroyed', 'NegReg', (46, 55))	('intestinal mucosal integrity', 'CPA', (56, 84))	('shallowed', 'NegReg', (90, 99))	('CDDP', 'Var', (0, 4))	('tight junctions', 'MPA', (16, 31))	('loosed', 'NegReg', (5, 11))	('CDDP', 'Chemical', '-', (0, 4))
288068	31293986	Disorder of the intestinal microbes community can affect the carbohydrate metabolism, as well as amino acids and nucleotides metabolism, and thus change the host's immune response homeostasis (Sun et al.,; Endesfelder et al.,; Mathewson et al.,; Zhernakova et al.,).	('carbohydrate metabolism', 'MPA', (61, 84))	('immune response homeostasis', 'MPA', (164, 191))	('affect', 'Reg', (50, 56))	('Disorder', 'Var', (0, 8))	('change', 'Reg', (146, 152))	('carbohydrate', 'Chemical', 'MESH:D002241', (61, 73))
288070	31293986	For example, CDDP activates the alpha-L-fucosidase pathway (3.2.1.51) (Table S2), which is commonly used as an indicator for early diagnosis of primary liver cancer.	('CDDP', 'Var', (13, 17))	('primary liver cancer', 'Disease', (144, 164))	('liver cancer', 'Phenotype', 'HP:0002896', (152, 164))	('CDDP', 'Chemical', '-', (13, 17))	('primary liver cancer', 'Disease', 'MESH:D006528', (144, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('activates', 'PosReg', (18, 27))
288072	31293986	Chemotherapy with CDDP alters the original state of the glucose metabolism, wherein it decreases mannosyl-glycoprotein endo-beta-N-acetylglucosaminidase and increases mannosyl-oligosaccharidealpha-1,2-mannosidase (Tables S3, S5), which were previously associated with a chemotherapy-induced inflammatory environment (Ramos et al.,).	('CDDP', 'Chemical', '-', (18, 22))	('decreases', 'NegReg', (87, 96))	('glucose', 'Chemical', 'MESH:D005947', (56, 63))	('glucose metabolism', 'MPA', (56, 74))	('men', 'Species', '9606', (311, 314))	('CDDP', 'Var', (18, 22))	('increases', 'PosReg', (157, 166))
288077	31293986	CEH was found to significantly raise the relative abundance of Bacteroides, which able to ferment glucose, lactose, maltose, fructose, raffinose, arabinose, cellobiose, rhamnose, and other carbohydrates.	('rhamnose', 'Chemical', 'MESH:D012210', (169, 177))	('CEH', 'Var', (0, 3))	('CEH', 'Chemical', '-', (0, 3))	('arabinose', 'Chemical', 'MESH:D001089', (146, 155))	('arabinose', 'Protein', (146, 155))	('lactose', 'Chemical', 'MESH:D007785', (107, 114))	('lactose', 'MPA', (107, 114))	('maltose', 'MPA', (116, 123))	('cellobiose', 'Chemical', 'MESH:D002475', (157, 167))	('glucose', 'Chemical', 'MESH:D005947', (98, 105))	('maltose', 'Chemical', 'MESH:D008320', (116, 123))	('cellobiose', 'MPA', (157, 167))	('raise', 'PosReg', (31, 36))	('Bacteroides', 'Species', '817', (63, 74))	('men', 'Species', '9606', (93, 96))	('ferment glucose', 'MPA', (90, 105))	('fructose', 'Chemical', 'MESH:D005632', (125, 133))	('raffinose', 'Chemical', 'MESH:D011887', (135, 144))	('carbohydrates', 'Chemical', 'MESH:D002241', (189, 202))
288110	30835010	Although endoscopic submucosal dissection (ESD) has enabled the en bloc resection of large-sized superficial esophageal neoplasms, esophageal ESD has a possibility of causing esophageal stricture, which results in dysphagia, vomiting and weight loss.	('esophageal stricture', 'Phenotype', 'HP:0002043', (175, 195))	('esophageal neoplasms', 'Disease', (109, 129))	('weight loss', 'Disease', 'MESH:D015431', (238, 249))	('esophageal ESD', 'Var', (131, 145))	('weight loss', 'Phenotype', 'HP:0001824', (238, 249))	('dysphagia', 'Disease', 'MESH:D003680', (214, 223))	('vomiting', 'Disease', 'MESH:D014839', (225, 233))	('neoplasms', 'Phenotype', 'HP:0002664', (120, 129))	('dysphagia', 'Disease', (214, 223))	('weight loss', 'Disease', (238, 249))	('esophageal neoplasms', 'Disease', 'MESH:D004938', (109, 129))	('esophageal stricture', 'Disease', (175, 195))	('vomiting', 'Phenotype', 'HP:0002013', (225, 233))	('vomiting', 'Disease', (225, 233))	('esophageal neoplasms', 'Phenotype', 'HP:0100751', (109, 129))	('neoplasm', 'Phenotype', 'HP:0002664', (120, 128))	('esophageal neoplasm', 'Phenotype', 'HP:0100751', (109, 128))	('dysphagia', 'Phenotype', 'HP:0002015', (214, 223))	('causing', 'Reg', (167, 174))
288120	30835010	A single-channel upper gastrointestinal endoscope (GIF-Q260J; Olympus Medical Systems, Tokyo, Japan) was used with a high-frequency generator (VIO-300D; ERBE Elektromedizin GmbH, Tubingen, Germany).	('upper gastrointestinal endoscope', 'Disease', (17, 49))	('Q260J', 'SUBSTITUTION', 'None', (55, 60))	('Q260J', 'Var', (55, 60))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (17, 49))
288159	30420592	In addition, EC patients with blood expression levels of high miR-21 (HR = 2.19, 95% CI = 1.31-3.68) and miR-223 had significantly shorter OS (P < 0.05).	('miR-21', 'Gene', (62, 68))	('high', 'Var', (57, 61))	('patients', 'Species', '9606', (16, 24))	('miR-223', 'Gene', '407008', (105, 112))	('EC', 'Phenotype', 'HP:0011459', (13, 15))	('miR-21', 'Gene', '406991', (62, 68))	('shorter', 'NegReg', (131, 138))	('miR-223', 'Gene', (105, 112))
288162	30420592	During the past 10 years, a substantial number of articles have reported the survival of esophageal carcinoma (EC) patients with dysregulated microRNA (miRNA) expression.	('EC', 'Phenotype', 'HP:0011459', (111, 113))	('patients', 'Species', '9606', (115, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('esophageal carcinoma', 'Disease', (89, 109))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (89, 109))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (89, 109))	('dysregulated', 'Var', (129, 141))	('miR', 'Gene', '220972', (152, 155))	('miR', 'Gene', (152, 155))
288166	30420592	As the high-throughput analysis develops, an increasing number of cancer-related non-coding RNAs have been recognized.	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (66, 72))	('non-coding RNAs', 'Var', (81, 96))
288188	30420592	Two studies reported the associations between low tissue miR-133a levels and OS, indicating that EC patients with low tissue miR-133a levels had significantly shorter OS than those with high levels (HR = 2.48, 95% CI = 1.50-4.12, P < 0.01, Fig.	('low', 'Var', (114, 117))	('EC', 'Phenotype', 'HP:0011459', (97, 99))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('shorter', 'NegReg', (159, 166))	('patients', 'Species', '9606', (100, 108))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (125, 128))
288189	30420592	Two studies covered the relationship between low tissue miR-133b levels and OS, showing that EC patients with low tissue miR-133b levels had significantly poorer OS than those with high levels (HR = 2.15, 95% CI = 1.27-3.62, P < 0.01, Fig.	('miR-133b', 'Gene', '442890', (56, 64))	('miR-133b', 'Gene', '442890', (121, 129))	('poorer', 'NegReg', (155, 161))	('miR-133b', 'Gene', (121, 129))	('miR-133b', 'Gene', (56, 64))	('patients', 'Species', '9606', (96, 104))	('low', 'Var', (110, 113))	('EC', 'Phenotype', 'HP:0011459', (93, 95))
288191	30420592	Two studies stressed the correlations between low tissue miR-203 levels and OS, indicating that EC patients with high tissue miR-203 levels had significantly shorter OS than those with low levels (HR = 2.83, 95% CI = 1.35-5.95, P < 0.01, Fig.	('high', 'Var', (113, 117))	('shorter', 'NegReg', (158, 165))	('miR-203', 'Gene', '406986', (125, 132))	('miR-203', 'Gene', (125, 132))	('miR-203', 'Gene', (57, 64))	('patients', 'Species', '9606', (99, 107))	('EC', 'Phenotype', 'HP:0011459', (96, 98))	('miR-203', 'Gene', '406986', (57, 64))
288192	30420592	Six studies emphasized the relevance between low tissue miR-375 levels and OS, showing that EC patients with low tissue miR-375 levels had significantly poorer OS than those with high levels (HR = 1.64, 95% CI = 1.05-2.58, P = 0.03, Supplementary Figure 3).	('patients', 'Species', '9606', (95, 103))	('EC', 'Phenotype', 'HP:0011459', (92, 94))	('miR-375', 'Gene', (56, 63))	('miR-375', 'Gene', '494324', (120, 127))	('low', 'Var', (109, 112))	('poorer', 'NegReg', (153, 159))	('miR-375', 'Gene', '494324', (56, 63))	('miR-375', 'Gene', (120, 127))
288194	30420592	Two studies analyzed the connections between high blood miR-21 levels and OS, suggesting that EC patients with high blood miR-21 levels had significantly worse OS than those with low levels (HR = 2.19, 95% CI = 1.31-3.68, P < 0.01, Fig.	('miR-21', 'Gene', (122, 128))	('miR-21', 'Gene', '406991', (122, 128))	('miR-21', 'Gene', (56, 62))	('EC', 'Phenotype', 'HP:0011459', (94, 96))	('miR-21', 'Gene', '406991', (56, 62))	('worse', 'NegReg', (154, 159))	('high', 'Var', (111, 115))	('patients', 'Species', '9606', (97, 105))
288201	30420592	miR-21 is the most studied miRNA, and EC patients with high tissue miR-21 levels have significantly shorter OS times than those with low levels.	('OS times', 'MPA', (108, 116))	('miR-21', 'Gene', '406991', (67, 73))	('miR-21', 'Gene', (0, 6))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('shorter', 'NegReg', (100, 107))	('miR', 'Gene', (0, 3))	('miR', 'Gene', '220972', (0, 3))	('patients', 'Species', '9606', (41, 49))	('EC', 'Phenotype', 'HP:0011459', (38, 40))	('high', 'Var', (55, 59))	('miR-21', 'Gene', (67, 73))	('miR-21', 'Gene', '406991', (0, 6))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))
288253	30386057	PET-CT scans have been shown to be of immense value in the primary staging of esophageal cancers Further, various studies have showed that PET-CT examination can change the clinical staging of esophageal cancers in up to 40% of the patients and also change the management in up to 34% of cases, as was evidenced in our patient as well.	('change', 'Reg', (250, 256))	('patient', 'Species', '9606', (319, 326))	('esophageal cancers', 'Disease', (78, 96))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('management', 'MPA', (261, 271))	('patients', 'Species', '9606', (232, 240))	('esophageal cancers', 'Disease', 'MESH:D004938', (78, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('PET-CT', 'Var', (139, 145))	('esophageal cancers', 'Disease', (193, 211))	('patient', 'Species', '9606', (232, 239))	('change', 'Reg', (162, 168))	('clinical', 'MPA', (173, 181))	('esophageal cancers', 'Disease', 'MESH:D004938', (193, 211))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
288295	28932606	PVS has been identified as a risk factor for developing squamous cell carcinoma of the upper aerodigestive tract in 3%-15% of patients mostly in women between 15 and 50 years of age and almost occurs in the postcricoid region.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Disease', 'MESH:D002277', (70, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('squamous cell carcinoma', 'Disease', (56, 79))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 79))	('carcinoma', 'Disease', (70, 79))	('PVS', 'Var', (0, 3))
288373	27110134	Botulinum toxin, a potent inhibitor of acetylcholine release from the presynaptic terminals by cleaving the SNAP-25 protein, is a useful treatment strategy for patients who are unable to tolerate more invasive therapies, such as PD or surgical myotomy.	('surgical myotomy', 'Disease', (235, 251))	('PD', 'Disease', 'MESH:D010300', (229, 231))	('men', 'Species', '9606', (142, 145))	('patients', 'Species', '9606', (160, 168))	('cleaving', 'Var', (95, 103))	('SNAP-25', 'Gene', (108, 115))	('SNAP-25', 'Gene', '6616', (108, 115))	('acetylcholine', 'Chemical', 'MESH:D000109', (39, 52))
288405	27110134	Two recent studies involving patients with megaesophagus revealed that surgical myotomy resulted in improvement of symptoms ranging from 72% to 92%.	('symptoms', 'MPA', (115, 123))	('patients', 'Species', '9606', (29, 37))	('men', 'Species', '9606', (107, 110))	('surgical myotomy', 'Var', (71, 87))
288440	27110134	The study demonstrated significantly improved symptomatic relief in those treated with LHM compared to those treated with PD at 12 months (89.3% vs 68.2%) and past 36 months (89.3% vs 56.3%).	('symptomatic relief', 'MPA', (46, 64))	('PD', 'Disease', 'MESH:D010300', (122, 124))	('improved', 'PosReg', (37, 45))	('LHM', 'Var', (87, 90))
288447	27110134	It also found a perforation rate for those treated with LHM to be double that of those treated with PD (4.8% vs 2.4%; P<0.05).	('LHM', 'Var', (56, 59))	('perforation', 'CPA', (16, 27))	('PD', 'Disease', 'MESH:D010300', (100, 102))
288515	26059686	In combinatory experiments, mice received intratumoral injection of AdF35 (1.875 x 108 pfu/mouse) and/or Ad5 (1.875 x 108 pfu/mouse) when the tumors reached to about 65 mm3 in volume.	('mouse', 'Species', '10090', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('AdF', 'Gene', '11034', (68, 71))	('tumor', 'Disease', (142, 147))	('Ad5', 'Gene', (105, 108))	('mice', 'Species', '10090', (28, 32))	('Ad5', 'Gene', '8081', (105, 108))	('mouse', 'Species', '10090', (91, 96))	('1.875', 'Var', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('AdF', 'Gene', (68, 71))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', (47, 52))
288543	26059686	These data thereby demonstrated that both the intrinsic and the extrinsic pathways were activated in T.Tn cells, whereas the intrinsic apoptosis was preferentially induced in YES-2 cells.	('YES-2', 'Gene', (175, 180))	('activated', 'PosReg', (88, 97))	('intrinsic', 'Pathway', (46, 55))	('YES-2', 'Gene', '7526', (175, 180))	('extrinsic pathways', 'Pathway', (64, 82))	('T.Tn', 'Var', (101, 105))
288551	26059686	Both YES-2 and T.Tn cells had mutated p53 genes and were susceptible to Ad5/p53-mediated cytotoxicity.	('YES-2', 'Gene', (5, 10))	('Ad5', 'Gene', (72, 75))	('cytotoxicity', 'Disease', (89, 101))	('mutated', 'Var', (30, 37))	('YES-2', 'Gene', '7526', (5, 10))	('p53 genes', 'Gene', (38, 47))	('Ad5', 'Gene', '8081', (72, 75))	('cytotoxicity', 'Disease', 'MESH:D064420', (89, 101))
288568	26059686	YES-2 cells were infected with AdF35/MK or AF35/Sur and Ad5/p53, and the cell lysate was tested for the viral amounts produced (Fig.	('Ad5', 'Gene', (56, 59))	('AF35/Sur', 'Var', (43, 51))	('YES-2', 'Gene', (0, 5))	('MK', 'Gene', '4192', (37, 39))	('AdF', 'Gene', '11034', (31, 34))	('Ad5', 'Gene', '8081', (56, 59))	('YES-2', 'Gene', '7526', (0, 5))	('AdF', 'Gene', (31, 34))
288588	26059686	YES-2 cells showed hyper-phosphorylated pRb, which could favor viral replications through enhanced cell cycle progression.	('viral replications', 'CPA', (63, 81))	('YES-2', 'Gene', (0, 5))	('pRb', 'Gene', (40, 43))	('hyper-phosphorylated', 'Var', (19, 39))	('favor', 'PosReg', (57, 62))	('pRb', 'Gene', '5925', (40, 43))	('enhanced', 'PosReg', (90, 98))	('YES-2', 'Gene', '7526', (0, 5))	('cell cycle progression', 'CPA', (99, 121))
288589	26059686	In contrast, hypo-phosphorylation of pRb in T.Tn cells rather suggested cell cycle arrest prior to cell death.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('pRb', 'Gene', '5925', (37, 40))	('cell cycle arrest', 'CPA', (72, 89))	('hypo-phosphorylation', 'Var', (13, 33))	('pRb', 'Gene', (37, 40))	('suggested', 'Reg', (62, 71))
288596	26059686	In contrast, the present study demonstrated that production of AdF35/MK or AdF35/Sur progenies was rather inhibited by co-transduced p53, which was probably linked with p53-mediated decrease of cell growth and acceleration of cell death.	('AdF', 'Gene', (63, 66))	('production', 'CPA', (49, 59))	('AdF35/Sur', 'Gene', (75, 84))	('MK', 'Gene', '4192', (69, 71))	('p53', 'Var', (133, 136))	('cell growth', 'CPA', (194, 205))	('inhibited', 'NegReg', (106, 115))	('decrease', 'NegReg', (182, 190))	('AdF', 'Gene', '11034', (63, 66))	('AdF', 'Gene', (75, 78))	('AdF', 'Gene', '11034', (75, 78))	('AdF35/Sur', 'Gene', '6833', (75, 84))
288599	26059686	showed that OBP-702, p53-expressing and TERT promoter-activated replication-competent Ad induced apoptosis in lung and esophageal carcinoma cells, but Hasei et al.	('TERT', 'Gene', '7015', (40, 44))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (119, 139))	('OBP', 'Gene', '29991', (12, 15))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (119, 139))	('Ad', 'Gene', '8081', (86, 88))	('OBP', 'Gene', (12, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('p53-expressing', 'Var', (21, 35))	('apoptosis', 'CPA', (97, 106))	('TERT', 'Gene', (40, 44))	('esophageal carcinoma', 'Disease', (119, 139))
288607	26059686	A possible upstream pathway to phosphorylate p53 remains uncharacterized, but Ad proteins synthesized during the replications such as Ad E1B-55 kDa and E4-ORF3 may regulate p53 expression at various levels even in an epigenetic manner.	('E1B', 'Gene', (137, 140))	('p53', 'Gene', (173, 176))	('E4-ORF3', 'Var', (152, 159))	('E1B', 'Gene', '594', (137, 140))	('regulate', 'Reg', (164, 172))	('expression', 'MPA', (177, 187))	('Ad', 'Gene', '8081', (78, 80))	('Ad', 'Gene', '8081', (134, 136))
288614	26059686	showed that replication-competent Ad with deletion of E1B-55 kDa molecules induced hyperploidy populations in normal cells, and suggested a possible linkage between the hyperploidy and increase expression of mitotic arrest-deficient 2 molecules, a major component of the M-phase checkpoint.	('increase', 'PosReg', (185, 193))	('hyperploidy populations', 'CPA', (83, 106))	('induced', 'Reg', (75, 82))	('mitotic arrest-deficient', 'Disease', (208, 232))	('E1B', 'Gene', '594', (54, 57))	('expression', 'MPA', (194, 204))	('E1B', 'Gene', (54, 57))	('deletion', 'Var', (42, 50))	('mitotic arrest-deficient', 'Disease', 'MESH:D006323', (208, 232))	('Ad', 'Gene', '8081', (34, 36))
288673	23775806	Partial stenosis with lumen >5mm was found in 61% patients, <=5mm stenosis in 18% and complete stenosis in 21% of patients at time of first dilation.	('stenosis', 'Disease', 'MESH:D003251', (66, 74))	('stenosis', 'Disease', 'MESH:D003251', (8, 16))	('stenosis', 'Disease', (95, 103))	('patients', 'Species', '9606', (50, 58))	('stenosis', 'Disease', 'MESH:D003251', (95, 103))	('<=5mm', 'Var', (60, 65))	('Partial', 'Disease', (0, 7))	('patients', 'Species', '9606', (114, 122))	('stenosis', 'Disease', (66, 74))	('stenosis', 'Disease', (8, 16))
288741	23762419	A Meta-Analysis of the Association between the hOGG1 Ser326Cys Polymorphism and the Risk of Esophageal Squamous Cell Carcinoma Genetic polymorphism of human 8-oxoguanine glycosylase 1 (hOGG1) Ser326Cys (rs1052133) has been implicated in the risk of Esophageal Squamous Cell Carcinoma (ESCC).	('hOGG1', 'Gene', (47, 52))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (92, 126))	('Carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('Ser326Cys', 'Var', (192, 201))	('Ser326Cys', 'SUBSTITUTION', 'None', (192, 201))	('Esophageal Squamous Cell Carcinoma', 'Disease', (92, 126))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (249, 283))	('rs1052133', 'Var', (203, 212))	('hOGG1', 'Gene', '4968', (185, 190))	('Esophageal Squamous Cell Carcinoma', 'Disease', (249, 283))	('Carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('human', 'Species', '9606', (151, 156))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('Ser326Cys', 'SUBSTITUTION', 'None', (53, 62))	('Ser326Cys', 'Var', (53, 62))	('hOGG1', 'Gene', (185, 190))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (260, 283))	('hOGG1', 'Gene', '4968', (47, 52))	('rs1052133', 'Mutation', 'rs1052133', (203, 212))
288742	23762419	We therefore performed a meta-analysis to derive a more precise estimation of the association between the hOGG1 Ser326Cys polymorphism and ESCC risk.	('hOGG1', 'Gene', (106, 111))	('Ser326Cys', 'Var', (112, 121))	('Ser326Cys', 'SUBSTITUTION', 'None', (112, 121))	('hOGG1', 'Gene', '4968', (106, 111))	('ESCC', 'Disease', (139, 143))
288743	23762419	A comprehensive search was conducted to identify eligible studies of hOGG1 Ser326Cys polymorphism and the risk of the ESCC.	('ESCC', 'Disease', (118, 122))	('hOGG1', 'Gene', '4968', (69, 74))	('Ser326Cys', 'SUBSTITUTION', 'None', (75, 84))	('Ser326Cys', 'Var', (75, 84))	('hOGG1', 'Gene', (69, 74))
288745	23762419	Overall, significant associations between the hOGG1 Ser326Cys polymorphism and ESCC risk were found in the recessive model: OR = 1.37 (95% CI: 1.06-1.76, p = 0.02).	('hOGG1', 'Gene', '4968', (46, 51))	('ESCC', 'Disease', (79, 83))	('hOGG1', 'Gene', (46, 51))	('Ser326Cys', 'SUBSTITUTION', 'None', (52, 61))	('Ser326Cys', 'Var', (52, 61))
288746	23762419	In the additive model, positive correlation was found between the number of Cys allele and the risk of ESCC in overall studies (PCC = 0.109, SE = 0.046, p = 0.02), Caucasian subgroup and population subgroup.	('ESCC', 'Disease', (103, 107))	('Cys allele', 'Var', (76, 86))	('Cys', 'Chemical', 'MESH:D003545', (76, 79))
288747	23762419	Under the published data, the hOGG1 Ser326Cys polymorphism is associated with ESCC risk in the recessive and additive model.	('ESCC', 'Disease', (78, 82))	('associated with', 'Reg', (62, 77))	('hOGG1', 'Gene', (30, 35))	('Ser326Cys', 'Var', (36, 45))	('Ser326Cys', 'SUBSTITUTION', 'None', (36, 45))	('hOGG1', 'Gene', '4968', (30, 35))
288748	23762419	Compared with the Ser/Ser and Ser/Cys genotype, Cys/Cys genotype might contribute to increased risk of ESCC.	('Cys/Cys genotype', 'Var', (48, 64))	('Cys', 'Chemical', 'MESH:D003545', (52, 55))	('Ser', 'Chemical', 'MESH:D012694', (18, 21))	('Ser', 'Chemical', 'MESH:D012694', (22, 25))	('Cys', 'Chemical', 'MESH:D003545', (34, 37))	('ESCC', 'Disease', (103, 107))	('Ser', 'Chemical', 'MESH:D012694', (30, 33))	('Cys', 'Chemical', 'MESH:D003545', (48, 51))
288749	23762419	And the risk of ESCC is positively correlated with the number of Cys allele.	('ESCC', 'Disease', (16, 20))	('Cys allele', 'Var', (65, 75))	('Cys', 'Chemical', 'MESH:D003545', (65, 68))
288753	23762419	Several studies have found out that DNA repair efficiency in cancer patients is lower than that of normal people, and the variants of the genes involved in DNA repair can lead to increasing risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('variants', 'Var', (122, 130))	('DNA repair', 'MPA', (36, 46))	('cancer', 'Disease', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('lead to', 'Reg', (171, 178))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('lower', 'NegReg', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('people', 'Species', '9606', (106, 112))
288754	23762419	The human 8-oxoguanine glycosylase 1 (hOGG1) gene, located on chromosome 3, encodes 8-hydroxygumine DNA glycosylase 1 (OGG1) that can repair damaged DNA by excising 8-dihydro-8-oxoguanine (8-OH-G).	('damaged', 'Var', (141, 148))	('hOGG1', 'Gene', '4968', (38, 43))	('human', 'Species', '9606', (4, 9))	('OGG1', 'Gene', (119, 123))	('OGG1', 'Gene', (39, 43))	('OGG1', 'Gene', '4968', (39, 43))	('8-dihydro-8-oxoguanine', 'Chemical', '-', (165, 187))	('hOGG1', 'Gene', (38, 43))	('8-OH-G', 'Chemical', '-', (189, 195))	('OGG1', 'Gene', '4968', (119, 123))	('excising', 'NegReg', (156, 164))
288755	23762419	Genetic variations in hOGG1 gene may alter glycosylase activity, increasing the cancer risk.	('hOGG1', 'Gene', (22, 27))	('alter', 'Reg', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('increasing', 'PosReg', (65, 75))	('Genetic variations', 'Var', (0, 18))	('hOGG1', 'Gene', '4968', (22, 27))	('glycosylase activity', 'MPA', (43, 63))	('cancer', 'Disease', (80, 86))
288756	23762419	There are several polymorphisms in the hOGG1 gene; and Ser326Cys polymorphism has attracted widespread attention.	('hOGG1', 'Gene', '4968', (39, 44))	('Ser326Cys', 'Var', (55, 64))	('hOGG1', 'Gene', (39, 44))	('Ser326Cys', 'SUBSTITUTION', 'None', (55, 64))
288757	23762419	With a Ser to Cys amino acid substitution at codon 326, Ser326Cys can affect the function of hOGG1.	('affect', 'Reg', (70, 76))	('Ser326Cys', 'SUBSTITUTION', 'None', (56, 65))	('function', 'MPA', (81, 89))	('hOGG1', 'Gene', '4968', (93, 98))	('Ser to Cys amino acid substitution at codon 326', 'Mutation', 'rs1052133', (7, 54))	('hOGG1', 'Gene', (93, 98))	('Ser to Cys amino acid substitution', 'Var', (7, 41))	('Ser326Cys', 'Var', (56, 65))
288759	23762419	A study indicated that compared to the 326Cys variant enzyme, the 326Ser enzyme of hOGG1 has a higher activity.	('326Ser enzyme', 'Var', (66, 79))	('hOGG1', 'Gene', '4968', (83, 88))	('326Cys', 'Chemical', '-', (39, 45))	('Ser', 'Chemical', 'MESH:D012694', (69, 72))	('higher', 'PosReg', (95, 101))	('activity', 'MPA', (102, 110))	('hOGG1', 'Gene', (83, 88))
288760	23762419	Many studies have focused on the association of Ser326Cys polymorphism in hOGG1 and ESCC risk, including several case-control studies.	('Ser326Cys', 'SUBSTITUTION', 'None', (48, 57))	('hOGG1', 'Gene', (74, 79))	('ESCC', 'Disease', (84, 88))	('hOGG1', 'Gene', '4968', (74, 79))	('Ser326Cys', 'Var', (48, 57))	('association', 'Interaction', (33, 44))
288761	23762419	In this meta-analysis, by searching individual dataset from all eligible case-control studies published to date, we aimed to estimate the role of hOGG1 Ser326Cys polymorphism in the risk of ESCC as well as to quantify the between-study heterogeneity and potential bias.	('ESCC', 'Disease', (190, 194))	('Ser326Cys', 'SUBSTITUTION', 'None', (152, 161))	('polymorphism', 'Var', (162, 174))	('hOGG1', 'Gene', '4968', (146, 151))	('hOGG1', 'Gene', (146, 151))	('Ser326Cys', 'Var', (152, 161))
288762	23762419	To identify all published studies that examined the association of hOOG1 Ser326Cys polymorphism with ESCC risks, we conducted a computerized literature search of following databases: PubMed, Web of Science, Medline, China Knowledge Resource Integrated Database (CNKI) and Wanfang database.	('Ser326Cys', 'SUBSTITUTION', 'None', (73, 82))	('ESCC', 'Disease', (101, 105))	('Ser326Cys', 'Var', (73, 82))
288763	23762419	The key words were as follows: ("esophageal cancer" OR "oesophageal cancer" OR "ESCC"), ("OGG1" OR "hOGG1" OR "8-Oxoguanine DNA glycosylase 1"), and ("polymorphism" OR "variation" OR "mutation" OR "SNP").	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('OGG1', 'Gene', (90, 94))	('OGG1', 'Gene', (101, 105))	('OGG1', 'Gene', '4968', (90, 94))	('OGG1', 'Gene', '4968', (101, 105))	('hOGG1', 'Gene', '4968', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('8-Oxoguanine DNA glycosylase', 'Gene', (111, 139))	('oesophageal cancer', 'Disease', (56, 74))	('esophageal cancer', 'Disease', (33, 50))	('oesophageal cancer', 'Disease', 'MESH:D009369', (56, 74))	('hOGG1', 'Gene', (100, 105))	('"polymorphism" OR "variation', 'Var', (150, 178))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('8-Oxoguanine DNA glycosylase', 'Gene', '4968', (111, 139))
288764	23762419	Studies included in this meta-analysis should meet the following criteria: firstly, evaluate the association between hOGG1 Ser326Cys polymorphism and ESCC risk; secondly, use a case-control design; thirdly, contain available genotype frequency or genotype frequency can be calculated.	('hOGG1', 'Gene', '4968', (117, 122))	('association', 'Interaction', (97, 108))	('ESCC', 'Disease', (150, 154))	('Ser326Cys', 'Var', (123, 132))	('hOGG1', 'Gene', (117, 122))	('Ser326Cys', 'SUBSTITUTION', 'None', (123, 132))
288766	23762419	We examined hOGG Ser326Cys genotypes under the dominant (Cys/Cys+Cys/Ser vs. Ser/Ser), recessive (Cys/Cys vs. Cys/Ser+Ser/Ser), and additive (Cys/Cys vs. Cys/Ser vs. Ser/Ser) models.	('Ser', 'Chemical', 'MESH:D012694', (69, 72))	('Cys', 'Chemical', 'MESH:D003545', (154, 157))	('Cys', 'Chemical', 'MESH:D003545', (61, 64))	('Ser326Cys', 'SUBSTITUTION', 'None', (17, 26))	('Ser326Cys', 'Var', (17, 26))	('Cys', 'Chemical', 'MESH:D003545', (146, 149))	('Ser', 'Chemical', 'MESH:D012694', (114, 117))	('Cys', 'Chemical', 'MESH:D003545', (98, 101))	('Ser', 'Chemical', 'MESH:D012694', (81, 84))	('Ser', 'Chemical', 'MESH:D012694', (170, 173))	('Cys', 'Chemical', 'MESH:D003545', (65, 68))	('Ser', 'Chemical', 'MESH:D012694', (122, 125))	('Ser', 'Chemical', 'MESH:D012694', (17, 20))	('Cys', 'Chemical', 'MESH:D003545', (57, 60))	('Cys/Cys', 'Var', (98, 105))	('Ser', 'Chemical', 'MESH:D012694', (158, 161))	('Cys', 'Chemical', 'MESH:D003545', (110, 113))	('Cys', 'Chemical', 'MESH:D003545', (142, 145))	('Cys', 'Chemical', 'MESH:D003545', (23, 26))	('Ser', 'Chemical', 'MESH:D012694', (118, 121))	('Ser', 'Chemical', 'MESH:D012694', (166, 169))	('Cys', 'Chemical', 'MESH:D003545', (102, 105))	('Ser', 'Chemical', 'MESH:D012694', (77, 80))
288767	23762419	The strength of the association between the hOGG1 Ser326Cys polymorphism and ESCC susceptibility was measured by odds ratios (ORs) with 95% confidence intervals (CIs).	('Ser326Cys', 'SUBSTITUTION', 'None', (50, 59))	('Ser326Cys', 'Var', (50, 59))	('ESCC', 'Disease', (77, 81))	('hOGG1', 'Gene', (44, 49))	('hOGG1', 'Gene', '4968', (44, 49))
288775	23762419	We carried out a meta-analysis of the hOGG1 Ser326Cys polymorphism overall, and in subgroups according to ethnic groups, published languages, DNA source of patients and the source of controls.	('patients', 'Species', '9606', (156, 164))	('hOGG1', 'Gene', '4968', (38, 43))	('hOGG1', 'Gene', (38, 43))	('Ser326Cys', 'Var', (44, 53))	('Ser326Cys', 'SUBSTITUTION', 'None', (44, 53))
288776	23762419	There was a significant association between the hOGG1 Ser326Cys and ESCC risk in the overall analysis in the recessive model (OR = 1.37, 95% CI 1.06-1.76, P = 0.02).	('hOGG1', 'Gene', '4968', (48, 53))	('ESCC', 'Disease', (68, 72))	('Ser326Cys', 'Var', (54, 63))	('Ser326Cys', 'SUBSTITUTION', 'None', (54, 63))	('hOGG1', 'Gene', (48, 53))
288777	23762419	In subgroup analysis, the hOGG1 Cys/Cys polymorphism was significantly associated with the risk of ESCC in the recessive model performed by ethnicity, published language, DNA source of patients and the source of control groups.	('Cys/Cys polymorphism', 'Var', (32, 52))	('Cys', 'Chemical', 'MESH:D003545', (32, 35))	('hOGG1', 'Gene', (26, 31))	('Cys', 'Chemical', 'MESH:D003545', (36, 39))	('ESCC', 'Disease', (99, 103))	('patients', 'Species', '9606', (185, 193))	('hOGG1', 'Gene', '4968', (26, 31))	('associated', 'Reg', (71, 81))
288778	23762419	We found that Cys/Cys variants in subgroups of Chinese language, Caucasian, controls of population and tissue increased ESCC risks, with the ORs of 1.49 (95% CI 1.12-1.96, p = 0.006), 1.64 (95% CI 1.12-2.40, p = 0.01), 1.50 (1.22-1.85, p = 0.0001), 1.79 (1.33-2.42, p = 0.001), respectively.	('Cys', 'Chemical', 'MESH:D003545', (18, 21))	('ESCC', 'Disease', (120, 124))	('increased ESCC', 'Phenotype', 'HP:0003565', (110, 124))	('Cys/Cys', 'Gene', (14, 21))	('variants', 'Var', (22, 30))	('Cys', 'Chemical', 'MESH:D003545', (14, 17))
288779	23762419	Positive correlation was found between the number of Cys allele and the risk of ESCC (PCC = 0.109, SE = 0.046, p = 0.02).	('Cys', 'Chemical', 'MESH:D003545', (53, 56))	('ESCC', 'Disease', (80, 84))	('Cys allele', 'Var', (53, 63))
288780	23762419	In subgroup analysis, the risk of ESCC is positively correlated with the number of Cys allele in Caucasian subgroup (PCC = 0.19, SE = 0.084, p = 0.02) and population subgroup (PCC = 0.12, SE = 0.055, p = 0.03).	('Cys', 'Var', (83, 86))	('Cys', 'Chemical', 'MESH:D003545', (83, 86))	('ESCC', 'Disease', (34, 38))
288783	23762419	Oxidative DNA damage occurs in a cell when the production of reactive oxygen species (ROS) exceeds the cell's antioxidant-defense capacity, leading to cell apoptosis and producing mutations in the DNA.	('mutations', 'Var', (180, 189))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (61, 84))	('ROS', 'Chemical', 'MESH:D017382', (86, 89))	('leading to', 'Reg', (140, 150))	('cell apoptosis', 'CPA', (151, 165))	('DNA', 'Gene', (197, 200))	('producing', 'Reg', (170, 179))
288784	23762419	Among many factors of oxidative DNA damage, 8-hydroy-2-deoxyguanine (8-OHdG) is one of the most abundant oxidative products of highly mutagenic because of its propensities to mispair with adenine during DNA replication and to cause ultimately GC to TA mutation.	('8-hydroy-2-deoxyguanine', 'Chemical', '-', (44, 67))	('mispair', 'Var', (175, 182))	('cause', 'Reg', (226, 231))	('adenine', 'Chemical', 'MESH:D000225', (188, 195))	('8-OHdG', 'Chemical', 'MESH:C067134', (69, 75))
288785	23762419	Many studies have reported that the hOGG1 gene could remove 8-OHdG from DNA by base excision repair (BER) pathway.	('hOGG1', 'Gene', '4968', (36, 41))	('gene', 'Var', (42, 46))	('hOGG1', 'Gene', (36, 41))	('8-OHdG', 'Chemical', 'MESH:C067134', (60, 66))
288787	23762419	A polymorphism of the hOGG1 has been identified, which caused an amino substitution from serine to cysteine in a codon 326.	('hOGG1', 'Gene', (22, 27))	('caused', 'Reg', (55, 61))	('amino substitution', 'Var', (65, 83))	('serine to cysteine in a codon 326', 'Mutation', 'rs1052133', (89, 122))	('hOGG1', 'Gene', '4968', (22, 27))
288789	23762419	Several of them have focused on the association between the hOGG1 Ser326Cys polymorphism and esophageal cancer risk, but the results were inconclusive.	('focused', 'Reg', (21, 28))	('Ser326Cys', 'SUBSTITUTION', 'None', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('hOGG1', 'Gene', (60, 65))	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('association', 'Interaction', (36, 47))	('hOGG1', 'Gene', '4968', (60, 65))	('Ser326Cys', 'Var', (66, 75))
288791	23762419	As far as we know, this is the first meta-analysis carried out with the aim of investigating the relationship between hOGG1 Ser326Cys polymorphism and ESCC risks.	('hOGG1', 'Gene', (118, 123))	('Ser326Cys', 'SUBSTITUTION', 'None', (124, 133))	('Ser326Cys', 'Var', (124, 133))	('ESCC', 'Disease', (151, 155))	('hOGG1', 'Gene', '4968', (118, 123))
288792	23762419	Comparing with the Ser/Ser and Ser/Cys genotype, Cys/Cys genotype might contribute to increase the risk of ESCC.	('increase', 'PosReg', (86, 94))	('Ser', 'Chemical', 'MESH:D012694', (31, 34))	('Cys', 'Chemical', 'MESH:D003545', (49, 52))	('Cys', 'Chemical', 'MESH:D003545', (35, 38))	('Cys', 'Chemical', 'MESH:D003545', (53, 56))	('Ser', 'Chemical', 'MESH:D012694', (23, 26))	('Ser', 'Chemical', 'MESH:D012694', (19, 22))	('ESCC', 'Disease', (107, 111))	('Cys/Cys genotype', 'Var', (49, 65))
288796	23762419	In subgroup analysis by esophageal cancer types, we found that the hOGG1 Ser326Cys polymorphism was significantly associated with ESCC in the Caucasian population.	('Ser326Cys', 'SUBSTITUTION', 'None', (73, 82))	('esophageal cancer', 'Disease', (24, 41))	('hOGG1', 'Gene', (67, 72))	('ESCC', 'Disease', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('associated', 'Reg', (114, 124))	('hOGG1', 'Gene', '4968', (67, 72))	('Ser326Cys', 'Var', (73, 82))
288797	23762419	Interestingly, we found a significant association between hOGG1 Ser326Cys polymorphism and ESCC in population controls group rather than controls based on the hospital.	('hOGG1', 'Gene', '4968', (58, 63))	('ESCC', 'Disease', (91, 95))	('hOGG1', 'Gene', (58, 63))	('Ser326Cys', 'Var', (64, 73))	('Ser326Cys', 'SUBSTITUTION', 'None', (64, 73))
288799	23762419	In conclusion, our meta-analysis suggests that the hOGG1 Ser326Cys polymorphism is associated with esophageal cancer susceptibility.	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('hOGG1', 'Gene', '4968', (51, 56))	('Ser326Cys', 'Var', (57, 66))	('Ser326Cys', 'SUBSTITUTION', 'None', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('associated', 'Reg', (83, 93))	('hOGG1', 'Gene', (51, 56))	('esophageal cancer', 'Disease', (99, 116))
288800	23762419	Cys/Cys carriers have more risk on ESCC rather than Ser/Ser and Ser/Cys carriers.	('Ser', 'Chemical', 'MESH:D012694', (52, 55))	('Ser', 'Chemical', 'MESH:D012694', (56, 59))	('Cys/Cys carriers', 'Var', (0, 16))	('Cys', 'Chemical', 'MESH:D003545', (68, 71))	('Cys', 'Chemical', 'MESH:D003545', (0, 3))	('Cys', 'Chemical', 'MESH:D003545', (4, 7))	('Ser', 'Chemical', 'MESH:D012694', (64, 67))	('ESCC', 'Disease', (35, 39))
288801	23762419	Each copy of Cys modifies the risk of ESCC in an additive form.	('copy', 'Var', (5, 9))	('ESCC', 'Disease', (38, 42))	('Cys', 'Gene', (13, 16))	('Cys', 'Chemical', 'MESH:D003545', (13, 16))	('modifies', 'Reg', (17, 25))
288804	23762419	Second, genotypes errors may also influence the results, because the quality control of genotypic was not well documented in some studies.	('results', 'MPA', (48, 55))	('errors', 'Var', (18, 24))	('men', 'Species', '9606', (115, 118))	('influence', 'Reg', (34, 43))	('genotypes', 'Var', (8, 17))
288806	23762419	That would lead to a better, comprehensive understanding of the association between hOGG1 Ser326Cys polymorphism and esophageal cancer risk.	('Ser326Cys', 'SUBSTITUTION', 'None', (90, 99))	('Ser326Cys', 'Var', (90, 99))	('esophageal cancer', 'Disease', (117, 134))	('hOGG1', 'Gene', (84, 89))	('lead to', 'Reg', (11, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('hOGG1', 'Gene', '4968', (84, 89))	('association', 'Interaction', (64, 75))
288828	19417629	The primary antibodies used were CK4 (1:100, Clone 6B10, Novocastra laboratories, Norwell, MA), CK5 (1:100, Clone EP1601Y, Abcam Inc, USA), CK8 (prediluted, Clone 35 betaH11, Dako,), CK14 (1:100, Clone LL002, NeoMarkers, Fremont, CA) and CK17 (1:20, Clone E3, Dako).	('CK4', 'Gene', (33, 36))	('CK5', 'Gene', '3852', (96, 99))	('CK17', 'Gene', '3872', (238, 242))	('CK17', 'Gene', (238, 242))	('CK14', 'Gene', (183, 187))	('CK8', 'Gene', '3856', (140, 143))	('CK4', 'Gene', '3851', (33, 36))	('CK5', 'Gene', (96, 99))	('CK8', 'Gene', (140, 143))	('CK14', 'Gene', '3861', (183, 187))	('1:100', 'Var', (101, 106))
288844	19417629	The epithelial or soft keratins (CK1-CK 20) are divided into two subfamilies, Type I (acidic, CK9-CK20) and Type II (basic, CK1- CK8) depending on their molecular weights and isoelectric point.	('CK8', 'Gene', '3856', (129, 132))	('CK8', 'Gene', (129, 132))	('CK1', 'Species', '2498238', (124, 127))	('CK1', 'Species', '2498238', (33, 36))	('CK9-CK20', 'Var', (94, 102))
288876	33130332	Chaperones and Ubiquitin Ligases Balance Mutant p53 Protein Stability in Esophageal and Other Digestive Cancers The incidence of esophageal adenocarcinoma (EAC) and other gastrointestinal (GI) cancers have risen dramatically, thus defining the oncogenic drivers to develop effective therapies are necessary.	('p53', 'Gene', (48, 51))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('adenocarcinoma', 'Disease', (140, 154))	('Esophageal', 'Disease', (73, 83))	('p53', 'Gene', '7157', (48, 51))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('Protein', 'Protein', (52, 59))	('Cancers', 'Disease', (104, 111))	('risen', 'PosReg', (206, 211))	('Cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('gastrointestinal (GI) cancers', 'Disease', 'MESH:D004067', (171, 200))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (129, 154))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('EAC', 'Phenotype', 'HP:0011459', (156, 159))	('Cancers', 'Disease', 'MESH:D009369', (104, 111))	('Mutant', 'Var', (41, 47))
288878	33130332	Around 70%-80% of BE cases that progress to dysplasia and cancer have detectable TP53 mutations.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BE', 'Phenotype', 'HP:0100580', (18, 20))	('dysplasia', 'Disease', 'MESH:C536170', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('dysplasia', 'Disease', (44, 53))	('cancer', 'Disease', (58, 64))	('TP53', 'Gene', (81, 85))
288879	33130332	Similarly, in other GI cancers higher rates of TP53 mutation are reported, which provide a significant survival advantage to dysplastic/cancer cells.	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('survival advantage', 'CPA', (103, 121))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('dysplastic', 'Disease', (125, 135))	('cancer', 'Disease', (23, 29))	('GI cancers', 'Disease', (20, 30))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('dysplastic', 'Disease', 'MESH:D004416', (125, 135))	('cancer', 'Disease', (136, 142))	('mutation', 'Var', (52, 60))	('GI cancers', 'Disease', 'MESH:D009369', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('TP53', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
288880	33130332	Targeting molecular chaperones that mediate mutant p53 stability may effectively induce mutant p53 degradation and improve cancer outcomes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('p53', 'Gene', (51, 54))	('induce', 'PosReg', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('degradation', 'MPA', (99, 110))	('mutant', 'Var', (88, 94))	('p53', 'Gene', (95, 98))	('cancer', 'Disease', (123, 129))	('improve', 'PosReg', (115, 122))	('mutant', 'Var', (44, 50))
288881	33130332	Statins can achieve this via disrupting the interaction between mutant p53 and the chaperone DNAJA1, promoting CHIP-mediated degradation of mutant p53, and statins are reported to significantly reduce the risk of BE progression to EAC.	('DNAJA1', 'Gene', (93, 99))	('CHIP-mediated degradation', 'MPA', (111, 136))	('EAC', 'Disease', (231, 234))	('disrupting', 'NegReg', (29, 39))	('mutant', 'Var', (140, 146))	('promoting', 'PosReg', (101, 110))	('p53', 'Gene', (71, 74))	('DNAJA1', 'Gene', '3301', (93, 99))	('EAC', 'Phenotype', 'HP:0011459', (231, 234))	('BE', 'Phenotype', 'HP:0100580', (213, 215))	('interaction', 'Interaction', (44, 55))	('mutant', 'Var', (64, 70))	('reduce', 'NegReg', (194, 200))	('p53', 'Gene', (147, 150))
288883	33130332	Besides the well-established role of MDM2 in p53 stability, we reported that individual isoforms of the E3 ubiquitin ligase GRAIL (RNF128) are critical, tissue-specific regulators of mutant p53 stability in BE progression to EAC, and targeting the interaction of mutant p53 with these isoforms may help mitigate EAC development.	('EAC', 'Phenotype', 'HP:0011459', (312, 315))	('EAC', 'Disease', (225, 228))	('mitigate', 'NegReg', (303, 311))	('RNF128', 'Gene', (131, 137))	('MDM2', 'Gene', (37, 41))	('MDM2', 'Gene', '4193', (37, 41))	('BE', 'Phenotype', 'HP:0100580', (207, 209))	('mutant', 'Var', (183, 189))	('p53', 'Gene', (190, 193))	('interaction', 'Interaction', (248, 259))	('GRAIL', 'Gene', '79589', (124, 129))	('RNF128', 'Gene', '79589', (131, 137))	('mutant', 'Var', (263, 269))	('p53', 'Gene', (270, 273))	('EAC', 'Disease', (312, 315))	('EAC', 'Phenotype', 'HP:0011459', (225, 228))	('GRAIL', 'Gene', (124, 129))
288884	33130332	In this review, we discuss the critical ubiquitin-proteasome and chaperone regulation of mutant p53 stability in EAC and other GI cancers with future insights as to how to affect mutant p53 stability, further noting how the precise p53 mutation may influence the efficacy of treatment strategies and identifying necessary directions for further research in this field.	('p53', 'Gene', (96, 99))	('EAC', 'Phenotype', 'HP:0011459', (113, 116))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('treatment strategies', 'CPA', (275, 295))	('GI cancers', 'Disease', (127, 137))	('EAC', 'Disease', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('GI cancers', 'Disease', 'MESH:D009369', (127, 137))	('mutant', 'Var', (89, 95))	('influence', 'Reg', (249, 258))
288885	33130332	TP53 mutations stabilize its protein and are frequently observed in Barrett's adenocarcinoma and other gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('TP53', 'Gene', (0, 4))	('observed', 'Reg', (56, 64))	('adenocarcinoma', 'Disease', (78, 92))	('adenocarcinoma', 'Disease', 'MESH:D000230', (78, 92))	('stabilize', 'PosReg', (15, 24))	('mutations', 'Var', (5, 14))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('protein', 'Protein', (29, 36))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (103, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('gastrointestinal cancers', 'Disease', (103, 127))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (103, 126))
288893	33130332	TP53 mutation often occurs early in the development of esophageal and gastric cancers and is associated with increased likelihood of progression from BE to EAC.	('TP53', 'Gene', (0, 4))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('BE', 'Phenotype', 'HP:0100580', (150, 152))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('gastric cancers', 'Disease', 'MESH:D013274', (70, 85))	('associated', 'Reg', (93, 103))	('esophageal', 'Disease', (55, 65))	('gastric cancers', 'Disease', (70, 85))	('gastric cancers', 'Phenotype', 'HP:0012126', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('EAC', 'Phenotype', 'HP:0011459', (156, 159))	('mutation', 'Var', (5, 13))
288894	33130332	TP53 mutation was detected in the nondysplastic BE tissue of progressors vs nonprogressors at frequencies of 46% and 3.4%, respectively, and overall, BE patients with TP53 mutation were more likely to progress by a factor of 13.8-fold.	('patients', 'Species', '9606', (153, 161))	('BE', 'Phenotype', 'HP:0100580', (150, 152))	('mutation', 'Var', (172, 180))	('BE', 'Phenotype', 'HP:0100580', (48, 50))	('progress', 'CPA', (201, 209))	('dysplastic', 'Disease', (37, 47))	('dysplastic', 'Disease', 'MESH:D004416', (37, 47))	('TP53', 'Gene', (167, 171))
288897	33130332	Moreover, 17p LOH also correlated with increased incidence of 4N and aneuploidy, suggesting that this event leaves cells more vulnerable to genetic instability and consequent cancer progression.	('aneuploidy', 'Disease', (69, 79))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('aneuploidy', 'Disease', 'MESH:D000782', (69, 79))	('17p LOH', 'Var', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
288899	33130332	The significance of TP53 alteration in driving progression in this context is confirmed in mouse models assessing gastric cancer development.	('gastric cancer', 'Disease', (114, 128))	('TP53', 'Gene', (20, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('alteration', 'Var', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('mouse', 'Species', '10090', (91, 96))
288901	33130332	In a study by Sethi et al, mice with Trp53 deletion in Lgr5+ gastric cells were significantly more likely to develop dysplasia compared with their Trp53 WT counterparts following each group's exposure to the carcinogens DCA/MNU.	('Lgr5', 'Gene', (55, 59))	('dysplasia', 'Disease', (117, 126))	('MNU', 'Chemical', 'MESH:D008770', (224, 227))	('deletion', 'Var', (43, 51))	('mice', 'Species', '10090', (27, 31))	('DCA', 'Chemical', 'MESH:D003999', (220, 223))	('Trp53', 'Gene', (37, 42))	('develop', 'PosReg', (109, 116))	('dysplasia', 'Disease', 'MESH:C536170', (117, 126))	('Lgr5', 'Gene', '14160', (55, 59))
288902	33130332	Organoids developed from Trp53 knockout dysplastic lesions exhibited upregulation in pathways related to inflammation, WNT, stem cell renewal, and cell cycle signaling.	('upregulation', 'PosReg', (69, 81))	('dysplastic lesions', 'Disease', 'MESH:D004416', (40, 58))	('inflammation', 'Disease', 'MESH:D007249', (105, 117))	('dysplastic lesions', 'Disease', (40, 58))	('pathways', 'Pathway', (85, 93))	('inflammation', 'Disease', (105, 117))	('Trp53', 'Gene', (25, 30))	('knockout', 'Var', (31, 39))
288903	33130332	Furthermore, in another study, TP53 mutation in gastric adenocarcinoma and EAC cell lines was found to contribute to primary tumor growth through GOF activity causing elevated hypoxia signaling.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('elevated hypoxia', 'Disease', 'MESH:D006973', (167, 183))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('TP53', 'Gene', (31, 35))	('mutation', 'Var', (36, 44))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (48, 70))	('gastric adenocarcinoma', 'Disease', (48, 70))	('tumor', 'Disease', (125, 130))	('elevated hypoxia', 'Disease', (167, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('contribute', 'Reg', (103, 113))	('activity', 'MPA', (150, 158))	('EAC', 'Phenotype', 'HP:0011459', (75, 78))
288904	33130332	Supporting this, mice with conditionally expressed Trp53R270H in gastric tissue developed dysplastic lesions with increased hypoxia signaling compared with their Trp53+/- counterparts after exposure to DCA and MNU.	('hypoxia', 'Disease', 'MESH:D000860', (124, 131))	('mice', 'Species', '10090', (17, 21))	('MNU', 'Chemical', 'MESH:D008770', (210, 213))	('increased', 'PosReg', (114, 123))	('DCA', 'Chemical', 'MESH:D003999', (202, 205))	('dysplastic lesions', 'Disease', 'MESH:D004416', (90, 108))	('Trp53R270H', 'Var', (51, 61))	('hypoxia', 'Disease', (124, 131))	('dysplastic lesions', 'Disease', (90, 108))
288909	33130332	Several studies, including in vivo mouse models, assess the role of TP53 mutation in gastrointestinal (GI) cancer development, and highlight the impact of loss of WT p53 function as well as mutant p53 GOF activities.	('TP53', 'Gene', (68, 72))	('gastrointestinal (GI) cancer', 'Disease', 'MESH:D004067', (85, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mouse', 'Species', '10090', (35, 40))	('mutant', 'Var', (190, 196))	('p53', 'Gene', (197, 200))	('function', 'MPA', (170, 178))	('mutation', 'Var', (73, 81))
288910	33130332	As mentioned, TP53 mutation in gastric adenocarcinoma and EAC is associated with promoting tumor growth through increasing hypoxia signaling.	('TP53', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('increasing', 'PosReg', (112, 122))	('hypoxia', 'Disease', 'MESH:D000860', (123, 130))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('hypoxia', 'Disease', (123, 130))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (31, 53))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('EAC', 'Disease', (58, 61))	('gastric adenocarcinoma', 'Disease', (31, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('promoting', 'PosReg', (81, 90))	('tumor', 'Disease', (91, 96))
288911	33130332	In the context of colorectal cancer, TP53 mutation is associated with functions that drive the evolution of adenoma to adenocarcinoma.	('adenoma to adenocarcinoma', 'Disease', (108, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('adenoma to adenocarcinoma', 'Disease', 'MESH:D000236', (108, 133))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('colorectal cancer', 'Disease', (18, 35))	('mutation', 'Var', (42, 50))	('TP53', 'Gene', (37, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))
288913	33130332	Mutant TP53 was also associated with the evolution of pancreatic intraepithelial neoplasia to aggressive pancreatic ductal adenocarcinoma.	('TP53', 'Gene', (7, 11))	('associated with', 'Reg', (21, 36))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (105, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('neoplasia', 'Phenotype', 'HP:0002664', (81, 90))	('Mutant', 'Var', (0, 6))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (65, 90))	('pancreatic intraepithelial neoplasia to aggressive pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D010195', (54, 137))
288914	33130332	In a pancreatic ductal adenocarcinoma mouse model, Morton et al compared the outcomes of mice with the driver mutation KrasG12D expressed in the pancreas alone (KC mice), alongside Trp53R172H/+ mutation (KPC mice) or alongside Trp53R172H/R172H mutation (KPPC mice).	('R172H', 'Mutation', 'p.R172H', (186, 191))	('mouse', 'Species', '10090', (38, 43))	('Trp53R172H/+', 'Var', (181, 193))	('KrasG12D', 'Gene', (119, 127))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (5, 37))	('R172H', 'Mutation', 'p.R172H', (238, 243))	('mice', 'Species', '10090', (164, 168))	('mice', 'Species', '10090', (89, 93))	('R172H', 'Mutation', 'p.R172H', (232, 237))	('pancreatic ductal adenocarcinoma', 'Disease', (5, 37))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (5, 37))	('mice', 'Species', '10090', (259, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('p53R172H', 'Mutation', 'p.R53,172H', (183, 191))	('mice', 'Species', '10090', (208, 212))	('p53R172H', 'Mutation', 'p.R53,172H', (229, 237))
288915	33130332	Complete loss of p53 through homozygous Trp53R172H/R172H mutation provided a significant survival advantage to the pancreatic cells of KPPC mice and led to rapid tumorigenesis, likely through enabling circumvention of KrasG12D-induced senescence and growth arrest.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('survival advantage', 'CPA', (89, 107))	('growth arrest', 'Disease', (250, 263))	('mice', 'Species', '10090', (140, 144))	('R172H', 'Mutation', 'p.R172H', (45, 50))	('tumor', 'Disease', (162, 167))	('growth arrest', 'Disease', 'MESH:D006323', (250, 263))	('loss', 'NegReg', (9, 13))	('growth arrest', 'Phenotype', 'HP:0001510', (250, 263))	('Trp53R172H/R172H', 'Var', (40, 56))	('p53', 'Gene', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('R172H', 'Mutation', 'p.R172H', (51, 56))
288916	33130332	In addition, the Trp53R172H mutation exhibited a GOF prometastatic effect, as 65% of KPC mice experienced metastatic spread to the liver, in contrast to 0% of their counterparts expressing heterozygous Trp53 knockout (Trp53loxP/+) rather than the Trp53 mutation in pancreatic cells.	('GOF', 'PosReg', (49, 52))	('p53R172H', 'Mutation', 'p.R53,172H', (19, 27))	('mice', 'Species', '10090', (89, 93))	('Trp53R172H mutation', 'Var', (17, 36))	('metastatic spread to the liver', 'CPA', (106, 136))	('prometastatic effect', 'CPA', (53, 73))
288917	33130332	In hepatocellular carcinoma (HCC), it is hypothesized that p53 mutation is a critical event due to the ability of certain p53 mutants (including p53R175H and p53R248W) to bind to and compromise the proapoptotic activity of the transcription factors p63 and p73.	('p53', 'Gene', (59, 62))	('hepatocellular carcinoma', 'Disease', (3, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('p53R175H', 'Var', (145, 153))	('proapoptotic activity', 'MPA', (198, 219))	('p53R175H', 'Mutation', 'p.R53,175H', (145, 153))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('p53R248W', 'Var', (158, 166))	('mutation', 'Var', (63, 71))	('p53R248W', 'Mutation', 'p.R53,248W', (158, 166))	('bind', 'Interaction', (171, 175))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('compromise', 'NegReg', (183, 193))	('p53', 'Gene', (122, 125))
288918	33130332	In a mouse model of HCC, however, p53 deficiency and Trp53R172H mutation led to similar phenotypic outcomes, including rates of survival, tumor incidence, and metastasis.	('p53', 'Gene', (34, 37))	('metastasis', 'CPA', (159, 169))	('tumor', 'Disease', (138, 143))	('HCC', 'Phenotype', 'HP:0001402', (20, 23))	('deficiency', 'Disease', 'MESH:D007153', (38, 48))	('p53R172H', 'Mutation', 'p.R53,172H', (55, 63))	('HCC', 'Disease', (20, 23))	('mouse', 'Species', '10090', (5, 10))	('Trp53R172H', 'Var', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('deficiency', 'Disease', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
288919	33130332	This study therefore suggests that in the context of HCC, p53 mutation may not carry tumorigenic properties beyond those of p53 deficiency.	('tumor', 'Disease', (85, 90))	('deficiency', 'Disease', (128, 138))	('deficiency', 'Disease', 'MESH:D007153', (128, 138))	('mutation', 'Var', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('HCC', 'Phenotype', 'HP:0001402', (53, 56))	('p53', 'Gene', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
288920	33130332	However, p53 mutation and p53 deficiency may impair p63 and p73 through different mechanisms, and p53 mutations other than human TP53R175H (mouse Trp53R172H) may possess GOF activities.	('mouse', 'Species', '10090', (140, 145))	('mutation', 'Var', (13, 21))	('human', 'Species', '9606', (123, 128))	('p63', 'CPA', (52, 55))	('impair', 'NegReg', (45, 51))	('p53', 'Gene', (9, 12))	('p53', 'Gene', (26, 29))	('mutations', 'Var', (102, 111))	('p53', 'Gene', (98, 101))	('deficiency', 'Disease', (30, 40))	('p73', 'CPA', (60, 63))	('p53R172H', 'Mutation', 'p.R53,172H', (148, 156))	('deficiency', 'Disease', 'MESH:D007153', (30, 40))
288921	33130332	The significance of mutant p53 in these varying gastrointestinal cancers suggests that targeting mutant p53 stability or its activity may serve as effective therapeutic approaches in many of these contexts.	('p53', 'Gene', (104, 107))	('activity', 'MPA', (125, 133))	('mutant', 'Var', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('gastrointestinal cancers', 'Disease', (48, 72))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (48, 72))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (48, 71))
288923	33130332	For example, in a yeast model by Resnick and Inga, the p53T123A mutant caused enhanced transactivation at the p53 REs for GADD45, CCNG1, CDKN1A and BAX, while the p53 hotspot mutant p53R282Q exhibited reduced activity at GADD45 and CCNG1 REs and failed to induce transcription at P21-3' and BAX-B REs.	('transactivation', 'MPA', (87, 102))	('yeast', 'Species', '4932', (18, 23))	('p53R282Q', 'Var', (182, 190))	('p53T123A', 'Var', (55, 63))	('enhanced', 'PosReg', (78, 86))
288924	33130332	For example, in studies using MEFs, heterozygous expression of p53 mutants Trp53R172H/+ or Trp53R270H/+ disrupted regulation of cell proliferation but did not hinder DNA damage-induced cell cycle arrest when compared with Trp53+/- MEFs.	('Trp53R270H/+', 'Var', (91, 103))	('arrest', 'Disease', (196, 202))	('mutants Trp53R172H/+', 'Var', (67, 87))	('p53', 'Gene', (63, 66))	('regulation', 'MPA', (114, 124))	('MEFs', 'CellLine', 'CVCL:9115', (30, 34))	('p53R172H', 'Mutation', 'p.R53,172H', (77, 85))	('hinder', 'NegReg', (159, 165))	('cell proliferation', 'CPA', (128, 146))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (185, 202))	('disrupted', 'NegReg', (104, 113))	('arrest', 'Disease', 'MESH:D006323', (196, 202))	('Trp53R172H/+', 'Var', (75, 87))	('MEFs', 'CellLine', 'CVCL:9115', (231, 235))
288925	33130332	Mutant p53 GOF activities represent novel, tumor-promoting functions differing from those of WT p53.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Mutant', 'Var', (0, 6))	('tumor', 'Disease', (43, 48))	('p53', 'Gene', (7, 10))
288926	33130332	These are attributed to the ability of p53 mutants to bind novel protein partners, including transcription factors such as Sp1, Yap1, NF-Y, CBP, NF-kappaB, VDR, SREBP, E2Fs, Smad2/Smad3, and p63/p73, thereby affecting regulation of novel target genes.	('VDR', 'Gene', (156, 159))	('CBP', 'Gene', '1387', (140, 143))	('CBP', 'Gene', (140, 143))	('Smad2', 'Gene', '4087', (174, 179))	('Yap1', 'Gene', '10413', (128, 132))	('regulation', 'MPA', (218, 228))	('VDR', 'Gene', '7421', (156, 159))	('Smad3', 'Gene', '4088', (180, 185))	('Smad2', 'Gene', (174, 179))	('p53', 'Gene', (39, 42))	('NF-kappaB', 'Gene', '4790', (145, 154))	('Yap1', 'Gene', (128, 132))	('mutants', 'Var', (43, 50))	('affecting', 'Reg', (208, 217))	('Smad3', 'Gene', (180, 185))	('NF-kappaB', 'Gene', (145, 154))
288929	33130332	Studies in human lung cancer cells and mouse models show that mutant p53 knockdown, inactivation or destabilization can impair or prevent tumor formation.	('prevent', 'NegReg', (130, 137))	('mutant', 'Var', (62, 68))	('p53', 'Gene', (69, 72))	('tumor', 'Disease', (138, 143))	('lung cancer', 'Disease', (17, 28))	('human', 'Species', '9606', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('mouse', 'Species', '10090', (39, 44))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('inactivation', 'Var', (84, 96))	('impair', 'NegReg', (120, 126))
288930	33130332	This suggests that cancers may display oncogenic addiction toward mutant p53, meaning the formation and maintenance of these tumor cells depends on the gain of function activity of mutant p53.	('mutant', 'Var', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('mutant', 'Var', (66, 72))	('p53', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('gain', 'PosReg', (152, 156))	('tumor', 'Disease', (125, 130))	('p53', 'Gene', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
288931	33130332	Mutant p53 protein is greatly stabilized in cancers including EAC.	('stabilized', 'MPA', (30, 40))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('protein', 'Protein', (11, 18))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('EAC', 'Phenotype', 'HP:0011459', (62, 65))	('EAC', 'Disease', (62, 65))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
288932	33130332	While WT p53 is maintained at low levels in the cell under normal conditions, mutant p53 accumulates to high levels in tumors, suggesting that specific mechanisms for stabilizing mutant p53 are at play.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('p53', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mutant', 'Var', (78, 84))
288933	33130332	Fully elucidating these mechanisms of stabilization may allow scientists to develop translational approaches to effectively targeting mutant p53 in cancers or precancerous states.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('p53', 'Gene', (141, 144))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancerous', 'Disease', 'MESH:D009369', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mutant', 'Var', (134, 140))	('cancerous', 'Disease', (162, 171))
288934	33130332	While most TP53 mutations found in cancers are missense mutations that occur in the DNA-binding domain, the precise amino acid change affects the mutant p53 protein properties, such as its ability to interact with DNA, GOF capabilities, and stability.	('missense', 'Var', (47, 55))	('affects', 'Reg', (134, 141))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('stability', 'MPA', (241, 250))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('interact', 'Interaction', (200, 208))	('mutant', 'Var', (146, 152))	('p53', 'Gene', (153, 156))	('GOF', 'MPA', (219, 222))	('ability', 'MPA', (189, 196))	('amino acid change', 'Var', (116, 133))	('cancers', 'Disease', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('protein', 'Protein', (157, 164))
288935	33130332	On the one hand, "contact mutants" (eg, p53R248Q and p53R273H) involve changes to sites that normally participate in direct DNA contact; this affects DNA binding capability but has little impact on protein folding.	('changes', 'Reg', (71, 78))	('p53R273H', 'Var', (53, 61))	('p53R248Q', 'Var', (40, 48))	('p53R248Q', 'Mutation', 'p.R53,248Q', (40, 48))	('affects', 'Reg', (142, 149))	('DNA binding', 'Interaction', (150, 161))	('p53R273H', 'Mutation', 'p.R53,273H', (53, 61))
288936	33130332	"Conformational mutants," such as p53R175H and p53R249S, on the other hand, carry amino acid changes that result in local or global unfolding.	('p53R175H', 'Mutation', 'p.R53,175H', (34, 42))	('local', 'MPA', (116, 121))	('p53R249S', 'Var', (47, 55))	('p53R175H', 'Var', (34, 42))	('p53R249S', 'Mutation', 'p.R53,249S', (47, 55))
288937	33130332	Figure 2 (upper panel) includes a list of common p53 mutations observed in BE, as well as information on their folding and functional statuses (Table 1), drawn from the International Agency for Research on Cancer p53 mutation database (version R20).	('p53', 'Gene', (49, 52))	('BE', 'Phenotype', 'HP:0100580', (75, 77))	('mutations', 'Var', (53, 62))	('Cancer', 'Disease', (206, 212))	('Cancer', 'Disease', 'MESH:D009369', (206, 212))	('Cancer', 'Phenotype', 'HP:0002664', (206, 212))
288938	33130332	For comparison, we also show the prevalence of these same p53 mutations in other gastrointestinal cancers (Figure 2, lower panel).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (81, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('gastrointestinal cancers', 'Disease', (81, 105))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (81, 104))	('p53', 'Gene', (58, 61))	('mutations', 'Var', (62, 71))
288940	33130332	Squamous cell types show a lower frequency of hot-spot mutations in Figure 2, as a fraction of all TP53 mutations (17% head and neck and 19% for esophageal squamous cell carcinoma compared with 39%, 32%, and 43% across esophageal, gastric, and colon adenocarcinoma, respectively) and are characterized by a broader spectrum of mutations, yet still a high rate of overall p53 mutation.	('colon adenocarcinoma', 'Disease', (244, 264))	('TP53', 'Gene', (99, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('mutations', 'Var', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (244, 264))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (145, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('esophageal squamous cell carcinoma', 'Disease', (145, 179))
288941	33130332	Other GI mucosal cancers show similar hotspot mutant frequencies to EAC/HGD (Figure 2, lower panel), with a reduction in overall p53 mutation rate down the alimentary canal, which may relate to local environment or shifts in cancer subtype frequencies.	('mutation', 'Var', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('GI mucosal cancers', 'Disease', 'MESH:D009369', (6, 24))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('GI mucosal cancers', 'Disease', (6, 24))	('cancer', 'Disease', (17, 23))	('p53', 'Gene', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('reduction', 'NegReg', (108, 117))
288945	33130332	Multiple mechanisms contribute to p53 accumulation, including posttranslational modifications of both p53 and MDM2, which act to prevent p53 ubiquitination.	('p53', 'Gene', (34, 37))	('prevent', 'NegReg', (129, 136))	('accumulation', 'PosReg', (38, 50))	('p53 ubiquitination', 'MPA', (137, 155))	('MDM2', 'Gene', '4193', (110, 114))	('p53', 'Gene', (102, 105))	('MDM2', 'Gene', (110, 114))	('posttranslational modifications', 'Var', (62, 93))
288948	33130332	Chronic mutant p53 stabilization in the context of cancers is largely attributed to differences in MDM2-mediated regulation as well as additional layers of regulation, notably protection by molecular chaperones, which register mutant p53 as a misfolded protein.	('p53', 'Gene', (234, 237))	('mutant', 'Var', (227, 233))	('MDM2', 'Gene', '4193', (99, 103))	('MDM2', 'Gene', (99, 103))	('mutant', 'Var', (8, 14))	('p53', 'Gene', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
288950	33130332	Mutant p53 expression in cancers is therefore regulated by 2 major opposing forces - degradation via the ubiquitin-proteasome system (UPS) and stabilization by chaperone machinery.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('expression', 'MPA', (11, 21))	('degradation', 'MPA', (85, 96))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('Mutant', 'Var', (0, 6))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('p53', 'Gene', (7, 10))
288951	33130332	In this review, we identify critical regulators of mutant p53 in these systems, then describe mechanisms by which the balance of the UPS and chaperone activity shift to promote mutant p53 stabilization in different cancer contexts, which may also be applicable to EAC.	('stabilization', 'MPA', (188, 201))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('p53', 'Gene', (184, 187))	('EAC', 'Phenotype', 'HP:0011459', (264, 267))	('mutant', 'Var', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('promote', 'PosReg', (169, 176))
288962	33130332	MDM2 can also target degradation of mutant p53.	('MDM2', 'Gene', '4193', (0, 4))	('mutant', 'Var', (36, 42))	('MDM2', 'Gene', (0, 4))	('p53', 'Gene', (43, 46))	('degradation', 'MPA', (21, 32))
288963	33130332	Mutant p53 is unable to drive transcription of the MDM2 gene, breaking the negative feedback loop that functions to minimize WT p53 expression.	('negative feedback loop', 'MPA', (75, 97))	('MDM2', 'Gene', '4193', (51, 55))	('MDM2', 'Gene', (51, 55))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))
288964	33130332	When the tissues of mice expressing mutant p53 were analyzed, mutant p53 accumulated to elevated levels in tumor tissue but not in normal tissue.	('mutant', 'Var', (62, 68))	('p53', 'Gene', (69, 72))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('elevated', 'PosReg', (88, 96))	('mice', 'Species', '10090', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('accumulated', 'MPA', (73, 84))
288965	33130332	This suggests that there must be additional mechanisms of mutant p53 stabilization that are unique to the tumor environment, providing justification for the importance of molecular chaperones in combating mutant p53 degradation.	('mutant', 'Var', (58, 64))	('p53', 'Gene', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mutant', 'Var', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('p53', 'Gene', (212, 215))	('degradation', 'MPA', (216, 227))	('tumor', 'Disease', (106, 111))
288972	33130332	By offering this protective function to mutant oncoproteins, Hsp90 activity can promote signaling pathways that drive tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Hsp90', 'Protein', (61, 66))	('activity', 'MPA', (67, 75))	('tumor', 'Disease', (118, 123))	('signaling pathways', 'Pathway', (88, 106))	('mutant', 'Var', (40, 46))	('promote', 'PosReg', (80, 87))	('oncoproteins', 'Protein', (47, 59))
288987	33130332	This ligase associates with p53 within the proline-rich region and ubiquitination results in p53 nuclear export and stabilization; conversely, compromising WWP1 activity induces p53 degradation.	('proline', 'Chemical', 'MESH:D011392', (43, 50))	('stabilization', 'MPA', (116, 129))	('p53 nuclear export', 'MPA', (93, 111))	('WWP1', 'Gene', '11059', (156, 160))	('results in', 'Reg', (82, 92))	('p53 degradation', 'MPA', (178, 193))	('ubiquitination', 'MPA', (67, 81))	('compromising', 'Var', (143, 155))	('WWP1', 'Gene', (156, 160))
288989	33130332	The exact consequences of substrate monoubiquitination have yet to be clarified, but evidence shows that p53 undergoes nuclear export and generally retains its stability after monoubiquitination by low levels of MDM2, as opposed to polyubiquitination mediated by high levels of MDM2, which results in p53 nuclear export and degradation.	('monoubiquitination', 'Var', (176, 194))	('degradation', 'MPA', (324, 335))	('MDM2', 'Gene', '4193', (212, 216))	('MDM2', 'Gene', (212, 216))	('p53', 'Gene', (105, 108))	('stability', 'MPA', (160, 169))	('MDM2', 'Gene', '4193', (278, 282))	('nuclear export', 'MPA', (305, 319))	('nuclear export', 'MPA', (119, 133))	('MDM2', 'Gene', (278, 282))
288990	33130332	The activity of WWP1 on mutant p53 has yet to be studied; however, this may be a topic worth investigating, as it may represent a mechanism through which ubiquitination contributes to mutant p53 stabilization in cancers.	('ubiquitination', 'MPA', (154, 168))	('WWP1', 'Gene', '11059', (16, 20))	('WWP1', 'Gene', (16, 20))	('mutant', 'Var', (184, 190))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('stabilization', 'MPA', (195, 208))	('p53', 'Gene', (191, 194))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
288998	33130332	The significance of p53 mutation in various gastrointestinal cancers coupled with perturbation of p53 regulators in the UPS and chaperone systems suggests that inducing p53 degradation through targeting ubiquitin ligases or molecular chaperones may help mitigate EAC as well as several related cancers.	('p53', 'Gene', (20, 23))	('EAC', 'Phenotype', 'HP:0011459', (263, 266))	('gastrointestinal cancers', 'Disease', (44, 68))	('p53', 'Gene', (169, 172))	('degradation', 'MPA', (173, 184))	('targeting ubiquitin ligases', 'Protein', (193, 220))	('EAC', 'Disease', (263, 266))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Disease', (294, 301))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('mutation', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (44, 68))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (44, 67))	('inducing', 'Var', (160, 168))
288999	33130332	Several mechanisms involving competition between molecular chaperones and E3 ligases have been discovered to assist with the stabilization of mutant p53 in cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('p53', 'Gene', (149, 152))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('mutant', 'Var', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('stabilization', 'MPA', (125, 138))
289000	33130332	HSP machinery can recognize mutant p53 as a misfolded protein, and Hsp70 and Hsp90, linked through the co-chaperone HOP have been shown to form complexes with mutant p53.	('HOP', 'Gene', (116, 119))	('mutant', 'Var', (28, 34))	('p53', 'Gene', (35, 38))	('complexes', 'Interaction', (144, 153))	('HSP', 'Gene', '7190', (0, 3))	('mutant', 'Var', (159, 165))	('p53', 'Gene', (166, 169))	('Hsp70', 'Gene', '3308', (67, 72))	('Hsp70', 'Gene', (67, 72))	('Hsp90', 'Protein', (77, 82))	('form', 'Reg', (139, 143))	('HOP', 'Gene', '10963', (116, 119))	('HSP', 'Gene', (0, 3))
289001	33130332	These complexes help stabilize both conformational and contact mutant p53, through inhibiting the ubiquitination activity of MDM2 and CHIP on mutant p53.	('p53', 'Gene', (149, 152))	('mutant', 'Var', (63, 69))	('p53', 'Gene', (70, 73))	('ubiquitination activity', 'MPA', (98, 121))	('mutant', 'Var', (142, 148))	('inhibiting', 'NegReg', (83, 93))	('CHIP', 'MPA', (134, 138))	('MDM2', 'Gene', '4193', (125, 129))	('MDM2', 'Gene', (125, 129))
289003	33130332	Additionally, the binding and release cycles of Hsp70 and Hsp90 can drive spontaneous folding of mutant p53 toward its native conformation.	('p53', 'Gene', (104, 107))	('Hsp70', 'Gene', (48, 53))	('mutant', 'Var', (97, 103))	('binding', 'Interaction', (18, 25))	('Hsp70', 'Gene', '3308', (48, 53))	('spontaneous folding', 'MPA', (74, 93))	('Hsp90', 'Protein', (58, 63))
289004	33130332	Accordingly, mutants of p53 that are predominantly well folded in the cell (eg, p53R273H) exhibit greater stability than p53 mutants that are predominantly denatured in the cell (eg, p53R175H).	('p53', 'Gene', (24, 27))	('p53R175H', 'Mutation', 'p.R53,175H', (183, 191))	('p53R273H', 'Mutation', 'p.R53,273H', (80, 88))	('p53R273H', 'Var', (80, 88))	('stability', 'MPA', (106, 115))
289005	33130332	Therefore, in cells with mutant p53 that is predominantly well folded, the refolding activity of Hsp70 and Hsp90 machinery helps sustain the high ratio of folded to unfolded mutant p53, acting as an additional means of reducing mutant p53 degradation.	('p53', 'Gene', (181, 184))	('Hsp90', 'Protein', (107, 112))	('mutant', 'Var', (25, 31))	('Hsp70', 'Gene', (97, 102))	('reducing', 'NegReg', (219, 227))	('high ratio', 'MPA', (141, 151))	('mutant', 'Var', (228, 234))	('p53', 'Gene', (32, 35))	('folded', 'MPA', (155, 161))	('degradation', 'MPA', (239, 250))	('refolding activity', 'MPA', (75, 93))	('Hsp70', 'Gene', '3308', (97, 102))	('mutant', 'Var', (174, 180))
289008	33130332	Furthermore, treatment of the cells with the proteasomal inhibitor MG132 in the absence or presence of 17-AAG revealed that Hsp90 inhibition caused increased ubiquitination of mutant p53.	('ubiquitination', 'MPA', (158, 172))	('17-AAG', 'Chemical', 'MESH:C112765', (103, 109))	('increased', 'PosReg', (148, 157))	('Hsp90', 'Protein', (124, 129))	('mutant', 'Var', (176, 182))	('p53', 'Gene', (183, 186))	('inhibition', 'NegReg', (130, 140))	('MG132', 'Chemical', 'MESH:C072553', (67, 72))
289009	33130332	Immunoprecipitation also revealed that following Hsp90 inhibition, p53R273H interacts with Hsp70 and CHIP.	('p53R273H', 'Var', (67, 75))	('interacts', 'Interaction', (76, 85))	('Hsp90', 'Protein', (49, 54))	('Hsp70', 'Gene', '3308', (91, 96))	('Hsp70', 'Gene', (91, 96))	('inhibition', 'NegReg', (55, 65))	('p53R273H', 'Mutation', 'p.R53,273H', (67, 75))
289010	33130332	A correlative study in EAC suggested that Hsp90 promotes the stability and activity of the oncoprotein, Her2, and therefore it would be reasonable to hypothesize that Hsp90 may protect mutant p53 in a similar manner in the EAC context, but confirmation would require specific investigation.	('Her2', 'Gene', (104, 108))	('EAC', 'Phenotype', 'HP:0011459', (23, 26))	('mutant', 'Var', (185, 191))	('promotes', 'PosReg', (48, 56))	('EAC', 'Phenotype', 'HP:0011459', (223, 226))	('activity', 'MPA', (75, 83))	('p53', 'Gene', (192, 195))	('Her2', 'Gene', '2064', (104, 108))	('stability', 'MPA', (61, 70))	('Hsp90', 'Protein', (42, 47))
289011	33130332	It is unlikely that many unfolded p53 mutants will reach their native conformation upon interaction with Hsp70 and Hsp90 machinery.	('p53', 'Gene', (34, 37))	('Hsp70', 'Gene', '3308', (105, 110))	('Hsp90', 'Protein', (115, 120))	('mutants', 'Var', (38, 45))	('Hsp70', 'Gene', (105, 110))	('interaction', 'Interaction', (88, 99))
289012	33130332	However, this interaction may lead to the formation of mutant p53 folding intermediates which expose sites that are vulnerable to aggregation to other proteins, including the tumor suppressor, TAp73alpha.	('lead to', 'Reg', (30, 37))	('tumor', 'Disease', (175, 180))	('interaction', 'Interaction', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('folding intermediates', 'MPA', (66, 87))	('mutant', 'Var', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('p53', 'Gene', (62, 65))
289013	33130332	The interaction between mutant p53 and TAp73alpha can be stabilized by interacting chaperones, including Hsp70, Hsp90, and the Hsp40 isoform, DNAJB1.	('mutant', 'Var', (24, 30))	('p53', 'Gene', (31, 34))	('interaction', 'Interaction', (4, 15))	('Hsp40', 'Gene', (127, 132))	('Hsp70', 'Gene', '3308', (105, 110))	('DNAJB1', 'Gene', (142, 148))	('Hsp40', 'Gene', '3337', (127, 132))	('TAp73alpha', 'Protein', (39, 49))	('Hsp70', 'Gene', (105, 110))	('Hsp90', 'Protein', (112, 117))	('DNAJB1', 'Gene', '3337', (142, 148))
289014	33130332	These mutant p53-TAp73alpha-HSP complexes can form pseudo-aggregates, which tend to evade degradation mechanisms, therefore contributing to the stability of mutant p53 in the cell.	('degradation', 'MPA', (90, 101))	('stability', 'MPA', (144, 153))	('mutant', 'Var', (6, 12))	('mutant', 'Var', (157, 163))	('contributing', 'Reg', (124, 136))	('HSP', 'Gene', '7190', (28, 31))	('p53', 'Gene', (164, 167))	('HSP', 'Gene', (28, 31))
289016	33130332	Additionally, overexpressed MDM2 can replace HSPs in these pseudo-aggregates, leading to mutant p53-TAp73alpha-MDM2 complexes, which form amyloid-like fibrils, enhancing mutant p53 aggregation in the cell and leading to augmented chemoresistance.	('HSP', 'Gene', (45, 48))	('augmented', 'PosReg', (220, 229))	('HSP', 'Gene', '7190', (45, 48))	('p53', 'Gene', (177, 180))	('MDM2', 'Gene', '4193', (111, 115))	('MDM2', 'Gene', (111, 115))	('aggregation', 'MPA', (181, 192))	('MDM2', 'Gene', '4193', (28, 32))	('MDM2', 'Gene', (28, 32))	('mutant', 'Var', (170, 176))	('enhancing', 'PosReg', (160, 169))	('chemoresistance', 'CPA', (230, 245))	('mutant', 'Var', (89, 95))
289017	33130332	Using the MDM2 inhibitor Nutlin-3, investigators were able to disrupt this complex and induce mutant p53 degradation.	('induce', 'Reg', (87, 93))	('p53', 'Gene', (101, 104))	('mutant', 'Var', (94, 100))	('degradation', 'MPA', (105, 116))	('MDM2', 'Gene', (10, 14))	('Nutlin-3', 'Chemical', 'MESH:C482205', (25, 33))	('MDM2', 'Gene', '4193', (10, 14))	('disrupt', 'Reg', (62, 69))
289018	33130332	The work of Tracz-Gaszewska et al suggests that cancer patients with TP53 mutation paired with MDM2 overexpression manifested worse prognosis than patients with only 1 of these conditions.	('mutation', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('TP53', 'Gene', (69, 73))	('MDM2', 'Gene', '4193', (95, 99))	('MDM2', 'Gene', (95, 99))	('patients', 'Species', '9606', (147, 155))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('patients', 'Species', '9606', (55, 63))
289019	33130332	Furthermore, this study shows that in breast invasive carcinoma patients, poor survival rate of patients with TP53 mutation and MDM2 overexpression correlated with high levels of chaperones in the Hsp40, Hsp70, and Hsp90 families, suggesting that the potential to form chaperone-mediated mutant p53-TAp73alpha-MDM2 complexes worsens prognosis.	('mutant', 'Var', (288, 294))	('mutation', 'Var', (115, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('breast invasive carcinoma', 'Disease', (38, 63))	('Hsp70', 'Gene', (204, 209))	('Hsp40', 'Gene', (197, 202))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (38, 63))	('MDM2', 'Gene', (128, 132))	('Hsp70', 'Gene', '3308', (204, 209))	('patients', 'Species', '9606', (96, 104))	('MDM2', 'Gene', '4193', (128, 132))	('MDM2', 'Gene', (310, 314))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (38, 63))	('patients', 'Species', '9606', (64, 72))	('TP53', 'Gene', (110, 114))	('worsens', 'NegReg', (325, 332))	('prognosis', 'CPA', (333, 342))	('MDM2', 'Gene', '4193', (310, 314))	('Hsp40', 'Gene', '3337', (197, 202))
289021	33130332	The work of Parrales et al demonstrates that the Hsp40 isoform DNAJA1 can also help protect conformational p53 mutants from CHIP-mediated degradation.	('DNAJA1', 'Gene', '3301', (63, 69))	('p53', 'Gene', (107, 110))	('Hsp40', 'Gene', (49, 54))	('mutants', 'Var', (111, 118))	('Hsp40', 'Gene', '3337', (49, 54))	('DNAJA1', 'Gene', (63, 69))
289022	33130332	These studies showed that the level of mevalonate-5-phosphate (MVP), a metabolite in the mevalonate pathway, regulates the interaction between conformational mutant p53 and DNAJA1.	('DNAJA1', 'Gene', (173, 179))	('conformational mutant', 'Var', (143, 164))	('p53', 'Gene', (165, 168))	('mevalonate-5-phosphate', 'Chemical', 'MESH:C045038', (39, 61))	('regulates', 'Reg', (109, 118))	('MVP', 'Chemical', 'MESH:C045038', (63, 66))	('mevalonate', 'Chemical', 'MESH:D008798', (89, 99))	('DNAJA1', 'Gene', '3301', (173, 179))	('interaction', 'Interaction', (123, 134))	('mevalonate', 'Chemical', 'MESH:D008798', (39, 49))
289023	33130332	Decreasing MVP levels through treatment with statins impaired the interaction between mutant p53 and DNAJA1 and in turn promoted CHIP-mediated ubiquitination and degradation of conformational mutant p53, including p53R156P, p53V157F, p53R175H, and p53Y220C.	('CHIP-mediated ubiquitination', 'MPA', (129, 157))	('p53', 'Gene', (199, 202))	('MVP', 'Chemical', 'MESH:C045038', (11, 14))	('interaction', 'Interaction', (66, 77))	('degradation', 'MPA', (162, 173))	('DNAJA1', 'Gene', (101, 107))	('p53', 'Gene', (93, 96))	('p53V157F', 'Var', (224, 232))	('promoted', 'PosReg', (120, 128))	('mutant', 'Var', (86, 92))	('p53Y220C', 'Var', (248, 256))	('impaired', 'NegReg', (53, 61))	('p53Y220C', 'Mutation', 'p.Y53,220C', (248, 256))	('p53R156P', 'Var', (214, 222))	('p53R175H', 'Var', (234, 242))	('DNAJA1', 'Gene', '3301', (101, 107))	('p53R175H', 'Mutation', 'p.R53,175H', (234, 242))
289024	33130332	While statins were able to induce degradation of conformational mutant p53 in this way, these drugs had minimal effects on WT p53 or the well-folded p53 contact mutants p53R273H and p53R280K.	('p53', 'Gene', (149, 152))	('p53R280K', 'Var', (182, 190))	('p53', 'Gene', (71, 74))	('conformational', 'Var', (49, 63))	('p53R273H', 'Mutation', 'p.R53,273H', (169, 177))	('p53R273H', 'Var', (169, 177))
289025	33130332	Reduction of mevalonate kinase, an enzyme that converts mevalonic acid to MVP, or DNAJA1 knockdown also enhanced mutant p53 degradation.	('degradation', 'MPA', (124, 135))	('mutant p53', 'Var', (113, 123))	('mevalonate kinase', 'Gene', (13, 30))	('enhanced', 'PosReg', (104, 112))	('DNAJA1', 'Gene', (82, 88))	('MVP', 'Chemical', 'MESH:C045038', (74, 77))	('mevalonic acid', 'Chemical', 'MESH:D008798', (56, 70))	('mevalonate kinase', 'Gene', '4598', (13, 30))	('DNAJA1', 'Gene', '3301', (82, 88))
289026	33130332	This study also suggests that this mechanism of DNAJA1-mediated protection of mutant p53 stability acts independently of Hsp70 and Hsp90 activity.	('Hsp70', 'Gene', (121, 126))	('DNAJA1', 'Gene', '3301', (48, 54))	('DNAJA1', 'Gene', (48, 54))	('p53', 'Gene', (85, 88))	('Hsp70', 'Gene', '3308', (121, 126))	('mutant', 'Var', (78, 84))
289027	33130332	The steady-state levels of conformational mutant p53 were not affected by Hsc70 knockdown in CAL33 cells (squamous cell carcinoma derived from tongue), and furthermore, the effects of lovastatin treatment or DNAJA1 knockdown on conformational mutant p53 degradation were not augmented by additionally knocking down Hsc70.	('degradation', 'MPA', (254, 265))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (106, 129))	('Hsc70', 'Gene', (315, 320))	('Hsc70', 'Gene', '3312', (74, 79))	('DNAJA1', 'Gene', '3301', (208, 214))	('Hsc70', 'Gene', '3312', (315, 320))	('lovastatin', 'Chemical', 'MESH:D008148', (184, 194))	('p53', 'Gene', (250, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Hsc70', 'Gene', (74, 79))	('conformational mutant', 'Var', (228, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('DNAJA1', 'Gene', (208, 214))	('squamous cell carcinoma', 'Disease', (106, 129))
289028	33130332	Overall these findings suggest that the stability of p53 conformational mutants is governed by the opposing actions of DNAJA1-mediated stabilization and CHIP-mediated degradation.	('DNAJA1', 'Gene', (119, 125))	('p53', 'Gene', (53, 56))	('DNAJA1', 'Gene', '3301', (119, 125))	('conformational', 'Var', (57, 71))
289029	33130332	As depicted in Figure 3, studies suggest that this competition between DNAJA1 (Hsp40) and CHIP acts as a significant layer of regulation of mutant p53 stability in BE progression.	('DNAJA1', 'Gene', (71, 77))	('Hsp40', 'Gene', (79, 84))	('Hsp40', 'Gene', '3337', (79, 84))	('stability', 'MPA', (151, 160))	('DNAJA1', 'Gene', '3301', (71, 77))	('BE', 'Phenotype', 'HP:0100580', (164, 166))	('mutant', 'Var', (140, 146))	('p53', 'Gene', (147, 150))
289034	33130332	On the one hand, Iso2 acts as a negative regulator, capable of effectively ubiquitinating both WT and mutant p53 and decreasing its steady state levels.	('mutant', 'Var', (102, 108))	('steady state levels', 'MPA', (132, 151))	('Iso2', 'Chemical', '-', (17, 21))	('p53', 'Gene', (109, 112))	('decreasing', 'NegReg', (117, 127))	('ubiquitinating', 'MPA', (75, 89))
289035	33130332	Iso1 on the other hand, exhibits limited ubiquitin ligase activity on WT and mutant p53, and is capable of increasing mutant p53 steady state levels and its half-life.	('steady', 'MPA', (129, 135))	('activity', 'MPA', (58, 66))	('Iso1', 'Gene', '10209', (0, 4))	('p53', 'Gene', (125, 128))	('mutant', 'Var', (118, 124))	('p53', 'Gene', (84, 87))	('increasing', 'PosReg', (107, 117))	('ubiquitin ligase', 'Enzyme', (41, 57))	('mutant', 'Var', (77, 83))	('Iso1', 'Gene', (0, 4))
289036	33130332	Furthermore, Iso1 knockdown reduced the clonogenic survival of mutant p53 bearing BE cells (CpD cells).	('reduced', 'NegReg', (28, 35))	('mutant', 'Var', (63, 69))	('p53', 'Gene', (70, 73))	('Iso1', 'Gene', (13, 17))	('BE', 'Phenotype', 'HP:0100580', (82, 84))	('clonogenic survival', 'CPA', (40, 59))	('Iso1', 'Gene', '10209', (13, 17))
289037	33130332	Correspondingly, over the course of BE to EAC progression, the stabilization of mutant p53 coincides with a change in the ratio of RNF128 isoforms, in which a significant decrease in Iso2 is observed, leading to a lower Iso2 to Iso1 ratio.	('mutant', 'Var', (80, 86))	('p53', 'Gene', (87, 90))	('RNF128', 'Gene', (131, 137))	('Iso1', 'Gene', (228, 232))	('Iso2', 'MPA', (183, 187))	('decrease', 'NegReg', (171, 179))	('RNF128', 'Gene', '79589', (131, 137))	('BE', 'Phenotype', 'HP:0100580', (36, 38))	('EAC', 'Phenotype', 'HP:0011459', (42, 45))	('Iso2', 'Chemical', '-', (220, 224))	('Iso2', 'Chemical', '-', (183, 187))	('Iso1', 'Gene', '10209', (228, 232))	('lower', 'NegReg', (214, 219))
289039	33130332	In addition, expression of MDM2 and MDMX remained relatively constant over the course of progression, contrasting with the shift in the Iso2 to Iso1 ratio which helps favor mutant p53 stabilization over degradation.	('Iso1', 'Gene', '10209', (144, 148))	('p53', 'Gene', (180, 183))	('MDMX', 'Gene', '4194', (36, 40))	('Iso2', 'Chemical', '-', (136, 140))	('mutant', 'Var', (173, 179))	('MDM2', 'Gene', '4193', (27, 31))	('MDMX', 'Gene', (36, 40))	('MDM2', 'Gene', (27, 31))	('favor', 'PosReg', (167, 172))	('Iso1', 'Gene', (144, 148))	('stabilization', 'MPA', (184, 197))	('degradation', 'MPA', (203, 214))
289040	33130332	Together, this data suggests that in BE tissues, RNF128 isoforms exert significant control over mutant p53 levels and likely take precedence over the activity of MDM2 and MDMX.	('levels', 'MPA', (107, 113))	('MDMX', 'Gene', (171, 175))	('mutant', 'Var', (96, 102))	('RNF128', 'Gene', (49, 55))	('p53', 'Gene', (103, 106))	('BE', 'Phenotype', 'HP:0100580', (37, 39))	('RNF128', 'Gene', '79589', (49, 55))	('control', 'MPA', (83, 90))	('MDMX', 'Gene', '4194', (171, 175))	('MDM2', 'Gene', '4193', (162, 166))	('MDM2', 'Gene', (162, 166))
289048	33130332	However, our results suggest that the presence of Iso1 reduces the ubiquitination activity of Iso2 on WT or mutant p53.	('presence', 'Var', (38, 46))	('ubiquitination activity', 'MPA', (67, 90))	('Iso1', 'Gene', (50, 54))	('mutant', 'Var', (108, 114))	('reduces', 'NegReg', (55, 62))	('p53', 'Gene', (115, 118))	('Iso1', 'Gene', '10209', (50, 54))	('Iso2', 'Chemical', '-', (94, 98))
289049	33130332	Iso1 may therefore promote mutant p53 stabilization by interacting with mutant p53 and preventing contact with Iso2 (Figure 3B, iii), as well as through a dominant negative effect in which Iso1 heterodimerizes with Iso2, compromising the efficiency of Iso2-mediated ubiquitination of mutant p53.	('promote', 'PosReg', (19, 26))	('Iso1', 'Gene', '10209', (189, 193))	('preventing', 'NegReg', (87, 97))	('mutant', 'Var', (27, 33))	('Iso2', 'Chemical', '-', (252, 256))	('compromising', 'NegReg', (221, 233))	('p53', 'Gene', (34, 37))	('contact', 'Interaction', (98, 105))	('mutant', 'Var', (72, 78))	('stabilization', 'MPA', (38, 51))	('interacting', 'Interaction', (55, 66))	('p53', 'Gene', (79, 82))	('Iso2', 'Chemical', '-', (215, 219))	('Iso1', 'Gene', (0, 4))	('Iso2', 'Chemical', '-', (111, 115))	('mutant', 'Var', (284, 290))	('Iso1', 'Gene', '10209', (0, 4))	('efficiency', 'MPA', (238, 248))	('Iso2-mediated ubiquitination', 'MPA', (252, 280))	('p53', 'Gene', (291, 294))	('Iso1', 'Gene', (189, 193))
289050	33130332	Work by Zheng et al, exploring the role of MDM2-B, showed this MDM2 isoform interacted with full-length MDM2 and exerted a dominant negative effect on MDM2-induced mutant p53 degradation.	('mutant', 'Var', (164, 170))	('interacted', 'Interaction', (76, 86))	('MDM2', 'Gene', '4193', (43, 47))	('MDM2', 'Gene', (43, 47))	('MDM2', 'Gene', '4193', (151, 155))	('MDM2', 'Gene', (151, 155))	('negative', 'NegReg', (132, 140))	('MDM2', 'Gene', '4193', (104, 108))	('MDM2', 'Gene', '4193', (63, 67))	('MDM2', 'Gene', (104, 108))	('MDM2', 'Gene', (63, 67))	('p53', 'Gene', (171, 174))	('degradation', 'MPA', (175, 186))
289051	33130332	This interaction was hypothesized to reduce mutant p53 degradation by increasing the cytoplasmic fraction of MDM2, leaving less of the full-length ligase in the nucleus where mutant p53 tends to accumulate.	('reduce', 'NegReg', (37, 43))	('MDM2', 'Gene', (109, 113))	('p53', 'Gene', (51, 54))	('degradation', 'MPA', (55, 66))	('interaction', 'Interaction', (5, 16))	('mutant', 'Var', (44, 50))	('MDM2', 'Gene', '4193', (109, 113))
289057	33130332	In the context of BE progression in which Iso1 becomes the dominant RNF128 isoform and promotes mutant p53 stability, beta-TrCP1-mediated Iso1 degradation can therefore help tilt the balance toward mutant p53 degradation, an area needing further investigation.	('RNF128', 'Gene', '79589', (68, 74))	('mutant', 'Var', (96, 102))	('beta-TrCP1', 'Gene', (118, 128))	('p53', 'Gene', (103, 106))	('Iso1', 'Gene', '10209', (42, 46))	('beta-TrCP1', 'Gene', '8945', (118, 128))	('Iso1', 'Gene', (42, 46))	('Iso1', 'Gene', '10209', (138, 142))	('BE', 'Phenotype', 'HP:0100580', (18, 20))	('stability', 'MPA', (107, 116))	('mutant', 'MPA', (198, 204))	('promotes', 'PosReg', (87, 95))	('RNF128', 'Gene', (68, 74))	('degradation', 'MPA', (209, 220))	('Iso1', 'Gene', (138, 142))
289062	33130332	The mechanism through which RNF128 Iso1 is able to stabilize mutant p53 is an open question.	('stabilize', 'Reg', (51, 60))	('RNF128 Iso1', 'Gene', (28, 39))	('RNF128 Iso1', 'Gene', '11074;10209', (28, 39))	('mutant', 'Var', (61, 67))	('p53', 'Gene', (68, 71))
289063	33130332	Given that MDM2 exhibits chaperone-like activity on WT p53, we hypothesize that Iso1 is also capable of chaperone-like activity that promotes mutant p53 stability.	('promotes', 'PosReg', (133, 141))	('chaperone-like', 'MPA', (25, 39))	('p53', 'Gene', (149, 152))	('Iso1', 'Gene', (80, 84))	('mutant', 'Var', (142, 148))	('stability', 'MPA', (153, 162))	('Iso1', 'Gene', '10209', (80, 84))	('MDM2', 'Gene', '4193', (11, 15))	('MDM2', 'Gene', (11, 15))
289065	33130332	In our lab's studies of RNF128 isoforms, we carried out experiments using the 3 most common p53 mutations found in EAC (p53R175H, p53R248Q, and p53R273H); the most common indel site p53R213; and the rare p53C135S mutation found in the commonly used EAC cell line (OE33).	('p53R248Q', 'Mutation', 'p.R53,248Q', (130, 138))	('EAC', 'Phenotype', 'HP:0011459', (249, 252))	('p53R273H', 'Mutation', 'p.R53,273H', (144, 152))	('p53R273H)', 'Var', (144, 153))	('p53R175H', 'Var', (120, 128))	('p53', 'Gene', (92, 95))	('p53R248Q', 'Var', (130, 138))	('p53R213', 'Var', (182, 189))	('p53R175H', 'Mutation', 'p.R53,175H', (120, 128))	('RNF128', 'Gene', (24, 30))	('EAC', 'Phenotype', 'HP:0011459', (115, 118))	('RNF128', 'Gene', '79589', (24, 30))
289066	33130332	It is worth noting that when assessing the impact of Iso1 on the steady state levels of p53R175H, p53R248Q, p53R213Q, and p53C135S, the conformational mutant p53R175H exhibited the greatest increase in expression (~10-fold), followed by p53R213Q (~4-fold).	('p53R213Q', 'Mutation', 'p.R53,213Q', (108, 116))	('p53R213Q', 'Mutation', 'p.R53,213Q', (237, 245))	('p53R213Q', 'Var', (108, 116))	('Iso1', 'Gene', (53, 57))	('increase', 'PosReg', (190, 198))	('p53R175H', 'Mutation', 'p.R53,175H', (88, 96))	('expression', 'MPA', (202, 212))	('p53R248Q', 'Var', (98, 106))	('p53R248Q', 'Mutation', 'p.R53,248Q', (98, 106))	('p53R175H', 'Var', (158, 166))	('p53R175H', 'Mutation', 'p.R53,175H', (158, 166))	('Iso1', 'Gene', '10209', (53, 57))	('p53C135S', 'Var', (122, 130))
289067	33130332	Iso2 was shown to effectively downregulate contact mutants, p53R273H and p53R248Q, but the steady-state levels of the other p53 mutants in the presence of Iso2 were not investigated.	('p53R248Q', 'Var', (73, 81))	('downregulate', 'NegReg', (30, 42))	('p53R248Q', 'Mutation', 'p.R53,248Q', (73, 81))	('Iso2', 'Chemical', '-', (0, 4))	('Iso2', 'Chemical', '-', (155, 159))	('p53R273H', 'Mutation', 'p.R53,273H', (60, 68))	('p53R273H', 'Var', (60, 68))
289068	33130332	The impact of each RNF128 isoform on different p53 mutations is therefore a topic for further investigation.	('p53', 'Gene', (47, 50))	('RNF128', 'Gene', '79589', (19, 25))	('RNF128', 'Gene', (19, 25))	('mutations', 'Var', (51, 60))
289069	33130332	A more thorough understanding of how chaperone and UPS machinery impacts specific p53 mutants may inform the development of personalized treatment strategies for Barrett's-associated cancers according to molecular signature.	('UPS machinery impacts', 'Disease', (51, 72))	('mutants', 'Var', (86, 93))	('cancers', 'Disease', (183, 190))	('UPS machinery impacts', 'Disease', 'MESH:D017118', (51, 72))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('inform', 'Reg', (98, 104))	('p53', 'Gene', (82, 85))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
289072	33130332	Congruently, treating CpD cells with simvastatin resulted in a reduction of mutant p53 levels and clonogenic cell survival.	('simvastatin', 'Chemical', 'MESH:D019821', (37, 48))	('mutant', 'Var', (76, 82))	('clonogenic cell survival', 'CPA', (98, 122))	('reduction', 'NegReg', (63, 72))	('p53', 'Protein', (83, 86))
289073	33130332	This likely occurs, at least in part, due to the mechanism proposed by Parrales et al, in which statins disrupt the interaction between mutant p53 and DNAJA1, promoting mutant p53 proteasomal degradation.	('p53', 'Protein', (176, 179))	('DNAJA1', 'Gene', '3301', (151, 157))	('disrupt', 'NegReg', (104, 111))	('proteasomal degradation', 'MPA', (180, 203))	('promoting', 'PosReg', (159, 168))	('mutant', 'Var', (169, 175))	('DNAJA1', 'Gene', (151, 157))	('mutant', 'Var', (136, 142))	('p53', 'Gene', (143, 146))	('interaction', 'Interaction', (116, 127))
289081	33130332	Several studies suggest that statins can play an antitumorigenic role through counteracting mutant p53 stabilization.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('mutant', 'Var', (92, 98))	('p53', 'Gene', (99, 102))
289083	33130332	Through an unknown mechanism, reducing MVP levels in this way disrupts the mutant p53 and Hsp40 interaction, permitting mutant p53 degradation by CHIP.	('interaction', 'Interaction', (96, 107))	('degradation', 'MPA', (131, 142))	('Hsp40', 'Gene', (90, 95))	('p53', 'Protein', (82, 85))	('disrupts', 'NegReg', (62, 70))	('MVP levels', 'MPA', (39, 49))	('mutant', 'Var', (75, 81))	('Hsp40', 'Gene', '3337', (90, 95))	('MVP', 'Chemical', 'MESH:C045038', (39, 42))	('mutant', 'Var', (120, 126))	('p53', 'Gene', (127, 130))
289084	33130332	Additionally, statins can impair Hsp90 function, resulting in elevated mutant p53 degradation by MDM2.	('Hsp90', 'Protein', (33, 38))	('mutant', 'Var', (71, 77))	('p53', 'Gene', (78, 81))	('degradation', 'MPA', (82, 93))	('MDM2', 'Gene', '4193', (97, 101))	('impair', 'NegReg', (26, 32))	('MDM2', 'Gene', (97, 101))	('elevated', 'PosReg', (62, 70))	('function', 'MPA', (39, 47))
289088	33130332	While many studies demonstrate the ability of statins to destabilize mutant p53 and impair growth of p53-driven cancer cells, these are mostly restricted to in vitro systems.	('cancer', 'Disease', (112, 118))	('p53', 'Gene', (76, 79))	('mutant', 'Var', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('growth', 'CPA', (91, 97))	('impair', 'NegReg', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('destabilize', 'NegReg', (57, 68))
289089	33130332	However, a recent study by Tutuska et al demonstrates the effect of statins in several mouse models, including mice with xenografts of various mutant p53 human cancer cell lines, mice with allografts of mutant p53 lymphoma lines, and an autochthonous model of mice with mutant p53-driven T lymphomas.	('lymphoma', 'Disease', 'MESH:D008223', (214, 222))	('T lymphomas', 'Disease', 'MESH:D016399', (288, 299))	('human', 'Species', '9606', (154, 159))	('mouse', 'Species', '10090', (87, 92))	('lymphoma', 'Disease', (290, 298))	('lymphoma', 'Disease', 'MESH:D008223', (290, 298))	('mice', 'Species', '10090', (179, 183))	('mice', 'Species', '10090', (260, 264))	('cancer', 'Disease', (160, 166))	('p53', 'Gene', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mutant', 'Var', (270, 276))	('lymphomas', 'Phenotype', 'HP:0002665', (290, 299))	('mutant', 'Var', (143, 149))	('lymphoma', 'Phenotype', 'HP:0002665', (214, 222))	('mutant', 'Var', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('lymphoma', 'Phenotype', 'HP:0002665', (290, 298))	('T lymphomas', 'Disease', (288, 299))	('mice', 'Species', '10090', (111, 115))	('lymphoma', 'Disease', (214, 222))	('p53', 'Gene', (210, 213))
289091	33130332	In an experiment using mice with MDA-MB-231 xenografts treated with pitavastatin and zoledronic acid, the 2 smallest tumors at endpoint had the lowest levels of mutant p53, justifying the connection between the antagonistic effect of statins on mutant p53 stabilization and reduction in tumor growth.	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('p53', 'Gene', (168, 171))	('pitavastatin', 'Chemical', 'MESH:C108475', (68, 80))	('mutant', 'Var', (161, 167))	('levels', 'MPA', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Disease', (117, 123))	('reduction', 'NegReg', (274, 283))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (33, 43))	('tumor', 'Disease', (287, 292))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('p53', 'Gene', (252, 255))	('mutant', 'Var', (245, 251))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (85, 100))	('tumor', 'Disease', (117, 122))	('lowest', 'NegReg', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('mice', 'Species', '10090', (23, 27))
289092	33130332	In the allograft and autochthonous models, rosuvastatin only exhibited a considerable therapeutic effect against p53R248Q/- (a DNA contact mutant) tumors, as opposed to p53R172H/R172H (conformational mutant) or p53-/- tumors.	('p53R172H', 'Mutation', 'p.R53,172H', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('rosuvastatin', 'Chemical', 'MESH:D000068718', (43, 55))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('p53R248Q/-', 'Var', (113, 123))	('R172H', 'Mutation', 'p.R172H', (178, 183))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('p53R248Q', 'Mutation', 'p.R53,248Q', (113, 121))	('R172H', 'Mutation', 'p.R172H', (172, 177))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
289093	33130332	The results by Tutuska et al suggest that statins are more effective in mitigating tumors driven by p53R248Q (a DNA contact mutant) compared with p53R172H (conformational mutant).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('p53R248Q', 'Mutation', 'p.R53,248Q', (100, 108))	('mitigating', 'NegReg', (72, 82))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('p53R172H', 'Mutation', 'p.R53,172H', (146, 154))	('p53R248Q', 'Var', (100, 108))
289094	33130332	This matches data by Turrell et al demonstrating that murine KrasG12D lung tumors expressing contact mutant p53R270H were more sensitive to statins compared with their counterparts harboring conformational mutant p53R172H.	('p53R270H', 'Var', (108, 116))	('murine', 'Species', '10090', (54, 60))	('more', 'PosReg', (122, 126))	('sensitive to statins', 'MPA', (127, 147))	('lung tumors', 'Disease', 'MESH:D008175', (70, 81))	('p53R172H', 'Mutation', 'p.R53,172H', (213, 221))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('lung tumors', 'Disease', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('lung tumors', 'Phenotype', 'HP:0100526', (70, 81))
289095	33130332	However, in the aforementioned study by Parrales et al, statin treatment in various human cancer cell lines lowered levels of conformational p53 mutants including p53R156P, p53V157F, p53R175H (corresponding to murine p53R172H), and p53Y220C but did not significantly reduce levels of contact mutants including p53R273H and p53R280K.	('murine', 'Species', '10090', (210, 216))	('conformational', 'MPA', (126, 140))	('p53Y220C', 'Var', (232, 240))	('p53R175H', 'Var', (183, 191))	('p53', 'Gene', (141, 144))	('p53R175H', 'Mutation', 'p.R53,175H', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('p53R156P', 'Var', (163, 171))	('p53R280K', 'Var', (323, 331))	('lowered', 'NegReg', (108, 115))	('human', 'Species', '9606', (84, 89))	('p53R172H', 'Mutation', 'p.R53,172H', (217, 225))	('p53Y220C', 'Mutation', 'p.Y53,220C', (232, 240))	('p53R273H', 'Mutation', 'p.R53,273H', (310, 318))	('p53V157F', 'Var', (173, 181))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('p53R273H', 'Var', (310, 318))
289096	33130332	Statins also lowered cell viability and colony formation more effectively in cancer cells driven by conformational mutant p53R175H compared with contact mutant p53R273H.	('colony formation', 'CPA', (40, 56))	('cell viability', 'CPA', (21, 35))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('lowered', 'NegReg', (13, 20))	('p53R175H', 'Var', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('p53R175H', 'Mutation', 'p.R53,175H', (122, 130))	('p53R273H', 'Mutation', 'p.R53,273H', (160, 168))
289097	33130332	Another study using murine and human pancreatic cell lines follows this trend, in which statins effectively reduced the levels of conformational p53 mutants (p53R172H, p53I255N, p53G245S, and p53Y220C) but not contact mutants (p53R273H and p53R248W).	('p53G245S', 'Mutation', 'p.G53,245S', (178, 186))	('p53Y220C', 'Var', (192, 200))	('p53', 'Gene', (145, 148))	('reduced', 'NegReg', (108, 115))	('conformational', 'MPA', (130, 144))	('murine', 'Species', '10090', (20, 26))	('p53R172H', 'Var', (158, 166))	('human', 'Species', '9606', (31, 36))	('p53R273H', 'Mutation', 'p.R53,273H', (227, 235))	('p53R172H', 'Mutation', 'p.R53,172H', (158, 166))	('p53R248W', 'Mutation', 'p.R53,248W', (240, 248))	('p53G245S', 'Var', (178, 186))	('p53Y220C', 'Mutation', 'p.Y53,220C', (192, 200))	('p53I255N', 'Var', (168, 176))
289098	33130332	Overall, studies analyzing anticancer effects of statins demonstrate considerable success, and it is worthwhile to continue investigating statin usage in mutant p53-driven cancers, including elucidating factors that affect its efficacy and whether statins may exhibit synergistic effects when combined with chemotherapeutics or other targeted therapies.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('p53-driven', 'Gene', (161, 171))	('cancers', 'Disease', (172, 179))	('cancer', 'Disease', (31, 37))	('mutant', 'Var', (154, 160))
289099	33130332	As described previously, HSP90 machinery plays roles in preventing MDM2 and CHIP-mediated ubiquitination of mutant p53 as well as facilitating the formation of aggregate structures that resist proteolysis.	('aggregate structures', 'MPA', (160, 180))	('MDM2', 'Gene', '4193', (67, 71))	('MDM2', 'Gene', (67, 71))	('mutant', 'Var', (108, 114))	('p53', 'Gene', (115, 118))	('formation', 'MPA', (147, 156))	('HSP90', 'Gene', (25, 30))	('HSP90', 'Gene', '3320', (25, 30))	('preventing', 'PosReg', (56, 66))	('CHIP-mediated ubiquitination', 'MPA', (76, 104))
289100	33130332	In these ways, Hsp90 counters the degradative forces of MDM2 and CHIP, promoting mutant p53 stabilization.	('stabilization', 'MPA', (92, 105))	('Hsp90', 'Protein', (15, 20))	('p53', 'Gene', (88, 91))	('promoting', 'PosReg', (71, 80))	('mutant', 'Var', (81, 87))	('MDM2', 'Gene', '4193', (56, 60))	('MDM2', 'Gene', (56, 60))
289101	33130332	Many Hsp90 inhibitors have shown promising results in inducing mutant p53 degradation, mitigating tumor progression, and prolonging the survival of p53R175H and p53R248Q knock-in mice.	('mitigating', 'NegReg', (87, 97))	('p53R248Q', 'Mutation', 'p.R53,248Q', (161, 169))	('p53R175H', 'Mutation', 'p.R53,175H', (148, 156))	('prolonging', 'PosReg', (121, 131))	('mice', 'Species', '10090', (179, 183))	('mutant', 'Var', (63, 69))	('p53', 'Gene', (70, 73))	('survival', 'CPA', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('degradation', 'MPA', (74, 85))	('Hsp90', 'Protein', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('p53R248Q', 'Var', (161, 169))	('tumor', 'Disease', (98, 103))	('inducing', 'Reg', (54, 62))	('p53R175H', 'Var', (148, 156))
289103	33130332	Through continuing to study RNF128 isoforms and associated proteins that ultimately regulate mutant p53 levels, we aim to uncover insightful ways to effectively mitigate EAC development.	('EAC', 'Phenotype', 'HP:0011459', (170, 173))	('EAC development', 'Disease', (170, 185))	('RNF128', 'Gene', '79589', (28, 34))	('mutant', 'Var', (93, 99))	('RNF128', 'Gene', (28, 34))	('p53', 'Gene', (100, 103))
289105	33130332	Molecular chaperones and co-chaperones including Hsp90, HOP, DNAJA1, and DNAJB1 as well as RNF128 Iso1 are associated with the accumulation of mutant p53.	('Hsp90', 'Protein', (49, 54))	('mutant', 'Var', (143, 149))	('HOP', 'Gene', '10963', (56, 59))	('DNAJB1', 'Gene', '3337', (73, 79))	('DNAJB1', 'Gene', (73, 79))	('DNAJA1', 'Gene', (61, 67))	('p53', 'Gene', (150, 153))	('HOP', 'Gene', (56, 59))	('DNAJA1', 'Gene', '3301', (61, 67))	('RNF128 Iso1', 'Gene', '11074;10209', (91, 102))	('RNF128 Iso1', 'Gene', (91, 102))
289106	33130332	Additionally, WWP1 is known to stabilize WT p53 and thus could also help stabilize mutant p53 in the tumor context.	('p53', 'Gene', (90, 93))	('mutant', 'Var', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('WWP1', 'Gene', '11059', (14, 18))	('WWP1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
289107	33130332	In the context of BE progression, statins may achieve this through compromising DNAJA1 interaction with mutant p53.	('BE', 'Phenotype', 'HP:0100580', (18, 20))	('DNAJA1', 'Gene', '3301', (80, 86))	('mutant', 'Var', (104, 110))	('p53', 'Gene', (111, 114))	('compromising', 'NegReg', (67, 79))	('interaction', 'Interaction', (87, 98))	('DNAJA1', 'Gene', (80, 86))
289108	33130332	As we learn more about RNF128 Iso1, we may discover effective methods to target its expression or compromise its stabilizing activity on mutant p53.	('compromise', 'NegReg', (98, 108))	('target', 'Reg', (73, 79))	('stabilizing activity', 'MPA', (113, 133))	('RNF128 Iso1', 'Gene', '11074;10209', (23, 34))	('expression', 'MPA', (84, 94))	('mutant', 'Var', (137, 143))	('p53', 'Gene', (144, 147))	('RNF128 Iso1', 'Gene', (23, 34))
289109	33130332	Other possible therapeutic approaches may rely on bolstering machinery that drives mutant p53 degradation, including proteasomal degradation by CHIP and RNF128 Iso2 and the yet unexplored role of beta-TrCP1 on mutant p53 protein stability.	('protein', 'MPA', (221, 228))	('p53', 'Gene', (90, 93))	('RNF128 Iso2', 'Gene', (153, 164))	('degradation', 'MPA', (94, 105))	('p53', 'Gene', (217, 220))	('mutant', 'Var', (83, 89))	('proteasomal degradation', 'MPA', (117, 140))	('RNF128 Iso2', 'Gene', '11074', (153, 164))	('beta-TrCP1', 'Gene', (196, 206))	('beta-TrCP1', 'Gene', '8945', (196, 206))
289113	33130332	Hsp70 and Hsp90 machinery associates with unfolded mutant p53 in productive folding complexes or aggregates.	('unfolded mutant', 'Var', (42, 57))	('Hsp90 machinery', 'Protein', (10, 25))	('Hsp70', 'Gene', '3308', (0, 5))	('p53', 'Gene', (58, 61))	('Hsp70', 'Gene', (0, 5))
289114	33130332	These features are advantageous for therapeutic approaches, as they provide potential to achieve a therapeutic window that targets cancerous cells harboring unfolded or misfolded mutant proteins while sparing healthy tissue.	('cancerous', 'Disease', (131, 140))	('mutant', 'Var', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancerous', 'Disease', 'MESH:D009369', (131, 140))	('proteins', 'Protein', (186, 194))
289116	33130332	Work with statins acts as a prototype of this concept, as these drugs impair DNAJA1-mediated stabilization and bolster CHIP-mediated degradation of conformational mutant p53, although we recognize therapeutic limitation of such an approach based on cancer type and p53 mutation specificity.	('DNAJA1', 'Gene', '3301', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('DNAJA1', 'Gene', (77, 83))	('impair', 'NegReg', (70, 76))	('p53', 'Gene', (170, 173))	('conformational mutant', 'Var', (148, 169))	('cancer', 'Disease', (249, 255))	('CHIP-mediated degradation', 'MPA', (119, 144))	('bolster', 'PosReg', (111, 118))	('stabilization', 'MPA', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
289119	33130332	Our lab is currently investigating regulation of RNF128 isoforms during BE progression to EAC, which is critical to understanding how their functions may be utilized to induce mutant p53 degradation.	('RNF128', 'Gene', (49, 55))	('degradation', 'MPA', (187, 198))	('mutant', 'Var', (176, 182))	('p53', 'Gene', (183, 186))	('RNF128', 'Gene', '79589', (49, 55))	('induce', 'Reg', (169, 175))	('EAC', 'Phenotype', 'HP:0011459', (90, 93))	('BE', 'Phenotype', 'HP:0100580', (72, 74))	('EAC', 'Disease', (90, 93))
289120	33130332	Hsp90 machinery, in coordination with Hsp70 machinery, can protect both conformational and contact p53 mutants from CHIP and MDM2-mediated degradation.	('p53', 'Gene', (99, 102))	('mutants', 'Var', (103, 110))	('Hsp70', 'Gene', '3308', (38, 43))	('MDM2', 'Gene', '4193', (125, 129))	('MDM2', 'Gene', (125, 129))	('Hsp70', 'Gene', (38, 43))
289121	33130332	However, mutant p53 stabilization through chaperone-mediated aggregation with other proteins like TAp73alpha and MDM2 exhibits specificity for conformational p53 mutants.	('MDM2', 'Gene', '4193', (113, 117))	('MDM2', 'Gene', (113, 117))	('mutants', 'Var', (162, 169))	('p53', 'Gene', (16, 19))	('mutant', 'Var', (9, 15))	('stabilization', 'MPA', (20, 33))	('chaperone-mediated', 'MPA', (42, 60))
289122	33130332	In addition, DNAJA1 protection of mutant p53 from CHIP-mediated degradation is effective for conformational mutant p53.	('DNAJA1', 'Gene', '3301', (13, 19))	('p53', 'Gene', (115, 118))	('DNAJA1', 'Gene', (13, 19))	('conformational', 'Var', (93, 107))	('mutant', 'Var', (34, 40))	('p53', 'Gene', (41, 44))
289123	33130332	Our lab has seen that RNF128 Iso1 was most effective in upregulating the conformational mutant, p53R175H, of the 4 mutants investigated.	('upregulating', 'PosReg', (56, 68))	('RNF128 Iso1', 'Gene', '11074;10209', (22, 33))	('RNF128 Iso1', 'Gene', (22, 33))	('p53R175H', 'Mutation', 'p.R53,175H', (96, 104))	('p53R175H', 'Var', (96, 104))
289124	33130332	Iso2 meanwhile, was shown to effectively downregulate contact mutants p53R248Q and p53R273H.	('p53R248Q', 'Var', (70, 78))	('p53R273H', 'Mutation', 'p.R53,273H', (83, 91))	('p53R248Q', 'Mutation', 'p.R53,248Q', (70, 78))	('p53R273H', 'Var', (83, 91))	('Iso2', 'Chemical', '-', (0, 4))	('downregulate', 'NegReg', (41, 53))
289125	33130332	As we continue to gain greater understanding of mutant p53 regulation by the UPS and chaperone systems in the context of EAC, which may also be applicable in certain GI cancers, we may develop promising methods of challenging these cancers' onset and advancement.	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('cancers', 'Disease', (169, 176))	('GI cancers', 'Disease', (166, 176))	('mutant', 'Var', (48, 54))	('p53', 'Gene', (55, 58))	('cancers', 'Disease', (232, 239))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('GI cancers', 'Disease', 'MESH:D009369', (166, 176))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('EAC', 'Phenotype', 'HP:0011459', (121, 124))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
289137	32047658	CSCs can cause cancer relapse, metastasis, multidrug resistance, and radiation resistance through their ability to arrest in the G0 phase, giving rise to new tumors.	('metastasis', 'CPA', (31, 41))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('CSCs', 'Var', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('giving rise to', 'Reg', (139, 153))	('drug resistance', 'Phenotype', 'HP:0020174', (48, 63))	('radiation resistance', 'CPA', (69, 89))	('multidrug resistance', 'MPA', (43, 63))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cause', 'Reg', (9, 14))
289155	32047658	Bonnet and Dick demonstrated in 1997 that CD34+/CD38- leukemia stem cells (LSCs) have the ability to differentiate and proliferate in SCID mice.	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('rat', 'Species', '10116', (23, 26))	('SCID', 'Disease', (134, 138))	('SCID', 'Disease', 'MESH:D053632', (134, 138))	('mice', 'Species', '10090', (139, 143))	('CD34+/CD38-', 'Var', (42, 53))	('rat', 'Species', '10116', (126, 129))	('proliferate', 'CPA', (119, 130))	('leukemia', 'Disease', (54, 62))	('leukemia', 'Disease', 'MESH:D007938', (54, 62))
289174	32047658	Breast CSCs have different expression patterns of surface biomarkers, such as CD44+, CD24-, SP, and ALDH+.	('CD24', 'Gene', '100133941', (85, 89))	('CD24', 'Gene', (85, 89))	('CD44+', 'Var', (78, 83))	('SP', 'Chemical', '-', (92, 94))	('ALDH+', 'Gene', (100, 105))
289220	32047658	Further studies showed that knockout of Sox2 inhibits glioblastoma cell proliferation and tumorigenicity, which suggests that Sox2 is the basis for maintaining the self-renewal ability of tumor-initiating cells (TICs).	('tumor', 'Disease', (188, 193))	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('TICs', 'Disease', (212, 216))	('TICs', 'Phenotype', 'HP:0100033', (212, 216))	('inhibits', 'NegReg', (45, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('TIC', 'Phenotype', 'HP:0100033', (212, 215))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('TICs', 'Disease', 'MESH:D020323', (212, 216))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Sox2', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('knockout', 'Var', (28, 36))	('rat', 'Species', '10116', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('glioblastoma', 'Disease', (54, 66))
289221	32047658	Sox2 also maintains the self-renewal of TICs in osteosarcomas, and downregulation of Sox2 drastically decreases its transformative characteristics and tumorigenesis ability in vitro.	('downregulation', 'Var', (67, 81))	('transformative characteristics', 'CPA', (116, 146))	('TICs', 'Disease', 'MESH:D020323', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('osteosarcomas', 'Disease', (48, 61))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('osteosarcomas', 'Disease', 'MESH:D012516', (48, 61))	('osteosarcomas', 'Phenotype', 'HP:0002669', (48, 61))	('self-renewal', 'CPA', (24, 36))	('TICs', 'Disease', (40, 44))	('decreases', 'NegReg', (102, 111))	('TICs', 'Phenotype', 'HP:0100033', (40, 44))	('TIC', 'Phenotype', 'HP:0100033', (40, 43))	('Sox2', 'Gene', (85, 89))
289237	32047658	The expression of KLF4 is downregulated with hypermethylation and loss of heterozygosity in colorectal CSCs and gastric CSCs.	('downregulated', 'NegReg', (26, 39))	('hypermethylation', 'Var', (45, 61))	('expression', 'MPA', (4, 14))	('KLF4', 'Gene', (18, 22))	('loss of heterozygosity', 'Var', (66, 88))	('LF', 'Phenotype', 'HP:0100507', (19, 21))	('colorectal CSCs and gastric CSCs', 'Disease', 'MESH:D015179', (92, 124))
289247	32047658	Previous studies have shown that deletion of the tumor suppressor gene p53 and MYC synergizes to induce hepatocyte proliferation and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('MYC', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('deletion', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (49, 54))	('p53', 'Gene', (71, 74))	('hepatocyte', 'MPA', (104, 114))	('p53', 'Gene', '7157', (71, 74))	('induce', 'PosReg', (97, 103))	('tumor', 'Disease', (133, 138))	('rat', 'Species', '10116', (122, 125))
289248	32047658	In addition to p53 deletion, overexpression of Bcl-2 and Bmi-1 and loss of p19ARF also assist MYC in regulating the survival and proliferation of CSCs.	('MYC', 'Disease', (94, 97))	('overexpression', 'PosReg', (29, 43))	('Bmi-1', 'Gene', '648', (57, 62))	('survival', 'CPA', (116, 124))	('Bmi-1', 'Gene', (57, 62))	('deletion', 'Var', (19, 27))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('Bcl-2', 'Gene', (47, 52))	('p19ARF', 'Gene', '1029', (75, 81))	('proliferation', 'CPA', (129, 142))	('loss', 'Var', (67, 71))	('rat', 'Species', '10116', (136, 139))	('Bcl-2', 'Gene', '596', (47, 52))	('p19ARF', 'Gene', (75, 81))	('assist', 'PosReg', (87, 93))
289251	32047658	In addition, inactivation of MYC results in HCC stem cells differentiating into hepatocytes and biliary duct cells to form bile duct structures, which might be associated with the loss of the tumor marker alpha-fetoprotein and increased expression of cytokeratin 8, hepatocyte markers, carcinoembryonic antigen, and the liver stem cell marker cytokeratin 19.	('HCC', 'Gene', (44, 47))	('tumor', 'Disease', (192, 197))	('increased', 'PosReg', (227, 236))	('inactivation', 'Var', (13, 25))	('cytokeratin 8', 'Gene', '3856', (251, 264))	('loss', 'NegReg', (180, 184))	('HCC', 'Gene', '619501', (44, 47))	('expression', 'MPA', (237, 247))	('cytokeratin 19', 'Gene', '3880', (343, 357))	('cytokeratin 19', 'Gene', (343, 357))	('HCC', 'Phenotype', 'HP:0001402', (44, 47))	('alpha-fetoprotein', 'MPA', (205, 222))	('carcinoembryonic', 'Disease', (286, 302))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('MYC', 'Gene', (29, 32))	('cytokeratin 8', 'Gene', (251, 264))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('carcinoembryonic', 'Disease', 'None', (286, 302))
289254	32047658	These studies indicate that MYC induces tumorigenesis with the help of other factors.	('tumor', 'Disease', (40, 45))	('MYC', 'Var', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))
289272	32047658	Aberrant Wnt signaling is found in many cancers, such as invasive ductal breast carcinomas, colorectal cancer, papillary thyroid cancer, esophageal cancer, and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('colorectal cancer', 'Disease', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('invasive ductal breast carcinomas', 'Disease', (57, 90))	('cancers', 'Disease', (40, 47))	('found', 'Reg', (26, 31))	('papillary thyroid cancer', 'Disease', (111, 135))	('breast carcinomas', 'Phenotype', 'HP:0003002', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('esophageal cancer', 'Disease', (137, 154))	('papillary thyroid cancer', 'Disease', 'MESH:C536915', (111, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('invasive ductal breast carcinomas', 'Disease', 'MESH:D018270', (57, 90))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('colorectal cancer', 'Disease', (92, 109))	('Wnt', 'Gene', (9, 12))	('thyroid cancer', 'Phenotype', 'HP:0002890', (121, 135))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (111, 135))	('Wnt', 'Gene', '114487', (9, 12))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
289274	32047658	Some Wnt activation is caused by mutations in Wnt components, such as Axin mutation in gastrointestinal cancers, APC mutation in colorectal cancer, and beta-catenin mutation in gastric cancer and liver cancer.	('Wnt', 'Gene', (46, 49))	('colorectal cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('liver cancer', 'Phenotype', 'HP:0002896', (196, 208))	('liver cancer', 'Disease', (196, 208))	('gastric cancer', 'Disease', 'MESH:D013274', (177, 191))	('Wnt', 'Gene', '114487', (46, 49))	('beta-catenin', 'Gene', (152, 164))	('mutations', 'Var', (33, 42))	('beta-catenin', 'Gene', '1499', (152, 164))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Wnt', 'Gene', (5, 8))	('mutation', 'Var', (75, 83))	('Wnt', 'Gene', '114487', (5, 8))	('gastric cancer', 'Phenotype', 'HP:0012126', (177, 191))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('gastrointestinal cancers', 'Disease', 'MESH:D005770', (87, 111))	('Axin', 'Gene', '8312', (70, 74))	('Axin', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('gastrointestinal cancers', 'Disease', (87, 111))	('APC', 'Disease', 'MESH:D011125', (113, 116))	('liver cancer', 'Disease', 'MESH:D006528', (196, 208))	('gastric cancer', 'Disease', (177, 191))	('APC', 'Disease', (113, 116))	('mutation', 'Var', (165, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('mutation', 'Var', (117, 125))
289275	32047658	GSK3 genes are critical for beta-catenin regulation; therefore, many researchers expect the occurrence of GSK3 mutations, but GSK3 mutations are not correlated with cancer occurrence.	('mutations', 'Var', (111, 120))	('beta-catenin', 'Gene', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('beta-catenin', 'Gene', '1499', (28, 40))	('GSK3', 'Gene', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (165, 171))
289292	32047658	MicroRNA-1246, miR-19, and miR-92a suppress the expression of AXIN and GSK3beta in CSCs.	('CSCs', 'Disease', (83, 87))	('MicroRNA-1246', 'Var', (0, 13))	('AXIN', 'Gene', (62, 66))	('expression', 'MPA', (48, 58))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('AXIN', 'Gene', '8312', (62, 66))	('GSK3beta', 'Gene', (71, 79))	('GSK3beta', 'Gene', '2931', (71, 79))	('miR', 'Gene', '220972', (15, 18))	('suppress', 'NegReg', (35, 43))	('miR', 'Gene', (15, 18))
289293	32047658	MicroRNA-544a downregulates GSK3beta in lung CSCs.	('GSK3beta', 'Gene', '2931', (28, 36))	('lung CSCs', 'Disease', (40, 49))	('downregulates', 'NegReg', (14, 27))	('MicroRNA-544a', 'Var', (0, 13))	('GSK3beta', 'Gene', (28, 36))
289294	32047658	MicroRNA-483-5p upregulates the expression of beta-catenin in gastric CSCs.	('upregulates', 'PosReg', (16, 27))	('beta-catenin', 'Gene', (46, 58))	('beta-catenin', 'Gene', '1499', (46, 58))	('expression', 'MPA', (32, 42))	('MicroRNA-483-5p', 'Var', (0, 15))	('gastric CSCs', 'Disease', (62, 74))
289307	32047658	The small-molecule inhibitor CWP232228 antagonizes the binding of beta-catenin to TCF in the nucleus to induce apoptosis in liver CSCs.	('beta-catenin', 'Gene', (66, 78))	('CWP232228', 'Var', (29, 38))	('beta-catenin', 'Gene', '1499', (66, 78))	('CWP232228', 'Chemical', 'MESH:C000600091', (29, 38))	('TCF', 'Gene', '3172', (82, 85))	('binding', 'Interaction', (55, 62))	('induce', 'PosReg', (104, 110))	('TCF', 'Gene', (82, 85))	('antagonizes', 'NegReg', (39, 50))	('apoptosis', 'CPA', (111, 120))
289312	32047658	Increased levels of CD44v6 mRNA in human pancreatic CSCs, lung CSCs, and colon CSCs promote migration and metastasis through the activation of beta-catenin.	('beta-catenin', 'Gene', '1499', (143, 155))	('promote', 'PosReg', (84, 91))	('CD44v6 mRNA', 'Var', (20, 31))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (41, 56))	('rat', 'Species', '10116', (95, 98))	('human', 'Species', '9606', (35, 40))	('activation', 'PosReg', (129, 139))	('pancreatic CSCs', 'Disease', (41, 56))	('beta-catenin', 'Gene', (143, 155))
289318	32047658	In 1917, studies discovered the Notch gene in a mutant Drosophila.	('Notch', 'Gene', (32, 37))	('mutant', 'Var', (48, 54))	('Notch', 'Gene', '31293', (32, 37))
289328	32047658	Moreover, post-translational modifications of Notch receptors change their affinity for ligands and their intracellular half-lives.	('Notch', 'Gene', '31293', (46, 51))	('change', 'Reg', (62, 68))	('post-translational modifications', 'Var', (10, 42))	('affinity for ligands', 'Interaction', (75, 95))	('Notch', 'Gene', (46, 51))
289329	32047658	Many studies on the Notch pathway in CSCs have shown that activation of Notch promotes cell survival, self-renewal, and metastasis and inhibits apoptosis.	('promotes', 'PosReg', (78, 86))	('Notch', 'Gene', (20, 25))	('self-renewal', 'CPA', (102, 114))	('activation', 'Var', (58, 68))	('cell survival', 'CPA', (87, 100))	('apoptosis', 'CPA', (144, 153))	('Notch', 'Gene', (72, 77))	('CSCs', 'Disease', (37, 41))	('Notch', 'Gene', '31293', (20, 25))	('metastasis', 'CPA', (120, 130))	('inhibits', 'NegReg', (135, 143))	('Notch', 'Gene', '31293', (72, 77))
289330	32047658	Aberrant Notch signaling (Notch1 and Notch4) promotes self-renewal and metastasis of breast and HCC stem cells.	('Notch', 'Gene', (26, 31))	('Notch4', 'Gene', (37, 43))	('Notch4', 'Gene', '4855', (37, 43))	('Aberrant', 'Var', (0, 8))	('Notch', 'Gene', '31293', (37, 42))	('HCC', 'Gene', (96, 99))	('Notch', 'Gene', '31293', (26, 31))	('metastasis', 'CPA', (71, 81))	('Notch', 'Gene', '31293', (9, 14))	('promotes', 'PosReg', (45, 53))	('Notch', 'Gene', (9, 14))	('HCC', 'Gene', '619501', (96, 99))	('Notch1', 'Gene', (26, 32))	('Notch', 'Gene', (37, 42))	('HCC', 'Phenotype', 'HP:0001402', (96, 99))	('self-renewal', 'CPA', (54, 66))	('Notch1', 'Gene', '4851', (26, 32))
289331	32047658	However, microRNA-34a downregulates Notch1.	('Notch1', 'Gene', '4851', (36, 42))	('microRNA-34a', 'Var', (9, 21))	('Notch1', 'Gene', (36, 42))	('downregulates', 'NegReg', (22, 35))
289362	32047658	Gorlin syndrome (basal cell nevus syndrome), an autosomal dominant condition, is associated with germline loss of the PTCH1 gene.	('basal cell nevus syndrome', 'Disease', 'MESH:D001478', (17, 42))	('PTCH1', 'Gene', (118, 123))	('basal cell nevus', 'Phenotype', 'HP:0002671', (17, 33))	('loss', 'Var', (106, 110))	('PTCH1', 'Gene', '5727', (118, 123))	('Gorlin syndrome', 'Disease', (0, 15))	('nevus', 'Phenotype', 'HP:0003764', (28, 33))	('basal cell nevus syndrome', 'Disease', (17, 42))
289364	32047658	Other Hh pathway components are also mutated in human cancers, such as Gli1 and Gli3 mutations in pancreatic adenocarcinoma, Gli1 gene amplification in glioblastoma, and SUFU (suppressor of fused) mutations in medulloblastoma.	('pancreatic adenocarcinoma', 'Disease', (98, 123))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('Gli1', 'Gene', (125, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (98, 123))	('human', 'Species', '9606', (48, 53))	('SUFU', 'Gene', (170, 174))	('glioblastoma', 'Disease', 'MESH:D005909', (152, 164))	('Gli1', 'Gene', '2735', (71, 75))	('mutated', 'Reg', (37, 44))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('Gli3', 'Gene', '2737', (80, 84))	('cancers', 'Disease', (54, 61))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (98, 123))	('mutations', 'Var', (197, 206))	('Gli1', 'Gene', '2735', (125, 129))	('medulloblastoma', 'Disease', 'MESH:D008527', (210, 225))	('mutations', 'Var', (85, 94))	('medulloblastoma', 'Phenotype', 'HP:0002885', (210, 225))	('glioblastoma', 'Disease', (152, 164))	('medulloblastoma', 'Disease', (210, 225))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('Gli3', 'Gene', (80, 84))	('Gli1', 'Gene', (71, 75))	('SUFU', 'Gene', '51684', (170, 174))
289415	32047658	CD44+ cells promote self-renewal, metastasis, and maintenance of ovarian CSCs by increasing the expression of RelA, RelB, and IKKalpha and mediating nuclear activation of p50/RelA (p50/p65) dimer.	('ovarian', 'Disease', 'MESH:D010049', (65, 72))	('nuclear', 'MPA', (149, 156))	('p50', 'Gene', '4790', (181, 184))	('CD44+', 'Var', (0, 5))	('self-renewal', 'CPA', (20, 32))	('expression', 'MPA', (96, 106))	('p65', 'Gene', (185, 188))	('p50', 'Gene', '4790', (171, 174))	('IKKalpha', 'Gene', '1147', (126, 134))	('p50', 'Gene', (181, 184))	('RelB', 'Gene', '5971', (116, 120))	('ovarian', 'Disease', (65, 72))	('RelA', 'Gene', (175, 179))	('p50', 'Gene', (171, 174))	('RelA', 'Gene', (110, 114))	('metastasis', 'CPA', (34, 44))	('IKKalpha', 'Gene', (126, 134))	('RelB', 'Gene', (116, 120))	('p65', 'Gene', '5970', (185, 188))	('promote', 'PosReg', (12, 19))	('increasing', 'PosReg', (81, 91))	('RelA', 'Gene', '5970', (175, 179))	('RelA', 'Gene', '5970', (110, 114))
289446	32047658	Based on current studies, JAK2 mutation and abnormal activation of STAT3 are prone to occur in many tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('JAK2', 'Gene', '3717', (26, 30))	('activation', 'PosReg', (53, 63))	('mutation', 'Var', (31, 39))	('tumors', 'Disease', (100, 106))	('JAK2', 'Gene', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('STAT3', 'Gene', (67, 72))
289447	32047658	Mutations in JAK2 have been reported in the majority of patients with myeloproliferative neoplasms, such as polycythemia vera, myelofibrosis, and thrombocythemia.	('patients', 'Species', '9606', (56, 64))	('reported', 'Reg', (28, 36))	('thrombocythemia', 'Phenotype', 'HP:0001894', (146, 161))	('polycythemia vera', 'Disease', (108, 125))	('myelofibrosis', 'Disease', (127, 140))	('myelofibrosis', 'Disease', 'MESH:D055728', (127, 140))	('JAK2', 'Gene', '3717', (13, 17))	('Mutations', 'Var', (0, 9))	('thrombocythemia', 'Disease', 'MESH:D013922', (146, 161))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (70, 98))	('myelofibrosis', 'Phenotype', 'HP:0011974', (127, 140))	('polycythemia vera', 'Disease', 'MESH:D011087', (108, 125))	('JAK2', 'Gene', (13, 17))	('neoplasms', 'Phenotype', 'HP:0002664', (89, 98))	('polycythemia', 'Phenotype', 'HP:0001901', (108, 120))	('myeloproliferative neoplasms', 'Disease', (70, 98))	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('thrombocythemia', 'Disease', (146, 161))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (70, 98))
289451	32047658	Furthermore, aberrant STAT5 signaling has been found in the pathogenesis of hematologic and solid organ malignancies.	('malignancies', 'Disease', 'MESH:D009369', (104, 116))	('found', 'Reg', (47, 52))	('hematologic', 'Disease', (76, 87))	('STAT5', 'Gene', '6776', (22, 27))	('malignancies', 'Disease', (104, 116))	('STAT5', 'Gene', (22, 27))	('aberrant', 'Var', (13, 21))
289483	32047658	Furthermore, silencing ShcA expression also induces activation of STAT4 in breast CSCs.	('ShcA', 'Gene', '6464', (23, 27))	('breast CSCs', 'Disease', (75, 86))	('STAT4', 'Gene', '6775', (66, 71))	('ShcA', 'Gene', (23, 27))	('STAT4', 'Gene', (66, 71))	('silencing', 'Var', (13, 22))	('activation', 'PosReg', (52, 62))
289488	32047658	AKT proteins are crucial effectors of PI3K and are directly activated in response to PI3K.	('activated', 'PosReg', (60, 69))	('PI3K', 'Var', (85, 89))	('AKT', 'Gene', '207', (0, 3))	('AKT', 'Gene', (0, 3))
289493	32047658	Studies show that mutations in PTEN lead to the inhibition of PI3K/mTOR signaling in glioblastoma multiforme.	('PTEN', 'Gene', (31, 35))	('PTEN', 'Gene', '5728', (31, 35))	('glioblastoma multiforme', 'Disease', (85, 108))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (67, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (85, 108))	('inhibition', 'NegReg', (48, 58))	('mutations', 'Var', (18, 27))
289494	32047658	However, deletion of PTEN in neural stem cells leads to a neoplastic phenotype that includes cell growth promotion, resistance to cell apoptosis, and increased migratory and invasive properties in vivo.	('rat', 'Species', '10116', (163, 166))	('cell growth promotion', 'CPA', (93, 114))	('deletion', 'Var', (9, 17))	('resistance to cell apoptosis', 'CPA', (116, 144))	('PTEN', 'Gene', (21, 25))	('increased', 'PosReg', (150, 159))	('PTEN', 'Gene', '5728', (21, 25))
289495	32047658	Inactivation of PTEN and activation of protein kinase B have been found in other solid tumors, such as myeloproliferative neoplasia and leukemia.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('leukemia', 'Disease', (136, 144))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('solid tumors', 'Disease', (81, 93))	('leukemia', 'Disease', 'MESH:D007938', (136, 144))	('protein kinase B', 'Gene', (39, 55))	('myeloproliferative neoplasia', 'Disease', (103, 131))	('solid tumors', 'Disease', 'MESH:D009369', (81, 93))	('PTEN', 'Gene', (16, 20))	('protein kinase B', 'Gene', '2185', (39, 55))	('myeloproliferative neoplasia', 'Disease', 'MESH:D009369', (103, 131))	('PTEN', 'Gene', '5728', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('neoplasia', 'Phenotype', 'HP:0002664', (122, 131))	('myeloproliferative neoplasia', 'Phenotype', 'HP:0005547', (103, 131))	('activation', 'PosReg', (25, 35))	('Inactivation', 'Var', (0, 12))
289501	32047658	Downregulation of PTEN induces PI3K activation to promote survival, maintenance of stemness, and tumorigenicity of CD133+/CD44+ prostate cancer stem-like cell populations.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('PTEN', 'Gene', (18, 22))	('promote', 'PosReg', (50, 57))	('CD133', 'Gene', (115, 120))	('PTEN', 'Gene', '5728', (18, 22))	('CD133', 'Gene', '8842', (115, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (128, 143))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('activation', 'PosReg', (36, 46))	('Downregulation', 'Var', (0, 14))	('survival', 'CPA', (58, 66))	('tumor', 'Disease', (97, 102))	('PI3K', 'Protein', (31, 35))	('prostate cancer', 'Phenotype', 'HP:0012125', (128, 143))	('prostate cancer', 'Disease', (128, 143))
289503	32047658	Activation of mTOR promotes the survival and proliferation of breast CSCs and nasopharyngeal carcinoma stem cells.	('mTOR', 'Gene', '2475', (14, 18))	('rat', 'Species', '10116', (52, 55))	('promotes', 'PosReg', (19, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('nasopharyngeal carcinoma', 'Disease', 'MESH:C538339', (78, 102))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (78, 102))	('breast CSCs', 'CPA', (62, 73))	('proliferation', 'CPA', (45, 58))	('Activation', 'Var', (0, 10))	('survival', 'CPA', (32, 40))	('nasopharyngeal carcinoma', 'Disease', (78, 102))	('mTOR', 'Gene', (14, 18))
289504	32047658	mTORC1 activation also increases aldehyde dehydrogenase 1 (ALDH1) activity in colorectal CSCs.	('ALDH1', 'Gene', '216', (59, 64))	('colorectal CSCs', 'Disease', 'MESH:D015179', (78, 93))	('mTORC1', 'Gene', '382056', (0, 6))	('activity', 'MPA', (66, 74))	('activation', 'Var', (7, 17))	('colorectal CSCs', 'Disease', (78, 93))	('aldehyde', 'MPA', (33, 41))	('mTORC1', 'Gene', (0, 6))	('increases', 'PosReg', (23, 32))	('ALDH1', 'Gene', (59, 64))
289505	32047658	Activation of mTORC2 upregulates the expression of the hepatic CSC marker EpCAM (epithelial cellular adhesion molecule) and tumorigenicity in hepatocellular CSCs.	('mTORC2', 'Gene', '74343', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('EpCAM', 'Gene', (74, 79))	('epithelial cellular adhesion molecule', 'Gene', '4072', (81, 118))	('epithelial cellular adhesion molecule', 'Gene', (81, 118))	('tumor', 'Disease', (124, 129))	('Activation', 'Var', (0, 10))	('upregulates', 'PosReg', (21, 32))	('EpCAM', 'Gene', '4072', (74, 79))	('expression', 'MPA', (37, 47))	('mTORC2', 'Gene', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
289522	32047658	Furthermore, expression of PPARgamma restrains YAP transcriptional activity to induce differentiation in osteosarcoma stem cells and melanoma cells.	('differentiation', 'CPA', (86, 101))	('induce', 'Reg', (79, 85))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('restrains', 'NegReg', (37, 46))	('expression', 'Var', (13, 23))	('YAP', 'Gene', '10413', (47, 50))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('PPARgamma', 'Gene', (27, 36))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('YAP', 'Gene', (47, 50))
289545	32047658	Downregulation of Notch1 and IKKalpha enhances NF-kappaB activation to promote the CD133+ cell population in melanoma CSCs.	('promote', 'PosReg', (71, 78))	('CD133', 'Gene', (83, 88))	('IKKalpha', 'Gene', '1147', (29, 37))	('CD133', 'Gene', '8842', (83, 88))	('IKKalpha', 'Gene', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('NF-kappaB', 'Gene', (47, 56))	('Notch1', 'Gene', (18, 24))	('melanoma', 'Disease', (109, 117))	('Downregulation', 'Var', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('Notch1', 'Gene', '4851', (18, 24))	('enhances', 'PosReg', (38, 46))	('activation', 'MPA', (57, 67))	('NF-kappaB', 'Gene', '4790', (47, 56))
289548	32047658	TGF-beta1 silencing decreases the expression of Smad2/3, beta-catenin, and cleaved-Notch1 to inhibit the activation of Wnt and Notch signaling in liver CSCs.	('expression', 'MPA', (34, 44))	('Notch', 'Gene', (83, 88))	('Notch1', 'Gene', (83, 89))	('Notch1', 'Gene', '4851', (83, 89))	('Smad2', 'Gene', '4087', (48, 53))	('beta-catenin', 'Gene', (57, 69))	('beta-catenin', 'Gene', '1499', (57, 69))	('TGF-beta1', 'Gene', (0, 9))	('decreases', 'NegReg', (20, 29))	('Notch', 'Gene', '31293', (127, 132))	('Smad2', 'Gene', (48, 53))	('TGF-beta1', 'Gene', '7040', (0, 9))	('inhibit', 'NegReg', (93, 100))	('Notch', 'Gene', '31293', (83, 88))	('silencing', 'Var', (10, 19))	('activation', 'MPA', (105, 115))	('Notch', 'Gene', (127, 132))	('Wnt', 'Gene', (119, 122))	('Wnt', 'Gene', '114487', (119, 122))
289553	32047658	Inhibition of TORC1/2 increases FGF1 and Notch1 expression.	('FGF1', 'Gene', '2246', (32, 36))	('Notch1', 'Gene', (41, 47))	('expression', 'MPA', (48, 58))	('FGF1', 'Gene', (32, 36))	('Notch1', 'Gene', '4851', (41, 47))	('Inhibition', 'Var', (0, 10))	('increases', 'PosReg', (22, 31))
289597	32047658	Jinushi and colleagues also reported that TAMs secrete MFG-E8, which maintains the self-renewal ability of colon and breast CSCs, and knockout of MFG-E8 significantly inhibits the tumorigenic ability in SCID mice.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('self-renewal', 'MPA', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('TAMs', 'Chemical', '-', (42, 46))	('MFG-E8', 'Gene', '17304', (55, 61))	('tumor', 'Disease', (180, 185))	('knockout', 'Var', (134, 142))	('MFG-E8', 'Gene', '17304', (146, 152))	('SCID', 'Disease', (203, 207))	('MFG-E8', 'Gene', (55, 61))	('SCID', 'Disease', 'MESH:D053632', (203, 207))	('MFG-E8', 'Gene', (146, 152))	('mice', 'Species', '10090', (208, 212))	('inhibits', 'NegReg', (167, 175))
289601	32047658	The ablation of TAMs inhibits the tumorigenesis of glioma stem cells.	('inhibits', 'NegReg', (21, 29))	('glioma', 'Disease', (51, 57))	('tumor', 'Disease', (34, 39))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('TAMs', 'Gene', (16, 20))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('ablation', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('TAMs', 'Chemical', '-', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
289622	32047658	MSCs not only promote tumor development but also inhibit cancer cell growth.	('men', 'Species', '9606', (35, 38))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('promote', 'PosReg', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('MSCs', 'Var', (0, 4))	('tumor', 'Disease', (22, 27))	('inhibit', 'NegReg', (49, 56))
289667	32047658	The latest antibodies against CSC surface markers, such as XmAb14045 (NCT02730312), flotetuzumab (NCT02152956), and talacotuzumab (NCT02472145), are also in clinical study.	('talacotuzumab', 'Chemical', '-', (116, 129))	('NCT02730312', 'Var', (70, 81))	('NCT02472145', 'Var', (131, 142))	('flotetuzumab', 'Chemical', '-', (84, 96))	('NCT02152956', 'Var', (98, 109))
289675	32047658	Combining EpCAM antibodies with chimeric antigen receptor T cell (CAR-T) technology has also been used in various types of cancers in phase I trials, such as NCT02915445, NCT03563326, NCT02729493, and NCT02725125.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('NCT02729493', 'Var', (184, 195))	('EpCAM', 'Gene', '4072', (10, 15))	('NCT02915445', 'Var', (158, 169))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('NCT02725125', 'Var', (201, 212))	('NCT03563326', 'Var', (171, 182))	('EpCAM', 'Gene', (10, 15))
289682	32047658	Considerable progress has been made in early clinical trials for Notch and Hh pathway inhibitors, while targeting the Wnt pathway has proven to be difficult.	('Wnt', 'Gene', (118, 121))	('Notch', 'Gene', (65, 70))	('Wnt', 'Gene', '114487', (118, 121))	('Notch', 'Gene', '31293', (65, 70))	('inhibitors', 'Var', (86, 96))
289687	32047658	Among them, MK-0752 (NCT00100152) was the first GSI used to treat T cell acute lymphoblastic leukemia in children in a phase I trial.	('T cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (66, 101))	('children', 'Species', '9606', (105, 113))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (73, 101))	('leukemia', 'Phenotype', 'HP:0001909', (93, 101))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (79, 101))	('NCT00100152', 'Var', (21, 32))	('GSI', 'Chemical', '-', (48, 51))	('MK-0752', 'Chemical', 'MESH:C554093', (12, 19))	('T cell acute lymphoblastic leukemia', 'Disease', (66, 101))
289688	32047658	MK-0752 also had no clinical activity in extracranial solid tumors in subsequent phase II trials.	('solid tumors', 'Disease', 'MESH:D009369', (54, 66))	('MK-0752', 'Chemical', 'MESH:C554093', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MK-0752', 'Var', (0, 7))	('solid tumors', 'Disease', (54, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
289691	32047658	In addition, combining MK-0752 with cisplatin treatment for ovarian cancer, docetaxel treatment for locally advanced or metastatic breast cancer, and gemcitabine treatment for ductal adenocarcinoma of the pancreas has shown good efficacy.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('men', 'Species', '9606', (51, 54))	('MK-0752', 'Var', (23, 30))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('ovarian cancer', 'Disease', (60, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('gemcitabine', 'Chemical', 'MESH:C056507', (150, 161))	('ductal adenocarcinoma of the pancreas', 'Disease', 'MESH:D021441', (176, 213))	('men', 'Species', '9606', (167, 170))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('MK-0752', 'Chemical', 'MESH:C554093', (23, 30))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('breast cancer', 'Disease', (131, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('ductal adenocarcinoma of the pancreas', 'Disease', (176, 213))	('docetaxel', 'Chemical', 'MESH:D000077143', (76, 85))	('men', 'Species', '9606', (91, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))
289693	32047658	In addition, RO4929097, another selective GSI, showed good anti-tumor activity in preclinical and early trials, but was not good for metastatic colorectal cancer, metastatic pancreatic adenocarcinoma, or recurrent platinum-resistant ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('ovarian cancer', 'Disease', 'MESH:D010051', (233, 247))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (174, 199))	('RO4929097', 'Var', (13, 22))	('GSI', 'Chemical', '-', (42, 45))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('colorectal cancer', 'Disease', (144, 161))	('ovarian cancer', 'Disease', (233, 247))	('pancreatic adenocarcinoma', 'Disease', (174, 199))	('ovarian cancer', 'Phenotype', 'HP:0100615', (233, 247))	('platinum', 'Chemical', 'MESH:D010984', (214, 222))	('RO4929097', 'Chemical', 'MESH:C545185', (13, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('tumor', 'Disease', (64, 69))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (174, 199))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
289694	32047658	Combinations of RO4929097 with gemcitabine, temsirolimus, cediranib, or capecitabine in advanced solid tumors, as well as with bevacizumab in recurrent high-grade glioma, are well tolerated and have modest clinical benefits.	('solid tumors', 'Disease', 'MESH:D009369', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('glioma', 'Disease', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('RO4929097', 'Var', (16, 25))	('gemcitabine', 'Chemical', 'MESH:C056507', (31, 42))	('rat', 'Species', '10116', (184, 187))	('Combinations', 'Interaction', (0, 12))	('RO4929097', 'Chemical', 'MESH:C545185', (16, 25))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('temsirolimus', 'Chemical', 'MESH:C401859', (44, 56))	('capecitabine', 'Chemical', 'MESH:D000069287', (72, 84))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('bevacizumab', 'Chemical', 'MESH:D000068258', (127, 138))	('solid tumors', 'Disease', (97, 109))	('cediranib', 'Chemical', 'MESH:C500926', (58, 67))
289695	32047658	However, NCT01154452, the combination of RO4929097 with vismodegib and vismodegib alone for patients with advanced osteosarcoma, showed no significant difference in a phase Ib trial.	('NCT01154452', 'Var', (9, 20))	('patients', 'Species', '9606', (92, 100))	('osteosarcoma', 'Disease', (115, 127))	('osteosarcoma', 'Phenotype', 'HP:0002669', (115, 127))	('osteosarcoma', 'Disease', 'MESH:D012516', (115, 127))	('RO4929097', 'Chemical', 'MESH:C545185', (41, 50))	('RO4929097', 'Var', (41, 50))
289696	32047658	The third oral GSI, PF-03084014, had good efficacy in desmoid tumors either in phase I or subsequent phase II studies.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('GSI', 'Chemical', '-', (15, 18))	('desmoid tumors', 'Disease', (54, 68))	('PF-03084014', 'Var', (20, 31))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('desmoid tumors', 'Phenotype', 'HP:0100245', (54, 68))	('PF', 'Chemical', 'MESH:C002997', (20, 22))	('desmoid tumors', 'Disease', 'MESH:C535944', (54, 68))
289698	32047658	Other selective GSIs, such as BMS-906024 (NCT01292655), BMS-986115 (NCT01986218), CB-103 (NCT03422679), LY3039478 (NCT02836600), and LY900009 (NCT01158404), have also entered the clinical trial stage, and the results still need to be verified.	('NCT03422679', 'Var', (90, 101))	('GSI', 'Chemical', '-', (16, 19))	('LY3039478 (NCT02836600', 'Var', (104, 126))	('NCT02836600', 'Var', (115, 126))	('LY3039478', 'Chemical', '-', (104, 113))	('NCT01292655', 'Var', (42, 53))	('LY900009', 'Chemical', 'MESH:C000609015', (133, 141))	('NCT01158404', 'Var', (143, 154))	('NCT01986218', 'Var', (68, 79))
289717	32047658	These combinations in a phase II trial for patients with recurrent medulloblastoma resulted in a complete or partial response in 50% of patients and have been used for other cancer treatments in phase I/II clinical trials, such as NCT02111187 for prostate cancer, NCT02027376 for breast cancer, and NCT02195973 for recurrent ovarian cancer.	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', (256, 262))	('men', 'Species', '9606', (186, 189))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('prostate cancer', 'Disease', 'MESH:D011471', (247, 262))	('prostate cancer', 'Phenotype', 'HP:0012125', (247, 262))	('NCT02027376', 'Var', (264, 275))	('NCT02195973', 'Var', (299, 310))	('prostate cancer', 'Disease', (247, 262))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', (333, 339))	('medulloblastoma', 'Disease', 'MESH:D008527', (67, 82))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (315, 339))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('medulloblastoma', 'Phenotype', 'HP:0002885', (67, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (280, 293))	('medulloblastoma', 'Disease', (67, 82))	('ovarian cancer', 'Disease', 'MESH:D010051', (325, 339))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('patients', 'Species', '9606', (43, 51))	('breast cancer', 'Disease', 'MESH:D001943', (280, 293))	('partial', 'NegReg', (109, 116))	('breast cancer', 'Disease', (280, 293))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('NCT02111187', 'Var', (231, 242))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('patients', 'Species', '9606', (136, 144))	('ovarian cancer', 'Disease', (325, 339))	('ovarian cancer', 'Phenotype', 'HP:0100615', (325, 339))
289721	32047658	Other selective SMO inhibitors, including taladegib (LY2940680) and saridegib (IPI-926), have also entered clinical trials for other cancers.	('IPI-926', 'Chemical', 'MESH:C541444', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('SMO', 'Gene', '6608', (16, 19))	('taladegib', 'Chemical', 'MESH:C581399', (42, 51))	('cancers', 'Disease', (133, 140))	('SMO', 'Gene', (16, 19))	('LY2940680', 'Chemical', 'MESH:C581399', (53, 62))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('LY2940680', 'Var', (53, 62))	('saridegib', 'Chemical', 'MESH:C541444', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
289728	32047658	NCT02050178, ipafricept combined with ab-paclitaxel and gemcitabine in patients with untreated stage IV pancreatic cancer, NCT02092363, ipafricept combined with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer, and NCT02069145, ipafricept combined with sorafenib in patients with HCC, are currently being investigated.	('sorafenib', 'Chemical', 'MESH:D000077157', (292, 301))	('HCC', 'Gene', (319, 322))	('patients', 'Species', '9606', (71, 79))	('pancreatic cancer', 'Disease', (104, 121))	('ovarian cancer', 'Disease', 'MESH:D010051', (234, 248))	('NCT02092363', 'Var', (123, 134))	('platinum', 'Chemical', 'MESH:D010984', (215, 223))	('carboplatin', 'Chemical', 'MESH:D016190', (176, 187))	('ab-paclitaxel', 'Chemical', '-', (38, 51))	('ovarian cancer', 'Disease', (234, 248))	('paclitaxel', 'Chemical', 'MESH:D017239', (161, 171))	('paclitaxel', 'Chemical', 'MESH:D017239', (41, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (234, 248))	('patients', 'Species', '9606', (305, 313))	('NCT02050178', 'Var', (0, 11))	('gemcitabine', 'Chemical', 'MESH:C056507', (56, 67))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('HCC', 'Gene', '619501', (319, 322))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('HCC', 'Phenotype', 'HP:0001402', (319, 322))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
289729	32047658	PRI-724, a beta-catenin inhibitor, inhibits the interaction between beta-catenin and its transcriptional coactivators.	('beta-catenin', 'Gene', (11, 23))	('PRI-724', 'Var', (0, 7))	('inhibits', 'NegReg', (35, 43))	('beta-catenin', 'Gene', '1499', (11, 23))	('interaction', 'Interaction', (48, 59))	('PRI-724', 'Chemical', 'MESH:C492448', (0, 7))	('beta-catenin', 'Gene', (68, 80))	('beta-catenin', 'Gene', '1499', (68, 80))
289730	32047658	Safety and efficacy testing of PRI-724 for patients with advanced myeloid malignancies (NCT01606579) and advanced or metastatic pancreatic cancer (NCT01764477) have been completed in phase I studies.	('NCT01764477', 'Var', (147, 158))	('PRI-724', 'Gene', (31, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('patients', 'Species', '9606', (43, 51))	('pancreatic cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('myeloid malignancies', 'Disease', (66, 86))	('NCT01606579', 'Var', (88, 99))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))	('myeloid malignancies', 'Disease', 'OMIM:601308', (66, 86))	('PRI-724', 'Chemical', 'MESH:C492448', (31, 38))
289731	32047658	CWP232291, another inhibitor of beta-catenin activity, has also been shown to be effective for AML (NCT03055286) in a phase I clinical study and for recurrent or refractory myeloma (NCT02426723) in a phase I/II clinical study.	('NCT03055286', 'Var', (100, 111))	('AML', 'Disease', 'MESH:D015470', (95, 98))	('beta-catenin', 'Gene', (32, 44))	('effective', 'Reg', (81, 90))	('AML', 'Phenotype', 'HP:0004808', (95, 98))	('myeloma', 'Disease', 'MESH:D009101', (173, 180))	('AML', 'Disease', (95, 98))	('beta-catenin', 'Gene', '1499', (32, 44))	('recurrent', 'Disease', (149, 158))	('CWP232291', 'Var', (0, 9))	('myeloma', 'Disease', (173, 180))
289732	32047658	Other Wnt signaling inhibitors have also been under clinical trial, including LGK974 (NCT02278133), ETC-159 (NCT02521844), and OMP-18R5 (NCT01973309, NCT01957007, and NCT02005315).	('NCT02521844', 'Var', (109, 120))	('NCT01957007', 'Var', (150, 161))	('NCT02278133', 'Var', (86, 97))	('Wnt', 'Gene', (6, 9))	('NCT01973309', 'Var', (137, 148))	('NCT02005315', 'Var', (167, 178))	('Wnt', 'Gene', '114487', (6, 9))
289743	32047658	LY2510924, a small cyclic peptide, is a potent and selective antagonist of CXCR4 and is well tolerated with no serious adverse events in a phase I trial.	('rat', 'Species', '10116', (97, 100))	('CXCR4', 'Gene', '7852', (75, 80))	('LY2510924', 'Var', (0, 9))	('CXCR4', 'Gene', (75, 80))	('LY2510924', 'Chemical', 'MESH:C000595455', (0, 9))
289744	32047658	However, the combination of LY2510924 with sunitinib for patients with metastatic renal cell carcinoma has no better effect than sunitinib alone in a phase II trial.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('patients', 'Species', '9606', (57, 65))	('LY2510924', 'Var', (28, 37))	('renal cell carcinoma', 'Disease', (82, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (82, 102))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (82, 102))	('sunitinib', 'Chemical', 'MESH:D000077210', (43, 52))	('sunitinib', 'Chemical', 'MESH:D000077210', (129, 138))	('LY2510924', 'Chemical', 'MESH:C000595455', (28, 37))
289745	32047658	The combination of LY2510924 with carboplatin/etoposide for patients with extensive small-cell lung cancer also had no significant effect compared with that of carboplatin/etoposide alone in a phase II study.	('carboplatin', 'Chemical', 'MESH:D016190', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('carboplatin', 'Chemical', 'MESH:D016190', (160, 171))	('patients', 'Species', '9606', (60, 68))	('etoposide', 'Chemical', 'MESH:D005047', (46, 55))	('LY2510924', 'Chemical', 'MESH:C000595455', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (84, 106))	('LY2510924', 'Var', (19, 28))	('small-cell lung cancer', 'Disease', (84, 106))	('etoposide', 'Chemical', 'MESH:D005047', (172, 181))
289746	32047658	The combination of LY2510924 with other drugs for gliomas (NCT03746080, NCT01977677, and NCT01288573) and multiple myeloma (NCT00103662, NCT01220375, and NCT00903968) is also under clinical trial.	('multiple myeloma', 'Disease', (106, 122))	('gliomas', 'Disease', (50, 57))	('LY2510924', 'Chemical', 'MESH:C000595455', (19, 28))	('NCT01220375', 'Var', (137, 148))	('NCT03746080', 'Var', (59, 70))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('multiple myeloma', 'Disease', 'MESH:D009101', (106, 122))	('NCT00103662', 'Var', (124, 135))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('multiple myeloma', 'Phenotype', 'HP:0006775', (106, 122))	('LY2510924', 'Var', (19, 28))
289776	31205566	Our study indicated that low LMR could serve as an independent worse prognostic marker in patients with ESCC.	('LMR', 'Chemical', '-', (29, 32))	('patients', 'Species', '9606', (90, 98))	('ESCC', 'Disease', (104, 108))	('low LMR', 'Var', (25, 32))
289810	31205566	As shown in Figure 1, the Kaplan-Meier curves indicated that patients with low LMR had a worse DFS (P=0.007, Figure 1A) and OS (P=0.018, Figure 1B) compared with high LMR group.	('DFS', 'MPA', (95, 98))	('low LMR', 'Var', (75, 82))	('OS', 'Chemical', '-', (124, 126))	('LMR', 'Chemical', '-', (79, 82))	('patients', 'Species', '9606', (61, 69))	('LMR', 'Chemical', '-', (167, 170))
289812	31205566	After adjustment for confounders, lymph node metastasis (P<0.001), nerve infiltration (P=0.003), treatment regimen (P<0.001) and LMR (P=0.003) were significantly associated with DFS (Table 4).	('DFS', 'Disease', (178, 181))	('associated', 'Reg', (162, 172))	('LMR', 'Var', (129, 132))	('LMR', 'Chemical', '-', (129, 132))	('lymph node metastasis', 'CPA', (34, 55))
289813	31205566	In the univariate analysis, we found that LMR was significantly associated with OS (P=0.018).	('OS', 'Chemical', '-', (80, 82))	('associated', 'Reg', (64, 74))	('LMR', 'Var', (42, 45))	('LMR', 'Chemical', '-', (42, 45))
289816	31205566	Above all, LMR was an independent prognostic factor for ESCC after esophageal radical surgery.	('ESCC', 'Disease', (56, 60))	('LMR', 'Var', (11, 14))	('LMR', 'Chemical', '-', (11, 14))
289819	31205566	In the present research, low LMR was discovered to be significantly related to sex (P<0.001), with 70% of patients being male.	('LMR', 'Chemical', '-', (29, 32))	('sex', 'Disease', (79, 82))	('patients', 'Species', '9606', (106, 114))	('low LMR', 'Var', (25, 32))
289824	31205566	Low LMR was correlated with the unfavorable prognosis of ESCC after radical surgery.	('ESCC', 'Disease', (57, 61))	('Low LMR', 'Var', (0, 7))	('LMR', 'Chemical', '-', (4, 7))
289825	31205566	We concluded that LMR was an independent prognostic factor for ESCC by using the Cox regression model.	('LMR', 'Var', (18, 21))	('ESCC', 'Disease', (63, 67))	('LMR', 'Chemical', '-', (18, 21))
289840	31205566	The author concluded that low LMR (LMR<=4.0) was correlated with the worse cancer specific survival and overall survival.	('overall survival', 'CPA', (104, 120))	('low LMR', 'Var', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('worse', 'NegReg', (69, 74))	('LMR', 'Chemical', '-', (35, 38))	('cancer', 'Disease', (75, 81))	('LMR', 'Var', (30, 33))	('LMR', 'Chemical', '-', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
289844	31205566	Based on 680 cases patients with primary diagnosis of ESCC, we found that low LMR was an independent prognostic factor in ESCC patients in China.	('patients', 'Species', '9606', (19, 27))	('ESCC', 'Disease', (122, 126))	('low', 'Var', (74, 77))	('LMR', 'MPA', (78, 81))	('patients', 'Species', '9606', (127, 135))	('LMR', 'Chemical', '-', (78, 81))
289854	30538564	We found that high NLR, PLR and low LMR were associated with poor overall survival/cancer-specific survival and event-free survival and malignant phenotypes such as deeper depth of invasion (T), positive lymph node metastasis (N), and advanced TNM stage.	('positive lymph node metastasis', 'CPA', (195, 225))	('high NLR', 'Var', (14, 22))	('PLR', 'Var', (24, 27))	('low LMR', 'Var', (32, 39))	('TNM', 'Gene', '10178', (244, 247))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('LMR', 'Chemical', '-', (36, 39))	('poor', 'NegReg', (61, 65))	('TNM', 'Gene', (244, 247))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
289861	30538564	Recent evidence suggested that a systemic inflammatory response is associated with tumor development, apoptosis inhibition, angiogenesis promotion, and damage of DNA, thus resulting in tumor progression and metastasis.	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (83, 88))	('resulting in', 'Reg', (172, 184))	('metastasis', 'CPA', (207, 217))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('DNA', 'Gene', (162, 165))	('damage', 'Var', (152, 158))	('promotion', 'PosReg', (137, 146))	('angiogenesis', 'CPA', (124, 136))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
289884	30538564	The overall analysis suggested that high NLR was associated with worse OS/CSS (HR =1.54, 95% CI =1.39-1.74, P<0.001, I2=53.9%, P=0.001).	('NLR', 'Gene', (41, 44))	('CSS', 'Gene', '55907', (74, 77))	('OS', 'Chemical', 'MESH:D009992', (71, 73))	('CSS', 'Gene', (74, 77))	('high', 'Var', (36, 40))
289886	30538564	We found high NLR was more common in males than in females (male vs female: OR =1.58, 95% CI =1.19-2.10, P=0.002); high NLR was associated with deeper depth of invasion (T3-T4 vs T1-T2: OR =1.95, 95% CI =1.46-2.60, P<0.001), longer tumor length (>=3 vs <3 cm: OR =2.82, 95% CI =1.67-4.77, P<0.001), positive lymph node metastasis (yes vs no: OR =1.27, 95% CI =1.03-1.57, P=0.026), and advanced stage (III-IV vs I-II: OR =1.47, 95% CI =1.28-1.69, P<0.001).	('high', 'Var', (115, 119))	('advanced stage', 'CPA', (385, 399))	('positive lymph node metastasis', 'CPA', (299, 329))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('longer tumor', 'Disease', 'MESH:D009369', (225, 237))	('longer tumor', 'Disease', (225, 237))
289889	30538564	We found that ESCC patients with high PLR may have worse OS/CSS (HR =1.37, 95% CI =1.25-1.51, P<0.001, I2=33.1%, P=0.125).	('patients', 'Species', '9606', (19, 27))	('CSS', 'Gene', '55907', (60, 63))	('high PLR', 'Var', (33, 41))	('CSS', 'Gene', (60, 63))	('ESCC', 'Disease', (14, 18))	('OS', 'Chemical', 'MESH:D009992', (57, 59))
289893	30538564	The combined HR for OS/CSS and EFS suggested that high LMR might be associated with better survival (HR =0.70, 95% CI =0.54-0.89, P<0.001 for OS/CSS; HR =0.65, 95% CI =0.43-0.99, P<0.001 for EFS, respectively.)	('survival', 'CPA', (91, 99))	('CSS', 'Gene', (145, 148))	('OS', 'Chemical', 'MESH:D009992', (142, 144))	('CSS', 'Gene', '55907', (23, 26))	('LMR', 'Chemical', '-', (55, 58))	('CSS', 'Gene', '55907', (145, 148))	('CSS', 'Gene', (23, 26))	('better', 'PosReg', (84, 90))	('OS', 'Chemical', 'MESH:D009992', (20, 22))	('high', 'Var', (50, 54))
289902	30538564	Other subgroup analyses suggested a significant association between high NLR and poor OS/CSS and EFS.	('OS', 'Chemical', 'MESH:D009992', (86, 88))	('high', 'Var', (68, 72))	('CSS', 'Gene', '55907', (89, 92))	('CSS', 'Gene', (89, 92))	('EFS', 'Disease', (97, 100))	('NLR', 'Gene', (73, 76))
289904	30538564	Low LMR was associated with poor OS/CSS in all subgroup analyses.	('CSS', 'Gene', '55907', (36, 39))	('LMR', 'Chemical', '-', (4, 7))	('OS', 'Chemical', 'MESH:D009992', (33, 35))	('CSS', 'Gene', (36, 39))	('Low LMR', 'Var', (0, 7))
289907	30538564	As systematic inflammatory markers, high neutrophil, platelet, and macrophage counts, low lymphocyte, and also high NLR, PLR, and low LMR have been recognized to be associated with unfavorable prognosis in solid tumors.	('high neutrophil', 'Var', (36, 51))	('solid tumors', 'Disease', (206, 218))	('low LMR', 'Var', (130, 137))	('associated', 'Reg', (165, 175))	('low lymphocyte', 'Var', (86, 100))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('low lymphocyte', 'Phenotype', 'HP:0001888', (86, 100))	('solid tumors', 'Disease', 'MESH:D009369', (206, 218))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('high', 'Var', (111, 115))	('LMR', 'Chemical', '-', (134, 137))
289909	30538564	We found that high NLR, PLR and low LMR were associated with poor survival and malignant phenotype such as deeper depth of invasion (T), positive lymph node metastasis (N), and advanced TNM stage.	('TNM', 'Gene', (186, 189))	('positive lymph node metastasis', 'CPA', (137, 167))	('PLR', 'Var', (24, 27))	('poor', 'NegReg', (61, 65))	('survival', 'CPA', (66, 74))	('TNM', 'Gene', '10178', (186, 189))	('LMR', 'Chemical', '-', (36, 39))	('low LMR', 'Var', (32, 39))
289931	30538564	In conclusion, our analysis suggested high NLR, PLR and low LMR were associated with poor survival and malignant phenotype in ESCC patients.	('patients', 'Species', '9606', (131, 139))	('LMR', 'MPA', (60, 63))	('NLR', 'MPA', (43, 46))	('high', 'Var', (38, 42))	('ESCC', 'Disease', (126, 130))	('PLR', 'MPA', (48, 51))	('LMR', 'Chemical', '-', (60, 63))
289934	29299035	Our aim here is to elucidate impact of ectopic expression of TWIST1 on OCT4 gene expression in esophageal squamous cell carcinoma (ESCC).	('OCT4 gene', 'Gene', (71, 80))	('esophageal squamous cell carcinoma', 'Disease', (95, 129))	('ectopic expression', 'Var', (39, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (95, 129))	('TWIST1', 'Gene', (61, 67))	('TWIST1', 'Gene', '7291', (61, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))
289939	29299035	This induced expression of TWIST1 caused significant upregulation of OCT4 in GFP-hTWIST1 KYSE-30 cells: nearly eight-fold higher.	('TWIST1', 'Gene', (82, 88))	('TWIST1', 'Gene', (27, 33))	('TWIST1', 'Gene', '7291', (82, 88))	('higher', 'PosReg', (122, 128))	('TWIST1', 'Gene', '7291', (27, 33))	('OCT4', 'MPA', (69, 73))	('upregulation', 'PosReg', (53, 65))	('expression', 'Var', (13, 23))	('hTWIST1', 'Gene', (81, 88))	('hTWIST1', 'Gene', '7291', (81, 88))
289941	29299035	Overexpressed TWIST1 can be correlated with upregulation of the cancer stem cell marker OCT4 and the protein may play critical regulatory role in OCT4 gene expression.	('Overexpressed', 'Var', (0, 13))	('cancer', 'Disease', (64, 70))	('TWIST1', 'Gene', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('TWIST1', 'Gene', '7291', (14, 20))	('upregulation', 'PosReg', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('OCT4', 'MPA', (88, 92))
289981	29299035	The performed functional study on ESCC cells showed an elevated level of MAGEA4 expression after TWIST1 ectopic expression, and confirmed indirect binding of TWIST1 to the MAGEA4 promoter region leading to increased expression of MAGEA4 at both the mRNA and protein levels.	('binding', 'Interaction', (147, 154))	('increased', 'PosReg', (206, 215))	('MAGEA4', 'Gene', (230, 236))	('MAGEA4', 'Gene', (172, 178))	('MAGEA4', 'Gene', '4103', (172, 178))	('expression', 'MPA', (216, 226))	('TWIST1', 'Gene', (97, 103))	('MAGEA4', 'Gene', (73, 79))	('MAGEA4', 'Gene', '4103', (230, 236))	('TWIST1', 'Gene', '7291', (97, 103))	('elevated', 'PosReg', (55, 63))	('ectopic expression', 'Var', (104, 122))	('MAGEA4', 'Gene', '4103', (73, 79))	('TWIST1', 'Gene', (158, 164))	('TWIST1', 'Gene', '7291', (158, 164))
290003	29299035	We showed that ectopic expression of TWIST1 in KYSE30 cells can upregulate OCT4 gene expression at the mRNA level.	('expression', 'MPA', (85, 95))	('ectopic expression', 'Var', (15, 33))	('OCT4 gene', 'Gene', (75, 84))	('upregulate', 'PosReg', (64, 74))	('TWIST1', 'Gene', (37, 43))	('TWIST1', 'Gene', '7291', (37, 43))
290009	29047233	Overexpression of miR-191 Predicts Poor Prognosis and Promotes Proliferation and Invasion in Esophageal Squamous Cell Carcinoma Accumulating evidence has shown that dysregulation of microRNA-191 (miR-191) is closely associated with tumorigenesis and progression in a wide range of cancers.	('miR-191', 'Gene', '406966', (196, 203))	('miR-191', 'Gene', (196, 203))	('associated', 'Reg', (216, 226))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('cancers', 'Disease', (281, 288))	('Esophageal Squamous Cell Carcinoma', 'Disease', (93, 127))	('Carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('Promotes', 'PosReg', (54, 62))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('tumor', 'Disease', (232, 237))	('Invasion', 'CPA', (81, 89))	('miR-191', 'Gene', '406966', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('miR-191', 'Gene', (18, 25))	('microRNA-191', 'Gene', (182, 194))	('dysregulation', 'Var', (165, 178))	('microRNA-191', 'Gene', '406966', (182, 194))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('Proliferation', 'CPA', (63, 76))
290019	29047233	Moreover, EGR1 knockdown by siRNA enhanced ESCC cell growth and invasion.	('EGR1', 'Gene', (10, 14))	('knockdown', 'Var', (15, 24))	('enhanced', 'PosReg', (34, 42))	('EGR1', 'Gene', '1958', (10, 14))	('invasion', 'CPA', (64, 72))	('ESCC cell growth', 'CPA', (43, 59))
290025	29047233	It is not surprising that miRNA dysregulation correlates with tumorigenesis in many cancers including ESCC.	('dysregulation', 'Var', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('ESCC', 'Disease', (102, 106))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('tumor', 'Disease', (62, 67))	('cancers', 'Disease', (84, 91))	('miRNA', 'Protein', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
290049	29047233	Wild-type 3'UTR of EGR1 and mutant constructs, which were produced via mutations in the binding site of miR-191 in EGR1's 3'UTR were cloned downstream of the Luciferase gene in the psiCHECK-2 Luciferase vector.	('miR-191', 'Gene', '406966', (104, 111))	('EGR1', 'Gene', (115, 119))	('miR-191', 'Gene', (104, 111))	('EGR1', 'Gene', (19, 23))	('mutations', 'Var', (71, 80))	('EGR1', 'Gene', '1958', (115, 119))	('EGR1', 'Gene', '1958', (19, 23))
290070	29047233	By doing so, we noted that ectopic miR-191 increased BrdU intensity, while miR-191 suppression decreased BrdU intensity in ESCC cells (Fig.	('miR-191', 'Gene', '406966', (35, 42))	('suppression decreased', 'NegReg', (83, 104))	('miR-191', 'Gene', (35, 42))	('BrdU intensity', 'MPA', (53, 67))	('ectopic', 'Var', (27, 34))	('BrdU intensity', 'MPA', (105, 119))	('miR-191', 'Gene', '406966', (75, 82))	('increased', 'PosReg', (43, 52))	('miR-191', 'Gene', (75, 82))
290077	29047233	In order to validate whether miR-191 directly bound 3'UTR of EGR1 to suppress its expression, reporter vectors containing wildtype or mutant EGR1 3'UTR binding sites were transfected into HEK293T and EC9706 cells, respectively.	('EGR1', 'Gene', '1958', (61, 65))	('EGR1', 'Gene', (141, 145))	('expression', 'MPA', (82, 92))	('HEK293T', 'CellLine', 'CVCL:0063', (188, 195))	('EGR1', 'Gene', '1958', (141, 145))	('EC9706', 'CellLine', 'CVCL:E307', (200, 206))	('miR-191', 'Gene', '406966', (29, 36))	('EGR1', 'Gene', (61, 65))	('miR-191', 'Gene', (29, 36))	('mutant', 'Var', (134, 140))	('suppress', 'NegReg', (69, 77))
290083	29047233	All of the MTT, plate clone formation, and BrdU assays indicated that down-regulation of EGR1 accelerated EC9706 cell proliferation and growth (Fig.	('EC9706 cell proliferation', 'CPA', (106, 131))	('down-regulation', 'Var', (70, 85))	('EC9706', 'CellLine', 'CVCL:E307', (106, 112))	('EGR1', 'Gene', '1958', (89, 93))	('EGR1', 'Gene', (89, 93))	('growth', 'CPA', (136, 142))	('MTT', 'Chemical', '-', (11, 14))	('accelerated', 'PosReg', (94, 105))
290084	29047233	Moreover, Transwell assay showed that EGR1 knockdown increased cell migration and invasion in vitro (Fig.	('EGR1', 'Gene', (38, 42))	('EGR1', 'Gene', '1958', (38, 42))	('knockdown', 'Var', (43, 52))	('cell migration', 'CPA', (63, 77))	('increased', 'PosReg', (53, 62))	('invasion in vitro', 'CPA', (82, 99))
290085	29047233	Collectively, these observations indicated that down-regulation of EGR1 promotes ESCC proliferation and invasion.	('down-regulation', 'Var', (48, 63))	('EGR1', 'Gene', (67, 71))	('EGR1', 'Gene', '1958', (67, 71))	('promotes', 'PosReg', (72, 80))	('invasion', 'CPA', (104, 112))	('ESCC proliferation', 'CPA', (81, 99))
290087	29047233	The dysregulated expression of several miRNAs, including miR-21, miR-126, miR-138, miR-183, miR-200b, miR-375, and miR-508, has been associated with ESCC in recent literature.	('miR-375', 'Gene', (102, 109))	('miR-200b', 'Gene', '406984', (92, 100))	('ESCC', 'Disease', (149, 153))	('miR-138', 'Var', (74, 81))	('miR-508', 'Gene', (115, 122))	('miR-21', 'Gene', '406991', (57, 63))	('expression', 'MPA', (17, 27))	('miR-200b', 'Gene', (92, 100))	('miR-508', 'Gene', '574513', (115, 122))	('miR-126', 'Gene', '406913', (65, 72))	('miR-375', 'Gene', '494324', (102, 109))	('miR-126', 'Gene', (65, 72))	('miR-21', 'Gene', (57, 63))	('dysregulated', 'Var', (4, 16))	('miR-183', 'Gene', '406959', (83, 90))	('miR-183', 'Gene', (83, 90))	('associated', 'Reg', (133, 143))
290107	29047233	Clinically, loss of EGR1 results in enhancive tumor transformation, followed by patient morbidity and mortality.	('EGR1', 'Gene', '1958', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('enhancive', 'PosReg', (36, 45))	('tumor', 'Disease', (46, 51))	('loss', 'Var', (12, 16))	('patient', 'Species', '9606', (80, 87))	('EGR1', 'Gene', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
290117	29069772	These findings were most evident in gastric cancer, where significant interactions in relation to OS were observed for CD3+, CD8+ and FoxP3+ with CD20+ cells (pinteraction =0.012, 0.009 and 0.007, respectively) and for FoxP3+ with IGKC+ cells (pinteraction =0.034).	('IGKC', 'Gene', (231, 235))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('gastric cancer', 'Disease', (36, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('CD3+', 'Var', (119, 123))	('CD20', 'Gene', '54474', (146, 150))	('FoxP3+', 'Var', (134, 140))	('interactions', 'Interaction', (70, 82))	('IGKC', 'Gene', '3514', (231, 235))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('CD20', 'Gene', (146, 150))	('OS', 'Chemical', '-', (98, 100))	('FoxP3+', 'Var', (219, 225))	('CD8', 'Gene', (125, 128))	('CD8', 'Gene', '925', (125, 128))
290126	29069772	In gastric cancer, dense infiltration of CD3+ and CD8+ TILs has been associated with an improved prognosis.	('CD8', 'Gene', (50, 53))	('CD8', 'Gene', '925', (50, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CD3+', 'Var', (41, 45))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
290127	29069772	In esophageal adenocarcinoma, no convincing prognostic value has been demonstrated for CD3+ or CD8+ T cells and high density of FoxP3+ Tregs has been associated with a poor prognosis.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (3, 28))	('CD3+', 'Var', (87, 91))	('CD8', 'Gene', '925', (95, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('esophageal adenocarcinoma', 'Disease', (3, 28))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (3, 28))	('CD8', 'Gene', (95, 98))
290139	29069772	In the entire cohort, there was a strong to very strong correlation between CD3+, CD8+ and FoxP3+ cells, with similar findings in esophageal and gastric cancer, respectively.	('gastric cancer', 'Disease', 'MESH:D013274', (145, 159))	('CD8', 'Gene', (82, 85))	('CD8', 'Gene', '925', (82, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (145, 159))	('FoxP3+', 'Var', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('correlation', 'Interaction', (56, 67))	('gastric cancer', 'Disease', (145, 159))	('CD3+', 'Var', (76, 80))	('esophageal', 'Disease', (130, 140))
290145	29069772	Using the classification and regression tree (CRT) based cutoff, high CD3+, CD8+ and FoxP3+ density was significantly associated with a prolonged TTR (p=0.013, p=0.006 and p<0.001, respectively).	('prolonged', 'PosReg', (136, 145))	('high CD3+', 'Var', (65, 74))	('TTR', 'MPA', (146, 149))	('FoxP3+ density', 'Var', (85, 99))	('CD8', 'Gene', (76, 79))	('CD8', 'Gene', '925', (76, 79))	('CD3+', 'Var', (70, 74))
290146	29069772	The association between high NKp46+ and TTR did not reach significance (p=0.054).	('TTR', 'Disease', (40, 43))	('NKp46', 'Gene', '9437', (29, 34))	('high', 'Var', (24, 28))	('NKp46', 'Gene', (29, 34))
290148	29069772	Using CRT based cutoff, high density of CD8+, FoxP3+ and NKp46+ were all significantly associated with a prolonged OS (p=0.009, p=0.008 and p=0.008, respectively).	('NKp46', 'Gene', (57, 62))	('CD8', 'Gene', '925', (40, 43))	('OS', 'Chemical', '-', (115, 117))	('FoxP3+', 'Var', (46, 52))	('prolonged', 'Disease', (105, 114))	('NKp46', 'Gene', '9437', (57, 62))	('associated with', 'Reg', (87, 102))	('CD8', 'Gene', (40, 43))
290149	29069772	Using the median value as cutoff high FoxP3+ and NKp46+ density was significantly associated with a prolonged OS (p=0.002, p=0.012, respectively).	('high FoxP3+', 'Var', (33, 44))	('associated', 'Reg', (82, 92))	('prolonged', 'Disease', (100, 109))	('OS', 'Chemical', '-', (110, 112))	('NKp46', 'Gene', '9437', (49, 54))	('NKp46', 'Gene', (49, 54))	('FoxP3+', 'Var', (38, 44))
290151	29069772	In multivariable analysis, high CD8+ and FoxP3+ density remained independent factors of a prolonged TTR (HR=0.30, 95% CI=0.12-0.77, and HR=0.55, 95% CI=0.34-0.89, respectively).	('TTR', 'MPA', (100, 103))	('CD8', 'Gene', (32, 35))	('FoxP3+ density', 'Var', (41, 55))	('CD8', 'Gene', '925', (32, 35))
290155	29069772	In the entire cohort the significant associations between high density of FoxP3+ and NKp46+ lymphocytes with a prolonged OS were confirmed in univariable analyses.	('OS', 'Chemical', '-', (121, 123))	('NKp46', 'Gene', (85, 90))	('FoxP3+', 'Var', (74, 80))	('high density', 'Var', (58, 70))	('NKp46', 'Gene', '9437', (85, 90))
290157	29069772	In esophageal tumors, high FoxP3+ density was significantly associated with a prolonged OS in univariable but not in multivariable Cox regression analysis.	('FoxP3+', 'Protein', (27, 33))	('high', 'Var', (22, 26))	('esophageal tumors', 'Disease', 'MESH:D004938', (3, 20))	('esophageal tumors', 'Phenotype', 'HP:0100751', (3, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('esophageal tumors', 'Disease', (3, 20))	('OS', 'Chemical', '-', (88, 90))	('prolonged OS', 'Disease', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('associated with', 'Reg', (60, 75))
290159	29069772	In gastric tumors, only high FoxP3+ density was significantly associated with a prolonged OS in the univariable model, but this association did not remain significant in the multivariable analysis.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('FoxP3+', 'Gene', (29, 35))	('OS', 'Chemical', '-', (90, 92))	('gastric tumors', 'Disease', 'MESH:D013274', (3, 17))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('associated', 'Reg', (62, 72))	('gastric tumors', 'Disease', (3, 17))	('prolonged OS', 'MPA', (80, 92))	('high', 'Var', (24, 28))	('gastric tumors', 'Phenotype', 'HP:0006753', (3, 17))
290165	29069772	As further shown in Table 5, a significant interaction was observed for FoxP3+ cells with IGKC+ cells in relation to OS in the entire cohort (pinteraction =0.023).	('IGKC', 'Gene', (90, 94))	('FoxP3+', 'Var', (72, 78))	('OS', 'Chemical', '-', (117, 119))	('IGKC', 'Gene', '3514', (90, 94))
290173	29069772	In line with several previous studies, high density of CD3+, CD8+ and FoxP3+ T lymphocytes was in general significantly associated with a favorable prognosis, regarding either or both TTR and OS.	('associated', 'Reg', (120, 130))	('TTR', 'Disease', (184, 187))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('high density', 'Var', (39, 51))	('OS', 'Chemical', '-', (192, 194))	('CD3+', 'Var', (55, 59))	('FoxP3+', 'Gene', (70, 76))
290176	29069772	In another study, high density of FoxP3+ stromal TILs was found to be an independent favorable prognostic factor, but no prognostic impact was demonstrated for CD3+, CD8+ or CD20+ TILs, in chemoradiotherapy-naive tumors from 52 patients with radically resected, distant metastasis free, gastric cancer of the cardia.	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('CD20', 'Gene', '54474', (174, 178))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('CD20', 'Gene', (174, 178))	('cancer of the cardia', 'Phenotype', 'HP:0100544', (295, 315))	('patients', 'Species', '9606', (228, 236))	('gastric cancer of the cardia', 'Disease', 'MESH:D013274', (287, 315))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('FoxP3+', 'Var', (34, 40))	('gastric cancer', 'Phenotype', 'HP:0012126', (287, 301))	('CD8', 'Gene', (166, 169))	('gastric cancer of the cardia', 'Disease', (287, 315))	('CD8', 'Gene', '925', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))
290177	29069772	However, contrasting findings have also been shown where infiltration of FoxP3+ TILs was found to be associated with poor prognosis in gastric cancer patients.	('gastric cancer', 'Disease', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('FoxP3+ TILs', 'Var', (73, 84))	('patients', 'Species', '9606', (150, 158))
290188	29069772	It should however be pointed out that previous studies have demonstrated concordant results regarding the prognostic value of high infiltration of B cells in colorectal cancer, as demonstrated both by the use of whole tissue sections and by the use of TMA, and the herein presented results regarding the prognostic value of CD3+, CD8+ and FoxP3+ TILs in gastric cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('gastric cancer', 'Disease', 'MESH:D013274', (354, 368))	('TMA', 'Chemical', '-', (252, 255))	('CD3+', 'Var', (324, 328))	('colorectal cancer', 'Disease', (158, 175))	('CD8', 'Gene', (330, 333))	('gastric cancer', 'Phenotype', 'HP:0012126', (354, 368))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('FoxP3+', 'Var', (339, 345))	('CD8', 'Gene', '925', (330, 333))	('colorectal cancer', 'Disease', 'MESH:D015179', (158, 175))	('gastric cancer', 'Disease', (354, 368))
290214	29069772	The number of FoxP3+ and NKp46+ cells (intratumoral, tumor-adjacent and stromal) was calculated manually by two independent investigators (MCS and KJ), the latter being a board certified pathologist.	('tumoral', 'Disease', (44, 51))	('tumoral', 'Disease', 'MESH:D009369', (44, 51))	('FoxP3+', 'Var', (14, 20))	('MCS', 'Gene', '4183', (139, 142))	('NKp46', 'Gene', '9437', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('MCS', 'Gene', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('NKp46', 'Gene', (25, 30))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (44, 49))
290246	28702133	In an experiment on 7,12-dimethylbenz[a]anthracene (DMBA) induced breast cancer in FNB/N type rats, it was revealed that DMBA resulted in higher expression of the genes involved in carcinogenesis, including c-myc and cyclin-D1, as well as activation of the NF-kB pathway.	('7,12-dimethylbenz', 'Chemical', '-', (20, 37))	('carcinogenesis', 'Disease', 'MESH:D063646', (181, 195))	('cyclin-D1', 'Gene', '58919', (217, 226))	('expression', 'MPA', (145, 155))	('cyclin-D1', 'Gene', (217, 226))	('c-myc', 'Gene', (207, 212))	('DMBA', 'Chemical', 'MESH:D015127', (121, 125))	('NF-kB', 'Gene', (257, 262))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('DMBA', 'Var', (121, 125))	('NF-kB', 'Gene', '309165', (257, 262))	('c-myc', 'Gene', '24577', (207, 212))	('activation', 'PosReg', (239, 249))	('FNB', 'Disease', (83, 86))	('FNB', 'Disease', 'None', (83, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('higher', 'PosReg', (138, 144))	('anthracene', 'Chemical', 'MESH:C034020', (40, 50))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('carcinogenesis', 'Disease', (181, 195))	('DMBA', 'Chemical', 'MESH:D015127', (52, 56))	('breast cancer', 'Disease', (66, 79))	('rats', 'Species', '10116', (94, 98))
290268	27795701	Overexpression and amplification of HER2 in gastric cancer leads to a poor prognosis, due to the initiation of progression and metastasis.	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('HER2', 'Gene', (36, 40))	('amplification', 'Var', (19, 32))	('HER2', 'Gene', '2064', (36, 40))	('gastric cancer', 'Disease', (44, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('metastasis', 'CPA', (127, 137))
290298	27795701	Besides its association with clinicopatholgical features, HER2 amplification is a promising target for targeted therapy.	('HER2', 'Gene', (58, 62))	('amplification', 'Var', (63, 76))	('HER2', 'Gene', '2064', (58, 62))
290307	27795701	As a result of this reassessment, the European Medicine Agency (EMA) restricted approval of trastuzumab to patients suffering from IHC +++ or ++/FISH + metastatic gastric or gastro-esophageal junction adenocarcinoma.	('gastro-esophageal junction adenocarcinoma', 'Disease', (174, 215))	('IHC +++ or ++/FISH +', 'Var', (131, 151))	('gastro-esophageal junction adenocarcinoma', 'Disease', 'MESH:D005764', (174, 215))	('patients', 'Species', '9606', (107, 115))	('esophageal junction adenocarcinoma', 'Phenotype', 'HP:0011459', (181, 215))	('trastuzumab', 'Chemical', 'MESH:D000068878', (92, 103))
290330	27795701	The mTOR inhibitor everolimus inhibits the mTOR/S6K signal, and therefore improves fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification.	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('improves', 'PosReg', (74, 82))	('S6K', 'Gene', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('fluorouracil-induced apoptosis', 'MPA', (83, 113))	('HER2', 'Gene', (143, 147))	('S6K', 'Gene', '6198', (48, 51))	('mTOR', 'Gene', (43, 47))	('inhibits', 'NegReg', (30, 38))	('gastric cancer', 'Disease', (117, 131))	('HER2', 'Gene', '2064', (143, 147))	('mTOR', 'Gene', '2475', (43, 47))	('everolimus', 'Chemical', 'MESH:D000068338', (19, 29))	('mTOR', 'Gene', (4, 8))	('fluorouracil', 'Chemical', 'MESH:D005472', (83, 95))	('mTOR', 'Gene', '2475', (4, 8))	('amplification', 'Var', (148, 161))
290333	27795701	AUY922, a member of the isoxazole HSP90 inhibitor family, might be a promising agent to overcome secondary trastuzumab resistance.	('AUY922', 'Var', (0, 6))	('HSP90', 'Gene', (34, 39))	('AUY922', 'Chemical', 'MESH:C528044', (0, 6))	('HSP90', 'Gene', '3320', (34, 39))	('trastuzumab', 'Chemical', 'MESH:D000068878', (107, 118))	('isoxazole', 'Chemical', 'MESH:D007555', (24, 33))
290385	27672265	Non-malignant diseases, such as genital warts, recurrent respiratory papillomatosis and oral papillomas, are attributable to low-risk HPV types, particularly HPV6 and 11.	('oral papillomas', 'Disease', 'MESH:D010212', (88, 103))	('genital warts', 'Phenotype', 'HP:0032301', (32, 45))	('respiratory papillomatosis', 'Disease', 'MESH:C535297', (57, 83))	('HPV6', 'Var', (158, 162))	('Non-malignant diseases', 'Disease', (0, 22))	('warts', 'Phenotype', 'HP:0200043', (40, 45))	('papillomas', 'Phenotype', 'HP:0012740', (93, 103))	('papilloma', 'Phenotype', 'HP:0012740', (69, 78))	('genital warts', 'Disease', (32, 45))	('oral papillomas', 'Disease', (88, 103))	('respiratory papillomatosis', 'Disease', (57, 83))	('HPV', 'Species', '10566', (158, 161))	('Non-malignant diseases', 'Disease', 'MESH:D009369', (0, 22))	('HPV', 'Species', '10566', (134, 137))	('papilloma', 'Phenotype', 'HP:0012740', (93, 102))
290391	27672265	pRb is a negative regulator of the cyclin-dependent kinase inhibitor p16INK4a (p16), and inactivation of pRb leads to up-regulation of p16.	('p16INK4a', 'Gene', '1029', (69, 77))	('p16', 'Gene', '1029', (79, 82))	('inactivation', 'Var', (89, 101))	('p16', 'Gene', '1029', (135, 138))	('up-regulation', 'PosReg', (118, 131))	('pRb', 'Gene', (105, 108))	('p16', 'Gene', (69, 72))	('p16', 'Gene', (79, 82))	('p16INK4a', 'Gene', (69, 77))	('p16', 'Gene', (135, 138))	('p16', 'Gene', '1029', (69, 72))
290441	27672265	They also calculated separate ORs for HPV16 (OR = 3.55) and HPV18 (OR = 1.25), and HPV16 was the most frequently observed subtype in ESCC.	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('HPV', 'Species', '10566', (38, 41))	('HPV', 'Species', '10566', (83, 86))	('SCC', 'Gene', '6317', (134, 137))	('HPV', 'Species', '10566', (60, 63))	('HPV16', 'Species', '333760', (83, 88))	('HPV16', 'Var', (83, 88))	('HPV16', 'Species', '333760', (38, 43))	('SCC', 'Gene', (134, 137))
290463	27672265	This study was the first to find that HPV positivity, which was detected by PCR, was significantly higher in patients with BD and EAC compared to controls and individuals with Barrett's metaplasia.	('higher', 'PosReg', (99, 105))	('patients', 'Species', '9606', (109, 117))	('HPV', 'Species', '10566', (38, 41))	('positivity', 'Var', (42, 52))	('HPV', 'Gene', (38, 41))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (176, 196))	('EAC', 'Gene', '1540', (130, 133))	("Barrett's metaplasia", 'Disease', (176, 196))	('EAC', 'Gene', (130, 133))
290467	27672265	Both an increasing hr-HPV viral load and integration into the host genome were significantly associated with disease severity in the Barrett's metaplasia-dysplasia-adenocarcinoma pathway.	("Barrett's metaplasia-dysplasia-adenocarcinoma", 'Disease', 'MESH:D001471', (133, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('hr-HPV', 'Gene', (19, 25))	('associated', 'Reg', (93, 103))	("Barrett's metaplasia-dysplasia-adenocarcinoma", 'Disease', (133, 178))	('HPV', 'Species', '10566', (22, 25))	('integration', 'Var', (41, 52))
290476	27672265	Furihata et al reported that high levels of p53 protein expression (probably due to p53 mutations) were inversely associated with HPV16 or 18 infection in esophageal cancers, and the prognoses of two groups, one with HPV16 or 18 infection and the other with p53 overexpression, were significantly poorer than the prognoses of the group with neither condition.	('infection in esophageal cancers', 'Disease', 'MESH:D004938', (142, 173))	('p53', 'Gene', (258, 261))	('mutations', 'Var', (88, 97))	('HPV16', 'Species', '333760', (130, 135))	('HPV16', 'Species', '333760', (217, 222))	('infection', 'Disease', (142, 151))	('infection', 'Disease', 'MESH:D007239', (142, 151))	('infection', 'Disease', (229, 238))	('infection', 'Disease', 'MESH:D007239', (229, 238))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('p53', 'Gene', '7157', (44, 47))	('p53', 'Gene', '7157', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('inversely', 'NegReg', (104, 113))	('infection in esophageal cancers', 'Disease', (142, 173))	('p53', 'Gene', '7157', (258, 261))	('p53', 'Gene', (44, 47))	('p53', 'Gene', (84, 87))	('associated', 'Reg', (114, 124))
290510	27672265	Although two recent meta-analyses have demonstrated a significant increase in colorectal cancer risk associated with the presence of the virus, the published literature does not provide convincing evidence for a strong association.	('increase', 'PosReg', (66, 74))	('presence', 'Var', (121, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('colorectal cancer', 'Disease', (78, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
290523	27672265	AIN2/3 is related to HPV in more than 90% of cases, particularly with serotype 16.	('HPV', 'Species', '10566', (21, 24))	('AIN', 'Phenotype', 'HP:0032187', (0, 3))	('HPV', 'Disease', (21, 24))	('serotype 16', 'Var', (70, 81))	('related', 'Reg', (10, 17))
290542	27672265	The slower rate noted for HPV16 in the anus was not surprising because HPV16 appears to be more important than the other hr-HPV types in anal cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('HPV16', 'Species', '333760', (71, 76))	('HPV', 'Species', '10566', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('HPV16', 'Species', '333760', (26, 31))	('HPV16', 'Var', (71, 76))	('HPV', 'Species', '10566', (26, 29))	('HPV', 'Species', '10566', (71, 74))	('anal cancer', 'Phenotype', 'HP:0032186', (137, 148))	('cancer', 'Disease', (142, 148))
290544	27672265	Anal sex behaviours, including anal intercourse, anal touching and lack of condom use during anal sex, were also associated with HPV16 persistence.	('HPV16', 'Gene', (129, 134))	('HPV16', 'Species', '333760', (129, 134))	('anal intercourse', 'Disease', (31, 47))	('anal intercourse', 'Phenotype', 'HP:0030214', (31, 47))	('Anal sex behaviours', 'Phenotype', 'HP:0030214', (0, 19))	('anal sex', 'Phenotype', 'HP:0030214', (93, 101))	('persistence', 'Var', (135, 146))	('Anal sex', 'Disease', (0, 8))	('associated', 'Reg', (113, 123))	('anal touching', 'Disease', (49, 62))
290571	27672265	Serup-Hansen et al found that p16 positivity was a strong independent prognostic factor for improved overall survival (OS) and disease-specific survival (DSS) in patients with anal carcinoma.	('DSS', 'Chemical', '-', (154, 157))	('patients', 'Species', '9606', (162, 170))	('p16', 'Gene', (30, 33))	('positivity', 'Var', (34, 44))	('overall survival', 'MPA', (101, 117))	('p16', 'Gene', '1029', (30, 33))	('carcinoma', 'Disease', 'MESH:D002277', (181, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('improved', 'PosReg', (92, 100))	('disease-specific', 'MPA', (127, 143))	('carcinoma', 'Disease', (181, 190))
290572	27672265	Rodel et al showed that a high HPV16 DNA load was an independent prognostic factor associated with improved locoregional tumour control and overall survival, and they also revealed increased locoregional control in patients with a high p16 labelling score compared to patients with low p16 expression.	('overall survival', 'CPA', (140, 156))	('patients', 'Species', '9606', (215, 223))	('high', 'Var', (231, 235))	('improved', 'PosReg', (99, 107))	('high', 'Var', (26, 30))	('p16', 'Gene', '1029', (286, 289))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('p16', 'Gene', '1029', (236, 239))	('locoregional control', 'CPA', (191, 211))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('HPV16', 'Species', '333760', (31, 36))	('p16', 'Gene', (286, 289))	('tumour', 'Disease', (121, 127))	('increased', 'PosReg', (181, 190))	('patients', 'Species', '9606', (268, 276))	('p16', 'Gene', (236, 239))	('HPV16', 'Gene', (31, 36))
290621	26918602	In rats, marked-ZD (3 mg Zn/kg diet) induces a proliferative esophagus with a 5-microRNA signature (miR-31, -223, -21, -146b, -146a) and promotes ESCC.	('Zn', 'Chemical', 'MESH:D015032', (25, 27))	('promotes', 'PosReg', (137, 145))	('rat', 'Species', '10116', (54, 57))	('rats', 'Species', '10116', (3, 7))	('proliferative', 'CPA', (47, 60))	('rat', 'Species', '10116', (3, 6))	('ESCC', 'Disease', (146, 150))	('induces', 'PosReg', (37, 44))	('miR-31', 'Var', (100, 106))
290622	26918602	Here we report that moderate and mild-ZD (6 and 12 mg Zn/kg diet) also induced esophageal hyperplasia, albeit less pronounced than induced by marked-ZD, with a 2-microRNA signature (miR-31, -146a).	('esophageal hyperplasia', 'Disease', (79, 101))	('mild-ZD', 'Var', (33, 40))	('Zn', 'Chemical', 'MESH:D015032', (54, 56))	('rat', 'Species', '10116', (24, 27))	('esophageal hyperplasia', 'Disease', 'MESH:D006965', (79, 101))
290623	26918602	On exposure to an environmental carcinogen, ~16% of moderate/mild-ZD rats developed ESCC, a cancer incidence significantly greater than for Zn-sufficient rats (0%) (P <= 0.05), but lower than marked-ZD rats (68%) (P < 0.001).	('rats', 'Species', '10116', (202, 206))	('greater', 'PosReg', (123, 130))	('rat', 'Species', '10116', (56, 59))	('cancer', 'Disease', (92, 98))	('ESCC', 'Disease', (84, 88))	('rats', 'Species', '10116', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('rats', 'Species', '10116', (69, 73))	('rat', 'Species', '10116', (154, 157))	('Zn', 'Chemical', 'MESH:D015032', (140, 142))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('rat', 'Species', '10116', (202, 205))	('moderate/mild-ZD', 'Var', (52, 68))	('rat', 'Species', '10116', (69, 72))
290624	26918602	Importantly, the high ESCC, marked-ZD esophagus had a 15-microRNA signature, resembling the human ESCC miRNAome, with miR-223, miR-21, and miR-31 as the top-up-regulated species.	('high ESCC', 'Phenotype', 'HP:0003565', (17, 26))	('miR-31', 'Var', (139, 145))	('miR-223', 'Var', (118, 125))	('miR-21', 'Var', (127, 133))	('15-microRNA signature', 'MPA', (54, 75))	('ZD esophagus', 'Phenotype', 'HP:0100580', (35, 47))	('human', 'Species', '9606', (92, 97))
290626	26918602	Additionally, Fbxw7, Pdcd4, and Stk40 (tumor-suppressor targets of miR-223, -21, and -31) were downregulated in marked-ZD cohort.	('Pdcd4', 'Gene', (21, 26))	('Stk40', 'Gene', '360230', (32, 37))	('Stk40', 'Gene', (32, 37))	('downregulated', 'NegReg', (95, 108))	('Fbxw7', 'Gene', '100360914', (14, 19))	('Fbxw7', 'Gene', (14, 19))	('miR-223', 'Var', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Pdcd4', 'Gene', '64031', (21, 26))	('tumor', 'Disease', (39, 44))
290640	26918602	Alterations in the expression of miRNA genes contribute to the pathogenesis of most human malignancies, including ESCC.	('malignancies', 'Disease', (90, 102))	('expression', 'MPA', (19, 29))	('miRNA genes', 'Gene', (33, 44))	('Alterations', 'Var', (0, 11))	('human', 'Species', '9606', (84, 89))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('rat', 'Species', '10116', (4, 7))	('contribute', 'Reg', (45, 55))
290655	26918602	As shown in the study design (Figure 1A), 191 rats (4-wk-old) were fed diets containing 3, 6, 12, or 60 mg Zn/kg to form respective ZD3T, ZD6T, ZD12T, and ZST (NMBA-treated tumor group, n = 25-27 rats/group), and ZD3, ZD6, ZD12, and ZS (diet group without NMBA treatment, n = 22 rats/group).	('NMBA', 'Chemical', 'MESH:C014707', (160, 164))	('rats', 'Species', '10116', (196, 200))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('Zn', 'Chemical', 'MESH:D015032', (107, 109))	('NMBA', 'Chemical', 'MESH:C014707', (256, 260))	('ZD3', 'Var', (213, 216))	('rats', 'Species', '10116', (279, 283))	('ZD6', 'Var', (218, 221))	('tumor', 'Disease', (173, 178))	('ZD12', 'Var', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('rats', 'Species', '10116', (46, 50))	('ZD3T', 'Var', (132, 136))	('ZD12T', 'Var', (144, 149))	('ZD6T', 'Var', (138, 142))
290659	26918602	First, we determined whether after 5 weeks of dietary regimen, moderate and mild-ZD also increased esophageal cellular proliferation, as did marked-ZD.	('mild-ZD', 'Var', (76, 83))	('rat', 'Species', '10116', (67, 70))	('esophageal cellular proliferation', 'CPA', (99, 132))	('rat', 'Species', '10116', (126, 129))	('increased', 'PosReg', (89, 98))
290661	26918602	ZD6 and ZD12 esophageal epithelia displayed abundant PCNA-positive nuclei in several cell layers, including suprabasal layers, although less prominent compared to ZD3 esophagus.	('PCNA', 'Gene', '25737', (53, 57))	('ZD6', 'Var', (0, 3))	('PCNA', 'Gene', (53, 57))	('esophageal epithelia', 'Disease', (13, 33))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (13, 33))	('ZD12', 'Var', (8, 12))	('esophageal epithelia', 'Disease', 'MESH:D004941', (13, 33))
290663	26918602	The cell proliferation index (% of intensely stained PCNA-positive nuclei) in ZD cohorts, namely, ZD3 (49+-2.9%), ZD6 (39+-2.7%), or ZD12 (31+-4%) esophagus, was significantly greater than ZS esophagus (23+-2.9%) (P < 0.001) (Figure 1B).	('PCNA', 'Gene', '25737', (53, 57))	('cell proliferation index', 'CPA', (4, 28))	('PCNA', 'Gene', (53, 57))	('rat', 'Species', '10116', (16, 19))	('ZD3', 'Var', (98, 101))	('ZD6', 'Var', (114, 117))	('greater', 'PosReg', (176, 183))
290664	26918602	Among the ZD cohorts, ZD3 showed significantly higher PCNA-labeling index than ZD6 or ZD12 esophagus (P < 0.001).	('ZD3', 'Var', (22, 25))	('higher', 'PosReg', (47, 53))	('PCNA', 'Gene', '25737', (54, 58))	('PCNA', 'Gene', (54, 58))
290665	26918602	At the conclusion of the study (22-weeks), ZS esophagus remained nonproliferative, whereas, ZD6 and ZD12 esophagus showed sustained proliferation with PCNA-positive nucleic in focal hyperplastic lesions (FHLs), a result consistent with the highly proliferative ZD3 esophagus, albeit less pronounced (Figure 1B, 22-weeks).	('PCNA', 'Gene', '25737', (151, 155))	('rat', 'Species', '10116', (75, 78))	('PCNA', 'Gene', (151, 155))	('rat', 'Species', '10116', (139, 142))	('focal hyperplastic lesions', 'Disease', (176, 202))	('ZD6', 'Var', (92, 95))	('rat', 'Species', '10116', (254, 257))
290666	26918602	These findings demonstrate that moderate/mild-ZD causes sustained esophageal cellular proliferation.	('moderate/mild-ZD', 'Var', (32, 48))	('rat', 'Species', '10116', (22, 25))	('rat', 'Species', '10116', (36, 39))	('esophageal', 'Disease', (66, 76))	('rat', 'Species', '10116', (93, 96))
290669	26918602	Moderate/mild-ZD rats also had higher body weight than marked-ZD rats, because of reduced food consumption in the latter group.	('rats', 'Species', '10116', (17, 21))	('Moderate/mild-ZD', 'Var', (0, 16))	('rat', 'Species', '10116', (65, 68))	('body weight', 'CPA', (38, 49))	('rats', 'Species', '10116', (65, 69))	('rat', 'Species', '10116', (4, 7))	('rat', 'Species', '10116', (17, 20))	('higher', 'PosReg', (31, 37))	('reduced', 'NegReg', (82, 89))	('food consumption', 'CPA', (90, 106))
290671	26918602	Moderate and mild-ZD groups had similar esophageal tumor incidence (~72%) and multiplicity (~4 tumors/esophagus), results that were significantly lower than those in marked-ZD (100%, 14+-4.5) but greater than ZS rats (29.6%, 0.92+-3.8) (P < 0.001).	('esophageal tumor', 'Disease', (40, 56))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('rats', 'Species', '10116', (212, 216))	('esophageal tumor', 'Phenotype', 'HP:0100751', (40, 56))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('lower', 'NegReg', (146, 151))	('mild-ZD', 'Var', (13, 20))	('multiplicity', 'CPA', (78, 90))	('rat', 'Species', '10116', (212, 215))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('rat', 'Species', '10116', (4, 7))	('esophageal tumor', 'Disease', 'MESH:D004938', (40, 56))	('tumors', 'Disease', (95, 101))
290675	26918602	These data established for the first time that mild and moderate-ZD enhances esophageal tumorigenesis and promotes progression to ESCC.	('progression', 'CPA', (115, 126))	('esophageal tumor', 'Disease', 'MESH:D004938', (77, 93))	('mild', 'Var', (47, 51))	('esophageal tumor', 'Disease', (77, 93))	('ESCC', 'Disease', (130, 134))	('promotes', 'PosReg', (106, 114))	('enhances', 'PosReg', (68, 76))	('rat', 'Species', '10116', (60, 63))	('esophageal tumor', 'Phenotype', 'HP:0100751', (77, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
290677	26918602	Whether moderate and mild-ZD also causes chronic inflammation in the esophagus was evaluated by analyzing the expression of six cancer-associated inflammation genes (S100a8, S100a9, Cxcl5, Ptgs2, Cxcl2, and Ilb1) using quantitative polymerase chain reaction (qPCR).	('Cxcl5', 'Gene', (182, 187))	('S100a9', 'Gene', (174, 180))	('Ptgs2', 'Gene', '29527', (189, 194))	('cancer', 'Disease', (128, 134))	('inflammation', 'Disease', 'MESH:D007249', (146, 158))	('moderate', 'Var', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('inflammation', 'Disease', 'MESH:D007249', (49, 61))	('Cxcl2', 'Gene', (196, 201))	('rat', 'Species', '10116', (12, 15))	('Ptgs2', 'Gene', (189, 194))	('inflammation', 'Disease', (146, 158))	('mild-ZD', 'Var', (21, 28))	('S100a8', 'Gene', (166, 172))	('inflammation', 'Disease', (49, 61))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('inflammation in the esophagus', 'Phenotype', 'HP:0100633', (49, 78))	('causes', 'Reg', (34, 40))	('Cxcl5', 'Gene', '60665', (182, 187))	('S100a9', 'Gene', '94195', (174, 180))	('S100a8', 'Gene', '116547', (166, 172))	('Cxcl2', 'Gene', '114105', (196, 201))
290678	26918602	Consistent with our previous study, the high tumor-burden, ZD3T esophagus showed upregulation of all six inflammation genes compared to its ZST counterpart (Figure 2C).	('esophagus', 'Disease', (64, 73))	('inflammation', 'Disease', 'MESH:D007249', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('inflammation', 'Disease', (105, 117))	('tumor', 'Disease', (45, 50))	('ZD3T', 'Var', (59, 63))	('upregulation', 'PosReg', (81, 93))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
290679	26918602	Importantly, ZD6T and ZD12T esophagus also showed statistically significant upregulation of four inflammation genes - S100a8, S100a9, Ptgs2, and Ilb1 (ZD6T vs ZST, ZD12T vs ZST, P < 0.05 to P < 0.001, Figure 2C).	('Ptgs2', 'Gene', (134, 139))	('inflammation', 'Disease', 'MESH:D007249', (97, 109))	('upregulation', 'PosReg', (76, 88))	('ZD12T', 'Var', (22, 27))	('inflammation', 'Disease', (97, 109))	('ZD6T', 'Var', (13, 17))	('ZD12T', 'Var', (164, 169))	('S100a9', 'Gene', '94195', (126, 132))	('Ptgs2', 'Gene', '29527', (134, 139))	('S100a9', 'Gene', (126, 132))	('Ilb1', 'Gene', (145, 149))	('S100a8', 'Gene', (118, 124))	('S100a8', 'Gene', '116547', (118, 124))
290681	26918602	These data establish that moderate/mild-ZD up-regulates key inflammation genes in esophageal tumourigenesis.	('up-regulates', 'PosReg', (43, 55))	('esophageal tumourigenesis', 'Disease', (82, 107))	('moderate/mild-ZD', 'Var', (26, 42))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('rat', 'Species', '10116', (30, 33))	('inflammation', 'Disease', (60, 72))
290690	26918602	These findings show that moderate and mild-ZD induces alterations in miRNA expression, including miR-31 and miR-146a.	('miR-31', 'Var', (97, 103))	('miR-146a', 'Gene', '100314241', (108, 116))	('rat', 'Species', '10116', (29, 32))	('moderate', 'Var', (25, 33))	('alterations', 'Reg', (54, 65))	('miR-146a', 'Gene', (108, 116))	('rat', 'Species', '10116', (58, 61))	('mild-ZD', 'Var', (38, 45))	('miRNA expression', 'MPA', (69, 85))
290691	26918602	Additionally, miRNA signatures distinguish the highly hyperplastic esophageal phenotype induced by marked-ZD from the less hyperplastic esophageal phenotype induced by moderate and mild-ZD.	('rat', 'Species', '10116', (172, 175))	('highly hyperplastic', 'MPA', (47, 66))	('marked-ZD', 'Var', (99, 108))
290693	26918602	ZD tumor miRNA profiles (ZD3T, ZD6T, and ZD12T) were distinctly different from ZS tumor (ZST) profile.	('ZD tumor', 'Disease', (0, 8))	('ZS tumor', 'Disease', (79, 87))	('ZS tumor', 'Disease', 'MESH:D015211', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ZD tumor', 'Disease', 'MESH:D009369', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('ZD12T', 'Var', (41, 46))
290694	26918602	Importantly, the high ESCC-burden, ZD3T esophagus had a 15-miRNA signature that resembled the human ESCC miRNAome.	('high ESCC', 'Phenotype', 'HP:0003565', (17, 26))	('15-miRNA signature', 'MPA', (56, 74))	('human', 'Species', '9606', (94, 99))	('ZD3T', 'Var', (35, 39))
290695	26918602	Among which, miR-31 and miR-223 are oncomiRs for human ESCC.	('miR-223', 'Var', (24, 31))	('human', 'Species', '9606', (49, 54))	('miR-31', 'Var', (13, 19))	('ESCC', 'Disease', (55, 59))
290696	26918602	Thus, moderate and mild-ZD induces alterations in miRNA expression, including miR-31 and miR-223.	('alterations', 'Reg', (35, 46))	('miRNA expression', 'MPA', (50, 66))	('mild-ZD', 'Var', (19, 26))	('rat', 'Species', '10116', (39, 42))	('moderate', 'Var', (6, 14))	('rat', 'Species', '10116', (10, 13))	('miR-223', 'Gene', (89, 96))	('miR-31', 'Gene', (78, 84))
290697	26918602	In addition, our data show that miRNA-signatures can distinguish the divergent ESCC progression in marked-ZD vs moderate/mild-ZD rat cohorts.	('rat', 'Species', '10116', (116, 119))	('rat', 'Species', '10116', (129, 132))	('ESCC', 'Disease', (79, 83))	('marked-ZD', 'Var', (99, 108))
290702	26918602	All 12 cases showed intense to moderate miR-31, miR-223, and miR-21 ISH signal in near serial sections of moderately to poorly differentiated ESCC tumor samples (Figure 5).	('rat', 'Species', '10116', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('miR-223', 'Var', (48, 55))	('ISH signal', 'MPA', (68, 78))	('miR-31', 'MPA', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('ESCC', 'Disease', (142, 146))	('rat', 'Species', '10116', (35, 38))	('miR-21', 'Gene', (61, 67))
290705	26918602	We then determined whether upregulation of oncogenic miR-223, -31, and -21 in ZD3T, ZD6T, and ZD12T esophagus is accompanied by down-regulation of their respective tumor suppressor targets, FXBW7, STK40, and PDCD4, by using qPCR (n = 7-10 rats/group).	('PDCD4', 'Gene', (208, 213))	('tumor', 'Disease', (164, 169))	('ZD12T', 'Var', (94, 99))	('rats', 'Species', '10116', (239, 243))	('PDCD4', 'Gene', '64031', (208, 213))	('STK40', 'Gene', (197, 202))	('upregulation', 'PosReg', (27, 39))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('STK40', 'Gene', '360230', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('down-regulation', 'NegReg', (128, 143))
290707	26918602	Pdcd4 was significantly reduced only in ZD3T and ZD6T esophagus vs its ZST counterpart (*P < 0.05, ***P < 0.001) (Figure 6A).	('ZD3T', 'Var', (40, 44))	('reduced', 'NegReg', (24, 31))	('esophagus', 'Disease', (54, 63))	('Pdcd4', 'Gene', '64031', (0, 5))	('ZD6T', 'Var', (49, 53))	('Pdcd4', 'Gene', (0, 5))
290716	26918602	That the three tumor suppressor targets are predicted to interact to alter network of cancer-related proteins provide support that miR-223, miR-21, and miR-31 have an important role in ESCC and may be useful therapeutic targets in ESCC.	('miR-21', 'Var', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('miR-31', 'Var', (152, 158))	('miR-223', 'Var', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('ESCC', 'Disease', (185, 189))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
290717	26918602	In humans, low dietary Zn intake is associated with an increased risk of ESCC.	('Zn', 'Chemical', 'MESH:D015032', (23, 25))	('ESCC', 'Disease', (73, 77))	('humans', 'Species', '9606', (3, 9))	('low dietary', 'Var', (11, 22))
290719	26918602	Using a well-characterized ZD rat esophageal cancer model, the current study demonstrates for the first time that ESCC initiation and progression, as well as miRNA dysregulation, depend on the extent of deficiency of dietary Zn.	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('ESCC', 'Disease', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('miRNA dysregulation', 'MPA', (158, 177))	('rat', 'Species', '10116', (84, 87))	('deficiency', 'Var', (203, 213))	('Zn', 'Chemical', 'MESH:D015032', (225, 227))	('rat', 'Species', '10116', (30, 33))
290724	26918602	Although marked-ZD led to significantly higher tumor/ESCC incidence than moderate or mild-ZD, no statistically significant difference was obtained in tumor or ESCC outcome between moderate-ZD and mild-ZD, despite a two-fold difference in Zn content.	('higher', 'PosReg', (40, 46))	('marked-ZD', 'Var', (9, 18))	('rat', 'Species', '10116', (77, 80))	('rat', 'Species', '10116', (184, 187))	('Zn', 'Chemical', 'MESH:D015032', (238, 240))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (47, 52))
290725	26918602	Additionally, they provide the first evidence that moderate to mild-ZD, combined with low doses of the environmental carcinogen NMBA, produces ESCC.	('rat', 'Species', '10116', (55, 58))	('NMBA', 'Chemical', 'MESH:C014707', (128, 132))	('ESCC', 'Disease', (143, 147))	('moderate', 'Var', (51, 59))
290727	26918602	Using the nanoString platform, miRNA expression profiles distinguished the highly preneoplastic/proliferative marked-ZD esophageal phenotype with a 5-miRNA signature (miR-31, -223, -21, -146b, -146a), from the less proliferative, mild-ZD phenotype with a 3-miRNA signature (miR-146a, -31, -223).	('esophageal', 'Disease', (120, 130))	('rat', 'Species', '10116', (103, 106))	('miR-31', 'Var', (167, 173))	('rat', 'Species', '10116', (222, 225))	('miR-146a', 'Gene', '100314241', (274, 282))	('miR-146a', 'Gene', (274, 282))
290729	26918602	In addition, miR-223 and miR-31 dysregulation is common to marked-ZD and moderate/mild-ZD tumor groups (Figure 4A).	('miR-223', 'Gene', (13, 20))	('dysregulation', 'Var', (32, 45))	('miR-31', 'Gene', (25, 31))	('rat', 'Species', '10116', (77, 80))	('ZD tumor', 'Disease', 'MESH:D009369', (87, 95))	('ZD tumor', 'Disease', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))
290733	26918602	In ESCC, patients with high miR-223 expression have a significantly poorer prognosis, presumably because of repression of the function of its tumor suppressor target FBXW7.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('high', 'Var', (23, 27))	('poorer', 'NegReg', (68, 74))	('tumor', 'Disease', (142, 147))	('miR-223', 'Gene', (28, 35))	('ESCC', 'Disease', (3, 7))	('repression', 'NegReg', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('expression', 'MPA', (36, 46))
290748	26918602	Weanling male rats were randomly divided into 4 dietary groups (ZD3, ZD6, ZD12, and ZS, n = 47-49 rats/group) and were tail-tattooed for identification.	('ZD3', 'Var', (64, 67))	('rats', 'Species', '10116', (98, 102))	('ZD12', 'Var', (74, 78))	('rats', 'Species', '10116', (14, 18))
290749	26918602	ZD rats were fed ad libitum and ZS rats were pair-fed to ZD6 animals to match the decreased food consumption of ZD6 rats.	('ZD6', 'Var', (112, 115))	('rats', 'Species', '10116', (116, 120))	('rats', 'Species', '10116', (3, 7))	('rats', 'Species', '10116', (35, 39))	('decreased', 'NegReg', (82, 91))
290767	26918602	Following deparaffinization, rehydration in graded alcohol and proteinase K treatment, tissue sections were hybridized with miR-31 probe (20 nM), miR-223 or miR-21 probe (50 nM) in hybridization buffer (Exiqon) at 50 C - 57 C for 14 h in a hybridizer (Dako, Glostrup, Denmark).	('miR-31', 'Var', (124, 130))	('miR-223', 'Var', (146, 153))	('paraffin', 'Chemical', 'MESH:D010232', (12, 20))	('alcohol', 'Chemical', 'MESH:D000438', (51, 58))	('rat', 'Species', '10116', (34, 37))
290787	23319971	The TSLC1 inhibited cell proliferation significantly in MTT assay, and the cell proliferation was slower in TTG than MG and UTG.	('TTG', 'Chemical', '-', (108, 111))	('MG', 'Chemical', '-', (117, 119))	('TSLC1', 'Gene', (4, 9))	('cell proliferation', 'CPA', (20, 38))	('MTT', 'Chemical', '-', (56, 59))	('slower', 'NegReg', (98, 104))	('inhibited', 'NegReg', (10, 19))	('TTG', 'Var', (108, 111))	('TSLC1', 'Gene', '23705', (4, 9))	('UTG', 'Chemical', '-', (124, 127))	('cell proliferation', 'CPA', (75, 93))
290788	23319971	After TSLC1 transfection, cell numbers increased in G0/G1 phase and decreased in S phase.	('TSLC1', 'Gene', (6, 11))	('S phase', 'CPA', (81, 88))	('decreased', 'NegReg', (68, 77))	('G0/G1 phase', 'CPA', (52, 63))	('increased', 'PosReg', (39, 48))	('cell numbers', 'CPA', (26, 38))	('transfection', 'Var', (12, 24))	('TSLC1', 'Gene', '23705', (6, 11))
290789	23319971	Forty-eight hours after transfection, the apoptosis rate and death rate of TTG were higher than MG and UTG.	('MG', 'Chemical', '-', (96, 98))	('TTG', 'Chemical', '-', (75, 78))	('apoptosis rate', 'CPA', (42, 56))	('UTG', 'Chemical', '-', (103, 106))	('death rate', 'CPA', (61, 71))	('higher', 'PosReg', (84, 90))	('TTG', 'Var', (75, 78))
290796	23319971	It has been found that the lack of TSLC1 expression is closely related to the occurrence and progression of these cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('TSLC1', 'Gene', '23705', (35, 40))	('expression', 'MPA', (41, 51))	('TSLC1', 'Gene', (35, 40))	('lack', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('related', 'Reg', (63, 70))
290833	23319971	It indicated that the cell proliferation was slower in TTG than both MG and UTG (p < 0.05, Table I).	('TTG', 'Chemical', '-', (55, 58))	('UTG', 'Chemical', '-', (76, 79))	('MG', 'Chemical', '-', (69, 71))	('slower', 'NegReg', (45, 51))	('TTG', 'Var', (55, 58))	('cell proliferation', 'CPA', (22, 40))
290854	23319971	In the current study, Eca109 cells were inhibited by the TSLC1 gene compared with the other two groups according to morphological changes.	('Eca109 cells', 'CPA', (22, 34))	('gene', 'Var', (63, 67))	('inhibited', 'NegReg', (40, 49))	('TSLC1', 'Gene', '23705', (57, 62))	('TSLC1', 'Gene', (57, 62))
290889	20431761	The body mass index (BMI) was calculated as the ratio of weight (kg) to the square of the height (m2), and according to the modified WHO criteria for the Asia-Pacific guidelines categorized as follows: normal (less than 23 kg/m2), overweight (23-24.9 kg/m2), and obese (more than 25 kg/m2).	('obese', 'Disease', 'MESH:D009765', (263, 268))	('overweight', 'Phenotype', 'HP:0025502', (231, 241))	('obese', 'Disease', (263, 268))	('more than 25', 'Var', (270, 282))	('23-24.9 kg/m2', 'Var', (243, 256))
291040	27053347	Taxanes are radiosensitizers and are efficacious against esophageal carcinoma; hence, the combination with RT likely produces a potent antineoplastic effect in esophageal cancer.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (57, 77))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (57, 77))	('combination', 'Var', (90, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('esophageal cancer', 'Disease', (160, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('Taxanes', 'Chemical', 'MESH:D043823', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('esophageal carcinoma', 'Disease', (57, 77))	('antineoplastic effect', 'MPA', (135, 156))
291093	33362370	Other causes include hepatic amyloidosis, a1-antitrypsin deficiency, hepatic porphyrian, parasitic infections mainly including schistosomiasis and clonorchiosis, circulatory disturbance such as Budd-Chiari syndrome, and right heart failure.	('infection', 'Disease', (99, 108))	('infection', 'Disease', 'MESH:D007239', (99, 108))	('Budd-Chiari syndrome', 'Disease', (194, 214))	('schistosomiasis', 'Disease', (127, 142))	('heart failure', 'Phenotype', 'HP:0001635', (226, 239))	('hepatic porphyrian', 'Disease', 'MESH:D056486', (69, 87))	('antitrypsin deficiency', 'Phenotype', 'HP:0032025', (45, 67))	('schistosomiasis', 'Disease', 'MESH:D012552', (127, 142))	('parasitic infections', 'Phenotype', 'HP:0030885', (89, 109))	('Budd-Chiari syndrome', 'Disease', 'MESH:D006502', (194, 214))	('hepatic amyloidosis', 'Disease', (21, 40))	('hepatic amyloidosis', 'Phenotype', 'HP:0012280', (21, 40))	('right heart failure', 'Disease', (220, 239))	('parasitic infections', 'Disease', (89, 109))	('circulatory disturbance', 'Disease', (162, 185))	('parasitic infections', 'Disease', 'MESH:D010272', (89, 109))	('right heart failure', 'Phenotype', 'HP:0001708', (220, 239))	('amyloidosis', 'Phenotype', 'HP:0011034', (29, 40))	('clonorchiosis', 'Disease', (147, 160))	('Budd-Chiari syndrome', 'Phenotype', 'HP:0002639', (194, 214))	('hepatic amyloidosis', 'Disease', 'MESH:D000686', (21, 40))	('deficiency', 'Var', (57, 67))	('a1-antitrypsin', 'Protein', (42, 56))	('hepatic porphyrian', 'Disease', (69, 87))	('infections', 'Disease', 'MESH:D007239', (99, 109))	('infections', 'Disease', (99, 109))	('right heart failure', 'Disease', 'MESH:D006333', (220, 239))
291127	33362370	CKD is defined as an eGFR level of < 60 mL/min/1.73 m2 for 3 mo regardless of the structural injury of the kidneys.	('CKD', 'Phenotype', 'HP:0012622', (0, 3))	('CKD', 'Var', (0, 3))	('structural injury of the kidneys', 'Disease', 'MESH:D058186', (82, 114))	('structural injury of the kidneys', 'Disease', (82, 114))
291199	30272328	Intron-pairing introns can trigger exon circularization.	('circ', 'Chemical', '-', (40, 44))	('trigger', 'Reg', (27, 34))	('exon circularization', 'MPA', (35, 55))	('Intron-pairing introns', 'Var', (0, 22))
291200	30272328	In addition, the human genome contains a mass of complementary sequences whose pairing can produce diverse circRNAs by alternative circularization.	('men', 'Species', '9606', (55, 58))	('human', 'Species', '9606', (17, 22))	('pairing', 'Var', (79, 86))	('produce', 'Reg', (91, 98))	('circ', 'Chemical', '-', (107, 111))	('circ', 'Chemical', '-', (131, 135))
291233	30272328	Zhang et al and Memczak et al demonstrated that circRNAs could regulate parental gene expression, and that circRNAs are widely detected in the nuclei with a small concentration on miRNA targets; most notably, inhibition of ciRNAs may have led to the reduced expression of their parental genes.	('expression', 'MPA', (258, 268))	('inhibition', 'Var', (209, 219))	('circ', 'Chemical', '-', (48, 52))	('regulate', 'Reg', (63, 71))	('ciRNAs', 'Gene', (223, 229))	('reduced', 'NegReg', (250, 257))	('miR', 'Gene', '220972', (180, 183))	('circ', 'Chemical', '-', (107, 111))	('miR', 'Gene', (180, 183))
291236	30272328	Thus, knockout of ci-ankrd52 may reduce parental gene expression.	('reduce', 'NegReg', (33, 39))	('ankrd52', 'Gene', (21, 28))	('ankrd52', 'Gene', '283373', (21, 28))	('knockout', 'Var', (6, 14))	('parental gene expression', 'MPA', (40, 64))
291239	30272328	Previous studies have demonstrated that circRNAs can act as sponges for RBPs by stably binding with trinucleotide repeat containing 6A, RNA quaking homolog KH domain containing RNA binding, mannose binding lectin, AGO proteins, Pol II, and eukaryotic initiation factor 4A-III, to form RNA-protein complexes (RPCs).	('mannose', 'Chemical', 'MESH:D008358', (190, 197))	('trinucleotide repeat', 'Var', (100, 120))	('RBP', 'Gene', '27303', (72, 75))	('binding', 'Interaction', (87, 94))	('eukaryotic initiation factor 4A-III', 'Gene', (240, 275))	('RBP', 'Gene', (72, 75))	('trinucleotide', 'Chemical', '-', (100, 113))	('eukaryotic initiation factor 4A-III', 'Gene', '9775', (240, 275))	('circ', 'Chemical', '-', (40, 44))
291251	30272328	For the first time, Yang et al recently reported that N6-methyladenosine (m6A) is the most common and abundant base modification of RNA and promotes the protein translation of circRNAs in the human body.	('m6A', 'Chemical', 'MESH:C010223', (74, 77))	('human', 'Species', '9606', (192, 197))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (54, 72))	('N6-methyladenosine', 'Var', (54, 72))	('promotes', 'PosReg', (140, 148))	('circ', 'Chemical', '-', (176, 180))	('protein translation', 'MPA', (153, 172))
291252	30272328	The group demonstrated that m6A motifs contained many circRNAs and only one m6A was required to drive translation initiation.	('m6A', 'Var', (28, 31))	('m6A', 'Chemical', 'MESH:C010223', (76, 79))	('m6A', 'Chemical', 'MESH:C010223', (28, 31))	('circRNAs', 'MPA', (54, 62))	('circ', 'Chemical', '-', (54, 58))
291279	30272328	The expression of an miRNA is dysregulated via different mechanisms in humans, such as miRNA gene amplification or deletion, the abnormal transcriptional regulation of miRNAs, and epigenetic changes in miRNA generation.	('deletion', 'Var', (115, 123))	('abnormal', 'Reg', (129, 137))	('humans', 'Species', '9606', (71, 77))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (168, 171))	('miR', 'Gene', (202, 205))	('miR', 'Gene', (21, 24))	('gene amplification', 'Var', (93, 111))	('miR', 'Gene', '220972', (202, 205))	('transcriptional regulation', 'MPA', (138, 164))	('miR', 'Gene', '220972', (87, 90))	('epigenetic changes', 'Var', (180, 198))	('miR', 'Gene', (87, 90))
291281	30272328	Compared to normal tissues, circRNAs were usually downregulated in tumor tissues and circRNA levels were significantly associated with clinical features including staging, age, gender and distant metastasis, due to errors in the back-splicing machinery of malignant tumors, the dysregulation of miRNAs due to the degradation of circRNAs in cancerous tissues, or the reduction in circRNAs as a result of increasing cell proliferation.	('cell proliferation', 'CPA', (414, 432))	('cancer', 'Disease', 'MESH:D009369', (340, 346))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (266, 271))	('increasing', 'PosReg', (403, 413))	('associated', 'Reg', (119, 129))	('malignant tumors', 'Disease', 'MESH:D018198', (256, 272))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('errors', 'Var', (215, 221))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('circ', 'Chemical', '-', (379, 383))	('malignant tumors', 'Disease', (256, 272))	('miR', 'Gene', '220972', (295, 298))	('circ', 'Chemical', '-', (85, 89))	('distant metastasis', 'CPA', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('dysregulation', 'Var', (278, 291))	('circ', 'Chemical', '-', (28, 32))	('cancer', 'Disease', (340, 346))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('circ', 'Chemical', '-', (328, 332))	('miR', 'Gene', (295, 298))	('downregulated', 'NegReg', (50, 63))
291285	30272328	Hsa_circ_002059, a representative circRNA, was observed to be downregulated in 101 gastric cancer tissues.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('circ', 'Chemical', '-', (4, 8))	('downregulated', 'NegReg', (62, 75))	('circ', 'Chemical', '-', (34, 38))	('gastric cancer', 'Disease', (83, 97))	('Hsa_circ_002059', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))
291291	30272328	Therefore, the abnormal expression of circPVT1 may reduce the anticancer effect of E2F2 and miR-125b.	('E2F2', 'Gene', '1870', (83, 87))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('circPVT1', 'Gene', (38, 46))	('abnormal expression', 'Var', (15, 34))	('reduce', 'NegReg', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('E2F2', 'Gene', (83, 87))	('cancer', 'Disease', (66, 72))
291292	30272328	Furthermore, circPVT1 was shown to facilitate the colony formation of gastric cancer by inhibiting miR-125.	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('colony formation', 'CPA', (50, 66))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('facilitate', 'PosReg', (35, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('circPVT1', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('inhibiting', 'NegReg', (88, 98))	('gastric cancer', 'Disease', (70, 84))
291294	30272328	Furthermore, the knockdown of hsa_circ_0000096 by siRNA has been observed to significantly inhibit cell proliferation and migration both in vitro and in vivo, and it also was found to suppress the progression of the cell cycle, arresting the S phase of cell transition from G0/G1 in gastric cancer cells.	('gastric cancer', 'Disease', (283, 297))	('inhibit', 'NegReg', (91, 98))	('hsa_circ_0000096', 'Var', (30, 46))	('arresting', 'PosReg', (228, 237))	('S phase of cell transition', 'CPA', (242, 268))	('gastric cancer', 'Disease', 'MESH:D013274', (283, 297))	('suppress', 'NegReg', (184, 192))	('circ', 'Chemical', '-', (34, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (283, 297))	('knockdown', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('progression', 'CPA', (197, 208))
291295	30272328	In addition, knockdown of hsa_circ_0000096 has been observed to suppress tumor growth in xenograft nude mouse models.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('hsa_circ_0000096', 'Gene', (26, 42))	('circ', 'Chemical', '-', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('suppress', 'NegReg', (64, 72))	('mouse', 'Species', '10090', (104, 109))	('tumor', 'Disease', (73, 78))	('knockdown', 'Var', (13, 22))
291299	30272328	The circRNA databases have revealed that hsa_circ_0000096 can bind with 17 different miRNAs.	('bind', 'Interaction', (62, 66))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('hsa_circ_0000096', 'Var', (41, 57))	('circ', 'Chemical', '-', (4, 8))	('circ', 'Chemical', '-', (45, 49))
291301	30272328	These previous studies have presented the clinical implications of hsa_circ_002059 and hsa_circ_0000096 as biomarkers, as determing their expression level is able to distinguish between normal gastric mucosa and gastric cancer tissue.	('distinguish', 'Reg', (166, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (212, 226))	('circ', 'Chemical', '-', (71, 75))	('expression level', 'MPA', (138, 154))	('circ', 'Chemical', '-', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('hsa_circ_002059', 'Var', (67, 82))	('hsa_circ_0000096', 'Var', (87, 103))	('gastric cancer', 'Disease', (212, 226))	('gastric cancer', 'Disease', 'MESH:D013274', (212, 226))
291312	30272328	Yao et al confirmed that in tissues from 101 patients with non-small cell lung cancer (NSCLC), circRNA_100876 was significantly upregulated when compared with the corresponding adjacent normal lung tissues.	('NSCLC', 'Disease', (87, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('circ', 'Chemical', '-', (95, 99))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('patients', 'Species', '9606', (45, 53))	('non-small cell lung cancer', 'Disease', (59, 85))	('upregulated', 'PosReg', (128, 139))	('circRNA_100876', 'Var', (95, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))
291313	30272328	Among the estimated clinicopathological results, the overexpression of circRNA_100876 was significantly associated with regional lymph node metastasis and advanced stages of the tumor.	('tumor', 'Disease', (178, 183))	('circ', 'Chemical', '-', (71, 75))	('overexpression', 'PosReg', (53, 67))	('regional lymph node metastasis', 'CPA', (120, 150))	('associated', 'Reg', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('circRNA_100876', 'Var', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
291314	30272328	Patients with NSCLC and elevated circRNA_100876 expression exhibited notably shorter overall survival than those with low expression.	('circ', 'Chemical', '-', (33, 37))	('NSCLC', 'Disease', (14, 19))	('overall survival', 'MPA', (85, 101))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (77, 84))	('circRNA_100876 expression', 'Var', (33, 58))
291315	30272328	This therefore suggested that circ_100876 may be a potential biomarker for tumor cell proliferation, progression and metastasis in NSCLC.	('NSCLC', 'Disease', (131, 136))	('circ_100876', 'Chemical', '-', (30, 41))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('circ_100876', 'Var', (30, 41))	('tumor', 'Disease', (75, 80))
291319	30272328	It has also been suggested that the aberrant expression of circ-ITCH may inhibit the expression of the target genes c-Myc and cyclin D1 of the Wnt/beta-catenin signaling pathway.	('aberrant expression', 'Var', (36, 55))	('ITCH', 'Gene', (64, 68))	('expression', 'MPA', (85, 95))	('beta-catenin', 'Gene', '1499', (147, 159))	('-ITCH', 'Phenotype', 'HP:0000989', (63, 68))	('circ', 'Chemical', '-', (59, 63))	('cyclin D1', 'Gene', '595', (126, 135))	('c-Myc', 'Gene', '4609', (116, 121))	('ITCH', 'Phenotype', 'HP:0000989', (64, 68))	('cyclin D1', 'Gene', (126, 135))	('beta-catenin', 'Gene', (147, 159))	('ITCH', 'Gene', '83737', (64, 68))	('c-Myc', 'Gene', (116, 121))	('inhibit', 'NegReg', (73, 80))
291326	30272328	hsa_circ_001569 has been demonstrated to promote CRC cell proliferation and invasion by blocking the downregulation of E2F5/BAG4/FMNL2 by miR-145.	('E2F5', 'Gene', '1875', (119, 123))	('E2F5', 'Gene', (119, 123))	('miR-145', 'Gene', '406937', (138, 145))	('hsa_circ_001569', 'Var', (0, 15))	('CRC cell proliferation', 'CPA', (49, 71))	('circ', 'Chemical', '-', (4, 8))	('downregulation', 'MPA', (101, 115))	('promote', 'PosReg', (41, 48))	('blocking', 'NegReg', (88, 96))	('miR-145', 'Gene', (138, 145))	('invasion', 'CPA', (76, 84))
291327	30272328	Subsequently, the group revealed that hsa_circ_001569 promotes cell proliferation by increasing the number of S and G2/M phase cells in the cell cycle.	('hsa_circ_001569', 'Var', (38, 53))	('increasing', 'PosReg', (85, 95))	('cell proliferation', 'CPA', (63, 81))	('circ', 'Chemical', '-', (42, 46))	('promotes', 'PosReg', (54, 62))
291329	30272328	Notably, unlike the other circRNAs that have been mentioned, hsa_circ_001569 may directly inhibit the transcriptional activity of miR-145, rather than inhibiting its expression.	('transcriptional activity', 'MPA', (102, 126))	('inhibit', 'NegReg', (90, 97))	('circ', 'Chemical', '-', (26, 30))	('miR-145', 'Gene', (130, 137))	('men', 'Species', '9606', (50, 53))	('inhibiting', 'NegReg', (151, 161))	('circ', 'Chemical', '-', (65, 69))	('miR-145', 'Gene', '406937', (130, 137))	('hsa_circ_001569', 'Var', (61, 76))	('expression', 'MPA', (166, 176))
291332	30272328	Furthermore, the expression of phosphorylated (p)-protein kinase B (Akt) was downregulated via this knockout, indicating that it may be involved in the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway, which is known to have roles in controlling cancer cell survival and the cell cycle.	('downregulated', 'NegReg', (77, 90))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('involved', 'Reg', (136, 144))	('Akt', 'Gene', '207', (68, 71))	('cancer', 'Disease', (252, 258))	('expression', 'MPA', (17, 27))	('knockout', 'Var', (100, 108))	('Akt', 'Gene', '207', (185, 188))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Akt', 'Gene', (68, 71))	('Akt', 'Gene', (185, 188))
291333	30272328	Guo et al demonstrated that hsa_circ_0000069 was also overexpressed in CRC, as determined by unsupervised hierarchical cluster analysis.	('CRC', 'Disease', (71, 74))	('circ', 'Chemical', '-', (32, 36))	('overexpressed', 'PosReg', (54, 67))	('hsa_circ_0000069', 'Var', (28, 44))
291334	30272328	Inhibition of hsa_circ_0000069 with siRNA may suppress cell proliferation, migration and invasion, as well as induce HT-29 cell arrest at the G0/G1 phase of the cell cycle.	('HT-29', 'Gene', (117, 122))	('suppress', 'NegReg', (46, 54))	('cell proliferation', 'CPA', (55, 73))	('induce', 'PosReg', (110, 116))	('circ', 'Chemical', '-', (18, 22))	('Inhibition', 'Var', (0, 10))	('HT-29', 'CellLine', 'CVCL:0320', (117, 122))	('migration', 'CPA', (75, 84))
291335	30272328	Hsa_circ_001988 was also found to be downregulated in CRC cell lines when compared with normal samples in 31 matched CRC tissues and non-cancerous colon mucosa.	('Hsa_circ_001988', 'Var', (0, 15))	('downregulated', 'NegReg', (37, 50))	('non-cancerous colon mucosa', 'Disease', 'MESH:D015179', (133, 159))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('non-cancerous colon mucosa', 'Disease', (133, 159))	('Hsa_circ_001988', 'Chemical', '-', (0, 15))	('CRC cell lines', 'CPA', (54, 68))
291338	30272328	These results indicate that hsa_circ_001988 may be a potential new biomarker of CRC prognosis.	('circ', 'Chemical', '-', (32, 36))	('CRC', 'Disease', (80, 83))	('hsa_circ_001988', 'Var', (28, 43))
291345	30272328	Previous studies have reported that several circRNAs, including hsa_circ_001059, hsa_circ_000167, hsa_circ_0067934, and circ-ITCH, may be involved in cancer-associated mortality in esophageal squamous cell carcinoma (ESCC).	('hsa_circ_000167', 'Var', (81, 96))	('circ', 'Chemical', '-', (120, 124))	('ITCH', 'Phenotype', 'HP:0000989', (125, 129))	('-ITCH', 'Phenotype', 'HP:0000989', (124, 129))	('hsa_circ_001059', 'Var', (64, 79))	('circ', 'Chemical', '-', (102, 106))	('hsa_circ_0067934', 'Var', (98, 114))	('cancer', 'Disease', (150, 156))	('ITCH', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('circ', 'Chemical', '-', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('circ', 'Chemical', '-', (68, 72))	('esophageal squamous cell carcinoma', 'Disease', (181, 215))	('circ', 'Chemical', '-', (85, 89))	('ITCH', 'Gene', '83737', (125, 129))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('involved', 'Reg', (138, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (181, 215))
291351	30272328	When considering other clinical factors, lymph node metastasis or tumor size was not associated with the expression of hsa_circ_0067934.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('circ', 'Chemical', '-', (123, 127))	('tumor', 'Disease', (66, 71))	('hsa_circ_0067934', 'Var', (119, 135))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
291352	30272328	Notably, TNM staging was applied to assess patient prognosis, and it is possible that hsa_circ_0067934 may also have the potential to become a biomarker for diagnosing ESCC.	('circ', 'Chemical', '-', (90, 94))	('hsa_circ_0067934', 'Var', (86, 102))	('ESCC', 'Disease', (168, 172))	('patient', 'Species', '9606', (43, 50))
291357	30272328	Generally, DCIS is deemed to be highly curable; however, some women with DCIS unfortunately suffer from the life-threatening type of invasive breast cancer, invasive ductal cancer (IDC); even though the invasive factors of progression remain unclear.	('suffer from', 'Reg', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('invasive breast cancer', 'Disease', 'MESH:D001943', (133, 155))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('DCIS', 'Var', (73, 77))	('invasive ductal cancer', 'Disease', 'MESH:D018270', (157, 179))	('invasive ductal cancer', 'Disease', (157, 179))	('invasive breast cancer', 'Disease', (133, 155))	('women', 'Species', '9606', (62, 67))
291360	30272328	hsa-circ-0001358 was found to be associated with five miRNAs, miR-200c-3p, miR-200b-3p, miR-376a-3p, miR-376b-3p and miR-429, as determined by the Starbase human Pan Cancer tool.	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (54, 57))	('miR', 'Gene', (117, 120))	('miR', 'Gene', (101, 104))	('Cancer', 'Disease', 'MESH:D009369', (166, 172))	('miR', 'Gene', (75, 78))	('miR-200b', 'Gene', '406984', (75, 83))	('miR-429', 'Gene', '554210', (117, 124))	('miR', 'Gene', '220972', (88, 91))	('miR', 'Gene', '220972', (62, 65))	('circ', 'Chemical', '-', (4, 8))	('hsa-circ-0001358', 'Var', (0, 16))	('miR', 'Gene', (88, 91))	('Cancer', 'Phenotype', 'HP:0002664', (166, 172))	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (62, 65))	('miR-200b', 'Gene', (75, 83))	('miR', 'Gene', '220972', (117, 120))	('miR-429', 'Gene', (117, 124))	('Cancer', 'Disease', (166, 172))	('human', 'Species', '9606', (156, 161))	('miR', 'Gene', '220972', (101, 104))
291366	30272328	Overexpression of circ-Foxo3 was found to significantly reduce proliferation and cell survival in the breast cancer cell line, MDA-MB-231.	('breast cancer', 'Disease', (102, 115))	('proliferation', 'CPA', (63, 76))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (127, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('circ', 'Chemical', '-', (18, 22))	('reduce', 'NegReg', (56, 62))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('circ-Foxo3', 'Var', (18, 28))	('cell survival', 'CPA', (81, 94))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
291367	30272328	Du et al injected MDA-MB-231 cells transfected with circ-Foxo3 subcutaneously in nude mice, demonstrating that circ-Foxo3 suppressed tumor growth.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('suppressed', 'NegReg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('nude mice', 'Species', '10090', (81, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (18, 28))	('circ', 'Chemical', '-', (52, 56))	('tumor', 'Disease', (133, 138))	('circ', 'Chemical', '-', (111, 115))	('circ-Foxo3', 'Var', (111, 121))
291375	30272328	Of the three mentioned above that were further verified through RT-qPCR, hsa_circ_0005075 was significantly associated with a number of clinicopathological factors of HCC patients.	('HCC', 'Gene', (167, 170))	('circ', 'Chemical', '-', (77, 81))	('hsa_circ_0005075', 'Var', (73, 89))	('patients', 'Species', '9606', (171, 179))	('HCC', 'Gene', '619501', (167, 170))	('associated', 'Reg', (108, 118))	('men', 'Species', '9606', (13, 16))
291377	30272328	Furthermore, larger liver cancer tumors were found to exhibit a higher expression level of hsa_circ_0005075 than smaller tumors, demonstrating that hsa_circ_0005075 may regulate tumor growth.	('higher', 'PosReg', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('liver cancer', 'Phenotype', 'HP:0002896', (20, 32))	('tumor', 'Disease', (178, 183))	('liver cancer tumors', 'Disease', 'MESH:D006528', (20, 39))	('circ', 'Chemical', '-', (95, 99))	('tumor', 'Disease', (121, 126))	('larger liver', 'Phenotype', 'HP:0002240', (13, 25))	('expression level', 'MPA', (71, 87))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (33, 38))	('hsa_circ_0005075', 'Var', (91, 107))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('regulate', 'Reg', (169, 177))	('liver cancer tumors', 'Disease', (20, 39))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('circ', 'Chemical', '-', (152, 156))	('tumors', 'Disease', (33, 39))
291378	30272328	Therefore, hsa_circ_0005075 is likely to be a promising biomarker for HCC.	('hsa_circ_0005075', 'Var', (11, 27))	('circ', 'Chemical', '-', (15, 19))	('HCC', 'Gene', (70, 73))	('HCC', 'Gene', '619501', (70, 73))
291382	30272328	It has been hypothesized that hsa_circ_0005075 may act as a miRNA sponge to suppress the expression of miR-23b-5p in cancer.	('hsa_circ_0005075', 'Var', (30, 46))	('expression', 'MPA', (89, 99))	('miR', 'Gene', '220972', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('miR', 'Gene', (60, 63))	('suppress', 'NegReg', (76, 84))	('miR-23b', 'Gene', '407011', (103, 110))	('circ', 'Chemical', '-', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('cancer', 'Disease', (117, 123))	('miR-23b', 'Gene', (103, 110))
291384	30272328	However, further study is required to elucidate the molecular mechanisms underlying the development of HCC and how hsa_circ_0005075 functions as a miRNA sponge.	('circ', 'Chemical', '-', (119, 123))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))	('men', 'Species', '9606', (95, 98))	('hsa_circ_0005075', 'Var', (115, 131))	('HCC', 'Gene', (103, 106))	('HCC', 'Gene', '619501', (103, 106))
291385	30272328	Hsa_circ_0001649 has also been indicated to have decreased expression in HCC tissues, when compared with that observed in adjacent liver tissues.	('HCC', 'Gene', '619501', (73, 76))	('circ', 'Chemical', '-', (4, 8))	('decreased', 'NegReg', (49, 58))	('expression', 'MPA', (59, 69))	('Hsa_circ_0001649', 'Var', (0, 16))	('HCC', 'Gene', (73, 76))
291387	30272328	These results demonstrated that the expression of hsa_circ_0001649 is negatively correlated with the metastasis of HCC and thus, could represent a potential marker of HCC prognosis.	('HCC', 'Gene', '619501', (115, 118))	('negatively', 'NegReg', (70, 80))	('HCC', 'Gene', (167, 170))	('hsa_circ_0001649', 'Var', (50, 66))	('metastasis', 'CPA', (101, 111))	('correlated', 'Reg', (81, 91))	('HCC', 'Gene', '619501', (167, 170))	('HCC', 'Gene', (115, 118))	('expression', 'MPA', (36, 46))	('circ', 'Chemical', '-', (54, 58))
291393	30272328	Using this method, the authors revealed that circ-transcription factor 25 (TCF25), circ-protein tyrosine kinase 2, circ-zinc finger RNA binding protein, and circBC048201 were significantly upregulated, and the two circRNA circ-family with sequence similarity 169 member A and circ-tripartite motif-containing 24 were both downregulated in bladder cancer tissues when compared with paired non-cancerous tissues.	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('non-cancer', 'Disease', (388, 398))	('upregulated', 'PosReg', (189, 200))	('TCF25', 'Gene', (75, 80))	('circ', 'Chemical', '-', (276, 280))	('circ', 'Chemical', '-', (214, 218))	('circ', 'Chemical', '-', (222, 226))	('circ', 'Chemical', '-', (157, 161))	('circ', 'Chemical', '-', (45, 49))	('circ-transcription factor 25', 'Gene', (45, 73))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('circ', 'Chemical', '-', (83, 87))	('bladder cancer', 'Disease', (339, 353))	('bladder cancer', 'Disease', 'MESH:D001749', (339, 353))	('circ', 'Chemical', '-', (115, 119))	('downregulated', 'NegReg', (322, 335))	('TCF25', 'Gene', '22980', (75, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (339, 353))	('non-cancer', 'Disease', 'MESH:D009369', (388, 398))	('circ-transcription factor 25', 'Gene', '22980', (45, 73))	('circBC048201', 'Var', (157, 169))
291398	30272328	Guarnerio et al demonstrated that cancer-associated chromosomal translocations result in the fusion of circRNAs (f-circRNAs), which are produced by the transcriptional exons of different genes that are affected post-translation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('chromosomal translocations', 'Var', (52, 78))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('circ', 'Chemical', '-', (103, 107))	('result in', 'Reg', (79, 88))	('circ', 'Chemical', '-', (115, 119))
291421	30272328	Analysis of laryngeal squamous cell cancers (LSCCs) revealed that hsa_circ_100855 and hsa_circ_104912, among the 698 identified aberrant circRNAs, were markedly upregulated and downregulated, respectively.	('circ', 'Chemical', '-', (137, 141))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('hsa_circ_100855', 'Var', (66, 81))	('upregulated', 'PosReg', (161, 172))	('hsa_circ_104912', 'Var', (86, 101))	('laryngeal squamous cell cancers', 'Disease', 'MESH:D002294', (12, 43))	('laryngeal squamous cell cancers', 'Disease', (12, 43))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (22, 42))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (22, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('circ', 'Chemical', '-', (70, 74))	('circ', 'Chemical', '-', (90, 94))	('downregulated', 'NegReg', (177, 190))
291423	30272328	The results of this previous study indicated that hsa_circ_100855 and hsa_circ_104912 may be potential neoteric biomarkers for the diagnosis and progression of LSCC.	('circ', 'Chemical', '-', (74, 78))	('hsa_circ_104912', 'Var', (70, 85))	('LSCC', 'Disease', (160, 164))	('hsa_circ_100855', 'Var', (50, 65))	('circ', 'Chemical', '-', (54, 58))
291453	30216763	Overexpression of sorcin has been reported to be associated with different cancers such as breast cancer, colorectal cancer, gastric cancer, leukemia, lung cancer, nasopharyngeal cancer, ovarian cancer, etc.	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('colorectal cancer', 'Disease', (106, 123))	('associated', 'Reg', (49, 59))	('lung cancer', 'Disease', (151, 162))	('Overexpression', 'Var', (0, 14))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (164, 185))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('ovarian cancer', 'Disease', (187, 201))	('leukemia', 'Phenotype', 'HP:0001909', (141, 149))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('sorcin', 'Protein', (18, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (164, 185))	('leukemia', 'Disease', 'MESH:D007938', (141, 149))	('leukemia', 'Disease', (141, 149))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Disease', (91, 104))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('nasopharyngeal cancer', 'Disease', (164, 185))
291456	30216763	Sorcin was also found to regulate apoptosis, as silencing of the same resulted in increased levels of proapoptotic genes and induced mitochondrial apoptotic pathway in cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('silencing', 'Var', (48, 57))	('levels of proapoptotic genes', 'MPA', (92, 120))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('induced', 'PosReg', (125, 132))	('mitochondrial apoptotic pathway', 'Pathway', (133, 164))	('increased', 'PosReg', (82, 91))	('cancer', 'Disease', (168, 174))
291457	30216763	Interestingly, mutations in the sorcin gene have been closely linked with poor overall survival in bladder cancer, brain lower-grade glioma, glioblastoma, glioblastoma multiforme, kidney renal clear cell carcinoma, and stomach adenocarcinoma.	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioblastoma', 'Disease', (155, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('glioblastoma', 'Disease', (141, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('poor', 'NegReg', (74, 78))	('mutations', 'Var', (15, 24))	('glioblastoma multiforme', 'Disease', (155, 178))	('stomach adenocarcinoma', 'Disease', (219, 241))	('linked', 'Reg', (62, 68))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (155, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (180, 213))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (219, 241))	('glioma', 'Disease', (133, 139))	('kidney renal clear cell carcinoma', 'Disease', (180, 213))	('bladder cancer', 'Disease', (99, 113))	('sorcin', 'Gene', (32, 38))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))
291473	30216763	In addition, silencing of this protein resulted in apoptosis and reverted MDR of cancer cells, and additionally, sorcin depletion reduced the levels of various proteins involved in angiogenesis, invasion, and metastasis.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('levels of various proteins', 'MPA', (142, 168))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('reduced', 'NegReg', (130, 137))	('depletion', 'MPA', (120, 129))	('MDR of', 'CPA', (74, 80))	('apoptosis', 'CPA', (51, 60))	('silencing', 'Var', (13, 22))
291484	30216763	These five EF-hands were found to pair with each other (EF1 with EF2 and EF3 with EF4).	('EF2', 'Gene', '1938', (65, 68))	('EF4', 'Gene', '60558', (82, 85))	('EF2', 'Gene', (65, 68))	('EF3', 'Var', (73, 76))	('EF4', 'Gene', (82, 85))
291501	30216763	Calcium (Ca2+) plays significant roles in neurons, including synaptic plasticity and apoptosis, and deregulation of this neuronal calcium signaling was known to be one of the central mechanisms of different neurodegenerative diseases such as Alzheimer's disease (AD).	('AD', 'Phenotype', 'HP:0002511', (263, 265))	('deregulation', 'Var', (100, 112))	('AD', 'Disease', 'MESH:D000544', (263, 265))	('AD', 'Disease', (263, 265))	('calcium', 'Chemical', 'MESH:D002118', (130, 137))	('neurodegenerative diseases', 'Disease', (207, 233))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (242, 261))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	("Alzheimer's disease", 'Disease', (242, 261))	('Ca2+', 'Chemical', 'MESH:D000069285', (9, 13))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (207, 233))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (242, 261))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (207, 233))
291503	30216763	Sorcin expression enhances the concentration of calcium in endoplasmic reticulum (ER), inhibits ER stress, and induces the resistance to apoptosis.	('calcium', 'Chemical', 'MESH:D002118', (48, 55))	('concentration of calcium', 'MPA', (31, 55))	('Sorcin', 'Gene', (0, 6))	('inhibits', 'NegReg', (87, 95))	('expression', 'Var', (7, 17))	('induces', 'Reg', (111, 118))	('resistance to apoptosis', 'CPA', (123, 146))	('ER stress', 'MPA', (96, 105))	('enhances', 'PosReg', (18, 26))
291504	30216763	Apart from calcium homeostasis, sorcin was also found to have a key role in the activation of mitosis and cytokinesis as loss of sorcin highly compromised the normal process of mitosis and cytokinesis.	('mitosis', 'Disease', 'None', (94, 101))	('compromised', 'NegReg', (143, 154))	('mitosis', 'Disease', (177, 184))	('loss', 'Var', (121, 125))	('mitosis', 'Disease', 'None', (177, 184))	('calcium', 'Chemical', 'MESH:D002118', (11, 18))	('sorcin', 'Protein', (129, 135))	('mitosis', 'Disease', (94, 101))
291509	30216763	Apart from this, sorcin also targets the sarcolemmal NCX1 (sodium/ calcium exchanger) and induces its expression in the cardiac muscles, and silencing of sorcin by miR-1 helps to regulate the myocardial contraction through calcium signaling.	('calcium', 'Chemical', 'MESH:D002118', (223, 230))	('sorcin', 'Gene', (154, 160))	('silencing', 'Var', (141, 150))	('calcium', 'Chemical', 'MESH:D002118', (67, 74))	('expression', 'MPA', (102, 112))	('induces', 'PosReg', (90, 97))	('myocardial contraction', 'CPA', (192, 214))	('NCX1', 'Gene', (53, 57))	('regulate', 'Reg', (179, 187))	('miR-1', 'Gene', '79187', (164, 169))	('NCX1', 'Gene', '6546', (53, 57))	('calcium signaling', 'MPA', (223, 240))	('miR-1', 'Gene', (164, 169))
291522	30216763	As observed from the cBioPortal for Cancer Genomics data, several mutations of sorcin protein are associated with different kind of cancers including bladder cancer, colorectal adenocarcinoma, prostate adenocarcinoma, skin cutaneous melanoma, sarcoma, and uterine corpus endometrial carcinoma, etc.	('mutations', 'Var', (66, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (223, 241))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colorectal adenocarcinoma, prostate adenocarcinoma', 'Disease', 'MESH:D000230', (166, 216))	('sorcin', 'Gene', (79, 85))	('Cancer', 'Disease', (36, 42))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('endometrial carcinoma', 'Disease', (271, 292))	('protein', 'Protein', (86, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('bladder cancer', 'Disease', 'MESH:D001749', (150, 164))	('bladder cancer', 'Disease', (150, 164))	('sarcoma', 'Disease', 'MESH:D012509', (243, 250))	('sarcoma', 'Disease', (243, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (271, 292))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (218, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('skin cutaneous melanoma', 'Disease', (218, 241))	('associated', 'Reg', (98, 108))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (271, 292))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))
291523	30216763	In line with this, RNA sequencing analysis of patient samples revealed amplification of SRI gene to be associated with various cancers, which was evident from the TCGA cBioPortal database.	('patient', 'Species', '9606', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('associated', 'Reg', (103, 113))	('amplification', 'Var', (71, 84))	('SRI', 'Gene', (88, 91))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('SRI', 'Gene', '6717', (88, 91))	('cancers', 'Disease', (127, 134))
291526	30216763	In addition to gene amplification, different mutations of SRI gene were also reported in the TCGA database, and frequency of SRI gene mutation observed in different cancers is as follows: colorectal cancer 0.16%, uterine cancer 0.36%, prostate cancer 0.4%, and sarcoma 0.38%.	('sarcoma', 'Disease', (261, 268))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('prostate cancer', 'Disease', (235, 250))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (199, 205))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (261, 268))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('uterine cancer', 'Phenotype', 'HP:0010784', (213, 227))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('SRI', 'Gene', '6717', (125, 128))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('cancer', 'Disease', (244, 250))	('SRI', 'Gene', '6717', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('mutation', 'Var', (134, 142))	('SRI', 'Gene', (125, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('SRI', 'Gene', (58, 61))	('prostate cancer', 'Disease', 'MESH:D011471', (235, 250))	('sarcoma', 'Disease', 'MESH:D012509', (261, 268))	('prostate cancer', 'Phenotype', 'HP:0012125', (235, 250))
291528	30216763	As mentioned earlier, according to the TCGA database, sorcin shows different mutations in different cancers such as X84_splice (splice mutation) in bladder cancer, D157N (missense mutation) in colorectal adenocarcinoma, A161T (missense mutation) & Q48*(nonsense mutation) in prostate adenocarcinoma, P28L (missense mutation) & C162F (missense mutation) in skin cutaneous melanoma, Y13Tfs *30(FS del mutation) in sarcoma, and A161T (missense mutation) & R106I (missense mutation) in uterine corpus endometrial carcinoma.	('D157N', 'Var', (164, 169))	('A161T', 'Mutation', 'rs1457132903', (220, 225))	('P28L', 'Mutation', 'p.P28L', (300, 304))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (275, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('A161T', 'Mutation', 'rs1457132903', (425, 430))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (412, 419))	('C162F', 'Mutation', 'p.C162F', (327, 332))	('endometrial carcinoma', 'Disease', (497, 518))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (193, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (509, 518))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (497, 518))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (497, 518))	('melanoma', 'Phenotype', 'HP:0002861', (371, 379))	('X84_splice', 'Var', (116, 126))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (356, 379))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (361, 379))	('skin cutaneous melanoma', 'Disease', (356, 379))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('R106I', 'Mutation', 'p.R106I', (453, 458))	('cancers', 'Disease', (100, 107))	('prostate adenocarcinoma', 'Disease', (275, 298))	('bladder cancer', 'Disease', 'MESH:D001749', (148, 162))	('bladder cancer', 'Disease', (148, 162))	('D157N', 'Mutation', 'rs754279084', (164, 169))	('A161T', 'Var', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('sarcoma', 'Disease', 'MESH:D012509', (412, 419))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('bladder cancer', 'Phenotype', 'HP:0009725', (148, 162))	('colorectal adenocarcinoma', 'Disease', (193, 218))	('sarcoma', 'Disease', (412, 419))	('Y13Tfs *30(FS del', 'Mutation', 'p.13,FSdelT', (381, 398))
291531	30216763	However, in some of the cancers, patients with altered sorcin showed more median month survival such as breast cancer (163.1 months), esophageal carcinoma (44.71 months), head and neck squamous cell carcinoma (71.16 months), ovarian serous cystadenocarcinoma (50.33 months), and skin cutaneous melanoma (297.67 months) (Table 1).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (279, 302))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (134, 154))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (225, 258))	('breast cancer', 'Disease', (104, 117))	('skin cutaneous melanoma', 'Disease', (279, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('altered', 'Var', (47, 54))	('esophageal carcinoma', 'Disease', (134, 154))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (284, 302))	('cancers', 'Disease', (24, 31))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (134, 154))	('neck squamous cell carcinoma', 'Disease', (180, 208))	('more', 'PosReg', (69, 73))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (180, 208))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (225, 258))	('patients', 'Species', '9606', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('ovarian serous cystadenocarcinoma', 'Disease', (225, 258))
291537	30216763	Cancer cells acquire MDR through ABC transporter family, resistance to apoptosis induction, autophagy, cancer stem cells, miRNA, hypoxia, DNA damage and repair, and epigenetic regulation.	('epigenetic', 'Var', (165, 175))	('hypoxia', 'Disease', 'MESH:D000860', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hypoxia', 'Disease', (129, 136))	('MDR', 'Gene', (21, 24))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('autophagy', 'CPA', (92, 101))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
291544	30216763	Silencing of sorcin resulted in the downregulation of these genes in addition to p-Akt and NF-kappaB levels inducing chemoresistance in myeloma cells (Figure 3).	('sorcin', 'Gene', (13, 19))	('downregulation', 'NegReg', (36, 50))	('NF-kappaB', 'Gene', '4790', (91, 100))	('NF-kappaB', 'Gene', (91, 100))	('myeloma', 'Disease', (136, 143))	('inducing', 'Reg', (108, 116))	('p-Akt', 'MPA', (81, 86))	('Silencing', 'Var', (0, 9))	('myeloma', 'Disease', 'MESH:D009101', (136, 143))	('chemoresistance', 'CPA', (117, 132))
291547	30216763	Likewise, chemoresistance to cisplatin in MDR cells is also associated with the co-amplification of sorcin.	('sorcin', 'Protein', (100, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('chemoresistance', 'CPA', (10, 25))	('co-amplification', 'Var', (80, 96))	('associated', 'Reg', (60, 70))
291549	30216763	Similarly, co-amplification of sorcin and MDR1 gene observed in leukemia can be taken as a good indicator of clinical drug resistance and prognosis of the disease.	('leukemia', 'Disease', (64, 72))	('sorcin', 'Gene', (31, 37))	('drug resistance', 'Phenotype', 'HP:0020174', (118, 133))	('MDR1', 'Gene', (42, 46))	('co-amplification', 'Var', (11, 27))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('MDR1', 'Gene', '5243', (42, 46))	('leukemia', 'Disease', 'MESH:D007938', (64, 72))
291550	30216763	Further proving the importance of sorcin in MDR, overexpression of sorcin in K562 cells by gene transfection led to the increase in drug resistance, from 4.1- to 22.5-fold, to various chemotherapeutic drugs such as doxorubicin, etoposide, homoharringtonine, and vincristine.	('K562', 'CellLine', 'CVCL:0004', (77, 81))	('doxorubicin', 'Chemical', 'MESH:D004317', (215, 226))	('drug resistance', 'MPA', (132, 147))	('increase', 'PosReg', (120, 128))	('etoposide', 'Chemical', 'MESH:D005047', (228, 237))	('gene transfection', 'Var', (91, 108))	('vincristine', 'Chemical', 'MESH:D014750', (262, 273))	('drug resistance', 'Phenotype', 'HP:0020174', (132, 147))	('homoharringtonine', 'Chemical', 'MESH:D000077863', (239, 256))	('overexpression', 'PosReg', (49, 63))
291563	30216763	Upregulation of sorcin in malignant cells significantly induces the cell proliferation, migration, and invasion, and knockdown of the same diminished the proliferation, migration, and invasion of cancer cells, revealing the importance of sorcin in the development and progression of cancer.	('Upregulation', 'PosReg', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cell proliferation', 'CPA', (68, 86))	('migration', 'CPA', (169, 178))	('cancer', 'Disease', (283, 289))	('induces', 'PosReg', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('migration', 'CPA', (88, 97))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('sorcin', 'Gene', (16, 22))	('diminished', 'NegReg', (139, 149))	('invasion', 'CPA', (103, 111))	('knockdown', 'Var', (117, 126))
291566	30216763	TCGA data analysis also showed alteration status of sorcin gene to be significantly associated with survival of cancer patients, suggesting the prognostic value of this protein.	('sorcin gene', 'Gene', (52, 63))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (119, 127))	('survival', 'Disease', (100, 108))	('associated', 'Reg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('alteration status', 'Var', (31, 48))
291608	29995243	A combination of 4 circulating miRNAs (miRNA-95-3p, 136-5p, 194-5p and 451a) has been found to distinguish Barrett's patients from controls with a sensitivity and specificity of 78 and 86%, respectively; however, this was an enriched population and a higher specificity is required before such a test can be rolled out in a primary care population for a disease of low prevalence in order to avoid a large number of false positives.	('patients', 'Species', '9606', (117, 125))	('miRNA-95-3p', 'Var', (39, 50))	('distinguish', 'Reg', (95, 106))	('Barrett', 'Disease', (107, 114))
291625	29995243	A multi-target stool DNA (MT-sDNA) test, which combines both mutant and methylated DNA markers and a fecal immunochemical test (FIT), recently performed favorably in a large cross-sectional validation study and has been approved by the US Food and Drug Administration (FDA) for the screening of asymptomatic, average risk individuals for colon cancer.	('colon cancer', 'Disease', (338, 350))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('colon cancer', 'Phenotype', 'HP:0003003', (338, 350))	('mutant', 'Var', (61, 67))	('colon cancer', 'Disease', 'MESH:D015179', (338, 350))
291639	29449271	We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy.	('EGFR', 'Gene', '1956', (178, 182))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('amplification', 'Var', (19, 32))	('EGFR', 'Gene', (178, 182))	('patients', 'Species', '9606', (51, 59))
291641	29449271	Pre and post-treatment tumor NGS, serial plasma ctDNA NGS, and tumor IHC/FISH for EGFR revealed pre-existing and/or acquired genomic events including EGFR negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC and HER2 amplification, and GNAS mutations serving as mechanisms of resistance.	('amplification', 'Var', (235, 248))	('KRAS', 'Gene', (187, 191))	('deletion', 'Var', (177, 185))	('MYC', 'Gene', '4609', (222, 225))	('GNAS', 'Gene', (254, 258))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('NRAS', 'Gene', (216, 220))	('EGFR', 'Gene', '1956', (150, 154))	('HER2', 'Gene', '2064', (230, 234))	('GNAS', 'Gene', '2778', (254, 258))	('PTEN', 'Gene', (172, 176))	('EGFR', 'Gene', (82, 86))	('tumor', 'Disease', (63, 68))	('PTEN', 'Gene', '5728', (172, 176))	('tumor IHC', 'Disease', 'MESH:D009369', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor IHC', 'Disease', (63, 72))	('HER2', 'Gene', (230, 234))	('tumor', 'Disease', (23, 28))	('EGFR', 'Gene', '1956', (82, 86))	('MYC', 'Gene', (222, 225))	('NRAS', 'Gene', '4893', (216, 220))	('EGFR', 'Gene', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('KRAS', 'Gene', '3845', (187, 191))	('amplification/mutation', 'Var', (192, 214))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
291643	29449271	EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', '1956', (47, 51))	('benefit', 'PosReg', (29, 36))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (47, 51))
291647	29449271	Median overall survival of stage IV GEA is 11-12 months with optimal palliative chemotherapy, and increases to 16 months for patients with HER2 amplified tumors with the addition of trastuzumab to first line chemotherapy.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('HER2', 'Gene', (139, 143))	('trastuzumab', 'Chemical', 'MESH:D000068878', (182, 193))	('HER2', 'Gene', '2064', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('amplified', 'Var', (144, 153))	('patients', 'Species', '9606', (125, 133))
291649	29449271	Recent examples include EGFR, MET, mTOR, and hedgehog pathway inhibitors - generally in genomically unselected patients.	('EGFR', 'Gene', '1956', (24, 28))	('hedgehog pathway', 'Pathway', (45, 61))	('mTOR', 'Gene', (35, 39))	('EGFR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (35, 39))	('inhibitors', 'Var', (62, 72))	('patients', 'Species', '9606', (111, 119))
291655	29449271	If HER2-targeted therapeutic development was devised in the same biologically unselected manner, it likely would have suffered the same fate as anti-EGFR therapy- to the detriment of that subset of patients with HER2 amplified tumors who we now understand to derive significant benefit from this targeted approach.	('HER2', 'Gene', '2064', (3, 7))	('amplified', 'Var', (217, 226))	('patients', 'Species', '9606', (198, 206))	('tumors', 'Disease', (227, 233))	('EGFR', 'Gene', '1956', (149, 153))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('HER2', 'Gene', (212, 216))	('EGFR', 'Gene', (149, 153))	('HER2', 'Gene', '2064', (212, 216))	('HER2', 'Gene', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
291657	29449271	Despite this patient selection hurdle representing only ~15% of GEA, screening for HER2 amplification by FISH enriched for those most likely to benefit based on strong pre-clinical rationale.	('clinical', 'Species', '191496', (172, 180))	('amplification', 'Var', (88, 101))	('patient', 'Species', '9606', (13, 20))	('HER2', 'Gene', (83, 87))	('HER2', 'Gene', '2064', (83, 87))
291660	29449271	Pre-clinical and clinical evidence suggest benefit of EGFR inhibitors for EGFR genomically-driven tumors.	('clinical', 'Species', '191496', (4, 12))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', '1956', (74, 78))	('inhibitors', 'Var', (59, 69))	('EGFR', 'Gene', (54, 58))	('EGFR', 'Gene', (74, 78))	('benefit', 'PosReg', (43, 50))	('clinical', 'Species', '191496', (17, 25))
291662	29449271	More relevantly, analyses were reported from two large phase III trials for squamous cell lung cancer evaluating the subset of patients with EGFR amplification or increased gene copy number.	('amplification', 'Var', (146, 159))	('EGFR', 'Gene', '1956', (141, 145))	('increased', 'PosReg', (163, 172))	('squamous cell lung cancer', 'Disease', (76, 101))	('EGFR', 'Gene', (141, 145))	('patients', 'Species', '9606', (127, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('gene copy number', 'Var', (173, 189))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (76, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (76, 101))
291664	29449271	Similarly, phase II evaluation of second-line or greater icotinib in advanced squamous esophageal cancer patients with either high expression by IHC or amplification by FISH demonstrated a 16.7% objective response rate and 46.3% disease control rate.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('amplification', 'Var', (152, 165))	('icotinib', 'Chemical', 'MESH:C531470', (57, 65))	('patients', 'Species', '9606', (105, 113))	('squamous esophageal cancer', 'Disease', 'MESH:D004938', (78, 104))	('squamous esophageal cancer', 'Disease', (78, 104))	('high expression', 'Var', (126, 141))	('disease control', 'CPA', (229, 244))
291665	29449271	Most relevant, however, are studies focusing on EGFR gene copy and benefit from anti-EGFR therapy in GEA samples and patients.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (85, 89))	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'Gene', (48, 52))	('copy', 'Var', (58, 62))	('patients', 'Species', '9606', (117, 125))	('gene copy', 'Var', (53, 62))
291666	29449271	Pre-clinical xenograft models of GEA demonstrated that all responders possessed >=4 EGFR copies and suggested an even smaller population of those with 'high' gene copy number having the highest probability of benefit.	('copies', 'Var', (89, 95))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (84, 88))	('clinical', 'Species', '191496', (4, 12))
291667	29449271	A post-hoc subset analysis of a phase II trial of FOLFOX with cetuximab in GEA confirmed an association between EGFR amplification and overall survival (p=0.011).	('EGFR', 'Gene', (112, 116))	('cetuximab', 'Chemical', 'MESH:D000068818', (62, 71))	('overall survival', 'MPA', (135, 151))	('FOLFOX', 'Chemical', '-', (50, 56))	('EGFR', 'Gene', '1956', (112, 116))	('amplification', 'Var', (117, 130))	('association', 'Interaction', (92, 103))
291672	29449271	Due to these pre-clinical and clinical subset analyses suggesting potential benefit of EGFR inhibitors for EGFR-amplified GEA patients, we sought to first describe the incidence of EGFR amplification in a large cohort of GEA patients across stages, and to evaluate for a direct correlation of gene copy number with protein expression levels.	('amplification', 'Var', (186, 199))	('EGFR', 'Gene', '1956', (87, 91))	('patients', 'Species', '9606', (225, 233))	('EGFR', 'Gene', (181, 185))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', (87, 91))	('EGFR', 'Gene', (107, 111))	('EGFR', 'Gene', '1956', (181, 185))	('patients', 'Species', '9606', (126, 134))	('clinical', 'Species', '191496', (30, 38))	('clinical', 'Species', '191496', (17, 25))
291673	29449271	We then prospectively screened 140 stage IV GEA clinic patients (in any line of therapy) over 27 months at our center for EGFR amplification and, when present and otherwise eligible, treated with EGFR monoclonal antibody therapy under IRB approved protocols, when appropriate.	('EGFR', 'Gene', (196, 200))	('patients', 'Species', '9606', (55, 63))	('EGFR', 'Gene', '1956', (196, 200))	('amplification', 'Var', (127, 140))	('EGFR', 'Gene', (122, 126))	('EGFR', 'Gene', '1956', (122, 126))
291674	29449271	We report their clinical responses and disease control to EGFR blockade as well as characterization of pre- and post-treatment tumor biopsies and serial circulating tumor DNA (ctDNA) next generation sequencing (NGS) in attempt to explain clinical outcomes, mechanisms of resistance, and to evaluate the contribution of NK-cell dependent ADCC to anti-tumoral effect.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('EGFR', 'Gene', '1956', (58, 62))	('clinical', 'Species', '191496', (238, 246))	('tumor', 'Disease', (127, 132))	('EGFR', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('blockade', 'Var', (63, 71))	('clinical', 'Species', '191496', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', (350, 355))	('tumor', 'Disease', (165, 170))
291677	29449271	EGFR-SRM ranged from <100 to 41383 amol/mug (median 575 amol/mug) (Figure 1C).	('EGFR', 'Gene', (0, 4))	('41383 amol/mug', 'Var', (29, 43))	('amol', 'Phenotype', 'HP:0004845', (56, 60))	('amol', 'Phenotype', 'HP:0004845', (35, 39))	('EGFR', 'Gene', '1956', (0, 4))
291678	29449271	EGFR/CEP7 ratio >=2 and SRM values >= 4000 amol/mug were strongly correlated (Fisher exact test p=0.002) in the cell lines.	('amol', 'Phenotype', 'HP:0004845', (43, 47))	('EGFR', 'Gene', (0, 4))	('SRM', 'MPA', (24, 27))	('>=2', 'Var', (16, 19))	('>= 4000 amol/mug', 'Var', (35, 51))	('EGFR', 'Gene', '1956', (0, 4))
291683	29449271	There was a statistically significant linear correlation between EGFR copy number and EGFR expression by SRM (Pearson correlation = 0.87, p<2.2x10-16), with a trend to significance when evaluating binary 'presence' or 'absence' of amplification versus expression (p=0.08).	('expression', 'MPA', (91, 101))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', (86, 90))	('copy number', 'Var', (70, 81))
291684	29449271	EGFR amplification was identified in 19/363 (5%) of overall patients across all disease stages in both the retrospective and prospective cohorts (Table 1A), 10/144 (7%) of retrospectively evaluated stage IV patients only (Table 1B), and 8/140 (6%) of prospectively screened stage IV patients only (Table 1C).	('stage IV', 'Disease', (198, 206))	('patients', 'Species', '9606', (207, 215))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (283, 291))	('EGFR', 'Gene', '1956', (0, 4))
291692	29449271	Concurrent genomic aberrations occurring in >5% of EGFR amplified samples in this dataset were mostly short variant events in tumor suppressors including TP53, CDKN2A, ARID1A, SMAD4, and CDH1, and amplifications of various oncogenes including MYC, ERBB2, KRAS, CCND1 and others (Figure 1F).	('EGFR', 'Gene', (51, 55))	('SMAD4', 'Gene', '4089', (176, 181))	('ERBB2', 'Gene', '2064', (248, 253))	('CDH1', 'Gene', '999', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('KRAS', 'Gene', '3845', (255, 259))	('MYC', 'Gene', '4609', (243, 246))	('CDH1', 'Gene', (187, 191))	('ARID1A', 'Gene', (168, 174))	('KRAS', 'Gene', (255, 259))	('amplifications', 'Var', (197, 211))	('EGFR', 'Gene', '1956', (51, 55))	('TP53', 'Gene', (154, 158))	('CDKN2A', 'Gene', (160, 166))	('CCND1', 'Gene', '595', (261, 266))	('ARID1A', 'Gene', '8289', (168, 174))	('SMAD4', 'Gene', (176, 181))	('CCND1', 'Gene', (261, 266))	('tumor', 'Disease', (126, 131))	('CDKN2A', 'Gene', '1029', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('ERBB2', 'Gene', (248, 253))	('MYC', 'Gene', (243, 246))	('TP53', 'Gene', '7157', (154, 158))
291693	29449271	Given the growing interest and importance of programmed-death-1 (PD-1) and programmed-death-1-ligand (PD-L1) checkpoint inhibition in GEA, we also assessed the incidence of PD-L1 positivity by tumor positivity score (TPS), tumor infiltrating lymphocytes (TILs) and combined positivity score (CPS) by EGFR amplification status (Table 2B, Figure 1G).	('programmed-death-1', 'Gene', (75, 93))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('CPS', 'Disease', (292, 295))	('programmed-death-1', 'Gene', '5133', (45, 63))	('positivity', 'Var', (179, 189))	('EGFR', 'Gene', '1956', (300, 304))	('programmed-death-1', 'Gene', '5133', (75, 93))	('PD-L1', 'Gene', (102, 107))	('PD-1', 'Gene', (65, 69))	('PD-1', 'Gene', '5133', (65, 69))	('tumor', 'Disease', (193, 198))	('PD-L1', 'Gene', '29126', (102, 107))	('PD-L1', 'Gene', (173, 178))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('PD-L1', 'Gene', '29126', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('CPS', 'Disease', 'MESH:D020165', (292, 295))	('programmed-death-1', 'Gene', (45, 63))	('EGFR', 'Gene', (300, 304))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
291695	29449271	EGFR amplified tumors had lower incidence of CPS positivity (17%) compared to non-amplified tumors (27%), that was not statistically significant.	('tumors', 'Disease', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('EGFR', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('amplified', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CPS', 'Disease', (45, 48))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('EGFR', 'Gene', '1956', (0, 4))	('CPS', 'Disease', 'MESH:D020165', (45, 48))	('tumors', 'Disease', (92, 98))	('lower', 'NegReg', (26, 31))
291696	29449271	In the overall University of Chicago cohort (N=363), which comprised of 223 retrospectively accrued and 140 prospectively accrued patients, there was no statistically significant difference in gender, race, age, stage, tumor grade, primary tumor location, or HER2 positivity between patients with EGFR amplification versus those without amplification (Table 1A).	('amplification', 'Var', (302, 315))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (240, 245))	('HER2', 'Gene', (259, 263))	('tumor', 'Disease', (219, 224))	('patients', 'Species', '9606', (283, 291))	('HER2', 'Gene', '2064', (259, 263))	('patients', 'Species', '9606', (130, 138))	('EGFR', 'Gene', '1956', (297, 301))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('EGFR', 'Gene', (297, 301))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
291697	29449271	However, amongst the EGFR amplified patients, 63% had esophageal or junctional tumors while 37% had distal gastric tumors, as compared to 53% and 47% in the non-amplified patients, respectively.	('EGFR', 'Gene', '1956', (21, 25))	('gastric tumors', 'Phenotype', 'HP:0006753', (107, 121))	('EGFR', 'Gene', (21, 25))	('esophageal', 'Disease', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (36, 44))	('gastric tumors', 'Disease', (107, 121))	('patients', 'Species', '9606', (171, 179))	('gastric tumors', 'Disease', 'MESH:D013274', (107, 121))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('esophageal', 'Disease', 'MESH:D004941', (54, 64))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('amplified', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
291702	29449271	The eighth patient, who had concurrent MET and HER2 amplification, was not eligible for EGFR-directed therapy due to poor clinical condition after failure of first line FOLFOX therapy and enrollment in hospice.	('HER2', 'Gene', (47, 51))	('FOLFOX', 'Chemical', '-', (169, 175))	('patient', 'Species', '9606', (11, 18))	('HER2', 'Gene', '2064', (47, 51))	('EGFR', 'Gene', '1956', (88, 92))	('MET', 'Var', (39, 42))	('clinical', 'Species', '191496', (122, 130))	('amplification', 'Var', (52, 65))	('EGFR', 'Gene', (88, 92))
291707	29449271	All 4 patients receiving cetuximab developed a stereotypical acneiform rash (which interestingly continued during treatment benefit, yet resolved by the time of disease progression), whereas the 3 patients receiving ABT-806 did not; this was consistent with low rash frequency in phase I evaluation of ABT-806.	('low rash', 'Disease', (258, 266))	('ABT-806', 'Chemical', 'MESH:C000604456', (302, 309))	('cetuximab', 'Chemical', 'MESH:D000068818', (25, 34))	('patients', 'Species', '9606', (197, 205))	('rash', 'Phenotype', 'HP:0000988', (71, 75))	('acneiform rash', 'Disease', 'MESH:D005076', (61, 75))	('patients', 'Species', '9606', (6, 14))	('low rash', 'Disease', 'MESH:D005076', (258, 266))	('cetuximab', 'Var', (25, 34))	('rash', 'Phenotype', 'HP:0000988', (262, 266))	('ABT-806', 'Chemical', 'MESH:C000604456', (216, 223))	('acneiform rash', 'Disease', (61, 75))
291711	29449271	Additional baseline mechanisms of resistance included co-amplification of HER2 (n=3, pts 2,4,8), NRAS (n=1, pt 4), KRAS (n=1, pt 6), MYC (n=4, pts 1,2,4,6) or CCNE1 (n=2, pts 4,6), as well as mutation in KRAS (n=1, pt 5) or mutation of another stimulatory G-protein alpha subunit, GNAS (n=1, pt 6) (Table 3, Figure 4A).	('KRAS', 'Gene', '3845', (115, 119))	('pts', 'Species', '9606', (143, 146))	('KRAS', 'Gene', (204, 208))	('MYC', 'Gene', '4609', (133, 136))	('CCNE1', 'Gene', '898', (159, 164))	('NRAS', 'Gene', (97, 101))	('KRAS', 'Gene', (115, 119))	('mutation', 'Var', (192, 200))	('HER2', 'Gene', (74, 78))	('pts', 'Species', '9606', (85, 88))	('mutation', 'Var', (224, 232))	('pts', 'Species', '9606', (171, 174))	('MYC', 'Gene', (133, 136))	('GNAS', 'Gene', (281, 285))	('NRAS', 'Gene', '4893', (97, 101))	('HER2', 'Gene', '2064', (74, 78))	('KRAS', 'Gene', '3845', (204, 208))	('CCNE1', 'Gene', (159, 164))	('GNAS', 'Gene', '2778', (281, 285))
291714	29449271	In a patient with retained EGFR amplification in tissue, acquired PTEN deletion contributed to resistance, along with de novo PIK3CA mutation identified in ctDNA (pt 1).	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('contributed', 'Reg', (80, 91))	('PIK3CA', 'Gene', (126, 132))	('PTEN', 'Gene', (66, 70))	('patient', 'Species', '9606', (5, 12))	('PTEN', 'Gene', '5728', (66, 70))	('resistance', 'MPA', (95, 105))	('deletion', 'Var', (71, 79))	('PIK3CA', 'Gene', '5290', (126, 132))
291730	29449271	Herein we quantified the incidence of EGFR amplification and consequent significant EGFR overexpression in 24 GEA cell lines and 502 samples from 363 GEA patients within the University of Chicago Gastrointestinal Tumor Bank, as well as from a large commercial NGS database of 4645 GEA patients.	('EGFR', 'Gene', '1956', (38, 42))	('Gastrointestinal Tumor', 'Phenotype', 'HP:0007378', (196, 218))	('Tumor', 'Phenotype', 'HP:0002664', (213, 218))	('EGFR', 'Gene', (38, 42))	('amplification', 'Var', (43, 56))	('overexpression', 'PosReg', (89, 103))	('patients', 'Species', '9606', (154, 162))	('EGFR', 'Gene', '1956', (84, 88))	('patients', 'Species', '9606', (285, 293))	('EGFR', 'Gene', (84, 88))
291731	29449271	We observed no statistically significant differences in clinicopathologic characteristics in patients with EGFR amplification versus those without amplification, other than a higher proportion in proximal EGJ tumors compared to distal gastric tumors, consistent with the known higher incidence of chromosomal instable (CIN) tumors proximally in the TCGA cohort.	('gastric tumors', 'Disease', (235, 249))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('gastric tumors', 'Disease', 'MESH:D013274', (235, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('EGFR', 'Gene', '1956', (107, 111))	('amplification', 'Var', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('chromosomal instable (CIN) tumors', 'Disease', 'MESH:D043171', (297, 330))	('EGFR', 'Gene', (107, 111))	('EGJ tumors', 'Disease', 'MESH:D009369', (205, 215))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('gastric tumors', 'Phenotype', 'HP:0006753', (235, 249))	('EGJ tumors', 'Disease', (205, 215))	('patients', 'Species', '9606', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
291732	29449271	We then prospectively screened patients for EGFR amplification and treated them with EGFR-targeting agents when possible.	('amplification', 'Var', (49, 62))	('EGFR', 'Gene', (85, 89))	('patients', 'Species', '9606', (31, 39))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (85, 89))
291734	29449271	Notwithstanding, a demonstrable and robust treatment response and disease control to EGFR antagonists was observed in this select population.	('antagonists', 'Var', (90, 101))	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (85, 89))
291741	29449271	Amongst University of Chicago tissue samples analyzed, EGFR amplification incidence ranged from 5-7% across all stages and cohorts, which is consistent with previous reports.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (55, 59))	('amplification', 'Var', (60, 73))
291742	29449271	Regarding incidence of EGFR amplification specifically in metastatic patients, this was similar in the retrospective and prospective stage IV patients (6%) suggesting a reflective prospective cohort.	('EGFR', 'Gene', '1956', (23, 27))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (142, 150))	('EGFR', 'Gene', (23, 27))	('amplification', 'Var', (28, 41))
291743	29449271	In the overall population, EGFR amplification trended to be more commonly observed in stage IV patients compared to non-amplified patients (79% vs 50% p=0.11, Table 1A).	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('patients', 'Species', '9606', (95, 103))	('amplification', 'Var', (32, 45))	('observed', 'Reg', (74, 82))	('patients', 'Species', '9606', (130, 138))	('stage IV', 'Disease', (86, 94))
291747	29449271	Our findings are also consistent with previous work demonstrating that CIN GEAs, which are more likely to harbor amplifications, tend to have proximal locations.	('amplifications', 'Var', (113, 127))	('CIN GEAs', 'Disease', 'MESH:D007674', (71, 79))	('CIN GEAs', 'Disease', (71, 79))
291750	29449271	Despite amplification of EGFR being found in only ~5-7% of GEAs, with the high global incidence of distal gastric cancer alone, this may represent nearly fifty thousand patients diagnosed each year with EGFR amplified GEA.	('EGFR', 'Gene', '1956', (203, 207))	('patients', 'Species', '9606', (169, 177))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', (203, 207))	('amplified', 'Var', (208, 217))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('gastric cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('EGFR', 'Gene', '1956', (25, 29))
291752	29449271	In this report, from 140 patients prospectively screened at one treatment center, we identified and treated seven patients with GEA with extreme amplification of EGFR (54-167 gene copies) in tissue biopsies.	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('54-167 gene copies', 'Var', (168, 186))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (114, 122))
291753	29449271	By chance, we did not encounter any patients with EGFR amplification with tissue gene copies between 8-53, but these patients are not uncommon as demonstrated in the Foundation Medicine GEA cohort (Figure 1E).	('amplification', 'Var', (55, 68))	('patients', 'Species', '9606', (36, 44))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', (50, 54))	('patients', 'Species', '9606', (117, 125))
291755	29449271	We demonstrated clinical benefit with anti-EGFR targeted therapy in clinical scenarios that historically have poor response rates to conventional therapies.	('targeted therapy', 'Var', (48, 64))	('EGFR', 'Gene', '1956', (43, 47))	('clinical', 'Species', '191496', (16, 24))	('clinical', 'Species', '191496', (68, 76))	('EGFR', 'Gene', (43, 47))
291763	29449271	Resistance mechanisms also included concomitant amplifications and mutations in genes putatively involved in circumventing EGFR signaling in the setting of anti-EGFR therapy, which we also observed in the larger Foundation Medicine GEA cohort (Figure 1F).	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', (161, 165))	('amplifications', 'Var', (48, 62))	('mutations', 'Var', (67, 76))	('EGFR', 'Gene', '1956', (123, 127))	('EGFR', 'Gene', '1956', (161, 165))
291768	29449271	However, as demonstrated on repeat biopsy, this therapy eventually selected for an EGFR amplified clone with concurrent downstream PTEN exon 6 deletion, along with persistence of the previously identified EGFR non-amplified region (Supplemental Figure S2A), as well as a de novo PIK3CA mutation in the ctDNA.	('EGFR', 'Gene', '1956', (83, 87))	('PTEN', 'Gene', (131, 135))	('EGFR', 'Gene', (83, 87))	('PTEN', 'Gene', '5728', (131, 135))	('EGFR', 'Gene', '1956', (205, 209))	('deletion', 'Var', (143, 151))	('EGFR', 'Gene', (205, 209))	('PIK3CA', 'Gene', (279, 285))	('mutation', 'Var', (286, 294))	('PIK3CA', 'Gene', '5290', (279, 285))
291773	29449271	Similarly, selective pressure with cetuximab led to expansion of pre-existing HER2, NRAS, and MYC amplified subclones and emergence of de novo GNAS mutation in pt 4, which all likely conferred therapeutic resistance in various sites within the patient (Figure 4E, Supplemental Figure S2D).	('cetuximab', 'Chemical', 'MESH:D000068818', (35, 44))	('conferred', 'Reg', (183, 192))	('NRAS', 'Gene', (84, 88))	('GNAS', 'Gene', (143, 147))	('MYC', 'Gene', (94, 97))	('HER2', 'Gene', (78, 82))	('patient', 'Species', '9606', (244, 251))	('NRAS', 'Gene', '4893', (84, 88))	('HER2', 'Gene', '2064', (78, 82))	('pt 4', 'Gene', (160, 164))	('mutation', 'Var', (148, 156))	('GNAS', 'Gene', '2778', (143, 147))	('MYC', 'Gene', '4609', (94, 97))	('expansion', 'PosReg', (52, 61))
291778	29449271	Pt 6 was unable to obtain drug after cycle 1 due to insurance denial, but presumably would have a more limited benefit in the face of pre-existing KRAS/MYC/CCNE1 amplifications and GNAS mutation in the ctDNA at baseline.	('MYC', 'Gene', '4609', (152, 155))	('KRAS', 'Gene', '3845', (147, 151))	('CCNE1', 'Gene', (156, 161))	('GNAS', 'Gene', (181, 185))	('amplifications', 'Var', (162, 176))	('MYC', 'Gene', (152, 155))	('KRAS', 'Gene', (147, 151))	('GNAS', 'Gene', '2778', (181, 185))	('CCNE1', 'Gene', '898', (156, 161))
291787	29449271	Data regarding the prognostic significance and natural progression of EGFR amplification remain unknown, but EGFR amplification and EGFR over-expression has been associated with shortened survival in some reports.	('amplification', 'Var', (114, 127))	('over-expression', 'PosReg', (137, 152))	('shortened', 'NegReg', (178, 187))	('EGFR', 'Gene', '1956', (132, 136))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (132, 136))	('EGFR', 'Gene', '1956', (109, 113))	('EGFR', 'Gene', (70, 74))	('EGFR', 'Gene', (109, 113))
291789	29449271	This may suggest that EGFR amplification portends a relatively favorable prognosis, but further larger studies will need to sort this out.	('amplification', 'Var', (27, 40))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
291792	29449271	Notably, each of these three patients had identified EGFR amplification in their original stage IV diagnostic samples as well as their profiling just prior to anti-EGFR therapy in later lines, suggesting stability (and dependence) over time of this aberration with standard therapies.	('patients', 'Species', '9606', (29, 37))	('EGFR', 'Gene', (164, 168))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', '1956', (164, 168))	('amplification', 'Var', (58, 71))
291794	29449271	PTEN deletion) after experiencing disease progression on anti-EGFR therapy.	('EGFR', 'Gene', '1956', (62, 66))	('deletion', 'Var', (5, 13))	('EGFR', 'Gene', (62, 66))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
291798	29449271	Of 13 patients in TRANS-COG with EGFR amplification who received gefitinib, none had objective response.	('gefitinib', 'Chemical', 'MESH:D000077156', (65, 74))	('TRANS-COG', 'Chemical', '-', (18, 27))	('EGFR', 'Gene', '1956', (33, 37))	('patients', 'Species', '9606', (6, 14))	('EGFR', 'Gene', (33, 37))	('amplification', 'Var', (38, 51))
291804	29449271	Interestingly, from a large Foundation Medicine cohort of GEA samples undergoing PD-L1 IHC testing, we observed a slightly lower rate of positivity by TPS, TILs, and CPS scoring in EGFR amplified tumors as compared to non-amplified tumors (Table 2B, Figure 1G).	('CPS', 'Disease', 'MESH:D020165', (166, 169))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('EGFR', 'Gene', (181, 185))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('amplified', 'Var', (186, 195))	('PD-L1', 'Gene', (81, 86))	('tumors', 'Disease', (196, 202))	('lower', 'NegReg', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('PD-L1', 'Gene', '29126', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('positivity', 'MPA', (137, 147))	('EGFR', 'Gene', '1956', (181, 185))	('CPS', 'Disease', (166, 169))	('tumors', 'Disease', (232, 238))
291806	29449271	SP142 has lower sensitivity and therefore possibly underestimates PD-L1 expression.	('PD-L1', 'Gene', '29126', (66, 71))	('lower', 'NegReg', (10, 15))	('underestimates', 'NegReg', (51, 65))	('expression', 'MPA', (72, 82))	('SP142', 'Chemical', '-', (0, 5))	('SP142', 'Var', (0, 5))	('sensitivity', 'MPA', (16, 27))	('PD-L1', 'Gene', (66, 71))
291809	29449271	In this study, results from "during therapy" biopsies imply that treatment with EGFR-directed monoclonal antibodies led to increased tumoral infiltration by CD3+ T cells and NKp46+ NK cells as well as increased PD-L1 expression, which suggested that consequent ADCC may create, or 'trigger', a reflexive immunosuppressed tumor environment.	('increased', 'PosReg', (123, 132))	('increased', 'PosReg', (201, 210))	('PD-L1', 'Gene', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('expression', 'MPA', (217, 227))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('ADCC', 'Disease', (261, 265))	('EGFR', 'Gene', '1956', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EGFR', 'Gene', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('NKp46', 'Gene', (174, 179))	('PD-L1', 'Gene', '29126', (211, 216))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (321, 326))	('increased PD', 'Phenotype', 'HP:0008151', (201, 213))	('NKp46', 'Gene', '9437', (174, 179))	('monoclonal antibodies', 'Var', (94, 115))
291810	29449271	On-treatment PD-L1 expression appeared more common in cases with persistent EGFR amplification, which also supports this proposed mechanism.	('expression', 'MPA', (19, 29))	('EGFR', 'Gene', '1956', (76, 80))	('amplification', 'Var', (81, 94))	('common', 'Reg', (44, 50))	('PD-L1', 'Gene', (13, 18))	('EGFR', 'Gene', (76, 80))	('PD-L1', 'Gene', '29126', (13, 18))
291814	29449271	In summary, we report EGFR amplification with overexpression in 5% (19/363) of a large GEA patient cohort.	('patient', 'Species', '9606', (91, 98))	('amplification', 'Var', (27, 40))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
291815	29449271	Prospectively, 6% (8/140) of stage IV advanced patients demonstrated EGFR amplification, of which seven patients were successfully treated with at least one dose of anti-EGFR monoclonal antibody therapy.	('stage IV advanced', 'Disease', (29, 46))	('EGFR', 'Gene', '1956', (69, 73))	('amplification', 'Var', (74, 87))	('EGFR', 'Gene', '1956', (170, 174))	('EGFR', 'Gene', (69, 73))	('patients', 'Species', '9606', (47, 55))	('EGFR', 'Gene', (170, 174))	('patients', 'Species', '9606', (104, 112))
291816	29449271	This is consistent with a similar-sized prospective study of HER2 amplification in plasma associated with an 80% response rate to targeted therapy in GEA.	('associated', 'Reg', (90, 100))	('HER2', 'Gene', '2064', (61, 65))	('amplification', 'Var', (66, 79))	('HER2', 'Gene', (61, 65))
291821	29449271	Novel trial designs, such as PANGEA, a type II expansion platform design trial in GEA, tests a treatment strategy of cytotoxic therapy plus matched targeted therapies across a number of biologic subgroups, including EGFR amplification.	('EGFR', 'Gene', '1956', (216, 220))	('EGFR', 'Gene', (216, 220))	('amplification', 'Var', (221, 234))
291826	29449271	These included AGS, CAT-2, CAT-3, CAT-4, CAT11B, CAT12, CAT13, CAT14A, CAT15pl, CP-A, CP-B, CP-C, CP-D, GM14667, HGC-27, Hs746T, KATO III, MKN-1, MKN-45, NCI-N87, OE19, OE33, SNU-1, SNU-16, SNU-5, ZR-75-30 obtained between 2008-2012.	('CAT14A', 'Var', (63, 69))	('CAT-3', 'Gene', '84889', (27, 32))	('CAT-4', 'Gene', (34, 39))	('AGS', 'Disease', (15, 18))	('CP-C', 'Var', (92, 96))	('CAT14A', 'Mutation', 'c.14CAT>A', (63, 69))	('CP-D', 'Gene', (98, 102))	('CAT-4', 'Gene', '6545', (34, 39))	('AGS', 'Disease', 'MESH:C535607', (15, 18))	('CAT-2', 'Gene', (20, 25))	('CP-A', 'Gene', '1357', (80, 84))	('CP-A', 'Gene', (80, 84))	('CAT15pl', 'Var', (71, 78))	('CP-D', 'Gene', '1362', (98, 102))	('CAT-3', 'Gene', (27, 32))	('CAT-2', 'Gene', '56302', (20, 25))
291838	29449271	Patients at the University of Chicago with metastatic GEA (any line of therapy) were prospectively screened for EGFR amplification between September 2014 to December 2016 with NGS using the Foundation One test (Foundation Medicine, Cambridge, MA).	('EGFR', 'Gene', (112, 116))	('Patients', 'Species', '9606', (0, 8))	('amplification', 'Var', (117, 130))	('EGFR', 'Gene', '1956', (112, 116))
291847	29449271	Centiles of EGFR copy number reported in the clinical G360 results were denoted by a '+' for absolute plasma copy number greater than 2.14 (<50th percentile), '++' for copy number greater than 2.4 but less than 4 (<90th percentile), or '+++' for copy number greater than 4 (>=90th percentile).	('EGFR', 'Gene', (12, 16))	("'++'", 'Var', (159, 163))	('EGFR', 'Gene', '1956', (12, 16))	("'+++'", 'Var', (236, 241))	('copy number greater than 2.4', 'Var', (168, 196))	('clinical', 'Species', '191496', (45, 53))
291849	29449271	Comparisons between EGFR amplified and non-amplified cases were performed using chi-square testing or a two-sided Fisher's exact test.	('amplified', 'Var', (25, 34))	('EGFR', 'Gene', '1956', (20, 24))	('EGFR', 'Gene', (20, 24))
291866	29472529	Over the last decade, researchers have established an association between aberrant miRNA expression and tumorigenesis of HCC.	('HCC', 'Gene', '619501', (121, 124))	('HCC', 'Phenotype', 'HP:0001402', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('miRNA expression', 'Protein', (83, 99))	('tumor', 'Disease', (104, 109))	('HCC', 'Gene', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('aberrant', 'Var', (74, 82))
291870	29472529	miRNAs could be oncogenes or tumor suppressors causing the upregulation of oncogenes or the inhibition of tumor suppressor genes or genes with functions related to cell differentiation or apoptosis in HCC.	('genes', 'Gene', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('HCC', 'Phenotype', 'HP:0001402', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('inhibition', 'NegReg', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('oncogenes', 'Gene', (75, 84))	('tumor', 'Disease', (29, 34))	('HCC', 'Gene', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('upregulation', 'PosReg', (59, 71))	('HCC', 'Gene', '619501', (201, 204))	('tumor', 'Disease', (106, 111))	('miRNAs', 'Var', (0, 6))
291912	29472529	The 3'UTR of NFIX containing the miR-HCC1 binding sites or mutant sites (Fig.	('HCC1', 'Gene', '6358', (37, 41))	('mutant', 'Var', (59, 65))	('HCC', 'Phenotype', 'HP:0001402', (37, 40))	('binding', 'Interaction', (42, 49))	('HCC1', 'Gene', (37, 41))
291922	29472529	Colony formation and MTT assays demonstrated that NFIX decreased cell viability, while knockdown of NFIX increased cell viability in Huh7 and HepG2 cells (Fig.	('Huh7', 'Gene', '284424', (133, 137))	('MTT', 'Chemical', 'MESH:C070243', (21, 24))	('cell viability', 'CPA', (65, 79))	('cell viability', 'CPA', (115, 129))	('decreased', 'NegReg', (55, 64))	('NFIX', 'Gene', (100, 104))	('Huh7', 'Gene', (133, 137))	('increased', 'PosReg', (105, 114))	('HepG2', 'CellLine', 'CVCL:0027', (142, 147))	('knockdown', 'Var', (87, 96))
291925	29472529	Migration and invasion assays showed that NFIX overexpression decreased, but knockdown of NFIX by pshR-NFIX increased the migration and invasion abilities in Huh7 and HepG2 cells (Fig.	('NFIX', 'Gene', (90, 94))	('Huh7', 'Gene', (158, 162))	('Huh7', 'Gene', '284424', (158, 162))	('increased', 'PosReg', (108, 117))	('knockdown', 'Var', (77, 86))	('HepG2', 'CellLine', 'CVCL:0027', (167, 172))	('pshR-NFIX', 'Gene', (98, 107))	('migration', 'CPA', (122, 131))	('invasion abilities', 'CPA', (136, 154))
291928	29472529	Conversely, knockdown of NFIX decreased the protein level of E-cadherin but enhanced the protein levels of ICAM-1 and vimentin (Fig.	('ICAM-1', 'Gene', '3383', (107, 113))	('vimentin', 'Gene', '7431', (118, 126))	('E-cadherin', 'Gene', (61, 71))	('vimentin', 'Gene', (118, 126))	('ICAM-1', 'Gene', (107, 113))	('knockdown', 'Var', (12, 21))	('E-cadherin', 'Gene', '999', (61, 71))	('protein levels', 'MPA', (89, 103))	('enhanced', 'PosReg', (76, 84))	('NFIX', 'Gene', (25, 29))	('protein level of', 'MPA', (44, 60))	('decreased', 'NegReg', (30, 39))
291937	29472529	A fragment containing the putative promoter and two LEF1 fragments (-2600 to -1912 kb, -2600 to -1319 kb) were cloned into pGL3-Basic vectors, named pGL3-Basic-p688 and pGL3-Basic-p1281, respectively.	('pGL3', 'Gene', '6391', (123, 127))	('pGL3', 'Gene', (149, 153))	('pGL3', 'Gene', (169, 173))	('LEF1', 'Gene', '51176', (52, 56))	('pGL3', 'Gene', (123, 127))	('-2600 to -1912', 'Var', (68, 82))	('pGL3', 'Gene', '6391', (149, 153))	('pGL3', 'Gene', '6391', (169, 173))	('LEF1', 'Gene', (52, 56))
291938	29472529	7b, the luciferase activity of pGL3-Basic-p688 and pGL3-Basic-p1281 were greater than 10-fold higher compared with the pGL3-Basic control, suggesting the fragments -2600 to 1319 kb contained a functional promoter.	('pGL3', 'Gene', '6391', (119, 123))	('luciferase', 'Enzyme', (8, 18))	('pGL3', 'Gene', (31, 35))	('pGL3', 'Gene', '6391', (51, 55))	('pGL3', 'Gene', '6391', (31, 35))	('activity', 'MPA', (19, 27))	('fragments -2600 to 1319 kb', 'Var', (154, 180))	('pGL3', 'Gene', (119, 123))	('pGL3', 'Gene', (51, 55))	('higher', 'PosReg', (94, 100))
291944	29472529	Luciferase reporter assays showed that alterations of LEF1 did not affect p688-del-LEF1-A activity (Fig.	('LEF1', 'Gene', '51176', (54, 58))	('LEF1', 'Gene', (54, 58))	('activity', 'MPA', (90, 98))	('LEF1', 'Gene', '51176', (83, 87))	('alterations', 'Var', (39, 50))	('LEF1', 'Gene', (83, 87))
291950	29472529	By contrast, the pri-miR-HCC1 level decreased upon the knockdown of LEF1.	('knockdown', 'Var', (55, 64))	('LEF1', 'Gene', '51176', (68, 72))	('HCC1', 'Gene', (25, 29))	('LEF1', 'Gene', (68, 72))	('HCC1', 'Gene', '6358', (25, 29))	('HCC', 'Phenotype', 'HP:0001402', (25, 28))	('decreased', 'NegReg', (36, 45))
291956	29472529	miRNAs play an important role in the initiation and progression of HCC, and aberrant miRNA expression levels are associated with cancer development and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('HCC', 'Gene', '619501', (67, 70))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('metastasis', 'CPA', (152, 162))	('miRNA expression levels', 'MPA', (85, 108))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('aberrant', 'Var', (76, 84))	('HCC', 'Gene', (67, 70))	('associated', 'Reg', (113, 123))
291978	29472529	The rescue experiments also demonstrated that restoration of NFIX expression abrogates the effect of miR-HCC1 on HCC.	('HCC1', 'Gene', '6358', (105, 109))	('HCC', 'Gene', '619501', (105, 108))	('HCC', 'Phenotype', 'HP:0001402', (105, 108))	('abrogates', 'NegReg', (77, 86))	('effect', 'MPA', (91, 97))	('HCC', 'Gene', '619501', (113, 116))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('restoration', 'Var', (46, 57))	('HCC1', 'Gene', (105, 109))	('HCC', 'Gene', (105, 108))	('NFIX', 'Protein', (61, 65))	('HCC', 'Gene', (113, 116))
292004	29472529	The promoter of LEF1 deletion-A and deletion-B fragments were cloned into the pGL3-Basic vector using DpnI site and KpnI-EcoRI sites, respectively.	('LEF1', 'Gene', '51176', (16, 20))	('LEF1', 'Gene', (16, 20))	('deletion-A', 'Var', (21, 31))	('pGL3', 'Gene', (78, 82))	('deletion-B fragments', 'Var', (36, 56))	('pGL3', 'Gene', '6391', (78, 82))
292038	29051037	In patients with low DRS, high-dose radiotherapy was associated with significantly improved OS compared to treatment with standard-dose radiotherapy (HR 0.22).	('high-dose radiotherapy', 'Var', (26, 48))	('improved', 'PosReg', (83, 91))	('DRS', 'Chemical', '-', (21, 24))	('low DRS', 'Var', (17, 24))	('patients', 'Species', '9606', (3, 11))	('OS', 'Chemical', '-', (92, 94))
292060	29051037	We hypothesized that variations in levels of c-miRNAs may predict response to radiotherapy and that characterization of c-miRNA signatures could aid in identification of patients who benefit from dose-escalation.	('patients', 'Species', '9606', (170, 178))	('aid', 'Reg', (145, 148))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('variations', 'Var', (21, 31))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', (122, 125))	('predict', 'Reg', (58, 65))	('response', 'CPA', (66, 74))
292115	29051037	While OS of patients in the high DRS group was similar regardless of radiation dose (HR 0.78, 95% CI 0.37-1.64), patients in the low DRS group showed improved OS after treatment with high-dose compared to standard-dose radiation (HR 0.22, 95% CI 0.10 - 0.48) (Figure 1).	('patients', 'Species', '9606', (12, 20))	('OS', 'Chemical', '-', (6, 8))	('OS', 'Chemical', '-', (159, 161))	('patients', 'Species', '9606', (113, 121))	('high-dose', 'Var', (183, 192))	('DRS', 'Chemical', '-', (133, 136))	('DRS', 'Chemical', '-', (33, 36))	('improved', 'PosReg', (150, 158))
292123	29051037	Patients with low DRS treated with high-dose radiotherapy exhibited improved OS compared to those treated with standard-dose.	('DRS', 'Chemical', '-', (18, 21))	('high-dose', 'Var', (35, 44))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (77, 79))	('low DRS', 'Disease', (14, 21))	('improved', 'PosReg', (68, 76))
292211	28315927	5, patients with low HLA-DR expression in the EAC tumor epithelium had a significantly shorter survival time compared to patients with high expression, in both EAC tumor core (Fig.	('EAC', 'Phenotype', 'HP:0011459', (46, 49))	('survival time', 'CPA', (95, 108))	('tumor', 'Disease', (164, 169))	('EAC', 'Phenotype', 'HP:0011459', (160, 163))	('HLA-DR', 'Protein', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('shorter', 'NegReg', (87, 94))	('patients', 'Species', '9606', (3, 11))	('low', 'Var', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('patients', 'Species', '9606', (121, 129))	('tumor', 'Disease', (50, 55))
292213	28315927	In the tumor leading edge epithelium in particular, low HLA-DR expression was associated with a significantly shorter survival (mean 29.8 months, 95% CI, range 17.5-42.2 months) than patients with high HLA-DR expression (mean 43.4 months, 95% CI, range 34.0-52.8 months), (p = 0.013).	('survival', 'MPA', (118, 126))	('tumor', 'Disease', (7, 12))	('shorter', 'NegReg', (110, 117))	('HLA-DR', 'Protein', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('patients', 'Species', '9606', (183, 191))	('low', 'Var', (52, 55))
292250	27331408	Convergent evidence from systematic analysis of GWAS revealed genetic basis of esophageal cancer Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with risk of esophageal cancer (EC).	('esophageal cancer', 'Disease', 'MESH:D004938', (222, 239))	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('single nucleotide polymorphisms', 'Var', (159, 190))	('associated', 'Reg', (198, 208))	('esophageal cancer', 'Disease', (222, 239))
292255	27331408	By comprehensive data search and collection, we obtained a total of 7 published GWAS of esophageal cancer -, in which the sample size ranged from four thousands to twenty thousands and the ethnic groups of samples were mainly Asian descent except one study with European descent, detecting 500 thousands to one million of SNPs from the whole genome in each GWAS.	('GWAS of esophageal cancer', 'Disease', 'MESH:D004938', (80, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('GWAS of esophageal cancer', 'Disease', (80, 105))	('SNPs', 'Var', (322, 326))
292263	27331408	ADH4, ADH1C) were identified to have significantly differential gene expression levels under different genotypes on esophageal tissues including esophagus muscularis and esophagus mucosa, as alcohol drinking has been considered as an important risk factor of EC, and previous animal studies also demonstrated impairment of aldehyde dehydrogenase could increase accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion.	('acetaldehyde-derived DNA damage', 'MPA', (377, 408))	('increase accumulation of acetaldehyde', 'Phenotype', 'HP:0003533', (352, 389))	('ADH4', 'Gene', '127', (0, 4))	('impairment', 'Var', (309, 319))	('acetaldehyde', 'Chemical', 'MESH:D000079', (377, 389))	('increase', 'PosReg', (352, 360))	('aldehyde dehydrogenase', 'Enzyme', (323, 345))	('ADH4', 'Gene', (0, 4))	('ADH1C', 'Gene', '126', (6, 11))	('alcohol drinking', 'Phenotype', 'HP:0030955', (191, 207))	('accumulation', 'MPA', (361, 373))	('alcohol', 'Chemical', 'MESH:D000438', (191, 198))	('ADH1C', 'Gene', (6, 11))	('ethanol', 'Chemical', 'MESH:D000431', (432, 439))
292314	27000746	Most patient's regular follow-ups included a physical examination, laboratory tests (including CA19-9, CA72-4, and CEA levels), chest radiography, ultrasonography or CT, and endoscopy.	('CA72-4', 'MPA', (103, 109))	('patient', 'Species', '9606', (5, 12))	('chest radiography', 'Disease', (128, 145))	('CEA', 'Gene', (115, 118))	('CA19-9', 'Var', (95, 101))	('CEA', 'Gene', '5670', (115, 118))
292496	22014037	In contrast, patients with more than 40% of HLA class I positivity were classified as the positive HLA class I group.	('positivity', 'Var', (56, 66))	('patients', 'Species', '9606', (13, 21))	('HLA class', 'Protein', (44, 53))
292499	22014037	However, patients with HLA class I positivity had significantly longer DFS than those without HLA class I positivity (p < 0.05) (Figure 2).	('patients', 'Species', '9606', (9, 17))	('DFS', 'MPA', (71, 74))	('longer', 'PosReg', (64, 70))	('positivity', 'Var', (35, 45))
292503	22014037	investigated HLA class I expression in breast cancer using a HC-10 antibody, and demonstrated that HLA class I negativity correlated with a better postoperative outcome.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('negativity', 'Var', (111, 121))	('breast cancer', 'Disease', (39, 52))
292604	18331622	Mixed GRP78/GRP94 protein-expression was heterogenous with more early tumor stages in patients with high GRP78/low GRP94 expression and more advanced tumors in patients with low GRP78/high GRP94 levels.	('GRP78', 'Gene', '3309', (6, 11))	('GRP94', 'Gene', '7184', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('advanced tumors', 'Disease', 'MESH:D020178', (141, 156))	('expression', 'MPA', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('GRP94', 'Gene', (189, 194))	('advanced tumors', 'Disease', (141, 156))	('patients', 'Species', '9606', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('high', 'Var', (100, 104))	('GRP94', 'Gene', '7184', (115, 120))	('GRP94', 'Gene', '7184', (12, 17))	('GRP78', 'Gene', '3309', (178, 183))	('GRP78', 'Gene', (178, 183))	('GRP94', 'Gene', (115, 120))	('GRP94', 'Gene', (12, 17))	('GRP78', 'Gene', (105, 110))	('GRP78', 'Gene', '3309', (105, 110))	('tumor', 'Disease', (150, 155))	('patients', 'Species', '9606', (160, 168))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('GRP78', 'Gene', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
292627	18331622	So increased protein expression that fails to correlate with gene expression level - like in our study for GRP78 and GRP94 in advanced tumor stages- may be related to posttranslational regulations or modifications like activating or inactivating phosphorylation or glycosylation.	('increased', 'PosReg', (3, 12))	('GRP94', 'Gene', (117, 122))	('activating', 'MPA', (219, 229))	('protein expression', 'MPA', (13, 31))	('GRP78', 'Gene', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('GRP78', 'Gene', '3309', (107, 112))	('GRP94', 'Gene', '7184', (117, 122))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('inactivating', 'Var', (233, 245))
292628	18331622	Another aspect that may draw attention to the role of GRPs in human cancers is the relationship between induction of GRPs and tumor resistance against chemotherapy (CTX) treatment, as reported very recently for breast and prostate cancer, where high GRP78 expression was associated with tumor resistance to CTX.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('associated', 'Reg', (271, 281))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CTX', 'Gene', '1593', (165, 168))	('GRP', 'Gene', '2922', (54, 57))	('expression', 'MPA', (256, 266))	('CTX', 'Gene', '1593', (307, 310))	('GRP', 'Gene', (54, 57))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (211, 237))	('high', 'Var', (245, 249))	('GRP', 'Gene', '2922', (117, 120))	('CTX', 'Gene', (165, 168))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('GRP78', 'Gene', (250, 255))	('GRP', 'Gene', (117, 120))	('tumor', 'Disease', (287, 292))	('CTX', 'Gene', (307, 310))	('GRP78', 'Gene', '3309', (250, 255))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('GRP', 'Gene', '2922', (250, 253))	('GRP', 'Gene', (250, 253))	('human', 'Species', '9606', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor', 'Disease', (126, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (222, 237))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))
292665	32769880	The including criteria for carcinoma patients were as follows: esophageal squamous cell carcinoma patients with pT3N0-2M0 and the including criteria for control participates were normal healthy medical volunteers confirmed by gastroscopy.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinoma', 'Disease', 'MESH:D009369', (88, 97))	('patients', 'Species', '9606', (37, 45))	('carcinoma', 'Disease', (27, 36))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('pT3N0-2M0', 'Var', (112, 121))	('patients', 'Species', '9606', (98, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinoma', 'Disease', (88, 97))	('carcinoma', 'Disease', 'MESH:D009369', (27, 36))
292702	32478897	These cells usually have abnormalities from the original tumor itself, but may also develop abnormalities due to genetic manipulation, or genetic and epigenetic changes during long-term passages.	('epigenetic changes', 'Var', (150, 168))	('genetic manipulation', 'Var', (113, 133))	('abnormalities', 'MPA', (25, 38))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('genetic', 'Var', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('develop', 'PosReg', (84, 91))	('tumor', 'Disease', (57, 62))	('abnormalities', 'MPA', (92, 105))
292732	32478897	This study demonstrated that the expression of host gene can be regulated via inducible shRNA knockdown, and these genetic modifications do not influence the host innate immune response, thereby unlocking a unique potential for molecular characterization of virus-host interactions in human airway epithelium.	('rat', 'Species', '10116', (18, 21))	('knockdown', 'Var', (94, 103))	('interactions', 'Interaction', (269, 281))	('human', 'Species', '9606', (285, 290))	('regulated', 'Reg', (64, 73))	('shRNA', 'Gene', (88, 93))	('expression', 'MPA', (33, 43))
292765	32478897	97  We also discovered a mutant HPV 11 genome from lesion tissues.	('mutant', 'Var', (25, 31))	('HPV 11', 'Gene', (32, 38))	('HPV 11', 'Species', '10580', (32, 38))
292768	32478897	99  Therefore, CR can be used for the generation of HPV-positive benign or malignant human lesions, anti-HPV discovery, and biology of both high- and low-risk HPVs through native viral infections or HPV DNA transfections in CR host epithelial cells.	('HPVs', 'Disease', (159, 163))	('HPV', 'Var', (199, 202))	('viral infections', 'Disease', (179, 195))	('viral infections', 'Disease', 'MESH:D001102', (179, 195))	('transfections', 'Var', (207, 220))	('HPVs', 'Disease', 'None', (159, 163))	('rat', 'Species', '10116', (42, 45))	('human', 'Species', '9606', (85, 90))
292815	32478897	However, ARB was less effective in inhibition of PsV infection, when ARB was added to cultures after removal of the virus inoculum, suggesting that ARB blocks an early step of life cycle of the Zika virus, and may also have postentry effects.	('infection', 'Disease', 'MESH:D007239', (53, 62))	('ARB', 'Var', (148, 151))	('Zika virus', 'Species', '64320', (194, 204))	('blocks', 'NegReg', (152, 158))	('infection', 'Disease', (53, 62))
292860	32478897	The results indicated that the CR RCC cells retained cancer-specific copy number alterations and somatic mutations as those in the corresponding original tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('rat', 'Species', '10116', (85, 88))	('copy number alterations', 'Var', (69, 92))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (34, 37))
292916	31196966	A number of studies have focused on the association of LEPR rs1137101 variants with susceptibility of cancer, however, the observed results were controversial.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('LEPR', 'Gene', '3953', (55, 59))	('cancer', 'Disease', (102, 108))	('variants', 'Var', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('association', 'Interaction', (40, 51))	('LEPR', 'Gene', (55, 59))	('rs1137101', 'Mutation', 'rs1137101', (60, 69))
292917	31196966	We searched literature on the relationship of LEPR rs1137101 G>A polymorphism with cancer risk by using PubMed and Embase databases, covering all publications up to 14 October 2018.	('LEPR', 'Gene', (46, 50))	('rs1137101', 'Mutation', 'rs1137101', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('LEPR', 'Gene', '3953', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('rs1137101 G>A', 'Var', (51, 64))	('cancer', 'Disease', (83, 89))
292918	31196966	After combining all eligible studies, we identified null relationship between LEPR gene rs1137101 G>A polymorphism and overall cancer risk [A vs. G: odds ratio (OR ) =  0.97, 95% confidence interval (CI ) =  0.89-1.06, P = 0.547; AA vs. GG: OR  =  0.93, 95% CI  =  0.78-1.13, P = 0.476; AA/GA vs. GG: OR  =  0.99, 95% CI  =  0.91-1.09, P= 0.890 and AA vs. GA/GG: OR  = 0.92, 95% CI  =  0.82-1.04, P= 0.198].	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('LEPR', 'Gene', (78, 82))	('rs1137101', 'Mutation', 'rs1137101', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('LEPR', 'Gene', '3953', (78, 82))	('cancer', 'Disease', (127, 133))	('rs1137101 G>A', 'Var', (88, 101))
292921	31196966	In summary, this analysis indicates that no significant association of cancer risk was identified to be correlated with rs1137101 G>A variants, even in stratified analyses.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('rs1137101 G>A', 'Var', (120, 133))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs1137101', 'Mutation', 'rs1137101', (120, 129))
292937	31196966	There are a number of common single nucleotide polymorphisms (SNPs) of the LEPR genes, which have been established.	('LEPR', 'Gene', (75, 79))	('LEPR', 'Gene', '3953', (75, 79))	('single nucleotide polymorphisms', 'Var', (29, 60))
292938	31196966	LEPR rs1137101 G>A polymorphism (Arg223Gln) is the most extensively studied association of this SNP with the development of cancer.	('association', 'Reg', (76, 87))	('LEPR', 'Gene', '3953', (0, 4))	('cancer', 'Disease', (124, 130))	('Arg223Gln', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('LEPR', 'Gene', (0, 4))	('rs1137101', 'Mutation', 'rs1137101', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('Arg223Gln', 'SUBSTITUTION', 'None', (33, 42))
292940	31196966	It leads to an Arg Gln altering in extracellular region.	('leads to', 'Reg', (3, 11))	('Arg', 'Chemical', 'MESH:D001120', (15, 18))	('Gln', 'Chemical', 'MESH:D005973', (19, 22))	('Arg Gln altering', 'Var', (15, 31))
292943	31196966	Recently, more studies concerning the association of LEPR rs1137101 locus with cancer risk were performed.	('rs1137101', 'Mutation', 'rs1137101', (58, 67))	('rs1137101', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('LEPR', 'Gene', (53, 57))	('LEPR', 'Gene', '3953', (53, 57))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
292945	31196966	To obtain the potentially eligible investigations on LEPR rs1137101 G>A polymorphism and cancer susceptibility, we conducted an electronic literature search on PubMed and Embase databases, covering all publications up to 14 October 2018, by using the following searching strategy: (Leptin receptor or LEPR or obese receptor or OBR or CD295) and (carcinoma or cancer or tumor or malignancy or neoplasms) and (polymorphism or SNP or variation).	('rs1137101', 'Mutation', 'rs1137101', (58, 67))	('LEPR', 'Gene', (301, 305))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('OBR', 'Gene', '3953', (327, 330))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', (369, 374))	('LEPR', 'Gene', '3953', (53, 57))	('obese', 'Disease', (309, 314))	('neoplasms', 'Phenotype', 'HP:0002664', (392, 401))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (369, 374))	('LEPR', 'Gene', (53, 57))	('obese', 'Disease', 'MESH:D009765', (309, 314))	('cancer', 'Disease', 'MESH:D009369', (359, 365))	('CD295', 'Gene', (334, 339))	('malignancy or neoplasms', 'Disease', 'MESH:D009369', (378, 401))	('Leptin receptor', 'Gene', (282, 297))	('OBR', 'Gene', (327, 330))	('carcinoma or cancer', 'Disease', 'MESH:D009369', (346, 365))	('rs1137101 G', 'Var', (58, 69))	('malignancy or neoplasms', 'Disease', (378, 401))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('Leptin receptor', 'Gene', '3953', (282, 297))	('CD295', 'Gene', '3953', (334, 339))	('carcinoma or cancer', 'Disease', (346, 365))	('LEPR', 'Gene', '3953', (301, 305))	('cancer', 'Disease', (359, 365))
292946	31196966	The major selection criteria were: (i) full-text study, (ii) assessing the relationship of LEPR rs1137101 variants with cancer susceptibility, (iii) designed as an unrelated case-control study, (iv) sufficient data could be obtained to calculate the odds ratio (OR) with 95% confidence interval (CI), and (v) genotype distribution conformation to Hardy-Weinberg equilibrium (HWE).	('Hardy-Weinberg equilibrium', 'Disease', (347, 373))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('variants', 'Var', (106, 114))	('rs1137101', 'Mutation', 'rs1137101', (96, 105))	('cancer', 'Disease', (120, 126))	('LEPR', 'Gene', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('LEPR', 'Gene', '3953', (91, 95))
292952	31196966	In this meta-analysis, 33 publications involving 44 independent case-control studies on the relationship of LEPR rs1137101 G>A polymorphism with cancer risk were recruited.	('cancer', 'Disease', (145, 151))	('LEPR', 'Gene', '3953', (108, 112))	('rs1137101 G>A', 'Var', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('LEPR', 'Gene', (108, 112))	('rs1137101', 'Mutation', 'rs1137101', (113, 122))
292954	31196966	After combining all eligible case-control studies, we identified null relationship between rs1137101 polymorphism in LEPR gene and overall cancer risk under four genetic models (A vs. G: OR  =  0.97, 95% CI  =  0.89-1.06, P=0.547; AA vs. GG: OR  =  0.93, 95% CI  =  0.78-1.13, P =0.476; AA/GA vs. GG: OR  =  0.99, 95% CI  =  0.91-1.09, P=0.890 and AA vs. GA/GG: OR  = 0.92, 95% CI  =  0.82-1.04, P=0.198, Figures 2-5).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('LEPR', 'Gene', '3953', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs1137101', 'Var', (91, 100))	('rs1137101', 'Mutation', 'rs1137101', (91, 100))	('LEPR', 'Gene', (117, 121))	('cancer', 'Disease', (139, 145))
292957	31196966	Recently, variants in LEPR gene and their potential associations with cancer risk have been explored.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('variants', 'Var', (10, 18))	('LEPR', 'Gene', (22, 26))	('cancer', 'Disease', (70, 76))	('LEPR', 'Gene', '3953', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
292958	31196966	Rs1137101 G>A polymorphism is one of the important variants in LEPR gene.	('Rs1137101 G>A', 'Var', (0, 13))	('Rs1137101', 'Mutation', 'Rs1137101', (0, 9))	('LEPR', 'Gene', (63, 67))	('LEPR', 'Gene', '3953', (63, 67))
292959	31196966	LEPR rs1137101 G>A polymorphism is located on the exon region of LEPR gene, and it has been thought to be involved in the development of cancer by a number of studies.	('rs1137101 G>A', 'Var', (5, 18))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('LEPR', 'Gene', '3953', (0, 4))	('LEPR', 'Gene', '3953', (65, 69))	('involved', 'Reg', (106, 114))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('LEPR', 'Gene', (0, 4))	('rs1137101', 'Mutation', 'rs1137101', (5, 14))	('cancer', 'Disease', (137, 143))	('LEPR', 'Gene', (65, 69))
292960	31196966	Several case-control studies reported that LEPR rs1137101 G>A polymorphism might be associated with the decreased risk of cancer.	('rs1137101', 'Mutation', 'rs1137101', (48, 57))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('LEPR', 'Gene', (43, 47))	('decreased', 'NegReg', (104, 113))	('rs1137101 G>A', 'Var', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('LEPR', 'Gene', '3953', (43, 47))
292965	31196966	reported that LEPR rs1137101 G>A SNP may affect plasma LEP levels and BMI.	('rs1137101 G>A', 'Var', (19, 32))	('LEPR', 'Gene', '3953', (14, 18))	('LEP', 'Gene', (55, 58))	('LEP', 'Gene', (14, 17))	('BMI', 'MPA', (70, 73))	('LEP', 'Gene', '3952', (55, 58))	('LEP', 'Gene', '3952', (14, 17))	('rs1137101', 'Mutation', 'rs1137101', (19, 28))	('LEPR', 'Gene', (14, 18))	('affect', 'Reg', (41, 47))
292967	31196966	However, null associations of LEPR rs1137101 locus with cancer susceptibility was identified, which was analogous to the results reported in previous meta-analyses, but unlike the other four meta-analyses.	('LEPR', 'Gene', '3953', (30, 34))	('associations', 'Interaction', (14, 26))	('rs1137101', 'Mutation', 'rs1137101', (35, 44))	('rs1137101', 'Var', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('LEPR', 'Gene', (30, 34))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
292968	31196966	The minor allele frequency of LEPR rs1137101 G>A polymorphism was difference among different populations, but in stratified analysis by race, null relationship was found.	('rs1137101 G>A', 'Var', (35, 48))	('LEPR', 'Gene', '3953', (30, 34))	('rs1137101', 'Mutation', 'rs1137101', (35, 44))	('LEPR', 'Gene', (30, 34))
292969	31196966	Additionally, results of stratified analyses by sample size and source of control both found no relationship between LEPR rs1137101 G>A polymorphism with overall cancer susceptibility, highlighting that these variables could not influence the negative findings either.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rs1137101 G>A', 'Var', (122, 135))	('cancer', 'Disease', (162, 168))	('LEPR', 'Gene', '3953', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('rs1137101', 'Mutation', 'rs1137101', (122, 131))	('LEPR', 'Gene', (117, 121))
292978	31196966	In summary, this meta-analysis may be the largest sample size so far to assess the potential association of cancer risk with rs1137101 G>A polymorphism in LEPR gene.	('rs1137101', 'Mutation', 'rs1137101', (125, 134))	('LEPR', 'Gene', '3953', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('LEPR', 'Gene', (155, 159))	('rs1137101 G>A', 'Var', (125, 138))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
292979	31196966	There is no significant association of cancer risk was identified to be correlated with rs1137101 G>A variants in the overall comparison, and the similar findings was also found in stratified analysis by ethnicity, cancer type, sample size, and source of control.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('rs1137101', 'Mutation', 'rs1137101', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('rs1137101 G>A', 'Var', (88, 101))
292981	30355311	Distinct esophageal adenocarcinoma molecular subtype has subtype-specific gene expression and mutation patterns Esophageal carcinoma (EC), consists of two histological types, esophageal squamous carcinoma (ESCC) and esophageal adenocarcinoma (EAC).	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (175, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (186, 204))	('esophageal adenocarcinoma molecular subtype', 'Disease', (9, 52))	('ESCC', 'Phenotype', 'HP:0011459', (206, 210))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (175, 204))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('EAC', 'Phenotype', 'HP:0011459', (243, 246))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (216, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (216, 241))	('esophageal squamous carcinoma', 'Disease', (175, 204))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (9, 34))	('EC', 'Phenotype', 'HP:0011459', (134, 136))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (9, 34))	('esophageal adenocarcinoma', 'Disease', (216, 241))	('esophageal adenocarcinoma molecular subtype', 'Disease', 'MESH:D004938', (9, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('Esophageal carcinoma', 'Disease', (112, 132))	('mutation', 'Var', (94, 102))
292997	30355311	The ratio of subtype I to subtype II EAC patients was 1:1.5, 1:1.7 and 1:0.7 for dataset TCGA, GSE13898 and GSE19417, respectively (Additional file 1: Table S1).	('EAC', 'Phenotype', 'HP:0011459', (37, 40))	('GSE13898', 'Var', (95, 103))	('patients', 'Species', '9606', (41, 49))	('EAC', 'Disease', (37, 40))	('GSE19417', 'Var', (108, 116))
292998	30355311	Subsequent Silhouette analysis indicated that 68% (60/88), 99% (74/75) and 100% (52/52) of samples in TCGA, GSE13898 and GSE19417 had positive silhouette values validating the assignments from consensus clustering.	('GSE13898', 'Var', (108, 116))	('men', 'Species', '9606', (182, 185))	('GSE19417', 'Var', (121, 129))	('TCGA', 'Gene', (102, 106))
293010	30355311	When analyzed all these 87 EAC cases as a population using MutSigCV analysis, 69 genes, including TP53, CDKN2A, MUC6, ARID1A, ERBB2 and SMAD4, were found significantly mutated in this cohort (p < 0.01).	('mutated', 'Var', (168, 175))	('SMAD4', 'Gene', '4089', (136, 141))	('CDKN2A', 'Gene', '1029', (104, 110))	('MUC6', 'Gene', '4588', (112, 116))	('ERBB2', 'Gene', '2064', (126, 131))	('SMAD4', 'Gene', (136, 141))	('ERBB2', 'Gene', (126, 131))	('EAC', 'Phenotype', 'HP:0011459', (27, 30))	('TP53', 'Gene', '7157', (98, 102))	('MUC6', 'Gene', (112, 116))	('CDKN2A', 'Gene', (104, 110))	('ARID1A', 'Gene', (118, 124))	('ARID1A', 'Gene', '8289', (118, 124))	('TP53', 'Gene', (98, 102))
293035	30355311	By analyzing the somatic mutations in view of the two molecular subtypes based on the TCGA dataset, we found that TP53 and CDKN2A are as reported to be commonly mutated in the majority of EAC patients regardless of subtypes, indicating that TP53 mutations may be early events in the development of EAC.	('TP53', 'Gene', '7157', (241, 245))	('EAC', 'Phenotype', 'HP:0011459', (298, 301))	('EAC', 'Phenotype', 'HP:0011459', (188, 191))	('patients', 'Species', '9606', (192, 200))	('TP53', 'Gene', (241, 245))	('TP53', 'Gene', '7157', (114, 118))	('mutations', 'Var', (246, 255))	('EAC', 'Disease', (188, 191))	('CDKN2A', 'Gene', (123, 129))	('men', 'Species', '9606', (290, 293))	('EAC', 'Disease', (298, 301))	('TP53', 'Gene', (114, 118))	('CDKN2A', 'Gene', '1029', (123, 129))	('mutated', 'Var', (161, 168))
293038	30355311	However, within our current study, SMAD4 was only found to be significantly mutated in subtype I, in contrast, ARID1A was only significantly mutated in subtype II EAC patients, indicating EAC subtype-specific mutation profile and possible subtype-specific tumorigenesis mechanism.	('EAC', 'Phenotype', 'HP:0011459', (188, 191))	('patients', 'Species', '9606', (167, 175))	('mutated', 'Var', (76, 83))	('ARID1A', 'Gene', '8289', (111, 117))	('SMAD4', 'Gene', '4089', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('ARID1A', 'Gene', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('EAC', 'Phenotype', 'HP:0011459', (163, 166))	('tumor', 'Disease', (256, 261))	('SMAD4', 'Gene', (35, 40))
293059	30355311	The same research group also knocked down KLK11 in colorectal cancer cell line and shown that decreasing of KLK11 expression inhibited the cell proliferation and enhanced the sensitivity to oxaliplatin.	('decreasing', 'NegReg', (94, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('knocked', 'Var', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('KLK11', 'Gene', '11012', (42, 47))	('KLK11', 'Gene', (42, 47))	('KLK11', 'Gene', (108, 113))	('cell proliferation', 'CPA', (139, 157))	('enhanced', 'PosReg', (162, 170))	('colorectal cancer', 'Disease', (51, 68))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (190, 201))	('KLK11', 'Gene', '11012', (108, 113))	('inhibited', 'NegReg', (125, 134))	('sensitivity to oxaliplatin', 'MPA', (175, 201))	('expression', 'MPA', (114, 124))
293145	26893358	In addition, we found that the expression of DEPTOR negatively regulates the tumorigenic activities of ESCC cell lines (KYSE150, KYSE510 and KYSE190).	('KYSE510', 'Var', (129, 136))	('negatively', 'NegReg', (52, 62))	('expression', 'Var', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('regulates', 'Reg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('KYSE150', 'Var', (120, 127))	('ESCC', 'Disease', (103, 107))	('tumor', 'Disease', (77, 82))	('DEPTOR', 'Gene', (45, 51))	('KYSE190', 'Var', (141, 148))
293146	26893358	Meanwhile, CRISPR/Cas9 mediated knockout of DEPTOR in KYSE-510 cells significantly promoted cellular proliferation, migration and invasion.	('knockout', 'Var', (32, 40))	('KYSE-510', 'CellLine', 'CVCL:1354', (54, 62))	('cellular proliferation', 'CPA', (92, 114))	('invasion', 'CPA', (130, 138))	('DEPTOR', 'Gene', (44, 50))	('promoted', 'PosReg', (83, 91))	('migration', 'CPA', (116, 125))
293147	26893358	In addition, in vivo assays further revealed that tumor growth was significantly inhibited in xenografts with ectopic DEPTOR expression as compared to untreated KYSE150 cells, and was markedly enhanced in DEPTOR knockout KYSE-510 cells.	('KYSE-510', 'CellLine', 'CVCL:1354', (221, 229))	('inhibited', 'NegReg', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('enhanced', 'PosReg', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('ectopic', 'Var', (110, 117))	('tumor', 'Disease', (50, 55))
293157	26893358	However, in other subsets of tumor like myeloma, thyroid carcinoma and breast cancer, DEPTOR acts as an oncogene and positively correlates with poor survival of tumor patients, since DEPTOR overexpression simultaneously suppresses S6K1, a downstream molecule of mTOR, and thus relieves the feedback inhibition from mTOR to PI3K, boosting AKT activity for cancer cells survival.	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('activity', 'MPA', (342, 350))	('mTOR', 'Gene', '2475', (315, 319))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('tumor', 'Disease', (161, 166))	('breast cancer', 'Disease', (71, 84))	('AKT', 'Gene', (338, 341))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (49, 66))	('S6K1', 'Gene', (231, 235))	('myeloma', 'Disease', 'MESH:D009101', (40, 47))	('cancer', 'Disease', (355, 361))	('thyroid carcinoma', 'Disease', (49, 66))	('mTOR', 'Gene', (262, 266))	('relieves', 'NegReg', (277, 285))	('cancer', 'Disease', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('boosting', 'PosReg', (329, 337))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (190, 204))	('AKT', 'Gene', '207', (338, 341))	('S6K1', 'Gene', '6198', (231, 235))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (49, 66))	('mTOR', 'Gene', '2475', (262, 266))	('myeloma', 'Disease', (40, 47))	('feedback inhibition', 'MPA', (290, 309))	('DEPTOR', 'Var', (183, 189))	('patients', 'Species', '9606', (167, 175))	('tumor', 'Disease', (29, 34))	('suppresses', 'NegReg', (220, 230))	('mTOR', 'Gene', (315, 319))	('cancer', 'Disease', 'MESH:D009369', (355, 361))
293169	26893358	Meanwhile, the tumor suppressive role of DEPTOR was also confirmed in another cell line KYSE-510 by knockout DEPTOR expression with CRISPER/Cas9 system, as KYSE-510 cells express a higher level of DEPTOR.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('KYSE-510', 'CellLine', 'CVCL:1354', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('DEPTOR expression', 'Gene', (109, 126))	('tumor', 'Disease', (15, 20))	('knockout', 'Var', (100, 108))	('KYSE-510', 'CellLine', 'CVCL:1354', (156, 164))
293180	26893358	Furthermore, Kaplan-Meier survival analysis demonstrated that patients with high DEPTOR expression levels had a higher five year survival rate than that with lower DEPTOR expression in a retrospective cohort study (Figure 1D, p = 0.0469).	('high', 'Var', (76, 80))	('patients', 'Species', '9606', (62, 70))	('higher', 'PosReg', (112, 118))	('five year survival rate', 'CPA', (119, 142))
293186	26893358	For the same consideration, we treated KYSE-510 cells, which expresses highest level of DEPTOR, with CRISPR/Cas9 system to knockout of DEPTOR (CRISPR-DEPTOR).	('DEPTOR', 'Gene', (135, 141))	('knockout', 'Var', (123, 131))	('KYSE-510', 'CellLine', 'CVCL:1354', (39, 47))	('CRISPR-DEPTOR', 'Gene', '64798', (143, 156))	('CRISPR-DEPTOR', 'Gene', (143, 156))
293187	26893358	As shown in Figure 3A and 3B, pcDNA3.1-DEPTOR displayed a reduced cell proliferation rate as compared to that of KYSE-150 parental cells and empty vector transfected cells, while CRISPR-DEPTOR cells proliferated significantly faster than control KYSE-510 cells.	('faster', 'PosReg', (226, 232))	('KYSE-510', 'CellLine', 'CVCL:1354', (246, 254))	('pcDNA3.1-DEPTOR', 'Var', (30, 45))	('cell proliferation rate', 'CPA', (66, 89))	('KYSE-150', 'CellLine', 'CVCL:1348', (113, 121))	('reduced', 'NegReg', (58, 65))	('CRISPR-DEPTOR', 'Gene', '64798', (179, 192))	('CRISPR-DEPTOR', 'Gene', (179, 192))	('proliferated', 'CPA', (199, 211))
293190	26893358	As shown in Figure 4A, DEPTOR expression was significantly increased in KYSE-150 cells as compared with untreated cells or empty vector-transfected cells.	('KYSE-150', 'CellLine', 'CVCL:1348', (72, 80))	('KYSE-150', 'Var', (72, 80))	('increased', 'PosReg', (59, 68))	('DEPTOR expression', 'MPA', (23, 40))
293192	26893358	As a natural inhibitor of mTOR, ectopic expression of DEPTOR resulted in the deactivation of AKT/mTOR pathway, as it inhibited the phosphorylation of AKT, mTOR, SGK1 and NDRG1 (Figure 4A).	('mTOR', 'Gene', (155, 159))	('DEPTOR', 'Gene', (54, 60))	('deactivation', 'NegReg', (77, 89))	('mTOR', 'Gene', '2475', (155, 159))	('NDRG1', 'Gene', (170, 175))	('AKT', 'Gene', (93, 96))	('mTOR', 'Gene', (97, 101))	('AKT', 'Gene', '207', (150, 153))	('mTOR', 'Gene', (26, 30))	('SGK1', 'Gene', '6446', (161, 165))	('mTOR', 'Gene', '2475', (97, 101))	('SGK1', 'Gene', (161, 165))	('mTOR', 'Gene', '2475', (26, 30))	('phosphorylation', 'MPA', (131, 146))	('AKT', 'Gene', '207', (93, 96))	('ectopic expression', 'Var', (32, 50))	('NDRG1', 'Gene', '10397', (170, 175))	('inhibited', 'NegReg', (117, 126))	('AKT', 'Gene', (150, 153))
293193	26893358	And in KYSE-510 cells, knockout of DEPTOR expression significantly enhanced the activation of AKT/mTOR pathway (Figure 4B).	('AKT', 'Gene', '207', (94, 97))	('DEPTOR expression', 'Gene', (35, 52))	('knockout', 'Var', (23, 31))	('AKT', 'Gene', (94, 97))	('mTOR', 'Gene', '2475', (98, 102))	('mTOR', 'Gene', (98, 102))	('KYSE-510', 'CellLine', 'CVCL:1354', (7, 15))	('enhanced', 'PosReg', (67, 75))
293198	26893358	Similarly, in KYSE-510 cells, ablation of DEPTOR significantly promoted tumor growth in nude mice as compared with normal KYSE-510 cells (Figure 5B, 5E and 5F).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('nude mice', 'Species', '10090', (88, 97))	('tumor', 'Disease', (72, 77))	('ablation', 'Var', (30, 38))	('KYSE-510', 'CellLine', 'CVCL:1354', (122, 130))	('promoted', 'PosReg', (63, 71))	('KYSE-510', 'CellLine', 'CVCL:1354', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('DEPTOR', 'Gene', (42, 48))
293207	26893358	Just like in multiple myeloma, one study reported that mTORC1 and mTORC2 inhibitors inhibit tumor growth, including DEPTOR, whereas another study revealed that DEPTOR silence induces cytoreductive effects on multiple myeloma (MM) cells.	('mTORC2', 'Gene', '74343', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('inhibit', 'NegReg', (84, 91))	('multiple myeloma', 'Disease', (13, 29))	('mTORC1', 'Gene', '382056', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('multiple myeloma', 'Phenotype', 'HP:0006775', (208, 224))	('cytoreductive effects', 'CPA', (183, 204))	('multiple myeloma', 'Disease', 'MESH:D009101', (208, 224))	('tumor', 'Disease', (92, 97))	('mTORC2', 'Gene', (66, 72))	('multiple myeloma', 'Phenotype', 'HP:0006775', (13, 29))	('inhibitors', 'Var', (73, 83))	('multiple myeloma', 'Disease', 'MESH:D009101', (13, 29))	('multiple myeloma', 'Disease', (208, 224))	('mTORC1', 'Gene', (55, 61))
293208	26893358	This may be due to that about 21-28% of human MMs were shown to harbor Cyclin D1/D3 or c-MAF/MAFB translocations, and possess copy number gains and associated expression increases of the genes within a 6 Mb region of chromosome 8q24 that contains DEPTOR.	('MAFB', 'Gene', '9935', (93, 97))	('gains', 'PosReg', (138, 143))	('Cyclin D1/D3', 'Gene', (71, 83))	('c-MAF', 'Gene', (87, 92))	('increases', 'PosReg', (170, 179))	('translocations', 'Var', (98, 112))	('c-MAF', 'Gene', '4094', (87, 92))	('Cyclin D1/D3', 'Gene', '595;896', (71, 83))	('expression', 'MPA', (159, 169))	('copy number', 'Var', (126, 137))	('MAFB', 'Gene', (93, 97))	('human', 'Species', '9606', (40, 45))
293210	26893358	Aberrant activation of the mTOR pathway has been identified in ESCC, and mTOR specific inhibitors, like everolimus, rapamycin and PP242, exert therapeutic effects both as a single agent and in combination with cisplatin.	('mTOR', 'Gene', '2475', (73, 77))	('activation', 'PosReg', (9, 19))	('mTOR', 'Gene', (73, 77))	('everolimus', 'Chemical', 'MESH:D000068338', (104, 114))	('PP242', 'Chemical', 'MESH:C572919', (130, 135))	('cisplatin', 'Chemical', 'MESH:D002945', (210, 219))	('PP242', 'Var', (130, 135))	('rapamycin', 'Chemical', 'MESH:D020123', (116, 125))	('ESCC', 'Disease', (63, 67))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))
293211	26893358	Among these inhibitor, PP242 is a dual mTORC1 and mTORC2 inhibitor that similar with DEPTOR, which has been reported to suppress proliferation, metastasis, and angiogenesis of gastric cancer cells through inhibition of the PI3K/AKT/mTOR pathway.	('mTORC2', 'Gene', (50, 56))	('mTOR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('AKT', 'Gene', (228, 231))	('angiogenesis', 'CPA', (160, 172))	('inhibition', 'NegReg', (205, 215))	('mTORC2', 'Gene', '74343', (50, 56))	('mTOR', 'Gene', '2475', (50, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('mTOR', 'Gene', (232, 236))	('PP242', 'Chemical', 'MESH:C572919', (23, 28))	('suppress', 'NegReg', (120, 128))	('mTORC1', 'Gene', (39, 45))	('AKT', 'Gene', '207', (228, 231))	('mTOR', 'Gene', (39, 43))	('proliferation', 'CPA', (129, 142))	('mTORC1', 'Gene', '382056', (39, 45))	('mTOR', 'Gene', '2475', (232, 236))	('gastric cancer', 'Disease', (176, 190))	('PP242', 'Var', (23, 28))	('mTOR', 'Gene', '2475', (39, 43))	('metastasis', 'CPA', (144, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))
293212	26893358	As far as the role of DEPTOR in ESCC progression, we found that ectopic expression of DEPTOR inhibited the activation of AKT/mTOR pathway, and suppressed proliferation, migration, and invasion as well as in vivo tumor growth of ESCC cells with relatively low DEPTOR expression.	('DEPTOR', 'Gene', (86, 92))	('invasion', 'CPA', (184, 192))	('mTOR', 'Gene', '2475', (125, 129))	('AKT', 'Gene', (121, 124))	('migration', 'CPA', (169, 178))	('suppressed', 'NegReg', (143, 153))	('mTOR', 'Gene', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('ectopic expression', 'Var', (64, 82))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('proliferation', 'CPA', (154, 167))	('AKT', 'Gene', '207', (121, 124))	('tumor', 'Disease', (212, 217))	('inhibited', 'NegReg', (93, 102))
293278	27149488	Clinical T stage was defined with these criteria: stage cT2, esophageal tumor wall thickness >5 mm with high enhancement and smooth outer membrane surface; cT3, esophageal tumor penetrated adventitia with irregular outer membrane surface; and cT4, esophageal tumor invaded adjacent structures including bronchi, aorta, pericardium, or vertebrae.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('invaded', 'Reg', (265, 272))	('esophageal tumor', 'Disease', 'MESH:D004938', (161, 177))	('adventitia', 'Disease', 'None', (189, 199))	('cT3', 'Gene', '285782', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('cT3', 'Gene', (156, 159))	('enhancement', 'PosReg', (109, 120))	('esophageal tumor', 'Disease', 'MESH:D004938', (248, 264))	('adventitia', 'Disease', (189, 199))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cT2', 'Gene', (56, 59))	('cT2', 'Gene', '386757', (56, 59))	('esophageal tumor', 'Disease', (61, 77))	('esophageal tumor', 'Phenotype', 'HP:0100751', (61, 77))	('cT4', 'Var', (243, 246))	('esophageal tumor', 'Disease', (161, 177))	('esophageal tumor', 'Phenotype', 'HP:0100751', (161, 177))	('esophageal tumor', 'Disease', (248, 264))	('esophageal tumor', 'Disease', 'MESH:D004938', (61, 77))	('esophageal tumor', 'Phenotype', 'HP:0100751', (248, 264))
293335	26619400	We profiled the mutations and changes in copy number that were identified by whole-exome sequencing and array-based comparative genomic hybridization in multiple regions within an ESCC from two patients.	('copy number', 'MPA', (41, 52))	('mutations', 'Var', (16, 25))	('patients', 'Species', '9606', (194, 202))
293336	26619400	The average mutational heterogeneity rate was 90% in all regions of the individual tumors in each patient; most somatic point mutations were nonsynonymous substitutions, small Indels occurred in untranslated regions of genes, and copy number alterations varied among multiple regions of a tumor.	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('patient', 'Species', '9606', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumor', 'Disease', (83, 88))	('point mutations', 'Var', (120, 135))	('nonsynonymous substitutions', 'Var', (141, 168))	('tumors', 'Disease', (83, 89))	('tumor', 'Disease', (289, 294))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
293339	26619400	Cancer is a disease of genome instability and a resulting accumulation of genetic and epigenetic alteration.	('epigenetic alteration', 'Var', (86, 107))	('genetic', 'Var', (74, 81))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
293346	26619400	We show here that each tumor region has substantial genomic heterogeneity with its own unique profile of mutations and copy number alterations.	('tumor', 'Disease', (23, 28))	('copy number alterations', 'Var', (119, 142))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (23, 28))
293351	26619400	PtA was diagnosed with ESCC without lymph node invasion, clinical stage was T2N0M0; PtB was diagnosed with advanced ESCC with lymph node metastasis, clinical stage was T3N2M0.	('PtA', 'Gene', (0, 3))	('ESCC', 'Disease', (23, 27))	('T3N2M0', 'Var', (168, 174))	('T2N0M0', 'Var', (76, 82))	('PtB', 'Gene', (84, 87))	('PtA', 'Gene', '171558', (0, 3))	('PtB', 'Gene', '5725', (84, 87))
293352	26619400	The non-silent mutations (nonsynonymous, stop-gain and splice site mutations) comprise more than 50% of the defined mutations in each tumor region (Supplementary Figures S1c and d).	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mutations', 'Var', (116, 125))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
293353	26619400	The predominant type of mutation in both patients is a C>T/G>A transition; the second most frequent mutation is an A>G/T>C transition in PtA, and a C>G/G>C transversion in PtB (Supplementary Figure S2).	('A>G/T>C', 'Var', (115, 122))	('C>G/G>C transversion', 'Var', (148, 168))	('C>T/G>A', 'Var', (55, 62))	('PtB', 'Gene', (172, 175))	('PtB', 'Gene', '5725', (172, 175))	('patients', 'Species', '9606', (41, 49))	('PtA', 'Gene', '171558', (137, 140))	('PtA', 'Gene', (137, 140))
293355	26619400	We then asked what genes are affected by the identified mutations across the tumor regions in each patient.	('patient', 'Species', '9606', (99, 106))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
293357	26619400	Similarly, all tumor regions in PtB, including the metastasis, shared only 11% of the 248 mutated genes with SPMs and 12% of the 117 mutated genes with Indels (Figures 1d and f).	('SPMs', 'Var', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('PtB', 'Gene', (32, 35))	('PtB', 'Gene', '5725', (32, 35))
293359	26619400	Both patients have similar average intratumor heterogeneity rates of approximately 90% for mutated genes with either SPMs or Indels.	('patients', 'Species', '9606', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('SPMs', 'Var', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Indels', 'Var', (125, 131))
293360	26619400	Copy number alterations in multiple regions of ESCC were surveyed using aCGH, and the amplifications and deletions of chromosomes were identified in each tumor region from PtA and PtB (Figure 2 and Supplementary Figures S3a and b).	('PtA', 'Gene', (172, 175))	('deletions', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('PtB', 'Gene', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PtA', 'Gene', '171558', (172, 175))	('PtB', 'Gene', '5725', (180, 183))	('tumor', 'Disease', (154, 159))
293361	26619400	In PtA, 430 chromosomal segments were amplified or deleted in at least one region and among them, 71 (17%) genomic loci were amplified and 8 (2%) genomic loci were deleted in all four regions of the tumor (Figure 2a).	('tumor', 'Disease', (199, 204))	('PtA', 'Gene', (3, 6))	('deleted', 'Var', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('PtA', 'Gene', '171558', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
293365	26619400	We note that the known frequent somatic CNVs, involving 3q26 (PRKCI gene amplification), 9p21 (SOX2 gene amplification) and 11q13.3 (CCTN gene amplification), were detected in this study.	('SOX2', 'Gene', (95, 99))	('SOX2', 'Gene', '6657', (95, 99))	('PRKCI', 'Gene', '5584', (62, 67))	('9p21', 'Var', (89, 93))	('PRKCI', 'Gene', (62, 67))
293367	26619400	To characterize intratumor heterogeneity of the non-silent mutated genes, we used the 'trunk' to represent ubiquitous mutations present in all regions of a tumor, the 'branch' to stand for heterogeneous mutations present in some, but not all regions of the tumor, and 'private' to correspond to mutations that are present in only one region of a tumor.	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mutations', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Disease', (346, 351))
293369	26619400	In PtB, 27 of 203 mutant genes were in the trunk, 76 mutant genes were located in the branch section and 100 genes were private mutations.	('PtB', 'Gene', '5725', (3, 6))	('mutant', 'Var', (18, 24))	('PtB', 'Gene', (3, 6))
293371	26619400	To determine whether these non-silent mutated genes are associated with cancer, we searched for our identified mutant genes in the COSMIC (Catalog Of Somatic Mutations In Cancer) database and other cancer-related studies.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Cancer', 'Disease', (171, 177))	('cancer', 'Disease', (198, 204))	('mutant', 'Var', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
293372	26619400	There are 52 recognized cancer gene mutations across the tumor regions in PtA and 55 recognized cancer gene mutations across the tumor regions in PtB, and they are listed on the right side of the respective heatmaps in Figures 3b and c. In the trunk of the heatmap, 8 of the 17 mutated genes in PtA and 9 of the 27 mutated genes in PtB are known cancer-associated genes.	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('cancer', 'Disease', (24, 30))	('tumor', 'Disease', (129, 134))	('PtA', 'Gene', (74, 77))	('cancer', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('PtA', 'Gene', '171558', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (57, 62))	('PtA', 'Gene', (295, 298))	('PtB', 'Gene', (332, 335))	('PtB', 'Gene', '5725', (332, 335))	('cancer', 'Disease', (346, 352))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PtA', 'Gene', '171558', (295, 298))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('mutations', 'Var', (108, 117))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('PtB', 'Gene', (146, 149))	('PtB', 'Gene', '5725', (146, 149))
293373	26619400	PtB is a more advanced case with adjacent lymph node metastasis and we note that the TP53 (C85X, C85Y) mutation was detected in all tumor regions of PtB (but not PtA) and the metastatic region (M) of PtB has 18 cancer-associated gene mutations.	('C85X', 'Mutation', 'p.C85X', (91, 95))	('PtA', 'Gene', (162, 165))	('tumor', 'Disease', (132, 137))	('PtB', 'Gene', (200, 203))	('PtB', 'Gene', '5725', (200, 203))	('TP53', 'Gene', (85, 89))	('PtA', 'Gene', '171558', (162, 165))	('PtB', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('C85Y', 'Var', (97, 101))	('PtB', 'Gene', '5725', (0, 3))	('PtB', 'Gene', (149, 152))	('PtB', 'Gene', '5725', (149, 152))	('C85X', 'Var', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('TP53', 'Gene', '7157', (85, 89))	('C85Y', 'Mutation', 'p.C85Y', (97, 101))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
293376	26619400	As well, the subclonal populations harbor their own private mutations, while continuing to maintain a stable phenotype or cancer property.	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
293377	26619400	PtA had a total of 232 detected mutations in UTRs and PtB had a total of 366.	('PtB', 'Gene', '5725', (54, 57))	('PtA', 'Gene', (0, 3))	('mutations', 'Var', (32, 41))	('UTRs', 'Gene', (45, 49))	('PtA', 'Gene', '171558', (0, 3))	('PtB', 'Gene', (54, 57))
293378	26619400	Two genes, CTDSPL2 (Chr15:44818173-44818173, an 'A' insertion) in region T3A and BCL7A (Chr12: 122498799-122498799, an 'A' insertion) in region T4A, were predicted to have mutations in 3'-UTR disrupting microRNA-binding sites that are recognized by miR129/129-5p and miR204/211, respectively.	('T4A', 'Mutation', 'rs780691617', (144, 147))	('mutations', 'Var', (172, 181))	('CTDSPL2', 'Gene', '51496', (11, 18))	('microRNA-binding sites', 'MPA', (203, 225))	('miR204', 'Gene', (267, 273))	('miR129/129-5p', 'Var', (249, 262))	('T3A', 'Mutation', 'c.3T>A', (73, 76))	('disrupting', 'NegReg', (192, 202))	('miR204', 'Gene', '406987', (267, 273))	('BCL7A', 'Gene', '605', (81, 86))	('BCL7A', 'Gene', (81, 86))	('CTDSPL2', 'Gene', (11, 18))
293379	26619400	The UTR mutations in PtB were not predicted to affect known microRNA-binding sites.	('PtB', 'Gene', (21, 24))	('microRNA-binding', 'MPA', (60, 76))	('PtB', 'Gene', '5725', (21, 24))	('mutations', 'Var', (8, 17))
293380	26619400	Nevertheless, the majority of identified UTR mutations in both PtA and PtB appear to be of unknown significance.	('PtB', 'Gene', '5725', (71, 74))	('mutations', 'Var', (45, 54))	('PtA', 'Gene', (63, 66))	('UTR', 'Gene', (41, 44))	('PtB', 'Gene', (71, 74))	('PtA', 'Gene', '171558', (63, 66))
293382	26619400	Most mutated genes do express and produce abnormal proteins and they may be components of different cancer pathways.	('components', 'Reg', (76, 86))	('proteins', 'Protein', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutated genes', 'Var', (5, 18))	('express', 'MPA', (22, 29))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('produce', 'Reg', (34, 41))
293387	26619400	For example, MUC17, MUC5B and MUC6 gene mutations in tumor region T4A of PtA (Table 1) predict the perturbation of O-glycan biosynthesis and processing, and the GO terms in T4A differ from GO terms in other tumor regions.	('MUC17', 'Gene', '140453', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('T4A', 'Mutation', 'rs780691617', (173, 176))	('PtA', 'Gene', (73, 76))	('MUC5B', 'Gene', '727897', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (40, 49))	('O-glycan', 'Chemical', '-', (115, 123))	('PtA', 'Gene', '171558', (73, 76))	('MUC5B', 'Gene', (20, 25))	('tumor', 'Disease', (207, 212))	('processing', 'MPA', (141, 151))	('MUC6', 'Gene', (30, 34))	('T4A', 'Mutation', 'rs780691617', (66, 69))	('MUC6', 'Gene', '4588', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('MUC17', 'Gene', (13, 18))	('tumor', 'Disease', (53, 58))	('O-glycan biosynthesis', 'MPA', (115, 136))
293388	26619400	Similarly, mutations in the tumor regions from PtB suggest heterogeneous signaling pathways and biological processes, such as the HGF, PIK3R2 and TP53 mutations, which are known to result in cancer pathway activation.	('mutations', 'Var', (11, 20))	('tumor', 'Disease', (28, 33))	('PIK3R2', 'Gene', (135, 141))	('HGF', 'Gene', '3082', (130, 133))	('heterogeneous', 'MPA', (59, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('cancer', 'Disease', (191, 197))	('HGF', 'Gene', (130, 133))	('TP53', 'Gene', (146, 150))	('PIK3R2', 'Gene', '5296', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutations', 'Var', (151, 160))	('PtB', 'Gene', (47, 50))	('PtB', 'Gene', '5725', (47, 50))	('biological processes', 'CPA', (96, 116))	('activation', 'PosReg', (206, 216))	('TP53', 'Gene', '7157', (146, 150))	('cancer', 'Disease', 'MESH:D009369', (191, 197))
293389	26619400	Mutations of genes CSN2, ESR1 and PIK3R2 may damage the prolactin-signaling pathway (Table 1).	('CSN2', 'Gene', '1447', (19, 23))	('PIK3R2', 'Gene', '5296', (34, 40))	('damage', 'NegReg', (45, 51))	('ESR1', 'Gene', (25, 29))	('prolactin-signaling pathway', 'Pathway', (56, 83))	('Mutations', 'Var', (0, 9))	('ESR1', 'Gene', '2099', (25, 29))	('PIK3R2', 'Gene', (34, 40))	('CSN2', 'Gene', (19, 23))
293390	26619400	These data indicate that the divergent complexity of mutations, which is identified by genotyping of the separate tumor regions, may inevitably change the biological functionalities that are linked to intratumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('change', 'Reg', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (206, 211))	('mutations', 'Var', (53, 62))	('tumor', 'Disease', (114, 119))	('biological functionalities', 'MPA', (155, 181))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
293398	26619400	We found extensive divergent mutational profiles of SPMs, Indels, copy number amplifications and deletions in the spatially separated samples within each tumor and metastasis with an average intratumor heterogeneity rate 90% (Figures 1 and 2).	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('copy number amplifications', 'Var', (66, 92))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('Indels', 'Var', (58, 64))	('deletions', 'Var', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('SPMs', 'Gene', (52, 56))	('tumor', 'Disease', (154, 159))
293400	26619400	The overall percentage of shared mutations between multiple tumor regions of ESCC in this study is dramatically lower than in other types of cancer such as clear cell renal cell carcinoma (30~35%) and high-grade serous ovarian cancers (52%).	('ESCC', 'Gene', (77, 81))	('mutations', 'Var', (33, 42))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (156, 187))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('tumor', 'Disease', (60, 65))	('serous ovarian cancers', 'Disease', (212, 234))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (212, 234))	('lower', 'NegReg', (112, 117))	('cancer', 'Disease', (141, 147))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (156, 187))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Disease', (227, 233))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('ovarian cancers', 'Phenotype', 'HP:0100615', (219, 234))	('clear cell renal cell carcinoma', 'Disease', (156, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
293406	26619400	For example, the mutated genes common in all tumor regions from PtA, BCL6B, MYH11, SUFU act as tumor suppressor genes, and mutations in BCL6B (Indel), MYH11(M816K) and SUFU(Y90S) could inactivate the gene function and contribute to tumorigenesis.	('BCL6B', 'Gene', (69, 74))	('tumor', 'Disease', (45, 50))	('M816K', 'Mutation', 'p.M816K', (157, 162))	('gene function', 'MPA', (200, 213))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('Y90S', 'Mutation', 'p.Y90S', (173, 177))	('contribute', 'Reg', (218, 228))	('SUFU', 'Gene', (83, 87))	('inactivate', 'NegReg', (185, 195))	('SUFU', 'Gene', '51684', (168, 172))	('tumor', 'Disease', (232, 237))	('PtA', 'Gene', (64, 67))	('MYH11', 'Gene', '4629', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('BCL6B', 'Gene', '255877', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('MYH11', 'Gene', (151, 156))	('PtA', 'Gene', '171558', (64, 67))	('BCL6B', 'Gene', (136, 141))	('tumor', 'Disease', (95, 100))	('SUFU', 'Gene', (168, 172))	('MYH11', 'Gene', '4629', (76, 81))	('BCL6B', 'Gene', '255877', (69, 74))	('SUFU', 'Gene', '51684', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('MYH11', 'Gene', (76, 81))	('mutations', 'Var', (123, 132))
293407	26619400	Over expression of DCBLD2 may act as an oncogene interacting with the EGFR and PI3K/Akt signaling pathways; gain of function of DCBLD2 mutation (Indel) could participate with cellular proliferative pathways to promote tumor progression.	('gain of function', 'PosReg', (108, 124))	('Akt', 'Gene', '207', (84, 87))	('EGFR', 'Gene', '1956', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('DCBLD2', 'Gene', '131566', (19, 25))	('Akt', 'Gene', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('participate', 'Reg', (158, 169))	('DCBLD2', 'Gene', (128, 134))	('promote', 'PosReg', (210, 217))	('EGFR', 'Gene', (70, 74))	('cellular', 'CPA', (175, 183))	('DCBLD2', 'Gene', (19, 25))	('mutation', 'Var', (135, 143))	('DCBLD2', 'Gene', '131566', (128, 134))
293410	26619400	CENPE is another trunk mutation gene in PtB and normally, it has a key role in the movement of chromosomes toward the metaphase plate during mitosis; the observed CENPE (Q1302E) gene mutation may disrupt its normal function and lead to chromosomal instability, but again, it only was found in PtB.	('CENPE', 'Gene', '1062', (163, 168))	('mitosis', 'Disease', 'None', (141, 148))	('PtB', 'Gene', '5725', (40, 43))	('disrupt', 'NegReg', (196, 203))	('chromosomal instability', 'Phenotype', 'HP:0040012', (236, 259))	('chromosomal instability', 'MPA', (236, 259))	('CENPE', 'Gene', (163, 168))	('normal function', 'MPA', (208, 223))	('CENPE', 'Gene', '1062', (0, 5))	('PtB', 'Gene', (293, 296))	('mutation', 'Var', (183, 191))	('PtB', 'Gene', '5725', (293, 296))	('PtB', 'Gene', (40, 43))	('lead to', 'Reg', (228, 235))	('mitosis', 'Disease', (141, 148))	('Q1302E', 'Mutation', 'rs751898156', (170, 176))	('CENPE', 'Gene', (0, 5))
293411	26619400	These mutations in UTRs and the dysregulation of their functions are usually not reported in current studies of intratumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('UTRs', 'Gene', (19, 23))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('mutations', 'Var', (6, 15))
293412	26619400	In our computational search, we found multiple microRNA-binding sites mutated in target genes CTDSPL2 in region T3A and BCL7A in region T4A from PtA.	('CTDSPL2', 'Gene', (94, 101))	('BCL7A', 'Gene', (120, 125))	('PtA', 'Gene', '171558', (145, 148))	('CTDSPL2', 'Gene', '51496', (94, 101))	('PtA', 'Gene', (145, 148))	('T4A', 'Mutation', 'rs780691617', (136, 139))	('T3A', 'Mutation', 'c.3T>A', (112, 115))	('mutated', 'Var', (70, 77))	('BCL7A', 'Gene', '605', (120, 125))
293415	26619400	The present analysis unequivocally indicates that clonal subpopulations co-exist in the primary tumor and a metastatic subpopulation may be derived by additional mutations from initially non-metastatic parental clones in the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('mutations', 'Var', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
293460	26556718	We and others have shown that (1) COX-2 expression is a frequent phenomenon in human ESCC tissue samples and that positive expression is related to lymphatic metastasis; (2) COX-2 inhibitors inhibit cell proliferation and induce apoptosis by inducing G0 / G1 cell-cycle arrest and down-regulating Bcl-2 expression and the inhibition of COX-2 leads to tumor reduction in vivo; and (3) a COX-2 inhibitor can inhibit migration and invasion of ESCC cells These findings thus provide compelling evidence that COX-2 is an obligatory player in ESCC and that blocking COX-2 is an important therapeutic targets of ESCC.	('COX-2', 'Gene', '5743', (34, 39))	('inhibit', 'NegReg', (191, 198))	('inhibit', 'NegReg', (406, 413))	('COX-2', 'Gene', (174, 179))	('COX-2', 'Gene', '5743', (386, 391))	('human', 'Species', '9606', (79, 84))	('cell proliferation', 'CPA', (199, 217))	('tumor', 'Disease', (351, 356))	('Bcl-2', 'Gene', (297, 302))	('expression', 'MPA', (303, 313))	('inhibitors', 'Var', (180, 190))	('down-regulating', 'NegReg', (281, 296))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('COX-2', 'Gene', '5743', (174, 179))	('G0 / G1 cell-cycle arrest', 'CPA', (251, 276))	('COX-2', 'Gene', (560, 565))	('COX-2', 'Gene', (386, 391))	('Bcl-2', 'Gene', '596', (297, 302))	('COX-2', 'Gene', (336, 341))	('COX-2', 'Gene', (504, 509))	('COX-2', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('COX-2', 'Gene', '5743', (560, 565))	('invasion', 'CPA', (428, 436))	('migration', 'CPA', (414, 423))	('inducing', 'PosReg', (242, 250))	('reduction', 'NegReg', (357, 366))	('COX-2', 'Gene', '5743', (336, 341))	('COX-2', 'Gene', '5743', (504, 509))	('apoptosis', 'CPA', (229, 238))
293461	26556718	So far, there are three main COX-2 block methods: COX-2 inhibitors, inhibitory transcription factors and post-transcriptional control.	('COX-2', 'Gene', (29, 34))	('COX-2', 'Gene', '5743', (29, 34))	('COX-2', 'Gene', (50, 55))	('inhibitors', 'Var', (56, 66))	('COX-2', 'Gene', '5743', (50, 55))
293472	26556718	The human ESCC cell lines KYSE30, KYSE70, KYSE150, KYSE410, KYSE450, KYSE510, EC9706, and EC109 were kindly provided by the Cancer Institute and Hospital, Chinese Academy of Medical Science.	('EC9706', 'CellLine', 'CVCL:E307', (78, 84))	('KYSE150', 'Var', (42, 49))	('human', 'Species', '9606', (4, 9))	('KYSE70', 'Var', (34, 40))	('KYSE510', 'Var', (69, 76))	('KYSE410', 'Var', (51, 58))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('KYSE450', 'Var', (60, 67))
293489	26556718	Stably transfected cells (1.5 x 106 in 0.2 mL) were injected subcutaneously into the right (EC9706 / EC109-miR-101) and left (EC9706 / EC109-vector) dorsal flank of severe combined immunodeficiency mice (SCID; Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences), five mice per group.	('SCID', 'Disease', (204, 208))	('immunodeficiency', 'Disease', (181, 197))	('immunodeficiency', 'Disease', 'MESH:D007153', (181, 197))	('EC9706', 'CellLine', 'CVCL:E307', (126, 132))	('SCID', 'Disease', 'MESH:D053632', (204, 208))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (165, 197))	('mice', 'Species', '10090', (294, 298))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (172, 197))	('EC9706 / EC109-vector', 'Var', (126, 147))	('mice', 'Species', '10090', (198, 202))	('miR-101', 'Gene', '387143', (107, 114))	('miR-101', 'Gene', (107, 114))	('EC9706', 'CellLine', 'CVCL:E307', (92, 98))	('immunodeficiency', 'Phenotype', 'HP:0002721', (181, 197))
293492	26556718	There were two groups (EC9706 / EC109-vector and EC9706 / EC109-miR-101) in the animal study and each group had five mice.	('miR-101', 'Gene', '387143', (64, 71))	('EC9706', 'CellLine', 'CVCL:E307', (23, 29))	('miR-101', 'Gene', (64, 71))	('EC9706 / EC109-vector', 'Var', (23, 44))	('mice', 'Species', '10090', (117, 121))	('EC9706', 'CellLine', 'CVCL:E307', (49, 55))
293505	26556718	First, we observed that both EC9706 and EC109 cells over-expressing ectopic miR-101 exhibited a morphological change with a decrease of volume compared to the typical morphology of parent cells and the vector-control (Fig 2A).	('over-expressing', 'PosReg', (52, 67))	('EC9706', 'CellLine', 'CVCL:E307', (29, 35))	('ectopic', 'Var', (68, 75))	('volume', 'MPA', (136, 142))	('decrease', 'NegReg', (124, 132))	('miR-101', 'Gene', '387143', (76, 83))	('miR-101', 'Gene', (76, 83))
293521	26556718	Based on this information, luciferase reporters containing mutant binding sites were constructed (Fig 5A), in order to verify whether COX-2 is a direct target of miR-101 in human ESCC.	('mutant', 'Var', (59, 65))	('COX-2', 'Gene', (134, 139))	('human', 'Species', '9606', (173, 178))	('miR-101', 'Gene', '387143', (162, 169))	('miR-101', 'Gene', (162, 169))	('COX-2', 'Gene', '5743', (134, 139))
293525	26556718	In addition, the proliferation, migration and invasion abilities of miR-101-transfected cells increased with PGE2 supplementation in the culture medium (Fig 5D and 5E; P < 0.001).	('proliferation', 'CPA', (17, 30))	('supplementation', 'Var', (114, 129))	('PGE2', 'Gene', (109, 113))	('miR-101', 'Gene', '387143', (68, 75))	('miR-101', 'Gene', (68, 75))	('increased', 'PosReg', (94, 103))	('migration', 'CPA', (32, 41))	('invasion abilities', 'CPA', (46, 64))	('PGE2', 'Chemical', 'MESH:D015232', (109, 113))
293570	24888266	The trial provided evidence that minimally invasive esophagectomy was associated with a lower incidence of in-hospital pulmonary infection (12% versus 34%) and a shorter hospital stay (median 11 days versus 14 days) compared to open surgery.	('minimally', 'Var', (33, 42))	('pulmonary infection', 'Disease', (119, 138))	('pulmonary infection', 'Phenotype', 'HP:0006532', (119, 138))	('pulmonary infection', 'Disease', 'MESH:D008171', (119, 138))	('lower', 'NegReg', (88, 93))
293583	24888266	Participants may enter the study if ALL of the following apply: (1) male or female patients, (2) over 18 years of age, (3) referred by the MDT for primary esophagectomy or esophagectomy following restaging after neoadjuvant chemotherapy (of any type including chemoradiotherapy), (4) confirmed histopathological evidence of esophageal or esophago-gastric junctional adenocarcinoma, squamous cell cancer, or high-grade dysplasia, (5) fit for preoperative anaesthesia and surgery, assessed by the MDT, (6) able to provide written informed consent, (7) endoscopic measurement before chemotherapy that the tumor starts more than 5 cm below the crico-pharyngeus, (8) endoscopic measurement before chemotherapy that the tumor involves less than 4 cm of the gastric wall, and (9) the final pretreatment tumor stage is between high-grade dysplasia and T4aN1M0.	('squamous cell cancer', 'Disease', (382, 402))	('tumor', 'Phenotype', 'HP:0002664', (602, 607))	('dysplasia', 'Disease', 'MESH:D004476', (830, 839))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (382, 402))	('tumor', 'Disease', (796, 801))	('squamous cell cancer', 'Disease', 'MESH:D002294', (382, 402))	('tumor', 'Disease', 'MESH:D009369', (796, 801))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Disease', (714, 719))	('tumor', 'Disease', (602, 607))	('esophago-gastric junctional adenocarcinoma', 'Disease', (338, 380))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('tumor', 'Phenotype', 'HP:0002664', (796, 801))	('esophago-gastric junctional adenocarcinoma', 'Phenotype', 'HP:0011459', (338, 380))	('tumor', 'Disease', 'MESH:D009369', (714, 719))	('tumor', 'Disease', 'MESH:D009369', (602, 607))	('dysplasia', 'Disease', (418, 427))	('esophago-gastric junctional adenocarcinoma', 'Disease', 'MESH:D013274', (338, 380))	('Participants', 'Species', '9606', (0, 12))	('dysplasia', 'Disease', (830, 839))	('T4aN1M0', 'Var', (844, 851))	('dysplasia', 'Disease', 'MESH:D004476', (418, 427))	('tumor', 'Phenotype', 'HP:0002664', (714, 719))
293654	21103258	Peroperative trauma due to lymph node dissection and mobilization of the duodenum have been suggested to induce postoperative pancreatitis.	('dissection', 'Var', (38, 48))	('postoperative pancreatitis', 'Disease', (112, 138))	('Peroperative trauma', 'Disease', 'MESH:D007431', (0, 19))	('Peroperative trauma', 'Disease', (0, 19))	('pancreatitis', 'Phenotype', 'HP:0001733', (126, 138))	('induce', 'Reg', (105, 111))	('postoperative pancreatitis', 'Disease', 'MESH:D010149', (112, 138))
293677	21103258	Patient B, a 72-year-old man with a T2N1M0 adenocarcinoma of the esophagus, underwent transthoracic esophagectomy.	('adenocarcinoma of the esophagus', 'Disease', (43, 74))	('man', 'Species', '9606', (25, 28))	('T2N1M0', 'Var', (36, 42))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (48, 74))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (43, 74))	('Patient', 'Species', '9606', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
293684	21103258	Patient C, a 52-year-old man with a T3N1M0 adenocarcinoma of the esophagus, underwent a transhiatal esophagectomy after neoadjuvant chemoradiotherapy.	('adenocarcinoma of the esophagus', 'Disease', (43, 74))	('man', 'Species', '9606', (25, 28))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (48, 74))	('T3N1M0', 'Var', (36, 42))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (43, 74))	('Patient', 'Species', '9606', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
293690	21103258	Patient D, a 78-year-old male with a T3N1M0 adenocarcinoma of the esophagus, underwent a transhiatal esophagectomy.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('adenocarcinoma of the esophagus', 'Disease', (44, 75))	('T3N1M0', 'Var', (37, 43))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (49, 75))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (44, 75))	('Patient', 'Species', '9606', (0, 7))
293746	32429496	GERD leads to chronic inflammation in the esophagus and reflux esophagitis.	('reflux esophagitis', 'Disease', 'MESH:D005764', (56, 74))	('inflammation', 'Disease', (22, 34))	('inflammation in the esophagus', 'Phenotype', 'HP:0100633', (22, 51))	('esophagitis', 'Phenotype', 'HP:0100633', (63, 74))	('inflammation', 'Disease', 'MESH:D007249', (22, 34))	('GERD', 'Var', (0, 4))	('leads to', 'Reg', (5, 13))	('reflux esophagitis', 'Disease', (56, 74))
293753	32429496	While the authors report an increased inflammatory tumor microenvironment and altered intestinal microbiome as potential mechanisms, HFD may also promote EAC through lipid dyshomeostasis and esophageal dysbiosis.	('increased', 'PosReg', (28, 37))	('EAC', 'Phenotype', 'HP:0011459', (154, 157))	('esophageal dysbiosis', 'Disease', 'MESH:D064806', (191, 211))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('lipid dyshomeostasis', 'Disease', (166, 186))	('EAC', 'Disease', (154, 157))	('HFD', 'Var', (133, 136))	('promote', 'PosReg', (146, 153))	('lipid dyshomeostasis', 'Disease', 'MESH:D011017', (166, 186))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('esophageal dysbiosis', 'Disease', (191, 211))
293779	32429496	ESI-L low concentration tuning mix (#G1969-85000) was purchased from Agilent Technologies (Mulgrave, VIC, Australia).	('VIC', 'Gene', (101, 104))	('VIC', 'Gene', '13615', (101, 104))	('#G1969-85000', 'Var', (36, 48))
293823	32429496	We hypothesized that obesity induced by chronic HFD will replicate the chronic inflammation due to interleukin-1beta overexpression, and leads to Barrett's-like epithelium development in wild-type mice.	('mice', 'Species', '10090', (197, 201))	('obesity', 'Phenotype', 'HP:0001513', (21, 28))	('interleukin-1beta', 'Gene', '16176', (99, 116))	('chronic', 'Var', (40, 47))	("Barrett's-like epithelium development", 'CPA', (146, 183))	('inflammation', 'Disease', (79, 91))	('obesity', 'Disease', 'MESH:D009765', (21, 28))	('obesity', 'Disease', (21, 28))	('interleukin-1beta', 'Gene', (99, 116))	('inflammation', 'Disease', 'MESH:D007249', (79, 91))	('leads to', 'Reg', (137, 145))
293826	32429496	Body weight was monitored weekly, and HFD +/- DCA mice had significantly higher body weight than Chow +/- DCA (q < 0.0001), but no difference in body weight was observed between mice +/- DCA in either diet group (Figure 1a).	('DCA', 'Chemical', 'MESH:D003840', (106, 109))	('mice', 'Species', '10090', (178, 182))	('body weight', 'CPA', (80, 91))	('DCA', 'Chemical', 'MESH:D003840', (187, 190))	('DCA', 'Chemical', 'MESH:D003840', (46, 49))	('HFD +/- DCA', 'Var', (38, 49))	('mice', 'Species', '10090', (50, 54))	('higher', 'PosReg', (73, 79))
293864	32429496	This result revealed major differences between the lipidome associated with dietary intervention (Figure 4) and that associated with esophageal pathology (Figure 5).	('lipid', 'Chemical', 'MESH:D008055', (51, 56))	('esophageal pathology', 'Disease', (133, 153))	('dietary intervention', 'Var', (76, 96))	('lipidome', 'MPA', (51, 59))	('associated', 'Reg', (60, 70))
293872	32429496	As evident in Figure 6a, a significant correlation was found between very long chain ceramides and the disease conditions inflammation and metaplasia.	('metaplasia', 'Disease', (139, 149))	('very long chain', 'Var', (69, 84))	('ceramides', 'Chemical', 'MESH:D002518', (85, 94))	('inflammation', 'Disease', 'MESH:D007249', (122, 134))	('inflammation', 'Disease', (122, 134))
293882	32429496	Very long chain ceramides have been reported to increase cancer proliferation, and evade growth suppressor and apoptotic signals.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('evade', 'NegReg', (83, 88))	('cancer', 'Disease', (57, 63))	('Very long chain', 'Var', (0, 15))	('ceramides', 'Chemical', 'MESH:D002518', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('increase', 'PosReg', (48, 56))
293906	32323849	RUNX3 inhibits the invasion and migration of esophageal squamous cell carcinoma by reversing the epithelial-mesenchymal transition through TGF-beta/Smad signaling Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor, and its inactivation may play a crucial role in the carcinogenesis process of numerous cancer types, including esophageal squamous cell carcinoma (ESCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('Runt-related transcription factor 3', 'Gene', '864', (163, 198))	('Runt-related transcription factor 3', 'Gene', (163, 198))	('reversing', 'NegReg', (83, 92))	('esophageal squamous cell carcinoma', 'Disease', (351, 385))	('carcinogenesis', 'Disease', 'MESH:D063646', (292, 306))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('Smad', 'Gene', '4089;4089', (148, 152))	('TGF-beta', 'Gene', '7039', (139, 147))	('inhibits', 'NegReg', (6, 14))	('ESCC', 'Disease', 'MESH:D000077277', (387, 391))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (45, 79))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('RUNX3', 'Gene', '864', (200, 205))	('epithelial-mesenchymal transition', 'CPA', (97, 130))	('TGF-beta', 'Gene', (139, 147))	('RUNX3', 'Gene', '864', (0, 5))	('numerous cancer', 'Disease', 'MESH:D009369', (318, 333))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (351, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (362, 385))	('inactivation', 'Var', (248, 260))	('tumor', 'Disease', (222, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('Smad', 'Gene', (148, 152))	('ESCC', 'Disease', (387, 391))	('RUNX3', 'Gene', (200, 205))	('numerous cancer', 'Disease', (318, 333))	('esophageal squamous cell carcinoma', 'Disease', (45, 79))	('carcinogenesis', 'Disease', (292, 306))	('RUNX3', 'Gene', (0, 5))
293907	32323849	We previously revealed that RUNX3 inactivation was correlated with lymph node metastasis (LNM) and ESCC recurrence.	('RUNX3', 'Gene', (28, 33))	('inactivation', 'Var', (34, 46))	('ESCC', 'Disease', (99, 103))	('ESCC', 'Disease', 'MESH:D000077277', (99, 103))	('correlated', 'Reg', (51, 61))	('lymph node', 'Disease', (67, 77))
293913	32323849	Notably, further analysis revealed that RUNX3 overexpression markedly inhibited the phosphorylation of Smad2/3; RUNX3-overexpressing cells also displayed less sensitivity to TGF-beta1-induced EMT than control cells.	('Smad2/3', 'Gene', (103, 110))	('Smad2/3', 'Gene', '4087;4088', (103, 110))	('RUNX3-overexpressing', 'Var', (112, 132))	('less', 'NegReg', (154, 158))	('inhibited', 'NegReg', (70, 79))	('phosphorylation', 'MPA', (84, 99))
293922	32323849	RUNX3 inactivation is involved in tumor development and metastasis through different processes, including the cell cycle, apoptosis, angiogenesis, EMT, invasion and migration.	('invasion', 'CPA', (152, 160))	('involved', 'Reg', (22, 30))	('tumor', 'Disease', (34, 39))	('inactivation', 'Var', (6, 18))	('apoptosis', 'CPA', (122, 131))	('angiogenesis', 'CPA', (133, 145))	('cell cycle', 'CPA', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('migration', 'CPA', (165, 174))	('RUNX3', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('EMT', 'CPA', (147, 150))
293982	32323849	Furthermore, restoration of RUNX3 expression led to a significant decrease in the expression of MMP-9 (Fig.	('MMP-9', 'Gene', '4318', (96, 101))	('RUNX3', 'Gene', (28, 33))	('expression', 'MPA', (34, 44))	('expression', 'MPA', (82, 92))	('MMP-9', 'Gene', (96, 101))	('decrease', 'NegReg', (66, 74))	('restoration', 'Var', (13, 24))
293991	32323849	Based on the results, the levels of pSmad2/3 significantly increased in the vector group, whereas no significant changes were evident in RUNX3-overexpressing cells (Fig.	('vector', 'Var', (76, 82))	('levels', 'MPA', (26, 32))	('Smad2/3', 'Gene', (37, 44))	('Smad2/3', 'Gene', '4087;4088', (37, 44))	('increased', 'PosReg', (59, 68))
293997	32323849	In an attempt to validate the biological function of RUNX3 in ESCC metastasis, Eca109 and EC9706 cells were transfected with a RUNX3-expressing lentivirus and it was revealed that restoration of RUNX3 expression attenuated invasion and migration abilities.	('RUNX3', 'Gene', (195, 200))	('attenuated', 'NegReg', (212, 222))	('restoration', 'Var', (180, 191))	('ESCC', 'Disease', 'MESH:D000077277', (62, 66))	('ESCC', 'Disease', (62, 66))
294004	32323849	Cumulative research has revealed that TGF-beta signaling is tightly controlled by the phosphorylation of R-Smads and that dephosphorylation of R-Smads disrupts signal relay.	('TGF-beta', 'Gene', (38, 46))	('disrupts', 'NegReg', (151, 159))	('Smad', 'Gene', (107, 111))	('Smad', 'Gene', (145, 149))	('signal relay', 'MPA', (160, 172))	('TGF-beta', 'Gene', '7039', (38, 46))	('dephosphorylation', 'Var', (122, 139))	('Smad', 'Gene', '4089;4089', (107, 111))	('Smad', 'Gene', '4089;4089', (145, 149))
294011	32323849	Our previous studies demonstrated that reactivation of RUNX3 by 5-azacytidine (an anticancer drug) inhibited the malignant behavior of ESCC cells.	('5-azacytidine', 'Var', (64, 77))	('ESCC', 'Disease', (135, 139))	('ESCC', 'Disease', 'MESH:D000077277', (135, 139))	('inhibited', 'NegReg', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('RUNX3', 'Gene', (55, 60))	('reactivation', 'MPA', (39, 51))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('5-azacytidine', 'Chemical', 'MESH:D001374', (64, 77))	('cancer', 'Disease', (86, 92))
294013	32323849	In the present study, evidence is provided that restoration of RUNX3 expression decreased the invasion and migration of ESCC cells by inhibiting EMT.	('RUNX3', 'Gene', (63, 68))	('inhibiting', 'NegReg', (134, 144))	('EMT', 'CPA', (145, 148))	('restoration', 'Var', (48, 59))	('ESCC', 'Disease', (120, 124))	('ESCC', 'Disease', 'MESH:D000077277', (120, 124))	('expression', 'MPA', (69, 79))	('decreased', 'NegReg', (80, 89))
294015	32323849	In our future studies, we will attempt to knock down RUNX3 and develop a lung metastasis model to further validate our results in vivo.	('lung metastasis', 'Disease', (73, 88))	('knock down', 'Var', (42, 52))	('RUNX3', 'Gene', (53, 58))	('lung metastasis', 'Disease', 'MESH:D009362', (73, 88))
294019	32323849	The findings herein support the hypothesis that targeted therapies for RUNX3 may serve as complementary treatment approaches to control postoperative LNM and improve the survival of ESCC patients.	('patients', 'Species', '9606', (187, 195))	('targeted therapies', 'Var', (48, 66))	('survival', 'MPA', (170, 178))	('control', 'Disease', (128, 135))	('improve', 'PosReg', (158, 165))	('ESCC', 'Disease', (182, 186))	('ESCC', 'Disease', 'MESH:D000077277', (182, 186))	('RUNX3', 'Gene', (71, 76))
294024	32025000	Early TP53 Alterations Engage Environmental Exposures to Promote Gastric Premalignancy in an Integrative Mouse Model Somatic alterations in cancer genes are being detected in normal and premalignant tissue, placing greater emphasis on gene-environment interactions that enable disease phenotypes.	('TP53', 'Gene', '22059', (6, 10))	('Gastric Premalignancy', 'Disease', (65, 86))	('TP53', 'Gene', (6, 10))	('Gastric Premalignancy', 'Disease', 'MESH:D013274', (65, 86))	('Alterations', 'Var', (11, 22))	('Mouse', 'Species', '10090', (105, 110))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('Promote', 'PosReg', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
294025	32025000	By combining early genetic alterations with disease-relevant exposures, we developed an integrative mouse model to study gastric premalignancy.	('gastric premalignancy', 'Disease', 'MESH:D013274', (121, 142))	('mouse', 'Species', '10090', (100, 105))	('gastric premalignancy', 'Disease', (121, 142))	('alterations', 'Var', (27, 38))
294026	32025000	Deletion of Trp53 in gastric cells confers a selective advantage and promotes the development of dysplasia in the setting of dietary carcinogens.	('dysplasia', 'Disease', (97, 106))	('Trp53', 'Gene', '22059', (12, 17))	('promotes', 'PosReg', (69, 77))	('dysplasia', 'Disease', 'MESH:C536170', (97, 106))	('Trp53', 'Gene', (12, 17))	('advantage', 'PosReg', (55, 64))	('Deletion', 'Var', (0, 8))
294028	32025000	Cell cycle regulators, most notably Cdkn2a, were upregulated by p53 inactivation in gastric premalignancy, serving as a barrier to disease progression.	('Cdkn2a', 'Gene', '12578', (36, 42))	('gastric premalignancy', 'Disease', 'MESH:D013274', (84, 105))	('Cdkn2a', 'Gene', (36, 42))	('gastric premalignancy', 'Disease', (84, 105))	('upregulated', 'PosReg', (49, 60))	('p53', 'Gene', (64, 67))	('inactivation', 'Var', (68, 80))	('Cell', 'CPA', (0, 4))
294029	32025000	Co-deletion of Cdkn2a and Trp53 in dysplastic gastric organoids promoted cancer phenotypes but also induced replication stress, exposing a susceptibility to DNA damage response pathway inhibitors.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('promoted', 'PosReg', (64, 72))	('Cdkn2a', 'Gene', '12578', (15, 21))	('Cdkn2a', 'Gene', (15, 21))	('Co-deletion', 'Var', (0, 11))	('Trp53', 'Gene', '22059', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('replication stress', 'CPA', (108, 126))	('dysplastic gastric organoids', 'Disease', 'MESH:D013274', (35, 63))	('induced', 'Reg', (100, 107))	('dysplastic gastric organoids', 'Disease', (35, 63))	('Trp53', 'Gene', (26, 31))
294045	32025000	It is now clear that premalignant lesions also incur early enabling mutations as evident from clonal hematopoiesis and intestinal metaplasia, the most recognized precursor lesion to GE adenocarcinoma.	('GE adenocarcinoma', 'Disease', (182, 199))	('GE adenocarcinoma', 'Disease', 'MESH:D000230', (182, 199))	('hematopoiesis', 'Disease', (101, 114))	('incur', 'Reg', (47, 52))	('mutations', 'Var', (68, 77))	('hematopoiesis', 'Disease', 'MESH:C536227', (101, 114))
294046	32025000	By comparing mutation patterns from matched patient-derived premalignant Barrett's esophagus (BE) and esophageal adenocarcinoma lesions, we found that TP53 is mutated early in the progression of GE malignancy, often occurring before dysplasia.	('patient', 'Species', '9606', (44, 51))	('mutated', 'Var', (159, 166))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (102, 127))	('TP53', 'Gene', (151, 155))	('adenocarcinoma lesions', 'Disease', 'MESH:D000230', (113, 135))	('esophageal adenocarcinoma', 'Disease', (102, 127))	('malignancy', 'Disease', 'MESH:D009369', (198, 208))	('dysplasia', 'Disease', 'MESH:C536170', (233, 242))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))	('malignancy', 'Disease', (198, 208))	('dysplasia', 'Disease', (233, 242))	('adenocarcinoma lesions', 'Disease', (113, 135))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (73, 92))
294047	32025000	Deep sequencing of noncancerous gastric epithelium from patients with gastritis showed that just under half harbored TP53 mutations.	('gastritis', 'Disease', (70, 79))	('patients', 'Species', '9606', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('TP53', 'Gene', (117, 121))	('cancer', 'Disease', (22, 28))	('harbored', 'Reg', (108, 116))	('gastritis', 'Disease', 'MESH:D005756', (70, 79))	('mutations', 'Var', (122, 131))	('gastritis', 'Phenotype', 'HP:0005263', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
294048	32025000	Furthermore, we found that TP53 is preferentially mutated in the subset of nondysplastic BE patients who progress to cancer.	('TP53', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (92, 100))	('mutated', 'Var', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('nondysplastic BE', 'Disease', 'None', (75, 91))	('nondysplastic BE', 'Disease', (75, 91))	('progress', 'PosReg', (105, 113))
294049	32025000	This sequence of genomic events is notably different than other gastrointestinal cancers, such as colorectal or pancreatic, in which TP53 is mutated relatively late in cancer development.	('mutated', 'Var', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('gastrointestinal cancers', 'Disease', (64, 88))	('colorectal or pancreatic', 'Disease', (98, 122))	('cancer', 'Disease', (81, 87))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (64, 88))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('colorectal or pancreatic', 'Disease', 'MESH:D015179', (98, 122))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TP53', 'Gene', (133, 137))
294050	32025000	Based upon these observations, we hypothesized that chronic inflammation and carcinogenic exposures enable selection of TP53 altered cells to promote premalignant lesions (Extended Data Fig.	('premalignant lesions', 'Disease', (150, 170))	('carcinogenic', 'Disease', 'MESH:D063646', (77, 89))	('carcinogenic', 'Disease', (77, 89))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('inflammation', 'Disease', (60, 72))	('promote', 'PosReg', (142, 149))	('TP53', 'Var', (120, 124))
294051	32025000	To test this hypothesis, we designed a new, integrative mouse model that combines disease-relevant exposures with tissue-specific TP53 alterations to study the development of gastric premalignancy.	('mouse', 'Species', '10090', (56, 61))	('gastric premalignancy', 'Disease', 'MESH:D013274', (175, 196))	('alterations', 'Var', (135, 146))	('gastric premalignancy', 'Disease', (175, 196))	('TP53', 'Gene', (130, 134))
294055	32025000	While untreated (n = 5) and DCA-alone treated (n = 7) mice did not develop premalignant lesions, 39% of MNU (n = 8) or DCA/MNU (n = 10) treated mice developed adenocarcinomas along the stomach lesser curvature (Extended Data Fig.	('mice', 'Species', '10090', (144, 148))	('DCA', 'Chemical', 'MESH:D003840', (28, 31))	('MNU', 'Chemical', 'MESH:D008770', (104, 107))	('DCA/MNU', 'Var', (119, 126))	('developed', 'PosReg', (149, 158))	('adenocarcinomas', 'Disease', 'MESH:D000230', (159, 174))	('adenocarcinomas', 'Disease', (159, 174))	('mice', 'Species', '10090', (54, 58))	('DCA', 'Chemical', 'MESH:D003840', (119, 122))	('MNU', 'Chemical', 'MESH:D008770', (123, 126))
294056	32025000	Whole exome sequencing (WES) analyses in these lesions showed mutation signatures enriched for CT substitutions consistent with exposure to MNU, which cause the formation of O6-alkylguanines (Extended Data Fig.	('O6-alkylguanines', 'Chemical', '-', (174, 190))	('O6-alkylguanines', 'MPA', (174, 190))	('substitutions', 'Var', (98, 111))	('cause', 'Reg', (151, 156))	('MNU', 'Chemical', 'MESH:D008770', (140, 143))
294061	32025000	Deletion of Trp53 in Lgr5+ cells of untreated mice did not lead to detectable premalignant lesions, suggesting that p53 loss alone is not sufficient to promote dysplasia (Fig.	('dysplasia', 'Disease', 'MESH:C536170', (160, 169))	('Trp53', 'Gene', '22059', (12, 17))	('dysplasia', 'Disease', (160, 169))	('mice', 'Species', '10090', (46, 50))	('Trp53', 'Gene', (12, 17))	('loss', 'NegReg', (120, 124))	('promote', 'PosReg', (152, 159))	('p53', 'Gene', (116, 119))	('Deletion', 'Var', (0, 8))
294062	32025000	When treated with DCA/MNU, however, Lgr5-p53KO mice demonstrated a 3.5-fold increase in dysplastic lesions compared to Lgr5-p53WT mice (Fig.	('mice', 'Species', '10090', (130, 134))	('dysplastic lesions', 'Disease', (88, 106))	('increase', 'PosReg', (76, 84))	('DCA', 'Chemical', 'MESH:D003840', (18, 21))	('MNU', 'Chemical', 'MESH:D008770', (22, 25))	('Lgr5-p53KO', 'Var', (36, 46))	('mice', 'Species', '10090', (47, 51))	('dysplastic lesions', 'Disease', 'MESH:D004416', (88, 106))
294064	32025000	WES showed that dysplastic lesions from treated Lgr5-p53KO mice harbored a greater burden of mutations compared to Lgr5-p53WT mice, consistent with p53 function in preserving the integrity of the genome (Fig.	('dysplastic lesions', 'Disease', 'MESH:D004416', (16, 34))	('dysplastic lesions', 'Disease', (16, 34))	('mice', 'Species', '10090', (59, 63))	('mutations', 'Var', (93, 102))	('mice', 'Species', '10090', (126, 130))	('integrity', 'MPA', (179, 188))	('Lgr5-p53KO', 'Var', (48, 58))
294066	32025000	Only MNU containing regimens developed premalignant lesions in Lgr5-p53KO mice, demonstrating the importance of carcinogens in this model (Extended Data Fig.	('mice', 'Species', '10090', (74, 78))	('Lgr5-p53KO', 'Var', (63, 73))	('MNU', 'Chemical', 'MESH:D008770', (5, 8))	('premalignant lesions', 'CPA', (39, 59))
294067	32025000	These results indicate that p53 deletion in gastric stem cells engages carcinogenic exposures to promote premalignant lesions.	('p53', 'Gene', (28, 31))	('deletion', 'Var', (32, 40))	('carcinogenic', 'Disease', 'MESH:D063646', (71, 83))	('carcinogenic', 'Disease', (71, 83))	('premalignant', 'Disease', (105, 117))	('promote', 'PosReg', (97, 104))
294068	32025000	To test whether p53 deletion in a distinct gastric compartment can promote premalignancy, we utilized Mist1-CreERT2 mice.	('mice', 'Species', '10090', (116, 120))	('malignancy', 'Disease', (78, 88))	('p53', 'Gene', (16, 19))	('deletion', 'Var', (20, 28))	('malignancy', 'Disease', 'MESH:D009369', (78, 88))	('promote', 'PosReg', (67, 74))
294069	32025000	Mist1 marks chief cells, which have been shown to respond to inflammation and undergo neoplastic transformation following genetic alterations.	('undergo', 'Reg', (78, 85))	('neoplastic transformation', 'CPA', (86, 111))	('Mist1', 'Gene', (0, 5))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('genetic alterations', 'Var', (122, 141))
294070	32025000	We crossed Mist1-CreERT2; Trp53F/F mice with R26-mTmG reporter mice to mark p53KO with eGFP.	('Trp53', 'Gene', '22059', (26, 31))	('mice', 'Species', '10090', (63, 67))	('mice', 'Species', '10090', (35, 39))	('p53KO', 'Var', (76, 81))	('Trp53', 'Gene', (26, 31))
294072	32025000	Untreated Mist1-p53KO mice did not develop dysplastic lesions for up to two years of monitoring, consistent with our results in Lgr5-p53KO mice.	('Mist1-p53KO', 'Var', (10, 21))	('dysplastic lesions', 'Disease', (43, 61))	('mice', 'Species', '10090', (139, 143))	('mice', 'Species', '10090', (22, 26))	('dysplastic lesions', 'Disease', 'MESH:D004416', (43, 61))
294073	32025000	Mist1-p53KO mice, however, developed over 2.5 times as many dysplastic lesions as Mist1-p53WT mice when subjected to DCA/MNU (Fig.	('Mist1-p53KO', 'Var', (0, 11))	('dysplastic lesions', 'Disease', 'MESH:D004416', (60, 78))	('dysplastic lesions', 'Disease', (60, 78))	('MNU', 'Chemical', 'MESH:D008770', (121, 124))	('DCA', 'Chemical', 'MESH:D003840', (117, 120))	('mice', 'Species', '10090', (94, 98))	('mice', 'Species', '10090', (12, 16))
294074	32025000	Indeed, invasive gastric adenocarcinomas arose only in DCA/MNU treated Mist1-p53KO mice (n = 2) at this early time-point.	('MNU', 'Chemical', 'MESH:D008770', (59, 62))	('DCA', 'Chemical', 'MESH:D003840', (55, 58))	('Mist1-p53KO', 'Var', (71, 82))	('mice', 'Species', '10090', (83, 87))	('invasive gastric adenocarcinomas', 'Disease', (8, 40))	('invasive gastric adenocarcinomas', 'Disease', 'MESH:D013274', (8, 40))
294076	32025000	These results demonstrate that p53 deletion in a distinct subpopulation of stomach cells promotes premalignancy when subjected to carcinogenic exposures.	('p53', 'Gene', (31, 34))	('carcinogenic', 'Disease', 'MESH:D063646', (130, 142))	('carcinogenic', 'Disease', (130, 142))	('promotes', 'PosReg', (89, 97))	('malignancy', 'Disease', 'MESH:D009369', (101, 111))	('deletion', 'Var', (35, 43))	('malignancy', 'Disease', (101, 111))
294080	32025000	MNU also led to p53 induction (Fig.	('MNU', 'Var', (0, 3))	('MNU', 'Chemical', 'MESH:D008770', (0, 3))	('p53', 'Protein', (16, 19))	('induction', 'PosReg', (20, 29))
294083	32025000	Together, these studies suggest that dietary nitrates can lead to growth arrest secondary to p53 induction and dsDNA damage.	('dietary nitrates', 'Var', (37, 53))	('growth arrest', 'Phenotype', 'HP:0001510', (66, 79))	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('p53', 'Gene', (93, 96))	('nitrates', 'Chemical', 'MESH:D009566', (45, 53))	('dsDNA damage', 'CPA', (111, 123))	('induction', 'PosReg', (97, 106))	('arrest', 'Disease', (73, 79))
294086	32025000	By contrast, CP-A p53KO cells exposed to MNU avoided G2/M arrest and gained a proliferative advantage relative to CP-A p53WT cells (Fig.	('MNU', 'Chemical', 'MESH:D008770', (41, 44))	('arrest', 'Disease', (58, 64))	('gained', 'PosReg', (69, 75))	('proliferative advantage', 'CPA', (78, 101))	('avoided', 'NegReg', (45, 52))	('MNU', 'Var', (41, 44))	('G2/M', 'Protein', (53, 57))	('arrest', 'Disease', 'MESH:D006323', (58, 64))
294091	32025000	p53KO gastric organoids displayed a growth advantage in MNU-containing media (Fig.	('p53KO', 'Var', (0, 5))	('MNU', 'Chemical', 'MESH:D008770', (56, 59))	('growth advantage', 'CPA', (36, 52))	('gastric organoids', 'CPA', (6, 23))
294095	32025000	By contrast, eGFP+ Mist1-p53KO gastric organoids, which initially represented 0.3% of early passage cultures, expanded by approximately 13-fold to 6.7% when passaged in MNU-containing media (Fig.	('expanded', 'PosReg', (110, 118))	('eGFP+ Mist1-p53KO', 'Var', (13, 30))	('MNU', 'Chemical', 'MESH:D008770', (169, 172))	('gastric organoids', 'CPA', (31, 48))
294100	32025000	Trp53 deletion was validated in organoids derived from Lgr5-p53KO mice using recombination-specific PCR (Extended Data Fig.	('Trp53', 'Gene', '22059', (0, 5))	('deletion', 'Var', (6, 14))	('mice', 'Species', '10090', (66, 70))	('Trp53', 'Gene', (0, 5))
294106	32025000	Alterations in p53 are strongly associated with genome doubling and the CIN subtype in human gastric cancer.	('CIN', 'Disease', 'MESH:D007674', (72, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('human', 'Species', '9606', (87, 92))	('Alterations', 'Var', (0, 11))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('p53', 'Gene', (15, 18))	('CIN', 'Disease', (72, 75))	('genome doubling', 'CPA', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associated', 'Reg', (32, 42))	('gastric cancer', 'Disease', (93, 107))
294108	32025000	To test whether deletion of p53 in dysplastic Lgr5-p53WT gastric organoids lead to genome doubling, we treated dys-Lgr5-p53WT organoids with AdenoCre.	('p53', 'Gene', (28, 31))	('genome doubling', 'MPA', (83, 98))	('deletion', 'Var', (16, 24))	('dysplastic', 'Disease', (35, 45))	('dysplastic', 'Disease', 'MESH:D004416', (35, 45))
294118	32025000	These analyses did not yield a clear pattern of mutations in Lgr5-p53KO dysplastic gastric lesions (Supplementary Table 1).	('dysplastic gastric lesions', 'Disease', (72, 98))	('Lgr5-p53KO', 'Gene', (61, 71))	('dysplastic gastric lesions', 'Disease', 'MESH:D013272', (72, 98))	('mutations', 'Var', (48, 57))
294119	32025000	As expected, Trp53 expression was attenuated in dys-Lgr5-p53KO organoids (Extended Data Fig.	('expression', 'MPA', (19, 29))	('dys-Lgr5-p53KO', 'Var', (48, 62))	('Trp53', 'Gene', '22059', (13, 18))	('Trp53', 'Gene', (13, 18))	('attenuated', 'NegReg', (34, 44))
294123	32025000	Four cytokines, Csf3, Cxcl10, Crfl1 and Ccl5, were consistently elevated in dLgr5-p53KO organoids (Extended Data Fig.	('elevated', 'PosReg', (64, 72))	('Csf3', 'Gene', (16, 20))	('Ccl5', 'Gene', (40, 44))	('Ccl5', 'Gene', '20304', (40, 44))	('dLgr5-p53KO', 'Var', (76, 87))	('Csf3', 'Gene', '12985', (16, 20))	('Cxcl10', 'Gene', (22, 28))	('Cxcl10', 'Gene', '15945', (22, 28))	('Crfl1', 'MPA', (30, 35))
294124	32025000	In addition to the p53 pathway, epithelial-to-mesenchymal transition (EMT), inflammation-associated, hypoxia, and stem cell pathways were downregulated in p53KO organoids compared to p53WT (Extended Data Fig.	('stem cell', 'CPA', (114, 123))	('inflammation', 'Disease', 'MESH:D007249', (76, 88))	('hypoxia', 'Disease', (101, 108))	('inflammation', 'Disease', (76, 88))	('epithelial-to-mesenchymal transition', 'CPA', (32, 68))	('downregulated', 'NegReg', (138, 151))	('p53 pathway', 'Pathway', (19, 30))	('p53KO', 'Var', (155, 160))	('hypoxia', 'Disease', 'MESH:D000860', (101, 108))
294125	32025000	This experiment suggested that either the duration of p53 loss or context of dysplasia contributed to the upregulation of these pathways in dys-Lgr5-p53KO premalignant lesions (Extended Data Fig.	('dys-Lgr5-p53KO', 'Var', (140, 154))	('loss', 'NegReg', (58, 62))	('dysplasia', 'Disease', 'MESH:C536170', (77, 86))	('dysplasia', 'Disease', (77, 86))	('p53', 'Gene', (54, 57))	('upregulation', 'PosReg', (106, 118))
294126	32025000	To distinguish between these scenarios, we examined gene expression profiles of organoids derived from nondysplastic gastric antrum tissue of untreated Lgr5-p53KO and Lgr5-p53WT mice.	('Lgr5-p53KO', 'Var', (152, 162))	('mice', 'Species', '10090', (178, 182))	('nondysplastic gastric', 'Disease', (103, 124))	('nondysplastic gastric', 'Disease', 'MESH:D013274', (103, 124))
294127	32025000	This comparison reflects gene expression changes in response to p53 inactivation that have occurred over a year in vivo without DCA/MNU (Fig.	('DCA', 'Chemical', 'MESH:D003840', (128, 131))	('p53', 'Gene', (64, 67))	('MNU', 'Chemical', 'MESH:D008770', (132, 135))	('inactivation', 'Var', (68, 80))
294128	32025000	We plotted pathways enriched in dys-Lgr5-p53KO (relative to dys-Lgr5-p53WT) against nondysplastic Lgr5-p53KO (relative to nondysplastic Lgr5-p53WT) organoids to identify gene-sets selectively enriched with p53 loss in dysplasia (Fig.	('p53', 'Gene', (206, 209))	('loss in dysplasia', 'Disease', 'MESH:D014786', (210, 227))	('loss in dysplasia', 'Disease', (210, 227))	('dysplastic', 'Disease', (125, 135))	('dysplastic', 'Disease', (87, 97))	('dysplastic', 'Disease', 'MESH:D004416', (125, 135))	('dysplastic', 'Disease', 'MESH:D004416', (87, 97))	('dys-Lgr5-p53KO', 'Var', (32, 46))
294131	32025000	Although elevated in nondysplastic Lgr5-p53KO organoids, IFN signaling pathways were more potently upregulated in dys-Lgr5-p53KO (Fig.	('dysplastic', 'Disease', (24, 34))	('upregulated', 'PosReg', (99, 110))	('dysplastic', 'Disease', 'MESH:D004416', (24, 34))	('dys-Lgr5-p53KO', 'Var', (114, 128))	('IFN signaling pathways', 'Pathway', (57, 79))
294132	32025000	Consistently, p53 mutant human gastric cancers demonstrated a significant correlation between CCL5 mRNA expression levels and IFN signaling by single-sample GSEA (Extended Data Fig.	('IFN signaling', 'MPA', (126, 139))	('p53', 'Gene', (14, 17))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('CCL5', 'Gene', (94, 98))	('mutant', 'Var', (18, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('human', 'Species', '9606', (25, 30))	('gastric cancers', 'Disease', 'MESH:D013274', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('gastric cancers', 'Disease', (31, 46))	('gastric cancers', 'Phenotype', 'HP:0012126', (31, 46))	('GSEA', 'Chemical', '-', (157, 161))	('CCL5', 'Gene', '6352', (94, 98))	('correlation', 'Interaction', (74, 85))
294133	32025000	These findings agree with recent literature and earlier results that implicated increased stem cell properties in p53KO dysplasia (Fig.	('dysplasia', 'Disease', 'MESH:C536170', (120, 129))	('increased', 'PosReg', (80, 89))	('dysplasia', 'Disease', (120, 129))	('p53KO', 'Var', (114, 119))	('stem cell properties', 'CPA', (90, 110))
294135	32025000	Moreover, dys-Lgr5-p53KO gastric organoids demonstrated elevated protein expression of WNT-target and stem cell transcription factor Sox9 by immunoblot (Figure 5d), which was not observed with p53 inactivation ex vivo or in nondysplastic organoids (Figure 5d), suggesting that the context of dysplasia is required.	('Sox9', 'Gene', (133, 137))	('elevated', 'PosReg', (56, 64))	('nondysplastic organoids', 'Disease', 'MESH:D054000', (224, 247))	('WNT-target', 'Gene', (87, 97))	('protein expression', 'MPA', (65, 83))	('dys-Lgr5-p53KO', 'Var', (10, 24))	('nondysplastic organoids', 'Disease', (224, 247))	('dysplasia', 'Disease', 'MESH:C536170', (292, 301))	('Sox9', 'Gene', '20682', (133, 137))	('dysplasia', 'Disease', (292, 301))
294137	32025000	Only dys-Lgr5-p53KO organoids were able to grow in media without WNT, R-spondin, and Noggin (Extended Data Fig.	('R-spondin', 'Gene', '192199', (70, 79))	('R-spondin', 'Gene', (70, 79))	('Noggin', 'Gene', '18121', (85, 91))	('Noggin', 'Gene', (85, 91))	('dys-Lgr5-p53KO', 'Var', (5, 19))
294140	32025000	mRNA levels of Cdkn2a were elevated two- to three-fold in p53KO and nondysplastic Lgr5-p53KO gastric organoids compared to their respective controls.	('Cdkn2a', 'Gene', '12578', (15, 21))	('Cdkn2a', 'Gene', (15, 21))	('p53KO', 'Var', (58, 63))	('elevated', 'PosReg', (27, 35))	('dysplastic', 'Disease', (71, 81))	('dysplastic', 'Disease', 'MESH:D004416', (71, 81))	('mRNA levels', 'MPA', (0, 11))
294141	32025000	However, dys-Lgr5-p53KO gastric organoids displayed a greater than 10-fold increase in Cdkn2a mRNA levels relative to dys-Lgr5-p53WT (Fig.	('Cdkn2a', 'Gene', '12578', (87, 93))	('Cdkn2a', 'Gene', (87, 93))	('mRNA levels', 'MPA', (94, 105))	('dys-Lgr5-p53KO', 'Var', (9, 23))	('increase', 'PosReg', (75, 83))
294143	32025000	We next asked whether p53 deletion in p53WT gastric premalignancy induces CDKN2A expression.	('p53', 'Var', (22, 25))	('induces', 'Reg', (66, 73))	('CDKN2A', 'Gene', (74, 80))	('gastric premalignancy', 'Disease', 'MESH:D013274', (44, 65))	('p53WT', 'Gene', (38, 43))	('gastric premalignancy', 'Disease', (44, 65))	('expression', 'MPA', (81, 91))
294144	32025000	Although CDKN2A is absent in CP-A cells, we observed upregulation of other CDKN1 and CDKN2 gene family members in CP-A p53KD cells (Extended Data Fig.	('CDKN1', 'Gene', (75, 80))	('CDKN2', 'Gene', (85, 90))	('CDKN2', 'Gene', '1029', (85, 90))	('upregulation', 'PosReg', (53, 65))	('p53KD', 'Var', (119, 124))	('CDKN2', 'Gene', '1029', (9, 14))	('CDKN2', 'Gene', (9, 14))	('CDKN1', 'Gene', '12575', (75, 80))
294145	32025000	Deletion of p53 in dys-Lgr5-p53WT organoids led to elevated protein expression of p16INK4A, a protein product of CDKN2A (Fig.	('p16INK4A', 'Gene', (82, 90))	('p16INK4A', 'Gene', '12578', (82, 90))	('p53', 'Gene', (12, 15))	('elevated', 'PosReg', (51, 59))	('protein expression', 'MPA', (60, 78))	('Deletion', 'Var', (0, 8))
294147	32025000	Greater nuclear p16INK4A staining (red) was observed in Lgr5-p53KO dysplasia (focal areas marked by dotted lines) relative to Lgr5-p53WT controls (Fig.	('Greater', 'PosReg', (0, 7))	('p16INK4A', 'Gene', (16, 24))	('p16INK4A', 'Gene', '12578', (16, 24))	('dysplasia', 'Disease', 'MESH:C536170', (67, 76))	('Lgr5-p53KO', 'Var', (56, 66))	('dysplasia', 'Disease', (67, 76))
294148	32025000	Using tissue from the Mist-p53KO mouse model, we observed greater nuclear p16 staining co-localized with eGFP+ Mist-p53KO cells in dysplastic lesions (Fig.	('greater', 'PosReg', (58, 65))	('Mist-p53KO', 'Var', (111, 121))	('nuclear p16', 'Protein', (66, 77))	('mouse', 'Species', '10090', (33, 38))	('dysplastic lesions', 'Disease', 'MESH:D004416', (131, 149))	('dysplastic lesions', 'Disease', (131, 149))
294149	32025000	These data indicate that inactivation of p53 leads to p16INK4A induction in gastric premalignancy.	('p16INK4A', 'Gene', (54, 62))	('p16INK4A', 'Gene', '12578', (54, 62))	('inactivation', 'Var', (25, 37))	('gastric premalignancy', 'Disease', (76, 97))	('induction', 'PosReg', (63, 72))	('p53', 'Gene', (41, 44))	('gastric premalignancy', 'Disease', 'MESH:D013274', (76, 97))
294152	32025000	There was also a subset of human gastric cancers with alterations in both CDKN2A and TP53 (Fig.	('gastric cancers', 'Disease', 'MESH:D013274', (33, 48))	('TP53', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('gastric cancers', 'Disease', (33, 48))	('gastric cancers', 'Phenotype', 'HP:0012126', (33, 48))	('human', 'Species', '9606', (27, 32))	('CDKN2A', 'Gene', (74, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('alterations', 'Var', (54, 65))
294153	32025000	Analysis of genomic alterations in human esophageal adenocarcinoma also showed significant co-occurrence of TP53 and CDKN2A alterations (Extended Data Fig.	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (41, 66))	('TP53', 'Gene', (108, 112))	('alterations', 'Var', (124, 135))	('human', 'Species', '9606', (35, 40))	('esophageal adenocarcinoma', 'Disease', (41, 66))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (41, 66))	('CDKN2A', 'Gene', (117, 123))
294155	32025000	In aggregate, these data support a model whereby CDKN2A/p16INK4A is upregulated in p53-altered dysplasia and subsequently inactivated during cancer progression.	('inactivated', 'NegReg', (122, 133))	('upregulated', 'PosReg', (68, 79))	('p53-altered', 'Var', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('dysplasia', 'Disease', 'MESH:C536170', (95, 104))	('dysplasia', 'Disease', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('p16INK4A', 'Gene', (56, 64))	('cancer', 'Disease', (141, 147))	('p16INK4A', 'Gene', '12578', (56, 64))
294157	32025000	A correlate to this hypothesis is that abrogating CDKN2A/p16INK4A may enable progression of p53-altered gastric premalignancy.	('p16INK4A', 'Gene', (57, 65))	('p16INK4A', 'Gene', '12578', (57, 65))	('gastric premalignancy', 'Disease', (104, 125))	('enable', 'PosReg', (70, 76))	('abrogating', 'Var', (39, 49))	('gastric premalignancy', 'Disease', 'MESH:D013274', (104, 125))
294159	32025000	In parallel, Cdkn2a alone was inactivated in dys-Lgr5-p53KO gastric organoids (Fig.	('Cdkn2a', 'Gene', (13, 19))	('dys-Lgr5-p53KO', 'Var', (45, 59))	('Cdkn2a', 'Gene', '12578', (13, 19))
294160	32025000	Deletion of Cdkn2a improved colony-forming ability of dys-Lgr5-p53KO gastric organoids grown in media with or without WNT (Fig.	('Cdkn2a', 'Gene', '12578', (12, 18))	('Cdkn2a', 'Gene', (12, 18))	('colony-forming ability', 'CPA', (28, 50))	('improved', 'PosReg', (19, 27))	('Deletion', 'Var', (0, 8))
294163	32025000	We suspected that abrogation of Cdkn2a and Trp53 may impart strain on cellular replication.	('abrogation', 'Var', (18, 28))	('Trp53', 'Gene', '22059', (43, 48))	('Cdkn2a', 'Gene', '12578', (32, 38))	('Cdkn2a', 'Gene', (32, 38))	('Trp53', 'Gene', (43, 48))	('strain', 'MPA', (60, 66))	('cellular replication', 'CPA', (70, 90))
294165	32025000	Indeed, phospho-CHK1 and phospho-RPA32, another indicator of replication stress, were induced in dys-Lgr5-p53WT-DKO but not dys-Lgr5-p53WT-control, -sgP53KO, and -sgP16KO gastric organoids (Fig.	('dys-Lgr5-p53WT-DKO', 'Var', (97, 115))	('induced', 'PosReg', (86, 93))	('CHK1', 'Gene', '12649', (16, 20))	('RPA32', 'Gene', '108689', (33, 38))	('RPA32', 'Gene', (33, 38))	('CHK1', 'Gene', (16, 20))
294166	32025000	Furthermore, phospho-CHK1 is elevated when p53 is deleted in CP-A cells, which are CDKN2A deficient (Fig.	('elevated', 'PosReg', (29, 37))	('CHK1', 'Gene', (21, 25))	('CHK1', 'Gene', '12649', (21, 25))	('p53', 'Gene', (43, 46))	('deleted', 'Var', (50, 57))
294167	32025000	These results indicated that premalignant lesions with co-alterations in Cdkn2a and Trp53 activate checkpoint responses associated with replication stress.	('Cdkn2a', 'Gene', '12578', (73, 79))	('checkpoint responses', 'CPA', (99, 119))	('Cdkn2a', 'Gene', (73, 79))	('Trp53', 'Gene', (84, 89))	('activate', 'PosReg', (90, 98))	('co-alterations', 'Var', (55, 69))	('Trp53', 'Gene', '22059', (84, 89))	('premalignant lesions', 'Disease', (29, 49))
294170	32025000	Gastric cancer cell lines with co-disruption of CDKN2A/TP53 showed significantly greater sensitivity to the CHK1/2 inhibitor AZD7762 compared to those with only one or neither gene altered (Fig.	('sensitivity', 'MPA', (89, 100))	('Gastric cancer', 'Disease', (0, 14))	('AZD7762', 'Chemical', 'MESH:C532363', (125, 132))	('Gastric cancer', 'Disease', 'MESH:D013274', (0, 14))	('CDKN2A/TP53', 'Gene', (48, 59))	('CHK1', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('CHK1', 'Gene', '12649', (108, 112))	('co-disruption', 'Var', (31, 44))	('greater', 'PosReg', (81, 88))
294171	32025000	Consistent with the drug-response, genetic knockdown of CHK1 or WEE1, a downstream mediator of ATR-CHK1 DDR, but not CHK2 showed preferential dependency in CDKN2A/TP53 co-disrupted gastric cancer (Extended Data Fig.	('CHK1', 'Gene', (99, 103))	('ATR', 'Gene', (95, 98))	('CHK2', 'Gene', '50883', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('co-disrupted', 'Var', (168, 180))	('CHK1', 'Gene', '12649', (99, 103))	('gastric cancer', 'Disease', (181, 195))	('WEE1', 'Gene', (64, 68))	('CHK1', 'Gene', (56, 60))	('ATR', 'Gene', '245000', (95, 98))	('CDKN2A/TP53 co-disrupted', 'Var', (156, 180))	('CHK2', 'Gene', (117, 121))	('WEE1', 'Gene', '22390', (64, 68))	('CHK1', 'Gene', '12649', (56, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (181, 195))	('gastric cancer', 'Phenotype', 'HP:0012126', (181, 195))
294173	32025000	KE39 is TP53 mutant and CDKN2A wildtype, whereas GSU is TP53 and CDKN2A co-disrupted.	('mutant', 'Var', (13, 19))	('KE39', 'Var', (0, 4))	('KE39', 'Chemical', '-', (0, 4))	('GSU', 'Chemical', '-', (49, 52))
294175	32025000	Furthermore, GSU was also significantly more sensitive to AZD1775, a potent WEE1 inhibitor, compared to KE39 (Extended Data Fig.	('more', 'PosReg', (40, 44))	('AZD1775', 'Chemical', 'MESH:C549567', (58, 65))	('WEE1', 'Gene', (76, 80))	('WEE1', 'Gene', '22390', (76, 80))	('GSU', 'Chemical', '-', (13, 16))	('KE39', 'Chemical', '-', (104, 108))	('sensitive', 'MPA', (45, 54))	('AZD1775', 'Var', (58, 65))
294176	32025000	Together, these data suggest that co-disruption of CDKN2A and TP53 may serve as a predictive biomarker for sensitivity to CHK1-WEE1 DDR inhibitors.	('CHK1', 'Gene', (122, 126))	('CHK1', 'Gene', '12649', (122, 126))	('TP53', 'Gene', (62, 66))	('co-disruption', 'Var', (34, 47))	('WEE1', 'Gene', (127, 131))	('WEE1', 'Gene', '22390', (127, 131))	('CDKN2A', 'Gene', (51, 57))
294177	32025000	We next investigated whether co-inactivating CDKN2A/TP53 in premalignant CP-A cells confers increased sensitivity to CHK1 inhibition.	('sensitivity', 'MPA', (102, 113))	('CDKN2A/TP53', 'Gene', (45, 56))	('co-inactivating', 'Var', (29, 44))	('CHK1', 'Gene', (117, 121))	('increased', 'PosReg', (92, 101))	('CHK1', 'Gene', '12649', (117, 121))
294178	32025000	Deletion of p53 in p16INK4A-deficient CP-A cells led to a significant increase in Prexasertib sensitivity at doses corresponding to phopho-CHK1 inhibition (Fig.	('increase', 'PosReg', (70, 78))	('p16INK4A', 'Gene', (19, 27))	('p16INK4A', 'Gene', '12578', (19, 27))	('p53', 'Gene', (12, 15))	('Prexasertib sensitivity', 'MPA', (82, 105))	('CHK1', 'Gene', (139, 143))	('Prexasertib', 'Chemical', 'MESH:C000608121', (82, 93))	('CHK1', 'Gene', '12649', (139, 143))	('Deletion', 'Var', (0, 8))
294180	32025000	dys-Lgr5-p53WT-DKO gastric organoids demonstrated greater sensitivity to Prexasertib than dys-Lgr5-p53WT-control (Fig.	('dys-Lgr5-p53WT-DKO', 'Var', (0, 18))	('sensitivity to Prexasertib', 'MPA', (58, 84))	('Prexasertib', 'Chemical', 'MESH:C000608121', (73, 84))
294181	32025000	Moreover, dys-Lgr5-p53KO-p16KO demonstrated even greater sensitivity to Prexasertib than dys-Lgr5-p53KO-control gastric organoids (Fig.	('dys-Lgr5-p53KO-p16KO', 'Var', (10, 30))	('Prexasertib', 'Chemical', 'MESH:C000608121', (72, 83))	('sensitivity to Prexasertib', 'MPA', (57, 83))	('greater', 'PosReg', (49, 56))
294182	32025000	To investigate other DDR pathway members, we tested ATR inhibitor AZD6738 and WEE1 inhibitor AZD1775.	('AZD6738', 'Chemical', 'MESH:C000611951', (66, 73))	('AZD6738', 'Var', (66, 73))	('ATR', 'Gene', '245000', (52, 55))	('AZD1775', 'Var', (93, 100))	('AZD1775', 'Chemical', 'MESH:C549567', (93, 100))	('WEE1', 'Gene', (78, 82))	('WEE1', 'Gene', '22390', (78, 82))	('ATR', 'Gene', (52, 55))
294183	32025000	Although dys-Lgr5-p53KO-p16KO were not preferentially sensitive to ATR inhibition, they did show increased sensitivity to WEE1 inhibition (Extended Data Fig.	('dys-Lgr5-p53KO-p16KO', 'Var', (9, 29))	('increased', 'PosReg', (97, 106))	('ATR', 'Gene', '245000', (67, 70))	('sensitivity', 'MPA', (107, 118))	('WEE1', 'Gene', (122, 126))	('WEE1', 'Gene', '22390', (122, 126))	('ATR', 'Gene', (67, 70))
294184	32025000	Overall, these data suggest that co-disruption of CDKN2A and TP53 in gastric premalignancy not only promotes cancer progression but also confers sensitivity to inhibition of the CHK1-WEE1 axis of the DDR pathway.	('WEE1', 'Gene', (183, 187))	('CDKN2A', 'Gene', (50, 56))	('WEE1', 'Gene', '22390', (183, 187))	('co-disruption', 'Var', (33, 46))	('gastric premalignancy', 'Disease', (69, 90))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('CHK1', 'Gene', (178, 182))	('cancer', 'Disease', (109, 115))	('promotes', 'PosReg', (100, 108))	('CHK1', 'Gene', '12649', (178, 182))	('gastric premalignancy', 'Disease', 'MESH:D013274', (69, 90))	('DDR pathway', 'Pathway', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('TP53', 'Gene', (61, 65))
294186	32025000	TP53 mutations are not only found in premalignant lesions but also predict progression to cancer .	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (5, 14))	('predict', 'Reg', (67, 74))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
294187	32025000	However, deleting Trp53 in gastric cells alone did not lead to dysplastic lesions after 2 years of observation in mice, suggesting that additional factors, such as pathogenic mutations or exposures, are necessary (Supplementary Note#5).	('deleting', 'Var', (9, 17))	('Trp53', 'Gene', (18, 23))	('lead to', 'Reg', (55, 62))	('Trp53', 'Gene', '22059', (18, 23))	('mice', 'Species', '10090', (114, 118))	('dysplastic lesions', 'Disease', 'MESH:D004416', (63, 81))	('dysplastic lesions', 'Disease', (63, 81))
294188	32025000	These results guided the development of an integrative mouse model that combines p53 alterations with carcinogenic exposures to study gene-environment interactions in gastric premalignancy.	('carcinogenic', 'Disease', 'MESH:D063646', (102, 114))	('carcinogenic', 'Disease', (102, 114))	('gastric premalignancy', 'Disease', 'MESH:D013274', (167, 188))	('mouse', 'Species', '10090', (55, 60))	('gastric premalignancy', 'Disease', (167, 188))	('p53', 'Gene', (81, 84))	('alterations', 'Var', (85, 96))
294192	32025000	In our model, the combination of dysplasia and p53 loss was required, consistent with data that dysregulation of a single pathway may not be sufficient to induce dedifferentiation (Supplementary Note#6).	('dysplasia', 'Disease', 'MESH:C536170', (33, 42))	('dysplasia', 'Disease', (33, 42))	('induce', 'Reg', (155, 161))	('dysregulation', 'Var', (96, 109))	('p53', 'Gene', (47, 50))	('loss', 'NegReg', (51, 55))	('dedifferentiation', 'CPA', (162, 179))
294194	32025000	Notwithstanding, these data may explain the substantially lower rates of somatic alterations in APC or CTNNB1 in gastric cancer compared to colorectal cancer (CRC).	('CTNNB1', 'Gene', '12387', (103, 109))	('lower', 'NegReg', (58, 63))	('colorectal cancer', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('CRC', 'Disease', 'MESH:D015179', (159, 162))	('gastric cancer', 'Disease', (113, 127))	('CTNNB1', 'Gene', (103, 109))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('alterations', 'Var', (81, 92))	('APC', 'Disease', (96, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('CRC', 'Disease', (159, 162))
294195	32025000	Arguing against tissue-specific predisposition, colitis-associated CRC, which also manifests with early TP53 mutations similar to GE cancer, have dramatically lower rates of WNT pathway alterations.	('CRC', 'Disease', (67, 70))	('TP53', 'Gene', (104, 108))	('colitis', 'Disease', 'MESH:D003092', (48, 55))	('colitis', 'Disease', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('lower', 'NegReg', (159, 164))	('WNT pathway alterations', 'Pathway', (174, 197))	('cancer', 'Disease', (133, 139))	('colitis', 'Phenotype', 'HP:0002583', (48, 55))	('mutations', 'Var', (109, 118))	('CRC', 'Disease', 'MESH:D015179', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
294196	32025000	Taken together, these data suggest that early TP53 mutations in gastric premalignancy may promote WNT signaling without requiring additional mutations in the pathway (Supplementary Note#7).	('mutations', 'Var', (51, 60))	('gastric premalignancy', 'Disease', 'MESH:D013274', (64, 85))	('TP53', 'Gene', (46, 50))	('promote', 'PosReg', (90, 97))	('gastric premalignancy', 'Disease', (64, 85))	('WNT signaling', 'Pathway', (98, 111))
294197	32025000	The CDKN2A locus encodes two gene products:p14ARF and p16INK4A51.	('CDKN2A', 'Gene', (4, 10))	('p16INK4A', 'Gene', (54, 62))	('p14ARF', 'Var', (43, 49))	('p16INK4A', 'Gene', '12578', (54, 62))
294198	32025000	p14ARF stabilizes p53 by physically inhibiting its ubiquitination by MDM2.	('MDM2', 'Gene', '17246', (69, 73))	('inhibiting', 'NegReg', (36, 46))	('p14ARF', 'Var', (0, 6))	('ubiquitination', 'MPA', (51, 65))	('MDM2', 'Gene', (69, 73))	('p53', 'Protein', (18, 21))
294201	32025000	Although CDKN2A is frequently deleted, mutated, or hypermethylated in BE, these lesions do not always progress to cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutated', 'Var', (39, 46))	('CDKN2A', 'Gene', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('hypermethylated', 'Var', (51, 66))	('cancer', 'Disease', (114, 120))
294202	32025000	In fact, CDKN2A inactivation has even been associated with a reduced risk of progression to esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (92, 117))	('CDKN2A', 'Gene', (9, 15))	('inactivation', 'Var', (16, 28))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (92, 117))	('reduced', 'NegReg', (61, 68))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (92, 117))
294203	32025000	By contrast, TP53 mutations were found in matched premalignant/cancer lesions, and also predicated progression to cancer in patients with nondysplastic BE.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('TP53', 'Gene', (13, 17))	('nondysplastic BE', 'Disease', (138, 154))	('patients', 'Species', '9606', (124, 132))	('nondysplastic BE', 'Disease', 'None', (138, 154))	('cancer lesions', 'Disease', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (114, 120))	('cancer lesions', 'Disease', 'MESH:D009369', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('mutations', 'Var', (18, 27))
294206	32025000	Co-deletion of TP53 and RB endowed neuroendocrine differentiation and resistance to enzalutamide in prostate cancer via SOX2 induction (Supplementary Note#8).	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('SOX2', 'Gene', (120, 124))	('neuroendocrine differentiation', 'CPA', (35, 65))	('SOX2', 'Gene', '20674', (120, 124))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('resistance to enzalutamide', 'MPA', (70, 96))	('Co-deletion', 'Var', (0, 11))	('TP53', 'Gene', (15, 19))	('enzalutamide', 'Chemical', 'MESH:C540278', (84, 96))	('prostate cancer', 'Disease', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
294207	32025000	An open question that remains is whether CDKN2A and TP53 co-inactivation in GE cancer promotes an alternative cellular state.	('co-inactivation', 'Var', (57, 72))	('alternative cellular state', 'MPA', (98, 124))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TP53', 'Gene', (52, 56))	('CDKN2A', 'Gene', (41, 47))	('promotes', 'PosReg', (86, 94))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
294209	32025000	Inactivation of p16INK4A appeared to increase replication stress (Figure 7d,g), rendering the DDR even more critical.	('replication stress', 'MPA', (46, 64))	('p16INK4A', 'Gene', (16, 24))	('p16INK4A', 'Gene', '12578', (16, 24))	('increase', 'PosReg', (37, 45))	('Inactivation', 'Var', (0, 12))
294213	32025000	Inactivation of CDKN2A in head and neck cancer induced replication stress and conferred sensitivity to CHK1 inhibition.	('replication stress', 'MPA', (55, 73))	('neck cancer', 'Disease', (35, 46))	('CDKN2A', 'Gene', (16, 22))	('CHK1', 'Gene', (103, 107))	('induced', 'Reg', (47, 54))	('conferred', 'Reg', (78, 87))	('head and neck cancer', 'Phenotype', 'HP:0012288', (26, 46))	('CHK1', 'Gene', '12649', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('neck cancer', 'Disease', 'MESH:D006258', (35, 46))	('Inactivation', 'Var', (0, 12))
294214	32025000	Therefore, inactivation of p16INK4A and p53, two critical regulators of cell cycle progression and DDR, may increase sensitivity of gastric cancer to CHK1 and WEE1 inhibitors.	('increase', 'PosReg', (108, 116))	('CHK1', 'Gene', (150, 154))	('gastric cancer', 'Disease', (132, 146))	('sensitivity', 'MPA', (117, 128))	('WEE1', 'Gene', (159, 163))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('p16INK4A', 'Gene', (27, 35))	('inactivation', 'Var', (11, 23))	('WEE1', 'Gene', '22390', (159, 163))	('p53', 'Gene', (40, 43))	('CHK1', 'Gene', '12649', (150, 154))	('p16INK4A', 'Gene', '12578', (27, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
294216	32025000	By combining early genomic alterations in Trp53 with disease-relevant exposures, we generated an integrative mouse model that yielded new insights into critical gene-environment interactions that promote gastric premalignancy, identifying barriers to transformation and ultimately nominating a new therapeutic approach for this deadly cancer.	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('interactions', 'Interaction', (178, 190))	('Trp53', 'Gene', (42, 47))	('gastric premalignancy', 'Disease', 'MESH:D013274', (204, 225))	('promote', 'PosReg', (196, 203))	('cancer', 'Disease', (335, 341))	('gastric premalignancy', 'Disease', (204, 225))	('Trp53', 'Gene', '22059', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('alterations', 'Var', (27, 38))	('mouse', 'Species', '10090', (109, 114))
294231	32025000	As a result, the mutant LSL-p53R270H mice are heterozygous for p53 (+/-) in every tissue and can only conditionally express p53R270H wherever Cre is activated.	('LSL-p53R270H', 'Var', (24, 36))	('R270H', 'Mutation', 'rs55819519', (31, 36))	('mutant LSL-p53R270H', 'Var', (17, 36))	('R270H', 'Mutation', 'rs55819519', (127, 132))	('p53R270H', 'Var', (124, 132))	('mice', 'Species', '10090', (37, 41))
294232	32025000	Nevertheless, in the setting of MNU exposure, the p53 +/- thymic tissue appears to be susceptible to losing the remaining wildtype copy and developing thymic lymphomas reliably within 3-4 months of carcinogen exposure initiation.	('developing', 'Reg', (140, 150))	('thymic lymphomas', 'Disease', (151, 167))	('losing', 'NegReg', (101, 107))	('lymphomas', 'Phenotype', 'HP:0002665', (158, 167))	('p53 +/-', 'Var', (50, 57))	('MNU', 'Chemical', 'MESH:D008770', (32, 35))	('lymphoma', 'Phenotype', 'HP:0002665', (158, 166))	('thymic lymphomas', 'Disease', 'MESH:D013953', (151, 167))	('wildtype copy', 'MPA', (122, 135))
294235	32025000	In other words, MNU-treated mice in which mutant p53R270H was not activated (green) or Lgr5-Cre was not present (orange), still died due to thymic lymphoma complications.	('mice', 'Species', '10090', (28, 32))	('MNU', 'Chemical', 'MESH:D008770', (16, 19))	('thymic lymphoma complications', 'Disease', (140, 169))	('lymphoma', 'Phenotype', 'HP:0002665', (147, 155))	('thymic lymphoma complications', 'Disease', 'MESH:D013953', (140, 169))	('p53R270H', 'Var', (49, 57))	('died', 'Reg', (128, 132))
294243	32025000	Human samples: Previously published whole exome sequencing data of laser capture microdissected areas of Barrett's esophagus, Barrett's with low/high grade dysplasia, and esophageal adenocarcinoma from esophagectomy specimens was reviewed for TP53 mutations, whole genome doubling, and copy number changes.	('Human', 'Species', '9606', (0, 5))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (171, 196))	('mutations', 'Var', (248, 257))	('dysplasia', 'Disease', (156, 165))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (105, 124))	('esophageal adenocarcinoma', 'Disease', (171, 196))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (171, 196))	('TP53', 'Gene', (243, 247))	('dysplasia', 'Disease', 'MESH:C536170', (156, 165))
294244	32025000	Areas of high grade dysplasia were seen that had TP53 mutations and WGD, suggesting that both develop before invasion.	('TP53', 'Gene', (49, 53))	('dysplasia', 'Disease', 'MESH:C536170', (20, 29))	('dysplasia', 'Disease', (20, 29))	('mutations', 'Var', (54, 63))
294273	32025000	The following chemical drugs were used: AZD7762 and Prexasertib are CHK1/2 inhibitors, AZD1775 is a WEE1 inhibitor, and AZD6738 is an ATR inhibitor.	('AZD6738', 'Var', (120, 127))	('CHK1', 'Gene', (68, 72))	('CHK1', 'Gene', '12649', (68, 72))	('Prexasertib', 'Chemical', 'MESH:C000608121', (52, 63))	('AZD7762', 'Var', (40, 47))	('AZD1775', 'Var', (87, 94))	('AZD7762', 'Chemical', 'MESH:C532363', (40, 47))	('AZD1775', 'Chemical', 'MESH:C549567', (87, 94))	('ATR', 'Gene', (134, 137))	('ATR', 'Gene', '245000', (134, 137))	('WEE1', 'Gene', (100, 104))	('AZD6738', 'Chemical', 'MESH:C000611951', (120, 127))	('WEE1', 'Gene', '22390', (100, 104))
294309	30559604	Moreover, studies have also revealed that high expression of IL-33 is associated with disease progression and poor prognosis in diverse cancers.	('IL-33', 'Gene', (61, 66))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('IL-33', 'Gene', '90865', (61, 66))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('associated', 'Reg', (70, 80))	('high', 'Var', (42, 46))	('disease progression', 'CPA', (86, 105))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
294385	29206831	Prognostic value of ALDH2 polymorphism for patients with oropharyngeal cancer in a Japanese population Half of Japanese possess a polymorphism of aldehyde dehydrogenase 2(ALDH2), while few white individuals possess this mutation.	('polymorphism', 'Var', (130, 142))	('ALDH2', 'Gene', '217', (20, 25))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (57, 77))	('ALDH2', 'Gene', (171, 176))	('patients', 'Species', '9606', (43, 51))	('ALDH2', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('aldehyde dehydrogenase 2', 'Gene', '217', (146, 170))	('oropharyngeal cancer', 'Disease', (57, 77))	('ALDH2', 'Gene', '217', (171, 176))	('aldehyde dehydrogenase 2', 'Gene', (146, 170))
294386	29206831	The purpose of this study was to investigate the possibility of ALDH2 polymorphism as a prognostic factor for oropharyngeal cancer (OPC) among Japanese population.	('ALDH2', 'Gene', '217', (64, 69))	('polymorphism', 'Var', (70, 82))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (110, 130))	('ALDH2', 'Gene', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('oropharyngeal cancer', 'Disease', (110, 130))
294393	29206831	ALDH2 polymorphism might be a promising prognostic factor for Japanese patients with p16-negative OPC.	('OPC', 'Disease', (98, 101))	('p16', 'Gene', (85, 88))	('polymorphism', 'Var', (6, 18))	('patients', 'Species', '9606', (71, 79))	('ALDH2', 'Gene', (0, 5))	('p16', 'Gene', '1029', (85, 88))	('ALDH2', 'Gene', '217', (0, 5))
294406	29206831	The most likely reason for this discrepancy is a difference between Japanese and white individuals in terms of the presence or absence of aldehyde dehydrogenase-2 (ALDH2) polymorphism, a key enzyme for the elimination of acetaldehyde.	('ALDH2', 'Gene', '217', (164, 169))	('absence', 'NegReg', (127, 134))	('ALDH2', 'Gene', (164, 169))	('aldehyde dehydrogenase-2', 'Gene', '217', (138, 162))	('acetaldehyde', 'Chemical', 'MESH:D000079', (221, 233))	('polymorphism', 'Var', (171, 183))	('aldehyde dehydrogenase-2', 'Gene', (138, 162))
294410	29206831	Until now, however, there has been no report on the prognostic significance of ALDH2 polymorphism for the survival rate of the patients with OPC.	('ALDH2', 'Gene', '217', (79, 84))	('OPC', 'Disease', (141, 144))	('patients', 'Species', '9606', (127, 135))	('ALDH2', 'Gene', (79, 84))	('polymorphism', 'Var', (85, 97))
294411	29206831	In this paper, to develop a personalized treatment strategy for individual Japanese patients with OPC, we investigated the prognostic value of ALDH2 polymorphism in addition to that of HVP-status and clinical characteristics for OPC patients.	('OPC', 'Disease', (98, 101))	('patients', 'Species', '9606', (84, 92))	('ALDH2', 'Gene', '217', (143, 148))	('men', 'Species', '9606', (46, 49))	('polymorphism', 'Var', (149, 161))	('ALDH2', 'Gene', (143, 148))	('patients', 'Species', '9606', (233, 241))
294421	29206831	To determine the genotype of ALDH2, ALDH2 1951G>A (rs671) was subjected to analysis.	('ALDH2', 'Gene', (29, 34))	('ALDH2', 'Gene', (36, 41))	('ALDH2', 'Gene', '217', (29, 34))	('1951G>A', 'Var', (42, 49))	('rs671', 'Mutation', 'rs671', (51, 56))	('1951G>A', 'Mutation', 'rs671', (42, 49))	('ALDH2', 'Gene', '217', (36, 41))
294454	29206831	In addition, 3-years OS rate of patients with ALDH2 heterozygote tended to be worse than that of patients with ALDH2 homozygote among p16-negative OPC (p = 0.15).	('ALDH2', 'Gene', (111, 116))	('patients', 'Species', '9606', (32, 40))	('worse', 'NegReg', (78, 83))	('OS rate', 'MPA', (21, 28))	('p16', 'Gene', (134, 137))	('ALDH2', 'Gene', '217', (46, 51))	('patients', 'Species', '9606', (97, 105))	('ALDH2', 'Gene', '217', (111, 116))	('p16', 'Gene', '1029', (134, 137))	('ALDH2', 'Gene', (46, 51))	('heterozygote', 'Var', (52, 64))
294455	29206831	Since drinkers with heterozygous ALDH2 are at high risk of HNSCC and esophageal cancer, as previous mentioned, we finally investigated the rates of second primary pharyngeal and esophageal cancers (SPPEC) for these patients according to ALDH2 genotype.	('patients', 'Species', '9606', (215, 223))	('heterozygous', 'Var', (20, 32))	('ALDH2', 'Gene', (33, 38))	('esophageal cancer', 'Disease', (69, 86))	('men', 'Species', '9606', (100, 103))	('esophageal cancers', 'Disease', (178, 196))	('ALDH2', 'Gene', '217', (237, 242))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancers', 'Disease', 'MESH:D004938', (178, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('ALDH2', 'Gene', (237, 242))	('ALDH2', 'Gene', '217', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('HNSCC', 'Disease', (59, 64))
294458	29206831	Moreover among patients with p16-negative OPC, SPPEC occurred more frequently in patients with heterozygous than in those with homozygous ALDH2 (49% vs 18%, p = 0.0065; Table 6).	('p16', 'Gene', (29, 32))	('patients', 'Species', '9606', (15, 23))	('ALDH2', 'Gene', '217', (138, 143))	('patients', 'Species', '9606', (81, 89))	('p16', 'Gene', '1029', (29, 32))	('ALDH2', 'Gene', (138, 143))	('SPPEC', 'Disease', (47, 52))	('heterozygous', 'Var', (95, 107))
294467	29206831	These findings led us to the notion that ALDH2 polymorphism might be a possible prognostic factor for OPC in Asian populations.	('ALDH2', 'Gene', '217', (41, 46))	('polymorphism', 'Var', (47, 59))	('OPC', 'Disease', (102, 105))	('ALDH2', 'Gene', (41, 46))
294468	29206831	The present study showed that heterozygous ALDH2 is more common in the patients with p16-negative OPC than in those with p16-positive OPC, suggesting that, in addition to alcohol consumption, heterozygous ALDH2 might also be a carcinogenic factor for patients with p16-negative OPC.	('heterozygous', 'Var', (192, 204))	('ALDH2', 'Gene', (43, 48))	('patients', 'Species', '9606', (71, 79))	('p16', 'Gene', (265, 268))	('patients', 'Species', '9606', (251, 259))	('carcinogenic', 'Disease', (227, 239))	('ALDH2', 'Gene', '217', (205, 210))	('p16', 'Gene', '1029', (265, 268))	('carcinogenic', 'Disease', 'MESH:D063646', (227, 239))	('p16', 'Gene', (121, 124))	('ALDH2', 'Gene', '217', (43, 48))	('OPC', 'Disease', (98, 101))	('p16', 'Gene', '1029', (121, 124))	('alcohol', 'Chemical', 'MESH:D000438', (171, 178))	('common', 'Reg', (57, 63))	('p16', 'Gene', (85, 88))	('heterozygous', 'Var', (30, 42))	('ALDH2', 'Gene', (205, 210))	('p16', 'Gene', '1029', (85, 88))
294472	29206831	Although further study consisting of large number of patients is required to draw a definitive conclusion, this finding suggests the possibility ALDH2 polymorphism may be a prognostic factor for the patients with HPV-negative OPC.	('polymorphism', 'Var', (151, 163))	('patients', 'Species', '9606', (53, 61))	('OPC', 'Disease', (226, 229))	('ALDH2', 'Gene', '217', (145, 150))	('patients', 'Species', '9606', (199, 207))	('ALDH2', 'Gene', (145, 150))	('HPV', 'Species', '10566', (213, 216))
294479	29206831	One possible explanation is that patients with heterozygous ALDH2 might continue to drink alcohol at a higher level even after the treatment of oropharyngeal cancer.	('heterozygous', 'Var', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('drink alcohol', 'MPA', (84, 97))	('patients', 'Species', '9606', (33, 41))	('ALDH2', 'Gene', (60, 65))	('oropharyngeal cancer', 'Disease', (144, 164))	('alcohol', 'Chemical', 'MESH:D000438', (90, 97))	('ALDH2', 'Gene', '217', (60, 65))	('men', 'Species', '9606', (136, 139))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (144, 164))
294481	29206831	Another possible mechanism is that OPC of the patients with heterozygous ALDH2 may be more likely to have TP53 mutation and DNA methylations which are associated poor prognosis, due to alcohol consumption.	('ALDH2', 'Gene', (73, 78))	('patients', 'Species', '9606', (46, 54))	('alcohol', 'Chemical', 'MESH:D000438', (185, 192))	('ALDH2', 'Gene', '217', (73, 78))	('mutation', 'Var', (111, 119))	('DNA', 'MPA', (124, 127))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
294483	29206831	Further multi-institutional studies consisting of a large number of patients using DNA extracted directly from patients' blood should therefore be performed to further explore the prognostic significance of ALDH2 polymorphism for patients with OPC.	('ALDH2', 'Gene', (207, 212))	('OPC', 'Disease', (244, 247))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (68, 76))	('ALDH2', 'Gene', '217', (207, 212))	('polymorphism', 'Var', (213, 225))	('patients', 'Species', '9606', (111, 119))
294485	29206831	Instead, ALDH2 polymorphism was found to be possible prognostic factor for patients with HPV-negative OPC.	('ALDH2', 'Gene', (9, 14))	('patients', 'Species', '9606', (75, 83))	('ALDH2', 'Gene', '217', (9, 14))	('HPV', 'Species', '10566', (89, 92))	('polymorphism', 'Var', (15, 27))	('OPC', 'Disease', (102, 105))
294487	29206831	To the best of our knowledge, ours is the first report on the possible impact of ALDH polymorphism and racial difference on the prognosis of patients with OPC.	('impact', 'Reg', (71, 77))	('OPC', 'Disease', (155, 158))	('polymorphism', 'Var', (86, 98))	('ALDH', 'Gene', (81, 85))	('patients', 'Species', '9606', (141, 149))
294496	29070852	TIVA during esophageal cancer surgery was associated with better postoperative survival rates compared with volatile anesthesia.	('postoperative survival rates', 'CPA', (65, 93))	('better', 'PosReg', (58, 64))	('VA', 'Chemical', '-', (2, 4))	('esophageal cancer', 'Disease', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('TIVA', 'Var', (0, 4))	('esophageal cancer', 'Disease', 'MESH:D004938', (12, 29))
294601	29033774	While chest pain, pulmonary embolism, renal dysfunction, and esophageal stenosis are known to occur as major adverse events associated with sclerotherapy, ligation could lead to complications such as esophageal laceration, transient dysphagia, chest pain, esophageal stricture, and ulcer-related bleeding.	('ulcer', 'Disease', 'MESH:D014456', (282, 287))	('chest pain', 'Phenotype', 'HP:0100749', (6, 16))	('pain', 'Phenotype', 'HP:0012531', (12, 16))	('chest pain', 'Phenotype', 'HP:0100749', (244, 254))	('dysphagia', 'Disease', 'MESH:D003680', (233, 242))	('pain', 'Phenotype', 'HP:0012531', (250, 254))	('esophageal stenosis', 'Disease', 'MESH:D004940', (61, 80))	('bleeding', 'Disease', 'MESH:D006470', (296, 304))	('dysphagia', 'Disease', (233, 242))	('ulcer', 'Disease', (282, 287))	('renal dysfunction', 'Disease', 'MESH:D007674', (38, 55))	('esophageal stricture', 'Disease', (256, 276))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (18, 36))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (61, 80))	('pulmonary embolism', 'Disease', (18, 36))	('pulmonary embolism', 'Disease', 'MESH:D011655', (18, 36))	('esophageal stenosis', 'Disease', (61, 80))	('bleeding', 'Disease', (296, 304))	('lead to', 'Reg', (170, 177))	('dysphagia', 'Phenotype', 'HP:0002015', (233, 242))	('chest pain', 'Disease', 'MESH:D002637', (6, 16))	('chest pain', 'Disease', 'MESH:D002637', (244, 254))	('esophageal stricture', 'Phenotype', 'HP:0002043', (256, 276))	('chest pain', 'Disease', (6, 16))	('chest pain', 'Disease', (244, 254))	('renal dysfunction', 'Disease', (38, 55))	('esophageal laceration', 'Disease', (200, 221))	('ligation', 'Var', (155, 163))	('renal dysfunction', 'Phenotype', 'HP:0000083', (38, 55))
294654	29033774	Previous reports have indicated that an elevated platelet count may be associated with an abnormal vWF multimer distribution in plasma.	('elevated', 'PosReg', (40, 48))	('abnormal', 'Var', (90, 98))	('elevated platelet count', 'Phenotype', 'HP:0001894', (40, 63))	('vWF', 'Gene', '7450', (99, 102))	('platelet count', 'MPA', (49, 63))	('vWF', 'Gene', (99, 102))
294665	28486494	Patients in SRC>=50% group had a lower overall survival rate (at 3-year 37.6%versus71.1%; at 5-year 0% versus 43.3%; p<0.001) compared with the control group.	('overall survival', 'MPA', (39, 55))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (33, 38))	('SRC>=50%', 'Var', (12, 20))
294667	28486494	Female sex, large tumor size and increasing TNM stage were independent prognostic factors for SRC >=50% esophageal carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumor', 'Disease', (18, 23))	('esophageal carcinoma', 'Disease', (104, 124))	('TNM', 'Gene', (44, 47))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (104, 124))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (104, 124))	('TNM', 'Gene', '10178', (44, 47))	('SRC >=50%', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('patients', 'Species', '9606', (125, 133))
294719	28486494	The median overall survival duration for patients in the SRC>=50% group was 29 months (95% confidence interval [CI]: 21 to 36), which was significantly shorter than that observed in the SRC<50% group (39 months, 95% CI: 33 to 44) and the reference group (56 months, 95% CI: 48 to 63).	('SRC>=50%', 'Var', (57, 65))	('patients', 'Species', '9606', (41, 49))	('shorter', 'NegReg', (152, 159))
294720	28486494	Patients in the SRC>=50% group had a lower overall survival rate (at 1-year 83.7%versus 94.1%, at 3-year 37.6%versus71.1%; at 5-year 0% versus 43.3%; p<0.001) compared with the reference group.	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (43, 59))	('SRC>=50%', 'Var', (16, 24))	('lower', 'NegReg', (37, 42))
294722	28486494	Examination of the association of individual variables with overall survival showed that female sex, large tumor size and increasing TNM stage were independent prognostic factors for patients with SRC >=50% esophageal carcinoma (Table 3).	('SRC >=50%', 'Var', (197, 206))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('TNM', 'Gene', (133, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('esophageal carcinoma', 'Disease', (207, 227))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (207, 227))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (207, 227))	('TNM', 'Gene', '10178', (133, 136))	('patients', 'Species', '9606', (183, 191))
294753	28099140	Finally, TUNEL assay, caspase 3 and Ki67 staining in tumor tissue proved that imetelstat sensitized esophageal cancer to radiation in vivo through promoting cell apoptosis and inhibiting cell proliferation.	('promoting', 'PosReg', (147, 156))	('Ki67', 'Gene', (36, 40))	('esophageal cancer', 'Disease', (100, 117))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cell apoptosis', 'CPA', (157, 171))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inhibiting', 'NegReg', (176, 186))	('Ki67', 'Gene', '17345', (36, 40))	('imetelstat', 'Var', (78, 88))	('caspase 3', 'Gene', (22, 31))	('tumor', 'Disease', (53, 58))	('cell proliferation', 'CPA', (187, 205))	('imetelstat', 'Chemical', 'MESH:C519562', (78, 88))	('caspase 3', 'Gene', '836', (22, 31))
294765	28099140	Furthermore, it has been reported that telomerase activity was remarkably elevated and inhibition of telomerase blocks proliferation of esophageal adenocarcinoma cells both in vitro and in vivo, while there was no report focusing on esophageal squamous cell carcinoma.	('blocks', 'NegReg', (112, 118))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (233, 267))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (244, 267))	('inhibition', 'Var', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('elevated', 'PosReg', (74, 82))	('telomerase', 'Enzyme', (39, 49))	('esophageal squamous cell carcinoma', 'Disease', (233, 267))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (136, 161))	('activity', 'MPA', (50, 58))	('esophageal adenocarcinoma', 'Disease', (136, 161))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (136, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('telomerase', 'Protein', (101, 111))	('proliferation', 'CPA', (119, 132))
294772	28099140	As shown in Figure 1A, exposure to imetelstat alone resulted in 69.7% cell survival for Kyse410 and 75.9% cell survival for Kyse520 compare to sense treatment.	('imetelstat', 'Chemical', 'MESH:C519562', (35, 45))	('Kyse520', 'Chemical', '-', (124, 131))	('Kyse410', 'Var', (88, 95))	('cell survival', 'CPA', (70, 83))	('Kyse410', 'Chemical', '-', (88, 95))	('cell survival', 'CPA', (106, 119))	('Kyse520', 'Var', (124, 131))
294774	28099140	Cell survival after 2, 4, 6 and 8 Gy irradiation of Kyse410 was 64.7%, 39.1%, 3.9% and 3.3%, whereas the expected additive survival should be 45.0%, 27.2%, 2.7% and 2.3%.	('Kyse410', 'Chemical', '-', (52, 59))	('Cell survival', 'CPA', (0, 13))	('Kyse410', 'Var', (52, 59))
294775	28099140	For Kyse520, the expected additive cell survival is approximately 61.4%, 38.3%, 17.4% and 6.5% theoretically.	('additive cell survival', 'CPA', (26, 48))	('Kyse520', 'Var', (4, 11))	('Kyse520', 'Chemical', '-', (4, 11))
294777	28099140	Figure 1B showed the survival curves of Kyse410 and Kyse520 after exposure to X-ray combined with the treatment of 5 muM imetelstat, which reflected the radiosensitizing effect.	('Kyse410', 'Var', (40, 47))	('imetelstat', 'Chemical', 'MESH:C519562', (121, 131))	('Kyse410', 'Chemical', '-', (40, 47))	('muM', 'Gene', '56925', (117, 120))	('Kyse520', 'Chemical', '-', (52, 59))	('muM', 'Gene', (117, 120))	('Kyse520', 'Var', (52, 59))
294784	28099140	As shown in Figure 2, TMZ significantly increased apoptosis percentage for both cell lines compared with the control group (p < 0.05).	('TMZ', 'Chemical', 'MESH:D000077204', (22, 25))	('increased', 'PosReg', (40, 49))	('TMZ', 'Var', (22, 25))	('apoptosis percentage', 'CPA', (50, 70))	('increased apoptosis percentage', 'Phenotype', 'HP:0030887', (40, 70))
294786	28099140	Imetelstat administration increased the apoptosis percentage to 38% for Kyse410 and 18% for Kyse520, significantly higher than those treated with sense (p < 0.05).	('apoptosis percentage', 'CPA', (40, 60))	('Kyse410', 'Chemical', '-', (72, 79))	('Kyse520', 'Var', (92, 99))	('Imetelstat', 'Chemical', 'MESH:C519562', (0, 10))	('Kyse410', 'Var', (72, 79))	('Kyse520', 'Chemical', '-', (92, 99))	('higher', 'PosReg', (115, 121))
294796	28099140	To study whether telomerase inhibition and telomere dysfunction was associated with a progressive impairment in the cell growth in vivo as well as in vitro, the tumor growth curve was pictured.	('telomerase', 'Protein', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('telomere dysfunction', 'Var', (43, 63))	('cell growth', 'CPA', (116, 127))	('inhibition', 'NegReg', (28, 38))	('tumor', 'Disease', (161, 166))
294800	28099140	More importantly, Kyse520 in imetelstat/radiation group showed a lag in tumor growth compared with mice receiving 2 Gy of irradiation alone or irradiation with sense, which confirmed that imetelstat made tumor more sensitive to radiotherapy.	('mice', 'Species', '10090', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('imetelstat', 'Chemical', 'MESH:C519562', (29, 39))	('more', 'PosReg', (210, 214))	('Kyse520', 'Chemical', '-', (18, 25))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Kyse520', 'Var', (18, 25))	('imetelstat', 'Chemical', 'MESH:C519562', (188, 198))
294805	28099140	Although TUNEL staining for tumor treated with sense or imetelstat showed relatively small number of apoptotic cells, the enhanced staining intensity in imetelstat group was still stronger than that in the sense group.	('imetelstat', 'Chemical', 'MESH:C519562', (56, 66))	('tumor', 'Disease', (28, 33))	('enhanced', 'PosReg', (122, 130))	('imetelstat', 'Var', (153, 163))	('staining intensity', 'MPA', (131, 149))	('imetelstat', 'Chemical', 'MESH:C519562', (153, 163))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('stronger', 'PosReg', (180, 188))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
294808	28099140	More importantly, the expression of caspase3 in imetelstat/radiation group was much higher than that in the sense/radiation group, which implies more apoptosis.	('caspase3', 'Protein', (36, 44))	('imetelstat/radiation', 'Var', (48, 68))	('expression', 'MPA', (22, 32))	('imetelstat', 'Chemical', 'MESH:C519562', (48, 58))	('higher', 'PosReg', (84, 90))
294809	28099140	Tumor subjected to sense or imetelstat only showed almost no expression of caspase3, which confirmed that imetelstat was not toxic to mice in vivo and the principal function of it was enhancing tumor sensitivity to radiation therapy.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('imetelstat', 'Chemical', 'MESH:C519562', (106, 116))	('mice', 'Species', '10090', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (200, 224))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('enhancing', 'PosReg', (184, 193))	('imetelstat', 'Var', (106, 116))	('tumor', 'Disease', (194, 199))	('caspase3', 'Gene', (75, 83))	('imetelstat', 'Chemical', 'MESH:C519562', (28, 38))
294819	28099140	More importantly, our research group has reported imetelstat increases radiation induced DNA breaks, which provided theoretical foundation for further researches.	('radiation induced DNA breaks', 'MPA', (71, 99))	('imetelstat', 'Var', (50, 60))	('imetelstat', 'Chemical', 'MESH:C519562', (50, 60))
294822	28099140	Further analysis showed that SER was larger for Kyse410 than Kyse520, 1.9 and 1.6 respectively.	('Kyse410', 'Chemical', '-', (48, 55))	('SER', 'MPA', (29, 32))	('larger', 'PosReg', (37, 43))	('SER', 'Chemical', '-', (29, 32))	('Kyse410', 'Var', (48, 55))	('Kyse520', 'Chemical', '-', (61, 68))
294823	28099140	These results indicated that Kyse520 is more radioresistant than Kyse410 cells, consisting with our previous results that radiation-induced DSB foci in Kyse410 are more in number and larger in size compared with the DSB foci in Kyse520 cells.	('Kyse410', 'Chemical', '-', (152, 159))	('DSB', 'Disease', (140, 143))	('Kyse520', 'Chemical', '-', (228, 235))	('Kyse520', 'Chemical', '-', (29, 36))	('Kyse410', 'Chemical', '-', (65, 72))	('Kyse410', 'Var', (152, 159))
294825	28099140	Our previous study reported that treatment of imetelstat and radiation showed synergistic increase and prolonged higher expression of DSB foci compared to cells treated with sense/radiation.	('expression', 'MPA', (120, 130))	('increase', 'PosReg', (90, 98))	('imetelstat', 'Var', (46, 56))	('DSB foci', 'Gene', (134, 142))	('higher', 'PosReg', (113, 119))	('imetelstat', 'Chemical', 'MESH:C519562', (46, 56))
294828	28099140	Cells react to DSBs by triggering the DNA damage signaling, which will further activate intracellular pathways including apoptotic signaling One our previous research reported that 17-AAG sensitize esophageal squamous cells to radiation by inhibiting cell proliferation and promote cell apoptosis.	('17-AAG', 'Chemical', 'MESH:C112765', (181, 187))	('17-AAG', 'Var', (181, 187))	('promote', 'PosReg', (274, 281))	('DSBs', 'Chemical', '-', (15, 19))	('cell proliferation', 'CPA', (251, 269))	('inhibiting', 'NegReg', (240, 250))	('cell apoptosis', 'CPA', (282, 296))	('sensitize', 'Reg', (188, 197))	('esophageal', 'Disease', (198, 208))
294843	28099140	Kyse410 and Kyse520 were pretreated with imetelstat and sense at a concentration of 1 muM for 40 days.	('imetelstat', 'Chemical', 'MESH:C519562', (41, 51))	('Kyse520', 'Var', (12, 19))	('muM', 'Gene', '56925', (86, 89))	('muM', 'Gene', (86, 89))	('Kyse410', 'Chemical', '-', (0, 7))	('Kyse410', 'Var', (0, 7))	('Kyse520', 'Chemical', '-', (12, 19))
294905	25197529	Life style and environmental factors including, tobacco smoking, opium abuse, drinking of hot tea, polycyclic aromatic hydrocarbons, low consumption of fresh fruit and vegetable, Low socioeconomic status poor oral hygiene, and positive family history of ESCC  have been and still remain as main suspected risk factors for the development of ESCC.	('poor oral', 'Phenotype', 'HP:0000160', (204, 213))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (99, 131))	('ESCC', 'Disease', (254, 258))	('tobacco', 'Species', '4097', (48, 55))	('polycyclic', 'Var', (99, 109))	('ESCC', 'Disease', (341, 345))
294906	21481789	Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene P120ctn interacts with E-cadherin, but no formal proof that p120ctn functions as a bone fide tumor suppressor gene has emerged.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('results in', 'Reg', (25, 35))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('inflammation', 'Disease', 'MESH:D007249', (66, 78))	('Deletion', 'Var', (0, 8))	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('p120-catenin', 'Gene', '12388', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('P120ctn', 'Gene', (137, 144))	('p120-catenin', 'Gene', (12, 24))	('P120ctn', 'Gene', '12388', (137, 144))	('tumor', 'Disease', (38, 43))	('inflammation', 'Disease', (66, 78))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('cancer', 'Disease', (83, 89))
294907	21481789	We report herein that p120ctn loss leads to tumor development in mice.	('mice', 'Species', '10090', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('p120ctn', 'Var', (22, 29))	('tumor', 'Disease', (44, 49))
294908	21481789	We have generated a conditional knockout model of p120ctn whereby mice develop pre-neoplastic and neoplastic lesions in the oral cavity, esophagus and squamous forestomach.	('neoplastic lesions in the oral cavity', 'Phenotype', 'HP:0100649', (98, 135))	('squamous forestomach', 'Disease', (151, 171))	('rat', 'Species', '10116', (12, 15))	('squamous forestomach', 'Disease', 'MESH:D013274', (151, 171))	('mice', 'Species', '10090', (66, 70))	('develop', 'PosReg', (71, 78))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (98, 116))	('p120ctn', 'Var', (50, 57))	('esophagus', 'Disease', (137, 146))
294912	21481789	The cardinal feature of the adherens junctions is the interaction between the cytoplasmic tail of classical type I (E-cadherin) and type II cadherins, and p120-catenin (p120ctn, also referred to as catenin, delta1 or Ctnnd1), which engenders stability of this specific junctions complex at the cell membrane.	('p120-catenin', 'Gene', '12388', (155, 167))	('Ctnnd1', 'Gene', (217, 223))	('p120ctn', 'Var', (169, 176))	('p120-catenin', 'Gene', (155, 167))	('Ctnnd1', 'Gene', '12388', (217, 223))	('interaction', 'Interaction', (54, 65))	('catenin, delta1', 'Gene', '12388;13388', (198, 213))
294913	21481789	Loss of p120ctn or its phosphorylation on serine-threonine residues is able to destabilize E-cadherin.	('serine', 'Chemical', 'MESH:D012694', (42, 48))	('threonine', 'Chemical', 'MESH:D013912', (49, 58))	('p120ctn', 'Var', (8, 15))	('E-cadherin', 'Protein', (91, 101))	('destabilize', 'NegReg', (79, 90))	('phosphorylation on serine-threonine residues', 'MPA', (23, 67))	('Loss', 'Var', (0, 4))
294914	21481789	The balance between adhesion and migration is regulated further by p120ctn's ability to regulate the activities of RhoA, Rac and Cdc42 through the amino-terminus of p120ctn, thereby orchestrating exquisite actin dynamics.	('regulate', 'Reg', (88, 96))	('Rac', 'Gene', '11651', (121, 124))	('p120ctn', 'Var', (165, 172))	('Cdc42', 'Gene', '12540', (129, 134))	('rat', 'Species', '10116', (36, 39))	('RhoA', 'Gene', (115, 119))	('RhoA', 'Gene', '11848', (115, 119))	('Rac', 'Gene', (121, 124))	('Cdc42', 'Gene', (129, 134))	('p120ctn', 'Var', (67, 74))	('activities', 'MPA', (101, 111))	('rat', 'Species', '10116', (189, 192))
294915	21481789	Furthermore, the bridge between p120ctn and these effectors of migration involves p190RhoGAP.	('p190RhoGAP', 'Gene', '232906', (82, 92))	('p190RhoGAP', 'Gene', (82, 92))	('p120ctn', 'Var', (32, 39))	('rat', 'Species', '10116', (66, 69))
294916	21481789	It has become increasingly clear that loss, downregulation or mislocalization of p120ctn helps to define diverse tumor types in the prostate, breast, pancreas, colon, skin, bladder and endometrium.	('prostate', 'Disease', (132, 140))	('tumor', 'Disease', (113, 118))	('endometrium', 'Disease', (185, 196))	('bladder', 'Disease', (173, 180))	('pancreas', 'Disease', (150, 158))	('downregulation', 'NegReg', (44, 58))	('breast', 'Disease', (142, 148))	('skin', 'Disease', (167, 171))	('colon', 'Disease', 'MESH:D015179', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('pancreas', 'Disease', 'MESH:D010190', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('p120ctn', 'Var', (81, 88))	('colon', 'Disease', (160, 165))
294918	21481789	This loss or mislocalization of p120ctn frequently leads to E-cadherin destabilization, endowing a cancer cell an advantage in cell migration by virtue of abrogation of cell adhesion.	('cell migration', 'CPA', (127, 141))	('rat', 'Species', '10116', (135, 138))	('leads to', 'Reg', (51, 59))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('loss', 'NegReg', (5, 9))	('p120ctn', 'Var', (32, 39))	('destabilization', 'NegReg', (71, 86))	('E-cadherin', 'Protein', (60, 70))	('cell adhesion', 'CPA', (169, 182))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('advantage', 'PosReg', (114, 123))
294919	21481789	Additionally, knockdown experiments using shRNA to p120ctn have demonstrated that p120ctn loss induces invasion in tumor cell lines with concomitant loss or down-regulation of E-cadherin, although collective invasion might involve also concurrent retention of membranous p120ctn and cadherin mediated (P- or E-cadherin) cell-cell contacts at least in vitro.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('E-cadherin', 'Protein', (176, 186))	('rat', 'Species', '10116', (71, 74))	('loss', 'NegReg', (90, 94))	('loss', 'NegReg', (149, 153))	('tumor', 'Disease', (115, 120))	('down-regulation', 'NegReg', (157, 172))	('invasion', 'CPA', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('p120ctn', 'Var', (82, 89))
294920	21481789	In aggregate, these data suggest a potential tumor suppressor role for p120ctn in various cancer types, but a causal role in vivo has yet to be demonstrated unequivocally.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', (45, 50))	('p120ctn', 'Var', (71, 78))	('rat', 'Species', '10116', (151, 154))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
294922	21481789	Deletion of p120ctn by homologous recombination in mice results in embryonic lethality.	('embryonic lethality', 'Disease', (67, 86))	('p120ctn', 'Var', (12, 19))	('mice', 'Species', '10090', (51, 55))	('embryonic lethality', 'Disease', 'MESH:D020964', (67, 86))
294923	21481789	Tissue-specific targeting of p120ctn has been utilized to study the role of p120ctn in development and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('p120ctn', 'Var', (76, 83))	('p120ctn', 'Var', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
294924	21481789	Targeted p120ctn deletion in the embryonic salivary gland forces a loss of acinar development and an adoption of a ductal cell fate.	('embryonic salivary', 'Disease', (33, 51))	('embryonic salivary', 'Disease', 'MESH:D012466', (33, 51))	('adoption', 'Reg', (101, 109))	('p120ctn', 'Var', (9, 16))	('loss', 'NegReg', (67, 71))	('acinar development', 'CPA', (75, 93))
294928	21481789	Recently, conditional p120ctn loss in the small intestine and colon was found to result in death by 21 days with evidence of mucosal erosion and bleeding, and recruitment of COX-2 expressing neutrophils, suggesting an underlying barrier defect.	('colon', 'Disease', 'MESH:D015179', (62, 67))	('death', 'Disease', 'MESH:D003643', (91, 96))	('p120ctn loss', 'Var', (22, 34))	('death', 'Disease', (91, 96))	('mucosal erosion', 'Phenotype', 'HP:0031446', (125, 140))	('COX-2', 'Gene', '17709', (174, 179))	('mucosal erosion and bleeding', 'Disease', 'MESH:D006470', (125, 153))	('colon', 'Disease', (62, 67))	('COX-2', 'Gene', (174, 179))
294929	21481789	Thus, to date, no tissue specific p120ctn knockout mouse models have been able to demonstrate that p120ctn loss results in the development of invasive cancer.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('loss', 'NegReg', (107, 111))	('mouse', 'Species', '10090', (51, 56))	('rat', 'Species', '10116', (89, 92))	('invasive cancer', 'Disease', (142, 157))	('p120ctn', 'Var', (99, 106))	('invasive cancer', 'Disease', 'MESH:D009362', (142, 157))
294930	21481789	The overarching goal of this study was to generate and characterize mechanistically a genetic mouse model in which conditional p120ctn loss in the squamous oral cavity, esophagus and forestomach results in cancer that phenocopies precisely the histologic features of human oral and esophageal squamous cell carcinomas (OSCC, ESCC, respectively).	('p120ctn', 'Var', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('esophageal squamous cell carcinomas', 'Disease', (282, 317))	('rat', 'Species', '10116', (46, 49))	('loss', 'NegReg', (135, 139))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (282, 317))	('carcinomas', 'Phenotype', 'HP:0030731', (307, 317))	('results in', 'Reg', (195, 205))	('mouse', 'Species', '10090', (94, 99))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (293, 317))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (206, 212))	('human', 'Species', '9606', (267, 272))
294932	21481789	A human tissue microarray (TMA) with matched normal and tumor esophageal squamous cell cancer (ESCC) tissues was evaluated for p120ctn expression by immunohistochemistry (IHC) (Figure 1A).	('p120ctn', 'Var', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor esophageal squamous cell cancer', 'Disease', (56, 93))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (73, 93))	('TMA', 'Disease', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('human', 'Species', '9606', (2, 7))	('TMA', 'Disease', 'MESH:D000783', (27, 30))	('tumor esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (56, 93))
294934	21481789	By contrast, 100% of the 69 ESCC tumors have p120ctn loss or cytoplasmic mislocalization (Figure 1B).	('p120ctn loss', 'Var', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('cytoplasmic mislocalization', 'CPA', (61, 88))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('ESCC', 'Disease', (28, 32))	('tumors', 'Disease', (33, 39))
294935	21481789	There is a statistically significant association (p=0.017) between decreased p120ctn and E-cadherin expression with odds ratio = 3.23 (95% CI: 1.13<O.R.<9.24).	('expression', 'MPA', (100, 110))	('p120ctn', 'Var', (77, 84))	('E-cadherin', 'Protein', (89, 99))	('decreased', 'NegReg', (67, 76))	('rat', 'Species', '10116', (121, 124))
294936	21481789	A panel of 14 human esophageal squamous tumor cell lines was analyzed for p120ctn and E-cadherin expression (Figure 1C).	('squamous tumor', 'Phenotype', 'HP:0002860', (31, 45))	('human', 'Species', '9606', (14, 19))	('esophageal squamous tumor', 'Disease', (20, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('p120ctn', 'Var', (74, 81))	('esophageal squamous tumor', 'Disease', 'MESH:D000077277', (20, 45))
294941	21481789	To elucidate the mechanistic roles of p120ctn in vivo, we generated spatially-targeted p120ctn deletion in the oral cavity, esophagus and squamous forestomach.	('rat', 'Species', '10116', (62, 65))	('p120ctn deletion', 'Var', (87, 103))	('squamous forestomach', 'Disease', (138, 158))	('squamous forestomach', 'Disease', 'MESH:D013274', (138, 158))
294945	21481789	To verify p120ctn loss in L2-Cre;p120loxP/loxP mice, p120ctn protein expression was assessed by immunofluorescence (IF).	('loss', 'NegReg', (18, 22))	('p120ctn', 'Var', (53, 60))	('p120ctn', 'Var', (10, 17))	('mice', 'Species', '10090', (47, 51))
294946	21481789	P120ctn was effectively lost in the epithelium in 2 month old L2-Cre;p120loxP/loxP mice compared to L2-Cre;p120+/+ control mice (Figure 2A).	('lost', 'NegReg', (24, 28))	('mice', 'Species', '10090', (83, 87))	('L2-Cre', 'Var', (62, 68))	('P120ctn', 'Gene', (0, 7))	('P120ctn', 'Gene', '12388', (0, 7))	('mice', 'Species', '10090', (123, 127))
294949	21481789	Histologic analysis at 9-12 months of age demonstrated severe dysplasia with invasive squamous cancer into the submucosa and muscle in L2Cre;p120loxP/loxP mice while all control mice (p120flox/flox, L2-Cre;p120+/+ and L2-Cre;p120+/loxP) had no abnormalities (Figure 3A).	('dysplasia', 'Disease', 'MESH:D004476', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mice', 'Species', '10090', (178, 182))	('invasive squamous cancer', 'Disease', 'MESH:D002294', (77, 101))	('L2Cre;p120loxP/loxP', 'Var', (135, 154))	('mice', 'Species', '10090', (155, 159))	('invasive squamous cancer', 'Disease', (77, 101))	('squamous cancer', 'Phenotype', 'HP:0002860', (86, 101))	('rat', 'Species', '10116', (49, 52))	('dysplasia', 'Disease', (62, 71))
294950	21481789	Approximately 70% of L2Cre;p120loxP/loxP mice develop tumors between 9-12 months of age while no tumors were detected in age-matched littermate control mice (Table S1, p<0.0001).	('L2Cre;p120loxP/loxP', 'Var', (21, 40))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('develop', 'PosReg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (97, 103))	('mice', 'Species', '10090', (152, 156))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumors', 'Disease', (54, 60))
294951	21481789	Invasive esophageal cancer was detected as early as 4 months of age in one L2Cre;p120loxP/loxP mouse.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('p120loxP/loxP', 'Var', (81, 94))	('esophageal cancer', 'Disease', (9, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (9, 26))	('mouse', 'Species', '10090', (95, 100))
294954	21481789	Analysis of L2-Cre;p120loxP/loxP forestomachs revealed severe hyperplasia, severe dysplasia and invasive cancers into the underlying desmoplastic and inflammatory stroma.	('p120loxP/loxP', 'Var', (19, 32))	('invasive cancers', 'Disease', 'MESH:D009362', (96, 112))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('desmoplastic', 'Disease', 'MESH:D018220', (133, 145))	('hyperplasia', 'Disease', 'MESH:D006965', (62, 73))	('dysplasia', 'Disease', (82, 91))	('invasive cancers', 'Disease', (96, 112))	('desmoplastic', 'Disease', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('dysplasia', 'Disease', 'MESH:D004476', (82, 91))	('hyperplasia', 'Disease', (62, 73))
294958	21481789	Significant loss of E-cadherin expression is noted in L2-Cre;p120loxP/loxP mice compared to L2-Cre;p120+/+ control mice with residual E-cadherin expression in some L2-Cre;p120loxP/loxP mice where it is cytoplasmic (Figure 2B).	('mice', 'Species', '10090', (75, 79))	('E-cadherin', 'Protein', (20, 30))	('loss', 'NegReg', (12, 16))	('L2-Cre', 'Var', (54, 60))	('mice', 'Species', '10090', (185, 189))	('E-cadherin', 'Protein', (134, 144))	('expression', 'MPA', (31, 41))	('L2-Cre', 'Var', (164, 170))	('mice', 'Species', '10090', (115, 119))
294959	21481789	In some mice, while p120ctn is lost and E-cadherin is either lost or cytoplasmic, there are occasional focal areas within tumors that retain both p120ctn and E-cadherin at the cell membrane (Figure 2C), the latter consistent with the notion of collective invasion observed in A431 cells in vitro.	('areas within tumors', 'Disease', (109, 128))	('p120ctn', 'Var', (20, 27))	('p120ctn', 'Var', (146, 153))	('A431', 'CellLine', 'CVCL:0037', (276, 280))	('mice', 'Species', '10090', (8, 12))	('areas within tumors', 'Disease', 'MESH:D001929', (109, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('E-cadherin', 'Protein', (158, 168))
294961	21481789	Normal proliferating basal cells express Ki-67 and K14 while normal differentiated suprabasal cells express keratins 4 and 13 (K4, K13) and harbor little proliferation.	('rat', 'Species', '10116', (110, 113))	('K14', 'Gene', (51, 54))	('Ki-67', 'Var', (41, 46))	('K13', 'Gene', '16663', (131, 134))	('K13', 'Gene', (131, 134))	('rat', 'Species', '10116', (161, 164))	('K14', 'Gene', '16664', (51, 54))	('rat', 'Species', '10116', (14, 17))
294962	21481789	Ki-67 expression was significantly increased in the esophageal epithelia and in the invasive cancers in L2-Cre;p120loxP/loxP mice compared to control mice (Figure S2, p=3 x 10-6).	('Ki-67', 'Gene', (0, 5))	('mice', 'Species', '10090', (150, 154))	('increased', 'PosReg', (35, 44))	('invasive cancers', 'Disease', (84, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('esophageal epithelia', 'Disease', (52, 72))	('expression', 'MPA', (6, 16))	('esophageal epithelia', 'Disease', 'MESH:D004941', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mice', 'Species', '10090', (125, 129))	('L2-Cre', 'Var', (104, 110))	('invasive cancers', 'Disease', 'MESH:D009362', (84, 100))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (52, 72))
294964	21481789	Keratin 4 expression as evaluated by qPCR is decreased 2.5 fold (p=0.014) in L2-Cre;p120loxP/loxP mice compared to L2-Cre;p120+/+ control mice (data not shown).	('Keratin 4', 'Gene', (0, 9))	('decreased', 'NegReg', (45, 54))	('expression', 'MPA', (10, 20))	('mice', 'Species', '10090', (138, 142))	('Keratin 4', 'Gene', '16682', (0, 9))	('mice', 'Species', '10090', (98, 102))	('L2-Cre;p120loxP/loxP', 'Var', (77, 97))
294966	21481789	Interestingly, beta-catenin expression was membranous in the esophagi of L2-Cre;p120loxP/loxP mice (Figure 3C), but lost in the oral cavity of the L2-Cre;p120loxP/loxP mice.	('beta-catenin', 'Gene', '12387', (15, 27))	('L2-Cre', 'Var', (73, 79))	('lost', 'NegReg', (116, 120))	('expression', 'MPA', (28, 38))	('mice', 'Species', '10090', (168, 172))	('beta-catenin', 'Gene', (15, 27))	('mice', 'Species', '10090', (94, 98))
294972	21481789	We then established cells from an esophageal tumor (designated as 714ET) as well as esophageal cell lines from p120ctnloxP/loxP mice that in turn were infected with retroviral Cre recominbase or a control vector (designated as F2-Cre and F2-Tomato, respectively).	('p120ctnloxP/loxP', 'Var', (111, 127))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('esophageal tumor', 'Disease', 'MESH:D004938', (34, 50))	('mice', 'Species', '10090', (128, 132))	('esophageal tumor', 'Disease', (34, 50))	('esophageal tumor', 'Phenotype', 'HP:0100751', (34, 50))	('Tomato', 'Species', '4081', (241, 247))
294973	21481789	Western blot analysis revealed complete p120ctn loss in both F2-Cre and 714ET cells and retained p120ctn expression in the control F2-Tomato cells (Figure 4B and quantified in Figure 4C-left panel).	('p120ctn', 'Var', (40, 47))	('Tomato', 'Species', '4081', (134, 140))	('loss', 'NegReg', (48, 52))	('p120ctn', 'Var', (97, 104))
294978	21481789	Splenic weights in L2-Cre;p120loxP/loxP mice were 5-fold greater than in control mice (p=0.0004) and there was also leukocytosis with increased segmented neutrophils, band neutrophils, eosinophils and monocytes (Table S2).	('eosinophils', 'CPA', (185, 196))	('Splenic weights', 'CPA', (0, 15))	('mice', 'Species', '10090', (81, 85))	('eosin', 'Chemical', 'MESH:D004801', (185, 190))	('leukocytosis', 'Disease', 'MESH:D007964', (116, 128))	('segmented neutrophils', 'CPA', (144, 165))	('leukocytosis', 'Phenotype', 'HP:0001974', (116, 128))	('L2-Cre;p120loxP/loxP', 'Var', (19, 39))	('band neutrophils', 'CPA', (167, 183))	('mice', 'Species', '10090', (40, 44))	('leukocytosis', 'Disease', (116, 128))	('increased', 'PosReg', (134, 143))	('greater', 'PosReg', (57, 64))
294980	21481789	Therefore, we analyzed the leukocyte fraction (CD45+ cells) for immature myeloid cells (defined phenotypically as Gr-1+ CD11b+ cells), macrophages (F4/80+), T cells (CD3+), B cells (CD19+), dendritic cells (CD11c+), and natural killer cells (CD49b+).	('CD19', 'Gene', '12478', (182, 186))	('F4/80', 'Gene', (148, 153))	('Gr-1', 'Gene', (114, 118))	('CD11c+', 'Var', (207, 213))	('F4/80', 'Gene', '13733', (148, 153))	('CD3', 'Gene', (166, 169))	('CD19', 'Gene', (182, 186))	('CD3', 'Gene', '12501', (166, 169))	('Gr-1', 'Gene', '546644', (114, 118))
294981	21481789	The percentage of CD45+ cells was approximately the same for normal vs. dysplastic vs. tumor tissues and spleens (Figure 4E).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CD45+', 'Var', (18, 23))	('dysplastic', 'Disease', 'MESH:D004416', (72, 82))	('tumor', 'Disease', (87, 92))	('dysplastic', 'Disease', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
294989	21481789	In order to evaluate the functional properties of the immature myeloid cells, we again purified Gr-1+ CD11b+ cells from tumor-bearing L2-Cre;p120loxP/loxP mice and found that these cells inhibited peptide-specific T cell responses in vitro (using OVA specific TCR-transgenic T cells) (Figure 4G).	('CD11b+', 'Gene', (102, 108))	('Gr-1', 'Gene', '546644', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('mice', 'Species', '10090', (155, 159))	('peptide-specific T cell responses', 'MPA', (197, 230))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Gr-1', 'Gene', (96, 100))	('transgenic', 'Species', '10090', (264, 274))	('p120loxP/loxP', 'Var', (141, 154))	('tumor', 'Disease', (120, 125))	('inhibited', 'NegReg', (187, 196))
294996	21481789	To evaluate the specific features of the microenvironment in the invasive cancers that develop in L2-Cre;p120loxP/loxP mice, a pronounced increase in fibrillar collagen was present in the tumor stroma consistent with the desmoplasia in human ESCC and OSCC (Figure 5D).	('human', 'Species', '9606', (236, 241))	('increase', 'PosReg', (138, 146))	('mice', 'Species', '10090', (119, 123))	('ESCC', 'Disease', (242, 246))	('fibrillar collagen', 'MPA', (150, 168))	('tumor stroma', 'Disease', (188, 200))	('invasive cancers', 'Disease', 'MESH:D009362', (65, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('desmoplasia', 'Disease', (221, 232))	('tumor stroma', 'Disease', 'MESH:D009369', (188, 200))	('L2-Cre', 'Var', (98, 104))	('OSCC', 'Disease', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('invasive cancers', 'Disease', (65, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('desmoplasia', 'Disease', 'None', (221, 232))
295003	21481789	Given the different lines of evidence for the tumor-promoting role of Gr-1+CD11+ cells in L2-Cre;p120loxP/loxP mice, we next sought to determine a relationship between myeloid cells and p120ctn loss in human ESCC.	('Gr-1', 'Gene', (70, 74))	('ESCC', 'Disease', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('human', 'Species', '9606', (202, 207))	('tumor', 'Disease', (46, 51))	('mice', 'Species', '10090', (111, 115))	('p120ctn loss', 'Var', (186, 198))	('Gr-1', 'Gene', '546644', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
295004	21481789	Increased myeloperoxidase (MPO) staining in the tumor stroma for myeloid lineage cells correlates with p120ctn loss (Figure 7A, p=0.05).	('myeloperoxidase', 'Gene', (10, 25))	('myeloperoxidase', 'Gene', '17523', (10, 25))	('p120ctn loss', 'Var', (103, 115))	('Increased', 'PosReg', (0, 9))	('tumor stroma', 'Disease', 'MESH:D009369', (48, 60))	('tumor stroma', 'Disease', (48, 60))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
295005	21481789	This raises the possibility that p120ctn loss might induce the recruitment of MPO+ cells in the pathogenesis of human ESCC.	('MPO+', 'Protein', (78, 82))	('induce', 'PosReg', (52, 58))	('human', 'Species', '9606', (112, 117))	('p120ctn loss', 'Var', (33, 45))	('recruitment', 'MPA', (63, 74))
295010	21481789	Disruption of this complex is a hallmark feature of epithelially-derived cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('Disruption', 'Var', (0, 10))
295011	21481789	P120ctn loss or mislocalization can destabilize E-cadherin.	('destabilize', 'NegReg', (36, 47))	('mislocalization', 'Var', (16, 31))	('loss', 'NegReg', (8, 12))	('P120ctn', 'Gene', (0, 7))	('P120ctn', 'Gene', '12388', (0, 7))	('E-cadherin', 'Protein', (48, 58))
295012	21481789	Definitive proof for p120ctn's functional role as a tumor suppressor gene in vivo has been elusive to date.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('p120ctn', 'Var', (21, 28))
295013	21481789	Targeted disruption of murine p120ctn in the salivary gland (MMTV-cre;p120ctnflox/flox), skin (K14-cre;p120ctnflox/flox) and intestine (Villin-Cre; p120ctnflox/flox) do not result in cancer.	('murine', 'Var', (23, 29))	('cancer', 'Disease', (183, 189))	('result in', 'Reg', (173, 182))	('K14', 'Gene', '16664', (95, 98))	('K14', 'Gene', (95, 98))	('murine', 'Species', '10090', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('MMTV', 'Species', '11757', (61, 65))	('p120ctn', 'Var', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
295018	21481789	How does p120ctn loss mechanistically cause invasive squamous cell cancers?	('invasive squamous cell cancers', 'Disease', (44, 74))	('invasive squamous cell cancers', 'Disease', 'MESH:D002294', (44, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cause', 'Reg', (38, 43))	('p120ctn', 'Var', (9, 16))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (53, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (53, 74))	('loss', 'NegReg', (17, 21))
295019	21481789	Concordant p120ctn and E-cadherin loss is likely favoring cancer cell migration and invasion.	('invasion', 'CPA', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('p120ctn', 'Var', (11, 18))	('E-cadherin', 'Protein', (23, 33))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('loss', 'NegReg', (34, 38))	('rat', 'Species', '10116', (73, 76))	('favoring', 'PosReg', (49, 57))
295020	21481789	Since p120ctn loss precedes E-cadherin loss in our model system, it is unclear to what extent E-cadherin destabilization or loss contributes to tumorigenesis.	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('p120ctn loss', 'Var', (6, 18))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
295022	21481789	In contrast to p120ctn loss in skin with activated MAPK, p120ctn loss in oral and esophageal keratinocytes do not have enhanced MAPK signaling.	('loss', 'NegReg', (65, 69))	('MAPK signaling', 'MPA', (128, 142))	('rat', 'Species', '10116', (95, 98))	('enhanced', 'PosReg', (119, 127))	('p120ctn', 'Var', (57, 64))
295024	21481789	The precise recapitulation of human ESCC (along with OSCC) by the conditional deletion of p120ctn is remarkable, and a definitive in vivo genetic demonstration of p120ctn deletion resulting in cancer.	('human', 'Species', '9606', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('rat', 'Species', '10116', (153, 156))	('p120ctn', 'Var', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('p120ctn deletion', 'Var', (163, 179))	('resulting in', 'Reg', (180, 192))	('ESCC', 'Disease', (36, 40))
295027	21481789	Immature myeloid cell recruitment has been noted by IL-1beta overexpression in the stomach with resulting inflammation and cancer, disruption of TGFbeta signaling in mammary carcinomas, knock-in of mutant K-ras to the pancreas and preparing the local pulmonary environment for metastasis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('knock-in', 'Var', (186, 194))	('carcinomas', 'Disease', (174, 184))	('overexpression', 'PosReg', (61, 75))	('K-ras', 'Gene', '16653', (205, 210))	('K-ras', 'Gene', (205, 210))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutant', 'Var', (198, 204))	('IL-1beta', 'Gene', '16176', (52, 60))	('inflammation', 'Disease', 'MESH:D007249', (106, 118))	('disruption', 'Var', (131, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))	('IL-1beta', 'Gene', (52, 60))	('carcinomas', 'Disease', 'MESH:D002277', (174, 184))	('pancreas', 'Disease', (218, 226))	('TGFbeta', 'Gene', (145, 152))	('inflammation', 'Disease', (106, 118))	('TGFbeta', 'Gene', '7040', (145, 152))	('pancreas', 'Disease', 'MESH:D010190', (218, 226))	('cancer', 'Disease', (123, 129))
295038	21481789	In summary, conditional p120ctn loss in the esophagus, oral cavity and forestomach leads to invasive squamous cell cancers, involving NFkappaB, Akt, Stat-3 activation, increased proliferation, and production of GM-CSF, M-CSF, MCP-1 and TNFalpha from tumor derived cells.	('Akt', 'Gene', (144, 147))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('activation', 'PosReg', (156, 166))	('M-CSF', 'Gene', (219, 224))	('NFkappaB', 'Gene', (134, 142))	('Akt', 'Gene', '11651', (144, 147))	('Stat-3', 'Gene', (149, 155))	('M-CSF', 'Gene', '12977', (219, 224))	('tumor', 'Disease', (250, 255))	('invasive squamous cell cancers', 'Disease', (92, 122))	('Stat-3', 'Gene', '20848', (149, 155))	('p120ctn', 'Var', (24, 31))	('MCP-1', 'Gene', (226, 231))	('TNFalpha', 'Gene', '21926', (236, 244))	('GM-CSF', 'Gene', '12981', (211, 217))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (101, 122))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('GM-CSF', 'Gene', (211, 217))	('loss', 'NegReg', (32, 36))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (101, 121))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('TNFalpha', 'Gene', (236, 244))	('invasive squamous cell cancers', 'Disease', 'MESH:D002294', (92, 122))	('M-CSF', 'Gene', (212, 217))	('increased', 'PosReg', (168, 177))	('proliferation', 'CPA', (178, 191))	('M-CSF', 'Gene', '12977', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('NFkappaB', 'Gene', '18033', (134, 142))	('rat', 'Species', '10116', (185, 188))	('MCP-1', 'Gene', '20296', (226, 231))
295040	21481789	These events likely contribute to cancer arising from p120ctn-deficient cells (Figure 7), which provide compelling evidence that p120ctn is indeed a bona fide tumor suppressor gene.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', (159, 164))	('cancer', 'Disease', (34, 40))	('p120ctn', 'Var', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('p120ctn-deficient', 'Var', (54, 71))
295044	21481789	First, strategies designed to restore wild-type p120ctn may provide a venue to ameliorate tumor progression.	('rat', 'Species', '10116', (9, 12))	('p120ctn', 'Var', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('rat', 'Species', '10116', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
295052	21481789	The parental F2 cells were established through the isolation of esophageal epithelia from p120loxP/loxP mice, infected with pBABE-tdTomato-SV40-nlsCre (designated as F2-Cre) or pBABE-tdTomato (designated as F2-Tomato), and stable clones were FACS selected for tdTomato.	('Tomato', 'Species', '4081', (210, 216))	('Tomato', 'Species', '4081', (185, 191))	('Tomato', 'Species', '4081', (262, 268))	('Tomato', 'Species', '4081', (132, 138))	('mice', 'Species', '10090', (104, 108))	('FACS', 'Gene', (242, 246))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (64, 84))	('pBABE-tdTomato-SV40-nlsCre', 'Var', (124, 150))	('FACS', 'Gene', '14081', (242, 246))	('p120loxP/loxP', 'Var', (90, 103))	('esophageal epithelia', 'Disease', (64, 84))	('esophageal epithelia', 'Disease', 'MESH:D004941', (64, 84))
295055	21481789	Antibodies used for IHC were the following: p120ctn (610134, BD Transduction), E-cadherin (610182, BD Transduction), K14 (PRB-155P, Covance), pAKT (9271, Cell Signaling), pMAPK (9101, Cell Signaling), NFkappaB-p65 subunit (4764, Cell Signaling), Ki67 (NCL-KI67p, Novacastra).	('NFkappaB', 'Gene', '18033', (201, 209))	('Ki67', 'Gene', '17345', (246, 250))	('K14', 'Gene', (117, 120))	('PRB', 'Gene', (122, 125))	('Ki67', 'Gene', (246, 250))	('4764', 'Var', (223, 227))	('PRB', 'Gene', '18667', (122, 125))	('NFkappaB', 'Gene', (201, 209))	('p120ctn', 'Var', (44, 51))	('610182', 'Var', (91, 97))	('K14', 'Gene', '16664', (117, 120))
295056	21481789	For IF, the following antibodies were used: Keratin 14 (PRB-155P, Covance), Fsp1 (DakoCytomation), beta-catenin (9562, Cell Signaling), p120ctn (61634, BD Transduction), E-cadherin (3195, Cell Signaling), c-myc (1472-1, Epitomics), myeloperoxidase (45977, Abcam), p-Stat3 (9145, Cell Signaling), alphaSMA (A2547, Sigma).	('myeloperoxidase', 'Gene', '17523', (232, 247))	('PRB', 'Gene', (56, 59))	('beta-catenin', 'Gene', '12387', (99, 111))	('PRB', 'Gene', '18667', (56, 59))	('alphaSMA', 'Gene', (296, 304))	('alphaSMA', 'Gene', '11475', (296, 304))	('Keratin 14', 'Gene', (44, 54))	('p-Stat3', 'MPA', (264, 271))	('myeloperoxidase', 'Gene', (232, 247))	('Keratin 14', 'Gene', '16664', (44, 54))	('beta-catenin', 'Gene', (99, 111))	('Fsp1', 'Gene', '20198', (76, 80))	('p120ctn', 'Var', (136, 143))	('Fsp1', 'Gene', (76, 80))
295060	21481789	Scoring of p120ctn, E-cadherin, and MPO IHC was based upon a quantitative evaluation of expression using a scale from 0 to 2 (0=absent, 1=mild-moderate, 2=high) and performed by Dr. Andres Klein-Szanto, pathologist, in a blinded fashion.	('p120ctn', 'Var', (11, 18))	('MPO', 'Gene', (36, 39))	('rat', 'Species', '10116', (147, 150))
295091	21481789	The molecular pathogenesis underlying these cancers involves p120-catenin (p120ctn), which is critical to epithelial homeostasis through the adherens junctions.	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('p120-catenin', 'Gene', (61, 73))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('p120ctn', 'Var', (75, 82))	('p120-catenin', 'Gene', '12388', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
295093	21481789	Thus, p120ctn loss in this mouse model proves its tumor suppressor role and establishes a platform for strategies designed for early detection, molecular imaging and targeted therapeutics in these cancers that have been elusive to date.	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('rat', 'Species', '10116', (105, 108))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('mouse', 'Species', '10090', (27, 32))	('cancers', 'Disease', (197, 204))	('p120ctn loss', 'Var', (6, 18))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', (50, 55))
295146	31545475	PIP3, the product of class I PI3K, recruits the serine-threonine kinase AKT, which contains a pleckstrin homology (PH) domain, and its activating kinase 3-phosphoinositide-dependent kinase 1 (PDK1) to cell membranes, allowing PDK1 to activate AKT.	('AKT', 'Gene', '207', (72, 75))	('activate', 'PosReg', (234, 242))	('PDK1', 'Gene', '5163', (192, 196))	('PDK1', 'Gene', '5163', (226, 230))	('AKT', 'Gene', '207', (243, 246))	('AKT', 'Gene', (72, 75))	('PDK1', 'Gene', (192, 196))	('PDK1', 'Gene', (226, 230))	('serine-threonine', 'Chemical', 'MESH:C061951', (48, 64))	('recruits', 'PosReg', (35, 43))	('AKT', 'Gene', (243, 246))	('PI3K', 'Var', (29, 33))
295176	31545475	Fragments containing the Rap1A promoter region or mutants of the predictive SP1-binding site were inserted upstream of the firefly luciferase coding sequences in the pGL3-basic reporter plasmid.	('pGL3', 'Gene', '6391', (166, 170))	('pGL3', 'Gene', (166, 170))	('mutants', 'Var', (50, 57))
295180	31545475	Briefly, for xenograft tumors, 5x106 cells (ECA109-shRap1A-NC or ECA109-shRap1A-4) were injected into the right dorsal flank of nude mice (n=6 per group).	('nude mice', 'Species', '10090', (128, 137))	('xenograft tumors', 'Disease', (13, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('ECA109-shRap1A-4', 'Var', (65, 81))	('xenograft tumors', 'Disease', 'MESH:D009369', (13, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
295198	31545475	2A and B) and the two most efficient silencing sequences, shRap1A1 and shRap1A4, were selected and used to establish ESCC cell lines with stable knockdown of Rap1A (Fig.	('ESCC', 'Disease', (117, 121))	('knockdown', 'Var', (145, 154))	('Rap1A', 'Gene', (158, 163))	('ESCC', 'Disease', 'MESH:C562729', (117, 121))
295208	31545475	However, the reduction of pAKT expression following Rap1A inhibition appeared to be minimal.	('AKT', 'Gene', (27, 30))	('inhibition', 'Var', (58, 68))	('AKT', 'Gene', '207', (27, 30))	('Rap1A', 'Gene', (52, 57))	('reduction', 'NegReg', (13, 22))
295216	31545475	The results indicated that ECA109 cells with Rap1A knockdown was associated with no significant difference in tumor size compared with control cells (Fig.	('knockdown', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('Rap1A', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
295226	31545475	With both AKT2 and KRAS amplification, enhanced alterations involving PI3K/AKT/mTOR signaling have been detected in the genomic profiling of ESCC.	('mTOR', 'Gene', (79, 83))	('alterations', 'Reg', (48, 59))	('mTOR', 'Gene', '2475', (79, 83))	('AKT', 'Gene', (10, 13))	('AKT', 'Gene', '207', (75, 78))	('KRAS', 'Gene', (19, 23))	('ESCC', 'Disease', 'MESH:C562729', (141, 145))	('KRAS', 'Gene', '3845', (19, 23))	('AKT', 'Gene', (75, 78))	('amplification', 'Var', (24, 37))	('AKT', 'Gene', '207', (10, 13))	('ESCC', 'Disease', (141, 145))	('AKT2', 'Gene', (10, 14))	('AKT2', 'Gene', '208', (10, 14))
295230	31545475	It was previously reported that the function of miR-196a in ESCC is correlated with the SNPrs6573 A/C genotype in the Rap1A 3'-UTR.	('ESCC', 'Disease', (60, 64))	('ESCC', 'Disease', 'MESH:C562729', (60, 64))	('miR-196a', 'Gene', (48, 56))	('correlated', 'Reg', (68, 78))	('SNPrs6573 A/C', 'Var', (88, 101))
295253	31200670	Survival analysis showed that high PRAF2 mRNA expression was associated with worse overall survival in ESCC patients.	('overall survival', 'MPA', (83, 99))	('patients', 'Species', '9606', (108, 116))	('high', 'Var', (30, 34))	('mRNA expression', 'MPA', (41, 56))	('ESCC', 'Disease', (103, 107))	('PRAF2', 'Gene', (35, 40))	('worse', 'NegReg', (77, 82))	('PRAF2', 'Gene', '11230', (35, 40))
295269	31200670	Furthermore, knockdown of PRAF2 expression in ESCC cells blocked cell growth and migration and stimulated cell apoptosis.	('cell growth', 'CPA', (65, 76))	('stimulated', 'PosReg', (95, 105))	('PRAF2', 'Gene', (26, 31))	('cell apoptosis', 'CPA', (106, 120))	('blocked', 'NegReg', (57, 64))	('PRAF2', 'Gene', '11230', (26, 31))	('knockdown', 'Var', (13, 22))
295301	31200670	Survival analysis indicated that ESCC patients with high PRAF2 mRNA expression had a decreased overall survival relative to those with low PRAF2 expression (median OS, 20.0 vs. 33.0 months, P < 0.001, Fig.	('PRAF2', 'Gene', (139, 144))	('decreased', 'NegReg', (85, 94))	('ESCC', 'Disease', (33, 37))	('PRAF2', 'Gene', '11230', (139, 144))	('PRAF2', 'Gene', '11230', (57, 62))	('PRAF2', 'Gene', (57, 62))	('overall survival', 'MPA', (95, 111))	('high', 'Var', (52, 56))	('patients', 'Species', '9606', (38, 46))	('OS', 'Gene', '17451', (164, 166))
295302	31200670	Then, multivariate analysis revealed that high PRAF2 mRNA expression (hazard ratio 2.05, 95% CI 1.10-3.85, P = 0.025) served as independent poor prognostic biomarker associated with decreased overall survival in patients with ESCC (Table 2).	('PRAF2', 'Gene', (47, 52))	('decreased', 'NegReg', (182, 191))	('PRAF2', 'Gene', '11230', (47, 52))	('ESCC', 'Disease', (226, 230))	('patients', 'Species', '9606', (212, 220))	('overall survival', 'MPA', (192, 208))	('high', 'Var', (42, 46))	('mRNA expression', 'MPA', (53, 68))
295305	31200670	CCK-8 assay indicated knockdown of PRAF2 time-dependently inhibited the viability of TE1 cells (Fig.	('knockdown', 'Var', (22, 31))	('viability of TE1 cells', 'CPA', (72, 94))	('inhibited', 'NegReg', (58, 67))	('PRAF2', 'Gene', (35, 40))	('PRAF2', 'Gene', '11230', (35, 40))
295306	31200670	Similarly, PRAF2 silencing significantly inhibited the colony formation (Fig.	('PRAF2', 'Gene', (11, 16))	('inhibited', 'NegReg', (41, 50))	('PRAF2', 'Gene', '11230', (11, 16))	('silencing', 'Var', (17, 26))	('colony formation', 'CPA', (55, 71))
295308	31200670	Knockdown of PRAF2 caused a G1 phase arrest in TE1 cells, and the cell number in S phase decreased (Fig.	('Knockdown', 'Var', (0, 9))	('PRAF2', 'Gene', '11230', (13, 18))	('G1 phase arrest', 'CPA', (28, 43))	('PRAF2', 'Gene', (13, 18))	('cell number in S phase', 'CPA', (66, 88))	('decreased', 'NegReg', (89, 98))
295310	31200670	Our study showed that depletion of PRAF2 exhibited a remarkably decrease of invasion ability in TE1 cells (Fig.	('decrease', 'NegReg', (64, 72))	('depletion', 'Var', (22, 31))	('PRAF2', 'Gene', (35, 40))	('PRAF2', 'Gene', '11230', (35, 40))	('invasion ability in TE1 cells', 'CPA', (76, 105))
295313	31200670	Results demonstrated that PRAF2 silencing cause a remarkable induction of apoptosis in TE1 cells (Fig.	('silencing', 'Var', (32, 41))	('apoptosis', 'CPA', (74, 83))	('PRAF2', 'Gene', (26, 31))	('PRAF2', 'Gene', '11230', (26, 31))
295325	31200670	In the present study, PRAF2 silencing impaired ESCC cell proliferation and cell cycle.	('PRAF2', 'Gene', '11230', (22, 27))	('PRAF2', 'Gene', (22, 27))	('ESCC', 'Disease', (47, 51))	('cell cycle', 'CPA', (75, 85))	('silencing', 'Var', (28, 37))	('impaired', 'NegReg', (38, 46))
295327	31200670	Though the function role of PRAF2 on cell apoptosis was not observed in tumors mentioned above, we found that knockdown of PRAF2 induced apoptosis of ESCC cells, and influenced the expression of apoptotic biomarkers which include BCL-XL, BAX, caspase3 and caspase9.	('knockdown', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (72, 78))	('BAX', 'Gene', (238, 241))	('caspase3', 'Gene', (243, 251))	('PRAF2', 'Gene', '11230', (28, 33))	('BAX', 'Gene', '581', (238, 241))	('PRAF2', 'Gene', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('BCL-XL', 'Gene', (230, 236))	('caspase9', 'Gene', '842', (256, 264))	('PRAF2', 'Gene', '11230', (123, 128))	('caspase3', 'Gene', '836', (243, 251))	('expression', 'MPA', (181, 191))	('apoptosis', 'CPA', (137, 146))	('caspase9', 'Gene', (256, 264))	('influenced', 'Reg', (166, 176))	('apoptotic biomarkers', 'MPA', (195, 215))	('BCL-XL', 'Gene', '598', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('PRAF2', 'Gene', (28, 33))
295328	31200670	These results indicated that PRAF2 silencing impaired ESCC cell growth via mitotic arrest and apoptosis.	('PRAF2', 'Gene', '11230', (29, 34))	('mitotic arrest', 'Disease', 'MESH:D006323', (75, 89))	('silencing', 'Var', (35, 44))	('PRAF2', 'Gene', (29, 34))	('ESCC', 'Disease', (54, 58))	('impaired', 'NegReg', (45, 53))	('mitotic arrest', 'Disease', (75, 89))	('apoptosis', 'CPA', (94, 103))
295333	31200670	Also, PRAF2 silencing decreased the invasiveness of ESCC cells.	('PRAF2', 'Gene', (6, 11))	('silencing', 'Var', (12, 21))	('PRAF2', 'Gene', '11230', (6, 11))	('invasiveness of ESCC cells', 'CPA', (36, 62))	('decreased', 'NegReg', (22, 31))
295370	31119034	OS was also improved in the DCF arm compared to the CF arm (HR: 0.77; p=0.02) at the cost of increased toxicity (69% versus 59% grade 3 and grade 4 toxicities, respectively).	('DCF', 'Var', (28, 31))	('OS', 'Chemical', '-', (0, 2))	('DCF', 'Chemical', '-', (28, 31))	('toxicities', 'Disease', (148, 158))	('toxicity', 'Disease', 'MESH:D064420', (103, 111))	('improved', 'PosReg', (12, 20))	('toxicity', 'Disease', (103, 111))	('toxicities', 'Disease', 'MESH:D064420', (148, 158))
295372	31119034	In REAL-2, 1,002 patients with metastatic or unresectable esophageal cancer, gastroesophageal junction adenocarcinoma, or gastric adenocarcinoma (esophageal adenocarcinoma: n=333 [33%]; gastroesophageal junction adenocarcinoma: n=248 [25%]) were randomized to ECF or variations of it including epirubicin, cisplatin, capecitabine; epirubicin, oxaliplatin, fluorouracil; and epirubicin, oxaliplatin, capecitabine, with a primary endpoint of OS.	('OS', 'Chemical', '-', (440, 442))	('capecitabine', 'Chemical', 'MESH:D000069287', (399, 411))	('gastroesophageal junction adenocarcinoma', 'Disease', 'MESH:D008309', (77, 117))	('gastric adenocarcinoma', 'Disease', (122, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('epirubicin', 'Chemical', 'MESH:D015251', (331, 341))	('capecitabine', 'Chemical', 'MESH:D000069287', (317, 329))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (386, 397))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('gastroesophageal junction adenocarcinoma', 'Disease', (77, 117))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (146, 171))	('esophageal cancer', 'Disease', (58, 75))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (146, 171))	('patients', 'Species', '9606', (17, 25))	('fluorouracil', 'Chemical', 'MESH:D005472', (356, 368))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (343, 354))	('variations', 'Var', (267, 277))	('epirubicin', 'Chemical', 'MESH:D015251', (374, 384))	('esophageal adenocarcinoma', 'Disease', (146, 171))	('gastroesophageal junction adenocarcinoma', 'Disease', 'MESH:D008309', (186, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (122, 144))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (306, 315))	('epirubicin', 'Chemical', 'MESH:D015251', (294, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('gastroesophageal junction adenocarcinoma', 'Disease', (186, 226))
295393	31119034	Median OS was 17.5 months in the dual HER2 blockade arm and 14.2 months in the control arm (HR: 0.84; p=0.056).	('dual', 'Var', (33, 37))	('OS', 'Chemical', '-', (7, 9))	('HER2', 'Gene', (38, 42))	('HER2', 'Gene', '2064', (38, 42))
295437	31119034	Patients with MET-amplified (at least 25% of the tumor with >=1 + MET expression by IHC) esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, or gastric adenocarcinoma (esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma n=187 [31%]) were randomized to epirubicin, cisplatin and capecitabine with or without rilotumumab (15 mg/kg) every 3 weeks with a primary endpoint was OS.	('OS', 'Chemical', '-', (408, 410))	('gastroesophageal junction adenocarcinoma', 'Disease', 'MESH:D008309', (215, 255))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('esophageal adenocarcinoma', 'Disease', (89, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('gastroesophageal junction adenocarcinoma', 'Disease', (215, 255))	('gastric adenocarcinoma', 'Disease', (161, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma', 'Disease', 'MESH:D000230', (185, 255))	('Patients', 'Species', '9606', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('esophageal adenocarcinoma', 'Disease', (185, 210))	('gastroesophageal junction adenocarcinoma', 'Disease', 'MESH:D008309', (116, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (300, 309))	('tumor', 'Disease', (49, 54))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (185, 210))	('epirubicin', 'Chemical', 'MESH:D015251', (288, 298))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (185, 210))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (161, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('gastroesophageal junction adenocarcinoma', 'Disease', (116, 156))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (89, 114))	('capecitabine', 'Chemical', 'MESH:D000069287', (314, 326))	('MET-amplified', 'Var', (14, 27))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (89, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('rilotumumab', 'Chemical', 'MESH:C524459', (343, 354))
295486	31119034	ORR was 12%, 24%, and 8% in the nivolumab alone, N1 + I3 and N3 + I1 arms, respectively.	('N1 + I3', 'Var', (49, 56))	('nivolumab', 'Chemical', 'MESH:D000077594', (32, 41))	('N3 + I1', 'Var', (61, 68))
295488	31119034	Eighteen-month OS was 25%, 28%, and 13% in the nivolumab alone, N1 + I3 and N3 + I1 arms, respectively.	('OS', 'Chemical', '-', (15, 17))	('N3 + I1', 'Var', (76, 83))	('nivolumab', 'Chemical', 'MESH:D000077594', (47, 56))	('N1 + I3', 'Var', (64, 71))
295490	31119034	It appears from the preliminary data that the N1 + I3 arm is the most active of the three approaches with regards to improving ORR and OS in this subset of patients.	('patients', 'Species', '9606', (156, 164))	('N1 + I3', 'Var', (46, 53))	('OS', 'Chemical', '-', (135, 137))	('improving', 'PosReg', (117, 126))
295493	31119034	There are many more checkpoint inhibitor combinations beyond CTLA-4, PD-1, and PD-L1 being trialed in esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma patients which are not being discussed in the review.	('esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma', 'Disease', 'MESH:D000230', (102, 172))	('CTLA-4', 'Gene', '1493', (61, 67))	('patients', 'Species', '9606', (173, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('PD-1', 'Gene', (69, 73))	('combinations', 'Var', (41, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('PD-1', 'Gene', '5133', (69, 73))	('PD-L1', 'Gene', (79, 84))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))	('CTLA-4', 'Gene', (61, 67))	('PD-L1', 'Gene', '29126', (79, 84))
295501	31119034	Although anti-NY-ESO-1 vaccines have not been pursued further in esophageal adenocarcinoma patients, there is an ongoing phase I study assessing whether autologous T-cells engineered to express an NY-ESO-1 targeting the T-cell receptor can play a role in progressive NY-ESO-1 overexpressing malignancies (NCT02457650).	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (65, 90))	('NY-ESO-1', 'Gene', (14, 22))	('patients', 'Species', '9606', (91, 99))	('NY-ESO-1', 'Gene', '246100', (14, 22))	('malignancies', 'Disease', (291, 303))	('NY-ESO-1', 'Gene', (197, 205))	('NY-ESO-1', 'Gene', '246100', (267, 275))	('NY-ESO-1', 'Gene', '246100', (197, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('NY-ESO-1', 'Gene', (267, 275))	('esophageal adenocarcinoma', 'Disease', (65, 90))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (65, 90))	('NCT02457650', 'Var', (305, 316))	('malignancies', 'Disease', 'MESH:D009369', (291, 303))
295504	31119034	In this study 79 patients received CF chemotherapy plus G17DT (500 mug every 4 weeks for four treatments) and were assessed for treatment response with a primary endpoint of ORR.	('500', 'Var', (63, 66))	('patients', 'Species', '9606', (17, 25))	('G17DT', 'Var', (56, 61))
295513	30208867	Despite Her-2 targeted therapy, her disease recurred and required repeated metastectomies.	('targeted therapy', 'Var', (14, 30))	('Her-2', 'Gene', (8, 13))	('Her-2', 'Gene', '2064', (8, 13))
295514	30208867	Digital cell sorting and targeted sequencing of cancer sub-clones from EAC and metastases revealed a completely mutated TP53, whereas the sorted stromal cells were wild-type.	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('metastases', 'Disease', (79, 89))	('mutated', 'Var', (112, 119))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
295524	30208867	We combined next generation sequencing (NGS) with a high-throughput cell sorting technique to separate stromal from cancer cells and identified diverse somatic mutations underlying the primary EAC and metastases.	('EAC', 'Disease', (193, 196))	('mutations', 'Var', (160, 169))	('metastases', 'Disease', (201, 211))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('metastases', 'Disease', 'MESH:D009362', (201, 211))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('EAC', 'Phenotype', 'HP:0011459', (193, 196))
295525	30208867	Whole Exome Sequencing (WES) of the primary EAC and the two metachronous chest metastases revealed a somatic heterozygous TP53 missense mutation (chr17:g.7577094G > A,NP_000537.3: p.Arg282Trp, rs28934574, Fig.	('TP53', 'Gene', (122, 126))	('EAC', 'Phenotype', 'HP:0011459', (44, 47))	('p.Arg282Trp', 'Var', (180, 191))	('rs28934574', 'Mutation', 'rs28934574', (193, 203))	('TP53', 'Gene', '7157', (122, 126))	('rs28934574', 'Var', (193, 203))	('chest metastases', 'Disease', (73, 89))	('g.7577094G > A,N', 'Mutation', 'rs28934574', (152, 168))	('chest metastases', 'Disease', 'MESH:D009362', (73, 89))	('p.Arg282Trp', 'Mutation', 'rs28934574', (180, 191))
295529	30208867	1cii), was consistent for a TP53 missense mutations.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('missense mutations', 'Var', (33, 51))
295531	30208867	Targeted NGS performed using the OncoSeek panel revealed that TP53 was completely mutated in the EAC and metastatic clusters, while wild-type in the stromal cells (Fig.	('EAC', 'Phenotype', 'HP:0011459', (97, 100))	('TP53', 'Gene', '7157', (62, 66))	('mutated', 'Var', (82, 89))	('TP53', 'Gene', (62, 66))
295536	30208867	ECHDC1 copy gains are present in COSMIC in two cases of esophageal cancer (COSG94494, COSMIC; http://cancer.sanger.ac.uk/).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (67, 73))	('esophageal cancer', 'Disease', (56, 73))	('cancer', 'Disease', (101, 107))	('copy gains', 'Var', (7, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('ECHDC1', 'Gene', '55862', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ECHDC1', 'Gene', (0, 6))
295538	30208867	The Her-2 rs1565923A > G intronic variant showed a ~ 100% frequency in the tumor populations and unsorted samples, suggesting a high level of copy-gains (Fig.	('rs1565923A > G', 'Var', (10, 24))	('rs1565923A > G', 'DBSNP_MENTION', 'None', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Her-2', 'Gene', '2064', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('Her-2', 'Gene', (4, 9))
295545	30208867	TP53 mutations are considered early genetic events in Barrett's esophagus associated with an increased risk of progression to cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TP53', 'Gene', '7157', (0, 4))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (54, 73))	('TP53', 'Gene', (0, 4))	("Barrett's esophagus", 'Disease', (54, 73))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (54, 73))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('associated', 'Reg', (74, 84))
295547	30208867	According to our data, the TP53 mutant allele was completely mutated in the primary cancer, indicating that the TP53 locus might have been involved in an early LOH event, which can explain the homozygous state of the p.Arg282Trp mutation.	('TP53', 'Gene', '7157', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('TP53', 'Gene', (27, 31))	('cancer', 'Disease', (84, 90))	('p.Arg282Trp', 'Mutation', 'rs28934574', (217, 228))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (112, 116))	('p.Arg282Trp', 'Var', (217, 228))	('TP53', 'Gene', (112, 116))
295548	30208867	This mutation is frequently reported in several cancers (COSM10704, COSMIC; http://cancer.sanger.ac.uk/) and, as constitutive mutation, causes Li Fraumeni syndrome (ClinVar id12347; https://www.ncbi.nlm.nih.gov/clinvar/), an inherited cancer disease, characterized by autosomal dominant inheritance due to heterozygous mutations in TP53, with early onset and multiple tumors within an individual, including soft tissue sarcomas and osteosarcomas, breast cancer, brain tumors, leukemia and adrenocortical carcinoma (OMIM #151623).	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (407, 427))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('multiple tumors', 'Disease', (359, 374))	('tumors', 'Phenotype', 'HP:0002664', (468, 474))	('cancer disease', 'Disease', 'MESH:D009369', (235, 249))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (489, 513))	('cancer', 'Disease', (48, 54))	('osteosarcomas', 'Disease', 'MESH:D012516', (432, 445))	('cancer', 'Disease', (454, 460))	('sarcomas', 'Disease', 'MESH:D012509', (419, 427))	('leukemia', 'Phenotype', 'HP:0001909', (476, 484))	('sarcomas', 'Phenotype', 'HP:0100242', (419, 427))	('adrenocortical carcinoma', 'Disease', (489, 513))	('cancer', 'Phenotype', 'HP:0002664', (454, 460))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('brain tumors', 'Disease', 'MESH:D001932', (462, 474))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('brain tumors', 'Phenotype', 'HP:0030692', (462, 474))	('osteosarcomas', 'Disease', (432, 445))	('sarcomas', 'Disease', (419, 427))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('TP53', 'Gene', '7157', (332, 336))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancer disease', 'Disease', (235, 249))	('leukemia', 'Disease', (476, 484))	('cancers', 'Disease', (48, 55))	('leukemia', 'Disease', 'MESH:D007938', (476, 484))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('heterozygous mutations', 'Var', (306, 328))	('tumor', 'Phenotype', 'HP:0002664', (468, 473))	('breast cancer', 'Phenotype', 'HP:0003002', (447, 460))	('osteosarcomas', 'Phenotype', 'HP:0002669', (432, 445))	('brain tumors', 'Disease', (462, 474))	('multiple tumors', 'Disease', 'MESH:D009369', (359, 374))	('tumors', 'Phenotype', 'HP:0002664', (368, 374))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (143, 163))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('Li Fraumeni syndrome', 'Disease', (143, 163))	('cancer', 'Disease', 'MESH:D009369', (454, 460))	('cancer', 'Disease', (235, 241))	('breast cancer', 'Disease', 'MESH:D001943', (447, 460))	('sarcomas', 'Disease', 'MESH:D012509', (437, 445))	('breast cancer', 'Disease', (447, 460))	('sarcomas', 'Phenotype', 'HP:0100242', (437, 445))	('carcinoma', 'Phenotype', 'HP:0030731', (504, 513))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (489, 513))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('sarcomas', 'Disease', (437, 445))	('mutation', 'Var', (5, 13))	('cancer', 'Disease', (83, 89))	('TP53', 'Gene', (332, 336))
295549	30208867	The complete loss of TP53 wild-type protein in the studied tumor provides a significant impact on prognosis and therapeutic options, since the p.Arg282Trp mutation abolishes specific DNA binding, allowing evasion from apoptosis and accelerating tumor progression.	('TP53', 'Gene', (21, 25))	('accelerating', 'PosReg', (232, 244))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('p.Arg282Trp', 'Mutation', 'rs28934574', (143, 154))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('specific DNA binding', 'Interaction', (174, 194))	('allowing', 'Reg', (196, 204))	('evasion from apoptosis', 'MPA', (205, 227))	('abolishes', 'NegReg', (164, 173))	('tumor', 'Disease', (245, 250))	('p.Arg282Trp', 'Var', (143, 154))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('TP53', 'Gene', '7157', (21, 25))
295550	30208867	The pharmacological reactivation of mutant TP53 emerged as a promising strategy using molecules that restore its wild-type activity, such as APR-246/PRIMA-1Met, which is already under clinical trials for different cancers, including EAC.	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('EAC', 'Phenotype', 'HP:0011459', (233, 236))	('cancers', 'Disease', (214, 221))	('APR', 'Gene', (141, 144))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('APR', 'Gene', '5366', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('mutant', 'Var', (36, 42))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('EAC', 'Disease', (233, 236))
295551	30208867	This molecule restores TP53 activity in presence of missense mutations and regulates several TP53-related pathways.	('TP53', 'Gene', (23, 27))	('activity', 'MPA', (28, 36))	('regulates', 'Reg', (75, 84))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('missense mutations', 'Var', (52, 70))	('TP53', 'Gene', '7157', (23, 27))	('restores', 'PosReg', (14, 22))
295553	30208867	In the present case, the TP53 mutation was shared by the EAC primary tumor and metastases (suggestive of an early origin) and we propose that restoring TP53 wild-type activity could be effective for metastases.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('TP53', 'Gene', (25, 29))	('tumor', 'Disease', (69, 74))	('mutation', 'Var', (30, 38))	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('TP53', 'Gene', '7157', (152, 156))	('TP53', 'Gene', '7157', (25, 29))	('TP53', 'Gene', (152, 156))	('metastases', 'Disease', (79, 89))	('metastases', 'Disease', (199, 209))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('metastases', 'Disease', 'MESH:D009362', (199, 209))
295557	30208867	However, trastuzumab-responsive patients may develop resistance, due to Her-2-dependent mechanisms such as the overexpression of proteins that mask the Her-2 receptor (e.g., MUC1), Her-2 alternative splicing, or Her-2-independent mechanisms.	('Her-2', 'Gene', '2064', (72, 77))	('alternative splicing', 'Var', (187, 207))	('develop', 'PosReg', (45, 52))	('patients', 'Species', '9606', (32, 40))	('Her-2', 'Gene', (152, 157))	('Her-2', 'Gene', (72, 77))	('resistance', 'MPA', (53, 63))	('trastuzumab', 'Chemical', 'MESH:D000068878', (9, 20))	('MUC1', 'Gene', (174, 178))	('overexpression', 'PosReg', (111, 125))	('MUC1', 'Gene', '4582', (174, 178))	('Her-2', 'Gene', '2064', (181, 186))	('Her-2', 'Gene', '2064', (212, 217))	('proteins', 'Protein', (129, 137))	('Her-2', 'Gene', (181, 186))	('Her-2', 'Gene', (212, 217))	('Her-2', 'Gene', '2064', (152, 157))
295564	30208867	We hypothesize that the acquired RNF146-ECHDC1 copy gain in the cells giving raise to the second metastasis, coupled to the loss of cells with HER2 amplification, might contributes to resistance and progression in metastatic EAC cancer.	('RNF146', 'Gene', (33, 39))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('gain', 'PosReg', (52, 56))	('copy', 'Var', (47, 51))	('ECHDC1', 'Gene', '55862', (40, 46))	('ECHDC1', 'Gene', (40, 46))	('HER2', 'Gene', (143, 147))	('HER2', 'Gene', '2064', (143, 147))	('contributes', 'Reg', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('RNF146', 'Gene', '81847', (33, 39))	('EAC', 'Phenotype', 'HP:0011459', (225, 228))
295566	30208867	Digital cell sorting and omics-technologies in a Barrett's-type EAC and two metachronous metastases revealed: (1) the true tumor cell mutational status of the somatic mutations and CNVs; (2) a progressive reduction of Her-2 copy-gains in the two recurrent metastases compared to the primary tumor, not detectable by ISH.	('copy-gains', 'Var', (224, 234))	('tumor', 'Disease', (123, 128))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('metastases', 'Disease', 'MESH:D009362', (256, 266))	('Her-2', 'Gene', '2064', (218, 223))	('reduction', 'NegReg', (205, 214))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('mutations', 'Var', (167, 176))	('metastases', 'Disease', (256, 266))	('metastases', 'Disease', 'MESH:D009362', (89, 99))	('Her-2', 'Gene', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('metastases', 'Disease', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
295567	30208867	We demonstrated that a genomic dissection of EAC and recurrent metastases could identify the tumor cell mutational status, as in this case for a TP53 mutation and Her2 copy-gains.	('Her2', 'Gene', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutation', 'Var', (150, 158))	('Her2', 'Gene', '2064', (163, 167))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('tumor', 'Disease', (93, 98))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('copy-gains', 'Var', (168, 178))	('metastases', 'Disease', (63, 73))
295606	29530057	Low TUSC7 also decreased overall survival of patients with EC, and overexpression of TUSC7 inhibited colony formation in vitro and tumor volume and weight in vivo.	('colony formation', 'CPA', (101, 117))	('TUSC7', 'Gene', '285194', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('TUSC7', 'Gene', (4, 9))	('TUSC7', 'Gene', (85, 90))	('overexpression', 'PosReg', (67, 81))	('inhibited', 'NegReg', (91, 100))	('TUSC7', 'Gene', '285194', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('patients', 'Species', '9606', (45, 53))	('decreased', 'NegReg', (15, 24))	('overall survival', 'CPA', (25, 41))	('Low', 'Var', (0, 3))
295611	29530057	Combined chemotherapy for the treatment of ESCC was cisplatin, 5-Fu and adriamycin, or cisplatin, 5-Fu and paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (107, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('5-Fu', 'Chemical', 'MESH:D005472', (63, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('ESCC', 'Disease', (43, 47))	('cisplatin', 'Var', (87, 96))	('adriamycin', 'Chemical', 'MESH:D004317', (72, 82))	('5-Fu', 'Chemical', 'MESH:D005472', (98, 102))
295615	29530057	si-TUSC7-1, si-TUSC7-2, pcDNA-TUSC7, miR-224 mimic, miR-224 inhibitor, si-DESC1, LV-TUSC7 and their non-specific control were synthesised by Invitrogen (Shanghai, China), and were transfected into cells using Lipofectamine 2000 (Invitrogen, USA).	('TUSC7', 'Gene', (30, 35))	('miR-224', 'Gene', '407009', (52, 59))	('TUSC7', 'Gene', '285194', (30, 35))	('TUSC7', 'Gene', (3, 8))	('TUSC7', 'Gene', '285194', (3, 8))	('miR-224', 'Gene', (37, 44))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (209, 227))	('TUSC7', 'Gene', '285194', (15, 20))	('miR-224', 'Gene', '407009', (37, 44))	('TUSC7', 'Gene', (84, 89))	('TUSC7', 'Gene', (15, 20))	('TUSC7', 'Gene', '285194', (84, 89))	('si-DESC1', 'Var', (71, 79))	('miR-224', 'Gene', (52, 59))
295633	29530057	EC9706 or KYSE30 cells at the logarithmic phase were seeded into culture solution containing DDP with the low concentration started from 0.5 muM.	('EC9706', 'Var', (0, 6))	('muM', 'Gene', '56925', (141, 144))	('muM', 'Gene', (141, 144))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))
295634	29530057	After digestion, 1 muM DDP was added for the treatment for 48 h. With this procedure of changing solution and gradually increasing DDP concentration, cell lines that can resistent to 10 muM DDP were obtained, and named EC9706/DDP or KYSE30/DDP.	('muM', 'Gene', (19, 22))	('EC9706', 'CellLine', 'CVCL:E307', (219, 225))	('EC9706/DDP', 'Var', (219, 229))	('muM', 'Gene', '56925', (186, 189))	('muM', 'Gene', '56925', (19, 22))	('muM', 'Gene', (186, 189))
295636	29530057	Then, the membranes were probed with first primary antibody anti-DESC1 (1:1000, Signalway Antibody, USA), anti-EGFR (1:1000, Invitrogen, USA), anti-p-AKT (1:1000, Invitrogen, USA), anti-AKT (1:1000, Cell Signaling, USA) and anti-GAPDH (1:1000, Invitrogen, USA) and the secondary horseradish peroxidase-conjugated antibody (Invitrogen, USA).	('anti-DESC1', 'Var', (60, 70))	('AKT', 'Gene', '207', (186, 189))	('EGFR', 'Gene', '1956', (111, 115))	('AKT', 'Gene', '207', (150, 153))	('EGFR', 'Gene', (111, 115))	('AKT', 'Gene', (186, 189))	('GAPDH', 'Gene', '2597', (229, 234))	('GAPDH', 'Gene', (229, 234))	('AKT', 'Gene', (150, 153))	('horseradish', 'Species', '3704', (279, 290))
295665	29530057	We also detected TUSC7 level in EC9706 and drug-resistant EC9706/DDP cells or KYSE30 and drug-resistant KYSE30/DDP cells, and found TUSC7 level was downregulated in drug-resistant ESCC cells (Fig.	('TUSC7', 'Gene', (17, 22))	('detected', 'Reg', (8, 16))	('TUSC7', 'Gene', '285194', (17, 22))	('EC9706', 'CellLine', 'CVCL:E307', (58, 64))	('EC9706/DDP', 'Var', (58, 68))	('downregulated', 'NegReg', (148, 161))	('TUSC7', 'Gene', (132, 137))	('TUSC7', 'Gene', '285194', (132, 137))	('ESCC', 'Disease', (180, 184))	('EC9706', 'CellLine', 'CVCL:E307', (32, 38))
295668	29530057	We further detected miR-224 level in EC9706 and drug-resistant EC9706/DDP cells or KYSE30 and drug-resistant KYSE30/DDP cells, and observed miR-224 level was upregulated in drug-resistant ESCC cells (Fig.	('detected', 'Reg', (11, 19))	('upregulated', 'PosReg', (158, 169))	('ESCC', 'Disease', (188, 192))	('EC9706', 'CellLine', 'CVCL:E307', (63, 69))	('miR-224', 'Gene', '407009', (140, 147))	('miR-224', 'Gene', (140, 147))	('EC9706/DDP', 'Var', (63, 73))	('miR-224', 'Gene', '407009', (20, 27))	('miR-224', 'Gene', (20, 27))	('EC9706', 'CellLine', 'CVCL:E307', (37, 43))
295682	29530057	To figure out whether DESC1 inhibited chemotherapy resistance of ESCC cells via EGFR/AKT, EC9706 or KYSE30 cells were transfected with si-NC, si-DESC1, si- DESC1 + DMSO, and si-DESC1 + AST1306 (EGFR inhibitor).	('chemotherapy resistance', 'CPA', (38, 61))	('DESC1', 'Gene', (22, 27))	('si-DESC1', 'Var', (142, 150))	('AKT', 'Gene', '207', (85, 88))	('EGFR', 'Gene', '1956', (80, 84))	('DMSO', 'Chemical', 'MESH:D004121', (164, 168))	('EGFR', 'Gene', (80, 84))	('EC9706', 'CellLine', 'CVCL:E307', (90, 96))	('inhibited', 'NegReg', (28, 37))	('si-NC', 'Var', (135, 140))	('EGFR', 'Gene', '1956', (194, 198))	('si- DESC1 + DMSO', 'Var', (152, 168))	('si-DESC1 + AST1306', 'Var', (174, 192))	('AKT', 'Gene', (85, 88))	('EGFR', 'Gene', (194, 198))	('AST1306', 'Chemical', 'MESH:C568037', (185, 192))
295683	29530057	7a and b, si-DESC1 promoted chemotherapy resistance of ESCC cells, while AST1306 reversed this effect.	('chemotherapy resistance', 'CPA', (28, 51))	('si-DESC1', 'Var', (10, 18))	('promoted', 'PosReg', (19, 27))	('AST1306', 'Chemical', 'MESH:C568037', (73, 80))
295684	29530057	Also, si-DESC1 upregulated expressions of EGFR and p-AKT, while AST1306 reversed this effect (Fig.	('EGFR', 'Gene', '1956', (42, 46))	('upregulated', 'PosReg', (15, 26))	('EGFR', 'Gene', (42, 46))	('AKT', 'Gene', '207', (53, 56))	('AST1306', 'Chemical', 'MESH:C568037', (64, 71))	('AKT', 'Gene', (53, 56))	('si-DESC1', 'Var', (6, 14))
295686	29530057	In order to confirm the regulatory role of TUSC7 in chemotherapy resistance in vivo, KYSE30 cells were transfected with LV-NC or LV-TUSC7 and subcutaneously injected into female nude mice.	('TUSC7', 'Gene', '285194', (43, 48))	('LV-NC', 'Var', (120, 125))	('nude mice', 'Species', '10090', (178, 187))	('TUSC7', 'Gene', (132, 137))	('TUSC7', 'Gene', '285194', (132, 137))	('TUSC7', 'Gene', (43, 48))
295693	29530057	Moreover, we also observed overexpression of TUSC7 inhibited tumor volume and weight.	('overexpression', 'Var', (27, 41))	('TUSC7', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TUSC7', 'Gene', '285194', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('inhibited', 'NegReg', (51, 60))	('tumor', 'Disease', (61, 66))
295707	29530057	In conclusion, our data proved that TUSC7 was downregulated and miR-224 was upregulated in ESCC, and high level of TUSC7 indicated better overall survival.	('TUSC7', 'Gene', (36, 41))	('overall survival', 'CPA', (138, 154))	('ESCC', 'Disease', (91, 95))	('miR-224', 'Gene', (64, 71))	('TUSC7', 'Gene', (115, 120))	('miR-224', 'Gene', '407009', (64, 71))	('TUSC7', 'Gene', '285194', (115, 120))	('downregulated', 'NegReg', (46, 59))	('better', 'PosReg', (131, 137))	('upregulated', 'PosReg', (76, 87))	('high', 'Var', (101, 105))	('TUSC7', 'Gene', '285194', (36, 41))
295716	28111536	When clinical findings need to be distinguished from pathological findings, descriptions such as "Although surgery was performed based on a preoperative finding of cT2,cN0, the pathological finding was pT3,pN1" are acceptable.	('cT2', 'Var', (164, 167))	('cN0', 'Var', (168, 171))	('pT3', 'Gene', '7694', (202, 205))	('pT3', 'Gene', (202, 205))
295818	24235843	It is now clear that overactivation of TLR-4, through various immune mediators, may cause immune response dysfunction, resulting in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('TLR-4', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('overactivation', 'Var', (21, 35))	('dysfunction', 'Disease', 'MESH:D006331', (106, 117))	('tumor', 'Disease', (132, 137))	('dysfunction', 'Disease', (106, 117))	('cause', 'Reg', (84, 89))	('resulting in', 'Reg', (119, 131))
295858	24235843	Killeen et al reported that LPS increases the expression of urokinase plasminogen activator and urokinase plasminogen activator receptor in colorectal cancer cells.	('colorectal cancer', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('LPS', 'Var', (28, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('urokinase', 'Protein', (60, 69))	('expression', 'MPA', (46, 56))	('increases', 'PosReg', (32, 41))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))
295859	24235843	LPS also enhances the colorectal cancer cell adhesion and invasion, but not in the presence of TLR-4 blocking antibody.	('enhances', 'PosReg', (9, 17))	('colorectal cancer', 'Disease', (22, 39))	('LPS', 'Var', (0, 3))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('invasion', 'CPA', (58, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))
295870	24235843	Anti-HMGB1 antibody was also shown to inhibit angiogenesis.	('HMGB1', 'Gene', '3146', (5, 10))	('HMGB1', 'Gene', (5, 10))	('inhibit', 'NegReg', (38, 45))	('antibody', 'Var', (11, 19))	('angiogenesis', 'CPA', (46, 58))
295916	24235843	A study of functional TLR-4 and mutated TLR-4 in mice found that mice with the former had less lung capillary permeability, less weight loss, leukocyte inflammation, and primary tumor formation.	('weight loss', 'Disease', (129, 140))	('less', 'NegReg', (90, 94))	('lung capillary permeability', 'MPA', (95, 122))	('tumor', 'Disease', (178, 183))	('lung capillary permeability', 'Phenotype', 'HP:0030005', (95, 122))	('leukocyte inflammation', 'Disease', 'MESH:D007249', (142, 164))	('TLR-4', 'Gene', (40, 45))	('weight loss', 'Phenotype', 'HP:0001824', (129, 140))	('mice', 'Species', '10090', (65, 69))	('mutated', 'Var', (32, 39))	('mice', 'Species', '10090', (49, 53))	('leukocyte inflammation', 'Disease', (142, 164))	('weight loss', 'Disease', 'MESH:D015431', (129, 140))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('less', 'NegReg', (124, 128))
295930	24235843	Single nucleotide polymorphism arrays have suggested that in patients with esophageal squamous cell carcinoma, genetic alterations in TLR-4 (9q32-q33) along with other chromosomal mutations are associated with higher cancer proliferation and metastasis.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('esophageal squamous cell carcinoma', 'Disease', (75, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('genetic alterations', 'Var', (111, 130))	('metastasis', 'CPA', (242, 252))	('patients', 'Species', '9606', (61, 69))	('TLR-4', 'Gene', (134, 139))	('associated', 'Reg', (194, 204))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (75, 109))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
295935	24235843	@@H. pylori infection leads to gastric inflammation, characterized histologically by surface epithelial degeneration and infiltration of the gastric mucosa, through acute and chronic inflammatory cells.	('leads to', 'Reg', (22, 30))	('infection', 'Var', (12, 21))	('gastric inflammation', 'Disease', (31, 51))	('gastric inflammation', 'Phenotype', 'HP:0005263', (31, 51))	('epithelial degeneration', 'Disease', (93, 116))	('H. pylori infection', 'Phenotype', 'HP:0005202', (2, 21))	('epithelial degeneration', 'Disease', 'MESH:D002277', (93, 116))	('gastric inflammation', 'Disease', 'MESH:D007249', (31, 51))	('H. pylori', 'Species', '210', (2, 11))
295942	24235843	Patients with poorly differentiated gastric adenocarcinomas have been shown to have Thr35 Ala polymorphism in the LRR of TLR-4, but not TLR-2, TLR-6, or TLR-9.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('gastric adenocarcinomas', 'Disease', (36, 59))	('TLR-9', 'Gene', '54106', (153, 158))	('TLR-9', 'Gene', (153, 158))	('Thr35', 'Var', (84, 89))	('polymorphism', 'Var', (94, 106))	('TLR-6', 'Gene', (143, 148))	('Patients', 'Species', '9606', (0, 8))	('TLR-6', 'Gene', '10333', (143, 148))	('Thr35 Ala', 'Mutation', 'p.T35A', (84, 93))	('TLR-4', 'Gene', (121, 126))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (36, 59))
295943	24235843	This finding supports the hypothesis that TLR-4 gene polymorphism is related to poorly-differentiated gastric adenocarcinoma.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (102, 124))	('gastric adenocarcinoma', 'Disease', (102, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('TLR-4', 'Gene', (42, 47))	('polymorphism', 'Var', (53, 65))	('related', 'Reg', (69, 76))
295944	24235843	In addition, a significantly higher risk of gastric carcinoma has been found with TLR-4 Ala896Gly polymorphism.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('gastric carcinoma', 'Disease', 'MESH:D013274', (44, 61))	('TLR-4', 'Gene', (82, 87))	('gastric carcinoma', 'Disease', (44, 61))	('Ala896Gly', 'Var', (88, 97))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (44, 61))	('Ala896Gly', 'SUBSTITUTION', 'None', (88, 97))
295945	24235843	A case-control study of 171 Italian gastric cancer patients and 151 controls reported TLR-4 Thr399Ile polymorphism, but not TLR-4 Asp299Gly polymorphism, is linked with increased risk of gastric cancer (P=0.023, hazard ratio [HR] =3.62).	('polymorphism', 'Var', (102, 114))	('gastric cancer', 'Disease', (187, 201))	('Thr399Ile', 'SUBSTITUTION', 'None', (92, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (187, 201))	('gastric cancer', 'Disease', (36, 50))	('Thr399Ile', 'Var', (92, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (187, 201))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (169, 201))	('patients', 'Species', '9606', (51, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('TLR-4', 'Gene', (86, 91))	('Asp299Gly', 'Chemical', '-', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
295946	24235843	Further, an increased risk of intestinal gastric cancer (P=0.006, HR=5.38), but not diffuse gastric cancer (P=0.612, HR=1.85) was reported in carriers of TLR-4 Thr399Ile allele.	('Thr399Ile', 'Var', (160, 169))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('gastric cancer', 'Disease', (92, 106))	('intestinal gastric cancer', 'Disease', 'MESH:D013274', (30, 55))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('TLR-4', 'Gene', (154, 159))	('increased risk of intestinal gastric cancer', 'Phenotype', 'HP:0006753', (12, 55))	('intestinal gastric cancer', 'Disease', (30, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('Thr399Ile', 'SUBSTITUTION', 'None', (160, 169))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
295947	24235843	Similar results were reported by repeated studies on the role of TLR-4 Asp299Gly/Thr399Ile single nucleotide polymorphism in relation to gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (137, 159))	('Thr399Ile', 'SUBSTITUTION', 'None', (81, 90))	('TLR-4', 'Gene', (65, 70))	('Thr399Ile', 'Var', (81, 90))	('Asp299Gly', 'Chemical', '-', (71, 80))	('gastric carcinogenesis', 'Disease', (137, 159))
295948	24235843	However, another case-control study carried out in Mexico reported neither TLR-4 Asp299Gly polymorphism (P=0.82) nor TLR-4 Thr399Ile polymorphism (P=0.2) was associated with significant incidence of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (199, 213))	('Asp299Gly', 'Var', (81, 90))	('TLR-4', 'Gene', (75, 80))	('Thr399Ile', 'SUBSTITUTION', 'None', (123, 132))	('Mexico', 'Species', '717522', (51, 57))	('TLR-4', 'Gene', (117, 122))	('gastric cancer', 'Disease', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('gastric cancer', 'Disease', 'MESH:D013274', (199, 213))	('Thr399Ile', 'Var', (123, 132))	('Asp299Gly', 'Chemical', '-', (81, 90))
295962	24235843	No association was reported with TLR-4 Asp299Gly and Thr399Ile polymorphism, in a group of IBD patients from Southern Italy, New Zealand, Germany, and Hungary.	('Thr399Ile', 'SUBSTITUTION', 'None', (53, 62))	('patients', 'Species', '9606', (95, 103))	('IBD', 'Phenotype', 'HP:0002037', (91, 94))	('Thr399Ile', 'Var', (53, 62))	('Asp299Gly', 'Chemical', '-', (39, 48))	('Asp299Gly', 'Var', (39, 48))	('TLR-4', 'Gene', (33, 38))
295963	24235843	However, some studies have suggested a significant link between TLR-4 Asp299Gly polymorphism and either ulcerative colitis or Crohn's disease or both.	('ulcerative colitis', 'Disease', (104, 122))	("Crohn's disease", 'Disease', 'MESH:D003424', (126, 141))	("Crohn's disease", 'Disease', (126, 141))	('ulcerative colitis', 'Disease', 'MESH:D003093', (104, 122))	('Asp299Gly', 'Chemical', '-', (70, 79))	('TLR-4', 'Gene', (64, 69))	('Asp299Gly polymorphism', 'Var', (70, 92))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (104, 122))	('colitis', 'Phenotype', 'HP:0002583', (115, 122))	("Crohn's disease", 'Phenotype', 'HP:0100280', (126, 141))
295964	24235843	In addition, a meta-analysis reported in 2010, showed a significant association between TLR-4 (Asp299Gly and Thr399Ile) polymorphism with ulcerative colitis (odds ratio [OR] =1.08, 95% confidence interval [CI]: 1.08-1.51), Crohn's disease (OR: 1.29, 95% CI: 1.08-1.54), and IBD (OR: 1.25, 95% CI: 1.06-1.48).	('ulcerative colitis', 'Disease', (138, 156))	('Asp299Gly', 'Var', (95, 104))	('TLR-4', 'Gene', (88, 93))	("Crohn's disease", 'Disease', (223, 238))	("Crohn's disease", 'Disease', 'MESH:D003424', (223, 238))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (138, 156))	('IBD', 'Phenotype', 'HP:0002037', (274, 277))	('Thr399Ile', 'SUBSTITUTION', 'None', (109, 118))	('ulcerative colitis', 'Disease', 'MESH:D003093', (138, 156))	('Thr399Ile', 'Var', (109, 118))	('IBD', 'Disease', (274, 277))	('colitis', 'Phenotype', 'HP:0002583', (149, 156))	('polymorphism', 'Var', (120, 132))	("Crohn's disease", 'Phenotype', 'HP:0100280', (223, 238))	('Asp299Gly', 'Chemical', '-', (95, 104))
295965	24235843	As well, TLR-4 Asp299Gly polymorphism was significantly higher in colorectal patients compared with normal healthy adults (P=0.0269).	('colorectal', 'Disease', (66, 76))	('patients', 'Species', '9606', (77, 85))	('Asp299Gly', 'Chemical', '-', (15, 24))	('colorectal', 'Disease', 'MESH:D015179', (66, 76))	('higher', 'PosReg', (56, 62))	('Asp299Gly polymorphism', 'Var', (15, 37))	('TLR-4', 'Gene', (9, 14))
295966	24235843	Also, studies report that LPS enhanced colorectal cancer cell adhesion and invasion, through TLR-4- and NF-kappaB-dependent activation of the urokinase plasminogen activator system and beta-1 integrin, which ultimately leads to tumor progression.	('LPS', 'Var', (26, 29))	('beta-1 integrin', 'Gene', (185, 200))	('enhanced', 'PosReg', (30, 38))	('activation', 'PosReg', (124, 134))	('invasion', 'CPA', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('leads to', 'Reg', (219, 227))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('tumor', 'Disease', (228, 233))	('beta-1 integrin', 'Gene', '3688', (185, 200))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('urokinase', 'MPA', (142, 151))	('colorectal cancer', 'Disease', (39, 56))
295967	24235843	In vivo data suggests TLR-4 inhibition has prolonged the survival rate of tumor-bearing mice (BALB/c).	('TLR-4', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('inhibition', 'Var', (28, 38))	('tumor', 'Disease', (74, 79))	('survival rate', 'CPA', (57, 70))	('mice', 'Species', '10090', (88, 92))	('prolonged', 'PosReg', (43, 52))
295973	24235843	On the other hand, diethylnitrosamine, a carcinogen, was shown to stimulate TLR-4 signaling in mice, resulting in an increase in the size and number of tumors, while the size and number of tumors were found be reduced in MyD88 deficient mice.	('diethylnitrosamine', 'Var', (19, 37))	('increase', 'PosReg', (117, 125))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('mice', 'Species', '10090', (237, 241))	('TLR-4 signaling', 'MPA', (76, 91))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (19, 37))	('stimulate', 'PosReg', (66, 75))	('tumors', 'Disease', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
295982	24235843	Longer survival (P=0.014) was noted among patients with neither TLR-4 nor HIF-1alpha over-expressed compared with patients who had both TLR-4 and HIF-1alpha overexpressed.	('Longer', 'PosReg', (0, 6))	('HIF-1alpha', 'Gene', '3091', (74, 84))	('over-expressed', 'Var', (85, 99))	('TLR-4', 'Gene', (64, 69))	('HIF-1alpha', 'Gene', (146, 156))	('HIF-1alpha', 'Gene', (74, 84))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (42, 50))	('HIF-1alpha', 'Gene', '3091', (146, 156))
296005	24235843	An immunohistochemical study on clinical carcinomas showed a significant association of high TLR-4 expression with local cancer proliferation and lymph node metastasis.	('high', 'Var', (88, 92))	('expression', 'MPA', (99, 109))	('lymph node metastasis', 'CPA', (146, 167))	('local', 'CPA', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Disease', (41, 51))	('carcinomas', 'Disease', 'MESH:D002277', (41, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TLR-4', 'Gene', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
296007	24235843	Tumors with high TLR-4 expression, but not TLR-9 expression, in mononuclear cells were found to have a higher probability of metastasis.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('metastasis', 'CPA', (125, 135))	('high', 'Var', (12, 16))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('TLR-9', 'Gene', '54106', (43, 48))	('TLR-4', 'Gene', (17, 22))	('TLR-9', 'Gene', (43, 48))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('expression', 'MPA', (23, 33))
296010	24235843	Incidents of relapses have been shown to be high in breast cancer patients harboring the TLR-4 Asp299Gly polymorphism who were treated with anthracycline-based chemotherapeutic drugs.	('Asp299Gly', 'Var', (95, 104))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('Asp299Gly', 'Chemical', '-', (95, 104))	('TLR-4', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('anthracycline', 'Chemical', 'MESH:D018943', (140, 153))	('patients', 'Species', '9606', (66, 74))
296011	24235843	This polymorphism also confers to an increased risk of breast cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('polymorphism', 'Var', (5, 17))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
296012	24235843	However, the levels of the TLR-4 Ala896Gly allele in breast cancer patients were not found to be significantly different from those levels in normal healthy Caucasian women.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('patients', 'Species', '9606', (67, 75))	('women', 'Species', '9606', (167, 172))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('Ala896Gly', 'SUBSTITUTION', 'None', (33, 42))	('Ala896Gly', 'Var', (33, 42))	('TLR-4', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
296025	24235843	Another laboratory finding has suggested that five ovarian cancer (OVCAR3, SKOV3, AD10, A2780, CP70) cells with TLR-4 ligation induced IL-1 receptor-associated kinase (IRAK)-4 activation, c-Jun phosphorylation, NF-kappaB activation, and IL-8, IL-6, VEGF, and monocyte chemotactic protein-1 (MCP)-1 production, all of which promote tumor survival and chemoresistance.	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('SKOV3', 'CellLine', 'CVCL:0532', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('AD10', 'Gene', (82, 86))	('IL-6', 'Gene', '3569', (243, 247))	('CP70', 'Var', (95, 99))	('IL-8', 'Gene', '3576', (237, 241))	('ovarian cancer', 'Disease', 'MESH:D010051', (51, 65))	('VEGF', 'Gene', '7422', (249, 253))	('activation', 'PosReg', (176, 186))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('VEGF', 'Gene', (249, 253))	('NF-kappaB', 'Protein', (211, 220))	('monocyte chemotactic protein-1 (MCP)-1', 'Gene', '6347', (259, 297))	('IL-6', 'Gene', (243, 247))	('IL-1 receptor-associated kinase (IRAK)-4', 'Gene', '51135', (135, 175))	('AD10', 'Gene', '780912', (82, 86))	('ovarian cancer', 'Disease', (51, 65))	('TLR-4', 'Gene', (112, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (51, 65))	('c-Jun', 'Gene', '3725', (188, 193))	('promote', 'PosReg', (323, 330))	('IL-8', 'Gene', (237, 241))	('c-Jun', 'Gene', (188, 193))	('laboratory finding', 'Phenotype', 'HP:0001939', (8, 26))	('ligation', 'Var', (118, 126))	('activation', 'PosReg', (221, 231))	('tumor', 'Disease', (331, 336))	('chemoresistance', 'CPA', (350, 365))
296037	24235843	TLR-4 expression was found to be inversely proportional (P<0.001) with the expression of p16INK4A, a marker of high-risk HPV infection.	('HPV infection', 'Disease', 'MESH:D030361', (121, 134))	('p16INK4A', 'Var', (89, 97))	('expression', 'MPA', (6, 16))	('TLR-4', 'Gene', (0, 5))	('HPV infection', 'Disease', (121, 134))
296038	24235843	There are limited studies that conclude on the role of TLR-4 in cervical cancer progression; thus, the TLR-4 Thr399Ile polymorphism (P=0.044, OR=2.51, 95% CI: 1.03-6.12) was, again, found to be significantly associated with early stages of cervical cancers among North Indian women.	('women', 'Species', '9606', (276, 281))	('cervical cancer', 'Disease', (64, 79))	('cervical cancers', 'Disease', (240, 256))	('Thr399Ile', 'SUBSTITUTION', 'None', (109, 118))	('cervical cancer', 'Disease', 'MESH:D002583', (64, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('associated with', 'Reg', (208, 223))	('Thr399Ile', 'Var', (109, 118))	('TLR-4', 'Gene', (103, 108))	('cervical cancer', 'Disease', 'MESH:D002583', (240, 255))	('cervical cancers', 'Disease', 'MESH:D002583', (240, 256))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
296045	24235843	Also, TLR-4 activation was found to increase the proangiogenic factor (VEGF) and immunosuppressive cytokine (TGF-beta1) secretion in human prostate adenocarcinoma (PC3) cells.	('prostate adenocarcinoma', 'Disease', (139, 162))	('increase', 'PosReg', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('TLR-4', 'Gene', (6, 11))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (139, 162))	('human', 'Species', '9606', (133, 138))	('PC3', 'Gene', (164, 167))	('VEGF', 'Gene', (71, 75))	('activation', 'Var', (12, 22))	('TGF-beta1', 'Gene', '7040', (109, 118))	('TGF-beta1', 'Gene', (109, 118))	('PC3', 'Gene', '3853', (164, 167))	('VEGF', 'Gene', '7422', (71, 75))
296046	24235843	Further, a knockdown of TLR-4 in PC3 cells resulted in the reduction of tumor cell migration and invasion.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('PC3', 'Gene', (33, 36))	('TLR-4', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('reduction', 'NegReg', (59, 68))	('PC3', 'Gene', '3853', (33, 36))	('invasion', 'CPA', (97, 105))	('knockdown', 'Var', (11, 20))
296048	24235843	In addition, single nucleotide polymorphism in the TLR-4 gene is suspected to be associated with the risk of prostate carcinoma.	('associated', 'Reg', (81, 91))	('single nucleotide polymorphism', 'Var', (13, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (109, 127))	('prostate carcinoma', 'Disease', (109, 127))	('TLR-4', 'Gene', (51, 56))	('prostate carcinoma', 'Disease', 'MESH:D011472', (109, 127))
296049	24235843	The sequence variant (11381 G/C, also known as rs11536889) in the 3'-untranslated region of the TLR-4 gene was found to be higher in patients with prostate carcinoma, in studies conducted on 1,383 Swedish patients and 157 Korean patients.	('prostate carcinoma', 'Phenotype', 'HP:0012125', (147, 165))	('patients', 'Species', '9606', (229, 237))	('rs11536889', 'Mutation', 'rs11536889', (47, 57))	('11381 G/C', 'Mutation', 'g.11381G>C', (22, 31))	('prostate carcinoma', 'Disease', (147, 165))	('patients', 'Species', '9606', (205, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('prostate carcinoma', 'Disease', 'MESH:D011472', (147, 165))	('patients', 'Species', '9606', (133, 141))	('TLR-4', 'Gene', (96, 101))	('higher', 'Reg', (123, 129))	('11381 G/C', 'Var', (22, 31))
296050	24235843	In one study, a significantly higher risk of prostate cancer (OR: 1.26; 95% CI: 1.01-1.57) was detected among men who had a single nucleotide polymorphism of TLR-4 (GC or CC) compared with the wild-type genotype (GG).	('prostate cancer', 'Disease', 'MESH:D011471', (45, 60))	('men', 'Species', '9606', (110, 113))	('prostate cancer', 'Phenotype', 'HP:0012125', (45, 60))	('prostate cancer', 'Disease', (45, 60))	('TLR-4', 'Gene', (158, 163))	('single nucleotide polymorphism', 'Var', (124, 154))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
296051	24235843	However, other studies found no association of prostate cancer (OR: 1.01; 95% CI: 0.79-1.29) with this rs11536889 sequence variant of TLR-4; one of these, a study involving 700 prostate cancer patients found that homozygosity of the variant alleles of these eight single-nucleotide polymorphisms of TLR-4 including rs2149356 were found to have a lower risk of prostate cancer.	('lower', 'NegReg', (346, 351))	('rs2149356', 'Mutation', 'rs2149356', (315, 324))	('prostate cancer', 'Disease', 'MESH:D011471', (177, 192))	('lower risk of prostate', 'Phenotype', 'HP:0008687', (346, 368))	('prostate cancer', 'Phenotype', 'HP:0012125', (177, 192))	('prostate cancer', 'Disease', 'MESH:D011471', (360, 375))	('prostate cancer', 'Disease', (177, 192))	('prostate cancer', 'Phenotype', 'HP:0012125', (360, 375))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('rs2149356', 'Var', (315, 324))	('prostate cancer', 'Disease', (360, 375))	('patients', 'Species', '9606', (193, 201))	('rs11536889', 'Mutation', 'rs11536889', (103, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (47, 62))	('prostate cancer', 'Phenotype', 'HP:0012125', (47, 62))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('prostate cancer', 'Disease', (47, 62))	('TLR-4', 'Gene', (299, 304))
296052	24235843	A case-control study of 506 incident advanced prostate cancer patients found two single nucleotide polymorphisms of TLR-4 (rs10759932 and rs2149356) were associated with a higher cancer risk.	('prostate cancer', 'Disease', (46, 61))	('rs10759932', 'Var', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('TLR-4', 'Gene', (116, 121))	('prostate cancer', 'Phenotype', 'HP:0012125', (46, 61))	('patients', 'Species', '9606', (62, 70))	('rs2149356', 'Mutation', 'rs2149356', (138, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (46, 61))	('rs2149356', 'Var', (138, 147))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (179, 185))	('cancer', 'Disease', (55, 61))	('rs10759932', 'Mutation', 'rs10759932', (123, 133))
296054	24235843	The inconsistent findings of the association of genetic polymorphism of TLRs with cancer progression clearly supports the need for further investigation in this field.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TLR', 'Gene', (72, 75))	('TLR', 'Gene', '37277', (72, 75))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('genetic polymorphism', 'Var', (48, 68))	('association', 'Interaction', (33, 44))
296082	33680935	Patients were excluded if (i) the chemoradiation was done outside Shanghai Chest Hospital, and the treatment details were missing; (ii) delivered radiation dose was less than 40 Gy or more than 50.4Gy; (iii) surgery was done within less than 4 weeks or more than 10 weeks after NCRT:indicating urgent and salvage resections, respectively.	('less', 'Var', (165, 169))	('age', 'Gene', '5973', (309, 312))	('age', 'Gene', (309, 312))	('Patients', 'Species', '9606', (0, 8))
296090	33680935	deltaDmin% was defined as the increase of esophageal minimum diameter on esophagogram after NCRT divided by pre-Dmin.	('Dmin', 'Chemical', '-', (112, 116))	('age', 'Gene', (47, 50))	('age', 'Gene', '5973', (47, 50))	('Dmin', 'Chemical', '-', (5, 9))	('deltaDmin', 'Var', (0, 9))
296091	33680935	Contrast-enhanced chest CT images were acquired with a variety of CT scanners according to standard clinical scanning protocols (120kV/140kV, 140~300mA, and slice thickness of 5 mm).	('120kV/140kV', 'Var', (129, 140))	('age', 'Gene', '5973', (29, 32))	('140~300mA', 'Var', (142, 151))	('age', 'Gene', (29, 32))
296154	33680935	In other words, the correct pCR prediction of RS+clinical model would lead to a net reduction of 16 avoidable surgeries in the 121 patients of our research cohort, equivalent to performing organ-saving strategy in 31.37% of the 51 true-pCR cases.	('reduction', 'NegReg', (84, 93))	('RS+clinical', 'Var', (46, 57))	('patients', 'Species', '9606', (131, 139))
296170	32629877	There are no reliable information on the actual frequency, significance and homogeneity of Y chromosome loss (LoY) in esophageal adenocarcinoma (EAC).	('adenocarcinoma', 'Disease', (129, 143))	('Y chromosome loss', 'Var', (91, 108))	('adenocarcinoma', 'Disease', 'MESH:D000230', (129, 143))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (118, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))
296173	32629877	LoY correlated with TP53 mutations (p = 0.003), KRAS amplification (p = 0.004), loss of ARID1a (p = 0.045) and presence of LAG3 (p = 0.018).	('mutations', 'Var', (25, 34))	('KRAS', 'Gene', (48, 52))	('TP53', 'Gene', (20, 24))	('ARID1a', 'Gene', (88, 94))	('KRAS', 'Gene', '3845', (48, 52))	('loss', 'NegReg', (80, 84))	('LAG3', 'Gene', (123, 127))	('LAG3', 'Gene', '3902', (123, 127))	('ARID1a', 'Gene', '8289', (88, 94))	('TP53', 'Gene', '7157', (20, 24))
296185	32629877	In bladder carcinoma, for example, loss of the Y chromosome is found in 30% of cases.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (3, 20))	('bladder carcinoma', 'Disease', (3, 20))	('bladder carcinoma', 'Disease', 'MESH:D001749', (3, 20))	('loss', 'Var', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
296192	32629877	Within the patients' cohort, lymph node metastases of 255 patients were available, and from these, 165 cases were analyzable for Y chromosome loss (LoY) (64.7%).	('Y chromosome loss', 'Var', (129, 146))	('metastases', 'Disease', (40, 50))	('metastases', 'Disease', 'MESH:D009362', (40, 50))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (11, 19))
296202	32629877	Analysis of the molecular marker profile showed a correlation between LoY and TP53 mutations and KRAS amplifications (p = 0.003 and p = 0.004, respectively), loss of chromatin remodeling protein ARID1a (SMARCA4) (p = 0.045) and presence of the immune checkpoint regulator of LAG3 (p = 0.018).	('mutations', 'Var', (83, 92))	('ARID1a', 'Gene', '8289', (195, 201))	('LoY', 'Gene', (70, 73))	('KRAS', 'Gene', (97, 101))	('SMARCA4', 'Gene', (203, 210))	('KRAS', 'Gene', '3845', (97, 101))	('ARID1a', 'Gene', (195, 201))	('LAG3', 'Gene', '3902', (275, 279))	('SMARCA4', 'Gene', '6597', (203, 210))	('LAG3', 'Gene', (275, 279))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('loss', 'NegReg', (158, 162))
296204	32629877	LoY was strongly associated with shortened overall-survival (OS) in the entire patients  cohort.	('shortened', 'NegReg', (33, 42))	('overall-survival', 'MPA', (43, 59))	('patients', 'Species', '9606', (79, 87))	('LoY', 'Var', (0, 3))
296209	32629877	The extent of Y-chromosome loss in adenocarcinomas of the esophagus has so far only been determined on small case numbers.	('adenocarcinomas', 'Disease', (35, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('Y-chromosome loss', 'Var', (14, 31))	('adenocarcinomas', 'Disease', 'MESH:D000230', (35, 50))
296214	32629877	TP53 mutations strongly correlate with instable genomes.	('instable genomes', 'CPA', (39, 55))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
296216	32629877	Further, the extremely high frequency of >50% of LoY suggests that there is a fitness advantage.	('fitness', 'Disease', 'MESH:D012640', (78, 85))	('LoY', 'Var', (49, 52))	('fitness', 'Disease', (78, 85))
296220	32629877	The LoY is described to be associated with shorter survival and risk of cancer in general.	('shorter', 'NegReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('LoY', 'Var', (4, 7))	('cancer', 'Disease', (72, 78))
296225	32629877	The LoY might affect survival through defective immune functions of blood cells by disrupting immunosurveillance enabling tumor development and expansion.	('immunosurveillance', 'CPA', (94, 112))	('defective immune functions', 'Phenotype', 'HP:0002721', (38, 64))	('affect', 'Reg', (14, 20))	('survival', 'CPA', (21, 29))	('men', 'Species', '9606', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('LoY', 'Var', (4, 7))	('disrupting', 'NegReg', (83, 93))	('expansion', 'CPA', (144, 153))	('tumor', 'Disease', (122, 127))
296231	32629877	LoY might render its cancer-promoting effect through tumor suppressor genes located on the X chromosome that have no homologous copy in males and that might respond to LoY by epigenetic silencing.	('epigenetic silencing', 'Var', (175, 195))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
296233	32629877	One study has shown that six of such genes show increased loss-of-function mutations in male tumor diseases (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3).	('KDM6A', 'Gene', (137, 142))	('MAGEC3', 'Gene', (148, 154))	('male tumor diseases', 'Disease', (88, 107))	('MAGEC3', 'Gene', '139081', (148, 154))	('CNKSR2', 'Gene', (115, 121))	('DDX3X', 'Gene', '1654', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ATRX', 'Gene', '546', (109, 113))	('CNKSR2', 'Gene', '22866', (115, 121))	('KDM5C', 'Gene', (130, 135))	('KDM6A', 'Gene', '7403', (137, 142))	('loss-of-function', 'NegReg', (58, 74))	('DDX3X', 'Gene', (123, 128))	('mutations', 'Var', (75, 84))	('KDM5C', 'Gene', '8242', (130, 135))	('male tumor diseases', 'Disease', 'MESH:D018567', (88, 107))	('ATRX', 'Gene', (109, 113))
296238	32629877	Interestingly, here we found a statistically significant association between tumors with LoY and loss of expression of ARID1a, a member of the relevant SWI-SNF chromatin remodeling complex.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('loss of expression', 'NegReg', (97, 115))	('LoY', 'Var', (89, 92))	('ARID1a', 'Gene', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ARID1a', 'Gene', '8289', (119, 125))
296239	32629877	This trend towards mutual exclusivity between LoY and SWI-SNF inactivation might indicate that LoY has an epigenetic effect that reduces the additional selective advantage of other epigenetic alterations on cancer development.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('LoY', 'Var', (95, 98))	('men', 'Species', '9606', (221, 224))	('inactivation', 'Var', (62, 74))	('selective advantage', 'MPA', (152, 171))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('reduces', 'NegReg', (129, 136))
296245	32629877	For colorectal, prostate, bladder and lung cancer studies showed a significant higher frequency of LoY in blood cells compared to healthy controls.	('lung cancer', 'Disease', (38, 49))	('bladder', 'Disease', 'MESH:D001745', (26, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('prostate', 'Disease', (16, 24))	('bladder', 'Disease', (26, 33))	('LoY', 'Var', (99, 102))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('colorectal', 'Disease', (4, 14))
296287	32622332	Notably, a series of gain- and loss-of-function assays elucidated that miR-20b-5p promoted ESCC cell proliferation, migration, and invasion both in vitro and in vivo.	('invasion', 'CPA', (131, 139))	('promoted', 'PosReg', (82, 90))	('miR-20b-5p', 'Chemical', '-', (71, 81))	('ESCC', 'Disease', (91, 95))	('miR-20b-5p', 'Var', (71, 81))	('migration', 'CPA', (116, 125))
296288	32622332	Luciferase reporter assays, western blot, and qRT-PCR revealed that RB1 and TP53INP1 were the direct targets of miR-20b-5p.	('miR-20b-5p', 'Chemical', '-', (112, 122))	('miR-20b-5p', 'Var', (112, 122))	('TP53INP1', 'Gene', (76, 84))	('TP53INP1', 'Gene', '94241', (76, 84))	('RB1', 'Gene', (68, 71))
296290	32622332	In contrast, the effects of miR-20b-5p depletion were impaired by RB1 and TP53INP1 knockdown.	('miR-20b-5p', 'Chemical', '-', (28, 38))	('miR-20b-5p', 'Var', (28, 38))	('TP53INP1', 'Gene', (74, 82))	('knockdown', 'Var', (83, 92))	('TP53INP1', 'Gene', '94241', (74, 82))	('RB1', 'Gene', (66, 69))
296291	32622332	Treatment with a miR-20b-5p antagomir dramatically increased tumor growth and inhibited RB1 and TP53INP1 protein expression in nude mice.	('TP53INP1', 'Gene', (96, 104))	('inhibited', 'NegReg', (78, 87))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TP53INP1', 'Gene', '94241', (96, 104))	('miR-20b-5p', 'Chemical', '-', (17, 27))	('nude mice', 'Species', '10090', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-20b-5p', 'Var', (17, 27))	('RB1', 'Protein', (88, 91))	('tumor', 'Disease', (61, 66))
296303	32622332	According to The Cancer Genome Atlas (TCGA) database (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga), along with the results of recent relevant research, miR-20b-5p expression has a significant increase in ESCC tissue and serum, and the increase becomes more significant due to the advanced stages of esophageal cancer (stages III and IV).	('Cancer', 'Disease', (17, 23))	('miR-20b-5p expression', 'Var', (192, 213))	('cancer', 'Disease', 'MESH:D009369', (350, 356))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('miR-20b-5p', 'Chemical', '-', (192, 202))	('cancer', 'Disease', (350, 356))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('increase', 'PosReg', (232, 240))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('ESCC', 'Disease', (244, 248))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('cancer', 'Disease', (66, 72))
296304	32622332	Until this study, the molecular mechanism by which miR-20b-5p could influence ESCC progression remained largely unknown.	('miR-20b-5p', 'Chemical', '-', (51, 61))	('influence', 'Reg', (68, 77))	('ESCC', 'Disease', (78, 82))	('miR-20b-5p', 'Var', (51, 61))
296308	32622332	Based on the confirmation of clinical relevance, the analyses also investigated how miR-20b-5p participates in various biological processes to control tumor development at the molecular level.	('miR-20b-5p', 'Var', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('control', 'PosReg', (143, 150))	('participates', 'Reg', (95, 107))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('investigated', 'Reg', (67, 79))	('miR-20b-5p', 'Chemical', '-', (84, 94))
296309	32622332	In order to clarify the influences of miR-20b-5p on ESCC progression, we used TCGA database to analyze miR-20b-5p expression in ESCC tissue.	('miR-20b-5p', 'Var', (103, 113))	('miR-20b-5p', 'Chemical', '-', (38, 48))	('ESCC', 'Disease', (52, 56))	('miR-20b-5p', 'Chemical', '-', (103, 113))
296316	32622332	The overexpression of miR-20b-5p showed significant association with the advanced tumor progression and the occurrence of lymph node metastasis, as detailed in the discovery group of Table 1.	('miR-20b-5p', 'Chemical', '-', (22, 32))	('miR-20b-5p', 'Var', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('lymph node metastasis', 'CPA', (122, 143))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('overexpression', 'PosReg', (4, 18))	('tumor', 'Disease', (82, 87))
296317	32622332	Also, from the clinical perspective, the results of Kaplan-Meier testing indicated that overexpressed miR-20b-5p was associated with reduced survival rates (Figure 2A).	('survival rates', 'CPA', (141, 155))	('miR-20b-5p', 'Var', (102, 112))	('miR-20b-5p', 'Chemical', '-', (102, 112))	('reduced', 'NegReg', (133, 140))
296323	32622332	According to the Kaplan-Meier survival test, the overexpressed miR-20b-5p showed significant correlation with the poor prognosis of ESCC patients (Figure 2E).	('miR-20b-5p', 'Var', (63, 73))	('patients', 'Species', '9606', (137, 145))	('overexpressed', 'PosReg', (49, 62))	('miR-20b-5p', 'Chemical', '-', (63, 73))	('ESCC', 'Disease', (132, 136))
296331	32622332	These data suggested that miR-20b-5p was a stable and relatively reliable diagnostic and predictive biomarker to discriminate ESCC patients from normal controls.	('patients', 'Species', '9606', (131, 139))	('miR-20b-5p', 'Var', (26, 36))	('ESCC', 'Disease', (126, 130))	('miR-20b-5p', 'Chemical', '-', (26, 36))
296341	32622332	Thereby, the results of cellular function assays demonstrated that the increased exogenous miR-20b-5p expression had markedly promoted the proliferation, colony formation, migration, and invasion processes of the KYSE30 and KYSE180 cells, as illustrated in Figures 4C-4H.	('miR-20b-5p', 'Chemical', '-', (91, 101))	('promoted', 'PosReg', (126, 134))	('miR-20b-5p', 'Var', (91, 101))	('KYSE180', 'CellLine', 'CVCL:1349', (224, 231))	('proliferation', 'CPA', (139, 152))	('colony formation', 'CPA', (154, 170))	('increased', 'PosReg', (71, 80))	('invasion processes', 'CPA', (187, 205))	('migration', 'CPA', (172, 181))
296356	32622332	The inhibition by miR-20b-5p on the RB1-3' UTR and TP53INP1-3' UTR was considered to be sequence-specific, because the luciferase activities of RB1-mutant (mut) and TP53INP1-mut could not be inhibited by introduction of the miR-20b-5p gene.	('TP53INP1', 'Gene', (165, 173))	('RB1-3', 'Gene', '5925;5934;81551', (36, 41))	('TP53INP1', 'Gene', (51, 59))	('miR-20b-5p', 'Chemical', '-', (224, 234))	('luciferase', 'Enzyme', (119, 129))	('RB1-mutant', 'Var', (144, 154))	('RB1-3', 'Gene', (36, 41))	('TP53INP1', 'Gene', '94241', (165, 173))	('TP53INP1', 'Gene', '94241', (51, 59))	('activities', 'MPA', (130, 140))	('miR-20b-5p', 'Chemical', '-', (18, 28))
296357	32622332	Therefore, it was concluded that the miR-20b-5p could directly bind to the 3' UTR of RB1 and TP53INP1.	('bind', 'Interaction', (63, 67))	('TP53INP1', 'Gene', (93, 101))	('miR-20b-5p', 'Var', (37, 47))	('TP53INP1', 'Gene', '94241', (93, 101))	('RB1', 'Gene', (85, 88))	('miR-20b-5p', 'Chemical', '-', (37, 47))
296359	32622332	The results proved that the migratory and invasive actions enhanced by the transfected miRNA mimic were counteracted by the presence of expression constructs, as detailed in Figures 7C-7F.	('enhanced', 'PosReg', (59, 67))	('migratory', 'CPA', (28, 37))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('transfected', 'Var', (75, 86))
296361	32622332	Thereby, depending on silencing the expression of RB1 and TP53INP1, the migration and invasion activities were found to be significantly enhanced, as illustrated in Figures 7I and 7J.	('enhanced', 'PosReg', (137, 145))	('TP53INP1', 'Gene', (58, 66))	('TP53INP1', 'Gene', '94241', (58, 66))	('silencing', 'Var', (22, 31))	('RB1', 'Gene', (50, 53))
296365	32622332	The transfection efficiency was shown by the overexpressed miR-20b-5p in the KYSE180 cells, which was checked with qRT-PCR, as shown in Figure 8A.	('transfection', 'MPA', (4, 16))	('overexpressed', 'PosReg', (45, 58))	('miR-20b-5p', 'Chemical', '-', (59, 69))	('miR-20b-5p', 'Var', (59, 69))	('KYSE180', 'CellLine', 'CVCL:1349', (77, 84))
296368	32622332	The growth curve of the transplanted tumor indicated obvious growth acceleration in the miR-20b-5p overexpression group compared to the controls (Figures 8B and 8C).	('miR-20b-5p', 'Chemical', '-', (88, 98))	('growth', 'CPA', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('miR-20b-5p', 'Var', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('growth', 'CPA', (61, 67))	('acceleration', 'PosReg', (68, 80))	('growth acceleration', 'Phenotype', 'HP:0001510', (61, 80))
296370	32622332	The mean volume and weight of the group with miR-20b-5p overexpression had significant increases, as detailed in Figure 8D.	('miR-20b-5p', 'Chemical', '-', (45, 55))	('miR-20b-5p', 'Var', (45, 55))	('increases', 'PosReg', (87, 96))
296373	32622332	In the group that had received the injections of the cells with overexpressed miR-20b-5p, the metastasis burdens in the lung, brain, liver, and bone were higher than those of the control group (Figures 8E and 8F).	('miR-20b-5p', 'Chemical', '-', (78, 88))	('higher', 'PosReg', (154, 160))	('metastasis burdens in the lung', 'CPA', (94, 124))	('miR-20b-5p', 'Var', (78, 88))
296375	32622332	The findings, depending on the mouse models, showed the regulatory function of miR-20b-5p to facilitate ESCC growth and metastasis.	('miR-20b-5p', 'Var', (79, 89))	('facilitate', 'PosReg', (93, 103))	('miR-20b-5p', 'Chemical', '-', (79, 89))	('mouse', 'Species', '10090', (31, 36))
296386	32622332	According to the results from the current study, the miR-20b-5p expression showed significant upregulation in the ESCC samples in comparison with the corresponding normal tissue samples.	('expression', 'MPA', (64, 74))	('ESCC', 'Disease', (114, 118))	('miR-20b-5p', 'Chemical', '-', (53, 63))	('upregulation', 'PosReg', (94, 106))	('miR-20b-5p', 'Var', (53, 63))
296387	32622332	Importantly, note that the miR-20b-5p overexpression could be detected using the serum samples taken from the ESCC patients.	('miR-20b-5p', 'Chemical', '-', (27, 37))	('miR-20b-5p', 'Var', (27, 37))	('ESCC', 'Disease', (110, 114))	('patients', 'Species', '9606', (115, 123))
296400	32622332	In previous research, aberrant promoter methylation was associated with the gene silencing function of several miRNAs in prostate cancer cases.	('prostate cancer', 'Disease', 'MESH:D011471', (121, 136))	('aberrant', 'Var', (22, 30))	('promoter', 'MPA', (31, 39))	('gene', 'MPA', (76, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (121, 136))	('prostate cancer', 'Disease', (121, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))
296402	32622332	Therefore, the present study hypothesized that this epigenetic mechanism could induce miR-20b-5p upregulation.	('miR-20b-5p', 'Gene', (86, 96))	('upregulation', 'PosReg', (97, 109))	('epigenetic', 'Var', (52, 62))	('miR-20b-5p', 'Chemical', '-', (86, 96))
296406	32622332	In line with this expectation, it was confirmed that the abnormally overexpressed miR-20b-5p could increase tumor cell proliferation, colony formation, and invasive potency.	('overexpressed', 'PosReg', (68, 81))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('miR-20b-5p', 'Chemical', '-', (82, 92))	('tumor', 'Disease', (108, 113))	('colony formation', 'CPA', (134, 150))	('miR-20b-5p', 'Var', (82, 92))	('increase', 'PosReg', (99, 107))	('invasive potency', 'CPA', (156, 172))
296408	32622332	To conclude, miR-20b-5p was tumorigenic for ESCC.	('ESCC', 'Disease', (44, 48))	('tumor', 'Disease', (28, 33))	('miR-20b-5p', 'Chemical', '-', (13, 23))	('miR-20b-5p', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
296409	32622332	Additionally, this study demonstrated that more remarkably increased expression levels of miR-20b-5p could be detected in the metastatic ESCC specimens, which were sampled from tumors at advanced stages.	('miR-20b-5p', 'Chemical', '-', (90, 100))	('expression levels', 'MPA', (69, 86))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('miR-20b-5p', 'Var', (90, 100))	('metastatic ESCC', 'Disease', (126, 141))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))	('increased', 'PosReg', (59, 68))
296410	32622332	Moreover, overexpressed miR-20b-5p facilitated tumor development in mice, while the overexpression was also positively associated with distant metastasis.	('mice', 'Species', '10090', (68, 72))	('distant metastasis', 'CPA', (135, 153))	('miR-20b-5p', 'Chemical', '-', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('miR-20b-5p', 'Var', (24, 34))	('tumor', 'Disease', (47, 52))	('facilitated', 'PosReg', (35, 46))
296418	32622332	Similarly, the results obtained in the current study showed that miR-20b-5p had certain associations with the growth and metastasis of ESCC.	('ESCC', 'Disease', (135, 139))	('metastasis', 'CPA', (121, 131))	('miR-20b-5p', 'Chemical', '-', (65, 75))	('growth', 'CPA', (110, 116))	('associations', 'Interaction', (88, 100))	('miR-20b-5p', 'Var', (65, 75))
296419	32622332	Therefore, the innovation of therapeutic techniques that target miR-20b-5p, in combination with the currently conventional first-line anti-ESCC therapy methods, might be particularly beneficial for ESCC patients prone to high risks of metastasis.	('patients', 'Species', '9606', (203, 211))	('miR-20b-5p', 'Chemical', '-', (64, 74))	('ESCC', 'Disease', (198, 202))	('miR-20b-5p', 'Var', (64, 74))
296420	32622332	To further identify the downstream signaling pathway underlying the above-mentioned functions of miR-20b-5p, this study selected the putative targets of miR-20b-5p in ESCC with cutting-edge bioinformatics tools.	('miR-20b-5p', 'Chemical', '-', (97, 107))	('miR-20b-5p', 'Var', (153, 163))	('ESCC', 'Disease', (167, 171))	('miR-20b-5p', 'Chemical', '-', (153, 163))
296421	32622332	The results of bioinformatics analysis revealed that miR-20b-5p could target the 3' UTR binding sites of mRNA RB1 and TP53INP1.	('miR-20b-5p', 'Chemical', '-', (53, 63))	('miR-20b-5p', 'Var', (53, 63))	('TP53INP1', 'Gene', (118, 126))	('mRNA RB1', 'Gene', (105, 113))	('TP53INP1', 'Gene', '94241', (118, 126))
296424	32622332	The tumor suppressor PTEN was reported to be targeted by miR-20b-5p.	('tumor', 'Disease', (4, 9))	('miR-20b-5p', 'Chemical', '-', (57, 67))	('miR-20b-5p', 'Var', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('PTEN', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('PTEN', 'Gene', '5728', (21, 25))
296426	32622332	Specifically, the aberrant RB1 level was known to inhibit the development of various cancer cells by modulating DNA replications, cell cycles, and apoptosis.	('DNA replications', 'CPA', (112, 128))	('modulating', 'Reg', (101, 111))	('cell cycles', 'CPA', (130, 141))	('inhibit', 'NegReg', (50, 57))	('aberrant', 'Var', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('apoptosis', 'CPA', (147, 156))	('RB1 level', 'Gene', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
296431	32622332	Despite the RB1 and TP53INP1, which were selected for investigation in this study, the other candidate targets, which also showed tumor-related regulatory functions, might have had some comparable effects on ESCC.	('TP53INP1', 'Gene', (20, 28))	('ESCC', 'Disease', (208, 212))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('TP53INP1', 'Gene', '94241', (20, 28))	('RB1', 'Var', (12, 15))	('effects', 'Reg', (197, 204))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
296432	32622332	Other related studies also proposed that the miR-20b-5p had the potency to facilitate cell proliferation and invasive processes via targeting BTG3 under the occurrence of NSCLC, which might contribute to the improvement of patient survival as a therapeutic target for NSCLC treatments in the future.	('targeting', 'Reg', (132, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (268, 273))	('BTG3', 'Gene', '10950', (142, 146))	('NSCLC', 'Disease', (268, 273))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('miR-20b-5p', 'Chemical', '-', (45, 55))	('NSCLC', 'Disease', 'MESH:D002289', (268, 273))	('cell proliferation', 'CPA', (86, 104))	('patient', 'Species', '9606', (223, 230))	('improvement', 'PosReg', (208, 219))	('facilitate', 'PosReg', (75, 85))	('BTG3', 'Gene', (142, 146))	('NSCLC', 'Disease', (171, 176))	('miR-20b-5p', 'Var', (45, 55))	('invasive processes', 'CPA', (109, 127))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
296433	32622332	Furthermore, inhibition of human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) could suppress the progression and metastasis of colorectal cancer (CRC) and improve the sensitivity of HCT-116 and HCT-116/5-fluorouracil (5-FU) cancer cells to 5-FU regulation via targeting miR-20b-5p.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('improve', 'PosReg', (174, 181))	('MALAT1', 'Gene', (89, 95))	('CRC', 'Phenotype', 'HP:0003003', (165, 168))	('human', 'Species', '9606', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('MALAT1', 'Gene', '378938', (89, 95))	('sensitivity', 'MPA', (186, 197))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('metastasis of colorectal cancer', 'Disease', 'MESH:D015179', (132, 163))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('CRC', 'Disease', 'MESH:D015179', (165, 168))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('5-FU', 'Chemical', '-', (237, 241))	('suppress', 'NegReg', (103, 111))	('5-FU', 'Chemical', '-', (259, 263))	('HCT-116', 'CellLine', 'CVCL:0291', (201, 208))	('miR-20b-5p', 'Gene', (289, 299))	('cancer', 'Disease', (157, 163))	('metastasis-associated lung adenocarcinoma transcript 1', 'Gene', '378938', (33, 87))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (221, 235))	('inhibition', 'Var', (13, 23))	('cancer', 'Disease', (243, 249))	('metastasis of colorectal cancer', 'Disease', (132, 163))	('HCT-116', 'CellLine', 'CVCL:0291', (213, 220))	('CRC', 'Disease', (165, 168))	('miR-20b-5p', 'Chemical', '-', (289, 299))
296434	32622332	Based on the aforementioned findings, the present study further clarified a new direction for future investigations on ESCC development, which suggested that the interactions between the target mRNAs and miR-20b-5p could become the clues for novel ESCC diagnostic or treatment methods.	('miR-20b-5p', 'Var', (204, 214))	('ESCC', 'Disease', (119, 123))	('interactions', 'Interaction', (162, 174))	('ESCC', 'Disease', (248, 252))	('miR-20b-5p', 'Chemical', '-', (204, 214))
296435	32622332	In summary, for the first time, this study reported valuable evidence that increased miR-20b-5p expressions induced by promoter hypomethylation could modulate ESCC growth and metastasis via targeting RB1 and TP53INP1.	('miR-20b-5p expressions', 'Gene', (85, 107))	('ESCC', 'Disease', (159, 163))	('RB1', 'Gene', (200, 203))	('TP53INP1', 'Gene', '94241', (208, 216))	('miR-20b-5p', 'Chemical', '-', (85, 95))	('TP53INP1', 'Gene', (208, 216))	('modulate', 'Reg', (150, 158))	('targeting', 'Reg', (190, 199))	('increased', 'PosReg', (75, 84))	('promoter hypomethylation', 'Var', (119, 143))
296436	32622332	Moreover, it was suggested that serum miR-20b-5p might be a clinically significant biomarker, which could be considered as an independent predictor for the OS rates of ESCC.	('miR-20b-5p', 'Var', (38, 48))	('ESCC', 'Disease', (168, 172))	('miR-20b-5p', 'Chemical', '-', (38, 48))
296437	32622332	Therefore, the findings in this study indicated that miR-20b-5p is a significant tumorigenic factor in ESCC, which is also a potential prognostic indicator and therapeutic target for ESCC treatments.	('miR-20b-5p', 'Chemical', '-', (53, 63))	('miR-20b-5p', 'Var', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ESCC', 'Disease', (103, 107))	('tumor', 'Disease', (81, 86))
296443	32622332	In the present study, the seven cell lines of human ESCC, namely TE1, EC109, KYSE30, KYSE150, KYSE180, KYSE450, and KYSE510, were offered by Cell Culture Center, Peking Union Medical College (Beijing, China) and Typical Culture Cell Bank, Chinese Academy of Sciences (Shanghai, China).	('KYSE180', 'Var', (94, 101))	('KYSE30', 'Var', (77, 83))	('KYSE510', 'Var', (116, 123))	('EC109', 'CellLine', 'CVCL:6898', (70, 75))	('KYSE450', 'Var', (103, 110))	('human', 'Species', '9606', (46, 51))	('KYSE150', 'Var', (85, 92))	('KYSE180', 'CellLine', 'CVCL:1349', (94, 101))
296482	32622332	The primary antibodies included anti-RB1, anti-TP53INP1, and anti-GAPDH (ab181616, ab202026, and ab8245; Abcam, Cambridge, UK); subsequently, the membranes were treated with goat anti-mouse immunoglobulin G (IgG) (1:2,000) or goat anti-rabbit IgG (1:3,000) secondary antibodies.	('TP53INP1', 'Gene', (47, 55))	('mouse', 'Species', '10090', (184, 189))	('anti-RB1', 'Var', (32, 40))	('TP53INP1', 'Gene', '94241', (47, 55))
296509	32622332	The Wilcoxon test was also used in order to compare the miR-20b-5p expressions between the ESCC tissue samples and the control esophageal tissue samples.	('miR-20b-5p', 'Chemical', '-', (56, 66))	('ESCC', 'Disease', (91, 95))	('miR-20b-5p', 'Var', (56, 66))
296571	30944675	Inherited mutations of certain genes, such as the GSTM1-null phenotype or CDH1 gene, have been found to increase the risk of stomach cancer.	('increase', 'PosReg', (104, 112))	('increase the risk of stomach cancer', 'Phenotype', 'HP:0006753', (104, 139))	('stomach cancer', 'Disease', 'MESH:D013274', (125, 139))	('stomach cancer', 'Phenotype', 'HP:0012126', (125, 139))	('stomach cancer', 'Disease', (125, 139))	('CDH1', 'Gene', (74, 78))	('GSTM1-null', 'Gene', (50, 60))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
296573	30944675	HDGC and loss of CDH1 are also associated with lobular breast cancer, prostate cancer, and colorectal cancer.	('HDGC', 'Disease', 'MESH:D013274', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('colorectal cancer', 'Disease', (91, 108))	('lobular breast cancer', 'Disease', (47, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('HDGC', 'Disease', (0, 4))	('lobular breast cancer', 'Disease', 'MESH:D013274', (47, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('associated', 'Reg', (31, 41))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (47, 68))	('loss', 'Var', (9, 13))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('CDH1', 'Gene', (17, 21))	('prostate cancer', 'Disease', (70, 85))
296574	30944675	IL-17 and IL-10, polymorphisms of the interleukin genes especially common in Asian populations, are also associated with an elevated risk of the neoplasm.	('polymorphisms', 'Var', (17, 30))	('neoplasm', 'Disease', (145, 153))	('interleukin', 'Gene', (38, 49))	('neoplasm', 'Phenotype', 'HP:0002664', (145, 153))	('IL-10', 'Gene', (10, 15))	('neoplasm', 'Disease', 'MESH:D009369', (145, 153))	('associated with', 'Reg', (105, 120))	('IL-17', 'Gene', (0, 5))
296578	30944675	Point mutations in the APC promoter appear to be drivers of the disorder.	('APC', 'Disease', (23, 26))	('Point mutations', 'Var', (0, 15))	('APC', 'Disease', 'MESH:D011125', (23, 26))
296579	30944675	Likewise, familial adenomatous polyposis (FAP), the most common form of familial intestinal gastric cancer, is an autosomal-dominant inherited predisposition to adenomatous polyps caused by germline mutations in the APC gene.	('caused by', 'Reg', (180, 189))	('FAP', 'Disease', (42, 45))	('germline mutations', 'Var', (190, 208))	('familial intestinal gastric cancer', 'Disease', (72, 106))	('familial adenomatous polyposis', 'Disease', (10, 40))	('familial intestinal gastric cancer', 'Disease', 'MESH:D013274', (72, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (19, 40))	('adenomatous polyps', 'Disease', (161, 179))	('APC', 'Disease', 'MESH:D011125', (216, 219))	('APC', 'Disease', (216, 219))	('FAP', 'Disease', 'MESH:C567782', (42, 45))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (10, 40))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (161, 179))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('adenomatous polyps', 'Disease', 'MESH:D018256', (161, 179))
296598	30944675	As it reduces the risk of esophageal inflammation, H. pylori has also been shown to protect against cardia gastric cancer.	('reduces', 'NegReg', (6, 13))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (26, 49))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('esophageal inflammation', 'Disease', 'MESH:D007249', (26, 49))	('cardia gastric cancer', 'Disease', (100, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal inflammation', 'Disease', (26, 49))	('H. pylori', 'Species', '210', (51, 60))	('cardia gastric cancer', 'Disease', 'MESH:D013274', (100, 121))	('H. pylori', 'Var', (51, 60))
296603	30944675	The risk of gastric cancer increases in a dose- and duration-dependent manner with the use of PPIs.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PPIs', 'Var', (94, 98))	('gastric cancer', 'Disease', (12, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (12, 26))	('gastric cancer', 'Phenotype', 'HP:0012126', (12, 26))
296607	30944675	Helicobacter pylori eradication in gastric ulcer patients may reduce the risk of developing gastric cancer.	('Helicobacter pylori', 'Protein', (0, 19))	('Helicobacter pylori', 'Species', '210', (0, 19))	('gastric ulcer', 'Disease', (35, 48))	('gastric cancer', 'Disease', (92, 106))	('eradication', 'Var', (20, 31))	('gastric ulcer', 'Disease', 'MESH:D013276', (35, 48))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('reduce', 'NegReg', (62, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('gastric ulcer', 'Phenotype', 'HP:0002592', (35, 48))	('patients', 'Species', '9606', (49, 57))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))
296619	30944675	Based on a meta-analysis of 10 studies, moderate alcohol consumption was shown to increase gastric cancer risk by 39%, while heavy consumption further worsened the odds.	('gastric cancer', 'Disease', (91, 105))	('moderate alcohol consumption', 'Var', (40, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (91, 105))	('increase', 'PosReg', (82, 90))	('increase gastric cancer', 'Phenotype', 'HP:0006753', (82, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('increase gastric', 'Phenotype', 'HP:0005207', (82, 98))
296628	30944675	Ingestion of salt has been shown to increase gastritis and the carcinogenic effects of known gastric carcinogens such as N-methyl-N-nitro-N-nitrosoguanidine (MNNG).	('MNNG', 'Chemical', 'MESH:D008769', (158, 162))	('N-methyl-N-nitro-N-nitrosoguanidine', 'Chemical', 'MESH:D008769', (121, 156))	('increase', 'PosReg', (36, 44))	('N-methyl-N-nitro-N-nitrosoguanidine', 'Var', (121, 156))	('gastritis', 'Phenotype', 'HP:0005263', (45, 54))	('gastritis and the carcinogenic', 'Disease', 'MESH:D005756', (45, 75))	('salt', 'Chemical', 'MESH:D012492', (13, 17))	('gastric carcinogens', 'Disease', 'MESH:D013274', (93, 112))	('gastric carcinogens', 'Disease', (93, 112))
296632	30944675	Preserved meats are rich in N-nitroso compounds, which can elicit a similar effect in the body.	('elicit', 'Reg', (59, 65))	('N-nitroso', 'Var', (28, 37))	('N-nitroso compounds', 'Chemical', '-', (28, 47))
296659	30944675	An increased risk of gastric cancer was associated with low SES.	('gastric cancer', 'Phenotype', 'HP:0012126', (21, 35))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (3, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('gastric cancer', 'Disease', (21, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (21, 35))	('low SES', 'Var', (56, 63))
296661	30944675	Higher education was closely associated with a reduced risk of gastric cancer, and this effect was more pronounced for cancer of the cardia when compared to non-cardia gastric cancer.	('cancer of the cardia', 'Disease', (119, 139))	('gastric cancer', 'Disease', (63, 77))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (157, 182))	('cancer of the cardia', 'Disease', 'MESH:D004938', (119, 139))	('Higher education', 'Var', (0, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('cancer of the cardia', 'Phenotype', 'HP:0100544', (119, 139))	('reduced risk of gastric cancer', 'Phenotype', 'HP:0006753', (47, 77))	('non-cardia gastric cancer', 'Disease', (157, 182))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('reduced', 'NegReg', (47, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
296664	30944675	Numerous studies have shown that blood group A is associated with a higher risk of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('gastric cancer', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('associated', 'Reg', (50, 60))	('higher risk of gastric cancer', 'Phenotype', 'HP:0006753', (68, 97))	('blood group A', 'Var', (33, 46))
296666	30944675	A large prospective population-based study in Scandinavia confirmed that blood type A is associated with a higher risk of gastric cancer and that blood group O is associated with a higher risk of peptic ulcers.	('blood type A', 'Var', (73, 85))	('peptic ulcers', 'Disease', (196, 209))	('blood group O', 'Var', (146, 159))	('peptic ulcers', 'Phenotype', 'HP:0004398', (196, 209))	('gastric cancer', 'Disease', (122, 136))	('higher risk of gastric cancer', 'Phenotype', 'HP:0006753', (107, 136))	('associated', 'Reg', (163, 173))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('peptic ulcers', 'Disease', 'MESH:D010437', (196, 209))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('peptic ulcer', 'Phenotype', 'HP:0004398', (196, 208))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
296705	30944675	However, NSAIDs also increase the risk of internal bleeding.	('internal bleeding', 'Disease', (42, 59))	('internal bleeding', 'Phenotype', 'HP:0011029', (42, 59))	('internal bleeding', 'Disease', 'MESH:D006470', (42, 59))	('NSAIDs', 'Var', (9, 15))
296707	30944675	Those with a family history of stomach cancer, or who have personally had invasive lobular breast cancer before age 50, are recommended to undergo genetic testing for abnormal changes in the CDH1 gene, which greatly increase the risk of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('increase the risk of gastric cancer', 'Phenotype', 'HP:0006753', (216, 251))	('gastric cancer', 'Phenotype', 'HP:0012126', (237, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('stomach cancer', 'Disease', (31, 45))	('increase', 'Reg', (216, 224))	('stomach cancer', 'Phenotype', 'HP:0012126', (31, 45))	('invasive lobular breast cancer', 'Disease', (74, 104))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (83, 104))	('CDH1', 'Gene', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('men', 'Species', '9606', (129, 132))	('invasive lobular breast cancer', 'Disease', 'MESH:D013274', (74, 104))	('gastric cancer', 'Disease', (237, 251))	('stomach cancer', 'Disease', 'MESH:D013274', (31, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (237, 251))	('abnormal changes', 'Var', (167, 183))
296712	30944675	While H. pylori infection is the most established risk factor, eradicating the bacterium may actually increase the risk of a subtype of the disease.	('H. pylori', 'Species', '210', (6, 15))	('eradicating', 'Var', (63, 74))	('H. pylori', 'Disease', (6, 15))	('H. pylori infection', 'Phenotype', 'HP:0005202', (6, 25))	('increase', 'PosReg', (102, 110))	('infection', 'Disease', (16, 25))	('infection', 'Disease', 'MESH:D007239', (16, 25))
296719	30559831	After randomizing 74 patients, the overall TP53 mutation rate was 79%.	('TP53', 'Gene', '7157', (43, 47))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', (43, 47))	('mutation', 'Var', (48, 56))
296722	30559831	Mark53 analysis clearly detected more mutations in the TP53 gene as compared to the cancer-specific p53 literature.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('p53', 'Gene', '7157', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (38, 47))	('p53', 'Gene', (100, 103))
296742	30559831	Based on an assumed TP53 mutation frequency of 60%, randomization of 84 patients was originally planned.	('mutation', 'Var', (25, 33))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (20, 24))	('patients', 'Species', '9606', (72, 80))
296750	30559831	After having randomized 74 patients, a mutated mark53 status was revealed to be present in 79% of the patients.	('mutated', 'Var', (39, 46))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (102, 110))	('mark53', 'Gene', (47, 53))
296754	30559831	This corresponds to a final TP53 mutation rate of 77.9%, with a 95% confidence interval of 71.3 to 83.3%.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))
296756	30559831	Variations between pre- and post-chemotherapy measurements were described as increased, decreased, or stable tumor length.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('Variations', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('decreased', 'NegReg', (88, 97))	('tumor', 'Disease', (109, 114))
296773	30559831	At the time of initiation of the   Pancho trial in 2007, the most important p53 databases reported a 40% prevalence for TP53 mutations in esophageal cancer (IARC TP53 Mutation Database, R12 release, Nov 07, http://www-p53.iarc.fr; UMD_TP53 Mutation Database, 2006, http://p53.free.fr).	('mutations', 'Var', (125, 134))	('TP53', 'Gene', '7157', (120, 124))	('esophageal cancer', 'Disease', (138, 155))	('p53', 'Gene', (272, 275))	('p53', 'Gene', '7157', (272, 275))	('p53', 'Gene', (76, 79))	('TP53', 'Gene', '7157', (162, 166))	('p53', 'Gene', '7157', (76, 79))	('TP53', 'Gene', (162, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('TP53', 'Gene', '7157', (235, 239))	('p53', 'Gene', (218, 221))	('IARC', 'Disease', 'None', (157, 161))	('p53', 'Gene', '7157', (218, 221))	('TP53', 'Gene', (235, 239))	('IARC', 'Disease', (157, 161))	('TP53', 'Gene', (120, 124))
296774	30559831	In 2007, we reported a 66% TP53 mutation rate in a phase II pilot study including 47 operable esophageal cancer patients analyzed with an early version of the mark53 test.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('esophageal cancer', 'Disease', (94, 111))	('patients', 'Species', '9606', (112, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutation', 'Var', (32, 40))
296776	30559831	The mark53 test was developed by the Medical University of Vienna p53research group to allow a virtually complete detection of genetic deviations of the TP53 gene.	('p53', 'Gene', '7157', (66, 69))	('genetic deviations', 'Var', (127, 145))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', (153, 157))	('p53', 'Gene', (66, 69))
296780	30559831	These findings suggest that TP53 mutations might be underreported in the literature.	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
296781	30559831	If TP53 mutations are in fact underreported, this may obstruct future evaluations analyzing whether the marker is of prognostic or rather predictive nature.	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('mutations', 'Var', (8, 17))	('obstruct', 'Reg', (54, 62))
296790	29659940	Although the mean pericardial dose and V40 Gy in the FFT group were smaller than those in the TFT group, the incidences of pericardial effusion after CCRT were similar in both groups.	('smaller', 'NegReg', (68, 75))	('pericardial dose', 'MPA', (18, 34))	('V40 Gy', 'Var', (39, 45))	('pericardial effusion', 'Disease', 'MESH:D010490', (123, 143))	('FFT', 'Chemical', '-', (53, 56))	('pericardial effusion', 'Phenotype', 'HP:0001698', (123, 143))	('pericardial effusion', 'Disease', (123, 143))
296791	29659940	As symptomatic pericardial effusion was not observed in patients with a pericardial V40 Gy of <40% or in the FFT group, it appears that FFT with a V40 Gy of <40% could help minimize symptomatic pericardial effusion.	('patients', 'Species', '9606', (56, 64))	('pericardial effusion', 'Disease', 'MESH:D010490', (15, 35))	('pericardial effusion', 'Disease', 'MESH:D010490', (194, 214))	('V40', 'Var', (147, 150))	('pericardial effusion', 'Phenotype', 'HP:0001698', (15, 35))	('pericardial effusion', 'Phenotype', 'HP:0001698', (194, 214))	('FFT', 'Chemical', '-', (109, 112))	('pericardial effusion', 'Disease', (15, 35))	('pericardial effusion', 'Disease', (194, 214))	('FFT', 'Chemical', '-', (136, 139))
296802	29659940	Therefore, this retrospective study evaluated dose-volume histogram (DVH) data for the pericardium to determine whether FFT decreased the incidence of pericardial effusion, compared with TFT, among patients who received definitive CCRT for thoracic esophageal cancer.	('patients', 'Species', '9606', (198, 206))	('FFT', 'Var', (120, 123))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (240, 266))	('decreased', 'NegReg', (124, 133))	('pericardial effusion', 'Disease', 'MESH:D010490', (151, 171))	('FFT', 'Chemical', '-', (120, 123))	('thoracic esophageal cancer', 'Disease', (240, 266))	('pericardial effusion', 'Phenotype', 'HP:0001698', (151, 171))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('pericardial effusion', 'Disease', (151, 171))
296824	29659940	Some differences were found between the FFT and TFT groups, with early-stage cancer being more frequent in the FFT group, and the initial field length tending to be longer in the TFT group.	('FFT', 'Chemical', '-', (111, 114))	('FFT', 'Chemical', '-', (40, 43))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('longer', 'PosReg', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('FFT', 'Var', (111, 114))
296838	29659940	The pericardial V40 Gy and mean dose in the FFT group were significantly smaller than those in the TFT group (P < 0.0001 and P = 0.0259, respectively).	('FFT', 'Var', (44, 47))	('FFT', 'Chemical', '-', (44, 47))	('pericardial V40 Gy', 'CPA', (4, 22))	('smaller', 'NegReg', (73, 80))
296839	29659940	Grade 3 pericardial effusion was observed in the TFT group (7%, 3/43), but was not observed in the FFT group (0/51; P = 0.0921, Fisher's exact test).	('pericardial effusion', 'Phenotype', 'HP:0001698', (8, 28))	('TFT', 'Var', (49, 52))	('pericardial effusion', 'Disease', (8, 28))	('FFT', 'Chemical', '-', (99, 102))	('pericardial effusion', 'Disease', 'MESH:D010490', (8, 28))
296841	29659940	The median time from the beginning of CCRT to pericardial drainage in the patients with Grade 3 pericardial effusion was 23 months (22 months, 23 months and 25 months), and the V40 Gy values in these patients were 40.3%, 47.6% and 78.8%, respectively.	('pericardial effusion', 'Disease', (96, 116))	('patients', 'Species', '9606', (200, 208))	('V40 Gy', 'Var', (177, 183))	('patients', 'Species', '9606', (74, 82))	('pericardial effusion', 'Disease', 'MESH:D010490', (96, 116))	('pericardial effusion', 'Phenotype', 'HP:0001698', (96, 116))
296846	29659940	Significant differences were observed in all dosimetric parameters between patients with and without pericardial effusion, although only V40 Gy was significantly associated with Grade 3 effusion.	('pericardial effusion', 'Phenotype', 'HP:0001698', (101, 121))	('pericardial effusion', 'Disease', (101, 121))	('patients', 'Species', '9606', (75, 83))	('associated', 'Reg', (162, 172))	('V40 Gy', 'Var', (137, 143))	('pericardial effusion', 'Disease', 'MESH:D010490', (101, 121))
296848	29659940	In the multivariate analysis, only V20 Gy was a significant risk factor for Grade 2-3 pericardial effusion (P = 0.001) (Table 5).	('pericardial effusion', 'Phenotype', 'HP:0001698', (86, 106))	('pericardial effusion', 'Disease', 'MESH:D010490', (86, 106))	('pericardial effusion', 'Disease', (86, 106))	('V20 Gy', 'Var', (35, 41))
296852	29659940	No previous data are available for comparing dose volumes between FFT and TFT for esophageal cancer, although FFT is a simple irradiation technique that is thought to decrease the heart volume that receives high doses.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('FFT', 'Chemical', '-', (66, 69))	('heart volume that receives high doses', 'MPA', (180, 217))	('decrease', 'NegReg', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('FFT', 'Var', (110, 113))	('esophageal cancer', 'Disease', (82, 99))	('FFT', 'Chemical', '-', (110, 113))
296853	29659940	When we compared FFT and TFT, we found that the V40 Gy and mean dose values in the FFT group were significantly smaller than those in the TFT group.	('smaller', 'NegReg', (112, 119))	('FFT', 'Disease', (83, 86))	('FFT', 'Chemical', '-', (17, 20))	('V40 Gy', 'Var', (48, 54))	('FFT', 'Chemical', '-', (83, 86))
296855	29659940	However, FFT did not decrease the incidence of all-grade pericardial effusion, compared with TFT, although TFT was a significant risk factor for symptomatic pericardial effusion (i.e.	('pericardial effusion', 'Disease', 'MESH:D010490', (57, 77))	('FFT', 'Chemical', '-', (9, 12))	('pericardial effusion', 'Disease', 'MESH:D010490', (157, 177))	('TFT', 'Var', (107, 110))	('pericardial effusion', 'Phenotype', 'HP:0001698', (57, 77))	('pericardial effusion', 'Disease', (57, 77))	('pericardial effusion', 'Phenotype', 'HP:0001698', (157, 177))	('pericardial effusion', 'Disease', (157, 177))	('symptomatic', 'Disease', (145, 156))
296865	29659940	reported that the most significant predictors of pericardial effusion after chemotherapy and radiotherapy were V5 Gy to V60 Gy of the heart.	('pericardial effusion', 'Disease', 'MESH:D010490', (49, 69))	('pericardial effusion', 'Disease', (49, 69))	('V5 Gy', 'Var', (111, 116))	('pericardial effusion', 'Phenotype', 'HP:0001698', (49, 69))
296866	29659940	have reported that V30 Gy of the pericardium/heart was the only independent risk factor for pericardial effusion after chemoradiotherapy.	('pericardial effusion', 'Phenotype', 'HP:0001698', (92, 112))	('V30 Gy', 'Var', (19, 25))	('pericardial effusion', 'Disease', 'MESH:D010490', (92, 112))	('pericardial effusion', 'Disease', (92, 112))
296869	29659940	In the present study, V20 Gy was a significant risk factor for pericardial effusion in the univariate and multivariate analyses, which suggests that a relatively low dose (e.g.	('pericardial effusion', 'Disease', 'MESH:D010490', (63, 83))	('pericardial effusion', 'Disease', (63, 83))	('V20 Gy', 'Var', (22, 28))	('pericardial effusion', 'Phenotype', 'HP:0001698', (63, 83))
296870	29659940	V20 Gy) can be related to all-grade pericardial effusion.	('related', 'Reg', (15, 22))	('pericardial effusion', 'Phenotype', 'HP:0001698', (36, 56))	('pericardial effusion', 'Disease', (36, 56))	('V20 Gy', 'Var', (0, 6))	('pericardial effusion', 'Disease', 'MESH:D010490', (36, 56))
296876	29659940	Moreover, the V40 Gy value in the FFT group was significantly smaller than that in the TFT group, and V40 Gy was significantly associated with symptomatic pericardial effusion.	('associated', 'Reg', (127, 137))	('V40 Gy value', 'MPA', (14, 26))	('smaller', 'NegReg', (62, 69))	('pericardial effusion', 'Disease', (155, 175))	('V40 Gy', 'Var', (102, 108))	('pericardial effusion', 'Disease', 'MESH:D010490', (155, 175))	('FFT', 'Chemical', '-', (34, 37))	('pericardial effusion', 'Phenotype', 'HP:0001698', (155, 175))
296877	29659940	Therefore, FFT appears to have provided a small V40 Gy and may be useful for minimizing the risk of symptomatic pericardial effusion.	('pericardial effusion', 'Disease', 'MESH:D010490', (112, 132))	('pericardial effusion', 'Phenotype', 'HP:0001698', (112, 132))	('V40', 'Var', (48, 51))	('pericardial effusion', 'Disease', (112, 132))	('FFT', 'Chemical', '-', (11, 14))
296888	29659940	To the best of our knowledge, this is the first report to indicate that, compared with TFT, FFT decreased the pericardial mean dose and V40 Gy values.	('FFT', 'Var', (92, 95))	('decreased', 'NegReg', (96, 105))	('FFT', 'Chemical', '-', (92, 95))	('V40 Gy values', 'MPA', (136, 149))	('pericardial mean dose', 'MPA', (110, 131))
296893	28588723	The expression of miR-655 was upregulated in ESCC cells through the transfection of miR-655 mimics, and the influence of miR-655 on proliferation and invasion ability of ESCC cells was observed.	('transfection', 'Var', (68, 80))	('miR-655', 'Gene', '724025', (18, 25))	('upregulated', 'PosReg', (30, 41))	('miR-655', 'Gene', '724025', (121, 128))	('expression', 'MPA', (4, 14))	('miR-655', 'Gene', '724025', (84, 91))	('ESCC', 'Disease', (45, 49))	('miR-655', 'Gene', (18, 25))	('miR-655', 'Gene', (121, 128))	('miR-655', 'Gene', (84, 91))
296898	28588723	In conclusion, the high-expression of miR-655 can inhibit the proliferation and invasion of ESCC, and plays a negative regulation role in the prognosis process of tumor patients.	('miR-655', 'Gene', '724025', (38, 45))	('invasion', 'CPA', (80, 88))	('patients', 'Species', '9606', (169, 177))	('ESCC', 'Disease', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('high-expression', 'Var', (19, 34))	('proliferation', 'CPA', (62, 75))	('inhibit', 'NegReg', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('miR-655', 'Gene', (38, 45))	('negative', 'NegReg', (110, 118))	('tumor', 'Disease', (163, 168))
296899	28588723	The targeted regulation of miR-655 can be used as a new treatment method of ESCC.	('miR-655', 'Gene', (27, 34))	('targeted regulation', 'Var', (4, 23))	('ESCC', 'Disease', (76, 80))	('miR-655', 'Gene', '724025', (27, 34))
296922	28588723	Results showed that compared with normal cells, the expression of miR-655 was low in 2 ESCC cell lines, and the relative expression of miR-655 was 0.21+-0.04 (KYSE410) and 0.357+-0.02 (EC9706) (Fig.	('miR-655', 'Gene', '724025', (66, 73))	('EC9706', 'Var', (185, 191))	('low', 'NegReg', (78, 81))	('expression', 'MPA', (52, 62))	('miR-655', 'Gene', (66, 73))	('EC9706', 'CellLine', 'CVCL:E307', (185, 191))	('miR-655', 'Gene', '724025', (135, 142))	('0.357+-0.02 (EC9706', 'Var', (172, 191))	('miR-655', 'Gene', (135, 142))	('KYSE410', 'Var', (159, 166))
296924	28588723	The influence of miR-655 mimics on miR-655 expression in ESCC cells was detected using RT-qPCR, and the results showed that miR-655 mimics increased the expression of miR-655 in KYSE410 cells 11.88-fold and in EC9706 cells 9.05-fold (Fig.	('miR-655', 'Gene', (167, 174))	('miR-655', 'Gene', '724025', (124, 131))	('miR-655', 'Gene', '724025', (35, 42))	('miR-655', 'Gene', (17, 24))	('increased', 'PosReg', (139, 148))	('miR-655', 'Gene', (35, 42))	('EC9706', 'CellLine', 'CVCL:E307', (210, 216))	('miR-655', 'Gene', (124, 131))	('expression', 'MPA', (153, 163))	('mimics', 'Var', (132, 138))	('miR-655', 'Gene', '724025', (167, 174))	('miR-655', 'Gene', '724025', (17, 24))
296926	28588723	Results showed that after the transfection of miR-655 mimics, the proliferation of KYSE410 and EC9706 was inhibited 47.33 and 54.92%, respectively, and the differences had statistical significance (P<0.01; Table II).	('EC9706', 'CellLine', 'CVCL:E307', (95, 101))	('proliferation', 'CPA', (66, 79))	('inhibited', 'NegReg', (106, 115))	('miR-655', 'Gene', '724025', (46, 53))	('EC9706', 'Var', (95, 101))	('miR-655', 'Gene', (46, 53))
296927	28588723	The influence of miR-655 on ESCC cell invasion was detected through Transwell cell invasion assay, and the results showed that after KYSE410 was transfected with miR-655 mimics, the number of cells crossing it was 215+-7 cells/HP in NC group and 66+-5 cells/HP in miR-655 transfection group, and the differences had statistical significance (P<0.01); after EC9706 was transfected with miR-655 mimics, the number of cells crossing it was 191+-6 cells/HP in NC group and only 72+-7 cells/HP in miR-655 transfection group, and the differences had statistical significance (P<0.01).	('miR-655', 'Gene', '724025', (492, 499))	('miR-655', 'Gene', '724025', (264, 271))	('EC9706', 'CellLine', 'CVCL:E307', (357, 363))	('miR-655', 'Gene', '724025', (162, 169))	('miR-655', 'Gene', (17, 24))	('miR-655', 'Gene', (385, 392))	('KYSE410', 'Var', (133, 140))	('miR-655', 'Gene', (492, 499))	('miR-655', 'Gene', (264, 271))	('miR-655', 'Gene', (162, 169))	('EC9706', 'Var', (357, 363))	('miR-655', 'Gene', '724025', (17, 24))	('miR-655', 'Gene', '724025', (385, 392))
296941	28588723	In order to study the influence of miR-655 on ESCC cells, an experimental study was further performed and the expression of miR-655 in cells was increased through the transfection.	('miR-655', 'Gene', '724025', (124, 131))	('miR-655', 'Gene', '724025', (35, 42))	('transfection', 'Var', (167, 179))	('increased', 'PosReg', (145, 154))	('miR-655', 'Gene', (35, 42))	('expression', 'MPA', (110, 120))	('miR-655', 'Gene', (124, 131))
296944	28588723	In addition, the clinical data showed that the median survival time of patients with high-expression of miR-655 was longer than those with low-expression of miR-655.	('longer', 'PosReg', (116, 122))	('miR-655', 'Gene', '724025', (104, 111))	('miR-655', 'Gene', (157, 164))	('patients', 'Species', '9606', (71, 79))	('high-expression', 'Var', (85, 100))	('miR-655', 'Gene', (104, 111))	('miR-655', 'Gene', '724025', (157, 164))
296994	27956436	Incidence rates for squamous cell carcinoma are also higher among AI/AN and API compared to white men (2.0 and 2.3 vs. 0.3, respectively).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('higher', 'PosReg', (53, 59))	('squamous cell carcinoma', 'Disease', (20, 43))	('AI/AN', 'Var', (66, 71))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('men', 'Species', '9606', (98, 101))
297023	27956436	AI/AN men had a higher rate of malignant neoplasms and unspecified carcinoma and a lower rate of adenocarcinoma compared to white men.	('neoplasm', 'Phenotype', 'HP:0002664', (41, 49))	('AI/AN', 'Var', (0, 5))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('neoplasms', 'Phenotype', 'HP:0002664', (41, 50))	('carcinoma', 'Disease', 'MESH:D002277', (67, 76))	('unspecified', 'Species', '32644', (55, 66))	('carcinoma', 'Disease', 'MESH:D002277', (102, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('malignant neoplasms', 'Disease', (31, 50))	('malignant neoplasms', 'Disease', 'MESH:D009369', (31, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinoma', 'Disease', (97, 111))	('carcinoma', 'Disease', (67, 76))	('men', 'Species', '9606', (130, 133))	('carcinoma', 'Disease', (102, 111))	('men', 'Species', '9606', (6, 9))
297028	27956436	AI/AN and API women had lower rates for all subtypes compared to white women with the only exception of a higher rate of squamous cell carcinoma among AI/AN compared to white women.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('AI/AN', 'Var', (151, 156))	('women', 'Species', '9606', (71, 76))	('lower', 'NegReg', (24, 29))	('women', 'Species', '9606', (175, 180))	('women', 'Species', '9606', (14, 19))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
297055	27956436	However, changes in tobacco blends and inhalation depth may be resulting in increasing peripheral adenocarcinomas of the lung.	('changes', 'Var', (9, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('adenocarcinomas of the lung', 'Disease', 'MESH:D000077192', (98, 125))	('tobacco', 'Species', '4097', (20, 27))	('increasing', 'PosReg', (76, 86))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (103, 125))	('adenocarcinomas of the lung', 'Disease', (98, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
297125	24860783	A large majority of the patients presented a locally advanced tumor T3N0-1 (n = 41) or T4 N0-1 (n = 5).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('T4 N0-1', 'Var', (87, 94))	('patients', 'Species', '9606', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
297183	24359800	The heart volumes decreased by 19.85%, while total lung volume increased by 52.54% in mDIBH, compared to FB (p < 0.05).	('mDIBH', 'Var', (86, 91))	('increased', 'PosReg', (63, 72))	('heart volumes', 'MPA', (4, 17))	('decreased', 'NegReg', (18, 27))	('mDIBH', 'Chemical', '-', (86, 91))
297184	24359800	The mean conformality index values and homogeneity index values for VMAT-DIBH (0.86, 1.07) were slightly worse than those for IMRT-FB (0.90, 1.05) and VMAT-FB (0.90, 1.06) (p > 0.05).	('homogeneity', 'MPA', (39, 50))	('VMAT-FB', 'Disease', (151, 158))	('VMAT-FB', 'Disease', 'None', (151, 158))	('VMAT-DIBH', 'Var', (68, 77))	('conformality', 'MPA', (9, 21))	('worse', 'NegReg', (105, 110))	('DIBH', 'Chemical', '-', (73, 77))
297219	24359800	The CI and HI values for VMAT-DIBH were slightly worse than those for IMRT-FB and VMAT-FB, and these differences were not statistically significant (p > 0.05).	('worse', 'NegReg', (49, 54))	('VMAT-DIBH', 'Var', (25, 34))	('DIBH', 'Chemical', '-', (30, 34))	('VMAT-FB', 'Disease', 'None', (82, 89))	('VMAT-FB', 'Disease', (82, 89))
297221	24359800	The VMAT-DIBH plan significantly reduced the mean dose and the V5 to V40 values for total lung compared with the IMRT-FB and VMAT-FB plans (except for V5, as shown in Table 2) (p < 0.05).	('DIBH', 'Chemical', '-', (9, 13))	('VMAT-DIBH', 'Var', (4, 13))	('VMAT-FB plans', 'Disease', (125, 138))	('reduced', 'NegReg', (33, 40))	('VMAT-FB plans', 'Disease', 'None', (125, 138))	('mean dose', 'MPA', (45, 54))	('V5 to V40 values', 'MPA', (63, 79))
297227	24359800	The estimated treatment time (from first filed beam-on to the last filed beam-off) for VMAT-DIBH (124 +- 0 s) was also shorter than that for VMAT-FB (170 +- 0 s), and was also significantly shorter than the measured treatment time for IMRT-FB (367.64 +- 33.90 s) (p < 0.05).	('shorter', 'NegReg', (119, 126))	('VMAT-FB', 'Disease', 'None', (141, 148))	('DIBH', 'Chemical', '-', (92, 96))	('VMAT-FB', 'Disease', (141, 148))	('VMAT-DIBH', 'Var', (87, 96))	('shorter', 'NegReg', (190, 197))
297230	24359800	While V20, V30, and the mean lung dose have been considered classic predictors of treatment-related pneumonitis, the predictive value of V5, V10, and V13 have also been considered.	('V30', 'Var', (11, 14))	('V13', 'Gene', '28816', (150, 153))	('pneumonitis', 'Disease', 'MESH:D011014', (100, 111))	('V13', 'Gene', (150, 153))	('V20', 'Var', (6, 9))	('pneumonitis', 'Disease', (100, 111))
297247	24359800	(2) DIBH can increase lung volume, thereby sparing normal lung tissue during treatment.	('sparing', 'NegReg', (43, 50))	('lung', 'MPA', (22, 26))	('increase', 'PosReg', (13, 21))	('DIBH', 'Chemical', '-', (4, 8))	('DIBH', 'Var', (4, 8))
297253	24359800	Heart volume with mDIBH was also significantly smaller than with FB, while the dose-volume indices for VMAT-DIBH were lower than those of IMRT-FB and VMAT-FB.	('mDIBH', 'Var', (18, 23))	('smaller', 'NegReg', (47, 54))	('DIBH', 'Chemical', '-', (19, 23))	('Heart volume', 'MPA', (0, 12))	('mDIBH', 'Chemical', '-', (18, 23))	('lower', 'NegReg', (118, 123))	('VMAT-FB', 'Disease', (150, 157))	('DIBH', 'Chemical', '-', (108, 112))	('VMAT-FB', 'Disease', 'None', (150, 157))
297282	24143324	Immunohistochemical studies demonstrated positivity for neuron-specific enolase, synaptophysin and chromogranin as supporting evidence of an esophageal carcinoid tumor (Fig.	('neuron-specific enolase', 'Gene', '2026', (56, 79))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('positivity', 'Var', (41, 51))	('esophageal carcinoid tumor', 'Disease', 'MESH:D002276', (141, 167))	('synaptophysin', 'Gene', (81, 94))	('neuron-specific enolase', 'Gene', (56, 79))	('carcinoid', 'Phenotype', 'HP:0100570', (152, 161))	('esophageal carcinoid', 'Phenotype', 'HP:0011459', (141, 161))	('esophageal carcinoid tumor', 'Disease', (141, 167))	('synaptophysin', 'Gene', '6855', (81, 94))
297305	20658532	In addition, reintroduction of SSBP2 in an ESCC cell line (TE1) that does not express SSBP2 and in the MSE-Het-1A cells inhibited expression of LRP6 and Dvl3, which are mediators of the Wnt signaling pathway.	('expression', 'MPA', (130, 140))	('Wnt', 'Gene', (186, 189))	('LRP6', 'Gene', '4040', (144, 148))	('Dvl3', 'Gene', (153, 157))	('MSE-Het-1A', 'Gene', (103, 113))	('Wnt', 'Gene', '7471;7472;89780;7474;7477;7480', (186, 189))	('LRP6', 'Gene', (144, 148))	('MSE-Het-1A', 'Gene', '101180900', (103, 113))	('inhibited', 'NegReg', (120, 129))	('ESCC', 'Phenotype', 'HP:0011459', (43, 47))	('SSBP2', 'Var', (31, 36))	('Dvl3', 'Gene', '1857', (153, 157))
297312	20658532	The progressive transformation of a normal cell to a malignant cell is accompanied by a series of genetic/epigenetic changes, which include inactivation of tumor suppressor genes (TSGs) and activation of oncogenes.	('inactivation', 'Var', (140, 152))	('activation', 'PosReg', (190, 200))	('oncogenes', 'CPA', (204, 213))	('TSG', 'Gene', (180, 183))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('TSG', 'Gene', '57045', (180, 183))	('tumor', 'Disease', (156, 161))
297313	20658532	One of major epigenetic events involved in functional inactivation of TSG in the process of malignant transformation is loss of gene expression by aberrant DNA methylation, which has appeared as an emerging molecular marker in human cancer.	('inactivation', 'Var', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('TSG', 'Gene', (70, 73))	('human', 'Species', '9606', (227, 232))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('TSG', 'Gene', '57045', (70, 73))	('gene expression', 'MPA', (128, 143))	('loss', 'NegReg', (120, 124))	('aberrant DNA methylation', 'Var', (147, 171))
297314	20658532	We have identified novel TSGs inactivated by promoter methylation in ESCC; e.g., N-methyl-d-aspartic acid receptor 2B (NMDAR2B) and neurofilament heavy chain polypeptide (NEFH).	('TSG', 'Gene', '57045', (25, 28))	('neurofilament heavy chain polypeptide', 'Gene', '4744', (132, 169))	('NMDAR2B', 'Gene', (119, 126))	('N-methyl-d-aspartic acid receptor 2B', 'Gene', '2904', (81, 117))	('NMDAR2B', 'Gene', '2904', (119, 126))	('NEFH', 'Gene', (171, 175))	('NEFH', 'Gene', '4744', (171, 175))	('N-methyl-d-aspartic acid receptor 2B', 'Gene', (81, 117))	('TSG', 'Gene', (25, 28))	('ESCC', 'Gene', (69, 73))	('neurofilament heavy chain polypeptide', 'Gene', (132, 169))	('ESCC', 'Phenotype', 'HP:0011459', (69, 73))	('promoter methylation', 'Var', (45, 65))
297315	20658532	In addition, correlations between aberrant gene methylation and smoking exposure are often observed in smoking-related human cancer; for example, hypermethylation of the APC and p16 promoters is associated with tobacco smoking in nonsmall cell lung carcinoma, colon cancer and cervical squamous cell carcinoma.	('p16', 'Gene', (178, 181))	('nonsmall cell lung carcinoma', 'Disease', (230, 258))	('colon cancer', 'Disease', 'MESH:D015179', (260, 272))	('p16', 'Gene', '1029', (178, 181))	('tobacco', 'Species', '4097', (211, 218))	('nonsmall cell lung carcinoma', 'Disease', 'MESH:D002289', (230, 258))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('colon cancer', 'Disease', (260, 272))	('cancer', 'Disease', (125, 131))	('human', 'Species', '9606', (119, 124))	('associated', 'Reg', (195, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('APC', 'Disease', 'MESH:D011125', (170, 173))	('APC', 'Disease', (170, 173))	('cervical squamous cell carcinoma', 'Disease', (277, 309))	('colon cancer', 'Phenotype', 'HP:0003003', (260, 272))	('cancer', 'Disease', (266, 272))	('hypermethylation', 'Var', (146, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('nonsmall cell lung carcinoma', 'Phenotype', 'HP:0030358', (230, 258))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (277, 309))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (286, 309))
297323	20658532	Moreover, we found aberrant methylation of SSBP2 in primary ESCC and a tumor suppressive role of SSBP2 through inhibition of Wnt signaling pathway.	('SSBP2', 'Gene', (97, 102))	('methylation', 'MPA', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('ESCC', 'Phenotype', 'HP:0011459', (60, 64))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SSBP2', 'Gene', (43, 48))	('aberrant', 'Var', (19, 27))	('Wnt', 'Gene', '7471;7472;89780;7474;7477;7480', (125, 128))	('Wnt', 'Gene', (125, 128))	('inhibition', 'NegReg', (111, 121))
297343	20658532	TOPflash and FOPflash have wild-type (TOP) or mutated (FOP) binding sites for the beta-catenin-TCF4/Lef complex, respectively.	('mutated', 'Var', (46, 53))	('TCF', 'Gene', (95, 98))	('TCF', 'Gene', '3172', (95, 98))	('beta-catenin', 'Gene', (82, 94))	('binding', 'Interaction', (60, 67))	('beta-catenin', 'Gene', '1499', (82, 94))
297359	20658532	The demethylating agent 5-Aza-dC increased the NEFH level in the control cells and further enhanced it in the MSE- and SSE-Het-1A cells.	('5-Aza-dC', 'Chemical', '-', (24, 32))	('NEFH', 'Gene', '4744', (47, 51))	('NEFH', 'Gene', (47, 51))	('MSE', 'Gene', '101180900', (110, 113))	('increased', 'PosReg', (33, 42))	('5-Aza-dC', 'Var', (24, 32))	('enhanced', 'PosReg', (91, 99))	('MSE', 'Gene', (110, 113))
297366	20658532	These results indicate that the SSBP2 methylation participates, at least in part, in the downregulation of gene transcription under MSE exposure.	('MSE', 'Gene', (132, 135))	('MSE', 'Gene', '101180900', (132, 135))	('methylation', 'Var', (38, 49))	('downregulation', 'NegReg', (89, 103))	('gene transcription', 'MPA', (107, 125))	('SSBP2', 'Gene', (32, 37))
297370	20658532	SSBP2 methylation was not observed in the nontumorigenic cell lines, HEK293 and Het-1A, but was observed in 8 of 11 ESCC ce11 lines (TE1, TE2, KYSE70, KYSE140, KYSE150, KYSE200, KYSE410 and KYSE520) by MSP with methylation-specific primers (M-SP) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('KYSE140', 'Var', (151, 158))	('tumor', 'Disease', (45, 50))	('KYSE150', 'Var', (160, 167))	('KYSE520', 'CellLine', 'CVCL:1355', (190, 197))	('TE2', 'Gene', (138, 141))	('KYSE70', 'Var', (143, 149))	('KYSE410', 'Var', (178, 185))	('TE2', 'Gene', '8260', (138, 141))	('KYSE200', 'Var', (169, 176))	('M-SP', 'Species', '29541', (241, 245))	('ESCC', 'Phenotype', 'HP:0011459', (116, 120))	('HEK293', 'CellLine', 'CVCL:0045', (69, 75))	('observed', 'Reg', (96, 104))	('KYSE520', 'Var', (190, 197))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
297381	20658532	Testing methylation of SSBP2 resulted in a highly discriminative receiver-operator characteristic (ROC) curve profile, clearly distinguishing ESCC from PN (Fig.	('ESCC', 'Phenotype', 'HP:0011459', (142, 146))	('SSBP2', 'Gene', (23, 28))	('ESCC', 'Disease', (142, 146))	('methylation', 'Var', (8, 19))	('PN', 'Species', '9606', (152, 154))
297385	20658532	SSBP2 mRNA expression was reactivated by treatment with 5-Aza-dC in KYSE410 and KYSE520 cells but not in KYSE30 cells (Fig.	('5-Aza-dC', 'Chemical', '-', (56, 64))	('KYSE410', 'Var', (68, 75))	('reactivated', 'PosReg', (26, 37))	('KYSE520', 'CellLine', 'CVCL:1355', (80, 87))	('mRNA expression', 'MPA', (6, 21))	('5-Aza-dC', 'Var', (56, 64))	('SSBP2', 'Gene', (0, 5))	('KYSE520', 'Var', (80, 87))
297396	20658532	SSBP2 expression significantly decreased Wnt7b level with a trend toward a decrease of Wnt1, Wnt2, Wnt3a and Wnt10b (Fig.	('Wnt1', 'Gene', (109, 113))	('Wnt1', 'Gene', '7471', (87, 91))	('Wnt7b', 'Gene', (41, 46))	('decrease', 'NegReg', (75, 83))	('Wnt10b', 'Gene', (109, 115))	('Wnt7b', 'Gene', '7477', (41, 46))	('Wnt3a', 'Gene', '89780', (99, 104))	('Wnt3a', 'Gene', (99, 104))	('decreased', 'NegReg', (31, 40))	('Wnt10b', 'Gene', '7480', (109, 115))	('Wnt2', 'Gene', '7472', (93, 97))	('Wnt1', 'Gene', '7471', (109, 113))	('Wnt1', 'Gene', (87, 91))	('SSBP2', 'Gene', (0, 5))	('expression', 'Var', (6, 16))	('Wnt2', 'Gene', (93, 97))
297399	20658532	Dvl3 expression was decreased by SSBP2 in TE1 and TE2 and slightly in TE4.	('TE2', 'Gene', '8260', (50, 53))	('expression', 'MPA', (5, 15))	('SSBP2', 'Var', (33, 38))	('TE2', 'Gene', (50, 53))	('decreased', 'NegReg', (20, 29))	('Dvl3', 'Gene', '1857', (0, 4))	('Dvl3', 'Gene', (0, 4))
297402	20658532	5a, right) were significantly decreased by SSBP2 overexpression in MSE-Het-1A cells, indicating that SSBP2 likely suppresses cell growth stimulated by chronic MSE exposure.	('MSE', 'Gene', '101180900', (159, 162))	('cell growth', 'CPA', (125, 136))	('MSE', 'Gene', (67, 70))	('MSE', 'Gene', '101180900', (67, 70))	('overexpression', 'Var', (49, 63))	('MSE-Het-1A', 'Gene', (67, 77))	('MSE-Het-1A', 'Gene', '101180900', (67, 77))	('SSBP2', 'Gene', (43, 48))	('MSE', 'Gene', (159, 162))	('suppresses', 'NegReg', (114, 124))	('decreased', 'NegReg', (30, 39))
297405	20658532	To investigate beta-catenin-TCF/Lef-dependent transcription after long-term CSE exposure, the luciferase reporters, TOP-flash and FOPflash, which have either wild-type (TOP) or mutated (FOP) binding sites for the beta-catenin-TCF4/Lef complex, were transfected into the control- and MSE-Het-1A cells.	('TCF', 'Gene', (226, 229))	('TCF', 'Gene', '3172', (226, 229))	('beta-catenin', 'Gene', '1499', (213, 225))	('TCF', 'Gene', (28, 31))	('TCF', 'Gene', '3172', (28, 31))	('mutated', 'Var', (177, 184))	('beta-catenin', 'Gene', (15, 27))	('MSE-Het-1A', 'Gene', (283, 293))	('binding', 'Interaction', (191, 198))	('beta-catenin', 'Gene', '1499', (15, 27))	('MSE-Het-1A', 'Gene', '101180900', (283, 293))	('beta-catenin', 'Gene', (213, 225))
297406	20658532	We found a 6-fold increase of TOP activity in the MSE-Het-1A cells compared to the contro1, which was decreased by SSBP2 overexpression (Fig.	('increase', 'PosReg', (18, 26))	('TOP activity', 'MPA', (30, 42))	('SSBP2', 'Gene', (115, 120))	('overexpression', 'Var', (121, 135))	('MSE-Het-1A', 'Gene', (50, 60))	('MSE-Het-1A', 'Gene', '101180900', (50, 60))
297416	20658532	The expression of LRP6, p-LRP6 and Wnt7b proteins was increased by SSBP2 knock-down in the Het-1A cells, but Dvl3, Naked2 and Wnt3a were not changed (Fig.	('Wnt7b', 'Gene', (35, 40))	('LRP6', 'Gene', '4040', (18, 22))	('Wnt3a', 'Gene', (126, 131))	('Naked2', 'Gene', (115, 121))	('Wnt7b', 'Gene', '7477', (35, 40))	('Naked2', 'Gene', '85409', (115, 121))	('Dvl3', 'Gene', (109, 113))	('LRP6', 'Gene', (18, 22))	('increased', 'PosReg', (54, 63))	('expression', 'MPA', (4, 14))	('SSBP2', 'Gene', (67, 72))	('knock-down', 'Var', (73, 83))	('Wnt3a', 'Gene', '89780', (126, 131))	('LRP6', 'Gene', '4040', (26, 30))	('Dvl3', 'Gene', '1857', (109, 113))	('LRP6', 'Gene', (26, 30))
297417	20658532	The levels of Axin1, WIF1 and Wnt5a/b were decreased by SSBP2 gene knock-down.	('WIF1', 'Gene', (21, 25))	('SSBP2', 'Gene', (56, 61))	('levels', 'MPA', (4, 10))	('WIF1', 'Gene', '11197', (21, 25))	('gene knock-down', 'Var', (62, 77))	('Axin1', 'Gene', (14, 19))	('Wnt5a/b', 'Gene', (30, 37))	('knock-down', 'Var', (67, 77))	('Axin1', 'Gene', '8312', (14, 19))	('decreased', 'NegReg', (43, 52))	('Wnt5a/b', 'Gene', '7474', (30, 37))
297425	20658532	In contrast, NMDAR2B was completely silenced even though only a few CpGs were methylated in the CSE-exposed cells, indicating that methylation in these CpGs might be sufficient to induce gene silencing or that CpG concordant methylation in other unexamined regions participated in downregulation of NMDAR2B expression.	('methylation', 'Var', (225, 236))	('gene', 'MPA', (187, 191))	('downregulation', 'NegReg', (281, 295))	('NMDAR2B', 'Gene', (13, 20))	('NMDAR2B', 'Gene', '2904', (13, 20))	('expression', 'MPA', (307, 317))	('NMDAR2B', 'Gene', (299, 306))	('NMDAR2B', 'Gene', '2904', (299, 306))
297431	20658532	Nonrandom interstitial deletion, translocations or paracentric inversions involving 5q11 to 5q13 have been frequently reported in refractory myelodysplasia, human acute myelogenous leukemia (AML) and solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (200, 212))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('translocations', 'Var', (33, 47))	('5q11 to 5q13', 'Gene', (84, 96))	('acute myelogenous leukemia', 'Disease', (163, 189))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('AML', 'Disease', 'MESH:D015470', (191, 194))	('leukemia', 'Phenotype', 'HP:0001909', (181, 189))	('AML', 'Phenotype', 'HP:0004808', (191, 194))	('myelodysplasia', 'Phenotype', 'HP:0002863', (141, 155))	('AML', 'Disease', (191, 194))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (163, 189))	('myelodysplasia', 'Disease', 'MESH:D009190', (141, 155))	('human', 'Species', '9606', (157, 162))	('reported', 'Reg', (118, 126))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (169, 189))	('solid tumors', 'Disease', (200, 212))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (163, 189))	('paracentric inversions', 'Var', (51, 73))	('myelodysplasia', 'Disease', (141, 155))
297433	20658532	We recently reported aberrant methylation of SSBP2 in prostate cancer and its tumor suppressive function in human prostate cancer cell lines.	('SSBP2', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('aberrant', 'Var', (21, 29))	('prostate cancer', 'Disease', (54, 69))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('human', 'Species', '9606', (108, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('tumor', 'Disease', (78, 83))	('methylation', 'MPA', (30, 41))	('prostate cancer', 'Disease', (114, 129))
297436	20658532	Aberrant reactivation of embryonic signaling pathways in adult cells such as Wnt can provide a driving force for tumor growth.	('tumor', 'Disease', (113, 118))	('Wnt', 'Gene', (77, 80))	('embryonic signaling pathways', 'Pathway', (25, 53))	('Wnt', 'Gene', '7471;7472;89780;7474;7477;7480', (77, 80))	('Aberrant', 'Var', (0, 8))	('reactivation', 'MPA', (9, 21))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
297437	20658532	Overexpression and reactivation of the Wnt pathway result in activation of beta-catenin/TCF-dependent transcription, which has been implicated in ESCC development.	('beta-catenin', 'Gene', '1499', (75, 87))	('ESCC', 'Phenotype', 'HP:0011459', (146, 150))	('Wnt', 'Gene', '7471;7472;89780;7474;7477;7480', (39, 42))	('ESCC development', 'Disease', (146, 162))	('reactivation', 'Var', (19, 31))	('Wnt', 'Gene', (39, 42))	('activation', 'PosReg', (61, 71))	('TCF', 'Gene', '3172', (88, 91))	('beta-catenin', 'Gene', (75, 87))	('TCF', 'Gene', (88, 91))
297446	20658532	In addition, SSBP2 gene knock-down in the Het-1A cells increased the LRP6 expression and its phosphorylation level.	('expression', 'MPA', (74, 84))	('SSBP2 gene', 'Gene', (13, 23))	('LRP6', 'Gene', (69, 73))	('LRP6', 'Gene', '4040', (69, 73))	('increased', 'PosReg', (55, 64))	('knock-down', 'Var', (24, 34))	('phosphorylation level', 'MPA', (93, 114))
297449	20658532	Although Axin1 and Naked2 expression were not affected by increased SSBP2 expression in the MSE-exposed cells, Axin1 was decreased by SSBP2 knock-down in the control-Het-1A cells and slightly increased by SSBP2 expression in TE1 cells.	('knock-down', 'Var', (140, 150))	('Axin1', 'Gene', '8312', (111, 116))	('Axin1', 'Gene', '8312', (9, 14))	('MSE', 'Gene', (92, 95))	('decreased', 'NegReg', (121, 130))	('MSE', 'Gene', '101180900', (92, 95))	('Naked2', 'Gene', (19, 25))	('Axin1', 'Gene', (111, 116))	('SSBP2', 'Gene', (134, 139))	('Axin1', 'Gene', (9, 14))	('Naked2', 'Gene', '85409', (19, 25))
297453	20658532	SSBP2 knock-down in HEK293 (Supporting Information Fig.	('HEK293', 'CellLine', 'CVCL:0045', (20, 26))	('SSBP2', 'Gene', (0, 5))	('knock-down', 'Var', (6, 16))
297456	20658532	However, the protein level of Wnt3a was not suppressed by SSBP2 overexpression in the MSE-Het-1A cells nor increased by SSBP2 gene knock-down in the control-Het-1A cells.	('protein level', 'MPA', (13, 26))	('Wnt3a', 'Gene', (30, 35))	('increased', 'PosReg', (107, 116))	('MSE-Het-1A', 'Gene', (86, 96))	('MSE-Het-1A', 'Gene', '101180900', (86, 96))	('SSBP2', 'Gene', (120, 125))	('knock-down', 'Var', (131, 141))	('Wnt3a', 'Gene', '89780', (30, 35))	('overexpression', 'Var', (64, 78))	('SSBP2', 'Gene', (58, 63))
297462	20658532	Sulindac also decreased baseline or MSE-activated Wnt expression, indicating that Sulindac can inhibit Wnt signaling upstream of beta-catenin.	('Sulindac', 'Chemical', 'MESH:D013467', (82, 90))	('Wnt', 'Gene', (50, 53))	('decreased', 'NegReg', (14, 23))	('MSE', 'Gene', (36, 39))	('MSE', 'Gene', '101180900', (36, 39))	('baseline', 'MPA', (24, 32))	('inhibit', 'NegReg', (95, 102))	('Sulindac', 'Var', (82, 90))	('Sulindac', 'Chemical', 'MESH:D013467', (0, 8))	('beta-catenin', 'Gene', (129, 141))	('Wnt', 'Gene', '7471;7472;89780;7474;7477;7480', (103, 106))	('Wnt', 'Gene', '7471;7472;89780;7474;7477;7480', (50, 53))	('beta-catenin', 'Gene', '1499', (129, 141))	('Wnt', 'Gene', (103, 106))
297466	20658532	In addition, the tumor suppressive function of SSBP2 is, at least in part, mediated through inhibition of Wnt signaling providing a personalized therapeutic approach for patients with SSBP2 methylated esophageal cancer.	('patients', 'Species', '9606', (170, 178))	('tumor', 'Disease', (17, 22))	('Wnt', 'Gene', '7471;7472;89780;7474;7477;7480', (106, 109))	('esophageal cancer', 'Disease', (201, 218))	('Wnt', 'Gene', (106, 109))	('SSBP2', 'Gene', (47, 52))	('methylated', 'Var', (190, 200))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (201, 218))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
297674	32726927	; Supervision, J.L., N.F.-N., C.P., M.P., L.B., M.B., A.M., J.S., and F.M.S.-J.	('M.P.', 'Var', (36, 40))	('M.B.', 'Var', (48, 52))	('F.M.S.-J', 'Var', (70, 78))	('up', 'Gene', '7378', (3, 5))	('L.B.', 'Var', (42, 46))
297675	32726927	; Validation, J.L., M.P., U.A., M.B., N.D., J.S., and F.M.S.-J.	('J.S.', 'Var', (44, 48))	('M.B.', 'Var', (32, 36))	('F.M.S.-J', 'Var', (54, 62))	('U', 'Gene', '7378', (26, 27))
297693	32816020	Additionally, changes were implemented to reduce the spread of the disease and because of concerns that contracting COVID-19 peri-operatively may have a major impact on morbidity and mortality.	('mortality', 'Disease', (183, 192))	('contracting', 'Var', (104, 115))	('COVID-19', 'Disease', 'MESH:C000657245', (116, 124))	('men', 'Species', '9606', (32, 35))	('reduce', 'NegReg', (42, 48))	('COVID-19', 'Disease', (116, 124))	('impact', 'Reg', (159, 165))	('spread', 'MPA', (53, 59))	('mortality', 'Disease', 'MESH:D003643', (183, 192))
297751	32816020	The second patient that was found to be COVID-19 positive presented after feeling faint to their local hospital.	('positive', 'Var', (49, 57))	('patient', 'Species', '9606', (11, 18))	('COVID-19', 'Disease', 'MESH:C000657245', (40, 48))	('COVID-19', 'Disease', (40, 48))
297863	32471425	Patients carrying the CRP 1846 T/T genotype showed LN metastasis significantly more frequently than those with other genotypes.	('frequently', 'PosReg', (84, 94))	('T/T', 'Var', (31, 34))	('CRP', 'Gene', (22, 25))	('CRP', 'Gene', '1401', (22, 25))	('LN metastasis', 'CPA', (51, 64))	('Patients', 'Species', '9606', (0, 8))
297890	29662006	MKR mice were generated by overexpressing a dominant-negative IGF1R specifically in skeletal muscle.	('dominant-negative', 'Var', (44, 61))	('mice', 'Species', '10090', (4, 8))	('IGF1R', 'Gene', (62, 67))	('overexpressing', 'PosReg', (27, 41))
297891	29662006	The transgene encodes for human IGF1R; it has a point mutation in the ATP-binding domain and is driven by the muscle creatine kinase promoter, resulting in the inactivation of IR and IGF1R exclusively in skeletal muscle.	('IGF1R', 'Gene', (183, 188))	('IR', 'Gene', '16337', (176, 178))	('inactivation', 'MPA', (160, 172))	('ATP', 'Chemical', 'MESH:D000255', (70, 73))	('point mutation in', 'Var', (48, 65))	('human', 'Species', '9606', (26, 31))
297895	29662006	According to previous work, MKR mice had reduced total body weight (BW) compared to WT controls (Figure 1).	('reduced', 'NegReg', (41, 48))	('reduced total body weight', 'Phenotype', 'HP:0004325', (41, 66))	('total body weight', 'MPA', (49, 66))	('mice', 'Species', '10090', (32, 36))	('MKR', 'Var', (28, 31))
297915	29662006	On the contrary, cancer incidence on MKR males was higher compared to MKR females (OR 12.80, 95% CI 1.38-118.32, p = 0.025).	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('MKR', 'Var', (37, 40))	('cancer', 'Disease', (17, 23))	('higher', 'PosReg', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
297925	29662006	C-peptide levels, a more stable and accurate marker of endogenous insulin secretion, were higher in MKR mice compared to their WT counterparts (Table S1, Supplementary Materials).	('MKR', 'Var', (100, 103))	('mice', 'Species', '10090', (104, 108))	('insulin', 'Gene', (66, 73))	('C-peptide levels', 'MPA', (0, 16))	('insulin', 'Gene', '3630', (66, 73))	('higher', 'PosReg', (90, 96))
297927	29662006	Leptin serum levels were significantly lower in MKR mice compared to age- and sex-matched WT mice.	('serum levels', 'MPA', (7, 19))	('Leptin', 'Gene', (0, 6))	('mice', 'Species', '10090', (52, 56))	('Leptin', 'Gene', '16846', (0, 6))	('mice', 'Species', '10090', (93, 97))	('MKR', 'Var', (48, 51))	('lower', 'NegReg', (39, 44))
297935	29662006	Insulin binding to the alpha-subunit results in the dimerization of the receptor, with the formation of the alpha2beta2 complex in the cell membrane, and the autophosphorylation of the beta-subunit at tyrosine residues [Y] 1158, 1162, and 1163, the first step in the activation of IR.	('dimerization', 'MPA', (52, 64))	('tyrosine', 'Chemical', 'MESH:D014443', (201, 209))	('autophosphorylation', 'MPA', (158, 177))	('[Y] 1158', 'Var', (219, 227))	('binding', 'Interaction', (8, 15))	('Insulin', 'Gene', '3630', (0, 7))	('Insulin', 'Gene', (0, 7))	('IR', 'Gene', '16337', (281, 283))
297937	29662006	Receptor phosphorylation level on tyrosine autophosphorylation sites was evaluated: both IR [pYpY1162/1163] and IGF1R [pYpY1135/1136] expression levels ratio were lower in MKR compared to WT mice of the same gender (Figure S1B, Supplementary Materials).	('IR', 'Gene', '16337', (89, 91))	('tyrosine', 'Chemical', 'MESH:D014443', (34, 42))	('mice', 'Species', '10090', (191, 195))	('MKR', 'Var', (172, 175))	('lower', 'NegReg', (163, 168))	('expression levels', 'MPA', (134, 151))
297942	29662006	Similarly, Cuzick's trend test showed a progressive increase in Akt phosphorylation on serine 473 residue across the four groups (z = +2.25, p = 0.024), with the highest expression in MKR males (Figure S1B).	('MKR', 'Var', (184, 187))	('increase', 'PosReg', (52, 60))	('Akt', 'Gene', '11651', (64, 67))	('Akt', 'Gene', (64, 67))	('serine', 'Chemical', 'MESH:D012694', (87, 93))
297973	29662006	IGF1R hyperactivation could lead to the increase in ERK1/2 protein phosphorylation (10-fold and 2.6-fold in dysplastic and cancer tissue, respectively), compared with basal state (Figure 2B).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ERK1/2 protein', 'Protein', (52, 66))	('protein', 'Protein', (59, 66))	('increase', 'PosReg', (40, 48))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('IGF1R', 'Gene', (0, 5))	('dysplastic', 'Disease', 'MESH:D004416', (108, 118))	('dysplastic', 'Disease', (108, 118))	('cancer', 'Disease', (123, 129))	('hyperactivation', 'Var', (6, 21))
297991	29662006	Analogous to MKR females, protein expression in esophageal tissue from MKR males showed a significant decrease of both IR and IGF1R expression in cancer compared with control tissue (Figure 5A).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('MKR', 'Var', (71, 74))	('IGF1R', 'Gene', (126, 131))	('decrease', 'NegReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('IR', 'Gene', '16337', (119, 121))	('expression', 'MPA', (132, 142))
298005	29662006	Immunohistochemistry staining of FFPE esophageal tissues showed HER2 positivity in both dysplastic and neoplastic lesions in ESCC and EASC, in WT and MKR mice, as previously described in human specimens.	('mice', 'Species', '10090', (154, 158))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (103, 121))	('positivity', 'Var', (69, 79))	('HER2', 'Protein', (64, 68))	('human', 'Species', '9606', (187, 192))	('dysplastic and neoplastic lesions', 'Disease', 'MESH:D021782', (88, 121))	('EASC', 'Disease', (134, 138))	('ESCC', 'Disease', (125, 129))
298016	29662006	With the total exclusion of the stomach, our mouse surgical model showed that refluxed duodenal content caused esophageal cancer without exposure to carcinogens, and without any prevalence between the two tumor histological types (47.4% were ESCC and 52.6% were EASC).	('ESCC', 'Disease', (242, 246))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('caused', 'Reg', (104, 110))	('mouse', 'Species', '10090', (45, 50))	('esophageal cancer', 'Disease', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('refluxed', 'Var', (78, 86))
298019	29662006	The metabolic status analysis of the mice before surgery showed, as expected, that MKR mice have higher serum insulin and C-peptide levels compared to age- and sex-matched WT mice.	('mice', 'Species', '10090', (175, 179))	('higher', 'PosReg', (97, 103))	('mice', 'Species', '10090', (87, 91))	('insulin', 'Gene', (110, 117))	('insulin', 'Gene', '3630', (110, 117))	('MKR', 'Var', (83, 86))	('mice', 'Species', '10090', (37, 41))
298020	29662006	Body weight was sensibly lower in MKR mice compared to the WT counterpart which tended to accumulate more adipose tissue than MKR mice, as confirmed by leptin serum level measurements.	('mice', 'Species', '10090', (130, 134))	('leptin', 'Gene', '16846', (152, 158))	('leptin', 'Gene', (152, 158))	('mice', 'Species', '10090', (38, 42))	('accumulate', 'PosReg', (90, 100))	('lower', 'NegReg', (25, 30))	('adipose tissue', 'MPA', (106, 120))	('MKR', 'Var', (34, 37))	('Body weight', 'CPA', (0, 11))
298025	29662006	On the basis of insulin and C-peptide serum levels, the four groups of animals were ordered lowest to highest as follows: WT females, WT males, MKR females and MKR males.	('insulin', 'Gene', '3630', (16, 23))	('insulin', 'Gene', (16, 23))	('MKR', 'Var', (144, 147))
298112	28765688	Indeed, although SVR is associated with improvement of hepatic venous pressure gradients and therefore a decreased risk of de novo esophageal varices, several studies show that viral clearance does not eliminate the risk of variceal progression, liver decompensation and death in patients with pre-established portal hypertension.	('portal hypertension', 'Phenotype', 'HP:0001409', (310, 329))	('liver', 'Disease', (246, 251))	('patients', 'Species', '9606', (280, 288))	('esophageal varices', 'Phenotype', 'HP:0002040', (131, 149))	('SVR', 'Var', (17, 20))	('hypertension', 'Disease', 'MESH:D006973', (317, 329))	('improvement', 'PosReg', (40, 51))	('death', 'Disease', 'MESH:D003643', (271, 276))	('death', 'Disease', (271, 276))	('hypertension', 'Disease', (317, 329))	('hypertension', 'Phenotype', 'HP:0000822', (317, 329))	('hepatic venous pressure gradients', 'MPA', (55, 88))	('variceal', 'Disease', (224, 232))
298113	28765688	Although evidence about the effects of direct antiviral agents (DAAs) on clinically significant outcomes is still scarce and with short follow-up, DAAs can decrease the burden of the disease if patients are timely treated before significant fibrosis and portal hypertension develops.	('patients', 'Species', '9606', (194, 202))	('DAA', 'Chemical', '-', (64, 67))	('burden of', 'MPA', (169, 178))	('hypertension', 'Disease', 'MESH:D006973', (261, 273))	('DAA', 'Chemical', '-', (147, 150))	('hypertension', 'Disease', (261, 273))	('fibrosis', 'Disease', (241, 249))	('fibrosis', 'Disease', 'MESH:D005355', (241, 249))	('hypertension', 'Phenotype', 'HP:0000822', (261, 273))	('decrease', 'NegReg', (156, 164))	('DAAs', 'Var', (147, 151))	('portal hypertension', 'Phenotype', 'HP:0001409', (254, 273))
298138	28765688	Another prospective study by Di Marco et al also showed that SVR was associated with a lower incidence of de novo esophageal varices in cirrhotic patients treated with PEG-INF and ribavirin (HR = 0.23, 95%CI: 0.11-0.48), although it was not associated with a decrease in variceal progression or liver decompensation in those with pre-existing varices.	('PEG-INF', 'Var', (168, 175))	('PEG-INF', 'Chemical', '-', (168, 175))	('esophageal varices', 'Phenotype', 'HP:0002040', (114, 132))	('ribavirin', 'Chemical', 'MESH:D012254', (180, 189))	('lower', 'NegReg', (87, 92))	('esophageal varices', 'Disease', (114, 132))	('SVR', 'Var', (61, 64))	('patients', 'Species', '9606', (146, 154))
298164	28765688	Indeed, although HCV eradication can decrease Child-Pugh and MELD scores in a subset of patients (decreasing the need of liver transplantation), it does not necessarily improve liver function and portal hypertension sufficiently to the point of a compensated patient with a functional live and the need for liver transplantation may persist but be delayed due to the MELD decrease (MELD purgatory).	('decrease', 'NegReg', (37, 45))	('patient', 'Species', '9606', (88, 95))	('MELD decrease', 'Disease', (367, 380))	('eradication', 'Var', (21, 32))	('improve liver function', 'Phenotype', 'HP:0001410', (169, 191))	('portal hypertension', 'Phenotype', 'HP:0001409', (196, 215))	('hypertension', 'Disease', 'MESH:D006973', (203, 215))	('patients', 'Species', '9606', (88, 96))	('hypertension', 'Phenotype', 'HP:0000822', (203, 215))	('liver function', 'MPA', (177, 191))	('Child', 'Species', '9606', (46, 51))	('MELD decrease', 'Disease', 'MESH:D012021', (367, 380))	('hypertension', 'Disease', (203, 215))	('HCV', 'Species', '11103', (17, 20))	('Child-Pugh', 'CPA', (46, 56))	('patient', 'Species', '9606', (259, 266))
298337	26630566	Although dose volume constraints for the target and organs-at-risk (OARs) may differ for individual IMRT plans, the following objectives were generally met: V20 < 30% for the bilateral lungs, the mean lung dose (MLD) < 20 Gy, and the maximum spinal cord dose < 45 Gy.	('V20', 'Var', (157, 160))	('MLD', 'Disease', 'MESH:D007966', (212, 215))	('MLD', 'Disease', (212, 215))
298396	26630566	The mean dose to the heart in 140 lung cancer patients treated with DCAT, IMRT or VMAT was 4.5 Gy, lower by 82% compared with the conventional techniques used in the 1990s.	('patients', 'Species', '9606', (46, 54))	('DCAT', 'Chemical', '-', (68, 72))	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('DCAT', 'Var', (68, 72))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
298552	24886814	Macrophage count was significantly associated with (p = 0.015) lymph node:stage in small cell esophageal carcinoma.	('associated', 'Reg', (35, 45))	('Macrophage count', 'Var', (0, 16))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (94, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('lymph node', 'Disease', (63, 73))	('small cell esophageal carcinoma', 'Disease', 'MESH:D018288', (83, 114))	('small cell esophageal carcinoma', 'Disease', (83, 114))
298588	24886814	Similarly, patients of high eosinophil infiltration group experienced significantly better survival (p = 0.027, Figure 2) when compared with patients in the low eosinophil infiltration group.	('high eosinophil infiltration', 'Var', (23, 51))	('low eosinophil', 'Phenotype', 'HP:0031891', (157, 171))	('survival', 'MPA', (91, 99))	('high eosinophil infiltration', 'Phenotype', 'HP:0001880', (23, 51))	('eosinophil infiltration', 'Phenotype', 'HP:0001880', (161, 184))	('better', 'PosReg', (84, 90))	('eosinophil infiltration', 'Phenotype', 'HP:0001880', (28, 51))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (141, 149))
298593	24886814	Kaplan-Meier analysis unveiled that, patients with high macrophage infiltration and high eosinophil infiltration had prolonged overall survival than patients with low macrophage and low eosinophil infiltration.	('patients', 'Species', '9606', (149, 157))	('high macrophage infiltration', 'Var', (51, 79))	('patients', 'Species', '9606', (37, 45))	('eosinophil infiltration', 'Phenotype', 'HP:0001880', (89, 112))	('high eosinophil infiltration', 'Phenotype', 'HP:0001880', (84, 112))	('low eosinophil', 'Phenotype', 'HP:0031891', (182, 196))	('prolonged', 'PosReg', (117, 126))	('overall survival', 'MPA', (127, 143))	('eosinophil infiltration', 'Phenotype', 'HP:0001880', (186, 209))
298607	24886814	In this study, patients belonging to the low macrophage infiltration group often experienced more regional lymph node metastases than patients in the high macrophage infiltration group.	('patients', 'Species', '9606', (15, 23))	('lymph node metastases', 'Disease', (107, 128))	('low macrophage infiltration', 'Var', (41, 68))	('patients', 'Species', '9606', (134, 142))	('lymph node metastases', 'Disease', 'MESH:D009362', (107, 128))
298618	24886814	reported that, patients with high macrophage infiltration had significant survival advantage in colorectal cancer.	('patients', 'Species', '9606', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('advantage', 'PosReg', (83, 92))	('colorectal cancer', 'Disease', (96, 113))	('high macrophage infiltration', 'Var', (29, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
298670	24886814	Chromogenic detection of CD68 was performed with 0.02% of 3,3'-diaminobenzidine and 0.005% of H2O2 in 0.05 mmol/L Tris-HCl buffer and counter stained with hematoxylin.	('0.005%', 'Var', (84, 90))	('Tris-HCl', 'Chemical', '-', (114, 122))	('H2O2', 'Chemical', 'MESH:D006861', (94, 98))	('CD68', 'Gene', '968', (25, 29))	('hematoxylin', 'Chemical', 'MESH:D006416', (155, 166))	('CD68', 'Gene', (25, 29))	("3,3'-diaminobenzidine", 'Chemical', 'MESH:D015100', (58, 79))
298695	24788754	Silencing PTK6 reduced ERK1/2 activation, but not AKT or STAT3 activation, while PTK6 overexpression increased ERK1/2 activation.	('ERK1/2', 'Gene', (111, 117))	('AKT', 'Gene', '207', (50, 53))	('PTK6', 'Gene', (81, 85))	('ERK1/2', 'Gene', '5595;5594', (111, 117))	('STAT3', 'Gene', '6774', (57, 62))	('PTK6', 'Gene', '5753', (81, 85))	('reduced', 'NegReg', (15, 22))	('AKT', 'Gene', (50, 53))	('PTK6', 'Gene', '5753', (10, 14))	('S', 'Chemical', 'MESH:D013455', (57, 58))	('activation', 'MPA', (118, 128))	('STAT3', 'Gene', (57, 62))	('PTK6', 'Gene', (10, 14))	('ERK1/2', 'Gene', '5595;5594', (23, 29))	('Silencing', 'Var', (0, 9))	('ERK1/2', 'Gene', (23, 29))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('activation', 'MPA', (30, 40))
298710	24788754	Anti-PTK6 antibody was obtained from Santa Cruz Biochemistry (Santa Cruz, CA), anti-p44/42 ERK1/2, anti-phospho-p44/42 ERK1/2 (Thr202/Tyr204), anti-p38 MAPK, anti-phospho-p38 MAPK (Thr180/Tyr182), anti-STAT3, and anti-phospho-STAT3 (Tyr705) antibodies were obtained from Cell Signaling Technology (Danvers, MA), and anti-beta-actin antibody was obtained from Sigma-Aldrich.	('p38', 'Gene', (148, 151))	('p44', 'Gene', (84, 87))	('S', 'Chemical', 'MESH:D013455', (276, 277))	('S', 'Chemical', 'MESH:D013455', (37, 38))	('p44', 'Gene', '10561', (84, 87))	('p38', 'Gene', (171, 174))	('S', 'Chemical', 'MESH:D013455', (226, 227))	('ERK1/2', 'Gene', (91, 97))	('P', 'Chemical', 'MESH:D010758', (5, 6))	('Thr180/Tyr182', 'Var', (181, 194))	('P', 'Chemical', 'MESH:D010758', (154, 155))	('beta-actin', 'Gene', (321, 331))	('STAT3', 'Gene', (226, 231))	('p38', 'Gene', '5594', (148, 151))	('P', 'Chemical', 'MESH:D010758', (177, 178))	('ERK1/2', 'Gene', (119, 125))	('ERK1/2', 'Gene', '5595;5594', (119, 125))	('S', 'Chemical', 'MESH:D013455', (202, 203))	('PTK6', 'Gene', '5753', (5, 9))	('p44', 'Gene', (112, 115))	('S', 'Chemical', 'MESH:D013455', (359, 360))	('p38', 'Gene', '5594', (171, 174))	('STAT3', 'Gene', '6774', (226, 231))	('p44', 'Gene', '10561', (112, 115))	('STAT3', 'Gene', (202, 207))	('PTK6', 'Gene', (5, 9))	('beta-actin', 'Gene', '728378', (321, 331))	('ERK1/2', 'Gene', '5595;5594', (91, 97))	('STAT3', 'Gene', '6774', (202, 207))	('S', 'Chemical', 'MESH:D013455', (62, 63))
298727	24788754	Loss-of-function analysis was performed using siRNAs targeting PTK6 (s11487, Ambion, Grand Island, NY: sense 5'-CAUCCAUGGUUAAGUCAUAtt-3', antisense 5'-UAUGACUUAACCAUGGAUGaa-3') and negative control (Silencer Select Negative Control #2 siRNA, Ambion).	('Loss-of-function', 'NegReg', (0, 16))	('s11487', 'Var', (69, 75))	('S', 'Chemical', 'MESH:D013455', (208, 209))	('PTK6', 'Gene', (63, 67))	('PTK6', 'Gene', '5753', (63, 67))	('S', 'Chemical', 'MESH:D013455', (199, 200))
298730	24788754	Human PTK6 cDNA (cloneID: 5746034) was purchased from Open Biosystems (Pittsburg, PA) and amplified by PCR using primers (5'-CCCAAGCTTATGGTGTCCCGGGACCAGGC, and 3'-CGGGATCCTCAGGTCGGGTTCTCGTAGC).	('Human', 'Species', '9606', (0, 5))	('P', 'Chemical', 'MESH:D010758', (82, 83))	("5'-CCCAAGCTTATGGTGTCCCGGGACCAGGC", 'Var', (122, 154))	('P', 'Chemical', 'MESH:D010758', (71, 72))	('P', 'Chemical', 'MESH:D010758', (6, 7))	('P', 'Chemical', 'MESH:D010758', (103, 104))	('PTK6', 'Gene', (6, 10))	('PTK6', 'Gene', '5753', (6, 10))
298747	24788754	After PTK6 expression was suppressed by gene silencing using siRNA (from Ambion) in 3 pancreatic cancer cell lines (Figure 2A), the migratory potential of pancreatic cancer cells were assayed using a Boyden chamber.	('gene silencing', 'Var', (40, 54))	('suppressed', 'NegReg', (26, 36))	('pancreatic cancer', 'Disease', (86, 103))	('expression', 'MPA', (11, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('pancreatic cancer', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('PTK6', 'Gene', (6, 10))	('PTK6', 'Gene', '5753', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('migratory potential', 'CPA', (132, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
298748	24788754	As shown in Figure 2B, gene silencing of PTK6 significantly reduced migration in all 3 pancreatic cancer cell lines (0.59 fold decrease in BXPC3, 0.61 in Panc1, 0.42 in MIAPaCa2, respectively, p<0.05 for each).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('pancreatic cancer', 'Disease', (87, 104))	('BXPC3', 'MPA', (139, 144))	('MIAPaCa2', 'CellLine', 'CVCL:0428', (169, 177))	('P', 'Chemical', 'MESH:D010758', (154, 155))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('decrease', 'NegReg', (127, 135))	('P', 'Chemical', 'MESH:D010758', (172, 173))	('PTK6', 'Gene', (41, 45))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('reduced', 'NegReg', (60, 67))	('PTK6', 'Gene', '5753', (41, 45))	('P', 'Chemical', 'MESH:D010758', (141, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('migration', 'CPA', (68, 77))	('gene silencing', 'Var', (23, 37))	('Panc1', 'CellLine', 'CVCL:0480', (154, 159))
298749	24788754	Cellular invasive potential was similarly assayed using Matrigel-coated Boyden chambers, and invasion was significantly reduced by gene silencing of PTK6 in all 3 pancreatic cancer cell lines, as shown in Figure 2C (0.49-fold decrease in BXPC3, 0.62 in Panc1, 0.39 in MIAPaCa2, respectively, p<0.05 for each).	('BXPC3', 'MPA', (238, 243))	('PTK6', 'Gene', (149, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (163, 180))	('P', 'Chemical', 'MESH:D010758', (240, 241))	('PTK6', 'Gene', '5753', (149, 153))	('Cellular invasive potential', 'CPA', (0, 27))	('decrease', 'NegReg', (226, 234))	('P', 'Chemical', 'MESH:D010758', (271, 272))	('Panc1', 'CellLine', 'CVCL:0480', (253, 258))	('pancreatic cancer', 'Disease', 'MESH:D010190', (163, 180))	('pancreatic cancer', 'Disease', (163, 180))	('gene silencing', 'Var', (131, 145))	('P', 'Chemical', 'MESH:D010758', (149, 150))	('invasion', 'CPA', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('reduced', 'NegReg', (120, 127))	('MIAPaCa2', 'CellLine', 'CVCL:0428', (268, 276))	('P', 'Chemical', 'MESH:D010758', (253, 254))
298750	24788754	These inhibitory effects of PTK6 gene silencing on cell migration and invasion were confirmed by the similar experiments using other siRNA targeting different sequence of PTK6 (from Invitrogen) (Figure S2).	('S', 'Chemical', 'MESH:D013455', (202, 203))	('cell migration', 'CPA', (51, 65))	('PTK6', 'Gene', (171, 175))	('PTK6', 'Gene', '5753', (171, 175))	('gene', 'Var', (33, 37))	('PTK6', 'Gene', '5753', (28, 32))	('PTK6', 'Gene', (28, 32))	('invasion', 'CPA', (70, 78))
298760	24788754	We used the selective inhibitor of ERK1/2, U0126 to inhibit ERK1/2 activity.	('inhibit', 'NegReg', (52, 59))	('ERK1/2', 'Gene', (35, 41))	('U0126', 'Var', (43, 48))	('ERK1/2', 'Gene', '5595;5594', (35, 41))	('activity', 'MPA', (67, 75))	('ERK1/2', 'Gene', (60, 66))	('U0126', 'Chemical', 'MESH:C113580', (43, 48))	('ERK1/2', 'Gene', '5595;5594', (60, 66))
298761	24788754	As shown in Figure 5A, PTK6-induced ERK/1/2 activation were completely blocked by U0126 at 10 microM.	('U0126', 'Var', (82, 87))	('ERK/1/2', 'Gene', (36, 43))	('PTK6', 'Gene', (23, 27))	('PTK6', 'Gene', '5753', (23, 27))	('ERK/1/2', 'Gene', '5595;5594', (36, 43))	('activation', 'PosReg', (44, 54))	('U0126', 'Chemical', 'MESH:C113580', (82, 87))
298762	24788754	When we assayed cellular migration and invasion of Panc1 and MIAPaCa 2 cells in the presence of U0126, U0126 reduced basal cellular migration and invasion and abolished the ability of PTK6 over-expression to stimulate them (Figure 5B).	('PTK6', 'Gene', '5753', (184, 188))	('Panc1', 'CellLine', 'CVCL:0480', (51, 56))	('reduced', 'NegReg', (109, 116))	('U0126', 'Chemical', 'MESH:C113580', (103, 108))	('U0126', 'Chemical', 'MESH:C113580', (96, 101))	('MIAPaCa 2', 'CellLine', 'CVCL:0428', (61, 70))	('invasion', 'CPA', (146, 154))	('abolished', 'NegReg', (159, 168))	('U0126', 'Var', (103, 108))	('U0126', 'Var', (96, 101))	('basal cellular migration', 'CPA', (117, 141))	('PTK6', 'Gene', (184, 188))
298768	24788754	Our key finding in this study is that PTK6 overexpression increases cellular migration and invasion and that PTK6 gene silencing, in contrast, decreases them in pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (161, 178))	('cellular migration', 'CPA', (68, 86))	('PTK6', 'Gene', '5753', (109, 113))	('increases', 'PosReg', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('decreases', 'NegReg', (143, 152))	('PTK6', 'Gene', (109, 113))	('invasion', 'CPA', (91, 99))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (161, 178))	('PTK6', 'Gene', (38, 42))	('PTK6', 'Gene', '5753', (38, 42))	('gene', 'Var', (114, 118))	('pancreatic cancer', 'Disease', (161, 178))
298789	24788754	The potential prognostic value of variation in PTK6 in pancreatic cancer awaits further study.	('PTK6', 'Gene', '5753', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('PTK6', 'Gene', (47, 51))	('variation', 'Var', (34, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('pancreatic cancer', 'Disease', (55, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))
298817	33544792	For image acquisition, optical plan-apochromatic corrected objectives with magnification of x4, x10, x20 and x40 were used.	('age', 'Gene', (6, 9))	('x20', 'Var', (101, 104))	('x40', 'Var', (109, 112))	('age', 'Gene', '5973', (6, 9))
298985	32432038	In vivo fluorescence imaging results demonstrated that bMED NPs could accumulate in tumor sites and achieve in vivo long-term circulation and continuous drug release.	('continuous drug release', 'MPA', (142, 165))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('accumulate', 'PosReg', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('achieve', 'PosReg', (100, 107))	('bMED', 'Var', (55, 59))
298986	32432038	In addition, bMED NPs exhibited significant antitumor effects in the esophageal cancer mouse model, which may provide a great platform for esophageal cancer chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', (48, 53))	('mouse', 'Species', '10090', (87, 92))	('w', 'Chemical', 'MESH:D014414', (100, 101))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('bMED', 'Var', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cancer', 'Disease', (80, 86))
299007	32432038	In addition, previous studies showed that the insertion of DOX into duplex DNA is the main reason for its anti-cancer activity through the inhibition of DNA replication, while, beta-elemene may exert its antitumor effect by mediating via a mitochondrial cytochrome c release-dependent apoptotic pathway and downregulating the expression of Bcl-2.	('w', 'Chemical', 'MESH:D014414', (299, 300))	('DOX', 'Chemical', 'MESH:D004317', (59, 62))	('beta-elemene', 'Chemical', 'MESH:C445979', (177, 189))	('cancer', 'Disease', (111, 117))	('insertion', 'Var', (46, 55))	('Bcl-2', 'Gene', '12043', (340, 345))	('expression', 'MPA', (326, 336))	('w', 'Chemical', 'MESH:D014414', (33, 34))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('downregulating', 'NegReg', (307, 321))	('tumor', 'Disease', (208, 213))	('w', 'Chemical', 'MESH:D014414', (309, 310))	('inhibition', 'NegReg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('mediating', 'Reg', (224, 233))	('DNA replication', 'MPA', (153, 168))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('Bcl-2', 'Gene', (340, 345))	('w', 'Chemical', 'MESH:D014414', (170, 171))
299123	32432038	The drugs CI values and concentrations for K510, K30, and K150 inhibition using the combinations DOX and beta-elemene at the proportions of 1:5 and 1:15, are shown in Tables S1, S2.	('beta-elemene', 'Chemical', 'MESH:C445979', (105, 117))	('DOX', 'Chemical', 'MESH:D004317', (97, 100))	('K150', 'Var', (58, 62))	('w', 'Chemical', 'MESH:D014414', (161, 162))	('K510', 'Var', (43, 47))	('K30', 'Var', (49, 52))	('inhibition', 'NegReg', (63, 73))
299161	32432038	As shown in Figure S2A, K30 cells that were treated with the bMED NPs had an upregulation of Bax protein expression and a downregulation of Bcl-2 protein expression.	('Bax', 'Gene', (93, 96))	('w', 'Chemical', 'MESH:D014414', (124, 125))	('downregulation', 'NegReg', (122, 136))	('w', 'Chemical', 'MESH:D014414', (39, 40))	('bMED', 'Var', (61, 65))	('Bax', 'Gene', '12028', (93, 96))	('w', 'Chemical', 'MESH:D014414', (6, 7))	('upregulation', 'PosReg', (77, 89))	('Bcl-2', 'Gene', '12043', (140, 145))	('Bcl-2', 'Gene', (140, 145))	('w', 'Chemical', 'MESH:D014414', (52, 53))
299167	32432038	After 14 days, the survival rate of mice was 80% in the bMED NPs treatment group; while, the survival rate was only 40% in the dual drugs group.	('survival rate', 'CPA', (19, 32))	('w', 'Chemical', 'MESH:D014414', (82, 83))	('mice', 'Species', '10090', (36, 40))	('w', 'Chemical', 'MESH:D014414', (107, 108))	('w', 'Chemical', 'MESH:D014414', (41, 42))	('bMED NPs', 'Var', (56, 64))
299171	32432038	The result of the hemolysis test showed that bMED NPs had lower hemolytic toxicity relative to triton-X and the dual drugs treatment group (Figure 6C).	('triton-X', 'Chemical', 'MESH:D017830', (95, 103))	('hemolysis', 'Disease', (18, 27))	('hemolytic toxicity', 'Disease', 'MESH:D064420', (64, 82))	('hemolysis', 'Disease', 'MESH:D006461', (18, 27))	('lower', 'NegReg', (58, 63))	('w', 'Chemical', 'MESH:D014414', (36, 37))	('w', 'Chemical', 'MESH:D014414', (60, 61))	('hemolytic toxicity', 'Disease', (64, 82))	('bMED NPs', 'Var', (45, 53))
299178	32432038	The strongest fluorescence was at 12 h. In the free-IR780 group, no significant signal accumulation was observed in the tumors.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('free-IR780', 'Var', (47, 57))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('w', 'Chemical', 'MESH:D014414', (27, 28))	('w', 'Chemical', 'MESH:D014414', (100, 101))
299179	32432038	Figure 7B showed that the bMED NPs significantly prolonged the in vivo circulation time of IR780.	('bMED', 'Var', (26, 30))	('in vivo circulation time', 'CPA', (63, 87))	('IR780', 'Gene', (91, 96))	('w', 'Chemical', 'MESH:D014414', (13, 14))	('prolonged', 'PosReg', (49, 58))
299191	32432038	There was no significant decrease in body weight and saline in the bMED NPs group, indicating that bMED NPs can reduce drug toxicity.	('reduce', 'NegReg', (112, 118))	('reduce drug toxicity', 'Phenotype', 'HP:0020173', (112, 132))	('bMED', 'Var', (99, 103))	('drug toxicity', 'Disease', (119, 132))	('w', 'Chemical', 'MESH:D014414', (6, 7))	('drug toxicity', 'Disease', 'MESH:D064420', (119, 132))	('w', 'Chemical', 'MESH:D014414', (42, 43))
299193	32432038	Statistically, bMED NPs group was significantly different from saline group (***p < 0.001), the bMED NPs group showed a significant anti-tumor effect than in the dual drugs group and the dual drugs group was more effective than the DOX and beta-elemene groups.	('tumor', 'Disease', (137, 142))	('w', 'Chemical', 'MESH:D014414', (114, 115))	('w', 'Chemical', 'MESH:D014414', (204, 205))	('w', 'Chemical', 'MESH:D014414', (30, 31))	('DOX', 'Chemical', 'MESH:D004317', (232, 235))	('bMED NPs', 'Var', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('beta-elemene', 'Chemical', 'MESH:C445979', (240, 252))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
299198	32432038	TUNEL staining was used to detect apoptosis and the results showed that treatment with bMED NPs could significantly induce apoptosis and inhibit tumor growth (Figure S3B).	('induce', 'PosReg', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('w', 'Chemical', 'MESH:D014414', (15, 16))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('w', 'Chemical', 'MESH:D014414', (82, 83))	('tumor', 'Disease', (145, 150))	('inhibit', 'NegReg', (137, 144))	('apoptosis', 'CPA', (123, 132))	('w', 'Chemical', 'MESH:D014414', (154, 155))	('bMED', 'Var', (87, 91))	('w', 'Chemical', 'MESH:D014414', (63, 64))	('S3B', 'Gene', '11778', (166, 169))	('S3B', 'Gene', (166, 169))
299229	32432038	The addition of HAase mimics the in vivo environment and significantly increase the efficiency of DOX release; thereby, demonstrating that the presence of HA provides bMED NPs with good targeting and drug delivery capabilities.	('w', 'Chemical', 'MESH:D014414', (176, 177))	('HA', 'Chemical', 'MESH:D006820', (155, 157))	('efficiency', 'MPA', (84, 94))	('DOX release', 'MPA', (98, 109))	('increase', 'PosReg', (71, 79))	('HA', 'Chemical', 'MESH:D006820', (16, 18))	('presence', 'Var', (143, 151))	('DOX', 'Chemical', 'MESH:D004317', (98, 101))
299230	32432038	To verify the distribution and targeting ability of bMED NPs in vivo, the changes in fluorescent signals, provided by surface modified IR780, were monitored in a subcutaneous tumor model of esophageal cancer for 96 h. The results showed that bMED NPs were well-targeted to tumors and effectively prolonged the circulating time in vivo compared to small molecule drugs alone, which was demonstrated from the efficiency of bMSN nanocarriers.	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('w', 'Chemical', 'MESH:D014414', (233, 234))	('tumor', 'Disease', (273, 278))	('circulating time', 'MPA', (310, 326))	('w', 'Chemical', 'MESH:D014414', (375, 376))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('w', 'Chemical', 'MESH:D014414', (256, 257))	('w', 'Chemical', 'MESH:D014414', (142, 143))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('w', 'Chemical', 'MESH:D014414', (381, 382))	('tumors', 'Disease', (273, 279))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (162, 180))	('bMSN', 'Chemical', '-', (421, 425))	('bMED NPs', 'Var', (242, 250))	('prolonged', 'PosReg', (296, 305))	('w', 'Chemical', 'MESH:D014414', (251, 252))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumors', 'Disease', 'MESH:D009369', (273, 279))
299239	32432038	To study the in vivo antitumor effects of bMED NPs, changes in mice body weight were monitored within 22 days, and the results showed that the mice in the bMED treatment group had substantially no change in body weight compared with the dual drugs treatment and the single drug treatment groups.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('w', 'Chemical', 'MESH:D014414', (80, 81))	('w', 'Chemical', 'MESH:D014414', (73, 74))	('tumor', 'Disease', (25, 30))	('w', 'Chemical', 'MESH:D014414', (228, 229))	('w', 'Chemical', 'MESH:D014414', (95, 96))	('mice', 'Species', '10090', (63, 67))	('w', 'Chemical', 'MESH:D014414', (130, 131))	('w', 'Chemical', 'MESH:D014414', (212, 213))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('bMED', 'Var', (155, 159))	('mice', 'Species', '10090', (143, 147))
299247	32432038	The results of the studies on the antitumor mechanism of bMED NPs showed that bMED can downregulate the expression of Bcl-2, increase the ratio of Bcl-2/Bax and cause apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('Bcl-2', 'Gene', '12043', (147, 152))	('Bax', 'Gene', (153, 156))	('cause', 'Reg', (161, 166))	('bMED', 'Var', (78, 82))	('increase', 'PosReg', (125, 133))	('apoptosis', 'CPA', (167, 176))	('ratio', 'MPA', (138, 143))	('Bcl-2', 'Gene', (118, 123))	('w', 'Chemical', 'MESH:D014414', (89, 90))	('expression', 'MPA', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Bcl-2', 'Gene', '12043', (118, 123))	('downregulate', 'NegReg', (87, 99))	('Bax', 'Gene', '12028', (153, 156))	('w', 'Chemical', 'MESH:D014414', (69, 70))	('Bcl-2', 'Gene', (147, 152))
299250	32432038	The above results indicated that bMED NPs had good antitumor effects in vitro and in vivo and could provide a good nanodrug platform for the treatment of esophageal cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('bMED', 'Var', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
299276	31513770	However, transmission of certain oral microbes can potentially promote disease in the distal gut in genetically susceptible hosts.	('transmission', 'Var', (9, 21))	('gut', 'Gene', '110006', (93, 96))	('disease', 'Disease', (71, 78))	('gut', 'Gene', (93, 96))	('promote', 'PosReg', (63, 70))
299316	31513770	In addition, B. thetaiotamicron dramatically increases colipase expression of ileal crypts and many genes associated with intestinal barrier function, immune responses, and host xenobiotic metabolism.	('thetaiotamicron', 'Chemical', '-', (16, 31))	('expression', 'MPA', (64, 74))	('colipase', 'Gene', (55, 63))	('increases', 'PosReg', (45, 54))	('B. thetaiotamicron', 'Var', (13, 31))	('colipase', 'Gene', '109791', (55, 63))	('genes', 'Gene', (100, 105))
299326	31513770	The presence of SFB may also mitigate the development of diabetes in the non-obese diabetic mouse model, although it does not appear to affect obesity outcomes following exposure to HF diet.	('obesity', 'Phenotype', 'HP:0001513', (143, 150))	('SFB', 'Species', '49118', (16, 19))	('SFB', 'Gene', (16, 19))	('obese diabetic', 'Disease', 'MESH:D003920', (77, 91))	('obese diabetic', 'Disease', (77, 91))	('obesity', 'Disease', 'MESH:D009765', (143, 150))	('mitigate', 'NegReg', (29, 37))	('obesity', 'Disease', (143, 150))	('diabetes', 'Disease', (57, 65))	('mouse', 'Species', '10090', (92, 97))	('presence', 'Var', (4, 12))	('diabetes', 'Disease', 'MESH:D003920', (57, 65))
299330	31513770	The distal gut microbiota (cecum, colon, and feces) also exhibit the diurnal variation that can be affected by circadian disruption by genetic manipulation, induction of jet lag, as well as to time of food intake.	('diurnal', 'MPA', (69, 76))	('gut', 'Gene', (11, 14))	('affected', 'Reg', (99, 107))	('gut', 'Gene', '110006', (11, 14))	('genetic manipulation', 'Var', (135, 155))
299334	31513770	NFIL3 was ultimately shown to contribute to diet-induced obesity via affecting lipid absorption, as Nfil3 knockout mice had decreased epithelial lipid levels and increased lipids in the stool, overall demonstrating an important microbiota, host circadian, and metabolic interaction in the ileum.	('rat', 'Species', '10116', (208, 211))	('lipid', 'Chemical', 'MESH:D008055', (172, 177))	('affecting', 'Reg', (69, 78))	('lipids', 'Chemical', 'MESH:D008055', (172, 178))	('Nfil3', 'Gene', '18030', (100, 105))	('obesity', 'Phenotype', 'HP:0001513', (57, 64))	('increased', 'PosReg', (162, 171))	('NFIL3', 'Gene', (0, 5))	('knockout', 'Var', (106, 114))	('lipid', 'Chemical', 'MESH:D008055', (145, 150))	('mice', 'Species', '10090', (115, 119))	('lipids in', 'MPA', (172, 181))	('lipid', 'Chemical', 'MESH:D008055', (79, 84))	('obesity', 'Disease', (57, 64))	('Nfil3', 'Gene', (100, 105))	('obesity', 'Disease', 'MESH:D009765', (57, 64))	('decreased', 'NegReg', (124, 133))	('NFIL3', 'Gene', '18030', (0, 5))	('lipid absorption', 'MPA', (79, 95))	('increased lipids', 'Phenotype', 'HP:0003077', (162, 178))	('epithelial lipid levels', 'MPA', (134, 157))
299355	31513770	Constipation induced by Loperamide, which slows intestinal transit, alters gut microbiota composition and functional capacity, which directly affected colonic contraction.	('gut', 'Gene', (75, 78))	('slows', 'NegReg', (42, 47))	('intestinal transit', 'MPA', (48, 66))	('colonic contraction', 'Disease', 'MESH:D003110', (151, 170))	('gut', 'Gene', '110006', (75, 78))	('Constipation', 'Disease', 'MESH:D003248', (0, 12))	('Loperamide', 'Chemical', 'MESH:D008139', (24, 34))	('alters', 'Reg', (68, 74))	('Constipation', 'Disease', (0, 12))	('Loperamide', 'Var', (24, 34))	('Constipation', 'Phenotype', 'HP:0002019', (0, 12))	('colonic contraction', 'Disease', (151, 170))	('functional capacity', 'MPA', (106, 125))	('slows intestinal transit', 'Phenotype', 'HP:0030897', (42, 66))	('affected', 'Reg', (142, 150))
299358	31513770	For instance, gastric Helicobacter pylori, can promote peptic ulcer diseases and gastric cancer in humans, whereas different species like Helicobacter hepaticus can cause colitis in susceptible mice.	('peptic ulcer', 'Phenotype', 'HP:0004398', (55, 67))	('Helicobacter hepaticus', 'Var', (138, 160))	('ulcer diseases', 'Disease', 'MESH:D014456', (62, 76))	('colitis', 'Phenotype', 'HP:0002583', (171, 178))	('promote', 'PosReg', (47, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric', 'Disease', (14, 21))	('humans', 'Species', '9606', (99, 105))	('gastric cancer', 'Disease', (81, 95))	('ulcer diseases', 'Disease', (62, 76))	('Helicobacter pylori', 'Species', '210', (22, 41))	('Helicobacter hepaticus', 'Species', '32025', (138, 160))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('colitis', 'Disease', 'MESH:D003092', (171, 178))	('mice', 'Species', '10090', (194, 198))	('colitis', 'Disease', (171, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
299367	31513770	Prior to improved hygiene, many individuals benefited from H. pylori through enhanced induction of gastric acid and mucosal immune mechanisms capable of deterring many pathogens.	('enhanced', 'PosReg', (77, 85))	('H. pylori', 'Species', '210', (59, 68))	('benefited', 'PosReg', (44, 53))	('gastric acid', 'MPA', (99, 111))	('induction', 'MPA', (86, 95))	('H. pylori', 'Var', (59, 68))	('deterring', 'NegReg', (153, 162))
299391	31513770	In mice that overexpress IEC IL15 (IL15tg), gut microbiota are affected throughout the intestine, with the most pronounced differences observed in the ileum.	('IL15', 'Gene', '16168', (35, 39))	('overexpress', 'PosReg', (13, 24))	('IEC', 'Var', (25, 28))	('gut', 'Gene', (44, 47))	('IL15', 'Gene', '16168', (29, 33))	('mice', 'Species', '10090', (3, 7))	('IL15', 'Gene', (35, 39))	('gut', 'Gene', '110006', (44, 47))	('IL15tg', 'Gene', '16168', (35, 41))	('IL15tg', 'Gene', (35, 41))	('affected', 'Reg', (63, 71))	('IL15', 'Gene', (29, 33))
299393	31513770	While the IL15Tg mice did not develop overt CD, these findings showed that altered IL-15 expression can significantly alter microbial community membership and function, possibly contributing to CD progression.	('contributing', 'Reg', (178, 190))	('expression', 'MPA', (89, 99))	('mice', 'Species', '10090', (17, 21))	('function', 'MPA', (159, 167))	('microbial community membership', 'CPA', (124, 154))	('IL15Tg', 'Gene', '16168', (10, 16))	('IL-15', 'Gene', (83, 88))	('altered', 'Var', (75, 82))	('IL-15', 'Gene', '16168', (83, 88))	('IL15Tg', 'Gene', (10, 16))	('alter', 'Reg', (118, 123))
299429	30606744	Furthermore, the 5-bp indel polymorphism (rs145204276) in the GAS5 promoter region also has a carcinogenic effect.	('carcinogenic', 'Disease', 'MESH:D063646', (94, 106))	('rs145204276', 'Mutation', 'rs145204276', (42, 53))	('carcinogenic', 'Disease', (94, 106))	('rs145204276', 'Var', (42, 53))
299430	30606744	The discovery of GAS5 and in-depth study of single nucleotide polymorphism (SNP) mechanism can provide a new way for the prevention and treatment of digestive system tumors.	('digestive system tumors', 'Phenotype', 'HP:0007378', (149, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('system tumors', 'Disease', (159, 172))	('single nucleotide polymorphism', 'Var', (44, 74))	('system tumors', 'Disease', 'MESH:D009369', (159, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
299433	30606744	Although lncRNAs have once been thought as the 'dark matter' of the genome, an abnormal expression of lncRNAs virtually participates in all stages of cancer development, including cancer initiation, progression, and metastasis.	('abnormal', 'Var', (79, 87))	('cancer initiation', 'Disease', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('progression', 'CPA', (199, 210))	('cancer', 'Disease', (150, 156))	('lncRNAs', 'Gene', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer initiation', 'Disease', 'MESH:D009369', (180, 197))	('metastasis', 'CPA', (216, 226))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('participates in', 'Reg', (120, 135))
299447	30606744	The exon 12-derived stem-loop region of lncRNA GAS5 was found to mimic the glucocorticoid receptor response element (GRE) structurally, and lncRNA GAS5 was shown to compete with GRE to associate with the DNA-binding domain of glucocorticoid receptor.	('glucocorticoid receptor', 'Gene', '2908', (75, 98))	('associate', 'Interaction', (185, 194))	('glucocorticoid receptor', 'Gene', '2908', (226, 249))	('glucocorticoid receptor', 'Gene', (75, 98))	('lncRNA GAS5', 'Var', (140, 151))	('glucocorticoid receptor', 'Gene', (226, 249))
299459	30606744	It was found that there is also a link between the 5-bp indel polymorphism (rs145204276) in the GAS5 promoter region and hepatocarcinoma.	('rs145204276', 'Mutation', 'rs145204276', (76, 87))	('link', 'Reg', (34, 38))	('hepatocarcinoma', 'Disease', 'None', (121, 136))	('rs145204276', 'Var', (76, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('hepatocarcinoma', 'Disease', (121, 136))
299460	30606744	Interestingly, the opposite of rs145204276 and GAS5, rs145204276 can increase the susceptibility of hepatocarcinoma.	('hepatocarcinoma', 'Disease', (100, 115))	('increase', 'PosReg', (69, 77))	('increase the susceptibility of hepatocarcinoma', 'Phenotype', 'HP:0001402', (69, 115))	('rs145204276', 'Mutation', 'rs145204276', (53, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('hepatocarcinoma', 'Disease', 'None', (100, 115))	('rs145204276', 'Var', (53, 64))	('rs145204276', 'Mutation', 'rs145204276', (31, 42))
299461	30606744	found that indel polymorphism rs145204276 may influence GAS5 transcriptional activity by affecting the methylation status of a CpG island in the promoter region of GAS5, thereby affecting its utility in suppressing tumors.	('influence', 'Reg', (46, 55))	('transcriptional activity', 'MPA', (61, 85))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('methylation status', 'MPA', (103, 121))	('rs145204276', 'Var', (30, 41))	('affecting', 'Reg', (178, 187))	('affecting', 'Reg', (89, 98))	('rs145204276', 'Mutation', 'rs145204276', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('suppressing', 'NegReg', (203, 214))	('GAS5', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))
299462	30606744	However, this tumor-promoting mechanism still needs further study, and how to determine the existence of indel polymorphism rs145204276 before treatment is a problem we need to further study.	('tumor', 'Disease', (14, 19))	('rs145204276', 'Mutation', 'rs145204276', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('rs145204276', 'Var', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
299467	30606744	In addition, patients with low levels of GAS5 mRNA have a shorter survival time, and statistical studies have found that the expression level of GAS5 can be an independent risk factor for colorectal cancer and a predictor of prognosis.	('shorter', 'NegReg', (58, 65))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('patients', 'Species', '9606', (13, 21))	('low levels', 'Var', (27, 37))	('expression', 'MPA', (125, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('survival time', 'CPA', (66, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('GAS5', 'Gene', (145, 149))
299472	30606744	found that rs145204276 also had the ability to enhance colorectal cancer susceptibility and promote lymph node metastasis of tumor in colorectal cancer tissues.	('enhance', 'PosReg', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('promote', 'PosReg', (92, 99))	('colorectal cancer', 'Disease', (134, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('rs145204276', 'Var', (11, 22))	('tumor', 'Disease', (125, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('colorectal cancer', 'Disease', (55, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('rs145204276', 'Mutation', 'rs145204276', (11, 22))
299476	30606744	In vitro, GAS5 was found to inhibit the viability, migration, and invasion of pancreatic cancer cells.	('viability', 'CPA', (40, 49))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('migration', 'CPA', (51, 60))	('GAS5', 'Var', (10, 14))	('pancreatic cancer', 'Disease', (78, 95))	('invasion', 'CPA', (66, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('inhibit', 'NegReg', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
299477	30606744	After transfection of pcDNA GAS5, the cell viability of the tumor cells was significantly reduced, the percentage of apoptosis was significantly increased, and the tumor weight was significantly reduced.	('tumor', 'Disease', (164, 169))	('reduced', 'NegReg', (195, 202))	('reduced', 'NegReg', (90, 97))	('transfection', 'Var', (6, 18))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('increased', 'PosReg', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('pcDNA GAS5', 'Var', (22, 32))
299483	30606744	In addition, scholars have found that GAS5 not only inhibits the proliferation of PC cells, but also has an impact on drug resistance of drug-resistant cells in recent years.	('proliferation', 'CPA', (65, 78))	('drug resistance', 'Phenotype', 'HP:0020174', (118, 133))	('inhibits', 'NegReg', (52, 60))	('GAS5', 'Var', (38, 42))	('PC', 'CellLine', 'CVCL:0152', (82, 84))	('drug resistance', 'MPA', (118, 133))	('impact', 'Reg', (108, 114))
299488	30606744	It has also been reported in the literature that GAS5 acts as a competitive endogenous RNA with miR-221 to inhibit PC cell growth, metastasis, and gemcitabine resistance.	('inhibit', 'NegReg', (107, 114))	('miR-221', 'Gene', (96, 103))	('gemcitabine resistance', 'CPA', (147, 169))	('metastasis', 'CPA', (131, 141))	('gemcitabine', 'Chemical', 'MESH:C056507', (147, 158))	('PC', 'CellLine', 'CVCL:0152', (115, 117))	('miR-221', 'Gene', '407006', (96, 103))	('GAS5', 'Var', (49, 53))
299493	30606744	The researchers said that GAS5 plays an important role in inhibiting the growth of gastric cancer and that knockdown of GAS5 will eliminate the cell cycle arrest of tumor cells.	('knockdown', 'Var', (107, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('GAS5', 'Gene', (120, 124))	('inhibiting', 'NegReg', (58, 68))	('growth', 'CPA', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('gastric cancer', 'Disease', (83, 97))	('eliminate', 'NegReg', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('tumor', 'Disease', (165, 170))
299506	30606744	In addition, some scholars have studied the role of GAS5 gene variant rs145204276 in gastric cancer cells.	('gastric cancer', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('GAS5', 'Gene', (52, 56))	('rs145204276', 'Var', (70, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))	('rs145204276', 'Mutation', 'rs145204276', (70, 81))
299507	30606744	found high expression of rs145204276 in gastric cancer cells, but he did not think that this is an expression that promotes gastric cancer cell proliferation but a protective mechanism of the body in gastric cancer cells.	('gastric cancer', 'Disease', (124, 138))	('gastric cancer', 'Disease', (200, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('gastric cancer', 'Disease', (40, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('rs145204276', 'Var', (25, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('promotes', 'PosReg', (115, 123))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))	('rs145204276', 'Mutation', 'rs145204276', (25, 36))
299508	30606744	However, its mechanism has not been studied in detail, so the mechanism of high expression of rs145204276 in gastric cancer cells is still unknown.	('rs145204276', 'Mutation', 'rs145204276', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('rs145204276', 'Var', (94, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))
299509	30606744	The discovery that GAS5 can improve the chemosensitivity of gastric cancer is considered to be very important and has good clinical application value, which deserves special attention.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('GAS5', 'Var', (19, 23))	('chemosensitivity', 'MPA', (40, 56))	('gastric cancer', 'Disease', (60, 74))	('improve', 'PosReg', (28, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))
299517	30606744	In vitro, it is found that miR-196a binds to exons via RISC to regulate the expression of GAS5 so as to inhibit tumors.	('RISC', 'Gene', (55, 59))	('miR-196a', 'Var', (27, 35))	('RISC', 'Gene', '59342', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('expression', 'MPA', (76, 86))	('regulate', 'Reg', (63, 71))	('GAS5', 'Gene', (90, 94))	('inhibit', 'NegReg', (104, 111))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('binds', 'Interaction', (36, 41))	('tumors', 'Disease', (112, 118))
299526	30606744	In recent years, lncRNAs have been found to play important regulatory roles in gene expression, and abnormal expression of lncRNA is increasingly recognized as a hallmark feature of cancer.	('lncRNA', 'Gene', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('abnormal', 'Var', (100, 108))	('expression', 'MPA', (109, 119))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))
299531	30606744	In this article, rs145204276 plays an important role in hepatocarcinoma, colorectal cancer, and gastric cancer tissues, and changes the original tumor suppressor effect of GAS5 (Figure 1).	('hepatocarcinoma', 'Disease', 'None', (56, 71))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('hepatocarcinoma', 'Disease', (56, 71))	('rs145204276', 'Var', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('rs145204276', 'Mutation', 'rs145204276', (17, 28))	('gastric cancer', 'Disease', (96, 110))	('changes', 'Reg', (124, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
299545	30210637	Results: The meta-analysis showed that high expression of CXCR7 predicted a high risk of LNM (pooled OR = 2.22, 95%CI: 1.41-3.50), high tumor grade (pooled OR = 1.94, 95%CI: 1.20-3.13), poor OS (pooled HR = 1.66, 95%CI: 1.30-2.03), and poor DFS/RFS (pooled HR = 1.82, 95%CI: 1.21-2.43).	('CXCR7', 'Gene', '57007', (58, 63))	('high tumor', 'Disease', (131, 141))	('high expression', 'Var', (39, 54))	('poor', 'NegReg', (236, 240))	('poor', 'Disease', (186, 190))	('OS', 'Chemical', '-', (191, 193))	('CXCR7', 'Gene', (58, 63))	('high tumor', 'Disease', 'MESH:D009369', (131, 141))	('LNM', 'Disease', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
299548	30210637	As in OS group, we divided the data based on analysis method and it turned out that overexpressed CXCR7 predicted worse OS both in multivariate analysis (pooled HR =1.57, 95%CI: 1.12-2.01) and univariate analysis subgroup (pooled HR =1.86, 95%CI: 1.23-2.49).	('OS', 'Chemical', '-', (6, 8))	('CXCR7', 'Gene', (98, 103))	('worse OS', 'Disease', (114, 122))	('overexpressed', 'Var', (84, 97))	('OS', 'Chemical', '-', (120, 122))	('CXCR7', 'Gene', '57007', (98, 103))
299595	30210637	The results showed that high expression of CXCR7 was significantly associated with poor OS in patients with solid tumors (pooled HR =1.66, 95%CI: 1.30-2.03, Figure 4A).	('patients', 'Species', '9606', (94, 102))	('CXCR7', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('poor OS', 'Disease', (83, 90))	('solid tumors', 'Disease', (108, 120))	('high', 'Var', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('OS', 'Chemical', '-', (88, 90))	('solid tumors', 'Disease', 'MESH:D009369', (108, 120))	('CXCR7', 'Gene', '57007', (43, 48))
299596	30210637	The results revealed that high expression of CXCR7 predicted worse survival both in multivariate analysis subgroup (pooled HR =1.57, 95%CI: 1.12-2.01) and univariate analysis subgroup (pooled HR =1.86, 95%CI: 1.23-2.49) (Figure 4B).	('high', 'Var', (26, 30))	('CXCR7', 'Gene', '57007', (45, 50))	('survival', 'MPA', (67, 75))	('CXCR7', 'Gene', (45, 50))	('worse', 'NegReg', (61, 66))
299598	30210637	7 datasets with 667 patients included in our meta-analysis, the results showed that high expression of CXCR7 had a potent correlation with unfavorable DFS/RFS (pooled HR = 1.82, 95%CI: 1.21-2.43, Figure 5).	('high', 'Var', (84, 88))	('CXCR7', 'Gene', '57007', (103, 108))	('patients', 'Species', '9606', (20, 28))	('CXCR7', 'Gene', (103, 108))	('unfavorable DFS/RFS', 'MPA', (139, 158))
299606	30210637	There were several signaling mechanisms involved in these processes, including aberrated expression of PI3K/AKT, MAPK/ERK, Rho/ROCK and mTOR signaling pathway.	('ERK', 'Gene', '5594', (118, 121))	('AKT', 'Gene', '207', (108, 111))	('expression', 'MPA', (89, 99))	('aberrated', 'Var', (79, 88))	('Rho/ROCK', 'Gene', (123, 131))	('ERK', 'Gene', (118, 121))	('AKT', 'Gene', (108, 111))	('mTOR', 'Gene', (136, 140))	('mTOR', 'Gene', '2475', (136, 140))
299626	30210637	In conclusion, our meta-analysis suggested that high expression of CXCR7 could act as a common maker to predict a high risk of LNM, especially in adenocarcinoma, high tumor grade and poor OS or DFS/RFS in patients with the solid tumor.	('high tumor', 'Disease', (162, 172))	('adenocarcinoma', 'Disease', 'MESH:D000230', (146, 160))	('CXCR7', 'Gene', (67, 72))	('patients', 'Species', '9606', (205, 213))	('LNM', 'Disease', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('solid tumor', 'Disease', (223, 234))	('high tumor', 'Disease', 'MESH:D009369', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('solid tumor', 'Disease', 'MESH:D009369', (223, 234))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('CXCR7', 'Gene', '57007', (67, 72))	('OS', 'Chemical', '-', (188, 190))	('poor OS', 'Var', (183, 190))	('adenocarcinoma', 'Disease', (146, 160))
299661	29414899	While single miRNA transfections resulted in significant increases in sensitivity towards 5-FU in about 63% of all experiments, only miR-125a-5p/miR-148a-3p co-transfection for KYSE-270 led to significantly better response to 5-FU compared to single transfected controls and increased sensitivity by about 16%.	('5-FU', 'Chemical', 'MESH:D005472', (226, 230))	('miR', 'Gene', '220972', (133, 136))	('miR', 'Gene', (13, 16))	('miR', 'Gene', (133, 136))	('miR', 'Gene', '220972', (13, 16))	('miR-125a', 'Gene', (133, 141))	('response to 5-FU', 'MPA', (214, 230))	('5-FU', 'Chemical', 'MESH:D005472', (90, 94))	('increases', 'PosReg', (57, 66))	('miR', 'Gene', '220972', (145, 148))	('miR-148a', 'Gene', '406940', (145, 153))	('miR', 'Gene', (145, 148))	('better', 'PosReg', (207, 213))	('miR-148a', 'Gene', (145, 153))	('sensitivity towards 5-FU', 'MPA', (70, 94))	('miR-125a', 'Gene', '406910', (133, 141))	('KYSE-270', 'Var', (177, 185))
299682	29414899	Similarly, high expression of miR-130a was associated with increasing sensitivity towards Gemcitabine in hepatoma, while others described that miR-130a increases resistance towards platinum-based chemotherapy in ovarian cancer.	('miR-130a', 'Gene', (143, 151))	('sensitivity towards Gemcitabine', 'MPA', (70, 101))	('miR-130a', 'Gene', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('increases', 'PosReg', (152, 161))	('hepatoma', 'Disease', (105, 113))	('miR-130a', 'Gene', '406919', (143, 151))	('Gemcitabine', 'Chemical', 'MESH:C056507', (90, 101))	('ovarian cancer', 'Disease', 'MESH:D010051', (212, 226))	('miR-130a', 'Gene', '406919', (30, 38))	('increasing', 'PosReg', (59, 69))	('resistance towards platinum-based chemotherapy', 'MPA', (162, 208))	('hepatoma', 'Disease', 'MESH:D006528', (105, 113))	('high', 'Var', (11, 15))	('ovarian cancer', 'Disease', (212, 226))	('platinum', 'Chemical', 'MESH:D010984', (181, 189))
299683	29414899	With regards to miR-148a, high miR-148a levels were shown to increase sensitivity towards Docetaxel and Paclitaxel in prostate cancer, while others did not find any impact of miR-148a expression on resistance towards Gemcitabine in pancreatic cancer.	('miR-148a', 'Gene', '406940', (16, 24))	('miR-148a', 'Gene', (16, 24))	('high', 'Var', (26, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (232, 249))	('increase', 'PosReg', (61, 69))	('Docetaxel', 'Chemical', 'MESH:D000077143', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('prostate cancer', 'Disease', 'MESH:D011471', (118, 133))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('Paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('pancreatic cancer', 'Disease', 'MESH:D010190', (232, 249))	('sensitivity towards Docetaxel', 'MPA', (70, 99))	('prostate cancer', 'Disease', (118, 133))	('miR-148a', 'Gene', '406940', (175, 183))	('Gemcitabine', 'Chemical', 'MESH:C056507', (217, 228))	('miR-148a', 'Gene', '406940', (31, 39))	('miR-148a', 'Gene', (175, 183))	('miR-148a', 'Gene', (31, 39))	('pancreatic cancer', 'Disease', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
299693	29414899	Finally, and most interestingly, we could show that simultaneous manipulation of the expression levels of two miRNAs exhibited an additive sensitizing effect towards cisplatin treatment in 50% (miR-125a-5p/miR-148a-3p) and 75% (miR-148a-3p/miR-130a-3p) of tested cell lines.	('cisplatin treatment', 'MPA', (166, 185))	('miR-130a', 'Gene', '406919', (240, 248))	('miR-125a', 'Gene', '406910', (194, 202))	('sensitizing effect', 'MPA', (139, 157))	('miR-148a', 'Gene', '406940', (228, 236))	('miR', 'Gene', '220972', (194, 197))	('miR-125a', 'Gene', (194, 202))	('miR-148a', 'Gene', (228, 236))	('miR-130a', 'Gene', (240, 248))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('miR', 'Gene', '220972', (240, 243))	('miR', 'Gene', (194, 197))	('miR', 'Gene', '220972', (206, 209))	('miR', 'Gene', (240, 243))	('miR', 'Gene', '220972', (110, 113))	('miR', 'Gene', '220972', (228, 231))	('expression', 'MPA', (85, 95))	('miR-148a', 'Gene', '406940', (206, 214))	('miR-148a', 'Gene', (206, 214))	('miR', 'Gene', (206, 209))	('manipulation', 'Var', (65, 77))	('miR', 'Gene', (110, 113))	('miR', 'Gene', (228, 231))
299702	29414899	Furthermore, our data clearly support the hypothesis that epigenetic regulation of chemotherapy resistance is a complex process with several miRNAs acting additively (and/or antagonistically) via simultaneous regulation of several resistance-relevant pathways on various key proteins within these pathways.	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', (141, 144))	('epigenetic regulation', 'Var', (58, 79))	('regulation', 'Reg', (209, 219))	('resistance-relevant pathways', 'Pathway', (231, 259))
299705	29414899	ESCC cell lines KYSE-70, KYSE-140, KYSE-180, KYSE-270, KYSE-410 and KYSE-520 (purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), Braunschweig, Germany) were cultured using standard media and techniques as described previously.	('von', 'Disease', 'MESH:D014842', (111, 114))	('KYSE-410', 'Var', (55, 63))	('von', 'Disease', (111, 114))
299706	29414899	We selected a panel of three miRNAs from a characteristic miRNA signature of resistant ESCC cells reported in our earlier study: hsa-miR-125a-5p (#MSY0000443), hsa-miR-130a-3p (#MIN0000425), and hsa-miR-1226-3p (#MSY0005577) (all miRNAs are available from Qiagen, Hilden, Germany).	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (133, 136))	('miR', 'Gene', (164, 167))	('miR-130a', 'Gene', (164, 172))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (29, 32))	('#MSY0000443', 'Var', (146, 157))	('miR-1226', 'Gene', (199, 207))	('miR', 'Gene', (58, 61))	('#MIN0000425', 'Var', (177, 188))	('miR', 'Gene', '220972', (230, 233))	('miR', 'Gene', '220972', (199, 202))	('miR-1226', 'Gene', '100302232', (199, 207))	('miR-125a', 'Gene', '406910', (133, 141))	('miR', 'Gene', '220972', (133, 136))	('miR', 'Gene', '220972', (164, 167))	('miR-125a', 'Gene', (133, 141))	('miR', 'Gene', (230, 233))	('miR', 'Gene', (199, 202))	('miR-130a', 'Gene', '406919', (164, 172))
299723	29414899	The respective primary antibodies were purchased from BD Bioscience, Heidelberg, Germany (559685, 551097, 610716), Biomol, Hamburg, Germany (A302-747A-T, A303-625A-T), Cell signaling, Danvers, MA, USA (5119, 2435, 2165, 9282, 9662, 9502), BioLegend, UK (653601, 607701, 657407) and Santa Cruz Biochtechnology, Dallas, TX, USA (sc-493).	('A302-747A-T', 'Mutation', 'c.302_747A,A>T', (141, 152))	('653601', 'Var', (254, 260))	('A303-625A-T', 'Mutation', 'c.303_625A,A>T', (154, 165))	('A302-747A-T', 'Var', (141, 152))	('A303-625A-T', 'Var', (154, 165))
299775	28087951	Ten patient samples were evaluated for EGFR mutations; however, direct sequencing analysis revealed no mutations in any of the tumor samples, likely due to the low mutation rate reported in ESCC.	('ESCC', 'Disease', (190, 194))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('rat', 'Species', '10116', (173, 176))	('tumor', 'Disease', (127, 132))	('patient', 'Species', '9606', (4, 11))	('mutations', 'Var', (44, 53))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
299776	28087951	EGFR mutation analysis was therefore discontinued.	('mutation', 'Var', (5, 13))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
299791	28087951	First, erlotinib disrupts cell growth pathways and enhances the sensitivity of cells to RT.	('sensitivity', 'MPA', (64, 75))	('cell', 'Pathway', (26, 30))	('erlotinib', 'Var', (7, 16))	('disrupts', 'NegReg', (17, 25))	('enhances', 'PosReg', (51, 59))	('erlotinib', 'Chemical', 'MESH:D000069347', (7, 16))
299813	28087951	Studies of non-small cell lung cancer (NSCLC) showed that patients with tumors expressing EGFR carrying a mutation were more likely to respond to erlotinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (72, 78))	('NSCLC', 'Disease', (39, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('respond to erlotinib', 'MPA', (135, 155))	('non-small cell lung cancer', 'Disease', (11, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('mutation', 'Var', (106, 114))	('more', 'PosReg', (120, 124))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('EGFR', 'Gene', (90, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (15, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (11, 37))	('patients', 'Species', '9606', (58, 66))	('EGFR', 'Gene', '1956', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (11, 37))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
299815	28087951	In vitro studies indicate that erlotinib enhances the radiation response at several levels, including cell cycle arrest, apoptosis induction, accelerated cellular repopulation, and DNA damage repair.	('cellular repopulation', 'CPA', (154, 175))	('arrest', 'Disease', (113, 119))	('radiation response', 'CPA', (54, 72))	('rat', 'Species', '10116', (148, 151))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (102, 119))	('apoptosis induction', 'CPA', (121, 140))	('erlotinib', 'Var', (31, 40))	('enhances', 'PosReg', (41, 49))	('arrest', 'Disease', 'MESH:D006323', (113, 119))	('DNA damage repair', 'CPA', (181, 198))	('accelerated', 'PosReg', (142, 153))	('erlotinib', 'Chemical', 'MESH:D000069347', (31, 40))
299819	28087951	In a preclinical study involving three human cancer cell lines with low, moderate, or very high EGFR expression, the extent of erlotinib-induced radiosensitization was proportional to the EGFR expression level.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('rat', 'Species', '10116', (77, 80))	('EGFR', 'Gene', (96, 100))	('expression', 'Var', (101, 111))	('human', 'Species', '9606', (39, 44))	('low', 'NegReg', (68, 71))	('EGFR', 'Gene', '1956', (188, 192))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('EGFR', 'Gene', (188, 192))	('erlotinib', 'Chemical', 'MESH:D000069347', (127, 136))	('EGFR', 'Gene', '1956', (96, 100))
299840	28087951	Inclusion criteria consisted of histologically confirmed squamous cell carcinoma of the esophagus or esophagogastric junction; ineligibility for surgery; Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0-2; age >= 18 years old; life expectancy >= 12 weeks; no prior palliative therapy; at least one bidimensional measurable disease as defined by RECIST ver 1.1; adequate organ function for treatment; absolute neutrophil count (ANC) >= 1000 cells/mm3; platelets >= 100000 cells/mm3; estimated creatinine clearance >= 50 mL/min, or serum creatinine < 1.5x institutional upper limit of normal (ULN); bilirubin <= 1.5x ULN; AST (SGOT) <= 2.5x ULN (5.0x ULN if hepatic metastases); ALT (SGPT) <= 2.5x ULN (5.0x ULN if hepatic metastases); 12-lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention; QTc interval <= 470 ms and without history of Torsades de Pointes or other symptomatic QTc abnormality; LVEF (by MUGA or echocardiogram) of >= 50%.	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (71, 97))	('hepatic metastases', 'Disease', (681, 699))	('<= 470', 'Var', (904, 910))	('hepatic metastases', 'Disease', (738, 756))	('QTc abnormality', 'Disease', 'MESH:D000014', (978, 993))	('hepatic metastases', 'Disease', 'MESH:D009362', (681, 699))	('Torsades de Pointes', 'Disease', (937, 956))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('hepatic metastases', 'Disease', 'MESH:D009362', (738, 756))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('Oncology', 'Phenotype', 'HP:0002664', (174, 182))	('squamous cell carcinoma of the esophagus', 'Disease', (57, 97))	('Torsades de Pointes', 'Disease', 'MESH:D016171', (937, 956))	('QTc abnormality', 'Disease', (978, 993))	('rat', 'Species', '10116', (167, 170))	('Torsades de Pointes', 'Phenotype', 'HP:0001664', (937, 956))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (57, 97))
299857	28087951	For gene mutation analysis, DNA was collected from primary esophageal tumor specimens using the phenol-chloroform extraction method after overnight digestion of the tissue using proteinase K. Mutation within the four tyrosine kinase domain exons (18-21) of EGFR that are frequently mutated in esophageal cancer was assessed using PCR-direct sequencing as previously reported.	('phenol', 'Chemical', 'MESH:D019800', (96, 102))	('chloroform', 'Chemical', 'MESH:D002725', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('esophageal tumor', 'Disease', 'MESH:D004938', (59, 75))	('EGFR', 'Gene', (257, 261))	('esophageal tumor', 'Phenotype', 'HP:0100751', (59, 75))	('Mutation', 'Var', (192, 200))	('esophageal cancer', 'Disease', (293, 310))	('esophageal tumor', 'Disease', (59, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (293, 310))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('EGFR', 'Gene', '1956', (257, 261))
299996	27872710	Our data also demonstrated a significant up-regulation of variant 4 in high-grade tumor samples, in comparison to the low-grade ones (P=0.04).	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('variant', 'Var', (58, 65))	('tumor', 'Disease', (82, 87))	('up-regulation', 'PosReg', (41, 54))
299997	27872710	Moreover, the ROC curve analysis demonstrated that the variant 4 of ROR has a potential to discriminate between tumor and non-tumor samples (AUC=0.66, P<0.05).	('ROR', 'Gene', '100885779', (68, 71))	('non-tumor', 'Disease', 'MESH:D009369', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('ROR', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (112, 117))	('non-tumor', 'Disease', (122, 131))	('variant 4', 'Var', (55, 64))	('tumor', 'Disease', (126, 131))
300031	27872710	The quantitative real-time PCR data revealed a significant up-regulation of variant 2 (fold change 1/67, P=0.025) and variant 4 (fold change 2/65, P=0.0002) in tumor specimens, in comparison to their paired non-tumor samples (Figure 1B).	('variant', 'Var', (76, 83))	('variant', 'Var', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('non-tumor', 'Disease', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', (160, 165))	('non-tumor', 'Disease', 'MESH:D009369', (207, 216))	('up-regulation', 'PosReg', (59, 72))
300033	27872710	In contrast, variant 4 had a significantly higher expression level in high grade (GIII) tumors, compared to the low grade (GI and GII) ones (P=0.04.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('higher', 'PosReg', (43, 49))	('variant 4', 'Var', (13, 22))	('expression level', 'MPA', (50, 66))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('GI', 'Disease', 'MESH:D005767', (130, 132))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('GI', 'Disease', 'MESH:D005767', (82, 84))	('GI', 'Disease', 'MESH:D005767', (123, 125))
300037	27872710	In contrast to linc-ROR and variant 2, variant 4 showed a better suitability to classify tumor and non-tumor samples of esophagus.	('linc-ROR', 'Gene', '100885779', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('non-tumor', 'Disease', 'MESH:D009369', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (89, 94))	('variant', 'Var', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('non-tumor', 'Disease', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('linc-ROR', 'Gene', (15, 23))
300044	27872710	Moreover, our data demonstrated a significant up-regulation of variant 4 (but neither linc-ROR nor variant 2) in high-grade ESCC tumors, suggesting a potential role for variant 4 in ESCC tumor progression.	('variant', 'Var', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('up-regulation', 'PosReg', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ESCC', 'Disease', (182, 186))	('ESCC tumors', 'Disease', (124, 135))	('ESCC tumors', 'Disease', 'MESH:D004938', (124, 135))	('linc-ROR', 'Gene', '100885779', (86, 94))	('tumor', 'Disease', (129, 134))	('linc-ROR', 'Gene', (86, 94))
300055	27872710	Accordingly, ectopic expression of linc-ROR diminished cell proliferation, inhibited KLF4 expression, and decreased the capacity of tumorosphere formation in U87 glioma cell line.	('decreased', 'NegReg', (106, 115))	('U87', 'CellLine', 'CVCL:0022', (158, 161))	('KLF4', 'Gene', '9314', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('diminished', 'NegReg', (44, 54))	('glioma', 'Disease', (162, 168))	('KLF4', 'Gene', (85, 89))	('inhibited', 'NegReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cell proliferation', 'CPA', (55, 73))	('linc-ROR', 'Gene', (35, 43))	('tumor', 'Disease', (132, 137))	('linc-ROR', 'Gene', '100885779', (35, 43))	('ectopic expression', 'Var', (13, 31))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))
300167	25611972	By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes.	('esophageal cancer', 'Disease', (240, 257))	('frequent', 'Reg', (95, 103))	('p21', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('5q11.2', 'Var', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('p21', 'Gene', '644914', (79, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (240, 257))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('EADC', 'Chemical', '-', (120, 124))	('LOH', 'Var', (52, 55))	('tumor', 'Disease', (19, 24))	('ESCC', 'Disease', (107, 111))
300181	25611972	In particular, deletions at chromosomal region 3p26.3-p14.2, that contains candidate tumor suppressor genes as FHIT, TGFBR2, FBLN2 and WNT7A, are one of the most frequent abnormalities in both ESCC and EADC, as well as deletions at 5p12, 5q11.2-q14.3 and 5q31.	('FHIT', 'Gene', '2272', (111, 115))	('tumor', 'Disease', (85, 90))	('ESCC', 'Disease', (193, 197))	('p14', 'Gene', '1029', (54, 57))	('TGFBR2', 'Gene', (117, 123))	('WNT7A', 'Gene', '7476', (135, 140))	('deletions', 'Var', (219, 228))	('FBLN2', 'Gene', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('FHIT', 'Gene', (111, 115))	('EADC', 'Chemical', '-', (202, 206))	('FBLN2', 'Gene', '2199', (125, 130))	('TGFBR2', 'Gene', '7048', (117, 123))	('p14', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('deletions', 'Var', (15, 24))	('WNT7A', 'Gene', (135, 140))
300185	25611972	Several studies have shown the frequent allelic loss at 9p21.3 chromosomal band, containing the tumor suppressor genes CDKN2A and CDKN2B, suggesting that their inactivation could be relevant for ESCC and EADC development.	('allelic', 'Var', (40, 47))	('p21', 'Gene', '644914', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('EADC', 'Chemical', '-', (204, 208))	('CDKN2B', 'Gene', (130, 136))	('tumor', 'Disease', (96, 101))	('CDKN2A', 'Gene', (119, 125))	('CDKN2B', 'Gene', '1030', (130, 136))	('ESCC', 'Disease', (195, 199))	('CDKN2A', 'Gene', '1029', (119, 125))	('EADC', 'Disease', (204, 208))	('p21', 'Gene', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
300200	25611972	DNAs from tumor and matched normal samples were analyzed using primers for the following microsatellite markers: D3S3727 (3p24.1), D5S2106 (5p12), D5S623 (5q11.2), D8S1130 (8p23.1), D9S942 and D9S171 (9p21.3), D13S260 (13q13.1), D13S267 (13q13.2), D17S1323 and D17S1327 (17q21.31); the forward primers were labeled at 5'-end with FAM, HEX or VIC fluorescent dyes (Sigma Aldrich, Milano, Italy).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('p21', 'Gene', (202, 205))	('D5S623', 'Var', (147, 153))	('D8S1130', 'Var', (164, 171))	('HEX', 'Gene', '3087', (335, 338))	('tumor', 'Disease', (10, 15))	('D13S260', 'Var', (210, 217))	('p21', 'Gene', '644914', (202, 205))	('D13S267', 'Var', (229, 236))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('D3S3727', 'Var', (113, 120))	('D17S1323', 'Var', (248, 256))	('D17S1327', 'Var', (261, 269))	('D5S2106', 'Var', (131, 138))	('HEX', 'Gene', (335, 338))
300215	25611972	3p24; 5p12; 5q11; 8p23; 9p21; 13q13; 17q21) (Table 2).	('p21', 'Gene', '644914', (25, 28))	('p21', 'Gene', (25, 28))	('3p24; 5p12; 5q11; 8p23', 'Var', (0, 22))
300222	25611972	No specific alterations at high frequency and shared by metachronous and spontaneous EADC were found; on the contrary, dissimilar frequencies at 5p12 (100% vs. 57%), and 17q21.31 (0% vs. 83%) were observed (Table 4).	('EADC', 'Chemical', '-', (85, 89))	('5p12', 'Var', (145, 149))	('17q21.31', 'Var', (170, 178))
300232	25611972	Contradictory results are available concerning second primary lung or breast cancers arisen after therapy for HL, with post-HL lung cancers exhibiting a LOH frequency similar to the sporadic counterpart, and post-HL breast cancers showing a significant higher frequency of allelic loss, compared with sporadic tumors.	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('breast cancers', 'Phenotype', 'HP:0003002', (70, 84))	('HL', 'CellLine', 'CVCL:2492', (213, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('HL', 'CellLine', 'CVCL:2492', (110, 112))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('lung cancers', 'Disease', 'MESH:D008175', (127, 139))	('sporadic tumors', 'Disease', (301, 316))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('HL', 'CellLine', 'CVCL:2492', (124, 126))	('second primary lung', 'Disease', (47, 66))	('sporadic tumors', 'Disease', 'MESH:D009369', (301, 316))	('lung cancers', 'Disease', (127, 139))	('HL', 'Phenotype', 'HP:0012189', (213, 215))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('breast cancers', 'Disease', 'MESH:D001943', (216, 230))	('breast cancers', 'Disease', (216, 230))	('HL', 'Phenotype', 'HP:0012189', (110, 112))	('lung cancers', 'Phenotype', 'HP:0100526', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('breast cancers', 'Phenotype', 'HP:0003002', (216, 230))	('allelic loss', 'Var', (273, 285))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('HL', 'Phenotype', 'HP:0012189', (124, 126))	('arisen', 'Reg', (85, 91))	('breast cancers', 'Disease', 'MESH:D001943', (70, 84))	('breast cancers', 'Disease', (70, 84))	('tumors', 'Phenotype', 'HP:0002664', (310, 316))
300242	25611972	However, the regions probed by D8S1130 (8p23.1), D13S260 (13q13.1), D17S1323 and D17S1327 (17q21.31) exhibited lower LOH frequency in metachronous tumors than in the sporadic ones with the D17S1327 reaching a statistical significance (p = 0.018).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('LOH', 'MPA', (117, 120))	('metachronous tumors', 'Disease', 'MESH:D016609', (134, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('D17S1327', 'Var', (81, 89))	('D8S1130', 'Var', (31, 38))	('D13S260', 'Var', (49, 56))	('D17S1323', 'Var', (68, 76))	('metachronous tumors', 'Disease', (134, 153))	('lower', 'NegReg', (111, 116))
300247	25611972	Indeed, allelic losses at chromosomal regions 3p24.1, 5q11.2, 9p21.3 and 13q13.2, were more common in metachronous ESCC than in metachronous EADC, as observed herein, and previously reported, for sporadic ESCC and EADC.	('EADC', 'Chemical', '-', (214, 218))	('p21', 'Gene', (63, 66))	('p21', 'Gene', '644914', (63, 66))	('metachronous', 'Disease', (102, 114))	('common', 'Reg', (92, 98))	('EADC', 'Disease', (214, 218))	('allelic losses', 'Var', (8, 22))	('ESCC', 'Disease', (205, 209))	('EADC', 'Chemical', '-', (141, 145))
300260	24522270	Meanwhile, recent large-scale genome analyses have identified frequent mutations in genes encoding chromatin-regulating proteins, especially in those encoding subunits of the SWI/SNF chromatin-remodeling complex, in various human cancers.	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('mutations', 'Var', (71, 80))	('human', 'Species', '9606', (224, 229))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancers', 'Disease', (230, 237))
300262	24522270	DOT1L inhibition in MLL-rearranged leukemia, EZH2 inhibition in EZH2-mutant or MLL-rearranged hematologic malignancies and SNF5-deficient tumors, BRD4 inhibition in various hematologic malignancies, and BRM inhibition in BRG1-deficient tumors have demonstrated promising anti-tumor effects in preclinical models, and these strategies are currently awaiting clinical application.	('tumor', 'Disease', (138, 143))	('hematologic malignancies', 'Disease', (94, 118))	('rat', 'Species', '10116', (325, 328))	('hematologic malignancies', 'Disease', (173, 197))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('BRM', 'Gene', (203, 206))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('EZH2-mutant', 'Var', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('inhibition', 'NegReg', (151, 161))	('SNF5-deficient tumors', 'Disease', 'MESH:D009369', (123, 144))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('hematologic malignancies', 'Disease', 'MESH:D019337', (94, 118))	('hematologic malignancies', 'Disease', 'MESH:D019337', (173, 197))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('inhibition', 'NegReg', (6, 16))	('BRD4', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('BRG1-deficient tumors', 'Disease', 'MESH:D009369', (221, 242))	('EZH2', 'Gene', (45, 49))	('DOT1L', 'Gene', (0, 5))	('leukemia', 'Phenotype', 'HP:0001909', (35, 43))	('tumor', 'Disease', (276, 281))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('MLL-rearranged leukemia', 'Disease', 'MESH:D007938', (20, 43))	('MLL-rearranged leukemia', 'Disease', (20, 43))	('BRG1-deficient tumors', 'Disease', (221, 242))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('inhibition', 'NegReg', (50, 60))	('rat', 'Species', '10116', (255, 258))	('DOT1L', 'Gene', '84444', (0, 5))	('tumor', 'Disease', (236, 241))	('SNF5-deficient tumors', 'Disease', (123, 144))
300265	24522270	Recent studies have revealed that several chromatin-regulating proteins play pivotal roles in the repair of DNA double-strand breaks (DSBs) generated by ionizing irradiation (IR), and that inhibition of their activities leads to radiosensitization of cancer cells in preclinical models.	('activities', 'MPA', (209, 219))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('radiosensitization', 'CPA', (229, 247))	('DSBs', 'Chemical', '-', (134, 138))	('inhibition', 'Var', (189, 199))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('repair', 'MPA', (98, 104))	('cancer', 'Disease', (251, 257))	('rat', 'Species', '10116', (144, 147))
300266	24522270	Furthermore, recent large-scale genome analyses have identified frequent mutations in genes encoding chromatin-regulating proteins, especially those encoding subunits of the SWI/SNF chromatin-remodeling complex, in various human cancers.	('human', 'Species', '9606', (223, 228))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('cancers', 'Disease', (229, 236))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('mutations', 'Var', (73, 82))
300272	24522270	Some histone modifiers attach substrates, such as phosphate, poly-ADP-ribosyl, acetyl, methyl, SUMOyl and ubiquityl groups to histone tails by covalent interaction, whereas other histone modifiers detach these groups from previously modified histones.	('covalent', 'MPA', (143, 151))	('poly-ADP-ribosyl', 'Var', (61, 77))	('acetyl', 'MPA', (79, 85))	('phosphate', 'Chemical', 'MESH:D010710', (50, 59))	('SUMOyl', 'MPA', (95, 101))	('ubiquityl groups', 'MPA', (106, 122))	('methyl', 'MPA', (87, 93))	('rat', 'Species', '10116', (35, 38))	('acetyl', 'Chemical', 'MESH:D003545', (79, 85))
300295	24522270	olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and NU7026, a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor (Table 3).	('poly (ADP-ribose) polymerase', 'Gene', '142', (12, 40))	('NU7026', 'Chemical', 'MESH:C479235', (63, 69))	('DNA-PKcs', 'Gene', (121, 129))	('olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('poly (ADP-ribose) polymerase', 'Gene', (12, 40))	('PARP', 'Gene', (42, 46))	('NU7026', 'Var', (63, 69))	('DNA-dependent protein kinase catalytic subunit', 'Gene', '5591', (73, 119))	('PARP', 'Gene', '142', (42, 46))	('DNA-dependent protein kinase catalytic subunit', 'Gene', (73, 119))	('DNA-PKcs', 'Gene', '5591', (121, 129))
300310	24522270	demonstrated in osteosarcoma cells that ACF1 and SNF2H, subunits of the CHRAC chromatin-remodeling complex, engage in an interaction with KU70, which is required for repair of DSBs generated by IR, and that knockdown of ACF1 or SHF2H results in radiosensitization.	('radiosensitization', 'MPA', (245, 263))	('DSBs', 'Chemical', '-', (176, 180))	('osteosarcoma', 'Phenotype', 'HP:0002669', (16, 28))	('rat', 'Species', '10116', (7, 10))	('ACF1', 'Gene', '11177', (40, 44))	('engage in', 'Reg', (108, 117))	('ACF1', 'Gene', (40, 44))	('SNF2H', 'Gene', '8467', (49, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('SNF2H', 'Gene', (49, 54))	('KU70', 'Gene', (138, 142))	('interaction', 'Interaction', (121, 132))	('ACF1', 'Gene', '11177', (220, 224))	('osteosarcoma', 'Disease', (16, 28))	('KU70', 'Gene', '2547', (138, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (16, 28))	('ACF1', 'Gene', (220, 224))	('knockdown', 'Var', (207, 216))	('SHF2H', 'Gene', (228, 233))	('rat', 'Species', '10116', (185, 188))
300311	24522270	Meanwhile, we showed that ablation of BRM, a catalytic subunit of the SWI/SNF chromatin-remodeling complex, leads to suppression of recruitment of KU70 to DSB sites after laser micro-irradiation in lung cancer cells, suggesting BRM as a target for radiosensitizing agents.	('suppression', 'NegReg', (117, 128))	('lung cancer', 'Disease', (198, 209))	('KU70', 'Gene', (147, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('recruitment', 'MPA', (132, 143))	('KU70', 'Gene', '2547', (147, 151))	('BRM', 'Gene', (38, 41))	('ablation', 'Var', (26, 34))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
300324	24522270	Recent large-scale genome analyses have identified frequent mutations in genes encoding chromatin-regulating proteins in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('human', 'Species', '9606', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('mutations', 'Var', (60, 69))
300325	24522270	Thus, aberrations in histone modification and chromatin remodeling play important roles in the genesis and development of malignant tumors.	('aberrations', 'Var', (6, 17))	('roles', 'Reg', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('malignant tumors', 'Disease', (122, 138))	('histone', 'Protein', (21, 28))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('malignant tumors', 'Disease', 'MESH:D018198', (122, 138))	('rat', 'Species', '10116', (10, 13))
300326	24522270	We focus in particular on mutations in genes encoding the SWI/SNF chromatin-remodeling complex because the mutation rates in these genes are extremely high in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('mutations', 'Var', (26, 35))	('rat', 'Species', '10116', (116, 119))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))
300331	24522270	The expression of E2F target genes in mouse embryonic fibroblasts is upregulated following inactivation of Snf5.	('mouse', 'Species', '10090', (38, 43))	('expression', 'MPA', (4, 14))	('Snf5', 'Gene', (107, 111))	('upregulated', 'PosReg', (69, 80))	('inactivation', 'Var', (91, 103))
300336	24522270	There are two distinct SWI/SNF complexes, BAF and PBAF, both of which consist of various subunits categorized as catalytic ATPase subunits, core subunits, or variant subunits (Fig.	('BAF', 'Gene', '8815', (42, 45))	('BAF', 'Gene', '8815', (51, 54))	('ATPase', 'Gene', (123, 129))	('BAF', 'Gene', (51, 54))	('variant', 'Var', (158, 165))	('BAF', 'Gene', (42, 45))	('ATPase', 'Gene', '1769', (123, 129))
300339	24522270	Variant subunits include ARID1A and ARID1B, mutually exclusive components of the BAF complex, and BAF180, BAF200 and BRD7, which are specific to the PBAF complex.	('BAF', 'Gene', '8815', (81, 84))	('BAF', 'Gene', '8815', (98, 101))	('BAF', 'Gene', '8815', (106, 109))	('ARID1A', 'Gene', (25, 31))	('BAF', 'Gene', '8815', (150, 153))	('BRD7', 'Gene', '29117', (117, 121))	('ARID1A', 'Gene', '8289', (25, 31))	('BAF200', 'Gene', '196528', (106, 112))	('ARID1B', 'Gene', (36, 42))	('BAF200', 'Gene', (106, 112))	('BAF180', 'Gene', '55193', (98, 104))	('BAF', 'Gene', (81, 84))	('BRD7', 'Gene', (117, 121))	('BAF', 'Gene', (98, 101))	('ARID1B', 'Gene', '57492', (36, 42))	('BAF', 'Gene', (106, 109))	('BAF180', 'Gene', (98, 104))	('BAF', 'Gene', (150, 153))	('Variant', 'Var', (0, 7))
300341	24522270	analyzed whole-exome sequencing data from 24 published studies encompassing 669 cases with 18 neoplastic diagnoses; their results demonstrated that mutations in the SWI/SNF genes are widespread across various cancers, with an overall frequency approaching that of TP53 mutations (19% in the SWI/SNF complex, 26% in TP53).	('mutations', 'Var', (148, 157))	('SWI/SNF', 'Gene', (165, 172))	('TP53', 'Gene', '7157', (264, 268))	('TP53', 'Gene', (264, 268))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('rat', 'Species', '10116', (137, 140))	('cancers', 'Disease', (209, 216))	('TP53', 'Gene', '7157', (315, 319))	('TP53', 'Gene', (315, 319))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
300344	24522270	Sequencing of the BRG1 gene from various cancer cell lines has demonstrated that BRG1 is mutated in a variety of human cancers, including >30% of non-small-cell lung carcinoma (NSCLC).	('cancer', 'Disease', (41, 47))	('human', 'Species', '9606', (113, 118))	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (150, 175))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancer', 'Disease', (119, 125))	('cancers', 'Disease', (119, 126))	('BRG1', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('rat', 'Species', '10116', (70, 73))	('BRG1', 'Gene', (81, 85))	('small-cell lung carcinoma', 'Disease', (150, 175))	('mutated', 'Var', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('NSCLC', 'Disease', (177, 182))
300345	24522270	Notably, most of the mutations identified are homozygous mutations and deletions, indicating that BRG1 plays a role as a tumor suppressor.	('deletions', 'Var', (71, 80))	('mutations', 'Var', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('BRG1', 'Gene', (98, 102))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
300346	24522270	A recent large-scale genome analysis confirmed that BRG1 mutations play a prominent role in aberrant chromatin remodeling in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (125, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('aberrant chromatin remodeling', 'MPA', (92, 121))	('mutations', 'Var', (57, 66))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('BRG1', 'Gene', (52, 56))
300347	24522270	BRG1 mutations were also identified recently in Burkitt lymphoma, medulloblastoma, and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (56, 64))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (48, 64))	('identified', 'Reg', (25, 35))	('esophageal cancer', 'Disease', (87, 104))	('medulloblastoma', 'Disease', 'MESH:D008527', (66, 81))	('mutations', 'Var', (5, 14))	('medulloblastoma', 'Phenotype', 'HP:0002885', (66, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('BRG1', 'Gene', (0, 4))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (48, 64))	('Burkitt lymphoma', 'Disease', (48, 64))	('medulloblastoma', 'Disease', (66, 81))
300349	24522270	A recent report showed that both genetic and epigenetic alterations are involved in the loss of BRG1 expression.	('rat', 'Species', '10116', (60, 63))	('loss', 'NegReg', (88, 92))	('BRG1', 'Gene', (96, 100))	('expression', 'MPA', (101, 111))	('epigenetic alterations', 'Var', (45, 67))
300350	24522270	Patients with rhabdoid tumor (RT) predisposition syndrome, in which RTs occur on a familial basis, harbor a heterozygous germline BRG1 mutation that truncates the encoded protein, and their RTs are homozygous for this mutation.	('truncates', 'NegReg', (149, 158))	('BRG1', 'Gene', (130, 134))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (14, 28))	('mutation', 'Var', (135, 143))	('rhabdoid tumor', 'Disease', (14, 28))	('protein', 'Protein', (171, 178))
300351	24522270	Mutations in SNF5, which are present in the germline of most cases of RT predisposition syndrome, were not detected in the patients analyzed in that study.	('SNF5', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (123, 131))
300355	24522270	However, in a mouse model in which lung tumors are induced by exposure to carbamate ethyl, inactivation of one or both Brm alleles led to a significant increase in the number of tumors, indicating that Brm plays a role as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('carbamate', 'Chemical', 'MESH:D002219', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('Brm', 'Gene', '67155', (202, 205))	('Brm', 'Gene', (202, 205))	('inactivation', 'Var', (91, 103))	('lung tumors', 'Disease', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumor', 'Disease', (178, 183))	('mouse', 'Species', '10090', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('Brm', 'Gene', '67155', (119, 122))	('Brm', 'Gene', (119, 122))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('increase', 'PosReg', (152, 160))	('tumors', 'Disease', (178, 184))	('lung tumors', 'Disease', 'MESH:D008175', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('lung tumors', 'Phenotype', 'HP:0100526', (35, 46))
300358	24522270	These findings suggest that epigenetic silencing of BRM may be critical for the development of a subset of cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('epigenetic silencing', 'Var', (28, 48))	('BRM', 'Gene', (52, 55))	('critical', 'Reg', (63, 71))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
300359	24522270	The SNF5 gene encodes a core regulatory subunit of the SWI/SNF complex and is inactivated via biallelic genetic alterations, including deletions and nonsense, missense and frameshift mutations, in nearly all RTs.	('nonsense', 'Var', (149, 157))	('frameshift mutations', 'Var', (172, 192))	('inactivated', 'NegReg', (78, 89))	('rat', 'Species', '10116', (116, 119))	('deletions', 'Var', (135, 144))	('SNF5', 'Gene', (4, 8))
300361	24522270	Germline SNF5 mutations also result in predisposition to meningioma and schwannoma.	('meningioma', 'Phenotype', 'HP:0002858', (57, 67))	('SNF5', 'Gene', (9, 13))	('meningioma and schwannoma', 'Disease', 'MESH:D009442', (57, 82))	('schwannoma', 'Phenotype', 'HP:0100008', (72, 82))	('predisposition', 'Reg', (39, 53))	('mutations', 'Var', (14, 23))	('predisposition to meningioma', 'Phenotype', 'HP:0005381', (39, 67))
300363	24522270	Furthermore, biallelic inactivation of Snf5 results in the development of sarcoma and lymphoma with a median onset of only 11 weeks, which is a remarkably rapid rate considering that the median onset of tumors induced by biallelic inactivation of p53 and Rb is 16 weeks in the same experimental model.	('lymphoma', 'Phenotype', 'HP:0002665', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('sarcoma and lymphoma', 'Disease', 'MESH:D012509', (74, 94))	('results in', 'Reg', (44, 54))	('p53', 'Gene', '7157', (247, 250))	('rat', 'Species', '10116', (161, 164))	('Snf5', 'Gene', (39, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('biallelic inactivation', 'Var', (13, 35))	('p53', 'Gene', (247, 250))
300365	24522270	However, somatic mutation of SNF5 is rarely detected in common cancers, indicating that, in contrast to mutations in other SWI/SNF genes detected in wide range of cancers, the SNF5 mutation is specific to a subset of non-epithelial malignancies.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('malignancies', 'Disease', (232, 244))	('SNF5', 'Gene', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutation', 'Var', (181, 189))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (221, 244))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('malignancies', 'Disease', 'MESH:D009369', (232, 244))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
300367	24522270	ARID1A is mutated in 46-57% of ovarian clear cell carcinomas, one of the most lethal subtypes of ovarian cancer, and in 30% of endometriosis-associated ovarian carcinomas.	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('mutated', 'Var', (10, 17))	('endometriosis-associated ovarian carcinomas', 'Disease', (127, 170))	('ovarian cancer', 'Disease', (97, 111))	('ARID1A', 'Gene', '8289', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('endometriosis', 'Phenotype', 'HP:0030127', (127, 140))	('ARID1A', 'Gene', (0, 6))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('endometriosis-associated ovarian carcinomas', 'Disease', 'MESH:D004715', (127, 170))	('ovarian clear cell carcinomas', 'Disease', (31, 60))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (31, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (152, 170))
300368	24522270	ARID1A mutations have also been detected in a variety of cancers including renal clear cell carcinoma, Burkitt lymphoma, hepatocellular carcinoma, transient cell carcinoma of the bladder, gastric adenocarcinoma, esophageal cancer, uterine serous endometrial cancer, neuroblastoma, pancreatic cancer, malignant melanoma, and medulloblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (266, 279))	('serous endometrial cancer', 'Phenotype', 'HP:0012887', (239, 264))	('gastric adenocarcinoma', 'Disease', (188, 210))	('carcinoma of the bladder', 'Disease', 'MESH:D001749', (162, 186))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (281, 298))	('hepatocellular carcinoma', 'Disease', (121, 145))	('malignant melanoma', 'Disease', (300, 318))	('medulloblastoma', 'Disease', 'MESH:D008527', (324, 339))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('Burkitt lymphoma', 'Disease', (103, 119))	('medulloblastoma', 'Phenotype', 'HP:0002885', (324, 339))	('medulloblastoma', 'Disease', (324, 339))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (103, 119))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('carcinoma of the bladder', 'Disease', (162, 186))	('cancers', 'Disease', (57, 64))	('endometrial cancer', 'Phenotype', 'HP:0012114', (246, 264))	('pancreatic cancer', 'Disease', 'MESH:D010190', (281, 298))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))	('mutations', 'Var', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (188, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('malignant melanoma', 'Phenotype', 'HP:0002861', (300, 318))	('detected', 'Reg', (32, 40))	('malignant melanoma', 'Disease', 'MESH:D008545', (300, 318))	('ARID1A', 'Gene', (0, 6))	('serous endometrial cancer', 'Disease', 'MESH:D016889', (239, 264))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (103, 119))	('pancreatic cancer', 'Disease', (281, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('esophageal cancer', 'Disease', 'MESH:D004938', (212, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('ARID1A', 'Gene', '8289', (0, 6))	('serous endometrial cancer', 'Disease', (239, 264))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (121, 145))	('neuroblastoma', 'Disease', (266, 279))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('neuroblastoma', 'Phenotype', 'HP:0003006', (266, 279))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (75, 101))	('esophageal cancer', 'Disease', (212, 229))	('renal clear cell carcinoma', 'Disease', (75, 101))
300369	24522270	ARID1A is also mutated in a subset of lung adenocarcinomas, although at a lower frequency than BRG1.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (38, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (38, 58))	('ARID1A', 'Gene', '8289', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('ARID1A', 'Gene', (0, 6))	('mutated', 'Var', (15, 22))	('lung adenocarcinomas', 'Disease', (38, 58))
300370	24522270	Most ARID1A mutations detected in cancer cells to date are inactivating mutations, indicating that ARID1A has a tumor-suppressive function.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('ARID1A', 'Gene', '8289', (5, 11))	('ARID1A', 'Gene', (99, 105))	('ARID1A', 'Gene', (5, 11))	('mutations', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Disease', (34, 40))	('tumor', 'Disease', (112, 117))	('inactivating', 'Var', (59, 71))	('ARID1A', 'Gene', '8289', (99, 105))
300372	24522270	found that ARID2, which encodes a SWI/SNF regulatory subunit, was mutated in ~10% of surgical specimens of hepatocellular carcinoma.	('ARID2', 'Gene', (11, 16))	('mutated', 'Var', (66, 73))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (107, 131))	('hepatocellular carcinoma', 'Disease', (107, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (107, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('ARID2', 'Gene', '196528', (11, 16))
300373	24522270	Large-scale exome sequencing in malignant melanoma also revealed that 7.4% of the cases harbored mutations in ARID2, most of which were inactivating mutations.	('mutations', 'Var', (97, 106))	('malignant melanoma', 'Disease', 'MESH:D008545', (32, 50))	('malignant melanoma', 'Disease', (32, 50))	('ARID2', 'Gene', (110, 115))	('malignant melanoma', 'Phenotype', 'HP:0002861', (32, 50))	('harbored', 'Reg', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('ARID2', 'Gene', '196528', (110, 115))
300374	24522270	In that study, ARID2 mutation was identified as one of the driver mutations resulting from C-to-T transitions caused by exposure to UV light; this is in contrast to other driver mutations in malignant melanoma, such as those in BRAF and NRAS, that are only weakly associated with UV-induced damage.	('malignant melanoma', 'Disease', (191, 209))	('BRAF', 'Gene', '673', (228, 232))	('NRAS', 'Gene', '4893', (237, 241))	('ARID2', 'Gene', '196528', (15, 20))	('malignant melanoma', 'Disease', 'MESH:D008545', (191, 209))	('BRAF', 'Gene', (228, 232))	('ARID2', 'Gene', (15, 20))	('malignant melanoma', 'Phenotype', 'HP:0002861', (191, 209))	('mutations', 'Var', (178, 187))	('NRAS', 'Gene', (237, 241))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
300375	24522270	ARID2 is also mutated in a small subset of esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('mutated', 'Var', (14, 21))	('ARID2', 'Gene', '196528', (0, 5))	('esophageal cancers', 'Disease', (43, 61))	('ARID2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('esophageal cancers', 'Disease', 'MESH:D004938', (43, 61))
300376	24522270	Most recently, mutations in the PBRM1 gene, which encodes a regulatory subunit protein, were identified in 41% of renal clear cell carcinomas, making PBRM1 the second most frequently mutated gene in renal cell carcinoma after VHL.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('PBRM1', 'Gene', (32, 37))	('PBRM1', 'Gene', (150, 155))	('renal clear cell carcinomas', 'Disease', (114, 141))	('PBRM1', 'Gene', '55193', (32, 37))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (199, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (199, 219))	('mutations', 'Var', (15, 24))	('PBRM1', 'Gene', '55193', (150, 155))	('identified', 'Reg', (93, 103))	('renal clear cell carcinomas', 'Disease', 'MESH:C538614', (114, 141))	('VHL', 'Gene', (226, 229))	('renal cell carcinoma', 'Disease', (199, 219))	('VHL', 'Gene', '7428', (226, 229))
300377	24522270	PBRM1 mutations have also been detected in esophageal cancer patients and in several breast cancer cell lines.	('detected', 'Reg', (31, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('PBRM1', 'Gene', (0, 5))	('patients', 'Species', '9606', (61, 69))	('PBRM1', 'Gene', '55193', (0, 5))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (6, 15))
300382	24522270	In most cases, the rearrangement results in the loss of the H3K4 HMT enzymatic activity.	('HMT', 'Gene', (65, 68))	('loss', 'NegReg', (48, 52))	('H3K4', 'Protein', (60, 64))	('HMT', 'Gene', '3176', (65, 68))	('rearrangement', 'Var', (19, 32))
300384	24522270	SETD2, another HMT specific for H3K36, is mutated in a small fraction of lung adenocarcinomas.	('lung adenocarcinomas', 'Disease', (73, 93))	('mutated', 'Var', (42, 49))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (73, 93))	('SETD2', 'Gene', '29072', (0, 5))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (73, 93))	('HMT', 'Gene', (15, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('SETD2', 'Gene', (0, 5))	('HMT', 'Gene', '3176', (15, 18))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
300385	24522270	On the other hand, activating mutations in the gene encoding EZH2, an HMT directed against H3K27 that is the catalytic subunit of the polycomb repressive complex 2 (PRC2), have been identified in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, myelodysplastic syndrome, and esophageal cancer.	('activating', 'PosReg', (19, 29))	('EZH2', 'Gene', (61, 65))	('HMT', 'Gene', (70, 73))	('B-cell lymphoma', 'Disease', (210, 225))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (210, 225))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (210, 225))	('lymphoma', 'Phenotype', 'HP:0002665', (246, 254))	('esophageal cancer', 'Disease', (286, 303))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (256, 280))	('HMT', 'Gene', '3176', (70, 73))	('mutations', 'Var', (30, 39))	('myelodysplastic syndrome', 'Disease', (256, 280))	('esophageal cancer', 'Disease', 'MESH:D004938', (286, 303))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('lymphoma', 'Phenotype', 'HP:0002665', (217, 225))	('follicular lymphoma', 'Disease', 'MESH:D008224', (235, 254))	('follicular lymphoma', 'Disease', (235, 254))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (256, 280))
300389	24522270	To date, the mechanisms by which mutations in histone modifiers are involved in carcinogenesis and tumor growth have not been fully elucidated.	('tumor', 'Disease', (99, 104))	('involved', 'Reg', (68, 76))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('carcinogenesis', 'Disease', (80, 94))
300391	24522270	In parallel with the elucidation of the genetic landscape of various human cancers by genome-wide sequencing analyses, large numbers of chemotherapeutic agents targeting gene mutations (i.e.	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('mutations', 'Var', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
300393	24522270	Cancers harboring activating gene mutations can be treated with specific inhibitors of the mutated gene products, thereby suppressing their abnormally high activity.	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('suppressing', 'NegReg', (122, 133))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('inhibitors', 'NegReg', (73, 83))	('activating', 'PosReg', (18, 28))	('mutations', 'Var', (34, 43))
300394	24522270	For example, selective cell killing by the tyrosine kinase inhibitors gefitinib, crizotinib, and vandetanib in cancer cells harboring EGFR mutation, ALK fusion, and RET fusion, respectively, has been demonstrated by our group and others, and these treatment strategies have been applied in the clinic.	('EGFR', 'Gene', '1956', (134, 138))	('RET', 'Gene', '5979', (165, 168))	('mutation', 'Var', (139, 147))	('EGFR', 'Gene', (134, 138))	('rat', 'Species', '10116', (207, 210))	('ALK', 'Gene', '238', (149, 152))	('vandetanib', 'Chemical', 'MESH:C452423', (97, 107))	('crizotinib', 'Chemical', 'MESH:D000077547', (81, 91))	('rat', 'Species', '10116', (260, 263))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gefitinib', 'Chemical', 'MESH:D000077156', (70, 79))	('RET', 'Gene', (165, 168))	('ALK', 'Gene', (149, 152))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cell killing', 'CPA', (23, 35))
300395	24522270	Meanwhile, for the treatment of cancers in which certain proteins or pathways are inactivated by genetic and/or epigenetic causes, strategies based on synthetic lethality have attracted a great deal of attention.	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('epigenetic', 'Var', (112, 122))	('rat', 'Species', '10116', (133, 136))	('proteins', 'Protein', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('inactivated', 'NegReg', (82, 93))
300399	24522270	Recently, inhibition of DOT1L, a HMT specific for H3K79, has emerged as a promising strategy for the treatment of MLL-rearranged leukemia.	('MLL-rearranged leukemia', 'Disease', (114, 137))	('DOT1L', 'Gene', (24, 29))	('HMT', 'Gene', (33, 36))	('HMT', 'Gene', '3176', (33, 36))	('inhibition', 'Var', (10, 20))	('leukemia', 'Phenotype', 'HP:0001909', (129, 137))	('rat', 'Species', '10116', (86, 89))	('DOT1L', 'Gene', '84444', (24, 29))	('MLL-rearranged leukemia', 'Disease', 'MESH:D007938', (114, 137))
300401	24522270	Rearrangement of MLL results in the loss of the H3K4 HMT domain and in-frame fusion of the amino-terminal region of MLL to diverse partner proteins.	('Rearrangement', 'Var', (0, 13))	('MLL', 'Gene', (116, 119))	('fusion', 'Interaction', (77, 83))	('MLL', 'Gene', (17, 20))	('loss', 'NegReg', (36, 40))	('HMT', 'Gene', (53, 56))	('HMT', 'Gene', '3176', (53, 56))
300402	24522270	In most cases, these fusions lead to more efficient recruitment of DOT1L to MLL target genes.	('DOT1L', 'Gene', (67, 72))	('recruitment', 'MPA', (52, 63))	('more', 'PosReg', (37, 41))	('DOT1L', 'Gene', '84444', (67, 72))	('fusions', 'Var', (21, 28))
300403	24522270	The resulting hypermethylation at H3K79 by DOT1L leads to aberrant expression of a characteristic set of genes, including HOXA9 and MEIS1, which drive leukemogenesis.	('HOXA9', 'Gene', '3205', (122, 127))	('hypermethylation', 'Var', (14, 30))	('leukemogenesis', 'Disease', (151, 165))	('DOT1L', 'Gene', (43, 48))	('HOXA9', 'Gene', (122, 127))	('leads to', 'Reg', (49, 57))	('H3K79', 'Protein', (34, 39))	('DOT1L', 'Gene', '84444', (43, 48))	('drive', 'Reg', (145, 150))	('expression', 'MPA', (67, 77))	('MEIS1', 'Gene', '4211', (132, 137))	('MEIS1', 'Gene', (132, 137))
300406	24522270	They reported that EPZ00477 selectively killed MLL-rearranged leukemia cells in culture and prolonged survival in a mouse xenograft model.	('survival', 'CPA', (102, 110))	('EPZ00477', 'Var', (19, 27))	('leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('MLL-rearranged leukemia', 'Disease', 'MESH:D007938', (47, 70))	('MLL-rearranged leukemia', 'Disease', (47, 70))	('mouse', 'Species', '10090', (116, 121))	('prolonged', 'PosReg', (92, 101))
300408	24522270	Continuous intravenous infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions.	('EPZ-5676', 'Var', (35, 43))	('MLL-rearranged leukemia', 'Disease', (72, 95))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('EPZ-5676', 'Chemical', 'MESH:C583893', (35, 43))	('tumor', 'Disease', (112, 117))	('rat', 'Species', '10116', (49, 52))	('MLL-rearranged leukemia', 'Disease', 'MESH:D007938', (72, 95))
300412	24522270	Y641 and A677 are hot spots for lymphoma-associated EZH2 mutations.	('Y641', 'Var', (0, 4))	('lymphoma', 'Phenotype', 'HP:0002665', (32, 40))	('EZH2', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('lymphoma', 'Disease', (32, 40))	('A677', 'Var', (9, 13))	('lymphoma', 'Disease', 'MESH:D008223', (32, 40))
300413	24522270	These mutations increase the activity of the encoded proteins, leading to elevated levels of trimethylated H3K27, thereby promoting proliferation of lymphoma cells.	('lymphoma', 'Phenotype', 'HP:0002665', (149, 157))	('H3K27', 'Protein', (107, 112))	('levels of trimethylated', 'MPA', (83, 106))	('rat', 'Species', '10116', (139, 142))	('elevated', 'PosReg', (74, 82))	('activity', 'MPA', (29, 37))	('increase', 'PosReg', (16, 24))	('proliferation', 'CPA', (132, 145))	('lymphoma', 'Disease', (149, 157))	('promoting', 'PosReg', (122, 131))	('proteins', 'Protein', (53, 61))	('mutations', 'Var', (6, 15))	('lymphoma', 'Disease', 'MESH:D008223', (149, 157))
300414	24522270	Several groups have developed selective small-molecule inhibitors of EZH2 HMT and demonstrated promising preclinical results.	('small-molecule', 'Var', (40, 54))	('HMT', 'Gene', (74, 77))	('EZH2', 'Gene', (69, 73))	('rat', 'Species', '10116', (89, 92))	('HMT', 'Gene', '3176', (74, 77))
300415	24522270	showed that the compound GSK126 decreased global methylation at H3K27 and reactivated silenced PRC2 target genes in EZH2-mutant DLBCL cell lines.	('reactivated', 'MPA', (74, 85))	('GSK126', 'Chemical', 'MESH:C577920', (25, 31))	('GSK126', 'Var', (25, 31))	('global methylation', 'MPA', (42, 60))	('EZH2-mutant', 'Var', (116, 127))	('H3K27', 'Protein', (64, 69))	('decreased', 'NegReg', (32, 41))
300417	24522270	developed another compound, El1, which when administered to DLBCL cells carrying the Y641 mutation also decreased the H3K27 methylation level genome-wide, activated PRC2 target genes, and decreased cell proliferation.	('PRC2', 'Gene', (165, 169))	('decreased', 'NegReg', (188, 197))	('rat', 'Species', '10116', (210, 213))	('El1', 'Gene', (28, 31))	('H3K27', 'Protein', (118, 123))	('decreased', 'NegReg', (104, 113))	('El1', 'Gene', '2035', (28, 31))	('cell proliferation', 'CPA', (198, 216))	('activated', 'PosReg', (155, 164))	('Y641', 'Var', (85, 89))
300419	24522270	reported that the compound EPZ005687 induced apoptotic cell death in lymphoma cells with heterozygous mutations in Y641 or A677, with minimal effect on the proliferation of wild-type cells.	('rat', 'Species', '10116', (163, 166))	('A677', 'Var', (123, 127))	('death', 'Disease', 'MESH:D003643', (60, 65))	('death', 'Disease', (60, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('lymphoma', 'Disease', (69, 77))	('induced', 'Reg', (37, 44))	('lymphoma', 'Disease', 'MESH:D008223', (69, 77))	('EPZ005687', 'Var', (27, 36))	('Y641', 'Gene', (115, 119))
300420	24522270	On the other hand, several studies have demonstrated that AML cells harboring MLL-AF9 fusion require EZH2 for survival, suggesting that EZH2 inhibition is also a candidate strategy to treat this disease.	('AF9', 'Gene', (82, 85))	('AML', 'Disease', 'MESH:D015470', (58, 61))	('rat', 'Species', '10116', (47, 50))	('fusion', 'Var', (86, 92))	('rat', 'Species', '10116', (174, 177))	('AML', 'Phenotype', 'HP:0004808', (58, 61))	('AML', 'Disease', (58, 61))	('AF9', 'Gene', '4300', (82, 85))
300424	24522270	Together, these studies provide hope for the establishment of novel treatment strategies against EZH2-mutant hematologic malignancies.	('rat', 'Species', '10116', (80, 83))	('EZH2-mutant', 'Var', (97, 108))	('hematologic malignancies', 'Disease', 'MESH:D019337', (109, 133))	('EZH2-mutant', 'Gene', (97, 108))	('hematologic malignancies', 'Disease', (109, 133))
300428	24522270	As discussed, cancers with gain-of-function gene mutations can be treated by inhibition of the mutated gene products.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('gain-of-function', 'PosReg', (27, 43))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
300429	24522270	However, in many cases, tumor growth is also driven by loss-of-function mutations in tumor-suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (72, 81))	('tumor', 'Disease', (24, 29))	('loss-of-function', 'NegReg', (55, 71))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
300431	24522270	Therefore, it is necessary to develop alternative strategies to treat cancers harboring inactivating mutations in tumor-suppressor genes.	('rat', 'Species', '10116', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('inactivating mutations', 'Var', (88, 110))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
300432	24522270	Synthetic lethality holds great promise as a strategy for specific killing of cancer cells possessing inactivating mutations that are not present in normal cells.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('rat', 'Species', '10116', (47, 50))	('inactivating mutations', 'Var', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
300433	24522270	The presence of one of these mutations in cancer cells, but not in normal cells, presents opportunities to selectively kill cancer cells by mimicking the effect of the second genetic mutation with targeted therapy.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
300436	24522270	Accordingly, silencing of BRM suppresses the growth of BRG1-deficient cancer cells relative to BRG1-proficient cancer cells (Fig.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('suppresses', 'NegReg', (30, 40))	('BRG1-deficient cancer', 'Disease', (55, 76))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('growth', 'MPA', (45, 51))	('BRG1-deficient cancer', 'Disease', 'MESH:D009369', (55, 76))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('BRM', 'Gene', (26, 29))	('silencing', 'Var', (13, 22))
300438	24522270	Moreover, in a conditional RNAi experiment using a mouse xenograft model, BRM depletion suppressed the growth of BRG1-deficient tumors.	('depletion', 'Var', (78, 87))	('BRG1-deficient tumors', 'Disease', (113, 134))	('mouse', 'Species', '10090', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('BRG1-deficient tumors', 'Disease', 'MESH:D009369', (113, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('growth', 'MPA', (103, 109))	('suppressed', 'NegReg', (88, 98))	('BRM', 'Gene', (74, 77))
300442	24522270	The genesis of the sarcoma in SNF5-heterozygous mice can be completely suppressed by deletion of EZH2.	('sarcoma', 'Disease', 'MESH:D012509', (19, 26))	('mice', 'Species', '10090', (48, 52))	('sarcoma', 'Disease', (19, 26))	('EZH2', 'Gene', (97, 101))	('deletion', 'Var', (85, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('genesis', 'CPA', (4, 11))	('suppressed', 'NegReg', (71, 81))
300443	24522270	showed that disruption of EZH2 by RNAi and/or 3-deazaneplanocin A, an indirect and general inhibitor of methyltransferases, impaired growth of SNF5-mutant atypical teratoid RT cells.	('impaired', 'NegReg', (124, 132))	('disruption', 'Var', (12, 22))	('EZH2', 'Gene', (26, 30))	('rat', 'Species', '10116', (166, 169))	('growth', 'MPA', (133, 139))	('SNF5-mutant', 'Gene', (143, 154))
300445	24522270	developed EPZ-6438, a selective small-molecule inhibitor of EZH2, and demonstrated that EPZ-6438 specifically killed SNF5-mutant malignant RT cells both in vitro and in vivo.	('rat', 'Species', '10116', (77, 80))	('EPZ-6438', 'Chemical', 'MESH:C000593333', (10, 18))	('killed', 'NegReg', (110, 116))	('EPZ-6438', 'Var', (88, 96))	('SNF5-mutant', 'Gene', (117, 128))	('EPZ-6438', 'Chemical', 'MESH:C000593333', (88, 96))
300446	24522270	EPZ-6438 decreased cellular H3K27 methylation levels and activated the PRC2 target gene CDKN2A in SNF5-mutant malignant RT cells, but not in wild-type cells.	('cellular', 'MPA', (19, 27))	('CDKN2A', 'Gene', (88, 94))	('CDKN2A', 'Gene', '1029', (88, 94))	('activated', 'PosReg', (57, 66))	('EPZ-6438', 'Chemical', 'MESH:C000593333', (0, 8))	('decreased', 'NegReg', (9, 18))	('SNF5-mutant', 'Gene', (98, 109))	('SNF5-mutant', 'Var', (98, 109))	('H3K27', 'Protein', (28, 33))
300448	24522270	SNF5 is inactivated through biallelic mutation in nearly all cases of malignant RTs and atypical teratoid RTs.	('SNF5', 'Gene', (0, 4))	('malignant RTs', 'Disease', (70, 83))	('rat', 'Species', '10116', (99, 102))	('biallelic mutation', 'Var', (28, 46))
300454	24522270	Consistent with this, they showed that JQ1 inhibits proliferation of diverse subtypes of AML cells.	('proliferation', 'CPA', (52, 65))	('AML', 'Disease', 'MESH:D015470', (89, 92))	('JQ1', 'Var', (39, 42))	('AML', 'Phenotype', 'HP:0004808', (89, 92))	('rat', 'Species', '10116', (59, 62))	('AML', 'Disease', (89, 92))	('inhibits', 'NegReg', (43, 51))
300456	24522270	showed that JQ1 prolongs survival of mice bearing multiple myeloma.	('JQ1', 'Var', (12, 15))	('survival', 'CPA', (25, 33))	('multiple myeloma', 'Phenotype', 'HP:0006775', (50, 66))	('prolongs', 'PosReg', (16, 24))	('multiple myeloma', 'Disease', 'MESH:D009101', (50, 66))	('multiple myeloma', 'Disease', (50, 66))	('mice', 'Species', '10090', (37, 41))
300457	24522270	developed another BRD4 inhibitor, I-BET151, and showed that this compound prolonged the lifespan of mice with mixed-lineage fusion leukemia treated with I-BET151.	('I-BET151', 'Chemical', 'MESH:C568713', (34, 42))	('mice', 'Species', '10090', (100, 104))	('lifespan', 'CPA', (88, 96))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('leukemia', 'Disease', 'MESH:D007938', (131, 139))	('I-BET151', 'Chemical', 'MESH:C568713', (153, 161))	('I-BET151', 'Var', (153, 161))	('leukemia', 'Disease', (131, 139))	('prolonged', 'PosReg', (74, 83))
300458	24522270	On the other hand, JQ1 also exerts an anti-tumor effect in nuclear protein in testis (NUT) midline carcinoma, a rare subtype of squamous cell carcinoma with an aggressive nature, in which t(15;19) chromosomal translocation results in a fusion between BRD4 and NUT.	('NUT', 'Gene', '256646', (260, 263))	('NUT', 'Gene', (260, 263))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('fusion', 'Interaction', (236, 242))	('testis', 'Disease', (78, 84))	('squamous cell carcinoma', 'Disease', (128, 151))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('JQ1', 'Var', (19, 22))	('BRD4', 'Gene', (251, 255))	('NUT', 'Gene', '256646', (86, 89))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('midline carcinoma', 'Disease', (91, 108))	('NUT', 'Gene', (86, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('midline carcinoma', 'Disease', 'MESH:D009436', (91, 108))	('tumor', 'Disease', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
300470	24522270	High frequencies of mutation in chromatin-regulating genes, especially in the SWI/SNF genes, highlight the pivotal roles of chromatin-regulating proteins in cancer cells, and thus offer rationales for targeting these mutations in cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('rat', 'Species', '10116', (186, 189))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('mutation', 'Var', (20, 28))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('SWI/SNF', 'Gene', (78, 85))
300471	24522270	DOT1L inhibition in MLL-rearranged leukemia, EZH2 inhibition in EZH2-mutant or MLL-rearranged hematologic malignancies and SNF5-deficient tumors, BRD4 inhibition in hematologic malignancies, and BRM inhibition in BRG1-deficient tumors all hold great promise and are awaiting clinical applications.	('EZH2-mutant', 'Gene', (64, 75))	('hematologic malignancies', 'Disease', (94, 118))	('SNF5-deficient tumors', 'Disease', (123, 144))	('EZH2-mutant', 'Var', (64, 75))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('inhibition', 'NegReg', (151, 161))	('SNF5-deficient tumors', 'Disease', 'MESH:D009369', (123, 144))	('hematologic malignancies', 'Disease', (165, 189))	('hematologic malignancies', 'Disease', 'MESH:D019337', (94, 118))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('hematologic malignancies', 'Disease', 'MESH:D019337', (165, 189))	('inhibition', 'NegReg', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('leukemia', 'Phenotype', 'HP:0001909', (35, 43))	('DOT1L', 'Gene', (0, 5))	('EZH2', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('MLL-rearranged leukemia', 'Disease', 'MESH:D007938', (20, 43))	('BRG1-deficient tumors', 'Disease', 'MESH:D009369', (213, 234))	('MLL-rearranged leukemia', 'Disease', (20, 43))	('inhibition', 'NegReg', (50, 60))	('BRG1-deficient tumors', 'Disease', (213, 234))	('DOT1L', 'Gene', '84444', (0, 5))	('BRD4', 'Gene', (146, 150))
300473	24522270	Accordingly, we recently reported that single-nucleotide polymorphisms in the BPTF gene, which encodes a bromodomain PHD finger transcription factor contained in the NURF chromatin-remodeling complex, affect the risk of lung adenocarcinoma in the Japanese population.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (220, 239))	('single-nucleotide polymorphisms', 'Var', (39, 70))	('BPTF', 'Gene', (78, 82))	('BPTF', 'Gene', '2186', (78, 82))	('affect', 'Reg', (201, 207))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (220, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('lung adenocarcinoma', 'Disease', (220, 239))
300474	24522270	Future studies will elucidate the molecular mechanisms underlying the effect of aberrant chromatin-regulating proteins on carcinogenesis and cancer progression, and will contribute to the establishment of personalized treatment based on the genetic profiles of tumors.	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('carcinogenesis', 'Disease', (122, 136))	('tumors', 'Disease', (261, 267))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('aberrant', 'Var', (80, 88))	('cancer', 'Disease', (141, 147))
300475	24522270	This work was supported by Grants-in-Aid from the Japan Society for the Promotion of Science for Young Scientists (B) KAKENHI (10643471) and (23701110), and from the Ministry of Education, Culture, Sports, Science and Technology of Japan for Scientific Research on Innovative Areas (22131006).	('Aid', 'Gene', (37, 40))	('10643471', 'Var', (127, 135))	('Aid', 'Gene', '57379', (37, 40))
300482	33474812	On stepwise regression, tumor stage, feeding tube during DCCRT, and change in primary tumor PET/CT SUVmax were significantly associated with OS and DFS.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', (86, 91))	('change', 'Var', (68, 74))	('associated', 'Reg', (125, 135))	('DCCRT', 'Chemical', '-', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('DFS', 'Disease', (148, 151))
300492	33474812	12  Similarly, the FFCD 9102 trial of 444 patients with potentially resectable T3N0-1M0 esophageal SCC who received induction chemoRT followed by additional chemoRT or surgery found that while surgically treated patients had significantly lower rates of locoregional recurrence (LRR) (34% v 43%) and were less likely to require palliative intervention for dysphagia, they had similar 2-year and median survival as compared to those who continued chemoRT, in addition to having worse quality of life outcomes and increased morbidity acutely.	('locoregional recurrence', 'Disease', (254, 277))	('dysphagia', 'Phenotype', 'HP:0002015', (356, 365))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('dysphagia', 'Disease', 'MESH:D003680', (356, 365))	('patients', 'Species', '9606', (212, 220))	('T3N0-1M0', 'Var', (79, 87))	('patients', 'Species', '9606', (42, 50))	('lower', 'NegReg', (239, 244))	('dysphagia', 'Disease', (356, 365))
300497	33474812	Inclusion criteria were histologically confirmed primary EC, T1a-T4, N0-N+ disease, Eastern Cooperative Group (ECOG) performance status <3, receipt of DCCRT to the esophagus with or without regional nodal RT, and at least one follow-up visit with imaging (either with computed tomography (CT), positron emission tomography (PET)/CT or esophagogastroduodenoscopy (EGD) per the discretion of the treating physician) documented in the electronic medical record post DCCRT end date.	('primary EC', 'Disease', (49, 59))	('T1a-T4', 'Var', (61, 67))	('N0-N+ disease', 'Var', (69, 82))	('DCCRT', 'Chemical', '-', (463, 468))	('DCCRT', 'Chemical', '-', (151, 156))
300510	33474812	OAR dose constraints typically were lung V20 (volume receiving 20 Gy or more) <20%, V5<60%, mean <20 Gy, heart V40<50%, kidney V18<50%, spinal cord maximum 45 Gy, small bowel maximum 54 Gy, V50<5%, stomach mean <30 Gy, and mean liver <30 Gy.	('OAR', 'Gene', (0, 3))	('V50<', 'Var', (190, 194))	('OAR', 'Gene', '4936', (0, 3))
300511	33474812	Deviations in target coverage and OAR doses were accepted at the discretion of the treating physician to ensure plan safety.	('OAR', 'Gene', '4936', (34, 37))	('OAR', 'Gene', (34, 37))	('Deviations', 'Var', (0, 10))
300544	33474812	On stepwise regression, increased clinical tumor stage (p = 0.013), no feeding tube post-chemoRT (<0.001), RT dose (p = 0.008), and <50% change in primary tumor PET/CT SUVmax (p = 0.005) were significantly associated with worse OS.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('<50%', 'Var', (132, 136))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('worse OS', 'Disease', (222, 230))	('tumor', 'Disease', (43, 48))	('increased', 'PosReg', (24, 33))
300571	33474812	In addition, fluorouracil patients were more likely to need a dose reduction or treatment, most commonly due to hematologic toxicity, suggesting decreased tolerability with this regimen.	('dose', 'MPA', (62, 66))	('tolerability', 'MPA', (155, 167))	('fluorouracil', 'Chemical', 'MESH:D005472', (13, 25))	('hematologic toxicity', 'Disease', (112, 132))	('patients', 'Species', '9606', (26, 34))	('hematologic toxicity', 'Disease', 'MESH:D006402', (112, 132))	('fluorouracil', 'Var', (13, 25))
300596	33174677	Immunohistochemical (IHC) staining showed CK (+), CgA (-), Syn (+), CD56 (+), P40 (-), CD20 (-), CD3 (-), Ki67 (80%+).	('P40', 'Gene', (78, 81))	('CD20', 'Gene', '54474', (87, 91))	('P40', 'Gene', '3578', (78, 81))	('CD20', 'Gene', (87, 91))	('CD3 (-', 'Var', (97, 103))	('Syn', 'Gene', '23336', (59, 62))	('Syn', 'Gene', (59, 62))	('CD56', 'Gene', '4684', (68, 72))	('CD56', 'Gene', (68, 72))
300611	33174677	While median OS with pembrolizumab versus chemotherapy (7.1 vs. 7.1 months) was similar in the treated population in the KEYNOTE-181 study, pembrolizumab plus chemotherapy versus chemotherapy alone successfully improved median OS (12.4 vs. 9.8 months) and progression-free survival (PFS) in the first-line treatment of advanced esophageal cancer patients in KEYNOTE-590, and even patients with a low percentage of PD-L1 expression were shown to benefit from combination therapy.	('PD-L1', 'Gene', (414, 419))	('pembrolizumab', 'Chemical', 'MESH:C582435', (21, 34))	('PD-L1', 'Gene', '29126', (414, 419))	('patients', 'Species', '9606', (346, 354))	('patients', 'Species', '9606', (380, 388))	('cancer', 'Disease', (339, 345))	('improved', 'PosReg', (211, 219))	('median OS', 'MPA', (220, 229))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('pembrolizumab', 'Var', (140, 153))	('pembrolizumab', 'Chemical', 'MESH:C582435', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('progression-free survival', 'CPA', (256, 281))
300616	33174677	In addition, no hyperprogression was observed in this case, although the patient had MDM2 amplification, which was considered as a risk factor of hyperprogression.	('MDM2', 'Gene', '4193', (85, 89))	('patient', 'Species', '9606', (73, 80))	('MDM2', 'Gene', (85, 89))	('amplification', 'Var', (90, 103))
300732	32727720	Parvimonas micra, the only species described at the genus level, is known to cause bacteremia, abdominal abscesses, endocarditis, and other infections.	('abdominal abscesses', 'Disease', (95, 114))	('cause', 'Reg', (77, 82))	('Parvimonas micra', 'Species', '33033', (0, 16))	('endocarditis', 'Disease', (116, 128))	('endocarditis', 'Disease', 'MESH:D004696', (116, 128))	('bacteremia', 'Phenotype', 'HP:0031864', (83, 93))	('endocarditis', 'Phenotype', 'HP:0100584', (116, 128))	('infections', 'Disease', 'MESH:D007239', (140, 150))	('abdominal abscesses', 'Phenotype', 'HP:0025181', (95, 114))	('infections', 'Disease', (140, 150))	('Parvimonas micra', 'Var', (0, 16))	('bacteremia', 'Disease', 'MESH:D016470', (83, 93))	('bacteremia', 'Disease', (83, 93))	('abscesses', 'Phenotype', 'HP:0025615', (105, 114))
300734	32727720	Previously, it has been shown in malignant and primary human oral epithelial cells that Porphyromonas gingivalis and its membrane fraction induces up-regulation of a number of genes involved in inflammation and cell proliferation and control, however specific data for CRC are lacking.	('Porphyromonas gingivalis', 'Species', '837', (88, 112))	('inflammation', 'Disease', 'MESH:D007249', (194, 206))	('inflammation', 'Disease', (194, 206))	('human', 'Species', '9606', (55, 60))	('Porphyromonas gingivalis', 'Var', (88, 112))	('up-regulation', 'PosReg', (147, 160))
300736	32727720	P. anaerobius has been shown to promote colon dysplasia in a mouse model, specifically interacting with TLR2 and TLR4 on colon cells to increase levels of reactive oxidative species, which promotes cholesterol synthesis and cell proliferation.	('colon dysplasia', 'Disease', (40, 55))	('cholesterol', 'Chemical', 'MESH:D002784', (198, 209))	('cell proliferation', 'CPA', (224, 242))	('promotes', 'PosReg', (189, 197))	('mouse', 'Species', '10090', (61, 66))	('TLR2', 'Gene', '24088', (104, 108))	('TLR4', 'Gene', (113, 117))	('increase', 'PosReg', (136, 144))	('cholesterol synthesis', 'MPA', (198, 219))	('P. anaerobius', 'Var', (0, 13))	('P. anaerobius', 'Species', '1261', (0, 13))	('TLR4', 'Gene', '21898', (113, 117))	('promote', 'PosReg', (32, 39))	('TLR2', 'Gene', (104, 108))	('levels of reactive oxidative species', 'MPA', (145, 181))	('colon dysplasia', 'Disease', 'MESH:D003110', (40, 55))	('interacting', 'Interaction', (87, 98))
300746	32727720	In the initiation stage, the microbiome may promote specific genetic mutations and chronic inflammation, but may also be involved in creating other tumor-promoting environments such as the development of obesity and the metabolic syndrome.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('promote', 'PosReg', (44, 51))	('genetic mutations', 'Var', (61, 78))	('tumor', 'Disease', (148, 153))	('inflammation', 'Disease', (91, 103))	('inflammation', 'Disease', 'MESH:D007249', (91, 103))	('obesity and the metabolic syndrome', 'Disease', 'MESH:D000067329', (204, 238))	('involved', 'Reg', (121, 129))	('obesity', 'Phenotype', 'HP:0001513', (204, 211))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
300895	27618106	have shown that high ADC values were associated with better response to chemoradiotherapy in esophageal cancer patients and higher survival rates.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('high', 'Var', (16, 20))	('esophageal cancer', 'Disease', (93, 110))	('ADC', 'MPA', (21, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('higher', 'PosReg', (124, 130))	('survival', 'CPA', (131, 139))	('patients', 'Species', '9606', (111, 119))
300936	27618106	These are very important clinical parameters in treatment decision where neoadjuvant chemoradiotherapy is offered in rectal cancer patients with T3 or higher or lymph node metastasis while T1-2 patients undergo surgical resections.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (194, 202))	('rectal cancer', 'Disease', 'MESH:D012004', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rectal cancer', 'Disease', (117, 130))	('rectal cancer', 'Phenotype', 'HP:0100743', (117, 130))	('T3 or', 'Var', (145, 150))
300955	25064463	Using organotypic reconstruct cultures (OTC) to model the interaction between epithelial and stromal cells that occur in dysplastic lesions, we show that loss of TGFbeta signaling promotes an invasive phenotype in both fibroblast and epithelial compartments.	('dysplastic lesions', 'Disease', 'MESH:D021782', (121, 139))	('promotes', 'PosReg', (180, 188))	('dysplastic lesions', 'Disease', (121, 139))	('TGFbeta', 'Gene', (162, 169))	('invasive phenotype', 'CPA', (192, 210))	('loss', 'Var', (154, 158))
300956	25064463	Employing immortalized esophageal keratinocytes established to reproduce common mutations of esophageal squamous cell carcinoma, we show that treatment of OTC with inhibitors of TGFbeta signaling (A83-01 or SB431542) enhances invasion of epithelial cells into a fibroblast-embedded Matrigel/collagen I matrix.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('mutations', 'Var', (80, 89))	('TGFbeta', 'Gene', (178, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('invasion', 'CPA', (226, 234))	('A83-01', 'Chemical', 'MESH:C507011', (197, 203))	('inhibitors', 'Var', (164, 174))	('esophageal squamous cell carcinoma', 'Disease', (93, 127))	('enhances', 'PosReg', (217, 225))	('SB431542', 'Chemical', 'MESH:C459179', (207, 215))
300957	25064463	Invasion induced by A83-01 is independent of proliferation but relies on protease activity and expression of ADAMTS-1 and can be altered by matrix density.	('Invasion', 'CPA', (0, 8))	('relies', 'Reg', (63, 69))	('A83-01', 'Var', (20, 26))	('A83-01', 'Chemical', 'MESH:C507011', (20, 26))	('ADAMTS-1', 'Gene', '9510', (109, 117))	('ADAMTS-1', 'Gene', (109, 117))
300961	25064463	Taken together, our data show increased invasion through inhibition of TGFbeta signaling altered epithelial-fibroblasts interactions, repressing markers of activated fibroblasts, and altering integrin-fibronectin interactions.	('fibronectin', 'Gene', '2335', (201, 212))	('inhibition', 'Var', (57, 67))	('invasion', 'CPA', (40, 48))	('interactions', 'Interaction', (213, 225))	('fibronectin', 'Gene', (201, 212))	('repressing', 'PosReg', (134, 144))	('altering', 'Reg', (183, 191))	('TGFbeta signaling', 'Gene', (71, 88))	('epithelial-fibroblasts interactions', 'CPA', (97, 132))	('increased', 'PosReg', (30, 39))	('markers', 'MPA', (145, 152))	('altered', 'Reg', (89, 96))
300962	25064463	These results suggest that inhibition of TGFbeta signaling modulates an array of pathways that combined promote multiple aspects of tumor invasion.	('modulates', 'Reg', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('TGFbeta', 'Gene', (41, 48))	('inhibition', 'Var', (27, 37))	('tumor', 'Disease', (132, 137))	('promote', 'PosReg', (104, 111))
300971	25064463	Inhibition of TGFbeta in mouse models targeting epithelia of the head-and-neck region by knock-out of TGFbetaRII or Smad4 alone has little impact on tissue homeostasis.	('mouse', 'Species', '10090', (25, 30))	('TGFbetaRII', 'Gene', '7048', (102, 112))	('knock-out', 'Var', (89, 98))	('TGFbeta', 'Gene', (14, 21))	('TGFbetaRII', 'Gene', (102, 112))
300973	25064463	Interestingly, knockout of TGFbeta signaling members in fibroblasts is sufficient to induce tumor formation.	('knockout', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('TGFbeta', 'Gene', (27, 34))	('tumor', 'Disease', (92, 97))	('induce', 'Reg', (85, 91))
300976	25064463	Using organotypic three-dimensional reconstruct cultures as a platform to study ESCC invasion, we have previously shown that expression of dominant-negative mutants of E-cadherin and TGFbetaRII in immortalized esophageal keratinocytes results in fibroblast-dependent epithelial cell invasion.	('SCC', 'Gene', '6317', (81, 84))	('TGFbetaRII', 'Gene', '7048', (183, 193))	('TGFbetaRII', 'Gene', (183, 193))	('E-cadherin', 'Gene', '999', (168, 178))	('results in', 'Reg', (235, 245))	('E-cadherin', 'Gene', (168, 178))	('SCC', 'Gene', (81, 84))	('fibroblast-dependent epithelial cell invasion', 'CPA', (246, 291))	('mutants', 'Var', (157, 164))
300977	25064463	Loss of TGFbeta signaling elicits an inflammatory response in both compartments mediated by IL1, TGFalpha and HB-EGF and induces the expression of the matrix metalloproteases ADAMTS-1 and MMP14.	('expression', 'MPA', (133, 143))	('TGFalpha', 'Gene', '7039', (97, 105))	('IL1', 'Gene', (92, 95))	('matrix', 'Protein', (151, 157))	('HB-EGF', 'Gene', '1839', (110, 116))	('ADAMTS-1', 'Gene', (175, 183))	('ADAMTS-1', 'Gene', '9510', (175, 183))	('IL1', 'Gene', '3552', (92, 95))	('MMP14', 'Gene', '4323', (188, 193))	('TGFbeta signaling', 'Gene', (8, 25))	('inflammatory response', 'CPA', (37, 58))	('HB-EGF', 'Gene', (110, 116))	('induces', 'Reg', (121, 128))	('TGFalpha', 'Gene', (97, 105))	('elicits', 'Reg', (26, 33))	('MMP14', 'Gene', (188, 193))	('Loss', 'Var', (0, 4))
300978	25064463	Moreover, loss of TGFbeta signaling inhibits ROBO1 expression in epithelial cells, promoting invasion in the underlying stroma.	('loss', 'Var', (10, 14))	('promoting', 'PosReg', (83, 92))	('inhibits', 'NegReg', (36, 44))	('expression', 'MPA', (51, 61))	('ROBO1', 'Gene', '6091', (45, 50))	('invasion in the underlying stroma', 'CPA', (93, 126))	('ROBO1', 'Gene', (45, 50))
300981	25064463	A83-01 was used at a final concentration of 1microM (Tocris, Bristol U.K.), SB431542 at 10microM (Tocris), GM6001 at 1microM (Tocris), Erlotinib at 25nM (LC Laboratories, Woburn, MA), rEGF at 10ng/mL (Life technologies, Grand Island, NY).	('SB431542', 'Var', (76, 84))	('GM6001', 'Chemical', 'MESH:C078131', (107, 113))	('Erlotinib', 'Chemical', 'MESH:D000069347', (135, 144))	('GM6001', 'Var', (107, 113))	('rEGF', 'Gene', '25313', (184, 188))	('rEGF', 'Gene', (184, 188))	('SB431542', 'Chemical', 'MESH:C459179', (76, 84))	('A83-01', 'Chemical', 'MESH:C507011', (0, 6))
301004	25064463	We have previously shown that immortalized esophageal epithelial cells expressing dominant-negative E-cadherin and dominant-negative TGFbetaRII (ECdnT) were more invasive than esophageal keratinocytes expressing wild-type or mutant E-cadherin alone when grown in a model of organotypic culture (OTC).	('invasive', 'CPA', (162, 170))	('E-cadherin', 'Gene', (232, 242))	('E-cadherin', 'Gene', '999', (232, 242))	('TGFbetaRII', 'Gene', '7048', (133, 143))	('dominant-negative', 'Var', (115, 132))	('TGFbetaRII', 'Gene', (133, 143))	('E-cadherin', 'Gene', (100, 110))	('E-cadherin', 'Gene', '999', (100, 110))	('dominant-negative', 'Var', (82, 99))
301009	25064463	As we observed that the disruption of TGFbeta signaling using dominant-negative mutant of TGFbetaRII together with functional loss of E-cadherin promotes cell invasion and the secretion of pro-inflammatory cytokines in esophageal keratinocytes, we set out to further explore the contributions by TGFbeta.	('cell invasion', 'CPA', (154, 167))	('TGFbetaRII', 'Gene', (90, 100))	('mutant', 'Var', (80, 86))	('E-cadherin', 'Gene', (134, 144))	('E-cadherin', 'Gene', '999', (134, 144))	('disruption', 'Var', (24, 34))	('TGFbetaRII', 'Gene', '7048', (90, 100))	('loss', 'NegReg', (126, 130))	('secretion of pro-inflammatory cytokines', 'MPA', (176, 215))	('promotes', 'PosReg', (145, 153))
301012	25064463	As the dominant-negative mutant TGFbetaRII only partially inhibits TGFbeta signaling, we added these compounds to completely abolish signaling in ECdnT cells.	('TGFbetaRII', 'Gene', '7048', (32, 42))	('mutant', 'Var', (25, 31))	('TGFbetaRII', 'Gene', (32, 42))	('inhibits', 'NegReg', (58, 66))	('abolish', 'NegReg', (125, 132))	('TGFbeta signaling', 'MPA', (67, 84))
301015	25064463	Analysis of cytokines expressed in the fibroblasts upon treatment with A83-01 in the ECdnT OTC showed an upregulation of IL1beta and TGFalpha similarly to the differences observed between ECdnT and E cells (Figure 1D), suggesting an association with the invasive phenotype.	('TGFalpha', 'Gene', (133, 141))	('upregulation', 'PosReg', (105, 117))	('A83-01', 'Var', (71, 77))	('A83-01', 'Chemical', 'MESH:C507011', (71, 77))	('IL1beta', 'Gene', (121, 128))	('TGFalpha', 'Gene', '7039', (133, 141))	('IL1beta', 'Gene', '3553', (121, 128))
301017	25064463	alphaSMA was downregulated following A83-01 treatment.	('downregulated', 'NegReg', (13, 26))	('alphaSMA', 'MPA', (0, 8))	('A83-01', 'Var', (37, 43))	('A83-01', 'Chemical', 'MESH:C507011', (37, 43))
301018	25064463	Similarly, the deposition of fibronectin into the matrix was reduced in the presence of A83-01, while the expression of vimentin in the fibroblasts was comparable between the different growth conditions (Figure 1E).	('vimentin', 'Gene', (120, 128))	('fibronectin', 'Gene', '2335', (29, 40))	('A83-01', 'Var', (88, 94))	('A83-01', 'Chemical', 'MESH:C507011', (88, 94))	('vimentin', 'Gene', '7431', (120, 128))	('fibronectin', 'Gene', (29, 40))	('reduced', 'NegReg', (61, 68))
301021	25064463	The addition of A83-01 had no effect on the proliferation of ECdnT.	('ECdnT', 'Disease', (61, 66))	('A83-01', 'Chemical', 'MESH:C507011', (16, 22))	('A83-01', 'Var', (16, 22))
301022	25064463	Similarly SB431542 induced only a slight increase of proliferation possibly indicating that inhibition of TGFbeta signaling was not complete after expression of the dominant-negative TGFbetaRII in ECdnT cells.	('TGFbetaRII', 'Gene', '7048', (183, 193))	('TGFbetaRII', 'Gene', (183, 193))	('SB431542', 'Var', (10, 18))	('SB431542', 'Chemical', 'MESH:C459179', (10, 18))
301025	25064463	We conclude that the increased epithelial cell invasion of ECdnT upon treatment with A83-01 is independent of their proliferative capacity.	('A83-01', 'Var', (85, 91))	('increased', 'PosReg', (21, 30))	('epithelial cell invasion', 'CPA', (31, 55))	('A83-01', 'Chemical', 'MESH:C507011', (85, 91))
301026	25064463	Inhibition of matrix metalloproteases using the chemical compound GM6001 led to a complete suppression of invasion for cells untreated or treated with A83-01 (Figure 3 A and B).	('A83-01', 'Chemical', 'MESH:C507011', (151, 157))	('GM6001', 'Chemical', 'MESH:C078131', (66, 72))	('Inhibition', 'NegReg', (0, 10))	('invasion', 'CPA', (106, 114))	('suppression', 'NegReg', (91, 102))	('matrix', 'Protein', (14, 20))	('GM6001', 'Var', (66, 72))
301028	25064463	Using a higher concentrated collagen matrix suppressed the invasive potential of ECdnT cultures without treatment, however, addition of A83-01 could still induce epithelial cell invasion into the high collagen matrix (Figure 3C and D).	('epithelial cell invasion into the', 'CPA', (162, 195))	('addition', 'Var', (124, 132))	('invasive potential', 'CPA', (59, 77))	('A83-01', 'Var', (136, 142))	('induce', 'PosReg', (155, 161))	('A83-01', 'Chemical', 'MESH:C507011', (136, 142))
301031	25064463	Inhibition of TGFbeta1 signaling was associated with a reduction in expression of many proteases; most associated with Smad regulation, with the notable exception of ADAMTS-1 (Figure 3E).	('reduction', 'NegReg', (55, 64))	('expression', 'MPA', (68, 78))	('proteases', 'Enzyme', (87, 96))	('TGFbeta1', 'Gene', '7040', (14, 22))	('Inhibition', 'Var', (0, 10))	('ADAMTS-1', 'Gene', '9510', (166, 174))	('TGFbeta1', 'Gene', (14, 22))	('ADAMTS-1', 'Gene', (166, 174))
301034	25064463	To analyze the secretion of matrix metalloproteases, we used OTC conditioned medium and show that MMP9 secretion is inhibited upon treatment with A83-01, whereas secretion of MMP14 in epithelial cells was only slightly affected (Figure 3G).	('MMP14', 'Gene', '4323', (175, 180))	('inhibited', 'NegReg', (116, 125))	('A83-01', 'Var', (146, 152))	('A83-01', 'Chemical', 'MESH:C507011', (146, 152))	('MMP14', 'Gene', (175, 180))	('MMP9', 'Gene', '4318', (98, 102))	('MMP9', 'Gene', (98, 102))
301035	25064463	Although the inhibition of invasion by GM6001 indicates the dependency of proteases activity for ECdnT invasion, we show that following treatment with A83-01 most metalloproteases examined were inhibited and therefore not likely to function in cell invasion downstream of TGFbeta inhibition.	('A83-01', 'Chemical', 'MESH:C507011', (151, 157))	('inhibited', 'NegReg', (194, 203))	('GM6001', 'Var', (39, 45))	('GM6001', 'Chemical', 'MESH:C078131', (39, 45))	('inhibition', 'NegReg', (13, 23))	('metalloproteases', 'Enzyme', (163, 179))	('A83-01', 'Var', (151, 157))
301036	25064463	Analysis of protease expression showed an upregulation of ADAMTS-1 in cells treated with A83-01 (Figure 3E).	('ADAMTS-1', 'Gene', '9510', (58, 66))	('ADAMTS-1', 'Gene', (58, 66))	('A83-01', 'Var', (89, 95))	('A83-01', 'Chemical', 'MESH:C507011', (89, 95))	('upregulation', 'PosReg', (42, 54))
301041	25064463	Incidentally, as amplification of EGFR is a frequent occurrence in ESCC, we aimed to identify the role of EGF family members in epithelial cell invasion in this model.	('SCC', 'Gene', '6317', (68, 71))	('EGFR', 'Gene', (34, 38))	('EGF', 'Gene', (106, 109))	('EGF', 'Gene', (34, 37))	('amplification', 'Var', (17, 30))	('EGF', 'Gene', '1950', (106, 109))	('SCC', 'Gene', (68, 71))	('EGF', 'Gene', '1950', (34, 37))	('EGFR', 'Gene', '1956', (34, 38))
301042	25064463	We already established that fibroblasts expressed more TGFalpha upon treatment with A83-01 (Figure 1D).	('TGFalpha', 'Gene', '7039', (55, 63))	('A83-01', 'Var', (84, 90))	('A83-01', 'Chemical', 'MESH:C507011', (84, 90))	('TGFalpha', 'Gene', (55, 63))	('more', 'PosReg', (50, 54))
301049	25064463	Western Blot analysis of the epithelial cells isolated from OTC showed a reduction in EGFR signaling following A8301 treatment, as measured by phosphorylation of ERK1/2 and by reduced level of EGFR protein, which is expected after internalization and degradation following stimulation of the receptor.	('A8301', 'Var', (111, 116))	('A8301', 'Chemical', '-', (111, 116))	('EGFR', 'Gene', '1956', (86, 90))	('reduced', 'NegReg', (176, 183))	('EGFR', 'Gene', '1956', (193, 197))	('phosphorylation', 'MPA', (143, 158))	('ERK1/2', 'Gene', (162, 168))	('EGFR', 'Gene', (86, 90))	('EGFR', 'Gene', (193, 197))	('ERK1/2', 'Gene', '5595;5594', (162, 168))	('reduction', 'NegReg', (73, 82))
301054	25064463	Analysis of integrin expression by qPCR showed an overall downregulation of expression in particular of integrin alphaV, alpha5 and alpha1 following A83-01 treatment (Figure 5A).	('integrin alphaV', 'Gene', (104, 119))	('alpha5', 'Protein', (121, 127))	('A83-01', 'Var', (149, 155))	('A83-01', 'Chemical', 'MESH:C507011', (149, 155))	('downregulation', 'NegReg', (58, 72))	('expression', 'MPA', (76, 86))	('alpha1', 'Protein', (132, 138))	('integrin alphaV', 'Gene', '3685', (104, 119))
301065	25064463	Much of this complex regulation is mediated by epithelial-stromal crosstalk, suggesting that loss of the TGFbeta signaling pathway in tumors has both cell autonomous and non-autonomous roles.	('tumors', 'Disease', (134, 140))	('TGFbeta', 'Gene', (105, 112))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('loss', 'Var', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
301067	25064463	TGFbeta signaling inhibition induces NFkB signaling in the gut and protects the colon in early stage colitis.	('colitis', 'Phenotype', 'HP:0002583', (101, 108))	('TGFbeta', 'Gene', (0, 7))	('colitis', 'Disease', 'MESH:D003092', (101, 108))	('NFkB signaling', 'MPA', (37, 51))	('colitis', 'Disease', (101, 108))	('induces', 'PosReg', (29, 36))	('inhibition', 'Var', (18, 28))	('colon', 'Disease', (80, 85))
301076	25064463	Interestingly, loss of TGFbeta signaling through targeted deletion of SMAD4 in T cells resulted in the onset of head-and-neck SCC supporting that the imbalance of TGFbeta signaling between epithelial cells and the stroma could be a key factor in the initiation of cancer.	('initiation of cancer', 'Disease', 'MESH:D009369', (250, 270))	('SCC', 'Gene', '6317', (126, 129))	('SMAD4', 'Gene', '4089', (70, 75))	('onset', 'PosReg', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('loss', 'NegReg', (15, 19))	('deletion', 'Var', (58, 66))	('imbalance', 'Phenotype', 'HP:0002172', (150, 159))	('SMAD4', 'Gene', (70, 75))	('initiation of cancer', 'Disease', (250, 270))	('SCC', 'Gene', (126, 129))
301080	25064463	Lysyl oxidase, which mediates collagen crosslinking, is also increased in the breast stroma of a PyMT-driven knock-out of TGFbetaRII.	('Lysyl oxidase', 'Gene', (0, 13))	('breast stroma', 'Disease', (78, 91))	('TGFbetaRII', 'Gene', '7048', (122, 132))	('knock-out', 'Var', (109, 118))	('increased', 'PosReg', (61, 70))	('TGFbetaRII', 'Gene', (122, 132))	('breast stroma', 'Disease', 'MESH:D001943', (78, 91))	('Lysyl oxidase', 'Gene', '4015', (0, 13))
301087	25064463	ADAMTS-1 cleaves the proteoglycans aggrecan and versican and has been shown to have a potential collagenase activity.	('versican', 'Protein', (48, 56))	('collagenase', 'CPA', (96, 107))	('ADAMTS-1', 'Gene', '9510', (0, 8))	('ADAMTS-1', 'Gene', (0, 8))	('proteoglycans aggrecan', 'Protein', (21, 43))	('cleaves', 'Var', (9, 16))	('aggrecan', 'Protein', (35, 43))
301090	25064463	We found that inhibition of TGFbeta signaling increased TGFalpha, HB-EGF and IL1beta expression, suggesting that TGFbeta signaling may regulate activation of EGFR signaling via ADAMTS-1 expression (Figure 7).	('ADAMTS-1', 'Gene', (177, 185))	('expression', 'MPA', (85, 95))	('EGFR', 'Gene', (158, 162))	('HB-EGF', 'Gene', '1839', (66, 72))	('TGFalpha', 'Gene', '7039', (56, 64))	('IL1beta', 'Gene', '3553', (77, 84))	('increased', 'PosReg', (46, 55))	('HB-EGF', 'Gene', (66, 72))	('IL1beta', 'Gene', (77, 84))	('TGFalpha', 'Gene', (56, 64))	('EGFR', 'Gene', '1956', (158, 162))	('inhibition', 'Var', (14, 24))	('ADAMTS-1', 'Gene', '9510', (177, 185))
301101	25064463	We show that loss of TGFbeta signaling inhibits the expression of ROBO1 and membrane localization, suggesting that the pro-invasive effect of loss of TGFbeta signaling could be regulated by the loss of chemorepulsion in the absence of increased secretion of chemotactic factors (Figure 7).	('chemorepulsion', 'CPA', (202, 216))	('loss', 'Var', (142, 146))	('expression', 'MPA', (52, 62))	('membrane localization', 'MPA', (76, 97))	('loss', 'NegReg', (194, 198))	('TGFbeta signaling', 'Gene', (150, 167))	('ROBO1', 'Gene', '6091', (66, 71))	('ROBO1', 'Gene', (66, 71))	('inhibits', 'NegReg', (39, 47))	('loss', 'Var', (13, 17))
301183	33404856	Inhibited MicroRNA-301 Restrains Angiogenesis and Cell Growth in Esophageal Squamous Cell Carcinoma by Elevating PTEN Esophageal squamous cell carcinoma (ESCC) is featured by early metastasis and late diagnosis.	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('Squamous Cell Carcinoma', 'Disease', (76, 99))	('Elevating', 'PosReg', (103, 112))	('MicroRNA-301', 'Gene', (10, 22))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('Cell Growth', 'CPA', (50, 61))	('Carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 152))	('Inhibited', 'Var', (0, 9))	('Angiogenesis', 'CPA', (33, 45))	('squamous cell carcinoma', 'Disease', (129, 152))	('PTEN', 'MPA', (113, 117))	('Restrains', 'NegReg', (23, 32))	('MicroRNA-301', 'Gene', '407027', (10, 22))
301195	33404856	An amount of miRNAs such as miR-4324, miR-889-3p and miR-9 have been found to be associated with the process of ESCC.	('miR-9', 'Var', (53, 58))	('miR-4324', 'Gene', '100422979', (28, 36))	('ESCC', 'Disease', (112, 116))	('miR-889-3p', 'Var', (38, 48))	('miR-4324', 'Gene', (28, 36))	('associated', 'Reg', (81, 91))
301198	33404856	Moreover, phosphatase and tensin homologue (PTEN) has been affirmed to be frequently disrupted in tumors and targeted by germ line mutations in cancer patients, which plays an inhibitive role of tumors.	('phosphatase and tensin homologue', 'Gene', '5728', (10, 42))	('mutations', 'Var', (131, 140))	('tumors', 'Disease', (98, 104))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('patients', 'Species', '9606', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Disease', (144, 150))	('PTEN', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
301255	33404856	MiR-301 expression was assessed, and we found that miR-301 was highly expressed in ESCC cells in comparison with HEEC, and the higher expression of miR-301 has also been found in ESCC tissues in contrast to the adjacent normal tissues.	('expression', 'MPA', (134, 144))	('MiR-301', 'Gene', '407027', (0, 7))	('ESCC', 'Disease', (179, 183))	('higher', 'PosReg', (127, 133))	('miR-301', 'Gene', (51, 58))	('MiR-301', 'Gene', (0, 7))	('miR-301', 'Var', (148, 155))
301260	33404856	have supported that inhibited miR-301 attenuated migration and invasion of breast cancer cells, and it has been reported that the migration and invasion of ESCC cells could be repressed by the inhibition of miR-130b and the elevation of PTEN.	('PTEN', 'Gene', (237, 241))	('attenuated', 'NegReg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('inhibited', 'Var', (20, 29))	('miR-301', 'Gene', (30, 37))	('miR-130b', 'Gene', '406920', (207, 215))	('invasion', 'CPA', (144, 152))	('inhibition', 'NegReg', (193, 203))	('miR-130b', 'Gene', (207, 215))	('elevation', 'PosReg', (224, 233))	('migration', 'CPA', (130, 139))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
301262	33404856	Another result in our research was that inhibited miR-301 overexpressed PTEN to promote cell apoptosis and induce cell cycle arrest at the G0/G1 phase in ESCC cells, and elevated miR-301 or reduced PTEN had the inverse results.	('elevated', 'PosReg', (170, 178))	('cell apoptosis', 'CPA', (88, 102))	('miR-301', 'Gene', (50, 57))	('arrest', 'Disease', 'MESH:D006323', (125, 131))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (114, 131))	('induce', 'Reg', (107, 113))	('arrest', 'Disease', (125, 131))	('miR-301', 'Protein', (179, 186))	('reduced', 'NegReg', (190, 197))	('PTEN', 'MPA', (198, 202))	('inhibited', 'Var', (40, 49))	('promote', 'PosReg', (80, 87))
301263	33404856	Similarly, it has been uncovered by a recent literature that activated PTEN induces cell cycle arrest and apoptosis in ESCC.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('ESCC', 'Disease', (119, 123))	('apoptosis', 'CPA', (106, 115))	('PTEN', 'Gene', (71, 75))	('induces', 'Reg', (76, 83))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('activated', 'Var', (61, 70))	('arrest', 'Disease', (95, 101))
301268	33404856	ESCC Esophageal squamous cell carcinoma PTEN Phosphatase and tensin homologue MVD Microvessel density EC Esophageal cancer miRNAs MicroRNAs LNM Lymph node metastasis UICC Union for International Cancer Control RT-qPCR Reverse transcription quantitative polymerase chain reaction 3'UTR 3'-Untranslated region WT Wild type MUT Mutant type HRP Horseradish peroxidase FBS Fetal bovine serum OE Overexpressed NC Negative control CCK-8 Cell counting kit DMEM Dulbecco's modified Eagle medium PI Propidium iodide FITC Fluorescein isothiocyanate MVD Microvessel density ANOVA Analysis of variance Yan Zhang finished study design, Bin Wang, Peiyan Hua and Ruimin Wang finished experimental studies, Bin Wang Guangxin Zhang and Chengyan Jin finished data analysis, and Bin Wang finished manuscript editing.	('Phosphatase', 'Gene', '5728', (45, 56))	('Cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('CCK', 'Gene', '885', (424, 427))	('Phosphatase', 'Gene', (45, 56))	('DMEM', 'Chemical', '-', (448, 452))	('kit', 'Gene', (444, 447))	('Horseradish', 'Species', '3704', (341, 352))	('Cancer', 'Disease', 'MESH:D009369', (195, 201))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 39))	('FITC', 'Chemical', 'MESH:D016650', (506, 510))	('Propidium iodide', 'Chemical', 'MESH:D011419', (489, 505))	('cancer', 'Disease', (116, 122))	('CCK', 'Gene', (424, 427))	('WT', 'Disease', 'MESH:C536751', (308, 310))	("Dulbecco's modified Eagle medium", 'Chemical', '-', (453, 485))	('Mutant', 'Var', (325, 331))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('squamous cell carcinoma', 'Disease', (16, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('FBS', 'Disease', (364, 367))	('Cancer', 'Phenotype', 'HP:0002664', (195, 201))	('FBS', 'Disease', 'MESH:D005198', (364, 367))	('Fluorescein isothiocyanate', 'Chemical', '-', (511, 537))	('kit', 'Gene', '3815', (444, 447))
301280	32819973	We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (170, 176))	('S228P', 'Mutation', 'p.S228P', (113, 118))	('cancer', 'Disease', (37, 43))	('IgG', 'Gene', (79, 82))	('IgG', 'Gene', '16017', (79, 82))	('promoted', 'PosReg', (161, 169))	('mice', 'Species', '10090', (187, 191))	('nivolumab', 'Chemical', 'MESH:D000077594', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('S228P', 'Var', (113, 118))
301287	32819973	IgG4 has a unique structure of Fab arm exchange (FAE) in which the two heavy and light chains of two different antibodies with different specificities are exchanged, resulting in an asymmetric bispecific antibody with reduced ability to bind to antigen and to form immune complexes.	('form', 'Reg', (260, 264))	('bind', 'Interaction', (237, 241))	('immune complexes', 'Interaction', (265, 281))	('IgG', 'Gene', (0, 3))	('IgG', 'Gene', '16017', (0, 3))	('ability', 'MPA', (226, 233))	('Fab', 'Gene', '2187', (31, 34))	('exchanged', 'Var', (155, 164))	('reduced', 'NegReg', (218, 225))	('Fab', 'Gene', (31, 34))	('antigen', 'Protein', (245, 252))
301393	32819973	In a separate but similar experiment of a colon cancer mouse model, we injected antibody to programmed cell death-1 (PD-1) (nivolumab), which is a widely used drug in cancer immune therapy and is also an IgG4 isotype with S228P mutation, which replaces a serine residue in the hinge region with a proline residue to prevent FAE and stabilize the protein.	('cancer', 'Disease', (167, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('cancer', 'Disease', (48, 54))	('proline', 'Chemical', 'MESH:D011392', (297, 304))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('stabilize', 'MPA', (332, 341))	('IgG', 'Gene', '16017', (204, 207))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('programmed cell death-1', 'Gene', (92, 115))	('mouse', 'Species', '10090', (55, 60))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('serine', 'Chemical', 'MESH:D012694', (255, 261))	('FAE', 'Disease', (324, 327))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('S228P', 'Mutation', 'p.S228P', (222, 227))	('nivolumab', 'Chemical', 'MESH:D000077594', (124, 133))	('colon cancer', 'Disease', (42, 54))	('programmed cell death-1', 'Gene', '18566', (92, 115))	('IgG', 'Gene', (204, 207))	('S228P mutation', 'Var', (222, 236))
301395	32819973	We found that IgG4, anti-PD-1 and in particular the Fc of anti-PD-1 groups produced much larger cancer masses in comparison with the groups with PBS and IgG1.	('IgG1', 'Gene', '16017', (153, 157))	('IgG', 'Gene', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('anti-PD-1', 'Var', (58, 67))	('IgG', 'Gene', (14, 17))	('IgG1', 'Gene', (153, 157))	('IgG', 'Gene', '16017', (14, 17))	('larger', 'PosReg', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('IgG', 'Gene', '16017', (153, 156))	('PBS', 'Chemical', '-', (145, 148))
301398	32819973	We found that the Fc of nivolumab reacted to IgG1 (online supplementary figure S3), and the S228P mutation did not seem to prevent Fc-Fc reaction taking place between nivolumab and other IgGs.	('nivolumab', 'Chemical', 'MESH:D000077594', (167, 176))	('IgG', 'Gene', (45, 48))	('IgG', 'Gene', '16017', (45, 48))	('IgG', 'Gene', (187, 190))	('nivolumab', 'Chemical', 'MESH:D000077594', (24, 33))	('IgG1', 'Gene', '16017', (45, 49))	('IgG', 'Gene', '16017', (187, 190))	('S228P', 'Var', (92, 97))	('S228P', 'Mutation', 'p.S228P', (92, 97))	('IgG1', 'Gene', (45, 49))
301473	32819973	Local increase of IgG4 molecule would lead to local immune inhibition that indirectly promotes cancer growth, and this effect was likely rendered by the Fc fragment of IgG4 rather than antigen-specific Fab fragment as claimed by others.	('IgG', 'Gene', (168, 171))	('IgG', 'Gene', '16017', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('IgG', 'Gene', (18, 21))	('cancer', 'Disease', (95, 101))	('Fab', 'Gene', '2187', (202, 205))	('Fc fragment', 'Var', (153, 164))	('promotes', 'PosReg', (86, 94))	('IgG', 'Gene', '16017', (18, 21))	('Fab', 'Gene', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('increase of IgG4 molecule', 'Phenotype', 'HP:0032300', (6, 31))	('increase', 'PosReg', (6, 14))
301487	32819973	We found that anti-PD-1 and its Fc fragment led to accelerated cancer growth in comparison with the controls.	('anti-PD-1', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('accelerated', 'PosReg', (51, 62))	('cancer', 'Disease', (63, 69))
301488	32819973	Recent awareness of hyperprogressive disease (HPD) associated with anti-PD-1 and anti-PD-L1 monoclonal antibody treatment for cancer has caught widespread attention, but no consensual explanation for this phenomenon has arrived.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hyperprogressive disease', 'Disease', (20, 44))	('HPD', 'Disease', (46, 49))	('PD-L1', 'Gene', '29126', (86, 91))	('hyperprogressive disease', 'Disease', 'MESH:D003141', (20, 44))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('HPD', 'Disease', 'MESH:D004421', (46, 49))	('anti-PD-1', 'Var', (67, 76))	('PD-L1', 'Gene', (86, 91))
301496	32819973	However, in our experiments this mutation did not seem to prevent Fc-Fc reaction (online supplementary figure S3) and the immune blockage effect of nivolumab (IgG4) Fc leading to the largest cancer size in our animal experiment (figure 5C, D).	('cancer', 'Disease', (191, 197))	('mutation', 'Var', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('immune blockage', 'Phenotype', 'HP:0002721', (122, 137))	('IgG', 'Gene', (159, 162))	('IgG', 'Gene', '16017', (159, 162))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('nivolumab', 'Chemical', 'MESH:D000077594', (148, 157))
301672	27835886	We hypothesized that the variation of GM-CSF during RT was correlated with cancer prognosis.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('GM-CSF', 'Gene', (38, 44))	('cancer', 'Disease', (75, 81))	('variation', 'Var', (25, 34))	('GM-CSF', 'Gene', '1437', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('correlated', 'Reg', (59, 69))
301723	27835886	We also showed that high pre-RT IFN-gamma also led to improved prognosis.	('IFN-gamma', 'Gene', '3458', (32, 41))	('IFN-gamma', 'Gene', (32, 41))	('high', 'Var', (20, 24))	('improved', 'PosReg', (54, 62))	('prognosis', 'CPA', (63, 72))
301768	27588484	Mutation of oncogenes and tumor suppressor genes is a primary force underlying oncogenesis and cancer progression.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Mutation', 'Var', (0, 8))	('cancer', 'Disease', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
301771	27588484	However, because tumors acquire many malignant traits through somatic mutations, the success of such approaches depends on identifying genetic variations in known oncogenes and tumor suppressor genes, and such variations strongly influencing gene expression or function.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('tumors', 'Disease', (17, 23))	('influencing', 'Reg', (230, 241))	('variations', 'Var', (210, 220))	('variations', 'Var', (143, 153))	('function', 'MPA', (261, 269))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (177, 182))	('gene expression', 'MPA', (242, 257))
301779	27588484	Here, we summarize previous studies demonstrating the role of epistasis in susceptibility to gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', (93, 117))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (93, 116))	('epistasis', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (93, 117))
301788	27588484	The rs1052134 single-nucleotide polymorphism (SNP) in the OGG1 gene encodes p.Ser326Cys, a substitution of Ser for Cys at amino acid 326 of the OGG1 protein.	('rs1052134', 'Mutation', 'rs1052134', (4, 13))	('OGG1', 'Gene', '4968', (144, 148))	('p.Ser326Cys', 'Mutation', 'rs1052133', (76, 87))	('OGG1', 'Gene', (58, 62))	('OGG1', 'Gene', (144, 148))	('rs1052134 single-nucleotide polymorphism', 'Var', (4, 44))	('Ser for Cys at amino acid 326', 'Mutation', 'rs1052133', (107, 136))	('OGG1', 'Gene', '4968', (58, 62))
301789	27588484	This OGG1 SNP interacts synergistically with MUTYH SNP rs3219489, encoding p.Gln324His and affecting glycosylase activity, to increase colorectal cancer risk (ORinteraction = 1.36).	('OGG1', 'Gene', (5, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('affecting', 'Reg', (91, 100))	('OGG1', 'Gene', '4968', (5, 9))	('rectal cancer', 'Phenotype', 'HP:0100743', (139, 152))	('MUTYH', 'Gene', (45, 50))	('MUTYH', 'Gene', '4595', (45, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('glycosylase activity', 'MPA', (101, 121))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('p.Gln324His', 'Var', (75, 86))	('increase', 'PosReg', (126, 134))	('colorectal cancer', 'Disease', (135, 152))	('p.Gln324His', 'Mutation', 'rs3219489', (75, 86))	('rs3219489', 'Mutation', 'rs3219489', (55, 64))
301790	27588484	The OGG1 Cys variant had multiple defects in DNA binding, repair and/or nuclear localization.	('DNA binding', 'Interaction', (45, 56))	('Cys', 'Var', (9, 12))	('nuclear localization', 'MPA', (72, 92))	('Cys', 'Chemical', 'MESH:D003545', (9, 12))	('OGG1', 'Gene', (4, 8))	('OGG1', 'Gene', '4968', (4, 8))	('defects', 'NegReg', (34, 41))	('repair', 'MPA', (58, 64))
301792	27588484	OGG1 directly interacts with XRCC1, and the OGG1 rs1052134 showed epistasis with two XRCC1 SNPs in colorectal cancer risk.	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))	('colorectal cancer', 'Disease', (99, 116))	('rs1052134', 'Mutation', 'rs1052134', (49, 58))	('OGG1', 'Gene', (44, 48))	('OGG1', 'Gene', '4968', (44, 48))	('XRCC1', 'Gene', (85, 90))	('XRCC1', 'Gene', '7515', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('OGG1', 'Gene', (0, 4))	('rectal cancer', 'Phenotype', 'HP:0100743', (103, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('OGG1', 'Gene', '4968', (0, 4))	('rs1052134', 'Var', (49, 58))	('epistasis', 'MPA', (66, 75))	('XRCC1', 'Gene', '7515', (85, 90))	('XRCC1', 'Gene', (29, 34))
301793	27588484	These included a synergistic interaction (ORinteraction = 1.34) with XRCC1 rs25487 encoding p.Arg399Gln, and a co-suppressive interaction (crude ORinteraction = 0.44) with XRCC1 rs1799782 encoding p.Arg194Trp.	('p.Arg399Gln', 'Var', (92, 103))	('p.Arg194Trp', 'Mutation', 'rs1799782', (197, 208))	('XRCC1', 'Gene', '7515', (69, 74))	('XRCC1', 'Gene', '7515', (172, 177))	('rs25487', 'Mutation', 'rs25487', (75, 82))	('p.Arg399Gln', 'Mutation', 'rs25487', (92, 103))	('rs1799782', 'Var', (178, 187))	('XRCC1', 'Gene', (69, 74))	('XRCC1', 'Gene', (172, 177))	('synergistic interaction', 'MPA', (17, 40))	('rs25487', 'Var', (75, 82))	('rs1799782', 'Mutation', 'rs1799782', (178, 187))
301794	27588484	Incidentally, the XRCC1 rs1799782 synergistically interacted (crude ORinteraction = 1.13) with the MUTYH rs3219489, albeit weakly, in colorectal cancer risk.	('XRCC1', 'Gene', '7515', (18, 23))	('colorectal cancer', 'Disease', (134, 151))	('MUTYH', 'Gene', (99, 104))	('MUTYH', 'Gene', '4595', (99, 104))	('interacted', 'Reg', (50, 60))	('rs3219489', 'Mutation', 'rs3219489', (105, 114))	('rs1799782', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('XRCC1', 'Gene', (18, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('rectal cancer', 'Phenotype', 'HP:0100743', (138, 151))	('rs1799782', 'Mutation', 'rs1799782', (24, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))
301798	27588484	Susceptibility to gastric cancer is associated with PARP1 rs1136410 encoding p.Val762Ala, along with the Ala variant, which displayed diminished enzymatic activity.	('gastric cancer', 'Disease', (18, 32))	('Susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (0, 32))	('PARP1', 'Gene', '142', (52, 57))	('rs1136410', 'Var', (58, 67))	('p.Val762Ala', 'Var', (77, 88))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('PARP1', 'Gene', (52, 57))	('Ala', 'Chemical', 'MESH:D000409', (105, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('Ala', 'Chemical', 'MESH:D000409', (85, 88))	('Susceptibility', 'Reg', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('rs1136410', 'Mutation', 'rs1136410', (58, 67))	('p.Val762Ala', 'Mutation', 'rs1136410', (77, 88))
301799	27588484	The PARP1 rs1136410 synergistically interacted (ORinteraction = 1.84) with XRCC1 rs25487 encoding p.Arg399Gln in gastric cancer risk.	('rs25487', 'Var', (81, 88))	('XRCC1', 'Gene', (75, 80))	('p.Arg399Gln', 'Var', (98, 109))	('interacted', 'Reg', (36, 46))	('rs25487', 'Mutation', 'rs25487', (81, 88))	('p.Arg399Gln', 'Mutation', 'rs25487', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('rs1136410', 'Mutation', 'rs1136410', (10, 19))	('XRCC1', 'Gene', '7515', (75, 80))	('PARP1', 'Gene', '142', (4, 9))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('rs1136410', 'Var', (10, 19))	('PARP1', 'Gene', (4, 9))
301800	27588484	Both risk-associated PARP1 and XRCC1 substitutions are expected to decrease base excision repair through reduced PARP1 ribosylation and XRCC1 recruitment.	('PARP1', 'Gene', '142', (21, 26))	('decrease', 'NegReg', (67, 75))	('XRCC1', 'Gene', '7515', (31, 36))	('recruitment', 'MPA', (142, 153))	('XRCC1', 'Gene', (136, 141))	('ribosylation', 'MPA', (119, 131))	('substitutions', 'Var', (37, 50))	('reduced', 'NegReg', (105, 112))	('PARP1', 'Gene', '142', (113, 118))	('XRCC1', 'Gene', (31, 36))	('XRCC1', 'Gene', '7515', (136, 141))	('PARP1', 'Gene', (113, 118))	('base excision repair', 'MPA', (76, 96))	('PARP1', 'Gene', (21, 26))
301803	27588484	These interactions, excluding the weak interaction between MUTYH and XRCC1 (rs1799782), may shape a linear network topology in the form of MUTYH-OGG1-XRCC1-PARP1 (Figure 2A), although the three interaction links were observed in two different studies for different cancers (two links in Polish colorectal cancer and one in Chinese gastric cancer).	('XRCC1', 'Gene', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('gastric cancer', 'Phenotype', 'HP:0012126', (331, 345))	('colorectal cancer', 'Disease', 'MESH:D015179', (294, 311))	('XRCC1', 'Gene', (69, 74))	('PARP1', 'Gene', (156, 161))	('colorectal cancer', 'Disease', (294, 311))	('rs1799782', 'Mutation', 'rs1799782', (76, 85))	('XRCC1', 'Gene', '7515', (150, 155))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('XRCC1', 'Gene', '7515', (69, 74))	('OGG1', 'Gene', (145, 149))	('OGG1', 'Gene', '4968', (145, 149))	('gastric cancer', 'Disease', (331, 345))	('MUTYH', 'Gene', (59, 64))	('PARP1', 'Gene', '142', (156, 161))	('colorectal cancer', 'Phenotype', 'HP:0003003', (294, 311))	('MUTYH', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('gastric cancer', 'Disease', 'MESH:D013274', (331, 345))	('MUTYH', 'Gene', '4595', (59, 64))	('interactions', 'Var', (6, 18))	('rectal cancer', 'Phenotype', 'HP:0100743', (298, 311))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('cancers', 'Disease', (265, 272))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('MUTYH', 'Gene', '4595', (139, 144))
301806	27588484	The SNP, rs1800975, in the 5' untranslated region of XPA, just four nucleotides upstream of the AUG start codon, is part of the Kozak sequence, which affects translation initiation efficiency.	('affects', 'Reg', (150, 157))	('rs1800975', 'Var', (9, 18))	('rs1800975', 'Mutation', 'rs1800975', (9, 18))	('initiation efficiency', 'Disease', (170, 191))	('initiation efficiency', 'Disease', 'MESH:D007319', (170, 191))	('XPA', 'Gene', '7507', (53, 56))	('XPA', 'Gene', (53, 56))
301807	27588484	This XPA rs1800975 synergistically interacted (OR'interaction = 1.76) with an XPC polymorphism, PAT S>L, in gastric cancer risk.	('XPC', 'Gene', '7508', (78, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (108, 122))	('rs1800975', 'Var', (9, 18))	('rs1800975', 'Mutation', 'rs1800975', (9, 18))	('XPA', 'Gene', '7507', (5, 8))	('XPC', 'Gene', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('XPA', 'Gene', (5, 8))	('interacted', 'Reg', (35, 45))	('gastric cancer', 'Disease', (108, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (108, 122))
301808	27588484	The XPC PAT polymorphism alone was not associated with cancer risk, but enhanced the effect of XPA rs1800975.	('XPC', 'Gene', '7508', (4, 7))	('XPC', 'Gene', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('effect', 'MPA', (85, 91))	('XPA', 'Gene', '7507', (95, 98))	('enhanced', 'PosReg', (72, 80))	('XPA', 'Gene', (95, 98))	('rs1800975', 'Var', (99, 108))	('rs1800975', 'Mutation', 'rs1800975', (99, 108))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
301809	27588484	The XPC PAT polymorphism is in linkage disequilibrium with XPC rs2228001 encoding p.Lys939Gln.	('rs2228001', 'Mutation', 'rs2228001', (63, 72))	('XPC', 'Gene', '7508', (4, 7))	('XPC', 'Gene', '7508', (59, 62))	('p.Lys939Gln', 'Mutation', 'rs2228001', (82, 93))	('p.Lys939Gln', 'Var', (82, 93))	('XPC', 'Gene', (59, 62))	('XPC', 'Gene', (4, 7))
301815	27588484	With respect to ADH1B rs1229984 encoding p.Arg47His, the Arg allele enzyme has lower catalytic activity for ethanol metabolism than the His allele enzyme.	('rs1229984', 'Var', (22, 31))	('ethanol', 'Chemical', 'MESH:D000431', (108, 115))	('ADH1B', 'Gene', (16, 21))	('catalytic activity', 'MPA', (85, 103))	('lower', 'NegReg', (79, 84))	('ADH1B', 'Gene', '125', (16, 21))	('p.Arg47His', 'Var', (41, 51))	('rs1229984', 'Mutation', 'rs1229984', (22, 31))	('p.Arg47His', 'Mutation', 'rs1229984', (41, 51))	('Arg', 'Chemical', 'MESH:D001120', (43, 46))	('Arg', 'Chemical', 'MESH:D001120', (57, 60))
301816	27588484	Regarding ALDH2 rs671 encoding p.Glu504Lys (also known as Glu487Lys), the Lys allele enzyme has lower activity than the Glu allele enzyme.	('rs671', 'Mutation', 'rs671', (16, 21))	('Glu', 'Chemical', 'MESH:D018698', (58, 61))	('Glu487Lys', 'SUBSTITUTION', 'None', (58, 67))	('p.Glu504Lys', 'Mutation', 'rs671', (31, 42))	('ALDH2', 'Gene', '217', (10, 15))	('lower', 'NegReg', (96, 101))	('Lys', 'Chemical', 'MESH:D008239', (74, 77))	('ALDH2', 'Gene', (10, 15))	('Lys', 'Chemical', 'MESH:D008239', (39, 42))	('Glu', 'Chemical', 'MESH:D018698', (33, 36))	('activity', 'MPA', (102, 110))	('p.Glu504Lys', 'Var', (31, 42))	('rs671', 'Var', (16, 21))	('Glu487Lys', 'Var', (58, 67))	('Glu', 'Chemical', 'MESH:D018698', (120, 123))	('Lys', 'Chemical', 'MESH:D008239', (64, 67))
301817	27588484	SNPs in both ADH1B and ALDH2 are associated with susceptibility to esophageal and gastric cancers in alcohol drinkers.	('ALDH2', 'Gene', (23, 28))	('alcohol', 'Chemical', 'MESH:D000438', (101, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (67, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (101, 117))	('gastric cancers', 'Phenotype', 'HP:0012126', (82, 97))	('ADH1B', 'Gene', (13, 18))	('susceptibility', 'Reg', (49, 63))	('SNPs', 'Var', (0, 4))	('associated', 'Reg', (33, 43))	('ADH1B', 'Gene', '125', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('ALDH2', 'Gene', '217', (23, 28))
301819	27588484	Further study is required to determine how the interaction between the two lower activity ADH1B (47Arg) and ALDH2 (504Lys) variants leads to increased cancer risk.	('interaction', 'Interaction', (47, 58))	('Arg', 'Chemical', 'MESH:D001120', (99, 102))	('ADH1B', 'Gene', '125', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Lys', 'Chemical', 'MESH:D008239', (118, 121))	('47Arg', 'Var', (97, 102))	('ALDH2', 'Gene', '217', (108, 113))	('504Lys', 'Var', (115, 121))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('ADH1B', 'Gene', (90, 95))	('lower activity', 'NegReg', (75, 89))	('ALDH2', 'Gene', (108, 113))
301824	27588484	Several studies have associated NQO1 polymorphisms with susceptibility to esophageal and cutaneous (skin) cancers.	('polymorphisms', 'Var', (37, 50))	('NQO1', 'Gene', (32, 36))	('NQO1', 'Gene', '1728', (32, 36))	('susceptibility', 'Reg', (56, 70))	('esophageal and cutaneous (skin) cancers', 'Disease', 'MESH:D012878', (74, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
301825	27588484	The Ser variant of NQO1 rs1800566 encoding p.Pro187Ser has reduced enzymatic activity and is associated with higher benzene toxicity compared with the Pro variant.	('rs1800566', 'Mutation', 'rs1800566', (24, 33))	('rs1800566', 'Var', (24, 33))	('reduced', 'NegReg', (59, 66))	('NQO1', 'Gene', (19, 23))	('Ser', 'Chemical', 'MESH:D012694', (4, 7))	('benzene', 'Chemical', 'MESH:D001554', (116, 123))	('p.Pro187Ser', 'Mutation', 'rs1800566', (43, 54))	('higher', 'PosReg', (109, 115))	('toxicity', 'Disease', 'MESH:D064420', (124, 132))	('Ser', 'Chemical', 'MESH:D012694', (51, 54))	('NQO1', 'Gene', '1728', (19, 23))	('enzymatic activity', 'MPA', (67, 85))	('toxicity', 'Disease', (124, 132))	('p.Pro187Ser', 'Var', (43, 54))
301826	27588484	This NQO1 SNP was associated with esophageal adenocarcinoma risk and synergistically interacted (ORinteraction = 1.16) with a promoter SNP of NQO2, rs2070999, which was not associated with esophageal adenocarcinoma risk.	('rs2070999', 'Var', (148, 157))	('NQO1', 'Gene', (5, 9))	('rs2070999', 'Mutation', 'rs2070999', (148, 157))	('NQO1', 'Gene', '1728', (5, 9))	('associated', 'Reg', (18, 28))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (34, 59))	('NQO2', 'Gene', (142, 146))	('esophageal adenocarcinoma', 'Disease', (34, 59))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (189, 214))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (34, 59))	('esophageal adenocarcinoma', 'Disease', (189, 214))	('NQO2', 'Gene', '4835', (142, 146))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (189, 214))
301831	27588484	A case-control study separately associated GSTT1- and GSTM1-null genotypes with increased gastric cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('genotypes', 'Var', (65, 74))	('GSTT1', 'Gene', '2952', (43, 48))	('GSTT1', 'Gene', (43, 48))	('GSTM1', 'Gene', '2944', (54, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('GSTM1', 'Gene', (54, 59))	('increased gastric', 'Phenotype', 'HP:0005207', (80, 97))	('increased gastric cancer', 'Phenotype', 'HP:0006753', (80, 104))	('gastric cancer', 'Disease', (90, 104))
301833	27588484	Deletion of GSTs might be associated with high levels of Helicobacter pylori-induced reactive oxygen species and thus increase susceptibility to inflammation-related cancer through enhanced DNA damage.	('GSTs', 'Gene', '373156', (12, 16))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('DNA damage', 'MPA', (190, 200))	('inflammation', 'Disease', (145, 157))	('increase', 'PosReg', (118, 126))	('inflammation', 'Disease', 'MESH:D007249', (145, 157))	('susceptibility', 'Reg', (127, 141))	('enhanced', 'PosReg', (181, 189))	('GSTs', 'Gene', (12, 16))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (85, 108))	('levels', 'MPA', (47, 53))	('Helicobacter pylori', 'Species', '210', (57, 76))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('associated', 'Reg', (26, 36))	('high levels of Helicobacter pylori', 'Phenotype', 'HP:0005202', (42, 76))	('Deletion', 'Var', (0, 8))
301834	27588484	APEX1 rs1130409 encoding p.Asp148Glu showed redundant interaction (OR'interaction = 0.85) with the GSTT1-null genotype, but suppressive interaction (OR'interaction = 0.77) with the GSTT1-GSTM1 double-null genotype in gastric cancer susceptibility.	('suppressive', 'NegReg', (124, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (217, 231))	('GSTM1', 'Gene', '2944', (187, 192))	('gastric cancer', 'Phenotype', 'HP:0012126', (217, 231))	('GSTM1', 'Gene', (187, 192))	('rs1130409', 'Mutation', 'rs1130409', (6, 15))	('GSTT1', 'Gene', (99, 104))	('p.Asp148Glu', 'Mutation', 'rs1130409', (25, 36))	('rs1130409', 'Var', (6, 15))	('GSTT1', 'Gene', (181, 186))	('GSTT1', 'Gene', '2952', (99, 104))	('APEX1', 'Gene', '328', (0, 5))	('GSTT1', 'Gene', '2952', (181, 186))	('APEX1', 'Gene', (0, 5))	('gastric cancer', 'Disease', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('p.Asp148Glu', 'Var', (25, 36))
301838	27588484	Alone, APEX1 rs1130409 was not associated with gastric cancer risk, suggesting that this SNP has an impact only in conjunction with the GSTT1- or double-null genotype.	('gastric cancer', 'Disease', (47, 61))	('GSTT1', 'Gene', '2952', (136, 141))	('rs1130409', 'Mutation', 'rs1130409', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('GSTT1', 'Gene', (136, 141))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('rs1130409', 'Var', (13, 22))	('APEX1', 'Gene', '328', (7, 12))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('APEX1', 'Gene', (7, 12))
301841	27588484	Additionally, this null genotype redundantly interacted (crude ORinteraction = 0.70) in sporadic colorectal cancer risk with NAT2 rs1799930 encoding p.Arg197Gln.	('rectal cancer', 'Phenotype', 'HP:0100743', (101, 114))	('p.Arg197Gln', 'Var', (149, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('NAT2', 'Gene', '10', (125, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('rs1799930', 'Mutation', 'rs1799930', (130, 139))	('colorectal cancer', 'Disease', (97, 114))	('rs1799930', 'Var', (130, 139))	('NAT2', 'Gene', (125, 129))	('p.Arg197Gln', 'Mutation', 'rs1799930', (149, 160))
301845	27588484	Synergistic interaction between CYP1A1 rs1048943 encoding p.Ile462Val and CYP2E1 rs2031920 was observed in Kashmir esophageal cancer (crude ORinteraction = 1.85).	('rs1048943', 'Var', (39, 48))	('rs1048943', 'Mutation', 'rs1048943', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('CYP1A1', 'Gene', (32, 38))	('p.Ile462Val', 'Var', (58, 69))	('Kashmir esophageal cancer', 'Disease', (107, 132))	('CYP2E1', 'Gene', '1571', (74, 80))	('p.Ile462Val', 'Mutation', 'rs1048943', (58, 69))	('CYP1A1', 'Gene', '1543', (32, 38))	('CYP2E1', 'Gene', (74, 80))	('rs2031920', 'Mutation', 'rs2031920', (81, 90))	('Kashmir esophageal cancer', 'Disease', 'MESH:D004938', (107, 132))
301847	27588484	Somatic, attenuating TP53 mutations are found in many human cancers.	('TP53', 'Gene', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('attenuating', 'NegReg', (9, 20))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))	('TP53', 'Gene', '7157', (21, 25))
301848	27588484	However, tumors can also arise from mutations in genes regulating the TP53 pathway without TP53 mutation itself.	('TP53', 'Gene', (91, 95))	('arise from', 'Reg', (25, 35))	('TP53', 'Gene', '7157', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (36, 45))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('TP53', 'Gene', (70, 74))	('tumors', 'Disease', (9, 15))	('TP53', 'Gene', '7157', (91, 95))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
301851	27588484	The Pro variant of TP53 rs1042522 encoding p.Arg72Pro is less potent in inducing apoptosis than the Arg variant.	('Arg', 'Chemical', 'MESH:D001120', (100, 103))	('Arg', 'Chemical', 'MESH:D001120', (45, 48))	('rs1042522', 'Var', (24, 33))	('apoptosis', 'CPA', (81, 90))	('p.Arg72Pro', 'Var', (43, 53))	('TP53', 'Gene', '7157', (19, 23))	('rs1042522', 'Mutation', 'rs1042522', (24, 33))	('TP53', 'Gene', (19, 23))	('p.Arg72Pro', 'Mutation', 'rs1042522', (43, 53))
301852	27588484	However, the Pro allele confers higher apoptotic capacity during chemotherapy in the presence of some somatic tumor-associated TP53 mutations, suggesting that the success of chemotherapy in inducing TP53-mediated apoptosis is dependent on a given patient's combined somatic and germline TP53 modifications.	('higher', 'PosReg', (32, 38))	('TP53', 'Gene', (199, 203))	('apoptotic capacity', 'MPA', (39, 57))	('patient', 'Species', '9606', (247, 254))	('mutations', 'Var', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('TP53', 'Gene', '7157', (199, 203))	('TP53', 'Gene', '7157', (287, 291))	('inducing', 'Reg', (190, 198))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('TP53', 'Gene', (287, 291))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
301853	27588484	For MDM2 rs2279744, the minor allele G has higher affinity for transcription factor SP1 than the major allele T, increases MDM2 expression and attenuates TP53-mediated apoptosis.	('attenuates', 'NegReg', (143, 153))	('TP53', 'Gene', (154, 158))	('higher', 'PosReg', (43, 49))	('MDM2', 'Gene', '4193', (123, 127))	('MDM2', 'Gene', (123, 127))	('rs2279744', 'Mutation', 'rs2279744', (9, 18))	('affinity', 'Interaction', (50, 58))	('MDM2', 'Gene', '4193', (4, 8))	('MDM2', 'Gene', (4, 8))	('rs2279744', 'Var', (9, 18))	('expression', 'MPA', (128, 138))	('transcription', 'Protein', (63, 76))	('increases', 'PosReg', (113, 122))	('TP53', 'Gene', '7157', (154, 158))
301855	27588484	While MDM2 and TP53 function within the same pathway, synergistic interactions were found between the minor alleles of MDM2 rs2279744 and TP53 rs1042522 in increasing the risk of colorectal (OR'interaction = 1.52), gastric (ORinteraction = 1.51) and esophageal (OR'interaction = 1.19) cancers.	('colorectal', 'Disease', 'MESH:D015179', (179, 189))	('rs2279744', 'Var', (124, 133))	('MDM2', 'Gene', '4193', (6, 10))	('TP53', 'Gene', (138, 142))	('TP53', 'Gene', '7157', (15, 19))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('esophageal', 'Disease', (250, 260))	('cancers', 'Disease', (285, 292))	('rs2279744', 'Mutation', 'rs2279744', (124, 133))	('MDM2', 'Gene', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('colorectal', 'Disease', (179, 189))	('rs1042522', 'Var', (143, 152))	('TP53', 'Gene', '7157', (138, 142))	('MDM2', 'Gene', '4193', (119, 123))	('esophageal', 'Disease', 'MESH:D004941', (250, 260))	('TP53', 'Gene', (15, 19))	('MDM2', 'Gene', (6, 10))	('rs1042522', 'Mutation', 'rs1042522', (143, 152))	('cancers', 'Disease', 'MESH:D009369', (285, 292))
301864	27588484	Some TGF-beta signaling genes were associated with colorectal cancer risk, and specifically TGFBR1 rs6478972 and SMAD7 rs11874392 exhibited suppressive epistasis (ORinteraction = 0.71).	('rs11874392', 'Var', (119, 129))	('SMAD7', 'Gene', (113, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('rs6478972', 'Mutation', 'rs6478972', (99, 108))	('TGF-beta', 'Gene', '7040', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('rs6478972', 'Var', (99, 108))	('associated', 'Reg', (35, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('TGFBR1', 'Gene', '7046', (92, 98))	('rs11874392', 'Mutation', 'rs11874392', (119, 129))	('TGF-beta', 'Gene', (5, 13))	('TGFBR1', 'Gene', (92, 98))	('suppressive', 'NegReg', (140, 151))	('colorectal cancer', 'Disease', (51, 68))	('SMAD7', 'Gene', '4092', (113, 118))	('rectal cancer', 'Phenotype', 'HP:0100743', (55, 68))
301865	27588484	TGFBR1 rs6478972 is in linkage disequilibrium with rs334348, which is located in the 3' untranslated region and might affect microRNA binding and consequently TGFBR1 protein levels.	('TGFBR1', 'Gene', '7046', (159, 165))	('TGFBR1', 'Gene', (159, 165))	('protein levels', 'MPA', (166, 180))	('rs334348', 'Var', (51, 59))	('rs6478972', 'Mutation', 'rs6478972', (7, 16))	('affect', 'Reg', (118, 124))	('rs334348', 'Mutation', 'rs334348', (51, 59))	('rs6478972', 'Var', (7, 16))	('microRNA binding', 'MPA', (125, 141))	('TGFBR1', 'Gene', '7046', (0, 6))	('TGFBR1', 'Gene', (0, 6))
301870	27588484	Among the four CHEK2 polymorphisms associated with colon cancer risk, three variants (del5395, 1100delC and c.444+1G>A) produce truncated proteins, and one (I157T) is a missense mutant.	('colon cancer', 'Disease', (51, 63))	('1100delC', 'Mutation', 'rs555607708', (95, 103))	('associated', 'Reg', (35, 45))	('I157T', 'Mutation', 'rs17879961', (157, 162))	('c.444+1G>A', 'Mutation', 'rs121908698', (108, 118))	('CHEK2', 'Gene', '11200', (15, 20))	('c.444+1G>A', 'Var', (108, 118))	('del5395', 'Mutation', 'c.del5395', (86, 93))	('colon cancer', 'Phenotype', 'HP:0003003', (51, 63))	('1100delC', 'Var', (95, 103))	('CHEK2', 'Gene', (15, 20))	('del5395', 'Var', (86, 93))	('colon cancer', 'Disease', 'MESH:D015179', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
301871	27588484	These four CHEK2 variations synergistically interacted (crude ORinteraction = 1.16) with CDKN1B rs2066827 encoding p.Val109Gly in colon cancer risk.	('CDKN1B', 'Gene', (89, 95))	('rs2066827', 'Var', (96, 105))	('CHEK2', 'Gene', '11200', (11, 16))	('variations', 'Var', (17, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('CHEK2', 'Gene', (11, 16))	('interacted', 'Reg', (44, 54))	('p.Val109Gly', 'Mutation', 'rs2066827', (115, 126))	('CDKN1B', 'Gene', '1027', (89, 95))	('colon cancer', 'Disease', (130, 142))	('p.Val109Gly', 'Var', (115, 126))	('rs2066827', 'Mutation', 'rs2066827', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
301877	27588484	Additionally, RPS6KB1 rs180515 exhibited synergistic epistasis (crude ORinteraction = 1.19) with PRKAG2 rs1104897, but RPS6KB1 rs180519 showed suppressive epistasis (crude ORinteraction = 0.80) with PIK3CA rs7640662 in rectal cancer susceptibility.	('rs7640662', 'Mutation', 'rs7640662', (206, 215))	('PRKAG2', 'Gene', '51422', (97, 103))	('PIK3CA', 'Gene', '5290', (199, 205))	('RPS6KB1', 'Gene', '6198', (14, 21))	('RPS6KB1', 'Gene', (119, 126))	('rs1104897', 'Mutation', 'rs1104897', (104, 113))	('suppressive', 'NegReg', (143, 154))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('rs1104897', 'Var', (104, 113))	('PIK3CA', 'Gene', (199, 205))	('rs180515', 'Mutation', 'rs180515', (22, 30))	('synergistic epistasis', 'MPA', (41, 62))	('rectal cancer', 'Phenotype', 'HP:0100743', (219, 232))	('RPS6KB1', 'Gene', (14, 21))	('PRKAG2', 'Gene', (97, 103))	('cancer', 'Disease', (226, 232))	('RPS6KB1', 'Gene', '6198', (119, 126))	('rs180519', 'Mutation', 'rs180519', (127, 135))	('rs180519', 'Var', (127, 135))	('rs180515', 'Var', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
301886	27588484	An MMP2 promoter SNP, rs243865, affects gene expression by altering SP1 transcription factor binding.	('affects', 'Reg', (32, 39))	('gene expression', 'MPA', (40, 55))	('MMP2', 'Gene', (3, 7))	('altering', 'Reg', (59, 67))	('binding', 'Interaction', (93, 100))	('rs243865', 'Mutation', 'rs243865', (22, 30))	('MMP2', 'Gene', '4313', (3, 7))	('SP1', 'Protein', (68, 71))	('rs243865', 'Var', (22, 30))
301887	27588484	This functional SNP was not associated with gastric cancer susceptibility, but its minor allele suppressed the gastric cancer risk-enhancing effect of the minor allele in the above-mentioned PARP1 rs1136410 (crude ORinteraction = 0.60).	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('rs1136410', 'Mutation', 'rs1136410', (197, 206))	('PARP1', 'Gene', '142', (191, 196))	('gastric cancer', 'Disease', (44, 58))	('rs1136410', 'Var', (197, 206))	('suppressed', 'NegReg', (96, 106))	('PARP1', 'Gene', (191, 196))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('gastric cancer', 'Disease', (111, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
301893	27588484	Lastly, there was a weakly synergistic interaction (OR'interaction = 1.11) between intronic rs10879357 of TPH2 and intergenic rs1571218 at human chromosome 20p12.3 in colorectal cancer susceptibility.	('rs1571218', 'Var', (126, 135))	('rs10879357', 'Mutation', 'rs10879357', (92, 102))	('synergistic interaction', 'Reg', (27, 50))	('colorectal cancer', 'Disease', (167, 184))	('rs10879357', 'Var', (92, 102))	('rs1571218', 'Mutation', 'rs1571218', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('TPH2', 'Gene', (106, 110))	('rectal cancer', 'Phenotype', 'HP:0100743', (171, 184))	('colorectal cancer', 'Disease', 'MESH:D015179', (167, 184))	('human', 'Species', '9606', (139, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (167, 184))
301894	27588484	Because both rs1571218 and nearby rs961253 are associated with colorectal cancer risk, this locus cancer risk association appears to be replicated.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rectal cancer', 'Phenotype', 'HP:0100743', (67, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('rs1571218', 'Var', (13, 22))	('rs1571218', 'Mutation', 'rs1571218', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (74, 80))	('colorectal cancer', 'Disease', (63, 80))	('rs961253', 'Mutation', 'rs961253', (34, 42))	('cancer', 'Disease', (98, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('associated', 'Reg', (47, 57))	('rs961253', 'Var', (34, 42))
301896	27588484	Meanwhile, TPH2 participates in serotonin synthesis and lack of serotonin has been associated with tumor growth reductions in a mouse model of colon cancer allografts.	('tumor', 'Disease', (99, 104))	('serotonin', 'Chemical', 'MESH:D012701', (64, 73))	('colon cancer', 'Phenotype', 'HP:0003003', (143, 155))	('reductions', 'NegReg', (112, 122))	('serotonin', 'Chemical', 'MESH:D012701', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colon cancer', 'Disease', 'MESH:D015179', (143, 155))	('mouse', 'Species', '10090', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('colon cancer', 'Disease', (143, 155))	('lack', 'Var', (56, 60))	('TPH2', 'Gene', (11, 15))	('serotonin', 'MPA', (64, 73))	('serotonin synthesis', 'MPA', (32, 51))
301910	27588484	Epistasis in cancer susceptibilityis detected more frequently and with increasing statistical power.	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Epistasis', 'Var', (0, 9))
301914	27588484	Fourth, epigenetic dysregulation is an emerging cancer characteristic.	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', (48, 54))	('epigenetic dysregulation', 'Var', (8, 32))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))
301915	27588484	Comprehensive mapping of epigenetic landscapes and noncoding RNAs in cancer cells has revealed that they play essential roles in cell proliferation, apoptosis and metastasis.	('apoptosis', 'CPA', (149, 158))	('cell proliferation', 'CPA', (129, 147))	('metastasis', 'CPA', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('roles', 'Reg', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('epigenetic landscapes', 'Var', (25, 46))	('cancer', 'Disease', (69, 75))
301922	27588484	Thus, single-cell analyses can reveal whether cancer susceptibility genes are mutated in an individual tumor cell, whether any germline polymorphisms are associated with somatic mutations of cancer hallmark genes, and whether there is epistasis between germline polymorphisms and somatic mutations in promotion of tumor development and progression.	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('cancer', 'Disease', (46, 52))	('tumor', 'Disease', (103, 108))	('progression', 'CPA', (336, 347))	('tumor', 'Disease', (314, 319))	('promotion', 'PosReg', (301, 310))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mutations', 'Var', (178, 187))	('associated', 'Reg', (154, 164))
301925	27588484	Finally, several perspectives are provided here regarding interactions among germline polymorphisms, epigenetic variations and somatic mutations in cancer susceptibility.	('cancer', 'Disease', (148, 154))	('epigenetic variations', 'Var', (101, 122))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('germline polymorphisms', 'Var', (77, 99))	('interactions', 'Interaction', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
301937	24500448	Although alcohol could have a corrosive effect, polyphenols present in wine have anti-oxidant properties and may reduce DNA damage.	('alcohol', 'Chemical', 'MESH:D000438', (9, 16))	('corrosive', 'CPA', (30, 39))	('reduce', 'NegReg', (113, 119))	('anti-oxidant properties', 'MPA', (81, 104))	('DNA damage', 'MPA', (120, 130))	('polyphenols', 'Chemical', 'MESH:D059808', (48, 59))	('polyphenols', 'Var', (48, 59))
301965	24500448	Alcohol consumption was divided into the standard categories (units per week): none, >0 to <7, >=7 to <14, >=14 to <21, >=21 to <28 and >=28.	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('>=21 to <28', 'Var', (120, 131))	('to <7', 'Species', '1214577', (88, 93))	('>=14 to <21', 'Var', (107, 118))
301966	24500448	BMI (kg/m2) was classed into 18.5 to <23 (lower normal), 23 to <25 (upper normal), >=25 to <30 (overweight), >=30 to <35 (obese) and >=35 (morbidly obese).	('>=25 to <30', 'Var', (83, 94))	('obese', 'Disease', 'MESH:D009765', (122, 127))	('overweight', 'Phenotype', 'HP:0025502', (96, 106))	('>=30 to <35', 'Var', (109, 120))	('obese', 'Disease', (122, 127))	('obese', 'Disease', 'MESH:D009765', (148, 153))	('obese', 'Disease', (148, 153))
302101	24389438	When the same analysis was performed on patients on the basis of whether they had received neoadjuvant therapy, we found that patients who had received neoadjuvant therapy had a very high initial rate of recurrence, followed by a sharp drop in the second year and a further drop in the third year; the rates then remained stable until year 5, before dropping thereafter.	('patients', 'Species', '9606', (40, 48))	('recurrence', 'MPA', (204, 214))	('neoadjuvant', 'Var', (152, 163))	('patients', 'Species', '9606', (126, 134))
302116	22028813	Cross-Platform Array Screening Identifies COL1A2, THBS1, TNFRSF10D and UCHL1 as Genes Frequently Silenced by Methylation in Melanoma Epigenetic regulation of tumor suppressor genes (TSGs) has been shown to play a central role in melanomagenesis.	('UCHL1', 'Gene', '7345', (71, 76))	('THBS1', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('melanomagenesis', 'Disease', 'None', (229, 244))	('COL1A2', 'Gene', '1278', (42, 48))	('THBS1', 'Gene', '7057', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('Silenced', 'NegReg', (97, 105))	('Melanoma', 'Disease', 'MESH:D008545', (124, 132))	('Methylation', 'Var', (109, 120))	('TSG', 'Gene', '57045', (182, 185))	('COL1A2', 'Gene', (42, 48))	('TNFRSF10D', 'Gene', '8793', (57, 66))	('TSG', 'Gene', (182, 185))	('Melanoma', 'Disease', (124, 132))	('tumor', 'Disease', (158, 163))	('Melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('UCHL1', 'Gene', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('melanomagenesis', 'Disease', (229, 244))	('TNFRSF10D', 'Gene', (57, 66))
302122	22028813	Aberrant epigenetic modifications are a feature of several human diseases, including cancer.	('human', 'Species', '9606', (59, 64))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Aberrant epigenetic modifications', 'Var', (0, 33))
302123	22028813	While several forms of epigenetic modification are known to exist, so far DNA methylation is the only one shown to directly target DNA and to be frequently aberrant in many tumor types.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('methylation', 'Var', (78, 89))	('aberrant', 'Reg', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))
302127	22028813	Both hypermethylation of CpG islands located in the promoters of tumor suppressor genes (TSGs) and global hypomethylation seem to play an important role during cancer development.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('role', 'Reg', (148, 152))	('tumor', 'Disease', (65, 70))	('global', 'MPA', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cancer', 'Disease', (160, 166))	('play', 'Reg', (130, 134))	('TSG', 'Gene', (89, 92))	('hypermethylation', 'Var', (5, 21))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TSG', 'Gene', '57045', (89, 92))
302128	22028813	Often TSGs are not primarily inactivated through mutation or deletion, but rather through targeted CpG island methylation.	('TSG', 'Gene', '57045', (6, 9))	('deletion', 'Var', (61, 69))	('mutation', 'Var', (49, 57))	('methylation', 'Var', (110, 121))	('TSG', 'Gene', (6, 9))
302130	22028813	Additionally, aberrant promoter methylation may also occur and lead to inactivation of TSGs which play a role in progression to malignancy.	('TSG', 'Gene', (87, 90))	('malignancy', 'Disease', 'MESH:D009369', (128, 138))	('TSG', 'Gene', '57045', (87, 90))	('aberrant', 'Var', (14, 22))	('promoter methylation', 'MPA', (23, 43))	('lead to', 'Reg', (63, 70))	('malignancy', 'Disease', (128, 138))	('inactivation', 'NegReg', (71, 83))
302131	22028813	During melanomagenesis, well-known TSGs, such as PTEN, CDKN2A/p16INK4A and RASSF1A often have expression reduced through CpG island methylation.	('TSG', 'Gene', (35, 38))	('PTEN', 'Gene', '5728', (49, 53))	('CDKN2A', 'Gene', '1029', (55, 61))	('p16INK4A', 'Gene', '1029', (62, 70))	('RASSF1A', 'Gene', '11186', (75, 82))	('melanomagenesis', 'Disease', (7, 22))	('TSG', 'Gene', '57045', (35, 38))	('melanomagenesis', 'Disease', 'None', (7, 22))	('reduced', 'NegReg', (105, 112))	('RASSF1A', 'Gene', (75, 82))	('p16INK4A', 'Gene', (62, 70))	('CpG', 'Var', (121, 124))	('expression', 'MPA', (94, 104))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('CDKN2A', 'Gene', (55, 61))	('PTEN', 'Gene', (49, 53))
302144	22028813	These new data were then integrated with previous data-sets of global mRNA expression and expression post-demethylation treatment in order to focus on identifying additional candidate TSGs down-regulated through promoter methylation.	('TSG', 'Gene', '57045', (184, 187))	('down-regulated', 'NegReg', (189, 203))	('TSG', 'Gene', (184, 187))	('promoter methylation', 'Var', (212, 232))
302145	22028813	Genes were further filtered to identify those in which >=60% methylation correlated with a 4-fold decrease in mRNA levels in at least 2 samples, together with an average post-demethylation re-expression fold-change of >4 across the panel of 11 melanoma lines ( Figure 1 ).	('melanoma lines', 'Disease', 'MESH:D008545', (244, 258))	('mRNA levels', 'MPA', (110, 121))	('methylation', 'Var', (61, 72))	('melanoma lines', 'Disease', (244, 258))	('decrease', 'NegReg', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))
302156	22028813	We then defined the average % of methylation for each gene as the average value across the melanoma cell line panel which was then compared to melanocytes.	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('methylation', 'Var', (33, 44))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))
302178	22028813	Simultaneously, in the Epityper assay, we included 30 fresh-frozen melanoma tumor samples and found that 13%, 15% and 30% of them respectively were methylated for COL1A2, THBS1 and TNFRSF10D ( Table 1 ).	('TNFRSF10D', 'Gene', (181, 190))	('melanoma tumor', 'Disease', (67, 81))	('THBS1', 'Gene', '7057', (171, 176))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('COL1A2', 'Gene', (163, 169))	('COL1A2', 'Gene', '1278', (163, 169))	('melanoma tumor', 'Disease', 'MESH:D008545', (67, 81))	('TNFRSF10D', 'Gene', '8793', (181, 190))	('THBS1', 'Gene', (171, 176))	('methylated', 'Var', (148, 158))
302189	22028813	The objective of this study was to combine different array platforms to strengthen the identification of novel TSGs inactivated by promoter methylation in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('promoter methylation', 'Var', (131, 151))	('TSG', 'Gene', (111, 114))	('inactivated by', 'Reg', (116, 130))	('TSG', 'Gene', '57045', (111, 114))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanoma', 'Disease', (155, 163))
302191	22028813	Using these criteria we identified and subsequently confirmed four genes silenced by DNA methylation in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('melanoma', 'Disease', (104, 112))	('DNA methylation', 'Var', (85, 100))
302192	22028813	We found 24%, 31%, 66% and 42% of cell lines and 13%, 15%, 30% and 21% of tumors were methylated for COL1A2, THBS1, TNFRSF10D and UCHL1 respectively.	('THBS1', 'Gene', (109, 114))	('TNFRSF10D', 'Gene', (116, 125))	('UCHL1', 'Gene', '7345', (130, 135))	('THBS1', 'Gene', '7057', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('methylated', 'Var', (86, 96))	('COL1A2', 'Gene', (101, 107))	('UCHL1', 'Gene', (130, 135))	('TNFRSF10D', 'Gene', '8793', (116, 125))	('COL1A2', 'Gene', '1278', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
302194	22028813	identified COL1A2 as methylated in 35% (7/20) to 89% (16/20) of melanoma tumor samples respectively.	('COL1A2', 'Gene', (11, 17))	('COL1A2', 'Gene', '1278', (11, 17))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma tumor', 'Disease', (64, 78))	('methylated', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('melanoma tumor', 'Disease', 'MESH:D008545', (64, 78))
302197	22028813	showed TNFRSF10D promoter methylation in 85% of their melanoma cell lines (17/20) and 80% of their fresh melanoma tumor samples (32/40).	('methylation', 'Var', (26, 37))	('TNFRSF10D', 'Gene', (7, 16))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma tumor', 'Disease', (105, 119))	('melanoma', 'Disease', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('melanoma', 'Disease', (54, 62))	('melanoma tumor', 'Disease', 'MESH:D008545', (105, 119))	('TNFRSF10D', 'Gene', '8793', (7, 16))
302205	22028813	Evidence for COL1A2 aberrant promoter methylation has been described in different cancer cells such as breast cancer, medulloblastoma, hepatoma, colorectal cancer and more recently in melanoma.	('COL1A2', 'Gene', '1278', (13, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('hepatoma', 'Disease', (135, 143))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Disease', (82, 88))	('breast cancer', 'Disease', (103, 116))	('medulloblastoma', 'Disease', 'MESH:D008527', (118, 133))	('colorectal cancer', 'Disease', (145, 162))	('medulloblastoma', 'Phenotype', 'HP:0002885', (118, 133))	('medulloblastoma', 'Disease', (118, 133))	('COL1A2', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', (110, 116))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('hepatoma', 'Disease', 'MESH:D006528', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('cancer', 'Disease', (156, 162))	('aberrant', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
302208	22028813	Down-regulation of THBS1 by methylation has been described in several cancer types such as neuroblastoma, colorectal and stomach cancers.	('stomach cancers', 'Phenotype', 'HP:0012126', (121, 136))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('THBS1', 'Gene', '7057', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal and stomach cancers', 'Disease', 'MESH:D015179', (106, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancer', 'Disease', (129, 135))	('neuroblastoma', 'Disease', 'MESH:D009447', (91, 104))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('Down-regulation', 'NegReg', (0, 15))	('neuroblastoma', 'Disease', (91, 104))	('neuroblastoma', 'Phenotype', 'HP:0003006', (91, 104))	('THBS1', 'Gene', (19, 24))	('methylation', 'Var', (28, 39))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
302209	22028813	Promoter hypermethylation of THBS1 was detected in brain metastases of solid tumors such as, melanoma, lung, ovarian and breast carcinomas and more recently associated with bad prognosis in penile squamous cell carcinoma.	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('ovarian and breast carcinomas', 'Disease', 'MESH:D001943', (109, 138))	('penile squamous cell carcinoma', 'Disease', 'MESH:D004414', (190, 220))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('Promoter hypermethylation', 'Var', (0, 25))	('lung', 'Disease', (103, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('breast carcinomas', 'Phenotype', 'HP:0003002', (121, 138))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('associated', 'Reg', (157, 167))	('THBS1', 'Gene', (29, 34))	('metastases of solid tumors', 'Disease', 'MESH:D009362', (57, 83))	('metastases of solid tumors', 'Disease', (57, 83))	('THBS1', 'Gene', '7057', (29, 34))	('penile squamous cell carcinoma', 'Disease', (190, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('detected', 'Reg', (39, 47))
302214	22028813	The current study details UCHL1 (ubiquitin COOH-terminal esterase L1) inactivation by promoter methylation in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('UCHL1', 'Gene', '7345', (26, 31))	('inactivation', 'NegReg', (70, 82))	('UCHL1', 'Gene', (26, 31))	('promoter methylation', 'Var', (86, 106))
302215	22028813	Originally identified in neurons and in cells of the diffuse neuroendocrine system, mutations in this gene have been associated with Parkinson disease.	('associated', 'Reg', (117, 127))	('neuroendocrine system', 'Disease', 'MESH:D018358', (61, 82))	('mutations', 'Var', (84, 93))	('Parkinson disease', 'Disease', (133, 150))	('Parkinson disease', 'Disease', 'MESH:D010300', (133, 150))	('neuroendocrine system', 'Disease', (61, 82))
302218	22028813	UCHL1 methylation has been reported in multiple tumors, such as esophageal, gastric, renal, prostate, head and neck squamous, ovarian, hepatocellular and colorectal cancers.	('ovarian', 'Disease', (126, 133))	('reported', 'Reg', (27, 35))	('esophageal', 'Disease', (64, 74))	('gastric', 'Disease', (76, 83))	('multiple tumors', 'Disease', 'MESH:D009369', (39, 54))	('methylation', 'Var', (6, 17))	('esophageal', 'Disease', 'MESH:D004941', (64, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))	('colorectal cancers', 'Disease', (154, 172))	('prostate', 'Disease', (92, 100))	('hepatocellular', 'Disease', (135, 149))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('UCHL1', 'Gene', (0, 5))	('multiple tumors', 'Disease', (39, 54))	('renal', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('UCHL1', 'Gene', '7345', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('colorectal cancers', 'Disease', 'MESH:D015179', (154, 172))
302219	22028813	Some studies even suggested the use of UCHL1 methylation as a biomarker for diagnosis and prognosis of certain tumors.	('UCHL1', 'Gene', '7345', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('UCHL1', 'Gene', (39, 44))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('methylation', 'Var', (45, 56))
302224	22028813	Our study confirms that this is likely to occur via hypermethylation of the UCHL1 regulatory region.	('hypermethylation', 'Var', (52, 68))	('UCHL1', 'Gene', (76, 81))	('regulatory', 'Gene', '5507', (82, 92))	('regulatory', 'Gene', (82, 92))	('UCHL1', 'Gene', '7345', (76, 81))
302225	22028813	Interestingly, all four genes (COL1A2, THBS1, TNFRSF10D and UCHL1) we identify here as methylated in melanoma, encode components that fit within the p53 ontology pathway.	('COL1A2', 'Gene', (31, 37))	('p53', 'Gene', (149, 152))	('TNFRSF10D', 'Gene', '8793', (46, 55))	('THBS1', 'Gene', '7057', (39, 44))	('COL1A2', 'Gene', '1278', (31, 37))	('melanoma', 'Disease', (101, 109))	('UCHL1', 'Gene', '7345', (60, 65))	('p53', 'Gene', '7157', (149, 152))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('TNFRSF10D', 'Gene', (46, 55))	('methylated', 'Var', (87, 97))	('UCHL1', 'Gene', (60, 65))	('THBS1', 'Gene', (39, 44))	('encode', 'Reg', (111, 117))
302227	22028813	In melanoma, direct inhibition of p53 by mutation is relatively infrequent (see for review).	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('mutation', 'Var', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
302228	22028813	Our finding of six candidate TSGs linked to p53 function that are subject to methylation in melanoma might indicate alternative mechanisms by which these cells abrogate p53 downstream signalling in this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('methylation', 'Var', (77, 88))	('tumor', 'Disease', (203, 208))	('p53', 'Gene', (169, 172))	('abrogate', 'NegReg', (160, 168))	('p53', 'Gene', '7157', (169, 172))	('TSG', 'Gene', (29, 32))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('p53', 'Gene', (44, 47))	('melanoma', 'Disease', (92, 100))	('p53', 'Gene', '7157', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('TSG', 'Gene', '57045', (29, 32))	('subject', 'Reg', (66, 73))
302230	22028813	In summary, we have used a multiplatform integrative approach to identify a short list of robust methylated genes in melanoma.	('methylated', 'Var', (97, 107))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
302234	22028813	Taken together, this suggests that COL1A2 is a gene for which methylation is more generally associated with tumorigenesis across different cancer types.	('associated with', 'Reg', (92, 107))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('COL1A2', 'Gene', (35, 41))	('COL1A2', 'Gene', '1278', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('methylation', 'Var', (62, 73))	('tumor', 'Disease', (108, 113))	('cancer', 'Disease', (139, 145))
302251	22028813	annotated as "orf" (C10orf116, FLJ20551, FLJ20647), and the presence of false positives on the Infinium Methylation chips (i.e.	('FLJ20647', 'Var', (41, 49))	('C10orf116', 'Gene', '10974', (20, 29))	('C10orf116', 'Gene', (20, 29))	('FLJ20551', 'Var', (31, 39))
302265	33038843	Three-dimensional computed tomography image-oriented successful thoracoscopic subtotal esophagectomy for an esophageal cancer patient with an anomalous right superior pulmonary vein: A case report Case of esophageal cancer associated with an aberrant V2.	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('associated', 'Reg', (223, 233))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('esophageal cancer', 'Disease', (205, 222))	('esophageal cancer', 'Disease', (108, 125))	('patient', 'Species', '9606', (126, 133))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('aberrant', 'Var', (242, 250))	('esophageal cancer', 'Disease', 'MESH:D004938', (205, 222))	('cancer', 'Disease', (216, 222))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
302270	33038843	A 77-year-old man had esophageal cancer associated with an aberrant V2 passing behind the right intermediate bronchus.	('aberrant', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('esophageal cancer', 'Disease', (22, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))	('associated', 'Reg', (40, 50))
302297	33038843	Although left-sided aberrant pulmonary venous return is uncommon, some anomalies of the right pulmonary vein such as aberrant V2, V4, and V6 have been reported as highly frequent among surgical cases of lung cancer surgery.	('anomalies of the right pulmonary vein', 'Disease', 'MESH:D000071078', (71, 108))	('aberrant V2', 'Var', (117, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('lung cancer', 'Disease', (203, 214))	('anomalies of the right pulmonary vein', 'Disease', (71, 108))	('lung cancer', 'Disease', 'MESH:D008175', (203, 214))
302298	33038843	In such cases with aberrant V2, there could be pitfalls including massive bleeding during subcarinal lymphadenectomy because anomalous RSPV is likely to involve the subcarinal nodal packet.	('bleeding', 'Disease', 'MESH:D006470', (74, 82))	('aberrant', 'Var', (19, 27))	('bleeding', 'Disease', (74, 82))
302300	33038843	evaluated the frequency and anatomical configuration of anomalous V2 using 3D-CT images in 303 patients with chest disorders.	('patients', 'Species', '9606', (95, 103))	('chest disorders', 'Disease', 'MESH:D013898', (109, 124))	('chest disorders', 'Phenotype', 'HP:0410167', (109, 124))	('chest disorders', 'Disease', (109, 124))	('anomalous', 'Var', (56, 65))
302303	33038843	reported an aberrant V2 passing behind the right intermediate bronchus and draining into the left atrium, which was recognized during subcarinal lymphadenectomy in thoracoscopic esophagectomy for esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('esophageal cancer', 'Disease', (196, 213))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('aberrant', 'Var', (12, 20))
302304	33038843	reported an aberrant V2 identified during laparoscopic transhiatal lower esophagectomy for esophageal cancer.	('esophageal cancer', 'Disease', (91, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('aberrant', 'Var', (12, 20))
302305	33038843	described an aberrant V2 in a patient with lower esophageal cancer, which was depicted on preoperative 3D-CT scans to pass behind the right intermediate bronchus and drain into RSPV.	('patient', 'Species', '9606', (30, 37))	('esophageal cancer', 'Disease', (49, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('aberrant', 'Var', (13, 21))
302306	33038843	A precise depiction of aberrant V2 on preoperative reconstructed 3D-CT images enabled us to make up a strategic plan for safely performing esophagectomy with subcarinal lymphadenectomy in our patient.	('esophagectomy', 'Disease', (139, 152))	('patient', 'Species', '9606', (192, 199))	('aberrant', 'Var', (23, 31))
302310	33038843	Thus, prone VATS-E would be beneficial for esophageal cancer patients with an aberrant pulmonary vein under preoperative 3D-CT image guidance.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('aberrant', 'Var', (78, 86))	('aberrant pulmonary vein', 'Phenotype', 'HP:0011718', (78, 101))	('patients', 'Species', '9606', (61, 69))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
302311	33038843	In summary, an aberrant V2 was clearly depicted on preoperative contrast-enhanced 3D-CT in a patient with lower thoracic esophageal cancer, which aided in a safe VATS-E with three-field lymphadenectomy, including subcarinal lymph nodes.	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (112, 138))	('aided in', 'Reg', (146, 154))	('thoracic esophageal cancer', 'Disease', (112, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('patient', 'Species', '9606', (93, 100))	('aberrant', 'Var', (15, 23))	('lower', 'Disease', (106, 111))
302366	32366237	Macroscopic findings showed SCC within the submucosal invasion (350 mum) and no metastatic lymph nodes at any site.	('350', 'Var', (64, 67))	('SCC', 'Gene', (28, 31))	('SCC', 'Phenotype', 'HP:0002860', (28, 31))	('SCC', 'Gene', '6317', (28, 31))
302389	32201541	Downregulation of PSCA promotes gastric cancer proliferation and is related to poor prognosis Background: Dysregulation of prostate stem cell antigen (PSCA) has been implicated in human cancers.	('promotes', 'PosReg', (23, 31))	('gastric cancer', 'Disease', (32, 46))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('Downregulation', 'NegReg', (0, 14))	('cancers', 'Disease', (186, 193))	('prostate stem cell antigen', 'Gene', '8000', (123, 149))	('prostate stem cell antigen', 'Gene', (123, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('PSCA', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('PSCA', 'Gene', '8000', (18, 22))	('human', 'Species', '9606', (180, 185))	('PSCA', 'Gene', (151, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('PSCA', 'Gene', '8000', (151, 155))	('Dysregulation', 'Var', (106, 119))	('implicated', 'Reg', (166, 176))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))
302407	32201541	In vitro MTS cell proliferation experiment and clonal formation experiment and in vivo nude mouse subcutaneous tumorigenesis experiment all proved that knockdown of PSCA gene can improve the proliferation ability of GC cells, while in vitro experiment proved that overexpression of PSCA can reduce the proliferation ability of GC cells.It was found that knockdown of PSCA gene can improve the proliferation ability of GC cells both in vitro and in vivo, while overexpression of PSCA can reduce the proliferation ability of GC cells in vitro.	('PSCA', 'Gene', (367, 371))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('knockdown', 'Var', (354, 363))	('GC', 'Disease', 'MESH:D013274', (523, 525))	('GC', 'Disease', 'MESH:D013274', (327, 329))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('improve', 'PosReg', (381, 388))	('tumor', 'Disease', (111, 116))	('GC', 'Disease', 'MESH:D013274', (418, 420))	('proliferation ability', 'CPA', (393, 414))	('mouse', 'Species', '10090', (92, 97))	('GC', 'Disease', 'MESH:D013274', (216, 218))
302420	32201541	PSCA is on chromosome 8q24.3 with a polymorphism that induced different risks for different cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('polymorphism', 'Var', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
302423	32201541	Recently, a genome-wide Association Study (GWAS) in Japan found that PSCA gene loci rs2294008, rs2976392 and other variants were associated with the incidence of gastric adenocarcinoma.	('associated with', 'Reg', (129, 144))	('PSCA gene', 'Gene', (69, 78))	('rs2976392', 'Var', (95, 104))	('rs2294008', 'Var', (84, 93))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (162, 184))	('gastric adenocarcinoma', 'Disease', (162, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('rs2294008', 'Mutation', 'rs2294008', (84, 93))	('rs2976392', 'Mutation', 'rs2976392', (95, 104))
302477	32201541	As shown in Figure E_b, the tumour volumes were significantly higher in the MKN45-shPSCA group than in the MKN45 group at every specific measuring time.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('higher', 'PosReg', (62, 68))	('tumour', 'Disease', (28, 34))	('MKN45-shPSCA', 'Var', (76, 88))
302480	32201541	Again, the tumour weights in the MKN45-shPSCA group were significantly greater than those in the MKN45 group (Figure E_a, P=0.037).	('MKN45-shPSCA', 'Var', (33, 45))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('greater', 'PosReg', (71, 78))	('tumour', 'Disease', (11, 17))
302489	32201541	Our study indicated that PSCA suppressed cell proliferation in GC, and knockdown of PSCA gene promotes cell proliferation both in vitro and in vivo.	('GC', 'Disease', 'MESH:D013274', (63, 65))	('cell proliferation in', 'CPA', (41, 62))	('suppressed', 'NegReg', (30, 40))	('cell proliferation', 'CPA', (103, 121))	('knockdown', 'Var', (71, 80))	('promotes', 'PosReg', (94, 102))	('PSCA', 'Gene', (84, 88))
302500	31632839	Pembrolizumab has demonstrated more than 50% response rate in microsatellite instability-high tumors, 15% response rate in tumors expressing programmed death ligand 1, and non-inferior outcome in first-line treatment compared to chemotherapy.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('microsatellite', 'Var', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
302505	31632839	compared gene expression patterns among 248 GC from Singaporean patients and identified 3 major subtypes: proliferative (characterized by high genomic instability, TP53 mutations and DNA hypomethylation), metabolic [more sensitive to 5-fluorouracil (5-FU) than other subtypes], and mesenchymal [with features of cancer stem cells; cell lines of this subtype particularly sensitive to inhibitors of phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway].	('TP53', 'Gene', '7157', (164, 168))	('TP53', 'Gene', (164, 168))	('5-FU', 'Chemical', 'MESH:D005472', (250, 254))	('mammalian target of rapamycin', 'Gene', '2475', (428, 457))	('mutations', 'Var', (169, 178))	('mammalian target of rapamycin', 'Gene', (428, 457))	('patients', 'Species', '9606', (64, 72))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (398, 418))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Disease', (312, 318))	('GC', 'Phenotype', 'HP:0012126', (44, 46))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (234, 248))	('mTOR', 'Gene', (464, 468))	('mTOR', 'Gene', '2475', (464, 468))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
302506	31632839	Using primary GC tumor tissue from 295 predominantly Caucasian patients not treated with prior chemotherapy or radiotherapy, the TCGA study showed about 9% with Epstein-Barr virus (EBV) infection associated with frequent phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, programmed death ligand 1/2 (PD-L1/PD-L2) overexpression and the best prognosis; 21% with microsatellite instability (MSI) associated with increased tumor mutation burden; 50% with chromosomal instability (CIN) associated with frequent amplifications of amplifications of vascular endothelial growth factor A (VEGFA) and receptor tyrosine kinase (RTK) genes such as human epidermal growth factor receptor 2 (HER2) as well as mutation of TP53; 20% genomically stable (GS) associated with frequent mutations in motility and adhesion genes as well as the worst prognosis.	('human', 'Species', '9606', (677, 682))	('receptor tyrosine kinase', 'Gene', '5979', (632, 656))	('PD-L2', 'Gene', (346, 351))	('CIN', 'Phenotype', 'HP:0040012', (517, 520))	('EBV', 'Species', '10376', (181, 184))	('epidermal growth factor receptor 2', 'Gene', '2064', (683, 717))	('receptor tyrosine kinase', 'Gene', (632, 656))	('VEGFA', 'Gene', '7422', (621, 626))	('CIN', 'Disease', 'MESH:D007674', (517, 520))	('PD-L1', 'Gene', (340, 345))	('chromosomal instability', 'Phenotype', 'HP:0040012', (492, 515))	('patients', 'Species', '9606', (63, 71))	('GS', 'Disease', 'MESH:D011125', (778, 780))	('Epstein-Barr virus', 'Disease', (161, 179))	('TP53', 'Gene', (748, 752))	('PD-L1', 'Gene', '29126', (340, 345))	('tumor', 'Disease', (460, 465))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:C106336', (221, 258))	('PIK3CA', 'Gene', '5290', (293, 299))	('tumor', 'Disease', (17, 22))	('epidermal growth factor receptor 2', 'Gene', (683, 717))	('Epstein-Barr virus', 'Disease', 'MESH:D020031', (161, 179))	('GC', 'Phenotype', 'HP:0012126', (14, 16))	('RTK', 'Gene', (658, 661))	('tumor', 'Disease', 'MESH:D009369', (460, 465))	('vascular endothelial growth factor', 'Gene', '7422', (583, 617))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('adhesion genes', 'Gene', (833, 847))	('motility', 'Gene', (820, 828))	('RTK', 'Gene', '5979', (658, 661))	('mutations', 'Var', (807, 816))	('CIN', 'Disease', (517, 520))	('associated', 'Reg', (782, 792))	('vascular endothelial growth factor', 'Gene', (583, 617))	('TP53', 'Gene', '7157', (748, 752))	('PD-L2', 'Gene', '80380', (346, 351))	('infection', 'Disease', (186, 195))	('PIK3CA', 'Gene', (293, 299))	('tumor', 'Phenotype', 'HP:0002664', (460, 465))	('infection', 'Disease', 'MESH:D007239', (186, 195))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('VEGFA', 'Gene', (621, 626))
302512	31632839	The information from these analyses has indicated several actionable genetic alterations such as HER2 amplification (~ 15%, more commonly seen in GEJ and CIN), mesenchymal-epithelial transition (MET) amplification (~ 20%), fibroblast growth factor receptor 2 (FGFR2) amplification/mutation (~ 5-10%), PD-L1 amplification (more commonly seen in EBV infection), MSI-high (~ 15%), etc.	('HER2', 'Gene', (97, 101))	('CIN', 'Disease', (154, 157))	('EBV', 'Species', '10376', (344, 347))	('PD-L1', 'Gene', (301, 306))	('amplification/mutation', 'Var', (267, 289))	('CIN', 'Disease', 'MESH:D007674', (154, 157))	('FGFR2', 'Gene', '2263', (260, 265))	('amplification', 'Var', (102, 115))	('CIN', 'Phenotype', 'HP:0040012', (154, 157))	('FGFR2', 'Gene', (260, 265))	('PD-L1', 'Gene', '29126', (301, 306))	('infection', 'Disease', (348, 357))	('infection', 'Disease', 'MESH:D007239', (348, 357))	('MSI-high', 'Disease', (360, 368))	('GEJ', 'Disease', (146, 149))	('amplification', 'Var', (307, 320))
302526	31632839	used panel testing including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplification, and found these genomic alterations were more commonly seen in resistant patients than responders; patients with tumors bearing no candidate genomic alterations had a significantly longer OS (16.1 versus 7.6 months; HR 0.38; 95% confidence interval [CI] 0.09-0.75; p = 0.015).	('PTEN', 'Gene', '5728', (48, 52))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('KRAS', 'Gene', '3845', (76, 80))	('EGFR', 'Gene', (67, 71))	('KRAS', 'Gene', (76, 80))	('EGFR', 'Gene', '1956', (29, 33))	('patients', 'Species', '9606', (195, 203))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('mutations', 'Var', (53, 62))	('EGFR', 'Gene', '1956', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('longer', 'PosReg', (277, 283))	('PTEN', 'Gene', (48, 52))	('tumors', 'Disease', (209, 215))	('KRAS', 'Gene', '3845', (38, 42))	('patients', 'Species', '9606', (169, 177))	('alterations', 'Var', (245, 256))	('EGFR', 'Gene', (29, 33))	('KRAS', 'Gene', (38, 42))
302528	31632839	Hepatocyte growth factor (HGF) was noted to be significantly lower in responders compared with that in non-responders (p = 0.014).	('lower', 'NegReg', (61, 66))	('HGF', 'Gene', '3082', (26, 29))	('HGF', 'Gene', (26, 29))	('responders', 'Var', (70, 80))
302547	31632839	Biomarker study on pre-treatment HER2 amplification in plasma circulating tumor DNA by next-generation sequencing and PD-L1 expression on archival tumor tissue by IHC (22C3 pharmDx) showed that both HER2 amplification and PD-L1 positivity predicted RR (24% versus 0% [p = 0.0655] and 36% versus 5% [p = 0.0367], respectively).	('HER2', 'Protein', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('PD-L1', 'Gene', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('PD-L1', 'Gene', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PD-L1', 'Gene', '29126', (118, 123))	('PD-L1', 'Gene', '29126', (222, 227))	('tumor', 'Disease', (74, 79))	('positivity', 'Var', (228, 238))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
302548	31632839	The RR was 57% and disease control rate (DCR; the proportion of patients with a best overall response of complete response [CR], partial response [PR], or stable disease [SD]) was 86% in patients whose tumors showed both HER2 amplification and PD-L1 expression.	('patients', 'Species', '9606', (187, 195))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('patients', 'Species', '9606', (64, 72))	('HER2', 'Protein', (221, 225))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('DCR', 'Gene', '1637', (41, 44))	('amplification', 'Var', (226, 239))	('DCR', 'Gene', (41, 44))	('PD-L1', 'Gene', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('PD-L1', 'Gene', '29126', (244, 249))
302559	31632839	In preclinical studies, DS-8201a demonstrated efficacy against T-DM1-resistant HER2-expressing as well as low HER2-expressing cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('DS-8201a', 'Var', (24, 32))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('DM1', 'Gene', (65, 68))	('HER2-expressing', 'Protein', (79, 94))	('DM1', 'Gene', '1760', (65, 68))
302560	31632839	In a phase I study, DS-8201a demonstrated promising antitumor activity in heavily pretreated patients with HER2 expressing GC with RR of about 40% and acceptable toxicities.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('GC', 'Phenotype', 'HP:0012126', (123, 125))	('toxicities', 'Disease', (162, 172))	('DS-8201a', 'Var', (20, 28))	('HER2 expressing', 'Protein', (107, 122))	('tumor', 'Disease', (56, 61))	('toxicities', 'Disease', 'MESH:D064420', (162, 172))	('patients', 'Species', '9606', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
302564	31632839	Preclinical studies have shown ZW25 enhances HER2 signal blockade and anti-tumor activity in HER2 expressing xenograft mouse models including GC.	('mouse', 'Species', '10090', (119, 124))	('enhances', 'PosReg', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('GC', 'Phenotype', 'HP:0012126', (142, 144))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('HER2', 'Protein', (45, 49))	('ZW25', 'Var', (31, 35))
302568	31632839	In preclinical studies, SBT6050 selectively activated innate and adaptive anti-tumor responses by monocytes and macrophages while sparing systemic immune toxicities.	('tumor', 'Disease', (79, 84))	('toxicities', 'Disease', 'MESH:D064420', (154, 164))	('SBT6050', 'Var', (24, 31))	('activated', 'PosReg', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('toxicities', 'Disease', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
302581	31632839	Afatinib is an irreversible pan-HER TKI that has been approved worldwide as a first-line treatment for advanced non-small cell lung cancer that harbors activating EGFR mutations.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (112, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('Afatinib', 'Chemical', 'MESH:C522924', (0, 8))	('EGFR', 'Gene', '1956', (163, 167))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (116, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('non-small cell lung cancer', 'Disease', (112, 138))	('EGFR', 'Gene', (163, 167))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (112, 138))	('activating', 'PosReg', (152, 162))	('mutations', 'Var', (168, 177))
302584	31632839	Afatinib is currently being evaluated in several phase II studies in combination with chemotherapy in advanced GC at 1st and 2nd lines (NCT01743365, NCT02501603 and NCT01522768).	('Afatinib', 'Chemical', 'MESH:C522924', (0, 8))	('NCT01743365', 'Var', (136, 147))	('NCT02501603', 'Var', (149, 160))	('GC', 'Phenotype', 'HP:0012126', (111, 113))	('NCT01522768', 'Var', (165, 176))
302591	31632839	reported the biological activity of varlitinib in HER-expressing advanced GC in a phase IIA study at 2014 European Society for Medical Oncology annual congress; they found suppressed signaling events of HER pathway in tumor samples after treatment with varlitinib.	('GC', 'Phenotype', 'HP:0012126', (74, 76))	('HER pathway', 'Pathway', (203, 214))	('varlitinib', 'Chemical', 'None', (253, 263))	('varlitinib', 'Chemical', 'None', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('suppressed', 'NegReg', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('varlitinib', 'Var', (253, 263))	('tumor', 'Disease', (218, 223))	('signaling events', 'MPA', (183, 199))	('Oncology', 'Phenotype', 'HP:0002664', (135, 143))
302596	31632839	Somatic mutations in HER2 may result in constitutive HER2 activation; however this study showed no response from neratinib in 5 GC patients with HER2 mutation.	('patients', 'Species', '9606', (131, 139))	('HER2', 'Gene', (145, 149))	('result', 'Reg', (30, 36))	('mutation', 'Var', (150, 158))	('neratinib', 'Chemical', 'MESH:C487932', (113, 122))	('GC', 'Phenotype', 'HP:0012126', (128, 130))	('HER2', 'Protein', (53, 57))	('HER2', 'Gene', (21, 25))	('activation', 'PosReg', (58, 68))
302597	31632839	Preclinical studies have shown that overexpression of VEGF could induce angiogenesis, and that inhibition of VEGF or VEGF receptor-2 (VEGFR-2) suppresses tumor growth.	('VEGF', 'Gene', (117, 121))	('VEGFR-2', 'Gene', (134, 141))	('tumor', 'Disease', (154, 159))	('overexpression', 'PosReg', (36, 50))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('induce', 'PosReg', (65, 71))	('angiogenesis', 'CPA', (72, 84))	('inhibition', 'Var', (95, 105))	('suppresses', 'NegReg', (143, 153))	('VEGFR-2', 'Gene', '3791', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('VEGF', 'Gene', '7422', (109, 113))	('VEGF', 'Gene', '7422', (54, 58))	('VEGF', 'Gene', '7422', (134, 138))	('VEGF', 'Gene', (54, 58))	('VEGF', 'Gene', '7422', (117, 121))	('VEGF', 'Gene', (109, 113))	('VEGF', 'Gene', (134, 138))	('VEGF receptor-2', 'Gene', (117, 132))	('VEGF receptor-2', 'Gene', '3791', (117, 132))
302632	31632839	Treating Apatinib with several enzymes, such as CYP2C9, CYP2D6, CYP2E2A, and UGT2B7, resulted in the production of four metabolites, with cis-3-hydroxy-apatinib-O-glucoronide (M9-2) identified as the major metabolite.	('production', 'MPA', (101, 111))	('Apatinib', 'Chemical', 'MESH:C553458', (9, 17))	('CYP2C9', 'Gene', '1559', (48, 54))	('UGT2B7', 'Gene', '7364', (77, 83))	('metabolites', 'MPA', (120, 131))	('resulted in', 'Reg', (85, 96))	('CYP2D6', 'Gene', '1565', (56, 62))	('CYP2D6', 'Gene', (56, 62))	('CYP2C9', 'Gene', (48, 54))	('cis-3-hydroxy-apatinib-O-glucoronide', 'Chemical', 'MESH:C553458', (138, 174))	('CYP2E2A', 'Var', (64, 71))	('UGT2B7', 'Gene', (77, 83))
302715	31632839	Pembrolizumab has been shown to overcome clinical resistance to trastuzumab in patients with advanced breast cancer overexpressing HER2 and PD-L1 positive advanced breast cancer.	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('HER2', 'Protein', (131, 135))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('overexpressing', 'Var', (116, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('breast cancer', 'Disease', (164, 177))	('PD-L1', 'Gene', (140, 145))	('patients', 'Species', '9606', (79, 87))	('PD-L1', 'Gene', '29126', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
302739	31632839	The primary anticancer mechanism of TAS-102 is distinct from 5-FU in that through incorporation into DNA, trifluridine induces DNA dysfunction such as DNA strand breaks.	('induces', 'Reg', (119, 126))	('DNA dysfunction', 'Disease', (127, 142))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('DNA strand breaks', 'Disease', (151, 168))	('S-1', 'Gene', '5707', (38, 41))	('cancer', 'Disease', (16, 22))	('trifluridine', 'Chemical', 'MESH:D014271', (106, 118))	('trifluridine', 'Var', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('incorporation', 'Var', (82, 95))	('S-1', 'Gene', (38, 41))
302759	31632839	Dysregulation of the FGFR signaling is associated with the development and progression of multiple malignancies.	('Dysregulation', 'Var', (0, 13))	('multiple malignancies', 'Disease', (90, 111))	('associated', 'Reg', (39, 49))	('FGFR signaling', 'Gene', (21, 35))	('multiple malignancies', 'Disease', 'MESH:C536827', (90, 111))
302760	31632839	Based on the TCGA dataset, the prevalence of FGFR genomic alterations in GC is 5-10%, and FGFR2b overexpression and FGFR2 gene amplification is associated with a poor prognosis in advanced GC.	('overexpression', 'PosReg', (97, 111))	('FGFR2', 'Gene', (90, 95))	('FGFR', 'Gene', (45, 49))	('FGFR2', 'Gene', '2263', (90, 95))	('FGFR2', 'Gene', '2263', (116, 121))	('GC', 'Phenotype', 'HP:0012126', (189, 191))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('FGFR2', 'Gene', (116, 121))	('gene amplification', 'Var', (122, 140))	('alterations', 'Var', (58, 69))
302761	31632839	AZD4547 is a TKI targeting FGFR1/2/3, but also inhibits colony stimulating factor 1 receptor, and vascular endothelial growth factor receptor 2.	('FGFR1/2/3', 'Gene', '2260;2263;2261', (27, 36))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('vascular endothelial growth factor receptor 2', 'Gene', '3791', (98, 143))	('vascular endothelial growth factor receptor 2', 'Gene', (98, 143))	('colony stimulating factor 1 receptor', 'Gene', '1436', (56, 92))	('colony stimulating factor 1 receptor', 'Gene', (56, 92))	('AZD4547', 'Var', (0, 7))	('FGFR1/2/3', 'Gene', (27, 36))	('inhibits', 'NegReg', (47, 55))
302762	31632839	AZD4547 exerted anti-cancer effect in FGFR amplified GC xenograft models.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR', 'Gene', (38, 42))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('GC', 'Phenotype', 'HP:0012126', (53, 55))	('AZD4547', 'Var', (0, 7))
302765	31632839	SHINE, a randomized phase II trial, compared AZD4547 versus paclitaxel in 71 advanced GC patients with FGFR2 amplification as second-line therapy (NCT01457846).	('AZD4547', 'Var', (45, 52))	('FGFR2', 'Gene', (103, 108))	('FGFR2', 'Gene', '2263', (103, 108))	('AZD4547', 'Chemical', 'MESH:C572463', (45, 52))	('GC', 'Phenotype', 'HP:0012126', (86, 88))	('amplification', 'Var', (109, 122))	('patients', 'Species', '9606', (89, 97))	('paclitaxel', 'Chemical', 'MESH:D017239', (60, 70))
302766	31632839	PFS was 1.8 months in AZD4547 versus 3.5 months in paclitaxel arm, and exploratory biomarker analyses revealed significant intratumor heterogeneity of FGFR2 amplification and poor concordance between amplification and FGFR2 mRNA expression.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('paclitaxel', 'Chemical', 'MESH:D017239', (51, 61))	('FGFR2', 'Gene', (151, 156))	('FGFR2', 'Gene', '2263', (151, 156))	('amplification', 'MPA', (157, 170))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('AZD4547', 'Var', (22, 29))	('FGFR2', 'Gene', (218, 223))	('FGFR2', 'Gene', '2263', (218, 223))	('tumor', 'Disease', (128, 133))	('AZD4547', 'Chemical', 'MESH:C572463', (22, 29))
302767	31632839	Therefore a suboptimal biomarker selection strategy might have explained why AZD4547 did not significantly improve PFS versus paclitaxel in this cohort of patients with advanced GC.	('GC', 'Phenotype', 'HP:0012126', (178, 180))	('AZD4547', 'Var', (77, 84))	('AZD4547', 'Chemical', 'MESH:C572463', (77, 84))	('patients', 'Species', '9606', (155, 163))	('PFS', 'MPA', (115, 118))	('paclitaxel', 'Chemical', 'MESH:D017239', (126, 136))
302772	31632839	Preclinical evaluation showed IMAB362 mediated antibody-dependent cellular cytotoxicity as well as complement-dependent cytotoxicity against GC cell lines expressing CLDN18.2; improved antitumor activity was noted in xenografted mice treated with IMAB362 plus chemotherapy compared with mice treated with chemotherapy alone.	('tumor', 'Disease', (189, 194))	('cytotoxicity', 'Disease', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cytotoxicity', 'Disease', (120, 132))	('improved', 'PosReg', (176, 184))	('GC', 'Phenotype', 'HP:0012126', (141, 143))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('CLDN18.2', 'Gene', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mice', 'Species', '10090', (229, 233))	('cytotoxicity', 'Disease', 'MESH:D064420', (120, 132))	('IMAB362', 'Var', (247, 254))	('complement-dependent cytotoxicity', 'Disease', 'MESH:D019966', (99, 132))	('mice', 'Species', '10090', (287, 291))	('complement-dependent cytotoxicity', 'Disease', (99, 132))
302773	31632839	Combination of IMAB362 with chemotherapy using epirubicin, oxaliplatin, and capecitabine showed significantly improved PFS and OS versus chemotherapy alone in FAST study, a randomized phase II first-line study in 161 patients with advanced HER2-negative GC expressing CLDN18.2 (>= 2+ staining intensity with the anti-CLDN18 43-14A monoclonal antibody in >= 40% tumor cells) (NCT01630083).	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('PFS', 'MPA', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('improved', 'PosReg', (110, 118))	('GC', 'Phenotype', 'HP:0012126', (254, 256))	('tumor', 'Disease', (361, 366))	('epirubicin', 'Chemical', 'MESH:D015251', (47, 57))	('IMAB362', 'Var', (15, 22))	('oxaliplatin', 'Chemical', 'MESH:C030110', (59, 70))	('patients', 'Species', '9606', (217, 225))	('Co', 'Chemical', 'MESH:C065987', (0, 2))	('capecitabine', 'Chemical', 'MESH:C110904', (76, 88))
302782	31632839	Retrospective biomarker study in REAL3 showed mutations either in KRAS (5.7%) or PIK3CA (2.5%) were negative prognostic factors.	('PIK3CA', 'Gene', (81, 87))	('mutations', 'Var', (46, 55))	('Ret', 'Gene', (0, 3))	('PIK3CA', 'Gene', '5290', (81, 87))	('Ret', 'Gene', '5979', (0, 3))	('KRAS', 'Gene', '3845', (66, 70))	('KRAS', 'Gene', (66, 70))
302787	31632839	Subgroup analysis of this study showed improved PFS and OS in patients with high EGFR-expression tumors who received nimotuzumab plus irinotecan.	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('PFS', 'CPA', (48, 51))	('irinotecan', 'Chemical', 'MESH:C051890', (134, 144))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('high', 'Var', (76, 80))	('improved', 'PosReg', (39, 47))	('patients', 'Species', '9606', (62, 70))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
302792	31632839	A preclinical study has shown inhibition of Hedgehog signaling leads to reversal of chemotherapy resistance in CD44 expressing GC cells.	('GC', 'Phenotype', 'HP:0012126', (127, 129))	('CD44', 'Gene', (111, 115))	('inhibition', 'Var', (30, 40))	('Hedgehog', 'Protein', (44, 52))	('CD44', 'Gene', '960', (111, 115))	('chemotherapy resistance', 'CPA', (84, 107))
302804	31632839	Cancer cells with BRCA1/2 mutation or ataxia telangiectasia mutated (ATM) deficiency cannot repair double-strand DNA breaks and are thus sensitive to PARP inhibition leading to synthetic lethality.	('telangiectasia', 'Phenotype', 'HP:0001009', (45, 59))	('deficiency', 'Var', (74, 84))	('BRCA1', 'Gene', '672', (18, 23))	('ATM', 'Gene', '472', (69, 72))	('mutation', 'Var', (26, 34))	('PARP', 'Gene', (150, 154))	('ataxia', 'Phenotype', 'HP:0001251', (38, 44))	('BRCA1', 'Gene', (18, 23))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('not', 'NegReg', (88, 91))	('ataxia telangiectasia mutated', 'Gene', (38, 67))	('PARP', 'Gene', '142', (150, 154))	('ATM', 'Gene', (69, 72))	('ataxia telangiectasia mutated', 'Gene', '472', (38, 67))	('repair double-strand DNA breaks', 'MPA', (92, 123))
302823	31632839	HGF receptor is encoded by the MET oncogene, and plays an important role in carcinogenesis by activating signaling pathways through RAS, PI3K, and STAT3.	('signaling pathways', 'Pathway', (105, 123))	('HGF receptor', 'Gene', (0, 12))	('HGF receptor', 'Gene', '4233', (0, 12))	('RAS', 'Protein', (132, 135))	('activating', 'PosReg', (94, 104))	('STAT3', 'Gene', '6774', (147, 152))	('STAT3', 'Gene', (147, 152))	('PI3K', 'Var', (137, 141))
302826	31632839	The mechanism of action is designed to selectively bind and neutralize HGF to block its interaction with the MET receptor, ultimately impeding the HGF/MET signaling pathway.	('neutralize', 'Var', (60, 70))	('HGF', 'Gene', '3082', (71, 74))	('HGF', 'Gene', (147, 150))	('HGF', 'Gene', (71, 74))	('HGF', 'Gene', '3082', (147, 150))	('block', 'NegReg', (78, 83))	('interaction', 'Interaction', (88, 99))	('impeding', 'NegReg', (134, 142))	('bind', 'Interaction', (51, 55))	('MET receptor', 'Protein', (109, 121))
302833	31632839	The correlation between MEK signature, KRAS alteration and treatment response to selumetinib has been demonstrated in GC cell lines.	('alteration', 'Var', (44, 54))	('MEK', 'Gene', (24, 27))	('MEK', 'Gene', '5609', (24, 27))	('selumetinib', 'Chemical', 'MESH:C517975', (81, 92))	('GC', 'Phenotype', 'HP:0012126', (118, 120))	('KRAS', 'Gene', (39, 43))	('KRAS', 'Gene', '3845', (39, 43))
302834	31632839	A phase II study of selumetinib plus docetaxel was conducted in South Korea as second-line chemotherapy in advanced GC using molecular screening to identify patients with KRAS mutant, KRAS amplified or wild-type KRAS with MEK signature (ClinicalTrials.gov Identifier: NCT02448290).	('MEK', 'Gene', (222, 225))	('KRAS', 'Gene', '3845', (212, 216))	('MEK', 'Gene', '5609', (222, 225))	('KRAS', 'Gene', (184, 188))	('mutant', 'Var', (176, 182))	('KRAS', 'Gene', '3845', (184, 188))	('patients', 'Species', '9606', (157, 165))	('KRAS', 'Gene', (212, 216))	('KRAS', 'Gene', (171, 175))	('GC', 'Phenotype', 'HP:0012126', (116, 118))	('KRAS', 'Gene', '3845', (171, 175))	('selumetinib', 'Chemical', 'MESH:C517975', (20, 31))	('docetaxel', 'Chemical', 'MESH:C067311', (37, 46))
302838	31632839	The pre-planned biomarker analysis showed that one patient with typical KRAS mutation (at codon 12) and one patient with KRAS amplification plus high MEK signature achieved PR.	('MEK', 'Gene', '5609', (150, 153))	('KRAS', 'Gene', (121, 125))	('KRAS', 'Gene', (72, 76))	('KRAS', 'Gene', '3845', (121, 125))	('mutation', 'Var', (77, 85))	('KRAS', 'Gene', '3845', (72, 76))	('patient', 'Species', '9606', (51, 58))	('patient', 'Species', '9606', (108, 115))	('MEK', 'Gene', (150, 153))
302839	31632839	Three patients with atypical KRAS mutation and low/intermediate MEK signature showed progressive disease.	('MEK', 'Gene', (64, 67))	('MEK', 'Gene', '5609', (64, 67))	('KRAS', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))	('low/intermediate', 'Var', (47, 63))	('patients', 'Species', '9606', (6, 14))	('KRAS', 'Gene', '3845', (29, 33))	('progressive disease', 'Disease', 'MESH:D018450', (85, 104))	('progressive disease', 'Disease', (85, 104))
302868	30602372	We show that PRAME promotes migration and invasion of TNBC cells through changes in expression of E-cadherin, N-cadherin, vimentin and ZEB1, core markers of an epithelial-to-mesenchymal transition.	('migration', 'CPA', (28, 37))	('promotes', 'PosReg', (19, 27))	('ZEB1', 'Gene', (135, 139))	('changes', 'Reg', (73, 80))	('ZEB1', 'Gene', '6935', (135, 139))	('E-cadherin', 'Protein', (98, 108))	('N-cadherin', 'Gene', (110, 120))	('invasion', 'CPA', (42, 50))	('expression', 'MPA', (84, 94))	('vimentin', 'Protein', (122, 130))	('PRAME', 'Var', (13, 18))	('N-cadherin', 'Gene', '1000', (110, 120))
302890	30602372	Aberrant expression of PRAME has been associated with poor prognosis and increased risk of metastasis in many solid tumors, whereas it has been found to predict a more favorable outcome in acute myeloid and lymphoblastic leukemia.	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('Aberrant expression', 'Var', (0, 19))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (207, 229))	('solid tumors', 'Disease', (110, 122))	('metastasis', 'CPA', (91, 101))	('myeloid and lymphoblastic leukemia', 'Phenotype', 'HP:0005531', (195, 229))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('leukemia', 'Phenotype', 'HP:0001909', (221, 229))	('PRAME', 'Gene', (23, 28))	('acute myeloid and lymphoblastic leukemia', 'Disease', 'MESH:D015470', (189, 229))
302892	30602372	Experimental evidence in melanoma demonstrates that PRAME is a dominant repressor of the retinoic acid signaling pathway, thereby inhibiting retinoic acid-induced differentiation, cell cycle arrest and apoptosis.	('inhibiting', 'NegReg', (130, 140))	('PRAME', 'Var', (52, 57))	('arrest', 'Disease', 'MESH:D006323', (191, 197))	('retinoic acid', 'Chemical', 'MESH:D014212', (89, 102))	('retinoic acid-induced differentiation', 'MPA', (141, 178))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('apoptosis', 'CPA', (202, 211))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('arrest', 'Disease', (191, 197))	('melanoma', 'Disease', (25, 33))	('retinoic acid', 'Chemical', 'MESH:D014212', (141, 154))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (180, 197))
302893	30602372	Additional reports in a wide range of cancers suggest that PRAME induces cell proliferation, inhibits apoptosis and reduces cytotoxic drug sensitivity.	('reduces', 'NegReg', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('apoptosis', 'CPA', (102, 111))	('induces', 'PosReg', (65, 72))	('inhibits', 'NegReg', (93, 101))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('cytotoxic drug sensitivity', 'MPA', (124, 150))	('drug sensitivity', 'Phenotype', 'HP:0020174', (134, 150))	('cell proliferation', 'CPA', (73, 91))	('PRAME', 'Var', (59, 64))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))
302895	30602372	This is the first in vitro study to investigate the role of PRAME in metastasis of triple negative breast cancer by manipulating its expression using 2 different approaches, either by silencing or overexpressing PRAME.	('expression', 'MPA', (133, 143))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('overexpressing', 'Var', (197, 211))	('breast cancer', 'Disease', (99, 112))	('manipulating', 'Reg', (116, 128))	('silencing', 'Var', (184, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
302896	30602372	We found that PRAME significantly increases both the migratory and invasive potential of triple negative breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('migratory', 'CPA', (53, 62))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('invasive potential', 'CPA', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('PRAME', 'Var', (14, 19))	('increases', 'PosReg', (34, 43))
302897	30602372	In addition, PRAME induced the expression of the key EMT-driver ZEB1 and of several EMT-associated genes that are involved in transcriptional regulation and inhibition of apoptosis such as SOX10, FOXC2, JAG1, TCF4, TWIST1, WNT11, SNAI1 and PDGFRB, while reducing the expression of BMP7 and TSPAN13.	('JAG1', 'Gene', '182', (203, 207))	('TWIST1', 'Gene', (215, 221))	('ZEB1', 'Gene', '6935', (64, 68))	('SNAI1', 'Gene', (230, 235))	('inhibition', 'NegReg', (157, 167))	('FOXC2', 'Gene', (196, 201))	('JAG1', 'Gene', (203, 207))	('expression', 'MPA', (31, 41))	('TSPAN13', 'Gene', '27075', (290, 297))	('BMP7', 'Gene', '655', (281, 285))	('SOX10', 'Gene', '6663', (189, 194))	('PRAME', 'Var', (13, 18))	('expression', 'MPA', (267, 277))	('BMP7', 'Gene', (281, 285))	('TCF4', 'Gene', '6925', (209, 213))	('PDGFRB', 'Gene', '5159', (240, 246))	('PDGFRB', 'Gene', (240, 246))	('ZEB1', 'Gene', (64, 68))	('TSPAN13', 'Gene', (290, 297))	('WNT11', 'Gene', (223, 228))	('SOX10', 'Gene', (189, 194))	('WNT11', 'Gene', '7481', (223, 228))	('TCF4', 'Gene', (209, 213))
302908	30602372	Specific 5'FAM-3'MGB Taqman gene expression primer/probe sets were purchased from Applied Biosystems to determine the mRNA expression of PRAME (Hs01022301_m1), TWIST1 (Hs01675818_s1), ZEB1 (Hs00232783_m1), MMP2 (Hs01548727_m1) & MMP9 (Hs00957562_m1).	('Hs00232783_m1', 'Var', (190, 203))	('ZEB1', 'Gene', (184, 188))	('ZEB1', 'Gene', '6935', (184, 188))	('Hs01548727_m1', 'Var', (212, 225))	('MMP2', 'Gene', (206, 210))	('MMP9', 'Gene', (229, 233))	('Hs01022301_m1', 'Var', (144, 157))	('Hs01675818_s1', 'Var', (168, 181))	('MMP2', 'Gene', '4313', (206, 210))	('MMP9', 'Gene', '4318', (229, 233))
302934	30602372	Using both techniques, we found that silencing of PRAME reduced tumor cell migration by an average of 40% (Fig.	('tumor', 'Disease', (64, 69))	('reduced', 'NegReg', (56, 63))	('silencing', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('PRAME', 'Gene', (50, 55))
302939	30602372	Silencing of PRAME in BT549 cells induced cadherin switching, as demonstrated by a decrease in N-cadherin expression in the absence of significant changes in E-cadherin expression.	('PRAME', 'Gene', (13, 18))	('N-cadherin', 'Gene', '1000', (95, 105))	('cadherin switching', 'MPA', (42, 60))	('BT549', 'CellLine', 'CVCL:1092', (22, 27))	('decrease', 'NegReg', (83, 91))	('induced', 'Reg', (34, 41))	('Silencing', 'Var', (0, 9))	('N-cadherin', 'Gene', (95, 105))
302943	30602372	Using a threshold of log2FC >= 1.5 or log2FC <= - 1.5, overexpression of PRAME induced the expression of 11 EMT-related genes (SNAI1, TCF4, TWIST1, FOXC2, IL1RN, MMP2, SOX10, WNT11, MMP3, PDGFRB, JAG1), while reducing the expression of 2 EMT-related genes (BMP7 and TSPAN13) (Fig.	('expression', 'MPA', (91, 101))	('reducing', 'NegReg', (209, 217))	('MMP2', 'Gene', (162, 166))	('IL1RN', 'Gene', (155, 160))	('PDGFRB', 'Gene', '5159', (188, 194))	('MMP3', 'Gene', '4314', (182, 186))	('PDGFRB', 'Gene', (188, 194))	('TCF4', 'Gene', '6925', (134, 138))	('JAG1', 'Gene', (196, 200))	('induced', 'PosReg', (79, 86))	('SOX10', 'Gene', '6663', (168, 173))	('IL1RN', 'Gene', '3557', (155, 160))	('FOXC2', 'Gene', (148, 153))	('BMP7', 'Gene', '655', (257, 261))	('MMP2', 'Gene', '4313', (162, 166))	('expression', 'MPA', (222, 232))	('TCF4', 'Gene', (134, 138))	('BMP7', 'Gene', (257, 261))	('log2FC <= -', 'Var', (38, 49))	('TWIST1', 'Gene', (140, 146))	('TSPAN13', 'Gene', '27075', (266, 273))	('SNAI1', 'Gene', (127, 132))	('SOX10', 'Gene', (168, 173))	('JAG1', 'Gene', '182', (196, 200))	('WNT11', 'Gene', (175, 180))	('TSPAN13', 'Gene', (266, 273))	('MMP3', 'Gene', (182, 186))	('WNT11', 'Gene', '7481', (175, 180))
302945	30602372	GO-disease inference revealed frequent aberration of the PRAME-differentially expressed genes in ovarian and esophageal cancer, suggesting that PRAME and its effectors may also play a role in these solid cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('ovarian and esophageal cancer', 'Disease', 'MESH:D010051', (97, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('aberration', 'Var', (39, 49))
302950	30602372	We found that PRAME overexpression increased protein expression of ZEB1 whereas silencing of PRAME reduced the protein expression of both ZEB1 and TWIST1 (Fig.	('ZEB1', 'Gene', '6935', (138, 142))	('increased', 'PosReg', (35, 44))	('silencing', 'Var', (80, 89))	('TWIST1', 'Gene', (147, 153))	('protein expression', 'MPA', (111, 129))	('ZEB1', 'Gene', '6935', (67, 71))	('protein expression', 'MPA', (45, 63))	('ZEB1', 'Gene', (67, 71))	('reduced', 'NegReg', (99, 106))	('ZEB1', 'Gene', (138, 142))
302953	30602372	Further, PRAME has been shown to increase cell proliferation and inhibit apoptosis in various cancer models.	('PRAME', 'Var', (9, 14))	('cell proliferation', 'CPA', (42, 60))	('increase', 'PosReg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('apoptosis', 'CPA', (73, 82))	('inhibit', 'NegReg', (65, 72))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
302955	30602372	In the present study, we provide experimental evidence that PRAME exerts its tumor-promoting function in part by increasing the cancer cell's motility, hence possibly enhancing its metastatic abilities.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('increasing', 'PosReg', (113, 123))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('enhancing', 'PosReg', (167, 176))	('metastatic abilities', 'CPA', (181, 201))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('PRAME', 'Var', (60, 65))	('tumor', 'Disease', (77, 82))	('cancer', 'Disease', (128, 134))
302957	30602372	Using several approaches, we show here that PRAME expression increases the cell motility of triple negative breast cancer cells.	('cell motility', 'CPA', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('PRAME expression', 'Var', (44, 60))	('increases', 'PosReg', (61, 70))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))
302958	30602372	Silencing of PRAME on the other hand reduced vimentin expression and induced a cadherin switch with a reduction in N-cadherin expression.	('cadherin switch', 'MPA', (79, 94))	('PRAME', 'Gene', (13, 18))	('vimentin', 'Protein', (45, 53))	('reduction', 'NegReg', (102, 111))	('N-cadherin', 'Gene', (115, 125))	('N-cadherin', 'Gene', '1000', (115, 125))	('reduced', 'NegReg', (37, 44))	('Silencing', 'Var', (0, 9))	('induced', 'Reg', (69, 76))
302966	30602372	We were able to demonstrate that PRAME manipulation alters the RNA expression of all 3 regulators, and in addition strongly affects the protein expression of ZEB1.	('RNA expression', 'MPA', (63, 77))	('manipulation', 'Var', (39, 51))	('alters', 'Reg', (52, 58))	('ZEB1', 'Gene', (158, 162))	('ZEB1', 'Gene', '6935', (158, 162))	('affects', 'Reg', (124, 131))	('protein expression', 'MPA', (136, 154))
302985	30602372	Ectopic expression of TSPAN13 in breast cancer cells has been reported to inhibit anchorage independent growth, increase apoptosis and reduce invasion.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('anchorage independent growth', 'CPA', (82, 110))	('breast cancer', 'Disease', (33, 46))	('TSPAN13', 'Gene', '27075', (22, 29))	('Ectopic expression', 'Var', (0, 18))	('inhibit', 'NegReg', (74, 81))	('TSPAN13', 'Gene', (22, 29))	('increase', 'PosReg', (112, 120))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('apoptosis', 'CPA', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('invasion', 'CPA', (142, 150))	('reduce', 'NegReg', (135, 141))
302987	30602372	We demonstrate that PRAME facilitates the transition to a mesenchymal phenotype through reprogramming of several EMT-genes, resulting in enhanced migration and invasion of triple negative breast cancer cells.	('enhanced', 'PosReg', (137, 145))	('migration', 'CPA', (146, 155))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('invasion', 'CPA', (160, 168))	('breast cancer', 'Disease', (188, 201))	('EMT-genes', 'Gene', (113, 122))	('PRAME', 'Var', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
302997	29237490	Silencing of linc-ROR significantly inhibited cell proliferation, motility, chemoresistance, and self-renewal capacity.	('inhibited', 'NegReg', (36, 45))	('linc-ROR', 'Gene', (13, 21))	('linc-ROR', 'Gene', '100885779', (13, 21))	('self-renewal capacity', 'CPA', (97, 118))	('motility', 'CPA', (66, 74))	('Silencing', 'Var', (0, 9))	('cell proliferation', 'CPA', (46, 64))	('chemoresistance', 'CPA', (76, 91))
303000	29237490	Moreover, linc-ROR disruption was sufficient to attenuate tumor growth and cancer stem cell marker expression in vivo.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('disruption', 'Var', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('attenuate', 'NegReg', (48, 57))	('cancer', 'Disease', (75, 81))	('linc-ROR', 'Gene', '100885779', (10, 18))	('linc-ROR', 'Gene', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
303013	29237490	Dysregulation of SOX9 has been further implicated in cancer progression as an oncogene, which promotes cell proliferation, inhibits senescence, and facilitates transformation.	('SOX9', 'Gene', (17, 21))	('cancer', 'Disease', (53, 59))	('implicated', 'Reg', (39, 49))	('Dysregulation', 'Var', (0, 13))	('senescence', 'CPA', (132, 142))	('SOX9', 'Gene', '6662', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cell proliferation', 'CPA', (103, 121))	('facilitates', 'PosReg', (148, 159))	('transformation', 'CPA', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('inhibits', 'NegReg', (123, 131))	('promotes', 'PosReg', (94, 102))
303014	29237490	In addition, high level of SOX9 expression was reported to confer the properties associated with cancer stem cell (CSC) and correlate with epithelial-mesenchymal transition (EMT) through triggering signaling cascades including the WNT/beta-catenin pathway.	('SOX9', 'Gene', (27, 31))	('cancer', 'Disease', (97, 103))	('epithelial-mesenchymal', 'Disease', (139, 161))	('expression', 'Var', (32, 42))	('SOX9', 'Gene', '6662', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('beta-catenin', 'Gene', (235, 247))	('triggering', 'Reg', (187, 197))	('beta-catenin', 'Gene', '1499', (235, 247))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
303020	29237490	ESCC cell lines Eca109, EC9706, KYSE150, and TE-1 and embryonic kidney cell line 293 T were purchased from the Cell Bank of Type Culture Collection of Chinese Academy of Sciences (Shanghai Institute of Biochemistry and Cell Biology).	('embryonic kidney', 'Disease', 'MESH:D007674', (54, 70))	('293 T', 'CellLine', 'CVCL:0063', (81, 86))	('EC9706', 'CellLine', 'CVCL:E307', (24, 30))	('KYSE150', 'Var', (32, 39))	('embryonic kidney', 'Disease', (54, 70))	('EC9706', 'Var', (24, 30))
303035	29237490	After blocking with 5% skimmed milk, the membrane was incubated with primary antibodies against SOX9 (AB5535, 1:2000; Millipore), E-cadherin (sc-8426, 1:100; Santa Cruz), vimentin (sc-6260, 1:100; Santa Cruz), beta-actin (sc-7963, 1:100; Santa Cruz), and appropriate secondary antibodies.	('sc-8426', 'Var', (142, 149))	('SOX9', 'Gene', (96, 100))	('E-cadherin', 'Gene', (130, 140))	('E-cadherin', 'Gene', '999', (130, 140))	('SOX9', 'Gene', '6662', (96, 100))	('vimentin', 'Gene', '7431', (171, 179))	('beta-actin', 'Gene', '728378', (210, 220))	('beta-actin', 'Gene', (210, 220))	('vimentin', 'Gene', (171, 179))	('sc-6260', 'Var', (181, 188))
303048	29237490	Accordingly, we found that knockdown of endogenous linc-ROR by siRNA resulted in a significant reduction of SOX9 expression in EC9706 cells (Fig.	('expression', 'MPA', (113, 123))	('knockdown', 'Var', (27, 36))	('SOX9', 'Gene', (108, 112))	('EC9706', 'CellLine', 'CVCL:E307', (127, 133))	('linc-ROR', 'Gene', (51, 59))	('SOX9', 'Gene', '6662', (108, 112))	('reduction', 'NegReg', (95, 104))	('linc-ROR', 'Gene', '100885779', (51, 59))
303059	29237490	We found that linc-ROR repression resulted in the sensitization of EC9706 cells to cisplatin, which is one of the most frequently used chemotherapeutic drug for esophageal cancer (Fig.	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('sensitization', 'MPA', (50, 63))	('repression', 'Var', (23, 33))	('linc-ROR', 'Gene', '100885779', (14, 22))	('linc-ROR', 'Gene', (14, 22))	('esophageal cancer', 'Disease', (161, 178))	('EC9706', 'CellLine', 'CVCL:E307', (67, 73))
303061	29237490	Furthermore, the combination of linc-ROR knockdown and cisplatin treatment synergistically reduced the number and the size of tumorspheres compared to that of cisplatin treatment alone.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('linc-ROR', 'Gene', '100885779', (32, 40))	('reduced', 'NegReg', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('knockdown', 'Var', (41, 50))	('linc-ROR', 'Gene', (32, 40))
303062	29237490	The expression of stemness-associated genes, including CD44, KLF4, NANOG, OCT4, and SOX2 was also markedly decreased by linc-ROR knockdown in concert with the reduced sphere-forming ability (Fig.	('KLF4', 'Gene', '9314', (61, 65))	('NANOG', 'Gene', (67, 72))	('KLF4', 'Gene', (61, 65))	('knockdown', 'Var', (129, 138))	('expression', 'MPA', (4, 14))	('SOX2', 'Gene', '6657', (84, 88))	('decreased', 'NegReg', (107, 116))	('linc-ROR', 'Gene', (120, 128))	('stemness-associated genes', 'Gene', (18, 43))	('SOX2', 'Gene', (84, 88))	('sphere-forming ability', 'CPA', (167, 189))	('OCT4', 'Gene', (74, 78))	('linc-ROR', 'Gene', '100885779', (120, 128))	('OCT4', 'Gene', '5460', (74, 78))	('CD44', 'Gene', '960', (55, 59))	('CD44', 'Gene', (55, 59))	('NANOG', 'Gene', '79923', (67, 72))
303081	29237490	The protein levels of SOX9 were also significantly decreased after knockdown of linc-ROR or overexpression of miR-145 (Fig.	('linc-ROR', 'Gene', (80, 88))	('SOX9', 'Gene', (22, 26))	('protein levels', 'MPA', (4, 18))	('miR-145', 'Gene', '406937', (110, 117))	('overexpression', 'PosReg', (92, 106))	('SOX9', 'Gene', '6662', (22, 26))	('knockdown', 'Var', (67, 76))	('decreased', 'NegReg', (51, 60))	('miR-145', 'Gene', (110, 117))	('linc-ROR', 'Gene', '100885779', (80, 88))
303085	29237490	Similarly, treatment with miRNA inhibitor cocktail promoted colony formation and partially abolished the inhibitory effect of linc-ROR knockdown (Fig.	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('knockdown', 'Var', (135, 144))	('inhibitory effect', 'MPA', (105, 122))	('linc-ROR', 'Gene', '100885779', (126, 134))	('colony formation', 'CPA', (60, 76))	('linc-ROR', 'Gene', (126, 134))	('promoted', 'PosReg', (51, 59))	('abolished', 'NegReg', (91, 100))
303088	29237490	Moreover, the increased chemosensitivity to cisplatin through knockdown of linc-ROR in EC9706 cells was abrogated upon inhibition of these candidate miRNAs (Fig.	('increased', 'PosReg', (14, 23))	('abrogated', 'NegReg', (104, 113))	('linc-ROR', 'Gene', (75, 83))	('linc-ROR', 'Gene', '100885779', (75, 83))	('inhibition', 'NegReg', (119, 129))	('miR', 'Gene', '220972', (149, 152))	('miR', 'Gene', (149, 152))	('EC9706', 'CellLine', 'CVCL:E307', (87, 93))	('chemosensitivity to cisplatin', 'MPA', (24, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('knockdown', 'Var', (62, 71))
303091	29237490	Combining silinc-ROR and miR-145 mimics synergistically inhibited colony formation and cell mobility in EC9706 cells compared to those of silinc-ROR or miR-145 mimics alone.	('miR-145', 'Gene', (152, 159))	('miR-145', 'Gene', '406937', (152, 159))	('linc-ROR', 'Gene', '100885779', (140, 148))	('linc-ROR', 'Gene', (140, 148))	('cell mobility', 'CPA', (87, 100))	('EC9706', 'CellLine', 'CVCL:E307', (104, 110))	('linc-ROR', 'Gene', '100885779', (12, 20))	('miR-145', 'Gene', (25, 32))	('inhibited', 'NegReg', (56, 65))	('miR-145', 'Gene', '406937', (25, 32))	('mimics', 'Var', (33, 39))	('colony formation', 'CPA', (66, 82))	('linc-ROR', 'Gene', (12, 20))
303093	29237490	To determine whether linc-ROR/miRNA axis-modulated proliferation, migration and invasion capacities, and chemoresistance were mediated by the target gene SOX9, we knocked down SOX9 expression using siRNA and investigated its effect on these phenotypes.	('knocked', 'Var', (163, 170))	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('SOX9', 'Gene', (154, 158))	('migration', 'CPA', (66, 75))	('SOX9', 'Gene', '6662', (154, 158))	('linc-ROR', 'Gene', (21, 29))	('linc-ROR', 'Gene', '100885779', (21, 29))	('SOX9', 'Gene', (176, 180))	('SOX9', 'Gene', '6662', (176, 180))
303095	29237490	Similarly, silencing of SOX9 markedly reduced the enhancing effects of miRNA inhibitors on colony formation (Fig.	('miR', 'Gene', (71, 74))	('silencing', 'Var', (11, 20))	('SOX9', 'Gene', (24, 28))	('reduced', 'NegReg', (38, 45))	('colony formation', 'CPA', (91, 107))	('SOX9', 'Gene', '6662', (24, 28))	('miR', 'Gene', '220972', (71, 74))
303098	29237490	Mice bearing EC9706-derived xenografts were intratumorally injected with cholesterol-conjugated linc-ROR siRNA every 3 days for six times and sacrificed 3 days later (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('EC9706', 'CellLine', 'CVCL:E307', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('linc-ROR', 'Gene', '100885779', (96, 104))	('EC9706-derived', 'Var', (13, 27))	('linc-ROR', 'Gene', (96, 104))	('cholesterol', 'Chemical', 'MESH:D002784', (73, 84))	('Mice', 'Species', '10090', (0, 4))
303101	29237490	These observations indicate that inhibition of linc-ROR expression decreases SOX9 activity in ESCC and as a result attenuates tumor growth.	('inhibition', 'Var', (33, 43))	('SOX9', 'Gene', '6662', (77, 81))	('linc-ROR', 'Gene', (47, 55))	('linc-ROR', 'Gene', '100885779', (47, 55))	('attenuates', 'NegReg', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('activity', 'MPA', (82, 90))	('decreases', 'NegReg', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('SOX9', 'Gene', (77, 81))	('tumor', 'Disease', (126, 131))
303102	29237490	Recent studies have demonstrated that linc-ROR dysregulation may be involved in carcinogenesis as well as cancer progression in several solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('solid tumors', 'Disease', (136, 148))	('involved', 'Reg', (68, 76))	('dysregulation', 'Var', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('linc-ROR', 'Gene', (38, 46))	('cancer', 'Disease', (106, 112))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('linc-ROR', 'Gene', '100885779', (38, 46))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('carcinogenesis', 'Disease', (80, 94))
303104	29237490	Accordingly, knockdown of linc-ROR suppressed the expression of SOX9.	('SOX9', 'Gene', '6662', (64, 68))	('linc-ROR', 'Gene', (26, 34))	('linc-ROR', 'Gene', '100885779', (26, 34))	('suppressed', 'NegReg', (35, 45))	('SOX9', 'Gene', (64, 68))	('knockdown', 'Var', (13, 22))	('expression', 'MPA', (50, 60))
303105	29237490	Loss-of-function approaches showed that linc-ROR depletion suppressed cell proliferation, cell motility, and chemoresistance in vitro and attenuated tumor growth in vivo, in line with recent evidences in other solid tumors such as breast and pancreatic cancer.	('Loss-of-function', 'NegReg', (0, 16))	('linc-ROR', 'Gene', '100885779', (40, 48))	('linc-ROR', 'Gene', (40, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (242, 259))	('breast and pancreatic cancer', 'Disease', 'MESH:D010190', (231, 259))	('attenuated tumor', 'Disease', (138, 154))	('chemoresistance', 'CPA', (109, 124))	('attenuated tumor', 'Disease', 'MESH:C538265', (138, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cell proliferation', 'CPA', (70, 88))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('solid tumors', 'Disease', (210, 222))	('suppressed', 'NegReg', (59, 69))	('cell motility', 'CPA', (90, 103))	('solid tumors', 'Disease', 'MESH:D009369', (210, 222))	('depletion', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
303106	29237490	Notably, we found that linc-ROR and SOX9 were overexpressed in tumorspheres compared with adherent cells, and linc-ROR disruption was sufficient to repress CSC marker expression in vitro and in vivo, as well as sphere-forming capacity, indicating they might coordinately regulate stemness in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('linc-ROR', 'Gene', (23, 31))	('expression', 'MPA', (167, 177))	('linc-ROR', 'Gene', '100885779', (23, 31))	('CSC', 'MPA', (156, 159))	('regulate', 'Reg', (271, 279))	('disruption', 'Var', (119, 129))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('SOX9', 'Gene', (36, 40))	('repress', 'NegReg', (148, 155))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('ESCC', 'Disease', (292, 296))	('linc-ROR', 'Gene', (110, 118))	('linc-ROR', 'Gene', '100885779', (110, 118))	('SOX9', 'Gene', '6662', (36, 40))	('sphere-forming capacity', 'CPA', (211, 234))
303108	29237490	The long noncoding RNA-miRNA-mRNA regulatory network has been widely affirmed recently, in which long noncoding RNA functions as a ceRNA to interfere with miRNA and reduces their regulatory effect on target mRNA.	('miR', 'Gene', '220972', (23, 26))	('long noncoding RNA', 'Var', (97, 115))	('reduces', 'NegReg', (165, 172))	('miR', 'Gene', (23, 26))	('regulatory effect on target mRNA', 'MPA', (179, 211))	('interfere', 'NegReg', (140, 149))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', (155, 158))
303112	29237490	Treatment with an inhibitor cocktail of all candidate miRNAs rescued linc-ROR knockdown-caused suppression of cell proliferation, cell motility, and chemoresistance.	('chemoresistance', 'CPA', (149, 164))	('cell motility', 'CPA', (130, 143))	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (54, 57))	('knockdown-caused', 'Var', (78, 94))	('linc-ROR', 'Gene', (69, 77))	('suppression', 'NegReg', (95, 106))	('cell proliferation', 'CPA', (110, 128))	('linc-ROR', 'Gene', '100885779', (69, 77))
303116	29237490	Therefore, aberrant expression of linc-ROR may serve as a novel mechanism underlying SOX9 deregulation, and the linc-ROR-miRNA-SOX9 regulatory network provides a novel vision to understand the oncogenic and tumor suppressor network puzzle.	('SOX9', 'Gene', (85, 89))	('expression', 'MPA', (20, 30))	('deregulation', 'MPA', (90, 102))	('linc-ROR', 'Gene', '100885779', (112, 120))	('tumor', 'Disease', (207, 212))	('linc-ROR', 'Gene', (112, 120))	('SOX9', 'Gene', '6662', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('linc-ROR', 'Gene', '100885779', (34, 42))	('SOX9', 'Gene', '6662', (85, 89))	('aberrant', 'Var', (11, 19))	('linc-ROR', 'Gene', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('SOX9', 'Gene', (127, 131))
303123	29142225	We find that mutated CSMD3 is associated with better prognosis in Asian patients.	('CSMD3', 'Gene', '114788', (21, 26))	('mutated', 'Var', (13, 20))	('patients', 'Species', '9606', (72, 80))	('CSMD3', 'Gene', (21, 26))
303126	29142225	Here, analysis of Chinese and TCGA ESCC patients reveals that Asian patients exhibit higher TP53, EP300 and NFE2L2 mutational frequencies, and mutated CSMD3 associates with better prognosis.	('EP300', 'Gene', (98, 103))	('CSMD3', 'Gene', (151, 156))	('CSMD3', 'Gene', '114788', (151, 156))	('higher', 'PosReg', (85, 91))	('patients', 'Species', '9606', (40, 48))	('mutational', 'MPA', (115, 125))	('TP53', 'Gene', (92, 96))	('patients', 'Species', '9606', (68, 76))	('TP53', 'Gene', '7157', (92, 96))	('better', 'PosReg', (173, 179))	('mutated', 'Var', (143, 150))	('NFE2L2', 'Gene', (108, 114))	('EP300', 'Gene', '2033', (98, 103))
303140	29142225	We therefore compared germline variations of two important alcohol metabolizing enzymes, ALDH2 (rs671) and ADH1B (rs1229984) in the three populations and found very similar patterns between Chinese and Vietnamese patients (Supplementary Fig.	('rs671', 'Var', (96, 101))	('ALDH2', 'Gene', (89, 94))	('ADH1B', 'Gene', '125', (107, 112))	('rs1229984', 'Mutation', 'rs1229984', (114, 123))	('rs1229984', 'Var', (114, 123))	('alcohol', 'Chemical', 'MESH:D000438', (59, 66))	('rs671', 'Mutation', 'rs671', (96, 101))	('patients', 'Species', '9606', (213, 221))	('ADH1B', 'Gene', (107, 112))	('ALDH2', 'Gene', '217', (89, 94))
303144	29142225	First, for TCGA patients, compared to the latest refined TCGA mutation data, 96.4% of our non-silent mutation (missense mutation, nonsense mutation and non-stop mutation) calls on the same patients were reported.	('TCGA', 'Disease', (11, 15))	('patients', 'Species', '9606', (189, 197))	('patients', 'Species', '9606', (16, 24))	('nonsense mutation', 'Var', (130, 147))
303150	29142225	We therefore examined the correlation of CSMD3 mutation status with patient survival times, which is orthogonal to the mutation rate analysis.	('examined', 'Reg', (13, 21))	('patient', 'Species', '9606', (68, 75))	('CSMD3', 'Gene', '114788', (41, 46))	('CSMD3', 'Gene', (41, 46))	('mutation', 'Var', (47, 55))
303151	29142225	We found that among Chinese patients with WES data (n = 78), patients with mutated CSMD3 showed significantly better survival time than those with the wild-type allele (Fig.	('CSMD3', 'Gene', (83, 88))	('CSMD3', 'Gene', '114788', (83, 88))	('patients', 'Species', '9606', (61, 69))	('mutated', 'Var', (75, 82))	('better', 'PosReg', (110, 116))	('survival time', 'CPA', (117, 130))	('patients', 'Species', '9606', (28, 36))
303155	29142225	These results suggest that the mutational status of CSMD3 is a prognostic marker for Asian populations.	('CSMD3', 'Gene', '114788', (52, 57))	('mutational status', 'Var', (31, 48))	('CSMD3', 'Gene', (52, 57))
303163	29142225	Specifically, TP53, NFE2L2, and EP300 showed a significantly higher mutation rate in Asian populations; while KRTAP9-1, LRFN5, and MAP2 showed the opposite patterns (Fig.	('TP53', 'Gene', '7157', (14, 18))	('NFE2L2', 'Var', (20, 26))	('TP53', 'Gene', (14, 18))	('LRFN5', 'Gene', (120, 125))	('higher', 'PosReg', (61, 67))	('KRTAP9-1', 'Gene', '728318', (110, 118))	('MAP2', 'Gene', (131, 135))	('MAP2', 'Gene', '4133', (131, 135))	('KRTAP9-1', 'Gene', (110, 118))	('LRFN5', 'Gene', '145581', (120, 125))	('mutation rate', 'MPA', (68, 81))	('EP300', 'Gene', (32, 37))	('EP300', 'Gene', '2033', (32, 37))
303165	29142225	Interestingly, the mutational status of these three genes showed marginally significant mutual exclusivity (CoMEt algorithm, Fig.	('CoMEt', 'Species', '302767', (108, 113))	('mutational', 'Var', (19, 29))	('mutual exclusivity', 'MPA', (88, 106))
303167	29142225	The TP53 mutations are widespread throughout the whole gene, while the mutations in EP300 are enriched in the domain of HAT_KAT11, as previously reported (Supplementary Fig.	('TP53', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('EP300', 'Gene', (84, 89))	('EP300', 'Gene', '2033', (84, 89))	('TP53', 'Gene', '7157', (4, 8))
303168	29142225	NFE2L2 (also known as NRF2) is of particular interest: this gene is a transcription factor that regulates many proteins involved in response to injury and inflammation as well as cellular defense against oxidative stress; NFE2L2-knockout mice are more susceptible to esophageal carcinogenesis than wild-type mice; and its mutations have been recently reported to enrich in Vietnamese patients.	('esophageal carcinogenesis', 'Disease', (267, 292))	('susceptible', 'Reg', (252, 263))	('mutations', 'Var', (322, 331))	('oxidative stress', 'Phenotype', 'HP:0025464', (204, 220))	('mice', 'Species', '10090', (238, 242))	('NRF2', 'Gene', '18024', (22, 26))	('patients', 'Species', '9606', (384, 392))	('regulates', 'Reg', (96, 105))	('NFE2L2-knockout', 'Var', (222, 237))	('mice', 'Species', '10090', (308, 312))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (267, 292))	('NRF2', 'Gene', (22, 26))	('injury and inflammation', 'Disease', 'MESH:D007249', (144, 167))
303171	29142225	To further investigate the potential effects of this SNP on NFE2L2 expression, we integrated the SNP data from International Cancer Genome Consortium (ICGC) whole-genome sequencing and TCGA RNA-seq data to compare the mRNA expression level of NFE2L2 between cancer samples with and without this SNP and found that the presence of this SNP was associated with a significantly lower NFE2L2 expression across cancer types (paired Wilcoxon signed rank test, P = 4.9 x 10-4, Fig.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (406, 412))	('expression', 'MPA', (388, 398))	('cancer', 'Disease', (406, 412))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('Cancer', 'Disease', (125, 131))	('presence', 'Var', (318, 326))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('lower', 'NegReg', (375, 380))	('NFE2L2', 'Gene', (381, 387))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (258, 264))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('SNP', 'Var', (335, 338))
303172	29142225	Interestingly, the mutational status for Asian patients was strongly associated with the allele status of this SNP (CoMEt, P = 1.7 x 10-2, Fig.	('patients', 'Species', '9606', (47, 55))	('mutational', 'Var', (19, 29))	('associated', 'Reg', (69, 79))	('CoMEt', 'Species', '302767', (116, 121))
303175	29142225	A key next step to implement precision cancer medicine is to identify race-specific mutated drivers, which will lay a critical foundation for developing novel therapeutic strategies that target different patient populations.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutated', 'Var', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patient', 'Species', '9606', (204, 211))
303189	29142225	We then used several popular callers, including Muse, MuTect2, SomaticSniper, Radia, and VarScan2, to identify somatic point mutations.	('Muse', 'Gene', '399806', (48, 52))	('point mutations', 'Var', (119, 134))	('Muse', 'Gene', (48, 52))
303190	29142225	To assess the accuracy of our mutation calls, we obtained TCGA MC3 mutation data from Synapse (syn5917256, version 0.2.8) and calculated the (median) fraction of MC3 non-silent mutations (e.g., missense, nonsense, and nonstop) called in our mutation set across the same set of TCGA samples and vice versa.	('MC3', 'Gene', (63, 66))	('MC3', 'Gene', (162, 165))	('nonsense', 'Var', (204, 212))	('MC3', 'Gene', '4159', (162, 165))	('MC3', 'Gene', '4159', (63, 66))	('missense', 'Var', (194, 202))	('nonstop', 'Var', (218, 225))
303195	29142225	The SNP status of rs113671272 in Chinese and Vietnamese patients with WES was inferred from off-target reads with a minimum of 3 read coverage.	('rs113671272', 'Mutation', 'rs113671272', (18, 29))	('patients', 'Species', '9606', (56, 64))	('rs113671272', 'Var', (18, 29))	('WES', 'Disease', (70, 73))
303196	29142225	To examine the SNP effects on the gene expression, we obtained the genotypes of rs113671272 in TCGA samples from ICGC whole-genome sequencing data, and obtained the mRNA expression level of NFE2L2 (based on the longest transcript uc002uli.3) from Fire Browser (http://firebrowse.org, version 2016_01_28).	('rs113671272', 'Var', (80, 91))	('mRNA expression', 'MPA', (165, 180))	('rs113671272', 'Mutation', 'rs113671272', (80, 91))	('NFE2L2', 'Gene', (190, 196))
303205	29179482	Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma To investigate whether FGFR1 gene amplification is associated with clinicopathologic characteristics and its potential impact on survival in patients with resected esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (106, 140))	('fibroblast growth factor receptor 1', 'Gene', (15, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (316, 339))	('associated', 'Reg', (192, 202))	('esophageal squamous cell carcinoma', 'Disease', (305, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('esophageal squamous cell carcinoma', 'Disease', (106, 140))	('FGFR1', 'Gene', (164, 169))	('patients', 'Species', '9606', (92, 100))	('fibroblast growth factor receptor 1', 'Gene', '2260', (15, 50))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (305, 339))	('Association', 'Interaction', (0, 11))	('patients', 'Species', '9606', (282, 290))	('amplification', 'Var', (56, 69))
303209	29179482	FGFR1 amplification was identified in 67 (12.1%) patients; these patients had significantly shorter OS (50.0 vs 32.0 months; log rank; P<0.001) as well as shorter DFS (47.0 vs 28.0 months; log rank; P<0.001) than those without FGFR1 amplification.	('OS', 'Chemical', '-', (100, 102))	('shorter', 'NegReg', (155, 162))	('FGFR1', 'Gene', (0, 5))	('patients', 'Species', '9606', (65, 73))	('DFS', 'MPA', (163, 166))	('patients', 'Species', '9606', (49, 57))	('amplification', 'Var', (6, 19))	('shorter', 'NegReg', (92, 99))
303210	29179482	Under a Cox proportional hazard model, FGFR1 amplification was associated with significantly shorter OS (adjusted hazard ratio [AHR]=1.61; 95% CI, 1.10-2.43, P=0.004) and DFS (AHR=1.72; 95%CI, 1.15-2.48; P<0.001).	('FGFR1', 'Gene', (39, 44))	('shorter', 'NegReg', (93, 100))	('OS', 'Chemical', '-', (101, 103))	('DFS', 'CPA', (171, 174))	('amplification', 'Var', (45, 58))
303211	29179482	Moreover, cases with high intratumoral FGFR1 expression showed significantly shorter OS and DFS than those with low FGFR1 expression.	('FGFR1', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('OS', 'Chemical', '-', (85, 87))	('tumor', 'Disease', (31, 36))	('high', 'Var', (21, 25))	('DFS', 'CPA', (92, 95))	('shorter', 'NegReg', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
303218	29179482	Further delineation of genetic alterations may help uncover aberrant molecular pathways, novel biologic markers and tumorigenic pathways, and eventually allowing successful targeted therapy.	('alterations', 'Var', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('uncover', 'Reg', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('molecular pathways', 'Pathway', (69, 87))	('tumor', 'Disease', (116, 121))
303221	29179482	FGFR1 amplification has been identified in breast cancer, head and neck squamous cell carcinoma, ovarian cancer, ESCC, bladder cancer and lung cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('FGFR1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('ESCC', 'Disease', (113, 117))	('bladder cancer', 'Disease', 'MESH:D001749', (119, 133))	('bladder cancer', 'Disease', (119, 133))	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (58, 95))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('identified', 'Reg', (29, 39))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (58, 95))	('lung cancer', 'Disease', (138, 149))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('breast cancer', 'Disease', (43, 56))	('ovarian cancer', 'Disease', (97, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('amplification', 'Var', (6, 19))
303222	29179482	investigated the prevalence of FGFR1 amplification in a tissue microarray containing 346 esophageal adenocarcinomas and 254 ESCCs using dual-labeling fluorescent in situ hybridization (FISH) analysis and found that FGFR1 amplification correlated with the histologic subtype of ESCC (9.4% vs. esophageal adenocarcinoma 1.6%, P<0.001).	('FGFR1', 'Gene', (215, 220))	('amplification', 'Var', (221, 234))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (89, 115))	('ESCC', 'Disease', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (89, 114))	('correlated', 'Reg', (235, 245))	('FGFR1', 'Gene', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('esophageal adenocarcinomas', 'Disease', (89, 115))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (89, 114))	('esophageal adenocarcinoma', 'Disease', (292, 317))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (292, 317))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (292, 317))
303223	29179482	studied 180 patients with resected ESCC and found FGFR1 amplification in 21.4% (37/173) patients; they observed that FGFR1 amplification was an independent predictor of prolonged OS in these patients.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (191, 199))	('patients', 'Species', '9606', (88, 96))	('prolonged OS', 'Disease', (169, 181))	('FGFR1', 'Gene', (117, 122))	('amplification', 'Var', (123, 136))	('OS', 'Chemical', '-', (179, 181))
303225	29179482	FGFR1 inhibition in cell lines and mouse models with FGFR1-amplified engrafted tumors suppressed tumor cell growth and induced apoptosis, suggesting that FGFR inhibitors may be an effective therapeutic option in SCCs with FGFR1 amplification.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('induced', 'Reg', (119, 126))	('FGFR1-amplified', 'Gene', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FGFR1', 'Gene', (0, 5))	('apoptosis', 'CPA', (127, 136))	('mouse', 'Species', '10090', (35, 40))	('tumor', 'Disease', (97, 102))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('suppressed', 'NegReg', (86, 96))	('inhibition', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('SCCs', 'Disease', (212, 216))
303239	29179482	The median FGFR1 gene copy number was 10 (range, 6 to 17) in ESCC patients with FGFR1 amplification and 2 (range, 2 to 5) in those without FGFR1 amplification.	('amplification', 'Var', (86, 99))	('ESCC', 'Disease', (61, 65))	('FGFR1', 'Gene', (11, 16))	('FGFR1', 'Gene', (80, 85))	('patients', 'Species', '9606', (66, 74))
303241	29179482	ESCC patients with and without FGFR1 amplification were comparable in the demographic and baseline variables except that the percentage of heavy drinkers was significantly higher in patients with FGFR1 amplification than those without FGFR1 amplification (86.6% vs 43.1%, P<0.001) (Table 1).	('patients', 'Species', '9606', (5, 13))	('FGFR1', 'Gene', (196, 201))	('higher', 'PosReg', (172, 178))	('patients', 'Species', '9606', (182, 190))	('amplification', 'Var', (202, 215))
303243	29179482	Kaplan-Meier analysis showed that ESCC patients with FGFR1 amplification had significantly shorter OS (32.0 months; range, 11.0 to 116.0 months) than those without FGFR1 amplification (50.0 months; range, 9.0 to 137.0 months) (log rank; P<0.001) (Figure 2).	('FGFR1', 'Gene', (53, 58))	('OS', 'Chemical', '-', (99, 101))	('patients', 'Species', '9606', (39, 47))	('ESCC', 'Disease', (34, 38))	('amplification', 'Var', (59, 72))	('shorter', 'NegReg', (91, 98))
303244	29179482	After adjustment for sex, pathologic stage, diabetes, adjuvant chemotherapy and other factors, FGFR1 amplification remained associated with significantly shorter OS (adjusted hazard ratio [AHR], 1.61; 95% CI, 1.10-2.43, P=0.004) (Table 2).	('amplification', 'Var', (101, 114))	('FGFR1', 'Gene', (95, 100))	('OS', 'Chemical', '-', (162, 164))	('men', 'Species', '9606', (12, 15))	('diabetes', 'Disease', (44, 52))	('diabetes', 'Disease', 'MESH:D003920', (44, 52))	('shorter', 'NegReg', (154, 161))
303245	29179482	The median DFS was 28.0 months (range, 7.0 to 116.0 months) for ESCC patients with FGFR1 amplification and 47.0 (range, 5.0 to 137.0 months) months in those without FGFR1 amplification.	('patients', 'Species', '9606', (69, 77))	('FGFR1', 'Gene', (83, 88))	('ESCC', 'Disease', (64, 68))	('amplification', 'Var', (89, 102))
303246	29179482	Kaplan-Meier analysis revealed that patients with FGFR1 amplification had significantly shorter DFS (log rank; P<0.001) (Figure 2).	('shorter', 'NegReg', (88, 95))	('patients', 'Species', '9606', (36, 44))	('FGFR1', 'Gene', (50, 55))	('DFS', 'MPA', (96, 99))	('amplification', 'Var', (56, 69))
303247	29179482	After adjusting for sex, pathologic stage, diabetes, and other variables, FGFR1 amplification was associated with shorter DFS (AHR=1.72; 95%CI, 1.15-2.48; P<0.001) (Table 3).	('amplification', 'Var', (80, 93))	('diabetes', 'Disease', 'MESH:D003920', (43, 51))	('DFS', 'MPA', (122, 125))	('shorter', 'NegReg', (114, 121))	('diabetes', 'Disease', (43, 51))	('FGFR1', 'Gene', (74, 79))
303248	29179482	A cutoff IHC score of 62 was used to stratify ESCC patients into the high FGFR1 expression group (n=81) and the low FGFR1 expression group (n=475).	('ESCC', 'Disease', (46, 50))	('patients', 'Species', '9606', (51, 59))	('FGFR1', 'Gene', (74, 79))	('high', 'Var', (69, 73))
303249	29179482	ESCC patients with high FGFR1 expression and those with low FGFR1 expression were comparable in the demographic and baseline variables except that the percentage of heavy drinkers was significantly higher in patients with high FGFR1 expression than those with low FGFR1 expression (79.0% vs 43.2%, P<0.001) (Supplementary Table 1, Supplementary Figure 2).	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (5, 13))	('high', 'Var', (222, 226))	('men', 'Species', '9606', (337, 340))	('FGFR1', 'Gene', (227, 232))	('FGFR1', 'Gene', (24, 29))	('men', 'Species', '9606', (314, 317))	('higher', 'PosReg', (198, 204))
303250	29179482	Furthermore, ESCC patients with FGFR1 amplification had significantly higher IHC scores (mean 121.8 +- 36.8; range, 78 to 242) than those without FGFR1 amplification (mean 22.1 +- 19.9; range, 0 to 75) (P<0.001) (Figure 3) and all patients with FGFR1 amplification fell into the high FGFR1 expression group.	('patients', 'Species', '9606', (231, 239))	('IHC scores', 'CPA', (77, 87))	('FGFR1 amplification', 'Var', (32, 51))	('ESCC', 'Disease', (13, 17))	('fell', 'Reg', (265, 269))	('patients', 'Species', '9606', (18, 26))	('higher', 'PosReg', (70, 76))	('amplification', 'Var', (38, 51))
303251	29179482	Moreover, patients with high intratumoral FGFR1 expression had shorter OS (31.0 vs 52.0 months in subjects with low FGFR1 expression; P<0.001) and DFS (28.0 vs 48.0 months; P<0.001) (Figure 4).	('tumor', 'Disease', (34, 39))	('FGFR1', 'Gene', (42, 47))	('shorter', 'NegReg', (63, 70))	('OS', 'Chemical', '-', (71, 73))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('DFS', 'CPA', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('patients', 'Species', '9606', (10, 18))
303256	29179482	Thirty-six patients with FGFR1 amplification received adjuvant therapy.	('patients', 'Species', '9606', (11, 19))	('FGFR1', 'Gene', (25, 30))	('amplification', 'Var', (31, 44))
303257	29179482	Compared to those with FGFR1 amplification receiving no adjuvant chemotherapy, these patients had significantly longer median OS (chemotherapy: 42.0 vs no chemotherapy 26.0 months; P=0.006) and median DFS (chemotherapy 38.0 vs no chemotherapy: 21.0 months; P=0.009) (Figure 5).	('amplification', 'Var', (29, 42))	('patients', 'Species', '9606', (85, 93))	('OS', 'Chemical', '-', (126, 128))	('DFS', 'MPA', (201, 204))	('longer', 'PosReg', (112, 118))
303262	29179482	FGFR1 amplification has been documented in ESCC and other cancer types; however, it still remains controversial whether FGFR1 amplification adversely impacts on the clinical outcome of ESCC patients.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('FGFR1', 'Gene', (120, 125))	('patients', 'Species', '9606', (190, 198))	('impacts', 'Reg', (150, 157))	('amplification', 'Var', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('ESCC', 'Disease', (185, 189))	('men', 'Species', '9606', (33, 36))	('cancer', 'Disease', (58, 64))
303264	29179482	We demonstrated that FGFR1 amplification was an independent adverse prognostic predictor of OS and DFS of ESCC patients.	('DFS', 'Disease', (99, 102))	('FGFR1', 'Gene', (21, 26))	('OS', 'Chemical', '-', (92, 94))	('amplification', 'Var', (27, 40))	('patients', 'Species', '9606', (111, 119))
303268	29179482	In head and neck squamous cell carcinoma, FGFR1 amplification was significantly associated with poor prognostic factors such as higher T stage, and visceral metastasis.	('FGFR1', 'Gene', (42, 47))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (3, 40))	('visceral metastasis', 'Disease', (148, 167))	('higher', 'Disease', (128, 134))	('associated', 'Reg', (80, 90))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('visceral metastasis', 'Disease', 'MESH:D009362', (148, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('amplification', 'Var', (48, 61))
303270	29179482	found no association between FGFR1 amplification and clinical outcome of ESCC patients while Kwon et al.	('amplification', 'Var', (35, 48))	('ESCC', 'Disease', (73, 77))	('FGFR1', 'Gene', (29, 34))	('patients', 'Species', '9606', (78, 86))
303271	29179482	showed that FGFR1 amplification was an independent predictor of prolonged OS of ESCC patients.	('FGFR1', 'Gene', (12, 17))	('predictor', 'Reg', (51, 60))	('patients', 'Species', '9606', (85, 93))	('amplification', 'Var', (18, 31))	('ESCC patients', 'Disease', (80, 93))	('prolonged OS', 'Disease', (64, 76))	('OS', 'Chemical', '-', (74, 76))
303272	29179482	investigated 526 curatively resected ESCC and showed that high FGFR1 amplification was associated with significantly shorter DFS and OS.	('DFS', 'CPA', (125, 128))	('shorter', 'NegReg', (117, 124))	('FGFR1', 'Gene', (63, 68))	('high', 'Var', (58, 62))	('OS', 'Chemical', '-', (133, 135))	('amplification', 'Var', (69, 82))
303273	29179482	Consistently, our study of 556 ESCC patients also showed that FGFR1 amplification was independently associated with worse OS and DFS.	('DFS', 'Disease', (129, 132))	('patients', 'Species', '9606', (36, 44))	('associated', 'Reg', (100, 110))	('FGFR1', 'Gene', (62, 67))	('OS', 'Chemical', '-', (122, 124))	('ESCC', 'Disease', (31, 35))	('amplification', 'Var', (68, 81))	('worse OS', 'Disease', (116, 124))
303275	29179482	Apart from genetic evidence, we further showed that high intratumoral FGFR1 expression was also associated with shorter OS and DFS, lending support to the proposition that FGFR1 amplification predicts poor clinical outcome of ESCC patients.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('patients', 'Species', '9606', (231, 239))	('DFS', 'MPA', (127, 130))	('tumor', 'Disease', (62, 67))	('ESCC', 'Disease', (226, 230))	('expression', 'MPA', (76, 86))	('FGFR1', 'Gene', (70, 75))	('high', 'Var', (52, 56))	('amplification', 'Var', (178, 191))	('OS', 'Chemical', '-', (120, 122))	('shorter', 'NegReg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
303278	29179482	Our study has demonstrated that FGFR1 amplification is an independent adverse predictor of OS of ESCC patients, suggesting that FGFR1 may be a promising molecular therapeutic target.	('FGFR1', 'Gene', (32, 37))	('patients', 'Species', '9606', (102, 110))	('OS of ESCC patients', 'Disease', (91, 110))	('OS', 'Chemical', '-', (91, 93))	('amplification', 'Var', (38, 51))
303284	29179482	Patients with FGFR1 amplification benefitted from adjuvant chemotherapy while patients without FGFR1 amplification did not.	('benefitted', 'PosReg', (34, 44))	('adjuvant', 'CPA', (50, 58))	('FGFR1', 'Gene', (14, 19))	('patients', 'Species', '9606', (78, 86))	('Patients', 'Species', '9606', (0, 8))	('amplification', 'Var', (20, 33))
303287	29179482	A novel finding of the current study is significant association between FGFR1 amplification and alcohol intake.	('FGFR1', 'Gene', (72, 77))	('amplification', 'Var', (78, 91))	('alcohol intake', 'Disease', (96, 110))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))
303288	29179482	We also found that the incidence of FGFR1 amplification rose as the amount of alcohol intake increased.	('alcohol', 'Chemical', 'MESH:D000438', (78, 85))	('FGFR1', 'Gene', (36, 41))	('amplification', 'Var', (42, 55))
303289	29179482	Our findings suggest that FGFR1 amplification may be a major oncogenic aberration in ESCC that is induced by alcohol abuse.	('alcohol abuse', 'Phenotype', 'HP:0030955', (109, 122))	('FGFR1', 'Gene', (26, 31))	('amplification', 'Var', (32, 45))	('ESCC', 'Disease', (85, 89))	('alcohol abuse', 'Disease', (109, 122))	('alcohol abuse', 'Disease', 'MESH:D000437', (109, 122))
303290	29179482	On the basis of this finding, ESCC patients with alcohol consumption more than 100 g/day may be targeted for screening for FGFR1 amplification.	('amplification', 'Var', (129, 142))	('FGFR1', 'Gene', (123, 128))	('ESCC', 'Disease', (30, 34))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))	('patients', 'Species', '9606', (35, 43))
303292	29179482	FGFR1 amplification was positively associated with alcohol consumption, which strongly implies that FGFR1 amplification is an oncogenic aberration caused by alcohol abuse.	('alcohol abuse', 'Disease', 'MESH:D000437', (157, 170))	('alcohol abuse', 'Phenotype', 'HP:0030955', (157, 170))	('associated', 'Reg', (35, 45))	('FGFR1', 'Gene', (0, 5))	('alcohol', 'Chemical', 'MESH:D000438', (157, 164))	('amplification', 'Var', (106, 119))	('FGFR1', 'Gene', (100, 105))	('alcohol consumption', 'Disease', (51, 70))	('alcohol', 'Chemical', 'MESH:D000438', (51, 58))	('alcohol abuse', 'Disease', (157, 170))	('amplification', 'Var', (6, 19))
303370	27556859	The UBE2C protein expression levels of five human ESCC cell lines (KYSE-70, KYSE-110, KYSE-140, KYSE-220, KYSE-510) and a human normal esophageal squamous epithelial cell line (Het-1A) were assessed by western blot (Figure 1C).	('human', 'Species', '9606', (44, 49))	('human', 'Species', '9606', (122, 127))	('UBE2C', 'Gene', '11065', (4, 9))	('UBE2C', 'Gene', (4, 9))	('Het-1A', 'CellLine', 'CVCL:3702', (177, 183))	('KYSE-140', 'Var', (86, 94))	('KYSE-220', 'Var', (96, 104))
303371	27556859	The KYSE-70, KYSE-110, KYSE-140 and KYSE-220 ESCC cells showed high-UBE2C expression, as compared to normal epithelial cell with low UBE2C expression.	('UBE2C', 'Gene', '11065', (68, 73))	('KYSE-140', 'Var', (23, 31))	('UBE2C', 'Gene', (68, 73))	('UBE2C', 'Gene', '11065', (133, 138))	('UBE2C', 'Gene', (133, 138))	('KYSE-220', 'Var', (36, 44))
303388	27556859	Overexpression of UBE2C causes chromosome missegregation and alters the cell cycle profile, thus facilitating cell proliferation.	('cell cycle profile', 'CPA', (72, 90))	('alters', 'Reg', (61, 67))	('facilitating', 'PosReg', (97, 109))	('UBE2C', 'Gene', '11065', (18, 23))	('causes', 'Reg', (24, 30))	('UBE2C', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('cell proliferation', 'CPA', (110, 128))	('chromosome missegregation', 'CPA', (31, 56))
303419	27556859	The five human esophageal squamous carcinoma cell lines (KYSE-70, KYSE-110, KYSE-140, KYSE-220, KYSE-510) and a human normal esophageal squamous epithelial cell line (Het-1A) were purchased from the DSMZ-German Collection of Microorganisms and Cell Cultures (Braunschweig, Germany).	('KYSE-510', 'Var', (96, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (26, 44))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (15, 44))	('human', 'Species', '9606', (9, 14))	('Het-1A', 'CellLine', 'CVCL:3702', (167, 173))	('esophageal squamous carcinoma', 'Disease', (15, 44))	('KYSE-220', 'Var', (86, 94))	('KYSE-140', 'Var', (76, 84))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (15, 44))	('human', 'Species', '9606', (112, 117))
303470	26867548	A video endoscope (GIF-H260Z, GIF-Q260J; Olympus, Tokyo, Japan) equipped with a 4-mm transparent cap (D-201-11804; Olympus) was used (Fig.	('H260Z', 'SUBSTITUTION', 'None', (23, 28))	('Q260J', 'Var', (34, 39))	('Q260J', 'SUBSTITUTION', 'None', (34, 39))	('H260Z', 'Var', (23, 28))
303652	26064820	However, local drug delivery from the DES has a risk of damaging the adjacent normal digestive tract mucosa, as well as causing non-target organ toxicity and systemic exposure.	('damaging', 'Reg', (56, 64))	('local drug delivery', 'Var', (9, 28))	('toxicity', 'Disease', 'MESH:D064420', (145, 153))	('toxicity', 'Disease', (145, 153))	('causing', 'Reg', (120, 127))
303672	25064471	Dosimetric Predictors of Esophageal Toxicity after Stereotactic Body Radiotherapy for Central Lung Tumors Stereotactic body radiotherapy (SBRT) to central lung tumors can cause esophageal toxicity, but little is known about the incidence or risk factors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('esophageal toxicity', 'Disease', 'MESH:D004935', (177, 196))	('cause', 'Reg', (171, 176))	('Esophageal Toxicity', 'Disease', (25, 44))	('central lung tumors', 'Disease', (147, 166))	('Tumors', 'Phenotype', 'HP:0002664', (99, 105))	('lung tumors', 'Phenotype', 'HP:0100526', (155, 166))	('central lung tumors', 'Disease', 'MESH:D008175', (147, 166))	('Central Lung Tumors', 'Disease', (86, 105))	('Tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Central Lung Tumors', 'Disease', 'MESH:D008175', (86, 105))	('Stereotactic body radiotherapy', 'Var', (106, 136))	('Stereotactic body', 'Phenotype', 'HP:0000733', (106, 123))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Esophageal Toxicity', 'Disease', 'MESH:D004935', (25, 44))	('esophageal toxicity', 'Disease', (177, 196))	('Lung Tumors', 'Phenotype', 'HP:0100526', (94, 105))	('Stereotactic Body', 'Phenotype', 'HP:0000733', (51, 68))
303693	25064471	Furthermore, whereas mean dose to the whole esophagus is commonly used to evaluate risk of toxicity in conventional RT, SBRT is associated with much smaller target and esophageal volumes and therefore it is less likely that a mean dose constraint would be clinically robust.	('target', 'MPA', (157, 163))	('SBRT', 'Var', (120, 124))	('smaller', 'NegReg', (149, 156))	('toxicity', 'Disease', 'MESH:D064420', (91, 99))	('toxicity', 'Disease', (91, 99))
303722	25064471	Cox models of using Vd showed significant correlation with E2a for values of d above 8.1 BED10, with the greatest statistical significance at d=44.8 BED10 (See Fig.	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('d=44.8', 'Var', (142, 148))	('correlation', 'Interaction', (42, 53))
303723	25064471	A combined Cox model using D3.8cc and V44.8 bed10 was generated but not found to be statistically significant, due to the high degree of correlation between the two variables.	('correlation', 'Interaction', (137, 148))	('V44.8 bed10', 'Var', (38, 49))	('Cox', 'Gene', (11, 14))	('Cox', 'Gene', '1351', (11, 14))	('D3.8cc', 'Var', (27, 33))
303725	25064471	The fitted logistic regression response curves, shown in Figure 2, suggest that values of Dmax <=52.9 BED10, and D5cc <= 26.3 BED10, result in predicted probabilities of complication less than 20%.	('D5cc', 'Chemical', '-', (113, 117))	('Dmax <=52.9', 'Var', (90, 101))	('complication', 'CPA', (170, 182))	('D5cc <=', 'Var', (113, 120))
303729	25064471	At two years, the probability of complication for those with D5cc > 14.4 BED10 was 24% (p<0.001), and for those with Dmax > 29.6 BED10 was 21% (p=0.051).	('D5cc > 14.4', 'Var', (61, 72))	('complication', 'CPA', (33, 45))	('D5cc', 'Chemical', '-', (61, 65))
303746	25064471	Logrank tests indicated that these metrics had significant ability to discriminate patients at high vs. low risk for acute esophageal complication, with Dv values above the median splits associated with complication rates in excess of 20%, while Dv values below the median splits were associated with complication rates well under 10%.	('esophageal complication', 'Disease', 'MESH:D004935', (123, 146))	('patients', 'Species', '9606', (83, 91))	('associated', 'Reg', (187, 197))	('complication', 'MPA', (203, 215))	('esophageal complication', 'Disease', (123, 146))	('Dv values', 'Var', (153, 162))
303747	25064471	In the case of D5cc, esophageal doses above the median split resulted in complication probability nearly 16 times that of doses below the median split.	('complication', 'CPA', (73, 85))	('D5cc', 'Var', (15, 19))	('D5cc', 'Chemical', '-', (15, 19))	('esophageal doses', 'MPA', (21, 37))
303759	25164541	Clinical study on postoperative recurrence in patients with pN0 esophageal squamous cell carcinoma Despite increasingly radical surgery for esophageal carcinoma, many patients still develop tumor recurrence after operation.	('esophageal carcinoma', 'Disease', (140, 160))	('patients', 'Species', '9606', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('develop', 'PosReg', (182, 189))	('esophageal squamous cell carcinoma', 'Disease', (64, 98))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (140, 160))	('patients', 'Species', '9606', (167, 175))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (140, 160))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('pN0', 'Var', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (64, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
303769	25164541	Locoregional recurrence was the most common recurrence pattern of patients with pN0 ESCC within 3 years after operation.	('pN0', 'Var', (80, 83))	('Locoregional recurrence', 'Disease', (0, 23))	('patients', 'Species', '9606', (66, 74))
303825	25164541	In summary, we have confirmed that locoregional recurrence was the most common recurrence pattern of patients with pN0 ESCC within 3 years after operation.	('patients', 'Species', '9606', (101, 109))	('locoregional recurrence', 'Disease', (35, 58))	('pN0', 'Var', (115, 118))
303827	25187833	Antisense oligodeoxynucleotide against human telomerase reverse transcriptase inhibits the proliferation of Eca-109 esophageal carcinoma cells Previous studies have demonstrated that the growth of tumor cells may be inhibited by antisense oligonucleotides (ASODNs) targeted against human telomerase (hTR) or human telomerase reverse transcriptase (hTERT), resulting in antitumor activity in a wide variety of tumors.	('tumor', 'Disease', (409, 414))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('hTR', 'Gene', '7012', (300, 303))	('telomerase reverse transcriptase', 'Gene', '7015', (45, 77))	('tumors', 'Disease', 'MESH:D009369', (409, 415))	('telomerase reverse transcriptase', 'Gene', (314, 346))	('tumor', 'Disease', 'MESH:D009369', (409, 414))	('ASODN', 'Chemical', '-', (257, 262))	('inhibits', 'NegReg', (78, 86))	('human', 'Protein', (308, 313))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (10, 30))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (116, 136))	('inhibited', 'NegReg', (216, 225))	('hTERT', 'Gene', '7015', (348, 353))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('human', 'Species', '9606', (308, 313))	('telomerase reverse transcriptase', 'Gene', '7015', (314, 346))	('human', 'Species', '9606', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('esophageal carcinoma', 'Disease', (116, 136))	('oligonucleotides', 'Chemical', 'MESH:D009841', (239, 255))	('tumors', 'Phenotype', 'HP:0002664', (409, 415))	('proliferation', 'CPA', (91, 104))	('hTERT', 'Gene', (348, 353))	('hTR', 'Gene', (300, 303))	('telomerase reverse transcriptase', 'Gene', (45, 77))	('tumor', 'Disease', (373, 378))	('antisense', 'Var', (229, 238))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (116, 136))	('human', 'Species', '9606', (282, 287))	('tumors', 'Disease', (409, 415))	('growth', 'CPA', (187, 193))	('tumor', 'Disease', 'MESH:D009369', (373, 378))	('Antisense', 'Var', (0, 9))	('tumor', 'Disease', (197, 202))
303833	25187833	The differences in inhibition rate between the PS-ASODN and blank control groups were statistically significant (P<0.05) when the concentration of the PS-ASODN was >=2 mumol/l, whereas no statistically significant difference was identified between the non-specific-ASODN and blank control groups.	('ASODN', 'Chemical', '-', (265, 270))	('ASODN', 'Chemical', '-', (50, 55))	('inhibition', 'NegReg', (19, 29))	('ASODN', 'Chemical', '-', (154, 159))	('PS-ASODN', 'Chemical', '-', (47, 55))	('PS-ASODN', 'Chemical', '-', (151, 159))	('PS-ASODN', 'Var', (151, 159))
303834	25187833	The inhibition rate increased gradually as the concentration of the PS-ASODN increased and with time, suggesting that the PS-ASODN inhibited the growth of Eca-109 cells in a concentration-dependent, time-dependent and sequence-specific manner.	('growth', 'CPA', (145, 151))	('PS-ASODN', 'Chemical', '-', (68, 76))	('inhibited', 'NegReg', (131, 140))	('PS-ASODN', 'Var', (122, 130))	('PS-ASODN', 'Chemical', '-', (122, 130))
303844	25187833	Numerous studies have shown that antisense gene therapy directed against telomerase RNA or hTERT components may effectively inhibit telomerase activity and induce apoptosis in gastric cancer, malignant gliomas, colon cancer and ovarian cancer.	('ovarian cancer', 'Disease', (228, 242))	('telomerase', 'Enzyme', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('malignant gliomas', 'Disease', (192, 209))	('ovarian cancer', 'Phenotype', 'HP:0100615', (228, 242))	('activity', 'MPA', (143, 151))	('colon cancer', 'Disease', (211, 223))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('inhibit', 'NegReg', (124, 131))	('apoptosis', 'CPA', (163, 172))	('hTERT', 'Gene', '7015', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('gliomas', 'Phenotype', 'HP:0009733', (202, 209))	('gastric cancer', 'Disease', (176, 190))	('antisense gene therapy', 'Var', (33, 55))	('ovarian cancer', 'Disease', 'MESH:D010051', (228, 242))	('malignant gliomas', 'Disease', 'MESH:D005910', (192, 209))	('colon cancer', 'Phenotype', 'HP:0003003', (211, 223))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('hTERT', 'Gene', (91, 96))	('induce', 'PosReg', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('colon cancer', 'Disease', 'MESH:D015179', (211, 223))
303845	25187833	Previous studies have also demonstrated that the growth of tumor cells may be inhibited by antisense oligodeoxynucleotides (ASODNs) that are targeted to the hTERT gene in a wide variety of tumor types.	('hTERT', 'Gene', (157, 162))	('tumor', 'Disease', (189, 194))	('inhibited', 'NegReg', (78, 87))	('tumor', 'Disease', (59, 64))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (101, 122))	('antisense', 'Var', (91, 100))	('hTERT', 'Gene', '7015', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('ASODN', 'Chemical', '-', (124, 129))
303873	25187833	The inhibition rate increased with time and as the concentration of PS-ASODN increased, which indicates that PS-ASODN inhibited the growth of Eca-109 cells in a concentration-, time- and sequence-specific manner.	('inhibited', 'NegReg', (118, 127))	('PS-ASODN', 'Chemical', '-', (109, 117))	('PS-ASODN', 'Var', (109, 117))	('PS-ASODN', 'Chemical', '-', (68, 76))	('growth', 'MPA', (132, 138))
303874	25187833	Living cells were observed using an inverted microscope and it was found that cells treated with N-ASODN and cells in the blank control group were all epithelial and adhered to the well, the cell outlines were clear, the cells were close together and proliferation was rapid (Fig.	('N-ASODN', 'Var', (97, 104))	('N-ASODN', 'Chemical', '-', (97, 104))	('proliferation', 'CPA', (251, 264))
303875	25187833	There was no significant difference between the treatment group (2 mumol/l PS-ASODN, 24 h) and control group in morphology; however, cell growth was slower in the PS-ASODN group (Fig.	('PS-ASODN', 'Chemical', '-', (163, 171))	('PS-ASODN', 'Var', (163, 171))	('cell growth', 'CPA', (133, 144))	('PS-ASODN', 'Chemical', '-', (75, 83))	('slower', 'NegReg', (149, 155))
303890	25187833	The mechanism of ASODN treatment is as follows: i) Combination with the target DNA sequence and establishment of a tri-chain structure (U-type complementation), prohibiting the replication or transfixion of the target gene; ii) combination with the particular sequence of mRNA to form a double chain structure that prevents the ribosome from binding to the target mRNA, resulting in the inhibition of the expression of mRNA or activation of RNase H, which degrades the target mRNA by degrading the unusual double chain structure of the hetero-molecules; iii) complementing to the end coding sequence or the bottom sequence of mRNA5' to inhibit the translation.	('binding', 'Interaction', (342, 349))	('inhibit', 'NegReg', (636, 643))	('expression', 'MPA', (405, 415))	('activation', 'PosReg', (427, 437))	('unusual double chain structure of the hetero-molecules', 'MPA', (498, 552))	('translation', 'MPA', (648, 659))	('combination', 'Var', (228, 239))	('ASODN', 'Chemical', '-', (17, 22))	('degrading', 'NegReg', (484, 493))	('inhibition', 'NegReg', (387, 397))	('mRNA', 'Protein', (419, 423))	('RNase H', 'Enzyme', (441, 448))
303892	25187833	In order to do this, chemically treated oligodeoxynucleotides are introduced into the ASODN, including modifications to the phosphate backbone and pentose units (primarily at the 2-hydroxy group of ribose).	('phosphate', 'Chemical', 'MESH:D010710', (124, 133))	('modifications', 'Var', (103, 116))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (40, 61))	('phosphate backbone', 'MPA', (124, 142))	('ASODN', 'Chemical', '-', (86, 91))	('ribose', 'Chemical', 'MESH:D012266', (198, 204))	('pentose', 'Chemical', 'MESH:D010429', (147, 154))
303896	25187833	However, whether antisense hTR decreases the activity of telomerase and inhibits tumor growth in all types of cancer (for example, esophageal cancer) requires further investigation.	('activity', 'MPA', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('decreases', 'NegReg', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('esophageal cancer', 'Disease', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('hTR', 'Gene', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('inhibits', 'NegReg', (72, 80))	('antisense', 'Var', (17, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('hTR', 'Gene', '7012', (27, 30))	('telomerase', 'Protein', (57, 67))	('tumor', 'Disease', (81, 86))	('cancer', 'Disease', (142, 148))
303898	25187833	In a previous study, we designed a PS-ASODN against hTR and applied it to Eca-109 cell cultures, and the results demonstrated that the PS-ASODN inhibited the activity of telomerase and inhibited tumor growth.	('PS-ASODN', 'Chemical', '-', (35, 43))	('tumor', 'Disease', (195, 200))	('activity', 'MPA', (158, 166))	('PS-ASODN', 'Chemical', '-', (135, 143))	('hTR', 'Gene', '7012', (52, 55))	('PS-ASODN', 'Var', (135, 143))	('telomerase', 'Enzyme', (170, 180))	('inhibited', 'NegReg', (185, 194))	('inhibited', 'NegReg', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('hTR', 'Gene', (52, 55))
303903	25187833	Shammas et al demonstrated that GRN163L, an antisense oligonucleotide targeting telomerase RNA, inhibited telomerase activity in bone marrow cells and induced cell death.	('GRN163L', 'Var', (32, 39))	('activity', 'MPA', (117, 125))	('GRN163L', 'Chemical', 'MESH:C519562', (32, 39))	('death', 'Disease', 'MESH:D003643', (164, 169))	('death', 'Disease', (164, 169))	('induced', 'Reg', (151, 158))	('inhibited', 'NegReg', (96, 105))	('oligonucleotide', 'Chemical', 'MESH:D009841', (54, 69))	('telomerase', 'Enzyme', (106, 116))
303904	25187833	Another study demonstrated that an antisense oligonucleotide specifically targeted against hTERT in human prostate cancer cells reduced telomerase activity, decreased proliferation and, eventually, induced cell death, indicating that hTERT is directly associated with the growth and proliferation of tumor cells.	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))	('death', 'Disease', 'MESH:D003643', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('reduced', 'NegReg', (128, 135))	('prostate cancer', 'Disease', (106, 121))	('decreased', 'NegReg', (157, 166))	('hTERT', 'Gene', '7015', (234, 239))	('antisense', 'Var', (35, 44))	('induced', 'Reg', (198, 205))	('telomerase activity', 'MPA', (136, 155))	('hTERT', 'Gene', '7015', (91, 96))	('hTERT', 'Gene', (234, 239))	('death', 'Disease', (211, 216))	('tumor', 'Disease', (300, 305))	('oligonucleotide', 'Chemical', 'MESH:D009841', (45, 60))	('human', 'Species', '9606', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('proliferation', 'CPA', (167, 180))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('hTERT', 'Gene', (91, 96))
303911	25187833	Using an inverted phase-contrast microscope, cells of the N-ASODN and blank groups grew well, close to the well wall and close together.	('N-ASODN', 'Var', (58, 65))	('grew', 'CPA', (83, 87))	('N-ASODN', 'Chemical', '-', (58, 65))
303922	24332033	The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway may operate in human disease.	('human', 'Species', '9606', (179, 184))	('polymorphism', 'Var', (110, 122))	('TSLP', 'Gene', (126, 130))	('increased', 'PosReg', (55, 64))	('allergic', 'Disease', 'MESH:D004342', (68, 76))	('allergic', 'Disease', (68, 76))	('patients', 'Species', '9606', (77, 85))	('EMH', 'Phenotype', 'HP:0001978', (152, 155))	('gain-of-function', 'PosReg', (93, 109))	('frequency of circulating progenitor cells', 'CPA', (4, 45))
303936	24332033	Systemic TSLP expression resulted in increases in the frequency and number of lineage negative (Lin-) CD34+ c-Kit+ progenitor cells in the spleen with a surface phenotype similar to that of bone marrow (BM)-resident granulocyte-monocyte progenitor (GMP) cells.	('expression', 'Var', (14, 24))	('GMP', 'Chemical', '-', (249, 252))	('lineage negative', 'CPA', (78, 94))	('increases', 'PosReg', (37, 46))	('TSLP', 'Gene', (9, 13))
303938	24332033	In addition, Lin- CD34+ c-Kit+ cells were identified in the spleen and blood of human donors and were increased in the blood of allergic patients with a gain-of-function polymorphism in TSLP that is associated with elevated TSLP expression.	('allergic', 'Disease', (128, 136))	('gain-of-function', 'PosReg', (153, 169))	('patients', 'Species', '9606', (137, 145))	('polymorphism', 'Var', (170, 182))	('human', 'Species', '9606', (80, 85))	('TSLP', 'Gene', (186, 190))	('donor', 'Species', '9606', (86, 91))	('allergic', 'Disease', 'MESH:D004342', (128, 136))
303948	24332033	Topical treatment with MC903 resulted in a significant increase in the percentage and total number of Lin- CD34+ c-Kit+ cells in the spleen compared to ethanol (EtOH)-treated controls (S. Fig.	('increase', 'PosReg', (55, 63))	('ethanol', 'Chemical', 'MESH:D000431', (152, 159))	('MC903', 'Var', (23, 28))	('EtOH', 'Chemical', 'MESH:D000431', (161, 165))	('MC903', 'Chemical', 'MESH:C055085', (23, 28))
303952	24332033	Administration of anti-TSLP neutralizing antibody also resulted in reduced progenitor cell responses following MC903 treatment (Fig.	('anti-TSLP', 'Gene', (18, 27))	('anti-TSLP', 'Var', (18, 27))	('MC903', 'Chemical', 'MESH:C055085', (111, 116))	('reduced', 'NegReg', (67, 74))	('progenitor cell responses', 'CPA', (75, 100))
303957	24332033	Consistent with published reports, BM-resident Lin- CD34+ c-Kit+ GMPs were predominately Sca-1-, CD16(32)hi, CD150- and also expressed the TSLPR (Fig.	('CD150', 'Gene', '6504', (109, 114))	('Sca-1', 'Gene', '6310', (89, 94))	('CD16(32)hi', 'Var', (97, 107))	('CD150', 'Gene', (109, 114))	('Sca-1', 'Gene', (89, 94))
303958	24332033	Similar to BM-resident GMPs, Lin- CD34+ c-Kit+ TSLP-elicited progenitor-like cells were Sca-1lo, CD16(32)+, CD150int and TSLPR+ (Fig.	('CD16(32)+', 'Var', (97, 106))	('Sca-1', 'Gene', (88, 93))	('CD150', 'Gene', '6504', (108, 113))	('Sca-1', 'Gene', '6310', (88, 93))	('CD150', 'Gene', (108, 113))
303984	24332033	4A-C), IL-25R-deficient mice treated with MC903 exhibited a significant population expansion of TSLP-elicited GMP-like cells (S. Fig.	('MC903', 'Var', (42, 47))	('mice', 'Species', '10090', (24, 28))	('population expansion', 'CPA', (72, 92))	('MC903', 'Chemical', 'MESH:C055085', (42, 47))	('IL-25R', 'Gene', (7, 13))	('GMP', 'Chemical', '-', (110, 113))	('IL-25R', 'Gene', '57890', (7, 13))
304008	24332033	Our findings demonstrate that TSLP elicits a distinct GMP-like cell population in the context of type 2 cytokine responses (Fig.	('GMP', 'Chemical', '-', (54, 57))	('GMP-like cell population', 'MPA', (54, 78))	('elicits', 'Reg', (35, 42))	('TSLP', 'Var', (30, 34))
304026	24332033	Although the causes of EoE remain unknown, a subset of EoE patients possess a gain-of-function single-nucleotide polymorphism (SNP) rs3806932 in TSLP that is associated with elevated TSLP expression and elevated granulocyte responses in the periphery.	('granulocyte responses', 'CPA', (212, 233))	('TSLP', 'Protein', (183, 187))	('expression', 'MPA', (188, 198))	('gain-of-function', 'PosReg', (78, 94))	('EoE', 'Phenotype', 'HP:0410151', (23, 26))	('elevated', 'PosReg', (174, 182))	('rs3806932', 'Var', (132, 141))	('TSLP', 'Gene', (145, 149))	('patients', 'Species', '9606', (59, 67))	('EoE', 'Disease', (55, 58))	('single-nucleotide polymorphism', 'Var', (95, 125))	('rs3806932', 'Mutation', 'rs3806932', (132, 141))	('EoE', 'Phenotype', 'HP:0410151', (55, 58))	('elevated', 'PosReg', (203, 211))
304027	24332033	Critically, allergic patients with the SNP rs3806932 (SNP+) presented with increased frequencies of Lin- CD34+ c-Kit+ cells in their peripheral blood compared to patients lacking a gain-of-function polymorphism (control) (Fig.	('patients', 'Species', '9606', (162, 170))	('allergic', 'Disease', 'MESH:D004342', (12, 20))	('allergic', 'Disease', (12, 20))	('Lin-', 'MPA', (100, 104))	('increased', 'PosReg', (75, 84))	('patients', 'Species', '9606', (21, 29))	('SNP', 'Var', (39, 42))	('rs3806932', 'Mutation', 'rs3806932', (43, 52))
304036	24332033	Exogenous and endogenous TSLP induced the population expansion of murine Lin- CD34+ c-Kit+ progenitor cells in the context of type 2 cytokine-associated infection or inflammation, and disruption of the TSLP-TSLPR signaling pathway prevented the accumulation of progenitor cells in the periphery.	('TSLP', 'Gene', (25, 29))	('inflammation', 'Disease', 'MESH:D007249', (166, 178))	('inflammation', 'Disease', (166, 178))	('murine', 'Species', '10090', (66, 72))	('prevented', 'NegReg', (231, 240))	('disruption', 'Var', (184, 194))
304041	24332033	Employing translational approaches we also demonstrated that EoE patients with a gain-of-function polymorphism associated with elevated expression of TSLP have significantly increased progenitor cell populations in their peripheral blood.	('TSLP', 'Gene', (150, 154))	('expression', 'MPA', (136, 146))	('EoE', 'Phenotype', 'HP:0410151', (61, 64))	('progenitor cell populations', 'CPA', (184, 211))	('gain-of-function', 'PosReg', (81, 97))	('elevated', 'PosReg', (127, 135))	('patients', 'Species', '9606', (65, 73))	('polymorphism', 'Var', (98, 110))	('increased', 'PosReg', (174, 183))
304045	24332033	The data presented in this manuscript identified a previously unrecognized role for TSLP as a critical regulator of EMH and suggest that in addition to activating terminally differentiated cells and promoting the central hematopoiesis of basophils, TSLP regulates EMH and influences the development of multiple myeloid effector cells in peripheral tissues.	('promoting', 'PosReg', (199, 208))	('EMH', 'Phenotype', 'HP:0001978', (264, 267))	('EMH', 'CPA', (264, 267))	('influences', 'Reg', (272, 282))	('TSLP', 'Var', (249, 253))	('regulates', 'Reg', (254, 263))	('hematopoiesis', 'Disease', (221, 234))	('EMH', 'Phenotype', 'HP:0001978', (116, 119))	('hematopoiesis', 'Disease', 'MESH:C536227', (221, 234))
304049	24332033	For example, genetic analyses of patient populations have demonstrated that gain-of-function mutations in the genes encoding TSLP or its receptor are associated with the development of asthma, allergic rhinitis and EoE.	('patient', 'Species', '9606', (33, 40))	('mutations', 'Var', (93, 102))	('asthma', 'Disease', 'MESH:D001249', (185, 191))	('rhinitis', 'Phenotype', 'HP:0012384', (202, 210))	('asthma', 'Disease', (185, 191))	('allergic rhinitis', 'Phenotype', 'HP:0003193', (193, 210))	('EoE', 'Phenotype', 'HP:0410151', (215, 218))	('allergic rhinitis', 'Disease', (193, 210))	('TSLP', 'Gene', (125, 129))	('asthma', 'Phenotype', 'HP:0002099', (185, 191))	('allergic rhinitis', 'Disease', 'MESH:D065631', (193, 210))	('gain-of-function', 'PosReg', (76, 92))	('EoE', 'Disease', (215, 218))
304051	24332033	Critically, our findings demonstrated that patients with a gain-of-function polymorphism in TSLP and suffering from EoE presented with exaggerated frequencies of Lin- CD34+ c-Kit+ cells in their peripheral blood.	('Lin- CD34+ c-Kit+', 'MPA', (162, 179))	('exaggerated', 'PosReg', (135, 146))	('patients', 'Species', '9606', (43, 51))	('gain-of-function', 'PosReg', (59, 75))	('EoE', 'Phenotype', 'HP:0410151', (116, 119))	('polymorphism', 'Var', (76, 88))	('TSLP', 'Gene', (92, 96))
304100	18841362	At dose level 4 (1000 mg/m2 gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropenia >= 7 days).	('1000 mg/m2', 'Var', (17, 27))	('DLT', 'Gene', (83, 86))	('neutropenia', 'Disease', 'MESH:D009503', (96, 107))	('patients', 'Species', '9606', (68, 76))	('gemcitabine', 'Chemical', 'MESH:C056507', (28, 39))	('neutropenia', 'Phenotype', 'HP:0001875', (96, 107))	('DLT', 'Gene', '146059', (83, 86))	('neutropenia', 'Disease', (96, 107))
304101	18841362	At dose level 3 (800 mg/m2 gemcitabine), one patient had a DLT (grade 3 neutropenia >= 7 days) among six evaluable patients.	('neutropenia', 'Disease', (72, 83))	('patients', 'Species', '9606', (115, 123))	('DLT', 'Gene', (59, 62))	('800 mg/m2', 'Var', (17, 26))	('gemcitabine', 'Chemical', 'MESH:C056507', (27, 38))	('neutropenia', 'Phenotype', 'HP:0001875', (72, 83))	('neutropenia', 'Disease', 'MESH:D009503', (72, 83))	('patient', 'Species', '9606', (45, 52))	('DLT', 'Gene', '146059', (59, 62))	('patient', 'Species', '9606', (115, 122))
304131	18841362	Eligible patients were, at baseline, >= 18 years old; had an Eastern Cooperative Oncology Group performance status (PS) <= 2; had biopsy-confirmed locally advanced, unresectable or metastatic solid malignancy; had adequate major organ function [absolute neutrophil count (ANC) >= 1,500/muL, hemoglobin >= 10 g/dL, platelet count > 100,000/muL, estimated creatinine clearance > 50 mL/min, total bilirubin < 1.5 times the upper limit of normal (ULN), aminotransferases < 2.5 times the ULN (or < 5 times the ULN in the case of liver metastasis), alkaline phosphatase < 2.5 times the ULN (or < 5 times the ULN in the case of liver metastasis or < 10 times the ULN in the case of bone metastasis)]; had received <= 3 chemotherapy regimens; had >= 1 non-irradiated measurable lesion; and had a life expectancy >= 12 weeks.	('patients', 'Species', '9606', (9, 17))	('muL', 'Gene', '4591', (339, 342))	('liver metastasis', 'Disease', 'MESH:D009362', (621, 637))	('muL', 'Gene', (339, 342))	('liver metastasis', 'Disease', (621, 637))	('Oncology', 'Phenotype', 'HP:0002664', (81, 89))	('> 50', 'Var', (375, 379))	('malignancy', 'Disease', 'MESH:D009369', (198, 208))	('muL', 'Gene', '4591', (286, 289))	('malignancy', 'Disease', (198, 208))	('liver metastasis', 'Disease', 'MESH:D009362', (524, 540))	('muL', 'Gene', (286, 289))	('liver metastasis', 'Disease', (524, 540))
304164	18841362	At dose level 3 (800 mg/m2 gemcitabine), there was one DLT (grade 3 ANC >= 7 days) among six evaluable patients.	('DLT', 'Gene', (55, 58))	('800 mg/m2', 'Var', (17, 26))	('gemcitabine', 'Chemical', 'MESH:C056507', (27, 38))	('patients', 'Species', '9606', (103, 111))	('DLT', 'Gene', '146059', (55, 58))
304165	18841362	At dose level 4 (1000 mg/m2 gemcitabine), two patients had DLT (grade 4 thrombocytopenia >= 7 days and grade 4 ANC >= 7 days in one patient, and grade 4 ANC >= 7 days in another patient) out of five evaluable patients.	('patient', 'Species', '9606', (46, 53))	('1000 mg/m2', 'Var', (17, 27))	('DLT', 'Gene', (59, 62))	('patients', 'Species', '9606', (46, 54))	('patient', 'Species', '9606', (209, 216))	('thrombocytopenia', 'Disease', 'MESH:D013921', (72, 88))	('patient', 'Species', '9606', (178, 185))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (72, 88))	('gemcitabine', 'Chemical', 'MESH:C056507', (28, 39))	('patients', 'Species', '9606', (209, 217))	('DLT', 'Gene', '146059', (59, 62))	('patient', 'Species', '9606', (132, 139))	('thrombocytopenia', 'Disease', (72, 88))
304196	18841362	FDR gemcitabine is expected to produce more neutropenia than bolus gemcitabine because prolonging the gemcitabine infusion produces higher intracellular concentrations of dFdCTP.	('higher', 'PosReg', (132, 138))	('gemcitabine', 'Chemical', 'MESH:C056507', (102, 113))	('neutropenia', 'Phenotype', 'HP:0001875', (44, 55))	('neutropenia', 'Disease', 'MESH:D009503', (44, 55))	('dFdCTP', 'MPA', (171, 177))	('prolonging', 'PosReg', (87, 97))	('gemcitabine', 'Chemical', 'MESH:C056507', (4, 15))	('FDR', 'Var', (0, 3))	('neutropenia', 'Disease', (44, 55))	('gemcitabine', 'Chemical', 'MESH:C056507', (67, 78))	('dFdCTP', 'Chemical', '-', (171, 177))	('intracellular concentrations', 'MPA', (139, 167))
304233	32201923	Downstaging was associated with longer survival than patients with no change (adenocarcinoma, median: 82 vs. 26 months, p < 0.001; SCC, median: NR vs. 29 months, p < 0.001).	('longer', 'PosReg', (32, 38))	('adenocarcinoma', 'Disease', (78, 92))	('patients', 'Species', '9606', (53, 61))	('adenocarcinoma', 'Disease', 'MESH:D000230', (78, 92))	('Downstaging', 'Var', (0, 11))	('SCC', 'Phenotype', 'HP:0002860', (131, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
304234	32201923	On Cox regression analysis, downstaging was associated with significantly longer survival in adenocarcinoma but not in SCC.	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('downstaging', 'Var', (28, 39))	('longer', 'PosReg', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('survival', 'MPA', (81, 89))	('adenocarcinoma', 'Disease', (93, 107))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
304240	32201923	Whilst its predecessors were based on patients who underwent treatment with surgery alone and did not receive neoadjuvant therapy, the current system uses data from those who have received neoadjuvant treatment, Neoadjuvant therapy has been shown to downstage the initial clinical staging (cTNM) of both tumor invasion (T) and nodal involvement (N).	('TNM', 'Gene', '10178', (291, 294))	('Neoadjuvant therapy', 'Var', (212, 231))	('nodal', 'Gene', (327, 332))	('nodal', 'Gene', '4838', (327, 332))	('tumor invasion', 'Disease', 'MESH:D009361', (304, 318))	('patients', 'Species', '9606', (38, 46))	('TNM', 'Gene', (291, 294))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('downstage', 'NegReg', (250, 259))	('tumor invasion', 'Disease', (304, 318))
304254	32201923	In patients with histology proven locally advanced resectable malignancy without metastases [cT1N+ or cT3N0-3 or tumors of questionable resectability (cT4)], neoadjuvant chemoradiotherapy followed by surgery is the main treatment option.	('tumors', 'Disease', (113, 119))	('malignancy', 'Disease', 'MESH:D009369', (62, 72))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('malignancy', 'Disease', (62, 72))	('metastases', 'Disease', (81, 91))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('metastases', 'Disease', 'MESH:D009362', (81, 91))	('cT3N0-3', 'Var', (102, 109))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
304283	32201923	In patients with adenocarcinoma, downstaging was associated with significantly longer survival than no change (median: 82 vs. 26 months, p < 0.001).	('survival', 'MPA', (86, 94))	('adenocarcinoma', 'Disease', (17, 31))	('downstaging', 'Var', (33, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (17, 31))	('longer', 'PosReg', (79, 85))	('patients', 'Species', '9606', (3, 11))
304285	32201923	In patients with SCC, downstaging was associated with significantly longer survival than no change (median: NR vs. 29, p < 0.001).	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('longer', 'PosReg', (68, 74))	('SCC', 'Disease', (17, 20))	('downstaging', 'Var', (22, 33))	('survival', 'MPA', (75, 83))	('patients', 'Species', '9606', (3, 11))
304291	32201923	In patients with adenocarcinoma, there were no significant differences in survival in patients with and without neoadjuvant therapy for T2N0, T3N0, and T3/4 N1 (Fig.	('adenocarcinoma', 'Disease', (17, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (17, 31))	('patients', 'Species', '9606', (3, 11))	('T3N0', 'Var', (142, 146))	('T3/4', 'Var', (152, 156))	('T2N0', 'Var', (136, 140))	('patients', 'Species', '9606', (86, 94))
304292	32201923	In patients with SCC, median survival was significantly longer for ypT2N0 compared with pT2N0 (median: NR vs. 71 months, p = 0.001) and for ypT3/4 N1 compared with pT3/4 N1 (median: 34 vs. 17 months, p = 0.048).	('median survival', 'MPA', (22, 37))	('ypT3/4 N1', 'Var', (140, 149))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('SCC', 'Disease', (17, 20))	('longer', 'PosReg', (56, 62))	('patients', 'Species', '9606', (3, 11))	('ypT2N0', 'Var', (67, 73))
304318	32201923	Comparison of outcomes between pTNM and ypTNM demonstrated a significant improvement in survival for patients who received neoadjuvant treatment who were T2 N0 for SCC but not for adenocarcinoma.	('TNM', 'Gene', (32, 35))	('patients', 'Species', '9606', (101, 109))	('pTN', 'Gene', '5764', (41, 44))	('improvement', 'PosReg', (73, 84))	('SCC', 'Phenotype', 'HP:0002860', (164, 167))	('pTN', 'Gene', '5764', (31, 34))	('SCC', 'Disease', (164, 167))	('T2 N0', 'Var', (154, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (180, 194))	('TNM', 'Gene', '10178', (42, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('survival', 'MPA', (88, 96))	('TNM', 'Gene', '10178', (32, 35))	('adenocarcinoma', 'Disease', (180, 194))	('pTN', 'Gene', (41, 44))	('TNM', 'Gene', (42, 45))	('pTN', 'Gene', (31, 34))
304322	32201923	It appears that both chemotherapy and chemoradiotherapy have a similar impact in downstaging disease and that downstaging confers a definite survival benefit, although this may be different between SCC and adenocarcinoma.	('downstaging', 'Var', (110, 121))	('SCC', 'Phenotype', 'HP:0002860', (198, 201))	('SCC', 'Disease', (198, 201))	('survival benefit', 'CPA', (141, 157))	('adenocarcinoma', 'Disease', (206, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('downstaging disease', 'Disease', (81, 100))	('adenocarcinoma', 'Disease', 'MESH:D000230', (206, 220))
304326	32201923	This may spare a subgroup of patients the adverse physiological impact of neoadjuvant oncological therapy, in whom, as identified by this paper, neoadjuvant therapy leads to static or worsening stage with no apparent improvement in survival.	('patients', 'Species', '9606', (29, 37))	('worsening', 'NegReg', (184, 193))	('neoadjuvant', 'Var', (145, 156))
304353	32560416	We hypothesized that partial or complete vagal denervation of the lung, bronchi, and pulmonary vasculature, that is typical for oncologic esophagectomies, causes a dysbalance of the autonomic nervous system innervating pulmonary structures and eventually impairs gas exchange.	('dysbalance of the autonomic nervous system', 'Phenotype', 'HP:0012332', (164, 206))	('partial or complete vagal', 'Var', (21, 46))	('pulmonary vasculature', 'Disease', (85, 106))	('vagal denervation', 'Phenotype', 'HP:0002886', (41, 58))	('dysbalance', 'MPA', (164, 174))	('impairs', 'NegReg', (255, 262))	('denervation', 'NegReg', (47, 58))	('gas exchange', 'MPA', (263, 275))	('causes', 'Reg', (155, 161))	('pulmonary vasculature', 'Disease', 'MESH:C565633', (85, 106))
304447	32560416	However, blood loss negatively correlated with P/FR on POD 3 in the OE group (see Table 6).	('negatively', 'NegReg', (20, 30))	('blood loss', 'Disease', (9, 19))	('blood loss', 'Disease', 'MESH:D006473', (9, 19))	('P/FR', 'Var', (47, 51))
304516	32373526	Bulky LNs was associated with poorer prognosis in ESCC patients undergoing definitive chemo-radiotherapy.	('patients', 'Species', '9606', (55, 63))	('SCC', 'Phenotype', 'HP:0002860', (51, 54))	('Bulky LNs', 'Var', (0, 9))	('ESCC', 'Disease', (50, 54))
304519	32373526	Our data suggest that response to CRT was associated with significantly improved survival in non-surgical patients with esophageal carcinoma.	('CRT', 'Gene', '799', (34, 37))	('esophageal carcinoma', 'Disease', (120, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('CRT', 'Gene', (34, 37))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (120, 140))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (120, 140))	('improved', 'PosReg', (72, 80))	('survival', 'MPA', (81, 89))	('patients', 'Species', '9606', (106, 114))	('response', 'Var', (22, 30))
304521	32373526	divided 143 metastatic LNs from 59 patients treated with dCRT into 4 groups and found that MTV-G4 (which had the largest MTV) had the lowest CR rate.	('CR rate', 'CPA', (141, 148))	('MTV-G4', 'Chemical', '-', (91, 97))	('CRT', 'Gene', (58, 61))	('CR', 'Chemical', '-', (58, 60))	('lowest', 'NegReg', (134, 140))	('MTV', 'Chemical', '-', (121, 124))	('CR', 'Chemical', '-', (141, 143))	('MTV', 'Chemical', '-', (91, 94))	('patients', 'Species', '9606', (35, 43))	('MTV-G4', 'Var', (91, 97))	('CRT', 'Gene', '799', (58, 61))
304524	32373526	According to the INT 0123 phase III trial, 50.40 Gy is the recommended CRT dose in the North America guideline.	('50.40 Gy', 'Var', (43, 51))	('CRT', 'Gene', (71, 74))	('CRT', 'Gene', '799', (71, 74))
304542	32373526	performed a retrospective evaluation of the failure patterns of 56 subjects with T4M0 and found only 1 patient had experienced isolated elective nodal failure.	('patient', 'Species', '9606', (103, 110))	('nodal failure', 'Disease', (145, 158))	('nodal failure', 'Disease', 'MESH:D006333', (145, 158))	('T4M0', 'Var', (81, 85))
304593	28285387	In the nonsurgical complication risk model, need of assistance with activities of daily living, COPD, previous CVD, ASA score class 3 and over, presence of esophageal cancer, and body mass index greater than 25 were selected as common risk factors for pneumonia, prolonged ventilation over 48 h, and renal failure.	('COPD', 'Phenotype', 'HP:0006510', (96, 100))	('COPD', 'Disease', 'MESH:D029424', (96, 100))	('pneumonia', 'Phenotype', 'HP:0002090', (252, 261))	('ASA', 'Chemical', '-', (116, 119))	('renal failure', 'Phenotype', 'HP:0000083', (300, 313))	('assistance with activities of daily living', 'Phenotype', 'HP:0031058', (52, 94))	('esophageal cancer', 'Disease', (156, 173))	('COPD', 'Disease', (96, 100))	('pneumonia', 'Disease', (252, 261))	('pneumonia', 'Disease', 'MESH:D011014', (252, 261))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('renal failure', 'Disease', 'MESH:D051437', (300, 313))	('presence', 'Var', (144, 152))	('renal failure', 'Disease', (300, 313))	('need of assistance with activities of daily living', 'Phenotype', 'HP:0031058', (44, 94))
304596	28285387	The C-index, a measure of model discrimination represented by the area under the receiver operating characteristic (ROC) curve, was 0.635 for SSI (95% CI, 0.613-0.657; p < 0.001), 0.614 for anastomotic leak (95% CI, 0.585-0.643; p < 0.001), 0.657 for pancreatic fistula (95% CI, 0.628-0.686; p < 0.001), 0.726 for pneumonia (95% CI, 0.697-0.755; p < 0.001), 0.758 for prolonged ventilation over 48 h (95% CI, 0.717-0.799; p < 0.001), and 0.795 for renal failure (95% CI, 0.749-0.841; p < 0.001) (Fig.	('pancreatic fistula', 'Phenotype', 'HP:0100844', (251, 269))	('0.758', 'Var', (358, 363))	('anastomotic leak', 'Disease', (190, 206))	('renal failure', 'Disease', 'MESH:D051437', (448, 461))	('renal failure', 'Disease', (448, 461))	('pneumonia', 'Disease', (314, 323))	('0.657', 'Var', (241, 246))	('pneumonia', 'Disease', 'MESH:D011014', (314, 323))	('0.795', 'Var', (438, 443))	('0.614', 'Var', (180, 185))	('renal failure', 'Phenotype', 'HP:0000083', (448, 461))	('pancreatic fistula', 'Disease', 'MESH:D010185', (251, 269))	('pancreatic fistula', 'Disease', (251, 269))	('anastomotic leak', 'Disease', 'MESH:D057868', (190, 206))	('0.726', 'Var', (304, 309))	('pneumonia', 'Phenotype', 'HP:0002090', (314, 323))
304598	28285387	The C-index was 0.634 for SSI (95% CI, 0.618-0.649; p < 0.001), 0.600 for anastomotic leak (95% CI, 0.581-0.619; p < 0.001), 0.694 for pancreatic fistula (95% CI, 0.675-0.713; p < 0.001), 0.732 for pneumonia (95% CI, 0.713-0.752; p < 0.001), 0.750 for prolonged ventilation over 48 h (95% CI 0.720-0.779; p < 0.001), and 0.807 for renal failure (95% CI, 0.772-0.841; p < 0.001).	('pancreatic fistula', 'Disease', 'MESH:D010185', (135, 153))	('pancreatic fistula', 'Disease', (135, 153))	('anastomotic leak', 'Disease', 'MESH:D057868', (74, 90))	('renal failure', 'Disease', (331, 344))	('pneumonia', 'Phenotype', 'HP:0002090', (198, 207))	('renal failure', 'Phenotype', 'HP:0000083', (331, 344))	('pancreatic fistula', 'Phenotype', 'HP:0100844', (135, 153))	('0.750', 'Var', (242, 247))	('anastomotic leak', 'Disease', (74, 90))	('pneumonia', 'Disease', (198, 207))	('pneumonia', 'Disease', 'MESH:D011014', (198, 207))	('0.694', 'Var', (125, 130))	('0.807', 'Var', (321, 326))	('renal failure', 'Disease', 'MESH:D051437', (331, 344))	('0.732', 'Var', (188, 193))	('0.600', 'Var', (64, 69))	('SSI', 'Disease', (26, 29))
304679	27308066	Epidemiologic results indicate that long-term exposure to PM2.5 increases mortality rates in the general population and contributes to lung cancer incidence.	('contributes', 'Reg', (120, 131))	('PM2.5', 'Var', (58, 63))	('mortality', 'CPA', (74, 83))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('increases', 'PosReg', (64, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
304744	27308066	Anti-H. pylori drugs or eradication of H. pylori has been shown to reduce gastric cancer.	('reduce', 'NegReg', (67, 73))	('H. pylori', 'Species', '210', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('gastric cancer', 'Disease', (74, 88))	('eradication', 'Var', (24, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('H. pylori', 'Gene', (39, 48))	('H. pylori', 'Species', '210', (5, 14))	('reduce gastric cancer', 'Phenotype', 'HP:0006753', (67, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))
304751	27308066	However, vaccination against HBV can lower HBV infection and presumably the risk of liver cancer.	('HBV infection', 'Disease', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HBV infection', 'Disease', 'MESH:D006509', (43, 56))	('vaccination', 'Var', (9, 20))	('liver cancer', 'Phenotype', 'HP:0002896', (84, 96))	('liver cancer', 'Disease', 'MESH:D006528', (84, 96))	('lower', 'NegReg', (37, 42))	('liver cancer', 'Disease', (84, 96))	('HBV', 'Gene', (29, 32))
304781	27308066	examined a combination of case-control and cohort studies and reported that alcohol consumption was associated with an increased risk of esophageal and gastric cancers but not lung cancer.	('alcohol consumption', 'Var', (76, 95))	('alcohol', 'Chemical', 'MESH:D000438', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (137, 167))	('gastric cancer', 'Phenotype', 'HP:0012126', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lung cancer', 'Disease', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('gastric cancers', 'Phenotype', 'HP:0012126', (152, 167))
304783	27308066	Notably, abstaining from alcohol has been shown to decrease cancer risk.	('abstaining', 'Var', (9, 19))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('alcohol', 'Chemical', 'MESH:D000438', (25, 32))	('decrease', 'NegReg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
304814	27308066	Physical activity has also been associated with a decreased risk of colon cancer and longer survival.	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('Physical activity', 'Var', (0, 17))	('decreased', 'NegReg', (50, 59))	('colon cancer', 'Disease', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
304835	24168184	The aggressive nature of cancer is associated to the abnormalities of a series molecular, including activation of tumor oncogenes, inactivation of tumor suppressor genes, reactivation of telomerase, and overexpression of growth factors and their receptors.	('activation', 'PosReg', (100, 110))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('abnormalities', 'Var', (53, 66))	('growth', 'Protein', (221, 227))	('tumor', 'Disease', (114, 119))	('reactivation', 'MPA', (171, 183))	('aggressive', 'Disease', (4, 14))	('overexpression', 'PosReg', (203, 217))	('inactivation', 'Var', (131, 143))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('telomerase', 'Protein', (187, 197))
304838	24168184	Several lines of evidence have revealed that KLF4 acts as tumor suppressor in GI cancer, and it negatively regulates cell proliferation and promotes tissue differentiation, and loss of KLF4 expression is a predictor of poor survival.	('tissue differentiation', 'CPA', (149, 171))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('negatively', 'NegReg', (96, 106))	('GI cancer', 'Disease', 'MESH:D009369', (78, 87))	('promotes', 'PosReg', (140, 148))	('cell proliferation', 'CPA', (117, 135))	('GI cancer', 'Phenotype', 'HP:0007378', (78, 87))	('KLF4', 'Gene', (185, 189))	('loss', 'Var', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('GI cancer', 'Disease', (78, 87))	('regulates', 'MPA', (107, 116))
304850	24168184	Besides canonical Wnt signaling pathway, disassembly of the E-cadherin adhesion complex can also lead to the displacement of p120, which represses the small G protein RhoA and results in the activation of Cdc42 and Rac1.	('Rac1', 'Gene', (215, 219))	('Rac1', 'Gene', '5879', (215, 219))	('p120', 'Gene', '1500', (125, 129))	('Cdc42', 'Gene', '998', (205, 210))	('E-cadherin', 'Gene', (60, 70))	('activation', 'PosReg', (191, 201))	('E-cadherin', 'Gene', '999', (60, 70))	('RhoA', 'Gene', (167, 171))	('Cdc42', 'Gene', (205, 210))	('displacement', 'Var', (109, 121))	('RhoA', 'Gene', '387', (167, 171))	('represses', 'NegReg', (137, 146))	('p120', 'Gene', (125, 129))
304864	24168184	Besides these clinical evidence, by an established system in RKO colon cancer cells, which had an inducible promoter of Klf4, Dang et al demonstrated that overexpression of KLF4 reduced colony formation, in vivo tumrigenecity, and cell migration and invasion.	('colon cancer', 'Disease', (65, 77))	('colony formation', 'CPA', (186, 202))	('invasion', 'CPA', (250, 258))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('KLF4', 'Var', (173, 177))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('overexpression', 'PosReg', (155, 169))	('reduced', 'NegReg', (178, 185))	('tumrigenecity', 'CPA', (212, 225))
304866	24168184	For example, in our previous studies, disruption of Klf4 in villin-positive antral mucosa cells (Villin-Cre(+);Klf4(fl/fl) mice) significantly increased the incidence of gastric tumors.	('Villin-Cre(+);Klf4', 'Gene', (97, 115))	('increased', 'PosReg', (143, 152))	('gastric tumors', 'Phenotype', 'HP:0006753', (170, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('Klf4', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('gastric tumors', 'Disease', (170, 184))	('disruption', 'Var', (38, 48))	('gastric tumors', 'Disease', 'MESH:D013274', (170, 184))	('Villin-Cre(+);Klf4', 'Gene', '16600', (97, 115))	('mice', 'Species', '10090', (123, 127))
304868	24168184	In another study, Katz et al generated gastric epithelia-specific Klf4 ablation mouse models and found that Klf4 mutant mice presented with increased proliferation and altered differentiation in the gastric epithelia, and they further demonstrated that p21WAF1/CIP1 was an in vivo target of Klf4.	('gastric epithelia', 'Disease', (39, 56))	('altered', 'Reg', (168, 175))	('mice', 'Species', '10090', (120, 124))	('Klf4', 'Gene', (108, 112))	('gastric epithelia', 'Disease', (199, 216))	('differentiation', 'CPA', (176, 191))	('mouse', 'Species', '10090', (80, 85))	('p21', 'Gene', '1026', (253, 256))	('gastric epithelia', 'Disease', 'MESH:D013274', (39, 56))	('p21', 'Gene', (253, 256))	('mutant', 'Var', (113, 119))	('increased', 'PosReg', (140, 149))	('gastric epithelia', 'Disease', 'MESH:D013274', (199, 216))
304874	24168184	But the molecular basis of the KLF4 inactivation in GI cancer is not fully demonstrated.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('GI cancer', 'Disease', (52, 61))	('GI cancer', 'Disease', 'MESH:D009369', (52, 61))	('inactivation', 'Var', (36, 48))	('GI cancer', 'Phenotype', 'HP:0007378', (52, 61))
304876	24168184	In gastric cancer, we provided evidence that promoter hypermethylation and hemizygous deletion contributed to the low levels of KLF4.	('hemizygous deletion', 'Var', (75, 94))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('low', 'NegReg', (114, 117))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('KLF4', 'MPA', (128, 132))
304878	24168184	Their further studies revealed that the decreased expression of KLF4 was the result of mutation of the putative tumor suppressor homeodomain protein, CDX2.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CDX2', 'Gene', (150, 154))	('CDX2', 'Gene', '1045', (150, 154))	('tumor', 'Disease', (112, 117))	('mutation', 'Var', (87, 95))	('decreased', 'NegReg', (40, 49))	('expression', 'MPA', (50, 60))
304879	24168184	In another study, Zhao et al provided evidence that the 5'-untranslated region of KLF4 was hypermethylated in colon cancer.	('colon cancer', 'Disease', (110, 122))	('KLF4', 'Gene', (82, 86))	('hypermethylated', 'Var', (91, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('colon cancer', 'Disease', 'MESH:D015179', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
304888	24168184	In mouse models, Katz et al found that Klf4 mutant mice showed increased proliferation and altered differentiation of the gastric epithelia, and p21WAF1/CIP1 was an in vivo target of KLF4.	('p21', 'Gene', '1026', (145, 148))	('increased', 'PosReg', (63, 72))	('mouse', 'Species', '10090', (3, 8))	('mice', 'Species', '10090', (51, 55))	('gastric epithelia', 'Disease', (122, 139))	('proliferation', 'CPA', (73, 86))	('gastric epithelia', 'Disease', 'MESH:D013274', (122, 139))	('p21', 'Gene', (145, 148))	('altered', 'Reg', (91, 98))	('differentiation', 'CPA', (99, 114))	('Klf4', 'Gene', (39, 43))	('mutant', 'Var', (44, 50))
304904	24168184	In gastric epithelia-specific Klf4 ablation mouse models, more than 50% decrease of mature zymogenic cells, but 4-fold increase in the number of TFF2/SP-positive mucue cells and 2-fold increase in the number of pit cells were found.	('increase', 'PosReg', (185, 193))	('gastric epithelia', 'Disease', 'MESH:D013274', (3, 20))	('TFF2', 'Gene', '21785', (145, 149))	('TFF2', 'Gene', (145, 149))	('pit cells', 'CPA', (211, 220))	('gastric epithelia', 'Disease', (3, 20))	('mature', 'CPA', (84, 90))	('SP', 'Chemical', 'MESH:C000604007', (150, 152))	('increase', 'PosReg', (119, 127))	('decrease', 'NegReg', (72, 80))	('ablation', 'Var', (35, 43))	('mouse', 'Species', '10090', (44, 49))
304911	24168184	Furthermore, in cancer stem cells, Leng Z et al provided evidence that KLF4 was overexpressed only in spheroid cells and knockdown KLF4 in cancer stem cells led to significant decrease of cancer stem cell markers, resistance to chemicals, invasion, migration, and tumorigenesis both in vitro and in vivo.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('decrease of cancer', 'Disease', 'MESH:D009369', (176, 194))	('tumor', 'Disease', (264, 269))	('cancer', 'Disease', (16, 22))	('resistance', 'CPA', (214, 224))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('knockdown', 'Var', (121, 130))	('invasion', 'CPA', (239, 247))	('decrease of cancer', 'Disease', (176, 194))	('migration', 'CPA', (249, 258))	('cancer', 'Disease', (188, 194))	('KLF4', 'Gene', (131, 135))	('cancer', 'Disease', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))
304914	24168184	Further mechanism research demonstrated that KLF4 was able to bind and suppress the activity of the Slug promoter, and ectopic Slug expression partially revert the KLF4-mediated phenotypes.	('Slug', 'Gene', '6591', (127, 131))	('revert', 'NegReg', (153, 159))	('bind', 'Interaction', (62, 66))	('Slug', 'Gene', (127, 131))	('Slug', 'Gene', '6591', (100, 104))	('ectopic', 'Var', (119, 126))	('activity', 'MPA', (84, 92))	('Slug', 'Gene', (100, 104))	('suppress', 'NegReg', (71, 79))
304929	24168184	Smad signaling also represses the expression of the microRNA-200 family through leading to the expression of ZEB transcription factors, afterwards, microRNA-200 family further increases the expression of ZEB at protein level and mRNA level in a feedback loop.	('microRNA-200 family', 'Var', (148, 167))	('ZEB', 'Gene', (109, 112))	('ZEB', 'Gene', (204, 207))	('represses', 'NegReg', (20, 29))	('ZEB', 'Gene', '9839', (204, 207))	('leading', 'Reg', (80, 87))	('increases', 'PosReg', (176, 185))	('Smad', 'Gene', '4089;4089', (0, 4))	('ZEB', 'Gene', '9839', (109, 112))	('expression', 'MPA', (190, 200))	('Smad', 'Gene', (0, 4))	('expression', 'MPA', (95, 105))
304938	24168184	TGF-beta and bone morphogenetic proteins (BMPs), also belongs to TGF-beta superfamily, down-regulated KLF4 via induction of microRNA-143 and microRNA-145 in modulation of vascular smooth muscle cell phenotype.	('TGF-beta', 'Gene', (65, 73))	('vascular smooth muscle cell phenotype', 'CPA', (171, 208))	('down-regulated', 'NegReg', (87, 101))	('KLF4', 'Protein', (102, 106))	('modulation', 'Reg', (157, 167))	('microRNA-145', 'Var', (141, 153))	('TGF-beta', 'Gene', '7040', (0, 8))	('TGF-beta', 'Gene', '7040', (65, 73))	('microRNA-143', 'Var', (124, 136))	('TGF-beta', 'Gene', (0, 8))
304939	24168184	Together these findings provide convincing evidence that there was a tight crosstalk between KLF4 and TGF-beta signaling pathways, and KLF4 may play a central role in tumor EMT through interaction with TGF-beta signaling.	('TGF-beta', 'Gene', (202, 210))	('crosstalk', 'Reg', (75, 84))	('KLF4', 'Pathway', (93, 97))	('interaction', 'Interaction', (185, 196))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('KLF4', 'Var', (135, 139))	('play', 'Reg', (144, 148))	('TGF-beta', 'Gene', '7040', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('TGF-beta', 'Gene', '7040', (202, 210))	('tumor', 'Disease', (167, 172))	('TGF-beta', 'Gene', (102, 110))
304955	24168184	Sellak H et al recently revealed that KLF4 antagonized beta-catenin/TCF binding in a series of normal and cancer cells, and the inhibition was concentration-dependent.	('beta-catenin', 'Gene', (55, 67))	('KLF4', 'Var', (38, 42))	('binding', 'Interaction', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('beta-catenin', 'Gene', '1499', (55, 67))	('cancer', 'Disease', (106, 112))	('TCF', 'Gene', '3172', (68, 71))	('antagonized', 'NegReg', (43, 54))	('TCF', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
304957	24168184	When colorectal cancer tumor suppressor adenomatous polyposis coli (APC) is inactivated by mutation, Wnt signaling is unimpeded with the nuclear accumulation of beta-catenin.	('beta-catenin', 'Gene', '1499', (161, 173))	('adenomatous polyposis coli', 'Disease', (40, 66))	('mutation', 'Var', (91, 99))	('APC', 'Phenotype', 'HP:0005227', (68, 71))	('colorectal cancer tumor', 'Disease', 'MESH:D015179', (5, 28))	('APC', 'Disease', 'MESH:D011125', (68, 71))	('APC', 'Disease', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (5, 22))	('colorectal cancer tumor', 'Disease', (5, 28))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (40, 66))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (40, 66))	('beta-catenin', 'Gene', (161, 173))
305025	21349154	The biological consequences of reduced augurin expression were evaluated by characterizing the CNS phenotype caused by Ecrg4 gene knockdown in developing zebrafish embryos.	('zebrafish', 'Species', '7955', (154, 163))	('augurin', 'Protein', (39, 46))	('reduced', 'NegReg', (31, 38))	('CNS', 'Disease', (95, 98))	('knockdown', 'Var', (130, 139))	('Ecrg4', 'Gene', (119, 124))	('expression', 'MPA', (47, 57))
305039	21349154	The fact that the Ecrg4 gene is down-regulated by hyper-methylation in many cancers suggests that its epigenetic control plays a role in the transformation of normal cells to cancer.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('hyper-methylation', 'Var', (50, 67))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Disease', (175, 181))	('Ecrg4 gene', 'Gene', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('down-regulated', 'NegReg', (32, 46))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
305043	21349154	If correct, the canonic epigenetic methylation of the Ecrg4 gene that characterizes augurin production may forecast the progenitor response to injury, and may therefore implicate the CP in defining the regenerative capacity of the CNS.	('progenitor response to injury', 'CPA', (120, 149))	('rat', 'Species', '10116', (208, 211))	('Ecrg4', 'Gene', (54, 59))	('epigenetic methylation', 'Var', (24, 46))	('forecast', 'PosReg', (107, 115))	('implicate', 'Reg', (169, 178))	('regenerative capacity', 'CPA', (202, 223))
305112	21349154	CPe and HEK cells were transduced with AdEcrg4 or AdGFP at a multiplicity of infection (MOI) of 100.	('HEK', 'CellLine', 'CVCL:M624', (8, 11))	('AdEcrg4', 'Var', (39, 46))	('AdGFP', 'Gene', (50, 55))	('infection', 'Disease', (77, 86))	('infection', 'Disease', 'MESH:D007239', (77, 86))
305130	21349154	Whereas the Ecrg4 open reading frame encodes a 148 amino acid protein however, post translational processing can potentially produce 8 peptides (Figure 1B) that include the (1) the full length Ecrg4 protein, (2) cleavage of the leader peptide from ECRG4 to generate the fragment called augurin, and two others that we termed ecilin (EC) and argilin (RG) that are predicted to be generated by furin-like cleavage and another two forms of augurin and argilin that are predicted from a thrombin consensus cleavage site that would release the last 16 amino acids of the carboxyl terminus peptide (Figure 1) to generate C 16-augurin and C 16-argilin.	('thrombin', 'Gene', '29251', (483, 491))	('C 16-argilin', 'MPA', (632, 644))	('rat', 'Species', '10116', (610, 613))	('argilin', 'Chemical', '-', (341, 348))	('rat', 'Species', '10116', (383, 386))	('argilin', 'Chemical', '-', (637, 644))	('argilin', 'Chemical', '-', (449, 456))	('thrombin', 'Gene', (483, 491))	('rat', 'Species', '10116', (261, 264))	('cleavage', 'Var', (212, 220))
305141	21349154	Unlike neurohypophyseal extracts (A. Roberton, personal communication and), immunoblotting did not reveal significant presence of the further processed peptides (Figure 1) including ecilin, the peptide corresponding to Ecrg4 amino acids 31-70, or argilin, the peptide corresponding to the C-terminus Ecrg4 amino acids 71-148 (Figure 1).	('Ecrg4 amino acids 71-148', 'Var', (300, 324))	('neurohypophyseal', 'Disease', 'MESH:D010900', (7, 23))	('argilin', 'Chemical', '-', (247, 254))	('neurohypophyseal', 'Disease', (7, 23))
305159	21349154	However, the number of BrdU positive cells was significantly decreased with AdEcrg4 injections (Figures 5C and 5D).	('decreased', 'NegReg', (61, 70))	('BrdU', 'Chemical', 'MESH:D001973', (23, 27))	('AdEcrg4 injections', 'Var', (76, 94))	('BrdU', 'Protein', (23, 27))
305165	21349154	The AdEcrg4 -treated rat brains however were virtually devoid of nestin staining in both SVZ (Panel 6B) ependyma and subependyma (Panel 6D).	('ependyma and subependyma', 'Disease', 'None', (104, 128))	('devoid', 'NegReg', (55, 61))	('nestin', 'Protein', (65, 71))	('rat', 'Species', '10116', (21, 24))	('AdEcrg4', 'Var', (4, 11))
305169	21349154	To this end, Ecrg4a morpholinos (MOs) were injected into developing zebrafish embryos at 1-2 cell stages using either a control MO (Figure 7A1) or an antisense Ecrg4a MOs (Figure 7A2).	('zebrafish', 'Species', '7955', (68, 77))	('Ecrg4a', 'Gene', '791762', (160, 166))	('morpholino', 'Chemical', 'MESH:D060172', (20, 30))	('Ecrg4a', 'Gene', (160, 166))	('antisense', 'Var', (150, 159))	('Ecrg4a', 'Gene', '791762', (13, 19))	('Ecrg4a', 'Gene', (13, 19))
305171	21349154	A second Ecrg4a MO was used to confirm and validate the reproducibility of the Ecrg4 knockdown phenotype (not shown).	('Ecrg4', 'Gene', (79, 84))	('knockdown', 'Var', (85, 94))	('Ecrg4a', 'Gene', '791762', (9, 15))	('Ecrg4a', 'Gene', (9, 15))
305177	21349154	Taken together, these data suggest that Ecrg4 gene knockdown dysinhibits cell proliferation of GFAP-positive cells.	('cell proliferation of GFAP-positive cells', 'CPA', (73, 114))	('Ecrg4', 'Gene', (40, 45))	('rat', 'Species', '10116', (85, 88))	('knockdown', 'Var', (51, 60))
305194	21349154	The hydrocephalus-like phenotype observed in developing zebrafish after gene knockdown could therefore still support the hypothesis that one or more of the peptide products of Ecrg4 are involved in regulation of fluid balance.	('Ecrg4', 'Gene', (176, 181))	('zebrafish', 'Species', '7955', (56, 65))	('knockdown', 'Var', (77, 86))	('hydrocephalus', 'Disease', (4, 17))	('involved', 'Reg', (186, 194))	('hydrocephalus', 'Phenotype', 'HP:0000238', (4, 17))	('hydrocephalus', 'Disease', 'MESH:D006849', (4, 17))
305207	21349154	As Ecrg4 gene expression is thought to be epigenetically regulated in cancer by hyper-methylation, it is particularly interesting to speculate that, in addition to mechanisms like transcription factors that control the response to injury, epigenetic dosing of the Ecrg4 gene expression by methylation might serve to regulate augurin production under physiological circumstances.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('epigenetic dosing', 'Var', (239, 256))	('Ecrg4', 'Gene', (264, 269))	('regulate', 'Reg', (316, 324))	('augurin production', 'MPA', (325, 343))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))	('Ecrg4', 'Gene', (3, 8))
305208	21349154	If so, the data presented here predict that these epigenetic changes would dose subependymal progenitor cell responsiveness after CNS injury.	('epigenetic changes', 'Var', (50, 68))	('subependymal', 'Disease', (80, 92))	('subependymal', 'Disease', 'MESH:D018315', (80, 92))	('dose', 'PosReg', (75, 79))
305211	21349154	The facts that (1) Ecrg4 expression is decreased following CNS injury, (2) Ecrg4 over-expression is growth inhibitory in the subependyma and (3) Ecrg4 gene knockdown induces a hydrocephalus phenotype in development, also suggest a novel role for augurin in the CP/ependymal biology.	('Ecrg4', 'Gene', (145, 150))	('subependyma', 'Disease', 'None', (125, 136))	('CP/ependymal', 'Disease', (261, 273))	('knockdown', 'Var', (156, 165))	('hydrocephalus', 'Phenotype', 'HP:0000238', (176, 189))	('CP/ependymal', 'Disease', 'MESH:C566991', (261, 273))	('expression', 'MPA', (25, 35))	('Ecrg4', 'Gene', (19, 24))	('Ecrg4', 'Gene', (75, 80))	('hydrocephalus', 'Disease', 'MESH:D006849', (176, 189))	('induces', 'Reg', (166, 173))	('subependyma', 'Disease', (125, 136))	('decreased', 'NegReg', (39, 48))	('hydrocephalus', 'Disease', (176, 189))	('over-expression', 'PosReg', (81, 96))
305356	27189061	qPCR were performed to examine expression level of stemness factors, mesenchymal markers, ATP-binding cassette (ABC) transporters, STAT3, miR-181b, CYLD.	('STAT3', 'Gene', (131, 136))	('ATP-binding', 'MPA', (90, 101))	('miR-181b', 'Chemical', '-', (138, 146))	('expression', 'MPA', (31, 41))	('CYLD', 'Gene', (148, 152))	('miR-181b', 'Var', (138, 146))	('CYLD', 'Gene', '1540', (148, 152))	('STAT3', 'Gene', '6774', (131, 136))
305363	27189061	Moreover, STAT3 directly activated miR-181b transcription in SFCs and miR-181b then potentiated p-STAT3 activity.	('transcription', 'MPA', (44, 57))	('potentiated', 'PosReg', (84, 95))	('STAT3', 'Gene', '6774', (98, 103))	('miR-181b', 'Chemical', '-', (35, 43))	('STAT3', 'Gene', (98, 103))	('STAT3', 'Gene', '6774', (10, 15))	('miR-181b', 'Chemical', '-', (70, 78))	('activated', 'PosReg', (25, 34))	('miR-181b', 'Var', (70, 78))	('miR-181b', 'Gene', (35, 43))	('STAT3', 'Gene', (10, 15))
305390	27189061	Additionally, miR-181b was expressed more significantly in papillary thyroid carcinoma than in counterpart normal tissue.	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (59, 86))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (59, 86))	('miR-181b', 'Chemical', '-', (14, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('miR-181b', 'Var', (14, 22))	('papillary thyroid carcinoma', 'Disease', (59, 86))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (69, 86))
305397	27189061	Finally, in clinical human ESCC there is a positive relationship between STAT3 and miR-181b and miR-181b is inversely association with CYLD.	('positive', 'PosReg', (43, 51))	('miR-181b', 'Chemical', '-', (96, 104))	('human', 'Species', '9606', (21, 26))	('clinical', 'Species', '191496', (12, 20))	('miR-181b', 'Chemical', '-', (83, 91))	('STAT3', 'Gene', (73, 78))	('miR-181b', 'Var', (96, 104))	('miR-181b', 'Var', (83, 91))	('association', 'Interaction', (118, 129))	('CYLD', 'Gene', (135, 139))	('inversely', 'NegReg', (108, 117))	('CYLD', 'Gene', '1540', (135, 139))	('STAT3', 'Gene', '6774', (73, 78))
305416	27189061	Tumors of SFC xenografts were three-fold larger and more vascular than in the parental xenografts (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SFC', 'Var', (10, 13))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('more', 'PosReg', (52, 56))	('vascular', 'CPA', (57, 65))
305424	27189061	Western blot analysis demonstrated that the p-STAT3 expression level in SFCs was higher than that in Eca109 parental cells (Fig.	('STAT3', 'Gene', (46, 51))	('SFCs', 'Var', (72, 76))	('higher', 'PosReg', (81, 87))	('STAT3', 'Gene', '6774', (46, 51))
305431	27189061	However, the relationship between STAT3 and miR-181b has not been investigated in SFCs.	('miR-181b', 'Chemical', '-', (44, 52))	('STAT3', 'Gene', (34, 39))	('STAT3', 'Gene', '6774', (34, 39))	('miR-181b', 'Var', (44, 52))
305443	27189061	Concordantly, forced expression of STAT3 increased the expression levels of primary-miR-181b and mature miR-181b (Fig.	('STAT3', 'Gene', (35, 40))	('increased', 'PosReg', (41, 50))	('expression levels', 'MPA', (55, 72))	('miR-181b', 'Chemical', '-', (104, 112))	('miR-181b', 'Chemical', '-', (84, 92))	('miR-181b', 'Var', (104, 112))	('STAT3', 'Gene', '6774', (35, 40))	('primary-miR-181b', 'Var', (76, 92))
305445	27189061	We found that the expression level of miR-181b in Eca109 SFCs increased significantly compared with in the parental cells (Fig.	('increased', 'PosReg', (62, 71))	('expression level', 'MPA', (18, 34))	('Eca109', 'Gene', (50, 56))	('miR-181b', 'Var', (38, 46))	('miR-181b', 'Chemical', '-', (38, 46))
305448	27189061	Moreover, SFCs transfected with the miR-181b mimic increased ABCB1, ABCG2, and MRP1 levels by more than two-fold (Fig.	('ABCB1', 'Gene', (61, 66))	('MRP1', 'Gene', '5243', (79, 83))	('ABCB1', 'Gene', '5243', (61, 66))	('ABCG2', 'Gene', '9429', (68, 73))	('increased', 'PosReg', (51, 60))	('miR-181b', 'Chemical', '-', (36, 44))	('MRP1', 'Gene', (79, 83))	('ABCG2', 'Gene', (68, 73))	('miR-181b', 'Var', (36, 44))
305455	27189061	4e), suggesting that miR-181b promotes the proliferation and colony formation of SFCs.	('promotes', 'PosReg', (30, 38))	('miR-181b', 'Var', (21, 29))	('miR-181b', 'Chemical', '-', (21, 29))	('colony formation', 'CPA', (61, 77))	('proliferation', 'CPA', (43, 56))
305470	27189061	According to previous studies, the 3'-untranslated region (UTR) of CYLD was identified as a target of miR-181b.	('miR-181b', 'Chemical', '-', (102, 110))	('miR-181b', 'Var', (102, 110))	('CYLD', 'Gene', '1540', (67, 71))	('CYLD', 'Gene', (67, 71))
305475	27189061	These results suggest that the reduction in CYLD is regulated at the post-transcriptional level and that the CYLD 3'-UTR is a target of miR-181b in Eca109 SFCs.	('CYLD', 'Gene', (44, 48))	('CYLD', 'Gene', '1540', (109, 113))	('CYLD', 'Gene', '1540', (44, 48))	('miR-181b', 'Chemical', '-', (136, 144))	('miR-181b', 'Var', (136, 144))	('CYLD', 'Gene', (109, 113))
305478	27189061	To determine whether CYLD is direct target of miR-181b, we engineered the 3'-UTR fragments, in which wild-type and mutant binding sites were inserted into the region immediately downstream of the luciferase reporter gene (Fig.	('CYLD', 'Gene', '1540', (21, 25))	('mutant', 'Var', (115, 121))	('CYLD', 'Gene', (21, 25))	('miR-181b', 'Chemical', '-', (46, 54))
305479	27189061	Luciferase reporter assays showed that miR-181b transfection significantly repressed the luciferase activity of the CYLD 3'-UTR, whereas mutations in the binding sites did not decreased the luciferase activity (Fig.	('miR-181b', 'Chemical', '-', (39, 47))	('miR-181b', 'Var', (39, 47))	('CYLD', 'Gene', (116, 120))	('CYLD', 'Gene', '1540', (116, 120))	('luciferase', 'Enzyme', (89, 99))	('repressed', 'NegReg', (75, 84))	('activity', 'MPA', (100, 108))
305482	27189061	6g), indicating that miR-181b regulates CYLD in SFCs at the post-transcriptional level.	('miR-181b', 'Var', (21, 29))	('miR-181b', 'Chemical', '-', (21, 29))	('regulates', 'Reg', (30, 39))	('CYLD', 'Gene', '1540', (40, 44))	('CYLD', 'Gene', (40, 44))
305483	27189061	Taken together, these results demonstrate that miR-181b regulates CYLD expression by directly targeting its 3'-UTR.	('miR-181b', 'Var', (47, 55))	('miR-181b', 'Chemical', '-', (47, 55))	("3'-UTR", 'MPA', (108, 114))	('CYLD', 'Gene', (66, 70))	('regulates', 'Reg', (56, 65))	('CYLD', 'Gene', '1540', (66, 70))	('targeting', 'Reg', (94, 103))
305485	27189061	To further assess the effect miR-181b targeting CYLD, the activities of NF-kappaB and IL-6 were measured.	('IL-6', 'Gene', '3569', (86, 90))	('CYLD', 'Gene', (48, 52))	('NF-kappaB', 'Gene', '4790', (72, 81))	('CYLD', 'Gene', '1540', (48, 52))	('NF-kappaB', 'Gene', (72, 81))	('miR-181b', 'Var', (29, 37))	('miR-181b', 'Chemical', '-', (29, 37))	('IL-6', 'Gene', (86, 90))
305486	27189061	miR-181b transfection increased NF-kappaB activity, while inhibition of miR-181b decreased this activity (Fig.	('miR-181b', 'Gene', (72, 80))	('activity', 'MPA', (42, 50))	('NF-kappaB', 'Gene', (32, 41))	('miR-181b', 'Chemical', '-', (0, 8))	('increased', 'PosReg', (22, 31))	('miR-181b', 'Chemical', '-', (72, 80))	('miR-181b', 'Gene', (0, 8))	('NF-kappaB', 'Gene', '4790', (32, 41))	('transfection', 'Var', (9, 21))
305490	27189061	These results further suggest that CYLD is a target of miR-181b.	('miR-181b', 'Var', (55, 63))	('CYLD', 'Gene', (35, 39))	('miR-181b', 'Chemical', '-', (55, 63))	('CYLD', 'Gene', '1540', (35, 39))
305491	27189061	To further explore that miR-181b regulates the SFC proliferation through CYLD pathway, soft agar experiment was employed.	('regulates', 'Reg', (33, 42))	('agar', 'Chemical', 'MESH:D000362', (92, 96))	('miR-181b', 'Var', (24, 32))	('CYLD', 'Gene', (73, 77))	('miR-181b', 'Chemical', '-', (24, 32))	('CYLD', 'Gene', '1540', (73, 77))
305496	27189061	In addition, we found an inverse correlation between miR-181b and CYLD (r = -0.867) (Fig.	('CYLD', 'Gene', '1540', (66, 70))	('miR-181b', 'Chemical', '-', (53, 61))	('CYLD', 'Gene', (66, 70))	('miR-181b', 'Var', (53, 61))
305516	27189061	Second, miR-181b increased the number of colonies of SFCs.	('miR-181b', 'Var', (8, 16))	('miR-181b', 'Chemical', '-', (8, 16))	('increased', 'PosReg', (17, 26))
305517	27189061	Western blot analysis showed that miR-181b increased p-STAT3 expression.	('STAT3', 'Gene', (55, 60))	('miR-181b', 'Chemical', '-', (34, 42))	('miR-181b', 'Var', (34, 42))	('increased', 'PosReg', (43, 52))	('STAT3', 'Gene', '6774', (55, 60))
305518	27189061	Third, both STAT3 and miR-181b inhibition sensitized SFCs to apoptosis.	('miR-181b', 'Chemical', '-', (22, 30))	('apoptosis', 'CPA', (61, 70))	('sensitized', 'Reg', (42, 52))	('STAT3', 'Gene', '6774', (12, 17))	('STAT3', 'Gene', (12, 17))	('miR-181b', 'Gene', (22, 30))	('inhibition', 'Var', (31, 41))
305525	27189061	Our results demonstrated that exogenous miR-181b increased NF-kappaB activity.	('miR-181b', 'Var', (40, 48))	('activity', 'MPA', (69, 77))	('NF-kappaB', 'Gene', '4790', (59, 68))	('increased', 'PosReg', (49, 58))	('NF-kappaB', 'Gene', (59, 68))	('miR-181b', 'Chemical', '-', (40, 48))
305526	27189061	In this study, the miR-181b mimic also increased IL-6 expression level.	('miR-181b', 'Chemical', '-', (19, 27))	('IL-6', 'Gene', '3569', (49, 53))	('miR-181b mimic', 'Var', (19, 33))	('increased', 'PosReg', (39, 48))	('IL-6', 'Gene', (49, 53))
305542	27189061	Membranes were blocked in TBST-0.1 % (0.1 % Tween-20 in Tris-base buffer) skim milk and blotted with primary antibodies including STAT3, p-STAT3, CYLD, and beta-actin (#9139, #9145, #8462, #4970,respectively, all from Cell Signaling Technology, Danvers, MA, USA) at 4  C overnight.	('#9139', 'Var', (168, 173))	('beta-actin', 'Gene', '728378', (156, 166))	('beta-actin', 'Gene', (156, 166))	('STAT3', 'Gene', '6774', (139, 144))	('TBST', 'Chemical', '-', (26, 30))	('STAT3', 'Gene', (139, 144))	('STAT3', 'Gene', '6774', (130, 135))	('#8462', 'Var', (182, 187))	('CYLD', 'Gene', (146, 150))	('CYLD', 'Gene', '1540', (146, 150))	('STAT3', 'Gene', (130, 135))	('Tween-20', 'Chemical', 'MESH:D011136', (44, 52))	('#4970', 'Var', (189, 194))	('Tris-base', 'Chemical', 'MESH:D014325', (56, 65))
305557	27189061	The corresponding mutant constructs were created by mutating the seed regions of the miR-181b-binding sites.	('mutating', 'Var', (52, 60))	('miR-181b', 'Chemical', '-', (85, 93))	('miR-181b-binding', 'Gene', (85, 101))
305565	27189061	Spearman analysis were employed to analyzed the relationship between STAT3 and miR-181b, miR-181b and CYLD.	('STAT3', 'Gene', (69, 74))	('CYLD', 'Gene', (102, 106))	('CYLD', 'Gene', '1540', (102, 106))	('miR-181b', 'Var', (89, 97))	('miR-181b', 'Chemical', '-', (89, 97))	('miR-181b', 'Var', (79, 87))	('miR-181b', 'Chemical', '-', (79, 87))	('STAT3', 'Gene', '6774', (69, 74))
305566	24710335	Lack of Association between Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) -1722T/C (rs733618) Polymorphism and Cancer Risk: From a Case-Control Study to a Meta-Analysis The association between cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene -1722T/C polymorphism (rs733618) and cancer has been widely assessed, and a definitive conclusion remains elusive.	('Cytotoxic T-lymphocyte Antigen 4', 'Gene', '1493', (28, 60))	('cytotoxic T-lymphocyte antigen 4', 'Gene', (189, 221))	('Cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('Cytotoxic T-lymphocyte Antigen 4', 'Gene', (28, 60))	('cytotoxic T-lymphocyte antigen 4', 'Gene', '1493', (189, 221))	('-1722T/C', 'Mutation', 'rs733618', (70, 78))	('CTLA-4', 'Gene', '1493', (223, 229))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('-1722T/C', 'Mutation', 'rs733618', (236, 244))	('CTLA-4', 'Gene', (223, 229))	('rs733618', 'Mutation', 'rs733618', (80, 88))	('CTLA-4', 'Gene', '1493', (62, 68))	('CTLA-4', 'Gene', (62, 68))	('cancer', 'Disease', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('rs733618', 'Mutation', 'rs733618', (259, 267))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('rs733618', 'Var', (259, 267))
305567	24710335	We first performed a hospital based case-control study to measure this association of esophageal cancer with CTLA-4 -1722T/C polymorphism in Han Chinese population, and then carried out a meta-analysis to obtain a comprehensive evaluation for this issue.	('esophageal cancer', 'Disease', (86, 103))	('polymorphism', 'Var', (125, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('CTLA-4 -1722T/C', 'Gene', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('association', 'Interaction', (71, 82))	('-1722T/C', 'Mutation', 'rs733618', (116, 124))
305569	24710335	This case-control study showed no significant difference in the genotype and allele distributions of CTLA-4 -1722T/C polymorphism between esophageal cancer cases and control subjects, in accord with the findings of the further meta-analysis in all genetic models.	('esophageal cancer', 'Disease', (138, 155))	('polymorphism', 'Var', (117, 129))	('-1722T/C', 'Mutation', 'rs733618', (108, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('CTLA-4 -1722T/C', 'Gene', (101, 116))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))
305574	24710335	Of late, a number of studies demonstrate that genetic variants of the genes that regulate the activation and proliferation of T lymphocytes and nature killer (NK) cells may influence cancer risk.	('cancer', 'Disease', (183, 189))	('influence', 'Reg', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('proliferation', 'CPA', (109, 122))	('genetic variants', 'Var', (46, 62))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
305575	24710335	In the last decade, single nucleotide polymorphisms (SNPs) have been extensively investigated, and many studies have examined the hypothesis that genetic variants of the immune genes may be relevant to the risk of a variety of cancers.	('relevant', 'Reg', (190, 198))	('variants', 'Var', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('single nucleotide polymorphisms', 'Var', (20, 51))	('cancers', 'Disease', (227, 234))	('cancers', 'Disease', 'MESH:D009369', (227, 234))
305579	24710335	CTLA-4 gene is located on chromosome 2q33, and is composed of four exons that encode several functional domains of the CTLA-4 protein and possess several vital SNPs, such as the +49A/G (rs231775), -318C/T (rs5742909), CT60G/A (rs3087243), -1661A/G (rs4553808), and -1722T/C (rs733618) SNPs, etc.	('rs5742909', 'Mutation', 'rs5742909', (206, 215))	('rs4553808', 'Mutation', 'rs4553808', (249, 258))	('rs231775', 'Var', (186, 194))	('rs733618', 'Mutation', 'rs733618', (275, 283))	('-318C/T', 'Mutation', 'rs5742909', (197, 204))	('-1661A/G', 'Mutation', 'rs4553808', (239, 247))	('-1722T/C', 'Mutation', 'rs733618', (265, 273))	('rs3087243', 'Mutation', 'rs3087243', (227, 236))	('rs3087243', 'Var', (227, 236))	('rs4553808', 'Var', (249, 258))	('CT60G', 'Mutation', 'c.60CT>G', (218, 223))	('rs231775', 'Mutation', 'rs231775', (186, 194))	('rs5742909', 'Var', (206, 215))	('CTLA-4', 'Gene', (119, 125))	('+49A/G', 'Mutation', 'rs231775', (178, 184))
305580	24710335	A meta-analysis showed that CTLA-4 +49A/G polymorphism may be a risk factor for cancer, whereas -318C/T and +6230G/A (CT60) polymorphisms were lack of association with cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('polymorphism', 'Var', (42, 54))	('risk', 'Reg', (64, 68))	('+49A/G', 'Mutation', 'rs231775', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CT60', 'Gene', (118, 122))	('+6230G/A', 'Mutation', 'rs3087243', (108, 116))	('-318C/T', 'Mutation', 'rs5742909', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('CT60', 'Gene', '348120', (118, 122))	('cancer', 'Disease', (80, 86))	('CTLA-4', 'Gene', (28, 34))
305581	24710335	Of late, Geng and colleagues reported a meta-analysis with a negative result on the association between CTLA-4 -1722T/C polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CTLA-4 -1722T/C', 'Gene', (104, 119))	('-1722T/C', 'Mutation', 'rs733618', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('polymorphism', 'Var', (120, 132))
305584	24710335	To further investigate this potential relationship, we decided to evaluate the association of CTLA-4 -1722T/C polymorphism with esophageal cancer risk in a hospital based case-control study, and then performed a comprehensive meta-analysis to derive a more precise result.	('polymorphism', 'Var', (110, 122))	('esophageal cancer', 'Disease', (128, 145))	('CTLA-4', 'Gene', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('association', 'Interaction', (79, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('-1722T/C', 'Mutation', 'rs733618', (101, 109))
305596	24710335	Embase, PubMed, and CBM (Chinese BioMedical Disc), as well as CNKI (China National Knowledge Infrastructure) database were searched up to August 1st, 2013 for publications investigating the association of CTLA-4 -1722T/C polymorphism with cancer risk.	('CTLA-4 -1722T/C polymorphism', 'Var', (205, 233))	('-1722T/C', 'Mutation', 'rs733618', (212, 220))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (239, 245))	('association', 'Interaction', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
305599	24710335	Included studies were qualified if they met the major included criteria: (1) designed as a retrospective or nested case-control study, (2) evaluated the CTLA-4 -1722T/C polymorphism and cancer risk, (3) provide genotype counts of CTLA-4 -1722T/C polymorphism between cancer cases and controls, and (4) control genotype distributions consistent with HWE.	('CTLA-4', 'Var', (230, 236))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('-1722T/C', 'Mutation', 'rs733618', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('-1722T/C', 'Mutation', 'rs733618', (160, 168))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
305605	24710335	The genotypic frequencies for CTLA-4 -1722T/C polymorphism among controls were used to evaluated deviation from the HWE, and the result was in HWE (P = 0.284) ( Table 2 ).	('polymorphism', 'Var', (46, 58))	('-1722T/C', 'Mutation', 'rs733618', (37, 45))	('CTLA-4', 'Gene', (30, 36))
305613	24710335	There was null association of CTLA-4 -1722T/C polymorphism with overall cancer risk in all genetic models ( Table 7  ,   Table 8  ,   Table 9  ,   Figure 2  , and   Figure 3 ).	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CTLA-4 -1722T/C', 'Gene', (30, 45))	('polymorphism', 'Var', (46, 58))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('-1722T/C', 'Mutation', 'rs733618', (37, 45))	('cancer', 'Disease', (72, 78))
305614	24710335	In a stratified analysis by cancer type, there was a decreased risk of gastric cancer in two genetic models: CC vs. TC+TT (OR, 0.36; 95% CI, 0.19-0.66; P = 0.001) and CC vs. TT (OR, 0.45; 95% CI, 0.23-0.86; P = 0.016) ( Table 8 ).	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('CC vs. TT', 'Var', (167, 176))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('TC+TT', 'Chemical', '-', (116, 121))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('decreased risk of gastric cancer', 'Phenotype', 'HP:0006753', (53, 85))	('decreased', 'NegReg', (53, 62))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
305620	24710335	To the best of our knowledge, this is the first case-control study investigating the association between CTLA-4 -1722T/C polymorphism and esophageal cancer risk.	('esophageal cancer', 'Disease', (138, 155))	('polymorphism', 'Var', (121, 133))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('CTLA-4 -1722T/C', 'Gene', (105, 120))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('-1722T/C', 'Mutation', 'rs733618', (112, 120))	('association', 'Interaction', (85, 96))
305623	24710335	Several meta-analyses showed that CTLA-4 -1722T/C polymorphism might be a risk factor for systemic lupus erythematosus susceptibility.	('systemic lupus erythematosus', 'Disease', (90, 118))	('-1722T/C', 'Mutation', 'rs733618', (41, 49))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (90, 118))	('polymorphism', 'Var', (50, 62))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (90, 118))	('CTLA-4', 'Gene', (34, 40))
305625	24710335	With a growing interest in the associations of genetic polymorphisms and cancer, several studies have examined the hypothesis that CTLA-4 -1722T/C polymorphism is relevant to the risk of a number of cancers; however, the results remain elusive.	('polymorphism', 'Var', (147, 159))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('-1722T/C', 'Mutation', 'rs733618', (138, 146))	('CTLA-4', 'Gene', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancers', 'Disease', (199, 206))
305627	24710335	One individual study has reported positive signal of CTLA-4 -1722T/C polymorphism with cancer; the other individual study has reported negative signal; however, as demonstrated in our overall genetic model results among 7098 subjects, there were non-significance, even in different population subgroups and different system.	('cancer', 'Disease', (87, 93))	('polymorphism', 'Var', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CTLA-4', 'Gene', (53, 59))	('-1722T/C', 'Mutation', 'rs733618', (60, 68))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
305630	24710335	First, this is to date the first case-control study detecting the association of CTLA-4 gene -1722T/C polymorphism with esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('association', 'Interaction', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('-1722T/C', 'Mutation', 'rs733618', (93, 101))	('gene -1722T/C polymorphism', 'Var', (88, 114))	('CTLA-4', 'Gene', (81, 87))	('esophageal cancer', 'Disease', (120, 137))
305633	24710335	Fifth, in this study, we focused on only -1722T/C polymorphism in CTLA-4, and did not consider other susceptibility genes or polymorphisms.	('CTLA-4', 'Gene', (66, 72))	('-1722T/C', 'Mutation', 'rs733618', (41, 49))	('only -1722T/C', 'Var', (36, 49))
305635	24710335	In summary, this case-control study along with a meta-analysis, failed to confirm the association between CTLA-4 -1722T/C polymorphism and cancer risk, even across different ethnic subgroups and different systems.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('polymorphism', 'Var', (122, 134))	('CTLA-4 -1722T/C', 'Gene', (106, 121))	('association', 'Interaction', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('-1722T/C', 'Mutation', 'rs733618', (113, 121))	('cancer', 'Disease', (139, 145))
305637	21460800	However, the relationship of HER2 amplification in esophageal adenocarcinoma with prognosis has not been well defined.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (51, 76))	('HER2', 'Gene', (29, 33))	('HER2', 'Gene', '2064', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('esophageal adenocarcinoma', 'Disease', (51, 76))	('amplification', 'Var', (34, 47))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (51, 76))
305642	21460800	In our studies, we have found that HER2 amplification does not associate with poor prognosis in total 232 esophageal adenocarcinoma patients by CISH and high density microarrays.	('CISH', 'Chemical', '-', (144, 148))	('HER2', 'Gene', (35, 39))	('HER2', 'Gene', '2064', (35, 39))	('esophageal adenocarcinoma', 'Disease', (106, 131))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (106, 131))	('amplification', 'Var', (40, 53))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (106, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('patients', 'Species', '9606', (132, 140))
305643	21460800	We further confirm the similar frequency of HER2 amplification by CISH (18.10%; 21/116) and SNP 6.0 microarrays (16.4%, 19/116) in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (131, 156))	('amplification', 'Var', (49, 62))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (131, 156))	('CISH', 'Chemical', '-', (66, 70))	('HER2', 'Gene', (44, 48))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (131, 156))	('HER2', 'Gene', '2064', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
305647	21460800	Gene amplification was found to be more frequent by CISH than protein overexpression in esophageal adenocarcinoma (18.10% vs 12.9%).	('frequent', 'Reg', (40, 48))	('CISH', 'Chemical', '-', (52, 56))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (88, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('Gene amplification', 'Var', (0, 18))
305650	21460800	Accumulation of genetic and epigenetic changes then results in progression to dysplasia and cancer in some individuals.	('epigenetic changes', 'Var', (28, 46))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('dysplasia and cancer', 'Disease', 'MESH:D009369', (78, 98))	('progression', 'PosReg', (63, 74))	('genetic', 'Var', (16, 23))	('results in', 'Reg', (52, 62))
305652	21460800	Identification of genetic alterations in EAC that offer potential for biologically targeted treatment is one of the best hopes to improve the selectivity of therapy and enhance patient survival.	('genetic alterations', 'Var', (18, 37))	('patient', 'Species', '9606', (177, 184))	('enhance', 'PosReg', (169, 176))	('EAC', 'Gene', (41, 44))
305655	21460800	Trastuzumab treatment in combination with chemotherapy for breast cancer patients with HER2 amplification/over-expression has shown a significant clinical efficacy in both the metastatic and adjuvant settings.	('HER2', 'Gene', '2064', (87, 91))	('amplification/over-expression', 'Var', (92, 121))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('amplification/over-expression', 'PosReg', (92, 121))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (0, 11))	('patients', 'Species', '9606', (73, 81))	('HER2', 'Gene', (87, 91))
305660	21460800	The guidelines for detection and interpretation of HER2 amplification/over-expression in breast cancer have been well established and anti-HER2 targeted treatment is routinely considered in the management of these patients.	('patients', 'Species', '9606', (214, 222))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('HER2', 'Gene', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('HER2', 'Gene', '2064', (139, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('HER2', 'Gene', (51, 55))	('amplification/over-expression', 'PosReg', (56, 85))	('amplification/over-expression', 'Var', (56, 85))	('HER2', 'Gene', '2064', (51, 55))
305694	21460800	Kaplan-Meir survival estimator and logrank test was used to analyze the patient survival between HER2 amplified group and non- HER2 amplified group.	('HER2', 'Gene', (97, 101))	('HER2', 'Gene', '2064', (97, 101))	('patient', 'Species', '9606', (72, 79))	('HER2', 'Gene', (127, 131))	('HER2', 'Gene', '2064', (127, 131))	('amplified', 'Var', (102, 111))
305698	21460800	In this cohort study, the median overall survival of HER2 amplification is 21 months and non- HER2 amplification is 25 months.	('HER2', 'Gene', '2064', (94, 98))	('HER2', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (53, 57))	('amplification', 'Var', (58, 71))	('HER2', 'Gene', (94, 98))
305699	21460800	No association was found with HER2 amplification and either disease free survival (p=0.709) or overall survival (p=0.27).	('HER2', 'Gene', '2064', (30, 34))	('amplification', 'Var', (35, 48))	('disease free survival', 'CPA', (60, 81))	('HER2', 'Gene', (30, 34))
305724	21460800	However, the frequency of HER2 amplification was found to be significantly higher (p=0.004) in moderately differentiated tumors (13/22) compared with poor or well differentiated tumors (1/6 and 7/61 respectively).	('moderately differentiated', 'CPA', (95, 120))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('higher', 'PosReg', (75, 81))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('HER2', 'Gene', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('HER2', 'Gene', '2064', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('amplification', 'Var', (31, 44))
305725	21460800	In the present study, we provide evidence that HER2 amplification does not associate with poor prognosis in total 232 EAC patients by CISH (116 patients) and high density microarrays (116 patients).	('EAC', 'Disease', (118, 121))	('HER2', 'Gene', (47, 51))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (144, 152))	('HER2', 'Gene', '2064', (47, 51))	('patients', 'Species', '9606', (122, 130))	('amplification', 'Var', (52, 65))	('CISH', 'Chemical', '-', (134, 138))
305726	21460800	We further confirm the frequency of HER2 amplification and overexpression in EAC and high grade dysplasia (see table 1) by various methods including high density microarrays, CISH and IHC.	('dysplasia', 'Disease', (96, 105))	('dysplasia', 'Disease', 'MESH:D004476', (96, 105))	('HER2', 'Gene', (36, 40))	('HER2', 'Gene', '2064', (36, 40))	('EAC', 'Disease', (77, 80))	('amplification', 'Var', (41, 54))	('overexpression', 'PosReg', (59, 73))	('CISH', 'Chemical', '-', (175, 179))
305728	21460800	Data on the association between HER2 amplification and survival duration in EAC are limited and conflicting.	('HER2', 'Gene', '2064', (32, 36))	('HER2', 'Gene', (32, 36))	('EAC', 'Disease', (76, 79))	('amplification', 'Var', (37, 50))
305729	21460800	found that patients with HER2 amplification (n=11) had shorter survival durations than did patients without amplification (n=43).	('patients', 'Species', '9606', (91, 99))	('survival durations', 'CPA', (63, 81))	('shorter', 'NegReg', (55, 62))	('amplification', 'Var', (30, 43))	('HER2', 'Gene', (25, 29))	('patients', 'Species', '9606', (11, 19))	('HER2', 'Gene', '2064', (25, 29))
305731	21460800	found that HER2 gene amplification was associated with increased disease-specific mortality on 3-dimensional fluorescence in situ hybridization (FISH) analysis in thick slides (16 mum), but not on FISH and immunohistochemical analyses in thin (4 mum) sections.	('HER2', 'Gene', (11, 15))	('increased', 'PosReg', (55, 64))	('amplification', 'Var', (21, 34))	('disease-specific', 'Disease', (65, 81))	('HER2', 'Gene', '2064', (11, 15))
305732	21460800	Our results indicate no association of HER2 amplification with patient survival in a large cohort studies (total 232 patients) by both CISH and high density microarrays.	('CISH', 'Chemical', '-', (135, 139))	('HER2', 'Gene', (39, 43))	('amplification', 'Var', (44, 57))	('HER2', 'Gene', '2064', (39, 43))	('patient', 'Species', '9606', (63, 70))	('patient', 'Species', '9606', (117, 124))	('patients', 'Species', '9606', (117, 125))
305739	21460800	Thus, the frequency of HER2 amplification in EAC appears to be consistent between studies with a range of 15-19% and this event appears not to occur prior to the development of HGD.	('HER2', 'Gene', '2064', (23, 27))	('HER2', 'Gene', (23, 27))	('amplification', 'Var', (28, 41))
305742	21460800	In current studies with high definition microarray analysis, 16.4% (19/116) had HER2 amplification detected.	('HER2', 'Gene', '2064', (80, 84))	('amplification', 'Var', (85, 98))	('HER2', 'Gene', (80, 84))
305748	21460800	With 2+ expression of HER2, only 36% of IHC 2+ cases were also FISH positive in gastric carcinoma.	('gastric carcinoma', 'Disease', (80, 97))	('2+ expression', 'Var', (5, 18))	('HER2', 'Gene', (22, 26))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('HER2', 'Gene', '2064', (22, 26))	('gastric carcinoma', 'Disease', 'MESH:D013274', (80, 97))
305754	21460800	The definition for HER2 overexpression should be 2+ and 3+ instead of 3+ only in breast and gastric cancer since all 2+ expression cases in EAC showed HER2 amplification by CISH.	('amplification', 'Var', (156, 169))	('HER2', 'Gene', (19, 23))	('gastric cancer', 'Disease', (92, 106))	('HER2', 'Gene', '2064', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('CISH', 'Chemical', '-', (173, 177))	('HER2', 'Gene', (151, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('HER2', 'Gene', '2064', (151, 155))	('breast', 'Disease', (81, 87))
305769	21460800	Our results showed that HER2 amplification is not a prognostic predictor for esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('amplification', 'Var', (29, 42))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (77, 102))	('esophageal adenocarcinoma', 'Disease', (77, 102))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (77, 102))	('HER2', 'Gene', (24, 28))	('HER2', 'Gene', '2064', (24, 28))
305770	21460800	However, HER2 amplification/overexpression in a subset of esophageal adenocarcinoma and high grade dysplasia and suggests that these patients would be potential candidates for anti-HER2 targeted treatment.	('dysplasia', 'Disease', 'MESH:D004476', (99, 108))	('HER2', 'Gene', '2064', (181, 185))	('HER2', 'Gene', (9, 13))	('patients', 'Species', '9606', (133, 141))	('HER2', 'Gene', '2064', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('HER2', 'Gene', (181, 185))	('dysplasia', 'Disease', (99, 108))	('amplification/overexpression', 'Var', (14, 42))	('esophageal adenocarcinoma', 'Disease', (58, 83))	('amplification/overexpression', 'PosReg', (14, 42))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (58, 83))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (58, 83))
305772	33846817	Several articles have reported that microRNA (miR)-485-5p inhibits the malignant phenotype in a number of cancer types, such as lung, gastric and breast cancer, but to the best of our knowledge, its function in ESCC has not been studied in depth until the present study.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('microRNA', 'Var', (36, 44))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung', 'Disease', (128, 132))	('inhibits', 'NegReg', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (106, 112))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('-5p', 'Chemical', '-', (54, 57))	('gastric', 'Disease', (134, 141))	('malignant phenotype', 'CPA', (71, 90))
305773	33846817	It is of great significance to probe the regulatory action and underlying mechanism of miR-485-5p in ESCC.	('miR-485-5p', 'Var', (87, 97))	('ESCC', 'Disease', (101, 105))	('miR-485-5p', 'Chemical', '-', (87, 97))
305775	33846817	The decrease in miR-485-5p expression was associated with a larger tumour size and poor histology and stage.	('tumour', 'Disease', (67, 73))	('miR-485-5p', 'Chemical', '-', (16, 26))	('expression', 'MPA', (27, 37))	('decrease', 'NegReg', (4, 12))	('miR-485-5p', 'Var', (16, 26))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (67, 73))
305776	33846817	The expression of miR-485-5p was relatively high in Eca 109 and TE-1 cells, but relatively low in KYSE 30.	('miR-485-5p', 'Chemical', '-', (18, 28))	('TE-1', 'CellLine', 'CVCL:1759', (64, 68))	('miR-485-5p', 'Var', (18, 28))	('expression', 'MPA', (4, 14))	('Eca', 'Chemical', '-', (52, 55))
305777	33846817	The overexpression of miR-485-5p inhibited cell proliferation, migration and invasion in vitro, whereas miR-485-5p knockdown did the opposite.	('invasion in vitro', 'CPA', (77, 94))	('miR-485-5p', 'Chemical', '-', (22, 32))	('miR-485-5p', 'Var', (22, 32))	('overexpression', 'PosReg', (4, 18))	('migration', 'CPA', (63, 72))	('cell proliferation', 'CPA', (43, 61))	('inhibited', 'NegReg', (33, 42))	('miR-485-5p', 'Chemical', '-', (104, 114))
305780	33846817	Further experiments showed that miR-485-5p directly targeted the 3'-untranslated region of FLOT-1.	('men', 'Species', '9606', (14, 17))	('miR-485-5p', 'Chemical', '-', (32, 42))	('FLOT-1', 'Gene', (91, 97))	('miR-485-5p', 'Var', (32, 42))	('FLOT-1', 'Gene', '10211', (91, 97))
305781	33846817	The overexpression of miR-485-5p significantly suppressed the mRNA and protein expression levels of FLOT-1, whereas knockdown had the reverse effects.	('suppressed', 'NegReg', (47, 57))	('miR-485-5p', 'Chemical', '-', (22, 32))	('FLOT-1', 'Gene', '10211', (100, 106))	('miR-485-5p', 'Var', (22, 32))	('FLOT-1', 'Gene', (100, 106))
305782	33846817	Furthermore, overexpression of miR-485-5p restrained epithelial-mesenchymal metastasis (EMT)-related factors at both the mRNA and protein levels.	('miR-485-5p', 'Var', (31, 41))	('overexpression', 'PosReg', (13, 27))	('restrained', 'NegReg', (42, 52))	('miR-485-5p', 'Chemical', '-', (31, 41))
305783	33846817	In summary, miR-485-5p was found to be an inhibitor of ESCC and may have potential as a novel target candidate for ESCC treatment.	('ESCC', 'Disease', (115, 119))	('men', 'Species', '9606', (125, 128))	('miR-485-5p', 'Chemical', '-', (12, 22))	('miR-485-5p', 'Var', (12, 22))	('ESCC', 'Protein', (55, 59))
305793	33846817	It has been found that miR-485-5p, which regulates different targets in various human cancers, has the ability to function as a suppressor tumour gene.	('tumour', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('miR-485-5p', 'Chemical', '-', (23, 33))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('miR-485-5p', 'Var', (23, 33))
305794	33846817	miR-485-5p downregulates the expression of tumour protein D54 and paired box 3 to inhibit the proliferation and invasion of glioma cells.	('miR-485-5p', 'Var', (0, 10))	('paired box 3', 'Gene', (66, 78))	('glioma', 'Disease', (124, 130))	('tumour', 'Disease', (43, 49))	('inhibit', 'NegReg', (82, 89))	('paired box 3', 'Gene', '5077', (66, 78))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('D54', 'Protein', (58, 61))	('downregulates', 'NegReg', (11, 24))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('expression', 'MPA', (29, 39))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('miR-485-5p', 'Chemical', '-', (0, 10))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
305795	33846817	However it can also reduce the O-GlcNAcylation of polycomb complex protein BMI-1 and inhibit proliferation by targeting CD147 in colorectal cancer.	('colorectal cancer', 'Disease', (129, 146))	('CD147', 'Gene', '682', (120, 125))	('proliferation', 'CPA', (93, 106))	('inhibit', 'NegReg', (85, 92))	('reduce', 'NegReg', (20, 26))	('BMI-1', 'Gene', (75, 80))	('CD147', 'Gene', (120, 125))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('O-GlcNAcylation', 'MPA', (31, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('targeting', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('BMI-1', 'Gene', '648', (75, 80))
305796	33846817	Han et al reported that O-linked N-acetylglucosamine transferase could be downregulated by the tumour suppressor miR-485-5p to inhibit the progression of ESCC, while in the present study another target was found, flotillin-1 (FLOT-1).	('O-linked N-acetylglucosamine transferase', 'Enzyme', (24, 64))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('FLOT-1', 'Gene', '10211', (226, 232))	('flotillin-1', 'Gene', (213, 224))	('FLOT-1', 'Gene', (226, 232))	('ESCC', 'Disease', (154, 158))	('tumour', 'Disease', (95, 101))	('miR-485-5p', 'Chemical', '-', (113, 123))	('inhibit', 'NegReg', (127, 134))	('miR-485-5p', 'Var', (113, 123))	('downregulated', 'NegReg', (74, 87))	('flotillin-1', 'Gene', '10211', (213, 224))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
305798	33846817	In the present study, it was verified that miR-485-5p expression was reduced in ESCC.	('reduced', 'NegReg', (69, 76))	('miR-485-5p', 'Var', (43, 53))	('miR-485-5p', 'Chemical', '-', (43, 53))	('ESCC', 'Disease', (80, 84))
305799	33846817	Cell proliferation, locomotion, invasion and epithelial-mesenchymal metastasis (EMT) were blocked by the overexpression of miR-485-5p.	('locomotion', 'CPA', (20, 30))	('overexpression', 'PosReg', (105, 119))	('miR-485-5p', 'Chemical', '-', (123, 133))	('blocked', 'NegReg', (90, 97))	('epithelial-mesenchymal metastasis', 'CPA', (45, 78))	('miR-485-5p', 'Var', (123, 133))	('Cell proliferation', 'CPA', (0, 18))	('invasion', 'CPA', (32, 40))
305800	33846817	As FLOT-1 is a direct target of miR-485-5p, and various reports have verified FLOT-1 plays an important role in promoting cancer progression, it was concluded that miR-485-5p suppresses ESCC by targeting FLOT-1 and inhibiting the EMT.	('miR-485-5p', 'Var', (164, 174))	('targeting', 'Reg', (194, 203))	('FLOT-1', 'Gene', '10211', (3, 9))	('FLOT-1', 'Gene', (204, 210))	('suppresses', 'NegReg', (175, 185))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('EMT', 'CPA', (230, 233))	('miR-485-5p', 'Chemical', '-', (32, 42))	('FLOT-1', 'Gene', (78, 84))	('FLOT-1', 'Gene', '10211', (78, 84))	('FLOT-1', 'Gene', '10211', (204, 210))	('miR-485-5p', 'Chemical', '-', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('FLOT-1', 'Gene', (3, 9))	('ESCC', 'Disease', (186, 190))	('inhibiting', 'NegReg', (215, 225))
305810	33846817	miR1N0000001-1-5; Guangzhou RiboBio Co., Ltd.), miR-485-5p inhibitor (cat.	('miR-485-5p', 'Chemical', '-', (48, 58))	('miR1', 'Gene', (0, 4))	('miR-485-5p inhibitor', 'Var', (48, 68))	('miR1', 'Gene', '83856', (0, 4))
305844	33846817	FLOT-1 expression in tissues was ranked according to the following scores: i) 0, -; ii) 1-2, +; iii) 3-4, ++; and iv) 5-6, +++.	('3-4', 'Var', (101, 104))	('FLOT-1', 'Gene', '10211', (0, 6))	('FLOT-1', 'Gene', (0, 6))
305847	33846817	The wild-type (WT) or mutant (MUT) miR-485-5p binding sequence of FLOT-1 was inserted into the pmirGLO plasmid (YouBio) to establish the recombinant luciferase reporter plasmids (FLOT-1 WT and FLOT-1 MUT).	('FLOT-1', 'Gene', (179, 185))	('miR-485-5p', 'Chemical', '-', (35, 45))	('FLOT-1', 'Gene', (193, 199))	('FLOT-1', 'Gene', '10211', (179, 185))	('FLOT-1', 'Gene', '10211', (66, 72))	('mutant', 'Var', (22, 28))	('FLOT-1', 'Gene', '10211', (193, 199))	('FLOT-1', 'Gene', (66, 72))
305848	33846817	293T cells (Procell Life Science & Technology Co., Ltd.) were co-transfected with pmirGLO, FLOT-1 WT or FLOT-1 MUT and miR-485-5p mimics or mimics-NC with Lipofectamine  2000.	('FLOT-1', 'Gene', (104, 110))	('and', 'Var', (115, 118))	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('FLOT-1', 'Gene', '10211', (104, 110))	('FLOT-1', 'Gene', (91, 97))	('miR-485-5p', 'Chemical', '-', (119, 129))	('FLOT-1', 'Gene', '10211', (91, 97))	('Lipofectamine  2000', 'Chemical', 'MESH:C086724', (155, 174))
305874	33846817	1A, human ESCC tissues exhibited lower expression of miR-485-5p than adjacent control tissues.	('human', 'Species', '9606', (4, 9))	('miR-485-5p', 'Chemical', '-', (53, 63))	('miR-485-5p', 'Var', (53, 63))	('expression', 'MPA', (39, 49))	('lower', 'NegReg', (33, 38))
305875	33846817	It was also demonstrated that the expression of miR-485-5p was strongly associated with the clinicopathological features of ESCC.	('miR-485-5p', 'Chemical', '-', (48, 58))	('miR-485-5p', 'Var', (48, 58))	('ESCC', 'Disease', (124, 128))	('associated', 'Reg', (72, 82))
305877	33846817	Decreased miR-485-5p expression was associated with a larger tumour size and poor differentiation and stages III/IV.	('miR-485-5p', 'Chemical', '-', (10, 20))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('stages', 'Disease', (102, 108))	('Decreased', 'NegReg', (0, 9))	('miR-485-5p', 'Var', (10, 20))	('expression', 'MPA', (21, 31))	('tumour', 'Disease', (61, 67))	('poor differentiation', 'CPA', (77, 97))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
305879	33846817	These data indicated that the expression of miR-485-5p was downregulated in ESCC tissues.	('expression', 'MPA', (30, 40))	('downregulated', 'NegReg', (59, 72))	('miR-485-5p', 'Chemical', '-', (44, 54))	('ESCC', 'Disease', (76, 80))	('miR-485-5p', 'Var', (44, 54))
305884	33846817	1C, the expression of miR-485-5p was significantly upregulated in mimics group and downregulated in the inhibitor group, compared with the control groups.	('miR-485-5p', 'Chemical', '-', (22, 32))	('downregulated', 'NegReg', (83, 96))	('miR-485-5p', 'Var', (22, 32))	('expression', 'MPA', (8, 18))	('upregulated', 'PosReg', (51, 62))
305886	33846817	Compared with Eca 109, KYSE 30 and TE-1 cells transfected with the inhibitor-NC, the proliferation rates of cells transfected with miR-485-5p inhibitor were increased.	('miR-485-5p', 'Chemical', '-', (131, 141))	('Eca', 'Chemical', '-', (14, 17))	('TE-1', 'CellLine', 'CVCL:1759', (35, 39))	('increased', 'PosReg', (157, 166))	('miR-485-5p inhibitor', 'Var', (131, 151))	('proliferation rates', 'CPA', (85, 104))
305887	33846817	Whereas, the inhibition rates of Eca 109, KYSE 30 and TE-1 cells transfected with miR-485-5p mimics were decreased in contrast to cells transfected with mimics-NC.	('miR-485-5p', 'Gene', (82, 92))	('TE-1', 'CellLine', 'CVCL:1759', (54, 58))	('miR-485-5p', 'Chemical', '-', (82, 92))	('inhibition', 'NegReg', (13, 23))	('mimics', 'Var', (93, 99))	('Eca', 'Chemical', '-', (33, 36))	('decreased', 'NegReg', (105, 114))
305888	33846817	The proliferation rate was significantly reduced in Eca 109, KYSE 30 and TE-1 cells transfected with miR-485-5p mimics compared with the mimics-NC group, while the opposite effect was observed in the inhibitor group (Fig.	('reduced', 'NegReg', (41, 48))	('miR-485-5p', 'Gene', (101, 111))	('miR-485-5p', 'Chemical', '-', (101, 111))	('Eca', 'Chemical', '-', (52, 55))	('TE-1', 'CellLine', 'CVCL:1759', (73, 77))	('proliferation rate', 'CPA', (4, 22))	('mimics', 'Var', (112, 118))
305889	33846817	Further investigation demonstrated the inhibitory role that miR-485-5p played in ESCC cells.	('miR-485-5p', 'Var', (60, 70))	('ESCC cells', 'Disease', (81, 91))	('miR-485-5p', 'Chemical', '-', (60, 70))
305891	33846817	Moreover, compared with the negative control, the invasion ratio was also decreased in Eca 109, KYSE 30 and TE-1 cell lines overexpressing miR-485-5p, but increased in the miR-485-5p knockdown group (Fig.	('miR-485-5p', 'Chemical', '-', (139, 149))	('invasion ratio', 'CPA', (50, 64))	('increased', 'PosReg', (155, 164))	('Eca', 'Chemical', '-', (87, 90))	('miR-485-5p', 'Var', (139, 149))	('TE-1', 'CellLine', 'CVCL:1759', (108, 112))	('decreased', 'NegReg', (74, 83))	('miR-485-5p', 'Chemical', '-', (172, 182))
305893	33846817	The overexpression of miR-485-5p reduced the migratory rate of ESCC cells (Fig.	('miR-485-5p', 'Chemical', '-', (22, 32))	('miR-485-5p', 'Var', (22, 32))	('reduced', 'NegReg', (33, 40))	('ESCC', 'Disease', (63, 67))	('migratory rate of', 'CPA', (45, 62))
305894	33846817	Additionally, the statistical results uncovered the suppressive role of miR-485-5p in the migration of ESCC cells (Fig.	('suppressive', 'NegReg', (52, 63))	('miR-485-5p', 'Var', (72, 82))	('migration of', 'CPA', (90, 102))	('ESCC', 'Disease', (103, 107))	('miR-485-5p', 'Chemical', '-', (72, 82))
305896	33846817	According to TargetScan, FLOT-1, which is an oncogene related to a number of malignancies, might also be a target gene of miR-485-5p (Fig.	('malignancies', 'Disease', (77, 89))	('FLOT-1', 'Gene', '10211', (25, 31))	('miR-485-5p', 'Chemical', '-', (122, 132))	('FLOT-1', 'Gene', (25, 31))	('miR-485-5p', 'Var', (122, 132))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))
305897	33846817	As Guo et al verified that the upregulation of FLOT-1 enhanced the malignant phenotype of lung adenocarcinoma cells in vitro, including cell proliferation, migration and invasion, it is of significance to explore whether the potential mechanism by which miR-485-5p inhibits ESCC is related to inhibition of the expression of FLOT-1.	('miR-485-5p', 'Var', (254, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('FLOT-1', 'Gene', '10211', (47, 53))	('lung adenocarcinoma', 'Disease', (90, 109))	('inhibits', 'NegReg', (265, 273))	('ESCC', 'Disease', (274, 278))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (90, 109))	('migration', 'CPA', (156, 165))	('FLOT-1', 'Gene', (325, 331))	('FLOT-1', 'Gene', (47, 53))	('FLOT-1', 'Gene', '10211', (325, 331))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('miR-485-5p', 'Chemical', '-', (254, 264))	('enhanced', 'PosReg', (54, 62))	('invasion', 'CPA', (170, 178))	('malignant phenotype of', 'CPA', (67, 89))	('cell proliferation', 'CPA', (136, 154))	('upregulation', 'PosReg', (31, 43))
305900	33846817	To confirm the predicted result, FLOT-1 expression was determined in ESCC cell lines transfected with miR-485-5p mimics or inhibitor via RT-qPCR and western blotting.	('inhibitor', 'Var', (123, 132))	('FLOT-1', 'Gene', (33, 39))	('miR-485-5p', 'Chemical', '-', (102, 112))	('FLOT-1', 'Gene', '10211', (33, 39))
305901	33846817	Both the mRNA and protein levels were relatively high in cells transfected with the inhibitor, whereas the cells transfected with miR-485-5p mimics showed the opposite effect in comparison with the control group (Fig.	('high', 'PosReg', (49, 53))	('inhibitor', 'Var', (84, 93))	('miR-485-5p', 'Chemical', '-', (130, 140))
305902	33846817	In addition, to further verify whether FLOT-1 is a direct target of miR-485-5p, a dual-luciferase reporter assay system was utilized.	('FLOT-1', 'Gene', (39, 45))	('miR-485-5p', 'Chemical', '-', (68, 78))	('miR-485-5p', 'Var', (68, 78))	('FLOT-1', 'Gene', '10211', (39, 45))
305910	33846817	To further confirm that miR-485-5p inhibited tumour progression through FLOT-1 inhibition in ESCC, functional recovery experiments were carried out.	('men', 'Species', '9606', (125, 128))	('miR-485-5p', 'Chemical', '-', (24, 34))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('FLOT-1', 'Gene', '10211', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('inhibition', 'NegReg', (79, 89))	('inhibited', 'NegReg', (35, 44))	('ESCC', 'Disease', (93, 97))	('tumour', 'Disease', (45, 51))	('FLOT-1', 'Gene', (72, 78))	('miR-485-5p', 'Var', (24, 34))
305914	33846817	These results suggested that the 3'UTR of FLOT-1 was a target of miR-485-5p, yet the interaction was abolished in this sequence by point mutations.	('miR-485-5p', 'Var', (65, 75))	('FLOT-1', 'Gene', '10211', (42, 48))	('point mutations', 'Var', (131, 146))	('FLOT-1', 'Gene', (42, 48))	('miR-485-5p', 'Chemical', '-', (65, 75))
305916	33846817	It has been reported that miR-485-5p can reverse EMT in non-small cell lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('miR-485-5p', 'Chemical', '-', (26, 36))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (56, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (60, 82))	('miR-485-5p', 'Var', (26, 36))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
305917	33846817	As the present study confirmed that miR-485-5p overexpression could inhibit the migration and invasion of ESCC cells, it was of significance to determine the association between miR-485-5p and EMT in ESCC cells by evaluating the mRNA and protein expression levels of EMT-associated factors.	('miR-485-5p', 'Var', (178, 188))	('inhibit', 'NegReg', (68, 75))	('miR-485-5p', 'Chemical', '-', (36, 46))	('miR-485-5p', 'Var', (36, 46))	('miR-485-5p', 'Chemical', '-', (178, 188))
305918	33846817	The RT-qPCR and western blotting results revealed that E-cadherin expression in Eca 109 and KYSE 30 cells transfected with miR-485-5p mimics was increased, whereas Vimentin, N-cadherin and ZEB1 expression levels were decreased (Fig.	('E-cadherin', 'Gene', (55, 65))	('E-cadherin', 'Gene', '999', (55, 65))	('decreased', 'NegReg', (217, 226))	('N-cadherin', 'Gene', (174, 184))	('Vimentin', 'Gene', '7431', (164, 172))	('increased', 'PosReg', (145, 154))	('expression', 'MPA', (66, 76))	('N-cadherin', 'Gene', '1000', (174, 184))	('ZEB1', 'Gene', '6935', (189, 193))	('miR-485-5p', 'Chemical', '-', (123, 133))	('miR-485-5p mimics', 'Var', (123, 140))	('Eca', 'Chemical', '-', (80, 83))	('ZEB1', 'Gene', (189, 193))	('Vimentin', 'Gene', (164, 172))
305919	33846817	To illustrate the influence of miR-485-5p on tumour growth in vivo, Eca 109 cells transfected with lentivirus-miR-485-5p were injected into the flanks of nude mice, while cells transfected with lentivirus-NC were utilized as the negative control (Fig.	('miR-485-5p', 'Chemical', '-', (110, 120))	('Eca', 'Chemical', '-', (68, 71))	('lentivirus-miR-485-5p', 'Var', (99, 120))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour growth', 'Disease', (45, 58))	('nude mice', 'Species', '10090', (154, 163))	('tumour growth', 'Disease', 'MESH:D006130', (45, 58))	('miR-485-5p', 'Chemical', '-', (31, 41))
305920	33846817	5C-E, the lentivirus-miR-485-5p group exhibited an observable decline in tumour volume and weight compared with the control group.	('tumour', 'Disease', (73, 79))	('lentivirus-miR-485-5p', 'Var', (10, 31))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('miR-485-5p', 'Chemical', '-', (21, 31))	('decline', 'NegReg', (62, 69))
305921	33846817	On day 32, the volume and weight of tumours transfected with lentivirus-miR-485-5p were 1,324.5+-201.39 mm3 and 0.45+-0.11 g, respectively, while those of the negative control were 2,482.83+-555.13 mm3 and 0.76+-0.15 g, respectively.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('lentivirus-miR-485-5p', 'Var', (61, 82))	('weight of tumours', 'Disease', (26, 43))	('weight of tumours', 'Disease', 'MESH:D009369', (26, 43))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('miR-485-5p', 'Chemical', '-', (72, 82))
305923	33846817	The protein expression levels of Ki-67, FLOT-1, N-cadherin and Vimentin, compared with those in the control group, were all obviously decreased in the lentivirus-miR-485-5p transfection group, while E-cadherin was elevated (Fig.	('decreased', 'NegReg', (134, 143))	('FLOT-1', 'Gene', '10211', (40, 46))	('Vimentin', 'Gene', (63, 71))	('Vimentin', 'Gene', '7431', (63, 71))	('FLOT-1', 'Gene', (40, 46))	('N-cadherin', 'Gene', (48, 58))	('E-cadherin', 'Gene', (199, 209))	('protein expression levels', 'MPA', (4, 29))	('Ki-67', 'Gene', (33, 38))	('N-cadherin', 'Gene', '1000', (48, 58))	('lentivirus-miR-485-5p transfection', 'Var', (151, 185))	('E-cadherin', 'Gene', '999', (199, 209))	('transfection', 'Var', (173, 185))	('miR-485-5p', 'Chemical', '-', (162, 172))
305924	33846817	In summary, miR-485-5p played roles as a tumour suppressor and apoptosis promotor of ESCC in vivo.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('miR-485-5p', 'Chemical', '-', (12, 22))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('ESCC', 'Disease', (85, 89))	('miR-485-5p', 'Var', (12, 22))	('apoptosis', 'CPA', (63, 72))	('tumour', 'Disease', (41, 47))
305928	33846817	miR-485-5p has been demonstrated to be a functional tumour suppressor.	('miR-485-5p', 'Var', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Disease', (52, 58))	('miR-485-5p', 'Chemical', '-', (0, 10))
305929	33846817	Duan et al reported that miR-485-5p functions as a tumour suppressor in gastric cancer by targeting 7,8-dihydro-8-oxoguanine triphosphatase.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('miR-485-5p', 'Var', (25, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('tumour', 'Disease', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('targeting', 'Reg', (90, 99))	('gastric cancer', 'Disease', (72, 86))	('miR-485-5p', 'Chemical', '-', (25, 35))
305930	33846817	Gao et al discovered that miR-485-5p blocks the WW domain-binding protein 2/Wnt signalling pathway to inhibit the progression of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (129, 153))	('miR-485-5p', 'Chemical', '-', (26, 36))	('miR-485-5p', 'Var', (26, 36))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (129, 153))	('progression', 'CPA', (114, 125))	('inhibit', 'NegReg', (102, 109))	('WW domain-binding protein 2/Wnt signalling pathway', 'Pathway', (48, 98))	('hepatocellular carcinoma', 'Disease', (129, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('blocks', 'NegReg', (37, 43))
305931	33846817	The inhibitory function of miR-485-5p has also been reported in thyroid cancer, cholangiocarcinoma, lung cancer, osteosarcoma, breast cancer and EC.	('thyroid cancer', 'Disease', 'MESH:D013964', (64, 78))	('reported', 'Reg', (52, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('thyroid cancer', 'Phenotype', 'HP:0002890', (64, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', (100, 111))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('osteosarcoma, breast cancer', 'Disease', 'MESH:D001943', (113, 140))	('cholangiocarcinoma', 'Disease', (80, 98))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (80, 98))	('thyroid cancer', 'Disease', (64, 78))	('miR-485-5p', 'Chemical', '-', (27, 37))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('miR-485-5p', 'Var', (27, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('inhibitory function', 'NegReg', (4, 23))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))
305932	33846817	Han et al discovered that miR-485-5p, which can downregulate the expression of O-linked N-acetylglucosamine transferase, represses the proliferation and invasion of EC cells.	('represses', 'NegReg', (121, 130))	('miR-485-5p', 'Chemical', '-', (26, 36))	('expression', 'MPA', (65, 75))	('miR-485-5p', 'Var', (26, 36))	('downregulate', 'NegReg', (48, 60))
305933	33846817	The present study showed that miR-485-5p was reduced in human ESCC, and that overexpression of miR-485-5p could suppress the proliferation, migration and invasion of ESCC cell lines.	('reduced', 'NegReg', (45, 52))	('overexpression', 'PosReg', (77, 91))	('proliferation', 'CPA', (125, 138))	('miR-485-5p', 'Chemical', '-', (30, 40))	('human', 'Species', '9606', (56, 61))	('invasion', 'CPA', (154, 162))	('miR-485-5p', 'Chemical', '-', (95, 105))	('suppress', 'NegReg', (112, 120))	('miR-485-5p', 'Var', (95, 105))	('ESCC', 'Disease', (62, 66))	('ESCC', 'Disease', (166, 170))
305934	33846817	Through bioinformatics prediction, FLOT-1 was identified as a potential target of miR-485-5p.	('FLOT-1', 'Gene', (35, 41))	('miR-485-5p', 'Chemical', '-', (82, 92))	('FLOT-1', 'Gene', '10211', (35, 41))	('miR-485-5p', 'Var', (82, 92))
305935	33846817	Previous studies have revealed that the dysregulation of FLOT is involved in various cancers.	('FLOT', 'Protein', (57, 61))	('dysregulation', 'Var', (40, 53))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('involved', 'Reg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
305937	33846817	Furthermore, Liu et al verified that highly expressed FLOT-2 facilitates proliferation, migration and invasion in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('proliferation', 'CPA', (73, 86))	('invasion', 'CPA', (102, 110))	('migration', 'CPA', (88, 97))	('FLOT-2', 'Gene', '2319', (54, 60))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('highly expressed', 'Var', (37, 53))	('FLOT-2', 'Gene', (54, 60))	('facilitates', 'PosReg', (61, 72))	('melanoma', 'Disease', (114, 122))
305940	33846817	Moreover, Jang et al reported that the sumoylation of FLOT-1 promotes EMT in metastatic prostate cancer.	('FLOT-1', 'Gene', '10211', (54, 60))	('prostate cancer', 'Disease', (88, 103))	('promotes', 'PosReg', (61, 69))	('FLOT-1', 'Gene', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('sumoylation', 'Var', (39, 50))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('EMT in', 'CPA', (70, 76))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))
305942	33846817	It was verified that the expression of FLOT-1 could be directly reduced by the upregulation of miR-485-5p in ESCC.	('expression', 'MPA', (25, 35))	('FLOT-1', 'Gene', (39, 45))	('miR-485-5p', 'Chemical', '-', (95, 105))	('miR-485-5p', 'Var', (95, 105))	('reduced', 'NegReg', (64, 71))	('FLOT-1', 'Gene', '10211', (39, 45))	('upregulation', 'PosReg', (79, 91))
305943	33846817	As shown in the present study, miR-485-5p overexpression inhibited cell proliferation, migration, invasion and EMT in ESCC, thus it is reasonable to conclude that miR-485-5p can inhibit these cell behaviours by repressing FLOT-1 expression.	('migration', 'CPA', (87, 96))	('ESCC', 'Disease', (118, 122))	('miR-485-5p', 'Chemical', '-', (163, 173))	('repressing', 'PosReg', (211, 221))	('inhibited', 'NegReg', (57, 66))	('invasion', 'CPA', (98, 106))	('miR-485-5p', 'Var', (163, 173))	('EMT', 'CPA', (111, 114))	('FLOT-1', 'Gene', (222, 228))	('inhibit', 'NegReg', (178, 185))	('cell proliferation', 'CPA', (67, 85))	('FLOT-1', 'Gene', '10211', (222, 228))	('miR-485-5p', 'Chemical', '-', (31, 41))	('expression', 'MPA', (229, 239))
305946	33846817	Overall, understanding the underlying actions of miR-485-5p in the pathogenesis of ESCC will increase the knowledge of the biological basis of tumour progression, which will increase the possibility of developing a novel diagnostic marker and original therapeutic strategy for ESCC.	('ESCC', 'Disease', (83, 87))	('miR-485-5p', 'Chemical', '-', (49, 59))	('miR-485-5p', 'Var', (49, 59))	('increase', 'PosReg', (93, 101))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('increase', 'PosReg', (174, 182))	('tumour', 'Disease', (143, 149))
306009	30891750	Thermal injury may increase ESCC risk by inducing inflammatory processes, which might directly affect DNA bases and/or increase the formation of carcinogenic N-nitroso compounds.	('DNA bases', 'MPA', (102, 111))	('inducing', 'Reg', (41, 49))	('increase ESCC', 'Phenotype', 'HP:0003565', (19, 32))	('Thermal injury', 'Var', (0, 14))	('N-nitroso compounds', 'Chemical', '-', (158, 177))	('affect', 'Reg', (95, 101))	('increase', 'PosReg', (119, 127))	('ESCC', 'Disease', (28, 32))	('carcinogenic', 'Disease', 'MESH:D063646', (145, 157))	('inflammatory processes', 'CPA', (50, 72))	('carcinogenic', 'Disease', (145, 157))
306012	30891750	In those studies, hot water by itself did not show positive results, but it increased the incidence of esophageal pre-neoplastic or neoplastic lesions induced by N-nitroso compounds.	('neoplastic lesions', 'Disease', 'MESH:D007680', (132, 150))	('water', 'Chemical', 'MESH:D014867', (22, 27))	('neoplastic lesions', 'Disease', (132, 150))	('esophageal pre-neoplastic', 'Disease', (103, 128))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (132, 150))	('N-nitroso compounds', 'Var', (162, 181))	('neoplastic or neoplastic lesions', 'Phenotype', 'HP:0002664', (118, 150))	('N-nitroso compounds', 'Chemical', '-', (162, 181))
306035	32055786	During DNA methylation, direct methylation of cytosine in CG dinucleotides, which is one of epigenetic modifications is believed to be an irreversible epigenetic event related to gene repression and tumorigenesis.	('tumor', 'Disease', (199, 204))	('cytosine', 'Chemical', 'MESH:D003596', (46, 54))	('dinucleotides', 'Chemical', 'MESH:C015772', (61, 74))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('methylation', 'Var', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
306039	32055786	TET2 mutations have been reported to be frequently observed in various cancers, such as leucocythemia, including acute myelocytic leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelodysplastic syndrome (MDS).	('chronic myelomonocytic leukemia', 'Disease', (146, 177))	('MDS', 'Disease', 'MESH:D009190', (216, 219))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (146, 177))	('acute myelocytic leukemia', 'Phenotype', 'HP:0004808', (113, 138))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('myelodysplastic syndrome', 'Disease', (190, 214))	('leucocythemia', 'Disease', (88, 101))	('MDS', 'Disease', (216, 219))	('myelocytic leukemia', 'Disease', 'MESH:D007951', (119, 138))	('myelocytic leukemia', 'Phenotype', 'HP:0012324', (119, 138))	('mutations', 'Var', (5, 14))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (146, 177))	('observed', 'Reg', (51, 59))	('TET2', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('CMML', 'Disease', (179, 183))	('CMML', 'Disease', 'MESH:D015477', (179, 183))	('leucocythemia', 'Disease', 'MESH:D007938', (88, 101))	('CMML', 'Phenotype', 'HP:0012325', (179, 183))	('leukemia', 'Phenotype', 'HP:0001909', (130, 138))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (190, 214))	('myelocytic leukemia', 'Disease', (119, 138))	('MDS', 'Phenotype', 'HP:0002863', (216, 219))	('leukemia', 'Phenotype', 'HP:0001909', (169, 177))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (190, 214))	('AML', 'Phenotype', 'HP:0004808', (140, 143))
306040	32055786	TET2 mutations were frequently identified in other hematologic malignancies including angioimmunoblastic T-cell lymphoma and mature lymphoid neoplasms.	('lymphoid neoplasms', 'Disease', (132, 150))	('TET2', 'Gene', (0, 4))	('neoplasms', 'Phenotype', 'HP:0002664', (141, 150))	('lymphoid neoplasms', 'Phenotype', 'HP:0002665', (132, 150))	('hematologic malignancies', 'Disease', (51, 75))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (105, 120))	('identified', 'Reg', (31, 41))	('cell lymphoma', 'Phenotype', 'HP:0012191', (107, 120))	('angioimmunoblastic T-cell lymphoma', 'Disease', (86, 120))	('mutations', 'Var', (5, 14))	('neoplasm', 'Phenotype', 'HP:0002664', (141, 149))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('angioimmunoblastic T-cell lymphoma', 'Disease', 'MESH:D016399', (86, 120))	('hematologic malignancies', 'Disease', 'MESH:D019337', (51, 75))	('lymphoid neoplasms', 'Disease', 'MESH:D008223', (132, 150))
306052	32055786	It was demonstrated that the loss or mutations of TET2 could have an influence on the differentiation and fate of CD4+ T cell, CD8+ T cell, and invariant natural killer T (iNKT) cells.	('CD8', 'Gene', (127, 130))	('differentiation', 'CPA', (86, 101))	('CD4', 'Gene', (114, 117))	('TET2', 'Gene', (50, 54))	('loss', 'NegReg', (29, 33))	('CD4', 'Gene', '920', (114, 117))	('CD8', 'Gene', '925', (127, 130))	('mutations', 'Var', (37, 46))	('influence', 'Reg', (69, 78))	('fate', 'CPA', (106, 110))
306056	32055786	The loss of TET2 confers abnormal CD4+ T cell proliferation and differentiation.	('CD4', 'Gene', (34, 37))	('CD4', 'Gene', '920', (34, 37))	('TET2', 'Gene', (12, 16))	('abnormal CD4+ T cell', 'Phenotype', 'HP:0005407', (25, 45))	('differentiation', 'CPA', (64, 79))	('loss', 'Var', (4, 8))
306062	32055786	Genome-wide analysis revealed an increase in 5-hmC in neuroectoderm genes in Sirt6 knockout embryonic stem cells.	('Sirt6', 'Gene', (77, 82))	('Sirt6', 'Gene', '51548', (77, 82))	('increase', 'PosReg', (33, 41))	('5-hmC in', 'MPA', (45, 53))	('knockout', 'Var', (83, 91))	('5-hmC', 'Chemical', 'MESH:C011865', (45, 50))
306073	32055786	The knock-down of TET2 inhibited gastric cancer, hepatocellular carcinoma growth, and cell proliferation.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (49, 73))	('gastric cancer', 'Disease', (33, 47))	('TET2', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (33, 47))	('inhibited', 'NegReg', (23, 32))	('hepatocellular carcinoma growth', 'Disease', (49, 80))	('knock-down', 'Var', (4, 14))	('hepatocellular carcinoma growth', 'Disease', 'MESH:D006528', (49, 80))	('cell proliferation', 'CPA', (86, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
306076	32055786	In this study, worse survival was significantly associated with low level of the oncogenic long noncoding RNA (lncRNA-ANRIL), and TET2 knock-down markedly up-regulated the expression of lncRNA-ANRIL, inhibitor of cyclin kinase 4a, inhibitor of cyclin kinase 4b, and alternative reading-frame.	('ANRIL', 'Gene', (193, 198))	('ANRIL', 'Gene', (118, 123))	('expression', 'MPA', (172, 182))	('knock-down', 'Var', (135, 145))	('TET2', 'Gene', (130, 134))	('ANRIL', 'Gene', '100048912', (193, 198))	('ANRIL', 'Gene', '100048912', (118, 123))	('up-regulated', 'PosReg', (155, 167))
306078	32055786	Subsequently, TET2 repressed E-cadherin expression by interacting with histone deacetylase 1 and reducing the levels of H3K9Ac and H4K16Ac, and attenuated beta-catenin transactivation in hepatocellular carcinoma cells.	('TET2', 'Gene', (14, 18))	('E-cadherin', 'Gene', (29, 39))	('E-cadherin', 'Gene', '999', (29, 39))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (187, 211))	('reducing', 'NegReg', (97, 105))	('H4K16Ac', 'Chemical', 'MESH:C024755', (131, 138))	('attenuated', 'NegReg', (144, 154))	('histone deacetylase 1', 'Gene', (71, 92))	('levels', 'MPA', (110, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (187, 211))	('H3K9Ac', 'MPA', (120, 126))	('beta-catenin', 'Gene', (155, 167))	('H4K16Ac', 'Var', (131, 138))	('beta-catenin', 'Gene', '1499', (155, 167))	('interacting', 'Interaction', (54, 65))	('hepatocellular carcinoma', 'Disease', (187, 211))	('histone deacetylase 1', 'Gene', '3065', (71, 92))	('H3K9Ac', 'Chemical', 'MESH:C024755', (120, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
306081	32055786	The loss of 5-hmC or TET2 might affect the development of esophageal squamous cell carcinoma and facilitate gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (108, 130))	('development', 'CPA', (43, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('5-hmC', 'Chemical', 'MESH:C011865', (12, 17))	('affect', 'Reg', (32, 38))	('esophageal squamous cell carcinoma', 'Disease', (58, 92))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (108, 130))	('5-hmC', 'Protein', (12, 17))	('facilitate', 'PosReg', (97, 107))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (58, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('TET2', 'Gene', (21, 25))	('loss', 'Var', (4, 8))
306086	32055786	For p53-null tumor cells, TET2 acted as a positive contributor to chemotherapy resistant properties, and the sensitivity of anti-cancer treatment increased after TET2 deletion.	('tumor', 'Disease', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('p53', 'Gene', '7157', (4, 7))	('TET2', 'Gene', (162, 166))	('increased', 'PosReg', (146, 155))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('chemotherapy resistant properties', 'CPA', (66, 99))	('deletion', 'Var', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('sensitivity', 'MPA', (109, 120))	('p53', 'Gene', (4, 7))
306088	32055786	Mutations of TET2 gene were frequently identified in myeloid malignancies with a frequency of 20% in MDS, 45% in CMML, 20% in AML, and 20% in myeloproliferative neoplasm.	('AML', 'Disease', (126, 129))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (142, 169))	('neoplasm', 'Phenotype', 'HP:0002664', (161, 169))	('myeloproliferative neoplasm', 'Disease', (142, 169))	('CMML', 'Disease', (113, 117))	('myeloid malignancies', 'Disease', 'OMIM:601308', (53, 73))	('MDS', 'Disease', (101, 104))	('myeloproliferative neoplasm', 'Disease', 'MESH:D009196', (142, 169))	('MDS', 'Disease', 'MESH:D009190', (101, 104))	('CMML', 'Disease', 'MESH:D015477', (113, 117))	('MDS', 'Phenotype', 'HP:0002863', (101, 104))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (39, 49))	('TET2', 'Gene', (13, 17))	('myeloid malignancies', 'Disease', (53, 73))	('CMML', 'Phenotype', 'HP:0012325', (113, 117))	('AML', 'Phenotype', 'HP:0004808', (126, 129))
306089	32055786	TET2 mutation showed adverse prognostic effect and inferior overall survival in AML patients.	('TET2', 'Gene', (0, 4))	('patients', 'Species', '9606', (84, 92))	('AML', 'Phenotype', 'HP:0004808', (80, 83))	('inferior', 'NegReg', (51, 59))	('overall', 'MPA', (60, 67))	('mutation', 'Var', (5, 13))
306090	32055786	Mutated TET2 showed a higher response rate to azacitidine in MDS and low blast count AMLs.	('higher', 'PosReg', (22, 28))	('response', 'MPA', (29, 37))	('low blast count AMLs', 'CPA', (69, 89))	('TET2', 'Gene', (8, 12))	('AML', 'Phenotype', 'HP:0004808', (85, 88))	('azacitidine', 'Chemical', 'MESH:D001374', (46, 57))	('MDS', 'Disease', (61, 64))	('MDS', 'Disease', 'MESH:D009190', (61, 64))	('MDS', 'Phenotype', 'HP:0002863', (61, 64))	('Mutated', 'Var', (0, 7))
306091	32055786	TET2 mutations occurred in early disease evolution in MDS.	('TET2', 'Gene', (0, 4))	('occurred', 'Reg', (15, 23))	('mutations', 'Var', (5, 14))	('MDS', 'Disease', (54, 57))	('MDS', 'Disease', 'MESH:D009190', (54, 57))	('MDS', 'Phenotype', 'HP:0002863', (54, 57))
306092	32055786	TET2 mutations were also found in T cell lymphomas and diffuse large B-cell lymphoma.	('TET2', 'Gene', (0, 4))	('lymphoma', 'Phenotype', 'HP:0002665', (76, 84))	('lymphoma', 'Disease', (41, 49))	('T cell lymphomas', 'Disease', 'MESH:D016399', (34, 50))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (69, 84))	('T cell lymphomas', 'Disease', (34, 50))	('lymphoma', 'Disease', 'MESH:D008223', (41, 49))	('mutations', 'Var', (5, 14))	('lymphomas', 'Phenotype', 'HP:0002665', (41, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (41, 49))	('T cell lymphomas', 'Phenotype', 'HP:0012190', (34, 50))	('lymphoma', 'Disease', (76, 84))	('cell lymphoma', 'Phenotype', 'HP:0012191', (71, 84))	('lymphoma', 'Disease', 'MESH:D008223', (76, 84))	('cell lymphoma', 'Phenotype', 'HP:0012191', (36, 49))	('found', 'Reg', (25, 30))
306094	32055786	The above gene mutations may together promote the development of various hematological malignancies.	('hematological malignancies', 'Phenotype', 'HP:0004377', (73, 99))	('mutations', 'Var', (15, 24))	('hematological malignancies', 'Disease', (73, 99))	('promote', 'PosReg', (38, 45))	('hematological malignancies', 'Disease', 'MESH:D019337', (73, 99))
306096	32055786	It was reported that a rare variation of TET2 was associated with prostate carcinoma in African-American.	('prostate carcinoma', 'Disease', (66, 84))	('prostate carcinoma', 'Disease', 'MESH:D011471', (66, 84))	('variation', 'Var', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('associated', 'Reg', (50, 60))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (66, 84))	('TET2', 'Gene', (41, 45))
306100	32055786	The current mechanistic understanding of TET2 mutations in relation to hematological malignancies has been clarified.	('hematological malignancies', 'Disease', 'MESH:D019337', (71, 97))	('mutations', 'Var', (46, 55))	('hematological malignancies', 'Phenotype', 'HP:0004377', (71, 97))	('hematological malignancies', 'Disease', (71, 97))	('TET2', 'Gene', (41, 45))
306148	31324827	In the training set, 103 patients with advanced ESCC (cT2-4N1M0) received CCRT during 2012-2016 as part of the NCT01551589 trial, although 20 patients were excluded from the present study based on M1 status (7 patients), age of >75 years (5 patients), and abnormal liver function (8 patients).	('abnormal liver function', 'Disease', (256, 279))	('abnormal liver function', 'Phenotype', 'HP:0002910', (256, 279))	('abnormal liver', 'Phenotype', 'HP:0001392', (256, 270))	('patients', 'Species', '9606', (283, 291))	('cT2-4N1M0', 'Var', (54, 63))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (210, 218))	('abnormal liver function', 'Disease', 'MESH:D056486', (256, 279))	('patients', 'Species', '9606', (142, 150))	('ESCC', 'Disease', (48, 52))	('patients', 'Species', '9606', (241, 249))
306169	31324827	The Beijing datasets included 283 patients who were treated for ESCC (56 patients received CCRT and 227 patients received RT alone), with CCRT being associated with prolonged PFS (P = 0.091) and OS (P = 0.003) (Fig.	('ESCC', 'Disease', (64, 68))	('PFS', 'MPA', (175, 178))	('CCRT', 'Var', (138, 142))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (104, 112))	('OS', 'Chemical', '-', (195, 197))
306170	31324827	In the high-risk compactness group, CCRT also provided prolonged PFS (P = 0.09) and OS (P = 0.01) (Fig.	('OS', 'Chemical', '-', (84, 86))	('PFS', 'MPA', (65, 68))	('CCRT', 'Var', (36, 40))	('prolonged', 'PosReg', (55, 64))
306175	31324827	Among 10 randomly selected pairing results, 6 pairs revealed that the high-risk patients experienced a PFS benefit from CCRT, although no benefits were observed in the low-to-moderate compactness groups (Table S3).	('benefit', 'PosReg', (107, 114))	('CCRT', 'Var', (120, 124))	('patients', 'Species', '9606', (80, 88))	('PFS', 'MPA', (103, 106))
306181	31324827	However, among patients without pCR, low-to-moderate compactness was associated with longer OS (P = 0.009) and PFS (P = 0.03) than in the high-risk group (Figure S4).	('low-to-moderate compactness', 'Var', (37, 64))	('patients', 'Species', '9606', (15, 23))	('PFS', 'CPA', (111, 114))	('OS', 'Chemical', '-', (92, 94))
306194	31324827	The RTOG8501 trial showed that CCRT significantly increased OS relative to RT alone.	('OS', 'Chemical', '-', (60, 62))	('increased', 'PosReg', (50, 59))	('CCRT', 'Var', (31, 35))
306199	31324827	Therefore, among patients in the low-risk group, KPS may help predict prolonged survival.	('KPS', 'Var', (49, 52))	('prolonged survival', 'CPA', (70, 88))	('patients', 'Species', '9606', (17, 25))
306214	29440931	Next, multivariate logistic regression analysis showed that therapeutic method (hazard ratio [HR]=1.225, P=0.032), NLR (HR=2.697, P=0.019), and VLN (HR=4.607, P=0.034) were independent risk factors for tumor response.	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('VLN', 'Var', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', (202, 207))
306243	29440931	The overall survival (OS) curves based on pretreatment VLN, DLN, NLR, and LMR were plotted using the Kaplan-Meier method, and differences were assessed by the log-rank test.	('VLN', 'Var', (55, 58))	('DLN', 'Var', (60, 63))	('OS', 'Chemical', '-', (22, 24))
306245	29440931	ROC curves were also plotted to verify the accuracy of VLN, DLN, NLR, and PLR for therapeutic effect and OS prediction.	('VLN', 'Var', (55, 58))	('DLN', 'Var', (60, 63))	('OS', 'Chemical', '-', (105, 107))
306251	29440931	A total of 119 patients with LNM after resection of esophageal carcinoma were grouped according to the median values of NLR, PLR, and the size of LNM, including VLN and DLN, as shown in Table 2.	('patients', 'Species', '9606', (15, 23))	('esophageal carcinoma', 'Disease', (52, 72))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (52, 72))	('DLN', 'Var', (169, 172))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (52, 72))	('VLN', 'Var', (161, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
306252	29440931	Next, multivariate logistic regression analysis showed that therapeutic method (HR=1.225, 95% CI: 1.085-2.837, P=0.032), NLR (HR=2.697, 95% CI: 1.201-7.429, P=0.019), and VLN (HR=4.607, 95% CI: 1.124-18.889, P=0.034) were independent risk factors for tumor response.	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('VLN', 'Var', (171, 174))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (251, 256))
306262	29440931	The results showed that NLR, VLN, DLN, and therapeutic method were considered independent prognostic factors for OS, whereas PLR did not indicate a statistical difference associated with OS (Table 3).	('DLN', 'Var', (34, 37))	('VLN', 'Var', (29, 32))	('OS', 'Chemical', '-', (187, 189))	('NLR', 'Disease', (24, 27))	('OS', 'Chemical', '-', (113, 115))
306272	29440931	Single-station LNM was the most common type of failure and the location of metastasis in the bilateral supraclavicular areas as well as the superior mediastinum was more frequent than in other regions.	('type of failure', 'Disease', (39, 54))	('metastasis', 'CPA', (75, 85))	('Single-station', 'Var', (0, 14))	('type of failure', 'Disease', 'MESH:D017093', (39, 54))
306278	29440931	The results found that patients who suffered the large tumor burden (VLN >= 48.12 cm3 and DLN >= 4.61 cm) had significantly worse therapeutic efficacy and OS than those who suffered small tumor burden (VLN < 48.12 cm3 and DLN < 4.61 cm).	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('OS', 'Chemical', '-', (155, 157))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('therapeutic efficacy', 'CPA', (130, 150))	('tumor', 'Disease', (55, 60))	('DLN >= 4.61 cm', 'Var', (90, 104))	('worse', 'NegReg', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('small tumor', 'Disease', 'MESH:D058405', (182, 193))	('small tumor', 'Disease', (182, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('VLN >= 48.12 cm3', 'Var', (69, 85))
306287	29440931	Furthermore, the multivariate analysis showed that only NLR < 3.33 had significantly better therapeutic efficacy (HR=2.697, 95% CI: 1.201-7.429, P=0.019) and OS (HR=2.000, 95% CI: 1.127-3.548, P=0.018) than those who had NLR >= 3.33 This study has several potential limitations.	('better', 'PosReg', (85, 91))	('therapeutic efficacy', 'CPA', (92, 112))	('OS', 'Chemical', '-', (158, 160))	('NLR < 3.33', 'Var', (56, 66))
306344	28754910	Foods containing beta-carotene, vitamin C, folate, pyridoxine, and vitamin E are negatively associated with esophageal cancer, and foods containing selenium is considered to be protective against gastric cancer.	('vitamin E', 'Chemical', 'MESH:D014810', (67, 76))	('selenium', 'Chemical', 'MESH:D012643', (148, 156))	('pyridoxine', 'Chemical', 'MESH:D011736', (51, 61))	('associated', 'Interaction', (92, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (196, 210))	('esophageal cancer', 'Disease', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('folate', 'Chemical', 'MESH:D005492', (43, 49))	('negatively', 'NegReg', (81, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('beta-carotene', 'Chemical', 'MESH:D019207', (17, 30))	('vitamin C', 'Chemical', 'MESH:D001205', (32, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (196, 210))	('gastric cancer', 'Disease', (196, 210))	('pyridoxine', 'Var', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
306418	26957908	In Asian countries, especially in South Korea and Japan, BRTO is performed more frequently than TIPS to treat gastric variceal hemorrhage, because BRTO is less invasive and reportedly improves hepatic function of the patients.	('improves', 'PosReg', (184, 192))	('hepatic function', 'MPA', (193, 209))	('BRTO', 'Var', (147, 151))	('patients', 'Species', '9606', (217, 225))	('gastric variceal hemorrhage', 'Disease', (110, 137))	('improves hepatic function', 'Phenotype', 'HP:0001410', (184, 209))	('gastric variceal hemorrhage', 'Disease', 'MESH:D006471', (110, 137))
306440	26957908	Thirteen patients had F3 GV, of which, 2 had active gastric variceal bleeding.	('patients', 'Species', '9606', (9, 17))	('gastric variceal bleeding', 'Disease', 'MESH:D004932', (52, 77))	('GV', 'Phenotype', 'HP:0030169', (25, 27))	('F3 GV', 'Var', (22, 27))	('gastric variceal bleeding', 'Disease', (52, 77))
306588	25147738	The cells were incubated for 24 hrs with IC50 of the Pd(II) complexes and control was maintained in RPMI-1640 medium supplemented with 10% FBS.	('FBS', 'Disease', 'MESH:D005198', (139, 142))	('FBS', 'Disease', (139, 142))	('Pd(II)', 'Chemical', '-', (53, 59))	('RPMI-1640 medium', 'Chemical', '-', (100, 116))	('IC50', 'Var', (41, 45))
306611	25147738	Flow cytometry analysis demonstrated that, with the IC50 values of the complexes, the population of AGS and HepG2 cells in the G2/M checkpoint was increased significantly with respect to controls.	('IC50 values', 'Var', (52, 63))	('HepG2', 'CellLine', 'CVCL:0027', (108, 113))	('increased', 'PosReg', (147, 156))	('AGS', 'Disease', (100, 103))	('G2/M checkpoint', 'CPA', (127, 142))	('AGS', 'Disease', 'MESH:C535607', (100, 103))
306613	25147738	The Pd complexes caused an S phase arrest in Kyse-30 cell line (measured at 24 h after treatment), which is not expected since Pd(II) complex treatment leads to DNA damage in the G2-M phase of the cell cycle (P < 0.05, for 23.92%, 21.31%, and 25.17% of complexes-1-3 treated cells, with respect to 16.6% of untreated cells, resp.)	('Pd', 'Chemical', 'MESH:D010165', (4, 6))	('S', 'Chemical', 'MESH:D013455', (27, 28))	('complexes', 'Var', (7, 16))	('N', 'Chemical', 'MESH:D009584', (162, 163))	('DNA damage', 'MPA', (161, 171))	('S phase arrest', 'CPA', (27, 41))	('Pd(II)', 'Chemical', '-', (127, 133))	('Pd', 'Chemical', 'MESH:D010165', (127, 129))	('G2-M phase of the cell cycle', 'CPA', (179, 207))
306653	24348823	Epigenetic silencing of checkpoint with fork-head associated and ring finger gene expression in esophageal cancer Checkpoint with fork-head associated and ring finger (CHFR) is a mitotic checkpoint gene with tumor-suppressor functions.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Disease', (208, 213))
306654	24348823	Previous studies have described the hypermethylation of the CpG island in the promoter region as a key mechanism involved in silencing tumor suppressor genes.	('silencing', 'NegReg', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('hypermethylation', 'Var', (36, 52))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
306657	24348823	Aberrant hypermethylation of the CHFR gene was observed in 13 of 29 primary esophageal cancers.	('Aberrant hypermethylation', 'Var', (0, 25))	('primary esophageal cancers', 'Disease', (68, 94))	('CHFR gene', 'Gene', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('observed', 'Reg', (47, 55))	('primary esophageal cancers', 'Disease', 'MESH:D004938', (68, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))
306659	24348823	Hypermethylation of the CHFR gene is a common event in the development of primary esophageal cancer.	('primary esophageal cancer', 'Disease', (74, 99))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('primary esophageal cancer', 'Disease', 'MESH:D004938', (74, 99))	('CHFR', 'Gene', (24, 28))
306660	24348823	CpG island hypermethylation of the promoter region in the CHFR gene is a key mechanism involved in silencing the CHFR gene in patients with esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('CHFR', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('hypermethylation', 'Var', (11, 27))	('silencing', 'NegReg', (99, 108))	('patients', 'Species', '9606', (126, 134))	('CHFR gene', 'Gene', (113, 122))	('esophageal cancer', 'Disease', (140, 157))
306668	24348823	To date, a growing number of studies have reported that the loss of tumor suppressor genes is often caused by epigenetic alterations, including methylation of DNA.	('tumor', 'Disease', (68, 73))	('epigenetic alterations', 'Var', (110, 132))	('caused', 'Reg', (100, 106))	('methylation', 'Var', (144, 155))	('DNA', 'Gene', (159, 162))	('loss', 'NegReg', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
306692	24348823	Amplification of the methylated DNA-specific PCR primers was observed in 13 of 29 primary esophageal cancers (44.8%), while that of the unmethylated primers was observed in 16 patients (55.2%).	('primary esophageal cancers', 'Disease', (82, 108))	('DNA-specific PCR', 'Gene', (32, 48))	('patients', 'Species', '9606', (176, 184))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('PCR', 'Gene', (45, 48))	('primary esophageal cancers', 'Disease', 'MESH:D004938', (82, 108))	('methylated', 'Var', (21, 31))	('observed', 'Reg', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Amplification', 'MPA', (0, 13))
306698	24348823	The epigenetically-mediated loss-of-gene function is a well-known mechanism involved in carcinogenesis.	('loss-of-gene function', 'NegReg', (28, 49))	('carcinogenesis', 'Disease', (88, 102))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))	('epigenetically-mediated', 'Var', (4, 27))
306699	24348823	Several tumor suppressor genes containing CpG islands can be silenced via methylation of the CpG island.	('methylation', 'Var', (74, 85))	('CpG', 'Gene', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('silenced', 'NegReg', (61, 69))
306700	24348823	Previously, aberrant methylation of the CHFR gene associated with gene silencing has been demonstrated in several studies, although it has not been fully clarified how the CHFR gene is regulated in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (198, 215))	('aberrant methylation', 'Var', (12, 32))	('methylation', 'Var', (21, 32))	('CHFR gene', 'Gene', (40, 49))	('esophageal cancer', 'Disease', (198, 215))	('gene', 'MPA', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
306702	24348823	The results indicate that aberrant methylation of the CHFR gene is frequently (44.8%) observed in esophageal cancer.	('observed', 'Reg', (86, 94))	('aberrant methylation', 'Var', (26, 46))	('CHFR', 'Gene', (54, 58))	('esophageal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
306708	24348823	Taken together, results of the present study indicate that aberrant hypermethylation of CpG islands is the key mechanism associated with transcriptional inactivation of the CHFR gene in patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('associated', 'Reg', (121, 131))	('esophageal cancer', 'Disease', (200, 217))	('aberrant hypermethylation', 'Var', (59, 84))	('CHFR', 'Gene', (173, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (200, 217))	('transcriptional', 'MPA', (137, 152))	('patients', 'Species', '9606', (186, 194))
306735	33939693	Cells that comprise this field are assumed at equal risk to acquire 1 or more driver mutations (with rate mu1) that allow premalignant (or "cancerized") stem cells to proliferate and to form dysplastic foci.	('dysplastic foci', 'Disease', (191, 206))	('dysplastic foci', 'Disease', 'MESH:D004416', (191, 206))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('proliferate', 'CPA', (167, 178))
306740	33939693	For a two-stage clonal expansion model (i.e., a single initiating mutational event is required to induce dysplastic cell proliferation), we have  with  and  with  Rather than fitting the model parameters p and q, we use the combinations g = -(p + q) = alpha - beta - mu2 (net cell proliferation) and pq = -alphamu2 (  malignant transformation).	('dysplastic', 'Disease', (105, 115))	('pq = -alphamu2', 'Var', (300, 314))	('dysplastic', 'Disease', 'MESH:D004416', (105, 115))
306764	33939693	Although environmental exposures, such as cigarette smoking, alcohol consumption may contribute to field formation later in life, the young-age signatures and time trends of the inferred premalignant field-defect suggest that other factors such as pediatric malnutrition and vitamin deficiencies may significantly influence ESCC incidence patterns in the US.	('ESCC', 'Disease', (324, 328))	('influence', 'Reg', (314, 323))	('alcohol', 'Chemical', 'MESH:D000438', (61, 68))	('malnutrition', 'Disease', (258, 270))	('contribute', 'Reg', (85, 95))	('men', 'Species', '9606', (16, 19))	('malnutrition', 'Disease', 'MESH:D044342', (258, 270))	('malnutrition', 'Phenotype', 'HP:0004395', (258, 270))	('deficiencies', 'Var', (283, 295))
306769	33939693	Importantly, the sporadic (independent) stem cell mutation scenario (Fig 3A) yields mutation rates that are implausible while the field-defect scenario yields estimates that are in line with the concept of an abnormal (defective) esophageal tissue in which rare (rate-limiting) mutations lead to the initiation of dysplasia.	('mutations', 'Var', (278, 287))	('lead to', 'Reg', (288, 295))	('initiation of dysplasia', 'Disease', 'MESH:D007319', (300, 323))	('mutation', 'Var', (50, 58))	('initiation of dysplasia', 'Disease', (300, 323))
306770	33939693	Since mutations in TP53 are found in virtually all ESCC and occur frequently in BE and EAC, it is plausible to assume that the first mutation in the field-defect involves TP53 LOH, associated with loss of TP53 tumor suppressor function, followed by a malignant transformation in response (or due) to the loss of TP53 control consistent with Knudson's two-hit model.	('TP53', 'Gene', (171, 175))	('mutation', 'Var', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('TP53', 'Gene', '7157', (205, 209))	('tumor', 'Disease', (210, 215))	('TP53', 'Gene', (205, 209))	('TP53', 'Gene', '7157', (171, 175))	('loss', 'NegReg', (197, 201))	('ESCC', 'Disease', (51, 55))	('LOH', 'Var', (176, 179))	('TP53', 'Gene', (19, 23))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', '7157', (312, 316))	('malignant transformation', 'CPA', (251, 275))	('mutations', 'Var', (6, 15))	('TP53', 'Gene', (312, 316))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
306775	33939693	Environmental exposures, such as cigarette smoking, alcohol and industrial exposures may well contribute to field formation later in life (and increased promotion of precursor lesions), however the young-age signatures and time trends of the inferred premalignant field-defect suggest that other factors such as pediatric malnutrition, iron deficiency anemia (IDA) and deficiencies of some B vitamins (e.g.	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (336, 358))	('malnutrition', 'Disease', (322, 334))	('malnutrition', 'Disease', 'MESH:D044342', (322, 334))	('iron deficiency anemia', 'Disease', (336, 358))	('malnutrition', 'Phenotype', 'HP:0004395', (322, 334))	('iron deficiency anemia', 'Disease', 'MESH:D018798', (336, 358))	('anemia', 'Phenotype', 'HP:0001903', (352, 358))	('deficiencies', 'Var', (369, 381))	('men', 'Species', '9606', (7, 10))	('alcohol', 'Chemical', 'MESH:D000438', (52, 59))
306887	29709526	Auto-antibodies to tumor associated antigens (TAAs) have been proposed as biomarkers for cancer due to their stability in serum.	('Auto-antibodies', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
306888	29709526	The most comprehensively studied TAA is P53, in which a mutation results in a non-functioning protein that has a longer half-life than the native protein, and the subsequent anti-P53 can be detected non-invasively in serum.	('P53', 'Gene', (40, 43))	('P53', 'Gene', '7157', (40, 43))	('P53', 'Gene', (179, 182))	('non-functioning', 'MPA', (78, 93))	('P53', 'Gene', '7157', (179, 182))	('mutation', 'Var', (56, 64))	('longer half-life', 'MPA', (113, 129))	('results in', 'Reg', (65, 75))
306895	29709526	Oncogenesis by way of modifications in DNA methylation occurs via two fundamental changes: (1) hypermethylation of CpG islands in gene promoters, which can silence tumor suppressor genes; and (2) hypomethylation of repetitive genetic elements, which may lead to genomic instability or oncogene activation.	('silence tumor', 'Disease', (156, 169))	('oncogene', 'CPA', (285, 293))	('hypomethylation', 'Var', (196, 211))	('lead to', 'Reg', (254, 261))	('activation', 'PosReg', (294, 304))	('modifications', 'Var', (22, 35))	('genomic', 'MPA', (262, 269))	('silence tumor', 'Disease', 'MESH:D009369', (156, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
306896	29709526	Methylated DNA markers (MDMs) have been shown to be broadly informative markers of neoplasia and are a critical component of a multi-target stool DNA test, FDA-approved for average risk colorectal cancer screening.	('MDM', 'Gene', (24, 27))	('MDM', 'Gene', '57152', (24, 27))	('neoplasia', 'Phenotype', 'HP:0002664', (83, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (186, 203))	('neoplasia', 'Disease', 'MESH:D009369', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('colorectal cancer', 'Phenotype', 'HP:0003003', (186, 203))	('Methylated', 'Var', (0, 10))	('neoplasia', 'Disease', (83, 92))	('colorectal cancer', 'Disease', (186, 203))
306903	29709526	In samples from non-endoscopic balloons from 86 individuals, tests of CCNA1 and VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity in another recently published study.	('tests', 'Var', (61, 66))	('CCNA1', 'Gene', (70, 75))	('VIM', 'Gene', (80, 83))	('CCNA1', 'Gene', '8900', (70, 75))	('VIM', 'Gene', '7431', (80, 83))
306908	29709526	Using a marker panel of 2-4 MDMs, the AUCs were 0.997 (95% CI 0.99-1.0), 0.99 (95% CI 0.98-1.0), and 0.97 (95% CI 0.93-0.99), for US, Iran, and China respectively, corresponding to sensitivities and specificities >95%.	('0.97', 'Var', (101, 105))	('0.99', 'Var', (73, 77))	('MDM', 'Gene', (28, 31))	('MDM', 'Gene', '57152', (28, 31))
306961	31551000	The accuracy rate in T2 staging was 77%, with 18 patients with T2 stage and 3 patients with overstaging.	('T2 stage', 'Var', (63, 71))	('T2 staging', 'Disease', (21, 31))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (49, 57))
306962	31551000	The accuracy rate for T3 stage was 42%, with 14 patients with T3 stage, 7 patients with understaging, and 8 patients with overstaging.	('T3 stage', 'Var', (62, 70))	('patients', 'Species', '9606', (74, 82))	('T3 stage', 'Disease', (22, 30))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (48, 56))
306989	31551000	Additionally, the prognoses in patients with positive lymph nodes were significantly worse than those with negative lymph nodes.	('positive lymph nodes', 'Var', (45, 65))	('patients', 'Species', '9606', (31, 39))	('worse', 'NegReg', (85, 90))
307034	31036015	Dose constraints for the lung were V20 Gy < 30%, V30 Gy < 20% and V20 Gy < 1000 ml; for the spinal cord a maximum dose (Dmax) of < 47 Gy; for the esophagus a Dmax < 74 Gy and for the heart a mean dose (Dmean) of < 35 Gy, D(33%) < 60 Gy und D(50%) < 45 Gy.	('Gy', 'Chemical', 'MESH:C022013', (53, 55))	('Gy', 'Chemical', 'MESH:C022013', (134, 136))	('Gy', 'Chemical', 'MESH:C022013', (252, 254))	('Gy', 'Chemical', 'MESH:C022013', (233, 235))	('Gy', 'Chemical', 'MESH:C022013', (217, 219))	('Gy', 'Chemical', 'MESH:C022013', (168, 170))	('< 47 Gy', 'Var', (129, 136))	('Gy', 'Chemical', 'MESH:C022013', (70, 72))	('V20', 'Var', (66, 69))	('Gy', 'Chemical', 'MESH:C022013', (39, 41))
307043	31036015	The resulting regression coefficient was 1516 HU/Gy (p = 0,000) for all values and 1439 HU/Gy (p = 0,000) and 1612 HU/Gy (p = 0,000) when looking at 12 weeks and 6 months separately.	('1439 HU/Gy', 'Var', (83, 93))	('1516 HU/Gy', 'Var', (41, 51))	('Gy', 'Chemical', 'MESH:C022013', (49, 51))	('1612 HU/Gy', 'Var', (110, 120))	('Gy', 'Chemical', 'MESH:C022013', (118, 120))	('Gy', 'Chemical', 'MESH:C022013', (91, 93))
307079	29262582	There was a significantly better 5-year CSS in patients with NLR/Alb <= 0.1 than patients with NLR/Alb > 0.1 (39.1% vs. 11.0%, P < 0.001).	('Alb', 'Gene', (99, 102))	('<= 0.1', 'Var', (69, 75))	('Alb', 'Gene', (65, 68))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (81, 89))	('CSS', 'Chemical', '-', (40, 43))	('Alb', 'Gene', '213', (99, 102))	('CSS', 'CPA', (40, 43))	('Alb', 'Gene', '213', (65, 68))	('better', 'PosReg', (26, 32))
307103	29262582	The areas under the curve (AUC) was 0.702 (95% CI: 0.635-0.763, P < 0.001) for CRP/Alb and 0.678 (95% CI: 0.574-0.716, P < 0.001) for NLR/Alb, respectively.	('0.678', 'Var', (91, 96))	('Alb', 'Gene', '213', (83, 86))	('Alb', 'Gene', (83, 86))	('CRP/Alb', 'Gene', (79, 86))	('Alb', 'Gene', (138, 141))	('CRP/Alb', 'Gene', '1401;213', (79, 86))	('Alb', 'Gene', '213', (138, 141))
307119	29262582	Kaplan-Meier analyses demonstrated that there was a significantly better 5-year CSS in patients with NLR/Alb <= 0.1 than patients with NLR/Alb > 0.1 (39.1% vs. 11.0%, P < 0.001).	('CSS', 'Chemical', '-', (80, 83))	('Alb', 'Gene', '213', (105, 108))	('better', 'PosReg', (66, 72))	('Alb', 'Gene', '213', (139, 142))	('<= 0.1', 'Var', (109, 115))	('CSS', 'CPA', (80, 83))	('Alb', 'Gene', (105, 108))	('patients', 'Species', '9606', (87, 95))	('Alb', 'Gene', (139, 142))	('patients', 'Species', '9606', (121, 129))
307164	28402940	Currently, increasing studies have reported that aberrant expression of specific microRNAs (miRs) as stable molecular biomarkers was associated with the prognosis of GIC patients and related to the targeted therapy, which provides potentially novel prevention strategies and advanced therapies.	('patients', 'Species', '9606', (170, 178))	('GIC', 'Disease', (166, 169))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('aberrant expression', 'Var', (49, 68))	('related', 'Reg', (183, 190))	('associated', 'Reg', (133, 143))
307173	28402940	At present, accumulative evidences have demonstrated that abnormal expression of miRs as stable molecular biomarkers presented potential huge prognostic values in GIC patients.	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (81, 84))	('GIC', 'Disease', (163, 166))	('abnormal', 'Var', (58, 66))	('patients', 'Species', '9606', (167, 175))	('expression', 'MPA', (67, 77))
307209	28402940	(1) Aberrant expression of different miRs was associated with the survival of patients and miR-21 as a stable molecular biomarker can predict the individual prognosis through detecting its expression levels in GIC patients.	('miR', 'Gene', (91, 94))	('expression levels', 'MPA', (189, 206))	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('patients', 'Species', '9606', (214, 222))	('expression', 'MPA', (13, 23))	('Aberrant', 'Var', (4, 12))	('miR-21', 'Gene', '406991', (91, 97))	('detecting', 'Reg', (175, 184))	('patients', 'Species', '9606', (78, 86))	('associated', 'Reg', (46, 56))	('miR-21', 'Gene', (91, 97))	('miR', 'Gene', '220972', (91, 94))
307212	28402940	(4) Abnormal miRs expression may provide a clinically valuable application for identifying patients with high risk at early stage avoiding advanced cancer progression.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('patients', 'Species', '9606', (91, 99))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Abnormal', 'Var', (4, 12))
307294	27124046	A definitive diagnosis may be obtained with pathological analysis and identification of positivity for S-100 and human melanoma black (HMB)-45 on immunohistochemical examination.	('HMB)-45', 'Gene', (135, 142))	('melanoma black', 'Disease', 'MESH:D008545', (119, 133))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('S-100', 'Gene', (103, 108))	('positivity', 'Var', (88, 98))	('melanoma black', 'Disease', (119, 133))	('human', 'Species', '9606', (113, 118))
307330	27124046	Mutations in the BRAF and KIT genes in subsets of melanoma have been reported.	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('BRAF', 'Gene', '673', (17, 21))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('KIT', 'Gene', (26, 29))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (17, 21))
307331	27124046	Langer et al detected a mutation of the c-KIT gene in 2 patients with PMME.	('patients', 'Species', '9606', (56, 64))	('PMME', 'Chemical', '-', (70, 74))	('c-KIT', 'Gene', '3815', (40, 45))	('detected', 'Reg', (13, 21))	('mutation', 'Var', (24, 32))	('PMME', 'Disease', (70, 74))	('c-KIT', 'Gene', (40, 45))
307332	27124046	BRAF inhibitors may be useful in the treatment of metastatic melanoma in patients with BRAF mutations.	('mutations', 'Var', (92, 101))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (87, 91))	('patients', 'Species', '9606', (73, 81))	('BRAF', 'Gene', '673', (87, 91))
307343	22684976	Survival in the BD-stent group was significantly longer than in the control group (9.2 vs. 2.4 weeks, p = 0.01).	('Survival', 'CPA', (0, 8))	('BD-stent', 'Var', (16, 24))	('longer', 'PosReg', (49, 55))	('BD-stent', 'Chemical', '-', (16, 24))
307389	22684976	At 2 weeks post-EEM, the last week that all five control animals were alive, the BD-stent group had a significantly less reduction in esophageal diameter (77.7 % vs. 26.6 %, p < 0.001) and degree of proximal dilation (175 % vs. 131 %, p = 0.04) compared with controls.	('esophageal diameter', 'CPA', (134, 153))	('less reduction', 'NegReg', (116, 130))	('BD-stent', 'Var', (81, 89))	('BD-stent', 'Chemical', '-', (81, 89))
307391	22684976	Survival in the BD-stent group was significantly longer than in the control group (9.2 weeks vs. 2.4, p = 0.01).	('Survival', 'CPA', (0, 8))	('BD-stent', 'Var', (16, 24))	('longer', 'PosReg', (49, 55))	('BD-stent', 'Chemical', '-', (16, 24))
307393	22684976	However, there was significantly greater shortening of the esophagus in the BD-stent group compared with the control group (43.4 +- 13.6 % vs. 59.6 +- 6.8 %, p = 0.045) immediately before euthanasia (Fig.	('shortening', 'NegReg', (41, 51))	('BD-stent', 'Var', (76, 84))	('BD-stent', 'Chemical', '-', (76, 84))
307414	25654238	Associations of PI3KR1 and mTOR Polymorphisms with Esophageal Squamous Cell Carcinoma Risk and Gene-Environment Interactions in Eastern Chinese Populations Single nucleotide polymorphisms (SNPs) in the PI3K/PTEN/AKT/mTOR signaling pathway may contribute to carcinogenesis.	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (51, 85))	('AKT', 'Gene', (212, 215))	('Associations', 'Interaction', (0, 12))	('PI3KR1', 'Gene', (16, 22))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('Esophageal Squamous Cell Carcinoma', 'Disease', (51, 85))	('PTEN', 'Gene', (207, 211))	('mTOR', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (207, 211))	('contribute', 'Reg', (243, 253))	('carcinogenesis', 'Disease', 'MESH:D063646', (257, 271))	('Carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('AKT', 'Gene', '207', (212, 215))	('mTOR', 'Gene', '2475', (216, 220))	('Single nucleotide polymorphisms', 'Var', (156, 187))	('mTOR', 'Gene', (216, 220))	('carcinogenesis', 'Disease', (257, 271))	('mTOR', 'Gene', '2475', (27, 31))
307417	25654238	Moreover, three mTOR haplotypes were associated with an increase in ESCC risk.	('ESCC', 'Disease', (68, 72))	('mTOR', 'Gene', '2475', (16, 20))	('increase', 'Reg', (56, 64))	('mTOR', 'Gene', (16, 20))	('haplotypes', 'Var', (21, 31))
307418	25654238	Our meta-analysis of mTOR rs2295080 and cancer risk provided further evidence that mTOR SNPs might modulate cancer susceptibility.	('mTOR', 'Gene', (83, 87))	('rs2295080', 'Mutation', 'rs2295080', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('rs2295080', 'Var', (26, 35))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mTOR', 'Gene', '2475', (83, 87))	('modulate', 'Reg', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mTOR', 'Gene', (21, 25))	('mTOR', 'Gene', '2475', (21, 25))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
307425	25654238	Besides well-established risk factors, such as poor nutritional status, low intake of fruits and vegetables, smoking, alcohol intake, and drinking hot beverages, genetic variation in some key genes has been also suggested to modulate ESCC risk.	('ESCC', 'Disease', (234, 238))	('genetic variation', 'Var', (162, 179))	('alcohol', 'Chemical', 'MESH:D000438', (118, 125))	('modulate', 'Reg', (225, 233))
307426	25654238	For example, numerous studies have demonstrated the existence of the association between ESCC risk and heritable genetic variants in genes involved in metabolism (e.g., Glutathione S-transferase Mu 1 and Methylenetetrahydrofolate reductase), DNA repair (e.g., X-ray repair cross-complementing protein 1 and Oxoguanine glycosylase), and cell cycle control (p53).	('Methylenetetrahydrofolate reductase', 'Gene', (204, 239))	('Glutathione S-transferase Mu 1', 'Gene', '2944', (169, 199))	('X-ray repair cross-complementing protein 1', 'Gene', '7515', (260, 302))	('Methylenetetrahydrofolate reductase', 'Gene', '4524', (204, 239))	('variants', 'Var', (121, 129))	('association', 'Interaction', (69, 80))	('ESCC', 'Disease', (89, 93))	('p53', 'Gene', '7157', (356, 359))	('Glutathione S-transferase Mu 1', 'Gene', (169, 199))	('X-ray repair cross-complementing protein 1', 'Gene', (260, 302))	('DNA', 'MPA', (242, 245))	('cell cycle control', 'CPA', (336, 354))	('p53', 'Gene', (356, 359))
307427	25654238	Apart from these, genetic variation in genes of other cancer-related pathways may also play a role in ESCC susceptibility.	('ESCC', 'Disease', (102, 106))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('play', 'Reg', (87, 91))	('genetic variation', 'Var', (18, 35))
307431	25654238	PI3Ks debuted in the cancer research field back in the mid-1980s.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (21, 27))	('PI3Ks', 'Var', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
307438	25654238	Accumulating evidence has shown that mutations in some genes (PIK3CA, RAS, PTEN, and AKT) of the pathway could result in neoplastic transformation in both cellular and animal models, suggesting a critical role of the pathway in carcinogenesis.	('result in', 'Reg', (111, 120))	('carcinogenesis', 'Disease', (228, 242))	('neoplastic transformation', 'CPA', (121, 146))	('PIK3CA', 'Gene', (62, 68))	('RAS', 'Gene', (70, 73))	('AKT', 'Gene', '207', (85, 88))	('mutations', 'Var', (37, 46))	('PTEN', 'Gene', (75, 79))	('PIK3CA', 'Gene', '5290', (62, 68))	('PTEN', 'Gene', '5728', (75, 79))	('AKT', 'Gene', (85, 88))	('carcinogenesis', 'Disease', 'MESH:D063646', (228, 242))
307439	25654238	Aberrant activation of this pathway has been closely related to various cancers, including ESCC.	('activation', 'PosReg', (9, 19))	('related', 'Reg', (53, 60))	('Aberrant', 'Var', (0, 8))	('ESCC', 'Disease', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
307440	25654238	For example, it was reported that 11.5% of the tumors from ESCC patients harbored PIK3CA mutations and that the aberrant activation of mTOR occurred in 69.5% and 25% of ESCC in Japanese patients and Caucasian patients in the Netherlands, respectively.	('tumors', 'Disease', (47, 53))	('ESCC', 'Disease', (169, 173))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('PIK3CA', 'Gene', (82, 88))	('patients', 'Species', '9606', (64, 72))	('mTOR', 'Gene', '2475', (135, 139))	('mTOR', 'Gene', (135, 139))	('PIK3CA', 'Gene', '5290', (82, 88))	('harbored', 'Reg', (73, 81))	('ESCC', 'Disease', (59, 63))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (209, 217))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('patients', 'Species', '9606', (186, 194))
307441	25654238	Given the profound influence of aberrant activation of PI3K and mTOR on ESCC carcinogenesis, it is plausible that some potentially functional SNPs in genes encoding these proteins are likely to modulate ESCC susceptibility.	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('carcinogenesis', 'Disease', (77, 91))	('modulate', 'Reg', (194, 202))	('PI3K', 'Var', (55, 59))	('mTOR', 'Gene', (64, 68))	('ESCC', 'Disease', (203, 207))	('mTOR', 'Gene', '2475', (64, 68))	('activation', 'PosReg', (41, 51))	('SNPs', 'Var', (142, 146))	('ESCC', 'Disease', (72, 76))
307442	25654238	In contrast to extensive investigations regarding the mutations in these pathway genes, there are only a few studies exploring cancer risk associated with genetic variation in the same pathway genes.	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('genetic variation', 'Var', (155, 172))	('cancer', 'Disease', (127, 133))
307443	25654238	demonstrated that single nucleotide polymorphisms (SNPs) in PIK3CA and mTOR/FRAP1 genes were significantly associated with risk of colon and rectal cancers, respectively.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('FRAP1', 'Gene', (76, 81))	('PIK3CA', 'Gene', (60, 66))	('single nucleotide polymorphisms', 'Var', (18, 49))	('associated', 'Reg', (107, 117))	('PIK3CA', 'Gene', '5290', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colon and rectal cancers', 'Disease', 'MESH:D012004', (131, 155))	('mTOR', 'Gene', '2475', (71, 75))	('FRAP1', 'Gene', '2475', (76, 81))	('mTOR', 'Gene', (71, 75))	('rectal cancer', 'Phenotype', 'HP:0100743', (141, 154))
307444	25654238	Moreover, our group has previously reported associations of mTOR rs1883965 and rs2536 with risk of cancers of the esophagus, stomach, and prostate.	('rs2536', 'Mutation', 'rs2536', (79, 85))	('rs1883965', 'Var', (65, 74))	('rs2536', 'Var', (79, 85))	('stomach', 'Disease', (125, 132))	('rs1883965', 'Mutation', 'rs1883965', (65, 74))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers of the esophagus', 'Disease', (99, 123))	('mTOR', 'Gene', '2475', (60, 64))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (99, 123))	('mTOR', 'Gene', (60, 64))	('associations', 'Reg', (44, 56))	('prostate', 'Disease', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (99, 123))
307445	25654238	Two independent studies indicated that the mTOR rs1883965 SNP was significantly associated with an increased risk of gastric cancer and ESCC.	('rs1883965 SNP', 'Var', (48, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('ESCC', 'Disease', (136, 140))	('rs1883965', 'Mutation', 'rs1883965', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('associated', 'Reg', (80, 90))	('mTOR', 'Gene', (43, 47))	('gastric cancer', 'Disease', (117, 131))	('mTOR', 'Gene', '2475', (43, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (99, 131))
307446	25654238	In the present study, we expanded our previous studies by comprehensively analyzing additional potentially functional SNPs in the genes encoding class I PI3Ks and mTOR for their association with ESCC risk in an Eastern Chinese population.	('class I PI3Ks and mTOR', 'Gene', '2475', (145, 167))	('ESCC', 'Disease', (195, 199))	('association', 'Interaction', (178, 189))	('SNPs', 'Var', (118, 122))
307450	25654238	The minor allele frequencies (MAFs) of the SNP in these controls were similar to those reported in the CHB data from HapMap: 0.19 vs. 0.175 for rs3730089, 0.12 vs. 0.128 for rs3730090, 0.21 vs. 0.239 for rs2295080, 0.19 vs. 0.18 for rs1057079, and 0.078 vs. 0.109 for rs1064261, respectively.	('rs2295080', 'Var', (204, 213))	('rs3730089', 'Mutation', 'rs3730089', (144, 153))	('rs1057079', 'Mutation', 'rs1057079', (233, 242))	('rs1057079', 'Var', (233, 242))	('rs3730090', 'Var', (174, 183))	('rs2295080', 'Mutation', 'rs2295080', (204, 213))	('rs3730090', 'Mutation', 'rs3730090', (174, 183))	('rs1064261', 'Mutation', 'rs1064261', (268, 277))	('rs1064261', 'Var', (268, 277))	('rs3730089', 'Var', (144, 153))
307453	25654238	However, significant ESCC risk associated with three mTOR SNPs, but not PIK3R1 SNPs, was each individually observed among subjects with BMI < 25.0 under the dominant genetic model (WV/VV vs. WW) (rs2295080: adjusted OR = 1.36, 95% CI = 1.07-1.73; rs1057079: OR = 1.31, 95% CI = 1.03-1.67, rs1014261: OR = 1.39, 95% CI = 1.01-1.92) (Tables 3,4,5).	('rs1014261', 'Var', (289, 298))	('rs2295080:', 'Var', (196, 206))	('rs2295080', 'Mutation', 'rs2295080', (196, 205))	('rs1057079', 'Mutation', 'rs1057079', (247, 256))	('PIK3R1', 'Gene', (72, 78))	('rs1057079', 'Var', (247, 256))	('ESCC', 'Disease', (21, 25))	('PIK3R1', 'Gene', '5295', (72, 78))	('mTOR', 'Gene', (53, 57))	('mTOR', 'Gene', '2475', (53, 57))	('rs1014261', 'Mutation', 'rs1014261', (289, 298))
307455	25654238	We further explored the combined effects of these three SNPs in stratified analyses by age, sex, smoking status, drinking status, and BMI and found that significantly increased ESCC risk was identified for subjects carrying at least one of the three putative risk genotypes (i.e., rs2295080 GT/GG, rs1057079 CT/CC, and rs1014261 AG/GG) among the following subgroups: >60 years of age (adjusted OR = 1.28, 95% CI = 1.01-1.65), males (adjusted OR = 1.28, 95% CI = 1.05-1.56), ever-smokers (adjusted OR = 1.31, 95% CI = 1.03-1.67), ever-drinkers (adjusted OR = 1.34, 95% CI = 1.00-1.79) or BMI < 25.0 (adjusted OR = 1.52, 95% CI = 1.20-1.94) (Table 5).	('rs1057079', 'Mutation', 'rs1057079', (298, 307))	('rs1014261 AG/GG', 'Var', (319, 334))	('rs1014261', 'Mutation', 'rs1014261', (319, 328))	('ESCC', 'Disease', (177, 181))	('rs1057079 CT/CC', 'Var', (298, 313))	('increased', 'PosReg', (167, 176))	('rs2295080 GT/GG', 'Var', (281, 296))	('increased ESCC', 'Phenotype', 'HP:0003565', (167, 181))	('rs2295080', 'Mutation', 'rs2295080', (281, 290))
307456	25654238	Moreover, while evaluating the strength of associations between mTOR SNPs and ESCC risk among subgroups with BMI < 25.0, the OR (1.52, 95% CI = 1.20-1.94) of combined risk genotypes was larger than the ORs (1.31, 95% CI = 1.03-1.67 for rs1057079; 1.39, 95% CI = 1.01-1.92 for rs1014261; 1.36, 95% CI = 1.07-1.73 for rs2295080) of any individual risk genotype (Table 5), indicating that there was likely a combined effect of these three SNPs.	('rs1057079', 'Var', (236, 245))	('rs1014261', 'Var', (276, 285))	('ESCC', 'Disease', (78, 82))	('rs2295080', 'Mutation', 'rs2295080', (316, 325))	('rs1014261', 'Mutation', 'rs1014261', (276, 285))	('mTOR', 'Gene', (64, 68))	('mTOR', 'Gene', '2475', (64, 68))	('associations', 'Interaction', (43, 55))	('rs1057079', 'Mutation', 'rs1057079', (236, 245))	('rs2295080', 'Var', (316, 325))
307457	25654238	To further investigate the existence of possible gene-environmental interaction in association with ESCC risk, high-order interactions assessed by using the MDR analysis was performed with inclusion of the five selected SNPs (i.e., rs3730089, rs3730090, rs2295080, rs1057079, and rs1014261) and five known risk factors (i.e., age, sex, smoking status, drinking status, and BMI).	('rs2295080', 'Mutation', 'rs2295080', (254, 263))	('rs3730090', 'Var', (243, 252))	('rs3730090', 'Mutation', 'rs3730090', (243, 252))	('rs1057079', 'Var', (265, 274))	('ESCC', 'Disease', (100, 104))	('rs3730089', 'Var', (232, 241))	('rs1014261', 'Mutation', 'rs1014261', (280, 289))	('rs1057079', 'Mutation', 'rs1057079', (265, 274))	('rs2295080', 'Var', (254, 263))	('rs3730089', 'Mutation', 'rs3730089', (232, 241))	('rs1014261', 'Var', (280, 289))
307460	25654238	As presented in Table 8, logistic regression analyses identified significant gene-environment interactions of BMI with either mTOR rs1057079 or rs2295080 SNPs.	('rs2295080', 'Mutation', 'rs2295080', (144, 153))	('BMI', 'Gene', (110, 113))	('rs1057079', 'Mutation', 'rs1057079', (131, 140))	('rs1057079', 'Var', (131, 140))	('mTOR', 'Gene', (126, 130))	('mTOR', 'Gene', '2475', (126, 130))	('rs2295080 SNPs', 'Var', (144, 158))
307461	25654238	Moreover, our results further showed significant gene-gene interactions of mTOR rs2295080 with either mTOR rs1057079 or rs1064261.	('rs2295080', 'Var', (80, 89))	('rs1064261', 'Var', (120, 129))	('interactions', 'Interaction', (59, 71))	('rs1057079', 'Mutation', 'rs1057079', (107, 116))	('rs2295080', 'Mutation', 'rs2295080', (80, 89))	('rs1064261', 'Mutation', 'rs1064261', (120, 129))	('mTOR', 'Gene', (102, 106))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('mTOR', 'Gene', '2475', (102, 106))
307462	25654238	To date, six published studies have explored the association of mTOR rs2295080 with the risk of various cancers but yielded conflicting results, whereas fewer studies on other mTOR SNPs have been published.	('mTOR', 'Gene', '2475', (176, 180))	('rs2295080', 'Mutation', 'rs2295080', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mTOR', 'Gene', (176, 180))	('association', 'Interaction', (49, 60))	('mTOR', 'Gene', (64, 68))	('mTOR', 'Gene', '2475', (64, 68))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('rs2295080', 'Var', (69, 78))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
307463	25654238	When all the data were combined, the mTOR rs2295080 SNP appeared to be modestly protective and significantly associated with a decreased cancer risk under most of the genetic models tested without obvious among-study heterogeneity (homozygous: OR = 0.79, 95% CI = 0.66-0.95; heterozygous: OR = 0.88, 95% CI = 0.78-1.02, dominant: OR = 0.87, 95% CI = 0.80-0.94, recessive: OR = 0.82, 95% CI = 0.69-0.90) (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('rs2295080 SNP', 'Var', (42, 55))	('decreased', 'NegReg', (127, 136))	('rs2295080', 'Mutation', 'rs2295080', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mTOR', 'Gene', (37, 41))	('cancer', 'Disease', (137, 143))	('mTOR', 'Gene', '2475', (37, 41))
307465	25654238	Numerous studies have indicated that potentially functional SNPs in the important genes may confer host genetic susceptibility to cancer.	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('SNPs', 'Var', (60, 64))
307467	25654238	In the present study, however, none of the studied SNPs in the PIKR1 and mTOR genes exhibited an association with ESCC risk.	('mTOR', 'Gene', '2475', (73, 77))	('ESCC', 'Disease', (114, 118))	('mTOR', 'Gene', (73, 77))	('association', 'Interaction', (97, 108))	('SNPs', 'Var', (51, 55))	('PIKR1', 'Gene', (63, 68))
307468	25654238	Actually, lack of the main effect of individual SNPs on cancer risk does not necessarily rule out these SNPs as etiologic factors, because these SNPs may have low penetrance in cancer susceptibility, compared with environmental and life style factors contributing to the risk.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('SNPs', 'Var', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
307470	25654238	For example, our stratified analysis by BMI suggested a significantly increased ESCC risk associated with mTOR rs2295080, rs1057079, and rs1014261, individually, among subjects with BMI<25.0.	('rs1057079', 'Var', (122, 131))	('rs1057079', 'Mutation', 'rs1057079', (122, 131))	('increased', 'PosReg', (70, 79))	('mTOR', 'Gene', '2475', (106, 110))	('rs2295080', 'Mutation', 'rs2295080', (111, 120))	('rs1014261', 'Var', (137, 146))	('increased ESCC', 'Phenotype', 'HP:0003565', (70, 84))	('rs1014261', 'Mutation', 'rs1014261', (137, 146))	('mTOR', 'Gene', (106, 110))	('rs2295080', 'Var', (111, 120))	('ESCC', 'Disease', (80, 84))
307473	25654238	For example, one study observed an association between mTOR rs2295080 and a reduced risk of renal cancer in 710 cases and 760 controls.	('rs2295080', 'Mutation', 'rs2295080', (60, 69))	('renal cancer', 'Disease', 'MESH:D007680', (92, 104))	('renal cancer', 'Phenotype', 'HP:0009726', (92, 104))	('mTOR', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mTOR', 'Gene', '2475', (55, 59))	('rs2295080', 'Var', (60, 69))	('reduced', 'NegReg', (76, 83))	('renal cancer', 'Disease', (92, 104))
307474	25654238	In addition, mTOR rs2295080 was also shown to protect against gastric cancer risk in a Chinese population.	('rs2295080', 'Mutation', 'rs2295080', (18, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('protect', 'Reg', (46, 53))	('mTOR', 'Gene', (13, 17))	('rs2295080', 'Var', (18, 27))	('mTOR', 'Gene', '2475', (13, 17))	('gastric cancer', 'Disease', (62, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))
307475	25654238	Functional analysis demonstrated that the rs2295080 variant G allele reduced transcriptional activity in both normal gastric mucosa epithelial cell lines (GES-1) and three different gastric cancer cell lines, compared with the wide-type T allele.	('rs2295080', 'Mutation', 'rs2295080', (42, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('reduced', 'NegReg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('rs2295080', 'Var', (42, 51))	('gastric cancer', 'Disease', (182, 196))	('transcriptional activity', 'MPA', (77, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))
307476	25654238	Moreover, mTOR mRNA expression levels in gastric cancer tissues with GT/GG genotypes were significantly lower than those with the TT genotype, indicating that mTOR rs2295080 may decrease gastric cancer risk by affecting mTOR transcription.	('mTOR', 'Gene', '2475', (220, 224))	('decrease gastric cancer', 'Phenotype', 'HP:0006753', (178, 201))	('gastric cancer', 'Phenotype', 'HP:0012126', (187, 201))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))	('mTOR', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('decrease', 'NegReg', (178, 186))	('mTOR', 'Gene', '2475', (10, 14))	('rs2295080', 'Mutation', 'rs2295080', (164, 173))	('gastric cancer', 'Disease', (187, 201))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('mTOR', 'Gene', (159, 163))	('lower', 'NegReg', (104, 109))	('affecting', 'Reg', (210, 219))	('transcription', 'MPA', (225, 238))	('mTOR', 'Gene', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('gastric cancer', 'Disease', 'MESH:D013274', (187, 201))	('mTOR', 'Gene', '2475', (159, 163))	('rs2295080', 'Var', (164, 173))	('gastric cancer', 'Disease', (41, 55))
307477	25654238	Similarly, our meta-analysis of seven studies with 4772 cases and 5264 controls found that rs2295080 was significantly associated with a reduced cancer risk under homogenous (GG vs.TT) and recessive (GG vs.TT/TG) genetic models.	('cancer', 'Disease', (145, 151))	('rs2295080', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('rs2295080', 'Mutation', 'rs2295080', (91, 100))	('reduced', 'NegReg', (137, 144))
307480	25654238	For example, in contrast with other cancers, our study indicated that mTOR rs2295080 variant genotypes (GT/GG) were associated with an increased ESCC risk, and the association became significant among subjects with BMI<25.0.	('mTOR', 'Gene', (70, 74))	('mTOR', 'Gene', '2475', (70, 74))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('increased ESCC', 'Phenotype', 'HP:0003565', (135, 149))	('rs2295080', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('rs2295080', 'Mutation', 'rs2295080', (75, 84))	('ESCC', 'Disease', (145, 149))
307481	25654238	One explanation for the discrepancy in the association studies is that the function of rs2295080 SNP may be tissue-specific, but the biological function of this SNP should be further examined in different types of cancer in future studies.	('rs2295080', 'Mutation', 'rs2295080', (87, 96))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('rs2295080', 'Var', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
307483	25654238	One earlier U.S. study of 1574 colon cancer cases and 1940 healthy controls revealed a significant association between mTOR rs1057079 variant genotypes and increased risk of colon and rectal cancers, while this SNP was also associated with tumor harboring TP53 mutations.	('colon cancer', 'Disease', (31, 43))	('rs1057079 variant', 'Var', (124, 141))	('tumor', 'Disease', (240, 245))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('variant', 'Var', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('rs1057079', 'Mutation', 'rs1057079', (124, 133))	('colon cancer', 'Disease', 'MESH:D015179', (31, 43))	('mTOR', 'Gene', (119, 123))	('colon and rectal cancers', 'Disease', 'MESH:D012004', (174, 198))	('TP53', 'Gene', '7157', (256, 260))	('colon cancer', 'Phenotype', 'HP:0003003', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('TP53', 'Gene', (256, 260))	('rectal cancer', 'Phenotype', 'HP:0100743', (184, 197))	('mTOR', 'Gene', '2475', (119, 123))
307484	25654238	The same study also found an association of PIK3CA rs7651265 SNP with rectal cancer risk.	('PIK3CA', 'Gene', (44, 50))	('rs7651265', 'Mutation', 'rs7651265', (51, 60))	('PIK3CA', 'Gene', '5290', (44, 50))	('rectal cancer', 'Disease', 'MESH:D012004', (70, 83))	('rs7651265 SNP', 'Var', (51, 64))	('rectal cancer', 'Disease', (70, 83))	('rectal cancer', 'Phenotype', 'HP:0100743', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('association', 'Interaction', (29, 40))
307489	25654238	In the present study, significant mTOR SNP-related increases in ERCC risk were detected among subjects with BMI<25, but not among those with BMI >= 25.0, suggesting that BMI was a significant effect modifier of ERCC risk associated with mTOR SNPs.	('mTOR', 'Gene', '2475', (237, 241))	('mTOR', 'Gene', (237, 241))	('mTOR', 'Gene', (34, 38))	('increases', 'PosReg', (51, 60))	('BMI<25', 'Var', (108, 114))	('ERCC', 'Disease', (211, 215))	('mTOR', 'Gene', '2475', (34, 38))	('ERCC', 'Disease', (64, 68))
307490	25654238	In the present study, we found a significant interaction between BMI and either mTOR rs1057079 or rs2295080 SNPs.	('rs1057079', 'Mutation', 'rs1057079', (85, 94))	('rs1057079', 'Var', (85, 94))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('rs2295080 SNPs', 'Var', (98, 112))	('rs2295080', 'Mutation', 'rs2295080', (98, 107))
307491	25654238	Our results also showed that mTOR rs2295080 significantly interacted with either mTOR rs1057079 or rs1064261, suggesting that these SNPs of interest might collectively confer and modulate ESCC susceptibility.	('confer', 'Reg', (168, 174))	('rs2295080', 'Mutation', 'rs2295080', (34, 43))	('ESCC', 'Disease', (188, 192))	('rs1064261', 'Var', (99, 108))	('mTOR', 'Gene', (29, 33))	('mTOR', 'Gene', '2475', (29, 33))	('rs1057079', 'Mutation', 'rs1057079', (86, 95))	('rs1064261', 'Mutation', 'rs1064261', (99, 108))	('rs2295080', 'Var', (34, 43))	('modulate', 'Reg', (179, 187))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))
307493	25654238	Failure to investigate the association of PIK3CA polymorphisms with ESCC risk is also a potential limitation.	('ESCC', 'Disease', (68, 72))	('PIK3CA', 'Gene', (42, 48))	('association', 'Interaction', (27, 38))	('PIK3CA', 'Gene', '5290', (42, 48))	('polymorphisms', 'Var', (49, 62))
307494	25654238	In summary, we found that rs2295080, rs1057079, and rs1064261 SNPs in the mTOR gene may modify the host's genetic susceptibility to ESCC risk; however, these effects were largely dependent on other risk factors, i.e., BMI, age, sex, smoking and drinking status.	('modify', 'Reg', (88, 94))	('rs2295080', 'Var', (26, 35))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('rs1064261 SNPs', 'Var', (52, 66))	('rs1064261', 'Mutation', 'rs1064261', (52, 61))	('rs2295080', 'Mutation', 'rs2295080', (26, 35))	('rs1057079', 'Mutation', 'rs1057079', (37, 46))	('ESCC', 'Disease', (132, 136))	('rs1057079', 'Var', (37, 46))
307505	25654238	Ultimately, we chose five SNPs (PIK3R1: rs3730089 and rs3730090; mTOR: rs1057079, rs1064261, and rs2295080) for the study.	('mTOR', 'Gene', (65, 69))	('rs3730090', 'Var', (54, 63))	('mTOR', 'Gene', '2475', (65, 69))	('rs3730090', 'Mutation', 'rs3730090', (54, 63))	('rs1064261', 'Var', (82, 91))	('rs1064261', 'Mutation', 'rs1064261', (82, 91))	('rs1057079', 'Mutation', 'rs1057079', (71, 80))	('PIK3R1', 'Gene', '5295', (32, 38))	('rs2295080', 'Mutation', 'rs2295080', (97, 106))	('rs3730089', 'Var', (40, 49))	('rs2295080', 'Var', (97, 106))	('rs3730089', 'Mutation', 'rs3730089', (40, 49))	('PIK3R1', 'Gene', (32, 38))
307507	25654238	In the present study, we defined the haplotype as a combination of rs2295080, rs1014261, and rs1057079 SNPs in the mTOR gene.	('rs2295080', 'Var', (67, 76))	('rs1014261', 'Var', (78, 87))	('mTOR', 'Gene', '2475', (115, 119))	('mTOR', 'Gene', (115, 119))	('rs1057079', 'Mutation', 'rs1057079', (93, 102))	('rs2295080', 'Mutation', 'rs2295080', (67, 76))	('rs1014261', 'Mutation', 'rs1014261', (78, 87))	('rs1057079 SNPs', 'Var', (93, 107))
307508	25654238	Risk genotypes used for the calculation were PIK3R1 rs3730089 AG/AA, PIK3R1 rs3730090 CT/TT, mTOR rs2295080 GT/GG, mTOR rs1057079 CT/CC, mTOR rs1064261 AG/GG.	('rs1064261', 'Mutation', 'rs1064261', (142, 151))	('mTOR', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (115, 119))	('mTOR', 'Gene', '2475', (93, 97))	('rs3730089', 'Mutation', 'rs3730089', (52, 61))	('PIK3R1', 'Gene', '5295', (45, 51))	('mTOR', 'Gene', (115, 119))	('PIK3R1', 'Gene', (45, 51))	('rs3730089 AG/AA', 'Var', (52, 67))	('PIK3R1', 'Gene', '5295', (69, 75))	('mTOR', 'Gene', (137, 141))	('PIK3R1', 'Gene', (69, 75))	('mTOR', 'Gene', '2475', (137, 141))	('rs2295080', 'Mutation', 'rs2295080', (98, 107))	('rs3730090 CT/TT', 'Var', (76, 91))	('rs3730090', 'Mutation', 'rs3730090', (76, 85))	('rs1057079', 'Mutation', 'rs1057079', (120, 129))
307509	25654238	Finally, a meta-analysis was conducted to evaluate the association between mTOR rs2295080 SNP and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs2295080 SNP', 'Var', (80, 93))	('rs2295080', 'Mutation', 'rs2295080', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))
307522	19525073	Patients given taxanes chemotherapy as induction and concurrent chemotherapy had significantly higher PMRR and clinical pneumonitis symptoms than did patients whose chemotherapy did not include taxanes.	('pneumonitis', 'Disease', 'MESH:D011014', (120, 131))	('taxanes', 'Var', (15, 22))	('PMRR', 'Chemical', '-', (102, 106))	('higher', 'PosReg', (95, 101))	('taxanes', 'Chemical', 'MESH:D043823', (15, 22))	('taxanes', 'Chemical', 'MESH:D043823', (194, 201))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (150, 158))	('PMRR', 'MPA', (102, 106))	('pneumonitis', 'Disease', (120, 131))
307535	19525073	reported that sequential adjuvant paclitaxel followed by radiotherapy for breast cancer was associated with a very low risk (4-5%) of clinically apparent pneumonitis which was comparable to that among patients treated without paclitaxel in a retrospective analysis of 189 evaluable patients prospectively randomized to receive treatment with or without paclitaxel.	('patients', 'Species', '9606', (201, 209))	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('paclitaxel', 'Var', (34, 44))	('patients', 'Species', '9606', (282, 290))	('pneumonitis', 'Disease', (154, 165))	('paclitaxel', 'Chemical', 'MESH:D017239', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pneumonitis', 'Disease', 'MESH:D011014', (154, 165))	('paclitaxel', 'Chemical', 'MESH:D017239', (353, 363))	('paclitaxel', 'Chemical', 'MESH:D017239', (226, 236))
307574	19525073	No statistically significant differences were noted between the distributions of MLD, V5, V10, V20 and V30 (Table 3) between the three groups.	('MLD', 'Disease', 'MESH:D007966', (81, 84))	('V10', 'Var', (90, 93))	('V30', 'Var', (103, 106))	('MLD', 'Disease', (81, 84))	('V20', 'Var', (95, 98))
307589	19525073	Overall, higher PMRR and radiation dosimetric parameters (V20, V30, MLD) were associated with shorter time to symptom development.	('V30', 'Var', (63, 66))	('shorter', 'NegReg', (94, 101))	('MLD', 'Disease', (68, 71))	('MLD', 'Disease', 'MESH:D007966', (68, 71))	('PMRR', 'MPA', (16, 20))	('PMRR', 'Chemical', '-', (16, 20))	('V20', 'Var', (58, 61))	('higher', 'PosReg', (9, 15))
307591	19525073	For example, when included in the model with V20, the p-values of PMRR and V20 were 0.05 and 0.02, respectively; when included with V30 the p-values were 0.04 and 0.01, respectively; and when included with MLD the p-values were 0.06 and 0.02, respectively.	('PMRR', 'Chemical', '-', (66, 70))	('V20', 'Var', (75, 78))	('MLD', 'Disease', 'MESH:D007966', (206, 209))	('PMRR', 'Var', (66, 70))	('MLD', 'Disease', (206, 209))
307593	19525073	We found that patients who had had taxanes in both induction and concurrent chemotherapy had a higher crude rate of pneumonitis symptoms (74%) than did those who had received taxanes as either induction or concurrent taxanes (62%) or no taxanes (46%) (Table 4).	('pneumonitis', 'Disease', 'MESH:D011014', (116, 127))	('pneumonitis', 'Disease', (116, 127))	('taxanes', 'Var', (35, 42))	('taxanes', 'Chemical', 'MESH:D043823', (217, 224))	('taxanes', 'Chemical', 'MESH:D043823', (237, 244))	('patients', 'Species', '9606', (14, 22))	('taxanes', 'Chemical', 'MESH:D043823', (35, 42))	('taxanes', 'Chemical', 'MESH:D043823', (175, 182))
307625	19525073	Time to first symptom was significantly associated with PMRR and radiation dosimetry parameters (MLD, V20, and V30), in that higher PMRR and higher MLD, V20, or V30 were associated with shorter time to first symptom.	('MLD', 'Disease', (97, 100))	('MLD', 'Disease', (148, 151))	('PMRR', 'MPA', (132, 136))	('V20', 'Var', (153, 156))	('PMRR', 'Chemical', '-', (56, 60))	('MLD', 'Disease', 'MESH:D007966', (97, 100))	('PMRR', 'Chemical', '-', (132, 136))	('shorter', 'NegReg', (186, 193))	('V30', 'Var', (161, 164))	('MLD', 'Disease', 'MESH:D007966', (148, 151))
307646	23717493	For example, several studies detected substantially higher TP53 mutation rates in cases with GCA than GNCA, while the TP53 mutation spectrum in GCA more closely resembled EAC.	('TP53', 'Gene', (59, 63))	('mutation', 'Var', (64, 72))	('GCA', 'Disease', (93, 96))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('higher', 'PosReg', (52, 58))	('TP53', 'Gene', '7157', (59, 63))
307709	23717493	We identified 511 genes whose expression was dysregulated in gastric cancer overall, including nearly one-half (n = 239, 47%) dysregulated in both GCA and GNCA, one-fourth dysregulated in GCA only (n = 128, 25%), and about one-fourth in GNCA only (n = 144, 28%).	('expression', 'MPA', (30, 40))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('GNCA', 'Disease', (155, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('GCA', 'Disease', (188, 191))	('GCA', 'Disease', (147, 150))	('dysregulated', 'Var', (126, 138))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))
307902	30001285	Consumption of garlic and its interactions with tobacco smoking and alcohol drinking on esophageal cancer in a Chinese population Garlic consumption has been inversely associated with esophageal cancer (EC), however, its interactions with tobacco smoking and alcohol consumption have never been evaluated in an epidemiological study.	('associated', 'Reg', (168, 178))	('tobacco', 'Species', '4097', (239, 246))	('alcohol drinking', 'Phenotype', 'HP:0030955', (68, 84))	('alcohol', 'Chemical', 'MESH:D000438', (259, 266))	('alcohol', 'Chemical', 'MESH:D000438', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('inversely', 'NegReg', (158, 167))	('cancer', 'Disease', (99, 105))	('Garlic', 'Species', '4682', (130, 136))	('Garlic', 'Var', (130, 136))	('garlic', 'Species', '4682', (15, 21))	('tobacco', 'Species', '4097', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
307954	30001285	After adjusting for confounding factors, high intake of garlic was inversely associated with ES among non-smokers and non-drinkers, only smokers, only drinkers, as well as individuals who were both smoking and drinking.	('garlic', 'Species', '4682', (56, 62))	('garlic', 'Var', (56, 62))	('ES', 'Chemical', 'MESH:D004540', (93, 95))	('inversely', 'NegReg', (67, 76))
307969	30001285	Five studies in line with our study reported significant inverse association of garlic consumption with EC risk among the Chinese population, while 4 studies found it insignificant.	('garlic', 'Species', '4682', (80, 86))	('inverse', 'NegReg', (57, 64))	('garlic', 'Var', (80, 86))	('Chi', 'Gene', (122, 125))	('Chi', 'Gene', '107779699', (122, 125))
308002	27588470	UBE2C is overexpressed in ESCC tissues and its abrogation attenuates the malignant phenotype of ESCC cell lines The esophageal squamous cell carcinoma (ESCC) is widely known as a highly lethal and poor understood cancer, then requiring the search for novel molecular markers to improve its management and patients survival.	('esophageal squamous cell carcinoma', 'Disease', (116, 150))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('UBE2C', 'Gene', (0, 5))	('attenuates', 'NegReg', (58, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('abrogation', 'Var', (47, 57))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (305, 313))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (116, 150))	('cancer', 'Disease', (213, 219))	('malignant phenotype', 'CPA', (73, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('UBE2C', 'Gene', '11065', (0, 5))
308016	27588470	Moreover, it has been already shown that high UBE2C expression is also related with a highly malignant phenotype and a poor survival suggesting its role in cancer progression.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('high', 'Var', (41, 45))	('UBE2C', 'Gene', '11065', (46, 51))	('expression', 'MPA', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('UBE2C', 'Gene', (46, 51))
308018	27588470	Our results show that UBE2C is highly expressed in ESCC samples, but not in normal mucosa, and that its abrogation is capable of altering proliferation and cell cycle profile of ESCC cell lines, by directly interfering with cyclin B1 protein levels.	('abrogation', 'Var', (104, 114))	('cyclin B1', 'Gene', (224, 233))	('cyclin B1', 'Gene', '891', (224, 233))	('proliferation', 'CPA', (138, 151))	('cell cycle profile', 'CPA', (156, 174))	('interfering', 'NegReg', (207, 218))	('ESCC', 'Disease', (51, 55))	('UBE2C', 'Gene', '11065', (22, 27))	('UBE2C', 'Gene', (22, 27))	('altering', 'Reg', (129, 137))
308040	27588470	Next, 72 hours after UBE2C knockdown, its depletion was confirmed by qRT-PCR and Western blotting.	('UBE2C', 'Gene', '11065', (21, 26))	('knockdown', 'Var', (27, 36))	('depletion', 'MPA', (42, 51))	('UBE2C', 'Gene', (21, 26))
308044	27588470	The effect of synchronization and UBE2C abrogation on growth rates was less pronounced in TE-13 cells which presented a statistically significant decrease in their proliferation only 72 hours after UBE2C knockdown, when compared with both control cells and cells transfected with scrambled siRNA (Figure 4D).	('knockdown', 'Var', (204, 213))	('proliferation', 'CPA', (164, 177))	('UBE2C', 'Gene', '11065', (34, 39))	('UBE2C', 'Gene', (34, 39))	('TE-13', 'CellLine', 'CVCL:4463', (90, 95))	('UBE2C', 'Gene', '11065', (198, 203))	('decrease', 'NegReg', (146, 154))	('UBE2C', 'Gene', (198, 203))
308047	27588470	Together, these results show that UBE2C silencing is capable of altering crucial cellular features, such as proliferation and cell cycle profile, and these effects are more evident in TE-1 cells.	('UBE2C', 'Gene', '11065', (34, 39))	('UBE2C', 'Gene', (34, 39))	('proliferation', 'CPA', (108, 121))	('cell cycle profile', 'CPA', (126, 144))	('silencing', 'Var', (40, 49))	('altering', 'Reg', (64, 72))
308065	27588470	First, after the transient knockdown of UBE2C in the ESCC cell lines TE-1 and TE-13, we observed a significant decrease in TE-1 cell growth, at all time intervals analyzed during 72 hours, while in TE-13 cells, the statistically significant difference was observed only at the time interval of 72 hours.	('knockdown', 'Var', (27, 36))	('TE-13', 'CellLine', 'CVCL:4463', (78, 83))	('TE-13', 'CellLine', 'CVCL:4463', (198, 203))	('decrease', 'NegReg', (111, 119))	('UBE2C', 'Gene', '11065', (40, 45))	('TE-1 cell growth', 'CPA', (123, 139))	('UBE2C', 'Gene', (40, 45))
308069	27588470	Moreover, the cell lines TE-1 and TE-13 knocked down for UBE2C showed an increased expression of cyclin B1, that was more pronounced in TE-1 cells, in comparison to the cell lines transfected with a scrambled oligonucleotide and untransfected cells.	('UBE2C', 'Gene', (57, 62))	('knocked down', 'Var', (40, 52))	('increased', 'PosReg', (73, 82))	('oligonucleotide', 'Chemical', 'MESH:D009841', (209, 224))	('cyclin B1', 'Gene', '891', (97, 106))	('cyclin B1', 'Gene', (97, 106))	('expression', 'MPA', (83, 93))	('UBE2C', 'Gene', '11065', (57, 62))	('TE-13', 'CellLine', 'CVCL:4463', (34, 39))
308071	27588470	Therefore, our results suggest that the reduced growth rates observed in the ESCC cell lines upon UBE2C silencing might be a consequence of the arrest in G2/M phase of cell cycle, that is induced by a reduced degradation of cyclin B1, caused by the suppression of UBE2C expression, that was particularly observed in TE-1 cell line.	('cyclin B1', 'Gene', '891', (224, 233))	('cyclin B1', 'Gene', (224, 233))	('UBE2C', 'Gene', '11065', (98, 103))	('silencing', 'Var', (104, 113))	('UBE2C', 'Gene', '11065', (264, 269))	('UBE2C', 'Gene', (264, 269))	('reduced growth rates', 'Phenotype', 'HP:0001510', (40, 60))	('reduced', 'NegReg', (201, 208))	('reduced', 'NegReg', (40, 47))	('growth', 'MPA', (48, 54))	('degradation', 'MPA', (209, 220))	('G2/M phase of cell cycle', 'CPA', (154, 178))	('UBE2C', 'Gene', (98, 103))
308073	27588470	Finally, the knockdown of UBE2C in the ESCC cell lines did not result in statistically significant differences in the apoptotic cell death rate (Supplementary Figure S3).	('UBE2C', 'Gene', '11065', (26, 31))	('knockdown', 'Var', (13, 22))	('UBE2C', 'Gene', (26, 31))
308074	27588470	On the other hand, Jiang and colleagues showed that UBE2C silencing was able to induce apoptosis of U251 glioma cell line, through TP53 and Bax activation.	('Bax', 'Gene', '581', (140, 143))	('U251', 'CellLine', 'CVCL:0021', (100, 104))	('UBE2C', 'Gene', '11065', (52, 57))	('glioma', 'Disease', (105, 111))	('UBE2C', 'Gene', (52, 57))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('activation', 'PosReg', (144, 154))	('apoptosis', 'CPA', (87, 96))	('Bax', 'Gene', (140, 143))	('induce', 'PosReg', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('silencing', 'Var', (58, 67))
308075	27588470	The absence of cell death after the knockdown of UBE2C in TE-1 and TE-13 cells could be related with the absence of the apoptotic pathway mediated by TP53 whose loss represents the most frequent molecular alteration in esophageal carcinogenesis, and is also present in the ESCC cell lines used in this study.	('absence', 'NegReg', (105, 112))	('TP53', 'Gene', (150, 154))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (219, 244))	('esophageal carcinogenesis', 'Disease', (219, 244))	('apoptotic pathway mediated', 'Pathway', (120, 146))	('knockdown', 'Var', (36, 45))	('UBE2C', 'Gene', '11065', (49, 54))	('UBE2C', 'Gene', (49, 54))	('loss', 'NegReg', (161, 165))	('TE-13', 'CellLine', 'CVCL:4463', (67, 72))	('TP53', 'Gene', '7157', (150, 154))
308090	27588470	Briefly: following transfection of TE-1 and TE-13 cells with either siRNA targeting UBE2C or fluorescent scrambled control siRNA, as previously described, cell pellets were resuspended in 500 muL of propidium iodide solution (PBS, 0.1% Triton X-100, 0.1% RNAse and 50 mug/mL propidium iodide - Sigma) and incubated for 5 min on ice.	('Triton X-100', 'Chemical', 'MESH:D017830', (236, 248))	('transfection', 'Var', (19, 31))	('propidium iodide', 'Chemical', 'MESH:D011419', (275, 291))	('UBE2C', 'Gene', '11065', (84, 89))	('PBS', 'Disease', 'MESH:D011535', (226, 229))	('UBE2C', 'Gene', (84, 89))	('propidium iodide', 'Chemical', 'MESH:D011419', (199, 215))	('TE-13', 'CellLine', 'CVCL:4463', (44, 49))	('PBS', 'Disease', (226, 229))
308216	27861358	One study reported that cervical cancer patients who were infected with HPV had a significantly better survival than those who were not while they were receiving radiation therapy.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('patients', 'Species', '9606', (40, 48))	('better', 'PosReg', (96, 102))	('infected', 'Var', (58, 66))	('HPV', 'Species', '10566', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('HPV', 'Gene', (72, 75))	('survival', 'CPA', (103, 111))
308287	27475906	After overnight fasting all individuals underwent upper gastrointestinal endoscopy with videogastroscope (GIF Q145 or GIF Q180, Olympus Medical, Hamburg, Germany).	('upper gastrointestinal', 'Disease', (50, 72))	('GIF Q180', 'Var', (118, 126))	('upper gastrointestinal', 'Disease', 'MESH:D005767', (50, 72))
308299	27475906	Alcohol consumption was consequently classified in 3 categories as most guidelines in different countries recommend that alcohol intake should not exceed 20g/day for men and 10g/day for women: abstainers, low alcohol consumption (<20g/day for men, <10g/day for women) and hazardous alcohol consumption (>=20g/day for men, >=10g/day women).	('women', 'Species', '9606', (186, 191))	('abstainers', 'Disease', (193, 203))	('men', 'Species', '9606', (334, 337))	('alcohol', 'Chemical', 'MESH:D000438', (209, 216))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('men', 'Species', '9606', (317, 320))	('men', 'Species', '9606', (111, 114))	('men', 'Species', '9606', (166, 169))	('hazardous alcohol', 'Phenotype', 'HP:0030955', (272, 289))	('women', 'Species', '9606', (332, 337))	('men', 'Species', '9606', (243, 246))	('<20g/day', 'Var', (230, 238))	('men', 'Species', '9606', (263, 266))	('men', 'Species', '9606', (188, 191))	('women', 'Species', '9606', (261, 266))	('alcohol', 'Chemical', 'MESH:D000438', (282, 289))	('alcohol', 'Chemical', 'MESH:D000438', (121, 128))
308364	27475906	However, combining the LTB4R antagonist LY293111 to gemcitabine did not add any benefit in terms of survival to chemotherapy-naive patients with advanced pancreatic carcinoma.	('patients', 'Species', '9606', (131, 139))	('LTB4R', 'Gene', '1241', (23, 28))	('gemcitabine', 'Chemical', 'MESH:C056507', (52, 63))	('pancreatic carcinoma', 'Disease', (154, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('LTB4R', 'Gene', (23, 28))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (154, 174))	('LY293111', 'Chemical', 'MESH:C094099', (40, 48))	('LY293111', 'Var', (40, 48))
308380	27475906	Furthermore, CYSLTR1 expression was correlated with enhanced levels of anti-apoptotic proteins in colon cancer and CYSLTR1 transfection resulted in prolonged survival of Caco-2 cancer cells in vitro.	('cancer', 'Disease', (177, 183))	('CYSLTR1', 'Gene', '10800', (115, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('CYSLTR1', 'Gene', (13, 20))	('Caco-2', 'CellLine', 'CVCL:0025', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('survival', 'CPA', (158, 166))	('prolonged', 'PosReg', (148, 157))	('CYSLTR1', 'Gene', (115, 122))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('transfection', 'Var', (123, 135))	('levels of anti-apoptotic proteins', 'MPA', (61, 94))	('colon cancer', 'Disease', (98, 110))	('CYSLTR1', 'Gene', '10800', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('enhanced', 'PosReg', (52, 60))
308381	27475906	With respect to the CYSLTR2 function, a study on 329 colorectal cancers showed a more favorable prognosis for patients with high nuclear CYSLTR2 staining in combination with low nuclear CYSLTR1 receptor.	('colorectal cancers', 'Disease', (53, 71))	('CYSLTR2', 'Gene', '57105', (20, 27))	('CYSLTR2', 'Gene', (137, 144))	('CYSLTR1', 'Gene', '10800', (186, 193))	('CYSLTR2', 'Gene', (20, 27))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('CYSLTR2', 'Gene', '57105', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('high nuclear', 'Var', (124, 136))	('colorectal cancers', 'Disease', 'MESH:D015179', (53, 71))	('patients', 'Species', '9606', (110, 118))	('CYSLTR1', 'Gene', (186, 193))
308382	27475906	Statistical analysis found high CYSLTR2 expression associated with a decreased risk of death.	('expression', 'MPA', (40, 50))	('decreased', 'NegReg', (69, 78))	('CYSLTR2', 'Gene', '57105', (32, 39))	('death', 'Disease', 'MESH:D003643', (87, 92))	('high', 'Var', (27, 31))	('CYSLTR2', 'Gene', (32, 39))	('death', 'Disease', (87, 92))
308383	27475906	In another study, aggressive CYSLTR2 negative breast cancer cells (MDA-MB-231) exhibited a decrease in migratory capacity after CYSLTR2 transfection which is associated with a reduction in metastatic potential.	('transfection', 'Var', (136, 148))	('CYSLTR2', 'Gene', '57105', (128, 135))	('CYSLTR2', 'Gene', (128, 135))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (67, 77))	('CYSLTR2', 'Gene', '57105', (29, 36))	('CYSLTR2', 'Gene', (29, 36))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', (46, 59))	('migratory capacity', 'CPA', (103, 121))	('decrease', 'NegReg', (91, 99))
308418	26748627	Overproduction of ROS can contribute to the immediate development of inflammatory processes.	('ROS', 'Chemical', '-', (18, 21))	('contribute', 'Reg', (26, 36))	('inflammatory processes', 'CPA', (69, 91))	('ROS', 'Protein', (18, 21))	('Overproduction', 'Var', (0, 14))
308500	26748627	The derivatives of Sennoside A has been reported to show effective antioxidative activities against H2O2, light, and gamma-radiation induced oxidative stress via the suppression of ROS production and scavenging of free radicals.	('H2O2', 'Chemical', 'MESH:D006861', (100, 104))	('ROS production', 'MPA', (181, 195))	('oxidative stress', 'MPA', (141, 157))	('ROS', 'Chemical', '-', (181, 184))	('antioxidative activities', 'MPA', (67, 91))	('Sennoside A', 'Chemical', 'MESH:C002839', (19, 30))	('scavenging', 'MPA', (200, 210))	('free radicals', 'MPA', (214, 227))	('suppression', 'NegReg', (166, 177))	('radicals', 'Chemical', '-', (219, 227))	('derivatives', 'Var', (4, 15))	('Sennoside A', 'Gene', (19, 30))	('free radical', 'Chemical', 'MESH:D005609', (214, 226))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))
308520	26748627	Activated ERK1/2 induces the dissociaton of IkappaBalpha to NF-kappaB, allowing the nuclear translocation and DNA-binding of NF-kappaB, and p38 induces the expression of p65 and p50.	('p65', 'Gene', (170, 173))	('induces', 'PosReg', (144, 151))	('p65', 'Gene', '25716', (170, 173))	('p50', 'Var', (178, 181))	('IkappaBalpha', 'Gene', (44, 56))	('nuclear translocation', 'MPA', (84, 105))	('IkappaBalpha', 'Gene', '25493', (44, 56))	('expression', 'MPA', (156, 166))	('dissociaton', 'MPA', (29, 40))	('p38', 'Gene', '81649', (140, 143))	('p38', 'Gene', (140, 143))	('DNA-binding', 'Interaction', (110, 121))
308521	26748627	In this study, increased expressions of p-ERK1/2 and p-p38 were observed in esophageal tissues of RE control rats, and were decreased by the administration of Rhei Rhizoma.	('rat', 'Species', '10116', (149, 152))	('p38', 'Gene', '81649', (55, 58))	('p-ERK1/2', 'Var', (40, 48))	('expressions', 'MPA', (25, 36))	('decreased', 'NegReg', (124, 133))	('Rhei Rhizoma', 'Disease', (159, 171))	('increased', 'PosReg', (15, 24))	('rat', 'Species', '10116', (109, 112))	('Rhei Rhizoma', 'Disease', 'None', (159, 171))	('rats', 'Species', '10116', (109, 113))	('p38', 'Gene', (55, 58))
308544	24137473	The results revealed that HPPH, in the range of 0.005-1 mug/ml, exhibited no cytotoxicity in the Eca109 cells without light exposure and that the in vitro efficiency of HPPH-mediated PDT was higher compared with that of Photofrin -mediated PDT.	('higher', 'PosReg', (191, 197))	('Photofrin', 'Chemical', 'MESH:D017323', (220, 229))	('HPPH', 'Chemical', 'MESH:C083998', (26, 30))	('cytotoxicity', 'Disease', (77, 89))	('HPPH-mediated', 'Var', (169, 182))	('cytotoxicity', 'Disease', 'MESH:D064420', (77, 89))	('HPPH', 'Chemical', 'MESH:C083998', (169, 173))	('PDT', 'CPA', (183, 186))
308550	24137473	In conclusion, the present study demonstrated that the phototoxicity of HPPH-mediated PDT is higher than that of Photofrin-mediated PDT of the same dose.	('higher', 'PosReg', (93, 99))	('Photofrin', 'Chemical', 'MESH:D017323', (113, 122))	('toxicity', 'Disease', (60, 68))	('HPPH-mediated', 'Var', (72, 85))	('HPPH', 'Chemical', 'MESH:C083998', (72, 76))	('toxicity', 'Disease', 'MESH:D064420', (60, 68))
308617	24137473	In addition, as shown in Table V, the percentage of lethality induced by 0.15, 0.3 and 0.6 mg/kg HPPH-mediated PDT was 37.5%.	('0.15', 'Var', (73, 77))	('HPPH-mediated', 'Gene', (97, 110))	('lethality', 'MPA', (52, 61))	('HPPH', 'Chemical', 'MESH:C083998', (97, 101))	('0.3', 'Var', (79, 82))	('0.6 mg/kg', 'Var', (87, 96))
308621	24137473	In addition, edema surrounded the tumors in the mice that were injected with PS, including 0.3-1 mg/kg HPPH and 10 mg/kg Photofrin, at day 1 following PDT.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('edema', 'Disease', (13, 18))	('mice', 'Species', '10090', (48, 52))	('Photofrin', 'Chemical', 'MESH:D017323', (121, 130))	('HPPH', 'Chemical', 'MESH:C083998', (103, 107))	('edema', 'Disease', 'MESH:D004487', (13, 18))	('edema', 'Phenotype', 'HP:0000969', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('0.3-1', 'Var', (91, 96))
308644	24137473	Several studies have demonstrated that high-fluence rate PDT may lead to treatment-limiting deficits in the available oxygen if the high rate of 1O2 generation outpaces the resupply of O2.	('treatment-limiting', 'Disease', (73, 91))	('PDT', 'Var', (57, 60))	('O2', 'Chemical', 'MESH:D010100', (146, 148))	('lead to', 'Reg', (65, 72))	('oxygen', 'Chemical', 'MESH:D010100', (118, 124))	('1O2', 'Chemical', '-', (145, 148))	('O2', 'Chemical', 'MESH:D010100', (185, 187))	('deficits in the available oxygen', 'MPA', (92, 124))
308645	24137473	3), indicating that HPPH-mediated PDT at a fluence rate of 20 mW/cm2 may result in treatment-limiting deficits in Eca109 cells.	('HPPH', 'Chemical', 'MESH:C083998', (20, 24))	('PDT', 'Var', (34, 37))	('result in', 'Reg', (73, 82))
308646	24137473	Numerous lines of evidence have indicated that HPPH-mediated PDT has shown significant cytotoxicity in vitro and antitumor efficacy in a number of tumor xenograft models.	('HPPH', 'Chemical', 'MESH:C083998', (47, 51))	('PDT', 'Var', (61, 64))	('tumor', 'Disease', (147, 152))	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (117, 122))	('cytotoxicity', 'Disease', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('HPPH-mediated PDT', 'Var', (47, 64))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
308648	24137473	In the present study, HPPH and Photofrin-mediated PDT were observed to exhibit a high cytotoxicity in vitro and antitumor efficacy in vivo in a concentration-dependent manner (Tables I-III; Fig.	('HPPH', 'Chemical', 'MESH:C083998', (22, 26))	('cytotoxicity', 'Disease', 'MESH:D064420', (86, 98))	('Photofrin', 'Chemical', 'MESH:D017323', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('PDT', 'Var', (50, 53))	('cytotoxicity', 'Disease', (86, 98))	('tumor', 'Disease', (116, 121))
308649	24137473	In addition, HPPH-mediated PDT had a higher efficacy than Photofrin-mediated PDT in the Eca109 cells and the xenografted Eca109 solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (128, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('efficacy', 'MPA', (44, 52))	('HPPH', 'Chemical', 'MESH:C083998', (13, 17))	('Photofrin', 'Chemical', 'MESH:D017323', (58, 67))	('solid tumors', 'Disease', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('HPPH-mediated', 'Var', (13, 26))
308656	24137473	A lower lethality was observed in mice following PDT with 0.15, 0.3 and 0.6 mg/kg HPPH over the course of the treatment.	('lethality', 'MPA', (8, 17))	('mice', 'Species', '10090', (34, 38))	('HPPH', 'Chemical', 'MESH:C083998', (82, 86))	('0.15', 'Var', (58, 62))	('0.3', 'Var', (64, 67))	('lower', 'NegReg', (2, 7))
308668	24137473	In conclusion, the present study demonstrated that the phototoxicity of HPPH-mediated PDT was higher than Photofrin-mediated PDT at the same concentration (dose) in vivo and in vitro, and that HPPH possessed lower toxicity than Photofrin at the dose that achieved the same efficacy.	('toxicity', 'Disease', (60, 68))	('HPPH-mediated', 'Var', (72, 85))	('HPPH', 'Chemical', 'MESH:C083998', (72, 76))	('Photofrin', 'Chemical', 'MESH:D017323', (106, 115))	('HPPH', 'Chemical', 'MESH:C083998', (193, 197))	('Photofrin', 'Chemical', 'MESH:D017323', (228, 237))	('toxicity', 'Disease', 'MESH:D064420', (60, 68))	('lower', 'NegReg', (208, 213))	('toxicity', 'Disease', 'MESH:D064420', (214, 222))	('higher', 'PosReg', (94, 100))	('toxicity', 'Disease', (214, 222))
308688	33194593	found an association between the M2/M1-ratio and liver metastasis in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('liver metastasis', 'Disease', 'MESH:D009362', (49, 65))	('M2/M1-ratio', 'Var', (33, 44))	('liver metastasis', 'Disease', (49, 65))	('colorectal cancer', 'Disease', (69, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))
308690	33194593	In patients with adenocarcinoma of the esophagus, a high M2/M1-ratio was associated with poor survival and lymph node metastasis, and in patients with squamous cell carcinoma (SCC) of the esophagus, a high infiltration of M2 macrophages was associated with worse survival and poor response to chemotherapy.	('M2/M1-ratio', 'MPA', (57, 68))	('lymph node metastasis', 'CPA', (107, 128))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 174))	('squamous cell carcinoma', 'Disease', (151, 174))	('adenocarcinoma', 'Disease', (17, 31))	('patients', 'Species', '9606', (137, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (17, 31))	('poor', 'NegReg', (89, 93))	('patients', 'Species', '9606', (3, 11))	('high', 'Var', (52, 56))	('SCC', 'Phenotype', 'HP:0002860', (176, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
308694	33194593	The standard surgical procedure for esophageal cancers (C15-C16.0B) was the two field Ivor Lewis esophagectomy with reconstruction by means of a gastric tube.	('esophageal cancers', 'Disease', 'MESH:D004938', (36, 54))	('C15-C16.0B', 'Var', (56, 66))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancers', 'Disease', (36, 54))
308698	33194593	Tumor stage was classified according to TNM 8, Siewert I and II tumors being classified as esophageal tumors (C15.0A-C16.0B) and Siewert III tumors as gastric tumors (C16.0C-C16.9).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('II tumors', 'Disease', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('esophageal tumors', 'Disease', (91, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('II tumors', 'Disease', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('esophageal tumors', 'Disease', 'MESH:D004938', (91, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('gastric tumors', 'Disease', 'MESH:D013274', (151, 165))	('gastric tumors', 'Phenotype', 'HP:0006753', (151, 165))	('esophageal tumors', 'Phenotype', 'HP:0100751', (91, 108))	('C15.0A-C16.0B', 'Var', (110, 123))	('TNM', 'Gene', '10178', (40, 43))	('TNM', 'Gene', (40, 43))	('II tumors', 'Disease', 'MESH:D009369', (61, 70))	('gastric tumors', 'Disease', (151, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('II tumors', 'Disease', 'MESH:D009369', (138, 147))
308784	32344892	Univariate and multivariate analyses showed that high tumor (T) status, positive lymph node metastasis, tumors located in the upper esophagus, and SDF-1alpha overexpression were significantly related to worse disease-free survival and overall survival.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('SDF-1', 'Gene', '6387', (147, 152))	('worse', 'NegReg', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('disease-free survival', 'CPA', (209, 230))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('SDF-1', 'Gene', (147, 152))	('positive lymph node metastasis', 'CPA', (72, 102))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('overexpression', 'PosReg', (158, 172))	('overall survival', 'CPA', (235, 251))	('high', 'Var', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
308802	32344892	showed that there was a significant difference in 5-year survival rates between ESCC patients with positive and negative SDF-1alpha, while the CXCR4-positive group had better 5-year survival rates compared to those with CXCR4- negative.	('negative', 'NegReg', (112, 120))	('positive', 'Var', (99, 107))	('CXCR4', 'Gene', '7852', (143, 148))	('CXCR4', 'Gene', (220, 225))	('CXCR4', 'Gene', '7852', (220, 225))	('SDF-1', 'Gene', '6387', (121, 126))	('SDF-1', 'Gene', (121, 126))	('patients', 'Species', '9606', (85, 93))	('CXCR4', 'Gene', (143, 148))	('ESCC', 'Disease', (80, 84))
308822	32344892	The 109 patients with low expression of SDF-1alpha were found to have significantly longer DFS compared to the 60 patients with overexpression of SDF-1alpha (50.0 months vs. 6.9 months, p < 0.001, Figure 2A).	('low expression', 'Var', (22, 36))	('SDF-1', 'Gene', (40, 45))	('patients', 'Species', '9606', (8, 16))	('SDF-1', 'Gene', '6387', (146, 151))	('SDF-1', 'Gene', (146, 151))	('DFS', 'CPA', (91, 94))	('patients', 'Species', '9606', (114, 122))	('SDF-1', 'Gene', '6387', (40, 45))	('longer', 'PosReg', (84, 90))
308823	32344892	The multivariable analysis revealed that T1-T2 (p < 0.001), negative N status (p = 0.002), ESCC located in the middle and lower esophagus (p = 0.006), and low expression of SDF-1alpha (p < 0.001) were independent predictive factors for better DFS.	('expression', 'MPA', (159, 169))	('T1-T2', 'Var', (41, 46))	('SDF-1', 'Gene', '6387', (173, 178))	('low', 'Var', (155, 158))	('SDF-1', 'Gene', (173, 178))
308832	32344892	In addition, T1-T2 status (p = 0.001), negative N status (p = 0.001), tumors located in the middle and lower esophagus (p = 0.002), and low expression of SDF-1alpha (p < 0.001) were independent prognostic predictors of better OS in a multivariate analysis.	('SDF-1', 'Gene', '6387', (154, 159))	('SDF-1', 'Gene', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('low expression', 'Var', (136, 150))	('T1-T2 status', 'Var', (13, 25))	('tumors', 'Disease', (70, 76))	('better OS', 'Disease', (219, 228))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
308842	32344892	reported that the SDF-1alpha/CXCR4 axis modulates chemotaxis, tumor migration, and angiogenesis by activating several signaling pathways, and an in vivo study also demonstrated that blocking the SDF-1alpha/CXCR4 axis results in a significant reduction in tumor cell progression in non-small cell lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (296, 307))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('SDF-1', 'Gene', '6387', (18, 23))	('SDF-1', 'Gene', (18, 23))	('CXCR4', 'Gene', '7852', (206, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (296, 307))	('chemotaxis', 'CPA', (50, 60))	('CXCR4', 'Gene', (206, 211))	('modulates', 'Reg', (40, 49))	('CXCR4', 'Gene', '7852', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('reduction', 'NegReg', (242, 251))	('CXCR4', 'Gene', (29, 34))	('blocking', 'Var', (182, 190))	('signaling pathways', 'Pathway', (118, 136))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (281, 307))	('tumor', 'Disease', (255, 260))	('lung cancer', 'Disease', (296, 307))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('activating', 'Reg', (99, 109))	('SDF-1', 'Gene', '6387', (195, 200))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (285, 307))	('SDF-1', 'Gene', (195, 200))	('tumor', 'Disease', (62, 67))	('angiogenesis', 'CPA', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
308844	32344892	Growing evidence has confirmed that the activation of SDF-1alpha/CXCR4 signaling promotes tumor cell proliferation, migration, survival, gene transcription, and blockade of the SDF-1alpha/CXCR4 axis reverses this phenomenon and results in cell cycle arrest, apoptosis, and the inhibition of downstream signaling.	('survival', 'CPA', (127, 135))	('inhibition', 'NegReg', (277, 287))	('SDF-1', 'Gene', '6387', (177, 182))	('men', 'Species', '9606', (218, 221))	('SDF-1', 'Gene', (177, 182))	('blockade', 'Var', (161, 169))	('tumor', 'Disease', (90, 95))	('CXCR4', 'Gene', '7852', (188, 193))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (239, 256))	('apoptosis', 'CPA', (258, 267))	('migration', 'CPA', (116, 125))	('arrest', 'Disease', (250, 256))	('CXCR4', 'Gene', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('CXCR4', 'Gene', '7852', (65, 70))	('activation', 'PosReg', (40, 50))	('CXCR4', 'Gene', (65, 70))	('SDF-1', 'Gene', '6387', (54, 59))	('gene transcription', 'MPA', (137, 155))	('SDF-1', 'Gene', (54, 59))	('downstream signaling', 'Pathway', (291, 311))	('results in', 'Reg', (228, 238))	('promotes', 'PosReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('arrest', 'Disease', 'MESH:D006323', (250, 256))
308847	32344892	Moreover, worse DFS and OS were noted in ESCC patients with overexpression of SDF-1alpha compared to those with low expression of SDF-1alpha.	('SDF-1', 'Gene', (78, 83))	('patients', 'Species', '9606', (46, 54))	('SDF-1', 'Gene', '6387', (130, 135))	('worse', 'NegReg', (10, 15))	('SDF-1', 'Gene', (130, 135))	('ESCC', 'Disease', (41, 45))	('SDF-1', 'Gene', '6387', (78, 83))	('DFS', 'MPA', (16, 19))	('overexpression', 'Var', (60, 74))
308850	32344892	In addition, SDF-1alpha overexpression enhanced ESCC tumor proliferation and AMD3100 decreased tumor cell growth irrespective of SDF-1alpha expression in vitro; AMD3100 also significantly decreased ESCC tumor size in an animal model.	('decreased tumor', 'Disease', 'MESH:D002303', (85, 100))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('AMD3100', 'Var', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('AMD3100', 'Chemical', 'MESH:C088327', (77, 84))	('decreased tumor', 'Disease', (85, 100))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('enhanced', 'PosReg', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('ESCC', 'Disease', (48, 52))	('tumor', 'Disease', (95, 100))	('decreased', 'NegReg', (188, 197))	('SDF-1', 'Gene', '6387', (13, 18))	('ESCC', 'Disease', (198, 202))	('SDF-1', 'Gene', (13, 18))	('AMD3100', 'Chemical', 'MESH:C088327', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('decreased ESCC', 'Phenotype', 'HP:0025022', (188, 202))	('tumor', 'Disease', (53, 58))	('SDF-1', 'Gene', '6387', (129, 134))	('SDF-1', 'Gene', (129, 134))
308875	28428633	Inhibition of glutathione metabolism attenuates esophageal cancer progression Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with regard to mortality and prognosis, and the 5-year survival rate for all patients diagnosed with ESCC remains poor.	('esophageal cancer', 'Disease', (48, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('glutathione', 'Chemical', 'MESH:D005978', (14, 25))	('glutathione', 'Protein', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('patients', 'Species', '9606', (220, 228))	('attenuates', 'NegReg', (37, 47))	('Inhibition', 'Var', (0, 10))	('deadly malignancy', 'Disease', 'MESH:D009369', (125, 142))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (78, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('Esophageal squamous cell carcinoma', 'Disease', (78, 112))	('deadly malignancy', 'Disease', (125, 142))
308915	28428633	Primary antibodies included anti-phospho-p65 antibody (Cell signaling #3033, 1:1000), anti-p65 antibody (Cell Signaling #6956, 1:1000), anti-IkappaBalpha antibody (Cell Signaling #3033, 1:1000), anti-IkappaBalpha antibody (Cell Signaling #9242, 1:1000), anti-phospho- IkappaBalpha antibody (Cell Signaling #6956, 1:2859) and anti-alpha-tubulin (Sigma-Aldrich #T-9026, 1:5000).	('p65', 'Gene', '19697', (91, 94))	('p65', 'Gene', (91, 94))	('IkappaBalpha', 'Gene', (268, 280))	('anti-phospho-', 'Var', (254, 267))	('IkappaBalpha', 'Gene', (141, 153))	('IkappaBalpha', 'Gene', '18035', (268, 280))	('p65', 'Gene', '19697', (41, 44))	('IkappaBalpha', 'Gene', (200, 212))	('p65', 'Gene', (41, 44))	('IkappaBalpha', 'Gene', '18035', (141, 153))	('IkappaBalpha', 'Gene', '18035', (200, 212))
308934	28428633	Finally, we validated that glutathione concentrations, GSH transferase and GSH peroxidase activity were inhibited in the esophageal tissues treated with BSO (Figures 3d-f).	('BSO', 'Chemical', 'MESH:D019328', (153, 156))	('GSH peroxidase', 'Enzyme', (75, 89))	('activity', 'MPA', (90, 98))	('GSH', 'Chemical', 'MESH:D005978', (55, 58))	('glutathione', 'Chemical', 'MESH:D005978', (27, 38))	('GSH transferase', 'Enzyme', (55, 70))	('glutathione concentrations', 'MPA', (27, 53))	('GSH', 'Chemical', 'MESH:D005978', (75, 78))	('BSO', 'Var', (153, 156))	('inhibited', 'NegReg', (104, 113))
308942	28428633	Furthermore, p-IkappaBalpha was significantly repressed by BSO (Figure 5a), thus suggesting that BSO blocks NF-kB signaling transduction.	('blocks', 'NegReg', (101, 107))	('BSO', 'Var', (97, 100))	('IkappaBalpha', 'Gene', (15, 27))	('BSO', 'Chemical', 'MESH:D019328', (59, 62))	('NF-kB signaling transduction', 'MPA', (108, 136))	('IkappaBalpha', 'Gene', '18035', (15, 27))	('BSO', 'Chemical', 'MESH:D019328', (97, 100))
308956	28428633	Silencing of p65 exhibits anti-proliferative effects and confers the chemo-drug sensitivity of the ESCC cells.	('p65', 'Gene', '19697', (13, 16))	('p65', 'Gene', (13, 16))	('anti-proliferative effects', 'CPA', (26, 52))	('drug sensitivity', 'Phenotype', 'HP:0020174', (75, 91))	('Silencing', 'Var', (0, 9))
309050	27029934	The dysregulation of miRNA expression has been identified in various cancers and suggests that miRNAs can function as classical oncogenes or tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (141, 146))	('miRNA expression', 'MPA', (21, 37))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
309129	26000878	In this study, we have demonstrated that ionizing radiation may induce epithelial-mesenchymal transition (EMT) accompanied with increased cell migration and invasion, through downregulation of phosphatase and tensin homolog (PTEN), and activation of Akt/GSK-3beta/Snail signaling.	('GSK-3beta', 'Gene', '2932', (254, 263))	('epithelial-mesenchymal transition', 'CPA', (71, 104))	('induce', 'PosReg', (64, 70))	('GSK-3beta', 'Gene', (254, 263))	('ionizing radiation', 'Var', (41, 59))	('phosphatase', 'Protein', (193, 204))	('Akt', 'Gene', '207', (250, 253))	('downregulation', 'NegReg', (175, 189))	('invasion', 'CPA', (157, 165))	('increased', 'PosReg', (128, 137))	('PTEN', 'Gene', (225, 229))	('activation', 'PosReg', (236, 246))	('Akt', 'Gene', (250, 253))	('cell migration', 'CPA', (138, 152))	('Snail', 'Gene', '6615', (264, 269))	('Snail', 'Gene', (264, 269))	('PTEN', 'Gene', '5728', (225, 229))
309134	26000878	Correspondingly, treatment with LY294002, a phosphatidylinositol-3-kinase inhibitor, mimicked PTEN overexpression effect in KYSE-150/RR cells, further suggesting a role for the Akt/GSK-3beta/Snail signaling in effects mediated through PTEN.	('Snail', 'Gene', '6615', (191, 196))	('PTEN', 'Gene', (94, 98))	('PTEN', 'Gene', '5728', (94, 98))	('Akt', 'Gene', (177, 180))	('PTEN', 'Gene', (235, 239))	('LY294002', 'Var', (32, 40))	('PTEN', 'Gene', '5728', (235, 239))	('GSK-3beta', 'Gene', '2932', (181, 190))	('GSK-3beta', 'Gene', (181, 190))	('Akt', 'Gene', '207', (177, 180))	('Snail', 'Gene', (191, 196))	('LY294002', 'Chemical', 'MESH:C085911', (32, 40))
309180	26000878	Migration and invasion assay demonstrated that the knockdown of PTEN resulted in a clear migratory phenotype in KYSE-150 cells when compared with the vehicle transfected cells (Fig 3D).	('PTEN', 'Gene', (64, 68))	('PTEN', 'Gene', '5728', (64, 68))	('migratory phenotype', 'CPA', (89, 108))	('knockdown', 'Var', (51, 60))
309195	26000878	As shown in Fig 4C, phosphorylation of Akt and GSK-3beta was upregulated in KYSE-150/RR cells but not in KYSE-150 Ctrl cells.	('upregulated', 'PosReg', (61, 72))	('Akt', 'Gene', '207', (39, 42))	('KYSE-150/RR', 'Var', (76, 87))	('phosphorylation', 'MPA', (20, 35))	('GSK-3beta', 'Gene', (47, 56))	('Akt', 'Gene', (39, 42))	('GSK-3beta', 'Gene', '2932', (47, 56))
309196	26000878	And the knockout of PTEN indeed facilitated the phosphorylation of Akt in KYSE-150 Ctrl cells, accompanied by an increase in phosphorylation of GSK-3beta (Fig 4C, middle).	('facilitated', 'PosReg', (32, 43))	('PTEN', 'Gene', '5728', (20, 24))	('Akt', 'Gene', (67, 70))	('phosphorylation', 'MPA', (48, 63))	('GSK-3beta', 'Gene', '2932', (144, 153))	('increase', 'PosReg', (113, 121))	('phosphorylation', 'MPA', (125, 140))	('knockout', 'Var', (8, 16))	('PTEN', 'Gene', (20, 24))	('Akt', 'Gene', '207', (67, 70))	('GSK-3beta', 'Gene', (144, 153))
309199	26000878	LY294002 (40 muM) inhibited Akt and GSK-3beta phosphorylation in KYSE-150/RR cells, and the expression of Snail was downregulated and that of E-cadherin protein was upregulated (Fig 4D).	('LY294002', 'Var', (0, 8))	('E-cadherin', 'Gene', (142, 152))	('Akt', 'Gene', (28, 31))	('downregulated', 'NegReg', (116, 129))	('E-cadherin', 'Gene', '999', (142, 152))	('Snail', 'Gene', '6615', (106, 111))	('Snail', 'Gene', (106, 111))	('muM', 'Gene', (13, 16))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('upregulated', 'PosReg', (165, 176))	('GSK-3beta', 'Gene', (36, 45))	('inhibited', 'NegReg', (18, 27))	('Akt', 'Gene', '207', (28, 31))	('GSK-3beta', 'Gene', '2932', (36, 45))	('muM', 'Gene', '56925', (13, 16))	('expression', 'MPA', (92, 102))
309217	26000878	Active GSK-3beta can phosphorylate Snail to facilitate its degradation, conversely inactivation of GSK-3beta, can stabilize Snail.	('degradation', 'MPA', (59, 70))	('GSK-3beta', 'Gene', '2932', (7, 16))	('GSK-3beta', 'Gene', (7, 16))	('Snail', 'Gene', '6615', (124, 129))	('inactivation', 'Var', (83, 95))	('stabilize', 'MPA', (114, 123))	('Snail', 'Gene', (124, 129))	('Snail', 'Gene', (35, 40))	('Snail', 'Gene', '6615', (35, 40))	('GSK-3beta', 'Gene', (99, 108))	('facilitate', 'PosReg', (44, 54))	('GSK-3beta', 'Gene', '2932', (99, 108))
309221	26000878	LY294002 inhibited Akt and GSK-3beta phosphorylation in KYSE-150/RR cells, and the expression of Snail was downregulated and E-cadherin protein was upregulated.	('LY294002', 'Var', (0, 8))	('inhibited', 'NegReg', (9, 18))	('E-cadherin', 'Gene', '999', (125, 135))	('Akt', 'Gene', '207', (19, 22))	('GSK-3beta', 'Gene', '2932', (27, 36))	('GSK-3beta', 'Gene', (27, 36))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('Akt', 'Gene', (19, 22))	('downregulated', 'NegReg', (107, 120))	('expression', 'MPA', (83, 93))	('Snail', 'Gene', '6615', (97, 102))	('Snail', 'Gene', (97, 102))	('E-cadherin', 'Gene', (125, 135))	('upregulated', 'PosReg', (148, 159))
309224	26000878	It has been reported that blockage of PI3K/Akt signaling attenuated vimentin expression in oral carcinoma cells.	('oral carcinoma', 'Disease', 'MESH:D020820', (91, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('expression', 'MPA', (77, 87))	('oral carcinoma', 'Disease', (91, 105))	('Akt', 'Gene', '207', (43, 46))	('vimentin', 'Gene', '7431', (68, 76))	('Akt', 'Gene', (43, 46))	('blockage', 'Var', (26, 34))	('attenuated', 'NegReg', (57, 67))	('vimentin', 'Gene', (68, 76))
309249	23737672	Recently, although triple-drug regimens, such as 5-Fu/capecitabine, DDP, and TXT, have shown some efficacy advantages for advanced/metastatic ESCC, their long-term outcome advantages are not obvious due to higher incidences of grade 3 or 4 toxicity.	('SCC', 'Gene', (143, 146))	('DDP', 'Gene', (68, 71))	('SCC', 'Gene', '6317', (143, 146))	('5-Fu/capecitabine', 'Var', (49, 66))	('toxicity', 'Disease', (240, 248))	('toxicity', 'Disease', 'MESH:D064420', (240, 248))	('5-Fu', 'Chemical', '-', (49, 53))	('DDP', 'Gene', '1678', (68, 71))	('capecitabine', 'Chemical', 'MESH:D000069287', (54, 66))	('advantages', 'PosReg', (107, 117))	('TXT', 'Chemical', 'MESH:D000077143', (77, 80))
309255	23737672	Clinical studies have shown that Nab-PTX is safe with increased objective response rate (ORR) and time to progression in metastatic breast cancer compared with solvent-based PTX and TXT, and great activity has also been shown in various other advanced solid tumors, including non-small-cell lung cancer (NSCLC) and pancreatic cancer.	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (280, 302))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('lung cancer', 'Disease', (291, 302))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (276, 302))	('pancreatic cancer', 'Disease', 'MESH:D010190', (315, 332))	('solid tumors', 'Disease', (252, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('Nab-PTX', 'Chemical', 'MESH:D017239', (33, 40))	('Nab-PTX', 'Var', (33, 40))	('TXT', 'Chemical', 'MESH:D000077143', (182, 185))	('PTX', 'Chemical', 'MESH:D017239', (174, 177))	('NSCLC', 'Disease', 'MESH:D002289', (304, 309))	('pancreatic cancer', 'Disease', (315, 332))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('lung cancer', 'Disease', 'MESH:D008175', (291, 302))	('solid tumors', 'Disease', 'MESH:D009369', (252, 264))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('NSCLC', 'Disease', (304, 309))	('breast cancer', 'Disease', (132, 145))	('objective', 'MPA', (64, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (291, 302))	('NSCLC', 'Phenotype', 'HP:0030358', (304, 309))	('PTX', 'Chemical', 'MESH:D017239', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (315, 332))	('increased', 'PosReg', (54, 63))
309313	23737672	The gp60-mediated endothelial cell transcytosis of albumin-bound PTX and subsequent albumin binding to SPARC enhances the penetration of Nab-PTX into the tumor interstitium, thus PTX accumulation in tumor was greater for Nab-PTX compared with traditional PTX in tumor mouse models.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('PTX', 'Chemical', 'MESH:D017239', (225, 228))	('Nab-PTX', 'Chemical', 'MESH:D017239', (137, 144))	('PTX', 'Chemical', 'MESH:D017239', (179, 182))	('PTX', 'Chemical', 'MESH:D017239', (255, 258))	('PTX', 'Chemical', 'MESH:D017239', (65, 68))	('tumor', 'Disease', (154, 159))	('binding', 'Interaction', (92, 99))	('mouse', 'Species', '10090', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('PTX', 'Chemical', 'MESH:D017239', (141, 144))	('gp60-mediated', 'Var', (4, 17))	('Nab-PTX', 'Chemical', 'MESH:D017239', (221, 228))	('tumor', 'Disease', (199, 204))	('enhances', 'PosReg', (109, 117))	('tumor', 'Disease', (262, 267))	('penetration', 'CPA', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
309330	22727408	These losses of cell function are usually either due to homozygous deletion or hypermethylation on promoter regions, which would normally function to inhibit cell proliferation and thereby suppress tumor growth.	('cell proliferation', 'CPA', (158, 176))	('hypermethylation', 'Var', (79, 95))	('inhibit', 'NegReg', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('rat', 'Species', '10116', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('suppress', 'NegReg', (189, 197))
309336	22727408	Genetic or epigenetic changes of BLU are frequent in NPC.	('BLU', 'Gene', (33, 36))	('NPC', 'Phenotype', 'HP:0100630', (53, 56))	('Genetic', 'Var', (0, 7))	('epigenetic changes', 'Var', (11, 29))	('frequent', 'Reg', (41, 49))	('BLU', 'Chemical', '-', (33, 36))	('NPC', 'Disease', (53, 56))
309344	22727408	This result suggests that expression of BLU downregulates cell proliferation either through apoptosis or by cell cycle regulation.	('apoptosis', 'CPA', (92, 101))	('rat', 'Species', '10116', (70, 73))	('BLU', 'Gene', (40, 43))	('expression', 'Var', (26, 36))	('cell proliferation', 'CPA', (58, 76))	('downregulates', 'NegReg', (44, 57))	('BLU', 'Chemical', '-', (40, 43))	('cell cycle regulation', 'CPA', (108, 129))	('expression', 'Species', '29278', (26, 36))
309351	22727408	AML-1-dependent transactivation is inhibited by fusion with ZMYND2 (also known as ETO).	('ZMYND2', 'Gene', (60, 66))	('fusion', 'Var', (48, 54))	('transactivation', 'MPA', (16, 31))	('AML-1', 'Gene', '861', (0, 5))	('ETO', 'Gene', (82, 85))	('ZMYND2', 'Gene', '862', (60, 66))	('inhibited', 'NegReg', (35, 44))	('AML-1', 'Gene', (0, 5))	('ETO', 'Gene', '862', (82, 85))
309370	22727408	A total of 1 x 105 CNE2 or EC109 cells were seeded in 12-well plates, and were transfected with pcDNA3.1-BLU, pcDNA3.1-TP53, empty vector pcDNA3.1 or were left untransfected.	('EC109', 'CellLine', 'CVCL:6898', (27, 32))	('CNE2', 'CellLine', 'CVCL:6889', (19, 23))	('pcDNA3.1-BLU', 'Var', (96, 108))	('BLU', 'Chemical', '-', (105, 108))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
309399	22727408	Analysis of PI incorporation shows that in comparison to the mock transfected cells, the majority of CNE-2 cells expressing BLU were in the G1 phase of the cell cycle (Figure 2D-F).	('rat', 'Species', '10116', (22, 25))	('BLU', 'Chemical', '-', (124, 127))	('CNE-2', 'CellLine', 'CVCL:6889', (101, 106))	('BLU', 'Var', (124, 127))	('G1 phase of the cell cycle', 'CPA', (140, 166))
309401	22727408	Consistent with its role in regulating G1/S phase progression, BLU expression dramatically reduced cyclin D1 level (Figure 3A).	('BLU expression', 'Var', (63, 77))	('BLU', 'Chemical', '-', (63, 66))	('cyclin D1', 'Gene', '595', (99, 108))	('expression', 'Species', '29278', (67, 77))	('reduced', 'NegReg', (91, 98))	('cyclin D1', 'Gene', (99, 108))
309408	22727408	Replication deficient viruses proliferate for weeks in hosts with cancer or other diseases, enabling the restored expression of a defected gene to achieve therapeutic goals.	('deficient', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('rat', 'Species', '10116', (37, 40))	('restored expression', 'MPA', (105, 124))	('expression', 'Species', '29278', (114, 124))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
309413	22727408	The genesis of cancer is a multi-step event, and aberrations involving genes on the 3p21 region, including homozygous deletions and promoter hypermethylation affecting cluster of TSGs, are early molecular changes in various human tumors.	('promoter hypermethylation', 'Var', (132, 157))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('rat', 'Species', '10116', (53, 56))	('human', 'Species', '9606', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
309419	22727408	It was demonstrated in the present study that BLU inhibited clonogenic growth of NPC and esophageal cancer cells in which endogenous expression of BLU is absent.	('esophageal cancer', 'Disease', (89, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('NPC', 'Phenotype', 'HP:0100630', (81, 84))	('BLU', 'Chemical', '-', (46, 49))	('BLU', 'Var', (46, 49))	('NPC', 'Disease', (81, 84))	('clonogenic growth', 'CPA', (60, 77))	('expression', 'Species', '29278', (133, 143))	('rat', 'Species', '10116', (14, 17))	('inhibited', 'NegReg', (50, 59))	('BLU', 'Chemical', '-', (147, 150))
309426	22727408	We have shown that cyclin D1 levels are significantly reduced in BLU-expressing cells.	('cyclin D1', 'Gene', '595', (19, 28))	('BLU', 'Chemical', '-', (65, 68))	('cyclin D1', 'Gene', (19, 28))	('BLU-expressing', 'Var', (65, 79))	('reduced', 'NegReg', (54, 61))
309431	22727408	It has been suggested that that tumor suppressors proteins with zinc finger domains may regulate cell proliferation via transcription regulation.	('regulate', 'Reg', (88, 96))	('zinc finger domains', 'Var', (64, 83))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('rat', 'Species', '10116', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('transcription regulation', 'MPA', (120, 144))	('cell proliferation', 'CPA', (97, 115))	('tumor', 'Disease', (32, 37))
309441	22727408	NPC: Nasopharyngeal carcinoma; EBV: Epstein-Barr virus; TSG: Tumor suppressor gene; ZMYND: Zinc finger myeloid nervy deformed epidermal auto regulatory factor-1 containing domain; JNK: c-Jun N-terminal kinase.	('Nasopharyngeal carcinoma', 'Disease', (5, 29))	('JNK', 'Gene', (180, 183))	('Nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (5, 29))	('JNK', 'Gene', '5599', (180, 183))	('c-Jun', 'Gene', '3725', (185, 190))	('deformed', 'Var', (117, 125))	('Epstein-Barr virus', 'Species', '10376', (36, 54))	('Nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (5, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('NPC', 'Phenotype', 'HP:0100630', (0, 3))	('Tumor', 'Phenotype', 'HP:0002664', (61, 66))	('c-Jun', 'Gene', (185, 190))	('EBV', 'Species', '10376', (31, 34))
309533	32231739	Furthermore, subtyping analyses revealed that IIaA15G2R1 and IIaA15G2R2 were the predominant subtypes in colorectal cancer, while IIaA13G2R2 subtype was first named and identified in colorectal and liver cancers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('IIaA15G2R1', 'Var', (46, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('liver cancer', 'Phenotype', 'HP:0002896', (198, 210))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('liver cancers', 'Phenotype', 'HP:0002896', (198, 211))	('colorectal and liver cancers', 'Disease', 'MESH:D015179', (183, 211))	('colorectal cancer', 'Disease', (105, 122))	('IIaA15G2R2', 'Var', (61, 71))
309536	32231739	Our results indicated that C. parvum were highly associated with gastrointestinal cancers, supporting that cryptosporidiosis could be a potential risk factor for these diseases.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('C. parvum', 'Species', '5807', (27, 36))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('associated', 'Reg', (49, 59))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (65, 89))	('gastrointestinal cancers', 'Disease', (65, 89))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (65, 88))	('C. parvum', 'Var', (27, 36))
309538	32231739	Genetic or epigenetic defects are considered to be the causative reasons for a variety of digestive malignancies.	('malignancies', 'Disease', (100, 112))	('malignancies', 'Disease', 'MESH:D009369', (100, 112))	('Genetic', 'Var', (0, 7))	('epigenetic defects', 'Var', (11, 29))
309612	32231739	IIaA13G2R2 was only observed in colorectal and liver cancers, whereas IIaA15G2R1 and IIaA15G2R2 were found in colorectal, gastric and small intestine cancers.	('colorectal', 'Disease', (110, 120))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('IIaA15G2R2', 'Var', (85, 95))	('colorectal and liver cancers', 'Disease', 'MESH:D015179', (32, 60))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('gastric and small intestine cancers', 'Disease', 'MESH:D013274', (122, 157))	('colorectal', 'Disease', (32, 42))	('small intestine cancer', 'Phenotype', 'HP:0100833', (134, 156))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('IIaA15G2R1', 'Var', (70, 80))	('colorectal', 'Disease', 'MESH:D015179', (110, 120))	('IIaA13G2R2', 'Var', (0, 10))	('liver cancer', 'Phenotype', 'HP:0002896', (47, 59))	('liver cancers', 'Phenotype', 'HP:0002896', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colorectal', 'Disease', 'MESH:D015179', (32, 42))
309613	32231739	In addition, IIaA15G2R2 subtype was also observed in esophageal cancer.	('IIaA15G2R2', 'Var', (13, 23))	('observed', 'Reg', (41, 49))	('esophageal cancer', 'Disease', (53, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
309639	32231739	Also, C. parvum of human origin can cause gastrointestinal and biliary adenocarcinoma in SCID mice.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cause', 'Reg', (36, 41))	('SCID', 'Disease', 'MESH:D053632', (89, 93))	('SCID', 'Disease', (89, 93))	('human', 'Species', '9606', (19, 24))	('C. parvum', 'Species', '5807', (6, 15))	('mice', 'Species', '10090', (94, 98))	('gastrointestinal and biliary adenocarcinoma', 'Disease', 'MESH:D004067', (42, 85))	('C. parvum', 'Var', (6, 15))
309648	32231739	BLAST analyses indicated that most of the 18S rRNA sequences obtained were 100% identity with the GenBank reference sequences: JX886768.1, JX886767.1, JX886766.1, JX886765.1 and FJ752165.1 (Table S4), which were all isolated from cattle, suggesting the potential zoonotic transmission.	('cattle', 'Species', '9913', (230, 236))	('JX886767.1', 'Var', (139, 149))	('JX886768.1', 'Var', (127, 137))	('FJ752165.1', 'Var', (178, 188))	('JX886766.1', 'Var', (151, 161))	('JX886765.1', 'Var', (163, 173))
309649	32231739	Previously, IIaA15G2R1 (one case) and IIcA5G3 (two cases) subtypes in colorectal cancer, and IIaA16G2R1 (one case) and IIaA17G2R1 (22 cases) subtypes in paediatric oncology have been identified.	('IIaA15G2R1', 'Var', (12, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('oncology', 'Phenotype', 'HP:0002664', (164, 172))	('colorectal cancer', 'Disease', (70, 87))	('IIaA16G2R1', 'Var', (93, 103))	('IIaA17G2R1', 'Var', (119, 129))
309651	32231739	We here identified that IIaA15G2R1, IIaA15G2R2 and IIaA13G2R2 were the subtypes responsible for C. parvum infections in gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('parvum infection', 'Disease', 'MESH:D007239', (99, 115))	('C. parvum', 'Species', '5807', (96, 105))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (120, 143))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('IIaA15G2R1', 'Var', (24, 34))	('infections in gastrointestinal cancers', 'Disease', (106, 144))	('parvum infection', 'Disease', (99, 115))	('responsible', 'Reg', (80, 91))	('IIaA13G2R2', 'Var', (51, 61))	('infections in gastrointestinal cancers', 'Disease', 'MESH:D004067', (106, 144))	('IIaA15G2R2', 'Var', (36, 46))
309653	32231739	For the prevalence of subtypes in colorectal cancer, IIaA15G2R1 and IIaA15G2R2 were the predominant subtypes and were detected in almost equal frequencies, whereas IIaA13G2R2 was only found in one case.	('IIaA15G2R1', 'Var', (53, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('IIaA15G2R2', 'Var', (68, 78))	('colorectal cancer', 'Disease', (34, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (34, 51))
309654	32231739	Additionally, both IIaA15G2R1 and IIaA15G2R2 were observed in small intestine cancer, but only IIaA15G2R2 has been found in esophageal cancer.	('cancer', 'Disease', (135, 141))	('esophageal cancer', 'Disease', (124, 141))	('IIaA15G2R2', 'Var', (34, 44))	('observed', 'Reg', (50, 58))	('cancer', 'Disease', (78, 84))	('IIaA15G2R1', 'Var', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('small intestine cancer', 'Phenotype', 'HP:0100833', (62, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
309657	32231739	IIaA15G2R1 is the most prevalent subtype for C. parvum worldwide and is mostly found in calves, while IIaA15G2R2 has been identified in calves and humans in the United States.	('calves', 'Species', '9913', (136, 142))	('C. parvum', 'Species', '5807', (45, 54))	('IIaA15G2R2', 'Var', (102, 112))	('prevalent', 'Reg', (23, 32))	('IIaA15G2R1', 'Var', (0, 10))	('humans', 'Species', '9606', (147, 153))	('calves', 'Species', '9913', (88, 94))
309661	32231739	However, available data suggested that Cryptosporidium spp., for its survival and transmission, can interfere with the cell signaling pathways and impact the gene expressions in host cells, thus, may secondarily promote the generation of gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', (238, 262))	('gene expressions', 'MPA', (158, 174))	('cell signaling pathways', 'Pathway', (119, 142))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (238, 262))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (238, 261))	('spp', 'Gene', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('spp', 'Gene', '81502', (55, 58))	('promote', 'PosReg', (212, 219))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('impact', 'Reg', (147, 153))	('Cryptosporidium', 'Var', (39, 54))	('Cryptosporidium', 'Species', '5808', (39, 54))	('interfere', 'NegReg', (100, 109))
309662	32231739	It has been shown that C. parvum can inhibit the apoptosis of infected biliary epithelia through activating the NF-kappaB signaling pathway.	('infected biliary epithelia', 'Disease', (62, 88))	('infected biliary epithelia', 'Disease', 'MESH:D001658', (62, 88))	('NF-kappaB signaling pathway', 'Pathway', (112, 139))	('inhibit', 'NegReg', (37, 44))	('C. parvum', 'Var', (23, 32))	('C. parvum', 'Species', '5807', (23, 32))	('activating', 'PosReg', (97, 107))	('apoptosis', 'CPA', (49, 58))
309682	31810000	An increasing body of evidence suggests that epigenetic changes play critical roles in the development of cancer stemness.	('cancer stemness', 'Disease', (106, 121))	('epigenetic changes', 'Var', (45, 63))	('cancer stemness', 'Disease', 'MESH:D009369', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
309683	31810000	LncRNAs can have either tumor-suppressing or tumor-promoting activities, and genome-wide association studies of different tumor samples found that mutations and/or altered expressions of lncRNA could be responsible for both tumorigenesis and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutations', 'Var', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (24, 29))	('expressions', 'MPA', (172, 183))	('metastasis', 'CPA', (242, 252))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('lncRNA', 'Gene', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('responsible', 'Reg', (203, 214))	('altered', 'Reg', (164, 171))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
309689	31810000	Although both MTA1 and MTA2 are generally considered as oncogenes mainly because they are capable of enhancing metastasis, MTA3 can serve as either a cancer repressor or an oncogene depending on cancer types.	('metastasis', 'CPA', (111, 121))	('MTA2', 'Gene', (23, 27))	('MTA3', 'Var', (123, 127))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('MTA2', 'Gene', '9219', (23, 27))	('cancer', 'Disease', (150, 156))	('enhancing', 'PosReg', (101, 110))	('MTA1', 'Gene', (14, 18))	('MTA1', 'Gene', '9112', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
309693	31810000	Of note, it has been suggested that MTA3-mediated epigenetic remodeling of chromatins may be involved in the regulation of cancer stemness.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer stemness', 'Disease', 'MESH:D009369', (123, 138))	('MTA3-mediated', 'Gene', (36, 49))	('epigenetic', 'Var', (50, 60))	('involved', 'Reg', (93, 101))	('cancer stemness', 'Disease', (123, 138))
309707	31810000	We chose four cell lines to examine the effect of MTA3 on the metastasis makers and found that knockdown MTA3 in ESCC cells leads to significant reduction and induction of the epithelial marker (E-cadherin) and mesenchymal markers (N-cadherin and vimentin), respectively (Figure S2B).	('N-cadherin', 'Gene', '1000', (232, 242))	('induction', 'PosReg', (159, 168))	('epithelial marker', 'CPA', (176, 193))	('reduction', 'NegReg', (145, 154))	('E-cadherin', 'Gene', (195, 205))	('MTA3', 'Gene', (105, 109))	('knockdown', 'Var', (95, 104))	('mesenchymal markers', 'CPA', (211, 230))	('E-cadherin', 'Gene', '999', (195, 205))	('vimentin', 'Gene', '7431', (247, 255))	('N-cadherin', 'Gene', (232, 242))	('vimentin', 'Gene', (247, 255))
309710	31810000	Figures S3C and S3D showed that tumors derived from EC9706 and EC109 cells were not only larger but also heavier when MTA3 is knocked down by shRNA (p < 0.01 for all).	('MTA3', 'Gene', (118, 122))	('EC9706', 'CellLine', 'CVCL:E307', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('larger', 'PosReg', (89, 95))	('tumors', 'Disease', (32, 38))	('heavier', 'PosReg', (105, 112))	('EC109', 'CellLine', 'CVCL:6898', (63, 68))	('EC9706', 'Var', (52, 58))
309711	31810000	On the other hand, the tumors derived from EC9706 and HKESC-1 cells were smaller and lighter when MTA3 is overexpressed (p < 0.01 for both; Figures S3E and S3F).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('lighter', 'NegReg', (85, 92))	('EC9706', 'Var', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('HKESC-1', 'CellLine', 'CVCL:D568', (54, 61))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('EC9706', 'CellLine', 'CVCL:E307', (43, 49))
309716	31810000	Finally, when these cells were injected into the tail vein of nude mice, more ESCC cells in the MTA3 knockdown group were found in the lungs (Figure 2D and 2E), which is substantiated with results of H&E staining (Figure 2G).	('MTA3', 'Gene', (96, 100))	('ESCC', 'Gene', (78, 82))	('H&E', 'Chemical', '-', (200, 203))	('nude mice', 'Species', '10090', (62, 71))	('knockdown', 'Var', (101, 110))
309720	31810000	Consistent with the qRT-PCR results, knockdown MTA3 has no effect on luciferase activity under the control of the Snai1 promoter (Figures S4E-S4G).	('Snai1', 'Gene', '6615', (114, 119))	('knockdown', 'Var', (37, 46))	('activity', 'MPA', (80, 88))	('MTA3', 'Gene', (47, 51))	('Snai1', 'Gene', (114, 119))	('luciferase', 'Enzyme', (69, 79))
309723	31810000	We then estimated MTA3's effect on mammosphere formation and found that knockdown and overexpression of MTA3 significantly (p < 0.01) increased and decreased the number of mammospheres, respectively (Figures 2I and S5A), suggesting that MTA3 possesses property against ESCC cancer stemness.	('cancer stemness', 'Disease', 'MESH:D009369', (274, 289))	('decreased', 'NegReg', (148, 157))	('overexpression', 'PosReg', (86, 100))	('cancer stemness', 'Disease', (274, 289))	('increased', 'PosReg', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('knockdown', 'Var', (72, 81))	('MTA3', 'Gene', (104, 108))
309725	31810000	Finally, CD44 increased dramatically in ESCC cells when MTA3 is knocked down (Figures 2M and S5D).	('increased', 'PosReg', (14, 23))	('CD44', 'Gene', (9, 13))	('knocked down', 'Var', (64, 76))	('MTA3', 'Gene', (56, 60))	('CD44', 'Gene', '960', (9, 13))
309727	31810000	To understand the mechanism in MTA3-regulated ESCC cancer stemness, we conducted a stemness PCR array and found that MTA3 knockdown leads to certain stemness-related genes to be up- or down-regulated, and 11 of them were elevated more than 1.5-fold (Figure S6A).	('stemness-related genes', 'Gene', (149, 171))	('ESCC', 'Disease', (46, 50))	('MTA3', 'Gene', (117, 121))	('elevated', 'PosReg', (221, 229))	('cancer stemness', 'Disease', (51, 66))	('down-regulated', 'NegReg', (185, 199))	('up-', 'PosReg', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('knockdown', 'Var', (122, 131))	('cancer stemness', 'Disease', 'MESH:D009369', (51, 66))
309730	31810000	However, luciferase reporter assays showed that MTA3 has no regulatory effect on SOX2 promoter (Figures S6F and S6G), suggesting that MTA3 could regulate SOX2 indirectly.	('S6G', 'Mutation', 'p.S6G', (112, 115))	('S6G', 'Var', (112, 115))	('SOX2', 'Gene', (81, 85))
309734	31810000	Results from both semi-quantitative PCR (Figure 3H) and qPCR (Figures 3I and S7A) demonstrated that MTA3 is recruited to the promoter region of the SOX2OT gene by GATA3 because knockdown of GATA3 abolished MTA3's repressive effect on SOX2OT and inhibited the MTA3's occupation on the promoter region of SOX2OT (Figures 3J-3L, S7B, and S7C).	('S7C', 'Mutation', 'rs749206235', (335, 338))	('GATA3', 'Gene', (190, 195))	('GATA3', 'Gene', (163, 168))	('abolished', 'NegReg', (196, 205))	('knockdown', 'Var', (177, 186))	('GATA3', 'Gene', '2625', (190, 195))	('GATA3', 'Gene', '2625', (163, 168))	('occupation', 'MPA', (266, 276))	('repressive effect', 'MPA', (213, 230))	('inhibited', 'NegReg', (245, 254))
309735	31810000	To determine which GATA3-binding site(s) is responsible for MTA3 recruitment, we conducted luciferase reporter assays with one, two, or three potential GATA3 being deleted (Figure 3M) from the SOX2OT promoter.	('GATA3', 'Gene', (152, 157))	('deleted', 'Var', (164, 171))	('GATA3', 'Gene', (19, 24))	('GATA3', 'Gene', '2625', (152, 157))	('GATA3', 'Gene', '2625', (19, 24))
309737	31810000	In addition, potential GATA3-binding site #1 is likely to be not involved in MTA3 recruitment because deletion of this site has no effect on MTA3-mediated repression.	('deletion', 'Var', (102, 110))	('GATA3', 'Gene', (23, 28))	('GATA3', 'Gene', '2625', (23, 28))
309738	31810000	However, sites #2 and #3 are likely to be responsible for the recruitment of GATA3/MTA3 complex because deleting either of them reduced MTA3-mediated repression significantly (p < 0.001, Figure 3O).	('reduced', 'NegReg', (128, 135))	('GATA3', 'Gene', (77, 82))	('deleting', 'Var', (104, 112))	('MTA3-mediated repression', 'MPA', (136, 160))	('GATA3', 'Gene', '2625', (77, 82))
309747	31810000	Kaplan-Meier analyses found that patients with ESCC in the high-SOX2 group had a poorer prognosis than those in the low-SOX2 group (p < 0.001; Figure 5E).	('ESCC', 'Disease', (47, 51))	('patients', 'Species', '9606', (33, 41))	('high-SOX2', 'Var', (59, 68))
309748	31810000	Correlation analyses also found that tumors with low levels of MTA3 were more likely to have high levels of SOX2 (p < 0.01; Figure 5F).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('high levels of SOX2', 'MPA', (93, 112))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('low', 'Var', (49, 52))	('MTA3', 'Protein', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
309750	31810000	Kaplan-Meier analyses found that overall survival of patients in the low-MTA3/high-SOX2 group is significantly worse than those in the high-MTA3/low-SOX2 (p < 0.001; Figure 5G), high-MTA3/low-SOX2, high-MTA3/high-SOX2, and low-MTA3/low-SOX2 (p < 0.001; Figure 5H) groups.	('patients', 'Species', '9606', (53, 61))	('worse', 'NegReg', (111, 116))	('low-MTA3/high-SOX2', 'Var', (69, 87))
309751	31810000	Finally, multivariate Cox regression analyses found that low-MTA3/high-SOX2 (HR, 3.273; 95% CI, 1.815 to 5.901, p = 0.000) can be used as independent prognostic indicators in ESCC patient prognosis (Table 1).	('low-MTA3/high-SOX2', 'Var', (57, 75))	('ESCC', 'Disease', (175, 179))	('patient', 'Species', '9606', (180, 187))
309754	31810000	To do so, we first used EC9706 cells to establish overexpression of MTA3 or SOX2 individually or in combinations (Figure 6A) as well as knockdown of MTA3 or SOX2 by specific shRNA individually or in combination (Figure 6B).	('EC9706', 'CellLine', 'CVCL:E307', (24, 30))	('overexpression', 'PosReg', (50, 64))	('knockdown', 'Var', (136, 145))
309757	31810000	Figures 6C and 6D show that the tumors derived from the cells with MTA3 overexpression were significantly smaller/lighter and the tumors derived from the cells overexpressing either SOX2OT or SOX2 were significantly bigger/heavier.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('overexpression', 'Var', (72, 86))	('smaller/lighter', 'NegReg', (106, 121))	('MTA3', 'Gene', (67, 71))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
309758	31810000	In addition, the size/weight of tumors derived from the cells overexpressing MTA3 with either SOX2OT or SOX2 was bigger/heavier than that with MTA3 overexpression alone but smaller/lighter than that with either SOX2OT or SOX2 overexpression.	('smaller/lighter', 'NegReg', (173, 188))	('MTA3', 'Var', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
309759	31810000	On the other hand, the tumors derived from the cells with MTA3 and SOX2 knockdown were bigger/heavier and smaller/lighter, respectively.	('MTA3', 'Gene', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('SOX2', 'Gene', (67, 71))	('knockdown', 'Var', (72, 81))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
309760	31810000	The size/weight of the tumors derived from the cells with knockdown of both MTA3 and SOX2 was similar to that of the control (Figure 6E).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('MTA3', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('SOX2', 'Gene', (85, 89))	('knockdown', 'Var', (58, 67))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
309771	31810000	This finding is in line with the fact that MTA3 is capable of inhibiting the initiation of primitive hematopoiesis in vertebrate embryos, repressing EMT in breast cancer cells, and suppressing Wnt4 pathway in mammary epithelial cells, implicating a role for MTA3 in regulation of stem cell properties.	('repressing', 'PosReg', (138, 148))	('EMT', 'CPA', (149, 152))	('initiation', 'CPA', (77, 87))	('hematopoiesis', 'Disease', (101, 114))	('MTA3', 'Var', (43, 47))	('suppressing', 'NegReg', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Wnt4', 'Gene', (193, 197))	('inhibiting', 'NegReg', (62, 72))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('Wnt4', 'Gene', '54361', (193, 197))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('hematopoiesis', 'Disease', 'MESH:C536227', (101, 114))
309782	31810000	It has been reported that GATA3 plays an important role in the regulation of CSC activities and loss of GATA3 contributes to breast cancer metastasis.	('GATA3', 'Gene', (104, 109))	('loss', 'Var', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('GATA3', 'Gene', '2625', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('GATA3', 'Gene', (26, 31))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('GATA3', 'Gene', '2625', (26, 31))
309783	31810000	In addition, GATA3 is mutated in >10% of breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('breast tumors', 'Phenotype', 'HP:0100013', (41, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('mutated', 'Var', (22, 29))	('breast tumors', 'Disease', 'MESH:D001943', (41, 54))	('breast tumors', 'Disease', (41, 54))	('GATA3', 'Gene', (13, 18))	('GATA3', 'Gene', '2625', (13, 18))
309784	31810000	Mutations in the second zinc finger domain of GATA3 diminishes or abolishes its DNA-binding ability and reduces its stability in human breast cancers.	('DNA-binding', 'Interaction', (80, 91))	('GATA3', 'Gene', (46, 51))	('diminishes', 'NegReg', (52, 62))	('reduces', 'NegReg', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancers', 'Phenotype', 'HP:0003002', (135, 149))	('GATA3', 'Gene', '2625', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('Mutations', 'Var', (0, 9))	('breast cancers', 'Disease', 'MESH:D001943', (135, 149))	('breast cancers', 'Disease', (135, 149))	('human', 'Species', '9606', (129, 134))	('abolishes', 'NegReg', (66, 75))	('stability', 'MPA', (116, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
309785	31810000	These findings altogether suggest that GATA3 mutations are "drivers" of breast cancer development.	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('GATA3', 'Gene', (39, 44))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('GATA3', 'Gene', '2625', (39, 44))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
309788	31810000	Of note, genetic changes (mutation, amplification, and deletion) of GATA3 are extremely rare in esophageal cancer (0.62%, Table S3).	('GATA3', 'Gene', '2625', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('amplification', 'Var', (36, 49))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('deletion', 'Var', (55, 63))	('GATA3', 'Gene', (68, 73))	('cancer', 'Disease', (107, 113))
309796	31810000	Based on the results mainly derived from overexpression and/or knockdown of different genes in cultured cells and xenograft mouse models, we were able to demonstrate that, by targeting/repressing the SOX2OT/SOX2 axis, MTA3 can suppress cancer stemness and EMT in ESCC.	('suppress', 'NegReg', (227, 235))	('ESCC', 'Disease', (263, 267))	('cancer stemness', 'Disease', (236, 251))	('targeting/repressing', 'Var', (175, 195))	('mouse', 'Species', '10090', (124, 129))	('targeting/repressing', 'PosReg', (175, 195))	('EMT', 'CPA', (256, 259))	('MTA3', 'Gene', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cancer stemness', 'Disease', 'MESH:D009369', (236, 251))
309797	31810000	However, the conclusions would be strengthened if the relevant experiments were conducted in tissue-specific MTA3 transgenic and/or MTA3 knockout mice.	('MTA3', 'Gene', (109, 113))	('transgenic', 'Var', (114, 124))	('mice', 'Species', '10090', (146, 150))
309848	31749632	The number of patients who obtained an OR type of primary tumor response was 36 in the low-SUVmax group versus 60 in the high-SUVmax group, with ORR values of 87.8% and 61.9%, respectively (P=0.004).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('low-SUVmax', 'Var', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('patients', 'Species', '9606', (14, 22))
309851	31749632	From the comparisons, we found that 71 (80.7%) patients had an OR type of primary tumor response in the high-LMR group (LMR>2.76), while there were only 26 (52.0%) patients who had an OR type of primary response in the low-LMR group (LMR<=2.76); this difference was statistically significant (P=0.001).	('LMR>2', 'Gene', (120, 125))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('LMR>2', 'Gene', '22853', (120, 125))	('patients', 'Species', '9606', (164, 172))	('tumor', 'Disease', (82, 87))	('high-LMR', 'Var', (104, 112))
309854	31749632	In univariate analysis, tumor stage (P=0.006, HR =0.210), SUVmax (P=0.004, HR =4.440) and LMR (P=0.001, HR =3.885) were associated with primary tumor response (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (144, 149))	('associated', 'Reg', (120, 130))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('LMR', 'Var', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
309883	31749632	Regarding esophageal cancer, Huang et al retrospectively analyzed data from 348 patients with esophageal squamous cell cancer who underwent radical surgery and found that the 5-year cancer-specific survival was significantly lower for patients with a peripheral LMR <= 2.93 than for patients with a peripheral LMR >2.93.	('patients', 'Species', '9606', (80, 88))	('lower', 'NegReg', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('patients', 'Species', '9606', (235, 243))	('patients', 'Species', '9606', (283, 291))	('esophageal cancer', 'Disease', 'MESH:D004938', (10, 27))	('cancer', 'Disease', (119, 125))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (94, 125))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('esophageal cancer', 'Disease', (10, 27))	('peripheral LMR <= 2.93', 'Var', (251, 273))	('cancer', 'Disease', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (105, 125))	('esophageal squamous cell cancer', 'Disease', (94, 125))
309885	31749632	The disease-free survival and overall survival of patients in the low-peripheral-LMR group were significantly lower than those in the high-peripheral-LMR group.	('patients', 'Species', '9606', (50, 58))	('disease-free survival', 'CPA', (4, 25))	('low-peripheral-LMR', 'Var', (66, 84))	('lower', 'NegReg', (110, 115))	('overall survival', 'CPA', (30, 46))
309892	31749632	In univariate and multivariate analyses, peripheral LMR was a significant predictive factor for primary tumor response.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('peripheral LMR', 'Var', (41, 55))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
309971	29353436	Immunohistochemistry was performed on all samples and identified 1-8 (median: 3) biomarkers per patient (most commonly: low TS, high TOPO1, high TOP2A).	('TOP2A', 'Gene', '7153', (145, 150))	('patient', 'Species', '9606', (96, 103))	('TOP2A', 'Gene', (145, 150))	('high TOPO1', 'Var', (128, 138))	('TS', 'Gene', '7298', (124, 126))
310036	29353436	For biomarkers that were IHC-tested in more than 35 patients, the most commonly identified actionable biomarker (34/40, 85.0%), was low/negative TS, which is associated with response to fluoropyrimidines and other folate analogs, followed by high TOPO1 (27/40, 67.5%), which is associated with response to irinotecan, high TOP2A (27/41, 65.9%), which is associated with response to anthracyclines, and negative/low ERCC1 (21/36, 58.3%), which is associated with response to platinum-based therapy (Table 3).	('ERCC1', 'Gene', (415, 420))	('anthracyclines', 'Chemical', 'MESH:D018943', (382, 396))	('TOP2A', 'Gene', '7153', (323, 328))	('ERCC1', 'Gene', '2067', (415, 420))	('fluoropyrimidine', 'Chemical', '-', (186, 202))	('TOP2A', 'Gene', (323, 328))	('low/negative', 'Var', (132, 144))	('irinotecan', 'Chemical', 'MESH:D000077146', (306, 316))	('TS', 'Gene', '7298', (145, 147))	('patients', 'Species', '9606', (52, 60))
310070	29353436	The biomarker analysis results in the current cohort are overall consistent with those in a recent study involving 230 gastric cancer specimens, in which positive TOPO1 was reported for 68% of patients, negative TS for 63% of patients, high TOP2A for 60% of patients, and negative ERCC1 for 55% of patients.	('ERCC1', 'Gene', '2067', (281, 286))	('TOP2A', 'Gene', '7153', (241, 246))	('patients', 'Species', '9606', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('TOP2A', 'Gene', (241, 246))	('positive', 'Var', (154, 162))	('high', 'Var', (236, 240))	('TOPO1', 'Gene', (163, 168))	('TS', 'Gene', '7298', (212, 214))	('gastric cancer', 'Disease', (119, 133))	('patients', 'Species', '9606', (298, 306))	('men', 'Species', '9606', (139, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('patients', 'Species', '9606', (226, 234))	('patients', 'Species', '9606', (258, 266))	('ERCC1', 'Gene', (281, 286))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))
310108	29147454	His lung cancer was diagnosed 8 years earlier, when he presented with T4N2M0 non-small cell lung cancer treated with combined modality therapy consisting of chemotherapy and radiation to a dose of 6,480 cGy in 180 cGy fractions which led to a 7-year progression-free interval.	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (77, 103))	('T4N2M0', 'Var', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (81, 103))	('lung cancer', 'Disease', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('non-small cell lung cancer', 'Disease', (77, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('lung cancer', 'Disease', 'MESH:D008175', (4, 15))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (77, 103))
310146	28594883	Increases in EC risk were observed with ever tobacco use, alcohol consumption, low consumption of green vegetables, a salty diet, illiteracy, and among Muslims; the four latter associations were significant.	('alcohol', 'Chemical', 'MESH:D000438', (58, 65))	('low', 'NegReg', (79, 82))	('Increases', 'PosReg', (0, 9))	('salt', 'Chemical', 'MESH:D012492', (118, 122))	('tobacco', 'Species', '4097', (45, 52))	('alcohol consumption', 'Var', (58, 77))	('illiteracy', 'Var', (130, 140))
310218	28594883	Interestingly, in a fully adjusted model limited to never tobacco users, the risk of EC was higher in qat users than in never users, although the precision of this estimate was poor.	('tobacco', 'Species', '4097', (58, 65))	('higher', 'PosReg', (92, 98))	('qat users', 'Var', (102, 111))
310287	28382133	They demonstrated that mutant form of PLCepsilon that lost its PIP2 hydrolyzing properties still can activate Ras-MAPK kinase pathway suggesting that this activation is due to Ras binding and GEF domain rather than to PIP2 hydrolysis.	('PIP2', 'Chemical', 'MESH:D019269', (63, 67))	('GEF', 'Gene', '9181', (192, 195))	('rat', 'Species', '10116', (12, 15))	('PLCepsilon', 'Gene', (38, 48))	('PIP2 hydrolyzing properties', 'MPA', (63, 90))	('Ras-MAPK kinase pathway', 'Pathway', (110, 133))	('PIP2', 'Chemical', 'MESH:D019269', (218, 222))	('activate', 'PosReg', (101, 109))	('GEF', 'Gene', (192, 195))	('binding', 'Interaction', (180, 187))	('rat', 'Species', '10116', (203, 206))	('mutant', 'Var', (23, 29))
310291	28382133	The same group described similar mechanisms of PLCepsilon activation in response to PDGF stimulation of hematopoietic BaF3 cells expressing PDGF receptor mutant that can activates Ras and Rap1 but not other types of PLC such as PLCgamma .	('activates', 'PosReg', (170, 179))	('Rap1', 'Gene', (188, 192))	('PLCepsilon', 'Enzyme', (47, 57))	('BaF3', 'CellLine', 'CVCL:0161', (118, 122))	('PDGF receptor', 'Gene', (140, 153))	('Rap1', 'Gene', '109905', (188, 192))	('Ras', 'Protein', (180, 183))	('activation', 'PosReg', (58, 68))	('mutant', 'Var', (154, 160))
310292	28382133	The activity of PLCepsilon was induced by PDGF treatment and abrogated by disruption of the Rap and Ras pathways with overexpression of the Rap GAP, Spa1 protein and dominant negative Ras, respectively.	('dominant negative Ras', 'Var', (166, 187))	('Ras pathways', 'Pathway', (100, 112))	('overexpression', 'PosReg', (118, 132))	('Rap', 'Gene', '4043', (140, 143))	('Spa1', 'Gene', (149, 153))	('disruption', 'NegReg', (74, 84))	('Rap', 'Gene', (92, 95))	('abrogated', 'NegReg', (61, 70))	('induced', 'Reg', (31, 38))	('Spa1', 'Gene', '6494', (149, 153))	('Rap', 'Gene', (140, 143))	('activity', 'MPA', (4, 12))	('Rap', 'Gene', '4043', (92, 95))
310296	28382133	Mutation of RA2 domain of PLCepsilon only partially inhibited this stimulation suggesting that GPCR can stimulate PLCepsilon in RA2-dependent and RA2-independent way.	('RA2', 'Gene', '474222', (12, 15))	('RA2', 'Gene', (12, 15))	('Mutation', 'Var', (0, 8))	('GPCR', 'Gene', (95, 99))	('GPCR', 'Gene', '23566', (95, 99))	('PLCepsilon', 'Gene', (114, 124))	('RA2', 'Gene', '474222', (128, 131))	('RA2', 'Gene', '474222', (146, 149))	('RA2', 'Gene', (128, 131))	('stimulate', 'PosReg', (104, 113))	('RA2', 'Gene', (146, 149))
310300	28382133	In the experiments with stimulation of PIP2 hydrolysis in the presence of RA2 mutant forms of PLCepsilon, Kelley and coworkers identified additional GTPases that stimulate PLCepsilon independently on RA2 binding including RalA and Rac.	('RA2', 'Gene', (200, 203))	('Rac', 'Gene', '207', (231, 234))	('RA2', 'Gene', (74, 77))	('GTP', 'Gene', (149, 152))	('Rac', 'Gene', (231, 234))	('PLCepsilon', 'MPA', (172, 182))	('stimulate', 'PosReg', (162, 171))	('PIP2', 'Chemical', 'MESH:D019269', (39, 43))	('RA2', 'Gene', '474222', (200, 203))	('mutant', 'Var', (78, 84))	('RA2', 'Gene', '474222', (74, 77))	('GTP', 'Gene', '92170', (149, 152))
310304	28382133	Analysis of the PLCE1 gene alterations using The Cancer Genome Atlas (TCGA) database demonstrates that PLCE1 is frequently mutated gene in the different types of tumors (Figure 2A).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('PLCE1', 'Gene', (16, 21))	('PLCE1', 'Gene', '51196', (16, 21))	('rat', 'Species', '10116', (92, 95))	('PLCE1', 'Gene', '51196', (103, 108))	('rat', 'Species', '10116', (31, 34))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', (162, 168))	('CG', 'Chemical', 'MESH:C028505', (71, 73))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PLCE1', 'Gene', (103, 108))	('alterations', 'Var', (27, 38))
310311	28382133	Study of Bai and coworkers showed that PLCepsilon Deltax/Deltax mice developed much less tumors (mostly papillomas) compared to PLCepsilon+/+ and PLCepsilon+/- (mostly adenocarcinomas) mice.	('tumors', 'Disease', (89, 95))	('papillomas', 'Disease', 'MESH:D010212', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('PLCepsilon Deltax/Deltax', 'Var', (39, 63))	('less', 'NegReg', (84, 88))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('papillomas', 'Disease', (104, 114))	('mostly adenocarcinomas', 'Disease', 'MESH:D000230', (161, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('mice', 'Species', '10090', (185, 189))	('mostly adenocarcinomas', 'Disease', (161, 183))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mice', 'Species', '10090', (64, 68))
310315	28382133	In contrast to the Kataoka's mice model where PLCepsilon was expressed in a shortened and catalytically inactive form, the knockout models described by Martins and coauthors either have a complete loss of the PLCepsilon expression (PLCepsilon-/-) or have expression of the mutant form of PLCepsilon with mutant RA domains enable to bind to Ras (PLCepsilonRAm/RAm).	('loss of the PLCepsilon', 'Disease', (197, 219))	('PLCepsilon-/-', 'Gene', (232, 245))	('Ras', 'Protein', (340, 343))	('expression', 'MPA', (220, 230))	('PLCepsilon-/-)', 'Gene', '74055', (232, 246))	('mutant', 'Var', (304, 310))	('mutant', 'Var', (273, 279))	('mice', 'Species', '10090', (29, 33))	('bind', 'Interaction', (332, 336))	('loss of the PLCepsilon', 'Disease', 'MESH:D015431', (197, 219))	('PLCepsilon', 'Gene', (288, 298))
310316	28382133	According to their findings, PLCepsilon cannot be considered as an oncogene for Ras-triggered skin cancers, but rather as tumor suppressor, because this study revealed that PLCepsilon-/- and to a lesser degree PLCepsilonRAm/RAm mice possessed increased susceptibility to tumor development as compared to the mice with PLCepsilon+/+ and PLCepsilon+/- genotype.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('rat', 'Species', '10116', (112, 115))	('PLCepsilonRAm/RAm', 'Var', (210, 227))	('mice', 'Species', '10090', (228, 232))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('skin cancers', 'Phenotype', 'HP:0008069', (94, 106))	('tumor', 'Disease', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PLCepsilon-/-', 'Gene', (173, 186))	('PLCepsilon-/-', 'Gene', '74055', (173, 186))	('skin cancers', 'Disease', (94, 106))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('susceptibility', 'Reg', (253, 267))	('skin cancers', 'Disease', 'MESH:D012878', (94, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('skin cancer', 'Phenotype', 'HP:0008069', (94, 105))	('mice', 'Species', '10090', (308, 312))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
310318	28382133	which have a complete loss of the PLCepsilon expression (PLCepsilon -/-) or express the mutant form of PLCepsilon (PLCepsilon RAm/RAm) were also used to investigate potential role of PLCepsilon in KRAS-driven lung tumor development.	('lung tumor', 'Phenotype', 'HP:0100526', (209, 219))	('loss of the PLCepsilon', 'Disease', (22, 44))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('lung tumor', 'Disease', (209, 219))	('mutant', 'Var', (88, 94))	('KRAS', 'Gene', (197, 201))	('lung tumor', 'Disease', 'MESH:D008175', (209, 219))	('KRAS', 'Gene', '3845', (197, 201))	('loss of the PLCepsilon', 'Disease', 'MESH:D015431', (22, 44))
310320	28382133	PLCepsilon -/- and PLCepsilon RAm/RAm mice were crossed with LSL-KrasG12D mice and expression of KrasG12D was induced by AdCre infection.	('mice', 'Species', '10090', (38, 42))	('infection', 'Disease', (127, 136))	('infection', 'Disease', 'MESH:D007239', (127, 136))	('KrasG12D', 'Var', (97, 105))	('mice', 'Species', '10090', (74, 78))
310322	28382133	Interestingly, analysis of the LSL-KrasG12D MEF cells revealed a rapid reduction of PLCepsilon expression after KrasG12D induction with AdCre.	('MEF', 'Gene', '2000', (44, 47))	('MEF', 'Gene', (44, 47))	('reduction', 'NegReg', (71, 80))	('PLCepsilon', 'Gene', (84, 94))	('KrasG12D', 'Var', (112, 120))
310329	28382133	Treatment of NSCLC cells with PLC inhibitor U-73122 resulted in upregulation of p53 level and induced cell apoptosis.	('NSCLC', 'Disease', (13, 18))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('cell apoptosis', 'CPA', (102, 116))	('p53', 'Gene', (80, 83))	('upregulation', 'PosReg', (64, 76))	('U-73122', 'Chemical', 'MESH:C060229', (44, 51))	('p53', 'Gene', '7157', (80, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (13, 18))	('induced', 'Reg', (94, 101))	('U-73122', 'Var', (44, 51))
310334	28382133	However, not only the level of PLCE1 expression but also single nucleotide polymorphism (SNP) of PLCE1 gene is associated with ESCC and GC carcinogenesis.	('carcinogenesis', 'Disease', (139, 153))	('PLCE1', 'Gene', (97, 102))	('PLCE1', 'Gene', '51196', (97, 102))	('PLCE1', 'Gene', '51196', (31, 36))	('ESCC', 'Disease', (127, 131))	('associated', 'Reg', (111, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (139, 153))	('GC', 'Phenotype', 'HP:0012126', (136, 138))	('PLCE1', 'Gene', (31, 36))	('single nucleotide polymorphism', 'Var', (57, 87))
310336	28382133	This study was conducted for more than 2,000 GC and ESCC cases and more than 3,000 control cases, and identified five SNPs on 10q23 that are mapped to the PLCE1 gene and have significant association to the risk of ESCC and GC development.	('PLCE1', 'Gene', '51196', (155, 160))	('GC', 'Phenotype', 'HP:0012126', (223, 225))	('ESCC', 'Disease', (214, 218))	('association', 'Reg', (187, 198))	('GC development', 'CPA', (223, 237))	('SNPs', 'Var', (118, 122))	('GC', 'Phenotype', 'HP:0012126', (45, 47))	('PLCE1', 'Gene', (155, 160))
310337	28382133	Two of these SNPs, rs2274223 and rs3765524 result in missense mutations in the coding region of PLCE1 gene and cause the amino acid substitutions His1927Arg in the C2 domain and Thr1777Ile in the catalytic domain, respectively.	('His1927Arg', 'Var', (146, 156))	('PLCE1', 'Gene', '51196', (96, 101))	('Thr1777Ile', 'SUBSTITUTION', 'None', (178, 188))	('rs2274223', 'Mutation', 'rs2274223', (19, 28))	('rs3765524', 'Mutation', 'rs3765524', (33, 42))	('rs2274223', 'Var', (19, 28))	('Thr1777Ile', 'Var', (178, 188))	('His1927Arg', 'SUBSTITUTION', 'None', (146, 156))	('rs3765524', 'Var', (33, 42))	('PLCE1', 'Gene', (96, 101))
310338	28382133	Interestingly, association of rs2274223 with CG was different for the different anatomical sites with a strongest association for tumors located in cardia.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('CG', 'Chemical', 'MESH:C028505', (45, 47))	('cardia', 'Disease', 'MESH:D004938', (148, 154))	('cardia', 'Disease', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('rs2274223', 'Mutation', 'rs2274223', (30, 39))	('rs2274223', 'Var', (30, 39))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('association', 'Interaction', (15, 26))
310341	28382133	This study confirmed association of rs2274223 with ESCC.	('rs2274223', 'Mutation', 'rs2274223', (36, 45))	('rs2274223', 'Var', (36, 45))	('association', 'Reg', (21, 32))	('ESCC', 'Disease', (51, 55))
310344	28382133	Later study of Wu and coworkers for more than 2,000 ESCC patients and over 2,000 control individuals also confirmed that this rs2274223 signature in PLCE1 gene is associated with ESCC risk.	('PLCE1', 'Gene', (149, 154))	('PLCE1', 'Gene', '51196', (149, 154))	('patients', 'Species', '9606', (57, 65))	('ESCC', 'Disease', (179, 183))	('associated with', 'Reg', (163, 178))	('rs2274223', 'Mutation', 'rs2274223', (126, 135))	('rs2274223', 'Var', (126, 135))
310345	28382133	Malik and coauthors studied the polymorphisms (rs2274223A>G, rs3765524C>T and rs7922612C>T) in 135 patients with esophageal cancer and 195 age and gender matched control patients from Kashmir valley, where the incidence of esophageal cancer is reported to be higher than 40% of all cancers.	('patients', 'Species', '9606', (170, 178))	('cancers', 'Disease', (282, 289))	('rs3765524C>T', 'DBSNP_MENTION', 'None', (61, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('esophageal cancer', 'Disease', (223, 240))	('rs2274223A>G', 'Var', (47, 59))	('rs7922612C>T', 'DBSNP_MENTION', 'None', (78, 90))	('rs2274223A>G', 'DBSNP_MENTION', 'None', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (99, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (223, 240))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('esophageal cancer', 'Disease', (113, 130))	('cancers', 'Disease', 'MESH:D009369', (282, 289))	('rs7922612C>T', 'Var', (78, 90))	('rs3765524C>T', 'Var', (61, 73))
310346	28382133	Researchers have showed that these SNPs did not have independent association with development of esophageal cancer, but the G2274223T3765524T7922612 haplotype was significantly associated with increased risk of EC.	('G2274223T3765524T7922612', 'Var', (124, 148))	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('associated', 'Reg', (177, 187))
310347	28382133	that included 550 patients with ESCC and 550 control individuals demonstrated that GA genotype of rs10882379 was significantly correlated with decreased ESCC risk, whereas AA genotype of rs829232 was significantly associated with a high ESCC risk in Chinese population as compared to GG genotype.	('rat', 'Species', '10116', (72, 75))	('rs10882379', 'Var', (98, 108))	('decreased', 'NegReg', (143, 152))	('rs829232', 'Var', (187, 195))	('rs10882379', 'Mutation', 'rs10882379', (98, 108))	('rs829232', 'Mutation', 'rs829232', (187, 195))	('high ESCC', 'Phenotype', 'HP:0003565', (232, 241))	('patients', 'Species', '9606', (18, 26))	('ESCC', 'Disease', (237, 241))	('decreased ESCC', 'Phenotype', 'HP:0025022', (143, 157))	('ESCC', 'Disease', (153, 157))
310349	28382133	This study concluded that rs2274223A>G correlates with an increased risk of both types of cancer, especially ESCC, However, the authors acknowledge that due to the retrospective character of the most of the data and high heterogeneity across the studies, which is attributed to a small number of participants and ethnic variations, their analysis might not be conclusive and needs the data from additional prospective studies for confirmation, One of the further reason for the discrepancy between the Chinese and African GWAS studies is a lower linkage disequilibrium (LD) which is an index of the non-random association between alleles at the different loci.	('rs2274223A>G', 'Var', (26, 38))	('ESCC', 'Disease', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs2274223A>G', 'DBSNP_MENTION', 'None', (26, 38))	('linkage disequilibrium', 'MPA', (546, 568))	('small', 'Chemical', '-', (280, 285))	('participants', 'Species', '9606', (296, 308))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
310351	28382133	Six of ten examined SNPs were predicted to lead to the loss of functionality for the different PLCepsilon domains including Ras-GEF domain (rs17417407), catalytic domain (rs3765524) or C2 domain (rs2274223).	('GEF', 'Gene', (128, 131))	('loss', 'NegReg', (55, 59))	('rs2274223', 'Mutation', 'rs2274223', (196, 205))	('rs3765524', 'Var', (171, 180))	('rs17417407', 'Mutation', 'rs17417407', (140, 150))	('GEF', 'Gene', '9181', (128, 131))	('rs3765524', 'Mutation', 'rs3765524', (171, 180))	('functionality', 'MPA', (63, 76))	('rs2274223', 'Var', (196, 205))	('rs17417407', 'Var', (140, 150))
310364	28382133	Analysis of the TCGA dataset for esophageal carcinoma suggests that frequent (10,9%) mutations of PLCE1 are associated with upregulation of the different pro-survival mechanisms such as PI3K, RAS/MAPK, WNT and calcium signaling pathways (Figure 3).	('upregulation', 'PosReg', (124, 136))	('pro-survival', 'CPA', (154, 166))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (33, 53))	('CG', 'Chemical', 'MESH:C028505', (17, 19))	('PI3', 'Gene', (186, 189))	('RAS/MAPK', 'Pathway', (192, 200))	('PLCE1', 'Gene', (98, 103))	('mutations', 'Var', (85, 94))	('PLCE1', 'Gene', '51196', (98, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('esophageal carcinoma', 'Disease', (33, 53))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (33, 53))	('calcium', 'Chemical', 'MESH:D002118', (210, 217))	('PI3', 'Gene', '5266', (186, 189))
310365	28382133	revealed that a non-synonymous SNP 2274223 A/G at 10q23 in PLCE1 gene is a shared susceptibility locus for gastric cancer and ESCC.	('2274223 A/G', 'SUBSTITUTION', 'None', (35, 46))	('PLCE1', 'Gene', '51196', (59, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('susceptibility', 'Reg', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ESCC', 'Disease', (126, 130))	('PLCE1', 'Gene', (59, 64))	('gastric cancer', 'Disease', (107, 121))	('2274223 A/G', 'Var', (35, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))
310367	28382133	PLCE1 rs2274223 A/G SNP analysis in 940 gastric cancer patients from China demonstrated that patients with AA genotype survived better that those with AG and GG genotypes.	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('gastric cancer', 'Disease', (40, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('patients', 'Species', '9606', (55, 63))	('rat', 'Species', '10116', (82, 85))	('PLCE1', 'Gene', '51196', (0, 5))	('PLCE1', 'Gene', (0, 5))	('better', 'PosReg', (128, 134))	('rs2274223', 'Mutation', 'rs2274223', (6, 15))	('rs2274223', 'Var', (6, 15))	('patients', 'Species', '9606', (93, 101))
310371	28382133	These results might potentially suggest different association between PLCepsilon gene polymorphism and carcinogenesis in Chinese and Caucasian populations.	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('polymorphism', 'Var', (86, 98))	('PLCepsilon gene', 'Gene', (70, 85))	('association', 'Interaction', (50, 61))	('carcinogenesis', 'Disease', (103, 117))
310372	28382133	have been confirmed by Wang and coauthors who demonstrated that 2 SNPs, rs2274223 and rs11187870, are significantly associated with a higher risk of gastric cancer in Han Chinese patients (cancer: n=1059; control n=1240).	('gastric cancer', 'Disease', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('rat', 'Species', '10116', (53, 56))	('rs11187870', 'Var', (86, 96))	('rs11187870', 'Mutation', 'rs11187870', (86, 96))	('cancer', 'Disease', (157, 163))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('rs2274223', 'Mutation', 'rs2274223', (72, 81))	('rs2274223', 'Var', (72, 81))	('associated', 'Reg', (116, 126))
310373	28382133	performed the meta-analysis for the eligible case-control studies which included 8281 cases and 10532 controls and showed that Asian patients, but not Europeans carrying PLCE1 rs2274223 A>G polymorphism are under the higher risk of digestive tract cancer development (particularly gastric and esophageal cancer).	('cancer', 'Disease', (248, 254))	('PLCE1', 'Gene', (170, 175))	('PLCE1', 'Gene', '51196', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('gastric', 'Disease', (281, 288))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Disease', (304, 310))	('esophageal cancer', 'Disease', (293, 310))	('rs2274223 A>G', 'Var', (176, 189))	('esophageal cancer', 'Disease', 'MESH:D004938', (293, 310))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('rs2274223', 'Mutation', 'rs2274223', (176, 185))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (232, 254))
310379	28382133	Blood vessel formation was decreased in low-grade PLCepsilon-/- adenomas compared to PLCepsilon+/+ ones; however, no such difference was observed in high-grade adenomas, indicating that PLCepsilon expression can augment blood vessel formation in tumors of intestine.	('blood vessel formation', 'CPA', (220, 242))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('adenomas', 'Disease', 'MESH:D000236', (160, 168))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('augment', 'PosReg', (212, 219))	('adenomas', 'Disease', 'MESH:D000236', (64, 72))	('decreased', 'NegReg', (27, 36))	('adenomas', 'Disease', (160, 168))	('adenomas', 'Disease', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('PLCepsilon-/-', 'Gene', '74055', (50, 63))	('tumors', 'Disease', (246, 252))	('PLCepsilon expression', 'Var', (186, 207))	('Blood vessel formation', 'CPA', (0, 22))	('PLCepsilon-/-', 'Gene', (50, 63))
310382	28382133	PLCE1 gene expression was significantly downregulated in colorectal cancer samples (n=137) as compared to normal colonic mucosa specimens (n=10), and low levels of PLCepsilon expression were strongly associated with mutations in KRAS gene.	('colorectal cancer', 'Disease', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('downregulated', 'NegReg', (40, 53))	('expression', 'MPA', (11, 21))	('KRAS', 'Gene', (229, 233))	('colorectal cancer', 'Disease', 'MESH:D015179', (57, 74))	('associated', 'Reg', (200, 210))	('colonic mucosa', 'Disease', 'MESH:D015179', (113, 127))	('colonic mucosa', 'Disease', (113, 127))	('PLCE1', 'Gene', (0, 5))	('KRAS', 'Gene', '3845', (229, 233))	('PLCE1', 'Gene', '51196', (0, 5))	('mutations', 'Var', (216, 225))	('PLCepsilon expression', 'MPA', (164, 185))
310389	28382133	Further analysis conducted in European population (controls: n=382, colorectal tumor: n=192) showed the common genetic variants of PLCE1 identified earlier in GWAS study were not associated with colorectal cancer development.	('PLCE1', 'Gene', (131, 136))	('associated', 'Reg', (179, 189))	('colorectal cancer', 'Phenotype', 'HP:0003003', (195, 212))	('PLCE1', 'Gene', '51196', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('colorectal cancer', 'Disease', 'MESH:D015179', (195, 212))	('colorectal cancer', 'Disease', (195, 212))	('colorectal tumor', 'Disease', (68, 84))	('colorectal tumor', 'Disease', 'MESH:D015179', (68, 84))	('variants', 'Var', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
310390	28382133	(controls: n=210, colorectal tumor: n=200) clearly showed that rs2274223 SNP was associated with higher risk of colorectal cancer development in Turkish and Caucasian people.	('colorectal cancer', 'Disease', (112, 129))	('rs2274223 SNP', 'Var', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('higher', 'PosReg', (97, 103))	('colorectal tumor', 'Disease', 'MESH:D015179', (18, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('people', 'Species', '9606', (167, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('rs2274223', 'Mutation', 'rs2274223', (63, 72))	('colorectal tumor', 'Disease', (18, 34))
310391	28382133	Interestingly, the study of Wang and coauthors demonstrated that rs2274223 A>G change might decrease level of PLCE1 expression and the variant G phenotype is associated with a high susceptibility to colorectal cancer in Chinese population (controls: n=416, colorectal tumor: n=417).	('colorectal tumor', 'Disease', 'MESH:D015179', (257, 273))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('PLCE1', 'Gene', (110, 115))	('decrease', 'NegReg', (92, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (199, 216))	('PLCE1', 'Gene', '51196', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('rs2274223 A>G', 'Var', (65, 78))	('rat', 'Species', '10116', (54, 57))	('colorectal cancer', 'Disease', (199, 216))	('level', 'MPA', (101, 106))	('colorectal tumor', 'Disease', (257, 273))	('colorectal cancer', 'Disease', 'MESH:D015179', (199, 216))	('rs2274223', 'Mutation', 'rs2274223', (65, 74))
310393	28382133	This study demonstrated that rs753724 and rs11187842 polymorphisms significantly differ between cancer patients and healthy individuals.	('rat', 'Species', '10116', (18, 21))	('rs11187842', 'Mutation', 'rs11187842', (42, 52))	('rs11187842', 'Var', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('rs753724', 'Mutation', 'rs753724', (29, 37))	('rs753724', 'Var', (29, 37))	('differ', 'Reg', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('patients', 'Species', '9606', (103, 111))	('cancer', 'Disease', (96, 102))
310398	28382133	have analyzed three potentially functional SNPs of PLCE1 in 1,098 patients with head and neck squamous cell carcinoma (HNSCC) and 1,090 controls matched by age and sex in non-hispanic whites.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (89, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('SNPs', 'Var', (43, 47))	('PLCE1', 'Gene', '51196', (51, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('neck squamous cell carcinoma', 'Disease', (89, 117))	('PLCE1', 'Gene', (51, 56))	('patients', 'Species', '9606', (66, 74))
310399	28382133	It has been shown that PLCE1 variants may have an effect on risk of HNSCC associated with tobacco and alcohol exposure (particularly for those tumors aroused at non-oropharyngeal sites).	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('PLCE1', 'Gene', (23, 28))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('PLCE1', 'Gene', '51196', (23, 28))	('alcohol', 'Chemical', 'MESH:D000438', (102, 109))	('variants', 'Var', (29, 37))	('effect', 'Reg', (50, 56))	('tobacco', 'Species', '4097', (90, 97))	('HNSCC', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
310400	28382133	showed that in head and neck cancer cell line HSC-3 PLCepsilon activation through RhoA-GTP can be blocked by overexpression of PZD domain of leukemia Rho-GEF (LARG) protein, suggesting that PZD domain of LARG can be a potential inhibitor of RhoA/PLCepsilon-mediated production of inositol-3-phosphates, release of Ca2+ from internal storages and thus starting the cascade of signaling events involved in development of head and neck cancer.	('RhoA', 'Gene', '387', (241, 245))	('head and neck cancer', 'Phenotype', 'HP:0012288', (419, 439))	('Ca2+', 'Chemical', 'MESH:D000069285', (314, 318))	('HSC-3', 'CellLine', 'CVCL:1288', (46, 51))	('LARG', 'Gene', (159, 163))	('GTP', 'Gene', '92170', (87, 90))	('head and neck cancer', 'Disease', 'MESH:D006258', (15, 35))	('leukemia Rho-GEF', 'Gene', '23365', (141, 157))	('leukemia', 'Phenotype', 'HP:0001909', (141, 149))	('head and neck cancer', 'Disease', 'MESH:D006258', (419, 439))	('LARG', 'Gene', '23365', (159, 163))	('LARG', 'Gene', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('RhoA', 'Gene', (82, 86))	('inositol-3-phosphates', 'Chemical', 'MESH:C052128', (280, 301))	('PZD domain', 'Var', (190, 200))	('release of Ca2+ from internal storages', 'MPA', (303, 341))	('RhoA', 'Gene', (241, 245))	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('LARG', 'Gene', '23365', (204, 208))	('leukemia Rho-GEF', 'Gene', (141, 157))	('GTP', 'Gene', (87, 90))	('head and neck cancer', 'Phenotype', 'HP:0012288', (15, 35))	('RhoA', 'Gene', '387', (82, 86))
310402	28382133	studied the effect of PLCepsilon gene silencing with small hairpin sh RNA on the invasive properties of T24 cells and showed the significant decrease of the invasive cell potential and downregulation of BCL2, MMP2 and MMP9 gene expression suggesting that PLCepsilon may act as an oncogene for bladder cancer.	('PLCepsilon', 'Gene', (22, 32))	('decrease', 'NegReg', (141, 149))	('MMP2', 'Gene', (209, 213))	('invasive cell potential', 'CPA', (157, 180))	('BCL2', 'Gene', (203, 207))	('small', 'Chemical', '-', (53, 58))	('hairpin', 'Chemical', '-', (59, 66))	('gene', 'Var', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('bladder cancer', 'Disease', 'MESH:D001749', (293, 307))	('bladder cancer', 'Disease', (293, 307))	('downregulation', 'NegReg', (185, 199))	('MMP2', 'Gene', '4313', (209, 213))	('bladder cancer', 'Phenotype', 'HP:0009725', (293, 307))	('MMP9', 'Gene', '4318', (218, 222))	('MMP9', 'Gene', (218, 222))	('expression', 'MPA', (228, 238))	('invasive properties of T24 cells', 'CPA', (81, 113))	('BCL2', 'Gene', '596', (203, 207))
310404	28382133	demonstrated that knockdown of PLCepsilon expression led to the inhibition of cell proliferation and accumulation of the cells in G0/G1 phase of cell cycle.	('knockdown', 'Var', (18, 27))	('rat', 'Species', '10116', (90, 93))	('PLCepsilon', 'Gene', (31, 41))	('inhibition', 'NegReg', (64, 74))	('rat', 'Species', '10116', (7, 10))	('accumulation', 'PosReg', (101, 113))	('cell proliferation', 'CPA', (78, 96))
310405	28382133	In addition, Cheng and coauthors showed the cyclin D downregulation in xenograft tumors derived from cells with knocked down PLCepsilon.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('cyclin D', 'Protein', (44, 52))	('downregulation', 'NegReg', (53, 67))	('knocked down', 'Var', (112, 124))	('PLCepsilon', 'Gene', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
310408	28382133	Interesting research has been carried out by the group of Indian researchers who studied the association of some genetic variants of PLCepsilon with susceptibility to gallbladder cancer in North Indian population.	('PLCepsilon', 'Gene', (133, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('variants', 'Var', (121, 129))	('gallbladder cancer', 'Disease', (167, 185))	('gallbladder cancer', 'Disease', 'MESH:D005706', (167, 185))	('susceptibility', 'Reg', (149, 163))
310410	28382133	Authors genotyped 641 patients (416 with gallbladder cancer and 225 controls) and proved that PLCepsilon polymorphisms previously found in GWAS study can be associated with gallbladder cancer; moreover, authors suggest the involvement of inflammation process in PLCepsilon-mediated gallbladder cancer development.	('gallbladder cancer', 'Disease', 'MESH:D005706', (282, 300))	('gallbladder cancer', 'Disease', (41, 59))	('associated', 'Reg', (157, 167))	('inflammation', 'Disease', 'MESH:D007249', (238, 250))	('gallbladder cancer', 'Disease', 'MESH:D005706', (41, 59))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('inflammation', 'Disease', (238, 250))	('gallbladder cancer', 'Disease', (173, 191))	('patients', 'Species', '9606', (22, 30))	('gallbladder cancer', 'Disease', 'MESH:D005706', (173, 191))	('bladder cancer', 'Phenotype', 'HP:0009725', (177, 191))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (286, 300))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('involvement', 'Reg', (223, 234))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('polymorphisms', 'Var', (105, 118))	('gallbladder cancer', 'Disease', (282, 300))
310413	28382133	This study showed that PLCepsilon expression was elevated in prostate cancer samples, and targeted silencing of PLCepsilon inhibited cell growth and proliferation of LNCaP and PC3 cells, decreased the expression levels of androgen receptor, Hes-1 and Notch, and blocked AR translocation to the nucleus.	('Notch', 'Gene', '4851', (251, 256))	('expression', 'MPA', (34, 44))	('blocked', 'NegReg', (262, 269))	('Notch', 'Gene', (251, 256))	('androgen receptor', 'Gene', (222, 239))	('PLCepsilon', 'Gene', (23, 33))	('androgen receptor', 'Gene', '367', (222, 239))	('Hes-1', 'Gene', '3280', (241, 246))	('decreased', 'NegReg', (187, 196))	('inhibited', 'NegReg', (123, 132))	('elevated', 'PosReg', (49, 57))	('Hes-1', 'Gene', (241, 246))	('rat', 'Species', '10116', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('AR translocation to the nucleus', 'MPA', (270, 301))	('expression levels', 'MPA', (201, 218))	('cell growth', 'CPA', (133, 144))	('PLCepsilon', 'Gene', (112, 122))	('silencing', 'Var', (99, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (61, 76))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))	('prostate cancer', 'Disease', (61, 76))	('LNCaP', 'CellLine', 'CVCL:0395', (166, 171))	('PC3', 'CellLine', 'CVCL:0035', (176, 179))
310419	28382133	This not only serves as additional energetic resource, but also generates a number of biologically active molecules such as diacylglycerol, cholesterol, ceramide, sphingosine, PIP2, IP3 which are involved in the activation of a variety of signaling pathways associated with cancer progression, metastases and therapy resistance e.g.	('IP3', 'Gene', (182, 185))	('diacylglycerol', 'Chemical', 'MESH:D004075', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cholesterol', 'Chemical', 'MESH:D002784', (140, 151))	('PIP2', 'Chemical', 'MESH:D019269', (176, 180))	('sphingosine', 'Chemical', 'MESH:D013110', (163, 174))	('cancer', 'Disease', (274, 280))	('metastases', 'Disease', (294, 304))	('rat', 'Species', '10116', (68, 71))	('ceramide', 'Chemical', 'MESH:D002518', (153, 161))	('IP3', 'Chemical', 'MESH:D015544', (182, 185))	('PIP2', 'Var', (176, 180))	('metastases', 'Disease', 'MESH:D009362', (294, 304))
310437	28382133	On the other hand, SNP polymorphism in one gene might have a little impact on cancer development and therefore be loosely related to the tumorigenesis.	('SNP polymorphism', 'Var', (19, 35))	('tumor', 'Disease', (137, 142))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('related', 'Reg', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
310450	28382133	The hypothesis of the link between PLCepsilon, inflammation and cancer has been also confirmed by Yang et al., who showed that knockdown of PLCepsilon by shRNA decreased not only PLCepsilon expression itself, but also the expression of inflammatory cytokines IL-6, TNF-alpha, IL-2beta and inflammation-associated genes TLR-4, MyD88 and phosphorylated STAT-3.	('IL-6', 'Gene', '3569', (259, 263))	('STAT-3', 'Gene', '6774', (351, 357))	('inflammation', 'Disease', (47, 59))	('decreased', 'NegReg', (160, 169))	('PLCepsilon', 'Gene', (140, 150))	('MyD88', 'Gene', '4615', (326, 331))	('inflammation', 'Disease', 'MESH:D007249', (289, 301))	('PLCepsilon', 'Gene', (179, 189))	('IL-6', 'Gene', (259, 263))	('cancer', 'Disease', (64, 70))	('expression', 'MPA', (190, 200))	('expression', 'MPA', (222, 232))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('TNF-alpha', 'Gene', '7124', (265, 274))	('inflammation', 'Disease', (289, 301))	('TNF-alpha', 'Gene', (265, 274))	('TLR-4', 'Gene', (319, 324))	('MyD88', 'Gene', (326, 331))	('IL-2beta', 'Gene', (276, 284))	('TLR-4', 'Gene', '7099', (319, 324))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('inflammation', 'Disease', 'MESH:D007249', (47, 59))	('STAT-3', 'Gene', (351, 357))	('knockdown', 'Var', (127, 136))
310495	26644907	In a trial which was conducted in 2009 the use of 500 mg Vitamin C, 400 IU Vitamin E or combination of the two, every other day for a median of 7.6 years did not reduce the incidence of prostate cancer or other cancers including leukemia, melanoma, lymphoma, and cancers of the bladder, pancreas, lung, colon, and rectum.	('Vitamin C', 'Var', (57, 66))	('lymphoma', 'Phenotype', 'HP:0002665', (249, 257))	('prostate cancer', 'Disease', 'MESH:D011471', (186, 201))	('pancreas', 'Disease', 'MESH:D010190', (287, 295))	('Vitamin E', 'Chemical', 'MESH:D014810', (75, 84))	('melanoma', 'Disease', (239, 247))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('leukemia', 'Phenotype', 'HP:0001909', (229, 237))	('prostate cancer', 'Phenotype', 'HP:0012125', (186, 201))	('cancers of the bladder', 'Phenotype', 'HP:0009725', (263, 285))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancers of the bladder', 'Disease', (263, 285))	('Vitamin C', 'Chemical', 'MESH:D001205', (57, 66))	('prostate cancer', 'Disease', (186, 201))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('cancers', 'Disease', (263, 270))	('leukemia', 'Disease', 'MESH:D007938', (229, 237))	('lung', 'Disease', (297, 301))	('leukemia', 'Disease', (229, 237))	('lymphoma', 'Disease', (249, 257))	('lymphoma', 'Disease', 'MESH:D008223', (249, 257))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('colon', 'Disease', (303, 308))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('reduce', 'NegReg', (162, 168))	('pancreas', 'Disease', (287, 295))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('cancers', 'Disease', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers of the bladder', 'Disease', 'MESH:D001749', (263, 285))
310514	26161052	Histopathology findings indicated squamous cell carcinoma (0-IIc type, T1a-MM, ly1, v0, HM(-), and VM(-)).	('squamous cell carcinoma', 'Disease', (34, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (34, 57))	('T1a-MM', 'Var', (71, 77))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (34, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
310547	24768332	Research Center 3 (Case Western Reserve University, Fred Hutchinson Cancer Center, Johns Hopkins University, Mayo Clinic, Washington University at St. Louis, University of North Carolina, University of Pennsylvania) aims to improve the understanding of genetic susceptibility, genomic alterations, and epigenetic changes in BE and EAC (Fig.	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Mayo', 'Species', '162683', (109, 113))	('Fred Hutchinson Cancer', 'Disease', 'MESH:D013590', (52, 74))	('epigenetic changes', 'Var', (302, 320))	('Fred Hutchinson Cancer', 'Disease', (52, 74))	('Hutchinson Cancer', 'Phenotype', 'HP:0012413', (57, 74))
310549	24768332	Aberrantly methylated CpG sites are being translated into noninvasive DNA based methods for detecting BE, dysplasia, and early EAC.	('dysplasia', 'Disease', (106, 115))	('Aberrantly methylated', 'Var', (0, 21))	('dysplasia', 'Disease', 'MESH:D004476', (106, 115))	('early EAC', 'Disease', (121, 130))
310571	24485404	Single nucleotide polymorphism at alcohol dehydrogenase-1B is associated with risk of esophageal squamous cell carcinoma Esophageal squamous incidence in many developed countries has increased dramatically over last decades, while the underlying mechanism of the biogenesis of ES was still unknown.	('Esophageal squamous', 'Disease', (121, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('Single nucleotide polymorphism', 'Var', (0, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('ES', 'Chemical', 'MESH:D004540', (277, 279))	('alcohol dehydrogenase-1B', 'Gene', (34, 58))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (86, 120))	('alcohol dehydrogenase-1B', 'Gene', '125', (34, 58))	('esophageal squamous cell carcinoma', 'Disease', (86, 120))
310573	24485404	Single nucleotide polymorphism (SNP) of alcohol dehydrogenase-1B (ADH1B) was performed, and the recombinant plasimd containing ADH1B was constructed.	('ADH1B', 'Gene', '125', (66, 71))	('Single nucleotide polymorphism', 'Var', (0, 30))	('ADH1B', 'Gene', '125', (127, 132))	('ADH1B', 'Gene', (127, 132))	('alcohol dehydrogenase-1B', 'Gene', (40, 64))	('alcohol dehydrogenase-1B', 'Gene', '125', (40, 64))	('ADH1B', 'Gene', (66, 71))
310576	24485404	Logistic regression analyses revealed that subjects carrying the GG variant homozygote had a significant 2.81-fold (adjusted OR = 2.81; 95% CI = 2.18-3.62) increased risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('variant', 'Var', (68, 75))	('esophageal cancer', 'Disease', (174, 191))	('esophageal cancer', 'Disease', 'MESH:D004938', (174, 191))
310577	24485404	We found that SNP of ADH1B (GG) significantly promotes cell proliferation in ESGG.	('ES', 'Chemical', 'MESH:D004540', (77, 79))	('SNP', 'Var', (14, 17))	('ESGG', 'Disease', (77, 81))	('cell proliferation', 'CPA', (55, 73))	('ADH1B', 'Gene', (21, 26))	('ADH1B', 'Gene', '125', (21, 26))	('promotes', 'PosReg', (46, 54))
310592	24485404	The genetic polymorphisms of alcohol-metabolizing enzymes modulate individual differences in alcohol-oxidizing capability and drinking behavior.	('polymorphisms', 'Var', (12, 25))	('alcohol', 'Chemical', 'MESH:D000438', (29, 36))	('alcohol-oxidizing capability', 'MPA', (93, 121))	('modulate', 'Reg', (58, 66))	('alcohol', 'Chemical', 'MESH:D000438', (93, 100))	('drinking behavior', 'CPA', (126, 143))
310598	24485404	The most frequently reported locus is ADH1B Arg47His (rs1229984).	('Arg47His', 'Var', (44, 52))	('rs1229984', 'Mutation', 'rs1229984', (54, 63))	('ADH1B', 'Gene', (38, 43))	('Arg47His', 'SUBSTITUTION', 'None', (44, 52))	('ADH1B', 'Gene', '125', (38, 43))
310600	24485404	A recent genome-wide association study identified the variation of ADH1B rs1229984 and ALDH2 rs671 polymorphisms as risk factors for esophageal cancer.	('rs671 polymorphisms', 'Var', (93, 112))	('rs1229984', 'Var', (73, 82))	('polymorphisms', 'Var', (99, 112))	('ADH1B', 'Gene', (67, 72))	('risk factors', 'Reg', (116, 128))	('rs1229984', 'Mutation', 'rs1229984', (73, 82))	('ALDH2', 'Gene', '217', (87, 92))	('ADH1B', 'Gene', '125', (67, 72))	('rs671', 'Mutation', 'rs671', (93, 98))	('ALDH2', 'Gene', (87, 92))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
310601	24485404	Another genome-wide association study reported that variations of ADH1B rs1229984 and ALDH2 rs671 coupled with alcohol drinking and smoking synergistically enhanced the risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (177, 194))	('ADH1B', 'Gene', '125', (66, 71))	('esophageal cancer', 'Disease', (177, 194))	('rs671', 'Mutation', 'rs671', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('ALDH2', 'Gene', '217', (86, 91))	('rs1229984', 'Var', (72, 81))	('variations', 'Var', (52, 62))	('rs1229984', 'Mutation', 'rs1229984', (72, 81))	('alcohol drinking', 'Phenotype', 'HP:0030955', (111, 127))	('ALDH2', 'Gene', (86, 91))	('enhanced', 'PosReg', (156, 164))	('ADH1B', 'Gene', (66, 71))	('rs671', 'Var', (92, 97))	('alcohol', 'Chemical', 'MESH:D000438', (111, 118))
310604	24485404	Here, we provided evidence that ADH1B rs1229984 GG is one of the risks to initiate the Human esophageal cancer.	('rs1229984', 'Mutation', 'rs1229984', (38, 47))	('ADH1B', 'Gene', (32, 37))	('rs1229984 GG', 'Var', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('ADH1B', 'Gene', '125', (32, 37))	('Human', 'Species', '9606', (87, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))
310605	24485404	Ectopic expression of ADH1B was able to significantly inhibit esophageal cancer in vitro and in vivo by increasing the consuming of alcohol.	('inhibit', 'NegReg', (54, 61))	('ADH1B', 'Gene', (22, 27))	('esophageal cancer', 'Disease', (62, 79))	('Ectopic expression', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ADH1B', 'Gene', '125', (22, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('consuming of alcohol', 'MPA', (119, 139))	('increasing', 'PosReg', (104, 114))	('alcohol', 'Chemical', 'MESH:D000438', (132, 139))
310617	24485404	PCR primers were designed for SNPs of the ADH1B genes.	('ADH1B', 'Gene', (42, 47))	('ADH1B', 'Gene', '125', (42, 47))	('SNPs', 'Var', (30, 34))
310638	24485404	Differences in the distributions of demographic characteristics, selected variables and genotypes of ADH1B variants between cases and normal controls were evaluated using the chi2 test.	('variants', 'Var', (107, 115))	('ADH1B', 'Gene', '125', (101, 106))	('ADH1B', 'Gene', (101, 106))
310640	24485404	Among the 1001 ESGG cases and the 1391 controls with DNA samples, genotyping was successful in 1001 (100%) cancer case and 1391 (100%) controls for ADH1B rs1229984.	('ES', 'Chemical', 'MESH:D004540', (15, 17))	('rs1229984', 'Var', (154, 163))	('rs1229984', 'Mutation', 'rs1229984', (154, 163))	('ADH1B', 'Gene', '125', (148, 153))	('ESGG', 'Disease', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('ADH1B', 'Gene', (148, 153))
310642	24485404	Genotyping of ADH1B rs1229984 SNP was successfully sequenced in all subjects.	('rs1229984 SNP', 'Var', (20, 33))	('rs1229984', 'Mutation', 'rs1229984', (20, 29))	('ADH1B', 'Gene', '125', (14, 19))	('ADH1B', 'Gene', (14, 19))
310643	24485404	The distribution of ADH1B rs1229984 SNP (Figure 2) was not correlated with gender and age both in ESCC patients or healthy controls (data not shown).	('rs1229984 SNP', 'Var', (26, 39))	('ES', 'Chemical', 'MESH:D004540', (98, 100))	('ESCC', 'Disease', (98, 102))	('ADH1B', 'Gene', (20, 25))	('ADH1B', 'Gene', '125', (20, 25))	('patients', 'Species', '9606', (103, 111))	('rs1229984', 'Mutation', 'rs1229984', (26, 35))
310645	24485404	In the univariate analyses, the genotype frequencies of ADH1B rs1229984 were 37.66% (AA), 39.96% (AG) and 22.38% (GG) in the patients, and 47.66% (AA), 41.55% (AG) and 10.79% (GG) in the control subjects.	('rs1229984', 'Var', (62, 71))	('rs1229984', 'Mutation', 'rs1229984', (62, 71))	('ADH1B', 'Gene', (56, 61))	('ADH1B', 'Gene', '125', (56, 61))	('patients', 'Species', '9606', (125, 133))
310646	24485404	In the recessive model, the ADH1B rs1229984 GG variant homozygote was associated with a 1.51-fold significantly increased risk of esophageal cancer compared with rs1229984 AA/AG genotypes (adjusted OR = 1.51, 95% CI = 1.28-1.80).	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('rs1229984', 'Mutation', 'rs1229984', (34, 43))	('rs1229984', 'Mutation', 'rs1229984', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rs1229984 GG', 'Var', (34, 46))	('ADH1B', 'Gene', (28, 33))	('ADH1B', 'Gene', '125', (28, 33))	('esophageal cancer', 'Disease', (130, 147))
310649	24485404	The enzyme was ADH1B activity can be varied according to the Polymorphism of the rs1229984.	('rs1229984', 'Var', (81, 90))	('ADH1B', 'Gene', (15, 20))	('ADH1B', 'Gene', '125', (15, 20))	('rs1229984', 'Mutation', 'rs1229984', (81, 90))	('activity', 'MPA', (21, 29))
310652	24485404	The tolerance of cells with ADH1B rs1229984 AA genotype was better than the rs1229984 GG genotype.	('better', 'PosReg', (60, 66))	('rs1229984', 'Mutation', 'rs1229984', (34, 43))	('rs1229984', 'Mutation', 'rs1229984', (76, 85))	('ADH1B', 'Gene', (28, 33))	('tolerance', 'CPA', (4, 13))	('ADH1B', 'Gene', '125', (28, 33))	('rs1229984 AA', 'Var', (34, 46))
310653	24485404	The Alcohol Pre-treatment experiment confirmed that the genotype of ADH1B rs1229984 was significantly associated with the tolerance to alcohol Pre-treatment.	('rs1229984', 'Var', (74, 83))	('alcohol', 'Chemical', 'MESH:D000438', (135, 142))	('tolerance to alcohol Pre-treatment', 'MPA', (122, 156))	('associated', 'Reg', (102, 112))	('ADH1B', 'Gene', (68, 73))	('ADH1B', 'Gene', '125', (68, 73))	('Alcohol', 'Chemical', 'MESH:D000438', (4, 11))	('rs1229984', 'Mutation', 'rs1229984', (74, 83))
310656	24485404	Multivariable logistic analysis revealed that the ADH1B rs1229984 GG genotype was associated with an increased risk of esophageal cancer, and that this effect was more evident among males, younger subjects and smokers.	('rs1229984', 'Mutation', 'rs1229984', (56, 65))	('ADH1B', 'Gene', (50, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('ADH1B', 'Gene', '125', (50, 55))	('rs1229984 GG', 'Var', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal cancer', 'Disease', (119, 136))
310657	24485404	Our results suggested a potential role of ADH1B SNPs on the etiology of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('ADH1B', 'Gene', (42, 47))	('ADH1B', 'Gene', '125', (42, 47))	('SNPs', 'Var', (48, 52))
310658	24485404	Two recent genome-wide association studies identified the variation of ADH1B rs1229984 as risk factors for esophageal cancer in a Japanese population.	('ADH1B', 'Gene', (71, 76))	('esophageal cancer', 'Disease', (107, 124))	('ADH1B', 'Gene', '125', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('rs1229984', 'Mutation', 'rs1229984', (77, 86))	('risk factors', 'Reg', (90, 102))	('rs1229984', 'Var', (77, 86))
310660	24485404	The reason for these inconsistent findings for ADH1B rs1229984 polymorphisms is unknown.	('ADH1B', 'Gene', (47, 52))	('rs1229984', 'Var', (53, 62))	('rs1229984', 'Mutation', 'rs1229984', (53, 62))	('ADH1B', 'Gene', '125', (47, 52))
310662	24485404	The genome instability induced by ethanol and acetaldehyde mediated pathways could explain ADH1B polymorphic effects on alcohol induced carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('ADH1B', 'Gene', (91, 96))	('carcinogenesis', 'Disease', (136, 150))	('ADH1B', 'Gene', '125', (91, 96))	('alcohol', 'Chemical', 'MESH:D000438', (120, 127))	('polymorphic', 'Var', (97, 108))	('ethanol', 'Chemical', 'MESH:D000431', (34, 41))	('acetaldehyde', 'Chemical', 'MESH:D000079', (46, 58))	('genome', 'MPA', (4, 10))
310663	24485404	In the present study, we also found a significant gene environment interaction between ADH1B rs1229984 polymorphisms and smoking habit, suggesting susceptibility to esophageal cancer.	('esophageal cancer', 'Disease', (165, 182))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('rs1229984', 'Mutation', 'rs1229984', (93, 102))	('susceptibility', 'Reg', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('rs1229984 polymorphisms', 'Var', (93, 116))	('polymorphisms', 'Var', (103, 116))	('ADH1B', 'Gene', (87, 92))	('ADH1B', 'Gene', '125', (87, 92))
310667	24485404	There are five ADH classes existing in humans and functional polymorphisms of ADH1B and ADH1C genes produce iso-enzymes with different maximal activities (Vmax) and affinities for ethanol.	('ADH', 'Gene', '124', (88, 91))	('ADH', 'Gene', '124', (78, 81))	('polymorphisms', 'Var', (61, 74))	('iso-enzymes', 'Enzyme', (108, 119))	('humans', 'Species', '9606', (39, 45))	('ADH', 'Gene', (88, 91))	('maximal activities', 'MPA', (135, 153))	('ADH1B', 'Gene', (78, 83))	('ADH', 'Gene', (78, 81))	('ADH1C', 'Gene', '126', (88, 93))	('ethanol', 'Chemical', 'MESH:D000431', (180, 187))	('ADH1B', 'Gene', '125', (78, 83))	('ADH1C', 'Gene', (88, 93))	('ADH', 'Gene', '124', (15, 18))	('ADH', 'Gene', (15, 18))
310668	24485404	One of the coding variant in ADH1B is rs1229984, which leads to the replacement of Arg48 with His48, is common in Asian populations and the enzymes with His48 oxidize ethanol approximately 70- to 80-fold faster than those with Arg48, eventually reduces their risk for alcoholism.	('His48', 'Chemical', '-', (153, 158))	('rs1229984', 'Var', (38, 47))	('alcoholism', 'Disease', (268, 278))	('rs1229984', 'Mutation', 'rs1229984', (38, 47))	('ADH1B', 'Gene', '125', (29, 34))	('alcoholism', 'Disease', 'MESH:D000437', (268, 278))	('Arg48', 'Chemical', '-', (227, 232))	('alcoholism', 'Phenotype', 'HP:0030955', (268, 278))	('Arg48', 'Chemical', '-', (83, 88))	('reduces', 'NegReg', (245, 252))	('oxidize', 'MPA', (159, 166))	('ethanol', 'Chemical', 'MESH:D000431', (167, 174))	('ADH1B', 'Gene', (29, 34))	('His48', 'Chemical', '-', (94, 99))
310674	24485404	In conclusion, the present study provided marked evidence that functional polymorphism of ADH1B rs1229984 may contribute to the risk of esophageal cancer.	('esophageal cancer', 'Disease', (136, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('ADH1B', 'Gene', '125', (90, 95))	('rs1229984', 'Var', (96, 105))	('rs1229984', 'Mutation', 'rs1229984', (96, 105))	('contribute', 'Reg', (110, 120))	('ADH1B', 'Gene', (90, 95))
310777	22429780	We now know that menthol affects membrane permeation of many compounds, including tobacco carcinogens, and may alter both tobacco uptake and cessation.	('tobacco uptake', 'MPA', (122, 136))	('membrane permeation of', 'MPA', (33, 55))	('tobacco', 'Species', '4097', (82, 89))	('menthol', 'Chemical', 'MESH:D008610', (17, 24))	('tobacco', 'Species', '4097', (122, 129))	('menthol', 'Var', (17, 24))	('affects', 'Reg', (25, 32))	('cessation', 'MPA', (141, 150))	('alter', 'Reg', (111, 116))
310874	22664791	Notably, a large-scale study by Burmeister et al revealed that 5-FU/CDDP (FP) plus radiation (35 Gy) followed by esophagectomy for ESCC improves DFS, but not for all patients including those with adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('5-FU/CDDP', 'Var', (63, 72))	('improves', 'PosReg', (136, 144))	('adenocarcinoma', 'Disease', (196, 210))	('5-FU', 'Chemical', 'MESH:D005472', (63, 67))	('DFS', 'MPA', (145, 148))	('adenocarcinoma', 'Disease', 'MESH:D000230', (196, 210))	('CDDP', 'Chemical', 'MESH:D002945', (68, 72))	('patients', 'Species', '9606', (166, 174))	('ESCC', 'Disease', (131, 135))
310884	22664791	As a result, ENI reduced the M1a failure rate, but was not associated with improved outcomes in the patients undergoing preoperative CRT.	('M1a failure', 'Disease', 'MESH:D017093', (29, 40))	('ENI', 'Var', (13, 16))	('patients', 'Species', '9606', (100, 108))	('M1a failure', 'Disease', (29, 40))	('CR', 'Chemical', '-', (133, 135))	('reduced', 'NegReg', (17, 24))
310902	23232108	Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR) induced by EGF in KYSE30 cells.	('Nimotuzumab', 'Chemical', 'MESH:C501466', (30, 41))	('phosphorylated', 'MPA', (52, 66))	('inhibited', 'NegReg', (42, 51))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('EGFR', 'Gene', (75, 79))	('EGF', 'Var', (92, 95))
310903	23232108	In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (P<0.05), and even after the administration of Nimotuzumab, the RT response of IGFBP-3 silenced KYSE30 cells was not enhanced (P>0.05).	('Nimotuzumab', 'Chemical', 'MESH:C501466', (154, 165))	('reduced', 'NegReg', (69, 76))	('KYSE30 cells radiosensitivity', 'CPA', (77, 106))	('short hairpin RNA', 'Gene', (37, 54))	('IGFBP-3', 'Gene', (26, 33))	('knockdown', 'Var', (13, 22))
310914	23232108	Recently, combination of radiotherapy and EGFR inhibitors was reported to improve local tumor control compared to irradiation alone, but it is also true that conflicting results exist.	('EGFR', 'Gene', '1956', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('improve', 'PosReg', (74, 81))	('inhibitors', 'Var', (47, 57))	('EGFR', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
310921	23232108	In our previous study, we found that Nimotuzumab could increase ESCC chemosensitivity to DDP by upregulating IGFBP-3 expression through EGFR-dependent pathway in vitro.	('Nimotuzumab', 'Var', (37, 48))	('increase', 'PosReg', (55, 63))	('ESCC', 'Disease', (64, 68))	('Nimotuzumab', 'Chemical', 'MESH:C501466', (37, 48))	('upregulating', 'PosReg', (96, 108))	('expression', 'MPA', (117, 127))	('increase ESCC', 'Phenotype', 'HP:0003565', (55, 68))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('IGFBP-3', 'Gene', (109, 116))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
310925	23232108	Both cell lines were cultured in RPMI 1640 medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum (Bioind, Kibbutz Beit, Israel) in a humidified 5% CO2 atmosphere at 37 C. In previous study, we have confirmed there is a higher level of EGFR protein expression in KYSE30 cells compared with that in TE-1 cells at baseline by Western blot and immunocytochemical staining analysis.	('RPMI 1640 medium', 'Chemical', '-', (33, 49))	('expression', 'MPA', (269, 279))	('CO2', 'Chemical', '-', (168, 171))	('EGFR', 'Gene', '1956', (256, 260))	('higher', 'PosReg', (240, 246))	('bovine', 'Species', '9913', (105, 111))	('TE-1', 'CellLine', 'CVCL:1759', (318, 322))	('KYSE30', 'Var', (283, 289))	('EGFR', 'Gene', (256, 260))
310969	23232108	We hypothesized that the multiple low-concentration cytokines in fetal bovine serum could only activate EGFR pathway in EGFR high-expression KYSE30 cells, however, this effect was not observed in TE-1 cells due to low-expression EGFR.	('TE-1', 'CellLine', 'CVCL:1759', (196, 200))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (229, 233))	('EGFR', 'Gene', (229, 233))	('EGFR', 'Gene', '1956', (120, 124))	('activate', 'PosReg', (95, 103))	('bovine', 'Species', '9913', (71, 77))	('high-expression', 'Var', (125, 140))	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'Gene', (120, 124))
310988	23232108	Previous studies reported that alteration in the expression and activity of growth factor receptors could not only directly perturb growth regulation, but also affect the sensitivity of cancer cells to various cytotoxic treatments, including RT.	('sensitivity', 'MPA', (171, 182))	('growth regulation', 'CPA', (132, 149))	('growth', 'Protein', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('expression', 'MPA', (49, 59))	('affect', 'Reg', (160, 166))	('activity', 'MPA', (64, 72))	('perturb', 'Reg', (124, 131))	('alteration', 'Var', (31, 41))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
310989	23232108	Several groups identified that EGFR inhibitors could improve RT response and local control of human tumors, providing a kind of additional agents in anti-cancer therapy.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('EGFR', 'Gene', '1956', (31, 35))	('inhibitors', 'Var', (36, 46))	('EGFR', 'Gene', (31, 35))	('cancer', 'Disease', (154, 160))	('tumors', 'Disease', (100, 106))	('RT response', 'CPA', (61, 72))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('human', 'Species', '9606', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('improve', 'PosReg', (53, 60))
310993	23232108	Our results demonstrated that although Nimotuzumab alone failed to inhibit ESCC cells growth, we did observe as well that Nimotuzumab dramatically enhanced radiation response of ESCC KYSE30 cell line (the cells with overexpression of EGFR) both in vitro and in vivo, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis.	('enhanced', 'PosReg', (147, 155))	('EGFR', 'Gene', (234, 238))	('Nimotuzumab', 'Chemical', 'MESH:C501466', (39, 50))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('Nimotuzumab', 'Chemical', 'MESH:C501466', (122, 133))	('colony formation', 'CPA', (329, 345))	('Nimotuzumab', 'Var', (122, 133))	('increased', 'PosReg', (283, 292))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('EGFR', 'Gene', '1956', (234, 238))	('radiation response', 'CPA', (156, 174))
311012	23232108	To determine if IGFBP-3 participates in Nimotuzumab-enhanced radiosensitivity of ESCC cells with high expression of EGFR, we first knocked down the levels of IGFBP-3 in KYSE30 cells by specific shRNA against IGFBP-3 gene and found that silence of IGFBP-3 dramatically reduced ESCC cell radiosensitivity.	('Nimotuzumab', 'Chemical', 'MESH:C501466', (40, 51))	('reduced ESCC cell radiosensitivity', 'Phenotype', 'HP:0010997', (268, 302))	('knocked', 'Var', (131, 138))	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('SCC', 'Phenotype', 'HP:0002860', (277, 280))	('reduced', 'NegReg', (268, 275))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (52, 77))	('silence', 'Var', (236, 243))	('ESCC cell radiosensitivity', 'CPA', (276, 302))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('IGFBP-3', 'Gene', (247, 254))
311096	31885720	Caspase-8 promoter methylation results in the loss of gene expression, which is associated with tumor severity in a variety of different tumor types.	('methylation', 'Var', (19, 30))	('tumor', 'Disease', (137, 142))	('gene expression', 'MPA', (54, 69))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss', 'NegReg', (46, 50))	('tumor', 'Disease', (96, 101))	('Caspase-8', 'Gene', '841', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('Caspase-8', 'Gene', (0, 9))
311097	31885720	The methylation-mediated silencing of key apoptosis-associated genes serves an important role in the pathogenesis and development of therapeutic resistance in human cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('methylation-mediated', 'Var', (4, 24))	('apoptosis-associated genes', 'Gene', (42, 68))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('silencing', 'NegReg', (25, 34))
311136	31885720	The univariate analysis revealed a significant association between the expression of EPHB4 and family history, metastasis, and tumor size, position and stage.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('metastasis', 'CPA', (111, 121))	('tumor', 'Disease', (127, 132))	('EPHB4', 'Gene', '2050', (85, 90))	('expression', 'Var', (71, 81))	('EPHB4', 'Gene', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
311275	29482649	Inhibition of mitosis does not cause the death of cells, but apoptosis does.	('mitosis', 'Disease', (14, 21))	('mitosis', 'Disease', 'None', (14, 21))	('Inhibition', 'Var', (0, 10))
311304	29482649	The patients in Arm A received induction chemotherapy with 5-FU 700 mg/m2, d1-5, DDP 15 mg/m2, d1-5, and PTX 200 mg/m2, civ 24 h, q4w * 2 and then CCR with 5-FU 300 mg/m2, civ 96 h, and PTX 50 mg/m2, d1, qw * 5.	('5-FU', 'Chemical', 'MESH:D005472', (59, 63))	('q4w *', 'Var', (130, 135))	('PTX', 'Chemical', 'MESH:D017239', (105, 108))	('PTX', 'Chemical', 'MESH:D017239', (186, 189))	('CR', 'Chemical', 'MESH:D002857', (148, 150))	('DDP', 'Gene', '1678', (81, 84))	('d1-5', 'Gene', '25802;1734;1735;397', (75, 79))	('d1-5', 'Gene', '25802;1734;1735;397', (95, 99))	('d1-5', 'Gene', (75, 79))	('d1-5', 'Gene', (95, 99))	('patients', 'Species', '9606', (4, 12))	('5-FU 700 mg/m2', 'Var', (59, 73))	('5-FU', 'Chemical', 'MESH:D005472', (156, 160))	('DDP', 'Gene', (81, 84))
311305	29482649	The patients in Arm B received induction chemotherapy with PTX 175 mg/m2, d1, and DDP 75 mg/m2, d1, q3w * 2 and then CCR with DDP 30 mg/m2, and PTX 60 mg/m2, civ 96 h, qw * 5.	('DDP', 'Gene', (82, 85))	('DDP', 'Gene', (126, 129))	('CR', 'Chemical', 'MESH:D002857', (118, 120))	('q3w *', 'Var', (100, 105))	('PTX', 'Chemical', 'MESH:D017239', (144, 147))	('DDP', 'Gene', '1678', (82, 85))	('patients', 'Species', '9606', (4, 12))	('DDP', 'Gene', '1678', (126, 129))	('PTX', 'Chemical', 'MESH:D017239', (59, 62))
311327	29482649	WBC >= 3*109/L, Hemoglobin >=9 g/dL, Neutrophils >=1.5 x 109/L, Platelet count (Plt) >=100*109/L, ALAT and ASAT < 2.5 * ULN, TBIL< 1.5 * ULN, Creatinine < 1.5 *ULN.	('Creatinine', 'MPA', (142, 152))	('>=100*109/L', 'Var', (85, 96))	('Creatinine', 'Chemical', 'MESH:D003404', (142, 152))	('TBIL', 'MPA', (125, 129))	('ALAT', 'Disease', (98, 102))	('ALAT', 'Disease', 'None', (98, 102))	('TBIL', 'Chemical', '-', (125, 129))
311345	29482649	Chemotherapy should be administered with 25% dose reduction if ANC < 0.5 x 109/L, Plt < 25 x 109/L or >=Grade 3 non-hematological toxicities.	('< 0.5 x 109/L', 'Var', (67, 80))	('toxicities', 'Disease', (130, 140))	('toxicities', 'Disease', 'MESH:D064420', (130, 140))	('Plt < 25 x 109/L', 'Var', (82, 98))
311379	28424552	Overall, the OS and PFS of patients with CTC counts >=3 or >=5/7.5 mL of PB before surgery were significantly shorter than those of patients with CTC counts <3 or <5/7.5 mL.	('>=5/7.5 mL', 'Var', (59, 69))	('shorter', 'NegReg', (110, 117))	('patients', 'Species', '9606', (27, 35))	('PFS', 'CPA', (20, 23))	('patients', 'Species', '9606', (132, 140))
311460	28424552	Matsushita et al studied 90 patients with ESCC and reported that the presence of CTCs was significantly correlated with distant metastases, such as pleural dissemination and hematogenous metastasis.	('metastases', 'Disease', (128, 138))	('presence', 'Var', (69, 77))	('correlated', 'Reg', (104, 114))	('pleural dissemination', 'Disease', 'MESH:D010995', (148, 169))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('pleural dissemination', 'Disease', (148, 169))	('CTCs', 'Gene', (81, 85))	('patients', 'Species', '9606', (28, 36))	('hematogenous metastasis', 'Disease', (174, 197))
311467	28424552	Our results showed an association between CTC count and the presence of metastasis, and the results for patients with ESCC demonstrated that the presence of >=5 CTCs can predict tumor recurrence and decreased survival time.	('tumor', 'Disease', (178, 183))	('survival time', 'CPA', (209, 222))	('decreased', 'NegReg', (199, 208))	('presence', 'Var', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('patients', 'Species', '9606', (104, 112))
311474	28424552	In colorectal cancer, a value of >=3 CTCs has commonly been used as a cutoff, and Cohen et al reported that the median PFS and OS of patients with metastatic colorectal cancer were nearly twice as high for patients with a few CTCs (<3 CTCs/7.5 mL blood) relative to patients with elevated CTCs (>=3 CTCs).	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('PFS', 'MPA', (119, 122))	('patients', 'Species', '9606', (266, 274))	('high', 'PosReg', (197, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('colorectal cancer', 'Disease', (158, 175))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('colorectal cancer', 'Disease', (3, 20))	('patients', 'Species', '9606', (206, 214))	('<3 CTCs/7.5', 'Var', (232, 243))	('elevated CTCs', 'Phenotype', 'HP:0003236', (280, 293))	('colorectal cancer', 'Disease', 'MESH:D015179', (158, 175))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
311480	28424552	Multivariate Cox regression was utilized to investigate factors associated with survival time, and the results showed that CTC >=5/7.5 mL blood, lymph node status, presence of metastasis, and pathologic stage were associated with significantly shortened OS and PFS.	('metastasis', 'CPA', (176, 186))	('Cox', 'Gene', (13, 16))	('shortened', 'NegReg', (244, 253))	('PFS', 'CPA', (261, 264))	('CTC >=5/7.5', 'Var', (123, 134))	('presence', 'Var', (164, 172))	('Cox', 'Gene', '1351', (13, 16))
311495	26486567	AMACR and cyclin D1 expression levels were not correlated with prevalent or incident neoplasia; however, high p53 expression (>5%) was associated with prevalent advanced neoplasia on surveillance biopsy (P = 0.04) and with an increased risk of progression to advanced neoplasia (HR = 12; P = 0.03).	('neoplasia', 'Disease', (170, 179))	('high', 'Var', (105, 109))	('p53', 'Gene', (110, 113))	('neoplasia', 'Disease', 'MESH:D009369', (85, 94))	('neoplasia', 'Phenotype', 'HP:0002664', (268, 277))	('neoplasia', 'Phenotype', 'HP:0002664', (85, 94))	('p53', 'Gene', '7157', (110, 113))	('AMACR', 'Gene', '23600', (0, 5))	('neoplasia', 'Phenotype', 'HP:0002664', (170, 179))	('neoplasia', 'Disease', 'MESH:D009369', (268, 277))	('neoplasia', 'Disease', (85, 94))	('neoplasia', 'Disease', 'MESH:D009369', (170, 179))	('AMACR', 'Gene', (0, 5))	('cyclin D1', 'Gene', '595', (10, 19))	('expression', 'MPA', (114, 124))	('neoplasia', 'Disease', (268, 277))	('cyclin D1', 'Gene', (10, 19))
311530	26486567	There was no association between clinico-demographic parameters, endoscopic parameters, or AMACR or cyclin D1 expression levels and the presence of prevalent neoplasia or advanced prevalent neoplasia (Tables 1 and 2 and data not shown); high p53 expression (>5%), however, was associated with the presence of advanced prevalent neoplasia (Table 2).	('neoplasia', 'Disease', (190, 199))	('neoplasia', 'Disease', 'MESH:D009369', (158, 167))	('cyclin D1', 'Gene', (100, 109))	('p53', 'Gene', (242, 245))	('p53', 'Gene', '7157', (242, 245))	('neoplasia', 'Phenotype', 'HP:0002664', (190, 199))	('neoplasia', 'Disease', (158, 167))	('neoplasia', 'Disease', (328, 337))	('AMACR', 'Gene', (91, 96))	('neoplasia', 'Disease', 'MESH:D009369', (190, 199))	('AMACR', 'Gene', '23600', (91, 96))	('neoplasia', 'Phenotype', 'HP:0002664', (328, 337))	('high', 'Var', (237, 241))	('expression', 'MPA', (246, 256))	('neoplasia', 'Phenotype', 'HP:0002664', (158, 167))	('neoplasia', 'Disease', 'MESH:D009369', (328, 337))	('cyclin D1', 'Gene', '595', (100, 109))
311533	26486567	Patient age, sex, hiatal hernia length, body mass index (BMI), family history of EAC, esophagitis or BE mucosal irregularities (as determined by endoscopy), aspirin or NSAID use, and current or former smoking or alcohol abuse, AMACR and cyclin D1 expression levels were not associated with neoplastic progression or advanced neoplastic progression (Tables 3 and 4, and data not shown); however, high p53 expression (>5%) was associated with progression to advanced neoplasia on univariate analysis (hazard ratio 12; P = 0.03) (Table 5).	('BE', 'Phenotype', 'HP:0100580', (101, 103))	('p53', 'Gene', (400, 403))	('alcohol abuse', 'Disease', (212, 225))	('alcohol abuse', 'Disease', 'MESH:D000437', (212, 225))	('AMACR', 'Gene', '23600', (227, 232))	('hiatal hernia', 'Disease', 'MESH:D006551', (18, 31))	('hiatal hernia', 'Disease', (18, 31))	('esophagitis', 'Disease', (86, 97))	('alcohol abuse', 'Phenotype', 'HP:0030955', (212, 225))	('esophagitis', 'Disease', 'MESH:D004941', (86, 97))	('hernia', 'Phenotype', 'HP:0100790', (25, 31))	('high', 'Var', (395, 399))	('neoplasia', 'Disease', 'MESH:D009369', (465, 474))	('cyclin D1', 'Gene', (237, 246))	('esophagitis', 'Phenotype', 'HP:0100633', (86, 97))	('neoplasia', 'Disease', (465, 474))	('hiatal hernia', 'Phenotype', 'HP:0002036', (18, 31))	('cyclin D1', 'Gene', '595', (237, 246))	('expression', 'MPA', (404, 414))	('EAC', 'Phenotype', 'HP:0011459', (81, 84))	('p53', 'Gene', '7157', (400, 403))	('neoplasia', 'Phenotype', 'HP:0002664', (465, 474))	('Patient', 'Species', '9606', (0, 7))	('AMACR', 'Gene', (227, 232))
311536	26486567	Due to the greater half-life of mutant p53, the protein accumulates and its nuclear expression can be assessed by immunohistochemical analysis.	('accumulates', 'PosReg', (56, 67))	('protein', 'Protein', (48, 55))	('greater', 'PosReg', (11, 18))	('mutant', 'Var', (32, 38))	('p53', 'Gene', (39, 42))	('half-life', 'MPA', (19, 28))	('p53', 'Gene', '7157', (39, 42))
311551	29270239	Targeted bisulfite sequencing identified a panel of DNA methylation-based biomarkers for esophageal squamous cell carcinoma (ESCC) DNA methylation has been implicated as a promising biomarker for precise cancer diagnosis.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('cancer', 'Disease', (204, 210))	('methylation', 'Var', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('or', 'Gene', '31118', (86, 88))	('esophageal squamous cell carcinoma', 'Disease', (89, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('or', 'Gene', '31118', (193, 195))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('bisulfite', 'Chemical', 'MESH:C042345', (9, 18))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (89, 123))
311557	29270239	In the discovery stage, five hyper-methylated CpG sites were selected as candidate biomarkers for further analysis as shown below: cg15830431, P = 2.20 x 10-4; cg19396867, P = 3.60 x 10-4; cg20655070, P = 3.60 x 10-4; cg26671652, P = 5.77 x 10-4; and cg27062795, P = 3.60 x 10-4.	('cg27062795', 'Chemical', '-', (251, 261))	('cg26671652', 'Var', (218, 228))	('cg20655070', 'Var', (189, 199))	('cg19396867', 'Chemical', '-', (160, 170))	('cg26671652', 'Chemical', '-', (218, 228))	('or', 'Gene', '31118', (95, 97))	('cg15830431', 'Var', (131, 141))	('cg19396867', 'Var', (160, 170))	('cg15830431', 'Chemical', '-', (131, 141))	('cg27062795', 'Var', (251, 261))	('cg20655070', 'Chemical', '-', (189, 199))
311560	29270239	Methylation profiles of the five genomic regions covering cg15830431 (STK3), cg19396867, cg20655070, cg26671652 (ZNF418), and cg27062795 (ZNF542) can be used for effective methylation-based testing for ESCC diagnosis.	('cg26671652', 'Var', (101, 111))	('or', 'Gene', '31118', (159, 161))	('cg15830431', 'Var', (58, 68))	('ZNF418', 'Gene', '147686', (113, 119))	('ZNF542', 'Gene', (138, 144))	('cg19396867', 'Chemical', '-', (77, 87))	('ESCC', 'Disease', (202, 206))	('or', 'Gene', '31118', (199, 201))	('cg15830431', 'Chemical', '-', (58, 68))	('cg26671652', 'Chemical', '-', (101, 111))	('cg20655070', 'Chemical', '-', (89, 99))	('cg27062795', 'Chemical', '-', (126, 136))	('ZNF542', 'Gene', '147947', (138, 144))	('cg19396867', 'Var', (77, 87))	('cg27062795', 'Var', (126, 136))	('cg20655070', 'Var', (89, 99))	('ZNF418', 'Gene', (113, 119))
311567	29270239	Numerous studies have suggested that the altered DNA methylation patterns in tumor tissues may silence the tumor suppressor genes and activate the oncogenes through hyper/hypo methylation.	('or', 'Gene', '31118', (121, 123))	('or', 'Gene', '31118', (80, 82))	('altered', 'Var', (41, 48))	('hyper/hypo methylation', 'Var', (165, 187))	('activate', 'PosReg', (134, 142))	('tumor', 'Disease', (107, 112))	('or', 'Gene', '31118', (110, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('oncogenes', 'Gene', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (77, 82))	('silence', 'NegReg', (95, 102))
311568	29270239	In addition, DNA methylation alterations have been found to occur early in the carcinogenesis and therefore could be applied as a promising biomarker for cancer early detection.	('or', 'Gene', '31118', (104, 106))	('cancer', 'Disease', (154, 160))	('alterations', 'Var', (29, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('methylation alterations', 'Var', (17, 40))	('carcinogenesis', 'Disease', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DNA', 'Gene', (13, 16))	('or', 'Gene', '31118', (151, 153))
311580	29270239	1), cg15830431 (P = 2.20 x 10-4), cg19396867 (P = 3.60 x 10-4), cg20655070 (P = 1.71 x 10-3), cg26671652 (P = 5.77 x 10-4), and cg27062795 (P = 3.60 x 10-4) were selected for further validation.	('cg27062795', 'Chemical', '-', (128, 138))	('cg26671652', 'Chemical', '-', (94, 104))	('cg15830431', 'Var', (4, 14))	('cg27062795', 'Var', (128, 138))	('cg19396867', 'Chemical', '-', (34, 44))	('cg20655070', 'Chemical', '-', (64, 74))	('cg15830431', 'Chemical', '-', (4, 14))	('cg26671652', 'Var', (94, 104))	('cg19396867', 'Var', (34, 44))	('cg20655070', 'Var', (64, 74))	('or', 'Gene', '31118', (172, 174))
311581	29270239	Among them, cg19396867 and cg20655070 were not in the regulatory regions of specific genes, while cg15830431 (STK3, CpG Island), cg26671652 (ZNF418, CpG Shore), and cg27062795 (ZNF542, CpG Island) were either in CpG islands or the CpG shores of a gene.	('or', 'Gene', '31118', (224, 226))	('or', 'Gene', '31118', (155, 157))	('cg27062795', 'Chemical', '-', (165, 175))	('ZNF418', 'Gene', (141, 147))	('cg20655070', 'Var', (27, 37))	('cg19396867', 'Chemical', '-', (12, 22))	('cg26671652', 'Var', (129, 139))	('cg15830431', 'Chemical', '-', (98, 108))	('cg20655070', 'Chemical', '-', (27, 37))	('cg19396867', 'Var', (12, 22))	('ZNF418', 'Gene', '147686', (141, 147))	('ZNF542', 'Gene', (177, 183))	('or', 'Gene', '31118', (61, 63))	('or', 'Gene', '31118', (237, 239))	('cg26671652', 'Chemical', '-', (129, 139))	('ZNF542', 'Gene', '147947', (177, 183))	('cg15830431', 'Var', (98, 108))	('cg27062795', 'Var', (165, 175))
311593	29270239	A logistic regression model was then applied and showed significant hyper-methylation of the five selected CpG sites in the ESCCs (Table 2, cg15830431, P = 1.25 x 10-6; cg19396867, P = 2.71 x 10-11; cg20655070, P = 8.04 x 10-10; cg26671652, P = 4.82 x 10-11; cg27062795, P = 1.23 x 10-12).	('cg15830431', 'Var', (140, 150))	('cg26671652', 'Var', (229, 239))	('cg19396867', 'Chemical', '-', (169, 179))	('cg27062795', 'Var', (259, 269))	('cg19396867', 'Var', (169, 179))	('cg27062795', 'Chemical', '-', (259, 269))	('cg15830431', 'Chemical', '-', (140, 150))	('cg26671652', 'Chemical', '-', (229, 239))	('cg20655070', 'Chemical', '-', (199, 209))	('hyper-methylation', 'PosReg', (68, 85))	('cg20655070', 'Var', (199, 209))
311616	29270239	DNA methylation plays a key role in the gene expression regulation and therefore has great potential as a non-invasive biomarker for cancer diagnosis and prognosis.	('gene expression regulation', 'MPA', (40, 66))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('or', 'Gene', '31118', (77, 79))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (133, 139))	('or', 'Gene', '31118', (130, 132))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
311618	29270239	Previous studies have found several candidate methylation biomarkers for ESCC detection and prognosis as well as treatment response.	('ESCC', 'Disease', (73, 77))	('methylation', 'Var', (46, 57))	('or', 'Gene', '31118', (70, 72))
311623	29270239	In addition, the subgroup analyses identified that the diagnostic performance of the methylation testing is much better in the non-alcohol-consuming patients than in the ESCC patients who consume alcohol, suggesting the importance of taking the epidemiological data into considerations when performing ESCC diagnosis.	('alcohol', 'Chemical', 'MESH:D000438', (131, 138))	('methylation', 'Var', (85, 96))	('patients', 'Species', '9606', (149, 157))	('or', 'Gene', '31118', (70, 72))	('better', 'PosReg', (113, 119))	('alcohol', 'Chemical', 'MESH:D000438', (196, 203))	('patients', 'Species', '9606', (175, 183))	('or', 'Gene', '31118', (295, 297))	('or', 'Gene', '31118', (223, 225))
311625	29270239	Of the five genomic regions, two genomic regions covering cg19396867 and cg20655070 were not in the regulatory regions of specific genes.	('or', 'Gene', '31118', (107, 109))	('cg20655070', 'Chemical', '-', (73, 83))	('cg20655070', 'Var', (73, 83))	('cg19396867', 'Chemical', '-', (58, 68))	('cg19396867', 'Var', (58, 68))
311626	29270239	However, the H3k4me3, H3k4me1, and H3k27ac status of these two regions from the ENCODE project showed that these regions might be associated with the enhancers, indicating that the regions might also have important regulatory functions (data not shown).	('H3k4me1', 'Var', (22, 29))	('or', 'Gene', '31118', (208, 210))	('H3k27ac', 'Var', (35, 42))	('or', 'Gene', '31118', (222, 224))	('H3k4me3', 'Var', (13, 20))
311627	29270239	In contrast, cg15830431 (STK3, CpG Island), cg26671652 (ZNF418, CpG Shore), and cg27062795 (ZNF542, CpG Island) were either in the CpG islands or the CpG shores of a gene.	('cg15830431', 'Var', (13, 23))	('cg26671652', 'Var', (44, 54))	('or', 'Gene', '31118', (70, 72))	('cg27062795', 'Chemical', '-', (80, 90))	('cg27062795', 'Var', (80, 90))	('ZNF418', 'Gene', (56, 62))	('cg15830431', 'Chemical', '-', (13, 23))	('or', 'Gene', '31118', (156, 158))	('ZNF418', 'Gene', '147686', (56, 62))	('ZNF542', 'Gene', (92, 98))	('cg26671652', 'Chemical', '-', (44, 54))	('or', 'Gene', '31118', (143, 145))	('ZNF542', 'Gene', '147947', (92, 98))
311629	29270239	A previous study has found that the deletion of STK3 in mouse liver results in tissue overgrowth and tumor development, demonstrating its importance in suppressing carcinogenesis.	('suppressing', 'NegReg', (152, 163))	('or', 'Gene', '31118', (141, 143))	('deletion', 'Var', (36, 44))	('or', 'Gene', '31118', (104, 106))	('tissue overgrowth', 'CPA', (79, 96))	('STK3', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('mouse', 'Species', '10090', (56, 61))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('overgrowth', 'Phenotype', 'HP:0001548', (86, 96))	('carcinogenesis', 'Disease', (164, 178))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
311630	29270239	Also, hyper-methylation of STK3 has been found in soft tissue sarcoma as well as head and neck squamous cell carcinoma, which is in accordance with the present study.	('found', 'Reg', (41, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (50, 69))	('STK3', 'Gene', (27, 31))	('or', 'Gene', '31118', (135, 137))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (50, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('soft tissue sarcoma', 'Disease', (50, 69))	('hyper-methylation', 'Var', (6, 23))	('squamous cell carcinoma', 'Disease', (95, 118))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 118))
311635	29270239	Studies have found hyper-methylation of ZNF542 in oropharyngeal squamous cell carcinoma and sporadic colorectal cancer.	('or', 'Gene', '31118', (94, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('ZNF542', 'Gene', '147947', (40, 46))	('or', 'Gene', '31118', (104, 106))	('hyper-methylation', 'Var', (19, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('or', 'Gene', '31118', (50, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('ZNF542', 'Gene', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 87))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (50, 87))	('squamous cell carcinoma', 'Disease', (64, 87))
311646	29270239	Compared with the other kinds of biomarkers, DNA methylation alterations may occur in advance of the alterations of mRNA and protein levels in the carcinogenesis thus might have a better early diagnosis potential.	('carcinogenesis', 'Disease', 'MESH:D063646', (147, 161))	('alterations', 'Reg', (61, 72))	('DNA', 'MPA', (45, 48))	('carcinogenesis', 'Disease', (147, 161))	('methylation', 'Var', (49, 60))
311661	29270239	Methylation profiles of the five genomic regions covering cg15830431 (STK3), cg19396867, cg20655070, cg26671652 (ZNF418), and cg27062795 (ZNF542) may be effective DNA methylation-based testing for ESCC diagnosis.	('cg26671652', 'Var', (101, 111))	('cg15830431', 'Var', (58, 68))	('ZNF418', 'Gene', '147686', (113, 119))	('ZNF542', 'Gene', (138, 144))	('ESCC', 'Disease', (197, 201))	('cg19396867', 'Chemical', '-', (77, 87))	('cg26671652', 'Chemical', '-', (101, 111))	('cg15830431', 'Chemical', '-', (58, 68))	('ZNF542', 'Gene', '147947', (138, 144))	('cg20655070', 'Chemical', '-', (89, 99))	('cg27062795', 'Chemical', '-', (126, 136))	('or', 'Gene', '31118', (194, 196))	('cg19396867', 'Var', (77, 87))	('cg27062795', 'Var', (126, 136))	('cg20655070', 'Var', (89, 99))	('ZNF418', 'Gene', (113, 119))
311677	29270239	Moreover, we further removed the CpG sites with SNPs in their primers and the CpG sites whose corresponding genes have been studied in ESCC carcinogenesis.	('ESCC', 'Disease', (135, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('carcinogenesis', 'Disease', (140, 154))	('or', 'Gene', '31118', (95, 97))	('or', 'Gene', '31118', (1, 3))	('SNPs', 'Var', (48, 52))
311680	29270239	Finally, five of our candidate biomarkers were selected for further validation: cg15830431, cg19396867, cg20655070, cg26671652, and cg27062795.	('cg20655070', 'Chemical', '-', (104, 114))	('cg27062795', 'Chemical', '-', (132, 142))	('cg20655070', 'Var', (104, 114))	('cg26671652', 'Var', (116, 126))	('cg19396867', 'Chemical', '-', (92, 102))	('cg27062795', 'Var', (132, 142))	('or', 'Gene', '31118', (57, 59))	('cg15830431', 'Var', (80, 90))	('cg19396867', 'Var', (92, 102))	('cg26671652', 'Chemical', '-', (116, 126))	('cg15830431', 'Chemical', '-', (80, 90))
311746	31849385	ELA improves prognosis, but the complication and mortality rates are high.	('mortality', 'Disease', (49, 58))	('ELA', 'Chemical', '-', (0, 3))	('prognosis', 'MPA', (13, 22))	('ELA', 'Var', (0, 3))	('mortality', 'Disease', 'MESH:D003643', (49, 58))
311776	30623099	Charlson comorbidity scores were calculated using the Deyo adaptation of the Charlson comorbidity index for the 13-month period prior to cancer diagnosis.18, 19, 20 Survival was defined as the time from diagnosis date to date of death.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('diagnosis.18', 'Var', (144, 156))	('cancer', 'Disease', (137, 143))	('death', 'Disease', 'MESH:D003643', (229, 234))	('death', 'Disease', (229, 234))
311842	29203855	CCT did not prolong progression-free survival (33.0 vs 18.0 months, P = 0.07, HR = 0.70, 95% CI, 0.48-1.04); however, CCT improved the median overall survival (53.4 vs 27.0 months, P = 0.04, HR = 0.67, 95% CI, 0.44-0.99) compared with dCRT alone.	('overall survival', 'MPA', (142, 158))	('dCRT', 'Gene', '45841', (235, 239))	('CCT', 'Var', (118, 121))	('dCRT', 'Gene', (235, 239))	('improved', 'PosReg', (122, 130))
311861	29203855	However, fewer patients had distant metastases in the CCT group than in the control group (15 [22.4%] of 67 versus 62 [43.7%] of 142, chi 2 = 8.85, P = 0.003).	('patients', 'Species', '9606', (15, 23))	('CCT', 'Var', (54, 57))	('fewer', 'NegReg', (9, 14))	('metastases', 'Disease', (36, 46))	('metastases', 'Disease', 'MESH:D009362', (36, 46))
311925	28940985	The biochemical parameters included: preoperative hemoglobin (<=90 or >90 g/L); preoperative albumin (<=34 g, >34 g/L); albumin within seven days after the surgery (<=28 or >28 g/L); and blood urea nitrogen and abnormal creatinine levels within seven days after surgery (yes, no).	('urea', 'Chemical', 'MESH:D014508', (193, 197))	('albumin', 'Gene', (120, 127))	('albumin', 'Gene', '213', (120, 127))	('abnormal creatinine levels', 'Phenotype', 'HP:0012100', (211, 237))	('<=34 g', 'Var', (102, 108))	('<=28', 'Var', (165, 169))	('<=90', 'Var', (62, 66))	('creatinine', 'Chemical', 'MESH:D003404', (220, 230))	('blood urea nitrogen', 'Phenotype', 'HP:0003138', (187, 206))	('albumin', 'Gene', (93, 100))	('albumin', 'Gene', '213', (93, 100))	('hemoglobin', 'MPA', (50, 60))	('blood urea nitrogen', 'MPA', (187, 206))	('abnormal creatinine levels', 'MPA', (211, 237))	('nitrogen', 'Chemical', 'MESH:D009584', (198, 206))
311926	28940985	The abnormal levels of postoperative blood urea nitrogen and creatinine were described as urea nitrogen >=15 mM or creatinine >=200 muM.	('urea', 'Chemical', 'MESH:D014508', (90, 94))	('urea', 'Chemical', 'MESH:D014508', (43, 47))	('creatinine', 'MPA', (115, 125))	('blood urea nitrogen', 'Phenotype', 'HP:0003138', (37, 56))	('creatinine', 'Chemical', 'MESH:D003404', (115, 125))	('nitrogen', 'Chemical', 'MESH:D009584', (48, 56))	('>=15', 'Var', (104, 108))	('>=200', 'Var', (126, 131))	('urea nitrogen', 'MPA', (90, 103))	('creatinine', 'Chemical', 'MESH:D003404', (61, 71))	('nitrogen', 'Chemical', 'MESH:D009584', (95, 103))
311965	28806990	Regarding the heart, a significant reduction was seen for Dmean and V5, but not for Dmin, Dmax, Dmedian and V10-V35.	('V35', 'Gene', '28474', (112, 115))	('Dmedian', 'Chemical', '-', (96, 103))	('Dmax', 'Chemical', '-', (90, 94))	('V35', 'Gene', (112, 115))	('Dmean', 'Chemical', '-', (58, 63))	('Dmean', 'Var', (58, 63))	('Dmin', 'Chemical', '-', (84, 88))	('reduction', 'NegReg', (35, 44))
311999	28806990	When using longitudinal margins of 2 cm a significant dose reduction was observed for Dmean, Dmax and V5-V35, whereas there was no significant difference for Dmin and Dmedian.	('Dmin', 'Chemical', '-', (158, 162))	('V35', 'Gene', (105, 108))	('V35', 'Gene', '28474', (105, 108))	('Dmax', 'Chemical', '-', (93, 97))	('dose', 'MPA', (54, 58))	('Dmedian', 'Chemical', '-', (167, 174))	('Dmax', 'MPA', (93, 97))	('Dmean', 'Chemical', '-', (86, 91))	('Dmean', 'Var', (86, 91))
312003	28806990	In addition to Dmean and V5 a significant reduction was seen for V10, V40 and V45 of the heart when comparing a longitudinal margin of 4 cm to a longitudinal margin of 3 cm in definite treatment plans.	('V10', 'Var', (65, 68))	('Dmean', 'Chemical', '-', (15, 20))	('V45', 'Var', (78, 81))	('V40', 'Var', (70, 73))	('reduction', 'NegReg', (42, 51))
312036	28806990	However, with a focus to the lungs, several studies demonstrated that mean lung dose and different dose-volume histogram (DVH) parameters like V20 or V30 are associated with the risk of developing a radiation pneumonitis.	('pneumonitis', 'Disease', 'MESH:D011014', (209, 220))	('associated', 'Reg', (158, 168))	('DVH', 'Chemical', '-', (122, 125))	('pneumonitis', 'Disease', (209, 220))	('V30', 'Var', (150, 153))	('V20', 'Var', (143, 146))
312042	28806990	that analyzed 94 patients with non-small cell lung cancer treated with simultaneous chemoradiation, V10 of the lungs was independently associated with the risk of radiation pneumonitis.	('non-small cell lung cancer', 'Disease', (31, 57))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (35, 57))	('pneumonitis', 'Disease', (173, 184))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (31, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('associated', 'Reg', (135, 145))	('patients', 'Species', '9606', (17, 25))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (31, 57))	('pneumonitis', 'Disease', 'MESH:D011014', (173, 184))	('V10', 'Var', (100, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
312043	28806990	Thereby, the risk of severe radiation pneumonitis was 5.7% in patients with V10 <= 50% and 29.2% in patients with V10 > 50%, respectively.	('V10 <= 50%', 'Var', (76, 86))	('V10', 'Var', (114, 117))	('pneumonitis', 'Disease', 'MESH:D011014', (38, 49))	('patients', 'Species', '9606', (100, 108))	('pneumonitis', 'Disease', (38, 49))	('patients', 'Species', '9606', (62, 70))
312069	28534989	Immunohistochemical analysis of ESCC specimens showed p75NTR expression in 39 of 95 (41.1%) patients, with a median of 13.2% (range, 3.0-80.1%) p75NTR-positive/Ki-67-negative cells, which were found to be associated with poorly differentiated histology.	('p75NTR expression', 'Var', (54, 71))	('poorly differentiated histology', 'Disease', (221, 252))	('patients', 'Species', '9606', (92, 100))	('p75NTR-positive/Ki-67-negative', 'Var', (144, 174))
312103	28534989	The numbers of p75NTR-positive cells and all tumor cells with nuclear staining were counted in three random fields of each section.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('p75NTR-positive', 'Var', (15, 30))
312108	28534989	Similarly, 36.5 and 43.1% p75NTR-positive and p75NTR-negative KYSE-140 cells, respectively, yielded negative results for Ki-67 (Fig.	('p75NTR-negative', 'Var', (46, 61))	('p75NTR-positive', 'Var', (26, 41))	('negative', 'NegReg', (100, 108))	('Ki-67', 'Gene', (121, 126))	('KYSE-140', 'CellLine', 'CVCL:1347', (62, 70))
312109	28534989	Flow cytometric analysis of p75NTR expression showed positive staining in 26.8 and 36.4% KYSE-30 and KYSE-140, respectively (Fig.	('KYSE-30', 'Var', (89, 96))	('KYSE-140', 'CellLine', 'CVCL:1347', (101, 109))	('KYSE-140', 'Var', (101, 109))
312111	28534989	Thus, 16.9 and 23.7% p75NTR-positive KYSE-30 and KYSE-140 cells, respectively, were in the G0-G1 phase of the cell cycle.	('G0-G1 phase of the cell cycle', 'CPA', (91, 120))	('KYSE-140', 'CellLine', 'CVCL:1347', (49, 57))	('p75NTR-positive', 'Var', (21, 36))
312113	28534989	The mRNA expression of p75NTR was significantly higher in p75NTR-positive/G0-1 and p75NTR-positive/S-G2-M cells than in p75NTR-negative/G0-1 or p75NTR-negative/S-G2-M cells (Fig.	('p75NTR', 'Var', (23, 29))	('higher', 'PosReg', (48, 54))	('mRNA expression', 'MPA', (4, 19))	('1 and p75', 'Gene', '7133', (77, 86))
312116	28534989	Results of real-time PCR showed that expression of stem cell-related genes such as Nanog, BMI-1 and p63 was significantly higher in p75NTR-positive/G0-1 KYSE-30 and KYSE-140 cells than in the other cell subsets, including p75NTR-positive/S-G2-M fraction KYSE-30 and KYSE-140 cells (Fig.	('p75NTR-positive/G0-1 KYSE-30', 'Var', (132, 160))	('BMI-1', 'Gene', (90, 95))	('p63', 'Gene', (100, 103))	('Nanog', 'Gene', (83, 88))	('higher', 'PosReg', (122, 128))	('KYSE-140', 'CellLine', 'CVCL:1347', (266, 274))	('p63', 'Gene', '8626', (100, 103))	('KYSE-140', 'CellLine', 'CVCL:1347', (165, 173))	('expression', 'MPA', (37, 47))	('stem cell-related genes', 'Gene', (51, 74))
312117	28534989	Furthermore, p75NTR-positive/G0-1 KYSE-30 and KYSE-140 cells showed the highest colony formation ability, with statistical significance, among the four cell subsets, while p75NTR-positive/S-G2-M KYSE-30 and KYSE-140 cells showed the second highest colony formation ability (Fig.	('KYSE-140', 'CellLine', 'CVCL:1347', (207, 215))	('KYSE-140', 'CellLine', 'CVCL:1347', (46, 54))	('colony formation ability', 'CPA', (248, 272))	('p75NTR-positive/G0-1', 'Var', (13, 33))	('colony formation ability', 'CPA', (80, 104))	('p75NTR-positive/S-G2-M', 'Var', (172, 194))
312119	28534989	Results of real-time PCR showed that the expression of ATP-binding cassette sub-family G member 2 (ABCG2) was significantly higher in p75NTR-positive cells than in p75NTR-negative cells, irrespective of their cell cycle status (Fig.	('expression', 'MPA', (41, 51))	('higher', 'PosReg', (124, 130))	('p75NTR-positive', 'Var', (134, 149))	('cassette sub-family G member 2 (ABCG2', 'Gene', '9429', (67, 104))
312120	28534989	On the other hand, expression of excision repair cross-complementation group 1 (ERCC1), which contributes to resistance against platinum-based chemotherapeutic drugs, was significantly higher in p75NTR-positive/G0-1 cells than in other cell subsets, including p75NTR-positive/S-G2-M cells (Fig.	('-complementation group 1 (ERCC1', 'Gene', '2067', (54, 85))	('expression', 'MPA', (19, 29))	('platinum', 'Chemical', 'MESH:D010984', (128, 136))	('higher', 'PosReg', (185, 191))	('p75NTR-positive/G0-1', 'Var', (195, 215))
312122	28534989	However, the viability of p75NTR-positive/G0-1 KYSE-30 cells was significantly higher than that of the other cell subsets at all CDDP concentrations.	('viability', 'CPA', (13, 22))	('higher', 'PosReg', (79, 85))	('p75NTR-positive/G0-1', 'Var', (26, 46))	('CDDP', 'Chemical', '-', (129, 133))
312123	28534989	Furthermore, the viability of p75NTR-positive/G0-1 KYSE-140 cells was significantly higher than that of the other cell subsets at CDDP concentrations of 100 and 200 microM (Fig.	('viability', 'CPA', (17, 26))	('p75NTR-positive/G0-1', 'Var', (30, 50))	('CDDP', 'Chemical', '-', (130, 134))	('KYSE-140', 'CellLine', 'CVCL:1347', (51, 59))	('higher', 'PosReg', (84, 90))
312125	28534989	Injection of 100 p75NTR-negative/G0-1 or p75NTR-negative/S-G2-M cells did not result in tumor development (Table I).	('tumor', 'Disease', (88, 93))	('p75NTR-negative/S-G2-M', 'Var', (41, 63))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
312126	28534989	The weights of tumors derived from p75NTR-positive/G0-1 cells were higher than those of tumors derived from p75NTR-positive/S-G2-M cells (Fig.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('higher', 'PosReg', (67, 73))	('weights', 'CPA', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumors', 'Disease', (15, 21))	('p75NTR-positive/G0-1', 'Var', (35, 55))
312127	28534989	Histological examination of xenograft tumors showed that a large percentage (83.4%) of cells in tumors derived from 300 p75NTR-positive/G0-1 cells showed p75NTR (red) and Ki-67 (brown) positivity.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('xenograft tumors', 'Disease', 'MESH:D009369', (28, 44))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('xenograft tumors', 'Disease', (28, 44))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('Ki-67', 'Var', (171, 176))
312128	28534989	The expression of p75NTR was positive (>5% of the cancer cells were stained in tumor) in 39 of 95 (41.1%) ESCC specimens, with positive staining observed in the first few layers of infiltrative margin (Fig.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cancer', 'Disease', (50, 56))	('tumor', 'Disease', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('ESCC', 'Disease', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('p75NTR', 'Var', (18, 24))
312129	28534989	p75NTR was correlated with tumor depth (P=0.032) and neoadjuvant chemotherapy (P=0.031).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('neoadjuvant chemotherapy', 'CPA', (53, 77))	('tumor', 'Disease', (27, 32))	('p75NTR', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
312130	28534989	However, no significant correlation was observed between p75NTR expression and other factors such as age, sex, tumor location, lymph node metastasis, distant metastasis, TNM classification, histology and postoperative tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('p75NTR', 'Var', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('postoperative tumor', 'Disease', (204, 223))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('postoperative tumor', 'Disease', 'MESH:D010149', (204, 223))
312133	28534989	p75NTR-positive staining was apparent in the first one to two layers from the infiltrative margin in well differentiated tumors.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('p75NTR-positive', 'Var', (0, 15))	('tumors', 'Disease', 'MESH:D009369', (121, 127))
312134	28534989	In contrast, p75NTR-positive staining was diffusely distributed in poorly differentiated tumors.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('p75NTR-positive', 'Var', (13, 28))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
312135	28534989	The median proportion of p75NTR-positive cells in 20 tumors was 28.7% (range, 12.9-94.0%) and that of p75NTR-positive/Ki-67-negative cells in 20 tumors was 13.2% (range, 3.0-80.1%).	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('p75NTR-positive', 'Var', (25, 40))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
312137	28534989	High proportion of p75NTR-positive/Ki-67-negative cells was correlated with poorly differentiated histology (P=0.02), postoperative tumor recurrence (P=0.007) and with the proportion of p75NTR-positive cells in tumors (P=0.01).	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('postoperative tumor', 'Disease', (118, 137))	('p75NTR-positive/Ki-67-negative', 'Var', (19, 49))	('poorly differentiated histology', 'CPA', (76, 107))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('postoperative tumor', 'Disease', 'MESH:D010149', (118, 137))
312138	28534989	Kaplan-Meier survival curves showed a trend of unfavorable postoperative prognosis in patients who had tumor with higher proportion of p75NTR-positive/Ki-67-negative cells, although there was no statistically significant correlation (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('p75NTR-positive/Ki-67-negative', 'Var', (135, 165))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('patients', 'Species', '9606', (86, 94))
312139	28534989	Recent studies involving ESCC cell lines have shown that p75NTR is expressed in a cell subset possessing CSC properties such as colony formation ability, tumorigenicity in mouse xenograft models and chemoresistance.	('chemoresistance', 'CPA', (199, 214))	('p75NTR', 'Var', (57, 63))	(' in a ', 'Gene', '9118', (76, 82))	('mouse', 'Species', '10090', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	(' in a ', 'Gene', (76, 82))	('colony formation ability', 'CPA', (128, 152))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
312140	28534989	Double immunostaining performed in the present study detected four distinct cell subsets based on the expression of p75NTR and Ki-67 and showed that 11.4 and 15.7% KYSE-30 and KYSE-140 cells, respectively, were p75NTR-positive quiescent cells (which are present in the resting phase of the cell cycle).	('KYSE-140', 'CellLine', 'CVCL:1347', (176, 184))	('Ki-67', 'Gene', (127, 132))	('p75NTR', 'Var', (116, 122))	('KYSE-140', 'Var', (176, 184))	('KYSE-30', 'Var', (164, 171))
312142	28534989	The above results along with the recent studies that detected quiescent CSCs with enhanced CSC phenotypes in solid tumors, suggest that p75NTR-positive/G0-1 cells are quiescent CSCs in ESCC.	('solid tumors', 'Disease', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('p75NTR-positive/G0-1', 'Var', (136, 156))	('ESCC', 'Disease', (185, 189))
312145	28534989	In the present study, 21.8 and 36.5% p75NTR-positive KYSE-30 and KYSE-140 cells, respectively, showed Ki-67 negativity.	('p75NTR-positive', 'Var', (37, 52))	('KYSE-140', 'CellLine', 'CVCL:1347', (65, 73))	('Ki-67', 'CPA', (102, 107))
312146	28534989	Flow cytometric analysis showed that 63.0 and 65.2% p75NTR-positive KYSE-30 and KYSE-140 cells, respectively, were in the G0/G1 phase of the cell cycle.	('p75NTR-positive', 'Var', (52, 67))	('G0/G1 phase of the cell cycle', 'CPA', (122, 151))	('KYSE-140', 'CellLine', 'CVCL:1347', (80, 88))
312147	28534989	Flow cytometric cell cycle assay performed in the present study showed that ~33.3% (21.8/63.0) and 56.0% (36.5/65.2) p75NTR-positive KYSE-30 and KYSE-140 cells, respectively, were in the G0 phase.	('KYSE-140', 'CellLine', 'CVCL:1347', (145, 153))	('G0 phase', 'CPA', (187, 195))	('p75NTR-positive', 'Var', (117, 132))
312158	28534989	In the present study, p75NTR-positive/G0-1 cells showed strong chemoresistance to CDDP.	('chemoresistance', 'CPA', (63, 78))	('CDDP', 'Chemical', '-', (82, 86))	('p75NTR-positive/G0-1', 'Var', (22, 42))
312163	28534989	In ESCC, expression of polymorphism in ERCC1 is a predictor of CDDP-based chemotherapy.	('expression', 'MPA', (9, 19))	('ERCC1', 'Gene', (39, 44))	('CDDP', 'Chemical', '-', (63, 67))	('polymorphism', 'Var', (23, 35))	('predictor', 'Reg', (50, 59))	('CDDP-based chemotherapy', 'Disease', (63, 86))
312164	28534989	Stem cell-related genes that were strongly expressed in p75NTR-positive/G0-1 cells, such as Nanog and BMI-1, are also involved in chemoresistance in different cancers.	('cancers', 'Disease', (159, 166))	('p75NTR-positive/G0-1', 'Var', (56, 76))	('involved in', 'Reg', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('chemoresistance', 'CPA', (130, 145))	('Stem cell-related genes', 'Gene', (0, 23))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
312165	28534989	These findings strongly suggest that p75NTR-positive/G0-1 cells are responsible for resistance to CDDP-based chemotherapy in ESCC.	('p75NTR-positive/G0-1', 'Var', (37, 57))	('CDDP', 'Chemical', '-', (98, 102))	('ESCC', 'Disease', (125, 129))
312166	28534989	Immunohistochemical staining of surgically resected ESCC specimens showed p75NTR-positive (>5% of the tumor cells were stained) in 41.1% patients who showed favorable postoperative survival, which is consistent with the results of previous studies.	('p75NTR-positive', 'Var', (74, 89))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('patients', 'Species', '9606', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
312167	28534989	On the other hand, clinical significance of very small number of the cells with p75NTR expression (when <=5% of the cancer cells were stained in a tumor) remains to be addressed.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('p75NTR expression', 'Var', (80, 97))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
312168	28534989	In addition, as was shown in a previous report, the expression of p75NTR decreases during progression of cancer in about half of ESCC tumors, resulting in complete loss of the expression in some cases.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (105, 111))	('expression', 'MPA', (176, 186))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('in a', 'Gene', '9118', (112, 116))	('in a', 'Gene', '9118', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('loss', 'NegReg', (164, 168))	('ESCC tumors', 'Disease', (129, 140))	(' in a ', 'Gene', (25, 31))	('In a', 'Gene', '9118', (0, 4))	('decreases', 'NegReg', (73, 82))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	(' in a ', 'Gene', '9118', (25, 31))	('in a', 'Gene', (112, 116))	('ESCC tumors', 'Disease', 'MESH:D004938', (129, 140))	('expression', 'MPA', (52, 62))	('p75NTR', 'Var', (66, 72))	('In a', 'Gene', (0, 4))
312169	28534989	Therefore, other CSC markers are needed in tumors in which the expression of p75NTR is completely lost.	('lost', 'NegReg', (98, 102))	('p75NTR', 'Var', (77, 83))	('expression', 'MPA', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
312170	28534989	In addition, the proportion of p75NTR-positive/Ki-67-negative cells was correlated with poorly differentiated histology and postoperative tumor recurrence, indicating that these cells represented relatively immature cells and are responsible for malignant potential in ESCC.	('p75NTR-positive/Ki-67-negative', 'Var', (31, 61))	('postoperative tumor', 'Disease', (124, 143))	('postoperative tumor', 'Disease', 'MESH:D010149', (124, 143))	('In a', 'Gene', '9118', (0, 4))	('ESCC', 'Disease', (269, 273))	('In a', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
312171	28534989	Kaplan-Meier survival curves showed that patients with tumors having a high proportion of p75NTR-positive/Ki-67-negative cells showed poor survival; however, the correlation was not statistically significant.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('p75NTR-positive/Ki-67-negative', 'Var', (90, 120))	('patients', 'Species', '9606', (41, 49))	('poor', 'NegReg', (134, 138))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
312173	28534989	In addition to p75NTR, CD44 and CD90 have been reported to be putative CSC markers in ESCC.	('p75NTR', 'Var', (15, 21))	('CD44', 'Var', (23, 27))	('CD90', 'Gene', '7070', (32, 36))	('CD90', 'Gene', (32, 36))	('In a', 'Gene', '9118', (0, 4))	('In a', 'Gene', (0, 4))	('ESCC', 'Disease', (86, 90))
312174	28534989	In a previous report from our laboratory, the p75NTR-positive CD44-negative fraction of KYSE-30 possessed CSC properties, such as stem cell-related gene expression, lower expression of differentiation markers, drug resistance and in vivo tumorigenicity.	('p75NTR-positive', 'Var', (46, 61))	('stem cell-related', 'CPA', (130, 147))	('expression', 'MPA', (171, 181))	('lower', 'NegReg', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('drug resistance', 'CPA', (210, 225))	('drug resistance', 'Phenotype', 'HP:0020174', (210, 225))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('In a', 'Gene', (0, 4))	('tumor', 'Disease', (238, 243))	('CD44', 'Gene', '960', (62, 66))	('In a', 'Gene', '9118', (0, 4))	('CD44', 'Gene', (62, 66))
312177	28534989	These observations indicate that p75NTR-positive/G0-1 fraction in this study is a specific subpopulation of ESCC with quiescent CSC properties, which cannot be identified using CD44 or CD90.	('CD90', 'Gene', '7070', (185, 189))	('CD44', 'Gene', '960', (177, 181))	('CD90', 'Gene', (185, 189))	('CD44', 'Gene', (177, 181))	('p75NTR-positive/G0-1', 'Var', (33, 53))	('ESCC', 'Disease', (108, 112))
312179	28534989	Immunohistochemical examination detected small number of p75NTR-positive/Ki-67-negative cells in surgically resected ESCC specimens and indicate that these cells were associated with poorly differentiated histology of ESCC tumor.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('associated with', 'Reg', (167, 182))	('ESCC tumor', 'Disease', 'MESH:D004938', (218, 228))	('p75NTR-positive/Ki-67-negative', 'Var', (57, 87))	('ESCC tumor', 'Disease', (218, 228))
312186	23520267	The 2-year OS rates in the low- and high-SUV groups were 100% and 41%, the PFS rates were 73% and 19%, the LC rates were 71% and 39%, and the CR rates were 100% and 32%, respectively.	('CR', 'Chemical', '-', (142, 144))	('PFS', 'CPA', (75, 78))	('low-', 'Var', (27, 31))	('high-SUV', 'Var', (36, 44))
312235	23520267	In response to this result, we divided the 56 patients into two groups according to their SUVmax values: <10 (low-SUV) and >=10 (high-SUV) using a ROC analysis; in the low- and high-SUV groups, T1-2 patients were 15 and 3, and T3-4 patients were 3 and 35.	('patients', 'Species', '9606', (46, 54))	('T1-2', 'Gene', '923;9173;292', (194, 198))	('patients', 'Species', '9606', (232, 240))	('low-', 'Var', (168, 172))	('patients', 'Species', '9606', (199, 207))	('T1-2', 'Gene', (194, 198))
312395	33488866	Similarly, significantly more cells overexpressing DEK were found in ESCC tissues (57.5%) in comparison with para-carcinoma samples (11.4%) and normal esophageal mucosa (0%, p < 0.001).	('DEK', 'Var', (51, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('more', 'PosReg', (25, 29))	('para-carcinoma', 'Disease', 'MESH:D002277', (109, 123))	('para-carcinoma', 'Disease', (109, 123))	('ESCC', 'Disease', (69, 73))
312407	33488866	demonstrated that the silencing of DEK had effects on the growth of CaSki cells with blocking the cell cycle in the G0/G1 phase, inhibiting cell proliferation, increasing cell apoptosis and inducing cell senescence.	('cell proliferation', 'CPA', (140, 158))	('increasing', 'PosReg', (160, 170))	('DEK', 'Gene', (35, 38))	('inhibiting', 'NegReg', (129, 139))	('cell apoptosis', 'CPA', (171, 185))	('CaSki', 'CellLine', 'CVCL:1100', (68, 73))	('silencing', 'Var', (22, 31))	('inducing', 'Reg', (190, 198))	('cell senescence', 'CPA', (199, 214))	('blocking', 'NegReg', (85, 93))	('cell cycle in the G0/G1 phase', 'CPA', (98, 127))
312411	33488866	reported that the DEK gene was overexpressed in colorectal cancer cell lines, while knock-down of DEK in DLD1 and SW620 cell lines reduced cell migration and increased irinotecan-induced apoptosis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('SW620', 'CellLine', 'CVCL:0547', (114, 119))	('irinotecan', 'Chemical', 'MESH:D000077146', (168, 178))	('irinotecan-induced', 'MPA', (168, 186))	('colorectal cancer', 'Disease', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('reduced', 'NegReg', (131, 138))	('cell migration', 'CPA', (139, 153))	('DEK', 'Gene', (98, 101))	('knock-down', 'Var', (84, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))	('increased', 'PosReg', (158, 167))
312433	33488866	Univariate analysis revealed that ESCC cases highly expressing DEK had markedly reduced disease-free and 5-year survival rates in comparison with patients lowly expressing DEK.	('DEK', 'Var', (63, 66))	('reduced disease-free', 'Disease', (80, 100))	('ESCC', 'Disease', (34, 38))	('reduced disease-free', 'Disease', 'MESH:D008569', (80, 100))	('patients', 'Species', '9606', (146, 154))
312436	33488866	As shown above (Table I, Figure 1), DEK was ubiquitously distributed in the nucleus of ESCC cells, with the rate of DEK expression (71.7%) markedly increased compared to para-carcinoma (21.4%) and normal esophageal tissues (13.9%, both p < 0.001).	('para-carcinoma', 'Disease', 'MESH:D002277', (170, 184))	('para-carcinoma', 'Disease', (170, 184))	('increased', 'PosReg', (148, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('DEK', 'Var', (116, 119))
312449	33488866	demonstrated that patients with high DEK expression had a lower overall survival rate than those with low DEK expression.	('overall survival', 'MPA', (64, 80))	('high DEK expression', 'Var', (32, 51))	('patients', 'Species', '9606', (18, 26))	('lower', 'NegReg', (58, 63))
312451	33488866	Our previous study reported that DEK overexpression was significantly associated with portal vein invasion, tumor size and poor prognosis in HCC patients, showing that patients with high DEK expression had a shorter overall survival time than those with low expression.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('overall survival', 'MPA', (216, 232))	('portal vein invasion', 'Disease', (86, 106))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('associated', 'Reg', (70, 80))	('tumor', 'Disease', (108, 113))	('high', 'Var', (182, 186))	('patients', 'Species', '9606', (168, 176))	('shorter', 'NegReg', (208, 215))	('HCC', 'Phenotype', 'HP:0001402', (141, 144))
312545	32190161	Moreover, inhibition of its specific receptor, CXCR-2, may lead to decreased invasiveness of EC.	('inhibition', 'Var', (10, 20))	('EC', 'Disease', 'MESH:D004938', (93, 95))	('CXCR-2', 'Gene', '3579', (47, 53))	('invasiveness', 'CPA', (77, 89))	('CXCR-2', 'Gene', (47, 53))	('decreased', 'NegReg', (67, 76))
312694	26321501	Berger et al and Rohatgi et al, among many others, have demonstrated that patients with a pathCR live significantly longer than those who have < pathCR.	('patients', 'Species', '9606', (74, 82))	('longer', 'PosReg', (116, 122))	('pathCR', 'Var', (90, 96))
312702	26321501	Patients with baseline T1N0 or T4anyN tumors were also excluded.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('Patients', 'Species', '9606', (0, 8))	('T4anyN', 'Var', (31, 37))
312715	26321501	The following 18F-FDG PET/CT parameters of the primary tumor were obtained: SUVmax, the TLG (total lesion glycolysis of the tumor), the difference in SUV max (DeltaSUVmax) and the difference in TLG (DeltaTLG) from baseline to interim and the DeltaSUVmax and DeltaTLG from baseline to post-CTRT 18F-FDG PET/CT.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('TLG', 'Chemical', '-', (204, 207))	('18F-FDG', 'Chemical', 'MESH:D019788', (294, 301))	('TLG', 'Chemical', '-', (194, 197))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('TLG', 'Chemical', '-', (263, 266))	('TLG', 'Chemical', '-', (88, 91))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', (55, 60))	('total lesion glycolysis of the tumor', 'Disease', 'MESH:C564972', (93, 129))	('total lesion glycolysis of the tumor', 'Disease', (93, 129))	('DeltaSUVmax', 'Var', (242, 253))	('SUV max', 'MPA', (150, 157))	('TLG', 'MPA', (194, 197))	('18F-FDG', 'Chemical', 'MESH:D019788', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
312717	26321501	In this prospective study, with a total sample size of 90 patients and assuming that 25% of these patients will achieve pathCR, we will have an 84% power to test the null hypothesis of H0: AUC= 0.6 (ie, poor discrimination) against the alternative hypothesis of H1: AUC = 0.8 (ie, good discrimination), using the two-sided asymptotic Z-test and at 0.05 significance level.	('test', 'Reg', (157, 161))	('H0: AUC= 0.6', 'Var', (185, 197))	('poor discrimination', 'Phenotype', 'HP:0001963', (203, 222))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (58, 66))
312759	26321501	In patients with SCC, the correlation of pathologic response was higher with TLG (AUC 0.93) than with SUVmax (AUC 0.71).	('TLG', 'Chemical', '-', (77, 80))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('SCC', 'Gene', '6317', (17, 20))	('patients', 'Species', '9606', (3, 11))	('TLG', 'Var', (77, 80))	('higher', 'PosReg', (65, 71))	('SCC', 'Gene', (17, 20))
312828	24553109	In vitro, infection with Ad-hTERT-E1a-HN could inhibit the growth of EC-109 cells significantly and also protect normal human liver cell line L02 from growth suppression in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays.	('human', 'Species', '9606', (120, 125))	('MTT', 'Chemical', 'MESH:C070243', (235, 238))	('hTERT', 'Gene', (28, 33))	('growth', 'CPA', (59, 65))	('EC-109', 'CellLine', 'CVCL:6898', (69, 75))	('3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (173, 233))	('growth suppression', 'CPA', (151, 169))	('inhibit', 'NegReg', (47, 54))	('protect', 'Reg', (105, 112))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (29, 40))	('infection', 'Var', (10, 19))	('hTERT', 'Gene', '7015', (28, 33))
312834	24553109	It has been shown that gene therapy can play a role as an adjuvant treatment modality for esophageal cancer.	('esophageal cancer', 'Disease', (90, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('gene therapy', 'Var', (23, 35))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
312853	24553109	In EC-109 cells (Figure 1B), the suppression of cells by infection with replication-competent adenoviruses (Ad-CMV-E1a, Ad-hTERT-E1a, Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN) increased significantly over the infection time, especially in those infected with Ad-CMV-E1a-HN or Ad-hTERT-E1a-HN.	('adenovirus', 'Species', '28285', (94, 104))	('hTERT', 'Gene', '7015', (155, 160))	('TERT-E1a', 'CellLine', 'CVCL:V078', (156, 164))	('EC-109', 'CellLine', 'CVCL:6898', (3, 9))	('hTERT', 'Gene', (123, 128))	('cells', 'CPA', (48, 53))	('Ad-CMV-E1a-HN', 'Var', (252, 265))	('hTERT', 'Gene', (272, 277))	('TERT-E1a', 'CellLine', 'CVCL:V078', (273, 281))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (156, 167))	('hTERT', 'Gene', (155, 160))	('Ad-CMV-E1a-HN', 'Var', (134, 147))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (273, 284))	('hTERT', 'Gene', '7015', (123, 128))	('TERT-E1a', 'CellLine', 'CVCL:V078', (124, 132))	('hTERT', 'Gene', '7015', (272, 277))
312854	24553109	Meanwhile, there was no significant difference between cells treated with Ad-CMV-HN or Ad-hTERT-HN.	('Ad-CMV-HN', 'Var', (74, 83))	('hTERT', 'Gene', (90, 95))	('hTERT', 'Gene', '7015', (90, 95))
312855	24553109	Furthermore, infection with Ad-CMV-E1a-HN, Ad-hTERT-E1a-HN, Ad-CMV-E1a or Ad-hTERT-E1a at an MOI of 10 or 100 obviously inhibited cell growth compared with treatment with the replication-incompetent adenoviruses after day 4.	('hTERT', 'Gene', '7015', (46, 51))	('TERT-E1a', 'CellLine', 'CVCL:V078', (78, 86))	('cell growth', 'CPA', (130, 141))	('inhibited', 'NegReg', (120, 129))	('hTERT', 'Gene', (46, 51))	('Ad-CMV-E1a', 'Var', (60, 70))	('TERT-E1a', 'CellLine', 'CVCL:V078', (47, 55))	('adenovirus', 'Species', '28285', (199, 209))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (47, 58))	('hTERT', 'Gene', '7015', (77, 82))	('Ad-CMV-E1a-HN', 'Var', (28, 41))	('hTERT', 'Gene', (77, 82))
312857	24553109	By contrast, the growth of L02 cells infected only with non-specific replication-competent adenoviruses (Ad-CMV-E1a or Ad-CMV-E1a-HN) was significantly inhibited at a MOI of 10 or 100 compared with infection at the MOI of 1 (Figure 1C).	('Ad-CMV-E1a-HN', 'Var', (119, 132))	('growth', 'MPA', (17, 23))	('inhibited', 'NegReg', (152, 161))	('adenovirus', 'Species', '28285', (91, 101))
312859	24553109	Additionally, Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN could effectively restrain the growth of cultured EC-109 cells.	('hTERT', 'Gene', '7015', (35, 40))	('growth', 'CPA', (79, 85))	('restrain', 'NegReg', (66, 74))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (36, 47))	('hTERT', 'Gene', (35, 40))	('Ad-CMV-E1a-HN', 'Var', (14, 27))	('EC-109', 'CellLine', 'CVCL:6898', (98, 104))
312864	24553109	Cytotoxicity was especially strong in the Ad-CMV-E1a-HN- and Ad-hTERT-E1a-HN-treated cells.	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (65, 76))	('hTERT', 'Gene', (64, 69))	('Cytotoxicity', 'Disease', (0, 12))	('Ad-CMV-E1a-HN-', 'Var', (42, 56))	('hTERT', 'Gene', '7015', (64, 69))	('Cytotoxicity', 'Disease', 'MESH:D064420', (0, 12))
312866	24553109	The percentages of live cells in EC-109 cells infected with Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN were obviously lower than those observed with recombinant adenoviruses (Figure 2B).	('lower', 'NegReg', (109, 114))	('adenovirus', 'Species', '28285', (152, 162))	('Ad-CMV-E1a-HN', 'Var', (60, 73))	('hTERT', 'Gene', (81, 86))	('hTERT', 'Gene', '7015', (81, 86))	('EC-109', 'CellLine', 'CVCL:6898', (33, 39))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (82, 93))
312867	24553109	Meanwhile, due to the loss of the tumor-specific effect of HN in L02 cells, only Ad-CMV-E1a- or Ad-CMV-E1a-HN-treated cells were cytotoxic and caused a higher proportion of apoptotic and/or necrotic cells (Figure 2C).	('necrotic', 'Disease', 'MESH:D009336', (190, 198))	('caused', 'Reg', (143, 149))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('apoptotic and/or', 'CPA', (173, 189))	('Ad-CMV-E1a-', 'Var', (81, 92))	('necrotic', 'Disease', (190, 198))	('loss', 'NegReg', (22, 26))	('cytotoxic', 'CPA', (129, 138))	('Ad-CMV-E1a-HN-treated', 'Var', (96, 117))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
312872	24553109	In L02 cells (Figure 2E), the sialic acid content of Ad-CMV-E1a- and Ad-CMV-E1a-HN-treated cells gradually decreased over the infection time, while cells infected with other recombinant adenoviruses retained significantly higher levels of sialic acid on the fourth day compared with those on the first day.	('adenovirus', 'Species', '28285', (186, 196))	('Ad-CMV-E1a-HN-treated', 'Var', (69, 90))	('Ad-CMV-E1a-', 'Var', (53, 64))	('higher', 'PosReg', (222, 228))	('sialic acid', 'Chemical', 'MESH:D019158', (239, 250))	('levels', 'MPA', (229, 235))	('sialic acid', 'Chemical', 'MESH:D019158', (30, 41))	('decreased', 'NegReg', (107, 116))	('sialic acid content', 'MPA', (30, 49))	('sialic acid', 'MPA', (239, 250))
312874	24553109	Interestingly, at day 2 after infection, the total sialic acid levels of cells treated with Ad-CMV-HN, Ad-hTERT-HN, Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN began to decrease, while others groups showed a rising trend of the total sialic acid content.	('Ad-CMV-HN', 'Var', (92, 101))	('hTERT', 'Gene', (137, 142))	('sialic acid', 'Chemical', 'MESH:D019158', (224, 235))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (138, 149))	('total sialic acid levels', 'MPA', (45, 69))	('hTERT', 'Gene', '7015', (106, 111))	('Ad-CMV-E1a-HN', 'Var', (116, 129))	('decrease', 'NegReg', (159, 167))	('hTERT', 'Gene', '7015', (137, 142))	('sialic acid', 'Chemical', 'MESH:D019158', (51, 62))	('total sialic acid content', 'MPA', (218, 243))	('hTERT', 'Gene', (106, 111))
312876	24553109	By day 4 post-infection, the sialic acid levels of the Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN treatment groups were almost eliminated.	('sialic acid levels', 'MPA', (29, 47))	('Ad-CMV-E1a-HN', 'Var', (55, 68))	('hTERT', 'Gene', '7015', (76, 81))	('sialic acid', 'Chemical', 'MESH:D019158', (29, 40))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (77, 88))	('hTERT', 'Gene', (76, 81))	('eliminated', 'NegReg', (118, 128))
312877	24553109	While the sialic acid levels in the Ad-CMV-HN and Ad-hTERT-HN groups decreased, they did not change significantly between the third and fourth day post-infection.	('Ad-CMV-HN', 'Var', (36, 45))	('hTERT', 'Gene', '7015', (53, 58))	('decreased', 'NegReg', (69, 78))	('sialic acid levels', 'MPA', (10, 28))	('sialic acid', 'Chemical', 'MESH:D019158', (10, 21))	('hTERT', 'Gene', (53, 58))
312878	24553109	However, the concentrations of sialic acid of the control group and the Ad-mock-, Ad-CMV-E1a- and Ad-hTERT-E1a-treated cells gradually increased, which was accompanied by cell proliferation.	('hTERT', 'Gene', '7015', (101, 106))	('concentrations of', 'MPA', (13, 30))	('TERT-E1a', 'CellLine', 'CVCL:V078', (102, 110))	('increased', 'PosReg', (135, 144))	('hTERT', 'Gene', (101, 106))	('Ad-CMV-E1a-', 'Var', (82, 93))	('sialic acid', 'Chemical', 'MESH:D019158', (31, 42))
312880	24553109	As shown in Figure 3A, significant quantities of cytochrome c were detected in the cytosol of Ad-CMV-E1a-, Ad-hTERT-E1a-, Ad-CMV-E1a-HN- and Ad-hTERT-E1a-HN-infected EC-109 cells.	('TERT-E1a', 'CellLine', 'CVCL:V078', (111, 119))	('Ad-CMV-E1a-', 'Var', (94, 105))	('hTERT', 'Gene', (144, 149))	('Ad-CMV-E1a-HN-', 'Var', (122, 136))	('TERT-E1a', 'CellLine', 'CVCL:V078', (145, 153))	('cytochrome c', 'Gene', '54205', (49, 61))	('hTERT', 'Gene', '7015', (110, 115))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (145, 156))	('hTERT', 'Gene', (110, 115))	('EC-109', 'CellLine', 'CVCL:6898', (166, 172))	('hTERT', 'Gene', '7015', (144, 149))	('cytochrome c', 'Gene', (49, 61))
312881	24553109	The levels of cytochrome c in cells treated with Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN were higher than in Ad-CMV-E1a- and Ad-hTERT-E1a-treated groups.	('higher', 'PosReg', (88, 94))	('cytochrome c', 'Gene', (14, 26))	('hTERT', 'Gene', (122, 127))	('hTERT', 'Gene', '7015', (70, 75))	('cytochrome c', 'Gene', '54205', (14, 26))	('TERT-E1a', 'CellLine', 'CVCL:V078', (123, 131))	('hTERT', 'Gene', (70, 75))	('TERT-E1a', 'CellLine', 'CVCL:V078', (71, 79))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (71, 82))	('hTERT', 'Gene', '7015', (122, 127))	('Ad-CMV-E1a-HN', 'Var', (49, 62))
312882	24553109	However, only Ad-CMV-E1a- and Ad-CMV-E1a-HN-treated L02 cells showed a small amount of released cytochrome c, while other recombinant adenovirus had no significant effects in the L02 cells.	('cytochrome c', 'Gene', '54205', (96, 108))	('adenovirus', 'Species', '28285', (134, 144))	('Ad-CMV-E1a-HN-treated', 'Var', (30, 51))	('Ad-CMV-E1a-', 'Var', (14, 25))	('cytochrome c', 'Gene', (96, 108))
312883	24553109	As shown in Figure 3B, significant DeltaPsim losses were detected in Ad-CMV-E1a-HN- (38.3%) and Ad-hTERT-E1a-HN-infected (42.2%) EC-109 cells, but not in the cells treated with the other recombinant adenoviruses.	('EC-109', 'CellLine', 'CVCL:6898', (129, 135))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (100, 111))	('hTERT', 'Gene', (99, 104))	('adenovirus', 'Species', '28285', (199, 209))	('hTERT', 'Gene', '7015', (99, 104))	('Ad-CMV-E1a-HN-', 'Var', (69, 83))	('DeltaPsim', 'MPA', (35, 44))	('losses', 'NegReg', (45, 51))
312884	24553109	The slight decrease in DeltaPsim was also detected in Ad-CMV-E1a- (65.9%) and Ad-hTERT-E1a-infected (54.2%) cells.	('TERT-E1a', 'CellLine', 'CVCL:V078', (82, 90))	('DeltaPsim', 'MPA', (23, 32))	('Ad-CMV-E1a-', 'Var', (54, 65))	('hTERT', 'Gene', '7015', (81, 86))	('decrease', 'NegReg', (11, 19))	('hTERT', 'Gene', (81, 86))
312885	24553109	In L02 cells, only the Ad-CMV-E1a and Ad-CMV-E1a-HN treatment resulted in a DeltaPsim loss of 64.6% and 59.7%, respectively, and the DeltaPsim values of L02 cells treated with other recombinant adenovirus were similar to that of the untreated group.	('DeltaPsim', 'MPA', (76, 85))	('adenovirus', 'Species', '28285', (194, 204))	('loss', 'NegReg', (86, 90))	('Ad-CMV-E1a', 'Var', (23, 33))	('Ad-CMV-E1a-HN', 'Var', (38, 51))
312887	24553109	EC-109 cells infected with Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN showed a significant increase in ROS of 60.8% and 67.4%, respectively, while in recombinant adenovirus-treated L02 cells, only Ad-CMV-E1a and Ad-CMV-E1a-HN could raise the levels of ROS by 50.9% and 52.5%, respectively.	('adenovirus', 'Species', '28285', (153, 163))	('raise the levels of ROS', 'Phenotype', 'HP:0025464', (223, 246))	('EC-109', 'CellLine', 'CVCL:6898', (0, 6))	('ROS', 'MPA', (94, 97))	('hTERT', 'Gene', (48, 53))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (49, 60))	('ROS', 'Chemical', 'MESH:D017382', (94, 97))	('ROS', 'MPA', (243, 246))	('increase', 'PosReg', (82, 90))	('ROS', 'Chemical', 'MESH:D017382', (243, 246))	('Ad-CMV-E1a-HN', 'Var', (27, 40))	('hTERT', 'Gene', '7015', (48, 53))
312894	24553109	Treatment of mice with Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN induced a potent anti-tumor response, especially in the Ad-hTERT-E1a-HN-infected group, in which the tumor volume was significantly reduced and close to regression.	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (117, 128))	('tumor', 'Disease', (158, 163))	('hTERT', 'Gene', (116, 121))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (45, 56))	('mice', 'Species', '10090', (13, 17))	('tumor', 'Disease', (79, 84))	('Ad-CMV-E1a-HN', 'Var', (23, 36))	('reduced', 'NegReg', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('hTERT', 'Gene', '7015', (116, 121))	('hTERT', 'Gene', '7015', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('hTERT', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
312895	24553109	By contrast, the Ad-hTERT-HN-, Ad-CMV-E1a- and Ad-hTERT-E1a-infected tumors slowly grew and gradually resumed their growth at six weeks.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('hTERT', 'Gene', (20, 25))	('resumed', 'PosReg', (102, 109))	('growth', 'MPA', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('hTERT', 'Gene', '7015', (50, 55))	('infected tumors', 'Disease', (60, 75))	('infected tumors', 'Disease', 'MESH:D009369', (60, 75))	('hTERT', 'Gene', '7015', (20, 25))	('TERT-E1a', 'CellLine', 'CVCL:V078', (51, 59))	('Ad-CMV-E1a-', 'Var', (31, 42))	('hTERT', 'Gene', (50, 55))
312896	24553109	In mice injected via the intravenous route (Figure 4B), tumors of the Ad-CMV-E1a-HN- and Ad-hTERT-E1a-HN-infected groups decreased most significantly in size, compared with the saline control, Ad-mock- and Ad-mock-infected groups.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mice', 'Species', '10090', (3, 7))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (93, 104))	('decreased', 'NegReg', (121, 130))	('tumors', 'Disease', (56, 62))	('hTERT', 'Gene', '7015', (92, 97))	('Ad-CMV-E1a-HN-', 'Var', (70, 84))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('saline', 'Chemical', 'MESH:D012965', (177, 183))	('hTERT', 'Gene', (92, 97))
312897	24553109	Growth of the Ad-CMV-E1a-, Ad-hTERT-E1a-, Ad-CMV-HN- and Ad-hTERT-HN-treated tumors were also suppressed, compared with saline-treated and Ad-mock-infected groups; however, there was no significant difference in growth rates of the tumors in these groups.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('hTERT', 'Gene', (60, 65))	('saline', 'Chemical', 'MESH:D012965', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('Ad-CMV-HN-', 'Var', (42, 52))	('TERT-E1a', 'CellLine', 'CVCL:V078', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('suppressed', 'NegReg', (94, 104))	('hTERT', 'Gene', '7015', (60, 65))	('hTERT', 'Gene', '7015', (30, 35))	('Growth', 'CPA', (0, 6))	('Ad-CMV-E1a-', 'Var', (14, 25))	('hTERT', 'Gene', (30, 35))	('tumors', 'Disease', (232, 238))
312900	24553109	The results from Figure 4A,C indicated that the intratumoral injection of Ad-CMV-E1a-HN or Ad-hTERT-E1a-HN could reduce tumor volume efficiently.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Ad-CMV-E1a-HN', 'Var', (74, 87))	('reduce', 'NegReg', (113, 119))	('hTERT', 'Gene', '7015', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('hTERT', 'Gene', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (120, 125))
312902	24553109	Although the tumors infected with Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN gradually resumed their growth after two weeks, their tumor volumes were the lowest compared with other groups.	('tumor', 'Disease', (13, 18))	('hTERT', 'Gene', '7015', (55, 60))	('resumed', 'PosReg', (78, 85))	('growth', 'MPA', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors infected', 'Disease', 'MESH:D009369', (13, 28))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (56, 67))	('hTERT', 'Gene', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('Ad-CMV-E1a-HN', 'Var', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors infected', 'Disease', (13, 28))	('lowest', 'NegReg', (145, 151))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
312903	24553109	The tumor volumes of the Ad-CMV-E1a-, Ad-hTERT-E1a-, Ad-CMV-HN- and Ad-hTERT-HN-infected groups were reduced compared with those of the saline-treated and Ad-mock-infected groups, while there were no significant differences between the groups.	('tumor', 'Disease', (4, 9))	('hTERT', 'Gene', '7015', (41, 46))	('Ad-CMV-HN-', 'Var', (53, 63))	('saline', 'Chemical', 'MESH:D012965', (136, 142))	('hTERT', 'Gene', (41, 46))	('reduced', 'NegReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('hTERT', 'Gene', '7015', (71, 76))	('TERT-E1a', 'CellLine', 'CVCL:V078', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Ad-CMV-E1a-', 'Var', (25, 36))	('hTERT', 'Gene', (71, 76))
312906	24553109	Ad-CMV-E1a-HN- and Ad-hTERT-E1a-HN-treated mice could reduce tumor burdens more significantly than other recombinant adenoviruses.	('mice', 'Species', '10090', (43, 47))	('Ad-CMV-E1a-HN-', 'Var', (0, 14))	('reduce', 'NegReg', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('hTERT', 'Gene', '7015', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (23, 34))	('adenovirus', 'Species', '28285', (117, 127))	('tumor', 'Disease', (61, 66))	('hTERT', 'Gene', (22, 27))
312908	24553109	As shown in Figure 4E, when the injections were performed intratumorally, infection with Ad-CMV-E1a, Ad-hTERT-E1a, Ad-CMV-E1a-HN or Ad-hTERT-E1a-HN significantly improved the mean survival time, while the saline-treated and Ad-mock-, Ad-CMV-HN- and Ad-hTERT-HN-infected groups had lower mean survival times of 48.5 days, 43.5 days, 59.5 days and 55.5 days, respectively.	('tumor', 'Disease', (63, 68))	('Ad-CMV-E1a-HN', 'Var', (115, 128))	('hTERT', 'Gene', '7015', (104, 109))	('hTERT', 'Gene', '7015', (135, 140))	('TERT-E1a', 'CellLine', 'CVCL:V078', (105, 113))	('improved', 'PosReg', (162, 170))	('TERT-E1a', 'CellLine', 'CVCL:V078', (136, 144))	('Ad-CMV-E1a', 'Var', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('hTERT', 'Gene', (104, 109))	('hTERT', 'Gene', (135, 140))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (136, 147))	('hTERT', 'Gene', '7015', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('hTERT', 'Gene', (252, 257))	('saline', 'Chemical', 'MESH:D012965', (205, 211))
312910	24553109	In the intravenously injected groups, Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN could increase survival rates of nude mice to the mean survival time of 63 days, which was significantly better than that observed in Ad-CMV-HN-, Ad-hTERT-HN-, Ad-CMV-E1a- and Ad-hTERT-E1a-infected groups (Figure 4F).	('hTERT', 'Gene', (59, 64))	('TERT-E1a', 'CellLine', 'CVCL:V078', (60, 68))	('hTERT', 'Gene', '7015', (221, 226))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (60, 71))	('hTERT', 'Gene', (251, 256))	('nude mice', 'Species', '10090', (105, 114))	('TERT-E1a', 'CellLine', 'CVCL:V078', (252, 260))	('increase', 'PosReg', (78, 86))	('hTERT', 'Gene', (221, 226))	('Ad-CMV-E1a-HN', 'Var', (38, 51))	('hTERT', 'Gene', '7015', (59, 64))	('better', 'PosReg', (177, 183))	('hTERT', 'Gene', '7015', (251, 256))	('survival rates', 'CPA', (87, 101))
312912	24553109	The results indicate that intravenous injections of Ad-CMV-E1a-HN and Ad-hTERT-E1a-HN conferred significant survival benefits in vivo.	('hTERT', 'Gene', '7015', (73, 78))	('hTERT', 'Gene', (73, 78))	('survival benefits', 'CPA', (108, 125))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (74, 85))	('Ad-CMV-E1a-HN', 'Var', (52, 65))
312918	24553109	previously showed that the anti-tumor effect of a conditionally replicating adenovirus (CRAd) vector modified by incorporation of an anti-angiogenesis inhibitor gene (CRAd-Cans) was even more potent than that of the replication-deficient adenovirus Ad5-Cans against pancreatic cancer both in vivo and in vitro.	('adenovirus', 'Species', '28285', (238, 248))	('adenovirus Ad5', 'Species', '28285', (238, 252))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (266, 283))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('pancreatic cancer', 'Disease', 'MESH:D010190', (266, 283))	('pancreatic cancer', 'Disease', (266, 283))	('potent', 'PosReg', (192, 198))	('tumor', 'Disease', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('adenovirus', 'Species', '28285', (76, 86))	('modified', 'Var', (101, 109))
312922	24553109	In the present study, we constructed a novel dual specific anti-tumor oncolytic adenovirus Ad-hTERT-E1a-HN by inserting NDV HN gene and hTERT promoter into a RAPAd.I adenovirus vector, as well as the control recombinant adenoviruses (Figure 1A).	('adenovirus', 'Species', '28285', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('hTERT', 'Gene', (136, 141))	('adenovirus', 'Species', '28285', (166, 176))	('hTERT', 'Gene', '7015', (94, 99))	('NDV', 'Species', '11176', (120, 123))	('hTERT', 'Gene', (94, 99))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (95, 106))	('hTERT', 'Gene', '7015', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('NDV HN gene', 'Gene', (120, 131))	('adenovirus', 'Species', '28285', (220, 230))	('inserting', 'Var', (110, 119))
312925	24553109	With the extension of infection times and the increase of the infective dose (a MOI of 1, 10 or 100), the inhibitory effects on EC-109 cells treated with Ad-CMV-E1a-HN and Ad-hTERTE1a-HN became more obvious than those with other recombinant adenoviruses.	('hTERT', 'Gene', (175, 180))	('inhibitory effects', 'MPA', (106, 124))	('EC-109', 'CellLine', 'CVCL:6898', (128, 134))	('Ad-CMV-E1a-HN', 'Var', (154, 167))	('hTERT', 'Gene', '7015', (175, 180))	('adenovirus', 'Species', '28285', (241, 251))
312926	24553109	In L02 cells, the inhibition was still obvious in Ad-CMV-E1a-HN-treated cells, compared with the slight inhibitory effect in the Ad-hTERT-E1a-HN-treated group.	('Ad-CMV-E1a-HN-treated', 'Var', (50, 71))	('hTERT', 'Gene', (132, 137))	('hTERT', 'Gene', '7015', (132, 137))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (133, 144))
312929	24553109	Several studies have shown that NDV can induce apoptosis in various cancer cell types by activating the mitochondrial death pathway (intrinsic pathway) and the death receptor pathway (extrinsic pathway), ultimately inducing caspase-dependent pathways in infected cells that lead to the biochemical and morphological changes characteristic of apoptosis.	('activating', 'Reg', (89, 99))	('caspase-dependent pathways', 'Pathway', (224, 250))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lead to', 'Reg', (274, 281))	('biochemical', 'MPA', (286, 297))	('apoptosis', 'Disease', (47, 56))	('death receptor pathway', 'Pathway', (160, 182))	('NDV', 'Var', (32, 35))	('mitochondrial death pathway', 'Pathway', (104, 131))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('inducing', 'Reg', (215, 223))	('NDV', 'Species', '11176', (32, 35))
312994	24553109	Each set contained eight groups (five mice per group), which were given either (1) saline; (2) Ad-mock; (3) Ad-CMV-HN; (4) Ad-hTERT-HN; (5) Ad-CMV-E1a; (6) Ad-hTERT-E1a; (7) Ad-CMV-E1a-HN; or (8) Ad-hTERT-E1a-HN.	('hTERT', 'Gene', (126, 131))	('TERT-E1a', 'CellLine', 'CVCL:V078', (200, 208))	('hTERT', 'Gene', '7015', (159, 164))	('TERT-E1a-HN', 'CellLine', 'CVCL:V078', (200, 211))	('mice', 'Species', '10090', (38, 42))	('hTERT', 'Gene', (199, 204))	('TERT-E1a', 'CellLine', 'CVCL:V078', (160, 168))	('saline', 'Chemical', 'MESH:D012965', (83, 89))	('hTERT', 'Gene', (159, 164))	('Ad-CMV-E1a', 'Var', (140, 150))	('Ad-CMV-E1a-HN', 'Var', (174, 187))	('hTERT', 'Gene', '7015', (126, 131))	('hTERT', 'Gene', '7015', (199, 204))
313066	23381956	The 5-year overall survival rate for esophageal cancer with MPC was relatively better than those without MPC (46.1% vs. 26.7%), although the difference did not reach statistical significance in univariate analysis (P = 0.09).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('MPC', 'Chemical', '-', (105, 108))	('better', 'PosReg', (79, 85))	('MPC', 'Chemical', '-', (60, 63))	('esophageal cancer', 'Disease', (37, 54))	('MPC', 'Var', (60, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
313122	23381956	The 5-year overall survival for esophageal cancer with MPC was relatively better than for those without MPC (46.1% vs. 26.7%), although the difference did not reach statistical significance (P = 0.09, Fig.	('better', 'PosReg', (74, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('MPC', 'Chemical', '-', (55, 58))	('MPC', 'Chemical', '-', (104, 107))	('MPC', 'Var', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('esophageal cancer', 'Disease', (32, 49))
313140	23381956	Furthermore, one surgical study showed that patients with MPC had a significantly better overall survival rate than those without MPC (P = 0.02).	('MPC', 'Var', (58, 61))	('patients', 'Species', '9606', (44, 52))	('better', 'PosReg', (82, 88))	('MPC', 'Chemical', '-', (130, 133))	('MPC', 'Chemical', '-', (58, 61))	('overall survival', 'CPA', (89, 105))
313142	23381956	One possible reason is that patients with MPC were significantly associated with an earlier stage of esophageal cancer than those without MPC as described above.	('MPC', 'Chemical', '-', (138, 141))	('MPC', 'Chemical', '-', (42, 45))	('MPC', 'Var', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('patients', 'Species', '9606', (28, 36))
313181	18844222	However, low serum PGI/II is usually a more accurate marker for this atrophy than PGI alone.	('low serum PGI', 'Phenotype', 'HP:0031817', (9, 22))	('low', 'Var', (9, 12))	('atrophy', 'Disease', (69, 76))	('PGI', 'Gene', (19, 22))	('PGI', 'Gene', (82, 85))	('PGI', 'Gene', '633', (19, 22))	('PGI', 'Gene', '633', (82, 85))	('atrophy', 'Disease', 'MESH:D001284', (69, 76))
313217	18844222	For a cutpoint of 100, for example, 56 (44.8%) of the case subjects and 119 (47.6%) of the control subjects had low PGI values, and the adjusted OR (95% CI) for the association between low PGI and ESD was 0.88 (0.55 - 1.39).	('PGI', 'Gene', '633', (189, 192))	('PGI', 'Gene', (116, 119))	('low', 'NegReg', (112, 115))	('PGI', 'Gene', (189, 192))	('low', 'Var', (185, 188))	('PGI', 'Gene', '633', (116, 119))	('ESD', 'Disease', (197, 200))
313279	33805904	Human MAIT cells express the TCR gene segment Valpha7.2 (also known as TRAV1-2) joined to Jalpha33 (also known as TRAJ33) and a restricted repertoire of TCRbeta chains.	('Human', 'Species', '9606', (0, 5))	('TCRbeta', 'Gene', '28695', (153, 160))	('TRAJ33', 'Gene', (114, 120))	('TRAV1-2', 'Gene', (71, 78))	('TCRbeta', 'Gene', (153, 160))	('Valpha7.2', 'Gene', (46, 55))	('TCR gene', 'Gene', (29, 37))	('Jalpha33', 'Var', (90, 98))	('TRAV1-2', 'Gene', '28692;28691', (71, 78))	('TRAJ33', 'Gene', '28722', (114, 120))
313280	33805904	Initial studies relied on antibodies specific for the Valpha7.2-Jalpha33 TCR and the CD3 co-receptor, with a combination of various surface proteins, such as CD161, CD26, CD218 (IL-18 receptor), and MDR1 for the identification of MAIT cells (Figure 1).	('CD161', 'Gene', (158, 163))	('CD26', 'Gene', '1803', (165, 169))	('CD161', 'Gene', '3820', (158, 163))	('MDR1', 'Gene', (199, 203))	('CD26', 'Gene', (165, 169))	('MDR1', 'Gene', '5243', (199, 203))	('IL-18', 'Gene', '3606', (178, 183))	('IL-18', 'Gene', (178, 183))	('CD218', 'Var', (171, 176))
313282	33805904	Most studies used a combination of Valpha7.2-Jalpha33, CD3, CD161, with only a handful using the MR1 tetramer for a definitive identification.	('Valpha7.2-Jalpha33', 'Var', (35, 53))	('CD161', 'Gene', '3820', (60, 65))	('CD3', 'Gene', (55, 58))	('CD161', 'Gene', (60, 65))	('tet', 'Chemical', 'MESH:C010349', (101, 104))
313307	33805904	Furthermore, a high Th1 to Th17 ratio has also been associated with a better prognosis for patients with colorectal cancer.	('high', 'Var', (15, 19))	('patients', 'Species', '9606', (91, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('Th1 to Th17 ratio', 'MPA', (20, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('colorectal cancer', 'Disease', (105, 122))
313341	33805904	Links have also been made between microbiome composition, antibiotic use, and the severity of esophageal cancers, suggesting that bacteria inhabiting the esophagus could impact the MAIT cell response to esophageal cancer cells.	('impact', 'NegReg', (170, 176))	('cancer', 'Disease', (214, 220))	('bacteria', 'Var', (130, 138))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('esophageal cancers', 'Disease', (94, 112))	('MAIT cell response to', 'CPA', (181, 202))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('esophageal cancers', 'Disease', 'MESH:D004938', (94, 112))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
313348	33805904	However, less double negative (DN) MAIT cells and PD-1+DN MAIT cells were found in these patients, and there was a positive association between high circulating PD-1+ DN MAIT cells and progression free survival (PFS).	('patients', 'Species', '9606', (89, 97))	('progression free survival', 'CPA', (185, 210))	('PD-1+ DN', 'Var', (161, 169))
313376	33805904	Metastases were reduced in MAIT cell-deficient MR1 knockout mice, and adoptive transfer of MAIT cells into MR1 knockouts increased lung metastases to levels similar to wild type mice, suggesting an MR1-independent mechanism.	('knockouts', 'Var', (111, 120))	('lung metastases', 'Disease', (131, 146))	('MR1', 'Gene', (47, 50))	('lung metastases', 'Disease', 'MESH:D009362', (131, 146))	('increased', 'PosReg', (121, 130))	('mice', 'Species', '10090', (178, 182))	('reduced', 'NegReg', (16, 23))	('Metastases', 'Disease', (0, 10))	('MR1', 'Gene', (107, 110))	('mice', 'Species', '10090', (60, 64))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))
313377	33805904	Notably, MR1 knockout mice have been shown to have alterations in other cell types, such as gammadelta T cells, and mice as a species have a different MAIT subset abundance profile compared to humans.	('mice', 'Species', '10090', (116, 120))	('alterations', 'Reg', (51, 62))	('MAIT subset abundance profile', 'MPA', (151, 180))	('humans', 'Species', '9606', (193, 199))	('knockout', 'Var', (13, 21))	('different', 'Reg', (141, 150))	('MR1', 'Gene', (9, 12))	('mice', 'Species', '10090', (22, 26))	('gammadelta', 'CPA', (92, 102))
313387	33805904	These results suggest that the PD-1 pathway may be involved in mediating MAIT cell dysfunction in certain cancers, and that, in addition to its canonical role in antitumor immunity, anti-PD-1 therapy may restore the expression of certain cytotoxic genes.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('cytotoxic genes', 'Gene', (238, 253))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('anti-PD-1', 'Var', (182, 191))	('tumor', 'Disease', (166, 171))	('expression', 'MPA', (216, 226))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('involved', 'Reg', (51, 59))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('restore', 'PosReg', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
313392	33805904	Furthermore, low levels of B-vitamin producing bacteria have been associated with higher risks of immunotherapy-related adverse events and less MAIT cell reconstitution in patients with blood disorders after a hematopoietic cell transplantation.	('immunotherapy-related adverse', 'Disease', (98, 127))	('blood disorders', 'Disease', (186, 201))	('less', 'NegReg', (139, 143))	('blood disorders', 'Disease', 'MESH:D007022', (186, 201))	('low', 'Var', (13, 16))	('patients', 'Species', '9606', (172, 180))
313397	33805904	As there is significant variation between individual's HLA gene loci, many patients cannot benefit from these treatments because of mismatching HLA alleles.	('HLA', 'Gene', (55, 58))	('patients', 'Species', '9606', (75, 83))	('mismatching', 'Var', (132, 143))
313496	31824776	Samples with VEGF-C expression had increased depth of invasion, lymphatic and lymph node metastasis, and worse TNM stage (all P < 0.001).	('increased', 'PosReg', (35, 44))	('TNM', 'Disease', (111, 114))	('depth of invasion', 'CPA', (45, 62))	('TNM', 'Disease', 'MESH:D009362', (111, 114))	('expression', 'Var', (20, 30))	('VEGF-C', 'Gene', '7424', (13, 19))	('VEGF-C', 'Gene', (13, 19))
313505	31824776	We then divided all samples into three subgroups: both expression, single expression, and negative expression of VEGF-C/MMP-9.	('MMP-9', 'Gene', (120, 125))	('VEGF-C', 'Gene', '7424', (113, 119))	('negative expression', 'NegReg', (90, 109))	('VEGF-C', 'Gene', (113, 119))	('MMP-9', 'Gene', '4318', (120, 125))	('single', 'Var', (67, 73))
313817	29533003	26 indicated that there was a 28% reduction in the risk of gastric cancer mortality with endoscopic screening, which has important implications for gastric cancer screening in rural Chinese areas.	('gastric cancer', 'Disease', (148, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('endoscopic screening', 'Var', (89, 109))	('reduction', 'NegReg', (34, 43))	('gastric cancer', 'Disease', (59, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))
313924	28253921	ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective The occurrence of more than 200 diseases, including cancer, can be attributed to alcohol drinking.	('cancer', 'Disease', (138, 144))	('polymorphism', 'Var', (6, 18))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('alcohol', 'Chemical', 'MESH:D000438', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('alcohol drinking', 'Phenotype', 'HP:0030955', (167, 183))	('ALDH2', 'Gene', (0, 5))	('cancers', 'Disease', (39, 46))	('alcohol', 'Chemical', 'MESH:D000438', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('ALDH2', 'Gene', '217', (0, 5))
313945	28253921	Table 1 summarizes the association between alcohol and alcohol-related cancers  The association between alcohol and head and neck cancer is one of the most studied and the results consistently showed an increased head and neck cancer risk associated with alcohol drinking.	('head and neck cancer', 'Phenotype', 'HP:0012288', (116, 136))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('head and neck cancer', 'Phenotype', 'HP:0012288', (213, 233))	('alcohol', 'Chemical', 'MESH:D000438', (43, 50))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('head and neck cancer', 'Disease', 'MESH:D006258', (116, 136))	('alcohol', 'Chemical', 'MESH:D000438', (255, 262))	('alcohol drinking', 'Phenotype', 'HP:0030955', (255, 271))	('head and neck cancer', 'Disease', 'MESH:D006258', (213, 233))	('alcohol', 'Chemical', 'MESH:D000438', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('alcohol', 'Chemical', 'MESH:D000438', (55, 62))	('alcohol drinking', 'Var', (255, 271))	('increased', 'PosReg', (203, 212))
313965	28253921	Individuals deficient in aldehyde dehydrogenase 2 (ALDH2), an enzyme that converts acetaldehyde, a carcinogenic metabolite of ethanol, to acetate, may have a higher risk of alcohol-related cancers.	('deficient', 'Var', (12, 21))	('carcinogenic', 'Disease', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('aldehyde dehydrogenase 2', 'Gene', '217', (25, 49))	('alcohol', 'Chemical', 'MESH:D000438', (173, 180))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('acetaldehyde', 'Chemical', 'MESH:D000079', (83, 95))	('aldehyde dehydrogenase 2', 'Gene', (25, 49))	('acetate', 'Chemical', 'MESH:D000085', (138, 145))	('ethanol', 'Chemical', 'MESH:D000431', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('ALDH2', 'Gene', (51, 56))	('carcinogenic', 'Disease', 'MESH:D063646', (99, 111))	('cancers', 'Disease', (189, 196))
313973	28253921	A striking genetic polymorphism that dramatically reduces ALDH2 enzyme activity and affects alcohol response is the variant ALDH2*2 allele.	('alcohol response', 'MPA', (92, 108))	('affects', 'Reg', (84, 91))	('alcohol response', 'Phenotype', 'HP:0030955', (92, 108))	('alcohol', 'Chemical', 'MESH:D000438', (92, 99))	('ALDH2', 'Protein', (58, 63))	('variant', 'Var', (116, 123))	('activity', 'MPA', (71, 79))	('reduces', 'NegReg', (50, 57))	('ALDH2*2', 'Gene', (124, 131))
313974	28253921	The variant ALDH2*2 allele is caused by a single point mutation (G to A) in exon 12, which leads to an amino acid substitution from glutamine to lysine (E487K).	('E487K', 'Var', (153, 158))	('lysine', 'Chemical', 'MESH:D008239', (145, 151))	('E487K', 'Mutation', 'rs671', (153, 158))	('glutamine', 'Chemical', 'MESH:D005973', (132, 141))	('caused by', 'Reg', (30, 39))	('leads to', 'Reg', (91, 99))	('ALDH2*2', 'Gene', (12, 19))
313975	28253921	The normal ALDH2*1 allele and the variant ALDH2*2 allele can be easily genotyped by the determination of single nucleotide polymorphism (SNP) rs671 from the human genome.	('ALDH2*2', 'Gene', (42, 49))	('rs671', 'Mutation', 'rs671', (142, 147))	('human', 'Species', '9606', (157, 162))	('variant', 'Var', (34, 41))
313976	28253921	Due to the tetrameric nature of the ALDH2 enzyme, the E487K mutation exhibits a dominant negative phenotype and affects both heterozygous and homozygous individuals who carry the variant allele.	('negative', 'NegReg', (89, 97))	('affects', 'Reg', (112, 119))	('E487K', 'Var', (54, 59))	('ALDH2', 'Gene', (36, 41))	('E487K', 'Mutation', 'rs671', (54, 59))
313978	28253921	Hence, the ALDH2*2 variant causes the well-known Asian Alcohol Flushing Syndrome which is characterized by facial flushing, palpitation, tachycardia, nausea, and unpleasant feelings when alcohol is consumed by these individuals.	('alcohol', 'Chemical', 'MESH:D000438', (187, 194))	('tachycardia', 'Disease', 'MESH:D013610', (137, 148))	('nausea', 'Disease', 'MESH:D009325', (150, 156))	('tachycardia', 'Disease', (137, 148))	('ALDH2*2', 'Gene', (11, 18))	('flushing', 'Phenotype', 'HP:0031284', (114, 122))	('Flushing', 'Phenotype', 'HP:0031284', (63, 71))	('variant', 'Var', (19, 26))	('Flushing Syndrome', 'Disease', 'MESH:D005483', (63, 80))	('causes', 'Reg', (27, 33))	('facial flushing', 'Disease', 'MESH:D005483', (107, 122))	('tachycardia', 'Phenotype', 'HP:0001649', (137, 148))	('Flushing Syndrome', 'Disease', (63, 80))	('Alcohol', 'Chemical', 'MESH:D000438', (55, 62))	('facial flushing', 'Disease', (107, 122))	('nausea', 'Phenotype', 'HP:0002018', (150, 156))	('palpitation', 'Phenotype', 'HP:0001962', (124, 135))	('nausea', 'Disease', (150, 156))
313981	28253921	Many studies have investigated the role of ALDH2 polymorphism and its interaction with alcohol consumption in the development of various cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('polymorphism', 'Var', (49, 61))	('men', 'Species', '9606', (121, 124))	('ALDH2', 'Gene', (43, 48))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('alcohol', 'Chemical', 'MESH:D000438', (87, 94))
313987	28253921	Overall, studies have indicated that ALDH2 polymorphism can modulate the association between alcohol drinking and head and neck cancer risk.	('ALDH2', 'Gene', (37, 42))	('alcohol', 'Chemical', 'MESH:D000438', (93, 100))	('modulate', 'Reg', (60, 68))	('association', 'Interaction', (73, 84))	('head and neck cancer', 'Phenotype', 'HP:0012288', (114, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('alcohol drinking', 'Phenotype', 'HP:0030955', (93, 109))	('polymorphism', 'Var', (43, 55))	('alcohol drinking', 'Disease', (93, 109))	('head and neck cancer', 'Disease', 'MESH:D006258', (114, 134))
313988	28253921	conducted a meta-analysis of 31 case-control studies and found that ALDH2*2/*2 was associated with a reduced risk of esophageal cancer (OR = 0.69, 95% CI: 0.48-0.98) while ALDH2*1/*2 was associated with an increased esophageal cancer risk (OR = 2.34, 95% CI: 1.75-3.13).	('esophageal cancer', 'Disease', (117, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (216, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('ALDH2*1/*2', 'Var', (172, 182))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('reduced', 'NegReg', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('esophageal cancer', 'Disease', (216, 233))	('ALDH2*2/*2', 'Var', (68, 78))
313990	28253921	reported that among alcohol drinkers, ALDH2*2/*2 was associated with an increased esophageal cancer risk (OR = 3.87, 95% CI: 1.67-8.96) compared to ALDH2*1/*1.	('ALDH2*2/*2', 'Var', (38, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (20, 36))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('alcohol', 'Chemical', 'MESH:D000438', (20, 27))	('esophageal cancer', 'Disease', (82, 99))
313994	28253921	Among the six studies that examined the interaction between ALDH2*2 and alcohol drinking on liver cancer risk, three found a synergistic interaction between ALDH2*2 allele and alcohol consumption to increase liver cancer risk, while three found no such interaction.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('liver cancer', 'Disease', (92, 104))	('alcohol', 'Chemical', 'MESH:D000438', (176, 183))	('liver cancer', 'Phenotype', 'HP:0002896', (208, 220))	('ALDH2*2', 'Gene', (157, 164))	('liver cancer', 'Disease', 'MESH:D006528', (208, 220))	('increase liver', 'Phenotype', 'HP:0002240', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('alcohol', 'Chemical', 'MESH:D000438', (72, 79))	('alcohol drinking', 'Phenotype', 'HP:0030955', (72, 88))	('increase liver cancer risk', 'Phenotype', 'HP:0001402', (199, 225))	('interaction', 'Interaction', (40, 51))	('allele', 'Var', (165, 171))	('increase', 'PosReg', (199, 207))	('liver cancer', 'Phenotype', 'HP:0002896', (92, 104))	('liver cancer', 'Disease', 'MESH:D006528', (92, 104))	('liver cancer', 'Disease', (208, 220))
313997	28253921	There is limited evidence regarding the association between ALDH2 polymorphism and risk of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('ALDH2', 'Gene', (60, 65))	('polymorphism', 'Var', (66, 78))	('association', 'Interaction', (40, 51))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
314001	28253921	Four studies, all from Japan, have investigated the association between ALDH2 polymorphism and colon cancer risk.	('investigated', 'Reg', (35, 47))	('colon cancer', 'Disease', 'MESH:D015179', (95, 107))	('colon cancer', 'Phenotype', 'HP:0003003', (95, 107))	('colon cancer', 'Disease', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ALDH2', 'Gene', (72, 77))	('polymorphism', 'Var', (78, 90))
314002	28253921	reported an increased risk of colon cancer (OR = 3.35, 95% CI: 1.51-7.45) associated with alcoholic carriers of ALDH2*2 allele compared to alcoholics with homozygous wild type.	('alcohol', 'Chemical', 'MESH:D000438', (139, 146))	('ALDH2*2', 'Gene', (112, 119))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('colon cancer', 'Disease', 'MESH:D015179', (30, 42))	('allele', 'Var', (120, 126))	('alcohol', 'Chemical', 'MESH:D000438', (90, 97))	('colon cancer', 'Disease', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
314010	28253921	However, influenced by social, cultural, and economic factors in the past few decades, such protection against alcohol dependence and alcohol abuse has gradually lost among the large populations of ALDH2*2 carriers.	('alcohol abuse', 'Phenotype', 'HP:0030955', (134, 147))	('alcohol dependence', 'Phenotype', 'HP:0030955', (111, 129))	('lost', 'NegReg', (162, 166))	('alcohol dependence and alcohol abuse', 'Disease', 'MESH:D000437', (111, 147))	('carriers', 'Var', (206, 214))	('ALDH2*2', 'Gene', (198, 205))
314016	28253921	The rapid and dangerous rise in alcohol consumption and dependence among ALDH2*2 carriers also underlines an urgent need for new public health policies and guidelines and active campaigns for public education and awareness in high ALDH2*2 prevalent countries.	('alcohol consumption and dependence', 'Disease', 'MESH:D000437', (32, 66))	('ALDH2*2', 'Gene', (73, 80))	('rise', 'PosReg', (24, 28))	('carriers', 'Var', (81, 89))
314017	28253921	Given the strong association between ALDH2 polymorphism and certain alcohol-related cancers, screening for ALDH2*2 allele may have several public health implications, including: 1) Identification of individuals at high risk of developing alcohol-related cancers; 2) Incorporation of ALDH2 polymorphism screening into alcohol cessation program for promoting alcohol abstinence or reducing alcohol consumption; 3) Using ALDH2 polymorphism as a prognostic indicator for alcohol-related cancers; 4) Targeting ALDH2 for chemoprevention; and 5) Setting guidelines for alcohol consumption among ALDH2 deficient individuals.	('alcohol', 'Chemical', 'MESH:D000438', (388, 395))	('alcohol', 'Chemical', 'MESH:D000438', (357, 364))	('cancers', 'Disease', 'MESH:D009369', (483, 490))	('alcohol', 'Chemical', 'MESH:D000438', (467, 474))	('alcohol', 'Chemical', 'MESH:D000438', (317, 324))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('alcohol abstinence', 'Disease', (357, 375))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('alcohol', 'Chemical', 'MESH:D000438', (562, 569))	('alcohol abstinence', 'Disease', 'MESH:D009357', (357, 375))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('polymorphism', 'Var', (43, 55))	('cancers', 'Disease', (254, 261))	('ALDH2', 'Gene', (588, 593))	('alcohol', 'Chemical', 'MESH:D000438', (68, 75))	('cancers', 'Phenotype', 'HP:0002664', (483, 490))	('cancers', 'Disease', (483, 490))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('alcohol', 'Chemical', 'MESH:D000438', (238, 245))	('cancer', 'Phenotype', 'HP:0002664', (483, 489))	('ALDH2', 'Gene', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('deficient', 'NegReg', (594, 603))	('cancers', 'Disease', (84, 91))	('ALDH2', 'Gene', (505, 510))	('cancers', 'Disease', 'MESH:D009369', (254, 261))
314025	28253921	The model included information on alcohol drinking, ALDH2 genotype or facial flushing after alcohol consumption, which is a physical symptom strongly associated with ALDH2*2 allele, cigarette smoking, and consumption of vegetables and fruits.	('associated', 'Reg', (150, 160))	('alcohol', 'Chemical', 'MESH:D000438', (92, 99))	('flushing', 'Phenotype', 'HP:0031284', (77, 85))	('alcohol drinking', 'Phenotype', 'HP:0030955', (34, 50))	('facial flushing', 'Disease', 'MESH:D005483', (70, 85))	('allele', 'Var', (174, 180))	('alcohol', 'Chemical', 'MESH:D000438', (34, 41))	('ALDH2*2', 'Gene', (166, 173))	('ALDH2', 'Gene', (52, 57))	('genotype', 'Var', (58, 66))	('facial flushing after alcohol', 'Phenotype', 'HP:0001033', (70, 99))	('facial flushing', 'Disease', (70, 85))
314027	28253921	built a risk prediction model of UADT cancer that incorporated information on sex, age, alcohol drinking, cigarette smoking, and ALDH2 genotype and reported that the risk model had a good discriminative ability with an area under the curve of more than 0.8.	('UADT cancer', 'Disease', 'MESH:D006258', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('genotype', 'Var', (135, 143))	('alcohol drinking', 'Phenotype', 'HP:0030955', (88, 104))	('UADT cancer', 'Disease', (33, 44))	('ALDH2', 'Gene', (129, 134))	('alcohol', 'Chemical', 'MESH:D000438', (88, 95))
314030	28253921	For other alcohol-related cancers, including liver cancer, breast cancer, and colorectal cancer, for which the evidence for the involvement of ALDH2 is more limited, more studies are needed to evaluate the interaction between ALDH2 polymorphism and alcohol drinking on the risk of these alcohol-related cancers.	('liver cancer', 'Phenotype', 'HP:0002896', (45, 57))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('interaction', 'Interaction', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('alcohol', 'Chemical', 'MESH:D000438', (287, 294))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('liver cancer', 'Disease', (45, 57))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancers', 'Phenotype', 'HP:0002664', (303, 310))	('cancers', 'Disease', (303, 310))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('colorectal cancer', 'Disease', (78, 95))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('breast cancer', 'Disease', (59, 72))	('men', 'Species', '9606', (135, 138))	('polymorphism', 'Var', (232, 244))	('cancers', 'Disease', 'MESH:D009369', (303, 310))	('alcohol', 'Chemical', 'MESH:D000438', (249, 256))	('alcohol drinking', 'Phenotype', 'HP:0030955', (249, 265))	('rectal cancer', 'Phenotype', 'HP:0100743', (82, 95))	('liver cancer', 'Disease', 'MESH:D006528', (45, 57))	('ALDH2', 'Gene', (226, 231))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('alcohol', 'Chemical', 'MESH:D000438', (10, 17))
314031	28253921	It is possible that the knowledge regarding ALDH2 genotype and the associated disease risk may motivate individuals to reduce alcohol consumption.	('genotype', 'Var', (50, 58))	('ALDH2', 'Gene', (44, 49))	('reduce', 'NegReg', (119, 125))	('alcohol', 'Chemical', 'MESH:D000438', (126, 133))	('alcohol consumption', 'MPA', (126, 145))
314032	28253921	Individuals with ALDH2*1/*1 received risk information on alcohol dependence while individuals with ALDH2*1/*2 received risk information on alcohol-related cancers.	('alcohol', 'Chemical', 'MESH:D000438', (139, 146))	('alcohol', 'Chemical', 'MESH:D000438', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ALDH2*1/*1', 'Var', (17, 27))	('ALDH2', 'Gene', (99, 104))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('alcohol dependence', 'Phenotype', 'HP:0030955', (57, 75))	('alcohol dependence', 'Disease', (57, 75))	('cancers', 'Disease', (155, 162))
314034	28253921	This suggested that it may be feasible to incorporate information on ALDH2 genotype and the associated disease risk into an alcohol cessation program to effectively reduce the consumption of alcohol.	('consumption of alcohol', 'MPA', (176, 198))	('genotype', 'Var', (75, 83))	('reduce', 'NegReg', (165, 171))	('alcohol', 'Chemical', 'MESH:D000438', (124, 131))	('ALDH2', 'Gene', (69, 74))	('alcohol', 'Chemical', 'MESH:D000438', (191, 198))
314035	28253921	More studies are needed to determine whether genetic testing of ALDH2 will achieve a long lasting effect for reducing the consumption of alcohol.	('ALDH2', 'Gene', (64, 69))	('alcohol', 'Chemical', 'MESH:D000438', (137, 144))	('genetic testing', 'Var', (45, 60))	('reducing', 'NegReg', (109, 117))	('consumption of alcohol', 'MPA', (122, 144))
314037	28253921	ALDH2 polymorphism may be used to predict the survival, recurrence, and development of second-primary or other alcohol-related cancers for patients with alcohol-related cancers, particularly for esophageal cancer and head and neck cancer.	('polymorphism', 'Var', (6, 18))	('cancers', 'Disease', (169, 176))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('alcohol', 'Chemical', 'MESH:D000438', (111, 118))	('esophageal cancer', 'Disease', (195, 212))	('ALDH2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('men', 'Species', '9606', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('patients', 'Species', '9606', (139, 147))	('head and neck cancer', 'Phenotype', 'HP:0012288', (217, 237))	('alcohol', 'Chemical', 'MESH:D000438', (153, 160))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('head and neck cancer', 'Disease', 'MESH:D006258', (217, 237))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
314041	28253921	conducted a follow-up study of 100 alcoholic men diagnosed with esophageal squamous cell carcinoma and observed that during the follow-period, individuals with ALDH2*1/*2 were at higher risk of developing metachronous squamous cell carcinoma in the esophagus, oral cavity, pharynx and larynx (age-adjusted hazard ratio = 3.38, 95% CI: 1.45-7.85; alcohol-adjusted hazard ratio = 4.27, 95% CI: 1.42-12.89) compared to individuals with ALDH2*1/*1.	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('men', 'Species', '9606', (45, 48))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (218, 241))	('esophageal squamous cell carcinoma', 'Disease', (64, 98))	('carcinoma in the esophagus', 'Phenotype', 'HP:0011459', (232, 258))	('alcohol', 'Chemical', 'MESH:D000438', (346, 353))	('developing', 'PosReg', (194, 204))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (218, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('squamous cell carcinoma', 'Disease', (218, 241))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('alcohol', 'Chemical', 'MESH:D000438', (35, 42))	('ALDH2*1/*2', 'Var', (160, 170))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (64, 98))
314043	28253921	However, once such role of ALDH2*2 has been proven, the follow-up schedule and methods for alcohol-related cancer patients may be tailored according to their ALDH2 genotypes to increase survival and improve early detection of cancer recurrence or second primary cancer.	('cancer', 'Disease', (262, 268))	('alcohol', 'Chemical', 'MESH:D000438', (91, 98))	('genotypes', 'Var', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('improve', 'PosReg', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('increase', 'PosReg', (177, 185))	('ALDH2', 'Gene', (158, 163))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('survival', 'CPA', (186, 194))	('cancer', 'Disease', (107, 113))	('early detection', 'CPA', (207, 222))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
314048	28253921	For example, in a study by Lee et al., compared to never drinkers with ALDH2*1/*1, drinking < 30 g of alcohol per day was associated with a 2.2 times increase in esophageal cancer risk for those with ALDH2*1/*1, but the risk increased by 14.5 times and 17.3 times, respectively, for those with ALDH2*1/*2 and ALDH2*2/*2.	('esophageal cancer', 'Disease', (162, 179))	('alcohol', 'Chemical', 'MESH:D000438', (102, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('ALDH2*1/*1', 'Var', (200, 210))
314054	28253921	Considering the carcinogenicity of acetaldehyde and the significantly increased risk for head and neck cancer, esophageal cancer, and other cancers for ALDH2*2 variant carriers, implementation of chemopreventive strategies may be a worthwhile effort for specific high-risk groups, such as ALDH2*2 individuals who are heavy drinkers or smokers or industrial workers who have a higher acetaldehyde exposure burden.	('head and neck cancer', 'Disease', 'MESH:D006258', (89, 109))	('carriers', 'Var', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('men', 'Species', '9606', (183, 186))	('acetaldehyde', 'Chemical', 'MESH:D000079', (35, 47))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('ALDH2*2', 'Gene', (289, 296))	('carcinogenic', 'Disease', (16, 28))	('ALDH2*2', 'Gene', (152, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('carcinogenic', 'Disease', 'MESH:D063646', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('variant carriers', 'Var', (160, 176))	('acetaldehyde', 'Chemical', 'MESH:D000079', (383, 395))	('head and neck cancer', 'Phenotype', 'HP:0012288', (89, 109))	('esophageal cancer', 'Disease', (111, 128))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
314059	28253921	One of the unique features of Alda-1 is that the compound not only increases the catalytic activity of the wild type ALDH2*1 enzyme, but can also correct the defect of the mutant ALDH2*2 enzyme.	('mutant', 'Var', (172, 178))	('defect', 'MPA', (158, 164))	('ALDH2*2', 'Gene', (179, 186))	('catalytic activity', 'MPA', (81, 99))	('Alda-1', 'Chemical', '-', (30, 36))	('increases', 'PosReg', (67, 76))	('ALDH2*1', 'Gene', (117, 124))	('correct', 'Reg', (146, 153))
314082	28223834	The patients with high expression of TGR5 exhibited significantly worse overall survival compared to the patients with nonhigh expression.	('patients', 'Species', '9606', (105, 113))	('overall survival', 'MPA', (72, 88))	('worse', 'NegReg', (66, 71))	('TGR5', 'Gene', (37, 41))	('patients', 'Species', '9606', (4, 12))	('high expression', 'Var', (18, 33))
314107	28223834	VDR polymorphisms are reported to influence the development of various types of cancers, such as breast, liver, prostate, brain, and colon.	('colon', 'Disease', (133, 138))	('VDR', 'Gene', '7421', (0, 3))	('liver', 'Disease', (105, 110))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('prostate', 'Disease', (112, 120))	('colon', 'Disease', 'MESH:D015179', (133, 138))	('breast', 'Disease', (97, 103))	('brain', 'Disease', (122, 127))	('polymorphisms', 'Var', (4, 17))	('influence', 'Reg', (34, 43))	('VDR', 'Gene', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
314127	28223834	A Kaplan-Meier survival estimator with a log-rank test was used to compare the patient survival rates between the TGR5 high-expression/amplification group and the TGR5 nonhigh expression/nonamplification group.	('high-expression/amplification', 'Var', (119, 148))	('TGR5', 'Gene', (114, 118))	('patient', 'Species', '9606', (79, 86))
314136	28223834	In contrast to the significant association between the survival time and TGR5 high expression previously described (p=0.0432), none of the other clinicopathologic characteristics, including age, gender, TNM staging, or differentiation, were significantly associated with TGR5 high expression (Table 3).	('high expression', 'Var', (276, 291))	('TNM', 'Gene', '10178', (203, 206))	('associated', 'Reg', (255, 265))	('TNM', 'Gene', (203, 206))	('TGR5', 'Gene', (271, 275))
314142	28223834	Using high density copy number microarrays, we analyzed 116 EAC specimens and identified TRG 5 amplification in 12.7% (14/116) of the cases.	('amplification', 'Var', (95, 108))	('TRG 5', 'Gene', (89, 94))	('TRG 5', 'Gene', '7198', (89, 94))
314145	28223834	The patients with TGR5 high expression exhibited significantly worse overall survival compared to the patients with nonhigh expression.	('overall survival', 'MPA', (69, 85))	('high expression', 'Var', (23, 38))	('worse', 'NegReg', (63, 68))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (4, 12))	('TGR5', 'Gene', (18, 22))
314164	28223834	In the stomach, activation of TGR5 antagonizes gastric cancer proliferation and migration in part by inhibiting STAT3 signaling and inhibits the gastric inflammation in part by antagonizing NK-kappaB signaling.	('antagonizing', 'NegReg', (177, 189))	('antagonizes', 'NegReg', (35, 46))	('gastric cancer', 'Disease', (47, 61))	('migration', 'CPA', (80, 89))	('STAT3', 'Gene', '6774', (112, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('NK-kappaB signaling', 'MPA', (190, 209))	('inhibits', 'NegReg', (132, 140))	('gastric inflammation', 'Disease', 'MESH:D007249', (145, 165))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('STAT3', 'Gene', (112, 117))	('TGR5', 'Gene', (30, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('gastric inflammation', 'Phenotype', 'HP:0005263', (145, 165))	('activation', 'Var', (16, 26))	('gastric inflammation', 'Disease', (145, 165))	('inhibiting', 'NegReg', (101, 111))
314170	28223834	In colorectal cancer and pancreatic ductal adenocarcinoma cell lines, RNA interference-mediated silencing of TGR5 inhibited DCA-induced EGFR, mitogen-activated protein kinase (MARK), and STAT3 signaling, blunted cyclin D1 expression and cell-cycle progression, which support that TGR5 may play an important role in gastrointestinal carcinogenesis.	('silencing', 'Var', (96, 105))	('colorectal cancer', 'Disease', (3, 20))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (25, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('gastrointestinal carcinogenesis', 'Disease', (315, 346))	('cyclin D1', 'Gene', (212, 221))	('pancreatic ductal adenocarcinoma', 'Disease', (25, 57))	('RNA interference-mediated', 'MPA', (70, 95))	('expression', 'MPA', (222, 232))	('EGFR', 'Gene', (136, 140))	('inhibited', 'NegReg', (114, 123))	('blunted', 'NegReg', (204, 211))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('STAT3', 'Gene', (187, 192))	('gastrointestinal carcinogenesis', 'Disease', 'MESH:D063646', (315, 346))	('cyclin D1', 'Gene', '595', (212, 221))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (25, 57))	('DCA', 'Chemical', '-', (124, 127))	('STAT3', 'Gene', '6774', (187, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TGR5', 'Gene', (109, 113))	('cell-cycle progression', 'CPA', (237, 259))	('EGFR', 'Gene', '1956', (136, 140))
314173	28223834	The amplification of the VDR gene in EAC detected by high resolution DNA microarray demonstrated the association with a worse prognosis; however, the high expression of VDR protein did not exhibit the association.	('VDR', 'Gene', (169, 172))	('VDR', 'Gene', '7421', (25, 28))	('VDR', 'Gene', '7421', (169, 172))	('amplification', 'Var', (4, 17))	('VDR', 'Gene', (25, 28))
314326	30159830	The pathological diagnosis was esophageal cancer (pT1bN0M0 pStage I).	('esophageal cancer', 'Disease', (31, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('pT1bN0M0 pStage', 'Var', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
314397	28542116	The prevalence of hepatic encephalopathy was higher in patients with spontaneous splenorenal shunt than in those without (18.2% vs. 4.3%), but the difference between them was not statistically significant (p=0.062).	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (18, 40))	('patients', 'Species', '9606', (55, 63))	('spontaneous splenorenal shunt', 'Var', (69, 98))	('encephalopathy', 'Phenotype', 'HP:0001298', (26, 40))	('higher', 'PosReg', (45, 51))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (18, 40))	('hepatic encephalopathy', 'Disease', (18, 40))
314402	28542116	Patients with spontaneous splenorenal shunt had significantly higher Child-Pugh (p=0.002) and MELD (p=0.017) scores than those without spontaneous splenorenal shunt, and the proportion of Child-Pugh class was significantly different between them (p=0.001).	('Child', 'Species', '9606', (188, 193))	('Child', 'Species', '9606', (69, 74))	('spontaneous splenorenal shunt', 'Var', (14, 43))	('Child-Pugh', 'CPA', (69, 79))	('higher', 'PosReg', (62, 68))	('Patients', 'Species', '9606', (0, 8))	('MELD', 'CPA', (94, 98))
314408	28542116	A major finding of our study was that the presence of spontaneous splenorenal shunt was associated with worse liver function (i.e., higher Child-Pugh and MELD scores) in liver cirrhosis.	('liver cirrhosis', 'Disease', (170, 185))	('higher', 'PosReg', (132, 138))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (170, 185))	('worse liver function', 'Phenotype', 'HP:0001410', (104, 124))	('liver function', 'MPA', (110, 124))	('liver cirrhosis', 'Disease', 'MESH:D008103', (170, 185))	('cirrhosis', 'Phenotype', 'HP:0001394', (176, 185))	('Child-Pugh', 'CPA', (139, 149))	('Child', 'Species', '9606', (139, 144))	('presence', 'Var', (42, 50))
314410	28542116	In addition, we should acknowledge that cirrhotic patients with spontaneous splenorenal shunt had higher total bilirubin, creatinine, and international normalized ratio and higher prevalence of hepatic encephalopathy and ascites.	('ascites', 'Disease', 'MESH:D001201', (221, 228))	('spontaneous splenorenal shunt', 'Var', (64, 93))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (194, 216))	('international normalized ratio', 'MPA', (138, 168))	('hepatic encephalopathy', 'Disease', (194, 216))	('patients', 'Species', '9606', (50, 58))	('ascites', 'Phenotype', 'HP:0001541', (221, 228))	('total bilirubin', 'MPA', (105, 120))	('encephalopathy', 'Phenotype', 'HP:0001298', (202, 216))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (194, 216))	('bilirubin', 'Chemical', 'MESH:D001663', (111, 120))	('higher', 'PosReg', (98, 104))	('higher total bilirubin', 'Phenotype', 'HP:0003573', (98, 120))	('creatinine', 'MPA', (122, 132))	('ascites', 'Disease', (221, 228))	('creatinine', 'Chemical', 'MESH:D003404', (122, 132))	('higher', 'PosReg', (173, 179))
314414	28542116	If it is true that the occurrence of spontaneous splenorenal shunt results in the deterioration of liver function, the potential mechanism may be as follows: hepatic perfusion is largely reduced in patients with spontaneous splenorenal shunt, thereby leading to the liver function abnormality.	('hepatic perfusion', 'MPA', (158, 175))	('patients', 'Species', '9606', (198, 206))	('deterioration of liver function', 'Phenotype', 'HP:0001410', (82, 113))	('spontaneous splenorenal shunt', 'Var', (212, 241))	('liver function abnormality', 'Disease', (266, 292))	('reduced', 'NegReg', (187, 194))	('liver function abnormality', 'Phenotype', 'HP:0002910', (266, 292))	('leading to', 'Reg', (251, 261))	('deterioration', 'MPA', (82, 95))	('liver function abnormality', 'Disease', 'MESH:D056486', (266, 292))	('liver function', 'MPA', (99, 113))
314431	27785069	Influence of MDM2 polymorphisms on squamous cell carcinoma susceptibility: a meta-analysis Controversial associations between single-nucleotide polymorphisms (rs2279744, rs937283, rs3730485) of the MDM2 gene and the etiology of squamous cell carcinomas (SCCs) have been reported.	('rs2279744', 'Mutation', 'rs2279744', (159, 168))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 58))	('MDM2', 'Gene', '4193', (13, 17))	('SCCs', 'Phenotype', 'HP:0002860', (254, 258))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (228, 252))	('associations', 'Interaction', (105, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (228, 251))	('squamous cell carcinoma', 'Disease', (35, 58))	('SCC', 'Phenotype', 'HP:0002860', (254, 257))	('squamous cell carcinomas', 'Disease', (228, 252))	('rs937283', 'Var', (170, 178))	('rs937283', 'Mutation', 'rs937283', (170, 178))	('SCC', 'Gene', '6317', (254, 257))	('rs2279744', 'Var', (159, 168))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (228, 251))	('rs3730485', 'Mutation', 'rs3730485', (180, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('MDM2', 'Gene', (198, 202))	('SCC', 'Gene', (254, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('MDM2', 'Gene', (13, 17))	('rs3730485', 'Var', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (242, 252))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (228, 252))	('MDM2', 'Gene', '4193', (198, 202))
314432	27785069	We systematically reviewed the available data and conducted an updated meta-analysis to evaluate the genetic effect of MDM2 polymorphisms in SCC susceptibility, using Stata/SE 12.0 software.	('SCC', 'Gene', (141, 144))	('MDM2', 'Gene', (119, 123))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('SCC', 'Gene', '6317', (141, 144))	('polymorphisms', 'Var', (124, 137))
314434	27785069	Overall, compared with the control group, a significantly increased SCC risk was observed for the MDM2 rs2279744 polymorphism in the Asian population (test of association: odds ratio [OR] 1.12, P=0.027 for G vs T; OR 1.26, P=0.016 for GG vs TT; OR 1.25, P<0.001 for GG vs TT + TG; and OR 1.08, P=0.023 for carrier G vs T).	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (68, 71))	('increased', 'PosReg', (58, 67))	('rs2279744', 'Var', (103, 112))	('MDM2', 'Gene', (98, 102))	('TG', 'Chemical', '-', (277, 279))	('SCC', 'Gene', (68, 71))	('rs2279744', 'Mutation', 'rs2279744', (103, 112))
314437	27785069	However, no significant difference between the control and case groups was obtained for MDM2 rs937283 or rs3730485 under any genetic model (all P>0.05).	('rs937283', 'Mutation', 'rs937283', (93, 101))	('MDM2', 'Gene', (88, 92))	('rs3730485', 'Mutation', 'rs3730485', (105, 114))	('rs3730485', 'Var', (105, 114))	('rs937283', 'Var', (93, 101))
314438	27785069	Our results highlight a positive association between the GG genotype of MDM2 rs2279744 polymorphism and an increased risk of esophageal SCC in the Asian population, which needs to be clarified by more large-scale studies.	('SCC', 'Gene', (136, 139))	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('polymorphism', 'Var', (87, 99))	('rs2279744', 'Mutation', 'rs2279744', (77, 86))	('SCC', 'Gene', '6317', (136, 139))	('rs2279744 polymorphism', 'Var', (77, 99))	('MDM2', 'Gene', (72, 76))
314440	27785069	The abnormal expression of the MDM2/TP53 genes is linked to carcinogenesis or malignant transformation.	('carcinogenesis', 'Disease', 'MESH:D063646', (60, 74))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('TP53', 'Gene', '7157', (36, 40))	('linked', 'Reg', (50, 56))	('carcinogenesis', 'Disease', (60, 74))	('malignant transformation', 'CPA', (78, 102))	('TP53', 'Gene', (36, 40))
314441	27785069	The SNPs of rs2279744 (T309G or SNP309), rs3730485 (del1518+/-) and rs937283 (A2164G), have been identified in the human MDM2 gene.	('T309G', 'Mutation', 'rs2279744', (23, 28))	('rs3730485 (del1518+/-', 'Var', (41, 62))	('rs2279744', 'Mutation', 'rs2279744', (12, 21))	('del1518', 'Mutation', 'c.del1518', (52, 59))	('human', 'Species', '9606', (115, 120))	('A2164G', 'Mutation', 'rs937283', (78, 84))	('rs937283 (A2164G', 'Var', (68, 84))	('rs3730485', 'Mutation', 'rs3730485', (41, 50))	('rs937283', 'Mutation', 'rs937283', (68, 76))	('MDM2', 'Gene', (121, 125))
314442	27785069	Previous reports have shown that MDM2 polymorphisms are associated with susceptibility to various clinical diseases, such as bladder cancer, hepatocellular carcinoma, myelodysplastic syndromes, and leukemia.	('MDM2', 'Gene', (33, 37))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (141, 165))	('leukemia', 'Phenotype', 'HP:0001909', (198, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('hepatocellular carcinoma', 'Disease', (141, 165))	('leukemia', 'Disease', 'MESH:D007938', (198, 206))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (141, 165))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (167, 192))	('myelodysplastic syndromes', 'Disease', (167, 192))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (167, 192))	('polymorphisms', 'Var', (38, 51))	('associated', 'Reg', (56, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('susceptibility', 'Reg', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('leukemia', 'Disease', (198, 206))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))
314445	27785069	The different effects of the genetic mutations within MDM2 have been reported to be related to the carcinogenesis of specific SCC types.	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('MDM2', 'Gene', (54, 58))	('related', 'Reg', (84, 91))	('genetic mutations', 'Var', (29, 46))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('SCC', 'Gene', '6317', (126, 129))	('carcinogenesis', 'Disease', (99, 113))	('SCC', 'Gene', (126, 129))
314446	27785069	For example, a lower plasma MDM2 level was observed in laryngeal SCC patients with the GT genotype of MDM2 rs2279744 than the TT genotype.	('plasma MDM2 level', 'MPA', (21, 38))	('SCC', 'Gene', (65, 68))	('MDM2', 'Gene', (102, 106))	('rs2279744', 'Var', (107, 116))	('patients', 'Species', '9606', (69, 77))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('lower', 'NegReg', (15, 20))	('rs2279744', 'Mutation', 'rs2279744', (107, 116))
314447	27785069	The prevalence of MDM2 rs2279744 might be involved in OSCC onset, rather than increased OSCC risks.	('SCC', 'Gene', '6317', (89, 92))	('SCC', 'Gene', (55, 58))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('involved', 'Reg', (42, 50))	('rs2279744', 'Mutation', 'rs2279744', (23, 32))	('SCC', 'Gene', '6317', (55, 58))	('MDM2', 'Gene', (18, 22))	('rs2279744', 'Var', (23, 32))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
314448	27785069	Although several previous meta-analyses on the correlation between MDM2 rs2279744 polymorphism and the risks of HNSCC, OSCC, or ESCC have been reported, another systematic evaluation with enlarged statistical power is still meaningful.	('rs2279744', 'Mutation', 'rs2279744', (72, 81))	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('SCC', 'Gene', '6317', (129, 132))	('rs2279744 polymorphism', 'Var', (72, 94))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('MDM2', 'Gene', (67, 71))	('SCC', 'Gene', '6317', (120, 123))	('SCC', 'Gene', (114, 117))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('polymorphism', 'Var', (82, 94))	('SCC', 'Gene', (129, 132))	('SCC', 'Gene', (120, 123))
314449	27785069	Moreover, the meta-analyses of the association between MDM2 rs937283 and rs3730485 polymorphisms and SCC risks, or between the MDM2 rs2279744 polymorphism and other SCC types, such as SSCC and CSCC, have not been reported yet.	('SCC', 'Gene', (165, 168))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('rs2279744', 'Var', (132, 141))	('SCC', 'Gene', (101, 104))	('rs3730485', 'Mutation', 'rs3730485', (73, 82))	('SCC', 'Gene', '6317', (194, 197))	('rs937283', 'Var', (60, 68))	('rs3730485', 'Var', (73, 82))	('SCC', 'Gene', '6317', (185, 188))	('rs937283', 'Mutation', 'rs937283', (60, 68))	('SCC', 'Gene', (194, 197))	('SCC', 'Gene', (185, 188))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('rs2279744', 'Mutation', 'rs2279744', (132, 141))	('MDM2', 'Gene', (127, 131))	('SSCC', 'Phenotype', 'HP:0002860', (184, 188))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('MDM2', 'Gene', (55, 59))	('SCC', 'Gene', '6317', (165, 168))	('SCC', 'Phenotype', 'HP:0002860', (194, 197))	('SCC', 'Gene', '6317', (101, 104))
314450	27785069	It was thus worthwhile carrying out an updated systematic review and meta-analysis, in order to reassess the genetic relationship between common MDM2 polymorphisms (rs2279744, rs937283, and rs3730485) and the overall risks of SCC.	('MDM2', 'Gene', (145, 149))	('SCC', 'Gene', (226, 229))	('SCC', 'Phenotype', 'HP:0002860', (226, 229))	('rs937283', 'Mutation', 'rs937283', (176, 184))	('SCC', 'Gene', '6317', (226, 229))	('rs3730485', 'Var', (190, 199))	('rs2279744', 'Mutation', 'rs2279744', (165, 174))	('rs3730485', 'Mutation', 'rs3730485', (190, 199))	('rs937283', 'Var', (176, 184))	('rs2279744', 'Var', (165, 174))
314451	27785069	The key terms were as follows: mouse double minute 2 homolog; proto-oncogene proteins c-mdm2; MDM2; MDM2 proto-oncogene, E3 ubiquitin protein ligase; human homolog of mouse double minute 2; murine double minute 2; polymorphism; mutation; SNP; single nucleotide polymorphism; T309G; rs2279744; A2164G; rs937283; del1518; rs3730485; G285C; rs117039649; squamous cell carcinoma; carcinoma, squamous cell; and SCC.	('murine', 'Species', '10090', (190, 196))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (351, 374))	('rs937283', 'Mutation', 'rs937283', (301, 309))	('rs3730485', 'Mutation', 'rs3730485', (320, 329))	('T309G', 'Mutation', 'rs2279744', (275, 280))	('SCC', 'Phenotype', 'HP:0002860', (406, 409))	('carcinoma', 'Disease', 'MESH:D002277', (376, 385))	('mouse', 'Species', '10090', (167, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (365, 374))	('squamous cell carcinoma', 'Disease', (351, 374))	('A2164G', 'Mutation', 'rs937283', (293, 299))	('mouse', 'Species', '10090', (31, 36))	('squamous cell', 'Disease', (387, 400))	('carcinoma', 'Disease', (365, 374))	('rs117039649', 'Var', (338, 349))	('A2164G', 'Var', (293, 299))	('mdm2', 'Gene', '4193', (88, 92))	('rs2279744', 'Mutation', 'rs2279744', (282, 291))	('SCC', 'Gene', '6317', (406, 409))	('human', 'Species', '9606', (150, 155))	('G285C', 'Mutation', 'rs117039649', (331, 336))	('SCC', 'Gene', (406, 409))	('del1518', 'Mutation', 'c.del1518', (311, 318))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (351, 374))	('carcinoma', 'Disease', 'MESH:D002277', (365, 374))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('carcinoma', 'Disease', (376, 385))	('rs937283; del1518; rs3730485; G285C; rs117039649', 'Var', (301, 349))	('single nucleotide polymorphism; T309G; rs2279744', 'Var', (243, 291))	('mdm2', 'Gene', (88, 92))	('rs117039649', 'Mutation', 'rs117039649', (338, 349))
314453	27785069	Eligible case-control studies needed to be linked to SCC risks and contain data on individual genotype numbers of MDM2 rs2279744, rs937283, and rs3730485 polymorphisms.	('MDM2', 'Gene', (114, 118))	('rs2279744', 'Var', (119, 128))	('rs3730485', 'Var', (144, 153))	('SCC', 'Gene', '6317', (53, 56))	('rs937283', 'Var', (130, 138))	('rs3730485', 'Mutation', 'rs3730485', (144, 153))	('SCC', 'Gene', (53, 56))	('rs937283', 'Mutation', 'rs937283', (130, 138))	('rs2279744', 'Mutation', 'rs2279744', (119, 128))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))
314458	27785069	A total of 25 case-control studies were enrolled for the meta-analysis of MDM2 rs2279744 and risks of SCC.	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('rs2279744', 'Var', (79, 88))	('SCC', 'Gene', '6317', (102, 105))	('MDM2', 'Gene', (74, 78))	('SCC', 'Gene', (102, 105))	('rs2279744', 'Mutation', 'rs2279744', (79, 88))
314459	27785069	As shown in Table 2, the results (G vs T, I2=70.0%, P<0.001; GG vs TT, I2=59.1%, P<0.001; TG vs TT, I2=72.9%, P<0.001; TG + GG vs TT, I2=73.7%, P<0.001; GG vs TT + TG, I2=36.3%, P=0.04; carrier G vs T, I2=31.5%, P=0.068) suggested that between-study heterogeneity existed for MDM2 rs2279744.	('MDM2', 'Gene', (276, 280))	('TG', 'Chemical', '-', (90, 92))	('rs2279744', 'Mutation', 'rs2279744', (281, 290))	('TG', 'Chemical', '-', (119, 121))	('TG', 'Chemical', '-', (164, 166))	('rs2279744', 'Var', (281, 290))
314461	27785069	These data revealed that the GG genotype of MDM2 rs2279744 was statistically associated with increased SCC susceptibility.	('rs2279744', 'Mutation', 'rs2279744', (49, 58))	('MDM2', 'Gene', (44, 48))	('SCC', 'Gene', (103, 106))	('rs2279744', 'Var', (49, 58))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCC', 'Gene', '6317', (103, 106))
314463	27785069	As shown in Table 3, a significantly increased SCC risk was observed in the Asian population in four models (G vs T, OR 1.12, P=0.027; GG vs TT, OR 1.26, P=0.016; GG vs TT + TG, OR 1.25, P<0.001; carrier G vs T, OR 1.08, P=0.023).	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('SCC', 'Gene', '6317', (47, 50))	('carrier G', 'Var', (196, 205))	('TG', 'Chemical', '-', (174, 176))	('SCC', 'Gene', (47, 50))
314464	27785069	These data further indicated an association between the GG genotype of MDM2 rs2279744 and increased SCC susceptibility in the Asian population.	('SCC', 'Gene', (100, 103))	('rs2279744', 'Mutation', 'rs2279744', (76, 85))	('increased', 'PosReg', (90, 99))	('rs2279744', 'Var', (76, 85))	('MDM2', 'Gene', (71, 75))	('SCC', 'Gene', '6317', (100, 103))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))
314468	27785069	These data further suggested that patients with the GG genotype of MDM2 rs2279744 appeared to be at a higher risk of developing ESCC in the Asian population.	('rs2279744', 'Mutation', 'rs2279744', (72, 81))	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('SCC', 'Gene', '6317', (129, 132))	('rs2279744', 'Var', (72, 81))	('MDM2', 'Gene', (67, 71))	('patients', 'Species', '9606', (34, 42))	('SCC', 'Gene', (129, 132))
314469	27785069	Next, pooled analysis for the association between the rs937283 and rs3730485 polymorphisms of MDM2 and the risks of SCC was conducted (Table 2).	('MDM2', 'Gene', (94, 98))	('SCC', 'Gene', (116, 119))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('rs937283', 'Var', (54, 62))	('rs3730485', 'Mutation', 'rs3730485', (67, 76))	('SCC', 'Gene', '6317', (116, 119))	('rs937283', 'Mutation', 'rs937283', (54, 62))	('rs3730485', 'Var', (67, 76))
314470	27785069	The data failed to provide strong evidence regarding the association between the rs937283 and rs3730485 polymorphisms of MDM2 and overall SCC susceptibility.	('SCC', 'Gene', (138, 141))	('rs937283', 'Var', (81, 89))	('rs3730485', 'Var', (94, 103))	('SCC', 'Gene', '6317', (138, 141))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('rs937283', 'Mutation', 'rs937283', (81, 89))	('rs3730485', 'Mutation', 'rs3730485', (94, 103))	('MDM2', 'Gene', (121, 125))
314471	27785069	The MDM2 rs2279744 polymorphism has been reported to suppress the p53 pathway via the modulation of MDM2 expression.	('p53', 'Gene', '7157', (66, 69))	('rs2279744', 'Mutation', 'rs2279744', (9, 18))	('MDM2', 'Gene', (4, 8))	('rs2279744', 'Var', (9, 18))	('suppress', 'NegReg', (53, 61))	('MDM2', 'Gene', (100, 104))	('expression', 'MPA', (105, 115))	('p53', 'Gene', (66, 69))
314476	27785069	Egger's funnel plots of publication bias for the allele (Figure 2B), homozygote (Figure 3B), heterozygote (Figure 4B), dominant (Figure 5B), and recessive (Figure 6B) models of MDM2 rs2279744 polymorphism are shown.	('rs2279744', 'Var', (182, 191))	('MDM2', 'Gene', (177, 181))	('rs2279744', 'Mutation', 'rs2279744', (182, 191))
314477	27785069	With regard to the sensitivity analysis, compared with overall meta-analysis data, no significant difference for the pooled OR value was observed when each study was omitted sequentially (Figure 2C for allele model of MDM2 rs2279744; Figure 3C for homozygote model; Figure 4C for heterozygote model; Figure 5C for dominant model; Figure 6C for recessive model; data not shown for others).	('MDM2', 'Gene', (218, 222))	('rs2279744', 'Var', (223, 232))	('rs2279744', 'Mutation', 'rs2279744', (223, 232))
314478	27785069	More and more studies on the possible role of the MDM2 rs2279744 polymorphism in the onset and development of cancer have been reported.	('MDM2', 'Gene', (50, 54))	('cancer', 'Disease', (110, 116))	('rs2279744', 'Mutation', 'rs2279744', (55, 64))	('rs2279744', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
314479	27785069	Hu et al performed a meta-analysis based on 25 published case-control studies, and reported that MDM2 rs2279744 seems to be associated with tumor susceptibility.	('rs2279744', 'Var', (102, 111))	('associated', 'Reg', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('rs2279744', 'Mutation', 'rs2279744', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('MDM2', 'Gene', (97, 101))	('tumor', 'Disease', (140, 145))
314480	27785069	Chen et al reported that the MDM2 rs2279744 polymorphism may be linked to an increased digestive tract cancer risk in the Asian population.	('rs2279744', 'Var', (34, 43))	('MDM2', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (87, 109))	('rs2279744', 'Mutation', 'rs2279744', (34, 43))	('linked to', 'Reg', (64, 73))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
314481	27785069	Here, we further focused on the potential effect of MDM2 rs2279744 in susceptibility to overall SCC and specific SCC types, including HNSCC, SSCC, ESCC, OSCC, CSCC, and LSCC.	('SCC', 'Phenotype', 'HP:0002860', (113, 116))	('SCC', 'Gene', '6317', (154, 157))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('SSCC', 'Phenotype', 'HP:0002860', (141, 145))	('SCC', 'Gene', (148, 151))	('SCC', 'Gene', (154, 157))	('MDM2', 'Gene', (52, 56))	('SCC', 'Gene', '6317', (170, 173))	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('SCC', 'Gene', '6317', (113, 116))	('SCC', 'Gene', (170, 173))	('SCC', 'Gene', '6317', (96, 99))	('SCC', 'Phenotype', 'HP:0002860', (142, 145))	('rs2279744', 'Var', (57, 66))	('SCC', 'Gene', (113, 116))	('SCC', 'Gene', '6317', (160, 163))	('SCC', 'Gene', (96, 99))	('SCC', 'Gene', '6317', (136, 139))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('SCC', 'Gene', (160, 163))	('SCC', 'Gene', '6317', (142, 145))	('SCC', 'Gene', (136, 139))	('SCC', 'Gene', (142, 145))	('rs2279744', 'Mutation', 'rs2279744', (57, 66))	('SCC', 'Gene', '6317', (148, 151))
314483	27785069	A meta-analysis by Liu et al based on seven articles with 1,629 cases and 2,472 controls showed that the G allele of the MDM2 rs2279744 polymorphism seemed to act as an important HNSCC protective factor in the Caucasian population, but not the Asian population.	('SCC', 'Gene', (181, 184))	('SCC', 'Phenotype', 'HP:0002860', (181, 184))	('SCC', 'Gene', '6317', (181, 184))	('rs2279744', 'Mutation', 'rs2279744', (126, 135))	('rs2279744', 'Var', (126, 135))	('MDM2', 'Gene', (121, 125))
314484	27785069	However, in our meta-analysis, we were unable to observe a significant association between HNSCC susceptibility and MDM2 rs2279744.	('rs2279744', 'Var', (121, 130))	('MDM2', 'Gene', (116, 120))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('SCC', 'Gene', '6317', (93, 96))	('rs2279744', 'Mutation', 'rs2279744', (121, 130))
314487	27785069	In our subgroup analysis, we tested the relationship between OSCC risk and MDM2 rs2279744.	('rs2279744', 'Mutation', 'rs2279744', (80, 89))	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('SCC', 'Gene', '6317', (62, 65))	('MDM2', 'Gene', (75, 79))	('rs2279744', 'Var', (80, 89))	('tested', 'Reg', (29, 35))	('SCC', 'Gene', (62, 65))
314489	27785069	We found that the MDM2 rs2279744 polymorphism did not appear to be associated with OSCC susceptibility, which is partly consistent with the results of Xie et al.	('SCC', 'Gene', '6317', (84, 87))	('MDM2', 'Gene', (18, 22))	('rs2279744', 'Mutation', 'rs2279744', (23, 32))	('SCC', 'Gene', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('rs2279744', 'Var', (23, 32))
314490	27785069	A meta-analysis by Chen et al based on six case-control studies, including 1,899 cases and 3,016 controls, showed that the MDM2 rs2279744 polymorphism may be associated with increased risks of overall esophageal cancer, including SCC and adenocarcinoma, especially in the Asian population.	('SCC', 'Gene', (230, 233))	('adenocarcinoma', 'Disease', 'MESH:D000230', (238, 252))	('associated', 'Reg', (158, 168))	('rs2279744', 'Mutation', 'rs2279744', (128, 137))	('MDM2', 'Gene', (123, 127))	('SCC', 'Phenotype', 'HP:0002860', (230, 233))	('SCC', 'Gene', '6317', (230, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('esophageal cancer', 'Disease', (201, 218))	('rs2279744', 'Var', (128, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (201, 218))	('adenocarcinoma', 'Disease', (238, 252))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
314494	27785069	The GG genotype of MDM2 rs2279744 was likely to confer an increased susceptibility to ESCC in elderly male patients in People's Republic of China.	('rs2279744', 'Var', (24, 33))	('MDM2', 'Gene', (19, 23))	('People', 'Species', '9606', (119, 125))	('susceptibility', 'Reg', (68, 82))	('SCC', 'Gene', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('SCC', 'Gene', '6317', (87, 90))	('rs2279744', 'Mutation', 'rs2279744', (24, 33))	('patients', 'Species', '9606', (107, 115))
314495	27785069	Considering the close association between MDM2 and p53, it is meaningful to investigate the role of gene-gene interaction between MDM2 and TP53 Arg72Pro polymorphism in SCC risks.	('Arg72Pro', 'SUBSTITUTION', 'None', (144, 152))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('TP53', 'Gene', '7157', (139, 143))	('SCC', 'Gene', (169, 172))	('SCC', 'Phenotype', 'HP:0002860', (169, 172))	('Arg72Pro', 'Var', (144, 152))	('TP53', 'Gene', (139, 143))	('SCC', 'Gene', '6317', (169, 172))
314497	27785069	The underlying molecular mechanism on the effect of MDM2 genetic variation in the incidence of ESCC remains unclear.	('SCC', 'Gene', (96, 99))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('SCC', 'Gene', '6317', (96, 99))	('genetic variation', 'Var', (57, 74))	('MDM2', 'Gene', (52, 56))
314498	27785069	The rs2279744 SNP within the promoter region of MDM2 can lead to a T-G substitution at the 309 nucleotide site, which is closely linked to the high expression of the MDM2 protein via higher binding affinity with the transcriptional activator SP1, and thus enhances the degradation of p53.	('rs2279744 SNP', 'Var', (4, 17))	('higher', 'PosReg', (183, 189))	('degradation', 'MPA', (269, 280))	('binding affinity', 'Interaction', (190, 206))	('lead to', 'Reg', (57, 64))	('enhances', 'PosReg', (256, 264))	('p53', 'Gene', (284, 287))	('p53', 'Gene', '7157', (284, 287))	('MDM2', 'Gene', (48, 52))	('rs2279744', 'Mutation', 'rs2279744', (4, 13))	('T-G', 'Disease', (67, 70))
314499	27785069	It was possible that MDM2 rs2279744 polymorphism is linked to the increased SCC risks, through influencing the role of p53 pathway in genomic stability and tumor prevention.	('linked', 'Reg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('SCC', 'Gene', (76, 79))	('p53', 'Gene', '7157', (119, 122))	('rs2279744', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('rs2279744', 'Mutation', 'rs2279744', (26, 35))	('MDM2', 'Gene', (21, 25))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('SCC', 'Gene', '6317', (76, 79))	('tumor', 'Disease', (156, 161))	('p53', 'Gene', (119, 122))	('influencing', 'Reg', (95, 106))	('genomic stability', 'CPA', (134, 151))
314500	27785069	Chen et al conducted a meta-analysis to investigate the relationship between positive MDM2 expression and clinicopathological characteristics of ESCC, and found that high MDM2 expression was associated with early primary tumor stage and increased risk of regional lymph node metastasis, but not the risk of distant metastasis.	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('primary tumor', 'Disease', 'MESH:D009369', (213, 226))	('SCC', 'Gene', (146, 149))	('MDM2', 'Gene', (171, 175))	('expression', 'MPA', (176, 186))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('SCC', 'Gene', '6317', (146, 149))	('associated', 'Reg', (191, 201))	('high', 'Var', (166, 170))	('primary tumor', 'Disease', (213, 226))	('regional lymph node metastasis', 'CPA', (255, 285))
314503	27785069	For instance, rs2279744 and rs937283 of MDM2 might be associated with the occurrence of OSCC patients with HPV16 L1 seropositivity.	('rs937283', 'Mutation', 'rs937283', (28, 36))	('rs2279744', 'Var', (14, 23))	('MDM2', 'Gene', (40, 44))	('rs2279744', 'Mutation', 'rs2279744', (14, 23))	('SCC', 'Gene', '6317', (89, 92))	('rs937283', 'Var', (28, 36))	('HPV16', 'Species', '333760', (107, 112))	('patients', 'Species', '9606', (93, 101))	('associated', 'Reg', (54, 64))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
314504	27785069	Very few publications resulted in small sample sizes for the analysis of MDM2 rs937283 and rs3730485.	('rs937283', 'Var', (78, 86))	('rs3730485', 'Mutation', 'rs3730485', (91, 100))	('rs937283', 'Mutation', 'rs937283', (78, 86))	('MDM2', 'Gene', (73, 77))	('rs3730485', 'Var', (91, 100))
314505	27785069	The same limitation of sample size existed in the meta-analysis of MDM2/TP53 double mutation and several subgroup analyses of the MDM2 rs2279744 polymorphism.	('rs2279744', 'Mutation', 'rs2279744', (135, 144))	('TP53', 'Gene', '7157', (72, 76))	('MDM2', 'Gene', (130, 134))	('TP53', 'Gene', (72, 76))	('rs2279744', 'Var', (135, 144))
314506	27785069	Larger and independent studies are required to validate the association between MDM2/TP53 mutations and susceptibility to different types of SCC.	('TP53', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('SCC', 'Gene', (141, 144))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('SCC', 'Gene', '6317', (141, 144))	('TP53', 'Gene', '7157', (85, 89))
314507	27785069	Our updated meta-analysis demonstrated that there is a positive association between increased overall SCC risks and the MDM2 rs2279744 polymorphism, rather than rs937283 or rs3730485.	('rs2279744', 'Mutation', 'rs2279744', (125, 134))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('rs2279744', 'Var', (125, 134))	('MDM2', 'Gene', (120, 124))	('rs937283', 'Mutation', 'rs937283', (161, 169))	('SCC', 'Gene', (102, 105))	('rs3730485', 'Mutation', 'rs3730485', (173, 182))
314508	27785069	We further provided evidence that the GG genotype of MDM2 rs2279744 is more likely to confer an increased genetic susceptibility to ESCC in the Asian population, particularly in Chinese.	('SCC', 'Gene', '6317', (133, 136))	('rs2279744', 'Var', (58, 67))	('MDM2', 'Gene', (53, 57))	('rs2279744', 'Mutation', 'rs2279744', (58, 67))	('SCC', 'Gene', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))
314509	27785069	MDM2 rs2279744 may be a valuable risk factor or diagnostic biomarker for patients with ESCC in People's Republic of China, and needs more supporting evidence.	('People', 'Species', '9606', (95, 101))	('rs2279744', 'Mutation', 'rs2279744', (5, 14))	('SCC', 'Gene', (88, 91))	('MDM2', 'Gene', (0, 4))	('rs2279744', 'Var', (5, 14))	('patients', 'Species', '9606', (73, 81))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
314517	25755255	Risk organ doses were lower in proton plans compared with X-ray plans.	('proton', 'Chemical', 'MESH:D011522', (31, 37))	('Risk', 'MPA', (0, 4))	('proton plans', 'Var', (31, 43))	('lower', 'NegReg', (22, 27))
314524	25755255	Compared with 4D intensity-modulated radiation therapy (IMRT), PBT reduces lung V5, V10, V20 and the mean lung dose (MLD) in dosimetric studies.	('PBT', 'Var', (63, 66))	('V20', 'MPA', (89, 92))	('lung', 'MPA', (75, 79))	('reduces', 'NegReg', (67, 74))	('V10', 'MPA', (84, 87))	('MLD', 'Disease', 'MESH:D007966', (117, 120))	('MLD', 'Disease', (117, 120))
314560	25755255	The irradiated OAR volume in patients with events of Grade >=2 was significantly higher than in those with events of Grade <=1.	('irradiated OAR volume', 'CPA', (4, 25))	('Grade >=2', 'Var', (53, 62))	('patients', 'Species', '9606', (29, 37))	('higher', 'PosReg', (81, 87))
314561	25755255	The data were used to calculate ROC curves, which gave cut-off values of V5 44.1% (specificity 93.1%, sensitivity 69.2%), V10 31.5% (93.1%, 69.2%), V20 22.5% (93.1%, 69.2%) and MLD 9.78 Gy (86.2%, 76.9%) for the lung; and V30 35.0% (86.2%, 76.9%), V40 27% (86.2%, 76.9%) and V50 18.9% (89.7%, 69.2%) for the heart.	('MLD', 'Disease', 'MESH:D007966', (177, 180))	('MLD', 'Disease', (177, 180))	('V20', 'Var', (148, 151))	('V30', 'Var', (222, 225))	('V40', 'Var', (248, 251))	('V50', 'Var', (275, 278))	('V10', 'Var', (122, 125))
314579	25755255	Compared with 4D IMRT, PBT can reduce V5, V10, V20 and MLD from 49.5% to 13.9%, 32.5% to 12%, 15.6% to 9.8%, and 9.65 Gy to 4.55 Gy, respectively.	('PBT', 'Var', (23, 26))	('reduce', 'NegReg', (31, 37))	('MLD', 'Disease', 'MESH:D007966', (55, 58))	('to 9', 'Species', '1214577', (100, 104))	('MLD', 'Disease', (55, 58))
314588	25755255	In our study however 11 of 14 patients with Stage IIIA-C esophageal cancer in the X-ray group experienced Grade 2 or severe cardiopulmonary events, whereas none of 9 patients with Stage IIIA-C in the proton group did.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('experienced', 'Reg', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Stage IIIA-C', 'Var', (44, 56))	('Grade 2', 'MPA', (106, 113))	('patients', 'Species', '9606', (30, 38))	('proton', 'Chemical', 'MESH:D011522', (200, 206))	('esophageal cancer', 'Disease', (57, 74))	('patients', 'Species', '9606', (166, 174))
314775	33659041	Results: Mean MRI tumor volume decreased by 30.1% and 50.8% in ADU-S100 and ADU-S100 + radiation animals and increased by 76.7% and 152.4% in placebo and placebo + radiation animals, respectively (P < 0.0001).	('tumor', 'Disease', (18, 23))	('decreased', 'NegReg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('ADU-S100', 'Chemical', '-', (63, 71))	('ADU-S100', 'Var', (63, 71))	('ADU-S100 + radiation', 'Var', (76, 96))	('increased', 'PosReg', (109, 118))	('ADU-S100', 'Chemical', '-', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
314778	33659041	Conclusions: ADU-S100 +/- radiation exhibits potent antitumor activity and a promising immunomodulatory profile in a de novo EAC.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ADU-S100', 'Chemical', '-', (13, 21))	('EAC', 'Disease', (125, 128))	('tumor', 'Disease', (56, 61))	('EAC', 'Phenotype', 'HP:0011459', (125, 128))	('ADU-S100 +/- radiation', 'Var', (13, 35))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
314801	33659041	Overall, a comparison of MRIs in the study groups between 32 and 40 weeks demonstrated a mean increase in percentage tumor volume of 76.7% and 152.4% in the P and P+R arms respectively, and a decrease of 30.1% and 50.8% in the S and S+R arms, respectively (ANOVA test p < 0.0001) - Figure 1A.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('increase', 'PosReg', (94, 102))	('tumor', 'Disease', (117, 122))	('rat', 'Species', '10116', (81, 84))	('P+R', 'Var', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
314802	33659041	In the P and P+R group, 76.5% and 80.0% of the rats demonstrated an increase in tumor volume, 17.6% and 10.0% had stable disease and the remaining 5.9% and 10.0% had a decrease in tumor volume, respectively.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('P+R', 'Var', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', (80, 85))	('rat', 'Species', '10116', (47, 50))	('increase', 'PosReg', (68, 76))	('decrease', 'NegReg', (168, 176))	('rat', 'Species', '10116', (59, 62))	('rats', 'Species', '10116', (47, 51))
314803	33659041	Following treatment with S and S+R, 0.0% and 0.0% of the rats demonstrated an increase in tumor volume, 60.0% and 22.2% had stable disease and the remaining 40.0% and 77.8% had a decrease in tumor volume, respectively (Fisher's exact test p =< 0.0001) - Figure 1B.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('decrease', 'NegReg', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('increase', 'PosReg', (78, 86))	('rat', 'Species', '10116', (57, 60))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('rat', 'Species', '10116', (69, 72))	('rats', 'Species', '10116', (57, 61))	('S+R', 'Var', (31, 34))
314808	33659041	TIL infiltration was upregulated with higher mean CD-8+ T-cell densities on- and post- treatment in P+R (mean on- = 43.5, p = 0.0009; mean post- = 23.2, p = 0.1044), S (mean on- = 63.4, p < .0001; mean post- = 54.3, p = 0.0010) and S+R (mean on- = 59.8, p = 0.0002; mean post- = 42.9, p = 0.0015) compared to P (mean on- = 3.1; mean post- = 5.1).	('CD-8', 'Gene', (50, 54))	('S+R', 'Var', (232, 235))	('upregulated', 'PosReg', (21, 32))	('P+R', 'Var', (100, 103))	('CD-8', 'Gene', '925', (50, 54))	('higher', 'PosReg', (38, 44))	('rat', 'Species', '10116', (10, 13))	('TIL infiltration', 'CPA', (0, 16))
314810	33659041	Subsequently, adaptive immune resistance depicted by total PD-L1 positive (immune stromal and tumor cells) was significantly enhanced in P+R (mean on- = 66.1, p = 0.0001; mean post- = 35.3, p = 0.0149), S (mean on- =72.6, p < .0001; mean post- =56.4, p = 0.0021) and S+R (mean on- = 62.5, p < .0001; mean post- = 71.0, p = 0.0015), compared to P (mean on- = 2.9; mean post- = 6.3).	('adaptive immune resistance', 'CPA', (14, 40))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('P+R', 'Var', (137, 140))	('tumor', 'Disease', (94, 99))	('PD-L1', 'Gene', (59, 64))	('enhanced', 'PosReg', (125, 133))	('PD-L1', 'Gene', '29126', (59, 64))
314814	33659041	In vivo, MRI was utilized in the current study to quantify preclinical change in tumor volume in response to treatment with ADU-S100 through the comparison of 30- and 40-week scans, with each rat serving as its own control.	('rat', 'Species', '10116', (192, 195))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ADU-S100', 'Chemical', '-', (124, 132))	('ADU-S100', 'Var', (124, 132))	('tumor', 'Disease', (81, 86))
314815	33659041	The results demonstrated that P and P+R animals exhibited 76.7% and 152.4% increase in mean tumor volume, respectively.	('increase', 'PosReg', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('P+R', 'Var', (36, 39))
314824	33659041	Our study in line with previous experiments successfully demonstrated enhanced PD-L1 expression, possibly by triggering an adaptive immune response, as suggested by increased infiltration of CD8+ T cells in tumors in S, S+R and P+R groups compared to P. These changes peaked on- treatment.	('expression', 'MPA', (85, 95))	('CD8', 'Gene', '925', (191, 194))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('rat', 'Species', '10116', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('PD-L1', 'Gene', (79, 84))	('enhanced', 'PosReg', (70, 78))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('rat', 'Species', '10116', (181, 184))	('tumors', 'Disease', (207, 213))	('CD8', 'Gene', (191, 194))	('P+R', 'Var', (228, 231))	('increased', 'PosReg', (165, 174))	('PD-L1', 'Gene', '29126', (79, 84))
314827	33659041	Single agent PD-1 inhibitors have demonstrated modest efficacy with response rates of approximately 12% in heavily pretreated gastroesophageal cancer patients, leading to clinical approvals in metastatic 3rd line setting for pembrolizumab and nivolumab (Japan only).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('PD-1', 'Gene', (13, 17))	('rat', 'Species', '10116', (77, 80))	('nivolumab', 'Chemical', 'MESH:D000077594', (243, 252))	('pembrolizumab', 'Chemical', 'MESH:C582435', (225, 238))	('patients', 'Species', '9606', (150, 158))	('rat', 'Species', '10116', (41, 44))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('inhibitors', 'Var', (18, 28))
314828	33659041	Earlier this year, based on the data from Keynote 181 and Keynote 180 the Food and Drug Administration approved pembrolizumab for patients with recurrent, locally advanced, or metastatic ESCC with CPS >= 10, after >= 1 lines of systemic therapy.	('ESCC', 'Disease', (187, 191))	('metastatic', 'CPA', (176, 186))	('CPS', 'Chemical', '-', (197, 200))	('patients', 'Species', '9606', (130, 138))	('pembrolizumab', 'Chemical', 'MESH:C582435', (112, 125))	('rat', 'Species', '10116', (96, 99))	('CPS >= 10', 'Var', (197, 206))
314837	33659041	Currently, based on encouraging data, NCT03172936, NCT02675439 and NCT03937141 are studying ICIs in combination with ADU-S100 in human lymphomas and solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (149, 161))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('NCT03937141', 'Var', (67, 78))	('ICIs', 'Gene', '57509', (92, 96))	('NCT03172936', 'Var', (38, 49))	('lymphomas', 'Disease', (135, 144))	('lymphomas', 'Disease', 'MESH:D008223', (135, 144))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('ICIs', 'Gene', (92, 96))	('lymphomas', 'Phenotype', 'HP:0002665', (135, 144))	('NCT02675439', 'Var', (51, 62))	('ADU-S100', 'Chemical', '-', (117, 125))	('human', 'Species', '9606', (129, 134))	('solid tumors', 'Disease', (149, 161))
314839	33659041	However, we did show PD-L1 upregulation on- or post- treatment with S and S+R hence substantially addressing this limitation.	('PD-L1', 'Gene', (21, 26))	('S+R', 'Var', (74, 77))	('upregulation', 'PosReg', (27, 39))	('PD-L1', 'Gene', '29126', (21, 26))
314914	32457351	The individuality of the TE series ESCC cell lines was confirmed by a short tandem repeat analysis at RIKEN and at the Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University (Sendai, Japan).	('men', 'Species', '9606', (185, 188))	('Cancer', 'Disease', 'MESH:D009369', (201, 207))	('short tandem repeat analysis', 'Var', (70, 98))	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Cancer', 'Disease', (201, 207))
314921	32457351	We named the TAM-like macrophages polarized by TE-8CM, TE-9CM, and TE-15CM as, respectively, TAM8, TAM9, and TAM15 cells.	('TE-15CM', 'Var', (67, 74))	('TAM', 'Chemical', '-', (109, 112))	('TAM', 'Chemical', '-', (99, 102))	('TAM', 'Chemical', '-', (13, 16))	('TE-8CM', 'Var', (47, 53))	('TE', 'Chemical', 'MESH:D013691', (55, 57))	('TAM8', 'Chemical', '-', (93, 97))	('TAM', 'Chemical', '-', (93, 96))	('TE', 'Chemical', 'MESH:D013691', (67, 69))	('TE', 'Chemical', 'MESH:D013691', (47, 49))	('TE-9CM', 'Var', (55, 61))
314923	32457351	The inhibitors against PI3K (LY294002, #9901) and MEK (PD98059, #9900) were purchased from Cell Signaling Technology (Danvers, MA).	('MEK', 'Enzyme', (50, 53))	('LY294002', 'Chemical', 'MESH:C085911', (29, 37))	('PI3K', 'Pathway', (23, 27))	('LY294002', 'Var', (29, 37))	('PD98059', 'Var', (55, 62))	('PD98059', 'Chemical', 'MESH:C093973', (55, 62))
314925	32457351	For the CCR5 knockdown by siRNA, 5 x 105 TE-8, TE-9, and TE-15 cells on 60 mm dishes were transfected by 20 nM siRNA against CCR5 (siCCR5, #sc-35062; Santa Cruz Biotechnology) using Lipofectamine  RNAiMAX (Invitrogen) for 2 days.	('TE', 'Chemical', 'MESH:D013691', (41, 43))	('TE', 'Chemical', 'MESH:D013691', (57, 59))	('CCR5', 'Gene', (8, 12))	('knockdown', 'Var', (13, 22))	('TE', 'Chemical', 'MESH:D013691', (47, 49))
314930	32457351	A quantitative RT-PCR was performed using the following probes: CCL3 (Hs00234142_m1), MMP2 (Hs01548727_m1), MMP9 (Hs00234579_m1), VEGFA (Hs00900054_m1), and GAPDH (Hs02786624_g1) (Applied Biosystems, Foster City, CA) on an ABI StepOne Real-time PCR system (Applied Biosystems) using TaqMan Gene Expression Master Mix (Applied Biosystems).	('Hs01548727_m1', 'Var', (92, 105))	('Hs00234579_m1', 'Var', (114, 127))	('Hs00900054_m1', 'Var', (137, 150))	('Hs02786624_g1', 'Var', (164, 177))	('GAPDH', 'Gene', '2597', (157, 162))	('Hs00234142_m1', 'Var', (70, 83))	('GAPDH', 'Gene', (157, 162))
314937	32457351	Rabbit polyclonal antibody against CCR1 (1:250, #ab1681; Abcam, Cambridge, UK), mouse monoclonal antibody against CCR5 (1:100, #sc-32304; Santa Cruz Biotechnology), rabbit polyclonal antibody against CCL3 (1:100, #LS-C384561; LifeSpan BioSciences, Seattle, WA), and the following rabbit monoclonal antibodies (all from Cell Signaling Technology): phosphorylated Akt (Ser473; 1:250, #4060), phosphorylated Akt (Thr308; 1:250, #2965), total Akt (1:500, #9272), phosphorylated ERK1/2 (Thr202/Tyr204; 1:250, #9101), total ERK1/2 (1:500, #9102), and beta-actin (1:1000, #4970).	('ERK1/2', 'Gene', '26417;26413', (474, 480))	('ERK1/2', 'Gene', (474, 480))	('beta-actin', 'Protein', (545, 555))	('Thr202/Tyr204; 1:250', 'Var', (482, 502))	('1:500', 'Var', (526, 531))	('ERK1/2', 'Gene', '26417;26413', (518, 524))	('mouse', 'Species', '10090', (80, 85))	('Ser473', 'Chemical', '-', (367, 373))	('ERK1/2', 'Gene', (518, 524))	('Thr308', 'Chemical', '-', (410, 416))
314938	32457351	The secondary antibodies were horseradish peroxidase (HRP)-linked donkey anti-rabbit IgG (1:1000, #NA934V) and HRP-linked sheep anti-mouse IgG (1:1000, #NA931V), both were purchased from GE Healthcare Life Sciences (Little Chalfont, UK).	('1:1000', 'Var', (90, 96))	('mouse', 'Species', '10090', (133, 138))	('1:1000', 'Var', (144, 150))	('horseradish', 'Species', '3704', (30, 41))
314939	32457351	For the IF examination, 1 x 105 cultured cells on coverslips were fixed with methanol for 10 min at -20  C and incubated with primary antibodies against CCR5 (1:25, #sc-32304; Santa Cruz Biotechnology), CCL3 (1:100, #LS-C384561; LifeSpan BioSciences), and CD204 (1:100, #SRA-E5; TransGenic, Kobe, Japan) at 4  C overnight.	('SRA', 'Gene', '4481', (271, 274))	('1:100', 'Var', (263, 268))	('CD204', 'Gene', '4481', (256, 261))	('CD204', 'Gene', (256, 261))	('methanol', 'Chemical', 'MESH:D000432', (77, 85))	('SRA', 'Gene', (271, 274))	('1:25', 'Var', (159, 163))	('CCR5', 'Gene', (153, 157))
314944	32457351	Next, 20 microM LY294002, 20 microM PD98059, or 20 microg/ml Maraviroc was added to the upper chambers, and the neutralizing antibody against CCL3 (400 ng/ml) was added to the lower chambers.	('LY294002', 'Chemical', 'MESH:C085911', (16, 24))	('PD98059', 'Chemical', 'MESH:C093973', (36, 43))	('LY294002', 'Var', (16, 24))	('Maraviroc', 'Chemical', 'MESH:D000077592', (61, 70))	('PD98059', 'Var', (36, 43))
314955	32457351	The primary antibodies were CCL3 (1:200, #LS-C384561; LifeSpan BioSciences), CCR5 (1:25, #sc-32304; Santa Cruz Biotechnology), CD68 (1:100, #Kp-1; Dako), CD163 (1:100, #10D6; Novocastra, Newcastle upon Tyne, UK), CD204 (1:50, #SRA-E5; TransGenic), and CD34 (1:50, #NU-4A1, Nichirei, Tokyo, Japan).	('CD163', 'Gene', '9332', (154, 159))	('1:25', 'Var', (83, 87))	('CD163', 'Gene', (154, 159))	('SRA', 'Gene', '4481', (227, 230))	('CD34', 'Gene', (252, 256))	('CD204', 'Gene', '4481', (213, 218))	('CD204', 'Gene', (213, 218))	('CD34', 'Gene', '947', (252, 256))	('CD68', 'Gene', (127, 131))	('CD68', 'Gene', '968', (127, 131))	('SRA', 'Gene', (227, 230))
314961	32457351	Compared with the CCL3 mRNA expression level in the PBMo-derived TAM-like macrophages (1.0 +- 0.0-folds), the expression levels were significantly higher in the PBMo-derived TAM-like macrophages polarized by TE-8CM (TAM8 cells, 1.7 +- 0.1-fold, p = 0.002), TE-9CM (TAM9 cells, 1.6 +- 0.1-fold, p = 0.018), and TE-15CM (TAM15 cells, 2.5 +- 0.2-fold, p = 0.002) (Fig.	('TE-15CM', 'Var', (310, 317))	('TAM8', 'Chemical', '-', (216, 220))	('TE-8CM', 'Var', (208, 214))	('TE', 'Chemical', 'MESH:D013691', (257, 259))	('TAM', 'Chemical', '-', (319, 322))	('expression levels', 'MPA', (110, 127))	('TE', 'Chemical', 'MESH:D013691', (310, 312))	('TE', 'Chemical', 'MESH:D013691', (208, 210))	('TAM', 'Chemical', '-', (174, 177))	('TAM', 'Chemical', '-', (216, 219))	('higher', 'PosReg', (147, 153))	('TAM', 'Chemical', '-', (65, 68))	('TAM', 'Chemical', '-', (265, 268))	('TE-9CM', 'Var', (257, 263))
314967	32457351	The expression levels of CCR1 in TE-8 (1.3 +- 0.1-fold, p = 0.017), TE-9 (1.4 +- 0.1-fold, p = 0.010), and TE-15 cells (1.3 +- 0.0-fold, p = 0.008) were also significantly higher than that in the Het-1A cells (1.0 +- 0.0-fold), but relatively much lower than the CCR5 expression levels in the three ESCC cell lines (Fig.	('expression levels', 'MPA', (4, 21))	('TE', 'Chemical', 'MESH:D013691', (68, 70))	('TE', 'Chemical', 'MESH:D013691', (107, 109))	('lower', 'NegReg', (248, 253))	('CCR1', 'Gene', (25, 29))	('higher', 'PosReg', (172, 178))	('TE-9', 'Var', (68, 72))	('TE', 'Chemical', 'MESH:D013691', (33, 35))
314974	32457351	We then silenced CCR5 in TE-8, TE-9, and TE-15 cells with the use of siRNA.	('CCR5', 'Gene', (17, 21))	('TE', 'Chemical', 'MESH:D013691', (25, 27))	('TE', 'Chemical', 'MESH:D013691', (31, 33))	('TE', 'Chemical', 'MESH:D013691', (41, 43))	('silenced', 'Var', (8, 16))
314975	32457351	The western blotting revealed that the phosphorylations of Akt and ERK at 10 min after rhCCL3 treatment were suppressed by the CCR5 knockdown in TE-8, TE-9, and TE-15 (Figs.	('suppressed', 'NegReg', (109, 119))	('TE', 'Chemical', 'MESH:D013691', (161, 163))	('Akt', 'Pathway', (59, 62))	('knockdown', 'Var', (132, 141))	('TE', 'Chemical', 'MESH:D013691', (151, 153))	('TE', 'Chemical', 'MESH:D013691', (145, 147))	('rhCCL3', 'Chemical', '-', (87, 93))	('phosphorylations', 'MPA', (39, 55))	('ERK', 'Pathway', (67, 70))	('CCR5', 'Gene', (127, 131))
314976	32457351	Our findings first revealed that rhCCL3 significantly promoted the migration and invasion of TE-8 cells, and the migration and invasion were significantly suppressed by the inhibition of PI3K/Akt and MEK/ERK pathways using LY294002 and PD98059, respectively (Fig.	('promoted', 'PosReg', (54, 62))	('rhCCL3', 'Chemical', '-', (33, 39))	('inhibition', 'NegReg', (173, 183))	('LY294002', 'Var', (223, 231))	('PD98059', 'Chemical', 'MESH:C093973', (236, 243))	('invasion', 'CPA', (81, 89))	('invasion', 'CPA', (127, 135))	('migration', 'CPA', (67, 76))	('suppressed', 'NegReg', (155, 165))	('LY294002', 'Chemical', 'MESH:C085911', (223, 231))	('TE', 'Chemical', 'MESH:D013691', (93, 95))	('rhCCL3', 'Gene', (33, 39))	('PD98059', 'Var', (236, 243))	('MEK/ERK pathways', 'Pathway', (200, 216))
314977	32457351	Maraviroc and CCR5 knockdown were also effective for suppressing the rhCCL3-mediated migration and invasion (Fig.	('Maraviroc', 'Chemical', 'MESH:D000077592', (0, 9))	('CCR5', 'Gene', (14, 18))	('knockdown', 'Var', (19, 28))	('rhCCL3-mediated', 'Protein', (69, 84))	('invasion', 'CPA', (99, 107))	('rhCCL3', 'Chemical', '-', (69, 75))	('suppressing', 'NegReg', (53, 64))
314979	32457351	4d, e, i, j), and observed that TAM8 also significantly promoted the migration and invasion of TE-8 cells, and that the migration and invasion were significantly suppressed by Maraviroc and neutralizing antibody against CCL3.	('neutralizing', 'Var', (190, 202))	('Maraviroc', 'Chemical', 'MESH:D000077592', (176, 185))	('invasion', 'CPA', (134, 142))	('migration', 'CPA', (120, 129))	('TAM8', 'Chemical', '-', (32, 36))	('invasion of TE-8 cells', 'CPA', (83, 105))	('suppressed', 'NegReg', (162, 172))	('promoted', 'PosReg', (56, 64))	('TE', 'Chemical', 'MESH:D013691', (95, 97))	('migration', 'CPA', (69, 78))
314993	32457351	After observing that a CCL3-CCR5 axis promoted the migration and invasion of the three ESCC cell lines via PI3K/Akt and MEK/ERK pathways as described above, we investigated whether CCL3 upregulated the expressions of matrix metalloprotease-2 (MMP-2) and matrix metalloprotease-9 (MMP-9), which are well known to contribute to cell invasion by extracellular matrix remodeling in the tumor microenvironment.	('upregulated', 'PosReg', (186, 197))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('matrix metalloprotease-2', 'Gene', (217, 241))	('MMP-2', 'Gene', (243, 248))	('migration', 'CPA', (51, 60))	('matrix metalloprotease-2', 'Gene', '4313', (217, 241))	('tumor', 'Disease', (382, 387))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('matrix metalloprotease-9', 'Gene', (254, 278))	('promoted', 'PosReg', (38, 46))	('MMP-9', 'Gene', '4318', (280, 285))	('MMP-2', 'Gene', '4313', (243, 248))	('invasion', 'CPA', (65, 73))	('matrix metalloprotease-9', 'Gene', '4318', (254, 278))	('MMP-9', 'Gene', (280, 285))	('CCL3', 'Var', (181, 185))
314998	32457351	Next, we investigated the MMP2, MMP9, and VEGFA mRNA expression levels after LY294002 or PD98059 treatment.	('LY294002', 'Chemical', 'MESH:C085911', (77, 85))	('PD98059', 'Var', (89, 96))	('LY294002', 'Var', (77, 85))	('PD98059', 'Chemical', 'MESH:C093973', (89, 96))
314999	32457351	TE-8 and TE-15 cells were treated with 100 ng/ml of rhCCL3 and 20 microM of LY294002 or PD98059 for the first 24 h, then they were treated with only rhCCL3 for the next 24 h. TE-9 cells were treated with 100 ng/ml of rhCCL3 and 20 microM of LY294002 or PD98059 for 48 h. The upregulated mRNA expression of MMP2 and VEGFA was suppressed by both LY294002 and PD98059 treatment (Fig.	('LY294002', 'Var', (344, 352))	('upregulated', 'PosReg', (275, 286))	('TE', 'Chemical', 'MESH:D013691', (9, 11))	('mRNA expression', 'MPA', (287, 302))	('TE', 'Chemical', 'MESH:D013691', (175, 177))	('TE', 'Chemical', 'MESH:D013691', (0, 2))	('suppressed', 'NegReg', (325, 335))	('VEGFA', 'Protein', (315, 320))	('LY294002', 'Chemical', 'MESH:C085911', (344, 352))	('rhCCL3', 'Chemical', '-', (149, 155))	('LY294002', 'Chemical', 'MESH:C085911', (76, 84))	('PD98059', 'Chemical', 'MESH:C093973', (88, 95))	('PD98059', 'Chemical', 'MESH:C093973', (357, 364))	('rhCCL3', 'Chemical', '-', (52, 58))	('MMP2', 'Protein', (306, 310))	('LY294002', 'Chemical', 'MESH:C085911', (241, 249))	('PD98059', 'Var', (357, 364))	('PD98059', 'Chemical', 'MESH:C093973', (253, 260))	('rhCCL3', 'Chemical', '-', (217, 223))
315000	32457351	In contrast, the MMP9 mRNA expression in TE-15 was upregulated by LY294002 or PD98059 with rhCCL3 treatment (Fig.	('PD98059', 'Chemical', 'MESH:C093973', (78, 85))	('rhCCL3', 'Chemical', '-', (91, 97))	('TE', 'Chemical', 'MESH:D013691', (41, 43))	('LY294002', 'Var', (66, 74))	('upregulated', 'PosReg', (51, 62))	('LY294002', 'Chemical', 'MESH:C085911', (66, 74))	('MMP9', 'Gene', (17, 21))	('PD98059', 'Var', (78, 85))
315006	32457351	A high expression of CCL3 did not significantly correlate with any of the clinicopathological factors, whereas a high expression of CCR5 was significantly correlated with deeper invasion (p = 0.016), presence of vascular invasion (p = 0.029), higher pathological stage (p = 0.041), higher numbers of infiltrating CD204+ TAMs (p = 0.006), and higher microvascular density (p = 0.006).	('higher pathological stage', 'CPA', (243, 268))	('high', 'Var', (113, 117))	('correlated', 'Reg', (155, 165))	('deeper invasion', 'CPA', (171, 186))	('higher', 'PosReg', (342, 348))	('microvascular density', 'CPA', (349, 370))	('TAMs', 'Chemical', '-', (320, 324))	('CCR5', 'Gene', (132, 136))	('CD204', 'Gene', '4481', (313, 318))	('CD204', 'Gene', (313, 318))	('vascular invasion', 'CPA', (212, 229))
315008	32457351	A high expression of CCL3 was significantly correlated with the patients' cause-specific survival (p = 0.041) (Fig.	('CCL3', 'Gene', (21, 25))	('patients', 'Species', '9606', (64, 72))	('high', 'Var', (2, 6))	('correlated', 'Reg', (44, 54))
315023	32457351	PDK1 phosphorylates Akt on Thr308, whereas mTORC2 phosphorylates Akt on Ser473.	('Ser473', 'Chemical', '-', (72, 78))	('mTORC2', 'Gene', (43, 49))	('mTORC2', 'Gene', '74343', (43, 49))	('PDK1', 'Gene', '5163', (0, 4))	('Thr308', 'Chemical', '-', (27, 33))	('PDK1', 'Gene', (0, 4))	('Thr308', 'Var', (27, 33))	('Akt', 'Pathway', (20, 23))
315037	32457351	All upregulated expressions of MMP2 and VEGFA after rhCCL3 treatment were suppressed by LY294002 and PD98059.	('LY294002', 'Chemical', 'MESH:C085911', (88, 96))	('suppressed', 'NegReg', (74, 84))	('PD98059', 'Chemical', 'MESH:C093973', (101, 108))	('MMP2', 'Protein', (31, 35))	('VEGFA', 'Protein', (40, 45))	('upregulated', 'PosReg', (4, 15))	('rhCCL3', 'Chemical', '-', (52, 58))	('LY294002', 'Var', (88, 96))	('PD98059', 'Var', (101, 108))	('expressions', 'MPA', (16, 27))
315039	32457351	In contrast, rhCCL3 treatment upregulated the MMP9 mRNA expression only in TE-15 cells, and paradoxically, the upregulated expression of MMP9 by rhCCL3 was further upregulated by LY294002 and PD98059.	('LY294002', 'Var', (179, 187))	('PD98059', 'Var', (192, 199))	('expression', 'MPA', (123, 133))	('upregulated', 'PosReg', (30, 41))	('upregulated', 'PosReg', (164, 175))	('rhCCL3', 'Gene', (145, 151))	('PD98059', 'Chemical', 'MESH:C093973', (192, 199))	('rhCCL3', 'Chemical', '-', (13, 19))	('LY294002', 'Chemical', 'MESH:C085911', (179, 187))	('MMP9', 'Gene', (46, 50))	('MMP9', 'Gene', (137, 141))	('TE', 'Chemical', 'MESH:D013691', (75, 77))	('mRNA expression', 'MPA', (51, 66))	('upregulated', 'PosReg', (111, 122))	('rhCCL3', 'Chemical', '-', (145, 151))
315040	32457351	CCL3-dependent MMP9 upregulation in ESCC cells may be not universal, and may occur via other signaling pathways, such as p38 MAPK, AMPK, or NF-kappaB, which were also reported to be activated downstream of CCL3-CCR5 axis.	('AMPK', 'Gene', (131, 135))	('AMPK', 'Gene', '5564', (131, 135))	('NF-kappaB', 'Gene', '4790', (140, 149))	('NF-kappaB', 'Gene', (140, 149))	('MMP9', 'Gene', (15, 19))	('upregulation', 'PosReg', (20, 32))	('p38', 'Var', (121, 124))
315041	32457351	The paradoxical MMP9 upregulation by LY294002 and PD98059 with rhCCL3 may be caused by the compensatory upregulation of other pathways due to Akt and ERK inhibition.	('upregulation', 'PosReg', (104, 116))	('PD98059', 'Chemical', 'MESH:C093973', (50, 57))	('rhCCL3', 'Gene', (63, 69))	('LY294002', 'Chemical', 'MESH:C085911', (37, 45))	('Akt', 'Pathway', (142, 145))	('upregulation', 'PosReg', (21, 33))	('LY294002', 'Var', (37, 45))	('rhCCL3', 'Chemical', '-', (63, 69))	('MMP9', 'Gene', (16, 20))	('PD98059', 'Var', (50, 57))	('ERK', 'CPA', (150, 153))
315052	32457351	The clinicopathological association between high CCR5 expression and deeper invasion supports the findings of promoted cell invasion and upregulated MMP2 mRNA expression in the three ESCC cell lines by rhCCL3 treatment.	('expression', 'MPA', (54, 64))	('high', 'Var', (44, 48))	('cell invasion', 'CPA', (119, 132))	('upregulated', 'PosReg', (137, 148))	('CCR5', 'Gene', (49, 53))	('deeper invasion', 'CPA', (69, 84))	('rhCCL3', 'Chemical', '-', (202, 208))	('promoted', 'PosReg', (110, 118))	('MMP2 mRNA', 'Gene', (149, 158))
315053	32457351	In addition, the clinicopathological association between high CCR5 expression and presence of vascular invasion or higher microvascular density supports our observation of upregulated VEGFA mRNA expression in the ESCC cell lines following the rhCCL3 treatment.	('expression', 'MPA', (195, 205))	('VEGFA', 'Protein', (184, 189))	('high', 'Var', (57, 61))	('vascular invasion', 'CPA', (94, 111))	('rhCCL3', 'Chemical', '-', (243, 249))	('upregulated', 'PosReg', (172, 183))	('CCR5', 'Gene', (62, 66))	('expression', 'MPA', (67, 77))
315055	32457351	In oral squamous cell carcinoma, the mean survival rate for patients with high numbers of CCL3-positive cells in the tumor parenchyma was shorter than that of the patients with low numbers of CCL3-positive cells, although not significantly.	('survival', 'MPA', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('patients', 'Species', '9606', (163, 171))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('tumor', 'Disease', (117, 122))	('patients', 'Species', '9606', (60, 68))	('shorter', 'NegReg', (138, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('CCL3-positive', 'Gene', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('high numbers', 'Var', (74, 86))
315059	32457351	Moreover, high expression of both CCL3 and CCR5 in the human ESCC tissue was significantly associated with poor overall, disease-free and cause-specific survivals.	('ESCC', 'Disease', (61, 65))	('human', 'Species', '9606', (55, 60))	('disease-free', 'CPA', (121, 133))	('expression', 'MPA', (15, 25))	('high', 'Var', (10, 14))	('CCL3', 'Gene', (34, 38))	('poor', 'NegReg', (107, 111))	('CCR5', 'Gene', (43, 47))	('associated', 'Reg', (91, 101))
315063	32457351	Many other types of CCR5 antagonists and inhibitors such as Vicriviroc, TAK-779, Met-CCL5 (Met-RANTES), OTR4120, OTR4131, anibamine, and DT-13 were also reported to inhibit the cell migration, invasion and/or metastasis of various malignancies including breast cancer, gastric cancer, pancreatic cancer and hepatocellular carcinoma in preclinical studies.	('OTR4120', 'Chemical', 'MESH:C533322', (104, 111))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (307, 331))	('breast cancer', 'Disease', 'MESH:D001943', (254, 267))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('breast cancer', 'Disease', (254, 267))	('pancreatic cancer', 'Disease', 'MESH:D010190', (285, 302))	('inhibitors', 'Var', (41, 51))	('malignancies', 'Disease', 'MESH:D009369', (231, 243))	('Met-CCL5', 'Var', (81, 89))	('invasion', 'CPA', (193, 201))	('malignancies', 'Disease', (231, 243))	('gastric cancer', 'Disease', (269, 283))	('anibamine', 'Chemical', 'MESH:C488244', (122, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (307, 331))	('pancreatic cancer', 'Disease', (285, 302))	('cell migration', 'CPA', (177, 191))	('DT-13', 'Chemical', '-', (137, 142))	('inhibit', 'NegReg', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('RANTES', 'Gene', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (269, 283))	('RANTES', 'Gene', '6352', (95, 101))	('hepatocellular carcinoma', 'Disease', (307, 331))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('OTR4120', 'Var', (104, 111))	('metastasis', 'CPA', (209, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (285, 302))	('OTR4131', 'Var', (113, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (269, 283))	('breast cancer', 'Phenotype', 'HP:0003002', (254, 267))	('TAK-779', 'Gene', (72, 79))	('OTR4131', 'Chemical', 'MESH:C542264', (113, 120))	('Vicriviroc', 'Chemical', 'MESH:C486781', (60, 70))	('TAK-779', 'Chemical', 'MESH:C119369', (72, 79))
315173	32487186	In this study, all patients received ENI and none experienced regional lymph node metastasis, even though they were at risk of subsequent lymph node metastasis.	('ENI', 'Chemical', '-', (37, 40))	('ENI', 'Var', (37, 40))	('regional lymph node metastasis', 'CPA', (62, 92))	('patients', 'Species', '9606', (19, 27))
315183	32487186	They observed a significantly higher cumulative incidence of cardiac-related deaths in the 3D-CRT group compared to that in the IMRT group.	('deaths', 'Disease', 'MESH:D003643', (77, 83))	('3D-CRT', 'Var', (91, 97))	('deaths', 'Disease', (77, 83))
315263	32441221	Similarly, the decreased expression of SEMA3F in 4 ESCC cell lines (Eca109, EC9706, KYSE70, and TE1) was demonstrated when compared to the normal cell line HET1A (all P < .01, Figure 1B).	('KYSE70', 'Var', (84, 90))	('EC9706', 'Var', (76, 82))	('expression', 'MPA', (25, 35))	('EC9706', 'CellLine', 'CVCL:E307', (76, 82))	('HET1A', 'CellLine', 'CVCL:3702', (156, 161))	('SEMA3F', 'Gene', (39, 45))	('decreased', 'NegReg', (15, 24))	('SEMA3F', 'Gene', '6405', (39, 45))
315277	32441221	The curves shown in Figure 4 revealed that patients having ESCC with low SEMA3F expression had shorter survival time compared with those with high SEMA3F expression (log-rank P = .007).	('SEMA3F', 'Gene', (147, 153))	('patients', 'Species', '9606', (43, 51))	('SEMA3F', 'Gene', '6405', (147, 153))	('SEMA3F', 'Gene', (73, 79))	('ESCC', 'Disease', (59, 63))	('SEMA3F', 'Gene', '6405', (73, 79))	('survival time', 'CPA', (103, 116))	('low', 'Var', (69, 72))	('shorter', 'NegReg', (95, 102))
315285	32441221	The functional experiment results indicated that knockdown of VEGF-C expression inhibited cell proliferation, migration, and invasion of Eca109 and TE1 cells (All P < .05, Figure 6C-H).	('knockdown', 'Var', (49, 58))	('VEGF-C', 'Gene', (62, 68))	('migration', 'CPA', (110, 119))	('cell proliferation', 'CPA', (90, 108))	('VEGF-C', 'Gene', '7424', (62, 68))	('inhibited', 'NegReg', (80, 89))
315297	32441221	Overexpression of NRP2 has been detected in various human cancers, and its promoting effect on cancer pathogenesis has also been reported.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (95, 101))	('NRP2', 'Gene', (18, 22))	('detected', 'Reg', (32, 40))	('human', 'Species', '9606', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NRP2', 'Gene', '8828', (18, 22))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('Overexpression', 'Var', (0, 14))	('cancers', 'Disease', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('promoting effect', 'PosReg', (75, 91))
315326	30380947	Clinical application of quantitative glycomics Aberrant glycosylation has been associated with many diseases.	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (47, 69))	('associated', 'Reg', (79, 89))	('Aberrant', 'Var', (47, 55))	('man', 'Species', '9606', (95, 98))
315353	30380947	Additionally, methylamidation/esterification of sialic acid permits the identification of linkage isomers.	('methylamidation/esterification', 'Var', (14, 44))	('methyl', 'Chemical', 'MESH:C031105', (14, 20))	('sialic acid', 'Chemical', 'MESH:D012794', (48, 59))	('sialic acid', 'Protein', (48, 59))	('ester', 'Chemical', 'MESH:D004952', (30, 35))
315358	30380947	Permethylation can significantly enhance MS signals, stablize labile glycan residues such as sialic acids and fucoses, thus ensuring accurate structural information by tandem MS experiments.	('stablize', 'MPA', (53, 61))	('enhance', 'PosReg', (33, 40))	('fucose', 'Chemical', 'MESH:D005643', (110, 116))	('sialic acids', 'Chemical', 'MESH:D012794', (93, 105))	('men', 'Species', '9606', (184, 187))	('MS signals', 'MPA', (41, 51))	('Permethylation', 'Var', (0, 14))	('methyl', 'Chemical', 'MESH:C031105', (3, 9))
315360	30380947	Despite the instability of ESI caused by the low flow rate of CE which is commonly amended by a sheath liquid, CE-MS facilitates glycomics with isomeric separation.	('men', 'Species', '9606', (84, 87))	('facilitates', 'PosReg', (117, 128))	('glycomics', 'MPA', (129, 138))	('CE-MS', 'Var', (111, 116))
315365	30380947	Glycosylation has been proved to be associated with carcinogenesis such as tumor adhesion, malignant transformation and metastasis.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (52, 66))	('malignant transformation', 'CPA', (91, 115))	('metastasis', 'CPA', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('carcinogenesis', 'Disease', (52, 66))	('associated', 'Reg', (36, 46))	('Glycosylation', 'Var', (0, 13))	('tumor', 'Disease', (75, 80))
315377	30380947	The levels of N5H4F1 glycan was assessed in a longitudinal study involving 10 breast cancer patients from early stage to late metastatic stage to define the potential of using the level of N5H4F1 as a breast cancer indicator.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('N5H4F1', 'Chemical', 'MESH:D006859', (189, 195))	('N5H4F1', 'Chemical', 'MESH:D006859', (14, 20))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('N5H4F1', 'Var', (189, 195))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('breast cancer', 'Disease', (201, 214))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
315378	30380947	The increasing levels of N5H4F1 in most late-stage breast cancer patient suggested that such glycan structure was a useful and reliable indicator of breast cancer progression and metastasis than cancer antigen (CA) 15-3 and carcinoembryonic antigen (CAE) (which are the most commonly used biomarker for breast cancer).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patient', 'Species', '9606', (65, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('carcinoembryonic antigen', 'Gene', '1048', (224, 248))	('N5H4F1', 'Chemical', 'MESH:D006859', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('N5H4F1', 'Var', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Disease', (149, 162))	('metastasis than cancer', 'Disease', (179, 201))	('metastasis than cancer', 'Disease', 'MESH:D009362', (179, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('increasing', 'PosReg', (4, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('carcinoembryonic antigen', 'Gene', (224, 248))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Disease', (51, 64))
315381	30380947	Total SLex abundance increased along with other three SLex glycans (N5H4F1, N6H4F1, and N5H5F2) in CTCs >= 5/7.5 mL group, which suggested a potential indicator for breast cancer metastasis.	('N5H4F1', 'Chemical', 'MESH:D006859', (68, 74))	('N6H4F1', 'Chemical', 'MESH:D006859', (76, 82))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('increased', 'PosReg', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('SLex glycans', 'Disease', 'None', (54, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('N5H4F1', 'Var', (68, 74))	('N5H5F2', 'Var', (88, 94))	('SLex abundance', 'MPA', (6, 20))	('N5H5F2', 'Chemical', 'MESH:C533290', (88, 94))	('N6H4F1', 'Var', (76, 82))	('SLex glycans', 'Disease', (54, 66))
315398	30380947	The increase in the expression levels of nine bisection N-glycans (N5H3, N5H4, F1N5H4, F1N5H5, N5H5S1, F1N5H5S1, F1N4H5S2, N5H6F1S3, and F1N5H5S2) were found to contribute to tumor suppression in NIF.	('tumor', 'Disease', (175, 180))	('F1N5H4', 'Var', (79, 85))	('F1N5H5S1', 'Var', (103, 111))	('N5H4', 'Var', (73, 77))	('N5H3', 'Var', (67, 71))	('N5H6F1S3', 'CellLine', 'CVCL:C551', (123, 131))	('F1N5H5', 'Var', (87, 93))	('N5H5S1', 'Var', (95, 101))	('N5H6F1S3', 'Var', (123, 131))	('F1N4H5S2', 'Var', (113, 121))	('F1N4H5S2', 'Chemical', 'MESH:C042345', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('increase', 'PosReg', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('F1N5H5S2', 'Var', (137, 145))	('expression levels', 'MPA', (20, 37))
315399	30380947	Five N-glycans (F1N4H4, F1N4H4 (branch isomer), F1N4H5, F1N5H5S1, and F1N2H3) levels in TIF correlated with that in paired serum.	('TIF', 'Gene', (88, 91))	('F1N4H5, F1N5H5S1', 'Chemical', 'MESH:D006859', (48, 64))	('F1N4H4', 'Var', (16, 22))	('F1N5H5S1', 'Var', (56, 64))	('F1N4H4, F1N4H4', 'Chemical', 'MESH:D006859', (16, 30))	('F1N4H5', 'Var', (48, 54))	('TIF', 'Gene', '7301', (88, 91))	('F1N4H4', 'Var', (24, 30))	('F1N2H3', 'Var', (70, 76))
315406	30380947	The combination of the levels of 3 glycans (N5H6S2, N6H7S3 and bisecting N5H4S1) effectively predicted HCC with 90% accuracy.	('HCC', 'Phenotype', 'HP:0001402', (103, 106))	('predicted', 'Reg', (93, 102))	('bisecting', 'Var', (63, 72))	('N5H6S2', 'Var', (44, 50))	('N6H7S3', 'Var', (52, 58))	('HCC', 'Gene', (103, 106))	('N5H6S2', 'Chemical', 'MESH:C042345', (44, 50))	('N5H4S1', 'Chemical', 'MESH:C042345', (73, 79))	('HCC', 'Gene', '619501', (103, 106))
315413	30380947	Among the observed strcutures, F1N5H6S2 and F1N6H7S3 were elevated in more than 70% of HCC patients.	('HCC', 'Gene', '619501', (87, 90))	('HCC', 'Phenotype', 'HP:0001402', (87, 90))	('F1N5H6S2', 'Var', (31, 39))	('patients', 'Species', '9606', (91, 99))	('F1N5H6S2', 'Chemical', 'MESH:C042345', (31, 39))	('HCC', 'Gene', (87, 90))	('F1N6H7S3', 'Var', (44, 52))	('elevated', 'PosReg', (58, 66))
315414	30380947	Additional correction analyses of these two glycans identified F1N5H6S2 as a significant HCC recurrent indicator and F1N6H7S3 as a significant prognosis indicator.	('HCC', 'Gene', (89, 92))	('F1N6H7S3', 'Var', (117, 125))	('F1N5H6S2', 'Var', (63, 71))	('HCC', 'Gene', '619501', (89, 92))	('F1N5H6S2', 'Chemical', 'MESH:C042345', (63, 71))	('HCC', 'Phenotype', 'HP:0001402', (89, 92))
315418	30380947	Combining bifucosylation degree and clinical marker AFP facilitated a significant improvement in the ability to discriminate HCC from cirrhosis patients.	('AFP', 'Gene', '174', (52, 55))	('HCC', 'Gene', '619501', (125, 128))	('HCC', 'Phenotype', 'HP:0001402', (125, 128))	('cirrhosis', 'Phenotype', 'HP:0001394', (134, 143))	('cirrhosis', 'Disease', 'MESH:D005355', (134, 143))	('bifucosylation', 'Var', (10, 24))	('patients', 'Species', '9606', (144, 152))	('AFP', 'Gene', (52, 55))	('men', 'Species', '9606', (89, 92))	('improvement', 'PosReg', (82, 93))	('HCC', 'Gene', (125, 128))	('cirrhosis', 'Disease', (134, 143))
315427	30380947	The comparison of AFP glycans from normal serum and HCC cells revealed a significant increase of core-fucosylated glycans in HCC cells (including an obvious increase of F1N4H5S2 and F1N4H5S1).	('core-fucosylated glycans', 'Protein', (97, 121))	('HCC', 'Phenotype', 'HP:0001402', (52, 55))	('HCC', 'Gene', '619501', (125, 128))	('AFP', 'Gene', '174', (18, 21))	('HCC', 'Phenotype', 'HP:0001402', (125, 128))	('increase', 'PosReg', (157, 165))	('HCC', 'Gene', (52, 55))	('F1N4H5S2', 'Var', (169, 177))	('F1N4H5S2', 'Chemical', 'MESH:C042345', (169, 177))	('AFP', 'Gene', (18, 21))	('HCC', 'Gene', (125, 128))	('increase', 'PosReg', (85, 93))	('HCC', 'Gene', '619501', (52, 55))	('F1N4H5S1', 'Var', (182, 190))
315436	30380947	Meanwhile, a decrease of bisecting structure and increase of tri- and tetra-antennary structure were observed, and particularly, N6H7S4 and N6H7F1S4 were found significantly increased in ovarian cancer.	('increase', 'PosReg', (49, 57))	('tetra', 'Species', '42554', (70, 75))	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('ovarian cancer', 'Disease', (187, 201))	('bisecting structure', 'MPA', (25, 44))	('decrease', 'NegReg', (13, 21))	('N6H7F1S4', 'CellLine', 'CVCL:4344', (140, 148))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('N6H7F1S4', 'Var', (140, 148))	('increased', 'PosReg', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('N6H7S4', 'Var', (129, 135))
315441	30380947	N-glycans N5H6, *F1N5H6S1, *F2N5H6S3, and *F1N6H7S1 were significantly over-expressed in ovarian samples.	('N-glycans', 'Protein', (0, 9))	('*F1N5H6S1', 'Var', (16, 25))	('N6H7S1', 'CellLine', 'CVCL:G340', (45, 51))	('*F1N6H7S1', 'Var', (42, 51))	('*F2N5H6S3', 'Var', (27, 36))	('over-expressed', 'PosReg', (71, 85))	('N5H6', 'Var', (10, 14))	('ovarian', 'Disease', 'MESH:D010049', (89, 96))	('ovarian', 'Disease', (89, 96))
315444	30380947	After desialylation and APTS labeling, glycans were analyzed by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) and mapped to pre-established database.	('LIF', 'Gene', (136, 139))	('desialylation', 'Var', (6, 19))	('APTS', 'Chemical', 'MESH:C098210', (24, 28))	('LIF', 'Gene', '3976', (136, 139))
315454	30380947	Four N-glycans (N4H3, F1N5H6, Man8 and N2H3) were found to have significant capacities to distinguish tumor, stromal, adipose, and necrotic tissue regions.	('N2H3', 'Var', (39, 43))	('Man', 'Species', '9606', (30, 33))	('necrotic', 'Disease', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('N4H3', 'Var', (16, 20))	('F1N5H6', 'Var', (22, 28))	('necrotic', 'Disease', 'MESH:D009336', (131, 139))	('Man8', 'Var', (30, 34))	('N4H3, F1N5H6', 'Chemical', 'MESH:D006859', (16, 28))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
315463	30380947	Bisecting structures were shown to exhibit up-regulation in metastatic colorectal cancer cell line LIM1215.	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('LIM1215', 'CellLine', 'CVCL:2574', (99, 106))	('Bisecting', 'Var', (0, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('up-regulation', 'PosReg', (43, 56))	('metastatic', 'CPA', (60, 70))
315473	30380947	The increase of bisecting glycans N5H3 and F1N5H4S1 might be a unique feature of CRC.	('F1N5H4S1', 'Var', (43, 51))	('bisecting', 'MPA', (16, 25))	('F1N5H4S1', 'Chemical', 'MESH:D006859', (43, 51))	('CRC', 'Disease', (81, 84))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('increase', 'PosReg', (4, 12))
315477	30380947	Relative abundance of Man5, N3H4, sialylated glycans and paucimannose (F1N2H2, N2H3, F1N2H3, and N2H4) were increased in carcinoma samples when compared with adenoma samples.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('F1N2H2', 'Var', (71, 77))	('paucimannose', 'Chemical', 'None', (57, 69))	('Man', 'Species', '9606', (22, 25))	('increased', 'PosReg', (108, 117))	('adenoma', 'Disease', (158, 165))	('carcinoma', 'Disease', 'MESH:D002277', (121, 130))	('carcinoma', 'Disease', (121, 130))	('F1N2H3', 'Var', (85, 91))	('Man5', 'Protein', (22, 26))	('sialylated glycans', 'Protein', (34, 52))	('H2, N2', 'Species', '114729', (75, 81))	('N3H4', 'Protein', (28, 32))	('adenoma', 'Disease', 'MESH:D000236', (158, 165))
315479	30380947	The increase of paucimannose and SLeA were associated with poor prognosis of advanced colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('SLeA', 'MPA', (33, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('paucimannose', 'Chemical', 'None', (16, 28))	('paucimannose', 'Var', (16, 28))	('increase', 'PosReg', (4, 12))
315481	30380947	F1N4H5 and N6H7S4 (all sialic acids are alpha2,3 linked) had the most significant decrease and increase in CRC, respectively.	('decrease', 'NegReg', (82, 90))	('N6H7S4', 'Var', (11, 17))	('increase', 'PosReg', (95, 103))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('F1N4H5', 'Var', (0, 6))	('sialic acids', 'Chemical', 'MESH:D012794', (23, 35))	('CRC', 'MPA', (107, 110))
315482	30380947	When considering the cancer stages, the decrease of F1N4H5 and F1N4H5S1 (sialic acid is alpha2,6 linked) could be a consistent biomarker across all CRC stages.	('decrease', 'NegReg', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('F1N4H5', 'Var', (52, 58))	('sialic acid', 'Chemical', 'MESH:D012794', (73, 84))	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('F1N4H5S1', 'Var', (63, 71))
315486	30380947	The decrease of 5 glycan expressions (Man5, N4H5, F1N3H4S1, N4H5S1, and F1N4H5S2) were considered as the potential biomarkers in CRC through ROC analysis and further validated on 19 cancer patients and 20 healthy people.	('F1N3H4S1', 'Var', (50, 58))	('N4H5', 'Var', (44, 48))	('N4H5S1', 'Var', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Man5', 'Var', (38, 42))	('F1N4H5S2', 'Var', (72, 80))	('F1N4H5S2', 'Chemical', 'MESH:C042345', (72, 80))	('decrease', 'NegReg', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('N4H5, F1N3H4S1, N4H5S1', 'Chemical', 'MESH:D006859', (44, 66))	('cancer', 'Disease', (182, 188))	('patients', 'Species', '9606', (189, 197))	('Man', 'Species', '9606', (38, 41))	('people', 'Species', '9606', (213, 219))	('CRC', 'Phenotype', 'HP:0003003', (129, 132))
315501	30380947	The analysis was based on the peak areas, among which N4H5F1S2, N6H6S2, N6H7, N5H6S2 (coeluted), F1N6H6S3, N6H7S3, N6H7S2, F1N5H6S3, N5H6F1S3 (coeluted), N7H4S4, N6H7F2S4 (coeluted) were significantly increased while N3H5S1, F1N4H4S1, F1N4H5, F1N5H4S1 (coeluted), F1N4H5S1, N5H5S1, N5H6, N3H6S1, F1N5H5S1 (coeluted) were significantly decreased in lung cancer patients.	('N7H4S4', 'Chemical', 'MESH:C042345', (154, 160))	('decreased', 'NegReg', (335, 344))	('F1N4H5S1', 'Var', (264, 272))	('N5H6F1S3', 'CellLine', 'CVCL:C551', (133, 141))	('F1N5H6S3', 'Chemical', 'MESH:C042345', (123, 131))	('lung cancer', 'Disease', 'MESH:D008175', (348, 359))	('increased', 'PosReg', (201, 210))	('F1N4H5S1, N5H5S1, N5H6, N3H6S1, F1N5H5S1', 'Chemical', 'MESH:D006859', (264, 304))	('N3H5S1, F1N4H4S1, F1N4H5, F1N5H4S1', 'Chemical', 'MESH:D006859', (217, 251))	('N4H5F1S2', 'Chemical', 'MESH:C042345', (54, 62))	('patients', 'Species', '9606', (360, 368))	('N7H4S4', 'Var', (154, 160))	('N6H7, N5H6S2', 'Chemical', 'MESH:D006859', (72, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (348, 359))	('lung cancer', 'Disease', (348, 359))	('N6H6S2', 'Chemical', 'MESH:C042345', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('N3H5S1', 'Gene', (217, 223))
315502	30380947	Also, the significant increase of N4H5F1S2, N6H6S2, N6H7, N5H6S2 and F1N6H6S3, N6H7S3, N6H7S2, F1N5H6S3, N5H6F1S3 were observed in all cancer stages.	('N5H6F1S3', 'CellLine', 'CVCL:C551', (105, 113))	('cancer', 'Disease', (135, 141))	('N6H6S2', 'Var', (44, 50))	('N4H5F1S2', 'Chemical', 'MESH:C042345', (34, 42))	('F1N6H6S3', 'Var', (69, 77))	('N5H6F1S3', 'Var', (105, 113))	('N6H6S2', 'Chemical', 'MESH:C042345', (44, 50))	('increase', 'PosReg', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('N5H6S2', 'Var', (58, 64))	('F1N5H6S3', 'Var', (95, 103))	('N6H7S3', 'Var', (79, 85))	('N4H5F1S2', 'Var', (34, 42))	('N6H7, N5H6S2', 'Chemical', 'MESH:D006859', (52, 64))	('N6H7S2', 'Var', (87, 93))	('N6H7', 'Var', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('F1N5H6S3', 'Chemical', 'MESH:C042345', (95, 103))
315508	30380947	Through ROC analysis of each glycan, four glycans were selected with AUC > 0.6 and FDR < 0.05, among which N4H3 and *F1N4H3 were overexpressed in NSCLC while *F1N4H5 and *F1N5H6 were decreased.	('N4H3', 'Var', (107, 111))	('SCLC', 'Phenotype', 'HP:0030357', (147, 151))	('*F1N4H3', 'Var', (116, 123))	('NSCLC', 'Disease', (146, 151))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('overexpressed', 'PosReg', (129, 142))
315511	30380947	The combination of these 4 features (*F1N5H4, *F1N6H5, bi-sialylation, and tetra-galactosylation) achieved a better diagnostic result (AUC of 0.74).	('tetra-galactosylation', 'Disease', (75, 96))	('tetra-galactosylation', 'Disease', 'MESH:C536498', (75, 96))	('*F1N5H4', 'Var', (37, 44))	('bi-sialylation', 'MPA', (55, 69))	('*F1N6H5', 'Var', (46, 53))
315540	30380947	Glycan F1N6H3 was found in the non-tumor region of the pancreas, while glycan Man8 was predominant in the tumor region of the tissue.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('non-tumor', 'Disease', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Man', 'Species', '9606', (78, 81))	('pancreas', 'Disease', 'MESH:D010190', (55, 63))	('non-tumor', 'Disease', 'MESH:C580335', (31, 40))	('tumor', 'Disease', (35, 40))	('pancreas', 'Disease', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('F1N6H3', 'Var', (7, 13))	('tumor', 'Disease', (106, 111))
315562	30380947	The decrease of two core fucosylated glycans, F1N4H5 and F1N4H4, was considered as potential biomarkers for esophageal cancer with more than 90% sensitivity and 85% specificity.	('F1N4H5', 'Var', (46, 52))	('F1N4H4', 'Var', (57, 63))	('esophageal cancer', 'Disease', (108, 125))	('decrease', 'NegReg', (4, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
315608	30380947	Also, for N4H5S1 and F1N4H5S1, the intensity ratio of high-mobility to low mobility isomers were significantly higher in esophageal adenocarcinoma patients.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (121, 146))	('N4H5S1', 'Var', (10, 16))	('high-mobility to low mobility isomers', 'MPA', (54, 91))	('intensity ratio', 'MPA', (35, 50))	('patients', 'Species', '9606', (147, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('higher', 'PosReg', (111, 117))	('F1N4H5S1', 'Var', (21, 29))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (121, 146))	('esophageal adenocarcinoma', 'Disease', (121, 146))
315640	30380947	Glycan isomer N4H5S2(6,6) was significantly increased in brain seeking cell line 231BR, suggesting this isomer could be a possible indicator for breast cancer brain metastasis.	('breast cancer brain metastasis', 'Disease', 'MESH:D001943', (145, 175))	('breast cancer brain metastasis', 'Disease', (145, 175))	('N4H5S2', 'Var', (14, 20))	('N4H5S2(6,6)', 'Chemical', 'MESH:C042345', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
315644	30380947	A significant increase of N4H5F1S1(6) and N4H5S1(6) can be observed in HCC patients.	('increase', 'PosReg', (14, 22))	('HCC', 'Gene', (71, 74))	('HCC', 'Gene', '619501', (71, 74))	('HCC', 'Phenotype', 'HP:0001402', (71, 74))	('patients', 'Species', '9606', (75, 83))	('N4H5F1S1', 'Var', (26, 34))	('N4H5F1S1(6)', 'Chemical', 'MESH:D006859', (26, 37))	('N4H5S1(6)', 'Chemical', 'MESH:D006859', (42, 51))
315648	30380947	It is known that glycans play significant roles in AD development and studies confirmed variation in protein sialylation and N-glycosylation in the brain of AD patients.	('patients', 'Species', '9606', (160, 168))	('N-glycosylation', 'MPA', (125, 140))	('AD', 'Phenotype', 'HP:0002511', (51, 53))	('protein', 'Protein', (101, 108))	('AD', 'Disease', 'MESH:D000544', (157, 159))	('AD', 'Disease', (157, 159))	('AD', 'Phenotype', 'HP:0002511', (157, 159))	('AD', 'Disease', 'MESH:D000544', (51, 53))	('men', 'Species', '9606', (61, 64))	('variation', 'Var', (88, 97))	('AD', 'Disease', (51, 53))
315662	30380947	Although no significant difference in free oligosaccharides between milk from women with GDM (n=8) and without GDM (n=16) was obtained, significant differences were shown between two groups for N-glycans derived from lactoferrin and sIgA.	('GDM', 'Var', (89, 92))	('lactoferrin', 'Chemical', 'MESH:C432397', (217, 228))	('women', 'Species', '9606', (78, 83))	('N-glycans', 'Protein', (194, 203))	('differences', 'Reg', (148, 159))
315663	30380947	Abundances of mannose, fucose, and sialylated sIgA glycans were decreased in the milk samples from GDM women, while higher abundances of lactoferrin fucosylated and sialylated N-glycans (36-72%) were observed.	('GDM', 'Var', (99, 102))	('fucose', 'Chemical', 'MESH:D005643', (23, 29))	('women', 'Species', '9606', (103, 108))	('mannose', 'Protein', (14, 21))	('sialylated sIgA glycans', 'Protein', (35, 58))	('lactoferrin fucosylated', 'Protein', (137, 160))	('fucose', 'Protein', (23, 29))	('lactoferrin fucosylated', 'Chemical', 'MESH:C517150', (137, 160))	('mannose', 'Chemical', 'MESH:D008358', (14, 21))	('Abundances', 'MPA', (0, 10))	('decreased', 'NegReg', (64, 73))
315666	30380947	The level of F1N4H4 were found significantly reduced in both male and female diabetic patients.	('diabetic', 'Disease', 'MESH:D003920', (77, 85))	('reduced', 'NegReg', (45, 52))	('level', 'MPA', (4, 9))	('diabetic', 'Disease', (77, 85))	('F1N4H4', 'Var', (13, 19))	('patients', 'Species', '9606', (86, 94))
315676	30380947	N-glycans profiles by MALDI-TOF/TOF-MS have shown that glycans F1N5H4 (bisecting), N5H5 (bisecting) and F1N6H3F1 are overexpressed in CHB patients.	('F1N5H4', 'Var', (63, 69))	('TOF', 'Gene', '55079', (28, 31))	('F1N6H3F1', 'Var', (104, 112))	('overexpressed', 'PosReg', (117, 130))	('CHB', 'Disease', 'None', (134, 137))	('N5H5', 'Var', (83, 87))	('TOF', 'Gene', (28, 31))	('TOF', 'Gene', '55079', (32, 35))	('TOF', 'Gene', (32, 35))	('patients', 'Species', '9606', (138, 146))	('CHB', 'Disease', (134, 137))
315677	30380947	In contrast, glycans F1N5H4 (bisecting), N3H5, N6H5 and F1N5H6 are overexpressed in CHC patients, compared to healthy individuals.	('N3H5', 'Var', (41, 45))	('N3H5, N6H5', 'Chemical', 'MESH:D006859', (41, 51))	('CHC', 'Disease', 'MESH:D019698', (84, 87))	('patients', 'Species', '9606', (88, 96))	('F1N5H6', 'Var', (56, 62))	('N6H5', 'Var', (47, 51))	('CHC', 'Disease', (84, 87))	('overexpressed', 'PosReg', (67, 80))	('F1N5H4', 'Var', (21, 27))
315678	30380947	The over-expression of bisecting glycan F1N5H4 was also observed in liver cancer.	('observed', 'Reg', (56, 64))	('liver cancer', 'Disease', (68, 80))	('over-expression', 'PosReg', (4, 19))	('F1N5H4', 'Var', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('liver cancer', 'Phenotype', 'HP:0002896', (68, 80))	('liver cancer', 'Disease', 'MESH:D006528', (68, 80))
315684	30380947	Many glycan structures, such as *F2N5H6S3 and F1N5H6S2, were observed the same up-/down-regulation in different diseases.	('F1N5H6S2', 'Var', (46, 54))	('up-/down-regulation', 'PosReg', (79, 98))	('F1N5H6S2', 'Chemical', 'MESH:C042345', (46, 54))	('Man', 'Species', '9606', (0, 3))
315821	30340465	Do polymorphisms in protein kinase catalytic subunit alpha-1 gene associated with cancer susceptibility?	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('polymorphisms', 'Var', (3, 16))	('associated', 'Reg', (66, 76))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
315822	30340465	a meta-analysis and systematic review Currently, several studies have demonstrated that PRKAA1 polymorphisms conduce to the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('polymorphisms', 'Var', (95, 108))	('conduce', 'Reg', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PRKAA1', 'Gene', (88, 94))	('PRKAA1', 'Gene', '5562', (88, 94))	('cancer', 'Disease', (139, 145))
315824	30340465	Thus, we performed a systematic review and meta-analysis of all enrolled eligible case-control studies to obtain a precise correlation between PRKAA1 polymorphism and cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('PRKAA1', 'Gene', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('polymorphism', 'Var', (150, 162))	('PRKAA1', 'Gene', '5562', (143, 149))
315827	30340465	Twenty-two case-control studies from 14 publications were enrolled, with 17,068 cases and 20,871 controls for rs13361707, and 2514 cases and 3193 controls for rs10074991.	('rs13361707', 'Var', (110, 120))	('rs10074991', 'Var', (159, 169))	('rs13361707', 'Mutation', 'rs13361707', (110, 120))	('rs10074991', 'Mutation', 'rs10074991', (159, 169))
315828	30340465	Overall, we identified that the PRKAA1 rs13361707 polymorphism is not significantly associated with cancer susceptibility under all five genetic models.	('rs13361707', 'Var', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PRKAA1', 'Gene', (32, 38))	('PRKAA1', 'Gene', '5562', (32, 38))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('rs13361707', 'Mutation', 'rs13361707', (39, 49))
315829	30340465	For rs10074991, we revealed a significant decrease risk in allelic comparison model (B vs. A: OR = 0.774, 95% CI = 0.642-0.931, PAdjust = 3.376*10- 2), heterozygote comparison model (BA vs. AA: OR = 0.779 95%CI = 0.691-0.877, PAdjust = 9.86*10- 10;), and dominant genetic model (BB + BA vs. AA: OR = 0.697 95%CI = 0.533-0.912, PAdjust = 4.211*10- 2;).	('rs10074991', 'Mutation', 'rs10074991', (4, 14))	('decrease', 'NegReg', (42, 50))	('rs10074991', 'Var', (4, 14))
315831	30340465	However, the Kaplan-Meier estimate showed that there is no significant difference of OS and RFS between the low and high PRKAA1 TPM groups in gastric cancer, breast cancer, and esophageal carcinoma.	('low', 'Var', (108, 111))	('gastric cancer', 'Disease', (142, 156))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('PRKAA1', 'Gene', (121, 127))	('PRKAA1', 'Gene', '5562', (121, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('esophageal carcinoma', 'Disease', (177, 197))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (177, 197))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (177, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
315832	30340465	To sum up, PRKAA1 rs13361707 polymorphism is not participant with the increased risk of cancer, while the A allele of PRKAA1 rs10074991 revealed a significant decrease risk.	('participant', 'Species', '9606', (49, 60))	('rs13361707 polymorphism', 'Var', (18, 41))	('PRKAA1', 'Gene', (11, 17))	('cancer', 'Disease', (88, 94))	('PRKAA1', 'Gene', '5562', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('PRKAA1', 'Gene', (118, 124))	('PRKAA1', 'Gene', '5562', (118, 124))	('rs10074991', 'Mutation', 'rs10074991', (125, 135))	('decrease', 'NegReg', (159, 167))	('rs13361707', 'Mutation', 'rs13361707', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('rs10074991', 'Var', (125, 135))
315840	30340465	Most of the publications concerned about PRKAA1 polymorphisms focused on its significantly positive association with gastric cancer (GC), as well as on breast cancer, but there are also some negative results.	('PRKAA1', 'Gene', (41, 47))	('PRKAA1', 'Gene', '5562', (41, 47))	('positive', 'PosReg', (91, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('polymorphisms', 'Var', (48, 61))	('breast cancer', 'Disease', (152, 165))	('gastric cancer', 'Disease', (117, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))
315842	30340465	Herein, we managed the meta-analysis to assess whether PRKAA1 polymorphisms affect susceptibility of cancer.	('affect', 'Reg', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('PRKAA1', 'Gene', '5562', (55, 61))	('cancer', 'Disease', (101, 107))	('PRKAA1', 'Gene', (55, 61))	('polymorphisms', 'Var', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
315844	30340465	All the eligible studies were enrolled following the details: 1) assess the correlation between the polymorphisms in PRKAA1 and cancer susceptibility; 2) case-control studies; 3) demonstrate the frequency of genotypes of all cases and controls, or could obtain it via calculating.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('PRKAA1', 'Gene', (117, 123))	('PRKAA1', 'Gene', '5562', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('polymorphisms', 'Var', (100, 113))	('cancer', 'Disease', (128, 134))
315849	30340465	We performed the meta-analyses in the pool, ORs with corresponding 95% CI was recorded to evaluated the strength of the correlation between PRKAA1 polymorphisms (rs13361707, rs10074991) and cancer susceptibility, the P value was adjusted by Bonferroni corrections, PAdjust = PZ * 5 models.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('rs10074991', 'Mutation', 'rs10074991', (174, 184))	('rs10074991', 'Var', (174, 184))	('rs13361707', 'Var', (162, 172))	('rs13361707', 'Mutation', 'rs13361707', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('PRKAA1', 'Gene', '5562', (140, 146))	('PRKAA1', 'Gene', (140, 146))
315851	30340465	Finally, 22 case-control studies from 14 publications were enrolled in our study, 17,068 cases and 20,871 controls for rs13361707, while 2514 cases and 3193 controls for rs10074991 (Table 1, Additional file 1: Table S1).	('rs13361707', 'Mutation', 'rs13361707', (119, 129))	('rs10074991', 'Mutation', 'rs10074991', (170, 180))	('rs13361707', 'Var', (119, 129))	('rs10074991', 'Var', (170, 180))
315853	30340465	We identified that the rs13361707 polymorphism is not related to the susceptibility of cancer under all five genetic models in the overall population (B vs. A: OR = 0.900, 95%CI = 0.776-1.042, PAdjust = 0.795; BB vs. AA: OR = 0.810, 95% CI = 0.601-1.092, PAdjust = 0.830; BA vs. AA: OR = 0.900, 95% CI = 0.768-1.054, PAdjust = 0.960; BA+AA vs. AA: OR = 0.569, 95% CI = 0.711-1.061, PAdjust = 0.840; and BB vs. BA+AA: OR = 0.965, 95% CI = 0.714-1.071, PAdjust = 0.965), and the stratified analysis also indicated no relationships in the subgroups of cancer type, ethnicity and source of control (Fig.	('rs13361707', 'Mutation', 'rs13361707', (23, 33))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (549, 555))	('rs13361707', 'Var', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (549, 555))	('cancer', 'Disease', (549, 555))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
315854	30340465	For rs10074991, we revealed a significant decrease risk in allelic comparison model (B vs. A: OR = 0.774, 95% CI = 0.642-0.931, PAdjust = 3.376*10- 2), heterozygote comparison model (BA vs. AA: OR = 0.779 95%CI = 0.691-0.877, PAdjust = 1.948*10- 4;), and dominant genetic model (BB + BA vs. AA: OR = 0.697 95%CI = 0.533-0.912, PAdjust = 4.211*10- 2;) (Fig.	('rs10074991', 'Mutation', 'rs10074991', (4, 14))	('decrease', 'NegReg', (42, 50))	('rs10074991', 'Var', (4, 14))
315855	30340465	3), and the subgroup of Asian people in rs10074991 shown a prevent potential for tumorigenesis in all five genetic models (B vs. A: OR = 0.704, 95%CI = 0.632-0.785, PAdjust = 1.085*10-9; BB vs. AA: OR = 0.489, 95% CI = 0.489 0.392-0.609, PAdjust = 9.86*10-10; BA vs. AA: OR = 0.675, 95% CI = 0.558-0.816, PAdjust = 2.473*10-4; BA+AA vs. AA: OR = 0.607, 95% CI = 0.507-0.727, PAdjust = 2.691*10-7; and BB vs. BA+AA: OR = 0.638, 95% CI = 0.534-0.762, PAdjust = 3.876*10-6).	('rs10074991', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('people', 'Species', '9606', (30, 36))	('rs10074991', 'Mutation', 'rs10074991', (40, 50))	('tumor', 'Disease', (81, 86))
315856	30340465	On the besides, potential publication bias of enrolled case-control studies was appraised by Begg's funnel plot and Egger's test, no publication bias was revealed in both rs13361707 and rs10074991 (Additional file 1: Figures S1 and S2, Table S5).	('rs13361707', 'Mutation', 'rs13361707', (171, 181))	('rs10074991', 'Mutation', 'rs10074991', (186, 196))	('rs13361707', 'Var', (171, 181))	('rs10074991', 'Var', (186, 196))
315859	30340465	The Kaplan-Meier estimate showed that there is no significant difference of OS and RFS between the low and high PRKAA1 TPM groups in gastric cancer (OS: Log-rank P = 0.48, RFS: Log-rank P = 0.38), breast cancer (OS: Log-rank P = 0.34, RFS: Log-rank P = 0.98), esophageal carcinoma (OS: Log-rank P = 0.096, RFS: Log-rank P = 0.7), and lung adenocarcinoma (OS: Log-rank P = 0.41, RFS: Log-rank P = 0.20).	('esophageal carcinoma', 'Disease', 'MESH:D004938', (260, 280))	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('PRKAA1', 'Gene', '5562', (112, 118))	('esophageal carcinoma', 'Disease', (260, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('gastric cancer', 'Disease', (133, 147))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('lung adenocarcinoma', 'Disease', (334, 353))	('breast cancer', 'Disease', (197, 210))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (260, 280))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('PRKAA1', 'Gene', (112, 118))	('gastric cancer', 'Disease', 'MESH:D013274', (133, 147))	('high', 'Var', (107, 111))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (334, 353))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (334, 353))
315863	30340465	On the other way, some publications reported that activated AMPK take pate in the activation of anti-inflammatory agents, as well as inhibition the inflammatory function of macrophage.The lack of anti-inflammatory function will occur with the allele mutation of PRKAA1 allele, and the patients would suffer from several epithelium disease.	('AMPK', 'Gene', '5562', (60, 64))	('AMPK', 'Gene', (60, 64))	('PRKAA1', 'Gene', (262, 268))	('PRKAA1', 'Gene', '5562', (262, 268))	('epithelium disease', 'Disease', (320, 338))	('anti-inflammatory function', 'MPA', (196, 222))	('allele mutation', 'Var', (243, 258))	('patients', 'Species', '9606', (285, 293))	('suffer', 'Reg', (300, 306))	('lack', 'NegReg', (188, 192))
315865	30340465	Currently, several studies have demonstrated that PRKAA1 polymorphisms conduce to the development of gastric cancer, Sun et al.	('polymorphisms', 'Var', (57, 70))	('gastric cancer', 'Disease', (101, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('conduce to', 'Reg', (71, 81))	('PRKAA1', 'Gene', (50, 56))	('PRKAA1', 'Gene', '5562', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
315868	30340465	There are several studies concerned about the polymorphisms of PRKAA1, and the variant sites include rs154268, rs3805486, rs461404, rs6882903, rs13361707 and rs10074991.	('PRKAA1', 'Gene', (63, 69))	('PRKAA1', 'Gene', '5562', (63, 69))	('rs3805486', 'Mutation', 'rs3805486', (111, 120))	('rs13361707', 'Mutation', 'rs13361707', (143, 153))	('rs10074991', 'Var', (158, 168))	('rs154268', 'Var', (101, 109))	('rs10074991', 'Mutation', 'rs10074991', (158, 168))	('rs461404', 'Mutation', 'rs461404', (122, 130))	('rs13361707', 'Var', (143, 153))	('rs154268', 'Mutation', 'rs154268', (101, 109))	('rs461404', 'Var', (122, 130))	('rs6882903', 'Mutation', 'rs6882903', (132, 141))	('rs3805486', 'Var', (111, 120))	('rs6882903', 'Var', (132, 141))
315869	30340465	After our comprehensive search and analyses, only rs13361707 and rs10074991 have 3 or more studies, so the other studies are excluded.	('rs13361707', 'Var', (50, 60))	('rs10074991', 'Var', (65, 75))	('rs13361707', 'Mutation', 'rs13361707', (50, 60))	('rs10074991', 'Mutation', 'rs10074991', (65, 75))
315870	30340465	suggested that rs13361707 polymorphism is remarkable related to an upgraded risk to gastric cancer in Asian and Caucasian, respectively.	('gastric cancer', 'Disease', (84, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('rs13361707', 'Mutation', 'rs13361707', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('rs13361707', 'Var', (15, 25))
315871	30340465	indicated the controversial result, in their study, rs13361707 of PRKAA1 doesn't affect the process of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('PRKAA1', 'Gene', (66, 72))	('PRKAA1', 'Gene', '5562', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rs13361707', 'Mutation', 'rs13361707', (52, 62))	('rs13361707', 'Var', (52, 62))	('gastric cancer', 'Disease', (103, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))
315874	30340465	In another case-control study conducted by Dai et al., they revealed that the polymorphism of rs13361707 also doesn't work in esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (126, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('rs13361707', 'Mutation', 'rs13361707', (94, 104))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (126, 160))	('rs13361707', 'Var', (94, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
315875	30340465	In current study, we identified that the rs13361707 polymorphism would not affect the susceptibility of cancer in the overall population.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs13361707', 'Mutation', 'rs13361707', (41, 51))	('rs13361707', 'Var', (41, 51))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
315878	30340465	revealed that rs10074991 is not associated with the tumorigenesis of breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('rs10074991', 'Mutation', 'rs10074991', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('rs10074991', 'Var', (14, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
315879	30340465	Rs10074991 and rs13361707 polymorphisms both located at the intron of PRKAA1, within the perfect LD (R2 = 1.00).	('PRKAA1', 'Gene', '5562', (70, 76))	('PRKAA1', 'Gene', (70, 76))	('Rs10074991', 'Mutation', 'Rs10074991', (0, 10))	('rs13361707', 'Mutation', 'rs13361707', (15, 25))	('Rs10074991', 'Var', (0, 10))	('rs13361707', 'Var', (15, 25))
315881	30340465	demonstrated that the rs13361707 LD block mainly spans PTGER4, TTC33, and PRKAA1 gene, and a remarkable relationships between rs13361707 and these three genes were shown in the results from GTEx, so the polymorphism of rs13361707 might influence the expression of PRKAA1.	('TTC33', 'Gene', '23548', (63, 68))	('rs13361707', 'Mutation', 'rs13361707', (126, 136))	('rs13361707', 'Var', (22, 32))	('PTGER4', 'Gene', (55, 61))	('PRKAA1', 'Gene', (264, 270))	('influence', 'Reg', (236, 245))	('PRKAA1', 'Gene', '5562', (264, 270))	('rs13361707', 'Mutation', 'rs13361707', (219, 229))	('PRKAA1', 'Gene', '5562', (74, 80))	('rs13361707', 'Var', (219, 229))	('PTGER4', 'Gene', '5734', (55, 61))	('TTC33', 'Gene', (63, 68))	('PRKAA1', 'Gene', (74, 80))	('expression', 'MPA', (250, 260))	('rs13361707', 'Mutation', 'rs13361707', (22, 32))
315883	30340465	For example, the allele frequency of rs10074991, rs13361707 for all the enrolled Asian population based studies are ranged from 40 to 60%, while the Caucasian population based studies are ranged about 80% (Additional file 1: Table S1), it might cause by the ethnic difference.	('rs13361707', 'Var', (49, 59))	('rs10074991', 'Var', (37, 47))	('rs10074991', 'Mutation', 'rs10074991', (37, 47))	('rs13361707', 'Mutation', 'rs13361707', (49, 59))
315885	30340465	Initially, we enrolled all eligible studies focused on the relationships between PRKAA1 polymorphisms and overall cancer risks to conducted a comprehensive meta-analysis.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('polymorphisms', 'Var', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('PRKAA1', 'Gene', '5562', (81, 87))	('PRKAA1', 'Gene', (81, 87))	('cancer', 'Disease', (114, 120))
315887	30340465	Then, most of the enrolled studies are concerned about GC, only 2 about ESCC, 1 about breast cancer, and 1 about lung cancer, therefore, the meta-analysis result might not be able to illustrated the impact of rs10074991 and rs13361707 in overall cancer risk.	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('rs10074991', 'Mutation', 'rs10074991', (209, 219))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('cancer', 'Disease', (246, 252))	('rs13361707', 'Mutation', 'rs13361707', (224, 234))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('breast cancer', 'Disease', (86, 99))	('rs13361707', 'Var', (224, 234))	('cancer', 'Disease', (118, 124))	('rs10074991', 'Var', (209, 219))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ESCC', 'Disease', (72, 76))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('lung cancer', 'Disease', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
315888	30340465	Our data have successfully elaborated that PRKAA1 rs13361707 polymorphism is not participant with increased risk of cancer, while the A allele of PRKAA1 rs10074991 revealed a significant decrease risk, especially in Asian population.	('rs13361707', 'Var', (50, 60))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('participant', 'Species', '9606', (81, 92))	('PRKAA1', 'Gene', (43, 49))	('PRKAA1', 'Gene', (146, 152))	('rs10074991', 'Mutation', 'rs10074991', (153, 163))	('PRKAA1', 'Gene', '5562', (43, 49))	('PRKAA1', 'Gene', '5562', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rs10074991', 'Var', (153, 163))	('decrease', 'NegReg', (187, 195))	('rs13361707', 'Mutation', 'rs13361707', (50, 60))
315890	30340465	AMP Adenosine monophosphate AMPK AMP-activated protein kinase ATP Adenosine triphosphate CIs Confidence intervals HWE Hardy-Weinberg Equilibrium mTORC1 Mammalian target of rapamycin complex 1 ORs Odds ratio SNP Single nucleotide polymorphism TPM Transcripts Per Kilobase Million MJL and FXY accessed information from literature for this article.	('AMP', 'Gene', (28, 31))	('Mammalian', 'Species', '9606', (152, 161))	('AMPK', 'Gene', (28, 32))	('AMP-activated protein kinase', 'Gene', '5562', (33, 61))	('Adenosine monophosphate', 'Chemical', 'MESH:D000249', (4, 27))	('mTORC1', 'Gene', (145, 151))	('mTORC1', 'Gene', '382056', (145, 151))	('AMP', 'Gene', '353', (28, 31))	('Single nucleotide polymorphism', 'Var', (211, 241))	('AMP', 'Gene', (33, 36))	('AMP', 'Gene', (0, 3))	('AMPK', 'Gene', '5562', (28, 32))	('TPM', 'Gene', (242, 245))	('AMP-activated protein kinase', 'Gene', (33, 61))	('MJL', 'Disease', 'None', (279, 282))	('AMP', 'Gene', '353', (33, 36))	('ATP', 'Chemical', 'MESH:D000255', (62, 65))	('MJL', 'Disease', (279, 282))	('AMP', 'Gene', '353', (0, 3))	('Adenosine triphosphate', 'Chemical', 'MESH:D000255', (66, 88))
315897	26159510	Among the originally analyzed 296 patients, 100 (33.7 %) patients had ypT0, including 78 patients (78 %) with ypT0N0, and 22 patients (22 %) with ypT0N1.	('ypT0', 'Disease', (70, 74))	('patients', 'Species', '9606', (57, 65))	('ypT0N0', 'Var', (110, 116))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (125, 133))
315899	26159510	Patients with ypT0N0 have significant improved 5-year OS and PFS than ypT0N1 patients (OS: 50.7 % vs 13.6 %, P = 0.004; PFS: 49.6 % vs 13.6 %, P = 0.003).	('improved', 'PosReg', (38, 46))	('ypT0N0', 'Var', (14, 20))	('PFS', 'CPA', (61, 64))	('OS', 'Chemical', '-', (87, 89))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (54, 56))	('patients', 'Species', '9606', (77, 85))
315901	26159510	Our results indicate that patients with ypT0N0 after preoperative radiotherapy had significantly better OS and PFS than patients with ypT0N1 in ESCC.	('OS', 'Chemical', '-', (104, 106))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (120, 128))	('better', 'PosReg', (97, 103))	('ypT0N0', 'Var', (40, 46))	('PFS', 'CPA', (111, 114))
315907	26159510	A previous study showed that when reclassified patient stage according to the AJCC 7th edition TNM criteria after neoadjuvant CRT, the 5-year overall survival (OS) of patients with ypT0N1 was significantly lower than ypT0N0 patients, and similar to pathologic partial response (pPR) stage II patients.	('CRT', 'Gene', '799', (126, 129))	('overall survival', 'MPA', (142, 158))	('TNM', 'Gene', (95, 98))	('patient', 'Species', '9606', (47, 54))	('CRT', 'Gene', (126, 129))	('patient', 'Species', '9606', (167, 174))	('patients', 'Species', '9606', (167, 175))	('patient', 'Species', '9606', (224, 231))	('lower', 'NegReg', (206, 211))	('patient', 'Species', '9606', (292, 299))	('pPR', 'Gene', '100528023', (278, 281))	('ypT0N1', 'Var', (181, 187))	('OS', 'Chemical', '-', (160, 162))	('patients', 'Species', '9606', (224, 232))	('TNM', 'Gene', '10178', (95, 98))	('patients', 'Species', '9606', (292, 300))	('pPR', 'Gene', (278, 281))
315942	26159510	Patients with N0 status after neoadjuvant radiotherapy have significant improved 5-year OS and PFS than N1 patients (P = 0.004 and P = 0.003 respectively, Fig.	('N0 status', 'Var', (14, 23))	('improved', 'PosReg', (72, 80))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (88, 90))	('patients', 'Species', '9606', (107, 115))	('PFS', 'CPA', (95, 98))
315946	26159510	Our results showed that OS and PFS of patients with ypT0N1 after neoadjuvant RT were significantly worse than those of patients with ypT0N0, which indicated that residual nodal metastases after neoadjuvant RT does influence the prognosis of patients with pCR of the primary tumor underwent preoperative RT plus surgery.	('influence', 'Reg', (214, 223))	('OS', 'Chemical', '-', (24, 26))	('patients', 'Species', '9606', (119, 127))	('metastases', 'Disease', (177, 187))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('ypT0N1', 'Var', (52, 58))	('PFS', 'CPA', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('patients', 'Species', '9606', (38, 46))	('metastases', 'Disease', 'MESH:D009362', (177, 187))	('tumor', 'Disease', (274, 279))	('patients', 'Species', '9606', (241, 249))	('worse', 'NegReg', (99, 104))
315955	26159510	For ypT0N1 patients, the number of lymph node metastases of 1-3 and >=4 were 17/100 and 5/100 respectively.	('patients', 'Species', '9606', (11, 19))	('lymph node metastases', 'Disease', (35, 56))	('ypT0N1', 'Var', (4, 10))	('lymph node metastases', 'Disease', 'MESH:D009362', (35, 56))
315958	26159510	The previous Korean study showed that when reclassified according to the AJCC 7th edition TNM criteria, the 5-year survival of patients with ypT0N1 was similar to pPR stage II patients.	('patients', 'Species', '9606', (176, 184))	('pPR', 'Gene', (163, 166))	('pPR', 'Gene', '100528023', (163, 166))	('TNM', 'Gene', '10178', (90, 93))	('patients', 'Species', '9606', (127, 135))	('ypT0N1', 'Var', (141, 147))	('TNM', 'Gene', (90, 93))
315960	26159510	Thus we recommend that future revisions may take consideration of patients with pathologic ypT0N1 for esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('ypT0N1', 'Var', (91, 97))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('patients', 'Species', '9606', (66, 74))
316022	26095281	Rahadiani et al reported that high podoplanin expression was significantly correlated with tumor status, depth of invasion, and lymphatic and vascular invasion, and was associated with a poorer prognosis in ESCC.	('ESCC', 'Disease', (207, 211))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('high', 'Var', (30, 34))	('correlated', 'Reg', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('expression', 'MPA', (46, 56))	('tumor', 'Disease', (91, 96))	('podoplanin', 'Protein', (35, 45))
316232	23303625	We examined the incidence over the study period of all stages of EAC, defined anatomically as being located in the esophagus and histologically as adenocarcinoma (International Classification of Diseases for Oncology, third edition [ICD-O-3] codes 8140-8141, 8143-8145, 8190-8231, 8260-8263, 8310, 8401, 8480-8490, 8550-8551, 8570-8574, and 8576).	('EAC', 'Gene', (65, 68))	('8576', 'Var', (341, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('8401', 'Var', (298, 302))	('Oncology', 'Phenotype', 'HP:0002664', (208, 216))	('8190-8231', 'Var', (270, 279))	('8550-8551', 'Var', (315, 324))	('adenocarcinoma', 'Disease', (147, 161))	('adenocarcinoma', 'Disease', 'MESH:D000230', (147, 161))	('8143-8145', 'Var', (259, 268))	('8140-8141', 'Var', (248, 257))	('EAC', 'Phenotype', 'HP:0011459', (65, 68))	('8260-8263', 'Var', (281, 290))	('EAC', 'Gene', '1540', (65, 68))	('8310', 'Var', (292, 296))	('8570-8574', 'Var', (326, 335))	('8480-8490', 'Var', (304, 313))
316379	23678472	In the univariate analysis for early rebleeding, the presence of HCC (OR: 4.418, 95% CI: 1.457-13.402, p=0.009) and PVT (OR: 4.500, 95% CI: 1.561-12.969, p=0.005) were independent predictive factors (Table 3).	('HCC', 'Phenotype', 'HP:0001402', (65, 68))	('bleeding', 'Disease', 'MESH:D006470', (39, 47))	('bleeding', 'Disease', (39, 47))	('HCC', 'Gene', (65, 68))	('presence', 'Var', (53, 61))	('PVT', 'Phenotype', 'HP:0030242', (116, 119))	('HCC', 'Gene', '619501', (65, 68))
316391	23678472	However, EVL was associated with a lower rate of late rebleeding and there was a trend toward longer survival and time-to-rebleeding.	('bleeding', 'Disease', 'MESH:D006470', (56, 64))	('bleeding', 'Disease', (56, 64))	('EVL', 'Var', (9, 12))	('late', 'CPA', (49, 53))	('EVL', 'Chemical', '-', (9, 12))	('lower', 'NegReg', (35, 40))	('longer', 'PosReg', (94, 100))	('bleeding', 'Disease', 'MESH:D006470', (124, 132))	('bleeding', 'Disease', (124, 132))
316630	31710585	PPI therapy is associated with a 71% decrease in the risk of high-grade dysplasia and adenocarcinoma in patients with Barrett esophagus (OR 0.29, 95% CI 0.12-0.79).	('decrease', 'NegReg', (37, 45))	('Barrett', 'Disease', (118, 125))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (118, 135))	('PPI therapy', 'Var', (0, 11))	('patients', 'Species', '9606', (104, 112))	('dysplasia and adenocarcinoma', 'Disease', 'MESH:D000230', (72, 100))
316632	31710585	A meta-analysis demonstrated that aspirin and NSAIDs led to a 32% reduction in the risk of adenocarcinoma (OR 0.68, 95% CI 0.56-0.83).	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('aspirin', 'Chemical', 'MESH:D001241', (34, 41))	('NSAIDs', 'Var', (46, 52))	('adenocarcinoma', 'Disease', (91, 105))	('reduction', 'NegReg', (66, 75))
316645	31710585	Its deficiency has also been associated with increased risk of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (63, 88))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (63, 88))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (63, 88))	('deficiency', 'Var', (4, 14))
316660	31710585	A key part of treatment during this time is maximal acid suppression with a PPI twice daily and a histamine-2 blocker at night.	('acid suppression', 'MPA', (52, 68))	('PPI', 'Var', (76, 79))	('men', 'Species', '9606', (19, 22))
316665	31710585	Cryotherapy produces cellular injury by rapid freezing and thawing of tissue using a cryogen such as liquid nitrogen or nitrous oxide.	('cellular injury', 'CPA', (21, 36))	('nitrous oxide', 'Chemical', 'MESH:D009609', (120, 133))	('Cryotherapy', 'Var', (0, 11))	('nitrogen', 'Chemical', 'MESH:D009584', (108, 116))
316672	31710585	In another trial of 136 patients with low-grade dysplasia followed for 3 years, Phoa et al demonstrated that radiofrequency ablation reduced the rate of progression to high-grade dysplasia by 25% and to adenocarcinoma by 7.4% compared with endoscopic surveillance.	('low-grade dysplasia', 'Disease', (38, 57))	('adenocarcinoma', 'Disease', (203, 217))	('dysplasia', 'Disease', 'MESH:D015792', (179, 188))	('radiofrequency', 'Var', (109, 123))	('adenocarcinoma', 'Disease', 'MESH:D000230', (203, 217))	('low-grade dysplasia', 'Disease', 'MESH:D008228', (38, 57))	('patients', 'Species', '9606', (24, 32))	('dysplasia', 'Disease', (179, 188))	('reduced', 'NegReg', (133, 140))	('dysplasia', 'Disease', 'MESH:D015792', (48, 57))	('dysplasia', 'Disease', (48, 57))
316677	31710585	Eradication of intestinal metaplasia was achieved in 77% of ablation patients vs 2% of patients with the sham therapy.	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (87, 95))	('intestinal metaplasia', 'Disease', (15, 36))	('ablation', 'Var', (60, 68))
316706	31908394	Analysis of data from TCGA database revealed that control samples showed significantly lower CASC9 expression than carcinoma tissue samples (P < 0.001); the low CASC9 expression group had a higher survival rate than the high CASC9 expression group (P = 0.011), and the patient group showed significantly increased expression of serum CASC9, with the area under the curve (AUC) of 0.933.	('expression', 'MPA', (99, 109))	('CASC9', 'Gene', '101805492', (334, 339))	('CASC9', 'Gene', (225, 230))	('CASC9', 'Gene', (161, 166))	('survival rate', 'CPA', (197, 210))	('carcinoma', 'Disease', 'MESH:D002277', (115, 124))	('CASC9', 'Gene', '101805492', (93, 98))	('increased', 'PosReg', (304, 313))	('patient', 'Species', '9606', (269, 276))	('CASC9', 'Gene', (334, 339))	('lower', 'NegReg', (87, 92))	('CASC9', 'Gene', '101805492', (225, 230))	('CASC9', 'Gene', '101805492', (161, 166))	('CASC9', 'Gene', (93, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Disease', (115, 124))	('low', 'Var', (157, 160))	('expression', 'MPA', (314, 324))	('higher', 'PosReg', (190, 196))
316707	31908394	CASC9 expression was related to tumor size, combined hepatitis, tumor, node, metastasis (TNM) staging, lymph node metastasis, differentiation and alpha fetoprotein, and the high CASC9 expression group showed lower 1-year, 3-year and 5-year survival rates than the low CASC9 expression group (all aP < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('alpha fetoprotein', 'Gene', '174', (146, 163))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('CASC9', 'Gene', (178, 183))	('CASC9', 'Gene', '101805492', (268, 273))	('lower', 'NegReg', (208, 213))	('CASC9', 'Gene', (0, 5))	('high', 'Var', (173, 177))	('hepatitis', 'Phenotype', 'HP:0012115', (53, 62))	('tumor', 'Disease', (32, 37))	('CASC9', 'Gene', '101805492', (178, 183))	('CASC9', 'Gene', (268, 273))	('hepatitis', 'Disease', 'MESH:D056486', (53, 62))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('alpha fetoprotein', 'Gene', (146, 163))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('hepatitis', 'Disease', (53, 62))	('CASC9', 'Gene', '101805492', (0, 5))
316709	31908394	Stage I+II patients with lymph node metastasis, low differentiation, and alpha fetoprotein > 200 ng/mL had a poor 5-year survival rate.	('lymph node metastasis', 'CPA', (25, 46))	('poor', 'NegReg', (109, 113))	('alpha fetoprotein', 'Gene', (73, 90))	('alpha fetoprotein', 'Gene', '174', (73, 90))	('> 200 ng/mL', 'Var', (91, 102))	('low', 'NegReg', (48, 51))	('patients', 'Species', '9606', (11, 19))
316710	31908394	High CASC9 expression is beneficial in the prognosis of HCC patients.	('HCC', 'Disease', (56, 59))	('High', 'Var', (0, 4))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('expression', 'MPA', (11, 21))	('patients', 'Species', '9606', (60, 68))	('CASC9', 'Gene', (5, 10))	('CASC9', 'Gene', '101805492', (5, 10))	('beneficial', 'PosReg', (25, 35))	('HCC', 'Disease', 'MESH:D006528', (56, 59))
316745	31908394	Analysis of data from TCGA database on CASC9 expression in HCC patients showed that control samples had significantly lower CASC9 expression than carcinoma tissue samples (P < 0.001), and the grouping of patients according to median CASC9 expression revealed that the low CASC9 expression group had a higher survival rate than the high CASC9 expression group (P = 0.011, Figure 1).	('expression', 'MPA', (130, 140))	('low', 'Var', (268, 271))	('higher', 'PosReg', (301, 307))	('CASC9', 'Gene', (124, 129))	('CASC9', 'Gene', '101805492', (39, 44))	('HCC', 'Disease', 'MESH:D006528', (59, 62))	('CASC9', 'Gene', (336, 341))	('CASC9', 'Gene', (233, 238))	('carcinoma', 'Disease', 'MESH:D002277', (146, 155))	('CASC9', 'Gene', (272, 277))	('patients', 'Species', '9606', (204, 212))	('CASC9', 'Gene', '101805492', (124, 129))	('CASC9', 'Gene', (39, 44))	('HCC', 'Disease', (59, 62))	('CASC9', 'Gene', '101805492', (336, 341))	('HCC', 'Phenotype', 'HP:0001402', (59, 62))	('CASC9', 'Gene', '101805492', (233, 238))	('CASC9', 'Gene', '101805492', (272, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('carcinoma', 'Disease', (146, 155))	('patients', 'Species', '9606', (63, 71))	('lower', 'NegReg', (118, 123))	('survival rate', 'CPA', (308, 321))
316771	31908394	It was found that the low CASC9 expression group had a higher survival rate than the high CASC9 expression group.	('low', 'Var', (22, 25))	('CASC9', 'Gene', (90, 95))	('survival rate', 'CPA', (62, 75))	('CASC9', 'Gene', '101805492', (90, 95))	('CASC9', 'Gene', (26, 31))	('CASC9', 'Gene', '101805492', (26, 31))	('higher', 'PosReg', (55, 61))
316795	31908394	In conclusion, high CASC9 expression is beneficial for the prognosis of HCC patients, and CASC9 is expected to be a potential diagnostic and prognostic indicator of HCC.	('high', 'Var', (15, 19))	('expression', 'MPA', (26, 36))	('HCC', 'Disease', (72, 75))	('patients', 'Species', '9606', (76, 84))	('HCC', 'Phenotype', 'HP:0001402', (72, 75))	('CASC9', 'Gene', (90, 95))	('CASC9', 'Gene', '101805492', (20, 25))	('CASC9', 'Gene', '101805492', (90, 95))	('HCC', 'Phenotype', 'HP:0001402', (165, 168))	('HCC', 'Disease', 'MESH:D006528', (165, 168))	('beneficial', 'PosReg', (40, 50))	('HCC', 'Disease', (165, 168))	('HCC', 'Disease', 'MESH:D006528', (72, 75))	('CASC9', 'Gene', (20, 25))
316813	31802902	The aim of this study was to investigate the expression characteristics of microRNA-186-5p in esophageal cancer (ECa) and its correlation with clinical progression and prognosis, and to further explore its underlying mechanisms.	('esophageal cancer', 'Disease', (94, 111))	('ECa', 'Disease', (113, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('microRNA-186-5p', 'Var', (75, 90))	('ECa', 'Disease', 'MESH:D004938', (113, 116))
316816	31802902	QRT-PCR results revealed that the expression of microRNA-186-5p in ECa tissues was remarkably lower than that in adjacent tissues, and the difference was statistically significant.	('expression', 'MPA', (34, 44))	('microRNA-186-5p', 'Var', (48, 63))	('ECa', 'Disease', (67, 70))	('lower', 'NegReg', (94, 99))	('ECa', 'Disease', 'MESH:D004938', (67, 70))
316817	31802902	Compared with patients with high expression of microRNA-186-5p, patients with low expression of microRNA-186-5p had higher incidence of pathological stage and lower overall survival rate.	('patients', 'Species', '9606', (64, 72))	('higher', 'PosReg', (116, 122))	('overall survival rate', 'CPA', (165, 186))	('pathological stage', 'CPA', (136, 154))	('microRNA-186-5p', 'Var', (96, 111))	('lower', 'NegReg', (159, 164))	('patients', 'Species', '9606', (14, 22))
316818	31802902	Besides, compared with the miR-NC group, the microRNA-186-5p mimics group had a significant decrease in proliferation and metastasis ability of ECa cells.	('decrease', 'NegReg', (92, 100))	('proliferation', 'CPA', (104, 117))	('microRNA-186-5p', 'Var', (45, 60))	('ECa', 'Disease', (144, 147))	('ECa', 'Disease', 'MESH:D004938', (144, 147))	('miR', 'Gene', (27, 30))	('miR', 'Gene', '220972', (27, 30))	('metastasis ability', 'CPA', (122, 140))
316821	31802902	The results suggested that microRNA-186-5p may inhibit cell proliferation of ECa by regulating HOXA9.	('HOXA9', 'Gene', (95, 100))	('microRNA-186-5p', 'Var', (27, 42))	('inhibit', 'NegReg', (47, 54))	('cell proliferation', 'CPA', (55, 73))	('ECa', 'Disease', (77, 80))	('HOXA9', 'Gene', '3205', (95, 100))	('regulating', 'Reg', (84, 94))	('ECa', 'Disease', 'MESH:D004938', (77, 80))
316840	31802902	Therefore, this study further explored the biological function of microRNA-186-5p in ECa and the specific molecular mechanism of whether microRNA-186-5p could regulate HOXA9, providing clues to explain the potential mechanism of the occurrence and development of ECa, hoping to discover potential biomarkers for the early diagnosis and population screening of ECa.	('HOXA9', 'Gene', '3205', (168, 173))	('microRNA-186-5p', 'Var', (137, 152))	('ECa', 'Disease', 'MESH:D004938', (85, 88))	('ECa', 'Disease', (360, 363))	('ECa', 'Disease', 'MESH:D004938', (360, 363))	('HOXA9', 'Gene', (168, 173))	('ECa', 'Disease', 'MESH:D004938', (263, 266))	('ECa', 'Disease', (263, 266))	('ECa', 'Disease', (85, 88))
316848	31802902	For recovery experiment, the HOXA9 overexpression plasmid was constructed and transfected into cells that had overexpressed microRNA-186-5p.	('HOXA9', 'Gene', (29, 34))	('microRNA-186-5p', 'Var', (124, 139))	('HOXA9', 'Gene', '3205', (29, 34))
316849	31802902	Cells were divided into three groups: miR-NC+NC group, micro-186-5p mimics+NC group, microRNA-186-5p mimics+HOXA9 group.	('microRNA-186-5p', 'Var', (85, 100))	('HOXA9', 'Gene', '3205', (108, 113))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('HOXA9', 'Gene', (108, 113))
316856	31802902	The expression of microRNA-186-5p in 45 pairs of ECa tissue specimens and adjacent ones as well as in cell lines was detected by qRT-PCR, and the results revealed that microRNA-186-5p was remarkably lower either in ECa tissues (P<0.001; Figure 1A) or cell lines (Figure 1B).	('ECa', 'Disease', (215, 218))	('microRNA-186-5p', 'Var', (168, 183))	('lower', 'NegReg', (199, 204))	('ECa', 'Disease', (49, 52))	('ECa', 'Disease', 'MESH:D004938', (49, 52))	('ECa', 'Disease', 'MESH:D004938', (215, 218))
316858	31802902	Chi-square test was used to analyze the relationship between microRNA-186-5p expression and age, gender, pathological stage, lymph node metastasis and distant metastasis of ECa patients.	('patients', 'Species', '9606', (177, 185))	('metastasis of ECa', 'Disease', (159, 176))	('microRNA-186-5p', 'Var', (61, 76))	('metastasis of ECa', 'Disease', 'MESH:D004938', (159, 176))
316859	31802902	As shown in Table 1, the low expression of microRNA-186-5p was positively correlated with the incidence of clinical stage and distant metastasis of ECa, but not with age, gender and lymph node metastasis.	('metastasis of ECa', 'Disease', (134, 151))	('metastasis of ECa', 'Disease', 'MESH:D004938', (134, 151))	('clinical stage', 'CPA', (107, 121))	('low', 'NegReg', (25, 28))	('expression', 'MPA', (29, 39))	('microRNA-186-5p', 'Var', (43, 58))
316861	31802902	Kaplan-Meier survival curves indicated that low expression of microRNA-186-5p was remarkably associated with poor prognosis of ECa, and the lower the expression level of microRNA-186-5p, the worse the prognosis (P<0.05; Figure 1C).	('low', 'NegReg', (44, 47))	('microRNA-186-5p', 'Var', (62, 77))	('lower', 'NegReg', (140, 145))	('ECa', 'Disease', (127, 130))	('ECa', 'Disease', 'MESH:D004938', (127, 130))	('expression', 'MPA', (48, 58))	('expression level', 'MPA', (150, 166))	('microRNA-186-5p', 'Var', (170, 185))
316862	31802902	These results suggested that microRNA-186-5p expression was correlated with pathological stage, distant metastasis and overall survival in ECa patients.	('ECa', 'Disease', 'MESH:D004938', (139, 142))	('microRNA-186-5p expression', 'Var', (29, 55))	('patients', 'Species', '9606', (143, 151))	('correlated', 'Reg', (60, 70))	('ECa', 'Disease', (139, 142))	('distant metastasis', 'CPA', (96, 114))
316865	31802902	As shown in Figure 2B and C, the proliferative capacity of ECa cells in the microRNA-186-5p mimics group was remarkably reduced compared to the miR-NC group.	('proliferative capacity', 'CPA', (33, 55))	('ECa', 'Disease', (59, 62))	('microRNA-186-5p', 'Var', (76, 91))	('ECa', 'Disease', 'MESH:D004938', (59, 62))	('miR', 'Gene', '220972', (144, 147))	('miR', 'Gene', (144, 147))	('reduced', 'NegReg', (120, 127))
316867	31802902	The Transwell migration assay showed (P<0.01; Figure 3) that the microRNA-186-5p mimics group had a significant decrease in migration and metastasis of ECa cells compared with the miR-NC group.	('decrease', 'NegReg', (112, 120))	('microRNA-186-5p', 'Var', (65, 80))	('metastasis of ECa', 'Disease', (138, 155))	('metastasis of ECa', 'Disease', 'MESH:D004938', (138, 155))	('miR', 'Gene', '220972', (180, 183))	('miR', 'Gene', (180, 183))
316869	31802902	To further validate the targeting of microRNA-186-5p to HOXA9, a luciferase reporter assay was performed.	('HOXA9', 'Gene', '3205', (56, 61))	('HOXA9', 'Gene', (56, 61))	('microRNA-186-5p', 'Var', (37, 52))
316870	31802902	The results showed that overexpression of microRNA-186-5p remarkably attenuated the luciferase activity of the wild-type HOXA9 vector, further demonstrating that HOXA9 can be targeted by microRNA-186-5p through this binding site (P<0.05; Figure 4A).	('microRNA-186-5p', 'Var', (42, 57))	('luciferase', 'Enzyme', (84, 94))	('attenuated', 'NegReg', (69, 79))	('HOXA9', 'Gene', '3205', (121, 126))	('HOXA9', 'Gene', '3205', (162, 167))	('microRNA-186-5p', 'Var', (187, 202))	('overexpression', 'PosReg', (24, 38))	('activity', 'MPA', (95, 103))	('HOXA9', 'Gene', (162, 167))	('HOXA9', 'Gene', (121, 126))
316874	31802902	In addition, the expression of microRNA-186-5p and HOXA9 were detected by qRT-PCR, and the results showed that microRNA-186-5p and HOXA9 were negatively correlated in ECa tissues (Figure 4E).	('ECa', 'Disease', (167, 170))	('ECa', 'Disease', 'MESH:D004938', (167, 170))	('HOXA9', 'Gene', '3205', (51, 56))	('negatively', 'NegReg', (142, 152))	('HOXA9', 'Gene', '3205', (131, 136))	('HOXA9', 'Gene', (51, 56))	('microRNA-186-5p', 'Var', (111, 126))	('HOXA9', 'Gene', (131, 136))
316875	31802902	These results indicated that microRNA-186-5p could bind to HOXA9 and that there was a negative correlation between the expression of microRNA-186-5p and HOXA9.	('microRNA-186-5p', 'Var', (133, 148))	('expression', 'MPA', (119, 129))	('HOXA9', 'Gene', '3205', (59, 64))	('HOXA9', 'Gene', (59, 64))	('HOXA9', 'Gene', '3205', (153, 158))	('negative', 'NegReg', (86, 94))	('bind', 'Interaction', (51, 55))	('HOXA9', 'Gene', (153, 158))
316876	31802902	To further explore the interaction between microRNA-186-5p and HOXA9 in ECa cells, we overexpressed HOXA9 in a cell line overexpressing microRNA-186-5p in ECa cells to confirm there may be some mutual regulation between HOXA9 and HOXA9.	('HOXA9', 'Gene', '3205', (63, 68))	('HOXA9', 'Gene', '3205', (220, 225))	('HOXA9', 'Gene', (230, 235))	('ECa', 'Disease', (155, 158))	('HOXA9', 'Gene', '3205', (100, 105))	('HOXA9', 'Gene', (63, 68))	('HOXA9', 'Gene', (100, 105))	('HOXA9', 'Gene', (220, 225))	('ECa', 'Disease', (72, 75))	('ECa', 'Disease', 'MESH:D004938', (155, 158))	('ECa', 'Disease', 'MESH:D004938', (72, 75))	('microRNA-186-5p', 'Var', (136, 151))	('HOXA9', 'Gene', '3205', (230, 235))
316879	31802902	These indicated that microRNA-186-5p modulated HOXA9 in ECa and that HOXA9 overexpression could reverse the inhibition effect of microRNA-186-5p on ECa cell proliferation and migration.	('HOXA9', 'Gene', (47, 52))	('HOXA9', 'Gene', '3205', (69, 74))	('modulated', 'Reg', (37, 46))	('HOXA9', 'Gene', (69, 74))	('ECa', 'Disease', (148, 151))	('ECa', 'Disease', (56, 59))	('ECa', 'Disease', 'MESH:D004938', (148, 151))	('migration', 'CPA', (175, 184))	('ECa', 'Disease', 'MESH:D004938', (56, 59))	('HOXA9', 'Gene', '3205', (47, 52))	('microRNA-186-5p', 'Var', (129, 144))
316880	31802902	Tumor refers to a new organism formed by cells in the body under the action of various tumorigenic factors, in which the cells in local tissues mutate at the gene level and lose the normal regulation of their growth, leading to unlimited abnormal proliferation and differentiation of cells.	('regulation', 'MPA', (189, 199))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutate', 'Var', (144, 150))	('differentiation', 'CPA', (265, 280))	('growth', 'MPA', (209, 215))	('lose', 'NegReg', (173, 177))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('leading to', 'Reg', (217, 227))
316890	31802902	A large number of studies have confirmed that the low expression of miRNA-186-5p existed in a variety of malignant tumor tissues, and the low expression of microRNA-186-5p also provided favorable conditions for the proliferation and metastasis of malignant tumor cells to a certain extent.	('expression', 'MPA', (54, 64))	('malignant tumor', 'Disease', (247, 262))	('miR', 'Gene', '220972', (68, 71))	('malignant tumor', 'Disease', 'MESH:D009369', (105, 120))	('miR', 'Gene', (68, 71))	('malignant tumor', 'Disease', 'MESH:D009369', (247, 262))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('malignant tumor', 'Disease', (105, 120))	('microRNA-186-5p', 'Var', (156, 171))	('low', 'NegReg', (138, 141))	('proliferation', 'CPA', (215, 228))	('metastasis', 'CPA', (233, 243))
316897	31802902	The functional detection in the analysis of abnormal miRNA mainly focused on the mutations in target gene binding.	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('mutations', 'Var', (81, 90))	('binding', 'Interaction', (106, 113))
316936	30909662	Moreover, the aberrant expression of this lncRNA was correlated with clinicopathological features in a number of malignancies, indicating it as a potential marker for early cancer detection (Shi et al., 2015; Yan et al., 2015; Qin et al., 2016; Cui et al., 2017).	('Qin', 'Gene', (227, 230))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('ncRNA', 'Gene', (43, 48))	('correlated', 'Reg', (53, 63))	('malignancies', 'Disease', (113, 125))	('aberrant', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('ncRNA', 'Gene', '54719', (43, 48))	('Qin', 'Gene', '2290', (227, 230))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))
316937	30909662	Dysregulation of lnc-PCAT-1 also designated as an independent prognostic factor for the overall survival (OS) rate of cancer patients (Shi et al., 2015; Yan et al., 2015; Qin et al., 2016; Cui et al., 2017).	('cancer', 'Disease', (118, 124))	('PCAT-1', 'Gene', (21, 27))	('Dysregulation', 'Var', (0, 13))	('Qin', 'Gene', '2290', (171, 174))	('PCAT-1', 'Gene', '100750225', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('overall', 'MPA', (88, 95))	('Qin', 'Gene', (171, 174))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('patients', 'Species', '9606', (125, 133))
316951	30909662	The overall and pooled results revealed that the high expression level of PCAT1 was significantly related to shorter overall survival in cancer patients (HR =1.9, 95% CI: 1.13-3.18, P<0.001).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('PCAT1', 'Gene', '100750225', (74, 79))	('overall survival', 'MPA', (117, 133))	('PCAT1', 'Gene', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Disease', (137, 143))	('high', 'Var', (49, 53))	('shorter', 'NegReg', (109, 116))
316957	30909662	Aberrant expression of some lncRNAs has been demonstrated to be associated with tumor progression, as well as with the clinical outcome in various cancers (Xue et al., 2016; Qian et al., 2017; Su et al., 2017; Zhuo and Kang., 2017).	('associated', 'Reg', (64, 74))	('Aberrant expression', 'Var', (0, 19))	('ncRNA', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ncRNA', 'Gene', '54719', (29, 34))	('tumor', 'Disease', (80, 85))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('Su', 'Chemical', 'MESH:C035067', (193, 195))
316964	30909662	Their result revealed the function of ncRNA transcriptome and confirmed dysregulation of three important target genes, BRCA2, CENPE and CENPF in prostate cancer.	('CENPF', 'Gene', (136, 141))	('ncRNA', 'Gene', '54719', (38, 43))	('prostate cancer', 'Disease', 'MESH:D011471', (145, 160))	('dysregulation', 'Var', (72, 85))	('CENPF', 'Gene', '1063', (136, 141))	('prostate cancer', 'Phenotype', 'HP:0012125', (145, 160))	('ncRNA', 'Gene', (38, 43))	('CENPE', 'Gene', '1062', (126, 131))	('BRCA2', 'Gene', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('prostate cancer', 'Disease', (145, 160))	('CENPE', 'Gene', (126, 131))	('BRCA2', 'Gene', '675', (119, 124))
316968	30909662	In the systematic review and meta-analysis, it was attempted to collect all published papers assessing the prognostic significance of long non-coding RNA PCAT-1 dysregulation in several cancers.	('long non-coding RNA', 'Var', (134, 153))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('PCAT-1', 'Gene', '100750225', (154, 160))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('PCAT-1', 'Gene', (154, 160))
316970	30909662	The analyses showed that the patients with high lncRNA PCAT-1 expression had evidently poorer overall survival rates than those with low PCAT-1 expression.	('patients', 'Species', '9606', (29, 37))	('overall survival', 'MPA', (94, 110))	('ncRNA', 'Gene', '54719', (49, 54))	('PCAT-1', 'Gene', (55, 61))	('PCAT-1', 'Gene', '100750225', (137, 143))	('poorer', 'NegReg', (87, 93))	('PCAT-1', 'Gene', '100750225', (55, 61))	('ncRNA', 'Gene', (49, 54))	('PCAT-1', 'Gene', (137, 143))	('expression', 'Var', (62, 72))
316985	30793520	Cumulative evidence for association between genetic polymorphisms and esophageal cancer susceptibility: A review with evidence from meta-analysis and genome-wide association studies An increasing number of publications had reported the association between single-nucleotide polymorphisms (SNPs) and esophageal cancer (EC) risk in the past decades.	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', (299, 316))	('single-nucleotide polymorphisms', 'Var', (256, 287))	('esophageal cancer', 'Disease', 'MESH:D004938', (299, 316))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('association', 'Interaction', (236, 247))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
316986	30793520	At last, 107 meta-analyses were considered to be in conformity with the inclusion criteria, yielding 51 variants associated with EC or esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('variants', 'Var', (104, 112))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (135, 169))	('esophageal squamous cell carcinoma', 'Disease', (135, 169))	('associated', 'Reg', (113, 123))
316987	30793520	In additional, five variants on five genes were rated as strong cumulative epidemiological evidence for a nominally significant association with EC and ESCC risk, including CYP1A1 rs1048943, EGF rs444903, HOTAIR rs920778, MMP2 rs243865, and PLCE1 rs2274223, 10 variants were rated as moderate, and 18 variants were rated as weak.	('MMP2', 'Gene', '4313', (222, 226))	('rs1048943', 'Mutation', 'rs1048943', (180, 189))	('CYP1A1', 'Gene', (173, 179))	('rs243865', 'Var', (227, 235))	('rs1048943', 'Var', (180, 189))	('rs2274223', 'Mutation', 'rs2274223', (247, 256))	('ESCC', 'Disease', (152, 156))	('rs2274223', 'Var', (247, 256))	('EGF', 'Gene', '1950', (191, 194))	('HOTAIR', 'Gene', '100124700', (205, 211))	('rs444903', 'Mutation', 'rs444903', (195, 203))	('CYP1A1', 'Gene', '1543', (173, 179))	('PLCE1', 'Gene', (241, 246))	('MMP2', 'Gene', (222, 226))	('PLCE1', 'Gene', '51196', (241, 246))	('rs444903', 'Var', (195, 203))	('rs920778', 'Mutation', 'rs920778', (212, 220))	('rs243865', 'Mutation', 'rs243865', (227, 235))	('rs920778', 'Var', (212, 220))	('HOTAIR', 'Gene', (205, 211))	('EGF', 'Gene', (191, 194))
316991	30793520	For EGF rs4444903, Xu et al15 performed a meta-analysis and found that the variant rs4444903 could decrease the risk of EC (OR = 0.73, 95% CI = 0.61-0.86), whereas Li et al16 found the variant rs4444903 could increase the risk of EC (OR = 1.17, 95% CI = 1.09-1.25).	('rs4444903', 'Mutation', 'rs4444903', (8, 17))	('rs4444903', 'Var', (193, 202))	('EGF', 'Gene', (4, 7))	('rs4444903', 'Mutation', 'rs4444903', (193, 202))	('decrease', 'NegReg', (99, 107))	('rs4444903', 'Mutation', 'rs4444903', (83, 92))	('EGF', 'Gene', '1950', (4, 7))	('rs4444903', 'Var', (83, 92))	('variant rs4444903', 'Var', (75, 92))
316993	30793520	Meanwhile, Abnet et al25 found variants on PLCE1 gene associated with ESCC risk and Wang et al24 found that the gene, C20orf54, had significant association with ESCC risk in Chinese population.	('association', 'Interaction', (144, 155))	('variants', 'Var', (31, 39))	('C20orf54', 'Gene', (118, 126))	('PLCE1', 'Gene', (43, 48))	('PLCE1', 'Gene', '51196', (43, 48))	('C20orf54', 'Gene', '113278', (118, 126))	('ESCC', 'Disease', (161, 165))	('ESCC', 'Disease', (70, 74))	('associated', 'Reg', (54, 64))
317000	30793520	Of these, 179 publications were excluded due to overlaps, 157 irrelevant articles were excluded for reading the title or abstract, 21 articles were excluded due to not meta-analysis, genetic polymorphism, or esophageal cancer, 19 articles were excluded due to not latest meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('esophageal cancer', 'Disease', (208, 225))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('genetic polymorphism', 'Var', (183, 203))
317001	30793520	Next, cumulative evidence were upgraded from moderate to strong for CYP1A1 rs1048943, PLCE1 rs2274223, MMP2 rs243865 in EC and HOTAIR rs920778 in ESCC, from weak to moderate for ADH1B rs1229984 and COX-2 rs20417 in EC, based on FPRP <0.05.	('CYP1A1', 'Gene', '1543', (68, 74))	('rs243865', 'Var', (108, 116))	('COX-2', 'Gene', (198, 203))	('ADH1B', 'Gene', (178, 183))	('ESCC', 'Disease', (146, 150))	('PLCE1', 'Gene', (86, 91))	('rs20417', 'Var', (204, 211))	('COX-2', 'Gene', '4513', (198, 203))	('PLCE1', 'Gene', '51196', (86, 91))	('rs1229984', 'Var', (184, 193))	('HOTAIR', 'Gene', '100124700', (127, 133))	('rs243865', 'Mutation', 'rs243865', (108, 116))	('rs1048943', 'Mutation', 'rs1048943', (75, 84))	('MMP2', 'Gene', (103, 107))	('rs20417', 'Mutation', 'rs20417', (204, 211))	('HOTAIR', 'Gene', (127, 133))	('CYP1A1', 'Gene', (68, 74))	('rs920778', 'Mutation', 'rs920778', (134, 142))	('rs920778', 'Var', (134, 142))	('rs1048943', 'Var', (75, 84))	('rs2274223', 'Mutation', 'rs2274223', (92, 101))	('rs2274223', 'Var', (92, 101))	('rs1229984', 'Mutation', 'rs1229984', (184, 193))	('ADH1B', 'Gene', '125', (178, 183))	('MMP2', 'Gene', '4313', (103, 107))
317002	30793520	Cumulative evidence were downgraded from strong to moderate for IL-18 -607C>A, MMP1 rs1799750, SLC52A3 rs13042395 and MDM2 rs2279744 in EC, and TNF-alpha rs1800629, C20orf54 rs13042395, microRNA124 rs531564 in ESCC, from moderate to weak for GSTT1 null/present, XRCC1 rs1799782, Hsa-mir rs3746444, hOGG1 rs1052133, STK15 rs2273535 in EC, and microRNA-34b/c rs4938723, NAT2 rapid/slow in ESCC, based on FPRP >0.2.	('rs13042395', 'Mutation', 'rs13042395', (174, 184))	('MDM2', 'Gene', (118, 122))	('GSTT1', 'Gene', '2952', (242, 247))	('rs1799782', 'Mutation', 'rs1799782', (268, 277))	('NAT2', 'Gene', '10', (368, 372))	('rs1800629', 'Var', (154, 163))	('rs1052133', 'Mutation', 'rs1052133', (304, 313))	('NAT2', 'Gene', (368, 372))	('rs3746444', 'Mutation', 'rs3746444', (287, 296))	('IL-18', 'Gene', (64, 69))	('GSTT1', 'Gene', (242, 247))	('MDM2', 'Gene', '4193', (118, 122))	('XRCC1', 'Gene', '7515', (262, 267))	('C20orf54', 'Gene', '113278', (165, 173))	('rs2273535', 'Mutation', 'rs2273535', (321, 330))	('MMP1', 'Gene', '4312', (79, 83))	('rs4938723', 'Mutation', 'rs4938723', (357, 366))	('rs1800629', 'Mutation', 'rs1800629', (154, 163))	('MMP1', 'Gene', (79, 83))	('SLC52A3', 'Gene', (95, 102))	('C20orf54', 'Gene', (165, 173))	('hOGG1', 'Gene', '4968', (298, 303))	('rs531564', 'Mutation', 'rs531564', (198, 206))	('STK15', 'Gene', (315, 320))	('hOGG1', 'Gene', (298, 303))	('IL-18', 'Gene', '3606', (64, 69))	('rs1052133', 'Var', (304, 313))	('rs2279744', 'Mutation', 'rs2279744', (123, 132))	('-607C>A', 'Mutation', 'rs1946518', (70, 77))	('TNF-alpha', 'Gene', '7124', (144, 153))	('rs13042395', 'Mutation', 'rs13042395', (103, 113))	('TNF-alpha', 'Gene', (144, 153))	('SLC52A3', 'Gene', '113278', (95, 102))	('STK15', 'Gene', '6790', (315, 320))	('rs1799750', 'Mutation', 'rs1799750', (84, 93))	('XRCC1', 'Gene', (262, 267))
317003	30793520	Finally, five SNPs on five genes were rated as strong for cumulative epidemiological evidence of association by combining Venice criteria and FPRP results, including CYP1A1 rs1048943, EGF rs444903, MMP2 rs243865, PLCE1 rs2274223 for EC and HOTAIR rs920778 for ESCC.	('MMP2', 'Gene', '4313', (198, 202))	('ESCC', 'Disease', (260, 264))	('PLCE1', 'Gene', (213, 218))	('PLCE1', 'Gene', '51196', (213, 218))	('rs920778', 'Mutation', 'rs920778', (247, 255))	('HOTAIR', 'Gene', '100124700', (240, 246))	('rs1048943', 'Mutation', 'rs1048943', (173, 182))	('rs243865', 'Var', (203, 211))	('rs444903', 'Mutation', 'rs444903', (188, 196))	('rs920778', 'Var', (247, 255))	('CYP1A1', 'Gene', (166, 172))	('rs444903', 'Var', (188, 196))	('HOTAIR', 'Gene', (240, 246))	('rs1048943', 'Var', (173, 182))	('EGF', 'Gene', '1950', (184, 187))	('MMP2', 'Gene', (198, 202))	('CYP1A1', 'Gene', '1543', (166, 172))	('rs243865', 'Mutation', 'rs243865', (203, 211))	('rs2274223', 'Mutation', 'rs2274223', (219, 228))	('rs2274223', 'Var', (219, 228))	('EGF', 'Gene', (184, 187))
317004	30793520	In addition, two variant (rs13042395 on C20orf54 and rs2274223 on PLCE1) were performed both in meta-analysis and in GWAS.	('PLCE1', 'Gene', (66, 71))	('PLCE1', 'Gene', '51196', (66, 71))	('rs2274223', 'Mutation', 'rs2274223', (53, 62))	('rs2274223', 'Var', (53, 62))	('C20orf54', 'Gene', (40, 48))	('C20orf54', 'Gene', '113278', (40, 48))	('rs13042395', 'Mutation', 'rs13042395', (26, 36))	('rs13042395', 'Var', (26, 36))
317005	30793520	In our meta-analysis results, 13 variants were not significantly associated with EC or ESCC risk.37, 42, 60, 78, 79 The variants (Arg399Gln on XRCC1) with sample sizes >10 000 were also not significantly associated with EC; further investigations for this variant may not be fruitful.	('EC', 'Disease', (220, 222))	('XRCC1', 'Gene', '7515', (143, 148))	('XRCC1', 'Gene', (143, 148))	('associated', 'Reg', (204, 214))	('Arg399Gln', 'Var', (130, 139))	('Arg399Gln', 'SUBSTITUTION', 'None', (130, 139))
317006	30793520	All in all, 13 SNPs were deemed to have significant association, as follows: ADH1B rs1229984, ALDH2 rs25848305, MDM2 rs2279744, XRCC1 rs1799782, TP53 rs1042522, CCND1 rs603965, COX-2 rs20417, EGF rs4444903, ERCC2 rs1799793, GSTM1 null/present, GSTT1 null/present, MTHFR rs1801131 and NQO1 rs1800566.	('NQO1', 'Gene', (284, 288))	('COX-2', 'Gene', '4513', (177, 182))	('rs20417', 'Mutation', 'rs20417', (183, 190))	('rs1229984', 'Var', (83, 92))	('TP53', 'Gene', '7157', (145, 149))	('rs1800566', 'Mutation', 'rs1800566', (289, 298))	('ALDH2', 'Gene', '217', (94, 99))	('CCND1', 'Gene', (161, 166))	('rs603965', 'Mutation', 'rs603965', (167, 175))	('GSTM1', 'Gene', '2944', (224, 229))	('rs4444903', 'Var', (196, 205))	('rs1799782', 'Var', (134, 143))	('rs2279744', 'Mutation', 'rs2279744', (117, 126))	('rs25848305', 'Mutation', 'rs25848305', (100, 110))	('XRCC1', 'Gene', '7515', (128, 133))	('EGF', 'Gene', '1950', (192, 195))	('ERCC2', 'Gene', (207, 212))	('rs1229984', 'Mutation', 'rs1229984', (83, 92))	('MTHFR', 'Gene', '4524', (264, 269))	('null/present', 'Var', (230, 242))	('MDM2', 'Gene', (112, 116))	('rs1801131', 'Var', (270, 279))	('rs4444903', 'Mutation', 'rs4444903', (196, 205))	('ADH1B', 'Gene', '125', (77, 82))	('ERCC2', 'Gene', '2068', (207, 212))	('TP53', 'Gene', (145, 149))	('GSTT1', 'Gene', '2952', (244, 249))	('rs20417', 'Var', (183, 190))	('rs1801131', 'Mutation', 'rs1801131', (270, 279))	('ALDH2', 'Gene', (94, 99))	('rs1042522', 'Var', (150, 159))	('GSTM1', 'Gene', (224, 229))	('ADH1B', 'Gene', (77, 82))	('MDM2', 'Gene', '4193', (112, 116))	('rs1799793', 'Mutation', 'rs1799793', (213, 222))	('rs2279744', 'Var', (117, 126))	('rs25848305', 'Var', (100, 110))	('EGF', 'Gene', (192, 195))	('rs603965', 'Var', (167, 175))	('COX-2', 'Gene', (177, 182))	('rs1042522', 'Mutation', 'rs1042522', (150, 159))	('NQO1', 'Gene', '1728', (284, 288))	('GSTT1', 'Gene', (244, 249))	('rs1799793', 'Var', (213, 222))	('MTHFR', 'Gene', (264, 269))	('rs1799782', 'Mutation', 'rs1799782', (134, 143))	('XRCC1', 'Gene', (128, 133))	('CCND1', 'Gene', '595', (161, 166))	('null/present', 'Var', (250, 262))
317007	30793520	Seven SNPs were deemed to have nonassociation: EPHX1 (rs2234922 and rs1051740), Fas 1800682, XPA rs1800975, microRNA146 rs2910164, microRNA196 rs11614913, XRCC1 rs25487.	('EPHX1', 'Gene', (47, 52))	('rs1800975', 'Mutation', 'rs1800975', (97, 106))	('XPA', 'Gene', (93, 96))	('XPA', 'Gene', '7507', (93, 96))	('XRCC1', 'Gene', '7515', (155, 160))	('rs11614913', 'Mutation', 'rs11614913', (143, 153))	('rs2910164', 'Mutation', 'rs2910164', (120, 129))	('EPHX1', 'Gene', '2052', (47, 52))	('rs2234922', 'Var', (54, 63))	('rs25487', 'Mutation', 'rs25487', (161, 168))	('XRCC1', 'Gene', (155, 160))	('rs1051740', 'Mutation', 'rs1051740', (68, 77))	('rs1051740', 'Var', (68, 77))	('rs2234922', 'Mutation', 'rs2234922', (54, 63))
317008	30793520	The results of two variants, EPHX1 (Try113His and His139Arg)81, 83, 84 and XRCC1 (Arg399Gln and Arg194Trp),74, 86, 87 should be prudently interpreted due to similar sample size.	('Try113His', 'Var', (36, 45))	('XRCC1', 'Gene', (75, 80))	('XRCC1', 'Gene', '7515', (75, 80))	('EPHX1', 'Gene', '2052', (29, 34))	('Arg194Trp', 'Var', (96, 105))	('His139Arg', 'Var', (50, 59))	('Arg399Gln', 'Var', (82, 91))	('His139Arg', 'SUBSTITUTION', 'None', (50, 59))	('Arg194Trp', 'SUBSTITUTION', 'None', (96, 105))	('Arg399Gln', 'SUBSTITUTION', 'None', (82, 91))	('EPHX1', 'Gene', (29, 34))
317010	30793520	Five SNPs on five genes with strong evidence of association were identified, including CYP1A1 rs1048943, EGF rs444903, MMP2 rs243865, PLCE1 rs2274223 for assessing risk of EC and HOTAIR rs920778 for ESCC.	('HOTAIR', 'Gene', '100124700', (179, 185))	('PLCE1', 'Gene', (134, 139))	('rs243865', 'Var', (124, 132))	('rs920778', 'Mutation', 'rs920778', (186, 194))	('PLCE1', 'Gene', '51196', (134, 139))	('rs920778', 'Var', (186, 194))	('rs1048943', 'Mutation', 'rs1048943', (94, 103))	('HOTAIR', 'Gene', (179, 185))	('rs444903', 'Mutation', 'rs444903', (109, 117))	('CYP1A1', 'Gene', (87, 93))	('EGF', 'Gene', '1950', (105, 108))	('rs444903', 'Var', (109, 117))	('rs1048943', 'Var', (94, 103))	('MMP2', 'Gene', (119, 123))	('rs243865', 'Mutation', 'rs243865', (124, 132))	('CYP1A1', 'Gene', '1543', (87, 93))	('ESCC', 'Disease', (199, 203))	('EGF', 'Gene', (105, 108))	('MMP2', 'Gene', '4313', (119, 123))	('rs2274223', 'Mutation', 'rs2274223', (140, 149))	('rs2274223', 'Var', (140, 149))
317014	30793520	EGF, located on chromosome 4q25-q27,92, 93 participates in the process of proliferation and differentiation of cells94 and promotes gene transcription when EGF binds to its receptor.95 Quiet a few studies have identified the G allele promoted the EGF protein expression when EGF binds to its receptor which could interfering DNA folding and further increased susceptibility of a range of human cancers.96 Our review showed that the G allele of EGF +61A>G (rs4444903) polymorphism was rated as strong evidence of association with 1.38-fold increased risk of EC based on 1713 sample size.	('+61A>G', 'Mutation', 'rs4444903', (448, 454))	('rs4444903', 'Var', (456, 465))	('human', 'Species', '9606', (388, 393))	('EGF', 'Gene', '1950', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('EGF', 'Gene', (444, 447))	('EGF', 'Gene', '1950', (444, 447))	('EGF', 'Gene', (247, 250))	('EGF', 'Gene', (275, 278))	('EGF', 'Gene', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('cancers', 'Disease', (394, 401))	('EGF', 'Gene', '1950', (247, 250))	('EGF', 'Gene', '1950', (0, 3))	('EGF', 'Gene', '1950', (275, 278))	('rs4444903', 'Mutation', 'rs4444903', (456, 465))	('EGF', 'Gene', (156, 159))
317015	30793520	MMP-2 is a sort of zinc-dependent endopeptidases, which can regulate various cell behaviors such as tumor initiation and growth by modulating cell proliferation, apoptosis and angiogenesis.97, 98 The SNP (rs243865), located in the promoter region of the MMP-2, disrupts an Sp1-type promoter site (CCACC box) and then affects MMP-2 expression or activity, which was considered to be associated with development of cancer condition.99 Our review showed that the SNP (rs243865) was rates as strong evidence of association with EC risk (OR = 0.67, 95% CI = 0.55-0.80) under dominant model.	('cancer', 'Disease', (413, 419))	('MMP-2', 'Gene', (325, 330))	('cancer', 'Disease', 'MESH:D009369', (413, 419))	('MMP-2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('association', 'Interaction', (507, 518))	('rs243865', 'Mutation', 'rs243865', (205, 213))	('tumor initiation', 'Disease', (100, 116))	('MMP-2', 'Gene', (254, 259))	('SNP (rs243865', 'Var', (460, 473))	('rs243865', 'Mutation', 'rs243865', (465, 473))	('MMP-2', 'Gene', '4313', (325, 330))	('cancer', 'Phenotype', 'HP:0002664', (413, 419))	('MMP-2', 'Gene', '4313', (0, 5))	('MMP-2', 'Gene', '4313', (254, 259))	('tumor initiation', 'Disease', 'MESH:D009369', (100, 116))
317016	30793520	PLCE1, located on chromosome 10q23, participate in cell growth, differentiation, gene expression and oncogenesis.100, 101 Our review showed that this SNP (rs2274223) was rated as strong evidence of association with increased risk of EC for a common A to G transition of PLCE1 that may increase expression of PLCE1 protein102, 103 in a diverse population based on a sample size of over 20 000.	('increase', 'PosReg', (285, 293))	('rs2274223', 'Mutation', 'rs2274223', (155, 164))	('rs2274223', 'Var', (155, 164))	('protein102', 'Protein', (314, 324))	('expression', 'MPA', (294, 304))	('PLCE1', 'Gene', (308, 313))	('PLCE1', 'Gene', (270, 275))	('PLCE1', 'Gene', '51196', (308, 313))	('PLCE1', 'Gene', '51196', (270, 275))	('PLCE1', 'Gene', (0, 5))	('PLCE1', 'Gene', '51196', (0, 5))
317018	30793520	There are six variants showing moderate evidence of association in our review, all of which downgraded from strong to moderate: IL-8 -607C>A, MMP-1 rs1799750, TNF-alpha rs1800629, MicroRNA124 rs531564, SLC52A3 rs13042395 and MDM2 rs2279744 based on a high FPRP (> 0.2).	('MMP-1', 'Gene', '4312', (142, 147))	('SLC52A3', 'Gene', (202, 209))	('rs531564', 'Mutation', 'rs531564', (192, 200))	('IL-8', 'Gene', (128, 132))	('MDM2', 'Gene', (225, 229))	('rs1800629', 'Var', (169, 178))	('rs13042395', 'Var', (210, 220))	('SLC52A3', 'Gene', '113278', (202, 209))	('rs1799750', 'Var', (148, 157))	('MMP-1', 'Gene', (142, 147))	('MDM2', 'Gene', '4193', (225, 229))	('rs1800629', 'Mutation', 'rs1800629', (169, 178))	('rs13042395', 'Mutation', 'rs13042395', (210, 220))	('IL-8', 'Gene', '3576', (128, 132))	('TNF-alpha', 'Gene', '7124', (159, 168))	('rs1799750', 'Mutation', 'rs1799750', (148, 157))	('-607C>A', 'Mutation', 'rs1946518', (133, 140))	('rs2279744', 'Mutation', 'rs2279744', (230, 239))	('TNF-alpha', 'Gene', (159, 168))
317019	30793520	Additionally, SNP (rs13042395) on C20orf54 also showing moderate evidence of association with ESCC susceptibility, which downgraded from strong to moderate.	('association', 'Interaction', (77, 88))	('C20orf54', 'Gene', '113278', (34, 42))	('SNP (rs13042395', 'Var', (14, 29))	('rs13042395', 'Mutation', 'rs13042395', (19, 29))	('ESCC', 'Disease', (94, 98))	('C20orf54', 'Gene', (34, 42))
317020	30793520	Cumulative evidence of two variants (ADH1B rs1229984 and COX-2 rs20417) with risk of EC was upgraded from weak to moderate based on FPRP <0.05.	('ADH1B', 'Gene', (37, 42))	('rs20417', 'Mutation', 'rs20417', (63, 70))	('ADH1B', 'Gene', '125', (37, 42))	('COX-2', 'Gene', '4513', (57, 62))	('COX-2', 'Gene', (57, 62))	('rs1229984', 'Mutation', 'rs1229984', (43, 52))	('rs20417', 'Var', (63, 70))	('rs1229984', 'Var', (43, 52))
317021	30793520	Additional assessment of two variants were necessary, particularly the variant (COX-2 rs20417) since sample size of study for this variant are relatively small (a total of 3779 sample size).65, 106  Thirteen variants were found not to be significantly associated with EC risk, to include nine variants on seven genes and two mRNAs in a sample of approximately 4000 patients, at approximately 85% power to detect an OR of 1.15 under different model for a variant with MAF of 20%.	('patients', 'Species', '9606', (365, 373))	('rs20417', 'Mutation', 'rs20417', (86, 93))	('COX-2', 'Gene', (80, 85))	('COX-2', 'Gene', '4513', (80, 85))	('variants', 'Var', (208, 216))	('associated', 'Reg', (252, 262))
317022	30793520	Finally, only the susceptibility/incidence between genetic variants and EC risk were evaluated; however, other roles of genetic polymorphisms such as tumor progression, metastasis, drug resistance for EC were not be assessed due to lack of data or information.	('variants', 'Var', (59, 67))	('drug resistance', 'Phenotype', 'HP:0020174', (181, 196))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
317024	29428700	We created a decision analysis model representing two treatment strategies for cT2N0 esophageal cancer: 1) upfront esophagectomy which may be followed by adjuvant therapy for upstaged patients and 2) induction chemoradiation for all cT2N0 patients followed by esophagectomy.	('cT2N0', 'Var', (79, 84))	('cT2N0', 'Var', (233, 238))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('patients', 'Species', '9606', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('patients', 'Species', '9606', (239, 247))	('esophageal cancer', 'Disease', (85, 102))
317026	29428700	The optimal treatment strategy for cT2N0 esophageal cancer depends upon the accuracy of endoscopic ultrasound staging.	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cT2N0', 'Var', (35, 40))	('esophageal cancer', 'Disease', (41, 58))
317036	29428700	Since clinical staging is crucial in selecting appropriate treatments to maximize survival, diagnostic uncertainty in cT2N0 esophageal cancer has led to controversy about the optimal treatment strategy.	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('esophageal cancer', 'Disease', (124, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cT2N0', 'Var', (118, 123))
317039	29428700	Therefore, to address this problem, we created a decision analysis model to evaluate the role of neoadjuvant therapy versus upfront resection in cT2N0 esophageal cancer patients and to identify the threshold for benefit of induction chemoradiation.	('esophageal cancer', 'Disease', (151, 168))	('patients', 'Species', '9606', (169, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('cT2N0', 'Var', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
317041	29428700	To determine the optimal strategy for treatment of patients with cT2N0 esophageal cancer, we developed a decision analysis model using TreeAge Pro software (2016, Version R2.1, Williamstown, MA).	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cT2N0', 'Var', (65, 70))	('patients', 'Species', '9606', (51, 59))	('esophageal cancer', 'Disease', (71, 88))
317083	29428700	Our baseline model demonstrated that, overall, patients with cT2N0 cancer who underwent upfront esophagectomy have an estimated survival benefit of approximately 2-3 months compared to patients who underwent induction therapy followed by esophagectomy.	('survival', 'MPA', (128, 136))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (185, 193))	('cT2N0', 'Var', (61, 66))
317085	29428700	Survival for patients with less than pT2N0 is better with upfront surgery due to avoidance of unnecessary and likely harmful treatment in this population that could cause deconditioning, chemoradiation-related morbidity or mortality, treatment delay, and potentially increased surgical complications and mortality.	('surgical', 'CPA', (277, 285))	('deconditioning', 'Disease', (171, 185))	('patients', 'Species', '9606', (13, 21))	('less', 'Var', (27, 31))	('pT2N0', 'Var', (37, 42))
317104	29428700	In conclusion, this decision analysis provides evidence that induction chemoradiation improves survival in patients with cT2N0 esophageal cancer if the probability of EUS understaging is greater than 48.1%.	('esophageal cancer', 'Disease', (127, 144))	('cT2N0', 'Var', (121, 126))	('survival', 'MPA', (95, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('improves', 'PosReg', (86, 94))	('patients', 'Species', '9606', (107, 115))
317105	29428700	Several clinical factors including high tumor grade, presence of lymphovascular invasion, large tumor size, presence of dysphagia, or PET SUV greater than 2.5 increase the probability of EUS understaging and consequent pathologic upstaging and can guide a clinician to consider induction therapy.	('EUS', 'Disease', (187, 190))	('upstaging', 'PosReg', (230, 239))	('understaging', 'NegReg', (191, 203))	('dysphagia', 'Disease', 'MESH:D003680', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (96, 101))	('dysphagia', 'Disease', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (40, 45))	('high', 'Var', (35, 39))	('dysphagia', 'Phenotype', 'HP:0002015', (120, 129))
317108	29428700	Induction chemoradiation may offer a survival benefit over upfront surgery for clinical T2N0 esophageal cancer patients who have a greater than 48% probability of pathologic upstaging.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('T2N0', 'Var', (88, 92))	('patients', 'Species', '9606', (111, 119))
317109	29428700	This research aims to address the controversy in treating cT2N0 esophageal cancer that exists because of the inaccuracies in endoscopic ultrasound staging.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('cT2N0', 'Var', (58, 63))
317163	29467556	Both 100% circumference involvement (P = 0.002) and endoscopic CR (P = 0.035) were significantly associated with the occurrence of post-RT stenosis or TEF in multivariate analysis (Supplementary Table 1).	('CR', 'Chemical', '-', (63, 65))	('endoscopic', 'Var', (52, 62))	('post-RT stenosis', 'Disease', (131, 147))	('TEF', 'Phenotype', 'HP:0002575', (151, 154))	('TEF', 'Disease', (151, 154))
317217	27960044	Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population Genome-wide association studies have linked genetic variants at 9p21.3 to the risk of multiple cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (55, 89))	('multiple cancers', 'Disease', (200, 216))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('associated', 'Reg', (31, 41))	('variants', 'Var', (8, 16))	('multiple cancers', 'Disease', 'MESH:D009369', (200, 216))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('variants', 'Var', (166, 174))	('esophageal squamous cell carcinoma', 'Disease', (55, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
317219	27960044	We evaluated the genetic variants at 9p21.3 reported in cancer genome-wide association studies with a case-control study including 2139 ESCC cases and 2273 controls in a Chinese population, and measured the mRNA expression levels of MTAP,CDKN2A,CDKN2B, and CDKN2B-AS1 in paired ESCC tumor and adjacent normal tissues.	('CDKN2B', 'Gene', '1030', (257, 263))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('CDKN2B-AS1', 'Gene', '100048912', (257, 267))	('MTAP', 'Gene', (233, 237))	('cancer', 'Disease', (56, 62))	('MTAP', 'Gene', '4507', (233, 237))	('CDKN2B-AS1', 'Gene', (257, 267))	('variants', 'Var', (25, 33))	('mRNA expression levels', 'MPA', (207, 229))	('CDKN2B', 'Gene', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('CDKN2A', 'Gene', (238, 244))	('ESCC', 'Disease', (136, 140))	('CDKN2B', 'Gene', '1030', (245, 251))	('CDKN2B', 'Gene', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('CDKN2A', 'Gene', '1029', (238, 244))	('tumor', 'Disease', (283, 288))
317220	27960044	We found that the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per-allele odds ratio of 0.84 (95% confidence interval, 0.77-0.91; P = 2.95 x 10-5).	('decreased', 'NegReg', (76, 85))	('rs7023329', 'Mutation', 'rs7023329', (30, 39))	('ESCC', 'Disease', (94, 98))	('rs7023329', 'Var', (30, 39))
317221	27960044	The rs7023329-G allele was related to a high expression of MTAP (P = 0.020).	('rs7023329', 'Mutation', 'rs7023329', (4, 13))	('rs7023329-G', 'Var', (4, 15))	('MTAP', 'Gene', (59, 63))	('MTAP', 'Gene', '4507', (59, 63))
317222	27960044	The rs1679013-C allele was independently associated with an increased risk of ESCC with a per-allele odds ratio of 1.12 (95% confidence interval, 1.01-1.24; P = 0.039).	('rs1679013', 'Mutation', 'rs1679013', (4, 13))	('rs1679013-C', 'Var', (4, 15))	('ESCC', 'Disease', (78, 82))
317223	27960044	We also found that the carriers of the risk allele rs1679013-C had lower expression of CDKN2B than non-carriers (P = 0.035).	('rs1679013-C', 'Var', (51, 62))	('CDKN2B', 'Gene', (87, 93))	('CDKN2B', 'Gene', '1030', (87, 93))	('expression', 'MPA', (73, 83))	('lower', 'NegReg', (67, 72))	('rs1679013', 'Mutation', 'rs1679013', (51, 60))
317225	27960044	Therefore, our findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility.	('MTAP', 'Gene', '4507', (96, 100))	('expression', 'MPA', (82, 92))	('ESCC', 'Disease', (130, 134))	('contribute', 'Reg', (116, 126))	('CDKN2B', 'Gene', (105, 111))	('CDKN2B', 'Gene', '1030', (105, 111))	('variants', 'Var', (46, 54))	('MTAP', 'Gene', (96, 100))	('modulate', 'Reg', (69, 77))
317230	27960044	Subsequently, Gao et al.24 confirmed that genes involved in cell cycle and apoptosis regulation, including CDKN2A, were mutated in 99% of ESCC cases by sequencing on 113 tumor-normal pairs.	('CDKN2A', 'Gene', '1029', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('CDKN2A', 'Gene', (107, 113))	('ESCC', 'Disease', (138, 142))	('mutated', 'Var', (120, 127))
317238	27960044	Finally, we included rs7023329, rs3731217, rs3731239, rs1011970, and rs1679013 as tag SNPs to be genotyped in this study.	('rs1011970', 'Var', (54, 63))	('rs7023329', 'Var', (21, 30))	('rs3731239', 'Var', (43, 52))	('rs7023329', 'Mutation', 'rs7023329', (21, 30))	('rs3731217', 'Var', (32, 41))	('rs3731217', 'Mutation', 'rs3731217', (32, 41))	('rs1011970', 'Mutation', 'rs1011970', (54, 63))	('rs1679013', 'Mutation', 'rs1679013', (69, 78))	('rs1679013', 'Var', (69, 78))	('rs3731239', 'Mutation', 'rs3731239', (43, 52))
317245	27960044	In the additive model, the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per-allele OR of 0.84 (95% CI, 0.77-0.91; P = 2.95 x 10-5); in the codominant model, individuals carrying either AG or GG genotype showed a significantly reduced ESCC risk (OR = 0.68 and 0.72, respectively) compared with those with AA genotype.	('decreased', 'NegReg', (85, 94))	('reduced', 'NegReg', (269, 276))	('ESCC', 'Disease', (277, 281))	('rs7023329', 'Var', (39, 48))	('ESCC', 'Disease', (103, 107))	('rs7023329', 'Mutation', 'rs7023329', (39, 48))
317246	27960044	The C allele of rs1679013 was associated with an increased risk of ESCC with a per-allele OR of 1.12 (95% CI, 1.01-1.24; P = 0.039) in the additive model, and in the codominant model, individuals carrying CC genotype showed an increased ESCC risk (OR = 1.44, 95% CI, 1.06-1.96; P = 0.020) compared with those with TT genotype.	('ESCC', 'Disease', (67, 71))	('increased ESCC', 'Phenotype', 'HP:0003565', (227, 241))	('rs1679013', 'Mutation', 'rs1679013', (16, 25))	('rs1679013', 'Var', (16, 25))	('ESCC', 'Disease', (237, 241))
317247	27960044	After conditioned on each other for these two SNPs, the association results for both variants changed little; rs1679013 and rs7023329 might be independent loci for ESCC susceptibility (Table S4).	('rs1679013', 'Mutation', 'rs1679013', (110, 119))	('rs7023329', 'Var', (124, 133))	('ESCC', 'Disease', (164, 168))	('rs7023329', 'Mutation', 'rs7023329', (124, 133))	('rs1679013', 'Var', (110, 119))
317248	27960044	Furthermore, subgroup analyses stratified by age, gender, and smoking and drinking status, were carried out for the association of two SNPs (rs7023329 and rs1679013) and ESCC risk.	('association', 'Interaction', (116, 127))	('rs7023329', 'Var', (141, 150))	('rs7023329', 'Mutation', 'rs7023329', (141, 150))	('rs1679013', 'Mutation', 'rs1679013', (155, 164))	('rs1679013', 'Var', (155, 164))	('ESCC', 'Disease', (170, 174))
317249	27960044	As shown in Table 2, there were no significant differences between subgroups (P > 0.05 for heterogeneity tests) for associations of rs7023329 and rs1679013 with ESCC risk.	('rs7023329', 'Var', (132, 141))	('ESCC', 'Disease', (161, 165))	('rs7023329', 'Mutation', 'rs7023329', (132, 141))	('associations', 'Interaction', (116, 128))	('rs1679013', 'Var', (146, 155))	('rs1679013', 'Mutation', 'rs1679013', (146, 155))
317250	27960044	However, no significant associations were observed for the other three SNPs with ESCC risk (additive P = 0.581, 0.909, and 0.183 for rs3731239, rs3731217, and rs1011970, respectively) (Table 1).	('rs1011970', 'Mutation', 'rs1011970', (159, 168))	('rs3731239', 'Var', (133, 142))	('ESCC', 'Disease', (81, 85))	('rs3731217', 'Var', (144, 153))	('rs3731217', 'Mutation', 'rs3731217', (144, 153))	('rs3731239', 'Mutation', 'rs3731239', (133, 142))	('rs1011970', 'Var', (159, 168))
317251	27960044	Around the selected variants at 9p21.3 region, there are four important genes: MTAP, CDKN2A, CDKN2B, and CDKN2B-AS1 (Fig.	('variants', 'Var', (20, 28))	('CDKN2B', 'Gene', (93, 99))	('CDKN2B-AS1', 'Gene', '100048912', (105, 115))	('CDKN2B', 'Gene', '1030', (93, 99))	('MTAP', 'Gene', '4507', (79, 83))	('CDKN2B', 'Gene', (105, 111))	('CDKN2A', 'Gene', (85, 91))	('CDKN2B', 'Gene', '1030', (105, 111))	('CDKN2A', 'Gene', '1029', (85, 91))	('CDKN2B-AS1', 'Gene', (105, 115))	('MTAP', 'Gene', (79, 83))
317252	27960044	We next sought to determine whether rs7023329 and rs1679013 genotypes were associated with expression of these genes by quantitative RT-PCR analysis of ESCC tumors and adjacent normal tissues (Figs 2,S1).	('ESCC tumors', 'Disease', 'MESH:D004938', (152, 163))	('rs7023329', 'Mutation', 'rs7023329', (36, 45))	('rs1679013', 'Mutation', 'rs1679013', (50, 59))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('ESCC tumors', 'Disease', (152, 163))	('rs7023329', 'Var', (36, 45))	('associated', 'Reg', (75, 85))	('rs1679013', 'Var', (50, 59))
317253	27960044	We observed that the protective allele rs7023329-G was related to a high expression of MTAP (P = 0.020), and the carriers of the risk allele rs1679013-C had significantly lower expressions of CDKN2B than did non-carriers (P = 0.035) among adjacent normal tissues (Fig.	('rs7023329-G', 'Var', (39, 50))	('rs1679013-C', 'Var', (141, 152))	('MTAP', 'Gene', '4507', (87, 91))	('CDKN2B', 'Gene', '1030', (192, 198))	('CDKN2B', 'Gene', (192, 198))	('rs1679013', 'Mutation', 'rs1679013', (141, 150))	('expressions', 'MPA', (177, 188))	('MTAP', 'Gene', (87, 91))	('lower', 'NegReg', (171, 176))	('rs7023329', 'Mutation', 'rs7023329', (39, 48))
317256	27960044	These findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility.	('CDKN2B', 'Gene', '1030', (96, 102))	('MTAP', 'Gene', '4507', (87, 91))	('modulate', 'Reg', (60, 68))	('expression', 'MPA', (73, 83))	('contribute', 'Reg', (107, 117))	('variants', 'Var', (37, 45))	('ESCC', 'Disease', (121, 125))	('MTAP', 'Gene', (87, 91))	('CDKN2B', 'Gene', (96, 102))
317257	27960044	We found that the G allele of rs7023329 was significantly associated with a reduced risk of ESCC, whereas the C allele of rs1679013 was associated with an increased risk of ESCC.	('rs7023329', 'Mutation', 'rs7023329', (30, 39))	('ESCC', 'Disease', (92, 96))	('rs1679013', 'Var', (122, 131))	('rs1679013', 'Mutation', 'rs1679013', (122, 131))	('reduced', 'NegReg', (76, 83))	('rs7023329', 'Var', (30, 39))
317258	27960044	Further genotype-phenotype analysis confirmed that the protective allele rs7023329-G was related to a high expression of MTAP, which might increase the role of tumor suppressor MTAP.	('MTAP', 'Gene', '4507', (121, 125))	('MTAP', 'Gene', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('expression', 'MPA', (107, 117))	('rs7023329', 'Mutation', 'rs7023329', (73, 82))	('rs7023329-G', 'Var', (73, 84))	('increase', 'PosReg', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('MTAP', 'Gene', '4507', (177, 181))	('tumor', 'Disease', (160, 165))	('MTAP', 'Gene', (121, 125))
317259	27960044	We also found that the carriers of the risk allele rs1679013-C had lower expression of CDKN2B than did non-carriers.	('rs1679013-C', 'Var', (51, 62))	('CDKN2B', 'Gene', (87, 93))	('CDKN2B', 'Gene', '1030', (87, 93))	('expression', 'MPA', (73, 83))	('lower', 'NegReg', (67, 72))	('rs1679013', 'Mutation', 'rs1679013', (51, 60))
317260	27960044	CDKN2B, known as a tumor suppressor, was significantly downregulated in ESCC tumor tissues compared with adjacent normal tissues, which indicated that genetic variants at 9p21.3 may also be implicated with ESCC susceptibility.	('implicated', 'Reg', (190, 200))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('variants', 'Var', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ESCC', 'Disease', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CDKN2B', 'Gene', (0, 6))	('tumor', 'Disease', (19, 24))	('downregulated', 'NegReg', (55, 68))	('tumor', 'Disease', (77, 82))	('CDKN2B', 'Gene', '1030', (0, 6))
317261	27960044	The chromosome 9p21.3 region has been identified as a genetic susceptibility locus for a number of disease phenotypes, including heart disease, stroke, diabetes, and especially cancers.27, 28, 29 Recently, several GWAS have confirmed that variants in this region are related to multiple cancer risks, including glioma,12, 13, 14 melanoma,15, 16 basal cell carcinoma,17 nasopharyngeal carcinoma,18 breast cancer,19, 20 chronic lymphocytic leukemia,21 and childhood acute lymphoblastic leukemia.22 These associations suggest that multiple functional genetic variants may exist in this region and the genetic variants at 9p21.3 may also be pleiotropic.	('especially cancers', 'Disease', (166, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('leukemia', 'Phenotype', 'HP:0001909', (484, 492))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (369, 393))	('diabetes', 'Disease', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('breast cancer', 'Disease', 'MESH:D001943', (397, 410))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', (397, 410))	('stroke', 'Phenotype', 'HP:0001297', (144, 150))	('multiple cancer', 'Disease', 'MESH:D009369', (278, 293))	('14 melanoma', 'Disease', (326, 337))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (345, 365))	('acute lymphoblastic leukemia', 'Disease', (464, 492))	('glioma', 'Disease', (311, 317))	('stroke', 'Disease', 'MESH:D020521', (144, 150))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (464, 492))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (369, 393))	('variants', 'Var', (556, 564))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (418, 446))	('glioma', 'Disease', 'MESH:D005910', (311, 317))	('14 melanoma', 'Disease', 'MESH:D008545', (326, 337))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (464, 492))	('stroke', 'Disease', (144, 150))	('chronic lymphocytic leukemia', 'Disease', (418, 446))	('heart disease', 'Disease', 'MESH:D006331', (129, 142))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (345, 365))	('especially cancers', 'Disease', 'MESH:D009369', (166, 184))	('diabetes', 'Disease', 'MESH:D003920', (152, 160))	('multiple cancer', 'Disease', (278, 293))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (418, 446))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (470, 492))	('glioma', 'Phenotype', 'HP:0009733', (311, 317))	('heart disease', 'Disease', (129, 142))	('basal cell carcinoma', 'Disease', (345, 365))	('carcinoma', 'Phenotype', 'HP:0030731', (384, 393))	('melanoma', 'Phenotype', 'HP:0002861', (329, 337))	('nasopharyngeal carcinoma', 'Disease', (369, 393))	('leukemia', 'Phenotype', 'HP:0001909', (438, 446))	('breast cancer', 'Phenotype', 'HP:0003002', (397, 410))
317262	27960044	Two studies have reported that genetic variants in 9p21.3 (including rs3731239, rs1063192, rs2157719, rs615552, rs573687, rs4977756, and rs564398) were associated with ESCC in a Chinese population.25, 29 These variants mainly represent three independent signals according to the LD pattern in the 1000 Genomes Project data of Chinese population: signal 1, rs1063192 and rs4977756 (r 2 = 0.91); signal 2, rs2157719, rs615552, rs573687, and rs564398 (r 2 = 1.00); and signal 3, rs3731239.	('rs3731239', 'Var', (476, 485))	('rs4977756', 'Var', (370, 379))	('rs615552', 'Var', (415, 423))	('rs615552', 'Mutation', 'rs615552', (415, 423))	('rs2157719', 'Mutation', 'rs2157719', (404, 413))	('rs564398', 'Mutation', 'rs564398', (137, 145))	('rs573687', 'Var', (425, 433))	('rs1063192', 'Var', (356, 365))	('rs564398', 'Mutation', 'rs564398', (439, 447))	('rs3731239', 'Mutation', 'rs3731239', (476, 485))	('rs573687', 'Mutation', 'rs573687', (425, 433))	('rs4977756', 'Mutation', 'rs4977756', (370, 379))	('rs3731239', 'Mutation', 'rs3731239', (69, 78))	('rs1063192', 'Mutation', 'rs1063192', (80, 89))	('rs564398', 'Var', (439, 447))	('rs615552', 'Mutation', 'rs615552', (102, 110))	('rs1063192', 'Mutation', 'rs1063192', (356, 365))	('rs4977756', 'Mutation', 'rs4977756', (122, 131))	('rs2157719', 'Var', (404, 413))	('rs2157719', 'Mutation', 'rs2157719', (91, 100))	('rs573687', 'Mutation', 'rs573687', (112, 120))
317263	27960044	However, our findings with a larger sample size did not find a significant association between rs3731239 (signal 3) and ESCC risk.	('rs3731239', 'Var', (95, 104))	('rs3731239', 'Mutation', 'rs3731239', (95, 104))	('ESCC', 'Disease', (120, 124))
317264	27960044	Instead, we found that rs7023329 and rs1679013 were independently associated with ESCC risk.	('rs7023329', 'Mutation', 'rs7023329', (23, 32))	('rs1679013', 'Var', (37, 46))	('ESCC', 'Disease', (82, 86))	('associated', 'Reg', (66, 76))	('rs1679013', 'Mutation', 'rs1679013', (37, 46))	('rs7023329', 'Var', (23, 32))
317265	27960044	Recent studies showed that the 9p21.3 region was enriched in regulatory sequences such as enhancers that regulate the expression of genes in this region and downstream, thereby establishing a functional link between 9p21 genetic variation and immune signaling pathways.30 Our results confirmed that the carriers of the protective allele rs7023329-G had significantly higher expressions of MTAP than did non-carriers among adjacent normal tissues.	('MTAP', 'Gene', (389, 393))	('expressions', 'MPA', (374, 385))	('MTAP', 'Gene', '4507', (389, 393))	('higher', 'PosReg', (367, 373))	('rs7023329', 'Mutation', 'rs7023329', (337, 346))	('rs7023329-G', 'Var', (337, 348))
317266	27960044	It has been reported that loss of MTAP expression can exert a tumor-promoting effect in multiple cancers and MTAP may function as a tumor suppressor gene.31, 32, 33 Therefore, the rs7023329-G allele was related to high expression of MTAP, which might increase the role of tumor suppressor MTAP and ultimately result in a reduced ESCC risk.	('MTAP', 'Gene', (289, 293))	('MTAP', 'Gene', '4507', (289, 293))	('tumor', 'Disease', (132, 137))	('MTAP', 'Gene', (34, 38))	('MTAP', 'Gene', (233, 237))	('increase', 'PosReg', (251, 259))	('rs7023329-G', 'Var', (180, 191))	('multiple cancers', 'Disease', 'MESH:D009369', (88, 104))	('MTAP', 'Gene', '4507', (34, 38))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('MTAP', 'Gene', '4507', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (272, 277))	('ESCC', 'Disease', (329, 333))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('MTAP', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('multiple cancers', 'Disease', (88, 104))	('MTAP', 'Gene', '4507', (109, 113))	('rs7023329', 'Mutation', 'rs7023329', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (62, 67))	('reduced', 'NegReg', (321, 328))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
317267	27960044	Moreover, the ESCC-risk allele rs1679013-C was associated with reduced CDKN2B expression in our study.	('rs1679013-C', 'Var', (31, 42))	('expression', 'MPA', (78, 88))	('CDKN2B', 'Gene', (71, 77))	('reduced', 'NegReg', (63, 70))	('CDKN2B', 'Gene', '1030', (71, 77))	('rs1679013', 'Mutation', 'rs1679013', (31, 40))
317268	27960044	Analysis of the Encyclopedia of DNA Elements data, as implemented in the online tool HaploReg (http://broadinstitute.org/mammals/haploreg/haploreg.php), indicated that rs1679013 was located in a transcription regulatory region and may influence the chromatin structure and histone modifications by altering the transcription factor binding sites of OTX2, which may serve as a regulatory variant in the expression of CDKN2B, suggesting that modulation of CDKN2B expression may mediate ESCC susceptibility.	('binding', 'Interaction', (332, 339))	('influence', 'Reg', (235, 244))	('altering', 'Reg', (298, 306))	('CDKN2B', 'Gene', '1030', (416, 422))	('CDKN2B', 'Gene', '1030', (454, 460))	('transcription factor', 'MPA', (311, 331))	('modulation', 'Var', (440, 450))	('OTX2', 'Gene', '5015', (349, 353))	('ESCC', 'Disease', (484, 488))	('OTX2', 'Gene', (349, 353))	('rs1679013', 'Var', (168, 177))	('histone modifications', 'MPA', (273, 294))	('CDKN2B', 'Gene', (416, 422))	('rs1679013', 'Mutation', 'rs1679013', (168, 177))	('CDKN2B', 'Gene', (454, 460))	('chromatin', 'MPA', (249, 258))	('mediate', 'Reg', (476, 483))
317270	27960044	These data suggest that genetic variants in the MTAP/CDKN2A/2B/2B-AS1 cluster may modulate ESCC susceptibility through regulating expression levels of genes in the cluster.	('CDKN2A', 'Gene', (53, 59))	('MTAP', 'Gene', '4507', (48, 52))	('ESCC', 'Disease', (91, 95))	('CDKN2A', 'Gene', '1029', (53, 59))	('regulating', 'Reg', (119, 129))	('genetic variants', 'Var', (24, 40))	('modulate', 'Reg', (82, 90))	('expression levels', 'MPA', (130, 147))	('MTAP', 'Gene', (48, 52))
317271	27960044	In summary, in a relatively large case-control study in a Chinese population, we found two independent variants in 9p21.3 (rs7023329 and rs1679013) associated with ESCC risk and provided additional evidence for the role of 9p21.3 locus in ESCC development.	('rs7023329', 'Var', (123, 132))	('rs1679013', 'Var', (137, 146))	('rs7023329', 'Mutation', 'rs7023329', (123, 132))	('ESCC', 'Disease', (239, 243))	('rs1679013', 'Mutation', 'rs1679013', (137, 146))	('ESCC', 'Disease', (164, 168))	('9p21.3', 'Gene', (115, 121))	('associated with', 'Reg', (148, 163))
317277	27905170	The consensus groups, identical for both cell types were as follows: ypStage I comprised ypT0-2N0M0; ypStage II ypT3N0M0; ypStage IIIA ypT0-2N1M0; ypStage IIIB ypT3N1M0, ypT0-3N2, and ypT4aN0M0; ypStage IVA ypT4aN1-2, ypT4bN0-2, and ypTanyN3M0; and ypStage IVB ypTanyNanyM1.	('IVA', 'Disease', (203, 206))	('IVA', 'Disease', 'MESH:C538167', (203, 206))	('ypT4aN0M0', 'Var', (184, 193))
317278	27905170	Absence of equivalent pathologic (pTNM) categories for the peculiar neoadjuvant pathologic categories ypTisN0-3M0 and ypT0N0-3M0, dissimilar stage group compositions, and markedly different early- and intermediate-stage survival necessitated a unified, unique set of stage grouping for patients of either cell type who receive neoadjuvant therapy.	('ypT0N0-3M0', 'Var', (118, 128))	('patients', 'Species', '9606', (286, 294))	('ypTisN0-3M0', 'Var', (102, 113))
317300	27905170	Only for ypT2-3N0M0 cancers did it play a role, and not in an ordered progression; these cancers were broadly spread through Group 1 (ypT2N0M0G1 upper/middle esophagus), Group 2 (ypT2N0M0G2-3 lower esophagus), Group 3 (ypT2N0M0G2 upper/middle esophagus, ypT3N0M0 upper/middle esophagus, and ypT3N0M0G2 lower esophagus), Group 4 (ypT2N0M0G2-3 upper/middle esophagus and ypT3N0M0G3 lower esophagus), and group 5 (ypT3N0M0G2-3 upper/middle esophagus), with few entries per group and poor arrangement by grade and location.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('ypT2N0M0G1', 'Var', (134, 144))	('ypT2N0M0G2-3', 'Var', (329, 341))	('ypT3N0M0G2-3', 'Var', (411, 423))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('ypT2N0M0G2', 'Var', (219, 229))	('ypT3N0M0G3', 'Var', (369, 379))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
317301	27905170	Group 3 also contained ypT0-1N0M0 and Group 5 ypT1N2M0.	('ypT1', 'Gene', '5861', (46, 50))	('ypT1', 'Gene', (46, 50))	('ypT0-1N0M0', 'Var', (23, 33))
317303	27905170	There were too few ypTisN0-2M0, ypT1N2M0, ypT2-3N0M0G1 lower esophagus, ypT4aN2M0, and ypT4bN0-2M0 cancers to group.	('ypT4bN0-2M0', 'Var', (87, 98))	('ypT4aN2M0', 'Var', (72, 81))	('ypT1', 'Gene', '5861', (32, 36))	('ypT2-3N0M0G1', 'Var', (42, 54))	('ypTisN0-2M0', 'Var', (19, 30))	('ypT1', 'Gene', (32, 36))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('lower esophagus', 'Disease', (55, 70))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
317305	27905170	Group 1 was composed of ypT0-2N0M0 cancers confined to the esophageal wall, except for ypT2N0M0G3 cancers, which with ypT3N0M0 cancers comprised Group 2.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (98, 105))	('cancers', 'Disease', (127, 134))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('ypT0-2N0M0', 'Var', (24, 34))	('cancers', 'Disease', (35, 42))
317306	27905170	Group 3 was restricted to cancer confined to the esophageal wall with ypN1 regional nodal category and ypT4aN0M0 and ypT1N2M0.	('ypT1', 'Gene', (117, 121))	('ypT1', 'Gene', '5861', (117, 121))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('ypT4aN0M0', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('ypN1', 'Var', (70, 74))
317307	27905170	Group 4 was composed of ypT2N2M0, ypT3N1-2M0, and ypT4aN1M0 cancers.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('ypT4aN1M0', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('ypT3N1-2M0', 'Var', (34, 44))
317308	27905170	There were too few ypTisN0-2M0, ypT0N2M0, ypT4aN2M0, and ypT4bN0-2M0 patients to group.	('patients', 'Species', '9606', (69, 77))	('ypT0N2M0', 'Var', (32, 40))	('ypT4bN0-2M0', 'Var', (57, 68))	('ypT4aN2M0', 'Var', (42, 51))
317311	27905170	The groups were identical for squamous cell carcinoma and adenocarcinoma except that ypT2N0M0 moved from Group 1 squamous cell carcinoma to Group 2 adenocarcinoma as the sole entry, which then increased the cardinal number.	('ypT2N0M0', 'Var', (85, 93))	('squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (30, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (148, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('adenocarcinoma', 'Disease', (58, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (58, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('increased', 'PosReg', (193, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 136))	('adenocarcinoma', 'Disease', (148, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell carcinoma', 'Disease', (113, 136))	('squamous cell carcinoma', 'Disease', (30, 53))	('cardinal number', 'MPA', (207, 222))
317312	27905170	ypT4aN0M0 and ypT4aN1M0 squamous cell carcinoma moved to one group lower in adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (24, 47))	('ypT4aN0M0', 'Var', (0, 9))	('ypT4aN1M0', 'Var', (14, 23))	('squamous cell carcinoma', 'Disease', (24, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('adenocarcinoma', 'Disease', (76, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (24, 47))
317314	27905170	The only step required was combining ypT2N0M0 adenocarcinoma, the sole component of Group 2, with Group 1 cancers to form Consensus group I.	('adenocarcinoma', 'Disease', (46, 60))	('adenocarcinoma', 'Disease', 'MESH:D000230', (46, 60))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('ypT2N0M0', 'Var', (37, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
317315	27905170	Thus, Consensus group I was ypT0-2N0M0; Group II was ypT3N0M0; Group IIIA was ypT1-2N1M0; Group IIIB was ypT0-3N2, ypT3N1M0, and ypT4aN0M0; and Group IV was ypT4aN1-2M0, ypT4bN0-2M0, ypanyTN3M0, and ypM1.	('ypT4aN0M0', 'Var', (129, 138))	('ypT1', 'Gene', '5861', (78, 82))	('ypT1', 'Gene', (78, 82))
317321	27905170	ypT0-2 cancers have similar survival for each N category; ypT0-2N0M0 comprise ypStage I; ypT0-2N1M0 comprise ypStage IIIA; ypT0-2N2M0 plus ypT3N1-2M0 and ypT4aN0M0 comprise ypStage IIIB; and ypT0-2N3 plus ypT3N3M0, ypT4aN1-3, and ypT4bN0-3M0 comprise ypStage IVA.	('ypT0-2N3 plus ypT3N3M0', 'Var', (191, 213))	('IVA', 'Disease', 'MESH:C538167', (259, 262))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('ypT4aN0M0', 'Var', (154, 163))	('ypT4bN0-3M0', 'Var', (230, 241))	('ypT0-2N1M0', 'Var', (89, 99))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('ypT0-2N2M0', 'Var', (123, 133))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('cancers', 'Disease', (7, 14))	('IVA', 'Disease', (259, 262))	('ypT0-2N0M0', 'Var', (58, 68))
317327	27905170	However, downstaged subgroups ypT0N0M0 (22 patients), ypT1-2N0M0 (33 patients), ypT1-2N1M0 (49 patients), and ypT3-4N0M0 (36 patients) had better survival than expected from the overall WECC data.	('ypT1', 'Gene', (80, 84))	('patients', 'Species', '9606', (95, 103))	('patients', 'Species', '9606', (43, 51))	('ypT1', 'Gene', (54, 58))	('ypT1', 'Gene', '5861', (80, 84))	('ypT1', 'Gene', '5861', (54, 58))	('ypT3-4N0M0', 'Var', (110, 120))	('better', 'PosReg', (139, 145))	('patients', 'Species', '9606', (69, 77))	('survival', 'CPA', (146, 154))	('ypT0N0M0', 'Var', (30, 38))	('patients', 'Species', '9606', (125, 133))
317346	27905170	Absence of equivalent pathologic (pTNM) categories for the peculiar neoadjuvant pathologic categories ypTisN0-3M0 and ypT0N0-3M0, dissimilar stage group compositions, and markedly different early- and intermediate-stage survival profiles necessitated a single, unique set of stage grouping for patients of either cell type who receive neoadjuvant therapy.	('patients', 'Species', '9606', (294, 302))	('ypT0N0-3M0', 'Var', (118, 128))	('ypTisN0-3M0', 'Var', (102, 113))
317354	27015293	In all the patients examined, overall survival rates of the patients with tumors positive for PD-L1 or PD-L2 were significantly worse than those with tumors negative for PD-L1 or PD-L2 (P = 0.0010 and P = 0.0237, respectively).	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('overall survival rates', 'CPA', (30, 52))	('PD-L1', 'Var', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PD-L2', 'Gene', (179, 184))	('PD-L2', 'Gene', '80380', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('worse', 'NegReg', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('patients', 'Species', '9606', (11, 19))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('PD-L2', 'Gene', (103, 108))	('PD-L2', 'Gene', '80380', (103, 108))	('tumors', 'Disease', (74, 80))
317356	27015293	The patients with positive PD-L1 expression had a significantly higher rate of NAC history (P = 0.0139), but those with positive PD-L2 expression did not have a significantly high rate of NAC history (P = 0.6127).	('NAC', 'Chemical', '-', (188, 191))	('expression', 'Var', (33, 43))	('NAC', 'Chemical', '-', (79, 82))	('higher', 'PosReg', (64, 70))	('PD-L2', 'Gene', (129, 134))	('PD-L2', 'Gene', '80380', (129, 134))	('NAC history', 'Disease', (79, 90))	('patients', 'Species', '9606', (4, 12))	('PD-L1', 'Gene', (27, 32))
317357	27015293	There is no significant relationship between PD-L1 expression and response to chemotherapy (P = 0.3118), but patients with positive PD-L2 expression had significantly inferior responses to chemotherapy (P = 0.0034).	('positive', 'Var', (123, 131))	('PD-L2', 'Gene', (132, 137))	('PD-L2', 'Gene', '80380', (132, 137))	('patients', 'Species', '9606', (109, 117))	('inferior', 'NegReg', (167, 175))	('responses to chemotherapy', 'MPA', (176, 201))
317363	27015293	The PD-1 is an immune-checkpoint receptor that provides inhibitory signals in T-cell activation when engaged by its ligands (programmed death-1 ligands [PD-L]); PD1 ligand 1 (PD-L1) and PD1 ligand 2 (PD-L2).6 The PD-l/PD-L pathway plays a critical role in regulating the activity of T cells in effector phases against not only normal cells,7, 8 but also against tumor cells.6 Recently, multiple clinical trials have shown that the blockade of this pathway using antibodies specific to PD-1 or PD-L1 is associated with significant antitumor activity in patients with multiple types of cancer,9, 10 and extensive clinical development of this modality is in progress.	('PD1', 'Gene', '18566', (161, 164))	('PD-1', 'Gene', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (584, 590))	('PD-1', 'Gene', '5133', (4, 8))	('tumor', 'Disease', (534, 539))	('tumor', 'Disease', (362, 367))	('PD-l', 'Gene', '5133', (213, 217))	('blockade', 'Var', (431, 439))	('PD-L2', 'Gene', '80380', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (534, 539))	('PD-1', 'Gene', (485, 489))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('PD-L', 'Gene', (218, 222))	('PD-1', 'Gene', '5133', (485, 489))	('PD-L', 'Gene', '5133', (218, 222))	('patients', 'Species', '9606', (552, 560))	('PD1 ligand 2', 'Gene', (186, 198))	('PD-L', 'Gene', (200, 204))	('PD-L', 'Gene', (153, 157))	('PD-L2', 'Gene', (200, 205))	('PD-L', 'Gene', '5133', (200, 204))	('PD-L', 'Gene', (493, 497))	('PD-L', 'Gene', '5133', (153, 157))	('PD1 ligand 2', 'Gene', '80380', (186, 198))	('tumor', 'Phenotype', 'HP:0002664', (534, 539))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('PD-L', 'Gene', '5133', (493, 497))	('cancer', 'Disease', (584, 590))	('PD1', 'Gene', (186, 189))	('PD-L', 'Gene', (175, 179))	('PD-L', 'Gene', '5133', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (584, 590))	('PD1', 'Gene', (161, 164))	('PD-l', 'Gene', (213, 217))	('programmed death-1', 'Gene', (125, 143))	('PD1', 'Gene', '18566', (186, 189))	('programmed death-1', 'Gene', '5133', (125, 143))
317404	27015293	The patients with positive PD-L1 expression had a significantly higher rate of NAC history (P = 0.0139), but those with positive PD-L2 expression did not (P = 0.6127).	('expression', 'Var', (33, 43))	('NAC', 'Chemical', '-', (79, 82))	('higher', 'PosReg', (64, 70))	('PD-L2', 'Gene', (129, 134))	('PD-L2', 'Gene', '80380', (129, 134))	('NAC history', 'Disease', (79, 90))	('patients', 'Species', '9606', (4, 12))	('PD-L1', 'Gene', (27, 32))
317405	27015293	In all the patients examined in this study, overall survival rates of the patients with tumors positive for PD-L1 or PD-L2 were significantly worse than those with tumors negative for PD-L1 or PD-L2 (P = 0.0010 and P = 0.0237, respectively) (Fig.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('overall survival rates', 'CPA', (44, 66))	('PD-L1', 'Var', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('patients', 'Species', '9606', (74, 82))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('PD-L2', 'Gene', (193, 198))	('PD-L2', 'Gene', '80380', (193, 198))	('worse', 'NegReg', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('patients', 'Species', '9606', (11, 19))	('tumors', 'Disease', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('PD-L2', 'Gene', (117, 122))	('PD-L2', 'Gene', '80380', (117, 122))
317406	27015293	Multivariate analysis revealed that expression of PD-L1 is a significant predictive factor for overall survival (P = 0.0114) in patients with esophageal cancer treated with surgery (Table 2).	('esophageal cancer', 'Disease', (142, 159))	('PD-L1', 'Gene', (50, 55))	('expression', 'Var', (36, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('overall', 'MPA', (95, 102))	('patients', 'Species', '9606', (128, 136))
317410	27015293	Among the patients without NAC, there is no significant difference in the overall survival rate between patients with positive PD-L1 expression and those with negative PD-L1 expression.	('NAC', 'Chemical', '-', (27, 30))	('expression', 'Var', (133, 143))	('PD-L1', 'Gene', (127, 132))	('positive', 'Var', (118, 126))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (104, 112))
317429	27015293	These results might collectively suggest that PD-L1 and PD-L2 have significant impact on survival after chemotherapy but appear to do so through different means.	('PD-L1', 'Var', (46, 51))	('survival', 'CPA', (89, 97))	('impact', 'Reg', (79, 85))	('PD-L2', 'Gene', (56, 61))	('PD-L2', 'Gene', '80380', (56, 61))
317432	27015293	Surprisingly, the average IR score for PD-L1 in patients treated with NAC was significantly higher than that in patients not treated with NAC.	('PD-L1', 'Gene', (39, 44))	('higher', 'PosReg', (92, 98))	('NAC', 'Var', (70, 73))	('patients', 'Species', '9606', (112, 120))	('NAC', 'Chemical', '-', (138, 141))	('IR score', 'MPA', (26, 34))	('NAC', 'Chemical', '-', (70, 73))	('patients', 'Species', '9606', (48, 56))
317433	27015293	In contrast, the average IR score for PD-L2 in patients treated with NAC was not significantly different from that in patients not treated with NAC.	('NAC', 'Var', (69, 72))	('NAC', 'Chemical', '-', (144, 147))	('NAC', 'Chemical', '-', (69, 72))	('patients', 'Species', '9606', (47, 55))	('PD-L2', 'Gene', (38, 43))	('PD-L2', 'Gene', '80380', (38, 43))	('patients', 'Species', '9606', (118, 126))
317434	27015293	These results might suggest that expression of only PD-L1, but not PD-L2, in tumor cells could be induced by chemotherapy in esophageal cancer patients.	('PD-L2', 'Gene', (67, 72))	('induced', 'Reg', (98, 105))	('PD-L2', 'Gene', '80380', (67, 72))	('esophageal cancer', 'Disease', (125, 142))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('patients', 'Species', '9606', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('expression', 'MPA', (33, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('tumor', 'Disease', (77, 82))	('PD-L1', 'Var', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
317449	27148416	A high expression of COX2 correlated with a higher T staging (P = 0.014), lower differentiation degree (P = 0.002), lymph node metastasis (P = 0.009), recurrence status (P = 0.004), and tumor node metastasis (TNM) stage (P = 0.001).	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('T staging', 'CPA', (51, 60))	('high', 'Var', (2, 6))	('higher', 'PosReg', (44, 50))	('recurrence status', 'CPA', (151, 168))	('tumor node metastasis', 'Disease', 'MESH:D009362', (186, 207))	('COX2', 'Gene', (21, 25))	('lymph node metastasis', 'CPA', (116, 137))	('COX2', 'Gene', '5743', (21, 25))	('lower', 'NegReg', (74, 79))	('tumor node metastasis', 'Disease', (186, 207))
317500	27148416	In our study, the statistical results of survival analysis indicated that the five-year survival rate of patients with COX2 overexpression was lower than those without COX2 expression.	('patients', 'Species', '9606', (105, 113))	('COX2', 'Gene', '5743', (119, 123))	('COX2', 'Gene', (119, 123))	('overexpression', 'Var', (124, 138))	('lower', 'NegReg', (143, 148))	('COX2', 'Gene', (168, 172))	('COX2', 'Gene', '5743', (168, 172))
317507	27148416	Cox regression analysis indicated that the high expression of COX2 protein is an independent risk factor for prognosis.	('COX2', 'Gene', '5743', (62, 66))	('COX2', 'Gene', (62, 66))	('protein', 'Protein', (67, 74))	('high', 'Var', (43, 47))
317596	24796531	Conversely, TAM67, a dominant negative mutant of c-Jun, inhibited SPRR3 transactivation.	('SPRR3', 'Gene', (66, 71))	('TAM67', 'Var', (12, 17))	('SPRR3', 'Gene', '6707', (66, 71))	('inhibited', 'NegReg', (56, 65))	('TAM67', 'Chemical', '-', (12, 17))
317611	24796531	c-Jun is the critical component of transcription factor AP1, and becomes transcriptionally active upon phosphorylation at Ser63 and Ser73 within its N-terminal transactivation domain by JNK.	('transcriptionally active', 'MPA', (73, 97))	('Ser63', 'Chemical', '-', (122, 127))	('JNK', 'Gene', (186, 189))	('AP1', 'Gene', '3725', (56, 59))	('Ser73', 'Chemical', '-', (132, 137))	('Ser63', 'Var', (122, 127))	('AP1', 'Gene', (56, 59))	('JNK', 'Gene', '5599', (186, 189))	('Ser73', 'Var', (132, 137))
317618	24796531	Induction of Ets1 dramatically upregulated SPRRs expression, but involucrin was not changed using microarray analysis.	('SPRRs expression', 'MPA', (43, 59))	('Ets1', 'Gene', (13, 17))	('upregulated', 'PosReg', (31, 42))	('involucrin', 'Gene', (65, 75))	('Induction', 'Var', (0, 9))	('involucrin', 'Gene', '3713', (65, 75))
317636	24796531	PKC inhibitor (GF109203X), MEK1 inhibitor (PD98059) and JNK inhibitor (SP600125) were obtained from Calbiochem (Merck, Darmstadt, Germany).	('PD98059', 'Var', (43, 50))	('JNK', 'Gene', (56, 59))	('GF109203X', 'Var', (15, 24))	('GF109203X', 'Chemical', 'MESH:C070515', (15, 24))	('PD98059', 'Chemical', 'MESH:C093973', (43, 50))	('JNK', 'Gene', '5599', (56, 59))	('SP600125', 'Chemical', 'MESH:C432165', (71, 79))	('PKC', 'Disease', (0, 3))	('MEK1', 'Gene', '5604', (27, 31))	('SP600125', 'Var', (71, 79))	('MEK1', 'Gene', (27, 31))	('PKC', 'Disease', 'MESH:C537180', (0, 3))
317663	24796531	Next, we found that the expression level of c-Jun was low in esophageal cancer cell lines KYSE30, KYSE70, KYSE180 and KYSE450, but high in KYSE140, KYSE150 and KYSE410 (Figure 1C).	('expression level', 'MPA', (24, 40))	('high', 'PosReg', (131, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('low', 'NegReg', (54, 57))	('c-Jun', 'MPA', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('KYSE70', 'Var', (98, 104))	('KYSE450', 'Var', (118, 125))	('KYSE30', 'Var', (90, 96))	('KYSE180', 'Var', (106, 113))	('esophageal cancer', 'Disease', (61, 78))	('KYSE450', 'CellLine', 'CVCL:1353', (118, 125))
317675	24796531	As shown in Figure 2C, SPRR3 promoter activity was inhibited by TAM67 using luciferase report assay.	('TAM67', 'Var', (64, 69))	('TAM67', 'Chemical', '-', (64, 69))	('SPRR3', 'Gene', (23, 28))	('inhibited', 'NegReg', (51, 60))	('SPRR3', 'Gene', '6707', (23, 28))
317678	24796531	To further investigate whether the expression of c-Jun was regulated by MAPK pathway, we utilized the specific pharmacological inhibitors of PKC (GF109203X), JNK (SP600125) and MEK (PD98059) respectively to prevent MAPKs in response to TPA stimulation.	('PD98059', 'Var', (182, 189))	('SP600125', 'Var', (163, 171))	('PD98059', 'Chemical', 'MESH:C093973', (182, 189))	('JNK', 'Gene', (158, 161))	('MEK', 'Gene', (177, 180))	('PKC', 'Disease', (141, 144))	('JNK', 'Gene', '5599', (158, 161))	('MEK', 'Gene', '5609', (177, 180))	('GF109203X', 'Chemical', 'MESH:C070515', (146, 155))	('TPA', 'Chemical', 'MESH:D013755', (236, 239))	('MAPKs', 'Disease', (215, 220))	('PKC', 'Disease', 'MESH:C537180', (141, 144))	('GF109203X', 'Var', (146, 155))	('SP600125', 'Chemical', 'MESH:C432165', (163, 171))
317679	24796531	Indeed, GF109203X and SP600125 prominently inhibited the expression of SPRR3, whereas PD98059 had little effect in KYSE450 cells (Figure 2D).	('GF109203X', 'Chemical', 'MESH:C070515', (8, 17))	('expression', 'MPA', (57, 67))	('KYSE450', 'CellLine', 'CVCL:1353', (115, 122))	('SPRR3', 'Gene', '6707', (71, 76))	('GF109203X', 'Var', (8, 17))	('inhibited', 'NegReg', (43, 52))	('SP600125', 'Var', (22, 30))	('SP600125', 'Chemical', 'MESH:C432165', (22, 30))	('PD98059', 'Chemical', 'MESH:C093973', (86, 93))	('SPRR3', 'Gene', (71, 76))
317708	24796531	Knockouts of the major CE constituent loricrin or involucrin, envoplakin and periplakin significantly disrupt the barrier function of the skin.	('involucrin', 'Gene', (50, 60))	('barrier function of the skin', 'CPA', (114, 142))	('envoplakin', 'Gene', '2125', (62, 72))	('periplakin', 'Gene', (77, 87))	('involucrin', 'Gene', '3713', (50, 60))	('loricrin', 'Gene', (38, 46))	('Knockouts', 'Var', (0, 9))	('periplakin', 'Gene', '5493', (77, 87))	('loricrin', 'Gene', '4014', (38, 46))	('disrupt', 'NegReg', (102, 109))	('envoplakin', 'Gene', (62, 72))
317712	24796531	Previous study showed that cyclin D1 expression and hypermethlaytion or mutation of p16 are the critical early events.	('cyclin D1', 'Gene', (27, 36))	('p16', 'Gene', '1029', (84, 87))	('mutation', 'Var', (72, 80))	('expression', 'MPA', (37, 47))	('cyclin D1', 'Gene', '595', (27, 36))	('p16', 'Gene', (84, 87))
317721	24796531	A function for AP-1 activity in skin tumorigenesis has been identified using knockout and transgenic mice that modulate AP-1 components.	('transgenic mice', 'Species', '10090', (90, 105))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('modulate', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
317723	24796531	A transactivation mutant of c-Jun (TAM67) expressed under the Keratin 14 promoter or an inducible system produces a thickened, hyperproliferative, parakeratotic epidermis, but the epidermis is resistant to DMBA/TPA-dependent tumor formation.	('transactivation', 'PosReg', (2, 17))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('Keratin 14', 'Gene', (62, 72))	('mutant', 'Var', (18, 24))	('parakeratotic epidermis', 'CPA', (147, 170))	('hyperproliferative', 'CPA', (127, 145))	('tumor', 'Disease', (225, 230))	('DMBA', 'Chemical', 'MESH:C082386', (206, 210))	('TAM67', 'Chemical', '-', (35, 40))	('Keratin 14', 'Gene', '3861', (62, 72))	('TPA', 'Chemical', 'MESH:D013755', (211, 214))
317737	22629421	Frequent Occurrence of Mitochondrial DNA Mutations in Barrett's Metaplasia without the Presence of Dysplasia Barrett's esophagus (BE) is one of the most common premalignant lesions and can progress to esophageal adenocarcinoma (EA).	('Dysplasia', 'Disease', 'MESH:D004476', (99, 108))	('Mitochondrial DNA', 'Gene', (23, 40))	('esophageal adenocarcinoma', 'Disease', (201, 226))	("Barrett's Metaplasia", 'Disease', 'MESH:D001471', (54, 74))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (201, 226))	("Barrett's esophagus", 'Disease', (109, 128))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (109, 128))	('Dysplasia', 'Disease', (99, 108))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (201, 226))	('progress', 'Reg', (189, 197))	('Mutations', 'Var', (41, 50))	("Barrett's Metaplasia", 'Disease', (54, 74))
317738	22629421	The numerous molecular events may play a role in the neoplastic transformation of Barrett's mucosa such as the change of DNA ploidy, p53 mutation and alteration of adhesion molecules.	('adhesion molecules', 'Protein', (164, 182))	('mutation', 'Var', (137, 145))	('p53', 'Gene', '7157', (133, 136))	('DNA ploidy', 'MPA', (121, 131))	('alteration', 'Reg', (150, 160))	('p53', 'Gene', (133, 136))
317739	22629421	However, the molecular mechanism of the progression of BE to EA remains unclear and most studies of mitochondrial DNA (mtDNA) mutations in BE have performed on BE with the presence of dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (184, 193))	('dysplasia', 'Disease', (184, 193))	('mutations', 'Var', (126, 135))
317741	22629421	Eighteen patients (53%) exhibited mtDNA mutations which were not found in adjacent NT.	('mutations', 'Var', (40, 49))	('mtDNA', 'Gene', (34, 39))	('patients', 'Species', '9606', (9, 17))	('exhibited', 'Reg', (24, 33))
317745	22629421	High ROS level in BT may contribute to the development of mtDNA mutations, which may play a crucial role in disease progression and tumorigenesis in BE.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('High ROS level', 'Phenotype', 'HP:0025464', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mtDNA', 'Gene', (58, 63))	('contribute', 'Reg', (25, 35))	('tumor', 'Disease', (132, 137))	('mutations', 'Var', (64, 73))	('BT', 'Chemical', '-', (18, 20))	('ROS', 'Chemical', 'MESH:D017382', (5, 8))
317754	22629421	Accumulation in mutations in mtDNA, leading to an impairment of mitochondrial function, has been implicated in the etiology of aging, several degenerative pathologies, and tumorigenesis based on the presence of novel hetero-and homoplasmies.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('impairment of mitochondrial function', 'Phenotype', 'HP:0003287', (50, 86))	('implicated', 'Reg', (97, 107))	('mitochondrial function', 'MPA', (64, 86))	('tumor', 'Disease', (172, 177))	('mutations', 'Var', (16, 25))	('mtDNA', 'Gene', (29, 34))	('impairment', 'NegReg', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
317755	22629421	Somatic mtDNA mutations play a role in oncogenic transformation and they also can contribute to tumor progression by enhancing the metastatic potential of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('oncogenic transformation', 'CPA', (39, 63))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mtDNA', 'Gene', (8, 13))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (155, 160))	('contribute', 'Reg', (82, 92))	('enhancing', 'PosReg', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mutations', 'Var', (14, 23))
317759	22629421	Overall, BT-specific mtDNA mutations were observed in 53% (18/34) of all patients.	('mutations', 'Var', (27, 36))	('BT', 'Chemical', '-', (9, 11))	('mtDNA', 'Disease', (21, 26))	('patients', 'Species', '9606', (73, 81))	('observed', 'Reg', (42, 50))
317760	22629421	A gene scan (capillary electrophoresis) showed length heteroplasmies in 303 poly C, 16189 poly C and 514 CA repeats which were confirmed by TA cloning.	('poly C', 'Chemical', 'MESH:D011066', (76, 82))	('16189 poly C and', 'Var', (84, 100))	('poly C', 'Chemical', 'MESH:D011066', (90, 96))	('poly C', 'Var', (76, 82))
317763	22629421	BT-specific length heteroplasmic mutation at 16189 poly C displayed four types of patterns: 9C +10C +11C +12C, 3CT4C+5CT4C, 10C +11C +12C, 9C +10C +11C (2.9%/each) (Table 1).	('10C +11C +12C', 'Var', (124, 137))	('3CT4C+5CT4C', 'Var', (111, 122))	('16189 poly C', 'Var', (45, 57))	('9C +10C +11C +12C', 'Var', (92, 109))	('poly C', 'Chemical', 'MESH:D011066', (51, 57))	('BT', 'Chemical', '-', (0, 2))	('9C +10C +11C', 'Var', (139, 151))
317764	22629421	Specimens that showed dissimilarities in length heteroplasmy between patient adjacent NT and BT were 23% (8 cases) for 303 poly C, 2.9% (1 case) for 514 (CA) repeats and 11% (4 cases) for 16189 poly C. Three patients had BT-specific length heteroplasmic mutations arising in both 303 poly C and 16189 poly C stretch regions.	('patient', 'Species', '9606', (208, 215))	('BT', 'Chemical', '-', (221, 223))	('16189 poly C.', 'Var', (188, 201))	('514', 'Var', (149, 152))	('patients', 'Species', '9606', (208, 216))	('poly C', 'Chemical', 'MESH:D011066', (123, 129))	('poly C', 'Chemical', 'MESH:D011066', (194, 200))	('patient', 'Species', '9606', (69, 76))	('BT', 'Chemical', '-', (93, 95))	('poly C', 'Chemical', 'MESH:D011066', (284, 290))	('poly C', 'Chemical', 'MESH:D011066', (301, 307))
317773	22629421	Carcinogenesis is a long-term, multistep process driven by genetic and epigenetic changes in susceptible cells, which gain a selective growth advantage and undergo clonal expression.	('Carcinogenesis', 'Disease', (0, 14))	('Carcinogenesis', 'Disease', 'MESH:D063646', (0, 14))	('epigenetic changes', 'Var', (71, 89))	('gain', 'PosReg', (118, 122))
317780	22629421	Similar to other malignant tumors, carcinogenesis of EA is characterized by several genetic and epigenetic alterations with genetic instability (e.g., loss of heterozygote and/or ploidy), abnormal expression profiles of oncogenes (e.g., c-myc, VEGF and its receptors) and alterations in the DNA-methylation pattern (e.g., hypermethylation of p16, TIMP-3, DAPK, SOCS1 and SOCS3, and hypomethylation of CDX1.	('CDX1', 'Gene', '1044', (401, 405))	('TIMP-3', 'Gene', '7078', (347, 353))	('DAPK', 'Gene', '1612', (355, 359))	('tumor', 'Disease', (27, 32))	('abnormal', 'Reg', (188, 196))	('c-myc', 'Gene', (237, 242))	('SOCS1', 'Gene', (361, 366))	('DNA-methylation', 'MPA', (291, 306))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('carcinogenesis', 'Disease', (35, 49))	('p16', 'Gene', (342, 345))	('TIMP-3', 'Gene', (347, 353))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('SOCS3', 'Gene', (371, 376))	('carcinogenesis', 'Disease', 'MESH:D063646', (35, 49))	('hypomethylation', 'Var', (382, 397))	('oncogenes', 'Gene', (220, 229))	('hypermethylation', 'Var', (322, 338))	('p16', 'Gene', '1029', (342, 345))	('expression', 'MPA', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CDX1', 'Gene', (401, 405))	('SOCS3', 'Gene', '9021', (371, 376))	('SOCS1', 'Gene', '8651', (361, 366))	('alterations', 'Reg', (272, 283))	('c-myc', 'Gene', '4609', (237, 242))	('VEGF', 'Gene', '7422', (244, 248))	('DAPK', 'Gene', (355, 359))	('VEGF', 'Gene', (244, 248))
317782	22629421	Among the numerous molecular events that have been shown to play a role in the neoplastic transformation of Barrett's mucosa, only changes in DNA ploidy, increased proliferation, and alterations of the p53 gene have been suggested to be of potential help in the carcinogenesis.	('changes', 'Var', (131, 138))	('proliferation', 'CPA', (164, 177))	('help', 'Reg', (250, 254))	('alterations', 'Var', (183, 194))	('carcinogenesis', 'Disease', 'MESH:D063646', (262, 276))	('p53', 'Gene', '7157', (202, 205))	('increased', 'PosReg', (154, 163))	('DNA', 'MPA', (142, 145))	('carcinogenesis', 'Disease', (262, 276))	('p53', 'Gene', (202, 205))
317786	22629421	There is a 10~20 fold greater susceptibility of mtDNA to genetic mutation because mtDNA does not contain introns in comparison to nuclear DNA, the mtDNA repair system is inefficient and there is a higher exposure to ROS produced in the process of ATP synthesis.	('ATP', 'Chemical', 'MESH:D000255', (247, 250))	('ROS', 'Chemical', 'MESH:D017382', (216, 219))	('susceptibility', 'MPA', (30, 44))	('mutation', 'Var', (65, 73))
317793	22629421	mtDNA mutations in the current study were detected exclusively in BT samples but not in adjacent NT.	('mtDNA', 'Gene', (0, 5))	('BT', 'Chemical', '-', (66, 68))	('mutations', 'Var', (6, 15))
317794	22629421	The oxidative stress elicited by chronic inflammation increases the number of mtDNA mutations in BT and might correlate with a precancerous status.	('BT', 'Chemical', '-', (97, 99))	('inflammation increases', 'Disease', (41, 63))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('oxidative stress', 'Phenotype', 'HP:0025464', (4, 20))	('mutations', 'Var', (84, 93))	('mtDNA', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('inflammation increases', 'Disease', 'MESH:D007249', (41, 63))
317796	22629421	This high level of ROS might damage the mitochondria, leading to mtDNA mutations.	('mitochondria', 'MPA', (40, 52))	('damage', 'Reg', (29, 35))	('leading to', 'Reg', (54, 64))	('mutations', 'Var', (71, 80))	('mtDNA', 'Disease', (65, 70))	('ROS', 'Chemical', 'MESH:D017382', (19, 22))
317800	22629421	Recently one study reports that the frequency of specimens with the 4977 bp deletion increased in relation to the degree of dysplasia, so the mtDNA 4977 bp deletion may be useful as a biomarker to detect the severity.	('dysplasia', 'Disease', (124, 133))	('dysplasia', 'Disease', 'MESH:D004476', (124, 133))	('4977 bp deletion', 'Var', (68, 84))	('increased', 'PosReg', (85, 94))	('4977 bp deletion', 'Var', (148, 164))
317802	22629421	These mtDNA alterations in BT might further impair a respiratory chain defect resulting in increasing the mtDNA copy number to compensate for the deficiency in ATP.	('increasing', 'PosReg', (91, 101))	('impair', 'NegReg', (44, 50))	('alterations', 'Var', (12, 23))	('respiratory', 'MPA', (53, 64))	('respiratory chain defect', 'Phenotype', 'HP:0200125', (53, 77))	('mtDNA', 'Gene', (106, 111))	('BT', 'Chemical', '-', (27, 29))	('ATP', 'Chemical', 'MESH:D000255', (160, 163))
317804	22629421	BT-specific mtDNA mutations frequently occurred in both the mtDNA control and minisatellite regions due to excessive production of ROS.	('ROS', 'MPA', (131, 134))	('occurred', 'Reg', (39, 47))	('mtDNA', 'Gene', (12, 17))	('ROS', 'Chemical', 'MESH:D017382', (131, 134))	('BT', 'Chemical', '-', (0, 2))	('mutations', 'Var', (18, 27))
317805	22629421	High level of ROS in BT may contribute to development of mtDNA mutations, which may play a crucial role in pathophysiology of BE and furthermore progression to EA.	('mutations', 'Var', (63, 72))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('mtDNA', 'Gene', (57, 62))	('BT', 'Chemical', '-', (21, 23))	('contribute', 'Reg', (28, 38))
317819	22629421	A mixture of 25 microl containing 12.5 microl of 2xQuantitect SYBR green PCR master mix (Qiagen, Valencia, CA, USA), 400 microM CYTB primers F14909 (5'-TACTCACCAGACGCCTCAACCG-3') and R15396 (5'-TTATCGGA ATGGGAGGT GATTC-3') and 6 ng of total DNA was used for PCR with the Rotor-Gene real-time centrifugal DNA amplification system (Corbett Research, Sydney, Australia).	('CYTB', 'Gene', '4519', (128, 132))	('R15396', 'Var', (183, 189))	('CYTB', 'Gene', (128, 132))	('F14909', 'Var', (141, 147))
317918	21810561	Due to a lack of randomized studies there is the hypothesis that treatment options should be selected based on response rates detected by PET-CT. For gastric cancer tumor specific factors like p53, microsatellite instability, aberrant DNA hypermethylation and single nucleotide polymorphisms (SNP), which are related to chemotherapy response, are not known.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('p53', 'Gene', (193, 196))	('gastric cancer tumor', 'Disease', 'MESH:D013274', (150, 170))	('aberrant DNA hypermethylation', 'Var', (226, 255))	('microsatellite instability', 'MPA', (198, 224))	('p53', 'Gene', '7157', (193, 196))	('gastric cancer tumor', 'Disease', (150, 170))	('single nucleotide polymorphisms', 'Var', (260, 291))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))
317920	21810561	HER-2/neu (c-erbB-2, HER2) gene amplification and protein overexpression have been associated with poor prognosis in several solid tumors, including breast and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('HER-2/neu', 'Gene', (0, 9))	('gene amplification', 'Var', (27, 45))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HER-2/neu', 'Gene', '2064', (0, 9))	('c-erbB-2', 'Gene', (11, 19))	('c-erbB-2', 'Gene', '2064', (11, 19))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('associated', 'Reg', (83, 93))	('overexpression', 'PosReg', (58, 72))	('protein', 'Protein', (50, 57))	('tumors', 'Disease', (131, 137))	('HER2', 'Gene', '2064', (21, 25))	('HER2', 'Gene', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('gastric cancer', 'Phenotype', 'HP:0012126', (160, 174))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (149, 174))
317961	33836802	In addition to the more aggressive behavior of breast cancer diagnosed in young women, non-adherence to treatment is associated with increased risk of distant metastasis.	('women', 'Species', '9606', (80, 85))	('breast cancer', 'Disease', (47, 60))	('aggressive behavior', 'Phenotype', 'HP:0000718', (24, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('non-adherence', 'Var', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('distant metastasis', 'CPA', (151, 169))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
317970	33836802	Also, social determinants causing non-adherence in breast cancer treatment have been associated with a higher risk of distant spread and poor functional well-being.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('distant spread', 'CPA', (118, 132))	('non-adherence', 'Var', (34, 47))	('breast cancer', 'Disease', (51, 64))
318009	33836802	Horner's syndrome, or oculosympathetic paresis, is characterized by ipsilateral miosis, partial ptosis, and anhidrosis due to disruption of the sympathetic arc nerve passing from the hypothalamus through a long pathway to the eye.	('hypothalamus', 'Disease', (183, 195))	('oculosympathetic paresis', 'Phenotype', 'HP:0002277', (22, 46))	('hypothalamus', 'Disease', 'MESH:D007029', (183, 195))	('disruption', 'Var', (126, 136))	("Horner's syndrome", 'Phenotype', 'HP:0002277', (0, 17))	("Horner's syndrome", 'Disease', 'MESH:D006732', (0, 17))	('anhidrosis', 'Disease', (108, 118))	('ptosis', 'Phenotype', 'HP:0000508', (96, 102))	("Horner's syndrome", 'Disease', (0, 17))	('oculosympathetic', 'Disease', (22, 38))	('paresis', 'Disease', 'MESH:D010291', (39, 46))	('ptosis', 'Disease', (96, 102))	('miosis', 'Phenotype', 'HP:0000616', (80, 86))	('ipsilateral miosis', 'Disease', (68, 86))	('ptosis', 'Disease', 'MESH:C564553', (96, 102))	('arc nerve', 'Phenotype', 'HP:0030430', (156, 165))	('ipsilateral miosis', 'Disease', 'MESH:D015877', (68, 86))	('anhidrosis', 'Phenotype', 'HP:0000970', (108, 118))	('paresis', 'Disease', (39, 46))
318011	33836802	Disruption of the sympathetic trunk can occur in the central, preganglionic, and postganglionic nerves, in which trauma often affects the preganglionic nerve, whereas dysfunction of the postganglionic nerve causing acquired Horner's syndrome is mostly caused by Pancoast tumors or metastatic cancer.	('dysfunction', 'Var', (167, 178))	('Pancoast tumors', 'Disease', 'MESH:D010178', (262, 277))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('trauma', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	("Horner's syndrome", 'Disease', (224, 241))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('trauma', 'Disease', 'MESH:D014947', (113, 119))	("Horner's syndrome", 'Phenotype', 'HP:0002277', (224, 241))	('caused', 'Reg', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	("Horner's syndrome", 'Disease', 'MESH:D006732', (224, 241))	('cancer', 'Disease', (292, 298))	('Pancoast tumors', 'Disease', (262, 277))
318167	32547231	Radio-guided detection of sentinel lymph nodes (SLNs) in patients with preoperative T1N0M0 or T2N0M0 stage primary EC also showed that SLNs were mainly detected in these perigastric LNs.	('SLNs', 'Disease', 'None', (48, 52))	('SLNs', 'Disease', (48, 52))	('patients', 'Species', '9606', (57, 65))	('T1N0M0', 'Var', (84, 90))	('SLNs', 'Disease', 'None', (135, 139))	('T2N0M0', 'Var', (94, 100))	('SLNs', 'Disease', (135, 139))
318178	32192092	Dramatic changes in the expression of protein coding genes due to altered transcription factors activity or to epigenetic modifications orchestrate these events, intertwining with a microRNA regulatory network that is often disrupted in cancer cells.	('activity', 'MPA', (96, 104))	('protein', 'Protein', (38, 45))	('altered', 'Reg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('expression', 'MPA', (24, 34))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('epigenetic modifications', 'Var', (111, 135))	('transcription factors', 'Protein', (74, 95))	('cancer', 'Disease', (237, 243))	('changes', 'Reg', (9, 16))
318193	32192092	This phenomenon requires miR-143 and -145 activity, since genetic inactivation of the miR-143/145 cluster in adult tissues leads to impaired neointima formation upon vascular injury, correlating with disorganization of actin stress fibers and reduced migratory ability of miR-143 and -145-null SMCs.	('impaired neointima', 'Disease', 'MESH:D058426', (132, 150))	('genetic inactivation', 'Var', (58, 78))	('vascular injury', 'Disease', (166, 181))	('miR-143/145', 'Gene', (86, 97))	('disorganization', 'NegReg', (200, 215))	('migratory ability', 'CPA', (251, 268))	('vascular injury', 'Disease', 'MESH:D057772', (166, 181))	('reduced', 'NegReg', (243, 250))	('actin stress', 'Protein', (219, 231))	('impaired neointima', 'Disease', (132, 150))
318194	32192092	Accordingly, both microRNAs functionally converge on the regulation of a significant number of common target genes ultimately modulating the activity of SRF and actin dynamics, and miR-143/145-null mice display arterial hypotension.	('modulating', 'Reg', (126, 136))	('arterial hypotension', 'Phenotype', 'HP:0002615', (211, 231))	('activity', 'MPA', (141, 149))	('converge', 'Reg', (41, 49))	('miR-143/145-null', 'Var', (181, 197))	('hypotension', 'Disease', 'MESH:D007022', (220, 231))	('mice', 'Species', '10090', (198, 202))	('hypotension', 'Disease', (220, 231))
318195	32192092	In the same vein, interference with miR-145 expression in zebrafish affects the contractility of intestinal SMCs, with consequent defects in gut peristalsis and swim bladder inflation.	('swim bladder inflation', 'CPA', (161, 183))	('miR-145', 'Gene', (36, 43))	('zebrafish', 'Species', '7955', (58, 67))	('affects', 'Reg', (68, 75))	('defects', 'NegReg', (130, 137))	('contractility of intestinal SMCs', 'CPA', (80, 112))	('gut peristalsis', 'CPA', (141, 156))	('interference', 'Var', (18, 30))
318197	32192092	Moreover, the locus is located in the 5q33 fragile site of human chromosome 5 that is often deleted in cancer, and ectopic expression of both microRNAs was reported to inhibit proliferation, induce apoptosis, and/or suppress anchorage-independent growth, epithelial to mesenchymal transition (EMT) and tumor-forming ability of different cancer cell types both in vitro and in vivo.	('human', 'Species', '9606', (59, 64))	('anchorage-independent growth', 'CPA', (225, 253))	('apoptosis', 'CPA', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('cancer', 'Disease', (103, 109))	('tumor', 'Disease', (302, 307))	('proliferation', 'CPA', (176, 189))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('inhibit', 'NegReg', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('cancer', 'Disease', (337, 343))	('induce', 'PosReg', (191, 197))	('ectopic', 'Var', (115, 122))	('suppress', 'NegReg', (216, 224))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
318198	32192092	Several reports later challenged this concept for both miR-143 and miR-145, showing that their expression correlated with invasion, disease grade and progression in specific types of tumors.	('expression', 'MPA', (95, 105))	('miR-145', 'Gene', (67, 74))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('correlated with', 'Reg', (106, 121))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', (183, 189))	('miR-143', 'Var', (55, 62))
318205	32192092	Human breast cancer cell lines were shown to express reduced levels of miR-143 and -145 compared to the MCF10A immortalized normal epithelial cells and to normal tissue, and miR-145 but not miR-143 overexpression inhibited proliferation of several breast cancer cell lines.	('MCF10', 'CellLine', 'CVCL:5555', (104, 109))	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('proliferation', 'CPA', (223, 236))	('breast cancer', 'Disease', (6, 19))	('breast cancer', 'Disease', 'MESH:D001943', (248, 261))	('inhibited', 'NegReg', (213, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('reduced', 'NegReg', (53, 60))	('breast cancer', 'Disease', (248, 261))	('miR-145', 'Var', (174, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))
318210	32192092	Genetic loss has also been detected in ovarian carcinomas, while epigenetic silencing via CpG island methylation of the miR-145 promoter was demonstrated in different tumors.	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (39, 57))	('Genetic', 'Var', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('loss', 'NegReg', (8, 12))	('miR-145', 'Gene', (120, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('ovarian carcinomas', 'Disease', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (39, 57))
318215	32192092	Interestingly, some of the factors shown to be involved in microRNAs repression are at the same time targets of either miR-143 (LIMK1, SOX2) or miR-145 (ADAM17, NEDD9, SOX2) (Figure 1), potentially triggering a double negative feedback loop.	('triggering', 'Reg', (198, 208))	('SOX2', 'Gene', '6657', (168, 172))	('SOX2', 'Gene', (168, 172))	('ADAM17', 'Gene', (153, 159))	('SOX2', 'Gene', '6657', (135, 139))	('SOX2', 'Gene', (135, 139))	('NEDD9', 'Gene', '4739', (161, 166))	('NEDD9', 'Gene', (161, 166))	('miR-143', 'Var', (119, 126))	('LIMK1', 'Gene', '3984', (128, 133))	('LIMK1', 'Gene', (128, 133))	('ADAM17', 'Gene', '6868', (153, 159))	('miR-145', 'Var', (144, 151))
318222	32192092	Inhibition of miR-143 significantly reduced in vivo extravasation of the NeuT-STAT3C cells, suggesting a key role in enhancing colonization at distant organs.	('colonization', 'CPA', (127, 139))	('STAT3', 'Gene', '20848', (78, 83))	('extravasation', 'MPA', (52, 65))	('STAT3', 'Gene', (78, 83))	('enhancing', 'PosReg', (117, 126))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (36, 43))	('miR-143', 'Gene', (14, 21))
318225	32192092	Interestingly, increased DAB2 expression was also detected in HSCs from myelodysplastic syndrome patients presenting a deletion of the locus.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (72, 96))	('expression', 'MPA', (30, 40))	('deletion', 'Var', (119, 127))	('myelodysplastic syndrome', 'Disease', (72, 96))	('increased', 'PosReg', (15, 24))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (72, 96))	('DAB2', 'Gene', (25, 29))	('patients', 'Species', '9606', (97, 105))
318240	32192092	Finally, several functional single nucleotide polymorphisms (SNPs) have been identified in the regulatory regions of the two microRNAs, with most of the tested variants correlating with lower transcriptional activity and increased tumor risk.	('transcriptional activity', 'MPA', (192, 216))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('increased', 'PosReg', (221, 230))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (231, 236))	('lower', 'NegReg', (186, 191))	('variants', 'Var', (160, 168))
318241	32192092	The rs353292 variant, which displays reduced transcriptional activity in a Luciferase reporter assay, was shown to correlate with lower miR-143, but not miR-145, expression levels and CRC development in tumor samples.	('lower', 'NegReg', (130, 135))	('rs353292', 'Mutation', 'rs353292', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('expression levels', 'MPA', (162, 179))	('miR-143', 'MPA', (136, 143))	('CRC development', 'CPA', (184, 199))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('rs353292', 'Var', (4, 12))
318242	32192092	Similar findings were reported in the context of the rs4705342T > C and the rs4705343T > C variants, with the T alleles displaying reduced promoter activity and increased prostate cancer or cervical squamous cell carcinoma development.	('rs4705342T > C', 'DBSNP_MENTION', 'None', (53, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (171, 186))	('promoter activity', 'MPA', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('reduced', 'NegReg', (131, 138))	('rs4705343T > C', 'Var', (76, 90))	('increased prostate cancer', 'Disease', 'MESH:D011471', (161, 186))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 222))	('increased prostate cancer', 'Disease', (161, 186))	('rs4705343T > C', 'DBSNP_MENTION', 'None', (76, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('rs4705342T > C', 'Var', (53, 67))	('cervical squamous cell carcinoma', 'Disease', (190, 222))
318243	32192092	A few SNPs correlating with reduced transcription and lower cancer risk have also been described, as in the case of the rs353293 allele in the cluster's promoter, which dictates lower transcriptional activity of a luciferase reporter and was a protective genetic marker in bladder cancer.	('reduced', 'NegReg', (28, 35))	('luciferase', 'Enzyme', (214, 224))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('lower', 'NegReg', (178, 183))	('bladder cancer', 'Disease', 'MESH:D001749', (273, 287))	('bladder cancer', 'Disease', (273, 287))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('rs353293', 'Var', (120, 128))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('transcriptional activity', 'MPA', (184, 208))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('rs353293', 'Mutation', 'rs353293', (120, 128))	('transcription', 'MPA', (36, 49))	('lower', 'NegReg', (54, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (273, 287))
318247	32192092	miR-145 ectopic expression inhibited cell migration by reducing the levels of FASCIN1 (FSCN1), an actin bundling protein involved in cytoskeletal dynamics, and regulating several EMT features in several breast cancer cell lines.	('regulating', 'Reg', (160, 170))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('ectopic expression', 'Var', (8, 26))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Disease', (203, 216))	('reducing', 'NegReg', (55, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('inhibited', 'NegReg', (27, 36))	('miR-145', 'Gene', (0, 7))	('EMT features', 'CPA', (179, 191))	('cell migration', 'CPA', (37, 51))	('levels', 'MPA', (68, 74))
318250	32192092	ACTIVIN A, a cytokine of the TGF-beta superfamily that contributes to SMAD2 and SMAD3 activation, is targeted by miR-143 and miR-145 in a model of oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 175))	('miR-145', 'Var', (125, 132))	('activation', 'PosReg', (86, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('ACTIVIN A', 'Gene', (0, 9))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('targeted', 'Reg', (101, 109))	('SMAD2', 'Gene', (70, 75))	('miR-143', 'Var', (113, 120))	('oral squamous cell carcinoma', 'Disease', (147, 175))	('SMAD2', 'Gene', '4087', (70, 75))	('SMAD3', 'Gene', '4088', (80, 85))	('SMAD3', 'Gene', (80, 85))
318257	32192092	ZEB2 emerged as a target of miR-145 also in cervical cancer cells, resulting in a reduction in VIMENTIN and SNAIL, upregulation of E-CADHERIN and reduced migration and invasion.	('VIMENTIN', 'Gene', (95, 103))	('upregulation', 'PosReg', (115, 127))	('cancer', 'Disease', (53, 59))	('E-CADHERIN', 'Protein', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('reduction', 'NegReg', (82, 91))	('ZEB2', 'Gene', '9839', (0, 4))	('SNAIL', 'CPA', (108, 113))	('reduced', 'NegReg', (146, 153))	('VIMENTIN', 'Gene', '7431', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('ZEB2', 'Gene', (0, 4))	('miR-145', 'Var', (28, 35))
318266	32192092	Accordingly, miR-143 or -145 overexpression in NMuMG mouse mammary epithelial cells increased their motility, correlating with enhanced activity of a SMAD-reporter gene, increased expression of the EMT markers Snail and N-cadherin and downregulation of the epithelial markers E-CADHERIN, ZO1, ZO3, and OCCLUDIN.	('overexpression', 'PosReg', (29, 43))	('N-cadherin', 'Gene', (220, 230))	('miR-143 or -145', 'Var', (13, 28))	('increased', 'PosReg', (84, 93))	('activity', 'MPA', (136, 144))	('enhanced', 'PosReg', (127, 135))	('increased', 'PosReg', (170, 179))	('N-cadherin', 'Gene', '12558', (220, 230))	('Snail', 'Gene', (210, 215))	('mouse', 'Species', '10090', (53, 58))	('OCCLUDIN', 'Gene', '18260', (302, 310))	('motility', 'CPA', (100, 108))	('downregulation', 'NegReg', (235, 249))	('expression', 'MPA', (180, 190))	('ZO1', 'Gene', '21872', (288, 291))	('NMuMG', 'CellLine', 'CVCL:0075', (47, 52))	('OCCLUDIN', 'Gene', (302, 310))	('ZO1', 'Gene', (288, 291))	('E-CADHERIN', 'Protein', (276, 286))	('SMAD-reporter gene', 'Gene', (150, 168))	('Snail', 'Gene', '20613', (210, 215))
318284	32192092	In contrast, miR-143 or miR-145 overexpression in a human CRC cell line led to the downregulation of many components of apoptotic processes (i.e., SOD1, PRDX2 and PRDX6 for miR-143, and heat shock proteins, glutathione S-transferases and calreticulin for miR-145), suggesting miR-143-mediated cell survival.	('glutathione S-transferases', 'Enzyme', (207, 233))	('SOD1', 'Gene', '6647', (147, 151))	('apoptotic', 'CPA', (120, 129))	('PRDX6', 'Gene', '9588', (163, 168))	('shock proteins', 'Disease', 'MESH:D012769', (191, 205))	('calreticulin', 'Gene', '811', (238, 250))	('PRDX2', 'Gene', '7001', (153, 158))	('human', 'Species', '9606', (52, 57))	('shock', 'Phenotype', 'HP:0031273', (191, 196))	('miR-143', 'Gene', (13, 20))	('downregulation', 'NegReg', (83, 97))	('overexpression', 'Var', (32, 46))	('PRDX2', 'Gene', (153, 158))	('calreticulin', 'Gene', (238, 250))	('SOD1', 'Gene', (147, 151))	('miR-145', 'Gene', (24, 31))	('shock proteins', 'Disease', (191, 205))	('PRDX6', 'Gene', (163, 168))
318289	32192092	Thus, miRs-143 and -145 play a crucial role in epithelial homeostasis and tissue repair in the intestine by regulating the functions of mesenchymal cells, in keeping with their originally described ability to stimulate VSMCs differentiation during blood vessel injury.	('blood vessel injury', 'Disease', 'None', (248, 267))	('VSMCs differentiation', 'CPA', (219, 240))	('functions of mesenchymal cells', 'CPA', (123, 153))	('blood vessel injury', 'Disease', (248, 267))	('regulating', 'Reg', (108, 118))	('miRs-143', 'Var', (6, 14))
318291	32192092	In the context of cancer, it was shown that normal lung epithelium does not express either miR-143 or miR-145, and indeed their tumor-specific depletion did not enhance the development of lung adenocarcinoma in a genetic mouse model.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (188, 207))	('miR-143', 'Var', (91, 98))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (188, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('mouse', 'Species', '10090', (221, 226))	('depletion', 'MPA', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('miR-145', 'Var', (102, 109))	('tumor', 'Disease', (128, 133))	('lung adenocarcinoma', 'Disease', (188, 207))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
318298	32192092	In keeping with previous data, here miR-143 could positively regulate TGF-beta signaling, increasing SMAD2 phosphorylation and resulting in enhanced expression of collagen type III.	('collagen type III', 'Protein', (163, 180))	('enhanced', 'PosReg', (140, 148))	('miR-143', 'Var', (36, 43))	('SMAD2', 'Gene', (101, 106))	('SMAD2', 'Gene', '4087', (101, 106))	('expression', 'MPA', (149, 159))	('phosphorylation', 'MPA', (107, 122))	('increasing', 'PosReg', (90, 100))
318317	32232002	The abrogation of the CXCR4/CXCL12 axis results in reduced metastatic burden in a variety of mouse models of cancer.	('CXCR4/CXCL12 axis', 'MPA', (22, 39))	('reduced', 'NegReg', (51, 58))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('mouse', 'Species', '10090', (93, 98))	('cancer', 'Disease', (109, 115))	('metastatic burden', 'CPA', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('abrogation', 'Var', (4, 14))
318359	32232002	The survival rates of CXCR4 positive cells were higher under the treatment of DDP and TXT, compared with CXCR4 negative cells (Figure 3F).	('survival rates', 'CPA', (4, 18))	('higher', 'PosReg', (48, 54))	('DDP', 'Chemical', 'MESH:D002945', (78, 81))	('DDP', 'Var', (78, 81))
318375	32232002	CXCR4 and stemness-related transcription factors showed a significant decrease in animals with CQ treatment (Figures 6C,D).	('CQ treatment', 'Var', (95, 107))	('decrease', 'NegReg', (70, 78))	('CQ', 'Chemical', 'MESH:D002738', (95, 97))
318383	32232002	In human esophageal cancer, CXCR4 overexpression promoted cell invasion in vitro and tumor growth in vivo and indicated worse survival outcome.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Disease', (85, 90))	('CXCR4', 'Var', (28, 33))	('human', 'Species', '9606', (3, 8))	('cell invasion', 'CPA', (58, 71))	('esophageal cancer', 'Disease', (9, 26))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('promoted', 'PosReg', (49, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (9, 26))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
318423	31925999	In order to get a quantitative analytical result, we reviewed the dose-volume histogram (DVH) to determine the approximate maximum dose D2%, approximate minimum dose D98%, average dose Dmean, conformal index (, where  refers to the volume of PTV,  refers to the volume of PTV covered by the isodose line of 60Gy,  refers to the volume covered by 60Gy isodose line) and homogeneity index (, where  is the median absorbed dose of the PTV, , and  represent the dose received by 2% and 98% of the volume of PTV) of the PTVs of the two plans (Figure 3 shows the DVHs of both trials for the best and worst cases).24, 25, 26 Meanwhile, we compared the maximum dose and V40Gy of the SDLS, the maximum dose of spinal cord, the Dmean, V5Gy, V10Gy, V20Gy of both lungs, and the Dmean, V30Gy, V40Gy of heart of the two plans.	('PTV', 'Chemical', '-', (503, 506))	('PTV', 'Chemical', '-', (432, 435))	('PTV', 'Chemical', '-', (272, 275))	('PTV', 'Chemical', '-', (515, 518))	('V30Gy', 'Var', (774, 779))	('V40Gy', 'Var', (662, 667))	('V40Gy', 'Var', (781, 786))	('PTV', 'Chemical', '-', (242, 245))	('V10Gy', 'Var', (731, 736))
318441	31096474	The 1-, 3-, and 5-year OS rates in the non-CR group were lower than that in the CR group (P < .05).	('CR', 'Chemical', '-', (80, 82))	('CR', 'Chemical', '-', (43, 45))	('OS rates', 'CPA', (23, 31))	('non-CR', 'Var', (39, 45))	('lower', 'NegReg', (57, 62))
318442	31096474	Moreover, the 1-, 3-, and 5-year PFS rates in the non-CR group were lower than that in the CR group (P < .05).	('lower', 'NegReg', (68, 73))	('CR', 'Chemical', '-', (54, 56))	('CR', 'Chemical', '-', (91, 93))	('PFS rates', 'CPA', (33, 42))	('non-CR', 'Var', (50, 56))
318460	31096474	Recently, expression of VEGF was found to be associated with tumor angiogenesis, lymphatic metastasis, and survival in EC, and it is an independent prognostic factor for EC.	('EC', 'Phenotype', 'HP:0011459', (170, 172))	('VEGF', 'Gene', '7422', (24, 28))	('EC', 'Phenotype', 'HP:0011459', (119, 121))	('associated', 'Reg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('survival', 'CPA', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('VEGF', 'Gene', (24, 28))	('lymphatic metastasis', 'CPA', (81, 101))	('tumor', 'Disease', (61, 66))	('expression', 'Var', (10, 20))
318556	30310728	Changes in attenuation in contrast-enhanced CT (CECT) has been shown correlate better with response than changes in tumor size in hepatocellular carcinoma and gastrointestinal stromal tumor.	('attenuation', 'MPA', (11, 22))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Changes', 'Var', (0, 7))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (130, 154))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (159, 189))	('tumor', 'Disease', (116, 121))	('hepatocellular carcinoma and gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (130, 189))
318565	30310728	Almost all of the published (to our knowledge) FDG-PET studies quantify therapeutic response in tumors with SUVmax - the maximum standard uptake value (SUV) of FDG within a tumor.	('quantify', 'Reg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('FDG', 'Chemical', 'MESH:D019788', (160, 163))	('therapeutic response', 'CPA', (72, 92))	('SUVmax -', 'Var', (108, 116))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('FDG', 'Chemical', 'MESH:D019788', (47, 50))
318599	29474889	Aberrant DNA methylation triggers inflammation-associated cancers.	('inflammation', 'Disease', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('DNA', 'Protein', (9, 12))	('triggers', 'Reg', (25, 33))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('inflammation', 'Disease', 'MESH:D007249', (34, 46))
318604	29474889	The generation of inflammation-associated factors can also inactivate tumor-suppressor genes (e.g., P53 mutation), and activate oncogenes (e.g., KRAS mutation).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('inflammation', 'Disease', (18, 30))	('KRAS', 'Gene', (145, 149))	('tumor', 'Disease', (70, 75))	('oncogenes', 'CPA', (128, 137))	('inflammation', 'Disease', 'MESH:D007249', (18, 30))	('P53', 'Gene', (100, 103))	('KRAS', 'Gene', '3845', (145, 149))	('mutation', 'Var', (104, 112))	('P53', 'Gene', '7157', (100, 103))	('inactivate', 'NegReg', (59, 69))	('activate', 'PosReg', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
318605	29474889	(2) Immune regulation: Dysbiosis of the gut microbiota triggers a number of innate and adaptive immune responses involved in the tumor formation process.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Dysbiosis', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('adaptive immune responses', 'CPA', (87, 112))	('triggers', 'Reg', (55, 63))	('tumor', 'Disease', (129, 134))
318614	29474889	Known as a Class I risk factor, infection by H. pylori can stimulate immune responses and inflammation, regulate many signaling pathways, and induce achlorhydria, epithelial atrophy, and dysplasia.	('inflammation', 'Disease', 'MESH:D007249', (90, 102))	('achlorhydria', 'Phenotype', 'HP:0032448', (149, 161))	('epithelial atrophy', 'Disease', (163, 181))	('inflammation', 'Disease', (90, 102))	('immune responses', 'CPA', (69, 85))	('dysplasia', 'Disease', (187, 196))	('infection', 'Disease', 'MESH:D007239', (32, 41))	('stimulate', 'PosReg', (59, 68))	('H. pylori', 'Species', '210', (45, 54))	('achlorhydria', 'Disease', 'MESH:D000126', (149, 161))	('epithelial atrophy', 'Disease', 'MESH:D002277', (163, 181))	('induce', 'Reg', (142, 148))	('signaling pathways', 'Pathway', (118, 136))	('dysplasia', 'Disease', 'MESH:D004476', (187, 196))	('regulate', 'Reg', (104, 112))	('infection', 'Disease', (32, 41))	('H. pylori', 'Var', (45, 54))	('achlorhydria', 'Disease', (149, 161))
318615	29474889	Therefore, effective eradication of H. pylori could prevent gastric cancer.	('H. pylori', 'Species', '210', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('eradication', 'Var', (21, 32))	('gastric cancer', 'Disease', (60, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('prevent', 'NegReg', (52, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('H. pylori', 'Gene', (36, 45))
318620	29474889	Conversely, tumor suppressor pathways are inactivated with induced P53 mutations.	('P53', 'Gene', '7157', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('inactivated', 'NegReg', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutations', 'Var', (71, 80))	('tumor', 'Disease', (12, 17))	('P53', 'Gene', (67, 70))
318621	29474889	VacA can cause cell vacuolation and induce autophagy within human-derived gastric epithelial cells, by acting directly on mitochondria, upregulating MAP kinase and ERK1/2 expression, activating vascular endothelial growth factor, upregulating Wnt/beta-catenin signaling pathway which is essential for cell growth and differentiation, and inhibiting GSK3 via the PI3K/Akt signaling pathway.	('beta-catenin', 'Gene', '1499', (247, 259))	('cell vacuolation', 'Disease', (15, 31))	('activating', 'PosReg', (183, 193))	('inhibiting', 'NegReg', (338, 348))	('VacA', 'Var', (0, 4))	('MAP', 'Protein', (149, 152))	('upregulating', 'PosReg', (136, 148))	('vascular endothelial growth factor', 'Gene', '7422', (194, 228))	('upregulating', 'PosReg', (230, 242))	('autophagy', 'CPA', (43, 52))	('Akt', 'Gene', (367, 370))	('vascular endothelial growth factor', 'Gene', (194, 228))	('ERK1/2', 'Gene', (164, 170))	('expression', 'MPA', (171, 181))	('ERK1/2', 'Gene', '5595;5594', (164, 170))	('Akt', 'Gene', '207', (367, 370))	('GSK3', 'Pathway', (349, 353))	('induce', 'Reg', (36, 42))	('beta-catenin', 'Gene', (247, 259))	('cause', 'Reg', (9, 14))	('human', 'Species', '9606', (60, 65))
318622	29474889	Furthermore, H. pylori infection can cause methylations on CpG islands of E-cadherin and tumor-suppressor genes, including those encoding the trefoil factor 2 (TFF2) and a forkhead box transcriptional regulator (FOXD3), resulting in the significantly increased risk of adenocarcinoma in the stomach.	('increased risk of adenocarcinoma in the stomach', 'Phenotype', 'HP:0006753', (251, 298))	('FOXD3', 'Gene', (212, 217))	('TFF2', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('methylations', 'Var', (43, 55))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', '999', (74, 84))	('H. pylori', 'Disease', (13, 22))	('H. pylori', 'Species', '210', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('H. pylori infection', 'Phenotype', 'HP:0005202', (13, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('adenocarcinoma', 'Disease', 'MESH:D000230', (269, 283))	('adenocarcinoma', 'Disease', (269, 283))	('infection', 'Disease', (23, 32))	('cause', 'Reg', (37, 42))	('tumor', 'Disease', (89, 94))	('infection', 'Disease', 'MESH:D007239', (23, 32))
318669	29474889	Moreover, fragilysin induces proliferation of colonic epithelial cells and the expression of the oncogene c-myc .	('c-myc', 'Gene', (106, 111))	('expression', 'MPA', (79, 89))	('colonic epithelial cells', 'CPA', (46, 70))	('proliferation', 'CPA', (29, 42))	('c-myc', 'Gene', '4609', (106, 111))	('fragilysin', 'Var', (10, 20))
318674	29474889	Dysbiosis of the gut microbiota can thus promote the process of tumor formation in the large intestine tract.	('tumor formation in the large intestine tract', 'Phenotype', 'HP:0100834', (64, 108))	('tumor', 'Disease', (64, 69))	('promote', 'PosReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('Dysbiosis', 'Var', (0, 9))
318683	29474889	Overexpression of TLR4 results in the activation of beta-catenin and increased colitis-associated cancer development, whereas the inhibition of TLR4 expression is shown to protect against CRC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TLR4', 'Gene', (144, 148))	('increased', 'PosReg', (69, 78))	('colitis', 'Disease', 'MESH:D003092', (79, 86))	('beta-catenin', 'Gene', (52, 64))	('TLR4', 'Gene', (18, 22))	('colitis', 'Disease', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('beta-catenin', 'Gene', '1499', (52, 64))	('cancer', 'Disease', (98, 104))	('Overexpression', 'Var', (0, 14))	('CRC', 'Disease', (188, 191))	('colitis', 'Phenotype', 'HP:0002583', (79, 86))	('activation', 'PosReg', (38, 48))	('TLR4', 'Gene', '7099', (144, 148))	('TLR4', 'Gene', '7099', (18, 22))
318691	29474889	Furthermore, microbial dysbiosis can dysregulate the immune response and increase inflammation, resulting in PIK3CA mutations, which may accelerate the initiation and/or growth of rectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('PIK3CA', 'Gene', (109, 115))	('PIK3CA', 'Gene', '5290', (109, 115))	('accelerate', 'PosReg', (137, 147))	('dysbiosis can dysregulate', 'Disease', 'MESH:D064806', (23, 48))	('microbial dysbiosis', 'Disease', 'MESH:D064806', (13, 32))	('increase inflammation', 'Disease', (73, 94))	('dysregulate the immune response', 'Phenotype', 'HP:0002958', (37, 68))	('mutations', 'Var', (116, 125))	('growth', 'CPA', (170, 176))	('increase inflammation', 'Disease', 'MESH:D007249', (73, 94))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('microbial dysbiosis', 'Disease', (13, 32))	('dysbiosis can dysregulate', 'Disease', (23, 48))	('rectal cancers', 'Disease', 'MESH:D012004', (180, 194))	('rectal cancers', 'Disease', (180, 194))	('immune response', 'CPA', (53, 68))
318705	29474889	Additionally, some Helicobacter species, such as H. pylori, H. bilis, H. hepaticus, and H. ganmani, are specifically related to CCA, but not non-tumor diseases in the bile duct.	('CCA', 'Disease', (128, 131))	('tumor diseases', 'Disease', 'MESH:D009369', (145, 159))	('H. hepaticus', 'Species', '32025', (70, 82))	('Helicobacter', 'Species', '32025', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor diseases', 'Disease', (145, 159))	('H. pylori', 'Species', '210', (49, 58))	('H. ganmani', 'Var', (88, 98))	('related', 'Reg', (117, 124))	('H. ganmani', 'Species', '60246', (88, 98))	('H. bilis', 'Species', '37372', (60, 68))
318707	29474889	The LPS-TLR4 pathway promotes HCC, whereas removal of LPS or genetic inactivation of TLR4 could decrease HCC development.	('TLR4', 'Gene', (85, 89))	('HCC', 'Disease', (30, 33))	('genetic inactivation', 'Var', (61, 81))	('promotes', 'PosReg', (21, 29))	('TLR4', 'Gene', '7099', (8, 12))	('decrease', 'NegReg', (96, 104))	('TLR4', 'Gene', '7099', (85, 89))	('TLR4', 'Gene', (8, 12))	('HCC development', 'CPA', (105, 120))	('removal', 'Var', (43, 50))
318729	29474889	KRAS performs an essential function in normal tissue signaling, while KRAS gene mutations are present in over 90% of the cases of pancreatic adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('KRAS', 'Gene', '3845', (0, 4))	('mutations', 'Var', (80, 89))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (130, 155))	('KRAS', 'Gene', (70, 74))	('present', 'Reg', (94, 101))	('KRAS', 'Gene', '3845', (70, 74))	('KRAS', 'Gene', (0, 4))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (130, 155))	('pancreatic adenocarcinoma', 'Disease', (130, 155))
318730	29474889	LPS from H. pylori is confirmed to hyperstimulate mutations of KRAS genes and initiate the process of pancreatic carcinogenesis.	('KRAS', 'Gene', '3845', (63, 67))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (102, 127))	('mutations', 'Var', (50, 59))	('hyperstimulate', 'PosReg', (35, 49))	('initiate', 'Reg', (78, 86))	('H. pylori', 'Species', '210', (9, 18))	('pancreatic carcinogenesis', 'Disease', (102, 127))	('KRAS', 'Gene', (63, 67))
318793	29474889	The efficacy of programmed cell death protein 1 ligand 1 (PD-L1) inhibitors, another important immune-oncology therapy, is significantly augmented by Bifidobacterium administration.	('Bifidobacterium', 'Species', '216816', (150, 165))	('PD-L1', 'Disease', (58, 63))	('oncology', 'Phenotype', 'HP:0002664', (102, 110))	('inhibitors', 'Var', (65, 75))	('efficacy', 'MPA', (4, 12))	('PD-L1', 'Disease', 'MESH:D010300', (58, 63))	('augmented', 'PosReg', (137, 146))
318800	29474889	PHY906 (a Chinese herbal medicine) can restore the gut epithelium through stimulating the regeneration of intestinal stem or progenitor cells upon transformation by bacterial beta-glucuronidase, which is highly expressed by the gut microbiota.	('stimulating', 'PosReg', (74, 85))	('PHY906', 'Var', (0, 6))	('regeneration', 'CPA', (90, 102))	('beta-glucuronidase', 'Gene', (175, 193))	('herbal medicine', 'Species', '1407750', (18, 33))	('transformation', 'Var', (147, 161))	('beta-glucuronidase', 'Gene', '2990', (175, 193))
318801	29474889	It was reported that PHY906 administration in advanced CRC patients reduces the GI toxicity of irinotecan and exerts an anti-tumor effect.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PHY906', 'Var', (21, 27))	('irinotecan', 'Chemical', 'MESH:D000077146', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('toxicity', 'Disease', 'MESH:D064420', (83, 91))	('toxicity', 'Disease', (83, 91))	('tumor', 'Disease', (125, 130))	('patients', 'Species', '9606', (59, 67))	('reduces', 'NegReg', (68, 75))
318901	26844548	The aim of this study was to examine the expression and prognostic impact of human epidermal growth factor receptor 1 (HER1/EGFR) and 3 (HER3), as well as the occurrence of EGFR and KRAS mutations in gastric and esophageal adenocarcinoma.	('EGFR', 'Gene', '1956', (124, 128))	('KRAS', 'Gene', '3845', (182, 186))	('epidermal growth factor receptor', 'Gene', (83, 115))	('HER1', 'Gene', (119, 123))	('esophageal adenocarcinoma', 'Disease', (212, 237))	('EGFR', 'Gene', (124, 128))	('mutations', 'Var', (187, 196))	('EGFR', 'Gene', '1956', (173, 177))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (212, 237))	('HER3', 'Gene', '2065', (137, 141))	('HER3', 'Gene', (137, 141))	('epidermal growth factor receptor', 'Gene', '1956', (83, 115))	('EGFR', 'Gene', (173, 177))	('HER1', 'Gene', '1956', (119, 123))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (212, 237))	('KRAS', 'Gene', (182, 186))	('human', 'Species', '9606', (77, 82))
318905	26844548	High EGFR expression was an independent risk factor for shorter overall survival (OS), whereas high HER3 expression was associated with a borderline significant trend towards a longer OS.	('HER3', 'Gene', '2065', (100, 104))	('High', 'Var', (0, 4))	('OS', 'Chemical', '-', (184, 186))	('expression', 'MPA', (10, 20))	('EGFR', 'Gene', '1956', (5, 9))	('shorter', 'NegReg', (56, 63))	('overall survival', 'MPA', (64, 80))	('EGFR', 'Gene', (5, 9))	('OS', 'Chemical', '-', (82, 84))	('expression', 'MPA', (105, 115))	('HER3', 'Gene', (100, 104))
318917	26844548	by ligand binding, receptor overexpression or mutations, is deeply involved in the pathogenesis of several solid tumours.	('involved', 'Reg', (67, 75))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('mutations', 'Var', (46, 55))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('solid tumours', 'Disease', (107, 120))	('receptor', 'Protein', (19, 27))	('overexpression', 'PosReg', (28, 42))	('solid tumours', 'Disease', 'MESH:D009369', (107, 120))	('ligand binding', 'Interaction', (3, 17))
318921	26844548	There are several studies related to the expression and prognostic impact of EGFR and HER3 alterations in gastric adenocarcinoma.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (106, 128))	('gastric adenocarcinoma', 'Disease', (106, 128))	('HER3', 'Gene', (86, 90))	('alterations', 'Var', (91, 102))	('HER3', 'Gene', '2065', (86, 90))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))
318923	26844548	The aim of this study was to examine the immunohistochemical (IHC) expression of EGFR and HER3, as well as the occurrence of EGFR and KRAS mutations, in gastric and esophageal adenocarcinoma, with particular reference to their relationship with clinicopathological factors, HER2 expression, and OS.	('KRAS', 'Gene', '3845', (134, 138))	('HER3', 'Gene', (90, 94))	('mutations', 'Var', (139, 148))	('HER2', 'Gene', (274, 278))	('EGFR', 'Gene', '1956', (125, 129))	('HER3', 'Gene', '2065', (90, 94))	('gastric', 'Disease', (153, 160))	('esophageal adenocarcinoma', 'Disease', (165, 190))	('HER2', 'Gene', '2064', (274, 278))	('EGFR', 'Gene', (125, 129))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (165, 190))	('OS', 'Chemical', '-', (295, 297))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))	('KRAS', 'Gene', (134, 138))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
318934	26844548	The cells were maintained in Kaighn s modification of Ham s F-12 medium supplemented with 10% FBS and antibiotics (100 U/ml penicillin and 100 mug/ml streptomycin) in a humified 5% CO2 atmosphere at 37 C. Antibody validation was performed by quantitative real-time PCR (qPCR) and immunocytochemistry of cells following siRNA transfection against HER3.	('transfection', 'Var', (325, 337))	('F-12', 'Chemical', 'MESH:C007782', (60, 64))	('FBS', 'Disease', (94, 97))	('FBS', 'Disease', 'MESH:D005198', (94, 97))	('HER3', 'Gene', (346, 350))	('streptomycin', 'Chemical', 'MESH:D013307', (150, 162))	('HER3', 'Gene', '2065', (346, 350))	('CO2', 'Chemical', '-', (181, 184))	('penicillin', 'Chemical', 'MESH:D010406', (124, 134))
318935	26844548	For siRNA transfection, cells were seeded in T-25 flasks (5x105 cells) and incubated 72h at 37 C. The cells were then washed twice with PBS and received growth medium without FBS or antibiotics, together with lipofectamine 2000 and siRNA negative control or anti-HER3 (#s4780) in OptiMEM to a final siRNA concentration of 50 nM.	('FBS', 'Disease', (175, 178))	('lipofectamine 2000', 'Chemical', 'MESH:C086724', (209, 227))	('OptiMEM', 'Chemical', '-', (280, 287))	('FBS', 'Disease', 'MESH:D005198', (175, 178))	('#s4780', 'Var', (269, 275))	('HER3', 'Gene', '2065', (263, 267))	('HER3', 'Gene', (263, 267))	('PBS', 'Disease', 'MESH:D011535', (136, 139))	('PBS', 'Disease', (136, 139))
318945	26844548	The PyroMark Q24 system (QIAGEN) was used for pyrosequencing analysis of EGFR and KRAS mutations in DNA from 1 mm formalin-fixed, paraffin-embedded tumour tissue cores.	('tumour', 'Disease', (148, 154))	('EGFR', 'Gene', '1956', (73, 77))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('EGFR', 'Gene', (73, 77))	('formalin', 'Chemical', 'MESH:D005557', (114, 122))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('KRAS', 'Gene', (82, 86))	('paraffin', 'Chemical', 'MESH:D010232', (130, 138))	('KRAS', 'Gene', '3845', (82, 86))	('mutations', 'Var', (87, 96))
318947	26844548	Using therascreen KRAS Pyro Kit and EGFR Pyro Kit (QIAGEN) KRAS mutations of codon 12, 13 and 61 and EGFR deletions in exon 19 and mutations in exon 18 codon 719, exon 20 codon 768 plus 790 and exon 21 codon 858-861 were analysed.	('KRAS', 'Gene', '3845', (59, 63))	('KRAS', 'Gene', (18, 22))	('deletions', 'Var', (106, 115))	('KRAS', 'Gene', '3845', (18, 22))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('EGFR', 'Gene', '1956', (36, 40))	('mutations', 'Var', (64, 73))	('EGFR', 'Gene', (36, 40))	('KRAS', 'Gene', (59, 63))
318962	26844548	As regards EGFR, high (3) expression was associated with the shortest OS, compared with all other categories of expression, with significant differences in relation to negative (0) and weak (1) expression (Fig 4A), also using a dichotomized variable of 0-2 vs 3 (Fig 4C).	('high (3) expression', 'Var', (17, 36))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('OS', 'Chemical', '-', (70, 72))
318963	26844548	Conversely, patients with tumours expressing high levels of HER3 had a prolonged OS, although this difference was only significant between tumours with high (3) and negative (0) expression (Fig 4B), remaining borderline significant with a dichotomized variable of 0-2 vs 3 (Fig 4D).	('patients', 'Species', '9606', (12, 20))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('high levels', 'Var', (45, 56))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', (26, 33))	('tumours', 'Disease', (139, 146))	('HER3', 'Gene', (60, 64))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('HER3', 'Gene', '2065', (60, 64))	('OS', 'Chemical', '-', (81, 83))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('prolonged', 'PosReg', (71, 80))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
318969	26844548	Analyses of EGFR and KRAS mutations were successfully performed in 170/174 (97.7%) primary tumours.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('KRAS', 'Gene', '3845', (21, 25))	('primary tumours', 'Disease', 'MESH:D009369', (83, 98))	('mutations', 'Var', (26, 35))	('EGFR', 'Gene', '1956', (12, 16))	('primary tumours', 'Disease', (83, 98))	('KRAS', 'Gene', (21, 25))	('EGFR', 'Gene', (12, 16))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
318971	26844548	The distribution of KRAS mutation was similar in gastric and esophageal tumours, 3 (4.3%) and 4 (4.0%) respectively.	('KRAS', 'Gene', '3845', (20, 24))	('gastric and esophageal tumours', 'Disease', 'MESH:D013274', (49, 79))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('mutation', 'Var', (25, 33))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('KRAS', 'Gene', (20, 24))
318973	26844548	Kaplan Meier analysis revealed no significant correlation between KRAS mutation status and OS, neither in the entire cohort, nor in strata according to tumour location (data not shown).	('KRAS', 'Gene', '3845', (66, 70))	('mutation status', 'Var', (71, 86))	('OS', 'Chemical', '-', (91, 93))	('tumour location', 'Disease', (152, 167))	('tumour location', 'Disease', 'MESH:D009369', (152, 167))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('KRAS', 'Gene', (66, 70))
318975	26844548	There were no significant correlations between KRAS mutation status and expression of EGFR, HER2 or HER3, (data not shown).	('HER3', 'Gene', '2065', (100, 104))	('EGFR', 'Gene', '1956', (86, 90))	('HER2', 'Gene', '2064', (92, 96))	('HER2', 'Gene', (92, 96))	('EGFR', 'Gene', (86, 90))	('KRAS', 'Gene', (47, 51))	('mutation', 'Var', (52, 60))	('KRAS', 'Gene', '3845', (47, 51))	('HER3', 'Gene', (100, 104))
318977	26844548	High EGFR expression was found to be an independent risk factor for shorter OS, whereas high HER3 expression was associated with a borderline significant trend towards a longer OS.	('OS', 'Chemical', '-', (76, 78))	('High', 'Var', (0, 4))	('HER3', 'Gene', (93, 97))	('OS', 'Chemical', '-', (177, 179))	('EGFR', 'Gene', '1956', (5, 9))	('HER3', 'Gene', '2065', (93, 97))	('shorter OS', 'Disease', (68, 78))	('EGFR', 'Gene', (5, 9))	('expression', 'MPA', (98, 108))
318978	26844548	KRAS mutations were present in only 4% of the tumours and all tumours were EGFR wild-type.	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('EGFR', 'Gene', (75, 79))	('tumours', 'Disease', (46, 53))	('mutations', 'Var', (5, 14))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('EGFR', 'Gene', '1956', (75, 79))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('KRAS', 'Gene', (0, 4))	('tumours', 'Disease', (62, 69))	('KRAS', 'Gene', '3845', (0, 4))
318986	26844548	Activating mutations in KRAS are common in colorectal cancer but have also been reported in 5-16% of gastric and esophageal adenocarcinomas, causing unregulated signalling along its pathway, independently of EGFR status.	('colorectal cancer', 'Disease', (43, 60))	('KRAS', 'Gene', '3845', (24, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('causing', 'Reg', (141, 148))	('Activating mutations', 'Var', (0, 20))	('unregulated signalling', 'MPA', (149, 171))	('EGFR', 'Gene', '1956', (208, 212))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (113, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (43, 60))	('reported', 'Reg', (80, 88))	('EGFR', 'Gene', (208, 212))	('gastric and esophageal adenocarcinomas', 'Disease', 'MESH:D013274', (101, 139))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('KRAS', 'Gene', (24, 28))
318987	26844548	KRAS mutations do not appear to be prognostic in gastric or gastroesophageal junction adenocarcinoma.	('KRAS', 'Gene', (0, 4))	('gastric or gastroesophageal junction adenocarcinoma', 'Disease', 'MESH:D013274', (49, 100))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', '3845', (0, 4))
318988	26844548	As regards EGFR mutations, these appear to be rare in gastric and esophageal adenocarcinomas, as also supported by the results in this study wherein all tumours were found to be EGFR wild-type.	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('tumours', 'Disease', (153, 160))	('EGFR', 'Gene', '1956', (178, 182))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (66, 91))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('EGFR', 'Gene', (178, 182))	('mutations', 'Var', (16, 25))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('gastric and esophageal adenocarcinomas', 'Disease', 'MESH:D013274', (54, 92))
319005	26844548	HER3 expression has also been correlated with shorter OS in gastric as well as other cancer forms, but also with longer, or trends towards longer, OS in colorectal and breast cancer.	('HER3', 'Gene', (0, 4))	('OS', 'Chemical', '-', (147, 149))	('HER3', 'Gene', '2065', (0, 4))	('colorectal and breast cancer', 'Disease', 'MESH:D015179', (153, 181))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (175, 181))	('expression', 'Var', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', (85, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('OS', 'Chemical', '-', (54, 56))	('gastric', 'Disease', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
319010	26844548	While the lack of consistent results may raise questions with regard to the suitability of EGFR and HER3 as druggable targets in upper gastrointestinal cancer, it is noteworthy that many of the studies used different methods to evaluate EGFR and HER3 alterations, such as mutation analyses, gene copy number analyses, mRNA analyses and different antibodies and evaluation systems for IHC protein expression,.	('alterations', 'Var', (251, 262))	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', '1956', (237, 241))	('HER3', 'Gene', '2065', (100, 104))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (135, 158))	('EGFR', 'Gene', (237, 241))	('upper gastrointestinal cancer', 'Disease', (129, 158))	('HER3', 'Gene', (246, 250))	('upper gastrointestinal cancer', 'Disease', 'MESH:D004067', (129, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('EGFR', 'Gene', '1956', (91, 95))	('HER3', 'Gene', '2065', (246, 250))	('HER3', 'Gene', (100, 104))
319025	26844548	In contrast to previous findings regarding HER2 expression in the herein investigated cohort, conversion of EGFR or HER3 had no prognostic impact.	('EGFR', 'Gene', '1956', (108, 112))	('HER2', 'Gene', (43, 47))	('EGFR', 'Gene', (108, 112))	('HER2', 'Gene', '2064', (43, 47))	('conversion', 'Var', (94, 104))	('HER3', 'Gene', (116, 120))	('HER3', 'Gene', '2065', (116, 120))
319028	26844548	Moreover, KRAS mutations were found to be rare and all tumours were EGFR wild-type.	('tumours', 'Disease', (55, 62))	('KRAS', 'Gene', '3845', (10, 14))	('mutations', 'Var', (15, 24))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('EGFR', 'Gene', '1956', (68, 72))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('tumours', 'Disease', 'MESH:D009369', (55, 62))	('EGFR', 'Gene', (68, 72))	('KRAS', 'Gene', (10, 14))
319150	25250319	For this aim, four groups were considered: ECM scaffold alone, muscle tissue alone, and ECM plus either a partial (30%) or complete (100%) covering with muscle tissue.	('ECM', 'Gene', (43, 46))	('30', 'Var', (115, 117))	('ECM', 'Gene', '22915', (88, 91))	('ECM', 'Gene', '22915', (43, 46))	('ECM', 'Gene', (88, 91))
319171	25250319	However, the main limit of this strategy is the dislodgment of the stent which might cause bowel obstruction.	('bowel obstruction', 'Phenotype', 'HP:0005214', (91, 108))	('cause', 'Reg', (85, 90))	('bowel obstruction', 'Disease', (91, 108))	('rat', 'Species', '10116', (34, 37))	('dislodgment', 'Var', (48, 59))	('bowel obstruction', 'Disease', 'MESH:D015212', (91, 108))
319305	25250319	Reported findings suggest that urothelium presents mechanosensitive sodium ion channels as transducers of the parasympathetic nervous system involved in bladder sensation and that cyclical deformation induces connective tissue synthesis.	('transducers of', 'MPA', (91, 105))	('bladder sensation', 'Disease', 'MESH:D001745', (153, 170))	('mechanosensitive sodium ion channels', 'MPA', (51, 87))	('deformation', 'Var', (189, 200))	('bladder sensation', 'Phenotype', 'HP:0032171', (153, 170))	('induces', 'Reg', (201, 208))	('connective tissue synthesis', 'CPA', (209, 236))	('bladder sensation', 'Disease', (153, 170))
319350	25250319	Modified silk scaffolds have been implanted in a murine model for bladder augmentation and different results have been obtained, demonstrating that selective alterations in fabrication parameters can enhance the degradation rate of gel spun silk scaffolds in vivo while preserving their ability to support bladder tissue regeneration and function.	('murine', 'Species', '10090', (49, 55))	('rat', 'Species', '10116', (162, 165))	('gel spun silk scaffolds', 'CPA', (232, 255))	('rat', 'Species', '10116', (327, 330))	('rat', 'Species', '10116', (136, 139))	('degradation', 'MPA', (212, 223))	('alterations', 'Var', (158, 169))	('rat', 'Species', '10116', (224, 227))	('enhance', 'PosReg', (200, 207))	('bladder tissue regeneration', 'CPA', (306, 333))
319448	24438167	reported that knockdown of ErbB4 inhibited migration and invasion of the ESCC cell line Eca-109.	('ErbB4', 'Gene', '2066', (27, 32))	('ErbB4', 'Gene', (27, 32))	('inhibited', 'NegReg', (33, 42))	('knockdown', 'Var', (14, 23))
319500	24438167	However, mutation of the 3-nt sequence in the ErbB4 3'-UTR complementary to the miR-302b seed sequence restored the luciferase activity of the miR-302b transfected cells from 60% to 90%, showing that the action of miR-302b on ErbB4 depended on the presence of a single miR-302b cognate binding site within the 3'-UTR (Figure 2H and I).	('ErbB4', 'Gene', (226, 231))	('mutation', 'Var', (9, 17))	('miR-302b', 'Gene', (214, 222))	('ErbB4', 'Gene', '2066', (226, 231))	('miR-302b', 'Gene', '442894', (143, 151))	('miR-302b', 'Gene', '442894', (214, 222))	('miR-302b', 'Gene', (143, 151))	('ErbB4', 'Gene', (46, 51))	('luciferase', 'Enzyme', (116, 126))	('restored', 'PosReg', (103, 111))	('ErbB4', 'Gene', '2066', (46, 51))	('miR-302b', 'Gene', '442894', (269, 277))	('miR-302b', 'Gene', '442894', (80, 88))	('miR-302b', 'Gene', (269, 277))	('miR-302b', 'Gene', (80, 88))	('activity', 'MPA', (127, 135))
319511	24438167	Moreover, recent findings about somatic mutations that activate ErbB4 in metastatic melanoma have started to support a casual role of ErbB4 in carcinogenesis and to support the development of tools, such as ErbB4 antibodies, to target ErbB4 in cancer.	('ErbB4', 'Gene', (134, 139))	('ErbB4', 'Gene', '2066', (134, 139))	('ErbB4', 'Gene', '2066', (207, 212))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('ErbB4', 'Gene', '2066', (64, 69))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('activate', 'PosReg', (55, 63))	('mutations', 'Var', (40, 49))	('ErbB4', 'Gene', (235, 240))	('carcinogenesis', 'Disease', (143, 157))	('ErbB4', 'Gene', '2066', (235, 240))	('ErbB4', 'Gene', (207, 212))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('ErbB4', 'Gene', (64, 69))
319611	20211180	On univariate analysis, subjects with variceal progression had significantly higher baseline serum AST/ ALT, total bilirubin, and hyaluronic acid levels and significantly lower serum albumin and platelet levels compared to non-progressors (Table 2).	('hyaluronic acid levels', 'MPA', (130, 152))	('AST', 'Gene', '26503', (99, 102))	('higher', 'PosReg', (77, 83))	('higher baseline serum AST', 'Phenotype', 'HP:0031956', (77, 102))	('total bilirubin', 'MPA', (109, 124))	('bilirubin', 'Chemical', 'MESH:D001663', (115, 124))	('albumin', 'Gene', (183, 190))	('albumin', 'Gene', '213', (183, 190))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (130, 145))	('AST', 'Gene', (99, 102))	('variceal', 'Var', (38, 46))	('lower serum albumin', 'Phenotype', 'HP:0003073', (171, 190))	('lower', 'NegReg', (171, 176))
319622	20211180	The HALT-C Trial was designed to determine if maintenance peginterferon would reduce the rate of clinical and histological disease progression.	('HALT-C', 'Chemical', '-', (4, 10))	('reduce', 'NegReg', (78, 84))	('peginterferon', 'Var', (58, 71))
319654	20211180	In addition, the lower reported rate of de novo varices/ variceal progression with peginterferonalpha2b in CoPilot may relate to the absence of retreatment with full dose peginterferon and ribavirin prior to randomization.	('ribavirin', 'Chemical', 'MESH:D012254', (189, 198))	('varices/', 'Disease', (48, 56))	('peginterferonalpha2b', 'Var', (83, 103))
319655	20211180	This could result in the CoPilot patients receiving peginterferonalpha2b having a greater chance of virological suppression and reduced necrointlammation compared to those treated with peginterferonalpha2a in HALT-C.	('HALT-C', 'Chemical', '-', (209, 215))	('virological suppression', 'MPA', (100, 123))	('patients', 'Species', '9606', (33, 41))	('peginterferonalpha2b', 'Var', (52, 72))	('reduced', 'NegReg', (128, 135))	('necrointlammation', 'MPA', (136, 153))
319700	33484472	Afterward, the protein were denaturated and detected with the SDS-PAGE gel; besides, the incubated primary antibody were anti-TNK2 (#:ab185726, Abcam), anti-CDC42 (#:ab187643, Abcam), anti-Akt (#:ab8805, Abcam), anti-EGFR (#:ab52894, Abcam), and anti-GAPDH (#:ab8245, Abcam).	('Akt', 'Gene', (189, 192))	('TNK2', 'Gene', '10188', (126, 130))	('GAPDH', 'Gene', '2597', (251, 256))	('EGFR', 'Gene', (217, 221))	('#:ab185726', 'Var', (132, 142))	('GAPDH', 'Gene', (251, 256))	('#:ab187643', 'Var', (164, 174))	('CDC42', 'Gene', (157, 162))	('EGFR', 'Gene', '1956', (217, 221))	('Akt', 'Gene', '207', (189, 192))	('SDS', 'Chemical', 'MESH:D012967', (62, 65))	('#:ab8805', 'Var', (194, 202))	('TNK2', 'Gene', (126, 130))	('CDC42', 'Gene', '998', (157, 162))	('#:ab52894', 'Var', (223, 232))
319711	33484472	20 ,  21 ,  22  Even more, it is showed that the activated TNK2 (ACK1) could activate AKT Tyr176 phosphorylation to promote prostate cancer progression.	('TNK2', 'Gene', '10188', (59, 63))	('activate', 'PosReg', (77, 85))	('AKT', 'Gene', (86, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (124, 139))	('ACK1', 'Gene', '10188', (65, 69))	('promote', 'PosReg', (116, 123))	('activated', 'Var', (49, 58))	('ACK1', 'Gene', (65, 69))	('Tyr176', 'Chemical', '-', (90, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('TNK2', 'Gene', (59, 63))	('AKT', 'Gene', '207', (86, 89))	('prostate cancer', 'Disease', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
319788	33362391	The survival curves for preoperative albumin level showed longer OS times in patients with preoperative plasma albumin level > 45.2 g/L than in those with preoperative albumin level <= 45.2 g/L (Figure 2B).	('> 45.2 g/L', 'Var', (125, 135))	('OS times', 'MPA', (65, 73))	('albumin', 'Gene', '213', (168, 175))	('albumin', 'Gene', (168, 175))	('longer', 'PosReg', (58, 64))	('patients', 'Species', '9606', (77, 85))	('albumin', 'Gene', (111, 118))	('albumin', 'Gene', '213', (111, 118))	('albumin', 'Gene', (37, 44))	('albumin', 'Gene', '213', (37, 44))
319791	33362391	The survival curves for preoperative FAR showed shorter OS times in patients with FAR > 0.08 than in patients with FAR <= 0.08 (Figure 2C).	('patients', 'Species', '9606', (101, 109))	('OS times', 'MPA', (56, 64))	('FAR > 0.08', 'Var', (82, 92))	('patients', 'Species', '9606', (68, 76))	('shorter', 'NegReg', (48, 55))
319857	32643321	Both TMPO-AS1 overexpression and miR-498 knockdown weakened the effect of propofol on hypoxia-induced EC cell progression.	('TMPO-AS1', 'Gene', (5, 13))	('effect', 'MPA', (64, 70))	('TMPO-AS1', 'Gene', '100128191', (5, 13))	('hypoxia', 'Disease', (86, 93))	('hypoxia', 'Disease', 'MESH:D000860', (86, 93))	('weakened', 'NegReg', (51, 59))	('miR-498', 'Gene', (33, 40))	('knockdown', 'Var', (41, 50))	('propofol', 'Chemical', 'MESH:D015742', (74, 82))
319892	32643321	Wild TMPO-AS1 (TMPO-AS1 WT) or mutant TMPO-AS1 (TMPO-AS1 MUT) was inserted into the pGL3 vector (Promega, Madison, WI, USA).	('TMPO-AS1', 'Gene', (15, 23))	('TMPO-AS1', 'Gene', (5, 13))	('mutant', 'Var', (31, 37))	('pGL3', 'Gene', (84, 88))	('TMPO-AS1', 'Gene', '100128191', (38, 46))	('TMPO-AS1', 'Gene', '100128191', (48, 56))	('TMPO-AS1', 'Gene', (38, 46))	('TMPO-AS1', 'Gene', '100128191', (15, 23))	('TMPO-AS1', 'Gene', (48, 56))	('TMPO-AS1', 'Gene', '100128191', (5, 13))	('pGL3', 'Gene', '6391', (84, 88))
319893	32643321	Then, EC109 and KYSE70 cells were cotransfected with TMPO-AS1 WT or TMPO-AS1 MUT and miR-338-3p or miR-NC.	('TMPO-AS1', 'Gene', (53, 61))	('TMPO-AS1', 'Gene', (68, 76))	('miR-338-3p', 'Var', (85, 95))	('TMPO-AS1', 'Gene', '100128191', (53, 61))	('TMPO-AS1', 'Gene', '100128191', (68, 76))
319908	32643321	Subsequently, whether miR-498 was involved in propofol-regulated EC cell progression was investigated via transfection of anti-miR-498 into hypoxia-induced EC cells.	('hypoxia', 'Disease', 'MESH:D000860', (140, 147))	('anti-miR-498', 'Var', (122, 134))	('propofol', 'Chemical', 'MESH:D015742', (46, 54))	('hypoxia', 'Disease', (140, 147))
319909	32643321	As demonstrated in Fig 3e-h, cell migration and invasion were suppressed by propofol treatment, and then promoted by miR-498 knockdown.	('promoted', 'PosReg', (105, 113))	('knockdown', 'Var', (125, 134))	('miR-498', 'Gene', (117, 124))	('suppressed', 'NegReg', (62, 72))	('propofol', 'Chemical', 'MESH:D015742', (76, 84))
319910	32643321	Furthermore, miR-498 knockdown reversed the effect of propofol treatment on the levels of EMT markers and HIF-1alpha (Fig 3i and j).	('HIF-1alpha', 'Gene', (106, 116))	('EMT markers', 'MPA', (90, 101))	('miR-498', 'Gene', (13, 20))	('HIF-1alpha', 'Gene', '3091', (106, 116))	('knockdown', 'Var', (21, 30))	('propofol', 'Chemical', 'MESH:D015742', (54, 62))
319913	32643321	As shown in Fig 4b and c, miR-498 overexpression remarkably reduced the luciferase activity of TMPO-AS1 WT, and did not affect the luciferase activity of TMPO-AS1 MUT, meaning that TMPO-AS1 interacted with miR-498.	('overexpression', 'Var', (34, 48))	('activity', 'MPA', (83, 91))	('TMPO-AS1', 'Gene', (95, 103))	('TMPO-AS1', 'Gene', '100128191', (154, 162))	('TMPO-AS1', 'Gene', '100128191', (181, 189))	('TMPO-AS1', 'Gene', (154, 162))	('TMPO-AS1', 'Gene', (181, 189))	('reduced', 'NegReg', (60, 67))	('TMPO-AS1', 'Gene', '100128191', (95, 103))	('luciferase', 'Enzyme', (72, 82))
319917	32643321	Subsequently, our data suggested that miR-498 expression was remarkably upregulated by TMPO-AS1 knockdown and downregulated by TMPO-AS1 overexpression (Fig 4g).	('knockdown', 'Var', (96, 105))	('TMPO-AS1', 'Gene', '100128191', (127, 135))	('miR-498', 'Gene', (38, 45))	('TMPO-AS1', 'Gene', (127, 135))	('TMPO-AS1', 'Gene', '100128191', (87, 95))	('upregulated', 'PosReg', (72, 83))	('TMPO-AS1', 'Gene', (87, 95))	('expression', 'MPA', (46, 56))	('downregulated', 'NegReg', (110, 123))
319919	32643321	To explore whether TMPO-AS1 exerted its function via downregulating miR-498 expression, hypoxia-administered EC cells were transfected with si-NC, si-TMPO-AS1, si-TMPO-AS1  +  anti-NC, si-TMPO-AS1  +  anti-miR-498, respectively.	('TMPO-AS1', 'Gene', (163, 171))	('TMPO-AS1', 'Gene', (19, 27))	('si-NC', 'Var', (140, 145))	('hypoxia', 'Disease', 'MESH:D000860', (88, 95))	('TMPO-AS1', 'Gene', '100128191', (150, 158))	('hypoxia', 'Disease', (88, 95))	('TMPO-AS1', 'Gene', (188, 196))	('TMPO-AS1', 'Gene', (150, 158))	('expression', 'MPA', (76, 86))	('downregulating', 'NegReg', (53, 67))	('TMPO-AS1', 'Gene', '100128191', (163, 171))	('TMPO-AS1', 'Gene', '100128191', (19, 27))	('miR-498', 'Gene', (68, 75))	('TMPO-AS1', 'Gene', '100128191', (188, 196))
319920	32643321	As demonstrated in Fig 5a-d, TMPO-AS1 knockdown suppressed cell migration and invasion, whereas this action was weakened by miR-498 depletion.	('TMPO-AS1', 'Gene', (29, 37))	('invasion', 'CPA', (78, 86))	('cell migration', 'CPA', (59, 73))	('suppressed', 'NegReg', (48, 58))	('TMPO-AS1', 'Gene', '100128191', (29, 37))	('knockdown', 'Var', (38, 47))
319921	32643321	Moreover, we found that miR-498 depletion reversed the effect of TMPO-AS1 knockdown on the levels of EMT markers and HIF-1alpha (Fig 5e and f).	('TMPO-AS1', 'Gene', '100128191', (65, 73))	('knockdown', 'Var', (74, 83))	('TMPO-AS1', 'Gene', (65, 73))	('levels of EMT markers', 'MPA', (91, 112))	('HIF-1alpha', 'Gene', '3091', (117, 127))	('HIF-1alpha', 'Gene', (117, 127))
319940	32643321	31  For example, LncRNA PTCSC3 targeted miR-574-5p to decrease the level of miR-574-5p in cervical cancer.	('decrease', 'NegReg', (54, 62))	('miR-574-5p', 'MPA', (76, 86))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('PTCSC3', 'Gene', '100886964', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('miR-574-5p', 'Var', (40, 50))	('PTCSC3', 'Gene', (24, 30))
319952	31715145	Isoforms of RNF128 Regulate the Stability of Mutant P53 in Barrett's Esophageal Cells Barrett's esophagus (BE) can progress to dysplasia and esophageal adenocarcinoma (EAC), accompanied by mutations in TP53 that increase the stability of its product, p53.	('P53', 'Gene', '7157', (52, 55))	('dysplasia', 'Disease', 'MESH:C536170', (127, 136))	('stability', 'MPA', (225, 234))	('increase', 'PosReg', (212, 220))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (141, 166))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (141, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('mutations', 'Var', (189, 198))	('progress', 'PosReg', (115, 123))	('esophageal adenocarcinoma', 'Disease', (141, 166))	('P53', 'Gene', (203, 206))	('P53', 'Gene', (52, 55))	('dysplasia', 'Disease', (127, 136))	('Stability', 'MPA', (32, 41))	('RNF128', 'Gene', (12, 18))	('P53', 'Gene', '7157', (203, 206))	('RNF128', 'Gene', '79589', (12, 18))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (86, 105))	('Mutant', 'Var', (45, 51))
319956	31715145	Proteins were expressed from transfected plasmids or knocked down with small interfering RNAs in BE cells and analyzed by immunoblots and in immunoprecipitation and ubiquitin ligase assays.	('RNAs', 'Gene', (89, 93))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('small interfering', 'Var', (71, 88))
319957	31715145	Athymic nude mice bearing EAC xenograft tumors (grown from OE-33 cells) were given intraperitoneal injections of simvastatin; tumor growth was monitored and tumors were collected and analyzed by immunoblotting for levels of RNF128, p53, and acetylated p53.	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', (40, 46))	('p53', 'Var', (232, 235))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('RNF128', 'Var', (224, 230))	('nude mice', 'Species', '10090', (8, 17))	('acetylated', 'MPA', (241, 251))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('simvastatin', 'Chemical', 'MESH:D019821', (113, 124))	('tumors', 'Disease', (157, 163))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (126, 131))	('tumor', 'Disease', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
319963	31715145	Knockdown of Iso1 in BE and EAC cells led to degradation of the mutant form of p53 and reduced clonogenic survival.	('p53', 'Gene', (79, 82))	('reduced', 'NegReg', (87, 94))	('Iso1', 'Gene', (13, 17))	('degradation', 'NegReg', (45, 56))	('mutant', 'Var', (64, 70))	('Iso1', 'Gene', '10209', (13, 17))	('clonogenic survival', 'CPA', (95, 114))
319964	31715145	In contrast, Iso2 was a potent ligase that reduced levels of the mutant form of p53 in BE cells.	('levels', 'MPA', (51, 57))	('p53', 'Gene', (80, 83))	('mutant', 'Var', (65, 71))	('Iso2', 'Chemical', '-', (13, 17))	('reduced', 'NegReg', (43, 50))
319966	31715145	Simvastatin, which degrades the mutant form of p53, also degraded RNF128 Iso1 protein in BE cells and slowed growth of EAC xenograft tumors in mice.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('RNF128 Iso1', 'Gene', '11074;10209', (66, 77))	('tumors', 'Disease', (133, 139))	('RNF128 Iso1', 'Gene', (66, 77))	('degrades', 'NegReg', (19, 27))	('slowed', 'NegReg', (102, 108))	('Simvastatin', 'Chemical', 'MESH:D019821', (0, 11))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('slowed growth', 'Phenotype', 'HP:0001510', (102, 115))	('mutant', 'Var', (32, 38))	('growth', 'CPA', (109, 115))	('p53', 'Gene', (47, 50))	('degraded', 'NegReg', (57, 65))	('mice', 'Species', '10090', (143, 147))
319972	31715145	Our analysis of specific loci, comprehensive analyses of the specific DNA copy number changes, and gene mutations associated with and underlying EAC development reveal substantial molecular heterogeneity of EAC, yet 70% to 80% of dysplastic BE and EAC contain TP53 mutations (TP53*).	('TP53', 'Gene', (260, 264))	('mutations', 'Var', (265, 274))	('dysplastic', 'Disease', 'MESH:D004416', (230, 240))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('dysplastic', 'Disease', (230, 240))
319976	31715145	Treatment with simvastatin reduced RNF128 Iso1 protein levels to impact the TP53 steady-state level, thus reduced colony formation in immortalized BE cells containing TP53* and further inhibited tumor growth, suggesting potential strategies for reducing cancer development in patients with BE.	('patients', 'Species', '9606', (276, 284))	('reduced', 'NegReg', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Disease', (195, 200))	('TP53 steady-state level', 'MPA', (76, 99))	('simvastatin', 'Chemical', 'MESH:D019821', (15, 26))	('RNF128 Iso1', 'Gene', '11074;10209', (35, 46))	('inhibited', 'NegReg', (185, 194))	('RNF128 Iso1', 'Gene', (35, 46))	('TP53', 'Var', (167, 171))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (254, 260))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('reduced', 'NegReg', (106, 113))	('colony formation', 'CPA', (114, 130))
319977	31715145	ENSEMBL lists 2 observed isoforms for RNF128: ENST00000255499 (Iso1) encoding a 428aa protein, and ENST00000324342 (Iso2) which transcribes a 402aa protein.	('RNF128', 'Gene', (38, 44))	('ENST00000255499', 'Var', (46, 61))	('Iso2', 'Chemical', '-', (116, 120))	('Iso1', 'Gene', '10209', (63, 67))	('ENST00000324342', 'Var', (99, 114))	('Iso1', 'Gene', (63, 67))
320017	31715145	We observed a similar change in the log2 ratio of the 2 expressed isoforms in both cohorts, confirming the reduction of Iso2 mRNA identified by RNAseq (Figure 1C).	('Iso2', 'Chemical', '-', (120, 124))	('Iso2 mRNA', 'Var', (120, 129))	('N', 'Chemical', 'MESH:D009584', (127, 128))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('reduction', 'NegReg', (107, 116))
320022	31715145	Iso1 was significantly increased in HGD and EAC relative to BE/LGD, and highly correlated to nuclear accumulation of TP53 (r = 0.69; Figure 1D), and often indicative of TP53* mutation.	('HGD', 'Disease', (36, 39))	('Iso1', 'Gene', '10209', (0, 4))	('nuclear accumulation', 'MPA', (93, 113))	('increased in HGD', 'Phenotype', 'HP:0410246', (23, 39))	('increased', 'PosReg', (23, 32))	('TP53* mutation', 'Var', (169, 183))	('Iso1', 'Gene', (0, 4))	('correlated', 'Reg', (79, 89))
320024	31715145	When TP53* status was considered in 181 available BE samples (both RNAseq and validation cohorts), alongside 2 previously published EAC cohorts we observed approximately 70% of HGD and EAC samples contained TP53 mutations and significantly less frequent in the nondysplastic BE (19%) or LGD (33%) samples (Supplementary Table 6).	('contained', 'Reg', (197, 206))	('HGD', 'Disease', (177, 180))	('dysplastic', 'Disease', (264, 274))	('S', 'Chemical', 'MESH:D012694', (306, 307))	('dysplastic', 'Disease', 'MESH:D004416', (264, 274))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('TP53', 'Gene', (207, 211))	('mutations', 'Var', (212, 221))	('EAC', 'Disease', (185, 188))
320046	31715145	Using 2 different siRNAs, Iso1 knockdown caused TP53* loss in CpD cells with concomitant reduction in clonogenic survival (Figure 4B).	('clonogenic survival', 'CPA', (102, 121))	('TP53', 'Gene', (48, 52))	('Iso1', 'Gene', (26, 30))	('loss', 'NegReg', (54, 58))	('reduction', 'NegReg', (89, 98))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('Iso1', 'Gene', '10209', (26, 30))	('knockdown', 'Var', (31, 40))
320047	31715145	Loss of Iso2 had no major impact both on TP53* and clonogenic survival in CpD cells, whereas Iso2 knockdown in CpA cells resulted in TP53 accumulation and loss of clonogenic survival (Figure 4C and D).	('loss', 'NegReg', (155, 159))	('Iso2', 'Gene', (93, 97))	('Iso2', 'Chemical', '-', (8, 12))	('knockdown', 'Var', (98, 107))	('clonogenic survival', 'CPA', (51, 70))	('clonogenic survival', 'CPA', (163, 182))	('accumulation', 'PosReg', (138, 150))	('TP53', 'MPA', (133, 137))	('Iso2', 'Chemical', '-', (93, 97))
320048	31715145	At the transcript level, knockdown of one isoform caused compensatory upregulation of the other (Supplementary Figure 5A and B), also seen at the protein level using Iso1-specific antibody (Figure 4C).	('Iso1', 'Gene', (166, 170))	('upregulation', 'PosReg', (70, 82))	('S', 'Chemical', 'MESH:D012694', (97, 98))	('Iso1', 'Gene', '10209', (166, 170))	('knockdown', 'Var', (25, 34))
320051	31715145	Similar observations were noted following cotransfection of Iso1 and TP53R273H mutant in HEK-293 cells (Figure 4H).	('TP53R273H', 'Var', (69, 78))	('Iso1', 'Gene', (60, 64))	('HEK-293', 'CellLine', 'CVCL:0045', (89, 96))	('Iso1', 'Gene', '10209', (60, 64))	('S', 'Chemical', 'MESH:D012694', (0, 1))
320052	31715145	In CpA, we tested the effect of Iso1 overexpression on endogenous wild-type TP53, and in the presence of individually transfected TP53*, including C135S, R175H, R213Q, and R248Q mutations.	('R213Q', 'Var', (161, 166))	('C135S', 'Mutation', 'rs1057519975', (147, 152))	('Iso1', 'Gene', (32, 36))	('C135S', 'Var', (147, 152))	('R248Q', 'Var', (172, 177))	('R213Q', 'Mutation', 'rs587778720', (161, 166))	('Iso1', 'Gene', '10209', (32, 36))	('tested', 'Reg', (11, 17))	('R175H', 'Mutation', 'rs28934578', (154, 159))	('R248Q', 'Mutation', 'rs11540652', (172, 177))	('R175H', 'Var', (154, 159))
320060	31715145	In contrast, Iso1 overexpression reduced the abundance of TP53* (DDK-tagged TP53R248Q) polyubiquitinated species relative to basal polyubiquitination levels, suggesting an Iso1 protective effect on TP53* polyubiquitination (Figure 5B).	('abundance', 'MPA', (45, 54))	('TP53', 'Var', (58, 62))	('TP53R248Q', 'Gene', (76, 85))	('Iso1', 'Gene', '10209', (172, 176))	('Iso1', 'Gene', (13, 17))	('TP53R248Q', 'Gene', '7157', (76, 85))	('reduced', 'NegReg', (33, 40))	('Iso1', 'Gene', (172, 176))	('Iso1', 'Gene', '10209', (13, 17))
320061	31715145	Using cell-free ubiquitination assays, Iso2 efficiently polyubiquitinated both wild-type and TP53R273H, whereas Iso1 had limited TP53 polyubiquitination ability (Figure 5C).	('TP53R273H', 'Var', (93, 102))	('polyubiquitinated', 'MPA', (56, 73))	('Iso2', 'Chemical', '-', (39, 43))	('Iso1', 'Gene', (112, 116))	('Iso1', 'Gene', '10209', (112, 116))
320062	31715145	Using various mutant ubiquitin molecules (ie, K11R, K48R, and K63R), we noted differences in Iso2-mediated polyubiquitination linkage on wild-type and TP53R273H.	('TP53R273H', 'Var', (151, 160))	('differences', 'Reg', (78, 89))	('ubiquitin', 'Protein', (21, 30))	('K11R', 'Mutation', 'p.K11R', (46, 50))	('K48R', 'Var', (52, 56))	('K63R', 'Var', (62, 66))	('K63R', 'Mutation', 'rs768511675', (62, 66))	('Iso2-mediated polyubiquitination linkage', 'MPA', (93, 133))	('Iso2', 'Chemical', '-', (93, 97))	('K11R', 'Var', (46, 50))	('K48R', 'Mutation', 'p.K48R', (52, 56))
320066	31715145	These data were confirmed by overexpressing DDK-tagged Iso1 and V5-tagged Iso2 proteins in the presence and absence of DSS followed by immunoprecipitation and immunoblotting (Supplementary Figure 6B), showing Iso1-Iso2 heterodimers are preferred.	('DDK-tagged', 'Var', (44, 54))	('Iso1', 'Gene', '10209', (209, 213))	('DSS', 'Chemical', 'MESH:C019358', (119, 122))	('Iso2', 'Chemical', '-', (74, 78))	('S', 'Chemical', 'MESH:D012694', (121, 122))	('Iso2', 'Chemical', '-', (214, 218))	('overexpressing', 'PosReg', (29, 43))	('Iso1', 'Gene', '10209', (55, 59))	('Iso1', 'Gene', (209, 213))	('S', 'Chemical', 'MESH:D012694', (120, 121))	('S', 'Chemical', 'MESH:D012694', (175, 176))	('Iso1', 'Gene', (55, 59))
320076	31715145	As shown in Figure 6A and C, and quantified in Figure 6B and D, Iso2 has a shorter half-life (54 and 40 minutes in CpA and CpD cells, respectively) compared with Iso1 (100 and 120 minutes in CpA and CpD, respectively).	('half-life', 'MPA', (83, 92))	('Iso2', 'Chemical', '-', (64, 68))	('Iso2', 'Var', (64, 68))	('Iso1', 'Gene', '10209', (162, 166))	('shorter', 'NegReg', (75, 82))	('Iso1', 'Gene', (162, 166))
320079	31715145	Conversely, siRNA-mediated beta-TrCP1 knockdown increased RNF128 levels (Supplementary Figure 7A).	('increased', 'PosReg', (48, 57))	('S', 'Chemical', 'MESH:D012694', (73, 74))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('RNF128 levels', 'MPA', (58, 71))	('beta-TrCP1', 'Gene', (27, 37))	('knockdown', 'Var', (38, 47))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('beta-TrCP1', 'Gene', '8945', (27, 37))
320080	31715145	To define the role of serine (S) phosphorylation, we mutated S to alanine (A) (SA), which significantly stabilized the Iso2 protein and also affected Iso1 levels slightly (Figure 6F).	('S', 'Chemical', 'MESH:D012694', (30, 31))	('alanine', 'Chemical', 'MESH:D000409', (66, 73))	('Iso1', 'Gene', '10209', (150, 154))	('Iso2 protein', 'MPA', (119, 131))	('Iso2', 'Chemical', '-', (119, 123))	('mutated', 'Var', (53, 60))	('stabilized', 'PosReg', (104, 114))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('Iso1', 'Gene', (150, 154))	('serine', 'Chemical', 'MESH:D012694', (22, 28))	('affected', 'Reg', (141, 149))	('S', 'Chemical', 'MESH:D012694', (79, 80))
320089	31715145	Iso1 (428 aa) and Iso2 (402 aa) are predicted as 47 and 45 kDa respectively, yet the observed molecular weights were >65 kDa (Figure 4G, Supplementary Figure 8A), suggesting posttranslational modification, differentially impacted by the presence of wild-type and TP53*.	('Iso1', 'Gene', '10209', (0, 4))	('TP53*', 'Var', (263, 268))	('impacted', 'Reg', (221, 229))	('Iso2', 'Chemical', '-', (18, 22))	('Iso1', 'Gene', (0, 4))	('S', 'Chemical', 'MESH:D012694', (137, 138))
320092	31715145	We expressed either wild-type or SA mutants of DDK-tagged Iso2 in the presence or absence of V5-tagged Iso1.	('Iso2', 'Gene', (58, 62))	('Iso1', 'Gene', '10209', (103, 107))	('S', 'Chemical', 'MESH:D012694', (33, 34))	('DDK-tagged', 'Var', (47, 57))	('Iso2', 'Chemical', '-', (58, 62))	('Iso1', 'Gene', (103, 107))
320098	31715145	While examining simvastatin effects on the clonogenic survival of immortalized BE cells, we noted TP53*-driven CpD cells are more sensitive to simvastatin relative to wild-type TP53 containing CpA cells (Figure 7A).	('simvastatin', 'Chemical', 'MESH:D019821', (16, 27))	('simvastatin', 'Chemical', 'MESH:D019821', (143, 154))	('TP53*-driven', 'Var', (98, 110))	('more', 'PosReg', (125, 129))	('sensitive to simvastatin', 'MPA', (130, 154))
320100	31715145	Interestingly, siRNA-mediated Iso1 knockdown further sensitized CpD cells to simvastatin (Figure 7A), whereas Iso2 loss reduced simvastatin potency in TP53*-driven CpD and EAC cells (not shown).	('loss reduced', 'NegReg', (115, 127))	('knockdown', 'Var', (35, 44))	('simvastatin', 'Chemical', 'MESH:D019821', (77, 88))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('Iso2', 'Chemical', '-', (110, 114))	('Iso1', 'Gene', (30, 34))	('Iso1', 'Gene', '10209', (30, 34))	('simvastatin potency', 'MPA', (128, 147))	('sensitized', 'Reg', (53, 63))	('simvastatin', 'Chemical', 'MESH:D019821', (128, 139))	('Iso2', 'Gene', (110, 114))
320104	31715145	siRNA-mediated TP53* knockdown in OE33 cells resulted in 60% reduction in clonogenic survival, suggesting TP53* dependency (Figure 7B).	('TP53*', 'Gene', (15, 20))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('reduction', 'NegReg', (61, 70))	('knockdown', 'Var', (21, 30))	('clonogenic survival', 'CPA', (74, 93))
320111	31715145	To graphically summarize our findings, we propose a model (Supplementary Figure 11) incorporating our results and RNF128 isoform switching, to explain the increased TP53* stability during BE progression.	('stability', 'MPA', (171, 180))	('increased', 'PosReg', (155, 164))	('TP53*', 'Var', (165, 170))	('S', 'Chemical', 'MESH:D012694', (59, 60))
320112	31715145	TP53 gene mutations are the most frequent genetic alteration in EAC, occurring in >70% of cancers and often arise late in BE progression, with TP53* cells undergoing genome doubling and subsequent oncogenic amplifications.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('TP53 gene', 'Gene', (0, 9))	('EAC', 'Disease', (64, 67))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('mutations', 'Var', (10, 19))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
320113	31715145	Our observed frequency of TP53* in HGD is comparable to EAC (Supplementary Table 6), indicating the critical role of TP53* in BE progression and known higher risk of progression to EAC among patients diagnosed with HGD.	('patients', 'Species', '9606', (191, 199))	('EAC', 'Disease', (181, 184))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('TP53*', 'Var', (117, 122))
320117	31715145	The core spliceosome machinery is a reported target and effector of noncanonical ATM signaling, and we observed increased ATM/pATM expression in areas of HGD showing increased gammaH2AX (Figure 3A); however, we have not explored the link between RNF128 isoform changes and ATM signaling in BE progression.	('ATM', 'Gene', '472', (127, 130))	('ATM', 'Gene', (81, 84))	('increased', 'PosReg', (166, 175))	('ATM', 'Gene', (273, 276))	('ATM', 'Gene', (127, 130))	('ATM', 'Gene', (122, 125))	('ATM', 'Gene', '472', (81, 84))	('increased', 'PosReg', (112, 121))	('ATM', 'Gene', '472', (273, 276))	('gammaH2AX', 'Chemical', '-', (176, 185))	('ATM', 'Gene', '472', (122, 125))	('gammaH2AX', 'Var', (176, 185))
320126	31715145	Glycosylation was differentially impacted by wild-type and TP53*; Iso1 is hyper-modified in the presence of TP53*, whereas Iso2 was hypo-modified (Figure 4G and H).	('Glycosylation', 'MPA', (0, 13))	('hyper-modified', 'PosReg', (74, 88))	('TP53*', 'Var', (108, 113))	('Iso2', 'Chemical', '-', (123, 127))	('Iso1', 'Gene', '10209', (66, 70))	('Iso1', 'Gene', (66, 70))
320127	31715145	Green fluorescent protein-tagged (live cell imaging) or DDK-tagged (immunofluorescence staining) RNF128 constructs showed perinuclear and endosomal punctate localization (Supplementary Figure 8B and C; video link).	('S', 'Chemical', 'MESH:D012694', (171, 172))	('DDK-tagged', 'Var', (56, 66))	('RNF128', 'Gene', (97, 103))
320138	31715145	Using clonogenic survival assays, we noted that CpD BE cells containing TP53* are slightly more sensitive to simvastatin (half maximal inhibitory concentration [IC50] 40 nM) relative to wild-type TP53 containing CpA cells (IC50 95 nM), and Iso1 loss further sensitized CpD cells (IC50 ~6 nM).	('simvastatin', 'Chemical', 'MESH:D019821', (109, 120))	('Iso1', 'Gene', '10209', (240, 244))	('more', 'PosReg', (91, 95))	('loss', 'NegReg', (245, 249))	('simvastatin', 'MPA', (109, 120))	('sensitive', 'MPA', (96, 105))	('Iso1', 'Gene', (240, 244))	('TP53*', 'Var', (72, 77))
320139	31715145	In addition, in vivo treatment with simvastatin blocked tumor xenograft growth of TP53*-driven EAC (OE33) cells (Figure 7).	('simvastatin', 'Chemical', 'MESH:D019821', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('TP53', 'Var', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('blocked', 'NegReg', (48, 55))
320145	31715145	We provide a model for the regulation of RNF128 based on our data (Supplementary Figure 11), which may provide a potential basis for strategies to reduce the incidence of TP53*-driven EAC in patients with BE.	('RNF128', 'Gene', (41, 47))	('patients', 'Species', '9606', (191, 199))	('EAC', 'Disease', (184, 187))	('S', 'Chemical', 'MESH:D012694', (67, 68))	('TP53*-driven', 'Var', (171, 183))
320146	31715145	BE Barrett's esophagus DSS disuccinimidyl suberate EAC esophageal adenocarcinoma HGD high-grade dysplasia IC50 half maximal inhibitory concentration IFN interferon Iso1 RNF128 isoform 201 (ENST00000255499) Iso2 RNF128 isoform 202 (ENST00000324342) LGD low-grade dysplasia mRNA messenger RNA RNAseq RNA sequencing siRNA small interfering RNA TMA tissue microarray TP53 wild-type TP53 TP53* mutant TP53 Progression of Barrett's esophagus (BE) to dysplasia and esophageal adenocarcinoma (EAC) involves mutations in TP53 that increase the stability of its product, p53.	('TMA', 'Disease', 'MESH:D000783', (341, 344))	('dysplasia', 'Disease', 'MESH:C536170', (444, 453))	('HGD high', 'Phenotype', 'HP:0410246', (81, 89))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (55, 80))	("Barrett's esophagus", 'Disease', (416, 435))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('Iso1', 'Gene', (164, 168))	('esophageal adenocarcinoma', 'Disease', (55, 80))	('TMA', 'Disease', (341, 344))	('N', 'Chemical', 'MESH:D009584', (170, 171))	('N', 'Chemical', 'MESH:D009584', (338, 339))	('N', 'Chemical', 'MESH:D009584', (299, 300))	('DSS', 'Chemical', 'MESH:C019358', (23, 26))	('Iso1', 'Gene', '10209', (164, 168))	('increase', 'PosReg', (522, 530))	('TP53', 'Gene', (512, 516))	('N', 'Chemical', 'MESH:D009584', (274, 275))	('mutant', 'Var', (389, 395))	('disuccinimidyl', 'Chemical', '-', (27, 41))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (458, 483))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (3, 22))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (416, 435))	('carcinoma', 'Phenotype', 'HP:0030731', (474, 483))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (458, 483))	('dysplasia', 'Disease', (262, 271))	('dysplasia', 'Disease', (96, 105))	('N', 'Chemical', 'MESH:D009584', (232, 233))	('mutations', 'Var', (499, 508))	('N', 'Chemical', 'MESH:D009584', (288, 289))	('esophageal adenocarcinoma', 'Disease', (458, 483))	('dysplasia', 'Disease', (444, 453))	('p53', 'MPA', (561, 564))	('Iso2', 'Chemical', '-', (206, 210))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (55, 80))	('N', 'Chemical', 'MESH:D009584', (190, 191))	('TP53', 'Gene', (396, 400))	('N', 'Chemical', 'MESH:D009584', (292, 293))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('N', 'Chemical', 'MESH:D009584', (316, 317))	('dysplasia', 'Disease', 'MESH:C536170', (262, 271))	('LGD low', 'Phenotype', 'HP:0410245', (248, 255))	('dysplasia', 'Disease', 'MESH:C536170', (96, 105))	('stability of', 'MPA', (535, 547))
320147	31715145	We found that reduced isoform 2 of RNF128, an E3 ubiquitin ligase, promotes stabilization of mutant forms of p53 found in BE cells.	('promotes', 'PosReg', (67, 75))	('RNF128', 'Gene', (35, 41))	('E3 ubiquitin ligase', 'Gene', (46, 65))	('mutant', 'Var', (93, 99))	('p53', 'Gene', (109, 112))	('stabilization', 'MPA', (76, 89))	('E3 ubiquitin ligase', 'Gene', '79594', (46, 65))
320149	31715145	We discovered a process by which a mutant form of a protein that promotes carcinogenesis is stabilized in BE tissues, which might promote development of esophageal cancer.	('promote', 'PosReg', (130, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('protein', 'Protein', (52, 59))	('mutant', 'Var', (35, 41))	('carcinogenesis', 'Disease', (74, 88))	('esophageal cancer', 'Disease', (153, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
320154	31258734	Conversely, it has been reported that downregulation of the MAL gene by promoter hypermethylation is a hallmark of several adenocarcinomas.	('MAL gene', 'Gene', (60, 68))	('promoter hypermethylation', 'Var', (72, 97))	('adenocarcinomas', 'Disease', (123, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('downregulation', 'NegReg', (38, 52))	('adenocarcinomas', 'Disease', 'MESH:D000230', (123, 138))
320159	31258734	In this sense, it was demonstrated that point mutations, deletions, insertions, including GFP fusion at C-terminus were reasons why MAL could be no longer be incorporated into MR resulting in misdistribution of MAL.	('deletions', 'Var', (57, 66))	('point mutations', 'Var', (40, 55))	('insertions', 'Var', (68, 78))	('rat', 'Species', '10116', (29, 32))	('misdistribution', 'MPA', (192, 207))	('GFP', 'Gene', (90, 93))	('rat', 'Species', '10116', (165, 168))
320172	31258734	In fact MAL interacts with the HIV-Nef protein, increasing exosome release, and the lack of MAL impairs this process and has negative effects on the sorting of the exosomal marker CD63.	('lack', 'Var', (84, 88))	('CD63', 'Gene', '967', (180, 184))	('impairs', 'NegReg', (96, 103))	('Nef', 'Gene', (35, 38))	('Nef', 'Gene', '6285', (35, 38))	('CD63', 'Gene', (180, 184))	('exosome release', 'MPA', (59, 74))	('increasing', 'PosReg', (48, 58))
320174	31258734	In vitro studies showed that human MAL (hMAL) is capable of binding CPET and the second extracellular loop (SEL, aa 115 to 125) seems to be involved in CPET-MAL interaction because the insertion of a FLAG tag in this domain totally abolished the hMAL-CPET interaction.	('insertion', 'Var', (185, 194))	('interaction', 'Interaction', (256, 267))	('human', 'Species', '9606', (29, 34))	('abolished', 'NegReg', (232, 241))	('binding', 'Interaction', (60, 67))
320184	31258734	In this context, chemical-demethylation of DNA restored cellular levels of MAL-mRNA, and transgenic expression of MAL in tumor cells and cell lines reduced tumor growth in nude mice, diminished cell motility, blocked G1/S transition, and increased expression of Fas receptor and apoptosis in vitro.	('Fas receptor', 'Protein', (262, 274))	('tumor', 'Disease', (156, 161))	('chemical-demethylation', 'Var', (17, 39))	('DNA', 'Gene', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (121, 126))	('blocked', 'NegReg', (209, 216))	('expression', 'MPA', (248, 258))	('cellular levels of MAL-mRNA', 'MPA', (56, 83))	('transgenic', 'Species', '10090', (89, 99))	('cell motility', 'CPA', (194, 207))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('diminished', 'NegReg', (183, 193))	('restored', 'PosReg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('nude mice', 'Species', '10090', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('reduced', 'NegReg', (148, 155))	('increased', 'PosReg', (238, 247))	('apoptosis', 'CPA', (279, 288))	('G1/S transition', 'CPA', (217, 232))
320191	31258734	This does not agree with the M2 island reported from head and neck carcinomas, and interestingly, even though the authors still consider MAL a tumor suppressor gene they showed that hypermethylation of M2, but not M1, correlates with a higher survival of patients with gastric cancer.	('gastric cancer', 'Disease', (269, 283))	('higher', 'PosReg', (236, 242))	('neck carcinomas', 'Disease', 'MESH:D006258', (62, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (269, 283))	('tumor', 'Disease', (143, 148))	('gastric cancer', 'Phenotype', 'HP:0012126', (269, 283))	('patients', 'Species', '9606', (255, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('neck carcinomas', 'Disease', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('hypermethylation', 'Var', (182, 198))
320201	31258734	Hypomethylation of the region mapped from -462 to -266 in the MAL gene promoter partially correlates with increased levels of MAL-mRNA in ovarian tumor cells as well as in ovarian carcinoma cell lines.	('ovarian carcinoma', 'Disease', (172, 189))	('ovarian tumor', 'Disease', 'MESH:D010051', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('Hypomethylation', 'Var', (0, 15))	('levels', 'MPA', (116, 122))	('ovarian tumor', 'Disease', (138, 151))	('ovarian tumor', 'Phenotype', 'HP:0100615', (138, 151))	('increased', 'PosReg', (106, 115))	('MAL-mRNA', 'MPA', (126, 134))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (172, 189))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (172, 189))
320210	31258734	As we mentioned before, in lymphocytes, MAL is essential in transport of acylated forms of Src-like kinases Lck and Fyn to the GEMs; in agreement with this, MAL gene silencing impairs kinases transport 22,65].	('Fyn', 'Gene', (116, 119))	('Fyn', 'Gene', '2534', (116, 119))	('Lck', 'Gene', (108, 111))	('Src', 'Gene', '6714', (91, 94))	('Lck', 'Gene', '3932', (108, 111))	('gene silencing', 'Var', (161, 175))	('impairs', 'NegReg', (176, 183))	('Src', 'Gene', (91, 94))
320214	31258734	So far, no evidence has been reported regarding point mutations in the MAL gene as causative of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MAL', 'Gene', (71, 74))	('human', 'Species', '9606', (96, 101))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('point mutations', 'Var', (48, 63))	('cancers', 'Disease', (102, 109))
320215	31258734	However, Beder and coworkers found that both loss of heterozygosity and hypermethylation of the MAL promoter are relevant mechanisms for down regulation of MAL in head and neck squamous carcinomas.	('MAL', 'Gene', (156, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('neck squamous carcinomas', 'Disease', (172, 196))	('hypermethylation', 'Var', (72, 88))	('MAL', 'Gene', (96, 99))	('loss', 'NegReg', (45, 49))	('down regulation', 'NegReg', (137, 152))	('neck squamous carcinomas', 'Disease', 'MESH:D000077195', (172, 196))
320216	31258734	Thus, both hyper- and hypo-methylation of the MAL gene are associated with cancer progression, and so far, this dilemma only can be somewhat explained by the distinct expression levels of MAL in different cell types.	('MAL', 'Gene', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('associated', 'Reg', (59, 69))	('hyper-', 'Var', (11, 17))	('hypo-methylation', 'Var', (22, 38))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
320235	31258734	This effect it is mediated by increasing the expression of DNA-methyl transferases 1 and 3b, and it could be very interesting to test if MUC1 turns off MAL gene expression in adenocarcinoma cells.	('adenocarcinoma', 'Disease', (175, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('expression', 'MPA', (161, 171))	('increasing', 'PosReg', (30, 40))	('adenocarcinoma', 'Disease', 'MESH:D000230', (175, 189))	('expression', 'MPA', (45, 55))	('DNA-methyl transferases 1 and 3b', 'Gene', '1786;1789', (59, 91))	('MUC1', 'Var', (137, 141))	('turns', 'Reg', (142, 147))	('MAL gene', 'Gene', (152, 160))
320243	30117158	ORs for ever-drinking were stronger in ever-tobacco users (9.0, 95% CI: 3.4, 23.8, with few tobacco users who were never drinkers) than in never-tobacco users (2.6, 95% CI: 1.6, 4.1).	('tobacco', 'Species', '4097', (44, 51))	('tobacco', 'Species', '4097', (92, 99))	('ever-tobacco', 'Var', (39, 51))	('ever-drinking', 'Disease', (8, 21))	('tobacco', 'Species', '4097', (145, 152))
320356	30117158	For alcohol specifically, the relative proportions of the ALDH2 variant alleles are not known in East African populations.	('ALDH2', 'Gene', (58, 63))	('alcohol', 'Chemical', 'MESH:D000431', (4, 11))	('variant', 'Var', (64, 71))
320412	29414631	When compared to other upper aerodigestive or respiratory cancers in selected populations (US SEER white and black, Scotland, Calvados), although extremely rare, M:F lung cancer IRRs are 1.2 in US Whites in the 30s, and 2 in Scotland.	('respiratory cancers', 'Disease', (46, 65))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('M:F', 'Var', (162, 165))	('IRR', 'Gene', (178, 181))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('respiratory cancers', 'Disease', 'MESH:D012131', (46, 65))	('lung cancer', 'Disease', (166, 177))	('IRR', 'Gene', '3645', (178, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
320421	28407484	Antifungal treatment or depletion of autoreactive CD4 T cells rescues, whereas oral fungal administration promotes, ESCC development.	('SCC', 'Gene', (117, 120))	('rescues', 'PosReg', (62, 69))	('rat', 'Species', '10116', (99, 102))	('depletion', 'Var', (24, 33))	('CD4', 'Gene', (50, 53))	('SCC', 'Gene', '6317', (117, 120))	('CD4', 'Gene', '12504', (50, 53))
320422	28407484	Inhibition of inflammation or EGFR activity decreases fungal burden.	('inflammation', 'Disease', (14, 26))	('activity', 'MPA', (35, 43))	('EGFR', 'Gene', (30, 34))	('fungal burden', 'CPA', (54, 67))	('Inhibition', 'Var', (0, 10))	('inflammation', 'Disease', 'MESH:D007249', (14, 26))	('decreases', 'NegReg', (44, 53))	('EGFR', 'Gene', '13649', (30, 34))
320427	28407484	The defective central tolerance in APECED patients is due to mutations in the autoimmune regulator (AIRE) gene.	('APECED', 'Gene', (35, 41))	('autoimmune regulator', 'Gene', (78, 98))	('defective', 'NegReg', (4, 13))	('mutations', 'Var', (61, 70))	('autoimmune regulator', 'Gene', '326', (78, 98))	('AIRE', 'Gene', (100, 104))	('patients', 'Species', '9606', (42, 50))	('APECED', 'Gene', '326', (35, 41))	('central tolerance', 'CPA', (14, 31))
320431	28407484	Alterations in TCR Vbeta loci and increased Vbeta5.1 repertoire have been reported in APECED patients.	('APECED', 'Gene', (86, 92))	('Alterations', 'Var', (0, 11))	('repertoire', 'MPA', (53, 63))	('Vbeta5.1', 'Protein', (44, 52))	('TCR Vbeta loci', 'Gene', (15, 29))	('rat', 'Species', '10116', (4, 7))	('increased', 'PosReg', (34, 43))	('patients', 'Species', '9606', (93, 101))	('APECED', 'Gene', '326', (86, 92))
320441	28407484	IKKalpha functions as a tumor suppressor in the skin: its somatic ablation in keratinocytes expands epidermal-basal keratinocytes expressing keratin 5/14 (K5/14) and induces spontaneous skin SCC.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('ablation', 'Var', (66, 74))	('keratin 5/14', 'Gene', '110308;16664', (141, 153))	('rat', 'Species', '10116', (118, 121))	('tumor', 'Disease', (24, 29))	('rat', 'Species', '10116', (80, 83))	('expands', 'PosReg', (92, 99))	('keratin 5/14', 'Gene', (141, 153))	('K5/14', 'Gene', (155, 160))	('rat', 'Species', '10116', (143, 146))	('K5/14', 'Gene', '110308;16664', (155, 160))	('induces', 'Reg', (166, 173))	('SCC', 'Gene', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('SCC', 'Gene', '6317', (191, 194))
320442	28407484	IKKalpha deletion elevates EGFR activity by upregulating the transcription of Egf, HB-Egf, and a disintegrin and metalloproteinase domain (Adam) genes.	('EGFR', 'Gene', (27, 31))	('transcription', 'MPA', (61, 74))	('EGFR', 'Gene', '13649', (27, 31))	('elevates', 'PosReg', (18, 26))	('deletion', 'Var', (9, 17))	('activity', 'MPA', (32, 40))	('HB-Egf', 'Gene', (83, 89))	('IKKalpha', 'Gene', (0, 8))	('HB-Egf', 'Gene', '15200', (83, 89))	('Egf', 'Gene', (78, 81))	('upregulating', 'PosReg', (44, 56))
320443	28407484	Inactivation of EGFR prevents IKKalpha deletion-induced skin tumorigenesis.	('skin tumor', 'Disease', 'MESH:D012878', (56, 66))	('EGFR', 'Gene', (16, 20))	('skin tumor', 'Phenotype', 'HP:0008069', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('IKKalpha', 'Gene', (30, 38))	('deletion-induced', 'Var', (39, 55))	('Inactivation', 'Var', (0, 12))	('EGFR', 'Gene', '13649', (16, 20))	('skin tumor', 'Disease', (56, 66))
320444	28407484	Also, IKKalpha deletion promotes cell cycle progression and genomic instability, thereby accelerating skin tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('deletion', 'Var', (15, 23))	('rat', 'Species', '10116', (95, 98))	('skin tumor', 'Phenotype', 'HP:0008069', (102, 112))	('accelerating', 'PosReg', (89, 101))	('cell cycle progression', 'CPA', (33, 55))	('promotes', 'PosReg', (24, 32))	('skin tumor', 'Disease', (102, 112))	('genomic instability', 'CPA', (60, 79))	('skin tumor', 'Disease', 'MESH:D012878', (102, 112))	('IKKalpha', 'Gene', (6, 14))
320454	28407484	We observed that C57BL/6 kinase-dead IkkalphaKA/KA developed esophageal epithelial hyperplasia, and approximately 20% of IkkalphaKA/KA mice at 5 months of age developed ESCC (Figure 1A).	('SCC', 'Gene', '6317', (170, 173))	('esophageal epithelial hyperplasia', 'Disease', (61, 94))	('Ikkalpha', 'Gene', (121, 129))	('Ikkalpha', 'Gene', '12675', (121, 129))	('SCC', 'Gene', (170, 173))	('mice', 'Species', '10090', (135, 139))	('esophageal epithelial hyperplasia', 'Disease', 'MESH:D017573', (61, 94))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (61, 81))	('Ikkalpha', 'Gene', (37, 45))	('C57BL/6', 'Var', (17, 24))	('Ikkalpha', 'Gene', '12675', (37, 45))	('esophageal epithelial hyperplasia', 'Phenotype', 'HP:0012859', (61, 94))
320458	28407484	The K44A mutation destabilizes the IKKalpha protein in IkkalphaKA/KA mice (Figure 1B).	('K44A', 'Mutation', 'p.K44A', (4, 8))	('Ikkalpha', 'Gene', (55, 63))	('Ikkalpha', 'Gene', '12675', (55, 63))	('mice', 'Species', '10090', (69, 73))	('IKKalpha protein', 'Protein', (35, 51))	('K44A', 'Var', (4, 8))	('destabilizes', 'NegReg', (18, 30))
320461	28407484	These MESCCs highly expressed SCC hallmarks p63, K5/K14, and K6/K16, and expressed significantly increased or decreased levels of genes encoding proteins that regulate stem cell properties, cell cycle, DNA replication, epigenetic mechanisms, cell proliferation or survival, oxidative stress, DNA repair, inflammatory pathways, and PD-L1 (Figures 1C, S1C, and Table S2).	('SCC', 'Gene', '6317', (30, 33))	('increased', 'PosReg', (97, 106))	('oxidative stress', 'Phenotype', 'HP:0025464', (274, 290))	('levels of genes encoding proteins', 'MPA', (120, 153))	('K6/K16', 'Var', (61, 67))	('decreased', 'NegReg', (110, 119))	('SCC', 'Gene', (8, 11))	('p63', 'Var', (44, 47))	('SCC', 'Gene', (30, 33))	('SCC', 'Gene', '6317', (8, 11))	('rat', 'Species', '10116', (254, 257))
320485	28407484	A frequency of CD11c+ dendritic cells was decreased in the IkkalphaKA/KA thymus compared to the WT (Figure S2D).	('CD11c+', 'Var', (15, 21))	('Ikkalpha', 'Gene', '12675', (59, 67))	('decreased', 'NegReg', (42, 51))	('Ikkalpha', 'Gene', (59, 67))
320501	28407484	Also, K5.IKKalpha partially restored the size of the medullary regions and Treg numbers in the thymus, abolished the systemic inflammation and malignant phenotypes, and eliminated fungal infection in IkkalphaKA/KA;K5.IKKalpha mice (Figures 2F, 2G, S2H, and S2I).	('systemic inflammation', 'Disease', (117, 138))	('Treg numbers', 'CPA', (75, 87))	('K5.IKKalpha', 'Var', (6, 17))	('fungal infection', 'Disease', 'MESH:D009181', (180, 196))	('mice', 'Species', '10090', (226, 230))	('Ikkalpha', 'Gene', '12675', (200, 208))	('size', 'CPA', (41, 45))	('abolished', 'NegReg', (103, 112))	('systemic inflammation', 'Disease', 'MESH:D007249', (117, 138))	('Ikkalpha', 'Gene', (200, 208))	('fungal infection', 'Disease', (180, 196))	('malignant phenotypes', 'CPA', (143, 163))	('eliminated', 'NegReg', (169, 179))
320504	28407484	Flow cytometric analysis and IF staining verified that K5.IKKalpha restored numbers of K5+UEA-1+ and CD45+integrinalpha6+UEA-1+ mTECs in IkkalphaKA/KA;K5.IKKalpha thymuses compared to IkkalphaKA/KA thymuses (Figures 3A and S3A).	('CD45', 'Gene', '19264', (101, 105))	('Ikkalpha', 'Gene', '12675', (137, 145))	('CD45', 'Gene', (101, 105))	('K5.IKKalpha', 'Var', (55, 66))	('Ikkalpha', 'Gene', (184, 192))	('Ikkalpha', 'Gene', '12675', (184, 192))	('Ikkalpha', 'Gene', (137, 145))
320509	28407484	Increased Vbeta5.1 repertoire was detected in the T cells from two sibling patients with APECED who carried AIRE mutations and fungal infection, suggesting that IkkalphaKA/KA T cells carry a signature of increased Vbeta5.1 repertoire shared with APECED patients.	('Ikkalpha', 'Gene', (161, 169))	('fungal infection', 'Disease', (127, 143))	('Ikkalpha', 'Gene', '12675', (161, 169))	('APECED', 'Gene', '326', (246, 252))	('APECED', 'Gene', (246, 252))	('patients', 'Species', '9606', (253, 261))	('patients', 'Species', '9606', (75, 83))	('increased', 'PosReg', (204, 213))	('fungal infection', 'Disease', 'MESH:D009181', (127, 143))	('mutations', 'Var', (113, 122))	('APECED', 'Gene', '326', (89, 95))	('APECED', 'Gene', (89, 95))	('Vbeta5.1', 'Gene', (214, 222))
320522	28407484	The results suggest that IkkalphaKA/KA autoreactive T cells are associated with increased fungal infection, macrophage recruitment, and esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (136, 161))	('increased fungal infection', 'Disease', (80, 106))	('Ikkalpha', 'Gene', (25, 33))	('esophageal carcinogenesis', 'Disease', (136, 161))	('Ikkalpha', 'Gene', '12675', (25, 33))	('increased fungal infection', 'Phenotype', 'HP:0002841', (80, 106))	('increased fungal infection', 'Disease', 'MESH:D009181', (80, 106))	('autoreactive', 'Var', (39, 51))	('macrophage recruitment', 'CPA', (108, 130))
320557	28407484	We used clodronate-loaded liposomes to deplete macrophages in IkkalphaKA/KA mice and obtained results similar to those from aspirin treatment (data not shown); however, liposome treatment caused the death of 5 treated IkkalphaKA/KA mice in a group containing 10 mice.	('Ikkalpha', 'Gene', '12675', (218, 226))	('death', 'Disease', 'MESH:D003643', (199, 204))	('mice', 'Species', '10090', (262, 266))	('liposome', 'Var', (169, 177))	('death', 'Disease', (199, 204))	('Ikkalpha', 'Gene', (62, 70))	('Ikkalpha', 'Gene', '12675', (62, 70))	('aspirin', 'Chemical', 'MESH:D001241', (124, 131))	('mice', 'Species', '10090', (76, 80))	('clodronate', 'Chemical', 'MESH:D004002', (8, 18))	('Ikkalpha', 'Gene', (218, 226))	('caused', 'Reg', (188, 194))	('mice', 'Species', '10090', (232, 236))
320559	28407484	It has been reported that fungi can interact with and activate EGFR and that treatment with an EGFR inhibitor significantly reduces the severity of oropharyngeal candidiasis.	('EGFR', 'Gene', '13649', (95, 99))	('severity', 'MPA', (136, 144))	('oropharyngeal candidiasis', 'Disease', 'MESH:D009959', (148, 173))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '13649', (63, 67))	('reduces', 'NegReg', (124, 131))	('interact', 'Interaction', (36, 44))	('oropharyngeal candidiasis', 'Disease', (148, 173))	('inhibitor', 'Var', (100, 109))	('oropharyngeal candidiasis', 'Phenotype', 'HP:0002728', (148, 173))	('EGFR', 'Gene', (95, 99))
320561	28407484	We then treated IkkalphaKA/KA mice with GW2974, an EGFR inhibitor, for 30 days.	('GW2974', 'Var', (40, 46))	('mice', 'Species', '10090', (30, 34))	('EGFR', 'Gene', (51, 55))	('Ikkalpha', 'Gene', (16, 24))	('EGFR', 'Gene', '13649', (51, 55))	('GW2974', 'Chemical', 'MESH:C506645', (40, 46))	('Ikkalpha', 'Gene', '12675', (16, 24))
320577	28407484	We also examined the association between fungal infection and non-APECED-derived HESCCs in a cohort containing 50 human normal esophageal tissue specimens and 80 stage-II and III HESCCs expressing K5 and p63 from Chinese non-APECED patients (Figures S6B, S6C, and S6D).	('APECED', 'Gene', (66, 72))	('SCC', 'Gene', (181, 184))	('patients', 'Species', '9606', (232, 240))	('SCC', 'Gene', (83, 86))	('APECED', 'Gene', '326', (225, 231))	('fungal infection', 'Disease', (41, 57))	('APECED', 'Gene', (225, 231))	('p63', 'Var', (204, 207))	('SCC', 'Gene', '6317', (181, 184))	('SCC', 'Gene', '6317', (83, 86))	('human', 'Species', '9606', (114, 119))	('S6C', 'Mutation', 'p.S6C', (255, 258))	('fungal infection', 'Disease', 'MESH:D009181', (41, 57))	('APECED', 'Gene', '326', (66, 72))
320591	28407484	The mutations of CHUK that encodes IKKalpha were detected in HESCCs (Figure 7E from www.cbiportal.org).	('CHUK', 'Gene', (17, 21))	('SCC', 'Gene', (63, 66))	('SCC', 'Gene', '6317', (63, 66))	('mutations', 'Var', (4, 13))	('CHUK', 'Gene', '12675', (17, 21))
320625	28407484	The defects in immunity and epithelial cells together facilitate and promote the development of chronic fungal infection and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('chronic fungal infection', 'Phenotype', 'HP:0002841', (96, 120))	('chronic fungal infection', 'Disease', 'MESH:D009181', (96, 120))	('promote', 'PosReg', (69, 76))	('facilitate', 'PosReg', (54, 64))	('chronic fungal infection', 'Disease', (96, 120))	('defects', 'Var', (4, 11))
320627	28407484	Aire deletion alone may not be sufficient to cause defects in immunity and oncogenes/tumor suppressors for generating fungal infection associated-malignant phenotypes in Aire-/- mice.	('Aire', 'Gene', (170, 174))	('tumor', 'Disease', (85, 90))	('rat', 'Species', '10116', (111, 114))	('fungal infection', 'Disease', 'MESH:D009181', (118, 134))	('deletion', 'Var', (5, 13))	('mice', 'Species', '10090', (178, 182))	('Aire', 'Gene', '11634', (0, 4))	('Aire', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('fungal infection', 'Disease', (118, 134))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Aire', 'Gene', '11634', (170, 174))
320637	28407484	IKKalpha haplodeficiency promotes carcinogen-induced carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (53, 67))	('carcinogenesis', 'Disease', (53, 67))	('promotes', 'PosReg', (25, 33))	('haplodeficiency', 'Var', (9, 24))	('IKKalpha', 'Gene', (0, 8))
320640	28407484	Although normal T cells fight against fungal infection and tumor cells, PD-L1 blocks the antitumor activity of T cells.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('blocks', 'NegReg', (78, 84))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('fungal infection', 'Disease', (38, 54))	('tumor', 'Disease', (93, 98))	('fungal infection', 'Disease', 'MESH:D009181', (38, 54))	('PD-L1', 'Var', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
320705	28407484	Aspirin (A5376-100G: Acetylsalicylic acid) and GW 2974 (G0668) were purchased from Sigma.	('GW', 'Chemical', 'MESH:C032120', (47, 49))	('A5376-100G', 'SUBSTITUTION', 'None', (9, 19))	('A5376-100G', 'Var', (9, 19))	('Aspirin', 'Chemical', 'MESH:D001241', (0, 7))	('Acetylsalicylic acid', 'Chemical', 'MESH:D001241', (21, 41))	('G0668', 'Var', (56, 61))	('G0668', 'Chemical', '-', (56, 61))
320716	28407484	All the real-time PCR primers were purchased from Qiagen, including Il6 (PPM03015A-200), Tnfalpha (PPM03113G-200), Ifngamma (PPM03121A-200), Il4 (PPM03013F-200), Il13 (PPM03021B-200), Il17a (PPM03023A-200), Il17f (PPM05398E-200), Il22 (PPM05481A-200), Cxcl11 (PPM03192C-200), Gapdh (PPM02946E-200), Kif2c (Cat No.	('Cxcl11', 'Gene', '56066', (252, 258))	('Il6', 'Gene', '16193', (68, 71))	('Kif2c', 'Gene', (299, 304))	('PPM05398E-200', 'Var', (214, 227))	('Il13', 'Gene', (162, 166))	('Il13', 'Gene', '16163', (162, 166))	('PPM03192C-200', 'Var', (260, 273))	('Il6', 'Gene', (68, 71))	('PPM03021B-200', 'Var', (168, 181))	('Kif2c', 'Gene', '73804', (299, 304))	('PPM05481A-200', 'Var', (236, 249))	('PPM03013F-200', 'Var', (146, 159))	('Il17f', 'Gene', '257630', (207, 212))	('Il4', 'Gene', (141, 144))	('PPM03121A-200', 'Var', (125, 138))	('Il4', 'Gene', '16189', (141, 144))	('Il22', 'Gene', (230, 234))	('PPM03023A-200', 'Var', (191, 204))	('Il17f', 'Gene', (207, 212))	('PPM03113G-200', 'Var', (99, 112))	('Cxcl11', 'Gene', (252, 258))	('Il22', 'Gene', '50929', (230, 234))	('PPM02946E-200', 'Var', (283, 296))
320740	27836862	Phase I study of epigenetic priming with azacitidine prior to standard neoadjuvant chemotherapy for patients with resectable gastric and esophageal adenocarcinoma: Evidence of tumor hypomethylation as an indicator of major histopathologic response Epigenetic silencing of tumor suppressor genes (TSGs) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation.	('TSG', 'Gene', '57045', (296, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('patients', 'Species', '9606', (100, 108))	('TSG', 'Gene', (296, 299))	('cancer', 'Disease', (341, 347))	('tumor suppressor', 'Gene', '7248', (272, 288))	('tumor', 'Disease', (272, 277))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('Epigenetic silencing', 'Var', (248, 268))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (137, 162))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (137, 162))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('azacitidine', 'Chemical', 'MESH:D001374', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('esophageal adenocarcinoma', 'Disease', (137, 162))	('tumor suppressor', 'Gene', (272, 288))
320741	27836862	We postulated that pre-treatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs.	('TSG', 'Gene', '57045', (122, 125))	('5-azacitidine', 'Chemical', 'MESH:D001374', (48, 61))	('5-azacitidine', 'Var', (48, 61))	('reactivating', 'NegReg', (109, 121))	('increase', 'PosReg', (68, 76))	('TSG', 'Gene', (122, 125))	('efficacy', 'CPA', (81, 89))
320751	27836862	Epigenetic silencing of tumor suppressor genes (TSGs) is commonly observed in gastroesophageal cancer and is believed to play a role in oncogenesis, metastasis and chemotherapy resistance.	('TSG', 'Gene', (48, 51))	('observed', 'Reg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('role', 'Reg', (128, 132))	('metastasis', 'Disease', 'MESH:D009362', (149, 159))	('metastasis', 'Disease', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('TSG', 'Gene', '57045', (48, 51))	('gastroesophageal cancer', 'Disease', (78, 101))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (78, 101))	('Epigenetic silencing', 'Var', (0, 20))	('tumor suppressor', 'Gene', (24, 40))	('play', 'Reg', (121, 125))	('tumor suppressor', 'Gene', '7248', (24, 40))
320822	27836862	As expected, DNA methylation of HIST1H2AA was detected in all specimens tested.	('HIST1H2AA', 'Gene', '221613', (32, 41))	('HIST1H2AA', 'Gene', (32, 41))	('methylation', 'Var', (17, 28))	('detected', 'Reg', (46, 54))
320823	27836862	Tumor-associated methylation was observed most commonly at the HPP1 locus followed by TIMP3, ESR1 and then CDKN2A and MGMT (Figure 1B).	('TIMP3', 'Gene', '7078', (86, 91))	('CDKN2A', 'Gene', '1029', (107, 113))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('HPP1', 'Gene', (63, 67))	('Tumor-associated', 'Reg', (0, 16))	('observed', 'Reg', (33, 41))	('methylation', 'Var', (17, 28))	('MGMT', 'Gene', '4255', (118, 122))	('MGMT', 'Gene', (118, 122))	('ESR1', 'Gene', (93, 97))	('HPP1', 'Gene', '780897', (63, 67))	('CDKN2A', 'Gene', (107, 113))	('TIMP3', 'Gene', (86, 91))	('ESR1', 'Gene', '2099', (93, 97))
320824	27836862	Most patients had methylation of multiple tumor loci in their specimens with the exception of one patient who had no detectable methylation at any locus but HISTH2AA (Figure 1C).	('multiple tumor', 'Disease', (33, 47))	('patient', 'Species', '9606', (5, 12))	('patient', 'Species', '9606', (98, 105))	('patients', 'Species', '9606', (5, 13))	('multiple tumor', 'Disease', 'MESH:D009369', (33, 47))	('methylation', 'Var', (18, 29))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
320837	27836862	This supports the hypothesis that epigenetic priming can induce TSG expression during neoadjuvant chemotherapy.	('expression', 'MPA', (68, 78))	('epigenetic priming', 'Var', (34, 52))	('TSG', 'Gene', (64, 67))	('induce', 'PosReg', (57, 63))	('TSG', 'Gene', '57045', (64, 67))
320848	27836862	Epigenetic-primed VEOX chemotherapy can induce hypomethylation and expression of candidate TSGs in vivo.	('hypomethylation', 'MPA', (47, 62))	('Epigenetic-primed', 'Var', (0, 17))	('TSG', 'Gene', (91, 94))	('VEOX', 'Chemical', '-', (18, 22))	('expression', 'MPA', (67, 77))	('TSG', 'Gene', '57045', (91, 94))	('induce', 'PosReg', (40, 46))
320854	27836862	Previously, we found that epigenetic priming using the DHA decitabine prior to intensive induction chemotherapy for AML was no more toxic than standard chemotherapy alone and we did not identify a MTD.	('decitabine', 'Chemical', 'MESH:D000077209', (59, 69))	('epigenetic priming', 'Var', (26, 44))	('MTD', 'Gene', '4493', (197, 200))	('AML', 'Disease', 'MESH:D015470', (116, 119))	('AML', 'Phenotype', 'HP:0004808', (116, 119))	('MTD', 'Gene', (197, 200))	('AML', 'Disease', (116, 119))	('DHA', 'Chemical', '-', (55, 58))
320864	27836862	Our results support the hypothesis that azacitidine can hypomethylate tumor DNA and activate TSG expression.	('TSG', 'Gene', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TSG', 'Gene', '57045', (93, 96))	('hypomethylate tumor', 'Disease', 'MESH:D009369', (56, 75))	('azacitidine', 'Var', (40, 51))	('azacitidine', 'Chemical', 'MESH:D001374', (40, 51))	('hypomethylate tumor', 'Disease', (56, 75))	('activate', 'PosReg', (84, 92))	('expression', 'MPA', (97, 107))
320865	27836862	Prior studies have linked platinum resistance in ovarian cancer to hypermethylation and transcriptional silencing of key TSGs such as RASSF1A and have shown that platinum chemosensitivity can be restored to tumor cell lines by pretreatment with a DHA in vitro.	('TSG', 'Gene', (121, 124))	('silencing', 'NegReg', (104, 113))	('platinum', 'Chemical', 'MESH:D010984', (162, 170))	('RASSF1A', 'Gene', '11186', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('TSG', 'Gene', '57045', (121, 124))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('hypermethylation', 'Var', (67, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (49, 63))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('transcriptional', 'MPA', (88, 103))	('platinum', 'Chemical', 'MESH:D010984', (26, 34))	('linked', 'Reg', (19, 25))	('DHA', 'Chemical', '-', (247, 250))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (207, 212))	('RASSF1A', 'Gene', (134, 141))	('ovarian cancer', 'Disease', (49, 63))
320866	27836862	The demethylation and reexpression of RASSF1A in addition to MLH1 and HOXA11 was identified with "chemoresensitization" suggesting that epigenetic silencing of these key genes is a potential mechanism of platinum resistance.	('epigenetic silencing', 'Var', (136, 156))	('RASSF1A', 'Gene', (38, 45))	('MLH1', 'Gene', '4292', (61, 65))	('MLH1', 'Gene', (61, 65))	('HOXA11', 'Gene', (70, 76))	('platinum', 'Chemical', 'MESH:D010984', (204, 212))	('HOXA11', 'Gene', '3207', (70, 76))	('mechanism', 'Reg', (191, 200))	('RASSF1A', 'Gene', '11186', (38, 45))	('platinum resistance', 'Disease', (204, 223))
320869	27836862	In conclusion, epigenetic priming with azacitidine plus EOX was well-tolerated as a neoadjuvant approach for resectable gastroesophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('epigenetic priming', 'Var', (15, 33))	('EOX', 'Chemical', '-', (56, 59))	('gastroesophageal cancer', 'Disease', (120, 143))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (120, 143))	('azacitidine', 'Chemical', 'MESH:D001374', (39, 50))
320873	27836862	We expect that this study defining the feasibility of epigenetic priming in gastric and esophageal adenocarcinoma will translate to therapeutic advances in more common forms of cancer since transcriptional silencing of TSGs by DNA hypermethylation is seen in most, if not all, forms of cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (88, 113))	('TSG', 'Gene', '57045', (219, 222))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('hypermethylation', 'Var', (231, 247))	('gastric', 'Disease', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TSG', 'Gene', (219, 222))	('cancer', 'Disease', (286, 292))
320890	27833389	Multiple studies have reported a greater deterioration of the QOL after total gastrectomy (TG) than distal gastrectomy (DG), and it is thought that the more extensive the resection of the stomach, the greater the severity of PGS.	('PGS', 'Disease', (225, 228))	('QOL', 'MPA', (62, 65))	('PGS', 'Disease', 'MESH:C535773', (225, 228))	('TG', 'Chemical', '-', (91, 93))	('deterioration', 'MPA', (41, 54))	('resection', 'Var', (171, 180))
320986	26812616	Early-Stage Induction of SWI/SNF Mutations during Esophageal Squamous Cell Carcinogenesis The SWI/SNF chromatin remodeling complex is frequently inactivated by somatic mutations of its various components in various types of cancers, and also by aberrant DNA methylation.	('SWI/SNF', 'Gene', (25, 32))	('Esophageal Squamous Cell Carcinogenesis', 'Disease', (50, 89))	('Mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('SWI/SNF', 'Gene', (94, 101))	('inactivated', 'NegReg', (145, 156))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('cancers', 'Disease', (224, 231))	('mutations', 'Var', (168, 177))
320988	26812616	The SMARCA4 mutations were located in the Forkhead (85Ser>Leu) and SNF2 family N-terminal (882Glu>Lys) domains.	('mutations', 'Var', (12, 21))	('85Ser>Leu', 'Mutation', 'rs751542188', (52, 61))	('SMARCA4', 'Gene', (4, 11))	('882Glu>Lys', 'Mutation', 'p.E882K', (91, 101))
320989	26812616	The PBRM1 mutations were located in a bromodomain (80Asn>Ser) and an HMG-box domain (1,377Glu>Lys).	('PBRM1', 'Gene', (4, 9))	('mutations', 'Var', (10, 19))	('80Asn>Ser', 'Mutation', 'rs1195663483', (51, 60))	('377Glu>Lys', 'Mutation', 'p.E377K', (87, 97))
320990	26812616	For most mutations, their mutant allele frequency was 31-77% (mean 61%) of the fraction of cancer cells in the same samples, indicating that most of the cancer cells in individual ESCC samples had the SWI/SNF mutations on one allele, when present.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (91, 97))	('mutations', 'Var', (9, 18))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('SWI/SNF', 'Gene', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (209, 218))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
320991	26812616	These results showed that genetic and epigenetic alterations of the SWI/SNF complex are present in ESCCs, and suggested that genetic alterations are induced at an early stage of esophageal squamous cell carcinogenesis.	('ESCCs', 'Disease', (99, 104))	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (178, 217))	('epigenetic', 'Var', (38, 48))	('SWI/SNF complex', 'Gene', (68, 83))	('esophageal squamous cell carcinogenesis', 'Disease', (178, 217))
320992	26812616	Genetic alterations, such as somatic mutations, are deeply involved in human carcinogenesis by disrupting various cancer-related pathways.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Genetic alterations', 'Var', (0, 19))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('disrupting', 'NegReg', (95, 105))	('carcinogenesis', 'Disease', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (71, 76))	('cancer', 'Disease', (114, 120))
320993	26812616	Various components of the SWI/SNF complex are frequently mutated in various types of cancers.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('mutated', 'Var', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
320994	26812616	ARID1A is frequently mutated in ovarian clear cell carcinomas, hepatocellular carcinomas (HCCs), and gastric cancers; ARID2 in HCCs; PBRM1 in renal cell carcinomas; and SMARCA4 in small cell carcinomas of the ovary of hypercalcemic type (SCCOHT).	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('small cell carcinomas of the ovary of hypercalcemic type', 'Disease', 'MESH:D018288', (180, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('gastric cancers', 'Phenotype', 'HP:0012126', (101, 116))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (180, 201))	('mutated', 'Var', (21, 28))	('carcinomas of the ovary', 'Phenotype', 'HP:0100615', (191, 214))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (63, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (142, 163))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (63, 88))	('PBRM1', 'Gene', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('hepatocellular carcinomas', 'Disease', (63, 88))	('ARID1A', 'Gene', (0, 6))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (142, 163))	('ovarian clear cell carcinomas', 'Disease', (32, 61))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('renal cell carcinomas', 'Disease', (142, 163))	('ARID2', 'Gene', (118, 123))	('SMARCA4', 'Gene', (169, 176))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (32, 61))	('gastric cancers', 'Disease', (101, 116))	('gastric cancers', 'Disease', 'MESH:D013274', (101, 116))
320996	26812616	Components of the SWI/SNF complex, ACTL6B, SMARCA2, and SMARCD3, and those of the other types of chromatin remodeling complex, ATRX and SMARCA1, are aberrantly methylated in gastric cancers; ARID1A in invasive breast cancers; ARID1B in pancreatic cancers, and ACTL6B in hepatocellular carcinomas (HCCs).	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (236, 254))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (270, 295))	('SMARCA1', 'Gene', (136, 143))	('aberrantly methylated', 'Var', (149, 170))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('ACTL6B', 'Gene', (260, 266))	('pancreatic cancers', 'Disease', (236, 254))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (270, 295))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('invasive breast cancers', 'Disease', 'MESH:D001943', (201, 224))	('hepatocellular carcinomas', 'Disease', (270, 295))	('ARID1A', 'Gene', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('SMARCA1', 'Gene', '6594', (136, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (285, 295))	('breast cancers', 'Phenotype', 'HP:0003002', (210, 224))	('gastric cancers', 'Disease', (174, 189))	('gastric cancers', 'Disease', 'MESH:D013274', (174, 189))	('invasive breast cancers', 'Disease', (201, 224))	('pancreatic cancers', 'Disease', 'MESH:D010190', (236, 254))	('gastric cancers', 'Phenotype', 'HP:0012126', (174, 189))	('ARID1B', 'Gene', (226, 232))	('gastric cancer', 'Phenotype', 'HP:0012126', (174, 188))	('ARID1B', 'Gene', '57492', (226, 232))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
320997	26812616	It was found that genetic and epigenetic alterations of the SWI/SNF complex are present in ESCCs, and it was suggested that genetic alterations are induced at an early stage of esophageal squamous cell carcinogenesis.	('ESCCs', 'Disease', (91, 96))	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (177, 216))	('esophageal squamous cell carcinogenesis', 'Disease', (177, 216))	('epigenetic', 'Var', (30, 40))	('SWI/SNF complex', 'Gene', (60, 75))
321002	26812616	Nine human ESCC cell lines, KYSE30, KYSE140, KYSE170, KYSE180, KYSE220, KYSE270, KYSE410, KYSE450, and KYSE510, were obtained from the Japanese Collection of Research Bioresources (JCRB) Cell Bank.	('KYSE170', 'Var', (45, 52))	('KYSE410', 'Var', (81, 88))	('KYSE270', 'Var', (72, 79))	('KYSE180', 'Var', (54, 61))	('KYSE30', 'Var', (28, 34))	('KYSE450', 'Var', (90, 97))	('KYSE220', 'Var', (63, 70))	('human', 'Species', '9606', (5, 10))	('KYSE140', 'Var', (36, 43))
321004	26812616	KYSE140 was cultured in Ham's F12 medium containing 2% (v/v) FBS; KYSE30, KYSE170, KYSE180, KYSE220, KYSE270, KYSE410, KYSE450, and KYSE510 were cultured in Ham's F12/RPMI1640 medium containing 2% (v/v) FBS; IMR-32 was cultured in MEM medium containing 10% (v/v) FBS and non-essential amino acid (NEAA); and KELLY was cultured in RPMI1640 medium containing 10% (v/v) FBS.	('FBS', 'Disease', (203, 206))	('KYSE180', 'Var', (83, 90))	('FBS', 'Disease', 'MESH:D005198', (263, 266))	('KYSE220', 'Var', (92, 99))	('FBS', 'Disease', 'MESH:D005198', (61, 64))	('FBS', 'Disease', 'MESH:D005198', (367, 370))	('KYSE30', 'Var', (66, 72))	('FBS', 'Disease', (263, 266))	('FBS', 'Disease', 'MESH:D005198', (203, 206))	('KYSE170', 'Var', (74, 81))	('FBS', 'Disease', (61, 64))	('KYSE270', 'Var', (101, 108))	('FBS', 'Disease', (367, 370))
321010	26812616	The cancer cell fraction of an ESCC sample with mutation(s) of the SWI/SNF complex was analyzed by measuring DNA methylation levels of three genomic regions, TFAP2B, ARHGEF4, and RAPGEFL1, which are specifically methylated in ESCC cells.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('TFAP2B', 'Gene', (158, 164))	('ARHGEF4', 'Gene', (166, 173))	('mutation', 'Var', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('DNA methylation levels', 'MPA', (109, 131))
321016	26812616	The association between SWI/SNF alterations, namely SWI/SNF mutations and ACTL6B methylation, and tumor characteristics, namely clinical T stage, clinical N stage, and clinical M stage, was evaluated by the Fisher exact test.	('clinical', 'Species', '191496', (128, 136))	('SWI/SNF', 'Gene', (24, 31))	('clinical', 'Species', '191496', (146, 154))	('ACTL6B', 'Gene', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('SWI/SNF', 'Gene', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (60, 69))	('clinical', 'Species', '191496', (168, 176))
321018	26812616	The PBRM1 mutations were located in the bromodomain (80Asn>Ser) and the HMG-box domain (1377Glu>Lys).	('80Asn>Ser', 'Mutation', 'rs1195663483', (53, 62))	('PBRM1', 'Gene', (4, 9))	('1377Glu>Lys', 'Mutation', 'p.E1377K', (88, 99))	('mutations', 'Var', (10, 19))	('1377Glu>Lys', 'Var', (88, 99))
321019	26812616	To analyze the timing of the somatic mutations of the SWI/SNF complex, a cancer cell fraction was estimated for each of the eight ESCC samples with mutation(s) of the SWI/SNF complex, and the association between the fraction and mutant allele frequency was analyzed.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutation', 'Var', (148, 156))	('SWI/SNF', 'Gene', (167, 174))
321020	26812616	Theoretically, in the case that all the cancer cells in an ESCC sample have a somatic mutation on one allele of a specific gene and allelic imbalance of the region is absent, a mutant allele frequency is expected to be 50% of a cancer cell fraction (Fig 2A).	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('mutant', 'Var', (177, 183))	('mutation', 'Var', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('imbalance', 'Phenotype', 'HP:0002172', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
321021	26812616	The mutant allele frequency of five of the eight ESCC samples (#85, #89, #94, #127, and #169) was lower than their cancer cell fraction in the same samples, and ranged from 31 to 77% (mean 61%) of the cancer cell fraction (Fig 2B).	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (115, 121))	('#85', 'Var', (63, 66))	('mutant', 'Var', (4, 10))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('ESCC', 'Disease', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('lower', 'NegReg', (98, 103))
321022	26812616	In contrast, the mutant allele frequency of the other three ESCC samples (#20, #126, and #176) was higher than their cancer cell fraction, and ranged from 107% to 145% (mean 121%) of the cancer cell fraction (Fig 2B).	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (187, 193))	('higher', 'PosReg', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (117, 123))	('mutant', 'Var', (17, 23))
321023	26812616	This result showed that most of the cancer cells in some ESCC samples had SWI/SNF mutations on one allele, and suggested that somatic mutations of the SWI/SNF complex are induced at an early stage of esophageal cell carcinogenesis.	('SWI/SNF', 'Gene', (151, 158))	('esophageal cell carcinogenesis', 'Disease', (200, 230))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('esophageal cell carcinogenesis', 'Disease', 'MESH:D063646', (200, 230))	('cancer', 'Disease', (36, 42))	('mutations', 'Var', (82, 91))	('mutations', 'Var', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('SWI/SNF', 'Gene', (74, 81))
321024	26812616	Eighteen of the 52 ESCCs (34.6%) had aberrant methylation of ACTL6B at its promoter CpG island, but normal esophageal sample and non-cancerous tissue sample did not (Fig 3A and 3B).	('ACTL6B', 'Gene', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('methylation', 'MPA', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('aberrant', 'Var', (37, 45))
321026	26812616	To assess the role of aberrant DNA methylation of ACTL6B in esophageal squamous cell carcinogenesis, ACTL6B methylation and expression were analyzed in non-cancerous esophageal tissues.	('aberrant', 'Var', (22, 30))	('non-cancerous esophageal', 'Disease', (152, 176))	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (60, 99))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('non-cancerous esophageal', 'Disease', 'MESH:D004938', (152, 176))	('esophageal squamous cell carcinogenesis', 'Disease', (60, 99))	('ACTL6B', 'Gene', (50, 56))
321027	26812616	This result suggested that ACTL6B methylation was a passenger in esophageal squamous cell carcinogenesis.	('esophageal squamous cell carcinogenesis', 'Disease', (65, 104))	('methylation', 'Var', (34, 45))	('ACTL6B', 'Gene', (27, 33))	('passenger', 'Reg', (52, 61))	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (65, 104))
321031	26812616	Neither somatic mutations of the SWI/SNF complex nor aberrant ACTL6B methylation was associated with clinical T stage, clinical N stage, and clinical M stage (Table 3).	('clinical', 'Species', '191496', (141, 149))	('clinical', 'Species', '191496', (101, 109))	('ACTL6B', 'Gene', (62, 68))	('clinical', 'Species', '191496', (119, 127))	('methylation', 'Var', (69, 80))	('aberrant', 'Var', (53, 61))	('associated', 'Reg', (85, 95))
321032	26812616	Early-stage induction of alterations of the SWI/SNF complex during carcinogenesis has also been suggested for cancers other than ESCCs.	('alterations', 'Var', (25, 36))	('ESCCs', 'Disease', (129, 134))	('carcinogenesis', 'Disease', 'MESH:D063646', (67, 81))	('cancers', 'Disease', (110, 117))	('carcinogenesis', 'Disease', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('SWI/SNF complex', 'Gene', (44, 59))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
321033	26812616	During esophageal adenocarcinoma (EAC) development, somatic mutations of ARID1A and SMARCA4 are already present in benign metaplastic never-dysplastic Barrett's esophagus (NDBE).	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (7, 32))	("dysplastic Barrett's esophagus", 'Disease', (140, 170))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (140, 170))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (151, 170))	('SMARCA4', 'Gene', (84, 91))	('mutations', 'Var', (60, 69))	('ARID1A', 'Gene', (73, 79))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (7, 32))	('esophageal adenocarcinoma', 'Disease', (7, 32))
321034	26812616	During gastric carcinogenesis, aberrant methylation of an ISWI component, SMARCA1, was detected in normal gastric tissues of people infected with Helicobacter pylori, a potent gastric cancer inducer.	('SMARCA1', 'Gene', '6594', (74, 81))	('people', 'Species', '9606', (125, 131))	('detected', 'Reg', (87, 95))	('ISWI', 'Gene', (58, 62))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (7, 29))	('Helicobacter pylori', 'Species', '210', (146, 165))	('Helicobacter', 'Var', (146, 158))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('infected', 'Reg', (132, 140))	('gastric carcinogenesis', 'Disease', (7, 29))	('SMARCA1', 'Gene', (74, 81))	('methylation', 'MPA', (40, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('ISWI', 'Gene', '6594', (58, 62))	('gastric cancer', 'Disease', (176, 190))
321035	26812616	These early induction of genetic and epigenetic alterations of chromatin remodeling factors in multiple types of cancers suggested that their inactivation may be involved in predisposition to cancers (the formation of a field for cancerization).	('epigenetic alterations', 'Var', (37, 59))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancer', 'Disease', (113, 119))	('cancers', 'Disease', (113, 120))	('cancer', 'Disease', (192, 198))	('cancers', 'Disease', (192, 199))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('genetic', 'Var', (25, 32))	('inactivation', 'Var', (142, 154))	('involved', 'Reg', (162, 170))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
321036	26812616	The mutant allele frequencies of three ESCCs (#20, #126, and #176) were higher than their cancer cell fractions.	('#20', 'Var', (46, 49))	('mutant', 'Var', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('#176', 'Var', (61, 65))	('higher', 'PosReg', (72, 78))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
321039	26812616	Therefore, ACTL6B methylation was considered to be a passenger in esophageal squamous cell carcinogenesis.	('esophageal squamous cell carcinogenesis', 'Disease', (66, 105))	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (66, 105))	('ACTL6B', 'Gene', (11, 17))	('methylation', 'Var', (18, 29))
321040	26812616	In contrast, somatic mutations of other components of the SWI/SNF complex were likely to be drivers because the genes with the mutations were expressed in non-cancerous esophageal tissues (Fig 3A).	('mutations', 'Var', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-cancerous esophageal', 'Disease', (155, 179))	('non-cancerous esophageal', 'Disease', 'MESH:D004938', (155, 179))
321041	26812616	Mechanistically, disruption of the SWI/SNF complex has been reported to repress cell growth in other types of cancers.	('cancers', 'Disease', (110, 117))	('repress', 'NegReg', (72, 79))	('SWI/SNF', 'Gene', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('disruption', 'Var', (17, 27))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('cell growth', 'CPA', (80, 91))
321042	26812616	Therefore, it is likely that inactivation of the SWI/SNF complex is involved in esophageal squamous cell carcinogenesis by promoting cell growth rate.	('promoting', 'PosReg', (123, 132))	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (80, 119))	('SWI/SNF', 'Gene', (49, 56))	('esophageal squamous cell carcinogenesis', 'Disease', (80, 119))	('cell growth rate', 'CPA', (133, 149))	('inactivation', 'Var', (29, 41))
321045	26812616	In conclusion, genetic and epigenetic alterations of the SWI/SNF complex are present in ESCCs, and genetic alterations were suggested to have been induced at an early stage of esophageal squamous cell carcinogenesis.	('ESCCs', 'Disease', (88, 93))	('esophageal squamous cell carcinogenesis', 'Disease', (176, 215))	('SWI/SNF complex', 'Gene', (57, 72))	('epigenetic', 'Var', (27, 37))	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (176, 215))
321053	24376537	Surgical and oncological outcomes following McKeown MIE for esophageal cancer were acceptable and comparable with those of open-McKeown esophagectomy.	('MIE', 'Chemical', '-', (52, 55))	('esophageal cancer', 'Disease', (60, 77))	('McKeown MIE', 'Var', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
321137	24376537	The potential benefits of McKeown MIE are a more proximal resection margin and improved lymph node dissection.	('improved', 'PosReg', (79, 87))	('MIE', 'Chemical', '-', (34, 37))	('McKeown', 'Var', (26, 33))	('lymph node dissection', 'CPA', (88, 109))
321160	24376537	In our study, anastomotic leak occurred in 9 of 142 patients who underwent the McKeown MIE, which was similar to most other reported series of MIE approaches.	('MIE', 'Chemical', '-', (87, 90))	('anastomotic leak', 'Disease', 'MESH:D057868', (14, 30))	('anastomotic leak', 'Disease', (14, 30))	('McKeown', 'Var', (79, 86))	('MIE', 'Chemical', '-', (143, 146))	('patients', 'Species', '9606', (52, 60))
321179	24376537	Based on our experience and an analysis of the current literature, the McKeown MIE was associated with lower morbidity and mortality than the conventional open esophagectomy, especially for patients with early esophageal cancer.	('MIE', 'Chemical', '-', (79, 82))	('patients', 'Species', '9606', (190, 198))	('esophageal cancer', 'Disease', (210, 227))	('McKeown MIE', 'Var', (71, 82))	('lower', 'NegReg', (103, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (210, 227))	('morbidity', 'CPA', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))
321235	33138335	Conversely, 12 of the 33 patients (36.4%) with FIB-4 values <3.20 had all-grade varices, none of which were high-risk varices (Supplemental Figure S1).	('FIB-4', 'Gene', (47, 52))	('patients', 'Species', '9606', (25, 33))	('all-grade', 'Disease', (70, 79))	('<3.20', 'Var', (60, 65))
321237	33138335	Conversely, 25 of the 71 patients (35.2%) with FIB-4 values < 3.20 had all-grade varices.	('FIB-4', 'Gene', (47, 52))	('< 3.20', 'Var', (60, 66))	('all-grade', 'Disease', (71, 80))	('patients', 'Species', '9606', (25, 33))
321280	32296585	High-throughput metabolomics techniques can facilitate comprehensive identification and quantitative profiling of the entire spectrum of endogenous low molecular weight metabolites (< 1000 Da) in a single sample, which may not only aid in identifying promising novel biomarkers but also provide insights into cancer etiology, leading to the development of novel preventive approaches and therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('aid', 'Reg', (232, 235))	('insights', 'Reg', (295, 303))	('< 1000', 'Var', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('cancer', 'Disease', (309, 315))
321294	32296585	Metabolites of carbohydrate metabolism have been previously associated with UGI cancers (Table 2).	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('UGI cancers', 'Disease', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Metabolites', 'Var', (0, 11))	('carbohydrate', 'Chemical', 'MESH:D002241', (15, 27))	('associated', 'Reg', (60, 70))	('UGI cancers', 'Disease', 'MESH:D009369', (76, 87))
321304	32296585	Alterations in essential and non-essential amino acids were reported for UGI cancers (Table 3), the most frequent being valine, glutamate, and glutamine.	('glutamate', 'MPA', (128, 137))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('UGI cancers', 'Disease', (73, 84))	('Alterations', 'Var', (0, 11))	('valine', 'Chemical', 'MESH:D014633', (120, 126))	('valine', 'Var', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('glutamate', 'Chemical', 'MESH:D018698', (128, 137))	('glutamine', 'Var', (143, 152))	('glutamine', 'Chemical', 'MESH:D005973', (143, 152))	('UGI cancers', 'Disease', 'MESH:D009369', (73, 84))
321308	32296585	In addition, alterations in tryptophan were frequently reported in UGI cancers.	('tryptophan', 'Chemical', 'MESH:D014364', (28, 38))	('UGI cancers', 'Disease', 'MESH:D009369', (67, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('reported', 'Reg', (55, 63))	('UGI cancers', 'Disease', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tryptophan', 'MPA', (28, 38))	('alterations', 'Var', (13, 24))
321317	32296585	Metabolites of free fatty acid (FFA) oxidation are additionally known to be associated with UGI cancers.	('FFA', 'Chemical', 'MESH:D005230', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('associated', 'Reg', (76, 86))	('Metabolites', 'Var', (0, 11))	('UGI cancers', 'Disease', (92, 103))	('UGI cancers', 'Disease', 'MESH:D009369', (92, 103))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('free fatty acid', 'Chemical', 'MESH:D005230', (15, 30))
321331	32296585	Metabolic alterations have been shown to be closely associated with GC and EC, raising the profile of metabolomics as a promising tool for etiologic research and biomarker screening of UGI cancers.	('UGI cancers', 'Disease', (185, 196))	('alterations', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('associated', 'Reg', (52, 62))	('Metabolic', 'MPA', (0, 9))	('UGI cancers', 'Disease', 'MESH:D009369', (185, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('GC', 'Phenotype', 'HP:0012126', (68, 70))
321338	32296585	Although cancer cells favor glycolysis over oxidative phosphorylation, the increase in TCA cycle metabolites may rely on the process of anaplerosis, which refers to replenishment of TCA metabolites via generation of alpha-ketoglutarate from the source of glutamate by deaminating glutamine.	('cancer', 'Disease', (9, 15))	('deaminating', 'Var', (268, 279))	('glutamine', 'Protein', (280, 289))	('TCA', 'Chemical', 'MESH:D014233', (182, 185))	('glutamine', 'Chemical', 'MESH:D005973', (280, 289))	('TCA cycle metabolites', 'MPA', (87, 108))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TCA', 'Chemical', 'MESH:D014233', (87, 90))	('oxidative phosphorylation', 'MPA', (44, 69))	('glutamate', 'Chemical', 'MESH:D018698', (255, 264))	('glycolysis', 'MPA', (28, 38))	('increase', 'PosReg', (75, 83))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (216, 235))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
321339	32296585	The present review revealed frequent aberrant metabolism of glutamine and glutamate in UGI cancer patients, supporting the importance of the pathway in this cancer type.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('glutamate', 'Chemical', 'MESH:D018698', (74, 83))	('patients', 'Species', '9606', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('glutamine', 'Chemical', 'MESH:D005973', (60, 69))	('aberrant', 'Var', (37, 45))
321343	32296585	Prior studies have also reported alterations in tryptophan and kynurenine in UGI cancers, indicating that potential metabolic perturbations of the tryptophan/kynurenine catabolism pathway are associated with development of EC and GC.	('tryptophan', 'Chemical', 'MESH:D014364', (48, 58))	('tryptophan', 'Chemical', 'MESH:D014364', (147, 157))	('GC', 'Phenotype', 'HP:0012126', (230, 232))	('associated', 'Reg', (192, 202))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('kynurenine', 'Chemical', 'MESH:D007737', (158, 168))	('UGI cancers', 'Disease', 'MESH:D009369', (77, 88))	('alterations', 'Var', (33, 44))	('kynurenine', 'Chemical', 'MESH:D007737', (63, 73))	('UGI cancers', 'Disease', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
321369	30784231	Correlation between PLCE1 rs2274223 variant and digestive tract cancer: A meta-analysis The relationship between phospholipase C epsilon-1 (PLCE1) rs2274223 variant and digestive tract cancer remains inconclusive despite extensive investigations.	('tract cancer', 'Disease', 'MESH:D014571', (179, 191))	('tract cancer', 'Disease', 'MESH:D014571', (58, 70))	('phospholipase C epsilon-1', 'Gene', (113, 138))	('tract cancer', 'Disease', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tract cancer', 'Disease', (58, 70))	('phospholipase C epsilon-1', 'Gene', '51196', (113, 138))	('rs2274223', 'Mutation', 'rs2274223', (26, 35))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (48, 70))	('PLCE1', 'Gene', (140, 145))	('PLCE1', 'Gene', '51196', (140, 145))	('rs2274223', 'Var', (26, 35))	('PLCE1', 'Gene', (20, 25))	('PLCE1', 'Gene', '51196', (20, 25))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (169, 191))	('rs2274223', 'Mutation', 'rs2274223', (147, 156))	('rs2274223', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
321370	30784231	Pooled analyses suggested that PLCE1 rs2274223 variant was significantly correlated with the likelihood of esophageal cancer (dominant model: p < 0.001, OR = 0.77, 95% CI 0.72-0.83; recessive model: p < 0.001, OR = 1.28, 95% CI 1.12-1.45; additive model: p < 0.001, OR = 1.20, 95% CI 1.11-1.29; allele model: p < 0.001, OR = 0.80, 95% CI 0.74-0.88) and gastric cancer (recessive model: p = 0.001, OR = 1.27, 95% CI 1.10-1.47; allele model: p = 0.03, OR = 0.88, 95% CI 0.78-0.98) in overall population.	('gastric cancer', 'Phenotype', 'HP:0012126', (353, 367))	('PLCE1', 'Gene', '51196', (31, 36))	('esophageal cancer', 'Disease', (107, 124))	('rs2274223', 'Mutation', 'rs2274223', (37, 46))	('rs2274223', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('gastric cancer', 'Disease', (353, 367))	('gastric cancer', 'Disease', 'MESH:D013274', (353, 367))	('PLCE1', 'Gene', (31, 36))
321371	30784231	Our findings indicated that the PLCE1 rs2274223 variant might serve as a promising genetic biomarker of esophageal and gastric cancer in East Asians.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('esophageal', 'Disease', 'MESH:D004941', (104, 114))	('PLCE1', 'Gene', (32, 37))	('gastric cancer', 'Disease', (119, 133))	('PLCE1', 'Gene', '51196', (32, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('rs2274223', 'Mutation', 'rs2274223', (38, 47))	('esophageal', 'Disease', (104, 114))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('rs2274223', 'Var', (38, 47))
321379	30784231	Consequently, it is speculated that functional PLCE1 polymorphisms may be implicated in the pathogenesis of multiple malignant disorders.	('PLCE1', 'Gene', (47, 52))	('implicated', 'Reg', (74, 84))	('PLCE1', 'Gene', '51196', (47, 52))	('malignant disorders', 'Disease', (117, 136))	('malignant disorders', 'Disease', 'MESH:D009369', (117, 136))	('polymorphisms', 'Var', (53, 66))
321381	30784231	So far, some pilot studies were already conducted to investigate possible correlations between PLCE1 rs2274223 variant and the likelihood of digestive tract cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tract cancer', 'Disease', 'MESH:D014571', (151, 163))	('rs2274223', 'Var', (101, 110))	('tract cancer', 'Disease', (151, 163))	('PLCE1', 'Gene', (95, 100))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (141, 163))	('PLCE1', 'Gene', '51196', (95, 100))	('rs2274223', 'Mutation', 'rs2274223', (101, 110))
321382	30784231	Therefore, we conducted this meta-analysis to better analyze the roles of PLCE1 rs2274223 variant in digestive tract cancer.	('rs2274223', 'Mutation', 'rs2274223', (80, 89))	('rs2274223', 'Var', (80, 89))	('PLCE1', 'Gene', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PLCE1', 'Gene', '51196', (74, 79))	('tract cancer', 'Disease', 'MESH:D014571', (111, 123))	('tract cancer', 'Disease', (111, 123))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (101, 123))
321384	30784231	To test the research hypothesis of this meta-analysis, included studies should meet all the following criteria: (a) case-control study on correlations between PLCE1 rs2274223 variant and the likelihood of digestive tract cancer; (b) provide adequate data to calculate odds ratios (ORs) and 95% confidence intervals (CIs); (c) full text in English available.	('PLCE1', 'Gene', (159, 164))	('PLCE1', 'Gene', '51196', (159, 164))	('rs2274223', 'Mutation', 'rs2274223', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tract cancer', 'Disease', 'MESH:D014571', (215, 227))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (205, 227))	('rs2274223', 'Var', (165, 174))	('correlations', 'Interaction', (138, 150))	('tract cancer', 'Disease', (215, 227))
321385	30784231	Studies were excluded if one of the following criteria was fulfilled: (a) not relevant to PLCE1 rs2274223 variant and digestive tract cancer; (b) family-based association studies; (c) case reports or case series; (d) abstracts, reviews, comments, letters, and conference presentations.	('rs2274223', 'Mutation', 'rs2274223', (96, 105))	('rs2274223', 'Var', (96, 105))	('PLCE1', 'Gene', (90, 95))	('PLCE1', 'Gene', '51196', (90, 95))	('tract cancer', 'Disease', (128, 140))	('tract cancer', 'Disease', 'MESH:D014571', (128, 140))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (118, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
321386	30784231	The following data were extracted from all included studies: (a) the first author; (b) year of publication; (c) country and ethnicity of study subjects; (d) sample size; and (e) the distribution of PLCE1 rs2274223 variant in cases and controls.	('PLCE1', 'Gene', (198, 203))	('PLCE1', 'Gene', '51196', (198, 203))	('rs2274223', 'Mutation', 'rs2274223', (204, 213))	('rs2274223', 'Var', (204, 213))
321387	30784231	Moreover, the probability value (p value) of Hardy-Weinberg equilibrium (HWE) was also calculated based on genotypic frequency of PLCE1 rs2274223 variant in the control group.	('Hardy-Weinberg equilibrium', 'Disease', (45, 71))	('rs2274223', 'Mutation', 'rs2274223', (136, 145))	('rs2274223', 'Var', (136, 145))	('PLCE1', 'Gene', (130, 135))	('PLCE1', 'Gene', '51196', (130, 135))
321388	30784231	We calculated ORs and 95% CIs to estimate associations of PLCE1 rs2274223 variant with the likelihood of digestive tract cancer in dominant (AA vs. AG + GG), recessive (GG vs. AA + AG), additive (AG vs. AA + GG) and allele (A vs. G) models, and a p value of 0.05 or less was considered to be statistically significant.	('digestive tract cancer', 'Phenotype', 'HP:0007378', (105, 127))	('associations', 'Interaction', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tract cancer', 'Disease', 'MESH:D014571', (115, 127))	('tract cancer', 'Disease', (115, 127))	('rs2274223', 'Mutation', 'rs2274223', (64, 73))	('rs2274223', 'Var', (64, 73))	('PLCE1', 'Gene', (58, 63))	('PLCE1', 'Gene', '51196', (58, 63))
321390	30784231	Among included studies for PLCE1 rs2274223 variant and digestive tract cancer, fifteen studies were about esophageal cancer (7,907 cases and 12,141 controls), ten studies were about gastric cancer (9,783 cases and 9,904 controls) and four studies were about colorectal cancer (1,040 cases and 1,314 controls).	('digestive tract cancer', 'Phenotype', 'HP:0007378', (55, 77))	('gastric cancer', 'Disease', (182, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (258, 275))	('rs2274223', 'Mutation', 'rs2274223', (33, 42))	('rs2274223', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal cancer', 'Disease', (106, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))	('tract cancer', 'Disease', 'MESH:D014571', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('PLCE1', 'Gene', (27, 32))	('PLCE1', 'Gene', '51196', (27, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (258, 275))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('tract cancer', 'Disease', (65, 77))	('colorectal cancer', 'Disease', (258, 275))
321392	30784231	To the best of our knowledge, this is so far the most comprehensive meta-analysis on correlations between PLCE1 rs2274223 variant and digestive tract cancer, and our pooled analyses showed that the PLCE1 rs2274223 variant may serve as a genetic biomarker of esophageal cancer and gastric cancer in East Asians.	('tract cancer', 'Disease', (144, 156))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (134, 156))	('PLCE1', 'Gene', (198, 203))	('gastric cancer', 'Disease', 'MESH:D013274', (280, 294))	('PLCE1', 'Gene', '51196', (198, 203))	('esophageal cancer', 'Disease', 'MESH:D004938', (258, 275))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('esophageal cancer', 'Disease', (258, 275))	('rs2274223', 'Mutation', 'rs2274223', (112, 121))	('rs2274223', 'Var', (112, 121))	('gastric cancer', 'Phenotype', 'HP:0012126', (280, 294))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('PLCE1', 'Gene', (106, 111))	('PLCE1', 'Gene', '51196', (106, 111))	('tract cancer', 'Disease', 'MESH:D014571', (144, 156))	('rs2274223', 'Mutation', 'rs2274223', (204, 213))	('rs2274223', 'Var', (204, 213))	('gastric cancer', 'Disease', (280, 294))
321393	30784231	First, previous experimental studies revealed that the PLCE1 rs2274223 variant was correlated with an Arg-to-His change of PLCE1 protein, which may result in abnormal enzymatic activity and give rise to the development of multiple malignancies including digestive tract cancer (Ezgi et al., 2016; Palmer et al., 2012; Yang et al., 2012).	('His', 'Chemical', 'MESH:D006639', (109, 112))	('multiple malignancies', 'Disease', (222, 243))	('give rise to', 'Reg', (190, 202))	('PLCE1', 'Gene', (55, 60))	('PLCE1', 'Gene', '51196', (55, 60))	('abnormal', 'Reg', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('tract cancer', 'Disease', 'MESH:D014571', (264, 276))	('enzymatic activity', 'MPA', (167, 185))	('PLCE1', 'Gene', (123, 128))	('Arg-to-His', 'MPA', (102, 112))	('Arg', 'Chemical', 'MESH:D001120', (102, 105))	('PLCE1', 'Gene', '51196', (123, 128))	('result', 'Reg', (148, 154))	('tract cancer', 'Disease', (264, 276))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (254, 276))	('multiple malignancies', 'Disease', 'MESH:D009369', (222, 243))	('rs2274223', 'Mutation', 'rs2274223', (61, 70))	('rs2274223', 'Var', (61, 70))	('protein', 'Protein', (129, 136))
321396	30784231	Therefore, to better illustrate potential correlations of certain genetic variant with digestive tract cancer, we strongly recommend further studies to perform haplotype analyses and explore potential gene-gene interactions.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (87, 109))	('tract cancer', 'Disease', 'MESH:D014571', (97, 109))	('variant', 'Var', (74, 81))	('tract cancer', 'Disease', (97, 109))	('correlations', 'Interaction', (42, 54))
321398	30784231	Third, associations between PLCE1 rs2274223 variant and digestive tract cancer may also be influenced by gene-gene and gene-environmental interactions.	('associations', 'Interaction', (7, 19))	('tract cancer', 'Disease', 'MESH:D014571', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('influenced', 'Reg', (91, 101))	('tract cancer', 'Disease', (66, 78))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (56, 78))	('rs2274223', 'Mutation', 'rs2274223', (34, 43))	('rs2274223', 'Var', (34, 43))	('PLCE1', 'Gene', (28, 33))	('PLCE1', 'Gene', '51196', (28, 33))
321399	30784231	Overall, our meta-analysis suggested that the PLCE1 rs2274223 variant might serve as a potential biological marker of esophageal and gastric cancer in East Asians.	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('rs2274223', 'Var', (52, 61))	('PLCE1', 'Gene', (46, 51))	('PLCE1', 'Gene', '51196', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('esophageal', 'Disease', 'MESH:D004941', (118, 128))	('gastric cancer', 'Disease', (133, 147))	('esophageal', 'Disease', (118, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (133, 147))	('rs2274223', 'Mutation', 'rs2274223', (52, 61))
321400	30784231	Moreover, future investigations are needed to explore potential roles of PLCE1 rs2274223 variant in the development of other types of cancer.	('PLCE1', 'Gene', (73, 78))	('PLCE1', 'Gene', '51196', (73, 78))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('rs2274223', 'Mutation', 'rs2274223', (79, 88))	('rs2274223', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
321401	30510552	Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1 Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency.	('autosomal recessive disease', 'Disease', (156, 183))	('Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type', 'Disease', 'MESH:D002178', (0, 75))	('hypoparathyroidism', 'Disease', (325, 343))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (349, 370))	('chronic mucocutaneous candidiasis', 'Phenotype', 'HP:0002728', (284, 317))	('AIRE', 'Gene', (233, 237))	('AIRE', 'Gene', '326', (233, 237))	('caused by', 'Reg', (184, 193))	('hypoparathyroidism', 'Phenotype', 'HP:0000829', (325, 343))	('Chronic Mucocutaneous Candidiasis', 'Phenotype', 'HP:0002728', (0, 33))	('adrenal insufficiency', 'Disease', (349, 370))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (156, 183))	('autoimmune regulator', 'Gene', '326', (211, 231))	('ectodermal dystrophy', 'Phenotype', 'HP:0000968', (120, 140))	('autoimmune regulator', 'Gene', (211, 231))	('chronic mucocutaneous candidiasis', 'Disease', (284, 317))	('chronic mucocutaneous candidiasis', 'Disease', 'MESH:D002178', (284, 317))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (349, 370))	('APECED', 'Gene', (142, 148))	('hypoparathyroidism', 'Disease', 'MESH:D007011', (325, 343))	('mutations', 'Var', (194, 203))	('polyendocrinopathy candidiasis', 'Phenotype', 'HP:0005411', (89, 119))	('Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy', 'Disease', 'MESH:D016884', (78, 140))	('CMC', 'Phenotype', 'HP:0002728', (319, 322))	('APECED', 'Gene', '326', (142, 148))
321405	30510552	CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene.	('cytokine production', 'MPA', (157, 176))	('IL-17', 'Gene', '3605', (107, 112))	('AIRE', 'Gene', (243, 247))	('IL-17', 'Gene', (107, 112))	('AIRE', 'Gene', '326', (243, 247))	('Th17 cell response', 'CPA', (35, 53))	('defect in cytokine production', 'Phenotype', 'HP:0031407', (147, 176))	('CMC', 'Disease', (0, 3))	('mutations', 'Var', (226, 235))	('CMC', 'Phenotype', 'HP:0002728', (0, 3))	('decreased', 'NegReg', (91, 100))
321410	30510552	APS-1 is a monogenic, autosomal, recessive disease caused by a mutation in the autoimmune regulator (AIRE) gene on chromosome 21 (gene map locus 21q22.3).	('AIRE', 'Gene', '326', (101, 105))	('APS-1', 'Gene', '326', (0, 5))	('APS-1', 'Gene', (0, 5))	('recessive disease', 'Disease', 'MESH:D030342', (33, 50))	('mutation', 'Var', (63, 71))	('recessive disease', 'Disease', (33, 50))	('AIRE', 'Gene', (101, 105))	('autoimmune regulator', 'Gene', (79, 99))	('autoimmune regulator', 'Gene', '326', (79, 99))	('caused by', 'Reg', (51, 60))
321418	30510552	CMC is associated with the Finnish mutation c.769C>T (p.Arg257stop).	('p.Arg257stop', 'Mutation', 'rs121434254', (54, 66))	('c.769C>T', 'Var', (44, 52))	('associated', 'Reg', (7, 17))	('CMC', 'Disease', (0, 3))	('Finnish', 'Gene', (27, 34))	('CMC', 'Phenotype', 'HP:0002728', (0, 3))	('c.769C>T', 'Mutation', 'rs121434254', (44, 52))
321436	30510552	HIES, CARD9, IL12Rb1 deficiency, GOF-STAT1, and APECED/APS1 are syndromes where CMC has additional specific clinical features.	('HIES', 'Disease', 'MESH:D007589', (0, 4))	('APS1', 'Gene', '326', (55, 59))	('CMC', 'Phenotype', 'HP:0002728', (80, 83))	('CARD9', 'Gene', (6, 11))	('deficiency', 'Var', (21, 31))	('CARD9', 'Gene', '64170', (6, 11))	('IL12Rb1', 'Gene', '3594', (13, 20))	('STAT1', 'Gene', (37, 42))	('HIES', 'Disease', (0, 4))	('IL12Rb1', 'Gene', (13, 20))	('APS1', 'Gene', (55, 59))	('APECED', 'Gene', '326', (48, 54))	('STAT1', 'Gene', '6772', (37, 42))	('APECED', 'Gene', (48, 54))
321439	30510552	Recent literature has also described an autosomal recessive hyper-IgE syndrome (AR-HIES), caused by a deficiency in DOCK8, resulting in a variety of symptoms and diseases including atopy, autoimmunity risk, malignancies, recurrent viral/bacterial infections, and CMC.	('autosomal recessive hyper-IgE syndrome', 'Disease', (40, 78))	('DOCK8', 'Gene', (116, 121))	('HIES', 'Disease', 'MESH:D007589', (83, 87))	('CMC', 'Phenotype', 'HP:0002728', (263, 266))	('autoimmunity', 'Disease', (188, 200))	('malignancies', 'Disease', 'MESH:D009369', (207, 219))	('caused by', 'Reg', (90, 99))	('malignancies', 'Disease', (207, 219))	('CMC', 'Disease', (263, 266))	('deficiency', 'Var', (102, 112))	('autosomal recessive hyper-IgE syndrome', 'Disease', 'MESH:D007589', (40, 78))	('DOCK8', 'Gene', '81704', (116, 121))	('bacterial infections', 'Disease', (237, 257))	('autoimmunity', 'Disease', 'MESH:D001327', (188, 200))	('autoimmunity', 'Phenotype', 'HP:0002960', (188, 200))	('HIES', 'Disease', (83, 87))	('bacterial infections', 'Phenotype', 'HP:0002718', (237, 257))	('resulting in', 'Reg', (123, 135))	('bacterial infections', 'Disease', 'MESH:D001424', (237, 257))
321440	30510552	Patients who are deficient in DOCK8 have decreased Th17 cells.	('decreased', 'NegReg', (41, 50))	('DOCK8', 'Gene', (30, 35))	('Th17 cells', 'CPA', (51, 61))	('Patients', 'Species', '9606', (0, 8))	('deficient', 'Var', (17, 26))	('DOCK8', 'Gene', '81704', (30, 35))
321449	30510552	In humans, a mutation in the early-stop codon for Dectin-1 (Y238X) has been reported in a family with recurrent vulvovaginal candidiasis.	('Dectin-1', 'Gene', '64581', (50, 58))	('Y238X', 'Mutation', 'rs16910526', (60, 65))	('reported', 'Reg', (76, 84))	('vulvovaginal candidiasis', 'Disease', (112, 136))	('Y238X', 'Var', (60, 65))	('vulvovaginal candidiasis', 'Disease', 'MESH:D002181', (112, 136))	('humans', 'Species', '9606', (3, 9))	('recurrent vulvovaginal candidiasis', 'Phenotype', 'HP:0012204', (102, 136))	('Dectin-1', 'Gene', (50, 58))
321452	30510552	Another report demonstrated that patients receiving hematopoietic stem cell transplants who were heterozygous for Y238X had an increased incidence of gastrointestinal Candida colonization.	('patients', 'Species', '9606', (33, 41))	('Y238X', 'Var', (114, 119))	('gastrointestinal Candida', 'Disease', 'MESH:C536777', (150, 174))	('gastrointestinal Candida', 'Disease', (150, 174))	('Y238X', 'Mutation', 'rs16910526', (114, 119))	('increased incidence of gastrointestinal Candida', 'Phenotype', 'HP:0005401', (127, 174))
321453	30510552	Although Dectin-2-deficient mice had higher mortality and a higher kidney fungal burden after infection with C. albicans, the impact of Dectin-2 mutations on the human host response to C. albicans infection remains unclear.	('higher', 'PosReg', (37, 43))	('higher', 'PosReg', (60, 66))	('kidney fungal burden', 'Disease', 'MESH:D009181', (67, 87))	('mutations', 'Var', (145, 154))	('mice', 'Species', '10090', (28, 32))	('C. albicans', 'Species', '5476', (109, 120))	('Dectin-2', 'Gene', (136, 144))	('infection', 'Disease', (94, 103))	('human', 'Species', '9606', (162, 167))	('Dectin-2', 'Gene', '56620', (9, 17))	('infection', 'Disease', 'MESH:D007239', (94, 103))	('Dectin-2', 'Gene', '56620', (136, 144))	('higher kidney', 'Phenotype', 'HP:0000105', (60, 73))	('C. albicans', 'Species', '5476', (185, 196))	('kidney fungal burden', 'Disease', (67, 87))	('infection', 'Disease', (197, 206))	('Dectin-2', 'Gene', (9, 17))	('infection', 'Disease', 'MESH:D007239', (197, 206))
321455	30510552	Patients with CMC, autoimmune manifestations, other mild bacterial or viral infections, intracranial aneurysms, or SCC also had heterozygous missense gain-of-function (GOF) mutations of STAT1.	('autoimmune manifestations', 'Phenotype', 'HP:0002960', (19, 44))	('gain-of-function', 'PosReg', (150, 166))	('intracranial aneurysms', 'Phenotype', 'HP:0004944', (88, 110))	('mutations', 'Var', (173, 182))	('STAT1', 'Gene', (186, 191))	('STAT1', 'Gene', '6772', (186, 191))	('missense', 'Var', (141, 149))	('SCC', 'Gene', (115, 118))	('viral infections', 'Disease', 'MESH:D001102', (70, 86))	('CMC', 'Disease', (14, 17))	('intracranial aneurysms', 'Disease', 'MESH:D002532', (88, 110))	('Patients', 'Species', '9606', (0, 8))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('aneurysms', 'Phenotype', 'HP:0002617', (101, 110))	('intracranial aneurysms', 'Disease', (88, 110))	('viral infections', 'Disease', (70, 86))	('SCC', 'Gene', '6317', (115, 118))	('CMC', 'Phenotype', 'HP:0002728', (14, 17))
321482	30510552	The prevalence of CMC is reportedly higher in patients with the major Finnish AIRE mutation R257X than with other mutations.	('CMC', 'Phenotype', 'HP:0002728', (18, 21))	('higher', 'PosReg', (36, 42))	('patients', 'Species', '9606', (46, 54))	('AIRE', 'Gene', (78, 82))	('AIRE', 'Gene', '326', (78, 82))	('R257X', 'Var', (92, 97))	('R257X', 'Mutation', 'rs121434254', (92, 97))	('CMC', 'Disease', (18, 21))
321483	30510552	The prevalence is <20% in Iranian Jews affected by the Y85C mutation.	('Y85C', 'Mutation', 'rs179363882', (55, 59))	('Iranian Jews', 'Disease', (26, 38))	('Y85C', 'Var', (55, 59))
321484	30510552	studied 160 APECED patients with the most severe mutations, R257X (Finnish) and R139X (Sardinian) and the Norwegian mutation, 967-979Delta13 In contrast to the study of Puel et al., CMC was less prevalent in patients with the homozygous mutation 967-979Delta13 than with the other two mutations.	('967-979Delta13', 'Var', (246, 260))	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (19, 27))	('APECED', 'Gene', '326', (12, 18))	('R139X', 'Var', (80, 85))	('CMC', 'Disease', (182, 185))	('APECED', 'Gene', (12, 18))	('CMC', 'Phenotype', 'HP:0002728', (182, 185))	('R257X', 'Mutation', 'rs121434254', (60, 65))	('R139X', 'Mutation', 'rs121434256', (80, 85))	('R257X', 'Var', (60, 65))
321502	30510552	Extrinsic factors include alcohol, tobacco, betel quid, immunosuppression, radiation, oncogenic viruses (human papilloma virus), and Candida infection, while intrinsic factors include immune defects, iron or vitamin A deficiency, malnutrition, and defects in tumor suppressor genes.	('human papilloma virus', 'Species', '10566', (105, 126))	('immune defects', 'Phenotype', 'HP:0002721', (184, 198))	('alcohol', 'Chemical', 'MESH:D000438', (26, 33))	('Candida infection', 'Disease', 'MESH:C536777', (133, 150))	('defects', 'Var', (248, 255))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('vitamin A deficiency', 'Phenotype', 'HP:0004905', (208, 228))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('iron', 'Chemical', 'MESH:D007501', (200, 204))	('tobacco', 'Species', '4097', (35, 42))	('A deficiency, malnutrition', 'Disease', 'MESH:D044342', (216, 242))	('tumor', 'Disease', (259, 264))	('malnutrition', 'Phenotype', 'HP:0004395', (230, 242))	('papilloma', 'Phenotype', 'HP:0012740', (111, 120))	('Candida infection', 'Disease', (133, 150))
321524	30510552	The major molecular mechanisms leading to azole resistance were GOF mutations in TAC1, contributing to overexpression of CDR1 and CDR2, point mutations in ERG11, and six new TAC1 mutations were detected.	('leading', 'Reg', (31, 38))	('CDR2', 'Gene', '1039', (130, 134))	('TAC1', 'Gene', '6863', (174, 178))	('ERG11', 'Gene', (155, 160))	('point mutations', 'Var', (136, 151))	('TAC1', 'Gene', (81, 85))	('TAC1', 'Gene', (174, 178))	('CDR1', 'Gene', '1038', (121, 125))	('overexpression', 'PosReg', (103, 117))	('CDR2', 'Gene', (130, 134))	('azole resistance', 'MPA', (42, 58))	('mutations', 'Var', (68, 77))	('CDR1', 'Gene', (121, 125))	('GOF', 'PosReg', (64, 67))	('TAC1', 'Gene', '6863', (81, 85))	('azole', 'Chemical', 'MESH:D001393', (42, 47))
321550	30510552	who reported that autoantibodies neutralizing IL-22 and IL-17F (but not those against IL-17A) were correlated with CMC in a study of 162 APECED patients, a study by Sarkadi et al.	('neutralizing', 'Var', (33, 45))	('CMC', 'Phenotype', 'HP:0002728', (115, 118))	('CMC', 'Disease', (115, 118))	('IL-22', 'Gene', (46, 51))	('IL-17F', 'Gene', '112744', (56, 62))	('patients', 'Species', '9606', (144, 152))	('APECED', 'Gene', '326', (137, 143))	('correlated', 'Reg', (99, 109))	('APECED', 'Gene', (137, 143))	('IL-17F', 'Gene', (56, 62))
321561	30510552	However, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene.	('AIRE', 'Gene', (188, 192))	('cytokine production', 'MPA', (102, 121))	('IL-17', 'Gene', '3605', (52, 57))	('AIRE', 'Gene', '326', (188, 192))	('defect in cytokine production', 'Phenotype', 'HP:0031407', (92, 121))	('IL-17', 'Gene', (52, 57))	('mutations', 'Var', (171, 180))	('defect', 'NegReg', (92, 98))	('decreased', 'NegReg', (36, 45))
321563	29212180	PADI4 rs2240337 G>A polymorphism is associated with susceptibility of esophageal squamous cell carcinoma in a Chinese population Esophageal cancer (EC) remains one of the major causes of cancer incidence and mortality worldwide.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('cancer', 'Disease', (187, 193))	('Esophageal cancer', 'Disease', (129, 146))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('rs2240337', 'Mutation', 'rs2240337', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('Esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))	('esophageal squamous cell carcinoma', 'Disease', (70, 104))	('PADI4', 'Gene', '23569', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PADI4', 'Gene', (0, 5))	('rs2240337 G>A', 'Var', (6, 19))
321564	29212180	Genetic factors, such as single nucleotide polymorphisms (SNPs), may contribute to the carcinogenesis of EC.	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('carcinogenesis', 'Disease', (87, 101))	('single nucleotide polymorphisms', 'Var', (25, 56))	('contribute', 'Reg', (69, 79))
321566	29212180	Our findings suggested that the PADI4 rs2240337 GA/AA variants were significantly associated with decreased risk of ESCC.	('rs2240337', 'Mutation', 'rs2240337', (38, 47))	('rs2240337 GA/AA', 'Var', (38, 53))	('ESCC', 'Disease', (116, 120))	('PADI4', 'Gene', (32, 37))	('decreased', 'NegReg', (98, 107))
321568	29212180	Stratification analyses demonstrated that smoking significantly increased ESCC risk in PADI4 rs11203366 AG/AA, rs1886302 CC/CT, rs1635562 AT, rs1635564 CA and rs2477137 AC genotype.	('AT', 'Disease', 'None', (138, 140))	('rs1886302 CC/CT', 'Var', (111, 126))	('rs1886302', 'Mutation', 'rs1886302', (111, 120))	('ESCC', 'Disease', (74, 78))	('rs1635564 CA', 'Var', (142, 154))	('rs11203366 AG/AA', 'Var', (93, 109))	('rs11203366', 'Mutation', 'rs11203366', (93, 103))	('rs2477137 AC', 'Var', (159, 171))	('rs1635562', 'Mutation', 'rs1635562', (128, 137))	('rs1635564', 'Mutation', 'rs1635564', (142, 151))	('increased', 'PosReg', (64, 73))	('rs2477137', 'Mutation', 'rs2477137', (159, 168))	('increased ESCC', 'Phenotype', 'HP:0003565', (64, 78))
321569	29212180	Alcohol drinking increased ESCC risk in PADI4 rs11203366 AG, rs1635562 AT, rs1635564 CA, rs2477137 AC, rs1886302 CT genotype.	('increased ESCC', 'Phenotype', 'HP:0003565', (17, 31))	('AT', 'Disease', 'None', (71, 73))	('rs2477137 AC', 'Var', (89, 101))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('rs1635564', 'Mutation', 'rs1635564', (75, 84))	('Alcohol drinking', 'Phenotype', 'HP:0030955', (0, 16))	('ESCC', 'Disease', (27, 31))	('rs2477137', 'Mutation', 'rs2477137', (89, 98))	('rs11203366 AG', 'Var', (46, 59))	('rs1886302 CT', 'Var', (103, 115))	('rs11203366', 'Mutation', 'rs11203366', (46, 56))	('rs1635564 CA', 'Var', (75, 87))	('rs1635562', 'Mutation', 'rs1635562', (61, 70))	('rs1886302', 'Mutation', 'rs1886302', (103, 112))
321570	29212180	In younger cohort (<63 years), rs11203366 AA genotype was associated with increased risk of ESCC.	('rs11203366', 'Var', (31, 41))	('rs11203366', 'Mutation', 'rs11203366', (31, 41))	('ESCC', 'Disease', (92, 96))
321571	29212180	PADI4 rs1886302 CC variant was associated with ESCC susceptibility in female cohort.	('rs1886302', 'Mutation', 'rs1886302', (6, 15))	('PADI4', 'Gene', (0, 5))	('ESCC', 'Disease', (47, 51))	('rs1886302 CC', 'Var', (6, 18))
321572	29212180	Our study suggested that PADI4 rs2240337 G>A polymorphism may be correlated with individual susceptibility to ESCC.	('rs2240337', 'Mutation', 'rs2240337', (31, 40))	('rs2240337 G>A', 'Var', (31, 44))	('ESCC', 'Disease', (110, 114))
321573	29212180	PADI4 rs11203366, rs1886302, rs1635562, rs1635564 and rs2477137 polymorphisms were implicated with altered susceptibility of ESCC based on sex, age, smoking status and alcohol consumption.	('rs11203366', 'Mutation', 'rs11203366', (6, 16))	('rs1635564', 'Var', (40, 49))	('rs1635564', 'Mutation', 'rs1635564', (40, 49))	('rs1635562', 'Var', (29, 38))	('alcohol', 'Chemical', 'MESH:D000438', (168, 175))	('rs1886302', 'Var', (18, 27))	('rs11203366', 'Var', (6, 16))	('rs1635562', 'Mutation', 'rs1635562', (29, 38))	('rs2477137', 'Var', (54, 63))	('rs1886302', 'Mutation', 'rs1886302', (18, 27))	('ESCC', 'Disease', (125, 129))	('rs2477137', 'Mutation', 'rs2477137', (54, 63))
321584	29212180	In a small cohort of esophageal cancer patients (including ESCC and EAC), PADI4 rs10437048 and rs41265997 were found significantly associated with the risk of esophageal cancer.	('rs10437048', 'Var', (80, 90))	('esophageal cancer', 'Disease', (21, 38))	('patients', 'Species', '9606', (39, 47))	('rs41265997', 'Mutation', 'rs41265997', (95, 105))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('PADI4', 'Gene', (74, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (21, 38))	('esophageal cancer', 'Disease', (159, 176))	('associated', 'Reg', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ESCC', 'Disease', (59, 63))	('rs41265997', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('rs10437048', 'Mutation', 'rs10437048', (80, 90))
321586	29212180	When the PADI4 rs2240337 G>A SNP GG homozygote genotype (AA) was used as the reference group, both the GA heterozygote genotype (AB) and the AA mutated homozygote genotype (BB) were associated with a significantly decreased risk of ESCC (AB vs. AA: adjusted OR = 0.52, 95% CI = 0.39-0.71, p<0.0001; BB vs. AA: adjusted OR = 0.30, 95% CI = 0.13-0.68, p = 0.004).	('ESCC', 'Disease', (232, 236))	('PADI4', 'Gene', (9, 14))	('rs2240337 G>A', 'Var', (15, 28))	('rs2240337', 'Mutation', 'rs2240337', (15, 24))	('decreased', 'NegReg', (214, 223))
321587	29212180	Logistic regression analyses revealed that the PADI4 rs11203366 A>G, rs1886302 T>C, rs1635562 A>T, rs1635564 C>A, rs16825533 A>G, and rs2477137 C>A polymorphisms were not associated with the risk of ESCC.	('rs1886302 T>C', 'Var', (69, 82))	('rs1635564 C>A', 'Var', (99, 112))	('rs1635564', 'Mutation', 'rs1635564', (99, 108))	('rs2477137', 'Mutation', 'rs2477137', (134, 143))	('rs16825533 A>G', 'Var', (114, 128))	('rs1635562 A>T', 'Var', (84, 97))	('rs11203366', 'Mutation', 'rs11203366', (53, 63))	('rs2477137 C>A', 'Var', (134, 147))	('rs11203366 A>G', 'Var', (53, 67))	('ESCC', 'Disease', (199, 203))	('rs1635562', 'Mutation', 'rs1635562', (84, 93))	('rs16825533', 'Mutation', 'rs16825533', (114, 124))	('rs1886302', 'Mutation', 'rs1886302', (69, 78))
321588	29212180	After the Bonferroni correction, for PADI4 rs2240337 G>A, the padj = 0.031 for GA vs. GG after adjusted for age, sex, smoking and drinking status.	('PADI4', 'Gene', (37, 42))	('rs2240337', 'Mutation', 'rs2240337', (43, 52))	('rs2240337 G>A', 'Var', (43, 56))
321589	29212180	Furthermore, we analyzed the correlation between PADI4 rs2240337 G>A SNP and the clinic pathologic state.	('PADI4', 'Gene', (49, 54))	('rs2240337 G', 'Var', (55, 66))	('rs2240337', 'Mutation', 'rs2240337', (55, 64))
321590	29212180	However, PADI4 rs2240337 G>A SNP did not correlate with clinical tumor stage (p = 0.215) or grade (p = 0.497) (Table 4).	('tumor', 'Disease', (65, 70))	('PADI4', 'Gene', (9, 14))	('rs2240337 G>A', 'Var', (15, 28))	('rs2240337', 'Mutation', 'rs2240337', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
321592	29212180	We showed that smoking significantly increased ESCC risk in PADI4 rs11203366 AG/AA, rs1886302 CC/CT, rs1635562 AT, rs1635564 CA, rs2240337 AG and rs2477137 AC genotype.	('rs11203366', 'Mutation', 'rs11203366', (66, 76))	('AT', 'Disease', 'None', (111, 113))	('rs11203366 AG/AA', 'Var', (66, 82))	('rs1886302 CC/CT', 'Var', (84, 99))	('ESCC', 'Disease', (47, 51))	('rs1886302', 'Mutation', 'rs1886302', (84, 93))	('rs1635564 CA', 'Var', (115, 127))	('rs2240337', 'Mutation', 'rs2240337', (129, 138))	('rs2240337 AG', 'Var', (129, 141))	('rs2477137 AC', 'Var', (146, 158))	('rs1635562', 'Mutation', 'rs1635562', (101, 110))	('increased', 'PosReg', (37, 46))	('increased ESCC', 'Phenotype', 'HP:0003565', (37, 51))	('rs2477137', 'Mutation', 'rs2477137', (146, 155))	('rs1635564', 'Mutation', 'rs1635564', (115, 124))
321593	29212180	In younger cohort (<63 years), PADI4 rs16825533 AG genotype was associated with decreased risk of ESCC, while rs11203366 AA genotype was associated with increased risk of ESCC.	('PADI4', 'Gene', (31, 36))	('rs16825533', 'Mutation', 'rs16825533', (37, 47))	('rs11203366', 'Mutation', 'rs11203366', (110, 120))	('ESCC', 'Disease', (98, 102))	('rs11203366 AA', 'Var', (110, 123))	('decreased', 'NegReg', (80, 89))	('rs16825533 AG', 'Var', (37, 50))
321594	29212180	In the non-drinking cohort, PADI4 rs11203366 AA variant was associated with increased risk of ESCC.	('PADI4', 'Gene', (28, 33))	('rs11203366', 'Var', (34, 44))	('ESCC', 'Disease', (94, 98))	('rs11203366', 'Mutation', 'rs11203366', (34, 44))
321595	29212180	In the non-alcohol drinking cohort, PADI4 rs1886302 CC and CT variants were associated with decreased risk of ESCC.	('-alcohol drinking', 'Phenotype', 'HP:0030955', (10, 27))	('rs1886302 CC', 'Var', (42, 54))	('alcohol', 'Chemical', 'MESH:D000438', (11, 18))	('PADI4', 'Gene', (36, 41))	('ESCC', 'Disease', (110, 114))	('alcohol drinking', 'Phenotype', 'HP:0030955', (11, 27))	('decreased', 'NegReg', (92, 101))	('rs1886302', 'Mutation', 'rs1886302', (42, 51))
321596	29212180	In rs1635562 TT subgroup, elder people (>=63 years) were more susceptible to ESCC.	('people', 'Species', '9606', (32, 38))	('ESCC', 'Disease', (77, 81))	('rs1635562', 'Mutation', 'rs1635562', (3, 12))	('rs1635562', 'Var', (3, 12))
321603	29212180	We found that the PADI4 rs2240337 G>A SNP was significantly associated with decreased risk of ESCC after the Bonferroni correction.	('rs2240337', 'Mutation', 'rs2240337', (24, 33))	('decreased', 'NegReg', (76, 85))	('rs2240337 G>A', 'Var', (24, 37))	('ESCC', 'Disease', (94, 98))	('PADI4', 'Gene', (18, 23))
321604	29212180	PADI4 rs11203366, rs1886302, rs1635562, rs1635564 and rs2477137 polymorphisms were implicated with altered susceptibility of ESCC according to age, gender, smoking and alcohol drinking stratification analyses.	('rs11203366', 'Mutation', 'rs11203366', (6, 16))	('rs1635564', 'Var', (40, 49))	('rs1635564', 'Mutation', 'rs1635564', (40, 49))	('PADI4', 'Gene', (0, 5))	('rs1635562', 'Var', (29, 38))	('alcohol', 'Chemical', 'MESH:D000438', (168, 175))	('rs1886302', 'Var', (18, 27))	('rs11203366', 'Var', (6, 16))	('alcohol drinking', 'Phenotype', 'HP:0030955', (168, 184))	('rs1635562', 'Mutation', 'rs1635562', (29, 38))	('rs2477137', 'Var', (54, 63))	('rs1886302', 'Mutation', 'rs1886302', (18, 27))	('ESCC', 'Disease', (125, 129))	('rs2477137', 'Mutation', 'rs2477137', (54, 63))
321606	29212180	Additionally, the histone deaminating activity of PADI4 has been shown to downregulate the expression of numerous p53-dependent genes, including p21, PUMA, and GADD45.	('expression', 'MPA', (91, 101))	('p53', 'Gene', (114, 117))	('PADI4', 'Var', (50, 55))	('downregulate', 'NegReg', (74, 86))	('p53', 'Gene', '7157', (114, 117))	('p21', 'Gene', (145, 148))	('p21', 'Gene', '644914', (145, 148))	('histone deaminating activity', 'MPA', (18, 46))
321613	29212180	Of the seven SNPs, rs2240337 G>A was validated as an ESCC susceptibility locus, showing highly significant evidence both in heterozygote group (p<0.0001) and homozygote group (p<0.004).	('rs2240337', 'Mutation', 'rs2240337', (19, 28))	('ESCC', 'Disease', (53, 57))	('rs2240337 G>A', 'Var', (19, 32))
321614	29212180	A previous study in a small cohort of patients with EC (83 cases and 67 controls, including ESCC and EAC) has reported that the PADI4 rs10437048 genotype was significantly associated with decreased risk of EC, whereas rs41265997 were significantly associated with increased risk of EC.	('decreased', 'NegReg', (188, 197))	('rs41265997', 'Mutation', 'rs41265997', (218, 228))	('rs10437048', 'Mutation', 'rs10437048', (134, 144))	('PADI4', 'Gene', (128, 133))	('rs41265997', 'Var', (218, 228))	('rs10437048', 'Var', (134, 144))	('patients', 'Species', '9606', (38, 46))	('EAC', 'Phenotype', 'HP:0011459', (101, 104))
321615	29212180	In addition, the pairwise LD tagging approach for tagging SNPs selection in this study could possibly miss some SNPs in LD with rs2240337which were also susceptibility loci for ESCC.	('rs2240337which', 'Var', (128, 142))	('ESCC', 'Disease', (177, 181))	('rs2240337', 'Mutation', 'rs2240337', (128, 137))	('susceptibility', 'Reg', (153, 167))	('miss', 'NegReg', (102, 106))
321616	29212180	Rs2240337 is located in the intron region of PADI4 gene.	('PADI4', 'Gene', (45, 50))	('Rs2240337', 'Var', (0, 9))	('Rs2240337', 'Mutation', 'Rs2240337', (0, 9))
321617	29212180	One study showed that rs2240337 could influence the mRNA stability or maturation in vitro, while the association between this SNP and rheumatoid arthritis severity has also been reported.	('rs2240337', 'Var', (22, 31))	('mRNA stability', 'CPA', (52, 66))	('influence', 'Reg', (38, 47))	('arthritis', 'Phenotype', 'HP:0001369', (145, 154))	('rs2240337', 'Mutation', 'rs2240337', (22, 31))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (134, 154))	('maturation in vitro', 'CPA', (70, 89))	('rheumatoid arthritis', 'Disease', (134, 154))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (134, 154))
321618	29212180	As the sample size was limited in our study, the correlation between rs2240337 and the pathologic character of ESCC was not evident, further investigation is desirable to demonstrate the functional relevance of rs2240337 polymorphism in ESCC.	('rs2240337', 'Mutation', 'rs2240337', (69, 78))	('ESCC', 'Disease', (111, 115))	('rs2240337', 'Var', (69, 78))	('rs2240337', 'Mutation', 'rs2240337', (211, 220))	('ESCC', 'Gene', (237, 241))	('rs2240337', 'Var', (211, 220))
321620	29212180	This notion was in line with our finding, although PADI4 rs11203366, rs1886302, rs1635562, rs1635564, rs16825533 and rs2477137 were not associated with the susceptibility to ESCC, smoking significantly increased ESCC risk in PADI4 rs11203366 AG/AA, rs1886302 CC/CT, rs1635562 AT, rs1635564 CA and rs2477137 AC genotype, while alcohol drinking increased ESCC risk in PADI4 rs11203366 AG, rs1635562 AT, rs1635564 CA, rs2477137 AC, rs1886302 CT genotype.	('alcohol drinking', 'Phenotype', 'HP:0030955', (326, 342))	('ESCC', 'Disease', (353, 357))	('rs11203366 AG', 'Var', (372, 385))	('rs11203366', 'Mutation', 'rs11203366', (372, 382))	('rs1635564 CA', 'Var', (280, 292))	('alcohol', 'Chemical', 'MESH:D000438', (326, 333))	('rs2477137', 'Var', (297, 306))	('rs1886302', 'Mutation', 'rs1886302', (249, 258))	('rs2477137', 'Mutation', 'rs2477137', (117, 126))	('AT', 'Disease', 'None', (397, 399))	('rs1635562', 'Mutation', 'rs1635562', (266, 275))	('rs1635562', 'Mutation', 'rs1635562', (387, 396))	('rs16825533', 'Mutation', 'rs16825533', (102, 112))	('rs1886302 CC/CT', 'Var', (249, 264))	('rs1635564', 'Mutation', 'rs1635564', (401, 410))	('rs11203366', 'Mutation', 'rs11203366', (57, 67))	('rs1886302', 'Mutation', 'rs1886302', (429, 438))	('rs1635564', 'Mutation', 'rs1635564', (280, 289))	('rs2477137', 'Mutation', 'rs2477137', (297, 306))	('increased ESCC', 'Phenotype', 'HP:0003565', (202, 216))	('rs1635564', 'Mutation', 'rs1635564', (91, 100))	('AT', 'Disease', 'None', (276, 278))	('rs2477137 AC', 'Var', (415, 427))	('ESCC', 'Disease', (212, 216))	('rs1886302', 'Var', (429, 438))	('ESCC', 'Disease', (174, 178))	('rs1635562', 'Mutation', 'rs1635562', (80, 89))	('rs2477137', 'Mutation', 'rs2477137', (415, 424))	('rs1635564 CA', 'Var', (401, 413))	('rs11203366', 'Mutation', 'rs11203366', (231, 241))	('rs1886302', 'Mutation', 'rs1886302', (69, 78))	('increased ESCC', 'Phenotype', 'HP:0003565', (343, 357))
321621	29212180	Interestingly, despite the fact that rs2240337 SNP was associated with decreased risk of ESCC, smoking increased ESCC risk in PADI4 rs2240337 AG genotype as compared with non-smokers.	('ESCC', 'Disease', (113, 117))	('increased ESCC', 'Phenotype', 'HP:0003565', (103, 117))	('increased', 'PosReg', (103, 112))	('rs2240337 SNP', 'Var', (37, 50))	('rs2240337 AG', 'Var', (132, 144))	('rs2240337', 'Mutation', 'rs2240337', (37, 46))	('ESCC', 'Disease', (89, 93))	('rs2240337', 'Mutation', 'rs2240337', (132, 141))	('decreased', 'NegReg', (71, 80))
321624	29212180	Our study provides the evidence that polymorphism of PIDA4 rs2240337 G>A is associated with the altered susceptibility of ESCC.	('ESCC', 'Disease', (122, 126))	('associated', 'Reg', (76, 86))	('PIDA4', 'Gene', (53, 58))	('rs2240337', 'Mutation', 'rs2240337', (59, 68))	('polymorphism', 'Var', (37, 49))	('rs2240337 G>A', 'Var', (59, 72))
321626	29212180	Last but not least, refrained by the limited technical support, we have not evaluated the biological function of the SNP polymorphism in the carcinogenesis of ESCC in the current study.	('carcinogenesis', 'Disease', 'MESH:D063646', (141, 155))	('polymorphism', 'Var', (121, 133))	('carcinogenesis', 'Disease', (141, 155))	('ESCC', 'Disease', (159, 163))
321627	29212180	As rs2240337 is located in the intron region of PADI4 gene, therefore overexpression of wild type and mutant type PADI4 coding sequence does not work.	('rs2240337', 'Mutation', 'rs2240337', (3, 12))	('PADI4', 'Gene', (48, 53))	('rs2240337', 'Var', (3, 12))
321628	29212180	We speculate that rs2240337 may cause an alternative RNA splicing on PADI4 mRNA, thereby regulating the PADI4 protein function.	('PADI4', 'Gene', (69, 74))	('rs2240337', 'Mutation', 'rs2240337', (18, 27))	('regulating', 'Reg', (89, 99))	('protein', 'Protein', (110, 117))	('PADI4', 'Protein', (104, 109))	('rs2240337', 'Var', (18, 27))	('function', 'MPA', (118, 126))	('alternative RNA', 'MPA', (41, 56))	('cause', 'Reg', (32, 37))
321629	29212180	Further studies using an rs2240337 G>A mutation cell or mouse model are needed to clarify the mutant PADI4 function.	('PADI4', 'Gene', (101, 106))	('rs2240337 G>A', 'Var', (25, 38))	('mouse', 'Species', '10090', (56, 61))	('rs2240337', 'Mutation', 'rs2240337', (25, 34))
321632	29212180	PADI4 peptidylarginine deiminase type 4 ESCC esophageal squamous cell carcinoma EC esophageal cancer SNP Single nucleotide polymorphism LD linkage disequilibrium OR odds ratio CI confidential interval	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('Single nucleotide polymorphism', 'Var', (105, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('esophageal cancer', 'Disease', (83, 100))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (45, 79))	('carcinoma EC esophageal cancer', 'Phenotype', 'HP:0011459', (70, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('arginine', 'Chemical', 'MESH:D001120', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('esophageal squamous cell carcinoma', 'Disease', (45, 79))
321640	26897166	Patients with pN3a and pN3b showed distinct prognosis in all regions, and by introducing pN3a and pN3b into a cluster analysis, we established a new stage grouping with better stratification than AJCC7, especially among stage III subgroups.	('pN3a', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('pN3b', 'Var', (23, 27))
321670	26897166	The patients were divided into 25 groups according to their tumor/node status by combining five T categories (1/2/3/4a/4b) and five N categories (0/1/2/3a/3b), from T1N0, T1N1...to T4bN3b.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('T4bN3b', 'Var', (181, 187))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (60, 65))
321692	26897166	In contrast to esophageal cancer, where involvement of more than six nodes is not associated with worse survival than involvement of 6 nodes, in gastric cancer there was a significant difference in survival comparing N3a to N3b (Figure 1b).	('gastric cancer', 'Disease', 'MESH:D013274', (145, 159))	('gastric cancer', 'Phenotype', 'HP:0012126', (145, 159))	('N3a', 'Var', (217, 220))	('esophageal cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (15, 32))	('gastric cancer', 'Disease', (145, 159))
321694	26897166	With this modification, the distribution of patients in stage III subgroups changed (Figure 3) and the survival curves became more distinct from each other (Figure 4).	('modification', 'Var', (10, 22))	('changed', 'Reg', (76, 83))	('patients', 'Species', '9606', (44, 52))
321798	25078779	ATF4 promoted cell invasion and metastasis by promoting matrix metalloproteinase (MMP)-2 and MMP-7 expression, while its silencing significantly attenuated these activities both in vitro and in vivo.	('expression', 'MPA', (99, 109))	('silencing', 'Var', (121, 130))	('promoted', 'PosReg', (5, 13))	('ATF4', 'Gene', '468', (0, 4))	('attenuated', 'NegReg', (145, 155))	('cell invasion', 'CPA', (14, 27))	('metastasis', 'CPA', (32, 42))	('promoting', 'PosReg', (46, 55))	('MMP-7', 'Gene', (93, 98))	('ATF4', 'Gene', (0, 4))	('MMP-7', 'Gene', '4316', (93, 98))	('matrix metalloproteinase (MMP)-2', 'Gene', '4313', (56, 88))
321799	25078779	We report that ATF4 is a potential biomarker for ESCC prognosis and that its dysregulation may play a key role in the regulation of invasion and metastasis in ESCC cells.	('ATF4', 'Gene', (15, 19))	('dysregulation', 'Var', (77, 90))	('metastasis', 'CPA', (145, 155))	('play', 'Reg', (95, 99))	('ATF4', 'Gene', '468', (15, 19))	('ESCC', 'Disease', (49, 53))	('invasion', 'CPA', (132, 140))
321815	25078779	In addition, positive ATF4 expression indicated poorer prognoses than negative ATF4 expression in patients with ESCC.	('ATF4', 'Gene', '468', (79, 83))	('positive', 'Var', (13, 21))	('ATF4', 'Gene', (22, 26))	('ESCC', 'Disease', (112, 116))	('patients', 'Species', '9606', (98, 106))	('expression', 'MPA', (27, 37))	('ATF4', 'Gene', (79, 83))	('ATF4', 'Gene', '468', (22, 26))
321833	25078779	2C), while in the stage I and II groups, the patients with positive ATF4 protein expression had significantly shorter overall survival rates compared with those with negative expression (P<0.001 for both; Fig.	('overall survival', 'MPA', (118, 134))	('protein', 'Protein', (73, 80))	('ATF4', 'Gene', (68, 72))	('shorter', 'NegReg', (110, 117))	('positive', 'Var', (59, 67))	('patients', 'Species', '9606', (45, 53))	('ATF4', 'Gene', '468', (68, 72))
321838	25078779	Our results demonstrated that patients with positive ATF4 expression/lymph node metastasis (+) had poorer overall survival rates compared with those of the other patients (P<0.001; Fig.	('poorer', 'NegReg', (99, 105))	('patients', 'Species', '9606', (162, 170))	('overall survival rates', 'CPA', (106, 128))	('ATF4', 'Gene', (53, 57))	('ATF4', 'Gene', '468', (53, 57))	('patients', 'Species', '9606', (30, 38))	('positive', 'Var', (44, 52))
321841	25078779	Both the protein and mRNA levels of ATF4 were much higher in the TE-1HM cells than in the TE-1LM cells (Fig.	('ATF4', 'Gene', (36, 40))	('TE-1HM', 'Var', (65, 71))	('ATF4', 'Gene', '468', (36, 40))	('higher', 'PosReg', (51, 57))	('mRNA levels', 'MPA', (21, 32))	('protein', 'MPA', (9, 16))
321843	25078779	In addition, ATF4 levels following the knockdown of specific shRNAs in the TE-1HM cells were slightly higher compared with the parental TE-1LM cells (Fig.	('knockdown', 'Var', (39, 48))	('ATF4', 'Gene', (13, 17))	('higher', 'PosReg', (102, 108))	('TE-1HM', 'Var', (75, 81))	('ATF4', 'Gene', '468', (13, 17))
321844	25078779	Subsequently, a transwell assay showed that the silencing of endogenous ATF4 expression in the TE-1HM cells significantly reduced cell migration (2.52-fold) and invasion (2.72-fold) (Fig.	('silencing', 'Var', (48, 57))	('ATF4', 'Gene', '468', (72, 76))	('invasion', 'CPA', (161, 169))	('reduced', 'NegReg', (122, 129))	('ATF4', 'Gene', (72, 76))	('cell migration', 'CPA', (130, 144))
321846	25078779	Most of the mice that were implanted with the TE-1HM-SCR cells showed liver and lung metastases, whereas less metastases were detected in the mice that had been implanted with the TE-1HM-siATF4 cells (Fig.	('metastases', 'Disease', (110, 120))	('liver and lung metastases', 'Disease', 'MESH:D009362', (70, 95))	('TE-1HM-SCR', 'Var', (46, 56))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('mice', 'Species', '10090', (142, 146))	('metastases', 'Disease', (85, 95))	('siATF4', 'Chemical', '-', (187, 193))	('HM-SCR', 'CellLine', 'CVCL:4349', (50, 56))	('mice', 'Species', '10090', (12, 16))	('metastases', 'Disease', 'MESH:D009362', (85, 95))
321847	25078779	Although the number of mice that were injected with the TE-1HM-siATF4 cells did not significantly differ from that of the mice that were injected with TE-1HM-SCR, when the presence of tumor nodules was macroscopically examined, the mice that had been implanted with the TE-1HM-SCR cells showed more liver and lung metastases compared with those that had been implanted with the TE-1HM-siATF4 cells (Fig.	('liver and lung metastases', 'Disease', 'MESH:D009362', (299, 324))	('more', 'PosReg', (294, 298))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('mice', 'Species', '10090', (232, 236))	('mice', 'Species', '10090', (122, 126))	('TE-1HM-SCR', 'Var', (270, 280))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('siATF4', 'Chemical', '-', (385, 391))	('siATF4', 'Chemical', '-', (63, 69))	('HM-SCR', 'CellLine', 'CVCL:4349', (155, 161))	('tumor', 'Disease', (184, 189))	('HM-SCR', 'CellLine', 'CVCL:4349', (274, 280))	('mice', 'Species', '10090', (23, 27))
321849	25078779	Subsequently, the mice that were implanted with the TE-1HM-SCR cells did show statistically significant increases in liver and lung metastases compared with those that had been implanted with the TE-1HM-siATF4 cells following a repetition of the in vivo experiment using 10 mice per group (Table S1).	('siATF4', 'Chemical', '-', (203, 209))	('liver and lung metastases', 'Disease', 'MESH:D009362', (117, 142))	('HM-SCR', 'CellLine', 'CVCL:4349', (56, 62))	('mice', 'Species', '10090', (18, 22))	('increases', 'PosReg', (104, 113))	('TE-1HM-SCR', 'Var', (52, 62))	('mice', 'Species', '10090', (274, 278))
321852	25078779	The in vitro assays revealed that the ectopic expression of ATF4 led to 2.80- and 3.53-fold increases in the migration and invasion of the TE-1LM cells, respectively (Fig.	('ATF4', 'Gene', (60, 64))	('ectopic expression', 'Var', (38, 56))	('invasion of the TE-1LM cells', 'CPA', (123, 151))	('migration', 'CPA', (109, 118))	('ATF4', 'Gene', '468', (60, 64))	('increases', 'PosReg', (92, 101))
321854	25078779	ATF4 transfection led to significantly more liver and lung metastases compared with the empty vector-transfected control cells (Fig.	('transfection', 'Var', (5, 17))	('more', 'PosReg', (39, 43))	('liver and lung metastases', 'Disease', 'MESH:D009362', (44, 69))	('ATF4', 'Gene', (0, 4))	('ATF4', 'Gene', '468', (0, 4))
321855	25078779	Consistent with the afore mentioned results, ATF4 transfection led to similar findings compared with the empty vector-transfected Eca-109 cells (Table S2).	('ATF4', 'Gene', (45, 49))	('ATF4', 'Gene', '468', (45, 49))	('transfection', 'Var', (50, 62))
321876	25078779	Furthermore, the Kaplan-Meier analysis showed that the patients with ESCC and positive ATF4 expression had significantly worse prognoses than those with negative ATF4 expression.	('ESCC', 'Disease', (69, 73))	('ATF4', 'Gene', '468', (162, 166))	('positive', 'Var', (78, 86))	('ATF4', 'Gene', '468', (87, 91))	('ATF4', 'Gene', (87, 91))	('patients', 'Species', '9606', (55, 63))	('ATF4', 'Gene', (162, 166))
321883	25078779	In this study, our in vitro and in vivo data demonstrate that the overexpression of ATF4 promotes the migration and invasion of ESCC cells with low metastatic potential, while the silencing of ATF4 suppresses the migration and invasion of ESCC cells with high metastatic potential.	('ATF4', 'Gene', (84, 88))	('suppresses', 'NegReg', (198, 208))	('promotes', 'PosReg', (89, 97))	('silencing', 'Var', (180, 189))	('invasion', 'CPA', (116, 124))	('invasion', 'CPA', (227, 235))	('ATF4', 'Gene', '468', (193, 197))	('ATF4', 'Gene', '468', (84, 88))	('migration', 'CPA', (102, 111))	('overexpression', 'PosReg', (66, 80))	('migration', 'CPA', (213, 222))	('ATF4', 'Gene', (193, 197))
321907	25078779	The ratio of positive cells was calculated by comparing the number of stained tumor cells to the total number of tumor cells as follows: 0, staining of <=1%; 1, staining of 2-25%; 2, staining of 26-50%; 3, staining of 51-75%; and 4, staining of >75%.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('staining', 'Var', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
321916	25078779	The blots were probed with anti-ATF4 (sc-200, Santa Cruz), anti-MMP-1 (sc-21731, Santa Cruz), anti-MMP-2 (sc-13594, Santa Cruz), anti-MMP-7 (sc-8832, Santa Cruz), anti-MMP-9 (sc-21733, Santa Cruz), anti-MMP-13 (sc-30073, Santa Cruz), and anti-beta-actin (sc-47778, Santa Cruz).	('MMP-2', 'Gene', (99, 104))	('MMP-9', 'Gene', '4318', (168, 173))	('MMP-1', 'Gene', '4312', (203, 208))	('MMP-1', 'Gene', '4312', (64, 69))	('MMP-9', 'Gene', (168, 173))	('MMP-1', 'Gene', (64, 69))	('sc-8832', 'Var', (141, 148))	('MMP-7', 'Gene', (134, 139))	('MMP-1', 'Gene', (203, 208))	('sc-21733', 'Var', (175, 183))	('beta-actin', 'Gene', '728378', (243, 253))	('MMP-2', 'Gene', '4313', (99, 104))	('beta-actin', 'Gene', (243, 253))	('MMP-7', 'Gene', '4316', (134, 139))	('ATF4', 'Gene', '468', (32, 36))	('sc-30073', 'Var', (211, 219))	('ATF4', 'Gene', (32, 36))
322054	17114067	Irradiation to the pancreas causes necrosis and fibrosis similar to chronic pancreatitis.	('pancreatitis', 'Phenotype', 'HP:0001733', (76, 88))	('necrosis', 'Disease', (35, 43))	('pancreatitis', 'Disease', 'MESH:D010195', (76, 88))	('necrosis', 'Disease', 'MESH:D009336', (35, 43))	('pancreas', 'Disease', 'MESH:D010190', (19, 27))	('Irradiation', 'Var', (0, 11))	('fibrosis', 'Disease', (48, 56))	('fibrosis', 'Disease', 'MESH:D005355', (48, 56))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (68, 88))	('pancreatitis', 'Disease', (76, 88))	('pancreas', 'Disease', (19, 27))
322057	17114067	The kidney is radiosensitive and 28 Gy to both kidneys in 5 weeks or less frequently leads to renal failure.	('renal failure', 'Disease', 'MESH:D051437', (94, 107))	('leads to', 'Reg', (85, 93))	('renal failure', 'Disease', (94, 107))	('renal failure', 'Phenotype', 'HP:0000083', (94, 107))	('28 Gy', 'Var', (33, 38))
322136	31328033	Several studies showed that MPV and PC are associated with mortality in cardiovascular disease, such as ischemic cardiovascular disease and acute myocardial infarction.	('associated with', 'Reg', (43, 58))	('acute myocardial infarction', 'Disease', (140, 167))	('cardiovascular disease', 'Disease', (72, 94))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (113, 135))	('MPV', 'Var', (28, 31))	('cardiovascular disease', 'Disease', 'MESH:D002318', (72, 94))	('cardiovascular disease', 'Disease', 'MESH:D002318', (113, 135))	('myocardial infarction', 'Phenotype', 'HP:0001658', (146, 167))	('ischemic cardiovascular disease', 'Disease', (104, 135))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (72, 94))	('ischemic cardiovascular disease', 'Disease', 'MESH:D002318', (104, 135))	('acute myocardial infarction', 'Disease', 'MESH:D009203', (140, 167))	('mortality', 'Disease', (59, 68))
322137	31328033	Moreover, recent studies have shown that the ratio for MPV to PC (MPV/PC) is associated with prognosis in some malignancies, such as hepatocellular carcinoma and lung cancer.	('malignancies', 'Disease', (111, 123))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('MPV', 'Var', (55, 58))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('lung cancer', 'Disease', (162, 173))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('hepatocellular carcinoma', 'Disease', (133, 157))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (133, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('associated', 'Reg', (77, 87))
322162	31328033	When we set the cut-off points using ROC curve, the MPV/PC ratio (42.7% vs. 23.5%, P < 0.001), MPV (51.7% vs. 26.7%, P = 0.001), and PC (41.8% vs. 19.3%, P < 0.001) were also associated with CSS (D-F) (Figs.	('associated', 'Reg', (175, 185))	('CSS', 'Chemical', '-', (191, 194))	('MPV', 'Var', (95, 98))
322168	31328033	Moreover, studies have shown that MPV/PC ratio is associated with prognosis in some malignancies, such as hepatocellular carcinoma and lung cancer.	('malignancies', 'Disease', (84, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('hepatocellular carcinoma', 'Disease', (106, 130))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (106, 130))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('associated', 'Reg', (50, 60))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (106, 130))	('lung cancer', 'Disease', (135, 146))	('MPV/PC ratio', 'Var', (34, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
322177	31328033	demonstrated that 0.0491 might be the optimum cut-off point for MPV/PC ratio in hepatocellular carcinoma according to the ROC curve.	('0.0491', 'Var', (18, 24))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (80, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('hepatocellular carcinoma', 'Disease', (80, 104))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (80, 104))
322219	29977287	Accordingly, the so-called Baveno VI criteria stated that patients with LSM < 20 kPa (assessed by transient elastography (TE)) and with normal platelet count (PLT > 150,000/m3) can be considered very unlikely to have HVR (based on a reasonable risk of 5% of missed varices requiring treatment).	('patients', 'Species', '9606', (58, 66))	('LSM < 20 kPa', 'Var', (72, 84))	('HVR', 'Disease', (217, 220))
322284	29977287	Kaplan-Meyer curves confirmed ICG-r15 >= 22.9% (HR 5.491; 95% CI 2.681-11.245), HVPG >= 12 mmHg (HR 2.686; 95% CI 1.456-4.954), and presence of OV (HR 5.050; 95% CI 2.184-7.511) as risk factors for decompensation.	('ICG', 'Chemical', 'MESH:D007208', (30, 33))	('ICG-r15 >= 22.9', 'Var', (30, 45))	('HVPG >= 12 mmHg', 'Var', (80, 95))
322300	29463194	Clinical characteristics, the targeted protein expressions (including phosphatase and tensin homolog, phosphoinositide-3 kinase, AKT, p-AKT, mammalian target of rapamycin, p-mTOR, p70S6 kinase 1, p-P70S6K1, elongation initiation factor 4E binding protein-1, and p-4E-BP1, and survival rate were analyzed.	('p70S6 kinase', 'Gene', '6198', (180, 192))	('mTOR', 'Gene', '2475', (174, 178))	('p-P70S6K1', 'Var', (196, 205))	('4E-BP1', 'Gene', (264, 270))	('AKT', 'Gene', (136, 139))	('p70S6 kinase', 'Gene', (180, 192))	('AKT', 'Gene', '207', (129, 132))	('mammalian target of rapamycin', 'Gene', '2475', (141, 170))	('AKT', 'Gene', '207', (136, 139))	('4E-BP1', 'Gene', '1978', (264, 270))	('4E binding protein-1', 'Gene', (236, 256))	('phosphoinositide-3 kinase', 'Gene', '5290', (102, 127))	('mTOR', 'Gene', (174, 178))	('phosphoinositide-3 kinase', 'Gene', (102, 127))	('AKT', 'Gene', (129, 132))	('4E binding protein-1', 'Gene', '1978', (236, 256))	('mammalian target of rapamycin', 'Gene', (141, 170))
322301	29463194	Among them, phosphoinositide-3 kinase, AKT, p-AKT, mammalian target of rapamycin, p-mTOR, elongation initiation factor 4E binding protein-1, p70S6 kinase 1, and p-P70S6K1 proteins were significantly upregulated in tumor tissue.	('mTOR', 'Gene', '2475', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('AKT', 'Gene', (46, 49))	('phosphoinositide-3 kinase', 'Gene', '5290', (12, 37))	('AKT', 'Gene', (39, 42))	('mammalian target of rapamycin', 'Gene', '2475', (51, 80))	('4E binding protein-1', 'Gene', (119, 139))	('4E binding protein-1', 'Gene', '1978', (119, 139))	('p-P70S6K1', 'Var', (161, 170))	('AKT', 'Gene', '207', (46, 49))	('AKT', 'Gene', '207', (39, 42))	('mammalian target of rapamycin', 'Gene', (51, 80))	('tumor', 'Disease', (214, 219))	('p70S6 kinase', 'Gene', '6198', (141, 153))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('p70S6 kinase', 'Gene', (141, 153))	('upregulated', 'PosReg', (199, 210))	('mTOR', 'Gene', (84, 88))	('phosphoinositide-3 kinase', 'Gene', (12, 37))
322305	29463194	Overexpression of mammalian target of rapamycin was proved to be an independent adverse prognostic factor for overall survival in esophageal squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('mammalian target of rapamycin', 'Gene', '2475', (18, 47))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (141, 165))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (130, 165))	('mammalian target of rapamycin', 'Gene', (18, 47))	('esophageal squamous cell carcinomas', 'Disease', (130, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))
322317	29463194	Previous studies suggested that the abnormal expression of PTEN and the activation of PI3K/AKT/mTOR signaling pathway were involvedin tumorigenesis and affect ESCC patient prognosis.	('activation', 'PosReg', (72, 82))	('AKT', 'Gene', '207', (91, 94))	('PTEN', 'Gene', '5728', (59, 63))	('patient', 'Species', '9606', (164, 171))	('PTEN', 'Gene', (59, 63))	('abnormal', 'Var', (36, 44))	('involvedin', 'Reg', (123, 133))	('AKT', 'Gene', (91, 94))	('expression', 'MPA', (45, 55))	('affect', 'Reg', (152, 158))	('PI3', 'Gene', '5266', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mTOR', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (95, 99))	('PI3', 'Gene', (86, 89))	('ESCC patient', 'Disease', (159, 171))	('tumor', 'Disease', (134, 139))
322336	29463194	The proteins investigated were PTEN, PI3K, AKT, p-AKT, mTOR, p-mTOR, P70S6K1, p-P70S6K1, 4E-BP1, and p-4E-BP1.	('4E-BP1', 'Gene', (103, 109))	('PTEN', 'Gene', (31, 35))	('mTOR', 'Gene', (63, 67))	('mTOR', 'Gene', (55, 59))	('P70S6K1', 'Var', (69, 76))	('mTOR', 'Gene', '2475', (55, 59))	('4E-BP1', 'Gene', '1978', (89, 95))	('AKT', 'Gene', '207', (50, 53))	('PI3', 'Gene', '5266', (37, 40))	('PTEN', 'Gene', '5728', (31, 35))	('AKT', 'Gene', '207', (43, 46))	('4E-BP1', 'Gene', '1978', (103, 109))	('PI3', 'Gene', (37, 40))	('AKT', 'Gene', (50, 53))	('AKT', 'Gene', (43, 46))	('p-P70S6K1', 'Var', (78, 87))	('4E-BP1', 'Gene', (89, 95))	('mTOR', 'Gene', '2475', (63, 67))
322337	29463194	The significantly upregulated proteins in ESCC were PI3K (x2 = 5.354, P = .021), AKT (x2 = 7.256, P = .007), p-AKT (x2 = 5.747, P = .017), mTOR (x2 = 4.064, P = .044; Figure 1), p-mTOR (x2 = 9.425, P = .002), 4E-BP1 (x2 = 4.994, P = .025), P70S6K1 (x2 = 7.670, P = .006), and p-P70S6K1 (x2 = 4.945, P = .026).	('AKT', 'Gene', '207', (111, 114))	('PI3', 'Gene', (52, 55))	('mTOR', 'Gene', (180, 184))	('AKT', 'Gene', '207', (81, 84))	('mTOR', 'Gene', (139, 143))	('4E-BP1', 'Gene', '1978', (209, 215))	('mTOR', 'Gene', '2475', (180, 184))	('mTOR', 'Gene', '2475', (139, 143))	('p-P70S6K1', 'Var', (276, 285))	('AKT', 'Gene', (111, 114))	('AKT', 'Gene', (81, 84))	('PI3', 'Gene', '5266', (52, 55))	('upregulated', 'PosReg', (18, 29))	('4E-BP1', 'Gene', (209, 215))	('proteins', 'Protein', (30, 38))	('P70S6K1', 'Var', (240, 247))
322344	29463194	Univariate analysis demonstrated the prognostic factors for overall survival (OS) were tumor length (P = .002), differentiation (P = .006), T-stage (P < .001), N-stage (P < .001), PTEN expression (P = .044), mTOR expression (P = .011), and P70S6K1 expression (P = .009).	('P70S6K1 expression', 'Var', (240, 258))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('PTEN', 'Gene', (180, 184))	('tumor', 'Disease', (87, 92))	('PTEN', 'Gene', '5728', (180, 184))	('mTOR', 'Gene', (208, 212))	('mTOR', 'Gene', '2475', (208, 212))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('differentiation', 'CPA', (112, 127))
322345	29463194	The prognostic factors of the PI3K/AKT/mTOR pathway proteins for progression-free survival were mTOR expression (P = .010), p-mTOR expression (P = .015), and P70S6K1 expression (P = .007).	('mTOR', 'Gene', (96, 100))	('AKT', 'Gene', (35, 38))	('PI3', 'Gene', (30, 33))	('mTOR', 'Gene', (39, 43))	('mTOR', 'Gene', '2475', (39, 43))	('P70S6K1', 'Var', (158, 165))	('AKT', 'Gene', '207', (35, 38))	('mTOR', 'Gene', (126, 130))	('mTOR', 'Gene', '2475', (126, 130))	('mTOR', 'Gene', '2475', (96, 100))	('PI3', 'Gene', '5266', (30, 33))
322347	29463194	In order to evaluate the impact of prognostic protein biomarkers expressions (PTEN, mTOR, p-mTOR, and P70S6K1) on different tumor stages, we divided patients into subgroups on the basis of N-stage (N0 vs N1-3).	('patients', 'Species', '9606', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('PTEN', 'Gene', (78, 82))	('mTOR', 'Gene', '2475', (84, 88))	('PTEN', 'Gene', '5728', (78, 82))	('mTOR', 'Gene', (92, 96))	('mTOR', 'Gene', (84, 88))	('mTOR', 'Gene', '2475', (92, 96))	('P70S6K1', 'Var', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
322348	29463194	In the subgroup of N0, patients with high expression of mTOR (X2 = 12.354, P < .001) and p-mTOR (X2 = 4.549, P = .033) had significantly worse OS, but no statistical significance was found in the subgroup of N1 to N3.	('worse', 'NegReg', (137, 142))	('high expression', 'Var', (37, 52))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', '2475', (56, 60))	('patients', 'Species', '9606', (23, 31))	('mTOR', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (91, 95))
322349	29463194	And there were no statistical significance of PTEN and P70S6K1 expressions in each subgroup.	('PTEN', 'Gene', (46, 50))	('P70S6K1', 'Var', (55, 62))	('PTEN', 'Gene', '5728', (46, 50))
322351	29463194	We found a low expression of PTEN (P = .001) in pT3 and pT4 tumors, whereas the high expression of P70S6K1 (P = .003) in pT3 and pT4 tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('pT4', 'Disease', (56, 59))	('PTEN', 'Gene', (29, 33))	('PTEN', 'Gene', '5728', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('pT3', 'Gene', '7694', (48, 51))	('pT3', 'Gene', '7694', (121, 124))	('low', 'NegReg', (11, 14))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('pT3', 'Gene', (48, 51))	('expression', 'MPA', (15, 25))	('pT3', 'Gene', (121, 124))	('P70S6K1', 'Var', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', (60, 66))
322352	29463194	Patients with a high expression of p-mTOR (P = .008) or P70S6K1 (P = .005) tended to have tumors of more than 3 cm in maximum diameter.	('P70S6K1', 'Var', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('Patients', 'Species', '9606', (0, 8))	('mTOR', 'Gene', (37, 41))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('mTOR', 'Gene', '2475', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))
322353	29463194	The high expression of mTOR (P = .026), p-mTOR (P = .002), and P70S6K1 (P < .001) were related to lymph node metastases.	('mTOR', 'Gene', '2475', (42, 46))	('P70S6K1', 'Var', (63, 70))	('mTOR', 'Gene', (42, 46))	('metastases', 'Disease', (109, 119))	('high', 'PosReg', (4, 8))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (23, 27))	('related', 'Reg', (87, 94))	('metastases', 'Disease', 'MESH:D009362', (109, 119))
322355	29463194	Especially, the low expression of PTEN (P = .017) or the high expression of mTOR (P = .022), p-mTOR (P = .010), and P70S6K1 (P = .028) were correlated with advanced TNM stage.	('low', 'NegReg', (16, 19))	('expression', 'MPA', (20, 30))	('mTOR', 'Gene', (76, 80))	('TNM', 'Gene', '10178', (165, 168))	('mTOR', 'Gene', '2475', (76, 80))	('high', 'PosReg', (57, 61))	('TNM', 'Gene', (165, 168))	('P70S6K1', 'Var', (116, 123))	('mTOR', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (95, 99))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
322357	29463194	Phosphatase and tensin homolog expression was negative associated with p-AKT (P < .001), P70S6K1 (P < .001), and p-P70S6K1 (P = .019).	('negative', 'NegReg', (46, 54))	('Phosphatase', 'Protein', (0, 11))	('AKT', 'Gene', (73, 76))	('P70S6K1', 'Var', (89, 96))	('p-P70S6K1', 'Var', (113, 122))	('AKT', 'Gene', '207', (73, 76))
322359	29463194	P70S6K1 expression had a positive correlation with p-P70S6K1 (P < .001), p-AKT (P < .001), and p-4E-BP1 (P < .001) expression, as shown in Table 3.	('AKT', 'Gene', '207', (75, 78))	('p-P70S6K1', 'Var', (51, 60))	('4E-BP1', 'Gene', (97, 103))	('AKT', 'Gene', (75, 78))	('4E-BP1', 'Gene', '1978', (97, 103))	('P70S6K1', 'Var', (0, 7))
322370	29463194	Compared to nontumor tissues, PI3K, AKT, p-AKT, mTOR, p-mTOR, 4E-BP1, P70S6K1, and p-P70S6K1 were all upregulated in tumor tissues.	('AKT', 'Gene', '207', (43, 46))	('4E-BP1', 'Gene', '1978', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('upregulated', 'PosReg', (102, 113))	('P70S6K1', 'Var', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('p-P70S6K1', 'Var', (83, 92))	('AKT', 'Gene', (36, 39))	('4E-BP1', 'Gene', (62, 68))	('PI3', 'Gene', '5266', (30, 33))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', (48, 52))	('tumor', 'Disease', (15, 20))	('AKT', 'Gene', (43, 46))	('mTOR', 'Gene', '2475', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('AKT', 'Gene', '207', (36, 39))	('mTOR', 'Gene', '2475', (56, 60))	('tumor', 'Disease', (117, 122))	('PI3', 'Gene', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
322379	29463194	In contrast to PTEN that acts as a suppressor of this signaling pathway, activation of mTOR could increase growth signals and increase protein synthesis through the phosphorylation and inactivation of 4E-BP1 and P70S6K1.	('mTOR', 'Gene', '2475', (87, 91))	('protein synthesis', 'MPA', (135, 152))	('inactivation', 'NegReg', (185, 197))	('4E-BP1', 'Gene', (201, 207))	('PTEN', 'Gene', (15, 19))	('increase', 'PosReg', (98, 106))	('phosphorylation', 'MPA', (165, 180))	('PTEN', 'Gene', '5728', (15, 19))	('activation', 'Var', (73, 83))	('4E-BP1', 'Gene', '1978', (201, 207))	('P70S6K1', 'Var', (212, 219))	('increase', 'PosReg', (126, 134))	('growth signals', 'MPA', (107, 121))	('mTOR', 'Gene', (87, 91))
322380	29463194	Our study found patients with a high expression of p-mTOR or P70S6K1 tended to have tumors of more than 3 cm in maximum diameter.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patients', 'Species', '9606', (16, 24))	('mTOR', 'Gene', (53, 57))	('mTOR', 'Gene', '2475', (53, 57))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('P70S6K1', 'Var', (61, 68))
322381	29463194	Meanwhile, the overexpression of mTOR, p-mTOR, and P70S6K1 in tumors was closely related to the presence of lymph node metastases, advanced TNM stage.	('P70S6K1', 'Var', (51, 58))	('overexpression', 'PosReg', (15, 29))	('TNM', 'Gene', '10178', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('related', 'Reg', (81, 88))	('mTOR', 'Gene', '2475', (33, 37))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mTOR', 'Gene', (33, 37))	('TNM', 'Gene', (140, 143))	('metastases', 'Disease', (119, 129))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
322388	29463194	The level of expression of PTEN, mTOR, p-mTOR, and P70S6K1 were closely related to the presence of lymph node metastases.	('P70S6K1', 'Var', (51, 58))	('metastases', 'Disease', (110, 120))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('mTOR', 'Gene', '2475', (33, 37))	('mTOR', 'Gene', (33, 37))	('related', 'Reg', (72, 79))	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (27, 31))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))
322389	29463194	The expression of PTEN, mTOR, and P70S6K1 were correlated to the TNM stage and overall survival.	('PTEN', 'Gene', (18, 22))	('TNM', 'Gene', '10178', (65, 68))	('overall survival', 'CPA', (79, 95))	('PTEN', 'Gene', '5728', (18, 22))	('correlated', 'Reg', (47, 57))	('TNM', 'Gene', (65, 68))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))	('P70S6K1', 'Var', (34, 41))
322398	26608978	At the completion of CRF, the nutritional status in the NST group were much better than those in the control group, as evidenced by prealbumin (ALB), transferrin, and ALB parameters (P = 0.001, 0.000, and 0.000, respectively).	('ALB', 'Gene', '213', (144, 147))	('albumin', 'Gene', (135, 142))	('nutritional status', 'MPA', (30, 48))	('ALB', 'Gene', (144, 147))	('better', 'PosReg', (76, 82))	('ALB', 'Gene', '213', (167, 170))	('transferrin', 'Gene', '7018', (150, 161))	('transferrin', 'Gene', (150, 161))	('albumin', 'Gene', '213', (135, 142))	('ALB', 'Gene', (167, 170))	('NST', 'Var', (56, 59))
322415	26608978	NST has been found to reduce the incidence of complications, in-patient costs, and mortality rates.	('mortality', 'CPA', (83, 92))	('patient', 'Species', '9606', (64, 71))	('reduce', 'NegReg', (22, 28))	('NST', 'Var', (0, 3))
322444	26608978	The incidences of bone marrow suppression (Grade II and above) and complications related infection were both lower in the NST group than in the control group.	('lower', 'NegReg', (109, 114))	('infection', 'Disease', (89, 98))	('infection', 'Disease', 'MESH:D007239', (89, 98))	('bone marrow suppression', 'Disease', 'MESH:D001855', (18, 41))	('bone marrow suppression', 'Disease', (18, 41))	('NST', 'Var', (122, 125))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (18, 41))
322487	26941842	For example, Fe3O4 nanoparticles could rapidly generate heat when exposed to near-infrared (NIR) laser irradiation, and the mouse tumor (grown from human esophagus carcinoma cells) growth was found to be significantly inhibited by the photothermal effect of these Fe3O4 nanoparticles.	('inhibited', 'NegReg', (218, 227))	('Fe3O4', 'Var', (264, 269))	('Fe3O4', 'Chemical', '-', (264, 269))	('esophagus carcinoma', 'Disease', (154, 173))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mouse', 'Species', '10090', (124, 129))	('human', 'Species', '9606', (148, 153))	('esophagus carcinoma', 'Phenotype', 'HP:0011459', (154, 173))	('Fe3O4', 'Chemical', '-', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('tumor', 'Disease', (130, 135))	('esophagus carcinoma', 'Disease', 'MESH:D004938', (154, 173))	('rat', 'Species', '10116', (51, 54))
322533	26941842	The intracellular ROS levels generated by LP- HMNSs and LP-HMNS/SiO2/GQDs upon laser irradiation were measured in the same manner as described in our previous work.	('HMNSs', 'Chemical', '-', (46, 51))	('HMNS', 'Chemical', '-', (46, 50))	('SiO2', 'Chemical', 'MESH:D012822', (64, 68))	('LP', 'Chemical', 'MESH:D008070', (56, 58))	('LP', 'Chemical', 'MESH:D008070', (42, 44))	('rat', 'Species', '10116', (33, 36))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('GQDs', 'Chemical', '-', (69, 73))	('LP-HMNS/SiO2/GQDs', 'Var', (56, 73))	('HMNS', 'Chemical', '-', (59, 63))	('LP-', 'Var', (42, 45))
322549	26941842	The other controls included the following: an identical 96-well plate containing two wells of cells (in which only one well contained nanoparticles) that was not exposed to the magnetic field, and the cells containing lipids (2.5 mg/mL) and PVP (20 mg/mL) but without HMNSs that were exposed to the magnetic field.	('HMNSs', 'Chemical', '-', (268, 273))	('PVP', 'Chemical', 'MESH:D011205', (241, 244))	('lipids', 'Chemical', 'MESH:D008055', (218, 224))	('2.5', 'Var', (226, 229))	('20 mg/mL', 'Var', (246, 254))
322567	26941842	As has been shown previously, PI dye can only penetrate into damaged or dead cells, where it binds to DNA and emits red fluorescence (~617 nm wavelength), whereas Hoechst 33342 (a blue fluorescent dye) can penetrate both living and dead cells.	('PI dye', 'Var', (30, 36))	('binds', 'Interaction', (93, 98))	('rat', 'Species', '10116', (211, 214))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (163, 176))	('DNA', 'Protein', (102, 105))	('fluoresce', 'Chemical', '-', (120, 129))	('fluoresce', 'Chemical', '-', (185, 194))	('rat', 'Species', '10116', (51, 54))
322584	26941842	As shown in Figure 3C, when incubating cells with LP-HMNSs (HMNSs: 0.5 mg/mL) for 5 min and subsequently exposed to a magnetic field for 20 and 60 min, the average cell viabilities are 73.99+-5.36 and 57.84+-6.94%, respectively (P<0.01 between these two groups).	('LP-HMNSs', 'Var', (50, 58))	('HMNSs', 'Chemical', '-', (53, 58))	('LP-HMNSs', 'Chemical', '-', (50, 58))	('HMNSs', 'Chemical', '-', (60, 65))	('cell viabilities', 'CPA', (164, 180))
322586	26941842	Upon incubating the cells with LP-HMNSs (HMNSs: 0.5 mg/mL) for 30 min or 2 h and subsequently exposed to a magnetic field for 20 min, the cell viability was found to be 76.80+-4.53 or 70.39+-7.92%, respectively.	('LP-HMNSs', 'Chemical', '-', (31, 39))	('cell viability', 'CPA', (138, 152))	('LP-HMNSs', 'Var', (31, 39))	('HMNSs', 'Chemical', '-', (34, 39))	('HMNSs', 'Chemical', '-', (41, 46))
322607	26941842	These results indicate effective cancer cell killing by HMNSs upon NIR laser irradiation, whereas the liposomes and PVP, with or without laser irradiation, show insignificant effects.	('HMNSs', 'Chemical', '-', (56, 61))	('NIR laser', 'Var', (67, 76))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('HMNSs', 'Var', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('PVP', 'Chemical', 'MESH:D011205', (116, 119))
322631	26941842	As also shown in Figure 4B and (Supplementary Material: Figure S2), the temperature increase rate of the LP-HMNS/SiO2 is 1-2 C lower than that of the LP-HMNSs.	('HMNS', 'Chemical', '-', (108, 112))	('LP-HMNSs', 'Chemical', '-', (150, 158))	('SiO2', 'Chemical', 'MESH:D012822', (113, 117))	('LP-HMNS/SiO2', 'Var', (105, 117))	('rat', 'Species', '10116', (77, 80))	('HMNS', 'Chemical', '-', (153, 157))	('increase', 'PosReg', (84, 92))	('temperature', 'MPA', (72, 83))	('LP', 'Chemical', 'MESH:D008070', (105, 107))	('LP', 'Chemical', 'MESH:D008070', (150, 152))	('rat', 'Species', '10116', (93, 96))
322637	26941842	As also shown in Figure S3, the average ROS levels generated by the LP-HMNS/SiO2 with and without 671-nm laser irradiation are 4.39+-1.53 and 1.18+-0.64 times greater than the control, respectivel, as a reuslt of much higher ROS generated by GQDs than the SiO2 shell.	('GQDs', 'Chemical', '-', (242, 246))	('LP', 'Chemical', 'MESH:D008070', (68, 70))	('higher', 'PosReg', (218, 224))	('SiO2', 'Chemical', 'MESH:D012822', (256, 260))	('ROS', 'MPA', (225, 228))	('HMNS', 'Chemical', '-', (71, 75))	('greater', 'PosReg', (159, 166))	('LP-HMNS/SiO2', 'Var', (68, 80))	('rat', 'Species', '10116', (233, 236))	('ROS', 'Chemical', 'MESH:D017382', (225, 228))	('ROS levels', 'MPA', (40, 50))	('rat', 'Species', '10116', (55, 58))	('ROS', 'Chemical', 'MESH:D017382', (40, 43))	('SiO2', 'Chemical', 'MESH:D012822', (76, 80))
322641	26941842	Based on the absorption spectra of the DOX solution before and after mixing with the nanoparticles, we calculated the drug-loadings of the HMNS, HMNS/SiO2, and HMNS/SiO2/GQDs nanoparticles to be 0.02 g, 0.21 g, and 0.66 g of DOX/g HMNSs, respectively.	('HMNS', 'Chemical', '-', (145, 149))	('HMNSs', 'Chemical', '-', (231, 236))	('HMNS', 'Chemical', '-', (160, 164))	('HMNS', 'Chemical', '-', (139, 143))	('HMNS', 'Chemical', '-', (231, 235))	('SiO2', 'Chemical', 'MESH:D012822', (150, 154))	('HMNS/SiO2/GQDs', 'Var', (160, 174))	('SiO2', 'Chemical', 'MESH:D012822', (165, 169))	('DOX', 'Chemical', 'MESH:D004317', (225, 228))	('GQDs', 'Chemical', '-', (170, 174))	('drug-loadings', 'MPA', (118, 131))	('DOX', 'Chemical', 'MESH:D004317', (39, 42))
322642	26941842	A large amount of DOX was incorporated into the HMNS/SiO2/GQDs nanocomposites, which can be explained by the interactions between the GQDs and DOX, including pi-pi stacking, hydrogen bonding, and electrostatic interaction.	('interactions', 'Interaction', (109, 121))	('pi-pi stacking', 'Var', (158, 172))	('GQDs', 'Chemical', '-', (134, 138))	('electrostatic interaction', 'CPA', (196, 221))	('hydrogen', 'Chemical', 'MESH:D006859', (174, 182))	('SiO2', 'Chemical', 'MESH:D012822', (53, 57))	('hydrogen bonding', 'CPA', (174, 190))	('DOX', 'Chemical', 'MESH:D004317', (18, 21))	('rat', 'Species', '10116', (33, 36))	('HMNS', 'Chemical', '-', (48, 52))	('GQDs', 'Chemical', '-', (58, 62))	('DOX', 'Chemical', 'MESH:D004317', (143, 146))
322663	26941842	The phototoxicities of LP-HMNS/SiO2/GQDs to cancer cells are shown in Figure 8A(a) and Figure 8B.	('LP', 'Chemical', 'MESH:D008070', (23, 25))	('toxicities', 'Disease', (9, 19))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('HMNS', 'Chemical', '-', (26, 30))	('toxicities', 'Disease', 'MESH:D064420', (9, 19))	('GQDs', 'Chemical', '-', (36, 40))	('LP-HMNS/SiO2/GQDs', 'Var', (23, 40))	('SiO2', 'Chemical', 'MESH:D012822', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
322668	26941842	In addition, we found fast uptake of LP-HMNS/SiO2/GQDs by the cells.	('HMNS', 'Chemical', '-', (40, 44))	('LP', 'Chemical', 'MESH:D008070', (37, 39))	('SiO2', 'Chemical', 'MESH:D012822', (45, 49))	('uptake', 'MPA', (27, 33))	('GQDs', 'Chemical', '-', (50, 54))	('LP-HMNS/SiO2/GQDs', 'Var', (37, 54))
322698	26852678	Thus, early detection and ablation of the preceding dysplasias is a promising strategy for reducing the risk of adenocarcinoma.	('adenocarcinoma', 'Disease', (112, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('adenocarcinoma', 'Disease', 'MESH:D000230', (112, 126))	('dysplasias', 'Disease', 'MESH:D004476', (52, 62))	('ablation', 'Var', (26, 34))	('dysplasias', 'Disease', (52, 62))
322704	26852678	As many as 1.4 million individuals in the United States have IBDs and are at increased risk for the development of colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('IBDs', 'Phenotype', 'HP:0002037', (61, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('IBDs', 'Var', (61, 65))	('colorectal cancer', 'Disease', (115, 132))
322790	26852678	The variation of the RFA electrode contact with the esophagus and coagulated debris building up on the electrode surface during repeated ablation in one patient also can degrade the effectiveness of the radiofrequency energy delivery.	('radiofrequency energy delivery', 'MPA', (203, 233))	('variation', 'Var', (4, 13))	('effectiveness', 'MPA', (182, 195))	('patient', 'Species', '9606', (153, 160))	('degrade', 'NegReg', (170, 177))
322838	22182510	Therefore, targeted inhibition of Fzd7 represents a rational and promising new approach for cancer therapy.	('Fzd7', 'Gene', (34, 38))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('targeted inhibition', 'Var', (11, 30))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
322853	22182510	Mutations in Wnt/beta-catenin signaling components, aberrant epigenetic regulation of Wnt signaling antagonists and up-regulation of Wnt proteins and their receptors contribute to the development of a variety of diseases including cancer.	('beta-catenin', 'Gene', '1499', (17, 29))	('contribute', 'Reg', (166, 176))	('epigenetic regulation', 'MPA', (61, 82))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Wnt', 'Gene', '35975', (133, 136))	('Wnt', 'Gene', (13, 16))	('Wnt', 'Gene', (133, 136))	('Wnt', 'Gene', '35975', (13, 16))	('cancer', 'Disease', (231, 237))	('Wnt', 'Gene', '35975', (86, 89))	('Mutations', 'Var', (0, 9))	('aberrant', 'Var', (52, 60))	('up-regulation', 'PosReg', (116, 129))	('Wnt', 'Gene', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('beta-catenin', 'Gene', (17, 29))
322856	22182510	Disruption of Wnt/beta-catenin signaling represents an opportunity for rational cancer chemoprevention and therapy.	('beta-catenin', 'Gene', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('beta-catenin', 'Gene', '1499', (18, 30))	('Wnt', 'Gene', '35975', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Wnt', 'Gene', (14, 17))	('cancer', 'Disease', (80, 86))	('Disruption', 'Var', (0, 10))
322869	22182510	Aberrant activation of the Wnt/beta-catenin signaling pathway is a necessary initiating event in the genesis of most colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('activation', 'PosReg', (9, 19))	('beta-catenin', 'Gene', (31, 43))	('Aberrant', 'Var', (0, 8))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('colorectal cancers', 'Disease', 'MESH:D015179', (117, 135))	('beta-catenin', 'Gene', '1499', (31, 43))	('Wnt', 'Gene', '35975', (27, 30))	('Wnt', 'Gene', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('colorectal cancers', 'Disease', (117, 135))
322870	22182510	Although genetic mutations of the Wnt/beta-catenin signaling intracellular components APC, CTNNB1 (beta-catenin encoding gene) and Axin2 are major contributing factors for colorectal cancers, it is now recognized that additional modulation of Wnt/beta-catenin signaling is involved in colorectal tumor progression.	('Axin2', 'Gene', '8313', (131, 136))	('beta-catenin', 'Gene', '1499', (247, 259))	('APC', 'Phenotype', 'HP:0005227', (86, 89))	('APC', 'Disease', 'MESH:D011125', (86, 89))	('APC', 'Disease', (86, 89))	('mutations', 'Var', (17, 26))	('factors', 'Reg', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('Wnt', 'Gene', '35975', (243, 246))	('CTNNB1', 'Gene', (91, 97))	('Wnt', 'Gene', (243, 246))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('colorectal cancers', 'Disease', (172, 190))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('beta-catenin', 'Gene', (38, 50))	('Wnt', 'Gene', '35975', (34, 37))	('beta-catenin', 'Gene', '1499', (38, 50))	('Wnt', 'Gene', (34, 37))	('beta-catenin', 'Gene', (99, 111))	('beta-catenin', 'Gene', '1499', (99, 111))	('Axin2', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('colorectal cancers', 'Disease', 'MESH:D015179', (172, 190))	('colorectal tumor', 'Disease', 'MESH:D015179', (285, 301))	('CTNNB1', 'Gene', '1499', (91, 97))	('beta-catenin', 'Gene', (247, 259))	('colorectal tumor', 'Disease', (285, 301))
322872	22182510	The Fzd7 protein is abundantly expressed in colon cancer tissues and various colon cancer cell lines that also contain the APC or beta-catenin gene mutations.	('APC', 'Phenotype', 'HP:0005227', (123, 126))	('mutations', 'Var', (148, 157))	('Fzd7', 'Gene', (4, 8))	('colon cancer', 'Disease', 'MESH:D015179', (44, 56))	('APC', 'Disease', (123, 126))	('APC', 'Disease', 'MESH:D011125', (123, 126))	('colon cancer', 'Phenotype', 'HP:0003003', (44, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colon cancer', 'Disease', (44, 56))	('colon cancer', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('beta-catenin', 'Gene', (130, 142))	('beta-catenin', 'Gene', '1499', (130, 142))
322875	22182510	The overexpression of Fzd7 in colon cancer cell lines harboring APC and/or CTNNB1 mutations robustly increases beta-catenin/TCF activity and the subsequent expression of Wnt/beta-catenin target genes; whereas, siRNA knockdown of Fzd7 in colorectal cancer cells decreases beta-catenin/TCF activity, Wnt/beta-catenin target gene expression, cell viability, cell migration, and cell invasion.	('APC', 'Phenotype', 'HP:0005227', (64, 67))	('APC', 'Disease', 'MESH:D011125', (64, 67))	('decreases', 'NegReg', (261, 270))	('colorectal cancer', 'Phenotype', 'HP:0003003', (237, 254))	('beta-catenin', 'Gene', '1499', (271, 283))	('colon cancer', 'Disease', 'MESH:D015179', (30, 42))	('APC', 'Disease', (64, 67))	('TCF', 'Gene', '3172', (284, 287))	('beta-catenin', 'Gene', (174, 186))	('beta-catenin', 'Gene', '1499', (174, 186))	('CTNNB1', 'Gene', (75, 81))	('Wnt', 'Gene', '35975', (298, 301))	('beta-catenin', 'Gene', (302, 314))	('beta-catenin', 'Gene', (111, 123))	('Wnt', 'Gene', (298, 301))	('TCF', 'Gene', '3172', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cell invasion', 'CPA', (375, 388))	('beta-catenin', 'Gene', '1499', (302, 314))	('beta-catenin', 'Gene', '1499', (111, 123))	('colon cancer', 'Disease', (30, 42))	('Wnt', 'Gene', '35975', (170, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (237, 254))	('Wnt', 'Gene', (170, 173))	('colorectal cancer', 'Disease', (237, 254))	('TCF', 'Gene', (284, 287))	('cell viability', 'CPA', (339, 353))	('TCF', 'Gene', (124, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('cell migration', 'CPA', (355, 369))	('increases', 'PosReg', (101, 110))	('mutations', 'Var', (82, 91))	('CTNNB1', 'Gene', '1499', (75, 81))	('expression', 'MPA', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('beta-catenin', 'Gene', (271, 283))
322876	22182510	In addition, liver metastasis of stable Fzd7 siRNA HCT-116 cell transfectants in SCID mice was decreased to 40-50% compared to controls.	('decreased', 'NegReg', (95, 104))	('SCID', 'Disease', 'MESH:D053632', (81, 85))	('SCID', 'Disease', (81, 85))	('mice', 'Species', '10090', (86, 90))	('transfectants', 'Var', (64, 77))	('liver metastasis', 'CPA', (13, 29))	('HCT-116', 'CellLine', 'CVCL:0291', (51, 58))
322878	22182510	Together, these findings indicate that FZD7 plays a critical role in Wnt/beta-catenin signaling activation in colorectal cancer cells despite the presence of the APC or CTNNB1 mutation and that Fzd7 is a potential therapeutic target for colorectal cancer.	('beta-catenin', 'Gene', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (237, 254))	('CTNNB1', 'Gene', '1499', (169, 175))	('beta-catenin', 'Gene', '1499', (73, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('Wnt', 'Gene', '35975', (69, 72))	('Wnt', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('FZD7', 'Gene', '8324', (39, 43))	('CTNNB1', 'Gene', (169, 175))	('mutation', 'Var', (176, 184))	('colorectal cancer', 'Disease', 'MESH:D015179', (237, 254))	('activation', 'PosReg', (96, 106))	('FZD7', 'Gene', (39, 43))	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('colorectal cancer', 'Disease', (237, 254))	('APC', 'Phenotype', 'HP:0005227', (162, 165))	('APC', 'Disease', 'MESH:D011125', (162, 165))	('colorectal cancer', 'Disease', (110, 127))	('APC', 'Disease', (162, 165))	('presence', 'Reg', (146, 154))
322881	22182510	Increased Fzd7 expression, due to aberrant the canonical Wnt signaling pathway, may serve as a feed-forward mechanism to perpetuate Wnt/beta-catenin signaling, thus facilitating colorectal cancer progression and metastasis.	('metastasis', 'CPA', (212, 222))	('Wnt', 'Gene', (132, 135))	('beta-catenin', 'Gene', '1499', (136, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('Wnt', 'Gene', '35975', (57, 60))	('Fzd7', 'Gene', (10, 14))	('aberrant', 'Var', (34, 42))	('perpetuate', 'NegReg', (121, 131))	('colorectal cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('Wnt', 'Gene', (57, 60))	('Increased', 'PosReg', (0, 9))	('expression', 'MPA', (15, 25))	('facilitating', 'PosReg', (165, 177))	('Wnt', 'Gene', '35975', (132, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))	('beta-catenin', 'Gene', (136, 148))
322884	22182510	Mutations in the beta-catenin gene were found in 12-26% of HCCs, while mutations in APC and Axin2 are very rare.	('HCC', 'Phenotype', 'HP:0001402', (59, 62))	('beta-catenin', 'Gene', '1499', (17, 29))	('APC', 'Disease', (84, 87))	('HCC', 'Gene', (59, 62))	('Axin2', 'Gene', (92, 97))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (40, 45))	('Axin2', 'Gene', '8313', (92, 97))	('HCC', 'Gene', '619501', (59, 62))	('APC', 'Phenotype', 'HP:0005227', (84, 87))	('beta-catenin', 'Gene', (17, 29))	('APC', 'Disease', 'MESH:D011125', (84, 87))
322888	22182510	Furthermore, the up-regulation of Fzd7 expression correlated with increased levels of cytosolic/nuclear beta-catenin and cell migration, whereas enforced overexpression of a dominant-negative Fzd7 mutant in HCC cells suppressed Wnt/beta-catenin signaling and reduced cell motility.	('Fzd7', 'Gene', (34, 38))	('beta-catenin', 'Gene', (104, 116))	('HCC', 'Phenotype', 'HP:0001402', (207, 210))	('beta-catenin', 'Gene', '1499', (104, 116))	('beta-catenin', 'Gene', (232, 244))	('beta-catenin', 'Gene', '1499', (232, 244))	('up-regulation', 'PosReg', (17, 30))	('cell motility', 'CPA', (267, 280))	('cell migration', 'CPA', (121, 135))	('overexpression', 'PosReg', (154, 168))	('expression', 'MPA', (39, 49))	('increased', 'PosReg', (66, 75))	('HCC cells', 'CellLine', 'CVCL:0C55', (207, 216))	('mutant', 'Var', (197, 203))	('suppressed', 'NegReg', (217, 227))	('reduced', 'NegReg', (259, 266))	('Wnt', 'Gene', '35975', (228, 231))	('Fzd7', 'Gene', (192, 196))	('Wnt', 'Gene', (228, 231))
322891	22182510	While genetic mutations of the Wnt/beta-catenin signaling intracellular components APC, CTNNB1 and Axin2 are rare, dysfunction of the Wnt/beta-catenin pathway at the cell surface could result in the aberrant activation of Wnt/beta-catenin signaling in breast cancer cells.	('Wnt', 'Gene', '35975', (222, 225))	('Wnt', 'Gene', '35975', (134, 137))	('Wnt', 'Gene', (222, 225))	('CTNNB1', 'Gene', '1499', (88, 94))	('dysfunction', 'Disease', (115, 126))	('Wnt', 'Gene', (134, 137))	('Axin2', 'Gene', '8313', (99, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('activation', 'PosReg', (208, 218))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('mutations', 'Var', (14, 23))	('CTNNB1', 'Gene', (88, 94))	('breast cancer', 'Disease', (252, 265))	('dysfunction', 'Disease', 'MESH:D006331', (115, 126))	('APC', 'Phenotype', 'HP:0005227', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('APC', 'Disease', 'MESH:D011125', (83, 86))	('APC', 'Disease', (83, 86))	('beta-catenin', 'Gene', (226, 238))	('beta-catenin', 'Gene', (35, 47))	('beta-catenin', 'Gene', '1499', (226, 238))	('beta-catenin', 'Gene', (138, 150))	('beta-catenin', 'Gene', '1499', (138, 150))	('beta-catenin', 'Gene', '1499', (35, 47))	('Wnt', 'Gene', '35975', (31, 34))	('genetic mutations', 'Var', (6, 23))	('Axin2', 'Gene', (99, 104))	('Wnt', 'Gene', (31, 34))
322899	22182510	This stems from the observation that Fzd7-positive gastric cancers are associated with poor patient prognosis compared to Fzd7-negative gastric cancers.	('gastric cancers', 'Disease', 'MESH:D013274', (136, 151))	('Fzd7-positive', 'Var', (37, 50))	('patient', 'Species', '9606', (92, 99))	('gastric cancers', 'Disease', (136, 151))	('gastric cancers', 'Phenotype', 'HP:0012126', (136, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('gastric cancers', 'Disease', 'MESH:D013274', (51, 66))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('gastric cancers', 'Disease', (51, 66))	('gastric cancers', 'Phenotype', 'HP:0012126', (51, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))
322901	22182510	Treatment of ALL cells from patients or ALL cell lines with Wnt3a conditioned media increased beta-catenin stabilization and induced proliferation of ALL cells, suggesting that Fzd7 may facilitate ALL progression through the activation of Wnt/beta-catenin signaling.	('Wnt3a', 'Gene', (60, 65))	('facilitate', 'PosReg', (186, 196))	('increased', 'PosReg', (84, 93))	('proliferation', 'CPA', (133, 146))	('Fzd7', 'Var', (177, 181))	('Wnt', 'Gene', '35975', (60, 63))	('ALL', 'Phenotype', 'HP:0006721', (40, 43))	('Wnt', 'Gene', (60, 63))	('ALL', 'Phenotype', 'HP:0006721', (150, 153))	('patients', 'Species', '9606', (28, 36))	('ALL', 'Phenotype', 'HP:0006721', (197, 200))	('ALL', 'Phenotype', 'HP:0006721', (13, 16))	('beta-catenin', 'Gene', (94, 106))	('beta-catenin', 'Gene', '1499', (94, 106))	('beta-catenin', 'Gene', (243, 255))	('beta-catenin', 'Gene', '1499', (243, 255))	('Wnt', 'Gene', '35975', (239, 242))	('Wnt', 'Gene', (239, 242))	('ALL progression', 'CPA', (197, 212))	('Wnt3a', 'Gene', '89780', (60, 65))
322902	22182510	Fzd7 can activate the canonical and/or the non-canonical Wnt signaling pathways in different types of cancers based on the availability of the cognate Wnt proteins, the co-receptors, and the variation in sequence homology between the different Fzd isoforms.	('Fzd7', 'Var', (0, 4))	('Wnt', 'Gene', '35975', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Wnt', 'Gene', '35975', (151, 154))	('Wnt', 'Gene', (57, 60))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('Wnt', 'Gene', (151, 154))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('activate', 'PosReg', (9, 17))	('canonical and/or', 'Pathway', (22, 38))
322909	22182510	showed that Fzd2 and Fzd7 mediate canonical Wnt3a signaling in the human lung carcinoma H441 cell line.	('Fzd7', 'Var', (21, 25))	('mediate', 'Reg', (26, 33))	('Wnt3a', 'Gene', (44, 49))	('Fzd2', 'Gene', (12, 16))	('lung carcinoma H441', 'Disease', 'MESH:D008175', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Wnt3a', 'Gene', '89780', (44, 49))	('Fzd2', 'Gene', '2535', (12, 16))	('human', 'Species', '9606', (67, 72))	('lung carcinoma H441', 'Disease', (73, 92))
322911	22182510	Fzd7 can also activate PKCdelta (an nPKC family member, which is activated by diacylglycerol and not Ca2+) by recruiting it to the plasma membrane via Dvl, and active PKCdelta in turn activates JNK in Xenopus embryos.	('PKC', 'Gene', '112476', (167, 170))	('Fzd7', 'Var', (0, 4))	('activates', 'PosReg', (184, 193))	('Xenopus', 'Species', '8355', (201, 208))	('Ca2+', 'Chemical', 'MESH:D000069285', (101, 105))	('diacylglycerol', 'Chemical', 'MESH:D004075', (78, 92))	('JNK', 'Enzyme', (194, 197))	('PKC', 'Gene', '112476', (37, 40))	('PKC', 'Gene', (23, 26))	('PKC', 'Gene', (37, 40))	('recruiting', 'PosReg', (110, 120))	('PKC', 'Gene', (167, 170))	('PKC', 'Gene', '112476', (23, 26))
322922	22182510	It has been found that Fzd7 mRNA levels in human embryonic stem cells were up to 200-fold higher compared to differentiated cell types, and that shRNA-mediated knockdown of Fzd7 in human embryonic stem cells induced dramatic changes in the morphology of embryonic stem cell colonies, perturbation of expression levels of germ layer-specific marker genes, and a rapid loss of expression of the embryonic stem cell-specific transcription factor OCT4.	('morphology', 'CPA', (240, 250))	('changes', 'Reg', (225, 232))	('human', 'Species', '9606', (181, 186))	('perturbation', 'Reg', (284, 296))	('mRNA levels', 'MPA', (28, 39))	('knockdown', 'Var', (160, 169))	('expression levels', 'MPA', (300, 317))	('human', 'Species', '9606', (43, 48))	('OCT4', 'Gene', (443, 447))	('expression', 'MPA', (375, 385))	('Fzd7', 'Gene', (23, 27))	('higher', 'PosReg', (90, 96))	('OCT4', 'Gene', '5460', (443, 447))	('loss of', 'NegReg', (367, 374))	('Fzd7', 'Var', (173, 177))
322923	22182510	Stem cells that harbor APC mutations tend to proliferate and form adenomas, which ultimately can become cancerous with ensuing metastasis.	('mutations', 'Var', (27, 36))	('proliferate', 'CPA', (45, 56))	('adenomas', 'Disease', (66, 74))	('cancerous', 'Disease', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('APC', 'Disease', (23, 26))	('APC', 'Disease', 'MESH:D011125', (23, 26))	('cancerous', 'Disease', 'MESH:D009369', (104, 113))	('APC', 'Phenotype', 'HP:0005227', (23, 26))	('adenomas', 'Disease', 'MESH:D000236', (66, 74))
322935	22182510	The utilization of siRNA to knockdown the endogenous expression of Fzd7 decreases the invasive and metastatic potential of colon cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (123, 135))	('decreases', 'NegReg', (72, 81))	('colon cancer', 'Disease', 'MESH:D015179', (123, 135))	('Fzd7', 'Gene', (67, 71))	('knockdown', 'Var', (28, 37))	('colon cancer', 'Disease', (123, 135))
322936	22182510	Furthermore, Fzd7 shRNA suppresses Wnt/beta-catenin signaling and subsequent cell proliferation and tumor growth in vivo using TNBC cells.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Wnt', 'Gene', '35975', (35, 38))	('beta-catenin', 'Gene', '1499', (39, 51))	('suppresses', 'NegReg', (24, 34))	('beta-catenin', 'Gene', (39, 51))	('Wnt', 'Gene', (35, 38))	('Fzd7 shRNA', 'Var', (13, 23))	('cell proliferation', 'CPA', (77, 95))
322943	22182510	Furthermore, the expression of sFRPs and Dkk1 sensitizes Fzd7+ Wilm's tumor cells to Fzd7-Ab treatment.	('Dkk1', 'Gene', '22943', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('sensitizes', 'Reg', (46, 56))	('Dkk1', 'Gene', (41, 45))	("Wilm's tumor", 'Disease', (63, 75))	('Fzd7+', 'Disease', (57, 62))	("Wilm's tumor", 'Disease', 'MESH:D009396', (63, 75))	('expression', 'Var', (17, 27))	('sFRPs', 'Gene', (31, 36))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (63, 75))
322946	22182510	Another feasible method of treating cancer through modulation of Fzd7 may involve the use of soluble peptide fragments to antagonize Fzd7.	('Fzd7', 'Gene', (65, 69))	('modulation', 'Var', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Fzd7', 'Gene', (133, 137))
322949	22182510	The effects of sFzd7 on abating Wnt/beta-catenin signaling were accomplished by the competitive binding of the Fzd7 extracellular CRD with Wnt3, which activates the canonical Wnt signaling pathway.	('Wnt', 'Gene', (32, 35))	('Wnt', 'Gene', '35975', (139, 142))	('Wnt3', 'Gene', '7473', (139, 143))	('Wnt', 'Gene', (139, 142))	('CRD', 'Disease', 'OMIM:120970', (130, 133))	('Wnt', 'Gene', '35975', (175, 178))	('binding', 'Interaction', (96, 103))	('Wnt3', 'Gene', (139, 143))	('beta-catenin', 'Gene', (36, 48))	('Fzd7', 'Var', (111, 115))	('Wnt', 'Gene', (175, 178))	('CRD', 'Disease', (130, 133))	('Wnt', 'Gene', '35975', (32, 35))	('beta-catenin', 'Gene', '1499', (36, 48))	('activates', 'PosReg', (151, 160))
322951	22182510	The membrane-permeable RHPDs contain the KTLQSW motif of the cytoplasmic tail of Fzd7 and thereby are able to disrupt the interaction between Fzd7 and Dvl.	('interaction', 'Interaction', (122, 133))	('KTLQSW', 'Var', (41, 47))	('RHPD', 'Disease', 'OMIM:208540', (23, 27))	('disrupt', 'NegReg', (110, 117))	('RHPD', 'Disease', (23, 27))	('Fzd7', 'Gene', (81, 85))
322953	22182510	The therapeutic utility of disrupting PDZ protein-protein interactions was also shown by a small molecule inhibitor FJ9.	('disrupting', 'Var', (27, 37))	('FJ9', 'Chemical', '-', (116, 119))	('PDZ protein-protein interactions', 'Protein', (38, 70))
322954	22182510	FJ9 displayed beta-catenin-dependent anti-cancer activities such as inducing apoptosis in the LOX melanoma cell line and the H460 and H1703 non-small cell lung cancer cell lines and attenuating in vivo tumor growth in the H460 lung cancer mouse xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (232, 238))	('H460 lung cancer', 'Disease', 'MESH:D008175', (222, 238))	('H460', 'CellLine', 'CVCL:0459', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('H460 lung cancer', 'Disease', (222, 238))	('attenuating', 'NegReg', (182, 193))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('tumor', 'Disease', (202, 207))	('apoptosis', 'CPA', (77, 86))	('cancer', 'Disease', (160, 166))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('beta-catenin', 'Gene', (14, 26))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (140, 166))	('beta-catenin', 'Gene', '1499', (14, 26))	('FJ9', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (227, 238))	('non-small cell lung cancer', 'Disease', (140, 166))	('FJ9', 'Chemical', '-', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('cancer', 'Disease', (42, 48))	('melanoma', 'Disease', (98, 106))	('inducing', 'PosReg', (68, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('mouse', 'Species', '10090', (239, 244))	('H460', 'CellLine', 'CVCL:0459', (222, 226))
322976	17622239	Our analysis showed that Akt phosphorylation was unaffected by HPV16 infection.	('HPV16', 'Species', '333760', (63, 68))	('Akt', 'Gene', '207', (25, 28))	('HPV16', 'Gene', (63, 68))	('infection', 'Var', (69, 78))	('Akt', 'Gene', (25, 28))
323005	17622239	Thirty (29.4%) HPV16 positives and 1 (2.6%) HPV16 negatives were stained as degree II and above (P<0.002) (Table 2).	('HPV16', 'Species', '333760', (44, 49))	('HPV16', 'Species', '333760', (15, 20))	('HPV16', 'Gene', (15, 20))	('positives', 'Var', (21, 30))
323051	17622239	Recent studies also found that amplification of the PIK3CA gene accompanied by serine 473 phosphorylation of AKT is common in cervical cancers and it seems to be an independent event to HPV infection (Ma et al, 2000; Zhang et al, 2002; Bertelsen et al, 2006).	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('AKT', 'Gene', '207', (109, 112))	('serine 473 phosphorylation', 'MPA', (79, 105))	('cervical cancers', 'Disease', (126, 142))	('PIK3CA', 'Gene', (52, 58))	('HPV infection', 'Disease', 'MESH:D030361', (186, 199))	('cervical cancers', 'Disease', 'MESH:D002583', (126, 142))	('serine', 'Chemical', 'MESH:D012694', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('common', 'Reg', (116, 122))	('PIK3CA', 'Gene', '5290', (52, 58))	('AKT', 'Gene', (109, 112))	('HPV infection', 'Disease', (186, 199))	('amplification', 'Var', (31, 44))
323055	17622239	In addition, Kim et al (2006) reported that Akt phosphorylation contributes to radioresistance in cervical cancer.	('contributes', 'Reg', (64, 75))	('phosphorylation', 'Var', (48, 63))	('Akt', 'Gene', '207', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cervical cancer', 'Disease', 'MESH:D002583', (98, 113))	('radioresistance', 'CPA', (79, 94))	('cervical cancer', 'Disease', (98, 113))	('Akt', 'Gene', (44, 47))
323064	33626086	Body weight loss was significantly lower in the DFT group than in the JI group (-8.1% vs -16.1%, P = 0.001).	('weight loss', 'Phenotype', 'HP:0001824', (5, 16))	('DFT', 'Var', (48, 51))	('JI', 'Phenotype', 'HP:0004786', (70, 72))	('weight loss', 'Disease', 'MESH:D015431', (5, 16))	('lower', 'NegReg', (35, 40))	('JI', 'Chemical', '-', (70, 72))	('DFT', 'Chemical', '-', (48, 51))	('weight loss', 'Disease', (5, 16))
323065	33626086	Total protein and albumin levels were higher in the DFT group than in the JI group (0% vs -2.9%, P = 0.053, and -0.3% vs -6.1%, P = 0.077, respectively).	('JI', 'Chemical', '-', (74, 76))	('JI', 'Phenotype', 'HP:0004786', (74, 76))	('DFT', 'Var', (52, 55))	('albumin', 'Gene', (18, 25))	('albumin', 'Gene', '213', (18, 25))	('higher', 'PosReg', (38, 44))	('DFT', 'Chemical', '-', (52, 55))
323084	33626086	In the study period, 35 consecutive patients with primary cT1N0 or cT2N0 gastric cancer of the upper third of the stomach underwent PG at our institution.	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('PG', 'Chemical', '-', (132, 134))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('cT1', 'Gene', '1489', (58, 61))	('cancer of the upper third of the stomach', 'Phenotype', 'HP:0006753', (81, 121))	('cT1', 'Gene', (58, 61))	('cT2N0', 'Var', (67, 72))	('gastric cancer', 'Disease', (73, 87))
323113	33626086	The DFT group experienced significantly lesser blood loss than the JI group (250 ml vs 435 ml, P = 0.015).	('lesser', 'NegReg', (40, 46))	('DFT', 'Var', (4, 7))	('blood loss', 'Disease', 'MESH:D006473', (47, 57))	('DFT', 'Chemical', '-', (4, 7))	('blood loss', 'Disease', (47, 57))	('JI', 'Phenotype', 'HP:0004786', (67, 69))	('JI', 'Chemical', '-', (67, 69))
323114	33626086	In terms of postoperative complications (CD >= 3), an anastomotic leakage and a pancreatic fistula occurred only in the DFT group, but this did not significantly differ from the JI group (P = 0.412).	('DFT', 'Var', (120, 123))	('JI', 'Phenotype', 'HP:0004786', (178, 180))	('pancreatic fistula', 'Phenotype', 'HP:0100844', (80, 98))	('JI', 'Chemical', '-', (178, 180))	('anastomotic leakage', 'Disease', 'MESH:D057868', (54, 73))	('DFT', 'Chemical', '-', (120, 123))	('anastomotic leakage', 'Disease', (54, 73))	('pancreatic fistula', 'Disease', 'MESH:D010185', (80, 98))	('pancreatic fistula', 'Disease', (80, 98))
323118	33626086	The body weight loss percentage at 1 year after surgery in the DFT group was significantly lower than that in the JI group (-8.1% vs -16.1%, P = 0.001).	('lower', 'NegReg', (91, 96))	('DFT', 'Var', (63, 66))	('weight loss', 'Phenotype', 'HP:0001824', (9, 20))	('weight loss', 'Disease', 'MESH:D015431', (9, 20))	('DFT', 'Chemical', '-', (63, 66))	('JI', 'Chemical', '-', (114, 116))	('weight loss', 'Disease', (9, 20))	('JI', 'Phenotype', 'HP:0004786', (114, 116))
323119	33626086	Of clinical significance, the postoperative mean TP and Alb loss tended to be lower in the DFT group than in the JI group (0% vs -2.9%, P = 0.053 and -0.3% vs -6.1%, P = 0.077, respectively).	('JI', 'Chemical', '-', (113, 115))	('JI', 'Phenotype', 'HP:0004786', (113, 115))	('TP', 'Chemical', '-', (49, 51))	('DFT', 'Chemical', '-', (91, 94))	('DFT', 'Var', (91, 94))	('Alb loss', 'Disease', 'MESH:D014786', (56, 64))	('Alb loss', 'Disease', (56, 64))	('lower', 'NegReg', (78, 83))
323124	33626086	Overall, three (27%) and nine (53%) patients experienced digestive symptoms in the DFT and JI groups, respectively (P = 0.253).	('digestive symptoms', 'Disease', (57, 75))	('patients', 'Species', '9606', (36, 44))	('DFT', 'Var', (83, 86))	('DFT', 'Chemical', '-', (83, 86))	('JI', 'Chemical', '-', (91, 93))	('JI', 'Phenotype', 'HP:0004786', (91, 93))
323128	33626086	The current study investigated possible methods for reconstruction after PG for upper third cT1 or T2N0 gastric cancer that may be recommended for future surgeries.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('cT1', 'Gene', '1489', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('PG', 'Chemical', '-', (73, 75))	('cT1', 'Gene', (92, 95))	('T2N0', 'Var', (99, 103))	('gastric cancer', 'Disease', (104, 118))
323171	31611990	Previous studies have reported that EAC differs from esophageal squamous cell carcinoma (ESCC) in terms of genetic and environmental risk factors such as tobacco use, alcohol, obesity and germline mutations.	('obesity', 'Disease', (176, 183))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (53, 87))	('tobacco', 'Species', '4097', (154, 161))	('ESCC', 'Disease', 'MESH:C562729', (89, 93))	('EAC', 'Disease', (36, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('germline mutations', 'Var', (188, 206))	('EAC', 'Disease', 'MESH:D004941', (36, 39))	('ESCC', 'Disease', (89, 93))	('obesity', 'Phenotype', 'HP:0001513', (176, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('alcohol', 'Chemical', 'MESH:D000431', (167, 174))	('obesity', 'Disease', 'MESH:D009765', (176, 183))	('esophageal squamous cell carcinoma', 'Disease', (53, 87))
323184	31611990	Furthermore, Qu et al demonstrated that lncARSR mediates sunitinib resistance in renal cell carcinoma by competitively binding to miR-34/miR-449 to promote AXL receptor tyrosine kinase and c-MET expression.	('sunitinib', 'Chemical', 'MESH:C473478', (57, 66))	('lncARSR', 'Var', (40, 47))	('miR', 'Gene', '220972', (137, 140))	('c-MET', 'Gene', '4233', (189, 194))	('miR', 'Gene', '220972', (130, 133))	('AXL', 'Gene', (156, 159))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (81, 101))	('miR-34', 'Gene', '407040', (130, 136))	('c-MET', 'Gene', (189, 194))	('receptor tyrosine kinase', 'Gene', '5979', (160, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('miR', 'Gene', (137, 140))	('miR', 'Gene', (130, 133))	('renal cell carcinoma', 'Disease', (81, 101))	('receptor tyrosine kinase', 'Gene', (160, 184))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (81, 101))	('promote', 'PosReg', (148, 155))	('binding', 'Interaction', (119, 126))	('expression', 'MPA', (195, 205))	('miR-34', 'Gene', (130, 136))	('AXL', 'Gene', '558', (156, 159))
323202	31611990	Among these 26, 12 lncRNAs, AC007128.1, AC079354.3, AC246680.1, AL009178.2, AL135924.2, AL138789.1, AP003356.1, AP0033469.2, GK-IT1, HOTAIR, LINC01114 and LINC01768, were negatively correlated with OS (Fig.	('AL138789.1', 'Var', (88, 98))	('AP003356.1', 'Var', (100, 110))	('AL009178.2', 'Var', (64, 74))	('AL135924.2', 'Var', (76, 86))	('AP0033469.2', 'Var', (112, 123))	('LINC01114', 'Gene', (141, 150))	('GK-IT1', 'Gene', '106480740', (125, 131))	('AC007128.1', 'Var', (28, 38))	('LINC01768', 'Chemical', 'None', (155, 164))	('AC246680.1', 'Var', (52, 62))	('LINC01768', 'Var', (155, 164))	('HOTAIR', 'Gene', (133, 139))	('GK-IT1', 'Gene', (125, 131))	('negatively', 'NegReg', (171, 181))	('HOTAIR', 'Gene', '100124700', (133, 139))	('LINC01114', 'Gene', '284998', (141, 150))	('AC079354.3', 'Var', (40, 50))
323203	31611990	Conversely, the remaining 14 lncRNAs, AC004585.1, AC016395.1, AC024337.2, AC087491.1, AC093583.1, AC104211.1, AL022316.1, AL031429.1, CYP1B1-AS1, LINC00163, LINC00906, LINC01695, SLCO4A1-AS1 and UG0898H09, were positively correlated with OS (Fig.	('AL022316.1', 'Var', (110, 120))	('AC016395.1', 'Var', (50, 60))	('UG0898H09', 'Gene', (195, 204))	('CYP1B1-AS1', 'Gene', '285154;1545;5729', (134, 144))	('LINC00163', 'Gene', (146, 155))	('SLCO4A1-AS1', 'Gene', '100127888;28231;5729', (179, 190))	('AC087491.1', 'Var', (74, 84))	('AC004585.1', 'Var', (38, 48))	('LINC00906', 'Gene', '148145', (157, 166))	('AC024337.2', 'Var', (62, 72))	('LINC00163', 'Gene', '727699', (146, 155))	('correlated', 'Reg', (222, 232))	('LINC01695', 'Var', (168, 177))	('CYP1B1-AS1', 'Gene', (134, 144))	('AC093583.1', 'Var', (86, 96))	('LINC01695', 'Chemical', 'None', (168, 177))	('AC104211.1', 'Var', (98, 108))	('SLCO4A1-AS1', 'Gene', (179, 190))	('UG0898H09', 'Gene', '643763', (195, 204))	('AL031429.1', 'Var', (122, 132))	('LINC00906', 'Gene', (157, 166))
323205	31611990	The results demonstrated that the DEmRNAs were significantly enriched in the 'chemokine-mediated signaling pathway' (GO: 0070098), 'plasma membrane' (GO: 0005886) and 'calcium ion binding' (GO: 0005509) GO terms under 'biological process', 'cellular component' and 'molecular function', respectively (Fig.	('GO: 0005509', 'Var', (190, 201))	("'chemokine-mediated signaling pathway'", 'Pathway', (77, 115))	('calcium', 'Chemical', 'MESH:D002118', (168, 175))	('GO: 0005886', 'Var', (150, 161))	('GO: 0070098', 'Var', (117, 128))
323216	31611990	The dysregulation of lncRNA expression is involved in the pathogenesis of various types of solid tumor.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('lncRNA expression', 'Protein', (21, 38))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('dysregulation', 'Var', (4, 17))	('involved', 'Reg', (42, 50))	('tumor', 'Disease', (97, 102))
323218	31611990	According to this hypothesis, changes in the expression of one or multiple miRNA targets can alter the number of unbound miRNAs and lead to observable changes in miRNA activity.	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (75, 78))	('changes', 'Var', (30, 37))	('changes', 'Reg', (151, 158))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('alter', 'Reg', (93, 98))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))
323256	31190886	Silencing CDR1as increased the expression of miR-135b-5p and decreased the expression of hypoxia-inducible factor 1-alpha inhibitor (HIF1AN), thus increasing the proliferation capacity of ovarian cancer cells.	('increased', 'PosReg', (17, 26))	('hypoxia-inducible factor 1-alpha inhibitor', 'Gene', '55662', (89, 131))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ovarian cancer', 'Phenotype', 'HP:0100615', (188, 202))	('CDR1as', 'Gene', '103611090', (10, 16))	('HIF1AN', 'Gene', '55662', (133, 139))	('decreased', 'NegReg', (61, 70))	('ovarian cancer', 'Disease', 'MESH:D010051', (188, 202))	('HIF1AN', 'Gene', (133, 139))	('hypoxia-inducible factor 1-alpha inhibitor', 'Gene', (89, 131))	('increasing', 'PosReg', (147, 157))	('miR-135b-5p', 'Var', (45, 56))	('proliferation capacity', 'CPA', (162, 184))	('expression', 'MPA', (31, 41))	('ovarian cancer', 'Disease', (188, 202))	('CDR1as', 'Gene', (10, 16))	('Silencing', 'Var', (0, 9))	('expression', 'MPA', (75, 85))
323302	31190886	To explore the role of CDR1as in ovarian cancer, we determined the proliferation, invasion and migration of ovarian cancer cells after silencing or overexpressing CDR1as.	('migration of ovarian cancer', 'Disease', (95, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('CDR1as', 'Gene', '103611090', (163, 169))	('ovarian cancer', 'Disease', (33, 47))	('overexpressing', 'PosReg', (148, 162))	('silencing', 'Var', (135, 144))	('invasion', 'CPA', (82, 90))	('CDR1as', 'Gene', (23, 29))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('CDR1as', 'Gene', '103611090', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('migration of ovarian cancer', 'Disease', 'MESH:D010051', (95, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))	('CDR1as', 'Gene', (163, 169))
323304	31190886	The MTT and CCK8 assay results showed that the proliferation capacity of ovarian cancer cells was promoted after CDR1as silencing (Figure 2C and D).	('ovarian cancer', 'Disease', (73, 87))	('proliferation capacity', 'CPA', (47, 69))	('promoted', 'PosReg', (98, 106))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('CDR1as', 'Gene', (113, 119))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('silencing', 'Var', (120, 129))	('CDR1as', 'Gene', '103611090', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ovarian cancer', 'Disease', 'MESH:D010051', (73, 87))
323311	31190886	To further confirm the correlation between CDR1as and miR-135b-5p, we inhibited the expression of CDR1as in ovarian cancer cells.	('ovarian cancer', 'Disease', (108, 122))	('miR-135b-5p', 'Var', (54, 65))	('CDR1as', 'Gene', (43, 49))	('CDR1as', 'Gene', (98, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('CDR1as', 'Gene', '103611090', (43, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('expression', 'MPA', (84, 94))	('inhibited', 'NegReg', (70, 79))	('CDR1as', 'Gene', '103611090', (98, 104))
323312	31190886	The qRT-PCR assay results showed that silencing CDR1as can increase miR-135b-5p expression (Figure 4B).	('miR-135b-5p expression', 'MPA', (68, 90))	('CDR1as', 'Gene', (48, 54))	('CDR1as', 'Gene', '103611090', (48, 54))	('silencing', 'Var', (38, 47))	('increase', 'PosReg', (59, 67))
323315	31190886	Through the bioinformatics database (www.targetscan.org), we found that HIF1AN may be a target gene of miR-135b-5p (Figure 5A).	('HIF1AN', 'Gene', '55662', (72, 78))	('HIF1AN', 'Gene', (72, 78))	('miR-135b-5p', 'Var', (103, 114))
323317	31190886	The qRT-PCR assay results showed that the miR-135b-5p inhibitor increased the mRNA expression of HIF1AN (Figure 5B) and that silencing CDR1as reduced the mRNA expression of HIF1AN (Figure 5C).	('HIF1AN', 'Gene', '55662', (173, 179))	('silencing', 'Var', (125, 134))	('reduced', 'NegReg', (142, 149))	('mRNA expression', 'MPA', (78, 93))	('HIF1AN', 'Gene', '55662', (97, 103))	('mRNA expression', 'MPA', (154, 169))	('CDR1as', 'Gene', '103611090', (135, 141))	('increased', 'PosReg', (64, 73))	('HIF1AN', 'Gene', (97, 103))	('HIF1AN', 'Gene', (173, 179))	('CDR1as', 'Gene', (135, 141))
323320	31190886	The qRT-PCR and Western blot results revealed that a miR-135b-5p inhibitor blocked the downregulation of HIF1AN mRNA and protein after CDR1as silencing in ovarian cancer cells (Figure 6A and B).	('silencing', 'Var', (142, 151))	('HIF1AN', 'Gene', '55662', (105, 111))	('HIF1AN', 'Gene', (105, 111))	('CDR1as', 'Gene', '103611090', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('downregulation', 'NegReg', (87, 101))	('ovarian cancer', 'Disease', 'MESH:D010051', (155, 169))	('CDR1as', 'Gene', (135, 141))	('ovarian cancer', 'Disease', (155, 169))
323321	31190886	The MTT and CCK8 assay results showed that miR-135b-5p knockdown could significantly decrease the CDR1as silencing-mediated promotion of HO8910 and A2780 cell proliferation (Figure 6C and D).	('A2780 cell proliferation', 'CPA', (148, 172))	('miR-135b-5p', 'Var', (43, 54))	('promotion', 'PosReg', (124, 133))	('A2780', 'CellLine', 'CVCL:0134', (148, 153))	('CDR1as', 'Gene', (98, 104))	('silencing-mediated', 'NegReg', (105, 123))	('decrease', 'NegReg', (85, 93))	('HO8910', 'CellLine', 'CVCL:6868', (137, 143))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('CDR1as', 'Gene', '103611090', (98, 104))	('HO8910', 'CPA', (137, 143))
323336	31190886	Valeri et al revealed that miR-135b is a downstream effector of the PTEN/PI3K pathway that leads to increased proliferation and invasion and decreased apoptosis in colorectal cancer (CRC) mouse models.	('mouse', 'Species', '10090', (188, 193))	('colorectal cancer', 'Phenotype', 'HP:0003003', (164, 181))	('increased', 'PosReg', (100, 109))	('miR-135b', 'Var', (27, 35))	('colorectal cancer', 'Disease', (164, 181))	('CRC', 'Phenotype', 'HP:0003003', (183, 186))	('PTEN', 'Gene', '19211', (68, 72))	('PTEN', 'Gene', (68, 72))	('proliferation', 'CPA', (110, 123))	('decreased', 'NegReg', (141, 150))	('apoptosis', 'CPA', (151, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (164, 181))	('invasion', 'CPA', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
323337	31190886	In nonsmall cell lung cancer, miR-135b targets multiple key components of the Hippo pathway and LZTS1, thereby enhancing cancer cell invasion and migration in vitro and promoting cancer cell metastasis in vivo.	('migration', 'CPA', (146, 155))	('nonsmall cell lung cancer', 'Disease', (3, 28))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('miR-135b', 'Var', (30, 38))	('LZTS1', 'Gene', '11178', (96, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('promoting', 'PosReg', (169, 178))	('enhancing', 'PosReg', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('LZTS1', 'Gene', (96, 101))	('cancer', 'Disease', (179, 185))	('cancer', 'Disease', (121, 127))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (3, 28))
323338	31190886	In our study, miR-135b-5p promoted the proliferation of ovarian cancer cells by inhibiting the expression of HIF1AN.	('HIF1AN', 'Gene', '55662', (109, 115))	('HIF1AN', 'Gene', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (56, 70))	('promoted', 'PosReg', (26, 34))	('proliferation', 'CPA', (39, 52))	('inhibiting', 'NegReg', (80, 90))	('ovarian cancer', 'Disease', 'MESH:D010051', (56, 70))	('miR-135b-5p', 'Var', (14, 25))	('ovarian cancer', 'Disease', (56, 70))	('expression', 'MPA', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
323341	31190886	Our study found that miR-135b-5p can promote ovarian cancer cell proliferation by inhibiting the expression of HIF1AN.	('inhibiting', 'NegReg', (82, 92))	('promote', 'PosReg', (37, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('miR-135b-5p', 'Var', (21, 32))	('HIF1AN', 'Gene', (111, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (45, 59))	('HIF1AN', 'Gene', '55662', (111, 117))	('ovarian cancer', 'Disease', (45, 59))	('expression', 'MPA', (97, 107))
323351	30777052	High DNA methylation coincided with low mRNA and protein expression levels of SOX17 in pre-treatment endoscopic biopsy from ESCC patients with poor CCRT response.	('methylation', 'Var', (9, 20))	('DNA', 'MPA', (5, 8))	('low', 'NegReg', (36, 39))	('patients', 'Species', '9606', (129, 137))	('SOX17', 'Gene', (78, 83))	('expression', 'Species', '29278', (57, 67))	('ESCC', 'Disease', (124, 128))
323367	30777052	Notably, promoter hypermethylation of SOX17 gene leading to silence of SOX17 protein can be found in tumor of ~ 50% ESCC patients analyzed.	('promoter hypermethylation', 'Var', (9, 34))	('ESCC', 'Disease', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('SOX17', 'Gene', (71, 76))	('protein', 'Protein', (77, 84))	('silence', 'NegReg', (60, 67))	('patients', 'Species', '9606', (121, 129))	('SOX17 gene', 'Gene', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
323373	30777052	Re-expression of SOX17 was confirmed to sensitize radio-resistant ESCC cells to CCRT treatment in cell and xenograft models.	('expression', 'Species', '29278', (3, 13))	('sensitize', 'Reg', (40, 49))	('SOX17', 'Gene', (17, 22))	('Re-expression', 'Var', (0, 13))
323386	30777052	To construct the p21 promoter-Luciferase reporter plasmid, the DNA fragment corresponding to residues - 2276~ + 61 containing 24 SOX17 binding sites (predicted by PROMO) was PCR amplified.	('p21', 'Gene', '644914', (17, 20))	('p21', 'Gene', (17, 20))	('residues - 2276~ + 61', 'Var', (93, 114))
323428	30777052	In addition, DNA methylation and mRNA expression of SOX17 displayed significant inverse correlation (r = - 0.300, P = 0.015, Fig.	('expression', 'Species', '29278', (38, 48))	('DNA', 'MPA', (13, 16))	('SOX17', 'Gene', (52, 57))	('mRNA expression', 'MPA', (33, 48))	('methylation', 'Var', (17, 28))	('inverse', 'NegReg', (80, 87))
323431	30777052	In addition, IHC staining results demonstrated lower SOX17 protein expression in CCRT non-responders compared with CCRT responders (P = 0.021, Fig.	('lower', 'NegReg', (47, 52))	('non-responders', 'Var', (86, 100))	('SOX17 protein', 'Protein', (53, 66))	('expression', 'Species', '29278', (67, 77))	('rat', 'Species', '10116', (41, 44))	('CCRT', 'Disease', (81, 85))
323438	30777052	KYSE510-SOX17 stable cells displayed a decrease in cell viability compared with KYSE510-EV (empty vector) control cells when treated with various doses of cisplatin, radiation, and CCRT for 72 h (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('KYSE510-SOX17', 'Var', (0, 13))	('cell viability', 'CPA', (51, 65))	('decrease', 'NegReg', (39, 47))
323440	30777052	However, si-knockdown of SOX17 in KYSE510 cells led to an increase in cell viability upon cisplatin treatment as compared to si-control cells.	('increase', 'PosReg', (58, 66))	('si-knockdown', 'Var', (9, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('SOX17', 'Gene', (25, 30))	('cell viability', 'CPA', (70, 84))
323441	30777052	The enhanced cell viability by knocking down of SOX17 upon cisplatin treatment was confirmed in an addition cell line KYSE170 (Additional file 1: Figure S1).	('cell viability', 'CPA', (13, 27))	('knocking down', 'Var', (31, 44))	('SOX17', 'Gene', (48, 53))	('enhanced', 'PosReg', (4, 12))	('KYSE170', 'CellLine', 'CVCL:1358', (118, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))
323443	30777052	Importantly, SOX17 mRNA expression was significantly lower in KYSE510-R cells than KYSE510 parental cells (Fig.	('SOX17', 'Gene', (13, 18))	('expression', 'Species', '29278', (24, 34))	('mRNA expression', 'MPA', (19, 34))	('KYSE510-R', 'Var', (62, 71))	('lower', 'NegReg', (53, 58))
323444	30777052	These results suggested that low SOX17 mRNA expression occurred in radio-resistant ESCC cells in part due to hypermethylation of SOX17 promoter.	('low', 'NegReg', (29, 32))	('expression', 'Species', '29278', (44, 54))	('SOX17', 'Enzyme', (33, 38))	('hypermethylation', 'Var', (109, 125))
323450	30777052	Together, these results indicated that SOX17 re-expression sensitized ESCC radio-resistant cells to cisplatin, radiation and CCRT treatments.	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('expression', 'Species', '29278', (48, 58))	('sensitized', 'Reg', (59, 69))	('SOX17', 'Gene', (39, 44))	('re-expression', 'Var', (45, 58))	('cisplatin', 'MPA', (100, 109))
323452	30777052	Studies have reported that enhancement of DNA repair is crucial for the development of resistance, and defects in DNA repair pathways caused increase sensitivity to DNA-damaging agents such as chemotherapeutic agents and radiation in tumor cells.	('tumor', 'Disease', (234, 239))	('increase', 'PosReg', (141, 149))	('defects', 'Var', (103, 110))	('DNA repair pathways', 'Pathway', (114, 133))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('sensitivity to DNA-damaging', 'MPA', (150, 177))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
323454	30777052	Therefore, we hypothesized that SOX17 would transcriptionally down-regulate DNA repair-related genes and damage-responsive genes to sensitize ESCC cells to anti-cancer treatments.	('cancer', 'Disease', (161, 167))	('sensitize', 'Reg', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('DNA repair-related genes', 'Gene', (76, 100))	('SOX17', 'Var', (32, 37))	('down-regulate', 'NegReg', (62, 75))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('ESCC', 'Disease', (142, 146))
323458	30777052	The results showed that mRNA and protein expression levels of these genes were mostly up-regulated in the KYSE510-R compared with parental KYSE510 cells (Fig.	('KYSE510-R', 'Var', (106, 115))	('expression', 'Species', '29278', (41, 51))	('up-regulated', 'PosReg', (86, 98))
323464	30777052	Together these mRNA and protein results indicated that SOX17 overexpression sensitized ESCC resistant cells to anti-cancer treatment via down-regulation of DNA repair or damage-responsive genes.	('cancer', 'Disease', (116, 122))	('sensitized', 'Reg', (76, 86))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('expression', 'Species', '29278', (65, 75))	('SOX17', 'Gene', (55, 60))	('DNA', 'Gene', (156, 159))	('down-regulation', 'NegReg', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('overexpression', 'Var', (61, 75))	('damage-responsive', 'Gene', (170, 187))
323465	30777052	ChIP-qPCR showed the significantly enriched binding of SOX17 at BRCA1, BRCA2, RAD51, KU80, p21, NFAT5, REV3L and SIRT1 promoters in KYSE510-R-SOX17 cells as compared to that in KYSE510-R-EV cells (Fig.	('BRCA1', 'Gene', '672', (64, 69))	('NFAT5', 'Gene', '10725', (96, 101))	('KYSE510-R-SOX17', 'Var', (132, 147))	('SIRT1', 'Gene', '23411', (113, 118))	('RAD51', 'Gene', (78, 83))	('BRCA1', 'Gene', (64, 69))	('BRCA2', 'Gene', (71, 76))	('REV3L', 'Gene', (103, 108))	('KU80', 'Gene', (85, 89))	('SOX17', 'Gene', (55, 60))	('SIRT1', 'Gene', (113, 118))	('p21', 'Gene', (91, 94))	('REV3L', 'Gene', '5980', (103, 108))	('NFAT5', 'Gene', (96, 101))	('binding', 'Interaction', (44, 51))	('p21', 'Gene', '644914', (91, 94))	('BRCA2', 'Gene', '675', (71, 76))
323467	30777052	Both p21 and NFAT5 promoter activities were significantly inhibited in KYSE510-R-SOX17 than KYSE510-R-EV control cells (P < 0.001, Fig.	('p21', 'Gene', '644914', (5, 8))	('KYSE510-R-SOX17', 'Var', (71, 86))	('NFAT5', 'Gene', (13, 18))	('NFAT5', 'Gene', '10725', (13, 18))	('p21', 'Gene', (5, 8))	('inhibited', 'NegReg', (58, 67))
323476	30777052	7c) of xenografts in KYSE510-R-SOX17 mice group were decreased in comparison with those in KYSE510-R-EV mice group.	('KYSE510-R-SOX17', 'Var', (21, 36))	('decreased', 'NegReg', (53, 62))	('mice', 'Species', '10090', (104, 108))	('mice', 'Species', '10090', (37, 41))
323477	30777052	Importantly, tumors derived from KYSE510-R-SOX17 were highly sensitive to CCRT treatment in vivo.	('sensitive', 'MPA', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('KYSE510-R-SOX17', 'Var', (33, 48))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
323478	30777052	The results of our experiments using cell model suggested that SOX17 overexpression sensitized ESCC cells to CCRT response by downregulating the mRNA expression of DNA repair and DNA damage response gene.	('mRNA expression', 'MPA', (145, 160))	('DNA repair', 'Gene', (164, 174))	('SOX17', 'Gene', (63, 68))	('expression', 'Species', '29278', (73, 83))	('overexpression', 'Var', (69, 83))	('expression', 'Species', '29278', (150, 160))	('sensitized', 'Reg', (84, 94))	('CCRT response', 'MPA', (109, 122))	('downregulating', 'NegReg', (126, 140))
323479	30777052	The RT-qPCR results of xenograft tissues showed that mRNA expression of BRCA1, DNAPK, p21 and RAD51 decreased when SOX17 was overexpressed (KYSE510-R-SOX17 vs. KYSE510-R-EV) and the effects of downregulation were more dramatic in most of genes under CCRT treatment (KYSE510-R-SOX17 + CCRT vs. KYSE510-R-EV + CCRT) (Fig.	('KYSE510-R-EV', 'Var', (160, 172))	('p21', 'Gene', (86, 89))	('expression', 'Species', '29278', (58, 68))	('BRCA1', 'Gene', '672', (72, 77))	('DNAPK', 'Gene', (79, 84))	('KYSE510-R-SOX17', 'Var', (266, 281))	('p21', 'Gene', '644914', (86, 89))	('BRCA1', 'Gene', (72, 77))	('KYSE510-R-SOX17', 'Var', (140, 155))	('RAD51', 'Gene', (94, 99))	('decreased', 'NegReg', (100, 109))	('KYSE510-R-EV', 'Var', (293, 305))	('mRNA expression', 'MPA', (53, 68))
323485	30777052	Re-expression of SOX17 was confirmed to sensitize radio-resistant ESCC cells to radiation, cisplatin or CCRT treatment in cell and animal models.	('expression', 'Species', '29278', (3, 13))	('SOX17', 'Gene', (17, 22))	('Re-expression', 'Var', (0, 13))	('sensitize', 'Reg', (40, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))
323488	30777052	Here, we reveal a novel mechanism that SOX17 significantly decreased expression of genes involved in HR and NHEJ pathways via transcription regulation.	('transcription', 'MPA', (126, 139))	('decreased', 'NegReg', (59, 68))	('expression', 'Species', '29278', (69, 79))	('SOX17', 'Var', (39, 44))	('expression of genes', 'MPA', (69, 88))	('NHEJ pathways', 'Pathway', (108, 121))
323581	23999171	Insulin was positively associated with BE among those with GERD, but not among those without GERD (Table 4) (P for heterogeneity of OR = .08).	('associated', 'Interaction', (23, 33))	('positively', 'PosReg', (12, 22))	('BE', 'Phenotype', 'HP:0100580', (39, 41))	('Insulin', 'Gene', '3630', (0, 7))	('GERD', 'Var', (59, 63))	('Insulin', 'Gene', (0, 7))
323687	24475046	To facilitate the ROC curve analysis, the clinicopathologic characteristics were dichotomized as follows: AFP level (<=20 ng/ml vs.>20 ng/ml), tumor size (<=5 cm vs. >5 cm), tumor multiplicity (single vs. multiple), tumor differentiation (I + II vs. III + IV), stage (I + II vs. III + IV), vascular invasion (absence vs. presence), relapse (absence vs. presence) and survival status [death from HCC vs. others (censored, alive or death from other causes)].	('vascular invasion', 'CPA', (290, 307))	('relapse', 'CPA', (332, 339))	('death', 'Disease', (430, 435))	('<=20', 'Var', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (216, 221))	('death', 'Disease', 'MESH:D003643', (384, 389))	('AFP', 'Gene', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('AFP', 'Gene', '174', (106, 109))	('HCC', 'Gene', '619501', (395, 398))	('HCC', 'Phenotype', 'HP:0001402', (395, 398))	('HCC', 'Gene', (395, 398))	('death', 'Disease', 'MESH:D003643', (430, 435))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', (143, 148))	('death', 'Disease', (384, 389))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
323716	24475046	The tumor heterogeneity and the accumulation of genetic and epigenetic alterations probably lead to the prognostic variability of individuals with HCC.	('tumor', 'Disease', (4, 9))	('lead', 'Reg', (92, 96))	('HCC', 'Gene', (147, 150))	('HCC', 'Gene', '619501', (147, 150))	('epigenetic alterations', 'Var', (60, 82))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('genetic', 'Var', (48, 55))	('HCC', 'Phenotype', 'HP:0001402', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
323721	24475046	PTPN12, one member of the PTP family, has been identified as a potent tumor suppressor in human breast cancer and loss of PTPN12 phosphatase activity leads to aberrant acinar morphogenesis and cellular transformation in mammary epithelial cells.	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('PTP', 'Gene', '10076', (26, 29))	('human', 'Species', '9606', (90, 95))	('breast cancer', 'Disease', (96, 109))	('PTPN12', 'Gene', (122, 128))	('PTP', 'Gene', '10076', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('PTPN12', 'Gene', '5782', (0, 6))	('PTP', 'Gene', '10076', (0, 3))	('leads to', 'Reg', (150, 158))	('PTP', 'Gene', (26, 29))	('cellular transformation', 'CPA', (193, 216))	('activity', 'MPA', (141, 149))	('PTP', 'Gene', (122, 125))	('phosphatase', 'Enzyme', (129, 140))	('PTPN12', 'Gene', (0, 6))	('PTPN12', 'Gene', '5782', (122, 128))	('tumor', 'Disease', (70, 75))	('loss', 'Var', (114, 118))	('PTP', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
323738	24475046	As we know, the loss of cell-cell adhesion increases invasion and metastasis, which is an important step in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('increases', 'PosReg', (43, 52))	('loss', 'Var', (16, 20))	('cell-cell adhesion', 'Protein', (24, 42))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
323741	24475046	However, during the course of HCC tumorigenesis, PTPN12 might be compromised in HCC by deletion, inactivating sequence variants or loss of expression.	('HCC', 'Gene', (30, 33))	('HCC', 'Gene', '619501', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('PTPN12', 'Gene', (49, 55))	('HCC', 'Gene', '619501', (30, 33))	('HCC', 'Phenotype', 'HP:0001402', (80, 83))	('HCC', 'Phenotype', 'HP:0001402', (30, 33))	('loss of', 'NegReg', (131, 138))	('inactivating sequence variants', 'Var', (97, 127))	('expression', 'MPA', (139, 149))	('HCC', 'Gene', (80, 83))	('deletion', 'Var', (87, 95))	('PTPN12', 'Gene', '5782', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
323745	24475046	It has been well established that promoter hypermethylation is one important molecular mechanism leading to gene silencing of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('promoter hypermethylation', 'Var', (34, 59))	('gene', 'MPA', (108, 112))	('tumor', 'Disease', (126, 131))
323746	24475046	reported that promoter CpG island hypermethylation was found to occur much more frequently in cell lines or specimens with low PTPN12 expression, indicating that it is potentially an important mechanism underlying PTPN12 down-regulation.	('PTPN12', 'Gene', '5782', (214, 220))	('hypermethylation', 'Var', (34, 50))	('expression', 'MPA', (134, 144))	('PTPN12', 'Gene', (214, 220))	('low', 'NegReg', (123, 126))	('PTPN12', 'Gene', '5782', (127, 133))	('men', 'Species', '9606', (113, 116))	('PTPN12', 'Gene', (127, 133))
323772	21864251	In a randomized study comparing three cisplatin doublets, severe esophagitis was seen in 52% of patients treated with cisplatin/gemcitabine, compared to 39% of patients treated with cisplatin/paclitaxel and 25% of patients treated with cisplatin/vinorelbine.	('cisplatin', 'Chemical', 'MESH:D002945', (182, 191))	('patients', 'Species', '9606', (160, 168))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('patients', 'Species', '9606', (214, 222))	('esophagitis', 'Phenotype', 'HP:0100633', (65, 76))	('esophagitis', 'Disease', (65, 76))	('cisplatin/gemcitabine', 'Var', (118, 139))	('esophagitis', 'Disease', 'MESH:D004941', (65, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('gemcitabine', 'Chemical', 'MESH:C056507', (128, 139))	('vinorelbine', 'Chemical', 'MESH:D000077235', (246, 257))	('patients', 'Species', '9606', (96, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (236, 245))	('paclitaxel', 'Chemical', 'MESH:D017239', (192, 202))
323779	21864251	Interestingly, the median duration of esophagitis (any grade) was nearly doubled in patients receiving hyperfractionated radiotherapy (3.2 months) compared to patients treated with daily irradiation (1.8 months).	('esophagitis', 'Disease', 'MESH:D004941', (38, 49))	('hyperfractionated', 'Var', (103, 120))	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (159, 167))	('esophagitis', 'Phenotype', 'HP:0100633', (38, 49))	('esophagitis', 'Disease', (38, 49))
323788	21864251	Rates of acute grade >= 2 esophagitis are expected to surpass 30% as V70 exceeds 20%, V50 exceeds 40%, and V35 exceeds 50%, respectively.	('V70', 'Var', (69, 72))	('V35', 'Gene', '28474', (107, 110))	('esophagitis', 'Phenotype', 'HP:0100633', (26, 37))	('esophagitis', 'Disease', (26, 37))	('esophagitis', 'Disease', 'MESH:D004941', (26, 37))	('V35', 'Gene', (107, 110))	('V50', 'Var', (86, 89))
323816	21864251	Among the nine node-positive patients, IMRT decreased the predicted esophageal complication rate from 42% to 19%.	('patients', 'Species', '9606', (29, 37))	('decreased', 'NegReg', (44, 53))	('IMRT', 'Var', (39, 43))	('esophageal complication', 'Disease', (68, 91))
323875	19670330	Several shared abnormalities were identified, including chromosome 9p CNN-LOH (2 BE samples [20%]), deletion of CDKN2A (4 BE samples [40%]), and amplification of 17q12-21.2 involving the ERBB2, RARA and TOP2A genes (3.1Mb, 2 EAC [29%]).	('ERBB2', 'Gene', (187, 192))	('amplification', 'Var', (145, 158))	('CDKN2A', 'Gene', (112, 118))	('TOP2A', 'Gene', (203, 208))	('CDKN2A', 'Gene', '1029', (112, 118))	('BE', 'Phenotype', 'HP:0100580', (81, 83))	('RARA', 'Gene', '5914', (194, 198))	('BE', 'Phenotype', 'HP:0100580', (122, 124))	('deletion', 'Var', (100, 108))	('ERBB2', 'Gene', '2064', (187, 192))	('TOP2A', 'Gene', '7153', (203, 208))	('RARA', 'Gene', (194, 198))	('EAC', 'Phenotype', 'HP:0011459', (225, 228))
323877	19670330	Real-time PCR analysis confirmed deletion of this gene and decreased expression of BNC2 mRNA in the BE sample.	('BE', 'Phenotype', 'HP:0100580', (100, 102))	('decreased', 'NegReg', (59, 68))	('deletion', 'Var', (33, 41))	('expression', 'MPA', (69, 79))	('BNC2', 'Gene', '54796', (83, 87))	('BNC2', 'Gene', (83, 87))
323878	19670330	Furthermore, transfection and stable expression of BNC2 caused growth arrest of OE33 EAC cells, suggesting that BNC2 functions as a tumor suppressor gene in the esophagus, and that deletion of this gene occurs during the development of EAC.	('EAC', 'Phenotype', 'HP:0011459', (85, 88))	('growth arrest', 'CPA', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('transfection', 'Var', (13, 25))	('EAC', 'Disease', (236, 239))	('BNC2', 'Gene', '54796', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('BNC2', 'Gene', (112, 116))	('BNC2', 'Gene', '54796', (51, 55))	('tumor', 'Disease', (132, 137))	('BNC2', 'Gene', (51, 55))	('deletion', 'Var', (181, 189))	('growth arrest', 'Phenotype', 'HP:0001510', (63, 76))	('EAC', 'Phenotype', 'HP:0011459', (236, 239))
323900	19670330	To validate CNN-LOH, 3 independent SNP sequences (rs2296820, rs668026, and rs2890896) at chromosome 9p were queried in case #11.	('rs2296820', 'Mutation', 'rs2296820', (50, 59))	('rs2890896', 'Mutation', 'rs2890896', (75, 84))	('rs2890896', 'Var', (75, 84))	('rs668026', 'Mutation', 'rs668026', (61, 69))	('rs668026', 'Var', (61, 69))	('rs2296820', 'Var', (50, 59))
323901	19670330	Primer sequences were as follows: 5'-AAA TGA CCG CAC CTC TGA AG-3' and 5'-GAG AGC GGC AAA CCA TTA GA-3' for rs2296820, 5'-TTT GCT AGT CTC ACC ACT TGC-3' and 5'-CCT TGC ACA TTA TAA ACT CTC GAT-3' for rs668026, and 5'-GGAAGG GTAGGC TTC CTG AT-3' and 5'-TCT GTG TCT TTG GTT CTT TTT CA-3' for rs2890896.	('rs668026', 'Var', (199, 207))	('rs2890896', 'Var', (289, 298))	('TGA', 'Gene', '6899', (57, 60))	('GAT-3', 'Gene', '6538', (188, 193))	('TGA', 'Gene', '6899', (41, 44))	('TGA', 'Gene', (57, 60))	('TGA', 'Gene', (41, 44))	('rs668026', 'Mutation', 'rs668026', (199, 207))	('rs2890896', 'Mutation', 'rs2890896', (289, 298))	('GAT-3', 'Gene', (188, 193))	('rs2296820', 'Mutation', 'rs2296820', (108, 117))	('rs2296820', 'Var', (108, 117))
323915	19670330	Interestingly, EAC tissue from this patient exhibited 7 additional amplified regions, including 8p21.3 (0.9 Mb), 8p12 (2.5 Mb), 16p13.13 (0.8 Mb), 16p13.12 (1.2 Mb), 17q12-q21.2 (3.1 Mb), 17q21.32-q22 (4.1 Mb), and 17q23.2-q23.3 (5.0 Mb), as well as Xp22.13-p22.12 (3.5 Mb).	('p22', 'Gene', (258, 261))	('EAC', 'Phenotype', 'HP:0011459', (15, 18))	('p13', 'Gene', '440926', (130, 133))	('p13', 'Gene', (149, 152))	('17q12-q21.2', 'Var', (166, 177))	('17q21.32-q22', 'Var', (188, 200))	('17q23.2-q23.3', 'Var', (215, 228))	('p12', 'Gene', (114, 117))	('p13', 'Gene', '440926', (149, 152))	('p22', 'Gene', (251, 254))	('p22', 'Gene', '11261', (251, 254))	('p12', 'Gene', '56655', (114, 117))	('patient', 'Species', '9606', (36, 43))	('p22', 'Gene', '11261', (258, 261))	('p13', 'Gene', (130, 133))
323916	19670330	Unexpectedly, CNN-LOH of 9p-terminal - p13.2 (37.0 Mb) occurred in BE tissue from case #5, as did deletion of 9p21.3 (2.1 Mb) in BE tissue from case #7; however, these aberrations were not detected in their matched EAC tissues, possibly because contamination with normal cells masked this abnormality in the frank tumors.	('frank tumors', 'Disease', 'MESH:D001946', (308, 320))	('EAC', 'Phenotype', 'HP:0011459', (215, 218))	('p13', 'Gene', '440926', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('BE', 'Phenotype', 'HP:0100580', (67, 69))	('deletion', 'Var', (98, 106))	('BE', 'Phenotype', 'HP:0100580', (129, 131))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('frank tumors', 'Disease', (308, 320))	('p13', 'Gene', (39, 42))
323920	19670330	Shared abnormalities included two BE cases (#5 and #11) with 9p CNN-LOH; 2 BE cases (#10 and #11) with duplication of 8p23.3-p12; 2 BE cases (#8 and #10) with deletion of 21q11.2-q21.1.	('p12', 'Gene', '56655', (125, 128))	('BE', 'Phenotype', 'HP:0100580', (132, 134))	('duplication of', 'Var', (103, 117))	('BE', 'Phenotype', 'HP:0100580', (75, 77))	('p12', 'Gene', (125, 128))	('BE', 'Phenotype', 'HP:0100580', (34, 36))	('deletion', 'Var', (159, 167))
323922	19670330	In the BE sample, all 3 SNP sites (rs2296820, rs668026, and rs2890896) clearly showed only a single signal (Figure 2B).	('rs668026', 'Mutation', 'rs668026', (46, 54))	('rs2890896', 'Mutation', 'rs2890896', (60, 69))	('rs668026', 'Var', (46, 54))	('rs2890896', 'Var', (60, 69))	('rs2296820', 'Var', (35, 44))	('BE', 'Phenotype', 'HP:0100580', (7, 9))	('rs2296820', 'Mutation', 'rs2296820', (35, 44))
323926	19670330	Four BE samples (#8, #11, #7 and #10) showed deletion of the CDKN2A gene by SNP-chip analysis (Figure 2A and Table 3).	('CDKN2A', 'Gene', '1029', (61, 67))	('CDKN2A', 'Gene', (61, 67))	('deletion', 'Var', (45, 53))	('BE', 'Phenotype', 'HP:0100580', (5, 7))
323933	19670330	As shown in Figure 2A, the BE sample from case #11 clearly showed deletion involving the 9p22.3-p22.2 region (1.2 MB, circled); only one known gene, basonuclin 2 (BNC2), is located here.	('p22', 'Gene', (90, 93))	('p22', 'Gene', (96, 99))	('BE', 'Phenotype', 'HP:0100580', (27, 29))	('p22', 'Gene', '11261', (90, 93))	('BNC2', 'Gene', (163, 167))	('basonuclin 2', 'Gene', (149, 161))	('basonuclin 2', 'Gene', '54796', (149, 161))	('p22', 'Gene', '11261', (96, 99))	('deletion', 'Var', (66, 74))	('BNC2', 'Gene', '54796', (163, 167))
323951	19670330	Data suggest that breast cancers with amplification of ERBB2 and TOP2A have a better response when they receive the combination of both Trastuzumab/Herceptin and a TOP2A inhibitor.	('TOP2A', 'Gene', (164, 169))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (136, 147))	('TOP2A', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Herceptin', 'Chemical', 'MESH:D000068878', (148, 157))	('breast cancers', 'Phenotype', 'HP:0003002', (18, 32))	('breast cancers', 'Disease', 'MESH:D001943', (18, 32))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('breast cancers', 'Disease', (18, 32))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))	('amplification', 'Var', (38, 51))	('TOP2A', 'Gene', '7153', (164, 169))	('TOP2A', 'Gene', '7153', (65, 70))
323956	19670330	For example, the constitutively active forms of either JAK2 V617F mutant, FLT3-ITD, or an AML1/RUNX1 frameshift were found in a CNN-LOH region in AML cells from our SNP-chip analysis.	('AML1', 'Gene', (90, 94))	('V617F', 'Var', (60, 65))	('AML', 'Phenotype', 'HP:0004808', (90, 93))	('AML', 'Disease', (90, 93))	('AML', 'Disease', (146, 149))	('AML', 'Phenotype', 'HP:0004808', (146, 149))	('AML1', 'Gene', '861', (90, 94))	('FLT3-ITD', 'Disease', 'None', (74, 82))	('FLT3-ITD', 'Disease', (74, 82))	('JAK2', 'Gene', '3717', (55, 59))	('RUNX1', 'Gene', '861', (95, 100))	('V617F', 'SUBSTITUTION', 'None', (60, 65))	('RUNX1', 'Gene', (95, 100))	('AML', 'Disease', 'MESH:D015470', (90, 93))	('JAK2', 'Gene', (55, 59))	('AML', 'Disease', 'MESH:D015470', (146, 149))
323958	19670330	An activating mutation of MET (Y1253D) was detected in 15 (11%) of 138 oropharyngeal squamous cell carcinoma patients.	('patients', 'Species', '9606', (109, 117))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (71, 108))	('activating', 'PosReg', (3, 13))	('Y1253D', 'Mutation', 'p.Y1253D', (31, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('MET (Y1253D', 'Var', (26, 37))	('squamous cell carcinoma', 'Disease', (85, 108))
323959	19670330	An activating mutation of BRAF (V600E) was found in 66% of malignant melanomas, as well as at lower frequencies in a wide range of human cancers; in particular, 11% of Barrett's EACs have been reported to possess BRAF mutations.	('malignant melanomas', 'Disease', 'MESH:D008545', (59, 78))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	("Barrett's EACs", 'Phenotype', 'HP:0100580', (168, 182))	('malignant melanomas', 'Disease', (59, 78))	('BRAF', 'Gene', '673', (26, 30))	('V600E', 'Mutation', 'rs113488022', (32, 37))	('activating', 'PosReg', (3, 13))	('EAC', 'Phenotype', 'HP:0011459', (178, 181))	('BRAF', 'Gene', (26, 30))	('human', 'Species', '9606', (131, 136))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('V600E', 'Var', (32, 37))	('cancers', 'Disease', (137, 144))	('BRAF', 'Gene', (213, 217))	('BRAF', 'Gene', '673', (213, 217))	('malignant melanomas', 'Phenotype', 'HP:0002861', (59, 78))
323960	19670330	These findings prompted us to determine exon sequences at mutational hotspots (MET Y1253 and BRAF V600) in sample #10; however, these genes did not contain detectable mutations (data not shown).	('BRAF', 'Gene', (93, 97))	('MET Y1253', 'Var', (79, 88))	('BRAF', 'Gene', '673', (93, 97))
323961	19670330	In cancer cells, tumor suppressor genes are often inactivated by deletion, mutation and/or hypermethylation of their promoter regions.	('tumor', 'Disease', (17, 22))	('mutation', 'Var', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('hypermethylation', 'Var', (91, 107))	('inactivated', 'NegReg', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('deletion', 'Var', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
323962	19670330	The cyclin-dependent kinase inhibitor gene, CDKN2A, is homozygously or hemizygously deleted, mutationally inactivated, or hypermethylated in approximately 50%, 5%, and 60% of EACs, respectively, and hypermethylated or hemizygously deleted in up to 40% of BEs.	('inactivated', 'NegReg', (106, 117))	('mutationally', 'Var', (93, 105))	('BEs', 'Chemical', 'MESH:C012210', (255, 258))	('CDKN2A', 'Gene', (44, 50))	('EAC', 'Phenotype', 'HP:0011459', (175, 178))	('CDKN2A', 'Gene', '1029', (44, 50))	('hypermethylated', 'Var', (122, 137))	('BE', 'Phenotype', 'HP:0100580', (255, 257))
323963	19670330	These findings are consistent with our identification of CDKN2A deletions in 4 BE samples (40%) and emphasize that CDKN2A inactivation represents an early event in the BE-EAC carcinogenic cascade.	('CDKN2A', 'Gene', (115, 121))	('BE', 'Phenotype', 'HP:0100580', (79, 81))	('CDKN2A', 'Gene', (57, 63))	('CDKN2A', 'Gene', '1029', (115, 121))	('EAC', 'Phenotype', 'HP:0011459', (171, 174))	('deletions', 'Var', (64, 73))	('carcinogenic', 'Disease', 'MESH:D063646', (175, 187))	('CDKN2A', 'Gene', '1029', (57, 63))	('carcinogenic', 'Disease', (175, 187))	('BE', 'Phenotype', 'HP:0100580', (168, 170))
323969	19670330	Inactivation by methylation and/or deletion of several TSGs, including CDKN2A and TP53, are known to be involved in esophageal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('TP53', 'Gene', (82, 86))	('CDKN2A', 'Gene', (71, 77))	('tumor', 'Disease', (127, 132))	('CDKN2A', 'Gene', '1029', (71, 77))	('TSGs', 'Gene', (55, 59))	('involved', 'Reg', (104, 112))	('methylation', 'Var', (16, 27))	('deletion', 'Var', (35, 43))	('TP53', 'Gene', '7157', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Inactivation', 'Var', (0, 12))
323971	19670330	This inactivation could contribute to transformation to esophageal cancer cells.	('esophageal cancer', 'Disease', (56, 73))	('contribute', 'Reg', (24, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('inactivation', 'Var', (5, 17))
323972	19670330	These investigators found several chromosomal lesions that were similar to our data, including homozygous deletions of CDKN2A and FHIT, loss of copy number at 17p, and CNN-LOH at 17q25.3, further emphasizing the importance of these regions or genes in the development of EAC.	('deletions', 'Var', (106, 115))	('copy', 'MPA', (144, 148))	('FHIT', 'Gene', (130, 134))	('EAC', 'Phenotype', 'HP:0011459', (271, 274))	('CDKN2A', 'Gene', (119, 125))	('CDKN2A', 'Gene', '1029', (119, 125))	('EAC', 'Disease', (271, 274))	('loss', 'Var', (136, 140))	('CNN-LOH', 'Var', (168, 175))
323974	19670330	Furthermore, we have identified several novel genomic abnormalities in BE or EAC, notably CNN-LOH and inactivation of the zinc-finger gene, BNC2.	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('inactivation', 'Var', (102, 114))	('BE', 'Phenotype', 'HP:0100580', (71, 73))	('BNC2', 'Gene', '54796', (140, 144))	('CNN-LOH', 'Disease', (90, 97))	('BNC2', 'Gene', (140, 144))
324087	32211334	We examined prognostic potency of RAP1B for EAC patients by OSeac, and found that RAP1B was significantly associated with unfavorable OS in TCGA (P = 0.0464, HR: 2.0045, 95% CI: 1.0111-3.9741), GSE13898 (P = 0.0241, HR: 3.0920, 95% CI: 1.1596-8.2446) and GSE19417 (P = 0.0138, HR: 2.4119, 95% CI: 1.1965-4.8618).	('GSE13898', 'Var', (194, 202))	('associated with', 'Reg', (106, 121))	('RAP1B', 'Gene', (34, 39))	('RAP1B', 'Gene', '5908', (34, 39))	('TCGA', 'Disease', (140, 144))	('EAC', 'Disease', (44, 47))	('EAC', 'Disease', 'MESH:D004938', (44, 47))	('GSE19417', 'Var', (255, 263))	('patients', 'Species', '9606', (48, 56))	('RAP1B', 'Gene', (82, 87))	('RAP1B', 'Gene', '5908', (82, 87))
324123	30383737	Surgeon General reports also have concluded that the use of smokeless tobacco (i.e., snuff and chewing tobacco) causes cancers of the OCP and esophagus; cigar use causes cancers of the oral cavity, esophagus, larynx, and lung; and secondhand smoke exposure causes lung cancer.	('causes', 'Reg', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('lung cancer', 'Disease', 'MESH:D008175', (264, 275))	('oral cavity', 'Disease', (185, 196))	('esophagus', 'Disease', (142, 151))	('cancers of the oral cavity', 'Phenotype', 'HP:0100649', (170, 196))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('esophagus', 'Disease', (198, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('causes', 'Reg', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('lung cancer', 'Disease', (264, 275))	('tobacco', 'Species', '4097', (70, 77))	('tobacco', 'Species', '4097', (103, 110))	('cigar', 'Var', (153, 158))	('larynx', 'Disease', (209, 215))
324152	30383737	Anatomic sites were restricted to cancers with histology codes 8000-9049, 9056-9139, and 9141-9589 (excluding mesothelioma, Kaposi sarcoma, and hematopoietic cancers).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('hematopoietic cancers', 'Disease', 'MESH:D019337', (144, 165))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('9141-9589', 'Var', (89, 98))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('mesothelioma', 'Disease', (110, 122))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (124, 138))	('hematopoietic cancers', 'Disease', (144, 165))	('cancers', 'Disease', (158, 165))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (124, 138))	('Kaposi sarcoma', 'Disease', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('9056-9139', 'Var', (74, 83))
324346	30383737	Human and animal studies have found that functional nicotinic receptors are present on pancreatic islet and beta cells, and nicotine can reduce the release of insulin through neuronal nicotinic acetylcholine receptors on islet cells.	('Human', 'Species', '9606', (0, 5))	('pancreatic', 'Disease', 'MESH:D010195', (87, 97))	('pancreatic', 'Disease', (87, 97))	('nicotine', 'Var', (124, 132))	('reduce', 'NegReg', (137, 143))	('release of insulin', 'MPA', (148, 166))	('nicotine', 'Chemical', 'MESH:D009538', (124, 132))
324349	30383737	Findings from a recent meta-analysis show that increased fruit and vegetable intake is associated with decreased risk for pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('decreased', 'NegReg', (103, 112))	('increased', 'PosReg', (47, 56))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('pancreatic cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('fruit and', 'Var', (57, 66))
324446	30383737	Correspondingly, lung cancer incidence has decreased nearly four times faster in California than in the rest of the United States.	('decreased', 'NegReg', (43, 52))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('California', 'Var', (81, 91))
324498	26361581	However, TEE probe insertion in the presence of the coagulopathy common to end-stage liver disease can result in esophageal injury and variceal hemorrhage.	('end-stage liver disease', 'Disease', 'MESH:D058625', (75, 98))	('end-stage liver disease', 'Disease', (75, 98))	('hemorrhage', 'Disease', 'MESH:D006470', (144, 154))	('coagulopathy', 'Phenotype', 'HP:0003256', (52, 64))	('esophageal injury', 'Disease', (113, 130))	('coagulopathy', 'Disease', 'MESH:D001778', (52, 64))	('liver disease', 'Phenotype', 'HP:0001392', (85, 98))	('coagulopathy', 'Disease', (52, 64))	('esophageal injury', 'Disease', 'MESH:D004941', (113, 130))	('result in', 'Reg', (103, 112))	('hemorrhage', 'Disease', (144, 154))	('insertion', 'Var', (19, 28))
324540	26361581	We hypothesize that clamping of the portal system at the start of the anhepatic phase caused portal pressure to increase, leading to spontaneous rupture of the gastric varices in the patient without intraoperative TEE.	('gastric varices', 'Disease', (160, 175))	('clamping', 'Var', (20, 28))	('rupture', 'Disease', 'MESH:D012421', (145, 152))	('rupture', 'Disease', (145, 152))	('gastric varices', 'Phenotype', 'HP:0030169', (160, 175))	('increase', 'PosReg', (112, 120))	('leading to', 'Reg', (122, 132))	('patient', 'Species', '9606', (183, 190))	('portal pressure', 'MPA', (93, 108))
324583	25518924	Results of previous studies support the concept that miRNAs can function as tumor suppressors or oncogenes by regulating downstream target genes.	('miRNAs', 'Var', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('regulating', 'Reg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
324597	25518924	EC109 and EC9706 were purchased from Shanghai Tiancheng Technology Co., Ltd. Het-1A was purchased from Guangzhou Jennio Biotech Co., Ltd. EC109 and EC9706 were cultured in RPMI 1640 (HyClone, USA) containing 10% fetal bovine serum (HyClone, USA) and 1% penicillin/streptomycin (Sigma-Aldrich, USA) at 37 C with 5% CO2, whereas Het-1A was cultured in Dulbecco's modified Eagle's medium (HyClone, USA).	('EC9706', 'Var', (148, 154))	('EC9706', 'CellLine', 'CVCL:E307', (10, 16))	('EC109', 'Var', (138, 143))	('EC9706', 'CellLine', 'CVCL:E307', (148, 154))	('bovine', 'Species', '9913', (218, 224))
324621	25518924	The wild type and mutant 3'UTR of PDCD4 were cloned into the pmiR-RB miRNA reporter vector (synthesized by Ribobio, China) to confirm direct target association.	('PDCD4', 'Gene', (34, 39))	('PDCD4', 'Gene', '27250', (34, 39))	('association', 'Interaction', (148, 159))	('mutant', 'Var', (18, 24))
324623	25518924	The sequence that was complementary to the binding sites (positions 260-266 of PDCD4 3'UTR:GUGCCAU) was replaced by CACGGTA for mutagenesis (Fig.	('PDCD4', 'Gene', '27250', (79, 84))	('PDCD4', 'Gene', (79, 84))	('mutagenesis', 'Var', (128, 139))
324627	25518924	After transfection for 48 h, miR-183 expression was greatly changed in EC9706, according to the results of real-time RT-PCR analysis.	('miR-183', 'Gene', (29, 36))	('EC9706', 'Var', (71, 77))	('miR-183', 'Gene', '406959', (29, 36))	('changed', 'Reg', (60, 67))	('EC9706', 'CellLine', 'CVCL:E307', (71, 77))	('expression', 'MPA', (37, 47))
324648	25518924	Moreover, the cell cycle distribution of EC9706 cells showed that the percentage of cells at G1 phase significantly decreased in miR-183 mimic-transfected cells compared with NC (p < 0.05) (Figs.	('EC9706', 'CellLine', 'CVCL:E307', (41, 47))	('miR-183', 'Gene', '406959', (129, 136))	('miR-183', 'Gene', (129, 136))	('mimic-transfected', 'Var', (137, 154))	('cells at G1 phase', 'CPA', (84, 101))	('decreased', 'NegReg', (116, 125))
324652	25518924	RT-qPCR showed that PDCD4 slightly decreased in EC9706 cells treated by miR-183 mimic and increased in miR-183 inhibitor-treated cells, but no statistical differences were observed.	('increased', 'PosReg', (90, 99))	('PDCD4', 'Gene', (20, 25))	('EC9706', 'CellLine', 'CVCL:E307', (48, 54))	('PDCD4', 'Gene', '27250', (20, 25))	('decreased', 'NegReg', (35, 44))	('miR-183', 'Gene', '406959', (72, 79))	('miR-183', 'Gene', (72, 79))	('mimic', 'Var', (80, 85))	('miR-183', 'Gene', '406959', (103, 110))	('miR-183', 'Gene', (103, 110))
324662	25518924	EC9706 showed the lower expression level of miR-183 and the higher expression level of PDCD4 against Het-1A (Fig.	('expression level', 'MPA', (24, 40))	('EC9706', 'Var', (0, 6))	('higher', 'PosReg', (60, 66))	('miR-183', 'Gene', '406959', (44, 51))	('expression level', 'MPA', (67, 83))	('miR-183', 'Gene', (44, 51))	('lower', 'NegReg', (18, 23))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('PDCD4', 'Gene', (87, 92))	('PDCD4', 'Gene', '27250', (87, 92))
324700	25518924	A report from demonstrated that the loss of PDCD4 increased procaspase-3 expression, thereby leading to its activation and PARP cleavage even without apoptotic stimuli.	('PARP', 'Gene', '1302', (123, 127))	('PARP', 'Gene', (123, 127))	('PDCD4', 'Gene', (44, 49))	('procaspase-3', 'Gene', '836', (60, 72))	('PDCD4', 'Gene', '27250', (44, 49))	('increased', 'PosReg', (50, 59))	('loss', 'Var', (36, 40))	('activation', 'MPA', (108, 118))	('expression', 'MPA', (73, 83))	('procaspase-3', 'Gene', (60, 72))
324704	25518924	In addition, PDCD4 knockdown can up-regulate cyclin-D1expression through NF-kappaB activation and GSK3beta phosphorylation.	('knockdown', 'Var', (19, 28))	('PDCD4', 'Gene', (13, 18))	('GSK3beta', 'Gene', (98, 106))	('PDCD4', 'Gene', '27250', (13, 18))	('cyclin-D1', 'Gene', '595', (45, 54))	('up-regulate', 'PosReg', (33, 44))	('GSK3beta', 'Gene', '2932', (98, 106))	('cyclin-D1', 'Gene', (45, 54))	('NF-kappaB', 'Protein', (73, 82))	('activation', 'PosReg', (83, 93))
324745	25140320	reported a complete histologic resolution of Barrett's dysplasia in 54.5% of patients undergoing PDT and 88.7% of patients undergoing RFA.	("Barrett's dysplasia", 'Disease', (45, 64))	("Barrett's dysplasia", 'Disease', 'MESH:D001471', (45, 64))	('patients', 'Species', '9606', (77, 85))	('PDT', 'Var', (97, 100))	('patients', 'Species', '9606', (114, 122))
324794	25140320	Similarly, 81% of patients with HGD had complete eradication of dysplasia compared to 19% of patients in the sham control group.	('HGD', 'Var', (32, 35))	('eradication of dysplasia', 'Disease', 'MESH:D004476', (49, 73))	('eradication of dysplasia', 'Disease', (49, 73))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (93, 101))
324810	25140320	Patients with ultra-long segment BE did require more RFA sessions and had decreased durability of eradication, 65% versus 82%.	('ultra-long', 'Var', (14, 24))	('BE', 'Phenotype', 'HP:0100580', (33, 35))	('Patients', 'Species', '9606', (0, 8))	('decreased', 'NegReg', (74, 83))	('durability', 'MPA', (84, 94))
324820	25140320	Lower esophageal sphincter pressure and length and esophageal contraction amplitude were not affected by RFA.	('esophageal contraction amplitude', 'MPA', (51, 83))	('esophageal sphincter', 'Disease', (6, 26))	('esophageal sphincter', 'Disease', 'MESH:D009122', (6, 26))	('RFA', 'Var', (105, 108))	('sphincter pressure', 'Phenotype', 'HP:0002839', (17, 35))
324855	23615477	The cluster of aberrant expression of these metabolites in ESCC indicates the critical role of phospholipid metabolism in the oncogenesis of ESCC and suggests its potential ability to assess the risk of ESCC development in addition to currently used risk factors.	('expression', 'MPA', (24, 34))	('phospholipid', 'Chemical', 'MESH:D010743', (95, 107))	('ESCC', 'Gene', (59, 63))	('aberrant', 'Var', (15, 23))
324916	23615477	The cluster of aberrant expression of phospholipids in ESCC indicates that phospholipid metabolism plays a critical role in the oncogenesis of ESCC, which offers insight into the mechanism of carcinogenesis.	('phospholipid', 'Chemical', 'MESH:D010743', (75, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (192, 206))	('ESCC', 'Disease', (143, 147))	('phospholipid', 'Chemical', 'MESH:D010743', (38, 50))	('carcinogenesis', 'Disease', (192, 206))	('aberrant', 'Var', (15, 23))	('phospholipids', 'Chemical', 'MESH:D010743', (38, 51))
324997	23734090	It was speculated that high LES pressure might cause secondary achalasia in patients with anti-reflux surgery (Stylopoulos et al.,; Kraichely and Farrugia,).	('patients', 'Species', '9606', (76, 84))	('-reflux', 'Phenotype', 'HP:0002020', (94, 101))	('high', 'Var', (23, 27))	('cause', 'Reg', (47, 52))	('achalasia', 'Phenotype', 'HP:0002571', (63, 72))	('LES', 'Gene', '2525', (28, 31))	('LES', 'Gene', (28, 31))	('achalasia', 'Disease', (63, 72))	('achalasia', 'Disease', 'MESH:D004931', (63, 72))
325023	23734090	Drotaverine reduced the frequency of phasic contractions without affecting the amplitude (Figure 1) suggesting that drotaverine specifically inhibited the pacemaker frequency.	('drotaverine', 'Var', (116, 127))	('reduced', 'NegReg', (12, 19))	('phasic contractions', 'MPA', (37, 56))	('frequency', 'MPA', (24, 33))	('Drotaverine', 'Chemical', 'MESH:C005317', (0, 11))	('pacemaker frequency', 'MPA', (155, 174))	('inhibited', 'NegReg', (141, 150))	('drotaverine', 'Chemical', 'MESH:C005317', (116, 127))
325027	23734090	Indeed, ICC-IM have been shown to be stretch sensitive in the murine stomach (Won et al.,); stretch caused a marked increase in slow wave frequency that was dependent on the presence of ICC-IM.	('slow wave frequency', 'MPA', (128, 147))	('stretch', 'Var', (92, 99))	('increase', 'PosReg', (116, 124))	('murine', 'Species', '10090', (62, 68))
325041	23734090	Indeed, inhibition of nitrergic innervation increases the propagation velocity (Anand and Paterson,) hence loss of nitrergic innervation is a logical explanation for the simultaneous nature of swallow induced rhythmic contractions in the achalasia patient (Behar and Biancani,).	('loss', 'NegReg', (107, 111))	('rhythmic contractions in the achalasia', 'Disease', 'MESH:D004931', (209, 247))	('propagation velocity', 'MPA', (58, 78))	('rhythmic contractions in the achalasia', 'Disease', (209, 247))	('patient', 'Species', '9606', (248, 255))	('inhibition', 'Var', (8, 18))	('increases', 'PosReg', (44, 53))	('achalasia', 'Phenotype', 'HP:0002571', (238, 247))
325055	23734090	One can speculate that if nitric oxide keeps the ICC gap junctions relatively closed (the propagation of contractions in the esophagus is slow, compare 2 cm/s with 50 cm/s of the cardiac contraction), loss of nitrergic innervation could increase contraction velocity such that it appeared virtually simultaneous.	('increase contraction velocity', 'Phenotype', 'HP:0001649', (237, 266))	('increase', 'PosReg', (237, 245))	('nitrergic innervation', 'MPA', (209, 230))	('loss', 'Var', (201, 205))	('contraction velocity', 'MPA', (246, 266))	('nitric oxide', 'Chemical', 'MESH:D009569', (26, 38))
325071	33655027	Early-stage disease has a better prognosis, with 80 % to 90 % 5-year survival after surgical resection  , whereas locally advanced tumors (T3-T4, any N + ) carry a worse prognosis with 5-year survival of 20 % to 40 %  .	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('T3-T4', 'Var', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))
325110	33062275	18F-FAMT, L-[3-18F]-alpha-methyltyrosine is an amino-acid PET tracer useful for distinguishing malignant from benign lesions.	('PET', 'Gene', '22095', (58, 61))	('PET', 'Gene', (58, 61))	('18F-FAMT', 'Chemical', '-', (0, 8))	('L-[3-18F]-alpha-methyltyrosine', 'Chemical', '-', (10, 40))	('L-[3-18F]-alpha-methyltyrosine', 'Var', (10, 40))
325118	33062275	11C-MET has superior specificity than 18F-FDG in the tracing of malignant tumors, a fact that makes the discrimination of malignant from benign lesions more feasible.	('malignant tumors', 'Disease', (64, 80))	('11C-MET', 'Var', (0, 7))	('tracing', 'CPA', (53, 60))	('specificity', 'MPA', (21, 32))	('malignant tumors', 'Disease', 'MESH:D009369', (64, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('18F-FDG', 'Chemical', 'MESH:D019788', (38, 45))	('11C-MET', 'Chemical', '-', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
325129	33062275	123I-IMT as well as 18F-FET was found to be transported selectively by human LAT1 which is expressed in normal cells.	('LAT1', 'Gene', (77, 81))	('LAT1', 'Gene', '8140', (77, 81))	('123I-IMT', 'Var', (0, 8))	('18F-FET', 'Chemical', 'MESH:C545932', (20, 27))	('human', 'Species', '9606', (71, 76))
325130	33062275	It is still vague in human malignant tumors if 11C-MET, 18F-FET, and 123I-IMT are connected strongly with the amino-acid transporters like LAT1.	('11C-MET', 'Var', (47, 54))	('connected', 'Reg', (82, 91))	('LAT1', 'Gene', '8140', (139, 143))	('human', 'Species', '9606', (21, 26))	('LAT1', 'Gene', (139, 143))	('malignant tumors', 'Disease', (27, 43))	('amino-acid transporters', 'MPA', (110, 133))	('11C-MET', 'Chemical', '-', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('malignant tumors', 'Disease', 'MESH:D009369', (27, 43))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('123I-IMT', 'Var', (69, 77))	('18F-FET', 'Chemical', 'MESH:C545932', (56, 63))
325145	33062275	Alterations in FMISO accumulation within tumor cells calculate the early response to chemotherapy, and FMISO may have a role as a prognostic biomarker.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('Alterations', 'Var', (0, 11))	('FMISO', 'Chemical', 'MESH:C031843', (103, 108))	('FMISO', 'Chemical', 'MESH:C031843', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('early', 'MPA', (67, 72))
325161	33062275	There is close relation between 18F-FLT and Ki67 in NSCLC.	('Ki67', 'Chemical', '-', (44, 48))	('NSCLC', 'Disease', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('FLT', 'Gene', '2321', (36, 39))	('FLT', 'Gene', (36, 39))	('SCLC', 'Phenotype', 'HP:0030357', (53, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('Ki67', 'Var', (44, 48))
325162	33062275	There is also strong correlation not only between 18F-FLT uptake and Ki67 (p < 0.0001) but also between 18F-FLT uptake and 18F-FDG uptake.	('FLT', 'Gene', '2321', (108, 111))	('18F-FDG', 'Chemical', 'MESH:D019788', (123, 130))	('FLT', 'Gene', (108, 111))	('correlation', 'Interaction', (21, 32))	('Ki67', 'Chemical', '-', (69, 73))	('18F-FDG uptake', 'MPA', (123, 137))	('Ki67', 'Var', (69, 73))	('FLT', 'Gene', '2321', (54, 57))	('FLT', 'Gene', (54, 57))
325169	33062275	Huang concluded that apart from 18F-FLT, PET tracers may have significance as potential biomarkers of DNA synthesis like: 18F-(fluoroarabinofuranosyl) cytosine, 11C-labeled nucleosides, such as 11C-methionine, 11C-flumazenil, and 11C-4DST.	('11C-methionine', 'Chemical', '-', (194, 208))	('11C-flumazenil', 'Var', (210, 224))	('11C', 'Chemical', 'MESH:C000615233', (210, 213))	('11C-4DST', 'Chemical', '-', (230, 238))	('18F-(fluoroarabinofuranosyl) cytosine', 'Chemical', '-', (122, 159))	('PET', 'Gene', '22095', (41, 44))	('11C-4DST', 'Var', (230, 238))	('FLT', 'Gene', '2321', (36, 39))	('FLT', 'Gene', (36, 39))	('11C-flumazenil', 'Chemical', '-', (210, 224))	('11C', 'Chemical', 'MESH:C000615233', (194, 197))	('PET', 'Gene', (41, 44))	('11C', 'Chemical', 'MESH:C000615233', (161, 164))	('nucleosides', 'Chemical', 'MESH:D009705', (173, 184))	('11C', 'Chemical', 'MESH:C000615233', (230, 233))	('11C-methionine', 'Var', (194, 208))
325177	33062275	Investigators concentrate their attention to folate bonds in order to label the above with a radiotracer like 99mTc, 111In, 18F and 68Ga for nuclear medicine imaging (SPECT and PET).	('PET', 'Gene', (177, 180))	('68Ga', 'Var', (132, 136))	('folate', 'Chemical', 'MESH:D005492', (45, 51))	('111In', 'Var', (117, 122))	('PET', 'Gene', '22095', (177, 180))
325204	33062275	In a micro-PET experimental base, preclinical findings indicated favorable effects of 64Cu-DOTA-RGD tetramers and octamers in U87MG tumor bearing nude mice.	('tetramers', 'Protein', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PET', 'Gene', '22095', (11, 14))	('octamers', 'Protein', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('64Cu-DOTA-RGD tetramer', 'Chemical', '-', (86, 108))	('U87MG', 'CellLine', 'CVCL:0022', (126, 131))	('tumor', 'Disease', (132, 137))	('64Cu-DOTA-RGD', 'Gene', (86, 99))	('U87MG', 'Var', (126, 131))	('PET', 'Gene', (11, 14))	('nude mice', 'Species', '10090', (146, 155))
325205	33062275	More specifically, U87MG tumors could be depicted with high contrast with 64Cu-DOTA-RGD.	('64Cu-DOTA-RGD', 'Chemical', '-', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('U87MG', 'CellLine', 'CVCL:0022', (19, 24))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('U87MG', 'Var', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (25, 31))
325207	33062275	RGD octamers had noticeably higher affinity and specificity than tetramers.	('RGD', 'Chemical', 'MESH:C047981', (0, 3))	('RGD', 'Var', (0, 3))	('specificity', 'MPA', (48, 59))	('higher', 'PosReg', (28, 34))	('affinity', 'Interaction', (35, 43))
325219	33062275	Patients with NSCLC and high uptake of 18F-FAMT are strongly connected with worse prognosis after therapy.	('NSCLC', 'Disease', (14, 19))	('connected', 'Reg', (61, 70))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('18F-FAMT', 'Chemical', '-', (39, 47))	('Patients', 'Species', '9606', (0, 8))	('SCLC', 'Phenotype', 'HP:0030357', (15, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('high uptake', 'Var', (24, 35))
325324	33062275	Primary tumors with high FDG uptake are strongly connected with higher risk of occult nodal metastasis.	('FDG', 'Chemical', 'MESH:D019788', (25, 28))	('Primary tumors', 'Disease', 'MESH:D001932', (0, 14))	('Primary tumors', 'Disease', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('high', 'Var', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('connected', 'Reg', (49, 58))
325362	33062275	Depending on the site, the risk becomes greater for malignancy if there is loco-regional FDG avidity in breast, colon, thyroid or prostate.	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('breast', 'Disease', (104, 110))	('malignancy', 'Disease', (52, 62))	('loco-regional', 'Var', (75, 88))	('FDG', 'Chemical', 'MESH:D019788', (89, 92))	('colon', 'Disease', (112, 117))	('thyroid', 'Disease', (119, 126))
325396	33062275	Some PET isotopes are the following: 18F, 11C, 13N, 15O, 68Ga, and 82Rb.	('82Rb', 'Var', (67, 71))	('11C', 'Chemical', 'MESH:C000615233', (42, 45))	('PET', 'Gene', (5, 8))	('13N', 'Chemical', 'MESH:C000615247', (47, 50))	('68Ga', 'Var', (57, 61))	('15O', 'Var', (52, 55))	('PET', 'Gene', '22095', (5, 8))	('13N', 'Var', (47, 50))	('11C', 'Var', (42, 45))
325434	33062275	Furthermore, there was higher tumor to background ratio of [18F]FPDOPA than [18F]FDG in 1-h post-injection for both SPC-A-1 and H460 heterografts (p < 0.05).	('[18F]FPDOPA', 'Var', (59, 70))	(']FPDOPA', 'Chemical', '-', (63, 70))	('higher', 'PosReg', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('FDG', 'Chemical', 'MESH:D019788', (81, 84))	('tumor', 'Disease', (30, 35))
325453	33062275	In subgroup analysis, the PET/CT with 68Ga-DOTA-peptide was superior in the detection of typical carcinoids (91% detection rate, p < 0.001) while 18F-FDG PET/CT was superior to atypical carcinoid detection (100% detection rate, p = 0.04).	('atypical carcinoid', 'Phenotype', 'HP:0030446', (177, 195))	('PET', 'Gene', '22095', (154, 157))	('PET', 'Gene', (26, 29))	('68Ga-DOTA-peptide', 'Var', (38, 55))	('PET', 'Gene', (154, 157))	('carcinoids', 'Phenotype', 'HP:0100570', (97, 107))	('carcinoids', 'Disease', 'MESH:D002276', (97, 107))	('carcinoid', 'Phenotype', 'HP:0100570', (97, 106))	('carcinoids', 'Disease', (97, 107))	('Ga-DOTA-peptide', 'Chemical', '-', (40, 55))	('carcinoid', 'Disease', 'MESH:D002276', (97, 106))	('carcinoid', 'Disease', (186, 195))	('carcinoid', 'Disease', (97, 106))	('68Ga-DOTA', 'Chemical', '-', (38, 47))	('18F-FDG', 'Chemical', 'MESH:D019788', (146, 153))	('carcinoid', 'Phenotype', 'HP:0100570', (186, 195))	('carcinoid', 'Disease', 'MESH:D002276', (186, 195))	('PET', 'Gene', '22095', (26, 29))
325471	33062275	The high tumor-to-blood pool ratio for d-18F-FMT was negatively correlated with OS (p = 0.050) whereas for 18F-FDG, the same ratio was not associated with OS.	('d-18F-FMT', 'Chemical', '-', (39, 48))	('high tumor', 'Disease', 'MESH:D009369', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('negatively', 'NegReg', (53, 63))	('d-18F-FMT', 'Var', (39, 48))	('high tumor', 'Disease', (4, 14))	('18F-FDG', 'Chemical', 'MESH:D019788', (107, 114))
325528	33062275	in a clinical prospective study assessed the prognostic value of PET/CT using 18F-FAZA in patients with advanced NSCLC and compared it with 18F-FDG.	('PET', 'Gene', (65, 68))	('18F-FDG', 'Chemical', 'MESH:D019788', (140, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('PET', 'Gene', '22095', (65, 68))	('SCLC', 'Phenotype', 'HP:0030357', (114, 118))	('18F-FAZA', 'Var', (78, 86))	('NSCLC', 'Disease', (113, 118))	('patients', 'Species', '9606', (90, 98))	('F-FAZA', 'Chemical', '-', (80, 86))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
325543	33062275	D-18F-FMT is a novel fluorine-labeled tyrosine derivative which is transported directly via the (LAT1) L-amino-acid transporter and shows a faster clearance from the blood pool relative to the corresponding L-isomer.	('LAT1', 'Gene', '8140', (97, 101))	('tyrosine', 'Chemical', 'MESH:D014443', (38, 46))	('LAT1', 'Gene', (97, 101))	('D-18F-FMT', 'Chemical', '-', (0, 9))	('D-18F-FMT', 'Var', (0, 9))	('clearance', 'MPA', (147, 156))	('fluorine', 'Chemical', 'MESH:D005461', (21, 29))	('faster', 'PosReg', (140, 146))
325544	33062275	The investigators concluded that PET/CT imaging with the use of d-18F-FMT in patients with NSCLC and HNSCC was feasible and safe.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('PET', 'Gene', (33, 36))	('d-18F-FMT', 'Chemical', '-', (64, 73))	('patients', 'Species', '9606', (77, 85))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCLC', 'Phenotype', 'HP:0030357', (92, 96))	('NSCLC', 'Disease', (91, 96))	('d-18F-FMT', 'Var', (64, 73))	('PET', 'Gene', '22095', (33, 36))
325545	33062275	The preliminary results presented in this study suggest a lower sensitivity, but a higher specificity for d-18F-FMT compared to 18F-FDG as there was no uptake of d-18F-FMT in cases of inflammation.	('sensitivity', 'MPA', (64, 75))	('inflammation', 'Disease', 'MESH:D007249', (184, 196))	('d-18F-FMT', 'Chemical', '-', (106, 115))	('inflammation', 'Disease', (184, 196))	('specificity', 'MPA', (90, 101))	('18F-FDG', 'Chemical', 'MESH:D019788', (128, 135))	('d-18F-FMT', 'Var', (106, 115))	('d-18F-FMT', 'Chemical', '-', (162, 171))
325555	32226517	Methods and Materials: Between 2013 and 2016, 114 eligible patients with ESCC were recruited and randomly assigned to receive LCAHFIMRT+CT (58 patients) or CFIMRT+CT (56 patients) by a linear accelerator (6-MV X-ray) under image guidance.	('patients', 'Species', '9606', (170, 178))	('patients', 'Species', '9606', (143, 151))	('LCAHFIMRT+CT', 'Var', (126, 138))	('patients', 'Species', '9606', (59, 67))	('ESCC', 'Disease', (73, 77))
325558	32226517	Local recurrence and uncontrolled disease resulted in more deaths in the CFIMRT+CT group than in the LCAHFIMRT+CT group (58.9% vs. 39.7%) (P=0.040).	('death', 'Disease', (59, 64))	('death', 'Disease', 'MESH:D003643', (59, 64))	('CFIMRT+CT', 'Var', (73, 82))	('Local recurrence', 'CPA', (0, 16))
325574	32226517	The eligibility criteria were as follows: (1) histologically confirmed squamous cell carcinoma of the esophagus; (2) age 18~75 years old with Karnofsky performance status (KPS) scores >=60; (3) stage I to IV disease according to the 2017 (version 8.0) American Joint Committee on Cancer staging system, with the exception of T4b and M1 disease; (4) life expectancy of at least 6 months; (5) normal baseline laboratory tests (white blood cell count >=3.5x109/L, platelet count >=125x109/L, and hemoglobin >=115 g/L); (6) normal renal function (serum creatinine<106 micromol/L, blood urea<8.63 mmol/L); (7) normal liver function (total serum bilirubin<=20.5 micromol/L and aspartate transaminase and alanine transaminase levels lower than double the upper normal limit); and (8) adequate pulmonary function.	('>=115', 'Var', (504, 509))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('IV disease', 'Disease', (205, 215))	('squamous cell carcinoma of the esophagus', 'Disease', (71, 111))	('M1 disease', 'Disease', (333, 343))	('Cancer', 'Phenotype', 'HP:0002664', (280, 286))	('lower', 'NegReg', (726, 731))	('Cancer', 'Disease', (280, 286))	('total serum bilirubin', 'Phenotype', 'HP:0003573', (628, 649))	('IV disease', 'Disease', 'MESH:D020432', (205, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('pulmonary function', 'CPA', (786, 804))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (71, 111))	('normal liver function', 'Phenotype', 'HP:0001410', (605, 626))	('Cancer', 'Disease', 'MESH:D009369', (280, 286))	('adequate pulmonary function', 'Phenotype', 'HP:0005952', (777, 804))	('M1 disease', 'Disease', 'MESH:D015470', (333, 343))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (85, 111))	('transaminase levels lower', 'Phenotype', 'HP:0001410', (706, 731))	('liver function', 'MPA', (612, 626))	('>=125x109/L', 'Var', (476, 487))
325597	32226517	In terms of severe side effects: 2 cases of esophageal perforation and 2 cases of pulmonary fibrosis were noted in the LCAHFIMRT+CT group, whilst 1 case of esophageal perforation and 3 cases of pulmonary fibrosis were noted in the CFIMRT+CT group, which was not found to be a significant difference (P>0.05) (Table 3).	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (194, 212))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (82, 100))	('LCAHFIMRT+CT', 'Var', (119, 131))	('pulmonary fibrosis', 'Disease', (194, 212))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (82, 100))	('esophageal perforation', 'Disease', (44, 66))	('pulmonary fibrosis', 'Disease', (82, 100))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (194, 212))
325612	32226517	The results showed that the CR rate was 79.3% in the LCAHFIMRT+CT group, which was higher than that in the CFIMRT+CT group (61.8%).	('CR', 'Chemical', '-', (28, 30))	('LCAHFIMRT+CT', 'Var', (53, 65))	('higher', 'PosReg', (83, 89))	('CR rate', 'CPA', (28, 35))
325621	31205556	In the stratified analysis regarding gender, the similar trends occurred in both men and women, and BMI >=25.0 kg/m2 (adjusted OR 0.68, 95%CI 0.48-0.96) was associated with decreased esophageal squamous cell carcinoma risk in men.	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (183, 217))	('women', 'Species', '9606', (89, 94))	('BMI >=25.0 kg/m2', 'Var', (100, 116))	('men', 'Species', '9606', (91, 94))	('men', 'Species', '9606', (81, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('decreased', 'NegReg', (173, 182))	('esophageal squamous cell carcinoma', 'Disease', (183, 217))	('men', 'Species', '9606', (226, 229))
325622	31205556	Additionally, the esophageal squamous cell carcinoma risk attributable to sleep duration <7 h and regular snoring could be completely or partially diminished in subjects with BMI >=25.0 kg/m2.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (18, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (29, 52))	('diminished', 'NegReg', (147, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('BMI >=25.0 kg/m2', 'Var', (175, 191))	('esophageal squamous cell carcinoma', 'Disease', (18, 52))	('snoring', 'Phenotype', 'HP:0025267', (106, 113))
325665	31205556	We noticed that short sleep was related to increased risk of obesity, which acted as a mediator in cancer development.	('short sleep', 'Var', (16, 27))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('obesity', 'Disease', 'MESH:D009765', (61, 68))	('cancer', 'Disease', (99, 105))	('obesity', 'Disease', (61, 68))	('men', 'Species', '9606', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('obesity', 'Phenotype', 'HP:0001513', (61, 68))
325673	31205556	Disrupted breathing during sleep would cause sleep disturbance and intermittent hypoxemia.	('cause', 'Reg', (39, 44))	('sleep disturbance', 'Phenotype', 'HP:0002360', (45, 62))	('sleep disturbance and intermittent hypoxemia', 'Disease', 'MESH:D000860', (45, 89))	('Disrupted breathing', 'Phenotype', 'HP:0005957', (0, 19))	('hypoxemia', 'Phenotype', 'HP:0012418', (80, 89))	('breathing during sleep', 'Phenotype', 'HP:0010535', (10, 32))	('Disrupted', 'Var', (0, 9))
325674	31205556	Sleep disturbance could diminish immune function and stimulate the secretion of inflammatory cytokines, and thus increase gastro-esophageal reflux and the risk of cancers.	('esophageal reflux', 'Phenotype', 'HP:0002020', (129, 146))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('stimulate', 'PosReg', (53, 62))	('secretion of inflammatory cytokines', 'MPA', (67, 102))	('gastro-esophageal reflux', 'Disease', (122, 146))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('immune function', 'CPA', (33, 48))	('increase', 'PosReg', (113, 121))	('diminish immune function', 'Phenotype', 'HP:0002721', (24, 48))	('Sleep disturbance', 'Phenotype', 'HP:0002360', (0, 17))	('gastro-esophageal reflux', 'Disease', 'MESH:D005764', (122, 146))	('Sleep disturbance', 'Var', (0, 17))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('diminish', 'NegReg', (24, 32))
325808	28147252	Using the National Cancer Data Base (NCDB) from 2006-2012, patients with clinical stage T1b, N1-N3 or T2-T4a, N-/+, M0 adenocarcinoma of the middle or lower esophagus who underwent surgical resection were selected.	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('T2-T4a', 'Var', (102, 108))	('N1-N3', 'Var', (93, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('adenocarcinoma of the middle', 'Disease', 'MESH:D020244', (119, 147))	('N-/+', 'Var', (110, 114))	('patients', 'Species', '9606', (59, 67))	('adenocarcinoma of the middle', 'Disease', (119, 147))	('CD', 'Chemical', '-', (38, 40))	('T1b', 'Var', (88, 91))
325827	28147252	We queried the American College of Surgeons National Cancer Data Base (ACS-NCDB) 2006-2012 for all patients with adenocarcinoma of the middle and lower esophagus who were clinical stage T1b, N1-N3, M0 or T2-T4a, N-/+, M0 who had undergone surgery.	('CD', 'Chemical', '-', (76, 78))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('adenocarcinoma of the middle', 'Disease', 'MESH:D020244', (113, 141))	('N1-N3', 'Var', (191, 196))	('adenocarcinoma of the middle', 'Disease', (113, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('patients', 'Species', '9606', (99, 107))	('T2-T4a', 'Var', (204, 210))
325829	28147252	The following International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes were used to identify patients with adenocarcinoma: 8140-8148, 8200-8239, 8260-8263, 8480-8496, 8500-8503, and 8560-8573.	('adenocarcinoma', 'Disease', 'MESH:D000230', (135, 149))	('8500-8503', 'Var', (195, 204))	('8480-8496', 'Var', (184, 193))	('8140-8148', 'Var', (151, 160))	('Oncology', 'Phenotype', 'HP:0002664', (59, 67))	('8260-8263', 'Var', (173, 182))	('adenocarcinoma', 'Disease', (135, 149))	('8200-8239', 'Var', (162, 171))	('CD', 'Chemical', '-', (85, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('patients', 'Species', '9606', (121, 129))	('8560-8573', 'Var', (210, 219))
325924	29142537	Pathophysiologically, degeneration of myenteric plexus leads to high amplitude non-peristaltic contractions (vigorous achalasia) due to unopposed action of excitatory neurotransmitters.	('degeneration', 'Var', (22, 34))	('vigorous achalasia', 'Disease', 'MESH:D004931', (109, 127))	('high amplitude non-peristaltic contractions', 'MPA', (64, 107))	('achalasia', 'Phenotype', 'HP:0002571', (118, 127))	('vigorous achalasia', 'Disease', (109, 127))
326001	28746362	Site specific codes (C15.0-C15.5, C15.8, C15.9) were used to screen for tumors originating in the esophagus.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('C15.9', 'CellLine', 'CVCL:0H97', (41, 46))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('C15.8', 'Var', (34, 39))
326218	25749514	DC120 inhibited SP fraction, the sphere-forming ability in vitro and growth of primary xenografts as well as secondary xenografts' tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('sphere-forming ability in vitro', 'CPA', (33, 64))	('SP fraction', 'CPA', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('DC120', 'Var', (0, 5))	('tumor', 'Disease', (131, 136))	('inhibited', 'NegReg', (6, 15))	('SP', 'Chemical', '-', (16, 18))	('DC120', 'Chemical', 'MESH:C575445', (0, 5))	('growth of primary xenografts', 'CPA', (69, 97))
326220	25749514	A combination of DC120 and CDDP more effectively inhibited NPC cells compared with monotherapy in vitro and in vivo.	('DC120', 'Chemical', 'MESH:C575445', (17, 22))	('NPC', 'Disease', (59, 62))	('DC120', 'Var', (17, 22))	('CDDP', 'Gene', (27, 31))	('NPC', 'Phenotype', 'HP:0100630', (59, 62))	('inhibited', 'NegReg', (49, 58))	('CDDP', 'Chemical', '-', (27, 31))
326226	25749514	Loss or mutation of tumor suppressor PTEN, amplification or mutation of PI3K, activation or mutation of growth factor receptors and oncogenes, and amplification of AKT itself are involved in the activation of AKT in tumors.	('mutation', 'Var', (60, 68))	('mutation', 'Var', (92, 100))	('tumors', 'Disease', (216, 222))	('PTEN', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('amplification', 'Var', (147, 160))	('AKT', 'Gene', (164, 167))	('tumor', 'Disease', (216, 221))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('amplification', 'Var', (43, 56))	('Loss', 'NegReg', (0, 4))	('PTEN', 'Gene', '5728', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutation', 'Var', (8, 16))	('AKT', 'Gene', (209, 212))	('PI3K', 'Gene', (72, 76))	('AKT', 'Gene', '207', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('AKT', 'Gene', '207', (209, 212))	('activation', 'PosReg', (195, 205))	('tumor', 'Disease', (20, 25))
326235	25749514	Our data showed that DC120 inhibited the proliferation of human NPC CNE-2-S-18/SP and CNE-1/SP cells in vitro and in vivo and significantly reduced the self-renewal and tumor-initiating capacities of cancer stem-like SP cells via the induction of cell apoptosis.	('SP', 'Chemical', '-', (217, 219))	('DC120', 'Chemical', 'MESH:C575445', (21, 26))	('human', 'Species', '9606', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('CNE-1', 'CellLine', 'CVCL:6888', (86, 91))	('cell apoptosis', 'CPA', (247, 261))	('tumor', 'Disease', (169, 174))	('inhibited', 'NegReg', (27, 36))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('SP', 'Chemical', '-', (79, 81))	('NPC', 'Phenotype', 'HP:0100630', (64, 67))	('self-renewal', 'CPA', (152, 164))	('cancer', 'Disease', (200, 206))	('proliferation', 'CPA', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('DC120', 'Var', (21, 26))	('SP', 'Chemical', '-', (92, 94))	('reduced', 'NegReg', (140, 147))
326236	25749514	Additionally, we observed that DC120 suppressed the cancer stem-like SP cells through the inhibition of AKT kinase activity and the blockade of the PI3K/AKT downstream signaling pathway, further regulating Sox2 expression.	('Sox2', 'Gene', (206, 210))	('inhibition', 'NegReg', (90, 100))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('regulating', 'Reg', (195, 205))	('SP', 'Chemical', '-', (69, 71))	('AKT', 'Gene', (104, 107))	('AKT', 'Gene', '207', (153, 156))	('DC120', 'Chemical', 'MESH:C575445', (31, 36))	('blockade', 'NegReg', (132, 140))	('activity', 'MPA', (115, 123))	('DC120', 'Var', (31, 36))	('AKT', 'Gene', (153, 156))	('cancer', 'Disease', (52, 58))	('Sox2', 'Gene', '6657', (206, 210))	('expression', 'MPA', (211, 221))	('AKT', 'Gene', '207', (104, 107))	('suppressed', 'NegReg', (37, 47))
326237	25749514	Moreover, we found that the combination of DC120 and cisplatin (CDDP) has a significant synergistic effect, and DC120 could sensitize the inhibitory effect of CDDP on NPC cells.	('DC120', 'Var', (112, 117))	('synergistic effect', 'MPA', (88, 106))	('CDDP', 'Chemical', '-', (159, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('DC120', 'Chemical', 'MESH:C575445', (112, 117))	('CDDP', 'Chemical', '-', (64, 68))	('DC120', 'Chemical', 'MESH:C575445', (43, 48))	('NPC', 'Phenotype', 'HP:0100630', (167, 170))	('inhibitory effect', 'MPA', (138, 155))
326249	25749514	Our results indicated that the phosphorylation status of AKT on Thr308 and Ser473 and the phosphorylation levels of AKT downstream targets (FKHRL1 and GSK-3beta) were much higher in SP cells than those in NSP cells (Figure 2A), suggesting that the PI3K/AKT pathway was activated in NPC cancer stem-like SP cells.	('GSK-3beta', 'Gene', (151, 160))	('Ser473', 'Var', (75, 81))	('Ser473', 'Chemical', '-', (75, 81))	('AKT', 'Gene', (253, 256))	('NPC', 'Phenotype', 'HP:0100630', (282, 285))	('SP', 'Chemical', '-', (303, 305))	('phosphorylation status', 'MPA', (31, 53))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('higher', 'PosReg', (172, 178))	('AKT', 'Gene', '207', (57, 60))	('phosphorylation levels', 'MPA', (90, 112))	('FKHRL1', 'Gene', (140, 146))	('SP', 'Chemical', '-', (182, 184))	('AKT', 'Gene', (116, 119))	('SP', 'Chemical', '-', (206, 208))	('FKHRL1', 'Gene', '2309', (140, 146))	('NPC cancer', 'Disease', 'MESH:D052556', (282, 292))	('AKT', 'Gene', '207', (253, 256))	('Thr308', 'Chemical', '-', (64, 70))	('AKT', 'Gene', (57, 60))	('GSK-3beta', 'Gene', '2932', (151, 160))	('AKT', 'Gene', '207', (116, 119))	('NPC cancer', 'Disease', (282, 292))	('activated', 'PosReg', (269, 278))
326251	25749514	As the inhibition of substrate phosphorylation can reflect the inhibition of AKT activity, we examined whether DC120 (Figure 2C) could inhibit AKT and its downstream targets.	('AKT', 'Gene', (77, 80))	('AKT', 'Gene', (143, 146))	('AKT', 'Gene', '207', (77, 80))	('DC120', 'Chemical', 'MESH:C575445', (111, 116))	('inhibit', 'NegReg', (135, 142))	('AKT', 'Gene', '207', (143, 146))	('inhibition', 'NegReg', (7, 17))	('DC120', 'Var', (111, 116))	('substrate phosphorylation', 'MPA', (21, 46))	('activity', 'MPA', (81, 89))	('inhibition', 'NegReg', (63, 73))
326252	25749514	Figure 2D and 2E showed that the phosphorylation levels of FKHRL1 and GSK-3beta were all partially attenuated by DC120 dose and time dependently without affecting the amount of total proteins.	('phosphorylation levels', 'MPA', (33, 55))	('FKHRL1', 'Gene', (59, 65))	('GSK-3beta', 'Gene', '2932', (70, 79))	('GSK-3beta', 'Gene', (70, 79))	('DC120', 'Var', (113, 118))	('FKHRL1', 'Gene', '2309', (59, 65))	('DC120', 'Chemical', 'MESH:C575445', (113, 118))	('attenuated', 'NegReg', (99, 109))
326253	25749514	However, the phosphorylation of Thr308 and Ser473 on AKT increased concomitantly, although AKT kinase activity was inhibited, the conformational change of AKT led to its self-hyperphosphorylation.	('conformational change', 'MPA', (130, 151))	('AKT', 'Gene', (155, 158))	('AKT', 'Gene', '207', (91, 94))	('phosphorylation', 'MPA', (13, 28))	('Thr308', 'Var', (32, 38))	('self-hyperphosphorylation', 'MPA', (170, 195))	('Ser473', 'Var', (43, 49))	('Ser473', 'Chemical', '-', (43, 49))	('AKT', 'Gene', '207', (53, 56))	('AKT', 'Gene', (91, 94))	('increased', 'PosReg', (57, 66))	('activity', 'MPA', (102, 110))	('AKT', 'Gene', '207', (155, 158))	('AKT', 'Gene', (53, 56))	('Thr308', 'Chemical', '-', (32, 38))	('inhibited', 'NegReg', (115, 124))
326258	25749514	As shown in Figure 3A, exposure to DC120 resulted in a dose-dependent inhibition of cell viability, and compared with NSP cells, SP populations were more sensitive to DC120 especially at low doses for S-18 and CNE2 cells.	('inhibition', 'NegReg', (70, 80))	('DC120', 'Chemical', 'MESH:C575445', (35, 40))	('DC120', 'Var', (167, 172))	('sensitive', 'Reg', (154, 163))	('S', 'Chemical', 'MESH:D013455', (201, 202))	('cell viability', 'CPA', (84, 98))	('DC120', 'Chemical', 'MESH:C575445', (167, 172))	('SP', 'Chemical', '-', (129, 131))	('DC120', 'Var', (35, 40))	('CNE2', 'CellLine', 'CVCL:6889', (210, 214))	('S', 'Chemical', 'MESH:D013455', (129, 130))	('SP', 'Chemical', '-', (119, 121))	('S', 'Chemical', 'MESH:D013455', (119, 120))
326259	25749514	To examine whether DC120 could inhibit the SP phenotype in vitro, we performed a FACS analysis assay.	('S', 'Chemical', 'MESH:D013455', (84, 85))	('DC120', 'Chemical', 'MESH:C575445', (19, 24))	('SP', 'Chemical', '-', (43, 45))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('inhibit', 'NegReg', (31, 38))	('DC120', 'Var', (19, 24))
326260	25749514	As shown in Figure 3B, 2.5 mumol/L DC120 significantly decreased the number of SP cells by over 76% in the CNE-2-S-18 cell line (P < 0.01) and 23% in the CNE-1 cell line (P < 0.05), and 10 mumol/L produced a greater than 89% reduction of SP cells in the CNE-2-S-18 cell line (P < 0.01) and 71% in the CNE-1 cell line (P < 0.01).	('DC120', 'Chemical', 'MESH:C575445', (35, 40))	('reduction', 'NegReg', (225, 234))	('CNE-1', 'CellLine', 'CVCL:6888', (154, 159))	('SP', 'Chemical', '-', (79, 81))	('SP', 'Chemical', '-', (238, 240))	('decreased', 'NegReg', (55, 64))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (254, 264))	('DC120', 'Var', (35, 40))	('SP cells', 'CPA', (238, 246))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (107, 117))	('CNE-1', 'CellLine', 'CVCL:6888', (301, 306))
326261	25749514	To evaluate whether DC120 could suppress the formation of nasospheres in vitro, we exposed freshly sorted CNE-2-S-18/SP and CNE-1/SP cells to varying concentrations of DC120 and then cultured them for 7-14 days in the presence of the compound.	('SP', 'Chemical', '-', (117, 119))	('suppress', 'NegReg', (32, 40))	('DC120', 'Var', (20, 25))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (106, 116))	('SP', 'Chemical', '-', (130, 132))	('CNE-1', 'CellLine', 'CVCL:6888', (124, 129))	('DC120', 'Chemical', 'MESH:C575445', (20, 25))	('DC120', 'Chemical', 'MESH:C575445', (168, 173))
326262	25749514	As shown in Figures 3C and 3D, DC120 inhibited the formation of spheres.	('DC120', 'Chemical', 'MESH:C575445', (31, 36))	('DC120', 'Var', (31, 36))	('formation of spheres', 'CPA', (51, 71))	('inhibited', 'NegReg', (37, 46))
326265	25749514	These data showed that DC120 inhibited the cancer stem-like SP cells at similar concentrations to those that inhibited nasosphere formation and at approximately 7-fold lower concentrations than those that inhibited cancer cells as determined by the MTT assay.	('DC120', 'Var', (23, 28))	('inhibited', 'NegReg', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('MTT', 'Chemical', 'MESH:C070243', (249, 252))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', (43, 49))	('nasosphere formation', 'CPA', (119, 139))	('inhibited', 'NegReg', (109, 118))	('DC120', 'Chemical', 'MESH:C575445', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('SP', 'Chemical', '-', (60, 62))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
326266	25749514	To confirm whether DC120 inhibits the cancer stem-like SP cell phenotype by inducing apoptosis in vitro, an Annexin V-FITC/propidium iodide double staining assay was used to detect the apoptotic cells.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('inhibits', 'NegReg', (25, 33))	('SP', 'Chemical', '-', (55, 57))	('Annexin V', 'Gene', '308', (108, 117))	('apoptosis', 'CPA', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('inducing', 'Reg', (76, 84))	('DC120', 'Chemical', 'MESH:C575445', (19, 24))	('propidium iodide', 'Chemical', 'MESH:D011419', (123, 139))	('Annexin V', 'Gene', (108, 117))	('cancer', 'Disease', (38, 44))	('DC120', 'Var', (19, 24))
326267	25749514	In Figure 4A, the percentage of Annexin V-positive cells were higher in CNE-2-S-18/SP cells (6.5%, 15.6%, 75.9%) than that in CNE-2-S-18/NSP cells (5.9%, 10.8%, 61.5%), when CNE-2-S-18-SP/NSP cells treated with 2.5, 5 or 10 mumol/L DC120 for 48 hours.	('Annexin V', 'Gene', (32, 41))	('SP', 'Chemical', '-', (185, 187))	('CNE-2-S-18-SP', 'CellLine', 'CVCL:6889', (174, 187))	('SP', 'Chemical', '-', (83, 85))	('SP', 'Chemical', '-', (189, 191))	('SP', 'Chemical', '-', (138, 140))	('CNE-2-S-18/SP', 'Var', (72, 85))	('DC120', 'Chemical', 'MESH:C575445', (232, 237))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (126, 136))	('higher', 'PosReg', (62, 68))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (174, 184))	('Annexin V', 'Gene', '308', (32, 41))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (72, 82))
326271	25749514	These data indicated that DC120 indeed induced apoptosis in NPC SP cells, which was consistent with the results of the nasosphere-forming assay and SP analysis assays.	('DC120', 'Var', (26, 31))	('induced', 'Reg', (39, 46))	('apoptosis', 'CPA', (47, 56))	('SP', 'Chemical', '-', (148, 150))	('NPC', 'Phenotype', 'HP:0100630', (60, 63))	('DC120', 'Chemical', 'MESH:C575445', (26, 31))	('SP', 'Chemical', '-', (64, 66))
326274	25749514	Moreover, CDDP treatment increased the percentage of SP cells (Figure 5B), which was similar to other findings and may play a role in resistance.	('SP cells', 'CPA', (53, 61))	('increased', 'PosReg', (25, 34))	('SP', 'Chemical', '-', (53, 55))	('CDDP', 'Var', (10, 14))	('CDDP', 'Chemical', '-', (10, 14))
326275	25749514	We further examined the combination of CDDP and DC120, which had a significant synergistic effect (Figure 5C) and produced a combination index (CI) value of < 1 in both CNE-2-S-18 and CNE-1 cells (Table 2 and Table 3).	('DC120', 'Chemical', 'MESH:C575445', (48, 53))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (169, 179))	('synergistic', 'MPA', (79, 90))	('CDDP', 'Var', (39, 43))	('CDDP', 'Chemical', '-', (39, 43))	('DC120', 'Var', (48, 53))	('CNE-1', 'CellLine', 'CVCL:6888', (184, 189))	('combination', 'MPA', (125, 136))
326276	25749514	Although treatment with CDDP alone increased the proportions of cancer stem-like SP cells (Figure 5B), 5 mumol/L or 10 mumol/L DC120 plus 5 mumol/L CDDP significantly decreased the proportions of SP cells by over 76.9% (P < 0.01) or 81.7% (P < 0.01) in CNE-2-S-18 cells, and 66.9% (P < 0.01) or 97.8% (P < 0.01) in CNE-1 cells, respectively (Figure 5D).	('increased', 'PosReg', (35, 44))	('CNE-1', 'CellLine', 'CVCL:6888', (315, 320))	('CDDP', 'Chemical', '-', (148, 152))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('DC120', 'Var', (127, 132))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (253, 263))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('SP', 'Chemical', '-', (81, 83))	('DC120', 'Chemical', 'MESH:C575445', (127, 132))	('CDDP', 'Chemical', '-', (24, 28))	('SP', 'Chemical', '-', (196, 198))	('decreased', 'NegReg', (167, 176))
326278	25749514	administration of 8% solvent (negative control), DC120, CDDP, or DC120+CDDP on day 5 after implantation.	('DC120', 'Chemical', 'MESH:C575445', (49, 54))	('DC120+CDDP', 'Var', (65, 75))	('CDDP', 'Chemical', '-', (56, 60))	('CDDP', 'Chemical', '-', (71, 75))	('DC120', 'Var', (49, 54))	('DC120', 'Chemical', 'MESH:C575445', (65, 70))
326279	25749514	Treatment with DC120 noticeably suppressed the tumor growth, and the tumor growth inhibition (T/C %) was approximately 48.7% (P < 0.05; Figure 6A, Table 4).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('DC120', 'Var', (15, 20))	('tumor', 'Disease', (69, 74))	('DC120', 'Chemical', 'MESH:C575445', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (47, 52))	('suppressed', 'NegReg', (32, 42))
326281	25749514	DC120 plus CDDP treatment in vivo led to an even greater reduction in tumor growth, and the inhibitory rate was 78.7% (P < 0.01; Figure 6A, Table 4).	('CDDP', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CDDP', 'Chemical', '-', (11, 15))	('reduction', 'NegReg', (57, 66))	('tumor', 'Disease', (70, 75))	('DC120', 'Var', (0, 5))	('DC120', 'Chemical', 'MESH:C575445', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
326284	25749514	The proportion of SP cells isolated from DC120-treated tumors demonstrated a 44.6% reduction (P < 0.01; Figure 6B, 6C), and the number and size of the spheres significantly decreased 5 to 10 fold and 16 to 128 fold compared with controls (P < 0.05; Figure 6D, 6E).	('DC120-treated', 'Var', (41, 54))	('DC120', 'Chemical', 'MESH:C575445', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SP', 'Chemical', '-', (18, 20))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('reduction', 'NegReg', (83, 92))	('decreased', 'NegReg', (173, 182))
326285	25749514	However, the tumors treated with CDDP alone increased the proportion of SP cells by 9.1% (P < 0.05; Figure 6B, 6C), and had a similar nasosphere-forming ability compared with untreated controls (Figure 6D, 6E).	('CDDP', 'Var', (33, 37))	('SP', 'Chemical', '-', (72, 74))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('nasosphere-forming ability', 'CPA', (134, 160))	('CDDP', 'Chemical', '-', (33, 37))	('increased', 'PosReg', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
326286	25749514	Additionally, primary xenografts treated with DC120 and CDDP in combination displayed a 64.8% reduction in SP cells (P < 0.01; Figure 6B, 6C) and decreased nasosphere formation (Figure 6D, 6E), Furthermore, we injected 100,000 cells obtained from 4 groups of primary tumor cells into secondary recipient mice and examined the growth of the secondary tumors.	('tumors', 'Disease', (350, 356))	('reduction', 'NegReg', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumors', 'Disease', 'MESH:D009369', (350, 356))	('CDDP', 'Chemical', '-', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (350, 355))	('DC120', 'Var', (46, 51))	('mice', 'Species', '10090', (304, 308))	('nasosphere formation', 'CPA', (156, 176))	('CDDP', 'Gene', (56, 60))	('DC120', 'Chemical', 'MESH:C575445', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('SP cells', 'CPA', (107, 115))	('tumors', 'Phenotype', 'HP:0002664', (350, 356))	('SP', 'Chemical', '-', (107, 109))	('decreased', 'NegReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('tumor', 'Disease', (267, 272))
326287	25749514	We observed that cancer cells obtained from DC120-treated mice resulted in the slowest tumor recurrence, reaching a final tumor size ranging from 300 to 500 mm3 in the secondary mice (Figure 6F).	('DC120-treated', 'Var', (44, 57))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mice', 'Species', '10090', (178, 182))	('tumor', 'Disease', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mice', 'Species', '10090', (58, 62))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('DC120', 'Chemical', 'MESH:C575445', (44, 49))	('slowest', 'NegReg', (79, 86))	('tumor', 'Disease', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
326290	25749514	These data illustrated that DC120 in combination with CDDP showed a significant synergistic effect on the inhibition of NPC cells, and DC120 effectively sensitized NPC cells to CDDP therapy in vivo.	('DC120', 'Chemical', 'MESH:C575445', (28, 33))	('inhibition', 'MPA', (106, 116))	('DC120', 'Chemical', 'MESH:C575445', (135, 140))	('CDDP', 'Chemical', '-', (54, 58))	('CDDP', 'Chemical', '-', (177, 181))	('NPC', 'Phenotype', 'HP:0100630', (164, 167))	('sensitized', 'Reg', (153, 163))	('NPC', 'Phenotype', 'HP:0100630', (120, 123))	('DC120', 'Var', (135, 140))
326293	25749514	Inhibition of PI3K/AKT pathway by a PI3K inhibitor LY294002 or a kinase dead dominant-negative AKT mutant can up-regulate the levels of p27 in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('LY294002', 'Var', (51, 59))	('p27', 'Gene', '3429', (136, 139))	('p27', 'Gene', (136, 139))	('AKT', 'Gene', '207', (95, 98))	('AKT', 'Gene', (19, 22))	('AKT', 'Gene', '207', (19, 22))	('up-regulate', 'PosReg', (110, 121))	('AKT', 'Gene', (95, 98))	('levels', 'MPA', (126, 132))	('cancer', 'Disease', (143, 149))	('LY294002', 'Chemical', 'MESH:C085911', (51, 59))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mutant', 'Var', (99, 105))
326296	25749514	Our results showed that the protein expression level of p27 was up-regulated dose and time dependently in CNE-2-S-18 cells after treatment with DC120, while the protein expression and mRNA level of Sox2 was down-regulated dose and time dependently (Figure 7A, 7B).	('protein expression level', 'MPA', (28, 52))	('DC120', 'Var', (144, 149))	('protein expression', 'MPA', (161, 179))	('Sox2', 'Gene', '6657', (198, 202))	('mRNA level', 'MPA', (184, 194))	('p27', 'Gene', '3429', (56, 59))	('p27', 'Gene', (56, 59))	('Sox2', 'Gene', (198, 202))	('up-regulated', 'PosReg', (64, 76))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (106, 116))	('DC120', 'Chemical', 'MESH:C575445', (144, 149))	('down-regulated', 'NegReg', (207, 221))
326297	25749514	To further demonstrate the involvement of DC120 in the repression of Sox2 in NPC cells, two different p27 siRNAs were employed to knock down p27 in CNE-2-S-18 cells.	('DC120', 'Chemical', 'MESH:C575445', (42, 47))	('p27', 'Gene', '3429', (102, 105))	('p27', 'Gene', (102, 105))	('Sox2', 'Gene', (69, 73))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (148, 158))	('p27', 'Gene', '3429', (141, 144))	('NPC', 'Phenotype', 'HP:0100630', (77, 80))	('p27', 'Gene', (141, 144))	('knock down', 'Var', (130, 140))	('Sox2', 'Gene', '6657', (69, 73))
326299	25749514	Accordingly, the decrease of the Sox2 expression levels caused by DC120 was blocked when the expression of p27 was down-regulated.	('p27', 'Gene', (107, 110))	('DC120', 'Chemical', 'MESH:C575445', (66, 71))	('Sox2', 'Gene', '6657', (33, 37))	('decrease', 'NegReg', (17, 25))	('p27', 'Gene', '3429', (107, 110))	('Sox2', 'Gene', (33, 37))	('DC120', 'Var', (66, 71))
326300	25749514	To further verified Sox2 was the target gene to regulate the efficacy of the DC120, we found overexpression of Sox2 could prevent from decrease of the SP population in NPC cells by DC120 treatment (Figure 7D, 7E).	('SP population', 'CPA', (151, 164))	('DC120', 'Chemical', 'MESH:C575445', (181, 186))	('Sox2', 'Gene', (20, 24))	('SP', 'Chemical', '-', (151, 153))	('DC120', 'Var', (181, 186))	('Sox2', 'Gene', (111, 115))	('Sox2', 'Gene', '6657', (111, 115))	('NPC', 'Phenotype', 'HP:0100630', (168, 171))	('DC120', 'Chemical', 'MESH:C575445', (77, 82))	('Sox2', 'Gene', '6657', (20, 24))	('overexpression', 'PosReg', (93, 107))
326301	25749514	Furthermore, knockdown of the Sox2 by siRNA could decrease the proportion of SP cells in NPC (Figure S3A, S3B).	('Sox2', 'Gene', (30, 34))	('S', 'Chemical', 'MESH:D013455', (101, 102))	('Sox2', 'Gene', '6657', (30, 34))	('SP', 'Chemical', '-', (77, 79))	('NPC', 'Phenotype', 'HP:0100630', (89, 92))	('S', 'Chemical', 'MESH:D013455', (77, 78))	('S', 'Chemical', 'MESH:D013455', (30, 31))	('S', 'Chemical', 'MESH:D013455', (106, 107))	('knockdown', 'Var', (13, 22))	('NPC', 'Disease', (89, 92))	('decrease', 'NegReg', (50, 58))
326304	25749514	According to reports previous, at translational level, activities of Sox2 were controlled by several miRNAs, namely microRNA-145, microRNA-126, microRNA-9 and microRNA-21.	('Sox2', 'Gene', (69, 73))	('controlled', 'Reg', (79, 89))	('activities', 'MPA', (55, 65))	('microRNA-145', 'Var', (116, 128))	('microRNA-21', 'Var', (159, 170))	('microRNA-126', 'Var', (130, 142))	('microRNA-9', 'Var', (144, 154))	('Sox2', 'Gene', '6657', (69, 73))
326308	25749514	We then chose 20 miRNAs through the qRT-PCR, and our results showed that 9 miRNAs were up-regulated after treatment with DC120, which was consistent with the results of the microarray (Figure S4A).	('up-regulated', 'PosReg', (87, 99))	('DC120', 'Chemical', 'MESH:C575445', (121, 126))	('miRNAs', 'MPA', (75, 81))	('DC120', 'Var', (121, 126))	('S', 'Chemical', 'MESH:D013455', (192, 193))
326310	25749514	Similarly, DC120-treated cells showed a higher expression of miR-30a (5.3-fold) than control cells in real-time PCR (RT-PCR) analysis (Figure S4B).	('S', 'Chemical', 'MESH:D013455', (142, 143))	('higher', 'PosReg', (40, 46))	('miR-30a', 'Gene', (61, 68))	('DC120-treated', 'Var', (11, 24))	('miR-30a', 'Gene', '407029', (61, 68))	('expression', 'MPA', (47, 57))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('DC120', 'Chemical', 'MESH:C575445', (11, 16))
326311	25749514	These results indicated that miR-30a expression was up-regulated by DC120.	('up-regulated', 'PosReg', (52, 64))	('DC120', 'Var', (68, 73))	('miR-30a', 'Gene', '407029', (29, 36))	('expression', 'MPA', (37, 47))	('DC120', 'Chemical', 'MESH:C575445', (68, 73))	('miR-30a', 'Gene', (29, 36))
326318	25749514	Taken together, our results demonstrate that DC120 regulates Sox2 via up-regulation of p27 and miR-30a.	('miR-30a', 'Gene', (95, 102))	('up-regulation', 'PosReg', (70, 83))	('DC120', 'Chemical', 'MESH:C575445', (45, 50))	('p27', 'Gene', '3429', (87, 90))	('miR-30a', 'Gene', '407029', (95, 102))	('Sox2', 'Gene', '6657', (61, 65))	('DC120', 'Var', (45, 50))	('p27', 'Gene', (87, 90))	('Sox2', 'Gene', (61, 65))
326319	25749514	Here we report that a new compound DC120 selectively targeted NPC cancer stem-like SP cells and sensitized NPC cells to conventional chemotherapy in vitro and in vivo by blocking the AKT signaling pathway and inhibiting Sox2 expression.	('Sox2', 'Gene', (220, 224))	('DC120', 'Chemical', 'MESH:C575445', (35, 40))	('NPC', 'Phenotype', 'HP:0100630', (107, 110))	('SP', 'Chemical', '-', (83, 85))	('inhibiting', 'NegReg', (209, 219))	('AKT', 'Gene', (183, 186))	('blocking', 'NegReg', (170, 178))	('NPC cancer', 'Disease', 'MESH:D052556', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('NPC', 'Phenotype', 'HP:0100630', (62, 65))	('DC120', 'Var', (35, 40))	('NPC cancer', 'Disease', (62, 72))	('Sox2', 'Gene', '6657', (220, 224))	('expression', 'MPA', (225, 235))	('AKT', 'Gene', '207', (183, 186))
326330	25749514	Additionally in the presence of DC120 phosphorylation of AKT downstream targets such as FKHRL1 and GSK-3beta were markedly decreased in cancer stem-like SP cells.	('DC120', 'Var', (32, 37))	('GSK-3beta', 'Gene', '2932', (99, 108))	('phosphorylation', 'MPA', (38, 53))	('decreased', 'NegReg', (123, 132))	('FKHRL1', 'Gene', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('SP', 'Chemical', '-', (153, 155))	('DC120', 'Chemical', 'MESH:C575445', (32, 37))	('AKT', 'Gene', '207', (57, 60))	('cancer', 'Disease', (136, 142))	('GSK-3beta', 'Gene', (99, 108))	('FKHRL1', 'Gene', '2309', (88, 94))	('AKT', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
326331	25749514	Simultaneously, a concomitant increase in the Thr308 and Ser473 phosphorylation of AKT was also observed (Figure 2D, 2E), which might be caused by a feedback loop induced by DC120 or a direct consequence of DC120 binding to the ATP binding site of AKT, as we previously reported.	('AKT', 'Gene', '207', (83, 86))	('DC120', 'Var', (207, 212))	('binding', 'Interaction', (213, 220))	('AKT', 'Gene', (248, 251))	('Ser473', 'Chemical', '-', (57, 63))	('AKT', 'Gene', (83, 86))	('DC120', 'Chemical', 'MESH:C575445', (207, 212))	('DC120', 'Var', (174, 179))	('Thr308', 'MPA', (46, 52))	('S', 'Chemical', 'MESH:D013455', (57, 58))	('increase', 'PosReg', (30, 38))	('ATP', 'Chemical', 'MESH:D000255', (228, 231))	('Ser473 phosphorylation', 'MPA', (57, 79))	('Thr308', 'Chemical', '-', (46, 52))	('AKT', 'Gene', '207', (248, 251))	('DC120', 'Chemical', 'MESH:C575445', (174, 179))	('S', 'Chemical', 'MESH:D013455', (0, 1))
326333	25749514	Firstly, we found that SP cells were more sensitive to DC120 by MTT assays (Figure 3A), then we confirmed that DC120 noticeably suppressed cancer stem-like SP cells' self-renewal and tumor-initiating abilities by reducing the cancer stem-like SP cell fraction and nasosphere formation in vitro (Figure 3B and 3D).	('nasosphere formation', 'CPA', (264, 284))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('suppressed', 'NegReg', (128, 138))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('MTT', 'Chemical', 'MESH:C070243', (64, 67))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('DC120', 'Var', (111, 116))	('DC120', 'Chemical', 'MESH:C575445', (111, 116))	('reducing', 'NegReg', (213, 221))	('tumor', 'Disease', (183, 188))	('SP', 'Chemical', '-', (23, 25))	('cancer', 'Disease', (139, 145))	('DC120', 'Chemical', 'MESH:C575445', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('SP', 'Chemical', '-', (156, 158))	('cancer', 'Disease', (226, 232))	('SP', 'Chemical', '-', (243, 245))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
326334	25749514	It is worth noting that the concentrations of DC120 that were capable of suppressing nasosphere formation and the proportion of cancer stem-like SP cells were much lower than those that exhibited anti-proliferative effects in CNE-2-S-18 and CNE-1 cells (Figure 3B and 3D).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('lower', 'NegReg', (164, 169))	('SP', 'Chemical', '-', (145, 147))	('DC120', 'Chemical', 'MESH:C575445', (46, 51))	('CNE-1', 'CellLine', 'CVCL:6888', (241, 246))	('nasosphere formation', 'CPA', (85, 105))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('suppressing', 'NegReg', (73, 84))	('CNE-2-S-18', 'CellLine', 'CVCL:6889', (226, 236))	('DC120', 'Var', (46, 51))	('cancer', 'Disease', (128, 134))
326336	25749514	In addition, DC120 decreased the SP percentage in xenograft tumors, and single cells isolated from these tumors lost their nasosphere-forming capacity and reduced the regrowth of tumors in secondary mice (Figure 6B and 6F), which is the more compelling evidence that DC120 is able to effectively deplete cancer stem-like SP cells in vivo.	('tumors', 'Disease', (105, 111))	('lost', 'NegReg', (112, 116))	('cancer', 'Disease', (304, 310))	('SP', 'Chemical', '-', (33, 35))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('xenograft tumors', 'Disease', (50, 66))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('xenograft tumors', 'Disease', 'MESH:D009369', (50, 66))	('SP percentage', 'CPA', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('nasosphere-forming capacity', 'CPA', (123, 150))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumors', 'Disease', (60, 66))	('mice', 'Species', '10090', (199, 203))	('reduced', 'NegReg', (155, 162))	('DC120', 'Var', (13, 18))	('tumors', 'Disease', (179, 185))	('DC120', 'Chemical', 'MESH:C575445', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('SP', 'Chemical', '-', (321, 323))	('decreased', 'NegReg', (19, 28))	('DC120', 'Chemical', 'MESH:C575445', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
326339	25749514	Further study confirmed that DC120 decreased cancer stem-like SP cell viability mainly due to induction of apoptosis, as demonstrated by an increased sub-G1 population, Annexin V-positive cells and cleaved PARP in tumor samples (Figure 4A-4D).	('cancer', 'Disease', (45, 51))	('DC120', 'Var', (29, 34))	('SP', 'Chemical', '-', (62, 64))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('sub-G1 population', 'CPA', (150, 167))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('PARP', 'Gene', (206, 210))	('decreased', 'NegReg', (35, 44))	('DC120', 'Chemical', 'MESH:C575445', (29, 34))	('Annexin V', 'Gene', '308', (169, 178))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('Annexin V', 'Gene', (169, 178))	('tumor', 'Disease', (214, 219))	('cleaved', 'Var', (198, 205))	('apoptosis', 'CPA', (107, 116))	('increased', 'PosReg', (140, 149))	('PARP', 'Gene', '142', (206, 210))
326340	25749514	Therefore, we suggested that DC120 could inhibit AKT kinase activity and block its signaling pathway via induction of apoptosis in NPC cancer stem-like SP cells.	('apoptosis', 'CPA', (118, 127))	('DC120', 'Var', (29, 34))	('signaling pathway', 'Pathway', (83, 100))	('AKT', 'Gene', (49, 52))	('NPC', 'Phenotype', 'HP:0100630', (131, 134))	('SP', 'Chemical', '-', (152, 154))	('DC120', 'Chemical', 'MESH:C575445', (29, 34))	('block', 'NegReg', (73, 78))	('NPC cancer', 'Disease', 'MESH:D052556', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('inhibit', 'NegReg', (41, 48))	('activity', 'MPA', (60, 68))	('AKT', 'Gene', '207', (49, 52))	('NPC cancer', 'Disease', (131, 141))
326343	25749514	In our present study, we found that DC120 targeted AKT in cancer stem-like SP cells, and the effect was correlated with the reduction of pAKT and the increased expression of p27 (Figure 7A).	('expression', 'MPA', (160, 170))	('p27', 'Gene', '3429', (174, 177))	('p27', 'Gene', (174, 177))	('reduction', 'NegReg', (124, 133))	('targeted', 'Reg', (42, 50))	('DC120', 'Var', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('AKT', 'Gene', (51, 54))	('AKT', 'Gene', (138, 141))	('cancer', 'Disease', (58, 64))	('DC120', 'Chemical', 'MESH:C575445', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('SP', 'Chemical', '-', (75, 77))	('increased', 'PosReg', (150, 159))	('AKT', 'Gene', '207', (51, 54))	('AKT', 'Gene', '207', (138, 141))
326345	25749514	Further studies revealed that Sox2 was a crucial player in maintaining the stemness of GSC (Glioma stem cells) through miR-9, CSCs in HNSCC (Head and Neck squamous cell carcinoma) through miR-302, CSCs in breast tumors, mammalian neural stem cells, CD44+ cancer stem-like cells in EBV-associated nasopharyngeal carcinoma, cancer stem-cell from squamous-cell carcinoma and SP (side population) cells in NSCLC.	('Glioma', 'Phenotype', 'HP:0009733', (92, 98))	('S', 'Chemical', 'MESH:D013455', (127, 128))	('CD44', 'Gene', '960', (249, 253))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('EBV-associated', 'Disease', (281, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('nasopharyngeal carcinoma', 'Disease', (296, 320))	('CD44', 'Gene', (249, 253))	('S', 'Chemical', 'MESH:D013455', (403, 404))	('squamous-cell carcinoma', 'Disease', (344, 367))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('cancer', 'Disease', (255, 261))	('S', 'Chemical', 'MESH:D013455', (30, 31))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('mammalian', 'Species', '9606', (220, 229))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('Glioma', 'Disease', (92, 98))	('breast tumors', 'Disease', (205, 218))	('breast tumors', 'Disease', 'MESH:D001943', (205, 218))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (296, 320))	('carcinoma', 'Phenotype', 'HP:0030731', (358, 367))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('NSCLC', 'Disease', 'MESH:D002289', (402, 407))	('squamous-cell carcinoma', 'Disease', 'MESH:D002294', (344, 367))	('breast tumors', 'Phenotype', 'HP:0100013', (205, 218))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('Sox2', 'Gene', (30, 34))	('NSCLC', 'Disease', (402, 407))	('cancer', 'Disease', (322, 328))	('SP', 'Chemical', '-', (372, 374))	('S', 'Chemical', 'MESH:D013455', (88, 89))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (296, 320))	('S', 'Chemical', 'MESH:D013455', (136, 137))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (344, 367))	('Glioma', 'Disease', 'MESH:D005910', (92, 98))	('S', 'Chemical', 'MESH:D013455', (372, 373))	('Neck squamous cell carcinoma', 'Disease', (150, 178))	('S', 'Chemical', 'MESH:D013455', (198, 199))	('Sox2', 'Gene', '6657', (30, 34))	('Neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (150, 178))	('miR-302', 'Var', (188, 195))
326347	25749514	In this study, we also proved that knockdown of the Sox2 by siRNA could decrease the proportion of SP cells in NPC (Figure S3A, S3B).	('knockdown', 'Var', (35, 44))	('S', 'Chemical', 'MESH:D013455', (52, 53))	('Sox2', 'Gene', (52, 56))	('NPC', 'Phenotype', 'HP:0100630', (111, 114))	('S', 'Chemical', 'MESH:D013455', (128, 129))	('S', 'Chemical', 'MESH:D013455', (123, 124))	('NPC', 'Disease', (111, 114))	('decrease', 'NegReg', (72, 80))	('SP', 'Chemical', '-', (99, 101))	('S', 'Chemical', 'MESH:D013455', (99, 100))	('Sox2', 'Gene', '6657', (52, 56))
326348	25749514	Also, we found that DC120 could inhibit Sox2 expression through increasing p27 expression (Figure 7A).	('p27', 'Gene', (75, 78))	('expression', 'MPA', (79, 89))	('inhibit', 'NegReg', (32, 39))	('Sox2', 'Gene', '6657', (40, 44))	('increasing', 'PosReg', (64, 74))	('DC120', 'Var', (20, 25))	('Sox2', 'Gene', (40, 44))	('expression', 'MPA', (45, 55))	('p27', 'Gene', '3429', (75, 78))	('DC120', 'Chemical', 'MESH:C575445', (20, 25))
326354	25749514	Above all, our study proved that DC120 inhibited Sox2 via increasing p27 and miR-30a expression.	('expression', 'MPA', (85, 95))	('Sox2', 'Gene', (49, 53))	('inhibited', 'NegReg', (39, 48))	('DC120', 'Chemical', 'MESH:C575445', (33, 38))	('p27', 'Gene', '3429', (69, 72))	('miR-30a', 'Gene', '407029', (77, 84))	('increasing', 'PosReg', (58, 68))	('p27', 'Gene', (69, 72))	('Sox2', 'Gene', '6657', (49, 53))	('DC120', 'Var', (33, 38))	('miR-30a', 'Gene', (77, 84))
326355	25749514	Overexpression of Sox2 prevented from decrease of the SP population in NPC cells by DC120 treatment (Figure 7D, 7E).	('DC120', 'Var', (84, 89))	('NPC', 'Phenotype', 'HP:0100630', (71, 74))	('Sox2', 'Gene', (18, 22))	('DC120', 'Chemical', 'MESH:C575445', (84, 89))	('SP', 'Chemical', '-', (54, 56))	('Sox2', 'Gene', '6657', (18, 22))	('SP population', 'MPA', (54, 67))
326356	25749514	Combined with DC120-mediated Sox2 downregulation and repression of the SP population and knockdown of Sox2-induced decrease of the SP percentage, this result suggested that DC120 could repress SP population via down-regulation of Sox2.	('DC120', 'Var', (173, 178))	('DC120', 'Chemical', 'MESH:C575445', (14, 19))	('SP percentage', 'CPA', (131, 144))	('Sox2', 'Gene', '6657', (29, 33))	('repress', 'NegReg', (185, 192))	('SP', 'Chemical', '-', (131, 133))	('down-regulation', 'NegReg', (211, 226))	('downregulation', 'NegReg', (34, 48))	('DC120', 'Chemical', 'MESH:C575445', (173, 178))	('Sox2', 'Gene', '6657', (102, 106))	('Sox2', 'Gene', (29, 33))	('SP', 'Chemical', '-', (193, 195))	('SP', 'Chemical', '-', (71, 73))	('SP population', 'CPA', (193, 206))	('Sox2', 'Gene', '6657', (230, 234))	('decrease', 'NegReg', (115, 123))	('Sox2', 'Gene', (230, 234))	('Sox2', 'Gene', (102, 106))
326358	25749514	In this study, we found that DC120 could enhance NPC cells' chemosensitivity to CDDP therapy.	('DC120', 'Var', (29, 34))	('enhance', 'PosReg', (41, 48))	('NPC', 'Disease', (49, 52))	('CDDP', 'Chemical', '-', (80, 84))	('DC120', 'Chemical', 'MESH:C575445', (29, 34))	('chemosensitivity', 'CPA', (60, 76))	('NPC', 'Phenotype', 'HP:0100630', (49, 52))
326359	25749514	Although CDDP could inhibit cancer cell proliferation, NSP cells were more sensitive to CDDP than SP cells (Figure 5A), and it increased the percentage of cancer stem-like SP cells (Figure 5B), which further proved that conventional treatments target the bulk of cancer cells but do not affect CSCs.	('cancer', 'Disease', (263, 269))	('CDDP', 'Chemical', '-', (9, 13))	('CDDP', 'Chemical', '-', (88, 92))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('SP', 'Chemical', '-', (98, 100))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('S', 'Chemical', 'MESH:D013455', (172, 173))	('SP', 'Chemical', '-', (56, 58))	('S', 'Chemical', 'MESH:D013455', (98, 99))	('CDDP', 'Var', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('CDDP', 'Var', (88, 92))	('S', 'Chemical', 'MESH:D013455', (295, 296))	('inhibit', 'NegReg', (20, 27))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', (155, 161))	('SP', 'Chemical', '-', (172, 174))	('S', 'Chemical', 'MESH:D013455', (56, 57))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('increased', 'PosReg', (127, 136))
326360	25749514	However, DC120 effectively reversed the resistance of NPC cells to CDDP treatment (Figure 5C) and showed a synergistic effect in combination with CDDP (Table 2 and Table 3), which supports further exploration of the combination efficacy of DC120 with other anticancer agents in anticancer therapy.	('DC120', 'Chemical', 'MESH:C575445', (240, 245))	('CDDP', 'Chemical', '-', (146, 150))	('DC120', 'Chemical', 'MESH:C575445', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('NPC', 'Phenotype', 'HP:0100630', (54, 57))	('resistance', 'MPA', (40, 50))	('CDDP', 'Chemical', '-', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('DC120', 'Var', (9, 14))	('cancer', 'Disease', (282, 288))
326495	32064781	Overexpression of JAB1 promoted the proliferation, migration, and invasion of ESCC cells, and was significantly associated with poor prognosis of ESCC patients.	('promoted', 'PosReg', (23, 31))	('migration', 'CPA', (51, 60))	('JAB1', 'Gene', (18, 22))	('patients', 'Species', '9606', (151, 159))	('Overexpression', 'Var', (0, 14))	('proliferation', 'CPA', (36, 49))	('invasion', 'CPA', (66, 74))	('ESCC', 'Disease', (146, 150))	('associated', 'Reg', (112, 122))
326506	32064781	As previously reported by Wang and Tsai, JAB1 is a proto-oncogene that shows abnormal expression in a variety of human cancers and plays an essential role in the development and metastasis of cancers; a high level of JAB1 is often correlated with a poor prognosis.17, 18 Knockdown of JAB1 inhibits the proliferation of human tumor cells, suggesting that overexpression of JAB1 not only serves as a marker of malignant transformation, but also actually contributes to tumor cell proliferation.	('men', 'Species', '9606', (169, 172))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('overexpression', 'PosReg', (354, 368))	('human', 'Species', '9606', (113, 118))	('human', 'Species', '9606', (319, 324))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (467, 472))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('JAB1', 'Gene', (372, 376))	('JAB1', 'Gene', (284, 288))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('inhibits', 'NegReg', (289, 297))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('tumor', 'Disease', (325, 330))	('contributes', 'Reg', (452, 463))	('metastasis of cancers', 'Disease', (178, 199))	('tumor', 'Disease', (467, 472))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('Knockdown', 'Var', (271, 280))	('metastasis of cancers', 'Disease', 'MESH:D009362', (178, 199))	('tumor', 'Disease', 'MESH:D009369', (467, 472))
326514	32064781	Four human ESCC cell lines (including Eca109, KYSE150, KYSE450, and EC9706) and the HET-1A cell line were purchased from the Cell Bank of the Shanghai Institute in China and used in the experiments involved in this study.	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('KYSE150', 'Var', (46, 53))	('KYSE450', 'Var', (55, 62))	('men', 'Species', '9606', (192, 195))	('human', 'Species', '9606', (5, 10))
326542	32064781	The log-rank test indicated that ESCC patients with JAB1 overexpression had a markedly lower five-year survival rate compared to the low-expression group (27.7% vs. 54.2%, P = 0.001, Fig 1d, Table 2).	('ESCC', 'Disease', (33, 37))	('lower', 'NegReg', (87, 92))	('JAB1', 'Gene', (52, 56))	('five-year survival rate', 'CPA', (93, 116))	('patients', 'Species', '9606', (38, 46))	('overexpression', 'Var', (57, 71))
326544	32064781	JAB1 expression in Eca109 and EC9706 was upregulated and downregulated using lentivirus and siRNA, respectively.	('EC9706', 'CellLine', 'CVCL:E307', (30, 36))	('downregulated', 'NegReg', (57, 70))	('expression', 'MPA', (5, 15))	('JAB1', 'Gene', (0, 4))	('upregulated', 'PosReg', (41, 52))	('EC9706', 'Var', (30, 36))
326550	32064781	Additionally, it was noted that the relevant EMT indicators (E-cadherin, N-cadherin, twist, Vimentin, and Snail) were affected by JAB1 expression in the ESCC cell lines.	('Vimentin', 'Gene', '7431', (92, 100))	('Snail', 'Gene', '6615', (106, 111))	('E-cadherin', 'Gene', (61, 71))	('Snail', 'Gene', (106, 111))	('E-cadherin', 'Gene', '999', (61, 71))	('twist', 'Gene', '7291', (85, 90))	('twist', 'Gene', (85, 90))	('Vimentin', 'Gene', (92, 100))	('affected', 'Reg', (118, 126))	('N-cadherin', 'Gene', (73, 83))	('N-cadherin', 'Gene', '1000', (73, 83))	('expression', 'Var', (135, 145))	('JAB1', 'Gene', (130, 134))
326568	32064781	Many previous studies have shown that the EMT indicators are an essential factor affecting tumor metastasis.12, 13, 14, 15 We found that changes in JAB1 expression had a significant impact on the expression of various EMT indicators, which further affects ESCC metastasis via the EMT process.	('ESCC', 'Disease', (256, 260))	('expression', 'MPA', (196, 206))	('impact', 'Reg', (182, 188))	('JAB1', 'Gene', (148, 152))	('changes', 'Var', (137, 144))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('EMT', 'MPA', (218, 221))	('tumor metastasis', 'Disease', 'MESH:D009362', (91, 107))	('expression', 'MPA', (153, 163))	('affects', 'Reg', (248, 255))	('tumor metastasis', 'Disease', (91, 107))
326571	32064781	Changes in JAB1 expression affected the expression of a variety of antioncogenes in ESCC (Fig 4), which provided evidence for the impact of JAB1 on the degree of malignancy of ESCC in multiple directions and through a range of pathways.	('ESCC', 'Disease', (176, 180))	('expression', 'MPA', (40, 50))	('JAB1', 'Gene', (140, 144))	('impact', 'Reg', (130, 136))	('malignancy', 'Disease', 'MESH:D009369', (162, 172))	('JAB1', 'Gene', (11, 15))	('affected', 'Reg', (27, 35))	('malignancy', 'Disease', (162, 172))	('Changes', 'Var', (0, 7))
326580	32064781	Many patients with high JAB1 expression are expected to benefit from postoperative adjuvant therapy.	('patients', 'Species', '9606', (5, 13))	('high', 'Var', (19, 23))	('JAB1', 'Gene', (24, 28))	('benefit', 'PosReg', (56, 63))
326618	21422913	When we added systems characteristics to the regression model (Model 4), low-volume centers still had a higher odds of death compared to high-volume centers (OR 2.2, 95% CI 1.3-3.7), although the magnitude was substantially reduced.	('low-volume', 'Var', (73, 83))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))
326644	32154226	MiR-29c-3p Suppresses the Migration, Invasion and Cell Cycle in Esophageal Carcinoma via CCNA2/p53 Axis In the present study, we tried to describe the role of miR-29c-3p in esophageal carcinoma (EC) and the relationship of miR-29c-3p with CCNA2 as well as cell cycle, accordingly revealing the potential molecular mechanism across cell proliferation, migration and invasion.	('Invasion', 'CPA', (37, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('EC', 'Phenotype', 'HP:0011459', (195, 197))	('esophageal carcinoma', 'Disease', (173, 193))	('p53', 'Gene', '7157', (95, 98))	('EC', 'Disease', 'MESH:D004938', (195, 197))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('miR-29c', 'Gene', (223, 230))	('CCNA2', 'Gene', '890', (239, 244))	('MiR-29c-3p', 'Var', (0, 10))	('CCNA2', 'Gene', '890', (89, 94))	('Esophageal Carcinoma', 'Disease', (64, 84))	('Suppresses', 'NegReg', (11, 21))	('p53', 'Gene', (95, 98))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (173, 193))	('Carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (64, 84))	('miR-29c', 'Gene', '407026', (159, 166))	('si', 'Chemical', 'MESH:D012825', (369, 371))	('Cell Cycle', 'CPA', (50, 60))	('Esophageal Carcinoma', 'Disease', 'MESH:D004938', (64, 84))	('CCNA2', 'Gene', (239, 244))	('Migration', 'CPA', (26, 35))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (173, 193))	('miR-29c', 'Gene', (159, 166))	('CCNA2', 'Gene', (89, 94))	('miR-29c', 'Gene', '407026', (223, 230))
326650	32154226	MiR-29c-3p was shown to be significantly down-regulated in EC tissues and able to predict poor prognosis.	('si', 'Chemical', 'MESH:D012825', (101, 103))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('MiR-29c-3p', 'Var', (0, 10))	('down-regulated', 'NegReg', (41, 55))	('EC', 'Phenotype', 'HP:0011459', (59, 61))	('EC', 'Disease', 'MESH:D004938', (59, 61))
326652	32154226	MiR-29c-3p overexpression inhibited cell proliferation, migration and invasion, as well as arrested cells in G0/G1 phase.	('migration', 'CPA', (56, 65))	('cells in G0/G1 phase', 'CPA', (100, 120))	('inhibited', 'NegReg', (26, 35))	('MiR-29c-3p', 'Var', (0, 10))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('overexpression', 'PosReg', (11, 25))	('arrested', 'NegReg', (91, 99))	('invasion', 'CPA', (70, 78))	('cell proliferation', 'CPA', (36, 54))
326654	32154226	Silencing CCNA2 could suppress cell proliferation, migration and invasion, as well as activate p53 pathway, even was seen to reverse the inhibitory effect of PFTbeta on p53.	('CCNA2', 'Gene', (10, 15))	('p53', 'Gene', (169, 172))	('p53', 'Gene', '7157', (169, 172))	('cell proliferation', 'CPA', (31, 49))	('CCNA2', 'Gene', '890', (10, 15))	('activate', 'PosReg', (86, 94))	('suppress', 'NegReg', (22, 30))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('PFTbeta', 'Chemical', 'MESH:C558699', (158, 165))	('Silencing', 'Var', (0, 9))	('si', 'Chemical', 'MESH:D012825', (69, 71))
326656	32154226	MiR-29c-3p plays a regulatory role in EC tumorigenesis and development.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('MiR-29c-3p', 'Var', (0, 10))	('EC', 'Phenotype', 'HP:0011459', (38, 40))	('development', 'CPA', (59, 70))	('EC', 'Disease', 'MESH:D004938', (38, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('si', 'Chemical', 'MESH:D012825', (51, 53))
326657	32154226	MiR-29c-3p can target CCNA2 to mediate p53 signaling pathway, finally attributing to the inhibition of cell proliferation, migration and invasion, and making cells arrest in G0/G1 phase.	('CCNA2', 'Gene', '890', (22, 27))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('invasion', 'CPA', (137, 145))	('MiR-29c-3p', 'Var', (0, 10))	('cell proliferation', 'CPA', (103, 121))	('mediate', 'Reg', (31, 38))	('CCNA2', 'Gene', (22, 27))	('inhibition', 'NegReg', (89, 99))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('si', 'Chemical', 'MESH:D012825', (141, 143))
326662	32154226	Studies have found that the alteration of miRNAs expression can lead to the changes of oncogenes and tumor suppressor genes, thus affecting cell proliferation, migration, invasion and apoptosis in gastrointestinal neoplasms including ESCC.	('gastrointestinal neoplasms', 'Phenotype', 'HP:0007378', (197, 223))	('invasion', 'CPA', (171, 179))	('alteration', 'Var', (28, 38))	('ESCC', 'Disease', (234, 238))	('si', 'Chemical', 'MESH:D012825', (190, 192))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('expression', 'MPA', (49, 59))	('gastrointestinal neoplasms', 'Disease', 'MESH:D005770', (197, 223))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('oncogenes', 'Gene', (87, 96))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('affecting', 'Reg', (130, 139))	('apoptosis', 'CPA', (184, 193))	('changes', 'Reg', (76, 83))	('gastrointestinal neoplasms', 'Disease', (197, 223))	('cell proliferation', 'CPA', (140, 158))	('neoplasms', 'Phenotype', 'HP:0002664', (214, 223))	('ESCC', 'Disease', 'MESH:C562729', (234, 238))	('lead', 'Reg', (64, 68))	('migration', 'CPA', (160, 169))	('tumor', 'Disease', (101, 106))	('miRNAs', 'Protein', (42, 48))	('neoplasm', 'Phenotype', 'HP:0002664', (214, 222))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('gastrointestinal neoplasm', 'Phenotype', 'HP:0007378', (197, 222))
326683	32154226	Plasmids were all purchased from GenePharma (Shanghai, China), and transiently transfected into EC cells using Lipofectamine2000 (Thermo Fisher Scientific, Inc.), consequently forming six groups of NC mimic, miR-29c-3p mimic, NC inhibitor, miR-29c-3p inhibitor, si-NC, and si-CCNA2.	('si', 'Chemical', 'MESH:D012825', (184, 186))	('si', 'Chemical', 'MESH:D012825', (262, 264))	('EC', 'Disease', 'MESH:D004938', (96, 98))	('miR-29c', 'Gene', '407026', (208, 215))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('CCNA2', 'Gene', (276, 281))	('Lipofectamine2000', 'Chemical', 'MESH:C086724', (111, 128))	('miR-29c', 'Gene', (208, 215))	('si', 'Chemical', 'MESH:D012825', (273, 275))	('si-NC', 'Var', (262, 267))	('EC', 'Phenotype', 'HP:0011459', (96, 98))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('miR-29c', 'Gene', (240, 247))	('CCNA2', 'Gene', '890', (276, 281))	('miR-29c', 'Gene', '407026', (240, 247))
326702	32154226	CCNA2 vectors bearing mutant and wild type 3'UTR (MUT- and WT-3'UTR) were cloned into pmiRGLO (Promega, Madison, WI, United States), forming the luciferase reporter plasmids WT-CCNA2 and MUT-CCNA2.	('CCNA2', 'Gene', '890', (177, 182))	("WT-3'UTR", 'Gene', (59, 67))	('CCNA2', 'Gene', '890', (191, 196))	('CCNA2', 'Gene', '890', (0, 5))	('mutant', 'Var', (22, 28))	('CCNA2', 'Gene', (177, 182))	('CCNA2', 'Gene', (191, 196))	("WT-3'UTR", 'Gene', '8136', (59, 67))	('CCNA2', 'Gene', (0, 5))
326741	32154226	si-NC + PFTbeta group presented the lowest p53 expression, while in si-CCNA2 + PFTbeta group, p53 level was restored, indicating that CCNA2 silencing could abrogate the inhibitory effect of PFTbeta on p53 (Figure 4B).	('p53', 'Gene', (201, 204))	('inhibitory', 'MPA', (169, 179))	('CCNA2', 'Gene', (71, 76))	('p53', 'Gene', (43, 46))	('CCNA2', 'Gene', (134, 139))	('p53', 'Gene', '7157', (94, 97))	('PFTbeta', 'Chemical', 'MESH:C558699', (8, 15))	('si', 'Chemical', 'MESH:D012825', (0, 2))	('silencing', 'Var', (140, 149))	('abrogate', 'NegReg', (156, 164))	('p53', 'Gene', (94, 97))	('lowest', 'NegReg', (36, 42))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('CCNA2', 'Gene', '890', (71, 76))	('PFTbeta', 'Chemical', 'MESH:C558699', (79, 86))	('PFTbeta', 'Chemical', 'MESH:C558699', (190, 197))	('CCNA2', 'Gene', '890', (134, 139))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('p53', 'Gene', '7157', (201, 204))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('p53', 'Gene', '7157', (43, 46))
326744	32154226	Taken together, CCNA2 silencing could repress EC epithelial cell activities.	('CCNA2', 'Gene', '890', (16, 21))	('EC', 'Phenotype', 'HP:0011459', (46, 48))	('repress', 'NegReg', (38, 45))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('EC', 'Disease', 'MESH:D004938', (46, 48))	('CCNA2', 'Gene', (16, 21))	('silencing', 'Var', (22, 31))
326754	32154226	Renata reported that miR-21, miR-29c, miR-148, and miR-203 could serve as potential diagnostic and prognostic biomarkers in EAC and ESCC.	('EAC', 'Disease', 'MESH:D004941', (124, 127))	('miR-29c', 'Gene', '407026', (29, 36))	('miR-21', 'Gene', (21, 27))	('miR-29c', 'Gene', (29, 36))	('miR-148', 'Var', (38, 45))	('ESCC', 'Disease', 'MESH:C562729', (132, 136))	('EAC', 'Phenotype', 'HP:0011459', (124, 127))	('miR-21', 'Gene', '406991', (21, 27))	('miR-203', 'Gene', '406986', (51, 58))	('ESCC', 'Disease', (132, 136))	('miR-203', 'Gene', (51, 58))	('EAC', 'Disease', (124, 127))
326760	32154226	Silencing CCNA2 could decrease the inhibitory effect of miR-29c-3p on EC epithelial cell proliferation, migration and invasion.	('CCNA2', 'Gene', (10, 15))	('decrease', 'NegReg', (22, 30))	('inhibitory effect', 'MPA', (35, 52))	('EC', 'Disease', 'MESH:D004938', (70, 72))	('migration', 'CPA', (104, 113))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('CCNA2', 'Gene', '890', (10, 15))	('EC', 'Phenotype', 'HP:0011459', (70, 72))	('invasion', 'CPA', (118, 126))	('Silencing', 'Var', (0, 9))	('miR-29c', 'Gene', (56, 63))	('miR-29c', 'Gene', '407026', (56, 63))
326762	32154226	In addition, another study has showed that CCNA2 is involved in cytoskeleton dynamics behaviors and cell activities, and the dysregulation of CCNA2 expression can be used as a marker of metastasis.	('CCNA2', 'Gene', (142, 147))	('si', 'Chemical', 'MESH:D012825', (193, 195))	('CCNA2', 'Gene', '890', (43, 48))	('involved', 'Reg', (52, 60))	('CCNA2', 'Gene', (43, 48))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('CCNA2', 'Gene', '890', (142, 147))	('dysregulation', 'Var', (125, 138))
326768	32154226	Silencing CCNA2 could remarkably repress cell proliferation, migration and invasion.	('CCNA2', 'Gene', (10, 15))	('si', 'Chemical', 'MESH:D012825', (79, 81))	('invasion', 'CPA', (75, 83))	('cell proliferation', 'CPA', (41, 59))	('CCNA2', 'Gene', '890', (10, 15))	('repress', 'NegReg', (33, 40))	('Silencing', 'Var', (0, 9))
326770	32154226	When CCNA2 and p53 were simultaneously silenced, the protein level of p53 was seen to be up-regulated relative to that with p53 inhibitor alone, elucidating that silencing CCNA2 could promote p53 expression to some extent, thus activating p53 signaling pathway, consequently inhibiting cell proliferation, migration and invasion, and inducing cell arrest in G0/G1 phase.	('si', 'Chemical', 'MESH:D012825', (162, 164))	('inducing', 'Reg', (334, 342))	('inhibiting', 'NegReg', (275, 285))	('p53', 'Gene', (192, 195))	('p53', 'Gene', '7157', (239, 242))	('promote', 'PosReg', (184, 191))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('p53', 'Gene', '7157', (15, 18))	('CCNA2', 'Gene', (5, 10))	('cell proliferation', 'CPA', (286, 304))	('p53', 'Gene', (239, 242))	('invasion', 'CPA', (320, 328))	('activating', 'PosReg', (228, 238))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('silencing', 'Var', (162, 171))	('si', 'Chemical', 'MESH:D012825', (324, 326))	('CCNA2', 'Gene', (172, 177))	('migration', 'CPA', (306, 315))	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', '7157', (124, 127))	('p53', 'Gene', (15, 18))	('cell arrest in G0/G1 phase', 'CPA', (343, 369))	('p53', 'Gene', (124, 127))	('CCNA2', 'Gene', '890', (5, 10))	('p53', 'Gene', (70, 73))	('expression', 'MPA', (196, 206))	('si', 'Chemical', 'MESH:D012825', (243, 245))	('si', 'Chemical', 'MESH:D012825', (202, 204))	('CCNA2', 'Gene', '890', (172, 177))	('p53', 'Gene', '7157', (192, 195))	('up-regulated', 'PosReg', (89, 101))
326794	31742897	T3-T4 for T-stage and negative versus positive for N-stage.	('N', 'Chemical', 'MESH:D009584', (51, 52))	('T3-T4', 'Var', (0, 5))	('T-stage', 'Disease', (10, 17))
326830	30817615	The expression of matrix metallopeptidase 9 (MMP9), a member of the MMP family, can directly degrade the extracellular matrix.	('MMP9', 'Gene', '4318', (45, 49))	('MMP', 'Gene', (68, 71))	('MMP9', 'Gene', (45, 49))	('matrix metallopeptidase 9', 'Gene', '4318', (18, 43))	('MMP', 'Gene', (45, 48))	('MMP', 'Gene', '4313;4314;4318', (68, 71))	('MMP', 'Gene', '4313;4314;4318', (45, 48))	('expression', 'Var', (4, 14))	('matrix metallopeptidase 9', 'Gene', (18, 43))	('degrade', 'NegReg', (93, 100))
326831	30817615	It has been reported to be involved in esophageal carcinoma metastasis, and high level of MMP9 expression is associated with lymph node metastasis in esophageal carcinoma.	('high level', 'Var', (76, 86))	('esophageal carcinoma metastasis', 'Disease', (39, 70))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (150, 170))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (39, 59))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (150, 170))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (39, 59))	('esophageal carcinoma metastasis', 'Disease', 'MESH:D009362', (39, 70))	('MMP9', 'Gene', (90, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('involved', 'Reg', (27, 35))	('MMP9', 'Gene', '4318', (90, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('esophageal carcinoma', 'Disease', (150, 170))	('associated with', 'Reg', (109, 124))	('lymph', 'Disease', (125, 130))
326863	30817615	A correlation between CK-19 high expression and larger tumor size (P = .022) and venous/lymphatic invasion (P = .024) were observed.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CK-19', 'Gene', '3880', (22, 27))	('tumor', 'Disease', (55, 60))	('high expression', 'Var', (28, 43))	('venous/lymphatic invasion', 'CPA', (81, 106))	('CK-19', 'Gene', (22, 27))
326868	30817615	These results suggest that high expression uPA is associated with poor prognosis in ESCC patients.	('ESCC', 'Disease', (84, 88))	('uPA', 'Gene', (43, 46))	('uPA', 'Gene', '5328', (43, 46))	('patients', 'Species', '9606', (89, 97))	('ESCC', 'Disease', 'MESH:C562729', (84, 88))	('high expression', 'Var', (27, 42))
326944	30271214	In the multivariable Cox analysis, the patients' age at diagnosis, sex, tumor location, tumor grade, yp-T stage, and yp- mLNRS can independently predict patients' DSS (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('predict', 'Reg', (145, 152))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (72, 77))	('yp- mLNRS', 'Var', (117, 126))	('DSS', 'Chemical', '-', (163, 166))	('DSS', 'Disease', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
326982	29428966	Importantly, aberrant expressions of SLC52A3 are associated with stepwise development of esophageal squamous cell carcinoma (ESCC) as well as the survival rates of ESCC patients.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('patients', 'Species', '9606', (169, 177))	('aberrant expressions', 'Var', (13, 33))	('SLC52A3', 'Gene', (37, 44))	('SLC52A3', 'Gene', '113278', (37, 44))	('esophageal squamous cell carcinoma', 'Disease', (89, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('associated with', 'Reg', (49, 64))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (89, 123))
326990	29428966	Notably, a few reports indicated that lack of dietary riboflavin was associated with high risk for ESCC.	('riboflavin', 'Protein', (54, 64))	('lack of dietary riboflavin', 'Phenotype', 'HP:0100504', (38, 64))	('lack', 'Var', (38, 42))	('ESCC', 'Disease', (99, 103))	('riboflavin', 'Chemical', 'MESH:D012256', (54, 64))
327052	29428966	Using the same methods, the luciferase reporter plasmids, pGL4 (- 3825/- 2403), pGL4 (- 3391/- 2403), pGL4 (- 2849/- 2403), pGL4 (- 3288/- 2403), pGL4 (- 3020/- 2403), pGL4 (- 2935/- 2403), pGL4 (- 2897/- 2403), pGL4 (- 2897/- 2495), pGL4 (- 2897/- 2583), pGL4 (- 2897/- 2672), pGL4 (- 2897/- 2743), and pGL4 (- 2897/- 2782) were generated.	('pGL4', 'Gene', '6390', (190, 194))	('pGL4', 'Gene', '6390', (102, 106))	('pGL4', 'Gene', (278, 282))	('pGL4', 'Gene', '6390', (212, 216))	('pGL4', 'Gene', (168, 172))	('pGL4', 'Gene', (80, 84))	('pGL4', 'Gene', (190, 194))	('- 2897/- 2672', 'Var', (262, 275))	('pGL4', 'Gene', '6390', (124, 128))	('- 2897/- 2403', 'Var', (196, 209))	('pGL4', 'Gene', (212, 216))	('- 2897/- 2743', 'Var', (284, 297))	('pGL4', 'Gene', (102, 106))	('pGL4', 'Gene', (124, 128))	('pGL4', 'Gene', '6390', (234, 238))	('pGL4', 'Gene', '6390', (146, 150))	('pGL4', 'Gene', (234, 238))	('pGL4', 'Gene', '6390', (304, 308))	('- 2897/- 2495', 'Var', (218, 231))	('pGL4', 'Gene', (146, 150))	('- 3020/- 2403', 'Var', (152, 165))	('pGL4', 'Gene', '6390', (58, 62))	('pGL4', 'Gene', (304, 308))	('- 2897/- 2583', 'Var', (240, 253))	('- 3391/- 2403', 'Var', (86, 99))	('pGL4', 'Gene', (58, 62))	('- 2935/- 2403', 'Var', (174, 187))	('pGL4', 'Gene', '6390', (256, 260))	('pGL4', 'Gene', '6390', (168, 172))	('pGL4', 'Gene', '6390', (278, 282))	('pGL4', 'Gene', '6390', (80, 84))	('pGL4', 'Gene', (256, 260))
327053	29428966	Different deletion fragments of SLC52A3-5'FR (- 3020/- 2672) and luciferase reporter plasmids, pGL4 (Delta- 2935/- 2897), pGL4 (Delta- 2897/- 2849), pGL4 (Delta- 2935/- 2849), and pGL4 (Delta- 2782/- 2743), were constructed by GENEWIZ (Suzhou, China).	('- 3020/- 2672', 'Var', (46, 59))	('pGL4', 'Gene', (122, 126))	('Delta- 2935/- 2849', 'Var', (155, 173))	('pGL4', 'Gene', '6390', (180, 184))	('pGL4', 'Gene', '6390', (122, 126))	('pGL4', 'Gene', '6390', (95, 99))	('Delta- 2935/- 2897', 'Var', (101, 119))	('pGL4', 'Gene', (149, 153))	('pGL4', 'Gene', (180, 184))	('Delta- 2897/- 2849', 'Var', (128, 146))	('SLC52A3', 'Gene', (32, 39))	('pGL4', 'Gene', '6390', (149, 153))	('Delta- 2782/- 2743', 'Var', (186, 204))	('SLC52A3', 'Gene', '113278', (32, 39))	('pGL4', 'Gene', (95, 99))
327094	29428966	This new SLC52A3b variant encodes a protein of 415 amino acids with predicted molecular mass of 45 kDa.	('variant', 'Var', (18, 25))	('SLC52A3', 'Gene', '113278', (9, 16))	('encodes', 'Reg', (26, 33))	('SLC52A3', 'Gene', (9, 16))
327107	29428966	First, we determined the transport capacity of riboflavin by either SLC52A3a or SLC52A3b in KYSE150 and KYSE510 cells by measuring both riboflavin consumption in cell culture medium and intracellular riboflavin concentration using high-performance liquid chromatography (HPLC).	('riboflavin', 'Chemical', 'MESH:D012256', (136, 146))	('SLC52A3', 'Gene', (68, 75))	('SLC52A3', 'Gene', '113278', (68, 75))	('KYSE510', 'Var', (104, 111))	('riboflavin consumption', 'MPA', (136, 158))	('riboflavin', 'Chemical', 'MESH:D012256', (200, 210))	('transport capacity', 'MPA', (25, 43))	('KYSE150', 'CellLine', 'CVCL:1348', (92, 99))	('SLC52A3', 'Gene', (80, 87))	('KYSE510', 'CellLine', 'CVCL:1354', (104, 111))	('riboflavin', 'Chemical', 'MESH:D012256', (47, 57))	('SLC52A3', 'Gene', '113278', (80, 87))
327111	29428966	ESCC colony formation was also potently inhibited upon silencing of SLC52A3 (Fig.	('SLC52A3', 'Gene', (68, 75))	('inhibited', 'NegReg', (40, 49))	('SLC52A3', 'Gene', '113278', (68, 75))	('silencing', 'Var', (55, 64))	('ESCC colony formation', 'CPA', (0, 21))
327119	29428966	These data suggest that region - 2897/- 2849 operates as the basic (nontissue-specific) regulatory element of SLC52A3, and region - 2935/- 2897 might be an ESCC specific regulatory element.	('region - 2935/- 2897', 'Var', (123, 143))	('region - 2897/- 2849', 'Var', (24, 44))	('SLC52A3', 'Gene', (110, 117))	('SLC52A3', 'Gene', '113278', (110, 117))
327123	29428966	6a), and identified binding motifs for NF-kappaB p65/Rel-B (- 2760/- 2750, underlined) and STAT3 (- 2755/- 2745, italic).	('NF-kappaB', 'Gene', '4790', (39, 48))	('NF-kappaB', 'Gene', (39, 48))	('- 2760/- 2750', 'Var', (60, 73))	('binding', 'Interaction', (20, 27))	('Rel-B', 'Gene', (53, 58))	('STAT3', 'Gene', '6774', (91, 96))	('p65', 'Gene', (49, 52))	('Rel-B', 'Gene', '5971', (53, 58))	('- 2755/- 2745', 'Var', (98, 111))	('STAT3', 'Gene', (91, 96))	('p65', 'Gene', '5970', (49, 52))
327128	29428966	These results together confirmed that NF-kappaB p65 and Rel-B bound to NF-kappaB-binding motif (from nt - 2760 to nt - 2750) within TBS3 element of SLC52A3 5'-flanking region.	('SLC52A3', 'Gene', '113278', (148, 155))	('Rel-B', 'Gene', (56, 61))	('p65', 'Gene', '5970', (48, 51))	('Rel-B', 'Gene', '5971', (56, 61))	('NF-kappaB', 'Gene', (71, 80))	('NF-kappaB', 'Gene', '4790', (38, 47))	('from nt - 2760', 'Var', (96, 110))	('bound', 'Interaction', (62, 67))	('NF-kappaB', 'Gene', (38, 47))	('p65', 'Gene', (48, 51))	('SLC52A3', 'Gene', (148, 155))	('NF-kappaB', 'Gene', '4790', (71, 80))
327136	29428966	To further confirm the transcriptional regulation of NF-kappaB on TBS3 segment, we performed progressive deletions for reporter luciferase assay under the treatment of TNFalpha.	('NF-kappaB', 'Gene', '4790', (53, 62))	('NF-kappaB', 'Gene', (53, 62))	('TNFalpha', 'Gene', (168, 176))	('deletions', 'Var', (105, 114))	('TNFalpha', 'Gene', '7124', (168, 176))
327212	29581827	In addition, aberrant carcinogen has been found to bind to deoxyribonucleic acid in lymphocytes of hypertensive patients.	('deoxyribonucleic', 'Protein', (59, 75))	('patients', 'Species', '9606', (112, 120))	('hypertensive', 'Disease', 'MESH:D006973', (99, 111))	('hypertensive', 'Disease', (99, 111))	('bind', 'Interaction', (51, 55))	('aberrant', 'Var', (13, 21))
327215	29581827	Microvascular alterations, amplifying the haemodynamic load within microvascular network and inducing vasoconstriction within the microcirculation, could further lead to chronic endothelial injury and oxidative stress and promote tissue hypoxia.	('alterations', 'Var', (14, 25))	('vasoconstriction', 'MPA', (102, 118))	('oxidative stress', 'MPA', (201, 217))	('haemodynamic', 'MPA', (42, 54))	('promote', 'PosReg', (222, 229))	('endothelial injury', 'Disease', 'MESH:D014947', (178, 196))	('inducing', 'Reg', (93, 101))	('hypoxia', 'Disease', (237, 244))	('hypoxia', 'Disease', 'MESH:D000860', (237, 244))	('oxidative stress', 'Phenotype', 'HP:0025464', (201, 217))	('endothelial injury', 'Disease', (178, 196))	('lead to', 'Reg', (162, 169))
327323	28424936	The incidence of postoperative cardiac complications was significantly higher in the chemoradiotherapy group than in the chemotherapy group (17.4% vs. 6.9%; p = 0.006).	('higher', 'PosReg', (71, 77))	('postoperative cardiac complications', 'Disease', (17, 52))	('chemoradiotherapy', 'Var', (85, 102))	('postoperative cardiac complications', 'Disease', 'MESH:D011183', (17, 52))
327337	28424936	Although nCRT was associated with better tumor downstaging and more favorable tumor regression grades, equal rates of radical resections and comparable disease-free and overall survival outcomes were observed.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('nCRT', 'Var', (9, 13))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
327404	23708070	Strandqvist's first isoeffect curves in 1944 showed that fractionation resulted in a greater log cell kill of tumor cells while allowing normal tissue time to repair damage between fractions.	('fractionation', 'Var', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
327444	23708070	A recent meta-analysis using individual patient data identified several treatment-related risk factors for symptomatic pneumonitis that include a daily dose greater than 2 Gy, V20, lower-lobe tumor location, and concurrent platinum-based chemotherapy in patients older than 65 years (Table 2).	('patient', 'Species', '9606', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('lower-lobe tumor', 'Disease', (181, 197))	('V20', 'Var', (176, 179))	('patient', 'Species', '9606', (254, 261))	('lower-lobe tumor', 'Disease', 'MESH:D001932', (181, 197))	('pneumonitis', 'Disease', (119, 130))	('patients', 'Species', '9606', (254, 262))	('pneumonitis', 'Disease', 'MESH:D011014', (119, 130))	('platinum', 'Chemical', 'MESH:D010984', (223, 231))
327483	23708070	In addition, dietary changes help decrease both the incidence and severity and include a bland diet and avoidance of irritative substances to esophagus such as acidic or spicy foods, tobacco, coffee, and alcohol (Table 2).	('alcohol', 'Chemical', 'MESH:D000438', (204, 211))	('changes', 'Var', (21, 28))	('tobacco', 'Species', '4097', (183, 190))	('decrease', 'NegReg', (34, 42))
327498	25727889	Alterations in the levels of these molecules have been associated with the initiation and progression of several esophageal diseases and cancer in adults.	('esophageal diseases', 'Disease', 'MESH:D004935', (113, 132))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (55, 65))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('levels', 'MPA', (19, 25))	('cancer', 'Disease', (137, 143))	('esophageal diseases', 'Disease', (113, 132))	('rat', 'Species', '10116', (4, 7))
327502	25727889	Disruption of this unique patterning leads to the failure of foregut separation and the formation of a relatively common birth defect (approximately one out of 3500 newborns) known as esophageal atresia with/without tracheoesophageal fistula (EA/TEF) (see review by Jacobs et al.).	('tracheoesophageal fistula', 'Disease', (216, 241))	('esophageal atresia', 'Phenotype', 'HP:0002032', (184, 202))	('TEF', 'Gene', (246, 249))	('failure', 'NegReg', (50, 57))	('birth defect', 'Disease', 'MESH:D000014', (121, 133))	('TEF', 'Gene', '21685', (246, 249))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (216, 241))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (216, 241))	('birth defect', 'Disease', (121, 133))	('esophageal atresia', 'Disease', 'MESH:D004933', (184, 202))	('esophageal atresia', 'Disease', (184, 202))	('rat', 'Species', '10116', (73, 76))	('Disruption', 'Var', (0, 10))
327504	25727889	More importantly, recent studies suggest that reactivation of relevant signaling pathways (e.g., BMPs) or overexpression of some of the transcription factors are associated with the development of esophageal diseases including gastroesophageal reflux (GERD), Barrett's esophagus (BE), and esophageal cancers.	('reactivation', 'Var', (46, 58))	('esophageal cancers', 'Disease', (289, 307))	('signaling pathways', 'Pathway', (71, 89))	('esophageal diseases', 'Disease', 'MESH:D004935', (197, 216))	('GERD', 'Disease', (252, 256))	('BE', 'Phenotype', 'HP:0100580', (280, 282))	('overexpression', 'PosReg', (106, 120))	('esophageal cancers', 'Disease', 'MESH:D004938', (289, 307))	('cancers', 'Phenotype', 'HP:0002664', (300, 307))	('BMP', 'Gene', '649', (97, 100))	('GERD', 'Disease', 'MESH:D005764', (252, 256))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (227, 250))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('associated', 'Reg', (162, 172))	("Barrett's esophagus", 'Disease', (259, 278))	('gastroesophageal reflux', 'Disease', (227, 250))	('esophageal diseases', 'Disease', (197, 216))	('BMP', 'Gene', (97, 100))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (227, 250))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (259, 278))
327518	25727889	Consistent with this possibility, our live-imaging of actively separating E9.5 Sox2-EGFP foregut (EGFP labels all of the epithelium in the anterior foregut) shows a rostral translocation of a saddle-like structure that splits the anterior foregut into the trachea and esophagus (Figure 1(b) and (c)) (Movie 1).	('E9.5', 'Var', (74, 78))	('Sox2', 'Gene', (79, 83))	('rat', 'Species', '10116', (67, 70))	('Sox2', 'Gene', '20674', (79, 83))
327522	25727889	Studies of NOG-/- mutants suggested an abnormal detachment of the notochord from the early endoderm that took away endodermal cells, leaving too few epithelial cells for the establishment of the esophagus.	('NOG', 'Gene', (11, 14))	('mutants', 'Var', (18, 25))	('NOG', 'Gene', '18121', (11, 14))
327523	25727889	It is possible this abnormal delamination affects the restriction site, and movement of the saddle is stopped at this position, leading to the formation of TEF in the NOG-/- mutants (Figure 3(e) and (f)).	('leading to', 'Reg', (128, 138))	('TEF', 'Gene', (156, 159))	('TEF', 'Gene', '21685', (156, 159))	('NOG', 'Gene', '18121', (167, 170))	('NOG', 'Gene', (167, 170))	('mutants', 'Var', (174, 181))
327524	25727889	Alternatively, abnormal dorsal-ventral patterning of signaling molecules and transcription factors may shift the boundary between the future trachea and esophagus as seen in Sox2 hypomorphic and Nkx2.1-/- mutants.	('Nkx2.1', 'Gene', (195, 201))	('dorsal-ventral patterning', 'CPA', (24, 49))	('mutants', 'Var', (205, 212))	('Sox2', 'Gene', '20674', (174, 178))	('shift', 'Reg', (103, 108))	('Sox2', 'Gene', (174, 178))	('Nkx2.1', 'Gene', '21869', (195, 201))
327536	25727889	Mutants lacking Foxp2 in a Foxp1 heterozygous background completely lose the striated muscle.	('striated muscle', 'CPA', (77, 92))	('Foxp1', 'Gene', (27, 32))	('lose', 'NegReg', (68, 72))	('Foxp2', 'Gene', '114142', (16, 21))	('Foxp1', 'Gene', '108655', (27, 32))	('lacking', 'NegReg', (8, 15))	('Foxp2', 'Gene', (16, 21))	('Mutants', 'Var', (0, 7))
327537	25727889	In addition, Hoxc4 has also been implicated in muscle development, as removal of Hoxc4 leads to disorganized muscle layers over an extensive region in the mutant esophagus.	('removal', 'Var', (70, 77))	('Hoxc4', 'Gene', (81, 86))	('Hoxc4', 'Gene', (13, 18))	('mutant', 'Var', (155, 161))	('leads to', 'Reg', (87, 95))	('Hoxc4', 'Gene', '15423', (81, 86))	('Hoxc4', 'Gene', '15423', (13, 18))
327549	25727889	These epithelial cells also express high levels of the transcription factors P63 and Sox2 (Figure 5(a)).	('Sox2', 'Gene', '20674', (85, 89))	('P63', 'Var', (77, 80))	('Sox2', 'Gene', (85, 89))
327560	25727889	Deletion of Noggin leads to the ectopic formation of glandular units that are lined with secretory simple columnar epithelium.	('Noggin', 'Gene', '18121', (12, 18))	('Noggin', 'Gene', (12, 18))	('ectopic', 'MPA', (32, 39))	('leads to', 'Reg', (19, 27))	('Deletion', 'Var', (0, 8))
327564	25727889	The simple columnar epithelium in the esophagus of Shh-Cre; Rosa26loxp-stop-loxp-caBmpr1a mutants expresses high levels of K8 and K18 but not K5 and K14.	('Shh', 'Gene', '20423', (51, 54))	('K14', 'Gene', '16664', (149, 152))	('K14', 'Gene', (149, 152))	('mutants', 'Var', (90, 97))	('K18', 'Gene', '16668', (130, 133))	('Rosa26', 'Gene', '14910', (60, 66))	('Bmp', 'Gene', '649', (83, 86))	('K18', 'Gene', (130, 133))	('Rosa26', 'Gene', (60, 66))	('Shh', 'Gene', (51, 54))	('Bmp', 'Gene', (83, 86))
327568	25727889	In addition, inactivation of BMP signaling blocks the differentiation of epithelial cells in the Shh-Cre; Bmpr1aloxp/loxp mutants and all cells maintain high levels of P63 and SOX2.	('Bmp', 'Gene', '649', (106, 109))	('mutants', 'Var', (122, 129))	('Shh', 'Gene', (97, 100))	('blocks', 'NegReg', (43, 49))	('inactivation', 'Var', (13, 25))	('P63', 'MPA', (168, 171))	('BMP', 'Gene', '649', (29, 32))	('Shh', 'Gene', '20423', (97, 100))	('Bmp', 'Gene', (106, 109))	('differentiation of epithelial cells', 'CPA', (54, 89))	('BMP', 'Gene', (29, 32))
327576	25727889	Approximately 60% of Sox2EGFP/COND hypomorphic mutants develop EA/TEF, suggesting that SOX2 is critical for the separation of the anterior foregut into the esophagus and trachea.	('TEF', 'Gene', (66, 69))	('develop', 'Reg', (55, 62))	('Sox2', 'Gene', '20674', (21, 25))	('rat', 'Species', '10116', (116, 119))	('mutants', 'Var', (47, 54))	('Sox2', 'Gene', (21, 25))	('TEF', 'Gene', '21685', (66, 69))
327579	25727889	We also found that the activation of BMP signaling in the E14.5 epithelium is correlated with the squamous differentiation of progenitor cells concomitant with reductions in SOX2 protein levels.	('squamous differentiation of progenitor cells', 'CPA', (98, 142))	('BMP', 'Gene', '649', (37, 40))	('reductions', 'NegReg', (160, 170))	('activation', 'PosReg', (23, 33))	('SOX2 protein levels', 'MPA', (174, 193))	('E14.5', 'Var', (58, 63))	('BMP', 'Gene', (37, 40))
327588	25727889	Trp-63 (P63) is a member of the P53 protein family which includes three transcription factors: P63, P53, and P73.	('P53', 'Gene', '22060', (100, 103))	('P73', 'Gene', (109, 112))	('P53', 'Gene', '22060', (32, 35))	('Trp-63', 'Gene', (0, 6))	('P53', 'Gene', (100, 103))	('Trp-63', 'Gene', '22061', (0, 6))	('P73', 'Gene', '22062', (109, 112))	('P53', 'Gene', (32, 35))	('P63', 'Var', (95, 98))
327591	25727889	The mutants die of dehydration soon after birth.	('dehydration', 'Disease', 'MESH:D003681', (19, 30))	('mutants', 'Var', (4, 11))	('dehydration', 'Disease', (19, 30))	('die', 'Reg', (12, 15))	('dehydration', 'Phenotype', 'HP:0001944', (19, 30))
327592	25727889	When examined at birth, the epithelium in the mutant esophagus remains simple columnar with multiple cilia on the apical surface and K14 is not expressed in these cells.	('K14', 'Gene', '16664', (133, 136))	('K14', 'Gene', (133, 136))	('mutant', 'Var', (46, 52))
327595	25727889	We also found that the simple columnar epithelium lining the E18.5 P63-/- esophagus stains positively by Alcian blue at pH2.5 (Figure 6), indicative of mucin secretion, suggesting that P63 not only regulates epithelial stratification but also controls cell fate decisions.	('cell fate decisions', 'CPA', (252, 271))	('regulates', 'Reg', (198, 207))	('rat', 'Species', '10116', (221, 224))	('P63-/-', 'Var', (67, 73))	('epithelial stratification', 'CPA', (208, 233))	('Alcian blue', 'Chemical', 'MESH:D000423', (105, 116))	('E18.5 P63-/-', 'Var', (61, 73))	('controls', 'Reg', (243, 251))
327596	25727889	Notably, reduction in the protein levels of P63 has been found in human Barrett's biopsies.	('reduction', 'NegReg', (9, 18))	('human', 'Species', '9606', (66, 71))	('P63', 'Var', (44, 47))	('protein levels', 'MPA', (26, 40))
327597	25727889	A recent study demonstrates that P63 forms a complex with SOX2 and co-localizes at genetic loci to regulate common downstream target genes (e.g., ETV4) in human esophageal squamous cell lines.	('esophageal squamous', 'Disease', 'MESH:D000077277', (161, 180))	('P63', 'Var', (33, 36))	('esophageal squamous', 'Disease', (161, 180))	('rat', 'Species', '10116', (22, 25))	('human', 'Species', '9606', (155, 160))	('regulate', 'Reg', (99, 107))	('ETV4', 'Gene', (146, 150))	('complex', 'Interaction', (45, 52))	('ETV4', 'Gene', '2118', (146, 150))	('SOX2', 'Protein', (58, 62))
327603	25727889	Intriguingly, deletion of Keap1 leads to hyperkeratosis, characterized by excessive squamous differentiation of basal progenitor cells in the developing esophagus and forestomach.	('hyperkeratosis', 'Disease', 'MESH:D017488', (41, 55))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (41, 55))	('leads to', 'Reg', (32, 40))	('deletion', 'Var', (14, 22))	('Keap1', 'Gene', '50868', (26, 31))	('hyperkeratosis', 'Disease', (41, 55))	('Keap1', 'Gene', (26, 31))
327604	25727889	Complementary removal of Nrf2 in a Keap1 null background rescues the hyperkeratosis phenotype.	('hyperkeratosis', 'Disease', (69, 83))	('rescues', 'PosReg', (57, 64))	('Nrf2', 'Gene', '18024', (25, 29))	('Keap1', 'Gene', '50868', (35, 40))	('removal', 'Var', (14, 21))	('Nrf2', 'Gene', (25, 29))	('Keap1', 'Gene', (35, 40))	('hyperkeratosis', 'Disease', 'MESH:D017488', (69, 83))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (69, 83))
327605	25727889	In addition, simultaneous deletion of MafF and MafG, two downstream targets of NRF2, is also able to rescue the excessive differentiation of progenitor cells.	('NRF2', 'Gene', (79, 83))	('MafF', 'Gene', (38, 42))	('excessive differentiation of progenitor cells', 'CPA', (112, 157))	('MafF', 'Gene', '17133', (38, 42))	('deletion', 'Var', (26, 34))	('rescue', 'PosReg', (101, 107))	('MafG', 'Gene', '17134', (47, 51))	('NRF2', 'Gene', '18024', (79, 83))	('MafG', 'Gene', (47, 51))
327616	25727889	In addition, Hoxc4 null mutants not only have defects in muscle organization but also have defects in the epithelium such that it is hyperplastic and occludes the lumen.	('muscle organization', 'CPA', (57, 76))	('occludes', 'NegReg', (150, 158))	('mutants', 'Var', (24, 31))	('defects', 'NegReg', (91, 98))	('defects', 'NegReg', (46, 53))	('Hoxc4', 'Gene', (13, 18))	('hyperplastic', 'PosReg', (133, 145))	('Hoxc4', 'Gene', '15423', (13, 18))
327668	26766917	The randomized EVEREST study prescribed the patients who get <= grade 1 skin reactions (result from the fundamental treatment) with standard-dose (250 mg/m2/week) or dose-escalated (500 mg/m2/week) cetuximab in metastatic colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('colorectal cancer', 'Disease', (222, 239))	('patients', 'Species', '9606', (44, 52))	('rectal cancer', 'Phenotype', 'HP:0100743', (226, 239))	('colorectal cancer', 'Disease', 'MESH:D015179', (222, 239))	('colorectal cancer', 'Phenotype', 'HP:0003003', (222, 239))	('cetuximab', 'Chemical', 'MESH:D000068818', (198, 207))	('cetuximab', 'Gene', (198, 207))	('skin reactions', 'Phenotype', 'HP:0011123', (72, 86))	('500 mg/m2/week', 'Var', (182, 196))
327887	23556477	As shown in Figure 2D, normal mucosae of testing set were correctly located in the region of normal mucosae of training set, and the same results were obtained in esophageal cancers of testing set (R2Xcum = 0.17, R2Ycum = 0.531, Q2 Ycum = 0.322).	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('R2Ycum', 'Var', (213, 219))	('esophageal cancers', 'Disease', (163, 181))	('esophageal cancers', 'Disease', 'MESH:D004938', (163, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
327894	23556477	Interestingly, we identified dimethylamine (DMA), dimethylglycine (DMG), polyunsaturated fatty acids and histidine, which are associated with the stage of esophageal cancer.	('polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (73, 100))	('associated', 'Reg', (126, 136))	('polyunsaturated fatty acids', 'Var', (73, 100))	('dimethylamine', 'Chemical', 'MESH:C034516', (29, 42))	('dimethylglycine', 'MPA', (50, 65))	('esophageal cancer', 'Disease', (155, 172))	('dimethylamine', 'MPA', (29, 42))	('histidine', 'MPA', (105, 114))	('histidine', 'Chemical', 'MESH:D006639', (105, 114))	('DMA', 'Chemical', 'MESH:C034516', (44, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (155, 172))	('dimethylglycine', 'Chemical', 'MESH:C025138', (50, 65))	('DMG', 'Chemical', 'MESH:C025138', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
327913	23556477	Remarkably, the highly activated fatty acids metabolism, increased energy supplies and disturbance of choline metabolism are mainly responsible for the process of pathological development of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('highly activated', 'PosReg', (16, 32))	('choline', 'Chemical', 'MESH:D002794', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('energy supplies', 'MPA', (67, 82))	('choline metabolism', 'MPA', (102, 120))	('disturbance', 'Var', (87, 98))	('fatty acids', 'Chemical', 'MESH:D005227', (33, 44))	('increased energy supplies and disturbance of choline metabolism', 'Phenotype', 'HP:0025048', (57, 120))	('increased', 'PosReg', (57, 66))	('esophageal cancer', 'Disease', (191, 208))
328014	33650665	Zhai and coworkers also confirmed that when PLCE1 is knocked out, the transcriptional activity of SNAIL is particularly repressed.	('knocked out', 'Var', (53, 64))	('SNAIL', 'Gene', '6615', (98, 103))	('PLCE1', 'Gene', (44, 49))	('SNAIL', 'Gene', (98, 103))	('transcriptional activity', 'MPA', (70, 94))	('PLCE1', 'Gene', '51196', (44, 49))	('repressed', 'NegReg', (120, 129))
328054	33650665	Furthermore, the pathway analysis revealed that upregulated genes were involved in the metabolism of lipids, asparagine N-linked glycosylation, and constitutive signaling by AKT1 E17K in cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('E17K', 'Var', (179, 183))	('cancer', 'Disease', (187, 193))	('AKT1', 'Gene', (174, 178))	('E17K', 'SUBSTITUTION', 'None', (179, 183))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('asparagine N-linked glycosylation', 'MPA', (109, 142))	('metabolism of lipids', 'MPA', (87, 107))	('asparagine', 'Chemical', 'MESH:D001216', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('constitutive signaling', 'MPA', (148, 170))	('upregulated', 'PosReg', (48, 59))	('lipids', 'Chemical', 'MESH:D008055', (101, 107))	('AKT1', 'Gene', '207', (174, 178))
328056	33650665	5A-C, TUNEL and JC-1 staining experiments showed that the apoptosis rate of ESCC cells was markedly increased, whereas proliferation was significantly suppressed according to the EdU assays when PLCE1 was knocked down in the Eca109 ESCC cells.	('increased', 'PosReg', (100, 109))	('suppressed', 'NegReg', (151, 161))	('apoptosis rate', 'CPA', (58, 72))	('PLCE1', 'Gene', (195, 200))	('PLCE1', 'Gene', '51196', (195, 200))	('knocked down', 'Var', (205, 217))	('EdU', 'Chemical', '-', (179, 182))	('proliferation', 'CPA', (119, 132))	('N', 'Chemical', 'MESH:D009584', (8, 9))
328088	33650665	For instance, Li et al revealed that regulation of ZFAS1 by overexpression of miRNA-124 may mediate ESCC proliferation, invasion, migration, and apoptosis.	('regulation', 'Var', (37, 47))	('ZFAS1', 'Gene', (51, 56))	('miRNA-124', 'Gene', (78, 87))	('mediate', 'Reg', (92, 99))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('overexpression', 'PosReg', (60, 74))	('invasion', 'CPA', (120, 128))	('ESCC', 'Disease', (100, 104))	('ZFAS1', 'Gene', '441951', (51, 56))	('migration', 'CPA', (130, 139))	('apoptosis', 'CPA', (145, 154))
328091	33650665	Additionally, a previous report indicated that HOTAIRM1 functions as a ceRNA to regulate the expression of miR-129-5p and miR-495-3p in glioma progression and is positively correlated with OS in glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('miR-129-5p', 'Gene', (107, 117))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('HOTAIRM1', 'Gene', '100506311', (47, 55))	('correlated', 'Reg', (173, 183))	('HOTAIRM1', 'Gene', (47, 55))	('glioma', 'Disease', 'MESH:D005910', (195, 201))	('patients', 'Species', '9606', (202, 210))	('expression', 'MPA', (93, 103))	('glioma', 'Disease', (136, 142))	('glioma', 'Disease', (195, 201))	('miR-129-5p', 'Gene', '100302178', (107, 117))	('miR-495-3p', 'Var', (122, 132))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
328094	33650665	In our previous research, 14 DEmiRNAs in the ceRNA network were identified, among which hsa-miR-17-5p, hsa-miR-22-3p, and hsa-miR-1297 have been reported to be involved in tumorigenesis; hsa-miR-301b-3p and hsa-miR-455-5p have also been verified to be highly expressed in ESCA from the TCGA database (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('hsa-miR-17', 'Gene', '406952', (88, 98))	('hsa-miR-301b-3p', 'Var', (187, 202))	('hsa-miR-1297', 'Gene', (122, 134))	('tumor', 'Disease', (172, 177))	('hsa-miR-455', 'Gene', (207, 218))	('hsa-miR-22', 'Gene', (103, 113))	('ESCA', 'Disease', (272, 276))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('hsa-miR-17', 'Gene', (88, 98))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('hsa-miR-455', 'Gene', '619556', (207, 218))	('hsa-miR-22', 'Gene', '407004', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('hsa-miR-1297', 'Gene', '100302187', (122, 134))	('involved', 'Reg', (160, 168))
328120	32547645	No correlations were found with other molecular alterations (TP53 mutation, ERBB2 amplification) or survival rates.	('TP53', 'Gene', '7157', (61, 65))	('amplification', 'Var', (82, 95))	('TP53', 'Gene', (61, 65))	('ERBB2', 'Gene', (76, 81))	('ERBB2', 'Gene', '2064', (76, 81))
328157	32547645	However, a correlation between mesothelin expression and TP53 mutations (Ventana: p = 0.619, Novocastra: p = 0.592) and Her-2 amplification (Ventana: p = 0.905, Novocastra: p = 0.102) was not found, respectively.	('Her-2', 'Gene', '2064', (120, 125))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('Her-2', 'Gene', (120, 125))
328194	31691111	This review evaluates the existing literature that examines how variations in surgical and surgeon-related factors may influence the long-term survival of patients who undergo surgery for esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (188, 205))	('variations', 'Var', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('influence', 'Reg', (119, 128))	('patients', 'Species', '9606', (155, 163))	('esophageal cancer', 'Disease', (188, 205))
328241	31412935	DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity.	('DS-8895a', 'Var', (0, 8))	('cytotoxicity', 'Disease', (112, 124))	('human', 'Species', '9606', (14, 19))	('DS-8895a', 'Chemical', '-', (0, 8))	('EPHA2', 'Gene', '1969', (29, 34))	('cytotoxicity', 'Disease', 'MESH:D064420', (112, 124))	('enhance', 'PosReg', (76, 83))	('EPHA2', 'Gene', (29, 34))
328256	31412935	The exposure of DS-8895a seemed to increase dose-dependently and induce activated NK cells.	('induce', 'PosReg', (65, 71))	('DS-8895a', 'Var', (16, 24))	('activated NK cells', 'CPA', (72, 90))	('DS-8895a', 'Chemical', '-', (16, 24))
328269	31412935	Afucosylation of the carbohydrate chain in IgG1 Fc substantially potentiates the binding affinity of the IgG1 portion to FcgammaRIIIa/CD16, which results in enhancement of ADCC.	('potentiates', 'PosReg', (65, 76))	('FcgammaRIIIa', 'Gene', '2214', (121, 133))	('CD16', 'Gene', '2214', (134, 138))	('FcgammaRIIIa', 'Gene', (121, 133))	('ADCC', 'CPA', (172, 176))	('binding affinity', 'Interaction', (81, 97))	('CD16', 'Gene', (134, 138))	('enhancement', 'PosReg', (157, 168))	('IgG1', 'Gene', (43, 47))	('Afucosylation', 'Var', (0, 13))	('carbohydrate', 'Chemical', 'MESH:D002241', (21, 33))
328270	31412935	DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody (Additional file 1) that is afucosylated to enhance ADCC (POTELLIGENT ; BioWa Inc., Princeton, NJ, USA) and is expected to produce antitumor effects on EPHA2-overexpressing tumor cells through ADCC, as demonstrated in pre-clinical studies.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('DS-8895a', 'Var', (0, 8))	('tumor', 'Disease', (195, 200))	('EPHA2', 'Gene', (212, 217))	('tumor', 'Disease', (233, 238))	('human', 'Species', '9606', (14, 19))	('enhance', 'PosReg', (104, 111))	('DS-8895a', 'Chemical', '-', (0, 8))	('EPHA2', 'Gene', '1969', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('EPHA2', 'Gene', '1969', (212, 217))	('EPHA2', 'Gene', (29, 34))	('ADCC', 'MPA', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
328271	31412935	DS-8895a had neither complement-dependent cytotoxicity nor agonist activity against EPHA2 in vitro, and only weakly inhibited EPHRIN-A1-mediated phosphorylation of EPHA2.	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('DS-8895a', 'Var', (0, 8))	('inhibited', 'NegReg', (116, 125))	('EPHA2', 'Gene', (164, 169))	('EPHRIN-A1', 'Gene', '1942', (126, 135))	('EPHA2', 'Gene', '1969', (84, 89))	('EPHRIN-A1', 'Gene', (126, 135))	('DS-8895a', 'Chemical', '-', (0, 8))	('cytotoxicity', 'Disease', (42, 54))	('EPHA2', 'Gene', (84, 89))	('EPHA2', 'Gene', '1969', (164, 169))
328283	31412935	In Step 1, the dose of DS-8895a was sequentially increased from Level 1 (0.1 mg/kg) to Level 6 (20 mg/kg), and intravenously administered over 2 h every 2 weeks with a 28-day period for assessment of dose-limiting toxicity (DLT).	('DS-8895a', 'Var', (23, 31))	('DS-8895a', 'Chemical', '-', (23, 31))	('toxicity', 'Disease', 'MESH:D064420', (214, 222))	('toxicity', 'Disease', (214, 222))
328311	31412935	Blood and serum samples were collected to test circulating CD16-positive NK cells, NK activity, human leukocyte antigen (HLA)/killer cell immunoglobin-like receptor (KIR) mismatch, cytokines, and soluble EPHA2; a detailed blood sampling schedule is given in Additional file 6.	('mismatch', 'Var', (171, 179))	('human', 'Species', '9606', (96, 101))	('EPHA2', 'Gene', '1969', (204, 209))	('CD16', 'Gene', '2214', (59, 63))	('CD16', 'Gene', (59, 63))	('KIR', 'Gene', '3805', (166, 169))	('EPHA2', 'Gene', (204, 209))	('KIR', 'Gene', (166, 169))
328337	31412935	IRRs related to DS-8895a occurred in 13 patients (59.1%) in Step 1 and 6 (40.0%) in Step 2.	('DS-8895a', 'Chemical', '-', (16, 24))	('patients', 'Species', '9606', (40, 48))	('IRR', 'Gene', (0, 3))	('IRR', 'Gene', '3645', (0, 3))	('occurred', 'Reg', (25, 33))	('DS-8895a', 'Var', (16, 24))
328347	31412935	PK parameters (Cmax and AUC) increased with increasing dose of DS-8895a (Table 3) for both Cycles 1 and 2.	('DS-8895a', 'Chemical', '-', (63, 71))	('PK parameters', 'MPA', (0, 13))	('DS-8895a', 'Var', (63, 71))
328362	31412935	Mismatch of HLA/KIR polymorphism was detected in 20 patients (2 matched) in Step 1 and 14 patients (1 matched) in Step 2.	('KIR', 'Gene', '3805', (16, 19))	('detected', 'Reg', (37, 45))	('patients', 'Species', '9606', (90, 98))	('Mismatch', 'Var', (0, 8))	('patients', 'Species', '9606', (52, 60))	('KIR', 'Gene', (16, 19))
328367	31412935	Also, in this patient, the number of infiltrated CD3-positive cells increased after DS-8895a treatment.	('DS-8895a', 'Chemical', '-', (84, 92))	('increased', 'PosReg', (68, 77))	('patient', 'Species', '9606', (14, 21))	('DS-8895a', 'Var', (84, 92))
328368	31412935	Here we report the results of the first-in-human study of DS-8895a, an afucosylated, humanized anti-EPHA2 antibody.	('EPHA2', 'Gene', '1969', (100, 105))	('DS-8895a', 'Var', (58, 66))	('EPHA2', 'Gene', (100, 105))	('DS-8895a', 'Chemical', '-', (58, 66))	('human', 'Species', '9606', (85, 90))	('human', 'Species', '9606', (43, 48))
328369	31412935	DS-8895a was safe and well tolerated up to 20 mg/kg in patients with advanced solid tumors (Step 1) and EPHA2-positive gastric or esophageal cancer (Step 2).	('solid tumors', 'Disease', (78, 90))	('DS-8895a', 'Var', (0, 8))	('EPHA2', 'Gene', '1969', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('DS-8895a', 'Chemical', '-', (0, 8))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('gastric or esophageal cancer', 'Disease', (119, 147))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (55, 63))	('EPHA2', 'Gene', (104, 109))	('gastric or esophageal cancer', 'Disease', 'MESH:D013274', (119, 147))
328374	31412935	In this study, a decrease in CD16-positive NK cells and a transient increase in serum inflammatory cytokines were observed after DS-8895a administration, both of which indicate DS-8895a ADCC activity.	('CD16', 'Gene', '2214', (29, 33))	('DS-8895a', 'Chemical', '-', (129, 137))	('DS-8895a', 'Chemical', '-', (177, 185))	('CD16', 'Gene', (29, 33))	('decrease', 'NegReg', (17, 25))	('serum inflammatory cytokines', 'MPA', (80, 108))	('increase', 'PosReg', (68, 76))	('DS-8895a', 'Var', (129, 137))	('DS-8895a', 'Var', (177, 185))
328375	31412935	Reduction of CD16-positive NK cells was maintained for 24 h, which was consistent with reports of other ADCC-enhanced antibodies, suggesting a decrease in CD16-positive NK cells by ADCC.	('ADCC', 'Var', (181, 185))	('CD16', 'Gene', (155, 159))	('decrease', 'NegReg', (143, 151))	('CD16', 'Gene', '2214', (13, 17))	('CD16', 'Gene', (13, 17))	('CD16', 'Gene', '2214', (155, 159))
328381	31412935	The addition of an agonistic anti-CD137 monoclonal antibody with other antibodies, such as cetuximab or anti-CD20 antibody, has shown that activation of CD137 on NK cells enhanced their antitumor activity.	('enhanced', 'PosReg', (171, 179))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('CD137', 'Gene', (153, 158))	('CD137', 'Gene', '3604', (153, 158))	('tumor', 'Disease', (190, 195))	('activation', 'Var', (139, 149))	('cetuximab', 'Chemical', 'MESH:D000068818', (91, 100))	('CD20', 'Gene', '54474', (109, 113))	('CD137', 'Gene', '3604', (34, 39))	('CD20', 'Gene', (109, 113))	('CD137', 'Gene', (34, 39))
328382	31412935	A previous study suggested that the combination of HLA and KIR gene polymorphisms may affect ADCC activity.	('affect', 'Reg', (86, 92))	('polymorphisms', 'Var', (68, 81))	('KIR', 'Gene', '3805', (59, 62))	('KIR', 'Gene', (59, 62))	('ADCC activity', 'CPA', (93, 106))	('combination', 'Var', (36, 47))	('HLA', 'Gene', (51, 54))
328390	31412935	As the first-in-human study of DS-8895a, this study has provided initial insights into the safety and potential activity of DS-8895a in patients and their response to the drug, providing a valuable knowledge base for future studies of afucosylated, humanized antibodies for the treatment of solid tumors.	('solid tumors', 'Disease', (291, 303))	('DS-8895a', 'Chemical', '-', (124, 132))	('DS-8895a', 'Var', (124, 132))	('DS-8895a', 'Chemical', '-', (31, 39))	('patients', 'Species', '9606', (136, 144))	('solid tumors', 'Disease', 'MESH:D009369', (291, 303))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('human', 'Species', '9606', (249, 254))	('human', 'Species', '9606', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))
328394	31412935	This study showed that 20 mg/kg DS-8895a administered by infusion every 2 weeks was generally safe and well tolerated in patients with advanced solid tumors and that serum concentrations of DS-8895a increased in a dose-dependent manner.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('DS-8895a', 'Chemical', '-', (190, 198))	('solid tumors', 'Disease', (144, 156))	('serum concentrations', 'MPA', (166, 186))	('DS-8895a', 'Var', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('solid tumors', 'Disease', 'MESH:D009369', (144, 156))	('increased', 'PosReg', (199, 208))	('DS-8895a', 'Chemical', '-', (32, 40))	('patients', 'Species', '9606', (121, 129))
328487	28978001	Previously, high tenascin-C expression has been shown to associate to poor cellular differentiation, although with limited patient material.	('tenascin-C', 'Gene', '3371', (17, 27))	('patient', 'Species', '9606', (123, 130))	('high', 'Var', (12, 16))	('poor cellular differentiation', 'CPA', (70, 99))	('expression', 'MPA', (28, 38))	('tenascin-C', 'Gene', (17, 27))
328506	28978001	In addition, the results show that high tenascin-C expression in tumor stroma associates with advanced disease and reduced survival, and could therefore be used as a biomarker for esophageal adenocarcinoma with poor prognosis.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (180, 205))	('survival', 'CPA', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tenascin-C', 'Gene', (40, 50))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (180, 205))	('reduced', 'NegReg', (115, 122))	('tumor stroma', 'Disease', 'MESH:D009369', (65, 77))	('tumor stroma', 'Disease', (65, 77))	('expression', 'MPA', (51, 61))	('advanced disease', 'Disease', (94, 110))	('tenascin-C', 'Gene', '3371', (40, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('high', 'Var', (35, 39))	('esophageal adenocarcinoma', 'Disease', (180, 205))
328544	28978001	Life tables were calculated with the Kaplan-Meier method and compared between low and high (>=3) tenascin-C and fibronectin stromal expression density, and tumor/stroma percentage (<=50% and >50% or 0-25%, 26-50%, 51-75% and 76-100%).	('<=50%', 'Var', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('fibronectin', 'Gene', '2335', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tenascin-C', 'Gene', '3371', (97, 107))	('tumor', 'Disease', (156, 161))	('fibronectin', 'Gene', (112, 123))	('tenascin-C', 'Gene', (97, 107))
328611	25666644	It has also recently been shown to be able to identify lesions affecting the p53 gene, as an indicator of high grade dysplasia, with sensitivity of 86% and specificity of 100% and further clinical trials are ongoing.	('dysplasia', 'Disease', (117, 126))	('dysplasia', 'Disease', 'MESH:D004476', (117, 126))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('lesions', 'Var', (55, 62))
328771	31842421	It has been suggested that ED behavior including vomiting, laxative abuse, and restrictive food intake has a strong impact on the function of the GI tract; conversely, disablement of the GI function such as disordered motility can bolster typical symptoms of ED such as loss of appetite, self-induced vomiting, dysphagia, constipation, and bloating.	('constipation', 'Phenotype', 'HP:0002019', (322, 334))	('ED', 'Disease', 'MESH:D001068', (259, 261))	('vomiting', 'Disease', 'MESH:D014839', (301, 309))	('loss of appetite', 'Disease', 'MESH:D001068', (270, 286))	('restrictive food', 'Phenotype', 'HP:0000723', (79, 95))	('vomiting', 'Phenotype', 'HP:0002013', (301, 309))	('dysphagia', 'Disease', 'MESH:D003680', (311, 320))	('vomiting', 'Disease', (301, 309))	('bloating', 'Disease', (340, 348))	('constipation', 'Disease', 'MESH:D003248', (322, 334))	('disablement of the GI function', 'Phenotype', 'HP:0012719', (168, 198))	('disordered motility', 'Var', (207, 226))	('-induced vomiting', 'Phenotype', 'HP:0002572', (292, 309))	('dysphagia', 'Disease', (311, 320))	('ED', 'Phenotype', 'HP:0100738', (259, 261))	('ED', 'Disease', 'MESH:D001068', (27, 29))	('loss of appetite', 'Phenotype', 'HP:0004396', (270, 286))	('vomiting', 'Disease', 'MESH:D014839', (49, 57))	('bolster', 'PosReg', (231, 238))	('constipation', 'Disease', (322, 334))	('dysphagia', 'Phenotype', 'HP:0002015', (311, 320))	('bloating', 'Phenotype', 'HP:0003270', (340, 348))	('vomiting', 'Phenotype', 'HP:0002013', (49, 57))	('ED', 'Phenotype', 'HP:0100738', (27, 29))	('vomiting', 'Disease', (49, 57))	('loss of appetite', 'Disease', (270, 286))
328776	31842421	Dysregulations of these physiological processes can adversely affect eating behavior or provoke GI symptoms, such as exaggerated postprandial fullness, nausea and bloating.	('affect', 'Reg', (62, 68))	('postprandial fullness', 'MPA', (129, 150))	('bloating', 'Phenotype', 'HP:0003270', (163, 171))	('GI symptoms', 'Disease', 'MESH:D012817', (96, 107))	('Dysregulations', 'Var', (0, 14))	('exaggerated', 'PosReg', (117, 128))	('eating behavior', 'Phenotype', 'HP:0100738', (69, 84))	('affect eating behavior', 'Phenotype', 'HP:0100738', (62, 84))	('provoke', 'Reg', (88, 95))	('nausea', 'Disease', (152, 158))	('nausea', 'Phenotype', 'HP:0002018', (152, 158))	('GI symptoms', 'Disease', (96, 107))	('eating behavior', 'CPA', (69, 84))	('bloating', 'Disease', (163, 171))	('nausea', 'Disease', 'MESH:D009325', (152, 158))
328797	31842421	Lastly, bleeding can also occur as a result of tears in the esophagus (Mallory-Weiss Syndrome) due to vomiting.	('bleeding', 'Disease', (8, 16))	('vomiting', 'Phenotype', 'HP:0002013', (102, 110))	('tears', 'Var', (47, 52))	('vomiting', 'Disease', (102, 110))	('vomiting', 'Disease', 'MESH:D014839', (102, 110))	('Mallory-Weiss Syndrome', 'Disease', 'MESH:D008309', (71, 93))	('Mallory-Weiss Syndrome', 'Phenotype', 'HP:0032062', (71, 93))	('tears', 'Phenotype', 'HP:0009926', (47, 52))	('Mallory-Weiss Syndrome', 'Disease', (71, 93))
328843	31842421	Specifically, the defecatory disorders increased from 75 to 100% when BMI was less than 18 kg/m2 and from 60 to 75% when illness duration was longer than 5 years.	('less', 'Var', (78, 82))	('defecatory disorders', 'Disease', (18, 38))	('increased', 'PosReg', (39, 48))	('defecatory disorders', 'Disease', 'MESH:D009358', (18, 38))
328986	31001805	Alterations in CDKN2A/B and FHIT by high-resolution assays may serve as biomarkers of increased risk of progression to DAC when detected in BE tissues.	('CDKN2A/B', 'Gene', '1029;1030', (15, 23))	('Alterations', 'Var', (0, 11))	('DAC', 'Disease', (119, 122))	('DAC', 'Chemical', '-', (119, 122))	('CDKN2A/B', 'Gene', (15, 23))	('FHIT', 'Gene', (28, 32))	('FHIT', 'Gene', '2272', (28, 32))
328991	31001805	Overall, the presence of BE is associated with a 10-40 fold increased risk for the development of EAC; however, the overall rate of progression from non-dysplastic BE to EAC is only 0.1-0.5% per patient year, and recent analyses showed a pooled annual incidence of EAC in BE patients of 0.33%.	('patient', 'Species', '9606', (195, 202))	('patient', 'Species', '9606', (275, 282))	('EAC', 'Disease', (98, 101))	('presence', 'Var', (13, 21))	('patients', 'Species', '9606', (275, 283))
329003	31001805	We utilized clinical FFPE tissue samples and used high-definition and high-sensitivity detection single nucleotide polymorphism (SNP) arrays for identification of early genomic alterations that may underlie the molecular mechanisms of BE progression to DAC.	('DAC', 'Chemical', '-', (253, 256))	('alterations', 'Var', (177, 188))	('DAC', 'Disease', (253, 256))
329047	31001805	Deletion of FHIT, including exon 5, was found in 11/16 (69%) of pre-progression-BE cases but only in 1/21 (5%) of NvDBE1 (P=0.0004, Table 1) and 3/21 NvDBE2 (P=0.0032).	('FHIT', 'Gene', (12, 16))	('FHIT', 'Gene', '2272', (12, 16))	('pre-progression-BE', 'Disease', (64, 82))	('Deletion', 'Var', (0, 8))
329049	31001805	As summarized in Table 1, overall SCNAs in chromosome 9p including the CDKN2A/B gene were found in 11/16 cases (69%) of pre-progression-BE and in 4/21 (19%) NvDBE1 (P=0.0094) and 5/21 (24%) NvDBE2 (P=0.014) patients.	('patients', 'Species', '9606', (207, 215))	('found', 'Reg', (90, 95))	('pre-progression-BE', 'Disease', (120, 138))	('CDKN2A/B', 'Gene', '1029;1030', (71, 79))	('CDKN2A/B', 'Gene', (71, 79))	('SCNAs', 'Var', (34, 39))
329050	31001805	Hemizygous deletions of CDKN2A/B with partial (clonal) loss of heterozygosity (pLOH) were present in 25% of pre-progression-BE, 0% of NvDBE1, and 10% of NvDBE2, whereas deletions without pLOH (likely homozygous) were present in 31% of pre-progression-BE compared to 10% of NvDBE1 and 5% of NvDBE2.	('loss', 'NegReg', (55, 59))	('CDKN2A/B', 'Gene', (24, 32))	('heterozygosity', 'MPA', (63, 77))	('deletions', 'Var', (11, 20))	('CDKN2A/B', 'Gene', '1029;1030', (24, 32))
329051	31001805	Copy neutral pLOH (representing clonal somatic uniparental disomy) involving CDKN2A/B was detected in 13% of pre-progression-BE, 10% of NvDBE1 and 10% of NvDBE2 cases.	('uniparental disomy', 'Disease', 'MESH:D024182', (47, 65))	('detected', 'Reg', (90, 98))	('CDKN2A/B', 'Gene', '1029;1030', (77, 85))	('Copy neutral pLOH', 'Var', (0, 17))	('uniparental disomy', 'Disease', (47, 65))	('CDKN2A/B', 'Gene', (77, 85))	('pre-progression-BE', 'Disease', (109, 127))
329052	31001805	The size of SCNAs in chromosome 9p ranged from a very focal deletion of 8 kb involving CDKN2A/B to the complete 9p arm (Table 1 and Figure S2).	('deletion', 'Var', (60, 68))	('CDKN2A/B', 'Gene', (87, 95))	('CDKN2A/B', 'Gene', '1029;1030', (87, 95))
329053	31001805	Figure 3 shows a representative BE progressor patient, comparing normal tissue showing no evidence of deletions with pre-progression-BE carrying focal homozygous deletions of FHIT exon 5 and CDKN2A/B more than three years before diagnosis of EAC.	('patient', 'Species', '9606', (46, 53))	('EAC', 'Disease', (242, 245))	('CDKN2A/B', 'Gene', '1029;1030', (191, 199))	('FHIT', 'Gene', (175, 179))	('deletions', 'Var', (162, 171))	('FHIT', 'Gene', '2272', (175, 179))	('CDKN2A/B', 'Gene', (191, 199))
329054	31001805	The EAC tissue showed the same FHIT deletion as well as extended homozygous deletion of CDKN2A/B, loss of one arm of chromosome 9p, and uniparental somatic duplication of the other arm of 9p.	('deletion', 'Var', (76, 84))	('CDKN2A/B', 'Gene', '1029;1030', (88, 96))	('loss', 'NegReg', (98, 102))	('uniparental', 'Disease', 'MESH:D024182', (136, 147))	('CDKN2A/B', 'Gene', (88, 96))	('FHIT', 'Gene', (31, 35))	('FHIT', 'Gene', '2272', (31, 35))	('uniparental', 'Disease', (136, 147))
329055	31001805	Other somatic deletions were found in 56% of pre-progression-BE but not in NvDBE1 patients (P=0.0004) and only 1 (5%) of NvDBE2 patients (P=0.0019), and included hemizygous deletions with pLOH in 6p11.2 and 9p, and deletions without pLOH in 5q22.2, 12p13.31, 14q22.1, 18q21.2, and 20p12.3 (Table 2 and Figure S1).	('patients', 'Species', '9606', (82, 90))	('pLOH', 'Var', (188, 192))	('patients', 'Species', '9606', (128, 136))	('deletions', 'Var', (215, 224))
329065	31001805	Likewise, deletions or copy neutral pLOH of chromosome 9p involving CDKN2A/B were present in 19% of NvDBE1 and 24% of NvDBE2 but were more frequent in dysplasia/EAC (60%) and concurrent-BE (62%).	('CDKN2A/B', 'Gene', '1029;1030', (68, 76))	('deletions', 'Var', (10, 19))	('CDKN2A/B', 'Gene', (68, 76))	('dysplasia', 'Disease', 'MESH:C536170', (151, 160))	('copy neutral pLOH', 'Var', (23, 40))	('dysplasia', 'Disease', (151, 160))
329066	31001805	Copy number gains were more frequently seen in dysplasia/EAC (70%) and concurrent-BE (48%) than NvDBE1 (24%) or NvDBE2 (14%), Table 1, Figure 2 and Supplemental Figure S1.	('dysplasia', 'Disease', (47, 56))	('dysplasia', 'Disease', 'MESH:C536170', (47, 56))	('concurrent-BE', 'Disease', (71, 84))	('Copy number gains', 'Var', (0, 17))
329084	31001805	Our data are consistent with previous studies showing frequent CDKN2A/p16 inactivation in EAC, pre-neoplastic BE and dysplastic precursor lesions.	('CDKN2A', 'Gene', '1029', (63, 69))	('p16', 'Gene', '1029', (70, 73))	('inactivation', 'Var', (74, 86))	('p16', 'Gene', (70, 73))	('CDKN2A', 'Gene', (63, 69))	('EAC', 'Disease', (90, 93))
329086	31001805	Inactivation of CDKN2A/p16 confers increased susceptibility to a number of human cancers, including pancreatic, esophageal and other carcinomas and CDKN2A/p16 plays key roles in senescence and aging.	('p16', 'Gene', '1029', (155, 158))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('susceptibility', 'Reg', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('carcinomas', 'Disease', (133, 143))	('pancreatic', 'Disease', (100, 110))	('CDKN2A', 'Gene', '1029', (148, 154))	('Inactivation', 'Var', (0, 12))	('CDKN2A', 'Gene', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('carcinomas', 'Disease', 'MESH:D009369', (133, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('esophageal', 'Disease', (112, 122))	('p16', 'Gene', (23, 26))	('CDKN2A', 'Gene', '1029', (16, 22))	('p16', 'Gene', (155, 158))	('p16', 'Gene', '1029', (23, 26))	('pancreatic', 'Disease', 'MESH:D010195', (100, 110))	('human', 'Species', '9606', (75, 80))	('CDKN2A', 'Gene', (148, 154))
329088	31001805	Furthermore, p16 nuclear expression was lower in IM of progressors with somatic loss of CDKN2A/B than in IM of progressors without somatic loss of CDKN2A/B, albeit it did not reach statistical significance (P=0.053).	('CDKN2A/B', 'Gene', (147, 155))	('CDKN2A/B', 'Gene', '1029;1030', (88, 96))	('p16', 'Gene', (13, 16))	('loss', 'Var', (80, 84))	('CDKN2A/B', 'Gene', '1029;1030', (147, 155))	('p16', 'Gene', '1029', (13, 16))	('CDKN2A/B', 'Gene', (88, 96))	('lower', 'NegReg', (40, 45))
329089	31001805	In addition to the somatic structural genetic alterations identified in our study, inactivating mutations and epigenetic mechanisms such as CpG hypermethylation can contribute to reduced p16 expression in some BE cases.	('hypermethylation', 'Var', (144, 160))	('inactivating mutations', 'Var', (83, 105))	('p16', 'Gene', '1029', (187, 190))	('p16', 'Gene', (187, 190))	('expression', 'MPA', (191, 201))	('reduced', 'NegReg', (179, 186))
329093	31001805	Deletion of exon 5 results in loss of FHIT protein, however, the mechanistic implications of FHIT loss in BE progression remain to be well-characterized.	('FHIT loss', 'Disease', (93, 102))	('FHIT loss', 'Disease', 'MESH:D014786', (93, 102))	('FHIT', 'Gene', (38, 42))	('loss', 'NegReg', (30, 34))	('FHIT', 'Gene', '2272', (38, 42))	('FHIT', 'Gene', (93, 97))	('FHIT', 'Gene', '2272', (93, 97))	('Deletion', 'Var', (0, 8))
329094	31001805	Mutations in TP53 have been detected previously in non-dysplastic pre-progression-BE (46%), concurrent-BE (63% to 71%) and dysplasia/EAC (67% to 72%).	('TP53', 'Gene', (13, 17))	('detected', 'Reg', (28, 36))	('concurrent-BE', 'Disease', (92, 105))	('dysplasia', 'Disease', 'MESH:C536170', (123, 132))	('Mutations', 'Var', (0, 9))	('non-dysplastic pre-progression-BE', 'Disease', (51, 84))	('dysplasia', 'Disease', (123, 132))	('TP53', 'Gene', '7157', (13, 17))
329095	31001805	We identified TP53 mutations by NGS in 31% of our PP-BE samples, but TP53 mutations were present only in patients who also had FHIT or CDKN2A SCNAs, whereas there were no TP53 mutations in the NvDBE1 group (data not shown).	('TP53', 'Gene', (171, 175))	('CDKN2A', 'Gene', (135, 141))	('CDKN2A', 'Gene', '1029', (135, 141))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('patients', 'Species', '9606', (105, 113))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('FHIT', 'Gene', (127, 131))	('mutations', 'Var', (19, 28))	('FHIT', 'Gene', '2272', (127, 131))	('TP53', 'Gene', '7157', (171, 175))	('PP-BE', 'Chemical', '-', (50, 55))
329098	31001805	We also observed that the number of genomic alterations did not increase from pre-progression to concurrent-BE, suggesting that "molecular dysplasia" in BE at risk of progression can persist for several years, as assessed by genomic alterations in FHIT, CDKN2A and TP53 mutation, whereas TP53 LOH indicates late progression to dysplasia or EAC.	('dysplasia', 'Disease', 'MESH:C536170', (327, 336))	('dysplasia', 'Disease', 'MESH:C536170', (139, 148))	('mutation', 'Var', (270, 278))	('dysplasia', 'Disease', (327, 336))	('TP53', 'Gene', '7157', (265, 269))	('dysplasia', 'Disease', (139, 148))	('TP53', 'Gene', (288, 292))	('TP53', 'Gene', '7157', (288, 292))	('CDKN2A', 'Gene', (254, 260))	('TP53', 'Gene', (265, 269))	('EAC', 'Disease', (340, 343))	('alterations', 'Var', (233, 244))	('CDKN2A', 'Gene', '1029', (254, 260))	('FHIT', 'Gene', (248, 252))	('FHIT', 'Gene', '2272', (248, 252))
329099	31001805	The SNP-array method used in our study detected genomic alterations in either FHIT, CDKN2A or other somatic deletions in 81% of concurrent-BE cases, suggesting that this assay may be sensitive to predict concurrent dysplasia/EAC that may be missed in routine endoscopic surveillance.	('CDKN2A', 'Gene', (84, 90))	('FHIT', 'Gene', (78, 82))	('genomic alterations', 'Var', (48, 67))	('FHIT', 'Gene', '2272', (78, 82))	('CDKN2A', 'Gene', '1029', (84, 90))	('dysplasia', 'Disease', 'MESH:C536170', (215, 224))	('dysplasia', 'Disease', (215, 224))
329104	31001805	The fact that FHIT and CDKN2A copy number alterations are present in significantly higher frequency in non-dysplastic BE of progressors to dysplasia or cancer suggests that these changes may either play a key role in early steps of progression or represent biomarkers of other mechanisms that drive early progression.	('cancer', 'Disease', (152, 158))	('non-dysplastic', 'Disease', (103, 117))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('dysplasia', 'Disease', 'MESH:C536170', (139, 148))	('play', 'Reg', (198, 202))	('dysplasia', 'Disease', (139, 148))	('CDKN2A', 'Gene', (23, 29))	('FHIT', 'Gene', (14, 18))	('CDKN2A', 'Gene', '1029', (23, 29))	('FHIT', 'Gene', '2272', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('copy number alterations', 'Var', (30, 53))
329120	31102307	IL-1RA acts as a tumor suppressor, and its deletion promotes tumor progression by increasing VEGF-A expression in ESCC.	('tumor', 'Disease', (17, 22))	('ESCC', 'Disease', (114, 118))	('IL-1RA', 'Gene', (0, 6))	('deletion', 'Var', (43, 51))	('increasing', 'PosReg', (82, 92))	('expression', 'MPA', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('ESCC', 'Disease', 'MESH:C562729', (114, 118))	('VEGF-A', 'Gene', '7422', (93, 99))	('promotes', 'PosReg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('IL-1RA', 'Gene', '3557', (0, 6))	('VEGF-A', 'Gene', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (61, 66))
329146	31102307	Puromycin-resistant clones were expanded into cell lines as IL-1RA overexpressing cells (KYSE410-PIL-1RA or EC9706-IL-1RA) or empty control cells (KYSE410-pCDH or EC9706-pCDH).	('IL-1RA', 'Gene', (98, 104))	('KYSE410-pCDH', 'Var', (147, 159))	('IL-1RA', 'Gene', '3557', (115, 121))	('Puromycin', 'Chemical', 'MESH:D011691', (0, 9))	('overexpressing', 'PosReg', (67, 81))	('IL-1RA', 'Gene', (115, 121))	('IL-1RA', 'Gene', '3557', (60, 66))	('EC9706', 'CellLine', 'CVCL:E307', (108, 114))	('EC9706', 'CellLine', 'CVCL:E307', (163, 169))	('IL-1RA', 'Gene', '3557', (98, 104))	('KYSE410', 'CellLine', 'CVCL:1352', (89, 96))	('KYSE410', 'CellLine', 'CVCL:1352', (147, 154))	('IL-1RA', 'Gene', (60, 66))
329155	31102307	Pearson's chi-square test evaluating IL-1RA expression and clinicopathological features showed that the level of IL-1RA expression in EC was associated with clinical staging; low expression of IL-1RA meant advanced T staging, N staging, and TNM staging (P = 0.011; P = 0.049; P = 0.001, respectively) (Table 1).	('TNM', 'Gene', '10178', (241, 244))	('IL-1RA', 'Gene', (113, 119))	('IL-1RA', 'Gene', '3557', (193, 199))	('N staging', 'CPA', (226, 235))	('advanced', 'PosReg', (206, 214))	('IL-1RA', 'Gene', '3557', (37, 43))	('IL-1RA', 'Gene', '3557', (113, 119))	('associated', 'Reg', (141, 151))	('low', 'Var', (175, 178))	('TNM', 'Gene', (241, 244))	('T staging', 'CPA', (215, 224))	('IL-1RA', 'Gene', (193, 199))	('clinical', 'Species', '191496', (157, 165))	('IL-1RA', 'Gene', (37, 43))
329174	31102307	These results indicate that IL-1RA acts as a tumor suppressor, and its deletion promotes tumor progression by increasing VEGF-A expression.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('IL-1RA', 'Gene', '3557', (28, 34))	('VEGF-A', 'Gene', '7422', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('IL-1RA', 'Gene', (28, 34))	('tumor', 'Disease', (45, 50))	('VEGF-A', 'Gene', (121, 127))	('deletion', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('expression', 'MPA', (128, 138))	('promotes', 'PosReg', (80, 88))	('increasing', 'PosReg', (110, 120))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
329201	31117339	Systolic blood pressure <90 mm Hg was defined as hypotension, heart rate <50 beats/min as bradycardia, respiratory rate <8 breaths/min as bradypnea, and SpO2 <90% as hypoxemia.	('<50', 'Var', (73, 76))	('respiratory', 'MPA', (103, 114))	('bradycardia', 'Disease', (90, 101))	('hypotension', 'Phenotype', 'HP:0002615', (49, 60))	('bradypnea', 'Disease', (138, 147))	('hypoxemia', 'Disease', 'MESH:D000860', (166, 175))	('heart rate', 'MPA', (62, 72))	('Systolic', 'MPA', (0, 8))	('bradycardia', 'Disease', 'MESH:D001919', (90, 101))	('hypotension', 'Disease', 'MESH:D007022', (49, 60))	('bradycardia', 'Phenotype', 'HP:0001662', (90, 101))	('hypoxemia', 'Phenotype', 'HP:0012418', (166, 175))	('hypoxemia', 'Disease', (166, 175))	('hypotension', 'Disease', (49, 60))	('bradypnea', 'Disease', 'None', (138, 147))
329202	31117339	ESD was performed using a single-channel endoscope with a water jet system (GIF-Q260J; Olympus Medical Systems Co., Tokyo, Japan), with CO2 insufflation (UCR; Olympus Medical Systems).	('water jet', 'Phenotype', 'HP:0000969', (58, 67))	('Q260J', 'SUBSTITUTION', 'None', (80, 85))	('CO2', 'Chemical', '-', (136, 139))	('water', 'Chemical', 'MESH:D014867', (58, 63))	('insufflation', 'Disease', (140, 152))	('Q260J', 'Var', (80, 85))	('insufflation', 'Disease', 'None', (140, 152))
329299	30519280	The specimens were then incubated with the primary antibodies at 42 C, for 15 min, according to the following dilutions: Hsp 90-1:100; Hsp 27-1:4000; Hsp 16.2-1:1000; GHRH-R: 1:50.	('Hsp 27', 'Gene', (135, 141))	('Hsp 27', 'Gene', '3315', (135, 141))	('Hsp 90', 'Gene', (121, 127))	('Hsp 16.2-1:1000', 'Var', (150, 165))	('GHRH-R', 'Gene', '2692', (167, 173))	('GHRH-R', 'Gene', (167, 173))	('Hsp 90', 'Gene', '3320', (121, 127))
329315	30519280	Comparing the HPV status and the clinical response to CRT, we found that HPV positivity was associated with a higher rate of non-responder patients (71.4% non-responders vs. 28.6% responders), however, this difference was not significant (Chi-Square p = 0.058) (Table 2).	('HPV', 'Species', '10566', (14, 17))	('patients', 'Species', '9606', (139, 147))	('HPV', 'Species', '10566', (73, 76))	('HPV', 'Gene', (73, 76))	('positivity', 'Var', (77, 87))	('non-responder', 'MPA', (125, 138))
329322	30519280	We also found that patients with tumors that expressed Hsp-s at high levels had a significantly shorter overall survival, than patients with tumors that stained low for Hsp-s. (Figs.	('high', 'Var', (64, 68))	('shorter', 'NegReg', (96, 103))	('patients', 'Species', '9606', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('patients', 'Species', '9606', (127, 135))	('Hsp-s', 'Protein', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('overall survival', 'MPA', (104, 120))
329326	30519280	In high-ESCC-incidence countries, the HPV detection rate in tumor tissues is also significantly higher compared to low-ESCC-incidence countries (32.8-63.6% in China vs. 8.7-16.6% in North America).	('higher', 'PosReg', (96, 102))	('HPV', 'Species', '10566', (38, 41))	('high-ESCC-incidence', 'Var', (3, 22))	('HPV', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
329337	30519280	They both reported that HPV positive patients responded better to CRT and had a significantly more favorable survival compared to the HPV negative group; however, due to the relatively low number of patients involved, far-reaching conclusions could not be drawn.	('patients', 'Species', '9606', (37, 45))	('HPV', 'Species', '10566', (24, 27))	('responded', 'MPA', (46, 55))	('better', 'PosReg', (56, 62))	('CRT', 'MPA', (66, 69))	('positive', 'Var', (28, 36))	('favorable', 'PosReg', (99, 108))	('patients', 'Species', '9606', (199, 207))	('survival', 'CPA', (109, 117))	('HPV', 'Species', '10566', (134, 137))
329339	30519280	Therefore, in our study, HPV positivity was a negative prognostic factor in relation to multimodal therapy and to overall survival, though the differences were not significant.	('positivity', 'Var', (29, 39))	('negative', 'NegReg', (46, 54))	('HPV', 'Species', '10566', (25, 28))	('HPV', 'Gene', (25, 28))
329348	30519280	It is unclear why HPV positivity in ESCC patients proves to be a negative prognostic marker in certain regions of the world, while in others it is a positive prognostic marker.	('HPV', 'Species', '10566', (18, 21))	('HPV', 'Gene', (18, 21))	('negative', 'NegReg', (65, 73))	('patients', 'Species', '9606', (41, 49))	('positivity', 'Var', (22, 32))	('ESCC', 'Disease', (36, 40))
329350	30519280	The biology of HPV-positive oropharyngeal cancer is characterized by p53 degradation, retinoblastoma Rb pathway inactivation, and p16 upregulation, while, by contrast, tobacco-related oropharyngeal cancer is characterized by TP53 mutation and downregulation of CDKN2A (encoding p16).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (184, 204))	('retinoblastoma', 'Phenotype', 'HP:0009919', (86, 100))	('retinoblastoma', 'Disease', (86, 100))	('p16', 'Gene', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('TP53', 'Gene', (225, 229))	('inactivation', 'NegReg', (112, 124))	('upregulation', 'PosReg', (134, 146))	('p16', 'Gene', '1029', (130, 133))	('oropharyngeal cancer', 'Disease', (184, 204))	('HPV-positive oropharyngeal cancer', 'Disease', 'MESH:D009959', (15, 48))	('downregulation', 'NegReg', (243, 257))	('tobacco', 'Species', '4097', (168, 175))	('p16', 'Gene', (278, 281))	('mutation', 'Var', (230, 238))	('HPV-positive oropharyngeal cancer', 'Disease', (15, 48))	('CDKN2A', 'Gene', (261, 267))	('p16', 'Gene', '1029', (278, 281))	('retinoblastoma', 'Disease', 'MESH:D012175', (86, 100))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (28, 48))
329369	30519280	HPV positivity was accompanied by significantly increased expressions of Hsp 90 and 16.2.	('increased', 'PosReg', (48, 57))	('HPV', 'Species', '10566', (0, 3))	('Hsp 90', 'Gene', '3320', (73, 79))	('16.2', 'Protein', (84, 88))	('expressions', 'MPA', (58, 69))	('positivity', 'Var', (4, 14))	('Hsp 90', 'Gene', (73, 79))
329370	30519280	HPV-positive cases and cases expressing high intensity Hsp 90 and 16.2 levels showed a significantly poorer response to oncological treatment and worse overall survival.	('Hsp 90', 'Gene', '3320', (55, 61))	('HPV', 'Species', '10566', (0, 3))	('high intensity', 'Var', (40, 54))	('worse', 'NegReg', (146, 151))	('Hsp 90', 'Gene', (55, 61))	('poorer', 'NegReg', (101, 107))	('response', 'CPA', (108, 116))
329394	29541248	The Hippo pathway was first hypothesized to be important in human cancer when tissue overgrowth was observed in Drosophila melanogaster flies with mutations in the Hippo pathway.	('mutations', 'Var', (147, 156))	('Drosophila melanogaster', 'Species', '7227', (112, 135))	('overgrowth', 'Phenotype', 'HP:0001548', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('Hippo pathway', 'Pathway', (164, 177))	('human', 'Species', '9606', (60, 65))	('cancer', 'Disease', (66, 72))
329419	29541248	In the T stage, YAP1/pYAP was significantly increased in T3-4 compared with T1-2 stages (Fig.	('T3-4', 'Var', (57, 61))	('YAP', 'Gene', '10413', (16, 19))	('YAP', 'Gene', '10413', (22, 25))	('YAP', 'Gene', (16, 19))	('YAP', 'Gene', (22, 25))	('increased', 'PosReg', (44, 53))	('YAP1', 'Gene', '10413', (16, 20))	('YAP1', 'Gene', (16, 20))
329420	29541248	In the M stage, YAP1 mRNA and protein expression were significantly increased in N1-2 compared with N0 (Fig.	('YAP1', 'Gene', '10413', (16, 20))	('increased', 'PosReg', (68, 77))	('YAP1', 'Gene', (16, 20))	('N1-2', 'Var', (81, 85))
329423	29541248	Genes that were highly expressed in COAD and associated with biological processes were mainly associated with DNA duplication (positive regulation of G1/S transition, nucleotide excision repair and DNA duplex unwinding) (Fig.	('associated', 'Reg', (94, 104))	('COAD', 'Disease', 'MESH:D029424', (36, 40))	('COAD', 'Disease', (36, 40))	('DNA duplication', 'Var', (110, 125))
329438	29541248	WNT and TGF-beta signaling were significantly enriched in the high YAP1-expression group, as assessed by GSEA.	('TGF-beta signaling', 'MPA', (8, 26))	('GSEA', 'Chemical', '-', (105, 109))	('YAP1', 'Gene', (67, 71))	('enriched', 'PosReg', (46, 54))	('YAP1', 'Gene', '10413', (67, 71))	('high', 'Var', (62, 66))
329447	29541248	Wang et al reported that co-overexpression of YAP1 and TAZ is an independent predictor of prognosis for patients.	('co-overexpression', 'Var', (25, 42))	('TAZ', 'Gene', (55, 58))	('YAP1', 'Gene', (46, 50))	('YAP1', 'Gene', '10413', (46, 50))	('patients', 'Species', '9606', (104, 112))
329526	28819406	However, for patients with metastasis of N2 + N3 (3 or more locoregional lymph nodes), patients of Group S had significantly worse OS and DFS than those in the other two groups (p=0.04; p=0.004, respectively; Fig 2C&D).	('N2 + N3', 'Var', (41, 48))	('patients', 'Species', '9606', (13, 21))	('OS', 'Chemical', '-', (131, 133))	('worse', 'NegReg', (125, 130))	('DFS', 'MPA', (138, 141))	('patients', 'Species', '9606', (87, 95))
329722	26713674	Blockage of lymphatic flow in the left lower cervical area may allow retrograde spread and the involvement of more superior or contralateral neck nodes.	('Blockage', 'Var', (0, 8))	('Blockage of lymphatic flow', 'Phenotype', 'HP:0001004', (0, 26))	('allow', 'Reg', (63, 68))	('lower cervical area', 'Phenotype', 'HP:0000470', (39, 58))	('retrograde spread', 'CPA', (69, 86))	('men', 'Species', '9606', (102, 105))
329851	26713674	Depending on the location of metastases and whether it is single or multiple, surgery may play a role in the management of these patients and local resection may improve quality of life and can provide an excellent local disease control in the neck.	('quality of life', 'CPA', (170, 185))	('man', 'Species', '9606', (109, 112))	('patients', 'Species', '9606', (129, 137))	('metastases', 'Disease', (29, 39))	('men', 'Species', '9606', (115, 118))	('local disease control', 'CPA', (215, 236))	('metastases', 'Disease', 'MESH:D009362', (29, 39))	('local', 'Var', (142, 147))	('improve', 'PosReg', (162, 169))
329852	26713674	Excision of solitary metastatic lesions of a RCC after nephrectomy has been reported to achieve 41% survival at 2 years and 13% survival at 5 years, regardless of the time interval between nephrectomy and the diagnosis of the metastatic lesion.	('Excision', 'Var', (0, 8))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
329974	26713674	Demonstration of oligodendroglioma-specific 1p19q codeletion on tissue section by fluorescence in situ hybridization is a reliable technique for detection of this tumor.	('oligodendroglioma', 'Disease', (17, 34))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('1p19q codeletion', 'Var', (44, 60))	('oligodendroglioma', 'Disease', 'MESH:D009837', (17, 34))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))
330046	27215834	Second, with the advent of modern gene-array technology, some important molecular factors (e.g., VEGF mutation, HER2/neu overexpression) have proven to be predictive of survival.	('VEGF', 'Gene', (97, 101))	('mutation', 'Var', (102, 110))	('HER2/neu', 'Gene', '2064', (112, 120))	('HER2/neu', 'Gene', (112, 120))	('VEGF', 'Gene', '7422', (97, 101))	('overexpression', 'PosReg', (121, 135))
330051	27215834	The inclusion criteria were age at diagnosis (codes: 18-85+), histological types (codes: 8000-8576, 8940-8950 and 8980-8981), primary tumor site (codes: 150-155 and 158-159), tumor extension (codes: 10-80 for 1988-2003 and 100-800 for 2004-2007), regional nodes examined (codes:1-90), regional nodes of metastasis (codes: 0-90), survival months (codes: 3-479) and types of follow-up expected (codes: active follow-up).	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('8980-8981', 'Var', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('codes: 8000-8576', 'Var', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('8940-8950', 'Var', (100, 109))
330176	24168165	Thus, to knockdown the endogenous NRD1, we used siRNA1 in the following experiments.	('NRD1', 'Gene', '4898', (34, 38))	('knockdown', 'Var', (9, 18))	('NRD1', 'Gene', (34, 38))
330177	24168165	To investigate the possible antiproliferative effects of NRD1 knockdown, we performed an MTT assay 8 days after siRNA transfection.	('NRD1', 'Gene', (57, 61))	('MTT', 'Chemical', 'MESH:C070243', (89, 92))	('NRD1', 'Gene', '4898', (57, 61))	('knockdown', 'Var', (62, 71))
330181	24168165	On day 2, although there was no difference in cell viability between NRD1 knockdown TE1 cells and negative control siRNA-transfected TE1 cells, the invasiveness of NRD1 knockdown TE1 cells was less than that of the negative control siRNA-transfected TE1 cells.	('less', 'NegReg', (193, 197))	('NRD1', 'Gene', (164, 168))	('knockdown', 'Var', (169, 178))	('invasiveness', 'CPA', (148, 160))	('NRD1', 'Gene', (69, 73))	('NRD1', 'Gene', '4898', (164, 168))	('NRD1', 'Gene', '4898', (69, 73))
330182	24168165	The migration activity of NRD1 knockdown TE1 cells was significantly lower than that of negative control siRNA-transfected TE1 cells.	('NRD1', 'Gene', (26, 30))	('lower', 'NegReg', (69, 74))	('NRD1', 'Gene', '4898', (26, 30))	('migration activity', 'CPA', (4, 22))	('knockdown', 'Var', (31, 40))
330184	24168165	It is important to establish why NRD1 knockdown inhibits cell invasion activity.	('inhibits', 'NegReg', (48, 56))	('NRD1', 'Gene', '4898', (33, 37))	('cell invasion activity', 'CPA', (57, 79))	('NRD1', 'Gene', (33, 37))	('knockdown', 'Var', (38, 47))
330189	24168165	As shown in Figure3e, expression of MMP2 and MMP3 mRNA was significantly lower in NRD1 knockdown TE5 cells than in negative control siRNA-transfected TE5 cells.	('NRD1', 'Gene', (82, 86))	('MMP3', 'Gene', (45, 49))	('MMP2', 'Gene', '4313', (36, 40))	('NRD1', 'Gene', '4898', (82, 86))	('MMP2', 'Gene', (36, 40))	('lower', 'NegReg', (73, 78))	('expression', 'MPA', (22, 32))	('MMP3', 'Gene', '4314', (45, 49))	('knockdown', 'Var', (87, 96))
330190	24168165	Expression of MMP2 and MMP3 mRNA did not significantly differ between NRD1 knockdown TE1 cells and negative control siRNA-transfected TE1 cells.	('NRD1', 'Gene', '4898', (70, 74))	('MMP3', 'Gene', (23, 27))	('MMP2', 'Gene', (14, 18))	('knockdown', 'Var', (75, 84))	('MMP3', 'Gene', '4314', (23, 27))	('NRD1', 'Gene', (70, 74))	('MMP2', 'Gene', '4313', (14, 18))
330191	24168165	Expression of MMP1, MMP9, and MMP10 mRNA was not significantly different between NRD1 knockdown cells and negative control siRNA-transfected cells.	('MMP9', 'Gene', '4318', (20, 24))	('MMP1', 'Gene', '4312', (30, 34))	('knockdown', 'Var', (86, 95))	('MMP9', 'Gene', (20, 24))	('MMP10', 'Gene', (30, 35))	('MMP1', 'Gene', '4312', (14, 18))	('MMP10', 'Gene', '4319', (30, 35))	('NRD1', 'Gene', '4898', (81, 85))	('MMP1', 'Gene', (30, 34))	('MMP1', 'Gene', (14, 18))	('NRD1', 'Gene', (81, 85))
330198	24168165	Furthermore, the invasiveness of NRD1 knockdown cells was 60% less than that of the negative control siRNA-transfected cells.	('NRD1', 'Gene', '4898', (33, 37))	('NRD1', 'Gene', (33, 37))	('less', 'NegReg', (62, 66))	('knockdown', 'Var', (38, 47))	('invasiveness', 'CPA', (17, 29))
330202	24168165	Although we showed that knockdown of NRD1 inhibits invasion activity in esophageal cancer cell lines, the underlying mechanisms remain unclear.	('inhibits', 'NegReg', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('NRD1', 'Gene', '4898', (37, 41))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('NRD1', 'Gene', (37, 41))	('knockdown', 'Var', (24, 33))	('invasion activity', 'CPA', (51, 68))
330203	24168165	We found that expression of MMP2 and MMP3 mRNA could be inhibited by NRD1 knockdown.	('MMP3', 'Gene', (37, 41))	('MMP2', 'Gene', (28, 32))	('NRD1', 'Gene', (69, 73))	('knockdown', 'Var', (74, 83))	('expression', 'MPA', (14, 24))	('MMP3', 'Gene', '4314', (37, 41))	('inhibited', 'NegReg', (56, 65))	('MMP2', 'Gene', '4313', (28, 32))	('NRD1', 'Gene', '4898', (69, 73))
330204	24168165	Although NRD1 knockdown inhibited cell invasion activity in both TE1 and TE5 cells, inhibition of MMP2 and MMP3 mRNA expression was only observed in TE5 cells, and not in TE1 cells.	('NRD1', 'Gene', '4898', (9, 13))	('MMP3', 'Gene', '4314', (107, 111))	('MMP2', 'Gene', '4313', (98, 102))	('inhibited', 'NegReg', (24, 33))	('NRD1', 'Gene', (9, 13))	('cell invasion activity', 'CPA', (34, 56))	('knockdown', 'Var', (14, 23))	('MMP3', 'Gene', (107, 111))	('MMP2', 'Gene', (98, 102))
330206	24168165	Therefore, inhibition of invasion activity by NRD1 knockdown is likely to be due to inhibition of migration activity rather than inhibition of MMP2 or MMP3 expression.	('inhibition', 'NegReg', (84, 94))	('NRD1', 'Gene', '4898', (46, 50))	('MMP3', 'Gene', (151, 155))	('MMP2', 'Gene', '4313', (143, 147))	('migration activity', 'CPA', (98, 116))	('invasion activity', 'CPA', (25, 42))	('NRD1', 'Gene', (46, 50))	('MMP3', 'Gene', '4314', (151, 155))	('inhibition', 'NegReg', (11, 21))	('MMP2', 'Gene', (143, 147))	('knockdown', 'Var', (51, 60))
330208	24168165	Because nardilysin-induced migration occurs via the EGF receptor (EGFR), it is possible that inhibition of EGFR signaling is involved in reduction of migration activity by NRD1 knockdown.	('EGFR', 'Gene', '1956', (107, 111))	('EGF receptor', 'Gene', '1956', (52, 64))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('NRD1', 'Gene', (172, 176))	('nardilysin', 'Gene', '4898', (8, 18))	('knockdown', 'Var', (177, 186))	('EGFR', 'Gene', (107, 111))	('reduction', 'NegReg', (137, 146))	('migration activity', 'CPA', (150, 168))	('nardilysin', 'Gene', (8, 18))	('NRD1', 'Gene', '4898', (172, 176))	('EGF receptor', 'Gene', (52, 64))
330210	24168165	It has also been reported that nardilysin is one of the mutant p53-specific binding partners, and that interaction of mutant p53 with nardilysin enhances invasion activity.	('nardilysin', 'Gene', (134, 144))	('enhances', 'PosReg', (145, 153))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('invasion activity', 'CPA', (154, 171))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('interaction', 'Interaction', (103, 114))	('nardilysin', 'Gene', (31, 41))	('mutant', 'Var', (118, 124))	('nardilysin', 'Gene', '4898', (31, 41))	('nardilysin', 'Gene', '4898', (134, 144))
330211	24168165	Because our previous study revealed that p53 mutation status is not associated with prognosis of patients with ESCC, expression of nardilysin may affect prognosis in patients with ESCC showing p53 mutation.	('p53', 'Gene', '7157', (41, 44))	('p53', 'Gene', (193, 196))	('affect', 'Reg', (146, 152))	('p53', 'Gene', (41, 44))	('patients', 'Species', '9606', (166, 174))	('nardilysin', 'Gene', '4898', (131, 141))	('p53', 'Gene', '7157', (193, 196))	('nardilysin', 'Gene', (131, 141))	('prognosis', 'MPA', (153, 162))	('ESCC', 'Disease', (180, 184))	('mutation', 'Var', (197, 205))	('ESCC', 'Disease', (111, 115))	('patients', 'Species', '9606', (97, 105))
330216	25510966	The association between abnormal microRNA-10b expression and cancer risk: a meta-analysis Several studies have investigated the association between abnormal microRNA-10b expression and the risk of various developing cancers, but the results are inconsistent.	('microRNA-10b', 'Gene', '406903', (33, 45))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('microRNA-10b', 'Gene', (33, 45))	('cancer', 'Disease', (61, 67))	('microRNA-10b', 'Gene', '406903', (157, 169))	('abnormal', 'Var', (148, 156))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancers', 'Disease', (216, 223))	('microRNA-10b', 'Gene', (157, 169))	('cancer', 'Disease', (216, 222))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
330220	25510966	Of 13 included studies calculated for OR and diagnostic accuracy, it was shown that high-expression of microRNA-10b could be significantly associated with cancer risk (OR = 32.80, 95% CI: 11.90-90.37, P<0.0001), and the area under the summary receiver operating characteristic (SROC) curve for microRNA-10b high-expression in the diagnosis of cancer is 0.81, which suggested that high-expression of microRNA-10b can predict worse outcomes in some types of cancer and the regular monitoring of miR-10b expression might be useful in the clinical practice.	('cancer', 'Phenotype', 'HP:0002664', (456, 462))	('cancer', 'Disease', (343, 349))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('microRNA-10b', 'Gene', '406903', (399, 411))	('high-expression', 'Var', (84, 99))	('microRNA-10b', 'Gene', '406903', (294, 306))	('microRNA-10b', 'Gene', (399, 411))	('microRNA-10b', 'Gene', (294, 306))	('cancer', 'Disease', 'MESH:D009369', (456, 462))	('microRNA-10b', 'Gene', '406903', (103, 115))	('microRNA-10b', 'Gene', (103, 115))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('associated', 'Reg', (139, 149))	('cancer', 'Disease', (155, 161))	('miR-10b', 'Gene', (493, 500))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('high-expression', 'Var', (380, 395))	('miR-10b', 'Gene', '406903', (493, 500))	('cancer', 'Disease', (456, 462))
330221	25510966	Meanwhile, deregulated miRNAs have been found in different types of human diseases and cancers.	('human', 'Species', '9606', (68, 73))	('diseases and cancers', 'Disease', 'MESH:D009369', (74, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('found', 'Reg', (40, 45))	('deregulated', 'Var', (11, 22))	('miRNAs', 'MPA', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))
330230	25510966	Because the oncogenic or tumor suppressive properties of miR-10b are inconsistent and often ambiguous, we conducted a systematic review and meta-analysis from all eligible studies to evaluate a more precise association between abnormal miR-10b expression and the risk of developing multiple, independent types of cancer.	('multiple', 'Disease', (282, 290))	('miR-10b', 'Gene', '406903', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('miR-10b', 'Gene', (236, 243))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('miR-10b', 'Gene', (57, 64))	('tumor', 'Disease', (25, 30))	('abnormal', 'Var', (227, 235))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('expression', 'MPA', (244, 254))	('miR-10b', 'Gene', '406903', (236, 243))	('cancer', 'Disease', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (313, 319))
330246	25510966	We performed an overall analysis of the data from studies containing high-expression of miR-10b and ORs from a variety of cancers.	('miR-10b', 'Gene', (88, 95))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('high-expression', 'Var', (69, 84))	('miR-10b', 'Gene', '406903', (88, 95))
330247	25510966	Then, subgroup analysis by cancer type showed significant association between the high-expression of miR-10b and various types of cancer.	('miR-10b', 'Gene', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('high-expression', 'Var', (82, 97))	('miR-10b', 'Gene', '406903', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
330251	25510966	The pooled OR being greater than 1 indicates that high-expression of miR-10b may be significantly associated with the risk of cancer (Table 3).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('high-expression', 'Var', (50, 65))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('miR-10b', 'Gene', '406903', (69, 76))	('miR-10b', 'Gene', (69, 76))	('associated', 'Reg', (98, 108))
330265	25510966	In the past decade, increasing evidence has demonstrated that aberrant expression of several miRNAs correlates with certain oncogenes or cancer suppressors.	('miRNAs', 'Gene', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('aberrant', 'Var', (62, 70))	('correlates', 'Reg', (100, 110))	('cancer', 'Disease', (137, 143))
330276	25510966	High-expression of miR-10b had also been frequently reported in breast cancer, but the average fold-change was not significantly up-regulated (average FC: 1.77).	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('miR-10b', 'Gene', (19, 26))	('breast cancer', 'Disease', (64, 77))	('High-expression', 'Var', (0, 15))	('reported', 'Reg', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('miR-10b', 'Gene', '406903', (19, 26))
330297	25510966	It was expected that a meta-analysis of low miR-10b expressing studies containing pooled ORs and 95% CIs would be included in this study; they will be analyzed in the future when sufficient data can be collected.	('low', 'Var', (40, 43))	('miR-10b', 'Gene', (44, 51))	('miR-10b', 'Gene', '406903', (44, 51))
330298	25510966	In conclusion, we provide evidence that high-expression of miR-10b is significantly associated with cancer risk via a systematic meta-analysis.	('miR-10b', 'Gene', '406903', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('high-expression', 'Var', (40, 55))	('miR-10b', 'Gene', (59, 66))	('associated', 'Reg', (84, 94))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
330516	33330097	In addition to increasing the number of voxels included in the lesion, dilating the VOI also allows the analysis to be performed on the low-enhancement region of the tumor, potentially adding information on how the uptake decreases on the lesion boundary.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('dilating', 'Var', (71, 79))	('uptake', 'MPA', (215, 221))	('tumor', 'Disease', (166, 171))
330538	33330097	Figure 4A  reports the boxplot distribution of the MTV at PET1, the parameter most correlated to treatment outcome at logistic regression analysis.	('PET1', 'Gene', (58, 62))	('MTV', 'Var', (51, 54))	('PET1', 'Gene', '54738', (58, 62))	('MTV', 'Chemical', '-', (51, 54))
330565	33330097	However, the textural metrics, that correlate to treatment outcome, are associated to micro-variations of local metabolic activity thus indicating a possible role of spatial intra-tumor heterogeneity in predicting response.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('micro-variations', 'Var', (86, 102))	('local metabolic activity', 'MPA', (106, 130))
330579	29343623	We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus.	('cytosine', 'Chemical', 'MESH:D003596', (88, 96))	('methylation', 'Var', (143, 154))	('aberrant', 'Var', (79, 87))	('CCNA1', 'Gene', (166, 171))	('BE', 'Phenotype', 'HP:0100580', (112, 114))	('CCNA1', 'Gene', '8900', (166, 171))
330581	29343623	CCNA1 DNA methylation demonstrated an area under the curve (AUC)=0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker.	('neoplasia', 'Disease', (115, 124))	('CCNA1', 'Gene', '8900', (0, 5))	('BE-related metaplasia', 'Disease', (89, 110))	('neoplasia', 'Disease', 'MESH:D009369', (115, 124))	('neoplasia', 'Phenotype', 'HP:0002664', (115, 124))	('BE', 'Phenotype', 'HP:0100580', (89, 91))	('methylation', 'Var', (10, 21))	('CCNA1', 'Gene', (0, 5))	('BE', 'Phenotype', 'HP:0100580', (223, 225))
330586	29343623	Acquisition of aberrant cytosine methylation within CpG-rich genomic islands is a common accompaniment of many cancers and can serve as a neoplasia biomarker.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('neoplasia', 'Disease', 'MESH:D009369', (138, 147))	('neoplasia', 'Phenotype', 'HP:0002664', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cytosine', 'Chemical', 'MESH:D003596', (24, 32))	('aberrant', 'Var', (15, 23))	('neoplasia', 'Disease', (138, 147))
330587	29343623	We have previously reported that de novo DNA methylation of the CpG island overlapping the first exon of the vimentin gene (mVIM) is a highly sensitive BE biomarker that is present in biopsies of approximately 90% of BE patients, suggesting utility of mVIM as a potential biomarker for BE screening.	('BE', 'Phenotype', 'HP:0100580', (286, 288))	('mVIM', 'Gene', '22352', (252, 256))	('mVIM', 'Gene', (252, 256))	('BE', 'Phenotype', 'HP:0100580', (152, 154))	('vimentin', 'Gene', '7431', (109, 117))	('mVIM', 'Gene', (124, 128))	('patients', 'Species', '9606', (220, 228))	('vimentin', 'Gene', (109, 117))	('mVIM', 'Gene', '22352', (124, 128))	('BE', 'Phenotype', 'HP:0100580', (217, 219))	('DNA methylation', 'Var', (41, 56))
330600	29343623	2A), with mCCNA1 detected in 81% percent of nondysplastic BE, 68% percent of BE with high-grade dysplasia, and 90% percent of EAC, but in only 1% of normal squamous samples (classifying a tissue as methylated if it had >10% of methylated CCNA1 reads, and classifying a CCNA1 read as methylated when methylation was detected at >= 16 out of target 21 target CpG positions).	('CCNA1', 'Gene', (11, 16))	('dysplasia', 'Disease', (96, 105))	('BE', 'Phenotype', 'HP:0100580', (58, 60))	('dysplasia', 'Disease', 'MESH:D004476', (96, 105))	('mCCNA1', 'Gene', (10, 16))	('methylated', 'Var', (227, 237))	('CCNA1', 'Gene', (269, 274))	('CCNA1', 'Gene', '8900', (11, 16))	('mCCNA1', 'Gene', '12427', (10, 16))	('EAC', 'Phenotype', 'HP:0011459', (126, 129))	('CCNA1', 'Gene', (238, 243))	('BE', 'Phenotype', 'HP:0100580', (77, 79))	('CCNA1', 'Gene', '8900', (269, 274))	('EAC', 'Disease', (126, 129))	('detected', 'Reg', (17, 25))	('dysplastic', 'Disease', (47, 57))	('CCNA1', 'Gene', '8900', (238, 243))	('dysplastic', 'Disease', 'MESH:D004416', (47, 57))
330610	29343623	An optimal cutpoint, in which a sample was detected as positive if it had >3.12% methylated CCNA1 templates, maximized the sum of sensitivity plus specificity.	('methylated', 'Var', (81, 91))	('maximized', 'PosReg', (109, 118))	('CCNA1', 'Gene', (92, 97))	('CCNA1', 'Gene', '8900', (92, 97))
330631	29343623	Reassuringly for such a selective sampling approach, reanalysis of brushings from the distal esophagus showed smoking to have no significant effect on the extent of VIM and of CCNA1 methylation detectable in either the normal GE junction of control individuals or in cases with BE or Barrett's related neoplasia (table S5).	('neoplasia', 'Disease', (302, 311))	('CCNA1', 'Gene', (176, 181))	('methylation', 'Var', (182, 193))	('neoplasia', 'Disease', 'MESH:D009369', (302, 311))	('neoplasia', 'Phenotype', 'HP:0002664', (302, 311))	('CCNA1', 'Gene', '8900', (176, 181))	('BE', 'Phenotype', 'HP:0100580', (278, 280))
330651	29343623	In contrast, among individuals without BE or IM, assays for mVIM and for mCCNA1 were negative in all GE junction samples (n=55), whichincluded 15 cases with chronic carditis typified by columnar mucosa without IM (Table 3), and methylation was additionally negativein all distal esophagus samples (n=24).Together, these findings suggest that aberrant methylation occurs at the earliest stages of BE development, in those columnar mucosae that are actively evolving toward IM.	('aberrant', 'Var', (342, 350))	('carditis', 'Disease', 'MESH:D009205', (165, 173))	('mVIM', 'Gene', '22352', (60, 64))	('BE', 'Phenotype', 'HP:0100580', (39, 41))	('methylation', 'MPA', (351, 362))	('BE', 'Phenotype', 'HP:0100580', (396, 398))	('mCCNA1', 'Gene', (73, 79))	('carditis', 'Disease', (165, 173))	('mCCNA1', 'Gene', '12427', (73, 79))	('mVIM', 'Gene', (60, 64))
330653	29343623	Moreover, 2 of 13 individuals with H. pylori gastritis, who were at increased risk for but did not have gastric IM, were also positive for VIM or CCNA1 methylation.	('positive', 'Reg', (126, 134))	('CCNA1', 'Gene', (146, 151))	('gastritis', 'Phenotype', 'HP:0005263', (45, 54))	('H. pylori', 'Species', '210', (35, 44))	('gastritis', 'Disease', 'MESH:D005756', (45, 54))	('CCNA1', 'Gene', '8900', (146, 151))	('VIM', 'Protein', (139, 142))	('gastritis', 'Disease', (45, 54))	('H. pylori gastritis', 'Phenotype', 'HP:0005202', (35, 54))	('methylation', 'Var', (152, 163))
330661	29343623	These studies in the esophagus help to inform the larger understanding of the genesis of aberrant DNA methylation in human neoplasias.	('neoplasias', 'Disease', 'MESH:D009369', (123, 133))	('neoplasias', 'Phenotype', 'HP:0002664', (123, 133))	('human', 'Species', '9606', (117, 122))	('aberrant', 'Var', (89, 97))	('neoplasias', 'Disease', (123, 133))	('neoplasia', 'Phenotype', 'HP:0002664', (123, 132))
330663	29343623	First, VIM and CCNA1 methylation were both detected in epithelial fractions from microdissected FFPE samples of early and late BE lesions (Table 3).	('methylation', 'Var', (21, 32))	('CCNA1', 'Gene', (15, 20))	('VIM', 'Gene', (7, 10))	('BE', 'Phenotype', 'HP:0100580', (127, 129))	('CCNA1', 'Gene', '8900', (15, 20))
330670	29343623	S3), suggesting that VIM methylation may provide a mechanism for cancer cells to suppress EMT.	('VIM', 'Protein', (21, 24))	('EMT', 'CPA', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('methylation', 'Var', (25, 36))	('suppress', 'NegReg', (81, 89))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
330671	29343623	First, we have identified cytosine methylation of the CCNA1 locus as a methylation marker of Barrett's esophagus.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (93, 112))	('CCNA1', 'Gene', '8900', (54, 59))	('cytosine', 'Chemical', 'MESH:D003596', (26, 34))	('cytosine methylation', 'Var', (26, 46))	('CCNA1', 'Gene', (54, 59))	("Barrett's esophagus", 'Disease', (93, 112))
330691	29343623	Esophageal brushings were first used to validate findings from esophageal biopsies of methylated vimentin as a biomarker for detection of Barrett's esophagus.	('vimentin', 'Gene', '7431', (97, 105))	('vimentin', 'Gene', (97, 105))	('methylated', 'Var', (86, 96))	("Barrett's esophagus", 'Disease', (138, 157))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (138, 157))
330739	29269998	EET is the procedure of choice for patients with LGD, high-grade dysplasia (HGD), and T1a esophageal adenocarcinoma based on abundant data showing treatment efficacy and durability with an acceptable safety profile.	('dysplasia', 'Disease', (65, 74))	('esophageal adenocarcinoma', 'Disease', (90, 115))	('T1a', 'Var', (86, 89))	('dysplasia', 'Disease', 'MESH:D004476', (65, 74))	('LGD', 'Disease', (49, 52))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (90, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('patients', 'Species', '9606', (35, 43))	('EET', 'Chemical', '-', (0, 3))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (90, 115))
330760	29269998	Endoscopic resection is also the recommended therapy for T1a and T1b sm1 esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (73, 98))	('T1a', 'Var', (57, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (73, 98))	('esophageal adenocarcinoma', 'Disease', (73, 98))	('T1b sm1', 'Var', (65, 72))
330854	25888911	FH535 increases the radiosensitivity and reverses epithelial-to-mesenchymal transition of radioresistant esophageal cancer cell line KYSE-150R Acquired radioresistance has significantly compromised the efficacy of radiotherapy for esophageal cancer.	('reverses', 'NegReg', (41, 49))	('radioresistance', 'CPA', (152, 167))	('radiosensitivity', 'CPA', (20, 36))	('esophageal cancer', 'Disease', (231, 248))	('epithelial-to-mesenchymal transition', 'CPA', (50, 86))	('esophageal cancer', 'Disease', (105, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (231, 248))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('compromised', 'NegReg', (186, 197))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('FH535', 'Var', (0, 5))	('increases', 'PosReg', (6, 15))
330864	25888911	The expression of nuclear beta-catenin and nuclear translocation of beta-catenin from the cytoplasm was decreased after FH535 treatment.	('beta-catenin', 'Gene', '1499', (26, 38))	('nuclear translocation of', 'MPA', (43, 67))	('expression', 'MPA', (4, 14))	('decreased', 'NegReg', (104, 113))	('FH535', 'Chemical', 'MESH:C575430', (120, 125))	('beta-catenin', 'Gene', (26, 38))	('beta-catenin', 'Gene', (68, 80))	('FH535', 'Var', (120, 125))	('beta-catenin', 'Gene', '1499', (68, 80))
330865	25888911	FH535 also reversed EMT phenotypes by increasing E-cadherin expression.	('E-cadherin', 'Gene', '999', (49, 59))	('expression', 'MPA', (60, 70))	('FH535', 'Chemical', 'MESH:C575430', (0, 5))	('increasing', 'PosReg', (38, 48))	('E-cadherin', 'Gene', (49, 59))	('FH535', 'Var', (0, 5))
330866	25888911	The cell proliferation rates of KYSE-150R were dose-dependent and the radiation survival fraction was significantly decreased upon FH535 treatment.	('FH535', 'Var', (131, 136))	('radiation survival fraction', 'CPA', (70, 97))	('cell proliferation rates', 'CPA', (4, 28))	('FH535', 'Chemical', 'MESH:C575430', (131, 136))	('decreased', 'NegReg', (116, 125))
330867	25888911	Neutral comet assays indicated that FH535 impairs DNA double stranded break repair in KYSE-150R cells.	('DNA double stranded break repair', 'MPA', (50, 82))	('FH535', 'Chemical', 'MESH:C575430', (36, 41))	('comet', 'Species', '302767', (8, 13))	('impairs', 'NegReg', (42, 49))	('FH535', 'Var', (36, 41))
330869	25888911	EMT phenotypes can be reduced and the radiosensitivity of esophageal cancer cells can be enhanced by inhibiting the Wnt/beta-catenin pathway with FH535 treatment.	('radiosensitivity', 'CPA', (38, 54))	('beta-catenin', 'Gene', '1499', (120, 132))	('enhanced', 'PosReg', (89, 97))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('FH535', 'Var', (146, 151))	('FH535', 'Chemical', 'MESH:C575430', (146, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('EMT phenotypes', 'CPA', (0, 14))	('reduced', 'NegReg', (22, 29))	('beta-catenin', 'Gene', (120, 132))	('inhibiting', 'NegReg', (101, 111))
330878	25888911	Using the beta-Catenin/Tcf inhibitor FH535, the expression of Wnt/beta-catenin pathway proteins as well as EMT phenotypes were reduced, and at the same time, radiosensitivity was greatly increased.	('EMT phenotypes', 'CPA', (107, 121))	('Tcf', 'Gene', (23, 26))	('radiosensitivity', 'CPA', (158, 174))	('FH535', 'Chemical', 'MESH:C575430', (37, 42))	('beta-catenin', 'Gene', (66, 78))	('expression', 'MPA', (48, 58))	('beta-catenin', 'Gene', '1499', (66, 78))	('increased', 'PosReg', (187, 196))	('beta-Catenin', 'Gene', '1499', (10, 22))	('FH535', 'Var', (37, 42))	('reduced', 'NegReg', (127, 134))	('beta-Catenin', 'Gene', (10, 22))	('Tcf', 'Gene', '3172', (23, 26))
330898	25888911	After an overnight incubation, the cells were subcultured in three groups including: FH535 treated in different concentrations (5 muM, 10 muM, 15 muM, 20 muM), DMSO treated with the same volume as FH535 for 24 hours, and irradiation treated with a dose of 8 Gy high energy X-ray from a linear accelerator (Vairan 2300C/D, Salt Lake, USA).	('DMSO', 'Chemical', 'MESH:D004121', (160, 164))	('2300C/D', 'Var', (313, 320))	('FH535', 'Chemical', 'MESH:C575430', (197, 202))	('muM', 'Gene', (130, 133))	('muM', 'Gene', '56925', (138, 141))	('FH535', 'Chemical', 'MESH:C575430', (85, 90))	('muM', 'Gene', '56925', (146, 149))	('muM', 'Gene', (138, 141))	('2300C/D', 'SUBSTITUTION', 'None', (313, 320))	('muM', 'Gene', (146, 149))	('muM', 'Gene', '56925', (154, 157))	('muM', 'Gene', '56925', (130, 133))	('muM', 'Gene', (154, 157))
330904	25888911	From the three cell samples, two samples were then treated with 20 muM FH535 and DMSO for 24 hours, respectively.	('DMSO', 'Chemical', 'MESH:D004121', (81, 85))	('FH535', 'Chemical', 'MESH:C575430', (71, 76))	('muM', 'Gene', '56925', (67, 70))	('muM', 'Gene', (67, 70))	('FH535', 'Var', (71, 76))
330913	25888911	As shown in (Figure 2A), the expression of E-cadherin (CDH1) was decreased and the expressions of Vimentin (VIM), Snail, Slug and Twist were increased in KYSE-150R cells compared with those in KYSE-150 cells.	('Twist', 'Gene', '7291', (130, 135))	('CDH1', 'Gene', (55, 59))	('E-cadherin', 'Gene', (43, 53))	('VIM', 'Gene', (108, 111))	('Twist', 'Gene', (130, 135))	('decreased', 'NegReg', (65, 74))	('increased', 'PosReg', (141, 150))	('E-cadherin', 'Gene', '999', (43, 53))	('Slug', 'Gene', '6591', (121, 125))	('CDH1', 'Gene', '999', (55, 59))	('expressions', 'MPA', (83, 94))	('KYSE-150R', 'Var', (154, 163))	('VIM', 'Gene', '7431', (108, 111))	('Slug', 'Gene', (121, 125))	('Snail', 'Gene', '6615', (114, 119))	('Snail', 'Gene', (114, 119))	('expression', 'MPA', (29, 39))
330918	25888911	The phosphorylations of Thr 41 and Ser 45 in beta-catenin, the important regulatory sites for proteasomal degradation of the transcription factors, decreased in the KYSE-150R cells.	('Ser', 'Var', (35, 38))	('Ser', 'Chemical', 'MESH:D012694', (35, 38))	('beta-catenin', 'Gene', '1499', (45, 57))	('Thr 41', 'Var', (24, 30))	('decreased', 'NegReg', (148, 157))	('Thr', 'Chemical', 'MESH:D013912', (24, 27))	('phosphorylations', 'MPA', (4, 20))	('beta-catenin', 'Gene', (45, 57))
330919	25888911	The protein levels of cyclin D1 were significantly increased in KYSE-150R cells (Figure 3B).	('increased', 'PosReg', (51, 60))	('cyclin D1', 'Gene', (22, 31))	('cyclin D1', 'Gene', '595', (22, 31))	('KYSE-150R', 'Var', (64, 73))
330922	25888911	Western blot results demonstrated that nuclear beta-catenin decreased, while cytoplasmicbeta-catenin slightly increased (Figure 4A) after FH535 treatment.	('beta-catenin', 'Gene', '1499', (47, 59))	('decreased', 'NegReg', (60, 69))	('FH535', 'Var', (138, 143))	('increased', 'PosReg', (110, 119))	('beta-catenin', 'Gene', (88, 100))	('beta-catenin', 'Gene', (47, 59))	('FH535', 'Chemical', 'MESH:C575430', (138, 143))	('beta-catenin', 'Gene', '1499', (88, 100))
330924	25888911	The increased expression of beta-catenin in radioresistant KYSE-150R cells treated with FH535 was 0.044 +- 0.0002, then the average optical density of non-FH535 treated was 0.031 +- 0.0010 (P = 0.004) (Figure 4B).	('FH535', 'Chemical', 'MESH:C575430', (155, 160))	('beta-catenin', 'Gene', (28, 40))	('FH535', 'Chemical', 'MESH:C575430', (88, 93))	('beta-catenin', 'Gene', '1499', (28, 40))	('expression', 'MPA', (14, 24))	('FH535', 'Var', (88, 93))	('increased', 'PosReg', (4, 13))
330925	25888911	Next, we sought to test whether FH535 could affect the EMT markers in the treated KYSE-150R cell line.	('affect', 'Reg', (44, 50))	('FH535', 'Var', (32, 37))	('EMT markers', 'CPA', (55, 66))	('FH535', 'Chemical', 'MESH:C575430', (32, 37))
330926	25888911	A statistically significant increase of E-cadherin mRNA and decreases of Vimentin (VIM) Snail and GSK3beta mRNAs after FH535 treatment were observed in the KYSE-150R cells (Figure 5A).	('decreases', 'NegReg', (60, 69))	('FH535', 'Var', (119, 124))	('Snail', 'Gene', '6615', (88, 93))	('VIM', 'Gene', (83, 86))	('E-cadherin', 'Gene', (40, 50))	('E-cadherin', 'Gene', '999', (40, 50))	('FH535', 'Chemical', 'MESH:C575430', (119, 124))	('GSK3beta', 'Gene', (98, 106))	('Vimentin', 'Protein', (73, 81))	('VIM', 'Gene', '7431', (83, 86))	('GSK3beta', 'Gene', '2932', (98, 106))	('Snail', 'Gene', (88, 93))	('increase', 'PosReg', (28, 36))
330928	25888911	The increased expression of E-cadherin in radioresistant KYSE-150R cells treated with FH535 was 0.081 +- 0.0028, and the average optical density of group without FH535 treatment was 0.056 +- 0.0025 (p = 0.01).	('FH535', 'Var', (86, 91))	('expression', 'MPA', (14, 24))	('E-cadherin', 'Gene', (28, 38))	('E-cadherin', 'Gene', '999', (28, 38))	('FH535', 'Chemical', 'MESH:C575430', (86, 91))	('increased', 'PosReg', (4, 13))	('FH535', 'Chemical', 'MESH:C575430', (162, 167))
330930	25888911	The expression of Vimentin in radioresistant KYSE-150R cells treated with FH535 was 0.042 +- 0.0016, and the average optical density of group without FH535 treatment was 0.040 +- 0.0005 (p = 0.222).	('FH535', 'Chemical', 'MESH:C575430', (74, 79))	('Vimentin', 'Protein', (18, 26))	('expression', 'MPA', (4, 14))	('FH535', 'Chemical', 'MESH:C575430', (150, 155))	('FH535', 'Var', (74, 79))
330931	25888911	Interestingly, the Wnt pathway target gene Cyclin D1 was down-regulated specifically in the FH535 treatment group in both mRNA and protein level, indicating the inhibition of the Wnt/beta-catenin pathway.	('down-regulated', 'NegReg', (57, 71))	('beta-catenin', 'Gene', (183, 195))	('FH535', 'Chemical', 'MESH:C575430', (92, 97))	('Wnt', 'Gene', (19, 22))	('Cyclin D1', 'Gene', (43, 52))	('beta-catenin', 'Gene', '1499', (183, 195))	('FH535', 'Var', (92, 97))	('inhibition', 'NegReg', (161, 171))
330932	25888911	We tested whether FH535 could potentially act as a radiosensitizer for the KYSE-150R cells by CCK8 analysis and a colony forming assay.	('FH535', 'Chemical', 'MESH:C575430', (18, 23))	('tested', 'Reg', (3, 9))	('FH535', 'Var', (18, 23))
330934	25888911	The combined treatment of FH535 and irradiation (8 Gy) effectively suppressed the proliferation rates compared with FH535 treatment alone (Figure 6A).	('FH535', 'Chemical', 'MESH:C575430', (26, 31))	('FH535', 'Chemical', 'MESH:C575430', (116, 121))	('suppressed', 'NegReg', (67, 77))	('proliferation rates', 'CPA', (82, 101))	('FH535', 'Var', (26, 31))
330935	25888911	The results of colony forming assays showed that FH535 treatment significantly enhanced the radiotherapy effect in the KYSE-150R cells (Figure 6B).	('radiotherapy effect in the KYSE-150R', 'CPA', (92, 128))	('FH535', 'Chemical', 'MESH:C575430', (49, 54))	('FH535', 'Var', (49, 54))	('enhanced', 'PosReg', (79, 87))
330936	25888911	The SF2 (survival fraction at 2 Gy) in the KYSE-150R cells treated with FH535 and DMSO were (0.50 +- 0.05) and (0.80 +- 0.02), respectively (p < 0.05).	('DMSO', 'Var', (82, 86))	('SF2', 'Gene', '6426', (4, 7))	('FH535', 'Var', (72, 77))	('DMSO', 'Chemical', 'MESH:D004121', (82, 86))	('SF2', 'Gene', (4, 7))	('FH535', 'Chemical', 'MESH:C575430', (72, 77))
330938	25888911	The momentum was significantly increased in the FH535 treatment group (Figure 6C and D), implicating that the DNA DSB repairing was impaired by FH535 in the KYSE-150R cells.	('impaired', 'NegReg', (132, 140))	('FH535', 'Var', (144, 149))	('increased', 'PosReg', (31, 40))	('DNA DSB', 'Disease', (110, 117))	('FH535', 'Chemical', 'MESH:C575430', (144, 149))	('FH535', 'Chemical', 'MESH:C575430', (48, 53))
330940	25888911	Phenotypic changes similar to EMT and activation of the Wnt/beta-catenin signaling pathway were observed in KYSE-150R cells compared to its parental cells.	('activation', 'PosReg', (38, 48))	('beta-catenin', 'Gene', (60, 72))	('KYSE-150R cells', 'Var', (108, 123))	('beta-catenin', 'Gene', '1499', (60, 72))
330952	25888911	Previous studies have shown that FH535 is a synthetic inhibitor of the canonical Wnt/beta-catenin signaling pathway.	('FH535', 'Chemical', 'MESH:C575430', (33, 38))	('beta-catenin', 'Gene', (85, 97))	('FH535', 'Var', (33, 38))	('beta-catenin', 'Gene', '1499', (85, 97))
330954	25888911	Consistently, the expression of Wnt/beta-catenin pathway protein as well as EMT phenotypes in KYSE-150R cells were reduced with the treatment of FH535 in this study.	('reduced', 'NegReg', (115, 122))	('beta-catenin', 'Gene', (36, 48))	('FH535', 'Var', (145, 150))	('expression', 'MPA', (18, 28))	('beta-catenin', 'Gene', '1499', (36, 48))	('FH535', 'Chemical', 'MESH:C575430', (145, 150))	('EMT phenotypes', 'CPA', (76, 90))
330955	25888911	These results indicated that radioresistance in KYSE-150R cells can be reverted via EMT reversal and down-regulation of Wnt/beta-catenin pathway with FH535 treatment.	('beta-catenin', 'Gene', (124, 136))	('down-regulation', 'NegReg', (101, 116))	('beta-catenin', 'Gene', '1499', (124, 136))	('FH535', 'Chemical', 'MESH:C575430', (150, 155))	('EMT reversal', 'CPA', (84, 96))	('FH535', 'Var', (150, 155))	('radioresistance', 'CPA', (29, 44))
330958	25888911	Interestingly, in our study, FH535 not only acted as a potential radiosensitizer by blocking the Wnt/beta-catenin pathway, but also effectively suppressed EMT.	('EMT', 'CPA', (155, 158))	('FH535', 'Chemical', 'MESH:C575430', (29, 34))	('beta-catenin', 'Gene', (101, 113))	('suppressed', 'NegReg', (144, 154))	('blocking', 'NegReg', (84, 92))	('FH535', 'Var', (29, 34))	('beta-catenin', 'Gene', '1499', (101, 113))
330959	25888911	This mechanism was also observed in NSCLC in which FH535 could reverse the phenotype of TGF-b1-induced EMT, which is a potential treatment target for EMT reversal.	('EMT', 'CPA', (103, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('FH535', 'Var', (51, 56))	('TGF-b1', 'Gene', (88, 94))	('TGF-b1', 'Gene', '7040', (88, 94))	('NSCLC', 'Disease', (36, 41))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('FH535', 'Chemical', 'MESH:C575430', (51, 56))
330961	25888911	FH535 could reduce EMT phenotypes and increase esophageal cancer radiosensitivity.	('reduce', 'NegReg', (12, 18))	('increase esophageal cancer', 'Disease', (38, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('EMT phenotypes', 'CPA', (19, 33))	('FH535', 'Chemical', 'MESH:C575430', (0, 5))	('increase esophageal cancer', 'Disease', 'MESH:D004938', (38, 64))	('reduce EMT', 'Phenotype', 'HP:0032198', (12, 22))	('cancer radiosensitivity', 'Phenotype', 'HP:0010997', (58, 81))	('FH535', 'Var', (0, 5))
330962	25888911	Inhibiting the Wnt/beta-catenin pathway maybe a promising strategy to overcome radioresistance in the treatment of esophageal cancer radioresistance.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Inhibiting', 'Var', (0, 10))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('beta-catenin', 'Gene', (19, 31))	('beta-catenin', 'Gene', '1499', (19, 31))
330976	24548688	There is now accumulating evidence that the MetS also may be an important risk factor for several specific cancers as well as overall cancer mortality.	('MetS', 'Var', (44, 48))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
331003	24548688	Definition of severity of hypertension was grade I = systolic BP 140-159 or diastolic BP 90-99, grade II systolic BP = 160-179 or diastolic BP = 100-109 and grade III systolic BP >= 180 or diastolic BP >= 110.	('hypertension', 'Disease', 'MESH:D006973', (26, 38))	('diastolic', 'MPA', (76, 85))	('hypertension', 'Disease', (26, 38))	('systolic', 'Var', (105, 113))	('hypertension', 'Phenotype', 'HP:0000822', (26, 38))	('diastolic', 'MPA', (130, 139))
331029	24548688	The MetS has been demonstrated to be associated with several site-specific cancers, including liver, colorectal, breast, pancreatic, urinary bladder, and endometrial cancer.	('breast', 'Disease', (113, 119))	('endometrial cancer', 'Phenotype', 'HP:0012114', (154, 172))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('endometrial cancer', 'Disease', 'MESH:D016889', (154, 172))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('MetS', 'Var', (4, 8))	('cancers', 'Disease', (75, 82))	('colorectal', 'Disease', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('endometrial cancer', 'Disease', (154, 172))	('associated', 'Reg', (37, 47))	('pancreatic', 'Disease', 'MESH:D010195', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('liver', 'Disease', (94, 99))	('urinary bladder', 'Disease', (133, 148))	('pancreatic', 'Disease', (121, 131))
331041	24548688	An association between high blood glucose and an increased risk of cancer overall has been reported in several prospective studies.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('high blood glucose', 'Phenotype', 'HP:0003074', (23, 41))	('high blood', 'Var', (23, 33))	('glucose', 'Chemical', 'MESH:D005947', (34, 41))
331080	22919547	Ectopic gastric mucosa in the cyst may cause hemorrhage or perforation of the cyst or infection.	('Ectopic gastric', 'Phenotype', 'HP:0100802', (0, 15))	('cause', 'Reg', (39, 44))	('hemorrhage', 'Disease', (45, 55))	('perforation', 'CPA', (59, 70))	('infection', 'Disease', (86, 95))	('hemorrhage', 'Disease', 'MESH:D006470', (45, 55))	('infection', 'Disease', 'MESH:D007239', (86, 95))	('Ectopic', 'Var', (0, 7))
331086	22919547	Pericardial or mesothelial cysts result from aberrations in the formation of coelomic (somatic) cavities and are uncommon benign congenital anomalies.	('aberrations', 'Var', (45, 56))	('result from', 'Reg', (33, 44))	('congenital anomalies', 'Disease', 'MESH:D000013', (129, 149))	('mesothelial cysts', 'Disease', (15, 32))	('congenital anomalies', 'Disease', (129, 149))	('Pericardial', 'Disease', (0, 11))
331175	22919547	Lymphatic components of the malformation may contain cystic structures of various sizes ranging from macrocystic to microcystic.The contents of uncomplicated cystic lesions typically are hypointense on T1-weighted images and hyperintense on T2-weighted images, but following hemorrhage or infection fluid-fluid levels may be visible within these cystic lesions.	('cystic lesions', 'Disease', (158, 172))	('cystic lesions', 'Disease', 'MESH:D052177', (346, 360))	('hemorrhage', 'Disease', (275, 285))	('cystic lesions', 'Disease', 'MESH:D052177', (158, 172))	('macrocystic to microcystic', 'Disease', (101, 127))	('macrocystic to microcystic', 'Disease', 'MESH:D000236', (101, 127))	('hemorrhage', 'Disease', 'MESH:D006470', (275, 285))	('hypointense', 'Var', (187, 198))	('infection', 'Disease', (289, 298))	('hyperintense', 'Var', (225, 237))	('cystic lesions', 'Disease', (346, 360))	('infection', 'Disease', 'MESH:D007239', (289, 298))
331178	29949666	We sought to investigate risk factors for OS in ypT0-3N0M0 gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('ypT0-3N0M0', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gastric cancer', 'Disease', (59, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))
331179	29949666	From an institutional database of The University of Texas MD Anderson Cancer Center and the National Cancer Database (NCDB), we identified patients with ypT0-3N0M0 gastric adenocarcinoma who underwent R0 gastrectomy after chemotherapy or chemoradiation during 1995-2015 (MD Anderson) or 2006-2014 (NCDB).	('Cancer', 'Disease', 'MESH:D009369', (101, 107))	('patients', 'Species', '9606', (139, 147))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ypT0-3N0M0', 'Var', (153, 163))	('gastric adenocarcinoma', 'Disease', (164, 186))	('Cancer', 'Disease', (70, 76))	('Cancer', 'Disease', 'MESH:D009369', (70, 76))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer', 'Disease', (101, 107))
331183	29949666	The ypT category does not impact OS in ypT0-3N0M0 gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gastric cancer', 'Disease', (50, 64))	('ypT0-3N0M0', 'Var', (39, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))
331188	29949666	The results also indicated that ypN status plays the main role in OS prediction, and we observed uniformly long OS among patients with ypN0M0 status, regardless of ypT category (ypT0-3).	('long', 'PosReg', (107, 111))	('patients', 'Species', '9606', (121, 129))	('ypN0M0 status', 'Var', (135, 148))
331213	29949666	In both cohorts, survival curves were similar for patients with ypT0, ypT1, ypT2, and ypT3 disease, whereas patients with ypT4a and ypT4b disease appeared to have worse survival than those with ypT0-3 disease.	('ypT1', 'Gene', (70, 74))	('patients', 'Species', '9606', (50, 58))	('ypT1', 'Gene', '5861', (70, 74))	('ypT2', 'Var', (76, 80))	('ypT0', 'Var', (64, 68))	('ypT3 disease', 'Var', (86, 98))	('ypT4b', 'Var', (132, 137))	('patients', 'Species', '9606', (108, 116))	('ypT4a', 'Var', (122, 127))
331215	29949666	In this study of patients with ypT0-3N0M0 gastric cancer who underwent preoperative chemotherapy or chemoradiation therapy followed by R0 gastrectomy, we found that OS did not differ by ypT category in either the MD Anderson cohort or the NCDB cohort.	('ypT0-3N0M0', 'Var', (31, 41))	('gastric cancer', 'Phenotype', 'HP:0012126', (42, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (42, 56))	('patients', 'Species', '9606', (17, 25))	('gastric cancer', 'Disease', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
331216	29949666	Most notably, patients with ypT0N0 disease (pathologic complete response) did not have better OS than those with ypT1-3N0 disease.	('ypT1', 'Gene', '5861', (113, 117))	('patients', 'Species', '9606', (14, 22))	('ypT1', 'Gene', (113, 117))	('ypT0N0 disease', 'Var', (28, 42))
331217	29949666	In a previous study, we reported reasonable survival prediction by ypStage in the gastric cancer staging system in the eighth edition of the AJCC Cancer Staging Manual.	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('gastric cancer', 'Disease', (82, 96))	('Cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ypStage', 'Var', (67, 74))	('Cancer', 'Disease', (146, 152))	('Cancer', 'Disease', 'MESH:D009369', (146, 152))
331218	29949666	In that study, there were reasonable numbers of patients with ypT0N0 (n = 49), ypT1N0 (n = 44), ypT2N0 (n = 38), and ypT3N0 (n = 44) disease, and all of these subgroups had uniformly excellent OS (5-year OS rates >65%).	('ypT1', 'Gene', '5861', (79, 83))	('ypT0N0', 'Var', (62, 68))	('ypT2N0', 'Var', (96, 102))	('ypT3N0', 'Var', (117, 123))	('patients', 'Species', '9606', (48, 56))	('ypT1', 'Gene', (79, 83))
331222	29949666	As a result, in the esophageal cancer staging system in the eighth edition of the AJCC Cancer Staging Manual, patients with ypT0-2N0 disease are categorized as having ypStage I disease.	('esophageal cancer', 'Disease', (20, 37))	('ypT0-2N0 disease', 'Var', (124, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ypStage I disease', 'Disease', (167, 184))	('ypStage I disease', 'Disease', 'MESH:D009081', (167, 184))	('Cancer', 'Disease', (87, 93))	('patients', 'Species', '9606', (110, 118))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))
331223	29949666	In contrast, patients with ypT3N0 disease, who had worse outcome, are categorized as having ypStage II disease.	('ypT3N0 disease', 'Var', (27, 41))	('ypStage II disease', 'Disease', (92, 110))	('patients', 'Species', '9606', (13, 21))	('ypStage II disease', 'Disease', 'MESH:D005776', (92, 110))
331224	29949666	One potential reason why ypT3N0 disease was associated with worse survival in esophageal cancer but not gastric cancer is that ypT3 is defined as subserosal invasion in gastric cancer but adventitia invasion in esophageal cancer.	('gastric cancer', 'Disease', (169, 183))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('ypT3N0', 'Var', (25, 31))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('adventitia invasion', 'Disease', (188, 207))	('esophageal cancer', 'Disease', (211, 228))	('esophageal cancer', 'Disease', 'MESH:D004938', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('adventitia invasion', 'Disease', 'MESH:D009361', (188, 207))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('gastric cancer', 'Disease', (104, 118))	('worse', 'NegReg', (60, 65))
331228	29949666	One potential explanation for why OS did not differ by ypT category among patients with ypT0-3N0 gastric cancer is that effective treatment does not always downstage ypT category.	('gastric cancer', 'Disease', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('patients', 'Species', '9606', (74, 82))	('ypT0-3N0', 'Var', (88, 96))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('ypT', 'MPA', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
331234	29949666	Another study is needed to identify pathologic factors that can stratify patients with ypT0-3N0 gastric cancer with respect to survival, and that study should investigate the impact of tumor regression grade.	('tumor', 'Disease', (185, 190))	('ypT0-3N0', 'Var', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('gastric cancer', 'Disease', (96, 110))	('patients', 'Species', '9606', (73, 81))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))
331237	29949666	On the basis of the available data, achievement of ypN0 status appears to be an important predictor of good OS in gastric cancer.	('gastric cancer', 'Disease', (114, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('ypN0 status', 'Var', (51, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('good OS', 'Disease', (103, 110))
331242	29949666	This study analyzing an institutional database from a major cancer center in the United States and the NCDB found equivalent OS among patients with ypT0-3N0 gastric cancer who underwent R0 resection after preoperative therapy.	('gastric cancer', 'Phenotype', 'HP:0012126', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ypT0-3N0', 'Var', (148, 156))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('patients', 'Species', '9606', (134, 142))	('cancer', 'Disease', (60, 66))	('gastric cancer', 'Disease', (157, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('gastric cancer', 'Disease', 'MESH:D013274', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
331244	29949666	Further study is warranted, and most likely a multi-institutional effort will be required, to determine whether other clinicopathologic factors, including preoperative therapy regimen and pathologic tumor regression grade, can be used to better stratify patients with ypT0-3N0 gastric cancer with respect to OS.	('tumor', 'Disease', (199, 204))	('ypT0-3N0', 'Var', (268, 276))	('gastric cancer', 'Disease', 'MESH:D013274', (277, 291))	('gastric cancer', 'Disease', (277, 291))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('gastric cancer', 'Phenotype', 'HP:0012126', (277, 291))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('patients', 'Species', '9606', (254, 262))
331247	29247777	We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies.	('EAC', 'Gene', '1540', (72, 75))	('EAC', 'Gene', (72, 75))	('variants', 'Var', (187, 195))	('variants', 'Var', (32, 40))	('EAC', 'Phenotype', 'HP:0011459', (72, 75))	('BE', 'Phenotype', 'HP:0100580', (66, 68))
331269	29247777	BE and EAC are highly polygenic, with a number of overlapping genetic variants contributing to disease susceptibility.	('contributing', 'Reg', (79, 91))	('EAC', 'Phenotype', 'HP:0011459', (7, 10))	('variants', 'Var', (70, 78))	('EAC', 'Gene', '1540', (7, 10))	('BE', 'Phenotype', 'HP:0100580', (0, 2))	('EAC', 'Gene', (7, 10))
331270	29247777	Taking advantage of the genetic variants identified by recent large genome-wide association studies (GWAS) of BE and EAC, we aimed to derive a polygenic risk score (PRS) and develop a comprehensive risk prediction model based on the PRS and a panel of well-established risk factors for BE or EAC (i.e., GERD symptoms, smoking status, body mass index (BMI), and use of nonsteroidal anti-inflammatory drugs (NSAIDs)).	('BE', 'Phenotype', 'HP:0100580', (286, 288))	('EAC', 'Gene', (117, 120))	('BE', 'Phenotype', 'HP:0100580', (110, 112))	('EAC', 'Phenotype', 'HP:0011459', (292, 295))	('variants', 'Var', (32, 40))	('EAC', 'Gene', '1540', (292, 295))	('EAC', 'Phenotype', 'HP:0011459', (117, 120))	('GERD symptoms', 'Disease', (303, 316))	('EAC', 'Gene', (292, 295))	('EAC', 'Gene', '1540', (117, 120))
331277	29247777	The EAC cases were selected from the UK Stomach and Oesophageal Cancer Study and had International Classification of Diseases coding of malignant neoplasm of the esophagus (C15) and a pathological diagnosis of adenocarcinoma (M8140-8575).	('C15', 'Gene', '51316', (173, 176))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('M8140-8575', 'Var', (226, 236))	('Oesophageal Cancer', 'Disease', 'MESH:D009369', (52, 70))	('C15', 'Gene', (173, 176))	('neoplasm', 'Phenotype', 'HP:0002664', (146, 154))	('Oesophageal Cancer', 'Disease', (52, 70))	('EAC', 'Phenotype', 'HP:0011459', (4, 7))	('malignant neoplasm of the esophagus', 'Disease', 'MESH:D004938', (136, 171))	('EAC', 'Gene', '1540', (4, 7))	('adenocarcinoma', 'Disease', (210, 224))	('neoplasm of the esophagus', 'Phenotype', 'HP:0100751', (146, 171))	('EAC', 'Gene', (4, 7))	('adenocarcinoma', 'Disease', 'MESH:D000230', (210, 224))	('malignant neoplasm of the esophagus', 'Disease', (136, 171))
331280	29247777	We selected genetic variants reported to be associated at genome-wide significance (P < 5x10-8) with risk of BE and/or EAC in published GWAS.	('variants', 'Var', (20, 28))	('EAC', 'Phenotype', 'HP:0011459', (119, 122))	('BE and/or', 'Disease', (109, 118))	('BE', 'Phenotype', 'HP:0100580', (109, 111))	('EAC', 'Gene', '1540', (119, 122))	('EAC', 'Gene', (119, 122))
331283	29247777	In brief, all genotyped samples and variants met the following inclusion criteria: per variant and per sample missingness <= 3%; single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) > 1%; SNPs with P >= 0.0001 in controls and P >= 5 x 10-10 in BE and EAC cases for Hardy-Weinberg equilibrium, no familial relationships, extreme heterozygosity rate, or outliers.	('EAC', 'Phenotype', 'HP:0011459', (273, 276))	('BE', 'Phenotype', 'HP:0100580', (266, 268))	('EAC', 'Gene', '1540', (273, 276))	('Hardy-Weinberg equilibrium', 'Disease', (287, 313))	('EAC', 'Gene', (273, 276))	('SNPs', 'Var', (210, 214))	('variants', 'Var', (36, 44))	('single nucleotide polymorphisms', 'Var', (129, 160))	('variant', 'Var', (87, 94))
331328	29247777	PRS using expanded sets of genetic variants has been reported to improve discrimination for diseases such as coronary heart disease, breast, lung and prostate cancer.	('variants', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('coronary heart disease', 'Disease', (109, 131))	('improve', 'PosReg', (65, 72))	('coronary heart disease', 'Phenotype', 'HP:0001677', (109, 131))	('coronary heart disease', 'Disease', 'MESH:D003324', (109, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (150, 165))	('breast, lung and prostate cancer', 'Disease', 'MESH:D011471', (133, 165))
331330	29247777	In the present study, the PRS was associated with risks of BE and EAC, and accounted for 1.7% and 2.2% phenotypic variance of BE and EAC, respectively.	('EAC', 'Phenotype', 'HP:0011459', (133, 136))	('BE', 'Phenotype', 'HP:0100580', (59, 61))	('PRS', 'Var', (26, 29))	('BE', 'Phenotype', 'HP:0100580', (126, 128))	('EAC', 'Gene', '1540', (133, 136))	('EAC', 'Phenotype', 'HP:0011459', (66, 69))	('EAC', 'Gene', (133, 136))	('EAC', 'Gene', '1540', (66, 69))	('EAC', 'Gene', (66, 69))
331418	28135248	Five percent of cases, mostly with undetectable TERT, harbored ATRX or DAXX alterations, demonstrated elongated telomeres and increased telomeric repeat containing RNA (TERRA).	('alterations', 'Var', (76, 87))	('elongated', 'PosReg', (102, 111))	('ATRX', 'Gene', (63, 67))	('DAXX', 'Gene', '1616', (71, 75))	('TERT', 'Gene', (48, 52))	('telomeric repeat containing RNA', 'MPA', (136, 167))	('ATRX', 'Gene', '546', (63, 67))	('TERT', 'Gene', '7015', (48, 52))	('increased', 'PosReg', (126, 135))	('DAXX', 'Gene', (71, 75))	('telomeres', 'CPA', (112, 121))
331420	28135248	In this group, telomere length positively correlated with TP53 and RB1 mutations.	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('RB1', 'Gene', (67, 70))	('mutations', 'Var', (71, 80))	('correlated', 'Reg', (42, 52))	('telomere length', 'MPA', (15, 30))
331425	28135248	The telomerase enzymatic subunit is encoded by TERT, and while it is transcriptionally silent in most non-neoplastic cells, reactivation may endow a small population of cells with the ability to survive crisis, at which point they become immortalized.	('TERT', 'Gene', (47, 51))	('reactivation', 'Var', (124, 136))	('TERT', 'Gene', '7015', (47, 51))	('ran', 'Gene', (70, 73))	('ran', 'Gene', '5901', (70, 73))
331429	28135248	Deactivating mutations in ATRX and its binding partner DAXX were found tightly correlated with long telomeres in pancreatic neuroendocrine tumors and glioma.	('ATRX', 'Gene', (26, 30))	('DAXX', 'Gene', '1616', (55, 59))	('long telomeres', 'MPA', (95, 109))	('DAXX', 'Gene', (55, 59))	('Deactivating mutations', 'Var', (0, 22))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (124, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ATRX', 'Gene', '546', (26, 30))	('glioma', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('correlated', 'Reg', (79, 89))	('pancreatic neuroendocrine tumors', 'Disease', (113, 145))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (113, 145))
331430	28135248	Recent evidence suggested that loss of ATRX may contribute to ALT by promoting sustained sister telomere cohesion and chromatid exchange.	('ATRX', 'Gene', (39, 43))	('promoting', 'PosReg', (69, 78))	('ATRX', 'Gene', '546', (39, 43))	('loss', 'Var', (31, 35))	('contribute', 'Reg', (48, 58))	('ALT', 'Disease', (62, 65))	('chromatid exchange', 'CPA', (118, 136))
331442	28135248	We curated a core sample set that consisted of 473 T/N pairs with the most comprehensive molecular profiling and an extended set that consisted of 6,835 T/N pairs with varying numbers of cases profiled by each individual platform (Figure 1a, Online Methods).	('835 T/N', 'Var', (149, 156))	('835 T/N', 'SUBSTITUTION', 'None', (149, 156))	('473 T/N', 'Var', (47, 54))	('473 T/N', 'SUBSTITUTION', 'None', (47, 54))
331443	28135248	TERT promoter (TERTp) mutations, predominantly C250T and C228T, were detected in 27% of the extended set for the cases where TERTp status could be determined (n=1,581).	('C250T', 'Var', (47, 52))	('TERT', 'Gene', '7015', (15, 19))	('C250T', 'Mutation', 'c.250C>T', (47, 52))	('C228T', 'Mutation', 'c.228C>T', (57, 62))	('TERTp', 'Gene', (125, 130))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERTp', 'Gene', '7015', (125, 130))	('TERT', 'Gene', (125, 129))	('C228T', 'Var', (57, 62))	('TERTp', 'Gene', (15, 20))	('TERTp', 'Gene', '7015', (15, 20))	('TERT', 'Gene', '7015', (125, 129))	('TERT', 'Gene', (15, 19))
331444	28135248	In agreement with previous reports; high incidence of TERTp mutations was found in bladder cancer (42/60, 70%), liver cancer (73/162, 45%), melanoma (93/129, 72%), lower grade glioma (127/285, 45%) and glioblastoma (25/28, 89%, Supplementary Figure 4a).	('glioblastoma', 'Disease', 'MESH:D005909', (202, 214))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('TERTp', 'Gene', (54, 59))	('TERTp', 'Gene', '7015', (54, 59))	('glioma', 'Disease', (176, 182))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioblastoma', 'Disease', (202, 214))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('liver cancer', 'Disease', 'MESH:D006528', (112, 124))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('liver cancer', 'Phenotype', 'HP:0002896', (112, 124))	('bladder cancer', 'Disease', (83, 97))	('liver cancer', 'Disease', (112, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (60, 69))
331450	28135248	In the majority of TERTp structural variants (65%), at least one predicted super enhancer was found to directly overlap with the juxtaposed position (Supplementary Table 3).	('TERTp', 'Gene', (19, 24))	('TERTp', 'Gene', '7015', (19, 24))	('variants', 'Var', (36, 44))
331459	28135248	Taken together, we found somatic TERT alterations including TERTp mutations, TERT amplifications and TERT structural variants involving gene promoter or gene body in 32% of core set samples.	('TERT', 'Gene', '7015', (101, 105))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (60, 64))	('TERT', 'Gene', '7015', (77, 81))	('variants', 'Var', (117, 125))	('TERT', 'Gene', (101, 105))	('TERTp', 'Gene', (60, 65))	('TERTp', 'Gene', '7015', (60, 65))	('TERT', 'Gene', (60, 64))
331465	28135248	As previously described in pediatric brain tumors, TERT promoter probe cg11625005 demonstrated a strong correlation with TERT expression (Rho=0.52, FDR<0.0001).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('brain tumors', 'Phenotype', 'HP:0030692', (37, 49))	('pediatric brain tumors', 'Disease', (27, 49))	('TERT', 'Gene', (51, 55))	('correlation', 'Interaction', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cg11625005', 'Var', (71, 81))	('TERT', 'Gene', '7015', (51, 55))	('TERT', 'Gene', (121, 125))	('TERT', 'Gene', '7015', (121, 125))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (27, 49))
331470	28135248	TERTp methylation (two-sided t-test P<0.05) and TERTp mutations (two-sided t-test P<0.0001) were associated with relative TL shortening compared to other types of TERT alterations (Supplementary Figure 5c).	('TERTp', 'Gene', '7015', (0, 5))	('TERT', 'Gene', '7015', (163, 167))	('TERTp', 'Gene', (48, 53))	('TERTp', 'Gene', '7015', (48, 53))	('mutations', 'Var', (54, 63))	('TERT', 'Gene', (0, 4))	('shortening', 'NegReg', (125, 135))	('TERT', 'Gene', (48, 52))	('TERT', 'Gene', '7015', (0, 4))	('methylation', 'Var', (6, 17))	('TERT', 'Gene', (163, 167))	('TERT', 'Gene', '7015', (48, 52))	('TERTp', 'Gene', (0, 5))
331474	28135248	Focal TERC amplifications were associated with increased TERC expression (two-sided t-test P<0.0001) (Supplementary Figure 5d), and were enriched in TERT expressing samples (Odds Ratio (OR) 2.59, Fisher's Exact P<0.0001).	('TERT', 'Gene', '7015', (149, 153))	('TERC', 'Gene', (57, 61))	('TERC', 'Gene', (6, 10))	('amplifications', 'Var', (11, 25))	('TERC', 'Gene', '7012', (57, 61))	('increased', 'PosReg', (47, 56))	('TERT', 'Gene', (149, 153))	('TERC', 'Gene', '7012', (6, 10))
331484	28135248	TERC amplification was additionally associated with higher telomerase signature scores compared to non-amplified samples (two-sided t-test, P<0.0001), which may in part be explained by the co-expression patterns of TERT and TERC.	('TERT', 'Gene', '7015', (215, 219))	('amplification', 'Var', (5, 18))	('TERC', 'Gene', (0, 4))	('TERC', 'Gene', (224, 228))	('higher', 'PosReg', (52, 58))	('telomerase signature scores', 'MPA', (59, 86))	('TERC', 'Gene', '7012', (0, 4))	('TERT', 'Gene', (215, 219))	('TERC', 'Gene', '7012', (224, 228))
331487	28135248	We found alterations of ATRX and IDH1 as the most significantly associated with relative TL elongation (both FDR<0.0001; Figure 3a).	('associated', 'Reg', (64, 74))	('IDH1', 'Gene', (33, 37))	('ATRX', 'Gene', (24, 28))	('alterations', 'Var', (9, 20))	('IDH1', 'Gene', '3417', (33, 37))	('ATRX', 'Gene', '546', (24, 28))
331488	28135248	Since IDH1 mutations frequently co-occur with ATRX in glioma, we tested a model with both tumor type and IDH1 as covariates, and found IDH1 no longer associated with TL ratio (two-sided t-test P=0.15).	('associated', 'Reg', (150, 160))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('mutations', 'Var', (11, 20))	('IDH1', 'Gene', '3417', (6, 10))	('ATRX', 'Gene', '546', (46, 50))	('IDH1', 'Gene', (135, 139))	('IDH1', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH1', 'Gene', '3417', (135, 139))	('IDH1', 'Gene', '3417', (105, 109))	('glioma', 'Disease', (54, 60))	('ATRX', 'Gene', (46, 50))	('IDH1', 'Gene', (6, 10))	('TL ratio', 'MPA', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
331490	28135248	Alterations of the VHL were found to be associated with relative TL shortening (TL ratio 0.7, 95%CI 0.61-0.8, FDR<0.0001).	('relative TL shortening', 'MPA', (56, 78))	('Alterations', 'Var', (0, 11))	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('VHL', 'Disease', (19, 22))
331493	28135248	A linear regression model showed that in addition to older age, positive TERRA expression, TP53 deletion, TP53 mutations, ATRX deletion, ATRX structural variants and absent/undetectable TERT expression were all independently associated with relative TL elongation (Figure 3b-c).	('mutations', 'Var', (111, 120))	('ATRX', 'Gene', (137, 141))	('TP53', 'Gene', (91, 95))	('positive', 'PosReg', (64, 72))	('ATRX', 'Gene', (122, 126))	('ATRX', 'Gene', '546', (122, 126))	('TP53', 'Gene', '7157', (91, 95))	('ATRX', 'Gene', '546', (137, 141))	('deletion', 'Var', (127, 135))	('deletion', 'Var', (96, 104))	('variants', 'Var', (153, 161))	('TERT', 'Gene', '7015', (186, 190))	('associated', 'Reg', (225, 235))	('TERT', 'Gene', (186, 190))	('relative TL elongation', 'CPA', (241, 263))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
331494	28135248	Although DAXX has been linked to telomere length and ALT, DAXX mutations (n=51/6,835) and deletions (n=5/6,835) did not associate with TL.	('mutations', 'Var', (63, 72))	('DAXX', 'Gene', (58, 62))	('DAXX', 'Gene', '1616', (9, 13))	('deletions', 'Var', (90, 99))	('DAXX', 'Gene', (9, 13))	('DAXX', 'Gene', '1616', (58, 62))
331496	28135248	In addition to non-synonymous mutations and deletions, we detected ATRX structural variants from WGS data in 5% of the core set samples (n=26/473).	('variants', 'Var', (83, 91))	('ATRX', 'Gene', (67, 71))	('ATRX', 'Gene', '546', (67, 71))
331502	28135248	We observed a significant decrease in ATRX expression in samples showing mutations, deletions, fusions and structural variants compared to cases with wild type ATRX (Figure 4a).	('ATRX', 'Gene', '546', (160, 164))	('decrease', 'NegReg', (26, 34))	('structural variants', 'Var', (107, 126))	('ATRX', 'Gene', (38, 42))	('fusions', 'Var', (95, 102))	('ATRX', 'Gene', (160, 164))	('ATRX', 'Gene', '546', (38, 42))	('expression', 'MPA', (43, 53))	('mutations', 'Var', (73, 82))	('deletions', 'Var', (84, 93))
331503	28135248	We found that all of types of ATRX alteration associated with significantly longer TL compared to wild type ATRX, consistent with the previously established association between ATRX deactivation and ALT (Figure 4b).	('ATRX', 'Gene', (30, 34))	('ATRX', 'Gene', '546', (177, 181))	('longer', 'PosReg', (76, 82))	('ATRX', 'Gene', (108, 112))	('ATRX', 'Gene', '546', (30, 34))	('alteration', 'Var', (35, 45))	('ATRX', 'Gene', '546', (108, 112))	('ATRX', 'Gene', (177, 181))
331504	28135248	Recent studies found that ATRX knockdown resulted in elevated levels of telomeric repeat containing RNA (TERRA).	('ATRX', 'Gene', '546', (26, 30))	('ATRX', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))	('elevated', 'PosReg', (53, 61))
331505	28135248	Our results demonstrate a significantly higher fraction of TERRA expressing samples in all groups of ATRX altered samples (Figure 4c, Fisher's Exact test P<0.05) compared to the group of ATRX wild type samples.	('ATRX', 'Gene', '546', (187, 191))	('higher', 'PosReg', (40, 46))	('TERRA expressing', 'MPA', (59, 75))	('ATRX', 'Gene', (187, 191))	('ATRX', 'Gene', (101, 105))	('ATRX', 'Gene', '546', (101, 105))	('altered', 'Var', (106, 113))
331509	28135248	ATRX/DAXX mutations were found in 210 TERT expressing samples, representing 3% of the cohort.	('ATRX', 'Gene', (0, 4))	('DAXX', 'Gene', '1616', (5, 9))	('TERT', 'Gene', (38, 42))	('DAXX', 'Gene', (5, 9))	('ATRX', 'Gene', '546', (0, 4))	('TERT', 'Gene', '7015', (38, 42))	('mutations', 'Var', (10, 19))
331510	28135248	These events were in majority non-truncating, while ATRX/DAXX mutations in TERT-negative cases were mostly truncating (Supplementary Methods, Supplementary Figure 9a).	('non-truncating', 'MPA', (30, 44))	('mutations', 'Var', (62, 71))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('DAXX', 'Gene', '1616', (57, 61))	('ATRX', 'Gene', (52, 56))	('ATRX', 'Gene', '546', (52, 56))	('DAXX', 'Gene', (57, 61))
331511	28135248	TERT-expressing ATRX/DAXX mutants showed higher telomerase signature scores compared to ATRX/DAXX altered samples lacking TERT expression (Supplementary Figure 9b).	('TERT', 'Gene', (122, 126))	('DAXX', 'Gene', '1616', (93, 97))	('TERT', 'Gene', '7015', (122, 126))	('DAXX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (88, 92))	('ATRX', 'Gene', '546', (16, 20))	('TERT', 'Gene', (0, 4))	('DAXX', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (0, 4))	('telomerase signature scores', 'MPA', (48, 75))	('mutants', 'Var', (26, 33))	('higher', 'PosReg', (41, 47))	('DAXX', 'Gene', '1616', (21, 25))	('ATRX', 'Gene', (88, 92))	('ATRX', 'Gene', (16, 20))
331525	28135248	In addition to IDH1 and TP53, RB1 (TL ratio 1.5, 95%CI 1.2-1.87, FDR=0.001) and MDM2 (TL ratio 1.51, 95%CI 1.14-2, FDR=0.01) were revealed to associate with relatively long TLs.	('MDM2', 'Gene', (80, 84))	('IDH1', 'Gene', (15, 19))	('TP53', 'Gene', (24, 28))	('IDH1', 'Gene', '3417', (15, 19))	('RB1', 'Var', (30, 33))	('MDM2', 'Gene', '4193', (80, 84))	('TP53', 'Gene', '7157', (24, 28))
331526	28135248	The finding of RB1 is consistent with experimental data demonstrating markedly elongated telomeres in Rb1 deficient mice independent of telomerase.	('mice', 'Species', '10090', (116, 120))	('telomeres', 'CPA', (89, 98))	('deficient', 'Var', (106, 115))	('elongated', 'PosReg', (79, 88))	('Rb1', 'Gene', (102, 105))	('Rb1', 'Gene', '19645', (102, 105))
331527	28135248	In the opposite direction, somatic alterations in PBRM1 (TL ratio 0.67, 95%CI 0.55-0.83, FDR=0.001), NRAS (TL ratio 0.68, 95%CI 0.52-0.9, FDR=0.02) and VHL (TL ratio 0.7, 95%CI 0.57-0.85, FDR=0.002) were associated with relative TL shortening (Figure 5d).	('NRAS', 'Gene', (101, 105))	('PBRM1', 'Gene', (50, 55))	('alterations', 'Var', (35, 46))	('PBRM1', 'Gene', '55193', (50, 55))	('NRAS', 'Gene', '4893', (101, 105))	('VHL', 'Disease', (152, 155))	('VHL', 'Disease', 'MESH:D006623', (152, 155))
331537	28135248	This paradoxical association between TERT promoter methylation and increased TERT expression may result from loss of CTCF binding, a transcriptional repressor reported to bind to the unmethylated TERT promoter.	('TERT', 'Gene', (37, 41))	('binding', 'Interaction', (122, 129))	('ran', 'Gene', (134, 137))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (37, 41))	('TERT', 'Gene', '7015', (77, 81))	('ran', 'Gene', '5901', (134, 137))	('TERT', 'Gene', (196, 200))	('loss', 'NegReg', (109, 113))	('CTCF', 'Gene', (117, 121))	('TERT', 'Gene', '7015', (196, 200))	('increased', 'PosReg', (67, 76))	('methylation', 'Var', (51, 62))	('CTCF', 'Gene', '10664', (117, 121))
331538	28135248	Structural TERT variants have been documented and we detected these across several novel cancer types, including sarcoma, prostate and liver carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('liver carcinoma', 'Phenotype', 'HP:0001402', (135, 150))	('liver carcinoma', 'Disease', (135, 150))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('prostate', 'Disease', (122, 130))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('liver carcinoma', 'Disease', 'MESH:D006528', (135, 150))	('sarcoma', 'Disease', (113, 120))	('detected', 'Reg', (53, 61))	('cancer', 'Disease', (89, 95))	('TERT', 'Gene', (11, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('TERT', 'Gene', '7015', (11, 15))	('variants', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
331539	28135248	Hepatitis B virus and adeno-associated virus type 2 integration in TERT was found in about 5% of hepatocellular carcinomas.	('TERT', 'Gene', (67, 71))	('integration', 'Var', (52, 63))	('found', 'Reg', (76, 81))	('TERT', 'Gene', '7015', (67, 71))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (97, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (97, 121))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (97, 122))	('Hepatitis B virus', 'Species', '10407', (0, 17))	('adeno-associated virus type 2', 'Species', '10804', (22, 51))	('hepatocellular carcinomas', 'Disease', (97, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('Hepatitis B virus', 'Disease', (0, 17))
331544	28135248	An estimated 5-10% of TERC and TERRA carry the poly-A tails required for oligo-dT primer based RNA sequencing quantification.	('poly-A', 'Chemical', 'MESH:D011061', (47, 53))	('TERC', 'Gene', '7012', (22, 26))	('TERC', 'Gene', (22, 26))	('poly-A tails', 'Var', (47, 59))
331549	28135248	Deactivation of ATRX and/or DAXX has been related to ALT, and was observed in five percent of the cases in our core set.	('Deactivation', 'Var', (0, 12))	('ATRX', 'Gene', '546', (16, 20))	('DAXX', 'Gene', (28, 32))	('ALT', 'Disease', (53, 56))	('DAXX', 'Gene', '1616', (28, 32))	('related', 'Reg', (42, 49))	('ATRX', 'Gene', (16, 20))
331550	28135248	A detailed review of ATRX somatic changes revealed a large spectrum of potentially protein truncating changes, including inactivating mutations, deletions and structural variants.	('inactivating mutations', 'Var', (121, 143))	('protein truncating changes', 'MPA', (83, 109))	('structural variants', 'Var', (159, 178))	('ATRX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (21, 25))	('deletions', 'Var', (145, 154))
331552	28135248	Our analysis reinforced the association of inactivate ATRX/DAXX and ALT, demonstrating relative TL elongation in samples affected by somatic alterations in one of these two genes and a higher frequency of TERRA expression in tumors with these alterations.	('alterations', 'Var', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('DAXX', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ATRX', 'Gene', '546', (54, 58))	('TL elongation', 'CPA', (96, 109))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('affected', 'Reg', (121, 129))	('DAXX', 'Gene', '1616', (59, 63))	('tumors', 'Disease', (225, 231))	('ATRX', 'Gene', (54, 58))	('inactivate', 'Var', (43, 53))
331555	28135248	Such mechanisms may involve some RB1 and TP53 alterations, as somatic changes in these genes were associated with telomere elongation within this group.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('telomere elongation', 'CPA', (114, 133))	('RB1', 'Gene', (33, 36))	('changes', 'Var', (70, 77))	('associated', 'Reg', (98, 108))
331574	28135248	There was sufficient coverage for TERTp mutation calling in 903 samples, and we detected TERTp mutations in n=183, including C228T (n=128), C250T (n=49), C242/243T (n=5) and C169T (n=1).	('TERTp', 'Gene', '7015', (89, 94))	('C250T', 'Var', (140, 145))	('C250T', 'Mutation', 'c.250C>T', (140, 145))	('TERTp', 'Gene', '7015', (34, 39))	('C228T', 'Var', (125, 130))	('C169T', 'Var', (174, 179))	('detected', 'Reg', (80, 88))	('C169T', 'Mutation', 'c.169C>T', (174, 179))	('C242/243T', 'Var', (154, 163))	('C228T', 'Mutation', 'c.228C>T', (125, 130))	('TERTp', 'Gene', (89, 94))	('TERTp', 'Gene', (34, 39))
331577	28135248	Because we were only interested in variants involving TERT (chr5:1253287-1315162, including 20kb upstream of the TSS) and ATRX (chrX:76760356-77041719), variants not overlapping one of these regions were excluded.	('ATRX', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (54, 58))	('variants', 'Var', (35, 43))	('chrX:76760356-77041719', 'STRUCTURAL_ABNORMALITY', 'None', (128, 150))	('chr5:1253287-1315162', 'STRUCTURAL_ABNORMALITY', 'None', (60, 80))	('ATRX', 'Gene', '546', (122, 126))	('TERT', 'Gene', (54, 58))
331588	28135248	This analysis found overlapping super-enhancers in 11/17 TERTp structural variants, and this was significantly more than expected by chance (Chi-Square test P=0.001).	('super-enhancers', 'PosReg', (32, 47))	('variants', 'Var', (74, 82))	('TERTp', 'Gene', (57, 62))	('TERTp', 'Gene', '7015', (57, 62))
331589	28135248	For each structural variant proximal (adjacent to the TERT promoter) and distal breakpoint (juxtaposed to the TERT promoter) we calculated the number of reads mapping to each of three histone marks (H3K27ac, H3K27me3 and H3Kme1) individually within each tissue and cell/type.	('H3Kme1', 'Var', (221, 227))	('H3K27ac', 'Var', (199, 206))	('H3K27me3', 'Var', (208, 216))	('TERT', 'Gene', '7015', (54, 58))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('TERT', 'Gene', (54, 58))
331601	28135248	Spearman correlation was used to associate TERT expression and methylation, and to correlate gene expression and TL.	('TERT', 'Gene', (43, 47))	('methylation', 'Var', (63, 74))	('TERT', 'Gene', '7015', (43, 47))
331682	27599460	The areas under the curve predicting 3-year OS were 0.603 for CONUT, 0.561 for PLR, 0.564 for NLR, and 0.563 for GPS.	('CONUT', 'Disease', (62, 67))	('0.564', 'Var', (84, 89))	('OS', 'Chemical', '-', (44, 46))	('0.563', 'Var', (103, 108))
331683	27599460	The high-CONUT group was significantly associated with lower BMI, high-PLR, high-NLR, and GPS1/2 groups.	('GPS1/2', 'Gene', '2873;2874', (90, 96))	('GPS1/2', 'Gene', (90, 96))	('lower BMI', 'Phenotype', 'HP:0045082', (55, 64))	('high-CONUT', 'Var', (4, 14))	('lower', 'NegReg', (55, 60))	('high-PLR', 'Disease', (66, 74))	('BMI', 'MPA', (61, 64))
331684	27599460	On univariate analysis, high-CONUT, high-PLR, high-NLR, and GPS 1/2 groups were significantly associated with poorer OS and RFS.	('RFS', 'CPA', (124, 127))	('high-PLR', 'Var', (36, 44))	('poorer OS', 'CPA', (110, 119))	('OS', 'Chemical', '-', (117, 119))	('GPS 1/2', 'Gene', (60, 67))	('high-CONUT', 'Var', (24, 34))	('high-NLR', 'Var', (46, 54))	('GPS 1/2', 'Gene', '2873;2874', (60, 67))
331723	27599460	The OS and RFS rates were significantly lower in the high-CONUT (p < 0.001, p = 0.002), high-PLR (p = 0.023, p = 0.031), high-NLR (p = 0.016, p = 0.028), and GPS 1/2 (p < 0.001, p = 0.004) groups.	('high-CONUT', 'Var', (53, 63))	('OS', 'Chemical', '-', (4, 6))	('GPS 1/2', 'Gene', (158, 165))	('high-PLR', 'Var', (88, 96))	('GPS 1/2', 'Gene', '2873;2874', (158, 165))	('RFS rates', 'CPA', (11, 20))	('lower', 'NegReg', (40, 45))
331730	27599460	The proportion of patients who died of primary disease was significantly higher in the high-CONUT group than in the low-CONUT group (47.1 % vs. 20.8 %, p = 0.015), whereas there were no significant differences in the rates of patients who died of other disease, other cancer, and postoperative complications.	('cancer', 'Disease', (268, 274))	('primary disease', 'Disease', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('patients', 'Species', '9606', (226, 234))	('patients', 'Species', '9606', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('high-CONUT', 'Var', (87, 97))	('higher', 'PosReg', (73, 79))
331738	27599460	Indeed, the high-CONUT group was significantly associated with lower BMI, high-PLR, high-NLR, and GPS1/2.	('GPS1/2', 'Gene', '2873;2874', (98, 104))	('lower BMI', 'Phenotype', 'HP:0045082', (63, 72))	('lower', 'NegReg', (63, 68))	('high-NLR', 'MPA', (84, 92))	('BMI', 'MPA', (69, 72))	('GPS1/2', 'Gene', (98, 104))	('high-CONUT', 'Var', (12, 22))	('high-PLR', 'MPA', (74, 82))
331761	27599460	In the present study, the high-CONUT group was significantly associated with primary cancer death and poorer RFS.	('high-CONUT', 'Var', (26, 36))	('primary cancer death', 'Disease', 'MESH:D003643', (77, 97))	('primary cancer death', 'Disease', (77, 97))	('associated', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
331772	26459454	Main parameters analyzed were (1) LES: resting pressure (restP), 4-second integrated relaxation pressure; (2) esophageal body (EB): contractile integral of distal segment with myotomy (CI-DM) and proximal segment without myotomy (CI-PNM); and (3) upper esophageal sphincter (UES): relaxation pressure (UES-RP).	('upper esophageal sphincter', 'Disease', (247, 273))	('relaxation', 'MPA', (281, 291))	('myotomy', 'Var', (176, 183))	('CI-PNM', 'Chemical', '-', (230, 236))	('contractile', 'MPA', (132, 143))	('upper esophageal sphincter', 'Disease', 'MESH:D009122', (247, 273))
331776	26459454	Myotomy of the distal esophagus would attenuate proximal EB contraction and assist UES relaxation in achalasia patients after POEM.	('achalasia', 'Disease', (101, 110))	('achalasia', 'Disease', 'MESH:D004931', (101, 110))	('attenuate', 'NegReg', (38, 47))	('UES relaxation', 'CPA', (83, 97))	('patients', 'Species', '9606', (111, 119))	('achalasia', 'Phenotype', 'HP:0002571', (101, 110))	('assist', 'PosReg', (76, 82))	('Myotomy', 'Var', (0, 7))	('proximal EB contraction', 'MPA', (48, 71))
331809	26459454	POEM lowered the CI of EB contraction significantly in both distal segments with myotomy and proximal segments without myotomy (CI-DM: 43.95 [0.29-743.40] vs 3.79 [0-665.70] mmHg sec cm, P < 0.001; CI-PNM:1337.73 [2.30-9856.31] vs 480.85 [2.16-3121.83] mmHg sec cm, P < 0.001).	('lowered', 'NegReg', (5, 12))	('CI-PNM', 'Chemical', '-', (198, 204))	('myotomy', 'Var', (81, 88))
331814	26459454	The change of UES-RP was positively correlated with the CI of distal EB with myotomy and proximal EB without myotomy (CI-DM: correlation coefficient = 0.705, P < 0.001; CI-PNM: correlation coefficient = 0.755, P < 0.001).	('CI-PNM', 'Chemical', '-', (169, 175))	('distal EB', 'Disease', (62, 71))	('myotomy', 'Var', (77, 84))	('UES-RP', 'Gene', (14, 20))
331822	26459454	Wauters et al first reported that balloon dilation of the LES affects intraesophageal and UES pressures in a cohort of 50 achalasia patients and pointed out that there is a neural feedback mechanism existing between the tension in the esophageal wall and UES relaxation.	('achalasia', 'Phenotype', 'HP:0002571', (122, 131))	('intraesophageal', 'MPA', (70, 85))	('UES pressures', 'MPA', (90, 103))	('achalasia', 'Disease', (122, 131))	('affects', 'Reg', (62, 69))	('achalasia', 'Disease', 'MESH:D004931', (122, 131))	('balloon dilation', 'Var', (34, 50))	('patients', 'Species', '9606', (132, 140))
331931	25663893	Several hypotheses for these anticarcinogenic and antitumor effects have been proposed, including inhibition of nucleic acid synthesis, inhibition of free radical chain reactions and the generation of reactive oxygen species through eliminating free radicals, as well as conversion to vitamin A, which enhances carcinogen metabolism.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (201, 224))	('rat', 'Species', '10116', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('vitamin A', 'Chemical', 'MESH:D014801', (285, 294))	('eliminating', 'NegReg', (233, 244))	('carcinogen metabolism', 'MPA', (311, 332))	('nucleic acid synthesis', 'MPA', (112, 134))	('generation of reactive oxygen species', 'MPA', (187, 224))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('free radical chain reactions', 'MPA', (150, 178))	('enhances', 'PosReg', (302, 310))	('free radicals', 'MPA', (245, 258))	('inhibition', 'NegReg', (98, 108))	('free radical', 'Chemical', 'MESH:D005609', (245, 257))	('free radical', 'Chemical', 'MESH:D005609', (150, 162))	('conversion', 'Var', (271, 281))	('inhibition', 'NegReg', (136, 146))	('anticarcinogenic', 'CPA', (29, 45))	('tumor', 'Disease', (54, 59))
331940	25663893	Disorder in cell cycle regulation causes the endless proliferation of cells, leading to cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('causes', 'Reg', (34, 40))	('leading to', 'Reg', (77, 87))	('rat', 'Species', '10116', (60, 63))	('cell', 'Protein', (12, 16))	('Disorder', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
331944	25663893	However, certain studies have reported that crocetin induces cell cycle arrest in the G1 or G2 phase.	('cell cycle arrest in the G1', 'CPA', (61, 88))	('crocetin', 'Chemical', 'MESH:C010561', (44, 52))	('crocetin', 'Var', (44, 52))
331946	25663893	Apoptosis, or programmed cell death, is a gene-regulated phenomenon, and disequilibrium between cell proliferation and apoptosis is known to cause various diseases, including cancer.	('rat', 'Species', '10116', (108, 111))	('cause', 'Reg', (141, 146))	('cancer', 'Disease', (175, 181))	('Apoptosis', 'Disease', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('disequilibrium', 'Var', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
331965	25663893	There is a growing body of evidence indicating that crocetin may downregulate matrix metalloproteinases and intercellular adhesion molecule-1, and inhibit angiogenesis.	('crocetin', 'Chemical', 'MESH:C010561', (52, 60))	('intercellular adhesion molecule-1', 'Gene', (108, 141))	('downregulate', 'NegReg', (65, 77))	('inhibit', 'NegReg', (147, 154))	('crocetin', 'Var', (52, 60))	('angiogenesis', 'CPA', (155, 167))	('intercellular adhesion molecule-1', 'Gene', '3383', (108, 141))	('matrix', 'Protein', (78, 84))
331970	21217778	A novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors The critical 8p22 tumor suppressor deleted in liver cancer 1 (DLC1) is frequently inactivated by aberrant CpG methylation and/or genetic deletion and implicated in tumorigeneses of multiple tumor types.	('liver cancer', 'Disease', 'MESH:D006528', (178, 190))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('DLC1', 'Gene', '10395', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('DLC1', 'Gene', '10395', (194, 198))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('liver cancer', 'Phenotype', 'HP:0002896', (178, 190))	('DLC1', 'Gene', (50, 54))	('DLC1', 'Gene', (194, 198))	('genetic deletion', 'Var', (261, 277))	('liver cancer', 'Disease', (178, 190))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (296, 301))	('tumors', 'Disease', (125, 131))	('aberrant', 'Var', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('inactivated', 'NegReg', (214, 225))	('suppresses', 'NegReg', (55, 65))	('tumor', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (322, 327))
331974	21217778	CpG methylation of the DLC1-i4 promoter is associated with its silencing in tumor cells and was detected in 38-100% of multiple primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('detected', 'Reg', (96, 104))	('silencing', 'MPA', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('primary tumors', 'Disease', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('primary tumors', 'Disease', 'MESH:D009369', (128, 142))	('tumor', 'Disease', (136, 141))	('DLC1-i4', 'Gene', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
331979	21217778	Carcinogenesis involves multiple genetic/epigenetic events including the activation of oncogenes and inactivation of tumor suppressor genes (TSGs).	('Carcinogenesis', 'Disease', (0, 14))	('activation', 'PosReg', (73, 83))	('TSG', 'Gene', (141, 144))	('oncogenes', 'Protein', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('TSG', 'Gene', '57045', (141, 144))	('inactivation', 'Var', (101, 113))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
331980	21217778	In addition to genetic mutations, a growing body of evidence has shown that TSG inactivation occurs frequently through promoter CpG methylation, resulting in TSG silencing and subsequent loss of function, thereby contributing to neoplastic transformation.	('TSG', 'Gene', '57045', (158, 161))	('contributing', 'Reg', (213, 225))	('TSG', 'Gene', (76, 79))	('neoplastic transformation', 'CPA', (229, 254))	('inactivation', 'NegReg', (80, 92))	('loss of function', 'NegReg', (187, 203))	('TSG', 'Gene', '57045', (76, 79))	('TSG', 'Gene', (158, 161))	('methylation', 'Var', (132, 143))	('silencing', 'NegReg', (162, 171))
331981	21217778	Aberrant CpG methylation of TSG-associated CpG islands is a characteristic hallmark of tumor genomic DNA, and examples of methylation silenced TSGs include p16, MLH1, VHL, RAR-beta, SOCS1, PCDH10, RASAL and so on.	('TSG', 'Gene', '57045', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Aberrant', 'Var', (0, 8))	('PCDH10', 'Gene', (189, 195))	('VHL', 'Disease', (167, 170))	('VHL', 'Disease', 'MESH:D006623', (167, 170))	('methylation', 'Var', (122, 133))	('TSG', 'Gene', '57045', (28, 31))	('tumor', 'Disease', (87, 92))	('TSG', 'Gene', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('TSG', 'Gene', (28, 31))
331982	21217778	Deleted in liver cancer 1 (DLC1) gene (also known as ARHGAP7, STARD12, HP and p122-RhoGAP) was isolated by representational difference analysis from a sample of human hepatocellular carcinoma (HCC), and proposed as a candidate TSG because of its frequent deletion in hepatocellular carcinoma tumors and cell lines.	('human', 'Species', '9606', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (267, 291))	('DLC1', 'Gene', (27, 31))	('hepatocellular carcinoma tumors', 'Disease', 'MESH:D006528', (267, 298))	('TSG', 'Gene', '57045', (227, 230))	('STARD12', 'Gene', '10395', (62, 69))	('hepatocellular carcinoma', 'Disease', (167, 191))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('TSG', 'Gene', (227, 230))	('STARD12', 'Gene', (62, 69))	('liver cancer', 'Disease', 'MESH:D006528', (11, 23))	('ARHGAP7', 'Gene', '10395', (53, 60))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (267, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('liver cancer', 'Phenotype', 'HP:0002896', (11, 23))	('hepatocellular carcinoma tumors', 'Disease', (267, 298))	('liver cancer', 'Disease', (11, 23))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (167, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('HCC', 'Phenotype', 'HP:0001402', (193, 196))	('deletion', 'Var', (255, 263))	('ARHGAP7', 'Gene', (53, 60))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (167, 191))
331983	21217778	Located at 8p22, a site of recurrent deletion in breast, lung and prostate cancers, DLC1 encodes a protein of 1091-aa (amino acid) with extensive homology (86%) to the rat p122-RhoGAP, a GTPase-activating protein (GAP) specific for RhoA and Cdc42 that are involved in the regulation of cellular cytoskeleton organization and other functions.	('Cdc42', 'Gene', (241, 246))	('Cdc42', 'Gene', '64465', (241, 246))	('deletion', 'Var', (37, 45))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('RhoA', 'Gene', (232, 236))	('rat', 'Species', '10116', (168, 171))	('GTP', 'Chemical', 'MESH:D006160', (187, 190))	('RhoA', 'Gene', '117273', (232, 236))	('prostate cancers', 'Phenotype', 'HP:0012125', (66, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('DLC1', 'Gene', (84, 88))	('lung and prostate cancers', 'Disease', 'MESH:D011471', (57, 82))
331988	21217778	Loss of RhoGAP activity leads to aberrant activation of GTP-bound Rho proteins, which are involved in the regulation of the cell cycle, adhesion, morphogenesis, polarity and migration; and dysregulation of GTP-bound Rho proteins have been implicated in tumorigenesis.	('GTP-bound Rho proteins', 'Protein', (56, 78))	('rat', 'Species', '10116', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('GTP', 'Chemical', 'MESH:D006160', (206, 209))	('dysregulation', 'Var', (189, 202))	('activity', 'MPA', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('Loss', 'NegReg', (0, 4))	('GTP', 'Chemical', 'MESH:D006160', (56, 59))	('implicated', 'Reg', (239, 249))	('activation', 'PosReg', (42, 52))	('tumor', 'Disease', (253, 258))	('RhoGAP', 'Gene', (8, 14))
331991	21217778	In addition, DLC1 knockdown in the background of c-myc overexpression promotes the formation of liver tumors in a murine model.	('murine', 'Species', '10090', (114, 120))	('knockdown', 'Var', (18, 27))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('DLC1', 'Gene', (13, 17))	('liver tumors', 'Disease', 'MESH:D008113', (96, 108))	('expression', 'Species', '29278', (59, 69))	('liver tumors', 'Phenotype', 'HP:0002896', (96, 108))	('liver tumors', 'Disease', (96, 108))	('promotes', 'PosReg', (70, 78))	('formation of', 'CPA', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
331993	21217778	Here, we report the characterization of this novel isoform (designated DLC1-isoform 4 (DLC1-i4)), its mRNA expression and epigenetic alterations in multiple carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('expression', 'Species', '29278', (107, 117))	('multiple carcinomas', 'Disease', 'MESH:C537656', (148, 167))	('multiple carcinomas', 'Disease', (148, 167))	('rat', 'Species', '10116', (137, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('epigenetic alterations', 'Var', (122, 144))
331996	21217778	Subsequent BLAST searches identified 15 expressed sequence tags (Genbank accession: DA853751, DA409883, DA403097, DA401187, DA231722, DA328255, DA334650, BP287999, BP285601, CN388450, BX474714, BX474696, BP238467, CN388449 and BP287477) with their transcriptional start sites close to the two established by us.	('DA853751', 'Var', (84, 92))	('DA231722', 'Var', (124, 132))	('BX474714', 'Var', (184, 192))	('CN388450', 'Var', (174, 182))	('BP287477', 'Var', (227, 235))	('DA403097', 'Var', (104, 112))	('DA409883', 'Var', (94, 102))	('DA334650', 'Var', (144, 152))	('DA401187', 'Var', (114, 122))	('BX474696', 'Var', (194, 202))	('BP287999', 'Var', (154, 162))	('DA328255', 'Var', (134, 142))	('CN388449', 'CellLine', 'CVCL:B396', (214, 222))	('BP285601', 'Var', (164, 172))	('BP238467', 'Var', (204, 212))	('CN388449', 'Var', (214, 222))
332002	21217778	Potential transcription factor (TF)-binding sites predicted by three TF search programs (TFSEARCH, MotifSearch and MatInspector) suggest that the DLC1-i4 promoter might be regulated by TP53, E2F, STAT and heat-shock factor (Figure 2a).	('STAT', 'Disease', (196, 200))	('shock', 'Phenotype', 'HP:0031273', (210, 215))	('TP53', 'Gene', (185, 189))	('DLC1-i4', 'Gene', (146, 153))	('STAT', 'Disease', 'None', (196, 200))	('E2F', 'Var', (191, 194))	('TP53', 'Gene', '7157', (185, 189))
332007	21217778	Co-transfection of DLC1-i4 promoter construct with mutant p53 expression plasmids (G245C and R248W) into HCT116-p53KO, showed that only wild-type p53 could upregulate DLC1-i4 and control p21 promoter activities (10-fold and 2.5-fold, respectively) (Figure 2d).	('HCT116', 'CellLine', 'CVCL:0291', (105, 111))	('upregulate', 'PosReg', (156, 166))	('G245C', 'Mutation', 'rs28934573', (83, 88))	('expression', 'Species', '29278', (62, 72))	('R248W', 'Mutation', 'rs121912651', (93, 98))	('p53', 'Gene', (146, 149))	('G245C', 'Var', (83, 88))	('p21', 'Gene', (187, 190))	('mutant', 'Var', (51, 57))	('p53', 'Gene', '7157', (146, 149))	('DLC1-i4', 'Enzyme', (167, 174))	('R248W', 'Var', (93, 98))	('p53', 'Gene', (112, 115))	('p21', 'Gene', '644914', (187, 190))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (112, 115))	('p53', 'Gene', '7157', (58, 61))
332008	21217778	As the p53 mutants are defective in DNA-binding, this finding suggests that the ability of wild-type p53 to upregulate DLC1-i4 promoter activity is attributed to its DNA binding ability.	('upregulate', 'PosReg', (108, 118))	('mutants', 'Var', (11, 18))	('p53', 'Gene', '7157', (7, 10))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('DLC1-i4 promoter activity', 'MPA', (119, 144))	('p53', 'Gene', (7, 10))
332017	21217778	Collectively these results show that aberrant promoter CpG methylation is associated with DLC1-i4 silencing, and like DLC1-i2, is a frequent event in multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('DLC1-i4', 'Gene', (90, 97))	('silencing', 'NegReg', (98, 107))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('promoter CpG', 'MPA', (46, 58))	('multiple tumors', 'Disease', (150, 165))	('aberrant', 'Var', (37, 45))	('associated', 'Reg', (74, 84))	('multiple tumors', 'Disease', 'MESH:D009369', (150, 165))
332026	21217778	Weak DLC1-i4 expression with some demethylated alleles were also observed in DNMT1- knockout HCT116 cells (HCT116-1KO), but knocking-out DNMT3B seems to have little effect on DLC1-i4 reexpression, even though weak demethylated alleles were also detected.	('expression', 'Species', '29278', (185, 195))	('expression', 'Species', '29278', (13, 23))	('expression', 'MPA', (13, 23))	('DNMT1', 'Gene', (77, 82))	('HCT116', 'CellLine', 'CVCL:0291', (107, 113))	('DNMT3B', 'Gene', (137, 143))	('DNMT3B', 'Gene', '1789', (137, 143))	('DNMT1', 'Gene', '1786', (77, 82))	('knocking-out', 'Var', (124, 136))	('HCT116', 'CellLine', 'CVCL:0291', (93, 99))	('DLC1-i4', 'Gene', (5, 12))
332030	21217778	In addition, DLC1-i4 methylation was detected in 9/11 (82%) primary gastric, 10/13 (77%, with two weakly methylated) breast, 14/37 (38%) HCC and 11/11 (100%) colorectal carcinomas (Figure 5c and Table 2).	('DLC1-i4', 'Gene', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('HCC', 'Disease', (137, 140))	('methylation', 'Var', (21, 32))	('colorectal carcinomas', 'Disease', (158, 179))	('detected', 'Reg', (37, 45))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (158, 179))	('HCC', 'Phenotype', 'HP:0001402', (137, 140))	('primary gastric', 'Disease', (60, 75))
332033	21217778	These results indicate that DLC1-i4 methylation occurs frequently in tumors and affects DLC1-i4 expression.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('affects', 'Reg', (80, 87))	('expression', 'Species', '29278', (96, 106))	('DLC1-i4', 'Gene', (28, 35))	('expression', 'MPA', (96, 106))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('methylation', 'Var', (36, 47))	('DLC1-i4', 'Gene', (88, 95))
332036	21217778	Thus, DLC1-i4 is a functional tumor suppressor having growth inhibitory activities in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('growth', 'MPA', (54, 60))	('DLC1-i4', 'Var', (6, 13))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (30, 35))
332037	21217778	As DLC1-i1 shares structural domains with DLC1-i4 and DLC1-i2, we tested DLC1-i1 in the same assay and showed that DLC1-i1 is also a functional tumor suppressor (Supplementary Figure 5C).	('DLC1-i1', 'Var', (115, 122))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
332040	21217778	Similar to DLC1-i2, the DLC1-i4 promoter is hypermethylated in multiple tumor types including NPC, esophageal, gastric, breast, colorectal, cervical and HCC cell lines and primary tumors, which is associated with transcriptional silencing.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cervical', 'Disease', (140, 148))	('hypermethylated', 'Var', (44, 59))	('HCC', 'Disease', (153, 156))	('HCC', 'Phenotype', 'HP:0001402', (153, 156))	('primary tumors', 'Disease', 'MESH:D009369', (172, 186))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('colorectal', 'Disease', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('DLC1-i4', 'Gene', (24, 31))	('esophageal', 'Disease', (99, 109))	('tumor', 'Disease', (72, 77))	('gastric', 'Disease', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('breast', 'Disease', (120, 126))	('primary tumors', 'Disease', (172, 186))	('tumor', 'Disease', (180, 185))	('NPC', 'Disease', (94, 97))
332041	21217778	Methylation-mediated silencing could be reversed pharmacologically or by genetic double knockout of DNMT1 and DNMT3B.	('DNMT3B', 'Gene', (110, 116))	('DNMT3B', 'Gene', '1789', (110, 116))	('DNMT1', 'Gene', '1786', (100, 105))	('Methylation-mediated', 'Var', (0, 20))	('silencing', 'NegReg', (21, 30))	('DNMT1', 'Gene', (100, 105))
332042	21217778	In addition, ectopic-DLC1-i4 expression in carcinoma cells shows tumor suppressive properties.	('ectopic-DLC1-i4', 'Var', (13, 28))	('tumor', 'Disease', (65, 70))	('carcinoma', 'Disease', 'MESH:D002277', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('expression', 'Species', '29278', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('carcinoma', 'Disease', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
332043	21217778	In contrast, no methylation or silencing was detected in any of the immortalized normal cell line controls tested, indicating that DLC1-i4 methylation probably occurs late in carcinogenesis.	('carcinogenesis', 'Disease', (175, 189))	('carcinogenesis', 'Disease', 'MESH:D063646', (175, 189))	('DLC1-i4', 'Gene', (131, 138))	('methylation', 'Var', (139, 150))
332055	21217778	Our findings are corroborated by a recently published study in which DLC1beta (-DLC1-i1) and DLC1alpha (DLC1-i2) but not DLC1gamma (DLC1-i3) were shown to suppress stress fiber formation and HCC cell growth.	('HCC cell growth', 'CPA', (191, 206))	('HCC', 'Phenotype', 'HP:0001402', (191, 194))	('DLC1alpha', 'Var', (93, 102))	('stress fiber formation', 'CPA', (164, 186))	('DLC1beta', 'Var', (69, 77))	('rat', 'Species', '10116', (24, 27))	('suppress', 'NegReg', (155, 163))
332058	21217778	p53 is an important tumor suppressor, mutated in ~50% of all cancers.	('p53', 'Gene', (0, 3))	('mutated', 'Var', (38, 45))	('p53', 'Gene', '7157', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancers', 'Disease', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (20, 25))
332079	21217778	To assess the effect of p53 on DLC1-i4 promoter activity, concentrations of the p53 expression vector ranging from 1 to 500 ng (pcDNA3.1(+)TP53) or two mutant p53 expression constructs (G245C and R248W) (gifts from Bert Vogelstein) were cotransfected with 2microg of pGL2-DLC1i4-PF1/R(-1840/+140) and 100 ng pRL-SV40 into respective cells lines.	('R248W', 'Mutation', 'rs121912651', (196, 201))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('p53', 'Gene', (159, 162))	('R248W', 'Var', (196, 201))	('p53', 'Gene', '7157', (159, 162))	('p53', 'Gene', (80, 83))	('G245C', 'Mutation', 'rs28934573', (186, 191))	('expression', 'Species', '29278', (163, 173))	('G245C', 'Var', (186, 191))	('TP53', 'Gene', '7157', (139, 143))	('expression', 'Species', '29278', (84, 94))	('p53', 'Gene', '7157', (80, 83))	('TP53', 'Gene', (139, 143))	('-1840/+140', 'Var', (285, 295))	('rat', 'Species', '10116', (65, 68))
332085	21217778	The two mutant p53 expression constructs (G245C & R248W) were also gifts from Dr Bert Vogelstein.	('G245C', 'Mutation', 'rs28934573', (42, 47))	('G245C & R248W', 'Var', (42, 55))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('R248W', 'Mutation', 'rs121912651', (50, 55))	('expression', 'Species', '29278', (19, 29))
332096	33655918	The patient was clinically diagnosed with ESCC and staged as T4N1M1 Stage IV The patient was treated with CRT and immunotherapy.	('ESCC', 'Disease', (42, 46))	('T4N1M1', 'Var', (61, 67))	('patient', 'Species', '9606', (4, 11))	('patient', 'Species', '9606', (81, 88))
332108	33655918	PIK3CA mutations in domains can also activate cell signaling pathway and promote ESCC cell growth.	('activate', 'PosReg', (37, 45))	('ESCC', 'Disease', (81, 85))	('PIK3CA', 'Gene', (0, 6))	('cell signaling pathway', 'Pathway', (46, 68))	('PIK3CA', 'Gene', '5290', (0, 6))	('promote', 'PosReg', (73, 80))	('mutations', 'Var', (7, 16))
332109	33655918	The invasion is via activation of the PI3K/AKT/mTOR pathway by the increase of the kinase activity of PI3K.PIK3CA amplification could act as an independent poor prognostic factor in resected ESCC.	('amplification', 'Var', (114, 127))	('AKT', 'Gene', '207', (43, 46))	('PIK3CA', 'Gene', (107, 113))	('mTOR', 'Gene', '2475', (47, 51))	('AKT', 'Gene', (43, 46))	('mTOR', 'Gene', (47, 51))	('PIK3CA', 'Gene', '5290', (107, 113))	('ESCC', 'Disease', (191, 195))
332132	33655918	More than 50% of human cancers and germline DNA with inherited cancer syndromes of the family could coexist with mutated TP53 gene.	('human', 'Species', '9606', (17, 22))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('TP53', 'Gene', '7157', (121, 125))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('TP53', 'Gene', (121, 125))	('cancers', 'Disease', (23, 30))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('mutated', 'Var', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (63, 69))
332133	33655918	The mutant TP53 gene has been widely investigated in ESCC patients.	('mutant', 'Var', (4, 10))	('ESCC', 'Disease', (53, 57))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('patients', 'Species', '9606', (58, 66))
332134	33655918	Previous reports have suggested that mutated genes including TP53 (78% of patients), NOTCH1 (32%), ARID1A (13%), FAT1 (13%), CDKN2A (13%), and YAP1 amplification have been shown to be potentially useful biomarkers that can be used to predict treatment outcomes and identify patients with high risk of relapse.	('ARID1A', 'Gene', (99, 105))	('YAP1', 'Gene', '10413', (143, 147))	('TP53', 'Gene', '7157', (61, 65))	('NOTCH1', 'Gene', '4851', (85, 91))	('FAT1', 'Gene', '2195', (113, 117))	('CDKN2A', 'Gene', '1029', (125, 131))	('patients', 'Species', '9606', (274, 282))	('patients', 'Species', '9606', (74, 82))	('FAT1', 'Gene', (113, 117))	('NOTCH1', 'Gene', (85, 91))	('CDKN2A', 'Gene', (125, 131))	('mutated', 'Var', (37, 44))	('YAP1', 'Gene', (143, 147))	('TP53', 'Gene', (61, 65))	('ARID1A', 'Gene', '8289', (99, 105))
332135	33655918	Chen et al reinforced the idea that TP53 mutation played an essential role in the initiation of the tumorigenesis of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('TP53', 'Gene', '7157', (36, 40))	('mutation', 'Var', (41, 49))	('TP53', 'Gene', (36, 40))	('ESCC', 'Disease', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
332136	33655918	Kang et al made a conclusion that mutant TP53 G245C and R273H could have lost TP53 function in carcinogenesis.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('R273H', 'Var', (56, 61))	('R273H', 'Mutation', 'rs28934576', (56, 61))	('carcinogenesis', 'Disease', 'MESH:D063646', (95, 109))	('G245C', 'Mutation', 'rs28934573', (46, 51))	('G245C', 'Var', (46, 51))	('carcinogenesis', 'Disease', (95, 109))	('lost', 'NegReg', (73, 77))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))
332139	33655918	P53 R337L resulted in decreased TP53 tetramerization and trans-activation activity in cell cultures, which was expected to lead to a loss of function of the TP53 protein and inadequate chemoradiotherapy response.	('TP53', 'Gene', (157, 161))	('P53', 'Gene', (33, 36))	('loss of function', 'NegReg', (133, 149))	('trans-activation activity', 'CPA', (57, 82))	('P53', 'Gene', '7157', (33, 36))	('P53', 'Gene', (158, 161))	('TP53', 'Gene', '7157', (32, 36))	('P53', 'Gene', '7157', (158, 161))	('P53', 'Gene', (0, 3))	('R337L', 'Var', (4, 9))	('TP53', 'Gene', (32, 36))	('P53', 'Gene', '7157', (0, 3))	('R337L', 'Mutation', 'rs121912664', (4, 9))	('TP53', 'Gene', '7157', (157, 161))	('decreased', 'NegReg', (22, 31))
332140	33655918	Similarly, a transcoding mutation in exon 6 in the sample with a mutation rate of 15.71% also resulted in loss of p53 protein function and promoted cancer cell proliferation, survival, and metastasis.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('promoted', 'PosReg', (139, 147))	('function', 'MPA', (126, 134))	('p53', 'Gene', (114, 117))	('survival', 'CPA', (175, 183))	('p53', 'Gene', '7157', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutation', 'Var', (65, 73))	('loss', 'NegReg', (106, 110))	('metastasis', 'CPA', (189, 199))
332142	33655918	The 2-year overall survival rates of patients with wild-type TP53 and mutant TP53 were 55.6% vs 16.7%, and the median tumor-associated survival was 34.2 vs 8.9 months, respectively.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('TP53', 'Gene', '7157', (61, 65))	('patients', 'Species', '9606', (37, 45))	('mutant', 'Var', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', (61, 65))
332143	33655918	Besides, patients with mutant TP53 mutations have a three-fold increased risk of death (HR 3.01, CI 1.359-6.86).	('death', 'Disease', 'MESH:D003643', (81, 86))	('patients', 'Species', '9606', (9, 17))	('TP53', 'Gene', (30, 34))	('death', 'Disease', (81, 86))	('TP53', 'Gene', '7157', (30, 34))	('mutant', 'Var', (23, 29))	('mutations', 'Var', (35, 44))
332145	33655918	In addition, PIK3CA methylation rate in esophageal cancer significantly correlated with higher TNM staging.	('correlated', 'Reg', (72, 82))	('TNM', 'Gene', (95, 98))	('PIK3CA', 'Gene', (13, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PIK3CA', 'Gene', '5290', (13, 19))	('methylation', 'Var', (20, 31))	('TNM', 'Gene', '10178', (95, 98))	('esophageal cancer', 'Disease', (40, 57))
332150	33655918	In the patient's blood samples, we found the R337L mutation in exon 10 of the TP53 gene and the P191fs mutation in exon 6.	('P191fs', 'Mutation', 'p.P191fsX', (96, 102))	('R337L', 'Mutation', 'rs121912664', (45, 50))	('patient', 'Species', '9606', (7, 14))	('TP53', 'Gene', '7157', (78, 82))	('P191fs', 'Var', (96, 102))	('TP53', 'Gene', (78, 82))	('R337L', 'Var', (45, 50))
332151	33655918	These mutations may lead to the loss of the TP53 protein function and prevent it from exerting the tumor suppressing effect.	('tumor', 'Disease', (99, 104))	('function', 'MPA', (57, 65))	('protein', 'Protein', (49, 56))	('loss', 'NegReg', (32, 36))	('prevent', 'NegReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutations', 'Var', (6, 15))
332152	33655918	Instead, the mutant gene may be involved in the tumor promotion and progression.	('mutant', 'Var', (13, 19))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('involved', 'Reg', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
332153	33655918	In addition, the H1047R mutation in exon 21 of PIK3CA was found, which may lead to the continuous activation of PI3K/AKT signaling pathway, thereby enhancing the growth, proliferation, and migration capabilities of tumor cells.	('AKT', 'Gene', '207', (117, 120))	('PIK3CA', 'Gene', (47, 53))	('migration capabilities', 'CPA', (189, 211))	('PIK3CA', 'Gene', '5290', (47, 53))	('activation', 'PosReg', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('proliferation', 'CPA', (170, 183))	('AKT', 'Gene', (117, 120))	('growth', 'CPA', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('H1047R', 'SUBSTITUTION', 'None', (17, 23))	('H1047R', 'Var', (17, 23))	('enhancing', 'PosReg', (148, 157))	('tumor', 'Disease', (215, 220))
332154	33655918	Chen et al showed that co-mutation of TP53 and PIK3CA could be associated with poor survival in postneoadjuvant chemotherapy breast cancer patients and used as a potential prognosis marker in breast cancer.	('PIK3CA', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('PIK3CA', 'Gene', '5290', (47, 53))	('poor', 'NegReg', (79, 83))	('TP53', 'Gene', (38, 42))	('patients', 'Species', '9606', (139, 147))	('breast cancer', 'Disease', (192, 205))	('associated', 'Reg', (63, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('co-mutation', 'Var', (23, 34))	('TP53', 'Gene', '7157', (38, 42))
332169	31040700	Median PFS was significantly longer in the apatinib combination group than in the chemotherapy group (175 days vs 85 days, P=0.01).	('longer', 'PosReg', (29, 35))	('apatinib', 'Chemical', 'MESH:C553458', (43, 51))	('PFS', 'MPA', (7, 10))	('apatinib', 'Var', (43, 51))
332183	31040700	Other VEGF-targeting agents, such as aflibercept, DW10075, are also being evaluated in ongoing clinical trials.	('DW10075', 'Var', (50, 57))	('VEGF', 'Gene', '7422', (6, 10))	('VEGF', 'Gene', (6, 10))	('DW10075', 'Chemical', '-', (50, 57))
332237	31040700	In addition, our study uncovered that the addition of apatinib to chemotherapy, regardless of second- or third-line regimen, could significantly prolong mPFS (202 days vs 123 days, P=0.021; 123 days vs 54 days, P=0.024; Figure 1B and C).	('prolong', 'PosReg', (145, 152))	('addition', 'Var', (42, 50))	('mPFS', 'CPA', (153, 157))	('apatinib', 'Var', (54, 62))	('apatinib', 'Chemical', 'MESH:C553458', (54, 62))
332243	31040700	The results suggest that apatinib might become an alternative and viable approach for second- or further-line regimens and it might be particularly beneficial, to a large extent, for the survival of patients with advanced ESC.	('ESC', 'Disease', (222, 225))	('beneficial', 'PosReg', (148, 158))	('apatinib', 'Var', (25, 33))	('patients', 'Species', '9606', (199, 207))	('apatinib', 'Chemical', 'MESH:C553458', (25, 33))
332374	30761248	The cellular ratio F340/380 was increased by exposing the cells to sequential heat stimulation (44  C and 53  C, which is the putative activation temperature threshold for TRPV-1 and 2, respectively) 3, 6.	('cellular', 'MPA', (4, 12))	('rat', 'Species', '10116', (13, 16))	('increased', 'PosReg', (32, 41))	('TRPV-1 and 2', 'Gene', '7442;51393', (172, 184))	('rat', 'Species', '10116', (151, 154))	('F340/380', 'Var', (19, 27))
332380	30761248	3B, ratio F340/380 was enhanced by the application of capsaicin in a dose-dependent manner (capsaicin doses over 50 mum obtained similar effects to that of 50 mum, data not shown).	('enhanced', 'PosReg', (23, 31))	('F340/380', 'Var', (10, 18))	('capsaicin', 'Chemical', 'MESH:D002211', (54, 63))	('capsaicin', 'Chemical', 'MESH:D002211', (92, 101))	('rat', 'Species', '10116', (4, 7))
332390	30761248	S1B, [Ca2 +]i was elevated markedly in response to 20 mum capsaicin (P < 0.001 to [Ca2 +]i control) and the elevation was inhibited significantly by AMG9810 (10 nm) (P < 0.001 to [Ca2 +]i capsaicin), indicating that the oscillation of [Ca2 +]i was modulated by TRPV1.	('Ca2 +', 'Chemical', 'MESH:D000069285', (83, 88))	('capsaicin', 'Chemical', 'MESH:D002211', (188, 197))	('capsaicin', 'Chemical', 'MESH:D002211', (58, 67))	('Ca2 +', 'Chemical', 'MESH:D000069285', (180, 185))	('inhibited', 'NegReg', (122, 131))	('[Ca2 +]i', 'MPA', (5, 13))	('AMG9810', 'Chemical', 'MESH:C500530', (149, 156))	('Ca2 +', 'Chemical', 'MESH:D000069285', (236, 241))	('Ca2 +', 'Chemical', 'MESH:D000069285', (6, 11))	('elevated', 'PosReg', (18, 26))	('AMG9810', 'Var', (149, 156))
332391	30761248	A substantial rise in [Ca2 +]i (P < 0.01 to [Ca2 +]i control) was observed in the presence of O1821 (30 mum), a newly developed TRPV2 activator 43, while the rise in [Ca2 +]i was suppressed significantly by 100 mum tranilast (P < 0.01 to [Ca2 +]i O1821), suggesting that the mobilization of [Ca2 +]i was mediated by TRPV2.	('Ca2 +', 'Chemical', 'MESH:D000069285', (292, 297))	('rise', 'PosReg', (14, 18))	('Ca2 +', 'Chemical', 'MESH:D000069285', (45, 50))	('TRPV2', 'Gene', '51393', (316, 321))	('TRPV2', 'Gene', (128, 133))	('O1821', 'Var', (94, 99))	('Ca2 +', 'Chemical', 'MESH:D000069285', (23, 28))	('Ca2 +', 'Chemical', 'MESH:D000069285', (239, 244))	('TRPV2', 'Gene', '51393', (128, 133))	('[Ca2 +]i', 'MPA', (22, 30))	('Ca2 +', 'Chemical', 'MESH:D000069285', (167, 172))	('TRPV2', 'Gene', (316, 321))
332442	30761248	Notably, the TRPV2 agonist O1821 (Cayman Chemicals, Ann Arbor, Michigan, USA) is a new synthetic cannabinoid that effectively stimulates TRPV2, but does not stimulate TRPV1 or the cannabinoid receptors 43, 49.	('O1821', 'Var', (27, 32))	('stimulates', 'PosReg', (126, 136))	('TRPV2', 'Gene', (13, 18))	('cannabinoid', 'Chemical', 'MESH:D002186', (97, 108))	('TRPV2', 'Gene', (137, 142))	('cannabinoid', 'Chemical', 'MESH:D002186', (180, 191))	('TRPV2', 'Gene', '51393', (13, 18))	('TRPV2', 'Gene', '51393', (137, 142))
332453	30761248	Our previous study suggested that TRPV2 acts as an important enhancer for H2O2-induced cytotoxicity in HepG2 cells 56.	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('H2O2-induced', 'Var', (74, 86))	('H2O2', 'Chemical', 'MESH:D006861', (74, 78))	('cytotoxicity', 'Disease', (87, 99))	('TRPV2', 'Gene', (34, 39))	('enhancer', 'PosReg', (61, 69))	('HepG2', 'CellLine', 'CVCL:0027', (103, 108))	('TRPV2', 'Gene', '51393', (34, 39))
332465	30761248	Moreover, proliferation of Eca109 cells was promoted markedly by repeatedly brief heat stimulation (44  C) and this effect was inhibited significantly by AMG9810, which further confirmed that the activation of TRPV1 could promote the proliferation of ESCC cells (Fig.	('proliferation', 'CPA', (234, 247))	('promoted', 'PosReg', (44, 52))	('proliferation', 'CPA', (10, 23))	('AMG9810', 'Chemical', 'MESH:C500530', (154, 161))	('promote', 'PosReg', (222, 229))	('activation', 'Var', (196, 206))	('ESCC', 'Disease', (251, 255))	('rat', 'Species', '10116', (17, 20))	('rat', 'Species', '10116', (241, 244))	('TRPV1', 'Gene', (210, 215))
332476	30761248	Previous in vivo work reported that sensory neurons did not exhibit osmosensitive inward currents and the activation of peripheral osmoreceptors was abolished by knockout of TRPV4 62, revealing that TRPV4 is the key channel responding to osmotic stimuli, thus further supporting the notion that overactivation of TRPV4 plays a pro-migration role in ESCC cells.	('overactivation', 'PosReg', (295, 309))	('ESCC', 'Disease', (349, 353))	('TRPV4 62', 'Gene', (174, 182))	('rat', 'Species', '10116', (334, 337))	('knockout', 'Var', (162, 170))
332508	23102250	Various factors have been shown to increase the risk of ESCC, including tobacco smoking, heavy alcohol drinking, opium consumption, nass chewing, hot tea consumption,mate drinking, low intake of fruits and vegetables, nutrient deficiencies, tooth loss, and low socioeconomic status.	('ESCC', 'Disease', (56, 60))	('alcohol drinking', 'Phenotype', 'HP:0030955', (95, 111))	('tooth loss', 'Disease', (241, 251))	('tooth loss', 'Phenotype', 'HP:0006480', (241, 251))	('nass chewing', 'Disease', (132, 144))	('alcohol', 'Chemical', 'MESH:D000438', (95, 102))	('nass', 'Chemical', '-', (132, 136))	('opium', 'Disease', (113, 118))	('tobacco', 'Species', '4097', (72, 79))	('low', 'Var', (181, 184))	('tooth loss', 'Disease', 'MESH:D016388', (241, 251))	('mate drinking', 'Disease', (166, 179))
332516	23102250	This change results in PAHs binding to cellular macromolecules such as DNA, causing the formation of PAH-DNA adducts, which lead to mutations in proto-oncogenes and tumour-suppressor genes.	('results in', 'Reg', (12, 22))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('mutations', 'Var', (132, 141))	('binding', 'Interaction', (28, 35))	('PAH', 'Chemical', 'MESH:D011084', (101, 104))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('tumour', 'Disease', (165, 171))	('PAH', 'Chemical', 'MESH:D011084', (23, 26))	('lead to', 'Reg', (124, 131))	('PAHs', 'Chemical', 'MESH:D011084', (23, 27))
332547	23102250	Some PAH compounds, including benzo-a-anthracene, benzo-b-fluoranthene, benzo-j-fluoranthene, benzo-k-fluoranthene, benzo-a-pyrene, dibenz-a,h-anthracene, and indeno-1,2,3-c,d-pyrene, are considered to be human carcinogens.	('car', 'Gene', (211, 214))	('benzo-a-pyrene', 'Chemical', 'MESH:D001564', (116, 130))	('dibenz-a', 'Chemical', '-', (132, 140))	('indeno-1,2,3-c,d-pyrene', 'Chemical', 'MESH:C041508', (159, 182))	('benzo-j-fluoranthene', 'Var', (72, 92))	('benzo-b-fluoranthene', 'Chemical', 'MESH:C006703', (50, 70))	('benzo-a-anthracene', 'Chemical', 'MESH:C030935', (30, 48))	('benzo-k-fluoranthene', 'Chemical', 'MESH:C022921', (94, 114))	('benzo-j-fluoranthene', 'Chemical', 'MESH:C027704', (72, 92))	('h-anthracene', 'Chemical', '-', (141, 153))	('human', 'Species', '9606', (205, 210))	('PAH', 'Chemical', 'MESH:D011084', (5, 8))	('car', 'Gene', '653108', (211, 214))
332548	23102250	PAHs have been shown to induce carcinogenic changes in a number of human tissues.	('PAHs', 'Var', (0, 4))	('PAHs', 'Chemical', 'MESH:D011084', (0, 4))	('carcinogenic changes', 'Disease', 'MESH:D009402', (31, 51))	('human', 'Species', '9606', (67, 72))	('carcinogenic changes', 'Disease', (31, 51))
332552	23102250	Benzo-a-pyrene, the most common PAH to cause cancer in human, has benn classified as a group 1 carcinogen by IARC.	('car', 'Gene', '653108', (95, 98))	('car', 'Gene', (95, 98))	('Benzo-a-pyrene', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('human', 'Species', '9606', (55, 60))	('IARC', 'Disease', 'None', (109, 113))	('PAH', 'Chemical', 'MESH:D011084', (32, 35))	('IARC', 'Disease', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('Benzo-a-pyrene', 'Chemical', 'MESH:D001564', (0, 14))	('cancer', 'Disease', (45, 51))
332556	23102250	P53 mutations occur in about 40% of lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lung cancers', 'Disease', 'MESH:D008175', (36, 48))	('lung cancers', 'Phenotype', 'HP:0100526', (36, 48))	('occur', 'Reg', (14, 19))	('P53', 'Gene', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('lung cancers', 'Disease', (36, 48))	('mutations', 'Var', (4, 13))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
332558	23102250	So, PAH-induced P53 mutation was suggested as possible mechanism in the pathogenesis of lung cancer.	('lung cancer', 'Disease', (88, 99))	('PAH', 'Chemical', 'MESH:D011084', (4, 7))	('mutation', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('P53', 'Gene', (16, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
332559	23102250	PAH-induced P53 mutations are mostly G:C to T:A transversions, and they are poorly repaired.	('PAH', 'Chemical', 'MESH:D011084', (0, 3))	('P53', 'Gene', (12, 15))	('mutations', 'Var', (16, 25))
332560	23102250	Puisieux et al showed the direct role of PAHs in the induction of mutations in the P53 gene in lung cancer for the first time.	('mutations', 'Var', (66, 75))	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('PAHs', 'Chemical', 'MESH:D011084', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('P53', 'Gene', (83, 86))
332561	23102250	Recently, Gao et al suggested that PAHs may have the potential to induce P53 mutations in the cervix of mice.	('induce', 'Reg', (66, 72))	('mice', 'Species', '10090', (104, 108))	('PAHs', 'Chemical', 'MESH:D011084', (35, 39))	('mutations', 'Var', (77, 86))	('P53', 'Gene', (73, 76))
332562	23102250	It has been proposed that the most common locations of P53 mutations, known as mutational hotspots, are preferred targets for PAHs.	('PAHs', 'Chemical', 'MESH:D011084', (126, 130))	('mutations', 'Var', (59, 68))	('P53', 'Gene', (55, 58))
332564	23102250	Shen et al reported P53 mutation due to formation of PAH o-quinones, one of the ultimate carcinogens of PAHs, in cigarette smokers.	('car', 'Gene', '653108', (89, 92))	('car', 'Gene', (89, 92))	('PAHs', 'Chemical', 'MESH:D011084', (104, 108))	('P53', 'Gene', (20, 23))	('mutation', 'Var', (24, 32))	('PAH o-quinones', 'Chemical', '-', (53, 67))
332566	23102250	P53 mutation was reported to be attributed to direct PAH-induced DNA damage rather than selection of pre-existing endogenous mutations.	('P53', 'Gene', (0, 3))	('PAH', 'Chemical', 'MESH:D011084', (53, 56))	('mutation', 'Var', (4, 12))
332567	23102250	Because of the clear causal relationship between tobacco smoking and lung cancer, most previous investigations about PAH-induced P53 mutations have been conducted on lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('P53', 'Gene', (129, 132))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('tobacco', 'Species', '4097', (49, 56))	('PAH', 'Chemical', 'MESH:D011084', (117, 120))	('lung cancer', 'Disease', (69, 80))	('mutations', 'Var', (133, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
332569	23102250	Brennan et al reported a fourfold increase in the prevalence of P53 mutations in heavy smoking EC patients as compared to nonsmokers.	('mutations', 'Var', (68, 77))	('P53', 'Gene', (64, 67))	('patients', 'Species', '9606', (98, 106))	('heavy', 'Disease', (81, 86))
332570	23102250	The results of a recent study in northeastern Iran also suggested PAH-induced P53 mutations in ESCC cases.	('mutations', 'Var', (82, 91))	('PAH', 'Chemical', 'MESH:D011084', (66, 69))	('P53', 'Gene', (78, 81))	('ESCC cases', 'Disease', (95, 105))
332571	23102250	Further investigations are needed to clarify if PAH-induced P53 mutations play a major role in the pathogenesis of ESCC, as they do in the case of lung cancer.	('ESCC', 'Disease', (115, 119))	('P53', 'Gene', (60, 63))	('PAH', 'Chemical', 'MESH:D011084', (48, 51))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
332582	23102250	There was a striking dose-response relationship between the intensity of 8E11 and ESCC case status, suggesting a causal role for PAH exposure in the pathogenesis of ESCC (Table 1).	('8E11', 'Var', (73, 77))	('PAH', 'Chemical', 'MESH:D011084', (129, 132))	('ESCC', 'Disease', (165, 169))	('ESCC', 'Disease', (82, 86))
332662	23102250	Genetic factors may affect an individual's response to PAH exposure.	('response', 'MPA', (43, 51))	('affect', 'Reg', (20, 26))	('Genetic', 'Var', (0, 7))	('PAH', 'Chemical', 'MESH:D011084', (55, 58))
332664	23102250	But genetic polymorphisms may affect the activity of these enzymes and make individuals more or less susceptible to the carcinogenic effects the same PAH exposure.	('polymorphisms', 'Var', (12, 25))	('carcinogenic effects', 'Disease', 'MESH:D020018', (120, 140))	('carcinogenic effects', 'Disease', (120, 140))	('less', 'NegReg', (96, 100))	('affect', 'Reg', (30, 36))	('PAH', 'Chemical', 'MESH:D011084', (150, 153))	('activity', 'MPA', (41, 49))
332665	23102250	Roth et al showed an association between the inactive polymorphism of the GSTM1 gene and the presence of esophageal squamous dysplasia, the precursor of ESCC, in a PAH-exposed population in China.	('PAH', 'Chemical', 'MESH:D011084', (164, 167))	('esophageal squamous dysplasia', 'Disease', 'MESH:D000077277', (105, 134))	('GSTM1', 'Gene', '2944', (74, 79))	('association', 'Interaction', (21, 32))	('GSTM1', 'Gene', (74, 79))	('inactive polymorphism', 'Var', (45, 66))	('esophageal squamous dysplasia', 'Disease', (105, 134))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (116, 134))
332700	29151903	Elevated levels of F. nucleatum DNA in colorectal cancer tissue are associated with certain molecules and cell functions, including microsatellite instability, the CpG island methylator phenotype and hMLH1, and are also associated with a lower density of T cells.	('F. nucleatum', 'Var', (19, 31))	('associated', 'Reg', (68, 78))	('F. nucleatum', 'Species', '851', (19, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('microsatellite instability', 'MPA', (132, 158))	('hMLH1', 'Gene', (200, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('lower density of T cells', 'Phenotype', 'HP:0005403', (238, 262))	('hMLH1', 'Gene', '4292', (200, 205))	('colorectal cancer', 'Disease', (39, 56))
332760	29151903	This suggested that F. nucleatum may be associated with the progression of gastroenterological tract cancer, but not the progression of pancreatic and liver cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('liver cancer', 'Phenotype', 'HP:0002896', (151, 163))	('gastroenterological tract cancer', 'Disease', (75, 107))	('gastroenterological tract cancer', 'Phenotype', 'HP:0007378', (75, 107))	('F. nucleatum', 'Var', (20, 32))	('F. nucleatum', 'Species', '851', (20, 32))	('pancreatic and liver cancer', 'Disease', 'MESH:D010190', (136, 163))	('gastroenterological tract cancer', 'Disease', 'MESH:D014571', (75, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associated', 'Reg', (40, 50))
332774	28387541	High expression of HER2 protein as the result of gene amplification drives oncogenic signaling in adenocarcinomas of various organs and tissues of origin including esophagogastric, breast, ovarian, pancreatic, colorectal, uterine and other types (Figure 1, TCGA Datasets, cbioportal.org).	('colorectal', 'Disease', (210, 220))	('breast', 'Disease', (181, 187))	('drives', 'PosReg', (68, 74))	('protein', 'Protein', (24, 31))	('ovarian', 'Disease', (189, 196))	('adenocarcinomas', 'Disease', (98, 113))	('adenocarcinomas', 'Disease', 'MESH:D000230', (98, 113))	('pancreatic', 'Disease', 'MESH:D010195', (198, 208))	('pancreatic', 'Disease', (198, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('gene amplification', 'Var', (49, 67))	('colorectal', 'Disease', 'MESH:D015179', (210, 220))	('esophagogastric', 'Disease', (164, 179))	('oncogenic signaling', 'MPA', (75, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('HER2 protein', 'Protein', (19, 31))
332778	28387541	A variety of human cancers use HER2 as their "oncogenic driver" via amplification of the gene locus on chromosome 17 to increase the HER2 protein expression.	('human', 'Species', '9606', (13, 18))	('HER2 protein', 'Protein', (133, 145))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('increase', 'PosReg', (120, 128))	('amplification', 'Var', (68, 81))
332784	28387541	Trastuzumab binds to the extracellular juxtamembrane domain of HER2 receptor to the three loop regions of HER2 (residues 557-561 (loop 1), 570-573 (loop 2) and 593-603 (loop 3)).	('HER2', 'Protein', (63, 67))	('residues 557-561', 'Var', (112, 128))	('570-573', 'Var', (139, 146))	('binds', 'Interaction', (12, 17))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (0, 11))	('593-603', 'Var', (160, 167))
332787	28387541	Despite HER2 copy number and high expression predicting the benefit of trastuzumab in clinical trials in breast and esophagogastric cancers, only a minority of tumors respond to HER2 blockade with trastuzumab monotherapy.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('HER2', 'Protein', (178, 182))	('expression', 'MPA', (34, 44))	('gastric cancers', 'Phenotype', 'HP:0012126', (124, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('copy number', 'Var', (13, 24))	('HER2', 'Protein', (8, 12))	('breast and esophagogastric cancers', 'Disease', 'MESH:D001943', (105, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('trastuzumab', 'Chemical', 'MESH:D000068878', (71, 82))	('trastuzumab', 'Chemical', 'MESH:D000068878', (197, 208))	('tumors', 'Disease', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
332792	28387541	These clinical observations are supported by experimental models where HER2 knockdown induced apoptosis in cell culture, or alternatively tumor regression in vivo, only in cancer models with high HER2.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('knockdown', 'Var', (76, 85))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('HER2', 'Protein', (71, 75))	('induced', 'Reg', (86, 93))	('cancer', 'Disease', (172, 178))	('HER2', 'Protein', (196, 200))	('apoptosis', 'CPA', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
332799	28387541	Most compelling evidence has been inferred from the analyses of Fc receptor 2B (FCGR2B, variant I232T) polymorphisms in a large N9831 Alliance trial so that the carriers of I/I allele derived greater benefit from trastuzumab (P < 0.001) compared with the 232T carriers who did not (P = 0.81).	('trastuzumab', 'Chemical', 'MESH:D000068878', (213, 224))	('I/I allele', 'Var', (173, 183))	('I232T', 'Var', (96, 101))	('benefit', 'PosReg', (200, 207))	('polymorphisms', 'Var', (103, 116))	('FCGR2B', 'Gene', (80, 86))	('FCGR2B', 'Gene', '2213', (80, 86))	('I232T', 'SUBSTITUTION', 'None', (96, 101))
332803	28387541	Interestingly, a relatively smaller (<10%) subset of gastric cancers are associated with chronic integration of the Epstein-Barr virus genome and are likely caused by chronic viral persistence which is concurrent with PIK3CA mutations, DNA hypermethylation, and amplification of JAK2, PD-L1 and PD-L2.	('gastric cancers', 'Disease', (53, 68))	('gastric cancers', 'Phenotype', 'HP:0012126', (53, 68))	('mutations', 'Var', (225, 234))	('Epstein-Barr virus genome', 'Disease', 'MESH:D020031', (116, 141))	('caused by', 'Reg', (157, 166))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('Epstein-Barr virus genome', 'Disease', (116, 141))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('gastric cancers', 'Disease', 'MESH:D013274', (53, 68))	('PIK3CA', 'Gene', (218, 224))
332804	28387541	A subset of microsatellite instability (MSI) -high tumors carry a characteristic signature of extremely high mutational load and largely lacking chromosomal gains or losses.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lacking', 'NegReg', (137, 144))	('microsatellite instability', 'MPA', (12, 38))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('mutational', 'Var', (109, 119))
332805	28387541	The diffuse subset of gastric cancer demonstrates frequent mutations affecting components of the focal adhesion complex, RHOA, CDH1, CTNNA1, CTNNA2 and CTNNB1, which may contribute to loss of cell adhesion in this subtype of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('gastric cancer', 'Disease', 'MESH:D013274', (225, 239))	('CTNNA2', 'Gene', (141, 147))	('CTNNA1', 'Gene', (133, 139))	('CTNNA1', 'Gene', '1495', (133, 139))	('gastric cancer', 'Disease', (22, 36))	('CTNNB1', 'Gene', '1499', (152, 158))	('CTNNA2', 'Gene', '1496', (141, 147))	('cell adhesion', 'MPA', (192, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (225, 239))	('RHOA', 'Gene', '387', (121, 125))	('RHOA', 'Gene', (121, 125))	('loss', 'NegReg', (184, 188))	('gastric cancer', 'Disease', 'MESH:D013274', (22, 36))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('CTNNB1', 'Gene', (152, 158))	('CDH1', 'Gene', '999', (127, 131))	('gastric cancer', 'Disease', (225, 239))	('gastric cancer', 'Phenotype', 'HP:0012126', (22, 36))	('CDH1', 'Gene', (127, 131))
332806	28387541	Amplifications involving multiple oncogenic kinases, including EGFR, HER2, ErbB3, FGFR2, MET are most prevalent in the chromosome instability (CIN, roughly 1/3 of all cases) subtype of gastric cancer.	('EGFR', 'Gene', '1956', (63, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (185, 199))	('chromosome instability', 'Disease', (119, 141))	('ErbB3', 'Gene', '2065', (75, 80))	('MET', 'Gene', (89, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (185, 199))	('EGFR', 'Gene', (63, 67))	('chromosome instability', 'Phenotype', 'HP:0040012', (119, 141))	('CIN', 'Disease', (143, 146))	('prevalent', 'Reg', (102, 111))	('CIN', 'Disease', 'MESH:D007674', (143, 146))	('Amplifications', 'Var', (0, 14))	('gastric cancer', 'Disease', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('FGFR2', 'Gene', (82, 87))	('FGFR2', 'Gene', '2263', (82, 87))	('HER2', 'Gene', (69, 73))	('ErbB3', 'Gene', (75, 80))
332807	28387541	It is also worth noting that in several cases included in the TCGA datasets of esophageal and gastric cancer (cbioportal.org, Figure 1) the chromosomal amplifications involve several of these oncogenes in one tumor specimen.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (209, 214))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('chromosomal amplifications', 'Var', (140, 166))	('esophageal and gastric cancer', 'Disease', 'MESH:D013274', (79, 108))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
332811	28387541	The incidence of HER2 amplification in gastric cancer varies depending on the methods used and the heterogeneity of gastroesophageal tumors in each reported series.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('gastroesophageal tumors', 'Phenotype', 'HP:0100751', (116, 139))	('gastric cancer', 'Disease', (39, 53))	('gastroesophageal tumors', 'Disease', (116, 139))	('gastric cancer', 'Disease', 'MESH:D013274', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('amplification', 'Var', (22, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (39, 53))	('gastroesophageal tumors', 'Disease', 'MESH:D005764', (116, 139))	('HER2', 'Protein', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
332812	28387541	In the ToGA trial evaluating front-line trastuzumab with chemotherapy in advanced gastric cancer, the prevalence of HER2 amplification/positivity was the highest among carcinomas with intestinal histology (31.8%) compared to the diffuse type (6.1%), and was lower in metastatic sites (16.7%) compared to the stomach (21.4%) or gastroesophageal junction (32.2%).	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('carcinomas', 'Disease', (168, 178))	('amplification/positivity', 'Var', (121, 145))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('highest', 'Reg', (154, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('gastroesophageal junction', 'Disease', (327, 352))	('gastric cancer', 'Disease', (82, 96))	('HER2', 'Protein', (116, 120))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (327, 352))	('trastuzumab', 'Chemical', 'MESH:D000068878', (40, 51))	('carcinomas', 'Disease', 'MESH:D002277', (168, 178))
332815	28387541	However, microarray analysis using in situ hybridization and 2 IHC techniques on a large pool of 1040 primary tumors and matched 720 nodal metastases has recently called into question the accuracy of IHC in assessing HER2 overexpression: amplification was not associated with protein overexpression in about 10% of cases depending on the IHC method.	('amplification', 'Var', (238, 251))	('metastases', 'Disease', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('metastases', 'Disease', 'MESH:D009362', (139, 149))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))
332828	28387541	Patients were considered eligible for enrollment if they had either HER2 overexpression by IHC or gene amplification by ISH.	('gene amplification', 'Var', (98, 116))	('Patients', 'Species', '9606', (0, 8))	('HER2', 'Protein', (68, 72))	('overexpression', 'PosReg', (73, 87))
332830	28387541	An exploratory analysis limited to patients with classic higher HER2 positivity (IHC 3+ or IHC2+ and ISH ratio > 2.0) demonstrated an even greater survival advantage (16.0 vs. 11.8 months; HR 0.65).	('HER2', 'Protein', (64, 68))	('patients', 'Species', '9606', (35, 43))	('advantage', 'PosReg', (156, 165))	('IHC2+', 'Var', (91, 96))
332846	28387541	However, pertuzumab in combination with trastuzumab produced synergistic effects in patients with HER2-amplified breast cancer who have previously progressed on trastuzumab.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('patients', 'Species', '9606', (84, 92))	('breast cancer', 'Disease', (113, 126))	('pertuzumab', 'Chemical', 'MESH:C485206', (9, 19))	('trastuzumab', 'Chemical', 'MESH:D000068878', (161, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('synergistic effects', 'MPA', (61, 80))	('trastuzumab', 'Chemical', 'MESH:D000068878', (40, 51))	('HER2-amplified', 'Var', (98, 112))
332856	28387541	Such approach has been successfully tested in patients with HER2-positive metastatic or recurrent locally advanced breast cancer in the EMILIA trial where T-DM1 improved PFS and OS.	('patients', 'Species', '9606', (46, 54))	('T-DM1', 'Chemical', 'MESH:C550911', (155, 160))	('PFS', 'Disease', (170, 173))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('T-DM1', 'Var', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('improved', 'PosReg', (161, 169))
332865	28387541	The phase III TRIO-013/LOGiC trial evaluated capecitabine and oxaliplatin with or without lapatinib in patients with HER2 amplified gastric cancer and failed to show a survival benefit (12.2 vs. 10.5 months, HR 0.91; p=0.3492), although progression-free survival and response rate were significantly higher in the lapatinib arm.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (62, 73))	('HER2', 'Gene', (117, 121))	('gastric cancer', 'Disease', (132, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('capecitabine', 'Chemical', 'MESH:D000069287', (45, 57))	('lapatinib', 'Chemical', 'MESH:D000077341', (90, 99))	('TRIO', 'Gene', (14, 18))	('TRIO', 'Gene', '7204', (14, 18))	('lapatinib', 'Chemical', 'MESH:D000077341', (314, 323))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('higher', 'PosReg', (300, 306))	('amplified', 'Var', (122, 131))	('patients', 'Species', '9606', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
332875	28387541	Discordance in HER2 status between primary tumors and metastatic lesions may also confound the efficacy of HER2-directed agents.	('confound', 'NegReg', (82, 90))	('HER2', 'Protein', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('Discordance', 'Var', (0, 11))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
332895	28387541	As the result, these compensatory changes maintained PI3 kinase pathway activity leading to AKT-dependent cancer cell survival.	('activity', 'MPA', (72, 80))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('leading to', 'Reg', (81, 91))	('AKT', 'Gene', '207', (92, 95))	('cancer', 'Disease', (106, 112))	('changes', 'Var', (34, 41))	('AKT', 'Gene', (92, 95))	('PI3 kinase pathway', 'Pathway', (53, 71))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
332897	28387541	Recent studies showed indeed a better efficacy of combination of afatinib, a pan-EGFR irreversible kinase inhibitor, with cetuximab in non-small cell lung cancer with resistance T790M mutation and HER2 amplification in some cases Dual, or "vertical", blockade of the HER2 signaling axis that also precludes compensatory signaling loops through EGFR and ErbB3 have been effective in the preclinical models.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('combination', 'Interaction', (50, 61))	('non-small cell lung cancer', 'Disease', (135, 161))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (139, 161))	('ErbB3', 'Gene', (353, 358))	('ErbB3', 'Gene', '2065', (353, 358))	('afatinib', 'Chemical', 'MESH:D000077716', (65, 73))	('EGFR', 'Gene', '1956', (344, 348))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (135, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('T790M', 'Mutation', 'rs121434569', (178, 183))	('EGFR', 'Gene', (344, 348))	('cetuximab', 'Chemical', 'MESH:D000068818', (122, 131))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (135, 161))	('resistance T790M mutation', 'Var', (167, 192))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
332907	28387541	Alternative methods for assessing HER2 status include next generation sequencing, although the therapeutic significance of a HER2 mutations in gastro-esophageal adenocarcinoma is unknown at this time.	('HER2', 'Gene', (125, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('gastro-esophageal adenocarcinoma', 'Disease', 'MESH:D005764', (143, 175))	('mutations', 'Var', (130, 139))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (150, 175))	('gastro-esophageal adenocarcinoma', 'Disease', (143, 175))
332928	27188458	Downregulation of PFN2 inhibited, rather than proliferated, cell invasion and migration, as well as induced an EMT phenotype, including increased expression of epithelial marker E-cadherin, decreased mesenchymal marker Vimentin, Snail, Slug and ZEB1, and morphological changes in ESCC cells in vitro.	('ZEB1', 'Gene', (245, 249))	('EMT', 'CPA', (111, 114))	('expression', 'MPA', (146, 156))	('Snail', 'Gene', '6615', (229, 234))	('Downregulation', 'Var', (0, 14))	('decreased', 'NegReg', (190, 199))	('E-cadherin', 'Gene', (178, 188))	('morphological changes', 'CPA', (255, 276))	('E-cadherin', 'Gene', '999', (178, 188))	('Slug', 'Gene', (236, 240))	('Vimentin', 'Gene', '7431', (219, 227))	('ZEB1', 'Gene', '6935', (245, 249))	('induced', 'Reg', (100, 107))	('increased', 'PosReg', (136, 145))	('Snail', 'Gene', (229, 234))	('Vimentin', 'Gene', (219, 227))	('PFN2', 'Gene', (18, 22))	('inhibited', 'NegReg', (23, 32))	('mesenchymal marker', 'CPA', (200, 218))	('Slug', 'Gene', '6591', (236, 240))	('cell invasion', 'CPA', (60, 73))
332939	27188458	In addition, the disruption of profilin by gene deletion of PFN1 in null mice or by anti-profilin transfection in bovine oocytes, results in early embryonic death.	('gene deletion', 'Var', (43, 56))	('embryonic death', 'Disease', 'MESH:D003643', (147, 162))	('mice', 'Species', '10090', (73, 77))	('results in', 'Reg', (130, 140))	('profilin', 'Protein', (31, 39))	('disruption', 'Var', (17, 27))	('bovine', 'Species', '9913', (114, 120))	('PFN1', 'Gene', (60, 64))	('embryonic death', 'Disease', (147, 162))
332945	27188458	Other reports suggested that post-translational modifications, such as phosphorylation of PFN1 at Ser 137 or Tyr 129, could change the properties of cancer cells.	('phosphorylation', 'MPA', (71, 86))	('cancer', 'Disease', (149, 155))	('PFN1', 'Gene', (90, 94))	('Ser 137', 'Var', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Tyr 129', 'Var', (109, 116))	('Tyr', 'Chemical', 'MESH:D014443', (109, 112))	('change', 'Reg', (124, 130))	('Ser', 'Chemical', 'MESH:D012694', (98, 101))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
332997	27188458	The median survival time for patients with high PFN2 expression was 12 months (range, 1-96 months) and 42 months (range, 1-96 months) for patients with low PFN2 expression, which indicated that ESCC patients with high PFN2 expression had significantly shorter OS rates and greater risk of death than those with low PFN2 expression (log-rank test, chi2 = 5.203, P = 0.023) (Fig.	('patients', 'Species', '9606', (29, 37))	('PFN2', 'Gene', (218, 222))	('high', 'Var', (213, 217))	('OS', 'Chemical', '-', (260, 262))	('patients', 'Species', '9606', (199, 207))	('death', 'Disease', 'MESH:D003643', (289, 294))	('shorter', 'NegReg', (252, 259))	('death', 'Disease', (289, 294))	('patients', 'Species', '9606', (138, 146))	('OS rates', 'CPA', (260, 268))
333006	27188458	Subsequently, Transwell assays showed that depletion of PFN2 significantly suppressed the migration and invasion of Eca109 and EC9706 cell lines.	('suppressed', 'NegReg', (75, 85))	('PFN2', 'Gene', (56, 60))	('EC9706', 'CellLine', 'CVCL:E307', (127, 133))	('depletion', 'Var', (43, 52))
333023	27188458	Another important finding in this study was found that PFN2 expression was positively associated with invasion depth amongst Han patients with ESCC, as well as lymph node metastasis amongst Kazakh ESCC patients.	('PFN2', 'Gene', (55, 59))	('patients', 'Species', '9606', (129, 137))	('expression', 'Var', (60, 70))	('lymph node metastasis', 'CPA', (160, 181))	('associated', 'Reg', (86, 96))	('ESCC', 'Disease', (143, 147))	('patients', 'Species', '9606', (202, 210))	('invasion depth', 'CPA', (102, 116))
333034	27188458	In our study, E-cadherin was clearly up-regulated by the knockdown of PFN2.	('E-cadherin', 'Gene', '999', (14, 24))	('PFN2', 'Gene', (70, 74))	('knockdown', 'Var', (57, 66))	('up-regulated', 'PosReg', (37, 49))	('E-cadherin', 'Gene', (14, 24))
333038	27188458	In our study, silencing PFN2 significantly suppressed the expressions of Snail, Slug and ZEB1.	('PFN2', 'Gene', (24, 28))	('silencing', 'Var', (14, 23))	('expressions', 'MPA', (58, 69))	('Slug', 'Gene', '6591', (80, 84))	('Snail', 'Gene', '6615', (73, 78))	('ZEB1', 'Gene', (89, 93))	('Slug', 'Gene', (80, 84))	('ZEB1', 'Gene', '6935', (89, 93))	('Snail', 'Gene', (73, 78))	('suppressed', 'NegReg', (43, 53))
333041	27188458	Similarly, another mesenchymal marker, Vimentin, was obviously downregulated by the knockdown of PFN2.	('PFN2', 'Gene', (97, 101))	('knockdown', 'Var', (84, 93))	('downregulated', 'NegReg', (63, 76))	('Vimentin', 'Gene', (39, 47))	('Vimentin', 'Gene', '7431', (39, 47))
333137	26985391	The corrosive nature of iron can lead to hemorrhagic necrosis, ulceration and even perforation resulting in shock from hemorrhage and fluid loss.	('hemorrhage', 'Disease', 'MESH:D006470', (119, 129))	('lead to', 'Reg', (33, 40))	('corrosive', 'Var', (4, 13))	('iron', 'Chemical', 'MESH:D007501', (24, 28))	('shock', 'Phenotype', 'HP:0031273', (108, 113))	('fluid loss', 'MPA', (134, 144))	('hemorrhagic necrosis', 'Disease', (41, 61))	('shock', 'MPA', (108, 113))	('ulceration', 'Disease', (63, 73))	('hemorrhagic necrosis', 'Disease', 'MESH:D006470', (41, 61))	('hemorrhagic necrosis', 'Phenotype', 'HP:0010885', (41, 61))	('fluid loss', 'Phenotype', 'HP:0000969', (134, 144))	('hemorrhage', 'Disease', (119, 129))
333138	26985391	In addition, iron can cause mucosal injury in the form of epithelial distortion and ischemia.	('iron', 'Var', (13, 17))	('cause', 'Reg', (22, 27))	('ischemia', 'Disease', (84, 92))	('ischemia', 'Disease', 'MESH:D007511', (84, 92))	('mucosal injury', 'Disease', (28, 42))	('epithelial distortion', 'Disease', (58, 79))	('mucosal injury', 'Disease', 'MESH:D052016', (28, 42))	('iron', 'Chemical', 'MESH:D007501', (13, 17))
333172	26985391	It is unclear whether this finding is due to an increase in PPI use for the symptoms caused by iron-induced erosion, or whether the alkaline environment caused by the PPI may aid in iron deposition in the gastric mucosa.	('iron', 'Chemical', 'MESH:D007501', (95, 99))	('iron', 'Chemical', 'MESH:D007501', (144, 148))	('iron', 'Chemical', 'MESH:D007501', (182, 186))	('PPI', 'Var', (167, 170))	('aid', 'PosReg', (175, 178))	('iron deposition', 'MPA', (182, 197))
333177	26985391	Hereditary hemochromatosis is an autosomal recessive disorder associated with common mutations of the HFE gene: C282Y and H63D.	('C282Y', 'Var', (112, 117))	('HFE', 'Gene', '3077', (102, 105))	('autosomal recessive disorder', 'Disease', (33, 61))	('Hereditary hemochromatosis', 'Disease', 'MESH:D006432', (0, 26))	('Hereditary hemochromatosis', 'Disease', (0, 26))	('HFE', 'Gene', (102, 105))	('C282Y', 'Mutation', 'rs1800562', (112, 117))	('H63D', 'SUBSTITUTION', 'None', (122, 126))	('H63D', 'Var', (122, 126))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (33, 61))
333206	22761904	Recurrent chromosomal gains were frequently detected on 3q26-27, 5p15-14, 8p12, 8p22-24, 11q13, 13q21-31, 18p11 and 20q11-13, with frequent losses also found on 8p23-22, 11q22, 14q32 and 18q11-23.	('chromosomal', 'CPA', (10, 21))	('losses', 'NegReg', (140, 146))	('p11', 'Gene', (108, 111))	('5p15-14', 'Var', (65, 72))	('gains', 'PosReg', (22, 27))	('p11', 'Gene', '6281', (108, 111))
333213	22761904	Genomic amplifications and deletions contribute to human tumorigenesis by altering the expression levels of critical oncogenes and tumor suppressor genes (TSGs).	('contribute', 'Reg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('expression levels', 'MPA', (87, 104))	('human', 'Species', '9606', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('deletions', 'Var', (27, 36))	('altering', 'Reg', (74, 82))	('human tumorigenesis', 'CPA', (51, 70))
333214	22761904	11q13 (CCND1, EMS1), 3q26 (EIF5A2), 21q22 (ETS2), 8q24 (MYC), have been consistently observed in more than one studies.	('3q26', 'Var', (21, 25))	('EIF5A2', 'Gene', '56648', (27, 33))	('EMS1', 'Gene', (14, 18))	('EMS1', 'Gene', '2017', (14, 18))	('ETS2', 'Gene', (43, 47))	('MYC', 'Gene', (56, 59))	('EIF5A2', 'Gene', (27, 33))	('ETS2', 'Gene', '2114', (43, 47))	('21q22', 'Var', (36, 41))	('MYC', 'Gene', '4609', (56, 59))
333218	22761904	In this study, we profiled 10 commonly used ESCC cell lines originated from mainland Chinese (EC1, EC18 and EC109), Hong Kong Chinese (HKESC1, HKESC2, HKESC3 and SLMT1) and Japanese (KYSE70, KYSE410 and KYSE520) patients for whole-genome DNA copy number alterations using aCGH analysis.	('KYSE410', 'Var', (191, 198))	('EC1', 'Gene', (94, 97))	('KYSE520', 'Var', (203, 210))	('EC1', 'Gene', (108, 111))	('EC1', 'Gene', '4819', (108, 111))	('EC1', 'Gene', '4819', (94, 97))	('EC18', 'CellLine', 'CVCL:5V07', (99, 103))	('EC1', 'Gene', '4819', (99, 102))	('EC1', 'Gene', (99, 102))
333226	22761904	Meanwhile, cytogenetic and molecular genetic analyses demonstrated multiple genetic abnormalities in ESCC, including chromosomal losses and gains.	('chromosomal losses', 'Var', (117, 135))	('gains', 'PosReg', (140, 145))	('genetic abnormalities', 'Disease', 'MESH:D030342', (76, 97))	('ESCC', 'Disease', (101, 105))	('genetic abnormalities', 'Disease', (76, 97))
333233	22761904	Regions of high-level deletions containing known or candidate TSGs were also detected, including 18q11-23 containing SMAD2, SMAD4 and DCC (EC1, EC109, HKESC3, SLMT1 and KYSE70), 8p22 containing DLC1 (EC1, KYSE70, 410 and 520) and a region on 14q32 containing DLK1 and MEG3 (EC1, EC109 and KYSE70).	('DLK1', 'Gene', (259, 263))	('DLC1', 'Gene', (194, 198))	('deletions', 'Var', (22, 31))	('MEG3', 'Gene', '55384', (268, 272))	('EC1', 'Var', (274, 277))	('SMAD2', 'Gene', (117, 122))	('SMAD2', 'Gene', '4087', (117, 122))	('SMAD4', 'Gene', '4089', (124, 129))	('DLK1', 'Gene', '8788', (259, 263))	('DCC', 'Gene', (134, 137))	('DLC1', 'Gene', '10395', (194, 198))	('KYSE70', 'Var', (289, 295))	('MEG3', 'Gene', (268, 272))	('SMAD4', 'Gene', (124, 129))	('DCC', 'Gene', '1630', (134, 137))
333234	22761904	Other high-level deletions containing candidate TSGs include 4q21.23-21.3 (MAPK10, PTPN13 and ARGAP24), 7p21.2 (DGKB), 7q35 (CNTNAP2), 8q11 (CEBPD), 10p11 (PARD3), 13q31.1 (SPRY2) and 16q22-23 (ATBF1).	('7p21.2', 'Var', (104, 110))	('CNTNAP2', 'Gene', (125, 132))	('SPRY2', 'Gene', (173, 178))	('DGKB', 'Gene', (112, 116))	('ATBF1', 'Gene', '463', (194, 199))	('ARGAP24', 'Gene', (94, 101))	('MAPK10', 'Gene', (75, 81))	('CEBPD', 'Gene', (141, 146))	('DGKB', 'Gene', '1607', (112, 116))	('CEBPD', 'Gene', '1052', (141, 146))	('ATBF1', 'Gene', (194, 199))	('PARD3', 'Gene', '56288', (156, 161))	('PTPN13', 'Gene', (83, 89))	('MAPK10', 'Gene', '5602', (75, 81))	('SPRY2', 'Gene', '10253', (173, 178))	('PTPN13', 'Gene', '5783', (83, 89))	('PARD3', 'Gene', (156, 161))	('CNTNAP2', 'Gene', '26047', (125, 132))
333253	31582906	Overexpression of miR-145 or knockdown of AKT3 promoted DDP-induced cell cycle arrest and apoptosis, as well as reduced IC50 of DDP treatment, which was reversed by AKT3 overexpression.	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('miR-145', 'Gene', (18, 25))	('knockdown', 'Var', (29, 38))	('DDP', 'Gene', '1678', (56, 59))	('promoted', 'PosReg', (47, 55))	('AKT3', 'Gene', '10000', (42, 46))	('apoptosis', 'CPA', (90, 99))	('arrest', 'Disease', (79, 85))	('DDP', 'Gene', '1678', (128, 131))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('DDP', 'Gene', (128, 131))	('DDP', 'Gene', (56, 59))	('reduced', 'NegReg', (112, 119))	('IC50', 'MPA', (120, 124))	('AKT3', 'Gene', (165, 169))	('AKT3', 'Gene', '10000', (165, 169))	('AKT3', 'Gene', (42, 46))
333254	31582906	The expression level of MRP1, P-gp, CyclinD1, c-Myc and anti-apoptotic protein Bcl-2 were down-regulated, while pro-apoptotic protein Bax was up-regulated by miR-145.	('expression level', 'MPA', (4, 20))	('P-gp', 'Gene', '5243', (30, 34))	('CyclinD1', 'Gene', (36, 44))	('up-regulated', 'PosReg', (142, 154))	('c-Myc', 'Gene', '4609', (46, 51))	('MRP1', 'Gene', (24, 28))	('P-gp', 'Gene', (30, 34))	('miR-145', 'Var', (158, 165))	('down-regulated', 'NegReg', (90, 104))	('Bax', 'Gene', (134, 137))	('c-Myc', 'Gene', (46, 51))	('CyclinD1', 'Gene', '595', (36, 44))	('MRP1', 'Gene', '4363', (24, 28))	('Bcl-2', 'Gene', (79, 84))	('Bcl-2', 'Gene', '596', (79, 84))	('Bax', 'Gene', '581', (134, 137))
333256	31582906	miR-145 increased the sensitivity of ESCC to DDP, and facilitated DDP-induced apoptosis, cycle arrest by directly inhibiting PI3K/AKT signaling pathway to decrease multidrug resistance-associated proteins MRP1 and P-gp expression.	('apoptosis', 'CPA', (78, 87))	('ESCC', 'Disease', (37, 41))	('decrease', 'NegReg', (155, 163))	('AKT', 'Gene', '207', (130, 133))	('P-gp', 'Gene', '5243', (214, 218))	('MRP1', 'Gene', (205, 209))	('miR-145', 'Var', (0, 7))	('DDP', 'Gene', '1678', (45, 48))	('DDP', 'Gene', (45, 48))	('drug resistance', 'Phenotype', 'HP:0020174', (169, 184))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('inhibiting', 'NegReg', (114, 124))	('DDP', 'Gene', '1678', (66, 69))	('DDP', 'Gene', (66, 69))	('sensitivity', 'MPA', (22, 33))	('ESCC', 'Disease', 'MESH:C562729', (37, 41))	('AKT', 'Gene', (130, 133))	('multidrug resistance-associated', 'MPA', (164, 195))	('P-gp', 'Gene', (214, 218))	('expression', 'MPA', (219, 229))	('facilitated', 'PosReg', (54, 65))	('MRP1', 'Gene', '4363', (205, 209))	('increased', 'PosReg', (8, 17))	('arrest', 'Disease', (95, 101))
333275	31582906	Additionally, it was reported that miR-145 was significantly decreased in ESCC tissues by microRNA microarray, and miR-145 could be regarded as a potential tumor marker for diagnosis of ESCC.	('miR-145', 'Var', (115, 122))	('ESCC', 'Disease', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('ESCC', 'Disease', 'MESH:C562729', (186, 190))	('ESCC', 'Disease', 'MESH:C562729', (74, 78))	('tumor', 'Disease', (156, 161))	('decreased', 'NegReg', (61, 70))	('miR-145', 'Gene', (35, 42))	('ESCC', 'Disease', (186, 190))
333278	31582906	In the present study, we found that miR-145 could increase the sensitivity of ESCC to DDP and enhance the suppressive efficacy of DDP on ESCC growth.	('ESCC', 'Disease', (78, 82))	('DDP', 'Gene', (130, 133))	('miR-145', 'Var', (36, 43))	('sensitivity', 'MPA', (63, 74))	('enhance', 'PosReg', (94, 101))	('DDP', 'Gene', (86, 89))	('ESCC', 'Disease', (137, 141))	('increase', 'PosReg', (50, 58))	('DDP', 'Gene', '1678', (130, 133))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('ESCC', 'Disease', 'MESH:C562729', (137, 141))	('DDP', 'Gene', '1678', (86, 89))
333279	31582906	Furthermore, miR-145 could promote DDP-induced apoptosis, cycle arrest by directly inhibiting PI3K/AKT3 signaling pathway to decrease the expression level of MRP1, P-gp and proliferation-related proteins.	('arrest', 'Disease', (64, 70))	('P-gp', 'Gene', '5243', (164, 168))	('AKT3', 'Gene', '10000', (99, 103))	('MRP1', 'Gene', '4363', (158, 162))	('expression level', 'MPA', (138, 154))	('MRP1', 'Gene', (158, 162))	('apoptosis', 'CPA', (47, 56))	('arrest', 'Disease', 'MESH:D006323', (64, 70))	('DDP', 'Gene', (35, 38))	('promote', 'PosReg', (27, 34))	('P-gp', 'Gene', (164, 168))	('inhibiting', 'NegReg', (83, 93))	('miR-145', 'Var', (13, 20))	('decrease', 'NegReg', (125, 133))	('AKT3', 'Gene', (99, 103))	('DDP', 'Gene', '1678', (35, 38))
333302	31582906	The 3'-UTR of the wildtype AKT3 and a variant containing mutations in the putative binding site were inserted downstream of the firefly luciferase reporter into the psiCHECK-2 vector (Promega, Madison, WI, USA).	('AKT3', 'Gene', '10000', (27, 31))	('mutations', 'Var', (57, 66))	('AKT3', 'Gene', (27, 31))
333303	31582906	Constructed luciferase reporter plasmids (wildtype or mutant AKT3 plasmids) were co-transfected with miR-145 mimics or miR-NC into cells using Lipofectamine 2000.	('miR-145', 'Gene', (101, 108))	('mutant', 'Var', (54, 60))	('Lipofectamine', 'Chemical', 'MESH:C086724', (143, 156))	('AKT3', 'Gene', (61, 65))	('AKT3', 'Gene', '10000', (61, 65))
333332	31582906	qRT-PCR results demonstrated that increasing miR-145 significantly inhibited the mRNA level of AKT3 in EC109 and KYSE-30 cells (Fig.	('inhibited', 'NegReg', (67, 76))	('miR-145', 'Var', (45, 52))	('mRNA level of', 'MPA', (81, 94))	('AKT3', 'Gene', (95, 99))	('AKT3', 'Gene', '10000', (95, 99))
333339	31582906	These results demonstrated that AKT3 is one direct target of miR-145 in ESCC, and miR-145 can inhibit PI3K/AKT signaling pathway by directly down-regulating AKT3.	('AKT', 'Gene', (157, 160))	('down-regulating', 'NegReg', (141, 156))	('AKT', 'Gene', '207', (32, 35))	('AKT', 'Gene', (107, 110))	('ESCC', 'Disease', 'MESH:C562729', (72, 76))	('miR-145', 'Var', (82, 89))	('AKT3', 'Gene', (32, 36))	('AKT', 'Gene', (32, 35))	('AKT', 'Gene', '207', (157, 160))	('AKT3', 'Gene', '10000', (32, 36))	('AKT3', 'Gene', (157, 161))	('inhibit', 'NegReg', (94, 101))	('AKT', 'Gene', '207', (107, 110))	('ESCC', 'Disease', (72, 76))	('AKT3', 'Gene', '10000', (157, 161))
333343	31582906	3d, overexpression of miR-145 and knockdown of AKT3 could significantly reduce multidrug resistance-associated protein MRP1 and P-gp expression, while overexpression of AKT3 could reverse the above effects in miR-145-overexpressing cells.	('expression', 'MPA', (133, 143))	('MRP1', 'Gene', (119, 123))	('P-gp', 'Gene', '5243', (128, 132))	('miR-145', 'Gene', (22, 29))	('knockdown', 'Var', (34, 43))	('AKT3', 'Gene', (169, 173))	('AKT3', 'Gene', '10000', (169, 173))	('MRP1', 'Gene', '4363', (119, 123))	('P-gp', 'Gene', (128, 132))	('AKT3', 'Gene', (47, 51))	('reduce', 'NegReg', (72, 78))	('drug resistance', 'Phenotype', 'HP:0020174', (84, 99))	('AKT3', 'Gene', '10000', (47, 51))
333344	31582906	Corresponding to these changes, the pro-survival c-Myc, cyclinD1, and Bcl-2 levels were markedly reduced, while that of pro-apoptotic Bax was increased in miR-145 mimics or sh-AKT3-treated ESCC cells.	('c-Myc', 'Gene', '4609', (49, 54))	('cyclinD1', 'Gene', (56, 64))	('AKT3', 'Gene', (176, 180))	('increased', 'PosReg', (142, 151))	('Bcl-2', 'Gene', (70, 75))	('c-Myc', 'Gene', (49, 54))	('Bcl-2', 'Gene', '596', (70, 75))	('changes', 'Var', (23, 30))	('ESCC', 'Disease', 'MESH:C562729', (189, 193))	('reduced', 'NegReg', (97, 104))	('cyclinD1', 'Gene', '595', (56, 64))	('ESCC', 'Disease', (189, 193))	('AKT3', 'Gene', '10000', (176, 180))	('Bax', 'Gene', (134, 137))	('miR-145', 'Gene', (155, 162))	('Bax', 'Gene', '581', (134, 137))
333350	31582906	In EC109, overexpression of miR-145 and knockdown of AKT3 reduced the IC50 of DDP from 64.40 to 32.01 muM and 33.64 muM, respectively.	('DDP', 'Gene', (78, 81))	('muM', 'Gene', (116, 119))	('muM', 'Gene', (102, 105))	('knockdown', 'Var', (40, 49))	('AKT3', 'Gene', (53, 57))	('DDP', 'Gene', '1678', (78, 81))	('AKT3', 'Gene', '10000', (53, 57))	('overexpression', 'PosReg', (10, 24))	('reduced', 'NegReg', (58, 65))	('muM', 'Gene', '56925', (102, 105))	('muM', 'Gene', '56925', (116, 119))	('miR-145', 'Var', (28, 35))
333352	31582906	Similarly, overexpression of miR-145 and knockdown of AKT3 reduced the IC50 of DDP by 55.3% and 53.9%, which was abrogated by the co-overexpression of miR-145 and AKT3 in KYSE-30 cells (Fig.	('reduced', 'NegReg', (59, 66))	('DDP', 'Gene', (79, 82))	('AKT3', 'Gene', (54, 58))	('AKT3', 'Gene', (163, 167))	('AKT3', 'Gene', '10000', (163, 167))	('DDP', 'Gene', '1678', (79, 82))	('AKT3', 'Gene', '10000', (54, 58))	('knockdown', 'Var', (41, 50))
333353	31582906	To conclude, miR-145 inhibits the expression of AKT3, rendering ESCC cells more sensitive to DDP.	('DDP', 'Gene', '1678', (93, 96))	('inhibits', 'NegReg', (21, 29))	('ESCC', 'Disease', (64, 68))	('expression', 'MPA', (34, 44))	('AKT3', 'Gene', (48, 52))	('AKT3', 'Gene', '10000', (48, 52))	('DDP', 'Gene', (93, 96))	('miR-145', 'Var', (13, 20))	('ESCC', 'Disease', 'MESH:C562729', (64, 68))	('sensitive', 'MPA', (80, 89))
333358	31582906	Taken together, miR-145 renders ESCC cells more sensitive to DDP-induced cell cycle arrest and apoptosis.	('DDP', 'Gene', (61, 64))	('ESCC', 'Disease', (32, 36))	('miR-145', 'Var', (16, 23))	('more', 'PosReg', (43, 47))	('apoptosis', 'CPA', (95, 104))	('arrest', 'Disease', 'MESH:D006323', (84, 90))	('ESCC', 'Disease', 'MESH:C562729', (32, 36))	('DDP', 'Gene', '1678', (61, 64))	('arrest', 'Disease', (84, 90))	('sensitive', 'MPA', (48, 57))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (73, 90))
333362	31582906	Western blotting revealed that the expression of MRP1, P-gp, c-Myc, cyclin D1 and Bcl-2 was up-regulated while Bax was down-regulated in miR-145 inhibition and AKT3 overexpression group (Fig.	('P-gp', 'Gene', '5243', (55, 59))	('expression', 'MPA', (35, 45))	('cyclin D1', 'Gene', '595', (68, 77))	('inhibition', 'Var', (145, 155))	('down-regulated', 'NegReg', (119, 133))	('up-regulated', 'PosReg', (92, 104))	('Bcl-2', 'Gene', (82, 87))	('MRP1', 'Gene', '4363', (49, 53))	('Bax', 'Gene', (111, 114))	('Bax', 'Gene', '581', (111, 114))	('Bcl-2', 'Gene', '596', (82, 87))	('AKT3', 'Gene', '10000', (160, 164))	('P-gp', 'Gene', (55, 59))	('c-Myc', 'Gene', (61, 66))	('MRP1', 'Gene', (49, 53))	('AKT3', 'Gene', (160, 164))	('c-Myc', 'Gene', '4609', (61, 66))	('miR-145', 'Var', (137, 144))	('cyclin D1', 'Gene', (68, 77))
333366	31582906	Taken together, inhibition of miR-145 desensitized ESCC cells to DDP via directly up-regulating AKT3.	('ESCC', 'Disease', 'MESH:C562729', (51, 55))	('AKT3', 'Gene', (96, 100))	('AKT3', 'Gene', '10000', (96, 100))	('miR-145', 'Gene', (30, 37))	('desensitized', 'NegReg', (38, 50))	('up-regulating', 'PosReg', (82, 95))	('DDP', 'Gene', (65, 68))	('ESCC', 'Disease', (51, 55))	('DDP', 'Gene', '1678', (65, 68))	('inhibition', 'Var', (16, 26))
333380	31582906	In the present study, we reported a direct link between miR-145 and AKT3 in ESCC and demonstrated that miR-145 increased the chemosensitivity to DDP through inhibiting multidrug resistance-associated protein MRP1 and P-gp expression by directly suppressing PI3K/AKT signaling pathway.	('suppressing', 'NegReg', (245, 256))	('AKT', 'Gene', (262, 265))	('inhibiting', 'NegReg', (157, 167))	('AKT3', 'Gene', '10000', (68, 72))	('ESCC', 'Disease', (76, 80))	('miR-145', 'Var', (103, 110))	('P-gp', 'Gene', (217, 221))	('AKT3', 'Gene', (68, 72))	('AKT', 'Gene', '207', (262, 265))	('expression', 'MPA', (222, 232))	('AKT', 'Gene', (68, 71))	('DDP', 'Gene', '1678', (145, 148))	('DDP', 'Gene', (145, 148))	('MRP1', 'Gene', '4363', (208, 212))	('P-gp', 'Gene', '5243', (217, 221))	('increased', 'PosReg', (111, 120))	('multidrug', 'Protein', (168, 177))	('ESCC', 'Disease', 'MESH:C562729', (76, 80))	('AKT', 'Gene', '207', (68, 71))	('drug resistance', 'Phenotype', 'HP:0020174', (173, 188))	('MRP1', 'Gene', (208, 212))
333381	31582906	As a tumor suppressor, aberrant miR-145 expression is discovered in a variety of cancers.	('expression', 'MPA', (40, 50))	('discovered', 'Reg', (54, 64))	('miR-145', 'Gene', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('tumor', 'Disease', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('aberrant', 'Var', (23, 31))
333387	31582906	discovered that miR-145 sensitized ovarian cancer cells to the paclitaxel treatment by suppressing the expression of Sp1 and CDK6.	('paclitaxel', 'Chemical', 'MESH:D017239', (63, 73))	('miR-145', 'Var', (16, 23))	('sensitized', 'Reg', (24, 34))	('expression', 'MPA', (103, 113))	('Sp1', 'Gene', (117, 120))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('suppressing', 'NegReg', (87, 98))	('CDK6', 'Gene', (125, 129))	('CDK6', 'Gene', '1021', (125, 129))	('ovarian cancer', 'Disease', (35, 49))
333390	31582906	Additionally, miR-145 could enhance DDP-mediated anti-tumor efficacy in vivo.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('DDP', 'Gene', '1678', (36, 39))	('enhance', 'PosReg', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('DDP', 'Gene', (36, 39))	('miR-145', 'Var', (14, 21))
333391	31582906	These results fully indicated that miR-145 can increase the sensitivity of ESCC to DDP by targeting AKT3.	('AKT3', 'Gene', '10000', (100, 104))	('DDP', 'Gene', '1678', (83, 86))	('ESCC', 'Disease', (75, 79))	('AKT3', 'Gene', (100, 104))	('DDP', 'Gene', (83, 86))	('increase', 'PosReg', (47, 55))	('targeting', 'Reg', (90, 99))	('miR-145', 'Var', (35, 42))	('sensitivity', 'MPA', (60, 71))	('ESCC', 'Disease', 'MESH:C562729', (75, 79))
333395	31582906	Furthermore, we found for the first time that AKT3 was a target of miR-145 in ESCC, and overexpression of miR-145 promoted the sensitivity of ESCC to DDP by targeting AKT3 to inhibit PI3K/AKT signaling pathway.	('AKT', 'Gene', (167, 170))	('DDP', 'Gene', (150, 153))	('AKT3', 'Gene', (46, 50))	('AKT', 'Gene', (46, 49))	('inhibit', 'NegReg', (175, 182))	('AKT', 'Gene', (188, 191))	('ESCC', 'Disease', 'MESH:C562729', (142, 146))	('AKT', 'Gene', '207', (167, 170))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('AKT', 'Gene', '207', (46, 49))	('sensitivity', 'MPA', (127, 138))	('AKT', 'Gene', '207', (188, 191))	('promoted', 'PosReg', (114, 122))	('ESCC', 'Disease', (142, 146))	('AKT3', 'Gene', '10000', (167, 171))	('ESCC', 'Disease', (78, 82))	('targeting', 'Reg', (157, 166))	('DDP', 'Gene', '1678', (150, 153))	('AKT3', 'Gene', '10000', (46, 50))	('AKT3', 'Gene', (167, 171))	('miR-145', 'Var', (106, 113))
333404	31582906	Overexpression of AKT3 and knockdown of AKT3 could promote and inhibit the expression of multidrug resistance and cell proliferation-related proteins including MRP1, P-gp, c-Myc, Cyclin D1 and Bcl-2, respectively.	('P-gp', 'Gene', '5243', (166, 170))	('inhibit', 'NegReg', (63, 70))	('knockdown', 'Var', (27, 36))	('AKT3', 'Gene', '10000', (18, 22))	('Cyclin D1', 'Gene', '595', (179, 188))	('MRP1', 'Gene', '4363', (160, 164))	('AKT3', 'Gene', '10000', (40, 44))	('Cyclin D1', 'Gene', (179, 188))	('Bcl-2', 'Gene', (193, 198))	('P-gp', 'Gene', (166, 170))	('AKT3', 'Gene', (18, 22))	('multidrug', 'MPA', (89, 98))	('c-Myc', 'Gene', '4609', (172, 177))	('c-Myc', 'Gene', (172, 177))	('AKT3', 'Gene', (40, 44))	('Bcl-2', 'Gene', '596', (193, 198))	('drug resistance', 'Phenotype', 'HP:0020174', (94, 109))	('promote', 'PosReg', (51, 58))	('MRP1', 'Gene', (160, 164))	('expression', 'MPA', (75, 85))	('cell proliferation-related', 'CPA', (114, 140))
333408	31582906	It was reported that miR-145 could induce the cell cycle arrest and inhibit cell proliferation by inhibiting the expression of CDK4 and c-Myc in prostate cancer cells and non-small cell lung cancer cells.	('prostate cancer', 'Disease', 'MESH:D011471', (145, 160))	('arrest', 'Disease', 'MESH:D006323', (57, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (145, 160))	('induce', 'PosReg', (35, 41))	('prostate cancer', 'Disease', (145, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (171, 197))	('inhibiting', 'NegReg', (98, 108))	('c-Myc', 'Gene', (136, 141))	('expression', 'MPA', (113, 123))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (175, 197))	('miR-145', 'Var', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('c-Myc', 'Gene', '4609', (136, 141))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (46, 63))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (171, 197))	('CDK4', 'Gene', (127, 131))	('inhibit', 'NegReg', (68, 75))	('arrest', 'Disease', (57, 63))	('cell proliferation', 'CPA', (76, 94))	('non-small cell lung cancer', 'Disease', (171, 197))	('CDK4', 'Gene', '1019', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
333409	31582906	Additionally, miR-145 could sensitize ovarian cancer cells to paclitaxel by directly targeting CDK6 to reduce the expression of CDK6, along with downregulation of P-gp.	('P-gp', 'Gene', (163, 167))	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('targeting', 'Reg', (85, 94))	('CDK6', 'Gene', (95, 99))	('CDK6', 'Gene', '1021', (95, 99))	('ovarian cancer', 'Disease', 'MESH:D010051', (38, 52))	('paclitaxel', 'Chemical', 'MESH:D017239', (62, 72))	('P-gp', 'Gene', '5243', (163, 167))	('reduce', 'NegReg', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('expression', 'MPA', (114, 124))	('downregulation', 'NegReg', (145, 159))	('ovarian cancer', 'Disease', (38, 52))	('CDK6', 'Gene', (128, 132))	('CDK6', 'Gene', '1021', (128, 132))	('miR-145', 'Var', (14, 21))
333410	31582906	Furthermore, miR-145 inhibited cell proliferation and promoted cell apoptosis through negatively regulating mTOR signaling pathway and decreasing MMP-2 and MMP-9 expression, the Bax/Bcl-2 ratio and the activity of the caspase-3 cascade in human lung adenocarcinoma A549 cells.	('Bcl-2', 'Gene', (182, 187))	('mTOR', 'Gene', '2475', (108, 112))	('inhibited', 'NegReg', (21, 30))	('human', 'Species', '9606', (239, 244))	('MMP-2', 'Gene', '4313', (146, 151))	('promoted', 'PosReg', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('negatively regulating', 'NegReg', (86, 107))	('Bcl-2', 'Gene', '596', (182, 187))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (245, 264))	('MMP-9', 'Gene', '4318', (156, 161))	('miR-145', 'Var', (13, 20))	('MMP-9', 'Gene', (156, 161))	('MMP-2', 'Gene', (146, 151))	('cell proliferation', 'CPA', (31, 49))	('caspase-3', 'Gene', '836', (218, 227))	('activity', 'MPA', (202, 210))	('cell apoptosis', 'CPA', (63, 77))	('decreasing', 'NegReg', (135, 145))	('mTOR', 'Gene', (108, 112))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (245, 264))	('caspase-3', 'Gene', (218, 227))	('lung adenocarcinoma', 'Disease', (245, 264))	('expression', 'MPA', (162, 172))	('Bax', 'Gene', (178, 181))	('Bax', 'Gene', '581', (178, 181))
333412	31582906	Here, we observed that overexpression of miR-145 and knockdown of AKT3 could promote DDP-induced apoptosis and cycle arrest of ESCC cells.	('AKT3', 'Gene', (66, 70))	('overexpression', 'PosReg', (23, 37))	('promote', 'PosReg', (77, 84))	('AKT3', 'Gene', '10000', (66, 70))	('ESCC', 'Disease', (127, 131))	('knockdown', 'Var', (53, 62))	('arrest', 'Disease', (117, 123))	('DDP', 'Gene', '1678', (85, 88))	('ESCC', 'Disease', 'MESH:C562729', (127, 131))	('miR-145', 'Var', (41, 48))	('arrest', 'Disease', 'MESH:D006323', (117, 123))	('DDP', 'Gene', (85, 88))
333432	30112053	Numerous studies have indicated that certain genes act as tumor suppressors, and that several genes inhibit cancer cell migration, invasion and tumor progression in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (144, 149))	('invasion', 'CPA', (131, 139))	('genes', 'Var', (94, 99))	('ESCC', 'Disease', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('inhibit', 'NegReg', (100, 107))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
333438	30112053	GSM509787-GSM509803) and 17 samples of tumor tissues (with the ID nos.	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('GSM509787-GSM509803', 'Var', (0, 19))	('tumor', 'Disease', (39, 44))
333439	30112053	GSM509804-GSM509820) from patients with ESCC.	('ESCC', 'Disease', (40, 44))	('patients', 'Species', '9606', (26, 34))	('GSM509804-GSM509820', 'Var', (0, 19))
333457	30112053	These results suggest that the DEGs may be mainly involved in regulating the cell cycle and organogenesis, which are closely associated with tumorigenesis and tumor progression.	('DEGs', 'Var', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (141, 146))	('organogenesis', 'CPA', (92, 105))	('tumor', 'Disease', (159, 164))	('regulating', 'Reg', (62, 72))	('involved', 'Reg', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cell cycle', 'CPA', (77, 87))
333464	30112053	CDK4/6 inhibitor-SHR6390 was reported to exert an antitumor effect against ESCC.	('inhibitor-SHR6390', 'Var', (7, 24))	('ESCC', 'Disease', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('CDK4/6', 'Gene', (0, 6))
333468	30112053	It was demonstrated that abnormal levels of H2AF may be associated with poor survival of ESCC patients.	('H2AF', 'Protein', (44, 48))	('H2AF', 'Chemical', '-', (44, 48))	('patients', 'Species', '9606', (94, 102))	('associated', 'Reg', (56, 66))	('ESCC', 'Disease', (89, 93))	('abnormal levels', 'Var', (25, 40))
333527	29554098	For the study period, a statistically significant reduction was verified in the annual percentage change estimated for mortality due to ill-defined death certificates and those presenting codes referring to incomplete diagnosis for general cancer (195,197 to 199, 238 to 239 in CID-9 and C-76 to C-80 e C-97 in CID-10) as well as incomplete diagnosis for esophageal cancer (159 in CID-9 and C-26 in CID-10), shown in Table 1.	('C-26', 'Var', (391, 395))	('esophageal cancer', 'Disease', (355, 372))	('cancer', 'Disease', (366, 372))	('C', 'Chemical', 'MESH:D002244', (391, 392))	('cancer', 'Disease', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('C', 'Chemical', 'MESH:D002244', (296, 297))	('159', 'Var', (374, 377))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('reduction', 'NegReg', (50, 59))	('C', 'Chemical', 'MESH:D002244', (399, 400))	('C', 'Chemical', 'MESH:D002244', (288, 289))	('C', 'Chemical', 'MESH:D002244', (311, 312))	('C', 'Chemical', 'MESH:D002244', (278, 279))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('C', 'Chemical', 'MESH:D002244', (303, 304))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('C', 'Chemical', 'MESH:D002244', (381, 382))	('esophageal cancer', 'Disease', 'MESH:D004938', (355, 372))	('195,197', 'Var', (248, 255))	('C-76', 'Var', (288, 292))
333563	29554098	The stomach infected by this bacterium produces less acid and inhibits the synthesis of ghrelin, which induces satiety:ghrelin prevents obesity and promotes gastric emptying.	('obesity', 'Disease', 'MESH:D009765', (136, 143))	('inhibits', 'NegReg', (62, 70))	('acid', 'MPA', (53, 57))	('obesity', 'Disease', (136, 143))	('gastric emptying', 'CPA', (157, 173))	('prevents', 'NegReg', (127, 135))	('ghrelin', 'Chemical', 'MESH:D054439', (119, 126))	('ghrelin', 'Var', (119, 126))	('ghrelin', 'Chemical', 'MESH:D054439', (88, 95))	('promotes', 'PosReg', (148, 156))	('gastric emptying', 'Phenotype', 'HP:0002578', (157, 173))	('synthesis', 'MPA', (75, 84))	('obesity', 'Phenotype', 'HP:0001513', (136, 143))
333589	26575328	Positive/high Oct-4 was significantly associated with cancer stage in several kinds of cancer.	('cancer', 'Disease', (87, 93))	('associated with', 'Reg', (38, 53))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (54, 60))	('Positive/high', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Oct-4', 'Gene', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
333590	26575328	Specifically, positive/high Oct-4 was associated with cancer stage III/IV (fixed effects: OR = 1.53, 95% CI = 1.12-2.10), primary tumor (T3-4) (random effects: OR = 1.93, 95% CI = 0.99-3.77), and cancer grade of differentiation (intermediate-poor) (random effects: OR = 3.45, 95% CI = 1.5-7.61).	('primary tumor', 'Disease', 'MESH:D009369', (122, 135))	('positive/high', 'Var', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('associated', 'Reg', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', (196, 202))	('Oct-4', 'Gene', (28, 33))	('primary tumor', 'Disease', (122, 135))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
333591	26575328	These findings suggest that positive/high Oct-4 is more strongly linked to stage III/IV cancer and cancer grade of differentiation, and is correlated with malignant characteristics that lead to poor prognosis in different types of cancer, especially in Asian.	('positive/high', 'Var', (28, 41))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('linked', 'Reg', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (231, 237))	('Asian', 'Disease', (253, 258))	('cancer', 'Disease', (99, 105))	('IV cancer', 'Disease', 'MESH:D009369', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Oct-4', 'Gene', (42, 47))	('IV cancer', 'Disease', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
333595	26575328	For example, positive/high nestin may be more strongly linked to advanced cancer stage and correlated with malignant characteristics that lead to poor prognosis in different cancers, especially lung cancer.	('nestin', 'Protein', (27, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('especially lung cancer', 'Disease', (183, 205))	('especially lung cancer', 'Disease', 'MESH:D008175', (183, 205))	('linked', 'Reg', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', (74, 80))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('positive/high', 'Var', (13, 26))
333606	26575328	and Ji et al., only some reported a strong association between positive/high Oct-4 and cancer stage.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Oct-4', 'Gene', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('positive/high', 'Var', (63, 76))
333607	26575328	Because the limited sample size of individual studies limits their statistical power, it is important to summarize otherwise inconclusive results across multiple studies to provide evidence for an association of positive/high Oct-4 with cancer stage.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('Oct-4', 'Gene', (226, 231))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('positive/high', 'Var', (212, 225))	('association', 'Interaction', (197, 208))	('cancer', 'Disease', (237, 243))
333614	26575328	In order to elucidate the association of positive/high Oct-4 with cancer stage, we carried out a meta-analysis of all eligible studies.	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('positive/high Oct-4', 'Var', (41, 60))	('cancer', 'Disease', (66, 72))
333617	26575328	Ultimately, 11 studies on Oct-4 and cancer staging were deemed eligible for the final analysis; collectively, these studies included a total of 502 positive/high Oct-4 cases and 522 negative/low case-free controls.	('positive/high', 'Var', (148, 161))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Oct-4', 'Gene', (162, 167))
333624	26575328	When all eligible studies were pooled in the meta-analysis, there was evidence of an association between positive/high Oct-4 and cancer stage III/IV in different cancers.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (162, 168))	('cancers', 'Disease', (162, 169))	('positive/high', 'Var', (105, 118))	('cancer', 'Disease', (129, 135))	('Oct-4', 'Gene', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
333627	26575328	As shown in Figure 3A, an analysis stratified by primary tumor (T3-4) showed that a significant main effect remained (positive/high Oct-4 versus negative/low Oct-4: OR = 1.93, 95% CI = 0.99 - 3.77, P = 0.05).	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('primary tumor', 'Disease', 'MESH:D009369', (49, 62))	('primary tumor', 'Disease', (49, 62))	('positive/high Oct-4', 'Var', (118, 137))
333629	26575328	As show in Figure 3C, an analysis stratified by cancer grade of differentiation showed that the main effect remained (positive/high Oct-4 versus negative/low Oct-4: OR = 3.45, 95% CI = 1.56 - 7.61, P = 0.002).	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('positive/high Oct-4', 'Var', (118, 137))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))
333630	26575328	Statistically significant heterogeneity was observed between trials of the following analyses using the Q statistic: Oct-4 with cancer stage III/IV, positive/high Oct-4 versus negative/low Oct-4 (P = 0.19, I2 = 29%); Oct-4 with primary tumor (T3-4), positive/high Oct-4 versus negative/low Oct-4 (P = 0.01, I2 = 64%); Oct-4 with cancer grade of differentiation, positive/high Oct-4 versus negative/low Oct-4 (P = 0.003, I2 = 69%).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('positive/high Oct-4', 'Var', (362, 381))	('cancer', 'Disease', (329, 335))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('primary tumor', 'Disease', (228, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('primary tumor', 'Disease', 'MESH:D009369', (228, 241))	('cancer', 'Disease', (128, 134))
333640	26575328	Several clinical studies, including those by Ge et al., Dong et al., He et al., Li et al., and Ji et al., have reported that positive/high Oct-4 s strongly and significantly associated with cancer stage.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('associated with', 'Reg', (174, 189))	('positive/high', 'Var', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('Oct-4', 'Protein', (139, 144))
333643	26575328	Our meta-analysis provided evidence of a significant association between positive/high Oct-4 and cancer stage III/IV in different cancers.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (97, 103))	('positive/high Oct-4', 'Var', (73, 92))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancer', 'Disease', (130, 136))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
333645	26575328	The relationship of Oct-4 with cancer staging parameters suggests that positive/high Oct-4 can further inform the judgment of cancer malignancy based on basic TNM staging.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer malignancy', 'Disease', 'MESH:D009369', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('TNM', 'Gene', '10178', (159, 162))	('cancer malignancy', 'Disease', (126, 143))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('positive/high', 'Var', (71, 84))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('Oct-4', 'Gene', (85, 90))	('TNM', 'Gene', (159, 162))	('cancer', 'Disease', (31, 37))	('inform', 'Reg', (103, 109))
333658	26575328	Articles published as of May 2015 that included case-control or cohort studies related to the association of positive/high Oct-4 with cancer stage were collected.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('positive/high', 'Var', (109, 122))	('Oct-4', 'Gene', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
333659	26575328	The following criteria were used to select publications for further meta-analysis: (1) published in English and Chinese regardless of publication time; (2) evaluated associations between positive/high Oct-4 and cancer stage; (3) confirmed cancer patients pathologically; (4) included detailed cancer/TNM staging data; and (5) compared at least two groups (i.e., positive Oct-4 vs. negative Oct-4 or high Oct-4 vs. low Oct-4).	('cancer', 'Disease', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('patients', 'Species', '9606', (246, 254))	('cancer', 'Disease', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('TNM', 'Gene', '10178', (300, 303))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('positive Oct-4', 'Var', (362, 376))	('TNM', 'Gene', (300, 303))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
333663	26575328	The associations between positive/high Oct-4 and cancer stage were determined by measuring odds ratio (OR) and associated 95% confidence intervals (CIs).	('positive/high', 'Var', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Oct-4', 'Gene', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
333664	26575328	In summary, our meta-analysis provides evidence of an association between positive/high Oct-4 and cancer stage, especially in Asian.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Oct-4', 'Gene', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('positive/high', 'Var', (74, 87))	('cancer', 'Disease', (98, 104))	('Asian', 'Disease', (126, 131))
333665	26575328	Thus, positive/high Oct-4 may play a role in contributing to higher-grade cancer.	('contributing', 'Reg', (45, 57))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('Oct-4', 'Protein', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('positive/high', 'Var', (6, 19))
333675	25070798	They performed whole-genome sequencing of cancer cases in a discovery cohort (n=22), and identified 26 genes with recurrent mutations for targeted resequencing in an additional 90 cancer cases.	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
333676	25070798	The exceptions were SMAD4, which was mutated only in invasive cancers, and TP53, which was mutated only rarely (2.5%) in non-dysplastic BE but frequently in high-grade dysplasia (72%) and invasive cancer samples (69%.)	('dysplasia', 'Disease', (168, 177))	('TP53', 'Gene', '7157', (75, 79))	('SMAD4', 'Gene', '4089', (20, 25))	('dysplasia', 'Disease', 'MESH:D004476', (168, 177))	('invasive cancer', 'Disease', 'MESH:D009362', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('invasive cancer', 'Disease', (188, 203))	('invasive cancers', 'Disease', (53, 69))	('BE', 'Phenotype', 'HP:0100580', (136, 138))	('SMAD4', 'Gene', (20, 25))	('invasive cancer', 'Disease', 'MESH:D009362', (188, 203))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('mutated', 'Var', (37, 44))	('non-dysplastic BE', 'Disease', (121, 138))	('invasive cancers', 'Disease', 'MESH:D009362', (53, 69))	('TP53', 'Gene', (75, 79))
333677	25070798	While the presence of mutated TP53 in high grade dysplasia and its predictiveness of subsequent EA has been known for a number of years, a particularly exciting aspect of the research reported by Weaver, et al.	('TP53', 'Gene', (30, 34))	('dysplasia', 'Disease', (49, 58))	('dysplasia', 'Disease', 'MESH:D004476', (49, 58))	('mutated', 'Var', (22, 29))	('TP53', 'Gene', '7157', (30, 34))
333678	25070798	The authors established the ability of the Cytosponge to collect cells in which TP53 mutations can be reliably detected, despite low and variable allele fractions of mutant DNA (ranging from <1% to 36%).	('mutations', 'Var', (85, 94))	('mutant', 'Var', (166, 172))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))
333679	25070798	They further demonstrated the ability of this approach to identify the presence of high-grade dysplasia with 86% sensitivity (19 mutations detected in 22 individuals with high-grade BE) and 100% specificity (0 mutations detected in 67 individuals with non-dysplastic BE or with no BE).	('dysplasia', 'Disease', (94, 103))	('mutations', 'Var', (129, 138))	('BE', 'Phenotype', 'HP:0100580', (267, 269))	('dysplasia', 'Disease', 'MESH:D004476', (94, 103))	('BE', 'Phenotype', 'HP:0100580', (182, 184))	('BE', 'Phenotype', 'HP:0100580', (281, 283))
333682	25070798	A non-endoscopic test, such as the Cytosponge with TP53 mutation assays, would provide the primary care provider with an important tool to bridge this risk gap (Figure 1).	('mutation assays', 'Var', (56, 71))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (51, 55))
333685	24886123	Physical activity is associated with reduced risk of esophageal cancer, particularly esophageal adenocarcinoma: a systematic review and meta-analysis Physical activity has been inversely associated with risk of several cancers.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Physical', 'Var', (0, 8))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (85, 110))	('esophageal adenocarcinoma', 'Disease', (85, 110))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('esophageal cancer', 'Disease', (53, 70))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (85, 110))	('cancers', 'Disease', (219, 226))	('reduced', 'NegReg', (37, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
333690	24886123	Meta-analysis of published observational studies indicates that physical activity may be associated with reduced risk of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (121, 146))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (121, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('reduced', 'NegReg', (105, 112))	('physical activity', 'Var', (64, 81))	('esophageal adenocarcinoma', 'Disease', (121, 146))
333697	24886123	Physical activity has been associated with a reduced incidence and mortality from certain cancers, including proximal and distal colorectal cancer, gastric cancer, breast and endometrial cancers.	('colorectal cancer', 'Disease', (129, 146))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast and endometrial cancers', 'Disease', 'MESH:D016889', (164, 194))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('gastric cancer', 'Disease', (148, 162))	('Physical activity', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('endometrial cancer', 'Phenotype', 'HP:0012114', (175, 193))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('reduced', 'NegReg', (45, 52))	('cancers', 'Disease', (187, 194))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))
333738	24886123	On restricting analysis to the four high-quality studies, we observed that physical activity is associated with a 16% lower risk of esophageal cancer, though this association did not reach pre-specified statistical significance (OR, 0.84; 95% CI, 0.71-1.00; p = 0.05).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('esophageal cancer', 'Disease', (132, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('lower', 'NegReg', (118, 123))	('physical activity', 'Var', (75, 92))
333752	24886123	Physical activity has been shown to decrease chronic inflammation in intervention trials decreasing interleukin-6 and tumor necrosis factor-alpha, independent of weight loss.	('interleukin-6 and tumor necrosis factor-alpha', 'Gene', '3569;7124', (100, 145))	('weight loss', 'Disease', 'MESH:D015431', (162, 173))	('Physical', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('decreasing', 'NegReg', (89, 99))	('decreasing interleukin-6', 'Phenotype', 'HP:0030783', (89, 113))	('weight loss', 'Disease', (162, 173))	('chronic inflammation', 'Disease', 'MESH:D007249', (45, 65))	('chronic inflammation', 'Disease', (45, 65))	('weight loss', 'Phenotype', 'HP:0001824', (162, 173))	('decrease', 'NegReg', (36, 44))
333753	24886123	Additionally, exercise has been shown to have immunomodulatory effects, improving innate and acquired immune response, promoting tumor surveillance.	('exercise', 'Var', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('promoting', 'PosReg', (119, 128))	('improving', 'PosReg', (72, 81))
333754	24886123	Studies have also shown that aerobic exercise can decrease oxidative stress and enhance DNA repair mechanisms, decreasing carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))	('oxidative stress', 'MPA', (59, 75))	('carcinogenesis', 'Disease', (122, 136))	('decrease', 'NegReg', (50, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (59, 75))	('enhance', 'PosReg', (80, 87))	('aerobic', 'Var', (29, 36))	('decreasing', 'NegReg', (111, 121))	('DNA', 'CPA', (88, 91))
333783	24317510	As tumors may depend on amplified TF genes, they are potential targets for cancer therapy.	('amplified', 'Var', (24, 33))	('TF genes', 'Gene', (34, 42))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (75, 81))	('depend', 'Reg', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
333784	24317510	GATA4 and GATA6 are amplified in up to 30% of gastric and esophageal adenocarcinomas and GATA6 depletion in the latter specifically impairs anchorage-independent cell growth.	('anchorage-independent cell growth', 'CPA', (140, 173))	('depletion', 'Var', (95, 104))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (58, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('GATA6', 'Gene', (89, 94))	('GATA6', 'Gene', (10, 15))	('gastric', 'Disease', (46, 53))	('GATA4', 'Gene', (0, 5))	('impairs', 'NegReg', (132, 139))	('esophageal adenocarcinomas', 'Disease', (58, 84))
333786	24317510	Somatic copy number amplifications (SCNAs) or mutations of ERBB2, EGFR, MET, and FGFR2 offer avenues for targeted therapy in few patients.	('mutations', 'Var', (46, 55))	('EGFR', 'Gene', '1956', (66, 70))	('patients', 'Species', '9606', (129, 137))	('EGFR', 'Gene', (66, 70))	('copy number amplifications', 'Var', (8, 34))	('ERBB2', 'Gene', (59, 64))	('ERBB2', 'Gene', '2064', (59, 64))	('FGFR2', 'Gene', (81, 86))	('MET', 'Gene', (72, 75))	('FGFR2', 'Gene', '2263', (81, 86))
333787	24317510	Esophageal adenocarcinomas, which are closely related, frequently amplify GATA6 and GATA4, TF gene loci that show especially high expression in gastric and duodenal epithelia.	('expression', 'MPA', (130, 140))	('GATA6', 'Gene', (74, 79))	('duodenal epithelia', 'Disease', 'MESH:D004382', (156, 174))	('GATA4', 'Gene', (84, 89))	('Esophageal adenocarcinomas', 'Disease', (0, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('duodenal epithelia', 'Disease', (156, 174))	('amplify', 'Var', (66, 73))	('Esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (0, 26))
333790	24317510	Because gastric cancer frequently arises in a background of intestinal metaplasia, this partnership suggests that GATA gene amplifications may promote proliferative, crypt progenitor-like properties in stomach epithelial cells.	('proliferative', 'CPA', (151, 164))	('gastric cancer', 'Disease', (8, 22))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (60, 81))	('gastric cancer', 'Disease', 'MESH:D013274', (8, 22))	('GATA gene', 'Gene', (114, 123))	('promote', 'PosReg', (143, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (8, 22))	('amplifications', 'Var', (124, 138))	('intestinal metaplasia', 'Disease', (60, 81))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
333796	24317510	Among hundreds of diverse cancers, high-level GATA4 amplifications were largely confined to gastric cancer and GATA6 amplifications to stomach and pancreas adenocarcinomas (Suppl.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('pancreas adenocarcinomas', 'Disease', (147, 171))	('amplifications', 'Var', (117, 131))	('gastric cancer', 'Disease', (92, 106))	('GATA4', 'Gene', (46, 51))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('amplifications', 'Var', (52, 66))	('cancers', 'Disease', (26, 33))	('stomach', 'Disease', (135, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('pancreas adenocarcinomas', 'Disease', 'MESH:D010190', (147, 171))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('GATA6', 'Gene', (111, 116))
333803	24317510	Tumors with high GATA6 amplification showed significantly higher mRNA levels than diploid samples and GATA6 mRNA or protein (Suppl.	('mRNA levels', 'MPA', (65, 76))	('high', 'Var', (12, 16))	('Tumors', 'Disease', (0, 6))	('GATA6', 'Gene', (17, 22))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (58, 64))
333804	24317510	In summary, GATA6 amplification is common in gastric cancers and elevates expression, although tumors lacking amplification also may overexpress GATA6.	('expression', 'MPA', (74, 84))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('overexpress', 'PosReg', (133, 144))	('elevates', 'PosReg', (65, 73))	('GATA6', 'Gene', (12, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancers', 'Disease', 'MESH:D013274', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('gastric cancers', 'Disease', (45, 60))	('gastric cancers', 'Phenotype', 'HP:0012126', (45, 60))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('amplification', 'Var', (18, 31))	('tumors', 'Disease', (95, 101))	('GATA6', 'Gene', (145, 150))
333806	24317510	Protein expression among 9 gastric cancer lines was highest in HUG1N, at levels similar to those found in the CRC cell line Caco-2 (Fig.	('Caco-2', 'CellLine', 'CVCL:0025', (124, 130))	('gastric cancer', 'Phenotype', 'HP:0012126', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Protein expression', 'MPA', (0, 18))	('HUG1N', 'Var', (63, 68))	('highest', 'Reg', (52, 59))	('gastric cancer', 'Disease', (27, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (27, 41))
333819	24317510	GATA6 knockdown in Caco2, AGS and SNU16 cells resulted in smaller G1- and S-phase fractions and higher G2/M-phase fractions than control shRNA-treated cells, indicating M-phase dysfunction (Fig.	('Caco2', 'Gene', (19, 24))	('smaller', 'NegReg', (58, 65))	('AGS', 'Disease', (26, 29))	('M-phase dysfunction', 'Disease', 'MESH:C566367', (169, 188))	('G2/M-phase fractions', 'MPA', (103, 123))	('GATA6', 'Gene', (0, 5))	('AGS', 'Disease', 'MESH:C535607', (26, 29))	('M-phase dysfunction', 'Disease', (169, 188))	('knockdown', 'Var', (6, 15))	('higher', 'PosReg', (96, 102))
333856	24317510	Presence of both CDX2 and GATA6 in many gastric cancers reflects the prevalence of intestinal differentiation in this disease and their partnership may promote tissue-specific proliferation.	('gastric cancers', 'Disease', (40, 55))	('gastric cancers', 'Disease', 'MESH:D013274', (40, 55))	('gastric cancers', 'Phenotype', 'HP:0012126', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('partnership', 'Interaction', (136, 147))	('CDX2', 'Gene', (17, 21))	('GATA6', 'Gene', (26, 31))	('CDX2', 'Gene', '1045', (17, 21))	('intestinal differentiation', 'Disease', (83, 109))	('tissue-specific proliferation', 'CPA', (160, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))	('promote', 'PosReg', (152, 159))	('Presence', 'Var', (0, 8))
333865	24317510	Gastric cancer samples (n=125) used for synexpression analysis were derived from 4 GEO series, GSE19826, GSE2109 and GSE13911, GSE22377, and 24 additional tumors assayed on Affymetrix HG U133 Plus 2.0 arrays.	('GSE2109', 'Chemical', '-', (105, 112))	('Gastric cancer', 'Disease', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('Gastric cancer', 'Disease', 'MESH:D013274', (0, 14))	('GSE2109', 'Var', (105, 112))	('GSE22377', 'Var', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('GSE13911', 'Var', (117, 125))	('GSE19826', 'Var', (95, 103))
333866	24317510	Colon cancer samples (n=1732) are from GEO series GSE10714, GSE13059, GSE13067, GSE13294, GSE13471, GSE14333, GSE17536, GSE17537, GSE17538, GSE18088, GSE18105, GSE20916, GSE2109, GSE21510, GSE23878, GSE26682, GSE26906, GSE28702, GSE31595, GSE33113, GSE33114, GSE4107, GSE4183 and GSE9348, and 11 additional samples.	('GSE17536', 'Var', (110, 118))	('GSE4183', 'Var', (268, 275))	('GSE18105', 'Var', (150, 158))	('GSE26906', 'Var', (209, 217))	('Colon cancer', 'Disease', (0, 12))	('GSE17538', 'Var', (130, 138))	('GSE13471', 'Var', (90, 98))	('GSE33113', 'Var', (239, 247))	('GSE2109', 'Chemical', '-', (170, 177))	('GSE33114', 'Var', (249, 257))	('GSE28702', 'Var', (219, 227))	('Colon cancer', 'Phenotype', 'HP:0003003', (0, 12))	('GSE17537', 'Var', (120, 128))	('GSE13067', 'Var', (70, 78))	('GSE14333', 'Var', (100, 108))	('GSE21510', 'Var', (179, 187))	('GSE13294', 'Var', (80, 88))	('GSE23878', 'Var', (189, 197))	('GSE31595', 'Var', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('GSE4107', 'Var', (259, 266))	('Colon cancer', 'Disease', 'MESH:D015179', (0, 12))
333885	24317510	A distinct cluster containing the HUG1N and AGS cell lines corresponded to those that express high levels of GATA6 (probeset 210002_at) and GATA4 (probeset 205517_at) mRNAs, independent of presence of GATA4 or GATA6 probesets in the distance matrix calculation.	('AGS', 'Disease', (44, 47))	('AGS', 'Disease', 'MESH:C535607', (44, 47))	('GATA6', 'Gene', (109, 114))	('probeset 210002_at', 'Var', (116, 134))	('probeset 205517_at', 'Var', (147, 165))
333923	24570878	For instance, a method must be applied to generate such assays for more than 1,000 cancer-associated proteins that, for instance, are functionally related to candidate cancer driver mutations.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('rat', 'Species', '10116', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('related', 'Reg', (147, 154))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('000 cancer', 'Disease', 'MESH:D009369', (79, 89))	('mutations', 'Var', (182, 191))	('000 cancer', 'Disease', (79, 89))
333959	19058177	The present study investigated the possible tumor inhibitory effects of two antioxidants, alpha-tocopherol (389 ppm and 778 ppm), N-acetylcysteine (NAC, 500 ppm and 1,000 ppm), and their combination (389 ppm and 500 ppm, respectively), as well as an antacid therapeutic agent, omeprazole (1,400 ppm).	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (130, 146))	('389 ppm', 'Var', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (90, 106))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('omeprazole', 'Chemical', 'MESH:D009853', (277, 287))	('389 ppm', 'Var', (108, 115))	('tumor', 'Disease', (44, 49))	('NAC', 'Chemical', 'MESH:D000111', (148, 151))
333962	19058177	alpha-Tocopherol dose-dependently decreased the incidence of EAC (P=0.03), with 778 ppm alpha-tocopherol reducing the incidence of EAC to 59% (16/27) in comparison to 84% (26/31) in the control group (P=0.04).	('778 ppm', 'Var', (80, 87))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (88, 104))	('decreased', 'NegReg', (34, 43))	('EAC', 'Disease', (131, 134))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (0, 16))	('EAC', 'Disease', (61, 64))	('reducing', 'NegReg', (105, 113))
333964	19058177	NAC at 500 ppm and 1,000 ppm did not significantly decrease EAC incidence; however, the combination of alpha-tocopherol 389 ppm and NAC 500 ppm significantly reduced the incidence of EAC to 55% (15/27) (P=0.02).	('NAC', 'Chemical', 'MESH:D000111', (132, 135))	('EAC', 'Disease', (183, 186))	('NAC', 'Var', (132, 135))	('EAC', 'Disease', (60, 63))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (103, 119))	('NAC', 'Chemical', 'MESH:D000111', (0, 3))	('reduced', 'NegReg', (158, 165))
333978	19058177	Both oxidative stress and aberrant arachidonic acid metabolism are believed to contribute to carcinogenesis in the esophagus.	('arachidonic acid', 'Chemical', 'MESH:D016718', (35, 51))	('oxidative stress', 'Phenotype', 'HP:0025464', (5, 21))	('carcinogenesis', 'Disease', (93, 107))	('aberrant', 'Var', (26, 34))	('arachidonic acid metabolism', 'MPA', (35, 62))	('contribute', 'Reg', (79, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (93, 107))	('aberrant arachidonic acid metabolism', 'Phenotype', 'HP:0020197', (26, 62))
333986	19058177	Some suggest that PPI has chemopreventive effect by inflammation relief and decreased epithelial proliferation; while others suggest PPI may promote EAC by producing hypergastrinemia and allowing bile acid-induced mutagenesis in a neutral environment.	('bile acid', 'Chemical', 'MESH:D001647', (196, 205))	('inflammation', 'Disease', (52, 64))	('rat', 'Species', '10116', (104, 107))	('allowing', 'PosReg', (187, 195))	('hypergastrinemia', 'Disease', 'None', (166, 182))	('PPI', 'Var', (133, 136))	('decreased', 'NegReg', (76, 85))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (166, 182))	('promote', 'PosReg', (141, 148))	('hypergastrinemia', 'Disease', (166, 182))	('bile acid-induced mutagenesis', 'MPA', (196, 225))	('inflammation', 'Disease', 'MESH:D007249', (52, 64))	('epithelial proliferation', 'CPA', (86, 110))	('EAC', 'Disease', (149, 152))
334025	19058177	The average body weight of EGDA rats was 8% lower than that of the non-operated control rats, but was not statistically significant.	('lower', 'NegReg', (44, 49))	('rat', 'Species', '10116', (32, 35))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (74, 77))	('rats', 'Species', '10116', (32, 36))	('EGDA', 'Var', (27, 31))	('body weight', 'CPA', (12, 23))	('rats', 'Species', '10116', (88, 92))	('EGDA', 'Chemical', '-', (27, 31))
334028	19058177	Supplementation with 389 ppm or 778 ppm alpha-tocopherol increased the serum alpha-tocopherol concentration by 57% (from 30.7 mumol/L to 48.2 mumol/L) or 79.8% (to 55.2 mumol/L, p<0.05), respectively.	('alpha-tocopherol increased', 'Phenotype', 'HP:0100513', (40, 66))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (77, 93))	('rat', 'Species', '10116', (101, 104))	('serum alpha-tocopherol concentration', 'MPA', (71, 107))	('alpha-tocopherol', 'Protein', (40, 56))	('increased', 'PosReg', (57, 66))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (40, 56))	('778 ppm', 'Var', (32, 39))
334058	19058177	alpha-Tocopherol (778 ppm) treatment appear to decrease the positively stained cells compared with the surgical control (Figure 4), but the effect was not statistically significant.	('778 ppm', 'Var', (18, 25))	('alpha-Tocopherol', 'Protein', (0, 16))	('decrease', 'NegReg', (47, 55))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (0, 16))	('positively stained', 'MPA', (60, 78))
334059	19058177	The combination of alpha-tocopherol (389 ppm) and NAC (500 ppm) significantly reduced the number of positively stained cells relative to the surgical control (Figure 4).	('NAC', 'Chemical', 'MESH:D000111', (50, 53))	('389 ppm', 'Var', (37, 44))	('reduced', 'NegReg', (78, 85))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (19, 35))
334067	19058177	One population-based case-control study in Sweden suggest that subjects with a high intake of vitamin C, beta-carotene, and alpha-tocopherol have 40-50% reduced risk of EAC.	('beta-carotene', 'Chemical', 'MESH:D019207', (105, 118))	('EAC', 'Disease', (169, 172))	('reduced', 'NegReg', (153, 160))	('vitamin C', 'Chemical', 'MESH:D001205', (94, 103))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (124, 140))	('alpha-tocopherol', 'Var', (124, 140))	('high intake of vitamin C', 'Phenotype', 'HP:0100510', (79, 103))
334092	19058177	PPI treatment may also induce squamous re-epithelialization which covers more advanced malignancies in Barrett's glands located in submucosa.	('squamous', 'Disease', (30, 38))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('PPI', 'Var', (0, 3))	("Barrett's glands", 'Phenotype', 'HP:0100580', (103, 119))	('malignancies', 'Disease', (87, 99))
334143	28241109	Notable differences existed for gastroesophageal reflux disease symptoms (72% Barrett's vs 20% controls; p<0.001), H. pylori positivity (44% vs 63%; p<0.001), and manual occupation (61% vs 51%; p=0.046).	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (32, 55))	('positivity', 'Var', (125, 135))	('gastroesophageal reflux disease symptoms', 'Disease', 'MESH:D005764', (32, 72))	('H. pylori', 'Species', '210', (115, 124))	('H. pylori', 'Disease', (115, 124))	('gastroesophageal reflux disease symptoms', 'Disease', (32, 72))	('pylori positivity', 'Phenotype', 'HP:0005202', (118, 135))
334218	33365079	Peripheral blood circulating tumor (ct)DNA provides information of tumor genetic alterations and has been confirmed as a potential non-invasive biomarker for several types of cancer.	('genetic alterations', 'Var', (73, 92))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
334222	33365079	Patients with lymph node metastases (LNM) exhibited a higher number of pre-radiation mutations compared with those without LNM.	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (85, 94))	('metastases', 'Disease', (25, 35))	('metastases', 'Disease', 'MESH:D009362', (25, 35))
334269	33365079	All of the TP53 variations were either missense or non-sense and were annotated in the COSMIC (Table SII) database.	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('non-sense', 'Var', (51, 60))	('variations', 'Var', (16, 26))	('missense', 'Var', (39, 47))
334282	33365079	A total of 12 out of 17 (71%) LN-positive patients and 29% (2/7) of LN-negative patients harbored mutations in the first post-radiation plasma sample, and more mutations were detected in patients with LNM (Fig.	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (80, 88))	('LNM', 'Disease', (201, 204))	('mutations', 'Var', (98, 107))	('patients', 'Species', '9606', (42, 50))
334288	33365079	Patients who were ctDNA-positive exhibited a marginally significant reduction in PFS (P=0.047) time and a significantly decreased OS (P=0.005) time compared with those in patients who were ctDNA-negative (Fig.	('decreased', 'NegReg', (120, 129))	('patients', 'Species', '9606', (171, 179))	('ctDNA-positive', 'Var', (18, 32))	('Patients', 'Species', '9606', (0, 8))	('reduction', 'NegReg', (68, 77))
334289	33365079	Abnormal tumor biomarkers CEA, CA19-9, and CA72-4 did not exhibit a significant association with PFS (P=0.323) or OS (P=0.258) times (Fig.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('CEA', 'Gene', (26, 29))	('Abnormal tumor', 'Phenotype', 'HP:0002664', (0, 14))	('CEA', 'Gene', '1084', (26, 29))	('CA72-4', 'Var', (43, 49))	('Abnormal tumor', 'Disease', 'MESH:D009369', (0, 14))	('Abnormal tumor', 'Disease', (0, 14))
334291	33365079	Multivariate Cox proportional hazard regression analysis revealed that the presence of ctDNA in the initial post-radiation plasma sample was an independent prognostic factor for patients with ESCC (P=0.011; Table III).	('ctDNA', 'Gene', (87, 92))	('patients', 'Species', '9606', (178, 186))	('ESCC', 'Disease', (192, 196))	('presence', 'Var', (75, 83))
334293	33365079	Mutations in both P1 and P10 were undetectable following radiation therapy, which was consistent with the clinical findings, demonstrating that both patients were disease-free during follow-up.	('Mutations', 'Var', (0, 9))	('P10', 'Gene', (25, 28))	('P10', 'Gene', '6281', (25, 28))	('patients', 'Species', '9606', (149, 157))
334314	33365079	The most prevalent mutated genes encoded tumor suppressor proteins.	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutated genes', 'Var', (19, 32))
334315	33365079	A notable difference was noted in the number of mutations in the post-radiation samples was the disappearance of NOTCH1 mutations, which were only detected in baseline samples.	('NOTCH1', 'Gene', '4851', (113, 119))	('NOTCH1', 'Gene', (113, 119))	('mutations', 'Var', (120, 129))
334316	33365079	This result suggested that cancer cell populations harboring NOTCH1 mutations may be more sensitive to radiation therapy, as previously described.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('more', 'PosReg', (85, 89))	('NOTCH1', 'Gene', '4851', (61, 67))	('NOTCH1', 'Gene', (61, 67))	('cancer', 'Disease', (27, 33))	('mutations', 'Var', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('sensitive', 'MPA', (90, 99))
334317	33365079	Future large-scale studies should aim to investigate the efficacy of radiation in patients harboring NOTCH1 mutations and notably clonal NOTCH1.	('NOTCH1', 'Gene', '4851', (101, 107))	('NOTCH1', 'Gene', (101, 107))	('mutations', 'Var', (108, 117))	('patients', 'Species', '9606', (82, 90))	('NOTCH1', 'Gene', '4851', (137, 143))	('NOTCH1', 'Gene', (137, 143))
334322	33365079	In a previous study, the quantification of tumor mutations in each patient, using digital droplet PCR revealed that patients with stage I disease rarely exhibited >10 copies per 5 ml plasma.	('mutations', 'Var', (49, 58))	('patient', 'Species', '9606', (116, 123))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('patient', 'Species', '9606', (67, 74))
334327	33365079	Nevertheless, the use of integrated digital error suppression technology, based on a molecular barcode, ensures that ctDNA mutations can be detected at VAFs as low as 0.1%, such as in lung cancer.	('ctDNA', 'Gene', (117, 122))	('digital error suppression', 'Disease', 'MESH:D011596', (36, 61))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('digital error suppression', 'Disease', (36, 61))	('lung cancer', 'Disease', (184, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('mutations', 'Var', (123, 132))
334348	31598376	Leakage may adversely affect the survival of patients with advanced gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('affect', 'Reg', (22, 28))	('gastric cancer', 'Disease', (68, 82))	('patients', 'Species', '9606', (45, 53))	('Leakage', 'Var', (0, 7))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))
334391	29950896	In the meta-analysis, six papers with 1321 patients were included and patients with high INHBA level had worse prognosis than patients with low INHBA level (HR 2.50, 95% CI 1.75-3.57, P<0.0001).	('patients', 'Species', '9606', (70, 78))	('high', 'Var', (84, 88))	('INHBA', 'Gene', '3624', (89, 94))	('patients', 'Species', '9606', (43, 51))	('INHBA', 'Gene', '3624', (144, 149))	('low INHBA', 'Phenotype', 'HP:0011905', (140, 149))	('INHBA', 'Gene', (144, 149))	('patients', 'Species', '9606', (126, 134))	('INHBA', 'Gene', (89, 94))
334468	29950896	Previous studies have shown that the expression of INHBA is associated with prognosis of different types of cancer patients.	('expression', 'Var', (37, 47))	('patients', 'Species', '9606', (115, 123))	('associated', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('INHBA', 'Gene', (51, 56))	('INHBA', 'Gene', '3624', (51, 56))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
334469	29950896	Okano et al reported that high expression of INHBA gene was associated with significantly poorer 5-year OS in colorectal cancer.	('high expression', 'Var', (26, 41))	('OS', 'Chemical', '-', (104, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('poorer', 'NegReg', (90, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('INHBA', 'Gene', '3624', (45, 50))	('5-year OS', 'CPA', (97, 106))	('colorectal cancer', 'Disease', (110, 127))	('INHBA', 'Gene', (45, 50))
334470	29950896	Oshima et al found that gastric cancer patients with high INHBA expression showed significantly worse OS when compared to those with low INHBA expression.	('OS', 'Chemical', '-', (102, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('high', 'Var', (53, 57))	('low INHBA', 'Phenotype', 'HP:0011905', (133, 142))	('patients', 'Species', '9606', (39, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('INHBA', 'Gene', '3624', (58, 63))	('INHBA', 'Gene', '3624', (137, 142))	('gastric cancer', 'Disease', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('INHBA', 'Gene', (137, 142))	('INHBA', 'Gene', (58, 63))
334474	29950896	What is more, the meta-analysis comprised nine studies of INHBA expression in six different types of cancer, showing that INHBA expression is a promising predictor of patient survival in solid tumors.	('expression', 'Var', (128, 138))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('solid tumors', 'Disease', 'MESH:D009369', (187, 199))	('INHBA', 'Gene', '3624', (122, 127))	('cancer', 'Disease', (101, 107))	('patient', 'Species', '9606', (167, 174))	('INHBA', 'Gene', '3624', (58, 63))	('INHBA', 'Gene', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('solid tumors', 'Disease', (187, 199))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('INHBA', 'Gene', (58, 63))
334475	29950896	Our results confirmed and extended the fact that high INHBA expression predicts poor prognosis in solid tumors to ESCC.	('solid tumors', 'Disease', (98, 110))	('expression', 'MPA', (60, 70))	('INHBA', 'Gene', '3624', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('INHBA', 'Gene', (54, 59))	('solid tumors', 'Disease', 'MESH:D009369', (98, 110))	('high', 'Var', (49, 53))
334482	29950896	On the other hand, Seder et al found that INHBA was overexpressed in esophageal adenocarcinoma and promoted cell proliferation by promoter demethylation and histone acetylation.	('overexpressed', 'PosReg', (52, 65))	('INHBA', 'Gene', '3624', (42, 47))	('promoted', 'PosReg', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('histone acetylation', 'MPA', (157, 176))	('cell proliferation', 'CPA', (108, 126))	('esophageal adenocarcinoma', 'Disease', (69, 94))	('INHBA', 'Gene', (42, 47))	('promoter demethylation', 'Var', (130, 152))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (69, 94))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (69, 94))
334551	27239206	Overproduction of ROS can contribute to the immediate development of inflammatory process.	('inflammatory process', 'CPA', (69, 89))	('contribute', 'Reg', (26, 36))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('ROS', 'Protein', (18, 21))	('Overproduction', 'Var', (0, 14))
334630	27239206	Accordingly, gross mucosal injury ratio in RE rats significantly increased compared with normal rats, but RC200 and RC400 pretreatment led to a significant decrease (p < 0.01, p < 0.001, resp.)	('increased', 'PosReg', (65, 74))	('mucosal injury', 'Disease', (19, 33))	('rat', 'Species', '10116', (46, 49))	('RC200', 'Var', (106, 111))	('rats', 'Species', '10116', (96, 100))	('mucosal injury', 'Disease', 'MESH:D052016', (19, 33))	('rat', 'Species', '10116', (96, 99))	('rats', 'Species', '10116', (46, 50))	('RC400', 'Var', (116, 121))	('decrease', 'NegReg', (156, 164))	('rat', 'Species', '10116', (34, 37))
334632	27239206	The reduced ROS level both RC200 and RC400 recovered nearly to those of normal (Figure 4(a)).	('RC400', 'Var', (37, 42))	('ROS level', 'MPA', (12, 21))	('ROS', 'Chemical', 'MESH:D017382', (12, 15))	('reduced', 'NegReg', (4, 11))
334635	27239206	However, RC400 administration significantly regulated the nuclear Nrf-2 and cytosolic HO-1 expressions in the esophagus of reflux-induced esophagitis rats (p < 0.01, p < 0.05, resp.).	('rats', 'Species', '10116', (150, 154))	('HO-1', 'Gene', (86, 90))	('cytosolic', 'MPA', (76, 85))	('esophagitis', 'Disease', (138, 149))	('Nrf-2', 'Gene', '83619', (66, 71))	('RC400', 'Var', (9, 14))	('esophagitis', 'Disease', 'MESH:D004941', (138, 149))	('rat', 'Species', '10116', (150, 153))	('regulated', 'Reg', (44, 53))	('rat', 'Species', '10116', (23, 26))	('esophagitis', 'Phenotype', 'HP:0100633', (138, 149))	('HO-1', 'Gene', '24451', (86, 90))	('Nrf-2', 'Gene', (66, 71))
334638	27239206	Herein, SOD and HO-1 protein expressions in RC400-treated rats were increased significantly, whereas catalase showed a tendency to increase (without significance) in the esophagus.	('HO-1', 'Gene', '24451', (16, 20))	('increase', 'PosReg', (131, 139))	('rats', 'Species', '10116', (58, 62))	('catalase', 'Gene', (101, 109))	('SOD', 'MPA', (8, 11))	('catalase', 'Gene', '24248', (101, 109))	('HO-1', 'Gene', (16, 20))	('RC400-treated', 'Var', (44, 57))	('increased', 'PosReg', (68, 77))
334641	27239206	Particularly, p-IkappaBalpha level was lowered nearly to that of normal rats by RC-mix 400 mg/kg treatment.	('lowered', 'NegReg', (39, 46))	('IkappaBalpha', 'Gene', (16, 28))	('IkappaBalpha', 'Gene', '25493', (16, 28))	('RC-mix', 'Chemical', '-', (80, 86))	('rats', 'Species', '10116', (72, 76))	('400 mg/kg', 'Var', (87, 96))
334645	27239206	Moreover, COX-2 and IL-6 decreased significantly in all RC experimental rats and, above all, the administration of RC400 reduced nearly to normal levels or below in the esophagus.	('rat', 'Species', '10116', (72, 75))	('rat', 'Species', '10116', (105, 108))	('RC400', 'Var', (115, 120))	('decreased', 'NegReg', (25, 34))	('reduced', 'NegReg', (121, 128))	('rats', 'Species', '10116', (72, 76))	('IL-6', 'Gene', (20, 24))	('IL-6 decreased', 'Phenotype', 'HP:0030783', (20, 34))	('COX-2', 'Gene', '29527', (10, 15))	('COX-2', 'Gene', (10, 15))	('IL-6', 'Gene', '24498', (20, 24))
334646	27239206	iNOS and TNF-alpha protein expression exhibited no significant changes in RC100 and RC200 but RC400 reduced significantly.	('iNOS', 'Gene', (0, 4))	('reduced', 'NegReg', (100, 107))	('RC400', 'Var', (94, 99))	('iNOS', 'Gene', '24599', (0, 4))	('TNF-alpha', 'Gene', '24835', (9, 18))	('TNF-alpha', 'Gene', (9, 18))
334665	27239206	However, the lesion score was significantly attenuated in both RC200 and RC400 animal groups, suggesting the potential therapeutic effect of RC-mix against RE.	('RC200', 'Var', (63, 68))	('RC-mix', 'Chemical', '-', (141, 147))	('RC400', 'Var', (73, 78))	('lesion score', 'CPA', (13, 25))	('attenuated', 'NegReg', (44, 54))
334668	27239206	ROS causes oxidative damage in cellular components such as DNA, proteins, and membrane lipids.	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('causes', 'Reg', (4, 10))	('lipids', 'Chemical', 'MESH:D008055', (87, 93))	('proteins', 'Protein', (64, 72))	('oxidative damage in', 'MPA', (11, 30))
334669	27239206	Overproduction of ROS results in oxidative stress, which leads to oxidative damage in cells by altering the structure of biomacromolecules, and this process has been implicated in a number of diseases.	('oxidative stress', 'Phenotype', 'HP:0025464', (33, 49))	('implicated', 'Reg', (166, 176))	('results in', 'Reg', (22, 32))	('oxidative damage', 'MPA', (66, 82))	('oxidative stress', 'MPA', (33, 49))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('Overproduction', 'Var', (0, 14))	('altering', 'Reg', (95, 103))	('structure of biomacromolecules', 'MPA', (108, 138))	('ROS', 'Gene', (18, 21))	('leads to', 'Reg', (57, 65))
334683	27239206	In this study, the oral administration of RC-mix tended to increase SOD and catalase activities in a dose-dependent manner and the level of SOD became significantly higher in RC400 treated animals.	('SOD', 'Enzyme', (68, 71))	('rat', 'Species', '10116', (32, 35))	('RC-mix', 'Chemical', '-', (42, 48))	('catalase', 'Gene', (76, 84))	('increase SOD', 'Phenotype', 'HP:0410246', (59, 71))	('higher', 'PosReg', (165, 171))	('catalase', 'Gene', '24248', (76, 84))	('RC400', 'Var', (175, 180))	('increase', 'PosReg', (59, 67))
334691	27239206	Namely, the administration of RC400 significantly suppressed NF-kappaB activation through the marked inhibition of IkappaBalpha phosphorylation.	('suppressed', 'NegReg', (50, 60))	('inhibition', 'NegReg', (101, 111))	('IkappaBalpha', 'Gene', '25493', (115, 127))	('NF-kappaB', 'Protein', (61, 70))	('IkappaBalpha', 'Gene', (115, 127))	('rat', 'Species', '10116', (20, 23))	('RC400', 'Var', (30, 35))	('activation', 'MPA', (71, 81))
334701	27239206	Whereas RC100 and RC200 did not significantly affect the expression of TNF-alpha the latter was significantly reduced by RC400 treatment.	('TNF-alpha', 'Gene', (71, 80))	('RC400', 'Var', (121, 126))	('TNF-alpha', 'Gene', '24835', (71, 80))	('reduced', 'NegReg', (110, 117))
334704	27239206	Furthermore, the anti-inflammatory effects of RC-mix suggested that the inactivation of NF-kappaB by blocking the phosphorylation of IkappaBalpha led to the inhibition of the release of proinflammatory cytokines and mediators, reducing the inflammatory damage that is typical in the esophageal mucosa of rats with reflux esophagitis (Figure 8).	('reflux esophagitis', 'Disease', 'MESH:D005764', (314, 332))	('NF-kappaB', 'Protein', (88, 97))	('blocking', 'NegReg', (101, 109))	('reducing', 'NegReg', (227, 235))	('inflammatory damage', 'MPA', (240, 259))	('inhibition', 'NegReg', (157, 167))	('inactivation', 'Var', (72, 84))	('phosphorylation', 'MPA', (114, 129))	('IkappaBalpha', 'Gene', '25493', (133, 145))	('IkappaBalpha', 'Gene', (133, 145))	('RC-mix', 'Chemical', '-', (46, 52))	('rats', 'Species', '10116', (304, 308))	('esophagitis', 'Phenotype', 'HP:0100633', (321, 332))	('reflux esophagitis', 'Disease', (314, 332))
334723	25885411	Intrinsic immune system defects in SLE, combined with exposure to cytotoxic medications, foster the emergence of site-specific cancers.	('SLE', 'Disease', 'MESH:D008180', (35, 38))	('SLE', 'Disease', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('defects', 'Var', (24, 31))
334788	25885411	Significant concern is that the baseline immune system defects in this disease, combined with exposures to cytotoxic and immunosuppressive medications, may increase malignancy susceptibility.	('increase', 'PosReg', (156, 164))	('malignancy', 'Disease', (165, 175))	('malignancy', 'Disease', 'MESH:D009369', (165, 175))	('defects', 'Var', (55, 62))
334791	25885411	Second, translocations involving the juxtaposition of an oncogene adjacent to an important gene for immune cell function may favor the emergence of a lymphoma.	('lymphoma', 'Disease', (150, 158))	('favor', 'PosReg', (125, 130))	('translocations', 'Var', (8, 22))	('lymphoma', 'Disease', 'MESH:D008223', (150, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (150, 158))
334794	25885411	Third, the use of immunosuppressive agents may lead to lymphoma by direct mutagenesis or by disturbing immune surveillance.	('lead to', 'Reg', (47, 54))	('lymphoma', 'Phenotype', 'HP:0002665', (55, 63))	('lymphoma', 'Disease', (55, 63))	('disturbing', 'Reg', (92, 102))	('lymphoma', 'Disease', 'MESH:D008223', (55, 63))	('mutagenesis', 'Var', (74, 85))	('immune surveillance', 'MPA', (103, 122))
334825	20584779	Cultured ESCC cells exposed to B[a]P in vitro showed dose-dependent staining with 8E11, but not with 5D11.	('B[a]P', 'Chemical', 'MESH:D001564', (31, 36))	('staining', 'MPA', (68, 76))	('8E11', 'Var', (82, 86))	('8E11', 'Chemical', '-', (82, 86))
334872	20584779	Because 8E11 reacts with a wide range of adducted products, most of which are found in the cytoplasm, it is expected to produce predominantly cytoplasmic staining.	('8E11', 'Var', (8, 12))	('8E11', 'Chemical', '-', (8, 12))	('adducted', 'MPA', (41, 49))
334939	21362516	During the early 1990's, the use of PET expanded into hospitals and diagnostic clinics as more and more medical communities began to realize the utility of PET in clinical applications, particularly in oncology for cancer staging, assessing treatment strategies, and monitoring the effects of therapy with appropriate radiotracers.	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('men', 'Species', '9606', (246, 249))	('oncology', 'Phenotype', 'HP:0002664', (202, 210))	('PET', 'Var', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
334967	21362516	Tumors metabolize glucose by aerobic glycolysis partly through activation of oncogenes such as AKT, MYC, RAS or loss of tumor suppressors, including p53, which are then further enhanced by stabilization of the hypoxia-induced factor (HIF) via adaptive response to a hypoxic microenvironment, or through pathways that stabilize HIF under non-hypoxic conditions.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MYC', 'Gene', '4609', (100, 103))	('hypoxia', 'Disease', 'MESH:D000860', (210, 217))	('hypoxic conditions', 'Disease', 'MESH:D009135', (341, 359))	('enhanced', 'PosReg', (177, 185))	('AKT', 'Gene', '207', (95, 98))	('p53', 'Gene', '7157', (149, 152))	('Tumors', 'Disease', (0, 6))	('metabolize glucose', 'MPA', (7, 25))	('tumor', 'Disease', (120, 125))	('p53', 'Gene', (149, 152))	('men', 'Species', '9606', (286, 289))	('hypoxic conditions', 'Disease', (341, 359))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('RAS', 'Gene', (105, 108))	('activation', 'PosReg', (63, 73))	('MYC', 'Gene', (100, 103))	('glucose', 'Chemical', 'MESH:D005947', (18, 25))	('oncogenes', 'Gene', (77, 86))	('stabilization', 'Var', (189, 202))	('AKT', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('hypoxia', 'Disease', (210, 217))
335057	21362516	reported that two year disease free survival was 72% in patients whose lesions demonstrated SUV<9 x as opposed to 37% in those with lesions with SUV>9.	('patients', 'Species', '9606', (56, 64))	('SUV<9 x', 'Var', (92, 99))	('disease free survival', 'CPA', (23, 44))
335099	21362516	An FDG-PET evaluation of 98 patients with primary pancreatic cancer showed that the overall survival of the group in which SUVmax was <an 7.5 was better than that of the group in which it was >7.5.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('pancreatic cancer', 'Disease', (50, 67))	('FDG', 'Gene', '23583', (3, 6))	('pancreatic cancer', 'Disease', 'MESH:D010190', (50, 67))	('FDG', 'Gene', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('better', 'PosReg', (146, 152))	('<an', 'Var', (134, 137))	('patients', 'Species', '9606', (28, 36))
335148	21362516	Anti-18F-FACBC is a synthetic L-leucine analog that has shown promising results in a human patient with glioblastoma multiforme.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (104, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('Anti-18F-FACBC', 'Var', (0, 14))	('L-leucine', 'Chemical', 'MESH:D007930', (30, 39))	('glioblastoma multiforme', 'Disease', (104, 127))	('patient', 'Species', '9606', (91, 98))	('human', 'Species', '9606', (85, 90))	('ACBC', 'Chemical', '-', (10, 14))
335149	21362516	Anti-18F-FACBC also has been demonstrated to have excellent uptake within primary and metastatic prostate carcinoma with little renal excretion compared to FDG (Figure 3).	('FDG', 'Gene', (156, 159))	('renal excretion', 'Disease', 'MESH:D007674', (128, 143))	('primary', 'Disease', (74, 81))	('Anti-18F-FACBC', 'Var', (0, 14))	('uptake', 'MPA', (60, 66))	('metastatic prostate carcinoma', 'Phenotype', 'HP:0012125', (86, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('prostate carcinoma', 'Disease', (97, 115))	('renal excretion', 'Disease', (128, 143))	('prostate carcinoma', 'Disease', 'MESH:D011472', (97, 115))	('FDG', 'Gene', '23583', (156, 159))	('ACBC', 'Chemical', '-', (10, 14))
335151	21362516	Additionally, anti-18F-FACBC is relatively unique among amino acids because it has low associated radioactivity in the urine, which simplifies the interpretation of the genitourinary tract and pelvic images.	('radioactivity', 'MPA', (98, 111))	('ACBC', 'Chemical', '-', (24, 28))	('anti-18F-FACBC', 'Var', (14, 28))
335467	31568655	A stable cell strain with HOXB7 knockdown of KYSE150 and KYSE450 was established to explore the effect on cisplatin sensitivity.	('knockdown', 'Var', (32, 41))	('HOXB7', 'Gene', '3217', (26, 31))	('HOXB7', 'Gene', (26, 31))	('KYSE150', 'Var', (45, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))
335470	31568655	High expression of HOXB7 was associated with cisplatin resistance and worse chemotherapy efficacy.	('High', 'Var', (0, 4))	('chemotherapy efficacy', 'CPA', (76, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('worse', 'NegReg', (70, 75))	('HOXB7', 'Gene', '3217', (19, 24))	('cisplatin resistance', 'MPA', (45, 65))	('associated', 'Reg', (29, 39))	('HOXB7', 'Gene', (19, 24))
335471	31568655	HOXB7 knockdown reinforced cisplatin sensitivity.	('HOXB7', 'Gene', '3217', (0, 5))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('cisplatin sensitivity', 'MPA', (27, 48))	('reinforced', 'PosReg', (16, 26))	('knockdown', 'Var', (6, 15))	('HOXB7', 'Gene', (0, 5))
335473	31568655	HOXB7 knockdown was related to the downregulation of Ku70, Ku80 and DNA-PKcs as well as arrested cell cycle in S phase.	('HOXB7', 'Gene', '3217', (0, 5))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('Ku70', 'Gene', '2547', (53, 57))	('Ku80', 'Gene', (59, 63))	('DNA-PKcs', 'Gene', '5591', (68, 76))	('Ku80', 'Gene', '7520', (59, 63))	('downregulation', 'NegReg', (35, 49))	('arrest', 'Disease', (88, 94))	('knockdown', 'Var', (6, 15))	('DNA-PKcs', 'Gene', (68, 76))	('Ku70', 'Gene', (53, 57))	('HOXB7', 'Gene', (0, 5))
335490	31568655	11  Knockdown of HOXC6 expression in multidrug resistance cells increased their sensitivity to paclitaxel via its regulation of MDR-1.	('HOXC6', 'Gene', '3223', (17, 22))	('HOXC6', 'Gene', (17, 22))	('MDR-1', 'Gene', (128, 133))	('drug resistance', 'Phenotype', 'HP:0020174', (42, 57))	('regulation', 'MPA', (114, 124))	('Knockdown', 'Var', (4, 13))	('MDR-1', 'Gene', '5243', (128, 133))	('paclitaxel', 'Chemical', 'MESH:D017239', (95, 105))	('increased', 'PosReg', (64, 73))	('sensitivity to paclitaxel', 'MPA', (80, 105))
335501	31568655	19   In this study, we found that ESCC cells with higher expression of HOXB7 were more resistant to cisplatin and knockdown of HOXB7 led to increased chemosensitivity and decreased expression of Ku70, Ku80, DNA-PKcs.	('HOXB7', 'Gene', (127, 132))	('higher', 'PosReg', (50, 56))	('expression', 'MPA', (181, 191))	('Ku70', 'Gene', (195, 199))	('decreased', 'NegReg', (171, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('knockdown', 'Var', (114, 123))	('Ku80', 'Gene', (201, 205))	('DNA-PKcs', 'Gene', (207, 215))	('HOXB7', 'Gene', '3217', (71, 76))	('resistant to cisplatin', 'MPA', (87, 109))	('chemosensitivity', 'CPA', (150, 166))	('Ku70', 'Gene', '2547', (195, 199))	('increased', 'PosReg', (140, 149))	('Ku80', 'Gene', '7520', (201, 205))	('HOXB7', 'Gene', (71, 76))	('HOXB7', 'Gene', '3217', (127, 132))	('DNA-PKcs', 'Gene', '5591', (207, 215))
335523	31568655	The proteins were separated on a 10% SDS-PAGE gel and transferred to a PVDF membrane followed by western blot analysis, then immunoreacted with anti-HOXB7 (Abcam, ab51237 at 1:50), anti-Ku70 (Abcam, ab92450 at 1:1000), anti-Ku80 (Abcam, ab80592 at 1:1000), anti-DNA-PKcs (CST, #5591 at 1:1000), anti-gamma-H2AX (CST, #9718 at 1:1000) and anti-GAPDH (ZSGB-BIO, ZS-25778 at 1:1000).	('Ku80', 'Gene', (224, 228))	('GAPDH', 'Gene', (343, 348))	('CST', 'Gene', (312, 315))	('Abcam', 'Var', (192, 197))	('anti-gamma-H2AX', 'Var', (295, 310))	('DNA-PKcs', 'Gene', (262, 270))	('Ku70', 'Gene', '2547', (186, 190))	('HOXB7', 'Gene', '3217', (149, 154))	('CST', 'Gene', (272, 275))	('Ku70', 'Gene', (186, 190))	('gamma-H2AX', 'Chemical', '-', (300, 310))	('CST', 'Gene', '106478911', (312, 315))	('HOXB7', 'Gene', (149, 154))	('Ku80', 'Gene', '7520', (224, 228))	('DNA-PKcs', 'Gene', '5591', (262, 270))	('CST', 'Gene', '106478911', (272, 275))	('GAPDH', 'Gene', '2597', (343, 348))
335533	31568655	Then the protein lysate samples of KYSE150 and KYSE450 was added to the immobilized GST-tagged HOXB7 and incubate at 4 C at least 1 hour with gentle rocking motion on a rotating platform.	('KYSE450', 'Var', (47, 54))	('HOXB7', 'Gene', '3217', (95, 100))	('HOXB7', 'Gene', (95, 100))
335543	31568655	Each 8-week-old female Balb/C nude mice was subcutaneously inoculated with 3 x 106 cells of KYSE150 and KYSE450 in 150 mul PBS into the right groin.	('KYSE450', 'Var', (104, 111))	('nude mice', 'Species', '10090', (30, 39))	('KYSE150', 'Var', (92, 99))	('PBS', 'Chemical', 'MESH:D007854', (123, 126))
335560	31568655	To determine the effects of HOXB7 expression on the response to cisplatin, we selected KYSE150 and KYSE450 cell lines as subjects because KYSE150 was the most resistant whereas KYSE450 was the most sensitive.	('HOXB7', 'Gene', (28, 33))	('resistant', 'NegReg', (159, 168))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('KYSE150', 'Var', (138, 145))	('HOXB7', 'Gene', '3217', (28, 33))
335564	31568655	This means that knockdown of HOXB7 increases the sensitivity to cisplatin.	('increases', 'PosReg', (35, 44))	('sensitivity to cisplatin', 'MPA', (49, 73))	('HOXB7', 'Gene', '3217', (29, 34))	('knockdown', 'Var', (16, 25))	('HOXB7', 'Gene', (29, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))
335571	31568655	This means that cisplatin causes DNA damage and then sequentially activates the DNA damage repair.	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))	('cisplatin', 'Var', (16, 25))	('DNA', 'Disease', (33, 36))	('activates', 'PosReg', (66, 75))
335574	31568655	Therefore, it is proposed that HOXB7 knockdown may increase chemosensitivity partially through disrupting DNA damage response.	('increase', 'PosReg', (51, 59))	('chemosensitivity', 'MPA', (60, 76))	('disrupting', 'NegReg', (95, 105))	('HOXB7', 'Gene', '3217', (31, 36))	('HOXB7', 'Gene', (31, 36))	('knockdown', 'Var', (37, 46))	('DNA damage response', 'MPA', (106, 125))
335575	31568655	Previously, it has been shown that knockdown of HOXB7 induced cell cycle arrest in G1/S phase.	('HOXB7', 'Gene', '3217', (48, 53))	('knockdown', 'Var', (35, 44))	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('HOXB7', 'Gene', (48, 53))	('arrest', 'Disease', (73, 79))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))
335577	31568655	By flow cytometry analysis, the results showed that knockdown of HOXB7 in KYSE150 and KYSE450 decreased cell cycle arrest in G1 induced by cisplatin but increased cells in S phase (Fig 5).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('HOXB7', 'Gene', (65, 70))	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('increased', 'PosReg', (153, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('KYSE450', 'Var', (86, 93))	('arrest', 'Disease', (115, 121))	('decreased', 'NegReg', (94, 103))	('HOXB7', 'Gene', '3217', (65, 70))	('knockdown', 'Var', (52, 61))	('cells in S phase', 'CPA', (163, 179))
335579	31568655	21  Thus, we suggested that knockdown of HOXB7 enhanced chemosensitivity through inducing S phase arrest.	('arrest', 'Disease', (98, 104))	('HOXB7', 'Gene', '3217', (41, 46))	('enhanced', 'PosReg', (47, 55))	('HOXB7', 'Gene', (41, 46))	('knockdown', 'Var', (28, 37))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('chemosensitivity', 'MPA', (56, 72))	('inducing', 'Reg', (81, 89))
335581	31568655	22  It was implied that knockdown of HOXB7 sensitized cells to cisplatin through decreased G1 arrest, led to declined NHEJ repair activity, which was confirmed by another evidence that NHEJ components Ku70, Ku80 and DNA-PKcs expression was decreased in HOXB7-knockdown cells.	('decreased', 'NegReg', (240, 249))	('arrest', 'Disease', (94, 100))	('expression', 'MPA', (225, 235))	('decreased', 'NegReg', (81, 90))	('DNA-PKcs', 'Gene', (216, 224))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('declined', 'NegReg', (109, 117))	('HOXB7', 'Gene', '3217', (253, 258))	('Ku80', 'Gene', (207, 211))	('HOXB7', 'Gene', (253, 258))	('Ku70', 'Gene', '2547', (201, 205))	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('HOXB7', 'Gene', '3217', (37, 42))	('HOXB7', 'Gene', (37, 42))	('DNA-PKcs', 'Gene', '5591', (216, 224))	('knockdown', 'Var', (24, 33))	('Ku70', 'Gene', (201, 205))	('NHEJ', 'CPA', (118, 122))	('Ku80', 'Gene', '7520', (207, 211))
335593	31568655	As discussed above, HOXB7 is involved in DNA damage repair through interaction with Ku70/Ku80/DNA-PKcs to mediate cisplatin resistance, and knockdown of HOXB7 increases chemosensitivity through cell cycle arrest and downregulates expression of Ku70/Ku80/DNA-PKcs.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (194, 211))	('HOXB7', 'Gene', '3217', (153, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('HOXB7', 'Gene', (153, 158))	('Ku80', 'Gene', (249, 253))	('Ku80', 'Gene', '7520', (89, 93))	('arrest', 'Disease', (205, 211))	('knockdown', 'Var', (140, 149))	('Ku70', 'Gene', '2547', (244, 248))	('DNA-PKcs', 'Gene', '5591', (94, 102))	('Ku70', 'Gene', '2547', (84, 88))	('downregulates', 'NegReg', (216, 229))	('interaction', 'Interaction', (67, 78))	('Ku80', 'Gene', (89, 93))	('DNA-PKcs', 'Gene', (254, 262))	('Ku70', 'Gene', (244, 248))	('increases', 'PosReg', (159, 168))	('chemosensitivity', 'CPA', (169, 185))	('expression', 'MPA', (230, 240))	('arrest', 'Disease', 'MESH:D006323', (205, 211))	('Ku70', 'Gene', (84, 88))	('HOXB7', 'Gene', '3217', (20, 25))	('HOXB7', 'Gene', (20, 25))	('Ku80', 'Gene', '7520', (249, 253))	('DNA-PKcs', 'Gene', (94, 102))	('cisplatin resistance', 'MPA', (114, 134))	('DNA-PKcs', 'Gene', '5591', (254, 262))
335596	31568655	Extensive researches have demonstrated that HXR9 causes apoptosis and inhibits tumor survival in a variety of tumor types, including ESCC.	('tumor', 'Disease', (79, 84))	('ESCC', 'Disease', (133, 137))	('HXR9', 'Chemical', '-', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('inhibits', 'NegReg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('apoptosis', 'CPA', (56, 65))	('HXR9', 'Var', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
335598	31568655	The results showed that a combination of HXR9 and cisplatin synergistically inhibited cell viability (Fig 6a,b).	('HXR9', 'Var', (41, 45))	('cell viability', 'CPA', (86, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('HXR9', 'Chemical', '-', (41, 45))	('inhibited', 'NegReg', (76, 85))
335599	31568655	The growth of tumors treated with combination therapy was significantly slower than that of tumors treated with cisplatin or HXR9 alone.	('growth', 'CPA', (4, 10))	('combination', 'Var', (34, 45))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('slower', 'NegReg', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('HXR9', 'Chemical', '-', (125, 129))
335603	31568655	Moreover, HXR9 undermined the expression of Ku70, Ku80, and DNA-PKcs induced by cisplatin (Fig 8a), and HXR9 reinforced the effects of cisplatin to induce DNA damage and cell apoptosis.	('expression', 'MPA', (30, 40))	('DNA-PKcs', 'Gene', '5591', (60, 68))	('Ku70', 'Gene', '2547', (44, 48))	('undermined', 'NegReg', (15, 25))	('HXR9', 'Var', (104, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('Ku80', 'Gene', '7520', (50, 54))	('Ku80', 'Gene', (50, 54))	('DNA damage', 'CPA', (155, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('DNA-PKcs', 'Gene', (60, 68))	('HXR9', 'Chemical', '-', (10, 14))	('Ku70', 'Gene', (44, 48))	('HXR9', 'Chemical', '-', (104, 108))	('reinforced', 'PosReg', (109, 119))	('induce', 'PosReg', (148, 154))	('cell apoptosis', 'CPA', (170, 184))
335620	31568655	In the present study, high expression of HOXB7 was determined to be associated with cisplatin resistance in ESCC cells and chemotherapy efficacy of ESCC patients.	('high expression', 'Var', (22, 37))	('HOXB7', 'Gene', '3217', (41, 46))	('associated', 'Reg', (68, 78))	('patients', 'Species', '9606', (153, 161))	('HOXB7', 'Gene', (41, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('cisplatin resistance', 'MPA', (84, 104))
335633	31568655	However, the NHEJ repair pathway is error-prone and could introduce potentially deleterious mutations and chromosomal abnormalities, which initiate tumorigenesis.	('chromosomal abnormalities', 'Disease', (106, 131))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (106, 131))	('initiate', 'PosReg', (139, 147))	('tumor', 'Disease', (148, 153))	('mutations', 'Var', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
335637	31568655	It was found that cytotoxicity is increased with exposure to cisplatin during S phase, 21  thus, one reason of the sensitive phenotype in ESCC cells was that knockdown of HOXB7 increased S phase arrest.	('arrest', 'Disease', (195, 201))	('cytotoxicity', 'Disease', 'MESH:D064420', (18, 30))	('increased', 'PosReg', (34, 43))	('increased', 'PosReg', (177, 186))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('HOXB7', 'Gene', '3217', (171, 176))	('knockdown', 'Var', (158, 167))	('cytotoxicity', 'Disease', (18, 30))	('arrest', 'Disease', 'MESH:D006323', (195, 201))	('HOXB7', 'Gene', (171, 176))
335638	31568655	Another reason was that knockdown of HOXB7 decreased Ku70, Ku80 and DNA-PKcs expression upon exposure to cisplatin, which impaired the DNA damage repair activity.	('expression', 'MPA', (77, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('DNA damage repair activity', 'MPA', (135, 161))	('Ku70', 'Gene', '2547', (53, 57))	('DNA-PKcs', 'Gene', '5591', (68, 76))	('HOXB7', 'Gene', '3217', (37, 42))	('HOXB7', 'Gene', (37, 42))	('Ku80', 'Gene', '7520', (59, 63))	('impaired', 'NegReg', (122, 130))	('Ku70', 'Gene', (53, 57))	('DNA-PKcs', 'Gene', (68, 76))	('knockdown', 'Var', (24, 33))	('decreased', 'NegReg', (43, 52))	('Ku80', 'Gene', (59, 63))
335640	31568655	Hence, we identified high HOXB7 expression as a novel pathway of intrinsic resistance to cisplatin in ESCC.	('ESCC', 'Disease', (102, 106))	('intrinsic resistance to cisplatin', 'MPA', (65, 98))	('high', 'Var', (21, 25))	('HOXB7', 'Gene', '3217', (26, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('HOXB7', 'Gene', (26, 31))
335647	31568655	Moreover, it was found that disruption of HOXB7/PBX by HXR9 caused transcription alteration of genes such as MPL, IL-15, IL-23A and IL-24, which encode cytokines involved in regulating the activation of JAK-STAT signaling pathway or induction of apoptosis in our previous study.	('IL-15', 'Gene', '3600', (114, 119))	('HOXB7', 'Gene', '3217', (42, 47))	('HOXB7', 'Gene', (42, 47))	('MPL', 'Gene', (109, 112))	('IL-23A', 'Gene', '51561', (121, 127))	('disruption', 'Var', (28, 38))	('IL-24', 'Gene', (132, 137))	('MPL', 'Gene', '4352', (109, 112))	('IL-24', 'Gene', '11009', (132, 137))	('HXR9', 'Gene', (55, 59))	('IL-15', 'Gene', (114, 119))	('IL-23A', 'Gene', (121, 127))	('HXR9', 'Chemical', '-', (55, 59))	('transcription alteration', 'MPA', (67, 91))
335649	31568655	In conclusion, our study demonstrated that high HOXB7 expression confers chemoresistance in ESCC cells through interaction with Ku70, Ku80, DNA-PKcs and inducing cell cycle arrest, and downregulating its expression or disrupting its function enhances chemosensitivity.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (162, 179))	('function', 'MPA', (233, 241))	('Ku70', 'Gene', (128, 132))	('arrest', 'Disease', (173, 179))	('interaction', 'Interaction', (111, 122))	('HOXB7', 'Gene', '3217', (48, 53))	('chemosensitivity', 'CPA', (251, 267))	('HOXB7', 'Gene', (48, 53))	('Ku80', 'Gene', '7520', (134, 138))	('DNA-PKcs', 'Gene', '5591', (140, 148))	('inducing', 'PosReg', (153, 161))	('downregulating', 'NegReg', (185, 199))	('arrest', 'Disease', 'MESH:D006323', (173, 179))	('expression', 'MPA', (204, 214))	('Ku70', 'Gene', '2547', (128, 132))	('Ku80', 'Gene', (134, 138))	('enhances', 'PosReg', (242, 250))	('chemoresistance', 'CPA', (73, 88))	('high', 'Var', (43, 47))	('DNA-PKcs', 'Gene', (140, 148))
335671	32093260	The miR-200 family consists of five members (141, 200a, 200b, 200c, and 429) and is strongly involved in EMT by directly targeting and inhibiting ZEB1 and ZEB2, which themselves are negative regulators of E-cadherin.	('ZEB2', 'Gene', (155, 159))	('ZEB1', 'Gene', '6935', (146, 150))	('E-cadherin', 'Gene', (205, 215))	('E-cadherin', 'Gene', '999', (205, 215))	('miR-200', 'Gene', (4, 11))	('ZEB2', 'Gene', '9839', (155, 159))	('involved', 'Reg', (93, 101))	('inhibiting', 'NegReg', (135, 145))	('141', 'Var', (45, 48))	('ZEB1', 'Gene', (146, 150))
335679	32093260	The clinical significance of miR-205 is underlined not only by the observation that the expression levels of miR-205 show a constant decline during EC progression but also by the fact that low levels of miR-205 are associated with poor prognosis of EC patients.	('miR-205', 'Gene', (29, 36))	('patients', 'Species', '9606', (252, 260))	('miR-205', 'Gene', (109, 116))	('EC', 'Disease', 'MESH:D004938', (148, 150))	('miR-205', 'Gene', '406988', (29, 36))	('low levels', 'Var', (189, 199))	('miR-205', 'Gene', '406988', (109, 116))	('EC', 'Disease', 'MESH:D004938', (249, 251))	('expression levels', 'MPA', (88, 105))	('miR-205', 'Gene', (203, 210))	('decline', 'NegReg', (133, 140))	('miR-205', 'Gene', '406988', (203, 210))
335752	32093260	Furthermore, as the N-status is a key factor for applicability of ESD, the study was designed to retrospectively compare EMT markers in localized pT1a tumors with pN0 status and tumors with pN1 status (pT3 in our cohort).	('pT1', 'Gene', '58492', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Disease', (151, 157))	('pT3', 'Gene', '7694', (202, 205))	('pN1', 'Gene', (190, 193))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('pT3', 'Gene', (202, 205))	('pN0 status', 'Var', (163, 173))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('pT1', 'Gene', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('pN1', 'Gene', '5270', (190, 193))
335762	31781483	Both AXL and c-MET have been reported to be independent prognostic factors for ESCC.	('ESCC', 'Disease', 'MESH:C562729', (79, 83))	('ESCC', 'Disease', (79, 83))	('c-MET', 'Var', (13, 18))
335765	31781483	We demonstrated that both R428 and cabozantinib significantly inhibited the growth of CE81T and KYSE-70 ESCC cells and showed by wound-healing assay that they both inhibited ESCC cell migration.	('R428', 'Var', (26, 30))	('ESCC', 'Disease', 'MESH:C562729', (174, 178))	('cabozantinib', 'Chemical', 'MESH:C558660', (35, 47))	('ESCC', 'Disease', 'MESH:C562729', (104, 108))	('growth', 'CPA', (76, 82))	('ESCC', 'Disease', (174, 178))	('inhibited', 'NegReg', (164, 173))	('inhibited', 'NegReg', (62, 71))	('ESCC', 'Disease', (104, 108))
335767	31781483	R428 alone significantly inhibited ESCC tumor growth compared to the vehicle; however, no synergistic effect with cisplatin was observed.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('R428', 'Var', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('ESCC', 'Disease', 'MESH:C562729', (35, 39))	('inhibited', 'NegReg', (25, 34))	('tumor', 'Disease', (40, 45))	('ESCC', 'Disease', (35, 39))
335769	31781483	Collectively, our study demonstrated that both cabozantinib and R428 inhibit ESCC growth in cell and xenograft models.	('ESCC', 'Disease', (77, 81))	('cabozantinib', 'Chemical', 'MESH:C558660', (47, 59))	('inhibit', 'NegReg', (69, 76))	('ESCC', 'Disease', 'MESH:C562729', (77, 81))	('R428', 'Var', (64, 68))
335783	31781483	The c-MET RTK is also an independent prognostic factor for ESCC.	('ESCC', 'Disease', 'MESH:C562729', (59, 63))	('ESCC', 'Disease', (59, 63))	('c-MET', 'Var', (4, 9))
335785	31781483	A c-MET inhibitor significantly inhibited the invasive activity in ESCC cells under the stimulation of its ligand HGF.	('ESCC', 'Disease', (67, 71))	('inhibited', 'NegReg', (32, 41))	('c-MET', 'Protein', (2, 7))	('ESCC', 'Disease', 'MESH:C562729', (67, 71))	('inhibitor', 'Var', (8, 17))	('invasive activity in', 'CPA', (46, 66))
335789	31781483	The therapeutic potential of R428 has also been demonstrated in highly invasive esophageal adenocarcinoma cells and in ESCC cells.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('invasive esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (71, 105))	('ESCC', 'Disease', (119, 123))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('R428', 'Var', (29, 33))	('ESCC', 'Disease', 'MESH:C562729', (119, 123))	('invasive esophageal adenocarcinoma', 'Disease', (71, 105))
335797	31781483	CE81T/VGH (CE81T) and KYSE-70 are human ESCC cell lines derived from a Taiwanese and Japanese population, respectively.	('ESCC', 'Disease', (40, 44))	('human', 'Species', '9606', (34, 39))	('CE81T/VGH (CE81T', 'Var', (0, 16))	('ESCC', 'Disease', 'MESH:C562729', (40, 44))
335802	31781483	The primary antibodies for western blotting were anti-AXL polyclonal antibody (pAb) (#8661, Cell Signaling Technology [CST]), anti-phospho-AXL (Tyr702, D12B2, CST) monoclonal antibody (mAb) (#5724, CST), anti-MET mAb (#8198, CST), anti-phospho-MET mAb (#3126, CST), anti-MMP1 mAb (#MAB901, R&D systems), anti-ERK 1 (K-23) pAb (Santa Cruz), anti-phospho-p44/42 Erk1/2 (Thr202/Tyr204) mAb (#4370, CST), anti-Akt pAb (#9272, CST), anti-phospho-Akt pAb (Ser473) (#9271, CST), anti-actin mAb (clone C4, Millipore), and anti-alpha-tubulin mAb (DM1A, Abcam).	('Tyr', 'Chemical', 'MESH:C042696', (144, 147))	('p44', 'Gene', (353, 356))	('Tyr', 'Chemical', 'MESH:C042696', (375, 378))	(') (#', 'Var', (456, 460))	('phospho-MET', 'Chemical', 'MESH:C098756', (236, 247))	('ERK', 'Gene', '5594', (309, 312))	('p44', 'Gene', '10561', (353, 356))	('Ser473', 'Chemical', 'MESH:C530429', (450, 456))	('phospho-AXL', 'Chemical', 'MESH:C082281', (131, 142))	('ERK', 'Gene', (309, 312))
335813	31781483	In the current study, we first evaluated the efficacy of three potential AXL and c-MET small-molecule inhibitors in ESCC cells.	('ESCC', 'Disease', (116, 120))	('AXL', 'Protein', (73, 76))	('ESCC', 'Disease', 'MESH:C562729', (116, 120))	('small-molecule', 'Var', (87, 101))
335814	31781483	Figure 1 exhibits the dose-dependent cytotoxicities of R428, BMS-777607, or cabozantinib treatment for 48 h (Figure 1A) or 72 h (Figure 1B) in CE81T ESCC cells.	('ESCC', 'Disease', (149, 153))	('cytotoxicities', 'Disease', (37, 51))	('BMS-777607', 'Gene', (61, 71))	('cytotoxicities', 'Disease', 'MESH:D064420', (37, 51))	('R428', 'Var', (55, 59))	('cabozantinib', 'Chemical', 'MESH:C558660', (76, 88))	('ESCC', 'Disease', 'MESH:C562729', (149, 153))	('BMS-777607', 'Chemical', 'MESH:C550356', (61, 71))	('cabozantinib', 'Gene', (76, 88))
335815	31781483	The cytotoxicity of R428 and cabozantinib was more evident compared to BMS-777607.	('R428', 'Var', (20, 24))	('cytotoxicity', 'Disease', (4, 16))	('BMS-777607', 'Chemical', 'MESH:C550356', (71, 81))	('cabozantinib', 'Chemical', 'MESH:C558660', (29, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))	('cabozantinib', 'Gene', (29, 41))
335816	31781483	In CE81T cells, the IC50 values of R428 and cabozantinib were 1.98 and 4.61 muM, respectively, when treated for 72 h (Figure 1D).	('cabozantinib', 'Gene', (44, 56))	('cabozantinib', 'Chemical', 'MESH:C558660', (44, 56))	('R428', 'Var', (35, 39))
335822	31781483	Both ERK and phospho-ERK (pERK) levels exhibited a significant increase after treatment with R428 (Figure 2A).	('increase', 'PosReg', (63, 71))	('ERK', 'Gene', '5594', (5, 8))	('(pERK)', 'Gene', '9451', (25, 31))	('ERK', 'Gene', (27, 30))	('ERK', 'Gene', (5, 8))	('R428', 'Var', (93, 97))	('ERK', 'Gene', '5594', (21, 24))	('ERK', 'Gene', '5594', (27, 30))	('ERK', 'Gene', (21, 24))	('pERK', 'Gene', (26, 30))
335834	31781483	Both cabozantinib and R428 markedly suppressed the migration activity in CE81T cells significantly compared to control (Figure 4).	('suppressed', 'NegReg', (36, 46))	('R428', 'Var', (22, 26))	('cabozantinib', 'Chemical', 'MESH:C558660', (5, 17))	('migration activity', 'CPA', (51, 69))
335836	31781483	The tumor volume was analyzed in the vehicle control group and the groups treated for 14 days with R428, cisplatin, or R428 combined with cisplatin.	('tumor', 'Disease', (4, 9))	('R428', 'Var', (119, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
335837	31781483	The body weight of mice was significantly decreased in those treated with R428 alone at day 14 (Figure 5A) and was also significantly reduced in the cisplatin-treated group at days 10 and 14 post-treatment (P < 0.01, Figure 5A).	('decreased', 'NegReg', (42, 51))	('body weight', 'CPA', (4, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('reduced', 'NegReg', (134, 141))	('R428', 'Var', (74, 78))	('mice', 'Species', '10090', (19, 23))
335840	31781483	R428 significantly reduced the tumor volume compared to the vehicle control (P < 0.01, Figure 5C).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('R428', 'Var', (0, 4))	('tumor', 'Disease', (31, 36))	('reduced', 'NegReg', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
335842	31781483	The average AKT and phospho-AKT levels were also less in R428-treated mice than in the controls (P < 0.001 and P = 0.041).	('mice', 'Species', '10090', (70, 74))	('R428-treated', 'Var', (57, 69))	('less', 'NegReg', (49, 53))
335864	31781483	It has been reported that about 87% of ESCC tissue expresses c-MET.	('ESCC', 'Disease', 'MESH:C562729', (39, 43))	('c-MET', 'Var', (61, 66))	('ESCC', 'Disease', (39, 43))
335866	31781483	However, MET DNA amplification is rarely found in cancers.	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Disease', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('MET DNA amplification', 'Var', (9, 30))
335871	31781483	Our study demonstrated the efficacy of R428, but not of BMS-777607 (Figure 1), in inhibiting ESCC cell growth.	('BMS-777607', 'Chemical', 'MESH:C550356', (56, 66))	('inhibiting', 'NegReg', (82, 92))	('ESCC', 'Disease', 'MESH:C562729', (93, 97))	('ESCC', 'Disease', (93, 97))	('R428', 'Var', (39, 43))
335872	31781483	Although BMS-777607 has been found to inhibit cell growth in a xenograft model of gastric carcinoma and to suppress the metastatic phenotype of HGF-induced prostate cancer, we did not observe a significant effect of BMS-777607 on the viability of either CE81T or KYSE-70 ESCC cells (Figure 1).	('ESCC', 'Disease', 'MESH:C562729', (271, 275))	('suppress', 'NegReg', (107, 115))	('prostate cancer', 'Disease', (156, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('BMS-777607', 'Chemical', 'MESH:C550356', (9, 19))	('cell growth', 'CPA', (46, 57))	('gastric carcinoma', 'Disease', (82, 99))	('ESCC', 'Disease', (271, 275))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (82, 99))	('inhibit', 'NegReg', (38, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('gastric carcinoma', 'Disease', 'MESH:D013274', (82, 99))	('metastatic phenotype', 'CPA', (120, 140))	('BMS-777607', 'Var', (9, 19))	('BMS-777607', 'Chemical', 'MESH:C550356', (216, 226))
335873	31781483	In addition to viability, R428 also suppressed the migration activity of ESCC cells (Figure 4).	('R428', 'Var', (26, 30))	('suppressed', 'NegReg', (36, 46))	('ESCC', 'Disease', 'MESH:C562729', (73, 77))	('migration activity', 'CPA', (51, 69))	('ESCC', 'Disease', (73, 77))
335874	31781483	R428 alone also significantly decreased ESCC tumor growth compared to vehicle in the mouse model (Figure 5), however, not as remarkably as cabozantinib did.	('ESCC', 'Disease', (40, 44))	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('R428', 'Var', (0, 4))	('tumor', 'Disease', (45, 50))	('decreased ESCC', 'Phenotype', 'HP:0025022', (30, 44))	('cabozantinib', 'Chemical', 'MESH:C558660', (139, 151))	('ESCC', 'Disease', 'MESH:C562729', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('decreased', 'NegReg', (30, 39))
335875	31781483	R428 has been reported to synergize with cisplatin to enhance the cell death of mesothelioma and to suppress liver micrometastasis of breast cancer.	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('liver micrometastasis of breast cancer', 'Disease', (109, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('R428', 'Var', (0, 4))	('cell death', 'CPA', (66, 76))	('mesothelioma', 'Disease', (80, 92))	('enhance', 'PosReg', (54, 61))	('liver micrometastasis of breast cancer', 'Disease', 'MESH:D001943', (109, 147))	('suppress', 'NegReg', (100, 108))
335876	31781483	We observed a synergistic effect of R428 and cisplatin on ESCC cells at 48 h post-treatment (Figure 3A).	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('ESCC', 'Disease', 'MESH:C562729', (58, 62))	('R428', 'Var', (36, 40))	('ESCC', 'Disease', (58, 62))	('synergistic effect', 'MPA', (14, 32))
335881	31781483	There are several ongoing phase II clinical trials combining R428 and other targeted immunotherapeutic agents to treat malignant diseases, including NSCLC, breast cancer, melanoma, and acute myeloid leukemia.	('R428', 'Var', (61, 65))	('leukemia', 'Phenotype', 'HP:0001909', (199, 207))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (185, 207))	('NSCLC', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('acute myeloid leukemia', 'Disease', (185, 207))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('malignant diseases', 'Disease', (119, 137))	('malignant diseases', 'Disease', 'None', (119, 137))	('breast cancer', 'Disease', (156, 169))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (185, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (191, 207))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
335884	31781483	In the current study, we found that treatment with R428 or cabozantinib also increased AXL expression in the cell model (Figure 2).	('cabozantinib', 'Chemical', 'MESH:C558660', (59, 71))	('cabozantinib', 'Gene', (59, 71))	('R428', 'Var', (51, 55))	('AXL expression', 'MPA', (87, 101))	('increased', 'PosReg', (77, 86))
335891	31781483	In conclusion, our study is the first to demonstrate the efficacy of cabozantinib and R428 in both ESCC cell and xenograft models.	('cabozantinib', 'Chemical', 'MESH:C558660', (69, 81))	('cabozantinib', 'Gene', (69, 81))	('ESCC', 'Disease', (99, 103))	('R428', 'Var', (86, 90))	('ESCC', 'Disease', 'MESH:C562729', (99, 103))
335981	28481265	The average spectral transmittance increases in the order of CE81T and CE81T-4 because the changes caused by cancer cell progression altered the structure of the cells.	('CE81T-4', 'CellLine', 'CVCL:Y190', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('increases', 'PosReg', (35, 44))	('cancer', 'Disease', (109, 115))	('CE81T-4', 'Var', (71, 78))	('CE81T', 'Var', (61, 66))	('spectral transmittance', 'MPA', (12, 34))	('structure', 'MPA', (145, 154))	('altered', 'Reg', (133, 140))
335983	28481265	Figure 5 shows the Raman spectra of the two ESCC lines (CE81T and CE81T-4).	('CE81T-4', 'CellLine', 'CVCL:Y190', (66, 73))	('CE81T-4', 'Var', (66, 73))	('CE81T', 'Var', (56, 61))
335984	28481265	The spectra of CE81T and CE81T-4 cells showed considerable Raman peak shifts from 1321 cm-1 to 1452, 1540, 1580, and 1655 cm-1; these peak shifts are attributed to lipids, amino acids, CH2, nuclear acids, tryptophan, and amide C=O, respectively.	('amide', 'Chemical', 'MESH:D000577', (221, 226))	('lipids', 'Chemical', 'MESH:D008055', (164, 170))	('CE81T-4', 'Var', (25, 32))	('CE81T', 'Var', (15, 20))	('CH2', 'Chemical', '-', (185, 188))	('tryptophan', 'Chemical', 'MESH:D014364', (205, 215))	('CE81T-4', 'CellLine', 'CVCL:Y190', (25, 32))
335985	28481265	The above results indicate that CE81T-4 cells were more invasive than CE81T cells.	('invasive', 'CPA', (56, 64))	('CE81T-4', 'CellLine', 'CVCL:Y190', (32, 39))	('CE81T-4', 'Var', (32, 39))
335990	28481265	Moreover, the admittance change increased linearly with cell number for all cell types; the slopes are 0.0129 and 0.0321 for the CE81T and CE81T-4 cells, respectively.	('CE81T-4', 'Var', (139, 146))	('CE81T', 'Var', (129, 134))	('admittance change', 'MPA', (14, 31))	('CE81T-4', 'CellLine', 'CVCL:Y190', (139, 146))
335994	28481265	At the same cell concentration, CE81T-4 cells generate a higher admittance than CE81T cells.	('admittance', 'MPA', (64, 74))	('CE81T-4', 'CellLine', 'CVCL:Y190', (32, 39))	('CE81T-4', 'Var', (32, 39))	('higher', 'PosReg', (57, 63))
335995	28481265	From Figure 6, we clearly observe that CE81T-4 cells tend to cluster more strongly than CE81T cells.	('CE81T-4', 'Var', (39, 46))	('CE81T-4', 'CellLine', 'CVCL:Y190', (39, 46))	('strongly', 'PosReg', (74, 82))	('cluster', 'CPA', (61, 68))
336004	28481265	Subsequently, electrical impedance-based measurements were performed for various cell numbers of CE81T and CE81T-4 cells with a sinusoidal function signal at an amplitude of 1 Vpp and a frequency of 4 kHz.	('sinusoidal', 'MPA', (128, 138))	('CE81T-4', 'CellLine', 'CVCL:Y190', (107, 114))	('CE81T-4', 'Var', (107, 114))
336058	27618866	Among 16 patients with SMI in CR, 12 underwent additional treatment (esophagectomy in five, radiation or chemoradiation in six, and chemotherapy in one), and three of these patients died of disease progression, lung cancer, and sepsis.	('patients', 'Species', '9606', (9, 17))	('men', 'Species', '9606', (63, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('sepsis', 'Disease', 'MESH:D018805', (228, 234))	('SMI', 'Var', (23, 26))	('patients', 'Species', '9606', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('CR', 'Chemical', '-', (30, 32))	('sepsis', 'Disease', (228, 234))	('sepsis', 'Phenotype', 'HP:0100806', (228, 234))	('lung cancer', 'Disease', (211, 222))
336093	27246611	Genetic variants of DNA repair genes predict the survival of patients with esophageal squamous cell cancer receiving platinum-based adjuvant chemotherapy Adjuvant chemotherapy in patients with resected esophageal squamous cell cancer (ESCC) remains controversial for its uncertain role in improving overall survival (OS).	('squamous cell cancer', 'Phenotype', 'HP:0002860', (213, 233))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (202, 233))	('platinum', 'Chemical', 'MESH:D010984', (117, 125))	('esophageal squamous cell cancer', 'Disease', (75, 106))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (86, 106))	('OS', 'Chemical', '-', (317, 319))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('DNA repair genes', 'Gene', (20, 36))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('variants', 'Var', (8, 16))	('esophageal squamous cell cancer', 'Disease', (202, 233))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (75, 106))	('patients', 'Species', '9606', (179, 187))	('predict', 'Reg', (37, 44))
336094	27246611	Nucleotide excision repair (NER) removes DNA-adducts in tumor cells induced by the platinum-based chemotherapy and thus may modulate efficacy of the treatment.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Nucleotide', 'Var', (0, 10))	('tumor', 'Disease', (56, 61))	('platinum', 'Chemical', 'MESH:D010984', (83, 91))	('DNA-adducts', 'MPA', (41, 52))	('men', 'Species', '9606', (154, 157))	('efficacy', 'CPA', (133, 141))	('removes', 'NegReg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('modulate', 'Reg', (124, 132))
336095	27246611	The present study evaluated if single nucleotide polymorphisms (SNPs) of NER genes were prognostic biomarkers in ESCC patients treated with platinum-based adjuvant chemotherapy (PAC).	('PAC', 'Phenotype', 'HP:0006699', (178, 181))	('ESCC', 'Disease', (113, 117))	('NER genes', 'Gene', (73, 82))	('single nucleotide polymorphisms', 'Var', (31, 62))	('PAC', 'Chemical', '-', (178, 181))	('platinum', 'Chemical', 'MESH:D010984', (140, 148))	('patients', 'Species', '9606', (118, 126))
336096	27246611	The analysis included 572 patients, for whom six SNPs of NER genes [i.e., XPC (rs1870134 and rs2228001), ERCC2/XPD rs238406 and ERCC5/XPG (rs2094258, rs2296147 and rs873601)] were detected with the TaqMan assay.	('XPG', 'Gene', (134, 137))	('rs1870134', 'Mutation', 'rs1870134', (79, 88))	('rs238406', 'Mutation', 'rs238406', (115, 123))	('rs1870134', 'Var', (79, 88))	('rs2296147', 'Mutation', 'rs2296147', (150, 159))	('rs2094258', 'Mutation', 'rs2094258', (139, 148))	('rs238406', 'Var', (115, 123))	('rs2094258', 'Var', (139, 148))	('rs2228001', 'Mutation', 'rs2228001', (93, 102))	('patients', 'Species', '9606', (26, 34))	('rs2228001', 'Var', (93, 102))	('rs2296147', 'Var', (150, 159))	('XPG', 'Gene', '2073', (134, 137))	('rs873601', 'Mutation', 'rs873601', (164, 172))
336099	27246611	We found that ERCC5/XPG rs2094258 and rs873601 and ERCC2/XPD rs238406 SNPs were independently associated with poorer DFS and OS of ESCC patients [ERCC5/XPG rs2094258: CT+TT vs. CC: adjusted hazards ratio (adjHR) = 1.68 and P = 0.012 for DFS; adjHR = 1.99 and P = 0.0001 for OS; ERCC5/XPG rs873601: GA+GG vs. AA: adjHR = 1.59 and P = 0.024 for DFS; adjHR = 1.91 and P = 0.0005 for OS; ERCC2/XPD rs238406: TT vs. GG+GT: adjHR = 1.43 and P = 0.020 for DFS; adjHR = 1.52 and P = 0.008 for OS].	('XPG', 'Gene', (20, 23))	('rs873601', 'Mutation', 'rs873601', (288, 296))	('XPG', 'Gene', '2073', (284, 287))	('rs2094258', 'Mutation', 'rs2094258', (156, 165))	('ESCC', 'Disease', (131, 135))	('OS', 'Chemical', '-', (485, 487))	('OS', 'Chemical', '-', (274, 276))	('XPG', 'Gene', (152, 155))	('OS', 'Chemical', '-', (380, 382))	('XPG', 'Gene', '2073', (20, 23))	('OS', 'Chemical', '-', (125, 127))	('rs873601', 'Mutation', 'rs873601', (38, 46))	('rs873601', 'Var', (38, 46))	('rs2094258', 'Mutation', 'rs2094258', (24, 33))	('XPG', 'Gene', (284, 287))	('XPG', 'Gene', '2073', (152, 155))	('rs238406', 'Mutation', 'rs238406', (61, 69))	('patients', 'Species', '9606', (136, 144))	('poorer', 'NegReg', (110, 116))	('rs238406', 'Mutation', 'rs238406', (394, 402))	('rs2094258', 'Var', (24, 33))
336114	27246611	Although one did not yield the expected results, the other larger trial found an enhanced 5-year disease free survival (DFS) for patients with lymph node metastasis.	('patients', 'Species', '9606', (129, 137))	('disease free survival', 'CPA', (97, 118))	('enhanced', 'PosReg', (81, 89))	('lymph node metastasis', 'Var', (143, 164))
336115	27246611	Traditionally, the anatomic and pathologic staging has been the most commonly used prognostic factors in EC patients, but it did not provide sufficient information for evaluating the efficacy of PAC, because it did not account for host factors, because genetic variants may interact with PAC and thus play a role in determining clinical response and prognosis of the patients.	('interact', 'Reg', (274, 282))	('genetic variants', 'Var', (253, 269))	('PAC', 'Phenotype', 'HP:0006699', (195, 198))	('PAC', 'Chemical', '-', (288, 291))	('play', 'Reg', (301, 305))	('role', 'Reg', (308, 312))	('patients', 'Species', '9606', (367, 375))	('PAC', 'Phenotype', 'HP:0006699', (288, 291))	('PAC', 'Protein', (288, 291))	('PAC', 'Chemical', '-', (195, 198))	('patients', 'Species', '9606', (108, 116))
336122	27246611	Several studies suggested that single nucleotide polymorphisms (SNPs) in these three genes might be responsible for the variation in DNA repair capacity, leading to individual variation in cancer susceptibility and treatment response.	('variation', 'Var', (120, 129))	('single nucleotide polymorphisms', 'Var', (31, 62))	('treatment response', 'CPA', (215, 233))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('variation', 'Reg', (176, 185))	('leading to', 'Reg', (154, 164))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('DNA repair capacity', 'MPA', (133, 152))	('men', 'Species', '9606', (220, 223))	('cancer', 'Disease', (189, 195))
336124	27246611	Therefore, we hypothesize that potentially functional SNPs of the three NER genes may modulate prognosis of EC patients treated with PAC.	('modulate', 'Reg', (86, 94))	('PAC', 'Phenotype', 'HP:0006699', (133, 136))	('SNPs', 'Var', (54, 58))	('NER', 'Gene', (72, 75))	('PAC', 'Chemical', '-', (133, 136))	('patients', 'Species', '9606', (111, 119))
336125	27246611	In this study, we selected six well-studied potentially functional SNPs of the NER genes, including three from ERCC5/XPG (rs2094258 at 5' near gene, rs22961475 at 5' untranslated region (UTR) and rs873601 at 3'UTR), one from ERCC2/XPD (rs238406 at codon Arg156Arg) and two from XPC (rs1870134 at codon Val16Leu and rs2228001 at codon Lys939Gln) and evaluated their roles in survival of ethnic Han Chinese patients in eastern China.	('Lys939Gln', 'Mutation', 'rs2228001', (334, 343))	('Arg156Arg', 'Mutation', 'rs238406', (254, 263))	('rs1870134 at', 'Var', (283, 295))	('XPG', 'Gene', '2073', (117, 120))	('rs22961475', 'Mutation', 'rs22961475', (149, 159))	('rs2094258', 'Mutation', 'rs2094258', (122, 131))	('rs1870134', 'Mutation', 'rs1870134', (283, 292))	('Val16Leu', 'Mutation', 'rs1870134', (302, 310))	('rs22961475', 'Var', (149, 159))	('rs238406 at codon Arg156Arg', 'Var', (236, 263))	('rs873601', 'Mutation', 'rs873601', (196, 204))	('rs873601', 'Var', (196, 204))	('rs2094258', 'Var', (122, 131))	('rs2228001', 'Mutation', 'rs2228001', (315, 324))	('NER', 'Gene', (79, 82))	('rs2228001', 'Var', (315, 324))	('XPG', 'Gene', (117, 120))	('rs238406', 'Mutation', 'rs238406', (236, 244))	('patients', 'Species', '9606', (405, 413))	('Chinese', 'Species', '10029', (397, 404))
336148	27246611	In the multivariate analyses with adjustment for all the variables listed in Table 1, we found that DFS of the patients was significantly associated with ERCC5/XPG rs2094258 (CT+TT vs. CC: adjHR = 1.68, 95 % CI 1.23-2.31, and P = 0.012), rs873601 (GG+GA vs. AA: adjHR = 1.59, 95 % CI 1.06-2.37, and P = 0.024), and ERCC2/XPD rs238406 (TT vs. GG+GT: adjHR = 1.43, 95 % CI 1.06-1.93, and P = 0.020) (Table 2).	('rs2094258', 'Var', (164, 173))	('rs238406', 'Mutation', 'rs238406', (325, 333))	('patients', 'Species', '9606', (111, 119))	('XPG', 'Gene', '2073', (160, 163))	('associated', 'Reg', (138, 148))	('DFS', 'Disease', (100, 103))	('rs238406', 'Var', (325, 333))	('men', 'Species', '9606', (40, 43))	('XPG', 'Gene', (160, 163))	('ERCC2/XPD', 'Gene', (315, 324))	('rs2094258', 'Mutation', 'rs2094258', (164, 173))	('rs873601', 'Mutation', 'rs873601', (238, 246))	('rs873601', 'Var', (238, 246))
336149	27246611	Similarly, we also found in the multivariate analyses that OS of the patients was significantly associated with ERCC5/XPG rs2094258 (CT+TT vs. CC: adjHR = 1.99, 95 % CI 1.40-2.81, and P = 0.0001), rs873601 (GG+GA vs. AA: adjHR = 1.91, 95 % CI 1.21-2.99, and P = 0.0005), and ERCC2/XPD rs238406 (TT vs. GG+GT: adjHR = 1.52, 95 % CI 1.12-2.03, and P = 0.008) (Table 2).	('OS', 'Chemical', '-', (59, 61))	('rs238406', 'Var', (285, 293))	('rs873601', 'Mutation', 'rs873601', (197, 205))	('rs873601', 'Var', (197, 205))	('XPG', 'Gene', '2073', (118, 121))	('patients', 'Species', '9606', (69, 77))	('rs2094258', 'Mutation', 'rs2094258', (122, 131))	('XPG', 'Gene', (118, 121))	('rs2094258', 'Var', (122, 131))	('rs238406', 'Mutation', 'rs238406', (285, 293))
336150	27246611	To evaluate the collective effect of the significant SNPs on patients' DFS and OS, we combined the risk genotypes of ERCC5/XPG rs2094258CT/TT and rs873601 GA/GG and ERCC2/XPD rs238406 TT for DFS and OS into a genotype score as the number of risk genotypes (NRG).	('OS', 'Chemical', '-', (199, 201))	('rs873601 GA/GG', 'Var', (146, 160))	('XPG', 'Gene', (123, 126))	('OS', 'Chemical', '-', (79, 81))	('rs873601', 'Mutation', 'rs873601', (146, 154))	('rs2094258CT/TT', 'Var', (127, 141))	('patients', 'Species', '9606', (61, 69))	('XPG', 'Gene', '2073', (123, 126))	('rs238406 TT', 'Var', (175, 186))	('rs238406', 'Mutation', 'rs238406', (175, 183))	('rs2094258', 'Mutation', 'rs2094258', (127, 136))	('DFS', 'Disease', (191, 194))
336152	27246611	For DFS, with the increasing NRG, patients had an increased risk of disease progression, compared with those carrying zero risk genotypes (Ptrend < 0.0001) (Table 2; Fig.	('patients', 'Species', '9606', (34, 42))	('disease progression', 'CPA', (68, 87))	('DFS', 'Var', (4, 7))
336161	27246611	In this study, we reported that some SNPs of the NER genes, such as ERCC5/XPG rs2094258 and rs873601 and ERCC2/XPD rs238406, may independently or jointly influence the prognosis of ESCC patients treated with PAC in eastern China.	('NER genes', 'Gene', (49, 58))	('rs238406', 'Mutation', 'rs238406', (115, 123))	('PAC', 'Chemical', '-', (208, 211))	('influence', 'Reg', (154, 163))	('rs238406', 'Var', (115, 123))	('rs873601', 'Mutation', 'rs873601', (92, 100))	('rs873601', 'Var', (92, 100))	('XPG', 'Gene', '2073', (74, 77))	('ESCC', 'Disease', (181, 185))	('rs2094258', 'Mutation', 'rs2094258', (78, 87))	('rs2094258', 'Var', (78, 87))	('PAC', 'Phenotype', 'HP:0006699', (208, 211))	('patients', 'Species', '9606', (186, 194))	('XPG', 'Gene', (74, 77))
336163	27246611	In the present study, we found that ERCC5/XPG rs2094258 CT/TT genotypes were associated with a decreased DFS and OS in ESCC patients treated with PAC.	('decreased', 'NegReg', (95, 104))	('XPG', 'Gene', '2073', (42, 45))	('DFS', 'MPA', (105, 108))	('PAC', 'Chemical', '-', (146, 149))	('rs2094258', 'Mutation', 'rs2094258', (46, 55))	('ESCC', 'Disease', (119, 123))	('rs2094258', 'Var', (46, 55))	('XPG', 'Gene', (42, 45))	('PAC', 'Phenotype', 'HP:0006699', (146, 149))	('OS', 'Chemical', '-', (113, 115))	('patients', 'Species', '9606', (124, 132))
336165	27246611	The rs2094258 SNP is located in the 5' UTR of ERCC5/XPG, which is a putative transcription factor binding site.	('rs2094258 SNP', 'Var', (4, 17))	('XPG', 'Gene', (52, 55))	('XPG', 'Gene', '2073', (52, 55))	('rs2094258', 'Mutation', 'rs2094258', (4, 13))
336166	27246611	In the present study, we found that the ERCC2/XPD rs238406 TT genotype was associated with a reduced DFS and OS in ESCC patients, but few studies have reported its role in prognosis of cancer patients.	('ESCC', 'Disease', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('rs238406', 'Mutation', 'rs238406', (50, 58))	('reduced', 'NegReg', (93, 100))	('patients', 'Species', '9606', (192, 200))	('rs238406', 'Var', (50, 58))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('OS', 'Chemical', '-', (109, 111))	('DFS', 'MPA', (101, 104))	('cancer', 'Disease', (185, 191))
336167	27246611	One Taiwan study found that ERCC2/XPD rs238406 CC (or GG of its antisense) instead of the AA (or TT of its antisense) genotype of 185 ESCC patients with neoadjuvant chemoirradiation followed by esophagectomy could additively increase risk of death and disease progression in cisplatin-based neoadjuvant concurrent chemoradiation therapy.	('death', 'Disease', (242, 247))	('cisplatin', 'Chemical', 'MESH:D002945', (275, 284))	('patients', 'Species', '9606', (139, 147))	('increase', 'PosReg', (225, 233))	('ESCC', 'Disease', (134, 138))	('disease progression', 'CPA', (252, 271))	('rs238406', 'Mutation', 'rs238406', (38, 46))	('rs238406 CC', 'Var', (38, 49))	('death', 'Disease', 'MESH:D003643', (242, 247))
336169	27246611	Another study showed that rs238406 AA carriers had less efficiency of DNA adduct formation in their lymphocytes, suggesting that cells with the rs238406 AA genotype may have a highly-efficient capability to remove DNA adducts, leading to a relatively quicker recovery from the genotoxic effects of PAC and thus drug resistance with shortened DFS and OS.	('PAC', 'Phenotype', 'HP:0006699', (298, 301))	('recovery', 'MPA', (259, 267))	('drug resistance', 'MPA', (311, 326))	('PAC', 'Chemical', '-', (298, 301))	('rs238406', 'Mutation', 'rs238406', (26, 34))	('rs238406', 'Mutation', 'rs238406', (144, 152))	('OS', 'Chemical', '-', (350, 352))	('rs238406 AA', 'Var', (144, 155))	('drug resistance', 'Phenotype', 'HP:0020174', (311, 326))	('genotoxic', 'CPA', (277, 286))	('quicker', 'PosReg', (251, 258))
336170	27246611	On the other hand, the rs238406 AA genotype may lead to patients' relatively mild therapeutic toxicity.	('patients', 'Species', '9606', (56, 64))	('rs238406', 'Mutation', 'rs238406', (23, 31))	('rs238406 AA', 'Var', (23, 34))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('toxicity', 'Disease', (94, 102))
336171	27246611	For example, one study demonstrated that patients with the rs238406 AA genotype, who received oxaliplatin-based chemotherapy, suffered less grade 3 toxicities.	('less', 'NegReg', (135, 139))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (94, 105))	('toxicities', 'Disease', (148, 158))	('patients', 'Species', '9606', (41, 49))	('toxicities', 'Disease', 'MESH:D064420', (148, 158))	('rs238406', 'Mutation', 'rs238406', (59, 67))	('rs238406 AA', 'Var', (59, 70))
336173	27246611	We also found that patients with the ERCC5/XPG rs873601 GA/GG genotypes had an increased risk of progression and death of ESCC after PAC, which was not reported before.	('PAC', 'Phenotype', 'HP:0006699', (133, 136))	('patients', 'Species', '9606', (19, 27))	('ESCC', 'Disease', (122, 126))	('death', 'Disease', 'MESH:D003643', (113, 118))	('death', 'Disease', (113, 118))	('rs873601', 'Var', (47, 55))	('XPG', 'Gene', '2073', (43, 46))	('PAC', 'Chemical', '-', (133, 136))	('rs873601', 'Mutation', 'rs873601', (47, 55))	('XPG', 'Gene', (43, 46))
336174	27246611	One study reported that the rs873601 G allele was associated with better PFS and OS of patients with advanced NSCLC, which may be disease-specific and need to be validated in future studies.	('PFS', 'Disease', (73, 76))	('NSCLC', 'Disease', (110, 115))	('better', 'PosReg', (66, 72))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('OS', 'Chemical', '-', (81, 83))	('patients', 'Species', '9606', (87, 95))	('rs873601', 'Mutation', 'rs873601', (28, 36))	('rs873601 G', 'Var', (28, 38))
336180	27246611	In summary, we identified that ERCC5/XPG rs2094258 CT/TT and rs873601 GA/GG and ERCC2/XPD rs238406 TT genotypes may independently or jointly affect survival of ESCC patients treated with PAC.	('ESCC', 'Disease', (160, 164))	('affect', 'Reg', (141, 147))	('rs2094258', 'Mutation', 'rs2094258', (41, 50))	('rs2094258', 'Var', (41, 50))	('rs238406', 'Mutation', 'rs238406', (90, 98))	('PAC', 'Chemical', '-', (187, 190))	('survival', 'MPA', (148, 156))	('rs238406', 'Var', (90, 98))	('rs873601', 'Mutation', 'rs873601', (61, 69))	('rs873601', 'Var', (61, 69))	('XPG', 'Gene', '2073', (37, 40))	('PAC', 'Phenotype', 'HP:0006699', (187, 190))	('patients', 'Species', '9606', (165, 173))	('XPG', 'Gene', (37, 40))
336182	27246611	adjHR adjusted hazards ratio AUC area under the receiver operator characteristic curve CI confidence interval DFS disease free survival EC esophageal cancer ESCC esophageal squamous cancer cell HG high-risk group LG low-risk group MPRCT multicenter prospective randomized controlled trial NER nucleotide excision repair NRG number of risk genotypes OS overall survival ROC receiver operating characteristic PAC platinum-based adjuvant chemotherapy SNP single nucleotide polymorphism UTR untranslated region	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('squamous cancer', 'Phenotype', 'HP:0002860', (173, 188))	('esophageal squamous cancer', 'Disease', (162, 188))	('PAC', 'Chemical', '-', (407, 410))	('esophageal cancer', 'Disease', (139, 156))	('PAC', 'Phenotype', 'HP:0006699', (407, 410))	('platinum', 'Chemical', 'MESH:D010984', (411, 419))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (162, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('single nucleotide polymorphism', 'Var', (452, 482))	('OS', 'Chemical', '-', (349, 351))
336188	22237988	BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not.	('BE', 'Phenotype', 'HP:0100580', (79, 81))	('dysplasia', 'Disease', (115, 124))	('high-grade', 'Var', (15, 25))	('mesothelin', 'Gene', '10232', (59, 69))	('expressed', 'Reg', (49, 58))	('dysplasia', 'Disease', 'MESH:D004476', (115, 124))	('dysplasia', 'Disease', (26, 35))	('dysplasia', 'Disease', 'MESH:D004476', (26, 35))	('BE', 'Phenotype', 'HP:0100580', (0, 2))	('mesothelin', 'Gene', (59, 69))
336193	22237988	Based on this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin are potential markers of neoplastic progression in BE and in EAC (NCT01393483).	('mesothelin', 'Gene', '10232', (89, 99))	('EAC', 'Phenotype', 'HP:0011459', (161, 164))	('mesothelin', 'Gene', (89, 99))	('NCT01393483', 'Var', (166, 177))	('BE', 'Phenotype', 'HP:0100580', (151, 153))
336489	31488165	In post-operative outcomes MIRDAVR group had significantly shorter mean aortic cross clamp (47.3 vs. 80.1 min) and cardiopulmonary bypass periods (63.7 vs. 104 min) than CONVAVR group.	('MIRDAVR', 'Var', (27, 34))	('aortic', 'CPA', (72, 78))	('shorter', 'NegReg', (59, 66))	('rat', 'Species', '10116', (11, 14))	('MIRDAVR', 'Chemical', '-', (27, 34))
336490	31488165	MIRDAVR had less intensive care unit stay and ventilation times compared to CONVAVR group, however, this did not reach statistical significance.	('MIRDAVR', 'Chemical', '-', (0, 7))	('ventilation times', 'CPA', (46, 63))	('MIRDAVR', 'Var', (0, 7))	('less', 'NegReg', (12, 16))
336491	31488165	In octogenarians, MIRDAVR group had not only significantly shorter intraoperative periods but also significantly less intensive care unit stay (30.9 vs. 65.6 hours) and ventilation times (11.7 vs. 21.2 hours) compared to CONVAVR group.	('MIRDAVR', 'Chemical', '-', (18, 25))	('MIRDAVR', 'Var', (18, 25))	('less', 'NegReg', (113, 117))	('shorter', 'NegReg', (59, 66))	('rat', 'Species', '10116', (75, 78))	('ventilation times', 'CPA', (169, 186))	('intensive care unit stay', 'CPA', (118, 142))
336492	31488165	In high risk patients (logEuroscore>10%), MIRDAVR group had also significantly shorter cardiopulmonary bypass periods but not significantly less aortic cross clamp time.	('MIRDAVR', 'Var', (42, 49))	('cardiopulmonary bypass periods', 'MPA', (87, 117))	('shorter', 'NegReg', (79, 86))	('patients', 'Species', '9606', (13, 21))	('MIRDAVR', 'Chemical', '-', (42, 49))
336595	31488165	Results  Cross-clamp, cardiopulmonary bypass, and circulatory arrest times of all the patients were (250+-78), (171+-70) and (31+-10) minutes, respectively.	('circulatory arrest', 'Disease', 'MESH:D012769', (50, 68))	('circulatory arrest', 'Disease', (50, 68))	('250+-78', 'Var', (101, 108))	('patients', 'Species', '9606', (86, 94))
336631	31488165	The thrombosis of false lumen in the arch level was higher in the Arch+SET group and AR+FS group, while AR+TBS and AR+SET group all showed decreased ratio of thrombosis of false lumen.	('rat', 'Species', '10116', (149, 152))	('AR+TBS', 'Chemical', '-', (104, 110))	('thrombosis', 'Disease', (4, 14))	('SE', 'Disease', 'None', (118, 120))	('SE', 'Disease', 'None', (71, 73))	('thrombosis', 'Disease', 'MESH:D013927', (158, 168))	('AR+FS', 'Var', (85, 90))	('AR+FS', 'Chemical', '-', (85, 90))	('thrombosis', 'Disease', 'MESH:D013927', (4, 14))	('AR', 'Chemical', '-', (104, 106))	('men', 'Species', '9606', (180, 183))	('men', 'Species', '9606', (26, 29))	('higher', 'PosReg', (52, 58))	('AR', 'Chemical', '-', (115, 117))	('AR', 'Chemical', '-', (85, 87))	('thrombosis', 'Disease', (158, 168))
336758	31488165	Results  The data suggests that postoperative treatment with trimetazidine leads to decrease in MDA production, CK-MB and TnT levels therefore to oxidative stress reduction and better myocardial cell protection by antioxidant status augmentation.	('decrease', 'NegReg', (84, 92))	('MDA', 'Chemical', 'MESH:D008315', (96, 99))	('trimetazidine', 'Var', (61, 74))	('MDA production', 'MPA', (96, 110))	('men', 'Species', '9606', (51, 54))	('TnT', 'Gene', (122, 125))	('oxidative stress reduction', 'MPA', (146, 172))	('MB', 'Chemical', 'MESH:D008751', (115, 117))	('men', 'Species', '9606', (236, 239))	('rat', 'Species', '10116', (39, 42))	('TnT', 'Gene', '162083', (122, 125))	('myocardial cell protection', 'CPA', (184, 210))	('oxidative stress', 'Phenotype', 'HP:0025464', (146, 162))	('better', 'PosReg', (177, 183))	('trimetazidine', 'Chemical', 'MESH:D014292', (61, 74))
337049	31488165	Methods  We analyzed data of 543 consecutive ECP (age=56.4+-8.8 years; tumor size=6+-3.5 cm) radically operated (R0) and monitored in 1975-2019 (m=405, f=138; esophagogastrectomies (EG) Garlock=280, EG Lewis=263, combined EG with resection of pancreas, liver, diaphragm, aorta, VCS, colon transversum, lung, trachea, pericardium, splenectomy=151; adenocarcinoma=308, squamous=225, mix=10; T1=126, T2=114, T3=178, T4=125; N0=275, N1=69, N2=199; G1=157, G2=139, G3=247; early EC=107, invasive=436).	('pancreas', 'Disease', (243, 251))	('G1=157', 'Var', (444, 450))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('adenocarcinoma', 'Disease', (347, 361))	('pancreas', 'Disease', 'MESH:D010190', (243, 251))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('G3=247', 'Var', (460, 466))	('adenocarcinoma', 'Disease', 'MESH:D000230', (347, 361))	('rat', 'Species', '10116', (106, 109))	('tumor', 'Disease', (71, 76))	('G2=139', 'Var', (452, 458))	('T3=178', 'Var', (405, 411))
337091	31488165	Significant risk factors for developing wound infection after cardiac surgery in our Department include: diabetes mellitus (P-0,000), BMI > 25 (P-0,001), duration/h of mechanical lungs ventilation in the ICU (P-0,030, P-0.0141), chronic congestive heart failure (P-0.0499) and low levels of albumin (P-0.310).	('rat', 'Species', '10116', (156, 159))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (105, 122))	('diabetes mellitus', 'Disease', (105, 122))	('congestive heart failure', 'Disease', 'MESH:D006333', (237, 261))	('low', 'NegReg', (277, 280))	('congestive heart failure', 'Phenotype', 'HP:0001635', (237, 261))	('men', 'Species', '9606', (91, 94))	('congestive heart failure', 'Disease', (237, 261))	('diabetes mellitus', 'Disease', 'MESH:D003920', (105, 122))	('infection', 'Disease', (46, 55))	('infection', 'Disease', 'MESH:D007239', (46, 55))	('BMI > 25', 'Var', (134, 142))	('heart failure', 'Phenotype', 'HP:0001635', (248, 261))
337158	31488165	Conclusions  Hybrid coronary revascularization in group of patients with intermediate-high SYNTAX Score can offer minimization of surgical trauma and better early postoperative results as compared with conventional coronary surgery.	('trauma', 'Disease', 'MESH:D014947', (139, 145))	('trauma', 'Disease', (139, 145))	('rat', 'Species', '10116', (170, 173))	('intermediate-high', 'Var', (73, 90))	('patients', 'Species', '9606', (59, 67))
337226	31488165	Although most patients are asymptomatic, PAVMs can cause dyspnoea from right-to-left shunt.	('dyspnoea', 'Disease', (57, 65))	('PA', 'Chemical', '-', (41, 43))	('dyspnoea', 'Disease', 'MESH:D004417', (57, 65))	('right-to-left shunt', 'Phenotype', 'HP:0001694', (71, 90))	('PAVMs', 'Var', (41, 46))	('cause', 'Reg', (51, 56))	('patients', 'Species', '9606', (14, 22))
337336	31488165	Patients underwent RFA had significantly worse respiratory lung function with mean of FEV1 respectively 60% vs 74% (P=0.001).	('rat', 'Species', '10116', (52, 55))	('worse', 'NegReg', (41, 46))	('respiratory lung function', 'MPA', (47, 72))	('Patients', 'Species', '9606', (0, 8))	('RFA', 'Var', (19, 22))
337337	31488165	Comparing the two groups, patients underwent sub-lobar resection had significant better survival than those underwent RFA with respectively 5 years survival of 89% vs 49% (P<0.001) (Graph 1).	('sub-lobar', 'Var', (45, 54))	('better', 'PosReg', (81, 87))	('patients', 'Species', '9606', (26, 34))
337398	31488165	Histological sectioning revealed that stapling of the pulmonary artery with Endo-GIA  i-Drive loaded with white and gray cartridges resulted in ruptures in the inner and middle membrane of the pulmonary artery.	('ruptures', 'Disease', 'MESH:D012421', (144, 152))	('ruptures', 'Disease', (144, 152))	('stapling', 'Var', (38, 46))	('Endo-GIA', 'Gene', (76, 84))
337459	31488165	Conclusion: Our recommendation is that for patients with concomitant carotid and coronary artery disease a combined surgical procedure is indicated , especially if they have life threatening coronary anatomy consisting of LM disease or proximal LAD stenosis or high-grade stenosis three-vessel disease (high SYNTAX score).	('coronary artery disease', 'Disease', 'MESH:D003324', (81, 104))	('LM disease', 'Disease', 'MESH:D030342', (222, 232))	('LM disease', 'Disease', (222, 232))	('patients', 'Species', '9606', (43, 51))	('proximal LAD stenosis', 'Disease', 'MESH:C535887', (236, 257))	('coronary artery disease', 'Disease', (81, 104))	('proximal LAD stenosis', 'Disease', (236, 257))	('high-grade stenosis', 'Var', (261, 280))	('men', 'Species', '9606', (21, 24))
337512	31488165	Among all the observed hemodynamic parameters, mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), pulmonary capillary pressure (PCP), central venous pressure (CVP), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), in general, showed improvement only with BR or MB + BR, but only the 1hMB + BR group had a better final MPAP and PVR.	('central venous pressure', 'MPA', (154, 177))	('cardiac output', 'Disease', (185, 199))	('PA', 'Chemical', '-', (112, 114))	('1hMB', 'Chemical', '-', (368, 372))	('men', 'Species', '9606', (325, 328))	('BR', 'Chemical', 'MESH:D001966', (340, 342))	('systemic vascular resistance', 'MPA', (226, 254))	('pulmonary vascular resistance', 'MPA', (262, 291))	('MB', 'Chemical', 'MESH:D008751', (346, 348))	('MB + BR', 'Var', (346, 353))	('MB', 'Chemical', 'MESH:D008751', (370, 372))	('PA', 'Chemical', '-', (404, 406))	('BR', 'Chemical', 'MESH:D001966', (351, 353))	('BR', 'Chemical', 'MESH:D001966', (375, 377))	('+ BR', 'Chemical', 'MESH:D001966', (373, 377))	('+ BR', 'Chemical', 'MESH:D001966', (349, 353))	('pulmonary capillary pressure', 'MPA', (118, 146))	('cardiac index', 'MPA', (206, 219))	('cardiac output', 'Disease', 'MESH:D002303', (185, 199))	('improvement', 'PosReg', (318, 329))	('mean arterial pressure', 'MPA', (47, 69))
337519	31488165	Animals that received NH4Cl also had lower weight gain during the study period.	('weight gain', 'Disease', 'MESH:D015430', (43, 54))	('lower', 'NegReg', (37, 42))	('weight gain', 'Phenotype', 'HP:0004324', (43, 54))	('NH4Cl', 'Var', (22, 27))	('NH4Cl', 'Chemical', 'MESH:D000643', (22, 27))	('lower weight', 'Phenotype', 'HP:0004325', (37, 49))	('weight gain', 'Disease', (43, 54))
337521	31488165	The CMA induced by NH4Cl through gavage infusions, and association of powdered juice, was more efficient than ad libitumoral administration.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('rat', 'Species', '10116', (133, 136))	('NH4Cl', 'Var', (19, 24))	('juice', 'Chemical', '-', (79, 84))	('association', 'Interaction', (55, 66))	('NH4Cl', 'Chemical', 'MESH:D000643', (19, 24))	('CMA', 'Disease', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
337590	31488165	Patients scheduled for elective surgery had debranching of aortic arch at the first stage and TEVAR at the second stage.	('aortic arch', 'CPA', (59, 70))	('TEVAR', 'Chemical', '-', (94, 99))	('debranching', 'Var', (44, 55))	('Patients', 'Species', '9606', (0, 8))
337784	30225162	In the antiviral group, PVD, PV-CI, HV-DI, vWF-Ag and sCD163 were all significantly reduced than the baseline values (P < 0.05), and PVV was significantly increased than the baseline value (P < 0.05).	('increased', 'PosReg', (155, 164))	('CD163', 'Gene', '9332', (55, 60))	('reduced', 'NegReg', (84, 91))	('antiviral', 'Var', (7, 16))	('vWF', 'Gene', '7450', (43, 46))	('CD163', 'Gene', (55, 60))	('vWF', 'Gene', (43, 46))
337840	30225162	Analysis of liver biochemical profiles (ALT, AST, ALB, TB and PT) showed steady improvements in the liver function in the antiviral group.	('antiviral', 'Var', (122, 131))	('liver function', 'MPA', (100, 114))	('improvements', 'PosReg', (80, 92))	('AST', 'Gene', (45, 48))	('ALB', 'Gene', '213', (50, 53))	('AST', 'Gene', '26503', (45, 48))	('ALB', 'Gene', (50, 53))	('TB', 'Chemical', 'MESH:D013725', (55, 57))
337841	30225162	However, non-antiviral group had significantly higher ALT, AST and PT (Table 2).	('AST', 'Gene', (59, 62))	('ALT', 'CPA', (54, 57))	('non-antiviral', 'Var', (9, 22))	('higher', 'PosReg', (47, 53))	('AST', 'Gene', '26503', (59, 62))
337872	30225162	In the current study, we found that the portal hemodynamic parameters and HV-DI had significant improvements in the antiviral therapy group, suggesting the alleviation of portal hypertension.	('hypertension', 'Disease', 'MESH:D006973', (178, 190))	('hypertension', 'Disease', (178, 190))	('hypertension', 'Phenotype', 'HP:0000822', (178, 190))	('portal hypertension', 'Phenotype', 'HP:0001409', (171, 190))	('antiviral therapy', 'Var', (116, 133))	('HV-DI', 'MPA', (74, 79))	('portal hemodynamic parameters', 'MPA', (40, 69))	('improvements', 'PosReg', (96, 108))
337894	29904722	It is strongly linked to carcinogenesis and new evidence proves that NAFLD is associated with higher risk of all-cause mortality and cancer-specific mortality among cancer survivors.	('all-cause mortality', 'CPA', (109, 128))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (25, 39))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('carcinogenesis', 'Disease', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('NAFLD', 'Var', (69, 74))
337907	29904722	The presence of NAFLD is closely associated with extrahepatic serious abnormalities including cardiovascular system with atherosclerosis/cardiovascular disease (CVD) and hypertension, endocrinopathies, T2DM, chronic kidney disease and osteoporosis.	('chronic kidney disease', 'Disease', (208, 230))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (137, 159))	('hypertension', 'Disease', 'MESH:D006973', (170, 182))	('osteoporosis', 'Disease', (235, 247))	('CVD', 'Phenotype', 'HP:0001626', (161, 164))	('endocrinopathies', 'Disease', 'MESH:C567425', (184, 200))	('hypertension', 'Disease', (170, 182))	('osteoporosis', 'Phenotype', 'HP:0000939', (235, 247))	('atherosclerosis', 'Phenotype', 'HP:0002621', (121, 136))	('chronic kidney disease', 'Disease', 'MESH:D051436', (208, 230))	('osteoporosis', 'Disease', 'MESH:D010024', (235, 247))	('endocrinopathies', 'Disease', (184, 200))	('hypertension', 'Phenotype', 'HP:0000822', (170, 182))	('atherosclerosis/cardiovascular disease', 'Disease', (121, 159))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (208, 230))	('atherosclerosis/cardiovascular disease', 'Disease', 'MESH:D002318', (121, 159))	('presence', 'Var', (4, 12))	('extrahepatic', 'Disease', (49, 61))	('NAFLD', 'Gene', (16, 21))	('kidney disease', 'Phenotype', 'HP:0000112', (216, 230))	('cardiovascular system', 'Disease', (94, 115))	('associated', 'Reg', (33, 43))	('T2DM', 'Disease', (202, 206))
337912	29904722	New evidence proves that NAFLD is associated with higher risk of all-cause mortality and cancer-specific mortality among cancer survivors.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('all-cause mortality', 'CPA', (65, 84))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('NAFLD', 'Var', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
337953	29904722	HIFalpha stabilization has a role in genetic alterations such as mutations in the Wnt/beta-catenin signaling pathway in colon carcinoma and other oncogenic events.	('beta-catenin', 'Gene', (86, 98))	('colon carcinoma', 'Disease', 'MESH:D015179', (120, 135))	('colon carcinoma', 'Disease', (120, 135))	('beta-catenin', 'Gene', '1499', (86, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('mutations', 'Var', (65, 74))
337977	29904722	Deregulation of wound healing promotes the development of progressive fibrosis, which determines liver prognosis.	('fibrosis', 'Disease', (70, 78))	('fibrosis', 'Disease', 'MESH:D005355', (70, 78))	('Deregulation', 'Var', (0, 12))
337982	29904722	Overactivation of this signaling may lead to many tumors such as pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('pancreatic cancer', 'Disease', (65, 82))	('lead to', 'Reg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('Overactivation', 'Var', (0, 14))
337984	29904722	There is evidence that children with NAFLD exhibited higher abundance of Gammaproteobacteria, Epsilonproteobacteria and Prevotella spp.	('higher', 'PosReg', (53, 59))	('NAFLD', 'Var', (37, 42))	('Gammaproteobacteria', 'Protein', (73, 92))	('Prevotella', 'CPA', (120, 130))	('children', 'Species', '9606', (23, 31))	('abundance', 'MPA', (60, 69))	('Epsilonproteobacteria', 'Protein', (94, 115))
338041	29904722	Some authors have reported higher circulating resistin levels in NAFLD than in control groups.	('resistin', 'Gene', '56729', (46, 54))	('NAFLD', 'Var', (65, 70))	('higher', 'PosReg', (27, 33))	('resistin', 'Gene', (46, 54))
338082	29904722	High BMI, which is the main risk factor of NAFLD development, is also listed among all proven risk factors of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (110, 135))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (110, 135))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (110, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('High BMI', 'Var', (0, 8))
338095	29904722	A meta-analysis published in 2011 revealed T2DM as a risk factor of pancreatic cancer regardless of gender.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('T2DM', 'Var', (43, 47))	('pancreatic cancer', 'Disease', (68, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))
338097	29904722	NAFLD should be considered as an independent risk factor of pancreatic cancer, but further studies are needed to clarify and confirm this suggestion.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('NAFLD', 'Var', (0, 5))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))
338099	29904722	NAFLD is associated with higher prevalence of colorectal lesions and cancer.	('colorectal lesions', 'Disease', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('colorectal lesions', 'Disease', 'MESH:D015179', (46, 64))	('NAFLD', 'Var', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
338108	29904722	The incidence of adenomatous polyps in patients with NAFLD vs. without NAFLD was respectively 628.0 vs. 185.2/105 persons/year (RR 1.94; 95% CI: 1.11-3.40), while that of colorectal cancer was 233.6 vs. 27.0/105 persons/year (RR 3.08; 95% CI: 1.02-9.34).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('patients', 'Species', '9606', (39, 47))	('persons', 'Species', '9606', (212, 219))	('colorectal cancer', 'Disease', (171, 188))	('adenomatous polyps', 'Disease', (17, 35))	('NAFLD', 'Var', (53, 58))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (17, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (171, 188))	('adenomatous polyps', 'Disease', 'MESH:D018256', (17, 35))	('persons', 'Species', '9606', (114, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))
338110	29904722	The prevalence of colorectal lesions was 34% in the NAFLD group and 21.7% in the control group (p < 0.001).	('NAFLD', 'Var', (52, 57))	('colorectal lesions', 'Disease', (18, 36))	('colorectal lesions', 'Disease', 'MESH:D015179', (18, 36))
338112	29904722	The analysis showed that 40% of male patients with NAFLD included in the study had colorectal lesions compared to 28.3% of those without NAFLD (p = 0.010), whereas 25.6% of female patients with NAFLD had colorectal lesions compared to 17.2% of those without NAFLD (p = 0.014).	('NAFLD', 'Var', (51, 56))	('colorectal lesions', 'Disease', 'MESH:D015179', (204, 222))	('patients', 'Species', '9606', (37, 45))	('colorectal lesions', 'Disease', (83, 101))	('colorectal lesions', 'Disease', 'MESH:D015179', (83, 101))	('colorectal lesions', 'Disease', (204, 222))	('patients', 'Species', '9606', (180, 188))
338120	29904722	including 127 patients found the prevalence of colorectal carcinoma to be significantly lower in patients with NAFLD (4.6%) compared to those without NAFLD (24.2%) (p = 0.001).	('colorectal carcinoma', 'Disease', (47, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lower', 'NegReg', (88, 93))	('patients', 'Species', '9606', (14, 22))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (47, 67))	('NAFLD', 'Var', (111, 116))	('patients', 'Species', '9606', (97, 105))
338122	29904722	NAFLD is related to increased risk of development of some extrahepatic cancers.	('extrahepatic cancers', 'Disease', 'MESH:D001651', (58, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('NAFLD', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('extrahepatic cancers', 'Disease', (58, 78))
338130	29904722	Dysregulation of adipose tissue derived hormones - adipokines - influences inflammation, fibrosis, angiogenesis, apoptosis and IR, with predominance of the pro-carcinogenic effect.	('IR', 'Phenotype', 'HP:0000855', (127, 129))	('influences', 'Reg', (64, 74))	('apoptosis', 'CPA', (113, 122))	('Dysregulation', 'Var', (0, 13))	('fibrosis', 'Disease', (89, 97))	('fibrosis', 'Disease', 'MESH:D005355', (89, 97))	('angiogenesis', 'CPA', (99, 111))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('inflammation', 'Disease', (75, 87))
338181	29538208	Because of the increased anastomosis numbers and technique complexity, postoperative complications, such as intestinal obstruction and anastomosis stricture, were shown to increase accordingly.	('intestinal obstruction', 'Disease', (108, 130))	('anastomosis', 'Var', (25, 36))	('increase', 'PosReg', (172, 180))	('increased', 'PosReg', (15, 24))	('intestinal obstruction', 'Phenotype', 'HP:0005214', (108, 130))	('intestinal obstruction', 'Disease', 'MESH:D007415', (108, 130))	('anastomosis', 'Disease', (135, 146))
338197	29029411	Flow cytometry and TUNEL staining both showed that combination of paclitaxel treatment and nestin knockdown resulted in greater induction of apoptosis of esophageal carcinoma cells as compared with the cells transfected with control siRNA (also treated with paclitaxel).	('paclitaxel', 'Chemical', 'MESH:D017239', (66, 76))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (154, 174))	('nestin', 'Gene', '10763', (91, 97))	('knockdown', 'Var', (98, 107))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (154, 174))	('nestin', 'Gene', (91, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('apoptosis', 'CPA', (141, 150))	('esophageal carcinoma', 'Disease', (154, 174))	('paclitaxel', 'Chemical', 'MESH:D017239', (258, 268))
338198	29029411	This study indicates that nestin knockdown enhances chemotherapeutic sensitivity of paclitaxel to esophageal carcinoma, and suggests that silencing of nestin could be a valuble therapeutic approach for enhancing drug sensitivity and thereby improving the treatment outcome of esophageal carcinoma patients.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (98, 118))	('enhances', 'PosReg', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('esophageal carcinoma', 'Disease', (276, 296))	('drug sensitivity', 'Phenotype', 'HP:0020174', (212, 228))	('drug sensitivity', 'MPA', (212, 228))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (276, 296))	('improving', 'PosReg', (241, 250))	('silencing', 'Var', (138, 147))	('nestin', 'Gene', '10763', (26, 32))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (98, 118))	('knockdown', 'Var', (33, 42))	('patients', 'Species', '9606', (297, 305))	('nestin', 'Gene', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('esophageal carcinoma', 'Disease', (98, 118))	('paclitaxel', 'Chemical', 'MESH:D017239', (84, 94))	('enhancing', 'PosReg', (202, 211))	('nestin', 'Gene', '10763', (151, 157))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (276, 296))	('nestin', 'Gene', (151, 157))
338209	29029411	In this study, we demonstrated that the expression level of nestin was correlated the invasiveness of esophageal carcinoma and inhibition of nestin enhanced paclitaxel sensitivity to apoptosis of esophageal carcinoma cells.	('expression', 'MPA', (40, 50))	('paclitaxel', 'Chemical', 'MESH:D017239', (157, 167))	('paclitaxel sensitivity to apoptosis', 'MPA', (157, 192))	('esophageal carcinoma', 'Disease', (196, 216))	('nestin', 'Gene', '10763', (60, 66))	('invasiveness of esophageal carcinoma', 'Disease', 'MESH:D004938', (86, 122))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (196, 216))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (102, 122))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (102, 122))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (196, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('invasiveness of esophageal carcinoma', 'Disease', (86, 122))	('nestin', 'Gene', (60, 66))	('inhibition', 'Var', (127, 137))	('enhanced', 'PosReg', (148, 156))	('nestin', 'Gene', '10763', (141, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('nestin', 'Gene', (141, 147))
338231	29029411	Furthermore, we were interested whether proconditioning the cells through nestin silencing could augment the chemotherapeutic sensitivity to paclitaxel.	('chemotherapeutic sensitivity to paclitaxel', 'MPA', (109, 151))	('nestin', 'Gene', '10763', (74, 80))	('paclitaxel', 'Chemical', 'MESH:D017239', (141, 151))	('nestin', 'Gene', (74, 80))	('silencing', 'Var', (81, 90))	('augment', 'NegReg', (97, 104))
338237	29029411	In summary, this study indicates that knockdown of nestin enhances the chemotherapeutic sensitivity to paclitaxel.	('nestin', 'Gene', (51, 57))	('paclitaxel', 'Chemical', 'MESH:D017239', (103, 113))	('chemotherapeutic sensitivity to paclitaxel', 'MPA', (71, 113))	('nestin', 'Gene', '10763', (51, 57))	('knockdown', 'Var', (38, 47))	('enhances', 'PosReg', (58, 66))
338253	29029411	The specific siRNA nestin sequences: sense (5'GUGCCAGCCUUUCUUAAGATT-3') and antisense (5'UCUUAAGAAAGGCUGGCACTT-3'); negative control: sensce (5'GCGACGAUCUGCCUAAGAUdTdT-3') and antisense (5'AUCUUAGGCAGAUCGUCGCdTdT-3').	('nestin', 'Gene', (19, 25))	("5'GUGCCAGCCUUUCUUAAGATT-3", 'Var', (44, 69))	('nestin', 'Gene', '10763', (19, 25))
338361	26869799	And, we observed that knocking down HIF-1alpha or HIF-2alpha individually inhibited the xenograft tumor angiogenesis and growth, and knocking them down simultaneously revealed a better inhibitory effect than knocking down either unit alone.	('inhibited', 'NegReg', (74, 83))	('HIF-1alpha or HIF-2alpha', 'Disease', 'None', (36, 60))	('knocking down', 'Var', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('HIF-1alpha or HIF-2alpha', 'Disease', (36, 60))	('knocking', 'Var', (133, 141))	('tumor', 'Disease', (98, 103))
338368	26869799	In this model with OSC-19 cell lines, metastasis to the cervical lymph node was markedly inhibited by cisplatin or peplomycin and the combination of neoadjuvant chemotherapy and tumor resection.	('tumor', 'Disease', (178, 183))	('OSC-19', 'CellLine', 'CVCL:3086', (19, 25))	('cisplatin', 'Var', (102, 111))	('inhibited', 'NegReg', (89, 98))	('metastasis to the cervical lymph node', 'CPA', (38, 75))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('peplomycin', 'Var', (115, 125))	('peplomycin', 'Chemical', 'MESH:D017663', (115, 125))
338384	26869799	With a NOD/SCID mouse model, Prince et al tested the tumorigenic potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples and found that the CD44+ population possessed the unique properties of self-renewal and differentiation.	('SCID', 'Gene', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('human', 'Species', '9606', (152, 157))	('mouse', 'Species', '10090', (16, 21))	('cancer', 'Disease', (103, 109))	('differentiation', 'CPA', (260, 275))	('self-renewal', 'CPA', (243, 255))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NOD', 'Gene', '1822', (7, 10))	('CD44+', 'Var', (191, 196))	('SCC', 'Gene', '6317', (160, 163))	('NOD', 'Gene', (7, 10))	('SCC', 'Gene', (160, 163))	('tested', 'Reg', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('SCID', 'Gene', '19090', (11, 15))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))	('SCID', 'Phenotype', 'HP:0004430', (11, 15))	('tumor', 'Disease', (53, 58))
338388	26869799	The NOG mouse model combines the features of SCID and IL-2 receptor gamma chain deficiency.	('SCID', 'Phenotype', 'HP:0004430', (45, 49))	('SCID', 'Gene', '19090', (45, 49))	('deficiency', 'Var', (80, 90))	('IL-2', 'Gene', '16183', (54, 58))	('mouse', 'Species', '10090', (8, 13))	('SCID', 'Gene', (45, 49))	('IL-2', 'Gene', (54, 58))
338431	26869799	DNA hypomethylation was shown to suppress oral squamous cell carcinogenesis in 4-NQO mice model.	('mice', 'Species', '10090', (85, 89))	('4-NQO', 'Chemical', 'MESH:D015112', (79, 84))	('hypomethylation', 'Var', (4, 19))	('oral squamous cell carcinogenesis', 'Disease', (42, 75))	('oral squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (42, 75))	('suppress', 'NegReg', (33, 41))
338433	26869799	Inactivation of VEGFR or EGFR could significantly suppress oral cancer development and progression in 4-NQO mouse model.	('EGFR', 'Gene', '13649', (17, 21))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', '13649', (25, 29))	('oral cancer', 'Disease', 'MESH:D009062', (59, 70))	('suppress', 'NegReg', (50, 58))	('mouse', 'Species', '10090', (108, 113))	('oral cancer', 'Disease', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('4-NQO', 'Chemical', 'MESH:D015112', (102, 107))	('progression', 'CPA', (87, 98))	('Inactivation', 'Var', (0, 12))	('EGFR', 'Gene', (17, 21))
338448	26869799	They found that various cancer-derived cytokines, such as IL-6, PTHrP, TNF-alpha, RANK, RANKL, osteoproteger, played important roles in the OSCC invading bone, and by inhibiting these cytokines, YM529 (a third-generation bisphosphonate) could suppress osteoclast-mediated bone invasion.	('TNF-alpha', 'Gene', '21926', (71, 80))	('cancer', 'Disease', (24, 30))	('PTHrP', 'Gene', '19227', (64, 69))	('bisphosphonate', 'Chemical', 'MESH:D004164', (221, 235))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('PTHrP', 'Gene', (64, 69))	('RANKL', 'Gene', (88, 93))	('rat', 'Species', '10116', (214, 217))	('YM529', 'Var', (195, 200))	('osteoclast-mediated bone invasion', 'CPA', (252, 285))	('RANKL', 'Gene', '21943', (88, 93))	('TNF-alpha', 'Gene', (71, 80))	('inhibiting', 'NegReg', (167, 177))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('SCC', 'Gene', '6317', (141, 144))	('IL-6', 'Gene', (58, 62))	('SCC', 'Gene', (141, 144))	('suppress', 'NegReg', (243, 251))	('IL-6', 'Gene', '16193', (58, 62))
338458	26869799	Ras as an oncogene, frequently activated by point mutations or overexpression, plays a crucial role in human tumors.	('point mutations', 'Var', (44, 59))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('human', 'Species', '9606', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
338463	26869799	Using K5-rTA, tet-ras, and tetO-LacZ transgenic mice, Raimondi et al proved that inducing expression of K-ras gene under the control of K5 promoter could trigger a full carcinogenesis.	('K-ras', 'Gene', '16653', (104, 109))	('inducing', 'Var', (81, 89))	('carcinogenesis', 'Disease', (169, 183))	('K-ras', 'Gene', (104, 109))	('trigger', 'Reg', (154, 161))	('expression', 'MPA', (90, 100))	('transgenic mice', 'Species', '10090', (37, 52))	('carcinogenesis', 'Disease', 'MESH:D063646', (169, 183))
338467	26869799	In a H-ras mutation model, male CB6F1-Tg-rasH2 @Jcl mice, Miyamoto et al demonstrated that 4-NQO more easily induced tongue and esophageal carcinogenesis.	('H-ras', 'Gene', (5, 10))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (128, 153))	('rat', 'Species', '10116', (80, 83))	('induced', 'Reg', (109, 116))	('mice', 'Species', '10090', (52, 56))	('esophageal carcinogenesis', 'Disease', (128, 153))	('4-NQO', 'Var', (91, 96))	('H-ras', 'Gene', '15461', (5, 10))	('4-NQO', 'Chemical', 'MESH:D015112', (91, 96))
338470	26869799	A type of dominant-negative p53 transgenic mouse was shown to be highly susceptible to 4-NQO with higher prevalence and more rapid development of OSCC.	('p53', 'Gene', (28, 31))	('SCC', 'Gene', (147, 150))	('4-NQO', 'Chemical', 'MESH:D015112', (87, 92))	('p53', 'Gene', '22059', (28, 31))	('transgenic', 'Species', '10090', (32, 42))	('dominant-negative', 'Var', (10, 27))	('SCC', 'Gene', '6317', (147, 150))	('susceptible', 'Reg', (72, 83))	('mouse', 'Species', '10090', (43, 48))
338472	26869799	In xeroderma pigmentosum group A gene-deficient (XPA-/-) mouse strain carrying mutant alleles for p53, treated with 4-NQO, Ide et al found the accelerated tongue tumor growth might be a consequence of haplonin sufficiency rather than the mutation of p53 in the context of nucleotide excision repair deficiency.	('rat', 'Species', '10116', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('xeroderma pigmentosum', 'Disease', (3, 24))	('p53', 'Gene', '22059', (98, 101))	('tumor', 'Disease', (162, 167))	('tongue tumor', 'Phenotype', 'HP:0100648', (155, 167))	('accelerated', 'PosReg', (143, 154))	('rat', 'Species', '10116', (222, 225))	('XPA-/-', 'Gene', (49, 55))	('mouse', 'Species', '10090', (57, 62))	('p53', 'Gene', (250, 253))	('p53', 'Gene', '22059', (250, 253))	('p53', 'Gene', (98, 101))	('XPA-/-)', 'Gene', '22590', (49, 56))	('4-NQO', 'Chemical', 'MESH:D015112', (116, 121))	('mutant alleles', 'Var', (79, 93))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (3, 24))
338476	26869799	Hyperproliferation, reduced apoptosis, and increased genomic instability are related to defective TGF-beta signal in epithelial cells.	('TGF-beta', 'Gene', '21803;21808', (98, 106))	('reduced', 'NegReg', (20, 27))	('rat', 'Species', '10116', (12, 15))	('genomic instability', 'CPA', (53, 72))	('apoptosis', 'CPA', (28, 37))	('increased', 'PosReg', (43, 52))	('TGF-beta', 'Gene', (98, 106))	('Hyperproliferation', 'Disease', (0, 18))	('defective', 'Var', (88, 97))
338478	26869799	Activation of either K-ras or H-ras in combination with TGF-betaRII deletion from mouse head-and-neck epithelia caused HNSCC with complete penetrance, some of which progressed to metastases.	('mouse', 'Species', '10090', (82, 87))	('H-ras', 'Gene', (30, 35))	('SCC', 'Gene', (121, 124))	('TGF-beta', 'Gene', (56, 64))	('deletion', 'Var', (68, 76))	('progressed', 'PosReg', (165, 175))	('TGF-beta', 'Gene', '21803;21808', (56, 64))	('caused', 'Reg', (112, 118))	('metastases', 'Disease', (179, 189))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('SCC', 'Gene', '6317', (121, 124))	('K-ras', 'Gene', (21, 26))	('K-ras', 'Gene', '16653', (21, 26))	('metastases', 'Disease', 'MESH:D009362', (179, 189))	('H-ras', 'Gene', '15461', (30, 35))
338479	26869799	With the same model system, their further findings demonstrated that the abrogation of TGF-beta signaling would continuously stimulate NF-kappaB, and then result in malignant progression.	('abrogation', 'Var', (73, 83))	('result in', 'Reg', (155, 164))	('TGF-beta', 'Gene', (87, 95))	('NF-kappaB', 'Protein', (135, 144))	('malignant progression', 'CPA', (165, 186))	('TGF-beta', 'Gene', '21803;21808', (87, 95))	('rat', 'Species', '10116', (58, 61))	('stimulate', 'PosReg', (125, 134))
338480	26869799	Bian et al developed an inducible mouse model by knocking out Tgf-betaR1 and Pten.	('knocking out', 'Var', (49, 61))	('mouse', 'Species', '10090', (34, 39))	('Tgf-betaR1', 'Gene', (62, 72))	('Pten', 'Gene', (77, 81))	('Pten', 'Gene', '19211', (77, 81))
338483	26869799	PI3K-mTOR inhibition can enhance TP53/p73 expression and significantly inhibit tumor growth alone.	('p73', 'Gene', (38, 41))	('tumor', 'Disease', (79, 84))	('enhance', 'PosReg', (25, 32))	('inhibit', 'NegReg', (71, 78))	('TP53', 'Gene', '22059', (33, 37))	('p73', 'Gene', '22062', (38, 41))	('TP53', 'Gene', (33, 37))	('inhibition', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('PI3K-mTOR', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
338489	26869799	To study the biological activities of the HPV 16 E6 and E7 genes in epithelial cells in vivo, transgenic mice with HPV 16 E6 and E7 were established and tumorigenicity by HPV 16 E6 and E7 was obtained.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('transgenic mice', 'Species', '10090', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('HPV 16', 'Species', '333760', (171, 177))	('HPV 16', 'Species', '333760', (42, 48))	('HPV', 'Var', (115, 118))	('HPV 16', 'Species', '333760', (115, 121))
338490	26869799	Further, Song et al have used transgenic mice that express HPV 16 E6 or E7 in the epidermis to find the mechanism by which HPV 16 E6 or E7 abrogates radiation-induced DNA damage responses in vivo through p53-dependent and p53-independent pathways.	('HPV 16 E6', 'Var', (123, 132))	('abrogates', 'NegReg', (139, 148))	('p53', 'Gene', '22059', (222, 225))	('p53', 'Gene', (204, 207))	('p53', 'Gene', '22059', (204, 207))	('HPV 16', 'Species', '333760', (123, 129))	('transgenic mice', 'Species', '10090', (30, 45))	('radiation-induced DNA damage responses', 'MPA', (149, 187))	('p53', 'Gene', (222, 225))	('HPV 16', 'Species', '333760', (59, 65))
338492	26869799	These mice exhibit a radiation response similar to that of the K14E6 (wild-type [WT]) mice, demonstrating that HPV16 E6 retains an ability to inactivate p53.	('inactivate', 'NegReg', (142, 152))	('HPV16 E6', 'Var', (111, 119))	('K14', 'Gene', '3861', (63, 66))	('mice', 'Species', '10090', (6, 10))	('rat', 'Species', '10116', (99, 102))	('mice', 'Species', '10090', (86, 90))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '22059', (153, 156))	('HPV16', 'Species', '333760', (111, 116))	('K14', 'Gene', (63, 66))
338495	26869799	Zinc-deficient mice with genetic COX-2 deletion developed significantly greater upper aerodigestive tract tumor than WT controls, and presented strong LTA(4)H immunostaining in induced tumors.	('tumor', 'Disease', (185, 190))	('COX-2', 'Gene', '17709', (33, 38))	('greater', 'PosReg', (72, 79))	('COX-2', 'Gene', (33, 38))	('tumors', 'Disease', (185, 191))	('deletion', 'Var', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('LTA(4)H', 'Gene', (151, 158))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('upper aerodigestive', 'CPA', (80, 99))	('LTA(4)H', 'Gene', '16993', (151, 158))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (106, 111))
338505	26869799	Andl et al developed two mouse models targeting ablation of Cdh1 and Tgfbr2 genes constitutively or inducibly in the oral-esophageal epithelium, which had long latency and could phenocopy the human disease quite accurately.	('Tgfbr2', 'Gene', (69, 75))	('human', 'Species', '9606', (192, 197))	('mouse', 'Species', '10090', (25, 30))	('Tgfbr2', 'Gene', '21813', (69, 75))	('Cdh1', 'Gene', '12550', (60, 64))	('ablation', 'Var', (48, 56))	('rat', 'Species', '10116', (216, 219))	('Cdh1', 'Gene', (60, 64))
338518	25068654	When grown in three-dimensional organotypic reconstruct cultures, esophageal keratinocytes expressing dominant-negative mutants of E-cadherin and TGFbeta receptor II showed activated Smad2 in the absence of functional TGFbeta receptor II.	('Smad2', 'Gene', (183, 188))	('Smad2', 'Gene', '4087', (183, 188))	('TGFbeta receptor II', 'Gene', '7048', (218, 237))	('TGFbeta receptor II', 'Gene', (218, 237))	('activated', 'PosReg', (173, 182))	('E-cadherin and TGFbeta receptor II', 'Gene', '999', (131, 165))	('TGFbeta receptor II', 'Gene', '7048', (146, 165))	('mutants', 'Var', (120, 127))	('TGFbeta receptor II', 'Gene', (146, 165))
338532	25068654	Our previous study showed increased cell invasion in Boyden chamber assays in response to Act A stimulation through an E-cadherin-dependent increase of the CD44 variant form in the esophageal cancer cell line TE11.	('esophageal cancer', 'Disease', (181, 198))	('CD44', 'Gene', (156, 160))	('CD44', 'Gene', '960', (156, 160))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('E-cadherin', 'Gene', (119, 129))	('variant', 'Var', (161, 168))	('increased', 'PosReg', (26, 35))	('cell invasion in Boyden chamber assays', 'CPA', (36, 74))	('E-cadherin', 'Gene', '999', (119, 129))	('increase', 'PosReg', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
338540	25068654	To better understand the complex role of Act A in esophageal cell invasion, we employed three-dimensional organotypic cultures to reconstitute the epithelium with squamous esophageal epithelial cells expressing wild-type full-length E-cadherin, dominant-negative mutant E-cadherin or dominant-negative mutant E-cadherin and TGFbeta receptor II (ECdnT).	('E-cadherin and TGFbeta receptor II', 'Gene', '999', (309, 343))	('EC', 'Gene', '999', (345, 347))	('E-cadherin', 'Gene', (270, 280))	('E-cadherin', 'Gene', '999', (270, 280))	('E-cadherin', 'Gene', (233, 243))	('E-cadherin', 'Gene', (309, 319))	('E-cadherin', 'Gene', '999', (309, 319))	('dominant-negative mutant', 'Var', (245, 269))	('E-cadherin', 'Gene', '999', (233, 243))	('dominant-negative mutant', 'Var', (284, 308))
338543	25068654	In vivo we show that loss of Act A can initiate tumorigenesis using xenograft models.	('loss', 'Var', (21, 25))	('tumor', 'Disease', (48, 53))	('Act A', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
338552	25068654	The following treatments were added to the organotypic cultures at the time of epithelial seeding and renewed with every media change: Five ng/ml recombinant human TGFbeta1, 10ng/ml Activin A, 100 ng/ml Follistatin and 600 ng/ml neutralizing antibody against Activin A (all from R&D Systems, Minneapolis, MN), or 1 microM A83-01 (Tocris, Bristol, UK) and 1 microM GM6001 (Millipore EMD, Billerica, MA).	('microM', 'Var', (357, 363))	('Activin', 'Gene', (182, 189))	('GM6001', 'Chemical', 'MESH:C078131', (364, 370))	('neutralizing', 'Var', (229, 241))	('human', 'Species', '9606', (158, 163))	('Activin', 'Gene', '83729', (259, 266))	('TGFbeta1', 'Gene', '7040', (164, 172))	('Activin', 'Gene', '83729', (182, 189))	('TGFbeta1', 'Gene', (164, 172))	('A83-01', 'Chemical', 'MESH:C507011', (322, 328))	('Activin', 'Gene', (259, 266))	('MN', 'CellLine', 'CVCL:U508', (305, 307))
338577	25068654	Keratinocytes expressing wild-type E-cadherin (E) form a non-invasive epithelial sheet, while expression of dominant-negative E-cadherin (EC) or combined expression of dominant-negative E-cadherin and TbetaRII (ECdnT) leads to a gradual increase of invasiveness as shown previously.	('E-cadherin', 'Gene', (186, 196))	('E-cadherin', 'Gene', '999', (35, 45))	('E-cadherin', 'Gene', '999', (186, 196))	('increase', 'PosReg', (237, 245))	('EC', 'Gene', '999', (138, 140))	('dominant-negative', 'Var', (168, 185))	('EC', 'Gene', '999', (211, 213))	('E-cadherin', 'Gene', (126, 136))	('invasiveness', 'CPA', (249, 261))	('E-cadherin', 'Gene', '999', (126, 136))	('dominant-negative', 'Var', (108, 125))	('E-cadherin and TbetaRII', 'Gene', '999;7048', (186, 209))	('E-cadherin', 'Gene', (35, 45))
338578	25068654	We have previously shown that expression of dominant-negative E-cadherin correlates with lower TbetaRII levels in EC cells, potentially due to a lack of its stabilization at the cell membrane (6).	('dominant-negative', 'Var', (44, 61))	('lower', 'NegReg', (89, 94))	('TbetaRII', 'Gene', '7048', (95, 103))	('EC', 'Gene', '999', (114, 116))	('stabilization', 'MPA', (157, 170))	('TbetaRII', 'Gene', (95, 103))	('E-cadherin', 'Gene', (62, 72))	('E-cadherin', 'Gene', '999', (62, 72))
338589	25068654	We compared protein lysates from conditions with Act A stimulation or neutralizing antibody to demonstrate that phosphorylation of Smad2 could be induced by Act A with high specificity.	('Act A', 'Var', (157, 162))	('phosphorylation', 'MPA', (112, 127))	('Smad2', 'Gene', '4087', (131, 136))	('Smad2', 'Gene', (131, 136))	('induced', 'Reg', (146, 153))
338592	25068654	Conversely, Act A neutralizing antibody inhibited vimentin expression (Figure 2c).	('neutralizing', 'Var', (18, 30))	('vimentin', 'Gene', (50, 58))	('vimentin', 'Gene', '7431', (50, 58))	('inhibited', 'NegReg', (40, 49))
338594	25068654	When using recombinant Follistatin, the endogenous inhibitor of Act A, or A83-01 (an inhibitor for ALK4, 5 and 7), MMP-9 secretion was reduced compared to untreated or Act A stimulated monolayer cultures (Figure 2d).	('MMP-9', 'Gene', '4318', (115, 120))	('MMP-9', 'Gene', (115, 120))	('ALK4', 'Gene', '91', (99, 103))	('A83-01', 'Var', (74, 80))	('reduced', 'NegReg', (135, 142))	('Act A', 'Gene', (64, 69))	('A83-01', 'Chemical', 'MESH:C507011', (74, 80))	('ALK4', 'Gene', (99, 103))
338617	25068654	Using a pan-MMP activity inhibitor GM6001, we could abolish ECdnT cell invasion, which could not be restored by Act A addition (Figure 5b).	('abolish', 'NegReg', (52, 59))	('EC', 'Gene', '999', (60, 62))	('GM6001', 'Chemical', 'MESH:C078131', (35, 41))	('GM6001', 'Var', (35, 41))
338625	25068654	In Boyden chamber migration assays, shINHBA-high and shINHBA-low cells showed increased chemotactic migration compared to parent and empty vector (pGIPZh) control cells (Figure 6b; Supplemental Figure 2a).	('shINHBA-high', 'Var', (36, 48))	('increased', 'PosReg', (78, 87))	('pGIPZ', 'Chemical', '-', (147, 152))	('chemotactic migration', 'CPA', (88, 109))
338628	25068654	After six weeks of growth, mice injected with shINHBA-high cells had larger tumors compared to pGIPZ-high and parental control cells (Figure 6d).	('larger', 'PosReg', (69, 75))	('mice', 'Species', '10090', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('shINHBA-high cells', 'Var', (46, 64))	('pGIPZ', 'Chemical', '-', (95, 100))
338639	25068654	While treatment with Follistatin and A83-01 enhanced cell invasion, it results in reduced MMP-9 and MMP-2 secretion as well as activity, indicating that other mechanisms are involved in cell invasion independent of MMP-9 and MMP-2 (unpublished data).	('MMP-2', 'Gene', '4313', (225, 230))	('MMP-9', 'Gene', '4318', (90, 95))	('A83-01', 'Var', (37, 43))	('MMP-9', 'Gene', (90, 95))	('A83-01', 'Chemical', 'MESH:C507011', (37, 43))	('MMP-2', 'Gene', (100, 105))	('MMP-9', 'Gene', '4318', (215, 220))	('MMP-2', 'Gene', (225, 230))	('MMP-2', 'Gene', '4313', (100, 105))	('cell invasion', 'CPA', (53, 66))	('reduced', 'NegReg', (82, 89))	('MMP-9', 'Gene', (215, 220))	('activity', 'MPA', (127, 135))	('enhanced', 'PosReg', (44, 52))
338642	25068654	Act A and TGFbeta overlap in their intracellular signaling cascades and function, as demonstrated by deletions of TGFbeta2, TGFbeta3 and the Act A subunit, ActivinbetaA, which result in cleft palate defects in the respective mouse models.	('TGFbeta2', 'Gene', '21808', (114, 122))	('cleft palate', 'Phenotype', 'HP:0000175', (186, 198))	('TGFbeta2', 'Gene', (114, 122))	('TGFbeta3', 'Gene', '21809', (124, 132))	('Activin', 'Gene', '83729', (156, 163))	('mouse', 'Species', '10090', (225, 230))	('Activin', 'Gene', (156, 163))	('cleft palate defects', 'Disease', (186, 206))	('palate defects', 'Phenotype', 'HP:0000174', (192, 206))	('deletions', 'Var', (101, 110))	('TGFbeta3', 'Gene', (124, 132))	('cleft palate defects', 'Disease', 'MESH:D002972', (186, 206))	('result in', 'Reg', (176, 185))
338643	25068654	Mutations in the TGFbeta/BMP signaling axis are frequent events in different types of cancer: Similar to a 10-bp polyadenine tract within the TGFbeta receptor type II gene that results in a frameshift mutation in GI cancers, a biallelic mutation in ACVR2 has been identified in colorectal and pancreatic cancer.	('identified', 'Reg', (264, 274))	('cancer', 'Disease', (304, 310))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancer', 'Disease', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('ACVR2', 'Gene', '92', (249, 254))	('results in', 'Reg', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('ACVR2', 'Gene', (249, 254))	('GI cancers', 'Disease', (213, 223))	('Mutations', 'Var', (0, 9))	('BMP', 'Gene', '649', (25, 28))	('cancer', 'Disease', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('polyadenine', 'Chemical', 'MESH:C000628261', (113, 124))	('frameshift mutation', 'Var', (190, 209))	('colorectal and pancreatic cancer', 'Disease', 'MESH:D010190', (278, 310))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('GI cancers', 'Disease', 'MESH:D009369', (213, 223))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (293, 310))	('BMP', 'Gene', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (86, 92))
338653	25068654	These observations indicate that changes in the balance between Act A- and BMP mediated signaling can affect the phenotype in a context-dependent manner.	('affect', 'Reg', (102, 108))	('changes', 'Var', (33, 40))	('BMP', 'Gene', '649', (75, 78))	('phenotype', 'MPA', (113, 122))	('BMP', 'Gene', (75, 78))	('balance', 'MPA', (48, 55))
338664	25068654	Knock-down of Act A in ECdnT cells using shRNA demonstrates epithelial cell-dependent effects of Act A, whereas the response of the stromal cells remains unaltered.	('epithelial cell-dependent effects', 'MPA', (60, 93))	('Act A', 'Var', (97, 102))	('EC', 'Gene', '999', (23, 25))
338667	25068654	However, when Act A-overexpressing mice were bred with transgenic animals carrying a dominant-negative deletion of the kinase-domain in the ActRIB, hyperplasia, hyperproliferation and abnormal keratinocyte organization could be rescued.	('dominant-negative', 'NegReg', (85, 102))	('hyperplasia', 'Disease', (148, 159))	('hyperplasia', 'Disease', 'MESH:D006965', (148, 159))	('mice', 'Species', '10090', (35, 39))	('ActRIB', 'Gene', (140, 146))	('hyperproliferation', 'CPA', (161, 179))	('abnormal keratinocyte organization', 'CPA', (184, 218))	('ActRIB', 'Gene', '11479', (140, 146))	('deletion', 'Var', (103, 111))
338669	25068654	Exogenous Act A treatment in the background of mutant TbetaRII did not inhibit cell invasion, an additional hint at signal regulation through Act A gradients.	('cell invasion', 'CPA', (79, 92))	('TbetaRII', 'Gene', '7048', (54, 62))	('inhibit', 'NegReg', (71, 78))	('TbetaRII', 'Gene', (54, 62))	('mutant', 'Var', (47, 53))
338678	25068654	However, as Follistatin induced epithelial cell invasion and knock-down of Act A similarly resulted in enhanced cell invasion and tumorigenesis, we propose that low levels of Act A result in elevated motility or invasive potential, while high Act A levels depending on the cellular context results in less invasion.	('knock-down', 'Var', (61, 71))	('cell invasion', 'CPA', (112, 125))	('elevated motility', 'Disease', 'MESH:D015835', (191, 208))	('epithelial cell invasion', 'CPA', (32, 56))	('invasive potential', 'CPA', (212, 230))	('elevated motility', 'Disease', (191, 208))	('Act A', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('enhanced', 'PosReg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
338679	25068654	ActR Activin A, Act A; Activin receptors E wild-type full-length E-cadherin EC dominant-negative mutant E-cadherin ECdnT dominant-negative mutant E-cadherin and TGFbeta receptor II nAb neutralizing antibody	('E-cadherin', 'Gene', (146, 156))	('EC', 'Gene', '999', (76, 78))	('E-cadherin', 'Gene', '999', (146, 156))	('Activin', 'Gene', '83729', (5, 12))	('EC', 'Gene', '999', (115, 117))	('E-cadherin and TGFbeta receptor II', 'Gene', '999', (146, 180))	('E-cadherin', 'Gene', (65, 75))	('E-cadherin', 'Gene', '999', (104, 114))	('mutant', 'Var', (97, 103))	('Activin', 'Gene', '83729', (23, 30))	('Activin', 'Gene', (5, 12))	('Activin', 'Gene', (23, 30))	('E-cadherin', 'Gene', (104, 114))	('E-cadherin', 'Gene', '999', (65, 75))
338854	22682539	Radiation dosimetry, patient demographic factors, and myocardial changes seen on 18F-FDG PET were correlated with subsequent cardiac toxicity.	('18F-FDG', 'Chemical', 'MESH:D019788', (81, 88))	('patient', 'Species', '9606', (21, 28))	('cardiac toxicity', 'Disease', 'MESH:D066126', (125, 141))	('cardiac toxicity', 'Disease', (125, 141))	('18F-FDG', 'Var', (81, 88))
338857	22682539	The mean heart V20 (79.7% vs. 67.2%, p=0.05), V30 (75.8% vs. 61.9%, p=0.04), and V40 (69.2% vs. 53.8%, p=0.03) were significantly higher in patients with symptomatic cardiac toxicity than those without.	('V40', 'Var', (81, 84))	('higher', 'PosReg', (130, 136))	('V30', 'Var', (46, 49))	('heart', 'MPA', (9, 14))	('cardiac toxicity', 'Disease', 'MESH:D066126', (166, 182))	('cardiac toxicity', 'Disease', (166, 182))	('patients', 'Species', '9606', (140, 148))
338858	22682539	We found the threshold for symptomatic cardiac toxicity to be a V20, V30 and V40 above 70%, 65% and 60%, respectively.	('V40', 'Var', (77, 80))	('V30', 'Var', (69, 72))	('V20', 'Var', (64, 67))	('cardiac toxicity', 'Disease', 'MESH:D066126', (39, 55))	('cardiac toxicity', 'Disease', (39, 55))
338924	22682539	However, when only symptomatic cardiac toxicity was considered, a significant difference was noted in mean WH-OAR V20, V30 and V40 between those patients with and without symptomatic cardiac toxicity.	('patients', 'Species', '9606', (145, 153))	('cardiac toxicity', 'Disease', (31, 47))	('WH-OAR', 'MPA', (107, 113))	('cardiac toxicity', 'Disease', 'MESH:D066126', (31, 47))	('cardiac toxicity', 'Disease', 'MESH:D066126', (183, 199))	('V40', 'Var', (127, 130))	('cardiac toxicity', 'Disease', (183, 199))	('V30', 'Var', (119, 122))
338928	22682539	There was a 14%, 14%, and 15% probability of a symptomatic cardiac toxicity if the WH-OAR V20, V30 and V40 was greater than 70%, 65%, and 60%, respectively.	('cardiac toxicity', 'Disease', 'MESH:D066126', (59, 75))	('cardiac toxicity', 'Disease', (59, 75))	('V20', 'Var', (90, 93))	('V30', 'Var', (95, 98))	('V40', 'Var', (103, 106))
338929	22682539	Conversely, symptomatic cardiac toxicity was not observed in any patient if the WH-OAR V20, V30 and V40 was below 70%, 65% or 60%, respectively.	('V20', 'Var', (87, 90))	('cardiac toxicity', 'Disease', 'MESH:D066126', (24, 40))	('cardiac toxicity', 'Disease', (24, 40))	('V40', 'Var', (100, 103))	('patient', 'Species', '9606', (65, 72))	('V30', 'Var', (92, 95))
338953	22682539	Left ventricular V20, V30 and V40 was not found to be associated with any cardiac toxicity.	('V30', 'Var', (22, 25))	('cardiac toxicity', 'Disease', (74, 90))	('V40', 'Var', (30, 33))	('cardiac toxicity', 'Disease', 'MESH:D066126', (74, 90))
338989	22682539	Because of the above limitations, the whole heart V20, V30 and V40 values reported above for symptomatic cardiac events in our patients will need validation by an independent data set with a large number of clinical events.	('patients', 'Species', '9606', (127, 135))	('V30', 'Var', (55, 58))	('V40', 'Var', (63, 66))
338990	22682539	A significant difference in the radiation dosimetric parameters of V20, V30 and V40 was noted between patients with and without symptomatic cardiac toxicity.	('cardiac toxicity', 'Disease', 'MESH:D066126', (140, 156))	('cardiac toxicity', 'Disease', (140, 156))	('V20', 'Var', (67, 70))	('V30', 'Var', (72, 75))	('patients', 'Species', '9606', (102, 110))	('V40', 'Var', (80, 83))
338991	22682539	In our cohort, we found the no symptomatic cardiac toxicity when the whole heart V20, V30 and V40 was kept below 70%, 65% or 60%, respectively.	('V40', 'Var', (94, 97))	('cardiac toxicity', 'Disease', 'MESH:D066126', (43, 59))	('cardiac toxicity', 'Disease', (43, 59))
339040	21437447	The four terminal nodes were reconstructed into two groups according to the possibility of the presence of LEV (P<0.001): a low-risk group consisted of node 3 (spleen width<=44.5 mm, portal vein diameter<=11.75 mm) and node 5 (spleen width<=44.5 mm, portal vein diameter>11.75 mm, prothrombin time<=17.05s), whose possibility of presence of LEV was 15.2% (14/92); a high-risk group consisted of node 2 (spleen width>44.5 mm) and node 6 (spleen width<=44.5 mm, portal vein diameter>11.75 mm, and prothrombin time>17.05s), whose possibility of presence of LEV was 83.2% (79/95).	('prothrombin', 'Gene', '2147', (281, 292))	('LEV', 'Chemical', '-', (554, 557))	('EV', 'Phenotype', 'HP:0002040', (342, 344))	('LEV', 'Chemical', '-', (107, 110))	('spleen', 'Var', (437, 443))	('EV', 'Phenotype', 'HP:0002040', (555, 557))	('prothrombin', 'Gene', (495, 506))	('spleen', 'Var', (403, 409))	('LEV', 'Chemical', '-', (341, 344))	('prothrombin', 'Gene', '2147', (495, 506))	('EV', 'Phenotype', 'HP:0002040', (108, 110))	('prothrombin', 'Gene', (281, 292))
339082	31650447	Patients received the combination therapy with apatinib (250-500 mg, once daily) plus S-1 (40-60 mg based on body surface area, twice daily).	('S-1', 'Gene', '5707', (86, 89))	('Patients', 'Species', '9606', (0, 8))	('apatinib', 'Chemical', 'MESH:C553458', (47, 55))	('S-1', 'Gene', (86, 89))	('250-500', 'Var', (57, 64))
339165	31765370	GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors G protein-coupled receptors (GPCRs) are the most widely targeted gene family for Food and Drug Administration (FDA)-approved drugs.	('copy number variation', 'Var', (77, 98))	('solid tumors', 'Disease', (102, 114))	('GPCR', 'Gene', '148', (144, 148))	('GPCR', 'Gene', '148', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('GPCR', 'Gene', (144, 148))	('GPCR', 'Gene', (0, 4))	('solid tumors', 'Disease', 'MESH:D009369', (102, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
339173	31765370	Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage.	('GPCR', 'Gene', '148', (8, 12))	('mutated', 'Var', (29, 36))	('GPCR', 'Gene', (8, 12))
339178	31765370	Expression of certain GPCRs appears to have prognostic relevance, and many GPCRs undergo widespread mutation and copy number variation.	('GPCR', 'Gene', '148', (75, 79))	('copy number variation', 'Var', (113, 134))	('undergo', 'Reg', (81, 88))	('GPCR', 'Gene', (75, 79))	('GPCR', 'Gene', (22, 26))	('GPCR', 'Gene', '148', (22, 26))
339182	31765370	One reason for their limited use is the notion that GPCRs are rarely mutated in cancer :although mutations occur in heterotrimeric GTP binding (G) proteins that GPCRs activate :and that GPCRs regulate pathways, such as Wnt, mitogen-activated protein kinase (MAPK), and Phosphoinositide 3-Kinase (PI3K) signaling, with mutations in cancer.	('mutations', 'Var', (97, 106))	('Wnt', 'Pathway', (219, 222))	('mutations', 'Var', (318, 327))	('GTP', 'Chemical', 'MESH:D006160', (131, 134))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GPCR', 'Gene', '148', (52, 56))	('GPCR', 'Gene', '148', (186, 190))	('Phosphoinositide 3-Kinase', 'Gene', '5293', (269, 294))	('GPCR', 'Gene', (52, 56))	('GPCR', 'Gene', '148', (161, 165))	('GPCR', 'Gene', (186, 190))	('regulate', 'Reg', (192, 200))	('GPCR', 'Gene', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Phosphoinositide 3-Kinase', 'Gene', (269, 294))	('cancer', 'Disease', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
339184	31765370	To define the landscape of GPCRs in cancer, we undertook an integrated analysis of Differential Expression (DE), mutations, and copy number variation (CNV) of GPCRs, which are annotated by the Guide to Pharmacology database (GtoPdb), in 20 types of solid tumors (Table 1 and S1 and S2 Tables).	('GPCR', 'Gene', '148', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('cancer', 'Disease', (36, 42))	('solid tumors', 'Disease', 'MESH:D009369', (249, 261))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('GPCR', 'Gene', (27, 31))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('GPCR', 'Gene', '148', (159, 163))	('copy number variation', 'Var', (128, 149))	('solid tumors', 'Disease', (249, 261))	('GPCR', 'Gene', (159, 163))
339225	31765370	We compiled a list of GPCRs overexpressed in solid tumors with fold-changes and FDR along with expression in TPM (for median expression and within-group comparisons of different genes) and Counts Per Million (CPM; for intergroup comparisons of the same gene).	('TPM', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('GPCR', 'Gene', (22, 26))	('solid tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('TPM', 'Chemical', '-', (109, 112))	('GPCR', 'Gene', '148', (22, 26))	('fold-changes', 'Var', (63, 75))
339276	31765370	EDNRB, which is highly overexpressed in SKCM, promotes migration and transformation of melanocytes and melanoma cells, and inhibition of EDNRB is pro-apoptotic.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('EDNRB', 'Gene', (0, 5))	('inhibition', 'Var', (123, 133))	('migration', 'CPA', (55, 64))	('transformation', 'CPA', (69, 83))	('EDNRB', 'Gene', (137, 142))	('transformation of melanocytes', 'Phenotype', 'HP:0002861', (69, 98))	('EDNRB', 'Gene', '1910', (0, 5))	('promotes', 'PosReg', (46, 54))	('EDNRB', 'Gene', '1910', (137, 142))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
339290	31765370	GPCR expression appears largely independent of driver mutations, such as in BRCA HR+ IDC tumors with either PI3KA or TP53 mutations (Fig 7A-7C); both groups have similar GPCR expression and DE of the same GPCRs compared to normal breast tissue.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('GPCR', 'Gene', '148', (0, 4))	('PI3KA', 'Gene', (108, 113))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('BRCA HR+ IDC tumors', 'Disease', 'MESH:D001919', (76, 95))	('BRCA', 'Phenotype', 'HP:0003002', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('GPCR', 'Gene', '148', (205, 209))	('GPCR', 'Gene', (0, 4))	('BRCA HR+ IDC tumors', 'Disease', (76, 95))	('mutations', 'Var', (122, 131))	('GPCR', 'Gene', '148', (170, 174))	('GPCR', 'Gene', (205, 209))	('GPCR', 'Gene', (170, 174))
339291	31765370	Similar results occur for lung adenocarcinoma (LUAD) and stomach adenocarcinoma (STAD) that have or lack TP53 mutations.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('mutations', 'Var', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('stomach adenocarcinoma', 'Disease', (57, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('lung adenocarcinoma', 'Disease', (26, 45))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (57, 79))
339315	31765370	In SKCM, which has the highest mutation burden among TCGA tumor types, the most highly overexpressed GPCRs (GPR143, EDNRB, and GPR56) are mutated in <2% of SKCM tumors, whereas frequently mutated GPCRs (e.g., GPR98, mutated in nearly 40% of tumors) typically have low expression.	('GPCR', 'Gene', '148', (196, 200))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('GPCR', 'Gene', (196, 200))	('GPCR', 'Gene', '148', (101, 105))	('GPR98', 'Gene', (209, 214))	('tumor', 'Disease', (161, 166))	('GPR56', 'Gene', (127, 132))	('GPCR', 'Gene', (101, 105))	('tumor', 'Disease', (58, 63))	('GPR143', 'Gene', (108, 114))	('tumor', 'Disease', (241, 246))	('SKCM tumors', 'Disease', (156, 167))	('SKCM tumors', 'Disease', 'MESH:D009369', (156, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EDNRB', 'Gene', '1910', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('EDNRB', 'Gene', (116, 121))	('GPR98', 'Gene', '84059', (209, 214))	('mutated', 'Var', (138, 145))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('overexpressed', 'PosReg', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('GPR56', 'Gene', '9289', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', (241, 247))	('GPR143', 'Gene', '4935', (108, 114))
339319	31765370	Furthermore, as discussed in the following sections on GPCR mutation, mutations to these GPCRs are predicted to have no functional impact and are not enriched significantly for mutations at specific sites; thus, overexpressed GPCRs in tumors are not expected to be altered in their function by mutations.	('GPCR', 'Gene', '148', (226, 230))	('mutations', 'Var', (70, 79))	('GPCR', 'Gene', '148', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('GPCR', 'Gene', (226, 230))	('GPCR', 'Gene', '148', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('GPCR', 'Gene', (89, 93))	('GPCR', 'Gene', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('tumors', 'Disease', (235, 241))	('overexpressed', 'PosReg', (212, 225))
339321	31765370	Tissues and tumors typically express >150 GPCRs (at detection thresholds >0.1 TPM) that couple to the major types of G proteins (Gs, Gi/o, Gq/11, G12/13), most frequently Gi/Go and Gq/G11 (S7A and S7B Fig).	('Gi/Go', 'Var', (171, 176))	('S7', 'Gene', '6264', (189, 191))	('GPCR', 'Gene', '148', (42, 46))	('S7', 'Gene', '6264', (197, 199))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('TPM', 'Chemical', '-', (78, 81))	('GPCR', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('couple', 'Reg', (88, 94))
339363	31765370	Analysis of 5,103 TCGA samples in 20 tumor types (S3 Table; 21 tumor types if one divides ESCA into esophageal adenocarcinoma and squamous cell carcinomas) revealed many GPCRs with frequent nonsilent mutations (Figs 11A and S8A), including a more frequently mutated subset (Fig 11A, inset).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('squamous cell carcinomas', 'Disease', (130, 154))	('mutations', 'Var', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (100, 125))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('GPCR', 'Gene', '148', (170, 174))	('GPCR', 'Gene', (170, 174))	('tumor', 'Disease', (63, 68))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (130, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (130, 154))	('adenocarcinoma', 'Disease', (111, 125))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
339366	31765370	SKCM has the highest frequency: approximately 40% of SKCM tumors have GPR98 mutations (Fig 11C and 11H).	('GPR98', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('SKCM tumors', 'Disease', (53, 64))	('SKCM tumors', 'Disease', 'MESH:D009369', (53, 64))	('GPR98', 'Gene', '84059', (70, 75))
339368	31765370	Certain GPCRs are mutated in >10% of specific tumor types (Fig 11C).	('GPCR', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mutated', 'Var', (18, 25))	('tumor', 'Disease', (46, 51))	('GPCR', 'Gene', '148', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
339370	31765370	Frequently mutated GPCRs (e.g., GPR98, GPR112, and BAI3) are more likely to be mutated as Nmut increases (Fig 11E, SKCM as an example).	('BAI3', 'Gene', (51, 55))	('GPCR', 'Gene', (19, 23))	('mutated', 'Var', (79, 86))	('GPR112', 'Gene', '139378', (39, 45))	('GPR98', 'Gene', (32, 37))	('GPR112', 'Gene', (39, 45))	('GPCR', 'Gene', '148', (19, 23))	('GPR98', 'Gene', '84059', (32, 37))	('BAI3', 'Gene', '577', (51, 55))
339371	31765370	The relationship between Nmut and likelihood of GPR98 mutation is similar in SKCM and other cancers (Fig 11F); this is also observed for other frequently mutated GPCRs.	('mutation', 'Var', (54, 62))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('GPR98', 'Gene', '84059', (48, 53))	('GPCR', 'Gene', '148', (162, 166))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('SKCM', 'Disease', (77, 81))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('GPCR', 'Gene', (162, 166))	('GPR98', 'Gene', (48, 53))
339372	31765370	Hence, the likelihood of a GPCR being mutated appears to depend on the accumulation of genome damage and to be independent of the mechanisms for the mutations.	('GPCR', 'Gene', (27, 31))	('mutated', 'Var', (38, 45))	('GPCR', 'Gene', '148', (27, 31))
339374	31765370	Mutations of certain GPCRs, such as GPR98, may thus serve as a bellwether for genome-wide DNA damage.	('GPCR', 'Gene', '148', (21, 25))	('GPCR', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('GPR98', 'Gene', (36, 41))	('GPR98', 'Gene', '84059', (36, 41))
339375	31765370	Missense mutations and in-frame deletions are the most frequent nonsilent mutations in GPCR genes (S8C and S8D Fig and S5 Table).	('in-frame deletions', 'Var', (23, 41))	('GPCR', 'Gene', (87, 91))	('GPCR', 'Gene', '148', (87, 91))	('Missense mutations', 'Var', (0, 18))
339376	31765370	Mutations in frequently mutated GPCRs occur at many sites (S9A Fig), which contrasts with the smaller number of such sites in common oncogenes, e.g., KRAS.	('mutated', 'Var', (24, 31))	('GPCR', 'Gene', (32, 36))	('occur', 'Reg', (38, 43))	('Mutations', 'Var', (0, 9))	('GPCR', 'Gene', '148', (32, 36))	('KRAS', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (150, 154))
339377	31765370	Certain GPCR genes (e.g., GPR98) may be in genomic regions vulnerable to dysregulation of DNA damage and repair and belong to a subset of mutated genes; GPR98 mutations frequently occur alongside other frequently mutated genes such as TTN and MUC16 (S10A-S10G Fig).	('TTN', 'Gene', (235, 238))	('GPR98', 'Gene', '84059', (26, 31))	('GPCR', 'Gene', (8, 12))	('TTN', 'Gene', '7273', (235, 238))	('MUC16', 'Gene', '94025', (243, 248))	('mutations', 'Var', (159, 168))	('occur', 'Reg', (180, 185))	('GPR98', 'Gene', (153, 158))	('S10A', 'SUBSTITUTION', 'None', (250, 254))	('GPR98', 'Gene', (26, 31))	('GPR98', 'Gene', '84059', (153, 158))	('GPCR', 'Gene', '148', (8, 12))	('MUC16', 'Gene', (243, 248))	('S10G', 'Mutation', 'p.S10G', (255, 259))	('S10A', 'Var', (250, 254))
339383	31765370	Survival analysis of metastatic SKCM samples was performed in order to evaluate the impact on tumors of somatic nonsilent mutations to GPR98, GPR112, or other frequently mutated GPCRs.	('GPCR', 'Gene', '148', (178, 182))	('GPR112', 'Gene', '139378', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GPR98', 'Gene', (135, 140))	('GPR112', 'Gene', (142, 148))	('mutations', 'Var', (122, 131))	('tumors', 'Disease', (94, 100))	('GPR98', 'Gene', '84059', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('GPCR', 'Gene', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
339386	31765370	We find the same result in other tumor types as well and thus conclude that somatic nonsilent mutations to GPCRs have no impact on patient survival.	('mutations', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('GPCR', 'Gene', '148', (107, 111))	('tumor', 'Disease', (33, 38))	('patient', 'Species', '9606', (131, 138))	('GPCR', 'Gene', (107, 111))
339389	31765370	As cell-surface receptors, frequently mutated, well-expressed GPCRs may represent neo-antigens.	('GPCR', 'Gene', '148', (62, 66))	('mutated', 'Var', (38, 45))	('cell-surface', 'Protein', (3, 15))	('GPCR', 'Gene', (62, 66))
339390	31765370	For SKCM, which has the most GPCR mutations among tumors types surveyed, DE analysis of primary melanomas and distant metastases that have or lack GPCR mutations (e.g., GPR98 and LPHN2) revealed little evidence that these mutations alter the tumor transcriptome, implying that such GPCR mutations are likely passenger, rather than driver, mutations (Figs 11H and S8C and S8D).	('LPHN2', 'Gene', '23266', (179, 184))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('mutations', 'Var', (287, 296))	('tumor', 'Disease', (242, 247))	('GPCR', 'Gene', '148', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('GPCR', 'Gene', '148', (147, 151))	('GPCR', 'Gene', (29, 33))	('alter', 'Reg', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('GPCR', 'Gene', '148', (282, 286))	('GPR98', 'Gene', (169, 174))	('GPCR', 'Gene', (147, 151))	('mutations', 'Var', (222, 231))	('GPCR', 'Gene', (282, 286))	('tumor', 'Disease', (50, 55))	('LPHN2', 'Gene', (179, 184))	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('melanomas', 'Disease', (96, 105))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('GPR98', 'Gene', '84059', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('metastases', 'Disease', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('tumors', 'Disease', (50, 56))
339391	31765370	Conversely, previous work has suggested that for known oncogenes (e.g., for TP53), there are often widespread transcriptomic changes associated with specific mutations.	('transcriptomic changes', 'MPA', (110, 132))	('TP53', 'Gene', (76, 80))	('mutations', 'Var', (158, 167))	('TP53', 'Gene', '7157', (76, 80))
339392	31765370	We found similar behavior for other tumors (e.g., BLCA) that have frequent GPCR mutations.	('GPCR', 'Gene', '148', (75, 79))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('mutations', 'Var', (80, 89))	('GPCR', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('BLCA', 'Phenotype', 'HP:0009725', (50, 54))
339393	31765370	As a further approach, we evaluated GPCR mutations, predicting the likelihood of functional consequences and site-specific enrichment of the mutations via MutSig 2CV version 3.1 (gdac.broadinstitute.org).	('GPCR', 'Gene', '148', (36, 40))	('GPCR', 'Gene', (36, 40))	('mutations', 'Var', (141, 150))
339394	31765370	The majority of GPCRs frequently mutated (Fig 11I, SKCM as example) show nonsilent mutations that are nonsignificant in terms of enrichment (compared to the background mutation rate of silent mutations over the same regions) for individual mutation sites.	('GPCR', 'Gene', '148', (16, 20))	('GPCR', 'Gene', (16, 20))	('mutated', 'Var', (33, 40))
339395	31765370	These mutations are not predicted to be functional (calculated from estimations of functional impact of mutations based on whether mutated regions are highly evolutionarily conserved) by MutSig 2CV, consistent with the idea that the frequent GPCR mutations are likely passenger and not driver mutations.	('mutations', 'Var', (247, 256))	('GPCR', 'Gene', '148', (242, 246))	('GPCR', 'Gene', (242, 246))
339401	31765370	Single-copy/heterozygous deletions of GPCRs are widespread, whereas homozygous deletions are rare (Fig 13A and 13D).	('GPCR', 'Gene', '148', (38, 42))	('Single-copy/heterozygous', 'Var', (0, 24))	('GPCR', 'Gene', (38, 42))
339402	31765370	GPCR genes with single-copy deletions are generally not significantly expressed in tumors or normal tissues, implying that such deletions lack functional effects, but exceptions exist.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('GPCR', 'Gene', '148', (0, 4))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('GPCR', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('single-copy deletions', 'Var', (16, 37))
339411	31765370	However, tumors with amplification of GPR160 show a higher likelihood (approximately 33%, p = 0.003, Fig 13H) of expressing GPR160 at levels above the median for OV.	('GPR160', 'Gene', '26996', (124, 130))	('GPR160', 'Gene', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('GPR160', 'Gene', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('OV', 'Phenotype', 'HP:0100615', (162, 164))	('tumors', 'Disease', (9, 15))	('amplification', 'Var', (21, 34))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('GPR160', 'Gene', '26996', (38, 44))
339416	31765370	In this study, we identified mutations, CNVs, and alterations in mRNA expression of GPCRs in a range of solid tumors.	('GPCR', 'Gene', (84, 88))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('alterations', 'Reg', (50, 61))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mRNA expression', 'MPA', (65, 80))	('GPCR', 'Gene', '148', (84, 88))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
339418	31765370	Mutations of certain GPCRs have been implicated in cancer, but a comprehensive analysis of GPCR amplification, expression, and DE has been lacking.	('GPCR', 'Gene', '148', (21, 25))	('implicated', 'Reg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('GPCR', 'Gene', (21, 25))	('GPCR', 'Gene', (91, 95))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('GPCR', 'Gene', '148', (91, 95))
339423	31765370	GPCR mutations appear to reflect accumulation of DNA damage and mutations across the genome and may be tumor markers for this process.	('DNA damage', 'MPA', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GPCR', 'Gene', '148', (0, 4))	('tumor', 'Disease', (103, 108))	('mutations', 'Var', (5, 14))	('GPCR', 'Gene', (0, 4))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
339429	31765370	Known driver mutations do not appear to influence GPCR expression in tumors, but we excluded rare mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GPCR', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('GPCR', 'Gene', '148', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('mutations', 'Var', (13, 22))
339461	31765370	GPCR mutations, CNV, and DE thus occur at a high frequency in solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('GPCR', 'Gene', '148', (0, 4))	('mutations', 'Var', (5, 14))	('GPCR', 'Gene', (0, 4))	('solid tumors', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('occur', 'Reg', (33, 38))	('solid tumors', 'Disease', 'MESH:D009369', (62, 74))
339478	31765370	The two methods yielded nearly identical results (S11C and S11D Fig).	('S11D', 'SUBSTITUTION', 'None', (59, 63))	('S11D', 'Var', (59, 63))	('S11C', 'SUBSTITUTION', 'None', (50, 54))	('S11C', 'Var', (50, 54))
339480	31765370	EBseq and edgeR yielded very similar results (S11A and S11B Fig), in particular for GPCRs, implying that assumptions implicit in the DE analysis via edgeR/TMM normalization do not skew or bias the results.	('GPCR', 'Gene', (84, 88))	('S11B', 'SUBSTITUTION', 'None', (55, 59))	('S11B', 'Var', (55, 59))	('S11A', 'Var', (46, 50))	('GPCR', 'Gene', '148', (84, 88))	('S11A', 'SUBSTITUTION', 'None', (46, 50))
339514	31765370	In general, DE of GPCRs is similar whether TCGA normal tissue or GTEx tissue is compared to TCGA tumor samples (e.g., S11E and S11F Fig), suggesting that such differences are unlikely to impact upon the general conclusions of this study.	('S11F', 'Mutation', 'p.S11F', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('S11F', 'Var', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('GPCR', 'Gene', '148', (18, 22))	('tumor', 'Disease', (97, 102))	('S11E', 'Mutation', 'p.S11E', (118, 122))	('GPCR', 'Gene', (18, 22))	('GTEx', 'Chemical', '-', (65, 69))
339525	31765370	This method was also used to evaluate the significance of associations between expression of GPCRs and presence of specific driver mutations (e.g., presence or absence of mutations to TP53 or KRAS) and association between GPCR mRNA expression and the thresholded GISTIC 2.0 CNV call.	('absence', 'NegReg', (160, 167))	('association', 'Interaction', (202, 213))	('GPCR', 'Gene', (222, 226))	('TP53', 'Gene', '7157', (184, 188))	('GPCR', 'Gene', '148', (93, 97))	('TP53', 'Gene', (184, 188))	('GPCR', 'Gene', '148', (222, 226))	('KRAS', 'Gene', (192, 196))	('mutations', 'Var', (171, 180))	('GPCR', 'Gene', (93, 97))	('KRAS', 'Gene', '3845', (192, 196))
339622	31200588	In patients treated with fluorupyrimidine- and/or platinum-based triplets, severe nausea has been described in 7-21% and severe diarrhea has been described in 3-19% of patients.	('nausea', 'Phenotype', 'HP:0002018', (82, 88))	('nausea', 'Disease', (82, 88))	('platinum', 'Chemical', 'MESH:D010984', (50, 58))	('nausea', 'Disease', 'MESH:D009325', (82, 88))	('fluorupyrimidine-', 'Var', (25, 42))	('diarrhea', 'Phenotype', 'HP:0002014', (128, 136))	('diarrhea', 'Disease', 'MESH:D003967', (128, 136))	('severe diarrhea', 'Phenotype', 'HP:0002028', (121, 136))	('diarrhea', 'Disease', (128, 136))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (168, 176))	('fluorupyrimidine', 'Chemical', '-', (25, 41))
339708	30653123	Furthermore, patients with stage I/II ESCC or lymph node (LN) positivity in the ENI arm had significantly better 5-year OS than their counterparts in the IFI arm.	('better', 'PosReg', (106, 112))	('5-year OS', 'CPA', (113, 122))	('patients', 'Species', '9606', (13, 21))	('ESCC', 'Disease', (38, 42))	('OS', 'Chemical', '-', (120, 122))	('ENI', 'Var', (80, 83))
339709	30653123	In addition, for LN positivity patients treated with definitive radiotherapy alone, ENI tended to prolong OS compared with IFI (P = .035).	('positivity', 'Var', (20, 30))	('patients', 'Species', '9606', (31, 39))	('prolong', 'PosReg', (98, 105))	('ENI', 'Var', (84, 87))	('OS', 'Chemical', '-', (106, 108))
339711	30653123	Using IMRT, ENI is superior to IFI in improving OS of ESCC patients, with acceptable toxicities that were comparable to those to IFI, especially for LN positivity ESCC patients treated with definitive irradiation alone.	('OS', 'Chemical', '-', (48, 50))	('ESCC', 'Disease', (54, 58))	('toxicities', 'Disease', 'MESH:D064420', (85, 95))	('LN positivity', 'Var', (149, 162))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (168, 176))	('improving', 'PosReg', (38, 47))	('toxicities', 'Disease', (85, 95))
339747	30653123	Furthermore, our univariate analysis showed that, after PSM, female gender, T1 + 2, N0, stage I/II, tumor length <=7 cm, tumor volume <=50 cm3, chemotherapy, and ENI were associated with significantly better 5-year OS.	('T1 + 2', 'Var', (76, 82))	('OS', 'Chemical', '-', (215, 217))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (121, 126))	('ENI', 'Var', (162, 165))	('better', 'PosReg', (201, 207))	('chemotherapy', 'CPA', (144, 156))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
339750	30653123	Moreover, univariate analysis showed that, after PSM, female gender, T1 + 2, N0, stage I/II, tumor length <=7 cm, tumor volume > 50 cm3, and chemotherapy were associated with significantly better 5-year PFS.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('T1 + 2', 'Var', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (93, 98))	('better', 'PosReg', (189, 195))	('PFS', 'CPA', (203, 206))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
339751	30653123	Multivariate survival analyses using the Cox proportional hazards regression model showed that female gender, T1 + 2, N0, stage I/II, and >=4 cycles of chemotherapy were significant predictors of longer LRFFS and DMFS (Table 3).	('DMFS', 'Chemical', '-', (213, 217))	('T1 + 2', 'Var', (110, 116))	('DMFS', 'CPA', (213, 217))	('LRFFS', 'CPA', (203, 208))
339752	30653123	Grade 3 and 4 acute radiation esophagitis was reported in 3.8% and 0.6% patients in the ENI arm and 4.1% and 0.3% in the IFI arm (Table 4).	('ENI', 'Var', (88, 91))	('acute radiation esophagitis', 'Disease', 'MESH:D004194', (14, 41))	('acute radiation esophagitis', 'Disease', (14, 41))	('esophagitis', 'Phenotype', 'HP:0100633', (30, 41))	('patients', 'Species', '9606', (72, 80))
339754	30653123	Grade >= 3 acute radiation pneumonitis was seen 2.5% of patients in the ENI arm and 2.9% in the IFI arm (P = .1000).	('patients', 'Species', '9606', (56, 64))	('pneumonitis', 'Disease', 'MESH:D011014', (27, 38))	('ENI', 'Var', (72, 75))	('pneumonitis', 'Disease', (27, 38))
339756	30653123	In late toxicities, grade >= 3 RT-related toxicities including esophageal stricture, fistula, pulmonary toxicity, and hemorrhage were observed in 14.6% in the ENI arm and 16.6% in the IFI arm (P = .593).	('esophageal stricture', 'Disease', (63, 83))	('fistula', 'Disease', 'MESH:D005402', (85, 92))	('pulmonary toxicity', 'Disease', 'MESH:D008171', (94, 112))	('toxicities', 'Disease', (8, 18))	('RT-related', 'Disease', (31, 41))	('toxicities', 'Disease', 'MESH:D064420', (42, 52))	('ENI', 'Var', (159, 162))	('observed', 'Reg', (134, 142))	('toxicities', 'Disease', 'MESH:D064420', (8, 18))	('esophageal stricture', 'Phenotype', 'HP:0002043', (63, 83))	('hemorrhage', 'Disease', (118, 128))	('pulmonary toxicity', 'Disease', (94, 112))	('hemorrhage', 'Disease', 'MESH:D006470', (118, 128))	('fistula', 'Disease', (85, 92))	('toxicities', 'Disease', (42, 52))
339760	30653123	Furthermore, patients with T1 + 2, N0, or stage I/II in the ENI arm had better 5-year PFS than their counterparts in the IFI arm.	('PFS', 'CPA', (86, 89))	('patients', 'Species', '9606', (13, 21))	('T1 + 2', 'Var', (27, 33))	('better', 'PosReg', (72, 78))
339763	30653123	Moreover, we found that patients with LN positivity in the ENI arm had significantly better 5-year OS than their counterparts in the IFI arm in the RT group (P = .035), as shown in Table 6.	('better', 'PosReg', (85, 91))	('5-year OS', 'CPA', (92, 101))	('LN positivity', 'Var', (38, 51))	('ENI', 'Var', (59, 62))	('patients', 'Species', '9606', (24, 32))	('OS', 'Chemical', '-', (99, 101))
339776	30653123	However, for N+ patients treated with RT alone, our subgroup analysis showed that a significantly higher 5-year OS in the ENI arm than the IFI arm, which was not similar with the Yun-Jie Cheng's meta-analysis.	('OS', 'Chemical', '-', (112, 114))	('higher', 'PosReg', (98, 104))	('patients', 'Species', '9606', (16, 24))	('ENI', 'Var', (122, 125))
339780	30653123	Ji et al showed that IFI may deliver considerable incidental dose to elective regions for patients with T1-4N0M0, which has significant impact on the control of micrometastasis.	('patients', 'Species', '9606', (90, 98))	('impact', 'Reg', (136, 142))	('micrometastasis', 'CPA', (161, 176))	('T1-4N0M0', 'Var', (104, 112))
339794	30653123	We showed that ENI was associated with a significantly better 5-year OS and LRFFS, and suggested that ENI could decrease LRR in the elective field, thus impacting on OS.	('ENI', 'Var', (102, 105))	('decrease', 'NegReg', (112, 120))	('LRFFS', 'CPA', (76, 81))	('LRR in the elective field', 'MPA', (121, 146))	('OS', 'Chemical', '-', (69, 71))	('OS', 'Chemical', '-', (166, 168))	('better', 'PosReg', (55, 61))	('5-year OS', 'CPA', (62, 71))	('impacting', 'Reg', (153, 162))	('ENI', 'Var', (15, 18))
339801	30653123	In the RTOG 85-01 study, 10% patients treated with CRT experienced life-threatening toxicities, while 2% of patients receiving RT alone experienced acute grade 4 toxicities without fatalities due to toxic effect.	('CRT', 'Var', (51, 54))	('patients', 'Species', '9606', (29, 37))	('toxicities', 'Disease', (162, 172))	('toxicities', 'Disease', (84, 94))	('toxicities', 'Disease', 'MESH:D064420', (162, 172))	('patients', 'Species', '9606', (108, 116))	('toxicities', 'Disease', 'MESH:D064420', (84, 94))
339834	30483821	In comparison, Notch signaling was proven to promote the differentiation of stem cells and the activation of Hes family proteins, Myc, p21, and Cyclin D3.	('Myc', 'Gene', '4609', (130, 133))	('Notch signaling', 'Var', (15, 30))	('Myc', 'Gene', (130, 133))	('differentiation of stem cells', 'CPA', (57, 86))	('Cyclin D3', 'Gene', '896', (144, 153))	('activation', 'PosReg', (95, 105))	('Cyclin D3', 'Gene', (144, 153))	('promote', 'PosReg', (45, 52))	('p21', 'Gene', (135, 138))	('Hes', 'Gene', (109, 112))	('p21', 'Gene', '644914', (135, 138))	('Hes', 'Gene', '3280', (109, 112))
339843	30483821	The following siRNA sequences (GenePharma, Shanghai, China) were used: siRNA-beta-catenin: sense, 5'-GUCCUGUAUGAGUGGGAACTT-3'; antisense, 5'-GUUCCCACUCAUACAGGACTT-3'.	('beta-catenin', 'Gene', (77, 89))	('antisense', 'Var', (127, 136))	('GUUCCCACUCAUACAGGACTT', 'Chemical', '-', (141, 162))	('beta-catenin', 'Gene', '1499', (77, 89))
339855	30483821	The following primers were used to detect specific mRNAs (Invitrogen, Shanghai, China): c-myc (forward, 5'-ACCACCAGCAGCGACTCT-3'; reverse, 5'-GCTGTGAGGAGGTTTGCTGT-3'); Oct-4A (forward, 5'-GAGAATTTGTTCCTGCAGTGC-3'; reverse, 5'-GTTCCCAATTCCTTCCTTAGTG-3'); Cyclin D1 (forward, 5'-GATCAAGTGTGACCCGGACT-3'; reverse, 5'-TCCTCCTCTTCCTCCTCCTC-3'); Hes 1 (forward, 5'-TGAAGGATTCCAAAAATAAAATTCTCTGGG-3'; reverse, 5'-CGCCTCTTCTCCATGATAGGCTTTGATGAC-3'); beta-catenin (forward, 5'-GCCCAGGACCTCATGGAT-3'; reverse, 5'-CCAAAATCCATTTGTATTGTTACTCC-3'); Notch1 (forward, 5'-CACTGTGGGCGGGTCC-3'; reverse, 5'-GTTGTATTGGTTCGGCACCAT-3').	('forward', 'Var', (543, 550))	('Hes 1', 'Gene', '3280', (340, 345))	('Cyclin D1', 'Gene', '595', (254, 263))	('beta-catenin', 'Gene', (442, 454))	('Notch1', 'Gene', (535, 541))	('c-myc', 'Gene', '4609', (88, 93))	('Hes 1', 'Gene', (340, 345))	('Cyclin D1', 'Gene', (254, 263))	('c-myc', 'Gene', (88, 93))	('beta-catenin', 'Gene', '1499', (442, 454))	('Notch1', 'Gene', '4851', (535, 541))
339902	30483821	In addition, knocking down beta-catenin or Notch 1 gene expression significantly inhibited the IL-23-induced arrest of CD133-IL-23R+ TE-1 cells, as detected by flow cytometry of CFSE labeling (cells co-transfected for 3 days, 55.17 +- 3.71%; NC cells, 84.50 +- 4.09%; siRNA-beta-catenin cells, 66.50 +- 9.67%; and siRNA-Notch1 cells, 70.67 +- 5.72%; cells co-transfected for 6 days, 11.83 +- 5.08%; Fig.	('knocking down', 'Var', (13, 26))	('IL-23R', 'Gene', '149233', (125, 131))	('beta-catenin', 'Gene', '1499', (27, 39))	('Notch1', 'Gene', (320, 326))	('Notch 1', 'Gene', '4851', (43, 50))	('inhibited', 'NegReg', (81, 90))	('Notch1', 'Gene', '4851', (320, 326))	('beta-catenin', 'Gene', (274, 286))	('Notch 1', 'Gene', (43, 50))	('CD133', 'Gene', (119, 124))	('beta-catenin', 'Gene', '1499', (274, 286))	('IL-23R', 'Gene', (125, 131))	('beta-catenin', 'Gene', (27, 39))	('CD133', 'Gene', '8842', (119, 124))
339912	30483821	Moreover, the tumors treated with IL-23 showed no evident volume changes, but once exposed to FR, the significant decreased weight occurred with or without inhibitors and anti-IL-23 (Fig.	('FR', 'Chemical', 'MESH:D005605', (94, 96))	('decreased weight', 'Phenotype', 'HP:0004325', (114, 130))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('decreased', 'NegReg', (114, 123))	('anti-IL-23', 'Var', (171, 181))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('weight', 'MPA', (124, 130))
339931	30483821	For example, Notch signaling is likely to inhibit specific differentiation lineages and to maintain the sustainability of self-renewal tumor populations in intestinal epithelial cells, hematopoietic stem cells and esophageal adenocarcinoma cells, and these features are characteristics of stemness.	('esophageal adenocarcinoma cells', 'Disease', 'MESH:D004938', (214, 245))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (214, 239))	('esophageal adenocarcinoma cells', 'Disease', (214, 245))	('tumor', 'Disease', (135, 140))	('Notch signaling', 'Var', (13, 28))	('sustainability', 'CPA', (104, 118))	('specific differentiation lineages', 'CPA', (50, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('inhibit', 'NegReg', (42, 49))	('maintain', 'PosReg', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
339938	30483821	Here, we demonstrated the role of IL-23 in G0/1 phase arrest of IL-23R+ ESCCs; specifically, Notch induction led to cell cycle progression before the S phase, whereas Wnt resulted in cells at the G0/1 phase, and ultimately reduced apoptosis caused by radiation.	('apoptosis', 'CPA', (231, 240))	('Notch induction', 'Var', (93, 108))	('reduced', 'NegReg', (223, 230))	('IL-23R', 'Gene', (64, 70))	('led to', 'Reg', (109, 115))	('cell cycle progression', 'CPA', (116, 138))	('IL-23R', 'Gene', '149233', (64, 70))
339953	29158807	In the vitro experiments, knocking down the expression of PBR inhibited proliferation, colony formation and migration of ESCC cells, and regulated EMT-associated proteins (up-regulation of E-cadherin, ZO-1 and beta-catenin and concomitant with down-regulation of Fibronectin and N-cadherin).	('colony formation', 'CPA', (87, 103))	('proliferation', 'CPA', (72, 85))	('regulated', 'Reg', (137, 146))	('PBR', 'Gene', '706', (58, 61))	('knocking down', 'Var', (26, 39))	('E-cadherin', 'Gene', '999', (189, 199))	('E-cadherin', 'Gene', (189, 199))	('PBR', 'Gene', (58, 61))	('expression', 'Var', (44, 54))	('Fibronectin', 'Gene', '2335', (263, 274))	('down-regulation', 'NegReg', (244, 259))	('migration', 'CPA', (108, 117))	('N-cadherin', 'Gene', (279, 289))	('N-cadherin', 'Gene', '1000', (279, 289))	('beta-catenin', 'Gene', (210, 222))	('Fibronectin', 'Gene', (263, 274))	('up-regulation', 'PosReg', (172, 185))	('ZO-1', 'Gene', '7082', (201, 205))	('beta-catenin', 'Gene', '1499', (210, 222))	('EMT-associated proteins', 'Protein', (147, 170))	('inhibited', 'NegReg', (62, 71))	('ZO-1', 'Gene', (201, 205))
339968	29158807	At the same time, PBR ligands have been shown to induce apoptosis in melanoma, hepatocellular, breast, oesophageal and colon carcinoma cell lines.	('colon carcinoma', 'Disease', (119, 134))	('oesophageal', 'Disease', (103, 114))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('PBR', 'Gene', (18, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('ligands', 'Var', (22, 29))	('hepatocellular', 'Disease', (79, 93))	('PBR', 'Gene', '706', (18, 21))	('induce', 'PosReg', (49, 55))	('apoptosis', 'CPA', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('breast', 'Disease', (95, 101))	('melanoma', 'Disease', (69, 77))	('colon carcinoma', 'Disease', 'MESH:D015179', (119, 134))
339974	29158807	Intriguingly, in addition to its prognostic significance, we also found that knockdown of PBR could inhibit the proliferation, colony formation ability, migration ability, and epithelial-mesenchymal transition (EMT) related proteins in ESCC cell lines.	('PBR', 'Gene', '706', (90, 93))	('colony formation ability', 'CPA', (127, 151))	('PBR', 'Gene', (90, 93))	('knockdown', 'Var', (77, 86))	('proliferation', 'CPA', (112, 125))	('inhibit', 'NegReg', (100, 107))	('migration ability', 'CPA', (153, 170))
339996	29158807	KYSE140 or KYSE410 (15x104 and 10x105 cells, respectively) cells in 200 microl of FBS-free RPMI were seeded in the top of a Transwell (BD Biosciences, San Jose, USA) chamber 48 hours post-transfection, while the lower chambers were filled with DMEM with 10% FBS.	('FBS', 'Disease', (258, 261))	('DMEM', 'Chemical', '-', (244, 248))	('FBS-free RPMI', 'Disease', (82, 95))	('FBS', 'Disease', 'MESH:D005198', (82, 85))	('FBS', 'Disease', 'MESH:D005198', (258, 261))	('FBS-free RPMI', 'Disease', 'MESH:D005198', (82, 95))	('KYSE410', 'Var', (11, 18))	('FBS', 'Disease', (82, 85))
340024	29158807	Moreover, down-regulated PBR expression in esophageal squamous cells KYSE140 and KYSE410 caused a dramatic decrease in both the size and number of colonies (Fig.	('PBR', 'Gene', (25, 28))	('KYSE410', 'Var', (81, 88))	('KYSE140', 'Var', (69, 76))	('size', 'CPA', (128, 132))	('down-regulated', 'NegReg', (10, 24))	('decrease', 'NegReg', (107, 115))	('PBR', 'Gene', '706', (25, 28))	('expression', 'MPA', (29, 39))
340027	29158807	After a 24-hour incubation, the number of cells that migrated in the groups with siPBR treatments was significantly less than in the NC group (Fig.	('treatments', 'Var', (87, 97))	('less', 'NegReg', (116, 120))	('siPBR', 'Chemical', '-', (81, 86))	('siPBR', 'Gene', (81, 86))
340030	29158807	Intriguingly, we found that knocking down the PBR expression in ESCC cells can up-regulate the expression of E-cadherin, ZO-1 and beta-catenin, and concomitantly down-regulated the expression of Fibronectin and N-cadherin expression (Fig.	('expression', 'MPA', (181, 191))	('knocking down', 'Var', (28, 41))	('ZO-1', 'Gene', '7082', (121, 125))	('Fibronectin', 'Gene', '2335', (195, 206))	('N-cadherin', 'Gene', '1000', (211, 221))	('PBR', 'Gene', '706', (46, 49))	('Fibronectin', 'Gene', (195, 206))	('E-cadherin', 'Gene', (109, 119))	('up-regulate', 'PosReg', (79, 90))	('down-regulated', 'NegReg', (162, 176))	('PBR', 'Gene', (46, 49))	('E-cadherin', 'Gene', '999', (109, 119))	('ZO-1', 'Gene', (121, 125))	('beta-catenin', 'Gene', (130, 142))	('N-cadherin', 'Gene', (211, 221))	('expression', 'MPA', (95, 105))	('beta-catenin', 'Gene', '1499', (130, 142))
340041	29158807	Recently, studies have reported that the differential gene expression of PBR in 17 pairs ESCC and normal tissues and PBR ligands induce apoptosis in ESCC cells, but the prognostic value of PBR in ESCC has not been investigated.	('PBR', 'Gene', '706', (117, 120))	('PBR', 'Gene', (189, 192))	('induce', 'Reg', (129, 135))	('ESCC', 'Disease', (149, 153))	('PBR', 'Gene', '706', (73, 76))	('PBR', 'Gene', '706', (189, 192))	('PBR', 'Gene', (117, 120))	('apoptosis', 'CPA', (136, 145))	('PBR', 'Gene', (73, 76))	('differential gene expression', 'Var', (41, 69))
340057	29158807	Reviewing the previous results regarding the association between PBR and lymphoid nodal metastasis, suggests that the function of PBR has a large effect on the metastasis of ESCC.	('PBR', 'Gene', (130, 133))	('PBR', 'Gene', (65, 68))	('function', 'Var', (118, 126))	('ESCC', 'Disease', (174, 178))	('metastasis', 'CPA', (160, 170))	('effect', 'Reg', (146, 152))	('lymphoid nodal metastasis', 'Disease', (73, 98))	('lymphoid nodal metastasis', 'Disease', 'MESH:D009362', (73, 98))	('PBR', 'Gene', '706', (130, 133))	('PBR', 'Gene', '706', (65, 68))
340061	29158807	Intriguingly, knocking down PBR expression in ESCC cell lines can caused up-regulation of Z0-1, beta-catenin and E-cadherin, accompanied by the down-regulation of Fibronectin and N-cadherin.	('Z0-1', 'Protein', (90, 94))	('PBR', 'Gene', '706', (28, 31))	('beta-catenin', 'Gene', '1499', (96, 108))	('knocking down', 'Var', (14, 27))	('up-regulation', 'PosReg', (73, 86))	('N-cadherin', 'Gene', (179, 189))	('PBR', 'Gene', (28, 31))	('E-cadherin', 'Gene', (113, 123))	('N-cadherin', 'Gene', '1000', (179, 189))	('down-regulation', 'NegReg', (144, 159))	('Fibronectin', 'Gene', '2335', (163, 174))	('E-cadherin', 'Gene', '999', (113, 123))	('Fibronectin', 'Gene', (163, 174))	('beta-catenin', 'Gene', (96, 108))
340067	29158807	Some previous reports showed that the expression of PBR could influence chemosensitivity in some cancers, but we failed to clarify whether this relationship exists in ESCC, because our study was limited to enrolled patients who underwent radical esophagectomy without chemotherapy.	('chemosensitivity', 'MPA', (72, 88))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('patients', 'Species', '9606', (215, 223))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('PBR', 'Gene', '706', (52, 55))	('PBR', 'Gene', (52, 55))	('expression', 'Var', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('influence', 'Reg', (62, 71))
340073	29158807	Besides that, knocking down PBR contributed to decreased proliferation, colony formation, and migration in ESCC cells, and also regulated EMT-associated proteins.	('PBR', 'Gene', '706', (28, 31))	('colony formation', 'CPA', (72, 88))	('regulated', 'Reg', (128, 137))	('knocking down', 'Var', (14, 27))	('PBR', 'Gene', (28, 31))	('migration', 'CPA', (94, 103))	('EMT-associated proteins', 'MPA', (138, 161))	('proliferation', 'CPA', (57, 70))	('decreased', 'NegReg', (47, 56))
340081	27764786	We found that the combined expression of both B7-H3 and B7-H4 could be used as a valuable risk factor for predicting the prognosis of esophageal cancer patients (P=0.003).	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('B7-H3', 'Var', (46, 51))	('B7-H4', 'Var', (56, 61))	('esophageal cancer', 'Disease', (134, 151))	('patients', 'Species', '9606', (152, 160))
340082	27764786	Moreover the status of these patients with high expression of both B7-H3 and B7-H4, was positively and significantly associated with the tumor invasion depth (P=0.0414) and TNM stage (P=0.0414).	('B7-H4', 'Var', (77, 82))	('patients', 'Species', '9606', (29, 37))	('tumor', 'Disease', (137, 142))	('associated', 'Reg', (117, 127))	('TNM', 'Gene', '10178', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('B7-H3', 'Var', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('TNM', 'Gene', (173, 176))
340083	27764786	The Cox multivariate proportional hazards regression analysis revealed that the tumor size (P=0.007), the TNM stage (P=0.024) and the status of both B7-H3 and B7-H4 high expression (P=0.011), could be used as an independent risk factor for predicting patients' postoperative prognosis, respectively.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('TNM', 'Gene', '10178', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('TNM', 'Gene', (106, 109))	('B7-H3', 'Var', (149, 154))	('patients', 'Species', '9606', (251, 259))	('B7-H4', 'Gene', (159, 164))
340084	27764786	In conclusion, our data indicated that the combined application of B7-H3 and B7-H4 expression can be effectively used as a prognostic marker in esophageal cancer patients.	('patients', 'Species', '9606', (162, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('B7-H4 expression', 'Var', (77, 93))	('B7-H3', 'Var', (67, 72))	('esophageal cancer', 'Disease', (144, 161))
340092	27764786	In the present study, we focused on analyzing the possibility of using combined B7-H3 and B7-H4 expression, as a prognostic tool for predicting esophageal cancer patient's prognosis.	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('B7-H4', 'Var', (90, 95))	('B7-H3', 'Var', (80, 85))	('patient', 'Species', '9606', (162, 169))	('esophageal cancer', 'Disease', (144, 161))
340093	27764786	Thus we have analyzed the expression of both B7-H3 and B7-H4 protein on the esophageal tumor tissue samples and correlated the expression with the clinical characteristics of these patients.	('esophageal tumor', 'Disease', (76, 92))	('esophageal tumor', 'Phenotype', 'HP:0100751', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('B7-H4', 'Var', (55, 60))	('patients', 'Species', '9606', (181, 189))	('esophageal tumor', 'Disease', 'MESH:D004938', (76, 92))
340094	27764786	The immunohistochemistry analysis showed that positive expression of B7-H3 and B7-H4 was predominantly on the membrane and in the cytoplasm of esophageal cancer cells (Figure 1A).	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('B7-H4', 'Var', (79, 84))	('B7-H3', 'Var', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('esophageal cancer', 'Disease', (143, 160))
340097	27764786	Moreover, the adjacent normal esophageal cancer tissues were used as control, and we found that both B7-H3 and B7-H4 were weakly expressed on esophageal epithelial cells of normal tissues (Figure 1E).	('esophageal cancer', 'Disease', 'MESH:D004938', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('B7-H4', 'Var', (111, 116))	('B7-H3', 'Var', (101, 106))	('esophageal cancer', 'Disease', (30, 47))
340113	27764786	In present study, found that patients with high expression of both B7-H3 and B7-H4 tended to have increased invasion as well as high TNM stage.	('B7-H4', 'Var', (77, 82))	('patients', 'Species', '9606', (29, 37))	('TNM', 'Gene', (133, 136))	('increased', 'PosReg', (98, 107))	('invasion', 'CPA', (108, 116))	('B7-H3', 'Var', (67, 72))	('TNM', 'Gene', '10178', (133, 136))
340114	27764786	Moreover, we identified that the combination of B7-H3 and B7-H4 expression could be used as a valuable risk factor for predicting the prognoses of esophageal cancer patients.	('esophageal cancer', 'Disease', (147, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('B7-H3', 'Var', (48, 53))	('patients', 'Species', '9606', (165, 173))	('B7-H4 expression', 'Var', (58, 74))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
340116	27764786	Thus, our data suggested that the assessment of combined expression of B7-H3 and B7-H4 can be effectively used as prognostic predictor in esophageal cancer patients.	('patients', 'Species', '9606', (156, 164))	('esophageal cancer', 'Disease', (138, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('men', 'Species', '9606', (40, 43))	('B7-H4', 'Var', (81, 86))	('B7-H3', 'Var', (71, 76))
340215	27006756	Raloxifene has been associated mainly with an increase in thromboembolic events.	('thromboembolic', 'Disease', 'MESH:D013923', (58, 72))	('thromboembolic events', 'Phenotype', 'HP:0001907', (58, 79))	('increase', 'PosReg', (46, 54))	('Raloxifene', 'Chemical', 'MESH:D020849', (0, 10))	('thromboembolic', 'Disease', (58, 72))	('Raloxifene', 'Var', (0, 10))
340260	27006756	Epidemiologic studies indicate that diabetics treated with metformin have a decreased cancer risk compared with those on other antidiabetic medications , .	('metformin', 'Var', (59, 68))	('antidiabetic', 'Disease', 'None', (127, 139))	('diabetics', 'Disease', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('decreased', 'NegReg', (76, 85))	('metformin', 'Chemical', 'MESH:D008687', (59, 68))	('antidiabetic', 'Disease', (127, 139))	('diabetics', 'Disease', 'MESH:D003920', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
340269	27006756	Thus, in the Alpha-Tocopherol Beta-Carotene (ATBC) Cancer Prevention Study, beta-carotene supplementation was associated with an increase in lung cancer risk as well as in risk of other cancers, notably prostate and stomach .	('beta-carotene', 'Protein', (76, 89))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancers', 'Disease', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ATBC', 'Chemical', '-', (45, 49))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('men', 'Species', '9606', (96, 99))	('Alpha-Tocopherol', 'Chemical', 'MESH:D024502', (13, 29))	('Beta-Carotene', 'Chemical', 'MESH:D019207', (30, 43))	('Cancer', 'Disease', (51, 57))	('supplementation', 'Var', (90, 105))	('stomach', 'Disease', (216, 223))	('beta-carotene', 'Chemical', 'MESH:D019207', (76, 89))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('prostate', 'Disease', (203, 211))	('Cancer', 'Disease', 'MESH:D009369', (51, 57))	('increase in lung cancer', 'Disease', (129, 152))	('increase in lung cancer', 'Disease', 'MESH:D008175', (129, 152))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))
340286	27006756	In 1997, expert panels at the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research had concluded that dietary vitamin C could reduce the risk of the stomach (probably) as well as mouth, pharynx, esophagus, lung, pancreas, and cervical cancers (possibly), but in their updated report in 2007, only the evidence with respect to esophageal cancer was considered probable and there was no evidence that vitamin C supplementation modifies the risk of cancer , .	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('esophageal cancer', 'Disease', (354, 371))	('cancer', 'Disease', (263, 269))	('vitamin C', 'Chemical', 'MESH:D001205', (138, 147))	('Cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Disease', 'MESH:D009369', (474, 480))	('cancer', 'Disease', (365, 371))	('Cancer', 'Disease', (36, 42))	('mouth', 'Disease', (207, 212))	('esophagus', 'Disease', (223, 232))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('cervical cancers', 'Disease', (254, 270))	('pharynx', 'Disease', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('stomach', 'Disease', (177, 184))	('dietary', 'Var', (130, 137))	('cervical cancers', 'Disease', 'MESH:D002583', (254, 270))	('men', 'Species', '9606', (443, 446))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('reduce', 'NegReg', (154, 160))	('pancreas', 'Disease', (240, 248))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('cancer', 'Disease', (474, 480))	('lung', 'Disease', (234, 238))	('Cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (474, 480))	('esophageal cancer', 'Disease', 'MESH:D004938', (354, 371))	('vitamin C', 'Chemical', 'MESH:D001205', (427, 436))	('pancreas', 'Disease', 'MESH:D010190', (240, 248))
340308	27006756	In its updated report of 2014 on prostate cancer, the WCRF concluded that there is limited suggestive evidence that low plasma concentrations of selenium are associated with increased prostate cancer risk, but no conclusions can be drawn on the basis of the existing evidence for selenium supplementation .	('selenium', 'Chemical', 'MESH:D012643', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('prostate cancer', 'Disease', (33, 48))	('selenium', 'Chemical', 'MESH:D012643', (280, 288))	('increased prostate cancer', 'Disease', 'MESH:D011471', (174, 199))	('prostate cancer', 'Disease', 'MESH:D011471', (184, 199))	('low', 'Var', (116, 119))	('increased prostate cancer', 'Disease', (174, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('prostate cancer', 'Phenotype', 'HP:0012125', (184, 199))	('prostate cancer', 'Disease', 'MESH:D011471', (33, 48))	('men', 'Species', '9606', (295, 298))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))
340313	27006756	In a meta-analysis of observational studies, flavonol and flavone intake, but not other flavonoid subclass or total flavonoid intake, were associated with a decreased breast cancer risk, especially among post-menopausal women .	('breast cancer', 'Disease', (167, 180))	('flavone', 'Chemical', 'MESH:C043562', (58, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('flavonoid', 'Chemical', 'MESH:D005419', (88, 97))	('flavonol', 'Var', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('flavonoid', 'Chemical', 'MESH:D005419', (116, 125))	('men', 'Species', '9606', (209, 212))	('men', 'Species', '9606', (222, 225))	('flavonol', 'Chemical', 'MESH:C041477', (45, 53))	('decreased', 'NegReg', (157, 166))	('women', 'Species', '9606', (220, 225))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
340382	26822225	As a result, adjacent epithelial cells showed little expression of cyclin-dependent kinase inhibitor (CKI), high-level COX2, increased proliferation and decreased apoptosis.	('apoptosis', 'CPA', (163, 172))	('increased', 'PosReg', (125, 134))	('CKI', 'Gene', (102, 105))	('COX2', 'Gene', (119, 123))	('cyclin-dependent kinase inhibitor', 'Gene', (67, 100))	('COX2', 'Gene', '4513', (119, 123))	('high-level', 'Var', (108, 118))	('proliferation', 'CPA', (135, 148))	('decreased', 'NegReg', (153, 162))	('CKI', 'Gene', '1033', (102, 105))	('expression', 'MPA', (53, 63))	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (67, 100))
340409	26822225	respectively injected OE33 (EAC cell line), OE33+NFs and OE33+CAFs into three groups of mice.	('OE33+CAFs', 'Var', (57, 66))	('OE33', 'Chemical', '-', (44, 48))	('OE33', 'Chemical', '-', (57, 61))	('OE33', 'Var', (22, 26))	('OE33', 'Chemical', '-', (22, 26))	('OE33+NFs', 'Var', (44, 52))	('EAC', 'Phenotype', 'HP:0011459', (28, 31))	('mice', 'Species', '10090', (88, 92))
340456	26822225	This could be impaired by MET inhibitor PHA-665752 and FGFR inhibitor PD-173074.	('PD-173074', 'Var', (70, 79))	('PD-173074', 'Chemical', 'MESH:C115711', (70, 79))	('PHA-665752', 'Var', (40, 50))
340509	21258512	Figure 1  shows representative EOCT images of Barrett's esophagus without dysplasia (A), with low grade dysplasia (B), and with high grade dysplasia (C) which illustrate these image features.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (46, 65))	('dysplasia', 'Disease', (104, 113))	('dysplasia', 'Disease', (139, 148))	('dysplasia', 'Disease', 'MESH:D004476', (104, 113))	("Barrett's esophagus without dysplasia", 'Disease', (46, 83))	('dysplasia', 'Disease', (74, 83))	('dysplasia', 'Disease', 'MESH:D004476', (139, 148))	('EOCT', 'Chemical', '-', (31, 35))	('low grade', 'Var', (94, 103))	('dysplasia', 'Disease', 'MESH:D004476', (74, 83))	("Barrett's esophagus without dysplasia", 'Disease', 'MESH:D001471', (46, 83))
340611	19347410	Esophageal motility disorder or erroneous diagnosis, i.e., another primary disease than GERD, were the causes of failure of the previous operation in 62 patients (2.0%).	('Esophageal motility disorder', 'Disease', (0, 28))	('Esophageal motility disorder', 'Disease', 'MESH:D015154', (0, 28))	('patients', 'Species', '9606', (153, 161))	('erroneous diagnosis', 'Var', (32, 51))
340622	19347410	Causes of conversion were dense adhesions (n = 57, 39.3%), severe intraoperative bleeding (n = 11, 7.6%), poor visualization (n = 3, 2.1%), and other (n = 15, 10.3%).	('intraoperative bleeding', 'Disease', 'MESH:D016063', (66, 89))	('poor', 'Var', (106, 110))	('intraoperative bleeding', 'Disease', (66, 89))
340632	19347410	It has also been suggested that a too tight fundoplication can cause an achalasia-like clinical picture.	('too', 'Var', (34, 37))	('achalasia', 'Disease', 'MESH:D004931', (72, 81))	('cause', 'Reg', (63, 68))	('achalasia', 'Phenotype', 'HP:0002571', (72, 81))	('achalasia', 'Disease', (72, 81))
340644	32587768	Mutations in the FHL1 gene are associated with various myopathies.	('associated', 'Reg', (31, 41))	('myopathies', 'Phenotype', 'HP:0003198', (55, 65))	('Mutations', 'Var', (0, 9))	('myopathies', 'Disease', 'MESH:D009135', (55, 65))	('myopathies', 'Disease', (55, 65))	('FHL1', 'Gene', (17, 21))
340661	32587768	Anomalies in the FHL1 gene have been identified as the causative factor in various myopathies, such as X-linked myopathy, muscular dystrophy, myofibrillar myopathy, inflammatory myopathy, reducing body myopathy, and others.	('muscular dystrophy', 'Disease', (122, 140))	('muscular dystrophy', 'Disease', 'MESH:D009136', (122, 140))	('myopathy', 'Disease', 'MESH:D009135', (178, 186))	('myopathies', 'Phenotype', 'HP:0003198', (83, 93))	('myopathy', 'Disease', 'MESH:D009135', (202, 210))	('myopathies', 'Disease', (83, 93))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (122, 140))	('causative factor', 'Reg', (55, 71))	('myofibrillar myopathy', 'Disease', (142, 163))	('myopathy', 'Phenotype', 'HP:0003198', (155, 163))	('myopathy', 'Disease', (155, 163))	('inflammatory myopathy', 'Phenotype', 'HP:0009071', (165, 186))	('FHL1', 'Gene', (17, 21))	('myopathy', 'Phenotype', 'HP:0003198', (178, 186))	('myopathy', 'Disease', (178, 186))	('myopathy', 'Disease', 'MESH:D009135', (155, 163))	('myopathy', 'Disease', (202, 210))	('myopathy', 'Phenotype', 'HP:0003198', (202, 210))	('identified', 'Reg', (37, 47))	('myopathy', 'Disease', 'MESH:D009135', (112, 120))	('myopathies', 'Disease', 'MESH:D009135', (83, 93))	('Anomalies', 'Var', (0, 9))	('myofibrillar myopathy', 'Disease', 'MESH:C580316', (142, 163))	('X-linked myopathy', 'Disease', 'MESH:D009135', (103, 120))	('X-linked myopathy', 'Disease', (103, 120))	('myofibrillar myopathy', 'Phenotype', 'HP:0003715', (142, 163))	('myopathy', 'Phenotype', 'HP:0003198', (112, 120))	('myopathy', 'Disease', (112, 120))
340683	32587768	FHL1C is the shorter variant of FHL1 encoding a 22.0 kDa protein that is identical to FHL1 over the first two and a half N-terminal LIM domains but contains different protein sequences at the C-terminus, with a 27 residue putative RBP-Jkappa binding region similar to that in FHL1B.	('FHL1C', 'Var', (0, 5))	('FHL1B', 'Gene', (276, 281))	('LIM', 'Gene', (132, 135))	('LIM', 'Gene', '10611', (132, 135))	('RBP-Jkappa', 'Gene', '3516', (231, 241))	('FHL1', 'Gene', (32, 36))	('RBP-Jkappa', 'Gene', (231, 241))	('FHL1B', 'Gene', '2273', (276, 281))
340695	32587768	FHL1 silencing inhibited myoblast differentiation and expression of ATG5 and ATG7.	('expression', 'MPA', (54, 64))	('inhibited', 'NegReg', (15, 24))	('ATG7', 'Gene', '10533', (77, 81))	('FHL1', 'Gene', (0, 4))	('silencing', 'Var', (5, 14))	('ATG7', 'Gene', (77, 81))	('ATG5', 'Gene', '9474', (68, 72))	('myoblast differentiation', 'CPA', (25, 49))	('ATG5', 'Gene', (68, 72))
340697	32587768	Another report showed that FHL1 overexpression enhances migration and proliferation of primary human pulmonary artery smooth muscle cells (PASMCs).	('migration', 'CPA', (56, 65))	('human', 'Species', '9606', (95, 100))	('rat', 'Species', '10116', (77, 80))	('FHL1', 'Gene', (27, 31))	('proliferation', 'CPA', (70, 83))	('enhances', 'PosReg', (47, 55))	('overexpression', 'Var', (32, 46))	('rat', 'Species', '10116', (59, 62))
340699	32587768	The group generated a knock-in mouse model with the same FHL1 mutation as human X-linked scapuloperoneal myopathy, one of the known FHL1-related diseases.	('myopathy', 'Disease', 'MESH:D009135', (105, 113))	('mouse', 'Species', '10090', (31, 36))	('scapuloperoneal myopathy', 'Phenotype', 'HP:0009054', (89, 113))	('mutation', 'Var', (62, 70))	('human', 'Species', '9606', (74, 79))	('myopathy', 'Phenotype', 'HP:0003198', (105, 113))	('FHL1', 'Gene', (57, 61))	('myopathy', 'Disease', (105, 113))	('rat', 'Species', '10116', (14, 17))
340700	32587768	In their study, 20 month-old mutant female mice showed signs of cardiomyopathy on echocardiograms, with increased systolic diameter and lower fractional shortening.	('mice', 'Species', '10090', (43, 47))	('lower', 'NegReg', (136, 141))	('cardiomyopathy', 'Disease', (64, 78))	('increased', 'PosReg', (104, 113))	('fractional shortening', 'MPA', (142, 163))	('mutant', 'Var', (29, 35))	('systolic diameter', 'MPA', (114, 131))	('myopathy', 'Phenotype', 'HP:0003198', (70, 78))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (64, 78))	('cardiomyopathy', 'Disease', 'MESH:D009202', (64, 78))
340701	32587768	Proteomic analyses indicated that abnormalities of the integrin signaling pathway (ISP) were associated with cardiac dysfunction, implicating ISP dysregulation in the pathogenesis of FHL1 myopathy.	('myopathy', 'Disease', 'MESH:D009135', (188, 196))	('myopathy', 'Disease', (188, 196))	('myopathy', 'Phenotype', 'HP:0003198', (188, 196))	('integrin signaling pathway', 'Pathway', (55, 81))	('associated', 'Reg', (93, 103))	('cardiac dysfunction', 'Disease', (109, 128))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (109, 128))	('abnormalities', 'Var', (34, 47))
340705	32587768	Consistent with this finding, knockdown of FHL1 markedly inhibited CHIKV21 infection and release of infectious particles.	('CHIKV21 infection', 'Disease', (67, 84))	('FHL1', 'Gene', (43, 47))	('release of infectious particles', 'MPA', (89, 120))	('inhibited', 'NegReg', (57, 66))	('CHIKV21 infection', 'Disease', 'MESH:D007239', (67, 84))	('knockdown', 'Var', (30, 39))
340714	32587768	identified FHL1 as a tumor suppressor gene on chromosome X inactivated by promoter methylation in gastrointestinal cancer.	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (98, 121))	('tumor', 'Disease', (21, 26))	('inactivated', 'NegReg', (59, 70))	('gastrointestinal cancer', 'Disease', (98, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('FHL1', 'Gene', (11, 15))	('promoter methylation', 'Var', (74, 94))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (98, 121))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
340715	32587768	Consistently, methylation-silencing of FHL1 has been detected in multiple gastric and colon cancer cell lines and surgical gastrointestinal cancer specimens.	('colon cancer', 'Disease', (86, 98))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (123, 146))	('methylation-silencing', 'Var', (14, 35))	('gastrointestinal cancer', 'Disease', (123, 146))	('detected', 'Reg', (53, 61))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (123, 146))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('FHL1', 'Gene', (39, 43))
340717	32587768	Analogous to these findings, FHL1 gene silencing through CpG hypermethylation is reported to promote proliferation, migration, and invasion activities of human bladder cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('rat', 'Species', '10116', (108, 111))	('human', 'Species', '9606', (154, 159))	('invasion activities', 'CPA', (131, 150))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('promote', 'PosReg', (93, 100))	('bladder cancer', 'Disease', (160, 174))	('proliferation', 'CPA', (101, 114))	('silencing', 'NegReg', (39, 48))	('rat', 'Species', '10116', (119, 122))	('hypermethylation', 'Var', (61, 77))	('migration', 'CPA', (116, 125))	('FHL1', 'Gene', (29, 33))
340727	32587768	FHL1 methylation is additionally involved in the associated mechanisms in human liver cancer.	('involved', 'Reg', (33, 41))	('methylation', 'Var', (5, 16))	('FHL1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('liver cancer', 'Phenotype', 'HP:0002896', (80, 92))	('liver cancer', 'Disease', 'MESH:D006528', (80, 92))	('human', 'Species', '9606', (74, 79))	('liver cancer', 'Disease', (80, 92))
340729	32587768	A recent epigenetic analysis identified FHL1 as a tumor suppressor gene in human liver cancer and indicated that EZH2-imediated H3K27me3 is involved in epigenetic repression of FHL1 in HCC.	('liver cancer', 'Disease', 'MESH:D006528', (81, 93))	('human', 'Species', '9606', (75, 80))	('HCC', 'Phenotype', 'HP:0001402', (185, 188))	('epigenetic', 'Var', (152, 162))	('liver cancer', 'Disease', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('liver cancer', 'Phenotype', 'HP:0002896', (81, 93))	('EZH2', 'Gene', '2146', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('HCC', 'Disease', (185, 188))	('H3K27me3', 'Var', (128, 136))	('FHL1', 'Gene', (40, 44))	('FHL1', 'Gene', (177, 181))	('tumor', 'Disease', (50, 55))	('EZH2', 'Gene', (113, 117))
340742	32587768	Their results showed that tumors expressing low levels of FHL1 displayed deeper invasive ability into the serosal layer.	('low levels', 'Var', (44, 54))	('FHL1', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('invasive ability into the serosal layer', 'CPA', (80, 119))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('deeper', 'PosReg', (73, 79))	('tumors', 'Disease', (26, 32))
340754	32587768	MiR-105 was further identified as a direct target of LINC00261 and FHL1 as a novel downstream target of miR-105.	('miR-105', 'Chemical', '-', (104, 111))	('LINC00261', 'Gene', (53, 62))	('MiR-105', 'Gene', (0, 7))	('LINC00261', 'Gene', '140828', (53, 62))	('MiR-105', 'Chemical', '-', (0, 7))	('miR-105', 'Var', (104, 111))	('FHL1', 'Gene', (67, 71))
340757	32587768	Significant downregulation of FHL1 was demonstrated in all oral squamous cell carcinoma (OSCC)-derived cell lines and tissues from human patients, mediated by CpG hypermethylation of the FHL1 promoter region.	('downregulation', 'NegReg', (12, 26))	('CpG hypermethylation', 'Var', (159, 179))	('FHL1', 'Gene', (30, 34))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 87))	('hypermethylation', 'Var', (163, 179))	('rat', 'Species', '10116', (46, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('human', 'Species', '9606', (131, 136))	('patients', 'Species', '9606', (137, 145))	('oral squamous cell carcinoma', 'Disease', (59, 87))	('FHL1', 'Gene', (187, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))
340767	32587768	Knockdown of FHL1 in HCC cells rendered the cells more sensitive to paclitaxel than oxaliplatin.	('FHL1', 'Gene', (13, 17))	('more', 'PosReg', (50, 54))	('Knockdown', 'Var', (0, 9))	('HCC', 'Phenotype', 'HP:0001402', (21, 24))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (84, 95))	('paclitaxel', 'Chemical', 'MESH:D017239', (68, 78))	('sensitive to paclitaxel', 'MPA', (55, 78))
340768	32587768	Inhibition of FHL1 function could be explored as a potential therapeutic strategy to increase the anticancer activity of the drug.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rat', 'Species', '10116', (75, 78))	('FHL1', 'Gene', (14, 18))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Inhibition', 'Var', (0, 10))	('increase', 'PosReg', (85, 93))
340771	32587768	Interestingly, no significant differences in DFS and OS of non-treated breast cancer patients were observed between groups with high and low FHL1 expression.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('low', 'NegReg', (137, 140))	('FHL1', 'Gene', (141, 145))	('patients', 'Species', '9606', (85, 93))	('high', 'Var', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
340772	32587768	Consistently, knockdown of FHL1 in vitro increased the sensitivity of cancer cells to ionizing radiation (IR).	('increased', 'PosReg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('FHL1', 'Gene', (27, 31))	('sensitivity', 'MPA', (55, 66))	('knockdown', 'Var', (14, 23))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
340778	32587768	The collective results indicate that inhibition of LIM protein or use of eLIM may present novel strategies for improving tumor response to radiotherapy.	('inhibition', 'Var', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('LIM', 'Gene', '10611', (51, 54))	('LIM', 'Gene', (74, 77))	('tumor', 'Disease', (121, 126))	('rat', 'Species', '10116', (98, 101))	('LIM', 'Gene', (51, 54))	('LIM', 'Gene', '10611', (74, 77))	('improving', 'PosReg', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
340780	32587768	Specifically, Src phosphorylates the protein at two tyrosine residues, Y149 and Y272.	('Y149', 'Var', (71, 75))	('tyrosine', 'Chemical', 'MESH:D014443', (52, 60))	('Src', 'Gene', '6714', (14, 17))	('Src', 'Gene', (14, 17))	('Y272', 'Var', (80, 84))
340781	32587768	Following phosphorylation, FHL1 translocates into the nucleus where it binds the transcription factor BCLAF1.	('FHL1', 'Gene', (27, 31))	('BCLAF1', 'Gene', '9774', (102, 108))	('BCLAF1', 'Gene', (102, 108))	('binds', 'Interaction', (71, 76))	('phosphorylation', 'Var', (10, 25))
340783	32587768	Consistent with previous reports, wild-type FHL1 repressed cell growth and migration in vitro and a nonphosphorylatable mutant of FHL1 exerted an even stronger inhibitory effect on cell growth and migration.	('inhibitory', 'NegReg', (160, 170))	('FHL1', 'Gene', (130, 134))	('rat', 'Species', '10116', (200, 203))	('rat', 'Species', '10116', (78, 81))	('migration', 'CPA', (75, 84))	('cell growth', 'CPA', (181, 192))	('cell growth', 'CPA', (59, 70))	('mutant', 'Var', (120, 126))
340784	32587768	Conversely, a phosphomimetic mutant of FHL1 promoted proliferation and migration.	('promoted', 'PosReg', (44, 52))	('rat', 'Species', '10116', (60, 63))	('rat', 'Species', '10116', (74, 77))	('migration', 'CPA', (71, 80))	('proliferation', 'CPA', (53, 66))	('phosphomimetic', 'Var', (14, 28))	('FHL1', 'Gene', (39, 43))
340785	32587768	When cells expressing different FHL1 mutants were injected into mice, similar effects were observed in vivo.	('mutants', 'Var', (37, 44))	('FHL1', 'Gene', (32, 36))	('mice', 'Species', '10090', (64, 68))
340786	32587768	Cells expressing phosphomimetic FHL1 grew faster and displayed larger tumors than those expressing wild-type or nonphosphorylatable FHL1.	('larger', 'PosReg', (63, 69))	('faster', 'PosReg', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('grew', 'CPA', (37, 41))	('FHL1', 'Var', (32, 36))	('tumors', 'Disease', (70, 76))	('phosphomimetic FHL1', 'Var', (17, 36))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
340794	32587768	Upon phosphorylation, FHL1 translocates to the nucleus where it acts as a tumor promoter (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('phosphorylation', 'Var', (5, 20))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('FHL1', 'Gene', (22, 26))
340798	32587768	FHL1 was further identified as an independent predictor of poor outcomes in AML when combined with prognosis-related clinical factors and genetic abnormalities, such as MLL-PTD, TP53, and RUNX1 mutations.	('RUNX1', 'Gene', '861', (188, 193))	('TP53', 'Gene', '7157', (178, 182))	('FHL1', 'Gene', (0, 4))	('AML', 'Disease', (76, 79))	('TP53', 'Gene', (178, 182))	('AML', 'Phenotype', 'HP:0004808', (76, 79))	('mutations', 'Var', (194, 203))	('MLL-PTD', 'Disease', (169, 176))	('genetic abnormalities', 'Disease', 'MESH:D030342', (138, 159))	('MLL-PTD', 'Disease', 'MESH:C537633', (169, 176))	('RUNX1', 'Gene', (188, 193))	('genetic abnormalities', 'Disease', (138, 159))	('AML', 'Disease', 'MESH:D015470', (76, 79))
340800	32587768	Furthermore, FHL1 was highly expressed in LSCs and its knockdown enhanced the sensitivity of AML cells to cytarabine in vitro, supporting the involvement of FHL1 in chemotherapy resistance and relapse of AML.	('sensitivity', 'MPA', (78, 89))	('knockdown', 'Var', (55, 64))	('FHL1', 'Gene', (13, 17))	('AML', 'Disease', 'MESH:D015470', (204, 207))	('AML', 'Phenotype', 'HP:0004808', (93, 96))	('AML', 'Disease', (93, 96))	('AML', 'Disease', (204, 207))	('cytarabine', 'Chemical', 'MESH:D003561', (106, 116))	('enhanced', 'PosReg', (65, 73))	('AML', 'Phenotype', 'HP:0004808', (204, 207))	('AML', 'Disease', 'MESH:D015470', (93, 96))	('involvement', 'Reg', (142, 153))
340806	32587768	Mutations in the FHL1 gene have been identified as the cause of several skeletal muscle diseases.	('skeletal muscle diseases', 'Disease', (72, 96))	('skeletal muscle diseases', 'Disease', 'MESH:D005207', (72, 96))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (37, 47))	('cause', 'Reg', (55, 60))	('FHL1', 'Gene', (17, 21))
340808	32587768	FHL1 is widely downregulated in various cancers, mainly through gene silencing owing to CpG hypermethylation.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('FHL1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('gene', 'MPA', (64, 68))	('cancers', 'Disease', (40, 47))	('CpG hypermethylation', 'Var', (88, 108))	('hypermethylation', 'Var', (92, 108))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('downregulated', 'NegReg', (15, 28))
340812	32587768	Another recent study by our group implicated phosphorylated FHL1 induced by Src in tumor cell growth and migration.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('rat', 'Species', '10116', (108, 111))	('tumor', 'Disease', (83, 88))	('phosphorylated', 'Var', (45, 59))	('Src', 'Gene', (76, 79))	('migration', 'CPA', (105, 114))	('Src', 'Gene', '6714', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('FHL1', 'Gene', (60, 64))
340816	32587768	In view of our finding that phosphorylation of FHL1 dramatically alters the role of FHL1 from tumor suppressor to promoter, it is worth investigating whether other types of PTM, such as acetylation and ubquitination, regulate subcellular location and cellular function of FHL1.	('phosphorylation', 'Var', (28, 43))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('alters', 'Reg', (65, 71))	('regulate', 'Reg', (217, 225))
340817	32587768	Perhaps the most promising area of future study is elucidation of the precise roles and regulatory mechanisms of FHL1 in both nuclear and cytoplasmic compartments, which should offer novel insights into how aberrant FHL1 expression and modification patterns influence tumor progression and provide new avenues for therapeutic intervention.	('FHL1', 'Gene', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (268, 273))	('aberrant', 'Var', (207, 215))	('influence', 'Reg', (258, 267))	('FHL1', 'Gene', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
341012	31511035	The risk factors of breast cancer are related to family history (BRCA1or BRCA2 mutations), influence endogenous estrogen exposure (such as early age at menarche, later age at menopause, late age at first birth, nulliparity, and fewer children), alcohol drinking, physical inactivity, excess body weight.	('alcohol drinking', 'Phenotype', 'HP:0030955', (245, 261))	('BRCA1', 'Gene', '672', (65, 70))	('BRCA2', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('alcohol', 'Chemical', 'MESH:D000438', (245, 252))	('lip', 'Gene', (214, 217))	('breast cancer', 'Disease', (20, 33))	('BRCA1', 'Gene', (65, 70))	('BRCA2', 'Gene', '675', (73, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('excess body weight', 'Phenotype', 'HP:0004324', (284, 302))	('lip', 'Gene', '23049', (214, 217))	('endogenous estrogen exposure', 'MPA', (101, 129))	('age at menopause', 'Phenotype', 'HP:0008209', (168, 184))	('children', 'Species', '9606', (234, 242))	('mutations', 'Var', (79, 88))
341047	31114363	Furthermore, CDKN3 inhibition resulted in reduced expression of RAD51, which plays a pivotal role in DDR.	('CDKN3', 'Gene', (13, 18))	('expression', 'MPA', (50, 60))	('reduced', 'NegReg', (42, 49))	('RAD51', 'Gene', '5888', (64, 69))	('inhibition', 'Var', (19, 29))	('CDKN3', 'Gene', '1033', (13, 18))	('RAD51', 'Gene', (64, 69))
341127	31114363	Cell cycle analysis showed that CDKN3 knockdown led to a decrease in the time spent in the G2/M phase transition, compared to NC and BLANK (Figure 3H-I).	('decrease', 'NegReg', (57, 65))	('CDKN3', 'Gene', '1033', (32, 37))	('time spent in the G2/M phase transition', 'CPA', (73, 112))	('CDKN3', 'Gene', (32, 37))	('knockdown', 'Var', (38, 47))
341128	31114363	Furthermore, CDKN3 knockdown significantly decreased tumor volume using a xenograft tumor model in vivo (Figure 3J-K), which was accompanied by decreasing intensity of Ki-67 fluorescence (Figure 3L).	('CDKN3', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Ki-67 fluorescence', 'MPA', (168, 186))	('knockdown', 'Var', (19, 28))	('CDKN3', 'Gene', '1033', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('intensity', 'MPA', (155, 164))	('tumor', 'Disease', (84, 89))	('decreasing', 'NegReg', (144, 154))	('tumor', 'Disease', (53, 58))	('decreased', 'NegReg', (43, 52))
341136	31114363	Western blot assays were used to assure the knockdown performance of shCDKN3 in EC109R and OE19R (Figure 4E).	('CDKN3', 'Gene', '1033', (71, 76))	('CDKN3', 'Gene', (71, 76))	('OE19R', 'Var', (91, 96))
341137	31114363	CDKN3 knockdown significantly decreased the IC50 over twofold in EC109R and OE19R cells (Figure 4F and G, Table 1).	('CDKN3', 'Gene', '1033', (0, 5))	('knockdown', 'Var', (6, 15))	('IC50', 'MPA', (44, 48))	('CDKN3', 'Gene', (0, 5))	('decreased', 'NegReg', (30, 39))
341140	31114363	Knockdown of CDKN3 improved cisplatin chemosensitivity in both ESCC and EA compared with the controls (Figure 4J and K).	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('CDKN3', 'Gene', (13, 18))	('Knockdown', 'Var', (0, 9))	('CDKN3', 'Gene', '1033', (13, 18))	('EA', 'Phenotype', 'HP:0011459', (72, 74))	('cisplatin chemosensitivity', 'MPA', (28, 54))	('ESCC', 'Disease', (63, 67))	('improved', 'PosReg', (19, 27))
341145	31114363	CDKN3 inhibition was able to increase gammaH2AX foci counts greatly induced by cisplatin (Figure 5A and B).	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('gammaH2AX', 'Protein', (38, 47))	('increase', 'PosReg', (29, 37))	('CDKN3', 'Gene', '1033', (0, 5))	('gammaH2AX', 'Chemical', '-', (38, 47))	('inhibition', 'Var', (6, 16))	('CDKN3', 'Gene', (0, 5))
341160	31114363	These results indicated that ectopic RAD51 expression can reverse cisplatin resistance, which can be regulated by inhibition of CDKN3.	('CDKN3', 'Gene', '1033', (128, 133))	('ectopic', 'Var', (29, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('expression', 'Var', (43, 53))	('CDKN3', 'Gene', (128, 133))	('cisplatin resistance', 'MPA', (66, 86))	('RAD51', 'Gene', (37, 42))	('RAD51', 'Gene', '5888', (37, 42))	('reverse', 'NegReg', (58, 65))
341167	31114363	CDKN3 is responsible for the dephosphorylation of Thr-161/Thr-160 in CDK1/CDK2 and thus prevents CDK1/CDK2 activation that occurs via phosphorylation.	('CDK2', 'Gene', (102, 106))	('Thr', 'Chemical', 'MESH:D013912', (50, 53))	('prevents', 'NegReg', (88, 96))	('CDK2', 'Gene', '1017', (74, 78))	('CDK2', 'Gene', '1017', (102, 106))	('Thr', 'Chemical', 'MESH:D013912', (58, 61))	('CDKN3', 'Gene', '1033', (0, 5))	('CDK1', 'Gene', '983', (97, 101))	('CDK1', 'Gene', (69, 73))	('dephosphorylation', 'MPA', (29, 46))	('activation', 'PosReg', (107, 117))	('CDK1', 'Gene', '983', (69, 73))	('CDK2', 'Gene', (74, 78))	('CDK1', 'Gene', (97, 101))	('CDKN3', 'Gene', (0, 5))	('Thr-161/Thr-160', 'Var', (50, 65))
341170	31114363	et al discovered that CDK1 inactivation mediates mitotic exit and that CDKN3 inhibits residual CDK1 activity to ensure normal mitotic exit.	('CDKN3', 'Gene', '1033', (71, 76))	('inactivation', 'Var', (27, 39))	('CDK1', 'Gene', (22, 26))	('CDK1', 'Gene', (95, 99))	('CDK1', 'Gene', '983', (22, 26))	('CDK1', 'Gene', '983', (95, 99))	('mitotic exit', 'CPA', (126, 138))	('mitotic exit', 'CPA', (49, 61))	('CDKN3', 'Gene', (71, 76))	('mediates', 'Reg', (40, 48))	('inhibits', 'NegReg', (77, 85))	('activity', 'MPA', (100, 108))
341175	31114363	Chau-Ting Yeh discovered that multiple forms of CDKN3 mutants and aberrant transcripts were present in hepatocellular cancerous tissues, but not in hepatitis tissues.	('CDKN3', 'Gene', (48, 53))	('cancerous', 'Disease', (118, 127))	('hepatitis', 'Phenotype', 'HP:0012115', (148, 157))	('hepatitis', 'Disease', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutants', 'Var', (54, 61))	('CDKN3', 'Gene', '1033', (48, 53))	('hepatitis', 'Disease', 'MESH:D056486', (148, 157))	('cancerous', 'Disease', 'MESH:D009369', (118, 127))
341176	31114363	The same research team found that truncated CDKN3 mutant prevents CDKN3 from exerting its inhibitory effect on CDK2, which suggested that dominant-negative CDKN3 mutants could interfere with normal CDKN3 function and inversely increase CDKN3 expression.	('mutant', 'Var', (50, 56))	('CDKN3', 'Gene', (236, 241))	('CDKN3', 'Gene', '1033', (198, 203))	('inhibitory effect', 'MPA', (90, 107))	('mutants', 'Var', (162, 169))	('CDKN3', 'Gene', (156, 161))	('CDKN3', 'Gene', (44, 49))	('CDK2', 'Gene', '1017', (111, 115))	('increase', 'PosReg', (227, 235))	('CDKN3', 'Gene', '1033', (236, 241))	('CDKN3', 'Gene', (66, 71))	('CDK2', 'Gene', (111, 115))	('function', 'MPA', (204, 212))	('interfere', 'NegReg', (176, 185))	('prevents', 'NegReg', (57, 65))	('CDKN3', 'Gene', '1033', (156, 161))	('CDKN3', 'Gene', '1033', (44, 49))	('CDKN3', 'Gene', (198, 203))	('CDKN3', 'Gene', '1033', (66, 71))	('expression', 'MPA', (242, 252))
341177	31114363	However, subsequent studies have failed to find any evidence of CDKN3 mutation in hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('CDKN3', 'Gene', '1033', (64, 69))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('mutation', 'Var', (70, 78))	('CDKN3', 'Gene', (64, 69))	('hepatocellular carcinoma', 'Disease', (82, 106))
341183	31114363	CDKN3 copy number variations accounted for 0.54%, and gene amplification accounted for 1.08% in ESCA (data not shown).	('ESCA', 'Disease', (96, 100))	('CDKN3', 'Gene', '1033', (0, 5))	('copy number variations', 'Var', (6, 28))	('gene amplification', 'Var', (54, 72))	('CDKN3', 'Gene', (0, 5))
341184	31114363	It is gratifying that our study discovered an association between CDKN3 hypomethylation and CDKN3 mRNA expression (Pearson r=-0.39263, P<0.0001).	('CDKN3', 'Gene', '1033', (92, 97))	('CDKN3', 'Gene', (66, 71))	('hypomethylation', 'Var', (72, 87))	('mRNA expression', 'MPA', (98, 113))	('association', 'Interaction', (46, 57))	('CDKN3', 'Gene', (92, 97))	('CDKN3', 'Gene', '1033', (66, 71))
341190	31114363	CDKN3 overexpression promoted ESCA progression by increasing the proportion of time spent in the G2/M phase of ESCA cells.	('ESCA', 'Disease', (30, 34))	('increasing', 'PosReg', (50, 60))	('overexpression', 'Var', (6, 20))	('CDKN3', 'Gene', '1033', (0, 5))	('promoted', 'PosReg', (21, 29))	('CDKN3', 'Gene', (0, 5))
341191	31114363	Previous studies have shown that high expression of CDKN3 can promote tumor invasion and metastasis; however, we didn't observe a clear correlation between high CDKN3 expression and metastasis of ESCA.	('high', 'Var', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ESCA', 'Disease', (196, 200))	('CDKN3', 'Gene', (52, 57))	('tumor', 'Disease', (70, 75))	('CDKN3', 'Gene', '1033', (161, 166))	('promote', 'PosReg', (62, 69))	('CDKN3', 'Gene', '1033', (52, 57))	('CDKN3', 'Gene', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
341230	29663379	We performed high-throughput miRNA-seq on a training set of two PR patients and one PD patients (GEO database, GSE91089), and preliminary data revealed that five miRNAs (upregulated in PR patients: miR-543, 1908-5p and 3120-5p; downregulated in PR patients: miR-651-5p and 450a-5p) may serve as putative predictive markers of this low-dose decitabine primed therapy (Fig.	('miR-651', 'Gene', (258, 265))	('miR-651', 'Gene', '723779', (258, 265))	('3120-5p', 'Var', (219, 226))	('miR-543', 'Gene', '100126335', (198, 205))	('miR-543', 'Gene', (198, 205))	('upregulated', 'PosReg', (170, 181))
341234	29663379	A low-dose regimen of decitabine was suggested as the "optimal dose" for the treatment of hematological malignancies (3.5-7 mg/m2) and solid tumors (2.5-10 mg/m2).44, 45 Emerging evidences suggested that this agent did not only work against cancer cells, but also impacted the host immunity.17, 21, 27 Our previous phase I study in patients with advanced hepatocellular carcinoma exhibited the massive inflammatory cell infiltration of tumor bed after low-dose decitabine treatment.28 The further study revealed that the low-dose decitabine could broaden the peripheral T cell receptor repertoire, promote T cell proliferation and increase IFN-gamma+ secretion.46 Our present and previous data demonstrated that low-dose decitabine may re-sensitized the cancer to immunotherapy and the clinical efficacy could be predicted with peripheral IFN-gamma+ T-cell frequency, which is required to be verified in further large-scale clinical trials.	('cancer to immunotherapy', 'CPA', (754, 777))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('low-dose', 'Var', (712, 720))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (355, 379))	('tumor', 'Phenotype', 'HP:0002664', (436, 441))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('IFN-gamma', 'Gene', '3458', (839, 848))	('IFN-gamma', 'Gene', (839, 848))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (355, 379))	('IFN-gamma', 'Gene', '3458', (640, 649))	('IFN-gamma', 'Gene', (640, 649))	('hematological malignancies', 'Disease', 'MESH:D019337', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (754, 760))	('re-sensitized', 'PosReg', (736, 749))	('hematological malignancies', 'Phenotype', 'HP:0004377', (90, 116))	('hepatocellular carcinoma', 'Disease', (355, 379))	('carcinoma', 'Phenotype', 'HP:0030731', (370, 379))	('hematological malignancies', 'Disease', (90, 116))
341258	28798532	CK7 positivity was observed throughout the mass; however, CK20 positivity was mainly observed on the surface of the mass and occasionally observed in deeper areas.	('CK20', 'Var', (58, 62))	('CK7', 'Gene', (0, 3))	('CK7', 'Gene', '477602', (0, 3))
341285	28771617	Increased 30-day mortality in patients undergoing elective surgical procedures on Fridays compared to earlier in the week has been demonstrated in several large cohort studies.	('30-day mortality', 'MPA', (10, 26))	('patients', 'Species', '9606', (30, 38))	('Fridays', 'Var', (82, 89))
341334	28771617	As illustrated in S2 Table, survival proportions seem to be better for patients operated Fridays compared to the days before.	('survival', 'CPA', (28, 36))	('patients', 'Species', '9606', (71, 79))	('better', 'PosReg', (60, 66))	('Fridays', 'Var', (89, 96))
341347	28420850	XP variant is a subtype of XP involving mutations in the POLH gene encoding DNA polymerase eta.	('mutations', 'Var', (40, 49))	('DNA polymerase eta', 'Gene', '5429', (76, 94))	('DNA polymerase eta', 'Gene', (76, 94))	('POLH', 'Gene', (57, 61))
341373	28420850	The relative had been clinically diagnosed with a possible XP variant because of the family history, strong photosensitivity leading to burn-like rashes since childhood, and irregular dark spots of the skin all over the body.	('photosensitivity', 'Phenotype', 'HP:0000992', (108, 124))	('rashes', 'Disease', (146, 152))	('rashes', 'Disease', 'MESH:D005076', (146, 152))	('strong photosensitivity', 'Phenotype', 'HP:0007537', (101, 124))	('variant', 'Var', (62, 69))	('rashes', 'Phenotype', 'HP:0000988', (146, 152))
341386	28420850	The major subtypes of XP include XP group A, which involves a defect in the XPA protein of the NER pathway, and XP variant, which involves a defect in DNA polymerase eta of the TLS pathway.	('TLS', 'Gene', (177, 180))	('variant', 'Var', (115, 122))	('DNA polymerase eta', 'Gene', '5429', (151, 169))	('defect', 'NegReg', (62, 68))	('XPA', 'Gene', '7507', (76, 79))	('defect', 'NegReg', (141, 147))	('XPA', 'Gene', (76, 79))	('TLS', 'Gene', '2521', (177, 180))	('NER pathway', 'Pathway', (95, 106))	('DNA polymerase eta', 'Gene', (151, 169))
341387	28420850	Although impairment of the NER and TLS pathways leads to the inability to repair ultraviolet radiation-induced DNA damage, patients with XP variant show mild photosensitivity and a moderately increased risk of developing skin cancer compared to those with XP group A.	('NER', 'Pathway', (27, 30))	('skin cancer', 'Disease', 'MESH:D012878', (221, 232))	('TLS', 'Gene', '2521', (35, 38))	('patients', 'Species', '9606', (123, 131))	('photosensitivity', 'Phenotype', 'HP:0000992', (158, 174))	('skin cancer', 'Phenotype', 'HP:0008069', (221, 232))	('variant', 'Var', (140, 147))	('skin cancer', 'Disease', (221, 232))	('TLS', 'Gene', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
341390	28420850	Several in vitro studies have shown that defective XPA protein and DNA polymerase eta reduce the proliferation and viability of cancer and normal cells.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('XPA', 'Gene', '7507', (51, 54))	('XPA', 'Gene', (51, 54))	('defective', 'Var', (41, 50))	('DNA polymerase eta', 'Gene', '5429', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('reduce', 'NegReg', (86, 92))	('DNA polymerase eta', 'Gene', (67, 85))	('cancer', 'Disease', (128, 134))
341391	28420850	Lung cancer A549 cells transfected with XPA antisense RNA show a reduction in cell viability after CDDP treatment.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('XPA', 'Gene', '7507', (40, 43))	('A549', 'CellLine', 'CVCL:0023', (12, 16))	('XPA', 'Gene', (40, 43))	('CDDP', 'Chemical', '-', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('antisense RNA', 'Var', (44, 57))	('reduction', 'NegReg', (65, 74))	('cell viability', 'CPA', (78, 92))
341392	28420850	Ovarian cancer cells with small interfering RNA-induced knockdown of POLH encoding DNA polymerase eta exhibit high sensitivity to CDDP.	('DNA polymerase eta', 'Gene', '5429', (83, 101))	('CDDP', 'Chemical', '-', (130, 134))	('cancer', 'Disease', (8, 14))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('DNA polymerase eta', 'Gene', (83, 101))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('POLH', 'Gene', (69, 73))	('sensitivity', 'MPA', (115, 126))	('knockdown', 'Var', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
341394	28420850	Additionally, DNA polymerase eta-deficient XP30RO fibroblasts from a patient with XP variant were highly sensitive to CDDP.	('CDDP', 'MPA', (118, 122))	('sensitive', 'MPA', (105, 114))	('variant', 'Var', (85, 92))	('DNA polymerase eta', 'Gene', '5429', (14, 32))	('CDDP', 'Chemical', '-', (118, 122))	('DNA polymerase eta', 'Gene', (14, 32))	('patient', 'Species', '9606', (69, 76))
341424	28420850	Physicians should therefore be aware that CDDP can potentially induce severe adverse events in patients with XP.	('CDDP', 'Chemical', '-', (42, 46))	('induce', 'Reg', (63, 69))	('CDDP', 'Var', (42, 46))	('patients', 'Species', '9606', (95, 103))
341478	27728966	Previous studies reported that recurrent dysphagia occurred more frequently with Ultraflex stents than with Polyflex stents or Niti-S stents, although Polyflex stents were associated with a high rate of stent migration.	('dysphagia', 'Disease', (41, 50))	('dysphagia', 'Disease', 'MESH:D003680', (41, 50))	('dysphagia', 'Phenotype', 'HP:0002015', (41, 50))	('Ultraflex stents', 'Var', (81, 97))
341487	27728966	In our study, patients treated with Ultraflex stents were at higher risk of stent-related complications than those treated with other stents (i.e., Niti-S stent or Evolution stent).	('Ultraflex stents', 'Var', (36, 52))	('stent-related complications', 'Disease', (76, 103))	('patients', 'Species', '9606', (14, 22))
341497	27728966	Therefore, chemotherapy can lead to tissue damage followed by esophageal wall atrophy, and such changes might increase the risk of stent-related complications.	('chemotherapy', 'Var', (11, 23))	('tissue damage', 'CPA', (36, 49))	('esophageal wall atrophy', 'Disease', 'MESH:D004941', (62, 85))	('esophageal wall atrophy', 'Disease', (62, 85))	('lead to', 'Reg', (28, 35))
341506	24007940	During the 1970s, mutagenesis screens in Drosophila uncovered a number of important developmental signaling pathways that have since been applicable to mechanisms for both mammalian development and cancer .	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('mutagenesis', 'Var', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Drosophila', 'Species', '7227', (41, 51))	('developmental signaling pathways', 'Pathway', (84, 116))	('mammalian', 'Species', '9606', (172, 181))
341507	24007940	The initial discovery uncovered a gene locus that when mutated induced the abnormal development of hair-like projections on flies (denticles) such that its physical appearance was reminiscent of the porcupine-like mammal called hedgehog.	('mutated', 'Var', (55, 62))	('induced', 'Reg', (63, 70))	('mammal', 'Species', '9606', (214, 220))
341541	24007940	Finally, a number of reports have implicated a role for non-ligand dependent tumor regulation in which mutant Ptch (Gorlin's syndrome) and SuFu or constitutively active Smo and Gli proteins initiate the cancer phenotype .	("Gorlin's syndrome", 'Disease', 'MESH:D001478', (116, 133))	('SuFu', 'Gene', (139, 143))	('mutant', 'Var', (103, 109))	('Ptch', 'Gene', (110, 114))	("Gorlin's syndrome", 'Disease', (116, 133))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('SuFu', 'Gene', '24069', (139, 143))	('tumor', 'Disease', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
341556	24007940	Recently, two genome-wide analyses of esophageal adenocarcionmas revealed polymorphisms at several gene loci including TP53, CDKN2A, SMAD4, the Major Histocompatibility Complex locus and chromosome 16q24.1, which associates with predisposition to Barrett's esophagus .	('polymorphisms', 'Var', (74, 87))	('esophageal adenocarcionmas', 'Disease', 'MESH:D004941', (38, 64))	('SMAD4', 'Gene', (133, 138))	("Barrett's esophagus", 'Disease', (247, 266))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (247, 266))	('TP53', 'Gene', (119, 123))	('SMAD4', 'Gene', '17128', (133, 138))	('CDKN2A', 'Gene', '12578', (125, 131))	('CDKN2A', 'Gene', (125, 131))	('TP53', 'Gene', '22059', (119, 123))	('esophageal adenocarcionmas', 'Disease', (38, 64))
341558	24007940	The Forkhead homeobox (FOX) transcription factor gene cluster (FOXF1, FOXC2, FOXL1, MTHFSD) has been implicated in foregut development (lung, esophagus and stomach) but also micro-deletions in the FOX locus generate a phenotype resembling VACTERL (vertebral anomalies, gastrointestinal atresias, congenital heart malformations, urinary tract malformations, lung anomalies and alveolar capillary dysplasia) .	('FOXC2', 'Gene', '14234', (70, 75))	('urinary tract malformations', 'Disease', 'MESH:D014570', (328, 355))	('FOXL1', 'Gene', (77, 82))	('micro-deletions', 'Var', (174, 189))	('congenital heart malformations', 'Disease', (296, 326))	('lung anomalies and alveolar capillary dysplasia', 'Disease', 'MESH:C536590', (357, 404))	('FOX', 'Gene', (197, 200))	('generate', 'Reg', (207, 215))	('gastrointestinal atresias', 'Disease', (269, 294))	('FOXL1', 'Gene', '14241', (77, 82))	('lung anomalies', 'Phenotype', 'HP:0002088', (357, 371))	('MTHFSD', 'Gene', '234814', (84, 90))	('FOXC2', 'Gene', (70, 75))	('MTHFSD', 'Gene', (84, 90))	('congenital heart malformations', 'Phenotype', 'HP:0001627', (296, 326))	('urinary tract malformations', 'Disease', (328, 355))	('capillary dysplasia', 'Phenotype', 'HP:0025104', (385, 404))	('FOXF1', 'Gene', (63, 68))	('gastrointestinal atresias', 'Phenotype', 'HP:0002589', (269, 294))	('vertebral anomalies', 'Phenotype', 'HP:0003468', (248, 267))	('FOXF1', 'Gene', '15227', (63, 68))	('urinary tract malformations', 'Phenotype', 'HP:0000079', (328, 355))	('congenital heart malformations', 'Disease', 'MESH:D006330', (296, 326))	('vertebral anomalies', 'Disease', (248, 267))	('vertebral anomalies', 'Disease', 'MESH:C535781', (248, 267))	('gastrointestinal atresias', 'Disease', 'MESH:D005767', (269, 294))
341559	24007940	At present, it is not clear whether the polymorphisms found in esophageal adenocarcinomas result in elevated or reduced expression of FOX transcription factors.	('expression', 'MPA', (120, 130))	('polymorphisms', 'Var', (40, 53))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (63, 89))	('reduced', 'NegReg', (112, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('esophageal adenocarcinomas', 'Disease', (63, 89))
341565	24007940	By contrast, gastrointestinal stromal tumors (GIST), which arise from the interstitial cells of Cajal are positive for tyrosine kinase receptors, e.g., cKit + (CD117) inhibited by imatinib or the platelet-derived growth factor (PDGF) receptor alpha+ ; while diffuse gastric cancers exhibit inactivating mutations in the E-cadherin gene (CDH1), an inhibitor of the pro-proliferative Wnt- catenin pathway .	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('inactivating mutations', 'Var', (290, 312))	('gastric cancer', 'Phenotype', 'HP:0012126', (266, 280))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('imatinib', 'Chemical', 'MESH:D000068877', (180, 188))	('gastric cancers', 'Disease', 'MESH:D013274', (266, 281))	('E-cadherin', 'Gene', (320, 330))	('inhibited', 'NegReg', (167, 176))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (13, 44))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (13, 44))	('CDH1', 'Gene', (337, 341))	('CDH1', 'Gene', '12550', (337, 341))	('E-cadherin', 'Gene', '12550', (320, 330))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('GIST', 'Phenotype', 'HP:0100723', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('gastrointestinal stromal tumors', 'Disease', (13, 44))	('gastric cancers', 'Disease', (266, 281))	('gastric cancers', 'Phenotype', 'HP:0012126', (266, 281))
341578	24007940	Indeed, mutations in Ptch1 and Smo are infrequent in gastric cancers .	('gastric cancers', 'Disease', (53, 68))	('gastric cancers', 'Phenotype', 'HP:0012126', (53, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('mutations', 'Var', (8, 17))	('Ptch1', 'Gene', '19206', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Smo', 'Gene', (31, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('gastric cancers', 'Disease', 'MESH:D013274', (53, 68))	('Ptch1', 'Gene', (21, 26))
341588	24007940	Clinically, this result might be related to non-canonical activation of Smo due to a Ptch mutation (Gorlin's syndrome) or Erk activation of Gli1 via growth factor induction of Ras.	('Erk', 'Gene', '13844', (122, 125))	('Smo', 'Disease', (72, 75))	("Gorlin's syndrome", 'Disease', 'MESH:D001478', (100, 117))	('activation', 'PosReg', (58, 68))	('mutation', 'Var', (90, 98))	("Gorlin's syndrome", 'Disease', (100, 117))	('Erk', 'Gene', (122, 125))	('Ptch', 'Gene', (85, 89))
341600	24007940	Moreover, Gli1 deletion in a mouse model of pancreatic cancer generated by expressing oncogenic KRAS impedes cancer progression .	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('Gli1', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('deletion', 'Var', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('cancer', 'Disease', (109, 115))	('KRAS', 'Gene', (96, 100))	('mouse', 'Species', '10090', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('KRAS', 'Gene', '16653', (96, 100))	('pancreatic cancer', 'Disease', (44, 61))	('cancer', 'Disease', (55, 61))	('impedes', 'NegReg', (101, 108))
341610	24007940	Diehl and coworkers have nicely shown that induction of Hh ligand expression in hepatocytes stimulates the accumulation of Hh-responsive myofibroblasts, which produce lactate and fuels the proliferation of adjacent malignant hepatocytes .	('proliferation', 'CPA', (189, 202))	('Hh ligand expression', 'Gene', (56, 76))	('lactate', 'Chemical', 'MESH:D019344', (167, 174))	('accumulation', 'MPA', (107, 119))	('produce lactate', 'MPA', (159, 174))	('induction', 'Var', (43, 52))
341613	24007940	However, recent studies by LaRusso and colleagues have demonstrated that the loss of primary cilia contributes to aberrant activation of both Erk and Hh signaling pathways .	('Erk', 'Gene', (142, 145))	('loss', 'Var', (77, 81))	('Erk', 'Gene', '13844', (142, 145))	('Hh signaling pathways', 'Pathway', (150, 171))	('activation', 'PosReg', (123, 133))	('primary', 'Protein', (85, 92))
341627	24007940	A prior study demonstrated that MDSCs induce gastric carcinoma on a murine Rag2-/- background in the absence of T-cells .	('induce', 'Reg', (38, 44))	('Rag2', 'Gene', (75, 79))	('gastric carcinoma', 'Disease', 'MESH:D013274', (45, 62))	('murine', 'Species', '10090', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('gastric carcinoma', 'Disease', (45, 62))	('MDSCs', 'Var', (32, 37))	('Rag2', 'Gene', '19374', (75, 79))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (45, 62))
341628	24007940	This result suggested that MDSCs promote gastric cancer in a T-cell independent manner.	('promote', 'PosReg', (33, 40))	('MDSCs', 'Var', (27, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('gastric cancer', 'Disease', (41, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
341647	24007940	However, the acute inflammatory response initiated by Helicobacter infection was diminished with gastric epithelial deletion of the Shh ligand or Smo loci demonstrating a role for canonical signaling during acute gastric inflammation .	('infection', 'Disease', 'MESH:D007239', (67, 76))	('diminished', 'NegReg', (81, 91))	('Helicobacter', 'Disease', (54, 66))	('gastric inflammation', 'Disease', (213, 233))	('gastric inflammation', 'Phenotype', 'HP:0005263', (213, 233))	('deletion', 'Var', (116, 124))	('acute inflammatory response', 'MPA', (13, 40))	('Helicobacter infection', 'Phenotype', 'HP:0005202', (54, 76))	('Helicobacter', 'Species', '214', (54, 66))	('gastric inflammation', 'Disease', 'MESH:D007249', (213, 233))	('infection', 'Disease', (67, 76))	('Smo', 'Gene', (146, 149))
341718	15716603	Aberrant iNOS expression may be one of the phenotypical changes in gene expression associated with carcinogenesis of esophageal adenocarcinoma.	('Aberrant', 'Var', (0, 8))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (117, 142))	('carcinogenesis of esophageal adenocarcinoma', 'Disease', (99, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('iNOS', 'Gene', (9, 13))	('associated', 'Reg', (83, 93))	('carcinogenesis of esophageal adenocarcinoma', 'Disease', 'MESH:D063646', (99, 142))
341721	15716603	A recent study demonstrated that lack of iNOS promoted intestinal tumorigenesis in the ApcMin/+ mice.	('promoted', 'PosReg', (46, 54))	('lack', 'Var', (33, 37))	('mice', 'Species', '10090', (96, 100))	('rat', 'Species', '10116', (22, 25))	('iNOS', 'Protein', (41, 45))	('intestinal tumorigenesis', 'CPA', (55, 79))
341722	15716603	In contrast, Ahn and Ohshima reported that administration of iNOS inhibitors resulted in significant decrease in adenoma development in the small bowel in the ApcMin/+ mice, and iNOS gene knockout ApcMin/+ mice developed fewer adenomas in both small and large bowels than in wild type mice.	('adenomas', 'Disease', (227, 235))	('fewer', 'NegReg', (221, 226))	('iNOS', 'Gene', (178, 182))	('adenoma', 'Disease', (113, 120))	('mice', 'Species', '10090', (206, 210))	('mice', 'Species', '10090', (285, 289))	('mice', 'Species', '10090', (168, 172))	('adenoma', 'Disease', 'MESH:D000236', (227, 234))	('large bowels', 'Phenotype', 'HP:0002037', (254, 266))	('adenoma', 'Disease', (227, 234))	('adenomas', 'Disease', 'MESH:D000236', (227, 235))	('inhibitors', 'Var', (66, 76))	('decrease', 'NegReg', (101, 109))	('iNOS', 'Gene', (61, 65))	('adenoma', 'Disease', 'MESH:D000236', (113, 120))	('rat', 'Species', '10116', (51, 54))
341728	15716603	Use of COX-2 inhibitors resulted in a reduction of the development of esophageal adenocarcinoma induced by duodenal reflux.	('esophageal adenocarcinoma', 'Disease', (70, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (70, 95))	('inhibitors', 'Var', (13, 23))	('duodenal reflux', 'Phenotype', 'HP:0002020', (107, 122))	('reduction', 'NegReg', (38, 47))	('duodenal reflux', 'MPA', (107, 122))	('COX-2', 'Gene', (7, 12))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (70, 95))	('COX-2', 'Gene', '26198', (7, 12))
341744	33157909	Immunohistochemistry demonstrated positive staining for cytokeratin (CK), CK5/6, and P63, and approximately 20% of the cells were positive for Ki67 (Fig.	('cytokeratin', 'Gene', (56, 67))	('Ki67', 'Var', (143, 147))	('positive', 'Reg', (130, 138))	('cytokeratin', 'Gene', '51727', (56, 67))	('CK', 'Gene', '51727', (74, 76))	('CK5/6', 'Gene', '3852', (74, 79))	('P63', 'Gene', (85, 88))	('CK5/6', 'Gene', (74, 79))	('P63', 'Gene', '8626', (85, 88))	('CK', 'Gene', '51727', (69, 71))
341822	32579769	Pembrolizumab was granted approval in December 2018 for the treatment of patients with unresectable/metastatic solid tumors harboring high microsatellite instability (MSI) or DNA mismatch repair (MMR) gene deficiency.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('deficiency', 'Disease', (206, 216))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('high', 'Var', (134, 138))	('deficiency', 'Disease', 'MESH:D007153', (206, 216))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('patients', 'Species', '9606', (73, 81))	('MMR', 'Gene', (196, 199))
341826	32579769	Cancer resistance to immune checkpoint inhibitors can be driven both by tumor cell-intrinsic (eg, PD-L1 expression, tumor mutation load, microsatellite instability-high status) and extrinsic factors (eg, TILs, TAMs, MDSCs) that contribute to immune evasion.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('microsatellite instability-high', 'Var', (137, 168))	('tumor', 'Disease', (72, 77))	('PD-L1', 'Gene', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (116, 121))	('TAMs', 'Chemical', 'MESH:D013629', (210, 214))
341833	32579769	20  In this trial, participants with high PD-L1 expression had a higher 1-y OS rate (35%) than those with PD-L1 low expression (22%).	('1-y OS rate', 'MPA', (72, 83))	('participants', 'Species', '9606', (19, 31))	('high', 'Var', (37, 41))	('PD-L1', 'Gene', (42, 47))	('higher', 'PosReg', (65, 71))
341834	32579769	The phase III KEYNOTE-181 trial demonstrated that patients with PD-L1 high expression (ie, CPS >= 10) had a median OS of 9.3 mo with pembrolizumab vs. 6.7 mo with chemotherapy (HR = 0.69), supporting that pembrolizumab as a new 2nd-line standard therapeutic option for esophageal cancers with high expression of PD-L1.	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('patients', 'Species', '9606', (50, 58))	('pembrolizumab', 'Chemical', 'MESH:C582435', (205, 218))	('PD-L1', 'Gene', (64, 69))	('pembrolizumab', 'Chemical', 'MESH:C582435', (133, 146))	('esophageal cancers', 'Disease', (269, 287))	('esophageal cancers', 'Disease', 'MESH:D004938', (269, 287))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('high expression', 'Var', (70, 85))
341838	32579769	33 ,  34  In a previous study, using a non-biased database of 305 curatively resected esophageal cancers, PD-L1 expression was found to be associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker.	('associated with', 'Reg', (139, 154))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('expression', 'Var', (112, 122))	('esophageal cancers', 'Disease', (86, 104))	('esophageal cancer', 'Disease', (190, 207))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('PD-L1', 'Gene', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('esophageal cancers', 'Disease', 'MESH:D004938', (86, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (190, 207))
341840	32579769	Given that PD-L2 demonstrates higher affinity for PD-1 compared with PD-L1, 35  the expression levels of PD-L1 as well as PD-L2 in ESCC may serve as predictive biomarkers for the utility of immune checkpoint inhibitors.	('PD-L2', 'Var', (122, 127))	('PD-L1', 'Var', (105, 110))	('affinity', 'Interaction', (37, 45))	('expression', 'MPA', (84, 94))	('PD-1', 'Gene', (50, 54))	('PD-1', 'Gene', '5133', (50, 54))
341844	32579769	Simultaneous evaluation of PD-L2 along with PD-L1 may result in an increased number of patients indicated for inhibitors of PD-1/PD-L1 signaling; these therapeutic approaches may yield favorable outcomes in patients negative for PD-L1 and positive for PD-L2 (Figure 3A).	('patients', 'Species', '9606', (207, 215))	('PD-1', 'Gene', (124, 128))	('PD-1', 'Gene', '5133', (124, 128))	('patients', 'Species', '9606', (87, 95))	('inhibitors', 'Var', (110, 120))
341845	32579769	Variations in the expression of human leucocyte antigens (HLA), which play a role in the presentation of tumor antigens to T cells, are involved in human cancers by influencing host defenses against tumor development.	('tumor', 'Disease', (199, 204))	('involved', 'Reg', (136, 144))	('influencing', 'Reg', (165, 176))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('HLA', 'Gene', '3117', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('human', 'Species', '9606', (148, 153))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('Variations', 'Var', (0, 10))	('HLA', 'Gene', (58, 61))	('cancers', 'Disease', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('human', 'Species', '9606', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (105, 110))
341848	32579769	Several studies focusing on the prognostic significance of HLA expression patterns in patients with ESCC have reported that alterations in HLA-A, HLA-B, HLA-C, HLA-F, HLA-DQA1, and HLA-G are correlated with survival in patients with ESCC.	('HLA', 'Gene', (153, 156))	('HLA-B', 'Gene', '3106', (146, 151))	('alterations', 'Var', (124, 135))	('HLA', 'Gene', (160, 163))	('HLA', 'Gene', '3117', (59, 62))	('HLA', 'Gene', (167, 170))	('HLA', 'Gene', '3117', (146, 149))	('correlated with', 'Reg', (191, 206))	('patients', 'Species', '9606', (86, 94))	('HLA-A', 'Gene', (139, 144))	('HLA', 'Gene', '3117', (139, 142))	('HLA-DQA1', 'Gene', (167, 175))	('survival', 'MPA', (207, 215))	('HLA', 'Gene', (181, 184))	('ESCC', 'Disease', (233, 237))	('patients', 'Species', '9606', (219, 227))	('HLA', 'Gene', '3117', (160, 163))	('HLA', 'Gene', '3117', (153, 156))	('HLA', 'Gene', '3117', (167, 170))	('HLA-B', 'Gene', (146, 151))	('HLA-DQA1', 'Gene', '3117', (167, 175))	('HLA-A', 'Gene', '3105', (139, 144))	('HLA', 'Gene', (59, 62))	('HLA', 'Gene', (146, 149))	('HLA', 'Gene', (139, 142))	('HLA', 'Gene', '3117', (181, 184))	('ESCC', 'Disease', (100, 104))
341850	32579769	41  Interestingly, high PD-L1 expression was a significant independent prognostic factor in patients with ESCC and high HLA class I expression.	('high', 'Var', (115, 119))	('expression', 'MPA', (30, 40))	('high', 'Var', (19, 23))	('ESCC', 'Disease', (106, 110))	('patients', 'Species', '9606', (92, 100))	('HLA', 'Gene', '3117', (120, 123))	('HLA', 'Gene', (120, 123))	('PD-L1', 'Protein', (24, 29))
341856	32579769	Effector/cytotoxic (CD3+ and CD8+) and memory (CD45RO+) T cells play crucial roles in antitumor immune response.	('CD45RO', 'Gene', (47, 53))	('CD8', 'Gene', '925', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('CD3+', 'Var', (20, 24))	('CD45RO', 'Gene', '5788', (47, 53))	('CD8', 'Gene', (29, 32))
341860	32579769	46 ,  47  Conversely, other TIL subsets including CD3+ or CD45RO+ lymphocytes appear not to be associated with patient survival.	('CD45RO', 'Gene', (58, 64))	('CD3+', 'Var', (50, 54))	('CD45RO', 'Gene', '5788', (58, 64))	('patient', 'Species', '9606', (111, 118))
341878	32579769	The presence of TAMs has been correlated with poor prognosis in various types of human cancers.	('cancers', 'Disease', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('TAMs', 'Chemical', 'MESH:D013629', (16, 20))	('presence', 'Var', (4, 12))	('human', 'Species', '9606', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
341879	32579769	49 ,  50 ,  51  Recently, high TAM density in esophageal cancer tissues is reportedly associated with shorter survival, suggesting a prognostic biomarker role of TAMs.	('shorter', 'NegReg', (102, 109))	('TAM', 'Protein', (31, 34))	('TAMs', 'Chemical', 'MESH:D013629', (162, 166))	('TAM', 'Chemical', '-', (162, 165))	('high', 'Var', (26, 30))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('TAM', 'Chemical', '-', (31, 34))
341893	32579769	59  LV305 upregulated the expression level of the New York ESCC-1 (NY-ESO-1) cancer testis antigen in DCs, promoting immune responses against NY-ESO-1-expressing tumors.	('LV305', 'Var', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('LV305', 'Chemical', '-', (4, 9))	('NY-ESO-1', 'Gene', '246100', (67, 75))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('promoting', 'PosReg', (107, 116))	('NY-ESO-1', 'Gene', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('NY-ESO-1', 'Gene', '246100', (142, 150))	('ESCC-1', 'Gene', (59, 65))	('cancer', 'Disease', (77, 83))	('cancer testis', 'Phenotype', 'HP:0010788', (77, 90))	('upregulated', 'PosReg', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('expression level', 'MPA', (26, 42))	('immune', 'MPA', (117, 123))	('NY-ESO-1', 'Gene', (67, 75))	('tumors', 'Disease', (162, 168))
341908	32579769	67   Tumor mutation burden (TMB) is defined as the total number of mutations, including both base substitutions and short insertions/deletions, per coding area of a tumor genome.	('TMB', 'Chemical', '-', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('base substitutions', 'Var', (93, 111))	('tumor', 'Disease', (165, 170))
341909	32579769	Although not all mutations generate neoantigens, more somatic mutations can lead to more neoantigens, more tumor-infiltrating T cells, and a stronger antitumor immune response.	('tumor', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('more', 'PosReg', (84, 88))	('more', 'PosReg', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('neoantigens', 'MPA', (89, 100))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('stronger', 'PosReg', (141, 149))	('mutations', 'Var', (17, 26))	('lead to', 'Reg', (76, 83))
341912	32579769	68  Greally et al examined the relationship between TMB and survival in 89 patients with esophagogastric cancer treated with immunotherapy and found that TMB was associated with a significant improvement in OS in univariate analyses.	('cancer', 'Disease', (105, 111))	('TMB', 'Var', (154, 157))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('TMB', 'Chemical', '-', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('improvement', 'PosReg', (192, 203))	('TMB', 'Chemical', '-', (154, 157))
341942	30666132	The pathology immunohistochemistry in our hospital indicated CK-L+, Syn++, CgA+, CD56++, Ki67+, CK-H-, CK7-, CK20+, TTF-1-, CD20-, CD3-, and S100-, implying MCC.	('TTF-1', 'Gene', '7270', (116, 121))	('S100-', 'Var', (141, 146))	('Syn', 'Gene', (68, 71))	('CD20', 'Gene', '54474', (124, 128))	('CK-H-', 'Var', (96, 101))	('CD3-', 'Var', (131, 135))	('Syn', 'Gene', '23336', (68, 71))	('CK20', 'Gene', (109, 113))	('TTF-1', 'Gene', (116, 121))	('CgA', 'Gene', '1113', (75, 78))	('CK7', 'Gene', (103, 106))	('CK20', 'Gene', '54474', (109, 113))	('MC', 'Chemical', 'MESH:D008748', (157, 159))	('CK7', 'Gene', '3855', (103, 106))	('CD56', 'Gene', (81, 85))	('CK-L+', 'Var', (61, 66))	('CgA', 'Gene', (75, 78))	('CD20', 'Gene', (124, 128))	('Ki67+', 'Var', (89, 94))	('CD56', 'Gene', '4684', (81, 85))
341965	30666132	Interestingly, polyomaviruses do not actually affect MCs.	('MC', 'Chemical', 'MESH:D008748', (53, 55))	('polyomaviruses', 'Species', '36362', (15, 29))	('MCs', 'Disease', (53, 56))	('polyomaviruses', 'Var', (15, 29))
341972	30666132	At the same time, NF+ combined with CK20+ also contributes to the differential diagnosis of MCC from other neuroendocrine carcinomas.	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (107, 132))	('MC', 'Chemical', 'MESH:D008748', (92, 94))	('contributes', 'Reg', (47, 58))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (107, 132))	('neuroendocrine carcinomas', 'Disease', (107, 132))	('NF+', 'Var', (18, 21))	('CK20', 'Gene', (36, 40))	('CK20', 'Gene', '54474', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('MCC', 'Disease', (92, 95))
342044	28717855	The following pretreatment factors were tested in the analyses: age (>=65 vs. <65 years), sex (male vs. female), ECOG PS (0 vs. 1 or 2), clinical T stage (T1, T2, T3 vs. T4), clinical N stage (N0 vs. N1), clinical M stage (M0 vs. M1a or M1b), histological subtype of SCC (well-differentiated or moderately differentiated vs. poorly differentiated vs. unknown), location of the primary tumor (upper vs. middle or lower), clinically diagnosed esophageal stenosis (absent vs. present), adjacent organ invasion mediated by LN metastasis (absent vs. present), intramural metastasis (absent vs. present), and the laboratory data described below, which were obtained upon enrollment in the trial.	('SCC', 'Gene', '6317', (267, 270))	('tumor', 'Phenotype', 'HP:0002664', (385, 390))	('primary tumor', 'Disease', 'MESH:D009369', (377, 390))	('M0', 'Var', (223, 225))	('esophageal stenosis', 'Disease', (441, 460))	('esophageal stenosis', 'Disease', 'MESH:D004940', (441, 460))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (441, 460))	('adjacent organ invasion', 'CPA', (483, 506))	('SCC', 'Gene', (267, 270))	('LN metastasis', 'CPA', (519, 532))	('primary tumor', 'Disease', (377, 390))
342045	28717855	The white blood cell count, neutrophil count, hemoglobin level (Hb), CRP level, albumin level, GPT, BUN, creatinine clearance (CrC), CEA level, and SCC level were dichotomized, with cutoff points at 10,000/mm3, 8000/mm3, 13 g/dL, 1.0 mg/dL, 3.5 g/dL, 30 IU/L, 15 mg/dL, 80 mL/min, 5 ng/mL, and 1.5 ng/mL, respectively.	('GPT', 'Gene', (95, 98))	('CRP', 'Gene', '1401', (69, 72))	('albumin', 'MPA', (80, 87))	('GPT', 'Gene', '2875', (95, 98))	('8000/mm3', 'Var', (211, 219))	('SCC', 'Gene', (148, 151))	('CEA', 'Gene', (133, 136))	('SCC', 'Gene', '6317', (148, 151))	('creatinine clearance', 'MPA', (105, 125))	('CRP', 'Gene', (69, 72))	('CEA', 'Gene', '5670', (133, 136))
342081	28717855	reported that GPS1/2 scores were closely associated with poor prognosis compared with patients with a GPS0 score with the same cancer stage as those in our study.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('GPS1/2', 'Gene', (14, 20))	('poor', 'CPA', (57, 61))	('GPS1/2', 'Gene', '2873;2874', (14, 20))	('scores', 'Var', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('patients', 'Species', '9606', (86, 94))
342098	27652294	A single-channel upper gastrointestinal endoscope (GIF-Q260J; Olympus, Tokyo, Japan) and a standard electrosurgical generator (VIO300D; ERBE Elektromedizin GmbH, Tubingen, Germany) were used.	('upper gastrointestinal endoscope', 'Disease', (17, 49))	('Q260J', 'SUBSTITUTION', 'None', (55, 60))	('Q260J', 'Var', (55, 60))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (17, 49))
342207	33613116	Notably, studies have shown that DHA exerts anticancer effects through various molecular mechanisms, such as inhibiting proliferation, inducing apoptosis, inhibiting tumor metastasis and angiogenesis, promoting immune function, inducing autophagy and endoplasmic reticulum (ER) stress.	('proliferation', 'CPA', (120, 133))	('inhibiting', 'NegReg', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', (48, 54))	('inhibiting', 'NegReg', (155, 165))	('DHA', 'Var', (33, 36))	('autophagy', 'CPA', (237, 246))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('promoting', 'PosReg', (201, 210))	('immune function', 'CPA', (211, 226))	('stress', 'Disease', 'MESH:D000079225', (278, 284))	('inducing', 'PosReg', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor metastasis', 'Disease', 'MESH:D009362', (166, 182))	('angiogenesis', 'CPA', (187, 199))	('stress', 'Disease', (278, 284))	('DHA', 'Chemical', 'MESH:C039060', (33, 36))	('apoptosis', 'CPA', (144, 153))	('inducing', 'PosReg', (228, 236))	('tumor metastasis', 'Disease', (166, 182))
342211	33613116	Remarkably, DHA has synergistic anti-tumor effects with a variety of clinical drugs, and preclinical and clinical studies provide stronger evidence of its anticancer potential.	('cancer', 'Disease', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('DHA', 'Chemical', 'MESH:C039060', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('DHA', 'Var', (12, 15))	('tumor', 'Disease', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
342220	33613116	DHA, with a molecular formula of C15H24O5 and a molecular weight of 284.35 (Figure 1), has been demonstrated to be an effective and fast-acting antimalarial drug with low toxicity.	('C15H24O5', 'Var', (33, 41))	('C15H24O5', 'Chemical', '-', (33, 41))	('malaria', 'Disease', (148, 155))	('low toxicity', 'Disease', (167, 179))	('low toxicity', 'Disease', 'MESH:D009800', (167, 179))	('DHA', 'Chemical', 'MESH:C039060', (0, 3))	('malaria', 'Disease', 'MESH:D008288', (148, 155))
342231	33613116	In general, DHA has been proven to have many anticancer effects, including inhibiting proliferation, inducing apoptosis, inhibiting tumor metastasis and angiogenesis, promoting immune function, inducing autophagy and endoplasmic reticulum (ER) stress (Figure 2).	('stress', 'Disease', 'MESH:D000079225', (244, 250))	('inducing', 'PosReg', (194, 202))	('tumor metastasis', 'Disease', (132, 148))	('apoptosis', 'CPA', (110, 119))	('cancer', 'Disease', (49, 55))	('inhibiting', 'NegReg', (75, 85))	('DHA', 'Chemical', 'MESH:C039060', (12, 15))	('angiogenesis', 'CPA', (153, 165))	('stress', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('proliferation', 'CPA', (86, 99))	('inhibiting', 'NegReg', (121, 131))	('autophagy', 'CPA', (203, 212))	('immune function', 'CPA', (177, 192))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('DHA', 'Var', (12, 15))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('promoting', 'PosReg', (167, 176))	('inducing', 'PosReg', (101, 109))	('tumor metastasis', 'Disease', 'MESH:D009362', (132, 148))
342238	33613116	Furthermore, DHA upregulated the expression of Bax and led to caspase-9 activation, and downregulated the expression of Bcl-2, Bcl-xL, Cyclin E, CDK2 and CDK4, which led to esophageal cancer cell cycle arrest.	('cancer', 'Disease', (184, 190))	('Cyclin E', 'Protein', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('DHA', 'Chemical', 'MESH:C039060', (13, 16))	('expression', 'MPA', (33, 43))	('downregulated', 'NegReg', (88, 101))	('CDK2', 'Gene', '1017', (145, 149))	('caspase-9', 'Gene', (62, 71))	('expression', 'MPA', (106, 116))	('CDK2', 'Gene', (145, 149))	('CDK4', 'Gene', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('activation', 'PosReg', (72, 82))	('DHA', 'Var', (13, 16))	('upregulated', 'PosReg', (17, 28))	('arrest', 'Disease', (202, 208))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (191, 208))	('led to', 'Reg', (166, 172))	('Bcl-xL', 'Gene', (127, 133))	('Bax', 'Gene', (47, 50))	('CDK4', 'Gene', '1019', (154, 158))	('Bcl-2', 'Gene', (120, 125))	('Bax', 'Gene', '581', (47, 50))	('Bcl-xL', 'Gene', '598', (127, 133))	('caspase-9', 'Gene', '842', (62, 71))	('arrest', 'Disease', 'MESH:D006323', (202, 208))	('Bcl-2', 'Gene', '596', (120, 125))
342239	33613116	observed that DHA inhibited the growth of A549 cells by inhibiting the protein kinase B (AKT)/glycogen synthase kinase-3beta (Gsk3beta)/Cyclin D1 signaling pathway and led to cell cycle arrest in the G1 phase.	('Cyclin D1', 'Gene', '595', (136, 145))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('AKT', 'Gene', '207', (89, 92))	('protein kinase B', 'Gene', (71, 87))	('Cyclin D1', 'Gene', (136, 145))	('DHA', 'Chemical', 'MESH:C039060', (14, 17))	('glycogen synthase kinase-3beta', 'Gene', (94, 124))	('arrest', 'Disease', (186, 192))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (175, 192))	('inhibited', 'NegReg', (18, 27))	('growth', 'CPA', (32, 38))	('Gsk3beta', 'Gene', '2931', (126, 134))	('DHA', 'Var', (14, 17))	('glycogen synthase kinase-3beta', 'Gene', '2932', (94, 124))	('inhibiting', 'NegReg', (56, 66))	('Gsk3beta', 'Gene', (126, 134))	('AKT', 'Gene', (89, 92))	('arrest', 'Disease', 'MESH:D006323', (186, 192))	('protein kinase B', 'Gene', '2185', (71, 87))
342240	33613116	Besides, DHA could inhibit the proliferation of hepatocellular carcinoma (HCC) cells by inducing cell cycle arrest in G2/M phase.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (97, 114))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (48, 72))	('DHA', 'Chemical', 'MESH:C039060', (9, 12))	('proliferation', 'CPA', (31, 44))	('HCC', 'Gene', '619501', (74, 77))	('inhibit', 'NegReg', (19, 26))	('hepatocellular carcinoma', 'Disease', (48, 72))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (48, 72))	('arrest', 'Disease', 'MESH:D006323', (108, 114))	('arrest', 'Disease', (108, 114))	('DHA', 'Var', (9, 12))	('inducing', 'Reg', (88, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('HCC', 'Gene', (74, 77))
342243	33613116	Furthermore, treating mice with DHA at a dose of 20 mg/kg could effectively inhibit colon tumor growth compared to those treated with the control regimen.	('inhibit', 'NegReg', (76, 83))	('DHA', 'Chemical', 'MESH:C039060', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('DHA', 'Var', (32, 35))	('colon tumor', 'Phenotype', 'HP:0100273', (84, 95))	('colon tumor', 'Disease', 'MESH:D003110', (84, 95))	('mice', 'Species', '10090', (22, 26))	('colon tumor', 'Disease', (84, 95))
342244	33613116	firstly revealed that knocking down the small GTPase Rac1 could strengthen the growth inhibition and cell cycle arrest induced by DHA in HCT116 and RKO colon cancer cell lines.	('RKO colon cancer', 'Disease', (148, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (101, 118))	('Rac1', 'Gene', (53, 57))	('strengthen', 'PosReg', (64, 74))	('Rac1', 'Gene', '5879', (53, 57))	('HCT116', 'CellLine', 'CVCL:0291', (137, 143))	('RKO colon cancer', 'Disease', 'MESH:D015179', (148, 164))	('arrest', 'Disease', 'MESH:D006323', (112, 118))	('growth inhibition', 'CPA', (79, 96))	('DHA', 'Chemical', 'MESH:C039060', (130, 133))	('knocking down', 'Var', (22, 35))	('arrest', 'Disease', (112, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (152, 164))
342248	33613116	found that DHA could increase the level of ROS in cells, thereby exerting a cytotoxic effect in cancer cells.	('increase the level of ROS', 'Phenotype', 'HP:0025464', (21, 46))	('DHA', 'Var', (11, 14))	('level', 'MPA', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('exerting', 'Reg', (65, 73))	('ROS', 'Chemical', 'MESH:D017382', (43, 46))	('ROS', 'MPA', (43, 46))	('cytotoxic effect', 'CPA', (76, 92))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('DHA', 'Chemical', 'MESH:C039060', (11, 14))	('increase', 'PosReg', (21, 29))	('cancer', 'Disease', (96, 102))
342256	33613116	Current studies have shown that DHA can significantly induce apoptosis of tumor cells in vitro and in vivo.	('apoptosis', 'CPA', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('DHA', 'Chemical', 'MESH:C039060', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('DHA', 'Var', (32, 35))	('tumor', 'Disease', (74, 79))	('induce', 'PosReg', (54, 60))
342258	33613116	These results indicated that the mitochondrial pathway exerted an important effect in the process of DHA-induced breast cancer cell apoptosis, and the imbalance of Bim/Bcl-2 interactions promoted this process (Figure 3).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('imbalance', 'Phenotype', 'HP:0002172', (151, 160))	('Bim', 'Gene', (164, 167))	('DHA', 'Chemical', 'MESH:C039060', (101, 104))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('mitochondrial pathway', 'Pathway', (33, 54))	('Bim', 'Gene', '10018', (164, 167))	('DHA-induced', 'Gene', (101, 112))	('promoted', 'PosReg', (187, 195))	('Bcl-2', 'Gene', (168, 173))	('Bcl-2', 'Gene', '596', (168, 173))	('imbalance', 'Var', (151, 160))
342266	33613116	More importantly, DHA was also shown to be able to induce apoptosis in ovarian cancer cells, and compared with a series of ARTs, DHA had the strongest effect.	('ovarian cancer', 'Disease', 'MESH:D010051', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))	('ARTs', 'Disease', 'MESH:C535388', (123, 127))	('ovarian cancer', 'Disease', (71, 85))	('DHA', 'Chemical', 'MESH:C039060', (129, 132))	('DHA', 'Var', (18, 21))	('induce', 'PosReg', (51, 57))	('apoptosis', 'CPA', (58, 67))	('DHA', 'Chemical', 'MESH:C039060', (18, 21))	('ARTs', 'Disease', (123, 127))
342273	33613116	Furthermore, DHA inhibited the growth of colon tumor by inducing apoptosis and increasing the expression of peroxisome proliferator-activated receptor gamma (PPARgamma).	('DHA', 'Var', (13, 16))	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (108, 156))	('growth', 'CPA', (31, 37))	('colon tumor', 'Disease', (41, 52))	('inducing', 'NegReg', (56, 64))	('colon tumor', 'Disease', 'MESH:D003110', (41, 52))	('increasing', 'PosReg', (79, 89))	('DHA', 'Chemical', 'MESH:C039060', (13, 16))	('PPARgamma', 'Gene', (158, 167))	('PPARgamma', 'Gene', '5468', (158, 167))	('inhibited', 'NegReg', (17, 26))	('apoptosis', 'CPA', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('expression', 'MPA', (94, 104))	('peroxisome proliferator-activated receptor gamma', 'Gene', (108, 156))	('colon tumor', 'Phenotype', 'HP:0100273', (41, 52))
342274	33613116	DHA was shown to inhibit the activity of glucose transporter-1 (GLUT1) and glycolytic pathway by inhibiting phosphatidyl-inositol-3-kinase (PI3K)/AKT pathway and downregulating the expression of hypoxia inducible factor-1alpha (HIF-1alpha), thereby inducing LNCaP cell apoptosis.	('phosphatidyl-inositol-3-kinase', 'Gene', (108, 138))	('AKT', 'Gene', '207', (146, 149))	('glucose transporter-1', 'Gene', '6513', (41, 62))	('HIF-1alpha', 'Gene', (228, 238))	('hypoxia inducible factor-1alpha', 'Gene', '3091', (195, 226))	('glycolytic pathway', 'Pathway', (75, 93))	('hypoxia inducible factor-1alpha', 'Gene', (195, 226))	('DHA', 'Var', (0, 3))	('downregulating', 'NegReg', (162, 176))	('GLUT1', 'Gene', '6513', (64, 69))	('LNCaP', 'CellLine', 'CVCL:0395', (258, 263))	('glucose transporter-1', 'Gene', (41, 62))	('expression', 'MPA', (181, 191))	('activity', 'MPA', (29, 37))	('AKT', 'Gene', (146, 149))	('inhibiting', 'NegReg', (97, 107))	('LNCaP cell apoptosis', 'CPA', (258, 278))	('HIF-1alpha', 'Gene', '3091', (228, 238))	('phosphatidyl-inositol-3-kinase', 'Gene', '5293', (108, 138))	('GLUT1', 'Gene', (64, 69))	('inhibit', 'NegReg', (17, 24))	('DHA', 'Chemical', 'MESH:C039060', (0, 3))	('inducing', 'Reg', (249, 257))
342277	33613116	Interestingly, DHA could inhibit the expression of PKM2 as well as inhibit lactic acid production and glucose uptake, thereby promoting the apoptosis of esophageal cancer cells.	('promoting', 'PosReg', (126, 135))	('lactic acid', 'Chemical', 'MESH:D019344', (75, 86))	('inhibit', 'NegReg', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('DHA', 'Chemical', 'MESH:C039060', (15, 18))	('PKM2', 'Gene', (51, 55))	('apoptosis', 'CPA', (140, 149))	('DHA', 'Var', (15, 18))	('PKM2', 'Gene', '5315', (51, 55))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('lactic acid production', 'MPA', (75, 97))	('inhibit', 'NegReg', (25, 32))	('expression', 'MPA', (37, 47))	('glucose', 'Chemical', 'MESH:D005947', (102, 109))	('glucose', 'CPA', (102, 109))
342278	33613116	Furthermore, DHA induced caspase-independent apoptosis-like cell death in Colo205, HCT15 and HCT116 colorectal cancer cells in the absence of oxygen.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('DHA', 'Var', (13, 16))	('HCT15', 'CellLine', 'CVCL:0292', (83, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('caspase', 'Gene', '834;841;842', (25, 32))	('DHA', 'Chemical', 'MESH:C039060', (13, 16))	('death', 'Disease', 'MESH:D003643', (65, 70))	('caspase', 'Gene', (25, 32))	('death', 'Disease', (65, 70))	('colorectal cancer', 'Disease', (100, 117))	('oxygen', 'Chemical', 'MESH:D010100', (142, 148))	('HCT116', 'CellLine', 'CVCL:0291', (93, 99))
342289	33613116	In addition, DHA was shown to inhibit the proliferation and EMT of SGC7901 gastric cancer cells and downregulated the expression of Snail and PI3K/AKT signaling pathway, thereby inhibiting metastasis.	('DHA', 'Var', (13, 16))	('proliferation', 'CPA', (42, 55))	('inhibit', 'NegReg', (30, 37))	('inhibiting', 'NegReg', (178, 188))	('gastric cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('SGC7901', 'Gene', (67, 74))	('DHA', 'Chemical', 'MESH:C039060', (13, 16))	('downregulated', 'NegReg', (100, 113))	('AKT', 'Gene', '207', (147, 150))	('EMT', 'CPA', (60, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('expression', 'MPA', (118, 128))	('Snail', 'Gene', '6615', (132, 137))	('Snail', 'Gene', (132, 137))	('metastasis', 'CPA', (189, 199))	('AKT', 'Gene', (147, 150))
342290	33613116	found that DHA suppressed the activation of cancer-associated fibroblasts (CAFs) and mouse cancer-associated fibroblasts (L-929-CAFs) by inhibiting transforming growth factor-beta (TGF-beta signaling and reducing the interaction between tumor and tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('suppressed', 'NegReg', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('transforming growth factor-beta', 'Gene', '7124', (148, 179))	('iron', 'Chemical', 'MESH:D007501', (261, 265))	('DHA', 'Chemical', 'MESH:C039060', (11, 14))	('interaction', 'Interaction', (217, 228))	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Disease', (247, 252))	('TGF-beta', 'Gene', '21802', (181, 189))	('inhibiting', 'NegReg', (137, 147))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('reducing', 'NegReg', (204, 212))	('DHA', 'Var', (11, 14))	('tumor', 'Disease', (237, 242))	('cancer', 'Disease', (91, 97))	('transforming growth factor-beta', 'Gene', (148, 179))	('cancer', 'Disease', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('TGF-beta', 'Gene', (181, 189))
342292	33613116	By using an ovarian HO8910PM xenograft tumor model, DHA was shown to inhibit tumor metastasis in vivo.	('DHA', 'Chemical', 'MESH:C039060', (52, 55))	('tumor metastasis', 'Disease', 'MESH:D009362', (77, 93))	('tumor metastasis', 'Disease', (77, 93))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('DHA', 'Var', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (77, 82))	('inhibit', 'NegReg', (69, 76))
342293	33613116	Interestingly, DHA inhibited the development of ovarian cancer by downregulating phosphorylated focal adhesion kinase (pFAK), MMP-2, von willebrand factor (vWF) and macrophage infiltration.	('inhibited', 'NegReg', (19, 28))	('MMP-2', 'Gene', (126, 131))	('downregulating', 'NegReg', (66, 80))	('DHA', 'Chemical', 'MESH:C039060', (15, 18))	('macrophage infiltration', 'CPA', (165, 188))	('von willebrand factor', 'Gene', '7450', (133, 154))	('vWF', 'Gene', '7450', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('MMP-2', 'Gene', '4313', (126, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('vWF', 'Gene', (156, 159))	('DHA', 'Var', (15, 18))	('von willebrand factor', 'Gene', (133, 154))	('phosphorylated', 'MPA', (81, 95))	('ovarian cancer', 'Disease', (48, 62))
342294	33613116	A recent study showed that DHA inhibited HNSCC cell migration and invasion by blocking the phosphorylation of STAT3 and polarization of M2 macrophages.	('phosphorylation', 'MPA', (91, 106))	('STAT3', 'Gene', '6774', (110, 115))	('HNSCC cell migration', 'CPA', (41, 61))	('DHA', 'Var', (27, 30))	('STAT3', 'Gene', (110, 115))	('DHA', 'Chemical', 'MESH:C039060', (27, 30))	('blocking', 'NegReg', (78, 86))	('inhibited', 'NegReg', (31, 40))	('invasion', 'CPA', (66, 74))	('polarization', 'CPA', (120, 132))
342298	33613116	observed that DHA could inhibit cell proliferation, migration, invasion, cancer stem cells and EMT of non-small cell lung cancer (NSCLC).	('lung cancer', 'Disease', (117, 128))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (106, 128))	('inhibit', 'NegReg', (24, 31))	('DHA', 'Chemical', 'MESH:C039060', (14, 17))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cell proliferation', 'CPA', (32, 50))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('migration', 'CPA', (52, 61))	('DHA', 'Var', (14, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('invasion', 'CPA', (63, 71))	('NSCLC', 'Disease', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (122, 128))	('EMT', 'CPA', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (102, 128))
342302	33613116	DHA also inhibited cell viability, migration, invasion and induced apoptosis of epithelial ovarian cancer (EOC) cells via inhibiting the hedgehog signaling pathway (Figure 3).	('inhibited', 'NegReg', (9, 18))	('inhibiting', 'NegReg', (122, 132))	('DHA', 'Var', (0, 3))	('migration', 'CPA', (35, 44))	('hedgehog signaling pathway', 'Pathway', (137, 163))	('apoptosis of epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (67, 105))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (80, 105))	('cell viability', 'CPA', (19, 33))	('apoptosis of epithelial ovarian cancer', 'Disease', (67, 105))	('induced', 'Reg', (59, 66))	('DHA', 'Chemical', 'MESH:C039060', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('invasion', 'CPA', (46, 54))
342303	33613116	A recent study identified that DHA inhibited the growth and invasion of gastric cancer cells and confirmed that Cyclin D1-CDK4-Rb signaling played an important role in this process.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('DHA', 'Var', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cyclin D1', 'Gene', '595', (112, 121))	('CDK4', 'Gene', '1019', (122, 126))	('Cyclin D1', 'Gene', (112, 121))	('CDK4', 'Gene', (122, 126))	('inhibited', 'NegReg', (35, 44))	('DHA', 'Chemical', 'MESH:C039060', (31, 34))	('gastric cancer', 'Disease', (72, 86))
342304	33613116	In addition, DHA could inhibit the proliferation, migration and invasion of MDA-MB-231 breast cancer cells with the AKT/steroid receptor coactivator (SRC) signaling pathway involved, thereby inhibiting breast tumor-induced osteolysis.	('breast tumor', 'Disease', (202, 214))	('osteolysis', 'Disease', 'MESH:D010014', (223, 233))	('SRC', 'Gene', '6714', (150, 153))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('DHA', 'Chemical', 'MESH:C039060', (13, 16))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (76, 86))	('breast cancer', 'Disease', (87, 100))	('inhibit', 'NegReg', (23, 30))	('SRC', 'Gene', (150, 153))	('DHA', 'Var', (13, 16))	('AKT/steroid receptor coactivator', 'Gene', (116, 148))	('invasion', 'CPA', (64, 72))	('migration', 'CPA', (50, 59))	('osteolysis', 'Phenotype', 'HP:0002797', (223, 233))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast tumor', 'Disease', 'MESH:D001943', (202, 214))	('AKT/steroid receptor coactivator', 'Gene', '6714', (116, 148))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('inhibiting', 'NegReg', (191, 201))	('proliferation', 'CPA', (35, 48))	('breast tumor', 'Phenotype', 'HP:0100013', (202, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('osteolysis', 'Disease', (223, 233))
342312	33613116	found that DHA inhibited angiogenesis and tumor growth in pancreatic cancer cells, reduced NF-kappaB DNA binding activity, and downregulated the pro-angiogenic gene in downstream.	('inhibited', 'NegReg', (15, 24))	('pancreatic cancer', 'Disease', (58, 75))	('DHA', 'Var', (11, 14))	('tumor', 'Disease', (42, 47))	('NF-kappaB', 'Gene', '4790', (91, 100))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('reduced', 'NegReg', (83, 90))	('NF-kappaB', 'Gene', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('downregulated', 'NegReg', (127, 140))	('pro-angiogenic', 'Gene', (145, 159))	('angiogenesis', 'CPA', (25, 37))	('DHA', 'Chemical', 'MESH:C039060', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))
342319	33613116	demonstrated that in a sheep red blood cell (sRBC) xenograft model, delayed-type hypersensitivity (DTH) was significantly increased in the treatment of DHA compared with that observed with the control regimen treatment.	('DHA', 'Chemical', 'MESH:C039060', (152, 155))	('hypersensitivity', 'Disease', 'MESH:D004342', (81, 97))	('sRBC', 'Chemical', '-', (45, 49))	('sheep', 'Species', '9940', (23, 28))	('DHA', 'Var', (152, 155))	('delayed-type hypersensitivity', 'Phenotype', 'HP:0002972', (68, 97))	('increased', 'PosReg', (122, 131))	('delayed-type', 'CPA', (68, 80))	('hypersensitivity', 'Disease', (81, 97))
342320	33613116	Besides, in a spontaneous mouse mammary tumor (SMMT) xenograft model, the level of IFN-gamma was increased, while those of IL-4 and splenic CD4+CD25+Foxp3+ regulatory T lymphocytes were significantly reduced with the DHA treatment.	('IFN-gamma', 'Gene', (83, 92))	('CD4', 'Gene', (140, 143))	('CD4', 'Gene', '12504', (140, 143))	('increased', 'PosReg', (97, 106))	('IL-4', 'Gene', (123, 127))	('DHA', 'Var', (217, 220))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('reduced', 'NegReg', (200, 207))	('Foxp3', 'Gene', '20371', (149, 154))	('IL-4', 'Gene', '16189', (123, 127))	('IFN-gamma', 'Gene', '15978', (83, 92))	('Foxp3', 'Gene', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mouse', 'Species', '10090', (26, 31))	('DHA', 'Chemical', 'MESH:C039060', (217, 220))
342323	33613116	Notably, DHA could promote the killing effect on pancreatic cancer cells by enhancing the proliferation of gammadelta T cells.	('killing effect', 'CPA', (31, 45))	('pancreatic cancer', 'Disease', (49, 66))	('gammadelta T cells', 'CPA', (107, 125))	('promote', 'PosReg', (19, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (49, 66))	('DHA', 'Chemical', 'MESH:C039060', (9, 12))	('proliferation', 'CPA', (90, 103))	('enhancing', 'PosReg', (76, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('DHA', 'Var', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
342325	33613116	A study of DHA in melanoma showed that DHA induced the proliferation of IFN-gamma+CD8+ T cells in tumor microenvironment and mouse spleens, while the number of CD4+CD25+Foxp3+ T cells and IL-10+CD4+CD25+ T cells returned to normal, thus enhancing the anti-tumor immunity of mice.	('IL-10', 'Gene', '16153', (188, 193))	('IFN-gamma', 'Gene', (72, 81))	('DHA', 'Chemical', 'MESH:C039060', (39, 42))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('tumor', 'Disease', (98, 103))	('CD4', 'Gene', '12504', (160, 163))	('mice', 'Species', '10090', (274, 278))	('mouse', 'Species', '10090', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('enhancing', 'PosReg', (237, 246))	('Foxp3', 'Gene', (169, 174))	('DHA', 'Chemical', 'MESH:C039060', (11, 14))	('DHA', 'Var', (39, 42))	('tumor', 'Disease', (256, 261))	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IL-10', 'Gene', (188, 193))	('CD4', 'Gene', (194, 197))	('Foxp3', 'Gene', '20371', (169, 174))	('IFN-gamma', 'Gene', '15978', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('CD4', 'Gene', (160, 163))	('CD4', 'Gene', '12504', (194, 197))	('iron', 'Chemical', 'MESH:D007501', (112, 116))	('melanoma', 'Disease', (18, 26))
342327	33613116	studied new targets for DHA in EOC cells and observed that DHA induced autophagy, while autophagy inhibitors (chloroquine and bafilomycin A) were able to reverse the cell growth inhibition and cycle arrest induced by DHA.	('arrest', 'Disease', (199, 205))	('DHA', 'Var', (59, 62))	('arrest', 'Disease', 'MESH:D006323', (199, 205))	('chloroquine', 'Chemical', 'MESH:D002738', (110, 121))	('autophagy', 'CPA', (71, 80))	('DHA', 'Chemical', 'MESH:C039060', (59, 62))	('cell growth inhibition', 'CPA', (166, 188))	('bafilomycin A', 'Chemical', 'MESH:C057620', (126, 139))	('DHA', 'Chemical', 'MESH:C039060', (24, 27))	('DHA', 'Chemical', 'MESH:C039060', (217, 220))
342332	33613116	Another study demonstrated that DHA inhibited the migration of esophageal cancer cells by inducing autophagy.	('inhibited', 'NegReg', (36, 45))	('DHA', 'Chemical', 'MESH:C039060', (32, 35))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('migration', 'CPA', (50, 59))	('cancer', 'Disease', (74, 80))	('inducing', 'Reg', (90, 98))	('DHA', 'Var', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('autophagy', 'CPA', (99, 108))
342346	33613116	Controversially, another recent study showed that DHA dimer NSC735847 was cytotoxic for colorectal cancer.	('colorectal cancer', 'Disease', (88, 105))	('NSC735847', 'Var', (60, 69))	('DHA', 'Chemical', 'MESH:C039060', (50, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('DHA', 'Var', (50, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
342359	33613116	The PEG-DHA conjugate showed a moderate drug loading value, better water solubility (82-163-fold that of DHA), and a better anticancer effect in vitro.	('better', 'PosReg', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('PEG-DHA', 'Chemical', '-', (4, 11))	('DHA', 'Chemical', 'MESH:C039060', (8, 11))	('water', 'Chemical', 'MESH:D014867', (67, 72))	('PEG-DHA', 'Var', (4, 11))	('DHA', 'Chemical', 'MESH:C039060', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('drug loading value', 'MPA', (40, 58))	('water solubility', 'MPA', (67, 83))	('cancer', 'Disease', (128, 134))
342360	33613116	Subsequently, tumor xenograft assay demonstrated PEG-DHA had stronger efficacy on inhibiting tumor growth than native DHA in NSCLC.	('DHA', 'Chemical', 'MESH:C039060', (118, 121))	('PEG-DHA', 'Chemical', '-', (49, 56))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('inhibiting', 'NegReg', (82, 92))	('PEG-DHA', 'Var', (49, 56))	('NSCLC', 'Disease', (125, 130))	('DHA', 'Chemical', 'MESH:C039060', (53, 56))	('tumor', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
342361	33613116	Owing to the excellent anticancer efficacy, high drug loading capacity, suitable molecular weight and minimal inherent impurities during conversion, 8armPEG40K-DHA was expected to undergo further clinical development for the treatment against NSCLC.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('DHA', 'Chemical', 'MESH:C039060', (160, 163))	('8armPEG40K-DHA', 'Var', (149, 163))	('PEG', 'Chemical', 'MESH:D011092', (153, 156))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('NSCLC', 'Disease', (243, 248))
342366	33613116	In this context, the liposomes disrupted vasculogenic mimicry (VM) channels and inhibited tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('liposomes', 'Var', (21, 30))	('tumor metastasis', 'Disease', 'MESH:D009362', (90, 106))	('tumor metastasis', 'Disease', (90, 106))	('vasculogenic mimicry', 'MPA', (41, 61))	('disrupted', 'NegReg', (31, 40))	('inhibited', 'NegReg', (80, 89))
342375	33613116	This combination used an original approach in the treatment of breast cancer, where oral iron salts such as ferrous sulfate or ferrous citrate would increase the iron content in breast tumor, making cells more susceptible to cytotoxic effects.	('iron', 'Chemical', 'MESH:D007501', (89, 93))	('breast tumor', 'Phenotype', 'HP:0100013', (178, 190))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('increase', 'PosReg', (149, 157))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('ferrous citrate', 'Chemical', 'MESH:C016600', (127, 142))	('iron', 'Chemical', 'MESH:D007501', (162, 166))	('breast cancer', 'Disease', (63, 76))	('breast tumor', 'Disease', 'MESH:D001943', (178, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('iron content', 'MPA', (162, 174))	('ferrous sulfate', 'Chemical', 'MESH:C020748', (108, 123))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('breast tumor', 'Disease', (178, 190))	('iron salts', 'Chemical', 'MESH:C000499', (89, 99))	('more', 'PosReg', (205, 209))	('ferrous', 'Var', (127, 134))
342384	33613116	Current research showed that DHA had a stronger anti-tumor effect in the synergy with a variety of chemotherapeutic drugs, and DHA could reverse the drug resistance of certain cancer cell lines.	('DHA', 'Var', (127, 130))	('stronger', 'PosReg', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('DHA', 'Chemical', 'MESH:C039060', (29, 32))	('drug resistance', 'CPA', (149, 164))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('drug resistance', 'Phenotype', 'HP:0020174', (149, 164))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('DHA', 'Chemical', 'MESH:C039060', (127, 130))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('reverse', 'NegReg', (137, 144))
342397	33613116	Notably, one study showed that DHA synergized with docetaxel, resulting in an enhanced anti-tumor efficacy and increased overall survival of xenografted mice.	('docetaxel', 'Chemical', 'MESH:D000077143', (51, 60))	('increased', 'PosReg', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('DHA', 'Var', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mice', 'Species', '10090', (153, 157))	('tumor', 'Disease', (92, 97))	('DHA', 'Chemical', 'MESH:C039060', (31, 34))	('enhanced', 'PosReg', (78, 86))
342402	33613116	Specifically, DHA inhibited gemcitabine-induced NF-kappaB activation.	('DHA', 'Var', (14, 17))	('NF-kappaB', 'Gene', '4790', (48, 57))	('gemcitabine', 'Chemical', 'MESH:C056507', (28, 39))	('inhibited', 'NegReg', (18, 27))	('activation', 'PosReg', (58, 68))	('NF-kappaB', 'Gene', (48, 57))	('DHA', 'Chemical', 'MESH:C039060', (14, 17))
342417	33613116	In addition, DHA was observed to induce apoptosis, increase the expression of p53 and Bak, decrease the expression of Mcl-1 and pERK, and activate caspase 3 and poly ADP-ribose polymerase (PARP).	('caspase 3', 'Gene', (147, 156))	('apoptosis', 'CPA', (40, 49))	('caspase 3', 'Gene', '836', (147, 156))	('PARP', 'Gene', (189, 193))	('DHA', 'Chemical', 'MESH:C039060', (13, 16))	('poly ADP-ribose polymerase', 'Gene', (161, 187))	('Bak', 'Gene', (86, 89))	('decrease', 'NegReg', (91, 99))	('Mcl-1', 'MPA', (118, 123))	('activate', 'PosReg', (138, 146))	('pERK', 'Gene', (128, 132))	('expression', 'MPA', (104, 114))	('pERK', 'Gene', '9451', (128, 132))	('p53', 'Gene', '7157', (78, 81))	('increase', 'PosReg', (51, 59))	('DHA', 'Var', (13, 16))	('expression', 'MPA', (64, 74))	('p53', 'Gene', (78, 81))	('Bak', 'Gene', '578', (86, 89))	('PARP', 'Gene', '142', (189, 193))	('poly ADP-ribose polymerase', 'Gene', '142', (161, 187))
342422	33613116	NSCLC cells typically harbour epidermal growth factor receptor (EGFR) or RAS mutations.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('RAS', 'Gene', (73, 76))	('harbour', 'Reg', (22, 29))	('epidermal growth factor receptor', 'Gene', '1956', (30, 62))	('mutations', 'Var', (77, 86))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('NSCLC', 'Disease', (0, 5))	('epidermal growth factor receptor', 'Gene', (30, 62))
342423	33613116	found that DHA combined with ABT-263 (a Bcl-2 family inhibitor) could induce apoptosis of NSCLC harbouring EGFR or RAS mutations.	('EGFR', 'Gene', '1956', (107, 111))	('DHA', 'Chemical', 'MESH:C039060', (11, 14))	('apoptosis', 'CPA', (77, 86))	('NSCLC', 'Disease', (90, 95))	('ABT', 'Chemical', 'MESH:C002502', (29, 32))	('EGFR', 'Gene', (107, 111))	('induce', 'PosReg', (70, 76))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('RAS', 'Gene', (115, 118))	('Bcl-2', 'Gene', (40, 45))	('Bcl-2', 'Gene', '596', (40, 45))	('mutations', 'Var', (119, 128))
342424	33613116	Specifically, DHA effectively inhibited the phosphorylation of STAT3, and STAT3 inactivation resulted in the down-regulation of Mcl-1 and survivin, thereby enhancing the cytotoxicity induced by ABT-263.	('cytotoxicity', 'Disease', (170, 182))	('phosphorylation', 'MPA', (44, 59))	('survivin', 'Protein', (138, 146))	('STAT3', 'Gene', '6774', (74, 79))	('inhibited', 'NegReg', (30, 39))	('DHA', 'Var', (14, 17))	('down-regulation', 'NegReg', (109, 124))	('inactivation', 'NegReg', (80, 92))	('ABT', 'Chemical', 'MESH:C002502', (194, 197))	('STAT3', 'Gene', (74, 79))	('cytotoxicity', 'Disease', 'MESH:D064420', (170, 182))	('STAT3', 'Gene', '6774', (63, 68))	('enhancing', 'PosReg', (156, 165))	('Mcl-1', 'Protein', (128, 133))	('STAT3', 'Gene', (63, 68))	('DHA', 'Chemical', 'MESH:C039060', (14, 17))
342425	33613116	These data provided a new treatment strategy for treating NSCLC with EGFR or RAS mutations.	('NSCLC', 'Disease', (58, 63))	('EGFR', 'Gene', '1956', (69, 73))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('EGFR', 'Gene', (69, 73))	('RAS', 'Gene', (77, 80))	('mutations', 'Var', (81, 90))
342434	33613116	showed that DHA enhanced PDT-induced cell growth inhibition and apoptosis, and an additional investigation further reported that DHA increased the sensitivity of esophageal cancer cells to PDT by inhibiting the NF-kappaB/HIF-1alpha/VEGF pathway.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('sensitivity', 'MPA', (147, 158))	('apoptosis', 'CPA', (64, 73))	('inhibiting', 'NegReg', (196, 206))	('HIF-1alpha', 'Gene', (221, 231))	('DHA', 'Chemical', 'MESH:C039060', (12, 15))	('PDT-induced', 'Gene', (25, 36))	('enhanced', 'PosReg', (16, 24))	('VEGF', 'Gene', '7422', (232, 236))	('cancer', 'Disease', (173, 179))	('DHA', 'Chemical', 'MESH:C039060', (129, 132))	('VEGF', 'Gene', (232, 236))	('DHA', 'Var', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cell growth inhibition', 'CPA', (37, 59))	('NF-kappaB', 'Gene', (211, 220))	('HIF-1alpha', 'Gene', '3091', (221, 231))	('increased', 'PosReg', (133, 142))	('NF-kappaB', 'Gene', '4790', (211, 220))	('DHA', 'Var', (129, 132))
342436	33613116	In a recent study, DHA was added to magnetic nanoparticles (MNP), and the MNP-DHA has shown an effect in the treatment of intractable breast cancer.	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('DHA', 'Chemical', 'MESH:C039060', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('MNP-DHA', 'Var', (74, 81))	('DHA', 'Chemical', 'MESH:C039060', (78, 81))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
342437	33613116	These studies showed that blank MNP had almost no cytotoxicity, whereas MNP-DHA had a significant inhibitory effect on two invasive breast cancer cell lines (MDA-MB-231 and MDA-MB-453 cells).	('cytotoxicity', 'Disease', (50, 62))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (158, 168))	('DHA', 'Chemical', 'MESH:C039060', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cytotoxicity', 'Disease', 'MESH:D064420', (50, 62))	('invasive breast cancer', 'Disease', 'MESH:D001943', (123, 145))	('MNP-DHA', 'Var', (72, 79))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (173, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('inhibitory', 'NegReg', (98, 108))	('invasive breast cancer', 'Disease', (123, 145))
342454	33613116	The cytochrome P450 (CYP) enzyme system can greatly influence the oxidative metabolism of drugs, and the modification of this system is an important factor influencing drug-drug interactions (DDIs).	('modification', 'Var', (105, 117))	('CYP', 'Gene', (21, 24))	('cytochrome P450', 'Gene', '4051', (4, 19))	('influencing', 'Reg', (156, 167))	('influence', 'Reg', (52, 61))	('CYP', 'Gene', '4051', (21, 24))	('drug-drug interactions', 'MPA', (168, 190))	('drug-drug interactions', 'Phenotype', 'HP:0020172', (168, 190))	('drug-drug interaction', 'Phenotype', 'HP:0020172', (168, 189))	('cytochrome P450', 'Gene', (4, 19))	('drug interaction', 'Phenotype', 'HP:0020172', (173, 189))	('oxidative metabolism of drugs', 'MPA', (66, 95))
342469	33613116	Thus, this study provided a basis that DHA could improve the clinical symptoms of advanced cervical cancer patients and it was well tolerated.	('DHA', 'Chemical', 'MESH:C039060', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('improve', 'PosReg', (49, 56))	('clinical symptoms', 'CPA', (61, 78))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patients', 'Species', '9606', (107, 115))	('DHA', 'Var', (39, 42))
342475	33613116	The other two clinical trials are phase II clinical trials for the treatment of systemic lupus erythematosus in China, with identification numbers CTR20171440 and NCT03396393, respectively.	('NCT03396393', 'Var', (163, 174))	('systemic lupus erythematosus', 'Disease', (80, 108))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (80, 108))	('CTR20171440', 'Var', (147, 158))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (80, 108))
342541	32268810	Activation of oncogenes and inactivation of tumor suppressor genes leading to abnormalities in intercellular signaling pathways may be one mechanism leading to radiation resistance in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('leading', 'Reg', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('inactivation', 'Var', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (184, 189))	('Activation', 'PosReg', (0, 10))	('intercellular signaling pathways', 'Pathway', (95, 127))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('oncogenes', 'Protein', (14, 23))	('tumor', 'Disease', (44, 49))
342546	32268810	also reported that abnormal regulation of miR-21 promoted the progression of esophageal cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('miR-21', 'Gene', (42, 48))	('abnormal regulation', 'Var', (19, 38))	('progression', 'CPA', (62, 73))	('miR-21', 'Gene', '406991', (42, 48))	('promoted', 'PosReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
342570	32268810	The primary antibodies used were anti-PTEN (1:200, Abcam, Cambridge, MA, USA) and anti-cleaved-poly (ADP-ribose) polymerase (PARP), and anti-cleaved-caspase 3 (1:1000; Cell Signaling Technology).	('PTEN', 'Gene', '5728', (38, 42))	('PARP', 'Gene', '142', (125, 129))	('poly (ADP-ribose) polymerase', 'Gene', '142', (95, 123))	('1:200', 'Var', (44, 49))	('caspase 3', 'Gene', (149, 158))	('caspase 3', 'Gene', '836', (149, 158))	('poly (ADP-ribose) polymerase', 'Gene', (95, 123))	('PARP', 'Gene', (125, 129))	('PTEN', 'Gene', (38, 42))
342599	32268810	Li et al.reported that inhibition of miR-21 increased the radiosensitivity of esophageal cancer cells by downregulating the expression of PTEN.PTEN is a tumor suppressor gene located on chromosome 10q23, which is mutated or deleted in a variety of tumors.	('radiosensitivity', 'CPA', (58, 74))	('tumors', 'Disease', (248, 254))	('cancer', 'Disease', (89, 95))	('miR-21', 'Gene', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (248, 253))	('PTEN', 'Gene', (138, 142))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('increased', 'PosReg', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('PTEN', 'Gene', '5728', (138, 142))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('PTEN', 'Gene', (143, 147))	('downregulating', 'NegReg', (105, 119))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('inhibition', 'Var', (23, 33))	('miR-21', 'Gene', '406991', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('expression', 'MPA', (124, 134))	('PTEN', 'Gene', '5728', (143, 147))
342605	32268810	We further confirmed our hypothesis by examining the expression of apoptotic proteins in the PTEN pathway after irradiation of TE-1 cells with miR-21 inhibitors, and found that miR-21 inhibitors significantly induced PARP activity and caspase 3 activity, and that this inhibition was also reversed by the addition of PTEN siRNA.	('PTEN', 'Gene', (93, 97))	('miR-21', 'Gene', '406991', (177, 183))	('PTEN', 'Gene', (317, 321))	('PTEN', 'Gene', '5728', (93, 97))	('miR-21', 'Gene', (143, 149))	('PTEN', 'Gene', '5728', (317, 321))	('PARP', 'Gene', '142', (217, 221))	('PARP', 'Gene', (217, 221))	('activity', 'MPA', (245, 253))	('caspase 3', 'Gene', (235, 244))	('caspase 3', 'Gene', '836', (235, 244))	('miR-21', 'Gene', (177, 183))	('activity', 'MPA', (222, 230))	('miR-21', 'Gene', '406991', (143, 149))	('inhibitors', 'Var', (184, 194))	('induced', 'PosReg', (209, 216))	('TE-1', 'CellLine', 'CVCL:1759', (127, 131))
342645	30057967	Despite its anti-tumor activity, EBRT can cause cataracts, exposure keratopathy, iris neovascularization, and radiation retinopathy.	('retinopathy', 'Phenotype', 'HP:0000488', (120, 131))	('keratopathy', 'Disease', (68, 79))	('radiation retinopathy', 'Disease', 'MESH:D004194', (110, 131))	('tumor', 'Disease', (17, 22))	('cataracts', 'Disease', 'MESH:D002386', (48, 57))	('iris neovascularization', 'Phenotype', 'HP:0011497', (81, 104))	('radiation retinopathy', 'Disease', (110, 131))	('cause', 'Reg', (42, 47))	('keratopathy', 'Disease', 'MESH:C562399', (68, 79))	('cataracts', 'Phenotype', 'HP:0000518', (48, 57))	('EBRT', 'Var', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('iris neovascularization', 'Disease', (81, 104))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cataracts', 'Disease', (48, 57))
342667	28657901	Increased intraepithelial CD3+ T-lymphocytes and high PD-L1 expression on tumor cells are associated with a favorable prognosis in esophageal squamous cell carcinoma and allow prognostic immunogenic subgrouping Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer associated with poor prognosis and additional therapeutic strategies must be implemented to optimize ESCC treatment.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('tumor', 'Disease', (74, 79))	('CD3', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (131, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (272, 289))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (211, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('esophageal cancer', 'Disease', (272, 289))	('PD-L1', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('PD-L1', 'Gene', '29126', (54, 59))	('CD3', 'Gene', '397455', (26, 29))	('high', 'Var', (49, 53))	('esophageal squamous cell carcinoma', 'Disease', (131, 165))	('Esophageal squamous cell carcinoma', 'Disease', (211, 245))
342670	28657901	High intraepithelial CD3+ TILs (CD3ihigh) and high PD-L1 expression on tumor cells (PD-L1high) were each significantly associated with improved overall- (OS) (CD3+: p = 0.019; PD-L1: p = 0.028), disease specific- (DSS) (CD3+: p = 0.05; PD-L1: p = 0.006) and disease free survival (DFS) (CD3+: p = 0.009; PD-L1: p < 0.001).	('CD3', 'Gene', '397455', (32, 35))	('DSS', 'Gene', '5376', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('overall-', 'CPA', (144, 152))	('CD3', 'Gene', '397455', (287, 290))	('TIL', 'Gene', '7096', (26, 29))	('disease free survival', 'CPA', (258, 279))	('high', 'Var', (46, 50))	('CD3', 'Gene', (159, 162))	('disease specific-', 'CPA', (195, 212))	('improved', 'PosReg', (135, 143))	('CD3', 'Gene', (32, 35))	('CD3', 'Gene', '397455', (21, 24))	('CD3', 'Gene', '397455', (220, 223))	('TIL', 'Gene', (26, 29))	('CD3', 'Gene', (287, 290))	('tumor', 'Disease', (71, 76))	('CD3', 'Gene', (21, 24))	('CD3', 'Gene', (220, 223))	('DSS', 'Gene', (214, 217))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('OS', 'Chemical', '-', (154, 156))	('CD3i', 'Chemical', '-', (32, 36))	('CD3', 'Gene', '397455', (159, 162))	('PD-L1', 'Gene', (51, 56))
342671	28657901	CD3ihigh- and PD-L1high cases were significantly associated with one another (p < 0.001).	('CD3ihigh-', 'Var', (0, 9))	('CD3i', 'Chemical', '-', (0, 4))	('PD-L1high', 'Disease', (14, 23))
342673	28657901	Our data not only associate CD3ihigh- and PD-L1high ESCC with a beneficial outcome, but also demonstrate PD-L1high- and CD3ihigh status to be closely intertwined.	('CD3ihigh-', 'Var', (28, 37))	('CD3i', 'Chemical', '-', (28, 32))	('CD3i', 'Chemical', '-', (120, 124))	('PD-L1high ESCC', 'Var', (42, 56))
342705	28657901	The resulting four subgroups were the following: subgroup 1: CD3ihigh / PD-L1high (27/125; 21.6%); subgroup 2: CD3ilow / PD-L1low (60/125; 48.0%); subgroup 3: CD3ilow / PD-L1high (21/125; 16.8%); subgroup 4: CD3ihigh / PD-L1low (17/125; 13.6%).	('CD3i', 'Chemical', '-', (61, 65))	('CD3i', 'Chemical', '-', (111, 115))	('CD3ilow / PD-L1low', 'Var', (111, 129))	('CD3i', 'Chemical', '-', (159, 163))	('CD3ilow / PD-L1high', 'Var', (159, 178))	('CD3i', 'Chemical', '-', (208, 212))
342718	28657901	While patients with CD3ihigh tumors displayed a mean OS of 96.4 months (DSS: 106.1 months; DFS: 104.9 months), mean OS (62.1 months) in cases harboring low CD3is was significantly shorter (DSS: 73.9 months; DFS: 78.1 months).	('low', 'NegReg', (152, 155))	('CD3i', 'Chemical', '-', (156, 160))	('DSS', 'Gene', '5376', (72, 75))	('CD3ihigh', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CD3i', 'Chemical', '-', (20, 24))	('CD3is', 'Gene', (156, 161))	('OS', 'Chemical', '-', (53, 55))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('OS', 'Chemical', '-', (116, 118))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Disease', (29, 35))	('DSS', 'Gene', (189, 192))	('DSS', 'Gene', '5376', (189, 192))	('DSS', 'Gene', (72, 75))
342723	28657901	As highlighted in Figure 3, PD-L1high ESCCs displayed improved OS (p=0.028), DSS (p=0.006) and DFS (p<0.001), while the extent of PD-L1+ TILs, PD-L1 staining intensity in TCs and PD-L1 copy number status were not associated with survival parameters.	('DFS', 'MPA', (95, 98))	('TIL', 'Gene', '7096', (137, 140))	('DSS', 'Gene', (77, 80))	('OS', 'Chemical', '-', (63, 65))	('DSS', 'Gene', '5376', (77, 80))	('TIL', 'Gene', (137, 140))	('improved', 'PosReg', (54, 62))	('TCs', 'Chemical', '-', (171, 174))	('PD-L1high', 'Var', (28, 37))
342724	28657901	Multivariate survival analyses (including gender, age, pT, pN) revealed improved survival parameters for CD3ihigh tumors (OS: p=0.011; DSS: p=0.045; DFS: p=0.004), diffusely distributed CD3is (OS: p=0.01; DSS: p=0.005; DFS: p=0.009), diffusely distributed CD8is (OS: p=0.005; DSS: p=0.03; DFS: p=0.01) and PD-L1high ESCCs (OS: p=0.026; DSS: p=0.009; DFS: p=0.001).	('survival', 'CPA', (81, 89))	('DSS', 'Gene', '5376', (276, 279))	('DSS', 'Gene', '5376', (135, 138))	('PD-L1high', 'Var', (306, 315))	('DSS', 'Gene', '5376', (205, 208))	('OS', 'Chemical', '-', (263, 265))	('OS', 'Chemical', '-', (193, 195))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('CD8', 'Gene', (256, 259))	('improved', 'PosReg', (72, 80))	('DSS', 'Gene', (336, 339))	('DSS', 'Gene', '5376', (336, 339))	('CD3i', 'Chemical', '-', (186, 190))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('CD3i', 'Chemical', '-', (105, 109))	('DSS', 'Gene', (276, 279))	('DSS', 'Gene', (135, 138))	('DSS', 'Gene', (205, 208))	('CD8', 'Gene', '925', (256, 259))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('OS', 'Chemical', '-', (323, 325))	('tumors', 'Disease', (114, 120))	('OS', 'Chemical', '-', (122, 124))
342725	28657901	Additional ESCC subgrouping based on T-cell infiltration (CD3i status) and PD-L1 status revealed the CD3ilow / PD-L1low subgroup to be significantly associated with reduced OS (p=0.031), DSS (p=0.012) and DFS (p=0.001) compared to the other subgroups.	('DSS', 'Gene', (187, 190))	('DSS', 'Gene', '5376', (187, 190))	('CD3ilow / PD-L1low', 'Var', (101, 119))	('CD3i', 'Chemical', '-', (58, 62))	('OS', 'Chemical', '-', (173, 175))	('CD3i', 'Chemical', '-', (101, 105))	('DFS', 'MPA', (205, 208))	('reduced', 'NegReg', (165, 172))
342728	28657901	In this study, we analyzed the composition of the IM in a comparatively large cohort of 125 primary resected, therapy-naive ESCCs and demonstrate CD3ihigh - as well as PD-L1high tumors not only to be significantly associated with one another, but also to be independent prognosticators of a beneficial ESCC disease course in uni- and multivariate statistical analyses.	('associated', 'Interaction', (214, 224))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('PD-L1high tumors', 'Disease', 'MESH:D010300', (168, 184))	('PD-L1high tumors', 'Disease', (168, 184))	('CD3i', 'Chemical', '-', (146, 150))	('ESCC', 'Disease', (302, 306))	('CD3ihigh -', 'Var', (146, 156))
342736	28657901	Pointing in the same direction, our data, generated with a robust and highly specific PD-L1 (SP263) antibody in a comparatively large and extensively investigated, therapy naive tumor series, associate PD-L1high ESCC with favorable OS, DSS and DFS survival in uni- and multivariate analyses.	('tumor', 'Disease', (178, 183))	('DSS', 'Gene', (236, 239))	('DSS', 'Gene', '5376', (236, 239))	('PD-L1high ESCC', 'Var', (202, 216))	('OS', 'Chemical', '-', (232, 234))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('DFS survival', 'CPA', (244, 256))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
342738	28657901	Noteworthy, PD-L1 copy number analysis revealed PD-L1 amplifications to be a far less frequent event in ESCC (2%) than in squamous cell carcinoma of the oral cavity (19%), indicating an intertumoral spread width regarding the biologic mechanisms underlying PD-L1 expression between primary squamous cell carcinomas of different localizations.	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (290, 314))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('carcinoma of the oral cavity', 'Phenotype', 'HP:0100649', (136, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('squamous cell carcinoma of the oral', 'Disease', 'MESH:D002294', (122, 157))	('squamous cell carcinoma of the oral cavity', 'Phenotype', 'HP:0030413', (122, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('tumor', 'Disease', (191, 196))	('squamous cell carcinoma of the oral', 'Disease', (122, 157))	('ESCC', 'Disease', (104, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (290, 313))	('PD-L1', 'Gene', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (290, 314))	('squamous cell carcinomas', 'Disease', (290, 314))	('carcinomas', 'Phenotype', 'HP:0030731', (304, 314))	('amplifications', 'Var', (54, 68))
342741	28657901	Nevertheless, as PD-L1high ESCC was significantly associated with a concurrent CD3ihigh, CD8ihigh and PD1ihigh status in our cohort, one might hypothesize that high PD-L1 expression in ESCC might rather be interpreted as an adaptive mechanism of a given cancer in response to an immunoactive tumor-host relationship, that could therefore contribute to an improved disease course and speculatively, to a potential response towards immune checkpoint therapy.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('CD8', 'Gene', (89, 92))	('tumor', 'Disease', (292, 297))	('CD8', 'Gene', '925', (89, 92))	('CD3i', 'Chemical', '-', (79, 83))	('disease course', 'CPA', (364, 378))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('improved', 'PosReg', (355, 363))	('PD-L1', 'Gene', (165, 170))	('cancer', 'Disease', (254, 260))	('PD1', 'Gene', (102, 105))	('PD1', 'Gene', '5133', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('PD-L1high', 'Var', (17, 26))
342743	28657901	Interestingly, our subgrouping approach, which represents a slightly adjusted version of the TIL/PD-L1 based cancer classification proposed by Teng et al., unmasked a comparatively large subgroup of "non-immunogenic", CD3ilow / PD-L1low ESCCs (48% of all tumors), which were significantly associated with reduced survival parameters in uni- and multivariate analyses, while certain tendencies, but no distinct differences in patient survival were observed between the other subgroups.	('survival', 'MPA', (313, 321))	('CD3ilow / PD-L1low', 'Var', (218, 236))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (255, 261))	('cancer', 'Disease', (109, 115))	('patient', 'Species', '9606', (425, 432))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('TIL', 'Gene', '7096', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('reduced', 'NegReg', (305, 312))	('CD3i', 'Chemical', '-', (218, 222))	('TIL', 'Gene', (93, 96))
342747	28657901	Summarizing, we investigated the contexture of ESCCs IM and demonstrate increased intraepithelial CD3+ TILs and high PD-L1 expression on tumor cells to be independent predictors of a beneficial clinical outcome in ESCC.	('ESCC', 'Disease', (214, 218))	('tumor', 'Disease', (137, 142))	('expression', 'MPA', (123, 133))	('increased', 'PosReg', (72, 81))	('TIL', 'Gene', '7096', (103, 106))	('high', 'Var', (112, 116))	('CD3', 'Gene', '397455', (98, 101))	('PD-L1', 'Gene', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('TIL', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('CD3', 'Gene', (98, 101))
342799	28344601	Patients with one of following situations were excluded from the study; severe esophageal obstruction, esophageal fistula, Karnofsky performance status < 70, cervical or gastroesophageal junction location, multiple/skip lesions, tumor length > 10 cm, metastatic disease at presentation or recurrent disease.	('esophageal obstruction', 'Phenotype', 'HP:0005240', (79, 101))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('esophageal obstruction', 'Disease', 'MESH:D004941', (79, 101))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('gastroesophageal', 'Disease', 'MESH:D005764', (170, 186))	('esophageal fistula', 'Disease', 'MESH:D004937', (103, 121))	('metastatic disease', 'Disease', (251, 269))	('tumor', 'Disease', (229, 234))	('Patients', 'Species', '9606', (0, 8))	('esophageal obstruction', 'Disease', (79, 101))	('esophageal fistula', 'Disease', (103, 121))	('gastroesophageal', 'Disease', (170, 186))	('multiple/skip lesions', 'Var', (206, 227))
342855	28344601	In contrast, brachytherapy may reduce the tumor volume providing potential better response to external chemoradiation and fewer complications due to reduced filed size.	('better', 'PosReg', (75, 81))	('tumor', 'Disease', (42, 47))	('reduce', 'NegReg', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('brachytherapy', 'Var', (13, 26))
342953	26772891	Barrett's esophagus: Medcode, 4614; read code, J101611 Barrett's ulcer of the esophagus: Medcode, 5596; read code, J102500 Medcodes: 4865, 56077, 64274, 8244, 44228, 99155, 63470, 61695, 42416, 54171, 1062, 30700, 53591, 41362, 50789, 67497, and 4865 Medcodes: 256, 48153, 10104, 33779, and 12086 PPI: BNF 010305* NSAIDSs: BNF 10010100* Statins: BNF 02120400* Insulin: 12300, 26795, 21459, 27151, 19029, 31466, 16142, 19877, 6447, 29567, 5892, 11337, 5021, 6209, 14345, 29953, 21583, 36920, 19491, 14299, 21590, 28442, 28101, 31465, 31467, 36355, 36356, 7318, 10264, 322, 38986, 18224, 14313, 14362, 5214, 26060, 23231, 12297, 14339, 14938, 10572, 18592, 24593, 1588, 1594, 1592, 7349, 9565, 14944, 1840, 21235, 16129, 26621, 36430, 15710, 12654, 12638, 27402, 22983, 22945, 23993, 17336, 41959, 24846, 4706, 30209, 14930, 13622, 26098, 25479, 4129, 27396, 9521, 1842, 36513, 9503, 14505, 12299, 24795, 23099, 10067, 7228, 6061, 7267, 13416, 4163, 14301, 14330, 10184, 6958, 35260, 6965, 7393, 7400, 5953, 10259, 7266, 6057, 10225, 7237, 36853, 7402, 28588, 13516, 14340, 36066, 15484, 18590, 38422, 30236, 8118, 7772, 7771, 14357, 10229, 4760, 43950, 14918, 5891, 1886, 9737, 10208, 1595, 1593, 14290, 14928, 10207, 15961, 25812, 11080, 10175, 14925, 27461, 5501, 23992, 46001, 35468, 33966, 13729, 14933, 13819, 28183, 30686, 4247, 7350, 1843, 10243, 14270, 4715, 39006, 42395, 18593, 10001, 39086, 28185, 36146, 31258, 5701, 5250, 27177, 43953, 34097, 10915, 10910, 7793, 17809, 22155, 1649, 4199, 4093, 10277, 16160, 4198, 43991, 19513, 11107, 8841, 25736, 25735, 36194, 16152, 21422, 28096, 33167, 33232, 44378, 19878, 41120, 13837, 14644, 29837, 9341, 21374, 21110, 14649, 11055, 11056, 21395, 22697, 42954, 21232, 45158, 20422, 30819, 24993, 15199, 25133, 44480, 24002, 35253, 21554, 31205, 2456, 5255, 10245, 2455, 3551, 7319, 2929, 5845, 2221, 2454, 7231, 7300, 1805, 2812, 3550, 10244, 12818, 5933, 4790, 13277, 3439, 3396, 2220, 10484, 27614, 1806, 21347, 10887, 17731, 8203, 22058, 26403, 20995, 9618, 24800, 8895, 36031, 14619, 27280, 2459, 10547, 18461, 7537, 18931, 9376, 1844, 8322, 1587, 17712, 12035, 16700, 41834, 16682, 26498, 4784, 44251, 34031, 6554, 6470, 11408, 6781, 5649, 13096, 15951, 14191, 13108, 17643, 11346, 11245, 11086, 12840, 11271, 14642, 6991, 9702, 6228, 5267, 7127, 9619, 11345, 43833, 43568, 12892, 13274, 37055, 38236, 6138, 6831, 5962, 37427, 10145, 40555, 42305, 44601, 42797, 26338, 15294, 15895, 10014, 10010, 10011, 10012, 10013, 10015, 10008, 10009, 10016, 10017, 18149, 5345, 4896, 6009, 7062, 16389, 5059, 5164, 5557, 6091, 38774, 38808, 17405, 29090, 17377, 6753, 6981, 22946, 17076, 33914, 19977, 28666, 35057, 35081, 35078, 7075, 35017, 35218, 20634, 28851, 31438, 31439, 20635, 20636, 39150, 6724, 1589, 1591, 13969, 5769, 11521, 21223, 13009, 5634, 14646, 5967, 6730, 30305, 16959, 5620, 7412, 10133, 6378, 5789, 11878, 16866, 13036, 18446, 24554, 22328, 30918, 31699, 25422, 9363, 1751, 13474, 22060, 34713, 40085, 2321, 23636, 38093.	('ulcer', 'Disease', 'MESH:D014456', (65, 70))	('ulcer', 'Disease', (65, 70))	('14330', 'Var', (955, 960))	('35260', 'Var', (975, 980))	('14301', 'Var', (948, 953))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (0, 19))	('ulcer of the esophagus', 'Phenotype', 'HP:0004791', (65, 87))	('Insulin', 'Gene', '3630', (360, 367))	('13416', 'Var', (935, 940))	('Insulin', 'Gene', (360, 367))
342954	26772891	Metformin: 39560, 25678, 26258, 40007, 40110, 39729, 16044, 38400, 7166, 7610, 45581, 39598, 7048, 38355, 40233, 39988, 11990, 44250, 735, 43270, 23, 33087, 34598, 34323, 34004, 34135, 34917, 34504, 93, 34836, 33674, 34020, 34742, 34697, 31146, 27501, 42161, 17580, 14164, 6855, 7325, 11760, 11737, 11609, 11610, 11604, 11717, 11601, 7375, 43684, 43619, 38551, 39203, 37902, 37874, 31077, 30316, 18220.	('34004', 'Var', (171, 176))	('43684', 'Var', (340, 345))	('37902', 'Var', (368, 373))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('7325', 'Var', (279, 283))	('33674', 'Var', (210, 215))	('11601', 'Var', (327, 332))	('37874', 'Var', (375, 380))	('34917', 'Var', (185, 190))	('34697', 'Var', (231, 236))	('11609', 'Var', (299, 304))	('31077', 'Var', (382, 387))	('11760', 'Var', (285, 290))	('11737', 'Var', (292, 297))	('11610', 'Var', (306, 311))	('11717', 'Var', (320, 325))	('34323', 'Var', (164, 169))	('14164', 'Var', (266, 271))	('34135', 'Var', (178, 183))	('43619', 'Var', (347, 352))
342956	20347813	Esophageal squamous cell dysplasia and delayed differentiation with deletion of Klf4 in murine esophagus Klf4 (Kruppel-like factor 4; GKLF) is a DNA-binding transcriptional regulator highly expressed in skin and gastrointestinal epithelia, specifically in regions of cellular differentiation.	('gastrointestinal epithelia', 'Disease', (212, 238))	('murine', 'Species', '10090', (88, 94))	('Klf4', 'Gene', '16600', (80, 84))	('GKLF', 'Gene', (134, 138))	('Kruppel-like factor 4', 'Gene', (111, 132))	('Esophageal squamous cell dysplasia', 'Disease', 'MESH:D000077277', (0, 34))	('Klf4', 'Gene', '16600', (105, 109))	('Kruppel-like factor 4', 'Gene', '16600', (111, 132))	('deletion', 'Var', (68, 76))	('GKLF', 'Gene', '16600', (134, 138))	('Klf4', 'Gene', (80, 84))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (11, 34))	('gastrointestinal epithelia', 'Disease', 'MESH:D005767', (212, 238))	('Klf4', 'Gene', (105, 109))	('delayed differentiation', 'CPA', (39, 62))	('Esophageal squamous cell dysplasia', 'Disease', (0, 34))
342965	20347813	Dysregulation of the normal balance of proliferation and differentiation may underlie disorders such as gastroesophageal reflux disease, which affects up to 44% of the US population and esophageal cancer, the 6th most common cause of cancer death worldwide.	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (104, 135))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('Dysregulation', 'Var', (0, 13))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (104, 127))	('esophageal cancer', 'Disease', (186, 203))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer death', 'Disease', 'MESH:D003643', (234, 246))	('cancer death', 'Disease', (234, 246))	('gastroesophageal reflux disease', 'Disease', (104, 135))
342977	20347813	In a contrasting experiment, ectopic expression of Klf4 using a tetracycline inducible keratin 5 promoter produces accelerated epidermal differentiation in the embryo.	('Klf4', 'Gene', (51, 55))	('ectopic expression', 'Var', (29, 47))	('accelerated', 'PosReg', (115, 126))	('keratin 5', 'Gene', (87, 96))	('epidermal differentiation in the embryo', 'CPA', (127, 166))	('tetracycline', 'Chemical', 'MESH:D013752', (64, 76))	('keratin 5', 'Gene', '110308', (87, 96))	('Klf4', 'Gene', '16600', (51, 55))
342978	20347813	To understand the role of Klf4 later in life, we utilized the Cre-loxP system to obtain tissue-specific deletion of Klf4 in the glandular epithelium of the stomach.	('Klf4', 'Gene', '16600', (26, 30))	('Klf4', 'Gene', (26, 30))	('Klf4', 'Gene', '16600', (116, 120))	('deletion', 'Var', (104, 112))	('Klf4', 'Gene', (116, 120))
342982	20347813	In this study, we used the ED-L2 promoter of the Epstein-Barr virus, previously shown to target expression to squamous epithelia of the tongue, esophagus and forestomach, to produce tissue specific gene ablation of Klf4.	('squamous epithelia', 'Phenotype', 'HP:0002860', (110, 128))	('squamous epithelia of the tongue', 'Phenotype', 'HP:0030413', (110, 142))	('squamous epithelia', 'Disease', 'MESH:D002294', (110, 128))	('Klf4', 'Gene', '16600', (215, 219))	('Epstein-Barr virus', 'Species', '10376', (49, 67))	('squamous epithelia', 'Disease', (110, 128))	('Klf4', 'Gene', (215, 219))	('gene', 'Var', (198, 202))
342984	20347813	Mice with loss of Klf4 in esophagus developed epithelial hypertrophy, with increased proliferation, altered cell morphology, and evidence of delayed cellular maturation.	('loss', 'Var', (10, 14))	('epithelial hypertrophy', 'Disease', 'MESH:D006984', (46, 68))	('altered', 'Reg', (100, 107))	('Klf4', 'Gene', (18, 22))	('epithelial hypertrophy', 'Disease', (46, 68))	('cell morphology', 'CPA', (108, 123))	('Mice', 'Species', '10090', (0, 4))	('increased', 'PosReg', (75, 84))	('Klf4', 'Gene', '16600', (18, 22))
342988	20347813	Mutant mice were homozygous for floxed Klf4 and hemizygous for the Cre transgene.	('Mutant', 'Var', (0, 6))	('Klf4', 'Gene', (39, 43))	('mice', 'Species', '10090', (7, 11))	('Klf4', 'Gene', '16600', (39, 43))
342996	20347813	While no beta-galactosidase expression was seen in esophageal tissues of mice containing Gt(ROSA)26tm1Sor without the ED-L2/Cre transgene (Fig.	('beta-galactosidase', 'Gene', '12091', (9, 27))	('mice', 'Species', '10090', (73, 77))	('26tm1Sor', 'Var', (97, 105))	('beta-galactosidase', 'Gene', (9, 27))
342997	20347813	To produce deletion of Klf4 in esophageal epithelia of adult mice, we crossed the ED-L2/Cre transgenic mice with Klf4loxP/loxP mice.	('esophageal epithelia', 'Disease', 'MESH:D004941', (31, 51))	('mice', 'Species', '10090', (127, 131))	('mice', 'Species', '10090', (61, 65))	('esophageal epithelia', 'Disease', (31, 51))	('mice', 'Species', '10090', (103, 107))	('Klf4', 'Gene', '16600', (113, 117))	('Klf4', 'Gene', '16600', (23, 27))	('transgenic mice', 'Species', '10090', (92, 107))	('Klf4', 'Gene', (113, 117))	('deletion', 'Var', (11, 19))	('Klf4', 'Gene', (23, 27))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (31, 51))
342998	20347813	We documented Klf4 gene ablation by PCR (data not shown) and demonstrated the targeted deletion of Klf4 by performing immunohistochemistry.	('Klf4', 'Gene', (14, 18))	('Klf4', 'Gene', '16600', (99, 103))	('deletion', 'Var', (87, 95))	('Klf4', 'Gene', '16600', (14, 18))	('Klf4', 'Gene', (99, 103))	('ablation', 'NegReg', (24, 32))
343003	20347813	1F), confirming Cre-mediated deletion of Klf4 in the esophagus.	('Klf4', 'Gene', '16600', (41, 45))	('deletion', 'Var', (29, 37))	('Klf4', 'Gene', (41, 45))
343017	20347813	S2), and the pattern of Klf4 deletion in these tissues was confirmed by immunohistochemistry (Fig.	('Klf4', 'Gene', '16600', (24, 28))	('deletion', 'Var', (29, 37))	('Klf4', 'Gene', (24, 28))
343018	20347813	Evidence of hypertrophy was also seen in the tongue and the skin on the ventral neck, where Klf4 was deleted in ED-L2/Cre;Klf4loxP/loxP mice.	('mice', 'Species', '10090', (136, 140))	('Klf4', 'Gene', '16600', (92, 96))	('deleted', 'Var', (101, 108))	('hypertrophy', 'Disease', 'MESH:D006984', (12, 23))	('Klf4', 'Gene', '16600', (122, 126))	('hypertrophy', 'Disease', (12, 23))	('Klf4', 'Gene', (92, 96))	('Klf4', 'Gene', (122, 126))
343020	20347813	In additional, no significant changes were observed in the forestomach of ED-L2/Cre;Klf4loxP/loxP mice, likely due to incomplete Klf4 deletion in this tissue.	('Klf4', 'Gene', '16600', (129, 133))	('Klf4', 'Gene', '16600', (84, 88))	('deletion', 'Var', (134, 142))	('Klf4', 'Gene', (129, 133))	('Klf4', 'Gene', (84, 88))	('mice', 'Species', '10090', (98, 102))
343022	20347813	To examine the effects of Klf4 deletion at the ultrastructural level, we performed transmission electron microscopy on esophageal epithelia from 3 month-old mice.	('mice', 'Species', '10090', (157, 161))	('Klf4', 'Gene', '16600', (26, 30))	('deletion', 'Var', (31, 39))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (119, 139))	('esophageal epithelia', 'Disease', 'MESH:D004941', (119, 139))	('Klf4', 'Gene', (26, 30))	('esophageal epithelia', 'Disease', (119, 139))
343042	20347813	Moreover, transgenic expression of Klf5 in esophagus results in increased basal cell proliferation.	('transgenic', 'Species', '10090', (10, 20))	('Klf5', 'Gene', (35, 39))	('basal cell proliferation', 'Phenotype', 'HP:0002671', (74, 98))	('Klf5', 'Gene', '12224', (35, 39))	('increased', 'PosReg', (64, 73))	('basal cell proliferation', 'CPA', (74, 98))	('transgenic expression', 'Var', (10, 31))
343069	20347813	Diseases of the esophagus are among the leading causes of morbidity and mortality in the United States and throughout the world, and in the esophagus and other tissues, disruption of the factors governing squamous epithelial homeostasis may lead to uncontrolled cell proliferation, inappropriate injury responses, dysplasia, and/or cancer.	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('squamous epithelia', 'Phenotype', 'HP:0002860', (205, 223))	('dysplasia', 'Disease', (314, 323))	('inappropriate injury', 'Disease', (282, 302))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('dysplasia', 'Disease', 'MESH:D004476', (314, 323))	('cancer', 'Disease', (332, 338))	('lead to', 'Reg', (241, 248))	('uncontrolled cell proliferation', 'CPA', (249, 280))	('squamous epithelial homeostasis', 'Disease', (205, 236))	('squamous epithelial homeostasis', 'Disease', 'MESH:D002294', (205, 236))	('inappropriate injury', 'Disease', 'MESH:D002640', (282, 302))	('disruption', 'Var', (169, 179))
343072	20347813	By utilizing the ED-L2 promoter to delete Klf4, we bypass the early lethality of Klf4 null mice and are uniquely qualified to evaluate the function of Klf4 in esophageal epithelial homeostasis in the adult.	('Klf4', 'Gene', (81, 85))	('Klf4', 'Gene', (151, 155))	('mice', 'Species', '10090', (91, 95))	('delete', 'Var', (35, 41))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (159, 179))	('Klf4', 'Gene', (42, 46))	('Klf4', 'Gene', '16600', (81, 85))	('Klf4', 'Gene', '16600', (151, 155))	('esophageal epithelial homeostasis', 'Disease', 'MESH:D002277', (159, 192))	('Klf4', 'Gene', '16600', (42, 46))	('esophageal epithelial homeostasis', 'Disease', (159, 192))
343073	20347813	Loss of Klf4 in squamous epithelia of the esophagus, as well as tongue and skin of the ventral neck, results in hypertrophy, hyperplasia, defects in differentiation, and dysplasia, all of which occur in the absence of any significant inflammatory response.	('defects', 'NegReg', (138, 145))	('hypertrophy', 'Disease', (112, 123))	('dysplasia', 'Disease', (170, 179))	('hyperplasia', 'Disease', (125, 136))	('squamous epithelia of the esophagus', 'Disease', (16, 51))	('hypertrophy', 'Disease', 'MESH:D006984', (112, 123))	('squamous epithelia', 'Phenotype', 'HP:0002860', (16, 34))	('differentiation', 'CPA', (149, 164))	('results in', 'Reg', (101, 111))	('Klf4', 'Gene', '16600', (8, 12))	('squamous epithelia of the esophagus', 'Disease', 'MESH:D004938', (16, 51))	('dysplasia', 'Disease', 'MESH:D004476', (170, 179))	('hyperplasia', 'Disease', 'MESH:D006965', (125, 136))	('Klf4', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))
343074	20347813	Previously, transgenic expression of human KLF4 was reported to induce squamous epithelial dysplasia in the skin.	('induce', 'Reg', (64, 70))	('KLF4', 'Gene', (43, 47))	('squamous epithelia', 'Phenotype', 'HP:0002860', (71, 89))	('transgenic', 'Species', '10090', (12, 22))	('transgenic expression', 'Var', (12, 33))	('human', 'Species', '9606', (37, 42))	('squamous epithelial dysplasia', 'Disease', (71, 100))	('squamous epithelial dysplasia', 'Disease', 'MESH:D002294', (71, 100))
343075	20347813	Our findings do not exclude that Klf4, as a critical mediator of the proliferation-differentiation equilibrium, must be carefully titrated and that both too much or too little can result in dysregulation and dysplasia.	('result in', 'Reg', (180, 189))	('Klf4', 'Gene', '16600', (33, 37))	('dysregulation and dysplasia', 'Disease', 'MESH:D021081', (190, 217))	('too', 'Var', (153, 156))	('Klf4', 'Gene', (33, 37))
343078	20347813	Unfortunately, due to patchy deletion of Klf4 in the skin of the ventral neck of ED-L2/Cre;Klf4loxP/loxP mice, leading to development of severe skin lesions, we have not been able to age the conditional Klf4 knockout mice beyond 6 months.	('deletion', 'Var', (29, 37))	('Klf4', 'Gene', (41, 45))	('Klf4', 'Gene', (203, 207))	('mice', 'Species', '10090', (217, 221))	('Klf4', 'Gene', '16600', (91, 95))	('Klf4', 'Gene', '16600', (203, 207))	('Klf4', 'Gene', '16600', (41, 45))	('skin lesions', 'Disease', (144, 156))	('mice', 'Species', '10090', (105, 109))	('Klf4', 'Gene', (91, 95))	('skin lesions', 'Disease', 'MESH:D012871', (144, 156))
343081	20347813	We are currently crossing Klf4Loxp/Loxp mice and ED-L2/Cre mice to different inbred strains in an attempt to minimize the effects of this patchy deletion of Klf4 in the skin and to allow for a more systematic evaluation of the consequence of loss of Klf4 in the esophagus.	('Klf4', 'Gene', (157, 161))	('mice', 'Species', '10090', (59, 63))	('minimize', 'NegReg', (109, 117))	('Klf4', 'Gene', '16600', (26, 30))	('Klf4', 'Gene', '16600', (250, 254))	('Klf4', 'Gene', '16600', (157, 161))	('mice', 'Species', '10090', (40, 44))	('Klf4', 'Gene', (26, 30))	('Klf4', 'Gene', (250, 254))	('deletion', 'Var', (145, 153))
343091	20347813	Nonetheless, we cannot exclude that loss of Klf4 in vivo alters the rate of cell migration and that this may also influence the development of epithelial hypertrophy and hyperplasia.	('influence', 'Reg', (114, 123))	('epithelial hypertrophy', 'Disease', (143, 165))	('hyperplasia', 'Disease', (170, 181))	('Klf4', 'Gene', '16600', (44, 48))	('loss', 'Var', (36, 40))	('epithelial hypertrophy', 'Disease', 'MESH:D006984', (143, 165))	('hyperplasia', 'Disease', 'MESH:D006965', (170, 181))	('Klf4', 'Gene', (44, 48))	('alters', 'Reg', (57, 63))
343100	20347813	Moreover, mutations in SLURP1 are the cause of Mal de Meleda, a rare autosomal recessive disease characterized by transgressive palmoplantar keratoderma or hyperkeratosis of the palms and soles.	('hyperkeratosis', 'Phenotype', 'HP:0000962', (156, 170))	('hyperkeratosis of the palms', 'Disease', 'MESH:C537050', (156, 183))	('Mal', 'Gene', (47, 50))	('hyperkeratosis of the palms', 'Disease', (156, 183))	('cause', 'Reg', (38, 43))	('transgressive palmoplantar keratoderma', 'Disease', (114, 152))	('hyperkeratosis of the palms and soles', 'Phenotype', 'HP:0000972', (156, 193))	('transgressive palmoplantar keratoderma', 'Disease', 'MESH:D007645', (114, 152))	('Mal', 'Gene', '17153', (47, 50))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (69, 96))	('SLURP1', 'Gene', (23, 29))	('autosomal recessive disease', 'Disease', (69, 96))	('mutations', 'Var', (10, 19))	('SLURP1', 'Gene', '57277', (23, 29))	('palmoplantar keratoderma', 'Phenotype', 'HP:0000982', (128, 152))
343105	20347813	In the esophagus specifically, loss of Klf4 produces epithelial hypertrophy, increased proliferation, altered cell morphology with evidence of delayed cellular maturation, and eventually esophageal epithelial dysplasia by six months of age.	('esophageal epithelial dysplasia', 'Disease', 'MESH:D002277', (187, 218))	('epithelial hypertrophy', 'Disease', (53, 75))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (187, 207))	('epithelial hypertrophy', 'Disease', 'MESH:D006984', (53, 75))	('proliferation', 'CPA', (87, 100))	('loss', 'Var', (31, 35))	('Klf4', 'Gene', '16600', (39, 43))	('cell morphology', 'CPA', (110, 125))	('increased', 'PosReg', (77, 86))	('esophageal epithelial dysplasia', 'Phenotype', 'HP:0012859', (187, 218))	('Klf4', 'Gene', (39, 43))	('altered', 'Reg', (102, 109))	('esophageal epithelial dysplasia', 'Disease', (187, 218))
343118	34040699	Many of these drugs exert an antitumor effect by inhibiting the activity of the abnormal tyrosine kinase resulting from a genetic aberration.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tyrosine kinase', 'Gene', (89, 104))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('genetic aberration', 'Var', (122, 140))	('activity', 'MPA', (64, 72))	('inhibiting', 'NegReg', (49, 59))	('tumor', 'Disease', (33, 38))	('tyrosine kinase', 'Gene', '7294', (89, 104))	('abnormal tyrosine kinase', 'Phenotype', 'HP:0010917', (80, 104))
343119	34040699	The use of agents against actionable gene mutations has shown a significantly higher response rate as well as longer survival compared to conventional chemotherapy in certain cancers.	('higher', 'PosReg', (78, 84))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('nab', 'Chemical', '-', (31, 34))	('response', 'MPA', (85, 93))	('cancers', 'Disease', (175, 182))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
343121	34040699	NSCLC harboring epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) fusion can be treated with anticancer drugs that target the aberrant gene products.	('anaplastic lymphoma kinase', 'Gene', (69, 95))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('lymphoma', 'Phenotype', 'HP:0002665', (80, 88))	('epidermal growth factor receptor', 'Gene', '1956', (16, 48))	('ALK', 'Gene', '238', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('EGFR', 'Gene', '1956', (50, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('cancer', 'Disease', (133, 139))	('ALK', 'Gene', (97, 100))	('anaplastic lymphoma kinase', 'Gene', '238', (69, 95))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (69, 88))	('epidermal growth factor receptor', 'Gene', (16, 48))	('EGFR', 'Gene', (50, 54))	('mutation', 'Var', (56, 64))	('NSCLC', 'Disease', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
343126	34040699	Similarly, United States National Comprehensive Cancer network guidelines recommend investigating the RAS [karst and national regulatory authorities (KRAS and NRAS)] mutation status in colorectal cancer (CRC) patients for the potential use of inhibitors for epidermal growth factor receptor mutations.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('NRAS', 'Gene', (159, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (185, 202))	('colorectal cancer', 'Phenotype', 'HP:0003003', (185, 202))	('colorectal cancer', 'Disease', (185, 202))	('epidermal growth factor receptor', 'Gene', (258, 290))	('NRAS', 'Gene', '4893', (159, 163))	('Cancer', 'Disease', (48, 54))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('patients', 'Species', '9606', (209, 217))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('epidermal growth factor receptor', 'Gene', '1956', (258, 290))	('CRC', 'Phenotype', 'HP:0003003', (204, 207))	('KRAS', 'Gene', (150, 154))	('mutation', 'Var', (166, 174))	('KRAS', 'Gene', '3845', (150, 154))
343127	34040699	Due to the ineffectiveness of anti-EGFR therapy for CRC patients with BRAF mutations, the identification of the BRAF mutation status was also recommended.	('patients', 'Species', '9606', (56, 64))	('BRAF', 'Gene', '673', (112, 116))	('BRAF', 'Gene', (112, 116))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('CRC', 'Phenotype', 'HP:0003003', (52, 55))	('mutations', 'Var', (75, 84))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', (70, 74))
343134	34040699	These EGFR mutation and/or overexpression activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK- extracellular signal-regulated kinase (ERK) pathways.	('EGFR', 'Gene', (6, 10))	('ERK', 'Gene', (162, 165))	('overexpression activate', 'PosReg', (27, 50))	('RAF', 'Gene', '22882', (114, 117))	('RAF', 'Gene', (114, 117))	('MEK', 'Gene', (118, 121))	('extracellular signal-regulated kinase', 'Gene', '5594', (123, 160))	('EGFR', 'Gene', '1956', (6, 10))	('mutation', 'Var', (11, 19))	('pro-oncogenic signaling pathways', 'Pathway', (62, 94))	('MEK', 'Gene', '5609', (118, 121))	('extracellular signal-regulated kinase', 'Gene', (123, 160))	('ERK', 'Gene', '5594', (162, 165))
343137	34040699	Because of the clinical significance of hot-spot KRAS mutations (codons 12 and 13) in patients with advanced CRC to anti-EGFR therapy resistance, KRAS mutation testing has become obligatory testing before managing anti-EGFR therapy.	('EGFR', 'Gene', '1956', (219, 223))	('KRAS', 'Gene', '3845', (49, 53))	('KRAS', 'Gene', (146, 150))	('EGFR', 'Gene', '1956', (121, 125))	('patients', 'Species', '9606', (86, 94))	('hot-spot', 'PosReg', (40, 48))	('EGFR', 'Gene', (219, 223))	('mutations', 'Var', (54, 63))	('KRAS', 'Gene', '3845', (146, 150))	('EGFR', 'Gene', (121, 125))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))	('KRAS', 'Gene', (49, 53))
343146	34040699	Poziotinib is currently being investigated in a global phase II clinical trial which is expected to evaluate the efficacy of poziotinib in patients with EC, GC, or CRC who have failed two or three lines of treatment (NCT03770988, NCT01746771, and NCT04172597).	('CRC', 'Phenotype', 'HP:0003003', (164, 167))	('NCT01746771', 'Var', (230, 241))	('NCT04172597', 'Var', (247, 258))	('patients', 'Species', '9606', (139, 147))	('Poziotinib', 'Chemical', 'MESH:C557213', (0, 10))	('EC', 'Chemical', '-', (153, 155))	('GC', 'Phenotype', 'HP:0012126', (157, 159))	('CRC', 'Disease', (164, 167))	('poziotinib', 'Chemical', 'MESH:C557213', (125, 135))	('NCT03770988', 'Var', (217, 228))
343148	34040699	One of the most familiar mechanisms of acquired resistance to EGFR blockade in mCRC are mutations in the extracellular domain (ECD) of the EGFR gene.	('EGFR', 'Gene', '1956', (62, 66))	('mutations in', 'Var', (88, 100))	('EGFR', 'Gene', (62, 66))	('EGFR', 'Gene', '1956', (139, 143))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('EGFR', 'Gene', (139, 143))	('EC', 'Chemical', '-', (127, 129))
343152	34040699	Patients were found to carry mutations in KRAS, NRAS, BRAF, EGRF, and MEK1 but also amplification of ERBB2, MET, FLT3, and KRAS.	('NRAS', 'Gene', '4893', (48, 52))	('MET', 'Gene', '79811', (108, 111))	('KRAS', 'Gene', (123, 127))	('EGRF', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (42, 46))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('Patients', 'Species', '9606', (0, 8))	('FLT3', 'Gene', (113, 117))	('ERBB2', 'Gene', (101, 106))	('MEK1', 'Gene', (70, 74))	('NRAS', 'Gene', (48, 52))	('KRAS', 'Gene', (42, 46))	('FLT3', 'Gene', '2322', (113, 117))	('mutations', 'Var', (29, 38))	('MET', 'Gene', (108, 111))	('ERBB2', 'Gene', '2064', (101, 106))	('MEK1', 'Gene', '5604', (70, 74))	('KRAS', 'Gene', '3845', (123, 127))
343154	34040699	BRAF mutation in CRC patients results in poor prognosis and resistance to treatment, leading to the need for a combination of multimolecular strategies.	('CRC', 'Phenotype', 'HP:0003003', (17, 20))	('patients', 'Species', '9606', (21, 29))	('mutation', 'Var', (5, 13))	('prognosis', 'MPA', (46, 55))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('resistance to treatment', 'MPA', (60, 83))
343155	34040699	Mutations in BRAF, which are detected in approx.	('BRAF', 'Gene', '673', (13, 17))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (13, 17))
343156	34040699	10% of CRC patients overall, are mutually exclusive of KRAS mutations and occur more frequently in patients with mismatch repair (MMR) deficiency.	('KRAS', 'Gene', (55, 59))	('CRC', 'Phenotype', 'HP:0003003', (7, 10))	('deficiency', 'Disease', (135, 145))	('KRAS', 'Gene', '3845', (55, 59))	('deficiency', 'Disease', 'MESH:D007153', (135, 145))	('patients', 'Species', '9606', (99, 107))	('CRC', 'Disease', (7, 10))	('patients', 'Species', '9606', (11, 19))	('mutations', 'Var', (60, 69))
343157	34040699	The most common BRAF mutation is valine (V) 600 glutamic acid (E), which results in an amino acid change from V to E, leading to a constitutive activation of BRAF by mimicking tyrosine kinase phosphorylation.	('mimicking', 'Reg', (166, 175))	('tyrosine kinase', 'Gene', (176, 191))	('valine', 'Chemical', 'MESH:D014633', (33, 39))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('valine', 'Var', (33, 39))	('tyrosine kinase', 'Gene', '7294', (176, 191))	('mutation', 'Var', (21, 29))	('BRAF', 'Gene', '673', (158, 162))	('activation', 'PosReg', (144, 154))	('amino', 'MPA', (87, 92))	('BRAF', 'Gene', (158, 162))	('glutamic acid', 'Chemical', 'MESH:D018698', (48, 61))
343158	34040699	The results of several experiments implied that anti-EGFR therapy is not effective for mCRC patients with BRAF V600E-mutation.	('V600E', 'Var', (111, 116))	('BRAF', 'Gene', '673', (106, 110))	('patients', 'Species', '9606', (92, 100))	('BRAF', 'Gene', (106, 110))	('V600E', 'SUBSTITUTION', 'None', (111, 116))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('CRC', 'Phenotype', 'HP:0003003', (88, 91))
343160	34040699	Based on the evidence that BRAF inhibition disrupts a negative feedback loop through EGFR and facilitates cellular proliferation, combined therapy consisting of both a BRAF inhibitor and an EGFR inhibitor would provide complemental benefit in patients with BRAF V600E-mutated mCRC.	('CRC', 'Phenotype', 'HP:0003003', (277, 280))	('EGFR', 'Gene', (85, 89))	('V600E', 'Var', (262, 267))	('EGFR', 'Gene', '1956', (190, 194))	('BRAF', 'Gene', '673', (168, 172))	('mCRC', 'Disease', (276, 280))	('BRAF', 'Gene', (168, 172))	('patients', 'Species', '9606', (243, 251))	('V600E', 'SUBSTITUTION', 'None', (262, 267))	('EGFR', 'Gene', '1956', (85, 89))	('negative feedback loop', 'MPA', (54, 76))	('cellular proliferation', 'CPA', (106, 128))	('BRAF', 'Gene', '673', (27, 31))	('EGFR', 'Gene', (190, 194))	('BRAF', 'Gene', (257, 261))	('BRAF', 'Gene', '673', (257, 261))	('BRAF', 'Gene', (27, 31))	('disrupts', 'NegReg', (43, 51))	('facilitates', 'PosReg', (94, 105))
343161	34040699	A clinical study investigating the combined inhibition of BRAF V600E with vemurafenib and EGFR with cetuximab + irinotecan in BRAF V600E-mutated mCRC patients is underway (NCT02164916).	('V600E', 'Var', (63, 68))	('irinotecan', 'Chemical', 'MESH:D000077146', (112, 122))	('cetuximab', 'Chemical', 'MESH:D000068818', (100, 109))	('V600E', 'SUBSTITUTION', 'None', (63, 68))	('V600E', 'Var', (131, 136))	('EGFR', 'Gene', '1956', (90, 94))	('patients', 'Species', '9606', (150, 158))	('BRAF', 'Gene', (126, 130))	('EGFR', 'Gene', (90, 94))	('mCRC', 'Disease', (145, 149))	('V600E', 'SUBSTITUTION', 'None', (131, 136))	('BRAF', 'Gene', '673', (126, 130))	('BRAF', 'Gene', '673', (58, 62))	('CRC', 'Phenotype', 'HP:0003003', (146, 149))	('vemurafenib', 'Chemical', 'MESH:D000077484', (74, 85))	('BRAF', 'Gene', (58, 62))
343165	34040699	Novel treatment combinations of BRAF and MEK inhibitors have started to demonstrate activity in early-phase trials of BRAF V600E mutant CRC.	('BRAF', 'Gene', '673', (118, 122))	('BRAF', 'Gene', '673', (32, 36))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('MEK', 'Gene', (41, 44))	('BRAF', 'Gene', (118, 122))	('BRAF', 'Gene', (32, 36))	('MEK', 'Gene', '5609', (41, 44))	('V600E', 'SUBSTITUTION', 'None', (123, 128))	('CRC', 'Disease', (136, 139))	('V600E', 'Var', (123, 128))
343167	34040699	The triple inhibition of EGFR, BRAF, and MEK was evaluated by using panitumumab, dabrafenib, and trametinib, respectively, and the treatment proved to be a tolerable and promising therapeutic strategy for BRAF V600E-mutant CRC, resulting in the overall response rate (ORR) of 21%, and median progression-free survival (PFS) of 4.2 mo.	('BRAF', 'Gene', (205, 209))	('EGFR', 'Gene', (25, 29))	('MEK', 'Gene', (41, 44))	('MEK', 'Gene', '5609', (41, 44))	('dabrafenib', 'Chemical', 'MESH:C561627', (81, 91))	('CRC', 'Phenotype', 'HP:0003003', (223, 226))	('CRC', 'Gene', (223, 226))	('panitumumab', 'Chemical', 'MESH:D000077544', (68, 79))	('V600E', 'Var', (210, 215))	('V600E', 'SUBSTITUTION', 'None', (210, 215))	('trametinib', 'Chemical', 'MESH:C560077', (97, 107))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', '673', (205, 209))	('EGFR', 'Gene', '1956', (25, 29))	('BRAF', 'Gene', (31, 35))
343174	34040699	The primary purpose of this trial is to compare the efficacy and safety of DS-8201a and physician's choice treatment in HER2-positive GC.	('HER2', 'Gene', (120, 124))	('HER2', 'Gene', '2064', (120, 124))	('DS-8201a', 'Chemical', 'MESH:C000614160', (75, 83))	('GC', 'Phenotype', 'HP:0012126', (134, 136))	('DS-8201a', 'Var', (75, 83))
343176	34040699	Ongoing studies are evaluating trastuzumab + pertuzumab vs cetuximab and irinotecan (NCT03365882), and tucatinib (ONT-380; a highly selective small molecule inhibitor of Her-kinase) and trastuzumab in patients with HER2-positive, previously treated advanced CRC (NCT03043313).	('patients', 'Species', '9606', (201, 209))	('pertuzumab', 'Chemical', 'MESH:C485206', (45, 55))	('CRC', 'Phenotype', 'HP:0003003', (258, 261))	('HER2', 'Gene', (215, 219))	('NCT03043313', 'Var', (263, 274))	('trastuzumab', 'Chemical', 'MESH:D000068878', (31, 42))	('HER2', 'Gene', '2064', (215, 219))	('tucatinib', 'Chemical', '-', (103, 112))	('trastuzumab', 'Chemical', 'MESH:D000068878', (186, 197))	('cetuximab', 'Chemical', 'MESH:D000068818', (59, 68))	('irinotecan', 'Chemical', 'MESH:D000077146', (73, 83))
343182	34040699	Hepatocyte growth factor (HGF)-ligand inhibition and silencing HOXB9 is expected to be a promising approach to regulate this resistance.	('HGF', 'Gene', '3082', (26, 29))	('Hepatocyte growth factor', 'Gene', '3082', (0, 24))	('silencing', 'Var', (53, 62))	('inhibition', 'NegReg', (38, 48))	('HOXB9', 'Gene', '3219', (63, 68))	('Hepatocyte growth factor', 'Gene', (0, 24))	('HGF', 'Gene', (26, 29))	('HOXB9', 'Gene', (63, 68))
343199	34040699	To date, erdafitinib was developed for treating patients with advanced or metastatic urothelial cancer with FGFR3 or FGFR2 alterations, accounting for 15%-20% of patients.	('advanced', 'Disease', (62, 70))	('patients', 'Species', '9606', (162, 170))	('urothelial cancer', 'Disease', (85, 102))	('FGFR2', 'Gene', (117, 122))	('FGFR2', 'Gene', '2263', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('FGFR3', 'Gene', '2261', (108, 113))	('patients', 'Species', '9606', (48, 56))	('urothelial cancer', 'Disease', 'MESH:D014523', (85, 102))	('erdafitinib', 'Chemical', 'MESH:C000604580', (9, 20))	('alterations', 'Var', (123, 134))	('FGFR3', 'Gene', (108, 113))
343200	34040699	Erdafitinib is now being evaluated in a multicenter phase II clinical trial which is expected to determine the efficiency of erdafitinib in ECC and GC patients with FGFR translocation or mutation (NCT02699606).	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('FGFR', 'Gene', (165, 169))	('patients', 'Species', '9606', (151, 159))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('ECC', 'Disease', (140, 143))	('erdafitinib', 'Chemical', 'MESH:C000604580', (125, 136))	('mutation', 'Var', (187, 195))	('EC', 'Chemical', '-', (140, 142))
343202	34040699	Despite extensive efforts evaluating the value of PI3K/AKT/mTOR inhibitors in GI cancer (e.g., BEZ235, NVP-BEZ235, OSI-027, MK-2206, KRX-0401, BYL719, and BKM120), several significant problems remain to be clarified regarding the molecular mechanisms underlying the targeting of the PI3K/AKT pathway in GI cancer and overcoming resistance.	('AKT', 'Gene', (55, 58))	('AKT', 'Gene', '207', (288, 291))	('GI cancer', 'Disease', (303, 312))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mTOR', 'Gene', '2475', (59, 63))	('BEZ235', 'Chemical', 'MESH:C531198', (95, 101))	('AKT', 'Gene', '207', (55, 58))	('GI cancer', 'Disease', 'MESH:D009369', (303, 312))	('GI cancer', 'Disease', (78, 87))	('GI cancer', 'Phenotype', 'HP:0007378', (303, 312))	('BEZ235', 'Chemical', 'MESH:C531198', (107, 113))	('BKM120', 'Chemical', 'MESH:C571178', (155, 161))	('AKT', 'Gene', (288, 291))	('MK-2206', 'Chemical', 'MESH:C548887', (124, 131))	('GI cancer', 'Disease', 'MESH:D009369', (78, 87))	('MK-2206', 'Var', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('GI cancer', 'Phenotype', 'HP:0007378', (78, 87))	('KRX', 'Chemical', '-', (133, 136))	('mTOR', 'Gene', (59, 63))
343209	34040699	BYL719 is a selective PI3Kalpha inhibitor that was reported to be equipotent against the wild-type and the most common somatic mutations of PI3Kalpha.	('PI3Kalpha', 'Gene', (140, 149))	('PI3Kalpha', 'Gene', '5290', (22, 31))	('mutations', 'Var', (127, 136))	('PI3Kalpha', 'Gene', (22, 31))	('PI3Kalpha', 'Gene', '5290', (140, 149))
343210	34040699	BYL719 has shown markedly selective efficacy in PIK3CA mutants.	('mutants', 'Var', (55, 62))	('PIK3CA', 'Gene', (48, 54))	('PIK3CA', 'Gene', '5290', (48, 54))
343212	34040699	AZD5363 is a novel AKT kinase inhibitor that has potential based on the genetic status of PIK3CA, PTEN.	('AZD5363', 'Var', (0, 7))	('AKT', 'Gene', '207', (19, 22))	('PIK3CA', 'Gene', (90, 96))	('PTEN', 'Gene', (98, 102))	('AZD5363', 'Chemical', 'MESH:C575618', (0, 7))	('PTEN', 'Gene', '5728', (98, 102))	('AKT', 'Gene', (19, 22))	('PIK3CA', 'Gene', '5290', (90, 96))
343213	34040699	A phase II study of AZD5363 in combination with paclitaxel in patients with GC harboring a PIK3CA mutation or amplification as a second-line chemotherapy was launched in 2015 (NCT02451956).	('PIK3CA', 'Gene', (91, 97))	('mutation', 'Var', (98, 106))	('PIK3CA', 'Gene', '5290', (91, 97))	('GC', 'Phenotype', 'HP:0012126', (76, 78))	('patients', 'Species', '9606', (62, 70))	('AZD5363', 'Chemical', 'MESH:C575618', (20, 27))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))
343219	34040699	In the majority of CRC and GC patients with microsatellite instability (MSI), inactivating mutations in the TGFBR2 gene were shown.	('GC', 'Phenotype', 'HP:0012126', (27, 29))	('CRC', 'Disease', (19, 22))	('TGFBR2', 'Gene', (108, 114))	('patients', 'Species', '9606', (30, 38))	('inactivating mutations', 'Var', (78, 100))	('microsatellite instability', 'MPA', (44, 70))	('TGFBR2', 'Gene', '7048', (108, 114))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))
343220	34040699	Mutations in Smad4, which have been identified in > 30% of CRC patients, have been said to disrupt TGF-beta signaling.	('TGF-beta', 'Gene', '7039', (99, 107))	('CRC', 'Phenotype', 'HP:0003003', (59, 62))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (63, 71))	('disrupt', 'NegReg', (91, 98))	('CRC', 'Disease', (59, 62))	('TGF-beta', 'Gene', (99, 107))	('Smad4', 'Gene', (13, 18))	('Smad4', 'Gene', '4089', (13, 18))
343222	34040699	M7824 (MSB0011359C) is a first-in-class bifunctional fusion protein composed of the extracellular domain of two TGF-beta receptor 2 (TGF-betaR2) molecules that serve as a TGF-beta sequestering or trap molecule fused to a fully humanized mAb against PD-L1.	('TGF-beta', 'Gene', '7039', (112, 120))	('TGF-beta', 'Gene', '7039', (133, 141))	('PD-L1', 'Gene', (249, 254))	('TGF-beta', 'Gene', '7039', (171, 179))	('human', 'Species', '9606', (227, 232))	('M7824', 'Chemical', '-', (0, 5))	('M7824', 'Var', (0, 5))	('PD-L1', 'Gene', '29126', (249, 254))	('TGF-beta', 'Gene', (133, 141))	('TGF-beta', 'Gene', (112, 120))	('TGF-beta', 'Gene', (171, 179))
343223	34040699	M7824 simultaneously blocks the PD-L1 and TGF-beta pathways of immune evasion.	('TGF-beta', 'Gene', (42, 50))	('PD-L1', 'Gene', (32, 37))	('M7824', 'Chemical', '-', (0, 5))	('TGF-beta', 'Gene', '7039', (42, 50))	('blocks', 'NegReg', (21, 27))	('M7824', 'Var', (0, 5))	('PD-L1', 'Gene', '29126', (32, 37))
343224	34040699	A phase 1 trial of M7824 with 19 patients with heavily pretreated advanced solid tumors, including CRC, revealed a manageable safety profile comparable to other anti-PD-1/PD-L1 antibodies (NCT02517398).	('M7824', 'Var', (19, 24))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('patients', 'Species', '9606', (33, 41))	('M7824', 'Chemical', '-', (19, 24))	('PD-L1', 'Gene', (171, 176))	('CRC', 'Disease', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('PD-L1', 'Gene', '29126', (171, 176))	('PD-1', 'Gene', (166, 170))	('CRC', 'Phenotype', 'HP:0003003', (99, 102))	('PD-1', 'Gene', '5133', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
343234	34040699	A potent and selective MET inhibitor, savolitinib, is being investigated in a phase II trial in patients with MET-amplified CRC (NCT03593641).	('MET', 'Gene', (23, 26))	('CRC', 'Disease', (124, 127))	('MET', 'Gene', '79811', (110, 113))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('MET', 'Gene', (110, 113))	('patients', 'Species', '9606', (96, 104))	('MET', 'Gene', '79811', (23, 26))	('NCT03593641', 'Var', (129, 140))	('savolitinib', 'Chemical', 'MESH:C000593259', (38, 49))
343237	34040699	Mutations of RNF43 and R-spondin fusion proteins, which mutually exclusively occur with APC mutations in CRC, were subsequently identified as a predictor of effective therapy targeting Wnt secretion.	('APC', 'Disease', 'MESH:D011125', (88, 91))	('APC', 'Disease', (88, 91))	('mutations', 'Var', (92, 101))	('R-spondin', 'Protein', (23, 32))	('RNF43', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('CRC', 'Gene', (105, 108))	('RNF43', 'Gene', '54894', (13, 18))
343238	34040699	Based on these results, a phase I/II trial of LGK974 was initiated for patients with mCRC harboring mutations of RNF43 or R-spondin fusions.	('mutations', 'Var', (100, 109))	('patients', 'Species', '9606', (71, 79))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('RNF43', 'Gene', '54894', (113, 118))	('RNF43', 'Gene', (113, 118))	('R-spondin', 'Protein', (122, 131))
343240	34040699	A current phase I/II study is evaluating the orally bioavailable and specific porcupine inhibitor WNT974 in patients with mCRC with BRAF V600 and ring finger protein 43 mutations or RSPO fusions, in combination with a BRAF inhibitor and anti-EGFR agent to mitigate acquired resistance through the Wnt-beta-catenin pathway (NCT02278133).	('BRAF', 'Gene', (132, 136))	('mutations', 'Var', (169, 178))	('RSPO', 'Gene', (182, 186))	('BRAF', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (218, 222))	('RSPO', 'Gene', '284654', (182, 186))	('EGFR', 'Gene', '1956', (242, 246))	('CRC', 'Phenotype', 'HP:0003003', (123, 126))	('WNT974', 'Gene', (98, 104))	('V600', 'Var', (137, 141))	('beta-catenin', 'Gene', (301, 313))	('EGFR', 'Gene', (242, 246))	('patients', 'Species', '9606', (108, 116))	('BRAF', 'Gene', '673', (132, 136))	('beta-catenin', 'Gene', '1499', (301, 313))	('mitigate', 'NegReg', (256, 264))	('acquired resistance', 'MPA', (265, 284))
343242	34040699	Foxy-5 is currently being tested in a resected CRC setting in the Neo Fox trial, in which standard therapy (surgery + FOLFOX 6-month regimen) + neo-adjuvant administration of Foxy-5 prior to and following surgery is being compared to standard therapy alone in patients with Wnt-5a low CRC (NCT03883802).	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('Wnt-5a', 'Gene', '7474', (274, 280))	('CRC', 'Phenotype', 'HP:0003003', (285, 288))	('patients', 'Species', '9606', (260, 268))	('NCT03883802', 'Var', (290, 301))	('Wnt-5a', 'Gene', (274, 280))
343258	34040699	Gene fusion is the most frequent molecular alteration occurring in this gene across different tumor types including GI cancer.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GI cancer', 'Disease', 'MESH:D009369', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (94, 99))	('GI cancer', 'Phenotype', 'HP:0007378', (116, 125))	('frequent', 'Reg', (24, 32))	('Gene fusion', 'Var', (0, 11))	('GI cancer', 'Disease', (116, 125))
343267	34040699	Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are orally bioavailable drugs that have been explored as anticancer agents.	('inhibitors', 'Var', (37, 47))	('CDK4/6', 'Gene', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('Cyclin-dependent kinase 4/6', 'Gene', '1019;1021', (0, 27))	('Cyclin-dependent kinase 4/6', 'Gene', (0, 27))	('cancer', 'Disease', (109, 115))	('CDK4/6', 'Gene', '1019;1021', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
343273	34040699	In hepatocellular carcinoma, epigenetic therapy with belinostat, a potent HDAC inhibitor, demonstrated that a 58% disease stabilization rate (i.e., CR + PR + SD) in tumors with high and low HR23B histoscores.	('disease stabilization', 'CPA', (114, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('low', 'Var', (186, 189))	('high', 'Var', (177, 181))	('tumors', 'Disease', (165, 171))	('HR23B', 'Gene', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('belinostat', 'Chemical', 'MESH:C487081', (53, 63))	('HR23B', 'Gene', '5887', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
343286	34040699	However, recent clinical trials using established inhibitors against HSP90 demonstrated limited clinical efficacy when the inhibitors were used as a monotherapy.	('HSP90', 'Gene', (69, 74))	('HSP90', 'Gene', '3320', (69, 74))	('inhibitors', 'Var', (50, 60))
343293	34040699	Immunotherapy has been shown to be aggressive in tumors containing a high mutation as confirmed in melanoma and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('high mutation', 'Var', (69, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (99, 123))
343294	34040699	An increased amount of mutations is responsible for the production of neoantigens, which leads to enhanced tumor immunogenicity.	('neoantigens', 'MPA', (70, 81))	('enhanced', 'PosReg', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
343302	34040699	ARID1A alterations are significantly associated with EBV infection, which in turn leads to longer PFS after anti-PD-1/PD-L1 immunotherapy, regardless of the microsatellite and tumor mutational burden status.	('PD-1', 'Gene', '5133', (113, 117))	('longer', 'PosReg', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PFS', 'MPA', (98, 101))	('PD-L1', 'Gene', (118, 123))	('ARID1A', 'Gene', '8289', (0, 6))	('tumor', 'Disease', (176, 181))	('PD-L1', 'Gene', '29126', (118, 123))	('ARID1A', 'Gene', (0, 6))	('associated', 'Reg', (37, 47))	('EBV infection', 'Disease', (53, 66))	('EBV infection', 'Disease', 'MESH:D020031', (53, 66))	('alterations', 'Var', (7, 18))	('PD-1', 'Gene', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
343305	34040699	Camrelizumab + apatinib in combination with liposomal paclitaxel and nedaplatin could be a new treatment option for patients with unresectable locally advanced or metastatic ESCC (NCT03603756).	('apatinib', 'Chemical', 'MESH:C553458', (15, 23))	('patients', 'Species', '9606', (116, 124))	('NCT03603756', 'Var', (180, 191))	('metastatic', 'CPA', (163, 173))	('ESCC', 'Disease', (174, 178))	('paclitaxel', 'Chemical', 'MESH:D017239', (54, 64))	('nedaplatin', 'Chemical', 'MESH:C053989', (69, 79))	('locally advanced', 'Disease', (143, 159))
343314	34040699	Traditionally, the advancement of such cancer vaccines started with peptides derived from tumor-associated antigens (TAAs), tumor-specific antigens, and cancer testis antigens.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer testis', 'Phenotype', 'HP:0010788', (153, 166))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', (153, 159))	('peptides', 'Var', (68, 76))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('TAAs', 'Disease', (117, 121))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (124, 129))	('TAAs', 'Disease', 'None', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
343337	34040699	Crizotinib is also currently being investigated in a clinical trial evaluating the efficacy of poziotinib in patients with mCRC and ALK mutation who have failed two or three lines of therapy (NCT03792568).	('patients', 'Species', '9606', (109, 117))	('mCRC', 'Gene', (123, 127))	('poziotinib', 'Chemical', 'MESH:C557213', (95, 105))	('mutation', 'Var', (136, 144))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('ALK', 'Gene', '238', (132, 135))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('ALK', 'Gene', (132, 135))
343338	34040699	Multi-kinase inhibitors, which broadly inhibit cancer-related kinases, also carry the risk of inhibiting kinases whose function is unknown.	('kinases', 'MPA', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('inhibit', 'NegReg', (39, 46))	('cancer', 'Disease', (47, 53))	('Multi-kinase', 'Var', (0, 12))	('inhibiting', 'NegReg', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
343345	34040699	The triple inhibition of EGFR, BRAF and MEK demonstrated synergistic activity for BRAF V600E-mutant CRC.	('MEK', 'Gene', '5609', (40, 43))	('CRC', 'Gene', (100, 103))	('EGFR', 'Gene', (25, 29))	('V600E', 'Var', (87, 92))	('BRAF', 'Gene', '673', (82, 86))	('CRC', 'Phenotype', 'HP:0003003', (100, 103))	('BRAF', 'Gene', (82, 86))	('V600E', 'SUBSTITUTION', 'None', (87, 92))	('BRAF', 'Gene', '673', (31, 35))	('EGFR', 'Gene', '1956', (25, 29))	('MEK', 'Gene', (40, 43))	('BRAF', 'Gene', (31, 35))
343385	33604380	In particular, evaluation of the mutations in immune cells is capable of predicting the outcome of patients with cancerous tumors.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous tumors', 'Disease', 'MESH:D009369', (113, 129))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (99, 107))	('cancerous tumors', 'Disease', (113, 129))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
343395	33604380	We discovered that the related immune cell infiltration signatures were differently expressed between low and high CDCA3 expression groups.	('CDCA3', 'Gene', (115, 120))	('high', 'Var', (110, 114))	('CDCA3', 'Gene', '83461', (115, 120))
343396	33604380	We also found that the higher proportion of CD8+ T cells, CD4+ T cells, and B cells appeared in the high CDCA3 expression group.	('CD8', 'Gene', (44, 47))	('CD8', 'Gene', '925', (44, 47))	('CD4', 'Gene', '920', (58, 61))	('CDCA3', 'Gene', '83461', (105, 110))	('high', 'Var', (100, 104))	('CDCA3', 'Gene', (105, 110))	('CD4', 'Gene', (58, 61))
343397	33604380	Our data suggested that the high CDCA3 expression promoted the infiltration of T cells and exhausted these cells, and the patients with high CDCA3 expression might have poorer outcomes by analyzing the information of HCC patients obtained from The Cancer Genome Atlas (TCGA) database.	('CDCA3', 'Gene', '83461', (141, 146))	('patients', 'Species', '9606', (221, 229))	('promoted', 'PosReg', (50, 58))	('CDCA3', 'Gene', (141, 146))	('expression', 'Var', (39, 49))	('CDCA3', 'Gene', '83461', (33, 38))	('CDCA3', 'Gene', (33, 38))	('patients', 'Species', '9606', (122, 130))	('Cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Cancer', 'Disease', (248, 254))	('high', 'Var', (28, 32))	('Cancer', 'Disease', 'MESH:D009369', (248, 254))	('HCC', 'Phenotype', 'HP:0001402', (217, 220))	('infiltration of T cells', 'CPA', (63, 86))
343407	33604380	Significance of HR referred to the ratio of risk rate produced by high CDCA3 expression to the risk rate produced by low CDCA3 expression, on the premise that p < 0.05.	('expression', 'MPA', (77, 87))	('CDCA3', 'Gene', (121, 126))	('CDCA3', 'Gene', '83461', (71, 76))	('CDCA3', 'Gene', (71, 76))	('high', 'Var', (66, 70))	('CDCA3', 'Gene', '83461', (121, 126))
343408	33604380	The higher the HR value, the bigger the ratio of risk rate produced by high CDCA3 expression on survival.	('CDCA3', 'Gene', '83461', (76, 81))	('expression', 'MPA', (82, 92))	('high', 'Var', (71, 75))	('CDCA3', 'Gene', (76, 81))	('HR value', 'MPA', (15, 23))
343419	33604380	Here, we established a standard to describe the association between CDCA3 expression and gene markers of infiltrating immune cells, where 0.00-0.29 was considered weak, 0.30-0.59 was considered moderate, 0.60-0.79 was considered strong, and 0.80-1.00 was considered very strong expression.	('CDCA3', 'Gene', '83461', (68, 73))	('0.30-0.59', 'Var', (169, 178))	('association', 'Interaction', (48, 59))	('CDCA3', 'Gene', (68, 73))
343425	33604380	Here, logrank p < 0.05 was statistically significant, and significance of HR referred to the ratio of risk rate produced by the application of high expression of CDCA3 to the risk rate produced by low expression of CDCA3.	('CDCA3', 'Gene', '83461', (162, 167))	('high expression', 'Var', (143, 158))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (215, 220))	('CDCA3', 'Gene', '83461', (215, 220))
343447	33604380	As revealed by PPS (HR = 0.67, 95%CI = 0.54-0.84, p = 0.00038) (Figure 2(j)), the high CDCA3 expression was associated with the better prognosis in gastric cancer because the HR < 1 and p < 0.05.	('PPS', 'Chemical', '-', (15, 18))	('gastric cancer', 'Disease', (148, 162))	('CDCA3', 'Gene', (87, 92))	('high', 'Var', (82, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('expression', 'MPA', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CDCA3', 'Gene', '83461', (87, 92))
343450	33604380	These results indicated that a high expression of CDCA3 had a strong association with poor outcomes for patients with various cancers, especially in HCC, and the correlation depended on the type of tumor.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HCC', 'Phenotype', 'HP:0001402', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('CDCA3', 'Gene', '83461', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancers', 'Disease', (126, 133))	('CDCA3', 'Gene', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('high', 'Var', (31, 35))	('tumor', 'Disease', (198, 203))	('patients', 'Species', '9606', (104, 112))	('expression', 'MPA', (36, 46))	('HCC', 'Disease', (149, 152))
343457	33604380	p < 0.05 was statistically significant, and the hazard ratio > 1 represented the higher risk factors produced by high CDCA3 expression affected in the prognosis of patients with different clinicopathologic features.	('high', 'Var', (113, 117))	('CDCA3', 'Gene', '83461', (118, 123))	('CDCA3', 'Gene', (118, 123))	('expression', 'MPA', (124, 134))	('patients', 'Species', '9606', (164, 172))	('affected', 'Reg', (135, 143))
343461	33604380	It was remarkable that the hazard ratio (HR) of CDCA3 expression in univariate analysis equaled to 2.075, the value of HR and the p < 0.001 both indicated that CDCA3 can predict the prognosis in HCC, and the hazard ratio revealed that the patients with high CDCA3 expression had 2.075 times of higher risk in poor OS than the patients with low CDCA3 expression in univariate analysis.	('CDCA3', 'Gene', (258, 263))	('high', 'Var', (253, 257))	('CDCA3', 'Gene', (48, 53))	('CDCA3', 'Gene', '83461', (344, 349))	('poor OS', 'Disease', (309, 316))	('CDCA3', 'Gene', (344, 349))	('patients', 'Species', '9606', (239, 247))	('patients', 'Species', '9606', (326, 334))	('CDCA3', 'Gene', '83461', (160, 165))	('CDCA3', 'Gene', (160, 165))	('HCC', 'Disease', (195, 198))	('HCC', 'Phenotype', 'HP:0001402', (195, 198))	('expression', 'Var', (264, 274))	('CDCA3', 'Gene', '83461', (258, 263))	('CDCA3', 'Gene', '83461', (48, 53))
343463	33604380	The results showed that high expression of CDCA3 was associated with poor outcomes in HCC patients, and it could act as a potential independent predictor of survival (HR = 2.037; 95%CI = 1.484-2.796; p < 0.001; Figure 3(d)) by excluding confounding factors.	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('high', 'Var', (24, 28))	('HCC', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
343464	33604380	Besides, the value of the hazard ratio revealed that the patients with high CDCA3 expression had 2.037 times of higher risk in poor OS than the patients with low CDCA3 expression.	('poor OS', 'Disease', (127, 134))	('CDCA3', 'Gene', '83461', (162, 167))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (76, 81))	('expression', 'Var', (82, 92))	('patients', 'Species', '9606', (144, 152))
343471	33604380	The results showed that high expression of CDCA3 was associated with poor prognosis of patients, high levels of infiltrating immune cells, and tumor purity in HCC and ACC.	('tumor', 'Disease', (143, 148))	('patients', 'Species', '9606', (87, 95))	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('ACC', 'Phenotype', 'HP:0006744', (167, 170))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('expression', 'MPA', (29, 39))	('HCC', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
343474	33604380	The high CDCA3 expression was also correlated with a poorer survival (OS: HR = 2.5, p = 6.4E - 07; DFS: HR = 1.8, p = 0.00026) (Figure S1 ac-ad) but was positively related to the infiltrating levels of B cells (partial cor = 0.252, p = 2.42E - 08), CD4+ T cells (partial cor = 0.222, p = 1.01E - 06), macrophages (partial cor = 0.207, p = 5.93E - 06), neutrophils (partial cor = 0.174, p = 1.35E - 04), and dendritic cells (partial cor = 0.229, p = 4.54E - 07) in LGG (Figure S2 s).	('CDCA3', 'Gene', '83461', (9, 14))	('CDCA3', 'Gene', (9, 14))	('related', 'Reg', (164, 171))	('expression', 'MPA', (15, 25))	('high', 'Var', (4, 8))	('CD4', 'Gene', (249, 252))	('CD4', 'Gene', '920', (249, 252))
343502	33604380	According to the univariate and multivariate analyses, we identified that T stage, M stage, and CDCA3 expression had significant prognostic values for predicting the survival of patients with HCC; in fact, the high expression determined poor OS of patients with HCC and suggested that increased CDCA3 expression deteriorated the state of patients with HCC.	('HCC', 'Phenotype', 'HP:0001402', (262, 265))	('HCC', 'Disease', (352, 355))	('CDCA3', 'Gene', (96, 101))	('increased', 'PosReg', (285, 294))	('HCC', 'Phenotype', 'HP:0001402', (352, 355))	('patients', 'Species', '9606', (178, 186))	('determined', 'Reg', (226, 236))	('HCC', 'Phenotype', 'HP:0001402', (192, 195))	('high', 'Var', (210, 214))	('CDCA3', 'Gene', '83461', (295, 300))	('patients', 'Species', '9606', (338, 346))	('patients', 'Species', '9606', (248, 256))	('HCC', 'Disease', (262, 265))	('CDCA3', 'Gene', (295, 300))	('CDCA3', 'Gene', '83461', (96, 101))
343506	33604380	Thus, CDCA3 expression can potentially influence the immunosuppressive effect in HCC.	('influence', 'Reg', (39, 48))	('HCC', 'Disease', (81, 84))	('expression', 'Var', (12, 22))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('immunosuppressive', 'MPA', (53, 70))	('CDCA3', 'Gene', '83461', (6, 11))	('CDCA3', 'Gene', (6, 11))
343517	33604380	According to the results of the univariate and multivariate analyses, T stage, M stage, and CDCA3 expression were important prognostic factors for the survival of patients with HCC; importantly, high CDCA3 expression had the potential to be an independent predictor for poor outcome for patients with HCC according to the results of multivariate analyses.	('patients', 'Species', '9606', (163, 171))	('HCC', 'Disease', (301, 304))	('CDCA3', 'Gene', '83461', (200, 205))	('expression', 'MPA', (206, 216))	('HCC', 'Phenotype', 'HP:0001402', (177, 180))	('HCC', 'Phenotype', 'HP:0001402', (301, 304))	('patients', 'Species', '9606', (287, 295))	('CDCA3', 'Gene', (200, 205))	('CDCA3', 'Gene', '83461', (92, 97))	('high', 'Var', (195, 199))	('CDCA3', 'Gene', (92, 97))
343744	32385885	Another line of investigation by this group showed that F. nucleatum potentiates intestinal tumorigenesis by modulating the antitumor immune system.108 Fusobacterium nucleatum were shown to expand myeloid-derived immune cell types such as Fox-alpha3 and T-reg cells that promote tumor progression by suppressing cytotoxic and effector T cells, thus diminishing local antitumor immunity.	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Disease', (371, 376))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', (92, 97))	('Fusobacterium nucleatum', 'Species', '851', (152, 175))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Fusobacterium', 'Var', (152, 165))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('suppressing', 'NegReg', (300, 311))	('promote', 'PosReg', (271, 278))	('diminishing', 'NegReg', (349, 360))	('F. nucleatum', 'Species', '851', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
343750	32385885	They also found that the abundance of P. gingivalis trended with a higher risk of esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('P. gingivalis', 'Species', '837', (38, 51))	('P. gingivalis', 'Var', (38, 51))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))
343751	32385885	These results are consistent with the findings of Gao et al,114 who reported that P. gingivalis was found in 61% of their samples of esophageal tissues from patients with esophageal squamous cell carcinoma, but was not detected in normal esophageal mucosa.	('P. gingivalis', 'Species', '837', (82, 95))	('esophageal squamous cell carcinoma', 'Disease', (171, 205))	('patients', 'Species', '9606', (157, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (171, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('P. gingivalis', 'Var', (82, 95))
343756	32385885	In a similar fashion, using data based on the National Health and Nutrition Examination Survey I study, Scannapieco et al146 found that poor oral hygiene was linked to chronic respiratory disease (n = 23 808; cases of chronic respiratory disease, n = 386).	('respiratory disease', 'Disease', (176, 195))	('respiratory disease', 'Disease', (226, 245))	('respiratory disease', 'Phenotype', 'HP:0011947', (176, 195))	('poor', 'Var', (136, 140))	('respiratory disease', 'Disease', 'MESH:D012140', (176, 195))	('poor oral', 'Phenotype', 'HP:0000160', (136, 145))	('al1', 'Species', '999426', (119, 122))	('respiratory disease', 'Disease', 'MESH:D012140', (226, 245))	('linked', 'Reg', (158, 164))	('respiratory disease', 'Phenotype', 'HP:0011947', (226, 245))
343759	32385885	Over time, the chronic stimulus from the diseased periodontium could lead to the generation of persistent, low-grade inflammation that may contribute to the carcinogenic process.80, 162 This is a likely mechanism through which periodontal disease may be linked to an increased risk of cancer.	('process.80', 'Var', (170, 180))	('periodontal disease', 'Disease', (227, 246))	('inflammation', 'Disease', (117, 129))	('periodontal disease', 'Disease', 'MESH:D010510', (227, 246))	('carcinogenic', 'Disease', 'MESH:D063646', (157, 169))	('inflammation', 'Disease', 'MESH:D007249', (117, 129))	('carcinogenic', 'Disease', (157, 169))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('diseased periodontium', 'Phenotype', 'HP:0000704', (41, 62))	('periodontal disease', 'Phenotype', 'HP:0000704', (227, 246))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('linked', 'Reg', (254, 260))
343872	27920560	Inclusion criteria were histologically confirmed stage III non-small cell lung cancer, receipt of definitive RT with or without chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status <=2, no previous history of thoracic RT, no distant metastasis, no previous or concurrent illness that would compromise completion of treatment, and available follow-up data.	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('non-small cell lung cancer', 'Disease', (59, 85))	('<=2', 'Var', (203, 206))	('Oncology', 'Phenotype', 'HP:0002664', (162, 170))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))
343925	27920560	Some studies reported that IMRT increases the amount of normal lung tissue exposed to a low dose of radiation and could potentially increase the risk of radiation pneumonitis.	('pneumonitis', 'Disease', 'MESH:D011014', (163, 174))	('IMRT', 'Var', (27, 31))	('pneumonitis', 'Disease', (163, 174))	('increases', 'PosReg', (32, 41))
343944	27357907	Phosphoinositide-3-kinase (PI3K) inhibitor, LY294002 suppressed p-AKT and p-mTOR, indicating PI3K is a common upstream mediator.	('AKT', 'Gene', (66, 69))	('mTOR', 'Gene', (76, 80))	('LY294002', 'Chemical', 'MESH:C085911', (44, 52))	('mTOR', 'Gene', '2475', (76, 80))	('LY294002', 'Var', (44, 52))	('AKT', 'Gene', '207', (66, 69))	('suppressed', 'NegReg', (53, 63))
343960	27357907	PI3K promotes tumor cell survival by triggering the activation of downstream mediators of AKT.	('PI3K', 'Var', (0, 4))	('tumor', 'Disease', (14, 19))	('AKT', 'Gene', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('promotes', 'PosReg', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('AKT', 'Gene', '207', (90, 93))	('activation', 'PosReg', (52, 62))
343964	27357907	mTOR is directly activated by AKT via phosphorylated at Ser2448, and can be indirectly activated by phosphorylation and inactivation of tuberous sclerosis complex 2, also termed tuberin, by AKT.	('Ser2448', 'Chemical', '-', (56, 63))	('AKT', 'Gene', '207', (190, 193))	('mTOR', 'Gene', '2475', (0, 4))	('AKT', 'Gene', '207', (30, 33))	('tuberin', 'Gene', '7249', (178, 185))	('activated', 'PosReg', (17, 26))	('tuberous sclerosis', 'Disease', (136, 154))	('AKT', 'Gene', (190, 193))	('Ser2448', 'Var', (56, 63))	('AKT', 'Gene', (30, 33))	('tuberin', 'Gene', (178, 185))	('inactivation', 'NegReg', (120, 132))	('mTOR', 'Gene', (0, 4))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (136, 154))
343973	27357907	A PI3K inhibitor, LY294002, and AKT inhibitor, triciribine, were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA).	('triciribine', 'Chemical', 'MESH:C023764', (47, 58))	('AKT', 'Gene', '207', (32, 35))	('LY294002', 'Var', (18, 26))	('AKT', 'Gene', (32, 35))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))
344011	27357907	EC109 cells that are not treated with VES express high levels of p-AKT, and downstream substrates p-Bad and p-caspase-9 (Fig.	('caspase-9', 'Gene', (110, 119))	('AKT', 'Gene', '207', (67, 70))	('p-Bad', 'Var', (98, 103))	('AKT', 'Gene', (67, 70))	('VES', 'Chemical', 'MESH:D024502', (38, 41))	('caspase-9', 'Gene', '842', (110, 119))	('EC109', 'CellLine', 'CVCL:6898', (0, 5))
344012	27357907	EC109 cells were treated with 25 microM VES for 12, 24 and 48 h, which reduced levels of p-AKT (Ser473/Thr308), p-Bad (Ser136), and p-caspase-9 (Ser196) in a time-dependent manner (Fig.	('Ser136', 'Chemical', '-', (119, 125))	('caspase-9', 'Gene', '842', (134, 143))	('VES', 'Chemical', 'MESH:D024502', (40, 43))	('AKT', 'Gene', '207', (91, 94))	('Thr308', 'Chemical', '-', (103, 109))	('Ser136', 'Var', (119, 125))	('AKT', 'Gene', (91, 94))	('caspase-9', 'Gene', (134, 143))	('Ser473/Thr308', 'Var', (96, 109))	('reduced', 'NegReg', (71, 78))	('p-Bad', 'MPA', (112, 117))	('Ser196', 'Var', (145, 151))	('EC109', 'CellLine', 'CVCL:6898', (0, 5))	('Ser196', 'Chemical', '-', (145, 151))	('Ser473', 'Chemical', '-', (96, 102))
344013	27357907	It also downregulated p-mTOR (Ser2448) and its substrates p-p70S6K (Thr389) and p-4E-BP1 (Thr37/46; Fig.	('Ser2448', 'Var', (30, 37))	('Thr37', 'Chemical', '-', (90, 95))	('4E-BP1', 'Gene', '1978', (82, 88))	('p70S6K', 'Gene', (60, 66))	('p70S6K', 'Gene', '6198', (60, 66))	('Ser2448', 'Chemical', '-', (30, 37))	('Thr389', 'Chemical', '-', (68, 74))	('4E-BP1', 'Gene', (82, 88))	('Thr389', 'Var', (68, 74))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))	('downregulated', 'NegReg', (8, 21))
344015	27357907	To investigate the underlying mechanisms of regulation of the levels of p-AKT and p-mTOR, EC109 cells were treated with 2 microM PI3K inhibitor LY294002 for 12 h. LY294002 decreased the p-AKT and its substrates p-Bad (Ser136) and p-caspase-9 (Ser196; Fig.	('caspase-9', 'Gene', '842', (232, 241))	('Ser196', 'Chemical', '-', (243, 249))	('p-Bad', 'Protein', (211, 216))	('decreased', 'NegReg', (172, 181))	('AKT', 'Gene', '207', (74, 77))	('caspase-9', 'Gene', (232, 241))	('EC109', 'CellLine', 'CVCL:6898', (90, 95))	('Ser136', 'Chemical', '-', (218, 224))	('LY294002', 'Var', (163, 171))	('mTOR', 'Gene', '2475', (84, 88))	('mTOR', 'Gene', (84, 88))	('LY294002', 'Chemical', 'MESH:C085911', (144, 152))	('AKT', 'Gene', '207', (188, 191))	('AKT', 'Gene', (74, 77))	('AKT', 'Gene', (188, 191))	('LY294002', 'Chemical', 'MESH:C085911', (163, 171))
344016	27357907	4A), in addition to p-mTOR (Ser2448) and its substrate p-p70S6 K (Thr389) (Fig.	('p70S6 K', 'Gene', '6198', (57, 64))	('p70S6 K', 'Gene', (57, 64))	('Ser2448', 'Var', (28, 35))	('mTOR', 'Gene', '2475', (22, 26))	('mTOR', 'Gene', (22, 26))	('Thr389', 'Chemical', '-', (66, 72))	('Ser2448', 'Chemical', '-', (28, 35))
344019	27357907	VES and the PI3K inhibitor decreased the expression levels of p-AKT and p-mTOR, and the combination of VES + PI3K inhibitor synergistically decreased expression levels of p-AKT and p-mTOR in comparison with individual treatments or the control (Fig.	('decreased', 'NegReg', (140, 149))	('expression levels', 'MPA', (41, 58))	('mTOR', 'Gene', (183, 187))	('mTOR', 'Gene', '2475', (183, 187))	('men', 'Species', '9606', (223, 226))	('AKT', 'Gene', '207', (173, 176))	('decreased', 'NegReg', (27, 36))	('VES', 'Chemical', 'MESH:D024502', (0, 3))	('mTOR', 'Gene', (74, 78))	('AKT', 'Gene', (173, 176))	('AKT', 'Gene', '207', (64, 67))	('mTOR', 'Gene', '2475', (74, 78))	('AKT', 'Gene', (64, 67))	('VES', 'Chemical', 'MESH:D024502', (103, 106))	('expression levels', 'MPA', (150, 167))	('combination', 'Var', (88, 99))
344038	27357907	The present study demonstrated that inhibition of PI3K/AKT signaling potentiates VES-induced apoptosis in esophageal cancer cells.	('VES', 'Chemical', 'MESH:D024502', (81, 84))	('VES-induced apoptosis', 'CPA', (81, 102))	('AKT', 'Gene', (55, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('inhibition', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('AKT', 'Gene', '207', (55, 58))	('esophageal cancer', 'Disease', (106, 123))	('potentiates', 'PosReg', (69, 80))
344041	27357907	Phosphorylation of Bad at Ser112 and Ser136 blocks its binding with Bcl-2 or Bcl-xL, promoting cell growth.	('blocks', 'NegReg', (44, 50))	('Bcl-xL', 'Gene', (77, 83))	('Ser136', 'Var', (37, 43))	('Ser112', 'Chemical', '-', (26, 32))	('Phosphorylation', 'Var', (0, 15))	('promoting', 'PosReg', (85, 94))	('cell growth', 'CPA', (95, 106))	('binding', 'Interaction', (55, 62))	('Ser136', 'Chemical', '-', (37, 43))	('Ser112', 'Var', (26, 32))	('Bcl-xL', 'Gene', '598', (77, 83))	('Bcl-2', 'Gene', (68, 73))	('Bcl-2', 'Gene', '596', (68, 73))
344044	27357907	In addition, LY294002 inhibition of PI3K reduced phosphorylation of Bad at Ser136, which suggested PI3K was involved in the regulation of AKT in esophageal cancer cells.	('reduced', 'NegReg', (41, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('Bad', 'Protein', (68, 71))	('AKT', 'Gene', (138, 141))	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('esophageal cancer', 'Disease', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('involved', 'Reg', (108, 116))	('phosphorylation', 'MPA', (49, 64))	('LY294002 inhibition', 'Var', (13, 32))	('Ser136', 'Chemical', '-', (75, 81))	('AKT', 'Gene', '207', (138, 141))
344046	27357907	It has been reported that AKT is involved in the inactivation of caspase-9 by phosphorylating caspase-9 at Ser196.	('caspase-9', 'Gene', (94, 103))	('AKT', 'Gene', '207', (26, 29))	('caspase-9', 'Gene', '842', (65, 74))	('Ser196', 'Var', (107, 113))	('caspase-9', 'Gene', '842', (94, 103))	('Ser196', 'Chemical', '-', (107, 113))	('AKT', 'Gene', (26, 29))	('caspase-9', 'Gene', (65, 74))	('phosphorylating', 'MPA', (78, 93))
344048	27357907	Thus, VES suppresses AKT activity to downregulate phosphorylation of caspase-9 at Ser196, and then contributes to mitochondria-dependent apoptosis.	('phosphorylation', 'MPA', (50, 65))	('contributes', 'Reg', (99, 110))	('downregulate', 'NegReg', (37, 49))	('Ser196', 'Chemical', '-', (82, 88))	('caspase-9', 'Gene', (69, 78))	('Ser196', 'Var', (82, 88))	('caspase-9', 'Gene', '842', (69, 78))	('VES', 'Chemical', 'MESH:D024502', (6, 9))	('AKT', 'Gene', '207', (21, 24))	('mitochondria-dependent', 'MPA', (114, 136))	('suppresses', 'NegReg', (10, 20))	('AKT', 'Gene', (21, 24))
344091	26331012	This third theory has been genetically demonstrated by the TP53 mutation analysis of carcinosarcoma.	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (59, 63))	('carcinosarcoma', 'Disease', (85, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('carcinosarcoma', 'Disease', 'MESH:D002296', (85, 99))	('TP53', 'Gene', '7157', (59, 63))
344151	24550648	To define the presence of LN recurrence in this study, the criteria on CT scans were: 1) cervical, mediastinal and upper abdominal LNs >=10 mm in short-axis diameter except the LNs in the subdiaphragmatic nodes >=8 mm, retropharyngeal nodes >=5 mm and supraclavicular regions >=5 mm; 2) a nodal mass with the central low-density necrosis strengthening the ring on enhanced CT; and 3) multiple nodes or an ill-defined mass in any level fusion in a LN area.	('>=10', 'Var', (135, 139))	('necrosis', 'Disease', (329, 337))	('necrosis', 'Disease', 'MESH:D009336', (329, 337))
344261	32650561	Eradication of H. pylori have coincided with increased prevalence of GERD and increased risk of BE.	('GERD', 'Disease', (69, 73))	('Eradication', 'Var', (0, 11))	('H. pylori', 'Gene', (15, 24))	('H. pylori', 'Species', '210', (15, 24))	('BE', 'Phenotype', 'HP:0100580', (96, 98))
344270	32650561	The effects of PPI treatment on the NERD and RE proteome showed reduced levels of protein disulfide isomerase and serum albumin associated with stress response and detoxication, respectively.	('albumin', 'Gene', (120, 127))	('PPI', 'Var', (15, 18))	('levels', 'MPA', (72, 78))	('albumin', 'Gene', '213', (120, 127))	('protein disulfide isomerase', 'Gene', '5034', (82, 109))	('stress', 'Disease', 'MESH:D000079225', (144, 150))	('reduced levels of protein disulfide isomerase', 'Phenotype', 'HP:0003568', (64, 109))	('reduced', 'NegReg', (64, 71))	('protein disulfide isomerase', 'Gene', (82, 109))	('stress', 'Disease', (144, 150))
344271	32650561	On the one hand, reduction of esophageal acid exposure by PPI decreases inflammation and proliferation.	('proliferation', 'CPA', (89, 102))	('decreases', 'NegReg', (62, 71))	('inflammation', 'Disease', (72, 84))	('esophageal acid exposure', 'MPA', (30, 54))	('PPI', 'Var', (58, 61))	('reduction', 'NegReg', (17, 26))	('inflammation', 'Disease', 'MESH:D007249', (72, 84))
344272	32650561	On the other hand, PPI therapy interferes with esophageal exposure to secondary bile acids, increases circulating gastrin levels, and induces COX-2 upregulation.	('COX-2', 'Gene', (142, 147))	('upregulation', 'PosReg', (148, 160))	('circulating gastrin levels', 'MPA', (102, 128))	('interferes', 'NegReg', (31, 41))	('PPI therapy', 'Var', (19, 30))	('bile acids', 'Chemical', 'MESH:D001647', (80, 90))	('increases', 'PosReg', (92, 101))	('esophageal exposure to secondary bile acids', 'MPA', (47, 90))	('increases circulating gastrin', 'Phenotype', 'HP:0500167', (92, 121))	('COX-2', 'Gene', '4513', (142, 147))	('induces', 'Reg', (134, 141))
344284	32650561	Dietary changes and subsequent availability of macronutrients can have a significant impact on gut microbiota composition, with a study showing increased lactobacillus composition in the distal esophagus of mice fed a high-fat diet.	('changes', 'Var', (8, 15))	('impact', 'Reg', (85, 91))	('gut microbiota', 'MPA', (95, 109))	('lactobacillus', 'Species', '1624', (154, 167))	('mice', 'Species', '10090', (207, 211))	('lactobacillus composition', 'MPA', (154, 179))	('increased', 'PosReg', (144, 153))
344323	31097034	The rate of progression-free survival was higher in patients with increased immune scores compared with the remaining patients (83.1% vs. 57.1%, p = 0.25).	('increased', 'PosReg', (66, 75))	('immune scores', 'Var', (76, 89))	('higher', 'PosReg', (42, 48))	('progression-free survival', 'CPA', (12, 37))	('patients', 'Species', '9606', (118, 126))	('patients', 'Species', '9606', (52, 60))
344337	31097034	Patients with esophageal cancer at clinical stages T1b-T4a and N0 or N+ were evaluated for surgery by a multidisciplinary team that included a medical oncologist, a radiation oncologist, a radiologist, and a thoracic surgeon.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('T1b-T4a', 'Var', (51, 58))	('esophageal cancer', 'Disease', (14, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('Patients', 'Species', '9606', (0, 8))
344347	31097034	TMB was measured by the number of somatic single nucleotide variants and indel mutations per megabase in the coding region.	('TMB', 'Chemical', '-', (0, 3))	('single nucleotide variants', 'Var', (42, 68))	('indel mutations', 'Var', (73, 88))
344348	31097034	In addition, known somatic alterations in COSMIC and truncations in tumor suppressor genes were excluded from the count.	('tumor', 'Disease', (68, 73))	('truncations', 'Var', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('OS', 'Chemical', '-', (43, 45))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
344353	31097034	The first primary antibodies for CD4 (ab133616, Abcam, dilution 1:100) were incubated for 30 min, followed by detection using the Polymer HRP Ms. + Rb (ARH1001EA, Perkin-Elmer) for 10 min.	('CD4', 'Gene', (33, 36))	('CD4', 'Gene', '920', (33, 36))	('ab133616', 'Var', (38, 46))
344366	31097034	Twenty-four pre-CCRT samples had missense, nonsense, or splicing mutations in the tumor suppressor gene, TP53, and these alterations were maintained in 11 samples after CCRT.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('nonsense', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('tumor', 'Disease', (82, 87))	('missense', 'Var', (33, 41))
344367	31097034	Although nine pre-CCRT samples had a missense mutation in the nuclear factor erythroid 2 like 2 gene, NFE2L2, only two post-CCRT samples retained that mutation.	('NFE2L2', 'Gene', '4780', (102, 108))	('nuclear factor erythroid 2 like 2', 'Gene', (62, 95))	('NFE2L2', 'Gene', (102, 108))	('missense mutation', 'Var', (37, 54))	('nuclear factor erythroid 2 like 2', 'Gene', '4780', (62, 95))
344371	31097034	We found that the TMB and neoantigen load were significantly lower in post-CCRT samples (p < 0.001) compared with pre-CCRT samples (Fig.	('TMB', 'MPA', (18, 21))	('lower', 'NegReg', (61, 66))	('post-CCRT', 'Var', (70, 79))	('neoantigen load', 'MPA', (26, 41))	('TMB', 'Chemical', '-', (18, 21))
344388	31097034	CCF estimation analysis showed that NFE2L2 p.D15E was the only unique variant in pCR samples.	('p.D15E', 'Mutation', 'p.D15E', (43, 49))	('NFE2L2', 'Gene', (36, 42))	('pCR', 'Disease', (81, 84))	('NFE2L2', 'Gene', '4780', (36, 42))	('p.D15E', 'Var', (43, 49))
344401	31097034	A gain-of-function NRF2 mutation confers resistance to therapy in ESCC cells.	('gain-of-function', 'PosReg', (2, 18))	('resistance', 'CPA', (41, 51))	('NRF2', 'Gene', '4780', (19, 23))	('SCC', 'Gene', (67, 70))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('NRF2', 'Gene', (19, 23))	('mutation', 'Var', (24, 32))	('SCC', 'Gene', '6317', (67, 70))
344402	31097034	However, our results showed no significant correlation between NFE2L2 missense mutations and the pCR of the study population (pCR rate of 14.3% in patients with NFE2L2 mutations vs. 20.0% in the remaining patients).	('patients', 'Species', '9606', (205, 213))	('pCR', 'Disease', (97, 100))	('NFE2L2', 'Gene', '4780', (161, 167))	('NFE2L2', 'Gene', '4780', (63, 69))	('missense mutations', 'Var', (70, 88))	('patients', 'Species', '9606', (147, 155))	('NFE2L2', 'Gene', (161, 167))	('NFE2L2', 'Gene', (63, 69))	('mutations', 'Var', (168, 177))
344403	31097034	It is possible that the missense mutations observed in our study population failed to affect NFE2L2 function and further analysis is needed to study the functional alteration of the mutated forms of NFE2L2 in the ESCC tissue samples.	('NFE2L2', 'Gene', '4780', (199, 205))	('affect', 'Reg', (86, 92))	('SCC', 'Gene', '6317', (214, 217))	('missense mutations', 'Var', (24, 42))	('function', 'MPA', (100, 108))	('NFE2L2', 'Gene', (199, 205))	('NFE2L2', 'Gene', '4780', (93, 99))	('SCC', 'Gene', (214, 217))	('SCC', 'Phenotype', 'HP:0002860', (214, 217))	('NFE2L2', 'Gene', (93, 99))
344413	31097034	Clinical trials have shown that high TMB increases the efficacy of immune checkpoint blockades in cancer immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('high', 'Var', (32, 36))	('increases', 'PosReg', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('immune', 'Protein', (67, 73))	('cancer', 'Disease', (98, 104))	('efficacy', 'MPA', (55, 63))	('TMB', 'Chemical', '-', (37, 40))
344616	29983028	Recently, genome-wide association studies (GWAS) have identified rs4946728 and rs1040411 non-coding single nucleotide polymorphisms (SNPs) located on chromosome 6q21 as a risk factor for RISM in pediatric HL.	('risk factor', 'Reg', (171, 182))	('rs4946728', 'Var', (65, 74))	('RISM', 'Disease', (187, 191))	('HL', 'CellLine', 'CVCL:2492', (205, 207))	('rs1040411', 'Var', (79, 88))	('rs4946728', 'Mutation', 'rs4946728', (65, 74))	('rs1040411', 'Mutation', 'rs1040411', (79, 88))
344619	29983028	Most cases occur 3 to 10 years after radiation or alkylating agents and accompanied by clonal unbalanced cytogenetic abnormalities, i.e., loss of chromosome 5 or 7 and mutation of TP53 gene.	('mutation', 'Var', (168, 176))	('TP53', 'Gene', (180, 184))	('TP53', 'Gene', '7157', (180, 184))
344620	29983028	Variants in drug metabolizing genes, DNA repair genes and genes that regulate hematopoietic environment are associated with increased susceptibility of treatment related leukemia.	('susceptibility', 'Reg', (134, 148))	('Variants', 'Var', (0, 8))	('DNA repair genes', 'Gene', (37, 53))	('associated', 'Reg', (108, 118))	('leukemia', 'Phenotype', 'HP:0001909', (170, 178))	('men', 'Species', '9606', (99, 102))	('leukemia', 'Disease', 'MESH:D007938', (170, 178))	('men', 'Species', '9606', (157, 160))	('leukemia', 'Disease', (170, 178))
344622	29983028	Alteration in the DNA repair protein may also lead to increased risk of second malignancies.	('Alteration', 'Var', (0, 10))	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('DNA repair protein', 'Gene', (18, 36))	('malignancies', 'Disease', (79, 91))	('DNA repair protein', 'Gene', '442459', (18, 36))	('lead', 'Reg', (46, 50))
344624	29983028	Mutation in this gene can lead to increased radio sensitivity and cancer susceptibility.	('radio sensitivity', 'CPA', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Mutation', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('increased', 'PosReg', (34, 43))	('cancer', 'Disease', (66, 72))
344635	29983028	However, latent period is <3 years after topoisomerase-II inhibitors and it is generally not preceded by MDS.	('inhibitors', 'Var', (58, 68))	('topoisomerase-II', 'Protein', (41, 57))	('MDS', 'Disease', (105, 108))	('MDS', 'Disease', 'MESH:D009190', (105, 108))
344688	29983028	However, the risk of a second rectal cancer was significantly lower in the 3D-CRT arm as compared to conventional RT (RR = 0.59; 95% CI, 0.40-0.88).	('rectal cancer', 'Disease', 'MESH:D012004', (30, 43))	('rectal cancer', 'Disease', (30, 43))	('rectal cancer', 'Phenotype', 'HP:0100743', (30, 43))	('lower', 'NegReg', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('3D-CRT', 'Var', (75, 81))
344712	29983028	Higher risk was associated with abdominal irradiation, high dose procarbazine and use of platinum drugs.	('abdominal irradiation', 'Disease', (32, 53))	('procarbazine', 'Chemical', 'MESH:D011344', (65, 77))	('high dose', 'Var', (55, 64))	('platinum', 'Chemical', 'MESH:D010984', (89, 97))
344740	27936467	The median cfDNA copy number was highest in esophageal cancer, followed by colorectal cancer and gastric cancer, which were all significantly higher than those of healthy individuals.	('highest', 'Reg', (33, 40))	('gastric cancer', 'Disease', (97, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('colorectal cancer', 'Disease', (75, 92))	('cfDNA', 'Gene', (11, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('copy number', 'Var', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('esophageal cancer', 'Disease', (44, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))
344753	27936467	In addition to quantitative differences in the cfDNA levels between cancer patients and healthy individuals, cfDNA molecules have been found to exhibit genetic or epigenetic alterations, including mutations and differences in methylation and genomic copy numbers compared with those from tumor cells.	('tumor', 'Disease', (288, 293))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('methylation', 'MPA', (226, 237))	('differences', 'Reg', (211, 222))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (197, 206))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('genomic copy numbers', 'Var', (242, 262))	('cancer', 'Disease', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('cfDNA', 'Gene', (109, 114))
344757	27936467	In gastric cancer, patients with high cfDNA levels were more likely to experience peritoneal recurrence and exhibited significantly lower 5-year overall survival rates than patients with low cfDNA levels.	('peritoneal recurrence', 'CPA', (82, 103))	('patients', 'Species', '9606', (19, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('patients', 'Species', '9606', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('experience', 'PosReg', (71, 81))	('gastric cancer', 'Disease', (3, 17))	('lower', 'NegReg', (132, 137))	('high cfDNA levels', 'Var', (33, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
344768	27936467	907-0.955) for stomach cancer, 0.980 (95% CI: 0.968-0.992) for colorectal cancer, and 0.952 (95% CI: 0.935-0.970) for all cancer types compared with the controls.	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('stomach cancer', 'Disease', 'MESH:D013274', (15, 29))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('0.980', 'Var', (31, 36))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', (74, 80))	('stomach cancer', 'Disease', (15, 29))	('colorectal cancer', 'Disease', (63, 80))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('stomach cancer', 'Phenotype', 'HP:0012126', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('0.952', 'Var', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
344839	27936467	cfDNA has clinical utility of for detecting and monitoring breast cancer, and cfDNA mutation profiling can also serve as a tool for identifying biomarkers in patients receiving tamoxifen.	('tamoxifen', 'Chemical', 'MESH:D013629', (177, 186))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('cfDNA', 'Gene', (78, 83))	('patients', 'Species', '9606', (158, 166))	('mutation', 'Var', (84, 92))
344850	27936467	Carcinogenesis and tumor progression are complex and progressive processes that are associated with numerous genetic and epigenetic alterations, some of which can also be detected in cfDNA, which may be more specific and accurate than protein biomarkers and have potential as blood biomarkers for cancer.	('Carcinogenesis', 'Disease', (0, 14))	('cancer', 'Disease', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('alterations', 'Var', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('associated', 'Reg', (84, 94))	('tumor', 'Disease', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('Carcinogenesis', 'Disease', 'MESH:D063646', (0, 14))
344872	27814637	Zn deficiency and malfunction of Zn transporters have been associated with many chronic diseases including cancer.	('Zn', 'Chemical', 'MESH:D015032', (0, 2))	('chronic diseases', 'Disease', 'MESH:D002908', (80, 96))	('chronic diseases', 'Disease', (80, 96))	('malfunction', 'Var', (18, 29))	('Zn', 'Chemical', 'MESH:D015032', (33, 35))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('associated', 'Reg', (59, 69))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Zn deficiency', 'Disease', 'MESH:D007153', (0, 13))	('Zn deficiency', 'Disease', (0, 13))	('cancer', 'Disease', (107, 113))
344886	27814637	There is increasing evidence that dysregulation and/or mutations in ZIP and ZnT transporter genes may result in functional disorders.	('ZIP', 'Gene', (68, 71))	('Zn', 'Chemical', 'MESH:D015032', (76, 78))	('mutations', 'Var', (55, 64))	('ZnT transporter', 'Gene', (76, 91))	('result in', 'Reg', (102, 111))	('dysregulation', 'MPA', (34, 47))	('functional disorders', 'Disease', (112, 132))	('ZIP', 'Gene', '1613', (68, 71))
344887	27814637	For example, ZnT8 with a single-nucleotide polymorphism (SNP) has been shown to be associated with increased risk of both type 1 and type 2 diabetes mellitus and a ZIP4 mutation results in acrodermatitis enteropathica.	('single-nucleotide polymorphism', 'Var', (25, 55))	('acrodermatitis enteropathica', 'Disease', (189, 217))	('mutation', 'Var', (169, 177))	('ZnT8', 'Gene', (13, 17))	('ZIP4', 'Gene', '55630', (164, 168))	('type 1', 'Disease', (122, 128))	('associated', 'Reg', (83, 93))	('type 2 diabetes mellitus', 'Disease', (133, 157))	('results in', 'Reg', (178, 188))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (133, 148))	('acrodermatitis enteropathica', 'Disease', 'MESH:C538178', (189, 217))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (140, 157))	('ZnT8', 'Gene', '169026', (13, 17))	('ZIP4', 'Gene', (164, 168))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (133, 157))
344931	27814637	Imaging and neurotoxicity studies demonstrated that Zn2+ can enter neurons through NMDA receptors and Ca2+-permeable AMPA/kainate (Ca-A/K) channels.	('Ca-A/K', 'Gene', (131, 137))	('Zn2+', 'Var', (52, 56))	('Zn2+', 'Chemical', 'MESH:D015032', (52, 56))	('Ca-A/K', 'Gene', '10194;1022', (131, 137))	('neurotoxicity', 'Disease', 'MESH:D020258', (12, 25))	('rat', 'Species', '10116', (41, 44))	('neurotoxicity', 'Disease', (12, 25))	('NMDA receptors', 'Protein', (83, 97))	('Ca2+', 'Chemical', 'MESH:D000069285', (102, 106))
344965	27814637	Although serum or plasma Zn is not a good biomarker for Zn deficiency, there is compelling evidence that dysregulated Zn homeostasis is indeed associated with many cancers.	('Zn deficiency', 'Disease', (56, 69))	('associated', 'Reg', (143, 153))	('Zn homeostasis', 'MPA', (118, 132))	('Zn', 'Chemical', 'MESH:D015032', (56, 58))	('Zn', 'Chemical', 'MESH:D015032', (25, 27))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Zn', 'Chemical', 'MESH:D015032', (118, 120))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('dysregulated', 'Var', (105, 117))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('Zn deficiency', 'Disease', 'MESH:D007153', (56, 69))
344991	27814637	In another words, the replenishment of Zn in the diet could reduce cell proliferation and induce apoptosis in esophageal epithelia and thus greatly reduce both tumor incidence and tumor size in the esophagi and forestomach of NMBA-treated animals.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (110, 130))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Zn', 'Chemical', 'MESH:D015032', (39, 41))	('reduce', 'NegReg', (60, 66))	('NMBA', 'Chemical', 'MESH:C014707', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('esophageal epithelia', 'Disease', 'MESH:D004941', (110, 130))	('tumor', 'Disease', (180, 185))	('induce', 'Reg', (90, 96))	('esophageal epithelia', 'Disease', (110, 130))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('reduce', 'NegReg', (148, 154))	('rat', 'Species', '10116', (79, 82))	('cell proliferation', 'CPA', (67, 85))	('tumor', 'Disease', (160, 165))	('apoptosis', 'CPA', (97, 106))	('replenishment', 'Var', (22, 35))
344999	27814637	Epidemiological studies have established a relationship between high breast tissue Zn levels and development of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('high', 'Var', (64, 68))	('breast cancer', 'Disease', (112, 125))	('Zn', 'Chemical', 'MESH:D015032', (83, 85))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast tissue Zn levels', 'MPA', (69, 92))
345025	27814637	Despite accumulating evidence to reveal dysregulated Zn transporters in cancers, whether the malfunction of Zn transporter is a "driver" or a "passenger" for carcinogenesis or tumorigenesis is still unclear.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Zn', 'Chemical', 'MESH:D015032', (108, 110))	('tumor', 'Disease', (176, 181))	('carcinogenesis', 'Disease', 'MESH:D063646', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('dysregulated', 'Var', (40, 52))	('Zn', 'Chemical', 'MESH:D015032', (53, 55))	('carcinogenesis', 'Disease', (158, 172))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
345026	27814637	It is also unclear whether the dysregulated Zn transporters per se or the consequent changes in Zn status exert these effects.	('dysregulated', 'Var', (31, 43))	('Zn', 'Chemical', 'MESH:D015032', (44, 46))	('Zn', 'Chemical', 'MESH:D015032', (96, 98))	('changes', 'Reg', (85, 92))
345050	27814637	Using mutagenesis approach, it was further demonstrated that inhibition by 30 microM ZnCl2 was impaired in TRPM5 mutants in which His at 896, and Glu at 926 and/or Glu at 939 in the outer pore loop were replaced with Gln.	('ZnCl2', 'Chemical', 'MESH:C016837', (85, 90))	('Gln', 'Chemical', 'MESH:D005973', (217, 220))	('His', 'Chemical', 'MESH:D006639', (130, 133))	('rat', 'Species', '10116', (50, 53))	('impaired', 'NegReg', (95, 103))	('ZnCl2', 'Gene', (85, 90))	('His at 896', 'Var', (130, 140))	('Glu', 'Chemical', 'MESH:D018698', (146, 149))	('Glu at 939', 'Var', (164, 174))	('TRPM5', 'Gene', (107, 112))	('inhibition', 'MPA', (61, 71))	('mutants', 'Var', (113, 120))	('Glu', 'Chemical', 'MESH:D018698', (164, 167))	('TRPM5', 'Gene', '29850', (107, 112))	('Glu at 926', 'Var', (146, 156))
345061	27814637	Multiple studies have reported dysregulated K+ channel expression in cancers.	('dysregulated', 'Var', (31, 43))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('K+ channel expression', 'MPA', (44, 65))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
345065	27814637	Recently, Schwab's team demonstrated that KCa3.1 channel gene (KCNN4) promoter is hypomethylated in an aggressive non-small cell lung carcinoma cell line and in patient samples.	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (114, 143))	('KCa3.1', 'Gene', '3783', (42, 48))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (114, 143))	('KCNN4', 'Gene', '3783', (63, 68))	('patient', 'Species', '9606', (161, 168))	('non-small cell lung carcinoma', 'Disease', (114, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('rat', 'Species', '10116', (31, 34))	('hypomethylated', 'Var', (82, 96))	('KCNN4', 'Gene', (63, 68))	('KCa3.1', 'Gene', (42, 48))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (118, 143))
345066	27814637	The loss of DNA methylation of the KCNN4 promoter was associated with increased KCa3.1 channel expression and function; both findings are strong indicators of poor prognosis in lung cancer.	('DNA', 'MPA', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('increased', 'PosReg', (70, 79))	('KCa3.1', 'Gene', (80, 86))	('KCNN4', 'Gene', (35, 40))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('function', 'MPA', (110, 118))	('KCNN4', 'Gene', '3783', (35, 40))	('KCa3.1', 'Gene', '3783', (80, 86))	('lung cancer', 'Disease', (177, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('loss', 'NegReg', (4, 8))	('methylation', 'Var', (16, 27))	('expression', 'MPA', (95, 105))
345077	27814637	Moreover, silencing KCa3.1 or TRPC1 reduced metastasis in vivo (unpublished data).	('TRPC1', 'Gene', '7220', (30, 35))	('TRPC1', 'Gene', (30, 35))	('KCa3.1', 'Gene', '3783', (20, 26))	('metastasis', 'CPA', (44, 54))	('reduced', 'NegReg', (36, 43))	('KCa3.1', 'Gene', (20, 26))	('silencing', 'Var', (10, 19))
345079	27814637	In particular, the presence of the TRPC, TRPM, and TRPV subfamilies correlates with malignant growth and cancer progression.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('presence', 'Var', (19, 27))	('correlates with', 'Reg', (68, 83))	('malignant growth', 'CPA', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TRP', 'Gene', (41, 44))	('TRP', 'Gene', '54822', (41, 44))	('TRP', 'Gene', (51, 54))	('TRP', 'Gene', '54822', (51, 54))	('TRP', 'Gene', (35, 38))	('TRP', 'Gene', '54822', (35, 38))
345088	27814637	Orai1 is reported to promote MDA-MB-231 breast cancer cell migration through the promotion of a high rate of focal adhesion turnover, while its knockdown reduces the spread of tumor cells in xenografted mice.	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('promotion', 'PosReg', (81, 90))	('rat', 'Species', '10116', (62, 65))	('focal adhesion turnover', 'MPA', (109, 132))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('mice', 'Species', '10090', (203, 207))	('tumor', 'Disease', (176, 181))	('Orai1', 'Gene', (0, 5))	('MDA-MB-231', 'Gene', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('rat', 'Species', '10116', (101, 104))	('promote', 'PosReg', (21, 28))	('Orai1', 'Gene', '84876', (0, 5))	('knockdown', 'Var', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (29, 39))	('reduces', 'NegReg', (154, 161))
345089	27814637	We also reported that elevated Orai1 was associated with poor prognosis in esophageal squamous cell carcinoma patients and inhibition of the Orai1 channels either by the pharmacological compounds or the knocking-down of Orai1 expression could block cancer cell proliferation and migration in vitro as well as tumor growth in vivo.	('Orai1', 'Gene', '84876', (31, 36))	('esophageal squamous cell carcinoma', 'Disease', (75, 109))	('Orai1', 'Gene', '84876', (141, 146))	('elevated', 'PosReg', (22, 30))	('cancer', 'Disease', (249, 255))	('knocking-down', 'Var', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('Orai1', 'Gene', '84876', (220, 225))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (75, 109))	('tumor', 'Disease', (309, 314))	('block', 'NegReg', (243, 248))	('rat', 'Species', '10116', (268, 271))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('inhibition', 'NegReg', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('Orai1', 'Gene', (31, 36))	('Orai1', 'Gene', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('rat', 'Species', '10116', (282, 285))	('Orai1', 'Gene', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('patients', 'Species', '9606', (110, 118))
345093	27814637	Indeed, silencing Orai3 leads to significant down regulation of cell proliferation and stops the cell cycle at the G1 phase along with an up regulation of cell apoptosis.	('up regulation', 'PosReg', (138, 151))	('Orai3', 'Gene', '93129', (18, 23))	('rat', 'Species', '10116', (76, 79))	('cell proliferation', 'CPA', (64, 82))	('down regulation', 'NegReg', (45, 60))	('silencing', 'Var', (8, 17))	('Orai3', 'Gene', (18, 23))	('stops', 'NegReg', (87, 92))	('cell apoptosis', 'CPA', (155, 169))	('cell cycle at the G1 phase', 'CPA', (97, 123))
345094	27814637	Moreover, knockdown of Orai3 results in a decrease of CDKs 4/2 (cyclin-dependent kinases) and cyclins D1/E expression concurrently with an up-regulation of p21Waf1/Cip1 (a cyclin-dependent kinase inhibitor) and p53 expression.	('Orai3', 'Gene', (23, 28))	('up-regulation', 'PosReg', (139, 152))	('cyclin-dependent kinases) and cyclins D1/E', 'Gene', '595', (64, 106))	('p53', 'Gene', (211, 214))	('expression', 'MPA', (107, 117))	('Cip1', 'Gene', '1026', (164, 168))	('CDKs 4/2', 'Gene', '1019;1017', (54, 62))	('p21', 'Gene', (156, 159))	('p53', 'Gene', '7157', (211, 214))	('decrease', 'NegReg', (42, 50))	('p21', 'Gene', '644914', (156, 159))	('Orai3', 'Gene', '93129', (23, 28))	('CDKs 4/2', 'Gene', (54, 62))	('Cip1', 'Gene', (164, 168))	('knockdown', 'Var', (10, 19))	('expression', 'MPA', (215, 225))
345101	27814637	Dysregulated Zn homeostasis may play a role more like a "driver" than a "passenger" in carcinogenesis or tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('Zn homeostasis', 'MPA', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Dysregulated', 'Var', (0, 12))	('carcinogenesis', 'Disease', (87, 101))	('Zn', 'Chemical', 'MESH:D015032', (13, 15))	('tumor', 'Disease', (105, 110))
345102	27814637	Traditionally, the diseases caused by inherited mutations that alter ion channel biophysical properties are called "channelopathies".	('channelopathies', 'Disease', (116, 131))	('channelopathies', 'Disease', 'MESH:D053447', (116, 131))	('mutations', 'Var', (48, 57))
345104	27814637	Since many cancers may be caused by the dysregulation of ion channel expression and/or activity, the cancers caused by Zn-dysregulated channel may be classified within the channelopathy family.	('channelopathy', 'Disease', 'MESH:D053447', (172, 185))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('activity', 'MPA', (87, 95))	('cancers', 'Disease', (101, 108))	('dysregulation', 'Var', (40, 53))	('Zn', 'Chemical', 'MESH:D015032', (119, 121))	('caused by', 'Reg', (26, 35))	('ion', 'Protein', (57, 60))	('channelopathy', 'Disease', (172, 185))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
345115	26578822	Recent studies revealed that RDW is associated with prognosis in several cancers, such as lung cancer and prostate cancer.	('cancers', 'Disease', (73, 80))	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('RDW', 'Var', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('prostate cancer', 'Disease', (106, 121))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('associated', 'Reg', (36, 46))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))
345152	25258650	Patients who had both elevated CRP (> 10 mg/L) and hypoalbuminurea (< 35 g/L) were assigned a score of 2.	('> 10 mg/L', 'Var', (36, 45))	('elevated', 'PosReg', (22, 30))	('elevated CRP', 'Phenotype', 'HP:0011227', (22, 34))	('hypoalbuminurea', 'Disease', (51, 66))	('Patients', 'Species', '9606', (0, 8))	('CRP', 'Gene', (31, 34))	('hypoalbuminurea', 'Disease', 'None', (51, 66))	('CRP', 'Gene', '1401', (31, 34))
345192	25258650	Pairwise comparisons between the three subgroups (mGPS of 0, 1 and 2) revealed that patients with a mGPS of 0 had significantly better 3-year OS (p = 0.007) and PFS (p = 0.021) rates than patients with a mGPS of 1.	('patients', 'Species', '9606', (84, 92))	('PFS', 'MPA', (161, 164))	('OS', 'Chemical', '-', (142, 144))	('patients', 'Species', '9606', (188, 196))	('mGPS of 0', 'Var', (100, 109))	('better', 'PosReg', (128, 134))
345193	25258650	Patients with a mGPS of 0 also had significantly better 3-year OS (p < 0.001) and PFS (p < 0.001) rates than patients with a mGPS of 2.	('mGPS of 0', 'Var', (16, 25))	('PFS', 'MPA', (82, 85))	('patients', 'Species', '9606', (109, 117))	('OS', 'Chemical', '-', (63, 65))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (49, 55))
345194	25258650	Additionally, patients with a mGPS of 1 had significantly better 3-year OS (p < 0.001) and PFS (p < 0.001) rates than patients with a mGPS of 2.	('OS', 'Chemical', '-', (72, 74))	('better', 'PosReg', (58, 64))	('PFS', 'MPA', (91, 94))	('patients', 'Species', '9606', (118, 126))	('mGPS of 1', 'Var', (30, 39))	('patients', 'Species', '9606', (14, 22))
345195	25258650	As there is duplication between albumin, CRP and the mGPS, only the mGPS was entered into the multivariate analysis.	('albumin', 'Protein', (32, 39))	('CRP', 'Gene', '1401', (41, 44))	('CRP', 'Gene', (41, 44))	('duplication', 'Var', (12, 23))
345199	25258650	This retrospective study of 212 patients revealed that the mGPS is an independent prognostic factor in patients with unresectable SCC undergoing chemoradiotherapy.	('SCC', 'Gene', (130, 133))	('patients', 'Species', '9606', (32, 40))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('SCC', 'Gene', '6317', (130, 133))	('mGPS', 'Var', (59, 63))	('patients', 'Species', '9606', (103, 111))
345202	25258650	However, a previous study indicated that a GPS of 1 was most commonly found to be the result of elevated CRP.	('GPS of 1', 'Var', (43, 51))	('CRP', 'Gene', (105, 108))	('CRP', 'Gene', '1401', (105, 108))	('elevated', 'PosReg', (96, 104))	('elevated CRP', 'Phenotype', 'HP:0011227', (96, 108))
345207	25258650	As CRP increased from normal (< 5 mg/L) to highly elevated (> 80 mg/L), there was a 1.4-fold (5-10 mg/L category) to 3.3-fold (> 80 mg/L category) increase in the risk of all-cause mortality.	('increased', 'PosReg', (7, 16))	('> 80 mg/L', 'Var', (60, 69))	('elevated', 'PosReg', (50, 58))	('CRP', 'Gene', '1401', (3, 6))	('increase', 'PosReg', (147, 155))	('CRP', 'Gene', (3, 6))	('all-cause mortality', 'MPA', (171, 190))	('CRP increased', 'Phenotype', 'HP:0011227', (3, 16))
345222	25258650	Post hoc pairwise comparisons between the three groups showed the OS and PFS rates of patients with a GPS of 1 were significantly different to patients with a GPS of 0 or 2, and there was a good stratification of the OS and PFS rates of the patients in the three groups.	('OS', 'Chemical', '-', (217, 219))	('OS', 'Chemical', '-', (66, 68))	('GPS of 1', 'Var', (102, 110))	('patients', 'Species', '9606', (143, 151))	('PFS', 'CPA', (73, 76))	('different', 'Reg', (130, 139))	('patients', 'Species', '9606', (241, 249))	('patients', 'Species', '9606', (86, 94))
345262	22100301	Previous data demonstrated that 63% of patients with nondysplastic BE overestimated their 1 year risk of esophageal cancer, and overestimators underwent an average of 0.14 additional surveillance endoscopies per year compared to non-overestimators, with a standard deviation of 0.3 endoscopies for both groups.	('overestimated', 'PosReg', (70, 83))	('patients', 'Species', '9606', (39, 47))	('BE', 'Phenotype', 'HP:0100580', (67, 69))	('esophageal cancer', 'Disease', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('overestimators', 'Var', (128, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))
345324	21054833	This study demonstrates that the density of CD45RO+ TILs is an independent prognostic factor in non-metastasized (stage I-IIA) Barrett's cancer patients and indicates an important role for the adaptive immunologic microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	("Barrett's cancer", 'Disease', 'MESH:D001471', (127, 143))	('non-metastasized', 'Disease', (96, 112))	('CD45RO+', 'Var', (44, 51))	('patients', 'Species', '9606', (144, 152))	("Barrett's cancer", 'Disease', (127, 143))	("Barrett's cancer", 'Phenotype', 'HP:0100580', (127, 143))	('CD45RO+ TILs', 'Chemical', '-', (44, 56))
345331	21054833	Several studies have demonstrated the presence of TILs in various solid human cancers, most recently showing the association of an abundance of CD3+, CD8+ or CD45RO+ lymphocytic tumor infiltration with a survival benefit for patients with gastric and colorectal cancer, as well as for patients with endometrial, cervical, ovarian, urothelial and hepatocellular carcinoma and melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (375, 383))	('CD8', 'Gene', '925', (150, 153))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (346, 370))	('ovarian', 'Disease', (322, 329))	('cervical', 'Disease', (312, 320))	('colorectal cancer', 'Phenotype', 'HP:0003003', (251, 268))	('human', 'Species', '9606', (72, 77))	('gastric', 'Disease', (239, 246))	('benefit', 'PosReg', (213, 220))	('survival', 'CPA', (204, 212))	('lymphocytic tumor', 'Disease', (166, 183))	('CD8', 'Gene', (150, 153))	('patients', 'Species', '9606', (225, 233))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('urothelial and hepatocellular carcinoma and melanoma', 'Disease', 'MESH:D006528', (331, 383))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('lymphocytic tumor', 'Disease', 'MESH:D009369', (166, 183))	('cancers', 'Disease', (78, 85))	('CD3+', 'Var', (144, 148))	('gastric', 'Disease', 'MESH:D013274', (239, 246))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (251, 268))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('CD45', 'Gene', (158, 162))	('endometrial', 'Disease', (299, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('CD45', 'Gene', '5788', (158, 162))	('colorectal cancer', 'Disease', (251, 268))	('patients', 'Species', '9606', (285, 293))
345351	21054833	All cases were therefore classified into low- and high-density groups for each marker, that is CD3+ low, CD8+ low, and CD45RO+ low (low-density groups) and CD3+ high, CD8+ high, and CD45RO+ high (high-density groups).	('CD8', 'Gene', (105, 108))	('CD45', 'Gene', (182, 186))	('CD45', 'Gene', '5788', (119, 123))	('CD8', 'Gene', '925', (105, 108))	('CD8', 'Gene', (167, 170))	('CD8', 'Gene', '925', (167, 170))	('CD45', 'Gene', '5788', (182, 186))	('CD3+ high', 'Var', (156, 165))	('CD45', 'Gene', (119, 123))
345356	21054833	There was a significant correlation between the TIL levels of CD3+ and CD8+ TILs (P < 0.001; r = 0.54), CD3+ and CD45RO+ TILs (P < 0.001, r = 0.4) and CD8+ and CD45RO+ TILs (P < 0.001; r = 0.53).	('CD8', 'Gene', '925', (71, 74))	('CD8', 'Gene', (151, 154))	('CD8', 'Gene', '925', (151, 154))	('CD45RO+ TILs', 'Chemical', '-', (160, 172))	('CD45RO+', 'Var', (113, 120))	('CD3+', 'Var', (104, 108))	('CD45RO+ TILs', 'Chemical', '-', (113, 125))	('CD8', 'Gene', (71, 74))
345357	21054833	Cut-off levels with prognostic relevance were 0.9 for CD3+, 0.5 for CD8+ and 2.0 for CD45RO+.	('CD8', 'Gene', (68, 71))	('CD45', 'Gene', '5788', (85, 89))	('CD8', 'Gene', '925', (68, 71))	('CD3+', 'Var', (54, 58))	('CD45', 'Gene', (85, 89))
345359	21054833	Moreover, high CD3+ and high CD45RO+ levels were associated with less recurrence of disease (P = 0.005 and P = 0.018, respectively).	('CD3+', 'MPA', (15, 19))	('high CD45RO+ level', 'Phenotype', 'HP:0410375', (24, 42))	('high CD45RO+ levels', 'Phenotype', 'HP:0410375', (24, 43))	('CD45', 'Gene', (29, 33))	('less', 'NegReg', (65, 69))	('high', 'Var', (24, 28))	('CD45', 'Gene', '5788', (29, 33))	('recurrence of disease', 'CPA', (70, 91))
345360	21054833	Furthermore, low levels of CD45RO+ immune cells showed a trend for an association with a higher frequency of lymph node metastasis (P = 0.065), and grading (P = 0.091).	('CD45', 'Gene', '5788', (27, 31))	('lymph node metastasis', 'CPA', (109, 130))	('low', 'Var', (13, 16))	('grading', 'CPA', (148, 155))	('low levels of CD45RO+ immune cells', 'Phenotype', 'HP:0410378', (13, 47))	('CD45', 'Gene', (27, 31))
345361	21054833	In Kaplan-Meier survival analysis, a correlation between higher infiltration levels and survival was observed for CD3+ and CD45RO+ lymphocytes, but not for CD8+ lymphocytes (Figure 1).	('survival', 'CPA', (88, 96))	('CD45', 'Gene', '5788', (123, 127))	('higher', 'PosReg', (57, 63))	('CD3+', 'Var', (114, 118))	('CD45', 'Gene', (123, 127))	('infiltration levels', 'MPA', (64, 83))	('CD8', 'Gene', (156, 159))	('CD8', 'Gene', '925', (156, 159))
345363	21054833	Similar results were observed for overall survival: CD3+ high and CD45RO+ high groups had a more favorable outcome than the corresponding low groups (median CD3+ high: 33.0 months versus CD3+ low 25.1 months, median CD45RO+ high: 33.0 months versus 13.6 months) (P = 0.010 each) (Figure 1D-F).	('CD45', 'Gene', (66, 70))	('CD3+ high', 'Var', (52, 61))	('CD45', 'Gene', '5788', (216, 220))	('CD45', 'Gene', '5788', (66, 70))	('CD45', 'Gene', (216, 220))	('CD3+ high', 'Var', (157, 166))
345372	21054833	Expression patterns of CD8+ and CD45RO+ TILs had no independent prognostic value, nor did the combination of CD3+CD8+CD45RO+ TILs.	('CD8', 'Gene', (23, 26))	('CD8', 'Gene', (113, 116))	('CD8', 'Gene', '925', (23, 26))	('CD8', 'Gene', '925', (113, 116))	('CD45RO+ TILs', 'Chemical', '-', (117, 129))	('CD45RO+ TILs', 'Chemical', '-', (32, 44))	('CD45RO+ TILs', 'Var', (32, 44))
345373	21054833	Disease-free and overall patient survival correlated with a high density of CD45RO+ TILs in pN0 patients, but not in pN1 patients (Figure 3).	('pN0', 'Disease', (92, 95))	('Disease-free', 'CPA', (0, 12))	('patient', 'Species', '9606', (96, 103))	('patient', 'Species', '9606', (25, 32))	('CD45RO+ TILs', 'Chemical', '-', (76, 88))	('CD45RO+ TILs', 'Var', (76, 88))	('patients', 'Species', '9606', (96, 104))	('pN1', 'Gene', '5270', (117, 120))	('patient', 'Species', '9606', (121, 128))	('patients', 'Species', '9606', (121, 129))	('pN1', 'Gene', (117, 120))
345374	21054833	pN0 patients with a high density of CD45RO+ cells had a significant more favorable outcome than did patients with low CD45RO+ levels (disease-free survival: P = 0.001, overall survival: P = 0.041) (Figure 3A and 3C).	('low CD45RO+ levels', 'Phenotype', 'HP:0410378', (114, 132))	('CD45', 'Gene', (36, 40))	('CD45', 'Gene', (118, 122))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (4, 12))	('CD45', 'Gene', '5788', (36, 40))	('high density of CD45RO+ cells', 'Phenotype', 'HP:0410375', (20, 49))	('CD45', 'Gene', '5788', (118, 122))	('pN0', 'Var', (0, 3))
345379	21054833	Furthermore, the CD3+ low group showed a higher frequency of lymph node metastasis than the corresponding high group (P = 0.025) and for the CD45RO+ low group there was a trend for a higher presence of lymph node metastases (P = 0.065) (Table 1).	('CD45', 'Gene', (141, 145))	('CD3+ low', 'Var', (17, 25))	('lymph node metastasis', 'CPA', (61, 82))	('lymph node metastases', 'Disease', 'MESH:D009362', (202, 223))	('CD45', 'Gene', '5788', (141, 145))	('lymph node metastases', 'Disease', (202, 223))
345382	21054833	Moreover, high infiltration levels of CD45RO+ and CD3+ T-cells were correlated with a lower rate of recurrence.	('CD3+', 'Var', (50, 54))	('CD45', 'Gene', (38, 42))	('CD45', 'Gene', '5788', (38, 42))
345384	21054833	A study on gastric cancer demonstrated the independent prognostic value of the density of CD3+, CD8+, and CD45RO+ lymphocytes for regional lymph node metastasis and patient survival.	('CD45', 'Gene', '5788', (106, 110))	('CD8', 'Gene', (96, 99))	('regional lymph node metastasis', 'CPA', (130, 160))	('patient', 'Species', '9606', (165, 172))	('gastric cancer', 'Phenotype', 'HP:0012126', (11, 25))	('CD8', 'Gene', '925', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('CD45', 'Gene', (106, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (11, 25))	('gastric cancer', 'Disease', (11, 25))	('CD3+', 'Var', (90, 94))
345392	21054833	A recent work with a cohort of 106 adenocarcinomas of the esophagus failed to show a prognostic influence of CD3+ and CD8+ TILs, whereas in our cohort patients benefit from a high CD3+ lymphocytic infiltration.	('CD3+', 'Var', (109, 113))	('patients', 'Species', '9606', (151, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('adenocarcinomas of the esophagus', 'Disease', (35, 67))	('CD8', 'Gene', '925', (118, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('CD8', 'Gene', (118, 121))	('adenocarcinomas of the esophagus', 'Disease', 'MESH:C562730', (35, 67))
345398	21054833	In the current study, high levels of CD45RO+ TILs were significantly associated with improved survival in Barrett's cancer, on the one hand in the whole study cohort as well in the subgroup of non-metastasized patients.	('improved', 'PosReg', (85, 93))	("Barrett's cancer", 'Phenotype', 'HP:0100580', (106, 122))	('survival', 'MPA', (94, 102))	('CD45RO+ TILs', 'Chemical', '-', (37, 49))	('patients', 'Species', '9606', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	("Barrett's cancer", 'Disease', (106, 122))	('CD45RO+ TILs', 'Var', (37, 49))	("Barrett's cancer", 'Disease', 'MESH:D001471', (106, 122))
345404	21054833	CD45RO+ and CD3+ TILs within Barrett's cancer may serve as criteria for selection and monitoring of patients for adjuvant immunotherapeutic strategies and can be a reliable prognostic marker to predict favorable outcome in patient subgroups.	('CD45', 'Gene', '5788', (0, 4))	('CD3+', 'Var', (12, 16))	("Barrett's cancer", 'Disease', (29, 45))	('patient', 'Species', '9606', (100, 107))	('patient', 'Species', '9606', (223, 230))	('patients', 'Species', '9606', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	("Barrett's cancer", 'Disease', 'MESH:D001471', (29, 45))	("Barrett's cancer", 'Phenotype', 'HP:0100580', (29, 45))	('CD45', 'Gene', (0, 4))
345441	33062589	Moreover, the continuous dilation exerted by the stent on the esophageal wall diminishes during degradation; thus, the use of BDS may cause stent displacement and restructure, which needs endoscopic monitoring on a regular basis.	('stent displacement', 'CPA', (140, 158))	('cause', 'Reg', (134, 139))	('DS', 'Chemical', 'MESH:D003903', (127, 129))	('use', 'Var', (119, 122))	('BDS', 'Gene', (126, 129))	('restructure', 'CPA', (163, 174))
345495	33062589	Histologically, MMC can appreciably reduce the number of fibroblasts, the degree of inflammation, and the content of collagen; its inhibitory effect on the proliferation of fibroblasts is dose dependent.	('content of collagen', 'MPA', (106, 125))	('reduce', 'NegReg', (36, 42))	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('inflammation', 'Disease', (84, 96))	('MMC', 'Var', (16, 19))	('MMC', 'Chemical', 'MESH:D016685', (16, 19))
345499	33062589	Another study also confirmed that MMC could prolong the symptom-free period of dysphagia and reduce the number of dilatation procedures in patients with benign esophageal stricture.	('dysphagia', 'Phenotype', 'HP:0002015', (79, 88))	('patients', 'Species', '9606', (139, 147))	('symptom-free', 'MPA', (56, 68))	('dysphagia', 'Disease', (79, 88))	('dilatation', 'Phenotype', 'HP:0002617', (114, 124))	('prolong', 'PosReg', (44, 51))	('benign esophageal stricture', 'Disease', (153, 180))	('dysphagia', 'Disease', 'MESH:D003680', (79, 88))	('MMC', 'Chemical', 'MESH:D016685', (34, 37))	('esophageal stricture', 'Phenotype', 'HP:0002043', (160, 180))	('reduce', 'NegReg', (93, 99))	('MMC', 'Var', (34, 37))
345502	33062589	The results suggested that the degrees of esophageal stricture and submucosal fibrosis in dogs treated with 5-FLC were observably lower than those in the untreated group.	('lower', 'NegReg', (130, 135))	('submucosal fibrosis', 'Disease', (67, 86))	('5-FLC', 'Var', (108, 113))	('esophageal', 'Disease', (42, 52))	('esophageal stricture', 'Phenotype', 'HP:0002043', (42, 62))	('5-FLC', 'Chemical', '-', (108, 113))	('dogs', 'Species', '9615', (90, 94))	('submucosal fibrosis', 'Disease', 'MESH:D005355', (67, 86))
345555	33062589	A recent study suggested that ERI was superior to EBD in relieving anastomotic stricture after esophagectomy.	('anastomotic stricture', 'Disease', 'MESH:D003251', (67, 88))	('ERI', 'Var', (30, 33))	('EBD', 'Chemical', '-', (50, 53))	('anastomotic stricture', 'Disease', (67, 88))	('stricture after esophagectomy', 'Phenotype', 'HP:0002043', (79, 108))
345556	33062589	Despite the fact that only a single case of post-ESD stricture has been studied and the exact number of balloon dilatation procedures required for refractory stricture remains uncertain, ERI can be viewed as a new treatment for patients with post-ESD stricture, which is particularly the case for those who have failed multiple EBD treatments.	('patients', 'Species', '9606', (228, 236))	('EBD', 'Chemical', '-', (328, 331))	('died', 'Disease', (75, 79))	('post-ESD stricture', 'Disease', (242, 260))	('died', 'Disease', 'MESH:D003643', (75, 79))	('ERI', 'Var', (187, 190))	('dilatation', 'Phenotype', 'HP:0002617', (112, 122))
345606	32312286	According to the Comprehensive Registry of Esophageal Cancer in Japan, the incidence of T4b esophageal cancer accounts for approximately 6.7% of all patients with esophageal cancer (approximately 1500 patients per year).	('patients', 'Species', '9606', (201, 209))	('T4b', 'Var', (88, 91))	('patients', 'Species', '9606', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Cancer', 'Disease', (54, 60))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
345654	32312286	Also, as the incidence of T4b esophageal cancer is estimated approximately at 1500 patients per year in Japan, we expect the Japanese Accelerated Approval Program will allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need.	('T4b', 'Var', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
345678	31908476	Epigenetic and genetic alterations of miRNAs are common events in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('miR', 'Gene', '220972', (38, 41))	('Epigenetic', 'Var', (0, 10))	('genetic alterations', 'Var', (15, 34))	('miR', 'Gene', (38, 41))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
345711	31908476	In 2013, Li and colleagues reported that miR-451 inhibits CRC cell growth by downregulating the P13K/AKT pathway.	('CRC', 'Phenotype', 'HP:0003003', (58, 61))	('CRC', 'Disease', 'MESH:D015179', (58, 61))	('AKT', 'Gene', '207', (101, 104))	('P13K', 'Var', (96, 100))	('inhibits', 'NegReg', (49, 57))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('AKT', 'Gene', (101, 104))	('P13K', 'SUBSTITUTION', 'None', (96, 100))	('downregulating', 'NegReg', (77, 91))	('CRC', 'Disease', (58, 61))
345747	31908476	In 2008, Martinez et al reported that miR-451 expression was lower in cell lines containing human papilloma virus-16 and/or -18 DNA than in normal cervical cells.	('lower', 'NegReg', (61, 66))	('human papilloma virus', 'Species', '10566', (92, 113))	('human papilloma virus-16', 'Var', (92, 116))	('papilloma', 'Phenotype', 'HP:0012740', (98, 107))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('expression', 'MPA', (46, 56))
345748	31908476	miR-451 expression was higher in the multidrug resistant (MDR) human cervical cancer cell line KB-3-1 than in its parental cell line KB-V1, and miR-451 antagomirs decreased P-glycoprotein expression and increased doxorubicin sensitivity in MDR cancer cells.	('P-glycoprotein', 'Gene', (173, 187))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('increased', 'PosReg', (203, 212))	('human', 'Species', '9606', (63, 68))	('higher', 'PosReg', (23, 29))	('doxorubicin', 'Chemical', 'MESH:D004317', (213, 224))	('P-glycoprotein', 'Gene', '5243', (173, 187))	('expression', 'MPA', (8, 18))	('antagomirs', 'Var', (152, 162))	('KB-V1', 'CellLine', 'CVCL:2089', (133, 138))	('cancer', 'Disease', (78, 84))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', '220972', (144, 147))	('multidrug resistant', 'Disease', (37, 56))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('miR', 'Gene', (0, 3))	('miR', 'Gene', (144, 147))	('decreased', 'NegReg', (163, 172))	('doxorubicin sensitivity', 'MPA', (213, 236))
345810	31908476	Phua et al found that fecal miR-451 had a sensitivity of 88% and specificity of 100% in detecting CRC.	('CRC', 'Disease', (98, 101))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('fecal', 'Var', (22, 27))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))	('CRC', 'Disease', 'MESH:D015179', (98, 101))
345812	31908476	These data indicate that the abnormal expression of miR-451 is associated with the cancer disease state and that miR-451 has great clinical potential as a noninvasive diagnostic biomarker for numerous human cancers.	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('miR', 'Gene', '220972', (113, 116))	('cancer disease', 'Disease', (83, 97))	('miR', 'Gene', (113, 116))	('cancers', 'Disease', (207, 214))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('associated', 'Reg', (63, 73))	('abnormal', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('human', 'Species', '9606', (201, 206))	('miR', 'Gene', '220972', (52, 55))	('cancer disease', 'Disease', 'MESH:D009369', (83, 97))	('miR', 'Gene', (52, 55))
345821	31908476	In 2018, Wang et al reported that knockdown of long ncRNA TATDN1 increased the expression of miR-451 and improved cisplatin sensitivity of NSCLC in vitro and in vivo by targeting TRIM66.	('increased', 'PosReg', (65, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('expression', 'MPA', (79, 89))	('TRIM66', 'Gene', '9866', (179, 185))	('TATDN1', 'Gene', '83940', (58, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('TATDN1', 'Gene', (58, 64))	('knockdown', 'Var', (34, 43))	('TRIM66', 'Gene', (179, 185))	('cisplatin sensitivity of NSCLC', 'MPA', (114, 144))	('miR', 'Gene', '220972', (93, 96))	('improved', 'PosReg', (105, 113))	('miR', 'Gene', (93, 96))	('targeting', 'Reg', (169, 178))	('SCLC', 'Phenotype', 'HP:0030357', (140, 144))
345833	31908476	In addition, they showed that dysregulation of miR-451/c-Myc-survivin/rad-51 signaling is responsible for radioresistance in DTX-resistant LAD cells.	('DTX', 'Chemical', 'MESH:C081705', (125, 128))	('c-Myc', 'Gene', '4609', (55, 60))	('dysregulation', 'Var', (30, 43))	('miR', 'Gene', '220972', (47, 50))	('LAD', 'Phenotype', 'HP:0030078', (139, 142))	('miR', 'Gene', (47, 50))	('c-Myc', 'Gene', (55, 60))	('radioresistance', 'CPA', (106, 121))	('rad-51', 'Gene', (70, 76))	('LAD', 'Disease', (139, 142))	('LAD', 'Disease', 'MESH:C538231', (139, 142))	('responsible', 'Reg', (90, 101))	('rad-51', 'Gene', '5888', (70, 76))
345835	31908476	Zhang et al found that high miR-451 expression enhanced radiosensitivity in nasopharyngeal carcinoma cells by inhibiting the repair of irradiation-induced double-strand breaks and increasing cell apoptosis.	('enhanced', 'PosReg', (47, 55))	('high', 'Var', (23, 27))	('radiosensitivity', 'MPA', (56, 72))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (76, 100))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (47, 72))	('repair of irradiation-induced double-strand breaks', 'MPA', (125, 175))	('inhibiting', 'NegReg', (110, 120))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('miR', 'Gene', '220972', (28, 31))	('increasing', 'PosReg', (180, 190))	('miR', 'Gene', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Disease', (91, 100))
345843	31908476	Re-expression of miR-451 could reverse EMT to a mesenchymal-epithelial transition in vitro and in vivo and could inhibit invasion and metastasis of the two DTX-resistant LAD cells.	('reverse', 'NegReg', (31, 38))	('DTX', 'Chemical', 'MESH:C081705', (156, 159))	('EMT to a mesenchymal-epithelial transition', 'CPA', (39, 81))	('miR', 'Gene', '220972', (17, 20))	('LAD', 'Phenotype', 'HP:0030078', (170, 173))	('miR', 'Gene', (17, 20))	('inhibit', 'NegReg', (113, 120))	('Re-expression', 'Var', (0, 13))	('LAD', 'Disease', (170, 173))	('LAD', 'Disease', 'MESH:C538231', (170, 173))
345848	31908476	Tumor initiation and progression are complex processes involving consecutive gene mutations and changes in the fundamental biological behavior of cells caused by changes in their neighboring stroma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (82, 91))	('changes', 'Reg', (96, 103))	('men', 'Species', '9606', (116, 119))	('fundamental biological behavior of cells', 'MPA', (111, 151))
345898	31788647	Grades 3 and 4 toxicity was higher in NACT patients receiving cisplatin and 5-fluorouracil (5-FU) but postoperative morbidity was similar in both groups.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('5-fluorouracil', 'Var', (76, 90))	('patients', 'Species', '9606', (43, 51))	('higher', 'PosReg', (28, 34))	('cisplatin', 'Var', (62, 71))	('toxicity', 'Disease', 'MESH:D064420', (15, 23))	('toxicity', 'Disease', (15, 23))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (76, 90))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))
345939	31772939	Patients undergoing McKeown esophagogastrectomy are exposed to a higher risk of infection compared with those receiving other types of surgery.	('Patients', 'Species', '9606', (0, 8))	('McKeown', 'Var', (20, 27))	('infection', 'CPA', (80, 89))
345948	31772939	demonstrated that ALB level <35 g/L was an independent risk factor for postoperative infectious complications in patients with hepatocellular cancer.	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('<35 g/L', 'Var', (28, 35))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (127, 148))	('hepatocellular cancer', 'Disease', (127, 148))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (127, 148))	('ALB', 'MPA', (18, 21))
345987	31558865	Other equipment and accessories included: A high-frequency generator (VIO200D; ERBE ELEKTROMEDIZIN GMBH, Germany), argon plasma coagulation (APC) unit (APC-ICC200; ERBE ELEKTROMEDIZIN GMBH, Germany), IT knife (KD -611L, Olympus, Tokyo, Japan), Dual-knife (KD-650L/Q, Olympus, Tokyo, Japan), injection needle (NM-200U-0423, Olympus, Tokyo, Japan), and hemostatic forceps (FD-410 LR, Olympus, Tokyo, Japan).	('argon', 'Chemical', 'MESH:D001128', (115, 120))	('KD', 'Var', (210, 212))	('NM-200U-0423', 'Var', (309, 321))	('hemostatic forceps', 'Disease', (351, 369))	('hemostatic forceps', 'Disease', 'MESH:D020141', (351, 369))	('KD-650L/Q', 'Var', (256, 265))
346005	31558865	The histology and invasion depth were as follows: Intraepithelial neoplasia, 131 (35.1%); mucosal invasion, 194 (52.0%); SM < 200 mum invasion, 21 (5.6%); and SM >= 200 mum invasion 26 (7.0%).	('SM >= 200 mum invasion', 'Var', (159, 181))	('SM < 200 mum', 'Var', (121, 133))	('mucosal invasion', 'CPA', (90, 106))	('Intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (50, 75))	('neoplasia', 'Phenotype', 'HP:0002664', (66, 75))	('Intraepithelial neoplasia', 'Disease', (50, 75))	('Intraepithelial neoplasia', 'Disease', 'MESH:D018290', (50, 75))
346032	31558865	An RCT reported that the incidence of MWTs was significantly lower with CO2 insufflation than with air insufflation (0% vs 15.6%) during gastric ESD, because CO2 can be rapidly absorbed compared to air.	('MWT', 'Disease', 'MESH:D008309', (38, 41))	('lower', 'NegReg', (61, 66))	('CO2', 'Chemical', 'MESH:D002245', (158, 161))	('MWT', 'Phenotype', 'HP:0032062', (38, 41))	('CO2 insufflation', 'Var', (72, 88))	('CO2', 'Chemical', 'MESH:D002245', (72, 75))	('MWT', 'Disease', (38, 41))
346092	23426188	The RNA interference (RNAi) technique was used to knock down the expression of SRF in Eca-109 cells.	('SRF', 'Gene', '6722', (79, 82))	('SRF', 'Gene', (79, 82))	('knock', 'Var', (50, 55))
346104	23426188	Altered expression of the E-cadherin/beta-catenin complex is associated with de-differentiation, invasion and metastasis of tumors.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('E-cadherin', 'Gene', (26, 36))	('de-differentiation', 'CPA', (77, 95))	('Altered', 'Var', (0, 7))	('beta-catenin', 'Gene', (37, 49))	('metastasis of tumors', 'Disease', 'MESH:D009362', (110, 130))	('E-cadherin', 'Gene', '999', (26, 36))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('expression', 'MPA', (8, 18))	('metastasis of tumors', 'Disease', (110, 130))	('associated', 'Reg', (61, 71))	('invasion', 'CPA', (97, 105))	('beta-catenin', 'Gene', '1499', (37, 49))
346119	23426188	Cells were transfected with small interfering RNA (siRNA) against SRF using the Lipofectamine 2000 transfection reagent according to the manufacturer's instructions (Shanghai GenePharma Co., Ltd, China).	('small', 'Var', (28, 33))	('SRF', 'Gene', '6722', (66, 69))	('Lipofectamine', 'Chemical', 'MESH:C086724', (80, 93))	('SRF', 'Gene', (66, 69))
346120	23426188	siRNA with the following sequences were obtained from GenePharma: i) siRNA-SRF-1107: sense: 5'-GCAAGGCACUGAUUCAGA CTT-3' and antisense: 5'-GUCUGAAUCAGUGCCUUG CTT-3' (in our preliminary experiment, we found that siRNA-SRF 1107 had a higher effect than others measured by real-time PCR and western blot analysis); ii) Negative-siRNA: sense: 5'-UUCUCCGAACGUGUCACGUTT-3' and antisense 5'-ACGUGACACGUUCGGAGAATT-3'.	('SRF', 'Gene', (75, 78))	('SRF', 'Gene', '6722', (217, 220))	('antisense', 'Var', (371, 380))	('SRF', 'Gene', (217, 220))	('SRF', 'Gene', '6722', (75, 78))
346130	23426188	Membranes were blocked with 5% non-fat milk and incubated overnight at 4 C with the primary antibody [anti-SRF; anti-E-cadherin (sc-7870); anti-beta-catenin (sc-7870); anti-cyclin D1 (sc-8376); anti-beta-actin (sc-47778); Santa Cruz Biotechnology] followed by alkaline phosphatase-conjugated secondary antibodies (E030220, E020210; Earthox, San Francisco, CA, USA).	('beta-catenin', 'Gene', (144, 156))	('cyclin D1', 'Gene', '595', (173, 182))	('E030220', 'Var', (314, 321))	('beta-catenin', 'Gene', '1499', (144, 156))	('cyclin D1', 'Gene', (173, 182))	('SRF', 'Gene', '6722', (107, 110))	('beta-actin', 'Gene', '728378', (199, 209))	('beta-actin', 'Gene', (199, 209))	('SRF', 'Gene', (107, 110))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))	('E020210', 'Var', (323, 330))
346132	23426188	The following oligonucleotide primers specific for human genes were used in this study: SRF, sense 5'-CTTAACATGGCATCTTCGACACT-3' and antisense 5'-CTTAACCTCTAATCCCCATTGCT-3'; GAPDH, sense 5'-GGGAAACTGTGGCGTGAT-3' and antisense 5'-TGGGTGTCGCTGTTGAAGT-3'.	('GAPDH', 'Gene', (174, 179))	('SRF', 'Gene', (88, 91))	('human', 'Species', '9606', (51, 56))	('SRF', 'Gene', '6722', (88, 91))	("antisense 5'-TGGGTGTCGCTGTTGAAGT-3", 'Var', (216, 250))	('GAPDH', 'Gene', '2597', (174, 179))
346145	23426188	Therefore, SRF silencing may arrest the cell cycle at the G1 phase in Eca-109 cells.	('arrest', 'PosReg', (29, 35))	('SRF', 'Gene', '6722', (11, 14))	('cell cycle at the G1 phase', 'CPA', (40, 66))	('silencing', 'Var', (15, 24))	('SRF', 'Gene', (11, 14))
346166	23426188	We also found that SRF gene silencing strongly inhibits the cellular invasion that accompanies the upregulation of E-cadherin.	('cellular invasion', 'CPA', (60, 77))	('SRF', 'Gene', (19, 22))	('upregulation', 'PosReg', (99, 111))	('E-cadherin', 'Gene', '999', (115, 125))	('SRF', 'Gene', '6722', (19, 22))	('E-cadherin', 'Gene', (115, 125))	('gene silencing', 'Var', (23, 37))	('inhibits', 'NegReg', (47, 55))
346242	21406386	We observed suggestive evidence that modest alcohol drinking, particularly less than one drink per day, might be associated with reduced EA and EGJA risk.	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('alcohol drinking', 'Phenotype', 'HP:0030955', (44, 60))	('EA', 'Phenotype', 'HP:0011459', (137, 139))	('reduced', 'NegReg', (129, 136))	('EGJA', 'Chemical', '-', (144, 148))	('EGJA', 'Disease', (144, 148))	('less than', 'Var', (75, 84))
346244	21406386	For example, moderate alcohol drinking could be associated with aspects of a healthy lifestyle, such that the observed association reflects confounding.	('alcohol drinking', 'Phenotype', 'HP:0030955', (22, 38))	('associated', 'Reg', (48, 58))	('moderate alcohol drinking', 'Var', (13, 38))	('alcohol', 'Chemical', 'MESH:D000438', (22, 29))
346267	21406386	Moderate alcohol consumption was associated with reduced EA and EGJA cancer risk, though these findings need to be examined further in future prospective cohort studies.	('alcohol', 'Chemical', 'MESH:D000438', (9, 16))	('Moderate alcohol consumption', 'Var', (0, 28))	('reduced', 'NegReg', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('EGJA', 'Chemical', '-', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('EA', 'Phenotype', 'HP:0011459', (57, 59))	('cancer', 'Disease', (69, 75))
346270	21406386	Heavy alcohol consumption is an established cause of esophageal squamous cell carcinoma, but associations with esophageal adenocarcinoma have been inconsistent in past studies.	('esophageal adenocarcinoma', 'Disease', (111, 136))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (111, 136))	('cause', 'Reg', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Heavy alcohol consumption', 'Phenotype', 'HP:0030955', (0, 25))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (53, 87))	('alcohol', 'Chemical', 'MESH:D000438', (6, 13))	('Heavy alcohol consumption', 'Var', (0, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (111, 136))	('esophageal squamous cell carcinoma', 'Disease', (53, 87))
346276	33376519	LINC00488 stimulates the progression of esophageal cancer by targeting microRNA-485-5p Esophageal cancer is the eighth most prevalent malignancy in the world and China has a high incidence of esophageal cancer.	('LINC00488', 'Gene', (0, 9))	('eighth', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('age', 'Gene', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Disease', (98, 104))	('malignancy', 'Disease', (134, 144))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('age', 'Gene', (92, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (192, 209))	('age', 'Gene', '5973', (197, 200))	('esophageal cancer', 'Disease', (192, 209))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('age', 'Gene', '5973', (45, 48))	('eighth', 'Disease', 'MESH:D061285', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('age', 'Gene', '5973', (92, 95))	('cancer', 'Disease', (203, 209))	('microRNA-485-5p', 'Var', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('LINC00488', 'Gene', '677779', (0, 9))	('malignancy', 'Disease', 'MESH:D009369', (134, 144))	('age', 'Gene', (197, 200))	('cancer', 'Disease', (51, 57))	('esophageal cancer', 'Disease', (40, 57))
346286	33376519	Silencing LINC00488 attenuated the viability, migration and wound healing of OE19 and OE33 cells.	('migration', 'CPA', (46, 55))	('viability', 'CPA', (35, 44))	('LINC00488', 'Gene', '677779', (10, 19))	('LINC00488', 'Gene', (10, 19))	('wound healing', 'CPA', (60, 73))	('Silencing', 'Var', (0, 9))	('attenuated', 'NegReg', (20, 30))
346306	33376519	miRNA-485-5p is reported to affect the development of several malignant tumors in humans, such as esophageal and lung cancer.	('affect', 'Reg', (28, 34))	('miRNA-485-5p', 'Chemical', '-', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('miRNA-485-5p', 'Var', (0, 12))	('lung cancer', 'Disease', (113, 124))	('age', 'Gene', '5973', (103, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('development', 'CPA', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('age', 'Gene', (103, 106))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('malignant tumors', 'Disease', (62, 78))	('malignant tumors', 'Disease', 'MESH:D009369', (62, 78))	('humans', 'Species', '9606', (82, 88))
346339	33376519	In addition, Kaplan-Meier curves illustrated worse prognosis in patients with high expression of LINC00488 compared with those with low expression (P<0.05) (Fig.	('high expression', 'Var', (78, 93))	('LINC00488', 'Gene', '677779', (97, 106))	('LINC00488', 'Gene', (97, 106))	('patients', 'Species', '9606', (64, 72))
346344	33376519	The Transwell assay revealed migration was attenuated after silencing LINC00488 expression in OE19 and OE33 cells compared with sh-NC (Fig.	('migration', 'CPA', (29, 38))	('attenuated', 'NegReg', (43, 53))	('expression', 'MPA', (80, 90))	('silencing', 'Var', (60, 69))	('LINC00488', 'Gene', (70, 79))	('LINC00488', 'Gene', '677779', (70, 79))
346349	33376519	miRNA-485-5p was the most significantly upregulated by transfection of sh-LINC00488-1 (Fig.	('miRNA-485-5p', 'Chemical', '-', (0, 12))	('LINC00488', 'Gene', '677779', (74, 83))	('LINC00488', 'Gene', (74, 83))	('transfection', 'Var', (55, 67))	('upregulated', 'PosReg', (40, 51))
346350	33376519	In esophageal cancer tissues and cells, miRNA-485-5p was markedly downregulated (Fig.	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('downregulated', 'NegReg', (66, 79))	('miRNA-485-5p', 'Var', (40, 52))	('miRNA-485-5p', 'Chemical', '-', (40, 52))
346351	33376519	A negative correlation between expression levels of miRNA-485-5p and LINC00488 in esophageal cancer tissues was identified (r=0.748; P<0.05; Fig.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('negative', 'NegReg', (2, 10))	('miRNA-485-5p', 'Var', (52, 64))	('expression levels', 'MPA', (31, 48))	('miRNA-485-5p', 'Chemical', '-', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('LINC00488', 'Gene', '677779', (69, 78))	('LINC00488', 'Gene', (69, 78))	('esophageal cancer', 'Disease', (82, 99))
346352	33376519	Kaplan-Meier curves illustrated significantly worse prognosis in patients expressing low levels of miRNA-485-5p compared with those with high levels (P<0.05) (Fig.	('miRNA-485-5p', 'Chemical', '-', (99, 111))	('miRNA-485-5p', 'Var', (99, 111))	('patients', 'Species', '9606', (65, 73))	('low levels', 'Var', (85, 95))
346353	33376519	In addition, bioinformatics analysis reported that miR-485-5p could bind to LINC00488 mutant and wild-type sequences.	('miR-485', 'Gene', '574436', (51, 58))	('miR-485', 'Gene', (51, 58))	('mutant', 'Var', (86, 92))	('bind', 'Interaction', (68, 72))	('LINC00488', 'Gene', (76, 85))	('5p', 'Chemical', '-', (59, 61))	('LINC00488', 'Gene', '677779', (76, 85))
346357	33376519	The decreased proliferation rate owing to LINC00488-knockdown was reversed by silencing miRNA-485-5p (Fig.	('miRNA-485-5p', 'Gene', (88, 100))	('decreased', 'NegReg', (4, 13))	('proliferation rate', 'CPA', (14, 32))	('silencing', 'Var', (78, 87))	('LINC00488', 'Gene', '677779', (42, 51))	('LINC00488', 'Gene', (42, 51))	('miRNA-485-5p', 'Chemical', '-', (88, 100))
346358	33376519	Notably, reduced migratory cell number and wound closure percentage owing to LINC00488-knockdown were also reversed by silencing miRNA-485-5p expression (Fig.	('age', 'Gene', (64, 67))	('silencing', 'Var', (119, 128))	('LINC00488', 'Gene', (77, 86))	('migratory cell number', 'CPA', (17, 38))	('LINC00488', 'Gene', '677779', (77, 86))	('age', 'Gene', '5973', (64, 67))	('reduced', 'NegReg', (9, 16))	('miRNA-485-5p', 'Chemical', '-', (129, 141))	('miRNA-485-5p', 'Protein', (129, 141))
346367	33376519	Silencing LINC00488 attenuated the proliferative and migratory potentials of OE19 and OE33 cells.	('Silencing', 'Var', (0, 9))	('LINC00488', 'Gene', (10, 19))	('LINC00488', 'Gene', '677779', (10, 19))	('attenuated', 'NegReg', (20, 30))
346371	33376519	miRNA-485-5p was downregulated in esophageal cancer and its low level predicted a poor prognosis in patients with esophageal cancer.	('miRNA-485-5p', 'Chemical', '-', (0, 12))	('esophageal cancer', 'Disease', (34, 51))	('miRNA-485-5p', 'Var', (0, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('downregulated', 'NegReg', (17, 30))	('esophageal cancer', 'Disease', (114, 131))	('patients', 'Species', '9606', (100, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))
346373	33376519	Rescue experiments showed that knockdown of miRNA-485-5p reversed the attenuated proliferative and migratory potentials of esophageal cancer cells with LINC00488-knockdown.	('esophageal cancer', 'Disease', (123, 140))	('attenuated', 'NegReg', (70, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('miRNA-485-5p', 'Chemical', '-', (44, 56))	('miRNA-485-5p', 'Var', (44, 56))	('LINC00488', 'Gene', '677779', (152, 161))	('LINC00488', 'Gene', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
346375	33376519	Notably, further animal and high-quality clinical studies are needed to provide more comprehensive understanding of the association between LINC00488, miRNA-485-5p and esophageal cancer in the future.	('esophageal cancer', 'Disease', (168, 185))	('miRNA-485-5p', 'Chemical', '-', (151, 163))	('miRNA-485-5p', 'Var', (151, 163))	('association', 'Interaction', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('LINC00488', 'Gene', (140, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('LINC00488', 'Gene', '677779', (140, 149))
346379	32398095	Neddylation inhibition activates the protective autophagy through NF-kappaB-catalase-ATF3 Axis in human esophageal cancer cells Protein neddylation plays a tumor-promoting role in esophageal cancer.	('esophageal cancer', 'Disease', (180, 197))	('activates', 'PosReg', (23, 32))	('NF-kappaB', 'Gene', '4790', (66, 75))	('tumor', 'Disease', (156, 161))	('ATF3', 'Gene', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('catalase', 'Gene', (76, 84))	('catalase', 'Gene', '847', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('protective autophagy', 'CPA', (37, 57))	('inhibition', 'NegReg', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('ATF3', 'Gene', '467', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (180, 197))	('NF-kappaB', 'Gene', (66, 75))	('neddylation', 'Var', (136, 147))	('human', 'Species', '9606', (98, 103))
346384	32398095	The proliferation inhibition induced by MLN4924 was evaluated by ATPLite assay and apoptosis was evaluated by Annexin V /PI double staining.	('inhibition', 'NegReg', (18, 28))	('proliferation', 'CPA', (4, 17))	('MLN4924', 'Chemical', 'MESH:C539933', (40, 47))	('Annexin V', 'Gene', '308', (110, 119))	('Annexin V', 'Gene', (110, 119))	('MLN4924', 'Var', (40, 47))
346385	32398095	For the first time, we reported that MLN4924, a specific inhibitor of Nedd8-activating enzyme, promoted the expression of ATF3 to induce autophagy in esophageal cancer.	('esophageal cancer', 'Disease', (150, 167))	('induce', 'PosReg', (130, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('promoted', 'PosReg', (95, 103))	('Nedd8', 'Gene', '4738', (70, 75))	('ATF3', 'Gene', '467', (122, 126))	('MLN4924', 'Chemical', 'MESH:C539933', (37, 44))	('Nedd8', 'Gene', (70, 75))	('ATF3', 'Gene', (122, 126))	('autophagy', 'CPA', (137, 146))	('MLN4924', 'Var', (37, 44))	('expression', 'MPA', (108, 118))
346386	32398095	Mechanistically, MLN4924 inhibited the activity of CRLs and induced the accumulation of its substrate IkappaBalpha to block NF-kappaB activation and Catalase expression.	('activation', 'MPA', (134, 144))	('expression', 'MPA', (158, 168))	('Catalase', 'Gene', '847', (149, 157))	('MLN4924', 'Var', (17, 24))	('CRL', 'Gene', (51, 54))	('Catalase', 'Gene', (149, 157))	('block', 'NegReg', (118, 123))	('activity', 'MPA', (39, 47))	('MLN4924', 'Chemical', 'MESH:C539933', (17, 24))	('IkappaBalpha', 'Gene', '4792', (102, 114))	('accumulation', 'MPA', (72, 84))	('NF-kappaB', 'Gene', '4790', (124, 133))	('CRL', 'Gene', '133396', (51, 54))	('inhibited', 'NegReg', (25, 34))	('NF-kappaB', 'Gene', (124, 133))	('IkappaBalpha', 'Gene', (102, 114))
346387	32398095	As a result, MLN4924 activated ATF3-induced protective autophagy, thereby inhibiting MLN4924-induced apoptosis, which could be alleviated by ATF3 silencing.	('inhibiting', 'NegReg', (74, 84))	('protective autophagy', 'CPA', (44, 64))	('ATF3', 'Gene', (31, 35))	('ATF3', 'Gene', (141, 145))	('MLN4924', 'Chemical', 'MESH:C539933', (85, 92))	('MLN4924', 'Chemical', 'MESH:C539933', (13, 20))	('apoptosis', 'CPA', (101, 110))	('activated', 'PosReg', (21, 30))	('ATF3', 'Gene', '467', (31, 35))	('MLN4924-induced', 'Var', (85, 100))	('ATF3', 'Gene', '467', (141, 145))	('MLN4924', 'Var', (13, 20))
346388	32398095	In our study, we elucidates a novel mechanism of NF-kappaB/Catalase/ATF3 pathway in MLN4924-induced protective autophagy in esophageal cancer cells, which provides a sound rationale and molecular basis for combinational anti-ESCC therapy with knockdown ATF3 and neddylation inhibitor (e.g.	('Catalase', 'Gene', (59, 67))	('ATF3', 'Gene', '467', (253, 257))	('esophageal cancer', 'Disease', (124, 141))	('ATF3', 'Gene', '467', (68, 72))	('MLN4924', 'Chemical', 'MESH:C539933', (84, 91))	('ATF3', 'Gene', (253, 257))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('Catalase', 'Gene', '847', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ATF3', 'Gene', (68, 72))	('MLN4924-induced', 'Var', (84, 99))	('NF-kappaB', 'Gene', '4790', (49, 58))	('NF-kappaB', 'Gene', (49, 58))
346395	32398095	Accumulated studies show that protein neddylation is elevated in multiple human cancers and inhibition of this pathway has been developed as a promising anticancer strategy.	('inhibition', 'Var', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('elevated', 'PosReg', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (157, 163))	('human', 'Species', '9606', (74, 79))	('protein', 'Protein', (30, 37))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
346397	32398095	MLN4924 could block cullin neddylation to inhibit the activation of CRLs, thus inducing the accumulation of tumor-suppressive CRL substrates to inhibit tumor growth and metastasis both in vitro and in vivo.	('CRL', 'Gene', (126, 129))	('tumor', 'Disease', (108, 113))	('inhibit', 'NegReg', (144, 151))	('activation', 'MPA', (54, 64))	('CRL', 'Gene', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('inducing', 'Reg', (79, 87))	('tumor', 'Disease', (152, 157))	('CRL', 'Gene', '133396', (126, 129))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('MLN4924', 'Var', (0, 7))	('accumulation', 'MPA', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CRL', 'Gene', '133396', (68, 71))	('cullin', 'Gene', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cullin', 'Gene', '143384', (20, 26))	('inhibit', 'NegReg', (42, 49))
346398	32398095	For its significant anticancer efficacy and well-tolerated toxicity, MLN4924 has been advanced into several phase II/III clinical trials against several solid tumors and hematologic malignancies.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('MLN4924', 'Var', (69, 76))	('hematologic malignancies', 'Disease', 'MESH:D019337', (170, 194))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('toxicity', 'Disease', 'MESH:D064420', (59, 67))	('toxicity', 'Disease', (59, 67))	('tumors', 'Disease', (159, 165))	('hematologic malignancies', 'Disease', (170, 194))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('MLN4924', 'Chemical', 'MESH:C539933', (69, 76))
346399	32398095	Mechanistic studies showed that MLN4924 effectively induced DNA re-replication stress/DNA damage response, cell-cycle arrest, apoptosis or senescence in a cell-type-dependent manner.	('senescence', 'CPA', (139, 149))	('MLN4924', 'Chemical', 'MESH:C539933', (32, 39))	('stress', 'Disease', 'MESH:D000079225', (79, 85))	('arrest', 'Disease', 'MESH:D006323', (118, 124))	('apoptosis', 'CPA', (126, 135))	('stress', 'Disease', (79, 85))	('MLN4924', 'Var', (32, 39))	('arrest', 'Disease', (118, 124))	('induced', 'Reg', (52, 59))
346400	32398095	Moreover, MLN4924 also induced pro-survival autophagic responses in cancer cells partially via modulating the HIF1-REDD1-TSC1 or Deptor-mTORC1 pathways.	('HIF1', 'Gene', (110, 114))	('mTORC1', 'Gene', '382056', (136, 142))	('REDD1', 'Gene', '54541', (115, 120))	('MLN4924', 'Var', (10, 17))	('Deptor', 'Gene', '64798', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('HIF1', 'Gene', '3091', (110, 114))	('Deptor', 'Gene', (129, 135))	('REDD1', 'Gene', (115, 120))	('pro-survival autophagic responses', 'CPA', (31, 64))	('mTORC1', 'Gene', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('TSC1', 'Gene', '7248', (121, 125))	('modulating', 'Reg', (95, 105))	('MLN4924', 'Chemical', 'MESH:C539933', (10, 17))	('induced', 'PosReg', (23, 30))	('TSC1', 'Gene', (121, 125))
346405	32398095	Here, for the first time, we reported that neddylation inhibition with MLN4924 induces the accumulation of ATF3 to trigger pro-survival autophagy by modulating NF-kappaB-Catalase-ROS-ATF3 axis in esophageal cancer cells, highlighting targeting ATF3-mediated autophagy as a potential strategy to enhance neddylation-targeted anti-ESCC therapy.	('NF-kappaB', 'Gene', (160, 169))	('ATF3', 'Gene', '467', (183, 187))	('NF-kappaB', 'Gene', '4790', (160, 169))	('inhibition', 'NegReg', (55, 65))	('ATF3', 'Gene', (107, 111))	('neddylation', 'Protein', (43, 54))	('MLN4924', 'Var', (71, 78))	('trigger', 'PosReg', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('ATF3', 'Gene', (183, 187))	('Catalase', 'Gene', (170, 178))	('ATF3', 'Gene', '467', (244, 248))	('modulating', 'Reg', (149, 159))	('pro-survival', 'CPA', (123, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('MLN4924', 'Chemical', 'MESH:C539933', (71, 78))	('ROS', 'Chemical', 'MESH:D017382', (179, 182))	('Catalase', 'Gene', '847', (170, 178))	('ATF3', 'Gene', '467', (107, 111))	('esophageal cancer', 'Disease', (196, 213))	('ATF3', 'Gene', (244, 248))
346421	32398095	Since MLN4924 treatment induced the accumulation of ATF4, a member of ATF/CREB subfamily, in esophageal cancer cells, we reasoned whether neddylation inhibition could affect the expression of other members of ATF/CREB subfamily, such as ATF3.	('ATF3', 'Gene', (237, 241))	('CREB', 'Gene', '1385', (74, 78))	('esophageal cancer', 'Disease', (93, 110))	('expression', 'MPA', (178, 188))	('MLN4924', 'Chemical', 'MESH:C539933', (6, 13))	('ATF4', 'Gene', (52, 56))	('ATF', 'Gene', (237, 240))	('ATF4', 'Gene', '468', (52, 56))	('ATF', 'Gene', '2668', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CREB', 'Gene', (213, 217))	('ATF', 'Gene', '2668', (209, 212))	('ATF', 'Gene', (70, 73))	('ATF', 'Gene', '2668', (52, 55))	('affect', 'Reg', (167, 173))	('ATF', 'Gene', (209, 212))	('CREB', 'Gene', '1385', (213, 217))	('ATF3', 'Gene', '467', (237, 241))	('CREB', 'Gene', (74, 78))	('MLN4924', 'Var', (6, 13))	('ATF', 'Gene', (52, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('ATF', 'Gene', '2668', (237, 240))	('accumulation', 'PosReg', (36, 48))
346422	32398095	Therefore, we determined the effects of MLN4924 on the expression of ATF3 in EC1 and Kyse450 cells.	('ATF3', 'Gene', (69, 73))	('MLN4924', 'Chemical', 'MESH:C539933', (40, 47))	('ATF3', 'Gene', '467', (69, 73))	('MLN4924', 'Var', (40, 47))	('EC1', 'Gene', (77, 80))	('EC1', 'Gene', '4819', (77, 80))
346423	32398095	We found that MLN4924 significantly induced the accumulation of ATF3 in both EC1 and Kyse450 cells (Fig.	('ATF3', 'Gene', '467', (64, 68))	('MLN4924', 'Var', (14, 21))	('accumulation', 'PosReg', (48, 60))	('ATF3', 'Gene', (64, 68))	('EC1', 'Gene', (77, 80))	('EC1', 'Gene', '4819', (77, 80))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))
346425	32398095	Unexpectedly, the half-life of ATF3 was not influenced upon the inactivation of neddylation-CRL axis by MLN4924 (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (104, 111))	('ATF3', 'Gene', (31, 35))	('MLN4924', 'Var', (104, 111))	('CRL', 'Gene', '133396', (92, 95))	('ATF3', 'Gene', '467', (31, 35))	('CRL', 'Gene', (92, 95))
346429	32398095	1g-h, the expression of ATF3 in transcriptional level was statistically elevated in EC1 and Kyse450 cells upon MLN4924 treatment.	('elevated', 'PosReg', (72, 80))	('MLN4924', 'Chemical', 'MESH:C539933', (111, 118))	('MLN4924', 'Var', (111, 118))	('expression', 'MPA', (10, 20))	('ATF3', 'Gene', '467', (24, 28))	('EC1', 'Gene', '4819', (84, 87))	('EC1', 'Gene', (84, 87))	('ATF3', 'Gene', (24, 28))
346430	32398095	These findings collectively demonstrated that MLN4924 induced the transactivation of ATF3.	('transactivation', 'MPA', (66, 81))	('ATF3', 'Gene', '467', (85, 89))	('MLN4924', 'Chemical', 'MESH:C539933', (46, 53))	('MLN4924', 'Var', (46, 53))	('ATF3', 'Gene', (85, 89))
346431	32398095	We investigated whether and how ATF3 mediates MLN4924-induced cellular responses.	('ATF3', 'Gene', '467', (32, 36))	('MLN4924-induced', 'Var', (46, 61))	('ATF3', 'Gene', (32, 36))	('MLN4924', 'Chemical', 'MESH:C539933', (46, 53))
346432	32398095	As shown, MLN4924 induced the conversion of LC3-I to LC3-II, a classical marker of autophagy, in dose-dependent and time-dependent manner in EC1 and Kyse450 cells (Fig.	('MLN4924', 'Var', (10, 17))	('EC1', 'Gene', '4819', (141, 144))	('EC1', 'Gene', (141, 144))	('conversion', 'MPA', (30, 40))	('LC3', 'Gene', '84557', (44, 47))	('LC3', 'Gene', '84557', (53, 56))	('MLN4924', 'Chemical', 'MESH:C539933', (10, 17))	('LC3', 'Gene', (44, 47))	('LC3', 'Gene', (53, 56))
346434	32398095	As expected, CQ and BafA1 enhanced, while 3MA inhibited the accumulation of LC3-II, indicating that autophagic flux was intact and supraphysiological autophagic response was induced by MLN4924 treatment (Fig.	('enhanced', 'PosReg', (26, 34))	('MLN4924', 'Var', (185, 192))	('BafA1', 'Chemical', 'MESH:C040929', (20, 25))	('3MA', 'Chemical', 'MESH:C025946', (42, 45))	('induced', 'Reg', (174, 181))	('LC3', 'Gene', '84557', (76, 79))	('LC3', 'Gene', (76, 79))	('autophagic flux', 'CPA', (100, 115))	('MLN4924', 'Chemical', 'MESH:C539933', (185, 192))	('inhibited', 'NegReg', (46, 55))	('CQ', 'Chemical', 'MESH:D002738', (13, 15))
346435	32398095	To determine the potential role of ATF3 in MLN4924-induced autophagy, the expression of ATF3 is down-regulated via siRNA silencing.	('expression', 'MPA', (74, 84))	('ATF3', 'Gene', '467', (88, 92))	('siRNA', 'MPA', (115, 120))	('ATF3', 'Gene', (35, 39))	('ATF3', 'Gene', (88, 92))	('down-regulated', 'NegReg', (96, 110))	('MLN4924', 'Chemical', 'MESH:C539933', (43, 50))	('MLN4924-induced', 'Var', (43, 58))	('ATF3', 'Gene', '467', (35, 39))
346436	32398095	2e-f, the ATF3 knockdown completely blocked the conversion of LC3-I to LC3-II upon MLN4924 treatment, indicating a crucial role of ATF3 in MLN4924-induced autophagy in esophageal cancer cells.	('LC3', 'Gene', '84557', (62, 65))	('esophageal cancer', 'Disease', (168, 185))	('LC3', 'Gene', (62, 65))	('MLN4924', 'Var', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('ATF3', 'Gene', (131, 135))	('blocked', 'NegReg', (36, 43))	('MLN4924', 'Chemical', 'MESH:C539933', (139, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('ATF3', 'Gene', '467', (10, 14))	('MLN4924-induced', 'Var', (139, 154))	('LC3', 'Gene', '84557', (71, 74))	('conversion', 'MPA', (48, 58))	('LC3', 'Gene', (71, 74))	('MLN4924', 'Chemical', 'MESH:C539933', (83, 90))	('ATF3', 'Gene', '467', (131, 135))	('ATF3', 'Gene', (10, 14))
346440	32398095	Next we determined the role of ATF3-mediated autophagy response upon MLN4924 treatment in esophageal cancer cells.	('ATF3', 'Gene', (31, 35))	('MLN4924', 'Var', (69, 76))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ATF3', 'Gene', '467', (31, 35))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('MLN4924', 'Chemical', 'MESH:C539933', (69, 76))
346441	32398095	Firstly, we blocked autophagy via both pharmacological (siRNA silencing of autophagy essential gene Beclin1) and genetic approaches (using autophagy inhibitor CQ), and found that blocking autophagy significantly enhanced the MLN4924-induced proliferation inhibition in EC1 and Kyse450 cells (Fig.	('enhanced', 'PosReg', (212, 220))	('CQ', 'Chemical', 'MESH:D002738', (159, 161))	('MLN4924', 'Chemical', 'MESH:C539933', (225, 232))	('EC1', 'Gene', '4819', (269, 272))	('EC1', 'Gene', (269, 272))	('Beclin1', 'Gene', (100, 107))	('blocking', 'Var', (179, 187))	('proliferation inhibition', 'CPA', (241, 265))	('MLN4924-induced', 'Var', (225, 240))	('autophagy', 'CPA', (188, 197))	('Beclin1', 'Gene', '8678', (100, 107))
346442	32398095	3a-b), indicating the pro-survival role of MLN4924-induced autophagy.	('MLN4924-induced', 'Var', (43, 58))	('autophagy', 'CPA', (59, 68))	('MLN4924', 'Chemical', 'MESH:C539933', (43, 50))
346443	32398095	Consistently, the inhibition of autophagic response by siBeclin1 and CQ significantly enhanced MLN4924-induced apoptosis (Fig.	('inhibition', 'NegReg', (18, 28))	('Beclin1', 'Gene', (57, 64))	('MLN4924', 'Chemical', 'MESH:C539933', (95, 102))	('CQ', 'Chemical', 'MESH:D002738', (69, 71))	('Beclin1', 'Gene', '8678', (57, 64))	('enhanced', 'PosReg', (86, 94))	('MLN4924-induced', 'Var', (95, 110))	('autophagic response', 'CPA', (32, 51))
346445	32398095	Furthermore, we found that ATF3 knockdown significantly enhanced MLN4924-induced proliferation inhibition (Fig.	('MLN4924-induced', 'Var', (65, 80))	('MLN4924', 'Chemical', 'MESH:C539933', (65, 72))	('proliferation inhibition', 'CPA', (81, 105))	('ATF3', 'Gene', '467', (27, 31))	('enhanced', 'PosReg', (56, 64))	('ATF3', 'Gene', (27, 31))
346446	32398095	In addition, ATF3 knockdown significantly enhanced MLN4924-induced apoptosis, as evidenced by the accumulation of cleaved PARP (Fig.	('accumulation', 'PosReg', (98, 110))	('apoptosis', 'CPA', (67, 76))	('MLN4924-induced', 'Var', (51, 66))	('PARP', 'Gene', (122, 126))	('ATF3', 'Gene', '467', (13, 17))	('enhanced', 'PosReg', (42, 50))	('ATF3', 'Gene', (13, 17))	('MLN4924', 'Chemical', 'MESH:C539933', (51, 58))	('PARP', 'Gene', '1302', (122, 126))
346448	32398095	These results demonstrated that MLN4924 induced the ATF3-mediated autophagy as a pro-survival signal in esophageal cancer cells.	('MLN4924', 'Chemical', 'MESH:C539933', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('MLN4924', 'Var', (32, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('ATF3', 'Gene', '467', (52, 56))	('induced', 'PosReg', (40, 47))	('ATF3', 'Gene', (52, 56))
346449	32398095	Previous studies indicated that ROS could induce ATF3 expression and MLN4924 could induce ROS production in cancer cells.	('MLN4924', 'Var', (69, 76))	('induce', 'Reg', (42, 48))	('induce', 'Reg', (83, 89))	('ROS', 'Chemical', 'MESH:D017382', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ROS production', 'MPA', (90, 104))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('ATF3', 'Gene', '467', (49, 53))	('ROS', 'Chemical', 'MESH:D017382', (32, 35))	('MLN4924', 'Chemical', 'MESH:C539933', (69, 76))	('cancer', 'Disease', (108, 114))	('ATF3', 'Gene', (49, 53))
346450	32398095	Based on these findings, we determined whether MLN4924-induced ATF3 accumulation is mediated by ROS.	('accumulation', 'PosReg', (68, 80))	('mediated', 'Reg', (84, 92))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('ROS', 'Protein', (96, 99))	('MLN4924', 'Chemical', 'MESH:C539933', (47, 54))	('ATF3', 'Gene', '467', (63, 67))	('MLN4924-induced', 'Var', (47, 62))	('ATF3', 'Gene', (63, 67))
346451	32398095	We firstly detected cellular ROS level with the cell permeable ROS indicator, 2', 7'-dichlorodihydrofuorescein diacetate (H2-DCFDA), and found that MLN4924 significantly induced ROS production in both EC1 and Kyse450 cells (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (148, 155))	('ROS production', 'MPA', (178, 192))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('EC1', 'Gene', (201, 204))	('MLN4924', 'Var', (148, 155))	('EC1', 'Gene', '4819', (201, 204))	('induced', 'PosReg', (170, 177))	('H2-DCFDA', 'Chemical', 'MESH:C110400', (122, 130))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))	('ROS', 'Chemical', 'MESH:D017382', (178, 181))
346452	32398095	Furthermore, we determined the role of ROS in MLN4924-induced ATF3 expression and autophagy.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('ATF3', 'Gene', (62, 66))	('MLN4924', 'Chemical', 'MESH:C539933', (46, 53))	('ATF3', 'Gene', '467', (62, 66))	('MLN4924-induced', 'Var', (46, 61))	('autophagy', 'CPA', (82, 91))	('expression', 'MPA', (67, 77))
346454	32398095	4c) induced by MLN4924.	('induced', 'Reg', (4, 11))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('MLN4924', 'Var', (15, 22))
346455	32398095	Given that Catalase and SOD1, as ubiquitous antioxidant enzymes, could inhibit the generation of ROS, we determine whether MLN4924 regulates the expression of Catalase or SOD1.	('Catalase', 'Gene', '847', (11, 19))	('Catalase', 'Gene', '847', (159, 167))	('generation of ROS', 'MPA', (83, 100))	('SOD1', 'Gene', '6647', (171, 175))	('Catalase', 'Gene', (11, 19))	('Catalase', 'Gene', (159, 167))	('inhibit', 'NegReg', (71, 78))	('MLN4924', 'Chemical', 'MESH:C539933', (123, 130))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('regulates', 'Reg', (131, 140))	('MLN4924', 'Var', (123, 130))	('SOD1', 'Gene', (171, 175))	('SOD1', 'Gene', (24, 28))	('SOD1', 'Gene', '6647', (24, 28))
346456	32398095	4d-e, MLN4924 significantly reduced the expression of Catalase at protein and mRNA levels but do not reduce the expression of SOD1.	('expression', 'MPA', (40, 50))	('MLN4924', 'Var', (6, 13))	('reduced', 'NegReg', (28, 35))	('mRNA', 'MPA', (78, 82))	('Catalase', 'Gene', (54, 62))	('Catalase', 'Gene', '847', (54, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (6, 13))	('SOD1', 'Gene', (126, 130))	('SOD1', 'Gene', '6647', (126, 130))
346457	32398095	In order to determine the role of Catalase in MLN4924-induced ROS production and autophagy, Catalase was ectopically expressed in EC1 and Kyse450 cells with or without MLN4924 treatment.	('Catalase', 'Gene', (34, 42))	('EC1', 'Gene', '4819', (130, 133))	('EC1', 'Gene', (130, 133))	('MLN4924', 'Chemical', 'MESH:C539933', (46, 53))	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('MLN4924-induced', 'Var', (46, 61))	('Catalase', 'Gene', (92, 100))	('MLN4924', 'Chemical', 'MESH:C539933', (168, 175))	('Catalase', 'Gene', '847', (92, 100))	('Catalase', 'Gene', '847', (34, 42))
346458	32398095	Indeed, Catalase expression significantly reversed MLN4924-induced ROS production (Fig.	('MLN4924-induced', 'Var', (51, 66))	('Catalase', 'Gene', (8, 16))	('Catalase', 'Gene', '847', (8, 16))	('ROS', 'Chemical', 'MESH:D017382', (67, 70))	('MLN4924', 'Chemical', 'MESH:C539933', (51, 58))	('ROS production', 'MPA', (67, 81))
346459	32398095	Moreover, Catalase expression completely blocked the conversion of LC3-I to LC3-II upon MLN4924 treatment (Fig.	('conversion', 'MPA', (53, 63))	('LC3', 'Gene', '84557', (67, 70))	('MLN4924', 'Chemical', 'MESH:C539933', (88, 95))	('LC3', 'Gene', '84557', (76, 79))	('LC3', 'Gene', (76, 79))	('blocked', 'NegReg', (41, 48))	('MLN4924 treatment', 'Var', (88, 105))	('LC3', 'Gene', (67, 70))	('Catalase', 'Gene', (10, 18))	('Catalase', 'Gene', '847', (10, 18))
346460	32398095	These findings demonstrated that MLN4924 induced ROS/ATF3 axis to trigger autophagy by reducing Catalase expression in esophageal cancer cells.	('Catalase', 'Gene', (96, 104))	('ATF3', 'Gene', '467', (53, 57))	('trigger', 'PosReg', (66, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('ATF3', 'Gene', (53, 57))	('reducing', 'NegReg', (87, 95))	('autophagy', 'CPA', (74, 83))	('MLN4924', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Catalase', 'Gene', '847', (96, 104))	('esophageal cancer', 'Disease', (119, 136))
346461	32398095	Since Catalase serves as a classical target gene of NF-kappaB, we next determined whether the inhibitory effect of MLN4924 on Catalase expression and ATF3-induced autophagy is mediated by NF-kappaB pathway.	('Catalase', 'Gene', (6, 14))	('MLN4924', 'Chemical', 'MESH:C539933', (115, 122))	('NF-kappaB', 'Gene', '4790', (188, 197))	('ATF3', 'Gene', '467', (150, 154))	('NF-kappaB', 'Gene', (188, 197))	('MLN4924', 'Var', (115, 122))	('NF-kappaB', 'Gene', '4790', (52, 61))	('expression', 'MPA', (135, 145))	('NF-kappaB', 'Gene', (52, 61))	('ATF3', 'Gene', (150, 154))	('Catalase', 'Gene', (126, 134))	('Catalase', 'Gene', '847', (6, 14))	('Catalase', 'Gene', '847', (126, 134))
346463	32398095	As expected, MLN4924 treatment significantly inhibited global protein neddylation and Cullin1 neddylation, indicating the inactivation of CRL E3 ligase.	('inactivation', 'NegReg', (122, 134))	('MLN4924 treatment', 'Var', (13, 30))	('global protein neddylation', 'MPA', (55, 81))	('CRL', 'Gene', (138, 141))	('Cullin1', 'Gene', '8454', (86, 93))	('MLN4924', 'Chemical', 'MESH:C539933', (13, 20))	('inhibited', 'NegReg', (45, 54))	('Cullin1', 'Gene', (86, 93))	('CRL', 'Gene', '133396', (138, 141))
346465	32398095	Moreover, IkappaBalpha knockdown markedly attenuated MLN4924-induced reduction of Catalase, accumulation of ATF3 and induction of autophagy (Fig.	('ATF3', 'Gene', (108, 112))	('IkappaBalpha', 'Gene', (10, 22))	('attenuated', 'NegReg', (42, 52))	('MLN4924', 'Chemical', 'MESH:C539933', (53, 60))	('MLN4924-induced', 'Var', (53, 68))	('Catalase', 'Gene', '847', (82, 90))	('Catalase', 'Gene', (82, 90))	('autophagy', 'CPA', (130, 139))	('ATF3', 'Gene', '467', (108, 112))	('reduction', 'NegReg', (69, 78))	('IkappaBalpha', 'Gene', '4792', (10, 22))	('accumulation', 'PosReg', (92, 104))
346466	32398095	We further explored whether IkappaBalpha knockdown has the similar role of ATF3 knockdown-enhanced MLN4924-induced proliferation inhibition in EC1 and Kyse450 cells.	('EC1', 'Gene', '4819', (143, 146))	('EC1', 'Gene', (143, 146))	('knockdown-enhanced', 'Var', (80, 98))	('IkappaBalpha', 'Gene', (28, 40))	('ATF3', 'Gene', '467', (75, 79))	('knockdown-enhanced', 'PosReg', (80, 98))	('MLN4924', 'Chemical', 'MESH:C539933', (99, 106))	('proliferation', 'CPA', (115, 128))	('ATF3', 'Gene', (75, 79))	('inhibition', 'NegReg', (129, 139))	('MLN4924-induced', 'Var', (99, 114))	('IkappaBalpha', 'Gene', '4792', (28, 40))
346467	32398095	5c, IkappaBalpha knockdown also significantly increased MLN4924-induced proliferation inhibition.	('proliferation inhibition', 'CPA', (72, 96))	('IkappaBalpha', 'Gene', (4, 16))	('increased', 'PosReg', (46, 55))	('MLN4924-induced', 'Var', (56, 71))	('IkappaBalpha', 'Gene', '4792', (4, 16))	('MLN4924', 'Chemical', 'MESH:C539933', (56, 63))
346468	32398095	These findings collectively demonstrated that MLN4924 inhibited NF-kappaB pathway to reduce Catalase expression, which promoted the ROS generation to eventually induce ATF3 accumulation and autophagic response.	('inhibited', 'NegReg', (54, 63))	('autophagic response', 'CPA', (190, 209))	('NF-kappaB', 'Gene', '4790', (64, 73))	('MLN4924', 'Chemical', 'MESH:C539933', (46, 53))	('induce', 'PosReg', (161, 167))	('ROS', 'MPA', (132, 135))	('promoted', 'PosReg', (119, 127))	('reduce', 'NegReg', (85, 91))	('MLN4924', 'Var', (46, 53))	('NF-kappaB', 'Gene', (64, 73))	('Catalase', 'Gene', (92, 100))	('ATF3', 'Gene', '467', (168, 172))	('Catalase', 'Gene', '847', (92, 100))	('ROS', 'Chemical', 'MESH:D017382', (132, 135))	('reduce Catalase expression', 'Phenotype', 'HP:0012517', (85, 111))	('ATF3', 'Gene', (168, 172))
346470	32398095	Recently, protein neddylation pathway has emerged as a promising anti-ESCC target, as best supported by the discovery of overactivation of the neddylation pathway in esophageal cancer and the potent anti-ESCC effects of specific NAE inhibitor MLN4924 in preclinical trials.	('NAE', 'Chemical', '-', (229, 232))	('esophageal cancer', 'Disease', (166, 183))	('neddylation pathway', 'Pathway', (143, 162))	('MLN4924', 'Chemical', 'MESH:C539933', (243, 250))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('overactivation', 'PosReg', (121, 135))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('MLN4924', 'Var', (243, 250))
346471	32398095	In the present study, we reported for the first time to our knowledge that MLN4924 treatment induced the accumulation of ATF3 and ATF3-mediated autophagy via NF-kappaB-Catalase-ROS pathway.	('Catalase', 'Gene', (168, 176))	('ATF3', 'Gene', (121, 125))	('NF-kappaB', 'Gene', '4790', (158, 167))	('ATF3', 'Gene', '467', (130, 134))	('MLN4924', 'Chemical', 'MESH:C539933', (75, 82))	('NF-kappaB', 'Gene', (158, 167))	('ROS', 'Chemical', 'MESH:D017382', (177, 180))	('ATF3', 'Gene', (130, 134))	('MLN4924', 'Var', (75, 82))	('accumulation', 'PosReg', (105, 117))	('ATF3', 'Gene', '467', (121, 125))	('Catalase', 'Gene', '847', (168, 176))
346472	32398095	Functionally, blockage of MLN4924-induced protective autophagy by ATF3 deletion sensitized ESCC cells to MLN4924-induced apoptosis.	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('protective autophagy', 'CPA', (42, 62))	('deletion', 'Var', (71, 79))	('MLN4924', 'Chemical', 'MESH:C539933', (105, 112))	('ATF3', 'Gene', '467', (66, 70))	('MLN4924-induced', 'Var', (26, 41))	('blockage', 'NegReg', (14, 22))	('ATF3', 'Gene', (66, 70))
346473	32398095	These preclinical findings indicated that NF-kappaB-Catalase-ROS-ATF3 axis served as a new protective autophagy mechanism in esophageal cancer upon MLN4924 treatment, which provided a rationale for combinational anti-ESCC therapy with dual inhibition of neddylation and autophagy pathways.	('MLN4924', 'Chemical', 'MESH:C539933', (148, 155))	('Catalase', 'Gene', '847', (52, 60))	('Catalase', 'Gene', (52, 60))	('esophageal cancer', 'Disease', (125, 142))	('NF-kappaB', 'Gene', '4790', (42, 51))	('MLN4924', 'Var', (148, 155))	('ATF3', 'Gene', '467', (65, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('NF-kappaB', 'Gene', (42, 51))	('ATF3', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
346478	32398095	In this study, we found that MLN4924 treatment induced ATF3 expression to trigger autophagic response as a pro-survival signal while ATF3 silencing promoted cell apoptosis.	('ATF3', 'Gene', (55, 59))	('expression', 'MPA', (60, 70))	('silencing', 'NegReg', (138, 147))	('autophagic response', 'CPA', (82, 101))	('ATF3', 'Gene', '467', (133, 137))	('cell apoptosis', 'CPA', (157, 171))	('MLN4924', 'Chemical', 'MESH:C539933', (29, 36))	('ATF3', 'Gene', (133, 137))	('ATF3', 'Gene', '467', (55, 59))	('MLN4924', 'Var', (29, 36))	('promoted', 'PosReg', (148, 156))
346481	32398095	Thus, our findings that MLN4924-induced ATF3 activation acts as a pro-survival event in ESCC highlights the therapeutic value of targeting ATF3 and neddylation pathway for combinational ESCC therapy.	('ATF3', 'Gene', '467', (40, 44))	('ESCC', 'Disease', (88, 92))	('MLN4924-induced', 'Var', (24, 39))	('ATF3', 'Gene', (139, 143))	('ATF3', 'Gene', (40, 44))	('MLN4924', 'Chemical', 'MESH:C539933', (24, 31))	('activation', 'PosReg', (45, 55))	('ATF3', 'Gene', '467', (139, 143))
346484	32398095	In the present study, however, we showed that ATF3 was activated by MLN4924-induced ROS due to the inhibition of NF-kappaB-Catalase axis in ESCC cells, revealing a new mechanism by which NF-kappaB regulates ATF3.	('NF-kappaB', 'Gene', '4790', (113, 122))	('NF-kappaB', 'Gene', (187, 196))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('ATF3', 'Gene', (207, 211))	('ATF3', 'Gene', (46, 50))	('MLN4924', 'Chemical', 'MESH:C539933', (68, 75))	('NF-kappaB', 'Gene', '4790', (187, 196))	('inhibition', 'NegReg', (99, 109))	('NF-kappaB', 'Gene', (113, 122))	('Catalase', 'Gene', (123, 131))	('Catalase', 'Gene', '847', (123, 131))	('MLN4924-induced', 'Var', (68, 83))	('ATF3', 'Gene', '467', (207, 211))	('ATF3', 'Gene', '467', (46, 50))	('ROS', 'Protein', (84, 87))	('activated', 'PosReg', (55, 64))
346487	32398095	However, in the present study, we found that inactivation of NF-kappaB pathway upon MLN4924 treatment acts as a protective role by inducing the ATF3-mediated autophagy in esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('inactivation', 'Var', (45, 57))	('NF-kappaB', 'Gene', (61, 70))	('inducing', 'PosReg', (131, 139))	('MLN4924', 'Chemical', 'MESH:C539933', (84, 91))	('ATF3', 'Gene', '467', (144, 148))	('MLN4924', 'Var', (84, 91))	('ATF3', 'Gene', (144, 148))	('esophageal cancer', 'Disease', (171, 188))	('NF-kappaB', 'Gene', '4790', (61, 70))
346488	32398095	Consistently, IkappaBalpha knockdown activates NF-kappaB signaling to attenuate MLN4924-induced ATF3 expression and protective autophagy.	('protective autophagy', 'CPA', (116, 136))	('IkappaBalpha', 'Gene', (14, 26))	('MLN4924-induced', 'Var', (80, 95))	('MLN4924', 'Chemical', 'MESH:C539933', (80, 87))	('NF-kappaB', 'Gene', (47, 56))	('attenuate', 'NegReg', (70, 79))	('activates', 'PosReg', (37, 46))	('ATF3', 'Gene', '467', (96, 100))	('IkappaBalpha', 'Gene', '4792', (14, 26))	('ATF3', 'Gene', (96, 100))	('NF-kappaB', 'Gene', '4790', (47, 56))
346491	32398095	For example, LYN-1604, as a novel activator of ULK1, obviously up-regulated ATF3 to induce autophagy in triple negative breast cancer.	('ATF3', 'Gene', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('induce', 'PosReg', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('LYN-1604', 'Var', (13, 21))	('ULK1', 'Gene', (47, 51))	('ULK1', 'Gene', '8408', (47, 51))	('autophagy', 'CPA', (91, 100))	('ATF3', 'Gene', '467', (76, 80))	('up-regulated', 'PosReg', (63, 75))
346493	32398095	In the present study, we showed that MLN4924 induced autophagy dependent on ATF3 accumulation.	('ATF3', 'Gene', (76, 80))	('MLN4924', 'Chemical', 'MESH:C539933', (37, 44))	('autophagy', 'CPA', (53, 62))	('MLN4924', 'Var', (37, 44))	('ATF3', 'Gene', '467', (76, 80))
346495	32398095	In esophageal cancer cells, MLN4924 induces the expression of ATF3 by modulating NF-kappaB-Catalase-ROS pathway to trigger pro-survival autophagy, whereas targeting ATF3 blocks the autophagic response upon neddylation inhibition and thus sensitizes cancer cells to MLN4924-induced apoptosis.	('ATF3', 'Gene', (62, 66))	('MLN4924', 'Var', (28, 35))	('NF-kappaB', 'Gene', (81, 90))	('cancer', 'Disease', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('pro-survival autophagy', 'CPA', (123, 145))	('NF-kappaB', 'Gene', '4790', (81, 90))	('sensitizes', 'Reg', (238, 248))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('expression', 'MPA', (48, 58))	('trigger', 'PosReg', (115, 122))	('Catalase', 'Gene', (91, 99))	('MLN4924', 'Chemical', 'MESH:C539933', (265, 272))	('induces', 'Reg', (36, 43))	('blocks', 'NegReg', (170, 176))	('MLN4924', 'Chemical', 'MESH:C539933', (28, 35))	('esophageal cancer', 'Disease', (3, 20))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('modulating', 'Reg', (70, 80))	('autophagic response', 'CPA', (181, 200))	('Catalase', 'Gene', '847', (91, 99))	('ATF3', 'Gene', '467', (165, 169))	('ATF3', 'Gene', '467', (62, 66))	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('ATF3', 'Gene', (165, 169))	('targeting', 'Var', (155, 164))
346532	30511698	In achalasia patients, studies suggested that loss of NO-secreting esophageal myenteric plexus neurons caused imbalance of excitatory and inhibitory neurons, leading to altered manometry results.	('achalasia', 'Phenotype', 'HP:0002571', (3, 12))	('patients', 'Species', '9606', (13, 21))	('altered', 'Reg', (169, 176))	('loss', 'Var', (46, 50))	('imbalance', 'Phenotype', 'HP:0002172', (110, 119))	('achalasia', 'Disease', (3, 12))	('achalasia', 'Disease', 'MESH:D004931', (3, 12))	('manometry results', 'MPA', (177, 194))
346630	29599929	Poor oral health may increase systemic inflammation, resulting in a local overly aggressive immune response, and thus could have important implications for cancer development.	('systemic inflammation', 'Disease', 'MESH:D007249', (30, 51))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('Poor oral', 'Phenotype', 'HP:0000160', (0, 9))	('systemic inflammation', 'Disease', (30, 51))	('implications', 'Reg', (139, 151))	('Poor oral health', 'Var', (0, 16))	('men', 'Species', '9606', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('increase', 'PosReg', (21, 29))
346712	29599929	Carbohydrate intake was associated with increased risk cancer.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Carbohydrate intake', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('Carbohydrate', 'Chemical', 'MESH:D002241', (0, 12))
346726	28665915	The high expression of mTOR was associated with tumor stage (P=0.001), lymphatic metastasis (P=0.014), and differentiation (P=0.036).	('tumor', 'Disease', (48, 53))	('differentiation', 'CPA', (107, 122))	('lymphatic metastasis', 'CPA', (71, 91))	('mTOR', 'Gene', (23, 27))	('high', 'Var', (4, 8))	('mTOR', 'Gene', '2475', (23, 27))	('associated', 'Reg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
346728	28665915	The OS and DFS in patients in the high-periostin group were significantly shorter than those in the low-periostin group, (both P<0.001).	('shorter', 'NegReg', (74, 81))	('high-periostin', 'Var', (34, 48))	('DFS', 'CPA', (11, 14))	('patients', 'Species', '9606', (18, 26))
346741	28665915	Additionally, periostin binding with some integrins (alphavbeta3, alpha6beta4, and alphavbeta5) can interact with some cell surface receptors and then activate downstream proteins to promote tumor invasion and metastasis by PI3K-Akt and/or other signaling pathways.	('interact', 'Interaction', (100, 108))	('metastasis', 'CPA', (210, 220))	('activate', 'PosReg', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('binding', 'Interaction', (24, 31))	('Akt', 'Gene', (229, 232))	('alphavbeta5', 'Var', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('cell', 'Protein', (119, 123))	('proteins', 'Protein', (171, 179))	('promote', 'PosReg', (183, 190))	('Akt', 'Gene', '207', (229, 232))
346771	28665915	Kaplan-Meier analysis showed that OS in locally advanced ESCC patients with high expression of periostin (27.96+-2.12 months) was worse than in those with low expression of periostin (45.84+-2.82 months, Figure 3A), showing a significant difference (chi2=18.890, P=0.000, Table 3).	('ESCC', 'Disease', (57, 61))	('patients', 'Species', '9606', (62, 70))	('high expression', 'Var', (76, 91))
346773	28665915	Similarly, DFS in the high-periostin and high-mTOR groups was significantly worse than in the low-periostin and low-mTOR group, respectively (16.68+-1.62 months vs. 37.78+-3.52 months; 18.51+-1.56 months vs. 38.50+-4.48 months; both P<0.001; Figure 3C, 3D).	('high-periostin', 'Var', (22, 36))	('mTOR', 'Gene', '2475', (46, 50))	('DFS', 'MPA', (11, 14))	('mTOR', 'Gene', (46, 50))	('worse', 'NegReg', (76, 81))	('mTOR', 'Gene', (116, 120))	('mTOR', 'Gene', '2475', (116, 120))
346781	28665915	found that periostin was overexpressed in cells with both high EGFR expression and mutant p53 status.	('EGFR', 'Gene', '1956', (63, 67))	('p53', 'Gene', (90, 93))	('expression', 'MPA', (68, 78))	('mutant', 'Var', (83, 89))	('EGFR', 'Gene', (63, 67))	('p53', 'Gene', '7157', (90, 93))	('overexpressed', 'PosReg', (25, 38))	('high', 'PosReg', (58, 62))
346788	28665915	indicated that the sensitivity to cisplatin in EC9706 was increased after silencing mTOR expression by RNA interference cells, suggesting that the high expression of mTOR in ESCC was a common phenomenon in vivo and in vitro.	('EC9706', 'CellLine', 'CVCL:E307', (47, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('increased', 'PosReg', (58, 67))	('mTOR', 'Gene', (166, 170))	('mTOR', 'Gene', '2475', (166, 170))	('silencing', 'NegReg', (74, 83))	('mTOR', 'Gene', '2475', (84, 88))	('mTOR', 'Gene', (84, 88))	('EC9706', 'Var', (47, 53))	('sensitivity', 'MPA', (19, 30))
346792	28665915	found that high expression of mTOR was significantly associated with differentiation, invasion depth, lymph node metastasis, and tumor staging.	('invasion depth', 'CPA', (86, 100))	('differentiation', 'CPA', (69, 84))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('lymph node metastasis', 'CPA', (102, 123))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('associated', 'Reg', (53, 63))	('high', 'Var', (11, 15))	('mTOR', 'Gene', '2475', (30, 34))	('tumor', 'Disease', (129, 134))	('mTOR', 'Gene', (30, 34))
346801	28665915	Collectively, the results of our study suggest that abnormality of periostin and mTOR in locally advanced ESCC may be closely linked to multiple clinicopathologic features.	('abnormality', 'Var', (52, 63))	('locally advanced ESCC', 'Disease', (89, 110))	('mTOR', 'Gene', (81, 85))	('linked', 'Reg', (126, 132))	('mTOR', 'Gene', '2475', (81, 85))
346803	28665915	High expression of periostin and mTOR were independent risk factors determining the DFS and OS of patients with locally advanced ESCC, and might offer a potential target strategy for ESCC treatment in the future.	('DFS', 'Disease', (84, 87))	('High', 'Var', (0, 4))	('ESCC', 'Disease', (129, 133))	('mTOR', 'Gene', '2475', (33, 37))	('patients', 'Species', '9606', (98, 106))	('mTOR', 'Gene', (33, 37))	('ESCC', 'Disease', (183, 187))
346815	28060731	Folate deficiency can promote carcinogenesis by stimulating aberrant DNA methylation resulting in defective activation of oncogenes.	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('promote', 'PosReg', (22, 29))	('defective', 'NegReg', (98, 107))	('DNA', 'Protein', (69, 72))	('carcinogenesis', 'Disease', 'MESH:D063646', (30, 44))	('Folate deficiency', 'Phenotype', 'HP:0100507', (0, 17))	('carcinogenesis', 'Disease', (30, 44))	('deficiency', 'Var', (7, 17))	('activation', 'MPA', (108, 118))	('stimulating', 'PosReg', (48, 59))	('oncogenes', 'Protein', (122, 131))
346816	28060731	Low folate levels reduce de novo thymidylate biosynthesis that will induce uracil mis-incorporation during DNA repair and synthesis resulting in DNA mutagenesis that in addition to DNA strand breaks and chromosomal damage triggers malignant transformation.	('induce', 'Reg', (68, 74))	('mutagenesis', 'Var', (149, 160))	('triggers', 'Reg', (222, 230))	('folate', 'Chemical', 'MESH:D005492', (4, 10))	('malignant transformation', 'CPA', (231, 255))	('DNA', 'Gene', (145, 148))	('uracil mis', 'Phenotype', 'HP:0012127', (75, 85))	('Low folate levels', 'Phenotype', 'HP:0100507', (0, 17))	('uracil mis-incorporation', 'MPA', (75, 99))	('uracil', 'Chemical', 'MESH:D014498', (75, 81))	('reduce', 'NegReg', (18, 24))	('thymidylate biosynthesis', 'MPA', (33, 57))
346817	28060731	Although many epidemiologic studies have shown that low folate levels increase the risk of human cancers, the role of folate intake in esophageal cancers has remained controversial.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (146, 153))	('folate levels increase', 'Phenotype', 'HP:0032164', (56, 78))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancers', 'Disease', (97, 104))	('folate', 'Chemical', 'MESH:D005492', (56, 62))	('low folate levels', 'Phenotype', 'HP:0100507', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('esophageal cancers', 'Disease', (135, 153))	('folate', 'Chemical', 'MESH:D005492', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('esophageal cancers', 'Disease', 'MESH:D004938', (135, 153))	('human', 'Species', '9606', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('folate levels', 'MPA', (56, 69))	('low', 'Var', (52, 55))
346847	28060731	Since folate is a key modulator of DNA synthesis, repair and methylation, it was hypothesized to reduce cancer risk.	('methylation', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('folate', 'Chemical', 'MESH:D005492', (6, 12))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('reduce', 'NegReg', (97, 103))
346851	28060731	Evidence has suggested that low-folate status may contribute to carcinogenesis through complete conversion of dUMP via two mechanisms: (1) by conversion into dTMP, leading to uracil misincorporation into DNA, which could result in chromosomal breaks and mutations; and/or (2) by causing alterations in DNA methylation, which could in turn alter expression of proto-oncogenes and tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (379, 384))	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('methylation', 'MPA', (306, 317))	('conversion', 'Var', (142, 152))	('proto-oncogenes', 'Gene', (359, 374))	('dTMP', 'Chemical', 'MESH:D013938', (158, 162))	('uracil', 'Chemical', 'MESH:D014498', (175, 181))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (231, 249))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('DNA', 'Protein', (302, 305))	('uracil mis', 'Phenotype', 'HP:0012127', (175, 185))	('chromosomal breaks', 'CPA', (231, 249))	('mutations', 'CPA', (254, 263))	('contribute', 'Reg', (50, 60))	('alterations', 'Reg', (287, 298))	('folate', 'Chemical', 'MESH:D005492', (32, 38))	('result in', 'Reg', (221, 230))	('low-folate', 'Var', (28, 38))	('dUMP', 'Chemical', 'MESH:C007267', (110, 114))	('uracil', 'MPA', (175, 181))	('carcinogenesis', 'Disease', (64, 78))	('alter', 'Reg', (339, 344))	('low-folate status', 'Phenotype', 'HP:0100507', (28, 45))	('expression', 'MPA', (345, 355))	('tumor', 'Disease', (379, 384))	('misincorporation', 'Var', (182, 198))
346853	28060731	Animal experiments demonstrated that whereas folate deficiency promoted carcinogenesis in normal cells, its supplementation could promote cancer progression in established pre-neoplastic lesions.	('supplementation', 'Var', (108, 123))	('cancer', 'Disease', (138, 144))	('promote', 'PosReg', (130, 137))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (176, 194))	('folate', 'Chemical', 'MESH:D005492', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('deficiency', 'Var', (52, 62))	('folate', 'Gene', (45, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))	('promoted', 'PosReg', (63, 71))	('carcinogenesis', 'Disease', (72, 86))	('folate deficiency', 'Phenotype', 'HP:0100507', (45, 62))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
346961	26413146	(Level 4-5) Avoid nasogastric tube positioning as their validity to prevent vomiting and stricture formation has never been proven; nasogastric tubes have been reported to increase risks of gastric perforation, gastroesophageal reflux, and pneumonia.	('gastric perforation', 'Disease', (190, 209))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (211, 234))	('nasogastric tube', 'Phenotype', 'HP:0040288', (18, 34))	('nasogastric tubes', 'Var', (132, 149))	('prevent vomiting', 'Phenotype', 'HP:0002572', (68, 84))	('nasogastric tube', 'Phenotype', 'HP:0040288', (132, 148))	('vomiting', 'Phenotype', 'HP:0002013', (76, 84))	('pneumonia', 'Phenotype', 'HP:0002090', (240, 249))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (211, 234))	('gastroesophageal reflux', 'Disease', (211, 234))	('vomiting', 'Disease', (76, 84))	('vomiting', 'Disease', 'MESH:D014839', (76, 84))	('pneumonia', 'Disease', (240, 249))	('pneumonia', 'Disease', 'MESH:D011014', (240, 249))
346985	26413146	(Level 4) Caustic ingestion can induce SIRS or sepsis with a severe hypermetabolic and catabolic response.	('sepsis', 'Phenotype', 'HP:0100806', (47, 53))	('sepsis', 'Disease', (47, 53))	('hypermetabolic', 'Disease', (68, 82))	('hypermetabolic', 'Disease', 'MESH:C565498', (68, 82))	('sepsis', 'Disease', 'MESH:D018805', (47, 53))	('SIRS', 'Disease', 'None', (39, 43))	('induce', 'Reg', (32, 38))	('SIRS', 'Disease', (39, 43))	('ingestion', 'Var', (18, 27))
347175	33374780	also reported that the incidence of stricture in PGA sheet patients was comparable to that in TA injection patients (9.1% vs. 10.3%, respectively).	('TA', 'Chemical', 'MESH:D014222', (94, 96))	('PGA', 'Chemical', 'MESH:D011100', (49, 52))	('PGA', 'Var', (49, 52))	('stricture', 'Disease', (36, 45))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (107, 115))
347187	33374780	The incidence of stricture seven days after ESD was 71.4% in the CMC sheet group and 100% in the treatment-free group.	('CMC', 'Chemical', 'MESH:D002266', (65, 68))	('CMC sheet', 'Var', (65, 74))	('stricture', 'Disease', (17, 26))
347221	32886456	After propensity matching, the patients with a low TTS had significantly better PFS (P < .001, mPFS: 18.2 months vs 10 months) and an equivalent OS (P = .115, mOS: not reached vs 41 months).	('TTS', 'Chemical', '-', (51, 54))	('mOS', 'Gene', (159, 162))	('OS', 'Gene', '17451', (145, 147))	('mOS', 'Gene', '17451', (159, 162))	('low', 'Var', (47, 50))	('OS', 'Gene', '17451', (160, 162))	('patients', 'Species', '9606', (31, 39))	('better', 'PosReg', (73, 79))	('PFS', 'MPA', (80, 83))
347298	32886456	In the low TTS group, the range of time of NAC to colorectal cancer resection was 28-35 days and the median time was 32 days (IQR 30.0-45.0).	('TTS', 'Chemical', '-', (11, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('rectal cancer', 'Phenotype', 'HP:0100743', (54, 67))	('low', 'Var', (7, 10))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('NAC', 'Chemical', '-', (43, 46))	('colorectal cancer', 'Disease', (50, 67))
347311	32886456	In the univariate analyses, left hemicolon (P = .035), TTS < 5 weeks (P = .008), neutropenia (P = .006), clinical response (P < .001), targeted therapy (P = .004), and T3-T4 stage (P = .006) were associated with a favorable pathological response.	('neutropenia', 'Disease', 'MESH:D009503', (81, 92))	('TTS', 'Chemical', '-', (55, 58))	('neutropenia', 'Phenotype', 'HP:0001875', (81, 92))	('left hemicolon', 'Disease', (28, 42))	('targeted therapy', 'Var', (135, 151))	('neutropenia', 'Disease', (81, 92))
347313	32886456	In multivariate analysis, low TTS (OR = 3.397, 95% CI: 1.116-10.344, P = .031), targeted therapy (OR = 2.959, 95% CI: 1.050-8.336, P = .040), neutropenia (OR = 3.015, 95% CI: 1.077-8.437, P = .036), and clinical response (OR = 5.329, 95% CI: 1.785-15.910, P = .003) were independent indicators for a favorable histological response.	('neutropenia', 'Phenotype', 'HP:0001875', (142, 153))	('TTS', 'MPA', (30, 33))	('low', 'NegReg', (26, 29))	('neutropenia', 'Disease', (142, 153))	('TTS', 'Chemical', '-', (30, 33))	('neutropenia', 'Disease', 'MESH:D009503', (142, 153))	('targeted', 'Var', (80, 88))
347317	32886456	Univariate analysis revealed that age <= 60 years, non-R0 resection, major liver resection, TTS > 5 weeks, T3-T4 stage, node-positive primary tumor, homochronous resection, nonoxaliplatin-based regimen, >7 NAC cycles, and targeted therapy were associated with decreased PFS.	('decreased', 'NegReg', (260, 269))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('T3-T4', 'Var', (107, 112))	('NAC', 'Chemical', '-', (206, 209))	('non-R0 resection', 'Var', (51, 67))	('tumor', 'Disease', (142, 147))	('nonoxaliplatin-based regimen', 'Var', (173, 201))	('targeted therapy', 'CPA', (222, 238))	('PFS', 'Disease', (270, 273))	('homochronous resection', 'Var', (149, 171))	('nonoxaliplatin', 'Chemical', '-', (173, 187))	('TTS', 'Chemical', '-', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
347324	32886456	Major liver resection, TTS > 5 weeks, >7 NAC cycles, targeted therapy, and postoperative chemotherapy were associated with decreased PFS in univariate analysis.	('NAC', 'Chemical', '-', (41, 44))	('decreased', 'NegReg', (123, 132))	('targeted therapy', 'Var', (53, 69))	('TTS', 'Chemical', '-', (23, 26))	('PFS', 'Disease', (133, 136))
347345	32886456	This study revealed that patients with a high TTS were more likely to have unfavorable PFS, which was consistent with previous studies suggesting that postponing TTS impairs survival in many cancers, such as esophageal and ovarian cancers.	('PFS', 'Disease', (87, 90))	('survival', 'CPA', (174, 182))	('TTS', 'Var', (46, 49))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Disease', (191, 198))	('cancers', 'Disease', (231, 238))	('ovarian cancers', 'Phenotype', 'HP:0100615', (223, 238))	('TTS', 'Chemical', '-', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('patients', 'Species', '9606', (25, 33))	('high TTS', 'Var', (41, 49))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('ovarian cancer', 'Phenotype', 'HP:0100615', (223, 237))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('esophageal and ovarian cancers', 'Disease', 'MESH:D004941', (208, 238))	('TTS', 'Chemical', '-', (162, 165))	('impairs', 'NegReg', (166, 173))	('unfavorable', 'Disease', (75, 86))
347349	32886456	In addition, shrinkage of the primary tumor can stimulate residual tumor growth, which has been investigated in animal models.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('shrinkage', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('stimulate', 'PosReg', (48, 57))	('tumor', 'Disease', (67, 72))
347373	29220828	Dose-only models predicted grade 3 RE with AUC values of 0.750 (D2cc) and 0.727 (gEUD).	('D2cc', 'Chemical', '-', (64, 68))	('AUC', 'MPA', (43, 46))	('0.727', 'Var', (74, 79))	('grade 3 RE', 'Disease', (27, 37))
347393	29220828	We hypothesized that variations in pretreatment plasma cytokine levels may correlate with increased or decreased risk of RE.	('variations', 'Var', (21, 31))	('plasma cytokine levels', 'MPA', (48, 70))	('decreased', 'NegReg', (103, 112))	('men', 'Species', '9606', (43, 46))
347449	29220828	Additionally, with each dosimetric, there was an incremental decline in the risk of RE with increasing age, with ORs of 0.992/year (D2cc) and 0.991/year (gEUD).	('D2cc', 'Chemical', '-', (132, 136))	('decline', 'NegReg', (61, 68))	('men', 'Species', '9606', (54, 57))	('0.991/year', 'Var', (142, 152))
347474	29220828	We did not find evidence that variation in pretreatment plasma cytokine levels further improved performance, which represents a novel finding.	('improved', 'PosReg', (87, 95))	('performance', 'MPA', (96, 107))	('variation', 'Var', (30, 39))	('men', 'Species', '9606', (51, 54))
347540	28246468	In their initial work, they compared the clinical and histological characteristics of 3 groups: LE-No Granulocytes (LE-NG), LE-few granulocytes (LE-FG) and their control group which consisted of patients with "reflux esophagitis with increased IELs" (REIL).	('LE', 'Chemical', '-', (124, 126))	('LE', 'Chemical', '-', (145, 147))	('LE', 'Phenotype', 'HP:0006527', (116, 118))	('LE-few', 'Var', (124, 130))	('LE', 'Chemical', '-', (116, 118))	('patients', 'Species', '9606', (195, 203))	('LE-No', 'Var', (96, 101))	('reflux esophagitis', 'Disease', 'MESH:D005764', (210, 228))	('LE', 'Phenotype', 'HP:0006527', (96, 98))	('LE', 'Phenotype', 'HP:0006527', (145, 147))	('LE', 'Chemical', '-', (96, 98))	('reflux esophagitis', 'Disease', (210, 228))	('LE', 'Phenotype', 'HP:0006527', (124, 126))	('esophagitis', 'Phenotype', 'HP:0100633', (217, 228))
347541	28246468	Out of the 21 subjects in the LE-NG group, 11 were tested for motility abnormality, which was confirmed in 10 subjects.	('LE', 'Phenotype', 'HP:0006527', (30, 32))	('motility abnormality', 'Disease', (62, 82))	('motility abnormality', 'Disease', 'MESH:C563515', (62, 82))	('LE', 'Chemical', '-', (30, 32))	('LE-NG', 'Var', (30, 35))
347580	28246468	Despite the fact that PPIs have actually been associated with lymphocytic and collagenous colitis, they actually seem to be therapeutic in LE, most likely secondary to their anti-inflammatory effect.	('lymphocytic', 'Disease', (62, 73))	('LE', 'Phenotype', 'HP:0006527', (139, 141))	('LE', 'Chemical', '-', (139, 141))	('collagenous colitis', 'Disease', (78, 97))	('PPIs', 'Var', (22, 26))	('colitis', 'Phenotype', 'HP:0002583', (90, 97))	('associated', 'Reg', (46, 56))	('collagenous colitis', 'Disease', 'MESH:D046729', (78, 97))
347629	25809390	Postoperative complications were categorized using a modified Clavien-Dindo classification.16 The diagnosis of postoperative pneumonia was made in accordance with the Japanese Respiratory Society's Guidelines for Hospital Acquired Pneumonia in Adults.17 This diagnosis was contingent on the presence of pulmonary infiltrates in the standard chest radiography and at least two of the three criteria (i) pyrexia (>38.0 degrees), (ii) leukocytosis (>12 000/mm3) or leukocytopenia (<4000/mm3), and (iii) purulent airway exudates.	('leukocytopenia', 'Disease', 'MESH:D007970', (462, 476))	('pulmonary infiltrates', 'Phenotype', 'HP:0002113', (303, 324))	('leukocytopenia', 'Disease', (462, 476))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (111, 134))	('leukocytosis', 'Disease', 'MESH:D007964', (432, 444))	('pyrexia', 'Disease', 'MESH:D005334', (402, 409))	('leukocytosis', 'Phenotype', 'HP:0001974', (432, 444))	('pyrexia', 'Phenotype', 'HP:0001945', (402, 409))	('Pneumonia', 'Phenotype', 'HP:0002090', (231, 240))	('>12 000/mm3', 'Var', (446, 457))	('pneumonia', 'Phenotype', 'HP:0002090', (125, 134))	('postoperative pneumonia', 'Disease', (111, 134))	('leukocytosis', 'Disease', (432, 444))	('pyrexia', 'Disease', (402, 409))
347639	25809390	Postoperative hospital stays were shorter in the NTTE group than in the TTE group.	('NTTE', 'Var', (49, 53))	('TTE', 'Chemical', '-', (72, 75))	('Postoperative hospital stays', 'CPA', (0, 28))	('shorter', 'NegReg', (34, 41))	('TTE', 'Chemical', '-', (50, 53))	('NTTE', 'Chemical', '-', (49, 53))
347653	25809390	Leakage of intrathoracic anastomosis often results in empyema with occasionally life-threatening consequences, but did not in our series of patients, in whom none of these anastomotic failures led to lethal complications or required surgical interventions.	('results in', 'Reg', (43, 53))	('empyema', 'Disease', 'MESH:D004653', (54, 61))	('empyema', 'Disease', (54, 61))	('patients', 'Species', '9606', (140, 148))	('Leakage', 'Var', (0, 7))
347656	25809390	Conventional minimally invasive esophagectomy (MIE) has been reported to reduce mortality and morbidity18, 19; however, a recent report on the Japanese national database revealed that MIE prolongs operation times and increases the rate of surgical complications.32 Notably, this study also reported that postoperative pneumonia was not decreased in MIE (15.0% in MIE vs. 15.4% in open esophagectomy).	('pneumonia', 'Phenotype', 'HP:0002090', (318, 327))	('postoperative pneumonia', 'Disease', (304, 327))	('MIE', 'Chemical', '-', (184, 187))	('MIE', 'Var', (363, 366))	('MIE', 'Chemical', '-', (349, 352))	('MIE', 'Chemical', '-', (363, 366))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (304, 327))	('MIE', 'Chemical', '-', (47, 50))
347657	25809390	Meanwhile, in our current study, the occurrence of postoperative pneumonia was decreased in the NTTE group with a statistically marginal difference (0% in NTTE vs. 14% in TTE).	('TTE', 'Chemical', '-', (97, 100))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (51, 74))	('decreased', 'NegReg', (79, 88))	('TTE', 'Chemical', '-', (156, 159))	('postoperative pneumonia', 'Disease', (51, 74))	('pneumonia', 'Phenotype', 'HP:0002090', (65, 74))	('NTTE', 'Var', (96, 100))	('TTE', 'Chemical', '-', (171, 174))	('NTTE', 'Chemical', '-', (96, 100))	('NTTE', 'Chemical', '-', (155, 159))
347725	26334098	Although plasma fibrinogen level was significantly higher in T3-4 patients than that in T1-2 patients (P < 0.05), high pretreatment plasma fibrinogen level was correlated with poorer DMFS, RFS and OS both among T3-4 patients and T1-2 patients (P < 0.05).	('RFS', 'MPA', (189, 192))	('T3-4', 'Var', (61, 65))	('DMFS', 'MPA', (183, 187))	('fibrinogen', 'Gene', '2244', (139, 149))	('fibrinogen', 'Gene', (139, 149))	('fibrinogen', 'Gene', '2244', (16, 26))	('fibrinogen', 'Gene', (16, 26))	('DMFS', 'Chemical', '-', (183, 187))	('patients', 'Species', '9606', (216, 224))	('poorer', 'NegReg', (176, 182))	('patients', 'Species', '9606', (234, 242))	('high pretreatment plasma fibrinogen level', 'Phenotype', 'HP:0011899', (114, 155))	('higher', 'PosReg', (51, 57))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (66, 74))
347780	25016483	Among these patients, 26 patients with R1 (microscopic residual disease) or R2 (macroscopic residual disease) resections, 48 patients receiving preoperative therapy (chemotherapy and/or radiotherapy), 8 patients with histories of gastric cancer, 5 patients with synchronous cancers (gastric cancer or laryngeal cancer) and 4 patients with non-squamous cell carcinoma of the middle thoracic esophagus were excluded.	('synchronous cancers', 'Disease', 'MESH:D009378', (262, 281))	('synchronous cancers', 'Disease', (262, 281))	('gastric cancer', 'Disease', 'MESH:D013274', (230, 244))	('resections', 'Var', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('patients', 'Species', '9606', (125, 133))	('patients', 'Species', '9606', (12, 20))	('gastric cancer', 'Disease', (283, 297))	('non-squamous cell carcinoma of the middle thoracic esophagus', 'Disease', 'MESH:D002294', (339, 399))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('patients', 'Species', '9606', (203, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (357, 366))	('gastric cancer', 'Phenotype', 'HP:0012126', (230, 244))	('gastric cancer', 'Disease', 'MESH:D013274', (283, 297))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (248, 256))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('patients', 'Species', '9606', (325, 333))	('laryngeal cancer', 'Disease', 'MESH:D007822', (301, 317))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('gastric cancer', 'Disease', (230, 244))	('laryngeal cancer', 'Disease', (301, 317))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (343, 366))	('gastric cancer', 'Phenotype', 'HP:0012126', (283, 297))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (301, 317))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
347845	25016483	It should be noted that the features of patients in that study including age, tumor location and disease stage, differed between patients with RLN node metastasis and those without RLN node metastasis.	('patients', 'Species', '9606', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('RLN node metastasis', 'Var', (143, 162))	('tumor', 'Disease', (78, 83))
347853	25016483	As shown in the result of the univariate analysis, patients with adjuvant therapy had worse survival than those without adjuvant therapy.	('adjuvant therapy', 'Var', (65, 81))	('survival', 'MPA', (92, 100))	('patients', 'Species', '9606', (51, 59))	('worse', 'NegReg', (86, 91))
347932	22732872	However, our work demonstrates that focal EMR for nodular disease, which is commonly performed in the U.S., is not associated with either a decreased likelihood of successful eradication of intestinal metaplasia or an increased risk of esophageal stricture.	('decreased', 'NegReg', (140, 149))	('nodular disease', 'Disease', 'MESH:D020518', (50, 65))	('esophageal stricture', 'Phenotype', 'HP:0002043', (236, 256))	('nodular disease', 'Disease', (50, 65))	('esophageal stricture', 'Disease', (236, 256))	('intestinal metaplasia', 'Disease', (190, 211))	('focal', 'Var', (36, 41))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (190, 211))
347943	22732872	Additionally, in the previous Mayo study, stricture formation was more frequent in the RFA after EMR group (13.6%) compared with the RFA only group (8.7%), whereas in our study, no significant difference in stricture rate was observed.	('RFA after', 'Var', (87, 96))	('stricture formation', 'CPA', (42, 61))	('Mayo', 'Species', '162683', (30, 34))
347965	22703173	Recently emerging genetic studies have linked variants in the genes encoding the alpha3, alpha5, and beta4 nicotinic acetylcholine receptor subunits to smoking risk.	('nicotinic acetylcholine receptor', 'Gene', '1137', (107, 139))	('variants', 'Var', (46, 54))	('smoking', 'Disease', (152, 159))	('nicotinic acetylcholine receptor', 'Gene', (107, 139))
347966	22703173	However, the influence of these well-established genetic variants accounts for only a small portion of the heritability of alcohol and nicotine addiction, and it is likely that there are both common and rare risk variants yet to be identified.	('variants', 'Var', (57, 65))	('nicotine', 'Chemical', 'MESH:D009538', (135, 143))	('alcohol', 'Chemical', 'MESH:D000438', (123, 130))	('alcohol', 'Disease', (123, 130))
348006	22703173	Both of these studies provided evidence that loci on human chromosome 4 increase the risk for alcohol dependence.	('increase', 'PosReg', (72, 80))	('loci', 'Var', (45, 49))	('alcohol dependence', 'Disease', 'MESH:D000437', (94, 112))	('human', 'Species', '9606', (53, 58))	('alcohol dependence', 'Phenotype', 'HP:0030955', (94, 112))	('alcohol dependence', 'Disease', (94, 112))
348025	22703173	The majority of association studies investigating the role of alcohol-metabolizing genes in risk for alcohol-use disorders have focused on the well-characterized coding variants within ADH1B, ADH1C, and ALDH2 and on the phenotype of alcohol dependence.	('alcohol dependence', 'Disease', 'MESH:D000437', (233, 251))	('alcohol', 'Chemical', 'MESH:D000438', (101, 108))	('ADH1C', 'Gene', (192, 197))	('ALDH2', 'Gene', '217', (203, 208))	('alcohol dependence', 'Phenotype', 'HP:0030955', (233, 251))	('alcohol dependence', 'Disease', (233, 251))	('alcohol', 'Chemical', 'MESH:D000438', (233, 240))	('ADH1B', 'Gene', (185, 190))	('alcohol-use disorders', 'Disease', (101, 122))	('ALDH2', 'Gene', (203, 208))	('alcohol', 'Chemical', 'MESH:D000438', (62, 69))	('alcohol-use', 'Phenotype', 'HP:0030955', (101, 112))	('ADH1B', 'Gene', '125', (185, 190))	('ADH1C', 'Gene', '126', (192, 197))	('variants', 'Var', (169, 177))
348027	22703173	The reference allele is ADH1B*1, which encodes the beta1 subunit with an arginine at amino-acid positions 48 (Arg48) and 370 (Arg370).	('beta1', 'Gene', '10678', (51, 56))	('Arg48', 'Chemical', '-', (110, 115))	('Arg48', 'Var', (110, 115))	('Arg370', 'Chemical', '-', (126, 132))	('ADH1B', 'Gene', (24, 29))	('Arg370', 'Var', (126, 132))	('arginine', 'Chemical', 'MESH:D001120', (73, 81))	('ADH1B', 'Gene', '125', (24, 29))	('beta1', 'Gene', (51, 56))
348029	22703173	The ADH1B*3 allele, which encodes the beta3 subunit with a cysteine at position 370 (Cys370), is found primarily in people of African descent.	('Cys370', 'Chemical', '-', (85, 91))	('ADH1B', 'Gene', (4, 9))	('people', 'Species', '9606', (116, 122))	('ADH1B', 'Gene', '125', (4, 9))	('Cys370', 'Var', (85, 91))	('cysteine', 'Chemical', 'MESH:D003545', (59, 67))
348032	22703173	A meta-analysis of the ADH1B*2 allele in Han Chinese and Japanese showed that individuals who are homozygous for this variant (His48/His48) have a fivefold decrease in risk for alcohol dependence compared with individuals who are heterozygous for this variant (Arg48/His48).	('ADH1B', 'Gene', (23, 28))	('His48/His48', 'Var', (127, 138))	('His48', 'Chemical', '-', (267, 272))	('His48', 'Chemical', '-', (133, 138))	('ADH1B', 'Gene', '125', (23, 28))	('His48', 'Chemical', '-', (127, 132))	('alcohol dependence', 'Disease', 'MESH:D000437', (177, 195))	('alcohol dependence', 'Phenotype', 'HP:0030955', (177, 195))	('decrease', 'NegReg', (156, 164))	('Arg48', 'Chemical', '-', (261, 266))	('alcohol dependence', 'Disease', (177, 195))
348033	22703173	In Europeans, the risk for developing alcohol dependence is twofold lower in His48/His48 carriers compared with Arg48/His48 carriers.	('alcohol dependence', 'Disease', 'MESH:D000437', (38, 56))	('alcohol dependence', 'Phenotype', 'HP:0030955', (38, 56))	('His48', 'Chemical', '-', (118, 123))	('Arg48', 'Chemical', '-', (112, 117))	('lower', 'NegReg', (68, 73))	('alcohol dependence', 'Disease', (38, 56))	('His48', 'Chemical', '-', (77, 82))	('His48/His48', 'Var', (77, 88))	('His48', 'Chemical', '-', (83, 88))
348035	22703173	The protective effect of ADH1B*2 was not detectable by a GWAS approach in studies involving populations of European or African descent because none of the variants on these genotyping chips showed high linkage disequilibrium with this rare variant.	('linkage', 'Interaction', (202, 209))	('ADH1B', 'Gene', '125', (25, 30))	('ADH1B', 'Gene', (25, 30))	('variants', 'Var', (155, 163))
348038	22703173	The reference allele of the ADH1C gene is ADH1C*1, with an arginine at position 272 (Arg272) and an isoleucine at position 350 (Ile350).	('ADH1C', 'Gene', (42, 47))	('ADH1C', 'Gene', (28, 33))	('Arg272', 'Chemical', '-', (85, 91))	('Ile350', 'Chemical', '-', (128, 134))	('ADH1C', 'Gene', '126', (28, 33))	('arginine', 'Chemical', 'MESH:D001120', (59, 67))	('ADH1C', 'Gene', '126', (42, 47))	('Arg272', 'Var', (85, 91))
348039	22703173	The ADH1C*2 allele, with a glutamine at position 272 (Gln272) and a valine at position 350 (Val350), is common in Europeans and African Americans.	('ADH1C', 'Gene', (4, 9))	('Gln272', 'Var', (54, 60))	('Gln272', 'Chemical', '-', (54, 60))	('ADH1C', 'Gene', '126', (4, 9))	('valine', 'Chemical', 'MESH:D014633', (68, 74))	('Val350', 'Chemical', '-', (92, 98))	('glutamine', 'Chemical', 'MESH:D005973', (27, 36))
348044	22703173	The ALDH2*2 allele, which substitutes lysine for glutamate at position 504 (Lys504), results in a nearly inactive protein subunit that is unable to metabolize acetaldehyde.	('ALDH2', 'Gene', '217', (4, 9))	('lysine for glutamate at position 504', 'Mutation', 'rs671', (38, 74))	('Lys504', 'Chemical', '-', (76, 82))	('inactive', 'MPA', (105, 113))	('protein', 'Protein', (114, 121))	('ALDH2', 'Gene', (4, 9))	('results in', 'Reg', (85, 95))	('acetaldehyde', 'Chemical', 'MESH:D000079', (159, 171))	('Lys504', 'Var', (76, 82))
348046	22703173	Polymorphisms in other ADH genes have also been associated with alcohol dependence.	('alcohol dependence', 'Phenotype', 'HP:0030955', (64, 82))	('ADH', 'Gene', (23, 26))	('alcohol dependence', 'Disease', (64, 82))	('ADH', 'Gene', '10327', (23, 26))	('associated', 'Reg', (48, 58))	('Polymorphisms', 'Var', (0, 13))	('alcohol dependence', 'Disease', 'MESH:D000437', (64, 82))
348047	22703173	Studies have shown that variation in the ADH genes contributes substantially to variation in alcohol metabolism and consequently affects the risk for alcohol dependence.	('alcohol dependence', 'Phenotype', 'HP:0030955', (150, 168))	('alcohol dependence', 'Disease', (150, 168))	('affects', 'Reg', (129, 136))	('alcohol', 'Chemical', 'MESH:D000438', (150, 157))	('variation', 'Var', (24, 33))	('ADH', 'Gene', (41, 44))	('ADH', 'Gene', '10327', (41, 44))	('variation', 'Reg', (80, 89))	('alcohol metabolism', 'MPA', (93, 111))	('alcohol dependence', 'Disease', 'MESH:D000437', (150, 168))	('alcohol', 'Chemical', 'MESH:D000438', (93, 100))
348048	22703173	Although the variants ADH1B Arg48His and ADH1C Arg272Gln/Ile350Val are known to have a major effect on enzyme activity in vitro, these variants account for only a very small amount of the genetic variance in in vivo metabolism.	('ADH1C', 'Gene', '126', (41, 46))	('Arg272Gln', 'Var', (47, 56))	('enzyme activity', 'MPA', (103, 118))	('Arg272Gln', 'SUBSTITUTION', 'None', (47, 56))	('ADH1C', 'Gene', (41, 46))	('effect', 'Reg', (93, 99))	('ADH1B', 'Gene', (22, 27))	('Arg48His', 'Var', (28, 36))	('ADH1B', 'Gene', '125', (22, 27))	('Arg48His', 'SUBSTITUTION', 'None', (28, 36))	('Ile350Val', 'Chemical', '-', (57, 66))
348049	22703173	In vivo studies in Europeans demonstrated that variants in ADH7 are associated with the early stages of alcohol metabolism, with additional effects in ADH1A, ADH1B, and ADH4.	('ADH4', 'Gene', (169, 173))	('variants', 'Var', (47, 55))	('associated', 'Reg', (68, 78))	('ADH1A', 'Gene', (151, 156))	('ADH7', 'Gene', '131', (59, 63))	('ADH1B', 'Gene', (158, 163))	('ADH4', 'Gene', '127', (169, 173))	('ADH1A', 'Gene', '124', (151, 156))	('ADH1B', 'Gene', '125', (158, 163))	('alcohol', 'Chemical', 'MESH:D000438', (104, 111))	('ADH7', 'Gene', (59, 63))	('effects', 'Reg', (140, 147))
348050	22703173	Postabsorptive alcohol metabolism is affected by variants in the ADH7-ADH1C-ADH1B gene cluster.	('affected', 'Reg', (37, 45))	('alcohol', 'Chemical', 'MESH:D000438', (15, 22))	('ADH1C', 'Gene', '126', (70, 75))	('ADH1B', 'Gene', '125', (76, 81))	('variants', 'Var', (49, 57))	('Postabsorptive alcohol metabolism', 'MPA', (0, 33))	('ADH1C', 'Gene', (70, 75))	('ADH7', 'Gene', '131', (65, 69))	('ADH7', 'Gene', (65, 69))	('ADH1B', 'Gene', (76, 81))
348051	22703173	Approximately 20% of the total genetic variance for alcohol metabolism was attributed to the combined effects of variants in the ADH gene region.	('variants', 'Var', (113, 121))	('ADH', 'Gene', (129, 132))	('ADH', 'Gene', '10327', (129, 132))	('alcohol metabolism', 'MPA', (52, 70))	('alcohol', 'Chemical', 'MESH:D000438', (52, 59))
348054	22703173	A family study from the COGA group identified multiple SNPs in GABRA2 (which encodes the GABAA receptor alpha2 subunit) associated with increased risk for alcohol dependence.	('GABAA receptor alpha2 subunit', 'Gene', '2555', (89, 118))	('associated with', 'Reg', (120, 135))	('alcohol dependence', 'Disease', 'MESH:D000437', (155, 173))	('GABRA2', 'Gene', '2555', (63, 69))	('alcohol dependence', 'Disease', (155, 173))	('alcohol dependence', 'Phenotype', 'HP:0030955', (155, 173))	('GABAA receptor alpha2 subunit', 'Gene', (89, 118))	('SNPs', 'Var', (55, 59))	('GABRA2', 'Gene', (63, 69))
348056	22703173	Furthermore, one study showed that GABRA2 alleles affect the SRE (self-rating of the effects of alcohol), suggesting that genetic variations in GABRA2 might play a role in the risk for alcohol-use disorders by moderating the SRE.	('alcohol-use disorders', 'Disease', (185, 206))	('alcohol-use', 'Phenotype', 'HP:0030955', (185, 196))	('SRE', 'MPA', (225, 228))	('GABRA2', 'Gene', (144, 150))	('GABRA2', 'Gene', '2555', (35, 41))	('genetic variations', 'Var', (122, 140))	('SRE', 'MPA', (61, 64))	('play', 'Reg', (157, 161))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))	('affect', 'Reg', (50, 56))	('alcohol', 'Chemical', 'MESH:D000438', (185, 192))	('GABRA2', 'Gene', (35, 41))	('GABRA2', 'Gene', '2555', (144, 150))	('role', 'Reg', (164, 168))	('moderating', 'NegReg', (210, 220))
348057	22703173	Evidence from a functional MRI study suggested that a SNP in GABRA2 (rs279871) associated with alcohol dependence is also associated with the medial frontal response to alcohol cues.	('associated', 'Reg', (122, 132))	('associated', 'Reg', (79, 89))	('GABRA2', 'Gene', (61, 67))	('alcohol', 'Chemical', 'MESH:D000438', (95, 102))	('alcohol dependence', 'Disease', 'MESH:D000437', (95, 113))	('rs279871', 'Var', (69, 77))	('rs279871', 'Mutation', 'rs279871', (69, 77))	('SNP', 'Var', (54, 57))	('alcohol cues', 'Phenotype', 'HP:0030955', (169, 181))	('alcohol dependence', 'Phenotype', 'HP:0030955', (95, 113))	('GABRA2', 'Gene', '2555', (61, 67))	('medial frontal response to alcohol cues', 'MPA', (142, 181))	('alcohol', 'Chemical', 'MESH:D000438', (169, 176))	('alcohol dependence', 'Disease', (95, 113))
348059	22703173	Several studies have reported association of GABRG1 variants with the risk for alcohol dependence and drinking behaviors.	('GABRG1', 'Gene', (45, 51))	('alcohol dependence', 'Disease', 'MESH:D000437', (79, 97))	('alcohol dependence', 'Phenotype', 'HP:0030955', (79, 97))	('alcohol dependence', 'Disease', (79, 97))	('variants', 'Var', (52, 60))	('drinking', 'Disease', (102, 110))	('GABRG1', 'Gene', '2565', (45, 51))	('association', 'Interaction', (30, 41))
348060	22703173	Haplotype analyses have suggested that markers in the GABRA2 gene associated with alcohol dependence are in linkage disequilibrium with markers in the GABRG1 gene in many populations, indicating that the association with GABRA2 may be driven by variants in GABRG1.	('GABRA2', 'Gene', (221, 227))	('GABRG1', 'Gene', (151, 157))	('GABRG1', 'Gene', (257, 263))	('GABRG1', 'Gene', '2565', (257, 263))	('alcohol dependence', 'Phenotype', 'HP:0030955', (82, 100))	('GABRA2', 'Gene', (54, 60))	('alcohol dependence', 'Disease', (82, 100))	('associated', 'Reg', (66, 76))	('markers', 'Var', (39, 46))	('GABRA2', 'Gene', '2555', (221, 227))	('variants', 'Var', (245, 253))	('GABRG1', 'Gene', '2565', (151, 157))	('GABRA2', 'Gene', '2555', (54, 60))	('alcohol dependence', 'Disease', 'MESH:D000437', (82, 100))
348061	22703173	Despite multiple studies implicating SNPs in GABRA2 and GABRG1 in the risk for alcohol-related behaviors, the specific functional alleles underlying these associations have yet to be identified.	('GABRA2', 'Gene', '2555', (45, 51))	('SNPs', 'Var', (37, 41))	('GABRG1', 'Gene', (56, 62))	('GABRA2', 'Gene', (45, 51))	('alcohol', 'Chemical', 'MESH:D000438', (79, 86))	('alcohol-related behaviors', 'Disease', (79, 104))	('alcohol-related behaviors', 'Phenotype', 'HP:0030955', (79, 104))	('GABRG1', 'Gene', '2565', (56, 62))
348062	22703173	In summary, candidate gene studies have successfully detected functional variants in alcohol metabolism genes such as ADH1B, ADH1C, and ALDH2 associated with a risk of developing alcohol dependence in populations of Asian descent.	('alcohol dependence', 'Disease', (179, 197))	('ADH1C', 'Gene', '126', (125, 130))	('ADH1B', 'Gene', (118, 123))	('ALDH2', 'Gene', '217', (136, 141))	('ADH1C', 'Gene', (125, 130))	('alcohol', 'Chemical', 'MESH:D000438', (85, 92))	('ALDH2', 'Gene', (136, 141))	('variants', 'Var', (73, 81))	('ADH1B', 'Gene', '125', (118, 123))	('alcohol', 'Chemical', 'MESH:D000438', (179, 186))	('alcohol dependence', 'Phenotype', 'HP:0030955', (179, 197))	('associated with', 'Reg', (142, 157))	('alcohol dependence', 'Disease', 'MESH:D000437', (179, 197))
348071	22703173	The first GWAS using a case-control sample reported evidence that variants within the nicotinic acetylcholine receptor (nAChR) subunit genes on the long arm of human chromosomes 15 (CHRNA5-CHRNA3-CHRNB4) and 8 (CHRNA6-CHRNB3) influence risk for nicotine dependence, as defined by scores on the Fagerstrom test for nicotine dependence.	('nAChR', 'Gene', '1137', (120, 125))	('nicotinic acetylcholine receptor', 'Gene', (86, 118))	('CHRNA5', 'Gene', '1138', (182, 188))	('CHRNA3', 'Gene', '1136', (189, 195))	('nicotine', 'Chemical', 'MESH:D009538', (314, 322))	('CHRNB4', 'Gene', '1143', (196, 202))	('nAChR', 'Gene', (120, 125))	('influence', 'Reg', (226, 235))	('nicotine', 'Chemical', 'MESH:D009538', (245, 253))	('CHRNB4', 'Gene', (196, 202))	('variants', 'Var', (66, 74))	('CHRNA6-CHRNB3', 'Disease', (211, 224))	('nicotinic acetylcholine receptor', 'Gene', '1137', (86, 118))	('CHRNA6-CHRNB3', 'Disease', 'None', (211, 224))	('CHRNA3', 'Gene', (189, 195))	('nicotine dependence', 'Disease', (245, 264))	('CHRNA5', 'Gene', (182, 188))	('human', 'Species', '9606', (160, 165))
348073	22703173	Genome-wide association meta-analyses for CPD further confirmed that variants in CHRNA5, CHRNA3, and CHRNB4 are associated with the risk of developing heavy smoking.	('CHRNB4', 'Gene', (101, 107))	('CPD', 'Disease', (42, 45))	('CPD', 'Disease', 'MESH:C565865', (42, 45))	('variants', 'Var', (69, 77))	('CHRNA3', 'Gene', (89, 95))	('CHRNB4', 'Gene', '1143', (101, 107))	('CHRNA5', 'Gene', (81, 87))	('CHRNA3', 'Gene', '1136', (89, 95))	('associated', 'Reg', (112, 122))	('CHRNA5', 'Gene', '1138', (81, 87))
348074	22703173	showed that variation in the CHRNA6-CHRNB3 gene cluster on human chromosome 8 is associated with CPD at a genome-wide significance level.	('human', 'Species', '9606', (59, 64))	('CPD', 'Disease', (97, 100))	('CPD', 'Disease', 'MESH:C565865', (97, 100))	('CHRNA6-CHRNB3', 'Disease', (29, 42))	('CHRNA6-CHRNB3', 'Disease', 'None', (29, 42))	('variation', 'Var', (12, 21))	('associated', 'Reg', (81, 91))
348075	22703173	Genetic variation in nicotine metabolism also plays an important role in cigarette consumption and nicotine dependence.	('Genetic variation', 'Var', (0, 17))	('nicotine', 'Chemical', 'MESH:D009538', (99, 107))	('nicotine', 'Chemical', 'MESH:D009538', (21, 29))	('cigarette consumption', 'Disease', (73, 94))	('nicotine dependence', 'Disease', (99, 118))	('nicotine metabolism', 'MPA', (21, 40))
348077	22703173	Recent GWAS meta-analyses using subjects of European descent identified SNPs in the region of CYP2A6 associated with CPD.	('CPD', 'Disease', 'MESH:C565865', (117, 120))	('SNPs in', 'Var', (72, 79))	('CYP2A6', 'Gene', (94, 100))	('CPD', 'Disease', (117, 120))	('associated', 'Reg', (101, 111))	('CYP2A6', 'Gene', '1548', (94, 100))
348078	22703173	In parallel with these GWAS, several studies using a candidate gene approach have also reported the association of SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster with nicotine dependence and smoking quantity.	('nicotine', 'Chemical', 'MESH:D009538', (166, 174))	('CHRNA5', 'Gene', '1138', (127, 133))	('smoking quantity', 'Disease', (190, 206))	('CHRNB4', 'Gene', '1143', (141, 147))	('association', 'Interaction', (100, 111))	('CHRNA3', 'Gene', (134, 140))	('CHRNB4', 'Gene', (141, 147))	('nicotine dependence', 'Disease', (166, 185))	('CHRNA5', 'Gene', (127, 133))	('CHRNA3', 'Gene', '1136', (134, 140))	('SNPs', 'Var', (115, 119))
348079	22703173	Furthermore, a fine mapping study observed that the nonsynonymous SNP rs16969968 in exon 5 of CHRNA5 has consistent effects on the risk for nicotine dependence in both European (odds ratio of 1.40; 95% confidence interval, 1.23-1.59) and African (odds ratio of 2.04; 95% confidence interval, 1.15-3.62) populations, despite a large difference in allele frequency for the SNP.	('SNP', 'Var', (66, 69))	('CHRNA5', 'Gene', (94, 100))	('rs16969968', 'Mutation', 'rs16969968', (70, 80))	('CHRNA5', 'Gene', '1138', (94, 100))	('nicotine', 'Chemical', 'MESH:D009538', (140, 148))	('nicotine dependence', 'Disease', (140, 159))	('rs16969968', 'Var', (70, 80))	('effects', 'Reg', (116, 123))
348080	22703173	A second locus tagged by rs578776 in the 3' untranslated region of CHRNA3 that has low linkage disequilibrium with rs16969968 is associated with nicotine dependence in European Americans but not in African Americans.	('nicotine', 'Chemical', 'MESH:D009538', (145, 153))	('associated with', 'Reg', (129, 144))	('rs16969968', 'Var', (115, 125))	('rs578776', 'Var', (25, 33))	('CHRNA3', 'Gene', (67, 73))	('rs16969968', 'Mutation', 'rs16969968', (115, 125))	('CHRNA3', 'Gene', '1136', (67, 73))	('nicotine dependence', 'MPA', (145, 164))	('rs578776', 'Mutation', 'rs578776', (25, 33))
348081	22703173	Another linkage disequilibrium bin tagged by an intronic SNP in CHRNA5, rs588765, confers a protective effect for nicotine dependence in populations of European descent (Figure 3).	('nicotine', 'Chemical', 'MESH:D009538', (114, 122))	('CHRNA5', 'Gene', '1138', (64, 70))	('protective', 'NegReg', (92, 102))	('nicotine dependence', 'Disease', (114, 133))	('CHRNA5', 'Gene', (64, 70))	('rs588765', 'Var', (72, 80))	('rs588765', 'Mutation', 'rs588765', (72, 80))
348082	22703173	In Asians, a locus tagged by rs578776 overlapped with a locus tagged by rs588765, and variants in this distinctive linkage disequilibrium pattern were reported to influence smoking initiation, smoking cessation, and smoking quantity.	('influence', 'Reg', (163, 172))	('smoking initiation', 'CPA', (173, 191))	('smoking cessation', 'CPA', (193, 210))	('rs578776', 'Mutation', 'rs578776', (29, 37))	('variants', 'Var', (86, 94))	('smoking quantity', 'CPA', (216, 232))	('rs578776', 'Var', (29, 37))	('rs588765', 'Mutation', 'rs588765', (72, 80))
348084	22703173	One mechanism involves the variant rs16969968 (D398N), which likely alters protein structure and receptor function.	('function', 'MPA', (106, 114))	('rs16969968', 'Mutation', 'rs16969968', (35, 45))	('D398N', 'Var', (47, 52))	('alters', 'Reg', (68, 74))	('protein', 'Protein', (75, 82))	('D398N', 'SUBSTITUTION', 'None', (47, 52))
348085	22703173	An in vitro functional analysis demonstrated that the maximal response to agonist per receptor was twofold higher for the alpha4beta2alpha5D398 nAChR variant relative to the alpha4beta2alpha5N398 nAChR variant.	('beta2', 'Gene', (128, 133))	('nAChR', 'Gene', '1137', (144, 149))	('nAChR', 'Gene', '1137', (196, 201))	('nAChR', 'Gene', (144, 149))	('variant', 'Var', (150, 157))	('maximal response to agonist per receptor', 'MPA', (54, 94))	('nAChR', 'Gene', (196, 201))	('beta2', 'Gene', '10383', (180, 185))	('beta2', 'Gene', (180, 185))	('higher', 'PosReg', (107, 113))	('beta2', 'Gene', '10383', (128, 133))
348087	22703173	Several variants located upstream of the coding region and intronic regions of CHRNA5 (i.e., rs588765) are strongly associated with the variability in CHRNA5 mRNA expression observed in the human frontal cortex.	('CHRNA5', 'Gene', (79, 85))	('variability', 'MPA', (136, 147))	('CHRNA5', 'Gene', '1138', (151, 157))	('rs588765', 'Var', (93, 101))	('CHRNA5', 'Gene', '1138', (79, 85))	('human', 'Species', '9606', (190, 195))	('CHRNA5', 'Gene', (151, 157))	('rs588765', 'Mutation', 'rs588765', (93, 101))	('associated', 'Reg', (116, 126))
348088	22703173	Subjects homozygous for the minor allele of rs588765 showed a 2.9-fold increase in CHRNA5 mRNA expression compared with subjects homozygous for the major allele .	('rs588765', 'Mutation', 'rs588765', (44, 52))	('CHRNA5', 'Gene', (83, 89))	('CHRNA5', 'Gene', '1138', (83, 89))	('increase', 'PosReg', (71, 79))	('rs588765', 'Var', (44, 52))
348089	22703173	The rs588765 polymorphism and highly correlated variants are only weakly correlated with the D398N variant.	('D398N', 'Var', (93, 98))	('rs588765', 'Var', (4, 12))	('D398N', 'SUBSTITUTION', 'None', (93, 98))	('rs588765', 'Mutation', 'rs588765', (4, 12))
348090	22703173	The N398 variant, which greatly increases risk for nicotine dependence, occurs primarily on the background of low mRNA expression of CHRNA5.	('CHRNA5', 'Gene', '1138', (133, 139))	('nicotine', 'Chemical', 'MESH:D009538', (51, 59))	('nicotine dependence', 'Disease', (51, 70))	('N398', 'Var', (4, 8))	('CHRNA5', 'Gene', (133, 139))	('low', 'NegReg', (110, 113))	('mRNA expression', 'MPA', (114, 129))
348091	22703173	The risk for nicotine dependence is significantly lower when D398 occurs on a background of low CHRNA5 mRNA expression than when it occurs on a background of high CHRNA5 mRNA expression.	('lower', 'NegReg', (50, 55))	('CHRNA5', 'Gene', (163, 169))	('nicotine dependence', 'Disease', (13, 32))	('low', 'NegReg', (92, 95))	('CHRNA5', 'Gene', '1138', (96, 102))	('nicotine', 'Chemical', 'MESH:D009538', (13, 21))	('CHRNA5', 'Gene', '1138', (163, 169))	('CHRNA5', 'Gene', (96, 102))	('D398', 'Var', (61, 65))
348092	22703173	Studies examining genetic and environmental risks for nicotine dependence have shown that there is an interaction between environmental factors and the rs16969968 variant that has an effect on smoking.	('nicotine', 'Chemical', 'MESH:D009538', (54, 62))	('rs16969968', 'Var', (152, 162))	('effect', 'Reg', (183, 189))	('rs16969968', 'Mutation', 'rs16969968', (152, 162))	('men', 'Species', '9606', (129, 132))	('men', 'Species', '9606', (37, 40))	('smoking', 'Disease', (193, 200))	('interaction', 'Interaction', (102, 113))
348093	22703173	The genetic risk associated with rs16969968 was reduced in subjects with high levels of parent monitoring and increased in subjects with low levels of parent monitoring.	('rs16969968', 'Mutation', 'rs16969968', (33, 43))	('reduced', 'NegReg', (48, 55))	('rs16969968', 'Var', (33, 43))
348095	22703173	A study that sequenced all genes encoding nicotinic receptor subunits has demonstrated that the low-frequency coding variants R37H in CHRNA3 and T375I and T91I in CHRNB4 decrease the risk for nicotine dependence among regular smokers.	('R37H', 'Mutation', 'rs8192475', (126, 130))	('R37H', 'Var', (126, 130))	('T375I', 'Var', (145, 150))	('CHRNA3', 'Gene', (134, 140))	('nicotine', 'Chemical', 'MESH:D009538', (192, 200))	('CHRNB4', 'Gene', '1143', (163, 169))	('CHRNB4', 'Gene', (163, 169))	('T91I', 'Mutation', 'rs12914008', (155, 159))	('T375I', 'Mutation', 'rs61737499', (145, 150))	('decrease', 'NegReg', (170, 178))	('nicotine dependence', 'Disease', (192, 211))	('CHRNA3', 'Gene', '1136', (134, 140))	('T91I', 'Var', (155, 159))
348103	22703173	However, some studies have failed to detect any association between CYP2A6 variation and smoking status.	('variation', 'Var', (75, 84))	('CYP2A6', 'Gene', '1548', (68, 74))	('CYP2A6', 'Gene', (68, 74))
348116	22703173	A study using 708 DSM-IV cannabis-dependent cases and 2,346 cannabis-exposed nondependent controls from the Study of Addiction: Genetics and Environment data set showed a suggestive association between cannabis dependence and variants in the ANKFN1 gene on human chromosome 17.	('variants', 'Var', (226, 234))	('ANKFN1', 'Gene', (242, 248))	('human', 'Species', '9606', (257, 262))	('men', 'Species', '9606', (148, 151))	('cannabis dependence', 'Disease', 'MESH:D002189', (202, 221))	('ANKFN1', 'Gene', '162282', (242, 248))	('cannabis dependence', 'Disease', (202, 221))
348118	22703173	used a pooled GWAS approach to find variants associated with vulnerability to heroin addiction.	('heroin addiction', 'Disease', (78, 94))	('heroin', 'Chemical', 'MESH:D003932', (78, 84))	('associated', 'Reg', (45, 55))	('variants', 'Var', (36, 44))	('heroin addiction', 'Phenotype', 'HP:0030214', (78, 94))
348121	22703173	A nonsynonymous SNP in exon 1 of OPRM1, A118G, is the most commonly studied variant for opioid dependence, but its association is controversial.	('A118G', 'Var', (40, 45))	('opioid dependence', 'Disease', (88, 105))	('opioid dependence', 'Disease', 'MESH:D009293', (88, 105))	('OPRM1', 'Gene', (33, 38))	('A118G', 'Mutation', 'rs1799971', (40, 45))
348122	22703173	Several studies have reported a positive association between variants in OPRM1 and opiate (including heroin) dependence, whereas other studies did not detect an association.	('heroin', 'Chemical', 'MESH:D003932', (101, 107))	('opiate', 'Disease', (83, 89))	('OPRM1', 'Gene', (73, 78))	('positive', 'PosReg', (32, 40))	('variants', 'Var', (61, 69))
348123	22703173	A study using sensory neurons isolated from a humanized mouse model showed that the A118G missense variant of OPRM1 modulates the morphine and fentanyl pharmacological profile.	('morphine', 'Chemical', 'MESH:D009020', (130, 138))	('OPRM1', 'Gene', (110, 115))	('mouse', 'Species', '10090', (56, 61))	('human', 'Species', '9606', (46, 51))	('A118G missense', 'Var', (84, 98))	('fentanyl', 'Chemical', 'MESH:D005283', (143, 151))	('A118G', 'Mutation', 'rs1799971', (84, 89))	('modulates', 'Reg', (116, 125))
348124	22703173	Morphine is approximately fivefold less potent and 26% less efficacious in neurons with the 118GG genotype than it is in neurons with the 118AA genotype.	('less', 'NegReg', (55, 59))	('potent', 'MPA', (40, 46))	('less', 'NegReg', (35, 39))	('Morphine', 'Chemical', 'MESH:D009020', (0, 8))	('efficacious', 'MPA', (60, 71))	('118GG', 'Var', (92, 97))
348129	22703173	Several other variants in CNR1 have been reported to be associated with cannabis dependence, cannabis-dependence symptoms, cocaine dependence, and other substance dependences.	('cannabis-dependence symptoms', 'Disease', (93, 121))	('variants', 'Var', (14, 22))	('cocaine dependence', 'Disease', (123, 141))	('cannabis-dependence symptoms', 'Disease', 'MESH:D002189', (93, 121))	('associated', 'Reg', (56, 66))	('cocaine dependence', 'Disease', 'MESH:D019970', (123, 141))	('CNR1', 'Gene', (26, 30))	('cannabis dependence', 'Disease', 'MESH:D002189', (72, 91))	('cannabis dependence', 'Disease', (72, 91))
348130	22703173	Interestingly, the rs16969968 nonsynonymous variant in the alpha5 nicotinic acetylcholine receptor is also associated with cocaine dependence, but the minor allele reduces the risk for cocaine dependence, which is the opposite of the effect reported for nicotine dependence.	('reduces', 'NegReg', (164, 171))	('nicotinic acetylcholine receptor', 'Gene', (66, 98))	('associated', 'Reg', (107, 117))	('cocaine dependence', 'Disease', (123, 141))	('cocaine dependence', 'Disease', (185, 203))	('nicotinic acetylcholine receptor', 'Gene', '1137', (66, 98))	('cocaine dependence', 'Disease', 'MESH:D019970', (123, 141))	('cocaine dependence', 'Disease', 'MESH:D019970', (185, 203))	('rs16969968', 'Var', (19, 29))	('rs16969968', 'Mutation', 'rs16969968', (19, 29))	('nicotine', 'Chemical', 'MESH:D009538', (254, 262))
348132	22703173	In contrast to GWAS, sequencing of targeted genomic regions identified from GWAS or linkage analysis, or whole-exome or whole-genome sequencing, improves the ability to discover novel causative or highly penetrant mutations for human diseases.	('improves', 'PosReg', (145, 153))	('human', 'Species', '9606', (228, 233))	('mutations', 'Var', (214, 223))
348133	22703173	Rare variants have been shown to be risk factors for some complex disorders, but their role in psychiatric disorders and especially addiction-related phenotypes is largely unexplored.	('risk factors', 'Reg', (36, 48))	('psychiatric disorders', 'Phenotype', 'HP:0000708', (95, 116))	('psychiatric disorders', 'Disease', (95, 116))	('complex disorders', 'Disease', (58, 75))	('psychiatric disorder', 'Phenotype', 'HP:0000708', (95, 115))	('variants', 'Var', (5, 13))	('psychiatric disorders', 'Disease', 'MESH:D001523', (95, 116))
348134	22703173	A few studies have shown associations between rare variation in nicotinic receptor genes and nicotine dependence.	('associations', 'Interaction', (25, 37))	('nicotine dependence', 'Disease', (93, 112))	('nicotinic', 'Protein', (64, 73))	('rare variation', 'Var', (46, 60))	('nicotine', 'Chemical', 'MESH:D009538', (93, 101))
348135	22703173	Several variants in the alcohol metabolism genes (i.e., ADH1B) and nicotine metabolism genes (i.e., CYP2A6) have low frequencies (1%-5% minor allele frequency) and generally reduce risk for dependence, suggesting that human populations might be genetically predisposed to develop addiction, with rare variant alleles leading to reduced risk.	('CYP2A6', 'Gene', (100, 106))	('nicotine', 'Chemical', 'MESH:D009538', (67, 75))	('reduce', 'NegReg', (174, 180))	('variants', 'Var', (8, 16))	('alcohol', 'Chemical', 'MESH:D000438', (24, 31))	('dependence', 'Disease', (190, 200))	('ADH1B', 'Gene', (56, 61))	('human', 'Species', '9606', (218, 223))	('CYP2A6', 'Gene', '1548', (100, 106))	('ADH1B', 'Gene', '125', (56, 61))	('addiction', 'Disease', (280, 289))
348138	22703173	GWAS approaches have revealed that several SNPs within the nAChR gene cluster are significantly associated with the risk of lung cancer and COPD.	('COPD', 'Phenotype', 'HP:0006510', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('SNPs', 'Var', (43, 47))	('nAChR', 'Gene', '1137', (59, 64))	('COPD', 'Disease', 'MESH:D029424', (140, 144))	('associated with', 'Reg', (96, 111))	('COPD', 'Disease', (140, 144))	('nAChR', 'Gene', (59, 64))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
348141	22703173	Although SNPs at this locus are only weakly associated with lung cancer risk in those who have never smoked, they are associated with risk for other smoking-associated cancers and diseases.	('associated', 'Reg', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('SNPs at', 'Var', (9, 16))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('associated', 'Reg', (118, 128))
348143	22703173	However, some studies have suggested a direct link between CHRNA5-CHRNA3-CHRNB4 variants and lung cancer: The risk of lung cancer that can be attributed to the CHRNA5-CHRNA3-CHRNB4 variants is higher than can be explained by the variant's effect on smoking quantity, and the genetic risk for lung cancer and COPD remains after the risk associated with smoking has been statistically accounted for using CPD and the duration of smoking.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('COPD', 'Disease', (308, 312))	('CHRNA3', 'Gene', '1136', (66, 72))	('lung cancer', 'Disease', (292, 303))	('CHRNA3', 'Gene', '1136', (167, 173))	('lung cancer', 'Disease', (118, 129))	('CHRNB4', 'Gene', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('CHRNB4', 'Gene', (174, 180))	('CHRNA5', 'Gene', '1138', (59, 65))	('lung cancer', 'Disease', (93, 104))	('CHRNA3', 'Gene', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (292, 303))	('CHRNA5', 'Gene', (59, 65))	('CHRNA3', 'Gene', (167, 173))	('CPD', 'Disease', (403, 406))	('CPD', 'Disease', 'MESH:C565865', (403, 406))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (292, 303))	('variants', 'Var', (80, 88))	('CHRNB4', 'Gene', '1143', (73, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('CHRNA5', 'Gene', '1138', (160, 166))	('higher', 'PosReg', (193, 199))	('CHRNB4', 'Gene', '1143', (174, 180))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('CHRNA5', 'Gene', (160, 166))	('variants', 'Var', (181, 189))	('COPD', 'Phenotype', 'HP:0006510', (308, 312))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('COPD', 'Disease', 'MESH:D029424', (308, 312))
348148	22703173	SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster could therefore contribute to increased risk of nicotine dependence and to lung cancer independently and on two levels: (a) by increasing the number of cigarettes smoked and the likelihood of nicotine dependence, and (b) by inserting themselves into the pathophysiological cascade that leads to lung cancer.	('CHRNB4', 'Gene', (26, 32))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('nicotine', 'Chemical', 'MESH:D009538', (94, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('lung cancer', 'Disease', (341, 352))	('CHRNA5', 'Gene', '1138', (12, 18))	('CHRNA3', 'Gene', '1136', (19, 25))	('increasing', 'PosReg', (173, 183))	('CHRNA5', 'Gene', (12, 18))	('nicotine dependence', 'Disease', (238, 257))	('CHRNB4', 'Gene', '1143', (26, 32))	('nicotine', 'Chemical', 'MESH:D009538', (238, 246))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (341, 352))	('nicotine dependence', 'Disease', (94, 113))	('inserting', 'Reg', (270, 279))	('CHRNA3', 'Gene', (19, 25))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (341, 352))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('SNPs', 'Var', (0, 4))
348149	22703173	Variants in ADH1B and ALDH2 that influence alcohol consumption and alcohol dependence also play a role in the risk for upper aero-digestive tract (UADT) cancer.	('alcohol', 'Chemical', 'MESH:D000438', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('Variants', 'Var', (0, 8))	('ADH1B', 'Gene', (12, 17))	('ALDH2', 'Gene', (22, 27))	('cancer', 'Disease', (153, 159))	('alcohol dependence', 'Disease', (67, 85))	('alcohol', 'Chemical', 'MESH:D000438', (43, 50))	('ADH1B', 'Gene', '125', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('alcohol dependence', 'Disease', 'MESH:D000437', (67, 85))	('alcohol dependence', 'Phenotype', 'HP:0030955', (67, 85))	('upper aero-digestive tract', 'Disease', (119, 145))	('ALDH2', 'Gene', '217', (22, 27))
348154	22703173	GWAS have also identified a significant association between esophageal squamous cell cancer and SNPs on human chromosomes 4q21-23 and 12q24, which include the functional variants rs1229984 in ADH1B and rs671 in ALDH2, respectively.	('rs1229984', 'Var', (179, 188))	('rs1229984', 'Mutation', 'rs1229984', (179, 188))	('ALDH2', 'Gene', (211, 216))	('esophageal squamous cell cancer', 'Disease', (60, 91))	('rs671', 'Var', (202, 207))	('ADH1B', 'Gene', (192, 197))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (71, 91))	('human', 'Species', '9606', (104, 109))	('rs671', 'Mutation', 'rs671', (202, 207))	('ADH1B', 'Gene', '125', (192, 197))	('ALDH2', 'Gene', '217', (211, 216))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (60, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('SNPs', 'Disease', (96, 100))
348162	22703173	Recent GWAS have successfully identified variants in the alpha3, alpha5, and beta4 subunits of nAChR associated with risk of nicotine dependence.	('nAChR', 'Gene', '1137', (95, 100))	('variants', 'Var', (41, 49))	('nicotine', 'Chemical', 'MESH:D009538', (125, 133))	('nAChR', 'Gene', (95, 100))	('nicotine dependence', 'Disease', (125, 144))	('associated', 'Reg', (101, 111))
348170	20022228	Destruction or dysregulation of lymphatics, following injury, surgery or chronic inflammation also appears to exacerbate GI disease activity and morbidity.	('GI disease', 'Disease', 'MESH:D005767', (121, 131))	('exacerbate', 'PosReg', (110, 120))	('inflammation', 'Disease', 'MESH:D007249', (81, 93))	('inflammation', 'Disease', (81, 93))	('GI disease', 'Phenotype', 'HP:0011024', (121, 131))	('GI disease', 'Disease', (121, 131))	('dysregulation', 'Var', (15, 28))
348196	20022228	Mutations in SOX18 are linked with hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) associated with post-natal alopecia, permanent dilation of small blood vessels, and focal red lesions.	('SOX18', 'Gene', (13, 18))	('hypotrichosis-lymphedema-telangiectasia syndrome', 'Disease', 'MESH:C564327', (35, 83))	('HLTS', 'Disease', 'MESH:C564327', (85, 89))	('lymphedema', 'Phenotype', 'HP:0001004', (49, 59))	('HLTS', 'Disease', (85, 89))	('telangiectasia', 'Phenotype', 'HP:0001009', (60, 74))	('hypotrichosis-lymphedema-telangiectasia syndrome', 'Disease', (35, 83))	('Mutations', 'Var', (0, 9))	('SOX18', 'Gene', '20672', (13, 18))	('edema', 'Phenotype', 'HP:0000969', (54, 59))	('-lymphedema', 'Phenotype', 'HP:0001004', (48, 59))	('alopecia', 'Phenotype', 'HP:0001596', (118, 126))	('hypotrichosis', 'Phenotype', 'HP:0001006', (35, 48))	('linked', 'Reg', (23, 29))	('associated', 'Reg', (91, 101))
348199	20022228	Integrin a9 deficient mice show congenital chylothorax.	('deficient', 'Var', (12, 21))	('congenital chylothorax', 'Disease', (32, 54))	('mice', 'Species', '10090', (22, 26))	('chylothorax', 'Phenotype', 'HP:0010310', (43, 54))
348208	20022228	Interestingly, CALCRL is a Prox-1-dependent transcript and AM, CALCRL and RAMP2 knockout mice exhibit lymphedema with perinatal mortality.	('knockout', 'Var', (80, 88))	('AM', 'Gene', '11535', (75, 77))	('RAMP2', 'Gene', '54409', (74, 79))	('edema', 'Phenotype', 'HP:0000969', (107, 112))	('lymphedema', 'Phenotype', 'HP:0001004', (102, 112))	('RAMP2', 'Gene', (74, 79))	('exhibit', 'Reg', (94, 101))	('CALCRL', 'Gene', (63, 69))	('mice', 'Species', '10090', (89, 93))	('Prox-1', 'Gene', (27, 33))	('CALCRL', 'Gene', '54598', (63, 69))	('Prox-1', 'Gene', '19130', (27, 33))	('AM', 'Gene', '11535', (59, 61))	('CALCRL', 'Gene', (15, 21))	('lymphedema', 'Disease', (102, 112))	('CALCRL', 'Gene', '54598', (15, 21))	('lymphedema', 'Disease', 'MESH:D008209', (102, 112))
348213	20022228	At least one report suggests that lymphatic defects and a lymphedematous phenotype associated with VEGFR-3 missense mutations may involve dysregulated downstream NF-kappaB signaling.	('VEGFR-3', 'Gene', (99, 106))	('lymphedematous', 'Disease', (58, 72))	('lymphedema', 'Phenotype', 'HP:0001004', (58, 68))	('involve', 'Reg', (130, 137))	('lymphatic defects', 'Disease', 'MESH:D008206', (34, 51))	('NF-kappaB', 'Gene', '18033', (162, 171))	('missense mutations', 'Var', (107, 125))	('lymphatic defects', 'Disease', (34, 51))	('NF-kappaB', 'Gene', (162, 171))	('lymphedematous', 'Disease', 'None', (58, 72))	('edema', 'Phenotype', 'HP:0000969', (63, 68))	('VEGFR-3', 'Gene', '14257', (99, 106))
348223	20022228	C1galt1 O-glycan deficiency leads to blood/lymphatic misconnections and to fatty liver disease.	('fatty liver disease', 'Disease', 'MESH:D005234', (75, 94))	('blood/lymphatic misconnections', 'CPA', (37, 67))	('fatty liver disease', 'Disease', (75, 94))	('O-glycan', 'Protein', (8, 16))	('leads to', 'Reg', (28, 36))	('fatty liver', 'Phenotype', 'HP:0001397', (75, 86))	('deficiency', 'Var', (17, 27))	('C1galt1', 'Gene', '94192', (0, 7))	('C1galt1', 'Gene', (0, 7))	('liver disease', 'Phenotype', 'HP:0001392', (81, 94))	('O-glycan', 'Chemical', '-', (8, 16))
348225	20022228	While not specific to lymphatics, Ephrin b2 participates in forming lymphatic collecting ducts and capillaries from an existing lymphatic plexus, and Ephrin b2 deletion in both BECs and LECs leads to vessel malformation and hemorrhage.	('Ephrin b2', 'Gene', '13642', (150, 159))	('Ephrin b2', 'Gene', '13642', (34, 43))	('hemorrhage', 'Disease', (224, 234))	('Ephrin b2', 'Gene', (150, 159))	('deletion', 'Var', (160, 168))	('Ephrin b2', 'Gene', (34, 43))	('vessel malformation', 'CPA', (200, 219))	('LEC', 'Gene', '16839', (186, 189))	('hemorrhage', 'Disease', 'MESH:D006470', (224, 234))	('LEC', 'Gene', (186, 189))	('leads to', 'Reg', (191, 199))
348229	20022228	Other gene knockouts seen to produce lymphatic phenotypes include Elk (Ets-like gene 1)(causes an early chylothorax with dilated thoracic lymphatic vessels, but lacking lymphedema), podoplanin, (produces a hereditary lymphedema seen in the skin, legs and neck mediated by atypical lymphatic networks, and intestinal lymphangiectasia),.	('lymphedema', 'Disease', (169, 179))	('podoplanin', 'Gene', '14726', (182, 192))	('intestinal lymphangiectasia', 'Disease', 'MESH:D008201', (305, 332))	('lymphedema', 'Disease', 'MESH:D008209', (169, 179))	('intestinal lymphangiectasia', 'Phenotype', 'HP:0002593', (305, 332))	('knockouts', 'Var', (11, 20))	('produces', 'Reg', (195, 203))	('Elk', 'Gene', (66, 69))	('intestinal lymphangiectasia', 'Disease', (305, 332))	('podoplanin', 'Gene', (182, 192))	('hereditary lymphedema', 'Disease', (206, 227))	('chylothorax', 'Phenotype', 'HP:0010310', (104, 115))	('Elk', 'Gene', '270190', (66, 69))	('lymphedema', 'Phenotype', 'HP:0001004', (217, 227))	('edema', 'Phenotype', 'HP:0000969', (222, 227))	('lymphangiectasia', 'Phenotype', 'HP:0031842', (316, 332))	('lymphedema', 'Phenotype', 'HP:0001004', (169, 179))	('lymphedema', 'Disease', (217, 227))	('edema', 'Phenotype', 'HP:0000969', (174, 179))	('causes', 'Reg', (88, 94))	('hereditary lymphedema', 'Disease', 'MESH:D008209', (206, 227))	('lymphedema', 'Disease', 'MESH:D008209', (217, 227))
348302	20022228	Prox-1 is also necessary for adult liver homeostasis as its deletion produces several defects in the liver function.	('deletion', 'Var', (60, 68))	('defects', 'MPA', (86, 93))	('produces', 'Reg', (69, 77))	('Prox-1', 'Gene', (0, 6))	('Prox-1', 'Gene', '19130', (0, 6))	('liver function', 'MPA', (101, 115))
348312	20022228	The blockade or ligation of proximal pancreatic lymphatic efferent vessels provokes severe pancreatitis via release of toxic proteolytic enzymes.	('pancreatic', 'Disease', 'MESH:D010195', (37, 47))	('provokes', 'Reg', (75, 83))	('lymphatic efferent vessels', 'Phenotype', 'HP:0001004', (48, 74))	('pancreatitis', 'Phenotype', 'HP:0001733', (91, 103))	('pancreatitis', 'Disease', 'MESH:D010195', (91, 103))	('pancreatic', 'Disease', (37, 47))	('ligation', 'Var', (16, 24))	('pancreatitis', 'Disease', (91, 103))	('release of toxic proteolytic enzymes', 'MPA', (108, 144))
348317	20022228	Conditional deletion of Prox-1 causes exocrine cell apoptosis, inflammation and impaired function of the pancreas.	('Conditional deletion', 'Var', (0, 20))	('Prox-1', 'Gene', (24, 30))	('Prox-1', 'Gene', '19130', (24, 30))	('impaired function of the pancreas', 'Disease', 'MESH:D003072', (80, 113))	('impaired function of the pancreas', 'Disease', (80, 113))	('causes', 'Reg', (31, 37))	('inflammation', 'Disease', 'MESH:D007249', (63, 75))	('exocrine cell apoptosis', 'CPA', (38, 61))	('inflammation', 'Disease', (63, 75))
348326	20022228	Defects in GI lymphatic patterning and structure, lymphatic pump function and GI lymphatic obstruction or remodeling produce several forms of GI pathology and exacerbate GI injury.	('lymphatic obstruction', 'Phenotype', 'HP:0001004', (81, 102))	('GI pathology', 'Phenotype', 'HP:0011024', (142, 154))	('produce', 'Reg', (117, 124))	('GI injury', 'Disease', (170, 179))	('GI lymphatic obstruction', 'Disease', (78, 102))	('Defects', 'Var', (0, 7))	('exacerbate', 'PosReg', (159, 169))	('GI injury', 'Disease', 'MESH:D005767', (170, 179))	('GI lymphatic obstruction', 'Disease', 'MESH:D008206', (78, 102))
348355	20022228	These VEGFR-3 mutations lead to errors in lymphatic development and lymphatic failure.	('lymphatic failure', 'Disease', 'MESH:D008206', (68, 85))	('VEGFR-3', 'Gene', '14257', (6, 13))	('lymphatic failure', 'Disease', (68, 85))	('VEGFR-3', 'Gene', (6, 13))	('lymphatic development', 'CPA', (42, 63))	('lead to errors', 'Reg', (24, 38))	('lymphatic failure', 'Phenotype', 'HP:0001004', (68, 85))	('mutations', 'Var', (14, 23))
348358	20022228	Additionally, defects in reelin have also been suggested to mediate some forms of primary lymphedema.	('defects', 'Var', (14, 21))	('primary lymphedema', 'Disease', 'MESH:D008209', (82, 100))	('reelin', 'Gene', (25, 31))	('lymphedema', 'Phenotype', 'HP:0001004', (90, 100))	('primary lymphedema', 'Disease', (82, 100))	('edema', 'Phenotype', 'HP:0000969', (95, 100))	('reelin', 'Gene', '19699', (25, 31))	('mediate', 'Reg', (60, 67))
348360	20022228	According to Rezaie et al., FOXC2 mutations when present reflect lymphadema distichiasis rather than MDS.	('lymphadema distichiasis', 'Disease', (65, 88))	('MDS', 'Disease', (101, 104))	('FOXC2', 'Gene', (28, 33))	('MDS', 'Disease', 'MESH:D009190', (101, 104))	('rat', 'Species', '10116', (89, 92))	('distichiasis', 'Phenotype', 'HP:0009743', (76, 88))	('FOXC2', 'Gene', '14234', (28, 33))	('mutations', 'Var', (34, 43))	('lymphadema distichiasis', 'Disease', 'MESH:C537710', (65, 88))	('reflect', 'Reg', (57, 64))
348361	20022228	Lymphedema distichiasis is collection of >30 autosomal dominant mutations in FOXC2 (chromosome 16q24.3) causing a pubertal lymphedema and double row of eyelashes (distichiasis).	('Lymphedema distichiasis', 'Disease', (0, 23))	('lymphedema', 'Phenotype', 'HP:0001004', (123, 133))	('causing', 'Reg', (104, 111))	('edema', 'Phenotype', 'HP:0000969', (128, 133))	('double row of eyelashes', 'Phenotype', 'HP:0008496', (138, 161))	('edema', 'Phenotype', 'HP:0000969', (5, 10))	('lymphedema', 'Disease', (123, 133))	('Lymphedema distichiasis', 'Disease', 'MESH:C537710', (0, 23))	('FOXC2', 'Gene', '14234', (77, 82))	('distichiasis', 'Phenotype', 'HP:0009743', (11, 23))	('mutations', 'Var', (64, 73))	('distichiasis', 'Phenotype', 'HP:0009743', (163, 175))	('Lymphedema', 'Phenotype', 'HP:0001004', (0, 10))	('lymphedema', 'Disease', 'MESH:D008209', (123, 133))	('FOXC2', 'Gene', (77, 82))
348377	20022228	Fifty percent of all AS cases are in Norway with ~ 3% frequency in gene alteration in southern Norway alone.	('Norway', 'Disease', (37, 43))	('gene alteration', 'Var', (67, 82))	('rat', 'Species', '10116', (76, 79))
348379	20022228	It shows autosomal dominant inheritance and in ~50% of individuals is caused by a mutation in protein tyrosine phosphatase-N11, (SHP-2) (chromosome 12q24.1).	('mutation', 'Var', (82, 90))	('SHP-2', 'Gene', (129, 134))	('SHP-2', 'Gene', '19247', (129, 134))	('caused by', 'Reg', (70, 79))
348380	20022228	Mutations in KRAS and SOS1 have also been associated with the development of NS but lymphatic pathology is not a major symptom of NS.	('NS', 'Disease', 'MESH:D009404', (77, 79))	('NS', 'Disease', 'MESH:D009404', (130, 132))	('associated', 'Reg', (42, 52))	('SOS1', 'Gene', (22, 26))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', '16653', (13, 17))	('KRAS', 'Gene', (13, 17))	('SOS1', 'Gene', '20662', (22, 26))
348404	20022228	While TNF-alpha drives VEGF-C and lymphatic expansion in inflammation, antibodies to TNF-alpha relieve inflammation and increase lymphangiogenesis.	('antibodies', 'Var', (71, 81))	('TNF-alpha', 'Gene', (6, 15))	('inflammation', 'Disease', (103, 115))	('VEGF-C', 'Gene', '22341', (23, 29))	('inflammation', 'Disease', 'MESH:D007249', (103, 115))	('inflammation', 'Disease', 'MESH:D007249', (57, 69))	('lymphangiogenesis', 'CPA', (129, 146))	('TNF-alpha', 'Gene', '21926', (85, 94))	('VEGF-C', 'Gene', (23, 29))	('TNF-alpha', 'Gene', '21926', (6, 15))	('inflammation', 'Disease', (57, 69))	('increase', 'PosReg', (120, 128))	('relieve', 'NegReg', (95, 102))	('TNF-alpha', 'Gene', (85, 94))
348418	20022228	Obstruction of the cisterna chyli will also increase pancreatic edema and exacerbate forms of pancreatitis.	('pancreatitis', 'Phenotype', 'HP:0001733', (94, 106))	('pancreatitis', 'Disease', 'MESH:D010195', (94, 106))	('Obstruction', 'Var', (0, 11))	('pancreatic edema', 'Disease', (53, 69))	('increase', 'PosReg', (44, 52))	('pancreatitis', 'Disease', (94, 106))	('pancreatic edema', 'Disease', 'MESH:D004487', (53, 69))	('edema', 'Phenotype', 'HP:0000969', (64, 69))	('exacerbate', 'PosReg', (74, 84))
348419	20022228	Pissas et al., state that 'pancreatic edema...is essentially a "lymphatic" edema..' Experimental ligation of proximal pancreatic lymphatic efferents produced fatal necrotic pancreatitis.	('pancreatic edema', 'Disease', 'MESH:D004487', (27, 43))	('ligation', 'Var', (97, 105))	('pancreatic', 'Disease', 'MESH:D010195', (118, 128))	('edema', 'Disease', (38, 43))	('pancreatitis', 'Phenotype', 'HP:0001733', (173, 185))	('necrotic pancreatitis', 'Disease', 'MESH:D019283', (164, 185))	('pancreatic', 'Disease', (118, 128))	('edema', 'Disease', 'MESH:D004487', (75, 80))	('edema', 'Phenotype', 'HP:0000969', (75, 80))	('edema', 'Disease', 'MESH:D004487', (38, 43))	('necrotic pancreatitis', 'Disease', (164, 185))	('pancreatic', 'Disease', 'MESH:D010195', (27, 37))	('pancreatic edema', 'Disease', (27, 43))	('pancreatic', 'Disease', (27, 37))	('edema', 'Phenotype', 'HP:0000969', (38, 43))	('edema', 'Disease', (75, 80))	('lymphatic efferents', 'Phenotype', 'HP:0001004', (129, 148))
348448	20022228	Obstruction or hypertension in the liver or intestine, or blockage of peritoneal drainage increases ascitic fluid derived from these compartments.	('hypertension', 'Disease', (15, 27))	('hypertension', 'Phenotype', 'HP:0000822', (15, 27))	('ascitic fluid derived from', 'MPA', (100, 126))	('increases', 'PosReg', (90, 99))	('Obstruction', 'Var', (0, 11))	('hypertension', 'Disease', 'MESH:D006973', (15, 27))	('blockage', 'Var', (58, 66))
348449	20022228	Defects in lymphatic development and structure can also provoke 'chylous' ascites.	('ascites', 'Disease', (74, 81))	('ascites', 'Phenotype', 'HP:0001541', (74, 81))	('provoke', 'Reg', (56, 63))	('ascites', 'Disease', 'MESH:D001201', (74, 81))	('lymphatic development', 'CPA', (11, 32))	('Defects', 'Var', (0, 7))
348455	20022228	Studies with colorectal carcinoma showed tumor elevated D2-40+ lymphatic vessel density, which predicts lymphatic tumor invasion with better sensitivity (48/90) than PECAM-1/CD31 (37/90) or (H&E) (31/90).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('PECAM-1', 'Gene', (166, 173))	('tumor', 'Disease', (41, 46))	('lymphatic tumor', 'Phenotype', 'HP:0002665', (104, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CD31', 'Gene', '18613', (174, 178))	('tumor', 'Disease', (114, 119))	('PECAM-1', 'Gene', '18613', (166, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('colorectal carcinoma', 'Disease', (13, 33))	('CD31', 'Gene', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (13, 33))	('D2-40+', 'Var', (56, 62))
348456	20022228	Increased D2-40+ lymphatic density is correlated with lymphatic invasion and lymph node metastases (p<0.05) and is related to the depth of tumor invasion, positive vascular pedicle lymph nodes and liver metastases (p<0.05).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('correlated', 'Reg', (38, 48))	('lymph node metastases', 'Disease', 'MESH:D009362', (77, 98))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('lymph node metastases', 'Disease', (77, 98))	('tumor', 'Disease', (139, 144))	('liver metastases', 'Disease', (197, 213))	('liver metastases', 'Disease', 'MESH:D009362', (197, 213))	('lymphatic invasion', 'CPA', (54, 72))	('D2-40+', 'Var', (10, 16))	('related', 'Reg', (115, 122))
348461	20022228	Obstruction or obliteration of lymphatics produces an intense GI injury.	('GI injury', 'Disease', 'MESH:D005767', (62, 71))	('Obstruction', 'Var', (0, 11))	('rat', 'Species', '10116', (21, 24))	('GI injury', 'Disease', (62, 71))	('obliteration', 'Var', (15, 27))
348464	20022228	While defects in VEGFR-3, FoxC2 and SOX18 genes are known to contribute to errors in lymphatic development and produce different forms of lymphedema, their dysfunction explains only a small fraction of 1  lymphedema cases.	('lymphedema', 'Disease', (138, 148))	('edema', 'Phenotype', 'HP:0000969', (143, 148))	('lymphatic development', 'CPA', (85, 106))	('contribute', 'Reg', (61, 71))	('VEGFR-3', 'Gene', (17, 24))	('lymphedema', 'Disease', (205, 215))	('VEGFR-3', 'Gene', '14257', (17, 24))	('lymphedema', 'Disease', 'MESH:D008209', (138, 148))	('produce', 'Reg', (111, 118))	('edema', 'Phenotype', 'HP:0000969', (210, 215))	('SOX18', 'Gene', (36, 41))	('SOX18', 'Gene', '20672', (36, 41))	('lymphedema', 'Disease', 'MESH:D008209', (205, 215))	('lymphedema', 'Phenotype', 'HP:0001004', (138, 148))	('lymphedema', 'Phenotype', 'HP:0001004', (205, 215))	('FoxC2', 'Gene', (26, 31))	('defects', 'Var', (6, 13))	('errors', 'CPA', (75, 81))
348465	20022228	Ferrell et al., have also found single gene mutations in families with lymphedema within elastin microfibril interfacer (EMILIN1), lymphocyte cytosolic protein 2 (LCP2), fatty acid binding protein 4 (FABP4), protein tyrosine kinase SYK (SYK), neuropilin-2 (NRP2), SpSRY-box 17 (SOX17), VCAM-1, ROR orphan receptor C, and VEGF-B.	('elastin', 'Gene', (89, 96))	('LCP2', 'Gene', (163, 167))	('lymphocyte cytosolic protein 2', 'Gene', '16822', (131, 161))	('LCP2', 'Gene', '16822', (163, 167))	('neuropilin-2', 'Gene', '18187', (243, 255))	('SYK', 'Gene', (232, 235))	('lymphedema', 'Phenotype', 'HP:0001004', (71, 81))	('SpSRY-box 17', 'Gene', (264, 276))	('VEGF-B', 'Gene', '22340', (321, 327))	('lymphedema', 'Disease', (71, 81))	('edema', 'Phenotype', 'HP:0000969', (76, 81))	('fatty acid binding protein 4', 'Gene', '11770', (170, 198))	('SOX17', 'Gene', (278, 283))	('FABP4', 'Gene', '11770', (200, 205))	('SpSRY-box 17', 'Gene', '20671', (264, 276))	('EMILIN1', 'Gene', '100952', (121, 128))	('lymphedema', 'Disease', 'MESH:D008209', (71, 81))	('neuropilin-2', 'Gene', (243, 255))	('NRP2', 'Gene', (257, 261))	('VEGF-B', 'Gene', (321, 327))	('NRP2', 'Gene', '18187', (257, 261))	('SYK', 'Gene', '20963', (232, 235))	('SYK', 'Gene', (237, 240))	('VCAM-1, ROR orphan receptor C', 'Gene', '22329', (286, 315))	('fatty acid binding protein 4', 'Gene', (170, 198))	('EMILIN1', 'Gene', (121, 128))	('SOX17', 'Gene', '20671', (278, 283))	('lymphocyte cytosolic protein 2', 'Gene', (131, 161))	('elastin', 'Gene', '13717', (89, 96))	('mutations', 'Var', (44, 53))	('FABP4', 'Gene', (200, 205))	('SYK', 'Gene', '20963', (237, 240))
348472	20022228	Ang-2 deficient mice  fail to develop lymphatics in ear skin and mesentery, do not exhibit a collecting vessel phenotype, and are considered to be a model of intestinal lymphangiodysplasia.	('Ang-2', 'Gene', (0, 5))	('intestinal lymphangiodysplasia', 'Disease', 'MESH:D007410', (158, 188))	('intestinal lymphangiodysplasia', 'Disease', (158, 188))	('deficient', 'Var', (6, 15))	('Ang-2', 'Gene', '11601', (0, 5))	('mice', 'Species', '10090', (16, 20))
348473	20022228	In humans, FoxC2 mutations produce lymphedema-distichiasis  and FoxC2 haplo-insufficient mice have defects in lymphatic patterning, valve defects and lymph reflux, the homozygous FOXC2-/- phenotype is lethal.	('lymph reflux', 'MPA', (150, 162))	('FOXC2', 'Gene', '14234', (179, 184))	('lymph reflux', 'Phenotype', 'HP:0001004', (150, 162))	('distichiasis', 'Phenotype', 'HP:0009743', (46, 58))	('mutations', 'Var', (17, 26))	('lymphedema-distichiasis', 'Disease', 'MESH:C537710', (35, 58))	('lymphedema-distichiasis', 'Disease', (35, 58))	('FoxC2', 'Gene', (11, 16))	('FOXC2', 'Gene', (179, 184))	('defects', 'NegReg', (99, 106))	('valve defects', 'Phenotype', 'HP:0005148', (132, 145))	('humans', 'Species', '9606', (3, 9))	('produce', 'Reg', (27, 34))	('valve defects', 'Disease', 'MESH:D006349', (132, 145))	('lymphatic patterning', 'CPA', (110, 130))	('mice', 'Species', '10090', (89, 93))	('lymphedema', 'Phenotype', 'HP:0001004', (35, 45))	('edema', 'Phenotype', 'HP:0000969', (40, 45))	('valve defects', 'Disease', (132, 145))	('FoxC2', 'Gene', (64, 69))
348481	20022228	Alterations in the levels of these vasoregulatory factors could modulate adipose tissue vascularity.	('adipose tissue vascularity', 'CPA', (73, 99))	('Alterations', 'Var', (0, 11))	('rat', 'Species', '10116', (4, 7))	('modulate', 'Reg', (64, 72))
348573	33329968	A subset of patients (approximately 15-30%) with esophageal adenocarcinoma have amplification or overexpression of HER2, a human epidermal growth factor receptor that stimulates cell multiplication and resists apoptosis; hence strongly linked with a risk of recurrence and a grave prognosis.	('overexpression', 'PosReg', (97, 111))	('epidermal growth factor receptor', 'Gene', (129, 161))	('amplification', 'Var', (80, 93))	('HER2', 'Gene', (115, 119))	('adenocarcinoma', 'Disease', (60, 74))	('patients', 'Species', '9606', (12, 20))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (49, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('stimulates', 'PosReg', (167, 177))	('linked with', 'Reg', (236, 247))	('HER2', 'Gene', '2064', (115, 119))	('epidermal growth factor receptor', 'Gene', '1956', (129, 161))	('human', 'Species', '9606', (123, 128))	('resists apoptosis', 'CPA', (202, 219))	('adenocarcinoma', 'Disease', 'MESH:D000230', (60, 74))	('cell multiplication', 'CPA', (178, 197))
348577	33329968	Subjects who received trastuzumab had a relatively higher response rate and improved overall survival compared to those who did not receive trastuzumab.	('trastuzumab', 'Chemical', 'MESH:D000068878', (22, 33))	('trastuzumab', 'Chemical', 'MESH:D000068878', (140, 151))	('improved', 'PosReg', (76, 84))	('trastuzumab', 'Var', (22, 33))	('response', 'MPA', (58, 66))	('higher', 'PosReg', (51, 57))	('overall survival', 'MPA', (85, 101))
348585	33329968	Future research should also aim to evaluate the long-term safety of maintenance therapy with trastuzumab and the prognostic value of HER2 positivity in gastric or GEJ adenocarcinoma.	('gastric or GEJ adenocarcinoma', 'Disease', 'MESH:D013274', (152, 181))	('HER2', 'Gene', (133, 137))	('HER2', 'Gene', '2064', (133, 137))	('positivity', 'Var', (138, 148))	('trastuzumab', 'Chemical', 'MESH:D000068878', (93, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('gastric or GEJ adenocarcinoma', 'Disease', (152, 181))
348600	32047721	In conclusion, MELK enhances tumorigenesis, migration, invasion and metastasis of ESCC cells via activation of FOXM1 signaling pathway, suggesting MELK is a potential therapeutic target for ESCC patients, even those in an advanced stage.	('ESCC', 'Disease', (190, 194))	('FOXM1 signaling pathway', 'Pathway', (111, 134))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('activation', 'PosReg', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('enhances', 'PosReg', (20, 28))	('tumor', 'Disease', (29, 34))	('invasion', 'CPA', (55, 63))	('metastasis', 'CPA', (68, 78))	('patients', 'Species', '9606', (195, 203))	('MELK', 'Var', (15, 19))	('migration', 'CPA', (44, 53))
348611	32047721	Moreover, MELK overexpression was also found in chronic lymphocytic leukemia (CLL) cells, and positively correlated with advanced stage, higher WBC count, increased beta2-MG level, elevated LDH, unmutated IGHV, deletion of 17p13, positive ZAP-70 and inferior prognosis of CLL patients.	('patients', 'Species', '9606', (276, 284))	('CLL', 'Disease', (272, 275))	('ZAP-70', 'Gene', '7535', (239, 245))	('lymphocytic leukemia', 'Disease', (56, 76))	('LDH', 'MPA', (190, 193))	('IGHV', 'Gene', '28402', (205, 209))	('beta2', 'Gene', (165, 170))	('beta2', 'Gene', '23545', (165, 170))	('ZAP-70', 'Gene', (239, 245))	('increased', 'PosReg', (155, 164))	('IGHV', 'Gene', (205, 209))	('correlated', 'Reg', (105, 115))	('WBC count', 'CPA', (144, 153))	('CLL', 'Disease', 'MESH:D015451', (272, 275))	('CLL', 'Disease', (78, 81))	('leukemia', 'Phenotype', 'HP:0001909', (68, 76))	('deletion', 'Var', (211, 219))	('CLL', 'Phenotype', 'HP:0005550', (272, 275))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (48, 76))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (56, 76))	('17p13', 'Protein', (223, 228))	('overexpression', 'PosReg', (15, 29))	('higher', 'PosReg', (137, 143))	('CLL', 'Disease', 'MESH:D015451', (78, 81))	('elevated', 'PosReg', (181, 189))	('CLL', 'Phenotype', 'HP:0005550', (78, 81))
348618	32047721	Notably, it revealed that high MELK protein expression was also significantly associated with higher pathological tumor-nodule-metastasis stage, vascular invasion.	('associated', 'Reg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('expression', 'MPA', (44, 54))	('high', 'Var', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('vascular invasion', 'Disease', 'MESH:D019043', (145, 162))	('tumor', 'Disease', (114, 119))	('MELK protein', 'Protein', (31, 43))	('vascular invasion', 'Disease', (145, 162))
348619	32047721	Moreover, the abnormal expression of MELK was related to cervical cancer metastasis at early stage.	('cervical cancer', 'Disease', 'MESH:D002583', (57, 72))	('MELK', 'Protein', (37, 41))	('related', 'Reg', (46, 53))	('cervical cancer', 'Disease', (57, 72))	('abnormal', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('expression', 'MPA', (23, 33))
348622	32047721	Indeed, ectopic expression of MELK drastically promoted gastric cancer cell proliferation, migration and invasion in vitro and accelerated tumor growth and peritoneal spreading and metastasis in nude mice.	('invasion', 'CPA', (105, 113))	('migration', 'CPA', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('ectopic expression', 'Var', (8, 26))	('promoted', 'PosReg', (47, 55))	('MELK', 'Gene', (30, 34))	('accelerated', 'PosReg', (127, 138))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('nude mice', 'Species', '10090', (195, 204))	('gastric cancer', 'Disease', (56, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
348624	32047721	In contrast, knockdown of MELK significantly suppressed tumor cell proliferation, colony formation, stemness, and tumorigenicity, and induced apoptosis, mitosis, and DNA damage both in vitro and in nude mice models in gastric cancer, hepatocellular carcinoma and cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cervical cancer', 'Disease', 'MESH:D002583', (263, 278))	('cervical cancer', 'Disease', (263, 278))	('gastric cancer', 'Phenotype', 'HP:0012126', (218, 232))	('knockdown', 'Var', (13, 22))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (234, 258))	('MELK', 'Gene', (26, 30))	('induced', 'Reg', (134, 141))	('nude mice', 'Species', '10090', (198, 207))	('stemness', 'CPA', (100, 108))	('tumor', 'Disease', (114, 119))	('DNA damage', 'CPA', (166, 176))	('mitosis', 'Disease', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (234, 258))	('gastric cancer', 'Disease', (218, 232))	('tumor', 'Disease', (56, 61))	('colony formation', 'CPA', (82, 98))	('mitosis', 'Disease', 'OMIM:604588', (153, 160))	('suppressed', 'NegReg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('hepatocellular carcinoma', 'Disease', (234, 258))	('gastric cancer', 'Disease', 'MESH:D013274', (218, 232))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('apoptosis', 'CPA', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
348630	32047721	Human ESCC cell lines TE-1, EC109, KYSE70, KYSE30, KYSE450, KYSE150, and EC9706 and one immortalized normal esophageal epithelial cell line Het-1A were obtained and cultured as our previously described.	('Human', 'Species', '9606', (0, 5))	('EC9706', 'Var', (73, 79))	('KYSE450', 'Var', (51, 58))	('KYSE150', 'Var', (60, 67))	('EC9706', 'CellLine', 'CVCL:E307', (73, 79))	('KYSE70', 'Var', (35, 41))	('KYSE30', 'Var', (43, 49))	('EC109', 'CellLine', 'CVCL:6898', (28, 33))
348647	32047721	#88588), phospho-eIF4B (Ser406, Cat.	('phospho', 'Chemical', 'MESH:C033601', (9, 16))	('eIF4B', 'Gene', '1975', (17, 22))	('Ser406', 'Var', (24, 30))	('eIF4B', 'Gene', (17, 22))	('Ser406', 'Chemical', 'MESH:C530429', (24, 30))
348671	32047721	For tumorigenic model, mice (6 mice per group) were subcutaneously implanted with the indicated ESCC cells with MELK overexpression or knockdown (5 x 106 per mice) into the left dorsal flank of each mouse.	('tumor', 'Disease', (4, 9))	('mouse', 'Species', '10090', (199, 204))	('knockdown', 'Var', (135, 144))	('mice', 'Species', '10090', (158, 162))	('mice', 'Species', '10090', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('overexpression', 'PosReg', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mice', 'Species', '10090', (23, 27))
348679	32047721	To determine MELK expression in human ESCC, we firstly analyzed the transcript expression of MELK in two cohorts of ESCC patients from GEO database, the results showed that the mRNA level of MELK in GSE20347 dataset was much higher in ESCC tissues than that in the corresponding normal tissues (Figure 1A); Similar results were observed in GSE23400 dataset, which composes of 53 pairs of ESCC specimens (tumor and matched normal cases) (Figure 1B).	('ESCC', 'Disease', (235, 239))	('GSE20347', 'Var', (199, 207))	('higher', 'PosReg', (225, 231))	('tumor', 'Disease', 'MESH:D009369', (404, 409))	('tumor', 'Phenotype', 'HP:0002664', (404, 409))	('tumor', 'Disease', (404, 409))	('mRNA level', 'MPA', (177, 187))	('human', 'Species', '9606', (32, 37))	('patients', 'Species', '9606', (121, 129))
348680	32047721	Consistently, the levels of MELK protein were obviously higher in ESCC cells, especially in TE-1, KYSE30, KYSE450 and EC9706 cells (Figure 1D).	('KYSE450', 'Var', (106, 113))	('levels', 'MPA', (18, 24))	('ESCC', 'Disease', (66, 70))	('EC9706', 'CellLine', 'CVCL:E307', (118, 124))	('higher', 'PosReg', (56, 62))	('MELK protein', 'Protein', (28, 40))	('Co', 'Chemical', 'MESH:C065987', (0, 2))
348684	32047721	Given that the expression of MELK was lower in KYSE70 and EC109 cells, they were used for gain-of-function analysis.	('EC109', 'CellLine', 'CVCL:6898', (58, 63))	('MELK', 'Gene', (29, 33))	('lower', 'NegReg', (38, 43))	('KYSE70', 'Var', (47, 53))	('expression', 'MPA', (15, 25))
348688	32047721	As shown in Figure 2D, the number of individual colonies was much larger in MELK-expressing KYSE70 cells than that of KYSE70-Vector group; Similar phenomenon was found in EC109 cells (Figure 2D, right).	('larger', 'PosReg', (66, 72))	('EC109', 'CellLine', 'CVCL:6898', (171, 176))	('MELK-expressing KYSE70', 'Var', (76, 98))	('KYSE70', 'Var', (92, 98))
348689	32047721	We next explored whether silencing MELK suppresses in vitro tumorigenicity of ESCC cells.	('silencing', 'Var', (25, 34))	('ESCC', 'Disease', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('suppresses', 'NegReg', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MELK', 'Protein', (35, 39))	('tumor', 'Disease', (60, 65))
348691	32047721	Interestingly, knockdown of MELK drastically inhibited the cell viabilities in both KYSE30 and EC9706 cells (Figure 2F).	('EC9706', 'CellLine', 'CVCL:E307', (95, 101))	('knockdown', 'Var', (15, 24))	('MELK', 'Gene', (28, 32))	('inhibited', 'NegReg', (45, 54))	('cell viabilities', 'CPA', (59, 75))
348694	32047721	The data showed that the migration abilities of KYSE30 and EC9706 cells were obviously inhibited by MELK shRNAs in a wound healing assay (Figure 3D).	('EC9706', 'Var', (59, 65))	('EC9706', 'CellLine', 'CVCL:E307', (59, 65))	('inhibited', 'NegReg', (87, 96))	('wound healing assay', 'CPA', (117, 136))	('migration abilities', 'CPA', (25, 44))
348702	32047721	In contrast, knockdown of MELK by both specific shRNAs drastically inhibited the phosphorylation of FOXM1 (Thr600) (Figure 4A, right); But, overexpression or knockdown of MELK hardly influenced the protein levels of FOXM1 (Figure 4A), phospho-eIF4B (Ser406), phospho-SQSTM1 (Thr269/Ser272), SQSTM1 and eIF4B (Figure S1).	('phosphorylation', 'MPA', (81, 96))	('Ser406', 'Var', (250, 256))	('Ser406', 'Chemical', 'MESH:C530429', (250, 256))	('protein levels', 'MPA', (198, 212))	('knockdown', 'Var', (13, 22))	('FOXM1', 'Gene', (100, 105))	('SQSTM1', 'Gene', (267, 273))	('inhibited', 'NegReg', (67, 76))	('Ser272', 'Chemical', 'MESH:C530429', (282, 288))	('SQSTM1', 'Gene', (291, 297))	('phospho', 'Chemical', 'MESH:C033601', (259, 266))	('eIF4B', 'Gene', '1975', (243, 248))	('phospho', 'Chemical', 'MESH:C033601', (235, 242))	('SQSTM1', 'Gene', '8878', (267, 273))	('SQSTM1', 'Gene', '8878', (291, 297))	('eIF4B', 'Gene', (243, 248))	('Thr269/Ser272', 'Var', (275, 288))	('phospho', 'Chemical', 'MESH:C033601', (81, 88))	('eIF4B', 'Gene', '1975', (302, 307))	('MELK', 'Gene', (171, 175))	('knockdown', 'Var', (158, 167))	('eIF4B', 'Gene', (302, 307))
348705	32047721	Interestingly, ectopic expression of MELK drastically upregulated the protein levels of PLK1, Cyclin B1 and Aurora B, but not SKP2 (Figure 4A, left); Vice versa, silencing MELK led to an opposing results (Figure 4A, right).	('protein levels', 'MPA', (70, 84))	('silencing', 'Var', (162, 171))	('upregulated', 'PosReg', (54, 65))	('Cyclin B1', 'MPA', (94, 103))	('PLK1', 'Protein', (88, 92))	('MELK', 'Gene', (37, 41))	('SKP2', 'Gene', '6502', (126, 130))	('MELK', 'Gene', (172, 176))	('ectopic', 'MPA', (15, 22))	('SKP2', 'Gene', (126, 130))
348706	32047721	To determine whether knockdown of FOXM1 attenuates the oncogene function of MELK in ESCC cells, two different shRNA oligonucleotides targeting the coding sequence of human FOXM1 (shFOXM1#1 and shFOXM1#2) were stably transduced into MELK-overexpressing KYSE70 and EC109 cells.	('human', 'Species', '9606', (166, 171))	('EC109', 'CellLine', 'CVCL:6898', (263, 268))	('oncogene function', 'MPA', (55, 72))	('FOXM1', 'Gene', (34, 39))	('knockdown', 'Var', (21, 30))	('attenuates', 'NegReg', (40, 50))	('FOXM1', 'Gene', (172, 177))
348707	32047721	Consistently, knockdown of FOXM1 in KYSE70-MELK and EC109-MELK cells obviously decreased the number of colonies in solid plates (Figure 4B, middle) and attenuated the colony formation abilities in soft agar assays (Figure 4B, right).	('colony formation abilities in soft agar assays', 'CPA', (167, 213))	('decreased', 'NegReg', (79, 88))	('EC109-MELK', 'CellLine', 'CVCL:6898', (52, 62))	('attenuated', 'NegReg', (152, 162))	('knockdown', 'Var', (14, 23))	('FOXM1', 'Gene', (27, 32))	('Co', 'Chemical', 'MESH:C065987', (0, 2))
348708	32047721	Moreover, the wound-healing and Boyden chamber assays displayed that the migration and invasion of MELK-overexpressing KYSE70 and EC109 cells were obviously inhibited by FOXM1 shRNAs (Figure 4C).	('migration', 'CPA', (73, 82))	('FOXM1 shRNAs', 'Var', (170, 182))	('inhibited', 'NegReg', (157, 166))	('EC109', 'CellLine', 'CVCL:6898', (130, 135))	('invasion', 'CPA', (87, 95))
348709	32047721	Furthermore, knocking down of FOXM1 drastically suppressed MMP-2 and MMP-9 expression in MELK-overexpressing ESCC cells, compared to the corresponding control group (Figure 4D).	('knocking down', 'Var', (13, 26))	('MMP-9', 'Gene', '4318', (69, 74))	('MMP-2', 'Gene', (59, 64))	('MMP-9', 'Gene', (69, 74))	('FOXM1', 'Gene', (30, 35))	('suppressed', 'NegReg', (48, 58))	('MMP-2', 'Gene', '4313', (59, 64))	('expression', 'MPA', (75, 85))
348718	32047721	Moreover, the expression of MELK and PLK1 was greatly upregulated in MELK-overexpressing group, compared to that derived from the Vector-treated mice (Figure 5C).	('MELK-overexpressing group', 'Var', (69, 94))	('upregulated', 'PosReg', (54, 65))	('PLK1', 'Gene', (37, 41))	('expression', 'MPA', (14, 24))	('MELK', 'Gene', (28, 32))	('mice', 'Species', '10090', (145, 149))
348721	32047721	Similarly, the size and weight of tumors were also obviously inhibited by MELK shRNA (Figure 5F), suggesting that silencing MELK suppressed the tumor growth of ESCC cell in nude mice.	('tumor', 'Disease', (144, 149))	('ESCC', 'Disease', (160, 164))	('suppressed', 'NegReg', (129, 139))	('tumor', 'Disease', (34, 39))	('weight of tumors', 'Disease', (24, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('nude mice', 'Species', '10090', (173, 182))	('silencing', 'Var', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('weight of tumors', 'Disease', 'MESH:D015431', (24, 40))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('MELK', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
348722	32047721	Consistently, IHC staining displayed that the levels of Ki67, MELK, and PLK1 were significantly impaired by MELK shRNA (Figure 5G).	('Ki67', 'Gene', (56, 60))	('PLK1', 'Gene', (72, 76))	('Ki67', 'Gene', '17345', (56, 60))	('levels', 'MPA', (46, 52))	('MELK shRNA', 'Var', (108, 118))	('impaired', 'NegReg', (96, 104))	('Co', 'Chemical', 'MESH:C065987', (0, 2))
348728	32047721	To further confirm this conclusion, we then examined whether silencing MELK suppresses ESCC cell metastasis in nude mice.	('nude mice', 'Species', '10090', (111, 120))	('MELK', 'Gene', (71, 75))	('silencing', 'Var', (61, 70))	('ESCC', 'Disease', (87, 91))	('suppresses', 'NegReg', (76, 86))
348748	32047721	In contrast, silencing FOXM1 by shRNAs dramatically attenuated the tumor-promoting effects of MELK on ESCC cells; (3) Overexpression or knockdown of FOXM1 hardly changed the protein levels of MELK.	('FOXM1', 'Gene', (149, 154))	('attenuated', 'NegReg', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('FOXM1', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('silencing', 'Var', (13, 22))
348753	32047721	Overexpression of MELK was also associated with distant metastasis, lymph node involvement and poor prognosis in GC patients.	('patients', 'Species', '9606', (116, 124))	('associated', 'Reg', (32, 42))	('Overexpression', 'Var', (0, 14))	('lymph node involvement', 'CPA', (68, 90))	('MELK', 'Gene', (18, 22))	('GC', 'Phenotype', 'HP:0012126', (113, 115))	('distant metastasis', 'CPA', (48, 66))
348758	32047721	More importantly, ectopic expression of MELK also enhanced the lung metastasis of EC109 cells in animal model.	('MELK', 'Gene', (40, 44))	('ectopic expression', 'Var', (18, 36))	('EC109', 'CellLine', 'CVCL:6898', (82, 87))	('enhanced', 'PosReg', (50, 58))	('lung metastasis of EC109 cells in animal model', 'CPA', (63, 109))
348759	32047721	In line with our findings, ectopic expression of MELK remarkably facilitated the migration, invasion and metastasis of GC cells; Vice versa, inhibition of MELK by shRNA or pharmacology inhibitor significantly suppressed GC cell migration and invasion, and inhibited the peritoneal spreading and metastasis in nude mice.	('GC cell migration', 'CPA', (220, 237))	('invasion', 'CPA', (242, 250))	('GC', 'Phenotype', 'HP:0012126', (119, 121))	('inhibited', 'NegReg', (256, 265))	('invasion', 'CPA', (92, 100))	('suppressed', 'NegReg', (209, 219))	('nude mice', 'Species', '10090', (309, 318))	('GC', 'Phenotype', 'HP:0012126', (220, 222))	('metastasis of GC cells', 'CPA', (105, 127))	('ectopic expression', 'Var', (27, 45))	('inhibition', 'Var', (141, 151))	('MELK', 'Gene', (49, 53))	('migration', 'CPA', (81, 90))	('facilitated', 'PosReg', (65, 76))	('MELK', 'Gene', (155, 159))
348761	32047721	reported that knocking down MELK in the presence of TGF-beta promoted EMT and cell migration in the lung cancer A549 cells.	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('knocking down', 'Var', (14, 27))	('EMT', 'CPA', (70, 73))	('promoted', 'PosReg', (61, 69))	('TGF-beta', 'Gene', (52, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('MELK', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cell migration in', 'CPA', (78, 95))	('TGF-beta', 'Gene', '7039', (52, 60))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
348764	32047721	Collectively, these findings indicated MELK is a potential therapeutic target and small molecule inhibitors targeting MELK might be effective for the treatment of ESCC patients, even among those patients with advanced-stage disease.	('ESCC', 'Disease', (163, 167))	('MELK', 'Gene', (118, 122))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (168, 176))	('small molecule inhibitors', 'Var', (82, 107))	('Co', 'Chemical', 'MESH:C065987', (0, 2))	('inhibitors', 'Var', (97, 107))
348768	31427973	Wee1 Inhibitor AZD1775 Effectively Inhibits the Malignant Phenotypes of Esophageal Squamous Cell Carcinoma In Vitro and In Vivo Esophageal squamous cell carcinoma (ESCC) is a common malignant diagnosed cancer with increasing incidence rate and few treatment options.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('p', 'Chemical', 'MESH:D010758', (259, 260))	('AZD1775', 'Var', (15, 22))	('p', 'Chemical', 'MESH:D010758', (131, 132))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('Esophageal squamous cell carcinoma', 'Disease', (128, 162))	('p', 'Chemical', 'MESH:D010758', (75, 76))	('Wee1', 'Gene', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('Carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (72, 106))	('Wee1', 'Gene', '7465', (0, 4))	('p', 'Chemical', 'MESH:D010758', (65, 66))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (128, 162))	('cancer', 'Disease', (202, 208))	('Inhibits', 'NegReg', (35, 43))	('AZD1775', 'Chemical', 'MESH:C549567', (15, 22))	('Esophageal Squamous Cell Carcinoma', 'Disease', (72, 106))
348771	31427973	AZD1775 also diminished cell migration and invasion as well as the expression of MMP-2 and MMP-9.	('AZD1775', 'Var', (0, 7))	('diminished', 'NegReg', (13, 23))	('MMP-2', 'Gene', '4313', (81, 86))	('MMP-9', 'Gene', '4318', (91, 96))	('expression', 'MPA', (67, 77))	('MMP-9', 'Gene', (91, 96))	('MMP-2', 'Gene', (81, 86))
348772	31427973	In addition, there was a synergism between AZD1775 and 5-fluorouracil or cisplatin in inducing cell death.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('AZD1775', 'Var', (43, 50))	('cell death', 'CPA', (95, 105))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (55, 69))
348773	31427973	In summary, our data suggest that the Wee1 inhibitor AZD1775 may be a potential therapeutic agent and warrants a clinical trial for patients with ESCC, even those with metastasis.	('patient', 'Species', '9606', (132, 139))	('AZD1775', 'Var', (53, 60))	('ESCC', 'Disease', (146, 150))	('patients', 'Species', '9606', (132, 140))
348777	31427973	Importantly, high expression of Wee1 has been associated with tumor metastasis and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('high', 'Var', (13, 17))	('tumor metastasis', 'Disease', 'MESH:D009362', (62, 78))	('Wee1', 'Gene', (32, 36))	('tumor metastasis', 'Disease', (62, 78))	('associated', 'Reg', (46, 56))
348778	31427973	Indeed, overexpression of Wee1 significantly promotes the proliferation, migration, and invasion in gastric cancer cells; Vice versa, RNA interference (RNAi)-mediated knockdown of Wee1 dramatically suppresses these effects.	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('migration', 'CPA', (73, 82))	('suppresses', 'NegReg', (198, 208))	('invasion', 'CPA', (88, 96))	('proliferation', 'CPA', (58, 71))	('Wee1', 'Gene', (180, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('knockdown', 'Var', (167, 176))	('promotes', 'PosReg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('gastric cancer', 'Disease', (100, 114))	('Wee1', 'Gene', (26, 30))
348781	31427973	AZD1775 exerts antiproliferative effect and induces apoptosis in acute lymphoblastic leukemia cells, lung cancer cells, colorectal cancer cells, and laryngeal squamous cell carcinoma cells and in human xenografts in nude mice.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('AZD1775', 'Var', (0, 7))	('antiproliferative effect', 'CPA', (15, 39))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (71, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('colorectal cancer', 'Disease', (120, 137))	('apoptosis', 'CPA', (52, 61))	('laryngeal squamous cell carcinoma', 'Disease', (149, 182))	('lung cancer', 'Disease', (101, 112))	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('acute lymphoblastic leukemia', 'Disease', (65, 93))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (65, 93))	('induces', 'PosReg', (44, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (65, 93))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (149, 182))	('mice', 'Species', '10090', (221, 225))	('nude mice', 'Species', '10090', (216, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))
348782	31427973	Of note, AZD1775 has been reported to potentiate the antitumor efficacies by DNA-damaging agents including gemcitabine, carboplatin, or cisplatin at tolerated doses in nude rats.	('carboplatin', 'Chemical', 'MESH:D016190', (120, 131))	('potentiate', 'PosReg', (38, 48))	('antitumor efficacies', 'CPA', (53, 73))	('gemcitabine', 'Chemical', 'MESH:C056507', (107, 118))	('AZD1775', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('rats', 'Species', '10116', (173, 177))
348783	31427973	In addition, AZD1775 displays a synergistic antitumor activity when combined with Sirt1 inhibitor Ex527 in lung cancer xenograft model in vivo.	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('Sirt1', 'Gene', (82, 87))	('antitumor activity', 'CPA', (44, 62))	('lung cancer', 'Disease', (107, 118))	('combined', 'Interaction', (68, 76))	('Sirt1', 'Gene', '23411', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('AZD1775', 'Var', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
348784	31427973	A phase I study about Wee1 inhibitor AZD1775 alone or in combination with gemcitabine, cisplatin (CDDP), or carboplatin in patients with advanced solid tumors showed that AZD1775 was tolerable and safe as a single agent or in combination with chemotherapy at doses associated with target engagement.	('AZD1775', 'Var', (171, 178))	('solid tumors', 'Disease', 'MESH:D009369', (146, 158))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('CDDP', 'Chemical', '-', (98, 102))	('solid tumors', 'Disease', (146, 158))	('AZD1775', 'Gene', (37, 44))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
348785	31427973	Encouragingly, a phase II study also provided clinical proof that AZD1775 could enhance carboplatin efficacy in patients with TP53-mutated ovarian cancer refractory or resistant to first-line platinum-based therapy within 3 months.	('AZD1775', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('TP53', 'Gene', (126, 130))	('ovarian cancer', 'Disease', (139, 153))	('ovarian cancer', 'Phenotype', 'HP:0100615', (139, 153))	('enhance', 'PosReg', (80, 87))	('carboplatin efficacy', 'MPA', (88, 108))	('platinum', 'Chemical', 'MESH:D010984', (192, 200))	('ovarian cancer', 'Disease', 'MESH:D010051', (139, 153))	('TP53', 'Gene', '7157', (126, 130))
348804	31427973	ESCC cells were exposed to 0.5 muM AZD1775 for different durations.	('AZD1775', 'Var', (35, 42))	('muM', 'Gene', (31, 34))	('muM', 'Gene', '56925', (31, 34))
348823	31427973	Western blotting analysis also showed that AZD1775 dose-dependently promoted the expression of the phospho-Histone H3 at the S10 site (premature mitosis marker) and gammaH2A.X (DNA damage marker), without alternating the expression of Wee1, CDK1, histone H3, and H2A.X ( Figure 1D ).	('premature mitosis', 'Disease', 'MESH:C536271', (135, 152))	('promoted', 'PosReg', (68, 76))	('AZD1775', 'Var', (43, 50))	('premature mitosis', 'Disease', (135, 152))	('expression', 'MPA', (81, 91))
348826	31427973	Furthermore, upon AZD1775 treatment, the protein levels of MMP-2 and MMP-9, two critical enzymes involved in degrading the extracellular matrix, which play an important role in tumor-invasive and metastatic processes in various malignant cancers including ESCC, were greatly decreased ( Figure 4D ), Collectively, these data suggest that AZD1775 effectively inhibits the expression of MMP-2 and MMP-9 as well as the migration and invasion of ESCC cells.	('malignant cancers', 'Disease', (228, 245))	('ESCC', 'Disease', (442, 446))	('MMP-9', 'Gene', (395, 400))	('extracellular matrix', 'MPA', (123, 143))	('malignant cancers', 'Disease', 'MESH:D009369', (228, 245))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('AZD1775', 'Var', (338, 345))	('degrading', 'NegReg', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('invasion', 'CPA', (430, 438))	('ESCC', 'Disease', (256, 260))	('migration', 'CPA', (416, 425))	('expression', 'MPA', (371, 381))	('inhibits', 'NegReg', (358, 366))	('decreased', 'NegReg', (275, 284))	('MMP-2', 'Gene', (385, 390))	('AZD1775', 'Var', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('protein levels', 'MPA', (41, 55))
348827	31427973	Taken together, these data suggest that, like AZD1775, specifically silencing Wee1 diminishes the aggressiveness of ESCC cells.	('aggressiveness', 'Disease', (98, 112))	('aggressiveness', 'Phenotype', 'HP:0000718', (98, 112))	('diminishes', 'NegReg', (83, 93))	('Wee1', 'Gene', (78, 82))	('aggressiveness', 'Disease', 'MESH:D001523', (98, 112))	('silencing', 'Var', (68, 77))
348829	31427973	The results showed that AZD1775 had no significant toxicity to ESCC cells; 5-FU or CDDP alone induced minimal lethality either ( Figures 6B, D ).	('lethality', 'MPA', (110, 119))	('AZD1775', 'Var', (24, 31))	('toxicity', 'Disease', 'MESH:D064420', (51, 59))	('toxicity', 'Disease', (51, 59))
348830	31427973	Moreover, tumors in the AZD1775-treated animals showed increased expression of phospho-histone H3 (Ser 10) and gammaH2A.X compared to those from the vehicle-treated mice ( Figure 7C ).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('increased', 'PosReg', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('gammaH2A.X', 'Protein', (111, 121))	('phospho-histone', 'Protein', (79, 94))	('expression', 'MPA', (65, 75))	('Ser', 'Chemical', 'MESH:D012694', (99, 102))	('AZD1775-treated', 'Var', (24, 39))
348831	31427973	Increasing evidence showed that AZD1775 can induce significant apoptosis in various cancers including sarcomas, glioblastoma, lung cancer, and gastric cancer.	('sarcomas', 'Disease', (102, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('glioblastoma', 'Disease', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('AZD1775', 'Var', (32, 39))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('gastric cancer', 'Disease', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('apoptosis', 'CPA', (63, 72))	('sarcomas', 'Disease', 'MESH:D012509', (102, 110))	('sarcomas', 'Phenotype', 'HP:0100242', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))
348832	31427973	In agreement with these findings, in our study, we observed that AZD1775 treatment indeed led to an increase in cell apoptosis in ESCC cells, as demonstrated by a dose- and time-dependent increase in annexin-V-binding cells and upregulation of cleaved PARP and caspase-3.	('cell apoptosis', 'CPA', (112, 126))	('AZD1775', 'Var', (65, 72))	('PARP', 'Protein', (252, 256))	('upregulation', 'PosReg', (228, 240))	('increase', 'PosReg', (188, 196))	('caspase-3', 'Enzyme', (261, 270))	('cleaved', 'MPA', (244, 251))	('annexin-V', 'Gene', '308', (200, 209))	('annexin-V', 'Gene', (200, 209))
348833	31427973	recently reported that a combination of bioavailable AZD1775 and ATR inhibitor AZD6738 strongly suppressed metastasis with minimal side effects in an orthotopic breast cancer model.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('metastasis', 'CPA', (107, 117))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('AZD6738', 'Chemical', 'MESH:C000611951', (79, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('AZD6738', 'Var', (79, 86))	('breast cancer', 'Disease', (161, 174))	('suppressed', 'NegReg', (96, 106))	('AZD1775', 'Var', (53, 60))	('ATR', 'Gene', '545', (65, 68))	('ATR', 'Gene', (65, 68))
348836	31427973	Previous studies showed that the antitumor effects of AZD1775 are limited to p53-deficient cancer cells, in particular when combined with other agents.	('deficient cancer', 'Disease', 'MESH:D009369', (81, 97))	('antitumor effects', 'CPA', (33, 50))	('p53-deficient cancer', 'Disease', (77, 97))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('AZD1775', 'Var', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('p53-deficient cancer', 'Disease', 'MESH:D009369', (77, 97))
348839	31427973	In addition, AZD1775 sensitizes acute myelogenous leukemia to cytarabine, medulloblastoma cell lines to cisplatin, and high-grade glioma cell lines to irradiation, independently of p53 functionality.	('medulloblastoma', 'Phenotype', 'HP:0002885', (74, 89))	('myelogenous leukemia', 'Disease', (38, 58))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (38, 58))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (32, 58))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (38, 58))	('glioma', 'Disease', (130, 136))	('medulloblastoma', 'Disease', (74, 89))	('cytarabine', 'Chemical', 'MESH:D003561', (62, 72))	('sensitizes', 'Reg', (21, 31))	('medulloblastoma', 'Disease', 'MESH:D008527', (74, 89))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('AZD1775', 'Var', (13, 20))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
348840	31427973	reported that the p21 (a downstream target of p53)-deficient cancer cells are more sensitive to AZD1775 alone or in combination with ionizing radiation, whereas both cell lines used in this study have been demonstrated to express p21.	('AZD1775', 'Var', (96, 103))	('p21', 'Gene', (230, 233))	('p21', 'Gene', '644914', (230, 233))	('p21', 'Gene', (18, 21))	('p21', 'Gene', '644914', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('sensitive', 'MPA', (83, 92))
348848	29532228	In addition, knockout of MLL2 could inhibit EMT by up-regulation of E-Cadherin and Smad7 as well as down-regulation of Vimentin and p-Smad2/3 in ESCC cells.	('up-regulation', 'PosReg', (51, 64))	('Smad7', 'Gene', '4092', (83, 88))	('inhibit', 'NegReg', (36, 43))	('E-Cadherin', 'Gene', (68, 78))	('knockout', 'Var', (13, 21))	('EMT', 'CPA', (44, 47))	('Smad7', 'Gene', (83, 88))	('E-Cadherin', 'Gene', '999', (68, 78))	('Vimentin', 'Gene', (119, 127))	('down-regulation', 'NegReg', (100, 115))	('MLL2', 'Gene', (25, 29))	('Vimentin', 'Gene', '7431', (119, 127))
348858	29532228	As most of the mutations were inactivated and predicted to produce protein products without the key methyltransferase domain, it was considered as a tumor-suppressor (Morin et al.	('produce', 'Reg', (59, 66))	('tumor-suppressor', 'Gene', (149, 165))	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('protein products', 'MPA', (67, 83))	('tumor-suppressor', 'Gene', '7248', (149, 165))
348860	29532228	MLL2 was also found to be frequently mutated in ESCC and conjectured as a tumor suppressor due to the inactivated mutations (Gao et al.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('mutations', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('MLL2', 'Gene', (0, 4))	('ESCC', 'Disease', (48, 52))
348862	29532228	Moreover, we knocked out MLL2 in Eca109 cells by CRISPR/Cas9 gene editing system to further explore the role of MLL2 and the possible mechanism underlying its involvement in ESCC cell progression, and further confirmed the result of in vitro study by IHC in cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('ESCC', 'Disease', (174, 178))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('knocked out', 'Var', (13, 24))	('cancer', 'Disease', (258, 264))	('MLL2', 'Gene', (25, 29))
348886	29532228	The human ESCC cell line Eca109 was purchased from WuHan University (Hubei, WuHan, China) and cultured in RPMI-1640 medium plus 10% fetal bovine serum and penicillin and streptomycin in a 5% CO2 humidified incubator at 37  C. CRISPR/Cas9 genome-editing technique can induce frame shift mutations at specific sites in the genome through a synthetic sgRNA that result in a loss-of-function allele.	('human', 'Species', '9606', (4, 9))	('CO2', 'Chemical', '-', (191, 194))	('loss-of-function', 'NegReg', (371, 387))	('streptomycin', 'Chemical', 'MESH:D013307', (170, 182))	('RPMI-1640 medium', 'Chemical', '-', (106, 122))	('bovine', 'Species', '9913', (138, 144))	('penicillin', 'Chemical', 'MESH:D010406', (155, 165))	('frame shift mutations', 'Var', (274, 295))
348888	29532228	MTT assay was used to evaluate the effect of MLL2 knockout on cell proliferation of Eca109 cell line.	('knockout', 'Var', (50, 58))	('MLL2', 'Gene', (45, 49))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))
348907	29532228	The MTT assay and colony formation assay results showed that knockout of MLL2 significantly reduced the proliferation ability of Eca109 cells compared with negative control (P < 0.05, Fig.	('MLL2', 'Gene', (73, 77))	('proliferation ability', 'CPA', (104, 125))	('knockout', 'Var', (61, 69))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('reduced', 'NegReg', (92, 99))
348909	29532228	The results showed that knockout of MLL2 significantly increased the expression of E-Cadherin and decreased the expression of Vimentin (P < 0.01, Fig.	('E-Cadherin', 'Gene', '999', (83, 93))	('Vimentin', 'Gene', '7431', (126, 134))	('Vimentin', 'Gene', (126, 134))	('increased', 'PosReg', (55, 64))	('MLL2', 'Gene', (36, 40))	('expression', 'MPA', (69, 79))	('E-Cadherin', 'Gene', (83, 93))	('knockout', 'Var', (24, 32))	('decreased', 'NegReg', (98, 107))	('expression', 'MPA', (112, 122))
348912	29532228	The results showed that the expression of Smad7 and Smad2/3 was markedly increased, while p-Smad2/3 expression was decreased in MLL2 knockout group than the control group (P < 0.01, Fig.	('increased', 'PosReg', (73, 82))	('Smad7', 'Gene', '4092', (42, 47))	('expression', 'MPA', (28, 38))	('knockout', 'Var', (133, 141))	('Smad7', 'Gene', (42, 47))	('Smad2/3', 'Gene', (52, 59))	('MLL2', 'Gene', (128, 132))
348921	29532228	And the expression of Vimentin in MLL2 high expression group was significantly higher than MLL2 low expression group (Table 3).	('MLL2 high expression', 'Var', (34, 54))	('expression', 'MPA', (8, 18))	('Vimentin', 'Gene', (22, 30))	('higher', 'PosReg', (79, 85))	('Vimentin', 'Gene', '7431', (22, 30))
348925	29532228	The high expression of MLL2 was closely associated with worse clinical outcomes in ESCC patients.	('MLL2', 'Protein', (23, 27))	('patients', 'Species', '9606', (88, 96))	('high', 'Var', (4, 8))	('ESCC', 'Disease', (83, 87))	('associated', 'Reg', (40, 50))
348926	29532228	The extensive mutation of MLL2 suggests that it may be involved in the development of various cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('involved', 'Reg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('extensive mutation', 'Var', (4, 22))	('MLL2', 'Gene', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
348927	29532228	found that knockdown of MLL2 at the early stage of B cell development could lead to an increase in germinal-center (GC) B cells and enhanced B cell proliferation in mice, ultimately resulted in the occurrence of GC-derived lymphomas similar to human tumors, suggesting a tumor suppressor role for MLL2.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('mice', 'Species', '10090', (165, 169))	('increase', 'PosReg', (87, 95))	('B cell proliferation', 'CPA', (141, 161))	('tumor', 'Disease', (250, 255))	('lymphomas', 'Disease', (223, 232))	('MLL2', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('lymphoma', 'Phenotype', 'HP:0002665', (223, 231))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('knockdown', 'Var', (11, 20))	('human', 'Species', '9606', (244, 249))	('tumor', 'Disease', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('enhanced', 'PosReg', (132, 140))	('tumors', 'Disease', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('lymphomas', 'Disease', 'MESH:D008223', (223, 232))	('resulted in', 'Reg', (182, 193))	('tumors', 'Disease', 'MESH:D009369', (250, 256))
348934	29532228	In addition, PCCs with MLL2 mutations exhibited significantly larger tumor size than those with other gene mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('MLL2', 'Gene', (23, 27))	('PCC', 'Phenotype', 'HP:0002666', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('mutations', 'Var', (28, 37))	('larger', 'PosReg', (62, 68))
348935	29532228	Another study in gastrointestinal diffuse large B-cell lymphoma showed that high expression of MLL2 was associated with higher clinical stage and poor patient survival (Ye et al.).	('clinical stage', 'CPA', (127, 141))	('patient survival', 'CPA', (151, 167))	('lymphoma', 'Phenotype', 'HP:0002665', (55, 63))	('higher', 'PosReg', (120, 126))	('patient', 'Species', '9606', (151, 158))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (48, 63))	('MLL2', 'Gene', (95, 99))	('high expression', 'Var', (76, 91))	('poor', 'NegReg', (146, 150))	('gastrointestinal diffuse large B-cell lymphoma', 'Disease', (17, 63))
348936	29532228	High level of MLL2 was also associated with poor prognosis in breast cancer (Kim et al.).	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('MLL2', 'Protein', (14, 18))	('High level', 'Var', (0, 10))
348942	29532228	Patients with high MLL2 expression had significantly poorer overall survival than those with low MLL2 expression, suggesting that high MLL2 expression may serve as a predictive marker of poor prognosis and may be a potential therapeutic target in ESCC.	('expression', 'MPA', (140, 150))	('high', 'Var', (130, 134))	('ESCC', 'Disease', (247, 251))	('MLL2', 'Gene', (135, 139))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (60, 76))	('poorer', 'NegReg', (53, 59))
348945	29532228	found that knockout of MLL2 in colorectal cancer cells could lead to altered expression of a variety of genes, including the decreased expression of Vimentin and increased expression of Smad7, which is the negative regulator of TGF-beta/Smad signaling through blocking the phosphorylation of Smad2/3 (p-Smad2/3) (Luo et al.).	('Smad', 'Gene', '4092', (303, 307))	('phosphorylation', 'MPA', (273, 288))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('Smad', 'Gene', (186, 190))	('TGF-beta', 'Gene', (228, 236))	('Smad', 'Gene', (303, 307))	('increased', 'PosReg', (162, 171))	('MLL2', 'Gene', (23, 27))	('Vimentin', 'Gene', '7431', (149, 157))	('expression', 'MPA', (135, 145))	('knockout', 'Var', (11, 19))	('Smad', 'Gene', '4092', (292, 296))	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('Smad', 'Gene', '4092', (237, 241))	('Vimentin', 'Gene', (149, 157))	('decreased', 'NegReg', (125, 134))	('altered', 'Reg', (69, 76))	('Smad7', 'Gene', '4092', (186, 191))	('colorectal cancer', 'Disease', (31, 48))	('Smad7', 'Gene', (186, 191))	('expression', 'MPA', (77, 87))	('Smad', 'Gene', (237, 241))	('Smad', 'Gene', (292, 296))	('Smad', 'Gene', '4092', (186, 190))	('TGF-beta', 'Gene', '7040', (228, 236))	('expression', 'MPA', (172, 182))	('blocking', 'NegReg', (260, 268))
348947	29532228	Our data showed that the expression levels of E-Cadherin and Smad7 were increased while the expression levels of Vimentin and p-Smad2/3 were decreased in MLL2 knockout group than the control group, which illustrated that knockout of MLL2 attenuated the EMT process and inhibited the TGF-beta/Smad signaling.	('Smad', 'Gene', '4092', (128, 132))	('EMT process', 'CPA', (253, 264))	('expression levels', 'MPA', (25, 42))	('TGF-beta', 'Gene', (283, 291))	('Smad', 'Gene', (128, 132))	('E-Cadherin', 'Gene', '999', (46, 56))	('Smad7', 'Gene', '4092', (61, 66))	('attenuated', 'NegReg', (238, 248))	('expression levels', 'MPA', (92, 109))	('Smad', 'Gene', '4092', (292, 296))	('Smad7', 'Gene', (61, 66))	('decreased', 'NegReg', (141, 150))	('Smad', 'Gene', '4092', (61, 65))	('Vimentin', 'Gene', '7431', (113, 121))	('E-Cadherin', 'Gene', (46, 56))	('increased', 'PosReg', (72, 81))	('knockout', 'Var', (221, 229))	('Smad', 'Gene', (292, 296))	('TGF-beta', 'Gene', '7040', (283, 291))	('Vimentin', 'Gene', (113, 121))	('Smad', 'Gene', (61, 65))	('inhibited', 'NegReg', (269, 278))	('MLL2', 'Gene', (233, 237))
348984	28810541	Accumulating evidence has indicated that deregulation of miRs is associated with human malignancies, and suggested that miRs may have a causal role in tumor initiation and progression, since they can function as oncogenes or tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('deregulation', 'Var', (41, 53))	('miR', 'Gene', '220972', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('miR', 'Gene', (57, 60))	('tumor initiation', 'Disease', (151, 167))	('miR', 'Gene', '220972', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('miR', 'Gene', (120, 123))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (225, 230))	('associated', 'Reg', (65, 75))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('human', 'Species', '9606', (81, 86))	('tumor initiation', 'Disease', 'MESH:D009369', (151, 167))	('malignancies', 'Disease', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
349056	28810541	A subgroup of genes in the myotubularin family encodes proteins that contain substitutions of residues within the C(X)5R active site motif and are catalytically inactive.	('myotubularin', 'Gene', '4534', (27, 39))	('myotubularin', 'Gene', (27, 39))	('substitutions', 'Var', (77, 90))
349073	28108736	Decreasing HOTAIR expression has been shown to inhibit the growth of human CRC stem cells.	('HOTAIR', 'Gene', '100124700', (11, 17))	('growth of human CRC stem cells', 'CPA', (59, 89))	('Decreasing', 'Var', (0, 10))	('human', 'Species', '9606', (69, 74))	('inhibit', 'NegReg', (47, 54))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('HOTAIR', 'Gene', (11, 17))
349089	28108736	High expression of MALAT-1 has been identified as a biomarker for poor prognosis in CRC.	('High', 'Var', (0, 4))	('MALAT-1', 'Gene', '378938', (19, 26))	('CRC', 'Disease', (84, 87))	('MALAT-1', 'Gene', (19, 26))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))
349096	28108736	Moreover, high expression of H19 is associated with tumor differentiation and tumor node metastasis (TNM) staging.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor node metastasis', 'Disease', (78, 99))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('H19', 'Gene', '283120', (29, 32))	('high', 'Var', (10, 14))	('tumor node metastasis', 'Disease', 'MESH:D009362', (78, 99))	('H19', 'Gene', (29, 32))	('associated', 'Reg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
349098	28108736	Gene mutations such as rs2839698 in H19 have been linked with susceptibility to CRC and may function as a potential prognostic factor.	('rs2839698', 'Var', (23, 32))	('CRC', 'Disease', (80, 83))	('rs2839698', 'Mutation', 'rs2839698', (23, 32))	('H19', 'Gene', '283120', (36, 39))	('linked', 'Reg', (50, 56))	('H19', 'Gene', (36, 39))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))
349108	28108736	The latest literature shows that GAS5 rs145204276 mutation is significantly associated with the susceptibility and progression in CRC, which implies that it contributes to lymphatic metastasis.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('GAS5', 'Gene', (33, 37))	('lymphatic metastasis', 'CPA', (172, 192))	('contributes', 'Reg', (157, 168))	('rs145204276', 'Var', (38, 49))	('associated', 'Reg', (76, 86))	('GAS5', 'Gene', '60674', (33, 37))	('rs145204276', 'Mutation', 'rs145204276', (38, 49))	('CRC', 'Disease', (130, 133))
349111	28108736	Antisense non-coding RNA in the INK4 locus (ANRIL) is a natural antisense noncoding RNA and it transcribed from the antisense cluster of the INK4b-ARF-INK4a gene.	('ANRIL', 'Gene', '100048912', (44, 49))	('INK4', 'Gene', '1029', (151, 155))	('INK4', 'Gene', (151, 155))	('INK4b', 'Gene', (141, 146))	('INK4', 'Gene', (141, 145))	('Antisense non-coding', 'Var', (0, 20))	('INK4b', 'Gene', '1030', (141, 146))	('ANRIL', 'Gene', (44, 49))	('INK4', 'Gene', (32, 36))	('INK4', 'Gene', '1029', (141, 145))	('INK4', 'Gene', '1029', (32, 36))
349128	28108736	Inhibition of TUG1 expression blocked the cell migration ability of colon cancer cells.	('TUG1', 'Gene', (14, 18))	('blocked', 'NegReg', (30, 37))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Inhibition', 'Var', (0, 10))	('colon cancer', 'Disease', (68, 80))	('TUG1', 'Gene', '55000', (14, 18))
349138	28108736	BRAF-activated lncRNA (BANCR) was originally identified in melanoma cells with 693 bp in length, is located before the repeating cycle of chromosome 9, is crucial for melanoma cell migration and is closely related to the BRAF gene V600E mutation.	('BRAF', 'Gene', (221, 225))	('BRAF-activated lncRNA', 'Gene', '100885775', (0, 21))	('melanoma cell migration', 'Disease', 'MESH:D008545', (167, 190))	('BANCR', 'Gene', '100885775', (23, 28))	('melanoma cell migration', 'Disease', (167, 190))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('V600E', 'Var', (231, 236))	('melanoma', 'Disease', (167, 175))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('BRAF-activated lncRNA', 'Gene', (0, 21))	('BRAF', 'Gene', '673', (221, 225))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('BANCR', 'Gene', (23, 28))	('V600E', 'Mutation', 'rs113488022', (231, 236))
349158	28108736	Moreover, the MEG3 rs7158663 AA genotype, not the GA genotype, significantly increases the risk of CRC.	('MEG3', 'Gene', '55384', (14, 18))	('rs7158663', 'Mutation', 'rs7158663', (19, 28))	('CRC', 'Disease', (99, 102))	('increases', 'PosReg', (77, 86))	('rs7158663 AA', 'Var', (19, 31))	('CRC', 'Phenotype', 'HP:0003003', (99, 102))	('MEG3', 'Gene', (14, 18))
349160	28108736	Methylation of ZNF582-AS1 is associated with poor survival of CRC patients.	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('Methylation', 'Var', (0, 11))	('ZNF582-AS1', 'Gene', '386758', (15, 25))	('CRC', 'Disease', (62, 65))	('poor', 'NegReg', (45, 49))	('associated', 'Reg', (29, 39))	('ZNF582-AS1', 'Gene', (15, 25))	('patients', 'Species', '9606', (66, 74))
349162	28108736	Higher levels of lncRNA-uc002kmd.1 result in the regulation of CD44 as a molecular decoy for miR211-3p to enhance cell proliferation in CRC.	('miR211', 'Gene', (93, 99))	('enhance', 'PosReg', (106, 113))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('lncRNA-uc002kmd.1', 'Var', (17, 34))	('CD44', 'Gene', '960', (63, 67))	('CD44', 'Gene', (63, 67))	('CRC', 'Disease', (136, 139))	('cell proliferation in', 'CPA', (114, 135))	('miR211', 'Gene', '406993', (93, 99))	('regulation', 'MPA', (49, 59))
349163	28108736	C-Myc represses the expression of tissue differentiation-inducing non-protein coding RNA (TINCR) through repressing sp1 transcriptive activity and loss of TINCR expression promotes proliferation and metastasis in CRC.	('proliferation', 'CPA', (181, 194))	('TINCR', 'Gene', (155, 160))	('C-Myc', 'Gene', (0, 5))	('CRC', 'Phenotype', 'HP:0003003', (213, 216))	('expression', 'MPA', (20, 30))	('TINCR', 'Gene', (90, 95))	('repressing', 'PosReg', (105, 115))	('promotes', 'PosReg', (172, 180))	('CRC', 'Disease', (213, 216))	('metastasis', 'CPA', (199, 209))	('TINCR', 'Gene', '257000', (90, 95))	('TINCR', 'Gene', '257000', (155, 160))	('loss', 'Var', (147, 151))	('sp1 transcriptive activity', 'MPA', (116, 142))	('C-Myc', 'Gene', '4609', (0, 5))
349167	28108736	PVT-1 or LOC285194 expression levels are an independent risk factor for overall survival in CRC.	('LOC285194', 'Var', (9, 18))	('overall', 'MPA', (72, 79))	('PVT-1', 'Gene', '5820', (0, 5))	('CRC', 'Disease', (92, 95))	('PVT-1', 'Gene', (0, 5))	('CRC', 'Phenotype', 'HP:0003003', (92, 95))
349169	28108736	Loc554202, LOC100287225 were identified to be tumorigenic in CRC.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('LOC100287225', 'Var', (11, 23))	('tumor', 'Disease', (46, 51))	('CRC', 'Disease', (61, 64))	('Loc554202', 'Var', (0, 9))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
349170	28108736	Lnc34a is upregulated in CRC, contributing to epigenetic miR-34a silencing and CRC proliferation.	('CRC', 'Phenotype', 'HP:0003003', (25, 28))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('epigenetic', 'Var', (46, 56))	('CRC proliferation', 'CPA', (79, 96))	('Lnc34a', 'Gene', (0, 6))	('miR-34a', 'Gene', '407040', (57, 64))	('silencing', 'NegReg', (65, 74))	('miR-34a', 'Gene', (57, 64))
349187	28108736	Moreover, CCAT2, H19, CASC11, TINCR, CCAL, cir-ITCH, and CTD903 are involved in the WNT pathway, which also regulates gene expression changes during EMT.	('CTD903', 'Var', (57, 63))	('H19', 'Gene', (17, 20))	('involved', 'Reg', (68, 76))	('CASC11', 'Gene', '100270680', (22, 28))	('ITCH', 'Gene', (47, 51))	('TINCR', 'Gene', '257000', (30, 35))	('CCAT2', 'Gene', (10, 15))	('cir', 'Gene', (43, 46))	('-ITCH', 'Phenotype', 'HP:0000989', (46, 51))	('cir', 'Gene', '9541', (43, 46))	('TINCR', 'Gene', (30, 35))	('ITCH', 'Gene', '83737', (47, 51))	('WNT pathway', 'Pathway', (84, 95))	('CASC11', 'Gene', (22, 28))	('H19', 'Gene', '283120', (17, 20))	('CCAT2', 'Gene', '101805488', (10, 15))
349214	28293080	Primary bile acids (cholic acid, taurocholic acid and glycocholic acid) and secondary bile acids (deoxycholic acid, taurodeoxycholic acid, glycodeoxycholic acid and taurolithocholic acid) have been shown to bind to TGR5 receptors.	('cholic acid', 'Chemical', 'MESH:D019826', (149, 160))	('glycocholic acid', 'Chemical', 'MESH:D006000', (54, 70))	('cholic acid', 'Chemical', 'MESH:D019826', (103, 114))	('TGR5 receptors', 'Protein', (215, 229))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (144, 160))	('cholic acid', 'Chemical', 'MESH:D019826', (126, 137))	('bind', 'Interaction', (207, 211))	('bile acids', 'Chemical', 'MESH:D001647', (8, 18))	('taurocholic acid', 'Chemical', 'MESH:D013656', (33, 49))	('cholic acid', 'Chemical', 'MESH:D019826', (20, 31))	('cholic acid', 'Chemical', 'MESH:D019826', (59, 70))	('deoxycholic', 'Var', (98, 109))	('taurolithocholic acid', 'Chemical', 'MESH:D013658', (165, 186))	('bile acids', 'Chemical', 'MESH:D001647', (86, 96))	('taurodeoxycholic acid', 'Chemical', 'MESH:D013657', (116, 137))	('glycodeoxycholic acid', 'Chemical', 'MESH:D006002', (139, 160))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (98, 114))	('cholic acid', 'Chemical', 'MESH:D019826', (38, 49))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (121, 137))	('cholic acid', 'Chemical', 'MESH:D019826', (175, 186))
349237	28293080	In addition, TGR5 mRNA was significantly higher in SK-GT-4 cells than in CP-D cells (Figure 1B).	('SK-GT-4', 'Var', (51, 58))	('SK-GT-4', 'CellLine', 'CVCL:2195', (51, 58))	('TGR5', 'Gene', (13, 17))	('higher', 'PosReg', (41, 47))	('mRNA', 'MPA', (18, 22))
349248	28293080	We have also reported that moderate to strong TGR5 staining is associated with decreased patient survival in all gastric adenocarcinomas, suggesting that TGR5 may be a negative prognostic marker in gastric cancer.	('staining', 'Var', (51, 59))	('patient survival', 'CPA', (89, 105))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (113, 136))	('gastric cancer', 'Disease', (198, 212))	('patient', 'Species', '9606', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('decreased', 'NegReg', (79, 88))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('gastric adenocarcinomas', 'Disease', (113, 136))	('TGR5', 'Gene', (46, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('moderate', 'Var', (27, 35))
349250	28293080	Moreover, Barrett's dysplastic cells CP-D had significantly higher levels of TGR5 mRNA than CP-A cells.	('CP-A', 'Gene', '1357', (92, 96))	('higher', 'PosReg', (60, 66))	('TGR5', 'Protein', (77, 81))	('levels', 'MPA', (67, 73))	("Barrett's dysplastic", 'Disease', (10, 30))	("Barrett's dysplastic", 'Disease', 'MESH:D001471', (10, 30))	('CP-D', 'Var', (37, 41))	('CP-A', 'Gene', (92, 96))
349251	28293080	EA cells SK-GT-4 had much higher levels of TGR5 mRNA than CP-A or CP-D.	('EA', 'Phenotype', 'HP:0011459', (0, 2))	('higher', 'PosReg', (26, 32))	('SK-GT-4', 'Var', (9, 16))	('levels', 'MPA', (33, 39))	('CP-A', 'Gene', '1357', (58, 62))	('CP-A', 'Gene', (58, 62))	('SK-GT-4', 'CellLine', 'CVCL:2195', (9, 16))	('TGR5', 'Protein', (43, 47))
349289	27771733	Imbalanced CTGF expression may trigger several pathological states, such as arthritis, fibrosis, and cancers.	('arthritis', 'Disease', (76, 85))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('Imbalanced', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('CTGF', 'Gene', '1490', (11, 15))	('cancers', 'Disease', (101, 108))	('CTGF', 'Gene', (11, 15))	('arthritis', 'Phenotype', 'HP:0001369', (76, 85))	('arthritis', 'Disease', 'MESH:D001168', (76, 85))	('fibrosis', 'Disease', 'MESH:D005355', (87, 95))	('fibrosis', 'Disease', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('trigger', 'Reg', (31, 38))
349306	27771733	All human ESCC cell lines used in this study, including EC1, Eca109, KYSE150, and KYSE180, were acquired from the Cell Center of the Shanghai Institute of Life Science (Chinese Academy of Science, Shanghai, China) and were cultured in RPMI1640 medium (Gibco, USA) containing 10% fetal bovine serum (FBS; Gibco), streptomycin (100 mg/ml; Gibco), and penicillin (100 units/ml; Gibco) at 37 C in an incubator with 5% CO2.	('human', 'Species', '9606', (4, 9))	('CO2', 'Chemical', '-', (414, 417))	('FBS', 'Disease', (299, 302))	('EC1', 'Gene', (56, 59))	('FBS', 'Disease', 'MESH:D005198', (299, 302))	('bovine', 'Species', '9913', (285, 291))	('EC1', 'Gene', '4819', (56, 59))	('KYSE180', 'Var', (82, 89))
349322	27771733	We constructed luciferase reporter vectors for the wild-type and mutant-type of CTGF 3' untranslated regions (UTR).	('CTGF', 'Gene', '1490', (80, 84))	('mutant-type', 'Var', (65, 76))	('CTGF', 'Gene', (80, 84))
349323	27771733	Either miR-145 mimics or control were co-transfected with the constructed wild-type or mutant-type luciferase reporter vector into Eca109 cells using Lipofectamine 2000 (Invitrogen).	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (150, 168))	('miR-145', 'Gene', (7, 14))	('mutant-type', 'Var', (87, 98))	('miR-145', 'Gene', '406937', (7, 14))
349348	27771733	However, miR-145 did not significantly affect the luciferase activity of CTGF with mutant-type 3'UTR (Figure 3B).	('mutant-type', 'Var', (83, 94))	('CTGF', 'Gene', '1490', (73, 77))	('CTGF', 'Gene', (73, 77))	('miR-145', 'Gene', (9, 16))	('miR-145', 'Gene', '406937', (9, 16))	('luciferase', 'Enzyme', (50, 60))	('activity', 'MPA', (61, 69))
349356	27771733	Invaded Eca109 cells transfected with miR-145 mimics (42.8+-5.5) and CTGF siRNA (45.2+-4.2) were notable fewer than those in the blank and scramble group (all P<0.05), while the difference between the miR-145 mimics and CTGF siRNA groups was insignificant (P>0.05).	('CTGF', 'Gene', (220, 224))	('miR-145', 'Gene', (201, 208))	('miR-145', 'Gene', '406937', (201, 208))	('CTGF', 'Gene', (69, 73))	('fewer', 'NegReg', (105, 110))	('CTGF', 'Gene', '1490', (69, 73))	('CTGF', 'Gene', '1490', (220, 224))	('miR-145', 'Gene', (38, 45))	('miR-145', 'Gene', '406937', (38, 45))	('mimics', 'Var', (46, 52))
349371	27771733	Moreover, our study demonstrated that miR-145 mimics inhibited the mRNA and protein expression level of CTGF in Eca109 cells, and miR-145 inhibitors can significantly elevate CTGF expression in Eca109 cells.	('elevate', 'PosReg', (167, 174))	('CTGF', 'Gene', '1490', (104, 108))	('inhibited', 'NegReg', (53, 62))	('CTGF', 'Gene', (104, 108))	('miR-145', 'Gene', (130, 137))	('expression', 'MPA', (180, 190))	('miR-145', 'Gene', '406937', (130, 137))	('CTGF', 'Gene', '1490', (175, 179))	('miR-145', 'Gene', (38, 45))	('CTGF', 'Gene', (175, 179))	('inhibitors', 'Var', (138, 148))	('miR-145', 'Gene', '406937', (38, 45))
349377	27771733	In addition, we discovered that the proliferation, migration, and invasion of Eca-109 cells were restricted by the knockdown of CTCF.	('migration', 'CPA', (51, 60))	('restricted', 'NegReg', (97, 107))	('CTCF', 'Gene', (128, 132))	('CTCF', 'Gene', '10664', (128, 132))	('invasion', 'CPA', (66, 74))	('knockdown', 'Var', (115, 124))
349378	27771733	reported that knockdown of CTGF in ESCC cells significantly inhibit cell growth, colony formation, and tumorigenicity in vivo.	('CTGF', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inhibit', 'NegReg', (60, 67))	('tumor', 'Disease', (103, 108))	('cell growth', 'CPA', (68, 79))	('colony formation', 'CPA', (81, 97))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('CTGF', 'Gene', '1490', (27, 31))
349383	27771733	Our experiments indicated that miR-145 mimics inhibit the expression of several mesenchymal markers, including N-cadherin, fibronectin, and vimentin, and stimulate the expression of E-cadherin, which is a typical epithelial cell maker.	('E-cadherin', 'Gene', '999', (182, 192))	('expression', 'MPA', (168, 178))	('inhibit', 'NegReg', (46, 53))	('N-cadherin', 'Gene', '1000', (111, 121))	('expression', 'MPA', (58, 68))	('fibronectin', 'Gene', '2335', (123, 134))	('stimulate', 'PosReg', (154, 163))	('E-cadherin', 'Gene', (182, 192))	('N-cadherin', 'Gene', (111, 121))	('miR-145', 'Gene', '406937', (31, 38))	('vimentin', 'Gene', '7431', (140, 148))	('miR-145', 'Gene', (31, 38))	('fibronectin', 'Gene', (123, 134))	('vimentin', 'Gene', (140, 148))	('mimics', 'Var', (39, 45))	('mesenchymal', 'CPA', (80, 91))
349384	27771733	Additionally, siRNA-mediated knockdown of CTGF specifically suppressed N-cadherin, fibronectin, and vimentin expression, and this is associated with increased E-cadherin expression.	('CTGF', 'Gene', '1490', (42, 46))	('E-cadherin', 'Gene', '999', (159, 169))	('CTGF', 'Gene', (42, 46))	('expression', 'MPA', (109, 119))	('knockdown', 'Var', (29, 38))	('fibronectin', 'Gene', (83, 94))	('suppressed', 'NegReg', (60, 70))	('increased', 'PosReg', (149, 158))	('N-cadherin', 'Gene', '1000', (71, 81))	('expression', 'MPA', (170, 180))	('fibronectin', 'Gene', '2335', (83, 94))	('vimentin', 'Gene', '7431', (100, 108))	('E-cadherin', 'Gene', (159, 169))	('N-cadherin', 'Gene', (71, 81))	('vimentin', 'Gene', (100, 108))
349390	27771733	Our experiments further demonstrated that both over-expression of miR-145 and knockdown of CTGF inhibited the proliferation, migration, and invasion of ESCC cells through their influence on EMT.	('over-expression', 'PosReg', (47, 62))	('migration', 'CPA', (125, 134))	('influence', 'Reg', (177, 186))	('knockdown', 'Var', (78, 87))	('EMT', 'CPA', (190, 193))	('proliferation', 'CPA', (110, 123))	('invasion', 'CPA', (140, 148))	('inhibited', 'NegReg', (96, 105))	('miR-145', 'Gene', (66, 73))	('CTGF', 'Gene', '1490', (91, 95))	('CTGF', 'Gene', (91, 95))	('miR-145', 'Gene', '406937', (66, 73))
349405	27112333	Because intestinal epithelia are regenerated by local intestinal stem cell (ISC) populations, which have been characterized in the GI tract of flies and mice in the past decade, deregulation of these stem cell functions, including proliferation and differentiation, has been associated with metaplastic and dysplastic lesions.	('dysplastic lesions', 'Disease', (307, 325))	('associated', 'Reg', (275, 285))	('proliferation', 'CPA', (231, 244))	('mice', 'Species', '10090', (153, 157))	('differentiation', 'CPA', (249, 264))	('dysplastic lesions', 'Disease', 'MESH:D021782', (307, 325))	('deregulation', 'Var', (178, 190))
349430	27112333	Another study has further analyzed EE cell diversity and found that Su(H)GBE+ (Notch active) enteroblasts can give rise to class II EE cells, in addition to ECs.	('give rise', 'Reg', (110, 119))	('Su(H)GBE+', 'Var', (68, 77))	('Notch', 'Gene', (79, 84))	('Notch', 'Gene', '31293', (79, 84))	('class II EE cells', 'CPA', (123, 140))
349466	27112333	For example, lineage tracing has shown that the loss of Dpp signaling pathway components causes differentiation defects in GSSCs, but not in PM-ISCs.	('loss', 'Var', (48, 52))	('GSSCs', 'Disease', (123, 128))	('Dpp', 'Gene', (56, 59))	('Dpp', 'Chemical', 'MESH:C038694', (56, 59))	('differentiation defects', 'CPA', (96, 119))
349467	27112333	Sustained Dpp expression along the GI tract is sufficient to induce ectopic copper cell formation in the AM, but not in the PM, indicating that additional regional determinants influence stem cell responses to Dpp signaling.	('expression', 'Var', (14, 24))	('ectopic', 'MPA', (68, 75))	('induce', 'PosReg', (61, 67))	('Dpp', 'Chemical', 'MESH:C038694', (10, 13))	('copper', 'Chemical', 'MESH:D003300', (76, 82))	('influence', 'Reg', (177, 186))	('Dpp', 'Chemical', 'MESH:C038694', (210, 213))	('Dpp', 'Gene', (10, 13))
349473	27112333	Wnt signaling is critically important for adult ISC proliferation, and loss of Wnt signaling in adult mice, via the genetic deletion of beta-catenin, the overexpression of the Wnt antagonist Dkk1 or by the deletion of the Wnt/TCF4 target gene Myc, leads to complete ablation of intestinal crypts.	('mice', 'Species', '10090', (102, 106))	('Wnt', 'Gene', '35975', (222, 225))	('Wnt', 'Gene', (222, 225))	('beta-catenin', 'Gene', '12387', (136, 148))	('deletion', 'Var', (206, 214))	('beta-catenin', 'Gene', (136, 148))	('TCF4', 'Gene', '21413', (226, 230))	('overexpression', 'PosReg', (154, 168))	('deletion', 'Var', (124, 132))	('Myc', 'Gene', (243, 246))	('ablation', 'NegReg', (266, 274))	('Wnt', 'Gene', '35975', (176, 179))	('Dkk1', 'Gene', (191, 195))	('Dkk1', 'Gene', '13380', (191, 195))	('Wnt', 'Gene', (176, 179))	('TCF4', 'Gene', (226, 230))	('Myc', 'Gene', '17869', (243, 246))	('Wnt', 'Gene', '35975', (0, 3))	('Wnt', 'Gene', '35975', (79, 82))	('Wnt', 'Gene', (0, 3))	('Wnt', 'Gene', (79, 82))	('loss', 'NegReg', (71, 75))
349477	27112333	Deletion of BMP receptor 1a leads to the expansion of proliferative stem cells and progenitor cells, and inhibition of BMP signaling results in the formation of ectopic crypts, indicating that BMP signaling negatively regulates ISC proliferation and self-renewal, potentially by inhibiting Wnt signaling.	('self-renewal', 'CPA', (250, 262))	('ISC proliferation', 'CPA', (228, 245))	('regulates', 'Reg', (218, 227))	('Wnt', 'Gene', '35975', (290, 293))	('inhibition', 'Var', (105, 115))	('Wnt', 'Gene', (290, 293))	('BMP', 'Gene', '33432', (12, 15))	('BMP', 'Gene', '33432', (193, 196))	('BMP', 'Gene', (12, 15))	('BMP', 'Gene', (193, 196))	('inhibiting', 'NegReg', (279, 289))	('negatively', 'NegReg', (207, 217))	('BMP', 'Gene', '33432', (119, 122))	('BMP', 'Gene', (119, 122))	('expansion', 'PosReg', (41, 50))	('Deletion', 'Var', (0, 8))
349478	27112333	These two pathways might also be influenced by Hh signaling, because constitutive activation of Hh signaling by inactivating the receptor patched1 (Ptch1) increases BMP signaling and reduces Wnt signaling activity in the adult mouse intestine, resulting in reduced epithelial precursor cells and in the premature differentiation of ECs.	('Wnt', 'Gene', (191, 194))	('BMP', 'Gene', '33432', (165, 168))	('BMP', 'Gene', (165, 168))	('reduced', 'NegReg', (257, 264))	('premature differentiation', 'CPA', (303, 328))	('increases', 'PosReg', (155, 164))	('mouse', 'Species', '10090', (227, 232))	('patched1', 'Gene', '19206', (138, 146))	('ECs', 'CPA', (332, 335))	('reduces', 'NegReg', (183, 190))	('inactivating', 'Var', (112, 124))	('Wnt', 'Gene', '35975', (191, 194))	('epithelial precursor cells', 'CPA', (265, 291))	('patched1', 'Gene', (138, 146))	('Ptch1', 'Gene', '19206', (148, 153))	('Ptch1', 'Gene', (148, 153))
349484	27112333	This perturbation is mediated by de-repression of the Wnt signaling pathway, demonstrated by the findings that Notch inhibition leads to activation of Wnt signaling and attenuation of the Wnt pathway rescues phenotypes induced by inhibitory antibodies against Notch.	('Notch', 'Gene', (260, 265))	('attenuation', 'Var', (169, 180))	('Wnt', 'Gene', '35975', (188, 191))	('Wnt', 'Gene', '35975', (54, 57))	('Wnt', 'Gene', (54, 57))	('Wnt', 'Gene', '35975', (151, 154))	('Notch', 'Gene', '31293', (260, 265))	('Wnt', 'Gene', (188, 191))	('Notch', 'Gene', (111, 116))	('Wnt', 'Gene', (151, 154))	('inhibitory antibodies', 'Var', (230, 251))	('activation', 'PosReg', (137, 147))	('inhibition', 'NegReg', (117, 127))	('Notch', 'Gene', '31293', (111, 116))	('de-repression', 'NegReg', (33, 46))
349503	27112333	These changes often predispose individuals to the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('changes', 'Var', (6, 13))	('predispose', 'Reg', (20, 30))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
349515	27112333	Epidemiological studies have reported the beneficial effects of eradicating H. pylori for the prevention of gastric cancer development.	('gastric cancer', 'Phenotype', 'HP:0012126', (108, 122))	('H. pylori', 'Gene', (76, 85))	('H. pylori', 'Species', '210', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('eradicating', 'Var', (64, 75))	('gastric cancer', 'Disease', (108, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (108, 122))
349527	27112333	A series of molecular alterations in epithelial cells, including mutations of the Wnt signaling suppressor adenomatosis polyposis coli (APC), the tumor suppressor gene p53, and the k-ras oncogene, drive the development of dysplasia or colorectal cancer from colitis in individuals with IBD.	('colitis', 'Disease', 'MESH:D003092', (258, 265))	('APC', 'Phenotype', 'HP:0005227', (136, 139))	('p53', 'Gene', '2768677', (168, 171))	('tumor', 'Disease', (146, 151))	('adenomatosis polyposis coli', 'Gene', (107, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (235, 252))	('p53', 'Gene', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('APC', 'Gene', (136, 139))	('colitis', 'Phenotype', 'HP:0002583', (258, 265))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('Wnt', 'Gene', '35975', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (235, 252))	('adenomatosis polyposis coli', 'Gene', '44642', (107, 134))	('Wnt', 'Gene', (82, 85))	('dysplasia', 'Disease', (222, 231))	('adenomatosis polyposis coli', 'Phenotype', 'HP:0005227', (107, 134))	('dysplasia', 'Disease', 'MESH:D004476', (222, 231))	('drive', 'Reg', (197, 202))	('colorectal cancer', 'Disease', (235, 252))	('IBD', 'Phenotype', 'HP:0002037', (286, 289))	('colitis', 'Disease', (258, 265))	('APC', 'Gene', '44642', (136, 139))	('mutations', 'Var', (65, 74))
349534	27112333	In the mouse intestine, loss of Cdx2 leads to the formation of a squamous epithelium that resembles the esophagus, whereas, in Barrett's esophagus, Cdx2 is ectopically expressed in metaplastic cells.	('loss', 'Var', (24, 28))	('Cdx2', 'Gene', (32, 36))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (127, 146))	('mouse', 'Species', '10090', (7, 12))
349536	27112333	These studies suggest that deregulation of crucial transcription factors or growth factor pathways triggers a cascade of events that eventually lead to metaplasia and dysplasia.	('triggers', 'Reg', (99, 107))	('deregulation', 'Var', (27, 39))	('lead to', 'Reg', (144, 151))	('metaplasia and dysplasia', 'Disease', 'MESH:D008679', (152, 176))
349539	27112333	The adult Drosophila GI tract is emerging as a powerful model in which to explore in mechanistic detail the origin and progression of metaplasias and dysplasias as a consequence of dysfunctions in ISC biology, microbe-host interactions and epithelial deregulation.	('dysfunctions', 'Var', (181, 193))	('metaplasias and dysplasias', 'Disease', 'MESH:D008679', (134, 160))	('Drosophila GI tract', 'Disease', 'MESH:D004067', (10, 29))	('Drosophila GI tract', 'Disease', (10, 29))
349551	27112333	In addition, a recent study shows that dysregulation of ISC niche signals, including EGFR ligands and cytokines that activate JAK/Stat signaling, contribute to the development of dysplasia and tumorigenesis from Notch-defective ISCs.	('dysregulation', 'Var', (39, 52))	('EGFR', 'Gene', (85, 89))	('contribute to', 'Reg', (146, 159))	('dysplasia', 'Disease', (179, 188))	('Notch', 'Gene', (212, 217))	('JAK', 'Gene', '32080', (126, 129))	('Stat', 'Gene', '42428', (130, 134))	('Stat', 'Gene', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Notch', 'Gene', '31293', (212, 217))	('JAK', 'Gene', (126, 129))	('tumor', 'Disease', (193, 198))	('EGFR', 'Gene', '37455', (85, 89))	('dysplasia', 'Disease', 'MESH:D004476', (179, 188))
349552	27112333	Furthermore, defects in endocytic degradation can cause intestinal dysplasia.	('cause', 'Reg', (50, 55))	('endocytic degradation', 'MPA', (24, 45))	('intestinal dysplasia', 'Disease', (56, 76))	('intestinal dysplasia', 'Disease', 'MESH:D007410', (56, 76))	('defects', 'Var', (13, 20))
349569	26486568	Cancer develops through a sequence of genetic and epigenetic changes that lead to activation of oncogenes and silencing of tumor suppressor genes, with progression from metaplasia through dysplasia to adenocarcinoma.	('tumor', 'Disease', (123, 128))	('silencing', 'NegReg', (110, 119))	('metaplasia', 'Disease', (169, 179))	('dysplasia to adenocarcinoma', 'Disease', (188, 215))	('dysplasia to adenocarcinoma', 'Disease', 'MESH:D000230', (188, 215))	('changes', 'Var', (61, 68))	('activation', 'PosReg', (82, 92))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('oncogenes', 'Gene', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('metaplasia', 'Disease', 'MESH:D008679', (169, 179))
349625	26486568	Acetic acid has been used for a long time to detect cervical intra-epithelial neoplasia during colposcopy; after its application, acetic acid initially causes an acetowhitening effect, which masks the submucosal capillaries and makes the mucosal surface prominent by rendering it more opaque, thus enhancing the surface pit-pattern and allowing for detailed examination of the mucosa.	('acetic acid', 'Chemical', 'MESH:D019342', (130, 141))	('acetowhitening', 'MPA', (162, 176))	('enhancing', 'PosReg', (298, 307))	('intra-epithelial neoplasia', 'Disease', 'MESH:D009369', (61, 87))	('Acetic acid', 'Chemical', 'MESH:D019342', (0, 11))	('intra-epithelial neoplasia', 'Disease', (61, 87))	('epithelial neoplasia', 'Phenotype', 'HP:0031492', (67, 87))	('neoplasia', 'Phenotype', 'HP:0002664', (78, 87))	('surface pit-pattern', 'MPA', (312, 331))	('opaque', 'MPA', (285, 291))	('acetic acid', 'Var', (130, 141))
349635	26486568	They showed that overall neoplasia detection rates were significantly higher in the acetic acid group than in the WLE group (12.5% vs. 2%; P = 0.001).	('acetic acid', 'Var', (84, 95))	('acetic acid', 'Chemical', 'MESH:D019342', (84, 95))	('neoplasia', 'Phenotype', 'HP:0002664', (25, 34))	('neoplasia', 'Disease', 'MESH:D009369', (25, 34))	('higher', 'PosReg', (70, 76))	('neoplasia', 'Disease', (25, 34))
349681	26486568	In their initial study, the researchers randomized 127 patients with dysplastic BE in a 2:1 ratio to either RFA ablation or a sham procedure and showed that, at 12-months follow-up, complete eradication of dysplasia was achieved in 81% of patients with RFA, compared with only 19% patients in the sham group (P < 0.001).	('BE', 'Phenotype', 'HP:0100580', (80, 82))	('eradication of dysplasia', 'Disease', (191, 215))	('patients', 'Species', '9606', (239, 247))	('patients', 'Species', '9606', (281, 289))	('RFA', 'Var', (253, 256))	('patients', 'Species', '9606', (55, 63))	('eradication of dysplasia', 'Disease', 'MESH:D004476', (191, 215))
349736	26586943	Non-operated and operated rats in which gastroesophageal reflux was surgically induced received both types of NPs (NP-DCM and NP-DCM-ASYNYDA) by intravenous route.	('NP-DCM', 'Chemical', '-', (115, 121))	('rats', 'Species', '10116', (26, 30))	('rat', 'Species', '10116', (26, 29))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (40, 63))	('NP-DCM-ASYNYDA', 'Var', (126, 140))	('NP-DCM', 'Chemical', '-', (126, 132))	('rat', 'Species', '10116', (7, 10))	('gastroesophageal reflux', 'Disease', (40, 63))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (40, 63))	('rat', 'Species', '10116', (20, 23))	('NP-DCM', 'Var', (115, 121))
349737	26586943	After injection of NP-DCM and NP-DCM-ASYNYDA, fluorescence was observed in rats affected by esophageal cancer, whereas no signal was observed in control non-operated rats, or in rats with simple esophagitis or Barrett's esophagus mucosa.	('rat', 'Species', '10116', (160, 163))	('esophagitis', 'Phenotype', 'HP:0100633', (195, 206))	('esophageal cancer', 'Disease', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rats', 'Species', '10116', (75, 79))	('rat', 'Species', '10116', (166, 169))	('rats', 'Species', '10116', (178, 182))	('NP-DCM', 'Chemical', '-', (19, 25))	('fluorescence', 'MPA', (46, 58))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (210, 229))	('rat', 'Species', '10116', (75, 78))	('NP-DCM-ASYNYDA', 'Var', (30, 44))	('rat', 'Species', '10116', (178, 181))	('rats', 'Species', '10116', (166, 170))	('esophagitis', 'Disease', (195, 206))	('esophagitis', 'Disease', 'MESH:D004941', (195, 206))	('NP-DCM', 'Var', (19, 25))	('NP-DCM', 'Chemical', '-', (30, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
349739	26586943	Interestingly, NP-DCM-ASYNYDA induced strong fluorescence intensity 24 hours after administration.	('fluorescence intensity', 'MPA', (45, 67))	('NP-DCM', 'Chemical', '-', (15, 21))	('NP-DCM-ASYNYDA', 'Var', (15, 29))	('rat', 'Species', '10116', (91, 94))
349755	26586943	In particular, they may have prolonged circulation time and additional modification of NPs with various "homing" molecules increases their affinity and specificity for tumor cells.	('modification', 'Var', (71, 83))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('affinity', 'MPA', (139, 147))	('circulation time', 'MPA', (39, 55))	('specificity', 'MPA', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('increases', 'PosReg', (123, 132))
349886	26586943	Interestingly, fluorescence intensity in EAC tissue was stronger in animals injected with NP-DCM-ASYNYDA compared with animals injected with NP-DCM in both groups, either in the short (30 minutes to 2 hours) and in the long (24 hours) period.	('NP-DCM', 'Chemical', '-', (90, 96))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('stronger', 'PosReg', (56, 64))	('fluorescence intensity', 'MPA', (15, 37))	('NP-DCM', 'Chemical', '-', (141, 147))	('NP-DCM-ASYNYDA', 'Var', (90, 104))
349932	22610002	These 41 patients were diagnosed during the same period of time, and their cryptogenic cirrhosis considered as cirrhotic-stage NAFLD when they had suffered from at least three of the following features of the metabolic syndrome before the diagnosis of cirrhosis was made: hypertension (BP >=130/>= 85 mmHg), diabetes mellitus (fasting blood glucose >= 126mg/dL), obesity (body mass index [BMI] >= 30 kg/m2), hypertriglyceridemia (>= 150 mg/dl), and low HDL-cholesterol (<50 mg/dl in women, <40 mg/dl in men).	('hypertriglyceridemia', 'Disease', 'MESH:D015228', (408, 428))	('hypertriglyceridemia', 'Disease', (408, 428))	('glucose', 'Chemical', 'MESH:D005947', (341, 348))	('obesity', 'Disease', 'MESH:D009765', (363, 370))	('low', 'Var', (449, 452))	('low HDL-cholesterol', 'Phenotype', 'HP:0003233', (449, 468))	('cirrhosis', 'Phenotype', 'HP:0001394', (87, 96))	('men', 'Species', '9606', (503, 506))	('men', 'Species', '9606', (485, 488))	('cirrhosis', 'Disease', (87, 96))	('women', 'Species', '9606', (483, 488))	('hypertension', 'Disease', 'MESH:D006973', (272, 284))	('cirrhosis', 'Disease', 'MESH:D005355', (252, 261))	('diabetes mellitus', 'Disease', (308, 325))	('hypertension', 'Disease', (272, 284))	('BP >=130/>=', 'Var', (286, 297))	('hypertriglyceridemia', 'Phenotype', 'HP:0002155', (408, 428))	('obesity', 'Phenotype', 'HP:0001513', (363, 370))	('cirrhosis', 'Phenotype', 'HP:0001394', (252, 261))	('cholesterol', 'Chemical', 'MESH:D002784', (457, 468))	('cirrhosis', 'Disease', (252, 261))	('hypertension', 'Phenotype', 'HP:0000822', (272, 284))	('metabolic syndrome', 'Disease', 'MESH:D008659', (209, 227))	('<50', 'Var', (470, 473))	('diabetes mellitus', 'Disease', 'MESH:D003920', (308, 325))	('metabolic syndrome', 'Disease', (209, 227))	('patients', 'Species', '9606', (9, 17))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (308, 325))	('obesity', 'Disease', (363, 370))	('cirrhosis', 'Disease', 'MESH:D005355', (87, 96))	('>= 150 mg/dl', 'Var', (430, 442))
349969	22610002	Also, patients with portal hypertension and stage 3-4 fibrosis had a significantly lower NAFLD activity score and lower ALT levels as compared to those with stage 0-2 (supplementary Table 3).	('NAFLD activity score', 'MPA', (89, 109))	('ALT levels', 'MPA', (120, 130))	('hypertension', 'Disease', 'MESH:D006973', (27, 39))	('stage 3-4', 'Var', (44, 53))	('portal hypertension', 'Phenotype', 'HP:0001409', (20, 39))	('lower', 'NegReg', (83, 88))	('hypertension', 'Disease', (27, 39))	('patients', 'Species', '9606', (6, 14))	('lower', 'NegReg', (114, 119))	('hypertension', 'Phenotype', 'HP:0000822', (27, 39))	('men', 'Species', '9606', (174, 177))	('fibrosis', 'Disease', 'MESH:D005355', (54, 62))	('fibrosis', 'Disease', (54, 62))
350034	32194717	For example, mutation of the KRAS proto-oncogene, GTPase (Kras) gene is commonly observed in the early stage of pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('mutation', 'Var', (13, 21))	('KRAS', 'Gene', (29, 33))	('GTPase', 'Gene', (50, 56))	('observed', 'Reg', (81, 89))	('KRAS', 'Gene', '3845', (29, 33))	('Kras', 'Gene', (58, 62))	('pancreatic cancer', 'Disease', (112, 129))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('Kras', 'Gene', '3845', (58, 62))
350037	32194717	Epigenetic silencing and transcriptional inactivation due to hypermethylation in the 5'promoter regions of specific genes, including tumor-suppressor genes, for example hMLH1, BRCA1, p16INK4a, can contribute to cancer progression.	('contribute', 'Reg', (197, 207))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('p16INK4a', 'Gene', '1029', (183, 191))	('BRCA1', 'Gene', '672', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Disease', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('transcriptional', 'MPA', (25, 40))	('BRCA1', 'Gene', (176, 181))	('tumor', 'Disease', (133, 138))	('hypermethylation', 'Var', (61, 77))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('hMLH1', 'Gene', '4292', (169, 174))	('hMLH1', 'Gene', (169, 174))	('Epigenetic', 'MPA', (0, 10))	('p16INK4a', 'Gene', (183, 191))
350038	32194717	Hypermethylation of the promoter regions of the cysteine dioxygenase 1 (CDO1), tachykinin precursor 1 (TAC1) and checkpoint with forkhead and ring finger domains (CHFR) genes has been reported in various types of cancer, including colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (231, 248))	('Hypermethylation', 'Var', (0, 16))	('colorectal cancer', 'Disease', (231, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('tachykinin precursor 1', 'Gene', '6863', (79, 101))	('TAC1', 'Gene', (103, 107))	('reported', 'Reg', (184, 192))	('CHFR', 'Gene', (163, 167))	('cysteine dioxygenase 1', 'Gene', (48, 70))	('cancer', 'Disease', (213, 219))	('tachykinin precursor 1', 'Gene', (79, 101))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cysteine dioxygenase 1', 'Gene', '1036', (48, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (231, 248))	('CHFR', 'Gene', '55743', (163, 167))	('CDO1', 'Gene', (72, 76))	('cancer', 'Disease', (242, 248))	('TAC1', 'Gene', '6863', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('CDO1', 'Gene', '1036', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
350043	32194717	Vedeld et al demonstrated that the promoter region of CDO1 in pancreatic cancer, formalin-fixed, paraffin-embedded (FFPE) samples was hypermethylated.	('paraffin', 'Chemical', 'MESH:D010232', (97, 105))	('hypermethylated', 'Var', (134, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (62, 79))	('pancreatic cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('formalin', 'Chemical', 'MESH:D005557', (81, 89))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 79))	('CDO1', 'Gene', '1036', (54, 58))	('CDO1', 'Gene', (54, 58))
350044	32194717	Furthermore, Henriksen et al reported that the promoter of TAC1 in the plasmatic nucleic acids of patients with pancreatic cancer was hypermethylated, and the promoter of CHFR was not hypermethylated.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('TAC1', 'Gene', '6863', (59, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('hypermethylated', 'Var', (134, 149))	('TAC1', 'Gene', (59, 63))	('patients', 'Species', '9606', (98, 106))	('CHFR', 'Gene', '55743', (171, 175))	('pancreatic cancer', 'Disease', (112, 129))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('CHFR', 'Gene', (171, 175))
350049	32194717	In addition, it has been reported that hypermethylation of CHFR is associated with tumor aggressiveness in gastric and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('CHFR', 'Gene', (59, 63))	('CHFR', 'Gene', '55743', (59, 63))	('colorectal cancer', 'Disease', (119, 136))	('tumor aggressiveness', 'Disease', (83, 103))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('gastric', 'Disease', (107, 114))	('associated', 'Reg', (67, 77))	('hypermethylation', 'Var', (39, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (83, 103))
350057	32194717	P8107S; New England BioLabs, Inc.) dissolved in digestion lysis buffer containing denaturing agents, including sodium dodecyl sulfate, at 55 C for 4 h. Subsequently, bisulfite conversion was performed using a Zymo EZ DNA Methylation kit (cat.	('P8107S', 'SUBSTITUTION', 'None', (0, 6))	('bisulfite conversion', 'MPA', (166, 186))	('bisulfite', 'Chemical', 'MESH:C042345', (166, 175))	('P8107S', 'Var', (0, 6))	('sodium dodecyl sulfate', 'Chemical', 'MESH:D012967', (111, 133))
350083	32194717	The epigenetic hypermethylation of the promoter CpG islands of tumor-suppressor genes, including APC, BRCA1, p16INK4a can induce transcription inactivation during tumorigenesis, which is often observed in pancreatic cancer.	('p16INK4a', 'Gene', (109, 117))	('pancreatic cancer', 'Disease', (205, 222))	('APC', 'Gene', (97, 100))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('p16INK4a', 'Gene', '1029', (109, 117))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (205, 222))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('BRCA1', 'Gene', '672', (102, 107))	('epigenetic hypermethylation', 'Var', (4, 31))	('APC', 'Gene', '324', (97, 100))	('BRCA1', 'Gene', (102, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (205, 222))	('induce', 'Reg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('transcription inactivation', 'MPA', (129, 155))
350087	32194717	Hypermethylation of the CDO1 gene promoter in only 20 pancreatic cancer tissues has been evaluated by Vedeld et al, who reported that promoter of CDO1 in 18 of the 20 pancreatic cancer tissues using FFPE samples is hypermethylated.	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('hypermethylated', 'Var', (215, 230))	('CDO1', 'Gene', '1036', (24, 28))	('CDO1', 'Gene', (24, 28))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('CDO1', 'Gene', '1036', (146, 150))	('CDO1', 'Gene', (146, 150))	('pancreatic cancer', 'Disease', (54, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (54, 71))	('pancreatic cancer', 'Disease', (167, 184))
350090	32194717	Furthermore, depletion of CDO1 increases oxidative stress in tumor cells, which induces tumor cell resistance to ROS and metastasis.	('tumor', 'Disease', (61, 66))	('metastasis', 'CPA', (121, 131))	('CDO1', 'Gene', '1036', (26, 30))	('ROS', 'Chemical', 'MESH:D017382', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('increases', 'PosReg', (31, 40))	('oxidative stress', 'Phenotype', 'HP:0025464', (41, 57))	('depletion', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('induces', 'PosReg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (88, 93))	('CDO1', 'Gene', (26, 30))	('oxidative stress', 'MPA', (41, 57))
350091	32194717	Hypermethylation of the CDO1 CpG island promoter has been reported in various types of cancer, including breast, lung (non-small cell type), colon, kidney (clear cell type), esophageal and pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (189, 206))	('Hypermethylation', 'Var', (0, 16))	('esophageal', 'Disease', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('pancreatic cancer', 'Disease', (189, 206))	('reported', 'Reg', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('esophageal', 'Disease', 'MESH:D004941', (174, 184))	('cancer', 'Disease', (87, 93))	('CDO1', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (189, 206))	('breast', 'Disease', (105, 111))	('kidney', 'Disease', (148, 154))	('colon', 'Disease', 'MESH:D015179', (141, 146))	('CDO1', 'Gene', '1036', (24, 28))	('colon', 'Disease', (141, 146))	('lung', 'Disease', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', (200, 206))
350094	32194717	These results also suggested that CDO1 methylation may occur before detection of morphological changes in pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (106, 123))	('methylation', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CDO1', 'Gene', '1036', (34, 38))	('CDO1', 'Gene', (34, 38))	('occur', 'Reg', (55, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (106, 123))	('pancreatic cancer', 'Disease', (106, 123))
350096	32194717	CDO1 promoter hypermethylation in pancreatic cancer tumorigenesis appears therefore to be similar to that in colorectal cancer.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('hypermethylation', 'Var', (14, 30))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CDO1', 'Gene', '1036', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('CDO1', 'Gene', (0, 4))	('tumor', 'Disease', (52, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('pancreatic cancer', 'Disease', (34, 51))
350097	32194717	TAC1 encodes preprotachykinin-1, which is converted to neurokinin A or substance P. Since neurokinin A inhibits cell proliferation in normal cell, TAC1 is therefore considered a tumor-suppressor gene, and hypermethylation of the TAC1 CpG island promoter has been observed in various types of cancer, including lung (non-small cell type) cancer, colon cancer, head and neck cancer, uterus cancer and pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('uterus cancer', 'Disease', (381, 394))	('inhibits', 'NegReg', (103, 111))	('observed', 'Reg', (263, 271))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('uterus cancer', 'Phenotype', 'HP:0010784', (381, 394))	('colon cancer', 'Disease', 'MESH:D015179', (345, 357))	('cell proliferation in', 'CPA', (112, 133))	('TAC1', 'Gene', '6863', (147, 151))	('tumor', 'Disease', (178, 183))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (399, 416))	('neurokinin A', 'Gene', (90, 102))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('hypermethylation', 'Var', (205, 221))	('TAC1', 'Gene', (0, 4))	('uterus cancer', 'Disease', 'MESH:D014594', (381, 394))	('cancer', 'Disease', (388, 394))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancer', 'Disease', (292, 298))	('cancer', 'Disease', (373, 379))	('cancer', 'Disease', 'MESH:D009369', (351, 357))	('TAC1', 'Gene', (229, 233))	('neurokinin A', 'Gene', (55, 67))	('neck cancer', 'Disease', 'MESH:D006258', (368, 379))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('substance P', 'Gene', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('neck cancer', 'Disease', (368, 379))	('colon cancer', 'Disease', (345, 357))	('head and neck cancer', 'Phenotype', 'HP:0012288', (359, 379))	('pancreatic cancer', 'Disease', 'MESH:D010190', (399, 416))	('cancer', 'Disease', (337, 343))	('neurokinin A', 'Gene', '6863', (90, 102))	('substance P', 'Gene', '6863', (71, 82))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TAC1', 'Gene', '6863', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('TAC1', 'Gene', (147, 151))	('cancer', 'Disease', (410, 416))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('neurokinin A', 'Gene', '6863', (55, 67))	('pancreatic cancer', 'Disease', (399, 416))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('cancer', 'Disease', 'MESH:D009369', (373, 379))	('TAC1', 'Gene', '6863', (229, 233))	('colon cancer', 'Phenotype', 'HP:0003003', (345, 357))	('cancer', 'Disease', (351, 357))
350099	32194717	Subsequently, TAC1 gene methylation is likely to occur during the early stage of tumorigenesis in colorectal cancer.	('colorectal cancer', 'Disease', (98, 115))	('TAC1', 'Gene', '6863', (14, 18))	('occur', 'Reg', (49, 54))	('methylation', 'Var', (24, 35))	('TAC1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (81, 86))
350101	32194717	Similar to CDO1, hypermethylation of TAC1 promoter was also detected in adjacent non-cancerous tissues, suggesting that TAC1 promoter methylation may occur during the early stage of tumorigenesis in pancreatic cancer.	('pancreatic cancer', 'Disease', (199, 216))	('methylation', 'Var', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancerous', 'Disease', (85, 94))	('TAC1', 'Gene', '6863', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('TAC1', 'Gene', (120, 124))	('CDO1', 'Gene', (11, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('CDO1', 'Gene', '1036', (11, 15))	('non-cancer', 'Disease', 'MESH:D009369', (81, 91))	('TAC1', 'Gene', '6863', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancerous', 'Disease', 'MESH:D009369', (85, 94))	('TAC1', 'Gene', (37, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('tumor', 'Disease', (182, 187))	('non-cancer', 'Disease', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
350103	32194717	Hypermethylation of the CHFR gene is crucial during esophageal and gastric cancer tumorigenesis.	('esophageal', 'Disease', 'MESH:D004941', (52, 62))	('CHFR', 'Gene', '55743', (24, 28))	('gastric cancer', 'Disease', (67, 81))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('esophageal', 'Disease', (52, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('tumor', 'Disease', (82, 87))	('CHFR', 'Gene', (24, 28))
350104	32194717	CHFR promoter methylation could also provide clinical information, including clinical response to taxane chemotherapy, since patients with gastric or esophageal cancer and with CHFR hypermethylation, or with CHFR gene silencing in gastric and esophageal cancer are thought to have good clinical responses to docetaxel and paclitaxel treatments.	('patients', 'Species', '9606', (125, 133))	('CHFR', 'Gene', (0, 4))	('CHFR', 'Gene', '55743', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('gastric or esophageal cancer', 'Disease', (139, 167))	('gene', 'Var', (213, 217))	('gastric or esophageal cancer', 'Disease', 'MESH:D013274', (139, 167))	('gastric and esophageal cancer', 'Disease', 'MESH:D013274', (231, 260))	('paclitaxel', 'Chemical', 'MESH:D017239', (322, 332))	('CHFR', 'Gene', (177, 181))	('CHFR', 'Gene', (208, 212))	('CHFR', 'Gene', '55743', (208, 212))	('docetaxel', 'Chemical', 'MESH:D000077143', (308, 317))	('taxane', 'Chemical', 'MESH:C080625', (98, 104))	('CHFR', 'Gene', '55743', (177, 181))	('hypermethylation', 'Var', (182, 198))
350106	32194717	Cleven et al reported that hypermethylation of CHFR in patients with colorectal cancer indicates poor prognosis of stage ll colorectal cancer.	('hypermethylation', 'Var', (27, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colorectal cancer', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colorectal cancer', 'Disease', (69, 86))	('CHFR', 'Gene', '55743', (47, 51))	('patients', 'Species', '9606', (55, 63))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('CHFR', 'Gene', (47, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))	('stage', 'Disease', (115, 120))
350107	32194717	Subsequently, CHFR methylation may serve for selecting chemotherapy agents for cancers of the digestive tract system, and could be considered a putative prognostic indicator in cancer therapy.	('CHFR', 'Gene', (14, 18))	('cancers', 'Disease', (79, 86))	('cancer', 'Disease', (177, 183))	('methylation', 'Var', (19, 30))	('CHFR', 'Gene', '55743', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
350111	32194717	In gastric and colorectal cancer, CHFR methylation has been reported to be associated with lymph node metastasis and prognosis.	('CHFR', 'Gene', (34, 38))	('gastric', 'Disease', (3, 10))	('CHFR', 'Gene', '55743', (34, 38))	('methylation', 'Var', (39, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (15, 32))	('lymph node metastasis', 'CPA', (91, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('associated', 'Reg', (75, 85))	('colorectal cancer', 'Disease', (15, 32))	('prognosis', 'CPA', (117, 126))
350112	32194717	Although the present study did not report the prognostic value of CHFR gene promoter methylation in patients with pancreatic cancer, it demonstrated that CHFR gene methylation was associated with lymph node metastasis in patients with pancreatic cancer.	('patients', 'Species', '9606', (221, 229))	('CHFR', 'Gene', '55743', (154, 158))	('CHFR', 'Gene', (66, 70))	('CHFR', 'Gene', '55743', (66, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (235, 252))	('methylation', 'Var', (164, 175))	('pancreatic cancer', 'Disease', 'MESH:D010190', (235, 252))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancer', 'Disease', (114, 131))	('patients', 'Species', '9606', (100, 108))	('pancreatic cancer', 'Disease', (235, 252))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('lymph node metastasis', 'CPA', (196, 217))	('associated with', 'Reg', (180, 195))	('CHFR', 'Gene', (154, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))
350121	32194717	These results suggest that the hypermethylation of CDO1 and TAC1 promoters may be related to early events in pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('TAC1', 'Gene', '6863', (60, 64))	('hypermethylation', 'Var', (31, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('CDO1', 'Gene', '1036', (51, 55))	('CDO1', 'Gene', (51, 55))	('related', 'Reg', (82, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('pancreatic cancer', 'Disease', (109, 126))	('TAC1', 'Gene', (60, 64))
350122	32194717	However, whether the hypermethylation of CDO1 and TAC1 may serve as biomarkers for the diagnosis of pancreatic cancer remains unknown.	('hypermethylation', 'Var', (21, 37))	('CDO1', 'Gene', '1036', (41, 45))	('CDO1', 'Gene', (41, 45))	('pancreatic cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (100, 117))	('TAC1', 'Gene', '6863', (50, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (100, 117))	('TAC1', 'Gene', (50, 54))
350154	31681212	Sufficient evidence from animal and epidemiological studies, such as the demonstration of a specific mutation in the TP53 gene, led to the AFB1 classification as a human carcinogen by the International Agency for Research on Cancer (IARC).	('Cancer', 'Phenotype', 'HP:0002664', (225, 231))	('human', 'Species', '9606', (164, 169))	('TP53', 'Gene', '7157', (117, 121))	('rat', 'Species', '10116', (80, 83))	('TP53', 'Gene', (117, 121))	('FB1', 'Chemical', 'MESH:C056933', (140, 143))	('mutation', 'Var', (101, 109))
350170	31681212	AOH and AME induce DNA strand breaks in cell lines, unscheduled DNA synthesis in cultured human amnion FL cells, chromosomal aberrations and sisters chromatid exchange in human peripheral blood lymphocytes, mutation in V79 cells and transformation of NIH 3T3 cells.	('DNA', 'MPA', (19, 22))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (113, 136))	('AOH', 'Chemical', 'None', (0, 3))	('rat', 'Species', '10116', (129, 132))	('human', 'Species', '9606', (90, 95))	('AME', 'Chemical', 'MESH:C018206', (8, 11))	('mutation', 'Var', (207, 215))	('human', 'Species', '9606', (171, 176))
350188	31681212	Thus, alterations of Sa to So ratio in tissues, urine and blood have been proposed as potential biomarkers of FB exposure, but studies have not allowed an accurate validation.	('Sa', 'Chemical', 'MESH:C005682', (21, 23))	('alterations', 'Var', (6, 17))	('FB', 'Chemical', 'MESH:C556348', (110, 112))	('So', 'Chemical', 'MESH:D013110', (27, 29))	('rat', 'Species', '10116', (30, 33))	('Sa to So ratio', 'MPA', (21, 35))	('rat', 'Species', '10116', (10, 13))	('rat', 'Species', '10116', (159, 162))
350205	31681212	Later, studies proved that TCDD can elevate the expression of the delta- aminolevulinate synthase enzyme that participates in the heme biosynthesis.	('TCDD', 'Chemical', 'MESH:D013749', (27, 31))	('aminolevulinate', 'Chemical', 'MESH:D000622', (73, 88))	('expression', 'MPA', (48, 58))	('heme', 'Chemical', 'MESH:D006418', (130, 134))	('TCDD', 'Var', (27, 31))	('elevate', 'PosReg', (36, 43))
350241	31681212	Analyses based on the terminal amino domain show a region of basic amino acids residues, followed by the hHLH motif.	('hHLH', 'Disease', (105, 109))	('amino', 'Chemical', 'MESH:D000596', (31, 36))	('amino', 'Chemical', 'MESH:D000596', (67, 72))	('basic amino acids residues', 'Var', (61, 87))
350267	31681212	Thanks to the exhaustive studies that have been conducted on the regulation of the expression of the cytochromes during AhR activation, it was possible to identify various genes that have AREs, which can be grouped as follows: Phase I genes of the metabolism of xenobiotics: CYP1A1, CYP1A2, CYP1B1, CYP2A5, CYP2S1, and CYP4B1.	('CYP4B1', 'Gene', (319, 325))	('CYP1B1', 'Gene', (291, 297))	('CYP1A1', 'Gene', (275, 281))	('CYP1A2', 'Gene', '1544', (283, 289))	('CYP1A1', 'Gene', '1543', (275, 281))	('CYP2S1', 'Gene', '29785', (307, 313))	('CYP4B1', 'Gene', '1580', (319, 325))	('CYP1A2', 'Gene', (283, 289))	('CYP1B1', 'Gene', '1545', (291, 297))	('CYP2A5', 'Var', (299, 305))	('CYP2S1', 'Gene', (307, 313))
350273	31681212	One aspect of the consequences of cytochrome activation is the generation of modifications of the xenobiotic compounds that induce their activation and achieve control of the receptor activation while reducing ligand concentrations in the cell.	('rat', 'Species', '10116', (67, 70))	('ligand concentrations', 'MPA', (210, 231))	('reducing', 'NegReg', (201, 209))	('activation', 'PosReg', (137, 147))	('modifications', 'Var', (77, 90))	('rat', 'Species', '10116', (224, 227))
350292	31681212	Alterations to the KLF6 gene are associated with various types of cancer, including astrocytomas and gliomas.	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('KLF6', 'Gene', (19, 23))	('astrocytomas and gliomas', 'Disease', 'MESH:D005910', (84, 108))	('associated', 'Reg', (33, 43))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('rat', 'Species', '10116', (4, 7))	('KLF6', 'Gene', '1316', (19, 23))	('cancer', 'Disease', (66, 72))
350307	31681212	An analysis of genes differentially-expressed by RNAseq (transcriptome) from rat livers revealed an at least twofold increase, to a total of 1026 genes.	('rat', 'Species', '10116', (77, 80))	('increase', 'PosReg', (117, 125))	('RNAseq', 'Var', (49, 55))
350329	31681212	The mRNA expression of phase II enzymes such as heme oxygenase-1, nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1, and glutamate cysteine ligase catalytic subunit were upregulated by the activation of Nrf2.	('glutamate cysteine ligase catalytic subunit', 'Enzyme', (140, 183))	('heme oxygenase-1', 'Enzyme', (48, 64))	('phase II enzymes', 'Enzyme', (23, 39))	('Nrf2', 'Gene', (222, 226))	('glutamate', 'Chemical', 'None', (140, 149))	('activation', 'Var', (208, 218))	('mRNA expression', 'MPA', (4, 19))	('nicotinamide adenine dinucleotide phosphate-quinone', 'Chemical', 'MESH:D009249', (66, 117))	('upregulated', 'PosReg', (189, 200))	('oxygen', 'Chemical', 'MESH:D010100', (53, 59))	('heme', 'Chemical', 'MESH:D006418', (48, 52))	('cysteine', 'Chemical', 'MESH:D003545', (150, 158))	('Nrf2', 'Gene', '4780', (222, 226))
350332	31681212	Induction of CYP enzymes by FB1 has been poorly investigated so far; but an increase of CYP1A activity in the liver of Wistar rats exposed to FB1 has been confirmed.	('increase', 'PosReg', (76, 84))	('Wistar rats', 'Species', '10116', (119, 130))	('activity', 'MPA', (94, 102))	('CYP1A', 'Enzyme', (88, 93))	('FB1', 'Chemical', 'MESH:C056933', (142, 145))	('FB1', 'Chemical', 'MESH:C056933', (28, 31))	('FB1', 'Var', (142, 145))
350345	31681212	Mutations can be produced in genes with important functions but they are also targets for mutagen modification such as p53 and K-Ras, among others.	('p53', 'Gene', '7157', (119, 122))	('K-Ras', 'Gene', '3845', (127, 132))	('Mutations', 'Var', (0, 9))	('K-Ras', 'Gene', (127, 132))	('p53', 'Gene', (119, 122))
350352	31681212	Certain polymorphisms can predispose tissues to cancer development, when they are exposed to aflatoxins.	('aflatoxins', 'Chemical', 'MESH:D000348', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('predispose', 'Reg', (26, 36))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('polymorphisms', 'Var', (8, 21))	('exposed', 'Reg', (82, 89))
350353	31681212	This field needs to be studied broadly since we know that at least some polymorphisms of enzymes like GCTP1, AKR, EPHX1, and EERC2 may participate in cancer development.	('EERC2', 'Gene', (125, 130))	('EPHX1', 'Gene', '2052', (114, 119))	('participate', 'Reg', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('GCTP1', 'Gene', (102, 107))	('AKR', 'Gene', (109, 112))	('cancer', 'Disease', (150, 156))	('polymorphisms', 'Var', (72, 85))	('EPHX1', 'Gene', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
350367	31695486	Besides, in ESCC cell lines KYSE70 and KYSE450, knocking down PKMYT1 allowed more cells to skip G2/M checkpoint to complete mitosis, which promoted cell apoptosis, inhibited cell proliferation, and prevented the EMT phenotype in vitro.	('cell proliferation', 'CPA', (174, 192))	('PKMYT1', 'Gene', '9088', (62, 68))	('promoted', 'PosReg', (139, 147))	('knocking down', 'Var', (48, 61))	('ESCC', 'Disease', (12, 16))	('G2/M checkpoint to complete mitosis', 'MPA', (96, 131))	('KYSE450', 'CellLine', 'CVCL:1353', (39, 46))	('PKMYT1', 'Gene', (62, 68))	('inhibited', 'NegReg', (164, 173))	('ESCC', 'Disease', 'MESH:C562729', (12, 16))	('EMT phenotype in vitro', 'CPA', (212, 234))	('prevented', 'NegReg', (198, 207))	('cell apoptosis', 'CPA', (148, 162))
350376	31695486	Normal cells repair DNA at G1/S checkpoint, whereas tumor cells repair DNA and shun immature cells entry into mitosis to prevent mitotic catastrophe at G2/M checkpoint because they have abrogated G1/S checkpoint due to the mutation of P53.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('abrogated', 'NegReg', (186, 195))	('tumor', 'Disease', (52, 57))	('P53', 'Gene', (235, 238))	('P53', 'Gene', '7157', (235, 238))	('mutation', 'Var', (223, 231))	('G1/S checkpoint', 'MPA', (196, 211))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
350380	31695486	A high frequency of TP53 mutations has been found in ESCC patients, but how PKMYT1 participates in the pathogenesis and development of ESCC have not been fully investigated.	('ESCC', 'Disease', (135, 139))	('mutations', 'Var', (25, 34))	('ESCC', 'Disease', (53, 57))	('TP53', 'Gene', (20, 24))	('PKMYT1', 'Gene', '9088', (76, 82))	('found', 'Reg', (44, 49))	('ESCC', 'Disease', 'MESH:C562729', (135, 139))	('PKMYT1', 'Gene', (76, 82))	('patients', 'Species', '9606', (58, 66))	('ESCC', 'Disease', 'MESH:C562729', (53, 57))	('TP53', 'Gene', '7157', (20, 24))
350381	31695486	In this study, we found that PKMYT1 was highly expressed in ESCC cell lines and ESCC patients, and high PKMYT1 expression induced poorer prognosis in patients with ESCC.	('PKMYT1', 'Gene', '9088', (104, 110))	('ESCC', 'Disease', (80, 84))	('ESCC', 'Disease', 'MESH:C562729', (164, 168))	('ESCC', 'Disease', (60, 64))	('PKMYT1', 'Gene', '9088', (29, 35))	('high', 'Var', (99, 103))	('expression', 'MPA', (111, 121))	('ESCC', 'Disease', (164, 168))	('patients', 'Species', '9606', (85, 93))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('patients', 'Species', '9606', (150, 158))	('PKMYT1', 'Gene', (104, 110))	('ESCC', 'Disease', 'MESH:C562729', (60, 64))	('poorer', 'NegReg', (130, 136))	('PKMYT1', 'Gene', (29, 35))
350391	31695486	Both ESCC cell lines (KYSE450, KYSE70) and immortalized human esophageal epithelial cell line HET-1A were purchased from Cell Bank of the Chinese Academy of Sciences (Shanghai, China).	('HET-1A', 'CellLine', 'CVCL:3702', (94, 100))	('ESCC', 'Disease', (5, 9))	('KYSE450', 'CellLine', 'CVCL:1353', (22, 29))	('human', 'Species', '9606', (56, 61))	('ESCC', 'Disease', 'MESH:C562729', (5, 9))	('KYSE450', 'Var', (22, 29))
350432	31695486	Then, we used Cox proportional hazards model with univariate and multivariate analysis to verify whether PKMYT1 can be used as an independent risk factor, these results indicated that high PKMYT1 expression was an independent risk factor (P=0.014) in patients with ESCC (Table 4).	('ESCC', 'Disease', (265, 269))	('PKMYT1', 'Gene', (105, 111))	('PKMYT1', 'Gene', '9088', (189, 195))	('expression', 'MPA', (196, 206))	('ESCC', 'Disease', 'MESH:C562729', (265, 269))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('PKMYT1', 'Gene', '9088', (105, 111))	('patients', 'Species', '9606', (251, 259))	('PKMYT1', 'Gene', (189, 195))	('high', 'Var', (184, 188))
350434	31695486	Also, we performed in-silico analysis of microarray gene expression data using an online survival analysis tool (data from http://kmplot.com/analysis/) to assess the prognostic effect of PKMYT1 in lung cancer, breast cancer, and gastric cancer, showing that high expression of PKMYT1 was related to poor prognosis (Figure 2A).	('PKMYT1', 'Gene', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('PKMYT1', 'Gene', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('lung cancer', 'Disease', 'MESH:D008175', (197, 208))	('gastric cancer', 'Disease', (229, 243))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('gastric cancer', 'Disease', 'MESH:D013274', (229, 243))	('PKMYT1', 'Gene', '9088', (187, 193))	('breast cancer', 'Disease', (210, 223))	('high', 'Var', (258, 262))	('PKMYT1', 'Gene', '9088', (277, 283))	('lung cancer', 'Disease', (197, 208))	('gastric cancer', 'Phenotype', 'HP:0012126', (229, 243))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
350438	31695486	Two different siRNAs were designed and transfected into those ESCC cells to knockdown PKMYT1 in ESCC cells (Figure 3B).	('ESCC', 'Disease', 'MESH:C562729', (96, 100))	('knockdown', 'Var', (76, 85))	('ESCC', 'Disease', 'MESH:C562729', (62, 66))	('PKMYT1', 'Gene', '9088', (86, 92))	('PKMYT1', 'Gene', (86, 92))	('ESCC', 'Disease', (96, 100))	('ESCC', 'Disease', (62, 66))
350439	31695486	Forty-eight hours after the transfection, cell cycle assays indicated that knocked down PKMYT1 expression reduced the G2/M phase in cell cycle (Figure 3C), and CCK-8 assays showed that knockdown of PKMYT1 significantly suppressed cell proliferation in KYSE450 cells compared with negative control group (Figure 3D).	('G2/M phase in cell cycle', 'CPA', (118, 142))	('PKMYT1', 'Gene', (198, 204))	('knocked down', 'Var', (75, 87))	('KYSE450', 'CellLine', 'CVCL:1353', (252, 259))	('suppressed', 'NegReg', (219, 229))	('PKMYT1', 'Gene', '9088', (198, 204))	('PKMYT1', 'Gene', '9088', (88, 94))	('knockdown', 'Var', (185, 194))	('cell proliferation in KYSE450 cells', 'CPA', (230, 265))	('reduced', 'NegReg', (106, 113))	('PKMYT1', 'Gene', (88, 94))
350440	31695486	This observation was further supported by reduced numbers of colony formation upon PKMYT1 knockdown (Figure 3E).	('reduced', 'NegReg', (42, 49))	('PKMYT1', 'Gene', '9088', (83, 89))	('knockdown', 'Var', (90, 99))	('colony formation', 'CPA', (61, 77))	('PKMYT1', 'Gene', (83, 89))
350442	31695486	Similar results were obtained when performing these analyses in KYSE70 cells following PKMYT1 knockdown.	('PKMYT1', 'Gene', '9088', (87, 93))	('knockdown', 'Var', (94, 103))	('PKMYT1', 'Gene', (87, 93))
350444	31695486	Transwell assays were used to investigate the effects of knockdown PKMYT1 on the invasion and migration capability in ESCC cells.	('ESCC', 'Disease', (118, 122))	('PKMYT1', 'Gene', (67, 73))	('migration capability', 'CPA', (94, 114))	('invasion', 'CPA', (81, 89))	('knockdown', 'Var', (57, 66))	('PKMYT1', 'Gene', '9088', (67, 73))	('ESCC', 'Disease', 'MESH:C562729', (118, 122))
350445	31695486	The transwell assays showed that there were fewer cells migrated in siRNA group than negative group in KYSE450 and KYSE70 cells (Figure 4A and B), indicating that PKMYT1 knockdown could inhibit the migration and invasion capacities of ESCC cells.	('ESCC', 'Disease', (235, 239))	('knockdown', 'Var', (170, 179))	('invasion capacities', 'CPA', (212, 231))	('inhibit', 'NegReg', (186, 193))	('PKMYT1', 'Gene', '9088', (163, 169))	('ESCC', 'Disease', 'MESH:C562729', (235, 239))	('PKMYT1', 'Gene', (163, 169))	('KYSE450', 'CellLine', 'CVCL:1353', (103, 110))
350463	31695486	We hypothesized that aberrant PKMYT1 expression was involved in abnormal proliferation and tumorigenesis in ESCC.	('aberrant', 'Var', (21, 29))	('PKMYT1', 'Gene', (30, 36))	('ESCC', 'Disease', 'MESH:C562729', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('involved', 'Reg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ESCC', 'Disease', (108, 112))	('PKMYT1', 'Gene', '9088', (30, 36))	('tumor', 'Disease', (91, 96))
350468	31695486	In cancer cells, G2 checkpoint is important for DNA repair because of the defective G1 checkpoint mechanism which is caused by a p53 mutation.	('defective', 'NegReg', (74, 83))	('mutation', 'Var', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('G1 checkpoint mechanism', 'Pathway', (84, 107))	('cancer', 'Disease', (3, 9))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('caused by', 'Reg', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
350475	31695486	In our assays, we detected decreased migration and invasion abilities in ESCC cell lines after PKMYT1 knockdown.	('ESCC', 'Disease', 'MESH:C562729', (73, 77))	('PKMYT1', 'Gene', (95, 101))	('decreased', 'NegReg', (27, 36))	('migration', 'CPA', (37, 46))	('knockdown', 'Var', (102, 111))	('invasion abilities', 'CPA', (51, 69))	('PKMYT1', 'Gene', '9088', (95, 101))	('ESCC', 'Disease', (73, 77))
350476	31695486	Moreover, PKMYT1 knockdown also triggered abnormal expression of several other molecular, such as increased expression of ECAD and decreased expression of NCAD, VIM, and Twist, which was also in line with previous studies.	('VIM', 'Gene', (161, 164))	('PKMYT1', 'Gene', '9088', (10, 16))	('NCAD', 'Gene', (155, 159))	('VIM', 'Gene', '7431', (161, 164))	('ECAD', 'Gene', '999', (122, 126))	('NCAD', 'Gene', '1000', (155, 159))	('decreased', 'NegReg', (131, 140))	('Twist', 'Gene', '7291', (170, 175))	('expression', 'MPA', (51, 61))	('increased', 'PosReg', (98, 107))	('expression', 'MPA', (141, 151))	('expression', 'MPA', (108, 118))	('knockdown', 'Var', (17, 26))	('PKMYT1', 'Gene', (10, 16))	('ECAD', 'Gene', (122, 126))	('Twist', 'Gene', (170, 175))
350482	31695486	We observed that reduced invasion and metastasis capacity and the changed expression of EMT-related biomarkers and decreased expression of p-AKT, p-mTOR, and p-S6 in ESCC cells due to PKMYT1 knockdown.	('expression', 'MPA', (74, 84))	('changed', 'Reg', (66, 73))	('mTOR', 'Gene', (148, 152))	('mTOR', 'Gene', '2475', (148, 152))	('PKMYT1', 'Gene', '9088', (184, 190))	('AKT', 'Gene', (141, 144))	('decreased', 'NegReg', (115, 124))	('knockdown', 'Var', (191, 200))	('expression', 'MPA', (125, 135))	('ESCC', 'Disease', 'MESH:C562729', (166, 170))	('p-S6', 'Gene', '338413', (158, 162))	('AKT', 'Gene', '207', (141, 144))	('p-S6', 'Gene', (158, 162))	('PKMYT1', 'Gene', (184, 190))	('ESCC', 'Disease', (166, 170))	('reduced', 'NegReg', (17, 24))
350483	31695486	Therefore, we speculated that PKMYT1 suppression could inhibit the expression of TWIST by inhibiting the activation of the AKT pathway, thus hindering the migration and metastasis of cells and promoting the apoptosis in ESCC cells.	('apoptosis', 'CPA', (207, 216))	('TWIST', 'Gene', (81, 86))	('PKMYT1', 'Gene', (30, 36))	('ESCC', 'Disease', 'MESH:C562729', (220, 224))	('hindering', 'NegReg', (141, 150))	('PKMYT1', 'Gene', '9088', (30, 36))	('TWIST', 'Gene', '7291', (81, 86))	('AKT', 'Gene', '207', (123, 126))	('suppression', 'Var', (37, 48))	('ESCC', 'Disease', (220, 224))	('promoting', 'PosReg', (193, 202))	('expression', 'MPA', (67, 77))	('inhibiting', 'NegReg', (90, 100))	('AKT', 'Gene', (123, 126))	('inhibit', 'NegReg', (55, 62))
350486	31695486	Several PKMYT1 inhibitors have been already developed, including the well-known tyrosine kinase inhibitors dasatinib and bosutinib, the pyridopyrimidine derivatives PD-0166285, PD-173952, PD-173955, and PD-180970 also have been identified by applying different approaches, and more novel molecular inhibitors are underway.	('PKMYT1', 'Gene', (8, 14))	('PD-180970', 'Chemical', 'MESH:C410732', (203, 212))	('tyrosine', 'Chemical', 'None', (80, 88))	('pyridopyrimidine', 'Chemical', 'None', (136, 152))	('PD-173952', 'Var', (177, 186))	('dasatinib', 'Chemical', 'MESH:C488369', (107, 116))	('PKMYT1', 'Gene', '9088', (8, 14))	('PD-180970', 'Var', (203, 212))	('PD-173955', 'Var', (188, 197))	('PD-0166285', 'Chemical', 'MESH:C440869', (165, 175))	('PD-0166285', 'Var', (165, 175))	('bosutinib', 'Chemical', 'MESH:C471992', (121, 130))	('PD-173955', 'Chemical', 'MESH:C403095', (188, 197))	('PD-173952', 'Chemical', 'MESH:C511991', (177, 186))
350494	31417276	The overall survival is shorter in patients with low SPINT1-AS1 expressed than those with high levels of SPINT1-AS1 (P=0.044), and SPINT1 mRNA expression level is associated with the OS (P=0.001).	('shorter', 'NegReg', (24, 31))	('SPINT1-AS1 expressed', 'Var', (53, 73))	('low', 'NegReg', (49, 52))	('overall', 'CPA', (4, 11))	('patients', 'Species', '9606', (35, 43))
350516	31417276	Compared with the matched normal tissues, the high SPINT1-AS1 expression was significantly related to the characters, including age (>65 years old vs <=65 years old: 59.0% vs 31.7%, P=0.007) and tumor size (<=4 cm vs >4 cm: 74.3% vs 51.7%, P=0.024).	('high', 'Var', (46, 50))	('tumor', 'Disease', (195, 200))	('related', 'Reg', (91, 98))	('expression', 'MPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
350520	31417276	As it is shown in Figure 3A, the OS is shorter in SPINT1-AS1 low-expressed patients than those of high levels of SPINT1-AS1 (P=0.044, HR=0.631, 95% CI: 0.403-0.989).	('patients', 'Species', '9606', (75, 83))	('shorter', 'NegReg', (39, 46))	('low-expressed', 'Var', (61, 74))	('SPINT1-AS1', 'Gene', (50, 60))
350536	31417276	From the survival analysis, we observed that patients with low levels of SPINT1-AS1 and SPINT1 mRNA expression had significantly shorter OS than those with high levels of SPINT1-AS1 and SPINT1 mRNA expression.	('low levels', 'Var', (59, 69))	('patients', 'Species', '9606', (45, 53))	('SPINT1', 'Gene', (88, 94))	('SPINT1-AS1', 'Var', (73, 83))	('shorter', 'NegReg', (129, 136))
350682	30777940	The risk of bleeding is moderately elevated in patients receiving nonaspirin antiplatelet or anticoagulant treatment, but not in patients receiving aspirin monotherapy.	('bleeding', 'Disease', 'MESH:D006470', (12, 20))	('bleeding', 'Disease', (12, 20))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (47, 55))	('aspirin', 'Chemical', 'MESH:D001241', (69, 76))	('nonaspirin', 'Var', (66, 76))	('elevated', 'PosReg', (35, 43))	('aspirin', 'Chemical', 'MESH:D001241', (148, 155))
350723	29851829	Regarding tumor location, definitive CCRT rather than surgery was usually preferred and a higher dose (60-70 Gy rather than around 50 Gy) was often favored for cervical NM-ESCC in contrast to NM-ESCC at other locations.	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('NM-ESCC', 'Var', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
350814	28430624	The cell death pathways evoked by mTHPC mediated PDT involve oxidative damage which may lead to apoptosis, autophagy or necrosis.	('necrosis', 'Disease', (120, 128))	('mTHPC mediated PDT', 'Var', (34, 52))	('lead', 'Reg', (88, 92))	('autophagy', 'CPA', (107, 116))	('necrosis', 'Disease', 'MESH:D009336', (120, 128))	('PDT', 'Var', (49, 52))	('cell death', 'CPA', (4, 14))	('mTHPC', 'Chemical', 'MESH:C072269', (34, 39))	('apoptosis', 'CPA', (96, 105))	('oxidative damage', 'MPA', (61, 77))
350816	28430624	It has been reported that upon PDT treatment there is an increase in ROS which can kill a portion of the cells immediately, while others undergo a death process which takes several hours.	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('treatment', 'Var', (35, 44))	('men', 'Species', '9606', (40, 43))	('ROS', 'MPA', (69, 72))
350817	28430624	mTHPC - PDT was reported to induce immediate DNA damage and reduction of RNA due to ROS production in PC-3 cells.	('mTHPC - PDT', 'Var', (0, 11))	('mTHPC', 'Chemical', 'MESH:C072269', (0, 5))	('PC-3', 'CellLine', 'CVCL:0035', (102, 106))	('reduction', 'NegReg', (60, 69))	('RNA due', 'MPA', (73, 80))	('ROS production', 'MPA', (84, 98))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('DNA damage', 'MPA', (45, 55))
350819	28430624	mTHPC - PDT also blocks proliferation and induces cell cycle arrest.	('mTHPC - PDT', 'Var', (0, 11))	('proliferation', 'CPA', (24, 37))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('mTHPC', 'Chemical', 'MESH:C072269', (0, 5))	('blocks', 'NegReg', (17, 23))	('induces', 'Reg', (42, 49))	('cell cycle arrest', 'CPA', (50, 67))	('rat', 'Species', '10116', (31, 34))
350823	28430624	PDT of prostate can produce areas of rectal mucosal necrosis, however these areas heal with the regeneration of normal mucosa.	('PDT', 'Var', (0, 3))	('rectal mucosal necrosis', 'Disease', 'MESH:D012002', (37, 60))	('rectal mucosal necrosis', 'Disease', (37, 60))	('rat', 'Species', '10116', (102, 105))
350833	28430624	mTHPC being lipophilic, accumulates mainly in membranes excluding the nucleus, while 5FdUr acts in the cytosol by inhibiting thymidylate synthase and is incorporated in RNA and DNA.	('thymidylate synthase', 'Gene', (125, 145))	('rat', 'Species', '10116', (160, 163))	('5FdUr', 'Chemical', 'MESH:C576827', (85, 90))	('mTHPC', 'Chemical', 'MESH:C072269', (0, 5))	('5FdUr', 'Var', (85, 90))	('thymidylate synthase', 'Gene', '7298', (125, 145))	('inhibiting', 'NegReg', (114, 124))
350848	28430624	On investigating the effects of TOOKAD PDT on the prostate and surrounding tissues in canine model, hemorrhagic necrosis was observed at one week post TOOKAD PDT in the prostate and prostatic urethra.	('TOOKAD PDT', 'Var', (151, 161))	('hemorrhagic necrosis', 'Disease', (100, 120))	('hemorrhagic necrosis', 'Disease', 'MESH:D006470', (100, 120))	('hemorrhagic necrosis', 'Phenotype', 'HP:0010885', (100, 120))	('canine', 'Species', '9615', (86, 92))
350876	28430624	In a study on effects of MLu and PDT delivery methods in normal canine prostate model, it was found that MLu - PDT initially caused inflammation and necrosis, followed by glandular atrophy and fibrosis.	('glandular atrophy', 'Disease', (171, 188))	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('MLu', 'Chemical', 'MESH:C102825', (25, 28))	('caused', 'Reg', (125, 131))	('inflammation', 'Disease', (132, 144))	('glandular atrophy', 'Disease', 'MESH:D002277', (171, 188))	('necrosis', 'Disease', (149, 157))	('canine', 'Species', '9615', (64, 70))	('MLu - PDT', 'Var', (105, 114))	('fibrosis', 'Disease', 'MESH:D005355', (193, 201))	('fibrosis', 'Disease', (193, 201))	('necrosis', 'Disease', 'MESH:D009336', (149, 157))	('MLu', 'Chemical', 'MESH:C102825', (105, 108))
350887	28430624	MLu - PDT causes a short term increase in serum PSA levels, which may be due to cellular damage, leading to release of PSA in circulation.	('PSA', 'Gene', '354', (48, 51))	('MLu', 'Chemical', 'MESH:C102825', (0, 3))	('PSA', 'Gene', (48, 51))	('increase', 'PosReg', (30, 38))	('PSA', 'Gene', (119, 122))	('MLu - PDT', 'Var', (0, 9))	('PSA', 'Gene', '354', (119, 122))	('release', 'MPA', (108, 115))
350892	28430624	A preliminary study on three patients found that total hemoglobin concentration (THC) and blood flow decreased during MLu - PDT along with a slight decrease tumor blood oxygen saturation.	('total hemoglobin concentration', 'MPA', (49, 79))	('patients', 'Species', '9606', (29, 37))	('MLu - PDT', 'Var', (118, 127))	('rat', 'Species', '10116', (180, 183))	('blood oxygen saturation', 'MPA', (163, 186))	('blood flow', 'MPA', (90, 100))	('tumor blood oxygen saturation', 'Phenotype', 'HP:0002637', (157, 186))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('decreased', 'NegReg', (101, 110))	('decrease tumor', 'Disease', 'MESH:D009369', (148, 162))	('decrease tumor', 'Disease', (148, 162))	('MLu', 'Chemical', 'MESH:C102825', (118, 121))	('oxygen', 'Chemical', 'MESH:D010100', (169, 175))	('decrease tumor blood oxygen', 'Phenotype', 'HP:0012418', (148, 175))	('rat', 'Species', '10116', (73, 76))
350915	28430624	Early studies comparing the photodynamic efficacy of Pba with Hematoporphyrin derivative (HpD) in Lewis lung carcinoma in mice found that Pba is a stronger PS as compared to HpD due to its longer wavelength of absorbance in the red region of the spectrum.	('mice', 'Species', '10090', (122, 126))	('Hematoporphyrin', 'Chemical', 'MESH:D006415', (62, 77))	('Pba', 'Chemical', 'MESH:C032623', (138, 141))	('Lewis lung carcinoma', 'Disease', (98, 118))	('longer', 'PosReg', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Pba', 'Var', (138, 141))	('Pba', 'Chemical', 'MESH:C032623', (53, 56))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (98, 118))
350994	25907101	In three cigar studies that also included pipe smoking, primary pipe/cigar smoking was associated with slight increases in all-cause mortality risks (MRs 1.09 to 1.37), and all of these associations just missed conventional thresholds for statistical significance with the lower bounds of the 95% confidence intervals being at least 0.98.	('I', 'Chemical', 'MESH:D007455', (0, 1))	('primary pipe/cigar smoking', 'Var', (56, 82))	('increases', 'PosReg', (110, 119))	('all-cause mortality', 'MPA', (123, 142))
351093	25634752	Genome-wide analyses have identified SMAD4 inactivation in a subset of tumors.	('SMAD4', 'Gene', (37, 42))	('SMAD4', 'Gene', '4089', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('inactivation', 'Var', (43, 55))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
351101	25634752	In summary, loss of Smad4 protein expression is an independent prognostic factor for TTR and OS that correlates with increased propensity for disease recurrence and poor survival in patients with esophageal adenocarcinoma after surgical resection.	('TTR', 'Disease', (85, 88))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (196, 221))	('esophageal adenocarcinoma', 'Disease', (196, 221))	('loss', 'Var', (12, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('patients', 'Species', '9606', (182, 190))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (196, 221))	('protein', 'Protein', (26, 33))	('Smad4', 'Gene', (20, 25))	('Smad4', 'Gene', '4089', (20, 25))
351111	25634752	Recently, Dulak et al identified recurrent mutations within various members of the transforming growth factor beta (TGF-beta)/Smad signaling pathway in 18% of esophageal adenocarcinomas.	('esophageal adenocarcinomas', 'Disease', (159, 185))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (159, 184))	('Smad', 'Gene', '4089;4089', (126, 130))	('transforming growth factor beta', 'Gene', '7040', (83, 114))	('mutations', 'Var', (43, 52))	('TGF-beta', 'Gene', '7040', (116, 124))	('TGF-beta', 'Gene', (116, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('transforming growth factor beta', 'Gene', (83, 114))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (159, 185))	('Smad', 'Gene', (126, 130))
351113	25634752	In addition, SMAD4 was subject to copy number loss in 34% of tumors.	('SMAD4', 'Gene', '4089', (13, 18))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('SMAD4', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('copy number loss', 'Var', (34, 50))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
351120	25634752	In fact, the loss of Smad4 has been shown to correlate with progression to metastasis and poor prognosis.	('loss', 'Var', (13, 17))	('Smad4', 'Gene', (21, 26))	('Smad4', 'Gene', '4089', (21, 26))	('progression to metastasis', 'CPA', (60, 85))
351158	25634752	The depth of tumor infiltration (pT staging) was classified as follows: 8 (4%) pT1a, 26 (13%) pT1b, 26 (13%) pT2, 141 (69%) pT3, and 4 (2%) pT4.	('tumor', 'Disease', (13, 18))	('pT2', 'Var', (109, 112))	('pT1a', 'Disease', (79, 83))	('pT3', 'Gene', '7694', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('pT3', 'Gene', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('pT1b', 'Var', (94, 98))
351195	25634752	In multivariate analysis, the absence of Smad4 expression was a negative, independent prognostic factor for both TTR and OS.	('Smad4', 'Gene', (41, 46))	('Smad4', 'Gene', '4089', (41, 46))	('absence', 'Var', (30, 37))	('TTR', 'Disease', (113, 116))	('negative', 'NegReg', (64, 72))	('expression', 'MPA', (47, 57))
351197	25634752	Although recent genome-wide analyses of esophageal adenocarcinoma have identified recurrent genetic alterations in SMAD4, little has been reported with regard to Smad4 and its role in the pathogenesis of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (204, 229))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (40, 65))	('Smad4', 'Gene', (162, 167))	('esophageal adenocarcinoma', 'Disease', (204, 229))	('esophageal adenocarcinoma', 'Disease', (40, 65))	('Smad4', 'Gene', '4089', (162, 167))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (204, 229))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (40, 65))	('SMAD4', 'Gene', '4089', (115, 120))	('genetic alterations', 'Var', (92, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('SMAD4', 'Gene', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
351199	25634752	Originally isolated as a tumor-suppressor gene in pancreatic cancer, SMAD4, also termed DPC4 (for Deleted in Pancreatic Cancer, locus 4), is inactivated in approximately 55% of pancreatic ductal adenocarcinomas, either by mutation with loss of heterozygosity or homozygous deletion.	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (177, 210))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (200, 210))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (109, 126))	('loss', 'NegReg', (236, 240))	('pancreatic ductal adenocarcinomas', 'Disease', (177, 210))	('SMAD4', 'Gene', (69, 74))	('DPC4', 'Gene', (88, 92))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('pancreatic cancer', 'Disease', 'MESH:D010190', (50, 67))	('DPC4', 'Gene', '4089', (88, 92))	('SMAD4', 'Gene', '4089', (69, 74))	('tumor', 'Disease', (25, 30))	('inactivated', 'NegReg', (141, 152))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (109, 126))	('pancreatic cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('mutation', 'Var', (222, 230))	('deletion', 'Var', (273, 281))	('Pancreatic Cancer', 'Disease', (109, 126))
351201	25634752	Tascilar et al immunolabeled a large cohort of surgically resected pancreatic ductal adenocarcinomas for Smad4 and found that the absence of protein expression correlated with poor OS and served as a negative, independent prognostic factor.	('protein', 'Protein', (141, 148))	('absence', 'Var', (130, 137))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (67, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('poor OS', 'Disease', (176, 183))	('pancreatic ductal adenocarcinomas', 'Disease', (67, 100))	('Smad4', 'Gene', (105, 110))	('Smad4', 'Gene', '4089', (105, 110))
351206	25634752	Both Maitra et al and Miyaki et al showed that the loss of Smad4 correlated with progression of colorectal cancer, especially distant metastasis.	('Smad4', 'Gene', (59, 64))	('Smad4', 'Gene', '4089', (59, 64))	('loss', 'Var', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('colorectal cancer', 'Disease', (96, 113))	('distant metastasis', 'CPA', (126, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
351211	25634752	This suggests that loss of SMAD4 is a late event in the pathogenesis of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (72, 97))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (72, 97))	('SMAD4', 'Gene', '4089', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('loss', 'Var', (19, 23))	('SMAD4', 'Gene', (27, 32))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (72, 97))
351223	25634752	However, in other malignancies, the inactivation of Smad4 has been reported to contribute to chemoresistance and may show a similar correlation in esophageal adenocarcinoma.	('Smad4', 'Gene', (52, 57))	('chemoresistance', 'CPA', (93, 108))	('Smad4', 'Gene', '4089', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('malignancies', 'Disease', 'MESH:D009369', (18, 30))	('contribute', 'Reg', (79, 89))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (147, 172))	('esophageal adenocarcinoma', 'Disease', (147, 172))	('malignancies', 'Disease', (18, 30))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (147, 172))	('inactivation', 'Var', (36, 48))
351225	25634752	The loss of Smad4 protein expression is an independent prognostic factor for both shorter TTR and poor OS and correlates with increased propensity for disease recurrence in patients with esophageal adenocarcinoma after surgical resection.	('expression', 'MPA', (26, 36))	('esophageal adenocarcinoma', 'Disease', (187, 212))	('patients', 'Species', '9606', (173, 181))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (187, 212))	('protein', 'Protein', (18, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('Smad4', 'Gene', (12, 17))	('Smad4', 'Gene', '4089', (12, 17))	('poor OS', 'Disease', (98, 105))	('TTR', 'MPA', (90, 93))	('loss', 'Var', (4, 8))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (187, 212))	('shorter', 'NegReg', (82, 89))
351346	25040886	These preliminary results are promising, as they suggest a possible association between dysregulated serum inflammatory molecules and the future development of certain cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('men', 'Species', '9606', (152, 155))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('dysregulated', 'Var', (88, 100))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('serum inflammatory molecules', 'MPA', (101, 129))
351392	25040886	Among patients who went on to develop lung cancer, elevated baseline levels of G-CSF (OR 27.68, 3.59-213.46), GM-CSF (OR 13.33, 2.97-59.89), IL-1Ralpha (OR 8.54, 2.39-30.55), and IL12-p70 (OR 8.33, 2.33-29.83) were most strongly associated with future cancer development.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('lung cancer', 'Disease', (38, 49))	('G-CSF', 'Gene', '1440', (79, 84))	('G-CSF', 'Gene', (79, 84))	('patients', 'Species', '9606', (6, 14))	('elevated', 'PosReg', (51, 59))	('GM-CSF', 'Gene', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('IL-1Ralpha', 'Gene', (141, 151))	('IL-1Ralpha', 'Gene', '3554', (141, 151))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('IL12-p70', 'Var', (179, 187))	('GM-CSF', 'Gene', '1437', (110, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('cancer', 'Disease', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('associated with', 'Reg', (229, 244))	('cancer', 'Disease', (43, 49))	('men', 'Species', '9606', (266, 269))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
351404	25040886	Elevated levels of IL-1Ralpha, IFN-alpha2, FGF-2, and IL-12p70 showed the strongest correlation with future esophageal cancer development.	('IFN-alpha2', 'Gene', '3440', (31, 41))	('FGF-2', 'Gene', '2247', (43, 48))	('esophageal cancer', 'Disease', (108, 125))	('FGF-2', 'Gene', (43, 48))	('IL-12p70', 'Var', (54, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('IL-1Ralpha', 'Gene', (19, 29))	('men', 'Species', '9606', (133, 136))	('IL-1Ralpha', 'Gene', '3554', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('IFN-alpha2', 'Gene', (31, 41))
351405	25040886	Among future lung cancer patients, elevated baseline levels of G-CSF, GM-CSF, IL-1Ralpha, and IL12-p70 showed the strongest association with cancer development.	('G-CSF', 'Gene', '1440', (63, 68))	('G-CSF', 'Gene', (63, 68))	('GM-CSF', 'Gene', (70, 76))	('elevated', 'PosReg', (35, 43))	('cancer', 'Disease', (18, 24))	('lung cancer', 'Disease', (13, 24))	('IL12-p70', 'Var', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('GM-CSF', 'Gene', '1437', (70, 76))	('IL-1Ralpha', 'Gene', '3554', (78, 88))	('cancer', 'Disease', (141, 147))	('IL-1Ralpha', 'Gene', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('patients', 'Species', '9606', (25, 33))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('men', 'Species', '9606', (155, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
351409	25040886	Nonetheless, the biomarkers found to be most strongly correlated with future lung and/or esophageal cancer in this study were either Th1-cell stimulating inflammatory molecules (IL-1Ralpha, IL-12p70, IFN-alpha2) or growth factors (FGF-2, G-CSF, GM-CSF).	('GM-CSF', 'Gene', (245, 251))	('esophageal cancer', 'Disease', (89, 106))	('G-CSF', 'Gene', (238, 243))	('FGF-2', 'Gene', (231, 236))	('IL-1Ralpha', 'Gene', '3554', (178, 188))	('GM-CSF', 'Gene', '1437', (245, 251))	('IFN-alpha2', 'Gene', '3440', (200, 210))	('IFN-alpha2', 'Gene', (200, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('IL-12p70', 'Var', (190, 198))	('lung', 'Disease', (77, 81))	('FGF-2', 'Gene', '2247', (231, 236))	('IL-1Ralpha', 'Gene', (178, 188))	('G-CSF', 'Gene', '1440', (238, 243))
351489	25551641	Non-aspirin NSAIDs (regardless of aspirin use) were significantly associated with a lower risk of alcohol-related, infection-related, obesity-related, and smoking-related cancers (Table 2).	('infection-related', 'Disease', (115, 132))	('alcohol-related', 'Disease', (98, 113))	('Non-aspirin', 'Var', (0, 11))	('alcohol', 'Chemical', 'MESH:D000438', (98, 105))	('obesity', 'Disease', 'MESH:D009765', (134, 141))	('obesity', 'Disease', (134, 141))	('aspirin', 'Chemical', 'MESH:D001241', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('aspirin', 'Chemical', 'MESH:D001241', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('lower', 'NegReg', (84, 89))	('obesity', 'Phenotype', 'HP:0001513', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
351490	25551641	For individual cancers, we also observed that overall NSAIDs were associated with significantly reduced risk of esophageal (HR 0.74, 95% CI 0.58-0.95), stomach (HR 0.73, 95% CI 0.58-0.93), liver (HR 0.59, 95% CI 0.44-0.78), colorectal (HR 0.79, 95% CI 0.73-0.86), prostate (HR 0.94, 95% CI 0.89-0.99), endometrial (HR 0.77, 95% CI 0.65-0.92), and lung (HR 0.89, 95% CI 0.83-0.96) cancers (data not in tables).	('colorectal', 'Disease', (224, 234))	('endometrial', 'Disease', (302, 313))	('stomach', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (380, 387))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('prostate', 'Disease', (264, 272))	('liver', 'Disease', (189, 194))	('lung', 'Disease', (347, 351))	('cancers', 'Disease', (15, 22))	('cancers', 'Disease', (380, 387))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (380, 387))	('NSAIDs', 'Var', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal', 'Disease', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('reduced', 'NegReg', (96, 103))
351492	25551641	Non-aspirin was associated with reduced risk of cancers of the esophagus (HR 0.74, 95% CI 0.62-0.89), stomach (HR 0.70, 95% CI 0.58-0.84), pancreas (HR 0.87, 95% CI 0.77-0.98), colorectum (HR 0.75, 95% CI 0.71-0.80), head and neck (HR 0.87, 95% CI 0.77-0.97), lung (HR 0.94, 95% CI 0.89-0.99), urinary bladder (HR 0.88, 95% CI 0.81-0.95), and myeloid monocytic leukemia (HR 0.77, 95% CI 0.63-0.94), prostate (HR 0.94, 95% CI 0.91-0.97), and endometrium (HR 0.87, 95% CI 0.76-1.00) (data not in tables).	('prostate', 'Disease', (399, 407))	('Non-aspirin', 'Var', (0, 11))	('myeloid monocytic leukemia', 'Disease', (343, 369))	('myeloid monocytic leukemia', 'Phenotype', 'HP:0012324', (343, 369))	('myeloid monocytic leukemia', 'Disease', 'MESH:D007951', (343, 369))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('reduced', 'NegReg', (32, 39))	('aspirin', 'Chemical', 'MESH:D001241', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('pancreas', 'Disease', (139, 147))	('cancers of the esophagus', 'Disease', (48, 72))	('leukemia', 'Phenotype', 'HP:0001909', (361, 369))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (48, 72))	('urinary bladder', 'Disease', (294, 309))	('lung', 'Disease', (260, 264))	('pancreas', 'Disease', 'MESH:D010190', (139, 147))	('endometrium', 'Disease', (441, 452))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (48, 72))	('colorectum', 'Disease', (177, 187))	('stomach', 'Disease', (102, 109))
351502	25551641	However, cancers of the esophagus, stomach, pancreas, colorectum, endometrium, head and neck, urinary bladder, leukemia, and NHL all had significant inverse dose response trend with non-aspirin NSAD use compared to non-use.	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('stomach', 'Disease', (35, 42))	('endometrium', 'Disease', (66, 77))	('cancers of the esophagus', 'Disease', (9, 33))	('pancreas', 'Disease', (44, 52))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (9, 33))	('urinary bladder', 'Disease', (94, 109))	('aspirin', 'Chemical', 'MESH:D001241', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('pancreas', 'Disease', 'MESH:D010190', (44, 52))	('leukemia', 'Disease', (111, 119))	('leukemia', 'Phenotype', 'HP:0001909', (111, 119))	('leukemia', 'Disease', 'MESH:D007938', (111, 119))	('NHL', 'Disease', (125, 128))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (9, 33))	('non-aspirin', 'Var', (182, 193))	('colorectum', 'Disease', (54, 64))
351512	25551641	Interestingly, the frequency of use of anti-cholesterol medication was significantly associated with excess overall cancer risk (HR 1.028, 95% CI 1.024-1.033), inflammation-related (HR 1.027, 95% CI 1.020-1.033), alcohol-related (HR 1.032, 95% CI 1.018-1.046), and smoking-related cancers (HR 1.055, 95% CI 1.047-1.063).	('alcohol-related', 'Disease', (213, 228))	('excess', 'PosReg', (101, 107))	('cholesterol', 'Chemical', 'MESH:D002784', (44, 55))	('inflammation', 'Disease', 'MESH:D007249', (160, 172))	('inflammation', 'Disease', (160, 172))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('alcohol', 'Chemical', 'MESH:D000438', (213, 220))	('anti-cholesterol', 'Var', (39, 55))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancers', 'Disease', (281, 288))
351518	25551641	Non-aspirin NSAID use was associated with lower risk of inflammation-related, alcohol-related, infection-related, obesity-related, smoking-related, head and neck, esophageal, stomach, pancreas, colorectal, lung, urinary bladder, endometrial and prostate cancers, and myeloid monocytic leukemia.	('endometrial and prostate cancers', 'Disease', 'MESH:D016889', (229, 261))	('Non-aspirin', 'Var', (0, 11))	('inflammation', 'Disease', (56, 68))	('leukemia', 'Phenotype', 'HP:0001909', (285, 293))	('pancreas', 'Disease', 'MESH:D010190', (184, 192))	('obesity', 'Disease', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('lung', 'Disease', (206, 210))	('alcohol-related', 'Disease', (78, 93))	('alcohol', 'Chemical', 'MESH:D000438', (78, 85))	('lower', 'NegReg', (42, 47))	('aspirin', 'Chemical', 'MESH:D001241', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('esophageal', 'Disease', (163, 173))	('obesity', 'Disease', 'MESH:D009765', (114, 121))	('myeloid monocytic leukemia', 'Disease', (267, 293))	('myeloid monocytic leukemia', 'Phenotype', 'HP:0012324', (267, 293))	('myeloid monocytic leukemia', 'Disease', 'MESH:D007951', (267, 293))	('prostate cancer', 'Phenotype', 'HP:0012125', (245, 260))	('stomach', 'Disease', (175, 182))	('pancreas', 'Disease', (184, 192))	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('prostate cancers', 'Phenotype', 'HP:0012125', (245, 261))	('colorectal', 'Disease', (194, 204))	('obesity', 'Phenotype', 'HP:0001513', (114, 121))	('urinary bladder', 'Disease', (212, 227))
351521	25551641	Both aspirin and non-aspirin NSAID use were associated with lower risk of all inflammation-related, alcohol-related, infection-related, obesity-related, and smoking-related cancers, and individual cancers including esophageal, stomach, liver, colorectal, endometrial, and lung cancers.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('aspirin', 'Chemical', 'MESH:D001241', (21, 28))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('inflammation', 'Disease', (78, 90))	('lung cancers', 'Disease', 'MESH:D008175', (272, 284))	('endometrial', 'Disease', (255, 266))	('aspirin', 'Chemical', 'MESH:D001241', (5, 12))	('lower', 'NegReg', (60, 65))	('stomach', 'Disease', (227, 234))	('liver', 'Disease', (236, 241))	('lung cancers', 'Disease', (272, 284))	('obesity', 'Disease', (136, 143))	('alcohol-related', 'Disease', (100, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (272, 283))	('lung cancers', 'Phenotype', 'HP:0100526', (272, 284))	('alcohol', 'Chemical', 'MESH:D000438', (100, 107))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('infection-related', 'Disease', (117, 134))	('obesity', 'Disease', 'MESH:D009765', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancers', 'Disease', (173, 180))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancers', 'Disease', (197, 204))	('cancers', 'Disease', (277, 284))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('inflammation', 'Disease', 'MESH:D007249', (78, 90))	('colorectal', 'Disease', (243, 253))	('non-aspirin', 'Var', (17, 28))	('esophageal', 'Disease', (215, 225))	('obesity', 'Phenotype', 'HP:0001513', (136, 143))
351533	25551641	A study of the effect of aspirin in the presence of Helicobacter pylori revealed that aspirin increases Helicobacter pylori-induced apoptosis and diminish Helicobacter pylori-induced hyperplasia.	('apoptosis', 'CPA', (132, 141))	('diminish', 'NegReg', (146, 154))	('hyperplasia', 'Disease', (183, 194))	('Helicobacter pylori', 'Species', '210', (155, 174))	('Helicobacter pylori', 'Species', '210', (52, 71))	('aspirin', 'Chemical', 'MESH:D001241', (86, 93))	('aspirin', 'Chemical', 'MESH:D001241', (25, 32))	('aspirin', 'Var', (86, 93))	('Helicobacter pylori', 'Species', '210', (104, 123))	('increases', 'PosReg', (94, 103))	('hyperplasia', 'Disease', 'MESH:D006965', (183, 194))	('Helicobacter', 'Disease', (104, 116))	('Helicobacter', 'Disease', (155, 167))
351583	24088706	Dysregulation of MAL has also been implicated in several other malignancies, including breast, cervical and HNSCC cancers.	('MAL', 'Gene', '4118', (17, 20))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('HNSCC cancers', 'Disease', 'MESH:D000077195', (108, 121))	('Dysregulation', 'Var', (0, 13))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('breast', 'Disease', (87, 93))	('MAL', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('malignancies', 'Disease', (63, 75))	('cervical', 'Disease', (95, 103))	('implicated', 'Reg', (35, 45))	('HNSCC cancers', 'Disease', (108, 121))
351585	24088706	Aberrant methylation of promoter CpG islands upstream of tumor suppressor genes is now well-established as a major mechanism of gene inactivation in human tumorigenesis, including ESCC and EAC, where it plays an important role in pathogenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('inactivation', 'NegReg', (133, 145))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (155, 160))	('human', 'Species', '9606', (149, 154))	('EAC', 'Phenotype', 'HP:0011459', (189, 192))	('Aberrant methylation', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('EAC', 'Disease', (189, 192))	('ESCC', 'Disease', (180, 184))
351586	24088706	Aberrant promoter methylation of MAL is indeed associated with inactivation of its expression in breast and colorectal cancers.	('Aberrant', 'Var', (0, 8))	('inactivation', 'NegReg', (63, 75))	('colorectal cancers', 'Disease', (108, 126))	('MAL', 'Gene', (33, 36))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('breast', 'Disease', (97, 103))	('promoter', 'MPA', (9, 17))	('MAL', 'Gene', '4118', (33, 36))	('colorectal cancers', 'Disease', 'MESH:D015179', (108, 126))	('expression', 'MPA', (83, 93))	('associated', 'Reg', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
351587	24088706	Therefore, we hypothesized that MAL might be inactivated via promoter hypermethylation in human esophageal cancers, and that hypermethylation of MAL could constitute an early event in the genesis of EAC.	('MAL', 'Gene', (32, 35))	('MAL', 'Gene', '4118', (145, 148))	('hypermethylation', 'Var', (125, 141))	('inactivated', 'NegReg', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancers', 'Disease', (96, 114))	('EAC', 'Phenotype', 'HP:0011459', (199, 202))	('human', 'Species', '9606', (90, 95))	('promoter hypermethylation', 'Var', (61, 86))	('esophageal cancers', 'Disease', 'MESH:D004938', (96, 114))	('MAL', 'Gene', '4118', (32, 35))	('MAL', 'Gene', (145, 148))	('EAC', 'Disease', (199, 202))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
351593	24088706	The mean NMV of MAL was significantly higher in BE (0.0681, p = 0000001), LGD (0.0945, p = 000004), HGD (0.0549, p = 0000001), D (0.0737, p = 00000001), EAC (0.0459, p = 0.000002), and ESCC (0.0042, p = 0.009) than in NE (0.0001; Student's t-test).	('MAL', 'Gene', (16, 19))	('0.0945', 'Var', (79, 85))	('NMV', 'MPA', (9, 12))	('0.0549', 'Var', (105, 111))	('MAL', 'Gene', '4118', (16, 19))	('higher', 'PosReg', (38, 44))	('BE', 'Phenotype', 'HP:0100580', (48, 50))	('0.0681', 'Var', (52, 58))	('EAC', 'Phenotype', 'HP:0011459', (153, 156))
351599	24088706	Similarly, segment lengths of BEs with hypermethylated MAL promoters (mean = 5.87 cm) were significantly greater than segment lengths of BEs with unmethylated MAL promoters (mean = 2.60 cm; p = 0.005, Student's t-test; Figure 3B).	('MAL', 'Gene', '4118', (55, 58))	('MAL', 'Gene', '4118', (159, 162))	('BE', 'Phenotype', 'HP:0100580', (30, 32))	('hypermethylated', 'Var', (39, 54))	('BEs', 'Chemical', 'MESH:C012210', (137, 140))	('MAL', 'Gene', (55, 58))	('BE', 'Phenotype', 'HP:0100580', (137, 139))	('MAL', 'Gene', (159, 162))	('BEs', 'Chemical', 'MESH:C012210', (30, 33))	('greater', 'PosReg', (105, 112))	('segment lengths', 'CPA', (11, 26))
351602	24088706	After 5-Aza-dC treatment, the NMV of MAL was diminished (0.4264, 0.1647 and 0.1414 on day 0, 2 and 4, respectively), while the mRNA level of MAL(0.0184 on day 0) was increased on day 2 (0.0643) and further increased on day 4 (0.0773, Figure 4).	('MAL', 'Gene', '4118', (141, 144))	('MAL', 'Gene', (37, 40))	('increased', 'PosReg', (206, 215))	('0.1414', 'Var', (76, 82))	('5-Aza-dC', 'Chemical', '-', (6, 14))	('increased', 'PosReg', (166, 175))	('MAL', 'Gene', '4118', (37, 40))	('diminished', 'NegReg', (45, 55))	('0.1647', 'Var', (65, 71))	('MAL', 'Gene', (141, 144))
351611	24088706	Whether hypermethylation of the MAL gene was a common event in esophageal carcinoma was thus still unknown.	('MAL', 'Gene', (32, 35))	('hypermethylation', 'Var', (8, 24))	('esophageal carcinoma', 'Disease', (63, 83))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (63, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('MAL', 'Gene', '4118', (32, 35))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (63, 83))
351618	24088706	These results suggest that hypermethylation of MAL may represent an early epigenetic event in these subjects, and that this event is highly prevalent in human esophageal adenocarcinomas.	('hypermethylation', 'Var', (27, 43))	('esophageal adenocarcinomas', 'Disease', (159, 185))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (159, 184))	('MAL', 'Gene', (47, 50))	('human', 'Species', '9606', (153, 158))	('prevalent', 'Reg', (140, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('MAL', 'Gene', '4118', (47, 50))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (159, 185))
351623	24088706	In a prospective cohort study of 309 Barrett's patients followed in the Seattle Barrett's Esophagus Project, a strong trend was observed, with a 5 cm difference in length associated with a 1.7-fold increase in cancer risk (95% CI, 0.8-3.8-fold), when patients with HGD at entrance were excluded.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (80, 99))	('patients', 'Species', '9606', (47, 55))	('5 cm', 'Var', (145, 149))	("Seattle Barrett's Esophagus", 'Disease', (72, 99))	("Seattle Barrett's Esophagus", 'Disease', 'MESH:D001471', (72, 99))	('patients', 'Species', '9606', (251, 259))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
351629	24088706	These experiments revealed that reversal of methylation and restoration of MAL expression were induced in OE33 cells by 5-Aza-dC treatment (Figure 4).	('MAL', 'Gene', (75, 78))	('5-Aza-dC', 'Var', (120, 128))	('MAL', 'Gene', '4118', (75, 78))	('5-Aza-dC', 'Chemical', '-', (120, 128))	('methylation', 'MPA', (44, 55))
351633	24088706	In conclusion, the current study shows that hypermethylation of the MAL gene promoter, leading to gene silencing, is a common event in human Barrett's-associated EAC and is associated with clinical risk factors of neoplastic progression.	("Barrett's-associated EAC", 'Disease', (141, 165))	('EAC', 'Disease', (162, 165))	('clinical', 'Species', '191496', (189, 197))	('MAL', 'Gene', (68, 71))	('human', 'Species', '9606', (135, 140))	('gene', 'MPA', (98, 102))	('hypermethylation', 'Var', (44, 60))	('associated', 'Reg', (173, 183))	('EAC', 'Phenotype', 'HP:0011459', (162, 165))	('silencing', 'NegReg', (103, 112))	('MAL', 'Gene', '4118', (68, 71))
351722	21372346	It has also been suggested that, as with sclerotherapy, variceal ligation may worsen the severity of portal hypertensive gastropathie.	('hypertensive gastropathie', 'Disease', 'MESH:D006973', (108, 133))	('variceal ligation', 'Var', (56, 73))	('portal hypertensive', 'Phenotype', 'HP:0001409', (101, 120))	('worsen', 'NegReg', (78, 84))	('hypertensive gastropathie', 'Disease', (108, 133))
351735	16451857	Previous studies of dry cleaners, primarily from the United States, indicated that exposure to tetrachloroethylene may cause an increased risk of cancer of the esophagus and cervix uteri and of non-Hodgkin lymphoma (NHL).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('NHL', 'Disease', (216, 219))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (198, 214))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (194, 214))	('tetrachloroethylene', 'Var', (95, 114))	('NHL', 'Disease', 'MESH:D008228', (216, 219))	('cervix uteri', 'Phenotype', 'HP:0000139', (174, 186))	('lymphoma', 'Phenotype', 'HP:0002665', (206, 214))	('cancer of the esophagus', 'Phenotype', 'HP:0100751', (146, 169))	('non-Hodgkin lymphoma', 'Disease', (194, 214))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (194, 214))	('tetrachloroethylene', 'Chemical', 'MESH:D013750', (95, 114))
351901	32359209	When omega = 1/k, it was assumed that all causes had contributed equally to the death.	('death', 'Disease', 'MESH:D003643', (80, 85))	('death', 'Disease', (80, 85))	('omega = 1/k', 'Var', (5, 16))
351994	32195194	However, cancer cells could evade immune surveillance through various mechanisms, including faulty recognition of neoantigens, inhibition of T-cell infiltration and suppression of effector T cells.	('evade', 'NegReg', (28, 33))	('cancer', 'Disease', (9, 15))	('faulty', 'Var', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('recognition', 'MPA', (99, 110))	('T-cell infiltration', 'CPA', (141, 160))	('neoantigens', 'Protein', (114, 125))	('inhibition', 'NegReg', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
351995	32195194	ICIs, especially programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, have demonstrated clinical benefit in multiple cancers and generated tremendous interest.	('multiple cancers', 'Disease', (125, 141))	('inhibitors', 'Var', (75, 85))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('PD-1', 'Gene', (63, 67))	('benefit', 'PosReg', (114, 121))	('PD-1', 'Gene', '5133', (63, 67))	('multiple cancers', 'Disease', 'MESH:D009369', (125, 141))	('PD-L1', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('PD-L1', 'Gene', '29126', (68, 73))
352036	32195194	There was a tendency toward better disease-free survival (DFS) in patients reached pCR in the primary tumor (HR = 0.33, p = 0.1).	('better', 'PosReg', (28, 34))	('primary tumor', 'Disease', (94, 107))	('CR', 'Chemical', '-', (84, 86))	('primary tumor', 'Disease', 'MESH:D009369', (94, 107))	('disease-free survival', 'CPA', (35, 56))	('pCR', 'Var', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('patients', 'Species', '9606', (66, 74))
352092	32195194	Future results will provide more safety and efficacy data on the combination of PD-1/PD-L1 inhibitors and CTLA-4 inhibitors.	('inhibitors', 'Var', (91, 101))	('CTLA-4', 'Gene', '1493', (106, 112))	('PD-L1', 'Gene', (85, 90))	('PD-L1', 'Gene', '29126', (85, 90))	('PD-1', 'Gene', (80, 84))	('PD-1', 'Gene', '5133', (80, 84))	('CTLA-4', 'Gene', (106, 112))
352149	32195194	The mOS of camrelizumab group was better than the chemotherapy group (8.3 vs. 6.2 months; HR = 0.71, 95% CI: 0.57-0.87, p = 0.001).	('camrelizumab', 'Var', (11, 23))	('camrelizumab', 'Chemical', '-', (11, 23))	('mOS', 'Gene', '17451', (4, 7))	('mOS', 'Gene', (4, 7))
352155	32195194	Generous clinical trials are investigating the role of PD-1/PD-L1 inhibitors in advanced EC as subsequent treatment (durvalumab: NCT01938612, NCT02639065; pembrolizumab: NCT02971956, NCT02998268; CS1001: NCT03312842, NCT03744403) or as second-line treatment (sintilimab: NCT03116152; tislelizumab: NCT03430843, toripalimab: NCT03474640; pembrolizumab: NCT03933449).	('toripalimab', 'Chemical', '-', (311, 322))	('sintilimab', 'Chemical', '-', (259, 269))	('NCT03744403', 'Var', (217, 228))	('pembrolizumab', 'Chemical', 'MESH:C582435', (337, 350))	('pembrolizumab', 'Chemical', 'MESH:C582435', (155, 168))	('PD-1', 'Gene', (55, 59))	('PD-L1', 'Gene', (60, 65))	('NCT02998268', 'Var', (183, 194))	('PD-1', 'Gene', '5133', (55, 59))	('durvalumab', 'Chemical', 'MESH:C000613593', (117, 127))	('PD-L1', 'Gene', '29126', (60, 65))	('tislelizumab', 'Chemical', '-', (284, 296))
352162	32195194	The combination of PD-1/PD-L1 inhibitors and anti-LAG-3 antibody is under investigation now (NCT03044613, NCT02460224) and is expected to produce a synergistic effect.	('produce', 'Reg', (138, 145))	('NCT03044613', 'Var', (93, 104))	('NCT02460224', 'Var', (106, 117))	('LAG-3', 'Gene', (50, 55))	('LAG-3', 'Gene', '3902', (50, 55))	('PD-L1', 'Gene', (24, 29))	('PD-1', 'Gene', (19, 23))	('combination', 'Interaction', (4, 15))	('PD-1', 'Gene', '5133', (19, 23))	('PD-L1', 'Gene', '29126', (24, 29))
352169	32195194	Epacadostat is an oral IDO inhibitor and is being investigated with PD-1/PD-L1 inhibitors (NCT03592407, NCT03277352).	('PD-1', 'Gene', '5133', (68, 72))	('NCT03592407', 'Var', (91, 102))	('IDO', 'Gene', '3620', (23, 26))	('PD-L1', 'Gene', '29126', (73, 78))	('IDO', 'Gene', (23, 26))	('NCT03277352', 'Var', (104, 115))	('PD-1', 'Gene', (68, 72))	('PD-L1', 'Gene', (73, 78))
352170	32195194	There are also novel multi-target antibodies, including SL-279252 (PD-1 and OX40L inhibitor) and INBRX-105 [PD-L1 and 41BB (CD137) inhibitor].	('PD-1', 'Gene', (67, 71))	('PD-L1', 'Gene', (108, 113))	('CD137', 'Gene', (124, 129))	('PD-1', 'Gene', '5133', (67, 71))	('OX40L', 'Gene', (76, 81))	('CD137', 'Gene', '3604', (124, 129))	('PD-L1', 'Gene', '29126', (108, 113))	('SL-279252', 'Chemical', '-', (56, 65))	('41BB', 'Gene', (118, 122))	('OX40L', 'Gene', '7292', (76, 81))	('SL-279252', 'Var', (56, 65))	('41BB', 'Gene', '3604', (118, 122))
352177	32195194	Furthermore, the KEYNOTE-181 trial revealed that in all PD-L1 positive patients, ESCC ones might have better ORR (22.0 vs. 18.0%), mPFS (3.2 vs. 2.1 months), and mOS (10.3 vs. 6.3 months) than EAC ones.	('PD-L1', 'Gene', '29126', (56, 61))	('EAC', 'Phenotype', 'HP:0011459', (193, 196))	('mPFS', 'CPA', (131, 135))	('better', 'PosReg', (102, 108))	('mOS', 'Gene', (162, 165))	('patients', 'Species', '9606', (71, 79))	('positive', 'Var', (62, 70))	('mOS', 'Gene', '17451', (162, 165))	('PD-L1', 'Gene', (56, 61))	('ORR', 'CPA', (109, 112))
352189	32195194	This was also supported by the trial KEYNOTE-181, which showed that pembrolizumab could significantly improve OS compared with chemotherapy in PD-L1 positive (CPS >= 10) EC patients (mOS: 9.3 vs. 6.7 months; HR = 0.69, 95% CI: 0.52-0.93, p = 0.0074).	('PD-L1', 'Gene', '29126', (143, 148))	('improve', 'PosReg', (102, 109))	('patients', 'Species', '9606', (173, 181))	('OS', 'Gene', '17451', (110, 112))	('OS', 'Gene', '17451', (184, 186))	('mOS', 'Gene', (183, 186))	('PD-L1', 'Gene', (143, 148))	('CPS >= 1', 'Gene', '1373', (159, 167))	('CPS >= 1', 'Gene', (159, 167))	('mOS', 'Gene', '17451', (183, 186))	('pembrolizumab', 'Var', (68, 81))	('pembrolizumab', 'Chemical', 'MESH:C582435', (68, 81))
352196	32195194	Furthermore, TILs were also associated with the clinical benefit from PD-1/PD-L1 inhibitors in melanoma.	('PD-L1', 'Gene', (75, 80))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('PD-L1', 'Gene', '29126', (75, 80))	('PD-1', 'Gene', (70, 74))	('PD-1', 'Gene', '5133', (70, 74))	('TILs', 'Var', (13, 17))	('benefit', 'PosReg', (57, 64))
352199	32195194	In another study of patients with melanoma, CD8+, CD3+, and CD45RO+ T-cell densities in pretreatment samples were associated with response to PD-1 inhibitor.	('CD8', 'Gene', (44, 47))	('CD3+', 'Var', (50, 54))	('CD8', 'Gene', '925', (44, 47))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('PD-1', 'Gene', '5133', (142, 146))	('response', 'MPA', (130, 138))	('associated with', 'Reg', (114, 129))	('PD-1', 'Gene', (142, 146))	('patients', 'Species', '9606', (20, 28))	('CD45RO+', 'Var', (60, 67))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))
352201	32195194	TMB is the number of non-synonymous somatic gene mutations (Mb) of sequenced DNA and higher TMB tumors are likely to produce more neoantigens, induce a specific T cell response, and further enhance the anti-tumor immunity.	('produce', 'Reg', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutations', 'Var', (49, 58))	('TMB', 'Chemical', '-', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('induce', 'PosReg', (143, 149))	('tumor', 'Disease', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('neoantigens', 'MPA', (130, 141))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('TMB tumors', 'Disease', 'MESH:D009369', (92, 102))	('T cell', 'MPA', (161, 167))	('TMB tumors', 'Disease', (92, 102))	('enhance', 'PosReg', (190, 197))	('more', 'PosReg', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (207, 212))	('TMB', 'Chemical', '-', (92, 95))
352202	32195194	High TMB correlates with clinical benefit from ICIs in patients with melanoma and NSCLC.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('High', 'Var', (0, 4))	('benefit', 'PosReg', (34, 41))	('patients', 'Species', '9606', (55, 63))	('NSCLC', 'Disease', (82, 87))	('TMB', 'Chemical', '-', (5, 8))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
352207	32195194	In phase Ib/II trial, NCT02915432, chemo-refractory ESSC patients received toripalimab and 11 (23.4%) patients with high TMB (>=12 Mutations/Mb) showed no significant advantage in ORR or OS.	('ESSC', 'Disease', (52, 56))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (102, 110))	('TMB', 'Chemical', '-', (121, 124))	('OS', 'Gene', '17451', (187, 189))	('ORR', 'CPA', (180, 183))	('NCT02915432', 'Var', (22, 33))	('toripalimab', 'Chemical', '-', (75, 86))
352209	32195194	Deficient DNA mismatch repair (dMMR) means a lack of these genes and produce a lot of short repeated sequences in the DNA (microsatellite) and more tumor-specific mutation (higher TMB).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('lack', 'NegReg', (45, 49))	('Deficient', 'Var', (0, 9))	('short repeated sequences', 'Var', (86, 110))	('tumor', 'Disease', (148, 153))	('TMB', 'Chemical', '-', (180, 183))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
352213	32195194	The trial NCT02915432 analyzed the amplification of the chromosome 11q13 region in ESSC patients received toripalimab.	('amplification', 'Var', (35, 48))	('patients', 'Species', '9606', (88, 96))	('ESSC', 'Disease', (83, 87))	('toripalimab', 'Chemical', '-', (106, 117))
352215	32195194	Patients without 11q13 amplification, had considerably better ORR (30.8 vs. 4.2%, p = 0.024) and mPFS (3.7 vs. 2.0 months; HR = 0.47, 95% CI: 0.24-0.91, p = 0.025).	('ORR', 'CPA', (62, 65))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (55, 61))	('11q13 amplification', 'Var', (17, 36))	('mPFS', 'CPA', (97, 101))
352239	30479571	As one of well documented miRNAs, miR-133b has been confirmed to be a tumor suppressor that inhibits the progression of various cancers.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('progression', 'CPA', (105, 116))	('cancers', 'Disease', (128, 135))	('miR-133b', 'Var', (34, 42))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('inhibits', 'NegReg', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
352241	30479571	Previous studies demonstrated that miR-133b could restrain cell invasion and metastasis via targeting EGFR in a variety of cancer cells, including ovarian cancer, non-small-cell lung cancer, and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (167, 189))	('targeting', 'Reg', (92, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('miR-133b', 'Var', (35, 43))	('ovarian cancer', 'Disease', 'MESH:D010051', (147, 161))	('restrain', 'NegReg', (50, 58))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('colorectal cancer', 'Phenotype', 'HP:0003003', (195, 212))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (163, 189))	('cancer', 'Disease', (206, 212))	('ovarian cancer', 'Disease', (147, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('colorectal cancer', 'Disease', 'MESH:D015179', (195, 212))	('EGFR', 'Gene', (102, 106))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancer', 'Disease', (195, 212))	('non-small-cell lung cancer', 'Disease', (163, 189))	('cancer', 'Disease', (123, 129))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (163, 189))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
352242	30479571	However, whether miR-133b can modulate metastases in ESCC through regulating EGFR expression has not been elucidated.	('ESCC', 'Disease', (53, 57))	('expression', 'MPA', (82, 92))	('metastases', 'Disease', (39, 49))	('miR-133b', 'Var', (17, 25))	('modulate', 'Reg', (30, 38))	('metastases', 'Disease', 'MESH:D009362', (39, 49))	('EGFR', 'Gene', (77, 81))
352243	30479571	However, the disorder of gene expression helped the cancer cells to escape anoikis, which resulted in the survival of cancer cells in lymph, blood and facilitated their regional or distant metastasis.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('regional or distant metastasis', 'CPA', (169, 199))	('disorder', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('facilitated', 'PosReg', (151, 162))	('escape anoikis', 'CPA', (68, 82))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
352246	30479571	demonstrated that inducing caspase-mediated anoikis inhibited the progression of hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('caspase-mediated anoikis', 'Protein', (27, 51))	('inducing', 'Var', (18, 26))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('progression', 'CPA', (66, 77))	('hepatocellular carcinoma', 'Disease', (81, 105))	('inhibited', 'NegReg', (52, 61))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))
352279	30479571	To evaluate the role of miR-133b in tumor formation, 5 x 106 KYSE150 and ECa109 cells that infected with lentivirus expressing miR-133b agomir or miR-133b NC (GeneChem, Shanghai, China) were injected subcutaneously into the axilla of nude mice.	('miR-133b', 'Gene', (127, 135))	('ECa109', 'CellLine', 'CVCL:6898', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('miR-133b NC', 'Var', (146, 157))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('nude mice', 'Species', '10090', (234, 243))	('tumor', 'Disease', (36, 41))
352280	30479571	The mice were randomly divided into four groups (n = 5 per group): KYSE150-miR-133b NC, KYSE150-miR-133b agomir, ECa109-miR-133b NC, ECa109-miR-133b agomir.	('mice', 'Species', '10090', (4, 8))	('KYSE150-miR-133b', 'Var', (67, 83))	('KYSE150-miR-133b', 'Var', (88, 104))	('ECa109-miR-133b', 'Var', (133, 148))	('ECa109', 'CellLine', 'CVCL:6898', (113, 119))	('ECa109', 'CellLine', 'CVCL:6898', (133, 139))	('ECa109-miR-133b NC', 'Var', (113, 131))
352290	30479571	Subsequently, the membranes were incubated with 5% skim milk for 1 h to block the non-specific binding and probed with primary antibodies against EGFR (1:2000, Abcam, Cambridge, UK), ITGB4 (1:1000, Abcam), p-FAK (1:1000, Abcam), FAK (1:1000, Abcam), Fibronectin (1:1000, Abcam), Vimentin (1:1000, Cell Signaling Technology, Danvers, MA, USA), N-cadherin (1:1000, Cell Signaling Technology), E-cadherin (1:1000, Cell Signaling Technology), matrix metalloproteinase 2 (MMP-2, 1:1000, Proteintech, Rosemont, Illinois, USA), MMP-9 (1:1000, Proteintech), Grb2 (1:1000, Proteintech), p-AKTThr308 (1:1000, Cell Signaling Technology), p-AKTSer473 (1:2000, Cell Signaling Technology), AKT (1:1000, Cell Signaling Technology), p-ERK1/2 (1:1000, Abcam), ERK1/2 (1:1000, Abcam), GAPDH (1:5000, Proteintech) at 4  C overnight, respectively.	('Vimentin', 'Gene', (279, 287))	('AKT', 'Gene', (580, 583))	('matrix metalloproteinase 2', 'Gene', '4313', (439, 465))	('matrix metalloproteinase 2', 'Gene', (439, 465))	('Fibronectin', 'Gene', '2335', (250, 261))	('AKT', 'Gene', '207', (676, 679))	('MMP-9', 'Gene', '4318', (521, 526))	('GAPDH', 'Gene', (767, 772))	('MMP-9', 'Gene', (521, 526))	('AKT', 'Gene', '207', (629, 632))	('Fibronectin', 'Gene', (250, 261))	('MMP-2', 'Gene', (467, 472))	('AKT', 'Gene', '207', (580, 583))	('N-cadherin', 'Gene', (343, 353))	('FAK', 'Gene', (208, 211))	('N-cadherin', 'Gene', '1000', (343, 353))	('1:1000', 'Var', (727, 733))	('1:1000', 'Var', (751, 757))	('E-cadherin', 'Gene', (391, 401))	('E-cadherin', 'Gene', '999', (391, 401))	('AKT', 'Gene', (676, 679))	('FAK', 'Gene', '5747', (208, 211))	('ERK1/2', 'Gene', (743, 749))	('FAK', 'Gene', (229, 232))	('ERK1/2', 'Gene', (719, 725))	('AKT', 'Gene', (629, 632))	('Vimentin', 'Gene', '7431', (279, 287))	('ERK1/2', 'Gene', '5595;5594', (743, 749))	('ERK1/2', 'Gene', '5595;5594', (719, 725))	('GAPDH', 'Gene', '2597', (767, 772))	('MMP-2', 'Gene', '4313', (467, 472))	('FAK', 'Gene', '5747', (229, 232))
352297	30479571	As expected, the protein levels of EGFR, ITGB4, and p-FAK in KYSE150, KYSE30, and ECa109 cells were distinctly enhanced (Fig.	('FAK', 'Gene', (54, 57))	('FAK', 'Gene', '5747', (54, 57))	('ITGB4', 'Gene', (41, 46))	('EGFR', 'Gene', (35, 39))	('enhanced', 'PosReg', (111, 119))	('KYSE150', 'Var', (61, 68))	('KYSE30', 'Var', (70, 76))	('ECa109', 'CellLine', 'CVCL:6898', (82, 88))	('protein levels', 'MPA', (17, 31))
352304	30479571	The results indicated that KYSE150 and ECa109 cells that were transfected with miR-133b agomir or shEGFR formed much fewer colonies, compared with the cells in miR-133b NC or shNC group.	('miR-133b', 'Gene', (79, 87))	('ECa109', 'CellLine', 'CVCL:6898', (39, 45))	('shEGFR', 'Var', (98, 104))	('colonies', 'CPA', (123, 131))	('fewer', 'NegReg', (117, 122))
352312	30479571	6a-d, miR-133b agomir or shEGFR caused obvious decrease in the protein levels of ITGB4, Grb2, p-FAK, p-AKTThr308, p-ATKSer473, and p-ERK1/2 in KYSE150 and ECa109 cells.	('AKT', 'Gene', '207', (103, 106))	('protein levels', 'MPA', (63, 77))	('ECa109', 'CellLine', 'CVCL:6898', (155, 161))	('miR-133b', 'Var', (6, 14))	('decrease', 'NegReg', (47, 55))	('AKT', 'Gene', (103, 106))	('FAK', 'Gene', (96, 99))	('FAK', 'Gene', '5747', (96, 99))	('Grb2', 'Protein', (88, 92))	('ITGB4', 'Gene', (81, 86))	('p-ATKSer473', 'Var', (114, 125))	('ERK1/2', 'Gene', '5595;5594', (133, 139))	('ERK1/2', 'Gene', (133, 139))
352316	30479571	The results suggested that the tumor volume and weight were decreased in mice that were injected with miR-133b overexpressing KYSE150 and ECa109 cells (Fig.	('decreased', 'NegReg', (60, 69))	('ECa109', 'CellLine', 'CVCL:6898', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mice', 'Species', '10090', (73, 77))	('tumor', 'Disease', (31, 36))	('KYSE150', 'Var', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
352319	30479571	The above results suggested that miR-133b inhibited the tumor growth and lung metastasis of ESCC cells in nude mice in vivo.	('miR-133b', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('nude mice', 'Species', '10090', (106, 115))	('inhibited', 'NegReg', (42, 51))	('lung metastasis of', 'CPA', (73, 91))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
352329	30479571	In this study, the protein levels of MMP-2 and MMP-9 in ESCC cells were suppressed by miR-133b overexpression and EGFR silencing.	('MMP-9', 'Gene', '4318', (47, 52))	('silencing', 'Var', (119, 128))	('MMP-2', 'Gene', '4313', (37, 42))	('protein levels', 'MPA', (19, 33))	('EGFR', 'Gene', (114, 118))	('overexpression', 'PosReg', (95, 109))	('miR-133b', 'Gene', (86, 94))	('suppressed', 'NegReg', (72, 82))	('MMP-9', 'Gene', (47, 52))	('MMP-2', 'Gene', (37, 42))
352330	30479571	It is recognized that anoikis resistance facilitates metastasis via triggering EMT.	('anoikis', 'Var', (22, 29))	('facilitates', 'PosReg', (41, 52))	('EMT', 'Gene', (79, 82))	('EMT', 'Gene', '3702', (79, 82))	('metastasis', 'CPA', (53, 63))
352334	30479571	According to the present study, the protein levels of Fibronection, Vimentin, and N-cadherin were down-regulated, while E-cadherin level was up-regulated in ESCC cells by miR-133b agomir or shEGFR treatment via targeting modulation of EGFR.	('Vimentin', 'Gene', '7431', (68, 76))	('miR-133b', 'Var', (171, 179))	('N-cadherin', 'Gene', (82, 92))	('up-regulated', 'PosReg', (141, 153))	('E-cadherin', 'Gene', (120, 130))	('protein levels of Fibronection', 'MPA', (36, 66))	('E-cadherin', 'Gene', '999', (120, 130))	('N-cadherin', 'Gene', '1000', (82, 92))	('EGFR', 'Gene', (235, 239))	('Vimentin', 'Gene', (68, 76))	('down-regulated', 'NegReg', (98, 112))
352346	30479571	Moreover, miR-133b inhibited the metastases of ESCC by regulating anoikis and anchorage-independent growth via targeting EGFR in vitro and in vivo.	('inhibited', 'NegReg', (19, 28))	('anchorage-independent growth', 'CPA', (78, 106))	('anoikis', 'CPA', (66, 73))	('metastases', 'Disease', (33, 43))	('miR-133b', 'Var', (10, 18))	('ESCC', 'Disease', (47, 51))	('EGFR', 'Gene', (121, 125))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('targeting', 'Reg', (111, 120))	('regulating', 'Reg', (55, 65))
352378	29361818	In order to potentiate the clinical use of curcumin, several research groups synthesized different curcumin analogues by molecular structure modifications, e.g., PGV-0/PGV-1 and EF31/UBS109 with respective anti-tumor effects in breast and pancreatic cancers.	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('curcumin', 'Chemical', 'MESH:D003474', (43, 51))	('breast', 'Disease', (228, 234))	('curcumin', 'Chemical', 'MESH:D003474', (99, 107))	('pancreatic cancers', 'Disease', (239, 257))	('pancreatic cancers', 'Disease', 'MESH:D010190', (239, 257))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('EF31/UBS109', 'Var', (178, 189))	('PGV-0/PGV-1', 'Gene', (162, 173))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (239, 257))
352433	29361818	To examine whether structural modifications of curcumin could enhance its anti-tumor effects in ESCC, we synthesized eight curcumin analogues (SSC-3, SSC-5, SSC-6, SSC-8, SSC-9, SSC-10, SSC-19, and SSC-20) (Fig.	('tumor', 'Disease', (79, 84))	('curcumin', 'Chemical', 'MESH:D003474', (123, 131))	('enhance', 'PosReg', (62, 69))	('curcumin', 'Chemical', 'MESH:D003474', (47, 55))	('SSC-5', 'Chemical', '-', (150, 155))	('ESCC', 'Disease', (96, 100))	('modifications', 'Var', (30, 43))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
352436	29361818	Among the eight analogues, SSC-5 elicited the best antitumor effect, such that more than 10-fold reduction in the IC50 was detected compared to curcumin (SLMT-1, 11.68-fold; HKESC-2, 27.98-fold; KYSE-270, 11.93-fold) (Table 1).	('reduction', 'NegReg', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SSC-5', 'Var', (27, 32))	('tumor', 'Disease', (55, 60))	('IC50', 'MPA', (114, 118))	('curcumin', 'Chemical', 'MESH:D003474', (144, 152))	('HKESC-2', 'CellLine', 'CVCL:D571', (174, 181))	('SSC-5', 'Chemical', '-', (27, 32))
352438	29361818	To consolidate the above finding, SSC-5 and SSC-19 were subjected to a second round of MTT cell proliferation assay in an additional panel of ESCC cell lines (HKESC-1, KYSE-150, KYSE-180, KYSE-410, and KYSE-450).	('KYSE-410', 'Var', (188, 196))	('KYSE-450', 'Var', (202, 210))	('HKESC-1', 'CellLine', 'CVCL:D568', (159, 166))	('MTT', 'Chemical', 'MESH:C070243', (87, 90))	('SSC-5', 'Chemical', '-', (34, 39))
352441	29361818	In SLMT-1 and KYSE-450 cells treated with SSC-5 and SSC-19, an induction of apoptosis as indicated by an increase in the percentage of cells in the sub-G1 phase, as well as a cell cycle arrest at the G2/M phase were demonstrated using flow cytometry (Fig.	('SSC-5', 'Var', (42, 47))	('SSC-19', 'Var', (52, 58))	('increase', 'PosReg', (105, 113))	('cell cycle arrest at the G2/M phase', 'CPA', (175, 210))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (175, 192))	('apoptosis', 'CPA', (76, 85))	('SSC-5', 'Chemical', '-', (42, 47))
352472	29361818	Its anti-tumor effects are mediated by different molecules and pathways, such as calcium homeostasis disruption, nuclear factor kappaB signaling inhibition, and DNA methylation modulation.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('calcium homeostasis disruption', 'MPA', (81, 111))	('calcium', 'Chemical', 'MESH:D002118', (81, 88))	('DNA', 'MPA', (161, 164))	('tumor', 'Disease', (9, 14))	('modulation', 'Var', (177, 187))	('nuclear', 'MPA', (113, 120))	('inhibition', 'NegReg', (145, 155))
352541	29058363	The four trocars were placed in the third (phi5 mm, port named S, surgeon) and sixth/seventh (phi10 mm, port named C, camera) intercostal spaces of the mid-axillary line, and the sixth (phi5 mm, port named E, exchange) and eighth/ninth intercostal (phi10 mm, named A, assistant) spaces of the subscapular line.	('eighth', 'Disease', 'MESH:D061285', (223, 229))	('phi10 mm', 'Var', (94, 102))	('eighth', 'Disease', (223, 229))
352545	29058363	Five ports were arranged: the subxiphoid (phi10 mm, port named A1, assistant 1); the right subcostal (phi5 mm, port named S2, surgeon 2); the right upper belly button on the clavicle midline (phi12 mm, port named S1, surgeon 1); and the left symmetrical to port S1 (phi5 mm, port named A2, assistant 2); and umbilicus (phi10 mm, port named C, camera) (Fig 2).	('phi12', 'Var', (192, 197))	('A2, assistant 2', 'Gene', '23545', (286, 301))	('A1, assistant 1', 'Gene', '597', (63, 78))	('S2, surgeon 2', 'Gene', '5708', (122, 135))	('phi10 mm', 'Var', (319, 327))	('S1, surgeon 1', 'Gene', '5707', (213, 226))	('phi10 mm', 'Var', (42, 50))
352569	29058363	To our knowledge, six meta-analyses comparing MIE to OE have been conducted.7, 10, 11, 12, 13, 14 Overall, MIE was associated with dramatically decreased pulmonary and cardiovascular complications, and a low incidence of chylothorax, while the incidence of RLN paralysis slightly increased, and anastomotic leakage incidence was almost the same.	('chylothorax', 'Phenotype', 'HP:0010310', (221, 232))	('paralysis', 'Disease', 'MESH:D010243', (261, 270))	('MIE', 'Var', (107, 110))	('MIE', 'Chemical', '-', (107, 110))	('MIE', 'Chemical', '-', (46, 49))	('decreased pulmonary and cardiovascular complications', 'Disease', 'MESH:D002318', (144, 196))	('paralysis', 'Phenotype', 'HP:0003470', (261, 270))	('chylothorax', 'Disease', (221, 232))	('paralysis', 'Disease', (261, 270))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (168, 196))	('OE', 'Chemical', '-', (53, 55))
352591	27682879	The previous clinical trials, which established NACRT and surgery as the current standard for locally advanced esophageal cancer, mostly included the patients with cM0, but not cM1a/b, stage according to the 6th edition of AJCC staging system.	('NACRT', 'Chemical', '-', (48, 53))	('cM0', 'Var', (164, 167))	('esophageal cancer', 'Disease', (111, 128))	('patients', 'Species', '9606', (150, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
352616	27682879	Among 168 patients who underwent surgery, 2-year rates of PFS and OS based on yp-stages were 58.8% and 79.8% in ypT0N0, 61.0% and 76.3% in ypT0N+, 48.7% and 66.3% in ypT+N0, and 22.7% and 55.4% in ypT+N+, respectively (Figure 2).	('ypT0N+', 'Var', (139, 145))	('OS', 'Chemical', '-', (66, 68))	('pT+N0', 'Chemical', '-', (167, 172))	('patients', 'Species', '9606', (10, 18))	('ypT0N0', 'Var', (112, 118))	('PFS', 'Disease', (58, 61))
352619	27682879	The significantly favorable factors on loco-regional control (LRC) at 2 years were negative surgical margin (p < 0.001), ypT0 (p = 0.001), cT1-2 (p = 0.040), pCR (p = 0.007), and ypN0 (p = 0.021).	('loco-regional control', 'CPA', (39, 60))	('ypT0', 'Var', (121, 125))	('pCR', 'Var', (158, 161))	('cT1-2', 'Gene', '266740', (139, 144))	('negative', 'NegReg', (83, 91))	('ypN0', 'Var', (179, 183))	('favorable', 'PosReg', (18, 27))	('cT1-2', 'Gene', (139, 144))
352620	27682879	Favorable factors on PFS at 2 years were negative surgical margin (p < 0.001), ypT0 (p = 0.001), pCR (p = 0.014), and ypN0 (p = 0.021), and those on OS were negative surgical margin (p < 0.001), ypT0 (p = 0.011), and age of 60 years or younger (p = 0.017).	('ypN0', 'Var', (118, 122))	('pCR', 'Disease', (97, 100))	('OS', 'Chemical', '-', (149, 151))	('negative', 'NegReg', (41, 49))
352622	27682879	Among all, the patients having metastasis to the supraclavicular and/or celiac LNs (cM1a/b group) showed numerically lower, but not significant, PFS (40.1% vs. 53.5%, p = 0.204) and OS (62.5% vs. 68.4%, p = 0.362) at 2 years, when compared to those having regional LN metastasis (cM0 group).	('patients', 'Species', '9606', (15, 23))	('lower', 'NegReg', (117, 122))	('PFS', 'MPA', (145, 148))	('metastasis', 'Var', (31, 41))	('OS', 'Chemical', '-', (182, 184))
352623	27682879	Among 168 patients who underwent surgery, pCR rate was numerically higher in cM0 group, but not significant (29.8% vs. 20.3%, p = 0.174), and the same trends were shown on PFS (42.5% vs. 54.6%, p = 0.279) and OS (67.4% vs. 69.3%, p = 0.515) at 2 years (Figure 3).	('higher', 'PosReg', (67, 73))	('cM0', 'Var', (77, 80))	('pCR', 'Disease', (42, 45))	('OS', 'Chemical', '-', (209, 211))	('patients', 'Species', '9606', (10, 18))
352631	27682879	This might be partly explained by the fact that OS at 2 years of patients with pT0N+ and pT+N0 (76.3% and 66.3%) were not different from that of patients achieving pCR (79.8%) (Figure 2).	('patients', 'Species', '9606', (145, 153))	('pT+N0', 'Var', (89, 94))	('OS', 'Chemical', '-', (48, 50))	('pT0N+', 'Var', (79, 84))	('pT+N0', 'Chemical', '-', (89, 94))	('patients', 'Species', '9606', (65, 73))
352719	33764979	Importantly, in this latter study, the highest risk of future variceal bleeding was associated with an SMS of 3 and 4 (odds ratio (OR), 144) compared to an SMS <=2, and the number of bleeding episodes per 10 months during the follow-up increased from 0 (95% CI 0 to 0.013) for patients with an SMS <2 to 0.82 (95% CI 0.41 to 1.47) for SMS = 4.	('bleeding', 'Disease', (183, 191))	('bleeding', 'Disease', 'MESH:D006470', (71, 79))	('bleeding episode', 'Phenotype', 'HP:0001892', (183, 199))	('patients', 'Species', '9606', (277, 285))	('bleeding', 'Disease', (71, 79))	('variceal bleeding', 'Disease', (62, 79))	('bleeding episodes', 'Phenotype', 'HP:0001892', (183, 200))	('SMS of 3', 'Var', (103, 111))	('bleeding', 'Disease', 'MESH:D006470', (183, 191))	('variceal bleeding', 'Disease', 'MESH:D014648', (62, 79))
352729	33764979	From a hemodynamic point of view, beta-blockage in patients with HSS appears to induce an increase in systemic resistance and a slight increase in pulmonary pressure, while significantly reducing the flow of all portal-afferent veins and of the Azygos vein.	('portal-afferent veins', 'Phenotype', 'HP:0025154', (212, 233))	('increase', 'PosReg', (90, 98))	('increase', 'PosReg', (135, 143))	('flow', 'MPA', (200, 204))	('HSS', 'Disease', (65, 68))	('pulmonary pressure', 'Disease', (147, 165))	('beta-blockage', 'Var', (34, 47))	('increase in pulmonary pressure', 'Phenotype', 'HP:0004890', (135, 165))	('reducing', 'NegReg', (187, 195))	('patients', 'Species', '9606', (51, 59))	('systemic resistance', 'MPA', (102, 121))	('pulmonary pressure', 'Disease', 'MESH:D006973', (147, 165))	('HSS', 'Phenotype', 'HP:0001981', (65, 68))
352839	31205550	Besides, a study had shown that CDKN3 dephosphorylated CDK1 at Thr161 in late mitosis and loss of CDKN3 can induce abnormal mitosis and supernumerary centrosomes.	('CDKN3', 'Gene', '1033', (32, 37))	('abnormal mitosis', 'Disease', (115, 131))	('mitosis', 'Disease', 'None', (124, 131))	('CDKN3', 'Gene', '1033', (98, 103))	('supernumerary centrosomes', 'CPA', (136, 161))	('loss', 'Var', (90, 94))	('mitosis', 'Disease', (78, 85))	('abnormal mitosis', 'Disease', 'MESH:D000014', (115, 131))	('CDK1', 'Gene', '983', (55, 59))	('Thr161', 'Chemical', '-', (63, 69))	('induce', 'Reg', (108, 114))	('CDKN3', 'Gene', (32, 37))	('CDK1', 'Gene', (55, 59))	('mitosis', 'Disease', 'None', (78, 85))	('CDKN3', 'Gene', (98, 103))	('mitosis', 'Disease', (124, 131))
352884	31205550	Patients with CDKN3 copy number variation (CNV) deletion (n=31) had a significant higher Disease-Free Survival (DFS) after surgery (Chisq=6.0, P=0.014) than patients without CNV deletion (n=110) (Figure 2A).	('CDKN3', 'Gene', (14, 19))	('copy number variation', 'Var', (20, 41))	('higher', 'PosReg', (82, 88))	('patients', 'Species', '9606', (157, 165))	('Patients', 'Species', '9606', (0, 8))	('CDKN3', 'Gene', '1033', (14, 19))	('deletion', 'Var', (48, 56))	('Disease-Free Survival', 'CPA', (89, 110))
352885	31205550	Correspondingly, DFS of patients with CNV amplification (n=43) was much lower compared to the ones without CNV amplification (n=98), with a strong tendency towards statistical significance (Chisq=3.7, P=0.053) (Figure 2B).	('DFS', 'MPA', (17, 20))	('CNV amplification', 'Var', (38, 55))	('lower', 'NegReg', (72, 77))	('patients', 'Species', '9606', (24, 32))
352888	31205550	MTS assays showed that CDKN3 overexpression promoted TE1 cells proliferating and CDKN3 knockdown decreased the proliferative ability of TE1 and KYSE70 cells (Fig.	('CDKN3', 'Gene', '1033', (23, 28))	('promoted', 'PosReg', (44, 52))	('proliferative ability', 'CPA', (111, 132))	('CDKN3', 'Gene', '1033', (81, 86))	('TE1 cells proliferating', 'CPA', (53, 76))	('SE', 'Disease', 'None', (146, 148))	('CDKN3', 'Gene', (23, 28))	('decreased', 'NegReg', (97, 106))	('CDKN3', 'Gene', (81, 86))	('knockdown', 'Var', (87, 96))
352889	31205550	Colony count was more in CDKN3 overexpression cells than those transfected with empty vector and was lower in CDKN3 siRNA interfering cell lines (Fig.	('overexpression', 'Var', (31, 45))	('CDKN3', 'Gene', (25, 30))	('more', 'PosReg', (17, 21))	('Colony count', 'CPA', (0, 12))	('CDKN3', 'Gene', (110, 115))	('lower', 'NegReg', (101, 106))	('CDKN3', 'Gene', '1033', (25, 30))	('CDKN3', 'Gene', '1033', (110, 115))
352890	31205550	To detect the influence of CDKN3 on cell cycle, flow cytometer was conducted and the results revealed that G1 phase cell percentage in CDKN3 overexpression TE1 cells was less than the vector group (P<0.01) and the S phase cell percentage changed in the opposite (P<0.05).	('CDKN3', 'Gene', (27, 32))	('TE1', 'Var', (156, 159))	('less', 'NegReg', (170, 174))	('CDKN3', 'Gene', (135, 140))	('CDKN3', 'Gene', '1033', (27, 32))	('G1 phase cell percentage', 'CPA', (107, 131))	('overexpression', 'PosReg', (141, 155))	('CDKN3', 'Gene', '1033', (135, 140))
352893	31205550	The result showed that both migration and invasion were increased in TE1 cell with overexpressed CDKN3 than control.	('migration', 'CPA', (28, 37))	('overexpressed', 'Var', (83, 96))	('increased', 'PosReg', (56, 65))	('CDKN3', 'Gene', (97, 102))	('invasion', 'CPA', (42, 50))	('CDKN3', 'Gene', '1033', (97, 102))
352907	31205550	Evidence supported CDKN3 as tumor suppressor gene was that with the progression of cancer, wild-type CDKN3 expression decreased and aberrant splicing transcription increased which owned a negative dominant and inhibited the dephosphorylation process of CDK2 completed by wild CDKN3 and then forced the G1/S transition.	('tumor', 'Disease', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CDKN3', 'Gene', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('CDKN3', 'Gene', '1033', (276, 281))	('G1/S transition', 'CPA', (302, 317))	('increased', 'PosReg', (164, 173))	('dephosphorylation process', 'MPA', (224, 249))	('CDKN3', 'Gene', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('inhibited', 'NegReg', (210, 219))	('CDKN3', 'Gene', '1033', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('CDK2', 'Gene', '1017', (253, 257))	('forced', 'Reg', (291, 297))	('aberrant', 'Var', (132, 140))	('decreased', 'NegReg', (118, 127))	('CDK2', 'Gene', (253, 257))	('CDKN3', 'Gene', '1033', (19, 24))	('CDKN3', 'Gene', (276, 281))	('splicing transcription', 'MPA', (141, 163))	('expression', 'MPA', (107, 117))	('cancer', 'Disease', (83, 89))
352934	31048097	Molecular heterogeneity has been demonstrated to contribute to the cancer recurrence and metastasis after treatment, and to be even resistant to treatment.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('men', 'Species', '9606', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Molecular heterogeneity', 'Var', (0, 23))	('contribute', 'Reg', (49, 59))	('men', 'Species', '9606', (150, 153))	('metastasis', 'CPA', (89, 99))
352979	31048097	Interestingly, TIGIT is highly expressed on both CD8+ T-cells and Tregs in many clinical tumor settings, and blockage of TIGIT can enhance T-cell function, particularly when used in combination with PD-1/PD-L1 blockade.	('TIGIT', 'Gene', (121, 126))	('PD-L1', 'Gene', '29126', (204, 209))	('blockage', 'Var', (109, 117))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('CD8', 'Gene', (49, 52))	('enhance', 'PosReg', (131, 138))	('CD8', 'Gene', '925', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('T-cell function', 'CPA', (139, 154))	('PD-L1', 'Gene', (204, 209))
352985	31048097	FOSL1, a downstream effector of oncogene KRAS and a component of the mitotic machinery, can be used as a prognostic marker to identify mutant KRAS in lung and pancreatic cancer patients with the worst survival outcome.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (159, 176))	('KRAS', 'Gene', (142, 146))	('lung', 'Disease', (150, 154))	('FOSL1', 'Gene', '8061', (0, 5))	('KRAS', 'Gene', '3845', (41, 45))	('pancreatic cancer', 'Disease', (159, 176))	('patients', 'Species', '9606', (177, 185))	('mutant', 'Var', (135, 141))	('KRAS', 'Gene', '3845', (142, 146))	('pancreatic cancer', 'Disease', 'MESH:D010190', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('KRAS', 'Gene', (41, 45))	('FOSL1', 'Gene', (0, 5))
352991	31048097	Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the primary enzymes involved in alcohol metabolism; carrying these genetic variants, such as alcohol dehydrogenase1C*1 (ADH1C*1) homozygotes, often confers a higher risk for alcohol-related cancers, such as esophageal adenocarcinoma and gastric cancer risk.	('gastric cancer', 'Disease', (303, 317))	('ADH', 'Gene', (186, 189))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('cancers', 'Disease', (256, 263))	('ADH', 'Gene', '124;126;127;131;131', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('gastric cancer', 'Disease', 'MESH:D013274', (303, 317))	('ADH', 'Gene', (23, 26))	('cancers', 'Disease', 'MESH:D009369', (256, 263))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (273, 298))	('ADH1C', 'Gene', (186, 191))	('gastric cancer', 'Phenotype', 'HP:0012126', (303, 317))	('ADH', 'Gene', '124;126;127;131;131', (186, 189))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (273, 298))	('ADH1C', 'Gene', '126', (186, 191))	('alcohol', 'Chemical', 'MESH:D000438', (98, 105))	('esophageal adenocarcinoma', 'Disease', (273, 298))	('variants', 'Var', (141, 149))	('alcohol', 'Chemical', 'MESH:D000438', (240, 247))	('alcohol', 'Chemical', 'MESH:D000438', (159, 166))
352996	31048097	FOXA1 siRNA can reduce the expression levels of both KRT7 and LOXL2; knockdown of either FOXA1 or LOXL2 could reduce invasion and migration of ESCC cells.	('FOXA1', 'Gene', (0, 5))	('FOXA1', 'Gene', (89, 94))	('KRT7', 'Gene', (53, 57))	('LOXL2', 'Gene', (98, 103))	('LOXL2', 'Gene', '4017', (98, 103))	('FOXA1', 'Gene', '3169', (0, 5))	('ESCC', 'Disease', (143, 147))	('expression', 'MPA', (27, 37))	('KRT7', 'Gene', '3855', (53, 57))	('LOXL2', 'Gene', (62, 67))	('FOXA1', 'Gene', '3169', (89, 94))	('knockdown', 'Var', (69, 78))	('reduce', 'NegReg', (110, 116))	('LOXL2', 'Gene', '4017', (62, 67))
353030	29658571	For example, Zha et al found that HOXA1 was overexpressed in hepatocellular carcinoma (HCC), and high HOXA1 expression was positively associated with the T classification, N classification, distant metastasis and the clinical stage of HCC patients.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (61, 85))	('overexpressed', 'PosReg', (44, 57))	('T classification', 'CPA', (154, 170))	('HCC', 'Gene', '619501', (87, 90))	('associated', 'Reg', (134, 144))	('distant metastasis', 'CPA', (190, 208))	('HCC', 'Gene', (87, 90))	('HOXA1', 'Gene', (102, 107))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (61, 85))	('HOXA1', 'Gene', '3198', (34, 39))	('N classification', 'CPA', (172, 188))	('HCC', 'Gene', '619501', (235, 238))	('hepatocellular carcinoma', 'Disease', (61, 85))	('HCC', 'Gene', (235, 238))	('HOXA1', 'Gene', (34, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('patients', 'Species', '9606', (239, 247))	('expression', 'MPA', (108, 118))	('HOXA1', 'Gene', '3198', (102, 107))	('high', 'Var', (97, 101))
353071	29658571	3F), indicating that high HOXA1 expression may be associated with increased survival time of NSCLC patients.	('increased', 'PosReg', (66, 75))	('NSCLC', 'Disease', (93, 98))	('associated', 'Reg', (50, 60))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('survival time', 'CPA', (76, 89))	('high', 'Var', (21, 25))	('patients', 'Species', '9606', (99, 107))	('HOXA1', 'Gene', (26, 31))	('expression', 'MPA', (32, 42))	('HOXA1', 'Gene', '3198', (26, 31))
353093	29658571	HOXA1 was confirmed as a tumorigenic gene, and high HOXA1 expression was associated with TNM stage and LNM.	('TNM stage', 'Disease', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('LNM', 'Disease', (103, 106))	('expression', 'MPA', (58, 68))	('tumor', 'Disease', (25, 30))	('high', 'Var', (47, 51))	('HOXA1', 'Gene', '3198', (52, 57))	('associated', 'Reg', (73, 83))	('HOXA1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('HOXA1', 'Gene', '3198', (0, 5))	('HOXA1', 'Gene', (52, 57))
353105	29658571	Liu et al found that p53 was the most commonly mutated gene in NSCLC, being mutated in 45-70% of LUAD samples and 60-80% of LUSC samples.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('mutated', 'Var', (76, 83))	('LUAD', 'Disease', (97, 101))	('p53', 'Gene', (21, 24))	('p53', 'Gene', '7157', (21, 24))
353119	29515971	Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Cancer Genome Atlas', 'Disease', (108, 127))	('tumor', 'Disease', (32, 37))	('screened', 'Reg', (181, 189))	('variation', 'Var', (194, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (108, 127))	('CYT', 'Gene', (207, 210))
353148	29515971	Using the Genomic Data Commons (GDC) Data Portal (The Cancer Genome Atlas, TCGA program3) and the GTEx web portal (Genotype-Tissue Expression project4), we extracted data from a total of 10,355 tumor resection samples and 2,935 normal samples and screened the variation of CYT across these 32 different cancer types and 28 different normal solid tissue types.	('CYT', 'Gene', (273, 276))	('Cancer Genome Atlas', 'Disease', (54, 73))	('cancer', 'Disease', (303, 309))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('variation', 'Var', (260, 269))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (54, 73))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('screened', 'Reg', (247, 255))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
353165	29515971	GZMA was stained with an anti-GZMA antibody produced in rabbit (HPA054134, 1:200 dilution, Sigma-Aldrich) and PRF1 using two different antibodies produced in rabbit (either HPA037940, 1:29 dilution, or CAB002436, 1:10 dilution, Sigma-Aldrich).	('rabbit', 'Species', '9986', (56, 62))	('CAB002436', 'Var', (202, 211))	('rabbit', 'Species', '9986', (158, 164))	('GZMA', 'Gene', (30, 34))	('GZMA', 'Gene', (0, 4))	('GZMA', 'Gene', '3001', (30, 34))	('GZMA', 'Gene', '3001', (0, 4))
353182	29515971	Importantly, we show for the first time that DLBCL and testicular cancer also rank among the top cytolytic active tumors, with DLBCL exhibiting even higher cytolytic levels compared to KIRC (>100 TPM).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('testicular cancer', 'Phenotype', 'HP:0010788', (55, 72))	('testicular cancer', 'Disease', (55, 72))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('DLBCL', 'Disease', (45, 50))	('cytolytic levels', 'MPA', (156, 172))	('higher', 'PosReg', (149, 155))	('DLBCL', 'Var', (127, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (55, 72))
353207	29515971	We next performed Kaplan-Meier survival analysis on 37 TCGA-datasets deriving from 25 different cancer types in order to estimate the risk of individual and/or simultaneous high (or low) PRF1 and GZMA expression on patient overall survival.	('high', 'Var', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('low', 'NegReg', (182, 185))	('GZMA', 'Gene', (196, 200))	('PRF1', 'Gene', (187, 191))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('GZMA', 'Gene', '3001', (196, 200))	('cancer', 'Disease', (96, 102))	('patient', 'Species', '9606', (215, 222))
353208	29515971	In TCGA-ACC, non-metastatic cutaneous melanoma ("m0" TCGA-SKCM), and bladder urothelial carcinoma (TCGA-BLCA but not the GSE32894 dataset), both individual and simultaneous high levels of PRF1 and GZMA were significantly associated with better prognosis.	('ACC', 'Phenotype', 'HP:0006744', (8, 11))	('non-metastatic cutaneous melanoma', 'Phenotype', 'HP:0012057', (13, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('bladder urothelial carcinoma', 'Disease', (69, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('high levels', 'Var', (173, 184))	('GZMA', 'Gene', (197, 201))	('GZMA', 'Gene', '3001', (197, 201))	('PRF1', 'Gene', (188, 192))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (69, 97))	('cutaneous melanoma', 'Disease', (28, 46))
353212	29515971	In TCGA-LIHC, only the individual high levels of PRF1 and GZMA were significantly associated with a positive effect on patient survival.	('GZMA', 'Gene', '3001', (58, 62))	('patient', 'Species', '9606', (119, 126))	('LIHC', 'Disease', (8, 12))	('PRF1', 'Gene', (49, 53))	('LIHC', 'Disease', 'None', (8, 12))	('high levels', 'Var', (34, 45))	('GZMA', 'Gene', (58, 62))
353213	29515971	A similar non-significant association of (individual or simultaneous) high GZMA and PRF1 expression with better effect on patient survival could also be observed in TCGA-MESO, ovarian cancer (GSE13876 and GSE49997), TCGA-STAD, TCGA-THCA, and TCGA-UCEC (Figure S1 in Supplementary Material).	('GZMA', 'Gene', '3001', (75, 79))	('patient', 'Species', '9606', (122, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('GSE49997', 'Var', (205, 213))	('TCGA-MESO', 'Disease', (165, 174))	('GSE13876', 'Var', (192, 200))	('TCGA-UCEC', 'Disease', (242, 251))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('GZMA', 'Gene', (75, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('high', 'Var', (70, 74))	('TCGA-THCA', 'Disease', (227, 236))	('TCGA-STAD', 'Disease', (216, 225))	('ovarian cancer', 'Disease', (176, 190))	('PRF1', 'Gene', (84, 88))
353214	29515971	These data suggest that high CYT is widely associated with an improved prognosis among the above-mentioned cancer types.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('improved', 'PosReg', (62, 70))	('high CYT', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
353215	29515971	On the contrary, across TCGA-LGG, BRCAs (GSE25066), and TCGA-THYM, both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both genes led to a significant shift toward positive effect (Figure 6B).	('BRCA', 'Gene', '672', (34, 38))	('GSE25066', 'Var', (41, 49))	('BRCA', 'Gene', (34, 38))	('GZMA', 'Gene', (115, 119))	('GZMA', 'Gene', '3001', (115, 119))	('PRF1', 'Gene', (124, 128))	('associated with', 'Reg', (148, 163))
353218	29515971	Analogous non-significant associations of (individual or simultaneous) high cytolytic levels with worse effect on patient survival were also observed in lung cancer (GSE30219, TCGA-LUAD, and TCGA-LUSC), TCGA-PAAD, TCGA-PRAD and GSE16560, and TCGA-READ (Figure S2 in Supplementary Material).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('lung cancer', 'Disease', (153, 164))	('high cytolytic levels', 'MPA', (71, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('patient', 'Species', '9606', (114, 121))	('GSE30219', 'Var', (166, 174))	('PAAD', 'Phenotype', 'HP:0006725', (208, 212))
353220	29515971	Depending on the probe used, it seemed that a combination of high PRF1 and low GZMA levels yields a better patient outcome (GSE39582, TCGA-COAD, TCGA-COADREAD).	('COAD', 'Disease', (150, 154))	('low', 'NegReg', (75, 78))	('GZMA', 'Gene', '3001', (79, 83))	('PRF1', 'MPA', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('high', 'Var', (61, 65))	('COAD', 'Disease', 'MESH:D029424', (150, 154))	('COAD', 'Disease', (139, 143))	('patient', 'Species', '9606', (107, 114))	('GZMA', 'Gene', (79, 83))
353226	29515971	In DLBCL (GSE10846, and GSE32918), using various combinations of distinct molecular probes for the two cytolytic genes (PRF1, 214617_AT, 1553681_A_AT, or ILMN_1740633; GZMA, 205488_AT, or ILMN_1779324), we could not provide any significant association with patient survival.	('GSE32918', 'Var', (24, 32))	('GZMA', 'Gene', '3001', (168, 172))	('ILMN_1740633', 'Var', (154, 166))	('patient', 'Species', '9606', (257, 264))	('AT', 'Disease', 'None', (133, 135))	('AT', 'Disease', 'None', (147, 149))	('GSE10846', 'Var', (10, 18))	('PRF1', 'Var', (120, 124))	('AT', 'Disease', 'None', (181, 183))	('GZMA', 'Gene', (168, 172))
353227	29515971	A similar absence of significant associations was also detected in glioblastoma (GSE4271, GSE13041, and TCGA-GBM) and non-metastatic HNSCs.	('glioblastoma', 'Disease', (67, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('non-metastatic HNSCs', 'Disease', (118, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('GSE13041', 'Var', (90, 98))	('GSE4271', 'Chemical', '-', (81, 88))	('GSE4271', 'Var', (81, 88))
353265	29515971	Among them, recurrent mutations in immune-related genes have been proposed, such as B2M, HLA-A, -B, and -C, and CASP8, as well as copy number aberrations in loci containing immunosuppressive factors, including the receptors PD-L1/2 and CTLA-4.	('B2M', 'Gene', (84, 87))	('CASP8', 'Gene', '841', (112, 117))	('B2M', 'Gene', '567', (84, 87))	('CTLA-4', 'Gene', '1493', (236, 242))	('copy number aberrations', 'Var', (130, 153))	('CTLA-4', 'Gene', (236, 242))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (89, 106))	('mutations', 'Var', (22, 31))	('PD-L1/2', 'Gene', '29126;80380', (224, 231))	('PD-L1/2', 'Gene', (224, 231))	('CASP8', 'Gene', (112, 117))
353270	29515971	Actually, recent clinical trials have demonstrated that blockage of this signaling can benefit patients with advanced melanoma, kidney, or non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (139, 165))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('patients', 'Species', '9606', (95, 103))	('blockage', 'Var', (56, 64))	('non-small cell lung cancer', 'Disease', (139, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (139, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('kidney', 'Disease', (128, 134))
353278	29515971	Importantly, CTLA-4 blockade was reported to associate with bowel inflammation in melanoma patients, signifying that its signaling is crucial for the preservation of immune homeostasis in the gut.	('associate', 'Reg', (45, 54))	('patients', 'Species', '9606', (91, 99))	('bowel inflammation', 'Phenotype', 'HP:0002037', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('CTLA-4', 'Gene', '1493', (13, 19))	('blockade', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('bowel inflammation', 'Disease', 'MESH:D007249', (60, 78))	('CTLA-4', 'Gene', (13, 19))	('bowel inflammation', 'Disease', (60, 78))
353284	29515971	Inhibition of both IDO and arginase can enhance intratumoral inflammation.	('IDO', 'Gene', '3620', (19, 22))	('IDO', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('arginase', 'Protein', (27, 35))	('enhance', 'PosReg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (53, 58))
353298	29515971	A very interesting improvement in the field was further made by Riaz et al., who showed that the mutation burden in melanoma patients decreases with successful anti-PD-1 blockade therapy, suggesting that the selection against mutant neoepitopes is a critical mechanism of action of this immunotherapy.	('Riaz', 'Gene', (64, 68))	('mutant', 'Var', (226, 232))	('mutation burden', 'MPA', (97, 112))	('PD-1', 'Gene', (165, 169))	('PD-1', 'Gene', '5133', (165, 169))	('Riaz', 'Gene', '23598', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('decreases', 'NegReg', (134, 143))	('patients', 'Species', '9606', (125, 133))
353302	29515971	Overall, it seems that CYT is part of an inflammatory environment in a premalignant state of certain tumor types, whereas, in others, oncogenic mutations, copy number aberrations, or viral infection can induce a tumor-promoting inflammatory microenvironment, within which complex interactions between different cell types regulate cancer development and metastasis.	('copy number aberrations', 'Var', (155, 178))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('induce', 'PosReg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('viral infection', 'Disease', 'MESH:D001102', (183, 198))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('viral infection', 'Disease', (183, 198))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('mutations', 'Var', (144, 153))	('tumor', 'Disease', (212, 217))
353309	29515971	In some tumor types (ACC, SKCM, BLCA, LIHC, MESO, OV, STAD, THCA, and UCEC), high CYT was associated with an improved outcome; whereas in others (LGG, BRCA, THYM, LUAD/LUSC, PAAD, PRAD, and READ) it is correlated with a worse outcome.	('BRCA', 'Gene', '672', (151, 155))	('LIHC', 'Disease', 'None', (38, 42))	('BRCA', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MESO', 'Disease', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ACC', 'Phenotype', 'HP:0006744', (21, 24))	('PAAD', 'Phenotype', 'HP:0006725', (174, 178))	('PAAD', 'Disease', (174, 178))	('improved', 'PosReg', (109, 117))	('LUAD/LUSC', 'Disease', (163, 172))	('tumor', 'Disease', (8, 13))	('THYM', 'Disease', (157, 161))	('PRAD', 'Disease', (180, 184))	('LIHC', 'Disease', (38, 42))	('high CYT', 'Var', (77, 85))
353310	29515971	Among LGG, THYM, and BRCA, we showed that both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both cytolytic genes led to a significant shift toward a positive effect.	('GZMA', 'Gene', (90, 94))	('associated', 'Reg', (123, 133))	('BRCA', 'Gene', (21, 25))	('PRF1', 'Gene', (99, 103))	('high', 'Var', (75, 79))	('GZMA', 'Gene', '3001', (90, 94))	('BRCA', 'Gene', '672', (21, 25))
353470	28524093	Likewise, the meta-analysis conducted by Bo and her colleagues showed that vitamin C intake was associated with a 42% reduction in esophageal cancer risk.	('reduction', 'NegReg', (118, 127))	('vitamin', 'Var', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('esophageal cancer', 'Disease', (131, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('vitamin C', 'Chemical', 'MESH:D001205', (75, 84))
353471	28524093	In the current meta-analysis, we found that calcium intake was associated with a 33% reduction in esophageal cancer risk in Asian populations, which supports another important piece of information for the chemoprevention of esophageal cancer.	('esophageal cancer', 'Disease', (224, 241))	('calcium', 'Chemical', 'MESH:D002118', (44, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (224, 241))	('reduction', 'NegReg', (85, 94))	('calcium intake', 'Var', (44, 58))	('esophageal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
353498	28103919	Survival analysis revealed that high ASPP2 expression was significantly associated with increased 5-year OS (P = 0.001) and DFS rates (P = 0.010) and that high P53 expression was significantly associated with a reduced 5-year DFS rate of ESCC patients (P = 0.015).	('high', 'Var', (32, 36))	('ESCC', 'Disease', (238, 242))	('P53', 'Gene', (160, 163))	('DFS rates', 'MPA', (124, 133))	('ASPP2', 'Gene', '7159', (37, 42))	('P53', 'Gene', '7157', (160, 163))	('patients', 'Species', '9606', (243, 251))	('expression', 'MPA', (164, 174))	('reduced', 'NegReg', (211, 218))	('DFS rate', 'MPA', (226, 234))	('increased', 'PosReg', (88, 97))	('OS', 'Chemical', '-', (105, 107))	('ASPP2', 'Gene', (37, 42))	('expression', 'MPA', (43, 53))	('high', 'Var', (155, 159))
353513	28103919	High ASPP2 expression has been reported to predict good prognosis in some tumors, including breast cancer, non-small cell lung cancer, diffuse large B cell lymphoma, and follicular center lymphoma.	('non-small cell lung cancer', 'Disease', (107, 133))	('ASPP2', 'Gene', '7159', (5, 10))	('follicular center lymphoma', 'Disease', 'MESH:D008224', (170, 196))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('High', 'Var', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (107, 133))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (92, 105))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('lymphoma', 'Phenotype', 'HP:0002665', (188, 196))	('ASPP2', 'Gene', (5, 10))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (107, 133))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (149, 164))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))	('follicular center lymphoma', 'Disease', (170, 196))	('diffuse large B cell lymphoma', 'Disease', (135, 164))	('large B cell', 'Phenotype', 'HP:0005404', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (74, 80))
353522	28103919	Patients were ineligible if they had cervical ESCC, stage T4b ESCC at the time of diagnosis, other concomitant malignancies, or severe organ disorders.	('stage T4b', 'Var', (52, 61))	('organ disorders', 'Disease', (135, 150))	('organ disorders', 'Disease', 'MESH:D019965', (135, 150))	('Patients', 'Species', '9606', (0, 8))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('cervical ESCC', 'Disease', (37, 50))	('malignancies', 'Disease', (111, 123))
353557	28103919	ASPP1 expression was not associated with survival rate, whereas high ASPP2 expression was significantly associated with increased 5-year OS rate (51.0% vs. 31.7%, P = 0.001) and 5-year DFS rate as compared with low ASPP2 expression (46.5% vs. 32.0%, P = 0.010), and low P53 expression was associated with increased 5-year DFS rate as compared with high P53 expression (78.6% vs. 61.4%, P = 0.015) (Fig.	('ASPP1', 'Gene', (0, 5))	('high', 'Var', (64, 68))	('P53', 'Gene', (270, 273))	('DFS', 'CPA', (185, 188))	('ASPP2', 'Gene', (69, 74))	('ASPP2', 'Gene', '7159', (215, 220))	('P53', 'Gene', '7157', (270, 273))	('P53', 'Gene', (353, 356))	('DFS', 'MPA', (322, 325))	('ASPP1', 'Gene', '23368', (0, 5))	('P53', 'Gene', '7157', (353, 356))	('increased', 'PosReg', (305, 314))	('ASPP2', 'Gene', (215, 220))	('ASPP2', 'Gene', '7159', (69, 74))	('OS', 'Chemical', '-', (137, 139))
353558	28103919	Univariate Cox analysis also indicated that low ASPP2 expression was a significant predictor of short OS [hazard ratio (HR): 0.527, 95% confidence interval (CI) 0.355-0.782, P = 0.001] and DFS (HR: 0.606, 95% CI 0.412-0.891, P = 0.011) and that high P53 expression was a predictor of short DFS (HR: 2.198, 95% CI 1.144-4.224, P = 0.018); ASPP1 expression had no significant association with survival (Table 2).	('expression', 'MPA', (54, 64))	('OS', 'Chemical', '-', (102, 104))	('ASPP2', 'Gene', (48, 53))	('P53', 'Gene', (250, 253))	('P53', 'Gene', '7157', (250, 253))	('short OS', 'Disease', (96, 104))	('Cox', 'Gene', (11, 14))	('Cox', 'Gene', '1351', (11, 14))	('low', 'Var', (44, 47))	('ASPP1', 'Gene', (338, 343))	('DFS', 'Disease', (189, 192))	('ASPP2', 'Gene', '7159', (48, 53))	('ASPP1', 'Gene', '23368', (338, 343))
353559	28103919	Multivariate Cox analysis indicated that low ASPP2 expression was an independent predictor of short OS (HR: 0.541, 95% CI 0.363-0.804, P = 0.002) and DFS (HR: 0.599, 95% CI 0.404-0.888, P = 0.011) and that low P53 expression was an independent predictor of long DFS (HR: 2.161, 95% CI 1.100-4.245, P = 0.025) (Table 3).	('DFS', 'Disease', (150, 153))	('Cox', 'Gene', (13, 16))	('ASPP2', 'Gene', (45, 50))	('OS', 'Chemical', '-', (100, 102))	('P53', 'Gene', (210, 213))	('short OS', 'Disease', (94, 102))	('low', 'Var', (41, 44))	('expression', 'MPA', (51, 61))	('P53', 'Gene', '7157', (210, 213))	('ASPP2', 'Gene', '7159', (45, 50))	('expression', 'MPA', (214, 224))	('Cox', 'Gene', '1351', (13, 16))
353562	28103919	For patients with stage I-II ESCC, the expression of ASPP1 showed no prognostic value; for patients with stage III ESCC, high ASPP1 expression was associated with long OS (P = 0.012) and DFS (P = 0.032) (Fig.	('patients', 'Species', '9606', (91, 99))	('ASPP1', 'Gene', '23368', (53, 58))	('OS', 'Chemical', '-', (168, 170))	('high', 'Var', (121, 125))	('ASPP1', 'Gene', '23368', (126, 131))	('DFS', 'Disease', (187, 190))	('ASPP1', 'Gene', (53, 58))	('patients', 'Species', '9606', (4, 12))	('expression', 'MPA', (132, 142))	('ASPP1', 'Gene', (126, 131))	('long OS', 'Disease', (163, 170))
353569	28103919	Interestingly, the expression of the well-known tumor suppressor p53 was also reported to be increased in several types of cancer, including ESCC, and its high expression was related with a mutation.	('mutation', 'Var', (190, 198))	('expression', 'MPA', (160, 170))	('high', 'PosReg', (155, 159))	('expression', 'MPA', (19, 29))	('p53', 'Gene', (65, 68))	('tumor', 'Disease', (48, 53))	('p53', 'Gene', '7157', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('increased', 'PosReg', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('related', 'Reg', (175, 182))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ESCC', 'Disease', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
353570	28103919	Wild-type (unphosphorylated) P53 is usually undetectable using immunohistochemistry, whereas mutant (phosphorylated) P53 with dominant-negative activities and oncogenic properties can be detected because its half-life is much longer.	('P53', 'Gene', (29, 32))	('P53', 'Gene', '7157', (29, 32))	('mutant', 'Var', (93, 99))	('P53', 'Gene', (117, 120))	('P53', 'Gene', '7157', (117, 120))
353571	28103919	High expression of mutant (phosphorylated) P53 has been observed in many malignancies.	('observed', 'Reg', (56, 64))	('P53', 'Gene', (43, 46))	('P53', 'Gene', '7157', (43, 46))	('malignancies', 'Disease', 'MESH:D009369', (73, 85))	('mutant', 'Var', (19, 25))	('malignancies', 'Disease', (73, 85))
353579	28103919	We also found that high P53 expression was associated with large tumor size, indicating that mutant P53 expression may be involved in tumor progression, which is consistent with a recent study.	('high', 'Var', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('involved', 'Reg', (122, 130))	('expression', 'MPA', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('P53', 'Gene', (100, 103))	('mutant', 'Var', (93, 99))	('P53', 'Gene', '7157', (100, 103))	('P53', 'Gene', (24, 27))	('associated', 'Reg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('P53', 'Gene', '7157', (24, 27))	('tumor', 'Disease', (134, 139))
353580	28103919	Although we did not detect a difference in ASPP1 expression between ESCCs and noncancerous tissues, high ASPP1 expression was associated with high degree of histological differentiation and shallow invasion of ESCCs, suggesting that high ASPP1 expression may inhibit tumor progression.	('ASPP1', 'Gene', '23368', (238, 243))	('cancerous', 'Disease', 'MESH:D009369', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('ASPP1', 'Gene', '23368', (43, 48))	('inhibit', 'NegReg', (259, 266))	('ASPP1', 'Gene', '23368', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('high', 'Var', (100, 104))	('expression', 'MPA', (111, 121))	('cancerous', 'Disease', (81, 90))	('shallow invasion', 'CPA', (190, 206))	('tumor', 'Disease', (267, 272))	('ASPP1', 'Gene', (238, 243))	('ASPP1', 'Gene', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ASPP1', 'Gene', (43, 48))
353583	28103919	Our study confirmed that high P53 expression was an independent predictor of short DFS, which was consistent with the results reported in literature.	('P53', 'Gene', (30, 33))	('expression', 'MPA', (34, 44))	('P53', 'Gene', '7157', (30, 33))	('short DFS', 'Disease', (77, 86))	('high', 'Var', (25, 29))
353584	28103919	Similar to ASPP2, patients with high P53 expression need more aggressive therapy modality and close follow-up to reduce the chance of relapse or metastasis.	('high', 'Var', (32, 36))	('P53', 'Gene', (37, 40))	('ASPP2', 'Gene', (11, 16))	('P53', 'Gene', '7157', (37, 40))	('ASPP2', 'Gene', '7159', (11, 16))	('patients', 'Species', '9606', (18, 26))
353585	28103919	Although high ASPP1 expression was not associated with the prognosis of the whole cohort, it was associated with prolonged OS and DFS of patients with stage III disease.	('expression', 'MPA', (20, 30))	('ASPP1', 'Gene', (14, 19))	('DFS', 'Disease', (130, 133))	('patients', 'Species', '9606', (137, 145))	('ASPP1', 'Gene', '23368', (14, 19))	('prolonged OS', 'Disease', (113, 125))	('associated', 'Reg', (97, 107))	('OS', 'Chemical', '-', (123, 125))	('high', 'Var', (9, 13))
353599	28102292	Notably, we detected hypomethylation and overexpression of several pro-inflammatory genes such as COX2, IL8 and IL23R, suggesting an important role of epigenetic regulation of these genes in the inflammatory cascade associated with EAC.	('IL8', 'Gene', (104, 107))	('IL8', 'Gene', '3576', (104, 107))	('hypomethylation', 'Var', (21, 36))	('EAC', 'Disease', (232, 235))	('COX2', 'Gene', (98, 102))	('IL23R', 'Gene', '149233', (112, 117))	('COX2', 'Gene', '4513', (98, 102))	('IL23R', 'Gene', (112, 117))	('overexpression', 'PosReg', (41, 55))
353604	28102292	The most frequent genetic changes that are implicated in EAC include silencing of p16 gene expression (by deletion or promoter hypermethylation), the loss of p53 expression (by mutation or deletion), and overexpression of cyclin D1.	('expression', 'MPA', (91, 101))	('mutation', 'Var', (177, 185))	('p53', 'Gene', '7157', (158, 161))	('p16', 'Gene', (82, 85))	('cyclin D1', 'Gene', '595', (222, 231))	('cyclin D1', 'Gene', (222, 231))	('p53', 'Gene', (158, 161))	('deletion', 'Var', (106, 114))	('expression', 'MPA', (162, 172))	('p16', 'Gene', '1029', (82, 85))	('loss', 'NegReg', (150, 154))	('deletion', 'Var', (189, 197))	('silencing', 'NegReg', (69, 78))	('overexpression', 'PosReg', (204, 218))
353605	28102292	Mutation analyses using whole-exome sequencing of EAC tumour-normal pairs confirmed that mutations of p53 are the most frequent alterations which occur in more than 50% of EAC, however, the frequency of mutation of any other individual gene falls below 5%.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('p53', 'Gene', '7157', (102, 105))	('tumour', 'Disease', (54, 60))	('falls', 'Phenotype', 'HP:0002527', (241, 246))	('mutations', 'Var', (89, 98))	('p53', 'Gene', (102, 105))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('EAC', 'Disease', (172, 175))
353611	28102292	This could explain why cancer cells develop coordinated genetic and/or epigenetic mechanisms to regulate their expression.	('cancer', 'Disease', (23, 29))	('epigenetic', 'Var', (71, 81))	('expression', 'MPA', (111, 121))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('regulate', 'Reg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
353628	28102292	Aberrant expression of these proteins has been associated with esophageal adenocarcinomas.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (63, 88))	('Aberrant', 'Var', (0, 8))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (63, 89))	('expression', 'MPA', (9, 19))	('associated', 'Reg', (47, 57))	('esophageal adenocarcinomas', 'Disease', (63, 89))
353634	28102292	Dysfunction of these transcription factors plays an important roles in tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Disease', (71, 77))	('Dysfunction', 'Var', (0, 11))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
353636	28102292	Activation of beta-catenin due to mutations and/or overexpression of components of the beta-catenin pathway have been associated with several tumours, including colorectal cancer, lung cancer, breast cancer, as well as gastric and esophageal adenocarcinoma.	('breast cancer', 'Disease', (193, 206))	('colorectal cancer', 'Disease', (161, 178))	('esophageal adenocarcinoma', 'Disease', (231, 256))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('beta-catenin', 'Gene', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('beta-catenin', 'Gene', '1499', (87, 99))	('lung cancer', 'Disease', (180, 191))	('associated', 'Reg', (118, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('overexpression', 'PosReg', (51, 65))	('tumours', 'Disease', (142, 149))	('beta-catenin', 'Gene', (14, 26))	('beta-catenin', 'Gene', '1499', (14, 26))	('Activation', 'PosReg', (0, 10))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (231, 256))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (231, 256))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('mutations', 'Var', (34, 43))
353639	28102292	TWIST1 is a basic helix-loop-helix (bHLH) transcription factor and its dysfunction is associated with epithelial-mesenchymal transition (EMT), contributing to tumour metastasis.	('TWIST1', 'Gene', (0, 6))	('tumour metastasis', 'Disease', 'MESH:D009362', (159, 176))	('TWIST1', 'Gene', '7291', (0, 6))	('associated', 'Reg', (86, 96))	('tumour metastasis', 'Disease', (159, 176))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('epithelial-mesenchymal transition', 'Disease', (102, 135))	('dysfunction', 'Var', (71, 82))	('contributing', 'Reg', (143, 155))
353642	28102292	Dysfunction of these GATA members has been related to various human cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Dysfunction', 'Var', (0, 11))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('related', 'Reg', (43, 50))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('GATA', 'Gene', (21, 25))	('GATA', 'Gene', '55278', (21, 25))
353658	28102292	Overall, 661,383 (92%) probes showed copy number (CN) aberration (gain or loss) in our samples.	('copy number', 'Var', (37, 48))	('gain or loss', 'Disease', 'MESH:D015430', (66, 78))	('gain or loss', 'Disease', (66, 78))
353659	28102292	Supplementary Figure S3 shows the probe-wise frequency of CN changes across the entire genome (autosome) for all 12 tumours.	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('CN changes', 'Var', (58, 68))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('tumours', 'Disease', (116, 123))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
353666	28102292	In agreement with our findings, deletion of CDKN2A is a common molecular mechanism for silencing expression of CDKN2A/p16 protein.	('deletion', 'Var', (32, 40))	('CDKN2A', 'Gene', (44, 50))	('p16', 'Gene', '1029', (118, 121))	('CDKN2A', 'Gene', '1029', (111, 117))	('CDKN2A', 'Gene', '1029', (44, 50))	('CDKN2A', 'Gene', (111, 117))	('p16', 'Gene', (118, 121))	('expression', 'MPA', (97, 107))	('silencing', 'NegReg', (87, 96))
353667	28102292	Of note, loss of functional p16 protein by deletions, mutations, or DNA methylation is an early event frequently detected during Barrett's tumorigenesis and progression to EAC.	('p16', 'Gene', '1029', (28, 31))	('deletions', 'Var', (43, 52))	('mutations', 'Var', (54, 63))	('loss', 'NegReg', (9, 13))	('p16', 'Gene', (28, 31))	('protein', 'Protein', (32, 39))	('EAC', 'Disease', (172, 175))
353670	28102292	Activation of the Wnt pathway through dysfunction of these genes has been observed in many cancers, in particular gastrointestinal tumours including esophageal adenocarcinoma.	('dysfunction', 'Var', (38, 49))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (149, 174))	('esophageal adenocarcinoma', 'Disease', (149, 174))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (149, 174))	('cancers', 'Disease', (91, 98))	('particular gastrointestinal tumours', 'Disease', (103, 138))	('particular gastrointestinal tumours', 'Disease', 'MESH:D004067', (103, 138))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('Activation', 'PosReg', (0, 10))	('Wnt', 'Gene', '54361;7474', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Wnt', 'Gene', (18, 21))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))
353673	28102292	Genes with copy number gains in our study also included well-known genes like CDK6 (25%, 3/12), KRAS (25%, 3/12), PIK3CA (16.7%, 2/12), and EGFR (16.7%, 2/12) (Supplementary Tables S2 and S3).	('PIK3CA', 'Gene', '5290', (114, 120))	('KRAS', 'Gene', '3845', (96, 100))	('CDK6', 'Gene', '1021', (78, 82))	('EGFR', 'Gene', (140, 144))	('CDK6', 'Gene', (78, 82))	('gains', 'PosReg', (23, 28))	('copy number', 'Var', (11, 22))	('PIK3CA', 'Gene', (114, 120))	('EGFR', 'Gene', '1956', (140, 144))	('KRAS', 'Gene', (96, 100))
353677	28102292	Supplementary Figure S5 shows the probe-wise frequency of aberrant methylation status (hyper or hypo) across the entire genome (autosome) for 12 tumour samples.	('hyper or hypo', 'Disease', (87, 100))	('tumour', 'Disease', (145, 151))	('aberrant', 'Var', (58, 66))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('methylation status', 'MPA', (67, 85))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('hyper or hypo', 'Disease', 'MESH:D052456', (87, 100))
353681	28102292	The roles of HOX genes methylation and downregulation in the biology of EAC or as biomarkers for cancer risk need to be determined.	('cancer', 'Disease', (97, 103))	('methylation', 'Var', (23, 34))	('EAC', 'Disease', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HOX genes', 'Gene', (13, 22))	('downregulation', 'NegReg', (39, 53))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
353683	28102292	Our results showed that DSC3 (desmocollin 3) is among the top genes that were significantly downregulated and hypermethylated.	('DSC3', 'Gene', (24, 28))	('desmocollin 3', 'Gene', '1825', (30, 43))	('downregulated', 'NegReg', (92, 105))	('desmocollin 3', 'Gene', (30, 43))	('DSC3', 'Gene', '1825', (24, 28))	('hypermethylated', 'Var', (110, 125))
353684	28102292	This finding is consistent with an earlier report showing silencing of DSC3 by DNA methylation in advanced stages of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (117, 142))	('DSC3', 'Gene', '1825', (71, 75))	('DSC3', 'Gene', (71, 75))	('methylation', 'Var', (83, 94))	('esophageal adenocarcinoma', 'Disease', (117, 142))	('silencing', 'NegReg', (58, 67))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (117, 142))
353689	28102292	Interestingly, our data demonstrate hypomethylation of several inflammation-related genes in EAC.	('inflammation', 'Disease', 'MESH:D007249', (63, 75))	('EAC', 'Disease', (93, 96))	('hypomethylation', 'Var', (36, 51))	('inflammation', 'Disease', (63, 75))
353692	28102292	Notably, PTGS2, also known as COX2, was also hypomethylated and overexpressed in our study.	('hypomethylated', 'Var', (45, 59))	('PTGS2', 'Gene', '5743', (9, 14))	('COX2', 'Gene', (30, 34))	('PTGS2', 'Gene', (9, 14))	('COX2', 'Gene', '4513', (30, 34))	('overexpressed', 'PosReg', (64, 77))
353696	28102292	We also detected DNA hypomethylation and overexpression of SPP1 and LYN.	('LYN', 'Gene', '4067', (68, 71))	('hypomethylation', 'Var', (21, 36))	('SPP1', 'Gene', '6696', (59, 63))	('SPP1', 'Gene', (59, 63))	('overexpression', 'PosReg', (41, 55))	('LYN', 'Gene', (68, 71))
353700	28102292	Taken together, our results indicate the existence of a strong pro-inflammatory and pro-invasive environment in the development of EAC and suggest a previously unexplored interaction between promoter DNA hypomethylation and activation of these genes and networks during esophageal tumourigenesis.	('tumour', 'Disease', 'MESH:D009369', (281, 287))	('EAC', 'Disease', (131, 134))	('tumour', 'Disease', (281, 287))	('hypomethylation', 'Var', (204, 219))	('activation', 'PosReg', (224, 234))	('tumour', 'Phenotype', 'HP:0002664', (281, 287))
353701	28102292	Among these genes, CDH17 and GATA6 are examples with significant gene overexpression, promoter hypomethylation and copy number amplification in EACs.	('GATA6', 'Gene', (29, 34))	('GATA6', 'Gene', '2627', (29, 34))	('CDH17', 'Gene', '1015', (19, 24))	('copy number amplification', 'Var', (115, 140))	('CDH17', 'Gene', (19, 24))	('overexpression', 'PosReg', (70, 84))
353705	28102292	We have discussed the importance of GATA6 in the above sections, and our results show a possible regulation of GATA6 by both genetic and epigenetic mechanisms in cancer cells (CN and methylation), and suggest an important role of GATA6 in esophageal tumourigenesis.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tumour', 'Disease', 'MESH:D009369', (250, 256))	('tumour', 'Disease', (250, 256))	('cancer', 'Disease', (162, 168))	('GATA6', 'Gene', '2627', (36, 41))	('GATA6', 'Gene', (36, 41))	('GATA6', 'Gene', '2627', (230, 235))	('GATA6', 'Gene', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('regulation', 'Reg', (97, 107))	('epigenetic', 'Var', (137, 147))	('GATA6', 'Gene', '2627', (111, 116))	('GATA6', 'Gene', (111, 116))
353706	28102292	On the other hand, ANXA8, ANXA8L1, and PPP2R2C were examples of downregulated genes with both DNA hypermethylation and copy number loss (Supplementary Table S2).	('PPP2R2C', 'Gene', (39, 46))	('ANXA8', 'Gene', '653145', (26, 31))	('PPP2R2C', 'Gene', '5522', (39, 46))	('copy number loss', 'Var', (119, 135))	('ANXA8', 'Gene', '653145', (19, 24))	('ANXA8L1', 'Gene', '728113', (26, 33))	('ANXA8L1', 'Gene', (26, 33))	('ANXA8', 'Gene', (19, 24))	('ANXA8', 'Gene', (26, 31))	('downregulated', 'NegReg', (64, 77))
353710	28102292	PPP2R2C is another interesting gene downregulated in EAC, with simultaneous copy number loss and hypermethylation (Supplementary Table S2).	('PPP2R2C', 'Gene', '5522', (0, 7))	('PPP2R2C', 'Gene', (0, 7))	('EAC', 'Disease', (53, 56))	('loss', 'NegReg', (88, 92))	('copy number', 'Var', (76, 87))	('downregulated', 'NegReg', (36, 49))	('hypermethylation', 'MPA', (97, 113))
353712	28102292	Our results indicate that dysfunction of these genes by both genetic and epigenetic interaction mechanisms may play an important role in Barrett's tumourigenesis and EAC.	('play', 'Reg', (111, 115))	('EAC', 'Disease', (166, 169))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('dysfunction', 'Var', (26, 37))	('tumour', 'Disease', (147, 153))
353713	28102292	Frequent copy number alterations highlight the chromosomal instability nature of these cancers.	('cancers', 'Disease', (87, 94))	('chromosomal instability', 'Phenotype', 'HP:0040012', (47, 70))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('copy number alterations', 'Var', (9, 32))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
353715	28102292	Integrated molecular analysis reveals complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas.	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (105, 131))	('epigenomic alterations', 'Var', (79, 101))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (105, 130))	('esophageal adenocarcinomas', 'Disease', (105, 131))	('interactions', 'Reg', (46, 58))
353731	27092320	When the gel comes into contact with blood or tissue fluids, the change in pH and salt concentration causes fiber formation and gelation that block the blood vessels in the hemorrhagic area and generate the hemostatic effects.	('generate', 'Reg', (194, 202))	('block', 'NegReg', (142, 147))	('hemostatic effects', 'CPA', (207, 225))	('fiber formation', 'CPA', (108, 123))	('blood vessels in the hemorrhagic area', 'CPA', (152, 189))	('change', 'Var', (65, 71))	('salt', 'Chemical', 'MESH:D012492', (82, 86))	('gelation', 'CPA', (128, 136))
353812	25464508	In contrast, SB431542 addition downregulated the expression of N-cadherin and Vimentin, but upregulated the expression of E-cadherin.	('upregulated', 'PosReg', (92, 103))	('SB431542', 'Chemical', 'MESH:C459179', (13, 21))	('E-cadherin', 'Gene', (122, 132))	('expression', 'MPA', (49, 59))	('N-cadherin', 'Gene', (63, 73))	('SB431542', 'Var', (13, 21))	('E-cadherin', 'Gene', '999', (122, 132))	('Vimentin', 'Gene', (78, 86))	('downregulated', 'NegReg', (31, 44))	('expression', 'MPA', (108, 118))	('N-cadherin', 'Gene', '1000', (63, 73))	('Vimentin', 'Gene', '7431', (78, 86))
353879	25464508	We evaluated the E-cadherin, Vimentin expression in response to SB431542 treatment, E-cadherin and vimentin protein levels were significant differences in the SB431542 treated ESCC cells as compared with controls, (Fig.2D, H, L, p<0.05, Y axis: optical densities of test bands versus beta-actin bands).	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('beta-actin', 'Gene', '728378', (284, 294))	('SB431542', 'Chemical', 'MESH:C459179', (64, 72))	('beta-actin', 'Gene', (284, 294))	('Vimentin', 'Gene', (29, 37))	('SB431542', 'Gene', (64, 72))	('Vimentin', 'Gene', '7431', (29, 37))	('E-cadherin', 'Gene', (17, 27))	('E-cadherin', 'Gene', '999', (17, 27))	('vimentin', 'Gene', '7431', (99, 107))	('SB431542', 'Chemical', 'MESH:C459179', (159, 167))	('SB431542', 'Var', (159, 167))	('vimentin', 'Gene', (99, 107))
353882	25464508	Thus, SB431542 may inhibit EMT process by blocking TGFbeta1/Smad signaling pathway.	('blocking', 'NegReg', (42, 50))	('inhibit', 'NegReg', (19, 26))	('EMT process', 'CPA', (27, 38))	('SB431542', 'Var', (6, 14))	('TGFbeta1', 'Gene', '7040', (51, 59))	('TGFbeta1', 'Gene', (51, 59))	('SB431542', 'Chemical', 'MESH:C459179', (6, 14))
353883	25464508	We further explored the role of SB431542 in blocking TGFbeta1-induced EMT and found that SB431542 could attenuate TGF beta1-mediated EMT in a dose-dependent manner (Fig.	('TGFbeta1', 'Gene', '7040', (53, 61))	('TGFbeta1', 'Gene', (53, 61))	('attenuate', 'NegReg', (104, 113))	('SB431542', 'Var', (89, 97))	('SB431542', 'Chemical', 'MESH:C459179', (89, 97))	('SB431542', 'Chemical', 'MESH:C459179', (32, 40))
353938	25464508	Our data have demonstrated that recombinant TGF-beta1, either in well or poor differentiated ESCC cells, may induce morphologic changes from cuboidal to spindle shape.	('induce', 'Reg', (109, 115))	('TGF-beta1', 'Gene', (44, 53))	('TGF-beta1', 'Gene', '7040', (44, 53))	('recombinant', 'Var', (32, 43))
353939	25464508	Interestingly, this morphologic change did not occur obviously in the presence of SB431542 when stimulated with TGF-beta1, suggesting an effective blockage of TGF-beta1 by SB-431542.	('SB-431542', 'Var', (172, 181))	('TGF-beta1', 'Gene', '7040', (159, 168))	('SB431542', 'Chemical', 'MESH:C459179', (82, 90))	('TGF-beta1', 'Gene', (159, 168))	('SB431542', 'Gene', (82, 90))	('blockage', 'NegReg', (147, 155))	('TGF-beta1', 'Gene', '7040', (112, 121))	('TGF-beta1', 'Gene', (112, 121))	('SB-431542', 'Chemical', 'MESH:C459179', (172, 181))
353946	25464508	SB432542 abrogates the function of TGF-beta1-induced EMT in keeping with a previous report.	('function', 'MPA', (23, 31))	('SB432542', 'Var', (0, 8))	('TGF-beta1', 'Gene', '7040', (35, 44))	('abrogates', 'NegReg', (9, 18))	('TGF-beta1', 'Gene', (35, 44))	('SB432542', 'Chemical', '-', (0, 8))
353973	24146981	Overexpression/mutation of histone lysine demethylases (KDMs) has been implicated in tumor initiation and progression.	('tumor initiation', 'Disease', (85, 101))	('implicated', 'Reg', (71, 81))	('Overexpression/mutation', 'Var', (0, 23))	('demethylase', 'Gene', (42, 53))	('tumor initiation', 'Disease', 'MESH:D009369', (85, 101))	('histone', 'Protein', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('demethylase', 'Gene', '8932', (42, 53))
353983	24146981	Following knockdown of PHF8 expression, we found significant inhibition of the proliferation of ESCC cells (TE-1, TE-2, and TE-8), indicating that PHF8 positively regulated the proliferation of ESCC cells (Figure 1).	('proliferation', 'CPA', (79, 92))	('inhibition', 'NegReg', (61, 71))	('TE-2', 'Gene', '8260', (114, 118))	('PHF8', 'Gene', (23, 27))	('TE-2', 'Gene', (114, 118))	('knockdown', 'Var', (10, 19))
353999	24146981	After PHF8 knockdown, the percentages of early- and late-stage apoptotic TE-1 cells were increased by 6- and 2-fold, respectively, whereas those of early- and late-stage apoptotic TE-2 cells were increased by 1.7- and 1.3-fold, respectively.	('TE-2', 'Gene', '8260', (180, 184))	('increased', 'PosReg', (89, 98))	('early-', 'CPA', (41, 47))	('TE-2', 'Gene', (180, 184))	('late-stage apoptotic TE-1 cells', 'CPA', (52, 83))	('PHF8', 'Gene', (6, 10))	('knockdown', 'Var', (11, 20))
354005	24146981	We found that tumors in nude mice formed by injection of TE-1 cells with knockdown of PHF8 expression were smaller compared with those formed by TE-1 cells expressing non-silencing shRNA or control cells (Figure 5A).	('tumors', 'Disease', (14, 20))	('PHF8', 'Gene', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('nude mice', 'Species', '10090', (24, 33))	('smaller', 'NegReg', (107, 114))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('knockdown', 'Var', (73, 82))
354006	24146981	The average volume of tumors in mice injected with cells expressing PHF8 shRNA was 1367.93+-281.05 mm3 compared with 2026.00+-479.75 mm3 and 2197.86+-453.57 mm3 in mice injected with cells expressing non-silencing shRNA and control cells, respectively (P = 0.047 and P = 0.010, respectively) (Figure 5B).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('PHF8 shRNA', 'Var', (68, 78))	('mice', 'Species', '10090', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mice', 'Species', '10090', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
354009	24146981	In tumors derived from cells expressing non-silencing shRNA or control cells, PHF8 expression was high, whereas an obvious reduction of PHF8 expression was observed in tumors derived from PHF8 shRNA-expressing TE-1 cells (Figure 5D and 5E).	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('non-silencing', 'Var', (40, 53))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('PHF8', 'Gene', (78, 82))	('reduction', 'NegReg', (123, 132))	('expression', 'MPA', (141, 151))	('expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
354012	24146981	Ki67 expression in tumors derived from PHF8 shRNA-expressing TE-1 cells was distinctly lower than that in tumors derived from cells expressing non-silencing shRNA or control cells (Figure 5F).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('expression', 'MPA', (5, 15))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('lower', 'NegReg', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Ki67', 'Gene', (0, 4))	('PHF8 shRNA-expressing', 'Var', (39, 60))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
354017	24146981	It is well known that carcinogenesis is a multistage process in which genetic and epigenetic changes lead to oncogene activation and tumor suppressor gene inactivation.	('activation', 'PosReg', (118, 128))	('inactivation', 'NegReg', (155, 167))	('oncogene', 'Protein', (109, 117))	('epigenetic changes', 'Var', (82, 100))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('carcinogenesis', 'Disease', (22, 36))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (22, 36))
354018	24146981	Aberrant DNA methylation of tumor suppressor genes is well documented in ESCC.	('tumor', 'Disease', (28, 33))	('Aberrant DNA methylation', 'Var', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('ESCC', 'Disease', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
354019	24146981	Our previous studies have shown that aberrant DNA methylation of the regulatory regions of human COX-2, SFRP1, SFRP2, and PTX3 genes plays a crucial role in the development of ESCC.	('ESCC', 'Disease', (176, 180))	('DNA methylation', 'MPA', (46, 61))	('COX-2', 'Gene', (97, 102))	('role', 'Reg', (149, 153))	('SFRP1', 'Gene', '6422', (104, 109))	('PTX3', 'Gene', (122, 126))	('PTX3', 'Gene', '5806', (122, 126))	('SFRP2', 'Gene', '6423', (111, 116))	('SFRP2', 'Gene', (111, 116))	('SFRP1', 'Gene', (104, 109))	('COX-2', 'Gene', '4513', (97, 102))	('aberrant', 'Var', (37, 45))	('human', 'Species', '9606', (91, 96))
354021	24146981	Overexpression/mutation of KDMs has been implicated in tumor initiation and progression.	('tumor initiation', 'Disease', 'MESH:D009369', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Overexpression/mutation', 'Var', (0, 23))	('KDMs', 'Gene', (27, 31))	('tumor initiation', 'Disease', (55, 71))	('implicated', 'Reg', (41, 51))
354024	24146981	In line with our results, there are reports showing that knockdown of PHF8 remarkably inhibits the proliferation of HeLa cancer cells.	('PHF8', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('inhibits', 'NegReg', (86, 94))	('HeLa cancer', 'Disease', 'MESH:D009369', (116, 127))	('knockdown', 'Var', (57, 66))	('proliferation', 'CPA', (99, 112))	('HeLa cancer', 'Disease', (116, 127))
354030	24146981	TE-1 cells are well differentiated and the TNM Classification of Malignant Tumors (TNM) stage is T3N0M0 stage 2a, whereas TE-2 cells are poorly differentiated with a TNM stage of T4N1M0 stage 3, and TE-8 cells are moderately differentiated with a TNM stage of T3N1M0 stage 3.	('TE-2', 'Gene', (122, 126))	('TNM', 'Gene', (166, 169))	('TNM', 'Gene', '10178', (247, 250))	('Malignant Tumors', 'Disease', (65, 81))	('TNM', 'Gene', (43, 46))	('T3N0M0 stage', 'Var', (97, 109))	('Tumors', 'Phenotype', 'HP:0002664', (75, 81))	('TNM', 'Gene', '10178', (166, 169))	('TNM', 'Gene', (247, 250))	('TNM', 'Gene', '10178', (83, 86))	('Malignant Tumors', 'Disease', 'MESH:D018198', (65, 81))	('TE-2', 'Gene', '8260', (122, 126))	('TNM', 'Gene', '10178', (43, 46))	('Tumor', 'Phenotype', 'HP:0002664', (75, 80))	('TNM', 'Gene', (83, 86))
354033	24146981	Overexpression or mutation of JmjC domain-containing KDMs has also been linked to many types of cancer, including PHF8 in prostate cancer.	('cancer', 'Disease', (131, 137))	('prostate cancer', 'Disease', 'MESH:D011471', (122, 137))	('JmjC', 'Gene', (30, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('linked', 'Reg', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('prostate cancer', 'Disease', (122, 137))	('PHF8', 'Disease', (114, 118))	('mutation', 'Var', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', (96, 102))
354081	24146981	Then, endogenous peroxidases were inactivated with 3% hydrogen peroxide and non-specific binding sites were blocked with 10% normal goat serum for 1 h. The sections were then incubated with the following primary antibodies (both purchased from Abcam): rabbit polyclonal anti-PHF8 (1:200) or anti-Ki67 (1:200) at 4 C overnight, followed by a biotinylated secondary antibody for 30 min.	('anti-Ki67 (1:200', 'Var', (291, 307))	('rabbit', 'Species', '9986', (252, 258))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (54, 71))	('1:200', 'Var', (302, 307))	('goat', 'Species', '9925', (132, 136))
354093	32160365	The PD-L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut-off 1%) and OS (11.33 vs 6.24 months, cut-off 1%).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('PFS', 'Disease', (72, 75))	('positivity', 'Var', (10, 20))	('PD-L1', 'Gene', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('PD-L1', 'Gene', '29126', (4, 9))
354157	32160365	Time to response results for a small number of responding patients (n = 2-5) were numerically shorter in negative patients compared with positive patients at all PD-L1 cut-off values (Table 2).	('PD-L1', 'Gene', '29126', (162, 167))	('Time', 'MPA', (0, 4))	('shorter', 'NegReg', (94, 101))	('negative', 'Var', (105, 113))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (146, 154))	('PD-L1', 'Gene', (162, 167))
354175	32160365	Studies investigating the relationship between response to treatment with other PD-1/PD-L1-targeted agents have generally shown that the presence of PD-L1 expression is related to response to treatment 21 ,  22 ,  23 ,  24 ; this relationship needs to be explored further with nivolumab.	('PD-L1', 'Gene', (149, 154))	('nivolumab', 'Chemical', 'MESH:D000077594', (277, 286))	('response to', 'MPA', (180, 191))	('PD-L1', 'Gene', '29126', (149, 154))	('PD-L1', 'Gene', (85, 90))	('presence', 'Var', (137, 145))	('PD-L1', 'Gene', '29126', (85, 90))	('PD-1', 'Gene', (80, 84))	('related', 'Reg', (169, 176))	('PD-1', 'Gene', '5133', (80, 84))
354177	32160365	25 ,  26 ,  27 ,  28 ,  29 ,  30 ,  31  Similar to the present study, patients with basal-like breast cancer showed that those with CD8+ TILs survived 3.5 years longer than those who did not 31  in other studies of patients with breast cancer, the presence of TILs was prognostic for both DFS and OS 28  and event-free survival.	('presence', 'Var', (248, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('TIL', 'Gene', (260, 263))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('breast cancer', 'Disease', (229, 242))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))	('TIL', 'Gene', '7096', (137, 140))	('patients', 'Species', '9606', (70, 78))	('breast cancer', 'Disease', (95, 108))	('CD8', 'Gene', '925', (132, 135))	('OS 28', 'Disease', (297, 302))	('TIL', 'Gene', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('DFS', 'Disease', (289, 292))	('TIL', 'Gene', '7096', (260, 263))	('patients', 'Species', '9606', (215, 223))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CD8', 'Gene', (132, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))	('prognostic', 'Reg', (269, 279))
354213	32280477	More recently, targeted next-generation sequencing has demonstrated shared genetic alterations between epidermoid metaplasia and esophageal squamous neoplasia, suggesting that epidermoid metaplasia is a potential precursor lesion and progression may be predicted by the presence of a TP53 mutation.	('epidermoid metaplasia', 'Disease', (176, 197))	('neoplasia', 'Phenotype', 'HP:0002664', (149, 158))	('esophageal squamous neoplasia', 'Disease', 'MESH:D000077277', (129, 158))	('mutation', 'Var', (289, 297))	('epidermoid', 'Disease', (103, 113))	('TP53', 'Gene', '7157', (284, 288))	('TP53', 'Gene', (284, 288))	('esophageal squamous neoplasia', 'Disease', (129, 158))	('squamous neoplasia', 'Phenotype', 'HP:0002860', (140, 158))
354224	32085741	Mechanistically, ropivacaine but not bupivacaine decreased the activities of Ras superfamily members with the dominant inhibitory effects on RhoA and Ras, independent of sodium channel blockade.	('bupivacaine', 'Chemical', 'MESH:D002045', (37, 48))	('RhoA', 'Gene', (141, 145))	('activities', 'MPA', (63, 73))	('RhoA', 'Gene', '387', (141, 145))	('decreased', 'NegReg', (49, 58))	('ropivacaine', 'Chemical', 'MESH:D000077212', (17, 28))	('ropivacaine', 'Var', (17, 28))	('Ras', 'Protein', (77, 80))
354225	32085741	Rescue studies using constitutively active Ras and Rho activator calpeptin demonstrated that ropivacaine inhibited migration mainly through RhoA whereas growth and survival were mainly inhibited through Ras in melanoma cells.	('ropivacaine', 'Var', (93, 104))	('migration', 'CPA', (115, 124))	('inhibited', 'NegReg', (105, 114))	('RhoA', 'Gene', (140, 144))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))	('RhoA', 'Gene', '387', (140, 144))	('ropivacaine', 'Chemical', 'MESH:D000077212', (93, 104))
354265	32085741	A375 harbors BRAF V600E mutation and is p53 positive whereas A431 contains wildtype BRAF.	('V600E', 'Var', (18, 23))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (84, 88))	('p53', 'Gene', (40, 43))	('BRAF', 'Gene', (13, 17))	('p53', 'Gene', '7157', (40, 43))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('A431', 'CellLine', 'CVCL:0037', (61, 65))
354305	32085741	After treatment of ropivacaine and lidocaine but not bupivacaine at concentration range from 0.25 to 2 mM, we observed a significant reduction on the migrated cell number and BrdU level, and an increase in the percentage of Annexin V in two cell lines which represent human melanoma model with different cellular origin and oncogenic mutations (Fig.	('mutations', 'Var', (334, 343))	('BrdU', 'Chemical', 'MESH:D001973', (175, 179))	('Annexin V', 'Gene', '308', (224, 233))	('Annexin V', 'Gene', (224, 233))	('lidocaine', 'Chemical', 'MESH:D008012', (35, 44))	('human', 'Species', '9606', (268, 273))	('ropivacaine', 'Chemical', 'MESH:D000077212', (19, 30))	('reduction', 'NegReg', (133, 142))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('increase', 'PosReg', (194, 202))	('melanoma', 'Disease', (274, 282))	('migrated cell number', 'CPA', (150, 170))	('bupivacaine', 'Chemical', 'MESH:D002045', (53, 64))	('BrdU level', 'MPA', (175, 185))
354344	31572524	Finally, by introduction of a double bond at the C2-C3 position in the dihydrokaempferol skeleton, KP is generated.	('rat', 'Species', '10116', (109, 112))	('dihydrokaempferol', 'Chemical', 'MESH:C080220', (71, 88))	('introduction', 'Reg', (12, 24))	('double bond', 'Var', (30, 41))
354379	31572524	These results suggest that KP modulates the expression of ANGPTL2 to ameliorate mastitis.	('mastitis', 'Disease', (80, 88))	('modulates', 'Var', (30, 39))	('rat', 'Species', '10116', (75, 78))	('mastitis', 'Disease', 'MESH:D008413', (80, 88))	('ANGPTL2', 'Gene', (58, 65))	('ANGPTL2', 'Gene', '23452', (58, 65))	('ameliorate', 'PosReg', (69, 79))
354403	31572524	It may also develop as a result of the presence of Helicobacter pylori, decreased blood flow, increased acid secretion and pepsin activity, imbalanced bile salt secretion, and reduced mucus and bicarbonate secretion.	('imbalanced bile salt secretion', 'MPA', (140, 170))	('Helicobacter pylori', 'Species', '210', (51, 70))	('reduced', 'NegReg', (176, 183))	('decreased', 'NegReg', (72, 81))	('increased', 'PosReg', (94, 103))	('imbalance', 'Phenotype', 'HP:0002172', (140, 149))	('Helicobacter pylori', 'Var', (51, 70))	('bicarbonate', 'Chemical', 'MESH:D001639', (194, 205))	('blood flow', 'MPA', (82, 92))
354406	31572524	In addition, ethanol markedly reduces the level of NO required for physiological functions in the gastric mucosa and decelerates the flow of gastric blood.	('gastric mucosa', 'Disease', 'MESH:D013274', (98, 112))	('ethanol', 'Chemical', 'MESH:D000431', (13, 20))	('level of NO required for physiological functions', 'MPA', (42, 90))	('ethanol', 'Var', (13, 20))	('rat', 'Species', '10116', (123, 126))	('decelerates', 'NegReg', (117, 128))	('flow of gastric blood', 'MPA', (133, 154))	('reduces', 'NegReg', (30, 37))	('N', 'Chemical', 'MESH:D009584', (51, 52))	('gastric mucosa', 'Disease', (98, 112))
354411	31572524	Since cancer cells tend to have a stubborn inclination to mutate or metastasize, and resistance to treatment is common, it is important to identify safe and effective drugs.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutate', 'Var', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('metastasize', 'CPA', (68, 79))	('cancer', 'Disease', (6, 12))
354423	31572524	Inhibition of caspase-9 expression further activates caspase-3, triggering a cascade of caspases, which triggers apoptosis.	('caspases', 'Gene', (88, 96))	('triggering', 'Reg', (64, 74))	('apoptosis', 'CPA', (113, 122))	('caspase-3', 'Gene', (53, 62))	('caspase-9', 'Gene', '842', (14, 23))	('activates', 'PosReg', (43, 52))	('caspases', 'Gene', '841;842', (88, 96))	('Inhibition', 'Var', (0, 10))	('caspase-9', 'Gene', (14, 23))	('cascade of', 'MPA', (77, 87))	('caspase-3', 'Gene', '836', (53, 62))	('triggers', 'Reg', (104, 112))
354431	31572524	It has been suggested that KP-3-O-rhamnoside triggers cell death intrinsically in MCF-7 cells via the mitochondrial caspase-9 signaling pathway and activation of poly ADP-ribose polymerase (PARP).	('cell death', 'CPA', (54, 64))	('caspase-9', 'Gene', '842', (116, 125))	('KP-3-O-rhamnoside', 'Var', (27, 44))	('KP-3-O-rhamnoside', 'Chemical', 'MESH:C067980', (27, 44))	('activation', 'PosReg', (148, 158))	('PARP', 'Gene', '142', (190, 194))	('poly ADP-ribose polymerase', 'Gene', '142', (162, 188))	('caspase-9', 'Gene', (116, 125))	('poly ADP-ribose polymerase', 'Gene', (162, 188))	('PARP', 'Gene', (190, 194))
354435	31572524	By analyzing the effects of KP on apoptosis and DNA damage, Zhu et al revealed that it effectively inhibited the proliferation of the triple-negative breast cancer cell line malondialdehyde (MDA)-MB-231; this effect was stronger in MDA-MB-231 cells than in the estrogen receptor-positive BT474 cell line.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('malondialdehyde', 'Chemical', 'MESH:D008315', (174, 189))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('inhibited', 'NegReg', (99, 108))	('estrogen receptor', 'Gene', (261, 278))	('breast cancer', 'Disease', (150, 163))	('estrogen receptor', 'Gene', '2099', (261, 278))	('MDA-MB-231', 'Var', (232, 242))	('rat', 'Species', '10116', (120, 123))	('malondialdehyde', 'MPA', (174, 189))	('proliferation', 'MPA', (113, 126))
354456	31572524	It was demonstrated that KP is able to regulate pro-apoptotic and anti-apoptotic protein expression by inducing apoptosis in A2780/CP70, A2780/WT and OVCAR-3 ovarian cancer cell lines.	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('inducing', 'PosReg', (103, 111))	('apoptosis', 'CPA', (112, 121))	('A2780/CP70', 'Var', (125, 135))	('A2780/WT', 'Var', (137, 145))	('ovarian cancer', 'Disease', 'MESH:D010051', (158, 172))	('ovarian cancer', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('rat', 'Species', '10116', (14, 17))
354460	31572524	Mutations and/or deletions in Chk2 are associated with multiple cancer types.	('deletions', 'Var', (17, 26))	('cancer', 'Disease', (64, 70))	('Chk2', 'Gene', '11200', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Mutations', 'Var', (0, 9))	('Chk2', 'Gene', (30, 34))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
354477	31572524	In APL, fusion between retinoic acid receptor-alpha and promyelocytic leukemia genes is common.	('retinoic acid receptor-alpha', 'Gene', (23, 51))	('APL', 'Disease', (3, 6))	('promyelocytic leukemia', 'Disease', 'MESH:D015473', (56, 78))	('promyelocytic leukemia', 'Disease', (56, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('fusion', 'Var', (8, 14))	('APL', 'Phenotype', 'HP:0004836', (3, 6))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (56, 78))	('retinoic acid receptor-alpha', 'Gene', '5914', (23, 51))	('APL', 'Disease', 'MESH:D015473', (3, 6))
354486	31572524	Inactivation of the PI3K/AKT signaling pathway and downstream proteins may be the mechanism by which KP exerts its effects against CCA and prevents its progression.	('AKT', 'Gene', (25, 28))	('prevents', 'NegReg', (139, 147))	('CCA', 'Disease', (131, 134))	('AKT', 'Gene', '207', (25, 28))	('CCA', 'Phenotype', 'HP:0030153', (131, 134))	('Inactivation', 'Var', (0, 12))	('CCA', 'Disease', 'MESH:D018281', (131, 134))
354499	31572524	Previous evidence has suggested that the methylation of genomic DNA is closely linked to bladder cancer.	('DNA', 'Gene', (64, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('linked', 'Reg', (79, 85))	('methylation', 'Var', (41, 52))	('bladder cancer', 'Disease', (89, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('genomic', 'Var', (56, 63))
354500	31572524	Therefore, modulating DNA methylation with potent and low toxicity agents is a key strategy to prevent and treat cancer.	('N', 'Chemical', 'MESH:D009584', (23, 24))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('rat', 'Species', '10116', (85, 88))	('toxicity', 'Disease', 'MESH:D064420', (58, 66))	('toxicity', 'Disease', (58, 66))	('cancer', 'Disease', (113, 119))	('modulating', 'Var', (11, 21))
354521	31572524	CCl4 induces lipid peroxidation, which causes membrane breakdown of hepatocytes to subsequently release marker enzymes of hepatotoxicity.	('causes', 'Reg', (39, 45))	('release marker enzymes', 'MPA', (96, 118))	('hepatotoxicity', 'Disease', 'MESH:D056486', (122, 136))	('membrane breakdown', 'MPA', (46, 64))	('lipid peroxidation', 'MPA', (13, 31))	('CCl4', 'Var', (0, 4))	('hepatotoxicity', 'Disease', (122, 136))	('induces', 'Reg', (5, 12))
354522	31572524	It has indicated that after KP 3-O-rutinoside and KP 3-O-glucoside treatment, serum total protein levels were increased, induction of serum aspartate aminotransferase serum alkaline phosphatase and liver malondialdehyde levels by CCl4 was prevented.	('KP 3-O-rutinoside', 'Chemical', 'MESH:C067980', (28, 45))	('increased', 'PosReg', (110, 119))	('KP 3-O-glucoside', 'Var', (50, 66))	('serum total protein levels', 'MPA', (78, 104))	('KP 3-O-glucoside', 'Chemical', 'MESH:C067980', (50, 66))	('aspartate', 'Chemical', 'None', (140, 149))	('aspartate aminotransferase serum', 'Phenotype', 'HP:0031956', (140, 172))	('malondialdehyde', 'Chemical', 'MESH:D008315', (204, 219))	('KP 3-O-rutinoside', 'Var', (28, 45))
354531	31572524	Zhou et al indicated that the protein levels of CYP2E1 in microsomes and mitochondria, heat shock protein 70 (Hsp70) in the cytosol and specificity protein 1 (SP1) in the nucleus and cytosol were reduced in the KP-treated group, and KP also increased the cell viability compared with that in the ethanol-treated group.	('ethanol', 'Chemical', 'MESH:D000431', (296, 303))	('increased', 'PosReg', (241, 250))	('CYP2E1', 'Gene', (48, 54))	('specificity protein 1', 'Gene', '6667', (136, 157))	('cell viability', 'CPA', (255, 269))	('specificity protein 1', 'Gene', (136, 157))	('Hsp70', 'Gene', '3308', (110, 115))	('Hsp70', 'Gene', (110, 115))	('heat shock protein 70', 'Gene', (87, 108))	('shock', 'Phenotype', 'HP:0031273', (92, 97))	('protein levels', 'MPA', (30, 44))	('heat shock protein 70', 'Gene', '3308', (87, 108))	('CYP2E1', 'Gene', '1571', (48, 54))	('KP-treated', 'Var', (211, 221))	('reduced', 'NegReg', (196, 203))
354565	31572524	Inhibition of vascular endothelial inflammation is considered a key point in the treatment of numerous vascular diseases, as excessively produced inflammatory mediators may cause irreversible vascular damage and lead to excessive loss of fluid from the circulation, resulting in insufficient tissue perfusion, organ dysfunction and death.	('tissue perfusion', 'CPA', (292, 308))	('vascular diseases', 'Disease', (103, 120))	('organ dysfunction', 'Disease', 'MESH:D009102', (310, 327))	('insufficient', 'NegReg', (279, 291))	('excessively', 'Var', (125, 136))	('lead', 'Reg', (212, 216))	('vascular damage', 'Disease', 'MESH:D014652', (192, 207))	('loss of fluid from the circulation', 'MPA', (230, 264))	('vascular damage', 'Disease', (192, 207))	('vascular endothelial inflammation', 'Phenotype', 'HP:0002633', (14, 47))	('vascular endothelial inflammation', 'Disease', 'MESH:D007249', (14, 47))	('organ dysfunction', 'Disease', (310, 327))	('vascular diseases', 'Disease', 'MESH:D014652', (103, 120))	('cause', 'Reg', (173, 178))	('vascular endothelial inflammation', 'Disease', (14, 47))	('endothelial inflammation', 'Phenotype', 'HP:0002633', (23, 47))
354577	31572524	Xiao et al performed analysis of the aorta and plasma from C57BL/6J control and ApoE-deficient mice treated with or without KP.	('ApoE', 'Gene', '11816', (80, 84))	('C57BL/6J', 'Var', (59, 67))	('mice', 'Species', '10090', (95, 99))	('ApoE', 'Gene', (80, 84))
354587	31572524	High-risk cerebrovascular disease is mainly caused by abnormal blood vessel thrombosis after hemostasis, which may include fibrinolytic system dysfunction caused by abnormal fibrinolytic factors, e.g.	('fibrinolytic system dysfunction', 'Disease', 'MESH:C565017', (123, 154))	('abnormal', 'Var', (165, 173))	('fibrinolytic system dysfunction', 'Disease', (123, 154))	('cerebrovascular disease', 'Disease', 'MESH:D002561', (10, 33))	('caused by', 'Reg', (44, 53))	('cerebrovascular disease', 'Disease', (10, 33))	('abnormal blood vessel thrombosis', 'Disease', (54, 86))	('abnormal fibrinolytic', 'Phenotype', 'HP:0040224', (165, 186))	('abnormal blood vessel thrombosis', 'Disease', 'MESH:D013927', (54, 86))
354610	31572524	In addition, after its oxidation, overactivated CaMKII promotes cell death, which may lead to arrhythmias, heart failure and sudden death.	('arrhythmias', 'Disease', (94, 105))	('arrhythmias', 'Phenotype', 'HP:0011675', (94, 105))	('heart failure', 'Disease', 'MESH:D006333', (107, 120))	('overactivated', 'Var', (34, 47))	('heart failure', 'Phenotype', 'HP:0001635', (107, 120))	('cell death', 'CPA', (64, 74))	('sudden death', 'Disease', 'MESH:D003645', (125, 137))	('promotes', 'PosReg', (55, 63))	('heart failure', 'Disease', (107, 120))	('sudden death', 'Disease', (125, 137))	('CaMKII', 'Gene', (48, 54))	('lead to', 'Reg', (86, 93))	('CaMKII', 'Gene', '818', (48, 54))	('arrhythmias', 'Disease', 'MESH:D001145', (94, 105))
354630	31572524	KP or thiadiazolidinone-8 increased the level of GSK-3beta phosphorylation and reduced the release of cytochrome C compared with the control and I/R groups.	('level', 'MPA', (40, 45))	('reduced', 'NegReg', (79, 86))	('I/R', 'Disease', (145, 148))	('GSK-3beta', 'Gene', '2932', (49, 58))	('GSK-3beta', 'Gene', (49, 58))	('I/R', 'Disease', 'MESH:D015427', (145, 148))	('cytochrome C', 'Gene', (102, 114))	('increased', 'PosReg', (26, 35))	('cytochrome C', 'Gene', '54205', (102, 114))	('thiadiazolidinone-8', 'Var', (6, 25))	('thiadiazolidinone', 'Chemical', 'MESH:C494356', (6, 23))
354644	31572524	Han et al hypothesized that inflammasomes are associated with immune homeostasis and their dysregulation leads to neurodegenerative disorders.	('inflammasomes', 'Var', (28, 41))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (114, 141))	('immune homeostasis', 'Disease', (62, 80))	('neurodegenerative disorders', 'Disease', (114, 141))	('dysregulation', 'MPA', (91, 104))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (114, 141))	('associated', 'Reg', (46, 56))	('leads to', 'Reg', (105, 113))
354673	31572524	In vivo, oral administration of KP resulted in a reduced infarct volume in mice after I/R injury and exerted an effect similar to mitochondrial protection in the infarcted area, indicating an association between succinic acid accumulation and I/R injury-induced nerve meta-mitochondrial dysfunction, and suggesting that modulation of Drp1 phosphorylation is a potential strategy for protecting neuronal mitochondrial integrity and treating ischemic stroke.	('nerve meta-mitochondrial dysfunction', 'Disease', (262, 298))	('succinic acid accumulation', 'MPA', (212, 238))	('infarcted', 'Disease', 'MESH:D007238', (162, 171))	('ischemic stroke', 'Disease', (440, 455))	('infarct volume', 'Disease', 'MESH:D007238', (57, 71))	('rat', 'Species', '10116', (372, 375))	('infarcted', 'Disease', (162, 171))	('I/R', 'Disease', (86, 89))	('reduced', 'NegReg', (49, 56))	('modulation', 'Var', (320, 330))	('rat', 'Species', '10116', (22, 25))	('ischemic stroke', 'Phenotype', 'HP:0002140', (440, 455))	('I/R', 'Disease', 'MESH:D015427', (86, 89))	('mice', 'Species', '10090', (75, 79))	('succinic acid', 'Chemical', 'MESH:D019802', (212, 225))	('I/R', 'Disease', (243, 246))	('nerve meta-mitochondrial dysfunction', 'Disease', 'MESH:D028361', (262, 298))	('association', 'Interaction', (192, 203))	('infarct volume', 'Disease', (57, 71))	('ischemic stroke', 'Disease', 'MESH:D002544', (440, 455))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (273, 298))	('I/R', 'Disease', 'MESH:D015427', (243, 246))	('stroke', 'Phenotype', 'HP:0001297', (449, 455))
354719	30264476	Epigenetic biomarkers of promoter DNA methylation in the new era of cancer treatment Promoter DNA methylation, which occurs on cytosine nucleotides across CpG islands, results in gene silencing and represents a major epigenetic alteration in human cancer.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cytosine nucleotides', 'Chemical', 'MESH:D003597', (127, 147))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('methylation', 'Var', (98, 109))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('gene', 'MPA', (179, 183))	('cancer', 'Disease', (68, 74))	('human', 'Species', '9606', (242, 247))
354725	30264476	Cancer clinics using such epigenetic biomarkers are entering a new era of enhanced decision-making with the potential for improved cancer prognosis.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('epigenetic biomarkers', 'Var', (26, 47))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
354728	30264476	Methylated cytosines can be bound by methyl-CpG-binding protein 2 (MeCP2), and the resulting protein-nucleotide can be incorporated into protein complexes that include histone modification enzymes (eg, histone deacetylase complex [HDAC])2 leading to dynamic changes in chromatin structure (Figure 1A).3 As a result, DNA methylation can result in gene silencing due to impaired access of transcription factors through condensed and closed chromatin (Figure 1B).	('MeCP2', 'Gene', '4204', (67, 72))	('cytosines', 'Chemical', 'MESH:D003596', (11, 20))	('MeCP2', 'Gene', (67, 72))	('methyl-CpG-binding protein 2', 'Gene', (37, 65))	('access', 'Interaction', (377, 383))	('gene', 'MPA', (346, 350))	('DNA methylation', 'Var', (316, 331))	('methyl-CpG-binding protein 2', 'Gene', '4204', (37, 65))	('impaired', 'NegReg', (368, 376))
354731	30264476	5, 6, 7 Rigorous screening by PUM has repeatedly unveiled novel cancer-prone methylation genes associated with tumor suppressive functions, such as the encoding homeobox only protein homeobox (HOPX) gene has been identified in various cancers,8, 9, 10, 11, 12 and HOPX expression has been independently revealed to be a biomarker representing differentiation or quiescent stem cell signatures in normal organ tissues.13, 14, 15, 16, 17 Hence, epigenetic changes in differentiation markers may be essential for the initiation of cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (528, 534))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('HOPX', 'Gene', '84525', (193, 197))	('HOPX', 'Gene', '84525', (264, 268))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancer', 'Disease', (64, 70))	('epigenetic changes', 'Var', (443, 461))	('cancer', 'Disease', 'MESH:D009369', (528, 534))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Disease', (111, 116))	('HOPX', 'Gene', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Disease', (235, 241))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancers', 'Disease', (235, 242))	('cancer', 'Disease', (528, 534))	('HOPX', 'Gene', (264, 268))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
354732	30264476	DNA methylation in primary cancer tissues does not necessarily represent cancer-specific methylation.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('methylation', 'Var', (4, 15))	('primary cancer', 'Disease', (19, 33))	('primary cancer', 'Disease', 'MESH:D009369', (19, 33))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
354737	30264476	This method is appealing for discovery screening of novel methylation events that represent novel TSG in primary tumors,4, 5, 6, 7 as well as the clear differentiation of primary tumors from the corresponding normal tissues (Figure 2A).	('primary tumors', 'Disease', 'MESH:D009369', (171, 185))	('primary tumors', 'Disease', 'MESH:D009369', (105, 119))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('methylation', 'Var', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('primary tumors', 'Disease', (171, 185))	('primary tumors', 'Disease', (105, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
354741	30264476	Intriguingly, this definition of hypermethylation by the Q-MSP technique was consistent with the results (presence or absence of methylation) of direct sequencing in gastric cancer cell lines.9 The use of a Q-MSP cut-off value to discriminate cancer tissues from normal tissues, therefore, is highly consistent with the empirical results of direct sequencing.	('gastric cancer', 'Disease', (166, 180))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Q-MSP', 'Var', (207, 212))
354742	30264476	Representative methylation values of the HOPX gene based on the cloned sequencing are shown for primary cancer and normal mucosa tissues in Figure 2B.22 These results demonstrate that hypomethylation is not synonymous with complete unmethylation.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('primary cancer', 'Disease', (96, 110))	('primary cancer', 'Disease', 'MESH:D009369', (96, 110))	('HOPX', 'Gene', (41, 45))	('hypomethylation', 'Var', (184, 199))	('HOPX', 'Gene', '84525', (41, 45))
354750	30264476	Since 2010, the frequent hypermethylation of the CDO1 gene has been reported in primary breast,33, 34 lung,19 biliary tract,35 esophageal squamous cell carcinoma (SCC)36 and adenocarcinoma,37 gastric,19 colorectal,19, 38 bladder,19 penile (SCC),39 kidney,40 prostate,41 endometrial,42 pancreatic43 and gallbladder cancer.44 The frequencies of the aberrations in CDO1 methylation in these cancers are high (Figure 3A).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (127, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('pancreatic', 'Disease', (285, 295))	('gallbladder cancer', 'Disease', 'MESH:D005706', (302, 320))	('adenocarcinoma', 'Disease', (174, 188))	('SCC', 'Phenotype', 'HP:0002860', (240, 243))	('SCC', 'Gene', (163, 166))	('CDO1', 'Gene', '1036', (362, 366))	('cancers', 'Phenotype', 'HP:0002664', (388, 395))	('CDO1', 'Gene', (49, 53))	('adenocarcinoma', 'Disease', 'MESH:D000230', (174, 188))	('SCC', 'Gene', '6317', (240, 243))	('cancers', 'Disease', (388, 395))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('SCC', 'Gene', (240, 243))	('gallbladder cancer', 'Disease', (302, 320))	('CDO1', 'Gene', '1036', (49, 53))	('esophageal squamous cell carcinoma', 'Disease', (127, 161))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('pancreatic', 'Disease', 'MESH:D010195', (285, 295))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('methylation', 'Var', (367, 378))	('CDO1', 'Gene', (362, 366))	('cancers', 'Disease', 'MESH:D009369', (388, 395))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('bladder cancer', 'Phenotype', 'HP:0009725', (306, 320))	('SCC', 'Gene', '6317', (163, 166))
354752	30264476	Specifically in esophageal cancer, CDO1 methylation was significantly higher in advanced SCC tumors with cStage II/III than in the superficial tumors with cStage I,36 and was significantly higher in larger-sized adenocarcinomas than in smaller-sized adenocarcinomas.37 Aberrant methylation of the CDO1 gene accumulated as the tumor progressed, as demonstrated in colorectal38 and gallbladder tumorigenesis44 (Figure 4A,B).	('adenocarcinomas', 'Disease', 'MESH:D000230', (212, 227))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('adenocarcinomas', 'Disease', (212, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('tumor', 'Disease', (392, 397))	('adenocarcinomas', 'Disease', 'MESH:D000230', (250, 265))	('adenocarcinomas', 'Disease', (250, 265))	('CDO1', 'Gene', (297, 301))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (392, 397))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('CDO1', 'Gene', (35, 39))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))	('tumor', 'Disease', (326, 331))	('CDO1', 'Gene', '1036', (297, 301))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('Aberrant', 'Var', (269, 277))	('tumors', 'Disease', (93, 99))	('SCC tumors', 'Disease', (89, 99))	('CDO1', 'Gene', '1036', (35, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (16, 33))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (143, 148))	('accumulated', 'PosReg', (307, 318))	('tumor', 'Disease', (93, 98))	('methylation', 'MPA', (278, 289))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('SCC tumors', 'Disease', 'MESH:D009369', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('esophageal cancer', 'Disease', (16, 33))	('colorectal38', 'Disease', (363, 375))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
354754	30264476	Cases with CDO1 hypermethylation also showed poorer prognosis than those with hypomethylation in primary breast,34 prostate,41 colorectal,38 gallbladder44 and esophageal cancers.36, 37 Interestingly, in primary breast cancer, CDO1 hypermethylation did not correlate significantly with markers of tumor progression such as TNM factors, while CDO1 hypermethylation was the strongest independent prognostic factor.34 Importantly, the prognostic relevance of CDO1 methylation was confirmed even in a prospective nationwide cohort study in the Netherlands of patients with renal cell carcinoma.40 These findings suggest that the methylation status of the CDO1 gene could be used as a prognostic marker in various human cancers.	('renal cell carcinoma', 'Disease', (568, 588))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('CDO1', 'Gene', (226, 230))	('cancers', 'Disease', (170, 177))	('human', 'Species', '9606', (708, 713))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('CDO1', 'Gene', (455, 459))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('patients', 'Species', '9606', (554, 562))	('CDO1', 'Gene', '1036', (226, 230))	('cancer', 'Phenotype', 'HP:0002664', (714, 720))	('methylation', 'Var', (624, 635))	('tumor', 'Disease', (296, 301))	('CDO1', 'Gene', (11, 15))	('esophageal cancers', 'Disease', (159, 177))	('CDO1', 'Gene', '1036', (455, 459))	('cancers', 'Phenotype', 'HP:0002664', (714, 721))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (579, 588))	('cancers', 'Disease', (714, 721))	('breast cancer', 'Disease', (211, 224))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (568, 588))	('CDO1', 'Gene', '1036', (11, 15))	('CDO1', 'Gene', (341, 345))	('esophageal cancers', 'Disease', 'MESH:D004938', (159, 177))	('CDO1', 'Gene', (650, 654))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('CDO1', 'Gene', '1036', (341, 345))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancers', 'Disease', 'MESH:D009369', (714, 721))	('CDO1', 'Gene', '1036', (650, 654))
354757	30264476	Promoter DNA methylation of the CDO1 gene is one of the most relevant changes across the whole genome, so methylation of this gene's promoter could be a highly promising epigenetic cancer biomarker candidate, even in human body fluids.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('human', 'Species', '9606', (217, 222))	('methylation', 'Var', (106, 117))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('CDO1', 'Gene', '1036', (32, 36))	('CDO1', 'Gene', (32, 36))	('cancer', 'Disease', (181, 187))
354758	30264476	Q-MSP can detect, at most, a 1/1000-dilution level of the fully methylated genes (Figure 2C); however, this detection level would not provide satisfactory sensitivity for detection of the marker in the plasma DNA of colorectal cancer (CRC) patients (in whom the CDO1 promoter is seen in 40% of stage IV disease).45 Digital PCR for CDO1 methylation (which can detect a 1/100 000 dilution of fully methylated CDO1) might be sufficient to detect cancer cells in plasma, as shown for VIMENTIN (VIM) gene hypermethylation in patients with CRC.46 However, CDO1 gene methylation was reported to be readily detected in the plasma of patients with lung cancer,47, 48 where Q-MSP detection of CDO1 methylation in plasma or serum showed 65% sensitivity with 74% specificity, and, when assessed in combination with the methylation of other HRMG, showed high sensitivity even in stage I disease.	('colorectal cancer', 'Disease', (216, 233))	('VIMENTIN', 'Gene', (480, 488))	('VIM', 'Gene', (480, 483))	('CDO1', 'Gene', '1036', (331, 335))	('lung cancer', 'Phenotype', 'HP:0100526', (639, 650))	('patients', 'Species', '9606', (625, 633))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('methylation', 'Var', (688, 699))	('CRC', 'Phenotype', 'HP:0003003', (235, 238))	('cancer', 'Disease', (644, 650))	('stage I disease', 'Disease', (866, 881))	('CDO1', 'Gene', (550, 554))	('cancer', 'Disease', (443, 449))	('cancer', 'Phenotype', 'HP:0002664', (644, 650))	('CRC', 'Phenotype', 'HP:0003003', (534, 537))	('CDO1', 'Gene', (407, 411))	('patients', 'Species', '9606', (520, 528))	('cancer', 'Phenotype', 'HP:0002664', (443, 449))	('colorectal cancer', 'Phenotype', 'HP:0003003', (216, 233))	('CDO1', 'Gene', (262, 266))	('lung cancer', 'Disease', (639, 650))	('CDO1', 'Gene', (683, 687))	('CDO1', 'Gene', '1036', (550, 554))	('patients', 'Species', '9606', (240, 248))	('cancer', 'Disease', (227, 233))	('VIMENTIN', 'Gene', '7431', (480, 488))	('CDO1', 'Gene', '1036', (407, 411))	('VIM', 'Gene', '7431', (490, 493))	('cancer', 'Disease', 'MESH:D009369', (644, 650))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('VIM', 'Gene', (490, 493))	('cancer', 'Disease', 'MESH:D009369', (443, 449))	('CDO1', 'Gene', '1036', (262, 266))	('CDO1', 'Gene', '1036', (683, 687))	('CDO1', 'Gene', (331, 335))	('colorectal cancer', 'Disease', 'MESH:D015179', (216, 233))	('lung cancer', 'Disease', 'MESH:D008175', (639, 650))	('VIM', 'Gene', '7431', (480, 483))
354763	30264476	The peritoneal DNA cytology test-positive gene (CY1) is a critical prognostic marker of gastric cancer, and CY1-positive cases represent stage IV disease.	('CY1-positive', 'Var', (108, 120))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('represent', 'Reg', (127, 136))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('CY1', 'Gene', (48, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('stage IV disease', 'Disease', (137, 153))
354767	30264476	These findings suggested that CDO1 methylation can reflect the presence of remnant cancer cells in the biopsies after treatment by neoadjuvant chemotherapy.	('CDO1', 'Gene', '1036', (30, 34))	('CDO1', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('methylation', 'Var', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
354768	30264476	Epigenetic biomarkers using HRMG can affect the accuracy of: (i) preoperative diagnosis; (ii) intraoperative diagnosis; (iii) pathological diagnosis; and (iv) follow-up surveillance on the therapeutic decision in cancer clinics.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('affect', 'Reg', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('Epigenetic', 'Var', (0, 10))	('cancer', 'Disease', (213, 219))	('HRMG', 'Gene', (28, 32))
354773	30264476	Results of those studies showed that CD1D methylation in the pancreatic juice yielded an AUC value of .92 for patients with pancreatic cancer compared to patients with normal pancreas and chronic pancreatitis.53 CD1D methylation in the pancreatic juice detected pancreatic cancer with 75% sensitivity and 95% specificity.	('CD1D', 'Gene', (212, 216))	('pancreatic', 'Disease', 'MESH:D010195', (124, 134))	('pancreatic cancer', 'Disease', (262, 279))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('pancreatic', 'Disease', (236, 246))	('pancreatic', 'Disease', (61, 71))	('pancreas', 'Disease', 'MESH:D010190', (175, 183))	('CD1D', 'Gene', (37, 41))	('pancreatic', 'Disease', (124, 134))	('pancreatic cancer', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('CD1D', 'Gene', '912', (212, 216))	('pancreatitis', 'Disease', 'MESH:D010195', (196, 208))	('pancreatic', 'Disease', 'MESH:D010195', (262, 272))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (262, 279))	('pancreatitis', 'Disease', (196, 208))	('methylation', 'Var', (217, 228))	('CD1D', 'Gene', '912', (37, 41))	('patients', 'Species', '9606', (154, 162))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('pancreatic', 'Disease', (262, 272))	('pancreatic', 'Disease', 'MESH:D010195', (236, 246))	('pancreatic', 'Disease', 'MESH:D010195', (61, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (262, 279))	('pancreas', 'Disease', (175, 183))	('detected', 'Reg', (253, 261))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('patients', 'Species', '9606', (110, 118))
354802	30264476	CDO1 methylation is one of the most frequent aberrations in gastric cancer tissues.	('frequent', 'Reg', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('methylation', 'Var', (5, 16))	('CDO1', 'Gene', '1036', (0, 4))	('CDO1', 'Gene', (0, 4))	('gastric cancer', 'Disease', (60, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))
354804	30264476	A prospective trial (UMIN000026191) is currently being conducted to confirm the utility of a DNA cytology test using CDO1 methylation in 400 cases of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('methylation', 'Var', (122, 133))	('CDO1', 'Gene', (117, 121))	('gastric cancer', 'Disease', (150, 164))	('CDO1', 'Gene', '1036', (117, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))
354805	30264476	Table 2 provides a comparison between the clinical features of CDO1 methylation and those of CEA mRNA (cDNA) and methylation combinations in the peritoneal fluid washing cytology test.	('clinical', 'Species', '191496', (42, 50))	('CEA', 'Gene', (93, 96))	('methylation', 'Var', (68, 79))	('CDO1', 'Gene', '1036', (63, 67))	('CEA', 'Gene', '1084', (93, 96))	('CDO1', 'Gene', (63, 67))	('peritoneal fluid', 'Phenotype', 'HP:0030995', (145, 161))
354807	30264476	Epigenetic information in the primary tumors should be considered in clinical decisions.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('clinical', 'Species', '191496', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('primary tumors', 'Disease', 'MESH:D009369', (30, 44))	('Epigenetic information', 'Var', (0, 22))	('primary tumors', 'Disease', (30, 44))
354812	30264476	Using HRMG for negative lymph nodes in stage I lung cancer, minimal residual disease in lymph nodes was detected, and such patients showed poorer prognosis than the other patients.68 This result indicated that the detected HRMG methylation may represent a micrometastasis of cancer cells in lymph nodes, which were not capable of being discerned by the conventional pathological searches.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('cancer', 'Disease', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('patients', 'Species', '9606', (123, 131))	('HRMG', 'Gene', (223, 227))	('micrometastasis', 'CPA', (256, 271))	('stage I lung cancer', 'Disease', (39, 58))	('patients', 'Species', '9606', (171, 179))	('stage I lung cancer', 'Disease', 'MESH:D008175', (39, 58))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('methylation', 'Var', (228, 239))
354813	30264476	In stage I lung cancer, postoperative adjuvant chemotherapy was not indicated; however, methylation-positive cases with the pathology-negative lymph nodes showed a 70% survival rate, and this patient selection method may be appropriate in candidates for adjuvant chemotherapy.	('patient', 'Species', '9606', (192, 199))	('stage I lung cancer', 'Disease', (3, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('stage I lung cancer', 'Disease', 'MESH:D008175', (3, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('methylation-positive', 'Var', (88, 108))
354815	30264476	Methylation genes harboring predictive value for anti-cancer drug efficacy provide attractive information for use in the development of therapeutic strategies.	('Methylation genes', 'Var', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (54, 60))
354826	30264476	The surgical decisions that are expected to be most immediately affected by epigenetic markers are those relating to indications of adjuvant therapy for stage I lung cancer or glioblastoma, although cancer diagnosis and surveillance also will be improved by the epigenetic markers.	('glioblastoma', 'Phenotype', 'HP:0012174', (176, 188))	('stage I lung cancer', 'Disease', 'MESH:D008175', (153, 172))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('epigenetic markers', 'Var', (76, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('stage I lung cancer', 'Disease', (153, 172))	('epigenetic markers', 'Var', (262, 280))	('glioblastoma', 'Disease', (176, 188))	('cancer', 'Disease', (199, 205))	('glioblastoma', 'Disease', 'MESH:D005909', (176, 188))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
354843	29568233	Then, tumor inhibition of lncRNA AK001796 knockdown was explored in vitro and in vivo.	('AK001796', 'Gene', '541471', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('AK001796', 'Gene', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('knockdown', 'Var', (42, 51))
354884	29568233	Cell proliferation was measured by using CCK8 assay, and the proliferation of ESCC cells (Eca-109 and TE-1 cells) was significantly inhibited after transfected with siRNA-AK1001796, in a time-dependent manner (Fig.	('inhibited', 'NegReg', (132, 141))	('TE-1', 'CellLine', 'CVCL:1759', (102, 106))	('transfected', 'Var', (148, 159))	('siRNA-AK1001796', 'Var', (165, 180))	('proliferation', 'CPA', (61, 74))
354887	29568233	To determine the potential molecular mechanisms of lncRNA AK001796 in the ESCC cells growth, we futher examined the expression of MDM2/p53 and its target gene p21 by western blot analysis.	('lncRNA', 'Var', (51, 57))	('MDM2/p53', 'Gene', (130, 138))	('p21', 'Gene', (159, 162))	('p21', 'Gene', '644914', (159, 162))	('AK001796', 'Gene', '541471', (58, 66))	('AK001796', 'Gene', (58, 66))
354900	29568233	We demonstrated that level of lncRNA AK001796 also positive related with the patients' TNM degrees, LN metastasis, tumor size and the tumor differentiation.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('AK001796', 'Gene', '541471', (37, 45))	('related', 'Reg', (60, 67))	('TNM', 'Gene', '10178', (87, 90))	('tumor', 'Disease', (115, 120))	('LN metastasis', 'CPA', (100, 113))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('lncRNA', 'Var', (30, 36))	('patients', 'Species', '9606', (77, 85))	('AK001796', 'Gene', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('TNM', 'Gene', (87, 90))	('tumor', 'Disease', (134, 139))
354904	29568233	And in our study we verified the lncRNA AK001796 can regulate cell growth and cell cycle in ESCC cells, and found that knockdown of lncRNA AK001796 contributed to the G2/M stage arrest both in Ech-109 and TE-1 cell lines.	('regulate', 'Reg', (53, 61))	('AK001796', 'Gene', '541471', (139, 147))	('AK001796', 'Gene', '541471', (40, 48))	('AK001796', 'Gene', (40, 48))	('G2/M stage arrest', 'CPA', (167, 184))	('AK001796', 'Gene', (139, 147))	('TE-1', 'CellLine', 'CVCL:1759', (205, 209))	('knockdown', 'Var', (119, 128))	('lncRNA', 'Gene', (132, 138))	('cell growth', 'CPA', (62, 73))	('cell cycle', 'CPA', (78, 88))
354906	29568233	In this study, we found that knockdown of lncRNA AK001796 upregulates p53 expression and inhibits MDM2 expression, suggesting that lncRNA AK001796 is involved in the regulation of MDM2/p53 singling on cell cycle and cell proliferation in ESCC cells.	('expression', 'MPA', (74, 84))	('AK001796', 'Gene', (138, 146))	('inhibits', 'NegReg', (89, 97))	('p53', 'Gene', (70, 73))	('MDM2 expression', 'MPA', (98, 113))	('AK001796', 'Gene', '541471', (49, 57))	('upregulates', 'PosReg', (58, 69))	('lncRNA', 'Var', (42, 48))	('AK001796', 'Gene', '541471', (138, 146))	('AK001796', 'Gene', (49, 57))
354919	29245989	Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates.	('qRT-PCR', 'Var', (22, 29))	('rat', 'Species', '10116', (37, 40))	('inhibition', 'NegReg', (55, 65))
354925	29245989	Recently reported analysis of The Cancer Genome Atlas (TCGA) indicates dysregulation of CDKN2A, the gene coding for the tumor suppressor p16, through deletion or epigenetic silencing in 81% of EAC/gastroesophageal junction cases and the associated significant upregulation of the cyclin dependent kinase (CDK) 4/6-cyclin D axis.	('EAC', 'Gene', '1540', (193, 196))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (197, 222))	('EAC', 'Gene', (193, 196))	('cyclin', 'Gene', (280, 286))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('gastroesophageal junction', 'Disease', (197, 222))	('CDKN2A', 'Gene', (88, 94))	('p16', 'Gene', (137, 140))	('deletion', 'Var', (150, 158))	('p16', 'Gene', '1029', (137, 140))	('cyclin', 'Gene', '5111', (314, 320))	('tumor', 'Disease', (120, 125))	('dysregulation', 'MPA', (71, 84))	('CDKN2A', 'Gene', '1029', (88, 94))	('epigenetic silencing', 'Var', (162, 182))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('upregulation', 'PosReg', (260, 272))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (34, 53))	('EAC', 'Phenotype', 'HP:0011459', (193, 196))	('cyclin', 'Gene', '5111', (280, 286))	('cyclin', 'Gene', (314, 320))	('Cancer Genome Atlas', 'Disease', (34, 53))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
354926	29245989	Specifically, amplification of the genes encoding CDK6 (7q21) and CDK4 (12q13) have been reported in 35% and 10% of gastroesophageal cancers, respectively.	('CDK6', 'Gene', (50, 54))	('CDK6', 'Gene', '1021', (50, 54))	('reported', 'Reg', (89, 97))	('gastroesophageal cancers', 'Disease', (116, 140))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('CDK4', 'Gene', (66, 70))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (116, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('amplification', 'Var', (14, 27))	('CDK4', 'Gene', '1019', (66, 70))
354931	29245989	Although many first generation non-selective CDK4/6 inhibitors failed in clinical development due to toxicity, current CDK4/6 inhibitors in clinical trials are well-tolerated and have demonstrated potential efficacy in a wide variety of tumor types.	('rat', 'Species', '10116', (169, 172))	('tumor', 'Disease', (237, 242))	('rat', 'Species', '10116', (191, 194))	('inhibitors', 'Var', (126, 136))	('CDK4/6', 'Gene', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('toxicity', 'Disease', 'MESH:D064420', (101, 109))	('toxicity', 'Disease', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('rat', 'Species', '10116', (24, 27))
354937	29245989	ELISA-based WST-1 reagent toxicity test established the ED50 for OE19, OE33, and FLO1 as 10muM, 6muM, and 14muM, respectively.	('OE33', 'Var', (71, 75))	('toxicity', 'Disease', 'MESH:D064420', (26, 34))	('toxicity', 'Disease', (26, 34))	('muM', 'Gene', '56925', (108, 111))	('OE19', 'Var', (65, 69))	('muM', 'Gene', '56925', (97, 100))	('muM', 'Gene', '56925', (91, 94))	('FLO1', 'Chemical', '-', (81, 85))	('muM', 'Gene', (97, 100))	('muM', 'Gene', (108, 111))	('muM', 'Gene', (91, 94))
354938	29245989	Flow cytometry showed Annexin-V-channeled total apoptosis increased with treatment by 123.9%, 103.7%, and 145.5% in OE19, OE33, and FLO1, respectively.	('OE19', 'Var', (116, 120))	('FLO1', 'Chemical', '-', (132, 136))	('increased', 'PosReg', (58, 67))	('Annexin-V', 'Gene', '308', (22, 31))	('OE33', 'Var', (122, 126))	('Annexin-V', 'Gene', (22, 31))	('apoptosis', 'CPA', (48, 57))
354954	29245989	Additionally, in vivo abemaciclib leads to a substantial reduction in tumor volume through downregulation of CDK4, CDK6, Cyclin D, Rb1, and E2F1 gene expression.	('downregulation', 'NegReg', (91, 105))	('expression', 'MPA', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CDK4', 'Gene', (109, 113))	('Rb1', 'Gene', (131, 134))	('tumor', 'Disease', (70, 75))	('reduction', 'NegReg', (57, 66))	('Cyclin', 'Gene', '5111', (121, 127))	('CDK4', 'Gene', '1019', (109, 113))	('CDK6', 'Gene', (115, 119))	('abemaciclib', 'Var', (22, 33))	('Rb1', 'Gene', '5925', (131, 134))	('E2F1', 'Gene', (140, 144))	('Cyclin', 'Gene', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('CDK6', 'Gene', '1021', (115, 119))
354980	29245989	We previously performed comparable studies to evaluate therapeutics for the treatment of EAC, such as hedgehog, heat shock protein 90 (Hsp90), and phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway inhibitors; however, CDK4/6 inhibition clearly provides maximal efficacy with minimal toxicity.	('mTOR', 'Gene', (213, 217))	('heat shock protein 90', 'Gene', (112, 133))	('EAC', 'Phenotype', 'HP:0011459', (89, 92))	('EAC', 'Gene', (89, 92))	('EAC', 'Gene', '1540', (89, 92))	('Hsp90', 'Gene', (135, 140))	('mammalian', 'Species', '9606', (177, 186))	('toxicity', 'Disease', 'MESH:D064420', (313, 321))	('Hsp90', 'Gene', '3320', (135, 140))	('toxicity', 'Disease', (313, 321))	('inhibition', 'Var', (255, 265))	('heat shock protein 90', 'Gene', '3320', (112, 133))	('mTOR', 'Gene', '2475', (213, 217))	('shock', 'Phenotype', 'HP:0031273', (117, 122))
354986	29245989	FLO1 cells were maintained in Dulbecco's Modified Eagle's medium (DMEM) with L-glutamine (Life Technologies, Grand Island, NY; 11965092) and supplemented with 10% Fetal Bovine Serum (FBS) (Life Technologies, Grand Island, NY; 26140079).	('FBS', 'Disease', (183, 186))	('DMEM', 'Chemical', '-', (66, 70))	('Bovine', 'Species', '9913', (169, 175))	('FBS', 'Disease', 'MESH:D005198', (183, 186))	("Dulbecco's Modified Eagle's medium", 'Chemical', '-', (30, 64))	('L-glutamine', 'Var', (77, 88))	('FLO1', 'Chemical', '-', (0, 4))	('L-glutamine', 'Chemical', 'MESH:D005973', (77, 88))
355006	29245989	Specific antibodies included CDK4 (Qiagen, Valencia, CA, # PPR06455B-200), CDK6 (Qiagen, Valencia, CA, # PPR50657A), Cyclin D (Qiagen, Valencia, CA, # PPR06517C), Rb1 (Qiagen, Valencia, CA, # PPR06558A-200), E2F1 (Qiagen, Valencia, CA, # PPR55684A-200), and PD-L1 (Cd274) (Qiagen, Valencia, CA, #PPR65311A).	('Rb1', 'Gene', (163, 166))	('Qiagen', 'Var', (127, 133))	('CDK4', 'Gene', (29, 33))	('CDK6', 'Gene', (75, 79))	('Cd274', 'Gene', (265, 270))	('CDK6', 'Gene', '1021', (75, 79))	('Cyclin', 'Gene', '5111', (117, 123))	('CDK4', 'Gene', '1019', (29, 33))	('Rb1', 'Gene', '5925', (163, 166))	('CA, # PPR55684A-200', 'Var', (232, 251))	('Cyclin', 'Gene', (117, 123))	('Cd274', 'Gene', '29126', (265, 270))
355007	29245989	Endogenous controls were B-Actin (Qiagen, Valencia, CA, #PPR06570C) and RPLP1 (Qiagen, Valencia, CA, #PPR42363C).	('RPLP1', 'Gene', (72, 77))	('CA, #PPR42363C', 'Var', (97, 111))	('RPLP1', 'Gene', '6176', (72, 77))
355053	26688665	Genetically engineered mouse and zebrafish models of cancer have been generated by a variety of interventions such as chemical or physical mutagenesis, viral infection, insertion of transgenes, homologous recombination, and the recently developed gene edition.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('zebrafish', 'Species', '7955', (33, 42))	('viral infection', 'Disease', 'MESH:D001102', (152, 167))	('mouse', 'Species', '10090', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('viral infection', 'Disease', (152, 167))	('insertion', 'Var', (169, 178))
355059	26688665	These data demonstrate that pancreatic cancer cells with disrupted mutant K-RAS exhibited reduced tumor growth and metastasis, and RhoA and RalA GTPase downstream of mutant K-RAS are involved in controlling cancer cells migration and invasion.	('reduced', 'NegReg', (90, 97))	('disrupted mutant', 'Var', (57, 73))	('invasion', 'CPA', (234, 242))	('tumor', 'Disease', (98, 103))	('K-RAS', 'Gene', '16653', (173, 178))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', (207, 213))	('pancreatic cancer', 'Disease', 'MESH:D010190', (28, 45))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('K-RAS', 'Gene', '16653', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('pancreatic cancer', 'Disease', (28, 45))	('RhoA', 'Gene', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('RhoA', 'Gene', '11848', (131, 135))	('K-RAS', 'Gene', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (28, 45))	('mutant', 'Var', (67, 73))	('K-RAS', 'Gene', (74, 79))
355103	26489668	Subsequent functional analyses suggested that the potential activation of RAC1 pathway, indicated by the increasing cellular invasion after mutation in gene ELMO1, might contribute to the tumorigenesis of esophagus.	('tumor', 'Disease', (188, 193))	('increasing', 'PosReg', (105, 115))	('cellular invasion', 'CPA', (116, 133))	('contribute', 'Reg', (170, 180))	('RAC1', 'Gene', '5879', (74, 78))	('ELMO1', 'Gene', '9844', (157, 162))	('mutation', 'Var', (140, 148))	('RAC1', 'Gene', (74, 78))	('activation', 'PosReg', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('ELMO1', 'Gene', (157, 162))	('esophagus', 'Disease', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
355106	26489668	proofed that the inhibition of notch pathway could promote the differentiation of esophageal cells towards Barrett-like metaplasia, which is a common cause of esophageal diseases, such as cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('differentiation', 'CPA', (63, 78))	('notch pathway', 'Pathway', (31, 44))	('inhibition', 'Var', (17, 27))	('metaplasia', 'Disease', 'MESH:D008679', (120, 130))	('metaplasia', 'Disease', (120, 130))	('esophageal diseases', 'Disease', 'MESH:D004935', (159, 178))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('promote', 'PosReg', (51, 58))	('cancer', 'Disease', (188, 194))	('esophageal diseases', 'Disease', (159, 178))
355127	26489668	Moreover, tumor development was observed via ectopic expression of DSG2 in mouse skin.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('observed', 'Reg', (32, 40))	('tumor', 'Disease', (10, 15))	('mouse', 'Species', '10090', (75, 80))	('DSG2', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('ectopic expression', 'Var', (45, 63))
355147	26489668	Previous studies reported that the aberrant expression of JAK2 was tightly correlated with the development of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('JAK2', 'Gene', '3717', (58, 62))	('esophageal cancer', 'Disease', (110, 127))	('aberrant expression', 'Var', (35, 54))	('JAK2', 'Gene', (58, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('correlated with', 'Reg', (75, 90))
355148	26489668	As proofed, inhibition of JAK2 could block the inflammation and growth process of esophageal cancer in vitro through JAK/STAT3 pathway, which thus indicated its pro-tumorigenic effects underlying the link between inflammation and cancer.	('STAT3', 'Gene', '6774', (121, 126))	('inhibition', 'Var', (12, 22))	('JAK2', 'Gene', '3717', (26, 30))	('inflammation', 'Disease', (47, 59))	('block', 'NegReg', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('inflammation', 'Disease', (213, 225))	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('JAK2', 'Gene', (26, 30))	('cancer', 'Disease', (230, 236))	('esophageal cancer', 'Disease', (82, 99))	('growth process', 'CPA', (64, 78))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', (165, 170))	('cancer', 'Disease', (93, 99))	('STAT3', 'Gene', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('inflammation', 'Disease', 'MESH:D007249', (47, 59))	('inflammation', 'Disease', 'MESH:D007249', (213, 225))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
355201	26489668	Basically, as major components of fibrillary collagens, aberrations of gene COL1, COL3, COL4 and COL5 could cause a wide range of diseases in diverse human tissues, such as bone and blood.	('human', 'Species', '9606', (150, 155))	('COL4', 'Gene', (88, 92))	('bone', 'Disease', 'MESH:D001847', (173, 177))	('bone', 'Disease', (173, 177))	('aberrations', 'Var', (56, 67))	('COL5', 'Gene', (97, 101))	('diseases', 'Disease', (130, 138))	('cause', 'Reg', (108, 113))	('COL1', 'Gene', (76, 80))	('COL3', 'Gene', (82, 86))
355203	26489668	As reported previously, aberrant alterations of cell adhesion were involved in almost every step of tumor progression, from the detachment of tumor cells at the primary sites to the formation of the secondary lesions.	('aberrant alterations', 'Var', (24, 44))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('involved', 'Reg', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cell', 'Protein', (48, 52))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
355214	26489668	In combination with crosstalk and pivot analysis, we showed that our functional module-based approach could not only include mechanisms that were already validated previously, but also provide a rich resource for potential candidate genes, interactions, pivot TFs and miRNAs that might play pivotal functions underlying the link in esophagus.	('miR', 'Gene', (268, 271))	('esophagus', 'Disease', (332, 341))	('miR', 'Gene', '220972', (268, 271))	('interactions', 'Var', (240, 252))
355218	26489668	Based on manually annotations, we reasoned that common DEGs like PKP2, DSG2 and DSC2, and common edges like interaction between IRS1 and JAK2 as potential candidates for future biological validation.	('IRS1', 'Gene', '3667', (128, 132))	('JAK2', 'Gene', '3717', (137, 141))	('interaction', 'Var', (108, 119))	('DSC2', 'Gene', (80, 84))	('IRS1', 'Gene', (128, 132))	('JAK2', 'Gene', (137, 141))	('PKP2', 'Gene', '5318', (65, 69))	('DSC2', 'Gene', '1824', (80, 84))	('PKP2', 'Gene', (65, 69))	('DSG2', 'Gene', (71, 75))
355226	26489668	Gene expression datasets were collected from the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) at the National Center for Biotechnology Information (NCBI).We downloaded CEL files of normal, esophagitis and esophageal cancer (GSE26886, GSE39491, GSE36223, GSE29001 and GSE20347), all of which were assessed using Affymetrix Human Genome U133 Plus 2.0 Array, together with an approximately equal number of normal and disease samples (see Table 1).	('Human', 'Species', '9606', (342, 347))	('esophagitis', 'Phenotype', 'HP:0100633', (209, 220))	('esophagitis', 'Disease', (209, 220))	('normal', 'Disease', (201, 207))	('GSE39491', 'Var', (254, 262))	('esophagitis', 'Disease', 'MESH:D004941', (209, 220))	('GSE26886', 'Var', (244, 252))	('GSE29001', 'Var', (274, 282))	('esophageal cancer', 'Disease', (225, 242))	('esophageal cancer', 'Disease', 'MESH:D004938', (225, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('GSE20347', 'Var', (287, 295))	('GSE36223', 'Var', (264, 272))
355254	32793453	EVT also causes temporary hypoperfusion in the defect edges, resulting in localized expression of hypoxia-inducible factor 1alpha with concomitant modulation of vascular endothelial growth factor expression, leading to an increase in angiogenesis.	('vascular endothelial growth factor', 'Gene', (161, 195))	('hypoxia-inducible factor 1alpha', 'Gene', '3091', (98, 129))	('EVT', 'Var', (0, 3))	('EVT', 'Chemical', '-', (0, 3))	('vascular endothelial growth factor', 'Gene', '7422', (161, 195))	('expression', 'MPA', (196, 206))	('hypoxia-inducible factor 1alpha', 'Gene', (98, 129))	('modulation', 'Reg', (147, 157))	('increase', 'PosReg', (222, 230))	('angiogenesis', 'CPA', (234, 246))	('expression', 'MPA', (84, 94))
355256	32793453	A randomized study reported that EVT had a positive effect on wound healing due to a significant decrease in the bacterial load compared with non-vacuum-treated wounds.	('EVT', 'Chemical', '-', (33, 36))	('wound healing', 'CPA', (62, 75))	('bacterial load', 'CPA', (113, 127))	('EVT', 'Var', (33, 36))	('decrease', 'NegReg', (97, 105))
355284	32793453	The overall closure rate was significantly higher in the EVT group than in the SEMS group.	('EVT', 'Var', (57, 60))	('closure rate', 'CPA', (12, 24))	('EVT', 'Chemical', '-', (57, 60))	('higher', 'PosReg', (43, 49))
355345	32630699	However, CCL5 is a double-edged sword in cancer, because it also promotes antitumor immunity by recruiting anti-tumor T cells and dendritic cells to the TME, and therefore enhances the immunotherapy response in different tumor types.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', (78, 83))	('CCL5', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('recruiting', 'PosReg', (96, 106))	('promotes', 'PosReg', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('enhances', 'PosReg', (172, 180))	('cancer', 'Disease', (41, 47))	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
355350	32630699	It is a promiscuous receptor that binds with high affinity to CCL5, CCL3, CCL4 and CCL8 (monocyte chemoattractant protein 2, MCP2).	('CCL3', 'Gene', '6348', (68, 72))	('binds', 'Interaction', (34, 39))	('CCL4', 'Gene', '6351', (74, 78))	('monocyte chemoattractant protein 2', 'Gene', '6355', (89, 123))	('MCP2', 'Gene', '6355', (125, 129))	('CCL4', 'Gene', (74, 78))	('CCL3', 'Gene', (68, 72))	('CCL8', 'Var', (83, 87))	('monocyte chemoattractant protein 2', 'Gene', (89, 123))	('MCP2', 'Gene', (125, 129))
355351	32630699	CCR5 engagement results in G protein activation and the activation of signal transduction cascades such as the protein kinase B (PKB, also known as Akt) and NF-kB pathways, cytoskeleton rearrangement and chemotactic cell migration.	('PKB', 'Gene', (129, 132))	('protein kinase B', 'Gene', (111, 127))	('CCR5', 'Gene', (0, 4))	('Akt', 'Gene', (148, 151))	('chemotactic cell migration', 'CPA', (204, 230))	('activation', 'PosReg', (37, 47))	('PKB', 'Gene', '2185', (129, 132))	('cytoskeleton', 'Pathway', (173, 185))	('protein kinase B', 'Gene', '2185', (111, 127))	('engagement', 'Var', (5, 15))	('Akt', 'Gene', '207', (148, 151))	('rat', 'Species', '10116', (224, 227))	('activation', 'PosReg', (56, 66))	('G protein', 'Protein', (27, 36))	('NF-kB pathways', 'Pathway', (157, 171))	('signal transduction cascades', 'Pathway', (70, 98))
355371	32630699	CCR5 inhibitors enhance both doxorubicin and gamma-irradiation cytoxicity.	('doxorubicin', 'Chemical', 'MESH:D004317', (29, 40))	('CCR5', 'Gene', (0, 4))	('toxicity', 'Disease', 'MESH:D064420', (65, 73))	('inhibitors', 'Var', (5, 15))	('toxicity', 'Disease', (65, 73))	('enhance', 'PosReg', (16, 23))	('doxorubicin', 'MPA', (29, 40))
355396	32630699	To study the CCL5/CCR5 axis in cancer, different approaches have been used: inhibition of CCR5 with antagonists, inhibition of CCL5 expression with neutralizing antibodies or gene silencing, and generation of CCL5-knockout mice.	('inhibition', 'NegReg', (76, 86))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('gene silencing', 'Var', (175, 189))	('mice', 'Species', '10090', (223, 227))	('inhibition', 'NegReg', (113, 123))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('CCR5', 'Gene', (90, 94))	('CCL5', 'Gene', (127, 131))	('rat', 'Species', '10116', (199, 202))	('expression', 'MPA', (132, 142))
355436	32630699	CCL5 secretion is increased by CD40 engagement in cHL cells or by their coculture with MSCs from HL-involved lymph nodes.	('CD40', 'Gene', '958', (31, 35))	('increased', 'PosReg', (18, 27))	('cHL', 'CellLine', 'CVCL:2492', (50, 53))	('CD40', 'Gene', (31, 35))	('CCL5 secretion', 'MPA', (0, 14))	('engagement', 'Var', (36, 46))
355437	32630699	The silencing of interferon regulatory factor 4 (IRF4), a transcription factor overexpressed by cHL cells and involved in cancer cell proliferation and survival, decreases CCL5 secretion.	('interferon regulatory factor 4', 'Gene', '3662', (17, 47))	('rat', 'Species', '10116', (141, 144))	('IRF4', 'Gene', '3662', (49, 53))	('IRF4', 'Gene', (49, 53))	('decreases', 'NegReg', (162, 171))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('interferon regulatory factor 4', 'Gene', (17, 47))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cHL', 'CellLine', 'CVCL:2492', (96, 99))	('CCL5 secretion', 'MPA', (172, 186))	('silencing', 'Var', (4, 13))
355443	32630699	In a heterospheroid model of TME interactions, generated by the three-dimensional coculture of cHL cells with HL-MSCs and monocytes, maraviroc counteracts heterospheroid formation and decreases cell viability.	('cHL', 'CellLine', 'CVCL:2492', (95, 98))	('maraviroc', 'Var', (133, 142))	('decreases', 'NegReg', (184, 193))	('cell viability', 'CPA', (194, 208))	('maraviroc', 'Chemical', 'MESH:D000077592', (133, 142))	('rat', 'Species', '10116', (51, 54))
355445	32630699	CCR5 and CCR1 are expressed by multiple myeloma (MM) cells and their engagement induces tumor cell survival, migration and homing to the bone marrow.	('CCR1', 'Gene', '1230', (9, 13))	('multiple myeloma', 'Phenotype', 'HP:0006775', (31, 47))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CCR5', 'Gene', (0, 4))	('engagement', 'Var', (69, 79))	('multiple myeloma', 'Disease', (31, 47))	('rat', 'Species', '10116', (112, 115))	('induces', 'PosReg', (80, 87))	('migration', 'CPA', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('homing to the bone marrow', 'CPA', (123, 148))	('tumor', 'Disease', (88, 93))	('CCR1', 'Gene', (9, 13))	('multiple myeloma', 'Disease', 'MESH:D009101', (31, 47))
355446	32630699	CCL5 increases MM cell migration that correlates with CCR5 expression levels.	('CCL5', 'Var', (0, 4))	('rat', 'Species', '10116', (26, 29))	('increases', 'PosReg', (5, 14))	('expression', 'MPA', (59, 69))	('MM cell migration', 'CPA', (15, 32))	('CCR5', 'Gene', (54, 58))
355453	32630699	Inhibition of CCR1 and CCR5 by antagonists or neutralizing antibodies partially reduces osteoclastogenesis, osteolytic lesions and MM-induced angiogenesis.	('osteolytic lesions', 'Phenotype', 'HP:0002797', (108, 126))	('osteolytic lesions', 'Disease', 'MESH:D030981', (108, 126))	('osteolytic lesions', 'Disease', (108, 126))	('CCR1', 'Gene', (14, 18))	('osteoclastogenesis', 'Disease', 'None', (88, 106))	('osteoclastogenesis', 'Disease', (88, 106))	('reduces', 'NegReg', (80, 87))	('Inhibition', 'Var', (0, 10))	('CCR1', 'Gene', '1230', (14, 18))	('MM-induced angiogenesis', 'CPA', (131, 154))	('CCR5', 'Gene', (23, 27))
355471	32630699	By silencing CCL5 and by using maraviroc, it was demonstrated that CCL5 overexpression is linked to acquired resistance to trastuzumab and that this phenomenon is mediated by ERK activation.	('trastuzumab', 'Chemical', 'MESH:D000068878', (123, 134))	('silencing', 'Var', (3, 12))	('acquired resistance to trastuzumab', 'MPA', (100, 134))	('rat', 'Species', '10116', (56, 59))	('linked', 'Reg', (90, 96))	('ERK', 'Gene', '5594', (175, 178))	('CCL5', 'Gene', (67, 71))	('maraviroc', 'Chemical', 'MESH:D000077592', (31, 40))	('CCL5', 'Gene', (13, 17))	('ERK', 'Gene', (175, 178))	('overexpression', 'PosReg', (72, 86))
355487	32630699	Silencing host CCL5 in bone marrow, in combination with maraviroc, had robust anti-tumor immunity effects and great therapeutic efficacy against breast cancer xenografts.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('maraviroc', 'Chemical', 'MESH:D000077592', (56, 65))	('CCL5', 'Gene', (15, 19))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
355491	32630699	CCL5 was found to promote tumor recurrence by recruiting CCR5-expressing macrophages, which contribute to collagen deposition in residual tumors.	('collagen', 'MPA', (106, 114))	('CCL5', 'Var', (0, 4))	('CCR5-expressing macrophages', 'CPA', (57, 84))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('promote', 'PosReg', (18, 25))	('recruiting', 'PosReg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
355493	32630699	Orthotopically implanted metastatic mammary tumors induce Treg accumulation in the lungs, a typical site of mammary tumor metastasis.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor metastasis', 'Disease', 'MESH:D009362', (116, 132))	('tumor metastasis', 'Disease', (116, 132))	('metastatic', 'Var', (25, 35))	('Treg', 'Chemical', '-', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Treg accumulation', 'CPA', (58, 75))
355518	32630699	In vitro, CCL5 increased the growth and migratory response of CRC cells.	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('rat', 'Species', '10116', (43, 46))	('CCL5', 'Var', (10, 14))	('increased', 'PosReg', (15, 24))
355519	32630699	In tumor xenografts, inhibition of CCL5 with neutralizing anti-CCL5 antibodies decreased growth, liver metastasis and peritoneal carcinosis.	('decreased growth', 'Phenotype', 'HP:0001510', (79, 95))	('tumor', 'Disease', (3, 8))	('decreased', 'NegReg', (79, 88))	('inhibition', 'Var', (21, 31))	('peritoneal carcinosis', 'Disease', (118, 139))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('growth', 'CPA', (89, 95))	('peritoneal carcinosis', 'Disease', 'MESH:D010534', (118, 139))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
355522	32630699	CCL5 promoted Treg migration into tumors and enhanced apoptosis of CD8+ T cells, which was associated with the increased release of TGF-beta by Tregs.	('apoptosis', 'CPA', (54, 63))	('CCL5', 'Var', (0, 4))	('release', 'MPA', (121, 128))	('tumors', 'Disease', (34, 40))	('promoted', 'PosReg', (5, 13))	('increased', 'PosReg', (111, 120))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('rat', 'Species', '10116', (22, 25))	('enhanced', 'PosReg', (45, 53))	('TGF-beta', 'Gene', (132, 140))	('Tregs', 'Chemical', '-', (144, 149))	('Treg', 'Chemical', '-', (144, 148))	('Treg', 'Chemical', '-', (14, 18))	('TGF-beta', 'Gene', '7039', (132, 140))	('CD8', 'Gene', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('CD8', 'Gene', '925', (67, 70))
355523	32630699	In mouse models of CRC, the knockdown of tumor cell CCL5 and the blockade of CCR5 signaling decreased Treg infiltration and apoptosis of tumor-infiltrating CD8+ T cells and reduced tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('knockdown', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('rat', 'Species', '10116', (149, 152))	('CCL5', 'Gene', (52, 56))	('CRC', 'Disease', (19, 22))	('apoptosis', 'CPA', (124, 133))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))	('CD8', 'Gene', '925', (156, 159))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (41, 46))	('reduced', 'NegReg', (173, 180))	('Treg', 'Chemical', '-', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('decreased', 'NegReg', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('CCR5 signaling', 'Gene', (77, 91))	('tumor', 'Disease', (181, 186))	('blockade', 'NegReg', (65, 73))	('mouse', 'Species', '10090', (3, 8))	('Treg infiltration', 'CPA', (102, 119))	('rat', 'Species', '10116', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('CD8', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
355525	32630699	This is likely due to the decreased secretion by TAMs of S100a9, a calcium-binding protein considered a pro-inflammatory mediator involved in CD8+ T cell migration into the low hypoxic area of tumor tissues.	('low hypoxic', 'Disease', (173, 184))	('secretion', 'MPA', (36, 45))	('calcium', 'Chemical', 'MESH:D002118', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('S100a9', 'Var', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('rat', 'Species', '10116', (157, 160))	('CD8', 'Gene', (142, 145))	('low hypoxic', 'Disease', 'MESH:D009800', (173, 184))	('CD8', 'Gene', '925', (142, 145))	('tumor', 'Disease', (193, 198))	('decreased', 'NegReg', (26, 35))	('TAMs', 'Chemical', 'MESH:D013629', (49, 53))
355544	32630699	Patchy CCR5 expression in cancer cells is a signature of liver metastases, and maraviroc was still effective in patients with CCR5 "patchiness".	('liver metastases', 'Disease', 'MESH:D009362', (57, 73))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('CCR5', 'Gene', (7, 11))	('patients', 'Species', '9606', (112, 120))	('maraviroc', 'Chemical', 'MESH:D000077592', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('expression', 'MPA', (12, 22))	('liver metastases', 'Disease', (57, 73))	('Patchy', 'Var', (0, 6))
355545	32630699	Patchy CCR5 expression was found associated with an immunosuppressive TME, characterized by a low cytotoxic-to-regulatory T cell ratio at the invasive margin, and increased markers of M2-TAM (immunosuppressive polarization).	('increased', 'PosReg', (163, 172))	('CCR5', 'Gene', (7, 11))	('rat', 'Species', '10116', (129, 132))	('TAM', 'Gene', (187, 190))	('immunosuppressive TME', 'Disease', (52, 73))	('associated', 'Reg', (33, 43))	('markers', 'MPA', (173, 180))	('Patchy', 'Var', (0, 6))	('TAM', 'Gene', '8205', (187, 190))
355555	32630699	CCL5 knockdown by small interfering RNA (siRNA) reduces cancer cell growth, migration and invasiveness and induces apoptosis.	('migration', 'CPA', (76, 85))	('knockdown', 'Var', (5, 14))	('invasiveness', 'CPA', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('reduces', 'NegReg', (48, 55))	('induces', 'Reg', (107, 114))	('rat', 'Species', '10116', (79, 82))	('apoptosis', 'CPA', (115, 124))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
355574	32630699	In patients with glioblastoma multiforme (GBM), high CCR5 expression associates with poor prognosis.	('CCR5', 'Gene', (53, 57))	('expression', 'MPA', (58, 68))	('glioblastoma multiforme', 'Disease', (17, 40))	('patients', 'Species', '9606', (3, 11))	('glioblastoma', 'Phenotype', 'HP:0012174', (17, 29))	('high', 'Var', (48, 52))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (17, 40))
355576	32630699	Down-modulation of CCR5 decreases U87 tumor xenograft growth.	('decreases', 'NegReg', (24, 33))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Down-modulation', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('U87', 'Gene', (34, 37))	('CCR5', 'Gene', (19, 23))	('U87', 'Gene', '641648', (34, 37))
355583	32630699	CCL5 silencing reduces mesenchymal GBM cell survival in vitro, and increases mouse glioblastoma survival in vivo (tumor xenograft).	('CCL5', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('silencing', 'Var', (5, 14))	('tumor', 'Disease', (114, 119))	('glioblastoma', 'Disease', (83, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('increases', 'PosReg', (67, 76))	('reduces', 'NegReg', (15, 22))	('mouse', 'Species', '10090', (77, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))
355595	32630699	By modulating CCL5 expression, miR-147 inhibits tumor cell growth, migration, and invasion in vitro.	('CCL5', 'Gene', (14, 18))	('expression', 'MPA', (19, 29))	('rat', 'Species', '10116', (70, 73))	('tumor', 'Disease', (48, 53))	('modulating', 'Reg', (3, 13))	('miR-147', 'Var', (31, 38))	('migration', 'CPA', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('inhibits', 'NegReg', (39, 47))	('invasion in vitro', 'CPA', (82, 99))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
355598	32630699	In vitro, EZH2 knockdown in lung cancer cells decreased CCL5 expression, resulting in reduced chemotaxis of macrophages.	('reduced', 'NegReg', (86, 93))	('knockdown', 'Var', (15, 24))	('CCL5', 'Gene', (56, 60))	('EZH2', 'Gene', '2146', (10, 14))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('chemotaxis of macrophages', 'CPA', (94, 119))	('EZH2', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Disease', (28, 39))	('decreased', 'NegReg', (46, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))
355599	32630699	In vivo, EZH2 knockdown reduced macrophage infiltration, leading to decreased tumor growth and metastasis formation.	('metastasis formation', 'CPA', (95, 115))	('macrophage', 'CPA', (32, 42))	('reduced', 'NegReg', (24, 31))	('decreased tumor', 'Disease', 'MESH:D002303', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('knockdown', 'Var', (14, 23))	('EZH2', 'Gene', (9, 13))	('EZH2', 'Gene', '2146', (9, 13))	('rat', 'Species', '10116', (49, 52))	('decreased tumor', 'Disease', (68, 83))
355605	32630699	In transgenic mouse melanoma models, the accumulation of CCR5+ MDSCs in primary tumors and metastatic lymph nodes correlated with tumor progression.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mouse', 'Species', '10090', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('accumulation', 'PosReg', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('CCR5+ MDSCs', 'Var', (57, 68))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('tumor', 'Disease', (130, 135))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
355608	32630699	Neutralization of CCR5 ligands increased the survival of tumor-bearing mice and decreased both the migration and immunosuppressive potential of MDSCs.	('mice', 'Species', '10090', (71, 75))	('ligands', 'Protein', (23, 30))	('increased', 'PosReg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('survival', 'CPA', (45, 53))	('decreased', 'NegReg', (80, 89))	('CCR5', 'Gene', (18, 22))	('Neutralization', 'Var', (0, 14))	('rat', 'Species', '10116', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
355613	32630699	Osteosarcoma cells express CCR5 and its engagement by CCL5 leads to the activations of alphavbeta3 integrin and the migration of osteosarcoma cells by activating NF-kB.	('activations', 'PosReg', (72, 83))	('alphavbeta3 integrin', 'Protein', (87, 107))	('CCR5', 'Gene', (27, 31))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('activating', 'PosReg', (151, 161))	('rat', 'Species', '10116', (119, 122))	('engagement', 'Var', (40, 50))	('Osteosarcoma', 'Disease', (0, 12))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('osteosarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('CCL5', 'Gene', (54, 58))	('migration', 'CPA', (116, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (5, 12))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('osteosarcoma', 'Disease', (129, 141))	('osteosarcoma', 'Disease', 'MESH:D012516', (129, 141))	('NF-kB', 'Protein', (162, 167))
355635	32630699	In accordance, anti-CCL5 antibody decreased tumor growth and the invasive property induced by miR-CAF co-injected in an orthotopic ovarian cancer mouse model, confirming CCL5 is a tumor-promoting factor.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('ovarian cancer', 'Disease', (131, 145))	('anti-CCL5', 'Var', (15, 24))	('decreased tumor', 'Disease', 'MESH:D002303', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('miR-CAF', 'Chemical', '-', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('invasive property', 'CPA', (65, 82))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (180, 185))	('mouse', 'Species', '10090', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('ovarian cancer', 'Phenotype', 'HP:0100615', (131, 145))	('ovarian cancer', 'Disease', 'MESH:D010051', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('decreased tumor', 'Disease', (34, 49))	('miR-CAF', 'Gene', (94, 101))
355647	32630699	Pancreatic cancer cell lines express high levels of CCR5, and CCL5 induced proliferation and increased the invasive potential of cancer cells.	('proliferation', 'CPA', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CCL5', 'Var', (62, 66))	('increased', 'PosReg', (93, 102))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('rat', 'Species', '10116', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('induced', 'PosReg', (67, 74))	('cancer', 'Disease', (11, 17))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
355660	32630699	CCL5 increases tumor growth by activating STAT5 and cyclin D1 pathways, enhanced tumor invasion and synergizes with IL-6.	('CCL5', 'Var', (0, 4))	('cyclin D1', 'Gene', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('STAT5', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('IL-6', 'Gene', (116, 120))	('enhanced', 'PosReg', (72, 80))	('activating', 'PosReg', (31, 41))	('tumor', 'Disease', (15, 20))	('increases', 'PosReg', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('STAT5', 'Gene', '6776', (42, 47))	('IL-6', 'Gene', '3569', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cyclin D1', 'Gene', '595', (52, 61))	('tumor', 'Disease', (81, 86))
355664	32630699	The down-regulation of CCR5 by miR-455-5p overexpression inhibited prostate cancer cell growth and induced apoptosis.	('prostate cancer', 'Disease', (67, 82))	('miR-455-5p', 'Var', (31, 41))	('induced', 'Reg', (99, 106))	('inhibited', 'NegReg', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (67, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('miR-455-5p', 'Chemical', '-', (31, 41))	('down-regulation', 'NegReg', (4, 19))	('apoptosis', 'CPA', (107, 116))	('CCR5', 'Gene', (23, 27))
355665	32630699	In human prostate cancer tissues, miR-455-5p levels are significantly lower than in healthy tissues, suggesting miR-455-5p as a possible prognostic and diagnostic biomarker.	('miR-455-5p levels', 'MPA', (34, 51))	('miR-455-5p', 'Chemical', '-', (112, 122))	('prostate cancer', 'Disease', (9, 24))	('human', 'Species', '9606', (3, 8))	('miR-455-5p', 'Chemical', '-', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('lower', 'NegReg', (70, 75))	('miR-455-5p', 'Var', (112, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (9, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (9, 24))
355688	32630699	Another strategy to slow cancer progression at the CCL5/CCR5 axis level is inhibition of CCL5 secretion, which can also be achieved by drugs that do not have CCL5 as their target.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('inhibition', 'Var', (75, 85))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('CCL5 secretion', 'MPA', (89, 103))	('cancer', 'Disease', (25, 31))	('rat', 'Species', '10116', (10, 13))
355780	31683612	First generation ureteral stents were made from silicone, which was replaced by polyethylene, but polyethylene becomes unstable in urine and leads to fractures.	('silicone', 'Chemical', 'MESH:D012828', (48, 56))	('fractures', 'Disease', (150, 159))	('polyethylene', 'Var', (98, 110))	('ureteral stents', 'Phenotype', 'HP:0000071', (17, 32))	('polyethylene', 'Chemical', 'MESH:D020959', (80, 92))	('fractures', 'Disease', 'MESH:D050723', (150, 159))	('polyethylene', 'Chemical', 'MESH:D020959', (98, 110))
355899	31683612	Later, stents were deformed and cracked, depending on the copolymer composition (PLGA 50/50 after six days, PLGA 60/40 after sixteen days, PLGA 71/29 after twenty days).	('PLGA', 'Chemical', 'MESH:D000077182', (139, 143))	('PLGA', 'Chemical', 'MESH:D000077182', (81, 85))	('copolymer', 'Chemical', '-', (58, 67))	('PLGA', 'Var', (139, 143))	('PLGA', 'Chemical', 'MESH:D000077182', (108, 112))	('PLGA 60/40', 'Var', (108, 118))
355969	31683612	Researchers have shown that ZnO NPs have a selective toxicity to bacteria, but exhibit a minimal effect on human cells.	('ZnO', 'Var', (28, 31))	('human', 'Species', '9606', (107, 112))	('toxicity', 'Disease', 'MESH:D064420', (53, 61))	('ZnO', 'Chemical', 'MESH:D015034', (28, 31))	('toxicity', 'Disease', (53, 61))
356009	31683612	Cleavage of functionalized polymers on the surface of the material can cause antibacterial activity.	('polymers', 'Chemical', 'MESH:D011108', (27, 35))	('Cleavage', 'Var', (0, 8))	('cause', 'Reg', (71, 76))	('antibacterial activity', 'CPA', (77, 99))
356011	31683612	PHMG affects the electrical properties of the surface of the polymer, which subsequently becomes antibacterial.	('polymer', 'Chemical', 'MESH:D011108', (61, 68))	('affects', 'Reg', (5, 12))	('PHMG', 'Var', (0, 4))	('PHMG', 'Chemical', 'MESH:C060540', (0, 4))	('antibacterial', 'MPA', (97, 110))
356078	31564803	The rate of family history of cancer was around 23.80% (25.39% with males and 22.46% with females).	('cancer', 'Disease', (30, 36))	('family', 'Var', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
356083	31564803	After adjusting potential confounding factors such as age, sex, socioeconomic status, EC-related behavioral and dietary factors, clinical symptoms, family history of cancer, as well as study regions, significantly increased PRs were found related to higher cancer prevention knowledge levels (aORQ4/Q1=1.511, 95% CI: 1.398-1.632, aORQ3/Q1=1.225, 95% CI: 1.138-1.319, and aORQ2/Q1=1.086, 95% CI: 1.012-1.165).	('higher', 'PosReg', (250, 256))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('EC', 'Disease', 'MESH:D004938', (86, 88))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('PRs', 'MPA', (224, 227))	('increased PR', 'Phenotype', 'HP:0008151', (214, 226))	('increased', 'PosReg', (214, 223))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', (257, 263))	('increased PRs', 'Phenotype', 'HP:0008151', (214, 227))	('aORQ2/Q1=1.086', 'Var', (371, 385))
356112	30578410	Epigenetic silencing of ZNF132 mediated by methylation-sensitive Sp1 binding promotes cancer progression in esophageal squamous cell carcinoma Epigenetic alteration of tumor suppression gene is one of the most significant indicators in human esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', (242, 276))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('ZNF132', 'Gene', '7691', (24, 30))	('promotes', 'PosReg', (77, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (108, 142))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (242, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (253, 276))	('cancer', 'Disease', (86, 92))	('tumor', 'Disease', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('Epigenetic alteration', 'Var', (143, 164))	('human', 'Species', '9606', (236, 241))	('ZNF132', 'Gene', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('esophageal squamous cell carcinoma', 'Disease', (108, 142))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
356115	30578410	Meanwhile, ZNF132 gene silencing mediated by hypermethylation was confirmed in both solid tissues and cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('hypermethylation', 'Var', (45, 61))	('ZNF132', 'Gene', '7691', (11, 17))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('ZNF132', 'Gene', (11, 17))
356117	30578410	We validated the Sp1-binding site in the ZNF132 promoter region with chromatin immunoprecipitation assay and demonstrated that the hypermethylation status could reduce the Sp1 transcript factor activity.	('ZNF132', 'Gene', '7691', (41, 47))	('Sp1 transcript factor activity', 'MPA', (172, 202))	('reduce', 'NegReg', (161, 167))	('hypermethylation status', 'Var', (131, 154))	('ZNF132', 'Gene', (41, 47))
356118	30578410	Our results suggest that ZNF132 plays an important role in the development of ESCC as a tumor suppressor gene and support the underlying mechanism caused by the DNA hypermethylation-mediated Sp1-binding decay and gene silencing.	('hypermethylation-mediated', 'Var', (165, 190))	('ZNF132', 'Gene', '7691', (25, 31))	('ESCC', 'Disease', (78, 82))	('gene', 'Var', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('Sp1-binding', 'Var', (191, 202))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('ZNF132', 'Gene', (25, 31))
356128	30578410	Multiple studies have confirmed that global hypomethylation induces genomic instability leading to cell transformation, and hypermethylation of promoter regions of the tumor suppressor genes facilitates tumorigenesis.	('induces', 'Reg', (60, 67))	('tumor', 'Disease', (203, 208))	('leading to', 'Reg', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (168, 173))	('hypermethylation', 'Var', (124, 140))	('genomic instability', 'MPA', (68, 87))	('facilitates', 'PosReg', (191, 202))	('global hypomethylation', 'Var', (37, 59))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('cell transformation', 'CPA', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
356129	30578410	Previous studies have shown that a broad range of genes are silenced by DNA hypermethylation in different cancer types.	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('silenced', 'NegReg', (60, 68))	('cancer', 'Disease', (106, 112))	('DNA hypermethylation', 'Var', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
356131	30578410	Hypermethylation of several candidate genes was identified and one of them is ZNF132, which belongs to C2H2 zinc finger protein family.	('ZNF132', 'Gene', (78, 84))	('Hypermethylation', 'Var', (0, 16))	('ZNF132', 'Gene', '7691', (78, 84))
356157	30578410	Ec-109 and CaEs-17 cells both treated by the plasmid pCD513B-ZNF132 and pCD513B for 48 h were incubated for 0, 24, 48, 72, 96, and 120 h in 96-well plates with 1000 cells/well.	('pCD513B-ZNF132', 'Gene', (53, 67))	('pCD513B', 'Var', (72, 79))	('CaEs-17', 'CellLine', 'CVCL:2401', (11, 18))	('pCD513B-ZNF132', 'Gene', '7691', (53, 67))
356158	30578410	The suspension of the Ec-109 cells treated by the plasmid pCD513B-ZNF132 and pCD513B was prepared in a non-serum medium with a density of 2 x 105 cells/ml, 200 mul suspension of this kind was plated on the top side of a polycarbonate Transwell filter coated with Matrigel in the upper chamber of the BioCoat  Invasion Chambers (BD, Bedford, MA, USA) and incubated at 37  C for 24 h, and 500 mul culture medium was added in each well, then the cells inside the upper chamber were removed with cotton swabs, invaded cells on the lower membrane surface were fixed in 4% paraformaldehyde, stained with crystal violet, and counted (five random fields per well at x100 magnification).	('pCD513B-ZNF132', 'Gene', '7691', (58, 72))	('pCD513B-ZNF132', 'Gene', (58, 72))	('formaldehyde', 'Chemical', 'MESH:D005557', (571, 583))	('pCD513B', 'Var', (77, 84))
356159	30578410	CaEs-17 and Ec-109 cells treated by the plasmid pCD513B-ZNF132 and pCD513B were seeded into 6-well plates at a density of 2 x 105 cells/well.	('pCD513B', 'Var', (67, 74))	('pCD513B-ZNF132', 'Gene', '7691', (48, 62))	('CaEs-17', 'CellLine', 'CVCL:2401', (0, 7))	('pCD513B-ZNF132', 'Gene', (48, 62))
356177	30578410	Four-week-old male BALB/c nude mice (nu/nu; n = 7) (Soochow University Laboratory Animal Center, China) were anesthetized with an isoflurane/propylene glycol mixture, and Ec-109 stable cell lines with pCD513B-ZNF132 or pCD513B were subcutaneously injected into each mouse (2.0 x 106 cells in 200 mul PBS.	('pCD513B-ZNF132', 'Gene', '7691', (201, 215))	('PBS', 'Chemical', '-', (300, 303))	('nude mice', 'Species', '10090', (26, 35))	('isoflurane', 'Chemical', 'MESH:D007530', (130, 140))	('pCD513B-ZNF132', 'Gene', (201, 215))	('pCD513B', 'Var', (219, 226))	('propylene glycol', 'Chemical', 'MESH:D019946', (141, 157))	('mouse', 'Species', '10090', (266, 271))
356190	30578410	Meanwhile, although TNM is not significantly associated with ZNF132 methylation (P = 0.71), we identified a significant association with the number of nearby lymph nodes (N value in TNM stage).	('ZNF132', 'Gene', (61, 67))	('ZNF132', 'Gene', '7691', (61, 67))	('methylation', 'Var', (68, 79))
356191	30578410	We did not detect other significant correlation between ZNF132 methylation and age (beta = 0.002, P = 0.395), gender (P = 0.28), drinking (P = 0.54), smoking (P = 0.78), and weight (P = 0.34).	('methylation', 'Var', (63, 74))	('ZNF132', 'Gene', '7691', (56, 62))	('ZNF132', 'Gene', (56, 62))
356192	30578410	We also examined the prediction performance of ZNF132 hypermethylation in ESCC diagnosis.	('ZNF132', 'Gene', (47, 53))	('hypermethylation', 'Var', (54, 70))	('ESCC diagnosis', 'Disease', (74, 88))	('ZNF132', 'Gene', '7691', (47, 53))
356193	30578410	The prediction model with logistic regression shows the sensitivity (70.8%), specificity (80.6%), and area under curve (AUC = 0.82) with the adjustment of ESCC main risk factors, including age, gender, smoking, and alcohol consumption, demonstrating that hypermethylation of ZNF132 could be taken as a strong diagnostic biomarker for ESCC (Table 2 and Fig.	('hypermethylation', 'Var', (255, 271))	('ZNF132', 'Gene', (275, 281))	('alcohol', 'Chemical', 'MESH:D000438', (215, 222))	('ZNF132', 'Gene', '7691', (275, 281))	('ESCC', 'Disease', (334, 338))
356203	30578410	The fact that epigenetic treatment modulates ZNF132 expression shows its potential as an epigenetic cancer therapy.	('ZNF132', 'Gene', '7691', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('modulates', 'Reg', (35, 44))	('epigenetic treatment', 'Var', (14, 34))	('expression', 'MPA', (52, 62))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('ZNF132', 'Gene', (45, 51))
356212	30578410	The percentage of apoptotic Ec-109 and CaEs-17 cells significantly increased by high expression of ZNF132 (Fig.	('CaEs-17', 'CellLine', 'CVCL:2401', (39, 46))	('increased', 'PosReg', (67, 76))	('ZNF132', 'Gene', (99, 105))	('ZNF132', 'Gene', '7691', (99, 105))	('high expression', 'Var', (80, 95))
356215	30578410	Ec-109 cells transfected with either the plasmid pCD513B-ZNF132 or pCD513B were inoculated into the BALB/c nude mice.	('pCD513B-ZNF132', 'Gene', (49, 63))	('pCD513B', 'Var', (67, 74))	('pCD513B-ZNF132', 'Gene', '7691', (49, 63))	('nude mice', 'Species', '10090', (107, 116))
356229	30578410	The results showed that the methylated Sp1-binding site dramatically led to a reduction of luciferase activity compared with the unmethylated one, suggesting that methylation of Sp1-binding site can inhibit ZNF132 transcriptional expression by interfering with the recruitment of Sp1 to ZNF132 promoter region (Fig.	('recruitment', 'MPA', (265, 276))	('transcriptional expression', 'MPA', (214, 240))	('luciferase', 'Enzyme', (91, 101))	('ZNF132', 'Gene', (287, 293))	('interfering', 'NegReg', (244, 255))	('ZNF132', 'Gene', (207, 213))	('ZNF132', 'Gene', '7691', (207, 213))	('reduction', 'NegReg', (78, 87))	('ZNF132', 'Gene', '7691', (287, 293))	('methylation', 'Var', (163, 174))	('activity', 'MPA', (102, 110))	('inhibit', 'NegReg', (199, 206))
356234	30578410	Combined with our results described above, the results revealed, at least in part, the mechanisms underlying the association of hypermethylation of the ZNF132 promoter region and ESCC.	('association', 'Interaction', (113, 124))	('hypermethylation', 'Var', (128, 144))	('ESCC', 'Disease', (179, 183))	('ZNF132', 'Gene', '7691', (152, 158))	('ZNF132', 'Gene', (152, 158))
356235	30578410	Methylation of Sp1-binding site prevents the transcriptional activator Sp1 from binding to ZNF132 promoter, silencing ZNF132 tumor suppressor gene.	('silencing', 'NegReg', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('ZNF132', 'Gene', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Methylation', 'Var', (0, 11))	('ZNF132', 'Gene', '7691', (118, 124))	('ZNF132', 'Gene', (91, 97))	('tumor', 'Disease', (125, 130))	('ZNF132', 'Gene', '7691', (91, 97))	('binding', 'Interaction', (80, 87))
356236	30578410	Further, there are not many studies focusing on mechanisms under which epigenetic changes in tumor suppressor gene promoter regions lead to human ESCC initiation and progression.	('epigenetic changes', 'Var', (71, 89))	('human ESCC', 'Disease', (140, 150))	('human', 'Species', '9606', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('lead to', 'Reg', (132, 139))	('progression', 'CPA', (166, 177))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
356239	30578410	The epigenetic changes in ZNF132 in ESCC patients samples have been determined by targeted bisulfite sequencing.	('epigenetic changes', 'Var', (4, 22))	('bisulfite', 'Chemical', 'MESH:C042345', (91, 100))	('ZNF132', 'Gene', (26, 32))	('patients', 'Species', '9606', (41, 49))	('ZNF132', 'Gene', '7691', (26, 32))	('ESCC', 'Disease', (36, 40))
356242	30578410	These results have led us to further explore the clinical value of hypermethylation of ZNF132 promoter.	('hypermethylation', 'Var', (67, 83))	('clinical', 'Species', '191496', (49, 57))	('ZNF132', 'Gene', '7691', (87, 93))	('ZNF132', 'Gene', (87, 93))
356243	30578410	Logistic regression analysis has revealed that hypermethylated ZNF132 is strongly associated with ESCC after adjustment for age, sex, smoking, and alcohol consumption.	('ZNF132', 'Gene', (63, 69))	('associated', 'Reg', (82, 92))	('ZNF132', 'Gene', '7691', (63, 69))	('alcohol', 'Chemical', 'MESH:D000438', (147, 154))	('ESCC', 'Disease', (98, 102))	('hypermethylated', 'Var', (47, 62))
356246	30578410	Taken together, ZNF132 hypermethylation is an independent diagnostic factor together with other risk factors, such as age, gender, smoking, and drinking.	('hypermethylation', 'Var', (23, 39))	('ZNF132', 'Gene', '7691', (16, 22))	('ZNF132', 'Gene', (16, 22))
356251	30578410	The results indicate the potential of demethylation drugs as a epigenetic cancer therapy.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('demethylation drugs', 'Var', (38, 57))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
356256	30578410	Our study is the first one to show both in vitro and in vivo the tumor suppression function of ZNF132, indicating the pathological importance of reducing ZNF132 expression by hypermethylation of its promoter region.	('tumor', 'Disease', (65, 70))	('expression', 'MPA', (161, 171))	('ZNF132', 'Gene', '7691', (95, 101))	('ZNF132', 'Gene', (95, 101))	('ZNF132', 'Gene', (154, 160))	('reducing', 'NegReg', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('ZNF132', 'Gene', '7691', (154, 160))	('hypermethylation', 'Var', (175, 191))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
356261	30578410	It was the first study to demonstrate that Sp1 can bind to the promoter region of ZNF132, and that the methylated site could prevent Sp1 from binding to the promoter.	('ZNF132', 'Gene', '7691', (82, 88))	('methylated', 'Var', (103, 113))	('binding', 'Interaction', (142, 149))	('ZNF132', 'Gene', (82, 88))	('prevent', 'NegReg', (125, 132))	('bind', 'Interaction', (51, 55))
356262	30578410	Our results, therefore, indicate that hypermethylation of the ZNF132 promoter region can reduce the ability of Sp1 to bind its DNA recognition elements, potentially damaging transactivation.	('hypermethylation', 'Var', (38, 54))	('bind', 'Interaction', (118, 122))	('reduce', 'NegReg', (89, 95))	('ability', 'MPA', (100, 107))	('ZNF132', 'Gene', '7691', (62, 68))	('damaging', 'Reg', (165, 173))	('transactivation', 'MPA', (174, 189))	('ZNF132', 'Gene', (62, 68))
356263	30578410	Moreover, our results imply that prevention of binding of Sp1 to the ZNF132 promoter region by hypermethylation may be one of the mechanisms for reducing ZNF132 expression in ESCC.	('ZNF132', 'Gene', (69, 75))	('expression', 'MPA', (161, 171))	('ZNF132', 'Gene', '7691', (69, 75))	('prevention', 'NegReg', (33, 43))	('ESCC', 'Disease', (175, 179))	('ZNF132', 'Gene', (154, 160))	('reducing', 'NegReg', (145, 153))	('hypermethylation', 'Var', (95, 111))	('ZNF132', 'Gene', '7691', (154, 160))	('binding', 'Interaction', (47, 54))
356264	30578410	In conclusion, our study for the first time demonstrated that ZNF132 promoter is hypermethylated in ESCC tissues, but not in adjacent control tissues.	('hypermethylated', 'Var', (81, 96))	('ESCC', 'Disease', (100, 104))	('ZNF132', 'Gene', '7691', (62, 68))	('ZNF132', 'Gene', (62, 68))
356267	30578410	Most importantly, the methylation status of ZNF132 promoter in the tumor tissues of ESCC patients is an independent prognostic factor, and has the potential use as a biomarker useful in prognosis of ESCC.	('ESCC', 'Disease', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patients', 'Species', '9606', (89, 97))	('methylation status', 'Var', (22, 40))	('ESCC', 'Disease', (199, 203))	('ZNF132', 'Gene', (44, 50))	('tumor', 'Disease', (67, 72))	('ZNF132', 'Gene', '7691', (44, 50))
356294	30047253	We identified patients who were diagnosed with esophageal cancer by the diagnostic codes (C15.0, C15.1, C15.2, C15.3, C15.4, C15.5, C15.8, and C15.9) and the morphology codes (8052, 8070, 8071, 8072, 8073, 8074, 8076, 8077, 8083, and 8084).	('C15.2', 'Var', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('8076', 'Var', (212, 216))	('C15.1', 'Var', (97, 102))	('8084', 'Var', (234, 238))	('8074', 'Var', (206, 210))	('patients', 'Species', '9606', (14, 22))	('C15.4', 'Var', (118, 123))	('C15.8', 'Var', (132, 137))	('C15.5', 'Var', (125, 130))	('8072', 'Var', (194, 198))	('C15.3', 'Var', (111, 116))	('C15.0', 'Var', (90, 95))	('8052', 'Var', (176, 180))	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('8071', 'Var', (188, 192))	('C15.9', 'Var', (143, 148))	('8077', 'Var', (218, 222))	('8073', 'Var', (200, 204))	('esophageal cancer', 'Disease', (47, 64))
356316	30047253	As seen in Figure 4B, the 5-year OS rate (27%) for patients with tumors less than 5 cm in length surpassed the 5-year OS rate (13.2%) for patients with tumors at least 5 cm in length.	('less than 5 cm', 'Var', (72, 86))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('OS', 'Chemical', '-', (118, 120))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('OS', 'Chemical', '-', (33, 35))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (51, 59))	('tumors', 'Disease', (152, 158))	('patients', 'Species', '9606', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
356346	30047253	The NCCN guidelines version 4.2017 recommended that patients with esophageal squamous cell carcinoma staging cT1b-T4a / N0-N+ or cT4b who medically unable to tolerate major surgery should receive definitive chemoradiation therapy (dCRT).	('cT4b', 'Var', (129, 133))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (66, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('CRT', 'Gene', '45841', (232, 235))	('CRT', 'Gene', (232, 235))	('men', 'Species', '9606', (40, 43))	('esophageal squamous cell carcinoma', 'Disease', (66, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('cT1b-T4a / N0-N+', 'Var', (109, 125))	('patients', 'Species', '9606', (52, 60))
356355	30047253	Several studies reported that at the same diagnostic stage, the addition of CRT leads to a survival benefit compared to surgery alone.	('CRT', 'Gene', '45841', (76, 79))	('addition', 'Var', (64, 72))	('survival benefit', 'CPA', (91, 107))	('CRT', 'Gene', (76, 79))
356384	28731203	In recent years, mounting evidences have pointed out that long non-coding RNAs (lncRNAs) play crucial roles in the risk and progression of diverse cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('long non-coding', 'Var', (58, 73))	('ncRNA', 'Gene', (81, 86))	('ncRNA', 'Gene', '220202', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))
356385	28731203	Multiple studies have indicated that a group of lncRNAs, which could regulate the expression of protein-coding genes at chromatin organization, transcriptional and post-transcriptional levels, are aberrantly expressed in ESCC.	('ncRNA', 'Gene', '220202', (49, 54))	('expression', 'MPA', (82, 92))	('aberrantly', 'Var', (197, 207))	('regulate', 'Reg', (69, 77))	('ncRNA', 'Gene', (49, 54))	('ESCC', 'Disease', (221, 225))
356391	28731203	The human ESCC cell lines Eca109 and TE-1 were purchased from the Cell Bank Type Culture Collection of Chinese Academy of Science (Shanghai, China) where cell lines were characterized by short-tandem-repeat DNA fingerprinting, mycoplasma detection and cell vitality detection.	('human', 'Species', '9606', (4, 9))	('mycoplasma', 'Disease', (227, 237))	('mycoplasma', 'Disease', 'MESH:D009175', (227, 237))	('TE-1', 'CellLine', 'CVCL:1759', (37, 41))	('short-tandem-repeat DNA', 'Var', (187, 210))
356435	28731203	As expected, after transfection PTENP1 expression was significantly increased in both Eca109 and TE-1 cells, respectively (Figure 1B).	('transfection', 'Var', (19, 31))	('PTENP1', 'Gene', (32, 38))	('PTENP1', 'Gene', '11191', (32, 38))	('TE-1', 'CellLine', 'CVCL:1759', (97, 101))	('expression', 'MPA', (39, 49))	('increased', 'PosReg', (68, 77))
356451	28731203	As shown by Figures 4A and 4B, xenografts derived from transfected group were significantly smaller compared with those derived from control mice in the checked time points.	('transfected', 'Var', (55, 66))	('xenografts', 'CPA', (31, 41))	('mice', 'Species', '10090', (141, 145))	('smaller', 'NegReg', (92, 99))
356470	28731203	PTENP1 is reported to be hyper-methylated in multiple cancers cells and cell lines.10, 32, 33, 34 For example, Marsit CJ identified PTENP1, rather than PTEN, was more likely to be hypermethylated in squamous cell carcinoma.34 The result was further validated in colorectal, breast and haematological cancer cell lines.33 Moreover, Yu et al identified lower expression of PTENP1 mRNA and hyper-methylation of PTENP1 promoter in clear-cell renal cell carcinoma cell lines and tissues.	('PTEN', 'Gene', (132, 136))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (427, 458))	('PTEN', 'Gene', '5728', (0, 4))	('PTENP1', 'Gene', (371, 377))	('PTEN', 'Gene', '5728', (371, 375))	('PTENP1', 'Gene', '11191', (371, 377))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 222))	('PTENP1', 'Gene', (132, 138))	('PTEN', 'Gene', '5728', (132, 136))	('PTENP1', 'Gene', '11191', (132, 138))	('clear-cell renal cell carcinoma', 'Disease', (427, 458))	('lower', 'NegReg', (351, 356))	('hyper-methylation', 'Var', (387, 404))	('PTENP1', 'Gene', (408, 414))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('PTENP1', 'Gene', '11191', (408, 414))	('PTEN', 'Gene', (408, 412))	('squamous cell carcinoma', 'Disease', (199, 222))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('multiple cancers', 'Disease', 'MESH:D009369', (45, 61))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('PTEN', 'Gene', (152, 156))	('expression', 'MPA', (357, 367))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (427, 458))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (438, 458))	('PTEN', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('PTEN', 'Gene', '5728', (408, 412))	('breast and haematological cancer', 'Disease', 'MESH:D001943', (274, 306))	('promoter', 'MPA', (415, 423))	('haematological cancer', 'Phenotype', 'HP:0004377', (285, 306))	('PTEN', 'Gene', '5728', (152, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (449, 458))	('PTEN', 'Gene', (371, 375))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('multiple cancers', 'Disease', (45, 61))	('PTENP1', 'Gene', (0, 6))	('mRNA', 'MPA', (378, 382))	('PTENP1', 'Gene', '11191', (0, 6))
356471	28731203	Further experiment in demethylation agent treated cancer cells confirmed that the lower expression of PTENP1 was due to hyper-methylation.10 Considering these facts, it is reasonable to infer the down-regulation of PTENP1 in ESCC may also due to the hyper-methylation of its DNA.	('ESCC', 'Disease', (225, 229))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('PTENP1', 'Gene', (215, 221))	('hyper-methylation', 'Var', (250, 267))	('PTENP1', 'Gene', (102, 108))	('PTENP1', 'Gene', '11191', (215, 221))	('down-regulation', 'NegReg', (196, 211))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('PTENP1', 'Gene', '11191', (102, 108))
356513	27310995	Compared between 1997 to 2004 and 2005 to 2010 periods, patients who underwent PEG in the later period has significantly lower percentages in local hospitals (4.7% vs 7.6%, P = 0.042) and significantly lower length of hospital stay (19.7 +- 34.0 vs 21.6 +- 42.2, P = 0.001); but has significantly higher medical costs (4395 +- 6259 vs 3550 +- 4034, P = 0.002) and higher CCI (3.17 +- 3.57 vs 3.64 +- 4.20, P < 0.001).	('higher', 'PosReg', (297, 303))	('patients', 'Species', '9606', (56, 64))	('length of hospital stay', 'MPA', (208, 231))	('lower', 'NegReg', (202, 207))	('PEG', 'Var', (79, 82))	('medical costs', 'CPA', (304, 317))	('lower', 'NegReg', (121, 126))	('PEG', 'Chemical', '-', (79, 82))	('CCI', 'MPA', (371, 374))
356548	27310995	Patients undergoing PEG may have comorbid illnesses, may not be able to tolerate hemodynamic disturbances, and may amplify the challenges of patient care.	('PEG', 'Var', (20, 23))	('patient', 'Species', '9606', (141, 148))	('Patients', 'Species', '9606', (0, 8))	('PEG', 'Chemical', '-', (20, 23))	('amplify', 'PosReg', (115, 122))	('have', 'Reg', (28, 32))
356569	27196126	Malnutrition commonly observed in esophageal cancer patients, and the presence of malnutrition is associated with poor clinical outcomes: impairing quality of life, performance status, immune functions, muscle function, and even survival in esophageal cancer patients.	('immune functions', 'CPA', (185, 201))	('Malnutrition', 'Phenotype', 'HP:0004395', (0, 12))	('survival', 'CPA', (229, 237))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('patients', 'Species', '9606', (259, 267))	('esophageal cancer', 'Disease', 'MESH:D004938', (241, 258))	('performance status', 'CPA', (165, 183))	('malnutrition', 'Phenotype', 'HP:0004395', (82, 94))	('muscle function', 'CPA', (203, 218))	('patients', 'Species', '9606', (52, 60))	('malnutrition', 'Disease', (82, 94))	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', (241, 258))	('presence', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('impairing', 'NegReg', (138, 147))	('quality of life', 'CPA', (148, 163))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('malnutrition', 'Disease', 'MESH:D044342', (82, 94))
356632	22091379	Most inlet patches are largely asymptomatic, but in problematic cases complications related to acid secretion such as esophagitis, ulcer, web, and stricture may produce symptoms such as chest and throat pain, dysphagia, globus sensation, and shortness of breath.	('ulcer', 'Disease', 'MESH:D014456', (131, 136))	('dysphagia', 'Disease', 'MESH:D003680', (209, 218))	('dysphagia', 'Disease', (209, 218))	('shortness of breath', 'Disease', 'MESH:D004417', (242, 261))	('pain', 'Disease', 'MESH:D010146', (203, 207))	('ulcer', 'Disease', (131, 136))	('esophagitis', 'Disease', (118, 129))	('complications', 'Var', (70, 83))	('esophagitis', 'Disease', 'MESH:D004941', (118, 129))	('chest', 'Disease', 'MESH:D002637', (186, 191))	('dysphagia', 'Phenotype', 'HP:0002015', (209, 218))	('globus sensation', 'Disease', (220, 236))	('pain', 'Phenotype', 'HP:0012531', (203, 207))	('web', 'Disease', (138, 141))	('esophagitis', 'Phenotype', 'HP:0100633', (118, 129))	('shortness of breath', 'Phenotype', 'HP:0002098', (242, 261))	('shortness of breath', 'Disease', (242, 261))	('pain', 'Disease', (203, 207))	('produce', 'Reg', (161, 168))	('chest', 'Disease', (186, 191))
356643	22091379	Ablation of inlet patches has been shown to relieve globus and has been used to successfully treat inlet patch dysplasia although its routine use in this context has not been determined.	('dysplasia', 'Disease', (111, 120))	('dysplasia', 'Disease', 'MESH:D004476', (111, 120))	('Ablation', 'Var', (0, 8))	('globus', 'MPA', (52, 58))	('relieve', 'PosReg', (44, 51))
356645	29950151	High TSTA3 Expression as a Candidate Biomarker for Poor Prognosis of Patients With ESCC Esophageal squamous cell carcinoma is the sixth most lethal cancer worldwide and the fourth most lethal cancer in China.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('TSTA3', 'Gene', '7264', (5, 10))	('High', 'Var', (0, 4))	('TSTA3', 'Gene', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (88, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Esophageal squamous cell carcinoma', 'Disease', (88, 122))	('Patients', 'Species', '9606', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
356649	29950151	It is not clear whether tissue-specific transplantation antigen P35B has any effect on the development of esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('esophageal squamous cell carcinoma', 'Disease', (106, 140))	('P35B', 'Var', (64, 68))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (106, 140))	('P35B', 'SUBSTITUTION', 'None', (64, 68))
356650	29950151	We used an immunohistochemical method to assess the expression of tissue-specific transplantation antigen P35B in 104 esophageal squamous cell carcinoma samples.	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('P35B', 'SUBSTITUTION', 'None', (106, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (118, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('P35B', 'Var', (106, 110))	('esophageal squamous cell carcinoma', 'Disease', (118, 152))
356651	29950151	The results showed tissue-specific transplantation antigen P35B expression was associated with some clinical features in patients, such as age (P = .017), clinical stage (P = .010), and lymph node metastasis (P = .043).	('associated', 'Reg', (79, 89))	('lymph node metastasis', 'CPA', (186, 207))	('P35B', 'SUBSTITUTION', 'None', (59, 63))	('patients', 'Species', '9606', (121, 129))	('P35B', 'Var', (59, 63))
356652	29950151	Kaplan-Meier analysis and log-rank test showed that patients with esophageal squamous cell carcinoma having high tissue-specific transplantation antigen P35B expression had a worse prognosis compared to the patients with low expression (P = .048).	('patients', 'Species', '9606', (207, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (66, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('P35B', 'Var', (153, 157))	('esophageal squamous cell carcinoma', 'Disease', (66, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('P35B', 'SUBSTITUTION', 'None', (153, 157))	('patients', 'Species', '9606', (52, 60))
356653	29950151	Multivariate Cox proportional hazards regression model showed that high expression of tissue-specific transplantation antigen P35B could predict poor prognosis for patients with esophageal squamous cell carcinoma independently.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (178, 212))	('high', 'Var', (67, 71))	('Cox', 'Gene', (13, 16))	('P35B', 'SUBSTITUTION', 'None', (126, 130))	('esophageal squamous cell carcinoma', 'Disease', (178, 212))	('patients', 'Species', '9606', (164, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('P35B', 'Var', (126, 130))	('Cox', 'Gene', '1351', (13, 16))
356654	29950151	In conclusion, abnormal fucosylation might participate in the progress of esophageal squamous cell carcinoma and tissue-specific transplantation antigen P35B may serve as a novel biomarker for prognosis of patients with esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (74, 108))	('esophageal squamous cell carcinoma', 'Disease', (220, 254))	('fucosylation', 'Protein', (24, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('P35B', 'Var', (153, 157))	('participate', 'Reg', (43, 54))	('abnormal', 'Var', (15, 23))	('patients', 'Species', '9606', (206, 214))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (74, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('P35B', 'SUBSTITUTION', 'None', (153, 157))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (220, 254))
356661	29950151	Tissue-specific transplantation antigen P35B (TSTA3), also known as GDP-4-keto-6-deoxy-d-mannose-3,5-epimerase-4-reductase, and GDP-d-mannose-4,6-dehydratase (GMD) participate in the de novo way and convert cellular GDP-d-mannose into GDP-l-fucose.	('GMD', 'Gene', '2762', (159, 162))	('GDP-4-keto-6-deoxy-d-mannose-3,5-epimerase-4-reductase', 'Gene', '7264', (68, 122))	('TSTA3', 'Gene', (46, 51))	('P35B', 'SUBSTITUTION', 'None', (40, 44))	('P35B', 'Var', (40, 44))	('GDP-d-mannose', 'Chemical', 'MESH:D006155', (128, 141))	('GDP-d-mannose', 'Chemical', 'MESH:D006155', (216, 229))	('GDP-d-mannose-4,6-dehydratase', 'Gene', '2762', (128, 157))	('TSTA3', 'Gene', '7264', (46, 51))	('GDP-l-fucose', 'Chemical', 'MESH:D006154', (235, 247))	('GDP-l-fucose', 'MPA', (235, 247))	('GMD', 'Gene', (159, 162))	('convert', 'MPA', (199, 206))
356665	29950151	Previously, we showed missense mutation frequency of TSTA3 gene was 2% in ESCC.	('TSTA3', 'Gene', '7264', (53, 58))	('ESCC', 'Disease', (74, 78))	('TSTA3', 'Gene', (53, 58))	('missense mutation frequency', 'Var', (22, 49))
356671	29950151	Our results indicated that abnormal expression of TSTA3 may contribute toward ESCC progression, and TSTA3 may act as a potential novel biomarker for prognosis of patients with ESCC.	('ESCC', 'Disease', (176, 180))	('abnormal', 'Var', (27, 35))	('patients', 'Species', '9606', (162, 170))	('TSTA3', 'Gene', (100, 105))	('ESCC', 'Disease', (78, 82))	('TSTA3', 'Gene', '7264', (50, 55))	('contribute', 'Reg', (60, 70))	('TSTA3', 'Gene', (50, 55))	('TSTA3', 'Gene', '7264', (100, 105))	('expression', 'MPA', (36, 46))
356687	29950151	The H-Score of TSTA3 protein ranged from 66.3158 to 297.3680 in ESCC tumor tissues, and the median was 184.926.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('297.3680', 'Var', (52, 60))	('TSTA3', 'Gene', '7264', (15, 20))	('tumor', 'Disease', (69, 74))	('TSTA3', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('protein', 'Protein', (21, 28))
356688	29950151	According to the ROC curve analyses (area under curve = 0.709, P = .00037, 95% confidence interval (CI), 0.600-0.818; Figure 2A), all cancer samples were divided into 2 groups: TSTA3low (H-Score <195.2735) and TSTA3high (H-Score >=195.2735).	('H-Score >=195.2735', 'Var', (221, 239))	('TSTA3', 'Gene', (210, 215))	('cancer', 'Disease', (134, 140))	('TSTA3', 'Gene', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('TSTA3', 'Gene', '7264', (210, 215))	('H-Score <195.2735', 'Var', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('TSTA3', 'Gene', '7264', (177, 182))
356709	29950151	Aberrations of glycosylation are involved in a number of diseases, such as tumorigenesis and chronic inflammation.	('involved', 'Reg', (33, 41))	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('inflammation', 'Disease', (101, 113))	('glycosylation', 'Protein', (15, 28))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Aberrations', 'Var', (0, 11))	('tumor', 'Disease', (75, 80))
356710	29950151	Fucosylation is one of the most common glycosylation modifications on glycoproteins and glycolipids, and abnormal fucosylation is closely related to the tumor.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Fucosylation', 'MPA', (0, 12))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('abnormal', 'Var', (105, 113))	('related', 'Reg', (138, 145))	('fucosylation', 'MPA', (114, 126))
356718	29950151	As our results showed in ESCC, TSTA3high patients tended to have a deeper invasion depth and a higher LN metastasis rate, which indicated that high TSTA3 may promote the invasion and metastasis of ESCC cells, more experiments are required for making clear whether such function is through aberrant fucosylation of glycoproteins.	('TSTA3', 'Gene', (148, 153))	('TSTA3', 'Gene', (31, 36))	('promote', 'PosReg', (158, 165))	('higher', 'PosReg', (95, 101))	('high', 'Var', (143, 147))	('patients', 'Species', '9606', (41, 49))	('ESCC', 'Disease', (25, 29))	('invasion depth', 'CPA', (74, 88))	('TSTA3', 'Gene', '7264', (148, 153))	('TSTA3', 'Gene', '7264', (31, 36))	('LN metastasis rate', 'CPA', (102, 120))
356723	29950151	Engineering anti-Lewis-Y hu3S193 and IGN311 antibodies have been tested as passive immunotherapy approaches of epithelial cancers and may be applied clinically.	('epithelial cancers', 'Disease', (111, 129))	('epithelial cancers', 'Disease', 'MESH:D000077216', (111, 129))	('hu3S193', 'Var', (25, 32))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('IGN311', 'Gene', (37, 43))
356729	29950151	AFP alpha-fetoprotein CI confidence interval ESCC esophageal squamous cell carcinoma FUTs fucosyltransferases GMD GDP-d-mannose-4,6-dehydratase H-Score Histoscore IHC immunohistochemical LN lymph node OS overall survival PH proportional hazards ROC receiver operating characteristic TSTA3 tissue-specific transplantation antigen P35B	('GMD', 'Gene', '2762', (110, 113))	('TSTA3', 'Gene', '7264', (283, 288))	('P35B', 'SUBSTITUTION', 'None', (329, 333))	('alpha-fetoprotein', 'Gene', (4, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('TSTA3', 'Gene', (283, 288))	('AFP', 'Gene', (0, 3))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('OS', 'Chemical', '-', (201, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('GDP-d-mannose-4,6-dehydratase', 'Gene', '2762', (114, 143))	('P35B', 'Var', (329, 333))	('AFP', 'Gene', '174', (0, 3))	('alpha-fetoprotein', 'Gene', '174', (4, 21))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))	('GMD', 'Gene', (110, 113))
356781	29132668	In the first study, which was performed in adults, avoidance of milk/dairy, gluten-containing grains, egg and legumes led to remission in 54% of patients.	('patients', 'Species', '9606', (145, 153))	('remission', 'Disease', (125, 134))	('avoidance', 'Var', (51, 60))
356826	28119804	Targeting derailed Ca2+ signaling for cancer therapy has become an emerging research area.	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('derailed', 'Var', (10, 18))	('cancer', 'Disease', (38, 44))
356831	28119804	Targeting the dysregulated Ca2+ channels/transporters/pumps may provide a promising chemotherapy for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('dysregulated', 'Var', (14, 26))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Ca2+ channels/transporters/pumps', 'MPA', (27, 59))
356847	28119804	Among these protein-binding domains, a significant one between amino acid 1390-1409 mediates the interaction with the BH4 domain of anti-apoptotic protein Bcl-2.	('Bcl-2', 'Gene', (155, 160))	('Bcl-2', 'Gene', '596', (155, 160))	('amino acid 1390-1409', 'Var', (63, 83))	('mediates', 'Reg', (84, 92))	('interaction', 'Interaction', (97, 108))	('BH4', 'Chemical', 'MESH:C003402', (118, 121))
356857	28119804	High expression of IP3R3 is associated with aggressiveness of colorectal carcinoma since it is related with decreased 5-year survival.	('High expression', 'Var', (0, 15))	('IP3R3', 'Gene', (19, 24))	('associated', 'Reg', (28, 38))	('5-year', 'MPA', (118, 124))	('aggressiveness', 'Phenotype', 'HP:0000718', (44, 58))	('decreased', 'NegReg', (108, 117))	('aggressiveness of colorectal carcinoma', 'Disease', (44, 82))	('aggressiveness of colorectal carcinoma', 'Disease', 'MESH:D015179', (44, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
356865	28119804	SERCA is responsible for replenishing ER Ca2+ stores, maintaining protein proper folding/maturation whereas dysregulated SERCA results in depleted or overloaded ER lumen Ca2+ stores, increased ER stress, dysregulated chaperones and synthesis of lipids.	('dysregulated', 'Var', (108, 120))	('increased', 'PosReg', (183, 192))	('ER stress', 'MPA', (193, 202))	('lipids', 'Chemical', 'MESH:D008055', (245, 251))	('ER lumen Ca2+ stores', 'MPA', (161, 181))	('dysregulated', 'MPA', (204, 216))	('depleted', 'NegReg', (138, 146))	('synthesis', 'MPA', (232, 241))	('overloaded', 'PosReg', (150, 160))	('protein proper folding/maturation', 'MPA', (66, 99))
356866	28119804	Mutations and altered expression levels of SERCA isoforms have been identified in various cancers, such as cancers of colon, gastric, lung, myeloid leukemia and choroid plexus tumors (Table 1).	('cancers', 'Disease', (90, 97))	('cancers', 'Disease', (107, 114))	('choroid plexus tumors', 'Disease', (161, 182))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('choroid plexus tumors', 'Phenotype', 'HP:0002190', (161, 182))	('myeloid leukemia', 'Disease', (140, 156))	('Mutations', 'Var', (0, 9))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('expression levels', 'MPA', (22, 39))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancers of colon', 'Disease', 'MESH:D015179', (107, 123))	('lung', 'Disease', (134, 138))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (161, 182))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('altered', 'Reg', (14, 21))	('cancers of colon', 'Disease', (107, 123))	('myeloid leukemia', 'Disease', 'MESH:D007951', (140, 156))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('SERCA', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gastric', 'Disease', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('identified', 'Reg', (68, 78))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
356875	28119804	On the other hand, knockdown of SPCA2 and low Ca2+ conditions are able to decrease activity of ERK1/2 pathway, which may result in decreased proliferation in breast cancer cells.	('decrease', 'NegReg', (74, 82))	('activity', 'MPA', (83, 91))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('knockdown', 'Var', (19, 28))	('decreased', 'NegReg', (131, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('proliferation', 'CPA', (141, 154))	('SPCA2', 'Gene', (32, 37))	('ERK1/2', 'Gene', (95, 101))	('ERK1/2', 'Gene', '5595;5594', (95, 101))	('SPCA2', 'Gene', '9914', (32, 37))
356878	28119804	The association between altered PMCAs and cancer has been reported in a few studies as well (Table 1).	('PMCAs', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('altered', 'Var', (24, 31))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
356888	28119804	Novel splice variants of T-type Ca2+ channel are commonly found in human glioma, breast, ovarian, prostate colon and esophageal cancer cells.	('glioma', 'Disease', (73, 79))	('breast, ovarian, prostate colon', 'Disease', 'MESH:D010051', (81, 112))	('esophageal cancer', 'Disease', (117, 134))	('splice variants', 'Var', (6, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('found', 'Reg', (58, 63))	('human', 'Species', '9606', (67, 72))	('T-type', 'Protein', (25, 31))
356894	28119804	For example, the presence of the TRPC, TRPM, and TRPV subfamilies correlates with malignant growth and cancer progression.	('TRPM', 'Protein', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('presence', 'Var', (17, 25))	('TRPC', 'Protein', (33, 37))	('correlates with', 'Reg', (66, 81))	('cancer', 'Disease', (103, 109))	('malignant growth', 'CPA', (82, 98))	('TRPV', 'Gene', (49, 53))
356906	28119804	Inhibition of Orai1 channel either by pharmacological compounds or knocking-down of Orai1 expression could block cancer cell proliferation and migration in vitro and tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('Orai1', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Inhibition', 'NegReg', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('block', 'NegReg', (107, 112))	('knocking-down', 'Var', (67, 80))	('tumor', 'Disease', (166, 171))	('cancer', 'Disease', (113, 119))	('Orai1', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
356929	28119804	Ca2+-ATPases can be easily targeted by shutting-down of these pumps to generate such toxic cytosolic Ca2+ concentrations for either apoptosis or necrosis.	('necrosis', 'Disease', (145, 153))	('necrosis', 'Disease', 'MESH:D009336', (145, 153))	('shutting-down', 'Var', (39, 52))
356938	28119804	G202, later termed as mipsagargin, significantly inhibits tumor progression including prostate, breast and bladder cancers, while presenting minimally toxicity to the host animals.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('breast and bladder cancers', 'Disease', 'MESH:D001749', (96, 122))	('toxicity', 'Disease', 'MESH:D064420', (151, 159))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('toxicity', 'Disease', (151, 159))	('inhibits', 'NegReg', (49, 57))	('bladder cancers', 'Phenotype', 'HP:0009725', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('prostate', 'Disease', (86, 94))	('G202', 'Var', (0, 4))
356939	28119804	G202 has showed promising results in several pre-clinical studies and is currently in phase II clinical trial for prostate cancer and progressive glioblastoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('glioblastoma', 'Disease', (146, 158))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))	('prostate cancer', 'Disease', (114, 129))	('G202', 'Var', (0, 4))
356942	28119804	In fact, as early as in 1990s, some structurally unrelated L-type VGCCs antagonists were tested for their potent inhibitory effects on breast tumor progression.	('inhibitory', 'NegReg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('antagonists', 'Var', (72, 83))	('breast tumor', 'Disease', 'MESH:D001943', (135, 147))	('breast tumor', 'Disease', (135, 147))	('VGCCs', 'Gene', (66, 71))	('breast tumor', 'Phenotype', 'HP:0100013', (135, 147))
356951	28119804	The imidazole compound SKF-96365 and related antimycotic compounds including econazole, miconazole, and clotrimazole can inhibit CRACs and some TRP channels.	('SKF-96365', 'Var', (23, 32))	('inhibit', 'NegReg', (121, 128))	('econazole', 'Chemical', 'MESH:D004464', (77, 86))	('CRACs', 'MPA', (129, 134))	('CRACs', 'Chemical', '-', (129, 134))	('TRP channels', 'Pathway', (144, 156))	('SKF-96365', 'Chemical', 'MESH:C063159', (23, 32))	('imidazole', 'Chemical', 'MESH:C029899', (4, 13))	('miconazole', 'Chemical', 'MESH:D008825', (88, 98))	('clotrimazole', 'Chemical', 'MESH:D003022', (104, 116))
356952	28119804	While SKF-96365 was firstly described to block receptor-mediated Ca2+ entry in human platelets, neutrophils and endothelial cells, it later was used to inhibit ovarian cancerous cell growth and tumorigenesis via reducing activities of different subtypes of TRPCs.	('inhibit', 'NegReg', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('human', 'Species', '9606', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('receptor-mediated Ca2+ entry', 'MPA', (47, 75))	('SKF-96365', 'Var', (6, 15))	('ovarian cancerous', 'Disease', 'MESH:D010051', (160, 177))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('activities', 'MPA', (221, 231))	('SKF-96365', 'Chemical', 'MESH:C063159', (6, 15))	('ovarian cancerous', 'Disease', (160, 177))	('ovarian cancer', 'Phenotype', 'HP:0100615', (160, 174))
356953	28119804	Treatment of SKF-96365 was reported to enhance radio-sensitization in glioblastoma, which contain high expressing levels of TRPC6 channels.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('TRPC6', 'Gene', (124, 129))	('SKF-96365', 'Var', (13, 22))	('radio-sensitization', 'MPA', (47, 66))	('glioblastoma', 'Disease', (70, 82))	('TRPC6', 'Gene', '7225', (124, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('enhance', 'PosReg', (39, 46))	('SKF-96365', 'Chemical', 'MESH:C063159', (13, 22))
356954	28119804	In addition, SKF-96365 can also cause cell cycle arrest at S and G2 phases in glioblastoma cells via enhancing reverse mode of the NCX1, independent of TRPCs.	('glioblastoma', 'Disease', (78, 90))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('SKF-96365', 'Var', (13, 22))	('cell cycle arrest', 'CPA', (38, 55))	('NCX1', 'Gene', (131, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('NCX1', 'Gene', '6546', (131, 135))	('enhancing', 'PosReg', (101, 110))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (38, 55))	('G2 phases', 'CPA', (65, 74))	('reverse mode', 'MPA', (111, 123))	('SKF-96365', 'Chemical', 'MESH:C063159', (13, 22))	('cause', 'Reg', (32, 37))
356960	28119804	GSK1016790A is a selective TRPV4 channel agonist developed recently.	('GSK1016790A', 'Var', (0, 11))	('GSK1016790A', 'Chemical', 'MESH:C530602', (0, 11))	('TRPV4', 'Gene', (27, 32))	('TRPV4', 'Gene', '59341', (27, 32))
356962	28119804	TRPV4 is able to regulate tumor angiogenesis and vessel maturation, thus GSK1016790A has been proposed to be used together with other anticancer drugs, such as cisplatin, to improve tumor penetration for more effective cancer therapy.	('cancer', 'Disease', (138, 144))	('improve', 'PosReg', (174, 181))	('GSK1016790A', 'Var', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', (26, 31))	('TRPV4', 'Gene', '59341', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('regulate', 'Reg', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('TRPV4', 'Gene', (0, 5))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('GSK1016790A', 'Chemical', 'MESH:C530602', (73, 84))	('vessel maturation', 'CPA', (49, 66))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
356969	28119804	Subcutaneous injection of either capsaicin or CPZ significantly suppresses PC-3 tumor growth by inducing apoptosis of tumor cells in vivo, suggesting they are promising chemotherapy drugs.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('inducing', 'Reg', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CPZ', 'Var', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('CPZ', 'Chemical', 'MESH:C071423', (46, 49))	('tumor', 'Disease', (80, 85))	('PC-3', 'Gene', (75, 79))	('suppresses', 'NegReg', (64, 74))	('PC-3', 'CellLine', 'CVCL:0035', (75, 79))	('tumor', 'Disease', (118, 123))	('capsaicin', 'Chemical', 'MESH:D002211', (33, 42))
356977	28119804	However, this effect is not specific for CRAC, as La3+ and Gd3+ also block other Ca2+ channels as well, such as Cav, TRP channel and PMCA.	('Ca2+ channels', 'MPA', (81, 94))	('CRAC', 'Chemical', '-', (41, 45))	('PMCA', 'Disease', (133, 137))	('block', 'NegReg', (69, 74))	('Gd3+', 'Chemical', 'MESH:C026226', (59, 63))	('La3+', 'Chemical', '-', (50, 54))	('Gd3+', 'Var', (59, 63))	('Cav', 'Gene', '858', (112, 115))	('La3+', 'Var', (50, 54))	('Cav', 'Gene', (112, 115))	('TRP', 'Gene', (117, 120))
356979	28119804	, demonstrated that SKF-96365 can inhibit breast cancer cell migration in vitro and reduce tumor growth and metastasis in vivo.	('reduce', 'NegReg', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('SKF-96365', 'Var', (20, 29))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('inhibit', 'NegReg', (34, 41))	('SKF-96365', 'Chemical', 'MESH:C063159', (20, 29))	('tumor', 'Disease', (91, 96))
356980	28119804	We also showed that SKF-96365 inhibited Orai1-mediated SOCE and intracellular Ca2+ oscillations in esophageal cancer cells and resulted in significant retarded tumor growth in nude mice.	('retarded tumor', 'Disease', 'MESH:D009369', (151, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('inhibited', 'NegReg', (30, 39))	('SKF-96365', 'Var', (20, 29))	('retarded tumor', 'Disease', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (64, 95))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Orai1-mediated', 'Gene', (40, 54))	('SKF-96365', 'Chemical', 'MESH:C063159', (20, 29))	('nude mice', 'Species', '10090', (176, 185))	('esophageal cancer', 'Disease', (99, 116))
356987	28119804	For example, DPB-162AE and DPB-163AE are constructed as dimers of 2-APB.	('DPB-163AE', 'Var', (27, 36))	('APB', 'Gene', '6051', (68, 71))	('DPB-162AE', 'Var', (13, 22))	('APB', 'Gene', (68, 71))
356991	28119804	AnCoA4 inhibits CRACs and attenuates T-cell activation both in in vitro and in vivo.	('AnCoA4', 'Var', (0, 6))	('inhibits', 'NegReg', (7, 15))	('CRACs', 'Chemical', '-', (16, 21))	('T-cell activation', 'CPA', (37, 54))	('CRACs', 'CPA', (16, 21))	('attenuates', 'NegReg', (26, 36))
356998	28119804	To achieve the IC50 values at nmol/L level, it requires pre-incubation of cells for more than 30 min, which suggests that RO2959 may act on Orai1 channels indirectly.	('RO2959', 'Chemical', '-', (122, 128))	('Orai1', 'Protein', (140, 145))	('RO2959', 'Var', (122, 128))	('act', 'Reg', (133, 136))
356999	28119804	The effect of RO2959 in cancer and molecular basis of drug action, including whether it affects the function and choreography of STIM1, are still unclear.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('RO2959', 'Chemical', '-', (14, 20))	('affects', 'Reg', (88, 95))	('STIM1', 'Gene', (129, 134))	('RO2959', 'Var', (14, 20))	('function', 'MPA', (100, 108))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('STIM1', 'Gene', '6786', (129, 134))
357001	28119804	In particular, E106 accounts for Ca2+ selectivity in Orai1 and can be blocked by extracellular protons.	('E106', 'Var', (15, 19))	('Orai1', 'Gene', (53, 58))	('E106', 'Chemical', '-', (15, 19))	('Ca2+ selectivity', 'MPA', (33, 49))
357002	28119804	This class of inhibitor includes SB01990, SPB06836, KM06293 and RH01882, which all present the capability to alter the pore geometry of Orai1 and diminishes SOCE.	('KM06293', 'Var', (52, 59))	('SB01990', 'Var', (33, 40))	('SOCE', 'MPA', (157, 161))	('alter', 'Reg', (109, 114))	('SB01990', 'Chemical', '-', (33, 40))	('diminishes', 'NegReg', (146, 156))	('pore geometry', 'MPA', (119, 132))	('Orai1', 'MPA', (136, 141))	('RH01882', 'Var', (64, 71))	('SPB06836', 'Var', (42, 50))
357003	28119804	Two pyrazole derivatives GSK-5503A and GSK-7975A slowly inhibit Orai1- and Orai3-mediated SOCE currents without affecting STIM1-Orai1 coupling.	('STIM1', 'Gene', '6786', (122, 127))	('Orai3', 'Gene', (75, 80))	('pyrazole', 'Chemical', 'MESH:C031280', (4, 12))	('GSK', 'Chemical', '-', (39, 42))	('STIM1', 'Gene', (122, 127))	('GSK', 'Chemical', '-', (25, 28))	('GSK-5503A', 'Var', (25, 34))	('Orai3', 'Gene', '93129', (75, 80))	('GSK-7975A', 'Var', (39, 48))	('inhibit', 'NegReg', (56, 63))
357005	28119804	The IC50 is increased 10-fold in the Orai1E106D and in 2-APB activated Orai3 channels, both of which are poorly selective for Ca2+ and exhibit wider pores than the Orai1WT channel.	('IC50', 'MPA', (4, 8))	('APB', 'Gene', '6051', (57, 60))	('Orai3', 'Gene', (71, 76))	('increased', 'PosReg', (12, 21))	('Orai1E106D', 'Var', (37, 47))	('Orai3', 'Gene', '93129', (71, 76))	('APB', 'Gene', (57, 60))
357007	28119804	The Pyr analogs, including Pyr2, 3, 6 and 10, show different selectivity on TRPC3 and Orai1/STIM1-mediated Ca2+ entry.	('STIM1', 'Gene', (92, 97))	('TRPC3', 'Gene', (76, 81))	('Pyr2', 'Var', (27, 31))	('STIM1', 'Gene', '6786', (92, 97))	('TRPC3', 'Gene', '7222', (76, 81))
357008	28119804	Pyr10 is potent and selective for TRPC3-mediated responses (18-fold), and Pyr6 prefers Orai1/STIM1, while Pyr3 equally blocked the two channels.	('TRPC3', 'Gene', (34, 39))	('Pyr6', 'Var', (74, 78))	('STIM1', 'Gene', '6786', (93, 98))	('TRPC3', 'Gene', '7222', (34, 39))	('Pyr10', 'Var', (0, 5))	('STIM1', 'Gene', (93, 98))
357009	28119804	The best-studied member of this group is Pyr2 (also known as BTP2 or YM-58483), a potent inhibitor for both CRAC and TRPC-mediated Ca2+ entry.	('TRPC-mediated Ca2+ entry', 'MPA', (117, 141))	('Pyr2', 'Var', (41, 45))	('CRAC', 'Chemical', '-', (108, 112))	('YM-58483', 'Chemical', 'MESH:C476308', (69, 77))
357014	28119804	Moreover, Synta66 has no effect on STIM1 puncta formation, suggesting that it does not inhibit the early steps of STIM1 activation and translocation to junctional ER-PM sites.	('STIM1', 'Gene', (114, 119))	('STIM1', 'Gene', '6786', (35, 40))	('ER-PM', 'Chemical', '-', (163, 168))	('STIM1', 'Gene', '6786', (114, 119))	('Synta', 'Chemical', '-', (10, 15))	('Synta66', 'Var', (10, 17))	('STIM1', 'Gene', (35, 40))
357015	28119804	CM2489 has completed phase I clinical trials for the treatment of moderate-to-severe plaque psoriasis.	('psoriasis', 'Disease', (92, 101))	('psoriasis', 'Phenotype', 'HP:0003765', (92, 101))	('CM2489', 'Var', (0, 6))	('psoriasis', 'Disease', 'MESH:D011565', (92, 101))
357026	28119804	A number of P2X7 receptor regulators, such as antagonist A-438079 and A-740003 are mainly studied in pain relief.	('P2X7 receptor', 'Gene', '5027', (12, 25))	('pain', 'Phenotype', 'HP:0012531', (101, 105))	('pain', 'Disease', 'MESH:D010146', (101, 105))	('P2X7 receptor', 'Gene', (12, 25))	('pain', 'Disease', (101, 105))	('A-740003', 'Var', (70, 78))
357030	28119804	Dysregulated Ca2+ homeostasis may play a role more like a "driver" than a "passenger" in carcinogenesis or tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('Ca2+ homeostasis', 'MPA', (13, 29))	('tumor', 'Disease', (107, 112))	('carcinogenesis', 'Disease', (89, 103))	('Dysregulated', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
357072	26003801	This revealed the evolutionary genomic landscape of EACs with the presence of heterogeneous driver mutations, parallel evolution, early genome doubling events and an association between high intratumor heterogeneity and poor response to NAC.	('EAC', 'Gene', '1540', (52, 55))	('NAC', 'Chemical', '-', (237, 240))	('tumor', 'Disease', (196, 201))	('EAC', 'Gene', (52, 55))	('mutations', 'Var', (99, 108))	('association', 'Interaction', (166, 177))	('EAC', 'Phenotype', 'HP:0011459', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
357073	26003801	Multi-region sequencing demonstrated a significant reduction in T>G mutations within a CTT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of C>A mutations within a CpC context following NAC.	('NAC', 'Chemical', '-', (255, 258))	('reduction', 'NegReg', (51, 60))	('T>G', 'Gene', (64, 67))	('mutations', 'Var', (68, 77))	('platinum', 'Chemical', 'MESH:D010984', (172, 180))	('C>A', 'Gene', (210, 213))
357085	26003801	Previous studies have shown that the evolution from Barrett's esophagus (BE) to adenocarcinoma of the esophagus is dominated by loss of TP53, genome doubling, chromosomal instability (CIN) and a high frequency of chromothripsis events resulting in genomic diversity and an increase in the prevalence of focal amplifications and copy number gains and losses.	('adenocarcinoma of the esophagus', 'Disease', (80, 111))	('copy number gains', 'Disease', (328, 345))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (80, 111))	('CIN', 'Phenotype', 'HP:0040012', (184, 187))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (52, 71))	('chromosomal instability', 'Phenotype', 'HP:0040012', (159, 182))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (52, 71))	('TP53', 'Gene', '7157', (136, 140))	('chromothripsis', 'Disease', 'MESH:D000072837', (213, 227))	('CIN', 'Disease', 'MESH:D007674', (184, 187))	('genomic diversity', 'MPA', (248, 265))	('losses', 'NegReg', (350, 356))	('chromothripsis', 'Disease', (213, 227))	('BE', 'Phenotype', 'HP:0100580', (73, 75))	('genome doubling', 'CPA', (142, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('CIN', 'Disease', (184, 187))	('TP53', 'Gene', (136, 140))	('focal', 'MPA', (303, 308))	('copy number gains', 'Disease', 'MESH:D015430', (328, 345))	('loss', 'Var', (128, 132))	("Barrett's esophagus", 'Disease', (52, 71))	('chromosomal instability', 'Disease', (159, 182))
357090	26003801	All tumors demonstrated spatial and temporal heterogeneity with a median of 55.63% of non-silent mutations being heterogeneous (range 12.6% to 69.4%) (Fig.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('non-silent mutations', 'Var', (86, 106))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
357091	26003801	The total number of non-silent mutations identified in these tumors (median = 213) was significantly greater (p=0.0109, Wilcoxon Rank Sum test) than the number of mutations identified if only a single tumor region had been sampled (median = 127.5), highlighting intratumor heterogeneity and the underestimation of mutational burden and clonal architecture from single samples in EAC (Supplementary Fig.	('EAC', 'Gene', '1540', (379, 382))	('tumors', 'Disease', (61, 67))	('mutations', 'Var', (31, 40))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('EAC', 'Gene', (379, 382))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (267, 272))	('non-silent mutations', 'Var', (20, 40))	('tumor', 'Disease', (201, 206))	('EAC', 'Phenotype', 'HP:0011459', (379, 382))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))
357097	26003801	To account for SNV heterogeneity driven by copy number events, we identified all mutations in genomic segments of copy number variation across tumor regions and filtered those whose absence, or low variant allele frequency, could be explained by copy number loss.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (81, 90))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
357100	26003801	We then classified somatic SNVs in known cancer genes into category 1-3 driver events depending on evidence supporting driver mutation status (see Supplementary Methods and Supplementary Table S3), with all other SNVs classified as category 4.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutation', 'Var', (126, 134))	('cancer', 'Disease', (41, 47))
357103	26003801	Interestingly, these data support our recent findings that mutations in PIK3R1 have a tendency to be later, subclonal, events across cancer types.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('PIK3R1', 'Gene', (72, 78))	('PIK3R1', 'Gene', '5295', (72, 78))	('cancer', 'Disease', (133, 139))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
357104	26003801	Additionally, we identified 10 frameshift indels within annotated driver genes, of which six were located on the trunk, including two in TP53 (EAC006 and EAC015).	('EAC', 'Phenotype', 'HP:0011459', (154, 157))	('EAC', 'Phenotype', 'HP:0011459', (143, 146))	('EAC', 'Gene', '1540', (154, 157))	('frameshift indels', 'Var', (31, 48))	('EAC', 'Gene', (154, 157))	('EAC', 'Gene', '1540', (143, 146))	('TP53', 'Gene', '7157', (137, 141))	('EAC', 'Gene', (143, 146))	('TP53', 'Gene', (137, 141))
357105	26003801	We also identified 15 of the 26 putative drivers reported in EAC and mutations in 7 of these 15 drivers were found to occur on the branches (SMAD4, TLR4, SLC39A12, TLL1, EYS, NUAK1 and DOCK2; Supplementary Fig.	('mutations', 'Var', (69, 78))	('TLR4', 'Gene', '7099', (148, 152))	('SLC39A12', 'Gene', (154, 162))	('EAC', 'Phenotype', 'HP:0011459', (61, 64))	('DOCK2', 'Gene', '1794', (185, 190))	('TLR4', 'Gene', (148, 152))	('SMAD4', 'Gene', '4089', (141, 146))	('TLL1', 'Gene', '7092', (164, 168))	('EAC', 'Gene', '1540', (61, 64))	('NUAK1', 'Gene', '9891', (175, 180))	('EYS', 'Gene', '346007', (170, 173))	('TLL1', 'Gene', (164, 168))	('EYS', 'Gene', (170, 173))	('EAC', 'Gene', (61, 64))	('DOCK2', 'Gene', (185, 190))	('SLC39A12', 'Gene', '221074', (154, 162))	('NUAK1', 'Gene', (175, 180))	('SMAD4', 'Gene', (141, 146))
357107	26003801	Supporting this, we identified a significantly greater number of driver mutations using the M-seq approach compared to a single biopsy for each of these tumors (p=0.041, Wilcoxon Rank Sum test) (Supplementary Fig.	('mutations', 'Var', (72, 81))	('M-seq', 'Var', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
357108	26003801	Next, to further resolve the clonal architecture of each tumor, we integrated copy number, variant allele frequencies and purity estimates to calculate the cancer cell fraction (CCF) of each mutation within each tumor region.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (57, 62))	('mutation', 'Var', (191, 199))	('tumor', 'Disease', (212, 217))
357110	26003801	Such mutations appear clonally dominant within one tumor region, but are not detectable in other tumor regions.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (51, 56))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
357112	26003801	Similarly, in EAC014, a mutation in SMAD4 (pR361H) was present in all cancer cells within region R3, but was undetectable in the remaining tumor regions.	('EAC', 'Gene', '1540', (14, 17))	('pR361H', 'Var', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('EAC', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SMAD4', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('EAC', 'Phenotype', 'HP:0011459', (14, 17))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('SMAD4', 'Gene', '4089', (36, 41))
357113	26003801	Conversely, mutations in SLC39A12 (pT37I) and TP53 (splice site) in EAC014 and EAC001 respectively were both found to be clonal in all tumor regions.	('EAC', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('mutations', 'Var', (12, 21))	('SLC39A12', 'Gene', (25, 33))	('TP53', 'Gene', '7157', (46, 50))	('tumor', 'Disease', (135, 140))	('EAC', 'Gene', '1540', (68, 71))	('TP53', 'Gene', (46, 50))	('EAC', 'Gene', (68, 71))	('EAC', 'Phenotype', 'HP:0011459', (79, 82))	('SLC39A12', 'Gene', '221074', (25, 33))	('EAC', 'Gene', '1540', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
357114	26003801	More generally, consistent with previous reports, mutations in TP53 were always identified as fully clonal, and, in every case, mutations in TP53 were accompanied by copy neutral LOH, highlighting the importance of mutations in TP53 as early driver events.	('TP53', 'Gene', '7157', (63, 67))	('mutations', 'Var', (128, 137))	('TP53', 'Gene', (63, 67))	('mutations', 'Var', (50, 59))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('TP53', 'Gene', '7157', (228, 232))	('TP53', 'Gene', (228, 232))
357126	26003801	Additionally, all tumors had evidence of ubiquitous TP53 disruption, either through mutation (7/8) or by amplification of MDM2 (EAC003), and all tumor regions showed evidence of GD.	('tumors', 'Disease', (18, 24))	('EAC', 'Gene', '1540', (128, 131))	('EAC', 'Gene', (128, 131))	('tumor', 'Disease', (18, 23))	('amplification', 'Var', (105, 118))	('MDM2', 'Gene', (122, 126))	('disruption', 'NegReg', (57, 67))	('TP53', 'Gene', (52, 56))	('tumor', 'Disease', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('MDM2', 'Gene', '4193', (122, 126))	('GD', 'Chemical', '-', (178, 180))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('TP53', 'Gene', '7157', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('mutation', 'Var', (84, 92))
357134	26003801	Across our cohort of 8 tumors, we identified 1090 genomic segments of copy number gain (>=1 copy number relative to ploidy), and 824 segments of copy number loss (<=1 copy number relative to ploidy).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('copy number', 'Var', (145, 156))	('copy number', 'Var', (70, 81))	('gain', 'PosReg', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
357152	26003801	In keeping with the findings of Meier and colleagues, who identified the presence of a platinum signature, with an enrichment of C>A mutations within a CpC context, following platinum treatment in C.elegans, we observed this specific mutational signature when the post NAC tumors were analyzed together (p=0.005) (Fig.	('platinum', 'Chemical', 'MESH:D010984', (87, 95))	('NAC', 'Chemical', '-', (269, 272))	('tumors', 'Disease', (273, 279))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('C>A', 'Gene', (129, 132))	('mutations', 'Var', (133, 142))	('C.elegans', 'Species', '6239', (197, 206))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('platinum', 'Chemical', 'MESH:D010984', (175, 183))	('tumors', 'Disease', 'MESH:D009369', (273, 279))
357161	26003801	However, some of these amplifications may have occurred via breakage fusion bridges and chromothripsis, resulting in double minute chromosomes which may be relatively resistant to targeted therapeutics.	('resulting in', 'Reg', (104, 116))	('double minute chromosomes', 'Var', (117, 142))	('chromothripsis', 'Disease', (88, 102))	('chromothripsis', 'Disease', 'MESH:D000072837', (88, 102))
357163	26003801	Interestingly, we observed a significant reduction in this mutational process in the late (branched) mutations with an associated relative increase in C>T at CpG sites, consistent with findings in clear cell renal cell carcinoma.	('mutations', 'Var', (101, 110))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (197, 228))	('clear cell renal cell carcinoma', 'Disease', (197, 228))	('C>T', 'MPA', (151, 154))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (208, 228))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (197, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('reduction', 'NegReg', (41, 50))
357165	26003801	A number of putative driver mutations identified by Dulak et al, SMAD4, TLR4, SLC39A12, TLL1, EYS, NUAK1 and DOCK2 were identified subclonally in our cohort of tumors suggesting these frequently occur later in tumor evolution.	('DOCK2', 'Gene', '1794', (109, 114))	('SMAD4', 'Gene', '4089', (65, 70))	('TLL1', 'Gene', (88, 92))	('EYS', 'Gene', '346007', (94, 97))	('NUAK1', 'Gene', '9891', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('NUAK1', 'Gene', (99, 104))	('TLL1', 'Gene', '7092', (88, 92))	('SLC39A12', 'Gene', (78, 86))	('TLR4', 'Gene', '7099', (72, 76))	('tumor', 'Disease', (210, 215))	('TLR4', 'Gene', (72, 76))	('DOCK2', 'Gene', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('SMAD4', 'Gene', (65, 70))	('tumor', 'Disease', (160, 165))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('EYS', 'Gene', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('SLC39A12', 'Gene', '221074', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
357166	26003801	Many of these driver mutations resulted in an illusion of clonality, highlighting the importance of considering regional intratumoral heterogeneity in this tumor type in order to fully dissect the evolutionary history of these tumors and to more accurately identify fully clonal events which may serve as tractable therapeutic targets.	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (126, 131))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('resulted in', 'Reg', (31, 42))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('mutations', 'Var', (21, 30))
357173	26003801	The observation that all patients, including those who derived limited clinical benefit from NAC, harbored residual disease with an increase in C>A mutations in a CpC context, known to occur in model organisms following platinum exposure, further emphasizes the importance of deciphering those patients who will not derive benefit from mutagenic cytotoxic chemotherapy.	('C>A', 'Gene', (144, 147))	('mutations', 'Var', (148, 157))	('residual disease', 'Disease', (107, 123))	('increase', 'PosReg', (132, 140))	('patients', 'Species', '9606', (294, 302))	('NAC', 'Chemical', '-', (93, 96))	('patients', 'Species', '9606', (25, 33))	('platinum', 'Chemical', 'MESH:D010984', (220, 228))
357174	26003801	Using M-seq we have identified considerable heterogeneity of non-silent mutations and the presence of subclonal driver mutations indicating that the incidence of driver mutations from single EAC samples may be underestimated, similar to recent observations in other tumor types.	('EAC', 'Gene', '1540', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('EAC', 'Gene', (191, 194))	('non-silent mutations', 'Var', (61, 81))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('EAC', 'Phenotype', 'HP:0011459', (191, 194))
357175	26003801	We find that mutations in TP53 as well as mutations in other tumor suppressor genes such as CDKN2A are early events, likely occurring before genome doubling, which was also found to be a ubiquitous event in all tumors.	('TP53', 'Gene', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('CDKN2A', 'Gene', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('CDKN2A', 'Gene', '1029', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('TP53', 'Gene', '7157', (26, 30))	('mutations', 'Var', (13, 22))	('tumors', 'Disease', (211, 217))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', (61, 66))
357184	26003801	Orthogonal validation was performed on all identified 685 non-silent mutations from 3 tumors (EAC001, EAC003 and EAC005).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EAC', 'Gene', (94, 97))	('EAC', 'Phenotype', 'HP:0011459', (113, 116))	('EAC', 'Phenotype', 'HP:0011459', (102, 105))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('EAC', 'Gene', '1540', (102, 105))	('EAC', 'Gene', '1540', (113, 116))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('EAC', 'Gene', (102, 105))	('EAC', 'Gene', (113, 116))	('EAC', 'Phenotype', 'HP:0011459', (94, 97))	('non-silent mutations', 'Var', (58, 78))	('EAC', 'Gene', '1540', (94, 97))
357188	26003801	In total, across all tumor regions, 100 mutations were filtered as being driven by copy number change.	('copy number change', 'Var', (83, 101))	('tumor', 'Disease', (21, 26))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
357194	26003801	Identification of amplifications encoding targetable oncogenes maintained through NAC, suggests the presence of stable vulnerabilities, unimpeded by cytotoxics, suitable for therapeutic intervention.	('cytotoxics', 'Disease', (149, 159))	('amplifications', 'Var', (18, 32))	('NAC', 'Chemical', '-', (82, 85))	('cytotoxics', 'Disease', 'MESH:D064420', (149, 159))
357279	25446010	NS398 (1 muM), a specific inhibitor of COX2 completely inhibited COX2 expression (Fig.	('NS398', 'Var', (0, 5))	('COX2', 'Gene', (39, 43))	('COX2', 'Gene', '4513', (39, 43))	('NS398', 'Chemical', 'MESH:C080955', (0, 5))	('expression', 'MPA', (70, 80))	('COX2', 'Gene', (65, 69))	('muM', 'Gene', '56925', (9, 12))	('COX2', 'Gene', '4513', (65, 69))	('inhibited', 'NegReg', (55, 64))	('muM', 'Gene', (9, 12))
357340	25446010	In addition, the anti-angiogenic effect of BRE was strongly associated with the downstream inhibition of PI3K/Akt and MAPK signaling pathways.	('MAPK signaling pathways', 'Pathway', (118, 141))	('Akt', 'Gene', (110, 113))	('BRE', 'Var', (43, 46))	('anti-angiogenic effect', 'CPA', (17, 39))	('inhibition', 'NegReg', (91, 101))	('Akt', 'Gene', '207', (110, 113))
357351	23285221	Potential Diagnostic Value of Serum p53 Antibody for Detecting Esophageal Cancer: A Meta-Analysis Mutant p53 protein overexpression has been reported to induce serum antibodies against p53.	('serum antibodies', 'MPA', (160, 176))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (63, 80))	('p53', 'Gene', (185, 188))	('p53', 'Gene', '7157', (185, 188))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('Esophageal Cancer', 'Disease', (63, 80))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('Mutant', 'Var', (98, 104))	('overexpression', 'PosReg', (117, 131))	('induce', 'PosReg', (153, 159))	('protein', 'Protein', (109, 116))
357364	23285221	Mutations in the tumor suppressor gene p53 are the most commonly observed genetic abnormalities in human cancers.	('tumor', 'Disease', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('genetic abnormalities', 'Disease', (74, 95))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('genetic abnormalities', 'Disease', 'MESH:D030342', (74, 95))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('human', 'Species', '9606', (99, 104))
357367	23285221	Mutations in this gene cause an accumulation of non-functional proteins, due to increased stability and a longer half-life of several hours compared with 20 min for the wild-type p53, which can be detected by immunoassay.	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('increased', 'PosReg', (80, 89))	('stability', 'MPA', (90, 99))	('Mutations', 'Var', (0, 9))	('accumulation', 'PosReg', (32, 44))	('non-functional proteins', 'MPA', (48, 71))
357406	23285221	A strong correlation was reported between p53 mutation and the presence of S-p53 Abs.	('p53', 'Gene', (42, 45))	('p53', 'Gene', '7157', (42, 45))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('mutation', 'Var', (46, 54))
357417	23285221	Because the ELISA assay is a quick and convenient assay for detecting p53 genetic alterations, s-p53 Abs may serve as a useful marker for routine screening in EC patient groups.	('p53', 'Gene', (97, 100))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('EC', 'Chemical', '-', (159, 161))	('p53', 'Gene', '7157', (97, 100))	('genetic alterations', 'Var', (74, 93))	('patient', 'Species', '9606', (162, 169))
357461	33632229	Defects of a mitotic checkpoint may bring about mistakes in the chromosome segregation, and the higher level of Cyclin B1 (CCNB1) is a marker of poor prognosis in many cancer types.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('bring about mistakes', 'Reg', (36, 56))	('Defects', 'Var', (0, 7))	('mitotic', 'CPA', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('CCNB1', 'Gene', (123, 128))	('cancer', 'Disease', (168, 174))	('chromosome segregation', 'CPA', (64, 86))	('Cyclin B1', 'Gene', '891', (112, 121))	('Cyclin B1', 'Gene', (112, 121))	('CCNB1', 'Gene', '891', (123, 128))
357467	33632229	GSE111044 included 3 ESCA tissues and corresponding 3 normal tissues from 3 patients.	('GSE111044', 'Var', (0, 9))	('patients', 'Species', '9606', (76, 84))	('ESCA', 'Disease', (21, 25))
357468	33632229	The experiment GSE20347 and GSE29001 were conducted on platform GPL571 (Affymetrix Human Genome U133A 2.0 Array), and GSE111044 was on platform GPL570 (Affymetrix Human Genome U133 Plus 2.0 Array).	('men', 'Species', '9606', (10, 13))	('Human', 'Species', '9606', (83, 88))	('GSE111044', 'Var', (118, 127))	('Human', 'Species', '9606', (163, 168))	('GSE29001', 'Var', (28, 36))
357509	33632229	Furthermore, abnormal CCNB1 expression is often associated with a variety of cancers, and CCNB1 can be used as a biomarker to predict cancer.	('CCNB1', 'Gene', (90, 95))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('associated', 'Reg', (48, 58))	('cancer', 'Disease', (77, 83))	('expression', 'MPA', (28, 38))	('cancers', 'Disease', (77, 84))	('cancer', 'Disease', (134, 140))	('CCNB1', 'Gene', (22, 27))	('CCNB1', 'Gene', '891', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('CCNB1', 'Gene', '891', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('abnormal', 'Var', (13, 21))
357541	26186253	Amplification of Her-2 has been described in tissue samples from different malignancies such as breast cancer, gastric cancer, and ovarian cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('ovarian cancer', 'Disease', (131, 145))	('Amplification', 'Var', (0, 13))	('Her-2', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('malignancies', 'Disease', (75, 87))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (131, 145))	('described', 'Reg', (32, 41))	('breast cancer', 'Disease', (96, 109))	('ovarian cancer', 'Disease', 'MESH:D010051', (131, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('Her-2', 'Gene', '2064', (17, 22))	('gastric cancer', 'Disease', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
357548	26186253	In this study, our aim was to investigate the frequency of Her-2 overexpression and amplification in esophageal adenocarcinoma and in its precursor lesions using immunohistochemistry (IHC) and dual in situ hybridization (DISH).	('adenocarcinoma', 'Disease', (112, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('adenocarcinoma', 'Disease', 'MESH:D000230', (112, 126))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (101, 126))	('amplification', 'Var', (84, 97))	('Her-2', 'Gene', '2064', (59, 64))	('overexpression', 'PosReg', (65, 79))	('Her-2', 'Gene', (59, 64))
357574	26186253	The associations between Her-2 gene amplification/Her-2 protein overexpression, chromosome 17 aneusomy, and the presence of BE, BE dysplasia (LGD or HGD), and ICA were evaluated by Pearson chi2 tests, with P < 0.05 considered significant.	('dysplasia', 'Disease', (131, 140))	('BE', 'Phenotype', 'HP:0100580', (128, 130))	('Her-2', 'Gene', (25, 30))	('Her-2', 'Gene', '2064', (50, 55))	('overexpression', 'PosReg', (64, 78))	('protein', 'Protein', (56, 63))	('aneusomy', 'Var', (94, 102))	('ICA', 'Disease', (159, 162))	('ICA', 'Chemical', '-', (159, 162))	('BE', 'Phenotype', 'HP:0100580', (124, 126))	('Her-2', 'Gene', (50, 55))	('Her-2', 'Gene', '2064', (25, 30))	('dysplasia', 'Disease', 'MESH:C536170', (131, 140))	('associations', 'Interaction', (4, 16))
357576	26186253	IHC for Her-2 protein was categorized at 4 levels based on the Food and Drug Administration's (FDA's) approved scoring system (0, 1, 2, 3); DISH for Her-2 gene was considered positive when amplified and negative when not amplified.	('amplified', 'Var', (189, 198))	('Her-2', 'Gene', '2064', (149, 154))	('Her-2', 'Gene', '2064', (8, 13))	('Her-2', 'Gene', (149, 154))	('Her-2', 'Gene', (8, 13))
357606	26186253	In a recent study, Fassan et al showed the early involvement of Her-2 amplification and protein overexpression in both gastric and Barrett oncogenesis.	('Barrett oncogenesis', 'Disease', (131, 150))	('gastric', 'Disease', (119, 126))	('Her-2', 'Gene', '2064', (64, 69))	('overexpression', 'PosReg', (96, 110))	('protein', 'Protein', (88, 95))	('Her-2', 'Gene', (64, 69))	('amplification', 'Var', (70, 83))
357610	26186253	As in prior studies, we also observed Her-2 protein overexpression and Her-2 gene amplification in a minority of LGD cases, suggesting the involvement of Her-2 in BE progression to dysplasia and carcinoma.	('Her-2', 'Gene', (38, 43))	('involvement', 'Reg', (139, 150))	('dysplasia and carcinoma', 'Disease', 'MESH:D009369', (181, 204))	('BE', 'Phenotype', 'HP:0100580', (163, 165))	('Her-2', 'Gene', '2064', (71, 76))	('amplification', 'Var', (82, 95))	('Her-2', 'Gene', '2064', (154, 159))	('Her-2', 'Gene', (154, 159))	('Her-2', 'Gene', '2064', (38, 43))	('overexpression', 'PosReg', (52, 66))	('protein', 'Protein', (44, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('Her-2', 'Gene', (71, 76))
357611	26186253	p53 alterations have been reported during the progression of BE.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('reported', 'Reg', (26, 34))	('alterations', 'Var', (4, 15))	('BE', 'Phenotype', 'HP:0100580', (61, 63))
357612	26186253	Aberrant p53 is accumulated in the nucleus of the neoplastic cells especially in HGD, and p53 IHC status has recently been shown to have diagnostic value and to predict neoplastic progression in patients with BE.	('predict', 'Reg', (161, 168))	('p53', 'Gene', (90, 93))	('neoplastic progression', 'CPA', (169, 191))	('Aberrant', 'Var', (0, 8))	('p53', 'Gene', '7157', (90, 93))	('HGD', 'Disease', (81, 84))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('patients', 'Species', '9606', (195, 203))	('BE', 'Phenotype', 'HP:0100580', (209, 211))
357614	26186253	Interestingly, Her-2 expression was associated with p53 overexpression especially in tumors that were at an early disease stage.	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('Her-2', 'Gene', '2064', (15, 20))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('Her-2', 'Gene', (15, 20))	('overexpression', 'PosReg', (56, 70))	('expression', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('associated', 'Reg', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
357615	26186253	Importantly, in our study, composed mostly of low-stage tumor cases (40 of the tumors were stage I and II), we found Her-2 overexpression in 28% and 24% of HGD and ICA, respectively, and gene amplification in 20% and 18% of HGD and ICA, respectively.	('Her-2', 'Gene', (117, 122))	('ICA', 'Disease', (164, 167))	('low-stage tumor', 'Disease', 'MESH:D009800', (46, 61))	('HGD', 'Disease', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ICA', 'Chemical', '-', (164, 167))	('low-stage tumor', 'Disease', (46, 61))	('overexpression', 'PosReg', (123, 137))	('gene amplification', 'Var', (187, 205))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('ICA', 'Chemical', '-', (232, 235))	('Her-2', 'Gene', '2064', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
357617	26186253	In their study, Yoon et al reported that only 17% of 713 esophageal adenocarcinomas were Her-2 positive and that Her-2 positivity was significantly associated with lower tumor grade, less invasive tumors, fewer malignant lymph nodes, and the presence of adjacent BE.	('positivity', 'Var', (119, 129))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('lower', 'NegReg', (164, 169))	('fewer', 'NegReg', (205, 210))	('tumor', 'Disease', (170, 175))	('invasive tumors', 'Disease', (188, 203))	('Her-2', 'Gene', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('Her-2', 'Gene', (89, 94))	('adenocarcinomas', 'Disease', 'MESH:D000230', (68, 83))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('BE', 'Phenotype', 'HP:0100580', (263, 265))	('adenocarcinomas', 'Disease', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (57, 82))	('Her-2', 'Gene', '2064', (113, 118))	('Her-2', 'Gene', '2064', (89, 94))	('invasive tumors', 'Disease', 'MESH:D009361', (188, 203))	('tumor', 'Disease', (197, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
357618	26186253	However, others have reported a statistically significant correlation between Her-2 amplification/overexpression and poor prognosis in this patient population.	('significant correlation', 'Reg', (46, 69))	('amplification/overexpression', 'Var', (84, 112))	('amplification/overexpression', 'PosReg', (84, 112))	('patient', 'Species', '9606', (140, 147))	('Her-2', 'Gene', '2064', (78, 83))	('Her-2', 'Gene', (78, 83))
357632	33122449	UCA1 was enriched in exosomes, and exosomal UCA1 was a promising biomarker for the diagnosis of esophageal cancer with 86.7% sensitivity and 70.2% specificity.	('exosomal', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('UCA1', 'Gene', '652995', (44, 48))	('UCA1', 'Gene', (44, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('UCA1', 'Gene', '652995', (0, 4))	('UCA1', 'Gene', (0, 4))
357634	33122449	Also, exosomal UCA1 was taken up by esophageal cancer cells and inhibited the progression of esophageal cancer in vitro and tumor growth in vivo.	('esophageal cancer', 'Disease', 'MESH:D004938', (36, 53))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('progression', 'CPA', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('inhibited', 'NegReg', (64, 73))	('UCA1', 'Gene', '652995', (15, 19))	('tumor', 'Disease', (124, 129))	('UCA1', 'Gene', (15, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancer', 'Disease', (36, 53))	('exosomal', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
357636	33122449	Conclusions: The results suggested that exosomal UCA1 inhibits tumorigenesis and progression of esophageal cancer in vitro and in vivo, and might be a promising biomarker for esophageal cancer.	('esophageal cancer', 'Disease', (175, 192))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('progression', 'CPA', (81, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('esophageal cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('exosomal', 'Var', (40, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('inhibits', 'NegReg', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('UCA1', 'Gene', '652995', (49, 53))	('UCA1', 'Gene', (49, 53))
357664	33122449	Furthermore, we performed ROC curves analysis to determine the potential of exosomal UCA1 as a non-invasive biomarker in esophageal cancer.	('exosomal', 'Var', (76, 84))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('UCA1', 'Gene', '652995', (85, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('UCA1', 'Gene', (85, 89))
357666	33122449	The sensitivity and specificity of exosomal UCA1 as a biomarker to predict the presence of esophageal cancer were 86.7% and 70.2%, respectively.	('exosomal', 'Var', (35, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('UCA1', 'Gene', '652995', (44, 48))	('UCA1', 'Gene', (44, 48))	('esophageal cancer', 'Disease', (91, 108))
357668	33122449	In both scenarios, the level of exosomal UCA1 did not alter in the different conditions (Figure 2C, 2D), indicating that exosomal UCA1 might be a potential biomarker for esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('exosomal', 'Var', (121, 129))	('esophageal cancer', 'Disease', (170, 187))	('UCA1', 'Gene', '652995', (41, 45))	('UCA1', 'Gene', '652995', (130, 134))	('UCA1', 'Gene', (41, 45))	('UCA1', 'Gene', (130, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))
357672	33122449	Meanwhile, the invasive and migratory abilities were also suppressed by forced expression of UCA1 in esophageal cancer cells (Figure 3D, 3E).	('UCA1', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('suppressed', 'NegReg', (58, 68))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('forced expression', 'Var', (72, 89))	('UCA1', 'Gene', '652995', (93, 97))
357690	33122449	Furthermore, H&E staining and immunohistochemistry assays were performed in mice tumor tissues, and the level of Ki67, a proliferation marker, was dramatically decreased in tumor tissues of mice treated with UCA1-vector and UCA1-Exo (Figure 6E, 6F).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('with', 'Var', (203, 207))	('the', 'MPA', (100, 103))	('Exo', 'Gene', '24127', (229, 232))	('Ki67', 'Gene', '17345', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('and', 'Var', (220, 223))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Disease', (81, 86))	('Exo', 'Gene', (229, 232))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('UCA1', 'Gene', '652995', (224, 228))	('UCA1', 'Gene', (224, 228))	('H&E', 'Chemical', '-', (13, 16))	('UCA1', 'Gene', '652995', (208, 212))	('Ki67', 'Gene', (113, 117))	('UCA1', 'Gene', (208, 212))	('tumor', 'Disease', (173, 178))	('dramatically', 'NegReg', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mice', 'Species', '10090', (190, 194))
357699	33122449	Furthermore, the anticancer effect of exosomal UCA1 inhibited tumor growth in vivo.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('exosomal', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('UCA1', 'Gene', '652995', (47, 51))	('UCA1', 'Gene', (47, 51))	('cancer', 'Disease', (21, 27))	('inhibited', 'NegReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
357703	33122449	Among these dysregulated lncRNAs, only UCA1 was significantly downregulated, which is consistent with the finding reported by Wang et al.. Increasing evidence suggests that exosomal lncRNAs are representative of the physiological status of exosome-releasing cells, then impacting the cellular processes of recipient cells.	('impacting', 'Reg', (270, 279))	('cellular processes of recipient cells', 'CPA', (284, 321))	('UCA1', 'Gene', '652995', (39, 43))	('exosomal', 'Var', (173, 181))	('UCA1', 'Gene', (39, 43))
357721	33122449	Furthermore, exosomal UCA1 suppressed tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('suppressed', 'NegReg', (27, 37))	('UCA1', 'Gene', '652995', (22, 26))	('UCA1', 'Gene', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('exosomal', 'Var', (13, 21))
357725	33122449	Also, miRNA-613 is associated with cell invasion and migration in triple-negative breast cancer through Daam1/RhoA signaling pathway.	('breast cancer', 'Disease', (82, 95))	('miRNA-613', 'Chemical', '-', (6, 15))	('miRNA-613', 'Var', (6, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('RhoA', 'Gene', '387', (110, 114))	('Daam1', 'Gene', '23002', (104, 109))	('associated with', 'Reg', (19, 34))	('cell invasion', 'CPA', (35, 48))	('Daam1', 'Gene', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('RhoA', 'Gene', (110, 114))
357727	33122449	Thus, the observation in this study suggests that miRNA-613 may be a potential biomarker for esophageal cancer if the further comprehensive investigation is carried out.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('miRNA-613', 'Chemical', '-', (50, 59))	('miRNA-613', 'Var', (50, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))
357728	33122449	In conclusion, the results suggest that exosomal UCA1 derived from normal cells can be taken up by esophageal cancer cells, then attenuating tumor tumorigenesis and development in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('tumor', 'Disease', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('attenuating', 'NegReg', (129, 140))	('development', 'CPA', (165, 176))	('exosomal', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('UCA1', 'Gene', '652995', (49, 53))	('UCA1', 'Gene', (49, 53))	('esophageal cancer', 'Disease', (99, 116))
357729	33122449	Also, our observations demonstrated that exosomal UCA1 has a high diagnostic value for patients with esophageal cancer.	('UCA1', 'Gene', '652995', (50, 54))	('UCA1', 'Gene', (50, 54))	('patients', 'Species', '9606', (87, 95))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('exosomal', 'Var', (41, 49))
357765	33122449	The plasmids carrying mutated miRNA-613 binding site were inserted into the same luciferase reporter to test binding specificity.	('test', 'Reg', (104, 108))	('miRNA-613', 'Gene', (30, 39))	('mutated', 'Var', (22, 29))	('miRNA-613', 'Chemical', '-', (30, 39))	('binding', 'Interaction', (109, 116))
357768	31599475	Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer Abnormal function of human body enzymes and epigenetic alterations such as DNA methylation have been shown to lead to human carcinogenesis.	('function', 'MPA', (116, 124))	('Lysyl oxidase', 'Gene', (0, 13))	('carcinogenesis', 'Disease', 'MESH:D063646', (231, 245))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('carcinogenesis', 'Disease', (231, 245))	('impacts disease', 'Disease', (14, 29))	('lead to', 'Reg', (217, 224))	('human', 'Species', '9606', (225, 230))	('human', 'Species', '9606', (128, 133))	('DNA methylation', 'Var', (182, 197))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('Lysyl oxidase', 'Gene', '4015', (0, 13))	('impacts disease', 'Disease', 'MESH:D014095', (14, 29))	('epigenetic alterations', 'Var', (151, 173))
357776	31599475	Silencing and enzymatic inhibition of LOX suppressed growth and reduced the invasion and migration ability of ESCC cell lines along with the downregulation of AKT and MMP2.	('AKT', 'Gene', '207', (159, 162))	('LOX', 'Gene', '4015', (38, 41))	('AKT', 'Gene', (159, 162))	('MMP2', 'Gene', '4313', (167, 171))	('LOX', 'Gene', (38, 41))	('suppressed', 'NegReg', (42, 52))	('growth', 'CPA', (53, 59))	('downregulation', 'NegReg', (141, 155))	('reduced', 'NegReg', (64, 71))	('Silencing', 'Var', (0, 9))	('MMP2', 'Gene', (167, 171))
357778	31599475	In vitro, LOX expression was upregulated following DNA demethylation.	('LOX', 'Gene', '4015', (10, 13))	('upregulated', 'PosReg', (29, 40))	('DNA demethylation', 'Var', (51, 68))	('LOX', 'Gene', (10, 13))
357783	31599475	In addition, we revealed that LOX expression was regulated epigenetically by genome-wide hypomethylation using in vitro assay and integrated gene analysis in tissues and cell lines.	('regulated', 'Reg', (49, 58))	('expression', 'MPA', (34, 44))	('LOX', 'Gene', '4015', (30, 33))	('LOX', 'Gene', (30, 33))	('hypomethylation', 'Var', (89, 104))
357789	31599475	Epigenetic alterations, such as DNA methylation, has been hugely implicated in human carcinogenesis.	('Epigenetic alterations', 'Var', (0, 22))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('human', 'Species', '9606', (79, 84))	('carcinogenesis', 'Disease', (85, 99))	('implicated', 'Reg', (65, 75))	('DNA', 'Disease', (32, 35))
357854	31599475	Interestingly, LOX knockdown suppressed cell proliferation 48 hours after transfection (P < .001) (Figure 2B).	('knockdown', 'Var', (19, 28))	('LOX', 'Gene', '4015', (15, 18))	('LOX', 'Gene', (15, 18))	('cell proliferation', 'CPA', (40, 58))	('suppressed', 'NegReg', (29, 39))
357856	31599475	We further revealed that there was a decrease in the expression of p-AKT following LOX knockdown (Figure 2D).	('decrease', 'NegReg', (37, 45))	('AKT', 'Gene', (69, 72))	('LOX', 'Gene', '4015', (83, 86))	('LOX', 'Gene', (83, 86))	('expression', 'MPA', (53, 63))	('AKT', 'Gene', '207', (69, 72))	('knockdown', 'Var', (87, 96))
357858	31599475	We showed that both LOX knockdown (Figure 2E) and enzymatic inhibition (Figure 2F) significantly reduced cell migration(P < .001) as there was a significant decrease in the distance moved by the tracked cells within Matrigel-coated wells in a 6-well plate within the 24-hour monitoring period by real-time (time-lapse) imaging assay.	('cell migration', 'CPA', (105, 119))	('LOX', 'Gene', (20, 23))	('decrease', 'NegReg', (157, 165))	('reduced', 'NegReg', (97, 104))	('knockdown', 'Var', (24, 33))	('distance moved', 'CPA', (173, 187))	('LOX', 'Gene', '4015', (20, 23))
357871	31599475	Moreover, we confirmed a decrease in LINE-1 methylation level (from 64% to 35%) after treatment with 5-AZA (Figure 4B).	('LINE-1 methylation level', 'MPA', (37, 61))	('5-AZA', 'Chemical', 'MESH:D000077209', (101, 106))	('decrease', 'NegReg', (25, 33))	('5-AZA', 'Var', (101, 106))
357873	31599475	Thus, we suggest that LOX expression might be regulated epigenetically by LINE-1 hypomethylation (genome-wide hypomethylation).	('LOX', 'Gene', '4015', (22, 25))	('LOX', 'Gene', (22, 25))	('hypomethylation', 'Var', (81, 96))	('LINE-1', 'Gene', (74, 80))
357874	31599475	To confirm the relationship between LOX expression and genome-wide hypomethylation, we undertook mRNA expression array analyses to determined upregulated and downregulated genes in LINE-1 hypomethylated and hypermethylated ESCC specimens.	('hypermethylated', 'Var', (207, 222))	('downregulated', 'NegReg', (158, 171))	('LOX', 'Gene', '4015', (36, 39))	('ESCC', 'Disease', (223, 227))	('LOX', 'Gene', (36, 39))	('hypomethylated', 'Var', (188, 202))	('upregulated', 'PosReg', (142, 153))
357876	31599475	An integrated analysis of genes in tissues and cell lines revealed 4 mostly upregulated genes (more than 2-fold change) with LOX being most highly upregulated gene in LINE-1 hypomethylated cases (Figure 5A).	('upregulated', 'PosReg', (147, 158))	('LOX', 'Gene', '4015', (125, 128))	('LOX', 'Gene', (125, 128))	('hypomethylated', 'Var', (174, 188))	('upregulated', 'PosReg', (76, 87))
357879	31599475	These findings certainly support that, in ESCC, LOX expression is related to LINE-1 hypomethylation (ie, global DNA hypomethylation).	('LOX', 'Gene', '4015', (48, 51))	('LOX', 'Gene', (48, 51))	('related', 'Reg', (66, 73))	('hypomethylation', 'Var', (84, 99))	('ESCC', 'Disease', (42, 46))
357895	31599475	In this study, LOX functional analysis was evaluated in vitro by knockdown of LOX with siRNA and inhibition of LOX enzymatic activity with BAPN.	('knockdown', 'Var', (65, 74))	('inhibition', 'NegReg', (97, 107))	('LOX', 'Gene', '4015', (111, 114))	('LOX', 'Gene', '4015', (15, 18))	('LOX', 'Gene', (111, 114))	('LOX', 'Gene', '4015', (78, 81))	('BAPN', 'Chemical', 'MESH:D000629', (139, 143))	('LOX', 'Gene', (15, 18))	('LOX', 'Gene', (78, 81))
357896	31599475	We showed that LOX knockdown and inhibition by BAPN led to significant reductions in cell proliferation.	('cell proliferation', 'CPA', (85, 103))	('knockdown', 'Var', (19, 28))	('inhibition', 'NegReg', (33, 43))	('reductions', 'NegReg', (71, 81))	('LOX', 'Gene', '4015', (15, 18))	('BAPN', 'Gene', (47, 51))	('LOX', 'Gene', (15, 18))	('BAPN', 'Chemical', 'MESH:D000629', (47, 51))
357899	31599475	We also focused on the role of LOX in cell migration and interestingly we showed that the migration ability of cells was reduced following LOX knockdown and enzymatic inhibition.	('migration ability of cells', 'CPA', (90, 116))	('LOX', 'Gene', '4015', (31, 34))	('LOX', 'Gene', (31, 34))	('reduced', 'NegReg', (121, 128))	('LOX', 'Gene', '4015', (139, 142))	('knockdown', 'Var', (143, 152))	('LOX', 'Gene', (139, 142))
357913	31599475	Moreover, our findings suggest that LOX expression is regulated epigenetically by DNA hypomethylation.	('LOX', 'Gene', '4015', (36, 39))	('hypomethylation', 'Var', (86, 101))	('LOX', 'Gene', (36, 39))
357931	29546098	In 2011, the FDA approved pegylated IFN-alpha, reducing its immunogenicity and increasing the agent's half-life by reducing its absorption rate following subcutaneous injection, as well as its clearance.	('clearance', 'MPA', (193, 202))	('reducing', 'NegReg', (47, 55))	('pegylated', 'Var', (26, 35))	('IFN-alpha', 'Gene', (36, 45))	('immunogenicity', 'MPA', (60, 74))	('increasing', 'PosReg', (79, 89))	('IFN-alpha', 'Gene', '3439', (36, 45))	('reducing', 'NegReg', (115, 123))	('absorption rate following subcutaneous injection', 'MPA', (128, 176))	('half-life', 'MPA', (102, 111))
357935	29546098	For example, based on preclinical data suggesting synergy between IFN-alpha and BRAF inhibitors in BRAF-mutated disease, two phase I/II clinical trials are currently evaluating the combination of IFN-alpha/peg-IFN-alpha and vemurafenib in BRAF-mutated MM (NCT01943422, NCT01959633).	('IFN-alpha', 'Gene', (210, 219))	('BRAF', 'Gene', (80, 84))	('vemurafenib', 'Chemical', 'MESH:D000077484', (224, 235))	('BRAF', 'Gene', (239, 243))	('NCT01943422', 'Var', (256, 267))	('BRAF', 'Gene', '673', (239, 243))	('IFN-alpha', 'Gene', '3439', (66, 75))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('IFN-alpha', 'Gene', '3439', (196, 205))	('IFN-alpha', 'Gene', (196, 205))	('IFN-alpha', 'Gene', (66, 75))	('BRAF', 'Gene', '673', (80, 84))	('IFN-alpha', 'Gene', '3439', (210, 219))
357941	29546098	Patients most likely to respond favorably include those with good performance status, limited cutaneous or subcutaneous disease, normal serum LDH, and NRAS mutations.	('mutations', 'Var', (156, 165))	('limited cutaneous', 'Disease', (86, 103))	('serum LDH', 'MPA', (136, 145))	('Patients', 'Species', '9606', (0, 8))	('NRAS', 'Gene', (151, 155))	('NRAS', 'Gene', '4893', (151, 155))
357951	29546098	Randomized phase II clinical trials are also exploring combinations of DC vaccines with radiation therapy and pre-vaccination IFN-alpha (NCT01973322), modified tumor cell-based vaccines with ipilimumab (NCT02054520), and DC vaccines with targeted tyrosine kinase inhibitors (NCT01876212).	('NCT02054520', 'Var', (203, 214))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('NCT01876212', 'Var', (275, 286))	('IFN-alpha', 'Gene', '3439', (126, 135))	('IFN-alpha', 'Gene', (126, 135))	('ipilimumab', 'Chemical', 'MESH:D000074324', (191, 201))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('NCT01973322', 'Var', (137, 148))
357956	29546098	Short culture time, youth and CD8 positivity of the tumor infiltrating lymphocytes (TILs) used, and high TIL number have all correlated with better ACT responses, though the need for further predictive prognostic biomarkers remains due to the financial, temporal, and toxicity-related burden associated with this treatment technique.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CD8', 'Gene', (30, 33))	('TIL', 'Gene', (105, 108))	('positivity', 'Var', (34, 44))	('CD8', 'Gene', '925', (30, 33))	('TIL', 'Gene', (84, 87))	('tumor', 'Disease', (52, 57))	('better', 'PosReg', (141, 147))	('toxicity', 'Disease', 'MESH:D064420', (268, 276))	('toxicity', 'Disease', (268, 276))	('TIL', 'Gene', '7096', (105, 108))	('TIL', 'Gene', '7096', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('ACT responses', 'MPA', (148, 161))
357969	29546098	Grade 3-4 ADRs were more frequent in the ipilimumab cohort (56.3% vs. 27.5%, p < 0.001).	('Grade 3-4 ADRs', 'Disease', (0, 14))	('ipilimumab', 'Chemical', 'MESH:D000074324', (41, 51))	('ipilimumab', 'Var', (41, 51))	('ADRs', 'Disease', (10, 14))
357973	29546098	For example, a meta-analysis of 15 randomized trials demonstrated superior survival with ipilimumab monotherapy compared to chemotherapy alone, a variety of chemotherapy combinations, biochemotherapy, and other immunotherapies including peptide vaccines, IL-2, and IFN-alpha.	('IL-2', 'Gene', '3558', (255, 259))	('superior', 'PosReg', (66, 74))	('monotherapy', 'Var', (100, 111))	('ipilimumab', 'Gene', (89, 99))	('IL-2', 'Gene', (255, 259))	('survival', 'MPA', (75, 83))	('ipilimumab', 'Chemical', 'MESH:D000074324', (89, 99))	('IFN-alpha', 'Gene', (265, 274))	('IFN-alpha', 'Gene', '3439', (265, 274))
357979	29546098	Other current avenues of research include combining CTLA-4 blockade and indolamine 2,3 deoxygenase inhibition (IDO, aberrantly expressed by tumors, breaks down tryptophan halting T cell growth, phase I/II, NCT01604889, Figure 2), as well as ipilimumab with ACT, with or without HD IL-2 (phase I, NCT01701674, NCT02210104).	('CTLA-4', 'Gene', (52, 58))	('tryptophan', 'Chemical', 'MESH:D014364', (160, 170))	('IL-2', 'Gene', (281, 285))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('HD', 'Disease', 'MESH:D006816', (278, 280))	('IDO', 'Gene', (111, 114))	('tumors', 'Disease', (140, 146))	('tryptophan', 'MPA', (160, 170))	('IL-2', 'Gene', '3558', (281, 285))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('breaks', 'Var', (148, 154))	('T cell growth', 'CPA', (179, 192))	('halting', 'NegReg', (171, 178))	('breaks down', 'Phenotype', 'HP:0001061', (148, 159))	('CTLA-4', 'Gene', '1493', (52, 58))	('indolamine', 'Chemical', 'MESH:C067042', (72, 82))	('IDO', 'Gene', '3620', (111, 114))	('ipilimumab', 'Chemical', 'MESH:D000074324', (241, 251))
357989	29546098	Overall response rates were higher in the nivolumab cohort (32% vs. 11%), and a reduction of at least 50% of the target tumor burden was achieved in 82% of nivolumab patients compared to 60% of the chemotherapy cohort.	('reduction', 'NegReg', (80, 89))	('nivolumab', 'Var', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('higher', 'PosReg', (28, 34))	('nivolumab', 'Chemical', 'MESH:D000077594', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('nivolumab', 'Chemical', 'MESH:D000077594', (156, 165))	('patients', 'Species', '9606', (166, 174))	('tumor', 'Disease', (120, 125))
358005	29546098	Attempts to block Programmed Death Ligands with mAbs (BMS-936559 and MPDL3280A) have not yielded results as promising as PD-1 blockade in MM, though phase I trials are currently investigating their efficacy in combination with BRAF inhibitors (NCT01656642) and IFN-alpha (NCT02174172).	('BMS-936559', 'Var', (54, 64))	('PD-1 blockade', 'Disease', (121, 134))	('PD-1 blockade', 'Disease', 'MESH:D010300', (121, 134))	('NCT01656642', 'Var', (244, 255))	('NCT02174172', 'Var', (272, 283))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (69, 78))	('BRAF', 'Gene', '673', (227, 231))	('IFN-alpha', 'Gene', '3439', (261, 270))	('IFN-alpha', 'Gene', (261, 270))	('BRAF', 'Gene', (227, 231))
358014	29546098	Blocking LAG-3 could thus help the body fight tumor cells on two fronts, and blocking PD-1 in conjunction, which also promotes immuno-tolerance of tumor antigens, might have a synergistic effect.	('LAG-3', 'Gene', (9, 14))	('LAG-3', 'Gene', '3902', (9, 14))	('tumor', 'Disease', (147, 152))	('blocking', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('help', 'PosReg', (26, 30))	('promotes', 'PosReg', (118, 126))	('PD-1', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('PD-1', 'Gene', '5133', (86, 90))	('immuno-tolerance', 'MPA', (127, 143))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
358022	29546098	A number of phase I-II clinical trials are investigating the topical TLR-7/8 agonist resiquimod and/or injectable TLR agonists in concert with protein vaccines as adjuvant treatment for resected stage II-IV disease (NCT00821652, NCT00960752, NCT 02126579, NCT02320305).	('TLR-7', 'Gene', '51284', (69, 74))	('NCT00821652', 'Var', (216, 227))	('II-IV disease', 'Disease', (201, 214))	('NCT00960752', 'Var', (229, 240))	('II-IV disease', 'Disease', 'MESH:D020432', (201, 214))	('NCT 02126579', 'Var', (242, 254))	('NCT02320305', 'Var', (256, 267))	('TLR-7', 'Gene', (69, 74))
358040	29546098	In light of preclinical evidence of synergy between DC therapy and RT, randomized trials are currently evaluating the use of dendritic and cytokine-induced killer (DC-CIK) cell therapy in combination with RT and chemoradiation therapy (CRT) compared to RT and CRT alone in localized and advanced esophageal cancer (NCT01691664, NCT01691625, respectively).	('NCT01691625', 'Var', (328, 339))	('NCT01691664', 'Var', (315, 326))	('esophageal cancer', 'Disease', (296, 313))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('DC-CIK', 'Chemical', '-', (164, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (296, 313))	('CR', 'Chemical', '-', (236, 238))	('CR', 'Chemical', '-', (260, 262))
358041	29546098	Other avenues of research involve a phase I assessment of tumor antigen (MAGE-A4) gene transduced T cell ACT in unresectable esophageal cancer (NCT02096614), and a phase II trial of cancer testis antigen (NY-ESO-1) gene transduced T cell ACT in combination with low-dose IL-2 in advanced esophagogastric cancer (NCT01795976).	('esophageal cancer', 'Disease', (125, 142))	('cancer testis', 'Disease', (182, 195))	('MAGE-A4', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('gene', 'Var', (82, 86))	('tumor', 'Disease', (58, 63))	('IL-2', 'Gene', (271, 275))	('gastric cancer', 'Phenotype', 'HP:0012126', (296, 310))	('NY-ESO-1', 'Gene', (205, 213))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer testis', 'Phenotype', 'HP:0010788', (182, 195))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('NY-ESO-1', 'Gene', '246100', (205, 213))	('MAGE-A4', 'Gene', '4103', (73, 80))	('gastric cancer', 'Disease', (296, 310))	('cancer testis', 'Disease', 'MESH:D013736', (182, 195))	('IL-2', 'Gene', '3558', (271, 275))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (296, 310))
358076	29546098	KRAS mutations are present in 90% of pancreatic adenocarcinomas.	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (37, 62))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (37, 63))	('pancreatic adenocarcinomas', 'Disease', (37, 63))	('KRAS', 'Gene', (0, 4))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (37, 63))	('KRAS', 'Gene', '3845', (0, 4))
358106	29546098	mutation-based) tumor-associated antigens, and whole cells.	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutation-based', 'Var', (0, 14))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (16, 21))
358107	29546098	"Self" antigens have included Carcinoembryonic Antigen (CEA), for which the presence of corresponding autoantibodies in CRC patients correlates with better prognosis and increased 2-year survival rates, Epithelial Cell-Adhesion Molecule (Ep-CAM), and mucin glycoprotein MUC1, among others, all of which are overexpressed by subsets of CRC tumor cells.	('CRC tumor', 'Disease', (335, 344))	('mucin', 'Gene', '100508689', (251, 256))	('CR', 'Chemical', '-', (120, 122))	('CR', 'Chemical', '-', (335, 337))	('Carcinoembryonic Antigen', 'Gene', (30, 54))	('patients', 'Species', '9606', (124, 132))	('CEA', 'Gene', '1048', (56, 59))	('CRC tumor', 'Disease', 'MESH:D015179', (335, 344))	('Ep-CAM', 'Gene', (238, 244))	('increased', 'PosReg', (170, 179))	('Epithelial Cell-Adhesion Molecule', 'Gene', '4072', (203, 236))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('Epithelial Cell-Adhesion Molecule', 'Gene', (203, 236))	('Ep-CAM', 'Gene', '4072', (238, 244))	('CEA', 'Gene', (56, 59))	('MUC1', 'Gene', (270, 274))	('presence', 'Var', (76, 84))	('MUC1', 'Gene', '4582', (270, 274))	('mucin', 'Gene', (251, 256))	('better', 'PosReg', (149, 155))	('Carcinoembryonic Antigen', 'Gene', '1048', (30, 54))
358113	29546098	"Non-self" tumor associated antigens previously targeted by experimental CRC vaccines include mutant p53 and RAS proteins.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('CR', 'Chemical', '-', (73, 75))	('tumor', 'Disease', (11, 16))	('mutant', 'Var', (94, 100))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('RAS proteins', 'Protein', (109, 121))
358114	29546098	In a study evaluating a mutant p53-exposed PBMC-based vaccine in 24 patients with malignant p53-mutated tumors (including 10 CRC patients), 45% (9/20) of evaluable patients experienced a detectable cellular immune response and PFS and OS were greater than expected (12.5 and 27.2 months, respectively).	('mutant', 'Var', (24, 30))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('CR', 'Chemical', '-', (125, 127))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('patients', 'Species', '9606', (129, 137))	('cellular immune response', 'CPA', (198, 222))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('experienced', 'Reg', (173, 184))	('patients', 'Species', '9606', (68, 76))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('p53', 'Gene', (92, 95))	('PFS', 'CPA', (227, 230))	('patients', 'Species', '9606', (164, 172))	('p53', 'Gene', '7157', (92, 95))
358135	29546098	In a phase IIb study, 217 NSCLC patients received TG4010 combined with first-line chemotherapy.	('NSCLC', 'Disease', (26, 31))	('TG4010', 'Var', (50, 56))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))	('patients', 'Species', '9606', (32, 40))
358136	29546098	Preliminary results showed a statistically significant improvement in PFS for non-squamous NSCLC patients treated with TG4010.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('improvement', 'PosReg', (55, 66))	('TG4010', 'Var', (119, 125))	('PFS', 'MPA', (70, 73))	('NSCLC', 'Disease', (91, 96))	('patients', 'Species', '9606', (97, 105))
358149	29546098	ORR was higher in patients with >= 1% PDL-1 staining (23% vs. 9%).	('PDL-1', 'Gene', '29126', (38, 43))	('ORR', 'MPA', (0, 3))	('PDL-1', 'Gene', (38, 43))	('staining', 'Var', (44, 52))	('patients', 'Species', '9606', (18, 26))	('higher', 'PosReg', (8, 14))
358151	29546098	Multiple trials are currently evaluating pembrolizumab in advanced lung cancer alone (NCT02007070), in comparison to chemotherapy (NCT02220894, NCT01905657), and in combination with chemotherapy (NCT01840579) and ipilimumab (NCT02039674).	('NCT02007070', 'Var', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('pembrolizumab', 'Chemical', 'MESH:C582435', (41, 54))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('ipilimumab', 'Chemical', 'MESH:D000074324', (213, 223))
358152	29546098	Experimental PD-L1 inhibitors BMS-936559, MPDL3280A, and MEDI4736 have all been evaluated in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('BMS-936559', 'Var', (30, 40))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('MPDL3280A', 'Var', (42, 51))	('PD-L1', 'Gene', (13, 18))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (42, 51))	('PD-L1', 'Gene', '29126', (13, 18))
358153	29546098	In a dose-escalation phase I trial, BMS936559 was administered to 75 NSCLC patients, yielding an ORR of 10.2% (5/49 patients).	('NSCLC', 'Disease', (69, 74))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (75, 83))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('BMS936559', 'Var', (36, 45))
358154	29546098	Another phase I trial assessed MPDL3280A in 53 heavily pre-treated NSCLC patients.	('MPDL3280A', 'Var', (31, 40))	('NSCLC', 'Disease', (67, 72))	('patients', 'Species', '9606', (73, 81))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (31, 40))
358157	29546098	Multiple phase I-III trials are currently evaluating MPDL3280A alone (NCT01846416, NCT01375842, NCT02031458) and in comparison to chemotherapy (NCT01903993, NCT02008227) in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (53, 62))	('NCT01375842', 'Var', (83, 94))	('lung cancer', 'Disease', (173, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('MPDL3280A', 'Var', (53, 62))
358158	29546098	A third phase I trial evaluated escalating doses of MEDI4736 Q2W or Q3W in 13 NSCLC patients.	('Q2W', 'Var', (61, 64))	('MEDI4736', 'Gene', (52, 60))	('patients', 'Species', '9606', (84, 92))	('NSCLC', 'Disease', (78, 83))	('Q3W', 'Var', (68, 71))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
358161	29546098	Another early phase I/II trial investigating the same combination in SCLC patients is recruiting (NCT01928394), and multiple other clinical trials are likewise evaluating the combination of anti-CTLA-4 and anti-PD-L1 therapy in lung cancer patients (NCT02261220, NCT02000947, NCT01975831).	('NCT02261220', 'Var', (250, 261))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('PD-L1', 'Gene', (211, 216))	('patients', 'Species', '9606', (74, 82))	('lung cancer', 'Disease', 'MESH:D008175', (228, 239))	('CTLA-4', 'Gene', '1493', (195, 201))	('PD-L1', 'Gene', '29126', (211, 216))	('patients', 'Species', '9606', (240, 248))	('CTLA-4', 'Gene', (195, 201))	('lung cancer', 'Disease', (228, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))	('SCLC', 'Disease', (69, 73))	('SCLC', 'Disease', 'MESH:D018288', (69, 73))
358264	28492717	Schwannomas have typical S100 positivity.	('positivity', 'Var', (30, 40))	('Schwannomas', 'Phenotype', 'HP:0100008', (0, 11))	('Schwannomas', 'Disease', (0, 11))	('Schwannomas', 'Disease', 'MESH:D009442', (0, 11))	('S100', 'Gene', (25, 29))	('S100', 'Gene', '6271', (25, 29))
358373	27767059	Compounds 3-8 and P10-P14 produce the characteristic fragment ion at m/z 165.0182 or 177.0182 in their MS/MS spectra (Figures S3-S13), indicating that they might be polycyclic polyprenylated acylphloroglucinols (PPAPs).	('m/z 165.0182', 'Var', (69, 81))	('acylphloroglucinols', 'Chemical', '-', (191, 210))	('177.0182', 'Var', (85, 93))	('PPAPs', 'Chemical', '-', (212, 217))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('P10-P14', 'Var', (18, 25))
358379	27767059	In the MS/MS spectrum of 1, the most abundant fragment peak (m/z 373) was due to the successive loss of an H2O and a prenyl unit C4H8 (56 Da).	('H2O', 'Protein', (107, 110))	('C4H8', 'Chemical', '-', (129, 133))	('C4H8', 'Var', (129, 133))	('H2O', 'Chemical', 'MESH:D014867', (107, 110))	('loss', 'NegReg', (96, 100))
358380	27767059	This fragment further dissociated by the loss of an H2O and a prenyl unit C4H8 to produce additional fragment ions at m/z 355 and 287.	('H2O', 'Chemical', 'MESH:D014867', (52, 55))	('C4H8', 'Chemical', '-', (74, 78))	('loss', 'NegReg', (41, 45))	('C4H8', 'Var', (74, 78))
358381	27767059	The 13C NMR and DEPT spectra showed 12 aromatic carbons (including five oxygenated), one carbonyl carbon, two oxygenated quaternary carbons, four sp3 methylene carbons, four sp3 methyl groups, and one methoxyl group.	('carbon', 'Chemical', 'MESH:D002244', (89, 95))	('carbon', 'Chemical', 'MESH:D002244', (98, 104))	('13C', 'Chemical', '-', (4, 7))	('carbon', 'Chemical', 'MESH:D002244', (48, 54))	('carbons', 'Chemical', 'MESH:D002244', (48, 55))	('sp3', 'Var', (174, 177))	('methoxyl', 'Chemical', '-', (201, 209))	('carbon', 'Chemical', 'MESH:D002244', (132, 138))	('carbons', 'Chemical', 'MESH:D002244', (160, 167))	('carbons', 'Chemical', 'MESH:D002244', (132, 139))	('carbon', 'Chemical', 'MESH:D002244', (160, 166))	('aromatic', 'MPA', (39, 47))
358393	27767059	The MS/MS spectrum of 3 showed a diagnostic fragment ion at m/z 165.0182 in the positive mode, suggesting that it might be a type B PPAP with no prenyl substituent at C-5 (Figure S3).	('C-5', 'Gene', (167, 170))	('C-5', 'Gene', '727', (167, 170))	('m/z 165.0182', 'Var', (60, 72))	('PPAP', 'Chemical', '-', (132, 136))
358397	27767059	In the HMBC spectrum, the long range correlations observed from the olefinic H-19 (deltaH 6.71, dd, J = 15.7, 7.7 Hz) signal to C-7 (deltaC 45.2) and C-8 (deltaC 41.9), along with correlations from olefinic H-20 (deltaH 6.16, d, J = 15.7 Hz) to the ketone resonance at deltaC 200.8 (C-21), which was in turn correlated with CH3-22, established a 3-buten-2-one side chain located at C-7.	('C-8', 'Gene', '3224', (150, 153))	('C-7', 'Gene', (382, 385))	('C', 'Chemical', 'MESH:D002244', (138, 139))	('H-2', 'Gene', (207, 210))	('C', 'Chemical', 'MESH:D002244', (274, 275))	('C-7', 'Gene', '730', (128, 131))	('C', 'Chemical', 'MESH:D002244', (10, 11))	('C-7', 'Gene', '730', (382, 385))	('C-21', 'Gene', (283, 287))	('C-21', 'Gene', '79718', (283, 287))	('deltaH', 'Chemical', '-', (213, 219))	('deltaC 200.8', 'Var', (269, 281))	('C', 'Chemical', 'MESH:D002244', (128, 129))	('C', 'Chemical', 'MESH:D002244', (382, 383))	('C-8', 'Gene', (150, 153))	('C', 'Chemical', 'MESH:D002244', (160, 161))	('H-2', 'Gene', '6019', (207, 210))	('C', 'Chemical', 'MESH:D002244', (150, 151))	('H-19', 'Gene', '283120', (77, 81))	('C', 'Chemical', 'MESH:D002244', (324, 325))	('7.7 Hz', 'CellLine', 'CVCL:Z674', (110, 116))	('C', 'Chemical', 'MESH:D002244', (283, 284))	('H-19', 'Gene', (77, 81))	('deltaH', 'Chemical', '-', (83, 89))	('3-buten-2-one', 'Chemical', 'MESH:C057920', (346, 359))	('C-7', 'Gene', (128, 131))
358411	27767059	The molecular formula of oblongifolin X (5) was determined to be C27H28O5 by HRESIMS.	('oblongifolin X', 'Disease', (25, 39))	('oblongifolin X', 'Disease', 'MESH:D005171', (25, 39))	('C27H28O5', 'Var', (65, 73))	('C27H28O5', 'Chemical', '-', (65, 73))
358424	27767059	The molecular formula C33H44O5 for 7 was calculated from the HREIMS of the ion peak [M + Na]+ m/z 543.3083 (calc.	('[M + Na]+ m/z 543.3083', 'Var', (84, 106))	('C33H44O5', 'Var', (22, 30))	('C33H44O5', 'Chemical', '-', (22, 30))
358506	27767059	The primary antibodies C-RAF (Cat.9422), MEK1/2 (Cat.9122), p-MEK (Ser217/221, Cat.9154), ERK (Cat.4695), p-ERK (Tyr202/Tyr204, Cat.4370), GAPDH (Cat.5174) and snail (Cat.3879) were purchased from Cell Signaling Technologies (Danvers, MA, USA).	('MEK', 'Gene', (62, 65))	('ERK', 'Gene', (108, 111))	('Ser217/221', 'Var', (67, 77))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('Cat.9422', 'CellLine', 'CVCL:6F73', (30, 38))	('Tyr202/Tyr204', 'Var', (113, 126))	('GAPDH', 'Gene', (139, 144))	('snail', 'Gene', (160, 165))	('C-RAF', 'Gene', '5894', (23, 28))	('Ser217', 'Chemical', '-', (67, 73))	('Cat.4695', 'Var', (95, 103))	('ERK', 'Gene', (90, 93))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('Cat.9154', 'CellLine', 'CVCL:T300', (79, 87))	('Tyr202', 'Chemical', '-', (113, 119))	('C-RAF', 'Gene', (23, 28))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('MEK', 'Gene', '5609', (41, 44))	('C', 'Chemical', 'MESH:D002244', (128, 129))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('Cat.4370', 'Var', (128, 136))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('Cat.9122', 'CellLine', 'CVCL:6F73', (49, 57))	('ERK', 'Gene', '5594', (108, 111))	('snail', 'Gene', '6615', (160, 165))	('MEK1/2', 'Gene', '5604;5605', (41, 47))	('MEK', 'Gene', '5609', (62, 65))	('MEK', 'Gene', (41, 44))	('MEK1/2', 'Gene', (41, 47))	('Tyr204', 'Chemical', '-', (120, 126))	('GAPDH', 'Gene', '2597', (139, 144))	('Cat.9422', 'Var', (30, 38))	('C', 'Chemical', 'MESH:D002244', (197, 198))	('Cat.5174', 'Var', (146, 154))	('C', 'Chemical', 'MESH:D002244', (30, 31))	('ERK', 'Gene', '5594', (90, 93))
358561	26781439	In a clinical study, combination chemotherapy using NDP and 5-FU has been reported to be a safe and effective method for treating advanced esophageal cancer.	('NDP', 'Var', (52, 55))	('esophageal cancer', 'Disease', (139, 156))	('NDP', 'Chemical', 'MESH:C053989', (52, 55))	('5-FU', 'Chemical', 'MESH:D005472', (60, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
358814	18756050	The incidence of infection was more frequent in patients with Child-Pugh class C (58 of 190 cases, 30.5%) than those with Child-Pugh class A or B (42 of 289, 14.5%; p<0.001).	('Child-Pugh class C', 'Var', (62, 80))	('Child', 'Species', '9606', (122, 127))	('infection', 'Disease', (17, 26))	('infection', 'Disease', 'MESH:D007239', (17, 26))	('Child', 'Species', '9606', (62, 67))	('patients', 'Species', '9606', (48, 56))
358872	32586155	Moreover, SPAG5 was identified as a direct target of miR-363, and the reintroduction of SPAG5 restored miR-363-induced effects.	('reintroduction', 'Var', (70, 84))	('miR-363', 'Gene', (103, 110))	('effects', 'MPA', (119, 126))	('SPAG5', 'Gene', (88, 93))	('miR-363', 'Gene', (53, 60))	('SPAG5', 'Gene', '10615', (88, 93))	('SPAG5', 'Gene', (10, 15))	('restored', 'PosReg', (94, 102))	('miR-363', 'Gene', '574031', (103, 110))	('SPAG5', 'Gene', '10615', (10, 15))	('miR-363', 'Gene', '574031', (53, 60))
358896	32586155	Eca109 and Ec9706 cells were co-transfected with SPAG5-WT or SPAG5-MT and miR-363 or miR-con.	('SPAG5', 'Gene', '10615', (49, 54))	('SPAG5', 'Gene', (61, 66))	('miR-363', 'Gene', '574031', (74, 81))	('miR-363', 'Gene', (74, 81))	('SPAG5', 'Gene', '10615', (61, 66))	('miR-con', 'Var', (85, 92))	('Ec9706', 'CellLine', 'CVCL:E307', (11, 17))	('SPAG5', 'Gene', (49, 54))
358913	32586155	miR-363 expression was confirmed as being significantly higher or lower in transfected cells than control cells by qRT-PCR (P < 0.05; Figure 2a and Figure 2b, respectively).	('lower', 'NegReg', (66, 71))	('miR-363', 'Gene', '574031', (0, 7))	('miR-363', 'Gene', (0, 7))	('expression', 'MPA', (8, 18))	('transfected', 'Var', (75, 86))	('higher', 'PosReg', (56, 62))
358922	32586155	Wild-type and mutant SPAG5 3'-UTR sequences containing the miR-363 binding site were then cloned using a luciferase reporter gene system to investigate whether miR-363 inhibits SPAG5 by binding to its 3'-UTR in ESCC (Figure 3a).	('miR-363', 'Gene', '574031', (160, 167))	('SPAG5', 'Gene', (177, 182))	('inhibits', 'NegReg', (168, 176))	('mutant', 'Var', (14, 20))	('miR-363', 'Gene', (160, 167))	('SPAG5', 'Gene', '10615', (177, 182))	('SPAG5', 'Gene', (21, 26))	('miR-363', 'Gene', '574031', (59, 66))	('binding', 'Interaction', (186, 193))	('SPAG5', 'Gene', '10615', (21, 26))	('miR-363', 'Gene', (59, 66))
358932	32586155	The dysregulation of miRNAs contributes to the pathogenesis of all types of cancer, and increasing evidence suggests that they play important roles in ESCC progression.	('dysregulation', 'Var', (4, 17))	('ESCC', 'Disease', (151, 155))	('miRNAs', 'Protein', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('contributes', 'Reg', (28, 39))	('roles', 'Reg', (142, 147))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
358950	32586155	In podocytes, SPAG5 down-regulation inhibited autophagy and aggravated apoptosis via the SPAG5/AKT/mTOR pathway, while miR-539 and miR-367-3p inhibited the progression of different cancers by directly targeting SPAG5.	('apoptosis', 'CPA', (71, 80))	('SPAG5', 'Gene', (89, 94))	('autophagy', 'CPA', (46, 55))	('SPAG5', 'Gene', '10615', (211, 216))	('aggravated', 'PosReg', (60, 70))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('miR-367-3p', 'Var', (131, 141))	('mTOR', 'Gene', (99, 103))	('AKT', 'Gene', '207', (95, 98))	('SPAG5', 'Gene', (14, 19))	('mTOR', 'Gene', '2475', (99, 103))	('SPAG5', 'Gene', '10615', (89, 94))	('down-regulation inhibited', 'NegReg', (20, 45))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('inhibited', 'NegReg', (142, 151))	('cancers', 'Disease', (181, 188))	('SPAG5', 'Gene', '10615', (14, 19))	('miR-539', 'Gene', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('SPAG5', 'Gene', (211, 216))	('miR-539', 'Gene', '664612', (119, 126))	('AKT', 'Gene', (95, 98))
359031	31245287	These cancers and their International Classification of Diseases for Oncology (ICD-O) codes are esophagus (C15), colon (C18), rectum (C19-20), kidney (C64), pancreas (C25), gallbladder (C23-24), postmenopausal breast (C50), endometrium (C54), and ovary (C56).	('C23', 'Gene', (186, 189))	('pancreas', 'Disease', (157, 165))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('C23', 'Gene', '4691', (186, 189))	('C15', 'Gene', '51316', (107, 110))	('endometrium', 'Disease', (224, 235))	('ovary', 'Disease', (247, 252))	('esophagus', 'Disease', (96, 105))	('C15', 'Gene', (107, 110))	('kidney', 'Disease', (143, 149))	('pancreas', 'Disease', 'MESH:D010190', (157, 165))	('Oncology', 'Phenotype', 'HP:0002664', (69, 77))	('colon', 'Disease', 'MESH:D015179', (113, 118))	('C19-20', 'Var', (134, 140))	('postmenopausal breast', 'Disease', (195, 216))	('men', 'Species', '9606', (199, 202))	('C18', 'Gene', '27241', (120, 123))	('colon', 'Disease', (113, 118))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('C18', 'Gene', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('rectum', 'Disease', (126, 132))	('gallbladder', 'Disease', (173, 184))
359135	29088869	Distinct effects of rs895819 on risk of different cancers: an update meta-analysis Previous studies have indicated an association between the genetic variant in pre-miR-27a rs895819 with A->G transition and cancer risk; however, the results remain inconsistent and somehow conflicting in different cancers.	('cancer', 'Disease', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('miR-27a', 'Gene', (165, 172))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('cancers', 'Disease', 'MESH:D009369', (298, 305))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('rs895819', 'Var', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('miR-27a', 'Gene', '407018', (165, 172))	('rs895819', 'Mutation', 'rs895819', (173, 181))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('cancers', 'Disease', (298, 305))	('cancer', 'Disease', (298, 304))	('rs895819', 'Mutation', 'rs895819', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
359137	29088869	The results showed that rs895819 was associated with an increased cancer risk (GG vs. AA/AG: OR = 1.15, 95% CI = 1.02-1.29).	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('rs895819', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('rs895819', 'Mutation', 'rs895819', (24, 32))	('cancer', 'Disease', (66, 72))
359138	29088869	Furthermore, stratification analyses revealed an association of rs895819 with increased cancer risk among Asians (GG vs. AA: OR = 1.17, 95% CI = 1.01-1.36; GG vs. AA/AG: OR = 1.18, 95% CI = 1.03-1.35), but not Caucasians.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('rs895819', 'Mutation', 'rs895819', (64, 72))	('association', 'Interaction', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('rs895819', 'Var', (64, 72))
359139	29088869	Interestingly, the [G] allele of rs895819 was significantly associated with decreased risk of breast cancer (G vs. A: OR = 0.91, 95% CI = 0.86-0.97).	('breast cancer', 'Disease', (94, 107))	('rs895819', 'Mutation', 'rs895819', (33, 41))	('decreased', 'NegReg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('rs895819', 'Var', (33, 41))
359140	29088869	However, rs895819 was associated with increased risk of colorectal cancer (GG vs. AA: OR = 1.56, 95% CI = 1.31-1.85; GG vs. AA/AG: OR = 1.53, 95% CI = 1.30-1.79; G vs. A: OR = 1.19, 95% CI = 1.09-1.30) and lung cancer (GG vs. AA/AG: OR = 1.43, 95% CI = 1.00-2.04).	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('rs895819', 'Mutation', 'rs895819', (9, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('lung cancer', 'Disease', (206, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('rs895819', 'Var', (9, 17))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))
359141	29088869	In addition, no association was found between rs895819 and risk of gastric cancer or esophageal cancer.	('rs895819', 'Mutation', 'rs895819', (46, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', (67, 81))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs895819', 'Var', (46, 54))	('esophageal cancer', 'Disease', (85, 102))
359142	29088869	In conclusion, our findings suggest distinct effects of rs895819 on risk of different cancers, and future well-designed studies with large samples are required to further validate our results.	('effects', 'Reg', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs895819', 'Var', (56, 64))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('rs895819', 'Mutation', 'rs895819', (56, 64))
359145	29088869	Dysregulation of miRNA expression has been found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases.	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('cardiovascular', 'Disease', (120, 134))	('tumorigenesis', 'CPA', (79, 92))	('relevance', 'Reg', (57, 66))
359146	29088869	Recent DNA sequencing has revealed SNPs in miRNA coding genes, both in miRNA seeding and loop regions.	('miR', 'Gene', (71, 74))	('SNPs', 'Var', (35, 39))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('miR', 'Gene', '220972', (71, 74))
359148	29088869	In addition, SNPs in seeding regions of miRNA genes may influence miRNA-mRNA interactions and eventually alter functions of miRNAs on targets.	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('alter', 'Reg', (105, 110))	('functions', 'MPA', (111, 120))	('miR', 'Gene', (66, 69))	('SNPs', 'Var', (13, 17))	('miR', 'Gene', '220972', (66, 69))	('influence', 'Reg', (56, 65))	('miR', 'Gene', '220972', (124, 127))	('miR', 'Gene', (124, 127))
359149	29088869	Accumulating studies showed that SNPs in miRNAs or their precursors are marked as novel genetic variations which may modify the cancer susceptibilities.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('SNPs', 'Var', (33, 37))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('modify', 'Reg', (117, 123))	('cancer', 'Disease', (128, 134))
359151	29088869	Previously, a common single nucleotide polymorphism in pre-miR-27a, rs895819, has been demonstrated to be associated with decreased risk of breast cancer risk, but later studies showed conflicting associations.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('rs895819', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('miR-27a', 'Gene', '407018', (59, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('rs895819', 'Mutation', 'rs895819', (68, 76))	('miR-27a', 'Gene', (59, 66))	('decreased', 'NegReg', (122, 131))
359152	29088869	Some other epidemiological studies indicated that rs895819 was associated with increased risk of gastric cancer, and the genotypes of rs895819 was correlated with miR-27a expression levels, however, other studies showed lack association of rs895819 with gastric cancer risk.	('miR-27a', 'Gene', (163, 170))	('gastric cancer', 'Disease', (97, 111))	('rs895819', 'Gene', (134, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (79, 111))	('rs895819', 'Mutation', 'rs895819', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('miR-27a', 'Gene', '407018', (163, 170))	('gastric cancer', 'Disease', (254, 268))	('rs895819', 'Mutation', 'rs895819', (134, 142))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (254, 268))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rs895819', 'Mutation', 'rs895819', (240, 248))	('correlated', 'Reg', (147, 157))	('rs895819', 'Var', (50, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (254, 268))
359153	29088869	Meta-analysis studies revealed that rs895819 was a functional SNP and may have some relation to colorectal cancer susceptibility, especially in Asians.	('rs895819', 'Mutation', 'rs895819', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))	('colorectal cancer', 'Disease', (96, 113))	('rs895819', 'Var', (36, 44))	('relation', 'Reg', (84, 92))
359154	29088869	Generally, the current available data were inconsistent about the effects of rs895819 on carcinogenesis in different cancers, this discrepancy maybe partially attributed to the heterogeneity of the cancer subtype, small sample size, and ethnicity of the study population.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('rs895819', 'Var', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('cancer', 'Disease', (198, 204))	('carcinogenesis', 'Disease', (89, 103))	('rs895819', 'Mutation', 'rs895819', (77, 85))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Disease', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
359155	29088869	Therefore, it is necessary to conduct a comprehensive review and meta-analysis of published data from all eligible studies on the association of rs895819 with cancer risk.	('cancer', 'Disease', (159, 165))	('rs895819', 'Mutation', 'rs895819', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('rs895819', 'Var', (145, 153))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('association', 'Interaction', (130, 141))
359156	29088869	In this study, we performed an update meta-analysis by including more recent publications to improve the efficiency and to drive a more precise estimation of the association between rs895819 SNP and cancer risks.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('rs895819', 'Mutation', 'rs895819', (182, 190))	('rs895819 SNP', 'Var', (182, 194))
359160	29088869	Five studies were excluded due to not related to miR-27a polymorphism, or no controls.	('polymorphism', 'Var', (57, 69))	('miR-27a', 'Gene', '407018', (49, 56))	('miR-27a', 'Gene', (49, 56))
359164	29088869	By pooling all the studies, rs895819 was associated with increased risk of cancer in recessive (OR = 1.15; 95% CI = 1.02-1.29) but not other model (Figures 2-6).	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('rs895819', 'Var', (28, 36))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs895819', 'Mutation', 'rs895819', (28, 36))
359165	29088869	In the subgroup analyses, rs895819 was associated with increased risk of cancer in homogeneous (OR = 1.17; 95% CI = 1.01-1.36) or recessive (OR = 1.18; 95% CI = 1.03-1.35) model in Asians, but no association of rs895819 with cancer risk was found in Caucasians.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('rs895819', 'Mutation', 'rs895819', (211, 219))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('rs895819', 'Var', (26, 34))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rs895819', 'Mutation', 'rs895819', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))
359166	29088869	Interestingly, the [G] allele of rs895819 was significantly associated with decreased risk of breast cancer (OR = 0.91; 95% CI = 0.86-0.97).	('breast cancer', 'Disease', (94, 107))	('rs895819', 'Mutation', 'rs895819', (33, 41))	('decreased', 'NegReg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('rs895819', 'Var', (33, 41))
359167	29088869	However, rs895819 was associated with increased risk of colorectal cancer in homogeneous (OR = 1.56; 95% CI = 1.31-1.85), recessive (OR = 1.53; 95% CI = 1.30-1.79) or additive model (OR = 1.19; 95% CI = 1.09-1.30), and with increased risk of lung cancer in recessive model (OR = 1.43; 95% CI = 1.00-2.04).	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('rs895819', 'Mutation', 'rs895819', (9, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('lung cancer', 'Disease', (242, 253))	('rs895819', 'Var', (9, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))
359168	29088869	In addition, rs895819 was not associated with risk of esophageal cancer or gastric cancer.	('rs895819', 'Var', (13, 21))	('gastric cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('rs895819', 'Mutation', 'rs895819', (13, 21))	('esophageal cancer', 'Disease', (54, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))
359169	29088869	For other types of cancers, pooled analysis showed lack of association between rs895819 and cancer risk, and we did not perform a meta-analysis for each cancer since only one study was included for different type cancer.	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancer', 'Disease', (19, 25))	('cancers', 'Disease', (19, 26))	('rs895819', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', (213, 219))	('rs895819', 'Mutation', 'rs895819', (79, 87))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('type cancer', 'Disease', 'MESH:D009369', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (92, 98))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('type cancer', 'Disease', (208, 219))	('cancer', 'Disease', 'MESH:D009369', (213, 219))
359170	29088869	In stratified analysis by the sources of controls, the rs895819 was significantly associated with increased cancer risk in homogeneous (OR = 1.21; 95% CI = 1.03-1.42), or recessive (OR = 1.21; 95% CI = 1.04-1.41) model when pooling twenty-six hospital-based case-control studies, but no association was found when pooling eight population-based studies.	('rs895819', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('rs895819', 'Mutation', 'rs895819', (55, 63))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
359172	29088869	As to breast cancer, except for recessive model, rs895819 is associated with reduced cancer risk in Caucasians but not Asians (Supplementary Table 1).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('breast cancer', 'Disease', (6, 19))	('rs895819', 'Var', (49, 57))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('reduced', 'NegReg', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('rs895819', 'Mutation', 'rs895819', (49, 57))
359173	29088869	For cancers from digestive system, we found significant association between rs895819 and increased risk of cancers from all digestive system when pooling 19 studies on esophageal, gastric, colorectal and liver cancers in recessive (OR = 1.23; 95% CI = 1.06-1.43) or homogeneous model (OR = 1.20; 95% CI = 1.01-1.43).	('rs895819', 'Mutation', 'rs895819', (76, 84))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal', 'Disease', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('liver cancers', 'Phenotype', 'HP:0002896', (204, 217))	('rs895819', 'Var', (76, 84))	('cancers', 'Disease', (4, 11))	('colorectal and liver cancers', 'Disease', 'MESH:D015179', (189, 217))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('gastric', 'Disease', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (210, 217))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
359175	29088869	However, no association was found between rs895819 and risk of upper aero digestive tract cancers when pooling 10 studies on esophageal and gastric cancers.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('gastric cancers', 'Disease', 'MESH:D013274', (140, 155))	('rs895819', 'Mutation', 'rs895819', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gastric cancers', 'Disease', (140, 155))	('gastric cancers', 'Phenotype', 'HP:0012126', (140, 155))	('rs895819', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tract cancers', 'Disease', (84, 97))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('tract cancers', 'Disease', 'MESH:D014571', (84, 97))
359176	29088869	For gastric cancer, rs895819 was not associated with risk of gastric cancer in Asians when pooling 7 studies.	('gastric cancer', 'Phenotype', 'HP:0012126', (4, 18))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs895819', 'Var', (20, 28))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('rs895819', 'Mutation', 'rs895819', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('gastric cancer', 'Disease', (4, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (4, 18))
359177	29088869	For colorectal cancer, we observed that rs895819 were associated with increased risk of colorectal cancer in Asians in homogenous, recessive or additive model, but no association was found in Caucasians.	('colorectal cancer', 'Disease', (88, 105))	('rs895819', 'Mutation', 'rs895819', (40, 48))	('colorectal cancer', 'Disease', (4, 21))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (4, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('rs895819', 'Var', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (4, 21))
359179	29088869	The Begg's test showed that the P value of rs895819 was 0.173, 0.553, 0.097, 0.767 or 0.192 for heterozygous, homozygous, dominant recessive and additive model, respectively, while the corresponding funnel plots showed symmetric distribution ( Figure 7).	('rs895819', 'Var', (43, 51))	('0.097', 'Var', (70, 75))	('0.767', 'Var', (77, 82))	('rs895819', 'Mutation', 'rs895819', (43, 51))	('0.553', 'Var', (63, 68))	('0.192', 'Var', (86, 91))
359180	29088869	The Egger's test also showed that all the P values of rs895819 was 0.405, 0.293, 0.085, 0.941 or 0.053 for heterozygous, homozygous, dominant recessive and additive model, respectively, suggesting that there was no significant publication bias in the present study.	('0.085', 'Var', (81, 86))	('rs895819', 'Var', (54, 62))	('rs895819', 'Mutation', 'rs895819', (54, 62))
359181	29088869	In this study, we performed an update meta-analysis and found that rs895819 was associated with increased cancer risk in recessive model when including 34 studies of all cancers (15,388 cases and 18,704 controls), and this association remained in Asians but not Caucasians.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancer', 'Disease', (170, 176))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('rs895819', 'Mutation', 'rs895819', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (106, 112))	('rs895819', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
359182	29088869	Interestingly, the [G] allele of rs895819 played protective role on breast cancer, but the rs895819 was associated with increased risk of colorectal cancer or lung cancer in recessive model.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('rs895819', 'Mutation', 'rs895819', (91, 99))	('rs895819', 'Mutation', 'rs895819', (33, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('colorectal cancer', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs895819', 'Var', (91, 99))	('rs895819', 'Var', (33, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))
359183	29088869	Based on 17 case-control studies with 7,813 cases and 9,602 controls, our previous meta-analysis did not suggest any association between rs895819 and cancer susceptibility, while rs895819 was associated with a reduced cancer risk in heterozygous, dominant or additive model in Caucasians but not in Asians.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('reduced', 'NegReg', (210, 217))	('cancer', 'Disease', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('rs895819', 'Var', (179, 187))	('rs895819', 'Mutation', 'rs895819', (137, 145))	('cancer', 'Disease', (150, 156))	('rs895819', 'Mutation', 'rs895819', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('rs895819', 'Var', (137, 145))
359184	29088869	By pooling 19 studies (17 articles) involving 7,800 cases and 9,060 controls, a recent study by Feng et al., failed to find any associations between rs895819 polymorphism and cancer risk, while statistically significantly reduced cancer risks were found among Asians for dominant contrast and a subtly decreased risk was observed in the Caucasian population for heterozygous or additive contrast.	('polymorphism', 'Var', (158, 170))	('rs895819', 'Mutation', 'rs895819', (149, 157))	('associations', 'Interaction', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('rs895819 polymorphism', 'Var', (149, 170))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('reduced', 'NegReg', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
359185	29088869	In the present study, by including 34 studies with almost twice number of subjects, we found that rs895819 was associated with increased cancer risk in recessive model for all population and Asians, but not Caucasians, suggesting a possible ethnic difference in the genetic and the environmental factors.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('rs895819', 'Mutation', 'rs895819', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('rs895819', 'Var', (98, 106))
359186	29088869	The discrepancy between these meta-analyses might be due to sample size of pooled studies, and whether the risk of rs895819 on cancer depends on ethnicity should be confirmed by more studies.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs895819', 'Mutation', 'rs895819', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('rs895819', 'Var', (115, 123))
359187	29088869	When stratified by the cancer type, our data was consistent with previous meta-analysis reports that the [G] allele of rs895819 was associated with decreased risk in breast cancer for all population and Caucasians, but not Asians.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('rs895819', 'Var', (119, 127))	('cancer', 'Disease', (173, 179))	('decreased', 'NegReg', (148, 157))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('rs895819', 'Mutation', 'rs895819', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
359188	29088869	For colorectal cancer, the study by Liu et al., pooling seven studies with 2,230 cases and 2,775 controls provided a moderate evidence for the association between rs895819 and increased risk of colorectal cancer under multiple genetic models for all population and Asians, but not Caucasians.	('rs895819', 'Mutation', 'rs895819', (163, 171))	('colorectal cancer', 'Disease', (4, 21))	('colorectal cancer', 'Disease', 'MESH:D015179', (194, 211))	('colorectal cancer', 'Phenotype', 'HP:0003003', (194, 211))	('rs895819', 'Var', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('colorectal cancer', 'Disease', 'MESH:D015179', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('colorectal cancer', 'Disease', (194, 211))	('colorectal cancer', 'Phenotype', 'HP:0003003', (4, 21))
359190	29088869	As to lung cancer, we for the first time showed an association of rs895819 with increased risk of lung cancer in dominant model although the included studies were very limited.	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('lung cancer', 'Disease', (6, 17))	('association', 'Interaction', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('rs895819', 'Var', (66, 74))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('rs895819', 'Mutation', 'rs895819', (66, 74))
359191	29088869	These findings suggested distinct effects of rs895819 on carcinogenesis in different types of cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('effects', 'Reg', (34, 41))	('carcinogenesis', 'Disease', 'MESH:D063646', (57, 71))	('carcinogenesis', 'Disease', (57, 71))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('rs895819', 'Var', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rs895819', 'Mutation', 'rs895819', (45, 53))	('cancers', 'Disease', (94, 101))
359193	29088869	Although the binding of the mature miRNA to target mRNAs may not be influenced by the rs895819 since rs895819 is not located in seeding sites, polymorphisms in the loop of pre-miRNAs could influence mature miRNAs processing and the expression levels of their mature forms.	('polymorphisms', 'Var', (143, 156))	('rs895819', 'Mutation', 'rs895819', (101, 109))	('miR', 'Gene', '220972', (206, 209))	('miR', 'Gene', (206, 209))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('influence', 'Reg', (189, 198))	('expression levels', 'MPA', (232, 249))	('miR', 'Gene', '220972', (176, 179))	('rs895819', 'Mutation', 'rs895819', (86, 94))	('miR', 'Gene', (176, 179))
359194	29088869	Previous studies showed that rs895819 was positive associated with serum expression of mature miR-27a in gastric cancer patients, but the molecular mechanism on regulation of miR-27a expression by rs895819 has not been investigated.	('serum expression', 'MPA', (67, 83))	('rs895819', 'Mutation', 'rs895819', (197, 205))	('miR-27a', 'Gene', '407018', (175, 182))	('rs895819', 'Mutation', 'rs895819', (29, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))	('miR-27a', 'Gene', '407018', (94, 101))	('gastric cancer', 'Disease', (105, 119))	('associated', 'Reg', (51, 61))	('positive', 'PosReg', (42, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (105, 119))	('patients', 'Species', '9606', (120, 128))	('miR-27a', 'Gene', (175, 182))	('rs895819', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('miR-27a', 'Gene', (94, 101))
359195	29088869	It remains unclear whether rs895819 affected the processing of miR-27a maturation or/and expression of mature miR-27a.	('miR-27a', 'Gene', (110, 117))	('expression', 'MPA', (89, 99))	('rs895819', 'Var', (27, 35))	('miR-27a', 'Gene', '407018', (63, 70))	('miR-27a', 'Gene', '407018', (110, 117))	('rs895819', 'Mutation', 'rs895819', (27, 35))	('miR-27a', 'Gene', (63, 70))	('affected', 'Reg', (36, 44))
359196	29088869	Our study showed distinct effects of rs895819 on cancer risk in different types of cancers, e.g., reduced risk of breast cancer vs. increased risk of colorectal or lung cancer, suggesting various roles of rs895819 in different cancer development since pre-miRNA is processed into mature miRNA via complex mechanisms.	('cancer', 'Disease', (169, 175))	('colorectal or lung cancer', 'Disease', (150, 175))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal or lung cancer', 'Disease', 'MESH:D015179', (150, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('reduced', 'NegReg', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Disease', (49, 55))	('miR', 'Gene', '220972', (256, 259))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('rs895819', 'Var', (37, 45))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('rs895819', 'Mutation', 'rs895819', (205, 213))	('miR', 'Gene', (256, 259))	('miR', 'Gene', '220972', (287, 290))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('miR', 'Gene', (287, 290))	('rs895819', 'Mutation', 'rs895819', (37, 45))	('cancer', 'Disease', (83, 89))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('breast cancer', 'Disease', (114, 127))	('cancer', 'Disease', (121, 127))	('cancers', 'Disease', (83, 90))
359197	29088869	The major limitation of this study is the heterogeneity for the rs895819 among these studies on different ethnic populations, even with same type cancer, and different types of cancers.	('type cancer', 'Disease', (141, 152))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('rs895819', 'Mutation', 'rs895819', (64, 72))	('type cancer', 'Disease', 'MESH:D009369', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('rs895819', 'Var', (64, 72))
359201	29088869	Fifthly, our findings on the association of rs895819 with risk of specific cancer were mathematically significant, but the real effects of rs895819 on specific cancer risk in real SNP model await further investigations.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (160, 166))	('rs895819', 'Mutation', 'rs895819', (44, 52))	('rs895819', 'Mutation', 'rs895819', (139, 147))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('association', 'Interaction', (29, 40))	('rs895819', 'Var', (44, 52))
359202	29088869	In summary, current data suggest that rs895819 may contribute to increased susceptibility to colorectal and lung cancers, but appears as a protective factor for breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('colorectal and lung cancers', 'Disease', 'MESH:D015179', (93, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Disease', (161, 174))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('rs895819', 'Var', (38, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('lung cancers', 'Phenotype', 'HP:0100526', (108, 120))	('rs895819', 'Mutation', 'rs895819', (38, 46))	('susceptibility', 'Reg', (75, 89))
359203	29088869	Since the studies on specific cancer included in this meta-analysis were still limited, the explanation of the current findings should be with caution and further well-designed studies with larger populations are required to clarify the distinct effects of rs895819 on cancer development in different types of cancers.	('cancer', 'Disease', (310, 316))	('cancers', 'Disease', 'MESH:D009369', (310, 317))	('cancers', 'Phenotype', 'HP:0002664', (310, 317))	('rs895819', 'Var', (257, 265))	('cancers', 'Disease', (310, 317))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('rs895819', 'Mutation', 'rs895819', (257, 265))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
359204	29088869	To identify the studies on the relationship between miR-27a polymorphism and cancer risk, we conducted systemic literature searching by retrieving databases and manual searching.	('miR-27a', 'Gene', (52, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('miR-27a', 'Gene', '407018', (52, 59))	('polymorphism', 'Var', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
359208	29088869	The crude ORs with 95% CIs were used to assess the strength of association between the miR-27a polymorphism rs895819 and cancer risk.	('miR-27a', 'Gene', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('miR-27a', 'Gene', '407018', (87, 94))	('rs895819', 'Var', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('rs895819', 'Mutation', 'rs895819', (108, 116))
359210	29088869	Secondly, the risks of (AG + GG vs. AA) and (GG vs. AA + AG) on cancer were evaluated, assuming dominant and recessive effects of the variant GG allele, respectively.	('variant', 'Var', (134, 141))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
359250	28428908	He subsequently received palliative radiation (3000 cGy) to the ascending colon cancer with improvement of anemia, and remained transfusion independent for more than 3 months.	('colon cancer', 'Phenotype', 'HP:0003003', (74, 86))	('anemia', 'Phenotype', 'HP:0001903', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colon cancer', 'Disease', 'MESH:D015179', (74, 86))	('3000 cGy', 'Var', (47, 55))	('colon cancer', 'Disease', (74, 86))	('anemia', 'Disease', 'MESH:D000740', (107, 113))	('anemia', 'Disease', (107, 113))
359362	26331816	Smoking was estimated to cause approximately 435,000 new cancers per year in China (approximately 360,000 in men and approximately 75,000 in women).	('women', 'Species', '9606', (141, 146))	('Smoking', 'Var', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cause', 'Reg', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('men', 'Species', '9606', (109, 112))	('men', 'Species', '9606', (143, 146))
359558	18956138	Patients were removed from the study if any toxicity endpoints were reached, if there was evidence of disease progression, for a major protocol violation, or if a number of dose attentuations were made (i.e., paclitaxel <40 mg/m2, irinotecan <40 mg/m2).	('irinotecan', 'Chemical', 'MESH:D000077146', (231, 241))	('<40 mg/m2', 'Var', (220, 229))	('Patients', 'Species', '9606', (0, 8))	('paclitaxel', 'Chemical', 'MESH:D017239', (209, 219))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('toxicity', 'Disease', (44, 52))
359639	21868761	Loss of transcription factor KLF5 in the context of p53 ablation drives invasive progression of human squamous cell cancer Squamous cell cancers account for more than half of all human cancers, and esophageal cancer is the sixth leading cause of cancer death worldwide.	('p53', 'Gene', (52, 55))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('KLF5', 'Gene', (29, 33))	('cancers', 'Disease', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('Squamous cell cancers', 'Disease', (123, 144))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer death', 'Disease', 'MESH:D003643', (246, 258))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('human', 'Species', '9606', (96, 101))	('Squamous cell cancers', 'Phenotype', 'HP:0002860', (123, 144))	('Loss', 'NegReg', (0, 4))	('squamous cell cancer', 'Disease', (102, 122))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (102, 122))	('cancer death', 'Disease', (246, 258))	('squamous cell cancer', 'Disease', 'MESH:D002294', (102, 122))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('Squamous cell cancers', 'Disease', 'MESH:D002294', (123, 144))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('esophageal cancer', 'Disease', 'MESH:D004938', (198, 215))	('ablation', 'Var', (56, 64))	('human', 'Species', '9606', (179, 184))	('p53', 'Gene', '7157', (52, 55))	('KLF5', 'Gene', '688', (29, 33))	('esophageal cancer', 'Disease', (198, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
359640	21868761	The majority of esophageal squamous cell carcinomas have identifiable p53 mutations, yet the same p53 mutations are found at comparable frequencies in pre-cancerous dysplasia, indicating that transformation requires additional somatic changes yet to be defined.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('cancerous dysplasia', 'Disease', (155, 174))	('p53', 'Gene', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancerous dysplasia', 'Disease', 'MESH:D009369', (155, 174))	('mutations', 'Var', (74, 83))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (27, 51))	('esophageal squamous cell carcinomas', 'Disease', (16, 51))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (16, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))
359641	21868761	Here we show that the zinc finger transcription factor KLF5 transactivates NOTCH1 in the context of p53 mutation or loss.	('NOTCH1', 'Gene', '4851', (75, 81))	('NOTCH1', 'Gene', (75, 81))	('mutation', 'Var', (104, 112))	('loss', 'NegReg', (116, 120))	('transactivates', 'PosReg', (60, 74))	('p53', 'Gene', (100, 103))
359642	21868761	KLF5 loss limited NOTCH1 activity and was sufficient on its own to transform primary human keratinocytes harboring mutant p53, leading to formation of invasive tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('NOTCH1', 'Gene', (18, 24))	('loss limited', 'NegReg', (5, 17))	('mutant', 'Var', (115, 121))	('invasive tumors', 'Disease', 'MESH:D009369', (151, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('activity', 'MPA', (25, 33))	('leading to', 'Reg', (127, 137))	('NOTCH1', 'Gene', '4851', (18, 24))	('invasive tumors', 'Disease', (151, 166))	('human', 'Species', '9606', (85, 90))	('p53', 'Gene', (122, 125))
359643	21868761	Restoration of NOTCH1 blocked transformation of KLF5-deficient and p53 mutant keratinocytes.	('KLF5-deficient', 'Disease', 'MESH:D007153', (48, 62))	('NOTCH1', 'Gene', '4851', (15, 21))	('NOTCH1', 'Gene', (15, 21))	('KLF5-deficient', 'Disease', (48, 62))	('blocked', 'NegReg', (22, 29))	('Restoration', 'Var', (0, 11))	('p53', 'Gene', (67, 70))	('mutant', 'Var', (71, 77))	('transformation', 'CPA', (30, 44))
359648	21868761	While alterations in a number of genes have been linked to the development of human esophageal squamous cell cancer, most genetic changes were identified by examining existing cancers.	('cancers', 'Disease', (176, 183))	('alterations', 'Var', (6, 17))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('linked', 'Reg', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (84, 115))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (95, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal squamous cell cancer', 'Disease', (84, 115))	('human', 'Species', '9606', (78, 83))
359650	21868761	p53 mutations are common in esophageal malignancy yet are early events and do not induce invasive squamous cell cancer by themselves, suggesting that part of the oncogenic pathway is missing.	('p53', 'Gene', (0, 3))	('common', 'Reg', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal malignancy', 'Phenotype', 'HP:0100751', (28, 49))	('invasive squamous cell cancer', 'Disease', (89, 118))	('invasive squamous cell cancer', 'Disease', 'MESH:D002294', (89, 118))	('esophageal malignancy', 'Disease', (28, 49))	('mutations', 'Var', (4, 13))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (98, 118))	('esophageal malignancy', 'Disease', 'MESH:D004938', (28, 49))
359651	21868761	In addition, the development of esophageal squamous cell cancer models that of other squamous cell cancers, which together account for nearly 1 million deaths annually and in which p53 mutation or loss-of-function is also frequent but not sufficient for transformation.	('p53', 'Gene', (181, 184))	('squamous cell cancers', 'Disease', 'MESH:D002294', (85, 106))	('esophageal squamous cell cancer', 'Disease', (32, 63))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('mutation', 'Var', (185, 193))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (32, 63))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (85, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (43, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('loss-of-function', 'NegReg', (197, 213))	('squamous cell cancers', 'Disease', (85, 106))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (85, 105))
359654	21868761	We hypothesized that KLF5 loss might synergize with p53 mutation or loss in squamous cells to promote transformation and tumorigenesis.	('KLF5', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('p53', 'Gene', (52, 55))	('tumor', 'Disease', (121, 126))	('loss', 'NegReg', (26, 30))	('promote', 'PosReg', (94, 101))	('mutation', 'Var', (56, 64))	('transformation', 'CPA', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
359655	21868761	Isolation of primary human esophageal keratinocytes (EPC2) and retroviral transduction of hTERT, SV40 T-antigen, H-RasG12V, and p53R175H to generate EPC2-hTERT, T-Te, T-TeRas, and EPC2-hTERT-p53R175H cells, respectively, have been previously described.	('hTERT', 'Gene', (154, 159))	('EPC2', 'Gene', '26122', (180, 184))	('EPC2', 'Gene', (180, 184))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (149, 159))	('hTERT', 'Gene', '7015', (90, 95))	('EPC2', 'Gene', '26122', (149, 153))	('hTERT', 'Gene', (185, 190))	('SV40', 'Var', (97, 101))	('EPC2', 'Gene', (149, 153))	('EPC2', 'Gene', '26122', (53, 57))	('human', 'Species', '9606', (21, 26))	('EPC2', 'Gene', (53, 57))	('hTERT', 'Gene', '7015', (154, 159))	('hTERT', 'Gene', (90, 95))	('hTERT', 'Gene', '7015', (185, 190))	('p53R175H', 'Var', (128, 136))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (180, 190))
359657	21868761	EPC1 cells were transduced with hTERT (EPC1-hTERT) and p53R175H (EPC1-hTERT-p53R175H) as for EPC2 cells.	('EPC2', 'Gene', '26122', (93, 97))	('EPC1', 'Gene', '80314', (39, 43))	('EPC2', 'Gene', (93, 97))	('EPC1', 'Gene', (39, 43))	('hTERT', 'Gene', '7015', (70, 75))	('EPC1', 'Gene', (0, 4))	('hTERT', 'Gene', (70, 75))	('hTERT', 'Gene', '7015', (32, 37))	('EPC1', 'Gene', '80314', (0, 4))	('EPC1', 'Gene', '80314', (65, 69))	('EPC1', 'Gene', (65, 69))	('hTERT', 'Gene', '7015', (44, 49))	('hTERT', 'Gene', (32, 37))	('p53R175H', 'Var', (55, 63))	('hTERT', 'Gene', (44, 49))
359659	21868761	The following cell lines were used: TE1, TE2, TE5, TE7, TE8, TE9, TE10, TE11, TE12.	('TE12', 'Var', (78, 82))	('TE2', 'Gene', '8260', (41, 44))	('TE11', 'Var', (72, 76))	('TE2', 'Gene', (41, 44))	('TE10', 'Var', (66, 70))
359676	21868761	N1PR-Luc, containing the 5' regulatory region of the human NOTCH1 gene from -961 to -1 upstream of the translation start site, and N1PRmt-Luc, created by mutating multiple p53-binding repeats located between nucleotides -880 and -783, were gifts of Dr. Tohru Kiyono (National Cancer Research Institute, Tokyo, Japan).	('Cancer', 'Disease', 'MESH:D009369', (276, 282))	('Cancer', 'Phenotype', 'HP:0002664', (276, 282))	('human', 'Species', '9606', (53, 58))	('NOTCH1', 'Gene', '4851', (59, 65))	('NOTCH1', 'Gene', (59, 65))	('mutating', 'Var', (154, 162))	('Cancer', 'Disease', (276, 282))
359704	21868761	Initially, we examined KLF5 expression in an established, step-wise esophageal transformation model in which primary human esophageal keratinocytes (EPC2 cells) were immortalized by hTERT without (EPC2-hTERT cells) or with SV40 T-antigen (T-Te cells), then transformed by H-rasV12G resulting in the creation of a tumorigenic, transformed cell line (T-TeRas cells).	('hTERT', 'Gene', '7015', (182, 187))	('hTERT', 'Gene', '7015', (202, 207))	('H-rasV12G', 'Var', (272, 281))	('tumor', 'Disease', (313, 318))	('hTERT', 'Gene', (182, 187))	('hTERT', 'Gene', (202, 207))	('human', 'Species', '9606', (117, 122))	('EPC2', 'Gene', (149, 153))	('EPC2', 'Gene', '26122', (149, 153))	('EPC2', 'Gene', '26122', (197, 201))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (197, 207))	('EPC2', 'Gene', (197, 201))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))
359705	21868761	Parental EPC2 and EPC2-hTERT cells, which retain normal growth control and senescence and show no malignant changes, expressed KLF5 at similar levels to T-Te cells (Figure S2), which lack functional p53 due to the presence of SV40 T-antigen but are not transformed.	('EPC2', 'Gene', (18, 22))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (18, 28))	('EPC2', 'Gene', '26122', (9, 13))	('EPC2', 'Gene', (9, 13))	('malignant changes', 'Phenotype', 'HP:0002664', (98, 115))	('SV40', 'Var', (226, 230))	('EPC2', 'Gene', '26122', (18, 22))
359706	21868761	The proximal promoter of KLF5 contains a large number of CpG islands (Figure S3A), which were hypermethylated in T-TeRas compared to parental EPC2-hTERT cells (Figure S3B-C), and demethylation treatment of T-TeRas cells reestablished KLF5 expression (Figure S3D), consistent with a role for promoter hypermethylation in silencing KLF5.	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (142, 152))	('demethylation', 'Var', (179, 192))	('KLF5', 'Gene', (234, 238))	('reestablished', 'PosReg', (220, 233))
359707	21868761	To determine the functional consequences of KLF5 and p53 loss in keratinocytes, we used shRNA to silence KLF5 in EPC2-hTERT cells, as well as EPC2-hTERT cells containing the hotspot mutation p53R175H (Figure S4A-B) or knockdown of p53 with shRNA (Figure S4C).	('p53R175H', 'Var', (191, 199))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (142, 152))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (113, 123))	('p53', 'Gene', (53, 56))	('KLF5', 'Gene', (105, 109))	('loss', 'NegReg', (57, 61))	('silence', 'NegReg', (97, 104))
359708	21868761	Of note, codon 175 is the most frequent mutation site in esophageal squamous cell cancers, and p53R175H inhibits p53 DNA binding, while also exerting some gain-of-function properties.	('esophageal squamous cell cancers', 'Disease', 'MESH:D002294', (57, 89))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('inhibits', 'NegReg', (104, 112))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('p53R175H', 'Var', (95, 103))	('p53', 'Protein', (113, 116))	('gain-of-function', 'PosReg', (155, 171))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (68, 89))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (68, 88))	('esophageal squamous cell cancers', 'Disease', (57, 89))
359709	21868761	The keratinocyte tumor suppressor NOTCH1 is a direct transcriptional target of p53, and we postulated that KLF5, an important transcriptional regulator, might be critical for maintenance of NOTCH1 expression in the context of p53 mutation or loss.	('tumor', 'Disease', (17, 22))	('NOTCH1', 'Gene', '4851', (34, 40))	('mutation', 'Var', (230, 238))	('loss', 'NegReg', (242, 246))	('NOTCH1', 'Gene', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('p53', 'Gene', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('NOTCH1', 'Gene', '4851', (190, 196))	('NOTCH1', 'Gene', (190, 196))
359710	21868761	In esophageal keratinocytes with wild-type p53, expression of NOTCH1 protein (Figure 1A) and mRNA (Figure 1B) was unchanged with KLF5 suppression alone, while cells with p53R175H or p53 knockdown had reduced full-length and intracellular NOTCH1 when KLF5 was suppressed.	('NOTCH1', 'Gene', (238, 244))	('mRNA', 'MPA', (93, 97))	('full-length', 'MPA', (208, 219))	('p53R175H', 'Var', (170, 178))	('expression', 'MPA', (48, 58))	('protein', 'Protein', (69, 76))	('reduced', 'NegReg', (200, 207))	('NOTCH1', 'Gene', '4851', (62, 68))	('NOTCH1', 'Gene', (62, 68))	('p53', 'Gene', (182, 185))	('NOTCH1', 'Gene', '4851', (238, 244))
359711	21868761	KLF5 suppression also inhibited Notch signaling in cells with p53R175H or p53 knockdown, as indicated by decreased expression of the Notch target HES1 (Figure 1C) and reduced CBF1 reporter activity (Figure 1D).	('CBF1', 'Gene', '3516', (175, 179))	('KLF5', 'Gene', (0, 4))	('inhibited', 'NegReg', (22, 31))	('HES1', 'Gene', '3280', (146, 150))	('knockdown', 'Var', (78, 87))	('CBF1', 'Gene', (175, 179))	('p53', 'Gene', (74, 77))	('Notch', 'Gene', '4851', (32, 37))	('suppression', 'NegReg', (5, 16))	('reduced', 'NegReg', (167, 174))	('expression', 'MPA', (115, 125))	('Notch', 'Gene', '4851', (133, 138))	('HES1', 'Gene', (146, 150))	('Notch', 'Gene', (32, 37))	('Notch', 'Gene', (133, 138))	('decreased', 'NegReg', (105, 114))	('p53R175H', 'Var', (62, 70))
359713	21868761	In EPC2-hTERT cells, p53 preferentially bound NOTCH1 (Figure 2A), but in cells with p53R175H or p53 suppression, we observed a reciprocal rise in KLF5 binding to NOTCH1 (Figure 2B).	('preferentially', 'PosReg', (25, 39))	('KLF5 binding', 'MPA', (146, 158))	('NOTCH1', 'Gene', '4851', (162, 168))	('NOTCH1', 'Gene', (162, 168))	('NOTCH1', 'Gene', '4851', (46, 52))	('NOTCH1', 'Gene', (46, 52))	('p53R175H', 'Var', (84, 92))	('bound', 'Interaction', (40, 45))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (3, 13))
359714	21868761	KLF5 induction in EPC2-hTERT-p53R175H cells (Figure 2C), but not parental EPC2-hTERT cells (Figure S5), activated both wild-type NOTCH1 reporter (N1PR) and a NOTCH1 reporter with mutations in the p53 binding sites (N1PRmt), while KLF5 suppression downregulated N1PR and N1PRmt (Figure 2D).	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (18, 28))	('NOTCH1', 'Gene', '4851', (129, 135))	('NOTCH1', 'Gene', (129, 135))	('NOTCH1', 'Gene', '4851', (158, 164))	('NOTCH1', 'Gene', (158, 164))	('downregulated', 'NegReg', (247, 260))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (74, 84))	('mutations', 'Var', (179, 188))	('activated', 'PosReg', (104, 113))	('p53', 'Gene', (196, 199))
359715	21868761	The effects of KLF5 on NOTCH1 were blocked by additional mutations to two KLF5 binding sites of the NOTCH1 reporter (N1PRmt2).	('NOTCH1', 'Gene', '4851', (23, 29))	('NOTCH1', 'Gene', (23, 29))	('mutations', 'Var', (57, 66))	('NOTCH1', 'Gene', '4851', (100, 106))	('NOTCH1', 'Gene', (100, 106))
359717	21868761	EMT in keratinocytes with KLF5 suppression and p53R175H was confirmed by induction of Snail, Twist, FOXC2, ZEB1, and ZEB2, the mesenchymal markers MMP2 and MMP3, downregulation of Desmoplakin, and the cadherin "switch" (Table 1, Figure S6D).	('MMP3', 'Gene', (156, 160))	('MMP2', 'Gene', (147, 151))	('Desmoplakin', 'Protein', (180, 191))	('ZEB1', 'Gene', '6935', (107, 111))	('induction', 'Reg', (73, 82))	('MMP3', 'Gene', '4314', (156, 160))	('FOXC2', 'Gene', '2303', (100, 105))	('p53R175H', 'Var', (47, 55))	('FOXC2', 'Gene', (100, 105))	('Snail', 'Gene', (86, 91))	('MMP2', 'Gene', '4313', (147, 151))	('Snail', 'Gene', '6615', (86, 91))	('ZEB2', 'Gene', '9839', (117, 121))	('downregulation', 'NegReg', (162, 176))	('ZEB2', 'Gene', (117, 121))	('ZEB1', 'Gene', (107, 111))
359722	21868761	Tumors from EPC2-hTERT-p53R175H-KLF5shRNA xenografts were characteristic of invasive squamous cell carcinoma (Figure 4B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 108))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (12, 22))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('EPC2-hTERT-p53R175H-KLF5shRNA', 'Var', (12, 41))	('invasive squamous cell carcinoma', 'Disease', (76, 108))
359723	21868761	In organotypic culture, keratinocytes with both KLF5 suppression and p53 mutation but not either alone showed neoplastic changes and invasion (Figure 4C), while induction of NICD in EPC2-hTERT-p53R175H-KLF5shRNA cells blocked these effects.	('neoplastic changes', 'CPA', (110, 128))	('p53', 'Gene', (69, 72))	('invasion', 'CPA', (133, 141))	('neoplastic changes', 'Phenotype', 'HP:0002664', (110, 128))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (182, 192))	('mutation', 'Var', (73, 81))
359724	21868761	Interestingly, EPC2-hTERT cells with KLF5 knockdown formed thin epithelia which lacked normal stratification, consistent with loss of the established functions of KLF5 in proliferation and migration of non-transformed esophageal keratinocytes.	('KLF5', 'Gene', (37, 41))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (15, 25))	('knockdown', 'Var', (42, 51))	('migration', 'CPA', (189, 198))
359732	21868761	As in T-TeRas cells, KLF5 expression in squamous cancer cells was restored by demethylation treatment.	('KLF5 expression', 'MPA', (21, 36))	('demethylation', 'Var', (78, 91))	('squamous cancer', 'Phenotype', 'HP:0002860', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('squamous cancer', 'Disease', 'MESH:D002294', (40, 55))	('squamous cancer', 'Disease', (40, 55))	('restored', 'PosReg', (66, 74))
359733	21868761	The pathobiology of esophageal squamous cell cancer is typical of cancers of stratified squamous epithelia, and p53 inactivation is common but not causative in these cancers.	('squamous cell cancer', 'Phenotype', 'HP:0002860', (31, 51))	('cancers', 'Disease', (166, 173))	('squamous epithelia', 'Disease', 'MESH:D002294', (88, 106))	('inactivation', 'Var', (116, 128))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('esophageal squamous cell cancer', 'Disease', (20, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('squamous epithelia', 'Phenotype', 'HP:0002860', (88, 106))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('squamous epithelia', 'Disease', (88, 106))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('p53', 'Gene', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (20, 51))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
359734	21868761	We thus examined whether KLF5 loss in the context of p53 loss or mutation was broadly applicable to squamous cell carcinogenesis.	('squamous cell carcinogenesis', 'Disease', (100, 128))	('squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (100, 128))	('p53', 'Gene', (53, 56))	('mutation', 'Var', (65, 73))	('loss', 'NegReg', (57, 61))	('loss', 'NegReg', (30, 34))	('KLF5', 'Protein', (25, 29))
359736	21868761	Most of these established cell lines contain known p53 mutations; in other cases, such as SiHa and HeLa, p53 is wild-type but is functionally inactivated by HPV.	('HeLa', 'CellLine', 'CVCL:0030', (99, 103))	('p53', 'Gene', (51, 54))	('SiHa', 'CellLine', 'CVCL:0032', (90, 94))	('mutations', 'Var', (55, 64))
359738	21868761	p53 mutations are relatively early events in squamous cell carcinogenesis but by themselves are not sufficient for the development of human squamous cell cancer.	('p53', 'Gene', (0, 3))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (140, 160))	('human', 'Species', '9606', (134, 139))	('squamous cell cancer', 'Disease', 'MESH:D002294', (140, 160))	('squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (45, 73))	('squamous cell cancer', 'Disease', (140, 160))	('mutations', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('squamous cell carcinogenesis', 'Disease', (45, 73))
359742	21868761	The effects of p53 mutations are variable, and almost 80% of p53 mutations in cancer are missense mutations, leading to the synthesis of a stable protein which lacks typical DNA-binding activity.	('cancer', 'Disease', (78, 84))	('synthesis', 'MPA', (124, 133))	('leading to', 'Reg', (109, 119))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('p53', 'Gene', (61, 64))	('mutations', 'Var', (65, 74))
359743	21868761	Nonetheless, since NOTCH1 is decreased and KLF5 binding to the NOTCH1 promoter increases in cells with knockdown of p53 by shRNA, these effects are not specific to p53R175H gain-of-function properties.	('KLF5', 'MPA', (43, 47))	('increases', 'PosReg', (79, 88))	('NOTCH1', 'Gene', '4851', (19, 25))	('NOTCH1', 'Gene', (19, 25))	('decreased', 'NegReg', (29, 38))	('NOTCH1', 'Gene', '4851', (63, 69))	('NOTCH1', 'Gene', (63, 69))	('knockdown', 'Var', (103, 112))	('p53', 'Gene', (116, 119))
359748	21868761	In mice with ApcMin/+ and KRASV12, Klf5 haploinsufficiency decreases the formation of premalignant intestinal adenomas; an effect of KLF5 on adenocarcinoma development in vivo has not been reported.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('adenomas', 'Disease', (110, 118))	('Klf5', 'Gene', (35, 39))	('mice', 'Species', '10090', (3, 7))	('haploinsufficiency decreases', 'Disease', 'MESH:D058495', (40, 68))	('ApcMin/+', 'Var', (13, 21))	('adenocarcinoma', 'Disease', (141, 155))	('haploinsufficiency decreases', 'Disease', (40, 68))	('KRASV12', 'Var', (26, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (141, 155))	('adenomas', 'Disease', 'MESH:D000236', (110, 118))
359752	21868761	Subsequent KLF5 loss leads to failure to transactivate NOTCH1 and, potentially, other target genes and drives squamous cell transformation and invasive cancer.	('drives', 'Reg', (103, 109))	('transactivate', 'Var', (41, 54))	('KLF5', 'Gene', (11, 15))	('invasive cancer', 'Disease', (143, 158))	('failure', 'NegReg', (30, 37))	('loss', 'NegReg', (16, 20))	('squamous cell transformation', 'Disease', (110, 138))	('invasive cancer', 'Disease', 'MESH:D009362', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('NOTCH1', 'Gene', '4851', (55, 61))	('NOTCH1', 'Gene', (55, 61))
359753	21868761	Thus, our findings explain why p53 loss or mutation may be necessary but not sufficient for development of human squamous cell cancers and suggest that KLF5 loss is a valuable diagnostic and therapeutic target for esophageal cancer, a significant cause of morbidity and mortality, for cancers of other stratified squamous epithelia, and, potentially, for other cancers associated with p53 mutation or loss.	('squamous epithelia', 'Disease', (313, 331))	('p53', 'Gene', (385, 388))	('cancers', 'Disease', (361, 368))	('squamous epithelia', 'Phenotype', 'HP:0002860', (313, 331))	('squamous epithelia', 'Disease', 'MESH:D002294', (313, 331))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('loss', 'NegReg', (401, 405))	('mutation', 'Var', (43, 51))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('mutation', 'Var', (389, 397))	('cancers', 'Disease', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('p53', 'Gene', (31, 34))	('cancers', 'Disease', (285, 292))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (361, 368))	('loss', 'NegReg', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (113, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (214, 231))	('human', 'Species', '9606', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('esophageal cancer', 'Disease', (214, 231))	('squamous cell cancers', 'Disease', (113, 134))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (113, 133))	('loss', 'NegReg', (157, 161))	('squamous cell cancers', 'Disease', 'MESH:D002294', (113, 134))	('cancers', 'Disease', 'MESH:D009369', (285, 292))	('cancers', 'Phenotype', 'HP:0002664', (361, 368))
359784	16638155	Furthermore, the interval between gastrectomy and development of oesophageal cancer in patients who underwent Billroth I reconstruction is reported to be shorter compared with those who underwent Billroth II reconstruction.	('reconstruction', 'Var', (121, 135))	('Billroth', 'Var', (110, 118))	('oesophageal cancer', 'Disease', (65, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('oesophageal cancer', 'Disease', 'MESH:D009369', (65, 83))	('patients', 'Species', '9606', (87, 95))
359929	31406271	Restoration of SMARCA2 expression alleviates the dependency on SMARCA4, while engineered loss of SMARCA2 renders ESCC models vulnerable to concomitant depletion of SMARCA4.	('SMARCA2', 'Gene', (15, 22))	('SMARCA2', 'Gene', '6595', (15, 22))	('Restoration', 'Var', (0, 11))	('alleviates', 'NegReg', (34, 44))	('dependency on SMARCA4', 'MPA', (49, 70))	('SMARCA2', 'Gene', (97, 104))	('SMARCA2', 'Gene', '6595', (97, 104))	('loss', 'NegReg', (89, 93))
359932	31406271	These findings expand the concept of SMARCA2/SMARCA4 paralog dependency and suggest that pharmacological inhibition of SMARCA4 represents a novel therapeutic opportunity for SMARCA2-deficient cancers.	('SMARCA2-deficient cancers', 'Disease', (174, 199))	('SMARCA2', 'Gene', (174, 181))	('SMARCA2', 'Gene', (37, 44))	('pharmacological', 'Var', (89, 104))	('SMARCA2', 'Gene', '6595', (37, 44))	('SMARCA2', 'Gene', '6595', (174, 181))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('SMARCA2-deficient cancers', 'Disease', 'MESH:D009369', (174, 199))	('SMARCA4', 'Gene', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
359934	31406271	Selective targeting of tumors harboring loss-of-function alterations of a synthetic lethal gene by pharmacological inhibition of the functional synthetic lethal partner has been proposed for cancer therapy.	('cancer', 'Disease', (191, 197))	('tumors', 'Disease', (23, 29))	('synthetic lethal gene', 'Gene', (74, 95))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('alterations', 'Var', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('loss-of-function', 'NegReg', (40, 56))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
359943	31406271	Most notably, the BAF ATPase function may be exerted by either SMARCA4 or its homologous paralog SMARCA2.	('SMARCA4', 'Var', (63, 70))	('BAF', 'Gene', '8815', (18, 21))	('BAF', 'Gene', (18, 21))	('exerted', 'Reg', (45, 52))	('ATPase', 'Gene', '1769', (22, 28))	('ATPase', 'Gene', (22, 28))	('SMARCA2', 'Gene', (97, 104))	('SMARCA2', 'Gene', '6595', (97, 104))
359944	31406271	Loss-of-function alterations of individual BAF complex components, such as bi-allelic inactivation of the BAF core component SMARCB1 in malignant rhabdoid tumors, are known oncogenic driver events, indicating a tumor suppressive role for BAF complexes.	('SMARCB1', 'Gene', '6598', (125, 132))	('SMARCB1', 'Gene', (125, 132))	('tumor', 'Disease', (155, 160))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (136, 161))	('BAF', 'Gene', '8815', (43, 46))	('tumor', 'Disease', (211, 216))	('BAF', 'Gene', '8815', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('BAF', 'Gene', '8815', (238, 241))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('alterations', 'Var', (17, 28))	('malignant rhabdoid tumors', 'Disease', (136, 161))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('BAF', 'Gene', (43, 46))	('Loss-of-function', 'NegReg', (0, 16))	('BAF', 'Gene', (106, 109))	('BAF', 'Gene', (238, 241))	('bi-allelic inactivation', 'Var', (75, 98))
359945	31406271	Cancer-associated BAF alterations do not result in complete abrogation of BAF activity, which would be detrimental for viability of most cells, implying that tumors are dependent on the aberrant function of the residual BAF complex.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('BAF', 'Gene', '8815', (18, 21))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('BAF', 'Gene', (220, 223))	('BAF', 'Gene', (18, 21))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('alterations', 'Var', (22, 33))	('BAF', 'Gene', '8815', (74, 77))	('activity', 'MPA', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('BAF', 'Gene', '8815', (220, 223))	('BAF', 'Gene', (74, 77))
359946	31406271	This is exemplified by the ATPase subunit SMARCA4, which is frequently inactivated by loss-of-function mutations or epigenetic silencing in non-small cell lung cancer (NSCLC) and other tumor types.	('SMARCA4', 'Gene', (42, 49))	('ATPase', 'Gene', (27, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('tumor', 'Disease', (185, 190))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('mutations', 'Var', (103, 112))	('ATPase', 'Gene', '1769', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('inactivated', 'NegReg', (71, 82))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('epigenetic silencing', 'Var', (116, 136))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (140, 166))	('loss-of-function', 'NegReg', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('non-small cell lung cancer', 'Disease', (140, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('NSCLC', 'Disease', (168, 173))
359953	31406271	Six ESCC models (KYSE-270, T.T, KYSE-30, KYSE-410, KSYE-510 and COLO-680N) displayed relative Robust Rank Aggregation (alpha-RRA) scores below -0.5 similar to the known essential genes CDK1, POLR2A and RPA3.	('KYSE-30', 'Var', (32, 39))	('KYSE-270', 'Var', (17, 25))	('COLO', 'Species', '307630', (64, 68))	('POLR2A', 'Gene', '5430', (191, 197))	('POLR2A', 'Gene', (191, 197))	('CDK1', 'Gene', (185, 189))	('KYSE-410', 'Var', (41, 49))	('CDK1', 'Gene', '983', (185, 189))	('RPA3', 'Gene', (202, 206))	('T.T', 'Var', (27, 30))	('KSYE-510', 'Var', (51, 59))	('RPA3', 'Gene', '6119', (202, 206))
359955	31406271	Reciprocal to the known dependency of SMARCA4-deficient cancer cell lines on SMARCA2, the majority of SMARCA4-dependent ESCC cell lines (KYSE-270, KYSE-30, KSYE-510 and COLO-680N) displayed low or non-detectable levels of SMARCA2 mRNA and protein expression (Supplementary Fig.	('SMARCA4-deficient cancer', 'Disease', 'MESH:D009369', (38, 62))	('KYSE-270', 'Var', (137, 145))	('SMARCA2', 'Gene', (77, 84))	('SMARCA2', 'Gene', '6595', (77, 84))	('KSYE-510', 'Var', (156, 164))	('SMARCA2', 'Gene', (222, 229))	('SMARCA2', 'Gene', '6595', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('SMARCA4-dependent', 'Gene', (102, 119))	('SMARCA4-deficient cancer', 'Disease', (38, 62))	('KYSE-30', 'Var', (147, 154))	('COLO-680N', 'Var', (169, 178))	('COLO', 'Species', '307630', (169, 173))
359963	31406271	No strong depletion effects were observed upon knock-out of SMARCA4 in the SMARCA2-proficient cell models KYSE-450, KYSE-140, KYSE-70 and KYSE-150 over a course of 28 days.	('knock-out', 'Var', (47, 56))	('depletion', 'MPA', (10, 19))	('SMARCA4', 'Gene', (60, 67))	('SMARCA2', 'Gene', (75, 82))	('SMARCA2', 'Gene', '6595', (75, 82))
359964	31406271	In contrast, targeting SMARCA4 in the SMARCA2-deficient cell models KYSE-270, KYSE-30, KYSE-510 and COLO-680N resulted in depletion effects similar or stronger than observed for the POLR2A positive control sgRNA (Fig.	('KYSE-270', 'Var', (68, 76))	('KYSE-510', 'Var', (87, 95))	('stronger', 'PosReg', (151, 159))	('POLR2A', 'Gene', '5430', (182, 188))	('SMARCA2', 'Gene', (38, 45))	('KYSE-30', 'Var', (78, 85))	('COLO', 'Species', '307630', (100, 104))	('depletion effects', 'MPA', (122, 139))	('COLO-680N', 'Var', (100, 109))	('SMARCA2', 'Gene', '6595', (38, 45))	('KYSE-510', 'CellLine', 'CVCL:1354', (87, 95))	('POLR2A', 'Gene', (182, 188))	('SMARCA4', 'Gene', (23, 30))
359965	31406271	With the exception of KYSE-30, DEXDc-targeted sgRNAs showed stronger and faster depletion than bromodomain-directed sgRNAs in SMARCA2-deficient cells (Fig.	('DEXDc-targeted', 'Var', (31, 45))	('SMARCA2', 'Gene', '6595', (126, 133))	('SMARCA2', 'Gene', (126, 133))	('depletion', 'MPA', (80, 89))
359967	31406271	Of note, SMARCA4 bromodomain-targeting, but not ATPase-directed, sgRNAs were included in the pooled sgRNA library.	('ATPase', 'Gene', (48, 54))	('bromodomain-targeting', 'Var', (17, 38))	('ATPase', 'Gene', '1769', (48, 54))	('SMARCA4', 'Gene', (9, 16))
359969	31406271	The requirement of SMARCA4 ATPase and bromodomain function in SMARCA2-deficient ESCC cells was further assessed by generating siRNA/sgRNA-resistant SMARCA4 (SMARCA4res) expression constructs harboring loss-of-function mutations within the DEXDc- (K785A) and bromodomains (N1540A) (Fig.	('SMARCA4res', 'Gene', (157, 167))	('ATPase', 'Gene', '1769', (27, 33))	('K785A', 'Mutation', 'p.K785A', (247, 252))	('ATPase', 'Gene', (27, 33))	('SMARCA2', 'Gene', (62, 69))	('N1540A', 'Var', (272, 278))	('loss-of-function', 'NegReg', (201, 217))	('SMARCA2', 'Gene', '6595', (62, 69))	('SMARCA4res', 'Gene', '6597', (157, 167))	('N1540A', 'Mutation', 'p.N1540A', (272, 278))
359970	31406271	Wild-type and mutant forms of SMARCA4res were stably transduced in KYSE-510 cells and SMARCA4res expression was monitored by capillary Western immunoassay.	('mutant', 'Var', (14, 20))	('KYSE-510', 'CellLine', 'CVCL:1354', (67, 75))	('SMARCA4res', 'Gene', (86, 96))	('SMARCA4res', 'Gene', '6597', (30, 40))	('SMARCA4res', 'Gene', '6597', (86, 96))	('SMARCA4res', 'Gene', (30, 40))
359971	31406271	Knock-down of SMARCA4 by siRNA led to depletion of SMARCA4 in parental KYSE-510 cells, but not in KYSE-510 cells expressing SMARCA4res variants (Fig.	('SMARCA4res', 'Gene', '6597', (124, 134))	('SMARCA4', 'Gene', (14, 21))	('SMARCA4', 'Gene', (51, 58))	('Knock-down', 'Var', (0, 10))	('KYSE-510', 'CellLine', 'CVCL:1354', (98, 106))	('KYSE-510', 'CellLine', 'CVCL:1354', (71, 79))	('SMARCA4res', 'Gene', (124, 134))	('variants', 'Var', (135, 143))	('depletion', 'MPA', (38, 47))
359974	31406271	While ectopic expression of bromodomain-mutant (N1540A) SMARCA4res also protected KYSE-510 cells from SMARCA4 knock-out, the ATP-binding deficient form (K785A) of SMARCA4res did not rescue the depletion of SMARCA4 sgRNA-expressing KYSE-510 cells (Fig.	('N1540A', 'Mutation', 'p.N1540A', (48, 54))	('KYSE-510', 'CellLine', 'CVCL:1354', (231, 239))	('SMARCA4res', 'Gene', (56, 66))	('SMARCA4res', 'Gene', '6597', (163, 173))	('KYSE-510', 'CellLine', 'CVCL:1354', (82, 90))	('depletion', 'MPA', (193, 202))	('SMARCA4res', 'Gene', (163, 173))	('K785A', 'Mutation', 'p.K785A', (153, 158))	('N1540A', 'Var', (48, 54))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('SMARCA4res', 'Gene', '6597', (56, 66))
359975	31406271	Wild-type and mutant forms of SMARCA4res were also stably expressed in the SMARCA2-deficient cell line KYSE-30 (Supplementary Fig.	('mutant', 'Var', (14, 20))	('SMARCA4res', 'Gene', '6597', (30, 40))	('SMARCA2', 'Gene', (75, 82))	('SMARCA2', 'Gene', '6595', (75, 82))	('SMARCA4res', 'Gene', (30, 40))
359978	31406271	To interrogate the synthetic lethal interaction of SMARCA2 and SMARCA4 in ESCC, we ectopically expressed wild-type, DEXDc- (K755A) and bromodomain-mutant (N1482A) forms of SMARCA2 (SMARCA2ect) in KYSE-510 cells lacking endogenous SMARCA2 expression (Fig.	('N1482A', 'Var', (155, 161))	('KYSE-510', 'CellLine', 'CVCL:1354', (196, 204))	('SMARCA2', 'Gene', (230, 237))	('SMARCA2', 'Gene', '6595', (230, 237))	('SMARCA2', 'Gene', (172, 179))	('SMARCA2', 'Gene', (181, 188))	('SMARCA2', 'Gene', '6595', (172, 179))	('SMARCA2', 'Gene', (51, 58))	('K755A', 'Mutation', 'p.K755A', (124, 129))	('SMARCA2', 'Gene', '6595', (181, 188))	('SMARCA2', 'Gene', '6595', (51, 58))	('N1482A', 'Mutation', 'p.N1482A', (155, 161))
359981	31406271	3C), bromodomain-mutant SMARCA2ect, but not the ATP-binding deficient variant rendered KYSE-510 cells inert to loss of SMARCA4 (Fig.	('bromodomain-mutant', 'Var', (5, 23))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('SMARCA2', 'Gene', (24, 31))	('SMARCA2', 'Gene', '6595', (24, 31))	('KYSE-510', 'CellLine', 'CVCL:1354', (87, 95))
359985	31406271	Strong depletion of SMARCA4 sgRNAs was not observed in SMARCA2-proficient clones, however, similar to KYSE-450 cells, loss of SMARCA2 rendered KYSE-150 cells dependent on SMARCA4 (Supplementary Fig.	('SMARCA2', 'Gene', (126, 133))	('SMARCA2', 'Gene', '6595', (126, 133))	('loss', 'Var', (118, 122))	('SMARCA2', 'Gene', (55, 62))	('SMARCA2', 'Gene', '6595', (55, 62))
359993	31406271	Ectopic expression of SMARCA4res-BDBRD9 rendered KYSE-30-SMARCA4res-BDBRD9 cells inert to SMARCA4-targeting sgRNAs, indicating functionality and sufficient expression of the bromodomain substituted SMARCA4 variant (Supplementary Fig.	('SMARCA4res', 'Gene', '6597', (22, 32))	('SMARCA4res', 'Gene', '6597', (57, 67))	('variant', 'Var', (206, 213))	('SMARCA4res', 'Gene', (57, 67))	('SMARCA4res', 'Gene', (22, 32))	('SMARCA4', 'Gene', (198, 205))
360002	31406271	Either SMARCA2 or SMARCA4 are sufficient to rescue from loss of SMARCA2 ATPase activity, further emphasizing the context-independent nature of SMARCA2/ SMARCA4 synthetic lethality.	('activity', 'MPA', (79, 87))	('ATPase', 'Gene', '1769', (72, 78))	('SMARCA2', 'Gene', (64, 71))	('SMARCA2', 'Gene', '6595', (64, 71))	('loss', 'Var', (56, 60))	('SMARCA2', 'Gene', (143, 150))	('SMARCA2', 'Gene', (7, 14))	('ATPase', 'Gene', (72, 78))	('SMARCA2', 'Gene', '6595', (7, 14))	('SMARCA2', 'Gene', '6595', (143, 150))
360009	31406271	Inactivating mutations of SMARCA4 are frequently observed in human cancer, most prominently in non-small cell lung cancer (NSCLC).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (95, 121))	('cancer', 'Disease', (115, 121))	('NSCLC', 'Disease', (123, 128))	('cancer', 'Disease', (67, 73))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (95, 121))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('Inactivating mutations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (99, 121))	('non-small cell lung cancer', 'Disease', (95, 121))	('SMARCA4', 'Gene', (26, 33))	('human', 'Species', '9606', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
360011	31406271	While homozygous deletion of Smarca4 is embryonic lethal, heterozygous loss of Smarca4 predisposes to tumor formation of epithelial origin.	('predisposes to', 'Reg', (87, 101))	('Smarca4', 'Gene', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('deletion', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('Smarca4', 'Gene', (79, 86))
360012	31406271	Lung-specific, conditional ablation of Smarca4 enhances tumor formation in a carcinogen-induced lung cancer model.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('enhances', 'PosReg', (47, 55))	('lung cancer', 'Disease', (96, 107))	('Smarca4', 'Gene', (39, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ablation', 'Var', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
360014	31406271	In contrast, loss-of-function mutations of SMARCA2 are primarily linked to developmental/neurological disorders.	('loss-of-function', 'NegReg', (13, 29))	('SMARCA2', 'Gene', (43, 50))	('SMARCA2', 'Gene', '6595', (43, 50))	('neurological disorders', 'Disease', 'MESH:D009422', (89, 111))	('mutations', 'Var', (30, 39))	('neurological disorders', 'Disease', (89, 111))
360015	31406271	Missense mutations or in-frame deletions affecting the ATPase function of SMARCA2 are causative for Nicolaides-Baraitser syndrome, a rare condition characterized by sparse hair, facial and limb abnormalities and intellectual disabilities.	('limb abnormalities', 'Phenotype', 'HP:0002813', (189, 207))	('Nicolaides-Baraitser syndrome', 'Disease', 'MESH:C536116', (100, 129))	('SMARCA2', 'Gene', (74, 81))	('ATPase', 'Gene', '1769', (55, 61))	('SMARCA2', 'Gene', '6595', (74, 81))	('sparse hair', 'Phenotype', 'HP:0008070', (165, 176))	('limb abnormalities and intellectual disabilities', 'Disease', 'MESH:D008607', (189, 237))	('Nicolaides-Baraitser syndrome', 'Disease', (100, 129))	('causative', 'Reg', (86, 95))	('in-frame deletions', 'Var', (22, 40))	('ATPase', 'Gene', (55, 61))	('intellectual disabilities', 'Phenotype', 'HP:0001249', (212, 237))	('Missense mutations', 'Var', (0, 18))
360018	31406271	A notable exception is adenoid cystic carcinoma (ACC), a rare type of cancer arising from salivary glands where mutations within the ATPase domain of SMARCA2 are found in approximately 5% of cases, indicating a potential tumor suppressive function of SMARCA2 in this context.	('SMARCA2', 'Gene', (150, 157))	('SMARCA2', 'Gene', '6595', (150, 157))	('adenoid cystic carcinoma', 'Disease', (23, 47))	('ATPase', 'Gene', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (23, 47))	('SMARCA2', 'Gene', (251, 258))	('tumor', 'Disease', (221, 226))	('SMARCA2', 'Gene', '6595', (251, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('ATPase', 'Gene', '1769', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
360020	31406271	Our data suggest that SMARCA4 inhibition would allow for a selective, cancer-cell directed therapy sparing normal, SMARCA2-expressing cells and tissues.	('inhibition', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SMARCA2', 'Gene', '6595', (115, 122))	('SMARCA2', 'Gene', (115, 122))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('SMARCA4', 'Gene', (22, 29))
360022	31406271	While it is difficult to define a threshold for expression of SMARCA2 that maintains sufficient BAF functionality in the absence of SMARCA4, the fact that homozygous loss of SMARCA4 is embryonic lethal, indicates that SMARCA2 cannot universally compensate for SMARCA4 function.	('SMARCA2', 'Gene', (218, 225))	('SMARCA2', 'Gene', '6595', (218, 225))	('BAF', 'Gene', (96, 99))	('SMARCA2', 'Gene', (62, 69))	('loss', 'Var', (166, 170))	('SMARCA2', 'Gene', '6595', (62, 69))	('BAF', 'Gene', '8815', (96, 99))	('SMARCA4', 'Gene', (174, 181))
360045	31406271	The respective primers were all ordered from Applied Biosystems, including house-keeping genes: 18 S rRNA (VIC /MGB, 4319413E), ACTB (VIC /MGB, 4326315E), GAPDH (VIC /MGB, 4326317E) and primers for SMARCA2 (Hs01030858_m1 MGB/FAM) and SMARCA4 (Hs00231324 MGB/FAM).	('Hs01030858_m1 MGB/FAM', 'Var', (207, 228))	('SMARCA2', 'Gene', (198, 205))	('GAPDH', 'Gene', '2597', (155, 160))	('SMARCA2', 'Gene', '6595', (198, 205))	('Hs00231324 MGB/FAM', 'Var', (243, 261))	('GAPDH', 'Gene', (155, 160))	('ACTB', 'Gene', (128, 132))	('ACTB', 'Gene', '60', (128, 132))
360051	31406271	For expression of SMARCA4res and SMARCA2ect the following constructs were generated by gene synthesis (GenScript, China) based on the SMARCA4 cDNA sequence NCBI NM_ 001128844.1 and SMARCA2 cDNA sequence NCBI NM_003070.5 and cloning into the parental pLVX vector (Clontech, Mountain View, CA, US): pLVX-empty-IRES-Hygro; pLVX-SMARCA4-wt-IRES-Hygro; pLVX-SMARCA4-ATP-binding deficient (K785A)-IRES-Hygro; pLVX-SMARCA4-BD-dead(N1540A)-IRES-Hygro; pLVX-SMARCA2-wt-IRES-Hygro; pLVX-SMARCA2-ATP-binding-deficient(K755A)-IRES-Hygro; pLVX-SMARCA2-BD-dead(N1482A)-IRES-Hygro; pLVX-SMARCA4res-BDBRD9-IRES-Hygro.	('SMARCA4res', 'Gene', '6597', (572, 582))	('SMARCA4res', 'Gene', (18, 28))	('SMARCA2', 'Gene', (181, 188))	('SMARCA2', 'Gene', '6595', (181, 188))	('N1482A', 'Mutation', 'p.N1482A', (547, 553))	('K785A', 'Mutation', 'p.K785A', (384, 389))	('K755A', 'Mutation', 'p.K755A', (507, 512))	('SMARCA2', 'Gene', (449, 456))	('SMARCA4res', 'Gene', '6597', (18, 28))	('SMARCA2', 'Gene', '6595', (449, 456))	('ATP', 'Chemical', 'MESH:D000255', (361, 364))	('ATP', 'Chemical', 'MESH:D000255', (485, 488))	('N1540A', 'Mutation', 'p.N1540A', (424, 430))	('SMARCA2', 'Gene', (477, 484))	('SMARCA2', 'Gene', '6595', (477, 484))	('SMARCA2', 'Gene', (531, 538))	('SMARCA2', 'Gene', (33, 40))	('SMARCA2', 'Gene', '6595', (531, 538))	('SMARCA2', 'Gene', '6595', (33, 40))	('N1482A', 'Var', (547, 553))	('SMARCA4res', 'Gene', (572, 582))
360054	31406271	For SMARCA2, domains were annotated according to UniProt entry P51531, bromodomain (BD) was annotated according to NCBI entry 6595 (cd05516).	('SMARCA2', 'Gene', (4, 11))	('SMARCA2', 'Gene', '6595', (4, 11))	('P51531', 'Var', (63, 69))
360112	28456788	Neoadjuvant chemoradiotherapy is recommended for resectable esophageal carcinoma (stages T1bN+, T2-4aN0-N+, and M0) in the NCCN guidelines, mainly based on the evidence of relevant meta-analysis and the CROSS study.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (60, 80))	('men', 'Species', '9606', (38, 41))	('OS', 'Chemical', '-', (205, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('esophageal carcinoma', 'Disease', (60, 80))	('T2-4aN0-N+', 'Var', (96, 106))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (60, 80))
360166	24906622	Deregulation of normal stem cell signaling may lead to the generation of cancer stem cells (CSCs); however, the molecular determinants of this process remain poorly understood.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Deregulation', 'Var', (0, 12))	('lead to', 'Reg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
360168	24906622	Expression of exogenous YAP1 in vitro or inhibition of its upstream negative regulators in vivo results in elevated SOX9 expression accompanied by the acquisition of CSCs properties.	('YAP1', 'Gene', (24, 28))	('CSCs properties', 'CPA', (166, 181))	('expression', 'Species', '29278', (121, 131))	('inhibition', 'NegReg', (41, 51))	('expression', 'MPA', (121, 131))	('Expression', 'Species', '29278', (0, 10))	('elevated', 'PosReg', (107, 115))	('SOX9', 'Gene', (116, 120))	('exogenous', 'Var', (14, 23))
360169	24906622	Conversely, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells attenuates CSC phenotypes in vitro and tumorigenecity in vivo.	('tumor', 'Disease', (113, 118))	('knockdown', 'Var', (27, 36))	('SOX9', 'Gene', (48, 52))	('CSC phenotypes', 'MPA', (85, 99))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('YAP1', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('attenuates', 'NegReg', (74, 84))
360170	24906622	The small molecule inhibitor of YAP1, Verteporfin (VP) significantly blocks CSCs properties in cells with high YAP1 and a high proportion of ALDH1+.	('high', 'Var', (106, 110))	('YAP1', 'Gene', (111, 115))	('blocks', 'NegReg', (69, 75))	('VP', 'Chemical', 'MESH:D000077362', (51, 53))	('Verteporfin', 'Chemical', 'MESH:D000077362', (38, 49))	('CSCs properties', 'CPA', (76, 91))
360175	24906622	The importance of YAP1 and deregulation of the Hippo pathway during cancer development and progression are emerging.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('deregulation', 'Var', (27, 39))	('Hippo pathway', 'Pathway', (47, 60))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))
360176	24906622	Studies in mice have demonstrated that conditional deletion of several Hippo-pathway proteins including Mst1/2 and Sav1 can lead to a dramatic increase in organ size and tumor formation at very high incidence, effects that are largely dependent on YAP1.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Hippo-pathway', 'Gene', (71, 84))	('Mst1/2', 'Gene', (104, 110))	('mice', 'Species', '10090', (11, 15))	('tumor', 'Disease', (170, 175))	('Sav1', 'Gene', '64010', (115, 119))	('organ size', 'CPA', (155, 165))	('increase', 'PosReg', (143, 151))	('deletion', 'Var', (51, 59))	('Sav1', 'Gene', (115, 119))
360178	24906622	Overexpression YAP1 in cancer cell lines can promote EMT and enhances in vitro invasion.	('expression', 'Species', '29278', (4, 14))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('enhances', 'PosReg', (61, 69))	('EMT', 'CPA', (53, 56))	('promote', 'PosReg', (45, 52))	('YAP1', 'Gene', (15, 19))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
360205	24906622	SKGT-4 (PIN20YAP1) cells (1x106) without (DOX-) or with (DOX+) YAP1 induction and further knockdown YAP1 (shYAP1) or SOX9 (shSOX9) were inoculated into nude mice (n=5 per group).	('hYAP1', 'Gene', (107, 112))	('nude mice', 'Species', '10090', (152, 161))	('DOX', 'Chemical', 'MESH:D004318', (57, 60))	('N2', 'Chemical', 'MESH:D009584', (10, 12))	('YAP1', 'Gene', (100, 104))	('knockdown', 'Var', (90, 99))	('SKGT-4', 'CellLine', 'CVCL:2195', (0, 6))	('YAP1', 'Gene', (63, 67))	('hYAP1', 'Gene', '10413', (107, 112))	('DOX', 'Chemical', 'MESH:D004318', (42, 45))
360225	24906622	Furthermore, immunofluorescence demonstrates that induction of YAP1 increases SOX9 expression in both SKGT-4 and KATO-TN cells (Figure 2C).	('increases', 'PosReg', (68, 77))	('YAP1', 'Gene', (63, 67))	('expression', 'Species', '29278', (83, 93))	('induction', 'Var', (50, 59))	('expression', 'MPA', (83, 93))	('SOX9', 'Gene', (78, 82))	('SKGT-4', 'CellLine', 'CVCL:2195', (102, 108))
360227	24906622	To determine if SOX9 expression is regulated by Hippo signaling pathway and whether Hippo/YAP1 signaling functions to regulate SOX9 in multiple primary and immortalized cells from diverse lineages, we examined the effect of genetically inactivating Hippo pathway components in primary mouse embryo fibroblast (MEF) cells and in immortalized fetal liver cells (B299).	('expression', 'Species', '29278', (21, 31))	('MEF', 'Disease', (310, 313))	('mouse', 'Species', '10090', (285, 290))	('MEF', 'Disease', 'None', (310, 313))	('B299', 'CellLine', 'CVCL:D765', (360, 364))	('genetically inactivating', 'Var', (224, 248))
360228	24906622	Deletion of Lats1/2 in MEFs that contain conditional alleles of Lats1/2 with adenovirus-cre transduction resulted in the upregulation of SOX9 protein levels (Figure 2D).	('Lats1', 'Gene', '16798', (12, 17))	('MEFs', 'CellLine', 'CVCL:9115', (23, 27))	('upregulation', 'PosReg', (121, 133))	('SOX9 protein levels', 'MPA', (137, 156))	('Lats1', 'Gene', '16798', (64, 69))	('Lats1', 'Gene', (12, 17))	('Lats1', 'Gene', (64, 69))	('Deletion', 'Var', (0, 8))
360230	24906622	Furthermore, transfection of human embryonic kidney (HEK293T) cells with constitutively active mutant YAP1S127A cDNA or with wild-type YAP1 induced SOX9 expression in concert with YAP1 induction (Figure 2F).	('HEK293T', 'CellLine', 'CVCL:0063', (53, 60))	('human', 'Species', '9606', (29, 34))	('induced', 'PosReg', (140, 147))	('embryonic kidney', 'Disease', (35, 51))	('YAP1S127A', 'Gene', (102, 111))	('embryonic kidney', 'Disease', 'MESH:D007674', (35, 51))	('expression', 'Species', '29278', (153, 163))	('expression', 'MPA', (153, 163))	('mutant', 'Var', (95, 101))	('SOX9', 'Protein', (148, 152))
360232	24906622	Real-time quantitative PCR in these mice confirmed the up-regulation of SOX9 in tumors from hippo mutant mice (Sav1-/- or Mst1/2-/-) compared with that of wild-type mice (Supplemental Figure 2A).	('mice', 'Species', '10090', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('up-regulation', 'PosReg', (55, 68))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('hippo', 'Gene', (92, 97))	('Sav1', 'Gene', '64010', (111, 115))	('SOX9', 'Gene', (72, 76))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('mice', 'Species', '10090', (36, 40))	('mice', 'Species', '10090', (105, 109))	('Sav1', 'Gene', (111, 115))	('mutant', 'Var', (98, 104))
360233	24906622	Immunohistochemical staining for YAP1 and SOX9 reveals elevated levels of YAP1 and SOX9 proteins in tumor tissues of alb-cre;Mst1/2 mutant mice compared to normal liver tissues (Supplemental Figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('alb', 'Gene', (117, 120))	('tumor', 'Disease', (100, 105))	('mutant', 'Var', (132, 138))	('levels', 'MPA', (64, 70))	('alb', 'Gene', '11657', (117, 120))	('mice', 'Species', '10090', (139, 143))	('elevated', 'PosReg', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Mst1/2', 'Gene', (125, 131))
360234	24906622	These data demonstrates that SOX9 is up-regulated in vivo in mouse tumors with inactivating Hippo pathway mutations.	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('up-regulated', 'PosReg', (37, 49))	('mouse', 'Species', '10090', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('SOX9', 'Gene', (29, 33))	('mutations', 'Var', (106, 115))	('inactivating', 'Var', (79, 91))	('tumors', 'Disease', (67, 73))	('Hippo', 'Gene', (92, 97))
360235	24906622	Hence, SOX9 expression can be elevated in multiple cell types by overexpression of YAP1 in vitro or by activation of endogenous YAP1 protein that occurs following deletion of Hippo pathway signaling components.	('deletion', 'Var', (163, 171))	('expression', 'Species', '29278', (69, 79))	('SOX9', 'Gene', (7, 11))	('endogenous', 'MPA', (117, 127))	('YAP1', 'Gene', (83, 87))	('elevated', 'PosReg', (30, 38))	('expression', 'Species', '29278', (12, 22))	('overexpression', 'PosReg', (65, 79))	('YAP1 protein', 'Protein', (128, 140))	('expression', 'MPA', (12, 22))	('activation', 'PosReg', (103, 113))
360242	24906622	To determine if the TEAD binding site in the SOX9 promoter is crucial for induction of SOX9 by YAP1 and Tead2, a mutation of the TEAD binding site in the SOX9 promoter was generated using site-directed mutagenesis as depicted in Figure 3D (insert).	('Tead2', 'Gene', '8463', (104, 109))	('mutation', 'Var', (113, 121))	('Tead2', 'Gene', (104, 109))
360243	24906622	Induction of SOX9 transcriptional activity by YAP1 and Tead2 was greatly diminished when mutations of the TEAD binding site in the SOX9 promoter were introduced (Figure 3D).	('Tead2', 'Gene', (55, 60))	('transcriptional activity', 'MPA', (18, 42))	('mutations', 'Var', (89, 98))	('Tead2', 'Gene', '8463', (55, 60))	('diminished', 'NegReg', (73, 83))	('SOX9', 'Gene', (13, 17))
360245	24906622	These findings further confirm the specificity of the chromatin immunoprecipitation assay, and that the interaction between YAP1 and SOX9 promoter was further enhanced when YAP1S127A was induced (DOX+) in SKGT-4 cells.	('DOX', 'Chemical', 'MESH:D004318', (196, 199))	('YAP1', 'Gene', (124, 128))	('interaction', 'Interaction', (104, 115))	('enhanced', 'PosReg', (159, 167))	('SKGT-4', 'CellLine', 'CVCL:2195', (205, 211))	('YAP1S127A', 'Var', (173, 182))
360249	24906622	In contrast, primary Eso cells that expressed YAP1S127A (DOX+) have a mesenchymal morphology and do not show signs of replicative senescence in that they can be cultured for more than 20 passages without reduced proliferative capacity (Figure 4A, right panel).	('DOX', 'Chemical', 'MESH:D004318', (57, 60))	('YAP1S127A', 'Var', (46, 55))	('mesenchymal morphology', 'CPA', (70, 92))
360250	24906622	To determine whether YAP1 expression can confer stem cell like properties in normal mouse Eso cells, sphere assays on ultra-low attachment plates were performed in defined media (see materials and methods).	('YAP1', 'Gene', (21, 25))	('expression', 'Var', (26, 36))	('stem cell like properties', 'CPA', (48, 73))	('mouse', 'Species', '10090', (84, 89))	('expression', 'Species', '29278', (26, 36))
360251	24906622	In the absence of exogenous YAP1S127A (DOX-), Eso cells were unable to form spheres under these conditions, whereas YAP1S127A induced cells (DOX+) gain the capacity to form spheres (Figure 4B).	('YAP1S127A', 'Var', (116, 125))	('DOX', 'Chemical', 'MESH:D004318', (141, 144))	('gain', 'PosReg', (147, 151))	('DOX', 'Chemical', 'MESH:D004318', (39, 42))
360253	24906622	Similarly, induction of YAP1S127A in immortalized, non-transformed B299 cells (PIN20YAP1) endows B299 cells with the capacity to form spheres, while B299 cells do not form spheres without YAP1 induction (DOX-) (Figure 4C and Figure 4D).	('B299', 'CellLine', 'CVCL:D765', (97, 101))	('B299', 'CellLine', 'CVCL:D765', (149, 153))	('YAP1S127A', 'Gene', (24, 33))	('induction', 'Var', (11, 20))	('B299', 'CellLine', 'CVCL:D765', (67, 71))	('form spheres', 'CPA', (129, 141))	('DOX', 'Chemical', 'MESH:D004318', (204, 207))	('N2', 'Chemical', 'MESH:D009584', (81, 83))
360257	24906622	Immunoblotting confirmed that the expression of YAP1 and SOX9 were higher in the doxycycline induced B299 cells (DOX+) compared with that of non-inducible B299 cells (DOX-) (Figure 4F).	('higher', 'PosReg', (67, 73))	('expression', 'MPA', (34, 44))	('B299', 'CellLine', 'CVCL:D765', (101, 105))	('DOX', 'Chemical', 'MESH:D004318', (113, 116))	('DOX', 'Chemical', 'MESH:D004318', (167, 170))	('expression', 'Species', '29278', (34, 44))	('YAP1', 'Gene', (48, 52))	('doxycycline', 'Chemical', 'MESH:D004318', (81, 92))	('doxycycline', 'Var', (81, 92))	('SOX9', 'Gene', (57, 61))	('B299', 'CellLine', 'CVCL:D765', (155, 159))
360269	24906622	Conversely, knockdown of YAP1 in JHESO cells decreased the proportion of ALDH1+ cells and double (ALDH1+/CD44+) positive cells, reduced expression of ALDH1 and CD44 in concert with significant reduction of tumorsphere size and number (Figure 5F).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('expression', 'MPA', (136, 146))	('CD44', 'Gene', (160, 164))	('YAP1', 'Gene', (25, 29))	('reduction of tumorsphere', 'Disease', (193, 217))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('reduced', 'NegReg', (128, 135))	('knockdown', 'Var', (12, 21))	('decreased', 'NegReg', (45, 54))	('ALDH1+', 'Protein', (73, 79))	('expression', 'Species', '29278', (136, 146))	('ALDH1', 'Protein', (150, 155))	('reduction of tumorsphere', 'Disease', 'MESH:D015431', (193, 217))
360274	24906622	Similarly, VP completely blocked tumorsphere formation in B299 cells with induction of YAP1 S127A (Figure 6E).	('S127A', 'Mutation', 'rs762471803', (92, 97))	('B299', 'CellLine', 'CVCL:D765', (58, 62))	('S127A', 'Var', (92, 97))	('YAP1', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('VP', 'Chemical', 'MESH:D000077362', (11, 13))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('blocked', 'NegReg', (25, 32))	('tumors', 'Disease', (33, 39))
360285	24906622	In addition, expression of YAP1, SOX9 and Ki67 are increased in SKGT4 DOX+ tumor tissues compared to the tumors from SKGT4 DOX-, while knockdown of either YAP1 or SOX9 greatly reduced the expression of these markers in concert with inhibition of tumor growth (Figure 7F).	('tumors', 'Disease', (105, 111))	('DOX+', 'Var', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('DOX', 'Chemical', 'MESH:D004318', (70, 73))	('tumor', 'Disease', (75, 80))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('DOX', 'Chemical', 'MESH:D004318', (123, 126))	('expression', 'Species', '29278', (13, 23))	('expression', 'Species', '29278', (188, 198))	('Ki67', 'Gene', '17345', (42, 46))	('reduced', 'NegReg', (176, 183))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (105, 110))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (246, 251))	('SOX9', 'Gene', (33, 37))	('SKGT4 DOX+', 'Var', (64, 74))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('YAP1', 'Gene', (27, 31))	('expression', 'MPA', (188, 198))	('expression', 'MPA', (13, 23))	('knockdown', 'Var', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Ki67', 'Gene', (42, 46))
360289	24906622	Genetic and pharmacological inhibition of YAP1 greatly abolishes tumorsphere forming capacity in vitro and tumorigenicity in vivo induced by the YAP1-SOX9 axis.	('abolishes', 'NegReg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('YAP1', 'Gene', (42, 46))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('inhibition', 'Var', (28, 38))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
360290	24906622	The Hippo signaling pathway is gaining recognition as an important player in both organ size control and tumorigenesis, since the disruption of several important components (Mst1/2, Sav1 and Lats1/2 and YAP1) in this pathway can lead to tumorigenesis.	('tumor', 'Disease', (237, 242))	('lead to', 'Reg', (229, 236))	('Sav1', 'Gene', '64010', (182, 186))	('disruption', 'Var', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('Sav1', 'Gene', (182, 186))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('Mst1', 'Gene', (174, 178))	('Mst1', 'Gene', '15235', (174, 178))
360300	24906622	In this study we show that inactivation of Hippo signaling or activation of YAP1 results in elevated SOX9 expression in a wide variety of cellular contexts, including in the liver of albumin-cre; Mst1/2 mutant mice, in Lats1/2 deficient MEFs cells, in non-tumorigenic B299 cells depleted of Sav1 or by expressing YAP1 in EC cells.	('elevated', 'PosReg', (92, 100))	('SOX9', 'Gene', (101, 105))	('B299', 'CellLine', 'CVCL:D765', (268, 272))	('inactivation', 'Var', (27, 39))	('mice', 'Species', '10090', (210, 214))	('expression', 'MPA', (106, 116))	('MEFs', 'CellLine', 'CVCL:9115', (237, 241))	('tumor', 'Disease', (256, 261))	('Lats1', 'Gene', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('Lats1', 'Gene', '16798', (219, 224))	('alb', 'Gene', '11657', (183, 186))	('activation', 'PosReg', (62, 72))	('mutant', 'Var', (203, 209))	('Sav1', 'Gene', '64010', (291, 295))	('expression', 'Species', '29278', (106, 116))	('alb', 'Gene', (183, 186))	('Sav1', 'Gene', (291, 295))	('YAP1', 'Gene', (76, 80))	('Mst1/2', 'Gene', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))
360301	24906622	Mutation of the conserved TEAD binding site disrupts SOX9 induction by YAP and Tead2 further confirming the requirement of the TEAD binding site for SOX9 induction by YAP1.	('disrupts', 'NegReg', (44, 52))	('Tead2', 'Gene', (79, 84))	('YAP', 'Gene', '10413', (71, 74))	('Mutation', 'Var', (0, 8))	('YAP', 'Gene', (71, 74))	('YAP', 'Gene', '10413', (167, 170))	('Tead2', 'Gene', '8463', (79, 84))	('induction', 'MPA', (58, 67))	('SOX9', 'Gene', (53, 57))	('YAP', 'Gene', (167, 170))
360302	24906622	Both YAP1 and SOX9 expression have been shown to confer malignant and CSC properties onto non-transformed cells.	('YAP1', 'Gene', (5, 9))	('expression', 'Var', (19, 29))	('expression', 'Species', '29278', (19, 29))	('SOX9', 'Gene', (14, 18))
360306	24906622	While SOX9 expression has previously been linked to poor survival and metastatic status of EACs, and elevated YAP1 expression has been noted in EAC, our current findings provide a mechanistic link between these independent observations.	('elevated', 'PosReg', (101, 109))	('expression', 'Species', '29278', (11, 21))	('SOX9', 'Gene', (6, 10))	('YAP1', 'Gene', (110, 114))	('EAC', 'Gene', '1540', (91, 94))	('expression', 'Species', '29278', (115, 125))	('metastatic status', 'CPA', (70, 87))	('EAC', 'Gene', (91, 94))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('expression', 'MPA', (115, 125))	('EAC', 'Gene', '1540', (144, 147))	('expression', 'Var', (11, 21))	('EAC', 'Gene', (144, 147))	('EAC', 'Phenotype', 'HP:0011459', (91, 94))	('linked', 'Reg', (42, 48))
360333	23460817	While a panel of biomarkers, including 9pLOH, 17pLOH, tetraploidy, and aneuploidy provide a method for predicting BE patient progression to cancer (RR = 38.7; 95% CI 10.8-138.5, p<0.001), little is known about the state of energy metabolism in BE.	('cancer', 'Disease', (140, 146))	('aneuploidy', 'Disease', (71, 81))	('17pLOH', 'Var', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tetraploidy', 'Var', (54, 65))	('patient', 'Species', '9606', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('9pLOH', 'Var', (39, 44))	('aneuploidy', 'Disease', 'MESH:D000782', (71, 81))
360346	23460817	CP-A was derived from a patient with metaplastic BE at early-stages with wild-type TP53 and low levels of genetic instability, while CP-B, CP-C and CP-D were derived from patients with later-stage BE containing mutations and/or deletions in both copies of TP53 and high levels of genetic alterations (Text S1 and Table S1).	('TP53', 'Gene', '7157', (83, 87))	('CP-B', 'Gene', '1360', (133, 137))	('CP-B', 'Gene', (133, 137))	('CP-C and CP-D', 'Gene', '1362', (139, 152))	('patient', 'Species', '9606', (171, 178))	('TP53', 'Gene', (83, 87))	('CP-A', 'Gene', '1357', (0, 4))	('CP-A', 'Gene', (0, 4))	('TP53', 'Gene', (256, 260))	('mutations', 'Var', (211, 220))	('patient', 'Species', '9606', (24, 31))	('patients', 'Species', '9606', (171, 179))	('TP53', 'Gene', '7157', (256, 260))	('deletions', 'Var', (228, 237))
360352	23460817	We also investigated two cell lines derived from esophageal squamous epithelium as potential controls, but the EPC-2 cell line (from the Carlo Maley lab, UCSF) was aneuploid (data not shown) and HET-1A cell-line was transformed by SV40 T-antigen, making them unsuitable as 'normal' esophageal squamous controls (Text S1).	('HET-1A', 'CellLine', 'CVCL:3702', (195, 201))	('EPC-2', 'Gene', '26122', (111, 116))	('EPC-2', 'Gene', (111, 116))	('SV40', 'Var', (231, 235))
360383	23460817	Image data were acquired using a Nikon-Ti microscopy platform equipped with a Sutter Instruments Lambda LS 300 W xenon arc lamp, 360/BP40 excitation and 460/BP50 emission filters, and automated stage.	('360/BP40', 'Var', (129, 137))	('BP50', 'Gene', '474207', (157, 161))	('xenon', 'Chemical', 'MESH:D014978', (113, 118))	('BP50', 'Gene', (157, 161))
360398	23460817	OCR was higher in CP-B and CP-C than in CP-A (p<10-7 and p<0.001 respectively; Figure 1b and Table S2).	('p<10-7', 'Gene', '5933', (46, 52))	('OCR', 'Chemical', '-', (0, 3))	('CP-B', 'Gene', '1360', (18, 22))	('OCR', 'MPA', (0, 3))	('CP-B', 'Gene', (18, 22))	('CP-C', 'Var', (27, 31))	('CP-C', 'Chemical', 'MESH:C015101', (27, 31))	('CP-A', 'Gene', '1357', (40, 44))	('CP-A', 'Gene', (40, 44))	('higher', 'PosReg', (8, 14))	('p<10-7', 'Gene', (46, 52))
360417	23460817	In cells having uncoupled mitochondria or a lower ADP/ATP ratio, a lower OCR increase would result upon 2,4-DNP addition, since the mitochondria are already functioning near maximum respiratory capacity.	('ATP', 'Chemical', 'MESH:D000255', (54, 57))	('lower', 'Var', (44, 49))	('OCR increase', 'MPA', (73, 85))	('ADP/ATP', 'MPA', (50, 57))	('ADP', 'Chemical', 'MESH:D000244', (50, 53))	('2,4-DNP', 'Chemical', 'MESH:D019297', (104, 111))	('OCR', 'Chemical', '-', (73, 76))
360428	23460817	30 nuclear-encoded genes that regulate glycolysis, oxidative phosphorylation, acid transport and hypoxia resistance were surveyed for somatic alterations; notably a single-copy of hypoxia-inducible factor 1alpha (HIF-1alpha) was deleted in both CP-C and CP-D (Table S6 and Text S2).	('hypoxia', 'Disease', (97, 104))	('hypoxia', 'Disease', 'MESH:D000860', (97, 104))	('CP-C and CP-D', 'Gene', '1362', (245, 258))	('hypoxia', 'Disease', (180, 187))	('hypoxia', 'Disease', 'MESH:D000860', (180, 187))	('HIF-1alpha', 'Gene', '3091', (213, 223))	('hypoxia-inducible factor 1alpha', 'Gene', '3091', (180, 211))	('deleted', 'Var', (229, 236))	('HIF-1alpha', 'Gene', (213, 223))	('hypoxia-inducible factor 1alpha', 'Gene', (180, 211))
360429	23460817	CP-B and CP-C also had more single-copy deletions in nuclear-encoded mitochondrial genes than CP-A (Table S7).	('CP-C', 'Chemical', 'MESH:C015101', (9, 13))	('single-copy deletions', 'Var', (28, 49))	('CP-B', 'Gene', '1360', (0, 4))	('CP-B', 'Gene', (0, 4))	('nuclear-encoded mitochondrial genes', 'Gene', (53, 88))	('CP-A', 'Gene', '1357', (94, 98))	('CP-A', 'Gene', (94, 98))
360444	23460817	This was also confirmed in an independent experiment in which oligomycin-treated BE cells had similar percentage OCR decreases, which corresponds to a similar contribution of ATP-generating coupled-respiration to total cellular OCR (Table S4).	('OCR', 'Chemical', '-', (113, 116))	('OCR', 'MPA', (113, 116))	('decreases', 'NegReg', (117, 126))	('ATP', 'Chemical', 'MESH:D000255', (175, 178))	('oligomycin-treated', 'Var', (62, 80))	('oligomycin', 'Chemical', 'MESH:D009840', (62, 72))	('OCR', 'Chemical', '-', (228, 231))
360450	23460817	OE-33 also had the highest levels of OCR and was sensitive to oligomycin, indicating a glycolytic cell line with functional mitochondria.	('OCR', 'Chemical', '-', (37, 40))	('OCR', 'MPA', (37, 40))	('oligomycin', 'Chemical', 'MESH:D009840', (62, 72))	('OE-33', 'Var', (0, 5))	('levels', 'MPA', (27, 33))
360452	23460817	Both copies of TP53 are mutated and/or altered in CP-B, CP-C, and CP-D (Table S1), which may be of significance since loss of TP53 has been reported to upregulate glycolysis and downregulate mitochondrial activity to produce the Warburg effect in several cell lines.	('CP-C', 'Chemical', 'MESH:C015101', (56, 60))	('CP-D', 'Gene', '1362', (66, 70))	('glycolysis', 'MPA', (163, 173))	('TP53', 'Gene', (126, 130))	('upregulate', 'PosReg', (152, 162))	('mitochondrial activity', 'MPA', (191, 213))	('downregulate', 'NegReg', (178, 190))	('Warburg effect', 'Disease', (229, 243))	('TP53', 'Gene', '7157', (15, 19))	('loss', 'Var', (118, 122))	('CP-D', 'Gene', (66, 70))	('TP53', 'Gene', (15, 19))	('CP-B', 'Gene', '1360', (50, 54))	('CP-B', 'Gene', (50, 54))	('altered', 'Reg', (39, 46))	('TP53', 'Gene', '7157', (126, 130))
360456	23460817	Overexpression of HIF-1alpha has been reported in other cancers and may result from degradation-insensitive forms of this protein or increases in mTOR activity.	('cancers', 'Disease', (56, 63))	('mTOR', 'Gene', '2475', (146, 150))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('mTOR', 'Gene', (146, 150))	('reported', 'Reg', (38, 46))	('HIF-1alpha', 'Gene', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Overexpression', 'Var', (0, 14))	('increases', 'PosReg', (133, 142))	('HIF-1alpha', 'Gene', '3091', (18, 28))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
360460	23460817	Although CP-A had the fewest nuclear genome alterations (Figure S1), it displayed the most mitochondrial genome mutations of all the cell lines (Table S7).	('mutations', 'Var', (112, 121))	('CP-A', 'Gene', (9, 13))	('CP-A', 'Gene', '1357', (9, 13))	('mitochondrial', 'MPA', (91, 104))
360461	23460817	Most of the CP-A mutations were heteroplasmic which indicates that multiple different clones were present.	('CP-A', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('CP-A', 'Gene', '1357', (12, 16))
360677	30271878	Moreover, diversity was independent of B-cell abundance, suggesting that the presence of EBV was associated with an increased and altered B-cell population.	('EBV', 'Gene', (89, 92))	('presence', 'Var', (77, 85))	('B-cell population', 'CPA', (138, 155))	('EBV', 'Species', '10376', (89, 92))
360745	30271878	Using a generalized linear model and adjusting for tumor type, we found that the assigned memory phenotype probability was significantly higher (P  <= 4.1 x 10-7), while the naive, nonactivated, phenotype was significantly lower in the EBV+ samples (P  <= 1.1 x 10-12) (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('higher', 'PosReg', (137, 143))	('tumor', 'Disease', (51, 56))	('memory phenotype', 'CPA', (90, 106))	('EBV', 'Species', '10376', (236, 239))	('EBV+', 'Var', (236, 240))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
360750	30271878	Using linear regression, conditioning on the 13 tumor types with more than 10 EBV samples, we found that samples with EBV had (i) significantly increased total BCR counts (P <= 1.4 x 10-20) and (ii) higher BCR diversity (P <= 8.3 x 10-27).	('tumor', 'Disease', (48, 53))	('EBV', 'Var', (118, 121))	('BCR diversity', 'CPA', (206, 219))	('higher', 'PosReg', (199, 205))	('EBV', 'Species', '10376', (118, 121))	('BCR counts', 'CPA', (160, 170))	('EBV', 'Species', '10376', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('increased', 'PosReg', (144, 153))
360795	30271878	A simulated sample was comprised of 1,000 50-bp paired-end reads randomly chosen (with replacement) from the genomes of 5 different viruses: NC_002549.1 (Ebola), NC_001802.1 (HIV-1), NC_001475.2 (dengue virus 3), NC_007605.1 (EBV), and NC_001716.2 (herpesvirus 7).	('NC_001802.1', 'Var', (162, 173))	('herpesvirus', 'Species', '39059', (249, 260))	('Ebola', 'Species', '1570291', (154, 159))	('NC_001475.2', 'Var', (183, 194))	('dengue virus 3', 'Species', '11069', (196, 210))	('NC_002549.1', 'Var', (141, 152))	('NC_001716.2', 'Var', (236, 247))	('HIV-1', 'Species', '11676', (175, 180))	('EBV', 'Species', '10376', (226, 229))	('NC_007605.1', 'Var', (213, 224))
360887	29050228	We conducted whole-exome sequencing and whole-genome SNP genotyping for 4-6 tumor subregions and 5-6 adjacent normal tissue sites and 1-3 lymph node metastases in two esophageal MANECs to detect somatic mutations and copy number alterations, and to explore their spatial heterogeneity and underlying clonal structure.	('lymph node metastases', 'Disease', (138, 159))	('copy number alterations', 'Var', (217, 240))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutations', 'Var', (203, 212))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('lymph node metastases', 'Disease', 'MESH:D009362', (138, 159))
360888	29050228	TP53 mutation, RB1 deletion or LOH, and PIK3CA, PTEN, KRAS, SOX2, DVL3, TP63 amplification appeared in all regions in both tumors.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('PTEN', 'Gene', '5728', (48, 52))	('RB1', 'Gene', (15, 18))	('TP53', 'Gene', '7157', (0, 4))	('TP63', 'Gene', (72, 76))	('PIK3CA', 'Gene', '5290', (40, 46))	('RB1', 'Gene', '5925', (15, 18))	('TP63', 'Gene', '8626', (72, 76))	('DVL3', 'Gene', '1857', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('DVL3', 'Gene', (66, 70))	('KRAS', 'Gene', '3845', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('PTEN', 'Gene', (48, 52))	('tumors', 'Disease', (123, 129))	('TP53', 'Gene', (0, 4))	('PIK3CA', 'Gene', (40, 46))	('deletion', 'Var', (19, 27))	('SOX2', 'Gene', '6657', (60, 64))	('KRAS', 'Gene', (54, 58))	('SOX2', 'Gene', (60, 64))	('LOH', 'NegReg', (31, 34))	('mutation', 'Var', (5, 13))
360889	29050228	Mutations falling in known cancer genes tended to show higher variant allele frequencies than those not falling in these genes in at least one of the cases.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('falling', 'Phenotype', 'HP:0002527', (10, 17))	('variant allele frequencies', 'MPA', (62, 88))	('falling', 'Phenotype', 'HP:0002527', (104, 111))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('higher', 'PosReg', (55, 61))
360892	29050228	A phenotypically normal tissue site carried most of the mutations found in neighboring tumor samples, implying field cancerization.	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancer', 'Disease', (117, 123))
360903	29050228	Inactivation of TP53 and RB1, SOX2 amplification, and recurrent mutations in histone modifying genes are frequent in SCLC.	('RB1', 'Gene', '5925', (25, 28))	('histone modifying genes', 'Gene', (77, 100))	('TP53', 'Gene', (16, 20))	('SCLC', 'Gene', (117, 121))	('SCLC', 'Gene', '7864', (117, 121))	('SCLC', 'Phenotype', 'HP:0030357', (117, 121))	('TP53', 'Gene', '7157', (16, 20))	('mutations', 'Var', (64, 73))	('SOX2', 'Gene', '6657', (30, 34))	('RB1', 'Gene', (25, 28))	('SOX2', 'Gene', (30, 34))	('Inactivation', 'Var', (0, 12))
360923	29050228	C>T transition was the most frequent mutation subtype in both cancers (Supplementary Table 3F).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('C>T transition', 'Var', (0, 14))	('frequent', 'Reg', (28, 36))	('cancers', 'Disease', (62, 69))
360927	29050228	To interpret the potential functional impact of the somatic variants (SNVs and Indels) we annotated them to highlight those falling in multiple lists of cancer-related genes, compiled from four types of sources (see Methods): (I) 635 general cancer genes, representing the union of 125 cancer drivers by Vogelstein, 179 significantly mutated genes by Lawrence et al, and 300 tumor suppressor genes (q<0.18) and 250 oncogenes (q<0.22) by Davoli et al; (II) 76 ESCC-related genes from sequencing studies; (III) 187 SCLC-related genes from sequencing studies; and (IV) 267 genes from the COSMIC Cancer Gene Census and containing at least one mutation that is a missense, nonsense, frameshift or splicing site.	('Cancer', 'Phenotype', 'HP:0002664', (592, 598))	('SCLC', 'Phenotype', 'HP:0030357', (513, 517))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Cancer', 'Disease', (592, 598))	('cancer', 'Disease', (286, 292))	('SCLC', 'Gene', '7864', (513, 517))	('SCLC', 'Gene', (513, 517))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('tumor', 'Disease', (375, 380))	('Cancer', 'Disease', 'MESH:D009369', (592, 598))	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('falling', 'Phenotype', 'HP:0002527', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('missense', 'Var', (658, 666))	('cancer', 'Disease', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
360928	29050228	Among the genes showing nonsilent mutations (nonsynonymous, stop-gain, stop-loss or Indels) in M7, TP53 is in all four lists.	('stop-gain', 'Var', (60, 69))	('TP53', 'Gene', (99, 103))	('Indels', 'Var', (84, 90))	('stop-loss', 'Var', (71, 80))	('nonsynonymous', 'Var', (45, 58))	('TP53', 'Gene', '7157', (99, 103))
360930	29050228	CSMD3 is also frequently mutated in ESCC.	('CSMD3', 'Gene', '114788', (0, 5))	('CSMD3', 'Gene', (0, 5))	('mutated', 'Var', (25, 32))	('ESCC', 'Disease', (36, 40))
360937	29050228	Genes mutated in M7, M9, or either had a higher overlap rate (2.1 ~ 5.6 fold) with ESCC- and SCLC-related genes than with the general cancer genes (Supplementary Table 3G), suggesting shared mutational profiles among MANEC, ESCC, and SCLC.	('SCLC', 'Gene', '7864', (234, 238))	('SCLC', 'Phenotype', 'HP:0030357', (234, 238))	('SCLC', 'Gene', (234, 238))	('SCLC', 'Gene', '7864', (93, 97))	('SCLC', 'Phenotype', 'HP:0030357', (93, 97))	('SCLC', 'Gene', (93, 97))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutated', 'Var', (6, 13))
360938	29050228	Consistent with this expectation, we found that, in M9, mutations in the cancer-related genes tended to have higher VAF compared with those not falling in these genes (Figure 3B).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('mutations', 'Var', (56, 65))	('VAF', 'CPA', (116, 119))	('falling', 'Phenotype', 'HP:0002527', (144, 151))	('higher', 'PosReg', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
360943	29050228	RB1 deletion (M7) or LOH (M9) were detected in all tumor regions.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('RB1', 'Gene', '5925', (0, 3))	('LOH', 'Var', (21, 24))	('tumor', 'Disease', (51, 56))	('deletion', 'Var', (4, 12))	('RB1', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
360945	29050228	Approximately 31.5% (34/108) of mutations in M7 and 63.5% (127/200) of mutations in M9 are not uniformly observed across all tumor or LN samples (Figure 3C).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('mutations', 'Var', (71, 80))	('mutations', 'Var', (32, 41))
360949	29050228	Samples from the upper left side, T1-T3, did not carry mutations in ASCC3, CPVL, or CUX1.	('CPVL', 'Gene', '54504', (75, 79))	('mutations', 'Var', (55, 64))	('CUX1', 'Gene', '1523', (84, 88))	('ASCC3', 'Gene', (68, 73))	('CUX1', 'Gene', (84, 88))	('CPVL', 'Gene', (75, 79))	('ASCC3', 'Gene', '10973', (68, 73))
360950	29050228	Trunk mutations were those present in all the tumor/LN samples (N4, T1-T4, LN6 in M7, and T1-T6, LN8, LN10, LN11 in M9); branch mutations were those present in some of the tumor/LN samples; while private mutations were present in only one of the samples.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('T1-T6', 'Var', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
360952	29050228	In both samples, all three classes of mutations implicated cancer-related genes as described above and marked in Figs 3C-3D.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (59, 65))	('implicated', 'Reg', (48, 58))
360960	29050228	In all, the clonal history of the two MANECs revealed complex sequences of mutagenesis and migration, with continuous and often early seeding of tumor cells into the adjacent lymph nodes.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('mutagenesis', 'Var', (75, 86))	('migration', 'CPA', (91, 100))
360964	29050228	As the Agilent WES platform has ~32.3 Mb targeted coding regions, the discovered mutations correspond to an average density of 3.4-6.3 mutations/Mb, in the mid-range among other cancer types.	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (81, 90))
360968	29050228	Genomic alterations shared by both patients including TP53 mutations, deletion (M7) or LOH (M9) of RB1, amplification of PIK3CA, PTEN, KRAS, SOX2, DVL3, and TP63.	('DVL3', 'Gene', '1857', (147, 151))	('DVL3', 'Gene', (147, 151))	('PTEN', 'Gene', (129, 133))	('TP53', 'Gene', '7157', (54, 58))	('PIK3CA', 'Gene', (121, 127))	('LOH', 'Var', (87, 90))	('TP63', 'Gene', (157, 161))	('RB1', 'Gene', (99, 102))	('patients', 'Species', '9606', (35, 43))	('deletion', 'Var', (70, 78))	('KRAS', 'Gene', '3845', (135, 139))	('TP63', 'Gene', '8626', (157, 161))	('PTEN', 'Gene', '5728', (129, 133))	('mutations', 'Var', (59, 68))	('RB1', 'Gene', '5925', (99, 102))	('amplification', 'Var', (104, 117))	('SOX2', 'Gene', (141, 145))	('SOX2', 'Gene', '6657', (141, 145))	('KRAS', 'Gene', (135, 139))	('PIK3CA', 'Gene', '5290', (121, 127))	('TP53', 'Gene', (54, 58))
360970	29050228	Trunk mutations in M7 and M9 highlighted five and 13 cancer-related genes, respectively, with TP53 as the only one shared between the two (Figure 3C).	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (6, 15))
360974	29050228	It was frequently mutated in both ESCC and SCLC, and is the most notable difference between N4 and its neighboring tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutated', 'Var', (18, 25))	('tumor', 'Disease', (115, 120))	('SCLC', 'Gene', '7864', (43, 47))	('SCLC', 'Phenotype', 'HP:0030357', (43, 47))	('SCLC', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
360987	29050228	First, we designed our study with the explicit goal to compare spatially separated sectors of each tumor, and to rank the mutations by their range of spatial distribution.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('mutations', 'Var', (122, 131))
360991	29050228	Interestingly, known cancer genes tended to carry mutations of higher clonal frequencies (Figure 3B), suggesting their action during early stages of cancer evolution.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (149, 155))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
361010	29050228	; (II) 76 ESCC-related genes from four sequencing-based studies; (III) 187 SCLC-related genes from three sequencing studies and (IV) 616 genes from the COSMIC Cancer Gene Census (downloaded from http://cancer.sanger.ac.uk/census, 03/06/2017), then selecting the subset of 267 genes with at least one of the following four mutation types: missense, frameshift, nonsense, and splice site.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('frameshift', 'Var', (348, 358))	('missense', 'Var', (338, 346))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('nonsense', 'Var', (360, 368))	('cancer', 'Disease', (202, 208))	('Cancer', 'Disease', (159, 165))	('Cancer', 'Phenotype', 'HP:0002664', (159, 165))	('SCLC', 'Gene', '7864', (75, 79))	('SCLC', 'Phenotype', 'HP:0030357', (75, 79))	('SCLC', 'Gene', (75, 79))	('Cancer', 'Disease', 'MESH:D009369', (159, 165))
361020	27565418	The expression of microRNA 574-3p as a predictor of postoperative outcome in patients with esophageal squamous cell carcinoma Despite advances in radical esophagectomies and adjuvant therapy, the postoperative prognosis in esophageal squamous cell carcinoma (ESCC) patients remains poor.	('esophageal squamous cell carcinoma', 'Disease', (91, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (223, 257))	('esophageal squamous cell carcinoma', 'Disease', (223, 257))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (265, 273))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (91, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('microRNA', 'Var', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
361063	27565418	Comparisons between the average expression levels of miRNAs in the 19 ESCC tumors and those in the 19 corresponding normal tissues revealed that the expression of 10 miRNAs (miR-16, miR-93, miR-200c, miR-15b, miR-25-3p, miR-34a, miR-181a, miR-107, miR-103a, and miR-151a) were more than twofold higher, while that of another 10 miRNAs (miR-133b, miR-513, miR-1224, miR-30c, miR-1236, miR-378a, miR-550a, miR-675, miR-149, and miR-1973) were more than twofold lower in the tumors than in their normal counterparts with statistical difference (Fig.	('miR-16', 'Gene', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('miR-34a', 'Gene', (220, 227))	('miR-675', 'Gene', '100033819', (404, 411))	('miR-200c', 'Gene', (190, 198))	('miR-103a', 'Var', (248, 256))	('miR-149', 'Gene', (413, 420))	('miR-550a', 'Var', (394, 402))	('ESCC tumors', 'Disease', 'MESH:D004938', (70, 81))	('miR-151a', 'Gene', '442893', (262, 270))	('miR-34a', 'Gene', '407040', (220, 227))	('miR-30c', 'Gene', '407031', (365, 372))	('miR-1973', 'Gene', '100302290', (426, 434))	('miR-133b', 'Gene', (336, 344))	('miR-513', 'Var', (346, 353))	('miR-16', 'Gene', '51573', (174, 180))	('miR-93', 'Gene', (182, 188))	('miR-25', 'Gene', '407014', (209, 215))	('miR-1236', 'Gene', (374, 382))	('miR-1224', 'Gene', (355, 363))	('tumors', 'Phenotype', 'HP:0002664', (472, 478))	('expression', 'MPA', (32, 42))	('miR-151a', 'Gene', (262, 270))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('miR-149', 'Gene', '406941', (413, 420))	('miR-1236', 'Gene', '100302242', (374, 382))	('miR-93', 'Gene', '407051', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('ESCC tumors', 'Disease', (70, 81))	('expression', 'MPA', (149, 159))	('miR-378a', 'Gene', '494327', (384, 392))	('miR-107', 'Gene', (239, 246))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (472, 478))	('miR-675', 'Gene', (404, 411))	('miR-30c', 'Gene', (365, 372))	('lower', 'NegReg', (459, 464))	('tumors', 'Disease', (75, 81))	('miR-133b', 'Gene', '442890', (336, 344))	('miR-15b', 'Gene', '406949', (200, 207))	('miR-1224', 'Gene', '100187716', (355, 363))	('miR-107', 'Gene', '406901', (239, 246))	('miR-181a', 'Var', (229, 237))	('miR-15b', 'Gene', (200, 207))	('higher', 'PosReg', (295, 301))	('miR-200c', 'Gene', '406985', (190, 198))	('miR-25', 'Gene', (209, 215))	('miR-1973', 'Gene', (426, 434))	('miR-378a', 'Gene', (384, 392))	('tumors', 'Disease', 'MESH:D009369', (472, 478))
361077	27565418	Among these 20 miRNAs, 13 miRNAs, such as miR-16, miR-93, miR-200c, miR-25-3p, miR-34a, miR-181a, miR-107, miR-103a, miR-151a, miR-149, miR-550a, miR-378a, and miR-30c, have been associated with the malignant potential of esophageal cancer.	('miR-30c', 'Gene', '407031', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('miR-93', 'Gene', '407051', (50, 56))	('miR-149', 'Gene', (127, 134))	('miR-25', 'Gene', '407014', (68, 74))	('miR-151a', 'Gene', '442893', (117, 125))	('miR-107', 'Gene', (98, 105))	('miR-30c', 'Gene', (160, 167))	('miR-200c', 'Gene', '406985', (58, 66))	('miR-378a', 'Gene', '494327', (146, 154))	('associated', 'Reg', (179, 189))	('miR-16', 'Gene', (42, 48))	('miR-181a', 'Var', (88, 96))	('miR-550a', 'Var', (136, 144))	('miR-149', 'Gene', '406941', (127, 134))	('miR-107', 'Gene', '406901', (98, 105))	('miR-200c', 'Gene', (58, 66))	('miR-151a', 'Gene', (117, 125))	('miR-93', 'Gene', (50, 56))	('miR-378a', 'Gene', (146, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (222, 239))	('miR-34a', 'Gene', (79, 86))	('miR-16', 'Gene', '51573', (42, 48))	('miR-103a', 'Var', (107, 115))	('miR-25', 'Gene', (68, 74))	('esophageal cancer', 'Disease', (222, 239))	('miR-34a', 'Gene', '407040', (79, 86))
361078	27565418	In addition, the other seven miRNAs, such as miR-15b-5p, miR-1973, miR-675-3p, miR-1236-3p, miR-1224-3p, miR-513a-5p, and miR-133b, have been associated with the malignant potential of other types of cancer.	('miR-15b', 'Gene', (45, 52))	('miR-1236', 'Gene', '100302242', (79, 87))	('miR-1973', 'Gene', (57, 65))	('miR-133b', 'Gene', (122, 130))	('miR-675-3p', 'Gene', (67, 77))	('miR-675-3p', 'Gene', '102465451', (67, 77))	('miR-1973', 'Gene', '100302290', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('miR-1224', 'Gene', '100187716', (92, 100))	('miR-15b', 'Gene', '406949', (45, 52))	('miR-1236', 'Gene', (79, 87))	('malignant potential', 'CPA', (162, 181))	('miR-513a-5p', 'Var', (105, 116))	('associated', 'Reg', (142, 152))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('miR-1224', 'Gene', (92, 100))	('cancer', 'Disease', (200, 206))	('miR-133b', 'Gene', '442890', (122, 130))
361087	27565418	In bladder cancer cells, miR-574-3p has been reported to target mesoderm development candidate 1 (MESDC1) miRNA, subsequently inhibiting cell proliferation, migration and invasion ability, and induced cell apoptosis.	('mesoderm development candidate 1', 'Gene', (64, 96))	('miR-574-3p', 'Gene', '693159', (25, 35))	('inhibiting', 'NegReg', (126, 136))	('induced', 'Reg', (193, 200))	('cell proliferation', 'CPA', (137, 155))	('invasion ability', 'CPA', (171, 187))	('MESDC1', 'Gene', (98, 104))	('MESDC1', 'Gene', '59274', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('mesoderm development candidate 1', 'Gene', '59274', (64, 96))	('migration', 'CPA', (157, 166))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('miRNA', 'Var', (106, 111))	('miR-574-3p', 'Gene', (25, 35))	('cell apoptosis', 'CPA', (201, 215))
361091	27565418	Overexpression of EGFR was also associated with aggressive biological behaviors in ESCC.	('EGFR', 'Gene', '1956', (18, 22))	('aggressive biological behaviors', 'CPA', (48, 79))	('EGFR', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('associated with', 'Reg', (32, 47))	('ESCC', 'Disease', (83, 87))
361151	27090811	In this patient, the decrease of white blood cell occurred due to the administration of PPI after the initial surgery and on the 24-h pH and bilirubin monitoring.	('PPI', 'Var', (88, 91))	('decrease', 'NegReg', (21, 29))	('bilirubin', 'Chemical', 'MESH:D001663', (141, 150))	('white blood cell', 'MPA', (33, 49))	('patient', 'Species', '9606', (8, 15))
361182	26121676	Median overall survival of patients who received nCRT plus surgery was 49 months, compared to 24 months for those who received surgery alone, and the 3-year overall survival was superior in the nCRT arm (hazard ratio (HR) = 0.66; 95% confidence interval (CI) 0.50-0.87; P=.003).	('superior', 'PosReg', (178, 186))	('nCRT', 'Var', (194, 198))	('patients', 'Species', '9606', (27, 35))
361183	26121676	Therefore, nCRT plus surgery is now considered the therapy of choice in the Netherlands and several other countries for potentially curable esophageal cancer (cT2-3N0-3M0 and cT1N1-3M0, according to the UICC TNM classification).	('TNM', 'Gene', (208, 211))	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cT1N1-3M0', 'Var', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('TNM', 'Gene', '10178', (208, 211))	('esophageal cancer', 'Disease', (140, 157))	('cT2-3N0-3M0', 'Var', (159, 170))
361300	25873500	In other words, regression was called if the patient's follow-up biopsy specimens demonstrated a lower degree of dysplasia in the sequence of HGD, low-grade dysplasia (LGD), indefinite for dysplasia (IFD), negative for dysplasia (NFD), and no IM.	('dysplasia', 'Disease', 'MESH:D004476', (219, 228))	('dysplasia', 'Disease', 'MESH:D004476', (189, 198))	('patient', 'Species', '9606', (45, 52))	('dysplasia', 'Disease', (157, 166))	('dysplasia', 'Disease', (113, 122))	('indefinite', 'Var', (174, 184))	('dysplasia', 'Disease', 'MESH:D004476', (157, 166))	('dysplasia', 'Disease', 'MESH:D004476', (113, 122))	('dysplasia', 'Disease', (219, 228))	('dysplasia', 'Disease', (189, 198))	('HGD', 'Disease', (142, 145))
361309	25873500	In the 299 cases with complete clinical data, PCM was more frequently found in patients with long-segment BE (42/115 [37%]) than in patients with short-segment BE (44/184 [24%], P = .0253).	('PCM', 'Chemical', '-', (46, 49))	('long-segment', 'Var', (93, 105))	('BE', 'Phenotype', 'HP:0100580', (160, 162))	('patients', 'Species', '9606', (79, 87))	('BE', 'Phenotype', 'HP:0100580', (106, 108))	('PCM', 'Disease', (46, 49))	('patients', 'Species', '9606', (132, 140))
361326	25873500	In addition, in our cohort, regardless of PCM or not, those patients with short-segment BE were four times more likely to regress than those with long-segment BE (Table 3).	('BE', 'Phenotype', 'HP:0100580', (159, 161))	('short-segment BE', 'Var', (74, 90))	('patients', 'Species', '9606', (60, 68))	('regress', 'CPA', (122, 129))	('BE', 'Phenotype', 'HP:0100580', (88, 90))	('PCM', 'Chemical', '-', (42, 45))
361330	25873500	Dysfunction of Paneth cells leads to disruption of the intestinal mucosal barrier, dysbiosis, and impaired regeneration, which contribute to the pathogenesis of intestinal inflammatory and infectious diseases, such as ileal Crohn disease and neonatal necrotizing enteritis.	('regeneration', 'CPA', (107, 119))	('neonatal necrotizing enteritis', 'Disease', (242, 272))	('Dysfunction', 'Var', (0, 11))	('neonatal necrotizing enteritis', 'Disease', 'MESH:D004751', (242, 272))	('infectious diseases', 'Disease', 'MESH:D003141', (189, 208))	('dysbiosis', 'Disease', (83, 92))	('dysbiosis', 'Disease', 'MESH:D064806', (83, 92))	('ileal Crohn disease', 'Disease', (218, 237))	('Crohn disease', 'Phenotype', 'HP:0100280', (224, 237))	('impaired', 'NegReg', (98, 106))	('ileal Crohn disease', 'Disease', 'MESH:D003424', (218, 237))	('infectious diseases', 'Disease', (189, 208))
361386	25066711	Although little is known about genetic predisposing factors associated with GBC, a few studies have reported mutations in KRAS, TP53, p16/CDKN2A, microsatellite instability, overexpression of COX2, VEGF, hTERT and ERBB2 in GBC.	('TP53', 'Gene', '7157', (128, 132))	('KRAS', 'Gene', '3845', (122, 126))	('CDKN2A', 'Gene', (138, 144))	('ERBB2', 'Gene', (214, 219))	('hTERT', 'Gene', '7015', (204, 209))	('KRAS', 'Gene', (122, 126))	('ERBB2', 'Gene', '2064', (214, 219))	('CDKN2A', 'Gene', '1029', (138, 144))	('TP53', 'Gene', (128, 132))	('COX2', 'Gene', (192, 196))	('hTERT', 'Gene', (204, 209))	('mutations', 'Var', (109, 118))	('VEGF', 'Gene', '7422', (198, 202))	('microsatellite instability', 'MPA', (146, 172))	('p16', 'Gene', (134, 137))	('COX2', 'Gene', '4513', (192, 196))	('VEGF', 'Gene', (198, 202))	('overexpression', 'PosReg', (174, 188))	('p16', 'Gene', '1029', (134, 137))
361391	25066711	The evolution of chronic gallbladder inflammation, or cholecystitis, into displasia, carcinoma in situ and progression to invasive carcinoma, tracks at the molecular level, with tumor suppressor gene silencing by DNA methylation, together with global and gene-specific loss of methylation.	('gallbladder inflammation', 'Phenotype', 'HP:0001082', (25, 49))	('gallbladder inflammation', 'Disease', 'MESH:D002764', (25, 49))	('cholecystitis', 'Disease', 'MESH:D002764', (54, 67))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (85, 102))	('tumor', 'Disease', (178, 183))	('carcinoma in situ', 'Disease', 'MESH:D002278', (85, 102))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('invasive carcinoma', 'Disease', (122, 140))	('displasia', 'Disease', 'None', (74, 83))	('silencing', 'NegReg', (200, 209))	('cholecystitis', 'Phenotype', 'HP:0001082', (54, 67))	('methylation', 'Var', (217, 228))	('invasive carcinoma', 'Disease', 'MESH:D009361', (122, 140))	('gallbladder inflammation', 'Disease', (25, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('DNA methylation', 'Var', (213, 228))	('displasia', 'Disease', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cholecystitis', 'Disease', (54, 67))	('carcinoma in situ', 'Disease', (85, 102))
361422	25066711	APC was methylated in six out of 19 (32%) of GBC samples and in one in seven (14%) of chronic cholecystitis samples.	('cholecystitis', 'Phenotype', 'HP:0001082', (94, 107))	('cholecystitis', 'Disease', (94, 107))	('GBC', 'Disease', (45, 48))	('APC', 'Gene', (0, 3))	('cholecystitis', 'Disease', 'MESH:D002764', (94, 107))	('APC', 'Gene', '324', (0, 3))	('methylated', 'Var', (8, 18))
361423	25066711	CDKN2A was methylated in five in 19 (26%) of GBC samples and in one of seven (14%) of chronic cholecystitis samples.	('cholecystitis', 'Phenotype', 'HP:0001082', (94, 107))	('cholecystitis', 'Disease', (94, 107))	('GBC', 'Disease', (45, 48))	('methylated', 'Var', (11, 21))	('cholecystitis', 'Disease', 'MESH:D002764', (94, 107))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))
361424	25066711	ESR1 was methylated in eight of 19 (42%) GBC samples and in zero out of seven (0%) of chronic cholecystitis samples.	('cholecystitis', 'Phenotype', 'HP:0001082', (94, 107))	('ESR1', 'Gene', (0, 4))	('cholecystitis', 'Disease', (94, 107))	('cholecystitis', 'Disease', 'MESH:D002764', (94, 107))	('ESR1', 'Gene', '2099', (0, 4))	('methylated', 'Var', (9, 19))	('GBC', 'Disease', (41, 44))
361425	25066711	MCAM was methylated in seven of 19 (37%) of GBC samples and in one out of seven (14%) of chronic cholecystitis samples.	('cholecystitis', 'Phenotype', 'HP:0001082', (97, 110))	('cholecystitis', 'Disease', 'MESH:D002764', (97, 110))	('GBC', 'Disease', (44, 47))	('methylated', 'Var', (9, 19))	('MCAM', 'Gene', (0, 4))	('MCAM', 'Gene', '4162', (0, 4))	('cholecystitis', 'Disease', (97, 110))
361426	25066711	MGMT was methylated in two out of seven (29%) of GBC samples and in one out of seven (14%) chronic cholecystitis samples.	('MGMT', 'Gene', (0, 4))	('GBC', 'Disease', (49, 52))	('cholecystitis', 'Disease', (99, 112))	('cholecystitis', 'Phenotype', 'HP:0001082', (99, 112))	('methylated', 'Var', (9, 19))	('cholecystitis', 'Disease', 'MESH:D002764', (99, 112))	('MGMT', 'Gene', '4255', (0, 4))
361427	25066711	PGP9.5 was methylated in four of of 19 (21%) GBC samples and in one of seven (14%) chronic cholecystitis samples.	('PGP9.5', 'Gene', '7345', (0, 6))	('GBC', 'Disease', (45, 48))	('cholecystitis', 'Phenotype', 'HP:0001082', (91, 104))	('methylated', 'Var', (11, 21))	('cholecystitis', 'Disease', (91, 104))	('PGP9.5', 'Gene', (0, 6))	('cholecystitis', 'Disease', 'MESH:D002764', (91, 104))
361428	25066711	RARbeta was methylated in seven out of 19 (37%) GBC samples and in two out of seven (29%) chronic cholecystitis samples.	('RARbeta', 'Gene', '5915', (0, 7))	('GBC', 'Disease', (48, 51))	('cholecystitis', 'Disease', (98, 111))	('RARbeta', 'Gene', (0, 7))	('cholecystitis', 'Phenotype', 'HP:0001082', (98, 111))	('cholecystitis', 'Disease', 'MESH:D002764', (98, 111))	('methylated', 'Var', (12, 22))
361429	25066711	SBPP2 was methylated in ten of 19 (53%) of GBC samples and in zero out of seven (0%) of chronic cholecystitis samples.	('cholecystitis', 'Disease', 'MESH:D002764', (96, 109))	('SBPP2', 'Gene', (0, 5))	('methylated', 'Var', (10, 20))	('GBC', 'Disease', (43, 46))	('cholecystitis', 'Disease', (96, 109))	('cholecystitis', 'Phenotype', 'HP:0001082', (96, 109))
361442	25066711	Promoter methylation in CpG islands of tumor suppressor genes has been demonstrated as a hallmark in cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Promoter methylation', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (39, 44))
361452	25066711	Our study was designed to identify a panel of epigenetic biomarkers that could discriminate between GBC and chronic cholecystitis, akin to a Phase I biomarker development trial.	('GBC', 'Disease', (100, 103))	('cholecystitis', 'Disease', (116, 129))	('cholecystitis', 'Phenotype', 'HP:0001082', (116, 129))	('epigenetic', 'Var', (46, 56))	('men', 'Species', '9606', (166, 169))	('cholecystitis', 'Disease', 'MESH:D002764', (116, 129))
361459	25066711	SSBP2 promoter methylation is associated with gene silencing in prostate cancer and esophageal carcinomas.	('methylation', 'Var', (15, 26))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (84, 105))	('SSBP2', 'Gene', '23635', (0, 5))	('gene', 'MPA', (46, 50))	('prostate cancer', 'Disease', (64, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('esophageal carcinomas', 'Disease', (84, 105))	('prostate cancer', 'Disease', 'MESH:D011471', (64, 79))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (84, 105))	('SSBP2', 'Gene', (0, 5))	('prostate cancer', 'Phenotype', 'HP:0012125', (64, 79))
361460	25066711	In prostate cancer, aberrant methylation was not detected in normal tissue, whereas 61.4% of the neoplastic samples showed the epigenetic alteration.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('epigenetic alteration', 'Var', (127, 148))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
361461	25066711	Methylation of this gene was reported to be present in 86% of esophageal cancer samples.	('Methylation', 'Var', (0, 11))	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('present', 'Reg', (44, 51))
361464	25066711	We observed a significant difference on SSBP2 DNA methylation frequency when comparing GBC and noncancer samples.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('SSBP2', 'Gene', '23635', (40, 45))	('GBC', 'Disease', (87, 90))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('SSBP2', 'Gene', (40, 45))	('methylation', 'Var', (50, 61))
361465	25066711	SSBP2 aberrant methylation in GBC, as well in other tumor types, might result in gene silencing which will impact in DNA replication and repair and genome stability.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('methylation', 'Var', (15, 26))	('genome stability', 'CPA', (148, 164))	('SSBP2', 'Gene', '23635', (0, 5))	('repair', 'CPA', (137, 143))	('tumor', 'Disease', (52, 57))	('SSBP2', 'Gene', (0, 5))	('gene', 'MPA', (81, 85))	('aberrant methylation', 'Var', (6, 26))	('impact', 'Reg', (107, 113))	('DNA replication', 'MPA', (117, 132))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('result', 'Reg', (71, 77))
361471	25066711	Promoter methylation of MCAM has been associated with advanced tumor stage in prostate cancer.	('tumor', 'Disease', (63, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (78, 93))	('associated with', 'Reg', (38, 53))	('prostate cancer', 'Disease', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Promoter methylation', 'Var', (0, 20))	('MCAM', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('MCAM', 'Gene', '4162', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (78, 93))
361479	25066711	Genetic alterations in ESR1 gene seem to have different impacts in the risk for GBC.	('Genetic alterations', 'Var', (0, 19))	('ESR1', 'Gene', '2099', (23, 27))	('GBC', 'Disease', (80, 83))	('ESR1', 'Gene', (23, 27))	('impacts', 'Reg', (56, 63))
361480	25066711	A susceptibility risk polymorphism on ESR1, rs1801132, is associated with higher risk to bile duct and ampulla of Vater cancers but not GBC.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs1801132', 'Mutation', 'rs1801132', (44, 53))	('ESR1', 'Gene', (38, 42))	('ampulla of Vater cancers', 'Disease', (103, 127))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('ESR1', 'Gene', '2099', (38, 42))	('ampulla of Vater cancers', 'Disease', 'MESH:C536534', (103, 127))	('rs1801132', 'Var', (44, 53))
361481	25066711	However, presence of the homozygous variant genotype for the marker rs2234693 (ESR1-397TT) is associated with significant higher risk to GBC (odds ratio: 1.8).	('rs2234693', 'Var', (68, 77))	('rs2234693', 'Mutation', 'rs2234693', (68, 77))	('ESR1', 'Gene', (79, 83))	('GBC', 'Disease', (137, 140))	('ESR1', 'Gene', '2099', (79, 83))
361482	25066711	Promoter methylation of ESR1 in association with gene silencing has been observed in other tumor types such as breast cancer, rectal cancer and cervical cancer.	('rectal cancer', 'Disease', 'MESH:D012004', (126, 139))	('ESR1', 'Gene', (24, 28))	('cervical cancer', 'Disease', 'MESH:D002583', (144, 159))	('rectal cancer', 'Disease', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cervical cancer', 'Disease', (144, 159))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Promoter methylation', 'Var', (0, 20))	('rectal cancer', 'Phenotype', 'HP:0100743', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('breast cancer', 'Disease', (111, 124))	('ESR1', 'Gene', '2099', (24, 28))	('tumor', 'Disease', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('gene', 'MPA', (49, 53))
361485	25066711	ESR1 hypermethylation followed by transcriptional blockade may result in downregulation of cell cycle and growth regulators, once this gene is known to have a role in transcription regulation by the recruitment of proteins of the transcriptional protein complex.	('growth', 'CPA', (106, 112))	('ESR1', 'Gene', (0, 4))	('recruitment', 'PosReg', (199, 210))	('hypermethylation', 'Var', (5, 21))	('ESR1', 'Gene', '2099', (0, 4))	('downregulation', 'NegReg', (73, 87))	('cell cycle', 'CPA', (91, 101))	('men', 'Species', '9606', (206, 209))
361486	25066711	Our cell line data supports the mechanistic link between promoter metylation and down-regulation of ESR1 in GBC.	('promoter metylation', 'Var', (57, 76))	('GBC', 'Disease', (108, 111))	('ESR1', 'Gene', (100, 104))	('down-regulation', 'NegReg', (81, 96))	('ESR1', 'Gene', '2099', (100, 104))
361487	25066711	Two of the three cell lines we tested, GBD1 and G415, have evidence of ESR1 promoter methylation and expression downregulation.	('methylation', 'Var', (85, 96))	('GBD1', 'Gene', (39, 43))	('downregulation', 'NegReg', (112, 126))	('ESR1', 'Gene', (71, 75))	('promoter', 'MPA', (76, 84))	('ESR1', 'Gene', '2099', (71, 75))	('expression', 'MPA', (101, 111))	('GBD1', 'Gene', '5244', (39, 43))
361488	25066711	Conversely, ESR1 downregulation in SNU308 does not seem to be under methylation control (Supplementary Figures 1C & D).	('ESR1', 'Gene', '2099', (12, 16))	('SNU308', 'Chemical', '-', (35, 41))	('SNU308', 'Var', (35, 41))	('downregulation', 'NegReg', (17, 31))	('men', 'Species', '9606', (95, 98))	('ESR1', 'Gene', (12, 16))
361490	25066711	Promoter methylation of APC and its role in tumorigenesis has been reported in rectal, esophageal, breast and cervical cancers.	('APC', 'Gene', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('rectal', 'Disease', (79, 85))	('breast and cervical cancers', 'Disease', 'MESH:D001943', (99, 126))	('Promoter methylation', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('esophageal', 'Disease', (87, 97))	('APC', 'Gene', '324', (24, 27))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
361492	25066711	Besides APC gene mutation, inactivation of APC by aberrant promoter methylation results in increased beta-catenin levels, which subsequently triggers tumor formation, through Wnt signaling.	('triggers', 'Reg', (141, 149))	('inactivation', 'Var', (27, 39))	('APC', 'Gene', '324', (43, 46))	('beta-catenin', 'Gene', '1499', (101, 113))	('beta-catenin', 'Gene', (101, 113))	('mutation', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('APC', 'Gene', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('increased', 'PosReg', (91, 100))	('aberrant', 'Var', (50, 58))	('tumor', 'Disease', (150, 155))	('APC', 'Gene', (43, 46))	('APC', 'Gene', '324', (8, 11))
361493	25066711	The relevance of APC hypermethylation in the development of GBC might be associated with the dysregulation of the Wnt pathway, showing the necessity of follow-up investigations on this important pathway.	('dysregulation', 'MPA', (93, 106))	('hypermethylation', 'Var', (21, 37))	('APC', 'Gene', (17, 20))	('men', 'Species', '9606', (52, 55))	('APC', 'Gene', '324', (17, 20))	('associated', 'Reg', (73, 83))	('GBC', 'Disease', (60, 63))	('Wnt pathway', 'Pathway', (114, 125))
361494	25066711	Silencing of CDKN2A by promoter methylation is frequently observed in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (70, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Silencing', 'NegReg', (0, 9))	('CDKN2A', 'Gene', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('promoter methylation', 'Var', (23, 43))	('solid tumors', 'Disease', (70, 82))	('CDKN2A', 'Gene', '1029', (13, 19))
361496	25066711	p16 protein binds to CDK4/6 inhibiting their ligation to cyclin D. In GBC, CDKN2A methylation has been described in multiple studies with varied frequencies, (14.5-80%) but there is no reported association with prognosis or clinicopathologic variables.	('described', 'Reg', (103, 112))	('methylation', 'Var', (82, 93))	('CDKN2A', 'Gene', (75, 81))	('GBC', 'Disease', (70, 73))	('p16', 'Gene', (0, 3))	('CDK4/6', 'Gene', '1019;1021', (21, 27))	('CDKN2A', 'Gene', '1029', (75, 81))	('CDK4/6', 'Gene', (21, 27))	('p16', 'Gene', '1029', (0, 3))
361497	25066711	Besides the fact that CDKN2A methylation showed no association with GBC, this gene is an important cell cycle regulator and further analysis on the epigenetic and genetic alterations in these tumors is critical for the comprehension of their biology.	('methylation', 'Var', (29, 40))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('CDKN2A', 'Gene', (22, 28))	('CDKN2A', 'Gene', '1029', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('GBC', 'Disease', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
361499	25066711	The aberrant methylation of this gene is known to be associated with response to alkylating chemotherapeutic agents in glioblastomas.	('methylation', 'MPA', (13, 24))	('glioblastomas', 'Phenotype', 'HP:0012174', (119, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('aberrant', 'Var', (4, 12))	('glioblastomas', 'Disease', 'MESH:D005909', (119, 132))	('associated', 'Reg', (53, 63))	('glioblastomas', 'Disease', (119, 132))
361500	25066711	reported MGMT methylation in 13% of GBC cases evaluated.	('methylation', 'Var', (14, 25))	('MGMT', 'Gene', '4255', (9, 13))	('MGMT', 'Gene', (9, 13))	('GBC', 'Disease', (36, 39))
361501	25066711	Here, maybe due to the fact that we used a more sensitive method for methylation detection, we found that 30% of GBC samples present methylation in this gene promoter, while the frequency in noncancer patients was 14%.	('patients', 'Species', '9606', (201, 209))	('cancer', 'Disease', (194, 200))	('methylation', 'Var', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('GBC', 'Disease', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
361502	25066711	MGMT DNA methylation, as well as in glioblastoma, seems to be associated to therapeutic response with alkylating agents.	('MGMT', 'Gene', (0, 4))	('methylation', 'Var', (9, 20))	('glioblastoma', 'Disease', 'MESH:D005909', (36, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('associated', 'Reg', (62, 72))	('glioblastoma', 'Disease', (36, 48))	('MGMT', 'Gene', '4255', (0, 4))
361504	25066711	Aberrant methylation of MGMT might be a useful tool to determine the better treatment modality to be applied in each GBC patient.	('MGMT', 'Gene', '4255', (24, 28))	('men', 'Species', '9606', (81, 84))	('Aberrant methylation', 'Var', (0, 20))	('patient', 'Species', '9606', (121, 128))	('MGMT', 'Gene', (24, 28))
361506	25066711	RARbeta is a tumor suppressor gene and loss of this gene plays an important role in tumorigenesis.	('tumor', 'Disease', (13, 18))	('RARbeta', 'Gene', '5915', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('RARbeta', 'Gene', (0, 7))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('loss', 'Var', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
361510	25066711	Methylation of RARbeta promoter region was observed in a significant proportion of cancer-free high-fat consumers.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('RARbeta', 'Gene', (15, 22))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('observed', 'Reg', (43, 51))	('RARbeta', 'Gene', '5915', (15, 22))	('cancer', 'Disease', (83, 89))
361512	25066711	This evidence indicates that presence of RARbeta promoter methylation may be associated with obesity in GBC patients.	('obesity', 'Disease', (93, 100))	('RARbeta', 'Gene', '5915', (41, 48))	('presence', 'Var', (29, 37))	('obesity', 'Phenotype', 'HP:0001513', (93, 100))	('RARbeta', 'Gene', (41, 48))	('patients', 'Species', '9606', (108, 116))	('obesity', 'Disease', 'MESH:D009765', (93, 100))	('associated', 'Reg', (77, 87))
361516	25066711	In a previous study, PGP9.5 methylation was detected in 84.6% of normal gall bladder epithelia and in only 27.2% of the GBC samples.	('PGP9.5', 'Gene', '7345', (21, 27))	('gall bladder epithelia', 'Disease', 'MESH:D005705', (72, 94))	('PGP9.5', 'Gene', (21, 27))	('detected', 'Reg', (44, 52))	('methylation', 'Var', (28, 39))	('gall bladder epithelia', 'Disease', (72, 94))
361532	25066711	A variety of genetic alterations (mutations, microsatellite instability and aberrant expression) are present in GBC and are associated with bad prognosis for patients harboring these changes.	('expression', 'MPA', (85, 95))	('microsatellite', 'MPA', (45, 59))	('aberrant', 'Var', (76, 84))	('GBC', 'Disease', (112, 115))	('patients', 'Species', '9606', (158, 166))	('mutations', 'Var', (34, 43))
361535	25066711	A panel of genetic and epigenetic changes would be even more relevant if proven to be detected in bodily fluids (bile, serum, plasma or urine) from GBC patients.	('GBC', 'Disease', (148, 151))	('epigenetic', 'Var', (23, 33))	('patients', 'Species', '9606', (152, 160))
361544	25066711	Further molecular studies involving larger cohorts that examine combined somatic mutations and epigenomic alterations in crucial genes in the GBC tumorigenesis process are essential to enable the clinical application of these markers in liquid biopsies, as they become part of routine clinical follow-up in the future.	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('epigenomic alterations', 'Var', (95, 117))
361590	25375190	In the research article entitled "DADS Suppresses Human Esophageal Xenograft Tumors through RAF/MEK/ERK and Mitochondria-Dependent Pathways" contributed by Dr. Hongbing Ma and his colleagues, the authors reported that the DADS suppresses esophageal tumors without any apparent signs of toxicity, which is in agreement with a strong increase of apoptosis both in vitro and in vivo.	('Human', 'Species', '9606', (50, 55))	('esophageal tumors', 'Phenotype', 'HP:0100751', (238, 255))	('Esophageal Xenograft Tumors', 'Disease', 'MESH:D004938', (56, 83))	('Esophageal Xenograft Tumors', 'Disease', (56, 83))	('toxicity', 'Disease', 'MESH:D064420', (286, 294))	('DADS', 'Chemical', 'MESH:C028009', (222, 226))	('Tumors', 'Phenotype', 'HP:0002664', (77, 83))	('toxicity', 'Disease', (286, 294))	('DADS', 'Var', (222, 226))	('esophageal tumors', 'Disease', (238, 255))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('MEK', 'Gene', '5609', (96, 99))	('ERK', 'Gene', '5594', (100, 103))	('RAF', 'Gene', '22882', (92, 95))	('esophageal tumors', 'Disease', 'MESH:D004938', (238, 255))	('DADS', 'Chemical', 'MESH:C028009', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('Suppresses', 'NegReg', (39, 49))	('MEK', 'Gene', (96, 99))	('suppresses', 'NegReg', (227, 237))	('RAF', 'Gene', (92, 95))	('ERK', 'Gene', (100, 103))
361597	25375190	In the research article entitled "Effects of the Novel Compound DK223 ([1E,2E-1,2-Bis(6-methoxy-2H-chromen-3-yl)methylene]hydrazine) on Migration and Proliferation of Human Keratinocytes and Primary Dermal Fibroblasts", Dr. Moonjae Cho and colleagues identified a novel compound DK223 ([1E,2E-1,2-bis(6-methoxy-2H-chromen-3-yl)methylene]hydrazine) that concomitantly induced human keratinocyte migration and dermal fibroblast proliferation.	('induced', 'PosReg', (367, 374))	('Human', 'Species', '9606', (167, 172))	('rat', 'Species', '10116', (433, 436))	('rat', 'Species', '10116', (397, 400))	('human keratinocyte migration', 'CPA', (375, 403))	('DK223', 'Var', (279, 284))	('rat', 'Species', '10116', (139, 142))	('rat', 'Species', '10116', (383, 386))	('rat', 'Species', '10116', (157, 160))	('human', 'Species', '9606', (375, 380))	('rat', 'Species', '10116', (175, 178))	('dermal fibroblast proliferation', 'CPA', (408, 439))
361598	25375190	They also found that DK223 simultaneously induced both keratinocyte migration via reactive oxygen species production and fibroblast proliferation via TGF-beta1 induction.	('DK223', 'Var', (21, 26))	('rat', 'Species', '10116', (71, 74))	('fibroblast proliferation', 'CPA', (121, 145))	('induced', 'PosReg', (42, 49))	('rat', 'Species', '10116', (139, 142))	('keratinocyte migration', 'CPA', (55, 77))	('rat', 'Species', '10116', (57, 60))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (82, 105))	('TGF-beta1', 'Gene', '7040', (150, 159))	('TGF-beta1', 'Gene', (150, 159))
361602	25375190	Compared with the existing prediction methods in this regard, iNR-Drug not only can yield a higher success rate, but is also featured by a user-friendly web-server, which is particularly useful for most experimental scientists to obtain their desired data in a timely manner.	('success', 'MPA', (99, 106))	('iNR-Drug', 'Var', (62, 70))	('rat', 'Species', '10116', (107, 110))
361629	32368143	miRNAs have been reported to exert their tumor-promoting or -inhibiting roles via inhibition of the target gene by base-pairing with its 3'-untranslated region.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('base-pairing', 'Var', (115, 127))	('-inhibiting', 'NegReg', (60, 71))	('inhibition', 'NegReg', (82, 92))	('miRNAs', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
361634	32368143	Previous evidence suggests that lncRNAs participate in the regulation of tumorigenesis via multiple pathways, including epigenetic modification, transcription modulation, RNA decay, and miRNA decoys.	('epigenetic modification', 'Var', (120, 143))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('participate', 'Reg', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('transcription', 'MPA', (145, 158))	('tumor', 'Disease', (73, 78))	('RNA decay', 'MPA', (171, 180))
361636	32368143	Recent evidence suggests that dysregulation of lncRNAs is closely associated with the development of human cancers, including ESCC.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('dysregulation', 'Var', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lncRNAs', 'Protein', (47, 54))	('associated', 'Reg', (66, 76))	('human', 'Species', '9606', (101, 106))	('ESCC', 'Disease', (126, 130))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
361665	32368143	Mutations were introduced into the miR-1248 binding sites in the UPK1A-AS1 sequence, followed by fusion with psiCHECK2 vector to generate MUT-UPK1A-AS1 constructs.	('miR-1248', 'Gene', (35, 43))	('UPK1A-AS1', 'Gene', '100862728', (65, 74))	('UPK1A-AS1', 'Gene', '100862728', (142, 151))	('Mutations', 'Var', (0, 9))	('UPK1A-AS1', 'Gene', (65, 74))	('UPK1A-AS1', 'Gene', (142, 151))	('miR-1248', 'Gene', '100302143', (35, 43))
361666	32368143	EC109 and KYSE30 cells were co-transfected with WT-UPK1A-AS1 or MUT-UPK1A-AS1 and miR-1248 or miR-NC, and luciferase activity was measured at 48 h post-transfection using the Dual-Luciferase Reporter Assay System (Promega).	('activity', 'MPA', (117, 125))	('UPK1A-AS1', 'Gene', '100862728', (68, 77))	('UPK1A-AS1', 'Gene', '100862728', (51, 60))	('UPK1A-AS1', 'Gene', (68, 77))	('miR-NC', 'Var', (94, 100))	('miR-1248', 'Gene', '100302143', (82, 90))	('UPK1A-AS1', 'Gene', (51, 60))	('miR-1248', 'Gene', (82, 90))
361695	32368143	Accumulating evidence suggests that disruption of lncRNAs is tightly associated with the development of human cancers, including ESCC.	('cancers', 'Disease', (110, 117))	('lncRNAs', 'Protein', (50, 57))	('ESCC', 'Disease', (129, 133))	('disruption', 'Var', (36, 46))	('associated', 'Reg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('human', 'Species', '9606', (104, 109))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
361698	32368143	In the last decades, hundreds of lncRNAs have been studied and identified in various human cancers, and abnormal expression of lncRNAs is a key mechanism underlying ESCC carcinogenesis.	('expression', 'MPA', (113, 123))	('carcinogenesis', 'Disease', (170, 184))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('mechanism underlying', 'Reg', (144, 164))	('cancers', 'Disease', (91, 98))	('abnormal', 'Var', (104, 112))	('ESCC', 'Disease', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('human', 'Species', '9606', (85, 90))
361725	29499953	In this study, we confirmed that miR-140 downregulates SMAD family member 3 (Smad3), which is a key downstream effector of the TGF-beta signaling pathway, at the translational level in the CRC cell lines.	('Smad', 'Gene', '4089;4089', (77, 81))	('downregulates', 'NegReg', (41, 54))	('miR-140', 'Var', (33, 40))	('Smad', 'Gene', (77, 81))	('TGF-beta', 'Gene', '7040', (127, 135))	('SMAD', 'Gene', (55, 59))	('SMAD', 'Gene', '4089;4089', (55, 59))	('TGF-beta', 'Gene', (127, 135))
361728	29499953	Furthermore, overexpression of miR-140 inhibits the tumor formation and metastasis of CRC in vivo, and silenced Smad3 has the similar effect.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Smad', 'Gene', '4089;4089', (112, 116))	('tumor', 'Disease', (52, 57))	('metastasis of', 'CPA', (72, 85))	('silenced', 'Var', (103, 111))	('miR-140', 'Gene', (31, 38))	('overexpression', 'PosReg', (13, 27))	('Smad', 'Gene', (112, 116))	('inhibits', 'NegReg', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
361738	29499953	Importantly, Smad3 has been confirmed as the direct target of microRNA-140-5p (miR-140) in a pluripotent mouse embryonic fibroblast cell line and alveolar epithelial cells (AECs).	('Smad', 'Gene', (13, 17))	('Smad', 'Gene', '4089;4089', (13, 17))	('mouse', 'Species', '10090', (105, 110))	('microRNA-140-5p', 'Var', (62, 77))
361743	29499953	We found that miR-140 expression is reduced in the CRC specimens and that the ectopic expression of miR-140 can suppress cell proliferation and induce cell-cycle G1 and G2 phase arrest, mediated in part through the downregulation of HDAC4 in the CRC and osteosarcoma cells.	('cell-cycle G1', 'CPA', (151, 164))	('induce', 'PosReg', (144, 150))	('downregulation', 'NegReg', (215, 229))	('arrest', 'Disease', (178, 184))	('osteosarcoma', 'Phenotype', 'HP:0002669', (254, 266))	('osteosarcoma', 'Disease', (254, 266))	('miR-140', 'Gene', (100, 107))	('miR-140', 'Gene', (14, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (254, 266))	('ectopic expression', 'Var', (78, 96))	('cell proliferation', 'CPA', (121, 139))	('suppress', 'NegReg', (112, 120))	('reduced', 'NegReg', (36, 43))	('HDAC4', 'Gene', (233, 238))	('HDAC4', 'Gene', '9759', (233, 238))	('expression', 'MPA', (22, 32))	('arrest', 'Disease', 'MESH:D006323', (178, 184))
361744	29499953	Several recent studies have demonstrated that miR-140 can inhibit tumor invasion and metastasis in hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through downregulating TGFBRI, FGF9, or IGF1R.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (134, 160))	('metastasis in hepatocellular carcinoma', 'Disease', 'MESH:D009362', (85, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('FGF9', 'Gene', (200, 204))	('IGF1R', 'Gene', (209, 214))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('IGF1R', 'Gene', '3480', (209, 214))	('FGF9', 'Gene', '2254', (200, 204))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (134, 160))	('tumor', 'Disease', (66, 71))	('TGFBRI', 'Gene', (192, 198))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('metastasis in hepatocellular carcinoma', 'Disease', (85, 123))	('NSCLC', 'Disease', (162, 167))	('non-small cell lung cancer', 'Disease', (134, 160))	('downregulating', 'NegReg', (177, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('inhibit', 'NegReg', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('miR-140', 'Var', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (138, 160))
361749	29499953	In this study, we found that Smad3 is the direct target of miR-140 in the CRC cell lines via the luciferase assay, and miR-140 regulates the expression of Smad3 at the translational level.	('Smad', 'Gene', (155, 159))	('miR-140', 'Var', (119, 126))	('Smad', 'Gene', (29, 33))	('regulates', 'Reg', (127, 136))	('expression', 'MPA', (141, 151))	('Smad', 'Gene', '4089;4089', (155, 159))	('Smad', 'Gene', '4089;4089', (29, 33))
361750	29499953	Ectopic expression of miR-140 inhibits the process of EMT, at least partially through targeting Smad3, and therefore suppresses the migratory and invasive capacities of CRC cells in vitro.	('Smad', 'Gene', '4089;4089', (96, 100))	('Ectopic expression', 'Var', (0, 18))	('suppresses', 'NegReg', (117, 127))	('inhibits', 'NegReg', (30, 38))	('targeting', 'Reg', (86, 95))	('miR-140', 'Gene', (22, 29))	('process of EMT', 'CPA', (43, 57))	('Smad', 'Gene', (96, 100))
361763	29499953	As Figure 1B shows, there was only a slight decrease in Smad3 mRNA expression after miR-140 transfection; by contrast, knockdown of Smad3 dramatically induced the Smad3 mRNA degradation.	('Smad', 'Gene', (132, 136))	('Smad', 'Gene', '4089;4089', (132, 136))	('Smad', 'Gene', (56, 60))	('Smad', 'Gene', (163, 167))	('induced', 'Reg', (151, 158))	('knockdown', 'Var', (119, 128))	('Smad', 'Gene', '4089;4089', (56, 60))	('Smad', 'Gene', '4089;4089', (163, 167))
361768	29499953	To further confirm Smad3 is regulated by miR-140, we performed the loss-of-function experiment by knocking down the endogenous miR-140 with inhibitor of miR-140 in HCT116 and RKO cells.	('Smad', 'Gene', '4089;4089', (19, 23))	('miR-140', 'Gene', (127, 134))	('HCT116', 'CellLine', 'CVCL:0291', (164, 170))	('RKO', 'CellLine', 'CVCL:0504', (175, 178))	('Smad', 'Gene', (19, 23))	('loss-of-function', 'NegReg', (67, 83))	('knocking', 'Var', (98, 106))
361770	29499953	Our results showed that knocking down endogenous miR-140 could restore the expressions of Smad3 and p-Smad3, compared to the negative controls (Figure 1D).	('knocking down', 'Var', (24, 37))	('Smad', 'Gene', '4089;4089', (102, 106))	('miR-140', 'Gene', (49, 56))	('Smad', 'Gene', (90, 94))	('restore', 'PosReg', (63, 70))	('Smad', 'Gene', '4089;4089', (90, 94))	('Smad', 'Gene', (102, 106))	('expressions', 'MPA', (75, 86))
361773	29499953	Smad2 has previously been confirmed to be the direct target of miR-140.	('Smad2', 'Gene', (0, 5))	('Smad2', 'Gene', '4087', (0, 5))	('miR-140', 'Var', (63, 70))
361777	29499953	In combination with these data, miR-140 could inhibit the TGF-beta signaling-pathway-related proteins Smad2 and Smad3 directly and indirectly downregulate Smad4, possibly via decreased Smad2 expression.	('Smad', 'Gene', (155, 159))	('Smad', 'Gene', '4089;4089', (102, 106))	('Smad2', 'Gene', (185, 190))	('TGF-beta', 'Gene', '7040', (58, 66))	('decreased', 'NegReg', (175, 184))	('Smad', 'Gene', (185, 189))	('inhibit', 'NegReg', (46, 53))	('Smad2', 'Gene', '4087', (102, 107))	('Smad4', 'Gene', (155, 160))	('Smad', 'Gene', (112, 116))	('Smad', 'Gene', '4089;4089', (155, 159))	('TGF-beta', 'Gene', (58, 66))	('miR-140', 'Var', (32, 39))	('Smad2', 'Gene', (102, 107))	('Smad', 'Gene', '4089;4089', (185, 189))	('Smad', 'Gene', (102, 106))	('Smad', 'Gene', '4089;4089', (112, 116))	('Smad4', 'Gene', '4089', (155, 160))	('Smad2', 'Gene', '4087', (185, 190))	('downregulate', 'NegReg', (142, 154))
361781	29499953	On the contrary, knocking down of endogenous miR-140 expression by the inhibitor significantly enhanced the migratory and invasive capacities of HCT116 and RKO cells (Figures 2D-2F).	('knocking', 'Var', (17, 25))	('miR-140', 'Gene', (45, 52))	('HCT116', 'CellLine', 'CVCL:0291', (145, 151))	('enhanced', 'PosReg', (95, 103))	('RKO', 'CellLine', 'CVCL:0504', (156, 159))
361783	29499953	As Figure 3A shows, either upregulated miR-140 or silenced Smad3 inhibited the CRC cell growth significantly when compared to the negative controls.	('Smad', 'Gene', '4089;4089', (59, 63))	('CRC cell growth', 'CPA', (79, 94))	('inhibited', 'NegReg', (65, 74))	('upregulated', 'PosReg', (27, 38))	('silenced', 'Var', (50, 58))	('Smad', 'Gene', (59, 63))	('miR-140', 'Gene', (39, 46))
361784	29499953	The results showed that both enforced expression of miR-140 and silenced Smad3 suppressed the number of colonies remarkably, as compared to the negative controls (Figure 3B).	('Smad', 'Gene', (73, 77))	('number of colonies', 'CPA', (94, 112))	('suppressed', 'NegReg', (79, 89))	('miR-140', 'Gene', (52, 59))	('Smad', 'Gene', '4089;4089', (73, 77))	('silenced', 'Var', (64, 72))
361787	29499953	miR-140 overexpression increased the level of E-cadherin and decreased the level of vimentin compared with the negative controls, and siRNA against Smad3 resembled the effect of miR-140 overexpression (Figure 4A).	('miR-140', 'Gene', (0, 7))	('Smad', 'Gene', (148, 152))	('E-cadherin', 'Protein', (46, 56))	('overexpression', 'Var', (8, 22))	('increased', 'PosReg', (23, 32))	('Smad', 'Gene', '4089;4089', (148, 152))	('decreased', 'NegReg', (61, 70))	('level of vimentin', 'MPA', (75, 92))
361793	29499953	Given the observed effects of miR-140 on CRC cell proliferation, migration, and invasion in vitro, we subsequently explored whether miR-140 inhibits the tumor progression and metastasis in vivo.	('inhibits', 'NegReg', (140, 148))	('migration', 'CPA', (65, 74))	('invasion', 'CPA', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('miR-140', 'Var', (132, 139))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('effects', 'Reg', (19, 26))	('CRC', 'Disease', (41, 44))	('miR-140', 'Gene', (30, 37))
361799	29499953	However, the tumor volumes in the miR-140-injected group were markedly smaller than those in the negative-control-injected group at all the time points (Figures 5A and 5B), and silenced Smad3 by shRNA reduced the tumor volume similarly with the miR-140-injected group.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', (13, 18))	('miR-140-injected', 'Var', (34, 50))	('Smad', 'Gene', (186, 190))	('smaller', 'NegReg', (71, 78))	('reduced', 'NegReg', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('Smad', 'Gene', '4089;4089', (186, 190))	('silenced', 'Var', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
361801	29499953	As Figure 5C shows, the expressions of Smad3, p-Smad3, and the downstream effector Zeb1 in the groups treated with either miR-140 or shRNA-Smad3 were significantly decreased as compared to the negative control.	('Smad', 'Gene', '4089;4089', (39, 43))	('Smad', 'Gene', (48, 52))	('decreased', 'NegReg', (164, 173))	('Zeb1', 'Gene', (83, 87))	('expressions', 'MPA', (24, 35))	('Smad', 'Gene', (139, 143))	('Smad', 'Gene', '4089;4089', (48, 52))	('Smad', 'Gene', (39, 43))	('miR-140', 'Var', (122, 129))	('Smad', 'Gene', '4089;4089', (139, 143))
361816	29499953	EMT is an indispensable process in the development, differentiation, and repair of multiple tissues and organs; however, inappropriate reactivation of EMT can promote carcinoma progression through a variety of mechanisms.	('EMT', 'Gene', (151, 154))	('carcinoma', 'Disease', 'MESH:D002277', (167, 176))	('inappropriate reactivation', 'Var', (121, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('promote', 'PosReg', (159, 166))	('carcinoma', 'Disease', (167, 176))
361818	29499953	The knockdown of Smad3 in MDA-MB-231 cells can prolong the latency and delay the bone metastasis of breast cancer.	('bone metastasis of breast cancer', 'Disease', 'MESH:D009362', (81, 113))	('knockdown', 'Var', (4, 13))	('Smad', 'Gene', '4089;4089', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (26, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('latency', 'CPA', (59, 66))	('bone metastasis of breast cancer', 'Disease', (81, 113))	('prolong', 'PosReg', (47, 54))	('Smad', 'Gene', (17, 21))	('delay', 'NegReg', (71, 76))
361828	29499953	We also confirmed the decrease of Smad2 protein by miR-140 in our study.	('miR-140', 'Var', (51, 58))	('decrease', 'NegReg', (22, 30))	('Smad2', 'Gene', '4087', (34, 39))	('protein', 'Protein', (40, 47))	('Smad2', 'Gene', (34, 39))
361829	29499953	Smad4 protein was decreased, possibly, due to the inhibition of Smad2 induced by the overexpression of miR-140.	('protein', 'Protein', (6, 13))	('miR-140', 'Var', (103, 110))	('decreased', 'NegReg', (18, 27))	('inhibition', 'NegReg', (50, 60))	('overexpression', 'PosReg', (85, 99))	('Smad2', 'Gene', (64, 69))	('Smad2', 'Gene', '4087', (64, 69))	('Smad4', 'Gene', (0, 5))	('Smad4', 'Gene', '4089', (0, 5))
361831	29499953	Except the aforementioned targets of miR-140, VEGF-A, ADAMTS5, and IGFBP5 have been confirmed to be involved in the inhibition of CRC invasion and metastasis induced by miR-140.	('miR-140', 'Gene', (37, 44))	('ADAMTS5', 'Gene', '11096', (54, 61))	('IGFBP5', 'Gene', (67, 73))	('CRC invasion', 'CPA', (130, 142))	('IGFBP5', 'Gene', '3488', (67, 73))	('miR-140', 'Var', (169, 176))	('ADAMTS5', 'Gene', (54, 61))	('inhibition', 'NegReg', (116, 126))	('VEGF-A', 'Gene', '7422', (46, 52))	('VEGF-A', 'Gene', (46, 52))	('metastasis', 'CPA', (147, 157))
361839	29499953	Our in vitro experiments showed that miR-140 suppresses the cell proliferation and colony formation capacity of CRC cells via downregulation of Smad3 (Figure 3).	('Smad', 'Gene', (144, 148))	('cell proliferation', 'CPA', (60, 78))	('downregulation', 'NegReg', (126, 140))	('Smad', 'Gene', '4089;4089', (144, 148))	('colony formation capacity of CRC cells', 'CPA', (83, 121))	('miR-140', 'Var', (37, 44))	('suppresses', 'NegReg', (45, 55))
361846	29499953	The famous miR-34a has become the first miRNA to start the clinical trial, opening a novel era in cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('miR-34a', 'Var', (11, 18))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('clinical', 'Species', '191496', (59, 67))
361861	29499953	The wild-type or mutant double-stranded oligonucleotides of Smad3 3'UTR were synthesized and inserted into the sites of SacI and XhoI of the GP-miRGLO vector (GenePharma, Shanghai, China).	('Smad', 'Gene', (60, 64))	('mutant', 'Var', (17, 23))	('Smad', 'Gene', '4089;4089', (60, 64))
361863	29499953	After 24 hr, cells in each well were co-transfected with 100 nM miR-140 mimic or negative miRNA and 200 ng GP-miRGLO constructs containing wild-type or mutant 3'UTR of Smad3 mRNA using Lipofectamine 2000.	('Smad', 'Gene', '4089;4089', (168, 172))	('mutant', 'Var', (152, 158))	('Smad', 'Gene', (168, 172))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (185, 203))
361882	29499953	Protein abundance of GAPDH (1:500, AP50811, Abgent) served as a control for protein loading.	('GAPDH', 'Gene', (21, 26))	('1:500', 'Var', (28, 33))	('GAPDH', 'Gene', '2597', (21, 26))	('AP50811', 'Var', (35, 42))
361888	29499953	Lentiviral vectors of miR-140 and negative control and shRNA against Smad3 were purchased from GeneChem (Shanghai, China).	('Smad', 'Gene', (69, 73))	('miR-140', 'Var', (22, 29))	('Smad', 'Gene', '4089;4089', (69, 73))
361891	29499953	Mice were randomly divided into three groups; group 1 was injected with lentivirus miR-140-transduced cells, group 2 was injected with lentivirus control-transduced cells, and group 3 was injected with lentivirus shRNA against Smad3-transduced cells.	('lentivirus', 'Var', (72, 82))	('Smad', 'Gene', (227, 231))	('Mice', 'Species', '10090', (0, 4))	('Smad', 'Gene', '4089;4089', (227, 231))
361907	25953424	EGFR amplification was associated with lymph node metastasis (P = 0.028), but not correlated with DFS and OS until 20 months.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('lymph node metastasis', 'CPA', (39, 60))	('EGFR', 'Gene', '1956', (0, 4))	('associated', 'Reg', (23, 33))	('OS', 'Chemical', '-', (106, 108))
361914	25953424	Esophageal cancers frequently show EGFR or HER2 gene amplification and overexpression.	('overexpression', 'PosReg', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('amplification', 'Var', (53, 66))	('HER2', 'Gene', (43, 47))	('Esophageal cancers', 'Disease', (0, 18))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('HER2', 'Gene', '2064', (43, 47))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('Esophageal cancers', 'Disease', 'MESH:D004938', (0, 18))
361915	25953424	And esophageal squamous cell carcinomas (ESCCs) predominantly show alterations of EGFR, whereas esophageal (Barrett's) adenocarcinomas (EACs) frequently show HER2 gene amplification and protein overexpression.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (15, 39))	('EGFR', 'Gene', (82, 86))	("esophageal (Barrett's) adenocarcinomas", 'Disease', 'MESH:D001471', (96, 134))	('overexpression', 'PosReg', (194, 208))	('esophageal squamous cell carcinomas', 'Disease', (4, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (4, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('amplification', 'PosReg', (168, 181))	('alterations', 'Var', (67, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('HER2', 'Gene', (158, 162))	('protein', 'Protein', (186, 193))	('HER2', 'Gene', '2064', (158, 162))	('EGFR', 'Gene', '1956', (82, 86))
361922	25953424	EGFR gene copy number variation may be more reliable than protein expression in predicting prognosis.	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('gene copy number variation', 'Var', (5, 31))
361923	25953424	However, reports on the influence of EGFR gene variation in ESCC patients have been equivocal.	('ESCC', 'Disease', (60, 64))	('EGFR', 'Gene', '1956', (37, 41))	('patients', 'Species', '9606', (65, 73))	('EGFR', 'Gene', (37, 41))	('variation', 'Var', (47, 56))
361924	25953424	In general, the relationships between tumor EGFR gene variation and protein expression have not been clearly defined, and the prognostic value of these tumor characteristics has not been well evaluated for ESCC.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('ESCC', 'Disease', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('variation', 'Var', (54, 63))
361925	25953424	Therefore, the aims of this study are to compare the six different scoring systems for EGFR expression, to explore the cut off value in assessing EGFR gene variation, and to investigate their prognostic significance in ESCC.	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', '1956', (146, 150))	('EGFR', 'Gene', (87, 91))	('EGFR', 'Gene', (146, 150))	('ESCC', 'Disease', (219, 223))	('variation', 'Var', (156, 165))
361930	25953424	The following patient characteristics were collected: gender, age, tumor site (upper, middle, and lower region of esophagus), histological grade, coagulative necrosis, nerve and vascular infiltration, mitotic index (numbers recorded as <=20 per 10 high power fields [HPF], 20-50/10HPF, or >= 50/10HPF), lymph node metastasis, and stage, as previously reported.	('necrosis', 'Disease', (158, 166))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('necrosis', 'Disease', 'MESH:D009336', (158, 166))	('20-50/10HPF', 'Var', (273, 284))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (146, 166))	('patient', 'Species', '9606', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('<=20 per', 'Var', (236, 244))	('tumor', 'Disease', (67, 72))	('lymph node metastasis', 'CPA', (303, 324))
361937	25953424	6) loss of expression: SI = 0; weak expression: SI = 1 in < 70 % or SI = 2 in < 30 % of cells in a tumor spot, moderate expression: SI = 1 in > 70 % or SI =2 in > 30 % of cells in a tumor spot and strong expression: SI = 2 in > 70 % or SI = 3 in > 30 % of cells in a tumor spot.	('tumor', 'Disease', (99, 104))	('SI =2', 'Var', (152, 157))	('SI = 1', 'Var', (132, 138))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('expression', 'MPA', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('SI = 2', 'Var', (68, 74))	('SI =', 'Var', (216, 220))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('SI =', 'Var', (48, 52))	('loss', 'NegReg', (3, 7))
361942	25953424	EGFR FISH-positive was defined as EGFR high polysomy or gene amplification.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (34, 38))	('gene amplification', 'Var', (56, 74))	('high polysomy', 'Var', (39, 52))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (34, 38))
361964	25953424	EGFR gene amplification was associated with EGFR protein overexpression in scoring system 1, 2, 3, 4, and 6, EGFR-FISH positive only in scoring system 1, 2 and 4.	('overexpression', 'PosReg', (57, 71))	('EGFR', 'Gene', (0, 4))	('associated', 'Reg', (28, 38))	('EGFR', 'Gene', '1956', (109, 113))	('amplification', 'Var', (10, 23))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', (109, 113))	('EGFR', 'Gene', '1956', (0, 4))
361965	25953424	On the basis of scoring system 1, 3 and 4, patients with trisomy and polysomy showed low mean IHC scores (206 and 197, 6.6 and 6.5, 94.6 and 100 respectively), whereas the mean IHC score increased when FISH abnormalities became more severe.	('FISH abnormalities', 'Disease', 'MESH:D000014', (202, 220))	('FISH abnormalities', 'Disease', (202, 220))	('IHC', 'MPA', (94, 97))	('low', 'NegReg', (85, 88))	('polysomy', 'Var', (69, 77))	('patients', 'Species', '9606', (43, 51))	('trisomy', 'Var', (57, 64))
361969	25953424	EGFR amplification was associated with the lymph node metastasis (P = 0.028), while high polysomy wasn't associated with this factor (P = 0.227).	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('lymph node metastasis', 'CPA', (43, 64))	('associated', 'Reg', (23, 33))	('EGFR', 'Gene', '1956', (0, 4))
361970	25953424	EGFR overexpression and gene amplification were evaluated for their potential prognostic significance.	('gene amplification', 'Var', (24, 42))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
361975	25953424	EGFR alterations in cancer can be divided mostly in two categories: mutations in exons 18-21 mainly identified in Asia lung adenocarcinoma, and gene and protein overexpression.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('EGFR', 'Gene', (0, 4))	('identified', 'Reg', (100, 110))	('Asia lung adenocarcinoma', 'Disease', 'MESH:D000077192', (114, 138))	('Asia lung adenocarcinoma', 'Disease', (114, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('protein', 'Protein', (153, 160))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('mutations in', 'Var', (68, 80))	('overexpression', 'PosReg', (161, 175))	('cancer', 'Disease', (20, 26))	('EGFR', 'Gene', '1956', (0, 4))
361977	25953424	EGFR gene variation and protein overexpression might be the candidate for predictive biomarker in ESCC.	('overexpression', 'PosReg', (32, 46))	('protein', 'Protein', (24, 31))	('EGFR', 'Gene', (0, 4))	('variation', 'Var', (10, 19))	('ESCC', 'Disease', (98, 102))	('EGFR', 'Gene', '1956', (0, 4))
361979	25953424	Therefore, we selected six different scoring systems presented in literature to focus upon the same ESCC samples with EGFR antibody.	('ESCC', 'Disease', (100, 104))	('EGFR', 'Gene', '1956', (118, 122))	('antibody', 'Var', (123, 131))	('EGFR', 'Gene', (118, 122))
361984	25953424	Firstly, EGFR gene status disclosed by our FISH included disomy, low trisomy, high trisomy, low polysomy, high polysomy and gene amplification, which was consistent with previous reports.	('high polysomy', 'Var', (106, 119))	('low trisomy', 'Var', (65, 76))	('gene amplification', 'Var', (124, 142))	('disomy', 'Disease', (57, 63))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('disomy', 'Disease', 'MESH:D024182', (57, 63))	('high trisomy', 'Var', (78, 90))	('low polysomy', 'Var', (92, 104))
361985	25953424	Secondly, EGFR gene amplification was associated with EGFR expression evaluated by scoring system 1, 2, 3, 4, 6 except 5, whereas EGFR-FISH positive was only associated with scoring system 1, 2 and 4.	('EGFR', 'Gene', '1956', (10, 14))	('associated', 'Reg', (38, 48))	('EGFR', 'Gene', (10, 14))	('expression', 'MPA', (59, 69))	('EGFR', 'Gene', '1956', (54, 58))	('amplification', 'Var', (20, 33))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (54, 58))	('EGFR', 'Gene', (130, 134))
361986	25953424	Thirdly, EGFR-FISH positive had no relationship with clinical features and prognosis; however, EGFR amplification was associated with lymph node metastasis, and patients with EGFR amplification had poorer prognosis whether in DFS or OS after 20 months survival.	('OS', 'Chemical', '-', (233, 235))	('amplification', 'Var', (100, 113))	('EGFR', 'Gene', (175, 179))	('DFS', 'Disease', (226, 229))	('EGFR', 'Gene', '1956', (9, 13))	('patients', 'Species', '9606', (161, 169))	('EGFR', 'Gene', (9, 13))	('lymph node metastasis', 'CPA', (134, 155))	('EGFR', 'Gene', '1956', (95, 99))	('associated', 'Reg', (118, 128))	('EGFR', 'Gene', '1956', (175, 179))	('EGFR', 'Gene', (95, 99))
361987	25953424	Therefore, EGFR amplification, not EGFR-FISH positive or high polysomy, seems to be a suitable cut off value in clinical practice.	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('amplification', 'Var', (16, 29))
361989	25953424	EGFR gene amplification was associated with protein overexpression in ESCC, and indicated poorer prognosis after 20 months survival.	('EGFR', 'Gene', (0, 4))	('associated', 'Reg', (28, 38))	('amplification', 'Var', (10, 23))	('ESCC', 'Disease', (70, 74))	('EGFR', 'Gene', '1956', (0, 4))	('protein overexpression', 'MPA', (44, 66))
362039	19948247	66 patients had endoscopic ultrasound (EUS) done prior to surgery with the following staging results: 3 T0N0 (4%), 39 T1N0 (60%), 2 T1N1 (3%), 18 T2N0 (27%), 3 T2N1 (4%) and 1 T3N0 (2%).	('T0N0', 'Var', (104, 108))	('T2N0', 'Var', (146, 150))	('T2N1', 'Var', (160, 164))	('patients', 'Species', '9606', (3, 11))	('T1N1', 'Var', (132, 136))	('T1N0', 'Var', (118, 122))
362050	19948247	The distribution of submucosal invasion in the esophagectomy specimens was: sm1 in 31 patients (39%), sm2 in 23 patients (29%) and sm3 in 26 patients (33%).	('sm1', 'Gene', '7911', (76, 79))	('sm3', 'Var', (131, 134))	('sm1', 'Gene', (76, 79))	('sm2', 'Var', (102, 105))	('patients', 'Species', '9606', (112, 120))	('sm3', 'Chemical', '-', (131, 134))	('patients', 'Species', '9606', (141, 149))	('patients', 'Species', '9606', (86, 94))
362119	32488984	PRKAA1 rs13361707 C/T polymorphism confers decreased susceptibility to esophageal cancer: A case-control study Several studies probed into the connection between esophageal cancer (EC) risk and PRKAA1 rs13361707 C/T polymorphism, but obtained insignificant findings.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('PRKAA1', 'Gene', (0, 6))	('PRKAA1', 'Gene', '5562', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (173, 179))	('rs13361707 C/T', 'Var', (7, 21))	('rs13361707', 'Mutation', 'rs13361707', (7, 17))	('PRKAA1', 'Gene', (194, 200))	('PRKAA1', 'Gene', '5562', (194, 200))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('rs13361707 C/T', 'Var', (201, 215))	('probed', 'Reg', (127, 133))	('decreased', 'NegReg', (43, 52))	('rs13361707', 'Mutation', 'rs13361707', (201, 211))
362120	32488984	Data suggested rs13361707 C/T polymorphism in PRKAA1 gene was significantly related with a lower risk for EC.	('rs13361707', 'Mutation', 'rs13361707', (15, 25))	('PRKAA1', 'Gene', (46, 52))	('rs13361707 C/T polymorphism', 'Var', (15, 42))	('PRKAA1', 'Gene', '5562', (46, 52))
362121	32488984	In summary, PRKAA1 rs13361707 C/T polymorphism is related to the risk and clinical properties of EC patients in East China.	('related', 'Reg', (50, 57))	('rs13361707', 'Mutation', 'rs13361707', (19, 29))	('PRKAA1', 'Gene', (12, 18))	('patients', 'Species', '9606', (100, 108))	('PRKAA1', 'Gene', '5562', (12, 18))	('rs13361707 C/T', 'Var', (19, 33))
362129	32488984	Rs13361707 C/T polymorphism is positioned in the first intron of PRKAA1 gene.	('Rs13361707', 'Mutation', 'Rs13361707', (0, 10))	('PRKAA1', 'Gene', '5562', (65, 71))	('PRKAA1', 'Gene', (65, 71))	('Rs13361707 C/T', 'Var', (0, 14))
362131	32488984	Besides, two Chinese studies investigating the relationship between EC risk and rs13361707 C/T polymorphism in PRKAA1 gene yielded no positive results.	('rs13361707 C/T', 'Var', (80, 94))	('PRKAA1', 'Gene', '5562', (111, 117))	('PRKAA1', 'Gene', (111, 117))	('rs13361707', 'Mutation', 'rs13361707', (80, 90))
362132	32488984	10 ,  11  Thus, the aims of this study were to explore the connection between this variant in PRKAA1 gene and EC susceptibility in Chinese individuals.	('variant', 'Var', (83, 90))	('PRKAA1', 'Gene', (94, 100))	('PRKAA1', 'Gene', '5562', (94, 100))
362133	32488984	In addition, we aimed to explore the relationship between PRKAA1 rs13361707 C/T polymorphism and clinical features of EC patients.	('PRKAA1', 'Gene', (58, 64))	('PRKAA1', 'Gene', '5562', (58, 64))	('rs13361707 C/T', 'Var', (65, 79))	('rs13361707', 'Mutation', 'rs13361707', (65, 75))	('patients', 'Species', '9606', (121, 129))
362138	32488984	13  Relationship between PRKAA1 rs13361707 C/T polymorphism and EC risk was assessed by logistic regression with multiple genetic models adjusted by age and gender.	('PRKAA1', 'Gene', '5562', (25, 31))	('PRKAA1', 'Gene', (25, 31))	('rs13361707', 'Mutation', 'rs13361707', (32, 42))	('rs13361707 C/T', 'Var', (32, 46))
362141	32488984	We found CC genotype or C allele carriers showed a decreased risk for EC patients (CC vs TT: OR, 0.64, 95% CI, 0.49-0.83; C vs T: 0.80, 0.70-0.91; both P = .001).	('patients', 'Species', '9606', (73, 81))	('C allele carriers', 'Var', (24, 41))	('decreased', 'NegReg', (51, 60))
362142	32488984	Data revealed that a protective role of rs13361707 C/T polymorphism in EC susceptibility was strengthened in the subgroups of males, smokers, drinkers, and individuals at age >= 60 years (Table 2).	('rs13361707', 'Mutation', 'rs13361707', (40, 50))	('strengthened', 'PosReg', (93, 105))	('rs13361707 C/T', 'Var', (40, 54))
362143	32488984	CC or TC + CC genotype was involved in avoidance of EC patients from differentiation deterioration, distant metastasis, and squamous cell carcinoma, indicating the rs13361707 C/T polymorphism participated in the pathological grading, distant metastasis, and histology of EC (Table 3).	('participated', 'Reg', (192, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('rs13361707 C/T', 'Var', (164, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('rs13361707', 'Mutation', 'rs13361707', (164, 174))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 147))	('squamous cell carcinoma', 'Disease', (124, 147))	('TC', 'Chemical', 'MESH:D013667', (6, 8))	('patients', 'Species', '9606', (55, 63))
362145	32488984	In this study, rs13361707 C/T polymorphism of PRKAA1 gene was related with a lower risk of EC in this tested Chinese Han population.	('lower', 'NegReg', (77, 82))	('PRKAA1', 'Gene', (46, 52))	('PRKAA1', 'Gene', '5562', (46, 52))	('rs13361707', 'Mutation', 'rs13361707', (15, 25))	('rs13361707 C/T', 'Var', (15, 29))
362146	32488984	Furthermore, rs13361707 C/T polymorphism was linked with pathological grading, distant metastasis, and squamous cell carcinoma.	('rs13361707 C/T', 'Var', (13, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('linked', 'Reg', (45, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('rs13361707', 'Mutation', 'rs13361707', (13, 23))	('squamous cell carcinoma', 'Disease', (103, 126))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 126))	('distant metastasis', 'CPA', (79, 97))
362147	32488984	A host of studies have evaluated the relationship between rs13361707 C/T polymorphism of PRKAA1 gene and the risk of several cancers.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('rs13361707 C/T', 'Var', (58, 72))	('cancers', 'Disease', (125, 132))	('rs13361707', 'Mutation', 'rs13361707', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('PRKAA1', 'Gene', (89, 95))	('PRKAA1', 'Gene', '5562', (89, 95))
362153	32488984	22  Another study implied rs13361707 C/T polymorphism was unrelated to lung cancer risk.	('rs13361707', 'Mutation', 'rs13361707', (26, 36))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('rs13361707 C/T', 'Var', (26, 40))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
362154	32488984	10 ,  11  Our study revealed that rs13361707 C/T polymorphism in PRKAA1 gene was related to EC susceptibility, which was consistent with the findings of the above meta-analysis.	('PRKAA1', 'Gene', (65, 71))	('rs13361707', 'Mutation', 'rs13361707', (34, 44))	('rs13361707 C/T', 'Var', (34, 48))	('PRKAA1', 'Gene', '5562', (65, 71))	('related', 'Reg', (81, 88))
362156	32488984	Additionally, rs13361707 C/T polymorphism was also found to be connected with the pathological grading, distant metastasis, and squamous cell carcinoma of EC patients.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('rs13361707 C/T', 'Var', (14, 28))	('connected', 'Reg', (63, 72))	('squamous cell carcinoma of EC', 'Disease', (128, 157))	('rs13361707', 'Mutation', 'rs13361707', (14, 24))	('patients', 'Species', '9606', (158, 166))	('squamous cell carcinoma of EC', 'Disease', 'MESH:D002294', (128, 157))	('distant metastasis', 'CPA', (104, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
362157	32488984	Third, the functions of PRKAA1 rs13361707 C/T polymorphism should be studied.	('PRKAA1', 'Gene', '5562', (24, 30))	('PRKAA1', 'Gene', (24, 30))	('rs13361707', 'Mutation', 'rs13361707', (31, 41))	('rs13361707 C/T', 'Var', (31, 45))
362161	32488984	The PRKAA1 rs13361707 C/T polymorphism is related to a lower risk of EC in the tested Chinese Han population.	('PRKAA1', 'Gene', (4, 10))	('PRKAA1', 'Gene', '5562', (4, 10))	('rs13361707', 'Mutation', 'rs13361707', (11, 21))	('rs13361707 C/T', 'Var', (11, 25))	('lower', 'NegReg', (55, 60))
362228	32118702	Thus, high expression of XIAP may over-activate Wnt/beta-catenin signaling and promote tumor growth.	('XIAP', 'Gene', '331', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('beta-catenin', 'Gene', (52, 64))	('Wnt', 'Gene', '7473', (48, 51))	('tumor', 'Disease', (87, 92))	('high expression', 'Var', (6, 21))	('beta-catenin', 'Gene', '1499', (52, 64))	('promote', 'PosReg', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Wnt', 'Gene', (48, 51))	('XIAP', 'Gene', (25, 29))	('over-activate', 'PosReg', (34, 47))
362249	32351293	In vitro and in vivo experiments showed that silencing Rpph1 expression led to higher sensitivity of esophageal cancer cells to radiotherapy, stronger apoptosis in esophageal cancer cells induced by radiotherapy, higher expression of Bax and caspase-3, and lower expression of Bcl-2 (Bax, caspase-3, and Bcl-2 are apoptosis-related proteins).	('caspase-3', 'Gene', (289, 298))	('Bax', 'Gene', '581', (234, 237))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('higher', 'PosReg', (213, 219))	('esophageal cancer', 'Disease', (101, 118))	('Bcl-2', 'Gene', '596', (277, 282))	('higher', 'PosReg', (79, 85))	('apoptosis', 'CPA', (151, 160))	('expression', 'MPA', (263, 273))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('esophageal cancer', 'Disease', (164, 181))	('lower', 'NegReg', (257, 262))	('Bcl-2', 'Gene', (304, 309))	('stronger', 'PosReg', (142, 150))	('silencing', 'Var', (45, 54))	('Bax', 'Gene', (284, 287))	('sensitivity', 'MPA', (86, 97))	('caspase-3', 'Gene', '836', (242, 251))	('Bcl-2', 'Gene', '596', (304, 309))	('Bax', 'Gene', '581', (284, 287))	('Rpph1', 'Gene', '85495', (55, 60))	('caspase-3', 'Gene', (242, 251))	('expression', 'MPA', (220, 230))	('Rpph1', 'Gene', (55, 60))	('Bax', 'Gene', (234, 237))	('caspase-3', 'Gene', '836', (289, 298))	('Bcl-2', 'Gene', (277, 282))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))
362250	32351293	Additionally, silencing Rpph1 attenuated radiation-induced G2/M phase arrest, and significantly inhibited the expression of proteins involved in cell proliferation, migration, and epithelial-mesenchymal transition regulation in esophageal cancer cells.	('silencing', 'Var', (14, 23))	('proteins', 'Protein', (124, 132))	('Rpph1', 'Gene', (24, 29))	('arrest', 'Disease', 'MESH:D006323', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('arrest', 'Disease', (70, 76))	('cell proliferation', 'CPA', (145, 163))	('inhibited', 'NegReg', (96, 105))	('esophageal cancer', 'Disease', (228, 245))	('expression of', 'MPA', (110, 123))	('migration', 'CPA', (165, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (228, 245))	('attenuated', 'NegReg', (30, 40))	('Rpph1', 'Gene', '85495', (24, 29))	('epithelial-mesenchymal transition regulation', 'CPA', (180, 224))
362252	32351293	Silencing Rpph1 expression can promote cell apoptosis, inhibit cell proliferation and migration, and increase radio-sensitivity.	('radio-sensitivity', 'CPA', (110, 127))	('cell apoptosis', 'CPA', (39, 53))	('Rpph1', 'Gene', (10, 15))	('increase', 'PosReg', (101, 109))	('promote', 'PosReg', (31, 38))	('Silencing', 'Var', (0, 9))	('inhibit', 'NegReg', (55, 62))	('Rpph1', 'Gene', '85495', (10, 15))
362265	32351293	A study revealed that lncRNA Rpph1 could inhibit breast cancer cell proliferation and tumor occurrence.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('Rpph1', 'Gene', '85495', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('lncRNA', 'Var', (22, 28))	('breast cancer', 'Disease', (49, 62))	('inhibit', 'NegReg', (41, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('Rpph1', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
362330	32351293	The siRNA-Rpph1 + IR group (6 Gy) had markedly fewer G2/M phase cells than the siRNA-NC + IR group (P < 0.05), implying that downregulation of Rpph1 expression can effectively alleviate radiation-induced G2/M phase arrest, thereby enhancing the sensitivity of the esophageal cancer cell lines TE-1 and Kyse150 to radiotherapy.	('esophageal cancer', 'Disease', (264, 281))	('Rpph1', 'Gene', (143, 148))	('Rpph1', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('downregulation', 'Var', (125, 139))	('TE', 'Chemical', 'MESH:D013691', (293, 295))	('esophageal cancer', 'Disease', 'MESH:D004938', (264, 281))	('arrest', 'Disease', 'MESH:D006323', (215, 221))	('alleviate', 'NegReg', (176, 185))	('enhancing', 'PosReg', (231, 240))	('sensitivity', 'MPA', (245, 256))	('arrest', 'Disease', (215, 221))	('Rpph1', 'Gene', '85495', (143, 148))	('Rpph1', 'Gene', '85495', (10, 15))
362348	32351293	This study reveals that serum lncRNA Rpph1 is associated with short-term responses, T stages, N stages, and clinical stages in patients with esophageal cancer, and can help diagnose esophageal cancer.	('serum', 'Var', (24, 29))	('esophageal cancer', 'Disease', (182, 199))	('Rpph1', 'Gene', '85495', (37, 42))	('N stages', 'CPA', (94, 102))	('T stages', 'CPA', (84, 92))	('esophageal cancer', 'Disease', (141, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('patients', 'Species', '9606', (127, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('associated', 'Reg', (46, 56))	('Rpph1', 'Gene', (37, 42))
362350	32351293	This study conducted regular follow-up for patients and found that esophageal cancer patients receiving radiotherapy had an overall survival rate of 42.17%, and that the 3-year overall survival rate was markedly lower in patients with high serum Rpph1 expression than in those with low serum Rpph1 expression.	('patients', 'Species', '9606', (221, 229))	('lower', 'NegReg', (212, 217))	('Rpph1', 'Gene', (292, 297))	('high serum', 'Var', (235, 245))	('patients', 'Species', '9606', (43, 51))	('Rpph1', 'Gene', '85495', (246, 251))	('patients', 'Species', '9606', (85, 93))	('esophageal cancer', 'Disease', (67, 84))	('overall survival', 'CPA', (177, 193))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Rpph1', 'Gene', (246, 251))	('expression', 'MPA', (252, 262))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('Rpph1', 'Gene', '85495', (292, 297))
362357	32351293	The results of the colony formation assay demonstrated that Rpph1 silencing did not affect the colony sizes of TE-1 and Kyse150 cells.	('Rpph1', 'Gene', '85495', (60, 65))	('Rpph1', 'Gene', (60, 65))	('TE', 'Chemical', 'MESH:D013691', (111, 113))	('silencing', 'Var', (66, 75))
362358	32351293	The cell-surviving fractions decreased with increasing irradiation doses in all transfection groups, with a stronger decrease in the siRNA-Rpph1 group, suggesting that silencing Rpph1 expression can significantly enhance cell sensitivity to radiotherapy.	('silencing', 'Var', (168, 177))	('Rpph1', 'Gene', (178, 183))	('cell-surviving fractions', 'CPA', (4, 28))	('enhance', 'PosReg', (213, 220))	('Rpph1', 'Gene', '85495', (139, 144))	('decreased', 'NegReg', (29, 38))	('Rpph1', 'Gene', (139, 144))	('Rpph1', 'Gene', '85495', (178, 183))	('cell sensitivity to radiotherapy', 'CPA', (221, 253))
362361	32351293	The apoptosis experiments in this study revealed that apoptosis of the siRNA-Rpph1 group was much stronger than that of the blank control group and the siRNA-NC group when TE-1 and Kyse150 cells were exposed to irradiation at a dose of 4 Gy and 6 Gy, indicating that Rpph1 silencing can increase radiation-induced cell apoptosis.	('apoptosis', 'CPA', (54, 63))	('stronger', 'PosReg', (98, 106))	('TE', 'Chemical', 'MESH:D013691', (172, 174))	('Rpph1', 'Gene', '85495', (267, 272))	('Rpph1', 'Gene', '85495', (77, 82))	('silencing', 'Var', (273, 282))	('Rpph1', 'Gene', (267, 272))	('increase', 'PosReg', (287, 295))	('Rpph1', 'Gene', (77, 82))
362362	32351293	After radiotherapy, the siRNA-Rpph1+IR group exhibited ramped-up Bax and caspase-3 expression, and a reduction in Bcl-2 expression (anti-apoptotic protein), suggesting that Rpph1 silencing can intensify the radio-sensitivity of esophageal cancer cells by promoting cell apoptosis.	('reduction', 'NegReg', (101, 110))	('Rpph1', 'Gene', (30, 35))	('esophageal cancer', 'Disease', (228, 245))	('expression', 'MPA', (83, 93))	('cell apoptosis', 'CPA', (265, 279))	('Bax', 'Gene', (65, 68))	('Bax', 'Gene', '581', (65, 68))	('silencing', 'Var', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('intensify', 'PosReg', (193, 202))	('Bcl-2', 'Gene', (114, 119))	('Rpph1', 'Gene', '85495', (173, 178))	('promoting', 'PosReg', (255, 264))	('caspase-3', 'Gene', '836', (73, 82))	('Bcl-2', 'Gene', '596', (114, 119))	('Rpph1', 'Gene', '85495', (30, 35))	('Rpph1', 'Gene', (173, 178))	('esophageal cancer', 'Disease', 'MESH:D004938', (228, 245))	('caspase-3', 'Gene', (73, 82))
362366	32351293	The siRNA-Rpph1+IR group (6 Gy) had significantly more G2/M phase cells than the siRNA-NC + IR group (P < 0.05), indicating that downregulation of Rpph1 expression can effectively alleviate radiation-induced G2/M phase arrest, thereby enhancing the radio-sensitivity of TE-1 and Kyse150 cells.	('downregulation', 'Var', (129, 143))	('arrest', 'Disease', 'MESH:D006323', (219, 225))	('arrest', 'Disease', (219, 225))	('Rpph1', 'Gene', (10, 15))	('Rpph1', 'Gene', (147, 152))	('Rpph1', 'Gene', '85495', (147, 152))	('TE', 'Chemical', 'MESH:D013691', (270, 272))	('alleviate', 'NegReg', (180, 189))	('enhancing', 'PosReg', (235, 244))	('Rpph1', 'Gene', '85495', (10, 15))	('G2/M phase cells', 'CPA', (55, 71))
362377	32351293	To a certain extent, silencing Rpph1 expression can promote cell apoptosis, inhibit cell proliferation and migration, relieve radiation-induced G2/M phase arrest, and enhance radio-sensitivity.	('enhance', 'PosReg', (167, 174))	('Rpph1', 'Gene', '85495', (31, 36))	('arrest', 'Disease', 'MESH:D006323', (155, 161))	('inhibit', 'NegReg', (76, 83))	('silencing', 'Var', (21, 30))	('relieve', 'NegReg', (118, 125))	('arrest', 'Disease', (155, 161))	('Rpph1', 'Gene', (31, 36))	('cell apoptosis', 'CPA', (60, 74))	('radio-sensitivity', 'CPA', (175, 192))	('promote', 'PosReg', (52, 59))
362391	32351293	The results of 3-year survival supported patients with low Rpph1 expression over those with high Rpph1 expression (P < 0.05).	('Rpph1', 'Gene', (59, 64))	('Rpph1', 'Gene', '85495', (97, 102))	('Rpph1', 'Gene', (97, 102))	('patients', 'Species', '9606', (41, 49))	('low', 'NegReg', (55, 58))	('Rpph1', 'Gene', '85495', (59, 64))	('expression', 'Var', (65, 75))
362392	32351293	Cytological studies indicated that silencing the expression of Rpph1 contributed to the enhancement of radio-sensitivity of esophageal cancer cells and cell apoptosis via regulating apoptosis-linked proteins, thus relieving the radiation-induced G2/M phase cell cycle arrest.	('radio-sensitivity', 'CPA', (103, 120))	('apoptosis-linked proteins', 'MPA', (182, 207))	('regulating', 'Reg', (171, 181))	('silencing', 'Var', (35, 44))	('esophageal cancer', 'Disease', (124, 141))	('cell apoptosis', 'CPA', (152, 166))	('arrest', 'Disease', 'MESH:D006323', (268, 274))	('Rpph1', 'Gene', (63, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('arrest', 'Disease', (268, 274))	('enhancement', 'PosReg', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('relieving', 'NegReg', (214, 223))	('Rpph1', 'Gene', '85495', (63, 68))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (257, 274))
362393	32351293	Silencing Rpph1 expression has an influence on the biological behavior of tumor cells and the enhancement of radio-sensitivity.	('enhancement', 'PosReg', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Rpph1', 'Gene', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('radio-sensitivity', 'CPA', (109, 126))	('influence', 'Reg', (34, 43))	('tumor', 'Disease', (74, 79))	('Silencing', 'Var', (0, 9))	('Rpph1', 'Gene', '85495', (10, 15))
362394	32351293	This study revealed the value of Rpph1 in the diagnosis of esophageal cancer and concluded that silencing Rpph1 expression can enhance the radiotherapy of tumor cells, illuminating a new target for the future treatment of esophageal cancer.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('esophageal cancer', 'Disease', (59, 76))	('silencing', 'Var', (96, 105))	('esophageal cancer', 'Disease', 'MESH:D004938', (222, 239))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('enhance', 'PosReg', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('Rpph1', 'Gene', '85495', (33, 38))	('tumor', 'Disease', (155, 160))	('Rpph1', 'Gene', '85495', (106, 111))	('Rpph1', 'Gene', (33, 38))	('esophageal cancer', 'Disease', (222, 239))	('Rpph1', 'Gene', (106, 111))
362498	32071596	Studies also found smoking can raise CEA levels.	('raise', 'PosReg', (31, 36))	('smoking', 'Var', (19, 26))	('CEA', 'Gene', '1048', (37, 40))	('raise CEA', 'Phenotype', 'HP:0031029', (31, 40))	('CEA', 'Gene', (37, 40))
362621	27130186	After 1 year, a better QoL is still observed for MIE in comparison with the open approach, while having the same survival.	('MIE', 'Var', (49, 52))	('MIE', 'Chemical', '-', (49, 52))	('QoL', 'MPA', (23, 26))
362673	27130186	This study suggests that POM is significantly reduced after MIE for EC.	('MIE', 'Chemical', '-', (60, 63))	('reduced', 'NegReg', (46, 53))	('MIE', 'Var', (60, 63))	('POM', 'Disease', (25, 28))
362706	24649245	Additionally, we have reported that preoperative CRT in UICC stage II/III (non-T4) ESCC contributed to tumor shrinkage, leading to higher resectability and longer patient survival.	('resectability', 'CPA', (138, 151))	('CRT', 'Var', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('patient survival', 'CPA', (163, 179))	('patient', 'Species', '9606', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('higher', 'PosReg', (131, 137))	('longer', 'PosReg', (156, 162))
362710	24649245	The eligibility criteria for the present study were as follows: age <80 years, adequate organ function (white blood cell count >=3,500, hemoglobin >=10 g/dl, aspartate aminotransferase/alanine aminotransferase <=2x upper limit of normal, platelet count >=100,000/mm3, serum creatinine <=1.3 mg/dl) and a performance status (Eastern Cooperative Oncology Group) of <2 at the time of admission.	('serum creatinine', 'MPA', (268, 284))	('>=10', 'Var', (147, 151))	('organ function', 'CPA', (88, 102))	('hemoglobin', 'MPA', (136, 146))	('Oncology', 'Phenotype', 'HP:0002664', (344, 352))	('creatinine', 'Chemical', 'MESH:D003404', (274, 284))
362784	24403269	High RAB25 expression is associated with good clinical outcome in patients with locally advanced head and neck squamous cell carcinoma Currently there are no molecular markers able to predict clinical outcome in locally advanced head and neck squamous cell carcinoma (HNSCC).	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (97, 134))	('locally', 'Disease', (80, 87))	('HNSCC', 'Phenotype', 'HP:0012288', (268, 273))	('neck squamous cell carcinoma', 'Disease', (106, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('High', 'Var', (0, 4))	('RAB25', 'Gene', (5, 10))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (106, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('expression', 'MPA', (11, 21))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (229, 266))	('patients', 'Species', '9606', (66, 74))	('neck squamous cell carcinoma', 'Disease', (238, 266))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (238, 266))	('RAB25', 'Gene', '57111', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
362806	24403269	Loss of RAB25 expression has been associated with tumor initiation and poor prognosis in colon, esophageal and estrogen receptor (ER)-negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('associated', 'Reg', (34, 44))	('RAB25', 'Gene', (8, 13))	('breast cancer', 'Disease', (143, 156))	('colon', 'Disease', (89, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('tumor initiation', 'Disease', 'MESH:D009369', (50, 66))	('esophageal', 'Disease', (96, 106))	('estrogen receptor', 'Gene', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('estrogen receptor', 'Gene', '2099', (111, 128))	('tumor initiation', 'Disease', (50, 66))	('ER', 'Gene', '2099', (130, 132))	('Loss', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
362836	24403269	mRNA expression was measured on an ABIPRISM 7000 Sequence Detection System (Life Technologies Ltd, Paisley, U.K.) using predesigned Taqman  Gene Expression Assays for RAB25 (Hs00220628_m1) and HPRT1 (Hs99999909_m1) (Life Technologies Ltd, Paisley, U.K.), as previously described.	('Hs99999909_m1', 'Var', (200, 213))	('Hs00220628_m1', 'Var', (174, 187))	('HPRT1', 'Gene', '3251', (193, 198))	('HPRT1', 'Gene', (193, 198))
362865	24403269	Patients were classified in two groups according to their risk of death, as a function of having low- or high-RAB25 mRNA levels, using classification and regression tree analysis (CART).	('low-', 'NegReg', (97, 101))	('CART', 'Gene', (180, 184))	('death', 'Disease', 'MESH:D003643', (66, 71))	('Patients', 'Species', '9606', (0, 8))	('high-RAB25', 'Var', (105, 115))	('death', 'Disease', (66, 71))	('CART', 'Gene', '9607', (180, 184))
362875	24403269	Multivariate Cox model analysis showed that expression of RAB25 was an independent risk factor for CSS (hazard ratio [HR]: 0.464, 95% confidence interval [CI] [0.212-1.017], P = 0.050) (Table S1).	('Cox', 'Gene', (13, 16))	('CSS', 'Gene', '55907', (99, 102))	('expression', 'Var', (44, 54))	('CSS', 'Gene', (99, 102))	('RAB25', 'Gene', (58, 63))	('Cox', 'Gene', '1351', (13, 16))
362879	24403269	Cox model analysis showed that a high expression of RAB25 was associated with a higher patient survival (HR: 0.64, CI 95% [0.42-0.97], P = 0.03).	('high expression', 'Var', (33, 48))	('Cox', 'Gene', '1351', (0, 3))	('patient survival', 'CPA', (87, 103))	('Cox', 'Gene', (0, 3))	('patient', 'Species', '9606', (87, 94))	('higher', 'PosReg', (80, 86))	('RAB25', 'Gene', (52, 57))
362885	24403269	The subset of patients with a low-RAB25 expression had lower LRFS, PFS, and CSS than patients with high-RAB25 expression.	('CSS', 'Gene', (76, 79))	('LRFS', 'CPA', (61, 65))	('patients', 'Species', '9606', (85, 93))	('lower', 'NegReg', (55, 60))	('low-RAB25 expression', 'Var', (30, 50))	('patients', 'Species', '9606', (14, 22))	('CSS', 'Gene', '55907', (76, 79))	('PFS', 'CPA', (67, 70))
362886	24403269	Multivariate Cox model analysis showed that RAB25 mRNA level was an independent risk factor for LRFS (HR: 3.00, 95% CI [1.46-6.17], P = 0.003), PFS (HR: 2.49, 95% CI [1.41-4.41], P = 0.002), and CSS (HR: 3.84, 95% CI [1.93-7.62], P < 0.001) in locally advanced HNSCC patients (Table 2).	('CSS', 'Gene', (195, 198))	('RAB25 mRNA level', 'Var', (44, 60))	('PFS', 'Disease', (144, 147))	('LRFS', 'Disease', (96, 100))	('patients', 'Species', '9606', (267, 275))	('Cox', 'Gene', (13, 16))	('HNSCC', 'Phenotype', 'HP:0012288', (261, 266))	('CSS', 'Gene', '55907', (195, 198))	('locally advanced HNSCC', 'Disease', (244, 266))	('Cox', 'Gene', '1351', (13, 16))
362893	24403269	Again, multivariate Cox model confirmed that RAB25 mRNA level was an independent risk factor for PFS and CSS (Table 2).	('CSS', 'Gene', '55907', (105, 108))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('PFS', 'Disease', (97, 100))	('RAB25 mRNA level', 'Var', (45, 61))	('CSS', 'Gene', (105, 108))
362914	24403269	Breast, bladder, and ovarian cancer studies have suggested that a high expression of RAB25 is associated with poor prognosis; however, these results are controversial.	('ovarian cancer', 'Phenotype', 'HP:0100615', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('RAB25', 'Gene', (85, 90))	('ovarian cancer', 'Disease', 'MESH:D010051', (21, 35))	('high', 'Var', (66, 70))	('ovarian cancer', 'Disease', (21, 35))
362916	24403269	showed that a high expression of RAB25 was associated with higher recurrence-free survival in breast cancer patients, but they observed that RAB25 loss its predictive value when they analyzed hormone receptor-positive tumors only.	('expression', 'MPA', (19, 29))	('hormone receptor', 'Gene', (192, 208))	('patients', 'Species', '9606', (108, 116))	('RAB25', 'Gene', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('hormone receptor', 'Gene', '3164', (192, 208))	('high', 'Var', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('loss', 'NegReg', (147, 151))	('higher', 'PosReg', (59, 65))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('recurrence-free', 'MPA', (66, 81))	('breast cancer', 'Disease', (94, 107))	('tumors', 'Disease', (218, 224))
362918	24403269	The increased sensitivity to cisplatin and cell proliferation we observed in the UM-SCC-74B cell line overexpressing RAB25 could explain why patients with high-RAB25 tumor expression obtain greater clinical benefit from genotoxic treatment than patients with low RAB25 tumor expression.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('high-RAB25', 'Var', (155, 165))	('patients', 'Species', '9606', (245, 253))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Disease', (269, 274))	('tumor', 'Disease', (166, 171))	('benefit', 'PosReg', (207, 214))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('RAB25', 'Gene', (117, 122))	('patients', 'Species', '9606', (141, 149))
362926	24403269	Loss of RAB25 expression could therefore increase the invasion and dissemination ability of tumor cells in patients, and consequently increase the risk of recurrences and development of lymph node or distant metastases.	('patients', 'Species', '9606', (107, 115))	('metastases', 'Disease', (208, 218))	('RAB25', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('recurrences', 'CPA', (155, 166))	('metastases', 'Disease', 'MESH:D009362', (208, 218))	('tumor', 'Disease', (92, 97))	('increase', 'PosReg', (134, 142))	('Loss', 'Var', (0, 4))	('increase', 'PosReg', (41, 49))
362930	24403269	RAB25-/- Smad3+/- mice showed large invasive lesions in a high percentage of animals.	('Smad3', 'Gene', (9, 14))	('mice', 'Species', '10090', (18, 22))	('RAB25-/-', 'Var', (0, 8))	('Smad3', 'Gene', '17127', (9, 14))	('invasive lesions', 'CPA', (36, 52))
362943	24403269	Our findings showed that loss of RAB25 expression is a common event in HNSCCs and supported its role as a tumor suppressor.	('loss', 'Var', (25, 29))	('RAB25', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('HNSCCs', 'Disease', (71, 77))	('HNSCC', 'Phenotype', 'HP:0012288', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('expression', 'MPA', (39, 49))	('tumor', 'Disease', (106, 111))
362947	24403269	described that loss of RAB25 promotes the development of intestinal neoplasia in mice.	('neoplasia', 'Phenotype', 'HP:0002664', (68, 77))	('mice', 'Species', '10090', (81, 85))	('intestinal neoplasia', 'Disease', (57, 77))	('RAB25', 'Gene', (23, 28))	('intestinal neoplasia', 'Disease', 'MESH:D009369', (57, 77))	('loss', 'Var', (15, 19))	('promotes', 'PosReg', (29, 37))
362949	24403269	showed that esophageal squamous cell carcinoma cells (ESCC) overexpressing RAB25 have a lower rate of tumor formation than ESCC cells with repressed RAB25 in an in vivo model.	('RAB25', 'Var', (75, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (12, 46))	('overexpressing RAB25', 'Var', (60, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('lower', 'NegReg', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('esophageal squamous cell carcinoma', 'Disease', (12, 46))
362950	24403269	After demethylation by exposure to 5-aza-20-deoxycitidine (5-aza-dC), mRNA levels of RAB25 increased in both cell lines, suggesting that promoter hypermethylation may play a role in silencing RAB25 expression in HNSCC.	('mRNA levels', 'MPA', (70, 81))	('5-aza-20-deoxycitidine', 'Chemical', '-', (35, 57))	('HNSCC', 'Disease', (212, 217))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (59, 67))	('demethylation', 'Var', (6, 19))	('RAB25', 'Gene', (192, 197))	('increased', 'PosReg', (91, 100))	('expression', 'MPA', (198, 208))	('HNSCC', 'Phenotype', 'HP:0012288', (212, 217))	('silencing', 'NegReg', (182, 191))
362963	24403269	(A) Classification and regression tree analysis separated patients treated with genotoxic treatment in two risk groups using RAB25 mRNA level in pretreatment tumor biopsy (<1.75 or >1.75).	('RAB25', 'Gene', (125, 130))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('patients', 'Species', '9606', (58, 66))	('<1.75', 'Var', (172, 177))
362967	24403269	(B) Hoechst assay showed a higher cell death rate in UM-SCC-74B RAB25 overexpressing cells than in UM-SCC-74B wild-type cells, after 24 h of exposure to cisplatin (15 mumol/L).	('death', 'Disease', 'MESH:D003643', (39, 44))	('death', 'Disease', (39, 44))	('UM-SCC-74B', 'Var', (53, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('Hoechst', 'Chemical', '-', (4, 11))	('RAB25', 'Gene', (64, 69))	('higher', 'PosReg', (27, 33))	('overexpressing', 'Var', (70, 84))
362978	23238586	For example, the incidence of gastric cancer following treatment with N-methyl-N'-nitro-N-nitrosoguanidine, a carcinogenic N-nitroso compound, is significantly higher in male than in female rats.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('higher', 'PosReg', (160, 166))	('N-nitroso', 'Chemical', '-', (123, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (30, 44))	('gastric cancer', 'Disease', (30, 44))	("N-methyl-N'-nitro-N-nitrosoguanidine", 'Chemical', 'MESH:D008769', (70, 106))	("N-methyl-N'-nitro-N-nitrosoguanidine", 'Var', (70, 106))	('rats', 'Species', '10116', (190, 194))	('men', 'Species', '9606', (60, 63))	('N-nitroso', 'Chemical', '-', (88, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (30, 44))
363126	29677645	Alterations in autophagy are associated with cancer pathogenesis, including ESCC; however, the functional role of autophagy in ESCC remains elusive.	('ESCC', 'Disease', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Alterations', 'Var', (0, 11))	('autophagy', 'CPA', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('associated', 'Reg', (29, 39))	('cancer', 'Disease', (45, 51))
363130	29677645	Despite extensive characterization of the genomic landscape of ESCC, which often features overexpression of epidermal growth factor receptor (EGFR) and Cyclin D1 as well as TP53 mutations, effective targeted therapies remain elusive.	('epidermal growth factor receptor', 'Gene', '1956', (108, 140))	('Cyclin D1', 'Gene', (152, 161))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('epidermal growth factor receptor', 'Gene', (108, 140))	('ESCC', 'Disease', (63, 67))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (173, 177))	('mutations', 'Var', (178, 187))	('Cyclin D1', 'Gene', '595', (152, 161))	('overexpression', 'PosReg', (90, 104))
363133	29677645	AV biogenesis is induced by upstream signals, including mammalian target of rapamycin (mTOR) inactivation and AMP-activated protein kinase (AMPK) activation.	('mTOR', 'Gene', '2475', (87, 91))	('activation', 'PosReg', (146, 156))	('AMP-activated protein kinase', 'Gene', '5562', (110, 138))	('AMP-activated protein kinase', 'Gene', (110, 138))	('induced', 'Reg', (17, 24))	('inactivation', 'Var', (93, 105))	('AMPK', 'Gene', (140, 144))	('AMPK', 'Gene', '5562', (140, 144))	('mammalian target of rapamycin', 'Gene', '2475', (56, 85))	('mammalian target of rapamycin', 'Gene', (56, 85))	('AV biogenesis', 'Disease', (0, 13))	('mTOR', 'Gene', (87, 91))
363135	29677645	Alterations in autophagy have been linked to human pathologies, including neurodegeneration, inflammatory bowel disease, and cancer.	('neurodegeneration', 'Phenotype', 'HP:0002180', (74, 91))	('linked', 'Reg', (35, 41))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (93, 119))	('Alterations', 'Var', (0, 11))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (93, 119))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('autophagy', 'CPA', (15, 24))	('neurodegeneration', 'Disease', (74, 91))	('human', 'Species', '9606', (45, 50))	('inflammatory bowel disease', 'Disease', (93, 119))	('neurodegeneration', 'Disease', 'MESH:D019636', (74, 91))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
363149	29677645	Co-occurrence of ATG7 deletions with amplification in NFE2L2, encoding the antioxidant mediator NRF2, support ATG7 as a critical mediator of oxidative stress.	('ATG7', 'Gene', (110, 114))	('NFE2L2', 'Gene', '4780', (54, 60))	('deletions', 'Var', (22, 31))	('ATG7', 'Gene', '10533', (17, 21))	('NRF2', 'Gene', (96, 100))	('NFE2L2', 'Gene', (54, 60))	('ATG7', 'Gene', '10533', (110, 114))	('ATG7', 'Gene', (17, 21))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))	('NRF2', 'Gene', '4780', (96, 100))
363151	29677645	Complementary BECLIN 1 knockdown and overexpression experiments further revealed a respective increase and decrease in invasion of EC9706 ESCC cells, supporting a potential functional role for BECLIN 1 downregulation in ESCC progression.	('BECLIN 1', 'Gene', '8678', (193, 201))	('BECLIN 1', 'Gene', (14, 22))	('BECLIN 1', 'Gene', (193, 201))	('invasion', 'CPA', (119, 127))	('EC9706', 'Var', (131, 137))	('ESCC', 'Disease', (220, 224))	('decrease', 'NegReg', (107, 115))	('downregulation', 'NegReg', (202, 216))	('EC9706', 'CellLine', 'CVCL:E307', (131, 137))	('BECLIN 1', 'Gene', '8678', (14, 22))
363153	29677645	Aberrant methylation of LC3Av1, transcriptional variant 1 of the LC3A isoform, was identified in a subset of human ESCC tumors concurrent with diminished protein expression.	('protein expression', 'MPA', (154, 172))	('human', 'Species', '9606', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('Aberrant', 'Var', (0, 8))	('LC3A', 'Gene', (24, 28))	('LC3A', 'Gene', '84557', (24, 28))	('identified', 'Reg', (83, 93))	('LC3A', 'Gene', (65, 69))	('LC3A', 'Gene', '84557', (65, 69))	('diminished', 'NegReg', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('methylation', 'MPA', (9, 20))	('ESCC tumors', 'Disease', (115, 126))	('ESCC tumors', 'Disease', 'MESH:D004938', (115, 126))
363154	29677645	Forty five percent of ESCC cell lines additionally displayed LC3Av1 gene silencing and ectopic LC3Av1 expression inhibited xenograft tumor growth of KYSE170 ESCC cells.	('LC3A', 'Gene', (61, 65))	('LC3A', 'Gene', (95, 99))	('LC3A', 'Gene', '84557', (61, 65))	('LC3A', 'Gene', '84557', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('inhibited', 'NegReg', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('ectopic', 'Var', (87, 94))
363162	29677645	In early-stage ESCC tumors, single nucleotide polymorphisms (SNPs) in the ATG5 gene locus correlated with prognosis and predicted early distant metastasis.	('single nucleotide polymorphisms', 'Var', (28, 59))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('ESCC tumors', 'Disease', 'MESH:D004938', (15, 26))	('early distant metastasis', 'CPA', (130, 154))	('correlated with', 'Reg', (90, 105))	('ATG5', 'Gene', '9474', (74, 78))	('prognosis', 'CPA', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ATG5', 'Gene', (74, 78))	('ESCC tumors', 'Disease', (15, 26))	('predicted', 'Reg', (120, 129))
363171	29677645	It is possible that co-analysis of LC3 along with other ESCC-relevant factors may prove to be an effective strategy toward improving the clinical utility of LC3 an ESCC biomarker as co-expression of LC3 and p53 has been shown to correlate poor prognosis.	('LC3', 'Gene', '84557', (199, 202))	('LC3', 'Gene', '84557', (35, 38))	('LC3', 'Gene', (157, 160))	('LC3', 'Gene', (199, 202))	('LC3', 'Gene', (35, 38))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '7157', (207, 210))	('co-expression', 'Var', (182, 195))	('LC3', 'Gene', '84557', (157, 160))
363172	29677645	With regard to post-therapeutic ESCC prognosis, high expression of LC3 has been shown to correlate with poor response to neoadjuvant chemotherapy.	('LC3', 'Gene', '84557', (67, 70))	('high expression', 'Var', (48, 63))	('LC3', 'Gene', (67, 70))
363173	29677645	Finally, a role for mitophagy in ESCC therapeutic response is suggested as upregulation of PINK1 was found in ESCC patients treated with preoperative chemotherapy as compared their treatment naive counterparts and high PINK1 expression predicted poor chemotherapeutic response.	('PINK1', 'Gene', (91, 96))	('high', 'Var', (214, 218))	('PINK1', 'Gene', '65018', (219, 224))	('patients', 'Species', '9606', (115, 123))	('PINK1', 'Gene', (219, 224))	('upregulation', 'PosReg', (75, 87))	('ESCC', 'Disease', (110, 114))	('PINK1', 'Gene', '65018', (91, 96))	('expression', 'MPA', (225, 235))
363180	29677645	MACC1 depletion reduced ESCC cell proliferation, migration and invasion concurrent with inhibition of autophagy.	('MACC1', 'Gene', '346389', (0, 5))	('inhibition', 'NegReg', (88, 98))	('migration', 'CPA', (49, 58))	('MACC1', 'Gene', (0, 5))	('reduced', 'NegReg', (16, 23))	('depletion', 'Var', (6, 15))	('invasion', 'CPA', (63, 71))	('ESCC', 'Disease', (24, 28))	('autophagy', 'CPA', (102, 111))
363207	29677645	For example, the bisaminoquinoline Lys05 triggers a greater deacidification of the lysosome compared to HCQ and has been shown to more effectively block autophagy in preclinical models.	('bisaminoquinoline', 'Chemical', '-', (17, 34))	('block', 'NegReg', (147, 152))	('deacidification of the lysosome', 'MPA', (60, 91))	('autophagy', 'CPA', (153, 162))	('Lys05', 'Chemical', 'MESH:C573930', (35, 40))	('Lys05', 'Var', (35, 40))	('HCQ', 'Chemical', 'MESH:D006886', (104, 107))
363208	29677645	Promising preclinical studies have been executed using inhibitors of ULK1, or the class II PI3K VPS34, to limit AV nucleation, as well as antagonists of ATG4B, a mediator of LC3 processing, to suppress AV elongation.	('LC3', 'Gene', (174, 177))	('AV nucleation', 'CPA', (112, 125))	('ULK1', 'Gene', (69, 73))	('limit', 'NegReg', (106, 111))	('PI3', 'Gene', '5266', (91, 94))	('ULK1', 'Gene', '8408', (69, 73))	('suppress', 'NegReg', (193, 201))	('antagonists', 'Var', (138, 149))	('PI3', 'Gene', (91, 94))	('VPS34', 'Gene', '5289', (96, 101))	('VPS34', 'Gene', (96, 101))	('ATG4B', 'Gene', (153, 158))	('inhibitors', 'Var', (55, 65))	('AV elongation', 'CPA', (202, 215))	('LC3', 'Gene', '84557', (174, 177))	('ATG4B', 'Gene', '23192', (153, 158))
363241	29223141	The aberrant choline metabolism in cancer cells is strongly correlated with the progression of malignancy.	('aberrant choline metabolism', 'Phenotype', 'HP:0025047', (4, 31))	('choline', 'Chemical', 'MESH:D002794', (13, 20))	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('aberrant', 'Var', (4, 12))	('correlated', 'Reg', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('malignancy', 'Disease', 'MESH:D009369', (95, 105))	('malignancy', 'Disease', (95, 105))
363313	29223141	In contrast, the CTL1 and CTL2 mRNA expression in HEEpiC was lower than that of KYSE series.	('lower', 'NegReg', (61, 66))	('CTL2', 'Gene', '57153', (26, 30))	('CTL1', 'Gene', (17, 21))	('mRNA expression', 'MPA', (31, 46))	('HEEpiC', 'Var', (50, 56))	('CTL2', 'Gene', (26, 30))
363336	29223141	Choline deficiency significantly inhibited cell viability and significantly increased caspase-3/7 activity in KYSE-180 cells.	('Choline deficiency', 'Phenotype', 'HP:0025048', (0, 18))	('increased', 'PosReg', (76, 85))	('KYSE-180', 'CellLine', 'CVCL:1349', (110, 118))	('Choline', 'Chemical', 'MESH:D002794', (0, 7))	('caspase-3/7', 'Gene', '836;840', (86, 97))	('deficiency', 'Var', (8, 18))	('Choline', 'Gene', (0, 7))	('activity', 'MPA', (98, 106))	('cell viability', 'CPA', (43, 57))	('caspase-3/7', 'Gene', (86, 97))	('inhibited', 'NegReg', (33, 42))
363377	29223141	The inhibition of choline transport decreased PCho and PC contents; cancer cells attempt to overcome this by activating an alternative mechanism for generating PCho and PC.	('PCho', 'Chemical', 'MESH:D010767', (160, 164))	('PCho', 'Chemical', 'MESH:D010767', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PCho', 'MPA', (46, 50))	('PC', 'Chemical', 'MESH:D010713', (169, 171))	('PC', 'Chemical', 'MESH:D010713', (55, 57))	('rat', 'Species', '10116', (153, 156))	('choline', 'Chemical', 'MESH:D002794', (18, 25))	('inhibition', 'Var', (4, 14))	('PC contents', 'MPA', (55, 66))	('choline transport', 'MPA', (18, 35))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('PCho', 'Disease', (160, 164))	('cancer', 'Disease', (68, 74))	('PC', 'Chemical', 'MESH:D010713', (46, 48))	('PC', 'Chemical', 'MESH:D010713', (160, 162))	('choline transport decreased', 'Phenotype', 'HP:0025048', (18, 45))	('decreased', 'NegReg', (36, 45))
363394	29223141	Altered DNA methylation and disruption of DNA repair have been reported in cancer patients.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Disease', (75, 81))	('DNA', 'Protein', (8, 11))	('Altered', 'Reg', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('methylation', 'Var', (12, 23))
363395	29223141	Therefore, epigenetic mechanisms play important roles in carcinogenesis.	('carcinogenesis', 'Disease', (57, 71))	('carcinogenesis', 'Disease', 'MESH:D063646', (57, 71))	('roles', 'Reg', (48, 53))	('epigenetic', 'Var', (11, 21))
363506	28212527	And, secondary endpoints were confirmed L-CR, local progression free survival (L-PFS), progression free survival (PFS), overall survival (OS), L-CR per lesions (Lesion L-CR), and confirmed Lesion L-CR.	('L-PFS', 'Chemical', '-', (79, 84))	('L-CR', 'Chemical', '-', (40, 44))	('L-CR', 'Chemical', '-', (143, 147))	('progression', 'Disease', (87, 98))	('L-CR', 'Chemical', '-', (196, 200))	('L-CR', 'Var', (143, 147))	('local progression free survival', 'CPA', (46, 77))	('overall survival', 'CPA', (120, 136))	('L-CR', 'Chemical', '-', (168, 172))	('L-CR', 'Disease', (40, 44))
363691	31053962	Tumor diameter (> 4 cm), poor differentiation, and pN3-4 have been reported as prognostic factors in ESCC.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('pN3-4', 'Var', (51, 56))	('SCC', 'Gene', (102, 105))
363765	30079377	CA-MRSA is a very rare cause of pericarditis and to date only 12 cases have been reported.	('pericarditis', 'Disease', 'MESH:D010493', (32, 44))	('pericarditis', 'Disease', (32, 44))	('CA-MRSA', 'Var', (0, 7))	('pericarditis', 'Phenotype', 'HP:0001701', (32, 44))
363771	30079377	A venous blood gas analysis revealed a pH of 7.219, pCO2 of 28.5 mm Hg, pO2 28.4 mm Hg, oxygen saturation of 32.6%, bicarbonate level of 8 mmol/L suggesting metabolic alkalosis.	('venous blood gas', 'Disease', (2, 18))	('oxygen saturation', 'MPA', (88, 105))	('pO2', 'Var', (72, 75))	('venous blood gas', 'Disease', 'MESH:D011007', (2, 18))	('metabolic alkalosis', 'Phenotype', 'HP:0200114', (157, 176))	('alkalosis', 'Phenotype', 'HP:0001948', (167, 176))	('bicarbonate level', 'MPA', (116, 133))
363877	28666313	Plausible mechanisms explaining the associations include heme iron, polycyclic aromatic hydrocarbons, dietary N-nitroso compounds (NOC) and endogenous nitrosation, that are potentially carcinogenic to humans.	('NOC', 'Chemical', '-', (131, 134))	('humans', 'Species', '9606', (201, 207))	('iron', 'Chemical', 'MESH:D007501', (62, 66))	('carcinogenic', 'Disease', 'MESH:D063646', (185, 197))	('carcinogenic', 'Disease', (185, 197))	('endogenous nitrosation', 'MPA', (140, 162))	('heme', 'Chemical', 'MESH:D006418', (57, 61))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (68, 100))	('N-nitroso compounds', 'Chemical', '-', (110, 129))	('polycyclic', 'Var', (68, 78))	('heme iron', 'Protein', (57, 66))
363892	28666313	In agreement with this study, Lin, 2015 reported direct but not significant association for waist circumference in a multivariate-adjusted model including BMI and smoking.	('men', 'Species', '9606', (8, 11))	('Lin', 'Var', (30, 33))	('waist circumference', 'Disease', (92, 111))
363912	29416661	Aberrant Gli1/2 expression was found in EAC patient tissues, and was significantly associated with increased EMT and AKT pathway activity.	('AKT', 'Gene', '207', (117, 120))	('EAC', 'Phenotype', 'HP:0011459', (40, 43))	('patient', 'Species', '9606', (44, 51))	('Gli1/2', 'Gene', (9, 15))	('Aberrant', 'Var', (0, 8))	('AKT', 'Gene', (117, 120))	('EMT and', 'CPA', (109, 116))	('increased', 'PosReg', (99, 108))	('expression', 'Species', '29278', (16, 26))	('expression', 'MPA', (16, 26))	('increased EMT', 'Phenotype', 'HP:0008151', (99, 112))
363915	29416661	Both Gli and AKT inhibition rescued E-cadherin expression and suppressed AKT phosphorylation.	('AKT', 'Gene', (73, 76))	('E-cadherin', 'Gene', (36, 46))	('inhibition', 'Var', (17, 27))	('rescued', 'PosReg', (28, 35))	('suppressed', 'NegReg', (62, 72))	('AKT', 'Gene', '207', (13, 16))	('Gli', 'Gene', '2735', (5, 8))	('E-cadherin', 'Gene', '999', (36, 46))	('expression', 'Species', '29278', (47, 57))	('Gli', 'Gene', (5, 8))	('AKT', 'Gene', '207', (73, 76))	('expression', 'MPA', (47, 57))	('AKT', 'Gene', (13, 16))
363916	29416661	This study provides evidence for a strong association between aberrant Gli1/2 expression and AKT/EMT markers in EAC; activated SHh/Gli signaling may be a critical component in promoting cell survival, metastases, and resistance to chemotherapy, and represents a promising avenue to target tumor proliferation and mobility.	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('Gli', 'Gene', (131, 134))	('cell survival', 'CPA', (186, 199))	('metastases', 'Disease', 'MESH:D009362', (201, 211))	('SHh', 'Gene', '6469', (127, 130))	('Gli', 'Gene', '2735', (71, 74))	('expression', 'Species', '29278', (78, 88))	('metastases', 'Disease', (201, 211))	('AKT', 'Gene', (93, 96))	('Gli', 'Gene', (71, 74))	('EAC', 'Disease', (112, 115))	('tumor', 'Disease', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('promoting', 'PosReg', (176, 185))	('SHh', 'Gene', (127, 130))	('aberrant', 'Var', (62, 70))	('AKT', 'Gene', '207', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('Gli', 'Gene', '2735', (131, 134))
363933	29416661	While some studies have shown that SHh/Gli inhibition block EMT, the exact mechanisms have not been elucidated.	('inhibition', 'Var', (43, 53))	('SHh', 'Gene', (35, 38))	('block', 'NegReg', (54, 59))	('Gli', 'Gene', (39, 42))	('EMT', 'CPA', (60, 63))	('Gli', 'Gene', '2735', (39, 42))	('SHh', 'Gene', '6469', (35, 38))
363937	29416661	Studies in melanoma and hepatocellular carcinoma have linked Gli1 to vascular/capsular invasion, advanced tumor stage, and upregulation of matrix metalloprotease (MMP)-2 and MMP-9, while siRNA silencing of Gli1 successfully reduced invasion and increased E-cadherin expression.	('expression', 'MPA', (266, 276))	('vascular/capsular invasion', 'CPA', (69, 95))	('melanoma and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (11, 48))	('Gli1', 'Gene', (61, 65))	('tumor', 'Disease', (106, 111))	('reduced', 'NegReg', (224, 231))	('Gli1', 'Gene', '2735', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('expression', 'Species', '29278', (266, 276))	('invasion', 'CPA', (232, 240))	('upregulation', 'PosReg', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('E-cadherin', 'Gene', (255, 265))	('E-cadherin', 'Gene', '999', (255, 265))	('Gli1', 'Gene', (206, 210))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (24, 48))	('Gli1', 'Gene', '2735', (61, 65))	('increased', 'PosReg', (245, 254))	('silencing', 'Var', (193, 202))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))
363938	29416661	Our lab recently studied upregulated signaling in lung cancer, investigating Gli1's inverse correlation with E-cadherin; inhibition of the SHh pathway upregulates E-cadherin expression and suppresses lung cancer cell migration.	('expression', 'Species', '29278', (174, 184))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('E-cadherin', 'Gene', (109, 119))	('inhibition', 'Var', (121, 131))	('E-cadherin', 'Gene', '999', (109, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('Gli1', 'Gene', (77, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('E-cadherin', 'Gene', (163, 173))	('SHh', 'Gene', (139, 142))	('E-cadherin', 'Gene', '999', (163, 173))	('upregulates', 'PosReg', (151, 162))	('expression', 'MPA', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('lung cancer', 'Disease', (50, 61))	('Gli1', 'Gene', '2735', (77, 81))	('SHh', 'Gene', '6469', (139, 142))	('suppresses', 'NegReg', (189, 199))
363940	29416661	Gli and EMT markers were found to be inversely correlated, and inhibition of the former minimized migration and invasion of EAC cells.	('Gli', 'Gene', '2735', (0, 3))	('EAC', 'Phenotype', 'HP:0011459', (124, 127))	('inhibition', 'Var', (63, 73))	('minimized', 'NegReg', (88, 97))	('Gli', 'Gene', (0, 3))
363956	29416661	As expected, N-Shh stimulation of cells significantly increased reporter activity in OE19 and OE33 (p < 0.05), while Gli-i treatment of transfected cells showed over 30% less relative reporter activity in both cell lines.	('Shh', 'Gene', (15, 18))	('OE19', 'Var', (85, 89))	('Gli', 'Gene', (117, 120))	('reporter activity', 'MPA', (64, 81))	('increased', 'PosReg', (54, 63))	('Gli', 'Gene', '2735', (117, 120))	('Shh', 'Gene', '6469', (15, 18))	('OE33', 'Var', (94, 98))
363968	29416661	In addition, functional analyses with siRNA knockdown of both Gli1 and Gli2 yielded western blot data consistent with earlier parts of the figure, showing decreased Gli1, Gli2, and EMT activity (as measured by E-cadherin, N-cadherin, and beta-catenin) in both OE19 and OE33 cell lines (Figure 3C).	('EMT activity', 'CPA', (181, 193))	('Gli1', 'Gene', '2735', (165, 169))	('N-cadherin', 'Gene', '1000', (222, 232))	('Gli2', 'Gene', '2736', (171, 175))	('Gli2', 'Gene', (71, 75))	('Gli1', 'Gene', (62, 66))	('Gli1', 'Gene', '2735', (62, 66))	('beta-catenin', 'Gene', (238, 250))	('Gli2', 'Gene', (171, 175))	('Gli2', 'Gene', '2736', (71, 75))	('decreased', 'NegReg', (155, 164))	('beta-catenin', 'Gene', '1499', (238, 250))	('knockdown', 'Var', (44, 53))	('E-cadherin', 'Gene', (210, 220))	('Gli1', 'Gene', (165, 169))	('N-cadherin', 'Gene', (222, 232))	('E-cadherin', 'Gene', '999', (210, 220))
363969	29416661	Taken together, these results strongly suggest that inhibition of Gli signaling may suppress EMT and cell cycle progression in EAC.	('Gli', 'Gene', (66, 69))	('EMT', 'CPA', (93, 96))	('Gli', 'Gene', '2735', (66, 69))	('EAC', 'Phenotype', 'HP:0011459', (127, 130))	('suppress', 'NegReg', (84, 92))	('cell cycle progression', 'CPA', (101, 123))	('inhibition', 'Var', (52, 62))	('EAC', 'Disease', (127, 130))
363973	29416661	Furthermore, in transwell invasion assays, both OE19 and OE33 demonstrated decreased invasion by approximately 50% following Gli-i treatment (Figure 5A, 5B).	('OE33', 'Var', (57, 61))	('Gli', 'Gene', (125, 128))	('OE19', 'Var', (48, 52))	('invasion', 'CPA', (85, 93))	('Gli', 'Gene', '2735', (125, 128))	('decreased', 'NegReg', (75, 84))
363976	29416661	OE19 and OE33 EAC cells were administered MK2206, an AKT inhibitor (AKT-i), and analyzed by western blot to determine protein levels of relevant pathway and EMT markers after 30 hours of incubation.	('MK2206', 'Chemical', 'MESH:C548887', (42, 48))	('protein levels', 'MPA', (118, 132))	('AKT', 'Gene', '207', (53, 56))	('AKT', 'Gene', '207', (68, 71))	('MK2206', 'Var', (42, 48))	('EAC', 'Phenotype', 'HP:0011459', (14, 17))	('AKT', 'Gene', (53, 56))	('AKT', 'Gene', (68, 71))
363981	29416661	Thus, inhibition of AKT and Gli signaling may serve as a promising avenue for decreased EMT and cell cycle activity, both of which are linked to greater aggression and viability in EAC.	('AKT', 'Gene', (20, 23))	('decreased EMT', 'Phenotype', 'HP:0032198', (78, 91))	('aggression', 'Phenotype', 'HP:0000718', (153, 163))	('Gli', 'Gene', (28, 31))	('Gli', 'Gene', '2735', (28, 31))	('aggression', 'Disease', (153, 163))	('aggression', 'Disease', 'MESH:D001523', (153, 163))	('cell cycle activity', 'CPA', (96, 115))	('EMT', 'CPA', (88, 91))	('EAC', 'Phenotype', 'HP:0011459', (181, 184))	('inhibition', 'Var', (6, 16))	('AKT', 'Gene', '207', (20, 23))	('decreased', 'NegReg', (78, 87))
363983	29416661	This study provides strong preliminary evidence that in vitro Gli inhibition impairs the migratory, invasive, and proliferative properties of EAC cells by reducing EMT.	('Gli', 'Gene', (62, 65))	('impairs', 'NegReg', (77, 84))	('Gli', 'Gene', '2735', (62, 65))	('reducing', 'NegReg', (155, 163))	('migratory', 'CPA', (89, 98))	('inhibition', 'Var', (66, 76))	('proliferative properties', 'CPA', (114, 138))	('invasive', 'CPA', (100, 108))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))
363985	29416661	Data also indicated strong relationships to increased m-TOR, p-S6K1, and phosphorylated AKT, which play important roles in tumorigenesis, resistance to therapy, and cancer aggression.	('cancer aggression', 'Disease', (165, 182))	('tumor', 'Disease', (123, 128))	('TOR', 'Gene', (56, 59))	('TOR', 'Gene', '6097', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('S6K1', 'Gene', (63, 67))	('AKT', 'Gene', '207', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('S6K1', 'Gene', '6198', (63, 67))	('AKT', 'Gene', (88, 91))	('cancer aggression', 'Disease', 'MESH:D009369', (165, 182))	('aggression', 'Phenotype', 'HP:0000718', (172, 182))	('phosphorylated', 'Var', (73, 87))	('increased', 'PosReg', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
363995	29416661	While Vismodegib shows promise for reducing tumor size and lengthening progression free survival times, two mutations (D477G, E518K) conferring resistance mechanisms have already been identified in relapsed patients.	('patients', 'Species', '9606', (207, 215))	('D477G', 'Var', (119, 124))	('E518K', 'Var', (126, 131))	('reducing', 'NegReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('D477G', 'Mutation', 'rs755399491', (119, 124))	('E518K', 'Mutation', 'p.E518K', (126, 131))	('lengthening', 'PosReg', (59, 70))	('tumor', 'Disease', (44, 49))	('progression', 'MPA', (71, 82))
364002	29416661	Inhibition of Gli and AKT pathway activity may thus serve as a potential therapeutic strategy for the treatment of human esophageal adenocarcinoma.	('activity', 'MPA', (34, 42))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (121, 146))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (121, 146))	('Gli', 'Gene', (14, 17))	('AKT', 'Gene', '207', (22, 25))	('Gli', 'Gene', '2735', (14, 17))	('human', 'Species', '9606', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('AKT', 'Gene', (22, 25))	('Inhibition', 'Var', (0, 10))	('esophageal adenocarcinoma', 'Disease', (121, 146))
364007	29416661	Cells were seeded one day before treatment with Gli inhibitor (Gli-i) or AKT inhibitor MK-2206 2HCI (AKT-i) (Selleck Chemicals, Houston, TX, USA), with or without N-Shh recombinant proteins (eBioscience, San Diego, CA, USA), and incubated for 30 hours, with DMSO vehicle as a control.	('Gli', 'Gene', (63, 66))	('AKT', 'Gene', '207', (101, 104))	('Shh', 'Gene', '6469', (165, 168))	('MK-2206', 'Var', (87, 94))	('Gli', 'Gene', (48, 51))	('AKT', 'Gene', (73, 76))	('MK-2206', 'Chemical', 'MESH:C548887', (87, 94))	('Gli', 'Gene', '2735', (48, 51))	('AKT', 'Gene', (101, 104))	('Gli', 'Gene', '2735', (63, 66))	('DMSO', 'Chemical', 'MESH:D004121', (258, 262))	('Shh', 'Gene', (165, 168))	('AKT', 'Gene', '207', (73, 76))
364012	29416661	To measure Gli-mediated Shh transcriptional activity, luciferase reporter constructs, 8x wild-type Gli binding site (8x Gliwt Luc) or 8x mutant Gli binding site (8x Glimut Luc) plasmids, and human Gli1 and Gli2 expression vectors (pcDNA3.1-Gli1/2) were co-transfected into EAC cell lines OE19 and OE33 in 24-well plates.	('Gli1', 'Gene', '2735', (240, 244))	('Gli', 'Gene', '2735', (240, 243))	('Gli2', 'Gene', (206, 210))	('Gli1', 'Gene', (197, 201))	('Shh', 'Gene', (24, 27))	('mutant', 'Var', (137, 143))	('Gli', 'Gene', '2735', (120, 123))	('Gli', 'Gene', (240, 243))	('Gli', 'Gene', '2735', (144, 147))	('expression vectors', 'Species', '29278', (211, 229))	('Gli', 'Gene', '2735', (206, 209))	('Gli', 'Gene', '2735', (197, 200))	('human', 'Species', '9606', (191, 196))	('Gli', 'Gene', (206, 209))	('Gli1', 'Gene', (240, 244))	('Gli', 'Gene', (120, 123))	('Gli', 'Gene', (144, 147))	('Shh', 'Gene', '6469', (24, 27))	('Gli2', 'Gene', '2736', (206, 210))	('Gli', 'Gene', '2735', (165, 168))	('Gli', 'Gene', (197, 200))	('Gli1', 'Gene', '2735', (197, 201))	('Gli', 'Gene', (165, 168))	('Gli', 'Gene', '2735', (99, 102))	('EAC', 'Phenotype', 'HP:0011459', (273, 276))	('Gli', 'Gene', '2735', (11, 14))	('Gli', 'Gene', (99, 102))	('Gli', 'Gene', (11, 14))
364032	29156838	Evidences implicated deficient folate is related to increased risks of many cancers.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('deficient folate', 'Phenotype', 'HP:0100507', (21, 37))	('cancers', 'Disease', (76, 83))	('folate', 'Chemical', 'MESH:D005492', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('deficient', 'Var', (21, 30))	('folate', 'Protein', (31, 37))
364034	29156838	The main carcinogenesis mechanisms of folate are inducing DNA strand breaks by causing uracil mis-incorporation into DNA and changing levels of DNA methylation.	('uracil mis', 'Phenotype', 'HP:0012127', (87, 97))	('folate', 'Var', (38, 44))	('inducing', 'PosReg', (49, 57))	('changing', 'Reg', (125, 133))	('folate', 'Chemical', 'MESH:D005492', (38, 44))	('uracil mis-incorporation into', 'MPA', (87, 116))	('causing', 'Reg', (79, 86))	('uracil', 'Chemical', 'MESH:D014498', (87, 93))	('DNA', 'MPA', (58, 61))	('levels', 'MPA', (134, 140))
364037	29156838	In addition, the polymorphisms of genes in folate metabolizing pathway may modulate the susceptibility of several cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('polymorphisms', 'Var', (17, 30))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('modulate', 'Reg', (75, 83))	('folate', 'Chemical', 'MESH:D005492', (43, 49))
364039	29156838	Two previous meta-analysis have estimated the associations of folate intakes and risks of esophageal, gastric and pancreatic carcinomas and indicated that increased folate intakes were associated with decreased risks of esophageal and pancreatic cancers.	('folate', 'Chemical', 'MESH:D005492', (165, 171))	('folate', 'MPA', (165, 171))	('increased folate intakes', 'Phenotype', 'HP:0032164', (155, 179))	('pancreatic carcinomas', 'Disease', (114, 135))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('increased', 'PosReg', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (235, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('associations', 'Interaction', (46, 58))	('increased folate', 'Phenotype', 'HP:0032164', (155, 171))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (114, 135))	('esophageal', 'Disease', (90, 100))	('gastric', 'Disease', (102, 109))	('esophageal and pancreatic cancers', 'Disease', 'MESH:D010190', (220, 253))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (235, 252))	('folate', 'Chemical', 'MESH:D005492', (62, 68))	('decreased', 'NegReg', (201, 210))	('intakes', 'Var', (172, 179))
364056	29156838	All these results were similar in subgroup analysis suggested that folate intake were comprehensive associated with reduced risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('esophageal cancer', 'Disease', (132, 149))	('folate', 'Var', (67, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('folate', 'Chemical', 'MESH:D005492', (67, 73))	('reduced', 'NegReg', (116, 123))
364057	29156838	As shown in Figure 3A, the linearity test of dose-response analysis suggested that with increased 100 mug/day folate intake from diet, the risk of esophageal cancer decreased 9% degree (OR=0.91, 95%CI=0.88-0.94).	('esophageal cancer', 'Disease', (147, 164))	('decreased', 'NegReg', (165, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('folate', 'Protein', (110, 116))	('100 mug/day', 'Var', (98, 109))	('increased', 'PosReg', (88, 97))	('folate', 'Chemical', 'MESH:D005492', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
364071	29156838	The pooled OR of case-control studies suggested a high dietary folate intake was associated with a statistically significant decreased risk of gastric cancer (OR=0.696, 95%CI=0.563-0.829).	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('high dietary folate intake', 'Phenotype', 'HP:0032164', (50, 76))	('decreased', 'NegReg', (125, 134))	('folate', 'Chemical', 'MESH:D005492', (63, 69))	('gastric cancer', 'Disease', (143, 157))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('high', 'Var', (50, 54))
364088	29156838	The pooled OR of case-control studies suggested a high dietary folate intake was associated with a statistically significant decreased risk of pancreatic cancer (OR=0.589, 95%CI=0.456-0.722).	('high', 'Var', (50, 54))	('high dietary folate intake', 'Phenotype', 'HP:0032164', (50, 76))	('decreased', 'NegReg', (125, 134))	('folate', 'Chemical', 'MESH:D005492', (63, 69))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))
364093	29156838	As shown in Figure 3C, the linearity test of dose-response analysis suggested that with increased 100 mug/day folate intake from diet, the risk of pancreatic cancer decreased 6% degree (OR=0.94, 95%CI=0.92-0.97,).	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('decreased', 'NegReg', (165, 174))	('folate', 'Protein', (110, 116))	('100 mug/day', 'Var', (98, 109))	('increased', 'PosReg', (88, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('folate', 'Chemical', 'MESH:D005492', (110, 116))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
364097	29156838	Two main mechanisms of folate deficiency leads to carcinogenesis: (1) by leading complete convention of dUMP to dTMP, which makes mis-incorporation of uracil into DNA and induces breaks and mutations of chromosome; and/or (2) inducing alternations in expression of critical proto-oncogenes and tumor suppressor genes by causing aberrant methylated level of DNA.	('alternations', 'MPA', (235, 247))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('deficiency leads to carcinogenesis', 'Disease', 'MESH:D063646', (30, 64))	('mis-incorporation', 'Var', (130, 147))	('breaks', 'MPA', (179, 185))	('induces', 'Reg', (171, 178))	('uracil', 'Chemical', 'MESH:D014498', (151, 157))	('causing', 'Reg', (320, 327))	('dUMP', 'Chemical', 'MESH:C007267', (104, 108))	('folate deficiency', 'Phenotype', 'HP:0100507', (23, 40))	('methylated level of DNA', 'MPA', (337, 360))	('tumor', 'Disease', (294, 299))	('inducing', 'Reg', (226, 234))	('deficiency leads to carcinogenesis', 'Disease', (30, 64))	('expression', 'MPA', (251, 261))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('dTMP', 'Chemical', 'MESH:D013938', (112, 116))	('mutations', 'MPA', (190, 199))	('folate', 'Chemical', 'MESH:D005492', (23, 29))
364098	29156838	In addition, the polymorphisms of 5,10-methylenetetrahydrofolate reductase, a critical junction protein in folate metabolizing pathway by leading folate metabolites to DNA methylation pathway and away from the DNA synthesis pathway, can regulate the susceptibilities of several cancers.	('cancers', 'Disease', 'MESH:D009369', (278, 285))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (39, 74))	('folate metabolites', 'MPA', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('cancers', 'Disease', (278, 285))	('folate', 'Chemical', 'MESH:D005492', (58, 64))	('polymorphisms', 'Var', (17, 30))	('folate', 'Chemical', 'MESH:D005492', (107, 113))	('DNA methylation pathway', 'Pathway', (168, 191))	('regulate', 'Reg', (237, 245))	('folate', 'Chemical', 'MESH:D005492', (146, 152))	('methylenetetrahydrofolate reductase', 'Gene', (39, 74))	('leading', 'PosReg', (138, 145))
364106	29156838	The results of dose-response analysis also indicated that with the folate intake > 450 mug/day, the risk of esophageal cancer would increase weakly comparing with the lowest OR, which suggested that a redundant and supplementary folate is not necessary.	('esophageal cancer', 'Disease', (108, 125))	('men', 'Species', '9606', (221, 224))	('> 450 mug/day', 'Var', (81, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('folate', 'Chemical', 'MESH:D005492', (67, 73))	('folate', 'Chemical', 'MESH:D005492', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
364120	29156838	And the excessive intake of folate may be a risk for gastric cancer since the highest values of 95%CI > 1.00.	('gastric cancer', 'Disease', (53, 67))	('folate', 'Chemical', 'MESH:D005492', (28, 34))	('excessive', 'Var', (8, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))
364166	27444612	High ApoA-I concentration is associated with increased risk of cancer, in particular head and neck squamous cell carcinoma, whereas the prognostic roles of ApoA-I, Apo-B, HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG) remain unclear.	('triglycerides', 'Chemical', 'MESH:D014280', (251, 264))	('cholesterol', 'Chemical', 'MESH:D002784', (229, 240))	('High', 'Var', (0, 4))	('neck squamous cell carcinoma', 'Disease', (94, 122))	('Apo-B', 'Gene', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('High ApoA-I concentration', 'Phenotype', 'HP:0031800', (0, 25))	('Apo-B', 'Gene', '338', (164, 169))	('TC', 'Chemical', '-', (242, 244))	('cholesterol', 'Chemical', 'MESH:D002784', (202, 213))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (94, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (85, 122))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('ApoA-I', 'Gene', (5, 11))	('TG', 'Chemical', 'MESH:D014280', (266, 268))	('cancer', 'Disease', (63, 69))
364220	27444612	Accumulating evidence indicates that acetaldehyde is predominantly responsible for the alcohol associated carcinogenesis, since acetaldehyde is carcinogenic, mutagenic, binds to DNA and protein, destroys folate, and results in secondary hyper-regeneration.	('destroys', 'NegReg', (195, 203))	('acetaldehyde', 'Var', (128, 140))	('folate', 'MPA', (204, 210))	('acetaldehyde', 'Chemical', 'MESH:D000079', (37, 49))	('carcinogenic', 'Disease', 'MESH:D063646', (144, 156))	('alcohol', 'Chemical', 'MESH:D000438', (87, 94))	('carcinogenic', 'Disease', (144, 156))	('folate', 'Chemical', 'MESH:D005492', (204, 210))	('protein', 'Protein', (186, 193))	('binds', 'Interaction', (169, 174))	('results in', 'Reg', (216, 226))	('DNA', 'Protein', (178, 181))	('acetaldehyde', 'Chemical', 'MESH:D000079', (128, 140))	('secondary hyper-regeneration', 'CPA', (227, 255))
364238	26761210	Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC.	('inhibition', 'Var', (22, 32))	('PD-L1', 'Gene', (36, 41))	('esophageal SCC', 'Disease', 'MESH:D004941', (87, 101))	('esophageal SCC', 'Disease', (87, 101))
364258	26761210	As shown in Table 1 and Figure 2a, positive staining for IL-6 was evident in 51% of the 162 cancer specimens, and a significant positive correlation was found in cancer specimen that expressed PD-L1 and IL-6.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', (162, 168))	('IL-6', 'Gene', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('PD-L1', 'Var', (193, 198))	('IL-6', 'Gene', '3569', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('IL-6', 'Gene', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('IL-6', 'Gene', '3569', (203, 207))
364264	26761210	As shown in Figure 2c, the IL-6 levels were also significantly higher in patients with PD-L1 positive staining compared with PD-L1 (-) group (p < 0.001).	('patients', 'Species', '9606', (73, 81))	('IL-6', 'Gene', '3569', (27, 31))	('positive staining', 'Var', (93, 110))	('IL-6', 'Gene', (27, 31))	('PD-L1', 'Gene', (87, 92))	('higher', 'PosReg', (63, 69))
364266	26761210	Flow cytometric analysis and IF data revealed that IL-6 neutralizing antibody significantly decreased the level of PD-L1 expression at the cell surface and the cytoplasm (Figure 3a-3b).	('level', 'MPA', (106, 111))	('neutralizing antibody', 'Var', (56, 77))	('IL-6', 'Gene', (51, 55))	('IL-6', 'Gene', '3569', (51, 55))	('decreased', 'NegReg', (92, 101))	('PD-L1', 'Gene', (115, 120))
364271	26761210	Furthermore, 47 among these patients received esophagectomy after neoadjuvant CCRT, PD-L1 staininig linked with lower complete pathologic response rate (pCR) (16% (3/18) in PD-L1(+) patients versus 31% (9/29) in PD-L1 (-) patients)).	('esophagectomy', 'Disease', (46, 59))	('complete', 'MPA', (118, 126))	('patients', 'Species', '9606', (222, 230))	('PD-L1 staininig', 'Var', (84, 99))	('patients', 'Species', '9606', (182, 190))	('PD-L1', 'Disease', (173, 178))	('patients', 'Species', '9606', (28, 36))	('lower', 'NegReg', (112, 117))
364272	26761210	As shown in Figure 4a-b, the level of PD-L1 in human esophageal cancer was increased by radiotherapy in the plasma membrane and cytoplasm of cancer cells when compared with nontreated cells.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('esophageal cancer', 'Disease', (53, 70))	('PD-L1', 'Var', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('increased', 'PosReg', (75, 84))	('human', 'Species', '9606', (47, 52))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
364274	26761210	Irradiation increased the ability of tumor cells to suppress nonspecific stimuli (anti-CD3/CD28 antibody )-mediated T cell proliferation, and anti-PD-L1 attenuated the ability of irradiated tumor cells-mediated T cell suppression (Figure 4c).	('suppress', 'NegReg', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('T cell suppression', 'CPA', (211, 229))	('T cell proliferation', 'CPA', (116, 136))	('anti-PD-L1', 'Var', (142, 152))	('CD28', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('attenuated', 'NegReg', (153, 163))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (37, 42))	('CD28', 'Gene', '940', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('nonspecific stimuli', 'MPA', (61, 80))
364275	26761210	Inhibition of PD-L1 combined with irradiation resulted in increased tumor cytolysis compared with anti-PD-L1 monotherapy or irradiation alone when tumor cells co-cultured with sorting CD8+ cells from patients (Figure 4d).	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('increased', 'PosReg', (58, 67))	('patients', 'Species', '9606', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Inhibition', 'Var', (0, 10))	('PD-L1', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CD8', 'Gene', (184, 187))	('CD8', 'Gene', '925', (184, 187))
364308	26761210	Blockade of PD-L1 effectively inhibit CD8+ T cells cytotoxicity against irradiated esophageal cancer cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (51, 63))	('PD-L1', 'Gene', (12, 17))	('esophageal cancer', 'Disease', (83, 100))	('inhibit', 'NegReg', (30, 37))	('Blockade', 'Var', (0, 8))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('CD8', 'Gene', (38, 41))	('cytotoxicity', 'Disease', (51, 63))	('CD8', 'Gene', '925', (38, 41))
364309	26761210	We demonstrated that the increase in PD-L1 expression on irradiated esophageal cancer cells was associated with a decreased T cell proliferation upon co-culture experiments, and anti-PD-L1 had reduced the suppressive ability for T cell proliferation.	('esophageal cancer', 'Disease', (68, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('PD-L1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('decreased T cell', 'Phenotype', 'HP:0005403', (114, 130))	('reduced', 'NegReg', (193, 200))	('decreased', 'NegReg', (114, 123))	('suppressive ability for T cell proliferation', 'CPA', (205, 249))	('increase', 'PosReg', (25, 33))	('expression', 'MPA', (43, 53))	('T cell proliferation', 'CPA', (124, 144))	('anti-PD-L1', 'Var', (178, 188))
364558	31257510	Consistent with the Kaplan-Meier analysis, DeltaCTC >=2/7.5 ml remained a strong predictor of poor prognosis [hazard ratio, (HR), 3.922; 95% CI: 0.907-16.951; P=0.047] in the multivariate Cox proportional hazards regression analysis.	('DeltaCTC >=2/7.5 ml', 'Var', (43, 62))	('Cox', 'Gene', '1351', (188, 191))	('Cox', 'Gene', (188, 191))
364584	31257510	Instead of considering a certain CTC number prior to surgery the cut-off value to predict prognosis, multivariate analysis revealed that DeltaCTC counts >=2/7.5 ml PB may be a strong prognostic indicator of PFS (HR, 3.922; 95% CI, 0.907-16.951; P<0.05) in patients with ESCC.	('SCC', 'Gene', '6317', (271, 274))	('patients', 'Species', '9606', (256, 264))	('FS', 'Disease', 'MESH:D018223', (208, 210))	('>=2/7.5', 'Var', (153, 160))	('DeltaCTC', 'MPA', (137, 145))	('SCC', 'Gene', (271, 274))
364599	30523643	The findings also demonstrated that the suppressive effect of GO-203 on TIGAR is related to the decrease of glutathione level, the increase of reactive oxygen species and the loss of mitochondrial transmembrane membrane potential.	('increase of reactive oxygen species', 'Phenotype', 'HP:0025464', (131, 166))	('reactive oxygen species', 'MPA', (143, 166))	('GO-203', 'Var', (62, 68))	('glutathione level', 'MPA', (108, 125))	('increase', 'PosReg', (131, 139))	('suppressive', 'NegReg', (40, 51))	('decrease', 'NegReg', (96, 104))	('glutathione', 'Chemical', 'MESH:D005978', (108, 119))	('GO-203', 'Chemical', 'MESH:C582521', (62, 68))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (143, 166))	('decrease of glutathione', 'Phenotype', 'HP:0003343', (96, 119))	('loss', 'NegReg', (175, 179))	('mitochondrial transmembrane membrane potential', 'MPA', (183, 229))
364600	30523643	In xenograft tissues, GO-203 inhibited the growth of ESCC cells and lead to the low expression of transmembrane C-terminal subunit (MUC1-C) and TIGAR.	('inhibited', 'NegReg', (29, 38))	('low', 'NegReg', (80, 83))	('MUC1-C', 'Gene', (132, 138))	('GO-203', 'Chemical', 'MESH:C582521', (22, 28))	('ESCC cells', 'CPA', (53, 63))	('growth', 'CPA', (43, 49))	('expression', 'MPA', (84, 94))	('GO-203', 'Var', (22, 28))
364612	30523643	Previous studies have shown that high levels of TIGAR expression are closely associated with poor clinical outcomes in patients with multiple types of cancer including chronic lymphocytic leukemia (Hong et al., 2016), invasive breast cancer (Won et al., 2012), Stages II and III colorectal cancer (Alkhayal et al., 2016), nasopharyngeal carcinoma (Wong et al., 2015; Zhao et al., 2016), and non-small-cell lung cancer (Shen et al., 2018).	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (391, 417))	('III colorectal cancer', 'Disease', 'MESH:D015179', (275, 296))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (168, 196))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('chronic lymphocytic leukemia', 'Disease', (168, 196))	('high levels', 'Var', (33, 44))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (322, 346))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (168, 196))	('leukemia', 'Phenotype', 'HP:0001909', (188, 196))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (151, 157))	('invasive breast cancer', 'Disease', (218, 240))	('lung cancer', 'Phenotype', 'HP:0100526', (406, 417))	('colorectal cancer', 'Phenotype', 'HP:0003003', (279, 296))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (391, 417))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('invasive breast cancer', 'Disease', 'MESH:D001943', (218, 240))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (395, 417))	('cancer', 'Disease', (411, 417))	('nasopharyngeal carcinoma', 'Disease', (322, 346))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('carcinoma', 'Phenotype', 'HP:0030731', (337, 346))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Disease', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('III colorectal cancer', 'Disease', (275, 296))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (322, 346))	('cancer', 'Disease', (234, 240))	('non-small-cell lung cancer', 'Disease', (391, 417))
364616	30523643	S6Ks lead to degradation of suppressor programmed cell death protein 4 (PDCD4), which is an eIF4A inhibitor in cancer cells (Dorrello et al., 2006).	('programmed cell death protein 4', 'Gene', (39, 70))	('eIF4A', 'Gene', '1974', (92, 97))	('programmed cell death protein 4', 'Gene', '27250', (39, 70))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('PDCD4', 'Gene', (72, 77))	('PDCD4', 'Gene', '27250', (72, 77))	('S6Ks', 'Var', (0, 4))	('degradation', 'MPA', (13, 24))	('cancer', 'Disease', (111, 117))	('eIF4A', 'Gene', (92, 97))
364620	30523643	And another report has described that effect of GO-203 is related to downregulation of the AKT-mTOR pathway and inhibition of cap-dependent translation of TIGAR protein (Ahmad et al., 2017).	('TIGAR protein', 'Protein', (155, 168))	('AKT', 'Gene', '207', (91, 94))	('GO-203', 'Var', (48, 54))	('cap', 'Chemical', '-', (126, 129))	('inhibition', 'NegReg', (112, 122))	('AKT', 'Gene', (91, 94))	('GO-203', 'Chemical', 'MESH:C582521', (48, 54))	('mTOR', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (95, 99))	('downregulation', 'NegReg', (69, 83))	('cap-dependent translation', 'MPA', (126, 151))
364627	30523643	Cells were treated with the PI3K inhibitor LY294002, AKT inhibitor GSK690693, and mTORC Inhibitor Rapamycin (Selleck Chemicals, Houston, TX).	('Rapamycin', 'Chemical', 'MESH:D020123', (98, 107))	('LY294002', 'Chemical', 'MESH:C085911', (43, 51))	('AKT', 'Gene', '207', (53, 56))	('GSK690693', 'Chemical', 'MESH:C528328', (67, 76))	('mTOR', 'Gene', (82, 86))	('LY294002', 'Var', (43, 51))	('mTOR', 'Gene', '2475', (82, 86))	('AKT', 'Gene', (53, 56))
364628	30523643	All proteins were prepared as described (Xin et al., 2018) and analyzed by immunoblotting with anti-p-AKT, anti-AKT and anti-S6K (OmnimAbs, California), anti-p-S6K1, anti-MUC1-C, anti-TIGAR, anti-PDCD4 (Abcam, San Francisco, CA), and anti-beta-actin (Boster, Wuhan, Hubei, China).	('Xin', 'Gene', '165904', (41, 44))	('Xin', 'Gene', (41, 44))	('S6K1', 'Gene', '6198', (160, 164))	('OmnimAbs', 'Chemical', '-', (130, 138))	('beta-actin', 'Gene', '728378', (239, 249))	('AKT', 'Gene', '207', (112, 115))	('beta-actin', 'Gene', (239, 249))	('PDCD4', 'Gene', (196, 201))	('AKT', 'Gene', '207', (102, 105))	('PDCD4', 'Gene', '27250', (196, 201))	('anti-MUC1-C', 'Var', (166, 177))	('S6K1', 'Gene', (160, 164))	('anti-S6K', 'Var', (120, 128))	('AKT', 'Gene', (112, 115))	('AKT', 'Gene', (102, 105))
364654	30523643	To verify whether TIGAR translation could be affected by AKT-mTORC-S6K pathway, PI3K inhibitor LY294002, and AKT inhibitor GSK690693 were applied in ECA109 cells.	('LY294002', 'Chemical', 'MESH:C085911', (95, 103))	('AKT', 'Gene', '207', (109, 112))	('TIGAR translation', 'MPA', (18, 35))	('AKT', 'Gene', '207', (57, 60))	('affected', 'Reg', (45, 53))	('LY294002', 'Var', (95, 103))	('mTOR', 'Gene', (61, 65))	('GSK690693', 'Chemical', 'MESH:C528328', (123, 132))	('mTOR', 'Gene', '2475', (61, 65))	('AKT', 'Gene', (109, 112))	('AKT', 'Gene', (57, 60))
364663	30523643	In addition, GO-203 reduced GSH levels and induced ROS production return to the original level after the addition of N-acetyl-L-cysteine (NAC).	('reduced', 'NegReg', (20, 27))	('GO-203', 'Var', (13, 19))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('GSH', 'Chemical', 'MESH:D005978', (28, 31))	('GO-203', 'Chemical', 'MESH:C582521', (13, 19))	('ROS production', 'MPA', (51, 65))	('NAC', 'Gene', (138, 141))	('NAC', 'Gene', '7504', (138, 141))	('GSH levels', 'MPA', (28, 38))	('return', 'PosReg', (66, 72))
364666	30523643	In the result, green fluorescence was increased in ECA109 and KYSE150 cells treated with GO-203, which confirmed the reduction of mitochondrial membrane potential (Figure 4a,b).	('GO-203', 'Var', (89, 95))	('reduction', 'NegReg', (117, 126))	('KYSE150', 'CellLine', 'CVCL:1348', (62, 69))	('GO-203', 'Chemical', 'MESH:C582521', (89, 95))	('green fluorescence', 'MPA', (15, 33))	('mitochondrial membrane potential', 'MPA', (130, 162))	('increased', 'PosReg', (38, 47))
364667	30523643	In the flow result, we find the apoptosis of ECA109 and KYSE150 cells that treated with GO-203 increased significantly, but not obvious in control CP-2 groups (Figure 5a, B).	('GO-203', 'Chemical', 'MESH:C582521', (88, 94))	('apoptosis', 'CPA', (32, 41))	('KYSE150', 'CellLine', 'CVCL:1348', (56, 63))	('GO-203', 'Var', (88, 94))
364686	30523643	GO-203 also reduced TIGAR protein expression in the treated ESCC cells, but there was no change in mRNA level.	('TIGAR protein', 'Protein', (20, 33))	('GO-203', 'Chemical', 'MESH:C582521', (0, 6))	('reduced', 'NegReg', (12, 19))	('GO-203', 'Var', (0, 6))
364690	30523643	In turn, S6K phosphorylates and thereby induces the degradation of PDCD4, an inhibitor of eIF4A RNA helicase activity that regulates translation of proteins (Dorrello et al., 2006).	('induces', 'Reg', (40, 47))	('PDCD4', 'Gene', (67, 72))	('eIF4A', 'Gene', '1974', (90, 95))	('degradation', 'MPA', (52, 63))	('S6K', 'Var', (9, 12))	('PDCD4', 'Gene', '27250', (67, 72))	('eIF4A', 'Gene', (90, 95))
364691	30523643	This study confirms that the targeting MUC1-C by GO-203 inhibits phosphorylation of AKT and S6K in ESCC cells.	('AKT', 'Gene', '207', (84, 87))	('inhibits', 'NegReg', (56, 64))	('MUC1-C', 'Protein', (39, 45))	('GO-203', 'Var', (49, 55))	('S6K', 'Protein', (92, 95))	('phosphorylation', 'MPA', (65, 80))	('AKT', 'Gene', (84, 87))	('GO-203', 'Chemical', 'MESH:C582521', (49, 55))
364693	30523643	GO-203 promotes PDCD4 expression, which is an inhibitor of elF4A helicase.	('PDCD4', 'Gene', (16, 21))	('PDCD4', 'Gene', '27250', (16, 21))	('GO-203', 'Var', (0, 6))	('promotes', 'PosReg', (7, 15))	('GO-203', 'Chemical', 'MESH:C582521', (0, 6))	('expression', 'MPA', (22, 32))
364695	30523643	In our study, it shows that the treatment of ESCC cells with PI3K inhibitor LY294002 and AKT inhibitor GSK690693 both downregulated TIGAR proteins.	('TIGAR proteins', 'Protein', (132, 146))	('LY294002', 'Var', (76, 84))	('AKT', 'Gene', '207', (89, 92))	('AKT', 'Gene', (89, 92))	('downregulated', 'NegReg', (118, 131))	('LY294002', 'Chemical', 'MESH:C085911', (76, 84))	('GSK690693', 'Chemical', 'MESH:C528328', (103, 112))
364700	30523643	With the GO-203 treatment of ESCC cells, GSH decreased and ROS increased, which suggest that inhibition of MUC1-C could deplete NADPH.	('GSH', 'Chemical', 'MESH:D005978', (41, 44))	('GO-203', 'Chemical', 'MESH:C582521', (9, 15))	('increased', 'PosReg', (63, 72))	('deplete', 'NegReg', (120, 127))	('ROS', 'Chemical', 'MESH:D017382', (59, 62))	('GSH', 'MPA', (41, 44))	('decreased', 'NegReg', (45, 54))	('NADPH', 'Gene', (128, 133))	('MUC1-C', 'Gene', (107, 113))	('ROS', 'MPA', (59, 62))	('NADPH', 'Gene', '1666', (128, 133))	('inhibition', 'Var', (93, 103))
364701	30523643	Changes in redox equilibrium caused by GO-203 significantly decreased the level of GSH.	('decreased', 'NegReg', (60, 69))	('level of GSH', 'MPA', (74, 86))	('GO-203', 'Chemical', 'MESH:C582521', (39, 45))	('GSH', 'Chemical', 'MESH:D005978', (83, 86))	('redox equilibrium', 'MPA', (11, 28))	('GO-203', 'Var', (39, 45))	('Changes', 'Reg', (0, 7))
364704	30523643	The previous research has confirmed that the MUC1-C translocates to the mitochondrial outer membrane during the stress response, thus attenuating the reducing of mitochondrial membrane potential (Ren et al., 2004, 2006).	('Ren', 'Gene', (196, 199))	('Ren', 'Gene', '5972', (196, 199))	('mitochondrial membrane potential', 'MPA', (162, 194))	('attenuating', 'NegReg', (134, 145))	('reducing', 'MPA', (150, 158))	('MUC1-C', 'Var', (45, 51))
364712	30523643	In immunohistochemistry results, we also found that targeting MUC1-C with GO-203 downregulated TIGAR expression in xenograft tissues and which confirmed the correlation between MUC1-C and TIGAR.	('TIGAR', 'Protein', (95, 100))	('downregulated', 'NegReg', (81, 94))	('GO-203', 'Chemical', 'MESH:C582521', (74, 80))	('targeting', 'Var', (52, 61))	('MUC1-C', 'Gene', (62, 68))	('expression', 'MPA', (101, 111))	('GO-203', 'Gene', (74, 80))
364716	30523643	In conclusions based on our study, MUC1-C affects tumor cell metabolism and alters cell apoptosis by regulating GSH levels, ROS production, and changes in mitochondrial membrane potential.	('regulating', 'Reg', (101, 111))	('mitochondrial membrane potential', 'MPA', (155, 187))	('GSH levels', 'MPA', (112, 122))	('affects', 'Reg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('ROS production', 'MPA', (124, 138))	('changes', 'Reg', (144, 151))	('alters', 'Reg', (76, 82))	('cell apoptosis', 'CPA', (83, 97))	('GSH', 'Chemical', 'MESH:D005978', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('MUC1-C', 'Var', (35, 41))
364740	30992701	An IT knife (KD-611L, Olympus, Tokyo, Japan), a Dual-Knife (KD-650L/Q, Olympus, Tokyo, Japan), an injection needle (NM-200U-0423, Olympus, Tokyo, Japan), and hemostatic forceps (FD-410 LR, Olympus, Tokyo, Japan) were used during the procedure.	('KD-650L/Q', 'Var', (60, 69))	('hemostatic forceps', 'Disease', 'MESH:D020141', (158, 176))	('hemostatic forceps', 'Disease', (158, 176))
364751	30992701	The macroscopic type was 0-IIa in 10 (8.1%) patients, 0-IIb in 28 (22.6%) patients, 0 - IIa + 0 - IIb in 39 (31.4%) patients, 0 - IIb + 0 - IIc in 3 (2.4%) patients, and 0 - IIa + 0 - IIc in 44 (35.5%) patients, according to the Paris classification.	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (116, 124))	('0 - IIa + 0 - IIb', 'Var', (84, 101))	('0-IIb', 'Var', (54, 59))	('patients', 'Species', '9606', (202, 210))	('0 - IIb + 0 - IIc', 'Var', (126, 143))
364802	30519331	It has been reported that the expression of LAG-3 was correlated with an improved survival in both non-small-cell lung cancer (NSCLC) patients and microsatellite instability-high (MSI-H) colon cancer patients.	('NSCLC', 'Disease', (127, 132))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (99, 125))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (99, 125))	('patients', 'Species', '9606', (200, 208))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('expression', 'Var', (30, 40))	('patients', 'Species', '9606', (134, 142))	('improved', 'PosReg', (73, 81))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (103, 125))	('LAG-3', 'Gene', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('survival', 'MPA', (82, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (187, 199))	('MSI-H) colon cancer', 'Disease', 'MESH:D015179', (180, 199))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('non-small-cell lung cancer', 'Disease', (99, 125))
364819	30519331	Around 71.1% of ESCC patients are at late T status (T3+T4), and 47% patients have lymph node metastasis.	('ESCC', 'Disease', (16, 20))	('lymph node metastasis', 'CPA', (82, 103))	('patients', 'Species', '9606', (21, 29))	('patients', 'Species', '9606', (68, 76))	('T3+T4', 'Var', (52, 57))
364832	30519331	The patients exhibiting a high LAG-3 expression presented a significantly longer OS (median, high vs low: 2202 vs 2664 days, log-rank test p=0.010) (Figure 1B).	('longer', 'PosReg', (74, 80))	('LAG-3', 'Gene', (31, 36))	('patients', 'Species', '9606', (4, 12))	('high', 'Var', (26, 30))
364835	30519331	However, high CD8 TIL was not associated with OS (median, high vs low: 1885 vs 1225 days, log-rank test p=0.696) (Supplemental Figure 2B).	('CD8', 'Gene', '925', (14, 17))	('CD8', 'Gene', (14, 17))	('high', 'Var', (9, 13))
364839	30519331	Interestedly, high CD8 TIL seems to have a correlation with good prognosis at T 1-2 status (supplemental figure 3A) and at early stages (supplemental figure 3C) but with a worse survival at late stages (supplemental figure 3D), suggesting that CD8 TIL exhaustion might play an important role in tumor progress at late stages.	('CD8', 'Gene', (19, 22))	('CD8', 'Gene', '925', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('high', 'Var', (14, 18))	('CD8', 'Gene', (244, 247))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('CD8', 'Gene', '925', (244, 247))	('tumor', 'Disease', (295, 300))
364842	30519331	Furthermore, the correlation of high LAG-3 expression and improved PFS was statistically significant in T1-2 status patients (median, high vs low: 2903 vs 859 days, log-rank test p=0.001) (Figure 2C), N0 status patients (median high vs low: 2787 vs 2331 days, log-rank test p=0.050) (Figure 2E), and clinical stages I-II patients (median, high vs low: 2592 vs 1168 days, log-rank test p=0.000) (Figure 2G) with ESCC.	('high', 'Var', (32, 36))	('improved', 'PosReg', (58, 66))	('patients', 'Species', '9606', (211, 219))	('LAG-3', 'Gene', (37, 42))	('patients', 'Species', '9606', (321, 329))	('patients', 'Species', '9606', (116, 124))	('T1-2 status', 'Disease', (104, 115))	('ESCC', 'Disease', (411, 415))	('PFS', 'MPA', (67, 70))
364846	30519331	Moreover, both high of CD4 TIL /CD8 TIL ratio and LAG-3 expression were associated with longer PFS, whereas low of CD4 TIL /CD8 TIL ratio and LAG-3 expression were associated with shorter PFS (median, high, moderate vs low: 2361, 1578 vs 557 days, log-rank test p=0.000) (Figure 2I).	('high', 'Var', (15, 19))	('CD8', 'Gene', '925', (32, 35))	('LAG-3', 'Gene', (50, 55))	('CD4', 'Gene', (115, 118))	('CD8', 'Gene', (124, 127))	('CD8', 'Gene', '925', (124, 127))	('CD4', 'Gene', '920', (115, 118))	('CD8', 'Gene', (32, 35))	('CD4', 'Gene', (23, 26))	('CD4', 'Gene', '920', (23, 26))
364853	30519331	Sigurd M. Hald reported that intraepithelial-LAG-3 and stromal-LAG-3 were both associated with improved Disease-specific Survival (DSS) and OS in NSCLC.	('intraepithelial-LAG-3', 'Var', (29, 50))	('NSCLC', 'Disease', (146, 151))	('Disease-specific Survival', 'CPA', (104, 129))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('improved', 'PosReg', (95, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('DSS', 'Chemical', '-', (131, 134))
364854	30519331	Additionally, LAG-3+ TILs are an independent positive prognostic factor in stage I-IIIB NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('LAG-3+ TILs', 'Var', (14, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('NSCLC', 'Disease', (88, 93))
364855	30519331	ESCC patients with higher LAG-3 expression was positively correlated with a better OS and PFS, especially in the patients at T1-2 status, N0 status, and early stages (I-II) (Figure 1 and 2).	('patients', 'Species', '9606', (5, 13))	('patients', 'Species', '9606', (113, 121))	('LAG-3', 'Gene', (26, 31))	('ESCC', 'Disease', (0, 4))	('PFS', 'CPA', (90, 93))	('expression', 'MPA', (32, 42))	('T1-2 status', 'Var', (125, 136))
364876	27917618	Immunohistochemical analysis showed that high MTH1 expression was significantly associated with deeper tumor invasion and venous invasion, advanced cancer stage, and poor overall survival (P = 0.0021) and disease-specific survival (P = 0.0013) compared with low MTH1 expression.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('poor', 'NegReg', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('high', 'Var', (41, 45))	('deeper tumor', 'Disease', 'MESH:D009369', (96, 108))	('disease-specific survival', 'CPA', (205, 230))	('venous invasion', 'CPA', (122, 137))	('overall survival', 'CPA', (171, 187))	('MTH1', 'Gene', (46, 50))	('deeper tumor', 'Disease', (96, 108))
364891	27917618	Presence of oxidized purine nucleosides in nuclear and mitochondrial DNA induces mutations during DNA replication or DNA strand breaks because of base excision repair, which may lead to cellular transformation, cellular senescence, or cell death and eventually various diseases.	('base', 'MPA', (146, 150))	('cellular senescence', 'CPA', (211, 230))	('lead to', 'Reg', (178, 185))	('death', 'Disease', 'MESH:D003643', (240, 245))	('death', 'Disease', (240, 245))	('induces', 'Reg', (73, 80))	('nucleosides', 'Chemical', 'MESH:D009705', (28, 39))	('mutations', 'Var', (81, 90))	('purine', 'Chemical', 'MESH:C030985', (21, 27))	('cellular transformation', 'CPA', (186, 209))
364895	27917618	Importantly, small-molecule inhibitors of MTH1 exerts tumor-specific cytotoxic effects, suggesting that it can be used as a candidate for developing a novel anticancer drug 16, 21.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('MTH1', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('small-molecule', 'Var', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('inhibitors', 'Var', (28, 38))	('cancer', 'Disease', (161, 167))	('tumor', 'Disease', (54, 59))
364934	27917618	In this study, patients in the high MTH1 expression group showed significantly poorer OS (P = 0.0021; Fig.	('high', 'Var', (31, 35))	('patients', 'Species', '9606', (15, 23))	('MTH1', 'Gene', (36, 40))	('poorer', 'NegReg', (79, 85))
364949	27917618	Furthermore, patients with ESCC showing strong and diffuse MTH1 immunoreactivity had higher cancer stage (Table 1) and showed poorer prognosis than those showing weak and focal MTH1 immunoreactivity (Fig.	('immunoreactivity', 'Var', (64, 80))	('cancer', 'Disease', (92, 98))	('higher', 'PosReg', (85, 91))	('MTH1', 'Gene', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('patients', 'Species', '9606', (13, 21))	('ESCC', 'Disease', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
364950	27917618	Importantly, high MTH1 expression was an independent predictor of poor DSS (Table 2).	('high', 'Var', (13, 17))	('MTH1', 'Gene', (18, 22))	('DSS', 'Chemical', '-', (71, 74))	('poor DSS', 'Disease', (66, 74))	('expression', 'MPA', (23, 33))
364959	27917618	High MTH1 expression may remove oxidized dNTPs and prevent their incorporation into DNA, thus promoting tumor survival and proliferation and contributing to the poor prognosis of patients with ESCC.	('ESCC', 'Disease', (193, 197))	('proliferation', 'CPA', (123, 136))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('High', 'Var', (0, 4))	('promoting', 'PosReg', (94, 103))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('oxidized dNTPs', 'MPA', (32, 46))	('dNTPs', 'Chemical', 'MESH:D010278', (41, 46))	('prevent', 'NegReg', (51, 58))	('remove', 'NegReg', (25, 31))	('patients', 'Species', '9606', (179, 187))	('MTH1', 'Gene', (5, 9))	('incorporation into DNA', 'MPA', (65, 87))
364963	27917618	Other studies indicated that aberrant stabilization of NRF2, a master transcriptional regulator that integrates antioxidant response 27, was also significantly associated with the poor prognosis of patients with ESCC 28, indicating that suppression of cellular ROS production promoted tumor progression.	('suppression', 'NegReg', (237, 248))	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('patients', 'Species', '9606', (198, 206))	('NRF2', 'Gene', (55, 59))	('ESCC 28', 'Disease', (212, 219))	('tumor', 'Disease', (285, 290))	('promoted', 'PosReg', (276, 284))	('ROS', 'Chemical', 'MESH:D017382', (261, 264))	('stabilization', 'MPA', (38, 51))	('aberrant', 'Var', (29, 37))	('NRF2', 'Gene', '4780', (55, 59))	('associated', 'Reg', (160, 170))
364966	27917618	In non-small-cell lung carcinoma, MTH1 mRNA expression level is correlated with KRAS mutation and expression level 29.	('lung carcinoma', 'Disease', (18, 32))	('lung carcinoma', 'Disease', 'MESH:D008175', (18, 32))	('KRAS', 'Gene', (80, 84))	('MTH1', 'Gene', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('mutation', 'Var', (85, 93))	('KRAS', 'Gene', '3845', (80, 84))	('correlated', 'Reg', (64, 74))	('expression', 'MPA', (98, 108))
364976	27917618	The potential of MTH1 inhibition as an anticancer therapy has been proposed and is currently under debate 16, 21, 35.	('inhibition', 'Var', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('MTH1', 'Protein', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
364988	24855009	The pathophysiology of RE is complex and involves diverse factors, including gastroesophageal reflux, gastric acid secretion, dysfunction of the anti-reflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms.	('gastric acid secretion', 'MPA', (102, 124))	('gastric emptying disturbances', 'Disease', (166, 195))	('abnormalities', 'Var', (201, 214))	('-reflux', 'Phenotype', 'HP:0002020', (149, 156))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (77, 100))	('gastric emptying', 'Phenotype', 'HP:0002578', (166, 182))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (77, 100))	('gastroesophageal reflux', 'Disease', (77, 100))	('dysfunction', 'Disease', (126, 137))
365017	24855009	However, eradication of H. pylori does not increase new GERD cases or worsen GERD symptoms (except in patients with hiatal hernia and corpus gastritis).	('H. pylori', 'Gene', (24, 33))	('GERD', 'Disease', (77, 81))	('hernia', 'Phenotype', 'HP:0100790', (123, 129))	('patients', 'Species', '9606', (102, 110))	('H. pylori', 'Species', '210', (24, 33))	('gastritis', 'Phenotype', 'HP:0005263', (141, 150))	('GERD', 'Disease', (56, 60))	('eradication', 'Var', (9, 20))	('worsen', 'NegReg', (70, 76))	('hiatal hernia and corpus gastritis', 'Disease', 'MESH:D006551', (116, 150))	('hiatal hernia', 'Phenotype', 'HP:0002036', (116, 129))
365042	24383423	Overexpression of MEKK3 has been reported to occur frequently in ovarian cancer that leads to increased NF-kappaB activity and increased expression of cell survival factors which ultimately contributes to their resistance to apoptosis.	('activity', 'MPA', (114, 122))	('expression', 'MPA', (137, 147))	('ovarian cancer', 'Disease', (65, 79))	('increased', 'PosReg', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (65, 79))	('MEKK3', 'Gene', '4215', (18, 23))	('MEKK3', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('ovarian cancer', 'Disease', 'MESH:D010051', (65, 79))	('NF-kappaB', 'Gene', '4790', (104, 113))	('NF-kappaB', 'Gene', (104, 113))	('increased', 'PosReg', (127, 136))
365093	24383423	The presence of MEKK3 in early preneoplastic lesions, and localized expression of MEKK3 in areas of high proliferative activity support the hypothesis that alteration in MEKK3 expression is an early event in esophageal tumorigenesis.	('MEKK3', 'Gene', '4215', (16, 21))	('alteration', 'Var', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('MEKK3', 'Gene', (16, 21))	('MEKK3', 'Gene', '4215', (82, 87))	('MEKK3', 'Gene', (82, 87))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('MEKK3', 'Gene', '4215', (170, 175))	('MEKK3', 'Gene', (170, 175))
365099	24383423	The significant increase in MEKK3 expression observed in ESCC (67.7% cases) as compared to normal esophageal tissues is another important finding of our study suggesting that accumulation of MEKK3 may be linked to increased risk of malignant transformation and might serve as a marker to identify the high-risk lesions.	('MEKK3', 'Gene', (191, 196))	('expression', 'MPA', (34, 44))	('accumulation', 'Var', (175, 187))	('MEKK3', 'Gene', '4215', (191, 196))	('ESCC', 'Disease', (57, 61))	('increase', 'PosReg', (16, 24))	('MEKK3', 'Gene', '4215', (28, 33))	('MEKK3', 'Gene', (28, 33))	('malignant transformation', 'CPA', (232, 256))
365112	21048924	ADH1B Arg47His Polymorphism Is Associated with Esophageal Cancer Risk in High-Incidence Asian Population: Evidence from a Meta-Analysis Incidence of Esophageal squamous cell carcinoma (ESCC) is prevalent in Asian populations, especially in the ones from the "Asian esophageal cancer belt" along the Silk Road and the ones from East Asia (including Japan).	('Esophageal Cancer', 'Disease', (47, 64))	('Arg47His', 'SUBSTITUTION', 'None', (6, 14))	('esophageal cancer', 'Disease', (265, 282))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (149, 183))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ADH1B', 'Gene', (0, 5))	('esophageal cancer', 'Disease', 'MESH:D004938', (265, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('Esophageal squamous cell carcinoma', 'Disease', (149, 183))	('ADH1B', 'Gene', '125', (0, 5))	('Arg47His', 'Var', (6, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (47, 64))
365113	21048924	The Arg47His (rs1229984) polymorphism of ADH1B is the highest in East Asians, and ancient migrations along the Silk Road were thought to be contributive to a frequent ADH1B*47His allele in Central Asians.	('ADH1B', 'Gene', '125', (41, 46))	('Arg47His', 'SUBSTITUTION', 'None', (4, 12))	('rs1229984', 'Var', (14, 23))	('ADH1B', 'Gene', (167, 172))	('rs1229984', 'Mutation', 'rs1229984', (14, 23))	('47His', 'Chemical', '-', (7, 12))	('Arg47His', 'Var', (4, 12))	('ADH1B', 'Gene', '125', (167, 172))	('47His', 'Chemical', '-', (173, 178))	('ADH1B', 'Gene', (41, 46))
365115	21048924	To investigate the association of ADH1B Arg47His with ESCC in Asian populations under a common ancestry scenario of the susceptibility loci, we combined all available studies into a meta-analysis.	('ESCC', 'Disease', (54, 58))	('Arg47His', 'Var', (40, 48))	('ADH1B', 'Gene', (34, 39))	('Arg47His', 'SUBSTITUTION', 'None', (40, 48))	('ADH1B', 'Gene', '125', (34, 39))	('association', 'Interaction', (19, 30))
365116	21048924	A dataset composed of 4,220 cases and 8,946 controls from twelve studies of Asian populations was analyzed for ADH1B Arg47His association with ESCC and its interactions with alcohol drinking and ALDH2 Glu504Lys.	('Glu504Lys', 'SUBSTITUTION', 'None', (201, 210))	('ADH1B', 'Gene', '125', (111, 116))	('alcohol drinking', 'Phenotype', 'HP:0030955', (174, 190))	('ALDH2', 'Gene', '217', (195, 200))	('association', 'Interaction', (126, 137))	('alcohol', 'Chemical', 'MESH:D000438', (174, 181))	('ALDH2', 'Gene', (195, 200))	('Arg47His', 'SUBSTITUTION', 'None', (117, 125))	('ESCC', 'Disease', (143, 147))	('Glu504Lys', 'Var', (201, 210))	('interactions', 'Interaction', (156, 168))	('ADH1B', 'Gene', (111, 116))	('Arg47His', 'Var', (117, 125))
365117	21048924	The ADH1B*47Arg allele was found to be associated to increased risk of ESCC, with the odds ratios (OR) being 1.62 (95% CI: 1.49-1.76) and 3.86 (2.96-5.03) for the His/Arg and the Arg/Arg genotypes, respectively.	('ESCC', 'Disease', (71, 75))	('ADH1B', 'Gene', (4, 9))	('Arg', 'Chemical', 'MESH:D001120', (183, 186))	('Arg/Arg', 'Var', (179, 186))	('Arg', 'Chemical', 'MESH:D001120', (12, 15))	('His', 'Chemical', 'MESH:D006639', (163, 166))	('ADH1B', 'Gene', '125', (4, 9))	('His/Arg', 'Var', (163, 170))	('Arg', 'Chemical', 'MESH:D001120', (167, 170))	('Arg', 'Chemical', 'MESH:D001120', (179, 182))
365118	21048924	When compared with the His/His genotype of non-drinkers, the Arg/Arg genotype can interact with alcohol drinking and greatly increase the risk of ESCC (OR = 20.69, 95%CI: 5.09-84.13).	('Arg', 'Chemical', 'MESH:D001120', (65, 68))	('Arg/Arg', 'Var', (61, 68))	('increase', 'PosReg', (125, 133))	('His', 'Chemical', 'MESH:D006639', (27, 30))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))	('alcohol drinking', 'Phenotype', 'HP:0030955', (96, 112))	('interact', 'Interaction', (82, 90))	('Arg', 'Chemical', 'MESH:D001120', (61, 64))	('ESCC', 'Disease', (146, 150))	('His', 'Chemical', 'MESH:D006639', (23, 26))
365119	21048924	Statistical tests also showed gene-gene interaction of ADH1B Arg+ with ALDH2 Lys+ can bring more risk to ESCC (OR  = 13.46, 95% CI: 2.32-78.07).	('ADH1B', 'Gene', '125', (55, 60))	('ESCC', 'Disease', (105, 109))	('Arg', 'Chemical', 'MESH:D001120', (61, 64))	('ALDH2', 'Gene', (71, 76))	('Lys', 'Chemical', 'MESH:D008239', (77, 80))	('ADH1B', 'Gene', (55, 60))	('ALDH2', 'Gene', '217', (71, 76))	('Arg+', 'Var', (61, 65))
365128	21048924	A polymorphism at codon 47 in exon 3 of the ADH1B gene, resulting in an amino acid transition from arginine (Arg) to histidine (His), brings super-active metabolization of ethanol.	('ADH1B', 'Gene', (44, 49))	('ethanol', 'Chemical', 'MESH:D000431', (172, 179))	('amino acid transition from', 'MPA', (72, 98))	('ADH1B', 'Gene', '125', (44, 49))	('arginine', 'Chemical', 'MESH:D001120', (99, 107))	('His', 'Chemical', 'MESH:D006639', (128, 131))	('polymorphism', 'Var', (2, 14))	('Arg', 'Chemical', 'MESH:D001120', (109, 112))	('brings', 'PosReg', (134, 140))	('histidine', 'Chemical', 'MESH:D006639', (117, 126))	('super-active metabolization of ethanol', 'MPA', (141, 179))
365129	21048924	About a 40-times maximum velocity has been identified for the fast His/His genotype of ADH1B compared to the less active Arg/Arg form.	('Arg', 'Chemical', 'MESH:D001120', (121, 124))	('Arg', 'Chemical', 'MESH:D001120', (125, 128))	('fast His/His', 'Var', (62, 74))	('His', 'Chemical', 'MESH:D006639', (67, 70))	('ADH1B', 'Gene', (87, 92))	('ADH1B', 'Gene', '125', (87, 92))	('His', 'Chemical', 'MESH:D006639', (71, 74))
365131	21048924	Such a distribution pattern was considered to be related to the selection of the Arg47His polymorphism of ADH1B, which was along the emergence and expansion of rice domestication in East Asia.	('Arg47His', 'SUBSTITUTION', 'None', (81, 89))	('ADH1B', 'Gene', (106, 111))	('ADH1B', 'Gene', '125', (106, 111))	('Arg47His', 'Var', (81, 89))	('rice', 'Species', '4530', (160, 164))
365132	21048924	As for ALDH2, a polymorphism resulting from the substitution of glutamate (Glu) by lysine (Lys) at residue 504 (also recognized as Glu487Lys) makes the new sequence encode a catalytically inactive subunit, whose respective ALDH2 Glu/Lys genotype has only 6.25% effectiveness of the normal ALDH2 Glu protein.	('lysine', 'Chemical', 'MESH:D008239', (83, 89))	('Glu487Lys', 'Var', (131, 140))	('ALDH2', 'Gene', '217', (223, 228))	('glutamate', 'Chemical', 'MESH:D018698', (64, 73))	('ALDH2', 'Gene', '217', (7, 12))	('Glu487Lys', 'SUBSTITUTION', 'None', (131, 140))	('Glu', 'Chemical', 'MESH:D018698', (131, 134))	('Glu', 'Chemical', 'MESH:D018698', (229, 232))	('Lys', 'Chemical', 'MESH:D008239', (91, 94))	('ALDH2', 'Gene', (223, 228))	('ALDH2', 'Gene', '217', (289, 294))	('ALDH2', 'Gene', (7, 12))	('Glu', 'Chemical', 'MESH:D018698', (75, 78))	('substitution', 'Var', (48, 60))	('Lys', 'Chemical', 'MESH:D008239', (137, 140))	('Glu', 'Chemical', 'MESH:D018698', (295, 298))	('Lys', 'Chemical', 'MESH:D008239', (233, 236))	('ALDH2', 'Gene', (289, 294))
365135	21048924	Various studies focused on ADH1B polymorphisms and its relationship to the risk of ESCC in Asian high-incidence populations.	('ADH1B', 'Gene', '125', (27, 32))	('ADH1B', 'Gene', (27, 32))	('polymorphisms', 'Var', (33, 46))	('ESCC', 'Disease', (83, 87))
365137	21048924	For example, ADH1B Arg/Arg was found associated with 1.2 and 74 times increased risk in non-drinkers and drinkers, respectively, compared to non-drinkers with the ADH1B His/His genotype.	('Arg/Arg', 'Var', (19, 26))	('ADH1B', 'Gene', '125', (163, 168))	('ADH1B', 'Gene', (13, 18))	('His', 'Chemical', 'MESH:D006639', (169, 172))	('ADH1B', 'Gene', '125', (13, 18))	('Arg', 'Chemical', 'MESH:D001120', (19, 22))	('His', 'Chemical', 'MESH:D006639', (173, 176))	('Arg', 'Chemical', 'MESH:D001120', (23, 26))	('ADH1B', 'Gene', (163, 168))
365139	21048924	Some of these studies also assessed the effect of gene-gene interaction between the ADH1B Arg47His and ALDH2 Glu504Lys polymorphisms on ESCC risk.	('ADH1B', 'Gene', (84, 89))	('assessed', 'Reg', (27, 35))	('Arg47His', 'Var', (90, 98))	('ESCC', 'Disease', (136, 140))	('Glu504Lys', 'Var', (109, 118))	('ALDH2', 'Gene', '217', (103, 108))	('ADH1B', 'Gene', '125', (84, 89))	('Glu504Lys', 'SUBSTITUTION', 'None', (109, 118))	('Arg47His', 'SUBSTITUTION', 'None', (90, 98))	('ALDH2', 'Gene', (103, 108))
365140	21048924	In search of a better precision under a wider scenario, we here performed a meta-analysis based on surveyed eligible studies to examine the association between ADH1B Arg47His polymorphism and ESCC risk in high-incidence Asian populations.	('Arg47His', 'Var', (166, 174))	('ADH1B', 'Gene', (160, 165))	('ESCC', 'Disease', (192, 196))	('ADH1B', 'Gene', '125', (160, 165))	('Arg47His', 'SUBSTITUTION', 'None', (166, 174))
365141	21048924	The following terms were jointly used for searching: "oesophageal cancer" or "esophageal cancer" and "ADH2" or "aldehyde dehydrogenase" or "ADH1B" or "polymorphism".	('oesophageal cancer', 'Disease', (54, 72))	('polymorphism', 'Var', (151, 163))	('oesophageal cancer', 'Disease', 'MESH:D009369', (54, 72))	('ADH1B', 'Gene', (140, 145))	('ADH2', 'Gene', '125', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ADH2', 'Gene', (102, 106))	('ADH1B', 'Gene', '125', (140, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
365142	21048924	The eligible for our meta-analysis were then all population-based case-control studies reporting association between ADH1B Arg47His variants and ESCC.	('association', 'Interaction', (97, 108))	('Arg47His', 'Var', (123, 131))	('ADH1B', 'Gene', (117, 122))	('Arg47His', 'SUBSTITUTION', 'None', (123, 131))	('ADH1B', 'Gene', '125', (117, 122))	('ESCC', 'Disease', (145, 149))
365144	21048924	A total of 12 studies examining the association of the ADH1B Arg47His polymorphism were found, out of which 3 articles analyzed the interaction between ADH1B and ALDH2 genes.	('ADH1B', 'Gene', '125', (152, 157))	('ADH1B', 'Gene', '125', (55, 60))	('ALDH2', 'Gene', '217', (162, 167))	('Arg47His', 'Var', (61, 69))	('interaction', 'Interaction', (132, 143))	('ADH1B', 'Gene', (55, 60))	('ADH1B', 'Gene', (152, 157))	('ALDH2', 'Gene', (162, 167))	('Arg47His', 'SUBSTITUTION', 'None', (61, 69))
365146	21048924	The risks of ESCC added by the ADH1B Arg47His variant were estimated for each study and the metadata as well via odds ratio (OR) using the Comprehensive Meta-analysis software version 2.0.	('ESCC', 'Disease', (13, 17))	('Arg47His', 'Var', (37, 45))	('ADH1B', 'Gene', (31, 36))	('Arg47His', 'SUBSTITUTION', 'None', (37, 45))	('ADH1B', 'Gene', '125', (31, 36))
365149	21048924	For the analysis of gene-gene interaction between ADH1B Arg47His and ALDH2*504Lys, the His/His and Glu/Glu was considered the reference genotype.	('His', 'Chemical', 'MESH:D006639', (61, 64))	('504Lys', 'Var', (75, 81))	('Arg47His', 'Var', (56, 64))	('ADH1B', 'Gene', (50, 55))	('Glu', 'Chemical', 'MESH:D018698', (103, 106))	('ALDH2', 'Gene', '217', (69, 74))	('Arg47His', 'SUBSTITUTION', 'None', (56, 64))	('ADH1B', 'Gene', '125', (50, 55))	('His', 'Chemical', 'MESH:D006639', (87, 90))	('ALDH2', 'Gene', (69, 74))	('His', 'Chemical', 'MESH:D006639', (91, 94))	('Glu', 'Chemical', 'MESH:D018698', (99, 102))	('Lys', 'Chemical', 'MESH:D008239', (78, 81))
365152	21048924	Twelve studies published in 1997 through to 2010 were about the relationship between the ADH1B Arg47His polymorphism and ESCC risks.	('Arg47His', 'Var', (95, 103))	('ADH1B', 'Gene', (89, 94))	('Arg47His', 'SUBSTITUTION', 'None', (95, 103))	('ADH1B', 'Gene', '125', (89, 94))	('relationship', 'Interaction', (64, 76))	('ESCC', 'Disease', (121, 125))
365155	21048924	Additionally, no significant publication bias was found in the results of Egger's test: p is 0.09 for Arg/Arg+Arg/His vs. His/His and 0.52 for Arg/Arg vs. His/His, respectively.	('Arg', 'Chemical', 'MESH:D001120', (110, 113))	('His', 'Chemical', 'MESH:D006639', (122, 125))	('Arg/Arg+Arg/His', 'Var', (102, 117))	('Arg/Arg', 'Var', (143, 150))	('His', 'Chemical', 'MESH:D006639', (126, 129))	('His', 'Chemical', 'MESH:D006639', (155, 158))	('His', 'Chemical', 'MESH:D006639', (159, 162))	('His', 'Chemical', 'MESH:D006639', (114, 117))	('Arg', 'Chemical', 'MESH:D001120', (102, 105))	('Arg', 'Chemical', 'MESH:D001120', (147, 150))	('Arg', 'Chemical', 'MESH:D001120', (106, 109))	('Arg', 'Chemical', 'MESH:D001120', (143, 146))
365156	21048924	When the homozygotes (Arg/Arg) and all Arg carriers (Arg/Arg +Arg/His) were compared with the homozygotes of His/His, significant differences were found between the groups of cases and controls.	('His', 'Chemical', 'MESH:D006639', (109, 112))	('differences', 'Reg', (130, 141))	('His', 'Chemical', 'MESH:D006639', (66, 69))	('Arg', 'Chemical', 'MESH:D001120', (22, 25))	('Arg', 'Chemical', 'MESH:D001120', (26, 29))	('Arg', 'Chemical', 'MESH:D001120', (39, 42))	('Arg', 'Chemical', 'MESH:D001120', (53, 56))	('Arg', 'Chemical', 'MESH:D001120', (57, 60))	('Arg', 'Chemical', 'MESH:D001120', (62, 65))	('His', 'Chemical', 'MESH:D006639', (113, 116))	('Arg/Arg', 'Var', (22, 29))
365158	21048924	Compared with non-drinkers who carried the ADH1B His/His genotype, drinkers with the ADH1B Arg/Arg or the Arg/His genotype can experience increased ESCC risk by 20.69 and 6.97 fold, respectively.	('His', 'Chemical', 'MESH:D006639', (53, 56))	('ADH1B', 'Gene', (43, 48))	('Arg/His', 'Var', (106, 113))	('His', 'Chemical', 'MESH:D006639', (49, 52))	('ADH1B', 'Gene', (85, 90))	('ADH1B', 'Gene', '125', (43, 48))	('Arg', 'Chemical', 'MESH:D001120', (95, 98))	('increased ESCC', 'Phenotype', 'HP:0003565', (138, 152))	('His', 'Chemical', 'MESH:D006639', (110, 113))	('Arg', 'Chemical', 'MESH:D001120', (91, 94))	('ADH1B', 'Gene', '125', (85, 90))	('ESCC', 'Disease', (148, 152))	('Arg', 'Chemical', 'MESH:D001120', (106, 109))	('Arg/Arg', 'Var', (91, 98))
365159	21048924	Combined result of Arg/His+Arg/Arg vs. His/His suggests that there is a significant association of the genotype with ESCC risk in drinkers (OR: 7.34, 95% CI: 2.10-25.71).	('His', 'Chemical', 'MESH:D006639', (39, 42))	('Arg', 'Chemical', 'MESH:D001120', (31, 34))	('Arg/His+Arg/Arg', 'Var', (19, 34))	('Arg', 'Chemical', 'MESH:D001120', (19, 22))	('ESCC', 'Disease', (117, 121))	('His', 'Chemical', 'MESH:D006639', (23, 26))	('His', 'Chemical', 'MESH:D006639', (43, 46))	('Arg', 'Chemical', 'MESH:D001120', (27, 30))
365160	21048924	The next step was to obtain more accurate estimates for the combined risk of ADH1B Arg/Arg genotype and alcohol drinking.	('ADH1B', 'Gene', (77, 82))	('Arg', 'Chemical', 'MESH:D001120', (83, 86))	('Arg', 'Chemical', 'MESH:D001120', (87, 90))	('ADH1B', 'Gene', '125', (77, 82))	('alcohol drinking', 'Phenotype', 'HP:0030955', (104, 120))	('alcohol drinking', 'Disease', (104, 120))	('alcohol', 'Chemical', 'MESH:D000438', (104, 111))	('Arg/Arg', 'Var', (83, 90))
365161	21048924	Since the standards for categorizing alcohol drinking status varied in literatures, we selected the category of heavy drinkers with the ADH1B Arg/Arg genotype from each of the literature as the case group, and set non-drinkers with the ADH1B His/His genotype as the reference group.	('alcohol drinking', 'Phenotype', 'HP:0030955', (37, 53))	('ADH1B', 'Gene', (236, 241))	('alcohol', 'Chemical', 'MESH:D000438', (37, 44))	('Arg', 'Chemical', 'MESH:D001120', (142, 145))	('Arg', 'Chemical', 'MESH:D001120', (146, 149))	('ADH1B', 'Gene', '125', (236, 241))	('ADH1B', 'Gene', (136, 141))	('ADH1B', 'Gene', '125', (136, 141))	('His', 'Chemical', 'MESH:D006639', (246, 249))	('Arg/Arg', 'Var', (142, 149))	('His', 'Chemical', 'MESH:D006639', (242, 245))
365162	21048924	Such a comparison reveals heavy-drinkers with the ADH1B Arg/Arg genotype had a 70.12-fold increase (95% CI: 40.60-121.10) of risk for ESCC (Figure S4).	('increase', 'PosReg', (90, 98))	('ADH1B', 'Gene', (50, 55))	('Arg', 'Chemical', 'MESH:D001120', (56, 59))	('ESCC', 'Disease', (134, 138))	('ADH1B', 'Gene', '125', (50, 55))	('Arg', 'Chemical', 'MESH:D001120', (60, 63))	('Arg/Arg', 'Var', (56, 63))
365164	21048924	Compared to the subjects having ADH1B His/His and ALDH2 Glu/Glu, ORs for those with ALDH2 Glu/Glu and ADH1B Arg+, ALDH2 Lys+ and ADH1B His/His, and ALDH2 Lys+ and ADH1B Arg+ were 3.66-13.46.	('ADH1B', 'Gene', (129, 134))	('His', 'Chemical', 'MESH:D006639', (38, 41))	('Arg', 'Chemical', 'MESH:D001120', (169, 172))	('ALDH2', 'Gene', '217', (148, 153))	('ALDH2', 'Gene', '217', (84, 89))	('ALDH2', 'Gene', (114, 119))	('Glu', 'Chemical', 'MESH:D018698', (94, 97))	('Glu', 'Chemical', 'MESH:D018698', (56, 59))	('ALDH2', 'Gene', (50, 55))	('ADH1B', 'Gene', '125', (32, 37))	('ADH1B', 'Gene', '125', (102, 107))	('Lys', 'Chemical', 'MESH:D008239', (120, 123))	('His', 'Chemical', 'MESH:D006639', (139, 142))	('ADH1B', 'Gene', (32, 37))	('ADH1B', 'Gene', (102, 107))	('His', 'Chemical', 'MESH:D006639', (42, 45))	('ALDH2', 'Gene', '217', (114, 119))	('Glu', 'Chemical', 'MESH:D018698', (60, 63))	('ALDH2', 'Gene', (148, 153))	('ALDH2', 'Gene', '217', (50, 55))	('ALDH2', 'Gene', (84, 89))	('ADH1B', 'Gene', '125', (163, 168))	('Arg', 'Chemical', 'MESH:D001120', (108, 111))	('ADH1B', 'Gene', '125', (129, 134))	('Glu', 'Chemical', 'MESH:D018698', (90, 93))	('Arg+', 'Var', (108, 112))	('Lys', 'Chemical', 'MESH:D008239', (154, 157))	('His', 'Chemical', 'MESH:D006639', (135, 138))	('ADH1B', 'Gene', (163, 168))
365174	21048924	The pooled ORs for response were 1.62 (95% CI: 1.49-1.76, P< 0.001) and 3.86 (95% CI: 2.96-5.03, p < 0.001) for Arg/Arg homozygotes and Arg carriers, respectively.	('Arg/Arg', 'Var', (112, 119))	('Arg', 'Chemical', 'MESH:D001120', (112, 115))	('Arg', 'Chemical', 'MESH:D001120', (136, 139))	('Arg', 'Var', (136, 139))	('Arg', 'Chemical', 'MESH:D001120', (116, 119))
365175	21048924	Many studies have noticed that the synergistic interaction between ADH1B polymorphism and alcohol drinking may exist in increased risk of ESCC.	('ADH1B', 'Gene', (67, 72))	('polymorphism', 'Var', (73, 85))	('alcohol drinking', 'Phenotype', 'HP:0030955', (90, 106))	('ADH1B', 'Gene', '125', (67, 72))	('alcohol', 'Chemical', 'MESH:D000438', (90, 97))	('ESCC', 'Disease', (138, 142))
365176	21048924	In this meta-analysis, the ESCC risk of individuals with the ADH1B Arg/His genotype and alcohol drinking is increased by 6 fold.	('alcohol', 'Disease', (88, 95))	('alcohol drinking', 'Phenotype', 'HP:0030955', (88, 104))	('ADH1B', 'Gene', (61, 66))	('alcohol', 'Chemical', 'MESH:D000438', (88, 95))	('increased', 'PosReg', (108, 117))	('Arg', 'Chemical', 'MESH:D001120', (67, 70))	('ADH1B', 'Gene', '125', (61, 66))	('ESCC', 'Disease', (27, 31))	('Arg/His', 'Var', (67, 74))	('His', 'Chemical', 'MESH:D006639', (71, 74))
365180	21048924	Many studies explored the interaction between the ADH1B Arg/His and the ALDH2*504Lys polymorphisms.	('504Lys', 'Var', (78, 84))	('ADH1B', 'Gene', (50, 55))	('Arg', 'Chemical', 'MESH:D001120', (56, 59))	('ALDH2', 'Gene', '217', (72, 77))	('ADH1B', 'Gene', '125', (50, 55))	('Lys', 'Chemical', 'MESH:D008239', (81, 84))	('Arg/His', 'Var', (56, 63))	('interaction', 'Interaction', (26, 37))	('ALDH2', 'Gene', (72, 77))	('His', 'Chemical', 'MESH:D006639', (60, 63))
365183	21048924	Adjustments over these covariates might help better disect the association between ADH1B Arg47His and the susceptibility of ESCC.	('Arg47His', 'SUBSTITUTION', 'None', (89, 97))	('ADH1B', 'Gene', (83, 88))	('Arg47His', 'Var', (89, 97))	('ADH1B', 'Gene', '125', (83, 88))	('ESCC', 'Disease', (124, 128))
365185	21048924	Together with alcohol drinking, especially heavy alcohol drinking, the Arg/Arg genotype can greatly increase the ESCC risk.	('ESCC', 'Disease', (113, 117))	('Arg', 'Chemical', 'MESH:D001120', (71, 74))	('alcohol drinking', 'Phenotype', 'HP:0030955', (49, 65))	('alcohol', 'Chemical', 'MESH:D000438', (14, 21))	('Arg', 'Chemical', 'MESH:D001120', (75, 78))	('alcohol drinking', 'Phenotype', 'HP:0030955', (14, 30))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))	('Arg/Arg', 'Var', (71, 78))	('increase', 'PosReg', (100, 108))
365186	21048924	This effect can be further strengthened by the gene-gene interaction between the ADH1B Arg47His and the ALDH2 Glu504Lys polymorphisms.	('Glu504Lys', 'SUBSTITUTION', 'None', (110, 119))	('ADH1B', 'Gene', (81, 86))	('ALDH2', 'Gene', '217', (104, 109))	('Arg47His', 'SUBSTITUTION', 'None', (87, 95))	('ADH1B', 'Gene', '125', (81, 86))	('Glu504Lys', 'Var', (110, 119))	('ALDH2', 'Gene', (104, 109))	('Arg47His', 'Var', (87, 95))
365191	32785606	Results showed that high expression of DLX6-AS1 was significantly closely associated with poor overall survival in tumor patients (hazard ratio (HR) = 2.30, confidence interval (95% CI): 1.70-3.09, P<0.01).	('DLX6-AS1', 'Gene', (39, 47))	('poor', 'NegReg', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('DLX6-AS1', 'Gene', '285987;1750;5729', (39, 47))	('high', 'Var', (20, 24))	('overall', 'MPA', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('patients', 'Species', '9606', (121, 129))	('associated', 'Reg', (74, 84))
365195	32785606	The development of cancer involves the ectopic movement, deletion, and expansion of chromosomes.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('ectopic movement', 'CPA', (39, 55))	('deletion', 'Var', (57, 65))	('cancer', 'Disease', (19, 25))	('expansion', 'CPA', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
365208	32785606	reported that high expression of DLX6-AS1 was associated with tumor size and advanced clinical stage in non-small cell lung, but no significant associations between DLX6 expression and histological grade or lymph node metastasis.	('DLX6-AS1', 'Gene', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('DLX6-AS1', 'Gene', '285987;1750;5729', (33, 41))	('tumor', 'Disease', (62, 67))	('DLX6', 'Gene', (33, 37))	('high', 'Var', (14, 18))	('DLX6', 'Gene', '1750', (33, 37))	('associated', 'Reg', (46, 56))	('DLX6', 'Gene', (165, 169))	('non-small cell lung', 'Disease', (104, 123))	('DLX6', 'Gene', '1750', (165, 169))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
365216	32785606	HR > 1, indicated that patients with high DLX6-AS1 expression had poor prognosis.	('patients', 'Species', '9606', (23, 31))	('DLX6-AS1', 'Gene', '285987;1750;5729', (42, 50))	('DLX6-AS1', 'Gene', (42, 50))	('high', 'Var', (37, 41))
365222	32785606	As shown in Table 2, high expression of DLX6-AS1 was significantly associated with tumor size (OR: 1.32, 95% CI: 1.07-1.62; Figure 2A), tumor stages (OR: 1.94, 95% CI: 1.64-2.30; Figure 2B), lymph node metastasis (OR: 1.63, 95% CI: 1.35-1.97; Figure 2C) and distant metastasis (OR: 1.69, 95% CI: 1.19-2.41; Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('DLX6-AS1', 'Gene', '285987;1750;5729', (40, 48))	('tumor', 'Disease', (83, 88))	('lymph node metastasis', 'CPA', (191, 212))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('high expression', 'Var', (21, 36))	('associated', 'Reg', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('distant metastasis', 'CPA', (258, 276))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (136, 141))	('DLX6-AS1', 'Gene', (40, 48))
365224	32785606	In this way, the results indicated that high DLX6-AS1 expression significantly increased the risk of poor clinicopathological features.	('high', 'Var', (40, 44))	('DLX6-AS1', 'Gene', '285987;1750;5729', (45, 53))	('DLX6-AS1', 'Gene', (45, 53))
365231	32785606	Several studies have suggested that DLX6-AS1 knockdown significantly attenuated cell motility, proliferation, and invasion.	('DLX6-AS1', 'Gene', '285987;1750;5729', (36, 44))	('attenuated', 'NegReg', (69, 79))	('cell motility', 'CPA', (80, 93))	('proliferation', 'CPA', (95, 108))	('DLX6-AS1', 'Gene', (36, 44))	('invasion', 'CPA', (114, 122))	('knockdown', 'Var', (45, 54))
365242	32785606	The results showed that high expression DLX6-AS1 was significantly closely correlated with poor outcomes in patients with various types of cancers.	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('DLX6-AS1', 'Gene', '285987;1750;5729', (40, 48))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('correlated', 'Reg', (75, 85))	('high expression', 'Var', (24, 39))	('patients', 'Species', '9606', (108, 116))	('DLX6-AS1', 'Gene', (40, 48))
365248	32785606	In summary, our study suggests that high levels of DLX6-AS1 expression are a valuable predictor of poor cancer prognosis in overall survival, TNM stage, tumor size, lymph node metastasis, and distant metastasis.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('TNM', 'Gene', '10178', (142, 145))	('DLX6-AS1', 'Gene', '285987;1750;5729', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('DLX6-AS1', 'Gene', (51, 59))	('tumor', 'Disease', (153, 158))	('lymph node metastasis', 'CPA', (165, 186))	('high levels', 'Var', (36, 47))	('TNM', 'Gene', (142, 145))	('distant metastasis', 'CPA', (192, 210))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('poor', 'Disease', (99, 103))
365268	30398503	Harvested cells were resuspended to 107 cells/mL in Dulbecco's Phosphate Buffered Saline (DPBS) with Ca2+ or Mg2+ (Thermo Fisher Scientific; Waltham, MA) supplemented with 2% fetal bovine serum (FBS).	('Mg2+', 'Var', (109, 113))	('Mg2+', 'Chemical', 'MESH:D008274', (109, 113))	('FBS', 'Disease', 'MESH:D005198', (195, 198))	('Ca2+', 'Chemical', 'MESH:D002118', (101, 105))	('FBS', 'Disease', (195, 198))	('Phosphate', 'Chemical', 'MESH:D010710', (63, 72))
365269	30398503	Separate aliquots containing ~ 2 x 105 cells were prepared, washed and treated with primary antibodies to various antigens (SLea, SLex, HECA-452 antigen, CD44, CD44v3, CD44v4, CD44v5, CD44v6, CD44v7, CD44v7/8, CD44v10, VCAM-1, ICAM-1, and CD65s) or the appropriately matched isotype control and incubated on ice for 30 minutes.	('CD44v6', 'Var', (184, 190))	('SLea', 'Disease', (124, 128))	('ICAM-1', 'Gene', (227, 233))	('CD44v7/8', 'Gene', (200, 208))	('SLea', 'Disease', 'None', (124, 128))	('CD44v7', 'Var', (192, 198))	('CD44v4', 'Var', (168, 174))	('CD44v10', 'Var', (210, 217))	('ICAM-1', 'Gene', '3383', (227, 233))	('CD44v7/8', 'Gene', '925', (200, 208))	('rat', 'Species', '10116', (4, 7))	('HECA-452', 'Chemical', 'MESH:C062643', (136, 144))	('CD44v5', 'Var', (176, 182))	('CD44v3', 'Var', (160, 166))
365274	30398503	Matched isotype control for the mAbs to SLea, CD44, CD44v3, CD44v4, CD44v5, CD44v6, CD44v7, CD44v10, and VCAM-1 was purified mouse IgG1 (mIgG).	('IgG1', 'Gene', '16017', (131, 135))	('CD44v10', 'Var', (92, 99))	('CD44v7', 'Var', (84, 90))	('IgG', 'Gene', '16059', (138, 141))	('SLea', 'Disease', (40, 44))	('mouse', 'Species', '10090', (125, 130))	('IgG', 'Gene', '16059', (131, 134))	('IgG', 'Gene', (138, 141))	('SLea', 'Disease', 'None', (40, 44))	('IgG1', 'Gene', (131, 135))	('CD44v5', 'Var', (68, 74))	('IgG', 'Gene', (131, 134))	('CD44v6', 'Var', (76, 82))
365275	30398503	Purified mouse IgM was utilized as an isotype matched control for mouse anti-human SLex and CD65s mAbs while mouse IgG2b was used for the mouse anti-human ICAM-1 and CD44v7/8 mAbs.	('ICAM-1', 'Gene', '3383', (155, 161))	('mouse', 'Species', '10090', (138, 143))	('mouse', 'Species', '10090', (66, 71))	('mouse', 'Species', '10090', (9, 14))	('ICAM-1', 'Gene', (155, 161))	('CD44v7/8', 'Gene', '925', (166, 174))	('IgG2b', 'Gene', '16016', (115, 120))	('CD65s', 'Var', (92, 97))	('human', 'Species', '9606', (149, 154))	('mouse', 'Species', '10090', (109, 114))	('IgG2b', 'Gene', (115, 120))	('human', 'Species', '9606', (77, 82))	('CD44v7/8', 'Gene', (166, 174))
365290	30398503	FITC-labeled goat anti-mouse IgG (H+L) pAb (Southern Biotech) was used to evaluate the presence of adsorbed anti-CD44v5 and mIgG on the 106-125 microm anti-CD44v5 and mIgG treated microspheres.	('IgG', 'Gene', (168, 171))	('IgG', 'Gene', '16059', (125, 128))	('mouse', 'Species', '10090', (23, 28))	('IgG', 'Gene', '16059', (29, 32))	('IgG', 'Gene', (125, 128))	('FITC', 'Chemical', 'MESH:D016650', (0, 4))	('IgG', 'Gene', '16059', (168, 171))	('anti-CD44v5', 'Var', (108, 119))	('IgG', 'Gene', (29, 32))
365302	30398503	In addition, we assayed for the expression of CD65s (VIM-2) (a sialylated carbohydrate), VCAM-1 (CD106) , ICAM-1 (CD54) , CD44 , and CD44 isoforms (e.g. )	('VIM-2', 'Gene', '100130535', (53, 58))	('ICAM-1', 'Gene', (106, 112))	('CD65s', 'Var', (46, 51))	('CD106', 'Gene', (97, 102))	('CD54', 'Gene', '3383', (114, 118))	('VIM-2', 'Gene', (53, 58))	('carbohydrate', 'Chemical', 'MESH:D002241', (74, 86))	('ICAM-1', 'Gene', '3383', (106, 112))	('VCAM-1', 'Gene', (89, 95))	('CD106', 'Gene', '7412', (97, 102))	('CD54', 'Gene', (114, 118))
365304	30398503	As shown in Figure 1, HEsEpiC cells treated with anti-SLea (KM231), anti-SLex (CSLEX-1), HECA-452 and anti-CD44 (515) exhibited no shift, slight shift, moderate shift, and large shift in fluorescence intensity relative to cells treated with an isotype matched control.	('rat', 'Species', '10116', (156, 159))	('HEsEpiC', 'Disease', 'None', (22, 29))	('shift', 'Reg', (178, 183))	('SLea', 'Disease', (54, 58))	('anti-SLex', 'Var', (68, 77))	('fluorescence intensity', 'MPA', (187, 209))	('SLea', 'Disease', 'None', (54, 58))	('HECA-452', 'Chemical', 'MESH:C062643', (89, 97))	('HEsEpiC', 'Disease', (22, 29))
365305	30398503	In contrast, OE19 cells treated with the same mAbs, exhibited dramatic shifts when treated with anti-SLea, anti-SLex, and HECA-452 but no shift when treated with anti-CD44.	('anti-SLex', 'Var', (107, 116))	('SLea', 'Disease', (101, 105))	('shifts', 'Reg', (71, 77))	('SLea', 'Disease', 'None', (101, 105))	('HECA-452', 'Chemical', 'MESH:C062643', (122, 130))
365306	30398503	In addition to the above, we investigated the relative expression of VCAM-1, ICAM-1, CD65s and the CD44 variants; v3, v4, v5, v6, v7, v7/8, v10.	('v10', 'Var', (140, 143))	('v7/8', 'Var', (134, 138))	('VCAM-1', 'Gene', (69, 75))	('ICAM-1', 'Gene', '3383', (77, 83))	('CD44', 'Gene', (99, 103))	('CD65s', 'Gene', (85, 90))	('ICAM-1', 'Gene', (77, 83))
365315	30398503	As shown in Figure 2A, OE19 cells treated with either the rmE-Sel or rhE-Sel exhibited a significant shift compared to the negative control OE19 cells treated with hIgG indicating that the E-selectin chimeras were bound to the OE19 cells.	('rhE', 'Gene', (69, 72))	('IgG', 'Gene', '16059', (165, 168))	('rhE', 'Gene', '81608', (69, 72))	('E-selectin', 'Protein', (189, 199))	('rmE-Sel', 'Var', (58, 65))	('IgG', 'Gene', (165, 168))	('bound', 'Interaction', (214, 219))	('shift', 'Reg', (101, 106))
365316	30398503	In contrast, HEsEpiC cells treated with either the rmE-Sel or rhE-Sel exhibited no shift compared to HEsEpiC cells treated with hIgG indicating that the E-selectin chimeras did not recognize the HEsEpiC cells (Figure 2B).	('HEsEpiC', 'Disease', (13, 20))	('HEsEpiC', 'Disease', 'None', (101, 108))	('rhE', 'Gene', '81608', (62, 65))	('HEsEpiC', 'Disease', (195, 202))	('HEsEpiC', 'Disease', 'None', (13, 20))	('IgG', 'Gene', '16059', (129, 132))	('HEsEpiC', 'Disease', 'None', (195, 202))	('rmE-Sel', 'Var', (51, 58))	('HEsEpiC', 'Disease', (101, 108))	('rhE', 'Gene', (62, 65))	('IgG', 'Gene', (129, 132))
365323	30398503	As shown in Figure 3A, rmE-Sel, rhE-Sel, and hIgG microspheres treated with FITC-labeled anti-human IgG antibody exhibited a pronounced increase in fluorescence relative to unconjugated microspheres treated with the same FITC-labeled antibody and rmE-Sel, rhE-Sel or hIgG microspheres not treated with the FITC-labeled antibody.	('rhE', 'Gene', (32, 35))	('FITC', 'Chemical', 'MESH:D016650', (221, 225))	('anti-human', 'Var', (89, 99))	('IgG', 'Gene', '16059', (46, 49))	('IgG antibody', 'Phenotype', 'HP:0003237', (100, 112))	('rhE', 'Gene', '81608', (256, 259))	('FITC-labeled anti-human', 'Var', (76, 99))	('IgG', 'Gene', '16059', (100, 103))	('IgG', 'Gene', '16059', (268, 271))	('fluorescence', 'MPA', (148, 160))	('rhE', 'Gene', '81608', (32, 35))	('human', 'Species', '9606', (94, 99))	('IgG', 'Gene', (46, 49))	('FITC', 'Chemical', 'MESH:D016650', (306, 310))	('FITC', 'Chemical', 'MESH:D016650', (76, 80))	('IgG', 'Gene', (100, 103))	('rhE', 'Gene', (256, 259))	('IgG', 'Gene', (268, 271))	('increase', 'PosReg', (136, 144))
365332	30398503	The selectivity (ratio of E-selectin microspheres on OE19 cells to E-selectin microspheres on HEsEpiC cells) was ~88 for rmE-Sel and ~56 for rhE-Sel.	('rhE', 'Gene', '81608', (141, 144))	('HEsEpiC', 'Disease', (94, 101))	('rat', 'Species', '10116', (17, 20))	('HEsEpiC', 'Disease', 'None', (94, 101))	('rmE-Sel', 'Var', (121, 128))	('rhE', 'Gene', (141, 144))
365335	30398503	As revealed in Figure 5, the rmE-Sel (Figure 5A) and rhE-Sel microspheres (Figure 5B) were again able to discriminate between OE19 and HEsEpiC cells.	('HEsEpiC', 'Disease', 'None', (135, 142))	('OE19', 'Var', (126, 130))	('discriminate', 'Reg', (105, 117))	('rhE', 'Gene', (53, 56))	('HEsEpiC', 'Disease', (135, 142))	('rhE', 'Gene', '81608', (53, 56))
365336	30398503	This is seen by comparing the level of adhesion observed on OE19 cells (black circles in each panel) to that observed on the HEsEpiC cells (grey squares in each panel).	('HEsEpiC', 'Disease', 'None', (125, 132))	('OE19', 'Var', (60, 64))	('HEsEpiC', 'Disease', (125, 132))	('adhesion', 'MPA', (39, 47))
365349	30398503	To provide further proof of concept, we sought to discriminate between OE21 squamous cell carcinoma and normal esophageal cells in the endoscopic adhesion assay.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', (76, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('OE21', 'Var', (71, 75))
365353	30398503	As shown in Figure 8, a significantly greater level of adhesion occurred between anti-CD44v5 microspheres and the OE21 cells compared to the level of adhesion that occurred between anti-CD44v5 microspheres and HEsEpiC cells.	('greater', 'PosReg', (38, 45))	('adhesion', 'MPA', (55, 63))	('anti-CD44v5', 'Var', (81, 92))	('HEsEpiC', 'Disease', (210, 217))	('HEsEpiC', 'Disease', 'None', (210, 217))
365355	30398503	Thus, the endoscopic adhesion assay can discriminate between normal esophageal cells and two types of esophageal cancer cells (OE19 adenocarcinoma and OE21 squamous cell carcinoma).	('adenocarcinoma', 'Disease', 'MESH:D000230', (132, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('OE21', 'Var', (151, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('squamous cell carcinoma', 'Disease', (156, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('esophageal cancer', 'Disease', (102, 119))	('adenocarcinoma', 'Disease', (132, 146))
365483	29490701	Consequently, DGE is reported to lead to decreased patient satisfaction and a prolonged hospital stay.	('decreased', 'NegReg', (41, 50))	('DGE', 'Phenotype', 'HP:0002578', (14, 17))	('patient', 'Species', '9606', (51, 58))	('DGE', 'Var', (14, 17))	('patient satisfaction', 'CPA', (51, 71))
365484	29490701	Although gastric tube reconstruction, rather than reconstruction of the entire stomach, has been sufficiently demonstrated to be associated with a significantly reduced risk of DGE, superior quality-of-life scores during the first postoperative year, and less reflux esophagitis, controversy surrounds the need for pyloric drainage procedures.	('reduced', 'NegReg', (161, 168))	('reflux esophagitis', 'Disease', 'MESH:D005764', (260, 278))	('DGE', 'Phenotype', 'HP:0002578', (177, 180))	('reflux esophagitis', 'Disease', (260, 278))	('gastric tube', 'Disease', (9, 21))	('reconstruction', 'Var', (22, 36))	('DGE', 'Disease', (177, 180))	('esophagitis', 'Phenotype', 'HP:0100633', (267, 278))	('superior', 'PosReg', (182, 190))
365560	29490701	One patient was re-explored on the first postoperative day because of bilious drainage from the midline abdominal incision due to a pinpoint hole at the pyloromyotomy.	('midline abdominal', 'Disease', 'MESH:D015746', (96, 113))	('patient', 'Species', '9606', (4, 11))	('midline abdominal', 'Disease', (96, 113))	('pinpoint', 'Var', (132, 140))	('bilious drainage from', 'MPA', (70, 91))
365565	29490701	In this study, the rate of postoperative pyloric dysfunction was found to be significantly lower in the botulinum toxin group.	('lower', 'NegReg', (91, 96))	('botulinum', 'Var', (104, 113))	('postoperative pyloric dysfunction', 'Disease', 'MESH:D010149', (27, 60))	('postoperative pyloric dysfunction', 'Disease', (27, 60))
365578	28694483	Importantly, mutations in ZFHX4, SPHKAP, NRXN1, KIAA1109, DNAH5 and KCNH7 were associated with poor survival.	('KIAA1109', 'Gene', '84162', (48, 56))	('associated', 'Reg', (79, 89))	('SPHKAP', 'Gene', (33, 39))	('DNAH5', 'Gene', '1767', (58, 63))	('KIAA1109', 'Gene', (48, 56))	('mutations', 'Var', (13, 22))	('poor', 'NegReg', (95, 99))	('NRXN1', 'Gene', '9378', (41, 46))	('SPHKAP', 'Gene', '80309', (33, 39))	('NRXN1', 'Gene', (41, 46))	('ZFHX4', 'Gene', (26, 31))	('KCNH7', 'Gene', '90134', (68, 73))	('KCNH7', 'Gene', (68, 73))	('ZFHX4', 'Gene', '79776', (26, 31))	('DNAH5', 'Gene', (58, 63))
365579	28694483	In addition, ZFHX4 was overexpressed in tumor tissues compared to normal controls, and knockdown of ZFHX4 in vitro significantly inhibited cell migration and invasion.	('inhibited', 'NegReg', (129, 138))	('ZFHX4', 'Gene', '79776', (13, 18))	('ZFHX4', 'Gene', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('ZFHX4', 'Gene', '79776', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('ZFHX4', 'Gene', (13, 18))	('knockdown', 'Var', (87, 96))
365580	28694483	Mutations in ZFHX4 were strongly associated with poor prognosis and the down-regulation of ZFHX4 inhibits the progression of esophageal squamous cell carcinoma.	('ZFHX4', 'Gene', '79776', (13, 18))	('down-regulation', 'NegReg', (72, 87))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (125, 159))	('inhibits', 'NegReg', (97, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('ZFHX4', 'Gene', (91, 96))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (33, 43))	('ZFHX4', 'Gene', '79776', (91, 96))	('esophageal squamous cell carcinoma', 'Disease', (125, 159))	('progression', 'CPA', (110, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('ZFHX4', 'Gene', (13, 18))
365586	28694483	It can be utilized to characterize the alterations of an individual cancer genome, providing a comprehensive way to identify somatic mutations that might contribute to the initiation and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('contribute', 'Reg', (154, 164))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('mutations', 'Var', (133, 142))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', (202, 208))
365588	28694483	Seventeen significantly mutated genes (SMGs), including TP53, PIK3CA, NOTHC1, CDKN2A, NFE2L2 and MLL2 mutated in at least 10% of ESCCs.	('MLL2', 'Gene', (97, 101))	('TP53', 'Gene', '7157', (56, 60))	('NOTHC1', 'Gene', (70, 76))	('CDKN2A', 'Gene', (78, 84))	('PIK3CA', 'Gene', (62, 68))	('SMG', 'Gene', (39, 42))	('NFE2L2', 'Gene', '4780', (86, 92))	('SMG', 'Gene', '23034', (39, 42))	('CDKN2A', 'Gene', '1029', (78, 84))	('TP53', 'Gene', (56, 60))	('MLL2', 'Gene', '8085', (97, 101))	('NFE2L2', 'Gene', (86, 92))	('PIK3CA', 'Gene', '5290', (62, 68))	('mutated', 'Var', (102, 109))
365591	28694483	We found that mutations in ZFHX4, SPHKAP, NRXN1, KIAA1109, DNAH5 and KCNH7 were associated with poor overall survival.	('KCNH7', 'Gene', '90134', (69, 74))	('KCNH7', 'Gene', (69, 74))	('DNAH5', 'Gene', '1767', (59, 64))	('NRXN1', 'Gene', '9378', (42, 47))	('KIAA1109', 'Gene', (49, 57))	('SPHKAP', 'Gene', (34, 40))	('ZFHX4', 'Gene', '79776', (27, 32))	('overall', 'MPA', (101, 108))	('NRXN1', 'Gene', (42, 47))	('associated', 'Reg', (80, 90))	('KIAA1109', 'Gene', '84162', (49, 57))	('poor', 'NegReg', (96, 100))	('DNAH5', 'Gene', (59, 64))	('mutations', 'Var', (14, 23))	('SPHKAP', 'Gene', '80309', (34, 40))	('ZFHX4', 'Gene', (27, 32))
365592	28694483	We also examined somatic mutations and expression profiles of ZFHX4 in The Cancer Genome Alas (TCGA) datasets and found that the mutations of ZFHX4 were also associated with poor overall survival of liver hepatocellular carcinoma patients.	('liver hepatocellular carcinoma', 'Disease', (199, 229))	('Alas', 'Chemical', 'MESH:D000409', (89, 93))	('ZFHX4', 'Gene', (62, 67))	('overall', 'MPA', (179, 186))	('associated with', 'Reg', (158, 173))	('Cancer', 'Disease', (75, 81))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (199, 229))	('ZFHX4', 'Gene', (142, 147))	('Cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (129, 138))	('ZFHX4', 'Gene', '79776', (62, 67))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (205, 229))	('ZFHX4', 'Gene', '79776', (142, 147))	('patients', 'Species', '9606', (230, 238))	('poor', 'NegReg', (174, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))
365594	28694483	In vitro siRNA-mediated silencing of ZFHX4 effectively inhibited migration and invasion abilities in two ESCC cell lines.	('ZFHX4', 'Gene', (37, 42))	('ZFHX4', 'Gene', '79776', (37, 42))	('inhibited', 'NegReg', (55, 64))	('silencing', 'Var', (24, 33))
365608	28694483	SMGs were analyzed with MutSigCV that detects genes associated with cancer as mutated more frequently than by chance.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutated', 'Var', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('SMG', 'Gene', (0, 3))	('SMG', 'Gene', '23034', (0, 3))	('cancer', 'Disease', (68, 74))
365620	28694483	siRNA molecule (GenePharma, China) sequences ZFHX4-siRNA 5'GCAGGUCUCGAGGAUUCAATT and 5'UUGAAUCCUCGAGACCUGCTT were used to knock down ZFHX4 expression.	('ZFHX4', 'Gene', (45, 50))	('knock', 'Var', (122, 127))	('ZFHX4', 'Gene', '79776', (45, 50))	('ZFHX4', 'Gene', (133, 138))	('expression', 'MPA', (139, 149))	('ZFHX4', 'Gene', '79776', (133, 138))
365626	28694483	Sixty-six percent (66%) of the somatic mutations are missense and indels, and were detected in 239 (54%) patients.	('patients', 'Species', '9606', (105, 113))	('missense', 'Var', (53, 61))	('mutations', 'Var', (39, 48))
365627	28694483	The 32,493 somatic mutations were located in 12,074 human genes, including 407 genes recorded in the Catalogue of Somatic Mutations in Cancer database (COSMIC).	('Cancer', 'Disease', 'MESH:D009369', (135, 141))	('human', 'Species', '9606', (52, 57))	('mutations', 'Var', (19, 28))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', (135, 141))
365628	28694483	Not surprisingly, TP53 mutations are the most common genetic events occurring in 79.4% patients, followed by nine genes mutated in more than 10% of the patients, including TNN (36.4%), MUC16 (16.3%), MLL2 (14.3%), CSMD3 (13.6%), NOTCH1 (12.6%), FAT1 (12.2%), PCLO (12.2%), SYNE1 (12.0%) and LRP1B (11.3%).	('MLL2', 'Gene', (200, 204))	('TP53', 'Gene', '7157', (18, 22))	('MUC16', 'Gene', '94025', (185, 190))	('CSMD3', 'Gene', (214, 219))	('LRP1B', 'Gene', (291, 296))	('FAT1', 'Gene', '2195', (245, 249))	('NOTCH1', 'Gene', (229, 235))	('mutations', 'Var', (23, 32))	('MUC16', 'Gene', (185, 190))	('NOTCH1', 'Gene', '4851', (229, 235))	('TP53', 'Gene', (18, 22))	('LRP1B', 'Gene', '53353', (291, 296))	('SYNE1', 'Gene', (273, 278))	('patients', 'Species', '9606', (152, 160))	('FAT1', 'Gene', (245, 249))	('CSMD3', 'Gene', '114788', (214, 219))	('SYNE1', 'Gene', '23345', (273, 278))	('MLL2', 'Gene', '8085', (200, 204))	('patients', 'Species', '9606', (87, 95))
365636	28694483	Kaplan-Meier analysis showed that mutations in ZFHX4, SPHKAP, NRXN1 and KIAA1109 were significantly (p < 0.05) correlated with poor overall survival (Fig.	('correlated', 'Reg', (111, 121))	('KIAA1109', 'Gene', '84162', (72, 80))	('overall survival', 'MPA', (132, 148))	('KIAA1109', 'Gene', (72, 80))	('SPHKAP', 'Gene', (54, 60))	('poor', 'NegReg', (127, 131))	('NRXN1', 'Gene', '9378', (62, 67))	('NRXN1', 'Gene', (62, 67))	('ZFHX4', 'Gene', (47, 52))	('SPHKAP', 'Gene', '80309', (54, 60))	('ZFHX4', 'Gene', '79776', (47, 52))	('mutations', 'Var', (34, 43))
365637	28694483	Notably, ZFHX4 mutations were detected in 8.6% (38/442) of the patients.	('ZFHX4', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('ZFHX4', 'Gene', '79776', (9, 14))	('patients', 'Species', '9606', (63, 71))	('detected', 'Reg', (30, 38))
365638	28694483	Missense mutations and frame-shift indels were the most deleterious mutation types in cancer, because they change gene-coding sequences, potentially altering protein functions.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('change', 'Reg', (107, 113))	('altering', 'Reg', (149, 157))	('gene-coding sequences', 'MPA', (114, 135))	('frame-shift indels', 'Var', (23, 41))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('protein functions', 'MPA', (158, 175))	('cancer', 'Disease', (86, 92))	('Missense mutations', 'Var', (0, 18))
365639	28694483	Overall survival of patients with ZFHX4 and SPHKAP mutations (missense and frame shift) decreased dramatically (log-rank test p value = 3.2 x 10-5 and 0.023, respectively, Fig.	('mutations', 'Var', (51, 60))	('ZFHX4', 'Gene', '79776', (34, 39))	('SPHKAP', 'Gene', (44, 50))	('patients', 'Species', '9606', (20, 28))	('decreased', 'NegReg', (88, 97))	('Overall survival', 'MPA', (0, 16))	('SPHKAP', 'Gene', '80309', (44, 50))	('ZFHX4', 'Gene', (34, 39))
365640	28694483	In addition, we identified two additional genes DNAH5 and KCNH7, whose missense mutations and frame-shift indels are strongly associated with patient survival (a log-rank test p-value of 0.016 and 0.034, respectively).	('missense mutations', 'Var', (71, 89))	('DNAH5', 'Gene', (48, 53))	('associated with', 'Reg', (126, 141))	('DNAH5', 'Gene', '1767', (48, 53))	('frame-shift indels', 'Var', (94, 112))	('patient survival', 'CPA', (142, 158))	('patient', 'Species', '9606', (142, 149))	('KCNH7', 'Gene', '90134', (58, 63))	('KCNH7', 'Gene', (58, 63))
365641	28694483	However, the missense and frame shift variations of NRXN1 and KIAA1109 were not associated with clinical outcomes (Fig.	('missense', 'Var', (13, 21))	('KIAA1109', 'Gene', '84162', (62, 70))	('KIAA1109', 'Gene', (62, 70))	('NRXN1', 'Gene', '9378', (52, 57))	('associated', 'Reg', (80, 90))	('NRXN1', 'Gene', (52, 57))
365644	28694483	4, 83 patients who carried at least one mutation in at least one of the six genes exhibited significantly poorer survival with a log-rank test p-value of 3.9 x 10-6, suggesting that integrating mutations of multiple genes could better predict patient overall survival.	('mutation', 'Var', (40, 48))	('poorer', 'NegReg', (106, 112))	('patient', 'Species', '9606', (243, 250))	('patient', 'Species', '9606', (6, 13))	('mutations', 'Var', (194, 203))	('survival', 'MPA', (113, 121))	('predict', 'Reg', (235, 242))	('patients', 'Species', '9606', (6, 14))
365645	28694483	As ZFHX4 mutations significantly contributed to poor survival of Chinese ESCC patients, we further examined the prognostic role of ZFHX4 mutations in 12 cancer types investigated by TCGA including ESCC and esophageal adenocarcinoma (EAD) of Vietnam, Brazil, United States and other populations.	('cancer', 'Disease', (153, 159))	('ZFHX4', 'Gene', '79776', (3, 8))	('ESCC', 'Disease', (197, 201))	('mutations', 'Var', (9, 18))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('esophageal adenocarcinoma', 'Disease', (206, 231))	('EAD', 'Phenotype', 'HP:0011459', (233, 236))	('examined', 'Reg', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('ZFHX4', 'Gene', (131, 136))	('EAD', 'Disease', (233, 236))	('ZFHX4', 'Gene', (3, 8))	('ZFHX4', 'Gene', '79776', (131, 136))	('mutations', 'Var', (137, 146))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (206, 231))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (206, 231))	('EAD', 'Disease', 'MESH:C566415', (233, 236))
365646	28694483	ZFHX4 mutations were widely detected in 12 cancer types as listed in Supplementary Table1.	('ZFHX4', 'Gene', '79776', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('detected', 'Reg', (28, 36))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('ZFHX4', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
365647	28694483	The mutation rate of ZFHX4 in 12 cancer types ranged from 2.2% (prostate adenocarcinoma, PRAD) to 43.8% (lung adenocarcinoma, LUAD).	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (64, 87))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ZFHX4', 'Gene', '79776', (21, 26))	('PRAD', 'Disease', (89, 93))	('lung adenocarcinoma', 'Disease', (105, 124))	('mutation', 'Var', (4, 12))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('prostate adenocarcinoma', 'Disease', (64, 87))	('ZFHX4', 'Gene', (21, 26))
365648	28694483	2A showed the distribution of somatic mutations on the gene body of ZFHX4 and several recurrent mutations in cancer were observed, such as p.L408fs/G407fs and p.P1042P/S.	('p.P1042P', 'Var', (159, 167))	('p.L408fs', 'FRAMESHIFT', 'None', (139, 147))	('ZFHX4', 'Gene', '79776', (68, 73))	('p.P1042P', 'SUBSTITUTION', 'None', (159, 167))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('G407fs', 'Mutation', 'p.G407fsX', (148, 154))	('p.L408fs', 'Var', (139, 147))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ZFHX4', 'Gene', (68, 73))
365649	28694483	2B, mutations of ZFHX4 were correlated with poor overall survival of liver hepatocellular carcinoma (LIHC) patients with a log-rank test p-value of 0.01.	('ZFHX4', 'Gene', (17, 22))	('liver hepatocellular carcinoma', 'Disease', (69, 99))	('LIHC', 'Disease', (101, 105))	('LIHC', 'Disease', 'None', (101, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('ZFHX4', 'Gene', '79776', (17, 22))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (69, 99))	('poor', 'NegReg', (44, 48))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('mutations', 'Var', (4, 13))	('patients', 'Species', '9606', (107, 115))
365650	28694483	However, although ZFHX4 mutations were observed in eight ESCC patients in the TCGA datasets, there was no correlation between ZFHX4 mutations and survival of ESCC patients, EAD (Supplementary Fig.	('patients', 'Species', '9606', (163, 171))	('ZFHX4', 'Gene', '79776', (126, 131))	('mutations', 'Var', (132, 141))	('ZFHX4', 'Gene', '79776', (18, 23))	('EAD', 'Disease', 'MESH:C566415', (173, 176))	('ESCC', 'Disease', (158, 162))	('EAD', 'Phenotype', 'HP:0011459', (173, 176))	('ZFHX4', 'Gene', (126, 131))	('patients', 'Species', '9606', (62, 70))	('ZFHX4', 'Gene', (18, 23))	('EAD', 'Disease', (173, 176))
365656	28694483	Given the facts that mutations in ZFHX4 were frequently observed in ESCC patients and were associated with poorer survival and that ZFHX4 was overexpressed in ESCC, we knocked down ZFHX4 expression in KYSE150 and TE-1 cell lines using RNA interference sequences to determine whether ZFHX4 plays an important role in ESCC progression.	('ZFHX4', 'Gene', '79776', (181, 186))	('mutations', 'Var', (21, 30))	('observed', 'Reg', (56, 64))	('knocked', 'Reg', (168, 175))	('ESCC', 'Disease', (68, 72))	('ZFHX4', 'Gene', '79776', (34, 39))	('ZFHX4', 'Gene', (181, 186))	('patients', 'Species', '9606', (73, 81))	('ZFHX4', 'Gene', (132, 137))	('ZFHX4', 'Gene', (283, 288))	('ZFHX4', 'Gene', '79776', (132, 137))	('ZFHX4', 'Gene', '79776', (283, 288))	('ESCC', 'Disease', (316, 320))	('ZFHX4', 'Gene', (34, 39))	('associated', 'Reg', (91, 101))
365659	28694483	5A, real time reverse transcription PCR (RT-PCR) assays showed that the mRNA expression of ZFHX4 was reduced by 78.1% in KYSE150 and 88.0% in TE1 due to siRNA silencing.	('KYSE150', 'Var', (121, 128))	('ZFHX4', 'Gene', (91, 96))	('reduced', 'NegReg', (101, 108))	('mRNA expression', 'MPA', (72, 87))	('ZFHX4', 'Gene', '79776', (91, 96))
365660	28694483	Transwell motility assays were used to estimate the effect of ZFHX4 gene knockdown on invasion ability.	('ZFHX4', 'Gene', '79776', (62, 67))	('ZFHX4', 'Gene', (62, 67))	('invasion ability', 'CPA', (86, 102))	('knockdown', 'Var', (73, 82))
365661	28694483	The invasion ability of KYSE150 cells with ZFHX4 gene knockdown is impaired by 15.1% compared with their control cells.	('knockdown', 'Var', (54, 63))	('invasion ability', 'CPA', (4, 20))	('impaired', 'NegReg', (67, 75))	('ZFHX4', 'Gene', (43, 48))	('ZFHX4', 'Gene', '79776', (43, 48))
365662	28694483	For TE-1, consistent with what was observed in KYSE150 cells, knockdown of ZFHX4 expression inhibited cell invasion ability by 26.0%.	('inhibited', 'NegReg', (92, 101))	('cell invasion ability', 'CPA', (102, 123))	('ZFHX4', 'Gene', (75, 80))	('ZFHX4', 'Gene', '79776', (75, 80))	('knockdown', 'Var', (62, 71))
365665	28694483	We also performed cell proliferation and apoptosis assays, but knockdown of ZFHX4 showed no significant effects on cell proliferation and apoptosis (results not shown).	('ZFHX4', 'Gene', '79776', (76, 81))	('ZFHX4', 'Gene', (76, 81))	('knockdown', 'Var', (63, 72))	('cell proliferation', 'CPA', (115, 133))
365666	28694483	In summary, these experimental results indicated that loss of ZFHX4 resulted in impaired migration and invasion abilities of ESCC cells.	('ZFHX4', 'Gene', (62, 67))	('impaired migration', 'Disease', 'MESH:D054081', (80, 98))	('invasion abilities of', 'CPA', (103, 124))	('ZFHX4', 'Gene', '79776', (62, 67))	('loss', 'Var', (54, 58))	('impaired migration', 'Disease', (80, 98))
365668	28694483	Survival analysis of frequently mutated genes in patients suggested that mutations in ZFHX4, SPHKAP, NRXN1, KIAA1109, DNAH5 and KCNH7 were associated with poor prognosis.	('SPHKAP', 'Gene', (93, 99))	('KIAA1109', 'Gene', '84162', (108, 116))	('ZFHX4', 'Gene', (86, 91))	('KCNH7', 'Gene', '90134', (128, 133))	('KCNH7', 'Gene', (128, 133))	('KIAA1109', 'Gene', (108, 116))	('ZFHX4', 'Gene', '79776', (86, 91))	('DNAH5', 'Gene', (118, 123))	('NRXN1', 'Gene', '9378', (101, 106))	('SPHKAP', 'Gene', '80309', (93, 99))	('associated', 'Reg', (139, 149))	('DNAH5', 'Gene', '1767', (118, 123))	('patients', 'Species', '9606', (49, 57))	('NRXN1', 'Gene', (101, 106))	('mutations', 'Var', (73, 82))
365669	28694483	Secondly, SMG analysis found that 26 genes were significantly mutated in ESCC, and 12 genes had not been reported as SMGs in previous ESCC studies.	('SMG', 'Gene', (117, 120))	('SMG', 'Gene', '23034', (117, 120))	('ESCC', 'Disease', (73, 77))	('SMG', 'Gene', (10, 13))	('SMG', 'Gene', '23034', (10, 13))	('mutated', 'Var', (62, 69))
365680	28694483	ZFHX4 silencing resulted in decreased tumorigenesis and prolonged cancer-free survival of glioblastoma.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('ZFHX4', 'Gene', '79776', (0, 5))	('ZFHX4', 'Gene', (0, 5))	('glioblastoma', 'Disease', 'MESH:D005909', (90, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('decreased', 'NegReg', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prolonged', 'PosReg', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('glioblastoma', 'Disease', (90, 102))	('silencing', 'Var', (6, 15))	('cancer', 'Disease', (66, 72))
365681	28694483	Our data provided strong evidence that mutations in ZFHX4 contribute to the development and progression of ESCC.	('ZFHX4', 'Gene', (52, 57))	('ZFHX4', 'Gene', '79776', (52, 57))	('mutations', 'Var', (39, 48))	('contribute', 'Reg', (58, 68))	('ESCC', 'Disease', (107, 111))
365682	28694483	We further examined the prognostic role of ZFHX4 mutations in 12 cancer types in TCGA.	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('examined', 'Reg', (11, 19))	('ZFHX4', 'Gene', (43, 48))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('ZFHX4', 'Gene', '79776', (43, 48))
365683	28694483	Mutations of ZFHX4 significantly contributed to the poor survival of LIHC patients (p = 0.012) as shown in Supplementary Fig.	('LIHC', 'Disease', 'None', (69, 73))	('ZFHX4', 'Gene', '79776', (13, 18))	('patients', 'Species', '9606', (74, 82))	('contributed', 'Reg', (33, 44))	('Mutations', 'Var', (0, 9))	('LIHC', 'Disease', (69, 73))	('poor', 'NegReg', (52, 56))	('ZFHX4', 'Gene', (13, 18))
365684	28694483	However, mutations of ZFHX4 were not significantly associated with patient survival of both ESCC and EAD in TCGA (Supplementary Fig.	('ESCC', 'Disease', (92, 96))	('EAD', 'Disease', (101, 104))	('mutations', 'Var', (9, 18))	('EAD', 'Disease', 'MESH:C566415', (101, 104))	('associated', 'Reg', (51, 61))	('ZFHX4', 'Gene', (22, 27))	('EAD', 'Phenotype', 'HP:0011459', (101, 104))	('ZFHX4', 'Gene', '79776', (22, 27))	('patient', 'Species', '9606', (67, 74))
365687	28694483	Secondly, only 8 of the 91 patients in the TCGA dataset carried ZFHX4 mutations.	('ZFHX4', 'Gene', '79776', (64, 69))	('mutations', 'Var', (70, 79))	('carried', 'Reg', (56, 63))	('patients', 'Species', '9606', (27, 35))	('ZFHX4', 'Gene', (64, 69))
365881	19884893	Inactivation of CCK-BR reduced proliferation and the number of DCLK1-positive or LGR5-positive cells in progastrin-overexpressing hGAS/+ mice, suggesting that CCK-BR expression is likely to be present on colonic stem and progenitor cells.	('proliferation', 'CPA', (31, 44))	('LGR5-positive', 'Gene', (81, 94))	('DCLK1-positive', 'Protein', (63, 77))	('CCK-BR', 'Gene', (16, 22))	('reduced', 'NegReg', (23, 30))	('rat', 'Species', '10116', (38, 41))	('Inactivation', 'Var', (0, 12))	('mice', 'Species', '10090', (137, 141))
365900	19884893	Furthermore, the CD34-positive fraction of SP cells seems to participate in epithelial regeneration in an innovative murine esophageal mucosal injury model, suggesting that the CD34-positive fraction of the SP cells also has the capacity for self-renewal.	('esophageal mucosal injury', 'Disease', 'MESH:D052016', (124, 149))	('SP', 'Chemical', 'MESH:C000604007', (207, 209))	('SP', 'Chemical', 'MESH:C000604007', (43, 45))	('CD34-positive', 'Var', (177, 190))	('esophageal mucosal injury', 'Disease', (124, 149))	('murine', 'Species', '10090', (117, 123))	('self-renewal', 'CPA', (242, 254))	('rat', 'Species', '10116', (93, 96))
365930	19884893	Pancreatic cancer stem cells, for example, were shown to express CD44, CD24, and ESA (epithelial specific antigen) (0.2-0.8% of pancreatic cancer cells), and had a 100-fold increased tumorigenic potential compared with non-tumorigenic cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CD24', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('increased', 'PosReg', (173, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('CD44', 'Var', (65, 69))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Disease', (223, 228))	('Pancreatic cancer', 'Disease', (0, 17))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('CD24', 'Gene', '100133941', (71, 75))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cancer', 'Disease', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cancer', 'Disease', (235, 241))	('pancreatic cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('ESA', 'Gene', (81, 84))	('cancer', 'Disease', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
365952	19884893	Tissue-restricted adult stem cells have for many years been the obvious candidate as a source of cancer stem cells, since in a chronically inflamed environment it is thought that they may slowly acquire a series of genetic and epigenetic changes that lead to loss of growth control and apoptotic programs, and finally the emergence of cancer stem cells.	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancer', 'Disease', (97, 103))	('loss', 'NegReg', (259, 263))	('cancer', 'Disease', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('epigenetic changes', 'Var', (227, 245))	('growth control', 'CPA', (267, 281))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('apoptotic programs', 'CPA', (286, 304))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
366017	19627616	Dominant negative p53 mutation, heterozygous loss of INK4a/Arf, antacid treatment, iron supplementation, or gastrectomy failed to promote esophageal adenocarcinoma in these mice.	('p53', 'Gene', (18, 21))	('mutation', 'Var', (22, 30))	('promote', 'PosReg', (130, 137))	('p53', 'Gene', '22059', (18, 21))	('INK4a/Arf', 'Gene', '12578', (53, 62))	('iron', 'Chemical', 'MESH:D007501', (83, 87))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (138, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('mice', 'Species', '10090', (173, 177))	('loss', 'NegReg', (45, 49))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (138, 163))	('INK4a/Arf', 'Gene', (53, 62))	('esophageal adenocarcinoma', 'Disease', (138, 163))
366025	19627616	Along with the progression of metaplasia, dysplasia and adenocarcinoma, p53 gene mutation and protein accumulation were frequently detected.	('p53', 'Gene', (72, 75))	('detected', 'Reg', (131, 139))	('mutation', 'Var', (81, 89))	('p53', 'Gene', '22059', (72, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('protein accumulation', 'MPA', (94, 114))	('metaplasia, dysplasia and adenocarcinoma', 'Disease', 'MESH:D008679', (30, 70))
366026	19627616	It has been reported that p16INK4a was frequently silenced by promoter hypermethylation in esophageal adenocarcinoma.	('promoter hypermethylation', 'Var', (62, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('silenced', 'NegReg', (50, 58))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (91, 116))	('p16INK4a', 'Gene', (26, 34))	('esophageal adenocarcinoma', 'Disease', (91, 116))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (91, 116))	('p16INK4a', 'Gene', '12578', (26, 34))
366027	19627616	p14Arf was also silenced by hypermethylation in some cases, yet to a less extent compared with p16INK4a .	('p14Arf', 'Var', (0, 6))	('p16INK4a', 'Gene', '12578', (95, 103))	('hypermethylation', 'Var', (28, 44))	('p16INK4a', 'Gene', (95, 103))
366052	19627616	p53A135V mice carrying a dominant negative mutation of p53 gene, which have a longer life span and compromised p53 function, were used to enhance carcinogenesis.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '22059', (0, 3))	('carcinogenesis', 'Disease', (146, 160))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '22059', (55, 58))	('mutation', 'Var', (43, 51))	('negative', 'NegReg', (34, 42))	('enhance', 'PosReg', (138, 145))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '22059', (111, 114))	('mice', 'Species', '10090', (9, 13))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))
366056	19627616	Two genetically modified mouse strains were obtained from Dr. Ming You's group at Washington University School of Medicine: A/J mice carrying three copies of an Ala-135-Val p53 mutant transgene; A/J mice with heterozygous knockout of INK4a/Arf .	('Ala-135-Val', 'Var', (161, 172))	('mice', 'Species', '10090', (199, 203))	('p53', 'Gene', (173, 176))	('INK4a/Arf', 'Gene', (234, 243))	('mouse', 'Species', '10090', (25, 30))	('p53', 'Gene', '22059', (173, 176))	('Ala-135-Val', 'SUBSTITUTION', 'None', (161, 172))	('mice', 'Species', '10090', (128, 132))	('mutant', 'Var', (177, 183))	('INK4a/Arf', 'Gene', '12578', (234, 243))
366085	19627616	At the end of the experiment, mice with reflux had slightly lower body weight than the non-operated control.	('rat', 'Species', '10116', (94, 97))	('mice', 'Species', '10090', (30, 34))	('body weight', 'CPA', (66, 77))	('reflux', 'Var', (40, 46))	('lower body weight', 'Phenotype', 'HP:0004325', (60, 77))	('lower', 'NegReg', (60, 65))
366104	19627616	In order to examine the expression pattern of mutant p53 protein in the esophageal epithelium, we immunostained p53 using a polyclonal p53 antibody.	('p53', 'Gene', (135, 138))	('p53', 'Gene', '22059', (135, 138))	('mutant', 'Var', (46, 52))	('p53', 'Gene', (53, 56))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '22059', (53, 56))	('p53', 'Gene', '22059', (112, 115))
366106	19627616	In contrast, strong nuclear staining was observed in the basal cells of esophageal epithelium of the p53A135V transgenic mice, suggesting accumulation of mutant p53 protein (Figure 4).	('transgenic mice', 'Species', '10090', (110, 125))	('protein', 'Protein', (165, 172))	('p53', 'Gene', (101, 104))	('accumulation', 'PosReg', (138, 150))	('p53', 'Gene', '22059', (101, 104))	('p53', 'Gene', (161, 164))	('mutant', 'Var', (154, 160))	('p53', 'Gene', '22059', (161, 164))
366115	19627616	It is known that patients after total or partial gastrectomy had increased risk of developing esophageal and laryngeal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('partial', 'Var', (41, 48))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 142))	('esophageal', 'Disease', (94, 104))	('patients', 'Species', '9606', (17, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('laryngeal squamous cell carcinoma', 'Disease', (109, 142))
366166	17912343	As shown in  Figure 3B , substantial percentages of these 32P-labeled variant decapeptides bound to cells within only a few minutes, with large amounts of radiolabeled cellular proteins appearing at two hours after exposing cells to the labeled peptides.	('32P', 'Chemical', 'MESH:C000615311', (58, 61))	('decapeptides', 'Protein', (78, 90))	('bound', 'Interaction', (91, 96))	('variant', 'Var', (70, 77))
366181	17912343	For example, after incubation of the labeled variant MA5 with Caco2 cells for two hours, three wash steps, and overnight incubation in medium, 88% of the originally retained 32P isotope was released.	('32P', 'Chemical', 'MESH:C000615311', (174, 177))	('MA5', 'Gene', (53, 56))	('MA5', 'Gene', '29944', (53, 56))	('variant', 'Var', (45, 52))
366209	33658400	Meanwhile, we also identified a relatively higher mutation frequency at the 404th arginine amino acid residue in the coding sequence of Fuz locus, and further demonstrated that mutant Fuz proteins perturb the pro-apoptotic function of Fuz.	('Fuz', 'Gene', (184, 187))	('arginine amino acid', 'Chemical', '-', (82, 101))	('pro-apoptotic function', 'CPA', (209, 231))	('mutant', 'Var', (177, 183))	('Fuz', 'Gene', (136, 139))	('perturb', 'NegReg', (197, 204))	('proteins', 'Protein', (188, 196))
366210	33658400	In summary, our study unveiled an intriguing relationship between Fuz dysregulation and cancer prognosis, and further provides mechanistic insights of Fuz's involvement in carcinogenesis.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('carcinogenesis', 'Disease', (172, 186))	('carcinogenesis', 'Disease', 'MESH:D063646', (172, 186))	('dysregulation', 'Var', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Fuz', 'Gene', (66, 69))
366211	33658400	Initial studies on the molecular functions of PCP pathway emphasize the relationship between PCP signaling and mammalian embryonic development, as exemplified by the fact that genetic alterations in PCP genes lead to severe neurodevelopmental deficits.	('mammalian', 'Species', '9606', (111, 120))	('neurodevelopmental deficits', 'Disease', (224, 251))	('lead to', 'Reg', (209, 216))	('PCP genes', 'Gene', (199, 208))	('neurodevelopmental deficits', 'Disease', 'MESH:D009461', (224, 251))	('genetic alterations', 'Var', (176, 195))
366227	33658400	Moreover, we demonstrated a tight correlation between Fuz transcription and Fuz DNA methylation level, and further showed that reduction of Fuz mRNA level in HNSC and LUAD tumor samples was achieved via hypermethylation of two independent CpG sites within Fuz promoter region.	('Fuz', 'MPA', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('hypermethylation', 'Var', (203, 219))	('LUAD tumor', 'Disease', (167, 177))	('HNSC', 'Phenotype', 'HP:0012288', (158, 162))	('LUAD tumor', 'Disease', 'MESH:D009369', (167, 177))	('reduction', 'NegReg', (127, 136))	('LUAD', 'Phenotype', 'HP:0030078', (167, 171))	('Fuz DNA methylation level', 'MPA', (76, 101))
366229	33658400	In summary, this study is the first report to provide an in-depth investigation of Fuz in multiple types of cancer, and further demonstrates the effects of Fuz promoter DNA methylation and coding sequence alterations in cancer.	('Fuz', 'Gene', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('effects', 'Reg', (145, 152))	('alterations', 'Var', (205, 216))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
366231	33658400	As shown in the Kaplan-Meier curves, Fuz expression was found to be significantly associated with the overall survival (OS) of patients from 8 types of cancer (Figure 1).	('associated with', 'Reg', (82, 97))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('patients', 'Species', '9606', (127, 135))	('overall survival', 'MPA', (102, 118))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Fuz expression', 'Var', (37, 51))
366238	33658400	As summarized in Supplementary Table 1, decreased level of Fuz was an independent predictor of worse OS of BRCA (HR, 0.9996; 95% Cl, 0.9993-1.000; p value, 0.0106) and KIRP (HR, 0.9988; 95% Cl, 0.9981-1.000; p value, 0.00241) patients, whereas high expression of Fuz was independently associated with worse OS of STAD (HR, 1.001; 95% Cl, 1.0002-1.001; p value, 0.00257) patients.	('BRCA', 'Phenotype', 'HP:0003002', (107, 111))	('STAD', 'Disease', (313, 317))	('Fuz', 'Gene', (263, 266))	('patients', 'Species', '9606', (370, 378))	('patients', 'Species', '9606', (226, 234))	('high expression', 'Var', (244, 259))	('decreased', 'NegReg', (40, 49))	('BRCA', 'Disease', (107, 111))
366253	33658400	Given that DNA methylation in gene promoter negatively controls gene transcription, we investigated whether the aberrant Fuz transcription is associated with alteration of Fuz promoter methylation in different types of cancer (Supplementary File 2).	('aberrant', 'Var', (112, 120))	('gene transcription', 'MPA', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))	('Fuz transcription', 'Gene', (121, 138))
366254	33658400	As shown in Figure 5A, 3 independent CpG methylation sites, cg11398523, cg21712019 and cg22708738, were identified within or close to a predicted CpG island in the Fuz promoter (Fuz+117/+347CpG).	('cg11398523', 'Chemical', '-', (60, 70))	('cg22708738', 'Chemical', '-', (87, 97))	('cg22708738', 'Var', (87, 97))	('cg11398523', 'Var', (60, 70))	('cg21712019', 'Var', (72, 82))
366255	33658400	The DNA methylation levels at sites cg11398523 and cg22708738 were found negatively associated with Fuz expression in multiple types of cancer, including ESCA, HNSC and LUAD (Figure 5A).	('associated', 'Interaction', (84, 94))	('cg11398523', 'Chemical', '-', (36, 46))	('ESCA', 'Phenotype', 'HP:0011459', (154, 158))	('cg22708738', 'Chemical', '-', (51, 61))	('ESCA', 'Disease', (154, 158))	('HNSC', 'Phenotype', 'HP:0012288', (160, 164))	('cg22708738', 'Var', (51, 61))	('negatively', 'NegReg', (73, 83))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('LUAD', 'Phenotype', 'HP:0030078', (169, 173))	('HNSC', 'Disease', (160, 164))	('cancer', 'Disease', (136, 142))	('LUAD', 'Disease', (169, 173))	('cg11398523', 'Var', (36, 46))	('Fuz expression', 'MPA', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('DNA methylation levels', 'MPA', (4, 26))
366258	33658400	We found that high Fuz DNA methylation at site cg11398523 and cg22708738 leads to reduced survival probabilities in HNSC and LUAD patients, respectively (Figure 6B, 6C).	('cg11398523', 'Chemical', '-', (47, 57))	('cg22708738', 'Chemical', '-', (62, 72))	('survival', 'MPA', (90, 98))	('LUAD', 'Phenotype', 'HP:0030078', (125, 129))	('cg22708738', 'Var', (62, 72))	('LUAD', 'Disease', (125, 129))	('patients', 'Species', '9606', (130, 138))	('reduced', 'NegReg', (82, 89))	('HNSC', 'Phenotype', 'HP:0012288', (116, 120))	('cg11398523', 'Var', (47, 57))	('HNSC', 'Disease', (116, 120))
366261	33658400	Although a tendency of high Fuz DNA methylation level at site cg11398523 was observed in ESCA patients with poor OS, the difference in survival probabilities between high and low Fuz DNA methylation groups was not statistically significant (Figure 6A).	('patients', 'Species', '9606', (94, 102))	('cg11398523', 'Var', (62, 72))	('ESCA', 'Phenotype', 'HP:0011459', (89, 93))	('ESCA', 'Disease', (89, 93))	('cg11398523', 'Chemical', '-', (62, 72))
366264	33658400	In addition to gene dysregulation, coding sequence alteration is another pathogenic hallmark of cancer.	('coding sequence alteration', 'Var', (35, 61))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))
366268	33658400	Several kinds of genetic alterations, including mutation, fusion, amplification and deep deletion in the Fuz gene were uncovered from various cancer types, with the highest alteration frequency found in endometrial carcinoma samples (Figure 7A, Supplementary Table 2).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (203, 224))	('amplification', 'Var', (66, 79))	('Fuz', 'Gene', (105, 108))	('fusion', 'Var', (58, 64))	('endometrial carcinoma', 'Disease', (203, 224))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('deep deletion', 'Var', (84, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('mutation', 'Var', (48, 56))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (203, 224))	('cancer', 'Disease', (142, 148))
366269	33658400	The FuzR404 arginine residue was found mutated in 4 tumor samples from bladder urothelial carcinoma, colorectal adenocarcinoma and uterine corpus endometrial carcinoma, and all these 4 mutated samples were caused by the single nucleotide substitution (Figure 7C).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumor', 'Disease', (52, 57))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (71, 99))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (146, 167))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (101, 126))	('endometrial carcinoma', 'Disease', (146, 167))	('bladder urothelial carcinoma', 'Disease', (71, 99))	('colorectal adenocarcinoma', 'Disease', (101, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (146, 167))	('FuzR404 arginine', 'Var', (4, 20))	('arginine', 'Chemical', 'MESH:D001120', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('caused by', 'Reg', (206, 215))	('single nucleotide substitution', 'Var', (220, 250))
366270	33658400	However, the missense mutation (c.G1211A) leads to a replacement of the arginine with glutamine (p.R404Q), whereas the nonsense mutation (c.C1210T) generates a truncated gene product (p.R404*; Figure 5C).	('p.R404*;', 'Var', (184, 192))	('arginine', 'MPA', (72, 80))	('c.C1210T', 'Mutation', 'rs200831588', (138, 146))	('leads to', 'Reg', (42, 50))	('c.G1211A', 'Mutation', 'rs137955120', (32, 40))	('glutamine', 'Chemical', 'MESH:D005973', (86, 95))	('glutamine', 'MPA', (86, 95))	('arginine', 'Chemical', 'MESH:D001120', (72, 80))	('p.R404Q', 'Mutation', 'rs137955120', (97, 104))	('c.G1211A', 'Var', (32, 40))	('p.R404*', 'Mutation', 'p.R404*', (184, 191))	('p.R404Q', 'Var', (97, 104))	('c.C1210T', 'Var', (138, 146))
366271	33658400	The mutant Fuz expression construct harboring R404* or R404Q mutation was generated (Supplementary Figure 5).	('R404Q', 'Mutation', 'rs137955120', (55, 60))	('R404Q', 'Var', (55, 60))	('R404*', 'SUBSTITUTION', 'None', (46, 51))	('R404*', 'Var', (46, 51))
366273	33658400	We then tested the activity of this apoptotic pathway in FuzR404* or FuzR404Q-expressing cells.	('tested', 'Reg', (8, 14))	('FuzR404*', 'Var', (57, 65))	('R404Q', 'Mutation', 'rs137955120', (72, 77))	('FuzR404Q-expressing', 'Var', (69, 88))	('activity', 'MPA', (19, 27))	('apoptotic pathway', 'Pathway', (36, 53))
366274	33658400	When overexpressed in our HEK293 cell model, the wildtype Fuz protein activates Dvl protein aggregation (from 12.22% to 50.17%), whereas such activation was attenuated in FuzR404* (27.57%) or FuzR404Q (27.18%) overexpression cells (Figure 8A, 8B).	('HEK293', 'CellLine', 'CVCL:0045', (26, 32))	('activates', 'PosReg', (70, 79))	('FuzR404*', 'Var', (171, 179))	('Dvl', 'Gene', (80, 83))	('FuzR404Q', 'Var', (192, 200))	('Dvl', 'Gene', '1855', (80, 83))
366275	33658400	Moreover, although expressed at comparable levels, the JNK-caspase-3 activation triggered by wildtype Fuz protein was found mitigated in FuzR404* or FuzR404Q-expressing cells (Figure 8C-8F).	('caspase-3', 'Gene', '836', (59, 68))	('R404Q', 'Mutation', 'rs137955120', (152, 157))	('FuzR404*', 'Var', (137, 145))	('mitigated', 'NegReg', (124, 133))	('JNK', 'Gene', '5599', (55, 58))	('FuzR404Q-expressing', 'Var', (149, 168))	('caspase-3', 'Gene', (59, 68))	('JNK', 'Gene', (55, 58))	('activation', 'PosReg', (69, 79))
366276	33658400	Taken together, these functional experiments suggest that mutation at 404th arginine residue perturbs the biological function of Fuz in triggering apoptosis.	('triggering', 'Reg', (136, 146))	('Fuz', 'Gene', (129, 132))	('mutation at 404th arginine', 'Var', (58, 84))	('perturbs', 'NegReg', (93, 101))	('biological function', 'MPA', (106, 125))	('apoptosis', 'CPA', (147, 156))	('arginine', 'Chemical', 'MESH:D001120', (76, 84))
366285	33658400	As one of the key pathogenic features, gene dysregulation leads to dysfunctions of essential signaling pathways, which in turn contribute to cancer development and progression.	('progression', 'CPA', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('essential signaling pathways', 'Pathway', (83, 111))	('gene dysregulation', 'Var', (39, 57))	('leads to', 'Reg', (58, 66))	('dysfunctions', 'MPA', (67, 79))	('contribute', 'Reg', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
366289	33658400	Somatic mutation in TP53 is one of the most frequent genetic alterations among human cancers, including HNSC.	('human', 'Species', '9606', (79, 84))	('HNSC', 'Disease', (104, 108))	('TP53', 'Gene', (20, 24))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('HNSC', 'Phenotype', 'HP:0012288', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Somatic mutation', 'Var', (0, 16))	('TP53', 'Gene', '7157', (20, 24))
366290	33658400	The variable TP53 mutational landscape in HNSC bears distinct activities of downstream pathological pathways, and mutant p53 dysregulates a range of oncogenic molecules in favor of malignant phenotype in HNSC cells.	('TP53', 'Gene', (13, 17))	('dysregulates', 'Reg', (125, 137))	('p53', 'Gene', (121, 124))	('activities', 'MPA', (62, 72))	('p53', 'Gene', '7157', (121, 124))	('HNSC', 'Phenotype', 'HP:0012288', (204, 208))	('mutant', 'Var', (114, 120))	('TP53', 'Gene', '7157', (13, 17))	('HNSC', 'Phenotype', 'HP:0012288', (42, 46))
366296	33658400	All these three CpG sites reside within or close to Fuz+117/+347CpG, and two of them were found negatively associated with Fuz expression in various cancer types, including ESCA, HNSC and LUAD (Figure 5B-5D).	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('negatively', 'NegReg', (96, 106))	('expression', 'MPA', (127, 137))	('Fuz+117/+347CpG', 'Var', (52, 67))	('associated', 'Reg', (107, 117))	('Fuz', 'Gene', (123, 126))	('ESCA', 'Disease', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HNSC', 'Phenotype', 'HP:0012288', (179, 183))	('LUAD', 'Disease', (188, 192))	('ESCA', 'Phenotype', 'HP:0011459', (173, 177))	('LUAD', 'Phenotype', 'HP:0030078', (188, 192))	('HNSC', 'Disease', (179, 183))
366298	33658400	demonstrated a negative correlation between Fuz expression and its promoter DNA methylation level in LIHC tumor samples at another CpG site, cg19763319, which is also close to the Fuz+117/+347CpG region.	('cg19763319', 'Var', (141, 151))	('promoter DNA methylation level', 'MPA', (67, 97))	('Fuz', 'Gene', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('LIHC tumor', 'Disease', (101, 111))	('negative', 'NegReg', (15, 23))	('LIHC tumor', 'Disease', 'MESH:D009369', (101, 111))
366299	33658400	Any possible dysregulation of the Fuz+117/+347CpG methylation level may contribute to the pathogenesis of human diseases, including cancer.	('cancer', 'Disease', (132, 138))	('human', 'Species', '9606', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('methylation', 'MPA', (50, 61))	('contribute', 'Reg', (72, 82))	('Fuz+117/+347CpG', 'Var', (34, 49))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
366301	33658400	Since FuzR404* and FuzR404Q mutations were identified in cancer patient samples, this functional evidence may provide more clues on how the perturbation of Fuz protein functions leads to the cell overproliferation in certain types of cancer.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('patient', 'Species', '9606', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', (57, 63))	('FuzR404*', 'Var', (6, 14))	('Fuz protein', 'Gene', (156, 167))	('perturbation', 'Var', (140, 152))	('cell overproliferation', 'CPA', (191, 213))	('FuzR404Q', 'Var', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (234, 240))
366302	33658400	Both R404* and R404Q mutations occur in the highly conserved 404th arginine residue within the Fuz Longin domain.	('arginine', 'Chemical', 'MESH:D001120', (67, 75))	('R404Q', 'Var', (15, 20))	('R404*', 'Var', (5, 10))	('R404Q', 'Mutation', 'rs137955120', (15, 20))	('R404*', 'SUBSTITUTION', 'None', (5, 10))
366304	33658400	Interestingly, the R404Q mutation was initially identified from human patients with neural tube defects, a severe neurological deficit due to the failure of neural tube closure during embryonic development, and Seo et al.	('patients', 'Species', '9606', (70, 78))	('human', 'Species', '9606', (64, 69))	('neural tube defects', 'Disease', 'MESH:D005184', (84, 103))	('R404Q', 'Mutation', 'rs137955120', (19, 24))	('neural tube defects', 'Phenotype', 'HP:0045005', (84, 103))	('R404Q', 'Var', (19, 24))	('neurological deficit', 'Phenotype', 'HP:0000707', (114, 134))	('neurological deficit', 'Disease', 'MESH:D009461', (114, 134))	('neural tube defects', 'Disease', (84, 103))	('failure of neural tube closure', 'Phenotype', 'HP:0045005', (146, 176))	('neurological deficit', 'Disease', (114, 134))
366306	33658400	The development of interventions targeting Fuz DNA methylation alteration and coding sequence mutations may be therapeutically beneficial towards carcinogenesis.	('Fuz', 'Gene', (43, 46))	('carcinogenesis', 'Disease', (146, 160))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))	('methylation alteration', 'Var', (51, 73))
366320	33658400	The genomic alteration profiles in Fuz, including mutations and copy number alterations, were obtained from 10,967 samples of 32 independent TCGA PanCancer Atlas Studies.	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Fuz', 'Gene', (35, 38))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('Cancer', 'Disease', (149, 155))	('copy number alterations', 'Var', (64, 87))
366322	33658400	Primers used for overlapping PCR were EcoRI-Fuz-F, 5`-CCGGAATTCATGGGGGAGGAGGGGAC-3`, FuzR404Q-F, 5`- ACCCATGGGCTGCAAAGCCTGGCC-3`, FuzR404Q-R, 5`- GGCCAGGCTTTGCAGCCCATGGGT-3` and KpnI-Fuz-R, 5`- CCGGGTACCGTAAGAAGTGGGGTGAGG-3`.	('FuzR404Q-R', 'Var', (130, 140))	('R404Q', 'Mutation', 'rs137955120', (88, 93))	('R404Q', 'Mutation', 'rs137955120', (133, 138))	('FuzR404Q-F', 'Var', (85, 95))
366330	33658400	For immunocytochemistry samples preparation, 0.3 mug pcDNA3.1 (zeo)-flag-Dvl, together with 0.5 mug EGFP-N1, Fuz-EGFP, FuzR404*-EGFP or FuzR404Q-EGFP, were used for transfection.	('FuzR404*-EGFP', 'Var', (119, 132))	('R404Q', 'Mutation', 'rs137955120', (139, 144))	('FuzR404Q-EGFP', 'Var', (136, 149))	('Dvl', 'Gene', (73, 76))	('Dvl', 'Gene', '1855', (73, 76))
366343	33658400	Primary antibodies used were anti-p-JNK (1:500, 9251, Cell Signaling Technology), anti-JNK (1:1,000, 9252, Cell Signaling Technology), anti-cleaved caspase-3 (1:500; 9664, Cell Signaling Technology), anti-GFP (1:2,000; 632381, Clontech Laboratories, Inc.) and anti-beta-tubulin (1:2,000; ab6046, Abcam).	('JNK', 'Gene', (87, 90))	('JNK', 'Gene', (36, 39))	('anti-GFP', 'Var', (200, 208))	('JNK', 'Gene', '5599', (87, 90))	('JNK', 'Gene', '5599', (36, 39))	('caspase-3', 'Gene', '836', (148, 157))	('anti-beta-tubulin', 'Var', (260, 277))	('caspase-3', 'Gene', (148, 157))
366360	32280759	ESD allows complete resection, defined as en bloc resection with a cancer-free margin, in >90% of cases; this is a much higher rate than that of EMR.9, 13, 14 However, ESD sometimes results in incomplete resection with a horizontal margin (HM)-positive status, especially when circumferential spread of the lesion is large or the lesion is located in a difficult location to remove.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('incomplete', 'NegReg', (193, 203))	('HM', 'Chemical', '-', (240, 242))	('ESD', 'Var', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
366422	29230340	Primary Esophageal Melanoma with Aberrant CD56 Expression: A Potential Diagnostic Pitfall Primary esophageal malignant melanoma (MM) is rare and extremely aggressive.	('CD56', 'Gene', '4684', (42, 46))	('Primary esophageal malignant melanoma', 'Disease', 'MESH:D008545', (90, 127))	('Primary esophageal malignant melanoma', 'Disease', (90, 127))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('CD56', 'Gene', (42, 46))	('Primary Esophageal Melanoma', 'Disease', 'MESH:D008545', (0, 27))	('Primary Esophageal Melanoma', 'Disease', (0, 27))	('Melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('malignant melanoma', 'Phenotype', 'HP:0002861', (109, 127))	('Aberrant', 'Var', (33, 41))
366425	29230340	Herein, we report a case of primary esophageal malignant melanoma with aberrant CD56 expression without accompanying synaptophysin or chromogranin expression.	('synaptophysin', 'Gene', '6855', (117, 130))	('esophageal malignant melanoma', 'Disease', (36, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('CD56', 'Gene', '4684', (80, 84))	('esophageal malignant melanoma', 'Disease', 'MESH:D008545', (36, 65))	('malignant melanoma', 'Phenotype', 'HP:0002861', (47, 65))	('synaptophysin', 'Gene', (117, 130))	('CD56', 'Gene', (80, 84))	('aberrant', 'Var', (71, 79))
366437	29230340	Molecular testing did not reveal a V600E or V600K mutation in the BRAF oncogene or in the C-kit oncogene.	('C-kit', 'Gene', (90, 95))	('V600E', 'Var', (35, 40))	('C-kit', 'Gene', '3815', (90, 95))	('BRAF', 'Gene', '673', (66, 70))	('V600K', 'Var', (44, 49))	('BRAF', 'Gene', (66, 70))	('V600E', 'Mutation', 'rs113488022', (35, 40))	('V600K', 'Mutation', 'rs121913227', (44, 49))
366460	29230340	They pointed out that aberrant expression of cytokeratin and neuroendocrine markers and intratumoral heterogeneity in the expression of certain antigens (i.e., S-100 protein) are important potential pitfalls in the diagnosis of MM.	('aberrant', 'Var', (22, 30))	('S-100', 'Gene', (160, 165))	('expression', 'MPA', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('S-100', 'Gene', '6271', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
366469	29230340	However, this aberrant expression of CD56 should remind pathologists about the heterogeneity of this tumor, and the possibility that MM may aberrantly express markers of divergent lineage.	('CD56', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('aberrant', 'Var', (14, 22))	('CD56', 'Gene', '4684', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
366474	26090615	In cell culture, YM155 decreased survivin levels and caused PARP-1 activation, poly-ADP polymer formation, and AIF translocation from the cytosol to the nucleus.	('activation', 'PosReg', (67, 77))	('AIF', 'Gene', '9131', (111, 114))	('survivin', 'Gene', '11799', (33, 41))	('poly-ADP polymer formation', 'MPA', (79, 105))	('AIF', 'Gene', (111, 114))	('PARP-1', 'Gene', (60, 66))	('YM155', 'Chemical', 'MESH:C523798', (17, 22))	('survivin', 'Gene', (33, 41))	('poly-ADP', 'Chemical', '-', (79, 87))	('YM155', 'Var', (17, 22))	('decreased', 'NegReg', (23, 32))
366476	26090615	Furthermore, FOS, JUN and c-MYC gene transcription, which is stimulated by activated PARP-1, was increased following YM155 treatment.	('increased', 'PosReg', (97, 106))	('c-MYC', 'Gene', '4609', (26, 31))	('YM155 treatment', 'Var', (117, 132))	('c-MYC', 'Gene', (26, 31))	('PARP-1', 'Gene', (85, 91))	('YM155', 'Chemical', 'MESH:C523798', (117, 122))	('FOS', 'MPA', (13, 16))
366477	26090615	Our data demonstrate that YM155 did not trigger apoptosis, but induced parthanatos, a cell death dependent on PARP-1 hyper-activation, and support clinical development of YM155 in ESCC.	('parthanatos', 'Disease', (71, 82))	('YM155', 'Chemical', 'MESH:C523798', (26, 31))	('YM155', 'Chemical', 'MESH:C523798', (171, 176))	('YM155', 'Var', (26, 31))	('YM155', 'Var', (171, 176))	('induced', 'Reg', (63, 70))	('ESCC', 'Disease', (180, 184))
366480	26090615	Several malignant cancers, including non-small cell lung cancer, metastatic breast cancer, melanoma, and non-Hodgkin's lymphoma, were clinically evaluated with YM155 alone and as part of combination treatments (http://www.clinicaltrials.gov).	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (105, 127))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('YM155', 'Chemical', 'MESH:C523798', (160, 165))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (109, 127))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (37, 63))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	("non-Hodgkin's lymphoma", 'Disease', (105, 127))	('lymphoma', 'Phenotype', 'HP:0002665', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('YM155', 'Var', (160, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (37, 63))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('malignant cancers', 'Disease', (8, 25))	('malignant cancers', 'Disease', 'MESH:D009369', (8, 25))	('non-small cell lung cancer', 'Disease', (37, 63))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (105, 127))
366481	26090615	YM155 alone or in combination decreases tumor growth, induces apoptosis, sensitizes resistant cells to apoptosis, and prolongs survival of tumor-bearing mice.	('decreases tumor', 'Disease', 'MESH:D009369', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('survival', 'CPA', (127, 135))	('decreases tumor', 'Disease', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('apoptosis', 'CPA', (62, 71))	('YM155', 'Var', (0, 5))	('mice', 'Species', '10090', (153, 157))	('prolongs', 'NegReg', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('induces', 'Reg', (54, 61))
366482	26090615	Previous data have demonstrated that YM155 mediates survivin suppression via directly binding and disrupting the interleukin enhancer-binding factor 3/NF110 transcription factor complex.	('YM155', 'Chemical', 'MESH:C523798', (37, 42))	('YM155', 'Var', (37, 42))	('binding', 'Interaction', (86, 93))	('survivin', 'Gene', (52, 60))	('NF110', 'Gene', '3609', (151, 156))	('suppression', 'NegReg', (61, 72))	('interleukin enhancer-binding factor 3', 'Gene', '3609', (113, 150))	('interleukin enhancer-binding factor 3', 'Gene', (113, 150))	('survivin', 'Gene', '11799', (52, 60))	('NF110', 'Gene', (151, 156))	('disrupting', 'NegReg', (98, 108))
366483	26090615	Recently, using a genome-wide insertional mutagenesis approach in the near-haploid human cell line KBM7, Kasap and colleagues demonstrated that YM155 is a general DNA intercalator that causes cytotoxicity via DNA damage and is dependent on the expression of the solute carrier gene SLC35F2.	('cytotoxicity', 'Disease', (192, 204))	('causes', 'PosReg', (185, 191))	('SLC35F2', 'Gene', '54733', (282, 289))	('human', 'Species', '9606', (83, 88))	('KBM7', 'CellLine', 'CVCL:A426', (99, 103))	('DNA damage', 'MPA', (209, 219))	('YM155', 'Chemical', 'MESH:C523798', (144, 149))	('SLC35F2', 'Gene', (282, 289))	('YM155', 'Var', (144, 149))	('cytotoxicity', 'Disease', 'MESH:D064420', (192, 204))
366484	26090615	There are additional factors affecting the cellular uptake of YM155, such as the human organic cation transporter 1 (OCT1/SLC22A1) in primary human hepatocytes.	('organic cation transporter 1', 'Gene', '6580', (87, 115))	('OCT1', 'Gene', (117, 121))	('cellular uptake', 'MPA', (43, 58))	('organic cation transporter 1', 'Gene', (87, 115))	('SLC22A1', 'Gene', (122, 129))	('human', 'Species', '9606', (142, 147))	('OCT1', 'Gene', '6580', (117, 121))	('human', 'Species', '9606', (81, 86))	('YM155', 'Chemical', 'MESH:C523798', (62, 67))	('SLC22A1', 'Gene', '6580', (122, 129))	('YM155', 'Var', (62, 67))
366491	26090615	In esophageal cancer cells, YM155 caused non-apoptotic cell death, a PARP-mediated cell death (parthanatos).	('PARP', 'Gene', '142', (69, 73))	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('non-apoptotic cell death', 'CPA', (41, 65))	('PARP', 'Gene', (69, 73))	('YM155', 'Chemical', 'MESH:C523798', (28, 33))	('YM155', 'Var', (28, 33))
366494	26090615	Genetic knockdown of PARP-1 or AIF abrogated YM155-induced parthanatos cell death, suggesting that PARP-1 and AIF were indispensable for YM155-mediated parthanatos induction.	('AIF', 'Gene', (31, 34))	('AIF', 'Gene', (110, 113))	('abrogated', 'NegReg', (35, 44))	('knockdown', 'Var', (8, 17))	('YM155', 'Chemical', 'MESH:C523798', (137, 142))	('YM155-induced', 'Gene', (45, 58))	('parthanatos cell death', 'CPA', (59, 81))	('PARP-1', 'Gene', (21, 27))	('YM155', 'Chemical', 'MESH:C523798', (45, 50))	('AIF', 'Gene', '9131', (31, 34))	('AIF', 'Gene', '9131', (110, 113))
366495	26090615	YM155 also reduced esophageal tumor growth and tumor weight in xenograft animal models without affecting mouse body weight.	('reduced', 'NegReg', (11, 18))	('esophageal tumor', 'Disease', (19, 35))	('esophageal tumor', 'Phenotype', 'HP:0100751', (19, 35))	('mouse', 'Species', '10090', (105, 110))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('YM155', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', (47, 52))	('esophageal tumor', 'Disease', 'MESH:D004938', (19, 35))
366496	26090615	These data emphasize the significance of PARP-dependent parthanatos induction by YM155 and should encourage clinical trials in ESCC.	('PARP', 'Gene', (41, 45))	('PARP', 'Gene', '142', (41, 45))	('YM155', 'Chemical', 'MESH:C523798', (81, 86))	('YM155', 'Var', (81, 86))
366501	26090615	1B, with KYSE140, KYSE150, KYSE170, KYSE410 and WHCO1 showing relatively high expression of SLC35F2 and survivin and KYSKE30, KYSE180 and KYSE510 showing relatively low expression levels of SLC35F2.	('SLC35F2', 'Gene', (92, 99))	('SLC35F2', 'Gene', '54733', (92, 99))	('expression', 'MPA', (78, 88))	('KYSE150', 'Var', (18, 25))	('KYSE410', 'Var', (36, 43))	('WHCO1', 'Gene', (48, 53))	('survivin', 'Gene', (104, 112))	('KYSE510', 'Var', (138, 145))	('survivin', 'Gene', '11799', (104, 112))	('KYSE180', 'Var', (126, 133))	('SLC35F2', 'Gene', '54733', (190, 197))	('KYSE510', 'CellLine', 'CVCL:1354', (138, 145))	('KYSE410', 'Chemical', '-', (36, 43))	('KYSKE30', 'Var', (117, 124))	('SLC35F2', 'Gene', (190, 197))	('KYSE170', 'Var', (27, 34))
366506	26090615	S1) demonstrate that both cell lines were exquisitely sensitive to YM155, whereas MEF cells showed no response to YM155 at concentrations below 100 nM.	('YM155', 'Chemical', 'MESH:C523798', (114, 119))	('YM155', 'Chemical', 'MESH:C523798', (67, 72))	('YM155', 'Var', (67, 72))	('sensitive', 'Reg', (54, 63))	('MEF', 'Disease', (82, 85))	('MEF', 'Disease', 'None', (82, 85))
366507	26090615	We also found that YM155 markedly suppressed colony formation compared with untreated cells (Fig.	('colony formation', 'CPA', (45, 61))	('suppressed', 'NegReg', (34, 44))	('YM155', 'Var', (19, 24))	('YM155', 'Chemical', 'MESH:C523798', (19, 24))
366509	26090615	2A and 2B, 12 h of exposure to YM155 changed the cell-cycle phase distribution of KYSE410 and KYSE150.	('KYSE150', 'Var', (94, 101))	('YM155', 'Var', (31, 36))	('KYSE410', 'Var', (82, 89))	('cell-cycle phase distribution', 'MPA', (49, 78))	('changed', 'Reg', (37, 44))	('KYSE410', 'Chemical', '-', (82, 89))	('YM155', 'Chemical', 'MESH:C523798', (31, 36))
366510	26090615	Significantly increased proportions of cells in S phase were detected in both KYSE410 and KYSE150 after YM155 treatment for 12 hours.	('increased', 'PosReg', (14, 23))	('KYSE150', 'Var', (90, 97))	('KYSE410', 'Var', (78, 85))	('cells in S phase', 'CPA', (39, 55))	('KYSE410', 'Chemical', '-', (78, 85))	('YM155', 'Chemical', 'MESH:C523798', (104, 109))
366511	26090615	However, the proportion of cells in G1 phase markedly decreased after YM155 treatment.	('YM155', 'Chemical', 'MESH:C523798', (70, 75))	('YM155 treatment', 'Var', (70, 85))	('decreased', 'NegReg', (54, 63))
366512	26090615	Taken together, these data suggest that both KYSE410 and KYSE150 esophageal cancer cell lines are sensitive in response to YM155 treatment.	('esophageal cancer', 'Disease', (65, 82))	('KYSE410', 'Chemical', '-', (45, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('KYSE150', 'Var', (57, 64))	('YM155', 'Var', (123, 128))	('YM155', 'Chemical', 'MESH:C523798', (123, 128))
366515	26090615	To further investigate whether YM155 treatment induces cell death via apoptosis, mitochondrial membrane potential, ROS and the active formation of caspases was examined by flow cytometry and western blot analysis.	('caspases', 'Gene', (147, 155))	('ROS', 'Chemical', '-', (115, 118))	('YM155 treatment', 'Var', (31, 46))	('caspases', 'Gene', '841;842', (147, 155))	('YM155', 'Chemical', 'MESH:C523798', (31, 36))
366516	26090615	The mitochondrial membrane potential was not decreased after 12 h of YM155 treatment (Fig.	('mitochondrial membrane potential', 'MPA', (4, 36))	('YM155', 'Chemical', 'MESH:C523798', (69, 74))	('YM155', 'Var', (69, 74))
366518	26090615	Treatment with YM155 for 12 or 24 h did not affect the cleavage of caspase-9 and caspase-3.	('caspase-9', 'Gene', '842', (67, 76))	('caspase-3', 'Gene', '836', (81, 90))	('YM155', 'Chemical', 'MESH:C523798', (15, 20))	('YM155', 'Var', (15, 20))	('caspase-9', 'Gene', (67, 76))	('caspase-3', 'Gene', (81, 90))	('cleavage', 'MPA', (55, 63))
366519	26090615	The levels of survivin and XIAP, an anti-apoptotic marker, were also measured after YM155 treatment.	('XIAP', 'Gene', (27, 31))	('XIAP', 'Gene', '331', (27, 31))	('YM155', 'Chemical', 'MESH:C523798', (84, 89))	('YM155', 'Var', (84, 89))	('survivin', 'Gene', (14, 22))	('survivin', 'Gene', '11799', (14, 22))
366520	26090615	Survivin expression decreased after YM155 treatment in KYSE150 cells but not KYSE410 cells, whereas XIAP protein levels greatly decreased in both cell lines (Fig.	('KYSE150', 'Var', (55, 62))	('XIAP', 'Gene', (100, 104))	('Survivin', 'Gene', '11799', (0, 8))	('YM155 treatment', 'Var', (36, 51))	('decreased', 'NegReg', (20, 29))	('XIAP', 'Gene', '331', (100, 104))	('YM155', 'Chemical', 'MESH:C523798', (36, 41))	('Survivin', 'Gene', (0, 8))	('decreased', 'NegReg', (128, 137))	('expression', 'MPA', (9, 19))	('KYSE410', 'Chemical', '-', (77, 84))
366521	26090615	Upon further analysis using transmission electron microscopy (TEM), KYSE410 cells treated with YM155 for 24 h displayed swollen mitochondria and discontinuous cytoplasmic membranes but lacked typical apoptotic features such as condensed nuclei, plasma membrane blebbing and apoptotic bodies (Fig.	('condensed nuclei', 'CPA', (227, 243))	('YM155', 'Chemical', 'MESH:C523798', (95, 100))	('lacked', 'NegReg', (185, 191))	('YM155', 'Var', (95, 100))	('apoptotic', 'CPA', (200, 209))	('plasma membrane blebbing', 'CPA', (245, 269))	('KYSE410', 'Chemical', '-', (68, 75))	('apoptotic bodies', 'CPA', (274, 290))
366522	26090615	Collectively, these results indicate that YM155 predominantly induced a non-apoptotic, caspase-independent form of cell death in KYSE410 and KYSE150 cells.	('non-apoptotic', 'CPA', (72, 85))	('induced', 'Reg', (62, 69))	('YM155', 'Chemical', 'MESH:C523798', (42, 47))	('KYSE410', 'Chemical', '-', (129, 136))	('YM155', 'Var', (42, 47))
366523	26090615	Although YM155 has been reported to induce caspase activation, the active cleavage of caspases was not detected in this study.	('YM155', 'Var', (9, 14))	('caspases', 'Gene', '841;842', (86, 94))	('caspase', 'Protein', (43, 50))	('activation', 'PosReg', (51, 61))	('caspases', 'Gene', (86, 94))	('YM155', 'Chemical', 'MESH:C523798', (9, 14))
366525	26090615	Recent data have shown that YM155 induces autophagy-dependent cell death in salivary adenoid cystic carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('salivary adenoid cystic carcinoma', 'Disease', (76, 109))	('autophagy-dependent cell death', 'CPA', (42, 72))	('induces', 'Reg', (34, 41))	('salivary adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (76, 109))	('YM155', 'Chemical', 'MESH:C523798', (28, 33))	('YM155', 'Var', (28, 33))
366527	26090615	S2, YM155 treatment did not produce time-dependent increases in LC3I, LC3II, Beclin and BNIP3 levels in KYSE410 cells, suggesting that YM155 did not induce autophagy.	('BNIP3', 'Gene', (88, 93))	('YM155', 'Var', (135, 140))	('LC3', 'Gene', (64, 67))	('KYSE410', 'Chemical', '-', (104, 111))	('BNIP3', 'Gene', '664', (88, 93))	('Beclin', 'MPA', (77, 83))	('LC3', 'Gene', '84557', (70, 73))	('LC3', 'Gene', (70, 73))	('YM155', 'Chemical', 'MESH:C523798', (4, 9))	('LC3', 'Gene', '84557', (64, 67))	('YM155', 'Chemical', 'MESH:C523798', (135, 140))
366529	26090615	The expression levels of mTOR, and the phosphorylation of AKT, S6, 4-EBP and ERK decreased after treatment with YM155 in KYSE410 but not KYSE150 cells, indicating that the decrease in the mTOR pathway may be associated with YM155-induced cell death (Fig.	('ERK decreased', 'Phenotype', 'HP:0000654', (77, 90))	('KYSE410', 'Chemical', '-', (121, 128))	('YM155', 'Var', (112, 117))	('mTOR', 'Gene', (25, 29))	('KYSE410', 'Var', (121, 128))	('decreased', 'NegReg', (81, 90))	('decrease', 'NegReg', (172, 180))	('mTOR', 'Gene', '2475', (25, 29))	('EBP', 'Gene', '10682', (69, 72))	('cell death', 'CPA', (238, 248))	('AKT', 'Gene', (58, 61))	('expression levels', 'MPA', (4, 21))	('phosphorylation', 'MPA', (39, 54))	('ERK', 'Gene', '5594', (77, 80))	('mTOR', 'Gene', (188, 192))	('YM155', 'Chemical', 'MESH:C523798', (112, 117))	('ERK', 'Gene', (77, 80))	('AKT', 'Gene', '207', (58, 61))	('EBP', 'Gene', (69, 72))	('mTOR', 'Gene', '2475', (188, 192))	('YM155', 'Chemical', 'MESH:C523798', (224, 229))	('YM155-induced', 'Var', (224, 237))
366530	26090615	Previous results have demonstrated that YM155 generates DNA damage and mediates DNA damage toxicity in a human myeloid leukemia cell line in vitro and in vivo.	('damage toxicity', 'Disease', (84, 99))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (111, 127))	('damage toxicity', 'Disease', 'MESH:D004194', (84, 99))	('YM155', 'Chemical', 'MESH:C523798', (40, 45))	('YM155', 'Var', (40, 45))	('myeloid leukemia', 'Disease', (111, 127))	('human', 'Species', '9606', (105, 110))	('myeloid leukemia', 'Disease', 'MESH:D007951', (111, 127))	('leukemia', 'Phenotype', 'HP:0001909', (119, 127))	('DNA damage', 'MPA', (56, 66))
366535	26090615	To further assess DNA damage after YM155 treatment, KYSE410 and KYSE 150 cells exposed to 20 nM YM155 for 12 or 24 h were evaluated by western blot analysis using an antibody recognizing both full-length and cleaved PARP.	('PARP', 'Gene', (216, 220))	('KYSE410', 'Chemical', '-', (52, 59))	('YM155', 'Chemical', 'MESH:C523798', (96, 101))	('YM155', 'Chemical', 'MESH:C523798', (35, 40))	('PARP', 'Gene', '142', (216, 220))	('YM155', 'Var', (96, 101))
366536	26090615	3D, treatment YM155 for either 12 or 24 h led to the significant time-dependent accumulation of full-length PARP.	('PARP', 'Gene', '142', (108, 112))	('PARP', 'Gene', (108, 112))	('YM155', 'Chemical', 'MESH:C523798', (14, 19))	('accumulation', 'PosReg', (80, 92))	('YM155', 'Var', (14, 19))
366537	26090615	Quantification of the ratio between PARP and actin in KYSE410 and KYSE150 cells is provided in Fig.	('PARP', 'Gene', '142', (36, 40))	('KYSE410', 'Chemical', '-', (54, 61))	('PARP', 'Gene', (36, 40))	('KYSE410', 'Var', (54, 61))
366538	26090615	Taken together, these data indicate that the loss of cellular viability in esophageal cancer cell lines after YM155 treatment is associated with YM155-mediated DNA damage.	('cellular viability', 'CPA', (53, 71))	('YM155', 'Var', (110, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('YM155-mediated', 'Var', (145, 159))	('loss', 'NegReg', (45, 49))	('esophageal cancer', 'Disease', (75, 92))	('YM155', 'Chemical', 'MESH:C523798', (145, 150))	('YM155', 'Chemical', 'MESH:C523798', (110, 115))
366539	26090615	It has been reported that massive DNA damage and PARP1 activation can induce a specific form of cell death termed "parthanatos," which is morphologically characterized by poly-ADP formation, the release of apoptosis-inducing factor (AIF) from the mitochondria, nuclear translocation of AIF and membrane rupture.	('PARP1', 'Gene', '142', (49, 54))	('damage', 'Var', (38, 44))	('PARP1', 'Gene', (49, 54))	('AIF', 'Gene', (286, 289))	('AIF', 'Gene', '9131', (286, 289))	('nuclear translocation', 'MPA', (261, 282))	('apoptosis-inducing factor', 'Gene', (206, 231))	('induce', 'Reg', (70, 76))	('poly-ADP', 'Chemical', '-', (171, 179))	('apoptosis-inducing factor', 'Gene', '9131', (206, 231))	('membrane rupture', 'CPA', (294, 310))	('AIF', 'Gene', (233, 236))	('AIF', 'Gene', '9131', (233, 236))	('activation', 'PosReg', (55, 65))
366541	26090615	4A, compared with untreated cells, YM155 treatment induced the accumulation of PARP1 in the nuclei.	('YM155', 'Chemical', 'MESH:C523798', (35, 40))	('accumulation', 'PosReg', (63, 75))	('YM155 treatment', 'Var', (35, 50))	('PARP1', 'Gene', '142', (79, 84))	('PARP1', 'Gene', (79, 84))
366543	26090615	Significant accumulation of PARP-1 and PAR was observed in the nuclear fraction of KYSE410 cells after treatment with YM155 for 12 or 24 h (Fig.	('YM155', 'Chemical', 'MESH:C523798', (118, 123))	('YM155', 'Var', (118, 123))	('KYSE410', 'Chemical', '-', (83, 90))	('PARP-1', 'Gene', (28, 34))	('PAR', 'Chemical', 'MESH:D011064', (39, 42))	('accumulation', 'PosReg', (12, 24))	('PAR', 'Chemical', 'MESH:D011064', (28, 31))
366546	26090615	Therefore, to further explore the PARP1-AIF pathway, we also assessed AIF release and translocation after treatment with YM155 for 12 and 24 h using immunofluorescence and western blot analysis.	('YM155', 'Var', (121, 126))	('AIF', 'Gene', '9131', (70, 73))	('AIF', 'Gene', (70, 73))	('AIF', 'Gene', '9131', (40, 43))	('AIF', 'Gene', (40, 43))	('translocation', 'MPA', (86, 99))	('PARP1', 'Gene', (34, 39))	('YM155', 'Chemical', 'MESH:C523798', (121, 126))	('PARP1', 'Gene', '142', (34, 39))
366548	26090615	To investigate the roles of PARP1 and AIF in YM155-induced parthanatos cell death, siRNA targeting PARP-1 and AIF were used to knock down PARP-1 and AIF expression in KYSE410 cells.	('AIF', 'Gene', '9131', (38, 41))	('PARP1', 'Gene', (28, 33))	('PARP1', 'Gene', '142', (28, 33))	('AIF', 'Gene', (110, 113))	('AIF', 'Gene', (149, 152))	('AIF', 'Gene', '9131', (149, 152))	('PARP-1', 'Gene', (138, 144))	('AIF', 'Gene', '9131', (110, 113))	('YM155', 'Chemical', 'MESH:C523798', (45, 50))	('KYSE410', 'Chemical', '-', (167, 174))	('knock down', 'Var', (127, 137))	('AIF', 'Gene', (38, 41))
366552	26090615	4G and 4F, the effect of YM155 was inhibited by PARP-1 or AIF knockdown using siRNA transfection in KYSE410 cells.	('YM155', 'Var', (25, 30))	('PARP-1', 'Gene', (48, 54))	('KYSE410', 'Chemical', '-', (100, 107))	('AIF', 'Gene', '9131', (58, 61))	('inhibited', 'NegReg', (35, 44))	('AIF', 'Gene', (58, 61))	('YM155', 'Chemical', 'MESH:C523798', (25, 30))	('knockdown', 'Var', (62, 71))
366554	26090615	To further investigate the mechanism of YM155-induced PARP-mediated parthanatos cell death in KYSE410 cells, Affymetrix Human Genome U133 plus 2.0 arrays were used to analyze mRNA changes in YM155-treated and untreated KYSE410 cells.	('Human', 'Species', '9606', (120, 125))	('KYSE410', 'Chemical', '-', (219, 226))	('YM155', 'Chemical', 'MESH:C523798', (191, 196))	('YM155-treated', 'Var', (191, 204))	('KYSE410', 'Chemical', '-', (94, 101))	('YM155', 'Chemical', 'MESH:C523798', (40, 45))	('PARP', 'Gene', '142', (54, 58))	('YM155-induced', 'Var', (40, 53))	('PARP', 'Gene', (54, 58))
366559	26090615	Canonical biological process of genes up-regulated in KYSE410 is available in Supplementary Tables 2.	('KYSE410', 'Chemical', '-', (54, 61))	('KYSE410', 'Var', (54, 61))	('up-regulated', 'PosReg', (38, 50))
366561	26090615	The mRNA levels of FOS, JUN, c-MYC, SLC30A2, CCNE, and NOXA were significantly elevated in KYSE410 cells after treatment with YM155 for 6 h. Furthermore, the mRNA levels of MLKL, BIRC5, CYCS, APAF1, CASP9 and HSPA1A, which are associated with apoptosis and necrosis, remained unchanged or slightly decreased in the YM155-treated KYSE410 cells (Fig.	('YM155', 'Chemical', 'MESH:C523798', (126, 131))	('BIRC5', 'Gene', '332', (179, 184))	('decreased', 'NegReg', (298, 307))	('BIRC5', 'Gene', (179, 184))	('CYCS', 'Gene', (186, 190))	('YM155', 'Chemical', 'MESH:C523798', (315, 320))	('mRNA levels', 'MPA', (158, 169))	('MLKL', 'Gene', (173, 177))	('necrosis', 'Disease', 'MESH:D009336', (257, 265))	('NOXA', 'Gene', '5366', (55, 59))	('HSPA1A', 'Gene', (209, 215))	('MLKL', 'Gene', '197259', (173, 177))	('KYSE410', 'Chemical', '-', (91, 98))	('KYSE410', 'Chemical', '-', (329, 336))	('c-MYC', 'Gene', '4609', (29, 34))	('CASP9', 'Gene', (199, 204))	('CYCS', 'Gene', '54205', (186, 190))	('CCNE', 'Gene', (45, 49))	('necrosis', 'Disease', (257, 265))	('APAF1', 'Gene', '317', (192, 197))	('NOXA', 'Gene', (55, 59))	('CASP9', 'Gene', '842', (199, 204))	('YM155-treated', 'Var', (315, 328))	('c-MYC', 'Gene', (29, 34))	('CCNE', 'Gene', '898', (45, 49))	('APAF1', 'Gene', (192, 197))	('HSPA1A', 'Gene', '3303', (209, 215))
366562	26090615	Therefore, transcript analysis demonstrates that YM155 treatment in KYSE410 cells facilitates the transcription of active PARP-regulated genes such as FOS, JUN, and c-MYC but not of apoptotic or necrotic genes.	('necrotic', 'Disease', (195, 203))	('facilitates', 'PosReg', (82, 93))	('FOS', 'Gene', (151, 154))	('JUN', 'Gene', (156, 159))	('PARP', 'Gene', (122, 126))	('necrotic', 'Disease', 'MESH:D009336', (195, 203))	('c-MYC', 'Gene', '4609', (165, 170))	('PARP', 'Gene', '142', (122, 126))	('YM155', 'Chemical', 'MESH:C523798', (49, 54))	('KYSE410', 'Chemical', '-', (68, 75))	('c-MYC', 'Gene', (165, 170))	('YM155', 'Var', (49, 54))	('transcription', 'MPA', (98, 111))
366563	26090615	Having shown that YM155 treatment induces PARP-1-dependent parthanatos cell death in esophageal cancer cells in vitro, we next investigated the efficacy of YM155 in inhibiting KYSE410 and KYSE150 tumor growth in a mouse xenograft model of esophageal cancer.	('tumor', 'Disease', (196, 201))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('KYSE410', 'Chemical', '-', (176, 183))	('inhibiting', 'NegReg', (165, 175))	('PARP-1-dependent', 'MPA', (42, 58))	('mouse', 'Species', '10090', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('KYSE410', 'Var', (176, 183))	('esophageal cancer', 'Disease', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('YM155', 'Chemical', 'MESH:C523798', (156, 161))	('esophageal cancer', 'Disease', (239, 256))	('YM155', 'Chemical', 'MESH:C523798', (18, 23))	('KYSE150', 'Var', (188, 195))	('YM155', 'Var', (156, 161))	('YM155', 'Var', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('parthanatos cell death', 'CPA', (59, 81))
366564	26090615	Mice bearing KYSE410 or KYSE150 tumors were inoculated for 10 days by intraperitoneal injection (i.p.)	('KYSE410', 'Var', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('KYSE150', 'Var', (24, 31))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Disease', (32, 38))	('KYSE410', 'Chemical', '-', (13, 20))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
366565	26090615	with 5 mg/kg YM155 respectively, in the YM155 treatment group (n = 5 for KYSE410 and KYSE150) or with 0.9% normal saline for the controls (n = 5 for KYSE410 and KYSE150).	('YM155', 'Chemical', 'MESH:C523798', (40, 45))	('KYSE410', 'Chemical', '-', (73, 80))	('KYSE410', 'Chemical', '-', (149, 156))	('YM155', 'Var', (40, 45))	('YM155', 'Chemical', 'MESH:C523798', (13, 18))	('KYSE150', 'Var', (85, 92))	('saline', 'Chemical', 'MESH:D012965', (114, 120))	('KYSE410', 'Var', (73, 80))
366566	26090615	6A, the average tumor burden at the beginning of the treatment was not significantly different between the YM155-treated and control groups.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('YM155', 'Chemical', 'MESH:C523798', (107, 112))	('YM155-treated', 'Var', (107, 120))
366567	26090615	YM155 treatment resulted in significant antitumor activity and reduced the growth of KYSE410 or KYSE150 xenograft tumors compared with the untreated group (Fig.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('reduced', 'NegReg', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('KYSE410', 'Var', (85, 92))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('growth', 'CPA', (75, 81))	('KYSE410', 'Chemical', '-', (85, 92))	('tumor', 'Disease', (44, 49))	('KYSE150', 'Var', (96, 103))
366569	26090615	There was a 66.3% reduction in tumor weight vs. the control group (P < 0.05) in the KYSE410 xenograft model and a 78.3% reduction in the KYSE150 xenograft model respectively (Fig.	('KYSE410', 'Var', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('reduction', 'NegReg', (120, 129))	('KYSE410', 'Chemical', '-', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('reduction', 'NegReg', (18, 27))
366570	26090615	To assess the biological effects of YM155-based therapy, tumors from KYSE410 and KYSE150 models were examined for markers of PARP-1, tumor cell proliferation (Ki67), and survivin.	('PARP-1', 'Gene', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('YM155', 'Chemical', 'MESH:C523798', (36, 41))	('KYSE410', 'Chemical', '-', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('KYSE150', 'Var', (81, 88))	('survivin', 'Gene', '11799', (170, 178))	('survivin', 'Gene', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumor', 'Disease', (57, 62))	('KYSE410', 'Var', (69, 76))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
366571	26090615	Changes in these markers reflected antitumor activity in response to YM155.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('YM155', 'Var', (69, 74))	('YM155', 'Chemical', 'MESH:C523798', (69, 74))
366572	26090615	More specifically, significant reductions in survivin, Ki67 and PARP were observed in the KYSE410 model after treatment with KYSE155 (Fig.	('Ki67', 'Protein', (55, 59))	('PARP', 'Gene', (64, 68))	('survivin', 'Gene', (45, 53))	('KYSE410', 'Chemical', '-', (90, 97))	('KYSE155', 'Var', (125, 132))	('PARP', 'Gene', '142', (64, 68))	('survivin', 'Gene', '11799', (45, 53))	('reductions', 'NegReg', (31, 41))
366573	26090615	6E, we propose a model to explain how YM155 induces PARP-mediated parthanatos cell death in ESCC cells: (i) the hyper-activation of PARP-1, leading to PAR and AIF translocation, (ii) the requirement of PARP-1 and AIF for YM155-induced necrosis, and (iii) the inhibition of mTOR pathways.	('PARP', 'Gene', '142', (132, 136))	('mTOR', 'Gene', (273, 277))	('PARP', 'Gene', (132, 136))	('YM155', 'Chemical', 'MESH:C523798', (38, 43))	('PARP', 'Gene', '142', (202, 206))	('PARP', 'Gene', '142', (52, 56))	('PARP', 'Gene', (202, 206))	('PAR', 'Chemical', 'MESH:D011064', (132, 135))	('PARP', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (273, 277))	('YM155', 'Var', (38, 43))	('PAR', 'Chemical', 'MESH:D011064', (202, 205))	('induces', 'Reg', (44, 51))	('necrosis', 'Disease', 'MESH:D009336', (235, 243))	('PAR', 'Chemical', 'MESH:D011064', (52, 55))	('necrosis', 'Disease', (235, 243))	('AIF', 'Gene', '9131', (159, 162))	('AIF', 'Gene', (159, 162))	('AIF', 'Gene', '9131', (213, 216))	('AIF', 'Gene', (213, 216))	('PAR', 'Chemical', 'MESH:D011064', (151, 154))	('YM155', 'Chemical', 'MESH:C523798', (221, 226))
366576	26090615	Previous studies have implicated apoptosis in YM155-induced cytotoxicity in multiple types of cancer.	('cytotoxicity', 'Disease', (60, 72))	('apoptosis', 'CPA', (33, 42))	('YM155-induced', 'Var', (46, 59))	('cytotoxicity', 'Disease', 'MESH:D064420', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('YM155', 'Chemical', 'MESH:C523798', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
366579	26090615	In this study, we found that YM155 partly reduced survivin expression in KYSE150 but not KYSE410 cells.	('KYSE150', 'Var', (73, 80))	('reduced', 'NegReg', (42, 49))	('YM155', 'Chemical', 'MESH:C523798', (29, 34))	('survivin', 'Gene', '11799', (50, 58))	('YM155', 'Var', (29, 34))	('expression', 'MPA', (59, 69))	('KYSE410', 'Chemical', '-', (89, 96))	('survivin', 'Gene', (50, 58))
366580	26090615	YM155 induced DNA damage response including gammaH2AX and PARP-1 hyper-activation.	('hyper-activation', 'PosReg', (65, 81))	('gammaH2AX', 'Protein', (44, 53))	('gammaH2AX', 'Chemical', '-', (44, 53))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('YM155', 'Var', (0, 5))	('DNA damage response', 'MPA', (14, 33))	('PARP-1', 'Gene', (58, 64))
366582	26090615	For the first time, YM155-induced PARP-1-dependent parthanatos cell death has been observed in esophageal cancer cells, and the underlying cytotoxic mechanism is tightly linked to PARP-1 hyper-activation leading to PAR formation and AIF translocation.	('hyper-activation', 'Var', (187, 203))	('PARP-1', 'Gene', (180, 186))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('PAR formation', 'MPA', (215, 228))	('PAR', 'Chemical', 'MESH:D011064', (34, 37))	('PAR', 'Chemical', 'MESH:D011064', (180, 183))	('AIF', 'Gene', '9131', (233, 236))	('PAR', 'Chemical', 'MESH:D011064', (215, 218))	('YM155', 'Chemical', 'MESH:C523798', (20, 25))	('PARP-1-dependent', 'Gene', (34, 50))	('AIF', 'Gene', (233, 236))	('parthanatos cell death', 'CPA', (51, 73))	('esophageal cancer', 'Disease', (95, 112))	('YM155-induced', 'Var', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
366583	26090615	Thus, YM155 is a novel inducer of PARP-1-dependent parthanatos cell death and has potential as an effective esophageal cancer treatment.	('esophageal cancer', 'Disease', (108, 125))	('inducer', 'PosReg', (23, 30))	('YM155', 'Chemical', 'MESH:C523798', (6, 11))	('YM155', 'Var', (6, 11))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('PARP-1-dependent', 'Gene', (34, 50))	('parthanatos cell death', 'CPA', (51, 73))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
366588	26090615	In this study, we found that YM155 selectively induces parthanatos cell death in KYSE410 and KSYE150 cells.	('YM155', 'Chemical', 'MESH:C523798', (29, 34))	('induces', 'Reg', (47, 54))	('YM155', 'Var', (29, 34))	('KYSE410', 'Chemical', '-', (81, 88))	('parthanatos cell death', 'CPA', (55, 77))
366589	26090615	This conclusion is based on the following observations in KYSE410 and KYSE150 cells undergoing YM155-induced cell death: (i) little nuclear fragmentation or caspase cleavage; (ii) the release of LDH, PARP-1 hyper-activation, poly-ADP polymer formation and translocation of AIF and (iii) the visualization of disrupted cytoplasmic membranes and cellular organ swelling using TEM.	('PARP-1', 'Gene', (200, 206))	('release', 'MPA', (184, 191))	('translocation', 'CPA', (256, 269))	('poly-ADP', 'Var', (225, 233))	('LDH', 'Protein', (195, 198))	('AIF', 'Gene', '9131', (273, 276))	('YM155', 'Chemical', 'MESH:C523798', (95, 100))	('AIF', 'Gene', (273, 276))	('KYSE410', 'Chemical', '-', (58, 65))	('poly-ADP', 'Chemical', '-', (225, 233))
366590	26090615	Furthermore, our data show that YM155 led to a significant time-dependent accumulation of full-length PARP after YM155 treatment.	('YM155', 'Chemical', 'MESH:C523798', (32, 37))	('PARP', 'Gene', (102, 106))	('YM155', 'Var', (32, 37))	('YM155 treatment', 'Var', (113, 128))	('YM155', 'Chemical', 'MESH:C523798', (113, 118))	('PARP', 'Gene', '142', (102, 106))	('accumulation', 'PosReg', (74, 86))
366592	26090615	In addition, knockdown of PARP1 using siRNA interference greatly reduced YM155-induced PARP-1 mediated parthanatos cell death in KYSE410 cells.	('parthanatos', 'CPA', (103, 114))	('reduced', 'NegReg', (65, 72))	('PARP-1', 'Gene', (87, 93))	('PARP1', 'Gene', '142', (26, 31))	('siRNA interference', 'MPA', (38, 56))	('PARP1', 'Gene', (26, 31))	('KYSE410', 'Chemical', '-', (129, 136))	('knockdown', 'Var', (13, 22))	('YM155', 'Chemical', 'MESH:C523798', (73, 78))
366594	26090615	Collectively, these results suggest that YM155-mediated PARP-1 hyper-activation enhances the antitumor effect through the formation of poly-ADP polymers as well as the translocation of AIF, ultimately leading to parthanatos cell death.	('leading to', 'Reg', (201, 211))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('hyper-activation enhances', 'PosReg', (63, 88))	('poly-ADP', 'MPA', (135, 143))	('YM155-mediated', 'Var', (41, 55))	('tumor', 'Disease', (97, 102))	('poly-ADP polymers', 'Chemical', '-', (135, 152))	('translocation', 'MPA', (168, 181))	('parthanatos cell death', 'CPA', (212, 234))	('AIF', 'Gene', '9131', (185, 188))	('YM155', 'Chemical', 'MESH:C523798', (41, 46))	('AIF', 'Gene', (185, 188))	('PARP-1', 'Gene', (56, 62))
366596	26090615	Consumption of NAD+ as a PARP-1 substrate generates poly-ADP polymer, which translocates to the cytosol to induce cell death via the nuclear translocation of AIF to effect large-scale DNA fragmentation.	('poly-ADP polymer', 'Var', (52, 68))	('induce', 'PosReg', (107, 113))	('AIF', 'Gene', '9131', (158, 161))	('cell death', 'CPA', (114, 124))	('AIF', 'Gene', (158, 161))	('poly-ADP', 'Chemical', '-', (52, 60))	('NAD+', 'Chemical', 'MESH:D009243', (15, 19))
366598	26090615	The current study shows that both apoptotic and necrotic machinery were attenuated during YM155-induced parthanatos cell death in KYSE410 and KYSE150 cells.	('YM155', 'Chemical', 'MESH:C523798', (90, 95))	('KYSE410', 'Var', (130, 137))	('KYSE150', 'Var', (142, 149))	('necrotic', 'Disease', (48, 56))	('apoptotic', 'CPA', (34, 43))	('attenuated', 'NegReg', (72, 82))	('necrotic', 'Disease', 'MESH:D009336', (48, 56))	('KYSE410', 'Chemical', '-', (130, 137))	('YM155-induced', 'Gene', (90, 103))	('parthanatos', 'CPA', (104, 115))
366599	26090615	Microarray analysis demonstrated that the transcription of BIRC5, CYCS, APAF1, CASP9, HSPA1A and MLKL, which are associated with apoptosis and necrosis, were decreased in YM155-treated KYSE410 cells.	('APAF1', 'Gene', (72, 77))	('KYSE410', 'Chemical', '-', (185, 192))	('necrosis', 'Disease', 'MESH:D009336', (143, 151))	('MLKL', 'Gene', '197259', (97, 101))	('BIRC5', 'Gene', '332', (59, 64))	('BIRC5', 'Gene', (59, 64))	('necrosis', 'Disease', (143, 151))	('HSPA1A', 'Gene', (86, 92))	('YM155', 'Chemical', 'MESH:C523798', (171, 176))	('CYCS', 'Gene', (66, 70))	('decreased', 'NegReg', (158, 167))	('HSPA1A', 'Gene', '3303', (86, 92))	('CASP9', 'Gene', (79, 84))	('CASP9', 'Gene', '842', (79, 84))	('APAF1', 'Gene', '317', (72, 77))	('transcription', 'MPA', (42, 55))	('YM155-treated', 'Var', (171, 184))	('MLKL', 'Gene', (97, 101))	('CYCS', 'Gene', '54205', (66, 70))
366600	26090615	Furthermore, autophagy-associated markers, including LC3I, LC3II, Beclin and BNIP3, did not increase in a time-dependent manner after YM155 treatment in KYSE410 cells, suggesting that YM155 did not induce autophagy.	('YM155', 'Chemical', 'MESH:C523798', (184, 189))	('BNIP3', 'Gene', (77, 82))	('LC3', 'Gene', '84557', (59, 62))	('KYSE410', 'Chemical', '-', (153, 160))	('LC3', 'Gene', (59, 62))	('YM155', 'Var', (134, 139))	('BNIP3', 'Gene', '664', (77, 82))	('YM155', 'Chemical', 'MESH:C523798', (134, 139))	('LC3', 'Gene', '84557', (53, 56))	('LC3', 'Gene', (53, 56))
366605	26090615	Based on transcription of upregulated genes, we further confirmed the excessive activation of PARP-1 upon YM155 treatment in esophageal cancer cells.	('PARP-1', 'Gene', (94, 100))	('esophageal cancer', 'Disease', (125, 142))	('YM155', 'Chemical', 'MESH:C523798', (106, 111))	('YM155', 'Var', (106, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('activation', 'PosReg', (80, 90))
366606	26090615	This is the first study demonstrating that YM155 causes hyper-activation of PARP1 and induces PARP-1-dependent parthanatos cell death.	('PARP1', 'Gene', '142', (76, 81))	('induces', 'Reg', (86, 93))	('PARP1', 'Gene', (76, 81))	('YM155', 'Chemical', 'MESH:C523798', (43, 48))	('YM155', 'Var', (43, 48))	('hyper-activation', 'MPA', (56, 72))	('parthanatos cell death', 'CPA', (111, 133))
366608	26090615	Further study is necessary to determine (i) why in esophageal cancer, YM155 initiates PARP-1 hyperactivation-mediated Parthanatos cell death as opposed to caspase-dependent apoptosis; (ii) how poly-ADP in the cytosol induces a death-signaling cascade and executes biological functions in the PARP-1-mediated pathway and; (iii) the identity of proteins targeted by PAR to explore the complex pathway from nuclear to mitochondria during the process of parthanatos.	('PARP-1-mediated pathway', 'Pathway', (292, 315))	('poly-ADP', 'Var', (193, 201))	('PAR', 'Chemical', 'MESH:D011064', (292, 295))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancer', 'Disease', (51, 68))	('induces', 'Reg', (217, 224))	('PAR', 'Chemical', 'MESH:D011064', (86, 89))	('death-signaling cascade', 'Pathway', (227, 250))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('poly-ADP', 'Chemical', '-', (193, 201))	('YM155', 'Chemical', 'MESH:C523798', (70, 75))	('PAR', 'Chemical', 'MESH:D011064', (364, 367))	('executes', 'Reg', (255, 263))
366609	26090615	In conclusion, we report that YM155 treatment can kill esophageal cancer cells by causing DNA damage, PARP-1 hyper-activity, and AIF translocation leading to PARP-1-dependent parthanatos cell death and that it reduced tumor burden in both in vitro and in animal models in vivo of esophageal cancer.	('reduced', 'NegReg', (210, 217))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (55, 72))	('tumor', 'Disease', (218, 223))	('esophageal cancer', 'Disease', 'MESH:D004938', (280, 297))	('DNA damage', 'MPA', (90, 100))	('hyper-activity', 'Disease', 'OMIM:612348', (109, 123))	('YM155 treatment', 'Var', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('PARP-1-dependent parthanatos', 'MPA', (158, 186))	('YM155', 'Chemical', 'MESH:C523798', (30, 35))	('esophageal cancer', 'Disease', (280, 297))	('PARP-1', 'Gene', (102, 108))	('hyper-activity', 'Disease', (109, 123))	('AIF', 'Gene', '9131', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('AIF', 'Gene', (129, 132))	('causing', 'Reg', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))
366618	26090615	After YM155 treatment for 24 or 48 h, cell viability was assessed with the CCK-8 assay (Dojindo, Japan), and the absorbency value was read using a Model 680 microplate reader (Bio-Rad, CA) according to the manufacturer's instructions.	('cell viability', 'CPA', (38, 52))	('Rad', 'Gene', (180, 183))	('Rad', 'Gene', '6236', (180, 183))	('YM155', 'Chemical', 'MESH:C523798', (6, 11))	('YM155', 'Var', (6, 11))
366640	26090615	When a tumor was detectable (approximately 14 days after subcutaneous injection), mice were randomly assigned to two groups, receiving either YM155 or 0.9% saline.	('YM155', 'Var', (142, 147))	('mice', 'Species', '10090', (82, 86))	('tumor', 'Disease', (7, 12))	('saline', 'Chemical', 'MESH:D012965', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('YM155', 'Chemical', 'MESH:C523798', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
366695	25013491	Polymorphism is a key characteristic of the tumor cells as they usually present in a cribriform, tubule or solid pattern.	('Polymorphism', 'Var', (0, 12))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
366739	21703265	With the increased dissemination of endoscopic ablative therapies, and the accumulating evidence that intervention in the setting of high-grade dysplasia averts EAC, endoscopic intervention is commonly performed in high-grade dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (144, 153))	('EAC', 'MPA', (161, 164))	('EAC', 'Phenotype', 'HP:0011459', (161, 164))	('averts', 'NegReg', (154, 160))	('high-grade', 'Var', (133, 143))	('dysplasia', 'Disease', (226, 235))	('dysplasia', 'Disease', (144, 153))	('dysplasia', 'Disease', 'MESH:D004476', (226, 235))
366842	21448698	Cessation of smoking is also associated with flares of ulcerative colitis, while nicotine is superior to placebo in the treatment of acute ulcerative colitis.	('Cessation', 'Var', (0, 9))	('ulcerative colitis', 'Disease', (55, 73))	('colitis', 'Phenotype', 'HP:0002583', (150, 157))	('acute ulcerative colitis', 'Disease', 'MESH:D003093', (133, 157))	('acute ulcerative colitis', 'Disease', (133, 157))	('men', 'Species', '9606', (125, 128))	('ulcerative colitis', 'Disease', 'MESH:D003093', (55, 73))	('nicotine', 'Chemical', 'MESH:D009538', (81, 89))	('colitis', 'Phenotype', 'HP:0002583', (66, 73))	('flares', 'Disease', (45, 51))	('ulcerative colitis', 'Disease', 'MESH:D003093', (139, 157))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (55, 73))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (139, 157))
366868	16566840	Research has shown that H. pylori can cause gastric cancer or MALT lymphoma in some individuals.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (67, 75))	('cause', 'Reg', (38, 43))	('H. pylori', 'Species', '210', (24, 33))	('gastric cancer', 'Disease', (44, 58))	('MALT lymphoma', 'Disease', (62, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('H. pylori', 'Var', (24, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('MALT lymphoma', 'Disease', 'MESH:D018442', (62, 75))
366890	16566840	Processes that encourage the loss of cellular control may be tumor initiators (directly causing mutations) or promoters (facilitating mutations).	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('mutations', 'Var', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
366908	16566840	Carriers were six times more likely to die of hepatobiliary carcinoma than matched controls.	('hepatobiliary carcinoma', 'Disease', (46, 69))	('Carriers', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('hepatobiliary carcinoma', 'Disease', 'MESH:D004066', (46, 69))
366909	16566840	Their findings also suggested a strong association between chronic carrier status and hepatobiliary carcinoma.	('hepatobiliary carcinoma', 'Disease', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('hepatobiliary carcinoma', 'Disease', 'MESH:D004066', (86, 109))	('chronic carrier status', 'Var', (59, 81))
366910	16566840	These studies also agreed, people who contracted typhoid but did not become carriers were not at higher risk of cancer.	('typhoid', 'Var', (49, 56))	('people', 'Species', '9606', (27, 33))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
366928	16566840	Most studies have focused on gene abnormalities and deletions ("loss of heterozygosity") at chromosomal regions harboring known or putative tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('deletions', 'Var', (52, 61))	('tumor', 'Disease', (140, 145))
366929	16566840	It appears, however, that TP53 inactivation has an important and early role in gallbladder carcinoma associated with gallstones and chronic inflammation.	('TP53', 'Gene', (26, 30))	('inactivation', 'Var', (31, 43))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (79, 100))	('gallstones', 'Disease', (117, 127))	('gallstones', 'Phenotype', 'HP:0001081', (117, 127))	('inflammation', 'Disease', 'MESH:D007249', (140, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('gallbladder carcinoma', 'Disease', (79, 100))	('TP53', 'Gene', '7157', (26, 30))	('gallstone', 'Phenotype', 'HP:0001081', (117, 126))	('gallstones', 'Disease', 'MESH:D042882', (117, 127))	('inflammation', 'Disease', (140, 152))
366930	16566840	This inactivation would abrogate the tumor suppressor function of the p53 protein resulting in impairments in cell cycle control, cellular repair and apoptosis.	('impairments', 'NegReg', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('apoptosis', 'CPA', (150, 159))	('cellular repair', 'CPA', (130, 145))	('men', 'Species', '9606', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('abrogate', 'NegReg', (24, 32))	('cell cycle control', 'CPA', (110, 128))	('protein', 'Protein', (74, 81))	('inactivation', 'Var', (5, 17))
366931	16566840	In contrast, KRAS mutations are frequent and early events in tumors associated with APBDJ but detected less often in gallbladder carcinomas associated with gallstones.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('APBDJ', 'Disease', (84, 89))	('gallstones', 'Disease', 'MESH:D042882', (156, 166))	('gallbladder carcinomas', 'Disease', (117, 139))	('gallstone', 'Phenotype', 'HP:0001081', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('KRAS', 'Gene', (13, 17))	('gallstones', 'Disease', (156, 166))	('gallbladder carcinomas', 'Disease', 'MESH:D005706', (117, 139))	('KRAS', 'Gene', '3845', (13, 17))	('gallstones', 'Phenotype', 'HP:0001081', (156, 166))	('mutations', 'Var', (18, 27))
366933	16566840	A mutation in this gene results in an abnormal protein implicated in several malignancies, including lung adenocarcinoma, ductal carcinoma of the pancreas and colorectal carcinoma among others.	('ductal carcinoma of the pancreas', 'Disease', 'MESH:D021441', (122, 154))	('protein', 'Protein', (47, 54))	('mutation', 'Var', (2, 10))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('ductal carcinoma of the pancreas', 'Disease', (122, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('malignancies', 'Disease', (77, 89))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (159, 179))	('lung adenocarcinoma', 'Disease', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (101, 120))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (122, 138))	('results in', 'Reg', (24, 34))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))	('colorectal carcinoma', 'Disease', (159, 179))	('implicated', 'Reg', (55, 65))
366940	16566840	Acute lower respiratory tract infection caused by C. pneumoniae seems often to precede attacks of asthma in both children and adults but is also involved in some exacerbations of chronic bronchitis.	('asthma', 'Disease', (98, 104))	('C. pneumoniae', 'Species', '83558', (50, 63))	('pneumonia', 'Phenotype', 'HP:0002090', (53, 62))	('asthma', 'Phenotype', 'HP:0002099', (98, 104))	('lower respiratory tract infection', 'Phenotype', 'HP:0002783', (6, 39))	('bronchitis', 'Phenotype', 'HP:0012387', (187, 197))	('C. pneumoniae', 'Var', (50, 63))	('chronic bronchitis', 'Disease', (179, 197))	('respiratory tract infection', 'Phenotype', 'HP:0011947', (12, 39))	('children', 'Species', '9606', (113, 121))	('involved', 'Reg', (145, 153))	('attacks', 'Disease', (87, 94))	('chronic bronchitis', 'Phenotype', 'HP:0004469', (179, 197))	('chronic bronchitis', 'Disease', 'MESH:D001991', (179, 197))	('respiratory tract infection', 'Disease', (12, 39))	('respiratory tract infection', 'Disease', 'MESH:D012141', (12, 39))	('asthma', 'Disease', 'MESH:D001249', (98, 104))
366957	16566840	Values between IgG >=512 and IgA >=40 were set as the criteria for chronic C. pneumoniae infections.	('pneumonia', 'Phenotype', 'HP:0002090', (78, 87))	('IgG >=512', 'Var', (15, 24))	('pneumoniae infections', 'Disease', 'MESH:D011014', (78, 99))	('C. pneumoniae', 'Species', '83558', (75, 88))	('pneumoniae infections', 'Disease', (78, 99))	('pneumoniae infection', 'Phenotype', 'HP:0002090', (78, 98))
366968	16566840	After adjusting for a history of chronic bronchitis or emphysema, lung cancer subjects were more likely to have IgA titers >=16 (55.4% vs. 51.3%) and >=256 (5.1% vs. 2.5%) to C. pneumoniae than controls.	('bronchitis', 'Phenotype', 'HP:0012387', (41, 51))	('emphysema', 'Disease', 'MESH:D004646', (55, 64))	('chronic bronchitis', 'Disease', (33, 51))	('lung cancer', 'Disease', (66, 77))	('>=256', 'Var', (150, 155))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('emphysema', 'Phenotype', 'HP:0002097', (55, 64))	('chronic bronchitis', 'Phenotype', 'HP:0004469', (33, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('IgA', 'MPA', (112, 115))	('chronic bronchitis', 'Disease', 'MESH:D001991', (33, 51))	('C. pneumoniae', 'Species', '83558', (175, 188))	('pneumonia', 'Phenotype', 'HP:0002090', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('emphysema', 'Disease', (55, 64))
366969	16566840	Individuals with antibody tiers IgA >=16 had 1.2 times the risk of lung cancer (95% confidence interval, 0.9-1.6) compared to those with lower titers.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('IgA >=16', 'Var', (32, 40))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
366970	16566840	Investigators reported a significant trend (P = 0.007) of increasing odds ratios with increasing IgA titers primarily due to an odds ratio of 2.8 (95% confidence interval, 1.1-6.7) associated with titers >=256.	('titers >=256', 'Var', (197, 209))	('rat', 'Species', '10116', (74, 77))	('rat', 'Species', '10116', (133, 136))	('IgA', 'Protein', (97, 100))	('increasing IgA titers', 'Phenotype', 'HP:0003261', (86, 107))
367014	16566840	In fact the S300 proteins were able to induce a 5-fold increase in PGE2 secretion from Caco-2 cells, as compared with cells stimulated with WEA.	('increase', 'PosReg', (55, 63))	('Caco-2', 'CellLine', 'CVCL:0025', (87, 93))	('PGE2 secretion', 'MPA', (67, 81))	('S300 proteins', 'Var', (12, 25))	('PGE2', 'Chemical', 'MESH:D015232', (67, 71))
367017	16566840	that S. bovis proteins also promoted cell proliferation by triggering mitogen-activated protein kinases (MAPKs), which can increase the incidence of cell transformation, the rate of genetic mutations and up-regulate COX-2.	('S. bovis', 'Species', '1335', (5, 13))	('genetic', 'Var', (182, 189))	('cell transformation', 'CPA', (149, 168))	('increase', 'PosReg', (123, 131))	('rat', 'Species', '10116', (174, 177))	('triggering', 'Reg', (59, 69))	('COX-2', 'Gene', (216, 221))	('up-regulate', 'PosReg', (204, 215))	('promoted', 'PosReg', (28, 36))	('rat', 'Species', '10116', (49, 52))	('cell proliferation', 'CPA', (37, 55))
367042	16566840	The authors suggested that although a single E coli isolate was not found in Crohn's ileal mucosa, some genotypes were more likely than others to be associated with chronic or early recurrent ileal lesions.	('ileal lesions', 'Disease', (192, 205))	('chronic', 'Disease', (165, 172))	('genotypes', 'Var', (104, 113))	('E coli', 'Species', '562', (45, 51))	('associated with', 'Reg', (149, 164))	('ileal lesions', 'Disease', 'MESH:D007077', (192, 205))
367048	16566840	IL-12Rbeta1 sequence analysis revealed genetic mutations that resulted in premature stop codons in the extracellular domain.	('IL-12Rbeta1', 'Gene', '3594', (0, 11))	('premature stop codons in the extracellular domain', 'MPA', (74, 123))	('IL-12Rbeta1', 'Gene', (0, 11))	('mutations', 'Var', (47, 56))
367057	16566840	For example, mutations affecting the epidermal growth factor receptor (EGFR) were significantly associated with specific genetic alterations.	('epidermal growth factor receptor', 'Gene', '1956', (37, 69))	('associated', 'Reg', (96, 106))	('rat', 'Species', '10116', (133, 136))	('EGFR', 'Gene', '1956', (71, 75))	('mutations', 'Var', (13, 22))	('epidermal growth factor receptor', 'Gene', (37, 69))	('EGFR', 'Gene', (71, 75))
367058	16566840	Supervised clustering analysis based on EGFR gene mutations elucidated a subgroup including all EGFR gene mutated tumors, which showed significantly shorter disease-free survival To analyze the genetic alterations of primary lung adenocarcinoma in a high-throughput way, Shibata et al.	('EGFR', 'Gene', (96, 100))	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('lung adenocarcinoma', 'Disease', (225, 244))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (225, 244))	('shorter', 'NegReg', (149, 156))	('EGFR', 'Gene', (40, 44))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('rat', 'Species', '10116', (206, 209))	('EGFR', 'Gene', '1956', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (225, 244))	('mutated', 'Var', (106, 113))	('EGFR', 'Gene', '1956', (96, 100))
367060	16566840	They identified a large number of chromosomal numerical alterations, including frequent amplifications.	('amplifications', 'MPA', (88, 102))	('chromosomal numerical alterations', 'Var', (34, 67))	('rat', 'Species', '10116', (60, 63))
367064	16566840	These alterations are associated with carcinogenesis and may either stimulate cellular aberrations or inhibit normal cell controls.	('alterations', 'Var', (6, 17))	('rat', 'Species', '10116', (91, 94))	('stimulate', 'PosReg', (68, 77))	('carcinogenesis', 'Disease', 'MESH:D063646', (38, 52))	('rat', 'Species', '10116', (10, 13))	('carcinogenesis', 'Disease', (38, 52))	('inhibit', 'NegReg', (102, 109))	('cellular aberrations', 'CPA', (78, 98))	('associated', 'Reg', (22, 32))	('normal cell controls', 'CPA', (110, 130))
367069	16566840	The CdtB unit of CDT is a DNAse that creates double-stranded DNA breaks causing cell cycle arrest, usually at the G2 checkpoint.	('CdtB', 'Gene', '982', (4, 8))	('causing', 'Reg', (72, 79))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('CD', 'Disease', 'MESH:D006223', (17, 19))	('cell cycle arrest', 'CPA', (80, 97))	('CD', 'Phenotype', 'HP:0100280', (17, 19))	('double-stranded', 'Var', (45, 60))	('CdtB', 'Gene', (4, 8))
367132	16566840	Aberrations in the cell surface carbohydrate structures have now been established as a universal characteristic of malignant transformation of cells, and cancer has been referred to as a molecular disease of the cell membrane glycoconjugates.	('rat', 'Species', '10116', (40, 43))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('carbohydrate', 'Chemical', 'MESH:D002241', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('rat', 'Species', '10116', (4, 7))	('Aberrations', 'Var', (0, 11))
367136	16566840	Factors that would suggest a protective role of a bacterial species include: (1) colonization lowers the risk of a certain cancer; (2) elimination or absence of colonization raises the risk, or (3) introduction of the bacteria or its toxins cures or causes remission of the cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('absence', 'NegReg', (150, 157))	('remission', 'CPA', (257, 266))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('lowers', 'NegReg', (94, 100))	('cancer', 'Disease', (274, 280))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('introduction', 'Var', (198, 210))	('cancer', 'Disease', (123, 129))	('elimination', 'Var', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('risk', 'MPA', (185, 189))	('causes', 'Reg', (250, 256))
367238	16566840	The authors found, however, that the absence of H. pylori infection, independent of cigarette smoking and BMI, was associated with an increase in the risk of development of EA.	('men', 'Species', '9606', (165, 168))	('infection', 'Disease', (58, 67))	('absence', 'Var', (37, 44))	('H. pylori', 'Gene', (48, 57))	('infection', 'Disease', 'MESH:D007239', (58, 67))	('H. pylori', 'Species', '210', (48, 57))	('H. pylori infection', 'Phenotype', 'HP:0005202', (48, 67))
367272	16566840	If eradication of H. pylori infection lowers the incidence of gastric cancer, however, it should be recommended for patients with corpus atrophy at all ages irrespective of the presence of reflux esophagitis or Barrett's esophagus, especially in populations having a high prevalence of gastric cancer.	("Barrett's esophagus", 'Disease', (211, 230))	('corpus atrophy', 'Disease', 'MESH:D001284', (130, 144))	('men', 'Species', '9606', (105, 108))	('gastric cancer', 'Disease', (62, 76))	('corpus atrophy', 'Disease', (130, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (286, 300))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (211, 230))	('patients', 'Species', '9606', (116, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (286, 300))	('H. pylori infection', 'Phenotype', 'HP:0005202', (18, 37))	('reflux esophagitis', 'Disease', (189, 207))	('esophagitis', 'Phenotype', 'HP:0100633', (196, 207))	('eradication', 'Var', (3, 14))	('H. pylori', 'Gene', (18, 27))	('lowers', 'NegReg', (38, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('infection', 'Disease', (28, 37))	('infection', 'Disease', 'MESH:D007239', (28, 37))	('H. pylori', 'Species', '210', (18, 27))	('reflux esophagitis', 'Disease', 'MESH:D005764', (189, 207))	('gastric cancer', 'Disease', (286, 300))
367301	16566840	The absence of H. pylori appears to elevate ghrelin which stimulates increased appetite in some individuals.	('appetite', 'MPA', (79, 87))	('ghrelin', 'Protein', (44, 51))	('increased', 'PosReg', (69, 78))	('increased appetite', 'Phenotype', 'HP:0002591', (69, 87))	('ghrelin', 'Chemical', 'MESH:D054439', (44, 51))	('H. pylori', 'Gene', (15, 24))	('absence', 'Var', (4, 11))	('elevate', 'PosReg', (36, 43))	('H. pylori', 'Species', '210', (15, 24))
367312	32444879	Patients after McKeown esophagectomy reported more problems with 'eating with others' compared to patients after Ivor Lewis esophagectomy (mean scores: 49.9 vs. 38.8).	('Patients', 'Species', '9606', (0, 8))	("'eating with others'", 'MPA', (65, 85))	('patients', 'Species', '9606', (98, 106))	('McKeown', 'Var', (15, 22))
367320	32444879	A recent systematic review found significantly more anastomotic leakages following a McKeown esophagectomy, which may be due to the longer gastric tube with likely a more impaired perfusion at the tip of the gastric tube than in the shorter gastric tube after Ivor Lewis.	('anastomotic leakages', 'Disease', 'MESH:D057868', (52, 72))	('McKeown', 'Var', (85, 92))	('anastomotic leakages', 'Disease', (52, 72))	('impaired', 'NegReg', (171, 179))	('perfusion', 'MPA', (180, 189))
367349	32444879	Patients after McKeown esophagectomy reported significantly more problems with eating with others compared to patients after Ivor Lewis esophagectomy (mean scores: 49.9 vs. 38.8; P = 0.042).	('McKeown', 'Var', (15, 22))	('eating with others', 'MPA', (79, 97))	('problems', 'Reg', (65, 73))	('Patients', 'Species', '9606', (0, 8))	('problems with eating', 'Phenotype', 'HP:0100738', (65, 85))	('patients', 'Species', '9606', (110, 118))
367358	32444879	However, after a McKeown esophagectomy, patients reported more problems with eating with others compared to patients after an Ivor Lewis esophagectomy.	('eating with others', 'MPA', (77, 95))	('patients', 'Species', '9606', (40, 48))	('McKeown', 'Var', (17, 24))	('problems', 'Reg', (63, 71))	('problems with eating', 'Phenotype', 'HP:0100738', (63, 83))	('patients', 'Species', '9606', (108, 116))
367362	32444879	Overall, our findings are different compared to the literature as we only found one impaired HR-QoL domain after McKeown compared to Ivor Lewis esophagectomy, even in patients with no or minor postoperative complications.	('McKeown', 'Var', (113, 120))	('impaired HR-QoL', 'Disease', 'MESH:D001919', (84, 99))	('impaired HR-QoL', 'Disease', (84, 99))	('patients', 'Species', '9606', (167, 175))
367367	32444879	A recent systematic review with a comprehensive meta-analysis found similar cardiac arrhythmia incidence but a higher incidence of pulmonary complications, anastomotic leakage, and vocal cord injury after minimally invasive McKeown compared to minimally invasive Ivor Lewis esophagectomy.	('pulmonary complications', 'Disease', 'MESH:D008171', (131, 154))	('minimally', 'Var', (205, 214))	('cardiac arrhythmia', 'Disease', (76, 94))	('pulmonary complications', 'Phenotype', 'HP:0006532', (131, 154))	('anastomotic leakage', 'Disease', 'MESH:D057868', (156, 175))	('anastomotic leakage', 'Disease', (156, 175))	('cord injury', 'Disease', (187, 198))	('cardiac arrhythmia', 'Disease', 'MESH:D001145', (76, 94))	('cardiac arrhythmia', 'Phenotype', 'HP:0011675', (76, 94))	('pulmonary complications', 'Disease', (131, 154))	('cord injury', 'Disease', 'MESH:D013119', (187, 198))
367377	32444879	Only one HR-QoL domain:more problems in eating with others:was found to be significantly poorer in the McKeown compared to the Ivor Lewis group, even in patients with no or minor postoperative complications.	('poorer', 'NegReg', (89, 95))	('patients', 'Species', '9606', (153, 161))	('eating', 'MPA', (40, 46))	('McKeown', 'Var', (103, 110))
367533	29942042	The SNPs rs2075650 and rs4420638 were linked to the most replications within a single reclassified phenotype; both were associated with Alzheimer's disease (AD).	("Alzheimer's disease", 'Disease', (136, 155))	('associated', 'Reg', (120, 130))	('rs4420638', 'Var', (23, 32))	('rs4420638', 'Mutation', 'rs4420638', (23, 32))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (136, 155))	('AD', 'Disease', 'MESH:D000544', (157, 159))	('AD', 'Disease', (157, 159))	('AD', 'Phenotype', 'HP:0002511', (157, 159))	('rs2075650', 'Mutation', 'rs2075650', (9, 18))	('rs2075650', 'Var', (9, 18))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (136, 155))
367540	29942042	The GWAS Catalog is a comprehensive database that archives genome-wide association studies (GWAS) investigating associations between single-nucleotide polymorphisms (SNPs) and a variety of phenotypes, ranging from psychiatric disorders (e.g.	('psychiatric disorders', 'Phenotype', 'HP:0000708', (214, 235))	('psychiatric disorders', 'Disease', (214, 235))	('single-nucleotide polymorphisms', 'Var', (133, 164))	('psychiatric disorders', 'Disease', 'MESH:D001523', (214, 235))	('associations', 'Interaction', (112, 124))
367546	29942042	In doing this, we have identified SNPs that have been repeatedly reported in association with the same disorder and that should thus bear better confidence.	('SNPs', 'Var', (34, 38))	('disorder', 'Disease', (103, 111))	('disorder', 'Disease', 'MESH:D030342', (103, 111))
367554	29942042	Here, we identified SNPs that have been associated with the same (or very similar) reclassified disorders or traits in two or more studies.	('disorder', 'Disease', (96, 104))	('SNPs', 'Var', (20, 24))	('disorder', 'Disease', 'MESH:D030342', (96, 104))
367558	29942042	The SNPs rs2075650 and rs4420638 were linked to the most replications within a single reclassified phenotype.	('rs2075650', 'Var', (9, 18))	('rs4420638', 'Mutation', 'rs4420638', (23, 32))	('rs4420638', 'Var', (23, 32))	('rs2075650', 'Mutation', 'rs2075650', (9, 18))
367559	29942042	rs2075650 was reported in association with Alzheimer's disease in eight different studies and in association with cognitive decline in one study.	('rs2075650', 'Mutation', 'rs2075650', (0, 9))	('rs2075650', 'Var', (0, 9))	("Alzheimer's disease", 'Disease', (43, 62))	('cognitive decline', 'Disease', (114, 131))	('cognitive decline', 'Disease', 'MESH:D003072', (114, 131))	('association', 'Reg', (26, 37))	('cognitive decline', 'Phenotype', 'HP:0001268', (114, 131))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (43, 62))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (43, 62))
367560	29942042	rs4420638 was linked to Alzheimer's disease in six studies and cognitive decline in one study.	('cognitive decline', 'Disease', 'MESH:D003072', (63, 80))	('cognitive decline', 'Phenotype', 'HP:0001268', (63, 80))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (24, 43))	('rs4420638', 'Var', (0, 9))	('linked', 'Reg', (14, 20))	("Alzheimer's disease", 'Disease', (24, 43))	('rs4420638', 'Mutation', 'rs4420638', (0, 9))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (24, 43))	('cognitive decline', 'Disease', (63, 80))
367561	29942042	rs2075650 is located in an intron of the TOMM40 gene, a mitochondria membrane protein.	('rs2075650', 'Mutation', 'rs2075650', (0, 9))	('TOMM40', 'Gene', '10452', (41, 47))	('rs2075650', 'Var', (0, 9))	('TOMM40', 'Gene', (41, 47))
367566	29942042	One study posits that rs2075650's relationship with AD is more attributable to its modest linkage disequilibrium with rs429358.	('rs2075650', 'Mutation', 'rs2075650', (22, 31))	('rs429358', 'Mutation', 'rs429358', (118, 126))	('rs429358', 'Var', (118, 126))	('AD', 'Phenotype', 'HP:0002511', (52, 54))	('AD', 'Disease', 'MESH:D000544', (52, 54))	('AD', 'Disease', (52, 54))	('rs2075650', 'Var', (22, 31))
367567	29942042	rs429358 is on the fourth exon of APOE and, along with rs7412, determines the APOE haplotype, where the variant epsilon4 is the strongest risk factor for AD.	('APOE', 'Gene', '348', (34, 38))	('rs7412', 'Mutation', 'rs7412', (55, 61))	('rs429358', 'Var', (0, 8))	('risk factor', 'Reg', (138, 149))	('APOE', 'Gene', (78, 82))	('AD', 'Disease', 'MESH:D000544', (154, 156))	('variant epsilon4', 'Var', (104, 120))	('AD', 'Disease', (154, 156))	('APOE', 'Gene', '348', (78, 82))	('APOE', 'Gene', (34, 38))	('rs429358', 'Mutation', 'rs429358', (0, 8))	('AD', 'Phenotype', 'HP:0002511', (154, 156))	('epsilon4', 'Var', (112, 120))
367568	29942042	Similarly, another SNP, rs429358, was associated with AD in three studies (Supplementary Table 2a).	('associated', 'Reg', (38, 48))	('AD', 'Phenotype', 'HP:0002511', (54, 56))	('AD', 'Disease', 'MESH:D000544', (54, 56))	('rs429358', 'Var', (24, 32))	('AD', 'Disease', (54, 56))	('rs429358', 'Mutation', 'rs429358', (24, 32))
367569	29942042	The SNP rs4420638 is located downstream of the APOC1 gene.	('APOC1', 'Gene', '341', (47, 52))	('APOC1', 'Gene', (47, 52))	('rs4420638', 'Mutation', 'rs4420638', (8, 17))	('rs4420638', 'Var', (8, 17))
367570	29942042	rs4420638's association with AD could also be related to its linkage disequilibrium with rs429358 and so is likely also not an entirely independent risk locus.	('AD', 'Phenotype', 'HP:0002511', (29, 31))	('AD', 'Disease', (29, 31))	('rs4420638', 'Var', (0, 9))	('rs4420638', 'Mutation', 'rs4420638', (0, 9))	('rs429358', 'Mutation', 'rs429358', (89, 97))	('AD', 'Disease', 'MESH:D000544', (29, 31))
367571	29942042	rs4420638 is a brain eQTL SNP for non-APOE genes, according to BRAINEAC.	('APOE', 'Gene', (38, 42))	('rs4420638', 'Var', (0, 9))	('rs4420638', 'Mutation', 'rs4420638', (0, 9))	('APOE', 'Gene', '348', (38, 42))
367573	29942042	They were associated with the SNPs rs1154155 and rs1051730, respectively, each in four different studies.	('rs1154155', 'Mutation', 'rs1154155', (35, 44))	('associated', 'Reg', (10, 20))	('rs1051730', 'Mutation', 'rs1051730', (49, 58))	('rs1154155', 'Var', (35, 44))	('rs1051730', 'Var', (49, 58))
367574	29942042	Additionally, rs1154155 was identified in three studies in association with narcolepsy and in one study in association with narcolepsy with cataplexy.	('rs1154155', 'Mutation', 'rs1154155', (14, 23))	('narcolepsy', 'Phenotype', 'HP:0030050', (124, 134))	('narcolepsy', 'Disease', (76, 86))	('narcolepsy', 'Disease', (124, 134))	('rs1154155', 'Var', (14, 23))	('cataplexy', 'Phenotype', 'HP:0002524', (140, 149))	('narcolepsy', 'Disease', 'MESH:D009290', (76, 86))	('association', 'Reg', (59, 70))	('narcolepsy', 'Phenotype', 'HP:0030050', (76, 86))	('narcolepsy', 'Disease', 'MESH:D009290', (124, 134))
367575	29942042	rs1154155 is mapped to the downstream region of TRAJ10, a gene in the TRAJ (T cell receptor alpha joining) gene cluster.	('rs1154155', 'Mutation', 'rs1154155', (0, 9))	('rs1154155', 'Var', (0, 9))	('TRAJ10', 'Gene', (48, 54))	('TRAJ10', 'Gene', '28745', (48, 54))
367576	29942042	rs1154155 is an eQTL SNP for mir208a in white matter.	('mir208a', 'Var', (29, 36))	('rs1154155', 'Var', (0, 9))	('rs1154155', 'Mutation', 'rs1154155', (0, 9))
367577	29942042	rs1051730 is a coding synonymous variant in CHRNA3 but is also an eQTL SNP for CHRNA5 in brain.	('CHRNA5', 'Gene', (79, 85))	('rs1051730', 'Mutation', 'rs1051730', (0, 9))	('CHRNA3', 'Gene', (44, 50))	('rs1051730', 'Var', (0, 9))	('CHRNA5', 'Gene', '1138', (79, 85))	('CHRNA3', 'Gene', '1136', (44, 50))
367583	29942042	Of these, the SNP rs17693963 (associated with schizophrenia, bipolar disorder, or schizoaffective disorder) was the strongest brain eQTL and was associated with expression of the gene ZNF389 in white matter (p = 2.8x10-10), among other brain regions.	('associated', 'Reg', (30, 40))	('schizophrenia', 'Disease', (46, 59))	('SNP', 'Var', (14, 17))	('ZNF389', 'Gene', (184, 190))	('rs17693963', 'Var', (18, 28))	('schizophrenia', 'Disease', 'MESH:D012559', (46, 59))	('rs17693963', 'Mutation', 'rs17693963', (18, 28))	('schizophrenia', 'Phenotype', 'HP:0100753', (46, 59))	('associated', 'Reg', (145, 155))	('ZNF389', 'Gene', '651302', (184, 190))	('bipolar disorder', 'Disease', 'MESH:D001714', (61, 77))	('schizoaffective disorder', 'Disease', 'MESH:D011618', (82, 106))	('bipolar disorder', 'Phenotype', 'HP:0007302', (61, 77))	('schizoaffective disorder', 'Disease', (82, 106))	('bipolar disorder', 'Disease', (61, 77))
367584	29942042	GTEx data also reported rs17693963 as an eQTL SNP in many tissues (including brain) and as being associated with several genes.	('associated', 'Reg', (97, 107))	('rs17693963', 'Var', (24, 34))	('rs17693963', 'Mutation', 'rs17693963', (24, 34))
367585	29942042	The second strongest brain eQTL was rs950169 (associated with schizophrenia).	('rs950169', 'Var', (36, 44))	('rs950169', 'Mutation', 'rs950169', (36, 44))	('schizophrenia', 'Phenotype', 'HP:0100753', (62, 75))	('associated', 'Reg', (46, 56))	('schizophrenia', 'Disease', 'MESH:D012559', (62, 75))	('schizophrenia', 'Disease', (62, 75))
367592	29942042	rs1051730 was linked to smoking behavior and nicotine dependence (combined into "nicotine-related phenotypes"), post bronchodilator FEV1, post bronchodilator FEV1/FVC ratio, pre bronchodilator FEV1, pre bronchodilator FEV1/FVC ratio, and lung cancer; rs2036527 was related to smoking behavior, post bronchodilator FEV1, post bronchodilator FEV1/FVC ratio, pre bronchodilator FEV1, and pre bronchodilator FEV1/FVC ratio; rs34684276-A was associated with post bronchodilator FEV1, post bronchodilator FEV1/FVC ratio, and nicotine dependence; and rs56113850-T was associated with nicotine metabolite ratio in current smokers, local histogram emphysema pattern, post bronchodilator FEV1, and post bronchodilator FEV1/FVC ratio.	('emphysema', 'Disease', (639, 648))	('nicotine', 'Chemical', 'MESH:D009538', (577, 585))	('nicotine', 'Chemical', 'MESH:D009538', (519, 527))	('rs34684276', 'Mutation', 'rs34684276', (420, 430))	('rs1051730', 'Mutation', 'rs1051730', (0, 9))	('lung cancer', 'Disease', 'MESH:D008175', (238, 249))	('rs56113850-T', 'Var', (544, 556))	('rs34684276-A', 'Var', (420, 432))	('nicotine metabolite ratio', 'MPA', (577, 602))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('emphysema', 'Phenotype', 'HP:0002097', (639, 648))	('rs56113850', 'Mutation', 'rs56113850', (544, 554))	('nicotine', 'Chemical', 'MESH:D009538', (81, 89))	('associated', 'Reg', (561, 571))	('emphysema', 'Disease', 'MESH:D004646', (639, 648))	('rs2036527', 'Mutation', 'rs2036527', (251, 260))	('lung cancer', 'Disease', (238, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('nicotine', 'Chemical', 'MESH:D009538', (45, 53))
367594	29942042	Additionally, rs6265 was associated with both body mass index and smoking behavior.	('body mass index', 'Disease', (46, 61))	('associated', 'Reg', (25, 35))	('rs6265', 'Var', (14, 20))	('smoking behavior', 'Disease', (66, 82))	('rs6265', 'Mutation', 'rs6265', (14, 20))
367598	29942042	Two other studies, one on alcohol dependence and the other on the effects of alcohol and smoking on esophageal cancer risk, found evidence for rs1229984 as a risk SNP.	('rs1229984', 'Mutation', 'rs1229984', (143, 152))	('alcohol', 'Chemical', 'MESH:D000438', (26, 33))	('alcohol', 'Chemical', 'MESH:D000438', (77, 84))	('esophageal cancer', 'Disease', (100, 117))	('rs1229984', 'Var', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('alcohol dependence', 'Phenotype', 'HP:0030955', (26, 44))
367600	29942042	rs671 was associated with drinking behavior, coronary heart disease, alcohol consumption (maxi-drinks) and response to alcohol consumption (flushing) in small samples of Han Chinese participants, esophageal cancer, serum alpha1-antitrypsin levels, body mass index, mean corpuscular hemoglobin concentration, serum creatinine, and hematological and biochemical traits.	('rs671', 'Var', (0, 5))	('mean corpuscular hemoglobin concentration', 'Phenotype', 'HP:0025548', (265, 306))	('rs671', 'Mutation', 'rs671', (0, 5))	('associated', 'Reg', (10, 20))	('alcohol', 'Chemical', 'MESH:D000438', (119, 126))	('flushing', 'Phenotype', 'HP:0031284', (140, 148))	('alcohol consumption', 'Disease', (69, 88))	('coronary heart disease', 'Disease', (45, 67))	('coronary heart disease', 'Phenotype', 'HP:0001677', (45, 67))	('alpha1-antitrypsin', 'Gene', (221, 239))	('creatinine', 'Chemical', 'MESH:D003404', (314, 324))	('flushing', 'Disease', (140, 148))	('serum creatinine', 'MPA', (308, 324))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('alcohol', 'Chemical', 'MESH:D000438', (69, 76))	('mean corpuscular hemoglobin concentration', 'MPA', (265, 306))	('drinking behavior', 'Disease', (26, 43))	('coronary heart disease', 'Disease', 'MESH:D003324', (45, 67))	('alpha1-antitrypsin', 'Gene', '5265', (221, 239))	('participants', 'Species', '9606', (182, 194))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('flushing', 'Disease', 'MESH:D005483', (140, 148))	('esophageal cancer', 'Disease', (196, 213))
367601	29942042	A study assessing Han Chinese drinkers and nondrinkers identified rs11066280, a SNP also associated with blood pressure phenotypes, esophageal cancer, coronary heart disease, thoracic-to-hip circumference ratio, metabolite levels, and triglycerides, in other studies.	('blood', 'MPA', (105, 110))	('associated', 'Reg', (89, 99))	('triglycerides', 'MPA', (235, 248))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('rs11066280', 'Mutation', 'rs11066280', (66, 76))	('esophageal cancer', 'Disease', (132, 149))	('metabolite levels', 'MPA', (212, 229))	('triglycerides', 'Chemical', 'MESH:D014280', (235, 248))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('coronary heart disease', 'Disease', (151, 173))	('rs11066280', 'Var', (66, 76))	('coronary heart disease', 'Phenotype', 'HP:0001677', (151, 173))	('thoracic-to-hip circumference ratio', 'Disease', (175, 210))	('coronary heart disease', 'Disease', 'MESH:D003324', (151, 173))
367602	29942042	The SNP rs1800562 was associated with transferrin glycosylation, which is relevant to alcohol consumption, as well as with iron status biomarkers, hematological parameters, hepcidin levels, cardiovascular disease risk factors, cholesterol, hemoglobin, and red blood cell traits.	('hepcidin', 'Gene', '57817', (173, 181))	('SNP rs1800562', 'Var', (4, 17))	('iron', 'Chemical', 'MESH:D007501', (123, 127))	('cardiovascular disease', 'Disease', (190, 212))	('alcohol', 'Chemical', 'MESH:D000438', (86, 93))	('cholesterol', 'Chemical', 'MESH:D002784', (227, 238))	('transferrin', 'Gene', '7018', (38, 49))	('rs1800562', 'Mutation', 'rs1800562', (8, 17))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (190, 212))	('associated', 'Reg', (22, 32))	('hepcidin', 'Gene', (173, 181))	('cardiovascular disease', 'Disease', 'MESH:D002318', (190, 212))	('transferrin', 'Gene', (38, 49))
367603	29942042	rs12229654 was linked to body mass index, glycemic traits, HDL cholesterol, gamma glutamyl transpeptidase, and alcohol consumption.	('gamma glutamyl transpeptidase', 'Gene', '102724197', (76, 105))	('rs12229654', 'Var', (0, 10))	('gamma glutamyl transpeptidase', 'Gene', (76, 105))	('linked', 'Reg', (15, 21))	('glycemic', 'Disease', (42, 50))	('body mass index', 'Disease', (25, 40))	('alcohol consumption', 'Disease', (111, 130))	('rs12229654', 'Mutation', 'rs12229654', (0, 10))	('cholesterol', 'Chemical', 'MESH:D002784', (63, 74))	('HDL cholesterol', 'Disease', (59, 74))	('alcohol', 'Chemical', 'MESH:D000438', (111, 118))
367604	29942042	rs2074356 was linked to alcohol consumption, QT interval, gamma glutamyl transpeptidase, HDL cholesterol, esophageal cancer, glycemic traits, biomedical quantitative traits, and renal function-related traits (BUN), and rs3811647 was linked to hepcidin levels, iron status biomarkers, alcohol consumption (transferrin glycosylation), and hereditary hemochromatosis-related traits (HFE mutation homozygotes).	('rs2074356', 'Mutation', 'rs2074356', (0, 9))	('alcohol', 'Chemical', 'MESH:D000438', (24, 31))	('hereditary hemochromatosis', 'Disease', 'MESH:D006432', (337, 363))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('rs3811647', 'Var', (219, 228))	('alcohol', 'Chemical', 'MESH:D000438', (284, 291))	('rs3811647', 'Mutation', 'rs3811647', (219, 228))	('hereditary hemochromatosis', 'Disease', (337, 363))	('rs2074356', 'Var', (0, 9))	('esophageal cancer', 'Disease', (106, 123))	('hepcidin', 'Gene', (243, 251))	('HFE', 'Gene', '3077', (380, 383))	('iron', 'Chemical', 'MESH:D007501', (260, 264))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gamma glutamyl transpeptidase', 'Gene', (58, 87))	('transferrin', 'Gene', (305, 316))	('cholesterol', 'Chemical', 'MESH:D002784', (93, 104))	('hepcidin', 'Gene', '57817', (243, 251))	('linked', 'Reg', (14, 20))	('HFE', 'Gene', (380, 383))	('transferrin', 'Gene', '7018', (305, 316))	('gamma glutamyl transpeptidase', 'Gene', '102724197', (58, 87))	('linked', 'Reg', (233, 239))
367607	29942042	rs10761741-T has been identified as a SNP risk allele for vascular endothelial growth factor levels and years of education.	('vascular endothelial growth factor', 'Gene', (58, 92))	('vascular endothelial growth factor', 'Gene', '7422', (58, 92))	('rs10761741', 'Mutation', 'rs10761741', (0, 10))	('rs10761741-T', 'Var', (0, 12))
367608	29942042	In the case of the former, the T allele at this locus seemed to indicate greater epinephrine-induced platelet aggregation and higher circulating VEGF levels.	('epinephrine', 'Chemical', 'MESH:D004837', (81, 92))	('VEGF', 'Gene', (145, 149))	('greater', 'PosReg', (73, 80))	('higher', 'PosReg', (126, 132))	('T allele', 'Var', (31, 39))	('platelet aggregation', 'Disease', (101, 121))	('platelet aggregation', 'Disease', 'MESH:D001791', (101, 121))	('platelet aggregation', 'Phenotype', 'HP:0003540', (101, 121))	('VEGF', 'Gene', '7422', (145, 149))	('epinephrine-induced platelet aggregation', 'Phenotype', 'HP:0008148', (81, 121))
367610	29942042	rs2456973 was associated with vitiligo, a skin disorder, and educational attainment.	('vitiligo', 'Gene', (30, 38))	('rs2456973', 'Var', (0, 9))	('associated', 'Reg', (14, 24))	('skin disorder', 'Disease', (42, 55))	('vitiligo', 'Gene', '246319', (30, 38))	('skin disorder', 'Disease', 'MESH:D012871', (42, 55))	('vitiligo', 'Phenotype', 'HP:0001045', (30, 38))	('skin disorder', 'Phenotype', 'HP:0000951', (42, 55))	('rs2456973', 'Mutation', 'rs2456973', (0, 9))
367611	29942042	One meta-analysis reported rs12193446-A as the strongest SNP risk allele for refractive error x education interaction.	('refractive error', 'Phenotype', 'HP:0000545', (77, 93))	('rs12193446-A', 'Var', (27, 39))	('refractive error', 'Disease', (77, 93))	('rs12193446', 'Mutation', 'rs12193446', (27, 37))
367612	29942042	Another study also revealed rs12193446-A as the SNP allele most strongly determining ocular axial length.	('ocular axial length', 'CPA', (85, 104))	('determining', 'Reg', (73, 84))	('ocular axial length', 'Phenotype', 'HP:0007800', (85, 104))	('rs12193446', 'Mutation', 'rs12193446', (28, 38))	('rs12193446-A', 'Var', (28, 40))
367613	29942042	The SNP rs12553324 was found to be associated with level of educational attainment and, in a separate study, was also identified as an area of interest for bipolar disorder.	('SNP', 'Var', (4, 7))	('bipolar disorder', 'Disease', 'MESH:D001714', (156, 172))	('bipolar disorder', 'Phenotype', 'HP:0007302', (156, 172))	('associated', 'Reg', (35, 45))	('bipolar disorder', 'Disease', (156, 172))	('rs12553324', 'Mutation', 'rs12553324', (8, 18))
367623	29942042	In particular, rs13107325-T was linked to schizophrenia, as well as to body mass index, HDL cholesterol, blood pressure, and N-terminal pro b-type natriuretic peptide in acute coronary syndrome.	('rs13107325-T', 'Var', (15, 27))	('N-terminal pro b-type natriuretic peptide', 'MPA', (125, 166))	('blood pressure', 'Disease', (105, 119))	('schizophrenia', 'Phenotype', 'HP:0100753', (42, 55))	('cholesterol', 'Chemical', 'MESH:D002784', (92, 103))	('HDL cholesterol', 'MPA', (88, 103))	('coronary syndrome', 'Disease', (176, 193))	('coronary syndrome', 'Phenotype', 'HP:0001677', (176, 193))	('coronary syndrome', 'Disease', 'MESH:D003324', (176, 193))	('linked', 'Reg', (32, 38))	('schizophrenia', 'Disease', 'MESH:D012559', (42, 55))	('schizophrenia', 'Disease', (42, 55))	('rs13107325', 'Mutation', 'rs13107325', (15, 25))
367625	29942042	rs8042374 was associated with schizophrenia and lung cancer, a finding that is not incredibly surprising given the high rates of smoking in schizophrenics.	('schizophrenia and lung cancer', 'Disease', 'MESH:D008175', (30, 59))	('rs8042374', 'Var', (0, 9))	('associated', 'Reg', (14, 24))	('rs8042374', 'Mutation', 'rs8042374', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('schizophrenia', 'Phenotype', 'HP:0100753', (30, 43))
367631	29942042	For example, the SNP rs1006737 in the CACNA1C gene was linked to schizophrenia, with a p of 2 x 10-8, but with bipolar disorder at p = 7 x 10-8.	('CACNA1C', 'Gene', '775', (38, 45))	('bipolar disorder', 'Disease', 'MESH:D001714', (111, 127))	('bipolar disorder', 'Phenotype', 'HP:0007302', (111, 127))	('linked', 'Reg', (55, 61))	('CACNA1C', 'Gene', (38, 45))	('bipolar disorder', 'Disease', (111, 127))	('rs1006737', 'Mutation', 'rs1006737', (21, 30))	('SNP rs1006737', 'Var', (17, 30))	('schizophrenia', 'Disease', 'MESH:D012559', (65, 78))	('schizophrenia', 'Disease', (65, 78))	('schizophrenia', 'Phenotype', 'HP:0100753', (65, 78))
367638	29942042	For example, rs1051730 was mapped to smoking and some related physical conditions, including lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('rs1051730', 'Mutation', 'rs1051730', (13, 22))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('rs1051730', 'Var', (13, 22))
367689	29082268	Some Se-based compounds such as methaneselenol/methylselenol induce caspase-mediated apoptosis in p53 mutant cancer cells.	('mutant', 'Var', (102, 108))	('induce', 'PosReg', (61, 67))	('Se', 'Chemical', 'MESH:D012643', (5, 7))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('methaneselenol', 'Chemical', 'MESH:C019003', (32, 46))	('methylselenol', 'Chemical', 'MESH:C019003', (47, 60))	('cancer', 'Disease', (109, 115))	('p53', 'Gene', (98, 101))	('caspase-mediated apoptosis', 'CPA', (68, 94))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('p53', 'Gene', '7157', (98, 101))
367708	29082268	Studies have shown that the risk of EC from alcohol consumption depends on the average daily intake and not the duration of the habit, thus binge drinking increases EC risk.	('increases', 'PosReg', (155, 164))	('binge drinking', 'Phenotype', 'HP:0100739', (140, 154))	('binge drinking', 'Var', (140, 154))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))
367719	29082268	Inside the squamous epithelial cells, ethanol metabolism causes oxidative damage to DNA, proteins, and lipids due to the production of reactive oxygen species, and affects fatty acid metabolism.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (135, 158))	('fatty acid', 'Chemical', 'MESH:D005227', (172, 182))	('ethanol', 'Chemical', 'MESH:D000431', (38, 45))	('DNA', 'MPA', (84, 87))	('lipids', 'Chemical', 'MESH:D008055', (103, 109))	('ethanol metabolism', 'Var', (38, 56))	('affects', 'Reg', (164, 171))	('fatty acid metabolism', 'MPA', (172, 193))	('production of reactive oxygen species', 'MPA', (121, 158))	('proteins', 'Protein', (89, 97))	('oxidative damage', 'MPA', (64, 80))
367722	29082268	These adducts interfere with DNA repair mechanism, leading to errors in replication and/or mutations in oncogenes and tumor suppressor genes, ultimately leading to cancer.	('errors', 'Var', (62, 68))	('oncogenes', 'Gene', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('leading to', 'Reg', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cancer', 'Disease', (164, 170))	('mutations', 'Var', (91, 100))	('interfere', 'NegReg', (14, 23))	('tumor', 'Disease', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('leading to', 'Reg', (51, 61))
367724	29082268	In addition to intracellular acetaldehyde, acetaldehyde from extracellular sources is also carcinogenic and may contribute to EC development.	('carcinogenic', 'Disease', (91, 103))	('acetaldehyde', 'Chemical', 'MESH:D000079', (29, 41))	('acetaldehyde', 'Chemical', 'MESH:D000079', (43, 55))	('contribute', 'Reg', (112, 122))	('acetaldehyde', 'Var', (43, 55))	('men', 'Species', '9606', (136, 139))	('carcinogenic', 'Disease', 'MESH:D063646', (91, 103))
367749	29082268	TOC results from mutations in RHBDF2 which impacts N-terminal loop domain of iRHOM proteins, iRHOM1 and iRHOM2.	('iRHOM', 'Protein', (77, 82))	('iRHOM2', 'Gene', (104, 110))	('RHBDF2', 'Gene', (30, 36))	('iRHOM2', 'Gene', '79651', (104, 110))	('impacts', 'Reg', (43, 50))	('iRHOM1', 'Gene', (93, 99))	('iRHOM1', 'Gene', '64285', (93, 99))	('RHBDF2', 'Gene', '79651', (30, 36))	('mutations', 'Var', (17, 26))	('N-terminal loop domain', 'MPA', (51, 73))
367752	29082268	In most high-incidence EC regions, P53 is mutated in ~90% of EC patients.	('patients', 'Species', '9606', (64, 72))	('mutated', 'Var', (42, 49))	('P53', 'Gene', '7157', (35, 38))	('P53', 'Gene', (35, 38))
367822	27895815	Like all human malignancies they are characterized by accumulation of mutations which lead to inactivation of tumor suppressor genes or activation of oncogenes.	('malignancies', 'Disease', (15, 27))	('mutations', 'Var', (70, 79))	('inactivation', 'MPA', (94, 106))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('human', 'Species', '9606', (9, 14))	('oncogenes', 'Gene', (150, 159))	('activation', 'PosReg', (136, 146))	('malignancies', 'Disease', 'MESH:D009369', (15, 27))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
367844	27895815	TP53 mutations are identified in about 50% of esophageal cancers and are associated with poorer survival.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('esophageal cancers', 'Disease', (46, 64))	('esophageal cancers', 'Disease', 'MESH:D004938', (46, 64))
367846	27895815	Inactivating mutations of NOTCH1 are identified in about 20% of ESCCs but not in EACs.	('EAC', 'Phenotype', 'HP:0011459', (81, 84))	('NOTCH1', 'Gene', '4851', (26, 32))	('NOTCH1', 'Gene', (26, 32))	('ESCCs', 'Disease', (64, 69))	('Inactivating mutations', 'Var', (0, 22))
367848	27895815	A number of genes that can be used as predictive markers for targeted therapy have been explored for somatic mutations in esophageal adenocarcinoma, including genes of the RAF/MEK/ERK (MAPK) kinase pathway such as EGFR, BRAF, KRAS, PIK3CA.	('KRAS', 'Gene', '3845', (226, 230))	('PIK3CA', 'Gene', '5290', (232, 238))	('ERK', 'Gene', (180, 183))	('EGFR', 'Gene', '1956', (214, 218))	('KRAS', 'Gene', (226, 230))	('MAPK', 'Gene', (185, 189))	('RAF', 'Gene', '22882', (221, 224))	('BRAF', 'Gene', '673', (220, 224))	('BRAF', 'Gene', (220, 224))	('PIK3CA', 'Gene', (232, 238))	('RAF', 'Gene', '22882', (172, 175))	('MAPK', 'Gene', '5594', (185, 189))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (122, 147))	('RAF', 'Gene', (221, 224))	('mutations', 'Var', (109, 118))	('EGFR', 'Gene', (214, 218))	('MEK', 'Gene', '5609', (176, 179))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (122, 147))	('ERK', 'Gene', '5594', (180, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('RAF', 'Gene', (172, 175))	('esophageal adenocarcinoma', 'Disease', (122, 147))	('MEK', 'Gene', (176, 179))
367855	27895815	Thus the trastuzumab-platinum regimen is currently used for the 15% of the EACs patients that test positive for HER2 (ERBB2) amplification or overexpression.	('overexpression', 'PosReg', (142, 156))	('ERBB2', 'Gene', (118, 123))	('amplification', 'Var', (125, 138))	('patients', 'Species', '9606', (80, 88))	('HER2', 'Gene', (112, 116))	('HER2', 'Gene', '2064', (112, 116))	('platinum', 'Chemical', 'MESH:D010984', (21, 29))	('trastuzumab', 'Chemical', 'MESH:D000068878', (9, 20))	('ERBB2', 'Gene', '2064', (118, 123))	('EAC', 'Phenotype', 'HP:0011459', (75, 78))
367864	27895815	Genetic and epigenetic alterations play important role in GCs therefore, targeted therapy based on the biology of the individual patient could improve treatment outcome.	('GCs', 'Disease', (58, 61))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('epigenetic alterations', 'Var', (12, 34))	('Genetic', 'Var', (0, 7))	('patient', 'Species', '9606', (129, 136))
367865	27895815	ERBB2 amplifications occur frequently in gastric tumors (2%-27%).	('gastric tumors', 'Phenotype', 'HP:0006753', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('ERBB2', 'Gene', '2064', (0, 5))	('amplifications', 'Var', (6, 20))	('gastric tumors', 'Disease', 'MESH:D013274', (41, 55))	('ERBB2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('gastric tumors', 'Disease', (41, 55))
367867	27895815	Several molecular targeted agents associated with a survival benefit in other cancer types are now under clinical investigation for the treatment of gastric cancer, including inhibitors of EGFR, MET, FGFR, VEGF, and PI3K.	('gastric cancer', 'Disease', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('EGFR', 'Gene', '1956', (189, 193))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('VEGF', 'Gene', '7422', (206, 210))	('EGFR', 'Gene', (189, 193))	('MET', 'Gene', (195, 198))	('cancer', 'Disease', (78, 84))	('inhibitors', 'Var', (175, 185))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('FGFR', 'Gene', (200, 204))	('VEGF', 'Gene', (206, 210))
367868	27895815	Additionally, CDH1 gene mutations at the somatic level are considered of prognostic significance.	('mutations', 'Var', (24, 33))	('CDH1', 'Gene', (14, 18))	('CDH1', 'Gene', '999', (14, 18))
367870	27895815	The presence of somatic mutations and copy number variations (CNV) in many cancer driver genes has been revealed.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('copy number variations', 'Var', (38, 60))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
367879	27895815	Additionally, in 5%-10% of the cases without cKIT mutations, the TK receptor PDGFRA is mutated.	('cKIT', 'Gene', (45, 49))	('mutated', 'Var', (87, 94))	('cKIT', 'Gene', '3815', (45, 49))	('PDGFRA', 'Gene', '5156', (77, 83))	('PDGFRA', 'Gene', (77, 83))
367882	27895815	Patients with mutations in exon 11 of the cKIT are highly responsive to imatinib, while the presence of a mutation in exon 9 of this gene implies intermediate response rates and necessitates a double dose of drug administration.	('responsive to imatinib', 'MPA', (58, 80))	('imatinib', 'Chemical', 'MESH:D000068877', (72, 80))	('cKIT', 'Gene', (42, 46))	('Patients', 'Species', '9606', (0, 8))	('cKIT', 'Gene', '3815', (42, 46))	('mutations in exon 11', 'Var', (14, 34))
367888	27895815	Genetic alterations in colorectal cancer include mainly single-base substitutions (SBS).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('colorectal cancer', 'Disease', (23, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (23, 40))	('SBS', 'Disease', (83, 86))	('single-base substitutions', 'Var', (56, 81))	('SBS', 'Disease', 'MESH:C536611', (83, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (23, 40))
367900	27895815	However, anti-EGFR treatment is not effective in patients harboring activating mutations in genes that participate in the intracellular transduction RAS/RAF/MEK/ERK pathway.	('EGFR', 'Gene', '1956', (14, 18))	('MEK', 'Gene', (157, 160))	('EGFR', 'Gene', (14, 18))	('MEK', 'Gene', '5609', (157, 160))	('ERK', 'Gene', (161, 164))	('ERK', 'Gene', '5594', (161, 164))	('RAF', 'Gene', '22882', (153, 156))	('patients', 'Species', '9606', (49, 57))	('RAF', 'Gene', (153, 156))	('mutations', 'Var', (79, 88))
367901	27895815	In total, activating mutations in the RAS genes, mainly in codons 12, 13 or 61, occur in approximately 20% of all human cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('activating', 'PosReg', (10, 20))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('RAS genes', 'Gene', (38, 47))	('mutations', 'Var', (21, 30))
367902	27895815	Mutations in KRAS account for about 85% of all RAS mutations in human tumors, NRAS for about 15%, and HRAS for less than 1%.	('HRAS', 'Gene', (102, 106))	('human', 'Species', '9606', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutations', 'Var', (51, 60))	('KRAS', 'Gene', '3845', (13, 17))	('NRAS', 'Gene', (78, 82))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('HRAS', 'Gene', '3265', (102, 106))	('NRAS', 'Gene', '4893', (78, 82))	('KRAS', 'Gene', (13, 17))	('RAS', 'Gene', (47, 50))
367903	27895815	Which particular RAS gene is mutated seems to be tumor specific.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('RAS gene', 'Gene', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutated', 'Var', (29, 36))
367904	27895815	Colonic, pancreatic and lung cancers have high frequencies of KRAS mutations.	('KRAS', 'Gene', (62, 66))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('KRAS', 'Gene', '3845', (62, 66))	('pancreatic and lung cancers', 'Disease', 'MESH:D010190', (9, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mutations', 'Var', (67, 76))	('lung cancers', 'Phenotype', 'HP:0100526', (24, 36))	('Colonic', 'Disease', (0, 7))
367905	27895815	Acquired mutations in KRAS and NRAS are commonly used to identify colorectal cancer patients who are unlikely to benefit from anti-EGFR therapy.	('patients', 'Species', '9606', (84, 92))	('mutations', 'Var', (9, 18))	('NRAS', 'Gene', '4893', (31, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('KRAS', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('KRAS', 'Gene', '3845', (22, 26))	('NRAS', 'Gene', (31, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
367906	27895815	Approximately 40% of colorectal cancer tumors harbor mutations in the KRAS gene, with the majority of the mutations occurring in codons 12, 13 and 61.	('colorectal cancer tumors', 'Disease', (21, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (21, 38))	('KRAS', 'Gene', (70, 74))	('colorectal cancer tumors', 'Disease', 'MESH:D015179', (21, 45))	('KRAS', 'Gene', '3845', (70, 74))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
367907	27895815	In 5% of the colorectal cancer cases a mutation occurs in the NRAS gene.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('NRAS', 'Gene', '4893', (62, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('colorectal cancer', 'Disease', (13, 30))	('mutation occurs', 'Var', (39, 54))	('NRAS', 'Gene', (62, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
367909	27895815	Mutations in the BRAF gene (exons 11 and 15) have been detected in about 12% of colorectal cancers and are mutually exclusive with RAS mutations.	('detected', 'Reg', (55, 63))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('BRAF', 'Gene', '673', (17, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('colorectal cancers', 'Disease', 'MESH:D015179', (80, 98))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancers', 'Disease', (80, 98))
367910	27895815	The BRAF activating aberrations, result in constitutive BRAF kinase activity, ERK signaling, proliferation and transformation.	('aberrations', 'Var', (20, 31))	('transformation', 'CPA', (111, 125))	('BRAF', 'Gene', '673', (56, 60))	('proliferation', 'CPA', (93, 106))	('ERK', 'Gene', '5594', (78, 81))	('activating', 'PosReg', (9, 19))	('ERK', 'Gene', (78, 81))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (56, 60))
367911	27895815	The majority of BRAF mutations are observed in exon 15 (codon 600) and a minority of mutations are observed in exon 11.	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('mutations', 'Var', (21, 30))
367912	27895815	Several studies have reported that patients with metastatic CRC (mCRC) that harbor BRAF mutations do not respond to the anti-EGFR antibody agents cetuximab or panitumumab.	('metastatic CRC', 'Disease', (49, 63))	('cetuximab', 'Chemical', 'MESH:D000068818', (146, 155))	('EGFR', 'Gene', '1956', (125, 129))	('mutations', 'Var', (88, 97))	('not', 'NegReg', (101, 104))	('EGFR', 'Gene', (125, 129))	('respond', 'MPA', (105, 112))	('BRAF', 'Gene', '673', (83, 87))	('patients', 'Species', '9606', (35, 43))	('panitumumab', 'Chemical', 'MESH:D000077544', (159, 170))	('BRAF', 'Gene', (83, 87))
367913	27895815	However it is unclear if the presence of BRAF mutations in CRC cancer can be used as a predictive marker or if it has only a prognostic value, independent of treatment, since different studies arrive at controversial conclusions concerning its clinical significance.	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('BRAF', 'Gene', '673', (41, 45))	('BRAF', 'Gene', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('CRC', 'Disease', (59, 62))	('cancer', 'Disease', (63, 69))
367915	27895815	Mutations in PIK3CA stimulate downstream AKT-mTOR signaling pathways, thereby promoting growth-factor independent growth, cell invasion and metastasis.	('growth-factor independent growth', 'CPA', (88, 120))	('PIK3CA', 'Gene', (13, 19))	('stimulate', 'PosReg', (20, 29))	('PIK3CA', 'Gene', '5290', (13, 19))	('promoting', 'PosReg', (78, 87))	('Mutations', 'Var', (0, 9))	('metastasis', 'CPA', (140, 150))	('AKT', 'Gene', '207', (41, 44))	('mTOR', 'Gene', '2475', (45, 49))	('cell invasion', 'CPA', (122, 135))	('AKT', 'Gene', (41, 44))	('mTOR', 'Gene', (45, 49))
367916	27895815	PIK3CA mutations have been reported in multiple malignancies, including approximately 25% of gastric, 4% of lung, 25% of breast, and 20% of colorectal cancers.	('reported', 'Reg', (27, 35))	('breast', 'Disease', (121, 127))	('colorectal cancers', 'Disease', 'MESH:D015179', (140, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung', 'Disease', (108, 112))	('colorectal cancers', 'Disease', (140, 158))	('PIK3CA', 'Gene', (0, 6))	('malignancies', 'Disease', 'MESH:D009369', (48, 60))	('gastric', 'Disease', (93, 100))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('malignancies', 'Disease', (48, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('mutations', 'Var', (7, 16))
367917	27895815	The majority (80%) of PIK3CA mutations cluster in 2 "hotspot" regions, the helical domain (exon 9) and the kinase domain (exon 20).	('PIK3CA', 'Gene', '5290', (22, 28))	('cluster', 'Reg', (39, 46))	('PIK3CA', 'Gene', (22, 28))	('mutations', 'Var', (29, 38))
367918	27895815	Concomitant PIK3CA mutations in exons 9 and 20 seem to be linked to significantly worse cancer-specific survival.	('PIK3CA', 'Gene', '5290', (12, 18))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('worse', 'NegReg', (82, 87))	('PIK3CA', 'Gene', (12, 18))
367919	27895815	PIK3CA mutations may also be associated with clinical resistance to EGFR-targeted monoclonal antibodies, but there have been conflicting results.	('PIK3CA', 'Gene', (0, 6))	('EGFR', 'Gene', '1956', (68, 72))	('PIK3CA', 'Gene', '5290', (0, 6))	('associated', 'Reg', (29, 39))	('EGFR', 'Gene', (68, 72))	('mutations', 'Var', (7, 16))
367920	27895815	A meta-analysis comprising 864 patients, from 11 studies, with colorectal cancer treated with cetuximab or panitumumab-based therapy showed that PIK3CA mutations, particularly in exon 20, are significantly associated with worse response and shorter progression-free and overall survival.	('PIK3CA', 'Gene', '5290', (145, 151))	('shorter', 'NegReg', (241, 248))	('mutations', 'Var', (152, 161))	('cetuximab', 'Chemical', 'MESH:D000068818', (94, 103))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('colorectal cancer', 'Disease', (63, 80))	('patients', 'Species', '9606', (31, 39))	('PIK3CA', 'Gene', (145, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('worse', 'NegReg', (222, 227))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('panitumumab', 'Chemical', 'MESH:D000077544', (107, 118))
367921	27895815	Somatic PIK3CA mutations have also been associated with superior colorectal cancer-specific survival in patients who regularly intake aspirin after diagnosis.	('aspirin', 'Chemical', 'MESH:D001241', (134, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('PIK3CA', 'Gene', '5290', (8, 14))	('mutations', 'Var', (15, 24))	('colorectal cancer', 'Disease', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PIK3CA', 'Gene', (8, 14))	('patients', 'Species', '9606', (104, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))	('superior', 'PosReg', (56, 64))
367922	27895815	PIK3CA activating mutations may also predict sensitivity to inhibitors of the PI3K-AKT-mTOR pathway.	('AKT', 'Gene', '207', (83, 86))	('mTOR', 'Gene', (87, 91))	('mTOR', 'Gene', '2475', (87, 91))	('activating', 'PosReg', (7, 17))	('sensitivity', 'MPA', (45, 56))	('AKT', 'Gene', (83, 86))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('predict', 'Reg', (37, 44))	('mutations', 'Var', (18, 27))
367924	27895815	A number of rare gene mutations occurring in the PI3K/AKT/mTOR pathway are potentially actionable in colorectal cancer.	('mTOR', 'Gene', (58, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('AKT', 'Gene', '207', (54, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('mutations', 'Var', (22, 31))	('AKT', 'Gene', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('actionable', 'Reg', (87, 97))	('mTOR', 'Gene', '2475', (58, 62))
367926	27895815	PTEN gene mutations occur in about 5% of colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('occur', 'Reg', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('colorectal cancers', 'Disease', 'MESH:D015179', (41, 59))	('colorectal cancers', 'Disease', (41, 59))	('mutations', 'Var', (10, 19))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
367927	27895815	PTEN inactivating mutations and PTEN loss have as a consequence the upregulation of the PI3K/ AKT pathway.	('AKT', 'Gene', '207', (94, 97))	('PTEN', 'Gene', (32, 36))	('AKT', 'Gene', (94, 97))	('PTEN', 'Gene', '5728', (32, 36))	('upregulation', 'PosReg', (68, 80))	('loss', 'NegReg', (37, 41))	('PTEN', 'Gene', (0, 4))	('inactivating mutations', 'Var', (5, 27))	('PTEN', 'Gene', '5728', (0, 4))
367928	27895815	Currently, the prognostic and predictive significance of PTEN mutations or PTEN loss of expression is under investigation.	('loss of expression', 'NegReg', (80, 98))	('PTEN', 'Gene', (57, 61))	('PTEN', 'Gene', (75, 79))	('PTEN', 'Gene', '5728', (57, 61))	('PTEN', 'Gene', '5728', (75, 79))	('mutations', 'Var', (62, 71))
367934	27895815	The only mutation observed is the activating mutation E17K, which is also observed in other types of cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('E17K', 'Mutation', 'rs121434592', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('E17K', 'Var', (54, 58))
367936	27895815	AKT1 E17K mutations have also been associated with primary resistance to cetuximab.	('AKT1', 'Gene', '207', (0, 4))	('cetuximab', 'Chemical', 'MESH:D000068818', (73, 82))	('AKT1', 'Gene', (0, 4))	('associated', 'Reg', (35, 45))	('primary resistance to cetuximab', 'MPA', (51, 82))	('E17K', 'Mutation', 'rs121434592', (5, 9))	('E17K', 'Var', (5, 9))
367939	27895815	Sporadic MSI-H tumors can be distinguished from the hereditary ones through somatic mutation analysis of the BRAF gene or loss of MLH1 expression.	('mutation analysis', 'Var', (84, 101))	('MLH1', 'Gene', '4292', (130, 134))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('MLH1', 'Gene', (130, 134))	('Sporadic MSI-H tumors', 'Disease', 'MESH:D009369', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Sporadic MSI-H tumors', 'Disease', (0, 21))	('expression', 'MPA', (135, 145))	('loss', 'NegReg', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
367941	27895815	Similarly, hMLH1 promoter methylation rarely occurs in Lynch syndrome-associated cancers, while is common in sporadic MSI-high cancers.	('methylation', 'Var', (26, 37))	('Lynch syndrome-associated cancers', 'Disease', 'MESH:D055847', (55, 88))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('hMLH1', 'Gene', (11, 16))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('MSI-high cancers', 'Disease', (118, 134))	('MSI-high cancers', 'Disease', 'MESH:D009369', (118, 134))	('hMLH1', 'Gene', '4292', (11, 16))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('Lynch syndrome-associated cancers', 'Disease', (55, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
367951	27895815	In a retrospectively performed study by Yothers et al, RS was the strongest predictor of disease recurrence independent of other factors, such as T-stage, mismatch repair status, number of nodes examined, tumor grade, and lymphovascular invasion.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mismatch repair status', 'Var', (155, 177))	('lymphovascular invasion', 'CPA', (222, 245))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('disease', 'Disease', (89, 96))
367974	27895815	The goal of their use is to increase the percentage of patients with detected actionable alterations and with copy number data, allowing them to be included in clinical trials.	('patients', 'Species', '9606', (55, 63))	('alterations', 'Var', (89, 100))	('copy number data', 'Var', (110, 126))	('increase', 'PosReg', (28, 36))
368103	26157293	NAPOLI-1 study was a Phase III trial that randomized patients with metastatic pancreatic cancer who had progressed on gemcitabine-based chemotherapy to receive either 5-FU/LV alone or in combination with MM-398, nanoliposomal encapsulation of irinotecan with significant improvement in survival observed in the combination arm.	('5-FU', 'Chemical', 'MESH:D005472', (167, 171))	('survival', 'MPA', (286, 294))	('nanoliposomal encapsulation', 'Var', (212, 239))	('patients', 'Species', '9606', (53, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('irinotecan', 'Chemical', 'MESH:D000077146', (243, 253))	('MM-398', 'Chemical', 'MESH:C584112', (204, 210))	('gemcitabine', 'Chemical', 'MESH:C056507', (118, 129))	('LV', 'Chemical', 'MESH:D002955', (172, 174))	('pancreatic cancer', 'Disease', (78, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('improvement', 'PosReg', (271, 282))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
368111	26157293	The investigators observed similar median PFS among patients who received onartuzumab and those who received placebo (6.77 months vs. 6.97 months).	('PFS', 'MPA', (42, 45))	('onartuzumab', 'Chemical', 'MESH:C584058', (74, 85))	('onartuzumab', 'Var', (74, 85))	('patients', 'Species', '9606', (52, 60))
368112	26157293	In the subgroup of patients whose tumors were MET positive PFS was 5.95 months among those receiving onartuzumab and 6.8 months among those who received placebo.	('onartuzumab', 'Var', (101, 112))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('patients', 'Species', '9606', (19, 27))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('onartuzumab', 'Chemical', 'MESH:C584058', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
368114	26157293	presented the results of the Phase I study of the use of AMG 337 (an oral MET kinase inhibitor) among patients with MET-amplified gastroesophageal, gastric or esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('gastroesophageal', 'Disease', (130, 146))	('patients', 'Species', '9606', (102, 110))	('MET-amplified', 'Var', (116, 129))	('gastric or esophageal cancers', 'Disease', (148, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('AMG', 'Gene', (57, 60))	('gastric or esophageal cancers', 'Disease', 'MESH:D013274', (148, 177))
368154	24456340	All of the patients received endoscopic examinations with NBI and ME which has powerful 80 times optical magnification (EVIS LUCERA CLV-260NBI, GIF-H260Z endoscopy, Olympus Medical Systems Corp, Tokyo, Japan), and chromoendoscopy with Lugol's solution (Sigma-Aldrich, St. Louis, Missouri, USA).	('Missouri', 'Disease', (279, 287))	('ME', 'Chemical', '-', (66, 68))	("Lugol's solution", 'Chemical', 'MESH:C010389', (235, 251))	('H260Z', 'SUBSTITUTION', 'None', (148, 153))	('H260Z', 'Var', (148, 153))	('patients', 'Species', '9606', (11, 19))
368196	24456340	In this study, we have found that drinking alcohol, lower BMI, and advanced stages of the index H&N cancer were associated with a higher risk for synchronous esophageal neoplasia, and the endoscopy examination by the NBI system with ME may be the best screening modality available.	('lower BMI', 'Phenotype', 'HP:0045082', (52, 61))	('alcohol', 'Chemical', 'MESH:D000438', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('H&N cancer', 'Disease', 'MESH:D009369', (96, 106))	('lower BMI', 'Var', (52, 61))	('synchronous esophageal neoplasia', 'Disease', (146, 178))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (158, 178))	('H&N cancer', 'Disease', (96, 106))	('neoplasia', 'Phenotype', 'HP:0002664', (169, 178))	('synchronous esophageal neoplasia', 'Disease', 'MESH:D009378', (146, 178))	('ME', 'Chemical', '-', (233, 235))
368254	32583000	Furthermore, the knockdown of MCM6 inhibited cell proliferation, migration and invasion and promoted cell apoptosis, and made cells arrested in S stage.	('cell apoptosis', 'CPA', (101, 115))	('migration', 'CPA', (65, 74))	('promoted', 'PosReg', (92, 100))	('cell proliferation', 'CPA', (45, 63))	('MCM6', 'Gene', (30, 34))	('inhibited', 'NegReg', (35, 44))	('knockdown', 'Var', (17, 26))	('invasion', 'CPA', (79, 87))	('MCM6', 'Gene', '4175', (30, 34))
368255	32583000	In particular, the aberrantly elevated expression of MCM6 is a potential biomarker for ESCC diagnosis and treatment.	('MCM6', 'Gene', (53, 57))	('MCM6', 'Gene', '4175', (53, 57))	('aberrantly', 'Var', (19, 29))	('elevated', 'PosReg', (30, 38))	('ESCC', 'Disease', (87, 91))	('expression', 'MPA', (39, 49))
368268	32583000	In total, 4 microarray datasets (GSE63941, GSE26886, GSE17351 and GSE77861), which were related to ESCC based on the platform of GPL570 Affymetrix Human Genome U133 Plus 2.0 Array, were extracted from the GEO database .	('GSE17351', 'Var', (53, 61))	('GSE77861', 'Var', (66, 74))	('Human', 'Species', '9606', (147, 152))	('ESCC', 'Disease', (99, 103))	('GSE26886', 'Var', (43, 51))	('GSE63941', 'Var', (33, 41))
368335	32583000	Additionally, the association between the MCM6 expression status and ESCC clinicopathological features was explored, and statistical analysis revealed that the positive staining ratio of MCM6 was significantly associated with lymphatic metastasis and infiltration depth (Table I).	('MCM6', 'Gene', '4175', (42, 46))	('associated with', 'Reg', (210, 225))	('MCM6', 'Gene', '4175', (187, 191))	('infiltration depth', 'CPA', (251, 269))	('MCM6', 'Gene', (187, 191))	('MCM6', 'Gene', (42, 46))	('lymphatic metastasis', 'CPA', (226, 246))	('positive staining ratio', 'Var', (160, 183))
368345	32583000	The results confirmed that cells were arrested in the S stage following siMCM6 transfection, which indicated that the knockdown of MCM6 inhibited DNA reduplication activity, thereby inhibiting cell proliferation (Fig.	('knockdown', 'Var', (118, 127))	('MCM6', 'Gene', (74, 78))	('MCM6', 'Gene', '4175', (131, 135))	('inhibited', 'NegReg', (136, 145))	('inhibiting', 'NegReg', (182, 192))	('DNA reduplication activity', 'MPA', (146, 172))	('MCM6', 'Gene', '4175', (74, 78))	('cell proliferation', 'CPA', (193, 211))	('MCM6', 'Gene', (131, 135))
368347	32583000	The results revealed that the knockdown of MCM6 promoted the apoptosis of ESCC cells (Fig.	('apoptosis', 'CPA', (61, 70))	('MCM6', 'Gene', (43, 47))	('ESCC', 'Disease', (74, 78))	('MCM6', 'Gene', '4175', (43, 47))	('knockdown', 'Var', (30, 39))	('promoted', 'PosReg', (48, 56))
368348	32583000	The wound-healing assay revealed that the negative control cells exhibited a more rapid wound closure rate than the knockdown group, suggesting that the migratory ability was significantly suppressed after MCM6 was silenced (Fig.	('MCM6', 'Gene', (206, 210))	('silenced', 'Var', (215, 223))	('suppressed', 'NegReg', (189, 199))	('MCM6', 'Gene', '4175', (206, 210))	('migratory ability', 'CPA', (153, 170))
368349	32583000	7D) cells in the bottom chamber evidently decreased compared to the negative control group following the knockdown of MCM6.	('MCM6', 'Gene', (118, 122))	('decreased', 'NegReg', (42, 51))	('MCM6', 'Gene', '4175', (118, 122))	('knockdown', 'Var', (105, 114))
368350	32583000	These results suggested that the knockdown of MCM6 significantly inhibited ESCC cell migration and invasion.	('MCM6', 'Gene', (46, 50))	('knockdown', 'Var', (33, 42))	('MCM6', 'Gene', '4175', (46, 50))	('invasion', 'CPA', (99, 107))	('inhibited', 'NegReg', (65, 74))
368360	32583000	Firstly, in order to further validate aberrant MCM6 expression in EC using bioinformatics tools, Oncomine, UALCAN and GEPIA were also utilized to examine the expression level of MCM6.	('Oncomine', 'Chemical', '-', (97, 105))	('MCM6', 'Gene', '4175', (178, 182))	('MCM6', 'Gene', (47, 51))	('aberrant', 'Var', (38, 46))	('MCM6', 'Gene', '4175', (47, 51))	('MCM6', 'Gene', (178, 182))
368370	32583000	The results indicated that the knockdown of MCM6 inhibited the cell proliferative, migratory and invasive ability, and promoted cell apoptosis; the cell cycle assay also revealed that the cells were arrested at the S stage.	('MCM6', 'Gene', (44, 48))	('promoted', 'PosReg', (119, 127))	('cell proliferative', 'CPA', (63, 81))	('MCM6', 'Gene', '4175', (44, 48))	('knockdown', 'Var', (31, 40))	('inhibited', 'NegReg', (49, 58))	('cell apoptosis', 'CPA', (128, 142))
368381	31881010	Strikingly, a wide range of core clock genes are epigenetically altered in lung adenocarcinomas and lung squamous cell carcinomas but not esophageal carcinomas.	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (75, 95))	('esophageal carcinomas', 'Disease', (138, 159))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (100, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('epigenetically altered', 'Var', (49, 71))	('lung squamous cell carcinomas', 'Disease', (100, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (105, 129))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (100, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (75, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('clock', 'Gene', '9575', (33, 38))	('lung adenocarcinomas', 'Disease', (75, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (138, 158))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (138, 159))	('clock', 'Gene', (33, 38))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (138, 159))
368395	31881010	Another study highlighted the lethal effects of the pharmacological activation of NRD1/2.	('NRD1/2', 'Gene', '4898', (82, 88))	('pharmacological activation', 'Var', (52, 78))	('NRD1/2', 'Gene', (82, 88))
368398	31881010	reported that mice knocking out Cry1 and Cry2 unexpectedly displayed the autoimmune phenotype of higher serum IgG levels and antinuclear antibodies.	('antinuclear antibodies', 'MPA', (125, 147))	('higher serum IgG levels', 'Phenotype', 'HP:0003237', (97, 120))	('higher', 'PosReg', (97, 103))	('Cry2', 'Gene', (41, 45))	('IgG', 'Gene', '16059', (110, 113))	('mice', 'Species', '10090', (14, 18))	('Cry1', 'Gene', '12952', (32, 36))	('knocking out', 'Var', (19, 31))	('Cry2', 'Gene', '12953', (41, 45))	('antinuclear antibodies', 'Phenotype', 'HP:0003493', (125, 147))	('IgG', 'Gene', (110, 113))	('Cry1', 'Gene', (32, 36))
368399	31881010	Interestingly, another independent group found that loss of BMAL1, which is another key component of circadian clock, induced T cell-associated CNS autoimmune diseases.	('BMAL1', 'Gene', '406', (60, 65))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (148, 167))	('loss', 'Var', (52, 56))	('BMAL1', 'Gene', (60, 65))	('autoimmune diseases', 'Disease', 'MESH:D001327', (148, 167))	('clock', 'Gene', (111, 116))	('clock', 'Gene', '9575', (111, 116))	('autoimmune diseases', 'Disease', (148, 167))	('induced', 'Reg', (118, 125))
368411	31881010	As for LUAD and LUSC, over a half of core circadian clock genes was differently methylated between tumors and controls (Figure 1).	('LUAD', 'Phenotype', 'HP:0030078', (7, 11))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('LUAD', 'Disease', (7, 11))	('LUAD', 'Disease', 'MESH:C538231', (7, 11))	('differently', 'Reg', (68, 79))	('clock', 'Gene', '9575', (52, 57))	('clock', 'Gene', (52, 57))	('methylated', 'Var', (80, 90))	('LUSC', 'Disease', 'MESH:D002294', (16, 20))	('LUSC', 'Disease', (16, 20))	('LUSC', 'Phenotype', 'HP:0030359', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
368413	31881010	We also found that methylation downregulated almost all the circadian clock gene expressions in thoracic cancers (Figure 1).	('methylation', 'Var', (19, 30))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('clock', 'Gene', (70, 75))	('circadian', 'MPA', (60, 69))	('downregulated', 'NegReg', (31, 44))	('thoracic cancers', 'Disease', (96, 112))	('clock', 'Gene', '9575', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('thoracic cancers', 'Disease', 'MESH:D009369', (96, 112))
368414	31881010	These data supports that core circadian clock genes are epigenetically altered in thoracic cancers.	('clock', 'Gene', '9575', (40, 45))	('clock', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('thoracic cancers', 'Disease', 'MESH:D009369', (82, 98))	('thoracic cancers', 'Disease', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('epigenetically altered', 'Var', (56, 78))
368418	31881010	In other words, disruption of circadian clock may trigger the dysfunction of cell cycle, thus inducing the tumor growth, which was in accordance with another independent group's publication.	('trigger', 'Reg', (50, 57))	('clock', 'Gene', (40, 45))	('clock', 'Gene', '9575', (40, 45))	('tumor', 'Disease', (107, 112))	('disruption', 'Var', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('inducing', 'Reg', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cell cycle', 'CPA', (77, 87))
368425	31881010	Previous evidence has shown that disruption of circadian clock could accelerate tumorigenesis and circadian genes were closely correlated with prognosis.	('disruption', 'Var', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('clock', 'Gene', '9575', (57, 62))	('clock', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('accelerate', 'PosReg', (69, 79))
368452	31881010	Our results showed that a high fraction of clock molecules are epigenetically and transcriptionally down-regulated in LUAD and LUSC samples.	('clock', 'Gene', '9575', (43, 48))	('clock', 'Gene', (43, 48))	('down-regulated', 'NegReg', (100, 114))	('LUAD', 'Disease', (118, 122))	('LUAD', 'Disease', 'MESH:C538231', (118, 122))	('LUSC', 'Disease', 'MESH:D002294', (127, 131))	('transcriptionally', 'MPA', (82, 99))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('epigenetically', 'Var', (63, 77))	('LUSC', 'Phenotype', 'HP:0030359', (127, 131))	('LUSC', 'Disease', (127, 131))
368466	31881010	We collected the Illumina human methylation, single nucleotide variation, and mRNA normalized RPKM values from LUAD, LUSC, and ESCA patients (n = 576, 533, and 196, respectively).	('ESCA', 'Disease', (127, 131))	('LUSC', 'Disease', 'MESH:D002294', (117, 121))	('LUSC', 'Phenotype', 'HP:0030359', (117, 121))	('single nucleotide variation', 'Var', (45, 72))	('LUSC', 'Disease', (117, 121))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('LUAD', 'Disease', (111, 115))	('ESCA', 'Disease', 'MESH:D004938', (127, 131))	('LUAD', 'Disease', 'MESH:C538231', (111, 115))	('ESCA', 'Phenotype', 'HP:0011459', (127, 131))	('patients', 'Species', '9606', (132, 140))	('human', 'Species', '9606', (26, 31))
368611	29865163	However, one study reported a statistically significant association between high exercise levels and a low risk of recurrence and all-cause mortality of colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('significant association', 'Reg', (44, 67))	('rectal cancer', 'Phenotype', 'HP:0100743', (157, 170))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('high exercise levels', 'Phenotype', 'HP:0003546', (76, 96))	('high', 'Var', (76, 80))	('colorectal cancer', 'Disease', (153, 170))
368624	29865163	Ongoing studies are being designed and conducted to test the hypothesis that exercise is safe and improves treatment response, quality of life, and survival in patients, and reduces toxicities for various malignant diseases including those in the digestive system.	('men', 'Species', '9606', (112, 115))	('patients', 'Species', '9606', (160, 168))	('survival', 'CPA', (148, 156))	('malignant diseases', 'Disease', (205, 223))	('improves', 'PosReg', (98, 106))	('toxicities', 'Disease', 'MESH:D064420', (182, 192))	('quality of life', 'CPA', (127, 142))	('treatment response', 'CPA', (107, 125))	('toxicities', 'Disease', (182, 192))	('exercise', 'Var', (77, 85))	('malignant diseases', 'Disease', 'MESH:D009369', (205, 223))	('reduces', 'NegReg', (174, 181))
368715	29865163	In a phase II clinical study of 246 patients, PEGylated hyaluronidase (PEGPH20), that degrades hyaluronan in the tumor-associated stroma, in combination with nab-paclitaxel and gemcitabine, significantly prolonged progression-free survival (PFS) and overall survival (OS), as compared to nab-paclitaxel and gemcitabine.	('tumor', 'Disease', (113, 118))	('paclitaxel', 'Chemical', 'MESH:D017239', (292, 302))	('nab', 'Chemical', '-', (288, 291))	('paclitaxel', 'Chemical', 'MESH:D017239', (162, 172))	('patients', 'Species', '9606', (36, 44))	('nab', 'Chemical', '-', (158, 161))	('overall survival', 'CPA', (250, 266))	('gemcitabine', 'Chemical', 'MESH:C056507', (307, 318))	('PEGylated', 'Var', (46, 55))	('prolonged', 'PosReg', (204, 213))	('gemcitabine', 'Chemical', 'MESH:C056507', (177, 188))	('hyaluronan', 'Chemical', 'MESH:D006820', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('progression-free survival', 'CPA', (214, 239))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('degrades', 'NegReg', (86, 94))	('hyaluronan', 'MPA', (95, 105))
368716	29865163	Moreover, this study suggested that hyaluronic acid is a potential predictive biomarker of tumor response to PEGPH20.	('PEGPH20', 'Var', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('hyaluronic', 'MPA', (36, 46))	('PEGPH20', 'Chemical', '-', (109, 116))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (36, 51))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
368746	29865163	Technological advances in the next generation sequencing of human genomes have improved genetic testing for the screening of various malignant diseases, particularly cancers of the digestive system.	('cancers', 'Disease', (166, 173))	('genetic', 'Var', (88, 95))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('improved', 'PosReg', (79, 87))	('malignant diseases', 'Disease', 'MESH:D009369', (133, 151))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('malignant diseases', 'Disease', (133, 151))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('human', 'Species', '9606', (60, 65))
368758	29865163	Potential risks and limitations, though, include the higher likelihood of identifying one or more variants of uncertain significance and the likelihood that a mutation may be identified in a gene for which our knowledge base is still evolving with regards to the spectrum of associated cancers, the estimated lifetime risks of these cancers, as well as appropriate management guidelines.	('cancers', 'Phenotype', 'HP:0002664', (286, 293))	('cancers', 'Disease', (286, 293))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('cancers', 'Phenotype', 'HP:0002664', (333, 340))	('cancers', 'Disease', (333, 340))	('mutation', 'Var', (159, 167))	('cancers', 'Disease', 'MESH:D009369', (333, 340))	('men', 'Species', '9606', (371, 374))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('cancers', 'Disease', 'MESH:D009369', (286, 293))
368759	29865163	In addition, unexpected findings may be identified such as a gene mutation that is not consistent with the family history of cancer or a mutation in a recessive gene that has reproductive implications.	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (137, 145))
368763	29865163	Patients with germline mutations that predispose to various malignant diseases will likely benefit from screening tests for early detection of tumors and taking appropriate measures for preventive and therapeutic interventions.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('malignant diseases', 'Disease', 'MESH:D009369', (60, 78))	('malignant diseases', 'Disease', (60, 78))	('Patients', 'Species', '9606', (0, 8))	('germline mutations', 'Var', (14, 32))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
368894	22197937	The majority of cases are caused by mutations in the PKHD1 gene, which encodes for fibrocystin/polycystin.	('fibrocystin', 'Gene', (83, 94))	('fibrocystin', 'Gene', '5314', (83, 94))	('caused by', 'Reg', (26, 35))	('mutations', 'Var', (36, 45))	('PKHD1', 'Gene', '5314', (53, 58))	('PKHD1', 'Gene', (53, 58))
369082	21123005	Mean dose-volume parameters for all four plans (50.4-Gy 2D-CRT, 50.4-Gy IMRT, 64.8-Gy 2D-CRT, and 64.8-Gy SIB-IMRT) for 10 patients are listed in the Table.	('50.4-Gy IMRT', 'Var', (64, 76))	('50.4-Gy 2D-CRT', 'Var', (48, 62))	('patients', 'Species', '9606', (123, 131))
369084	21123005	Both the mean lung dose and the lung V20 were significantly lower with IMRT, from 9.9 Gy to 7.4 Gy (a 25% reduction, p = 0.003) and from 19% to 13% (p = 0.007).	('IMRT', 'Var', (71, 75))	('lung', 'MPA', (14, 18))	('to 7', 'Species', '1214577', (89, 93))	('lower', 'NegReg', (60, 65))
369222	32197486	Using a cutoff value of >2 CTCs to be considered as CTC positive, patients with CTCs showed significantly shorter relapse-free (p = 0.020) and overall survival (p = 0.015) (Figure 3).	('shorter', 'NegReg', (106, 113))	('CTCs', 'Var', (80, 84))	('relapse-free', 'CPA', (114, 126))	('overall survival', 'CPA', (143, 159))	('patients', 'Species', '9606', (66, 74))
369310	31921290	As can be seen, the AUCs of PMFMDA, CMFMDA, IMCMDA, NCPMDA, RLSMDA, and RWRMDA are 0.9187, 0.8928, 0.8372, 0.8792, 0.8333, and 0.8168, respectively.	('0.8928', 'Var', (91, 97))	('0.8372', 'Var', (99, 105))	('0.8792', 'Var', (107, 113))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('0.8333', 'Var', (115, 121))
369314	31921290	As shown in  Figure 3 , the AUPRs of PMFMDA, CMFMDA, IMCMDA, NCPMDA, RLSMDA, and RWRMDA are 0.3535, 0.3428, 0.2509, 0.1176, 0.1234, and 0.1369 respectively, indicating that PMFMDA performed best in predicting miRNAs-disease associations.	('0.1176', 'Var', (116, 122))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('miRNAs-disease associations', 'Disease', (209, 236))	('N', 'Chemical', 'MESH:D009584', (61, 62))
369367	31921290	11171369, 61272395, 61370171, 61300128, 61472127, 61572178, 61672214, and 61772192), and the Natural Science Foundation of Hunan, China (Grant Nos.	('61772192', 'Var', (74, 82))	('61672214', 'Var', (60, 68))	('61472127', 'Var', (40, 48))	('61300128', 'Var', (30, 38))	('61572178', 'Var', (50, 58))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('61370171', 'Var', (20, 28))
369450	31579708	It can dynamically observe tumor vessel perfusion with superior diagnostic performance for residual tumors after transarterial chemoembolization (TACE) compared to CE-CT (sensitivity and accuracy of detecting residual tumor with CE-US 95.6 % and 96.2 % versus CE-CT 76.2 % and 77.7 %, respectively)  .	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('CE-US', 'Var', (229, 234))
369452	31579708	If cytohistopathological results are inconclusive, KRAS mutation can be analyzed as it provides high diagnostic yield in EUS-guided histopathological evaluation  .	('mutation', 'Var', (56, 64))	('KRAS', 'Gene', '3845', (51, 55))	('KRAS', 'Gene', (51, 55))
369470	31579708	Patients with peri-ECV and perforator veins      and/or with large para-ECV       are more likely to experience variceal recurrence and rebleeding.	('variceal recurrence', 'Disease', (112, 131))	('Patients', 'Species', '9606', (0, 8))	('peri-ECV', 'Var', (14, 22))	('rebleeding', 'CPA', (136, 146))
369510	31139019	mRNA expression datasets of GSE29001, GSE20347, GSE100942, and GSE38129, containing 63 pairs of ESCC and non-tumor tissues data, were integrated and deeply analyzed.	('GSE20347', 'Var', (38, 46))	('non-tumor', 'Disease', 'MESH:D009369', (105, 114))	('GSE100942', 'Var', (48, 57))	('GSE38129', 'Var', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('non-tumor', 'Disease', (105, 114))
369513	31139019	The functional enrichment of DEGs in ESCC were mainly correlated with cell cycle, DNA replication, deleted in colorectal cancer (DCC) mediated attractive signaling pathway, and Netrin-1 signaling pathway.	('deleted in colorectal cancer', 'Gene', '1630', (99, 127))	('Netrin-1', 'Gene', (177, 185))	('ESCC', 'Disease', (37, 41))	('DEGs', 'Var', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('attractive signaling pathway', 'Pathway', (143, 171))	('cell cycle', 'CPA', (70, 80))	('DCC', 'Gene', (129, 132))	('DCC', 'Gene', '1630', (129, 132))	('correlated', 'Reg', (54, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('Netrin-1', 'Gene', '9423', (177, 185))	('deleted in colorectal cancer', 'Gene', (99, 127))	('DNA replication', 'CPA', (82, 97))
369526	31139019	In the study, four mRNA expression profiles were downloaded (GSE29001, GSE20347, GSE100942, and GSE38129) from GEO database, from which there are 63 pairs of ESCC and non-tumor tissues data available.	('non-tumor', 'Disease', 'MESH:D009369', (167, 176))	('GSE100942', 'Var', (81, 90))	('GSE29001', 'Var', (61, 69))	('GSE38129', 'Var', (96, 104))	('non-tumor', 'Disease', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('GSE20347', 'Var', (71, 79))
369537	31139019	PPI network is crucial for molecular processes, and abnormal PPI is the basis of many diseases, including tumors.	('basis', 'Reg', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('PPI', 'Gene', (61, 64))	('abnormal', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
369550	31139019	The data were in keeping with the knowledge that abnormality of cell cycle and cell growth regulators was the major cause of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cause', 'Reg', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('abnormality', 'Var', (49, 60))
369558	31139019	Here, we found that the downregulated DEGs were involved in two nervous system-related pathways (DCC mediated signaling pathway and Netrin-1 signaling pathway).	('DCC', 'Gene', (97, 100))	('downregulated', 'NegReg', (24, 37))	('DCC', 'Gene', '1630', (97, 100))	('Netrin-1', 'Gene', '9423', (132, 140))	('involved', 'Reg', (48, 56))	('DEGs', 'Var', (38, 42))	('Netrin-1', 'Gene', (132, 140))
369562	31139019	For example, AURKA and TPX2 belong to the "Role of Ran in mitotic spindle regulation" pathway, and TPX2 knockdown could inhibit the cell proliferation of ESCC cells.	('Ran', 'Gene', '5901', (51, 54))	('AURKA', 'Gene', (13, 18))	('TPX2', 'Gene', (23, 27))	('TPX2', 'Gene', (99, 103))	('ESCC', 'Disease', (154, 158))	('inhibit', 'NegReg', (120, 127))	('TPX2', 'Gene', '22974', (23, 27))	('Ran', 'Gene', (51, 54))	('cell proliferation of', 'CPA', (132, 153))	('TPX2', 'Gene', '22974', (99, 103))	('AURKA', 'Gene', '6790', (13, 18))	('knockdown', 'Var', (104, 113))	('mitotic spindle regulation" pathway', 'Pathway', (58, 93))
369582	31139019	NDC80 and BUB1 were changed most often (6% and 5%), these include amplification, mutation and so on.	('amplification', 'Var', (66, 79))	('BUB1', 'Gene', (10, 14))	('mutation', 'Var', (81, 89))	('BUB1', 'Gene', '699', (10, 14))	('NDC80', 'Gene', (0, 5))	('changed', 'Reg', (20, 27))
369584	31139019	Real-Time PCR results revealed that the mRNA expressions of the 9 hub genes (except for CCNA2) were upregulated in EC109 cells (ESCC cell line) as compared to Het-1A cells (esophageal squamous epithelial cell line) (Additional file 1: Figure S5).	('CCNA2', 'Gene', '890', (88, 93))	('Het-1A', 'CellLine', 'CVCL:3702', (159, 165))	('EC109', 'CellLine', 'CVCL:6898', (115, 120))	('hub', 'Gene', '1993', (66, 69))	('mRNA expressions', 'MPA', (40, 56))	('esophageal squamous epithelial', 'Disease', (173, 203))	('upregulated', 'PosReg', (100, 111))	('CCNA2', 'Gene', (88, 93))	('esophageal squamous epithelial', 'Disease', 'MESH:D000077277', (173, 203))	('EC109', 'Var', (115, 120))	('hub', 'Gene', (66, 69))
369591	31139019	miR-543, miR-495-3p, and miR-590-3p were the top three miRNAs with the most target genes.	('miR-495-3p', 'Var', (9, 19))	('miR-590-3p', 'Var', (25, 35))	('miR-543', 'Gene', '100126335', (0, 7))	('miR-543', 'Gene', (0, 7))
369613	31139019	miRNA-hub gene network revealed the importance of epigenetic regulation in ESCC.	('epigenetic regulation', 'Var', (50, 71))	('hub', 'Gene', (6, 9))	('ESCC', 'Disease', (75, 79))	('hub', 'Gene', '1993', (6, 9))
369622	31139019	Dysregulated expression of collagen family members was the foundation of cancer invasion and migration.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('expression', 'MPA', (13, 23))	('migration', 'CPA', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Dysregulated', 'Var', (0, 12))
369623	31139019	Many studies have demonstrated that the ectopic expression of the above genes could be the cause of cancer development, resulting in genetic mutations, epigenetic alterations, and activation of oncogenic signaling pathways or processes (such as EMT, extracellular matrix (ECM) remodeling, VEGFR3 signaling pathway, and Wnt signaling pathway, etc.).	('cause', 'Reg', (91, 96))	('mutations', 'Var', (141, 150))	('Wnt signaling pathway', 'Pathway', (319, 340))	('ectopic expression', 'Var', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('epigenetic', 'CPA', (152, 162))	('EMT', 'Gene', (245, 248))	('VEGFR3', 'Gene', (289, 295))	('oncogenic signaling pathways', 'Pathway', (194, 222))	('EMT', 'Gene', '3702', (245, 248))	('extracellular', 'CPA', (250, 263))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('processes', 'CPA', (226, 235))	('activation', 'PosReg', (180, 190))	('VEGFR3', 'Gene', '2324', (289, 295))
369628	31139019	ErbB1 was overexpressed and mutated in several tumors, including breast cancer.	('overexpressed', 'PosReg', (10, 23))	('tumors', 'Disease', (47, 53))	('mutated', 'Var', (28, 35))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('ErbB1', 'Gene', '1956', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ErbB1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
369630	31139019	have found that ErbB inhibitors could inhibit cell migration of ESCC cells through distinct signaling pathways (ERK1/2, Akt, STAT3, and RhoA), suggesting the powerful clues for developing ErbB targeted therapies.	('RhoA', 'Gene', '387', (136, 140))	('STAT3', 'Gene', (125, 130))	('ErbB', 'Gene', (16, 20))	('ErbB', 'Gene', '1956', (188, 192))	('ERK1/2', 'Gene', '5595;5594', (112, 118))	('ErbB', 'Gene', '1956', (16, 20))	('Akt', 'Gene', '207', (120, 123))	('ErbB', 'Gene', (188, 192))	('inhibitors', 'Var', (21, 31))	('cell migration', 'CPA', (46, 60))	('ERK1/2', 'Gene', (112, 118))	('RhoA', 'Gene', (136, 140))	('signaling pathways', 'Pathway', (92, 110))	('inhibit', 'NegReg', (38, 45))	('Akt', 'Gene', (120, 123))	('STAT3', 'Gene', '6774', (125, 130))
369693	30917608	Typical risk factors for these oral epithelial cancers can be subdivided into three groups: chronic irritants of the aerodigestive tract (e.g., tobacco and alcoholic beverages), genetic syndromes caused by genomic instability and DNA repair defects, and human papillomavirus infections leading to cell cycle alterations.	('genetic syndromes', 'Disease', (178, 195))	('genetic syndromes', 'Disease', 'MESH:D030342', (178, 195))	('oral epithelial cancers', 'Disease', (31, 54))	('leading to', 'Reg', (286, 296))	('oral epithelial cancers', 'Disease', 'MESH:D009062', (31, 54))	('human', 'Species', '9606', (254, 259))	('papillomavirus infections', 'Phenotype', 'HP:0012740', (260, 285))	('papilloma', 'Phenotype', 'HP:0012740', (260, 269))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('alcohol', 'Chemical', 'MESH:D000438', (156, 163))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('papillomavirus infections', 'Disease', (260, 285))	('cell cycle alterations', 'CPA', (297, 319))	('caused', 'Reg', (196, 202))	('papillomavirus infections', 'Disease', 'MESH:D030361', (260, 285))	('cell cycle alterations', 'Phenotype', 'HP:0011018', (297, 319))	('tobacco', 'Species', '4097', (144, 151))	('rat', 'Species', '10116', (312, 315))	('defects', 'Var', (241, 248))
369694	30917608	Patients with a history of tobacco consumption have more gene mutations associated with tumor growth than non-tobacco users, especially when combined with the abuse of alcohol.	('abuse of alcohol', 'Phenotype', 'HP:0030955', (159, 175))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tobacco', 'Species', '4097', (27, 34))	('alcohol', 'Chemical', 'MESH:D000438', (168, 175))	('Patients', 'Species', '9606', (0, 8))	('gene mutations', 'Var', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tobacco', 'Species', '4097', (110, 117))	('tumor', 'Disease', (88, 93))
369699	30917608	Normal epithelial cells might develop into cancerous cells as a consequence of specific genetic alterations, gene deletions/amplifications or epigenetic modifications.	('gene deletions/amplifications', 'Var', (109, 138))	('cancerous', 'Disease', (43, 52))	('epithelia', 'Disease', 'None', (7, 16))	('genetic alterations', 'Var', (88, 107))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('epigenetic modifications', 'Var', (142, 166))	('epithelia', 'Disease', (7, 16))	('rat', 'Species', '10116', (100, 103))	('cancerous', 'Disease', 'MESH:D009369', (43, 52))
369701	30917608	It is required for cell fate decisions at multiple stages of embryonic development as well as in the adult organism, while dysregulation of the pathway is associated with genetic and acquired diseases, including cancer.	('associated', 'Reg', (155, 165))	('dysregulation', 'Var', (123, 136))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
369702	30917608	In mammals, four Notch receptors have been described (Notch1, Notch2, Notch3, and Notch4) and five ligands: two of the Jagged family (Jagged 1 and Jagged2) and three members of the Delta-like family (Dll1, Dll3, Dll4).	('Jagged 1', 'Gene', '182', (134, 142))	('Dll3', 'Gene', '10683', (206, 210))	('Notch4', 'Gene', '4855', (82, 88))	('Dll3', 'Gene', (206, 210))	('Notch3', 'Gene', '4854', (70, 76))	('Notch2', 'Gene', (62, 68))	('Notch4', 'Gene', (82, 88))	('Notch1', 'Var', (54, 60))	('Notch3', 'Gene', (70, 76))	('Dll4', 'Gene', (212, 216))	('Jagged 1', 'Gene', (134, 142))	('Dll4', 'Gene', '54567', (212, 216))	('Notch2', 'Gene', '4853', (62, 68))	('Dll1', 'Gene', (200, 204))	('Dll1', 'Gene', '28514', (200, 204))
369706	30917608	Upon S3 cleavage, the NICD binds to importin alpha3, alpha4, or alpha7 with its nuclear localizing sequence (NLS).	('binds', 'Interaction', (27, 32))	('S3 cleavage', 'Var', (5, 16))	('importin alpha3', 'Gene', (36, 51))	('importin alpha3', 'Gene', '3839', (36, 51))	('alpha4', 'Protein', (53, 59))	('alpha7', 'Protein', (64, 70))
369709	30917608	Recently, noncanonical activation of Notch has been associated with tumorigenic events in various cancers (breast cancer tumor progression, leukemia and hematopoietic proliferation, neuroblastoma models).	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rat', 'Species', '10116', (174, 177))	('cancers', 'Disease', (98, 105))	('breast cancer tumor', 'Disease', 'MESH:D001943', (107, 126))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (107, 126))	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('neuroblastoma', 'Disease', (182, 195))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('neuroblastoma', 'Phenotype', 'HP:0003006', (182, 195))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('associated', 'Reg', (52, 62))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('hematopoietic proliferation', 'Disease', (153, 180))	('neuroblastoma', 'Disease', 'MESH:D009447', (182, 195))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('noncanonical activation', 'Var', (10, 33))	('breast cancer tumor', 'Disease', (107, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('leukemia', 'Disease', (140, 148))	('leukemia', 'Disease', 'MESH:D007938', (140, 148))	('Notch', 'Gene', (37, 42))
369725	30917608	Mutations in the Notch pathway lead to a variety of disorders and malformations.	('malformations', 'Disease', 'MESH:D000014', (66, 79))	('malformations', 'Disease', (66, 79))	('lead to', 'Reg', (31, 38))	('Mutations', 'Var', (0, 9))	('Notch pathway', 'Pathway', (17, 30))
369727	30917608	The interaction Notch-Jagged has been directly associated with misregulated fusion, and mutant mouse models for Jagged2 develop palate clefting.	('palate clefting', 'Phenotype', 'HP:0000175', (128, 143))	('Notch-Jagged', 'Gene', (16, 28))	('develop', 'Reg', (120, 127))	('palate clefting', 'Disease', (128, 143))	('mutant', 'Var', (88, 94))	('Jagged2', 'Gene', (112, 119))	('palate clefting', 'Disease', 'MESH:D002972', (128, 143))	('mouse', 'Species', '10090', (95, 100))
369729	30917608	Based on genetic screenings, most cases are thought to be caused by mutations in the Jagged1 and Notch2 genes.	('Notch2', 'Gene', '4853', (97, 103))	('Jagged1', 'Gene', (85, 92))	('mutations', 'Var', (68, 77))	('Notch2', 'Gene', (97, 103))	('caused by', 'Reg', (58, 67))	('Jagged1', 'Gene', '182', (85, 92))
369732	30917608	During vasculature establishment and maintenance, the altered expression of Notch3 and Notch4 receptors results in arteriovenous malformation.	('Notch4', 'Gene', (87, 93))	('arteriovenous malformation', 'Phenotype', 'HP:0100026', (115, 141))	('arteriovenous malformation', 'Disease', 'MESH:D001165', (115, 141))	('Notch3', 'Gene', '4854', (76, 82))	('arteriovenous malformation', 'Disease', (115, 141))	('Notch3', 'Gene', (76, 82))	('altered expression', 'Var', (54, 72))	('Notch4', 'Gene', '4855', (87, 93))	('expression', 'Var', (62, 72))	('results in', 'Reg', (104, 114))
369739	30917608	Loss of Notch1 promotes a tumor-inducing effect, impairing barrier integrity and generating a wound-like environment in the underlying stroma.	('impairing', 'NegReg', (49, 58))	('wound-like environment', 'MPA', (94, 116))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Notch1', 'Gene', (8, 14))	('rat', 'Species', '10116', (85, 88))	('barrier', 'MPA', (59, 66))	('generating', 'Reg', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('Loss', 'Var', (0, 4))
369742	30917608	Inactivating mutations of Notch1 can be found in approximately 10% of all cases of squamous cell carcinoma including the oral cavity, indicating that Notch1 is one of the most mutated gene in squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (192, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('squamous cell carcinoma', 'Disease', (83, 106))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 106))	('Inactivating mutations', 'Var', (0, 22))	('found', 'Reg', (40, 45))	('Notch1', 'Gene', (26, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('carcinoma including the oral cavity', 'Phenotype', 'HP:0100649', (97, 132))	('squamous cell carcinoma', 'Disease', (192, 215))
369765	30917608	Macrophages found in the tumor microenvironment participate in the regulation of vasculature remodeling, and strongly express Notch1, Notch2, and Notch4, together with VEGFR1 (Figure 3).	('Notch4', 'Gene', (146, 152))	('participate', 'Reg', (48, 59))	('VEGFR1', 'Gene', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('Notch2', 'Gene', (134, 140))	('tumor', 'Disease', (25, 30))	('vasculature remodeling', 'MPA', (81, 103))	('Notch1', 'Var', (126, 132))	('Notch2', 'Gene', '4853', (134, 140))	('Notch4', 'Gene', '4855', (146, 152))	('VEGFR1', 'Gene', '2321', (168, 174))
369767	30917608	In lung cancer, VEGF directly affects expression of Dll4 in tumor vessels, as well as in neuroblastoma models, where blocking VEGFR2 increases the level of Jagged1 expression and consequent Notch1 hyperactivation.	('Notch1', 'MPA', (190, 196))	('affects', 'Reg', (30, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('neuroblastoma', 'Disease', (89, 102))	('tumor', 'Disease', (60, 65))	('neuroblastoma', 'Phenotype', 'HP:0003006', (89, 102))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('neuroblastoma', 'Disease', 'MESH:D009447', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('blocking', 'Var', (117, 125))	('Jagged1', 'Gene', '182', (156, 163))	('Dll4', 'Gene', '54567', (52, 56))	('VEGFR2', 'Gene', (126, 132))	('lung cancer', 'Disease', (3, 14))	('expression', 'MPA', (38, 48))	('Jagged1', 'Gene', (156, 163))	('Dll4', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('increases', 'PosReg', (133, 142))	('VEGFR2', 'Gene', '3791', (126, 132))	('VEGF', 'Gene', '7422', (16, 20))	('expression', 'MPA', (164, 174))	('VEGF', 'Gene', '7422', (126, 130))	('hyperactivation', 'PosReg', (197, 212))	('VEGF', 'Gene', (16, 20))	('VEGF', 'Gene', (126, 130))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
369772	30917608	Finally, blocking Notch in tumor vasculature significantly reduces tumor growth, suggesting that endothelial Notch is a potential target for disrupting tumor microenvironment and pathological progression.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('reduces', 'NegReg', (59, 66))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('disrupting tumor', 'Disease', (141, 157))	('disrupting tumor', 'Disease', 'MESH:D019958', (141, 157))	('tumor', 'Disease', (67, 72))	('blocking', 'Var', (9, 17))
369777	30917608	Dysregulation of EMT can result in scar formation and fibrosis with consequent malfunctioning of the organ.	('EMT', 'Gene', (17, 20))	('scar formation', 'CPA', (35, 49))	('Dysregulation', 'Var', (0, 13))	('scar', 'Phenotype', 'HP:0100699', (35, 39))	('result in', 'Reg', (25, 34))	('fibrosis', 'Disease', 'MESH:D005355', (54, 62))	('fibrosis', 'Disease', (54, 62))
369782	30917608	Additionally, changes in the cadherins panel of expression result in dramatic structural changes in epithelium, and specifically in the adherens junctions deprived of E-cadherin expression.	('structural changes', 'CPA', (78, 96))	('E-cadherin', 'Gene', (167, 177))	('E-cadherin', 'Gene', '999', (167, 177))	('changes', 'Var', (14, 21))	('cadherins', 'Protein', (29, 38))
369788	30917608	In a subset of lung cancer cells, Gefitinib-resistant cells displayed an EMT phenotype as well as an increase in Notch1 expression, when compared to their parental cells.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('expression', 'MPA', (120, 130))	('EMT phenotype', 'CPA', (73, 86))	('increase', 'PosReg', (101, 109))	('Gefitinib', 'Chemical', 'MESH:D000077156', (34, 43))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('Gefitinib-resistant', 'Var', (34, 53))	('lung cancer', 'Disease', (15, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('Notch1', 'Gene', (113, 119))
369789	30917608	On the other hand, when Notch1 was ablated in parental lung carcinoma cells, EMT was inhibited.	('inhibited', 'NegReg', (85, 94))	('EMT', 'CPA', (77, 80))	('ablated', 'Var', (35, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('parental lung carcinoma', 'Disease', (46, 69))	('parental lung carcinoma', 'Disease', 'MESH:D063129', (46, 69))	('Notch1', 'Gene', (24, 30))
369790	30917608	Gefitinib-sensitive parental cells were capable of acquiring an EMT phenotype upon Notch1 overexpression, which leads to the conclusion that Notch1 is a key player in the regulation of EMT.	('overexpression', 'Var', (90, 104))	('EMT phenotype', 'CPA', (64, 77))	('Notch1', 'Gene', (83, 89))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))
369811	30917608	In this context, Notch1 plays a coordinating role, as inhibition of the Notch-Hes1 signaling inhibits CSC phenotype in OSCC (Figure 3).	('inhibition', 'Var', (54, 64))	('Hes1', 'Gene', (78, 82))	('Hes1', 'Gene', '3280', (78, 82))	('inhibits', 'NegReg', (93, 101))	('OSCC', 'Disease', (119, 123))	('CSC', 'Disease', (102, 105))
369814	30917608	In more than 50% of T-ALL cases, the patients have a chromosomal translocation (q34; q34.3) resulting in a truncated Notch receptor, which leads to a constantly active Notch1.	('patients', 'Species', '9606', (37, 45))	('T-ALL', 'Phenotype', 'HP:0006727', (20, 25))	('truncated', 'Var', (107, 116))	('q34; q34.3', 'Var', (80, 90))	('leads to', 'Reg', (139, 147))	('Notch receptor', 'Protein', (117, 131))	('Notch1', 'MPA', (168, 174))
369841	30917608	Elevated levels of the Notch1 receptor have been found during CAF activation, as shown in melanoma, where Notch1-expression negatively influences cancer growth and invasion.	('Notch1-expression', 'Var', (106, 123))	('cancer', 'Disease', (146, 152))	('melanoma', 'Disease', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('levels', 'MPA', (9, 15))	('negatively', 'NegReg', (124, 134))	('CAF', 'Gene', (62, 65))	('influences', 'Reg', (135, 145))	('invasion', 'CPA', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('CAF', 'Gene', '8850', (62, 65))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
369849	30917608	In regard to tumor-suppressing roles, it could be shown that blockage of NF-kB, as well as Ras, leads to invasive epidermal neoplasia mediated by the activity of tumor necrosis factor/c-Jun N-terminal kinase (TNF/JNK).	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('invasive epidermal neoplasia', 'Disease', (105, 133))	('tumor necrosis', 'Disease', 'MESH:D009336', (162, 176))	('TNF/JNK', 'Gene', '7124;5599', (209, 216))	('NF-kB', 'Gene', (73, 78))	('tumor', 'Disease', (162, 167))	('leads to', 'Reg', (96, 104))	('neoplasia', 'Phenotype', 'HP:0002664', (124, 133))	('TNF/JNK', 'Gene', (209, 216))	('invasive epidermal neoplasia', 'Disease', 'MESH:D009369', (105, 133))	('tumor necrosis', 'Disease', (162, 176))	('blockage', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('activity', 'MPA', (150, 158))
369856	30917608	Similarly, in an in vivo model for HNSCC, activation of Notch1 resulted in reduced tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('HNSCC', 'Disease', (35, 40))	('tumor', 'Disease', (83, 88))	('Notch1', 'Gene', (56, 62))	('activation', 'Var', (42, 52))	('reduced', 'NegReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
369863	30917608	Notch1 activation leads to an increased level of the E3 ubiquitin ligase mouse double minute homolog 2 (MDM2), which targets p53 for subsequent degradation (Figure 4).	('level', 'MPA', (40, 45))	('E3 ubiquitin ligase', 'Protein', (53, 72))	('Notch1', 'Gene', (0, 6))	('activation', 'Var', (7, 17))	('mouse', 'Species', '10090', (73, 78))	('increased', 'PosReg', (30, 39))	('degradation', 'MPA', (144, 155))
369867	30917608	Aberration in the EGFR-PI3K-AKT pathways is a hallmark for oral cancer, where the cytoplasmatic phosphorylated form of AKT is expressed in more than 64% of cases (Figure 4).	('EGFR', 'Gene', '1956', (18, 22))	('AKT', 'Gene', (28, 31))	('oral cancer', 'Disease', 'MESH:D009062', (59, 70))	('AKT', 'Gene', '207', (119, 122))	('EGFR', 'Gene', (18, 22))	('oral cancer', 'Disease', (59, 70))	('AKT', 'Gene', (119, 122))	('rat', 'Species', '10116', (4, 7))	('AKT', 'Gene', '207', (28, 31))	('Aberration', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
369869	30917608	Blockage of AKT and PI3K phosphorylation induces cell cycle arrest and apoptosis in OSCC cells.	('Blockage', 'Var', (0, 8))	('AKT', 'Gene', '207', (12, 15))	('apoptosis', 'CPA', (71, 80))	('PI3K', 'Protein', (20, 24))	('AKT', 'Gene', (12, 15))	('arrest', 'Disease', 'MESH:D006323', (60, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))	('arrest', 'Disease', (60, 66))
369872	30917608	In a screening for Notch1 inactivating mutation, the oncogenic phenotype was associated with activation of the EGF-PI3K/AKT pathway and resulted in increased cell proliferation, EMT, and invasion in OSCC cell lines.	('AKT', 'Gene', (120, 123))	('inactivating mutation', 'Var', (26, 47))	('activation', 'PosReg', (93, 103))	('cell proliferation', 'CPA', (158, 176))	('increased', 'PosReg', (148, 157))	('rat', 'Species', '10116', (170, 173))	('EGF', 'Gene', '1950', (111, 114))	('AKT', 'Gene', '207', (120, 123))	('EMT', 'CPA', (178, 181))	('Notch1', 'Gene', (19, 25))	('invasion', 'CPA', (187, 195))	('EGF', 'Gene', (111, 114))
369875	30917608	In OSCC, activation of the Wnt pathway can occur in absence of beta-catenin and colon-cancer specific mutations, suggesting that altered epigenetic changes might compensate for the canonical activation of the pathway (Figure 4).	('beta-catenin', 'Gene', (63, 75))	('activation', 'PosReg', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('beta-catenin', 'Gene', '1499', (63, 75))	('Wnt pathway', 'Pathway', (27, 38))	('colon-cancer', 'Disease', (80, 92))	('mutations', 'Var', (102, 111))	('colon-cancer', 'Disease', 'MESH:D015179', (80, 92))	('OSCC', 'Disease', (3, 7))
369877	30917608	Mutations in HH-pathways have been found in basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma, and normally correlate with an hyperactivation of the pathway.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('medulloblastoma', 'Disease', 'MESH:D008527', (66, 81))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (87, 103))	('HH-pathways', 'Gene', (13, 24))	('medulloblastoma', 'Phenotype', 'HP:0002885', (66, 81))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (44, 64))	('Mutations', 'Var', (0, 9))	('hyperactivation', 'PosReg', (136, 151))	('basal cell carcinoma', 'Disease', (44, 64))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (44, 64))	('rhabdomyosarcoma', 'Disease', (87, 103))	('medulloblastoma', 'Disease', (66, 81))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (87, 103))	('found', 'Reg', (35, 40))
369889	30917608	As the p53 gene is mutated in 70% of HNSCC, this mouse was further crossed with p53+/- and p53-/- mice, resulting in mice that develop invasive oral-esophageal squamous cell carcinoma.	('develop', 'PosReg', (127, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('mutated', 'Var', (19, 26))	('mice', 'Species', '10090', (117, 121))	('mouse', 'Species', '10090', (49, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('oral-esophageal squamous cell carcinoma', 'Disease', (144, 183))	('oral-esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (144, 183))	('p53', 'Gene', (7, 10))	('mice', 'Species', '10090', (98, 102))
369894	30917608	Upon induced-ablation of the two genes, mice develop hyperplasia in the oral epithelium.	('induced-ablation', 'Var', (5, 21))	('hyperplasia', 'Disease', (53, 64))	('hyperplasia', 'Disease', 'MESH:D006965', (53, 64))	('mice', 'Species', '10090', (40, 44))	('hyperplasia in the oral epithelium', 'Phenotype', 'HP:0410340', (53, 87))
369895	30917608	The loss of Tgfbr1 and Pten was shown to lead to cancer-related inflammation as well as cancer stem cell expansion in the basal epithelial layer of this model.	('epithelia', 'Disease', 'None', (128, 137))	('cancer', 'Disease', (88, 94))	('epithelia', 'Disease', (128, 137))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Pten', 'Gene', (23, 27))	('inflammation', 'Disease', 'MESH:D007249', (64, 76))	('Tgfbr1', 'Gene', (12, 18))	('inflammation', 'Disease', (64, 76))	('lead to', 'Reg', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('loss', 'Var', (4, 8))
369899	30917608	Overexpression of KrasG12D under the control of cK5 affects the basal epithelium, while under the regulation of cK14, alterations are mainly found in the basal layer of oral mucosa and the tongue.	('alterations', 'Reg', (118, 129))	('KrasG12D', 'Var', (18, 26))	('rat', 'Species', '10116', (122, 125))	('cK5', 'Gene', (48, 51))	('affects', 'Reg', (52, 59))
369908	30917608	Inhibiting Notch1 in an HNSCC xenograft mouse model resulted in reduced cancer stem cell renewal.	('Inhibiting', 'Var', (0, 10))	('Notch1', 'Gene', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('reduced', 'NegReg', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mouse', 'Species', '10090', (40, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (24, 29))	('cancer', 'Disease', (72, 78))
369939	30992079	The CD44+ CSCs had ability to form tumors in NUDE mice.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('NUDE mice', 'Species', '10090', (45, 54))	('CD44+', 'Var', (4, 9))
369940	30992079	MAML1 silencing caused a significant decrease (p = 0.019) and ectopic expression caused a significant increase in migration of CD44+ CSCs (p = 0.012).	('decrease', 'NegReg', (37, 45))	('migration', 'CPA', (114, 123))	('increase', 'PosReg', (102, 110))	('MAML1', 'Gene', (0, 5))	('MAML1', 'Gene', '9794', (0, 5))	('silencing', 'Var', (6, 15))	('ectopic expression', 'Var', (62, 80))
369941	30992079	Moreover, MAML1 silencing and ectopic expression significantly increased and decreased 5FU resistance, respectively (p < 0.05).	('increased', 'PosReg', (63, 72))	('5FU', 'Chemical', 'MESH:D005472', (87, 90))	('silencing', 'NegReg', (16, 25))	('ectopic expression', 'Var', (30, 48))	('MAML1', 'Gene', '9794', (10, 15))	('5FU resistance', 'CPA', (87, 101))	('MAML1', 'Gene', (10, 15))	('decreased', 'NegReg', (77, 86))
369942	30992079	MAML1 silencing significantly increased the number of cells in G1 phase (p = 0.008), and its ectopic expression significantly increased the number of CD44+ CSCS in S phase (p = 0.037).	('silencing', 'Var', (6, 15))	('CD44+ CSCS', 'CPA', (150, 160))	('ectopic expression', 'MPA', (93, 111))	('cells in G1 phase', 'CPA', (54, 71))	('increased', 'PosReg', (30, 39))	('MAML1', 'Gene', '9794', (0, 5))	('MAML1', 'Gene', (0, 5))	('increased', 'PosReg', (126, 135))
369954	30992079	Some CD44+ CSCs have epithelial-mesenchymal transition (EMT) ability, and contribute to tumor progression and metastasis.	('epithelial-mesenchymal transition', 'CPA', (21, 54))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('metastasis', 'CPA', (110, 120))	('contribute', 'Reg', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CD44+ CSCs', 'Var', (5, 15))	('tumor', 'Disease', (88, 93))
369959	30992079	Subsequently, CSL activation is done by substitution of transcriptional co-repressors, including CIR, SMRT/N-CoR, and KyoT2, and recruitment of co-activators, including CBP/p300 and mastermind-like proteins (MAML).	('CIR', 'Gene', (97, 100))	('CBP/p300', 'Gene', '1387;2033', (169, 177))	('CSL', 'Gene', (14, 17))	('N-CoR', 'Gene', (107, 112))	('CIR', 'Gene', '9541', (97, 100))	('substitution', 'Var', (40, 52))	('SMRT', 'Gene', '9612', (102, 106))	('SMRT', 'Gene', (102, 106))	('CBP/p300', 'Gene', (169, 177))	('CSL', 'Gene', '3516', (14, 17))	('activation', 'PosReg', (18, 28))	('N-CoR', 'Gene', '9611', (107, 112))
369978	30992079	The samples were blocked and then incubated at 4  C for 16 h with the primary antibodies: anti-P63 (1:1000, BD Biosciences), anti-cytokeratin 18 (1:500, DakoCytomation), anti-cytokeratin 19 (1:500, Miltenyi Biotech), anti-CD117 (1:2000, Dako), or anti-CD44 (1:1000, Dako), and then with secondary antibody.	('P63', 'Gene', (95, 98))	('1:1000', 'Var', (100, 106))	('anti-CD44', 'Var', (247, 256))	('cytokeratin 18', 'Gene', (130, 144))	('1:500', 'Var', (146, 151))	('anti-CD117', 'Var', (217, 227))	('cytokeratin 19', 'Gene', '3880', (175, 189))	('cytokeratin 19', 'Gene', (175, 189))	('cytokeratin 18', 'Gene', '3875', (130, 144))	('P63', 'Gene', '8626', (95, 98))	('1:500', 'Var', (191, 196))
369980	30992079	Slides were incubated with anti-p63 antibody (1:500, Abcam), anti-cytokeratin 18 (1:500, Novocastra), and anti-CD44 (1:1000, Dako) overnight at 4  C. Finally, the slides were incubated with secondary antibodies for 30 min at 37  C and visualized with diaminobenzidine.	('diaminobenzidine', 'Chemical', '-', (251, 267))	('cytokeratin 18', 'Gene', (66, 80))	('p63', 'Gene', (32, 35))	('anti-CD44', 'Var', (106, 115))	('cytokeratin 18', 'Gene', '3875', (66, 80))	('p63', 'Gene', '8626', (32, 35))
369998	30992079	Moreover, the isolated CD44+ cells had SALL4, DPPA2, CD44V3, CD44V6, CD44S, and BMI1 over expression.	('BMI1', 'Gene', (80, 84))	('SALL4', 'Gene', '57167', (39, 44))	('over expression', 'PosReg', (85, 100))	('CD44V6', 'Var', (61, 67))	('CD44V3', 'Gene', (53, 59))	('SALL4', 'Gene', (39, 44))	('BMI1', 'Gene', '648', (80, 84))	('DPPA2', 'Gene', (46, 51))	('DPPA2', 'Gene', '151871', (46, 51))	('CD44S', 'Var', (69, 74))
370007	30992079	Therefore, MAML1, as the main component of the NOTCH transcription machinery, was targeted by ectopic expression and silencing.	('MAML1', 'Gene', '9794', (11, 16))	('MAML1', 'Gene', (11, 16))	('ectopic expression', 'Var', (94, 112))	('silencing', 'Var', (117, 126))
370012	30992079	The results showed that CSC migration increased significantly after the MAML1 ectopic expression (p = 0.012).	('MAML1', 'Gene', (72, 77))	('MAML1', 'Gene', '9794', (72, 77))	('ectopic expression', 'Var', (78, 96))	('CSC migration', 'CPA', (24, 37))	('increased', 'PosReg', (38, 47))
370022	30992079	MAML1 ectopic expression also increased the 5FU resistance in CD44+ transfected cells in comparison with non-transfected CD44+ CSCs (14.1 microm/l vs. 8.395 microm/l, IC50) (p <= 0.005) (Fig.	('CD44+ transfected', 'Var', (62, 79))	('5FU', 'Chemical', 'MESH:D005472', (44, 47))	('5FU resistance', 'MPA', (44, 58))	('increased', 'PosReg', (30, 39))	('ectopic expression', 'Var', (6, 24))	('MAML1', 'Gene', (0, 5))	('MAML1', 'Gene', '9794', (0, 5))
370027	30992079	After transfection with MAML1 shRNA, CD44+ CSCs significantly accumulated at G1 phase, with a concomitant reduction in S phase (p = 0.008).	('accumulated', 'PosReg', (62, 73))	('G1 phase', 'CPA', (77, 85))	('reduction', 'NegReg', (106, 115))	('CD44+', 'Var', (37, 42))	('MAML1', 'Gene', (24, 29))	('MAML1', 'Gene', '9794', (24, 29))
370028	30992079	Following the MAML1 silencing, number of accumulated cells in G1 phase increased 10% and number of cells in S phase decreased 6.85%.	('MAML1', 'Gene', (14, 19))	('MAML1', 'Gene', '9794', (14, 19))	('silencing', 'Var', (20, 29))	('increased', 'PosReg', (71, 80))
370029	30992079	In contrast with the silencing, MAML1 ectopic expression significantly increased number of cells in S phase and decreased number of cells in G1 phase with 7.36% and 12.01%, respectively (p = 0.037) (Fig.	('MAML1', 'Gene', (32, 37))	('MAML1', 'Gene', '9794', (32, 37))	('ectopic expression', 'Var', (38, 56))	('increased', 'PosReg', (71, 80))	('decreased', 'NegReg', (112, 121))
370046	30992079	We showed that MAML1 silencing significantly reduced cell migration.	('reduced', 'NegReg', (45, 52))	('MAML1', 'Gene', (15, 20))	('MAML1', 'Gene', '9794', (15, 20))	('cell migration', 'CPA', (53, 67))	('silencing', 'Var', (21, 30))
370047	30992079	On the other hand, MAML1 ectopic expression significantly increased the metastatic behavior of isolated CSCs.	('metastatic behavior of isolated CSCs', 'CPA', (72, 108))	('increased', 'PosReg', (58, 67))	('MAML1', 'Gene', (19, 24))	('MAML1', 'Gene', '9794', (19, 24))	('ectopic expression', 'Var', (25, 43))
370048	30992079	Moreover, cell cycle analysis showed that MAML1 silencing in CD44+ CSCs significantly increased the number of cells in G1 phase while ectopic expression significantly increased the number of cells in S phase.	('MAML1', 'Gene', '9794', (42, 47))	('silencing', 'Var', (48, 57))	('increased', 'PosReg', (86, 95))	('increased', 'PosReg', (167, 176))	('MAML1', 'Gene', (42, 47))
370052	30992079	MAML1 silenced cells also had lower resistance than the intact CD44+-CSCs.	('lower', 'NegReg', (30, 35))	('silenced', 'Var', (6, 14))	('resistance', 'MPA', (36, 46))	('MAML1', 'Gene', (0, 5))	('MAML1', 'Gene', '9794', (0, 5))
370064	27766781	Consistently, patients in the POCRT group had significantly longer median OS than patients in the SA group (34 vs. 26 months, respectively).	('POCRT', 'Var', (30, 35))	('POCRT', 'Chemical', '-', (30, 35))	('longer', 'PosReg', (60, 66))	('patients', 'Species', '9606', (82, 90))	('SA', 'Chemical', '-', (98, 100))	('OS', 'Chemical', '-', (74, 76))	('patients', 'Species', '9606', (14, 22))
370111	27766781	Analogously, patients in the POCRT group had significantly better survival than those in the SA group, with a median OS of 34 months (95% CI 26.1-41.9) in the POCRT group compared with 26 months (95% CI 23.4-28.6) in the SA group (P = 0.048, Fig.	('OS', 'Chemical', '-', (117, 119))	('SA', 'Chemical', '-', (221, 223))	('SA', 'Chemical', '-', (93, 95))	('patients', 'Species', '9606', (13, 21))	('POCRT', 'Var', (159, 164))	('better', 'PosReg', (59, 65))	('survival', 'CPA', (66, 74))	('POCRT', 'Chemical', '-', (159, 164))	('POCRT', 'Chemical', '-', (29, 34))
370128	27766781	In our analysis, OS and DFS were obviously improved in patients who received POCRT compared with the group who received SA.	('POCRT', 'Var', (77, 82))	('DFS', 'CPA', (24, 27))	('SA', 'Chemical', '-', (120, 122))	('improved', 'PosReg', (43, 51))	('patients', 'Species', '9606', (55, 63))	('OS', 'Chemical', '-', (17, 19))	('POCRT', 'Chemical', '-', (77, 82))
370133	27766781	In our study, there was a substantial difference in the DRR between the POCRT and SA groups, and the POCRT group experienced an improved distant control rate and further improved DFS and OS.	('DFS', 'CPA', (179, 182))	('DRR', 'MPA', (56, 59))	('improved', 'PosReg', (128, 136))	('improved', 'PosReg', (170, 178))	('OS', 'Chemical', '-', (187, 189))	('POCRT', 'Var', (101, 106))	('distant control rate', 'CPA', (137, 157))	('POCRT', 'Chemical', '-', (72, 77))	('SA', 'Chemical', '-', (82, 84))	('POCRT', 'Chemical', '-', (101, 106))
370214	27453171	The tumor volume was significantly less in the THZ and RT group than in the control group.	('tumor', 'Disease', (4, 9))	('less', 'NegReg', (35, 39))	('THZ', 'Var', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('THZ', 'Chemical', '-', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
370215	27453171	The tumor volume was significantly less in the THZ + RT group than in the THZ group and the RT group (Figure 5A).	('tumor', 'Disease', (4, 9))	('THZ + RT', 'Var', (47, 55))	('less', 'NegReg', (35, 39))	('THZ', 'Chemical', '-', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('THZ', 'Chemical', '-', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
370237	27453171	Recent research suggests that in head and neck squamous cell cancer (HNSCC) and small-cell lung cancer(SCLC), the combination of radiation and inhibitor of anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-xL induced more apoptosis than the summation of their separate effects, which means down-regulation of Bcl-2 and Bcl-xL possess the capacity to radio-sensitize cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('Bcl-2', 'Gene', '596', (309, 314))	('Bcl-2', 'Gene', '596', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('apoptosis', 'CPA', (222, 231))	('cancer', 'Disease', (366, 372))	('Bcl-xL', 'Gene', (202, 208))	('Bcl-2', 'Gene', (171, 176))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('cancer', 'Disease', (96, 102))	('SCLC', 'Disease', 'MESH:D018288', (103, 107))	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (42, 67))	('Bcl-xL', 'Gene', '598', (202, 208))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (33, 67))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('inhibitor', 'Var', (143, 152))	('Bcl-xL', 'Gene', (319, 325))	('Bcl-2', 'Gene', '596', (171, 176))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (47, 67))	('Bcl-xL', 'Gene', '598', (319, 325))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('cancer', 'Disease', (61, 67))	('down-regulation', 'NegReg', (290, 305))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (80, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('small-cell lung cancer', 'Disease', (80, 102))	('SCLC', 'Disease', (103, 107))	('Bcl-2', 'Gene', (309, 314))	('Bcl-2', 'Gene', (192, 197))	('neck squamous cell cancer', 'Disease', (42, 67))	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('SCLC', 'Phenotype', 'HP:0030357', (103, 107))
370243	27453171	LY294002 and wortmannin, well-studied specific PI3K inhibitors, respectively sensitize cancer cells to radiation through inactivation of PKB and lead to inhibition of cellular DNA-PK.	('LY294002', 'Var', (0, 8))	('cancer', 'Disease', (87, 93))	('inhibition', 'NegReg', (153, 163))	('PKB', 'Gene', (137, 140))	('inactivation', 'NegReg', (121, 133))	('sensitize', 'Reg', (77, 86))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('wortmannin', 'Chemical', 'MESH:D000077191', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('PKB', 'Gene', '207;11651;208', (137, 140))
370244	27453171	Palomid 529 (Akt inhibitor), RAD001 (mTOR inhibitor), and BEZ235 (dual PI3K/mTOR inhibitor) lead to more apoptosis and DNA double-strand breaks, increased apoptosis, and decreased number of tumor blood vessels, cell death in a PTEN-independent manner, and autophagic cell death.	('cell death', 'CPA', (211, 221))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PTEN', 'Gene', (227, 231))	('BEZ235', 'Var', (58, 64))	('DNA double-strand breaks', 'MPA', (119, 143))	('Palomid 529', 'Var', (0, 11))	('apoptosis', 'CPA', (155, 164))	('RAD001', 'Var', (29, 35))	('PTEN', 'Gene', '5728', (227, 231))	('RAD001', 'Chemical', 'MESH:D000068338', (29, 35))	('increased', 'PosReg', (145, 154))	('more', 'PosReg', (100, 104))	('tumor', 'Disease', (190, 195))	('autophagic cell death', 'CPA', (256, 277))	('Palomid 529', 'Chemical', 'MESH:C533469', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('apoptosis', 'CPA', (105, 114))	('BEZ235', 'Chemical', 'MESH:C531198', (58, 64))	('decreased', 'NegReg', (170, 179))
370256	25755254	The D10 dose for X-rays in TE2, KYSE70, A549, NCI-H460 and WiDr cells was 2.1, 6.7, 8.0, 4.8 and 7.1 Gy, respectively, whereas that for carbon-ion beams was 0.9, 2.5, 2.7, 1.8 and 3.5 Gy, respectively.	('carbon', 'Chemical', 'MESH:D002244', (136, 142))	('KYSE70', 'Var', (32, 38))	('TE2', 'Gene', '8260', (27, 30))	('D10', 'Gene', (4, 7))	('D10', 'Gene', '89832', (4, 7))	('rays', 'Species', '255564', (19, 23))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('TE2', 'Gene', (27, 30))	('A549', 'Var', (40, 44))	('NCI-H460', 'CellLine', 'CVCL:0459', (46, 54))
370272	25755254	This immune activating pathway plays a significant role in the prognosis of breast cancer because patients carrying a TLR4 loss-of-function allele relapse more quickly.	('loss-of-function', 'NegReg', (123, 139))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('TLR4', 'Gene', '7099', (118, 122))	('patients', 'Species', '9606', (98, 106))	('allele', 'Var', (140, 146))	('breast cancer', 'Disease', (76, 89))	('TLR4', 'Gene', (118, 122))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
370294	25755254	The D10 X-ray doses in TE2, KYSE70, A549, NCI-H460 and WiDr cells were 2.1, 6.7, 8.0, 4.8 and 7.1 Gy, respectively, whereas those for carbon-ion beams were 0.9, 2.5, 2.7, 1.8 and 3.5 Gy, respectively.	('TE2', 'Gene', '8260', (23, 26))	('TE2', 'Gene', (23, 26))	('A549', 'CellLine', 'CVCL:0023', (36, 40))	('KYSE70', 'Var', (28, 34))	('NCI-H460', 'CellLine', 'CVCL:0459', (42, 50))	('A549', 'Var', (36, 40))	('D10 X', 'Mutation', 'p.D10X', (4, 9))	('carbon', 'Chemical', 'MESH:D002244', (134, 140))
370295	25755254	The RBE values (calculated at the D10 doses) for TE2, KYSE70, A549, NCI-H460 and WiDr cells were 2.3, 2.7, 3.0, 2.7 and 2.0, respectively.	('NCI-H460', 'CellLine', 'CVCL:0459', (68, 76))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('KYSE70', 'Var', (54, 60))	('D10', 'Gene', (34, 37))	('D10', 'Gene', '89832', (34, 37))	('TE2', 'Gene', '8260', (49, 52))	('TE2', 'Gene', (49, 52))
370331	25340007	LY6K172-191-LP-specific Th1 immunologic response following 1 week in vitro stimulation of PBMCs with LY6K172-191-LP were detected in 16 of 21 HNMT patients (76%) vaccinated with CTL-epitope peptides and 1 of 11 HNMT patients (9%) prior to vaccination, but not in 9 healthy donors.	('HNMT', 'Phenotype', 'HP:0012288', (142, 146))	('HNMT', 'Disease', 'None', (142, 146))	('HNMT', 'Disease', (142, 146))	('LY6K172', 'Chemical', '-', (101, 108))	('HNMT', 'Disease', 'None', (211, 215))	('donor', 'Species', '9606', (273, 278))	('patients', 'Species', '9606', (216, 224))	('LY6K172-191-LP', 'Var', (101, 115))	('HNMT', 'Disease', (211, 215))	('Th', 'Chemical', '-', (24, 26))	('peptides', 'Chemical', 'MESH:D010455', (190, 198))	('Th1 immunologic response', 'MPA', (24, 48))	('LP', 'Chemical', '-', (12, 14))	('LY6K172', 'Chemical', '-', (0, 7))	('patients', 'Species', '9606', (147, 155))	('HNMT', 'Phenotype', 'HP:0012288', (211, 215))	('LY6K172-191-LP-specific', 'Var', (0, 23))	('LP', 'Chemical', '-', (113, 115))
370353	25340007	We found that LY6K172-191-LP successfully triggered Th1-cell responses in individuals expressing several common HLA allelic variants, including HLA-DR, -DP or -DQ alleles, and that efficient cross-presentation of the LY6K172-191-LP induced LY6K177-186-A24 SP-specific CTLs.	('LY6K172-191-LP', 'Var', (217, 231))	('HLA', 'Gene', '3123', (112, 115))	('LY6K177-186-A24', 'Gene', '54742', (240, 255))	('LY6K172-191-LP', 'Var', (14, 28))	('Th1-cell responses', 'CPA', (52, 70))	('LY6K177-186-A24', 'Gene', (240, 255))	('HLA', 'Gene', (112, 115))	('HLA', 'Gene', '3123', (144, 147))	('Th', 'Chemical', '-', (52, 54))	('SP', 'Chemical', '-', (256, 258))	('LY6K172', 'Chemical', '-', (217, 224))	('HLA', 'Gene', (144, 147))	('LP', 'Chemical', '-', (229, 231))	('LP', 'Chemical', '-', (26, 28))	('LY6K172', 'Chemical', '-', (14, 21))
370354	25340007	In addition, we also observed LY6K172-191-LP enhanced induction of LY6K177-186-A24 SP-specific CTLs in PBMCs from healthy donors and HNMT patients.	('induction', 'MPA', (54, 63))	('HNMT', 'Phenotype', 'HP:0012288', (133, 137))	('SP', 'Chemical', '-', (83, 85))	('LY6K172', 'Chemical', '-', (30, 37))	('LP', 'Chemical', '-', (42, 44))	('HNMT', 'Disease', 'None', (133, 137))	('LY6K177-186-A24', 'Gene', '54742', (67, 82))	('donor', 'Species', '9606', (122, 127))	('LY6K177-186-A24', 'Gene', (67, 82))	('HNMT', 'Disease', (133, 137))	('LY6K172-191-LP', 'Var', (30, 44))	('patients', 'Species', '9606', (138, 146))
370358	25340007	Another peptide, LY6K119-142-LP, was also predicted to be a potent HLA class II-binding peptide, although it did not include a known CTL-epitope sequence.	('HLA', 'Gene', (67, 70))	('LY6K119', 'Chemical', '-', (17, 24))	('LY6K119-142-LP', 'Var', (17, 31))	('LP', 'Chemical', '-', (29, 31))	('HLA', 'Gene', '3123', (67, 70))
370359	25340007	Therefore, 2 candidate LPs, LY6K119-142-LP and LY6K172-191-LP, both of which were predicted to have a strong binding affinity for HLA-class II molecules (e.g., HLA-DP5, -DR8, -DR9, or -DR15), were synthesized for subsequent analyses.	('LP', 'Chemical', '-', (23, 25))	('HLA', 'Gene', '3123', (160, 163))	('HLA-DP', 'Gene', (160, 166))	('binding affinity', 'Interaction', (109, 125))	('HLA', 'Gene', '3123', (130, 133))	('HLA', 'Gene', (160, 163))	('LY6K119-142-LP', 'Var', (28, 42))	('Th', 'Chemical', '-', (0, 2))	('LP', 'Chemical', '-', (59, 61))	('LPs', 'Chemical', 'MESH:D008070', (23, 26))	('LY6K172', 'Chemical', '-', (47, 54))	('HLA', 'Gene', (130, 133))	('LY6K172-191-LP', 'Var', (47, 61))	('LY6K119', 'Chemical', '-', (28, 35))	('HLA-DP', 'Gene', '3115', (160, 166))	('LP', 'Chemical', '-', (40, 42))
370361	25340007	These CD4+ T cells were stimulated at weekly intervals with autologous DCs or PBMCs pulsed with either LY6K119-142-LP or LY6K172-191-LP, as described in Materials and Methods.	('CD4', 'Gene', (6, 9))	('LY6K172', 'Chemical', '-', (121, 128))	('LP', 'Chemical', '-', (133, 135))	('CD4', 'Gene', '920', (6, 9))	('LY6K172-191-LP', 'Var', (121, 135))	('Th', 'Chemical', '-', (0, 2))	('LY6K119-142-LP', 'Var', (103, 117))	('LY6K119', 'Chemical', '-', (103, 110))	('LP', 'Chemical', '-', (115, 117))
370363	25340007	The Th cells generated from HLA-DP5+ HD1 produced a significant amount of IFNgamma in response to LY6K119-142-LP-pulsed PBMCs in an HLA-DP-dependent manner (Fig.	('IFNgamma', 'Protein', (74, 82))	('LY6K119-142-LP-pulsed', 'Var', (98, 119))	('HD1', 'Gene', '5339', (37, 40))	('HLA-DP', 'Gene', '3115', (28, 34))	('LY6K119', 'Chemical', '-', (98, 105))	('Th', 'Chemical', '-', (0, 2))	('LP', 'Chemical', '-', (110, 112))	('Th', 'Chemical', '-', (4, 6))	('HLA-DP', 'Gene', '3115', (132, 138))	('HLA-DP', 'Gene', (28, 34))	('HD1', 'Gene', (37, 40))	('HLA-DP', 'Gene', (132, 138))
370364	25340007	The bulk Th cells also specifically recognized HLA-DP5-expressing L cells (L-DP5) pulsed with LY6K119-142-LP in an HLA-DP-dependent manner, but not irrelevant peptide (EBNA)-pulsed L-DP5 cells or LY6K119-142-LP-pulsed HLA-DR4-expressing L cells (L-DR4; Fig.	('DR4', 'Gene', '3126', (248, 251))	('DR4', 'Gene', (222, 225))	('HLA', 'Gene', '3123', (115, 118))	('Th', 'Chemical', '-', (9, 11))	('HLA', 'Gene', '3123', (218, 221))	('Th', 'Chemical', '-', (0, 2))	('HLA', 'Gene', (47, 50))	('LY6K119', 'Chemical', '-', (94, 101))	('DR4', 'Gene', '3126', (222, 225))	('HLA-DP', 'Gene', '3115', (47, 53))	('LY6K119', 'Chemical', '-', (196, 203))	('HLA-DP', 'Gene', (47, 53))	('LY6K119-142-LP', 'Var', (94, 108))	('LP', 'Chemical', '-', (208, 210))	('DR4', 'Gene', (248, 251))	('HLA', 'Gene', (115, 118))	('LP', 'Chemical', '-', (106, 108))	('HLA', 'Gene', '3123', (47, 50))	('HLA', 'Gene', (218, 221))	('HLA-DP', 'Gene', '3115', (115, 121))	('HLA-DP', 'Gene', (115, 121))
370365	25340007	These results indicated that LY6K119-142-LP was specifically presented by HLA-DP5.	('HLA-DP', 'Gene', '3115', (74, 80))	('LY6K119', 'Chemical', '-', (29, 36))	('LP', 'Chemical', '-', (41, 43))	('HLA-DP', 'Gene', (74, 80))	('Th', 'Chemical', '-', (0, 2))	('LY6K119-142-LP', 'Var', (29, 43))
370366	25340007	To investigate whether LY6K119-142-LP induces responses in Th cells restricted by other HLA class II molecules, CD4+ T-cells from DR8+ and DR15+ healthy donors (HD2 and HD3) were also tested.	('CD4', 'Gene', '920', (112, 115))	('HLA', 'Gene', '3123', (88, 91))	('LY6K119', 'Chemical', '-', (23, 30))	('donor', 'Species', '9606', (153, 158))	('HD3', 'Gene', (169, 172))	('HLA', 'Gene', (88, 91))	('Th', 'Chemical', '-', (59, 61))	('LP', 'Chemical', '-', (35, 37))	('HD2', 'Gene', '3066', (161, 164))	('HD3', 'Gene', '8841', (169, 172))	('HD2', 'Gene', (161, 164))	('CD4', 'Gene', (112, 115))	('LY6K119-142-LP', 'Var', (23, 37))
370367	25340007	We confirmed that LY6K119-142-LP also stimulates HLA-DR8-restricted Th cells and HLA-DR15-restricted Th cells (Fig.	('LP', 'Chemical', '-', (30, 32))	('HLA', 'Gene', '3123', (81, 84))	('Th', 'Chemical', '-', (68, 70))	('HLA', 'Gene', (81, 84))	('stimulates', 'PosReg', (38, 48))	('Th', 'Chemical', '-', (101, 103))	('HLA', 'Gene', '3123', (49, 52))	('HLA', 'Gene', (49, 52))	('LY6K119', 'Chemical', '-', (18, 25))	('LY6K119-142-LP', 'Var', (18, 32))
370368	25340007	Thus, LY6K119-142-LP binds to HLA-DP5, HLA-DR8, and HLA-DR15, suggesting that LY6K119-142-LP encompasses several Th cell epitopes presented by high frequency HLA class II molecules.	('HLA', 'Gene', (52, 55))	('HLA-DP', 'Gene', '3115', (30, 36))	('LP', 'Chemical', '-', (18, 20))	('Th', 'Chemical', '-', (113, 115))	('LY6K119-142-LP', 'Var', (78, 92))	('HLA', 'Gene', '3123', (30, 33))	('HLA', 'Gene', '3123', (39, 42))	('LY6K119', 'Chemical', '-', (78, 85))	('HLA', 'Gene', '3123', (158, 161))	('HLA', 'Gene', (30, 33))	('HLA-DP', 'Gene', (30, 36))	('HLA', 'Gene', (39, 42))	('LY6K119', 'Chemical', '-', (6, 13))	('LP', 'Chemical', '-', (90, 92))	('Th', 'Chemical', '-', (0, 2))	('HLA', 'Gene', (158, 161))	('HLA', 'Gene', '3123', (52, 55))
370369	25340007	Next, we assessed whether LY6K172-191-LP, a peptide spanning a known CTL-epitope, could also generate active Th cells.	('Th', 'Chemical', '-', (109, 111))	('LP', 'Chemical', '-', (38, 40))	('Th cells', 'CPA', (109, 117))	('LY6K172', 'Chemical', '-', (26, 33))	('LY6K172-191-LP', 'Var', (26, 40))
370370	25340007	The Th cells originating from 2 HLA-DR15+ donors (HD2 and HD3) produced a significant amount of IFNgamma in response to LY6K172-191-LP-pulsed PBMCs in an HLA-DR-dependent manner.	('LY6K172-191-LP-pulsed', 'Var', (120, 141))	('HLA', 'Gene', '3123', (154, 157))	('HLA', 'Gene', (32, 35))	('HD2', 'Gene', '3066', (50, 53))	('HLA', 'Gene', (154, 157))	('HD3', 'Gene', '8841', (58, 61))	('HD2', 'Gene', (50, 53))	('Th', 'Chemical', '-', (0, 2))	('IFNgamma', 'Protein', (96, 104))	('Th', 'Chemical', '-', (4, 6))	('LY6K172', 'Chemical', '-', (120, 127))	('donor', 'Species', '9606', (42, 47))	('LP', 'Chemical', '-', (132, 134))	('HLA', 'Gene', '3123', (32, 35))	('HD3', 'Gene', (58, 61))
370371	25340007	The bulk Th cells specifically recognized HLA-DR15 expressing L cells (L-DR15) pulsed with LY6K172-191-LP in an HLA-DR-dependent manner (Fig.	('Th', 'Chemical', '-', (9, 11))	('HLA', 'Gene', '3123', (112, 115))	('LY6K172', 'Chemical', '-', (91, 98))	('Th', 'Chemical', '-', (0, 2))	('LP', 'Chemical', '-', (103, 105))	('HLA', 'Gene', (112, 115))	('HLA', 'Gene', '3123', (42, 45))	('LY6K172-191-LP', 'Var', (91, 105))	('HLA', 'Gene', (42, 45))
370372	25340007	CD4+ T-cells from an HLA-DR15-negative donor (HD4) were tested to investigate whether LY6K172-191-LP can induce Th cells restricted by other HLA class II molecules.	('LP', 'Chemical', '-', (98, 100))	('Th', 'Chemical', '-', (112, 114))	('CD4', 'Gene', '920', (0, 3))	('LY6K172-191-LP', 'Var', (86, 100))	('donor', 'Species', '9606', (39, 44))	('HLA', 'Gene', '3123', (21, 24))	('HD4', 'Gene', '9759', (46, 49))	('HLA', 'Gene', (21, 24))	('HD4', 'Gene', (46, 49))	('LY6K172', 'Chemical', '-', (86, 93))	('HLA', 'Gene', '3123', (141, 144))	('HLA', 'Gene', (141, 144))	('CD4', 'Gene', (0, 3))
370373	25340007	LY6K172-191-LP could stimulate HLA-DQ-restricted bulk Th cells originating from this donor (Fig.	('LY6K172-191-LP', 'Var', (0, 14))	('Th', 'Chemical', '-', (54, 56))	('stimulate', 'PosReg', (21, 30))	('donor', 'Species', '9606', (85, 90))	('HLA', 'Gene', '3123', (31, 34))	('LP', 'Chemical', '-', (12, 14))	('LY6K172', 'Chemical', '-', (0, 7))	('HLA', 'Gene', (31, 34))
370374	25340007	Indeed, LY6K172-191-LP robustly generated Th cells expressing IFNgamma, suggesting that LY6K172-191-LP also encompasses several Th cell epitopes.	('LY6K172', 'Chemical', '-', (8, 15))	('LP', 'Chemical', '-', (20, 22))	('Th', 'Chemical', '-', (42, 44))	('LY6K172', 'Chemical', '-', (88, 95))	('LP', 'Chemical', '-', (100, 102))	('LY6K172-191-LP', 'Var', (88, 102))	('LY6K172-191-LP', 'Var', (8, 22))	('Th', 'Chemical', '-', (128, 130))
370375	25340007	In these healthy donors, LY6K177-186-A24 SP control failed to stimulate LY6K172-191-LP-specific Th cells (Fig.	('SP', 'Chemical', '-', (41, 43))	('LY6K177-186-A24', 'Gene', '54742', (25, 40))	('LY6K172-191-LP-specific', 'Var', (72, 95))	('LY6K177-186-A24', 'Gene', (25, 40))	('Th', 'Chemical', '-', (96, 98))	('donor', 'Species', '9606', (17, 22))	('LP', 'Chemical', '-', (84, 86))	('LY6K172', 'Chemical', '-', (72, 79))
370383	25340007	LY6K172-191-LP-specific Th-clone from HD4 produced a large amount of these cytokines after stimulation, suggesting LY6K172-191-LP can potently induce multifunctional Th1 cells (Fig.	('HD4', 'Gene', '9759', (38, 41))	('LP', 'Chemical', '-', (127, 129))	('LY6K172', 'Chemical', '-', (115, 122))	('LY6K172-191-LP', 'Var', (115, 129))	('induce', 'PosReg', (143, 149))	('multifunctional Th1 cells', 'CPA', (150, 175))	('Th', 'Chemical', '-', (24, 26))	('HD4', 'Gene', (38, 41))	('LP', 'Chemical', '-', (12, 14))	('LY6K172', 'Chemical', '-', (0, 7))	('Th', 'Chemical', '-', (166, 168))
370385	25340007	The lysosomal-associated membrane protein 1a (LAMP1a, also known as CD107a) was detected on the LY6K119-142-LP-specific bulk Th1 cells (HD1, HD2 and HD3) and LY6K172-191-LP-specific bulk Th1 cells (HD2, HD3, and HD4) stimulated with cognate peptides (Fig.	('CD107a', 'Gene', (68, 74))	('HD3', 'Gene', '8841', (203, 206))	('peptides', 'Chemical', 'MESH:D010455', (241, 249))	('LY6K119', 'Chemical', '-', (96, 103))	('HD3', 'Gene', (149, 152))	('LY6K119-142-LP-specific', 'Var', (96, 119))	('Th', 'Chemical', '-', (0, 2))	('LP', 'Chemical', '-', (108, 110))	('Th', 'Chemical', '-', (125, 127))	('stimulated', 'PosReg', (217, 227))	('HD2', 'Gene', '3066', (141, 144))	('HD2', 'Gene', '3066', (198, 201))	('lysosomal-associated membrane protein 1', 'Gene', (4, 43))	('HD3', 'Gene', '8841', (149, 152))	('LAMP1', 'Gene', '3916', (46, 51))	('HD4', 'Gene', (212, 215))	('LY6K172', 'Chemical', '-', (158, 165))	('LP', 'Chemical', '-', (170, 172))	('Th', 'Chemical', '-', (187, 189))	('HD2', 'Gene', (141, 144))	('HD4', 'Gene', '9759', (212, 215))	('HD3', 'Gene', (203, 206))	('HD1', 'Gene', (136, 139))	('CD107a', 'Gene', '3916', (68, 74))	('HD2', 'Gene', (198, 201))	('HD1', 'Gene', '5339', (136, 139))	('LY6K172-191-LP-specific', 'Var', (158, 181))	('lysosomal-associated membrane protein 1', 'Gene', '3916', (4, 43))	('LAMP1', 'Gene', (46, 51))
370394	25340007	We also found that the number of specific IFNgamma-spots per 105 CTL-epitope vaccinated patient-derived PBMCs immunoreactive against LY6K119-142-LP and LY6K172-191-LP were significantly larger than in PBMCs from healthy donors (Fig.	('patient', 'Species', '9606', (88, 95))	('LY6K172', 'Chemical', '-', (152, 159))	('LP', 'Chemical', '-', (164, 166))	('LY6K119', 'Chemical', '-', (133, 140))	('LY6K119-142-LP', 'Var', (133, 147))	('LY6K172-191-LP', 'Var', (152, 166))	('LP', 'Chemical', '-', (145, 147))	('donor', 'Species', '9606', (220, 225))
370395	25340007	Although the increase of LY6K119-142-LP-specific spots from vaccinated patient PBMCs was not significant compared with those derived from HNMT patients before vaccination, the mean number of LY6K172-191-LP-specific IFNgamma spots in vaccinated patient PBMCs was significantly larger than that of HNMT patients before vaccination (Fig.	('HNMT', 'Disease', 'None', (296, 300))	('patient', 'Species', '9606', (143, 150))	('LP', 'Chemical', '-', (203, 205))	('HNMT', 'Disease', (296, 300))	('LY6K172', 'Chemical', '-', (191, 198))	('HNMT', 'Disease', (138, 142))	('HNMT', 'Phenotype', 'HP:0012288', (296, 300))	('patients', 'Species', '9606', (301, 309))	('LY6K172-191-LP-specific', 'Var', (191, 214))	('patients', 'Species', '9606', (143, 151))	('LY6K119', 'Chemical', '-', (25, 32))	('patient', 'Species', '9606', (244, 251))	('HNMT', 'Phenotype', 'HP:0012288', (138, 142))	('patient', 'Species', '9606', (71, 78))	('LP', 'Chemical', '-', (37, 39))	('patient', 'Species', '9606', (301, 308))	('HNMT', 'Disease', 'None', (138, 142))
370396	25340007	The proportion of donors responding to LY6K172-191-LP in HNMT patients after vaccination was also significantly higher than in HNMT patients before vaccination (P < 0.05; Fig.	('HNMT', 'Phenotype', 'HP:0012288', (57, 61))	('HNMT', 'Phenotype', 'HP:0012288', (127, 131))	('higher', 'PosReg', (112, 118))	('LY6K172', 'Chemical', '-', (39, 46))	('Th', 'Chemical', '-', (0, 2))	('LY6K172-191-LP', 'Var', (39, 53))	('LP', 'Chemical', '-', (51, 53))	('HNMT', 'Disease', 'None', (57, 61))	('HNMT', 'Disease', 'None', (127, 131))	('HNMT', 'Disease', (57, 61))	('HNMT', 'Disease', (127, 131))	('donor', 'Species', '9606', (18, 23))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (132, 140))
370400	25340007	HLA-Class II alleles of LY6K119-142-LP-specific HLA-DR-restricted Th1 cells derived from 2 HNMT patients were negative for HLA-DR8 and -DR15 (Fig.	('LP', 'Chemical', '-', (36, 38))	('HNMT', 'Phenotype', 'HP:0012288', (91, 95))	('HLA', 'Gene', '3123', (123, 126))	('Th', 'Chemical', '-', (66, 68))	('HLA', 'Gene', '3123', (0, 3))	('HLA', 'Gene', (123, 126))	('LY6K119-142-LP-specific', 'Var', (24, 47))	('LY6K119', 'Chemical', '-', (24, 31))	('HLA', 'Gene', (0, 3))	('HLA', 'Gene', '3123', (48, 51))	('HNMT', 'Disease', (91, 95))	('HNMT', 'Disease', 'None', (91, 95))	('patients', 'Species', '9606', (96, 104))	('HLA', 'Gene', (48, 51))
370402	25340007	HLA-Class II alleles of LY6K172-191-LP-specific HLA-DR-restricted Th1 cells in 5 HNMT patients were negative for HLA-DR15 (Fig.	('LP', 'Chemical', '-', (36, 38))	('HLA', 'Gene', '3123', (113, 116))	('HNMT', 'Phenotype', 'HP:0012288', (81, 85))	('LY6K172-191-LP-specific', 'Var', (24, 47))	('HLA', 'Gene', (113, 116))	('Th', 'Chemical', '-', (66, 68))	('HLA', 'Gene', '3123', (0, 3))	('HLA', 'Gene', (0, 3))	('HLA', 'Gene', '3123', (48, 51))	('HNMT', 'Disease', 'None', (81, 85))	('HNMT', 'Disease', (81, 85))	('LY6K172', 'Chemical', '-', (24, 31))	('HLA', 'Gene', (48, 51))	('patients', 'Species', '9606', (86, 94))
370403	25340007	3D; LY6K172-191-LP; HNMT31, 41, 42, 107, and 108).	('LP', 'Chemical', '-', (16, 18))	('HNMT', 'Disease', (20, 24))	('LY6K172-191-LP', 'Var', (4, 18))	('HNMT', 'Phenotype', 'HP:0012288', (20, 24))	('LY6K172', 'Chemical', '-', (4, 11))	('HNMT', 'Disease', 'None', (20, 24))
370404	25340007	These results suggest that LY6K119-142-LP and LY6K172-191-LP can be recognized by Th1 cells restricted by other HLA-Class II molecules not previously identified by the in vitro experiments assaying lymphocytes from healthy donors.	('Th', 'Chemical', '-', (82, 84))	('LY6K172', 'Chemical', '-', (46, 53))	('HLA', 'Gene', '3123', (112, 115))	('LP', 'Chemical', '-', (58, 60))	('Th', 'Chemical', '-', (0, 2))	('HLA', 'Gene', (112, 115))	('LY6K119-142-LP', 'Var', (27, 41))	('LY6K119', 'Chemical', '-', (27, 34))	('LY6K172-191-LP', 'Var', (46, 60))	('LP', 'Chemical', '-', (39, 41))	('donor', 'Species', '9606', (223, 228))
370406	25340007	Next, we tested whether LY6K172-191-LP-pulsed DCs could stimulate LY6K177-186-A24 SP-specific bulk CTLs via cross-presentation of LY6K172-191-LP.	('LP', 'Chemical', '-', (36, 38))	('bulk CTLs', 'CPA', (94, 103))	('LY6K177-186-A24', 'Gene', '54742', (66, 81))	('LY6K172', 'Chemical', '-', (130, 137))	('LY6K172-191-LP-pulsed', 'Var', (24, 45))	('LY6K177-186-A24', 'Gene', (66, 81))	('stimulate', 'PosReg', (56, 65))	('LP', 'Chemical', '-', (142, 144))	('SP', 'Chemical', '-', (82, 84))	('LY6K172-191-LP', 'Var', (130, 144))	('LY6K172', 'Chemical', '-', (24, 31))
370412	25340007	We next investigated whether LY6K172-191-LP-pulsed autologous DCs could induce expansion of LY6K177-186-A24 SP-specific CTLs.	('LY6K177-186-A24', 'Gene', '54742', (92, 107))	('LY6K177-186-A24', 'Gene', (92, 107))	('SP', 'Chemical', '-', (108, 110))	('LP', 'Chemical', '-', (41, 43))	('LY6K172', 'Chemical', '-', (29, 36))	('LY6K172-191-LP-pulsed', 'Var', (29, 50))
370415	25340007	These results suggest that the expansion of LY6K177-186-A24 SP-specific CTLs was induced by DC cross-presentation of LY6K172-191-LP.	('LY6K177-186-A24', 'Gene', (44, 59))	('LY6K172-191-LP', 'Var', (117, 131))	('LP', 'Chemical', '-', (129, 131))	('SP', 'Chemical', '-', (60, 62))	('induced', 'Reg', (81, 88))	('Th', 'Chemical', '-', (0, 2))	('SP-specific', 'Gene', (60, 71))	('LY6K177-186-A24', 'Gene', '54742', (44, 59))	('LY6K172', 'Chemical', '-', (117, 124))
370416	25340007	We next assessed whether LY6K172-191-LP could induce in vitro expansion of LY6K177-186-A24 SP-specific CTLs among PBMCs obtained from 5 HNMT patients vaccinated with LY6K177-186-A24 SP.	('LY6K177-186-A24', 'Gene', (75, 90))	('HNMT', 'Phenotype', 'HP:0012288', (136, 140))	('LP', 'Chemical', '-', (37, 39))	('LY6K172-191-LP', 'Var', (25, 39))	('LY6K172', 'Chemical', '-', (25, 32))	('LY6K177-186-A24', 'Gene', '54742', (166, 181))	('SP', 'Chemical', '-', (91, 93))	('HNMT', 'Disease', 'None', (136, 140))	('HNMT', 'Disease', (136, 140))	('LY6K177-186-A24', 'Gene', (166, 181))	('LY6K177-186-A24', 'Gene', '54742', (75, 90))	('patients', 'Species', '9606', (141, 149))	('SP', 'Chemical', '-', (182, 184))
370417	25340007	HNMT patient PBMCs were cultured with 10 mug/mL LY6K172-191-LP to which 20 IU/mL IL-2 and 5 ng/mL IL-7 were added on days 0 and 2.	('HNMT', 'Disease', (0, 4))	('LY6K172', 'Chemical', '-', (48, 55))	('patient', 'Species', '9606', (5, 12))	('LY6K172-191-LP', 'Var', (48, 62))	('LP', 'Chemical', '-', (60, 62))	('HNMT', 'Phenotype', 'HP:0012288', (0, 4))	('IL-2 and 5', 'Gene', '3558;3567', (81, 91))	('IL-7', 'Gene', '3574', (98, 102))	('IL-7', 'Gene', (98, 102))	('HNMT', 'Disease', 'None', (0, 4))
370420	25340007	The tetramer+ cells were markedly expanded by 1-wk in vitro stimulation of PBMCs with LY6K172-191-LP (without adding LY6K177-186-A24 SP) with the frequency of LY6K177-186-A24 SP-specific CTLs increasing to 0.35% of CD8+ T-cells.	('expanded', 'PosReg', (34, 42))	('CD8', 'Gene', '925', (215, 218))	('LP', 'Chemical', '-', (98, 100))	('SP', 'Chemical', '-', (175, 177))	('LY6K177-186-A24', 'Gene', '54742', (117, 132))	('LY6K172-191-LP', 'Var', (86, 100))	('LY6K177-186-A24', 'Gene', '54742', (159, 174))	('LY6K177-186-A24', 'Gene', (159, 174))	('LY6K177-186-A24', 'Gene', (117, 132))	('Th', 'Chemical', '-', (0, 2))	('LY6K172', 'Chemical', '-', (86, 93))	('SP', 'Chemical', '-', (133, 135))	('CD8', 'Gene', (215, 218))
370424	25340007	These results suggest that LY6K177-186-A24 SP-specific CTLs might be augmented by DC cross-presentation of LY6K172-191-LP without direct stimulation by LY6K177-186-A24 SP in HNMT patients.	('LY6K177-186-A24', 'Gene', '54742', (27, 42))	('LP', 'Chemical', '-', (119, 121))	('HNMT', 'Phenotype', 'HP:0012288', (174, 178))	('LY6K172', 'Chemical', '-', (107, 114))	('augmented', 'PosReg', (69, 78))	('LY6K172-191-LP', 'Var', (107, 121))	('LY6K177-186-A24', 'Gene', (27, 42))	('Th', 'Chemical', '-', (0, 2))	('LY6K177-186-A24', 'Gene', '54742', (152, 167))	('SP', 'Chemical', '-', (43, 45))	('patients', 'Species', '9606', (179, 187))	('SP', 'Chemical', '-', (168, 170))	('HNMT', 'Disease', 'None', (174, 178))	('LY6K177-186-A24', 'Gene', (152, 167))	('CTLs', 'CPA', (55, 59))	('HNMT', 'Disease', (174, 178))	('DC cross-presentation', 'MPA', (82, 103))
370425	25340007	Similar results were obtained from 9 of 11 HNMT patients vaccinated with LY6K177-186-A24 SP when the PBMCs were cultured with a mixture of LY6K119-142-LP and LY6K172-191-LP (Fig.	('HNMT', 'Phenotype', 'HP:0012288', (43, 47))	('LY6K172-191-LP', 'Var', (158, 172))	('LY6K119', 'Chemical', '-', (139, 146))	('LY6K177-186-A24', 'Gene', '54742', (73, 88))	('LY6K172', 'Chemical', '-', (158, 165))	('LP', 'Chemical', '-', (151, 153))	('HNMT', 'Disease', 'None', (43, 47))	('HNMT', 'Disease', (43, 47))	('LY6K177-186-A24', 'Gene', (73, 88))	('LP', 'Chemical', '-', (170, 172))	('LY6K119-142-LP', 'Var', (139, 153))	('patients', 'Species', '9606', (48, 56))	('SP', 'Chemical', '-', (89, 91))
370428	25340007	HLA-A24-restricted LY6K177-186-A24 SP-specific CTLs were significantly induced by culturing PBMCs from 3 HLA-A24+ healthy donors (HD1, HD3, HD4) with LY6K172-191-LP for 2 wk (Fig.	('LY6K177-186-A24', 'Gene', (19, 34))	('HD4', 'Gene', '9759', (140, 143))	('SP', 'Chemical', '-', (35, 37))	('HLA-A', 'Gene', '3105', (0, 5))	('donor', 'Species', '9606', (122, 127))	('induced', 'PosReg', (71, 78))	('LY6K177-186-A24', 'Gene', '54742', (19, 34))	('SP-specific', 'Gene', (35, 46))	('HD3', 'Gene', (135, 138))	('LY6K172-191-LP', 'Var', (150, 164))	('HD1', 'Gene', (130, 133))	('HLA-A', 'Gene', (105, 110))	('LY6K172', 'Chemical', '-', (150, 157))	('HLA-A', 'Gene', (0, 5))	('HD1', 'Gene', '5339', (130, 133))	('LP', 'Chemical', '-', (162, 164))	('HD3', 'Gene', '8841', (135, 138))	('HD4', 'Gene', (140, 143))	('HLA-A', 'Gene', '3105', (105, 110))
370429	25340007	Next, humanized transgenic mice expressing HLA-A24 were immunized 3 times with LY6K172-191-LP.	('LY6K172', 'Chemical', '-', (79, 86))	('human', 'Species', '9606', (6, 11))	('LY6K172-191-LP', 'Var', (79, 93))	('HLA-A', 'Gene', (43, 48))	('transgenic mice', 'Species', '10090', (16, 31))	('HLA-A', 'Gene', '3105', (43, 48))	('LP', 'Chemical', '-', (91, 93))
370431	25340007	The CD8+ T-cells isolated from LY6K172-191-LP-vaccinated HLA-A24 mice produced IFNgamma in response to stimulation with bone marrow-derived DCs pulsed with the LY6K177-186-A24 SP (Fig.	('LP', 'Chemical', '-', (43, 45))	('LY6K172-191-LP-vaccinated', 'Var', (31, 56))	('SP', 'Chemical', '-', (176, 178))	('HLA-A', 'Gene', (57, 62))	('CD8', 'Gene', (4, 7))	('mice', 'Species', '10090', (65, 69))	('Th', 'Chemical', '-', (0, 2))	('CD8', 'Gene', '925', (4, 7))	('IFNgamma', 'Protein', (79, 87))	('LY6K177-186-A24', 'Gene', '54742', (160, 175))	('LY6K172', 'Chemical', '-', (31, 38))	('HLA-A', 'Gene', '3105', (57, 62))	('LY6K177-186-A24', 'Gene', (160, 175))
370432	25340007	These results demonstrate that following uptake LY6K172-191-LP, APCs can cross-prime LY6K177-186-A24 SP-specific CTLs in vitro and in vivo.	('LY6K172', 'Chemical', '-', (48, 55))	('APC', 'Disease', 'MESH:D011125', (64, 67))	('LY6K172-191-LP', 'Var', (48, 62))	('LY6K177-186-A24', 'Gene', (85, 100))	('LP', 'Chemical', '-', (60, 62))	('APC', 'Disease', (64, 67))	('Th', 'Chemical', '-', (0, 2))	('SP', 'Chemical', '-', (101, 103))	('LY6K177-186-A24', 'Gene', '54742', (85, 100))
370443	25340007	This result was reproducible in that similar results were obtained using CTLs derived from HNMT31 and HNMT42 showing that either LY6K119-142-LP or LY6K172-191-LP could enhance CTL responses to LY6K177-186-A24 SP (Fig.	('HNMT', 'Phenotype', 'HP:0012288', (102, 106))	('LY6K172-191-LP', 'Var', (147, 161))	('HNMT', 'Phenotype', 'HP:0012288', (91, 95))	('enhance', 'PosReg', (168, 175))	('LY6K119', 'Chemical', '-', (129, 136))	('HNMT', 'Disease', (102, 106))	('LY6K119-142-LP', 'Var', (129, 143))	('Th', 'Chemical', '-', (0, 2))	('LP', 'Chemical', '-', (141, 143))	('HNMT', 'Disease', 'None', (102, 106))	('LY6K172', 'Chemical', '-', (147, 154))	('CTL', 'MPA', (176, 179))	('HNMT', 'Disease', 'None', (91, 95))	('LY6K177-186-A24', 'Gene', (193, 208))	('LP', 'Chemical', '-', (159, 161))	('LY6K177-186-A24', 'Gene', '54742', (193, 208))	('SP', 'Chemical', '-', (209, 211))	('HNMT', 'Disease', (91, 95))
370446	25340007	A known CTL-epitope, LY6K177-186-A24 SP was embedded within LY6K172-191-LP.	('LY6K172-191-LP', 'Var', (60, 74))	('LY6K177-186-A24', 'Gene', '54742', (21, 36))	('LY6K177-186-A24', 'Gene', (21, 36))	('LP', 'Chemical', '-', (72, 74))	('LY6K172', 'Chemical', '-', (60, 67))	('SP', 'Chemical', '-', (37, 39))
370449	25340007	In this study, we determined that LY6K177-186-A24 SP-specific CTLs can be induced by cross-presentation of LY6K172-191-LP in vitro and in vivo.	('LY6K177-186-A24', 'Gene', (34, 49))	('LP', 'Chemical', '-', (119, 121))	('LY6K172', 'Chemical', '-', (107, 114))	('induced', 'Reg', (74, 81))	('LY6K172-191-LP', 'Var', (107, 121))	('SP-specific', 'Gene', (50, 61))	('SP', 'Chemical', '-', (50, 52))	('LY6K177-186-A24', 'Gene', '54742', (34, 49))
370455	25340007	Interestingly, the frequency of LY6K172-191-LP-specific Th cell responses and the number of IFNgamma-producing LY6K172-191-LP-specific Th1 cells in HNMT patients after CTL-epitope vaccination were significantly larger than those detected in patients prior to vaccination.	('LP', 'Chemical', '-', (44, 46))	('HNMT', 'Disease', 'None', (148, 152))	('LY6K172', 'Chemical', '-', (111, 118))	('patients', 'Species', '9606', (153, 161))	('HNMT', 'Disease', (148, 152))	('LY6K172', 'Chemical', '-', (32, 39))	('LP', 'Chemical', '-', (123, 125))	('larger', 'PosReg', (211, 217))	('Th', 'Chemical', '-', (56, 58))	('HNMT', 'Phenotype', 'HP:0012288', (148, 152))	('LY6K172-191-LP-specific', 'Var', (32, 55))	('Th', 'Chemical', '-', (135, 137))	('patients', 'Species', '9606', (241, 249))
370463	25340007	Vaccination with LY6K172-191-LP may, therefore, potentially elicit combined Th and CTL responses.	('LY6K172-191-LP', 'Var', (17, 31))	('elicit', 'Reg', (60, 66))	('LY6K172', 'Chemical', '-', (17, 24))	('Th', 'Chemical', '-', (76, 78))	('LP', 'Chemical', '-', (29, 31))
370469	25340007	Based on the HLA-subtypes found to be capable of antigen presentation from studies using healthy donors, LY6K119-142-LP and LY6K172-191-LP are predicted to be useful in approximately 82% of the total population.	('LP', 'Chemical', '-', (136, 138))	('LY6K119', 'Chemical', '-', (105, 112))	('LY6K172', 'Chemical', '-', (124, 131))	('donor', 'Species', '9606', (97, 102))	('LY6K119-142-LP', 'Var', (105, 119))	('HLA', 'Gene', '3123', (13, 16))	('LY6K172-191-LP', 'Var', (124, 138))	('LP', 'Chemical', '-', (117, 119))	('HLA', 'Gene', (13, 16))
370470	25340007	We showed that LY6K119-142-LP induced HLA-DP5, HLA-DR8, or HLA-DR15-restricted Th cells in healthy donors and also induced HLA-DR or HLA-DQ-restricted Th cells in 3 HNMT patients (HNMT31, 41, and 107).	('HNMT', 'Disease', 'None', (180, 184))	('HLA', 'Gene', '3123', (123, 126))	('donor', 'Species', '9606', (99, 104))	('HLA', 'Gene', '3123', (59, 62))	('HNMT', 'Disease', (165, 169))	('HNMT', 'Phenotype', 'HP:0012288', (165, 169))	('HNMT', 'Disease', (180, 184))	('HLA', 'Gene', (133, 136))	('Th', 'Chemical', '-', (151, 153))	('HNMT', 'Phenotype', 'HP:0012288', (180, 184))	('HLA', 'Gene', (47, 50))	('Th', 'Chemical', '-', (79, 81))	('HLA', 'Gene', (38, 41))	('induced', 'PosReg', (30, 37))	('LY6K119-142-LP', 'Var', (15, 29))	('patients', 'Species', '9606', (170, 178))	('LY6K119', 'Chemical', '-', (15, 22))	('HLA-DP', 'Gene', '3115', (38, 44))	('LP', 'Chemical', '-', (27, 29))	('HLA', 'Gene', (123, 126))	('HLA-DP', 'Gene', (38, 44))	('HLA', 'Gene', (59, 62))	('HLA', 'Gene', '3123', (133, 136))	('HLA', 'Gene', '3123', (47, 50))	('induced', 'PosReg', (115, 122))	('HLA', 'Gene', '3123', (38, 41))	('HNMT', 'Disease', 'None', (165, 169))
370472	25340007	We also showed that LY6K172-191-LP induced HLA-DR15 or HLA-DQ-restricted Th cells in healthy donors.	('HLA', 'Gene', '3123', (43, 46))	('LY6K172-191-LP', 'Var', (20, 34))	('HLA', 'Gene', (43, 46))	('HLA', 'Gene', '3123', (55, 58))	('induced', 'Reg', (35, 42))	('Th', 'Chemical', '-', (73, 75))	('LY6K172', 'Chemical', '-', (20, 27))	('HLA', 'Gene', (55, 58))	('LP', 'Chemical', '-', (32, 34))	('donor', 'Species', '9606', (93, 98))
370473	25340007	Although we observed that the presence of HLA-DR-restricted LY6K172-191-LP-specific Th cells in 7 HNMT patients, HLA-Class II alleles of 5 HNMT patients (HNMT31, 41, 42, 107, and 108) were negative for HLA-DR15.	('LY6K172', 'Chemical', '-', (60, 67))	('HLA', 'Gene', '3123', (202, 205))	('HLA', 'Gene', '3123', (113, 116))	('HNMT', 'Disease', 'None', (139, 143))	('HLA', 'Gene', '3123', (42, 45))	('HNMT', 'Disease', 'None', (154, 158))	('HNMT', 'Disease', 'None', (98, 102))	('LY6K172-191-LP-specific', 'Var', (60, 83))	('Th', 'Chemical', '-', (84, 86))	('HNMT', 'Disease', (139, 143))	('HNMT', 'Phenotype', 'HP:0012288', (139, 143))	('HLA', 'Gene', (202, 205))	('HNMT', 'Disease', (98, 102))	('HNMT', 'Disease', (154, 158))	('HNMT', 'Phenotype', 'HP:0012288', (154, 158))	('HNMT', 'Phenotype', 'HP:0012288', (98, 102))	('HLA', 'Gene', (113, 116))	('LP', 'Chemical', '-', (72, 74))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (103, 111))	('HLA', 'Gene', (42, 45))
370495	25340007	Mouse fibroblast cell lines (L-cells), genetically engineered to express the HLA class II heterodimeric pairs DR4 (DRB1*04:05) and L-DR4, DR8 (DRB1*08:03) and L-DR8, DR15 (DRB1*15:02) and L-DR15, or DP5 (DPB1*05:01) and L-DP5, were used as antigen-presenting cells (APCs).	('DR4', 'Gene', (133, 136))	('heterodimeric', 'Protein', (90, 103))	('DPB1', 'Gene', (204, 208))	('DRB1', 'Gene', '3123', (172, 176))	('HLA', 'Gene', (77, 80))	('DPB1', 'Gene', '3115', (204, 208))	('DRB1', 'Gene', '3123', (115, 119))	('DR4', 'Gene', '3126', (110, 113))	('DR4', 'Gene', '3126', (133, 136))	('DRB1', 'Gene', (172, 176))	('APC', 'Disease', 'MESH:D011125', (266, 269))	('APC', 'Disease', (266, 269))	('DRB1', 'Gene', (115, 119))	('DRB1', 'Gene', '3123', (143, 147))	('Mouse fibroblast', 'CellLine', 'CVCL:0594', (0, 16))	('L-DR8', 'Var', (159, 164))	('HLA', 'Gene', '3123', (77, 80))	('DRB1', 'Gene', (143, 147))	('DR4', 'Gene', (110, 113))
370499	25340007	The 24-mer LP, LY6K119-142-LP (KWTEPYCVIAAVKIFPRFFMVAKQ) was predicted to have a strong binding affinity to multiple HLA class II molecules encoded by DPB1*05:01, DRB1*08:03, DRB1*09:01, and DRB1*15:02 genes.	('HLA', 'Gene', (117, 120))	('DRB1', 'Gene', '3123', (163, 167))	('DRB1', 'Gene', '3123', (191, 195))	('LY6K119', 'Chemical', '-', (15, 22))	('DRB1', 'Gene', (163, 167))	('DRB1', 'Gene', (191, 195))	('DPB1', 'Gene', (151, 155))	('binding affinity', 'Interaction', (88, 104))	('LP', 'Chemical', '-', (27, 29))	('LP', 'Chemical', '-', (11, 13))	('Th', 'Chemical', '-', (0, 2))	('DRB1', 'Gene', '3123', (175, 179))	('DPB1', 'Gene', '3115', (151, 155))	('DRB1', 'Gene', (175, 179))	('HLA', 'Gene', '3123', (117, 120))	('LY6K119-142-LP', 'Var', (15, 29))
370500	25340007	The 20-mer LP, LY6K172-191-LP (KCCKIRYCNLEGPPINSSVF) was predicted to have a strong binding affinity to HLA class II molecules encoded by DRB1*09:01 and DRB1*15:02 genes and identified as a LP that spanned a known 10-mer CTL-epitope (LY6K177-186-A24 SP) recognized by HLA-A24-restricted CTLs (Fig.	('LY6K177-186-A24', 'Gene', '54742', (234, 249))	('binding affinity', 'Interaction', (84, 100))	('DRB1', 'Gene', '3123', (138, 142))	('Th', 'Chemical', '-', (0, 2))	('HLA-A', 'Gene', '3105', (268, 273))	('LY6K172-191-LP', 'Var', (15, 29))	('HLA', 'Gene', '3123', (104, 107))	('DRB1', 'Gene', (138, 142))	('HLA', 'Gene', (268, 271))	('DRB1', 'Gene', '3123', (153, 157))	('LP', 'Chemical', '-', (27, 29))	('LP', 'Chemical', '-', (11, 13))	('DRB1', 'Gene', (153, 157))	('LY6K172', 'Chemical', '-', (15, 22))	('LY6K177-186-A24', 'Gene', (234, 249))	('SP', 'Chemical', '-', (250, 252))	('LP', 'Chemical', '-', (190, 192))	('HLA-A', 'Gene', (268, 273))	('HLA', 'Gene', '3123', (268, 271))	('HLA', 'Gene', (104, 107))
370523	25340007	DCs were pulsed with 16 muM each LY6K177-186-A24 SP, LY6K172-191-LP, or control LP for 3 h, and washed 3 times.	('LY6K177-186-A24', 'Gene', (33, 48))	('SP', 'Chemical', '-', (49, 51))	('LY6K172', 'Chemical', '-', (53, 60))	('LP', 'Chemical', '-', (65, 67))	('LP', 'Chemical', '-', (80, 82))	('LY6K172-191-LP', 'Var', (53, 67))	('LY6K177-186-A24', 'Gene', '54742', (33, 48))
370527	25340007	Fresh PBMCs from 5 HNMT patients vaccinated with LY6K177-186-A24 SP were cultured at 1 x 105/well with 10 mug/mL LY6K172-191-LP in a 96-well plate.	('SP', 'Chemical', '-', (65, 67))	('LY6K177-186-A24', 'Gene', '54742', (49, 64))	('LP', 'Chemical', '-', (125, 127))	('HNMT', 'Disease', 'None', (19, 23))	('LY6K172', 'Chemical', '-', (113, 120))	('HNMT', 'Disease', (19, 23))	('LY6K177-186-A24', 'Gene', (49, 64))	('patients', 'Species', '9606', (24, 32))	('LY6K172-191-LP', 'Var', (113, 127))	('HNMT', 'Phenotype', 'HP:0012288', (19, 23))
370530	25340007	To assess induction of LY6K177-186-A24 SP-specific CTLs from HLA-A24+ donors (HD1, HD3, and HD4) by stimulation with LY6K172-191-LP in vitro, 2 x 106 cells/well PBMCs were incubated with 7 muM LY6K172-191-LP in 24-well plates for 2 wk without addition of cytokines.	('HLA-A', 'Gene', '3105', (61, 66))	('HD1', 'Gene', (78, 81))	('LY6K172-191-LP', 'Var', (117, 131))	('LY6K177-186-A24', 'Gene', (23, 38))	('LP', 'Chemical', '-', (129, 131))	('LY6K172', 'Chemical', '-', (193, 200))	('HD4', 'Gene', (92, 95))	('HD1', 'Gene', '5339', (78, 81))	('HD3', 'Gene', (83, 86))	('HLA-A', 'Gene', (61, 66))	('SP', 'Chemical', '-', (39, 41))	('HD3', 'Gene', '8841', (83, 86))	('LP', 'Chemical', '-', (205, 207))	('LY6K172-191-LP', 'Var', (193, 207))	('HD4', 'Gene', '9759', (92, 95))	('LY6K177-186-A24', 'Gene', '54742', (23, 38))	('donor', 'Species', '9606', (70, 75))	('LY6K172', 'Chemical', '-', (117, 124))
370535	25340007	Seven days after the third vaccination with LY6K172-191-LP, CD8+ T cells were isolated from inguinal lymph nodes by positive selection with magnetic microbeads (Miltenyi Biotec).	('CD8', 'Gene', '925', (60, 63))	('LY6K172', 'Chemical', '-', (44, 51))	('LP', 'Chemical', '-', (56, 58))	('Biotec', 'Chemical', '-', (170, 176))	('LY6K172-191-LP', 'Var', (44, 58))	('CD8', 'Gene', (60, 63))
370539	25340007	In another experiment, fresh PBMCs obtained from HNMT patients vaccinated with LY6K177-186-A24 SP were plated in a 96-well, round-bottomed culture plate (1 x 105 cells/well), followed by addition of 10 mug/mL LY6K177-186-A24 SP alone or LY6K177-186-A24 SP applied together with either control LP, LY6K119-142-LP, or LY6K172-191-LP (10 mug/mL) in a final volume of 200 muL AIM-V supplemented with 5% human decomplemented plasma without addition of cytokines.	('LY6K177-186-A24', 'Gene', '54742', (209, 224))	('LY6K119-142-LP', 'Var', (297, 311))	('patients', 'Species', '9606', (54, 62))	('LP', 'Chemical', '-', (309, 311))	('SP', 'Chemical', '-', (225, 227))	('LP', 'Chemical', '-', (293, 295))	('human', 'Species', '9606', (399, 404))	('LY6K177-186-A24', 'Gene', (237, 252))	('LY6K177-186-A24', 'Gene', (79, 94))	('SP', 'Chemical', '-', (95, 97))	('HNMT', 'Disease', 'None', (49, 53))	('LY6K177-186-A24', 'Gene', '54742', (237, 252))	('LY6K177-186-A24', 'Gene', '54742', (79, 94))	('LY6K172-191-LP', 'Var', (316, 330))	('SP', 'Chemical', '-', (253, 255))	('LY6K172', 'Chemical', '-', (316, 323))	('LY6K119', 'Chemical', '-', (297, 304))	('HNMT', 'Disease', (49, 53))	('LP', 'Chemical', '-', (328, 330))	('LY6K177-186-A24', 'Gene', (209, 224))	('HNMT', 'Phenotype', 'HP:0012288', (49, 53))
370541	25340007	Fresh PBMCs obtained from 23 HNMT patients before and after CTL-epitope peptide-vaccination were cultured at 2 x 106 cells/well in 24-well plates with a mixture of 10 mug/mL each LY6K119-142-LP and LY6K172-191-LP in a final volume of 2 mL AIM-V supplemented with 5% human decomplemented plasma at 37  C. IL-2 and IL-7 were added on days 0 and 2.	('IL-7', 'Gene', (313, 317))	('LY6K119-142-LP', 'Var', (179, 193))	('HNMT', 'Disease', 'None', (29, 33))	('LY6K172', 'Chemical', '-', (198, 205))	('HNMT', 'Disease', (29, 33))	('LP', 'Chemical', '-', (191, 193))	('LY6K172-191-LP', 'Var', (198, 212))	('LY6K119', 'Chemical', '-', (179, 186))	('LP', 'Chemical', '-', (210, 212))	('patients', 'Species', '9606', (34, 42))	('IL-2', 'Gene', (304, 308))	('IL-2', 'Gene', '3558', (304, 308))	('IL-7', 'Gene', '3574', (313, 317))	('human', 'Species', '9606', (266, 271))	('HNMT', 'Phenotype', 'HP:0012288', (29, 33))
370555	23800042	Injection of CXCR4 siRNA transfected cells inhibited tumor growth in a xenograft model compared with blank and negative control groups (p <0.05).	('CXCR4', 'Var', (13, 18))	('inhibited', 'NegReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
370585	23800042	After siRNA interference KYSE-150 for 48 h, compared with negative control and blank control group, CXCR4 mRNA expression was inhibited in CXCR4 siRNA1 group and CXCR4 siRNA2 group.	('CXCR4 mRNA expression', 'MPA', (100, 121))	('expression', 'Species', '29278', (111, 121))	('CXCR4 siRNA1', 'Var', (139, 151))	('inhibited', 'NegReg', (126, 135))
370588	23800042	In order to detect the effects of CXCR4 on invasion of esophageal carcinoma, we used transwell invasion assay and found that KYSE-150 and TE-13 penetrating cells transfected with CXCR4 siRNA1 and CXCR4 siRNA2 reduced significantly compared to negative control and blank control group (Figure 3).	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('CXCR4', 'Var', (179, 184))	('esophageal carcinoma', 'Disease', (55, 75))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (55, 75))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (55, 75))	('reduced', 'NegReg', (209, 216))
370591	23800042	It can be seen that inhibition of CXCR4 expression in vitro could not only decreased the invasion and metastasis but also inhibit the proliferation.	('CXCR4 expression', 'MPA', (34, 50))	('expression', 'Species', '29278', (40, 50))	('inhibition', 'Var', (20, 30))	('inhibit', 'NegReg', (122, 129))	('proliferation', 'CPA', (134, 147))	('decreased', 'NegReg', (75, 84))
370597	23800042	The results showed that the siRNA of targeting CXCR4 inhibited tumor growth in a xenograft model.	('tumor', 'Disease', (63, 68))	('inhibited', 'NegReg', (53, 62))	('targeting', 'Var', (37, 46))	('CXCR4', 'MPA', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
370598	23800042	In nude mice esophageal carcinoma cell xenografts model, expression of CXCR4 mRNA in CXCR4 siRNA1 and CXCR4 siRNA2 group were lower significantly than in negative control and blank control group (Figure 6), The results showed that CXCR4 siRNA inhibited xenografts tumor tissue CXCR4 mRNA expression effectively in vivo.	('expression', 'MPA', (57, 67))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (13, 33))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('lower', 'NegReg', (126, 131))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (13, 33))	('inhibited', 'NegReg', (243, 252))	('tumor', 'Disease', (264, 269))	('expression', 'Species', '29278', (57, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('CXCR4', 'Var', (231, 236))	('nude mice', 'Species', '10090', (3, 12))	('expression', 'Species', '29278', (288, 298))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('esophageal carcinoma', 'Disease', (13, 33))
370626	19138977	H. pylori is now a known cause of gastric and duodenal ulcers, noncardia gastric adenocarcinoma, and gastric MALT lymphoma.	('gastric MALT lymphoma', 'Disease', (101, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('gastric MALT lymphoma', 'Phenotype', 'HP:0045038', (101, 122))	('ulcers', 'Disease', (55, 61))	('H. pylori', 'Species', '210', (0, 9))	('duodenal ulcers', 'Phenotype', 'HP:0002588', (46, 61))	('ulcers', 'Disease', 'MESH:D014456', (55, 61))	('noncardia gastric adenocarcinoma', 'Disease', 'MESH:D013274', (63, 95))	('cause', 'Reg', (25, 30))	('H. pylori', 'Var', (0, 9))	('gastric MALT lymphoma', 'Disease', 'MESH:D018442', (101, 122))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('noncardia gastric adenocarcinoma', 'Disease', (63, 95))
370675	19138977	Similar to the overall association, every subgroup analysis showed an inverse association between H. pylori positivity and EAC risk.	('H. pylori', 'Protein', (98, 107))	('H. pylori', 'Species', '210', (98, 107))	('positivity', 'Var', (108, 118))	('EAC', 'Disease', (123, 126))	('inverse', 'NegReg', (70, 77))	('pylori positivity', 'Phenotype', 'HP:0005202', (101, 118))
370700	19138977	Our results suggest that CagA-positive strains of H. pyloriwhich constitute the majority of H. pylori strains, may protect against EAC, and that increasing EAC rates may be partly due to the decline of H. pylori in human populations.	('H. pylori', 'Species', '210', (92, 101))	('protect', 'Reg', (115, 122))	('EAC', 'Disease', (131, 134))	('CagA', 'Gene', (25, 29))	('EAC', 'Disease', (156, 159))	('decline', 'NegReg', (191, 198))	('strains', 'Var', (102, 109))	('H. pylori', 'Species', '210', (202, 211))	('CagA', 'Gene', '6279', (25, 29))	('H. pylori', 'Gene', (92, 101))	('H. pylori', 'Species', '210', (50, 59))	('human', 'Species', '9606', (215, 220))
370704	19138977	H. pylori may decrease risk of EAC by reducing acid production in the stomach and hence reducing acid reflux to the esophagus.	('acid production in the stomach', 'MPA', (47, 77))	('acid reflux to the esophagus', 'MPA', (97, 125))	('H. pylori', 'Species', '210', (0, 9))	('reducing', 'NegReg', (38, 46))	('acid reflux', 'Phenotype', 'HP:0002020', (97, 108))	('H. pylori', 'Var', (0, 9))	('EAC', 'Disease', (31, 34))	('reducing', 'NegReg', (88, 96))
370735	19138977	In conclusion, we found an inverse association between CagA-positive strains of H. pylori and risk of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (102, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('H. pylori', 'Gene', (80, 89))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (102, 127))	('inverse', 'NegReg', (27, 34))	('CagA', 'Gene', (55, 59))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))	('CagA', 'Gene', '6279', (55, 59))	('H. pylori', 'Species', '210', (80, 89))	('strains', 'Var', (69, 76))
370772	21447180	Immunofluorescence assays supported this finding and showed accumulation and nuclear translocation of beta-catenin in cells expressing t-DARPP.	('t-DARPP', 'Var', (135, 142))	('beta-catenin', 'Gene', '1499', (102, 114))	('t-DARPP', 'Chemical', '-', (135, 142))	('beta-catenin', 'Gene', (102, 114))	('accumulation', 'PosReg', (60, 72))	('nuclear translocation', 'MPA', (77, 98))
370790	21447180	Dysregulation and aberrant activation of Wnt pathways or mutations in beta-catenin or adenomatous polyposis coli (APC) often results in increased beta-catenin accumulation.	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (86, 112))	('beta-catenin', 'Gene', (70, 82))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (86, 112))	('beta-catenin', 'Gene', (146, 158))	('Wnt pathways', 'Pathway', (41, 53))	('APC', 'Phenotype', 'HP:0005227', (114, 117))	('beta-catenin', 'Gene', '1499', (70, 82))	('adenomatous polyposis coli', 'Disease', (86, 112))	('mutations', 'Var', (57, 66))	('beta-catenin', 'Gene', '1499', (146, 158))	('APC', 'Gene', (114, 117))	('activation', 'PosReg', (27, 37))	('increased', 'PosReg', (136, 145))	('APC', 'Gene', '324', (114, 117))
370793	21447180	In the absence of Wnt/Wingless ligand activation, beta-catenin exists in the cytoplasm as a multi-protein complex with scaffold protein Axin, APC, PP2A (protein phosphatase 2A), GSK-3beta, and CK1 (casein kinase I).	('GSK-3beta', 'Gene', (178, 187))	('Axin', 'Gene', (136, 140))	('CK1', 'Gene', (193, 196))	('APC', 'Phenotype', 'HP:0005227', (142, 145))	('APC', 'Gene', (142, 145))	('beta-catenin', 'Gene', (50, 62))	('CK1', 'Species', '2498238', (193, 196))	('PP2A', 'Var', (147, 151))	('Axin', 'Gene', '8312', (136, 140))	('APC', 'Gene', '324', (142, 145))	('beta-catenin', 'Gene', '1499', (50, 62))	('GSK-3beta', 'Gene', '2932', (178, 187))
370796	21447180	AKT-mediated phosphorylation and inactivation of GSK-3beta leads to hypophosphorylation and stabilization of cytosolic beta-catenin with subsequent accumulation and translocation into the nucleus.	('AKT', 'Gene', (0, 3))	('beta-catenin', 'Gene', '1499', (119, 131))	('hypophosphorylation', 'Disease', 'None', (68, 87))	('GSK-3beta', 'Gene', (49, 58))	('stabilization', 'MPA', (92, 105))	('GSK-3beta', 'Gene', '2932', (49, 58))	('translocation into the nucleus', 'MPA', (165, 195))	('accumulation', 'PosReg', (148, 160))	('beta-catenin', 'Gene', (119, 131))	('AKT', 'Gene', '207', (0, 3))	('hypophosphorylation', 'Disease', (68, 87))	('inactivation', 'Var', (33, 45))
370802	21447180	The specificity of beta-catenin/TCF was confirmed by the co-transfection of different expression vectors with mutant pFopFlash reporter.	('mutant', 'Var', (110, 116))	('TCF', 'Gene', (32, 35))	('TCF', 'Gene', '3172', (32, 35))	('beta-catenin', 'Gene', (19, 31))	('beta-catenin', 'Gene', '1499', (19, 31))	('expression vectors', 'Species', '29278', (86, 104))	('pFopFlash', 'Gene', (117, 126))
370803	21447180	In line with these findings, the immunofluorescence studies indicated a significant increase (P < 0.001) in the percentage of cells showing accumulation and nuclear localization of beta-catenin in cells transfected with t-DARPP as compared to empty vector control; AGS (86% vs 13%) and MKN28 (80% vs 26%) gastric cancer cells and FLO-1 (86% vs 20%) (Figure 2).	('gastric cancer', 'Phenotype', 'HP:0012126', (305, 319))	('beta-catenin', 'Gene', '1499', (181, 193))	('accumulation', 'MPA', (140, 152))	('gastric cancer', 'Disease', (305, 319))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('gastric cancer', 'Disease', 'MESH:D013274', (305, 319))	('increase', 'PosReg', (84, 92))	('AGS', 'Disease', (265, 268))	('t-DARPP', 'Var', (220, 227))	('t-DARPP', 'Chemical', '-', (220, 227))	('nuclear localization', 'MPA', (157, 177))	('AGS', 'Disease', 'MESH:C535607', (265, 268))	('beta-catenin', 'Gene', (181, 193))
370813	21447180	Western blot analysis indicated that phosphorylation of AKT at Ser473 was remarkably higher in AGS, MKN28 and FLO-1 cells stably expressing t-DARPP as compared to the control cells (Figure 4), thus providing an explanation for the increase in GSK-3beta (Ser9) phosphorylation.	('AGS', 'Disease', (95, 98))	('AKT', 'Gene', '207', (56, 59))	('phosphorylation', 'MPA', (37, 52))	('higher', 'PosReg', (85, 91))	('AKT', 'Gene', (56, 59))	('AGS', 'Disease', 'MESH:C535607', (95, 98))	('t-DARPP', 'Var', (140, 147))	('t-DARPP', 'Chemical', '-', (140, 147))	('GSK-3beta', 'Gene', '2932', (243, 252))	('GSK-3beta', 'Gene', (243, 252))	('Ser9', 'Chemical', '-', (254, 258))	('Ser473', 'Chemical', '-', (63, 69))
370818	21447180	The knockdown of t-DARPP led to a remarkable decrease in the levels of phosphorylated GSK-3beta, beta-catenin, c-MYC, and Cyclin D1 (Figure 5).	('GSK-3beta', 'Gene', (86, 95))	('c-MYC', 'Gene', '4609', (111, 116))	('beta-catenin', 'Gene', (97, 109))	('Cyclin D1', 'Gene', '595', (122, 131))	('c-MYC', 'Gene', (111, 116))	('GSK-3beta', 'Gene', '2932', (86, 95))	('t-DARPP', 'Gene', (17, 24))	('t-DARPP', 'Chemical', '-', (17, 24))	('decrease', 'NegReg', (45, 53))	('beta-catenin', 'Gene', '1499', (97, 109))	('Cyclin D1', 'Gene', (122, 131))	('knockdown', 'Var', (4, 13))
370820	21447180	Our data demonstrate a significant abrogation of pAKT (Ser473) and pGSK-3beta (Ser9) after treatment with LY492002 for 30 min and 2 h (Figure 5C).	('Ser473', 'Chemical', '-', (55, 61))	('LY492002', 'Chemical', '-', (106, 114))	('pGSK-3beta', 'Chemical', '-', (67, 77))	('abrogation', 'NegReg', (35, 45))	('AKT', 'Gene', '207', (50, 53))	('LY492002', 'Var', (106, 114))	('AKT', 'Gene', (50, 53))	('pGSK-3beta', 'CPA', (67, 77))	('Ser9', 'Chemical', '-', (79, 83))
370829	21447180	Alterations in beta-catenin signaling are a common finding in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Alterations', 'Var', (0, 11))	('beta-catenin', 'Gene', (15, 27))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('beta-catenin', 'Gene', '1499', (15, 27))	('cancers', 'Disease', (70, 77))
370830	21447180	Using the beta-catenin/TCF luciferase reporter (pTopFlash) to measure the activation of beta-catenin/TCF complex, t-DARPP increased the activity of this reporter in gastric and esophageal cancer cell models.	('beta-catenin', 'Gene', (10, 22))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('beta-catenin', 'Gene', '1499', (10, 22))	('TCF', 'Gene', (101, 104))	('TCF', 'Gene', '3172', (101, 104))	('t-DARPP', 'Chemical', '-', (114, 121))	('beta-catenin', 'Gene', (88, 100))	('gastric and esophageal cancer', 'Disease', 'MESH:D013274', (165, 194))	('TCF', 'Gene', (23, 26))	('TCF', 'Gene', '3172', (23, 26))	('increased', 'PosReg', (122, 131))	('t-DARPP', 'Var', (114, 121))	('activity', 'MPA', (136, 144))	('beta-catenin', 'Gene', '1499', (88, 100))
370835	21447180	The in vitro cell models expressing t-DARPP demonstrated up-regulation of Cyclin D1 and c-MYC protein levels.	('c-MYC', 'Gene', '4609', (88, 93))	('t-DARPP', 'Chemical', '-', (36, 43))	('t-DARPP', 'Var', (36, 43))	('Cyclin D1', 'Gene', '595', (74, 83))	('c-MYC', 'Gene', (88, 93))	('Cyclin D1', 'Gene', (74, 83))	('up-regulation', 'PosReg', (57, 70))
370842	21447180	In line with these findings, the knockdown of exogenous and endogenous t-DARPP led to a dramatic reduction of p-GSK-3beta (Ser9) and beta-catenin protein levels.	('reduction', 'NegReg', (97, 106))	('beta-catenin', 'Gene', '1499', (133, 145))	('t-DARPP', 'Gene', (71, 78))	('t-DARPP', 'Chemical', '-', (71, 78))	('knockdown', 'Var', (33, 42))	('Ser9', 'Chemical', '-', (123, 127))	('beta-catenin', 'Gene', (133, 145))	('GSK-3beta', 'Gene', (112, 121))	('GSK-3beta', 'Gene', '2932', (112, 121))
370846	21447180	Previous reports suggested that t-DARPP provides anti-apoptotic and chemotherapeutic resistance properties to cancer cells through the activation of AKT and up-regulation of Bcl2.	('t-DARPP', 'Chemical', '-', (32, 39))	('cancer', 'Disease', (110, 116))	('Bcl2', 'Gene', (174, 178))	('activation', 'PosReg', (135, 145))	('chemotherapeutic resistance properties', 'CPA', (68, 106))	('AKT', 'Gene', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Bcl2', 'Gene', '596', (174, 178))	('up-regulation', 'PosReg', (157, 170))	('anti-apoptotic', 'CPA', (49, 63))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('AKT', 'Gene', '207', (149, 152))	('t-DARPP', 'Var', (32, 39))
370853	21447180	AGS cell lines stably expressing t-DARPP or pcDNA3 empty vector were generated by transfection with respective expression plasmids using Lipofectamine 2000 (Invitrogen) followed by selection with 400 mug/mL of G418 antibiotic (Mediatech, Cellgro, Manassas, VA, USA) for three weeks.	('t-DARPP', 'Var', (33, 40))	('expression', 'Species', '29278', (111, 121))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (137, 155))	('G418', 'Chemical', 'MESH:C010680', (210, 214))	('t-DARPP', 'Chemical', '-', (33, 40))	('AGS', 'Disease', (0, 3))	('AGS', 'Disease', 'MESH:C535607', (0, 3))	('pcDNA3', 'Gene', (44, 50))
370861	21447180	TCF luciferase reporter gene constructs, pTopFlash and its mutant pFopFlash were purchased from Upstate Biotechnology (Waltham, MA, USA).	('TCF', 'Gene', (0, 3))	('mutant', 'Var', (59, 65))	('pFopFlash', 'Gene', (66, 75))	('TCF', 'Gene', '3172', (0, 3))
370863	21447180	AGS and MKN28 cells stably expressing t-DARPP or control vector and FLO-1 cells transiently expressing t-DARPP or control vector, were seeded onto an 8-chamber culture slide (BD Falcon, Bedford, MA, USA) (3 x 104 cells per chamber).	('AGS', 'Disease', (0, 3))	('t-DARPP', 'Chemical', '-', (38, 45))	('t-DARPP', 'Var', (38, 45))	('t-DARPP', 'Chemical', '-', (103, 110))	('AGS', 'Disease', 'MESH:C535607', (0, 3))
370883	21447180	In order to confirm t-DARPP-mediated regulation of TCF/beta-catenin activity via the PI3K/AKT pathway, we used LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) to specifically inhibit phosphatidylinositol 3-Kinase activity.	('beta-catenin', 'Gene', (55, 67))	('TCF', 'Gene', (51, 54))	('TCF', 'Gene', '3172', (51, 54))	('inhibit', 'NegReg', (187, 194))	('phosphatidylinositol 3-Kinase', 'Gene', '5290', (195, 224))	('AKT', 'Gene', (90, 93))	('LY294002', 'Var', (111, 119))	('beta-catenin', 'Gene', '1499', (55, 67))	('2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one', 'Chemical', 'MESH:C085911', (121, 169))	('AKT', 'Gene', '207', (90, 93))	('t-DARPP', 'Chemical', '-', (20, 27))	('LY294002', 'Chemical', 'MESH:C085911', (111, 119))	('phosphatidylinositol 3-Kinase', 'Gene', (195, 224))
370885	21447180	This study was supported by grants from the National Institute of Health; R01CA93999 (WER); R01CA CA133738 (WER), Vanderbilt SPORE in Gastrointestinal Cancer (P50 CA95103), Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404).	('Cancer', 'Disease', 'MESH:D009369', (191, 197))	('Cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Gastrointestinal Cancer', 'Disease', (134, 157))	('Gastrointestinal Cancer', 'Phenotype', 'HP:0007378', (134, 157))	('Cancer', 'Disease', 'MESH:D009369', (151, 157))	('Cancer', 'Disease', (151, 157))	('Gastrointestinal Cancer', 'Disease', 'MESH:D004067', (134, 157))	('R01CA CA133738', 'Var', (92, 106))	('P30', 'Gene', '201161', (206, 209))	('Digestive Disease', 'Phenotype', 'HP:0011024', (238, 255))	('Cancer', 'Phenotype', 'HP:0002664', (151, 157))	('P30', 'Gene', (206, 209))	('Cancer', 'Disease', (191, 197))
370963	32811869	Functional experiments showed that knockdown EIF3J-AS1 inhibited ECa growth and metastasis through in vitro and in vivo experiments.	('knockdown', 'Var', (35, 44))	('EIF3J-AS1', 'Gene', '645212', (45, 54))	('ECa growth', 'CPA', (65, 75))	('ECa', 'CellLine', 'CVCL:6898', (65, 68))	('inhibited', 'NegReg', (55, 64))	('EIF3J-AS1', 'Gene', (45, 54))
370965	32811869	Overall, EIF3J-AS1 may exhibit an oncogenic function in ECa via acting as a sponge for miR-373-3p to up-regulate AKT1 mRNA level, and may serve as a potential therapeutic target and a prognostic biomarker for ECa patients.	('miR-373-3p', 'Var', (87, 97))	('EIF3J-AS1', 'Gene', (9, 18))	('ECa', 'CellLine', 'CVCL:6898', (209, 212))	('up-regulate', 'PosReg', (101, 112))	('ECa', 'Disease', (56, 59))	('patients', 'Species', '9606', (213, 221))	('miR-373-3p', 'Chemical', '-', (87, 97))	('AKT1', 'Gene', '207', (113, 117))	('ECa', 'CellLine', 'CVCL:6898', (56, 59))	('AKT1', 'Gene', (113, 117))	('EIF3J-AS1', 'Gene', '645212', (9, 18))
370974	32811869	Further, significantly enhanced level of CASC11 was observed in ECa tissues while its silencing impeded the progression of ECa by regulating KLF6 expression.	('enhanced', 'PosReg', (23, 31))	('ECa', 'Disease', (123, 126))	('silencing', 'Var', (86, 95))	('KLF6', 'Gene', (141, 145))	('ECa', 'CellLine', 'CVCL:6898', (123, 126))	('CASC11', 'Gene', (41, 47))	('ECa', 'CellLine', 'CVCL:6898', (64, 67))	('CASC11', 'Gene', '100270680', (41, 47))	('impeded', 'NegReg', (96, 103))	('KLF6', 'Gene', '1316', (141, 145))	('level', 'MPA', (32, 37))
370976	32811869	Meanwhile, EIF3J-AS1 induced by H3K27 promoted colorectal cancer proliferation and inhibited apoptosis via miR-3163/YAP1 axis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('EIF3J-AS1', 'Gene', (11, 20))	('H3K27', 'Var', (32, 37))	('inhibited', 'NegReg', (83, 92))	('EIF3J-AS1', 'Gene', '645212', (11, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('miR-3163', 'Gene', (107, 115))	('promoted', 'PosReg', (38, 46))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('miR-3163', 'Gene', '100423029', (107, 115))	('apoptosis', 'CPA', (93, 102))	('YAP1', 'Gene', '10413', (116, 120))	('YAP1', 'Gene', (116, 120))
370994	32811869	After incubating for one full day, transfection of the reporter vector pmirGLO from Promega harboring the WT (wild-type) or MUT (mutant) EIF3J-AS1 was done into ECa cell combined with miR-373-3p.	('EIF3J-AS1', 'Gene', '645212', (137, 146))	('ECa', 'CellLine', 'CVCL:6898', (161, 164))	('EIF3J-AS1', 'Gene', (137, 146))	('pmirGLO', 'Gene', (71, 78))	('miR-373-3p', 'Chemical', '-', (184, 194))	('mutant', 'Var', (129, 135))
371004	32811869	Three shRNA sequence for knocking down EIF3J-AS1(shRNA#1: 5'-GGAACUCCCUGCCUUCAUCCUUU-3'; shRNA#2: 5'-AGGCUGGAAACUGCCACCAACUUAA-3'; shRNA#3: 5'-GGCCCGUUUUGGGAACUAACCCAA-3') and the corresponding negative control (sh-NC: 5'-UUUCUCCGAACGUGUCACGUTT-3') were synthesized by GenePharma (Shanghai, China).	('EIF3J-AS1', 'Gene', (39, 48))	('EIF3J-AS1', 'Gene', '645212', (39, 48))	('knocking', 'Var', (25, 33))
371023	32811869	Results showed that EIF3J-AS1 knockdown reduced migration and invasion of TE-1and TE-8 cells (Fig.	('migration', 'CPA', (48, 57))	('EIF3J-AS1', 'Gene', '645212', (20, 29))	('invasion of TE-1and TE-8 cells', 'CPA', (62, 92))	('reduced', 'NegReg', (40, 47))	('knockdown', 'Var', (30, 39))	('EIF3J-AS1', 'Gene', (20, 29))
371024	32811869	Following, we injected indicated treated EcaTE-1 cells (sh-NC vs. sh-EIF3J2-AS1group) into the lateral tail vein of nude mice, the results indicating that knocking EIF3J2-AS1 group showed fewer numbers of metastatic foci and higher survival rate compared to sh-NC group (Fig.	('higher', 'PosReg', (225, 231))	('J2-AS1', 'CellLine', 'CVCL:6412', (73, 79))	('nude mice', 'Species', '10090', (116, 125))	('lateral tail', 'Phenotype', 'HP:0002825', (95, 107))	('J2-AS1', 'CellLine', 'CVCL:6412', (168, 174))	('metastatic foci', 'CPA', (205, 220))	('EIF3J2-AS1', 'Var', (164, 174))	('fewer', 'NegReg', (188, 193))	('survival rate', 'CPA', (232, 245))
371025	32811869	Meanwhile, tumor formation was delayed in sh-EIF3J2-AS1group knockdown group compared to sh-NC group (Fig.	('J2-AS1', 'CellLine', 'CVCL:6412', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('delayed', 'NegReg', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('sh-EIF3J2-AS1group', 'Var', (42, 60))
371029	32811869	To investigate this, the starBase tool (https://starbase.sysu.edu.cn/) was applied to screen the potential miRNAs that interact with B4GALT1-AS1 and the potential target miRNA of EIF3J-AS1 was miR-373-3p (Fig.	('B4GALT1-AS1', 'Gene', '101929639;2683;5729', (133, 144))	('EIF3J-AS1', 'Gene', '645212', (179, 188))	('miR-373-3p', 'Var', (193, 203))	('B4GALT1-AS1', 'Gene', (133, 144))	('EIF3J-AS1', 'Gene', (179, 188))	('miR-373-3p', 'Chemical', '-', (193, 203))
371032	32811869	We next increased miR-373-3p level by transferring miR-373-3p mimic in ECa cells.	('ECa', 'CellLine', 'CVCL:6898', (71, 74))	('miR-373-3p mimic', 'Var', (51, 67))	('increased', 'PosReg', (8, 17))	('miR-373-3p', 'Chemical', '-', (51, 61))	('miR-373-3p level', 'MPA', (18, 34))	('miR-373-3p', 'Chemical', '-', (18, 28))
371033	32811869	3D, the activity of luciferase reduced remarkably due to miR-373-3p in indicated Eca cells transfected with EIF3J-AS1-WT, although it had no inhibitory effect on the activity of luciferase in EIF3J-AS1-MUT transfected cells.	('miR-373-3p', 'Chemical', '-', (57, 67))	('EIF3J-AS1', 'Gene', (108, 117))	('reduced', 'NegReg', (31, 38))	('EIF3J-AS1-MUT', 'Gene', (192, 205))	('EIF3J-AS1-MUT', 'Gene', '4594', (192, 205))	('activity', 'MPA', (8, 16))	('miR-373-3p', 'Var', (57, 67))	('EIF3J-AS1', 'Gene', '645212', (192, 201))	('luciferase', 'Enzyme', (20, 30))	('EIF3J-AS1', 'Gene', '645212', (108, 117))	('EIF3J-AS1', 'Gene', (192, 201))
371041	32811869	We then used a luciferase reporter assay approach to determine whether miR-373-3p was able to bind to its predicted target sequence in the AKT1 3'-untranslated region (UTR).	('miR-373-3p', 'Chemical', '-', (71, 81))	('bind', 'Interaction', (94, 98))	('miR-373-3p', 'Var', (71, 81))	('AKT1', 'Gene', '207', (139, 143))	('AKT1', 'Gene', (139, 143))
371042	32811869	We found that miR-373-3p mimic transfection was able to inhibit the activity of a wild-type (WT) AKT1 3'-UTR luciferase reporter, whereas it had no effect on a reporter in which its putative binding site had been mutated, consistent with the ability of miR-373-3p to directly bind to this 3'-UTR region (Fig.	('miR-373-3p mimic', 'Var', (14, 30))	('miR-373-3p', 'Chemical', '-', (253, 263))	('AKT1', 'Gene', '207', (97, 101))	('AKT1', 'Gene', (97, 101))	('activity', 'MPA', (68, 76))	('miR-373-3p', 'Chemical', '-', (14, 24))	('inhibit', 'NegReg', (56, 63))
371045	32811869	The data revealed that transfection with miR-373-3p inhibitor resulted in a significant decrease in miR-373-3p expression in ECa cells (Fig.	('ECa', 'CellLine', 'CVCL:6898', (125, 128))	('miR-373-3p inhibitor', 'Var', (41, 61))	('miR-373-3p expression', 'MPA', (100, 121))	('decrease', 'NegReg', (88, 96))	('miR-373-3p', 'Chemical', '-', (41, 51))	('miR-373-3p', 'Chemical', '-', (100, 110))
371047	32811869	4F) caused by EIF3J-AS1 knock down was reversed in ECa cells through miR-373-3p inhibitor re-introduction.	('EIF3J-AS1', 'Gene', '645212', (14, 23))	('knock', 'Var', (24, 29))	('miR-373-3p', 'Chemical', '-', (69, 79))	('ECa', 'CellLine', 'CVCL:6898', (51, 54))	('EIF3J-AS1', 'Gene', (14, 23))
371051	32811869	Furthermore, the decreased migration and invasion ability of ECa cells caused by EIF3J-AS1 knock down was reversed in ECa cells through up-regulated AKT1or decreased AKT1 via miR-373-3p inhibitor (Fig.	('migration', 'CPA', (27, 36))	('EIF3J-AS1', 'Gene', '645212', (81, 90))	('decreased', 'NegReg', (17, 26))	('miR-373-3p', 'Chemical', '-', (175, 185))	('invasion ability', 'CPA', (41, 57))	('AKT1', 'Gene', '207', (166, 170))	('ECa', 'CellLine', 'CVCL:6898', (61, 64))	('knock down', 'Var', (91, 101))	('AKT1', 'Gene', '207', (149, 153))	('decreased', 'NegReg', (156, 165))	('AKT1', 'Gene', (149, 153))	('AKT1', 'Gene', (166, 170))	('EIF3J-AS1', 'Gene', (81, 90))	('up-regulated', 'PosReg', (136, 148))	('ECa', 'CellLine', 'CVCL:6898', (118, 121))
371053	32811869	The dysregulation of lncRNAs is increasing linked to tumorigenesis, with both oncogenic and tumor suppressor functions reported.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('dysregulation', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('lncRNAs', 'Protein', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('linked', 'Reg', (43, 49))	('tumor', 'Disease', (92, 97))
371063	32811869	MiR-373-3p, transcribed from chromosome 19q13.42, with the function of cancer inhibition or promotion, belongs to the miRNAs-371-372-373 family and is commonly deregulated in many cancers.	('MiR-373-3p', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Disease', (71, 77))	('cancers', 'Disease', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('MiR-373-3p', 'Chemical', '-', (0, 10))	('promotion', 'PosReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
371064	32811869	And recently, it is proven that miR-373-3p plays a vital role in the regulation of breast cancer, testicular germ cell tumors, etc.	('miR-373-3p', 'Chemical', '-', (32, 42))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('miR-373-3p', 'Var', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('germ cell tumors', 'Phenotype', 'HP:0100728', (109, 125))
371065	32811869	Nevertheless, the role and inherent mechanisms of miR-373-3p in human Eca development remains to be assessed.	('miR-373-3p', 'Var', (50, 60))	('human', 'Species', '9606', (64, 69))	('miR-373-3p', 'Chemical', '-', (50, 60))	('Eca', 'Disease', (70, 73))
371066	32811869	Here, we could confirm that the one of targets of miR-373-3p is AKT1.	('AKT1', 'Gene', (64, 68))	('miR-373-3p', 'Chemical', '-', (50, 60))	('AKT1', 'Gene', '207', (64, 68))	('miR-373-3p', 'Var', (50, 60))
371067	32811869	We could prove the suppression of AKT1 by miR-373-3p in ECa cell lines.	('AKT1', 'Gene', '207', (34, 38))	('AKT1', 'Gene', (34, 38))	('miR-373-3p', 'Chemical', '-', (42, 52))	('suppression', 'NegReg', (19, 30))	('miR-373-3p', 'Var', (42, 52))	('ECa', 'CellLine', 'CVCL:6898', (56, 59))
371068	32811869	AKT1 was an oncogene in several cancer diseases including osteosarcoma, pancreatic ductal adenocarcinoma, colorectal cancer, and breast cancer.Recently, lncRNAs have been implicated in the miRNA/AKT1 axis modulation in human cancers.	('cancer diseases', 'Disease', (32, 47))	('colorectal cancer', 'Disease', (106, 123))	('AKT1', 'Gene', (0, 4))	('osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('cancers', 'Disease', (225, 232))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (72, 104))	('AKT1', 'Gene', '207', (195, 199))	('cancer diseases', 'Disease', 'MESH:D009369', (32, 47))	('modulation', 'Reg', (205, 215))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('pancreatic ductal adenocarcinoma', 'Disease', (72, 104))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('lncRNAs', 'Var', (153, 160))	('osteosarcoma', 'Disease', (58, 70))	('AKT1', 'Gene', (195, 199))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (72, 104))	('breast cancer', 'Disease', (129, 142))	('AKT1', 'Gene', '207', (0, 4))	('human', 'Species', '9606', (219, 224))	('implicated', 'Reg', (171, 181))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
371075	32811869	The ECa cell lines advancement and tumorigenesis are promoted by EIF3J-AS1 by miR-373-3p sponging and positively regulating AKT1 expression.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('EIF3J-AS1', 'Gene', (65, 74))	('promoted', 'PosReg', (53, 61))	('expression', 'MPA', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('miR-373-3p', 'Chemical', '-', (78, 88))	('regulating', 'Reg', (113, 123))	('AKT1', 'Gene', '207', (124, 128))	('tumor', 'Disease', (35, 40))	('AKT1', 'Gene', (124, 128))	('ECa', 'CellLine', 'CVCL:6898', (4, 7))	('EIF3J-AS1', 'Gene', '645212', (65, 74))	('miR-373-3p', 'Var', (78, 88))	('ECa cell lines advancement', 'CPA', (4, 30))
371081	32788880	Moreover, we found that MYH9 knock-down led to inhibition of cell migration and invasion.	('invasion', 'CPA', (80, 88))	('MYH9', 'Gene', '4627', (24, 28))	('inhibition', 'NegReg', (47, 57))	('MYH9', 'Gene', (24, 28))	('knock-down', 'Var', (29, 39))
371082	32788880	PCR-array showed MYH9 knockdown led to a significant change of genes expression associated with angiogenesis and epithelial-to-mesenchymal transition (EMT).	('knockdown', 'Var', (22, 31))	('MYH9', 'Gene', (17, 21))	('angiogenesis', 'CPA', (96, 108))	('epithelial-to-mesenchymal transition', 'CPA', (113, 149))	('change', 'Reg', (53, 59))	('genes expression', 'MPA', (63, 79))	('MYH9', 'Gene', '4627', (17, 21))
371084	32788880	Conclusions: Collectively, our study identifies a novel role and mechanism of MYH9, highlights a significance of MYH9 as a metastatic biomarker, and offers potential therapeutic targets for ESCC patients harboring MYH9 mutations.	('ESCC', 'Disease', (190, 194))	('MYH9', 'Gene', (113, 117))	('MYH9', 'Gene', (214, 218))	('MYH9', 'Gene', (78, 82))	('patients', 'Species', '9606', (195, 203))	('MYH9', 'Gene', '4627', (113, 117))	('MYH9', 'Gene', '4627', (214, 218))	('MYH9', 'Gene', '4627', (78, 82))	('mutations', 'Var', (219, 228))
371088	32788880	Over the past decades, researchers have found mutations in several genes, such as TP53 , NOTCH1 , and PIK3CA , show a relatively close relationship with the appearance and development of ESCC by using next-generation sequencing technology.	('ESCC', 'Disease', (187, 191))	('TP53', 'Gene', (82, 86))	('relationship', 'Reg', (135, 147))	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', (102, 108))	('NOTCH1', 'Gene', '4851', (89, 95))	('NOTCH1', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (102, 108))	('TP53', 'Gene', '7157', (82, 86))
371089	32788880	Next-generation sequencing technology is able to accurately detect the whole genomic information of cancer cells in great detail, and is especially advantageous for the discovery of new, low frequency mutant genes by bioinformatics analysis of obtained data.	('mutant', 'Var', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
371090	32788880	In fact, significant mutant genes screened as the "driver genes" in tumorigenesis with the help of bioinformatics and statistical analysis owing to their mutation frequency is not lower than a certain threshold value.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutant', 'Var', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
371098	32788880	Our study identifies a novel role and mechanism of MYH9 contributes to ESCC progression, provide several possible therapeutic targets for ESCC patients harboring MYH9 mutations.	('MYH9', 'Gene', '4627', (51, 55))	('ESCC', 'Disease', (71, 75))	('MYH9', 'Gene', '4627', (162, 166))	('mutations', 'Var', (167, 176))	('patients', 'Species', '9606', (143, 151))	('MYH9', 'Gene', (51, 55))	('contributes', 'Reg', (56, 67))	('MYH9', 'Gene', (162, 166))
371104	32788880	All of the esophageal cancer cell lines, including KYSE140, KYSE180, ECA109, KYSE410, KYSE510, KYSE150, and TE1 were stored at the Translational Medicine Research Center of the Shanxi Medical University (Taiyuan, China).	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('KYSE410', 'Var', (77, 84))	('KYSE140', 'Var', (51, 58))	('cancer', 'Disease', (22, 28))	('KYSE510', 'Var', (86, 93))	('KYSE180', 'Var', (60, 67))	('KYSE150', 'Var', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
371124	32788880	The analysis result of ICGC database showed that MYH9 was mutated in multiple common tumors (Figure 1).	('MYH9', 'Gene', '4627', (49, 53))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))	('MYH9', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutated', 'Var', (58, 65))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
371125	32788880	Moreover, we found that 90% (223/248) mutations of MYH9 were located in the CDS region in COSMIC database.	('MYH9', 'Gene', '4627', (51, 55))	('CDS', 'Chemical', 'MESH:D002104', (76, 79))	('MYH9', 'Gene', (51, 55))	('mutations', 'Var', (38, 47))	('located', 'Reg', (61, 68))
371126	32788880	Therefore, we hypothesized that the MYH9 mutation is closely related to carcinogenesis.	('MYH9', 'Gene', (36, 40))	('related', 'Reg', (61, 68))	('MYH9', 'Gene', '4627', (36, 40))	('mutation', 'Var', (41, 49))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))	('carcinogenesis', 'Disease', (72, 86))
371131	32788880	In addition, after analyzing the TCGA (The Cancer Genome Atlas) databases of CESC (cervical squamous carcinoma) (Figure 3A) and HNSC (Head and neck squamous cancer) (Figure 3B), we found that high MYH9 expression level was strongly associated with shortened survival period of patients.	('Cancer', 'Disease', (43, 49))	('squamous cancer', 'Phenotype', 'HP:0002860', (148, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('neck squamous cancer', 'Disease', 'MESH:D006258', (143, 163))	('Cancer', 'Disease', 'MESH:D009369', (43, 49))	('MYH9', 'Gene', (197, 201))	('Head and neck squamous cancer', 'Phenotype', 'HP:0012288', (134, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('high', 'Var', (192, 196))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (92, 110))	('shortened', 'NegReg', (248, 257))	('neck squamous cancer', 'Disease', (143, 163))	('patients', 'Species', '9606', (277, 285))	('cervical squamous carcinoma', 'Disease', 'MESH:D002294', (83, 110))	('MYH9', 'Gene', '4627', (197, 201))	('expression level', 'MPA', (202, 218))	('cervical squamous carcinoma', 'Disease', (83, 110))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
371132	32788880	Therefore, high MYH9 expression may be one of the most important markers in prognosis of squamous cell carcinoma.	('MYH9', 'Gene', (16, 20))	('expression', 'MPA', (21, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('MYH9', 'Gene', '4627', (16, 20))	('high', 'Var', (11, 15))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('squamous cell carcinoma', 'Disease', (89, 112))
371139	32788880	To explore the specific mechanism MYH9 utilizes as an oncogene in ESCC, PCR-array experiments were performed for a comparative analysis between the KYSE140 and KYSE140-MYH9sh cells.	('MYH9', 'Gene', '4627', (168, 172))	('MYH9', 'Gene', (34, 38))	('KYSE140', 'Var', (148, 155))	('ESCC', 'Disease', (66, 70))	('MYH9', 'Gene', (168, 172))	('MYH9', 'Gene', '4627', (34, 38))
371143	32788880	Our results demonstrated that angiogenesis was inhibited after MYH9 knockdown in ESCC cells, directly indicating the promotion effect of MYH9 on angiogenesis (Figure 6B).	('promotion', 'PosReg', (117, 126))	('inhibited', 'NegReg', (47, 56))	('MYH9', 'Gene', '4627', (63, 67))	('MYH9', 'Gene', (137, 141))	('angiogenesis', 'CPA', (30, 42))	('knockdown', 'Var', (68, 77))	('MYH9', 'Gene', '4627', (137, 141))	('MYH9', 'Gene', (63, 67))
371144	32788880	And, we detected with the help of qPCR the changes in expression of angiogenesis and EMT-related markers in knockdown of MYH9 and its control cells of ESCC.	('expression', 'MPA', (54, 64))	('knockdown', 'Var', (108, 117))	('angiogenesis', 'CPA', (68, 80))	('MYH9', 'Gene', '4627', (121, 125))	('MYH9', 'Gene', (121, 125))
371145	32788880	The results showed that after knocking down MYH9, the expression of angiogenesis markers FLT1, KDR, TEK, and VEGFC decreased, and the expression of mesothelial cell markers SNAI2, KRT14 and CDH2 decreased (Figure 6C).	('TEK', 'Gene', '7010', (100, 103))	('KRT14', 'Gene', (180, 185))	('KDR', 'Gene', '3791', (95, 98))	('MYH9', 'Gene', '4627', (44, 48))	('FLT1', 'Gene', (89, 93))	('MYH9', 'Gene', (44, 48))	('FLT1', 'Gene', '2321', (89, 93))	('SNAI2', 'Gene', (173, 178))	('CDH2', 'Gene', (190, 194))	('expression', 'MPA', (134, 144))	('KDR', 'Gene', (95, 98))	('SNAI2', 'Gene', '6591', (173, 178))	('knocking down', 'Var', (30, 43))	('decreased', 'NegReg', (195, 204))	('VEGFC', 'Gene', (109, 114))	('expression', 'MPA', (54, 64))	('CDH2', 'Gene', '1000', (190, 194))	('TEK', 'Gene', (100, 103))	('angiogenesis', 'CPA', (68, 80))	('decreased', 'NegReg', (115, 124))	('VEGFC', 'Gene', '7424', (109, 114))	('KRT14', 'Gene', '3861', (180, 185))
371150	32788880	A series of ESCC-related mutant genes, including some star genes (NOTCH1, TP53, and PIK3C) and some low frequency mutant genes were identified.	('mutant', 'Var', (25, 31))	('ESCC-related', 'Disease', (12, 24))	('TP53', 'Gene', '7157', (74, 78))	('NOTCH1', 'Gene', '4851', (66, 72))	('PIK3C', 'Gene', (84, 89))	('TP53', 'Gene', (74, 78))	('NOTCH1', 'Gene', (66, 72))
371152	32788880	Moreover, the mutant MYH9 was found in a range of common tumors, and 90% (223/248) of the MYH9 mutations were located in the CDS region.	('MYH9', 'Gene', '4627', (21, 25))	('located', 'Reg', (110, 117))	('mutant', 'Var', (14, 20))	('CDS', 'Chemical', 'MESH:D002104', (125, 128))	('found', 'Reg', (30, 35))	('MYH9', 'Gene', '4627', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('MYH9', 'Gene', (21, 25))	('mutations', 'Var', (95, 104))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('MYH9', 'Gene', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
371153	32788880	Therefore, it is reasonable to believe that a mutation of MYH9 plays an important role in the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('MYH9', 'Gene', '4627', (58, 62))	('cancer', 'Disease', (109, 115))	('mutation', 'Var', (46, 54))	('role', 'Reg', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MYH9', 'Gene', (58, 62))
371158	32788880	Consistent with our research results, it was reported that expression of MYH9 is closely related to the malignant degree of cancer, and can be regarded as a marker for evaluating lymph node metastasis and poor prognosis in breast cancer, epithelial ovarian cancer and acute myeloid leukemia.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (238, 263))	('breast cancer', 'Disease', (223, 236))	('acute myeloid leukemia', 'Disease', (268, 290))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('epithelial ovarian cancer', 'Disease', (238, 263))	('ovarian cancer', 'Phenotype', 'HP:0100615', (249, 263))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', (230, 236))	('expression', 'Var', (59, 69))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (274, 290))	('MYH9', 'Gene', '4627', (73, 77))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (238, 263))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (268, 290))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('related', 'Reg', (89, 96))	('leukemia', 'Phenotype', 'HP:0001909', (282, 290))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (268, 290))	('MYH9', 'Gene', (73, 77))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', (257, 263))
371177	32788880	The aberrant expression of N-cadherin was significantly related to the differentiated degree, histological type, invasion and metastasis of gastric cancer.	('differentiated degree', 'CPA', (71, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('invasion', 'CPA', (113, 121))	('N-cadherin', 'Gene', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('metastasis of gastric cancer', 'Disease', (126, 154))	('aberrant expression', 'Var', (4, 23))	('N-cadherin', 'Gene', '1000', (27, 37))	('related', 'Reg', (56, 63))	('metastasis of gastric cancer', 'Disease', 'MESH:D013274', (126, 154))
371181	32788880	In conclusion, a low frequency mutant gene related to ESCC was found to play an important role in metastasis and angiogenesis of esophageal cancer cells.	('play', 'Reg', (72, 76))	('role', 'Reg', (90, 94))	('metastasis', 'CPA', (98, 108))	('cancer', 'Disease', (140, 146))	('angiogenesis', 'CPA', (113, 125))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('mutant gene', 'Var', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
371206	32148381	Body mass index (BMI) is a simple and objective nutritional parameter that is easily available to physicians, and studies in patients with cancer have suggested that low BMI may be associated with poor long-term outcomes.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('low BMI', 'Phenotype', 'HP:0045082', (166, 173))	('low', 'Var', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BMI', 'MPA', (170, 173))	('cancer', 'Disease', (139, 145))	('patients', 'Species', '9606', (125, 133))
371263	32148381	Although studies in patients with cancer have suggested that low BMI may be associated with poor long-term outcomes, there is no general consensus on the influence of BMI on survival in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('BMI', 'MPA', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('low BMI', 'Phenotype', 'HP:0045082', (61, 68))	('low', 'Var', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('esophageal cancer', 'Disease', (186, 203))	('cancer', 'Disease', (34, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
371265	32148381	They held the view that overweight or underweight alone should not contraindicate surgical resection for patients with ESCC, because there were no significant differences in overall and relapse-free survival among patients with low, normal and high BMI status in univariate and multivariate analyses.	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (214, 222))	('low', 'Var', (228, 231))	('ESCC', 'Disease', (119, 123))	('overweight', 'Phenotype', 'HP:0025502', (24, 34))	('high', 'Var', (244, 248))	('ESCC', 'Disease', 'MESH:C562729', (119, 123))
371386	28757556	Four upregulated miRNAs (miR-29a-3p, 128-3p, 223-3p and 3473) were identified by microarray analysis.	('upregulated', 'PosReg', (5, 16))	('3473', 'Var', (56, 60))	('miR-29a', 'Gene', '100314230', (25, 32))	('miR-29a', 'Gene', (25, 32))
371392	28757556	One reason for the high incidence of PPI-resistance in NERD is its heterogeneous pathogenesis, including abnormal esophageal acid exposure and esophageal hypersensitivity.	('hypersensitivity', 'Disease', (154, 170))	('PPI-resistance', 'Var', (37, 51))	('ERD', 'Disease', 'None', (56, 59))	('esophageal acid', 'Chemical', '-', (114, 129))	('ERD', 'Disease', (56, 59))	('hypersensitivity', 'Disease', 'MESH:D004342', (154, 170))
371407	28757556	Microarray analysis revealed an upregulation of miR-29a-3p, miR-128-3p, miR-223-3p and miR-3473 in reflux esophagitis (p < 0.05 compared to controls).	('esophagitis', 'Phenotype', 'HP:0100633', (106, 117))	('miR-128-3p', 'Var', (60, 70))	('upregulation', 'PosReg', (32, 44))	('miR-223', 'Gene', (72, 79))	('reflux esophagitis', 'Disease', (99, 117))	('reflux esophagitis', 'Disease', 'MESH:D005764', (99, 117))	('miR-3473', 'Gene', '102466618', (87, 95))	('miR-29a', 'Gene', '100314230', (48, 55))	('miR-29a', 'Gene', (48, 55))	('miR-223', 'Gene', '100314060', (72, 79))	('miR-3473', 'Gene', (87, 95))
371419	28757556	The expression levels of miR-29a-3p and miR-128-3p in reflux esophagitis were significantly lower than those of the controls on day 3 (Figure 4A,B).	('expression levels', 'MPA', (4, 21))	('miR-128-3p', 'Var', (40, 50))	('miR-29a', 'Gene', '100314230', (25, 32))	('miR-29a', 'Gene', (25, 32))	('reflux esophagitis', 'Disease', (54, 72))	('reflux esophagitis', 'Disease', 'MESH:D005764', (54, 72))	('esophagitis', 'Phenotype', 'HP:0100633', (61, 72))	('lower', 'NegReg', (92, 97))
371444	28757556	MicroRNA-29a and 29b-1 are processed from chromosome 7, and miR-29b-2 and 29c are transcribed from chromosome 1.	('MicroRNA-29a', 'Var', (0, 12))	('miR-29b-2', 'Gene', '100314007', (60, 69))	('miR-29b-2', 'Gene', (60, 69))
371445	28757556	Since forced overexpression of miR-29 markedly suppresses collagen 1 A1 mRNA and protein expression, miR-29 plays an anti-fibrotic role in the liver and other organs.	('miR-29', 'Var', (101, 107))	('suppresses', 'NegReg', (47, 57))	('miR-29', 'Chemical', '-', (31, 37))	('overexpression', 'PosReg', (13, 27))	('miR-29', 'Gene', (31, 37))	('miR-29', 'Chemical', '-', (101, 107))
371447	28757556	Second, we identified that the expression of esophageal miR-223-3p in reflux esophagitis was significantly increased compared with control tissue, and expression gradually decreased during the acute to chronic phases of reflux esophagitis.	('esophagitis', 'Phenotype', 'HP:0100633', (227, 238))	('increased', 'PosReg', (107, 116))	('esophageal', 'Var', (45, 55))	('miR-223', 'Gene', (56, 63))	('expression', 'MPA', (31, 41))	('reflux esophagitis', 'Disease', 'MESH:D005764', (220, 238))	('esophagitis', 'Phenotype', 'HP:0100633', (77, 88))	('reflux esophagitis', 'Disease', (220, 238))	('reflux esophagitis', 'Disease', (70, 88))	('miR-223', 'Gene', '100314060', (56, 63))	('reflux esophagitis', 'Disease', 'MESH:D005764', (70, 88))
371451	28757556	The roles of E2F1 and STAT3 in chronic reflux esophagitis should be discussed.	('STAT3', 'Gene', '25125', (22, 27))	('reflux esophagitis', 'Disease', 'MESH:D005764', (39, 57))	('reflux esophagitis', 'Disease', (39, 57))	('E2F1', 'Var', (13, 17))	('chronic reflux', 'Phenotype', 'HP:0002020', (31, 45))	('STAT3', 'Gene', (22, 27))	('esophagitis', 'Phenotype', 'HP:0100633', (46, 57))
371480	28757556	In conclusion, our results demonstrated that exosomal miR-29a-3p might assist in the diagnosis of GERD, and increased expression of esophageal miR-223-3p was inversely associated with expression of E2F1 or STAT3 in esophageal tissue reflux esophagitis.	('ERD', 'Disease', 'None', (99, 102))	('STAT3', 'Gene', (206, 211))	('E2F1', 'Var', (198, 202))	('miR-223', 'Gene', (143, 150))	('esophagitis', 'Phenotype', 'HP:0100633', (240, 251))	('esophageal tissue reflux esophagitis', 'Disease', 'MESH:D005764', (215, 251))	('increased', 'PosReg', (108, 117))	('ERD', 'Disease', (99, 102))	('miR-223', 'Gene', '100314060', (143, 150))	('STAT3', 'Gene', '25125', (206, 211))	('esophageal', 'Gene', (132, 142))	('miR-29a', 'Gene', '100314230', (54, 61))	('rat', 'Species', '10116', (34, 37))	('expression', 'MPA', (118, 128))	('miR-29a', 'Gene', (54, 61))	('esophageal tissue reflux', 'Phenotype', 'HP:0002020', (215, 239))	('esophageal tissue reflux esophagitis', 'Disease', (215, 251))
371497	33946826	The CROSS study demonstrated that patients receiving nCRT followed by surgery have a significantly increased median overall survival than those receiving surgery alone (49.4 vs. 29.0 months, p = 0.003).	('patients', 'Species', '9606', (34, 42))	('overall survival', 'MPA', (116, 132))	('nCRT', 'Var', (53, 57))	('increased', 'PosReg', (99, 108))
371648	32290037	As the DeltaSMI (%/50 days) <-10.0%/50 days was significantly associated with OS, clinicopathologic characteristics and laboratory test results were compared between the excessive and non-excessive muscle loss groups, which are summarized in Table 3 and Table 4.	('muscle loss', 'Phenotype', 'HP:0003202', (198, 209))	('associated', 'Reg', (62, 72))	('muscle loss', 'Disease', (198, 209))	('muscle loss', 'Disease', 'MESH:D009135', (198, 209))	('<-10.0', 'Var', (28, 34))
371663	32290037	also found that DeltaSMI (%) <-12.5% was a significant prognostic factor for OS, and pre- and post-NAT sarcopenia were not associated with OS.	('<-12.5', 'Var', (29, 35))	('NAT sarcopenia', 'Disease', 'MESH:D055948', (99, 113))	('NAT sarcopenia', 'Disease', (99, 113))
371664	32290037	reported that a DeltaSMI (%) <-2.98% during NAT was related to poor OS in the multivariable analysis, whereas post-NAT sarcopenia did not significantly affect OS and complication rates.	('NAT sarcopenia', 'Disease', 'MESH:D055948', (115, 129))	('<-2.98', 'Var', (29, 35))	('poor', 'Disease', (63, 67))	('NAT sarcopenia', 'Disease', (115, 129))
371668	32290037	In a retrospective study with advanced pancreatic cancer patients, DeltaSMI (%) <-10.0% at the first evaluation was associated with a larger increase of NLR and poorer OS than DeltaSMI (%) >=-10.0%.	('NLR', 'Disease', (153, 156))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('increase', 'PosReg', (141, 149))	('patients', 'Species', '9606', (57, 65))	('<-10.0%', 'Var', (80, 87))	('poorer OS', 'CPA', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pancreatic cancer', 'Disease', (39, 56))	('DeltaSMI', 'Var', (67, 75))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))
371688	32290037	Cytotoxic agents such as cisplatin can promote muscle wasting by disrupting molecular signaling pathways, and NACRT can cause side effects such as nausea, vomiting, anorexia, dysphagia, and esophagitis.	('anorexia', 'Phenotype', 'HP:0002039', (165, 173))	('cause', 'Reg', (120, 125))	('nausea', 'Disease', (147, 153))	('disrupting', 'NegReg', (65, 75))	('vomiting', 'Disease', 'MESH:D014839', (155, 163))	('cisplatin', 'Var', (25, 34))	('anorexia', 'Disease', (165, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (25, 34))	('dysphagia', 'Disease', 'MESH:D003680', (175, 184))	('molecular signaling pathways', 'Pathway', (76, 104))	('nausea', 'Disease', 'MESH:D009325', (147, 153))	('vomiting', 'Phenotype', 'HP:0002013', (155, 163))	('esophagitis', 'Disease', (190, 201))	('vomiting', 'Disease', (155, 163))	('dysphagia', 'Disease', (175, 184))	('promote', 'PosReg', (39, 46))	('esophagitis', 'Disease', 'MESH:D004938', (190, 201))	('esophagitis', 'Phenotype', 'HP:0100633', (190, 201))	('anorexia', 'Disease', 'MESH:D000855', (165, 173))	('muscle wasting', 'Disease', (47, 61))	('dysphagia', 'Phenotype', 'HP:0002015', (175, 184))	('muscle wasting', 'Phenotype', 'HP:0003202', (47, 61))	('NACRT', 'Var', (110, 115))	('nausea', 'Phenotype', 'HP:0002018', (147, 153))	('NACRT', 'Chemical', '-', (110, 115))
371689	32290037	In addition, NAT reduces physical fitness and muscle strength in esophageal cancer patients.	('reduces physical fitness', 'Phenotype', 'HP:0003546', (17, 41))	('reduces', 'NegReg', (17, 24))	('esophageal cancer', 'Disease', (65, 82))	('muscle strength', 'CPA', (46, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NAT', 'Var', (13, 16))	('patients', 'Species', '9606', (83, 91))	('fitness', 'Disease', (34, 41))	('fitness', 'Disease', 'MESH:D012640', (34, 41))
371843	32194665	Brim et al determined that ADAM29 is associated with colorectal tumors, and it has also been revealed that the ADAM29 mutation affects the adhesion of melanoma cells to specific extracellular matrix proteins and promotes tumor invasion.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('promotes', 'PosReg', (212, 220))	('ADAM29', 'Gene', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('colorectal tumors', 'Disease', (53, 70))	('adhesion', 'MPA', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('ADAM29', 'Gene', '11086', (27, 33))	('ADAM29', 'Gene', (111, 117))	('associated', 'Reg', (37, 47))	('ADAM29', 'Gene', '11086', (111, 117))	('specific extracellular matrix proteins', 'Protein', (169, 207))	('tumor', 'Disease', (221, 226))	('colorectal tumors', 'Disease', 'MESH:D015179', (53, 70))	('mutation', 'Var', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', (64, 69))	('affects', 'Reg', (127, 134))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
371885	32194665	Furthermore, high ADAM29 expression was significantly associated with the pathological stage (P=0.024) and clinical stage (P=0.016).	('high', 'Var', (13, 17))	('ADAM29', 'Gene', '11086', (18, 24))	('expression', 'MPA', (25, 35))	('clinical stage', 'CPA', (107, 121))	('ADAM29', 'Gene', (18, 24))	('pathological stage', 'CPA', (74, 92))	('associated', 'Reg', (54, 64))
371890	32194665	Furthermore, high FAM135B expression was significantly associated with the pathological stage (P=0.006) and clinical stage (P=0.015).	('expression', 'MPA', (26, 36))	('high', 'Var', (13, 17))	('pathological stage', 'CPA', (75, 93))	('associated', 'Reg', (55, 65))	('clinical stage', 'CPA', (108, 122))	('FAM135B', 'Gene', (18, 25))	('FAM135B', 'Gene', '51059', (18, 25))
371892	32194665	High FAM135B expression occurred in zero cases (0%) in clinical stage I, five cases (22.7%) in clinical stage II: six cases (60%) in clinical stage III.	('expression', 'MPA', (13, 23))	('FAM135B', 'Gene', '51059', (5, 12))	('High', 'Var', (0, 4))	('FAM135B', 'Gene', (5, 12))
371901	32194665	Mutations of the ADAM29 gene predominantly occur in somatic cells, in the prolysin and propeptide domains, and are associated with increased collagen adhesion of types I and IV compared with wild-type ADAM29.	('increased', 'PosReg', (131, 140))	('collagen adhesion', 'CPA', (141, 158))	('propeptide', 'Chemical', '-', (87, 97))	('ADAM29', 'Gene', '11086', (201, 207))	('Mutations', 'Var', (0, 9))	('ADAM29', 'Gene', (201, 207))	('ADAM29', 'Gene', '11086', (17, 23))	('ADAM29', 'Gene', (17, 23))
371922	32194665	Furthermore, high FAM135B expression may be associated with endogenous phosphoglyceraldehyde dehydrogenase.	('associated', 'Reg', (44, 54))	('expression', 'MPA', (26, 36))	('high', 'Var', (13, 17))	('FAM135B', 'Gene', (18, 25))	('endogenous phosphoglyceraldehyde dehydrogenase', 'MPA', (60, 106))	('FAM135B', 'Gene', '51059', (18, 25))
371944	31871444	Systematic Review with Meta-analysis: Association of Helicobacter pylori Infection with Esophageal Cancer Helicobacter pylori is an important carcinogenic factor in gastric cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('Esophageal Cancer', 'Disease', (88, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Association', 'Interaction', (38, 49))	('Helicobacter pylori', 'Species', '210', (53, 72))	('Helicobacter', 'Species', '210', (53, 65))	('gastric cancer', 'Disease', (165, 179))	('Helicobacter pylori', 'Var', (106, 125))	('cancer', 'Disease', (173, 179))	('Helicobacter', 'Species', '210', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinogenic', 'Disease', (142, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (165, 179))	('Infection', 'Disease', 'MESH:D007239', (73, 82))	('Helicobacter pylori', 'Species', '210', (106, 125))	('Helicobacter pylori Infection', 'Phenotype', 'HP:0005202', (53, 82))	('Infection', 'Disease', (73, 82))	('carcinogenic', 'Disease', 'MESH:D063646', (142, 154))
371957	31871444	But some scholars believed that Helicobacter pylori infection can cause esophageal squamous cell carcinoma through gastric atrophy which may promote the excessive growth of bacteria and increase the production of endogenous nitrosamines, then lead to the esophageal squamous cell carcinoma.	('production of endogenous nitrosamines', 'MPA', (199, 236))	('nitrosamines', 'Chemical', 'MESH:D009602', (224, 236))	('gastric atrophy', 'Disease', (115, 130))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (32, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('Helicobacter', 'Disease', (32, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('increase', 'PosReg', (186, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('lead to', 'Reg', (243, 250))	('excessive growth', 'MPA', (153, 169))	('gastric atrophy', 'Disease', 'MESH:D013274', (115, 130))	('cause', 'Reg', (66, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('esophageal squamous cell carcinoma', 'Disease', (255, 289))	('infection', 'Var', (52, 61))	('esophageal squamous cell carcinoma', 'Disease', (72, 106))	('promote', 'PosReg', (141, 148))
371958	31871444	There are currently more reliable assumptions about this phenomenon: (1) Helicobacter pylori infection, accompanied by atrophy of gastric body and loss of parietal cells, resulting in reduced reflux, which reduces the incidence of reflux esophagitis and Barrett's esophagus; (2) Helicobacter pylori infection can induce apoptosis of esophageal adenocarcinoma cells progressing from Barrett's esophagus through Fas apoptotic pathway mediated by Caspase.	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (73, 102))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (333, 358))	('esophageal', 'Disease', (333, 343))	('reflux esophagitis', 'Disease', 'MESH:D005764', (231, 249))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (382, 401))	('Helicobacter pylori infection', 'Var', (279, 308))	('reflux esophagitis', 'Disease', (231, 249))	('induce', 'Reg', (313, 319))	('Fas apoptotic pathway', 'Pathway', (410, 431))	('esophagitis', 'Phenotype', 'HP:0100633', (238, 249))	('infection', 'Var', (299, 308))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (279, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (349, 358))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (254, 273))	('reflux', 'MPA', (192, 198))	('atrophy of gastric body', 'Disease', 'MESH:D013274', (119, 142))	('apoptosis', 'CPA', (320, 329))	('atrophy of gastric body', 'Disease', (119, 142))
371959	31871444	On the one hand, gastrin induced by Helicobacter pylori is a carcinogenic growth factor, which contributes to the canceration of the esophagus and stomach, especially playing a potential causal role in the progression of Barrett's esophageal neoplasm.	('contributes', 'PosReg', (95, 106))	('Helicobacter pylori', 'Var', (36, 55))	('neoplasm', 'Disease', (242, 250))	('esophageal neoplasm', 'Phenotype', 'HP:0100751', (231, 250))	('neoplasm', 'Phenotype', 'HP:0002664', (242, 250))	("Barrett's esophageal neoplasm", 'Phenotype', 'HP:0100580', (221, 250))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('neoplasm', 'Disease', 'MESH:D009369', (242, 250))	('canceration', 'MPA', (114, 125))
371960	31871444	On the other hand, Helicobacter pylori induces the expression of nuclear factor-kappa B (NF-kappaB) and cyclooxygenase- (COX-) 2 in esophageal epithelial cells and plays a role in the inflammation associated with Barrett's esophagus and tumorigenesis in the esophagus.	('role', 'Reg', (172, 176))	('tumor', 'Disease', (237, 242))	('COX-', 'Gene', (121, 125))	('inflammation', 'Disease', 'MESH:D007249', (184, 196))	('NF-kappaB', 'Gene', (89, 98))	("Barrett's esophagus", 'Disease', (213, 232))	('Helicobacter pylori', 'Var', (19, 38))	('inflammation', 'Disease', (184, 196))	('expression', 'MPA', (51, 61))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (213, 232))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('induces', 'PosReg', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('plays', 'Reg', (164, 169))
371968	31612046	These findings provide a novel and systematic perspective on the potential function of noncoding RNAs in ESCC.	('ESCC', 'Disease', 'MESH:C562729', (105, 109))	('ESCC', 'Phenotype', 'HP:0011459', (105, 109))	('ESCC', 'Disease', (105, 109))	('noncoding RNAs', 'Var', (87, 101))
371980	31612046	To the best of our knowledge, the role of noncoding RNAs in tumorigenesis and progression of ESCC remain unclear.	('ESCC', 'Phenotype', 'HP:0011459', (93, 97))	('ESCC', 'Disease', (93, 97))	('noncoding RNAs', 'Var', (42, 56))	('ESCC', 'Disease', 'MESH:C562729', (93, 97))
372001	31612046	RT-qPCR assays indicated that the expression of lncRNAs lnc-KLHDC7A-6:2 and LOC440173 was upregulated, whereas the expression of EPB41L4A-AS1 and SMAD5-AS1_3 was downregulated (Fig.	('SMAD5', 'Gene', '4090', (146, 151))	('AS1', 'Gene', '5729', (152, 155))	('EPB41L4A-AS1', 'Gene', (129, 141))	('expression', 'MPA', (34, 44))	('AS1', 'Gene', (152, 155))	('KLHDC7A', 'Gene', '127707', (60, 67))	('EPB41L4A-AS1', 'Gene', '114915', (129, 141))	('AS1', 'Gene', '5729', (138, 141))	('LOC440173', 'Var', (76, 85))	('SMAD5', 'Gene', (146, 151))	('downregulated', 'NegReg', (162, 175))	('upregulated', 'PosReg', (90, 101))	('KLHDC7A', 'Gene', (60, 67))	('AS1', 'Gene', (138, 141))	('LOC440173', 'Chemical', 'MESH:C492399', (76, 85))
372003	31612046	Compared with those of para-carcinoma tissues, data of the present study indicated that the mRNAs that were upregulated by lncRNAs and were associated with biological processes were associated to cell cycle and cell division (Fig.	('para-carcinoma', 'Disease', 'MESH:D002277', (23, 37))	('mRNAs', 'MPA', (92, 97))	('cell cycle', 'CPA', (196, 206))	('cell division', 'CPA', (211, 224))	('para-carcinoma', 'Disease', (23, 37))	('lncRNAs', 'Var', (123, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('upregulated', 'PosReg', (108, 119))
372012	31612046	For instance, circ-0078344, circ-0026599, circ-0036698 and NR-102741 are ceRNAs of different miRNAs that target transforming grown factor beta induced (TGFBI).	('circ-0078344', 'Var', (14, 26))	('circ-0036698', 'Var', (42, 54))	('NR-102741', 'Var', (59, 68))	('circ-0078344, circ-0026599, circ-0036698', 'Chemical', 'None', (14, 54))	('TGFBI', 'Gene', '7045', (152, 157))	('circ-0026599', 'Var', (28, 40))	('TGFBI', 'Gene', (152, 157))
372017	31612046	LncRNA has been widely reported to participate in a wide range of biological processes, and its dysregulated expression affects many human disease phenotypes, including those of cancers.	('dysregulated', 'Var', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('affects', 'Reg', (120, 127))	('cancers', 'Disease', (178, 185))	('LncRNA', 'Protein', (0, 6))	('human', 'Species', '9606', (133, 138))	('participate', 'Reg', (35, 46))
372033	31612046	The RNAs circ-0078344, circ-0026599, circ-0036698 and NR-102741 are ceRNAs of different miRNAs that target TGFBI.	('TGFBI', 'Gene', '7045', (107, 112))	('TGFBI', 'Gene', (107, 112))	('circ-0078344, circ-0026599, circ-0036698', 'Chemical', 'None', (9, 49))	('circ-0036698', 'Var', (37, 49))
372056	31612013	Normal stem cells are now being viewed as the primary source of CSCs, which are also known as cancer stem cells (CSCs) and tumor initiating cells, since genetic mutations in these cells result in cancer and other malignant tumors, which is mediated by the acquirement of self-renewal ability.	('result in', 'Reg', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('genetic mutations', 'Var', (153, 170))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', (223, 228))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('malignant tumors', 'Disease', (213, 229))	('malignant tumors', 'Disease', 'MESH:D009369', (213, 229))	('cancer', 'Disease', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
372058	31612013	In addition, the asymmetric division of CSCs can produce entire tumors that resemble the primary tumor.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('asymmetric division', 'Var', (17, 36))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('produce', 'Reg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
372072	31612013	Following the silencing of CD133, the stemness of CSCs was decreased.	('silencing', 'Var', (14, 23))	('CD133', 'Gene', (27, 32))	('CD133', 'Gene', '8842', (27, 32))	('decreased', 'NegReg', (59, 68))	('stemness of CSCs', 'CPA', (38, 54))
372107	31612013	Notably, the SP fraction of 5-FU resistant OE19 cells led to a marked upregulation of EMT-associated genes, when compared with the SP fraction of OE19 cells.	('5-FU resistant', 'Var', (28, 42))	('5-FU', 'Chemical', 'MESH:D005472', (28, 32))	('upregulation', 'PosReg', (70, 82))	('EMT-associated genes', 'Gene', (86, 106))
372118	31612013	The small-molecule inhibitor of YAP1, verteporfin, blocks ESCC CSC properties in cells with high YAP1 and a high proportion of ALDH1+ cells.	('high', 'Var', (92, 96))	('ALDH1', 'Gene', '216', (127, 132))	('ESCC', 'Disease', 'MESH:D018307', (58, 62))	('verteporfin', 'Chemical', 'MESH:C098350', (38, 49))	('YAP1', 'Gene', (97, 101))	('YAP1', 'Gene', '10413', (97, 101))	('blocks', 'NegReg', (51, 57))	('YAP1', 'Gene', (32, 36))	('ESCC', 'Disease', (58, 62))	('YAP1', 'Gene', '10413', (32, 36))	('ALDH1', 'Gene', (127, 132))
372119	31612013	Furthermore, Chen et al recently revealed that ALDH1 staining was positively linked to a higher clinical stage, higher loco-regional failure rate, and shorter survival time in ESCC.	('ESCC', 'Disease', (176, 180))	('loco-regional failure rate', 'CPA', (119, 145))	('clinical stage', 'CPA', (96, 110))	('shorter', 'NegReg', (151, 158))	('ESCC', 'Disease', 'MESH:D018307', (176, 180))	('staining', 'Var', (53, 61))	('survival time', 'CPA', (159, 172))	('ALDH1', 'Gene', (47, 52))	('linked', 'Reg', (77, 83))	('ALDH1', 'Gene', '216', (47, 52))
372133	31612013	Ad/TRAIL-E1 resulted in significant tumor growth suppression and longer survival in Seg-1R-bearing mice with no significant toxicity.	('mice', 'Species', '10090', (99, 103))	('Ad/TRAIL-E1', 'Var', (0, 11))	('suppression', 'NegReg', (49, 60))	('toxicity', 'Disease', 'MESH:D064420', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('longer', 'PosReg', (65, 71))	('toxicity', 'Disease', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
372140	31612013	It was also observed that ICAM1 and CD44 could have a compensation effect on maintaining the stemness characteristics of ESCC, suggesting that a combination of multi-targeting therapies should be considered to acquire a more potent therapeutic effect on ESCC CSCs.	('ESCC', 'Disease', 'MESH:D018307', (254, 258))	('CD44', 'Var', (36, 40))	('ESCC', 'Disease', 'MESH:D018307', (121, 125))	('stemness characteristics', 'CPA', (93, 117))	('ESCC', 'Disease', (254, 258))	('ESCC', 'Disease', (121, 125))
372164	31612013	Notably, several common stem cell surface markers, including CD44, CD133, CD338 (ABCG2), CD318 (CDCP1) and CD326 (EpCAM), were not observed be elevated.	('CD326', 'Var', (107, 112))	('EpCAM', 'Gene', (114, 119))	('CDCP1', 'Gene', (96, 101))	('CD318', 'Gene', (89, 94))	('CD338', 'Gene', (74, 79))	('CD318', 'Gene', '64866', (89, 94))	('CD44', 'MPA', (61, 65))	('EpCAM', 'Gene', '4072', (114, 119))	('CD133', 'Gene', (67, 72))	('CD133', 'Gene', '8842', (67, 72))	('CDCP1', 'Gene', '64866', (96, 101))	('ABCG2', 'Gene', (81, 86))	('ABCG2', 'Gene', '9429', (81, 86))	('CD338', 'Gene', '9429', (74, 79))
372167	31612013	Downregulation of miRNA-644a was suggested to promote ESCC aggressiveness and stem cell-like phenotype via dysregulation of paired like homeodomain 2.	('promote', 'PosReg', (46, 53))	('aggressiveness', 'Disease', 'MESH:D001523', (59, 73))	('ESCC', 'Disease', (54, 58))	('Downregulation', 'NegReg', (0, 14))	('paired like homeodomain 2', 'Gene', '5308', (124, 149))	('miRNA-644a', 'Gene', (18, 28))	('aggressiveness', 'Disease', (59, 73))	('ESCC', 'Disease', 'MESH:D018307', (54, 58))	('stem cell-like phenotype', 'CPA', (78, 102))	('dysregulation', 'Var', (107, 120))	('paired like homeodomain 2', 'Gene', (124, 149))	('aggressiveness', 'Phenotype', 'HP:0000718', (59, 73))
372173	31612013	In 2007, Eriksson et al reported that oncolytic adenoviruses Ad5/3-Delta24 and Ad5.pk7-Delta24 can selectively kill breast cancer-initiating CD44+CD24-/low cells, and Cho et al isolated and characterized CSCs in MMTV-Wnt-1 murine breast tumors.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('Ad5/3-Delta24', 'Var', (61, 74))	('breast tumors', 'Phenotype', 'HP:0100013', (230, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('murine', 'Species', '10090', (223, 229))	('MMTV', 'Species', '11757', (212, 216))	('breast tumors', 'Disease', (230, 243))	('CD24', 'Gene', '100133941', (146, 150))	('CD24', 'Gene', (146, 150))	('breast tumors', 'Disease', 'MESH:D061325', (230, 243))	('Ad5.pk7-Delta24', 'Var', (79, 94))
372179	31612013	Notably, HPV+ oropharyngeal squamous cell carcinomas had an improved prognosis and an increased sensitivity to radiation and chemotherapy compared with their HPV- counterparts; differences in the role of the host immune system can partly explain this deviation.	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (28, 51))	('sensitivity to', 'MPA', (96, 110))	('increased', 'PosReg', (86, 95))	('prognosis', 'MPA', (69, 78))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (28, 52))	('squamous cell carcinomas', 'Disease', (28, 52))	('oropharyngeal squamous cell carcinomas', 'Phenotype', 'HP:0012182', (14, 52))	('HPV', 'Species', '10566', (9, 12))	('improved', 'PosReg', (60, 68))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (28, 52))	('HPV+', 'Var', (9, 13))	('HPV', 'Species', '10566', (158, 161))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (96, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
372181	31612013	For example, the HPV E6 protein can dysregulate p53, which has been observed to be closely associated with CSCs.	('p53', 'Gene', (48, 51))	('protein', 'Protein', (24, 31))	('CSCs', 'Disease', (107, 111))	('p53', 'Gene', '7157', (48, 51))	('dysregulate', 'Var', (36, 47))	('HPV E6', 'Gene', (17, 23))	('HPV', 'Species', '10566', (17, 20))	('associated', 'Reg', (91, 101))
372182	31612013	p53 is 'the guardian of the genome', since genome mutation or instability leads to tumor occurrence.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('instability', 'Var', (62, 73))	('leads to', 'Reg', (74, 82))	('genome mutation', 'Var', (43, 58))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
372211	29962387	Reduction of the lymphadenectomy field and setting of lymphadenectomy areas with highest priority may be feasible when sentinel node (SN) navigation is appropriately performed in cN0 early-stage esophageal cancer.	('cN0', 'Var', (179, 182))	('esophageal cancer', 'Disease', (195, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))
372241	29962387	Although further studies are needed, reduction of the lymphadenectomy field and setting of lymphadenectomy areas with highest priority may be feasible when SN navigation is appropriately performed in cN0 early-stage esophageal cancer.	('cN0', 'Var', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('esophageal cancer', 'Disease', (216, 233))	('esophageal cancer', 'Disease', 'MESH:D004938', (216, 233))
372287	30172240	In this study, we report the ESCC transcriptome in a sample of patients from a Western population and analyze, for the first time, differentially expressed genes, mutations, and gene fusions, pointing to dysregulated signaling pathways potentially associated to ESCC carcinogenesis.	('mutations', 'Var', (163, 172))	('carcinogenesis', 'Disease', (267, 281))	('associated', 'Reg', (248, 258))	('patients', 'Species', '9606', (63, 71))	('ESCC', 'Disease', (262, 266))	('fusions', 'Var', (183, 190))	('carcinogenesis', 'Disease', 'MESH:D063646', (267, 281))
372294	30172240	Subsequently, these candidates were subjected to several filtering procedures, including removal of variations present in the nontumor adjacent mucosa; InDel alterations and A:T>G:C conversions were excluded in view of their high probability of representing RNA editing products.	('A:T>G:C conversions', 'Var', (174, 193))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('InDel alterations', 'Var', (152, 169))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
372319	30172240	Reanalysis of TCGA data revealed that, among the Wnt-related DEG herein analyzed, NKD2 and LRP5 were mutated or amplified (23% and 21%, respectively), while SFRP5, WNT7B, CDC25C, RHOC, PAX2, and SOST did not show alterations (Supplementary Figure 2).	('CDC25C', 'Gene', (171, 177))	('PAX2', 'Gene', (185, 189))	('SOST', 'Gene', '50964', (195, 199))	('NKD2', 'Gene', '85409', (82, 86))	('SOST', 'Gene', (195, 199))	('RHOC', 'Gene', '389', (179, 183))	('mutated', 'Var', (101, 108))	('RHOC', 'Gene', (179, 183))	('PAX2', 'Gene', '5076', (185, 189))	('CDC25C', 'Gene', '995', (171, 177))	('SFRP5', 'Gene', '6425', (157, 162))	('LRP5', 'Gene', '4041', (91, 95))	('LRP5', 'Gene', (91, 95))	('NKD2', 'Gene', (82, 86))	('amplified', 'Var', (112, 121))	('SFRP5', 'Gene', (157, 162))	('CG', 'Chemical', 'MESH:C028505', (15, 17))
372323	30172240	RNA-seq data from IS revealed a median of 65 point mutations per tumor (33-199) following removal of AT>GC conversions (Figure 2A).	('AT', 'Chemical', 'MESH:D001246', (101, 103))	('tumor', 'Disease', (65, 70))	('point mutations', 'Var', (45, 60))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('GC', 'Chemical', 'MESH:C057580', (104, 106))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
372327	30172240	Other frequently mutated genes were LOC389831 (42.9%), PI4KA (21.4%), MST1L (21.4%), HERC2 (21.4%), and NBPF9 (21.4%).	('NBPF9', 'Gene', '400818', (104, 109))	('HERC2', 'Gene', (85, 90))	('PI4KA', 'Gene', (55, 60))	('LOC389831', 'Var', (36, 45))	('MST1L', 'Gene', '11223', (70, 75))	('HERC2', 'Gene', '8924', (85, 90))	('PI4KA', 'Gene', '5297', (55, 60))	('NBPF9', 'Gene', (104, 109))	('MST1L', 'Gene', (70, 75))
372333	30172240	GC>AT was the second most frequent conversion (29.3%) in VS and the most frequent one in IS (45.5%); AT>TA and GC>TA were found in at least 10% of cases in both sets; InDel and GC>CG and AT>CG conversions showed smaller frequencies (Figure 3B).	('TA', 'Chemical', 'MESH:D013635', (104, 106))	('TA', 'Chemical', 'MESH:D013635', (114, 116))	('GC', 'Chemical', 'MESH:C057580', (177, 179))	('AT', 'Chemical', 'MESH:D001246', (101, 103))	('GC', 'Chemical', 'MESH:C057580', (111, 113))	('AT', 'Chemical', 'MESH:D001246', (187, 189))	('InDel', 'Var', (167, 172))	('CG', 'Chemical', 'MESH:C028505', (190, 192))	('AT>CG', 'Var', (187, 192))	('CG', 'Chemical', 'MESH:C028505', (180, 182))	('GC', 'Chemical', 'MESH:C057580', (0, 2))	('AT', 'Chemical', 'MESH:D001246', (3, 5))	('GC>CG', 'Var', (177, 182))
372334	30172240	Figure 3C shows the distribution of TP53 mutations per exon in IS and VS.	('mutations', 'Var', (41, 50))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
372335	30172240	Mutations were also identified in TP53 introns in VS, always coexisting with exonic mutations.	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))
372342	30172240	Moreover, as fusions might be a consequence of dysregulated DNA repair, mainly by nonhomologous end-joining (NHEJ), analysis of 14 NHEJ-related genes from the KEGG database showed that only ATR was overexpressed in tumor samples with fusions (P = .034) (Figure 4).	('ATR', 'Gene', '545', (190, 193))	('ATR', 'Gene', (190, 193))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('overexpressed', 'PosReg', (198, 211))	('tumor', 'Disease', (215, 220))	('fusions', 'Var', (234, 241))
372349	30172240	The ESCC2 subtype, more common among Eastern European and South American patients, was characterized by loss of function of KDM6A, KTM2D, PTEN and PIK3R1, CDK6 amplification and BST2 overexpression.	('BST2', 'Gene', (178, 182))	('PTEN', 'Gene', (138, 142))	('amplification', 'Var', (160, 173))	('PIK3R1', 'Gene', '5295', (147, 153))	('PTEN', 'Gene', '5728', (138, 142))	('PIK3R1', 'Gene', (147, 153))	('BST2', 'Gene', '684', (178, 182))	('loss of function', 'NegReg', (104, 120))	('KDM6A', 'Gene', (124, 129))	('CDK6', 'Gene', (155, 159))	('ESCC2', 'Disease', (4, 9))	('CDK6', 'Gene', '1021', (155, 159))	('patients', 'Species', '9606', (73, 81))	('KDM6A', 'Gene', '7403', (124, 129))	('overexpression', 'PosReg', (183, 197))
372351	30172240	These findings suggested that these alterations might play a role in ESCC development in South American patients.	('alterations', 'Var', (36, 47))	('play', 'Reg', (54, 58))	('ESCC development', 'Disease', (69, 85))	('patients', 'Species', '9606', (104, 112))
372352	30172240	Deregulation of Wnt signaling has been found in other tumors, albeit by different mechanisms.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('Wnt signaling', 'Pathway', (16, 29))	('Deregulation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
372353	30172240	proposed a new molecular classification for colorectal cancer, showing that APC mutations were present in 70% of cases, being more common (83%) in the consensus molecular subtype 2 (CMS2), followed by CMS3 (78%), CMS4 (66%), and CMS1 (40%).	('colorectal cancer', 'Disease', (44, 61))	('mutations', 'Var', (80, 89))	('common', 'Reg', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (44, 61))	('APC', 'Disease', 'MESH:D011125', (76, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('APC', 'Disease', (76, 79))
372355	30172240	Deregulation of CTNNB1, APC, and DVL1 expression was found in 21% of all invasive breast carcinomas, while this frequency was much higher (56%) in PAM50 Basal subtype.	('CTNNB1', 'Gene', (16, 22))	('breast carcinomas', 'Disease', (82, 99))	('DVL1', 'Gene', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('Deregulation', 'Var', (0, 12))	('expression', 'MPA', (38, 48))	('CTNNB1', 'Gene', '1499', (16, 22))	('breast carcinomas', 'Phenotype', 'HP:0003002', (82, 99))	('APC', 'Disease', 'MESH:D011125', (24, 27))	('DVL1', 'Gene', '1855', (33, 37))	('APC', 'Disease', (24, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('breast carcinomas', 'Disease', 'MESH:D001943', (82, 99))
372358	30172240	These authors showed that WNT7B silencing in myeloid cells resulted in reduction of breast tumor mass, volume, and lung metastases in a murine model.	('breast tumor', 'Phenotype', 'HP:0100013', (84, 96))	('reduction of breast tumor', 'Disease', (71, 96))	('lung metastases', 'Disease', (115, 130))	('murine', 'Species', '10090', (136, 142))	('lung metastases', 'Disease', 'MESH:D009362', (115, 130))	('reduction of breast tumor', 'Disease', 'MESH:D001943', (71, 96))	('silencing', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('volume', 'CPA', (103, 109))	('WNT7B', 'Gene', (26, 31))
372361	30172240	Mutation analysis revealed that TP53 was the most frequently mutated gene in ESCC, with approximately 70% of tumors showing at least one mutation, mainly missense (86%), and in exons 5 to 8 (90%).	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('missense', 'Var', (154, 162))	('ESCC', 'Disease', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
372362	30172240	Our RNA-seq analyses were more sensitive than previous ones based on Sanger sequencing pointing to TP53 mutations in 35% of Brazilian patients with ESCC.	('TP53', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('patients', 'Species', '9606', (134, 142))	('TP53', 'Gene', '7157', (99, 103))	('ESCC', 'Disease', (148, 152))
372363	30172240	It also confirmed TCGA and the International Cancer Genome Consortium (ICGC) studies showing TP53 as the only gene that was very frequently affected by mutations in ESCC (93% and 62%, respectively).	('GC', 'Chemical', 'MESH:C057580', (73, 75))	('mutations', 'Var', (152, 161))	('TP53', 'Gene', '7157', (93, 97))	('affected', 'Reg', (140, 148))	('TP53', 'Gene', (93, 97))	('ESCC', 'Gene', (165, 169))	('CG', 'Chemical', 'MESH:C028505', (72, 74))	('Cancer', 'Disease', (45, 51))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('CG', 'Chemical', 'MESH:C028505', (19, 21))
372364	30172240	LOC389831, a gene coding for uncharacterized isoforms, was the second most frequently mutated gene (43%) in our study, followed by PI4KA, HERC2, NBPF9, and MST1L, each with 21.4%.	('MST1L', 'Gene', '11223', (156, 161))	('MST1L', 'Gene', (156, 161))	('NBPF9', 'Gene', '400818', (145, 150))	('PI4KA', 'Gene', (131, 136))	('LOC389831', 'Var', (0, 9))	('HERC2', 'Gene', (138, 143))	('NBPF9', 'Gene', (145, 150))	('PI4KA', 'Gene', '5297', (131, 136))	('HERC2', 'Gene', '8924', (138, 143))
372372	30172240	Although half of the tumors herein studied showed fusions, none of them was recurrent or involved the same genes in different patients, and most of them involved syntenic loci.	('involved', 'Reg', (89, 97))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('fusions', 'Var', (50, 57))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('patients', 'Species', '9606', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
372374	30172240	This pointed to a likely occurrence of chromoanagenesis and formation of micronuclei initiated by error in mitotic segregation, a common event in malignancies with a highly dysregulated cell cycle like ESCC.	('dysregulated cell cycle', 'Phenotype', 'HP:0011018', (173, 196))	('chromoanagenesis', 'Disease', (39, 55))	('malignancies', 'Disease', 'MESH:D009369', (146, 158))	('error', 'Var', (98, 103))	('malignancies', 'Disease', (146, 158))	('mitotic segregation', 'CPA', (107, 126))
372375	30172240	Cells may thus enter in mitosis with micronuclei still undergoing DNA replication, resulting in chromosome fragmentation and repair of double-strand breaks by nonhomologous end joining (NHEJ), leading to deletions, translocations, and formation of double minute chromosomes.	('mitosis', 'Disease', 'None', (24, 31))	('repair', 'MPA', (125, 131))	('translocations', 'CPA', (215, 229))	('double minute chromosomes', 'CPA', (248, 273))	('enter', 'Reg', (15, 20))	('deletions', 'Var', (204, 213))	('chromosome fragmentation', 'CPA', (96, 120))	('mitosis', 'Disease', (24, 31))
372376	30172240	Double minute chromosomes have been reported in ESCC in association to amplification of two candidate oncogenes, FGFR1 and LETM2 .	('association', 'Reg', (56, 67))	('FGFR1', 'Gene', (113, 118))	('amplification', 'Var', (71, 84))	('LETM2', 'Gene', (123, 128))	('FGFR1', 'Gene', '2260', (113, 118))	('Double minute chromosomes', 'Var', (0, 25))	('LETM2', 'Gene', '137994', (123, 128))	('ESCC', 'Disease', (48, 52))
372377	30172240	Furthermore, the association between ATR overexpression and presence of fusions in our dataset further suggested the occurrence of chromoanagenesis in ESCC, although further studies are necessary for confirming this phenomenon.	('chromoanagenesis', 'Disease', (131, 147))	('ATR', 'Gene', '545', (37, 40))	('ATR', 'Gene', (37, 40))	('association', 'Interaction', (17, 28))	('ESCC', 'Disease', (151, 155))	('presence', 'Var', (60, 68))
372381	29867084	PTK7 overexpression increased the proliferation of TE-5 and TE-14 cells but decreased the proliferation of TE-6 and TE-10 cells.	('proliferation', 'CPA', (34, 47))	('increased', 'PosReg', (20, 29))	('TE-10', 'CellLine', 'CVCL:1760', (116, 121))	('PTK7', 'Gene', (0, 4))	('proliferation', 'CPA', (90, 103))	('expression', 'Species', '29278', (9, 19))	('decreased', 'NegReg', (76, 85))	('overexpression', 'Var', (5, 19))
372392	29867084	The functions of PTK7 are vital, as PTK7-deficient mice die perinatally with defects in neural tube closure and stereociliary bundle orientation similar to those observed in PCP mutant mice and frogs.	('PTK7-deficient', 'Disease', 'MESH:D007153', (36, 50))	('mutant', 'Var', (178, 184))	('PCP', 'Chemical', '-', (174, 177))	('stereociliary bundle orientation', 'CPA', (112, 144))	('mice', 'Species', '10090', (51, 55))	('defects', 'NegReg', (77, 84))	('mice', 'Species', '10090', (185, 189))	('PTK7-deficient', 'Disease', (36, 50))	('neural tube closure', 'Disease', 'MESH:D009436', (88, 107))	('defects in neural tube closure', 'Phenotype', 'HP:0045005', (77, 107))	('neural tube closure', 'Disease', (88, 107))
372394	29867084	For example, PTK7 increases the proliferation, survival, migration, and invasion of cells and wound healing by activating ERK, JNK, p38, and NF-kappaB signaling pathways, whereas it decreases apoptosis by suppressing the activation of caspase-9 and -10.	('decreases', 'NegReg', (182, 191))	('increases', 'PosReg', (18, 27))	('JNK', 'Pathway', (127, 130))	('p38', 'Gene', (132, 135))	('survival', 'CPA', (47, 55))	('migration', 'CPA', (57, 66))	('activating', 'PosReg', (111, 121))	('apoptosis', 'CPA', (192, 201))	('NF-kappaB', 'Gene', '4790', (141, 150))	('caspase-9 and -10', 'Gene', '842;843', (235, 252))	('proliferation', 'CPA', (32, 45))	('p38', 'Gene', '5594', (132, 135))	('PTK7', 'Var', (13, 17))	('suppressing', 'NegReg', (205, 216))	('ERK', 'Gene', (122, 125))	('ERK', 'Gene', '5594', (122, 125))	('NF-kappaB', 'Gene', (141, 150))
372408	29867084	Ectopic expression of PTK7 increased the proliferation of TE-5 and TE-14 cells (i.e., PTK7-low ESCC cells) (Fig.	('PTK7', 'Gene', (22, 26))	('increased', 'PosReg', (27, 36))	('Ectopic expression', 'Var', (0, 18))	('expression', 'Species', '29278', (8, 18))	('low ESCC', 'Phenotype', 'HP:0025022', (91, 99))	('proliferation', 'CPA', (41, 54))
372409	29867084	2b), whereas the proliferation of the PTK7-high TE-6 and TE-10 cells decreased with ectopic expression (Fig.	('proliferation', 'CPA', (17, 30))	('ectopic expression', 'Var', (84, 102))	('decreased', 'NegReg', (69, 78))	('expression', 'Species', '29278', (92, 102))	('TE-10', 'CellLine', 'CVCL:1760', (57, 62))
372410	29867084	This result was unexpected, as previous evidence showing PTK7 knockdown decreased the proliferation of TE-10 and TE-11 cells indicated that PTK7 is an oncogene in ESCC.	('ESCC', 'Disease', (163, 167))	('PTK7', 'Gene', (140, 144))	('decreased', 'NegReg', (72, 81))	('proliferation', 'CPA', (86, 99))	('TE-10', 'CellLine', 'CVCL:1760', (103, 108))	('PTK7', 'Gene', (57, 61))	('knockdown', 'Var', (62, 71))
372415	29867084	The maximal oncogenic effects were found in PTK7-low TE-5 and TE-14 cells transfected with 2 mug or PTK7-high TE-10 and TE-6 cells transfected with 1 mug of the PTK7 expression vector.	('PTK7-high', 'Var', (100, 109))	('oncogenic effects', 'CPA', (12, 29))	('expression', 'Species', '29278', (166, 176))	('TE-10', 'CellLine', 'CVCL:1760', (110, 115))	('PTK7-low', 'Var', (44, 52))
372425	29867084	However, a Kaplan-Meier survival plot showed that ESCC patients in the PTK7-high group had a significantly longer overall survival than those in the PTK7-low group (P = 0.011) (Fig.	('overall survival', 'MPA', (114, 130))	('PTK7-high', 'Var', (71, 80))	('longer', 'PosReg', (107, 113))	('patients', 'Species', '9606', (55, 63))	('ESCC', 'Disease', (50, 54))
372431	29867084	PTK7 knockdown decreased proliferation, survival, wound healing and invasion by inhibiting ERK, JNK, p38, Akt and FAK activation in ESCC TE-10 and TE-11 cells.	('proliferation', 'CPA', (25, 38))	('PTK7', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('p38', 'Gene', (101, 104))	('invasion', 'CPA', (68, 76))	('ERK', 'Gene', (91, 94))	('FAK', 'Gene', (114, 117))	('TE-10', 'CellLine', 'CVCL:1760', (137, 142))	('decreased', 'NegReg', (15, 24))	('FAK', 'Gene', '5747', (114, 117))	('p38', 'Gene', '5594', (101, 104))	('JNK', 'Pathway', (96, 99))	('wound healing', 'CPA', (50, 63))	('inhibiting', 'NegReg', (80, 90))	('Akt', 'Gene', (106, 109))	('activation', 'PosReg', (118, 128))	('ERK', 'Gene', '5594', (91, 94))	('Akt', 'Gene', '207', (106, 109))	('survival', 'CPA', (40, 48))
372433	29867084	Consistently, we found here that overexpression of PTK7 increased proliferation in PTK7-low ESCC TE-5 and TE-14 cells and that PTK7 knockdown decreased it in PTK7-high ESCC TE-6 and TE-10 cells.	('overexpression', 'PosReg', (33, 47))	('low ESCC', 'Phenotype', 'HP:0025022', (88, 96))	('knockdown', 'Var', (132, 141))	('increased', 'PosReg', (56, 65))	('PTK7', 'Gene', (51, 55))	('high ESCC', 'Phenotype', 'HP:0003565', (163, 172))	('proliferation', 'CPA', (66, 79))	('decreased', 'NegReg', (142, 151))	('TE-10', 'CellLine', 'CVCL:1760', (182, 187))	('expression', 'Species', '29278', (37, 47))	('PTK7', 'Gene', (127, 131))
372442	29867084	It appears that when levels of PTK7 are lower than that of KDR, PTK7 helps KDR molecules to oligomerize and activate, whereas high amounts of PTK7 inhibit this.	('KDR', 'Gene', (59, 62))	('KDR', 'Gene', '3791', (75, 78))	('oligomerize', 'MPA', (92, 103))	('activate', 'PosReg', (108, 116))	('PTK7', 'Var', (64, 68))	('KDR', 'Gene', (75, 78))	('KDR', 'Gene', '3791', (59, 62))
372446	29867084	1a and c), and PTK7 overexpression was also shown to decrease oncogenic effects in lung squamous cell carcinoma cells.	('expression', 'Species', '29278', (24, 34))	('overexpression', 'Var', (20, 34))	('decrease', 'NegReg', (53, 61))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (83, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 111))	('lung squamous cell carcinoma', 'Disease', (83, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('PTK7', 'Gene', (15, 19))	('oncogenic effects', 'CPA', (62, 79))
372447	29867084	Thus, in some cancer types with comparable, or even higher, PTK7 expression, the suppressive effect of PTK7 on oncogenic characteristics may be apparent.	('suppressive effect', 'NegReg', (81, 99))	('cancer', 'Disease', (14, 20))	('oncogenic characteristics', 'CPA', (111, 136))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('PTK7', 'Gene', (103, 107))	('expression', 'Species', '29278', (65, 75))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('expression', 'Var', (65, 75))	('PTK7', 'Gene', (60, 64))
372449	29867084	However, caution should be used with this strategy when considering the evidence showing PTK7 can biphasically regulate tumorigenesis, as the inhibition of PTK7 activity or removal of PTK7-positive cells may induce tumor progression.	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', (120, 125))	('induce', 'Reg', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('PTK7', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (215, 220))	('inhibition', 'Var', (142, 152))	('activity', 'MPA', (161, 169))
372457	29867084	Antibodies against phospho-Src (Tyr416), Src, phospho-Akt (Ser473), and Akt were purchased from Cell Signaling Technology (Danvers, MA, USA).	('Ser473', 'Chemical', '-', (59, 65))	('Akt', 'Gene', (72, 75))	('Akt', 'Gene', '207', (54, 57))	('Src', 'Gene', (27, 30))	('Src', 'Gene', (41, 44))	('Src', 'Gene', '6714', (27, 30))	('Src', 'Gene', '6714', (41, 44))	('Akt', 'Gene', (54, 57))	('Tyr416', 'Chemical', '-', (32, 38))	('Tyr416', 'Var', (32, 38))	('Akt', 'Gene', '207', (72, 75))
372530	28948524	Among 2944 recruited patients, 1554 patients receiving primary surgery met the inclusion criteria including 613 cN0pN0, 403 cN0pN+, 220 cN+pN0, and 318 cN+pN+ patients.	('patients', 'Species', '9606', (36, 44))	('cN0pN0', 'Var', (112, 118))	('patients', 'Species', '9606', (21, 29))	('cN0pN+', 'Var', (124, 130))	('patients', 'Species', '9606', (159, 167))
372540	28948524	The primary objective of the current study was to compare the long-term prognosis for cN0pN+ patient groups treated by primary surgery with cN0pN0, clinical N+/pathological N0 (cN+pN0), and cN+pN+ patient groups.	('cN0pN0', 'Var', (140, 146))	('patient', 'Species', '9606', (93, 100))	('patient', 'Species', '9606', (197, 204))	('cN0pN+', 'Gene', (86, 92))
372553	28948524	We further compared the overall and disease-free survivals between cN0pN+ and each of the other subgroups using Cox's proportional hazard model, and hazard ratios for cN0/pN+ relative to each of the other subgroups were calculated as effect sizes.	('Cox', 'Gene', (112, 115))	('Cox', 'Gene', '1351', (112, 115))	('cN0pN+', 'Var', (67, 73))
372564	28948524	The groups did not differ significantly in terms of baseline patient demographics, except for the proportion of malnutrition, which was increased in the cN+pN+ group (21.4%), the cN0pN+ group (19.1%), and the cN+pN0 group (13.6%) compared with the cN0pN0 group (7.3%) (Table 1).	('patient', 'Species', '9606', (61, 68))	('malnutrition', 'Disease', 'MESH:D044342', (112, 124))	('malnutrition', 'Disease', (112, 124))	('cN+pN+', 'Var', (153, 159))	('malnutrition', 'Phenotype', 'HP:0004395', (112, 124))	('cN0pN+', 'Var', (179, 185))
372565	28948524	The cN+pN+ and cN0pN+ groups had a significantly greater proportion of lower third esophageal tumors than the cN0pN0 and cN+pN0 groups.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('esophageal tumors', 'Disease', 'MESH:D004938', (83, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('esophageal tumors', 'Phenotype', 'HP:0100751', (83, 100))	('esophageal tumors', 'Disease', (83, 100))	('cN0pN+', 'Var', (15, 21))	('cN+pN+', 'Var', (4, 10))
372566	28948524	Compared with the cN0pN0 and cN+pN0 groups, the cN+pN+ and cN0pN+ groups showed an increase in the proportion of adenocarcinoma histologic subtype, poor tumor differentiation, pathologic T3 or T4 stage, pathologic stage 3 disease, and R1/2 resection margin.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('increase', 'PosReg', (83, 91))	('adenocarcinoma', 'Disease', (113, 127))	('T3 or T4 stage', 'CPA', (187, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (113, 127))	('tumor', 'Disease', (153, 158))	('cN0pN+', 'Var', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
372567	28948524	Subset analysis according to the histologic subtype showed that cN0pN+ had a significantly reduced 5-year overall survival (P < 0.001) and event-free survival (P < 0.001) compared with cN0pN0 in both the squamous cell and adenocarcinoma subgroups.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('cN0pN+', 'Var', (64, 70))	('event-free', 'CPA', (139, 149))	('adenocarcinoma subgroups', 'Disease', 'MESH:D000230', (222, 246))	('reduced', 'NegReg', (91, 98))	('overall survival', 'CPA', (106, 122))	('adenocarcinoma subgroups', 'Disease', (222, 246))
372570	28948524	The results of this large retrospective multicenter European study suggest that the long-term prognosis for cN0pN+ esophageal cancer patients is significantly worse than for cN0pN0 patients, but similar to that for cN+pN+ patients.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (133, 141))	('worse', 'NegReg', (159, 164))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('patients', 'Species', '9606', (181, 189))	('cN0pN+', 'Var', (108, 114))
372594	28948524	Subset analysis of the squamous cell carcinoma histologic subtype showed that cN0pN+ had a significantly reduced 5-year overall survival (hazard ratio [HR] 2.36; 95% confidence interval [CI] 1.82-3.07; P < 0.001) and event-free survival (HR 2.04; 95% CI 1.60-2.62; P < 0.001) compared with cN0pN0.	('cN0pN+', 'Var', (78, 84))	('event-free survival', 'CPA', (217, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('reduced', 'NegReg', (105, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('overall survival', 'CPA', (120, 136))	('squamous cell carcinoma', 'Disease', (23, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))
372595	28948524	Similarly, subset analysis of the adenocarcinoma histologic subtype showed that cN0pN+ had a significantly reduced 5-year overall survival (HR 4.08; 95% CI 3.05-5.48; P < 0.001) and event-free survival (HR 4.10; 95% CI 3.08-5.45; P < 0.001) compared with cN0pN0.	('adenocarcinoma', 'Disease', (34, 48))	('event-free survival', 'CPA', (182, 201))	('reduced', 'NegReg', (107, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('adenocarcinoma', 'Disease', 'MESH:D000230', (34, 48))	('cN0pN+', 'Var', (80, 86))	('overall survival', 'CPA', (122, 138))
372613	26314875	Of the patients treated with nCRT (n = 127) between 2005 and 2013, 23 were excluded because of the following criteria: incomplete medical records (n = 0), postoperative mortality (death within 90 days or in-hospital, n = 10), progressive disease within 3 months after surgery or microscopic irradical (R1; tumor cells <1 mm) longitudinal margins (n = 0) or follow-up <24 months (n = 13).	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('progressive disease', 'CPA', (226, 245))	('microscopic irradical', 'Var', (279, 300))	('tumor', 'Disease', (306, 311))	('patients', 'Species', '9606', (7, 15))
372652	26314875	(n = 269, 15,6 % nCRT) found a significantly better DFS and OS in patients with a RCP R0 resection.	('patients', 'Species', '9606', (66, 74))	('better', 'PosReg', (45, 51))	('RCP R0 resection', 'Var', (82, 98))	('DFS', 'MPA', (52, 55))
372737	24818169	Targeted Inhibition of mTOR Signaling Improves Sensitivity of Esophageal Squamous Cell Carcinoma Cells to Cisplatin mTOR is an evolutionarily conserved serine-threonine kinase with a central role in cell growth, invasion, and metastasis of tumors, and is activated in many cancers.	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('metastasis of tumors', 'Disease', (226, 246))	('Esophageal Squamous Cell Carcinoma', 'Disease', (62, 96))	('cancers', 'Disease', (273, 280))	('mTOR', 'Gene', '2475', (116, 120))	('Inhibition', 'Var', (9, 19))	('metastasis of tumors', 'Disease', 'MESH:D009362', (226, 246))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('Improves', 'PosReg', (38, 46))	('cancers', 'Disease', 'MESH:D009369', (273, 280))	('Cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('mTOR', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('Sensitivity', 'MPA', (47, 58))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('Carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('mTOR', 'Gene', (116, 120))	('mTOR', 'Gene', '2475', (23, 27))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (62, 96))
372802	24818169	The ratio of alive cells with mTOR siRNA was lower (P < 0.05) than that without mTOR siRNA at the same concentration of cisplatin.	('lower', 'NegReg', (45, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('mTOR siRNA', 'Var', (30, 40))
372816	24818169	The apoptosis of tumor cells of ESCC xenografts in groups each was determined by an in situ TUNEL assay and the results showed that there were 63, 54, and 102 apoptotic cells/1,500 cells in mTOR siRNA, cisplatin, and mTOR siRNA + cisplatin groups, respectively, compared to control group (6 apoptotic cells/1,500 cells) (P < 0.05 or <0.01, Table 4).	('cisplatin', 'Chemical', 'MESH:D002945', (202, 211))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (230, 239))	('mTOR', 'Var', (190, 194))
372818	24818169	The results above indicate that mTOR siRNA promotes apoptosis of ESCC cells and the effect of inducing apoptosis is stronger when it is combined with cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('mTOR', 'Var', (32, 36))	('apoptosis', 'CPA', (52, 61))	('promotes', 'PosReg', (43, 51))
372819	24818169	Since mTOR was identified and cloned in 1994, it has been examined in a wide array of cancer types and aberrantly activated mTOR pathway plays an essential role in the growth of different types of tumors including ESCC.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('ESCC', 'Disease', (214, 218))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('mTOR pathway', 'Pathway', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('aberrantly', 'Var', (103, 113))	('tumors', 'Disease', (197, 203))	('cancer', 'Disease', (86, 92))
372820	24818169	So far, several statuses of the effectors on the upstream and downstream of mTOR pathway such as amplification of a catalytic subunit of PI3K and loss or mutation of PTEN gene have been detected in many malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('PTEN', 'Gene', (166, 170))	('PI3K', 'Gene', (137, 141))	('mutation', 'Var', (154, 162))	('loss', 'Disease', 'MESH:D015431', (146, 150))	('PTEN', 'Gene', '5728', (166, 170))	('loss', 'Disease', (146, 150))	('malignant tumors', 'Disease', (203, 219))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('malignant tumors', 'Disease', 'MESH:D018198', (203, 219))
372825	24818169	The above-mentioned results indicate that the aberrantly activated mTOR may be a clinical diagnostic mark in ESCC.	('mTOR', 'Gene', (67, 71))	('aberrantly activated', 'Var', (46, 66))	('men', 'Species', '9606', (10, 13))	('ESCC', 'Disease', (109, 113))
372827	24818169	RNA silencing including both short interfering RNA (siRNA) and short hairpin RNA (shRNA) has been used in cancer research in vitro and in vivo.	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('short interfering', 'Var', (29, 46))	('cancer', 'Disease', (106, 112))	('short hairpin RNA', 'Gene', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
372828	24818169	In this study, we found that mTOR siRNA alone could lead to slow growth of tumors and the volume of tumors at termination of the experiment on day 15 was only 9-fold bigger than that on day 1 in the group of mTOR siRNA alone, but 17-fold in the control group, and there was a significant difference (P < 0.05) in comparison of mTOR siRNA alone with control groups.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('mTOR siRNA', 'Var', (29, 39))	('slow growth', 'CPA', (60, 71))	('tumors', 'Disease', (100, 106))	('men', 'Species', '9606', (135, 138))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('slow growth', 'Phenotype', 'HP:0001510', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (75, 81))
372833	24818169	Thus, we investigated the combination effect of mTOR siRNA and cisplatin to determine whether mTOR siRNA would potentiate the effects of cisplatin on ESCC.	('mTOR siRNA', 'Var', (94, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('potentiate', 'PosReg', (111, 121))	('ESCC', 'Disease', (150, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))
372838	24818169	Additionally, the number of apoptosis cells was the most in mTOR siRNA + cisplatin group (102 cells/1,500 cells) compared to that in mTOR siRNA (63 cells/1,500 cells) and cisplatin (54 cells/1,500 cells) alone group (P < 0.05).	('mTOR', 'Var', (60, 64))	('apoptosis cells', 'CPA', (28, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))
372840	24818169	Above all, mTOR pathway has important effects on the tumorigenesis and progression of ESCC and inhibition of mTOR pathway by mTOR siRNA promotes the sensitivity of cells to cisplatin.	('mTOR pathway', 'Pathway', (109, 121))	('effects', 'Reg', (38, 45))	('inhibition', 'Var', (95, 105))	('promotes', 'PosReg', (136, 144))	('mTOR', 'Gene', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('sensitivity', 'MPA', (149, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))	('tumor', 'Disease', (53, 58))	('ESCC', 'Disease', (86, 90))
372848	21448147	Activation of the membrane metalloproteinase, A Disintegrin And Metalloproteinase (ADAM-10), was identified as a likely cause for cleavage of e-cadherin by western blot and immunostaining and a role for e-cadherin in the increased junctional permeability in EE from GERD supported by showing increased permeability after deletion of e-cadherin in mouse EE.	('junctional permeability', 'MPA', (231, 254))	('increased', 'PosReg', (292, 301))	('deletion', 'Var', (321, 329))	('e-cadherin', 'Protein', (333, 343))	('increased', 'PosReg', (221, 230))	('mouse', 'Species', '10090', (347, 352))	('permeability', 'MPA', (302, 314))
372850	21448147	Based on the rabbit model, an early marker of acid damage to EE is an increase in junctional (paracellular) permeability.	('increase', 'PosReg', (70, 78))	('acid damage', 'Var', (46, 57))	('rabbit', 'Species', '9986', (13, 19))
372883	21448147	To delete e-cadherin four Tmx injection were performed every other day on KRT5-CreERT;e-cadherinflox/flox compound mutants and KRT5-CreERT;E-cadherinflox/+ control mice (Figure 1).	('E-cadherin', 'Gene', (139, 149))	('E-cadherin', 'Gene', '999', (139, 149))	('mice', 'Species', '10090', (164, 168))	('Tmx', 'Chemical', 'MESH:D013629', (26, 29))	('mutants', 'Var', (115, 122))
372887	21448147	To help establish a cause-and-effect relationship between cleaved e-cadherin and junctional permeability, we developed a unique model in which e-cadherin was conditionally deleted from the adult mouse EE.	('mouse', 'Species', '10090', (195, 200))	('deleted', 'Var', (172, 179))	('e-cadherin', 'Gene', (143, 153))
372895	21448147	Following the generation of KRT5-CreER;e-cadherinflox/flox (E-cadDelta/Delta) compound mutants and 5 days after performance of the last of four Tmx injections, little to no e-cadherin was detectable by qRT-PCR (Figure 7d) or by immunostaining in the adult mouse EE (Figure 7e).	('Tmx', 'Chemical', 'MESH:D013629', (144, 147))	('mutants', 'Var', (87, 94))	('KRT5-CreER;e-cadherinflox/flox', 'Gene', (28, 58))	('mouse', 'Species', '10090', (256, 261))
372896	21448147	Consistent with an increase in junctional permeability, the EE with deleted e-cadherin had DIS on EM (Figure 8) and significantly higher fluorescein flux than the EE from (untreated) littermate controls (Figure 7f).	('deleted', 'Var', (68, 75))	('fluorescein', 'Chemical', 'MESH:D019793', (137, 148))	('higher', 'PosReg', (130, 136))	('e-cadherin', 'Gene', (76, 86))	('fluorescein flux', 'MPA', (137, 153))	('junctional permeability', 'MPA', (31, 54))	('increase', 'PosReg', (19, 27))	('DIS', 'Chemical', '-', (91, 94))
372911	21448147	To test the hypothesis that loss of adhesion by e-cadherin could account for the observed increase in paracellular permeability in EE from GERD patients, we generated a mouse model in which e-cadherin was deleted from the EE.	('increase', 'PosReg', (90, 98))	('paracellular permeability', 'MPA', (102, 127))	('e-cadherin', 'Gene', (190, 200))	('patients', 'Species', '9606', (144, 152))	('deleted', 'Var', (205, 212))	('mouse', 'Species', '10090', (169, 174))
372912	21448147	Notably, it showed that deletion of e-cadherin resulted in DIS and a marked increase in paracellular (junctional) permeability.	('e-cadherin', 'Protein', (36, 46))	('DIS', 'MPA', (59, 62))	('increase', 'PosReg', (76, 84))	('DIS', 'Chemical', '-', (59, 62))	('deletion', 'Var', (24, 32))
372915	21448147	Since at times it is clinically and morphologically difficult to distinguish between eosinophilic esophagitis and GERD, the presence of C-terminal fragments of e-cadherin in biopsies of EE may prove to be of value as a biomarker of GERD.	('presence', 'Var', (124, 132))	('e-cadherin', 'Protein', (160, 170))	('esophagitis', 'Phenotype', 'HP:0100633', (98, 109))	('C-terminal fragments', 'Var', (136, 156))	('eosinophilic esophagitis', 'Disease', 'MESH:D004802', (85, 109))	('eosinophilic esophagitis', 'Phenotype', 'HP:0410151', (85, 109))	('eosinophilic esophagitis', 'Disease', (85, 109))
372985	33805401	NEO and HT-2 were quantified in both control and esophageal cancer patients, and differences were observed between both groups; HT-2 values were slightly higher in the esophageal cancer group (29.09 microg/g creatinine) compared to the control group (16.81 microg/g creatinine).	('esophageal cancer', 'Disease', (168, 185))	('HT-2', 'CellLine', 'CVCL:5T92', (128, 132))	('esophageal cancer', 'Disease', (49, 66))	('29.09', 'Var', (193, 198))	('patients', 'Species', '9606', (67, 75))	('NEO', 'Chemical', 'MESH:C016009', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('higher', 'PosReg', (154, 160))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('creatinine', 'Chemical', 'MESH:D003404', (208, 218))	('HT-2', 'CellLine', 'CVCL:5T92', (8, 12))	('creatinine', 'Chemical', 'MESH:D003404', (266, 276))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('HT-2', 'Gene', (128, 132))
373074	32441181	Here, hits were defined as having a z-score of -3 or greater in the EAC lines and a difference of at least 2 in one or both of the control cell lines (e.g., for a hit with a z-score of -3 in an EAC line, the z-score in the EPC-2 would have to be greater than or equal to -1).	('EPC-2', 'Gene', (223, 228))	('EAC', 'Gene', '280769', (194, 197))	('z-score of -3', 'Var', (174, 187))	('EPC-2', 'Gene', '26122', (223, 228))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('EAC', 'Gene', '280769', (68, 71))	('EAC', 'Gene', (194, 197))	('EAC', 'Gene', (68, 71))	('EAC', 'Phenotype', 'HP:0011459', (194, 197))
373097	32441181	Following one class of compounds identified in our primary phenotypic screen of 19,555 small molecules tested across all eight esophageal cell lines, we validated antimetabolites as selectively lethal to the EAC lines in vitro following dose-response studies.	('antimetabolites', 'Var', (163, 178))	('lethal', 'NegReg', (194, 200))	('EAC', 'Gene', '280769', (208, 211))	('EAC', 'Gene', (208, 211))	('EAC', 'Phenotype', 'HP:0011459', (208, 211))
373195	31857901	Studies have shown that, in deep crypt dysplasia, conventional dysplasia actually is present in about 47% of cases, and the former may share similar molecular signature, such as aneuploidy and mutated p53 expression pattern, similar to conventional dysplasia.	('expression', 'MPA', (205, 215))	('p53', 'Gene', (201, 204))	('aneuploidy', 'Disease', 'MESH:D000782', (178, 188))	('dysplasia', 'Disease', 'MESH:C536170', (249, 258))	('dysplasia', 'Disease', 'MESH:C536170', (39, 48))	('mutated', 'Var', (193, 200))	('dysplasia', 'Disease', (249, 258))	('deep crypt dysplasia', 'Disease', (28, 48))	('p53', 'Gene', '7157', (201, 204))	('deep crypt dysplasia', 'Disease', 'MESH:D058739', (28, 48))	('dysplasia', 'Disease', (39, 48))	('dysplasia', 'Disease', 'MESH:C536170', (63, 72))	('aneuploidy', 'Disease', (178, 188))	('dysplasia', 'Disease', (63, 72))
373223	31857901	Microscopically, the tumor could be categorized as well differentiated (more than 95% gland formation), moderately differentiated (50%-95% gland formation), or poorly differentiated carcinoma (less than 50% gland formation).	('tumor', 'Disease', (21, 26))	('carcinoma', 'Disease', (182, 191))	('poorly', 'Disease', (160, 166))	('gland formation', 'CPA', (86, 101))	('50%-95', 'Var', (131, 137))	('carcinoma', 'Disease', 'MESH:D009369', (182, 191))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
373233	31857901	In a subsequent study by the same group, the authors demonstrate strong nuclear p53 expression in biopsy with indefinite for dysplasia is associated with neoplasia progression.	('neoplasia', 'Disease', 'MESH:D009369', (154, 163))	('neoplasia', 'Phenotype', 'HP:0002664', (154, 163))	('dysplasia', 'Disease', (125, 134))	('p53', 'Gene', (80, 83))	('associated with', 'Reg', (138, 153))	('p53', 'Gene', '7157', (80, 83))	('neoplasia', 'Disease', (154, 163))	('nuclear', 'Var', (72, 79))	('dysplasia', 'Disease', 'MESH:C536170', (125, 134))
373240	31857901	Immunostain for p53 appears to increase diagnostic stratification in BE-surveillance biopsies and decrease the proportion of indefinite for dysplasia diagnoses.	('BE', 'Phenotype', 'HP:0100580', (69, 71))	('decrease', 'NegReg', (98, 106))	('p53', 'Gene', (16, 19))	('diagnostic stratification', 'MPA', (40, 65))	('Immunostain', 'Var', (0, 11))	('p53', 'Gene', '7157', (16, 19))	('dysplasia', 'Disease', 'MESH:C536170', (140, 149))	('dysplasia', 'Disease', (140, 149))	('increase', 'PosReg', (31, 39))
373241	31857901	Faint scattered p53 positivity within nuclei typically correlates with a wild-type gene status, whereas either strong nuclear positivity or complete absence (null pattern) of staining correlates best with TP53 mutations.	('mutations', 'Var', (210, 219))	('p53', 'Gene', (16, 19))	('TP53', 'Gene', '7157', (205, 209))	('TP53', 'Gene', (205, 209))	('correlates', 'Reg', (55, 65))	('p53', 'Gene', '7157', (16, 19))	('positivity', 'MPA', (20, 30))
373255	31857901	This type of specimen may pose diagnostic challenges to the pathologist and the pathologist should be aware of certain pitfalls, such as "buried BE/ buried neoplasia" and duplication of muscularis mucosae, and not overstage IMC as SMC in BE.	('neoplasia', 'Disease', (156, 165))	('BE', 'Phenotype', 'HP:0100580', (145, 147))	('BE', 'Phenotype', 'HP:0100580', (238, 240))	('neoplasia', 'Phenotype', 'HP:0002664', (156, 165))	('duplication', 'Var', (171, 182))	('neoplasia', 'Disease', 'MESH:D009369', (156, 165))
373335	30319273	Animal xenograft studies indicate that nab-paclitaxel is more rapidly distributed to tumor tissue, and clinical trials in breast and non-small-cell lung cancer have demonstrated increased ORRs in patients treated with nab-paclitaxel/platinum vs solvent-based paclitaxel/platinum.	('tumor', 'Disease', (85, 90))	('ORRs', 'MPA', (188, 192))	('nab', 'Chemical', '-', (39, 42))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (137, 159))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('patients', 'Species', '9606', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('platinum', 'Chemical', 'MESH:D010984', (233, 241))	('platinum', 'Chemical', 'MESH:D010984', (270, 278))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('breast', 'Disease', (122, 128))	('increased', 'PosReg', (178, 187))	('nab', 'Chemical', '-', (218, 221))	('paclitaxel', 'Chemical', 'MESH:D017239', (222, 232))	('non-small-cell lung cancer', 'Disease', (133, 159))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (133, 159))	('paclitaxel', 'Chemical', 'MESH:D017239', (259, 269))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('nab-paclitaxel/platinum', 'Var', (218, 241))
373608	28454222	In the present study, a short hairpin RNA (shRNA) lentiviral expression vector targeting the MMP-2 gene was constructed in order to observe the inhibitory effect of MMP-2 gene silencing on the growth of the KYSE150 esophageal carcinoma cell line in vivo.	('growth', 'MPA', (193, 199))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (215, 235))	('MMP-2', 'Gene', (165, 170))	('MMP-2', 'Gene', (93, 98))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (215, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('KYSE150', 'CellLine', 'CVCL:1348', (207, 214))	('esophageal carcinoma', 'Disease', (215, 235))	('silencing', 'NegReg', (176, 185))	('gene', 'Var', (171, 175))
373622	28454222	Our previous study demonstrated that MMP-2 knockdown using synthesized oligonucleotides inhibited the invasion and migration of the KYSE150 esophageal carcinoma cell line in vitro.	('inhibited', 'NegReg', (88, 97))	('esophageal carcinoma', 'Disease', (140, 160))	('oligonucleotides', 'Chemical', 'MESH:D009841', (71, 87))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (140, 160))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (140, 160))	('KYSE150', 'CellLine', 'CVCL:1348', (132, 139))	('oligonucleotides', 'Var', (71, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
373623	28454222	In the present study, lentiviral vectors targeting the MMP-2 gene were constructed and transfected into KYSE150 cells, in order to observe the inhibitory effect of MMP-2 silencing on the growth of esophageal carcinoma cells in nude mice.	('nude mice', 'Species', '10090', (227, 236))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (197, 217))	('silencing', 'Var', (170, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('MMP-2', 'Gene', (164, 169))	('KYSE150', 'CellLine', 'CVCL:1348', (104, 111))	('MMP-2', 'Gene', (55, 60))	('esophageal carcinoma', 'Disease', (197, 217))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (197, 217))
373627	28454222	The human MMP-2 gene (Gen Bank ID: 4313, NM_001127891.1, NM_004530.4) interference sequence was obtained using small hairpin (sh)RNA analysis software , and a Basic Local Alignment Search Tool analysis of the NCBI database  confirmed that it had no homology with other genes.	('NM_004530.4', 'Var', (57, 68))	('human', 'Species', '9606', (4, 9))	('MMP-2 gene', 'Gene', (10, 20))
373649	28454222	Western blotting demonstrated a significant reduction in MMP-2 protein expression in the KESY150 cells infected with shRNA-1 (0.187+-0.072 of beta-actin), shRNA-2 (0.261+-0.095 of beta-actin) and shRNA-3 (0.063+-0.016 of beta-actin), as compared with a non-targeting control (0.486+-0.021 of beta-actin) and blank control (0.577+-0.009 of beta-actin) (P<0.05; Fig.	('beta-actin', 'Gene', '728378', (142, 152))	('0.187+-0.072', 'Var', (126, 138))	('MMP-2', 'Gene', (57, 62))	('beta-actin', 'Gene', '728378', (221, 231))	('beta-actin', 'Gene', (142, 152))	('KESY150', 'CellLine', 'CVCL:B575', (89, 96))	('beta-actin', 'Gene', (221, 231))	('shRNA-2', 'Var', (155, 162))	('beta-actin', 'Gene', (339, 349))	('beta-actin', 'Gene', '728378', (339, 349))	('reduction', 'NegReg', (44, 53))	('beta-actin', 'Gene', '728378', (180, 190))	('beta-actin', 'Gene', '728378', (292, 302))	('beta-actin', 'Gene', (180, 190))	('beta-actin', 'Gene', (292, 302))
373652	28454222	These results suggest that knockdown of MMP-2 reduces the viability of KYSE150 cells in vitro.	('MMP-2', 'Gene', (40, 45))	('knockdown', 'Var', (27, 36))	('viability of KYSE150 cells in vitro', 'CPA', (58, 93))	('KYSE150', 'CellLine', 'CVCL:1348', (71, 78))	('reduces', 'NegReg', (46, 53))
373655	28454222	4), indicating that MMP-2 knockdown inhibited the tumorigenesis of esophageal cancer cells.	('inhibited', 'NegReg', (36, 45))	('MMP-2', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('knockdown', 'Var', (26, 35))	('esophageal cancer', 'Disease', (67, 84))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (50, 55))
373665	28454222	Subsequently, it was demonstrated that MMP-2-shRNA-3 reduced the viability of KYSE150 esophageal carcinoma cells in vitro and tumorigenesis in vivo, as compared with the NC and blank control groups.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('MMP-2-shRNA-3', 'Var', (39, 52))	('esophageal carcinoma', 'Disease', (86, 106))	('viability', 'CPA', (65, 74))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (86, 106))	('reduced', 'NegReg', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (86, 106))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('KYSE150', 'CellLine', 'CVCL:1348', (78, 85))	('tumor', 'Disease', (126, 131))
373731	27042229	The eligibility criteria included: (i) histological diagnosis of ESCC; (ii) age > 18 years; (iii) Eastern Cooperative Oncology Group (ECOG) performance status 0-2; (iv) at least one measurable lesion; (v) failure of the initial or second-line chemotherapy; (vi) no prior exposure to irinotecan or 5-fluorouracil (5-FU) as first-line chemotherapy; and (vii) adequate hematologic, hepatic, and renal functions (absolute neutrophil count > 1.5 x 109/l, platelet count > 100 x 109/l, total bilirubin <= 1.5 x upper limit of normal, aspartate transaminase and alanine transaminase <= 2 x upper limit of normal, and creatinine <= 1.5 mg/dl).	('irinotecan', 'Chemical', 'MESH:D000077146', (283, 293))	('platelet count', 'CPA', (450, 464))	('total bilirubin', 'MPA', (480, 495))	('hepatic', 'CPA', (379, 386))	('5-FU', 'Chemical', 'MESH:D005472', (313, 317))	('creatinine', 'MPA', (610, 620))	('hematologic', 'CPA', (366, 377))	('ESCC', 'Disease', (65, 69))	('fluorouracil', 'Chemical', 'MESH:D005472', (299, 311))	('Oncology', 'Phenotype', 'HP:0002664', (118, 126))	('> 100 x 109/l', 'Var', (465, 478))
373792	24383865	The antibody of MIC1 inhibited the tumor growth (P < 0.001), and showing preference for tumor tissues in xenograft model.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('antibody', 'Var', (4, 12))	('tumor', 'Disease', (35, 40))	('MIC1', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('inhibited', 'NegReg', (21, 30))	('tumor', 'Disease', (88, 93))
373800	24383865	Tumor markers such as SCC, CEA, CA199 and CA724, were often used as EC markers in clinical settings, but the effects were limited.	('CEA', 'Gene', '5670', (27, 30))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CA724', 'Var', (42, 47))	('CA199', 'Var', (32, 37))	('CA199', 'Chemical', '-', (32, 37))	('SCC', 'Gene', (22, 25))	('CA724', 'Chemical', '-', (42, 47))	('SCC', 'Gene', '6317', (22, 25))	('CEA', 'Gene', (27, 30))
373808	24383865	Furthermore, MIC1 protein is secreted into the blood circulation and acts as a cytokine, neutralizing the MIC1 by the antibody may play a role in the treatment of ESCC.	('SCC', 'Gene', '6317', (164, 167))	('play', 'Reg', (131, 135))	('neutralizing', 'Var', (89, 101))	('MIC1', 'Gene', (106, 110))	('SCC', 'Gene', (164, 167))
373821	24383865	One normal esophageal cell line Het-1A, human umbilical vein endothelial cells (HUVECs; both purchased from ATCC), and eight ESCC cell lines, EC9706, S4 (both established in our laboratory), KYSE30, KYSE150, KYSE-180, KYSE410, KYSE450, KYSE510 (gifts from Dr Y. Shimada, First Department of Surgery, Kyoto University, Kyoto, Japan), were used in our present study.	('S4', 'CellLine', 'CVCL:Z231', (150, 152))	('human', 'Species', '9606', (40, 45))	('HUVECs', 'CellLine', 'CVCL:2959', (80, 86))	('SCC', 'Gene', '6317', (126, 129))	('KYSE410', 'Var', (218, 225))	('Het-1A', 'CellLine', 'CVCL:3702', (32, 38))	('KYSE450', 'Var', (227, 234))	('EC9706', 'CellLine', 'CVCL:E307', (142, 148))	('KYSE510', 'Var', (236, 243))	('KYSE30', 'Var', (191, 197))	('KYSE150', 'Var', (199, 206))	('SCC', 'Gene', (126, 129))
373827	24383865	Serum level of CEA, CA199 and CA724 was detected by the related kit (Roche, Basel, Switzerland).	('CA724', 'Chemical', '-', (30, 35))	('CEA', 'Gene', (15, 18))	('CEA', 'Gene', '5670', (15, 18))	('CA199', 'Chemical', '-', (20, 25))	('CA724', 'Var', (30, 35))
373853	24383865	Using the 250 normal samples as negative controls, the receiver operating characteristic (ROC) curve of MIC1, SCC, CA199, CEA and CA724 for ESCC is shown in Figure 2(a).	('CEA', 'Gene', '5670', (122, 125))	('CA199', 'Chemical', '-', (115, 120))	('SCC', 'Gene', (141, 144))	('CA724', 'Chemical', '-', (130, 135))	('SCC', 'Gene', (110, 113))	('SCC', 'Gene', '6317', (141, 144))	('SCC', 'Gene', '6317', (110, 113))	('MIC1', 'Gene', (104, 108))	('CEA', 'Gene', (122, 125))	('CA724', 'Var', (130, 135))
373863	24383865	A multivariable Cox regression analysis revealed that serum MIC1 was an independent factor contributing to prognosis after correction for all of these factors (hazard ratio of recurrence: 1.789 [95%CI, 1.003-3.190], P = 0.050; hazard ratio of tumor death: 2.625 [95%CI, 1.347-5.115], P = 0.005; Table 2).	('tumor death', 'Disease', (243, 254))	('MIC1', 'Gene', (60, 64))	('Cox', 'Gene', '1351', (16, 19))	('tumor death', 'Disease', 'MESH:D003643', (243, 254))	('serum', 'Var', (54, 59))	('Cox', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
373883	24383865	These results suggest that neutralization of MIC1 reduces tumor angiogenesis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('reduces', 'NegReg', (50, 57))	('MIC1', 'Gene', (45, 49))	('neutralization', 'Var', (27, 41))
373887	24383865	Additionally, we explored the role of MIC1 in the ESCC progression and discovered the treatment value of MIC1 antibody against ESCC.	('antibody', 'Var', (110, 118))	('SCC', 'Gene', (51, 54))	('MIC1', 'Gene', (105, 109))	('SCC', 'Gene', (128, 131))	('SCC', 'Gene', '6317', (51, 54))	('SCC', 'Gene', '6317', (128, 131))
373903	24383865	Histological examination revealed that angiogenesis of neovascularization of antibody-treated tumors was significantly inhibited.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('inhibited', 'NegReg', (119, 128))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('angiogenesis of neovascularization', 'CPA', (39, 73))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('antibody-treated', 'Var', (77, 93))
373905	24383865	Therefore, our studies indicated that MIC1 may promote ESCC progression partially by the effect on the angiogenesis which is consistent with other reports, and clinical treatment against ESCC could be enhanced by strategies to simultaneously neutralize MIC1 in the tumor microenvironment by using anti-MIC1 antibody.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('SCC', 'Gene', '6317', (188, 191))	('angiogenesis', 'CPA', (103, 115))	('MIC1', 'Gene', (253, 257))	('tumor', 'Disease', (265, 270))	('promote', 'PosReg', (47, 54))	('SCC', 'Gene', (56, 59))	('enhanced', 'PosReg', (201, 209))	('MIC1', 'Gene', (38, 42))	('SCC', 'Gene', '6317', (56, 59))	('SCC', 'Gene', (188, 191))	('neutralize', 'Var', (242, 252))	('tumor', 'Disease', 'MESH:D009369', (265, 270))
373930	20946664	In addition, due to the multistep carcinogenesis, the clonal selection model implies that malignant transformation occurs by multiple mutations in a random single cell and subsequent clonal selection takes place.	('malignant transformation', 'CPA', (90, 114))	('mutations', 'Var', (134, 143))	('multistep carcinogenesis', 'Disease', (24, 48))	('multistep carcinogenesis', 'Disease', 'MESH:D063646', (24, 48))
374011	20946664	Moreover, we found a strong association between high MMP-1 expression and positive lymph node metastases (p = 0.016136582, Fisher's exact test, Table 1) in EAC patients (n = 60).	('metastases', 'Disease', (94, 104))	('MMP-1', 'Gene', (53, 58))	('patients', 'Species', '9606', (160, 168))	('EAC', 'Disease', (156, 159))	('MMP-1', 'Gene', '4312', (53, 58))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('expression', 'MPA', (59, 69))	('high', 'Var', (48, 52))
374013	20946664	Survival in subgroup with high MMP-1 expression of all EACs (n = 60; Figure 4, Table 1) was not significantly worse in comparison to the subgroup of patients with low expression of MMP-1 (Figure 4, Table 1).	('patients', 'Species', '9606', (149, 157))	('high', 'Var', (26, 30))	('MMP-1', 'Gene', '4312', (181, 186))	('MMP-1', 'Gene', (181, 186))	('MMP-1', 'Gene', '4312', (31, 36))	('MMP-1', 'Gene', (31, 36))
374028	20946664	Our findings of high MMP-1 expression being associated with lymph node metastases in patients with EAC indicate that MMP-1 expression may be involved in promotion of cancer progression in addition to other clinicopathological characteristics.	('associated', 'Reg', (44, 54))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('high', 'Var', (16, 20))	('MMP-1', 'Gene', '4312', (21, 26))	('metastases', 'Disease', (71, 81))	('MMP-1', 'Gene', '4312', (117, 122))	('expression', 'MPA', (27, 37))	('promotion', 'PosReg', (153, 162))	('patients', 'Species', '9606', (85, 93))	('MMP-1', 'Gene', (21, 26))	('MMP-1', 'Gene', (117, 122))	('metastases', 'Disease', 'MESH:D009362', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('involved', 'Reg', (141, 149))
374060	18425214	In addition, methylation of p16, IN x 3 and HPP1 have been shown to predict progression to HGD and EAC.	('p16', 'Gene', '1029', (28, 31))	('HPP1', 'Gene', '780897', (44, 48))	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('methylation', 'Var', (13, 24))	('HGD', 'Disease', (91, 94))	('p16', 'Gene', (28, 31))	('HPP1', 'Gene', (44, 48))	('EAC', 'Disease', (99, 102))	('predict', 'Reg', (68, 75))
374063	18425214	Similarly, p53 tumor suppressor gene point mutations have been reported in Barrett's metaplasia, and altered promoter DNA methylation has also been described for some tumor suppressor genes in Barrett's esophagus.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('point mutations', 'Var', (37, 52))	("Barrett's esophagus", 'Disease', (193, 212))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (193, 212))	('reported', 'Reg', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('promoter', 'MPA', (109, 117))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (75, 95))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	("Barrett's metaplasia", 'Disease', (75, 95))	('tumor', 'Disease', (167, 172))
374064	18425214	point mutations, methylation, or loss of heterozygosity) in normal squamous esophageal epithelium from patients with esophageal cancer.	('esophageal cancer', 'Disease', (117, 134))	('methylation', 'Var', (17, 28))	('point mutations', 'Var', (0, 15))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('patients', 'Species', '9606', (103, 111))	('loss of heterozygosity', 'Var', (33, 55))
374068	18425214	which found methylation of the CALCA, MGMT, and TIMP3 genes in the normal esophagus of a subset of patients with Barrett's-associated esophageal dysplasia and adenocarcinoma.	('MGMT', 'Gene', '4255', (38, 42))	('CALCA', 'Gene', (31, 36))	('esophageal dysplasia and adenocarcinoma', 'Disease', 'MESH:D004938', (134, 173))	('patients', 'Species', '9606', (99, 107))	('CALCA', 'Gene', '796', (31, 36))	('found', 'Reg', (6, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('TIMP3', 'Gene', (48, 53))	('methylation', 'Var', (12, 23))	('TIMP3', 'Gene', '7078', (48, 53))	('MGMT', 'Gene', (38, 42))
374081	18425214	Labeling was performed on 6 mug of aRNA by incorporating Cy3- or Cy5-labeled dCTP using random primers and Superscript reverse transcriptase.	('dCTP', 'Chemical', 'MESH:C024107', (77, 81))	('Cy3-', 'Var', (57, 61))	('Cy5-labeled', 'Var', (65, 76))	('Cy3', 'Chemical', '-', (57, 60))	('Cy5', 'Chemical', 'MESH:C085321', (65, 68))
374108	18425214	While molecular alterations in histologically normal squamous esophageal epithelium have previously been described adjacent to cancers, the current findings suggest that alterations in gene expression and gene expression pattern accompanying cancer can affect large portions of the normal squamous esophagus.	('gene expression', 'MPA', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('alterations', 'Var', (170, 181))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('affect', 'Reg', (253, 259))
374119	18425214	Histones H3 and H4 were deacetylated in gastric cancer cell lines showing aberrant methylation of CHFR, a mitotic checkpoint gene, suggesting a role for histone deacetylation in methylation-dependent gene silencing.	('CHFR', 'Gene', '55743', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Histones H3', 'Protein', (0, 11))	('aberrant methylation', 'Var', (74, 94))	('gastric cancer', 'Disease', (40, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('methylation', 'Var', (83, 94))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))	('CHFR', 'Gene', (98, 102))
374127	18425214	Dysregulation of keratin 8 is associated with esophageal carcinogenesis (; Glickman et al.	('associated', 'Reg', (30, 40))	('Dysregulation', 'Var', (0, 13))	('keratin 8', 'Gene', '3856', (17, 26))	('keratin 8', 'Gene', (17, 26))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (46, 71))	('esophageal carcinogenesis', 'Disease', (46, 71))
374131	18425214	In BRCA2-deficient murine cells, BUB1 mutants potentiate growth and cellular transformation.	('BRCA2', 'Gene', '12190', (3, 8))	('mutants', 'Var', (38, 45))	('BUB1', 'Gene', '12235', (33, 37))	('murine', 'Species', '10090', (19, 25))	('cellular transformation', 'CPA', (68, 91))	('BUB1', 'Gene', (33, 37))	('potentiate', 'PosReg', (46, 56))	('BRCA2', 'Gene', (3, 8))
374132	18425214	In addition, mutations in human BUB1B have demonstrated a dominant negative effect by disrupting the mitotic checkpoint when transfected into euploid colon cancer cell lines.	('mitotic checkpoint', 'CPA', (101, 119))	('BUB1B', 'Gene', (32, 37))	('euploid colon cancer', 'Disease', (142, 162))	('colon cancer', 'Phenotype', 'HP:0003003', (150, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('BUB1B', 'Gene', '701', (32, 37))	('disrupting', 'NegReg', (86, 96))	('mutations', 'Var', (13, 22))	('euploid colon cancer', 'Disease', 'MESH:D015179', (142, 162))	('human', 'Species', '9606', (26, 31))
374137	18425214	CA85069, CA95323, CA01808, CA106763, and CA77057.	('CA85069', 'Chemical', '-', (0, 7))	('CA01808', 'Var', (18, 25))	('CA77057', 'Var', (41, 48))	('CA01808', 'Chemical', '-', (18, 25))	('CA106763', 'Chemical', '-', (27, 35))	('CA106763', 'Var', (27, 35))	('CA95323', 'Chemical', '-', (9, 16))	('CA85069', 'Var', (0, 7))	('CA95323', 'Var', (9, 16))	('CA77057', 'Chemical', '-', (41, 48))
374214	32055930	PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin.	('age', 'Gene', '5973', (54, 57))	('enhances', 'PosReg', (17, 25))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('inhibition', 'Var', (6, 16))	('PARP1', 'Gene', '142', (0, 5))	('PARP1', 'Gene', (0, 5))	('age', 'Gene', (54, 57))
374231	32055930	PARP-1 and PARP-2 are the major enzymes involved in the recognition of DNA damage, such as single-strand, double-strand, and crosslink breaks.	('PARP-1', 'Gene', '142', (0, 6))	('age', 'Gene', (78, 81))	('PARP-2', 'Gene', '10038', (11, 17))	('age', 'Gene', '5973', (78, 81))	('double-strand', 'Var', (106, 119))	('single-strand', 'Var', (91, 104))	('PARP-2', 'Gene', (11, 17))	('PARP-1', 'Gene', (0, 6))	('crosslink breaks', 'Var', (125, 141))
374234	32055930	Therefore, a strong case could be made for the synergy of PARP inhibitors with PLD in enhancing the effects of DNA-damage.	('PLD', 'Chemical', 'MESH:C506643', (79, 82))	('PARP', 'Gene', '142', (58, 62))	('age', 'Gene', '5973', (118, 121))	('enhancing', 'PosReg', (86, 95))	('PARP', 'Gene', (58, 62))	('inhibitors', 'Var', (63, 73))	('age', 'Gene', (118, 121))
374239	32055930	A phase II study of single agent veliparib, 400mg orally BID, for recurrent ovarian cancers demonstrated an overall survival benefit of >26 months with an acceptable toxicity profile in patients with BRCA mutations regardless of platinum-status.	('veliparib', 'Chemical', 'MESH:C521013', (33, 42))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (66, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('BRCA', 'Gene', '672', (200, 204))	('mutations', 'Var', (205, 214))	('age', 'Gene', (27, 30))	('platinum', 'Chemical', 'MESH:D010984', (229, 237))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('BRCA', 'Gene', (200, 204))	('toxicity', 'Disease', 'MESH:D064420', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('toxicity', 'Disease', (166, 174))	('ovarian cancers', 'Phenotype', 'HP:0100615', (76, 91))	('recurrent ovarian cancers', 'Disease', (66, 91))	('recurrent ovarian cancers', 'Disease', 'MESH:D012008', (66, 91))	('age', 'Gene', '5973', (27, 30))	('patients', 'Species', '9606', (186, 194))
374243	32055930	Moreover, the Jonkers' mouse model of triple 'negative' breast cancer, based on mammary tissue conditional mutants of BRCA and p53 inactivated in breast tissue, supports further sensitivity of homologous recombination defective tumors to doxorubicin.	('p53', 'Gene', '22060', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutants', 'Var', (107, 114))	('BRCA', 'Gene', '672', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('tumors', 'Disease', (228, 234))	('BRCA', 'Gene', (118, 122))	('mouse', 'Species', '10090', (23, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('breast cancer', 'Disease', (56, 69))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('p53', 'Gene', (127, 130))	('doxorubicin', 'Chemical', 'MESH:D004317', (238, 249))
374247	32055930	Another study from Italy suggests longer survival following PLD (with oxaliplatin) in BRCA mutation carriers.	('mutation', 'Var', (91, 99))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (70, 81))	('BRCA', 'Gene', '672', (86, 90))	('longer', 'PosReg', (34, 40))	('PLD', 'Chemical', 'MESH:C506643', (60, 63))	('BRCA', 'Gene', (86, 90))	('survival', 'MPA', (41, 49))	('carriers', 'Reg', (100, 108))
374312	32055930	We documented the occurrence of squamous oral cancer in two patients after prolonged treatment with veliparib and PLD; both were ovarian cancer patients with BRCA 2 mutations.	('BRCA 2', 'Gene', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('PLD', 'Chemical', 'MESH:C506643', (114, 117))	('squamous oral cancer', 'Disease', 'MESH:D002294', (32, 52))	('ovarian cancer', 'Disease', 'MESH:D010051', (129, 143))	('patients', 'Species', '9606', (60, 68))	('ovarian cancer', 'Disease', (129, 143))	('patients', 'Species', '9606', (144, 152))	('veliparib', 'Chemical', 'MESH:C521013', (100, 109))	('squamous oral cancer', 'Disease', (32, 52))	('mutations', 'Var', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('BRCA 2', 'Gene', '675', (158, 164))
374331	32055930	The first patient had primary peritoneal cancer with a BRCA 2 mutation.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('primary peritoneal cancer', 'Disease', (22, 47))	('primary peritoneal cancer', 'Phenotype', 'HP:0030406', (22, 47))	('BRCA 2', 'Gene', '675', (55, 61))	('BRCA 2', 'Gene', (55, 61))	('patient', 'Species', '9606', (10, 17))	('mutation', 'Var', (62, 70))	('primary peritoneal cancer', 'Disease', 'MESH:D010534', (22, 47))
374333	32055930	The second patient had ovarian cancer with a BRCA 1 mutation.	('BRCA 1', 'Gene', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('BRCA 1', 'Gene', '672', (45, 51))	('ovarian cancer', 'Disease', (23, 37))	('patient', 'Species', '9606', (11, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('mutation', 'Var', (52, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))
374338	32055930	Of the 18 BRCA mutation carriers who were compliant with treatment, 11 (61%) had either a complete, partial or stable response for a significant duration.	('mutation', 'Var', (15, 23))	('BRCA', 'Gene', (10, 14))	('BRCA', 'Gene', '672', (10, 14))
374343	32055930	Figure 2 depicts overall progression free survival and overall survival data comparing BRCA mutation positive to BRCA negative patients and platinum sensitive to platinum resistant ovarian cancer patients.	('ovarian cancer', 'Phenotype', 'HP:0100615', (181, 195))	('platinum', 'Chemical', 'MESH:D010984', (162, 170))	('BRCA', 'Gene', '672', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('BRCA', 'Gene', (87, 91))	('patients', 'Species', '9606', (196, 204))	('patients', 'Species', '9606', (127, 135))	('platinum resistant ovarian cancer', 'Disease', 'MESH:D010051', (162, 195))	('mutation positive', 'Var', (92, 109))	('platinum resistant ovarian cancer', 'Disease', (162, 195))	('BRCA', 'Gene', '672', (113, 117))	('platinum', 'Chemical', 'MESH:D010984', (140, 148))	('BRCA', 'Gene', (113, 117))
374346	32055930	We noted a positive correlation between the AUC/mg of PLD (area under the curve on a plot of drug concentration in blood plasma vs time) and veliparib dose, p=0.001, and a negative correlation between PLD clearance (CL), p=0.001 and veliparib dose.	('PLD', 'Chemical', 'MESH:C506643', (201, 204))	('AUC/mg', 'Var', (44, 50))	('drug concentration in blood', 'Phenotype', 'HP:0020170', (93, 120))	('veliparib', 'Chemical', 'MESH:C521013', (233, 242))	('negative', 'NegReg', (172, 180))	('PLD', 'Chemical', 'MESH:C506643', (54, 57))	('PLD', 'Gene', (54, 57))	('veliparib', 'Chemical', 'MESH:C521013', (141, 150))	('PLD clearance', 'MPA', (201, 214))
374358	32055930	In addition, a cohort study demonstrated 5 cases of oral squamous cell carcinoma in BRCA mutation carriers who received PLD over 30-132 months with cumulative doses >1,699 mg/m2.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('mutation', 'Var', (89, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 80))	('BRCA', 'Gene', '672', (84, 88))	('PLD', 'Chemical', 'MESH:C506643', (120, 123))	('BRCA', 'Gene', (84, 88))	('oral squamous cell carcinoma', 'Disease', (52, 80))
374359	32055930	These 5 women notably were nonsmokers with no known risk factors for HPV and four (80%) were negative for p16 expression.In this current study, two patients with BRCA mutations and no prior PLD, one non-smoker and one with a remote smoking history, developed oral squamous cell carcinoma 2 and 2.5 years after discontinuing veliparib and PLD.	('PLD', 'Chemical', 'MESH:C506643', (338, 341))	('patients', 'Species', '9606', (148, 156))	('oral squamous cell carcinoma', 'Disease', (259, 287))	('BRCA', 'Gene', '672', (162, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (264, 287))	('women', 'Species', '9606', (8, 13))	('p16', 'Gene', (106, 109))	('PLD', 'Chemical', 'MESH:C506643', (190, 193))	('BRCA', 'Gene', (162, 166))	('mutations', 'Var', (167, 176))	('developed', 'PosReg', (249, 258))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (259, 287))	('veliparib', 'Chemical', 'MESH:C521013', (324, 333))	('p16', 'Gene', '1029', (106, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))
374365	32055930	Also, studies have shown that patients with BRCA mutations are associated with an increased risk for squamous cell tumors.	('squamous cell tumors', 'Disease', 'MESH:D002294', (101, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (49, 58))	('squamous cell tumors', 'Disease', (101, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (30, 38))	('BRCA', 'Gene', '672', (44, 48))	('BRCA', 'Gene', (44, 48))	('squamous cell tumors', 'Phenotype', 'HP:0002860', (101, 121))
374368	32055930	PARP inhibition targets specific DNA-repair pathways that increase susceptibility of cancers in patients with BRCA mutations.	('BRCA', 'Gene', '672', (110, 114))	('mutations', 'Var', (115, 124))	('DNA-repair pathways', 'Pathway', (33, 52))	('PARP', 'Gene', (0, 4))	('BRCA', 'Gene', (110, 114))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('PARP', 'Gene', '142', (0, 4))
374370	32055930	Furthermore, three PARP inhibitors have achieved FDA approvals for ovarian cancer and 1 PARP inhibitor has achieved FDA approval for advanced, HER2 negative breast cancer in patients with a germline BRCA mutation.	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('BRCA', 'Gene', (199, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('HER2', 'Gene', '2064', (143, 147))	('negative', 'NegReg', (148, 156))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('breast cancer', 'Disease', (157, 170))	('ovarian cancer', 'Disease', (67, 81))	('PARP', 'Gene', '142', (19, 23))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('PARP', 'Gene', (19, 23))	('germline', 'Var', (190, 198))	('PARP', 'Gene', '142', (88, 92))	('HER2', 'Gene', (143, 147))	('PARP', 'Gene', (88, 92))	('BRCA', 'Gene', '672', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
374374	32055930	Similarly, there was no significant difference in PFS and OS rates between BRCA mutation positive and negative patients in this trial, likely due to sample size.	('PFS', 'Disease', (50, 53))	('BRCA', 'Gene', (75, 79))	('BRCA', 'Gene', '672', (75, 79))	('mutation', 'Var', (80, 88))	('patients', 'Species', '9606', (111, 119))
374380	32055930	We believe veliparib is either preventing macrophage recovery or causing the macrophages to become more susceptible to PLD, limited macrophages ability to clear PLD.	('preventing', 'NegReg', (31, 41))	('age', 'Gene', (139, 142))	('age', 'Gene', '5973', (139, 142))	('limited', 'NegReg', (124, 131))	('age', 'Gene', '5973', (84, 87))	('PLD', 'Chemical', 'MESH:C506643', (119, 122))	('susceptible', 'MPA', (104, 115))	('age', 'Gene', (49, 52))	('veliparib', 'Chemical', 'MESH:C521013', (11, 20))	('PLD', 'Chemical', 'MESH:C506643', (161, 164))	('age', 'Gene', '5973', (49, 52))	('age', 'Gene', (84, 87))	('veliparib', 'Var', (11, 20))
374384	32055930	From previous clinical data, PLD had gastrointestinal side-effects and this may influence absorption of co-administered oral medications, such as veliparib in this trial, and thus result in a decreased bioavailability that directly influences apparent clearance.	('apparent clearance', 'MPA', (243, 261))	('decreased', 'NegReg', (192, 201))	('absorption', 'MPA', (90, 100))	('PLD', 'Chemical', 'MESH:C506643', (29, 32))	('bioavailability', 'MPA', (202, 217))	('PLD', 'Var', (29, 32))	('influences', 'Reg', (232, 242))	('influence', 'Reg', (80, 89))	('veliparib', 'Chemical', 'MESH:C521013', (146, 155))
374391	32055930	Another phase II study demonstrated a numerical but not statistically significant increases in both PFS and OS in patients with a germline BRCA mutation and recurrent/metastatic breast cancer when comparing veliparib and carboplatin/paclitaxel to a placebo and carboplatin/paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (233, 243))	('PFS', 'Disease', (100, 103))	('veliparib', 'Chemical', 'MESH:C521013', (207, 216))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('carboplatin', 'Chemical', 'MESH:D016190', (261, 272))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('mutation', 'Var', (144, 152))	('breast cancer', 'Disease', (178, 191))	('BRCA', 'Gene', '672', (139, 143))	('paclitaxel', 'Chemical', 'MESH:D017239', (273, 283))	('increases', 'PosReg', (82, 91))	('carboplatin', 'Chemical', 'MESH:D016190', (221, 232))	('BRCA', 'Gene', (139, 143))	('patients', 'Species', '9606', (114, 122))
374442	32701062	The multivariate analysis of OS (Figure 4A) of patients with stage II EC revealed that poor prognosis was related to age (patients aged 70-79 years and over 80 years compared to patients younger than 50 years), marital status (unmarried compared to married), sex (male compared to female), T_stage (T3 compared to T1), N_stage (N1 compared to N0), and grade (grades II and III compared to grade I).	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (122, 130))	('N1', 'Var', (328, 330))	('III', 'Disease', (373, 376))
374444	32701062	The multivariate analysis of OS (Figure 5A) of stage III patients indicated that poor prognosis was related to marital status (unmarried compared to married), T_stage (T4 compared to T3), N_stage (N1 compared to N0), and grade (grade III compared to grade I).	('T_stage', 'Disease', (159, 166))	('patients', 'Species', '9606', (57, 65))	('N1', 'Var', (197, 199))
374451	32701062	Per the Kaplan-Meier survival curve, both OS and ECSS of patients who underwent endoscopic therapy were significantly longer compared to patients received other types of surgery or without surgery (P < 0.05).	('patients', 'Species', '9606', (57, 65))	('longer', 'PosReg', (118, 124))	('patients', 'Species', '9606', (137, 145))	('endoscopic therapy', 'Var', (80, 98))
374506	32701062	We also found that the risk of non-cancer-related deaths increased significantly in stage III patients with surgery compared to no-surgery stage III patients, possibly due to poor tolerance to surgery, which could easily lead to complications or worsening of the underlying diseases.	('stage', 'Disease', (84, 89))	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (94, 102))	('surgery', 'Var', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('deaths', 'Disease', 'MESH:D003643', (50, 56))	('deaths', 'Disease', (50, 56))	('increased', 'PosReg', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('lead', 'Reg', (221, 225))
374533	31857778	The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of Type B2 in ME-NBI for the invasion depth of T1a muscularis mucosae and T1b upper submucosal layer were 68.4%/79.4%/50.0%/89.3%/76.8%, respectively, and those of Type B3 for the depth of T1b middle and deeper submucosal layers (SM2 and SM3) were 46.7%/100%/100%/89.3%/90.2%, respectively.	('SM3', 'Chemical', '-', (347, 350))	('T1a', 'Gene', '10630', (156, 159))	('T1a', 'Gene', (156, 159))	('Type B2', 'Var', (112, 119))	('ME-NBI', 'Chemical', '-', (123, 129))	('SM2', 'Gene', '53366', (339, 342))	('SM2', 'Gene', (339, 342))	('PPV', 'Chemical', '-', (57, 60))
374580	31857778	SUVmax values were distributed from 2.36 to 12.14, with a mean +- SD value of 4.00 +- 1.73, and those of positive FDG uptake lesion was significantly higher compared to those of negative lesion (5.15 +- 2.44 vs 3.37 +- 1.16; P < 0.001).	('higher', 'PosReg', (150, 156))	('lesion', 'Var', (125, 131))	('FDG', 'Chemical', 'MESH:D019788', (114, 117))
374582	31857778	Tumor invasion of pT1b showed higher SUVmax values than pTis and pT1a (5.62 +- 3.01 vs 3.58 +- 0.81; P < 0.01).	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('higher', 'PosReg', (30, 36))	('SUVmax values', 'MPA', (37, 50))	('Tumor', 'Disease', (0, 5))	('T1a', 'Gene', '10630', (66, 69))	('T1a', 'Gene', (66, 69))	('pT1b', 'Var', (18, 22))
374584	31857778	The sensitivity, specificity, PPV, NPV, and accuracy of Type B1 for the depth of T1a EP-LPM were 87.5%, 79.4%, 85.7%, 81.8%, and 84.1%, respectively, whereas those of Type B2 for the depth of T1a MM and T1b SM1 were 68.4%, 79.4%, 50.0%, 89.3%, and 76.8%, respectively.	('Type B1', 'Var', (56, 63))	('T1a', 'Gene', (81, 84))	('T1a', 'Gene', '10630', (81, 84))	('T1a', 'Gene', '10630', (192, 195))	('T1a', 'Gene', (192, 195))	('PPV', 'Chemical', '-', (30, 33))	('SM1', 'Gene', '7911', (207, 210))	('SM1', 'Gene', (207, 210))
374595	31857778	If positive FDG uptake was taken an indicator of T1b SM2-3, patients with positive FDG uptake had a worse prognosis than patients with negative uptake [5-year overall survival (5-year OS) rate, 75.0% vs 94.9%, Figure 1A].	('FDG', 'Chemical', 'MESH:D019788', (83, 86))	('patients', 'Species', '9606', (60, 68))	('SM2-3', 'Gene', '53366', (53, 58))	('FDG', 'Chemical', 'MESH:D019788', (12, 15))	('positive', 'Var', (74, 82))	('SM2-3', 'Gene', (53, 58))	('patients', 'Species', '9606', (121, 129))
374625	31857778	Therefore, high FDG uptake by primary tumors might also be associated with tumor infiltration of deep layers, occult lymph node micro-metastases, and, eventually, predict a poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('FDG', 'Protein', (16, 19))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('FDG', 'Chemical', 'MESH:D019788', (16, 19))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('metastases', 'Disease', (134, 144))	('associated', 'Reg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('high', 'Var', (11, 15))	('metastases', 'Disease', 'MESH:D009362', (134, 144))	('tumor', 'Disease', (75, 80))
374640	31857778	The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of Type B2 in ME-NBI for the invasion depth of T1a muscularis mucosae (MM) and T1b upper submucosal layer (SM1) were 68.4%/79.4%/50.0%/89.3%/76.8%, respectively, and those of Type B3 for the depth of T1b middle and deeper submucosal layers (SM2 and SM3) were 46.7%/100%/100%/89.3%/90.2%, respectively.	('SM3', 'Chemical', '-', (358, 361))	('SM2', 'Gene', (350, 353))	('T1a', 'Gene', '10630', (156, 159))	('T1a', 'Gene', (156, 159))	('SM1', 'Gene', '7911', (216, 219))	('SM1', 'Gene', (216, 219))	('Type B2', 'Var', (112, 119))	('ME-NBI', 'Chemical', '-', (123, 129))	('SM2', 'Gene', '53366', (350, 353))	('PPV', 'Chemical', '-', (57, 60))
374642	31857778	First, when the lesion showed that ME-NBI is type B1, the lesion is indication for endoscopic treatment, and it showed type B3, the lesion is indication for surgical resection or CRT.	('type B3', 'Var', (119, 126))	('ME-NBI', 'Disease', (35, 41))	('ME-NBI', 'Chemical', '-', (35, 41))
374653	31083715	The planning study showed SIB-IMRT improved target coverage without compromising the dose to the organs at risk, compared with 3DCRT.	('CRT', 'Gene', (129, 132))	('target', 'MPA', (44, 50))	('improved', 'PosReg', (35, 43))	('CRT', 'Gene', '811', (129, 132))	('SIB-IMRT', 'Var', (26, 34))
374690	31083715	Optimizations were performed for prescribing a dose of 60 Gy as D50% (Dx% represents the dose covering x% of the structure volume) of the PTV60 for eight patients from May 2009 to March 2011 and D95% of the PTV60 for 13 patients from April 2011 to March 2015.	('D95%', 'Var', (195, 199))	('PTV', 'Chemical', '-', (138, 141))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (220, 228))	('D50', 'Var', (64, 67))	('PTV', 'Chemical', '-', (207, 210))
374695	31083715	We used dose constraints for the PTV60 as follows: D2% <72 Gy, D98% >55.8 Gy, and D50% < 63 Gy; and for the PTVENI as follows: D98% > 45.9 Gy, D50% < 51 Gy, and D2% < 60 Gy.	('D50% <', 'Var', (82, 88))	('D2%', 'Var', (161, 164))	('D2% <', 'Var', (51, 56))	('PTV', 'Chemical', '-', (33, 36))	('D50% <', 'Var', (143, 149))	('PTV', 'Chemical', '-', (108, 111))	('D98% >', 'Var', (63, 69))	('D98% > 45.9 Gy', 'Var', (127, 141))
374710	31083715	To compare the coverage of the gross tumor and OARs between two types of SIB-IMRT and 3DCRT, we created the dose-volume histograms of the PTV60, bilateral lungs, PRVcord, thyroidout of PTV and brachial plexus.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('PTV', 'Chemical', '-', (185, 188))	('PTV60', 'Var', (138, 143))	('PTV', 'Chemical', '-', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('CRT', 'Gene', '811', (88, 91))	('CRT', 'Gene', (88, 91))
374711	31083715	Then, we calculated the D98%, D50%, D2%, homogeneity index (HI) and conformation number (CN) of the PTV60, V10Gy, V15Gy and V20Gy of the bilateral lungs; the maximum dose and D2 cm3 of the PRVcord, V50Gy and V60Gy; the mean dose of the thyroidout of PTV, V60Gy and D2 cm3 of the brachial plexus; and the maximum dose and D2 cm3 of the Vout of PTV, using each method.	('V15Gy', 'Var', (114, 119))	('V10Gy', 'Var', (107, 112))	('V50Gy', 'Var', (198, 203))	('V60Gy', 'Var', (208, 213))	('PTV', 'Chemical', '-', (100, 103))	('D98', 'Var', (24, 27))	('V20Gy', 'Var', (124, 129))	('V60Gy', 'Var', (255, 260))	('PTV', 'Chemical', '-', (250, 253))	('PTV', 'Chemical', '-', (343, 346))
374714	31083715	To evaluate the dosimetric differences between the two types of SIB-IMRT and 3DCRT, we used the Kruskal-Wallis test to compare the dose-volume indices of the PTV60, bilateral lungs, PRVcord, thyroidout of PTV, brachial plexus, and Vout of PTV.	('PTV', 'Chemical', '-', (158, 161))	('CRT', 'Gene', '811', (79, 82))	('PTV60', 'Var', (158, 163))	('CRT', 'Gene', (79, 82))	('PTV', 'Chemical', '-', (205, 208))	('PTV', 'Chemical', '-', (239, 242))
374724	31083715	M1LYM and unresectable statuses were associated with poor OS rate (P = <0.001 and 0.009).	('M1LYM', 'Var', (0, 5))	('OS', 'Chemical', '-', (58, 60))	('poor OS rate', 'CPA', (53, 65))
374738	31083715	All dose-volume indices of the PTV60 differed significantly between the three methods (P < 0.001), and the post hoc analysis showed that SIB-IMRT-D95% provided significantly better target coverage and target conformity of the PTV60 compared with 3DCRT (D98%, P < 0.001; D50%, P < 0.001; D2%, P < 0.001; HI, P = 0.0048; and CN, P < 0.001) and SIB-IMRT-D50% (D98%, P < 0.001; D50%, P < 0.001; D2%, P = 0.018; HI, P < 0.001; and CN, P = 0.0015).	('D50', 'Var', (374, 377))	('PTV', 'Chemical', '-', (226, 229))	('target conformity', 'CPA', (201, 218))	('better', 'PosReg', (174, 180))	('CRT', 'Gene', '811', (248, 251))	('CRT', 'Gene', (248, 251))	('PTV', 'Chemical', '-', (31, 34))	('target coverage', 'CPA', (181, 196))
374744	31083715	SIB-IMRT-D95% for this population improved the target coverage and the conformity of the PTV without compromising the dose to the OARs, compared with 3DCRT.	('improved', 'PosReg', (34, 42))	('CRT', 'Gene', '811', (152, 155))	('SIB-IMRT-D95%', 'Var', (0, 13))	('CRT', 'Gene', (152, 155))	('target coverage', 'CPA', (47, 62))	('conformity', 'MPA', (71, 81))	('PTV', 'Chemical', '-', (89, 92))
374748	31083715	The present study suggested that SIB-IMRT-D95% improved target coverage for CESCC.	('improved', 'PosReg', (47, 55))	('CESCC', 'Chemical', '-', (76, 81))	('SIB-IMRT-D95%', 'Var', (33, 46))	('target', 'MPA', (56, 62))	('CESCC', 'Disease', (76, 81))
374766	31083715	Based on this more appropriate study design, the present study showed the dosimetric superiority of SIB-IMRT-D95% compared with 3DCRT in terms of target coverage and conformality, without increasing the doses to the OARs.	('CRT', 'Gene', '811', (130, 133))	('CRT', 'Gene', (130, 133))	('target coverage', 'CPA', (146, 161))	('conformality', 'CPA', (166, 178))	('SIB-IMRT-D95%', 'Var', (100, 113))
374772	31083715	Though SIB-IMRT-D95% improved target coverage without increasing the dose to the OARs, compared with 3DCRT, locoregional area remained the major progression site in CESCC patients treated with SIB-IMRT.	('target coverage', 'MPA', (30, 45))	('improved', 'PosReg', (21, 29))	('CRT', 'Gene', '811', (103, 106))	('patients', 'Species', '9606', (171, 179))	('CESCC', 'Disease', (165, 170))	('CRT', 'Gene', (103, 106))	('SIB-IMRT-D95%', 'Var', (7, 20))	('CESCC', 'Chemical', '-', (165, 170))
374782	30741461	Here we found that knocked down SMAD4 could partially reverse TGF-beta-induced migration, invasion, and EMT progression in the ESCC cell line EC-1.	('migration', 'CPA', (79, 88))	('TGF-beta', 'Gene', (62, 70))	('SMAD4', 'Gene', (32, 37))	('EC-1', 'Gene', '4819', (142, 146))	('EMT progression', 'CPA', (104, 119))	('reverse', 'NegReg', (54, 61))	('EC-1', 'Gene', (142, 146))	('SMAD4', 'Gene', '4089', (32, 37))	('TGF-beta', 'Gene', '7040', (62, 70))	('knocked down', 'Var', (19, 31))	('invasion', 'CPA', (90, 98))
374834	30741461	And we found that knockdown Smad4 could partially reverse the decrease of E-cadherin expression and the increase of N-cadherin and vimentin expression induced by TGF-beta.	('increase', 'PosReg', (104, 112))	('knockdown', 'Var', (18, 27))	('expression', 'MPA', (85, 95))	('Smad4', 'Gene', (28, 33))	('N-cadherin', 'Gene', (116, 126))	('TGF-beta', 'Gene', '7040', (162, 170))	('expression', 'MPA', (140, 150))	('vimentin', 'Gene', '7431', (131, 139))	('Smad4', 'Gene', '4089', (28, 33))	('N-cadherin', 'Gene', '1000', (116, 126))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', '999', (74, 84))	('TGF-beta', 'Gene', (162, 170))	('vimentin', 'Gene', (131, 139))	('decrease', 'NegReg', (62, 70))
374835	30741461	Transwell assays and wound healing further indicated that the knockdown of SMAD4 could inhibit TGF-beta-induced migratory and invasive capabilities in EC-1 cells at the same time (Figure 2C,D).	('EC-1', 'Gene', '4819', (151, 155))	('TGF-beta', 'Gene', '7040', (95, 103))	('EC-1', 'Gene', (151, 155))	('SMAD4', 'Gene', (75, 80))	('TGF-beta', 'Gene', (95, 103))	('knockdown', 'Var', (62, 71))	('SMAD4', 'Gene', '4089', (75, 80))	('inhibit', 'NegReg', (87, 94))
374870	30741461	The acid residues cause the ligand, TbetaRI, and TbetaRII to form a receptor complex, and the activated TbetaRI further phosphorylates the downstream R-Smads, namely Smad2 and Smad3.	('TbetaRII', 'Gene', '7048', (49, 57))	('Smad2', 'Gene', '4087', (166, 171))	('complex', 'Interaction', (77, 84))	('Smad', 'Gene', (176, 180))	('Smad', 'Gene', (152, 156))	('TbetaRI', 'Gene', '7046', (49, 56))	('Smad', 'Gene', '4089;4089;17128;50554', (176, 180))	('TbetaRI', 'Gene', (36, 43))	('Smad', 'Gene', '4089;4089;17128;50554', (152, 156))	('TbetaRI', 'Gene', '7046', (104, 111))	('Smad2', 'Gene', (166, 171))	('Smad', 'Gene', (166, 170))	('acid residues', 'Var', (4, 17))	('Smad', 'Gene', '4089;4089;17128;50554', (166, 170))	('TbetaRII', 'Gene', (49, 57))	('TbetaRI', 'Gene', (104, 111))	('TbetaRI', 'Gene', (49, 56))	('Smad3', 'Gene', '4088', (176, 181))	('Smad3', 'Gene', (176, 181))	('TbetaRI', 'Gene', '7046', (36, 43))
374877	30741461	We provided evidence that knocking down of SMAD4 expression could partially reverse TGF-induced EMT progression, increases E-Cadherin protein expression, decreases N-Cadherin and vimentin protein expression, and inhibits the invasion and migration of EC-1 cells.	('inhibits', 'NegReg', (212, 220))	('vimentin', 'Gene', (179, 187))	('EC-1', 'Gene', '4819', (251, 255))	('SMAD4', 'Gene', (43, 48))	('EC-1', 'Gene', (251, 255))	('N-Cadherin', 'Gene', (164, 174))	('E-Cadherin', 'Gene', (123, 133))	('reverse', 'NegReg', (76, 83))	('N-Cadherin', 'Gene', '1000', (164, 174))	('E-Cadherin', 'Gene', '999', (123, 133))	('EMT progression', 'CPA', (96, 111))	('SMAD4', 'Gene', '4089', (43, 48))	('knocking down', 'Var', (26, 39))	('increases', 'PosReg', (113, 122))	('vimentin', 'Gene', '7431', (179, 187))	('TGF-induced', 'Disease', (84, 95))	('decreases', 'NegReg', (154, 163))
374882	30741461	More importantly, the exogenous expression of SMAD4 partially recovered the invasive and migratory ability of EC-1 cell lines, which was repressed by the overexpression of miR-130a-3p.	('recovered', 'PosReg', (62, 71))	('EC-1', 'Gene', '4819', (110, 114))	('SMAD4', 'Gene', '4089', (46, 51))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', (172, 175))	('exogenous', 'Var', (22, 31))	('EC-1', 'Gene', (110, 114))	('SMAD4', 'Gene', (46, 51))
374894	30305803	High ADS score was significantly associated with short 3 years' OS of ESCC patients (adjusted HR = 2.94, 95% CI 1.70-5.08).	('ESCC', 'Disease', (70, 74))	('patients', 'Species', '9606', (75, 83))	('OS', 'Chemical', '-', (64, 66))	('High', 'Var', (0, 4))
374940	30305803	A persistent chronic inflammatory response triggered by these environmental exposures in the patients contributed to constitutive activation of pro-inflammatory signaling pathways, and to promote mutation of P53, PIK3CA, RB1 and NFE2L2, consequently leading to onset and metastasis of ESCC.	('P53', 'Gene', (208, 211))	('NFE2L2', 'Gene', (229, 235))	('PIK3CA', 'Gene', (213, 219))	('NFE2L2', 'Gene', '4780', (229, 235))	('mutation', 'Var', (196, 204))	('promote', 'PosReg', (188, 195))	('P53', 'Gene', '7157', (208, 211))	('activation', 'PosReg', (130, 140))	('leading to', 'Reg', (250, 260))	('pro-inflammatory signaling pathways', 'Pathway', (144, 179))	('RB1', 'Gene', (221, 224))	('PIK3CA', 'Gene', '5290', (213, 219))	('ESCC', 'Disease', (285, 289))	('RB1', 'Gene', '5925', (221, 224))	('metastasis', 'CPA', (271, 281))	('patients', 'Species', '9606', (93, 101))
374993	28954034	Fails in esophageal myotomy may cause high pressure in staple line of resected diverticulum, and, therefore, breaking the line.	('high pressure', 'MPA', (38, 51))	('Fails', 'Var', (0, 5))	('esophageal myotomy', 'Disease', (9, 27))	('cause', 'Reg', (32, 37))	('esophageal myotomy', 'Disease', 'MESH:D004941', (9, 27))
375029	28045122	This network component consisting of three miRNAs (has-mir-30a, has-mir-181a-1, and has-mir-29c) is the signature component for all the aforementioned five cancers, and can be validated using simple literature search on PubMed Central database as demonstrated in Fig.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('has-mir-181a-1', 'Var', (64, 78))	('mir-29c', 'Gene', '407026', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mir-29c', 'Gene', (88, 95))	('has-mir-30a', 'Var', (51, 62))
375055	28045122	Regarding the first signature network component, hsa-mir-137, hsa-mir-330, hsa-mir-149, hsa-mir-107, hsa-mir-181b were among the miRNAs whose experimentally validated targets (such as CTBP1, CDC42, CDK6, E2F1, VEGFA, AKT1, KAT2B) affect the pathways which play a crucial role in glioblastoma biology.	('affect', 'Reg', (230, 236))	('VEGFA', 'Gene', (210, 215))	('hsa-mir-149', 'Gene', '406941', (75, 86))	('CDK6', 'Gene', '1021', (198, 202))	('KAT2B', 'Gene', '8850', (223, 228))	('hsa-mir-107', 'Gene', '406901', (88, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (279, 291))	('CTBP1', 'Gene', (184, 189))	('VEGFA', 'Gene', '7422', (210, 215))	('CDK6', 'Gene', (198, 202))	('CDC42', 'Gene', (191, 196))	('hsa-mir-181b', 'Var', (101, 113))	('hsa-mir-137', 'Gene', (49, 60))	('AKT1', 'Gene', '207', (217, 221))	('hsa-mir-137', 'Gene', '406928', (49, 60))	('E2F1', 'Gene', (204, 208))	('glioblastoma', 'Disease', (279, 291))	('CTBP1', 'Gene', '1487', (184, 189))	('CDC42', 'Gene', '998', (191, 196))	('glioblastoma', 'Phenotype', 'HP:0012174', (279, 291))	('hsa-mir-330', 'Gene', '442902', (62, 73))	('hsa-mir-330', 'Gene', (62, 73))	('AKT1', 'Gene', (217, 221))	('E2F1', 'Gene', '1869', (204, 208))	('pathways', 'Pathway', (241, 249))	('hsa-mir-149', 'Gene', (75, 86))	('KAT2B', 'Gene', (223, 228))	('hsa-mir-107', 'Gene', (88, 99))
375056	28045122	Deregulations of hsa-mir-137, hsa-mir-330 and hsa-mir-149 lead to effects in the glioma de novo pathway, VEGF signaling pathway and Notch signaling pathway.	('hsa-mir-137', 'Gene', '406928', (17, 28))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('Deregulations', 'Var', (0, 13))	('VEGF', 'Gene', (105, 109))	('glioma', 'Disease', (81, 87))	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('hsa-mir-149', 'Gene', (46, 57))	('hsa-mir-330', 'Gene', (30, 41))	('hsa-mir-149', 'Gene', '406941', (46, 57))	('hsa-mir-330', 'Gene', '442902', (30, 41))	('VEGF', 'Gene', '7422', (105, 109))	('hsa-mir-137', 'Gene', (17, 28))	('Notch signaling pathway', 'Pathway', (132, 155))	('effects', 'Reg', (66, 73))
375062	26330114	Inhibition of Rho-associated kinases disturbs the collective cell migration of stratified TE-10 cells The collective cell migration of stratified epithelial cells is considered to be an important phenomenon in wound healing, development, and cancer invasion; however, little is known about the mechanisms involved.	('Rho-associated', 'Protein', (14, 28))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('collective cell migration', 'CPA', (106, 131))	('Inhibition', 'Var', (0, 10))	('TE-10', 'CellLine', 'CVCL:1760', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('disturbs', 'NegReg', (37, 45))	('collective cell migration', 'CPA', (50, 75))
375074	26330114	Using this method to investigate the effects of Rho family proteins on collective cell migration, we found that the inhibition of ROCKs suppressed the collective migration of TE-10 cells, a cell line derived from human esophageal cancer tissue.	('ROCKs', 'Gene', (130, 135))	('human', 'Species', '9606', (213, 218))	('inhibition', 'Var', (116, 126))	('esophageal cancer', 'Disease', (219, 236))	('TE-10', 'CellLine', 'CVCL:1760', (175, 180))	('suppressed', 'NegReg', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('esophageal cancer', 'Disease', 'MESH:D004938', (219, 236))	('collective migration of TE-10 cells', 'CPA', (151, 186))
375086	26330114	Both Y27632 and HA1077, well-known ROCK inhibitors, reduced the distance that the wound edge moved at 24-72 h post-scraping (Fig.	('reduced', 'NegReg', (52, 59))	('Y27632', 'Var', (5, 11))	('Y27632', 'Chemical', 'MESH:C108830', (5, 11))	('HA1077', 'Chemical', 'MESH:C049347', (16, 22))	('distance', 'MPA', (64, 72))	('HA1077', 'Var', (16, 22))
375088	26330114	Furthermore, the leading edge of TE-10 cells migrated in a disordered fashion when treated with Y27632 or HA1077, whereas well-regulated movement was observed in control TE-10 cells as shown in the movies in Additional files 12, 13, 14 and 15.	('HA1077', 'Var', (106, 112))	('Y27632', 'Chemical', 'MESH:C108830', (96, 102))	('disordered fashion', 'Disease', (59, 77))	('leading edge', 'CPA', (17, 29))	('TE-10', 'CellLine', 'CVCL:1760', (170, 175))	('TE-10', 'CellLine', 'CVCL:1760', (33, 38))	('disordered fashion', 'Disease', 'MESH:D030342', (59, 77))	('Y27632', 'Var', (96, 102))	('HA1077', 'Chemical', 'MESH:C049347', (106, 112))
375091	26330114	Furthermore, knockdown of both ROCK1 and ROCK2 led to an estimated 20 % reduction in the migration distance of the wound edge (Fig.	('reduction', 'NegReg', (72, 81))	('ROCK1', 'Gene', '6093', (31, 36))	('migration distance of the wound edge', 'CPA', (89, 125))	('ROCK1', 'Gene', (31, 36))	('ROCK2', 'Gene', (41, 46))	('ROCK2', 'Gene', '9475', (41, 46))	('knockdown', 'Var', (13, 22))
375101	26330114	Notably, siRNA-mediated knockdown of RhoA, an upstream regulator of ROCKs, caused a significant increase in the migration speed of the leading row of cells (Figs.	('migration speed of the leading row of cells', 'CPA', (112, 155))	('RhoA', 'Gene', (37, 41))	('RhoA', 'Gene', '387', (37, 41))	('increase', 'PosReg', (96, 104))	('knockdown', 'Var', (24, 33))
375102	26330114	Concomitantly, the migration speed of the stratified area in the RhoA knockdown cells decreased significantly.	('RhoA', 'Gene', '387', (65, 69))	('knockdown', 'Var', (70, 79))	('migration speed of the stratified area', 'CPA', (19, 57))	('decreased', 'NegReg', (86, 95))	('RhoA', 'Gene', (65, 69))
375107	26330114	In this study, we showed that ROCK protein levels were partially blocked by RNAi knockdown of ROCK expression; however, we could not determine the extent of the functional inhibition of ROCKs in the RhoA RNAi experiments.	('ROCK expression', 'Gene', (94, 109))	('knockdown', 'Var', (81, 90))	('ROCK protein levels', 'MPA', (30, 49))	('RhoA', 'Gene', (199, 203))	('blocked', 'NegReg', (65, 72))	('RhoA', 'Gene', '387', (199, 203))
375112	26330114	The following ROCK inhibitors were used in this study: Y-27632 (20 muM; Sigma-Aldrich, St. Louis, MO, USA) and hydroxyfasudil (HA1077, Fas-OH; 5 muM; Wako, Osaka, Japan).	('Fas', 'Chemical', 'MESH:C038178', (135, 138))	('muM', 'Gene', '56925', (145, 148))	('hydroxyfasudil', 'Chemical', 'MESH:C431085', (111, 125))	('HA1077', 'Var', (127, 133))	('muM', 'Gene', '56925', (67, 70))	('muM', 'Gene', (145, 148))	('Y-27632', 'Chemical', 'MESH:C108830', (55, 62))	('muM', 'Gene', (67, 70))	('HA1077', 'Chemical', 'MESH:C049347', (127, 133))
375116	26330114	Alexa Fluor 488- and Alexa Fluor 546-conjugated goat anti-mouse IgG antibodies (A11017 and A11030; Invitrogen, Carlsbad, CA, USA) were used as secondary antibodies at a 1:100 dilution.	('A11030', 'Var', (91, 97))	('mouse', 'Species', '10090', (58, 63))	('Alexa Fluor 546', 'Chemical', 'MESH:C481052', (21, 36))	('A11017', 'Var', (80, 86))	('goat', 'Species', '9925', (48, 52))	('Alexa Fluor 488', 'Chemical', '-', (0, 15))	('IgG antibodies', 'Phenotype', 'HP:0003237', (64, 78))
375120	26330114	TE-10 cells were maintained in Dulbecco's modified Eagle medium (DMEM) containing 10 % fetal bovine serum (FBS), 0.03 % glutamate, and 0.6 mug/mL kanamycin and were grown at 37  C with 5 % CO2 in a humidified tissue culture incubator.	('glutamate', 'Chemical', 'MESH:D018698', (120, 129))	('0.03', 'Var', (113, 117))	('kanamycin', 'Chemical', 'MESH:D007612', (146, 155))	('FBS', 'Disease', (107, 110))	('TE-10', 'CellLine', 'CVCL:1760', (0, 5))	("Dulbecco's modified Eagle medium", 'Chemical', '-', (31, 63))	('DMEM', 'Chemical', '-', (65, 69))	('CO2', 'Chemical', '-', (189, 192))	('bovine', 'Species', '9913', (93, 99))	('FBS', 'Disease', 'MESH:D005198', (107, 110))	('glutamate', 'Protein', (120, 129))
375195	24778482	Unlike the pulmonary parenchyma, which is a parallel functioning tissue, where every unit can function independent of the other, the esophagus is a serially functioning tissue, and damage to even a small volume of the esophagus from the radiation has serious consequences due to lack of redundancy.	('pulmonary parenchyma', 'Disease', (11, 31))	('damage', 'Var', (181, 187))	('pulmonary parenchyma', 'Disease', 'MESH:D010195', (11, 31))
375204	19835856	In the present study, Foxm1 was deleted conditionally in the developing SMC (smFoxm1-/- mice).	('Foxm1', 'Gene', (22, 27))	('mice', 'Species', '10090', (88, 92))	('deleted', 'Var', (32, 39))
375205	19835856	The majority of smFoxm1-/- mice died immediately after birth due to severe pulmonary hemorrhage, and structural defects in arterial wall and esophagus.	('pulmonary hemorrhage', 'Phenotype', 'HP:0040223', (75, 95))	('mice', 'Species', '10090', (27, 31))	('pulmonary hemorrhage', 'Disease', (75, 95))	('pulmonary hemorrhage', 'Disease', 'MESH:D006470', (75, 95))	('structural defects', 'CPA', (101, 119))	('smFoxm1-/-', 'Var', (16, 26))
375206	19835856	Depletion of Foxm1 in cultured SMC caused G2 arrest and decreased numbers of cells undergoing mitosis.	('mitosis', 'Disease', 'None', (94, 101))	('arrest', 'Disease', (45, 51))	('Foxm1', 'Gene', (13, 18))	('decreased', 'NegReg', (56, 65))	('Depletion', 'Var', (0, 9))	('mitosis', 'Disease', (94, 101))	('arrest', 'Disease', 'MESH:D006323', (45, 51))
375215	19835856	In our previous studies we demonstrated that Foxm1-/- mice die in utero between embryonic day 13.5 (E13.5) and E16.5 due to multiple abnormalities in development of the embryonic liver, lung, and heart.	('Foxm1-/-', 'Gene', (45, 53))	('embryonic liver', 'Disease', 'MESH:D017093', (169, 184))	('multiple abnormalities', 'Disease', 'MESH:D000015', (124, 146))	('embryonic liver', 'Disease', (169, 184))	('E16.5', 'Var', (111, 116))	('mice', 'Species', '10090', (54, 58))	('multiple abnormalities', 'Disease', (124, 146))
375218	19835856	Hepatocyte-specific deletion of Foxm1 in Albumin-Cre Foxm1fl/fl mice prevented formation of hepatocellular carcinoma (HCC) in adult mice by inducing p27kip1 tumor suppressor in HCC tumor cells and normal hepatocytes.	('mice', 'Species', '10090', (132, 136))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('Foxm1', 'Gene', (32, 37))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('prevented', 'NegReg', (69, 78))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('p27kip1', 'Gene', '12576', (149, 156))	('p27kip1', 'Gene', (149, 156))	('deletion', 'Var', (20, 28))	('hepatocellular carcinoma', 'Disease', (92, 116))	('mice', 'Species', '10090', (64, 68))	('HCC tumor', 'Disease', (177, 186))	('tumor', 'Disease', (157, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumor', 'Disease', (181, 186))	('HCC', 'Phenotype', 'HP:0001402', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('inducing', 'PosReg', (140, 148))	('HCC tumor', 'Disease', 'MESH:D006528', (177, 186))
375219	19835856	In response to the inflammatory mediator LPS, mice with endothelial-specific Foxm1 deletion (Tie2-Cre Foxm1fl/fl mice) displayed significantly increased lung vascular permeability and markedly increased mortality.	('Tie2', 'Gene', '21687', (93, 97))	('lung vascular permeability', 'CPA', (153, 179))	('increased', 'PosReg', (143, 152))	('Tie2', 'Gene', (93, 97))	('LPS', 'Chemical', 'MESH:D008070', (41, 44))	('mice', 'Species', '10090', (46, 50))	('increased', 'PosReg', (193, 202))	('deletion', 'Var', (83, 91))	('mice', 'Species', '10090', (113, 117))	('mortality', 'CPA', (203, 212))	('Foxm1', 'Gene', (77, 82))
375220	19835856	A conditional deletion of Foxm1 from precursors of cerebellar granule neurons caused a delay in brain development by interfering with Shh-induced neuroproliferation.	('Foxm1', 'Gene', (26, 31))	('interfering', 'NegReg', (117, 128))	('brain development', 'CPA', (96, 113))	('Shh', 'Gene', (134, 137))	('delay', 'NegReg', (87, 92))	('Shh', 'Gene', '20423', (134, 137))	('delay in brain development', 'Phenotype', 'HP:0001263', (87, 113))	('deletion', 'Var', (14, 22))
375221	19835856	Mice with pancreatic-specific deletion of Foxm1 displayed severe abnormalities in postnatal beta-cell mass expansion, causing impaired islet function and diabetes by 9 week of age.	('pancreatic', 'Disease', (10, 20))	('diabetes', 'Disease', (154, 162))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('islet function', 'CPA', (135, 149))	('Foxm1', 'Gene', (42, 47))	('deletion', 'Var', (30, 38))	('impaired', 'NegReg', (126, 134))	('Mice', 'Species', '10090', (0, 4))	('postnatal beta-cell mass expansion', 'CPA', (82, 116))	('pancreatic', 'Disease', 'MESH:D010195', (10, 20))
375224	19835856	Deletion of Foxm1 in the respiratory epithelium did not alter epithelial proliferation but inhibited lung maturation and caused respiratory failure after birth.	('lung maturation', 'CPA', (101, 116))	('caused', 'Reg', (121, 127))	('respiratory failure', 'Disease', (128, 147))	('inhibited', 'NegReg', (91, 100))	('respiratory failure', 'Disease', 'MESH:D012131', (128, 147))	('respiratory failure', 'Phenotype', 'HP:0002878', (128, 147))	('Foxm1', 'Gene', (12, 17))	('Deletion', 'Var', (0, 8))
375227	19835856	To investigate the role of Foxm1 in smooth muscle cells in vivo, we generated transgenic mice in which Foxm1-floxed allele was conditionally deleted using Cre recombinase transgene driven by a smooth muscle myosin heavy chain promoter (smMHC-Cre Foxm1fl/fl, or smFoxm1-/- mice).	('smMHC', 'Gene', '17880', (236, 241))	('Foxm1-floxed', 'Gene', (103, 115))	('deleted', 'Var', (141, 148))	('mice', 'Species', '10090', (89, 93))	('mice', 'Species', '10090', (272, 276))	('transgenic mice', 'Species', '10090', (78, 93))	('smMHC', 'Gene', (236, 241))
375228	19835856	We demonstrated that a majority of smFoxm1-/- mice died immediately after birth due to severe pulmonary hemorrhage, structural defects in arterial wall, and esophageal abnormalities.	('pulmonary hemorrhage', 'Disease', 'MESH:D006470', (94, 114))	('esophageal abnormalities', 'Disease', (157, 181))	('smFoxm1-/-', 'Var', (35, 45))	('mice', 'Species', '10090', (46, 50))	('esophageal abnormalities', 'Disease', 'MESH:D004941', (157, 181))	('structural defects', 'CPA', (116, 134))	('pulmonary hemorrhage', 'Disease', (94, 114))	('pulmonary hemorrhage', 'Phenotype', 'HP:0040223', (94, 114))
375229	19835856	Although Foxm1 deletion did not influence differentiation of smooth muscle cells, decreased cellular proliferation was observed in muscle layers of embryonic blood vessels and esophagus.	('embryonic blood vessels', 'Disease', 'MESH:D009383', (148, 171))	('cellular proliferation', 'CPA', (92, 114))	('deletion', 'Var', (15, 23))	('Foxm1', 'Gene', (9, 14))	('embryonic blood vessels', 'Disease', (148, 171))	('decreased', 'NegReg', (82, 91))
375230	19835856	In vitro experiments demonstrated that siRNA-mediated depletion of Foxm1 in cultured smooth muscle cells caused G2 arrest and decreased numbers of cells undergoing mitosis.	('depletion', 'Var', (54, 63))	('decreased', 'NegReg', (126, 135))	('Foxm1', 'Gene', (67, 72))	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('arrest', 'Disease', (115, 121))	('mitosis', 'Disease', (164, 171))	('mitosis', 'Disease', 'None', (164, 171))
375231	19835856	Depletion of Foxm1 in vitro and in vivo was associated with reduced expression of cell cycle regulatory genes, including cyclin B1, Cdk1-activator Cdc25b phosphatase, Polo-like 1 and JNK1 kinases, and cMyc transcription factor.	('Cdc25b', 'Gene', (147, 153))	('Cdk1', 'Gene', (132, 136))	('cell cycle regulatory genes', 'Gene', (82, 109))	('expression', 'MPA', (68, 78))	('cyclin B1', 'Gene', (121, 130))	('Cdk1', 'Gene', '12534', (132, 136))	('Foxm1', 'Gene', (13, 18))	('Myc', 'Gene', (202, 205))	('JNK1', 'Gene', '26419', (183, 187))	('Depletion', 'Var', (0, 9))	('Myc', 'Gene', '17869', (202, 205))	('reduced', 'NegReg', (60, 67))	('Cdc25b', 'Gene', '12531', (147, 153))	('JNK1', 'Gene', (183, 187))	('cyclin B1', 'Gene', '268697', (121, 130))
375252	19835856	We transfected 100 nM of either siFoxm1 or mutant siFoxm1 (mutFoxm1; mutated nucleotides are indicated by capital letters, 5'-gga ccU GuA uGc Gua cAu u-3') duplexes into human HAVSMC cells using Lipofectamine  2000 reagent (Invitrogen) in serum free tissue culture media as described previously.	('mutant', 'Var', (43, 49))	('Lipofectamine  2000', 'Chemical', 'MESH:C086724', (195, 214))	('siFoxm1', 'Gene', (50, 57))	('human', 'Species', '9606', (170, 175))
375267	19835856	However, deletion of Foxm1 caused a perinatal lethality in 87% of smFoxm1-/- mice within the first 24 hours after birth (Table 2).	('mice', 'Species', '10090', (77, 81))	('Foxm1', 'Gene', (21, 26))	('perinatal lethality', 'CPA', (36, 55))	('deletion', 'Var', (9, 17))
375272	19835856	1U-W and data not shown), which is consistent with beta-gal activity in smFoxm1-/-/ R26R embryos (Fig.	('beta-gal', 'Gene', '12091', (51, 59))	('beta-gal', 'Gene', (51, 59))	('smFoxm1-/-/', 'Var', (72, 83))	('R26R', 'Mutation', 'p.R26R', (84, 88))
375274	19835856	Embryonic esophageal muscle is composed of outer longitudinal and inner circumferential layers, both of which express Cre recombinase transgene in smFoxm1-/- mutant mice (Fig.	('mutant', 'Var', (158, 164))	('Embryonic esophageal', 'Disease', (0, 20))	('mice', 'Species', '10090', (165, 169))	('Embryonic esophageal', 'Disease', 'MESH:D004941', (0, 20))
375277	19835856	The structural abnormalities of the esophagus can interfere with proper functions of the gastrointestinal system, contributing to perinatal lethality in smFoxm1-/- newborn mice.	('interfere', 'NegReg', (50, 59))	('functions', 'MPA', (72, 81))	('gastrointestinal system', 'Disease', 'MESH:D005767', (89, 112))	('contributing', 'Reg', (114, 126))	('mice', 'Species', '10090', (172, 176))	('gastrointestinal system', 'Disease', (89, 112))	('smFoxm1-/-', 'Var', (153, 163))	('perinatal lethality', 'CPA', (130, 149))
375278	19835856	Interestingly, no intestinal, bronchial or stomach defects were found in smFoxm1-/- embryos or newborn mice (Figs.	('stomach defects', 'Disease', 'MESH:D013272', (43, 58))	('mice', 'Species', '10090', (103, 107))	('bronchial', 'Disease', (30, 39))	('stomach defects', 'Disease', (43, 58))	('smFoxm1-/-', 'Var', (73, 83))
375279	19835856	Finally, normal expression of CCSP (Clara cell marker) and proSPC (type II cell marker) was observed in smFoxm1-/- E18.5 airways when compared to either Foxm1fl/fl or smMHC-Cre-GFPtg/- embryos (Fig.	('smMHC', 'Gene', '17880', (167, 172))	('smMHC', 'Gene', (167, 172))	('smFoxm1-/- E18.5', 'Var', (104, 120))
375281	19835856	Pulmonary arteries from smFoxm1-/- mice displayed multiple hernias in arterial walls, disruption of vascular muscle layers, and accumulation of large cells with round nuclei (Fig.	('hernias', 'Phenotype', 'HP:0100790', (59, 66))	('hernias', 'Disease', (59, 66))	('hernias', 'Disease', 'MESH:D006547', (59, 66))	('smFoxm1-/-', 'Var', (24, 34))	('accumulation', 'PosReg', (128, 140))	('mice', 'Species', '10090', (35, 39))
375283	19835856	Morphological evidence of vascular leakage from perforated pulmonary arteries was also detected in smFoxm1-/- newborn mice (Fig.	('mice', 'Species', '10090', (118, 122))	('smFoxm1-/-', 'Var', (99, 109))	('detected', 'Reg', (87, 95))	('vascular leakage', 'CPA', (26, 42))
375285	19835856	Interestingly, hemorrhage was not observed in the liver, gut, brain and skeletal muscle of the smFoxm1-/- newborn mice, and the heart structure in smFoxm1-/- mice was normal (data not shown).	('mice', 'Species', '10090', (158, 162))	('hemorrhage', 'Disease', (15, 25))	('hemorrhage', 'Disease', 'MESH:D006470', (15, 25))	('mice', 'Species', '10090', (114, 118))	('smFoxm1-/-', 'Var', (95, 105))
375292	19835856	In E12.5 and E13.5 embryos, beta-gal activity was detected in pulmonary arteries, bronchi, stomach, cartilage, and aortic outflow and pulmonary trunks of the developing heart (Fig.	('cartilage', 'Disease', 'MESH:D002357', (100, 109))	('E13.5', 'Var', (13, 18))	('cartilage', 'Disease', (100, 109))	('E12.5', 'Var', (3, 8))	('activity', 'MPA', (37, 45))	('beta-gal', 'Gene', (28, 36))	('beta-gal', 'Gene', '12091', (28, 36))
375293	19835856	Similar beta-gal activity was observed in control and Foxm1 mutant embryos (Fig.	('mutant', 'Var', (60, 66))	('Foxm1', 'Gene', (54, 59))	('beta-gal', 'Gene', (8, 16))	('beta-gal', 'Gene', '12091', (8, 16))
375298	19835856	Although smFoxm1-/- esophagi contained less MyoD-positive cells compared to control Foxm1fl/fl embryos (Fig.	('MyoD', 'Gene', (44, 48))	('MyoD', 'Gene', '17927', (44, 48))	('smFoxm1-/-', 'Var', (9, 19))	('less', 'NegReg', (39, 43))
375301	19835856	In contrast, smFoxm1-/- newborn mice displayed an increased apoptosis in the lung (Fig.	('smFoxm1-/-', 'Var', (13, 23))	('mice', 'Species', '10090', (32, 36))	('apoptosis', 'CPA', (60, 69))
375302	19835856	Total numbers of caspase 3 positive cells were significantly increased in the lung of smFoxm1-/- mice when compared to either Foxm1fl/fl or smMHC-Cre-GFPtg/- lungs (Fig.	('caspase 3', 'Protein', (17, 26))	('smMHC', 'Gene', '17880', (140, 145))	('mice', 'Species', '10090', (97, 101))	('smFoxm1-/-', 'Var', (86, 96))	('increased', 'PosReg', (61, 70))	('smMHC', 'Gene', (140, 145))
375305	19835856	Although cellular proliferation in epithelial cells was normal, diminished Ki-67 staining was observed in smooth muscle cells of smFoxm1-/- embryos (Fig.	('smFoxm1-/-', 'Var', (129, 139))	('diminished', 'NegReg', (64, 74))	('staining', 'MPA', (81, 89))	('Ki-67', 'Gene', '17345', (75, 80))	('Ki-67', 'Gene', (75, 80))
375306	19835856	In comparison to control embryos, total numbers of Ki-67 positive smooth muscle cells were significantly decreased in smFoxm1-/- blood vessels and esophagi (Fig.	('Ki-67', 'Gene', (51, 56))	('smFoxm1-/-', 'Var', (118, 128))	('decreased', 'NegReg', (105, 114))	('Ki-67', 'Gene', '17345', (51, 56))
375310	19835856	These results suggest that depletion of Foxm1 in cultured smooth muscle cells caused a G2 arrest with accumulation of polyploid cells due to a significant decrease in mitotic progression.	('arrest', 'Disease', 'MESH:D006323', (90, 96))	('Foxm1', 'Gene', (40, 45))	('mitotic progression', 'CPA', (167, 186))	('arrest', 'Disease', (90, 96))	('decrease', 'NegReg', (155, 163))	('depletion', 'Var', (27, 36))
375315	19835856	Significantly decreased mRNA levels of IAP repeat-containing survivin protein, a known transcriptional target of Foxm1, were found in siFoxm1-transfected cells (Table 4).	('decreased', 'NegReg', (14, 23))	('siFoxm1-transfected', 'Var', (134, 153))	('survivin', 'Gene', '11799', (61, 69))	('IAP', 'Protein', (39, 42))	('mRNA levels', 'MPA', (24, 35))	('survivin', 'Gene', (61, 69))
375317	19835856	Consistent with Affymetrix microarray analysis (Table 4), Foxm1 depletion significantly decreased mRNA levels of cyclin B1, cyclin D1, Plk1, JNK1, and cMyc (Fig.	('cyclin D1', 'Gene', (124, 133))	('Plk1', 'Gene', (135, 139))	('depletion', 'Var', (64, 73))	('Foxm1', 'Gene', (58, 63))	('Plk1', 'Gene', '18817', (135, 139))	('cyclin B1', 'Gene', '268697', (113, 122))	('JNK1', 'Gene', '26419', (141, 145))	('decreased', 'NegReg', (88, 97))	('Myc', 'Gene', '17869', (152, 155))	('cyclin D1', 'Gene', '12443', (124, 133))	('Myc', 'Gene', (152, 155))	('cyclin B1', 'Gene', (113, 122))	('JNK1', 'Gene', (141, 145))
375320	19835856	The requirement for Foxm1 activity in smooth muscle cells was examined in smFoxm1-/- mice that contain a smooth muscle-specific deletion of exons 4 through 7, encoding the Foxm1 DNA binding domain and C-terminal transcriptional activation domains, both of which are essential for Foxm1 transcriptional activity.	('mice', 'Species', '10090', (85, 89))	('binding', 'Interaction', (182, 189))	('Foxm1', 'Gene', (172, 177))	('deletion', 'Var', (128, 136))
375321	19835856	Most of the smFoxm1-/- mice exhibited a perinatal lethality within the first 24 hours after birth because of severe pulmonary hemorrhage, and structural defects in arterial wall and esophagus.	('structural defects', 'CPA', (142, 160))	('pulmonary hemorrhage', 'Disease', (116, 136))	('pulmonary hemorrhage', 'Phenotype', 'HP:0040223', (116, 136))	('pulmonary hemorrhage', 'Disease', 'MESH:D006470', (116, 136))	('smFoxm1-/-', 'Var', (12, 22))	('mice', 'Species', '10090', (23, 27))
375328	19835856	Therefore, defects in cell proliferation in smFoxm1-/- smooth muscle cells may be a direct consequence of reduced Cdk2 and Cdk4 activity causing diminished DNA replication.	('smFoxm1-/-', 'Var', (44, 54))	('activity', 'MPA', (128, 136))	('Cdk4', 'Gene', (123, 127))	('Cdk2', 'Gene', '12566', (114, 118))	('Cdk2', 'Gene', (114, 118))	('diminished', 'NegReg', (145, 155))	('defects', 'NegReg', (11, 18))	('Cdk4', 'Gene', '12567', (123, 127))	('reduced', 'NegReg', (106, 113))	('DNA', 'MPA', (156, 159))	('cell proliferation', 'CPA', (22, 40))
375335	19835856	These results raise a possibility that the apoptotic phenotype in smFoxm1-/- mice was an indirect consequence of Foxm1 deficiency.	('Foxm1', 'Gene', (113, 118))	('apoptotic phenotype', 'CPA', (43, 62))	('mice', 'Species', '10090', (77, 81))	('deficiency', 'Var', (119, 129))
375336	19835856	Differential deletion of the serum response factor (SRF) binding sites (CArG boxes) revealed fundamental differences in importance of particular SRF-binding regions between smooth muscle subtypes.	('SRF', 'Gene', '20807', (52, 55))	('serum response factor', 'Gene', '20807', (29, 50))	('SRF', 'Gene', (145, 148))	('deletion', 'Var', (13, 21))	('serum response factor', 'Gene', (29, 50))	('SRF', 'Gene', (52, 55))	('SRF', 'Gene', '20807', (145, 148))
375339	19835856	Interestingly, approximately 13% of smFoxm1-/- mice survived after birth and developed a megacolon by 4 weeks of age (data not shown).	('developed', 'Reg', (77, 86))	('megacolon', 'CPA', (89, 98))	('mice', 'Species', '10090', (47, 51))	('smFoxm1-/-', 'Var', (36, 46))	('megacolon', 'Phenotype', 'HP:0002251', (89, 98))
375340	19835856	Since a histological structure of the intestine in these adult smFoxm1-/- mice was normal (data not shown), the megacolon may be a result of diminished muscular tone and/or intestinal contractility in these Foxm1 mutant mice.	('muscular tone', 'CPA', (152, 165))	('megacolon', 'Phenotype', 'HP:0002251', (112, 121))	('diminished muscular tone', 'Phenotype', 'HP:0001290', (141, 165))	('intestinal contractility', 'CPA', (173, 197))	('mice', 'Species', '10090', (220, 224))	('diminished', 'NegReg', (141, 151))	('mice', 'Species', '10090', (74, 78))	('Foxm1', 'Gene', (207, 212))	('megacolon', 'Disease', (112, 121))	('mutant', 'Var', (213, 219))
375341	19835856	In summary, smFoxm1-/- mice died immediately after birth due to severe pulmonary hemorrhage, structural defects in arterial wall, and esophageal abnormalities.	('pulmonary hemorrhage', 'Phenotype', 'HP:0040223', (71, 91))	('pulmonary hemorrhage', 'Disease', (71, 91))	('structural defects', 'CPA', (93, 111))	('esophageal abnormalities', 'Disease', (134, 158))	('pulmonary hemorrhage', 'Disease', 'MESH:D006470', (71, 91))	('esophageal abnormalities', 'Disease', 'MESH:D004941', (134, 158))	('smFoxm1-/-', 'Var', (12, 22))	('mice', 'Species', '10090', (23, 27))
375347	31834866	Overall, our study systematically analyzed large-scale methylation data and provided promising markers for the diagnosis and prognosis of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('esophageal cancer', 'Disease', (138, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('methylation', 'Var', (55, 66))
375358	31834866	Epigenetic markers, especially DNA methylation, is thought as an ideal marker for early detection of cancer, as it has advantages of cancer-specific methylation patterns, occurrence in early cancer stages, biological stability, and technical repeatability.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('methylation', 'Var', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
375360	31834866	Aberrant methylation is common in various types of cancers, including esophageal cancer, which contributes to carcinogenesis.	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('esophageal cancer', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('Aberrant methylation', 'Var', (0, 20))	('carcinogenesis', 'Disease', 'MESH:D063646', (110, 124))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('common', 'Reg', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Disease', (51, 58))	('carcinogenesis', 'Disease', (110, 124))
375361	31834866	Methylation-based markers have shown great potential for the diagnosis and survival prediction of solid tumors.	('solid tumors', 'Disease', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('Methylation-based', 'Var', (0, 17))	('solid tumors', 'Disease', 'MESH:D009369', (98, 110))
375366	31834866	When a noninvasive device was applied to collect samples for detecting TFPI2 hypermethylation for BE diagnosis, the sensitivity and specificity were 82.2% and 95.7%, respectively.	('TFPI2', 'Gene', (71, 76))	('TFPI2', 'Gene', '7980', (71, 76))	('BE', 'Disease', 'MESH:D001471', (98, 100))	('BE', 'Phenotype', 'HP:0100580', (98, 100))	('hypermethylation', 'Var', (77, 93))
375367	31834866	A study found that VIM gene methylation is a highly sensitive biomarker for BE, which could be detected in esophageal brushings.	('VIM', 'Gene', '7431', (19, 22))	('esophageal brushings', 'Disease', (107, 127))	('BE', 'Phenotype', 'HP:0100580', (76, 78))	('esophageal brushings', 'Disease', 'MESH:D004941', (107, 127))	('BE', 'Disease', 'MESH:D001471', (76, 78))	('VIM', 'Gene', (19, 22))	('methylation', 'Var', (28, 39))
375368	31834866	Moreover, using a novel swallowable balloon-based device that captures DNA samples for methylation analyses, a two marker panel of CCNA1 and VIM methylation for detecting BE and EAC from normal tissues provided more than 90% sensitivity and specificity.	('BE', 'Disease', 'MESH:D001471', (171, 173))	('CCNA1', 'Gene', (131, 136))	('EAC', 'Phenotype', 'HP:0011459', (178, 181))	('CCNA1', 'Gene', '8900', (131, 136))	('VIM', 'Gene', '7431', (141, 144))	('EAC', 'Disease', (178, 181))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('methylation', 'Var', (145, 156))	('EAC', 'Disease', 'MESH:D004941', (178, 181))	('VIM', 'Gene', (141, 144))
375398	31834866	Prognostic methylation classifier for EAC and ESCC specifically was developed to classify the patients into high risk and low risk, which could accurately estimate the prognosis of an individual patient Methylation-based markers researches for esophageal cancer have mainly been focused on hypermethylation in promoter region CpG island of numerous tumor suppressor genes, such as APC and CDKN2A, which thus were thought to be potential biomarkers for the diagnosis of BE and esophageal cancer.	('esophageal cancer', 'Disease', (244, 261))	('APC', 'Disease', 'MESH:D011125', (381, 384))	('APC', 'Disease', (381, 384))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('cancer', 'Phenotype', 'HP:0002664', (487, 493))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('patients', 'Species', '9606', (94, 102))	('ESCC', 'Disease', 'MESH:C562729', (46, 50))	('EAC', 'Phenotype', 'HP:0011459', (38, 41))	('patient', 'Species', '9606', (94, 101))	('CDKN2A', 'Gene', (389, 395))	('BE', 'Phenotype', 'HP:0100580', (469, 471))	('hypermethylation', 'Var', (290, 306))	('esophageal cancer', 'Disease', 'MESH:D004938', (476, 493))	('BE', 'Disease', 'MESH:D001471', (469, 471))	('EAC', 'Disease', (38, 41))	('EAC', 'Disease', 'MESH:D004941', (38, 41))	('ESCC', 'Disease', (46, 50))	('CDKN2A', 'Gene', '1029', (389, 395))	('tumor', 'Disease', (349, 354))	('patient', 'Species', '9606', (195, 202))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('esophageal cancer', 'Disease', (476, 493))
375413	31834866	For example, one of the diagnostic CpG sites (cg08858649) was within CpG island of TRIM15 gene, and single gene methylation had a c-statistic of 0.91 (95% CI: 0.88-0.99) in discriminating the combination of EAC and BE from normal mucosa.	('TRIM15', 'Gene', (83, 89))	('EAC', 'Disease', 'MESH:D004941', (207, 210))	('EAC', 'Disease', (207, 210))	('cg08858649', 'Var', (46, 56))	('BE', 'Phenotype', 'HP:0100580', (215, 217))	('TRIM15', 'Gene', '89870', (83, 89))	('EAC', 'Phenotype', 'HP:0011459', (207, 210))	('BE', 'Disease', 'MESH:D001471', (215, 217))
375414	31834866	A prognostic methylation marker (cg18276155) for EAC was located at a classic tumor suppressor gene of esophageal cancer, MCC gene.	('EAC', 'Disease', (49, 52))	('esophageal cancer', 'Disease', (103, 120))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cg18276155', 'Var', (33, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('tumor', 'Disease', (78, 83))	('MCC', 'Gene', (122, 125))	('EAC', 'Disease', 'MESH:D004941', (49, 52))
375416	31834866	Although the link between aberrant methylation and gene alterations is not yet known, our study suggested that aberrant methylation of MCC gene might contribute to progression of EAC via epigenetic regulation.	('epigenetic regulation', 'MPA', (187, 208))	('contribute', 'Reg', (150, 160))	('MCC gene', 'Gene', (135, 143))	('EAC', 'Phenotype', 'HP:0011459', (179, 182))	('EAC', 'Disease', 'MESH:D004941', (179, 182))	('EAC', 'Disease', (179, 182))	('aberrant methylation', 'Var', (111, 131))
375425	31834866	External validation sets of GSE52826, GSE74693, GSE79366, and GSE81334 were used to validate the predictive performance of the diagnostic classifier, including 66 NSE, 69 BE, 23 EAC, and 26 ESCC.	('ESCC', 'Disease', (190, 194))	('BE', 'Disease', 'MESH:D001471', (171, 173))	('EAC', 'Phenotype', 'HP:0011459', (178, 181))	('GSE81334', 'Var', (62, 70))	('GSE74693', 'Var', (38, 46))	('ESCC', 'Disease', 'MESH:C562729', (190, 194))	('EAC', 'Disease', (178, 181))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('GSE79366', 'Var', (48, 56))	('GSE52826', 'Var', (28, 36))	('EAC', 'Disease', 'MESH:D004941', (178, 181))
375444	31666092	Quantitative MRI analysis showed that the hyperintense area around the esophagus with severe ARIED was 1.41 mm wider than with no damage and MRI-only mice.	('mice', 'Species', '10090', (150, 154))	('ARIED', 'Var', (93, 98))	('hyperintense', 'MPA', (42, 54))	('severe ARIED', 'Var', (86, 98))
375454	31666092	ARIED can cause reduced food intake, nausea, dysplasia, odynophagia, anorexia, and other complications, which may interrupt treatment.	('food', 'CPA', (24, 28))	('dysplasia, odynophagia, anorexia', 'Disease', 'MESH:D000855', (45, 77))	('reduced food intake', 'Phenotype', 'HP:0011968', (16, 35))	('anorexia', 'Phenotype', 'HP:0002039', (69, 77))	('reduced', 'NegReg', (16, 23))	('nausea', 'Phenotype', 'HP:0002018', (37, 43))	('ARIED', 'Var', (0, 5))	('nausea', 'Disease', (37, 43))	('nausea', 'Disease', 'MESH:D009325', (37, 43))	('odynophagia', 'Phenotype', 'HP:0032043', (56, 67))
375544	31517842	Authors pointed out that anticytokeratin CAM5.2 is specific for CK8 and to a lesser extent, for the closely related CK7, but shows no reactivity with CK18 or CK19.	('CK18', 'Gene', (150, 154))	('CK8', 'Var', (64, 67))	('CK19', 'Gene', '3880', (158, 162))	('CK18', 'Gene', '3875', (150, 154))	('CK7', 'Gene', (116, 119))	('CK19', 'Gene', (158, 162))	('CK7', 'Gene', '3855', (116, 119))
375572	31517842	Combined strategies were used to analyze the datasets (201820_at/CK5, 209125_at/CK6a, 213680_at/CK6b, 214580_x_at/CK6c, 209016_s_at/CK7, 209016_s_at/ CK7, 209008_x_at/ CK8) gained from the ESCC GEO profiles GDS3838.	('CK6a', 'Gene', '3853', (80, 84))	('CK7', 'Gene', (132, 135))	('ESCC', 'Disease', 'MESH:C562729', (189, 193))	('CK7', 'Gene', '3855', (132, 135))	('CK6b', 'Gene', (96, 100))	('CK7', 'Gene', (150, 153))	('ESCC', 'Disease', (189, 193))	('CK7', 'Gene', '3855', (150, 153))	('CK6c', 'Gene', (114, 118))	('CK6b', 'Gene', '3854', (96, 100))	('CK6c', 'Gene', '286887', (114, 118))	('201820_at/CK5', 'Var', (55, 68))	('CK6a', 'Gene', (80, 84))
375586	31517842	There was no association between clinicopathological parameters and CAM5.2 staining, whereas Kaplan-Meier analysis of 315 patients showed that strong CAM5.2 staining was associated with poor OS (P = .0041) (Fig.	('patients', 'Species', '9606', (122, 130))	('staining', 'Var', (157, 165))	('CAM5.2', 'Gene', (150, 156))
375593	31517842	Furthermore, the multivariate Cox model showed significant association between CAM5.2 expression and DFS as well as OS in ESCC patients (Table 2), suggesting that CAM5.2 could be an independent prognostic factor for ESCC.	('CAM5.2', 'Var', (163, 169))	('Cox', 'Gene', (30, 33))	('ESCC', 'Disease', (122, 126))	('ESCC', 'Disease', (216, 220))	('patients', 'Species', '9606', (127, 135))	('CAM5.2', 'Gene', (79, 85))	('Cox', 'Gene', '1351', (30, 33))	('ESCC', 'Disease', 'MESH:C562729', (216, 220))	('ESCC', 'Disease', 'MESH:C562729', (122, 126))
375610	31517842	In conclusion, high expression of cytokeratin CAM5.2 in ESCC is associated with poor prognosis.	('ESCC', 'Disease', (56, 60))	('high', 'Var', (15, 19))	('cytokeratin CAM5.2', 'Protein', (34, 52))	('ESCC', 'Disease', 'MESH:C562729', (56, 60))
375626	31281465	Moreover, dysregulated circRNAs were implicated in osteogenesis, diabetes mellitus and brain dysfunction, especially cancer.	('especially cancer', 'Disease', 'MESH:D009369', (106, 123))	('dysregulated', 'Var', (10, 22))	('circ', 'Chemical', '-', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('implicated', 'Reg', (37, 47))	('diabetes mellitus', 'Disease', 'MESH:D003920', (65, 82))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (65, 82))	('brain dysfunction', 'Disease', (87, 104))	('osteogenesis', 'Disease', (51, 63))	('especially cancer', 'Disease', (106, 123))	('diabetes mellitus', 'Disease', (65, 82))	('brain dysfunction', 'Disease', 'MESH:D001927', (87, 104))
375628	31281465	Furthermore, circRNA_100338, one of the upregulated circRNAs, promoted invasive potential of hepatitis B-related hepatocellular carcinoma.	('circ', 'Chemical', '-', (13, 17))	('hepatitis', 'Phenotype', 'HP:0012115', (93, 102))	('circRNA_100338', 'Var', (13, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('hepatitis', 'Disease', 'MESH:D056486', (93, 102))	('hepatitis', 'Disease', (93, 102))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (113, 137))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (113, 137))	('circ', 'Chemical', '-', (52, 56))	('hepatocellular carcinoma', 'Disease', (113, 137))	('promoted', 'PosReg', (62, 70))	('invasive potential', 'CPA', (71, 89))
375638	31281465	Recently, some researchers have found that intron pairing, exon skipping, and RNA binding protein (RBP) pairing were the main reasons that drove the circularization of RNA (Figure 1).	('circ', 'Chemical', '-', (149, 153))	('RNA binding protein', 'Gene', '27303', (78, 97))	('RBP', 'Gene', (99, 102))	('exon skipping', 'Var', (59, 72))	('RNA binding protein', 'Gene', (78, 97))	('intron pairing', 'Var', (43, 57))	('RBP', 'Gene', '27303', (99, 102))
375642	31281465	A study reported that exon-skipping promoted the shaping of a spliced lariat containing the circularized exon.	('shaping', 'MPA', (49, 56))	('circ', 'Chemical', '-', (92, 96))	('exon-skipping', 'Var', (22, 35))	('promoted', 'PosReg', (36, 44))
375658	31281465	Deficiency of the ciRS-7 gene led to the dysfunction of draining, including sensorimotor gating damage and abnormal synaptic transmission.	('dysfunction', 'MPA', (41, 52))	('abnormal synaptic transmission', 'Phenotype', 'HP:0012535', (107, 137))	('ciRS-7', 'Gene', '103611090', (18, 24))	('draining', 'MPA', (56, 64))	('ciRS-7', 'Gene', (18, 24))	('sensorimotor gating', 'MPA', (76, 95))	('Deficiency', 'Var', (0, 10))
375659	31281465	A miR-7 target, the Fos gene, is upregulated in the ciRS-7 deficient group and showed a potential relationship with the behavioral phenotype in mouse.	('ciRS-7', 'Gene', '103611090', (52, 58))	('upregulated', 'PosReg', (33, 44))	('mouse', 'Species', '10090', (144, 149))	('Fos', 'Gene', (20, 23))	('miR-7', 'Gene', (2, 7))	('deficient', 'Var', (59, 68))	('ciRS-7', 'Gene', (52, 58))	('Fos', 'Gene', '14281', (20, 23))	('miR-7', 'Gene', '10859', (2, 7))
375666	31281465	It accelerated tumor growth and suppressed apoptosis by sponging miR-143 and releasing the miR-143 direct target, anti-apoptotic Bcl-2.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('apoptosis', 'CPA', (43, 52))	('miR-143', 'Gene', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('anti-apoptotic', 'MPA', (114, 128))	('miR-143', 'Gene', (65, 72))	('Bcl-2', 'Gene', (129, 134))	('sponging', 'Var', (56, 64))	('miR-143', 'Gene', '406935', (65, 72))	('Bcl-2', 'Gene', '596', (129, 134))	('accelerated', 'PosReg', (3, 14))	('tumor', 'Disease', (15, 20))	('miR-143', 'Gene', '406935', (91, 98))	('releasing', 'PosReg', (77, 86))	('suppressed', 'NegReg', (32, 42))
375667	31281465	Resembling circUBAP2, circ_0001982 presented a tumor suppressor effect by sponging miR-143 in breast cancer cells.	('breast cancer', 'Disease', (94, 107))	('tumor', 'Disease', (47, 52))	('circ', 'Chemical', '-', (22, 26))	('circ_0001982', 'Var', (22, 34))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('sponging', 'NegReg', (74, 82))	('miR-143', 'Gene', '406935', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('circ', 'Chemical', '-', (11, 15))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('miR-143', 'Gene', (83, 90))
375669	31281465	Through competitively binding miR-29b, silencing of circRNA_100290 markedly inhibited the expression level of CDK6.	('miR-29b', 'Gene', (30, 37))	('CDK6', 'Gene', (110, 114))	('CDK6', 'Gene', '1021', (110, 114))	('silencing', 'Var', (39, 48))	('circ', 'Chemical', '-', (52, 56))	('miR-29b', 'Gene', '407024', (30, 37))	('binding', 'Interaction', (22, 29))	('inhibited', 'NegReg', (76, 85))	('circRNA_100290', 'Var', (52, 66))	('expression level', 'MPA', (90, 106))
375697	31281465	Recently, a study showed that dysregulated circRNAs were implicated in radioresistant esophageal cancer cells.	('circ', 'Chemical', '-', (43, 47))	('dysregulated', 'Var', (30, 42))	('implicated', 'Reg', (57, 67))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('circRNAs', 'Gene', (43, 51))
375699	31281465	As we showed, dysregulated circRNAs exist in digestive cancers and may play important roles in digestive cancers (Table 1).	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('dysregulated', 'Var', (14, 26))	('cancers', 'Disease', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('circ', 'Chemical', '-', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
375704	31281465	Silencing circ-BANP expression inhibited colorectal cell proliferation, which implied that circ-BANP was an oncogene in colorectal cancer.	('colorectal cancer', 'Disease', (120, 137))	('circ', 'Chemical', '-', (91, 95))	('BANP', 'Gene', '54971', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('circ', 'Chemical', '-', (10, 14))	('colorectal cell proliferation', 'CPA', (41, 70))	('BANP', 'Gene', (15, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('BANP', 'Gene', '54971', (96, 100))	('inhibited', 'NegReg', (31, 40))	('Silencing', 'Var', (0, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('BANP', 'Gene', (96, 100))
375706	31281465	In esophageal squamous cell carcinoma, increased circ_0067934 was identified compared with adjacent normal tissues.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('circ_0067934', 'Var', (49, 61))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('circ', 'Chemical', '-', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))
375707	31281465	The results of knocking down circ_0067934 showed inhibiting effect on cancer cell proliferation and migration.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('knocking down', 'Var', (15, 28))	('circ_0067934', 'Gene', (29, 41))	('inhibiting', 'NegReg', (49, 59))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('circ', 'Chemical', '-', (29, 33))
375715	31281465	Inhibiting PTEN, which attenuates the activity of Akt or increasesPI3K and Akt, could block tumor cell apoptosis.	('PTEN', 'Gene', (11, 15))	('activity', 'MPA', (38, 46))	('Inhibiting', 'Var', (0, 10))	('Akt', 'Gene', '207', (50, 53))	('Akt', 'Gene', '207', (75, 78))	('increasesPI3K and Akt', 'Gene', '207', (57, 78))	('PTEN', 'Gene', '5728', (11, 15))	('Akt', 'Gene', (50, 53))	('Akt', 'Gene', (75, 78))	('block tumor', 'Disease', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('block tumor', 'Disease', 'MESH:D006327', (86, 97))	('attenuates', 'NegReg', (23, 33))
375719	31281465	There was low expression of circ-104916 in gastric cancer tissues.	('circ-104916', 'Var', (28, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (43, 57))	('gastric cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('expression', 'MPA', (14, 24))	('low', 'NegReg', (10, 13))	('gastric cancer', 'Phenotype', 'HP:0012126', (43, 57))	('circ', 'Chemical', '-', (28, 32))
375720	31281465	Overexpressed circ-104916 hindered cell proliferation, migration and invasion via regulating key factors of the EMT process.	('hindered', 'NegReg', (26, 34))	('circ-104916', 'Var', (14, 25))	('regulating', 'Reg', (82, 92))	('migration', 'CPA', (55, 64))	('cell proliferation', 'CPA', (35, 53))	('circ', 'Chemical', '-', (14, 18))	('invasion', 'CPA', (69, 77))	('EMT', 'Gene', (112, 115))	('EMT', 'Gene', '3702', (112, 115))
375731	31281465	In colorectal cancer, circ_001988 was reported as a new biomarker due to its significant clinical behavior.	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('circ_001988', 'Chemical', '-', (22, 33))	('colorectal cancer', 'Disease', (3, 20))	('circ_001988', 'Var', (22, 33))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
375738	31281465	To date, exon skipping, intron pairing and RBP pairing were the main reasons of RNA circularization.	('RBP', 'Gene', (43, 46))	('circ', 'Chemical', '-', (84, 88))	('exon skipping', 'Var', (9, 22))	('RBP', 'Gene', '27303', (43, 46))	('intron pairing', 'Var', (24, 38))
375755	30519325	Furthermore, cell proliferation, migration and invasion were significantly (P < 0.05) suppressed as compared to negative control while apoptotic rate was also found increased as a result of the knockdown of LINC01234.	('LINC01234', 'Gene', (207, 216))	('knockdown', 'Var', (194, 203))	('cell proliferation', 'CPA', (13, 31))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('invasion', 'CPA', (47, 55))	('apoptotic rate', 'CPA', (135, 149))	('suppressed', 'NegReg', (86, 96))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('increased', 'PosReg', (165, 174))	('LINC01234', 'Gene', '100506465', (207, 216))
375757	30519325	The impact of LINC01234 knockdown on cell migration, invasion, proliferation and apoptosis indicated that LINC01234 may represent a new marker and a potential therapeutic target for esophageal cancer.	('si', 'Chemical', 'MESH:D012825', (87, 89))	('esophageal cancer', 'Disease', (182, 199))	('proliferation', 'CPA', (63, 76))	('invasion', 'CPA', (53, 61))	('LINC01234', 'Gene', '100506465', (106, 115))	('apoptosis', 'CPA', (81, 90))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('LINC01234', 'Gene', '100506465', (14, 23))	('LINC01234', 'Gene', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('LINC01234', 'Gene', (14, 23))	('cell migration', 'CPA', (37, 51))	('knockdown', 'Var', (24, 33))
375766	30519325	Research evidence has showed that non-coding RNAs are important biological regulators which affect the phenotype of the cell from normal to cancerous.	('cancerous', 'Disease', 'MESH:D009369', (140, 149))	('non-coding RNAs', 'Var', (34, 49))	('affect', 'Reg', (92, 98))	('cancerous', 'Disease', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
375769	30519325	Dysregulated expression of lncRNAs is linked with many human diseases and cancers, including esophageal cancer.	('linked', 'Reg', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('expression', 'MPA', (13, 23))	('esophageal cancer', 'Disease', (93, 110))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('human', 'Species', '9606', (55, 60))	('diseases and cancers', 'Disease', 'MESH:D009369', (61, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('Dysregulated', 'Var', (0, 12))	('lncRNAs', 'Protein', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
375789	30519325	In the first step, epithelial cells were infected with HPV18 E6E7 then tumor-promoting factor TPA was added as the second step.	('HPV', 'Disease', 'MESH:D030361', (55, 58))	('E6E7', 'Var', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('TPA', 'Chemical', '-', (94, 97))	('HPV', 'Disease', (55, 58))	('tumor', 'Disease', (71, 76))
375803	30519325	To determine cell migration, esophageal cancer cells transfected with si-LINC01234 or si-NC were seeded into 6-well plates and allowed to grow to 90-95% confluence.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('si-NC', 'Var', (86, 91))	('esophageal cancer', 'Disease', (29, 46))	('LINC01234', 'Gene', '100506465', (73, 82))	('si-NC', 'Chemical', 'MESH:C052464', (86, 91))	('LINC01234', 'Gene', (73, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('si', 'Chemical', 'MESH:D012825', (86, 88))
375807	30519325	After two hours, 5 x 105 / mL cells transfected with si-LINC01234 or si-NC were suspended in serum-free medium and 200 mul were seeded in the upper chamber coated with matrigel, while 750uL DMEM with FBS (20%) was added in the lower chamber.	('si', 'Chemical', 'MESH:D012825', (53, 55))	('si-NC', 'Var', (69, 74))	('FBS', 'Disease', (200, 203))	('DMEM', 'Chemical', '-', (190, 194))	('si-NC', 'Chemical', 'MESH:C052464', (69, 74))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('LINC01234', 'Gene', '100506465', (56, 65))	('LINC01234', 'Gene', (56, 65))	('FBS', 'Disease', 'MESH:D005198', (200, 203))
375810	30519325	Cells were transfected with si-LINC01234 or si-NC in 6-well plate.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('si-NC', 'Var', (44, 49))	('si-NC', 'Chemical', 'MESH:C052464', (44, 49))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('LINC01234', 'Gene', '100506465', (31, 40))	('LINC01234', 'Gene', (31, 40))
375812	30519325	For colony forming experiments, CEC2 cells at a density of 1000 cells/well were seeded onthe six-well plate after transfection with si-LINC01234 or si-NC, maintained in DMEM medium containing FBS (15%).	('LINC01234', 'Gene', (135, 144))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('FBS', 'Disease', 'MESH:D005198', (192, 195))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('DMEM medium', 'Chemical', '-', (169, 180))	('si-NC', 'Var', (148, 153))	('FBS', 'Disease', (192, 195))	('si-NC', 'Chemical', 'MESH:C052464', (148, 153))	('LINC01234', 'Gene', '100506465', (135, 144))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('CEC2', 'CellLine', 'CVCL:D160', (32, 36))
375831	30519325	LINC01234 expression was down-regulated by approximately 70% in CEC2 cells by si-2 when compared with the siNC (Figure 1B, P < 0.05).	('CEC2', 'CellLine', 'CVCL:D160', (64, 68))	('LINC01234', 'Gene', '100506465', (0, 9))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('expression', 'MPA', (10, 20))	('LINC01234', 'Gene', (0, 9))	('si-2', 'Var', (78, 82))	('down-regulated', 'NegReg', (25, 39))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('si', 'Chemical', 'MESH:D012825', (78, 80))
375838	30519325	CCK8 assay revealed that cell growth was significantly decreased in esophageal cancer cell lines after Knockdown compared with the NC group (Figure 4A, P < 0.05).	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Knockdown', 'Var', (103, 112))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('decreased', 'NegReg', (55, 64))	('esophageal cancer', 'Disease', (68, 85))	('cell growth', 'CPA', (25, 36))
375840	30519325	The colony formation ability in CEC2 was also decreased by silencing the LINC01234 (Figure 4B, P < 0.05).	('colony formation ability', 'CPA', (4, 28))	('LINC01234', 'Gene', '100506465', (73, 82))	('decreased', 'NegReg', (46, 55))	('LINC01234', 'Gene', (73, 82))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('silencing', 'Var', (59, 68))	('CEC2', 'CellLine', 'CVCL:D160', (32, 36))
375858	30519325	This shows that the silencing of lncRNA may inhibit esophageal cancer migration, invasion, and proliferation ability in vitro.	('proliferation ability', 'CPA', (95, 116))	('inhibit', 'NegReg', (44, 51))	('invasion', 'CPA', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('lncRNA', 'Protein', (33, 39))	('silencing', 'Var', (20, 29))
375895	15822499	Duplications of the alimentary tract are rare congenital malformations.	('Duplications', 'Var', (0, 12))	('congenital malformations', 'Disease', (46, 70))	('congenital malformations', 'Disease', 'MESH:D000013', (46, 70))
375924	28894820	Patients receiving jejunal insertions had a significantly shorter hospitalization duration than did those receiving esophageal insertions.	('shorter', 'NegReg', (58, 65))	('jejunal insertion', 'Phenotype', 'HP:0004786', (19, 36))	('jejunal insertions', 'Var', (19, 37))	('Patients', 'Species', '9606', (0, 8))	('hospitalization duration', 'MPA', (66, 90))
375957	28894820	However, in the esophageal insertion cohort, irradiated patients had significantly higher complication and local infection rates than did non-irradiated patients (both p values < 0.05).	('local infection', 'CPA', (107, 122))	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (153, 161))	('irradiated', 'Var', (45, 55))	('complication', 'CPA', (90, 102))	('esophageal', 'Disease', (16, 26))	('higher', 'PosReg', (83, 89))
375961	28894820	However, subgroup analysis revealed that the duration of speechlessness was significantly longer in patients who underwent postoperative irradiation than in those who underwent preoperative irradiation (18.8 vs. 12.6 months).	('speechlessness', 'Disease', (57, 71))	('patients', 'Species', '9606', (100, 108))	('postoperative irradiation', 'Var', (123, 148))
375978	28894820	However, the important observation is that patients with jejunal insertion had significantly lower complication rates (leakage, stenosis, spontaneous extrusion, but mostly local infections) than patients with esophageal insertion.	('jejunal insertion', 'Var', (57, 74))	('patients', 'Species', '9606', (43, 51))	('leakage', 'Disease', (119, 126))	('jejunal insertion', 'Phenotype', 'HP:0004786', (57, 74))	('spontaneous extrusion', 'CPA', (138, 159))	('lower', 'NegReg', (93, 98))	('patients', 'Species', '9606', (195, 203))	('complication', 'CPA', (99, 111))	('stenosis', 'Disease', (128, 136))
375980	28894820	Hospitalization time was also more unfavorable (longer) for irradiated and for esophageal insertion patients.	('irradiated', 'Var', (60, 70))	('esophageal insertion', 'Disease', (79, 99))	('patients', 'Species', '9606', (100, 108))
376005	28670613	previously described that LSI led not only to delayed epithelialization and extended inflammation in the artificial ulcer but also to fibrotic changes and transmural destruction of the muscularis propria, using a canine model  .	('fibrotic changes', 'CPA', (134, 150))	('muscularis propria', 'Phenotype', 'HP:0030936', (185, 203))	('LSI', 'Var', (26, 29))	('canine', 'Species', '9615', (213, 219))	('transmural destruction', 'CPA', (155, 177))	('inflammation', 'Disease', 'MESH:D007249', (85, 97))	('inflammation', 'Disease', (85, 97))
376012	27911865	In addition, the HIF-1alpha expression and ROS production were also activated upon UK5099 application.	('HIF-1alpha', 'Gene', (17, 27))	('UK5099', 'Var', (83, 89))	('UK5099', 'Chemical', 'MESH:C043654', (83, 89))	('ROS', 'CPA', (43, 46))	('activated', 'PosReg', (68, 77))	('HIF-1alpha', 'Gene', '3091', (17, 27))	('ROS', 'Chemical', '-', (43, 46))
376013	27911865	It was further revealed that the UK5099-treated cells became significantly more resistant to chemotherapy and radiotherapy, and the UK5099-treated tumor cells also exhibited stronger invasive capacity compared to the parental cells.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('resistant to', 'CPA', (80, 92))	('stronger', 'PosReg', (174, 182))	('UK5099', 'Chemical', 'MESH:C043654', (132, 138))	('UK5099', 'Chemical', 'MESH:C043654', (33, 39))	('more', 'PosReg', (75, 79))	('invasive capacity', 'CPA', (183, 200))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('UK5099-treated', 'Var', (132, 146))	('UK5099-treated', 'Var', (33, 47))
376015	27911865	All these results together revealed the potential connection of altered MPC expression/activity with the Warburg metabolic reprogramming and tumor aggressiveness in cell lines and clinical samples.	('MPC', 'MPA', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('Warburg metabolic reprogramming', 'CPA', (105, 136))	('clinical samples', 'Species', '191496', (180, 196))	('tumor aggressiveness', 'Disease', (141, 161))	('aggressiveness', 'Phenotype', 'HP:0000718', (147, 161))	('altered', 'Var', (64, 71))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (141, 161))
376031	27911865	In addition, it has been verified that UK5099 and alpha-cyano-4-hydroxycinnamic acid are specific chemical inhibitors of MPC.	('UK5099', 'Var', (39, 45))	('alpha-cyano-4-hydroxycinnamic acid', 'Chemical', 'MESH:C007175', (50, 84))	('MPC', 'Disease', (121, 124))	('UK5099', 'Chemical', 'MESH:C043654', (39, 45))
376032	27911865	In our present study, we used the specific MPC inhibitor UK5099 to treat a panel of esophageal squamous carcinomas cell lines EC109, KYSE140 and KYSE450 and found that pharmaceutical inhibition of MPC activity dramatically suppressed OXPHOS, induced the Warburg effect and the aggressive cancer phenotype in esophageal squamous cancer cells.	('suppressed', 'NegReg', (223, 233))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (308, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('OXPHOS', 'MPA', (234, 240))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('esophageal squamous carcinomas', 'Disease', (84, 114))	('Warburg effect', 'CPA', (254, 268))	('inhibition', 'Var', (183, 193))	('esophageal squamous carcinomas', 'Disease', 'MESH:D000077277', (84, 114))	('aggressive cancer', 'Disease', 'MESH:D009369', (277, 294))	('induced', 'PosReg', (242, 249))	('UK5099', 'Chemical', 'MESH:C043654', (57, 63))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (95, 113))	('esophageal squamous cancer', 'Disease', (308, 334))	('squamous cancer', 'Phenotype', 'HP:0002860', (319, 334))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (84, 113))	('aggressive cancer', 'Disease', (277, 294))
376035	27911865	To select cancer cell lines expressing MPC1 and MPC2, immunocytochemiscal assay was used to screen the expression status in EC109, KYSE140 and KYSE450 cancer cells.	('MPC1', 'Var', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('MPC2', 'Var', (48, 52))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
376037	27911865	It was discovered that application of 40 muM UK5099 significantly reduced the pyruvate concentration in mitochondria and induced lactic secretion in media but had no obvious effect on the cell viability in the EC109, KYSE140 and KYSE450 cells, the pyruvate concentration in mitochondria of the three cell lines was shown in Figure 1C.	('reduced', 'NegReg', (66, 73))	('pyruvate', 'Chemical', 'MESH:D019289', (78, 86))	('muM', 'Gene', '56925', (41, 44))	('muM', 'Gene', (41, 44))	('pyruvate', 'Chemical', 'MESH:D019289', (248, 256))	('pyruvate concentration in mitochondria', 'MPA', (78, 116))	('UK5099', 'Var', (45, 51))	('lactic secretion in media', 'MPA', (129, 154))	('UK5099', 'Chemical', 'MESH:C043654', (45, 51))	('induced', 'Reg', (121, 128))
376039	27911865	Compared to the control cells, the EC109, KYSE140 and KYSE450 cancer cells treated with UK5099 exhibited significantly increased glucose consumption, both at the time points of 24 hours and 48 hours (Figure 2A, p < 0.001 for all three cell lines) culture.	('UK5099', 'Var', (88, 94))	('increased', 'PosReg', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('UK5099', 'Chemical', 'MESH:C043654', (88, 94))	('glucose', 'Chemical', 'MESH:D005947', (129, 136))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('increased glucose', 'Phenotype', 'HP:0003074', (119, 136))	('glucose consumption', 'MPA', (129, 148))
376040	27911865	Then L-lactatic acid assay revealed that extracellular lactic acid concentration increased significantly in the UK5099 treated EC109, KYSE140 and KYSE450 cells (Figure 2B, p = 0.007, 0.001 and 0.000, respectively), compared to the control cells.	('lactic acid concentration increased', 'Phenotype', 'HP:0003128', (55, 90))	('UK5099', 'Var', (112, 118))	('KYSE450', 'Var', (146, 153))	('UK5099', 'Chemical', 'MESH:C043654', (112, 118))	('lactic acid', 'Chemical', 'MESH:D019344', (55, 66))	('extracellular lactic acid concentration', 'MPA', (41, 80))	('increased', 'PosReg', (81, 90))	('L-lactatic acid', 'Chemical', '-', (5, 20))
376041	27911865	However, the quantity of the intracellular lactic acid was almost not influenced in all these three cell lines (Figure 2B, p = 0.121, 0.081 and 0.878, respectively), indicating significantly higher levels of lactic acid efflux in the cells treated with UK5099.	('higher', 'PosReg', (191, 197))	('lactic acid', 'Chemical', 'MESH:D019344', (208, 219))	('lactic acid', 'Chemical', 'MESH:D019344', (43, 54))	('levels', 'MPA', (198, 204))	('UK5099', 'Var', (253, 259))	('UK5099', 'Chemical', 'MESH:C043654', (253, 259))	('lactic acid efflux', 'MPA', (208, 226))
376042	27911865	At the meantime, the ATP production in the UK5099 treated EC109, KYSE140 and KYSE450 cells was discovered significantly lower (Figure 2C, p = 0.000, 0.013 and0.002, respectively).	('ATP production', 'MPA', (21, 35))	('lower', 'NegReg', (120, 125))	('UK5099', 'Var', (43, 49))	('ATP', 'Chemical', 'MESH:D000255', (21, 24))	('UK5099', 'Chemical', 'MESH:C043654', (43, 49))
376043	27911865	Afterward, to explore whether UK5099 treatment could drive glycolysis through upregulating the key glycolytic enzymes expression of the glycolysis pathway, glucose transporter 1 (GLUT1), hexokinase II (HK2) and lactate dehydrogenase A (LDHA) expressions were determined by Western blotting.	('GLUT1', 'Gene', (179, 184))	('LDHA', 'Gene', (236, 240))	('glucose transporter 1', 'Gene', '6513', (156, 177))	('UK5099', 'Var', (30, 36))	('lactate dehydrogenase A', 'Gene', (211, 234))	('lactate dehydrogenase A', 'Gene', '3939', (211, 234))	('HK2', 'Gene', (202, 205))	('UK5099', 'Chemical', 'MESH:C043654', (30, 36))	('glycolysis pathway', 'Pathway', (136, 154))	('expression', 'MPA', (118, 128))	('glucose transporter 1', 'Gene', (156, 177))	('glycolysis', 'MPA', (59, 69))	('drive', 'PosReg', (53, 58))	('upregulating', 'PosReg', (78, 90))
376044	27911865	As shown in Figure 2D, UK5099 application resulted in apparently higher levels GLUT1, HK2 and LDHA protein expressions in the treated tumor cells compared to the control cells.	('HK2', 'Protein', (86, 89))	('UK5099', 'Var', (23, 29))	('LDHA protein', 'Protein', (94, 106))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('UK5099', 'Chemical', 'MESH:C043654', (23, 29))	('GLUT1', 'Protein', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('higher', 'PosReg', (65, 71))	('tumor', 'Disease', (134, 139))
376049	27911865	Following 1muM oligomycin application, the UK5099 treated cells showed lower ATP-linked O2 consumption and higher proton leakage (Figure 3).	('UK5099', 'Var', (43, 49))	('proton leakage', 'MPA', (114, 128))	('muM', 'Gene', (11, 14))	('UK5099', 'Chemical', 'MESH:C043654', (43, 49))	('ATP-linked O2 consumption', 'MPA', (77, 102))	('O2', 'Chemical', 'MESH:D010100', (88, 90))	('muM', 'Gene', '56925', (11, 14))	('higher', 'PosReg', (107, 113))	('ATP', 'Chemical', 'MESH:D000255', (77, 80))	('oligomycin', 'Chemical', 'MESH:D009840', (15, 25))	('lower', 'NegReg', (71, 76))
376050	27911865	Although the maximum ECAR of the two groups was almost the same, the glycolytic reserved capacity of the UK5099 treated cells was significantly lower (Figure 3).	('UK5099 treated', 'Var', (105, 119))	('lower', 'NegReg', (144, 149))	('mum', 'Gene', '56925', (17, 20))	('UK5099', 'Chemical', 'MESH:C043654', (105, 111))	('glycolytic reserved capacity', 'MPA', (69, 97))	('mum', 'Gene', (17, 20))	('ECAR', 'MPA', (21, 25))
376052	27911865	This implied that the UK5099 treated cells were operating lower basic OCR capacity and lower reserved OCR capacity (Figure 3), suggesting defective mitochondrial OXPHOS function and increased glycolytic efflux in the UK5099-treated esophageal squamous cancer cells.	('increased', 'PosReg', (182, 191))	('glycolytic efflux', 'MPA', (192, 209))	('lower', 'NegReg', (58, 63))	('lower', 'NegReg', (87, 92))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (232, 258))	('esophageal squamous cancer', 'Disease', (232, 258))	('UK5099-treated', 'Var', (217, 231))	('UK5099', 'Chemical', 'MESH:C043654', (22, 28))	('mitochondrial OXPHOS function', 'MPA', (148, 177))	('squamous cancer', 'Phenotype', 'HP:0002860', (243, 258))	('defective', 'NegReg', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('basic OCR capacity', 'MPA', (64, 82))	('reserved OCR capacity', 'MPA', (93, 114))	('UK5099', 'Chemical', 'MESH:C043654', (217, 223))
376053	27911865	To investigate whether mitochondria function was influenced when imported pyruvate into mitochondria was inhibited by UK5099, the ROS production in esophageal squamous cancer cells was detected.	('pyruvate', 'Chemical', 'MESH:D019289', (74, 82))	('ROS', 'Chemical', '-', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('UK5099', 'Var', (118, 124))	('esophageal squamous cancer', 'Disease', (148, 174))	('UK5099', 'Chemical', 'MESH:C043654', (118, 124))	('mitochondria', 'MPA', (23, 35))	('inhibited', 'NegReg', (105, 114))	('squamous cancer', 'Phenotype', 'HP:0002860', (159, 174))	('imported pyruvate into mitochondria', 'MPA', (65, 100))	('influenced', 'Reg', (49, 59))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (148, 174))
376054	27911865	As shown in Figure 4, applications of 40 muM UK5099 in EC109, KYSE140 and KYSE450 cells significantly increased the production of ROS (p = 0.017,0.039 and 0.026,respectively), indicating potential possibility that ROS production from the perturbed mitochondrial electron transport chain or decreased antioxidant activity.	('decreased', 'NegReg', (290, 299))	('ROS', 'Chemical', '-', (130, 133))	('production', 'MPA', (116, 126))	('muM', 'Gene', '56925', (41, 44))	('perturbed', 'Reg', (238, 247))	('muM', 'Gene', (41, 44))	('ROS', 'MPA', (130, 133))	('UK5099', 'Chemical', 'MESH:C043654', (45, 51))	('UK5099', 'Var', (45, 51))	('increased', 'PosReg', (102, 111))	('ROS', 'Chemical', '-', (214, 217))
376055	27911865	As shown in Figure 5A, without x-ray irradiation, more UK5099 treated EC109 and KYSE140 cells (p = 0.027 and p = 0.044, respectively)survived the assay, compared to the control cells.	('UK5099', 'Var', (55, 61))	('UK5099', 'Chemical', 'MESH:C043654', (55, 61))	('survived the assay', 'CPA', (133, 151))
376060	27911865	However, UK5099 treated cells always displayed significantly increased cell viability compared to the control cells upon docetaxel application.	('UK5099', 'Var', (9, 15))	('UK5099', 'Chemical', 'MESH:C043654', (9, 15))	('docetaxel', 'Chemical', 'MESH:D000077143', (121, 130))	('increased', 'PosReg', (61, 70))	('cell viability', 'CPA', (71, 85))
376061	27911865	Upon application of 20nM docetaxel, the cell viability was 87.00%, 83.00% and 84.33% for the EC109, KYSE140 and KYSE 450 cells treated with UK5099, while the 71.67% (p = 0.002), 70% (p = 0.019) and 66.33% (p = 0.008) in the control cells, respectively.	('UK5099', 'Var', (140, 146))	('cell viability', 'CPA', (40, 54))	('docetaxel', 'Chemical', 'MESH:D000077143', (25, 34))	('UK5099', 'Chemical', 'MESH:C043654', (140, 146))
376062	27911865	For the cells treated with 40nM docetaxel, the cell viability was 72.33%, 75.33% and 81.00% for the EC109, KYSE140 and KYSE 450 cells treated with UK5099, while the 57.67% (p = 0.011), 61.33% (p = 0.021) and 57.67% (p = 0.01) in the control cells, respectively.	('docetaxel', 'Chemical', 'MESH:D000077143', (32, 41))	('UK5099', 'Chemical', 'MESH:C043654', (147, 153))	('UK5099', 'Var', (147, 153))	('cell viability', 'CPA', (47, 61))
376063	27911865	It was verified in this study that inhibition of MPC by UK5099 in EC109 cells led to a 157% migration increase compared to the control cells (Figure 6, p = 0.001).	('UK5099', 'Chemical', 'MESH:C043654', (56, 62))	('UK5099', 'Var', (56, 62))	('migration', 'CPA', (92, 101))	('increase', 'PosReg', (102, 110))	('inhibition', 'NegReg', (35, 45))
376064	27911865	For the KYSE140 cell line, the UK5099 treatment led to an 86% migration increase compared to the control cells (Figure 5, p = 0.006).	('migration', 'CPA', (62, 71))	('increase', 'PosReg', (72, 80))	('UK5099', 'Chemical', 'MESH:C043654', (31, 37))	('UK5099 treatment', 'Var', (31, 47))
376065	27911865	For theKYSE450 cell line, the UK5099 treatment led to a 118% migration compared to the control cells (Figure 6, p = 0.002).	('migration', 'CPA', (61, 70))	('UK5099 treatment', 'Var', (30, 46))	('UK5099', 'Chemical', 'MESH:C043654', (30, 36))
376066	27911865	All these results indicated a strong migration induction upon the MPC blocking by UK5099 in esophageal squamous cancer cells in vitro.	('squamous cancer', 'Phenotype', 'HP:0002860', (103, 118))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (92, 118))	('MPC', 'Protein', (66, 69))	('UK5099', 'Var', (82, 88))	('esophageal squamous cancer', 'Disease', (92, 118))	('UK5099', 'Chemical', 'MESH:C043654', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('migration induction', 'CPA', (37, 56))
376083	27911865	All these results verified that the UK5099 treated cancer cells exhibited decreased mitochondrial OXPHOS and enhanced aerobic glycolysis activity.	('UK5099', 'Var', (36, 42))	('aerobic glycolysis activity', 'MPA', (118, 145))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mitochondrial OXPHOS', 'MPA', (84, 104))	('UK5099', 'Chemical', 'MESH:C043654', (36, 42))	('decreased', 'NegReg', (74, 83))	('enhanced', 'PosReg', (109, 117))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
376091	27911865	Recently, the aberrant expression and activity of enzymes regulating aerobic glycolysis pathway showed crucial roles in tumor progression.	('activity', 'MPA', (38, 46))	('aberrant', 'Var', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('roles', 'Reg', (111, 116))	('tumor', 'Disease', (120, 125))	('expression', 'MPA', (23, 33))
376092	27911865	There were mounting evidence demonstrating that deregulation of lactate dehydrogenase A (LDHA), which executed the final step of glycolysis by converting the pyruvate to lactate, has been found in many tumors, including prostate cancer, ovarian cancer, breast cancer, osteosarcoma and colorectal cancer, and the upregulated LDHA could facilitate Warburg effect and the progression of tumors.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('tumors', 'Disease', 'MESH:D009369', (384, 390))	('ovarian cancer', 'Phenotype', 'HP:0100615', (237, 251))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('colorectal cancer', 'Phenotype', 'HP:0003003', (285, 302))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('deregulation', 'Var', (48, 60))	('osteosarcoma', 'Disease', (268, 280))	('osteosarcoma', 'Disease', 'MESH:D012516', (268, 280))	('lactate', 'Chemical', 'MESH:D019344', (64, 71))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('breast cancer', 'Disease', (253, 266))	('LDHA', 'Enzyme', (324, 328))	('found', 'Reg', (188, 193))	('lactate dehydrogenase A', 'Gene', '3939', (64, 87))	('facilitate', 'PosReg', (335, 345))	('tumors', 'Phenotype', 'HP:0002664', (384, 390))	('colorectal cancer', 'Disease', 'MESH:D015179', (285, 302))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('upregulated', 'PosReg', (312, 323))	('osteosarcoma', 'Phenotype', 'HP:0002669', (268, 280))	('ovarian cancer', 'Disease', 'MESH:D010051', (237, 251))	('colorectal cancer', 'Disease', (285, 302))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('lactate dehydrogenase A', 'Gene', (64, 87))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (384, 389))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumors', 'Disease', (384, 390))	('lactate', 'Chemical', 'MESH:D019344', (170, 177))	('prostate cancer', 'Disease', 'MESH:D011471', (220, 235))	('prostate cancer', 'Phenotype', 'HP:0012125', (220, 235))	('pyruvate', 'Chemical', 'MESH:D019289', (158, 166))	('tumors', 'Disease', (202, 208))	('Warburg effect', 'CPA', (346, 360))	('ovarian cancer', 'Disease', (237, 251))	('prostate cancer', 'Disease', (220, 235))
376104	27911865	In conclusion, we have shown that the inhibition of MPC by UK5099 enforces the esophageal squamous cancer cells to switch toward aerobic glycolysis, typical Warburg reprogramming, and endorses the cells with significantly higher survival capability against chemotherapy and radiotherapy, in addition to invasion and metastasis advantages.	('survival capability', 'CPA', (229, 248))	('UK5099', 'Chemical', 'MESH:C043654', (59, 65))	('higher', 'PosReg', (222, 228))	('switch', 'MPA', (115, 121))	('squamous cancer', 'Phenotype', 'HP:0002860', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('aerobic glycolysis', 'MPA', (129, 147))	('inhibition', 'NegReg', (38, 48))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (79, 105))	('esophageal squamous cancer', 'Disease', (79, 105))	('UK5099', 'Var', (59, 65))
376108	27911865	UK5099(PZ0160, Sigma-Aldrich, St. Louis, MO,USA), was optimized to a final concentration of 40 muM to reduce pyruvate transportation into mitochondrial based on a series of UK5099 dose tested in a range of 10 muM to 100 muM as previously published.	('muM', 'Gene', (209, 212))	('muM', 'Gene', '56925', (209, 212))	('reduce', 'NegReg', (102, 108))	('muM', 'Gene', (220, 223))	('UK5099', 'Chemical', 'MESH:C043654', (173, 179))	('muM', 'Gene', '56925', (95, 98))	('muM', 'Gene', (95, 98))	('pyruvate', 'Chemical', 'MESH:D019289', (109, 117))	('pyruvate transportation into mitochondrial', 'MPA', (109, 151))	('UK5099', 'Chemical', 'MESH:C043654', (0, 6))	('PZ0160', 'Var', (7, 13))	('muM', 'Gene', '56925', (220, 223))
376112	27911865	Cell lysates were centrifuged at 13000 g for 10 minutes at 4 C before aliquots of 20 mug proteins were resolved on SDS-PAGE, transferred onto polyvinylidenedifluoride transfer membrane(PVDF), and blotted for targeting antibodies:MPC1(HPA045119, Sigma-Aldrich, St. Louis, MO,USA, dilution 1:1000), MPC2(ab111380, abcam, Cambridge, UK, dilution 1:1000), GLUT1(Rabbit mAb#12939, cell signaling technology, Leiden, Netherlands, dilution 1:1000), HK2 (ab104836, abcam, Cambridge, UK, dilution 1:1000), LDHA (ab47010, abcam, Cambridge, UK, dilution 1:1000) and alpha-Tubulin antibody(T9026, Sigma-Aldrich, St. Louis, MO, USA dilution 1:3000).	('Rabbit', 'Species', '9986', (358, 364))	('ab104836', 'Var', (447, 455))	('T9026', 'Var', (578, 583))	('alpha-Tubulin', 'Gene', '100009327', (555, 568))	('alpha-Tubulin', 'Gene', (555, 568))
376236	23717443	HOTAIR is a potential biomarker for ESCC prognosis, and the dysregulation of HOTAIR may play an important role in ESCC progression.	('HOTAIR', 'Gene', '100124700', (0, 6))	('ESCC', 'Disease', (114, 118))	('dysregulation', 'Var', (60, 73))	('HOTAIR', 'Gene', (77, 83))	('HOTAIR', 'Gene', '100124700', (77, 83))	('HOTAIR', 'Gene', (0, 6))	('ESCC', 'Disease', (36, 40))
376240	23717443	Previous reports have shown that genetic changes frequently associated with the development of esophageal cancer include the p53 mutation, p16 inactivation, cyclin D1 amplification and c-Myc, GOLPH3 or EGFR overexpression.	('EGFR', 'Gene', (202, 206))	('c-Myc', 'Gene', (185, 190))	('c-Myc', 'Gene', '4609', (185, 190))	('p16', 'Gene', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('mutation', 'Var', (129, 137))	('p16', 'Gene', '1029', (139, 142))	('cyclin D1', 'Gene', (157, 166))	('EGFR', 'Gene', '1956', (202, 206))	('p53', 'Gene', '7157', (125, 128))	('cyclin D1', 'Gene', '595', (157, 166))	('amplification', 'PosReg', (167, 180))	('associated', 'Reg', (60, 70))	('inactivation', 'Var', (143, 155))	('GOLPH3', 'Gene', (192, 198))	('overexpression', 'PosReg', (207, 221))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('p53', 'Gene', (125, 128))	('GOLPH3', 'Gene', '64083', (192, 198))	('esophageal cancer', 'Disease', (95, 112))
376245	23717443	Using a series of HOTAIR deletion mutants, Tsai and colleagues identified that HOTAIR serves as a scaffold tether two distinct complexes PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation.	('HOTAIR', 'Gene', (79, 85))	('HOTAIR', 'Gene', (18, 24))	('LSD1', 'Gene', (189, 193))	('mutants', 'Var', (34, 41))	('LSD1', 'Gene', (146, 150))	('LSD1', 'Gene', '23028', (189, 193))	('HOTAIR', 'Gene', '100124700', (79, 85))	('LSD1', 'Gene', '23028', (146, 150))	('HOTAIR', 'Gene', '100124700', (18, 24))	('PRC2', 'Gene', (180, 184))	('deletion mutants', 'Var', (25, 41))	('histone', 'Protein', (219, 226))	('lysine', 'Chemical', 'MESH:D008239', (256, 262))	('PRC2', 'Gene', (137, 141))	('lysine', 'Chemical', 'MESH:D008239', (230, 236))	('lysine 4 demethylation', 'MPA', (256, 278))
376257	23717443	The following primer sequences were used to amplify HOTAIR: forward, GGTAGAAAAAGCAACCACGAAGC and reverse, ACATAAACCTCTGTCTGTGAGTGCC.	('ACATAAACCTCTGTCTGTGAGTGCC', 'Var', (106, 131))	('HOTAIR', 'Gene', (52, 58))	('HOTAIR', 'Gene', '100124700', (52, 58))
376297	23717443	HOTAIR silencing reduced the number of migrating TE-1 cells by approximately 50% compared with the negative control (Figure 5).	('HOTAIR', 'Gene', '100124700', (0, 6))	('TE-1', 'CellLine', 'CVCL:1759', (49, 53))	('HOTAIR', 'Gene', (0, 6))	('silencing', 'Var', (7, 16))	('reduced', 'NegReg', (17, 24))
376303	23717443	HOTAIR has been reported to associate with PRC2 and to epigenetically regulate multiple target genes.	('HOTAIR', 'Gene', '100124700', (0, 6))	('associate', 'Interaction', (28, 37))	('HOTAIR', 'Gene', (0, 6))	('epigenetically', 'Var', (55, 69))	('PRC2', 'Gene', (43, 47))
376313	23717443	The knockdown of HOTAIR suppresses the invasiveness of gastrointestinal stromal tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('HOTAIR', 'Gene', (17, 23))	('suppresses', 'NegReg', (24, 34))	('invasiveness of gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (39, 85))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (55, 85))	('invasiveness of gastrointestinal stromal tumor', 'Disease', (39, 85))	('knockdown', 'Var', (4, 13))	('HOTAIR', 'Gene', '100124700', (17, 23))
376314	23717443	Similarly, our data demonstrated that the silencing of HOTAIR suppressed the proliferation, migration and invasion of ESCC TE-1 cells.	('silencing', 'Var', (42, 51))	('TE-1', 'CellLine', 'CVCL:1759', (123, 127))	('HOTAIR', 'Gene', (55, 61))	('HOTAIR', 'Gene', '100124700', (55, 61))	('suppressed', 'NegReg', (62, 72))	('migration', 'CPA', (92, 101))	('invasion of ESCC TE-1 cells', 'CPA', (106, 133))	('proliferation', 'CPA', (77, 90))
376423	20516120	Genetic modulation of periostin promotes tumor cell migration and invasion as revealed in gain of and loss of function experiments.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('periostin', 'Gene', (22, 31))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Genetic modulation', 'Var', (0, 18))	('promotes', 'PosReg', (32, 40))	('invasion', 'CPA', (66, 74))
376424	20516120	Inhibition of EGFR signaling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting interdependence of two common genetic alterations with periostin function.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('Inhibition', 'NegReg', (0, 10))	('periostin', 'MPA', (100, 109))	('attenuate', 'NegReg', (90, 99))	('restoration', 'Var', (33, 44))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
376427	20516120	Several genetic alterations, such as amplification of the epidermal growth factor receptor (EGFR), dysregulation of cyclin D1 and somatic mutations in the DNA binding domain of the tumor suppressor p53, are involved in initiation and progression of ESCC.	('initiation', 'Disease', (219, 229))	('amplification', 'Var', (37, 50))	('initiation', 'Disease', 'MESH:D007319', (219, 229))	('dysregulation', 'MPA', (99, 112))	('involved', 'Reg', (207, 215))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('ESCC', 'Disease', (249, 253))	('p53', 'Gene', '7157', (198, 201))	('EGFR', 'Gene', '1956', (92, 96))	('mutations in', 'Var', (138, 150))	('epidermal growth factor receptor', 'Gene', (58, 90))	('binding', 'Interaction', (159, 166))	('epidermal growth factor receptor', 'Gene', '1956', (58, 90))	('p53', 'Gene', (198, 201))	('cyclin D1', 'Gene', (116, 125))	('tumor', 'Disease', (181, 186))	('cyclin D1', 'Gene', '595', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('EGFR', 'Gene', (92, 96))
376429	20516120	Previously, we had addressed this by modeling EGFR overexpression and p53 missense mutation (R175H) in primary human esophageal epithelial cells (EPC2), which have been immortalized by hTERT overexpression (designated as EPC2-hTERT-EGFR-p53R175H cells).	('EPC2', 'Gene', (146, 150))	('R175H', 'Mutation', 'rs28934578', (93, 98))	('hTERT', 'Gene', (185, 190))	('EGFR', 'Gene', '1956', (46, 50))	('missense mutation', 'Var', (74, 91))	('p53', 'Gene', '7157', (237, 240))	('human', 'Species', '9606', (111, 116))	('hTERT', 'Gene', '7015', (226, 231))	('p53', 'Gene', (237, 240))	('EGFR', 'Gene', (232, 236))	('R175H', 'Mutation', 'rs28934578', (240, 245))	('EPC2', 'Gene', '26122', (146, 150))	('p53', 'Gene', '7157', (70, 73))	('EPC2', 'Gene', (221, 225))	('EGFR', 'Gene', (46, 50))	('hTERT', 'Gene', '7015', (185, 190))	('hTERT', 'Gene', (226, 231))	('p53', 'Gene', (70, 73))	('EGFR', 'Gene', '1956', (232, 236))	('EPC2', 'Gene', '26122', (221, 225))
376431	20516120	Combined expression of these genes also resulted in anchorage-independent growth and in tumor formation in xenograft models, which was not observed in control cells overexpressing either EGFR or mutant p53 alone.	('resulted in', 'Reg', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('EGFR', 'Gene', '1956', (187, 191))	('EGFR', 'Gene', (187, 191))	('p53', 'Gene', '7157', (202, 205))	('anchorage-independent growth', 'CPA', (52, 80))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('mutant', 'Var', (195, 201))	('p53', 'Gene', (202, 205))
376432	20516120	Recent experimental results have provided mounting evidence that altered expression of cell adhesion molecules can contribute directly to tumor progression by modulating cell signaling.	('tumor', 'Disease', (138, 143))	('altered', 'Var', (65, 72))	('modulating', 'Reg', (159, 169))	('cell adhesion molecules', 'Protein', (87, 110))	('expression', 'MPA', (73, 83))	('cell signaling', 'MPA', (170, 184))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('contribute', 'Reg', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
376438	20516120	Indeed, not only is its expression induced in human ESCC and mouse tumor xenografts, but more importantly, genetic modulation of periostin also affects tumor invasion in a direct fashion.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('genetic modulation', 'Var', (107, 125))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('human', 'Species', '9606', (46, 51))	('mouse', 'Species', '10090', (61, 66))	('affects', 'Reg', (144, 151))	('tumor', 'Disease', (67, 72))
376446	20516120	Supernatants of the retroviruses encoding EGFR, mutant p53, periostin over-expression and shRNA vector constructs were collected 48 hrs.	('EGFR', 'Gene', '1956', (42, 46))	('mutant', 'Var', (48, 54))	('p53', 'Gene', '7157', (55, 58))	('p53', 'Gene', (55, 58))	('over-expression', 'PosReg', (70, 85))	('EGFR', 'Gene', (42, 46))
376449	20516120	Overexpression of EGFR, mutant p53 and periostin, as well as periostin knock-down was confirmed by Western blot analysis.	('mutant', 'Var', (24, 30))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))
376463	20516120	The first variable indicated cells with both EGFR overexpression and P53 mutation only and the second indicated cells with EGFR overexpression, P53 mutation and invasion.	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', '1956', (123, 127))	('EGFR', 'Gene', (45, 49))	('P53', 'Gene', (144, 147))	('P53', 'Gene', '7157', (144, 147))	('P53', 'Gene', (69, 72))	('mutation', 'Var', (73, 81))	('P53', 'Gene', '7157', (69, 72))	('EGFR', 'Gene', '1956', (45, 49))
376464	20516120	The third group (the reference group) included cells with a non-invading phenotype that had either EGFR overexpression or P53 mutation.	('EGFR', 'Gene', (99, 103))	('P53', 'Gene', (122, 125))	('mutation', 'Var', (126, 134))	('P53', 'Gene', '7157', (122, 125))	('EGFR', 'Gene', '1956', (99, 103))	('overexpression', 'PosReg', (104, 118))
376466	20516120	In order to characterize a gene expression profile underlying the invasive phenotype of invading EPC2-hTERT-EGFR-p53R175H cells, we profiled mRNA obtained from laser capture microdissected EPC-hTERT cells overexpressing EGFR and with a p53 missense mutation (R175H) that was either invasive or non-invasive in the organotypic culture model, as well as non-invasive cells that either overexpressed EGFR alone or had p53 (R175H) mutation alone, using Affymetrix U133-2 plus microarrays.	('p53', 'Gene', '7157', (415, 418))	('EPC-hTERT', 'CellLine', 'CVCL:4361', (189, 198))	('R175H', 'Mutation', 'rs28934578', (259, 264))	('R175H', 'Mutation', 'rs28934578', (116, 121))	('EGFR', 'Gene', '1956', (397, 401))	('hTERT', 'Gene', '7015', (102, 107))	('p53', 'Gene', (113, 116))	('hTERT', 'Gene', (193, 198))	('EGFR', 'Gene', '1956', (220, 224))	('p53', 'Gene', (415, 418))	('EPC2', 'Gene', (97, 101))	('missense mutation', 'Var', (240, 257))	('EGFR', 'Gene', '1956', (108, 112))	('p53', 'Gene', '7157', (236, 239))	('hTERT', 'Gene', (102, 107))	('p53', 'Gene', (236, 239))	('EGFR', 'Gene', (397, 401))	('EPC2', 'Gene', '26122', (97, 101))	('EGFR', 'Gene', (220, 224))	('R175H', 'Mutation', 'rs28934578', (420, 425))	('EGFR', 'Gene', (108, 112))	('hTERT', 'Gene', '7015', (193, 198))	('p53', 'Gene', '7157', (113, 116))
376485	20516120	An RNA interference approach with shRNA was used to induce stable knockdown of periostin expression in EPC2-hTERT-EGFR-p53R175H cells (Figure 3A).	('EPC2', 'Gene', (103, 107))	('hTERT', 'Gene', '7015', (108, 113))	('EGFR', 'Gene', '1956', (114, 118))	('hTERT', 'Gene', (108, 113))	('periostin', 'Gene', (79, 88))	('EGFR', 'Gene', (114, 118))	('knockdown', 'Var', (66, 75))	('EPC2', 'Gene', '26122', (103, 107))
376497	20516120	Given that periostin was identified initially in invading EPC-hTERT-EGFR-p53R175H cells through functional genomics and bioinformatic analysis, we hypothesized that periostin expression is dependent upon both activated EGFR signaling and p53 mutation.	('EGFR', 'Gene', '1956', (219, 223))	('p53', 'Gene', (73, 76))	('p53', 'Gene', (238, 241))	('EGFR', 'Gene', (219, 223))	('p53', 'Gene', '7157', (73, 76))	('p53', 'Gene', '7157', (238, 241))	('EPC-hTERT', 'CellLine', 'CVCL:4361', (58, 67))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', (68, 72))	('mutation', 'Var', (242, 250))
376503	20516120	Periostin protein expression was noted to be decreased when inhibited by AG1478 or 5-iminodaunorubicin or both (Figure 6B).	('Periostin', 'Gene', '10631', (0, 9))	('5-iminodaunorubicin', 'Chemical', 'MESH:C018979', (83, 102))	('AG1478', 'Var', (73, 79))	('decreased', 'NegReg', (45, 54))	('inhibited', 'NegReg', (60, 69))	('AG1478', 'Chemical', 'MESH:C101044', (73, 79))	('Periostin', 'Gene', (0, 9))
376504	20516120	Taken together, these data support the notion that periostin expression is modulated mechanistically by activated EGFR signaling and p53 mutation.	('mutation', 'Var', (137, 145))	('p53', 'Gene', '7157', (133, 136))	('EGFR', 'Gene', (114, 118))	('EGFR', 'Gene', '1956', (114, 118))	('p53', 'Gene', (133, 136))
376510	20516120	Second, periostin's direct functional role is underscored by overexpression and knockdown experiments in which genetic manipulation of periostin dramatically influences the degree of tumor invasion in organotypic culture.	('influences', 'Reg', (158, 168))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('periostin', 'Gene', (135, 144))	('genetic manipulation', 'Var', (111, 131))
376511	20516120	Third, EGFR signaling and p53 mutation, both canonical genetic alterations in ESCC, appear to converge upon periostin based upon luciferase reporter gene assays as well as inhibition of EGFR signaling and restoration of wild type p53 function.	('ESCC', 'Gene', (78, 82))	('EGFR', 'Gene', (7, 11))	('mutation', 'Var', (30, 38))	('function', 'MPA', (234, 242))	('p53', 'Gene', '7157', (230, 233))	('p53', 'Gene', (26, 29))	('EGFR', 'Gene', (186, 190))	('EGFR', 'Gene', '1956', (186, 190))	('p53', 'Gene', '7157', (26, 29))	('p53', 'Gene', (230, 233))	('inhibition', 'NegReg', (172, 182))	('EGFR', 'Gene', '1956', (7, 11))
376516	20516120	Significant changes such as loss of cell-cell contacts, disruptions in cell adhesion junctions and altered cell-extracellular matrix interactions within the tumor microenvironment converge to increase the ultimate metastatic potential of tumor cells.	('tumor', 'Disease', (157, 162))	('disruptions', 'Var', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (238, 243))	('cell', 'Protein', (71, 75))	('altered', 'Reg', (99, 106))	('cell-cell contacts', 'CPA', (36, 54))	('cell-extracellular matrix interactions', 'CPA', (107, 145))	('increase', 'PosReg', (192, 200))	('loss', 'NegReg', (28, 32))
376543	33537086	It can control cell-substrate adhesion and cytoskeletal dynamics through monomeric GTPases, as well as impact cell viability and growth via phosphorylation cascades, just to name two examples.	('monomeric', 'Var', (73, 82))	('GTPases', 'Protein', (83, 90))	('cell viability', 'CPA', (110, 124))	('GTP', 'Chemical', 'MESH:D006160', (83, 86))	('impact', 'Reg', (103, 109))	('cytoskeletal dynamics', 'CPA', (43, 64))	('control', 'Reg', (7, 14))	('growth', 'CPA', (129, 135))	('cell-substrate adhesion', 'CPA', (15, 38))
376571	33537086	In fact, targeting Sema4C/PlexinB2 signaling resulted in cell cycle arrest in G2/M phase, upregulation of tumor-suppressor genes and cell senescence.	('arrest', 'Disease', (68, 74))	('Sema4C', 'Gene', '54910', (19, 25))	('upregulation', 'PosReg', (90, 102))	('PlexinB2', 'Gene', '23654', (26, 34))	('tumor-suppressor', 'Gene', '7248', (106, 122))	('Sema4C', 'Gene', (19, 25))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (57, 74))	('PlexinB2', 'Gene', (26, 34))	('cell senescence', 'CPA', (133, 148))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor-suppressor', 'Gene', (106, 122))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('targeting', 'Var', (9, 18))
376574	33537086	Notably, increased Sema4C expression in breast cancer cells has also been associated with resistance to paclitaxel-based chemotherapy, while knocking-down its expression could partly recover drug sensitivity.	('expression', 'MPA', (26, 36))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('drug sensitivity', 'Phenotype', 'HP:0020174', (191, 207))	('Sema4C', 'Gene', '54910', (19, 25))	('knocking-down', 'Var', (141, 154))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('drug sensitivity', 'MPA', (191, 207))	('recover', 'PosReg', (183, 190))	('resistance to paclitaxel-based chemotherapy', 'MPA', (90, 133))	('increased', 'PosReg', (9, 18))	('Sema4C', 'Gene', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('associated', 'Reg', (74, 84))
376580	33537086	Interestingly, two clinical trials aimed at the assessment of these hypotheses have been planned (NCT03663153; NCT03662633).	('NCT03663153; NCT03662633', 'Var', (98, 122))	('NCT03662633', 'Var', (111, 122))	('men', 'Species', '9606', (54, 57))
376600	33537086	In keeping with these data, Sema4D knock-down in breast cancer cells was found to suppress tumor growth in vivo, angiogenesis, and bone metastases formation in mouse models.	('mouse', 'Species', '10090', (160, 165))	('angiogenesis', 'CPA', (113, 125))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('bone metastases', 'Disease', 'MESH:D009362', (131, 146))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('knock-down', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('breast cancer', 'Disease', (49, 62))	('bone metastases', 'Disease', (131, 146))	('suppress', 'NegReg', (82, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('tumor', 'Disease', (91, 96))	('Sema4D knock-down', 'Var', (28, 45))
376610	33537086	In particular, the treatment with an anti-Sema4D antibody was found to promote anti-cancer immune response in mouse models by favoring the recruitment of cytotoxic T lymphocytes.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('promote', 'PosReg', (71, 78))	('men', 'Species', '9606', (24, 27))	('cancer', 'Disease', (84, 90))	('men', 'Species', '9606', (146, 149))	('mouse', 'Species', '10090', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('recruitment of cytotoxic T lymphocytes', 'CPA', (139, 177))	('favoring', 'PosReg', (126, 134))	('anti-Sema4D', 'Var', (37, 48))
376621	33537086	Univariate analysis indicated that the overall survival and progression-free survival of epithelial ovarian cancer patients with high expression of Sema4D were lower than in patients with Sema4D-negative tumors.	('Sema4D', 'Gene', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('patients', 'Species', '9606', (115, 123))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (89, 114))	('high expression', 'Var', (129, 144))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('patients', 'Species', '9606', (174, 182))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (89, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumors', 'Disease', (204, 210))	('progression-free survival', 'CPA', (60, 85))	('epithelial ovarian cancer', 'Disease', (89, 114))	('overall survival', 'CPA', (39, 55))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('lower', 'NegReg', (160, 165))
376634	33537086	Similar to what reported above for breast cancer, experimental evidence indicated that Sema4C can promote EMT; moreover, it was found to sustain resistance to cisplatin-based chemotherapy in cervical cancer cells, while knocking-down its expression partly recovered drug sensitivity.	('EMT', 'Gene', (106, 109))	('cervical cancer', 'Disease', 'MESH:D002583', (191, 206))	('EMT', 'Gene', '3702', (106, 109))	('promote', 'PosReg', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cervical cancer', 'Disease', (191, 206))	('drug sensitivity', 'Phenotype', 'HP:0020174', (266, 282))	('drug sensitivity', 'MPA', (266, 282))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('men', 'Species', '9606', (56, 59))	('Sema4C', 'Gene', (87, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('knocking-down', 'Var', (220, 233))	('breast cancer', 'Disease', (35, 48))	('resistance to cisplatin-based chemotherapy', 'MPA', (145, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('Sema4C', 'Gene', '54910', (87, 93))
376636	33537086	Tumors with high expression of Sema4D showed abundant lymphangiogenesis, lymphatic vessel invasion, and the occurrence of lymph node metastases, possibly due to increased VEGF-C/D expression.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('metastases', 'Disease', 'MESH:D009362', (133, 143))	('expression', 'MPA', (180, 190))	('increased VEGF-', 'Phenotype', 'HP:0030269', (161, 176))	('lymphatic vessel invasion', 'CPA', (73, 98))	('Tumors', 'Disease', (0, 6))	('lymphangiogenesis', 'CPA', (54, 71))	('metastases', 'Disease', (133, 143))	('VEGF-C/D', 'Gene', '7424;2277', (171, 179))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('increased', 'PosReg', (161, 170))	('Sema4D', 'Gene', (31, 37))	('high expression', 'Var', (12, 27))	('VEGF-C/D', 'Gene', (171, 179))
376637	33537086	In addition, analysis of survival data provided compelling evidence that high levels of Sema4D were significantly associated with an unfavorable outcome in cervical cancer patients.	('cervical cancer', 'Disease', (156, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('high levels', 'Var', (73, 84))	('Sema4D', 'Protein', (88, 94))	('associated with', 'Reg', (114, 129))	('patients', 'Species', '9606', (172, 180))	('cervical cancer', 'Disease', 'MESH:D002583', (156, 171))
376640	33537086	These data suggests an important association between high Sema4D expression and reduced survival of cervical cancer patients.	('survival', 'CPA', (88, 96))	('high', 'Var', (53, 57))	('Sema4D', 'Protein', (58, 64))	('patients', 'Species', '9606', (116, 124))	('reduced', 'NegReg', (80, 87))	('expression', 'MPA', (65, 75))	('cervical cancer', 'Disease', (100, 115))	('cervical cancer', 'Disease', 'MESH:D002583', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
376660	33537086	Notably, chromosome 3 allelic loss and promoter hypermethylation are considered the main causes of Sema3B downregulation, and Sema3B reduced expresson was detected at mRNA and protein levels in ESCC tumor specimens.	('tumor', 'Disease', (199, 204))	('men', 'Species', '9606', (210, 213))	('downregulation', 'NegReg', (106, 120))	('expresson', 'MPA', (141, 150))	('promoter hypermethylation', 'Var', (39, 64))	('Sema3B', 'Gene', (99, 105))	('Sema3B', 'Var', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('loss', 'NegReg', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('reduced', 'NegReg', (133, 140))
376663	33537086	It is well known that Sema3B is involved in the regulation of apoptosis and cell growth in different tumor types; indeed Sema3B can block ESCC cells at the G1/S checkpoint through inhibition of the PI3K/AKT signaling transduction pathway, upregulation of p53 and p21 expression and downregulation of cyclin D1 expression.	('upregulation', 'PosReg', (239, 251))	('p21', 'Gene', (263, 266))	('ESCC', 'Disease', (138, 142))	('p53', 'Gene', (255, 258))	('p21', 'Gene', '644914', (263, 266))	('inhibition', 'NegReg', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('block', 'NegReg', (132, 137))	('downregulation', 'NegReg', (282, 296))	('expression', 'MPA', (310, 320))	('cyclin D1', 'Gene', (300, 309))	('AKT', 'Gene', (203, 206))	('Sema3B', 'Var', (121, 127))	('G1/S checkpoint', 'CPA', (156, 171))	('cyclin D1', 'Gene', '595', (300, 309))	('expression', 'MPA', (267, 277))	('tumor', 'Disease', (101, 106))	('AKT', 'Gene', '207', (203, 206))	('p53', 'Gene', '7157', (255, 258))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
376665	33537086	Also in gastric cardia adenocarcinoma (GCA) the loss of heterozygosity in chromosome 3p is one of the most frequent events, likely to impact on the expression of putative tumor suppressor genes, including SEMA3B.	('gastric cardia adenocarcinoma', 'Disease', (8, 37))	('loss of heterozygosity', 'Var', (48, 70))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('impact', 'Reg', (134, 140))	('SEMA3B', 'Gene', '7869', (205, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('expression', 'MPA', (148, 158))	('tumor', 'Disease', (171, 176))	('SEMA3B', 'Gene', (205, 211))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (8, 37))
376671	33537086	In summary, SEMA3B, SEMA3B-AS1, and miR-6872-5p seem to play a suppressor role in GCA tumor development, and their expression levels are coregulated by aberrant promoter hypermethylation and histone modification.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SEMA3B', 'Gene', '7869', (20, 26))	('SEMA3B', 'Gene', (20, 26))	('histone', 'Reg', (191, 198))	('SEMA3B-AS1', 'Gene', '101928931', (20, 30))	('tumor', 'Disease', (86, 91))	('SEMA3B-AS1', 'Gene', (20, 30))	('expression levels', 'MPA', (115, 132))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('aberrant', 'Var', (152, 160))	('miR-6872', 'Gene', (36, 44))	('GCA', 'Disease', (82, 85))	('suppressor', 'NegReg', (63, 73))	('miR-6872', 'Gene', '102465526', (36, 44))	('SEMA3B', 'Gene', (12, 18))	('men', 'Species', '9606', (99, 102))	('SEMA3B', 'Gene', '7869', (12, 18))	('promoter', 'MPA', (161, 169))
376681	33537086	Colorectal cancer (CRC) is considered a prime example of step-wise carcinogenesis, since the number of genetic alterations increases with the advancing histopathological stage of the disease, from early adenomatous lesions to invasive carcinomas and metastatic cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (67, 81))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('carcinogenesis', 'Disease', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('alterations', 'Var', (111, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('adenomatous lesions to invasive carcinomas', 'Disease', 'MESH:D011125', (203, 245))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (235, 245))	('Colorectal cancer', 'Disease', (0, 17))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('adenomatous lesions to invasive carcinomas', 'Disease', (203, 245))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))	('cancers', 'Disease', (261, 268))	('increases', 'PosReg', (123, 132))
376682	33537086	Consistent with data reported above for cervical cancer, the authors furthermore found that Sema3D expression in CRC was inversely correlated with lymph node metastasis; and Sema3D-silencing was found to promote cancer cell migration in vitro, consistent with the idea of a metastasis-inhibitory activity of this semaphorin.	('promote', 'PosReg', (204, 211))	('cervical cancer', 'Disease', 'MESH:D002583', (40, 55))	('sema', 'Gene', '7869', (313, 317))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cervical cancer', 'Disease', (40, 55))	('sema', 'Gene', (313, 317))	('cancer', 'Disease', (212, 218))	('Sema3D-silencing', 'Var', (174, 190))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('lymph node metastasis', 'CPA', (147, 168))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
376683	33537086	Univariate survival analysis of CRC patients showed that tumors expressing high levels of Sema3D are associated with longer survival than those expressing low levels.	('patients', 'Species', '9606', (36, 44))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('longer', 'PosReg', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('Sema3D', 'Protein', (90, 96))	('high levels', 'Var', (75, 86))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
376689	33537086	As for other cancers, Sema4D expression has furthermore been associated with CRC development.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancers', 'Disease', (13, 20))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('men', 'Species', '9606', (88, 91))	('CRC development', 'Disease', (77, 92))	('associated', 'Reg', (61, 71))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('Sema4D expression', 'Var', (22, 39))
376696	33537086	Indeed, anti-angiogenic drugs upregulated Sema4D levels in cancer cells and tumor tissues, and Sema4D can exert significant proangiogenic activity in tumors.	('Sema4D', 'Var', (95, 101))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('upregulated', 'PosReg', (30, 41))	('Sema4D levels', 'MPA', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('proangiogenic activity', 'CPA', (124, 146))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
376702	33537086	Notably, immunohistochemical detection of high Sema3D expression in primary PDAC was associated with wide metastatic disease and decreased patient survival.	('expression', 'MPA', (54, 64))	('PDAC', 'Phenotype', 'HP:0006725', (76, 80))	('wide metastatic disease', 'CPA', (101, 124))	('Sema3D', 'Protein', (47, 53))	('PDAC', 'Chemical', '-', (76, 80))	('patient survival', 'CPA', (139, 155))	('high', 'Var', (42, 46))	('decreased', 'NegReg', (129, 138))	('patient', 'Species', '9606', (139, 146))
376703	33537086	Moreover, Sema3D-depeleted cancer showed decreased invasive and metastatic potential in culture and in mouse models.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Sema3D-depeleted', 'Var', (10, 26))	('mouse', 'Species', '10090', (103, 108))	('cancer', 'Disease', (27, 33))	('decreased invasive', 'Disease', (41, 59))	('decreased invasive', 'Disease', 'MESH:D009361', (41, 59))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
376710	33537086	In another study based on IHC analysis, Sema3A expression with its co-receptor NRP1 in PDAC was instead correlated with poor patient prognosis.	('PDAC', 'Phenotype', 'HP:0006725', (87, 91))	('PDAC', 'Chemical', '-', (87, 91))	('patient', 'Species', '9606', (125, 132))	('PDAC', 'Disease', (87, 91))	('Sema3A expression', 'Var', (40, 57))
376718	33537086	Moreover, consistent with its activity promoting osteoclastogenesis and bone resorptive activity, the knock-down of Sema4D in HNSCC cells reduced bone invasion in preclinical mouse models.	('knock-down', 'Var', (102, 112))	('reduced', 'NegReg', (138, 145))	('osteoclastogenesis', 'Disease', 'None', (49, 67))	('Sema4D', 'Gene', (116, 122))	('osteoclastogenesis', 'Disease', (49, 67))	('bone invasion', 'CPA', (146, 159))	('promoting', 'PosReg', (39, 48))	('mouse', 'Species', '10090', (175, 180))	('bone resorptive activity', 'CPA', (72, 96))
376727	33537086	As mentioned above, SEMA3B is located in a site of frequent allele loss and hypermethylation in lung cancers, and experimental evidence indicated its role as tumor suppressor gene also in this context.	('tumor', 'Disease', (158, 163))	('SEMA3B', 'Gene', '7869', (20, 26))	('SEMA3B', 'Gene', (20, 26))	('lung cancers', 'Disease', (96, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('hypermethylation', 'Var', (76, 92))	('lung cancers', 'Disease', 'MESH:D008175', (96, 108))	('men', 'Species', '9606', (120, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lung cancers', 'Phenotype', 'HP:0100526', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('men', 'Species', '9606', (3, 6))
376744	33537086	The onset of mutations causing resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) represents a clinical challenge for the treatment of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('EGFR', 'Gene', (45, 49))	('lung cancer', 'Disease', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('mutations', 'Var', (13, 22))	('EGFR', 'Gene', '1956', (45, 49))	('men', 'Species', '9606', (134, 137))
376760	33537086	Thus, chemical castration is often used as a first-line therapy for advanced disease; however, the onset of hormonal therapy resistance is usually ensuing, largely through mutations of the androgen receptor (AR), aberrant AR signaling, or AR bypass mechanisms.	('mutations', 'Var', (172, 181))	('AR', 'Gene', '367', (208, 210))	('AR', 'Gene', '367', (239, 241))	('androgen receptor', 'Gene', '367', (189, 206))	('AR', 'Gene', '367', (222, 224))	('androgen receptor', 'Gene', (189, 206))
376764	33537086	identified several small molecule inhibitors of Sema3C that reduce the phosphorylation of EGFR, HER2/ErbB2, SHC, and MAPK, collectively providing evidence in experimental models that Sema3C inhibition may represent a promising avenue for developing targeted therapies against PC and possibly other cancer types.	('Sema3C', 'Gene', (48, 54))	('Sema3C', 'Gene', (183, 189))	('Sema3C', 'Gene', '10512', (48, 54))	('phosphorylation', 'MPA', (71, 86))	('Sema3C', 'Gene', '10512', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('EGFR', 'Gene', (90, 94))	('HER2', 'Gene', (96, 100))	('ErbB2', 'Gene', '2064', (101, 106))	('reduce', 'NegReg', (60, 66))	('SHC', 'Gene', (108, 111))	('PC', 'Gene', '5091', (276, 278))	('PC', 'Phenotype', 'HP:0012125', (276, 278))	('men', 'Species', '9606', (164, 167))	('EGFR', 'Gene', '1956', (90, 94))	('inhibitors', 'Var', (34, 44))	('MAPK', 'Gene', (117, 121))	('cancer', 'Disease', (298, 304))	('ErbB2', 'Gene', (101, 106))	('SHC', 'Gene', '6464', (108, 111))	('HER2', 'Gene', '2064', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
376768	33537086	Interestingly, Sema4F expression in cancer cells has been correlated with the induction of axonal sprouting in vitro, and with increased nerve density and perineural invasion in PC.	('nerve density', 'CPA', (137, 150))	('increased', 'PosReg', (127, 136))	('PC', 'Gene', '5091', (178, 180))	('expression', 'Var', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('Sema4F', 'Gene', '10505', (15, 21))	('PC', 'Phenotype', 'HP:0012125', (178, 180))	('axonal sprouting', 'CPA', (91, 107))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Sema4F', 'Gene', (15, 21))	('perineural invasion', 'CPA', (155, 174))
376780	33537086	As discussed above for osteolytic metastasis, Sema4D is actually expressed by osteoclasts and negatively regulates osteoblast activity and bone formation.	('regulates', 'Reg', (105, 114))	('negatively', 'NegReg', (94, 104))	('osteolytic metastasis', 'Disease', (23, 44))	('osteoblast activity', 'CPA', (115, 134))	('bone formation', 'CPA', (139, 153))	('osteolytic metastasis', 'Disease', 'MESH:D009362', (23, 44))	('Sema4D', 'Var', (46, 52))
376794	33537086	As introduced above, a large body of evidence obtained in experimental models in culture and in mice demonstrated that semaphorins act as regulators of tumor progression, and that interfering with their functions can significantly alter disease outcome.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('sema', 'Gene', (119, 123))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('sema', 'Gene', '7869', (119, 123))	('tumor', 'Disease', (152, 157))	('men', 'Species', '9606', (64, 67))	('disease', 'Disease', (237, 244))	('interfering', 'Var', (180, 191))	('alter', 'Reg', (231, 236))	('functions', 'MPA', (203, 212))
376801	33537086	In order to interfere with tumor-promoting semaphorins, function-blocking antibodies appear the most actual approach.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('sema', 'Gene', (43, 47))	('function-blocking', 'Var', (56, 73))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('sema', 'Gene', '7869', (43, 47))
376803	33537086	In particular, the safety and tolerability of VX15/2503 was validated in two independent phase-1 trials, enrolling over 50 patients bearing advanced solid tumors or multiple sclerosis (NCT01313065, NCT01764737).	('VX15/2503', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('NCT01313065', 'Var', (185, 196))	('patients', 'Species', '9606', (123, 131))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('multiple sclerosis', 'Disease', (165, 183))	('multiple sclerosis', 'Disease', 'MESH:D009103', (165, 183))	('NCT01764737', 'Var', (198, 209))
376807	33537086	Consistent with its activity limiting CTL infiltration in tumors, this drug is currently under evaluation in three distinct Phase-1b/2 trials for the treatment of advanced non-small-cell lung cancers, head and neck squamous cell cancers, or pancreatic and colorectal cancers, in combination with the immune checkpoint inhibitors anti-PD-L1 avelumab (NCT03268057), or anti-CTLA-4 ipilimumab and anti-PD1 nivolumab (NCT03690986, NCT03373188), respectively.	('lung cancers', 'Phenotype', 'HP:0100526', (187, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('pancreatic', 'Disease', 'MESH:D010195', (241, 251))	('colorectal cancers', 'Disease', 'MESH:D015179', (256, 274))	('PD-L1', 'Gene', (334, 339))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('PD-L1', 'Gene', '29126', (334, 339))	('pancreatic', 'Disease', (241, 251))	('nivolumab', 'Chemical', 'MESH:D000077594', (403, 412))	('neck squamous cell cancers', 'Disease', 'MESH:D002294', (210, 236))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('ipilimumab', 'Chemical', 'MESH:D000074324', (379, 389))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('lung cancers', 'Disease', 'MESH:D008175', (187, 199))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('colorectal cancer', 'Phenotype', 'HP:0003003', (256, 273))	('CTLA-4', 'Gene', '1493', (372, 378))	('NCT03690986', 'Var', (414, 425))	('colorectal cancers', 'Disease', (256, 274))	('men', 'Species', '9606', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('neck squamous cell cancers', 'Disease', (210, 236))	('tumors', 'Disease', (58, 64))	('CTLA-4', 'Gene', (372, 378))	('lung cancers', 'Disease', (187, 199))	('NCT03268057', 'Var', (350, 361))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (215, 236))	('NCT03373188', 'Var', (427, 438))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))
376809	33537086	However, so far, only the Sema3A inhibitors SM-216289/xanthofulvin and SM-345431/vinaxanthone were validated, which have been applied to promote tissue regeneration, e.g.	('vinaxanthone', 'Chemical', 'MESH:C086647', (81, 93))	('SM-345431', 'Chemical', 'MESH:C086647', (71, 80))	('SM-216289/xanthofulvin', 'Var', (44, 66))	('tissue regeneration', 'CPA', (145, 164))	('xanthofulvin', 'Chemical', 'MESH:C477901', (54, 66))	('promote', 'PosReg', (137, 144))	('SM-216289', 'Chemical', 'MESH:C477901', (44, 53))	('SM-345431/vinaxanthone', 'Var', (71, 93))
376836	33537086	Mutations have been infrequently reported, while genomic hypermethylation seems to be responsible for the downregulation of semaphorins acting as tumor suppressors.	('genomic hypermethylation', 'Var', (49, 73))	('downregulation', 'NegReg', (106, 120))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('sema', 'Gene', '7869', (124, 128))	('tumor', 'Disease', (146, 151))	('Mutations', 'Var', (0, 9))	('sema', 'Gene', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
376904	32859167	Type 2, primary ET, occurs when food or sputum containing Mycobacterium tuberculosis is swallowed; Mycobacterium tuberculosis adheres to the esophageal mucosa and causes tuberculosis infection, especially when the esophageal mucosa is damaged.	('Mycobacterium tuberculosis', 'Var', (99, 125))	('tuberculosis infection', 'Disease', 'MESH:D007239', (170, 192))	('ET', 'Gene', '79157', (16, 18))	('tuberculosis infection', 'Disease', (170, 192))	('Mycobacterium tuberculosis', 'Species', '1773', (99, 125))	('causes', 'Reg', (163, 169))	('Mycobacterium tuberculosis', 'Species', '1773', (58, 84))
376911	32859167	Esophageoscopic findings lack specificity, and pathological biopsies are sometimes disappointing; false-negative results often occur due to the failure to obtain definite caseous necrotizing granuloma and acid-fast bacilli.	('necrotizing granuloma', 'Disease', 'MESH:D006099', (179, 200))	('et', 'Gene', '79157', (76, 78))	('granuloma', 'Phenotype', 'HP:0032252', (191, 200))	('acid-fast', 'Var', (205, 214))	('necrotizing granuloma', 'Disease', (179, 200))
376949	32884895	We found CD68+, CD163+, and CD206+ TAMs distributed in both tumor stroma and tumor islets.	('tumor stroma and tumor', 'Disease', 'MESH:D009369', (60, 82))	('CD68+', 'Var', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CD163+', 'Var', (16, 22))	('CD206+', 'Var', (28, 34))
376954	32884895	done on 485 samples of colorectal cancer, the higher numbers of CD163+ cells were clearly associated with a good prognosis; a similar study on a cohort of 201 colorectal cancer patients that also demonstrated a tendency of better prognosis is the case of high CD163+ cell count, though these results were not statistically significant.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('colorectal cancer', 'Disease', (23, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (23, 40))	('high', 'Var', (255, 259))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('CD163+ cells', 'Var', (64, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (23, 40))	('colorectal cancer', 'Disease', (159, 176))
376955	32884895	At the same time, there are studies demonstrating opposite correlations, i.e., poor prognosis of the colorectal tumors showing high amount of CD163+ cells.	('CD163+ cells', 'Var', (142, 154))	('colorectal tumors', 'Disease', 'MESH:D015179', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('colorectal tumors', 'Disease', (101, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
376956	32884895	Similarly, for gastric cancer, there are reports of high CD163 as an indicator of good and bad prognosis.	('CD163', 'Gene', (57, 62))	('gastric cancer', 'Disease', (15, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (15, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (15, 29))	('high', 'Var', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
376957	32884895	have demonstrated that increased number of CD163+ cells is a marker of good prognosis of signet ring cell carcinoma and mucinous adenocarcinoma, while for other types of gastric cancer, it does not correlated with prognosis or is a marker of poor prognosis.	('ring cell carcinoma', 'Disease', 'MESH:D018279', (96, 115))	('ring cell carcinoma', 'Disease', (96, 115))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (120, 143))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mucinous adenocarcinoma', 'Disease', (120, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('CD163+ cells', 'Var', (43, 55))
376959	32884895	It was reported that high content of CD163+ cells is a marker of good prognosis in estrogen receptor negative breast cancer tumors.	('breast cancer tumors', 'Disease', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('estrogen receptor', 'Gene', (83, 100))	('estrogen receptor', 'Gene', '2099', (83, 100))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('CD163+ cells', 'Var', (37, 49))	('breast cancer tumors', 'Disease', 'MESH:D001943', (110, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
376961	32884895	Particularly, the presence of T cells (CD3+) and T cell subpopulations (e.g., CD4+, CD8+, and CD103+) was established to be markers of a good prognosis.	('CD4', 'Gene', '920', (78, 81))	('CD103', 'Gene', '3682', (94, 99))	('CD8+', 'Var', (84, 88))	('CD103', 'Gene', (94, 99))	('CD4', 'Gene', (78, 81))	('presence of T cells', 'Phenotype', 'HP:0100828', (18, 37))
377032	32755964	Although the efficacy and safety of lenvatinib for ATC patients have been largely accepted, it has been recognized that lenvatinib is associated with a high rate of treatment-related adverse events, including hypertension and proteinuria.	('proteinuria', 'Phenotype', 'HP:0000093', (226, 237))	('hypertension', 'Disease', 'MESH:D006973', (209, 221))	('lenvatinib', 'Var', (120, 130))	('lenvatinib', 'Chemical', 'MESH:C531958', (36, 46))	('lenvatinib', 'Chemical', 'MESH:C531958', (120, 130))	('proteinuria', 'Disease', 'MESH:D011507', (226, 237))	('ATC', 'Phenotype', 'HP:0011779', (51, 54))	('hypertension', 'Disease', (209, 221))	('hypertension', 'Phenotype', 'HP:0000822', (209, 221))	('patients', 'Species', '9606', (55, 63))	('proteinuria', 'Disease', (226, 237))
377033	32755964	Further caution is required in relation to wound-healing complications or perforation of the adjacent invading organs in patients undergoing VEGFR inhibitor treatment.	('VEGFR', 'Gene', (141, 146))	('inhibitor', 'Var', (147, 156))	('VEGFR', 'Gene', '3791', (141, 146))	('wound-healing', 'CPA', (43, 56))	('patients', 'Species', '9606', (121, 129))
377076	32210001	Final data indicate somatic activating mutation Q546K in PIK3CA gene, somatic frameshifts in PIH1D1 and FBXW7 genes, stop-gain in TP53BP1, and a few somatic mutations of unknown significance.	('PIH1D1', 'Gene', (93, 99))	('Q546K', 'Var', (48, 53))	('PIK3CA', 'Gene', '5290', (57, 63))	('TP53BP1', 'Gene', '7158', (130, 137))	('TP53BP1', 'Gene', (130, 137))	('activating', 'PosReg', (28, 38))	('FBXW7', 'Gene', '55294', (104, 109))	('Q546K', 'Mutation', 'rs121913286', (48, 53))	('frameshifts', 'Var', (78, 89))	('PIH1D1', 'Gene', '55011', (93, 99))	('FBXW7', 'Gene', (104, 109))	('PIK3CA', 'Gene', (57, 63))
377077	32210001	RNA sequencing analysis revealed upregulated expressions of MMP7, MMP9, BIRC5, and PD-L1 genes and strongly differential regulation of several molecular pathways linked with the mutations identified.	('BIRC5', 'Gene', (72, 77))	('upregulated', 'PosReg', (33, 44))	('MMP7', 'Gene', (60, 64))	('differential regulation', 'Reg', (108, 131))	('PD-L1', 'Gene', '29126', (83, 88))	('MMP9', 'Gene', (66, 70))	('MMP7', 'Gene', '4316', (60, 64))	('expressions', 'MPA', (45, 56))	('MMP9', 'Gene', '4318', (66, 70))	('PD-L1', 'Gene', (83, 88))	('mutations', 'Var', (178, 187))	('BIRC5', 'Gene', '332', (72, 77))
377092	32210001	This allowed to compare different methods of annotating tumor-specific mutations and to implement gene expression-based personalized prioritizing of targeted therapeutics.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutations', 'Var', (71, 80))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
377093	32210001	To our knowledge, this is the first report simultaneously using alternative comprehensive genomic, copy number variation, and transcriptomic approaches to characterize primary and metastatic disease in both tumor-only and matched tumor-normal modes to identify putative treatment options for the individual patient with GC.	('tumor', 'Disease', (230, 235))	('metastatic disease', 'Disease', 'MESH:C538445', (180, 198))	('patient', 'Species', '9606', (307, 314))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('copy', 'Var', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', (207, 212))	('metastatic disease', 'Disease', (180, 198))
377114	32210001	This allowed to identify the most probable individual case driver mutations using four alternative methods, to measure tumor mutational burden (TMB) using two methods, to establish gene expression levels of tumor marker genes, and to assess potential individual utility of immunotherapy using molecular pathway analysis.	('mutations', 'Var', (66, 75))	('tumor', 'Disease', (119, 124))	('TMB', 'Chemical', '-', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('gene expression', 'MPA', (181, 196))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
377115	32210001	WES-Obx pipeline was then applied to identify mutations using additional biosamples obtained from the same patient during surgical removal of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', (146, 151))	('patient', 'Species', '9606', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
377118	32210001	In the previous tests comparing results of different platforms for the same tumor biopsy sample, we were able to identify mutations but could not find out if they were of germline or somatic origin.	('mutations', 'Var', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
377120	32210001	WES-Obx platform was applied in tumor-only mode for the sole tumor biopsy sample, thus giving an output of 502 germline + somatic mutations (Supplementary File 2), and in the mode of comparison with reference normal tissues (tumor-reference mode), thus providing 37 and 38 somatic mutations identified for surgical tumor samples of esophageal and stomach localizations, respectively.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutations', 'Var', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (315, 320))
377121	32210001	This dramatic difference in the number of mutations identified most probably pointed to the extremely high proportion (>90%) of germline mutations and/or formalin fixation artifacts in the tumor-only mode of analysis.	('tumor', 'Disease', (189, 194))	('germline mutations', 'Var', (128, 146))	('formalin', 'Chemical', 'MESH:D005557', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
377122	32210001	Most of mutations identified in tumor-reference mode were also identified in a tumor-only mode.	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutations', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
377125	32210001	Final data indicate somatic activating mutation Q546K in the PIK3CA gene, somatic frameshifts in the PIH1D1 and FBXW7 genes, stop-gain in TP53BP1, and a few somatic mutations of unknown significance (Supplementary Files 1, 3 and 5).	('FBXW7', 'Gene', (112, 117))	('PIK3CA', 'Gene', (61, 67))	('Q546K', 'Var', (48, 53))	('PIK3CA', 'Gene', '5290', (61, 67))	('PIH1D1', 'Gene', (101, 107))	('activating', 'PosReg', (28, 38))	('Q546K', 'Mutation', 'rs121913286', (48, 53))	('PIH1D1', 'Gene', '55011', (101, 107))	('TP53BP1', 'Gene', '7158', (138, 145))	('TP53BP1', 'Gene', (138, 145))	('frameshifts', 'Var', (82, 93))	('FBXW7', 'Gene', '55294', (112, 117))
377137	32210001	Noteworthily, the second top upregulated molecular pathway was clinically actionable "Reactome PD1 signaling Pathway", which also contained mutated gene HLA-DRB1 (Figure 3).	('HLA-DRB1', 'Gene', (153, 161))	('HLA-DRB1', 'Gene', '3123', (153, 161))	('upregulated', 'PosReg', (29, 40))	('PD1', 'Gene', '5133', (95, 98))	('PD1', 'Gene', (95, 98))	('mutated', 'Var', (140, 147))
377158	31417277	In addition, qPCR showed that H19 was upregulated in KYSE150R cells, and survival fraction assays showed that knockdown of H19 decreased the survival fraction values.	('knockdown', 'Var', (110, 119))	('decreased', 'NegReg', (127, 136))	('upregulated', 'PosReg', (38, 49))	('survival fraction values', 'CPA', (141, 165))	('H19', 'Gene', '283120', (30, 33))	('H19', 'Gene', '283120', (123, 126))	('H19', 'Gene', (30, 33))	('H19', 'Gene', (123, 126))
377160	31417277	Conclusion: Our results demonstrate that H19 knockdown downregulates the WNT1 via upregulating miR-22-3p expression, which leads to the inhibition of cells proliferation, migration and stemness in the radioresistant ESCC cells.	('WNT1', 'Gene', (73, 77))	('upregulating', 'PosReg', (82, 94))	('H19', 'Gene', '283120', (41, 44))	('cells proliferation', 'CPA', (150, 169))	('miR-22-3p', 'Protein', (95, 104))	('inhibition', 'NegReg', (136, 146))	('stemness', 'Disease', (185, 193))	('stemness', 'Disease', 'MESH:D020295', (185, 193))	('migration', 'CPA', (171, 180))	('downregulates', 'NegReg', (55, 68))	('knockdown', 'Var', (45, 54))	('H19', 'Gene', (41, 44))
377171	31417277	Using bioinformatic analysis, it showed the aberrant expression of H19 in ESCC tissues and the correlation between H19 and poor prognosis.	('ESCC', 'Disease', (74, 78))	('H19', 'Gene', '283120', (67, 70))	('H19', 'Gene', '283120', (115, 118))	('H19', 'Gene', (67, 70))	('H19', 'Gene', (115, 118))	('expression', 'MPA', (53, 63))	('aberrant', 'Var', (44, 52))
377173	31417277	Accumulating evidence reveals that the dysregulated H19 acts as the tumorigenic and anti-tumorigenic roles in many tumors, such as bladder cancer, breast cancer.	('H19', 'Gene', '283120', (52, 55))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Disease', (68, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (89, 94))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('breast cancer', 'Disease', (147, 160))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumors', 'Disease', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (131, 145))	('bladder cancer', 'Disease', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('H19', 'Gene', (52, 55))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('dysregulated', 'Var', (39, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
377179	31417277	Meanwhile, researchers also revealed its roles in radioresistance, such as LIG4 mediates Wnt signalling-induced radioresistance; microRNA-324-3p regulates nasopharyngeal carcinoma radioresistance by directly targeting WNT2B; The inhibitory role of miR-301a in cell migration and the facilitating role of miR-301a in radiosensitivity have been found in radioresistant-ESCC cells.	('miR-301a', 'Gene', (248, 256))	('targeting', 'Reg', (208, 217))	('carcinoma', 'Disease', 'MESH:D002277', (170, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('LIG4', 'Gene', (75, 79))	('miR-301a', 'Gene', '407027', (304, 312))	('WNT2B', 'Gene', (218, 223))	('miR-301a', 'Gene', '407027', (248, 256))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (155, 179))	('WNT2B', 'Gene', '7482', (218, 223))	('LIG4', 'Gene', '3981', (75, 79))	('carcinoma', 'Disease', (170, 179))	('miR-301a', 'Gene', (304, 312))	('cell migration', 'CPA', (260, 274))	('regulates', 'Reg', (145, 154))	('microRNA-324-3p', 'Var', (129, 144))
377187	31417277	Furthermore, we observed that knockdown of H19 inhibits cells proliferation, migration, and stemness in radioresistant KYSE150 cells.	('stemness', 'Disease', 'MESH:D020295', (92, 100))	('stemness', 'Disease', (92, 100))	('migration', 'CPA', (77, 86))	('knockdown', 'Var', (30, 39))	('H19', 'Gene', (43, 46))	('inhibits', 'NegReg', (47, 55))	('H19', 'Gene', '283120', (43, 46))	('cells proliferation', 'CPA', (56, 75))
377188	31417277	In addition, knockdown of H19 downregulates WNT1 expression.	('downregulates', 'NegReg', (30, 43))	('expression', 'MPA', (49, 59))	('WNT1', 'Gene', (44, 48))	('H19', 'Gene', '283120', (26, 29))	('H19', 'Gene', (26, 29))	('knockdown', 'Var', (13, 22))
377193	31417277	Additionally, the starBase database was also used to assess the combination between H19, miR-22-3p and WNT1 in ESCC cells.	('miR-22-3p', 'Var', (89, 98))	('H19', 'Gene', '283120', (84, 87))	('H19', 'Gene', (84, 87))
377223	31417277	We found that the stemness-associated genes (OCT4, SOX2 and NANOG) were significantly higher in KYSE150R cells.	('OCT4', 'Gene', '5460', (45, 49))	('NANOG', 'Gene', '79923', (60, 65))	('NANOG', 'Gene', (60, 65))	('KYSE150R', 'Var', (96, 104))	('stemness', 'Disease', 'MESH:D020295', (18, 26))	('stemness', 'Disease', (18, 26))	('higher', 'PosReg', (86, 92))	('SOX2', 'Gene', '6657', (51, 55))	('OCT4', 'Gene', (45, 49))	('SOX2', 'Gene', (51, 55))
377226	31417277	We found that H19 expression was significantly upregulated in KYSE150R cells.	('H19', 'Gene', '283120', (14, 17))	('upregulated', 'PosReg', (47, 58))	('H19', 'Gene', (14, 17))	('KYSE150R', 'Var', (62, 70))	('expression', 'MPA', (18, 28))
377228	31417277	We found that knockdown of H19 decreased the survival fraction values with the increasing of radiation doses (Figure 3B, P<0.05).	('H19', 'Gene', '283120', (27, 30))	('H19', 'Gene', (27, 30))	('survival fraction', 'CPA', (45, 62))	('decreased', 'NegReg', (31, 40))	('knockdown', 'Var', (14, 23))
377229	31417277	The results suggested that knockdown of H19 inhibited cells proliferation and migration (Figure 3C, D, P<0.05).	('knockdown', 'Var', (27, 36))	('cells proliferation', 'CPA', (54, 73))	('inhibited', 'NegReg', (44, 53))	('H19', 'Gene', '283120', (40, 43))	('H19', 'Gene', (40, 43))
377230	31417277	The results showed that knockdown of H19 markedly decreased the sphere formation ability of KYSE150R cells (Figure 3E, P<0.05).	('sphere formation ability', 'CPA', (64, 88))	('decreased', 'NegReg', (50, 59))	('H19', 'Gene', (37, 40))	('H19', 'Gene', '283120', (37, 40))	('knockdown', 'Var', (24, 33))
377232	31417277	We found that knockdown of H19 restrained OCT4, SOX2, and NANOG expression levels (Figure 3F, P<0.05).	('OCT4', 'Gene', '5460', (42, 46))	('H19', 'Gene', '283120', (27, 30))	('SOX2', 'Gene', '6657', (48, 52))	('OCT4', 'Gene', (42, 46))	('restrained', 'NegReg', (31, 41))	('H19', 'Gene', (27, 30))	('SOX2', 'Gene', (48, 52))	('NANOG', 'Gene', '79923', (58, 63))	('NANOG', 'Gene', (58, 63))	('knockdown', 'Var', (14, 23))
377233	31417277	Taken together, these results revealed that knockdown of H19 inhibits cells proliferation, migration, and stemness in radioresistant KYSE150 cells.	('H19', 'Gene', '283120', (57, 60))	('stemness', 'Disease', 'MESH:D020295', (106, 114))	('stemness', 'Disease', (106, 114))	('knockdown', 'Var', (44, 53))	('migration', 'CPA', (91, 100))	('cells proliferation', 'CPA', (70, 89))	('H19', 'Gene', (57, 60))	('inhibits', 'NegReg', (61, 69))
377234	31417277	Based on the online starBase database, data showed that H19 and WNT 3'UTR contain the binding sites of miR-22-3p (Figure 4A).	('H19', 'Gene', '283120', (56, 59))	('binding', 'Interaction', (86, 93))	('miR-22-3p', 'Var', (103, 112))	('H19', 'Gene', (56, 59))
377235	31417277	H19-si was transfected into KYSE150R cells and the results showed that knockdown of H19 increased the levels of miR-22-3p expression (Figure 4B, P< 0.05).	('H19', 'Gene', (0, 3))	('knockdown', 'Var', (71, 80))	('increased', 'PosReg', (88, 97))	('levels of miR-22-3p expression', 'MPA', (102, 132))	('H19', 'Gene', '283120', (84, 87))	('H19', 'Gene', (84, 87))	('H19', 'Gene', '283120', (0, 3))
377237	31417277	The results showed that knockdown of H19 significantly decreased WNT1 expression at both the mRNA and protein levels in KYSE150R cells (Figure 4C, D).	('WNT1', 'Gene', (65, 69))	('decreased', 'NegReg', (55, 64))	('H19', 'Gene', (37, 40))	('H19', 'Gene', '283120', (37, 40))	('knockdown', 'Var', (24, 33))
377238	31417277	Taken together, knockdown of H19 upregulates miR-22-3p, while downregulates WNT1 expression.	('WNT1', 'Gene', (76, 80))	('miR-22-3p', 'MPA', (45, 54))	('upregulates', 'PosReg', (33, 44))	('knockdown', 'Var', (16, 25))	('H19', 'Gene', '283120', (29, 32))	('downregulates', 'NegReg', (62, 75))	('H19', 'Gene', (29, 32))
377248	31417277	H19 has been reported to target miR-194-5p, which was essential for development of colorectal adenocarcinoma.	('H19', 'Gene', (0, 3))	('colorectal adenocarcinoma', 'Disease', (83, 108))	('miR-194-5p', 'Var', (32, 42))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (83, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('H19', 'Gene', '283120', (0, 3))
377250	31417277	microRNA-153-3p enhances cell radiosensitivity by targeting BCL2 in human glioma.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('human', 'Species', '9606', (68, 73))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('enhances', 'PosReg', (16, 24))	('microRNA-153-3p', 'Var', (0, 15))	('cell radiosensitivity', 'Phenotype', 'HP:0010997', (25, 46))	('glioma', 'Disease', (74, 80))	('BCL2', 'Gene', '596', (60, 64))	('cell radiosensitivity', 'CPA', (25, 46))	('BCL2', 'Gene', (60, 64))	('targeting', 'Reg', (50, 59))
377251	31417277	microRNA-16-5p enhances radiosensitivity in prostate tumor cells.	('radiosensitivity', 'CPA', (24, 40))	('microRNA-16-5p', 'Var', (0, 14))	('enhances', 'PosReg', (15, 23))	('prostate tumor', 'Disease', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('prostate tumor', 'Phenotype', 'HP:0100787', (44, 58))	('prostate tumor', 'Disease', 'MESH:D011471', (44, 58))
377253	31417277	In addition, One study showed that microRNA 301a targets WNT1 to suppress cell proliferation and migration and enhance radiosensitivity in esophageal cancer cells.	('cell proliferation', 'CPA', (74, 92))	('microRNA 301a', 'Var', (35, 48))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (111, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('enhance', 'PosReg', (111, 118))	('esophageal cancer', 'Disease', (139, 156))	('WNT1', 'Gene', (57, 61))	('suppress', 'NegReg', (65, 73))	('radiosensitivity', 'CPA', (119, 135))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
377256	31417277	Transwell and sphere formation assays showed that cells migration and sphere formation ability were higher in KYSE150R, suggesting that radiation enhanced cells migration and stemness in ESCC cells.	('cells migration', 'CPA', (50, 65))	('stemness', 'Disease', 'MESH:D020295', (175, 183))	('stemness', 'Disease', (175, 183))	('enhanced', 'PosReg', (146, 154))	('higher', 'PosReg', (100, 106))	('KYSE150R', 'Var', (110, 118))	('cells migration', 'CPA', (155, 170))	('sphere formation ability', 'CPA', (70, 94))
377258	31417277	Furthermore, survival fraction assays showed that knockdown of H19 decreased the survival fraction values.	('H19', 'Gene', '283120', (63, 66))	('H19', 'Gene', (63, 66))	('knockdown', 'Var', (50, 59))	('survival fraction values', 'MPA', (81, 105))	('decreased', 'NegReg', (67, 76))
377262	31417277	Our findings may implicate that knockdown of H19 downregulates the WNT1 via upregulating miR-22-3p expression, which could contribute to the inhibition of cells proliferation, migration and stemness in the radioresistant ESCC cells.	('inhibition', 'NegReg', (141, 151))	('stemness', 'Disease', (190, 198))	('stemness', 'Disease', 'MESH:D020295', (190, 198))	('radioresistant', 'CPA', (206, 220))	('migration', 'CPA', (176, 185))	('H19', 'Gene', '283120', (45, 48))	('H19', 'Gene', (45, 48))	('knockdown', 'Var', (32, 41))	('WNT1', 'Gene', (67, 71))	('upregulating', 'PosReg', (76, 88))	('downregulates', 'NegReg', (49, 62))	('miR-22-3p expression', 'MPA', (89, 109))	('cells proliferation', 'CPA', (155, 174))
377333	30197939	In principle, regional lymph nodes were defined as the supraclavicular, cervical paraesophageal, and mediastinal lymph nodes (101, 104, 105, 106rec, 106pre, 106tb, and 107) to the carina for upper thoracic tumors, the mediastinal and perigastric lymph nodes (1, 2, 3, 7, 105, 106rec, 106pre, 106tb, 107, 108, 109, and 110) for midthoracic tumors, and the mediastinal, perigastric, and celiac lymph nodes (1, 2, 3, 7, 9, 105, 106rec, 106pre, 106tb, 107, 108, 109, and 110) for lower thoracic tumors.	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('thoracic tumors', 'Disease', (482, 497))	('tumor', 'Phenotype', 'HP:0002664', (491, 496))	('upper thoracic tumors', 'Disease', 'MESH:D013899', (191, 212))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Phenotype', 'HP:0002664', (491, 497))	('thoracic tumors', 'Disease', 'MESH:D013899', (197, 212))	('thoracic tumors', 'Disease', 'MESH:D013899', (482, 497))	('midthoracic tumors', 'Disease', (327, 345))	('106pre', 'Var', (433, 439))	('midthoracic tumors', 'Disease', 'MESH:D009369', (327, 345))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('thoracic tumors', 'Disease', 'MESH:D013899', (330, 345))	('upper thoracic tumors', 'Disease', (191, 212))
377444	29073141	The incidence of esophageal adenocarcinomas in EAs is five times higher than that in AAs, and so any excess of European ancestry at a SNP could be detecting a region harboring susceptibility variants for EAC and BE.	('esophageal adenocarcinomas', 'Disease', (17, 43))	('EAC', 'Phenotype', 'HP:0011459', (204, 207))	('EAC', 'Disease', (204, 207))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (17, 43))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (17, 42))	('variants', 'Var', (191, 199))	('BE', 'Phenotype', 'HP:0100580', (212, 214))
377460	29073141	Further sequencing of the two regions with a larger sample size will be conducted to locate genetic variants for esophageal adenocarcinoma and Barrett's esophagus and identify the mechanisms that explain resistance to the development of BE in individuals of African ancestry.	('variants', 'Var', (100, 108))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (143, 162))	('esophageal adenocarcinoma', 'Disease', (113, 138))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (113, 138))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (113, 138))	("Barrett's esophagus", 'Disease', (143, 162))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (143, 162))	('BE', 'Phenotype', 'HP:0100580', (237, 239))
377464	26085809	In addition, genomic deletions upstream to FOXF1 identified in ACDMPV patients have revealed that FOXF1 expression is tightly regulated by distal tissue-specific enhancers.	('patients', 'Species', '9606', (70, 78))	('FOXF1', 'Gene', (98, 103))	('FOXF1', 'Gene', (43, 48))	('deletions', 'Var', (21, 30))	('expression', 'MPA', (104, 114))
377465	26085809	Interestingly, FOXF1 has been found to be incompletely paternally imprinted in human lungs; characterized genomic deletions arose de novo exclusively on maternal chromosome 16, with most of them being Alu-Alu mediated.	('FOXF1', 'Gene', (15, 20))	('human', 'Species', '9606', (79, 84))	('deletions', 'Var', (114, 123))
377467	26085809	Additionally, epigenetic inactivation of FOXF1 has been reported in breast and colorectal cancers, whereas overexpression of FOXF1 has been associated with a number of other human cancers, e.g.	('cancers', 'Disease', (90, 97))	('associated', 'Reg', (140, 150))	('human', 'Species', '9606', (174, 179))	('colorectal cancers', 'Disease', 'MESH:D015179', (79, 97))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('reported', 'Reg', (56, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('colorectal cancers', 'Disease', (79, 97))	('epigenetic inactivation', 'Var', (14, 37))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('FOXF1', 'Gene', (41, 46))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('breast', 'Disease', (68, 74))
377469	26085809	Constitutional duplications of FOXF1 have recently been reported in congenital intestinal malformations.	('reported', 'Reg', (56, 64))	('intestinal malformations', 'Phenotype', 'HP:0002242', (79, 103))	('Constitutional duplications', 'Var', (0, 27))	('congenital intestinal malformations', 'Disease', (68, 103))	('congenital intestinal malformations', 'Disease', 'MESH:D000013', (68, 103))	('FOXF1', 'Gene', (31, 36))
377470	26085809	Thus, understanding the genomic and epigenetic complexity at the FOXF1 locus will improve diagnosis, prognosis, and treatment of ACDMPV and other human disorders associated with FOXF1 alterations.	('improve', 'PosReg', (82, 89))	('alterations', 'Var', (184, 195))	('human', 'Species', '9606', (146, 151))	('ACDMPV', 'Disease', (129, 135))	('FOXF1', 'Gene', (178, 183))	('FOXF1', 'Gene', (65, 70))
377473	26085809	The focus of this review is genomic and epigenetic complexity in the regulation of Forkhead Box F1 (FOXF1), previously known as Forkhead RElated ACtivator (FREAC-1) or Hepatocyte nuclear factor 3/fork head homolog (HFH-8), as well as functional consequences of genetic variants involving FOXF1 in human development and disease.	('FREAC-1', 'Gene', (156, 163))	('Forkhead Box F1', 'Gene', (83, 98))	('Forkhead Box F1', 'Gene', '2294', (83, 98))	('FREAC-1', 'Gene', '2294', (156, 163))	('genetic variants', 'Var', (261, 277))	('FOXF1', 'Gene', (288, 293))	('variants', 'Var', (269, 277))	('human', 'Species', '9606', (297, 302))	('HFH-8', 'Gene', '15227', (215, 220))	('FOXF1', 'Gene', (100, 105))	('HFH-8', 'Gene', (215, 220))
377483	26085809	The Foxf1+/- phenotype was associated with lung hypoplasia and various tracheal abnormalities such as esophageal atresia and tracheo-esophageal fistula.	('esophageal atresia', 'Disease', (102, 120))	('tracheal abnormalities', 'Disease', (71, 93))	('tracheal abnormalities', 'Disease', 'MESH:D014133', (71, 93))	('esophageal atresia', 'Disease', 'MESH:D004933', (102, 120))	('lung hypoplasia', 'Disease', (43, 58))	('associated', 'Reg', (27, 37))	('lung hypoplasia', 'Disease', 'MESH:D008171', (43, 58))	('esophageal atresia', 'Phenotype', 'HP:0002032', (102, 120))	('Foxf1+/- phenotype', 'Var', (4, 22))	('tracheo-esophageal fistula', 'Disease', 'MESH:D004937', (125, 151))	('tracheal abnormalities', 'Phenotype', 'HP:0002778', (71, 93))	('tracheo-esophageal fistula', 'Disease', (125, 151))	('tracheo-esophageal fistula', 'Phenotype', 'HP:0002575', (125, 151))	('lung hypoplasia', 'Phenotype', 'HP:0002089', (43, 58))
377494	26085809	Gall bladders in Foxf1+/- mice are smaller in size with severe structural abnormalities such as a deficient external smooth muscle cell layer.	('structural abnormalities', 'Disease', (63, 87))	('Foxf1+/-', 'Var', (17, 25))	('structural abnormalities', 'Disease', 'MESH:C566527', (63, 87))	('smaller', 'NegReg', (35, 42))	('mice', 'Species', '10090', (26, 30))
377495	26085809	In addition, Foxf1+/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury.	('Foxf1+/-', 'Var', (13, 21))	('CCl4', 'Gene', '20303', (112, 116))	('mice', 'Species', '10090', (22, 26))	('injury', 'Disease', (117, 123))	('abnormal liver', 'Phenotype', 'HP:0001392', (74, 88))	('injury', 'Disease', 'MESH:D058186', (117, 123))	('CCl4', 'Gene', (112, 116))	('abnormal liver regeneration', 'Disease', 'MESH:D056486', (74, 101))	('abnormal liver regeneration', 'Disease', (74, 101))	('defective', 'NegReg', (35, 44))	('stellate cell activation', 'CPA', (45, 69))
377496	26085809	Tissue-specific knock out of Foxf1 using Tie2-Cre transgene (endothelium and hematopoietic lineage specific) also leads to embryonic lethality in mice.	('knock out', 'Var', (16, 25))	('embryonic lethality', 'Disease', 'MESH:D020964', (123, 142))	('embryonic lethality', 'Disease', (123, 142))	('Tie2', 'Gene', '21687', (41, 45))	('leads to', 'Reg', (114, 122))	('mice', 'Species', '10090', (146, 150))	('Tie2', 'Gene', (41, 45))	('Foxf1', 'Gene', (29, 34))
377498	26085809	Endothelial specific deletion of Foxf1 (Pdgfb-CreER) at E9.5 was sufficient to cause polyhydramnios and reduced vascular branching in the placenta, yolk sac, and lung of E12.5 embryos.	('Foxf1', 'Gene', (33, 38))	('Pdgfb', 'Gene', '18591', (40, 45))	('polyhydramnios', 'Disease', (85, 99))	('reduced', 'NegReg', (104, 111))	('deletion', 'Var', (21, 29))	('cause', 'Reg', (79, 84))	('polyhydramnios', 'Phenotype', 'HP:0001561', (85, 99))	('vascular branching in the placenta', 'CPA', (112, 146))	('Pdgfb', 'Gene', (40, 45))
377500	26085809	Smooth muscle cell specific knockout of Foxf1 (smMHC-Cre) causes neonatal lethality and the loss of differentiated smooth muscle layers in esophagus.	('smMHC', 'Gene', '17880', (47, 52))	('causes', 'Reg', (58, 64))	('Foxf1', 'Gene', (40, 45))	('loss', 'NegReg', (92, 96))	('neonatal lethality', 'CPA', (65, 83))	('smMHC', 'Gene', (47, 52))	('knockout', 'Var', (28, 36))
377503	26085809	Interestingly, mice that overexpress Foxf1 by knocking-in Foxf1 at the ROSA26 locus also exhibit embryonic lethality.	('ROSA26', 'Gene', '14910', (71, 77))	('Foxf1', 'Gene', (37, 42))	('ROSA26', 'Gene', (71, 77))	('overexpress', 'PosReg', (25, 36))	('Foxf1', 'Gene', (58, 63))	('embryonic lethality', 'Disease', 'MESH:D020964', (97, 116))	('embryonic lethality', 'Disease', (97, 116))	('mice', 'Species', '10090', (15, 19))	('knocking-in', 'Var', (46, 57))
377507	26085809	In 2009, heterozygous genomic deletions and point mutations in FOXF1 were identified in patients with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV; MIM# 265380), suggesting that haploinsufficiency of the gene causes this rare lethal developmental disorder of the lung.	('point mutations', 'Var', (44, 59))	('Misalignment of Pulmonary Veins', 'Disease', (136, 167))	('patients', 'Species', '9606', (88, 96))	('haploinsufficiency', 'Disease', (207, 225))	('Misalignment of Pulmonary Veins', 'Disease', 'MESH:D010547', (136, 167))	('Capillary Dysplasia', 'Phenotype', 'HP:0025104', (111, 130))	('FOXF1', 'Gene', (63, 68))	('Alveolar Capillary Dysplasia', 'Disease', 'MESH:C536590', (102, 130))	('developmental disorder', 'Phenotype', 'HP:0001263', (262, 284))	('developmental disorder of the lung', 'Disease', (262, 296))	('developmental disorder of the lung', 'Disease', 'MESH:D008171', (262, 296))	('haploinsufficiency', 'Disease', 'MESH:D058495', (207, 225))	('causes', 'Reg', (238, 244))	('Alveolar Capillary Dysplasia', 'Disease', (102, 130))
377508	26085809	The cardinal diagnostic features of ACDMPV include misalignment (malposition) of pulmonary veins, medial thickening of smooth muscles in pulmonary arteries, hyperplasia of alveolar epithelium, and drastically decreased number of capillaries and lobular underdevelopment.	('misalignment', 'Var', (51, 63))	('hyperplasia of alveolar', 'Phenotype', 'HP:0009085', (157, 180))	('hyperplasia of alveolar epithelium', 'Disease', (157, 191))	('ACDMPV', 'Disease', (36, 42))	('pulmonary veins', 'Disease', 'MESH:D000071078', (81, 96))	('hyperplasia of alveolar epithelium', 'Disease', 'MESH:C536309', (157, 191))	('pulmonary veins', 'Disease', (81, 96))	('decreased', 'NegReg', (209, 218))
377517	26085809	The phenotype of Foxf1+/- mice partially resembles the symptoms seen in patients with ACDMPV.	('patients', 'Species', '9606', (72, 80))	('ACDMPV', 'Disease', (86, 92))	('Foxf1+/- mice', 'Var', (17, 30))	('mice', 'Species', '10090', (26, 30))
377518	26085809	Most Foxf1+/- mice (55-90%) die shortly after birth, exhibiting alveolar capillary dysplasia and additional cardiac and/or gastrointestinal defects.	('mice', 'Species', '10090', (14, 18))	('cardiac and/or', 'CPA', (108, 122))	('gastrointestinal defects', 'Phenotype', 'HP:0002012', (123, 147))	('alveolar capillary dysplasia', 'Disease', (64, 92))	('gastrointestinal defects', 'Disease', 'MESH:D005767', (123, 147))	('capillary dysplasia', 'Phenotype', 'HP:0025104', (73, 92))	('alveolar capillary dysplasia', 'Disease', 'MESH:C536590', (64, 92))	('gastrointestinal defects', 'Disease', (123, 147))	('Foxf1+/-', 'Var', (5, 13))
377521	26085809	Of note, mesodermal inactivation of Pten in mice leads to an ACD-like phenotype with evidence of failure in blood oxygenation.	('Pten', 'Gene', (36, 40))	('Pten', 'Gene', '19211', (36, 40))	('inactivation', 'Var', (20, 32))	('failure', 'Disease', 'MESH:D017093', (97, 104))	('leads to', 'Reg', (49, 57))	('failure', 'Disease', (97, 104))	('oxygen', 'Chemical', 'MESH:D010100', (114, 120))	('ACD-like phenotype', 'Disease', (61, 79))	('mice', 'Species', '10090', (44, 48))
377531	26085809	In addition to genomic deletions encompassing FOXF1, a comparable number of overlapping copy-number deletions upstream of FOXF1 and leaving the gene intact have been found in ACDMPV patients.	('FOXF1', 'Gene', (46, 51))	('FOXF1', 'Gene', (122, 127))	('ACDMPV', 'Disease', (175, 181))	('patients', 'Species', '9606', (182, 190))	('deletions', 'Var', (100, 109))	('found', 'Reg', (166, 171))
377536	26085809	Moreover, it is possible that some patients with ACDMPV that are FOXF1 mutation and deletion negative, may carry submicroscopic retrotransposon (e.g.	('mutation', 'Var', (71, 79))	('FOXF1', 'Gene', (65, 70))	('patients', 'Species', '9606', (35, 43))	('carry', 'Reg', (107, 112))
377544	26085809	In patients with ACDMPV for whom the parental origin of deletions involving the FOXF1 locus could be determined, all 24 studied arose de novo on the maternal chromosome 16, suggesting that FOXF1 is paternally imprinted in the human lungs.	('deletions', 'Var', (56, 65))	('FOXF1', 'Gene', (80, 85))	('patients', 'Species', '9606', (3, 11))	('human', 'Species', '9606', (226, 231))
377546	26085809	Furthermore, segregation analysis of a missense mutation in FOXF1 (c.416G>T; p. Arg139Leu)in a familial case of ACDMPV provided additional support for paternal imprinting of FOXF1 in humans.	('humans', 'Species', '9606', (183, 189))	('c.416G>T;', 'Var', (67, 76))	('Arg139Leu', 'Var', (80, 89))	('Arg139Leu', 'SUBSTITUTION', 'None', (80, 89))	('FOXF1', 'Gene', (60, 65))	('c.416G>T', 'Mutation', 'c.416G>T', (67, 75))	('missense mutation', 'Var', (39, 56))
377547	26085809	In a third of cases, trisomy rescue leads to maternal uniparental disomy 16 [UPD(16)], which is the most common UPD reported other than UPD(15), and often accompanied by confined placental mosaicism with trisomy 16 cell line.	('maternal uniparental disomy', 'Disease', 'MESH:D024182', (45, 72))	('trisomy rescue', 'Var', (21, 35))	('maternal uniparental disomy', 'Disease', (45, 72))	('leads to', 'Reg', (36, 44))
377550	26085809	In contrast to humans, Foxf1 has been found not to be imprinted in mice, with no difference in its expression between parental alleles in E15.5, E18.5, and P0.5 lungs from reciprocal crosses.	('expression', 'MPA', (99, 109))	('E18.5', 'Var', (145, 150))	('Foxf1', 'Gene', (23, 28))	('P0.5', 'Var', (156, 160))	('humans', 'Species', '9606', (15, 21))	('E15.5', 'Var', (138, 143))	('mice', 'Species', '10090', (67, 71))
377552	26085809	The perinatal mortality in Foxf1+/- mice also does not show a parent-of-origin inheritance pattern when investigated on the CD-1 and C57BL/6J backgrounds (unpublished data).	('Foxf1+/-', 'Var', (27, 35))	('mice', 'Species', '10090', (36, 40))	('CD-1', 'Gene', (124, 128))	('CD-1', 'Gene', '111334', (124, 128))
377553	26085809	Surviving Foxf1+/- Swiss Black pups up-regulated the level of Foxf1 to wild type levels and showed only mild abnormalities in alveolar septation without obvious vascular defects.	('abnormalities in alveolar', 'Phenotype', 'HP:0006477', (109, 134))	('up-regulated', 'PosReg', (36, 48))	('Foxf1+/-', 'Var', (10, 18))	('alveolar septation without obvious vascular defects', 'Disease', 'MESH:D002282', (126, 177))	('level', 'MPA', (53, 58))	('Foxf1', 'Gene', (62, 67))
377565	26085809	Mast cell chymases, tryptases, and the chemokine CXCL-12 essential for mast cell migration and chemotaxis were significantly up-regulated as previously described in Foxf1+/- lungs.	('CXCL-12', 'Gene', '20315', (49, 56))	('CXCL-12', 'Gene', (49, 56))	('up-regulated', 'PosReg', (125, 137))	('Foxf1+/-', 'Var', (165, 173))	('Mast cell chymases', 'Enzyme', (0, 18))	('tryptases', 'Enzyme', (20, 29))
377566	26085809	Numerous members of collagen genes were up-regulated in lungs of both ACDMPV patients and Foxf1+/- mice, suggesting that loss of FOXF1 may stimulate endothelial-mesenchymal transition leading to pulmonary fibrosis and lung dysfunction.	('stimulate', 'PosReg', (139, 148))	('mice', 'Species', '10090', (99, 103))	('lung dysfunction', 'Phenotype', 'HP:0005952', (218, 234))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (195, 213))	('lung dysfunction', 'Disease', 'MESH:D008171', (218, 234))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (195, 213))	('loss', 'Var', (121, 125))	('lung dysfunction', 'Disease', (218, 234))	('FOXF1', 'Gene', (129, 134))	('up-regulated', 'PosReg', (40, 52))	('patients', 'Species', '9606', (77, 85))	('pulmonary fibrosis', 'Disease', (195, 213))	('endothelial-mesenchymal transition', 'CPA', (149, 183))
377571	26085809	FOXF1 has been reported to be epigenetically inactivated by hypermethy-lation of its promoter in breast cancer cell lines and invasive ductal carcinomas.	('epigenetically', 'Var', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('inactivated', 'NegReg', (45, 56))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (126, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('invasive ductal carcinomas', 'Disease', (126, 152))	('FOXF1', 'Gene', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('hypermethy-lation', 'Var', (60, 77))	('breast cancer', 'Disease', (97, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
377578	26085809	Overexpression of FOXF1 promotes invasion and metastasis of breast carcinomas.	('breast carcinomas', 'Phenotype', 'HP:0003002', (60, 77))	('metastasis of breast carcinomas', 'Disease', 'MESH:D009362', (46, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('promotes', 'PosReg', (24, 32))	('Overexpression', 'Var', (0, 14))	('metastasis of breast carcinomas', 'Disease', (46, 77))	('FOXF1', 'Gene', (18, 23))
377583	26085809	Common variants mapping on chromosome 16q24.1 close to FOXF1 have also been associated with susceptibility to Barrett's esophagus and esophageal carcinoma (rs9936833), and breast cancer (rs1728400) in genome-wide association studies.	('susceptibility', 'Reg', (92, 106))	('esophageal carcinoma', 'Disease', (134, 154))	('FOXF1', 'Gene', (55, 60))	('rs1728400', 'Mutation', 'rs1728400', (187, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('rs1728400', 'Var', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (134, 154))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (134, 154))	('breast cancer', 'Disease', (172, 185))	('associated', 'Reg', (76, 86))	('rs9936833', 'Var', (156, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('rs9936833', 'Mutation', 'rs9936833', (156, 165))	("Barrett's esophagus", 'Disease', (110, 129))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (110, 129))
377584	26085809	Further analysis of the genomic region close to the SNP rs9936833, led to the identification of additional SNPs associated with susceptibility to esophageal carcinoma.	('rs9936833', 'Var', (56, 65))	('esophageal carcinoma', 'Disease', (146, 166))	('rs9936833', 'Mutation', 'rs9936833', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (146, 166))	('SNPs', 'Var', (107, 111))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (146, 166))	('associated', 'Reg', (112, 122))
377587	26085809	A patient harboring a complex de novo duplication-triplication rearrangement in 16q24.1-q24.3 involving FOXF1, presented with severe psychomotor disability, numerous dysmorphic features, and congenital malformations, including gut malrotation and gall bladder agenesis.	('psychomotor disability', 'Phenotype', 'HP:0025356', (133, 155))	('psychomotor disability', 'Disease', (133, 155))	('congenital malformations', 'Disease', (191, 215))	('duplication-triplication rearrangement', 'Var', (38, 76))	('presented', 'Reg', (111, 120))	('psychomotor disability', 'Disease', 'OMIM:616393', (133, 155))	('congenital malformations', 'Disease', 'MESH:D000013', (191, 215))	('malrotation', 'Disease', (231, 242))	('severe psychomotor disability', 'Phenotype', 'HP:0011344', (126, 155))	('bladder agenesis', 'Phenotype', 'HP:0010477', (252, 268))	('numerous dysmorphic features', 'Disease', 'MESH:D000013', (157, 185))	('malrotation', 'Disease', 'MESH:C562456', (231, 242))	('numerous dysmorphic features', 'Disease', (157, 185))	('gall bladder agenesis', 'Disease', 'MESH:D005705', (247, 268))	('gut malrotation', 'Phenotype', 'HP:0002566', (227, 242))	('patient', 'Species', '9606', (2, 9))	('gall bladder agenesis', 'Disease', (247, 268))	('FOXF1', 'Gene', (104, 109))
377591	26085809	Disruptions or amplifications in FOXF1 cause severe human disorders.	('cause', 'Reg', (39, 44))	('Disruptions', 'Var', (0, 11))	('FOXF1', 'Gene', (33, 38))	('severe human disorders', 'Disease', (45, 67))	('human', 'Species', '9606', (52, 57))	('amplifications', 'Var', (15, 29))
377635	25153136	EGFR and p-Sp1 staining were mainly observed in cell membranes and nuclei, respectively, whereas Fascin staining was more diffuse throughout the cytoplasm.	('EGFR', 'Gene', (0, 4))	('p-Sp1', 'Var', (9, 14))	('Fascin', 'Gene', '6624', (97, 103))	('Fascin', 'Gene', (97, 103))	('EGFR', 'Gene', '1956', (0, 4))	('p-Sp1', 'Species', '73787', (9, 14))
377640	25153136	Kaplan-Meier analysis provided further support that EGFR, p-Sp1, and Fascin were significant predictors of OS in both generation and validation datasets, except for EGFR in the validation dataset (Figure S3).	('EGFR', 'Gene', (165, 169))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('Fascin', 'Gene', (69, 75))	('Fascin', 'Gene', '6624', (69, 75))	('p-Sp1', 'Species', '73787', (58, 63))	('EGFR', 'Gene', '1956', (165, 169))	('p-Sp1', 'Var', (58, 63))
377641	25153136	In the generation dataset, the 3-year OS was significantly lower for the p-Sp1 and Fascin high-expression groups than the low-expression groups.	('p-Sp1', 'Species', '73787', (73, 78))	('p-Sp1', 'Gene', (73, 78))	('lower', 'NegReg', (59, 64))	('3-year OS', 'CPA', (31, 40))	('Fascin', 'Gene', (83, 89))	('Fascin', 'Gene', '6624', (83, 89))	('high-expression', 'Var', (90, 105))
377642	25153136	In the validation dataset, the 3- and 5-year OS were significantly lower for the EGFR, p-Sp1, and Fascin high-expression groups than the low-expression groups.	('Fascin', 'Gene', (98, 104))	('high-expression', 'Var', (105, 120))	('p-Sp1', 'Species', '73787', (87, 92))	('lower', 'NegReg', (67, 72))	('EGFR', 'Gene', '1956', (81, 85))	('Fascin', 'Gene', '6624', (98, 104))	('EGFR', 'Gene', (81, 85))
377651	25153136	Patients were subdivided into four subgroups: N0+low-risk, N0+high-risk, N1+low-risk, and N1+high-risk.	('Patients', 'Species', '9606', (0, 8))	('N0+low-risk', 'Var', (46, 57))	('N0+high-risk', 'Var', (59, 71))	('N1+high-risk', 'Var', (90, 102))
377661	25153136	EGFR is a particularly promising molecular target of therapy, as EGFR inhibitors have been widely applied to a variety of solid tumors, such as lung cancer, colorectal cancer, breast cancer, and even ESCC.	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('EGFR', 'Gene', (65, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('inhibitors', 'Var', (70, 80))	('ESCC', 'Disease', (200, 204))	('EGFR', 'Gene', (0, 4))	('solid tumors', 'Disease', (122, 134))	('colorectal cancer', 'Disease', (157, 174))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('lung cancer', 'Disease', (144, 155))	('EGFR', 'Gene', '1956', (65, 69))	('applied', 'Reg', (98, 105))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('solid tumors', 'Disease', 'MESH:D009369', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (176, 189))	('EGFR', 'Gene', '1956', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))
377713	25050929	The methylation of EPB41L3, GPX3, and COL14A1 genes were only found in ESCC patients' plasma, but not in normal individuals upon testing 42 ESCC patients and 50 healthy individuals.	('patients', 'Species', '9606', (145, 153))	('EPB41L3', 'Gene', '23136', (19, 26))	('COL14A1', 'Gene', (38, 45))	('patients', 'Species', '9606', (76, 84))	('ESCC', 'Disease', (71, 75))	('GPX3', 'Gene', '2878', (28, 32))	('methylation', 'Var', (4, 15))	('GPX3', 'Gene', (28, 32))	('COL14A1', 'Gene', '7373', (38, 45))	('found', 'Reg', (62, 67))	('EPB41L3', 'Gene', (19, 26))
377720	25050929	Both genetic and epigenetic aberrations are linked by intricate crosstalk, and can either individually or in synergy lead to the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('lead to', 'Reg', (117, 124))	('epigenetic aberrations', 'Var', (17, 39))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
377726	25050929	Furthermore, aberrant DNA methylation usually occurs somatically in cancers and can be detected in the blood circulation, so it may serve as a novel marker for cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('DNA', 'Protein', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', (68, 74))	('aberrant', 'Var', (13, 21))
377729	25050929	After analysis of the methylation differences and then in combination with independent gene expression data using BRB (Biometrics Research Branch)-Array Tools of the National Cancer Institute, a set of genes that are deregulated by aberrant DNA methylation in ESCC was identified.	('Cancer', 'Disease', (175, 181))	('Cancer', 'Disease', 'MESH:D009369', (175, 181))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('aberrant DNA methylation', 'Var', (232, 256))	('deregulated', 'PosReg', (217, 228))	('ESCC', 'Gene', (260, 264))
377756	25050929	After normalization, all 12 samples showed very similar signal distributions (Figure 1), which means with both hypermethylation and hypomethylation changes, tumor, adjacent normal and normal tissues are similar on overall methylation signals.	('tumor', 'Disease', (157, 162))	('hypermethylation', 'Var', (111, 127))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('hypomethylation changes', 'Var', (132, 155))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('changes', 'Var', (148, 155))
377758	25050929	To identify aberrant differential methylated CpG (DMC) in ESCC, we performed statistical analysis to pare down the selection of CpG sites based on DNA methylation differences (Figure 3).	('aberrant', 'Var', (12, 20))	('DMC', 'Chemical', '-', (50, 53))	('ESCC', 'Disease', (58, 62))
377760	25050929	These 66,857 DMCs included 18,146 hypermethylated CpG sites (hyper-DMCs) and 48,711 hypomethylated CpG sites (hypo-DMCs) in tumors compared with normal/adjacent normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('DMCs', 'Chemical', 'MESH:C023025', (115, 119))	('DMCs', 'Chemical', 'MESH:C023025', (67, 71))	('CpG', 'Gene', (50, 53))	('DMCs', 'Chemical', 'MESH:C023025', (13, 17))	('hypermethylated', 'Var', (34, 49))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))
377765	25050929	Among the 294 genes, 168 genes showed inverse correlation between DNA methylation and expression change, which means when compared with normal tissue, they were either hypermethylated with lower expression, or hypomethylated with higher expression in tumor tissue (Figure 3).	('tumor', 'Disease', (251, 256))	('expression', 'MPA', (195, 205))	('hypomethylated', 'Var', (210, 224))	('lower', 'NegReg', (189, 194))	('higher expression', 'PosReg', (230, 247))	('expression', 'MPA', (86, 96))	('hypermethylated', 'Var', (168, 183))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
377768	25050929	As we described above, the 168 genes were either hypermethylated with lower expression, or hypomethylated with higher expression in tumor tissue compared with normal tissue.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('hypomethylated', 'Var', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('lower', 'NegReg', (70, 75))	('expression', 'MPA', (76, 86))	('tumor', 'Disease', (132, 137))	('higher', 'PosReg', (111, 117))	('hypermethylated', 'Var', (49, 64))	('expression', 'MPA', (118, 128))
377774	25050929	Methylation of EPB41L3 was more frequently seen in patients with tumor size 5 cm than in patients with tumor size <5 cm (P = 0.044, Table 4).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (65, 70))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('patients', 'Species', '9606', (89, 97))	('seen', 'Reg', (43, 47))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('EPB41L3', 'Gene', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('EPB41L3', 'Gene', '23136', (15, 22))
377776	25050929	The methylation frequencies of GPX3 were lower in the pT1-2 and pN0-1 groups compared with the pT3 and pN2 groups, respectively.	('methylation frequencies', 'MPA', (4, 27))	('pT1', 'Gene', '58492', (54, 57))	('lower', 'NegReg', (41, 46))	('pN2', 'Gene', (103, 106))	('GPX3', 'Gene', (31, 35))	('GPX3', 'Gene', '2878', (31, 35))	('pN2', 'Gene', '351', (103, 106))	('pT1', 'Gene', (54, 57))	('pT3', 'Gene', '7694', (95, 98))	('pT3', 'Gene', (95, 98))	('pN0-1', 'Var', (64, 69))
377785	25050929	EPB41L3 hypermethylation was correlated with advanced pN classification (pN2) (87.5% vs. 17.6%) (P<0.001) (Table 6).	('hypermethylation', 'Var', (8, 24))	('pN2', 'Gene', (73, 76))	('EPB41L3', 'Gene', '23136', (0, 7))	('advanced pN classification', 'Disease', (45, 71))	('EPB41L3', 'Gene', (0, 7))	('pN2', 'Gene', '351', (73, 76))
377806	25050929	Restoration of EPB41L3 expression in non-small cell lung cancer or breast cancer cell lines significantly suppressed cell growth in vitro , and re-expression of EPB41L3 can induce extensive apoptotic cell death in ovarian cancer cells.	('EPB41L3', 'Gene', '23136', (161, 168))	('suppressed', 'NegReg', (106, 116))	('cell growth in vitro', 'CPA', (117, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (37, 63))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('EPB41L3', 'Gene', (161, 168))	('re-expression', 'Var', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('EPB41L3', 'Gene', '23136', (15, 22))	('ovarian cancer', 'Disease', 'MESH:D010051', (214, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (37, 63))	('death', 'Disease', (205, 210))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('EPB41L3', 'Gene', (15, 22))	('breast cancer', 'Disease', (67, 80))	('ovarian cancer', 'Disease', (214, 228))	('non-small cell lung cancer', 'Disease', (37, 63))	('ovarian cancer', 'Phenotype', 'HP:0100615', (214, 228))	('death', 'Disease', 'MESH:D003643', (205, 210))
377814	25050929	This result suggests that the methylation of EPB41L3 may be involved in the proliferation of cancer cells.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('methylation', 'Var', (30, 41))	('EPB41L3', 'Gene', '23136', (45, 52))	('EPB41L3', 'Gene', (45, 52))	('proliferation', 'CPA', (76, 89))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('involved', 'Reg', (60, 68))
377815	25050929	In addition, our results show that 77.8% of the pT3 samples are methylated, which is significantly higher than 26.7% in pT1-pT2 samples (P = 0.001).	('pT1', 'Gene', (120, 123))	('higher', 'PosReg', (99, 105))	('methylated', 'Var', (64, 74))	('pT3', 'Gene', '7694', (48, 51))	('pT3', 'Gene', (48, 51))	('pT1', 'Gene', '58492', (120, 123))
377818	25050929	Thus, the silencing of GPX3 may impair defenses against endogenous and exogenous genotoxic compounds, which could increase gene mutation rates.	('GPX3', 'Gene', '2878', (23, 27))	('GPX3', 'Gene', (23, 27))	('increase', 'PosReg', (114, 122))	('gene mutation rates', 'MPA', (123, 142))	('impair', 'NegReg', (32, 38))	('silencing', 'Var', (10, 19))
377819	25050929	GPX3 has been found to be frequently hypermethylated in prostate cancer, esophageal adenocarcinoma, and gastric cancer.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (73, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('GPX3', 'Gene', (0, 4))	('hypermethylated', 'Var', (37, 52))	('GPX3', 'Gene', '2878', (0, 4))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (73, 98))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal adenocarcinoma', 'Disease', (73, 98))	('gastric cancer', 'Disease', (104, 118))	('prostate cancer', 'Disease', (56, 71))
377823	25050929	This result is consistent with a previous study that found that the methylation of GPX3 promoter was more frequent in ESCC tumor tissues (71.4%) than in adjacent nontumor tissues (10.7%).	('ESCC tumor', 'Disease', 'MESH:D004938', (118, 128))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('methylation', 'Var', (68, 79))	('GPX3', 'Gene', (83, 87))	('frequent', 'Reg', (106, 114))	('GPX3', 'Gene', '2878', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('ESCC tumor', 'Disease', (118, 128))	('tumor', 'Disease', (165, 170))
377826	25050929	These results suggest that the methylation of GPX3 may be involved in the progression and lymphnoid metastais in ESCC.	('ESCC', 'Disease', (113, 117))	('lymphnoid metastais', 'CPA', (90, 109))	('involved', 'Reg', (58, 66))	('methylation', 'Var', (31, 42))	('GPX3', 'Gene', (46, 50))	('GPX3', 'Gene', '2878', (46, 50))
377831	25050929	Previous studies have shown that aberrant COL14A1 DNA methylation has been tested in renal cancer cell lines and primary renal cancers, and the methylation correlated with silencing or down-regulating of mRNA expression.	('down-regulating', 'NegReg', (185, 200))	('primary renal cancers', 'Disease', 'MESH:D007680', (113, 134))	('renal cancer', 'Phenotype', 'HP:0009726', (121, 133))	('renal cancer', 'Phenotype', 'HP:0009726', (85, 97))	('COL14A1', 'Gene', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('silencing', 'MPA', (172, 181))	('renal cancer', 'Disease', 'MESH:D007680', (85, 97))	('renal cancer', 'Disease', 'MESH:D007680', (121, 133))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('primary renal cancers', 'Disease', (113, 134))	('COL14A1', 'Gene', '7373', (42, 49))	('aberrant', 'Var', (33, 41))	('renal cancer', 'Disease', (85, 97))	('mRNA expression', 'MPA', (204, 219))
377837	25050929	This result suggests that aberrant methylation of COL14A1 may be associated with the lymph node metastasis of ESCC.	('aberrant methylation', 'Var', (26, 46))	('COL14A1', 'Gene', '7373', (50, 57))	('associated', 'Reg', (65, 75))	('COL14A1', 'Gene', (50, 57))	('ESCC', 'Disease', (110, 114))	('methylation', 'Var', (35, 46))	('lymph node metastasis', 'CPA', (85, 106))
377840	25050929	Several studies have revealed the presence of methylated DNA in the serum or plasma of patients with various types of malignancy, including bladder cancer, breast cancer, cervical cancer, colorectal cancer, hepatocellular carcinoma, lung cancer, non-Hodgkin lymphoma, melanoma, ovarian cancer, pancreatic cancer, and prostate cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('presence', 'Reg', (34, 42))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (246, 266))	('malignancy', 'Disease', 'MESH:D009369', (118, 128))	('hepatocellular carcinoma', 'Disease', (207, 231))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (294, 311))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('ovarian cancer', 'Disease', 'MESH:D010051', (278, 292))	('breast cancer', 'Disease', (156, 169))	('malignancy', 'Disease', (118, 128))	('DNA', 'Gene', (57, 60))	('methylated', 'Var', (46, 56))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))	('melanoma', 'Disease', (268, 276))	('colorectal cancer', 'Disease', (188, 205))	('pancreatic cancer', 'Disease', (294, 311))	('prostate cancer', 'Disease', 'MESH:D011471', (317, 332))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Disease', (233, 244))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (207, 231))	('cervical cancer', 'Disease', 'MESH:D002583', (171, 186))	('prostate cancer', 'Phenotype', 'HP:0012125', (317, 332))	('bladder cancer', 'Disease', 'MESH:D001749', (140, 154))	('cervical cancer', 'Disease', (171, 186))	('bladder cancer', 'Disease', (140, 154))	('pancreatic cancer', 'Disease', 'MESH:D010190', (294, 311))	('ovarian cancer', 'Disease', (278, 292))	('prostate cancer', 'Disease', (317, 332))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (250, 266))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('ovarian cancer', 'Phenotype', 'HP:0100615', (278, 292))	('non-Hodgkin lymphoma', 'Disease', (246, 266))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (207, 231))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (246, 266))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('lymphoma', 'Phenotype', 'HP:0002665', (258, 266))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('patients', 'Species', '9606', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (268, 276))
377843	25050929	These results indicate that not only there are obvious significant difference of aberrant DNA methylation of EPB41L3, GPX3 and COL14A1 in the plasma between ESCC patients and healthy individuals, but also the methylation frequency might be associated with the advanced tumor stages.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('EPB41L3', 'Gene', (109, 116))	('aberrant', 'Var', (81, 89))	('patients', 'Species', '9606', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Disease', (269, 274))	('ESCC', 'Disease', (157, 161))	('associated', 'Reg', (240, 250))	('COL14A1', 'Gene', '7373', (127, 134))	('EPB41L3', 'Gene', '23136', (109, 116))	('GPX3', 'Gene', (118, 122))	('GPX3', 'Gene', '2878', (118, 122))	('COL14A1', 'Gene', (127, 134))
377846	18692041	We found that Bmp signaling is prominently present in the anterior foregut where the tracheal primordium originates and targeted ablation of Bmp4 (Bmp4cko) resulted in a loss-of-trachea phenotype that closely resembles the Floyd type II pathology, the most common form of TA in humans.	('a loss-of-trachea', 'Disease', 'MESH:C557675', (168, 185))	('ablation', 'Var', (129, 137))	('a loss-of-trachea', 'Disease', (168, 185))	('humans', 'Species', '9606', (278, 284))	('Bmp4', 'Gene', (141, 145))
377855	18692041	Defective development of these organs results in congenital malformations in humans such as esophageal atresia and tracheoesophageal fistula (EA/TEF) and a spectrum of tracheal defects known as tracheal agenesis or atresia (TA).	('tracheal agenesis', 'Disease', (194, 211))	('tracheal defects', 'Phenotype', 'HP:0002778', (168, 184))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (115, 140))	('congenital malformations', 'Disease', 'MESH:D000013', (49, 73))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (115, 140))	('atresia', 'Disease', (103, 110))	('humans', 'Species', '9606', (77, 83))	('esophageal atresia', 'Phenotype', 'HP:0002032', (92, 110))	('atresia', 'Disease', 'MESH:D018633', (103, 110))	('tracheoesophageal fistula', 'Disease', (115, 140))	('results in', 'Reg', (38, 48))	('Defective', 'Var', (0, 9))	('atresia', 'Disease', (215, 222))	('atresia', 'Disease', 'MESH:D018633', (215, 222))	('esophageal atresia', 'Disease', 'MESH:D004933', (92, 110))	('esophageal atresia', 'Disease', (92, 110))	('congenital malformations', 'Disease', (49, 73))
377876	18692041	Indeed, we found almost complete loss of Bmp signaling as demonstrated by p-Smad1/5/8 immunostaining in the anterior ventral foregut endoderm and mesoderm corresponding to the tracheal rudiment in Bmp4cko embryos compared with wildtype at E9.0, prior to the emergence of the respiratory primordium (Fig.	('loss', 'NegReg', (33, 37))	('rat', 'Species', '10116', (280, 283))	('Bmp4cko', 'Var', (197, 204))	('Bmp signaling', 'MPA', (41, 54))	('rat', 'Species', '10116', (65, 68))
377878	18692041	Based on pSmad1/5/8 staining of all embryos examined (n=3), it appeared that Foxg1Cre-mediated Bmp4 deletion occurred effectively in the anterior ventral foregut.	('deletion', 'Var', (100, 108))	('Foxg1', 'Gene', (77, 82))	('Foxg1', 'Gene', '15228', (77, 82))	('Bmp4', 'Gene', (95, 99))
377889	18692041	At E9.25 (20-22 somites), a stage prior to the appearance of the respiratory rudiment and when no apparent abnormal morphology was evident in Bmp4cko foregut, Nkx2.1 expression level and distribution in the Bmp4cko foregut was comparable with wildtype (Fig.	('Nkx2.1', 'Gene', (159, 165))	('Nkx2.1', 'Gene', '21869', (159, 165))	('rat', 'Species', '10116', (70, 73))	('E9.25', 'Var', (3, 8))
377894	18692041	Taking into account the reduced Bmp4cko foregut size, we determined the BrdU-positive cells as percentage of total number of cells in Bmp4cko embryonic foreguts compared with wildtype littermates on five sequential sections of the upper foregut in each of three pairs of mutant or wildtype embryos; wildtype and mutant embryos were paired based on somite number within litters.	('BrdU', 'Chemical', 'MESH:D001973', (72, 76))	('Bmp4cko', 'Var', (134, 141))	('mutant', 'Var', (271, 277))
377896	18692041	BrdU pulse-labeling revealed a relatively lower percentage of proliferating epithelial cells in the Bmp4cko foregut (28.2-37.7%) compared with wildtype foregut (53.3-56.9%).	('Bmp4cko', 'Var', (100, 107))	('lower', 'NegReg', (42, 47))	('proliferating epithelial cells', 'CPA', (62, 92))	('BrdU', 'Chemical', 'MESH:D001973', (0, 4))	('rat', 'Species', '10116', (69, 72))
377897	18692041	Mesenchymal cells in the Bmp4cko foregut also displayed a lower proliferative capacity (25.0-41.6%) compared with wildtype foregut (48.8-52.2%) (Fig.	('Bmp4cko', 'Var', (25, 32))	('proliferative capacity', 'CPA', (64, 86))	('rat', 'Species', '10116', (71, 74))	('lower', 'NegReg', (58, 63))
377909	18692041	We note that p-Erk expression in the vessel endothelial cells remains unaffected in the mutant (Fig.	('Erk', 'Gene', '26413', (15, 18))	('expression', 'MPA', (19, 29))	('mutant', 'Var', (88, 94))	('Erk', 'Gene', (15, 18))
377910	18692041	This result indicates that loss of Bmp signaling has profound effects on Erk pathway activation, which may regulate tracheal proliferation and outgrowth.	('loss', 'Var', (27, 31))	('effects', 'Reg', (62, 69))	('Erk', 'Gene', (73, 76))	('Bmp', 'Protein', (35, 38))	('tracheal proliferation', 'CPA', (116, 138))	('rat', 'Species', '10116', (132, 135))	('activation', 'PosReg', (85, 95))	('regulate', 'Reg', (107, 115))	('Erk', 'Gene', '26413', (73, 76))
377930	18692041	Here, we found that pErk1/2 was almost completely lost in Bmp4cko ventral foregut suggesting that Erk signaling may be the underlying effector of Bmp4 pathway in regulating tracheal proliferation and outgrowth.	('tracheal proliferation', 'CPA', (173, 195))	('rat', 'Species', '10116', (189, 192))	('Erk', 'Gene', '26413', (98, 101))	('Erk1/2', 'Gene', (21, 27))	('Erk', 'Gene', '26413', (21, 24))	('Erk', 'Gene', (98, 101))	('Erk', 'Gene', (21, 24))	('lost', 'NegReg', (50, 54))	('Erk1/2', 'Gene', '26417;26413', (21, 27))	('Bmp4cko', 'Var', (58, 65))
377934	18692041	Interestingly, Smad4 (co-Smad) siRNA knockdown in HUVECs did not affect BMP-4 induced sprout length, suggesting that the ERK, but not Smad pathway, is necessary for endothelial cell sprouting.	('Smad4', 'Gene', (15, 20))	('knockdown', 'Var', (37, 46))	('Smad4', 'Gene', '17128', (15, 20))
377939	18692041	Our finding that Bmpcko mutants resemble the most common form of tracheal agenesis observed in human underscores the critical role of Bmp signaling in tracheal morphogenesis and provides a unique animal model to further elucidate the pathogenesis of this disease.	('tracheal agenesis', 'Disease', (65, 82))	('human', 'Species', '9606', (95, 100))	('Bmpcko', 'Chemical', '-', (17, 23))	('mutants', 'Var', (24, 31))
377947	18692041	Amplifications of Cre and Bmp4-lacZ allele generate a 480-bp product and a 339-bp product, respectively.	('Cre', 'Gene', (18, 21))	('Amplifications', 'Var', (0, 14))	('Bmp4-lacZ', 'Gene', (26, 35))	('rat', 'Species', '10116', (47, 50))
377965	19208741	Inactivation of the MAL gene in breast cancer is a common event that predicts benefit from adjuvant chemotherapy Dis-regulation of MAL (myelin and lymphocyte protein) has been implicated in several malignancies including esophageal, ovarian, and cervical cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('MAL', 'Gene', (20, 23))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('cervical cancers', 'Disease', (246, 262))	('implicated', 'Reg', (176, 186))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('esophageal', 'Disease', (221, 231))	('ovarian', 'Disease', (233, 240))	('breast cancer', 'Disease', (32, 45))	('cervical cancers', 'Disease', 'MESH:D002583', (246, 262))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('MAL', 'Gene', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('malignancies', 'Disease', 'MESH:D009369', (198, 210))	('Inactivation', 'Var', (0, 12))	('Dis-regulation', 'Var', (113, 127))	('MAL', 'Gene', '4118', (20, 23))	('malignancies', 'Disease', (198, 210))	('esophageal', 'Disease', 'MESH:D004941', (221, 231))	('MAL', 'Gene', '4118', (131, 134))	('myelin and lymphocyte protein', 'Gene', '4118', (136, 165))
377966	19208741	The MAL protein functions in apical transport in polarized-epithelial cells, therefore its disruption may lead to loss of organized polarity characteristic of most solid malignancies.	('malignancies', 'Disease', (170, 182))	('disruption', 'Var', (91, 101))	('loss', 'NegReg', (114, 118))	('epithelia', 'Disease', 'None', (59, 68))	('epithelia', 'Disease', (59, 68))	('organized polarity', 'MPA', (122, 140))	('MAL protein', 'Protein', (4, 15))	('malignancies', 'Disease', 'MESH:D009369', (170, 182))
377967	19208741	Bisulfite sequencing of the MAL promoter CpG island revealed hypermethylation in breast cancer cell lines and 69% of primary tumors analyzed compared to normal breast epithelial cells.	('breast cancer', 'Disease', (81, 94))	('primary tumors', 'Disease', (117, 131))	('breast epithelia', 'Disease', 'MESH:D001943', (160, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('primary tumors', 'Disease', 'MESH:D009369', (117, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('breast epithelia', 'Disease', (160, 176))	('hypermethylation', 'Var', (61, 77))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
377969	19208741	In a subset of breast cancer cell lines including T47D and MCF7 cells, promoter methylation correlated with transcriptional silencing that was reversible with the methylation inhibitor 5-Aza-2'-deoxycytidine.	('transcriptional', 'MPA', (108, 123))	("5-Aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (185, 207))	('promoter methylation', 'Var', (71, 91))	('T47D', 'CellLine', 'CVCL:0553', (50, 54))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('MCF7', 'CellLine', 'CVCL:0031', (59, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
377970	19208741	In addition, expression of MAL reduced motility and resulted in a redistribution of lipid raft components in MCF10A cells.	('reduced', 'NegReg', (31, 38))	('expression', 'Var', (13, 23))	('MAL', 'Gene', (27, 30))	('MCF10A', 'CellLine', 'CVCL:0598', (109, 115))	('lipid', 'Chemical', 'MESH:D008055', (84, 89))	('motility', 'CPA', (39, 47))	('redistribution of lipid raft components', 'MPA', (66, 105))
377973	19208741	Cancer can be caused by the accumulation of both genetic and epigenetic alterations frequently leading to downstream changes in gene expression patterns.	('gene expression patterns', 'MPA', (128, 152))	('epigenetic alterations', 'Var', (61, 83))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('genetic', 'Var', (49, 56))	('changes', 'Reg', (117, 124))	('caused by', 'Reg', (14, 23))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
377974	19208741	In the present study, we identify MAL as a novel epigenetically regulated gene in breast cancer.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('MAL', 'Gene', (34, 37))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('epigenetically regulated', 'Var', (49, 73))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
377976	19208741	In neoplasia, the barriers protecting the promoter CpG islands are commonly overridden with de novo methylation believed to begin at the distal ends of the island and then progressively spreading into the core.	('methylation', 'Var', (100, 111))	('neoplasia', 'Disease', (3, 12))	('neoplasia', 'Disease', 'MESH:D009369', (3, 12))	('neoplasia', 'Phenotype', 'HP:0002664', (3, 12))
377985	19208741	Our results show that hypermethylation of the MAL promoter is common in primary breast cancer and that in some cases, this methylation appears to impair gene transcription.	('MAL', 'Gene', (46, 49))	('primary breast cancer', 'Disease', 'MESH:D001943', (72, 93))	('methylation', 'Var', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('hypermethylation', 'Var', (22, 38))	('gene transcription', 'MPA', (153, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('primary breast cancer', 'Disease', (72, 93))	('impair', 'NegReg', (146, 152))
377986	19208741	Further, we describe a cancer-specific methylation pattern that should guide future epigenetic studies at this locus.	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('methylation', 'Var', (39, 50))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
377992	19208741	Comparing a series of cultured mammary epithelial cells ranging from benign primary cells derived from breast reductions (HMEC), immortalized cell lines from breast reductions, and cancer cell lines, we found that the methylation status in this region was highly variable (Fig.	('breast reductions', 'Disease', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast reductions', 'Disease', 'MESH:D001943', (103, 120))	('methylation', 'Var', (218, 229))	('epithelia', 'Disease', 'None', (39, 48))	('breast reductions', 'Disease', (103, 120))	('epithelia', 'Disease', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('breast reductions', 'Disease', 'MESH:D001943', (158, 175))
377995	19208741	These data indicate that the MAL promoter region may be a common target for hypermethylation in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hypermethylation', 'Var', (76, 92))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
378013	19208741	While only primary cancers that contained at least 50% cancer cells were used in the analysis of bulk tumor DNA, it is likely that our scoring of partial methylation underestimates the degree of methylation in these cases.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Disease', (19, 26))	('cancer', 'Disease', (19, 25))	('partial methylation', 'Var', (146, 165))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('underestimates', 'NegReg', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancer', 'Disease', (55, 61))
378014	19208741	Absence of methylation in normal breast epithelium suggests that hypermethylation in cancer is associated with the oncogenic process.	('hypermethylation', 'Var', (65, 81))	('oncogenic process', 'CPA', (115, 132))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('associated', 'Reg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
378027	19208741	Whereas flotillin-1 was found entirely in the soluble fraction in the vector control line (under G418 selection), introduction of MAL produced a dramatic redistribution of this protein into the insoluble fraction (Fig.	('flotillin-1', 'Gene', (8, 19))	('introduction', 'Var', (114, 126))	('flotillin-1', 'Gene', '10211', (8, 19))	('redistribution', 'MPA', (154, 168))
378030	19208741	In the transformed MCF7 and MD468 cells, a similar trend was observed in which MAL expression caused a reduction in motility (Supplementary Fig.	('MD468', 'CellLine', 'CVCL:6420', (28, 33))	('MCF7', 'CellLine', 'CVCL:0031', (19, 23))	('MAL expression', 'Var', (79, 93))	('motility', 'CPA', (116, 124))	('reduction', 'NegReg', (103, 112))
378032	19208741	Analyzing thirty-six primary tumors by quantitative RT-PCR we observed varying levels of mRNA expression with the average MAL expression in the methylated tumors (288 +- 62, expression normalized to beta2M) being lower than that observed in those lacking methylation (468 +- 171), however this difference did not reach statistical significance (p= 0.23) (Supplementary Fig.	('primary tumors', 'Disease', (21, 35))	('lower', 'NegReg', (213, 218))	('methylated', 'Var', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mRNA expression', 'MPA', (89, 104))	('primary tumors', 'Disease', 'MESH:D009369', (21, 35))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('288 +- 62', 'Var', (163, 172))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('MAL expression', 'MPA', (122, 136))
378034	19208741	Further, of the cancers that exhibited methylation (either partial or heavy), the majority were nuclear hormone receptor positive, while all of the unmethylated cancers for which data was available were ER/PR negative (Supplementary Table 1).	('cancers', 'Disease', (16, 23))	('methylation', 'Var', (39, 50))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('hormone receptor', 'Gene', '3164', (104, 120))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('hormone receptor', 'Gene', (104, 120))	('positive', 'Reg', (121, 129))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Disease', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
378035	19208741	Our earlier data demonstrated that the level of methylation is not an absolute predictor for basal mRNA expression, specifically in the HCC1937 and BT474 cell lines which contain promoter methylation but have high levels of MAL mRNA (Fig.	('methylation', 'Var', (188, 199))	('MAL mRNA', 'MPA', (224, 232))	('HCC1937', 'CellLine', 'CVCL:0290', (136, 143))
378043	19208741	However, in the group of patients who were not treated, absence of MAL staining was a significant predictor of disease progression (Fig.	('disease', 'Disease', (111, 118))	('patients', 'Species', '9606', (25, 33))	('absence', 'Var', (56, 63))
378044	19208741	MAL positive and negative tumors from patients who did not receive adjuvant chemotherapy were not significantly different based on age, nodal status, tumor size, or hormone receptor status (Supplementary Table 2) indicating that the MAL protein may be an independent predictor of benefit from chemotherapy.	('hormone receptor', 'Gene', (165, 181))	('hormone receptor', 'Gene', '3164', (165, 181))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('patients', 'Species', '9606', (38, 46))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('MAL protein', 'Var', (233, 244))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', (150, 155))	('tumors', 'Disease', (26, 32))
378045	19208741	Hypermethylation of gene promoters leading to transcriptional silencing is associated with the onset and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('transcriptional silencing', 'MPA', (46, 71))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('associated', 'Reg', (75, 85))
378046	19208741	Identification of genes that are epigenetically regulated in cancer can provide targets for early detection and therapeutics.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('epigenetically regulated', 'Var', (33, 57))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
378047	19208741	In this study we identified MAL as a novel epigenetically regulated gene in breast cancer.	('epigenetically', 'Var', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('MAL', 'Gene', (28, 31))
378057	19208741	Inhibiting methylation in these cells induced MAL to a level comparable to primary breast epithelia.	('methylation', 'MPA', (11, 22))	('Inhibiting', 'Var', (0, 10))	('breast epithelia', 'Disease', (83, 99))	('MAL', 'MPA', (46, 49))	('breast epithelia', 'Disease', 'MESH:D001943', (83, 99))
378061	19208741	This study is the first describing the epigenetic regulation of MAL in breast cancer, however, Mimori et al.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('epigenetic regulation', 'Var', (39, 60))	('MAL', 'Gene', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
378063	19208741	More recently, a genome wide search found that MAL was frequently hypermethylated in colon cancer correlating with reduced expression.	('expression', 'MPA', (123, 133))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('reduced', 'NegReg', (115, 122))	('MAL', 'Gene', (47, 50))	('colon cancer', 'Disease', 'MESH:D015179', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('hypermethylated', 'Var', (66, 81))	('colon cancer', 'Disease', (85, 97))
378064	19208741	These reports and our current data suggest that epigenetic silencing of MAL may be a common event involved in the initiation and progression of epithelial cancers.	('epithelial cancers', 'Disease', 'MESH:D000077216', (144, 162))	('involved', 'Reg', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('epigenetic silencing', 'Var', (48, 68))	('epithelial cancers', 'Disease', (144, 162))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('MAL', 'Gene', (72, 75))
378071	19208741	Hypermethylation of MAL was readily detectable in primary breast cancer specimens and microdissection confirmed that these events occur in the malignant epithelial cells within the tumor.	('primary breast cancer', 'Disease', (50, 71))	('tumor', 'Disease', (181, 186))	('malignant epithelia', 'Disease', 'MESH:D009369', (143, 162))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('MAL', 'Gene', (20, 23))	('primary breast cancer', 'Disease', 'MESH:D001943', (50, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('malignant epithelia', 'Disease', (143, 162))
378072	19208741	Similar to what was seen in certain breast cancer cell lines (HCC1937 and BT474), promoter methylation may explain down-regulation of MAL gene expression in some but not all primary breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancers', 'Phenotype', 'HP:0003002', (182, 196))	('primary breast cancer', 'Disease', 'MESH:D001943', (174, 195))	('breast cancer', 'Disease', (36, 49))	('expression', 'MPA', (143, 153))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('down-regulation', 'NegReg', (115, 130))	('MAL gene', 'Gene', (134, 142))	('breast cancers', 'Disease', 'MESH:D001943', (182, 196))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('breast cancers', 'Disease', (182, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('primary breast cancer', 'Disease', (174, 195))	('HCC1937', 'CellLine', 'CVCL:0290', (62, 69))	('promoter methylation', 'Var', (82, 102))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
378073	19208741	On average lower MAL mRNA expression was seen in the methylated tumors compared to unmethylated tumors, however, this difference did not reach statistical significance (Supplementary Fig.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('lower', 'NegReg', (11, 16))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('MAL mRNA expression', 'MPA', (17, 36))	('methylated', 'Var', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
378074	19208741	We observed a strong correlation of MAL hypermethylation with estrogen (p= 0.003) and progesterone receptor (p= 0.006) positive cancers (Supplementary Table 1).	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('progesterone receptor', 'Gene', (86, 107))	('cancers', 'Disease', (128, 135))	('progesterone receptor', 'Gene', '5241', (86, 107))	('estrogen', 'Disease', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('MAL', 'Var', (36, 39))
378077	19208741	showed that methylation of the BRCA1 promoter was more frequently observed in women with high-grade ER and PR negative tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('observed', 'Reg', (66, 74))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('women', 'Species', '9606', (78, 83))	('BRCA1', 'Gene', '672', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('BRCA1', 'Gene', (31, 36))	('methylation', 'Var', (12, 23))
378085	19208741	Disruption of MAL expression has been implicated in the etiology of several human cancer types.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('human', 'Species', '9606', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('implicated', 'Reg', (38, 48))	('MAL', 'Gene', (14, 17))	('Disruption', 'Var', (0, 10))
378092	19208741	Similar to an esophageal cancer cell line, expression of MAL in breast cells also reduced motility.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('esophageal cancer', 'Disease', (14, 31))	('expression', 'Var', (43, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('MAL', 'Gene', (57, 60))	('motility', 'CPA', (90, 98))	('reduced', 'NegReg', (82, 89))
378099	19208741	We are currently investigating whether loss of MAL protein expression makes breast cancer cells more responsive to the standard cytotoxic chemotherapies used in our cohort of patients.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MAL protein expression', 'Protein', (47, 69))	('more', 'PosReg', (96, 100))	('patients', 'Species', '9606', (175, 183))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('loss', 'Var', (39, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
378100	19208741	To our knowledge, this is the first paper implicating MAL expression in the development of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('MAL expression', 'Var', (54, 68))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
378147	32770356	In conclusion, our results suggest that highest adherence to the MedDiet was related to lower risk of cancer mortality in the general population, and all-cause mortality among cancer survivors as well as colorectal, head and neck, respiratory, gastric, liver and bladder cancer risks.	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('mortality', 'Disease', (109, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (263, 277))	('cancer mortality', 'Disease', (102, 118))	('cancer', 'Disease', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('adherence', 'Var', (48, 57))	('lower', 'NegReg', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('liver and bladder cancer', 'Disease', 'MESH:D001749', (253, 277))	('colorectal', 'Disease', (204, 214))	('mortality', 'Disease', 'MESH:D003643', (109, 118))	('mortality', 'Disease', (160, 169))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('respiratory', 'Disease', (231, 242))	('cancer mortality', 'Disease', 'MESH:D003643', (102, 118))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('gastric', 'Disease', (244, 251))	('colorectal', 'Disease', 'MESH:D015179', (204, 214))	('cancer', 'Disease', (176, 182))	('mortality', 'Disease', 'MESH:D003643', (160, 169))
378163	32770356	We previously conducted a systematic review and meta-analysis on the association between adherence to the MedDiet and risk of cancer, which was followed by two updates.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('adherence', 'Var', (89, 98))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('association', 'Interaction', (69, 80))
378173	32770356	Studies were included if they fulfilled the following criteria: (1) randomized controlled trials (RCTs), prospective cohort, case-cohort, nested case-control, or case-control studies, (2) conducted in adult population (aged >= 18 years) which (3) assessed association between adherence to MedDiet and (4) risk of cancer mortality, site-specific cancer, all-cause, cancer mortality or cancer reoccurrence among cancer survivors.	('cancer mortality', 'Disease', 'MESH:D003643', (313, 329))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('cancer mortality', 'Disease', (364, 380))	('assessed', 'Reg', (247, 255))	('MedDiet', 'Gene', (289, 296))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('cancer', 'Disease', 'MESH:D009369', (384, 390))	('adherence', 'Var', (276, 285))	('cancer', 'Disease', (364, 370))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('cancer mortality', 'Disease', (313, 329))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('all-cause', 'CPA', (353, 362))	('association', 'Interaction', (256, 267))	('cancer', 'Disease', (345, 351))	('cancer mortality', 'Disease', 'MESH:D003643', (364, 380))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('cancer', 'Disease', (410, 416))	('cancer', 'Disease', (384, 390))	('cancer', 'Disease', 'MESH:D009369', (364, 370))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('cancer', 'Disease', (313, 319))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))
378183	32770356	For breast cancer, pooled risk estimates were additionally compared by menopausal status (premenopausal/postmenopausal) and receptor expression (ER/PR/HER/mixed).	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('men', 'Species', '9606', (93, 96))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('ER/PR/HER/mixed', 'Var', (145, 160))	('men', 'Species', '9606', (108, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('premenopausal/postmenopausal', 'Phenotype', 'HP:0008209', (90, 118))	('men', 'Species', '9606', (71, 74))	('breast cancer', 'Disease', (4, 17))	('menopausal status', 'Phenotype', 'HP:0008209', (71, 88))
378188	32770356	Corresponding risk estimates were based on comparison of extreme quantiles (top quintile/quartile/tertile versus bottom), fixed cut-off points, per standard deviation, per-tertile or per-20 percentile increase in the MedDiet score.	('increase', 'PosReg', (201, 209))	('tertile versus bottom', 'Disease', (98, 119))	('MedDiet score', 'Gene', (217, 230))	('per-20 percentile', 'Var', (183, 200))	('tertile versus bottom', 'Disease', 'MESH:D005413', (98, 119))
378191	32770356	Highest versus lowest adherence to the MedDiet was associated with a lower risk of cancer mortality in cohort studies (RRcohort: 0.87, 95% CI 0.82-0.92; I2 = 83%), but not in one RCT (RRRCT: 0.75, 95% CI 0.17-3.33, I2 = NA).	('lowest', 'NegReg', (15, 21))	('adherence', 'Var', (22, 31))	('cancer mortality', 'Disease', (83, 99))	('cancer mortality', 'Disease', 'MESH:D003643', (83, 99))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lower', 'NegReg', (69, 74))
378194	32770356	Regarding colorectal cancer, the highest adherence to the MedDiet was linked to a reduced risk (RRobservational: 0.83, 95% CI 0.76-0.90, I2 = 82%; ORcase-control: 0.64, 95% CI 0.52-0.79, I2 = 89%, RRcohort: 0.92, 95% CI 0.87-0.99, I2 = 50%).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('adherence', 'Var', (41, 50))	('colorectal cancer', 'Disease', (10, 27))	('reduced', 'NegReg', (82, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (10, 27))
378210	32770356	The present analysis confirmed our previous findings on the inverse association of adherence to MedDiet on cancer mortality and colorectal cancer risk.	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('inverse', 'NegReg', (60, 67))	('cancer mortality', 'Disease', (107, 123))	('cancer mortality', 'Disease', 'MESH:D003643', (107, 123))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('adherence', 'Var', (83, 92))	('colorectal cancer', 'Disease', (128, 145))	('MedDiet', 'Gene', (96, 103))
378214	32770356	For the first time, we were able to observe an inverse association between adherence to the MedDiet and bladder, gastric and lung cancer incidence, as well as all-cause mortality among cancer survivors.	('adherence', 'Var', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mortality', 'Disease', (169, 178))	('cancer', 'Disease', (130, 136))	('inverse', 'NegReg', (47, 54))	('gastric', 'Disease', (113, 120))	('mortality', 'Disease', 'MESH:D003643', (169, 178))	('MedDiet', 'Gene', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('cancer', 'Disease', (185, 191))	('bladder', 'Disease', (104, 111))
378228	32770356	Whole grains contain alk(en)ylresorcinols, benzoxanizoids and phytosteroids, which exerted an inhibitory effect on model human cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('alk', 'Var', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('phytosteroids', 'Chemical', 'MESH:D010840', (62, 75))	('human', 'Species', '9606', (121, 126))	('benzoxanizoids', 'Chemical', '-', (43, 57))	('cancer', 'Disease', (127, 133))
378230	32770356	Apart from providing protective compounds, adherence to the MedDiet pattern decreases exposure to potential carcinogens by omitting intake of detrimental food items.	('omitting', 'NegReg', (123, 131))	('decreases', 'NegReg', (76, 85))	('detrimental food items', 'Disease', 'MESH:D005547', (142, 164))	('detrimental food items', 'Disease', (142, 164))	('exposure to potential carcinogens', 'MPA', (86, 119))	('adherence', 'Var', (43, 52))
378252	32770356	In conclusion, this systematic review and meta-analysis provides an updated body of evidence on the association between adherence to the MedDiet and risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('adherence', 'Var', (120, 129))	('association', 'Interaction', (100, 111))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))
378253	32770356	Our results suggest that highest adherence to the MedDiet was inversely associated with risk of cancer mortality in the general population, and all-cause mortality among cancer survivors as well as colorectal, head and neck, respiratory, gastric, liver and bladder cancer risks.	('cancer', 'Disease', (170, 176))	('liver and bladder cancer', 'Disease', 'MESH:D001749', (247, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('bladder cancer', 'Phenotype', 'HP:0009725', (257, 271))	('mortality', 'Disease', 'MESH:D003643', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('adherence', 'Var', (33, 42))	('cancer', 'Disease', (96, 102))	('cancer mortality', 'Disease', 'MESH:D003643', (96, 112))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal', 'Disease', (198, 208))	('gastric', 'Disease', (238, 245))	('mortality', 'Disease', (154, 163))	('respiratory', 'Disease', (225, 236))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer mortality', 'Disease', (96, 112))	('colorectal', 'Disease', 'MESH:D015179', (198, 208))	('mortality', 'Disease', (103, 112))	('mortality', 'Disease', 'MESH:D003643', (154, 163))	('inversely', 'NegReg', (62, 71))	('cancer', 'Disease', (265, 271))
378271	33081277	Recently, biomarkers including epigenetics and miRNA analysis findings, DNA content abnormalities, and loss of heterozygosity noted in biopsy findings have been reported to be additional reliable predictors of malignant transformation in affected patients.	('malignant transformation', 'CPA', (210, 234))	('miRNA analysis', 'MPA', (47, 61))	('epigenetics', 'Var', (31, 42))	('loss of heterozygosity', 'Var', (103, 125))	('abnormalities', 'Var', (84, 97))	('patients', 'Species', '9606', (247, 255))	('DNA', 'MPA', (72, 75))
378272	33081277	One of the most important biomarkers is aberrant expression and/or mutation of p53.	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', (79, 82))	('aberrant expression', 'Var', (40, 59))	('mutation', 'Var', (67, 75))
378284	33081277	reported that presence of ulceration in Barrett's segment was associated with EAC progression, with a HR of 1.72 (95% CI 1.08-2.76).	('presence', 'Var', (14, 22))	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('associated', 'Reg', (62, 72))	('EAC', 'Disease', (78, 81))	('ulcer', 'Disease', 'MESH:D014456', (26, 31))	('ulcer', 'Disease', (26, 31))
378289	33081277	reported that patients with one of severe esophagitis, nodularity, ulcer, or stricture as a marker had a 6.7 times (HR 6.7; 95% CI 1.3-35) greater risk, while those with two or more of those markers had a 14.1 times (HR 14.1; 95% CI 2.02-102) greater risk for development of EAC.	('patients', 'Species', '9606', (14, 22))	('esophagitis', 'Disease', (42, 53))	('stricture', 'Disease', (77, 86))	('esophagitis', 'Phenotype', 'HP:0100633', (42, 53))	('EAC', 'Phenotype', 'HP:0011459', (275, 278))	('ulcer', 'Disease', 'MESH:D014456', (67, 72))	('ulcer', 'Disease', (67, 72))	('EAC', 'Disease', (275, 278))	('esophagitis', 'Disease', 'MESH:D004938', (42, 53))	('nodularity', 'Var', (55, 65))
378326	33081277	Our analysis showed that inflammatory grade, COX-2 protein expression rate, and cellular proliferation in the PVs-invisible group were significantly greater as compared to the PVs-visible group.	('cellular proliferation', 'CPA', (80, 102))	('COX-2', 'Gene', '5743', (45, 50))	('greater', 'PosReg', (149, 156))	('PVs-invisible', 'Var', (110, 123))	('inflammatory grade', 'CPA', (25, 43))	('COX-2', 'Gene', (45, 50))
378335	33081277	Some investigators have reported that oxidative stress concomitant with COX-2 protein expression provokes angiogenesis in the stromal portion of Barrett's mucosa and subsequently plays an important role in malignant transformation of BE.	('malignant transformation', 'CPA', (206, 230))	('COX-2', 'Gene', (72, 77))	('COX-2', 'Gene', '5743', (72, 77))	('provokes', 'PosReg', (97, 105))	('oxidative stress', 'Phenotype', 'HP:0025464', (38, 54))	('angiogenesis', 'CPA', (106, 118))	('BE', 'Phenotype', 'HP:0100580', (234, 236))	('expression', 'Var', (86, 96))	('protein', 'Protein', (78, 85))	('oxidative stress', 'MPA', (38, 54))
378338	33081277	Genetic instability, which plays important roles in the initiation and progression of malignant tumors, is closely associated with loss of heterozygosity (LOH), abnormal functions in tumor suppressor genes, changes in DNA methylation, chromosomal aberrations, and dysregulation in cell cycle and signaling.	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (235, 258))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('DNA', 'MPA', (218, 221))	('chromosomal aberrations', 'Var', (235, 258))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('abnormal functions', 'Var', (161, 179))	('dysregulation', 'Var', (264, 277))	('loss of heterozygosity', 'Var', (131, 153))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (235, 257))	('cell cycle', 'CPA', (281, 291))	('tumor', 'Disease', (96, 101))	('signaling', 'CPA', (296, 305))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('Genetic', 'Disease', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('malignant tumors', 'Disease', (86, 102))	('malignant tumors', 'Disease', 'MESH:D009369', (86, 102))	('changes', 'Reg', (207, 214))
378340	33081277	Another showed aberrant expression of p53 protein as a representative biomarker for prediction of neoplastic progression in BE.	('aberrant expression', 'Var', (15, 34))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('protein', 'Protein', (42, 49))	('neoplastic progression', 'CPA', (98, 120))	('BE', 'Phenotype', 'HP:0100580', (124, 126))
378341	33081277	Moreover, the TP53 mutation was found in 46% of patients with EAC progression, and reported to be associated with EAC progression with an OR of 3.18 (95% CI 1.68-6.03) and an HR of 6.5 (95% CI 2.5-17.1).	('EAC', 'Disease', (114, 117))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('EAC', 'Phenotype', 'HP:0011459', (62, 65))	('EAC', 'Disease', (62, 65))	('EAC', 'Phenotype', 'HP:0011459', (114, 117))	('patients', 'Species', '9606', (48, 56))	('associated', 'Reg', (98, 108))
378342	33081277	Methylated genes are also considered to have important roles in Barrett's carcinogenesis.	("Barrett's carcinogenesis", 'Disease', (64, 88))	('Methylated genes', 'Var', (0, 16))	("Barrett's carcinogenesis", 'Disease', 'MESH:D063646', (64, 88))
378343	33081277	The expression of p16 methylation, a representative methylated predictor, was reported to contribute to an early event in neoplastic progression, along with expressions of cyclin A and p53.	('p53', 'Gene', (185, 188))	('p16', 'Gene', '1029', (18, 21))	('p53', 'Gene', '7157', (185, 188))	('cyclin A', 'Gene', (172, 180))	('p16', 'Gene', (18, 21))	('neoplastic progression', 'CPA', (122, 144))	('cyclin A', 'Gene', '890', (172, 180))	('contribute', 'Reg', (90, 100))	('methylation', 'Var', (22, 33))
378344	33081277	Hypermethylation of p16, RUNX3, and HPP1 genes was found in cases with dysplastic Barrett's lesions, which possibly occurred at an early stage in BE-associated neoplastic progression, and those three genes was also shown to predict progression risk.	('HPP1', 'Gene', '780897', (36, 40))	('predict', 'Reg', (224, 231))	('BE', 'Phenotype', 'HP:0100580', (146, 148))	('RUNX3', 'Gene', (25, 30))	('Hypermethylation', 'Var', (0, 16))	('p16', 'Gene', (20, 23))	('HPP1', 'Gene', (36, 40))	('RUNX3', 'Gene', '864', (25, 30))	("dysplastic Barrett's lesions", 'Disease', 'MESH:D001471', (71, 99))	("dysplastic Barrett's lesions", 'Disease', (71, 99))	('p16', 'Gene', '1029', (20, 23))	('found', 'Reg', (51, 56))
378351	33081277	reported that positive cyclin A expression was associated with increased risk of neoplastic progression, with an RR of 2.4 (95% CI 1.7-3.4), and di Pietro M et al.	('cyclin A', 'Gene', (23, 31))	('cyclin A', 'Gene', '890', (23, 31))	('neoplastic progression', 'CPA', (81, 103))	('positive', 'Var', (14, 22))	('expression', 'MPA', (32, 42))
378357	33081277	Moreover, microsomal glutathione S-transferase 1 (MGST1) expression, with elevation of some single nucleotide polymorphisms (SNPs) related to EAC risk in the oxidative stress pathway was also shown.	('EAC', 'Disease', (142, 145))	('elevation', 'PosReg', (74, 83))	('MGST1', 'Gene', (50, 55))	('oxidative stress', 'Phenotype', 'HP:0025464', (158, 174))	('microsomal glutathione S-transferase 1', 'Gene', '4257', (10, 48))	('single nucleotide polymorphisms', 'Var', (92, 123))	('microsomal glutathione S-transferase 1', 'Gene', (10, 48))	('oxidative stress pathway', 'Pathway', (158, 182))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))	('MGST1', 'Gene', '4257', (50, 55))
378360	33081277	In an investigation of aspergillus oryzae lectin (AOL) as a new biomarker, it was demonstrated that not only abnormal DNA ploidy but also AOL could be used to identify BE patients who were most likely to develop dysplastic Barrett's lesions.	('aspergillus oryzae', 'Species', '5062', (23, 41))	('ploidy', 'Disease', 'None', (122, 128))	('BE', 'Phenotype', 'HP:0100580', (168, 170))	('patients', 'Species', '9606', (171, 179))	('abnormal DNA', 'Var', (109, 121))	('develop', 'PosReg', (204, 211))	('ploidy', 'Disease', (122, 128))	("dysplastic Barrett's lesions", 'Disease', 'MESH:D001471', (212, 240))	("dysplastic Barrett's lesions", 'Disease', (212, 240))
378465	28930597	It was reported that blockade of SOCE, by STIM1 and Orai1 shRNAs or by pharmacological inhibitors, remarkably impaired the breast cancer cell mobility and invasiveness in vitro, and abrogated the lung metastasis of breast cancer cells in mouse models.	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('breast cancer', 'Disease', (215, 228))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('invasiveness in vitro', 'CPA', (155, 176))	('blockade', 'Var', (21, 29))	('impaired the breast cancer', 'Disease', (110, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mouse', 'Species', '10090', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('impaired the breast cancer', 'Disease', 'MESH:D001943', (110, 136))	('abrogated', 'NegReg', (182, 191))
378466	28930597	Strikingly, stimulation of SOCE by ectopic expression of STIM1 together with Orai1 was able to confer human mammary epithelial cells MCF-10A with ability to invade Matrigel, suggesting that activation of SOCE in non-invasive epithelial cells with invasiveness.	('MCF-10', 'CellLine', 'CVCL:5555', (133, 139))	('human', 'Species', '9606', (102, 107))	('ectopic expression', 'Var', (35, 53))	('STIM1', 'Gene', (57, 62))
378481	28930597	Blockade of SOCE in breast and cervical cancer cells lead to large peripheral focal adhesions that have slower assembly and disassembly rates, suggesting impaired focal adhesion turnover in these cells.	('Blockade', 'Var', (0, 8))	('focal adhesion turnover', 'MPA', (163, 186))	('impaired', 'NegReg', (154, 162))	('SOCE', 'Gene', (12, 16))	('cervical cancer', 'Disease', (31, 46))	('cervical cancer', 'Disease', 'MESH:D002583', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
378487	28930597	SOCE may also control focal adhesion turnover through focal adhesion kinases FAK and Pyk2, since SOCE inhibition also decreases the levels of active FAK and Pyk2.	('FAK', 'Gene', '5747', (77, 80))	('levels', 'MPA', (132, 138))	('FAK', 'Gene', (77, 80))	('Pyk2', 'Gene', '2185', (157, 161))	('Pyk2', 'Gene', (157, 161))	('Pyk2', 'Gene', (85, 89))	('inhibition', 'Var', (102, 112))	('Pyk2', 'Gene', '2185', (85, 89))	('decreases', 'NegReg', (118, 127))	('FAK', 'Gene', '5747', (149, 152))	('focal adhesion turnover', 'MPA', (22, 45))	('FAK', 'Gene', (149, 152))
378494	28930597	Interestingly, inhibition of calpain also results in large peripheral focal adhesion and defective focal adhesion disassembly, a phenotype that is reminiscent of focal adhesions in SOCE inhibited cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('pain', 'Phenotype', 'HP:0012531', (32, 36))	('defective', 'NegReg', (89, 98))	('pain', 'Disease', 'MESH:D010146', (32, 36))	('pain', 'Disease', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('focal adhesion disassembly', 'CPA', (99, 125))	('cancer', 'Disease', (196, 202))	('results in', 'Reg', (42, 52))	('inhibition', 'Var', (15, 25))
378513	28930597	There is now convincing evidence from animal models and human patient specimens suggesting that dysregulation of STIM and Orai proteins promotes the tumor metastasis and progression.	('STIM', 'Protein', (113, 117))	('promotes', 'PosReg', (136, 144))	('patient', 'Species', '9606', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('human', 'Species', '9606', (56, 61))	('Orai proteins', 'Protein', (122, 135))	('tumor metastasis', 'Disease', 'MESH:D009362', (149, 165))	('dysregulation', 'Var', (96, 109))	('tumor metastasis', 'Disease', (149, 165))
378514	28930597	Blockade of SOCE with pharmacological inhibitors or RNA interference inhibits the metastasis of breast cancer, melanoma, colorectal cancer, gastric cancer in xenograft models; on the other hand, ectopic expression of STIM1 in SW480 colorectal cancer cells promotes lung metastasis.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (232, 249))	('ectopic expression', 'Var', (195, 213))	('breast cancer', 'Disease', (96, 109))	('colorectal cancer', 'Disease', (121, 138))	('colorectal cancer', 'Disease', (232, 249))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('SW480', 'CellLine', 'CVCL:0546', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('inhibits', 'NegReg', (69, 77))	('gastric cancer', 'Disease', (140, 154))	('lung metastasis', 'CPA', (265, 280))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (232, 249))	('STIM1', 'Gene', (217, 222))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('promotes', 'PosReg', (256, 264))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('metastasis', 'CPA', (82, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
378515	28930597	Notably, blockade of SOCE not only inhibits spontaneous metastasis from primary tumor, but also reduces metastatic burden from intravenously injected metastatic cancer cells, suggesting that SOCE is critical for disseminated cancer cells to establish secondary tumor.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('reduces', 'NegReg', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('inhibits', 'NegReg', (35, 43))	('cancer', 'Disease', (225, 231))	('tumor', 'Disease', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('SOCE', 'Gene', (21, 25))	('blockade', 'Var', (9, 17))
378529	28930597	The single-nucleotide polymorphisms of ORAI1 gene in breast cancer are strongly associated with lymph node involvement and estrogen receptor status, suggesting the genetic variant of SOCE genes might predispose patients to breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('patients', 'Species', '9606', (211, 219))	('estrogen receptor', 'Gene', (123, 140))	('predispose', 'Reg', (200, 210))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('estrogen receptor', 'Gene', '2099', (123, 140))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('ORAI1', 'Gene', (39, 44))	('ORAI1', 'Gene', '84876', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (223, 236))	('associated', 'Reg', (80, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('single-nucleotide polymorphisms', 'Var', (4, 35))	('lymph node involvement', 'CPA', (96, 118))	('breast cancer', 'Disease', (53, 66))
378543	28930597	In glioblastoma and colorectal cancer, the overexpression of STIM2 appeared to be due to amplification of the 4p15 locus, which increases STIM2 gene copy numbers.	('STIM2', 'Gene', (61, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('STIM2', 'Gene', '57620', (138, 143))	('copy numbers', 'MPA', (149, 161))	('overexpression', 'PosReg', (43, 57))	('colorectal cancer', 'Disease', (20, 37))	('glioblastoma', 'Disease', (3, 15))	('increases', 'PosReg', (128, 137))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('STIM2', 'Gene', (138, 143))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('amplification', 'Var', (89, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('4p15', 'Gene', (110, 114))	('STIM2', 'Gene', '57620', (61, 66))
378550	28930597	The expression levels of HIF-1alpha in cancer could also be increased by non-hypoxic regulations (such as mutations of von Hippel-Lindau tumor suppressor).	('expression levels', 'MPA', (4, 21))	('HIF-1alpha in cancer', 'Disease', (25, 45))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (106, 115))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (119, 142))	('von Hippel-Lindau tumor', 'Disease', (119, 142))	('increased', 'PosReg', (60, 69))	('HIF-1alpha in cancer', 'Disease', 'MESH:D009369', (25, 45))
378565	28930597	Depletion of STIM1 and Orai1 decreased oscillation frequency and impaired the assembly of invadopodia, suggesting that oscillatory Ca2+ signal is required for the assembly of invadopodia.	('assembly', 'MPA', (78, 86))	('Orai1', 'Gene', (23, 28))	('Ca2', 'Gene', '760', (131, 134))	('oscillation frequency', 'MPA', (39, 60))	('Depletion', 'Var', (0, 9))	('Ca2', 'Gene', (131, 134))	('decreased', 'NegReg', (29, 38))	('STIM1', 'Gene', (13, 18))	('impaired', 'NegReg', (65, 73))
378576	28930597	Indeed, SOCE blockers SKF96365 and 2-APB have been used to inhibit tumor growth and metastasis in the xenograft mouse models for breast, cervical and esophageal cancers.	('esophageal cancers', 'Disease', (150, 168))	('SKF96365', 'Var', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('esophageal cancers', 'Disease', 'MESH:D004938', (150, 168))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('P', 'Chemical', 'MESH:D010758', (38, 39))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('tumor', 'Disease', (67, 72))	('inhibit', 'NegReg', (59, 66))	('mouse', 'Species', '10090', (112, 117))	('breast', 'Disease', (129, 135))	('cervical', 'Disease', (137, 145))
378590	28930597	There is now convincing evidence indicating that STIM and Orai proteins are overexpressed in solid tumors, and the overexpression of these proteins promotes tumor cell migration, invasion, proliferation, apoptosis resistance and chemoresistance.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (99, 104))	('apoptosis resistance', 'CPA', (204, 224))	('proliferation', 'CPA', (189, 202))	('overexpression', 'Var', (115, 129))	('chemoresistance', 'CPA', (229, 244))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('solid tumors', 'Disease', (93, 105))	('invasion', 'CPA', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('promotes', 'PosReg', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('solid tumors', 'Disease', 'MESH:D009369', (93, 105))
378750	27284256	Even though ENI may reduce the local/regional failures, substantial side effects may offset its survival benefits.	('ENI', 'Chemical', '-', (12, 15))	('local/regional failures', 'CPA', (31, 54))	('reduce', 'NegReg', (20, 26))	('ENI', 'Var', (12, 15))
378752	27284256	Thus, IFI may result in a reduced incidence of treatment toxicities that enable more patients to tolerate the CCRT.	('IFI', 'Var', (6, 9))	('toxicities', 'Disease', 'MESH:D064420', (57, 67))	('CR', 'Chemical', '-', (111, 113))	('patients', 'Species', '9606', (85, 93))	('toxicities', 'Disease', (57, 67))
378758	21373836	The goals of ablating Barrett's esophagus are to decrease esophageal cancer rates and to improve overall survival and quality of life.	('quality of life', 'CPA', (118, 133))	('improve', 'PosReg', (89, 96))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (22, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('decrease', 'NegReg', (49, 57))	('ablating', 'Var', (13, 21))
378778	21373836	Because cancer risk diminishes when comparing high-grade to low-grade and no dysplasia, other factors, such as the intervention's cost and side-effect profile, become more important in treatment decisions.	('cancer', 'Disease', (8, 14))	('dysplasia', 'Disease', (77, 86))	('high-grade', 'Var', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('men', 'Species', '9606', (190, 193))	('dysplasia', 'Disease', 'MESH:D004476', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('diminishes', 'NegReg', (20, 30))
378788	21373836	Although ablation has been demonstrated to cause reversion of epithelium to neosquamous in these subjects, and therefore, cosmetically at least, seems preferable to surveillance, further benefit must accrue to subjects to make it worth considering in subjects with lesser forms of dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (281, 290))	('ablation', 'Var', (9, 17))	('dysplasia', 'Disease', (281, 290))
378801	21373836	The major complications associated with argon plasma are pain and dysphagia, although strictures can occur at a rate of 5% to 10% (Table 2).	('dysphagia', 'Disease', (66, 75))	('argon', 'Var', (40, 45))	('dysphagia', 'Phenotype', 'HP:0002015', (66, 75))	('pain', 'Phenotype', 'HP:0012531', (57, 61))	('argon', 'Chemical', 'MESH:D001128', (40, 45))	('pain', 'Disease', 'MESH:D010146', (57, 61))	('dysphagia', 'Disease', 'MESH:D003680', (66, 75))	('pain', 'Disease', (57, 61))
378806	21373836	The primary outcome of this trial, disappearance of all high-grade dysplasia in biopsies at any time after enrollment, was achieved in 77% of patients treated with PDT versus 39% of the control arm (P<0.0001).	('PDT', 'Var', (164, 167))	('dysplasia', 'Disease', (67, 76))	('men', 'Species', '9606', (113, 116))	('dysplasia', 'Disease', 'MESH:D004476', (67, 76))	('patients', 'Species', '9606', (142, 150))	('disappearance', 'NegReg', (35, 48))
378819	21373836	Thirteen patients with nondysplastic BE or BE with low-grade dysplasia randomly assigned to receive 5-aminolevulinic acid and a fractionated dose of PDT had a 33%rateofcomplete histologicresponseafter the initial dose, compared with a 36% response rate in the 14 patients who received APC.	('dysplastic', 'Disease', 'MESH:D004416', (26, 36))	('PDT', 'Gene', (149, 152))	('patients', 'Species', '9606', (9, 17))	('5-aminolevulinic acid', 'Var', (100, 121))	('patients', 'Species', '9606', (263, 271))	('BE', 'Phenotype', 'HP:0100580', (37, 39))	('BE', 'Phenotype', 'HP:0100580', (43, 45))	('low-grade dysplasia', 'Disease', (51, 70))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (100, 121))	('dysplastic', 'Disease', (26, 36))	('low-grade dysplasia', 'Disease', 'MESH:D008228', (51, 70))
378899	21373836	Quality of life is an important patient-centered outcome that improves after ablation of BE.	('Quality', 'MPA', (0, 7))	('ablation', 'Var', (77, 85))	('BE', 'Phenotype', 'HP:0100580', (89, 91))	('improves', 'PosReg', (62, 70))	('patient', 'Species', '9606', (32, 39))
378918	33510845	Moreover, in patients with GI malignancies, MDSCs can lead to the suppression of T cells and natural killer cells.	('patients', 'Species', '9606', (13, 21))	('T cells', 'CPA', (81, 88))	('GI malignancies', 'Disease', (27, 42))	('GI malignancies', 'Disease', 'MESH:D009369', (27, 42))	('MDSCs', 'Var', (44, 49))	('suppression', 'NegReg', (66, 77))
378930	33510845	In a meta-analysis of 17 studies with 1115 patients with GI malignancies, patients with a higher number of MDSCs at tumor sites and peripheral blood had higher mortality rates (hazard ratio: 3.35, 95% confidence interval: 1.46-7.68; P = 0.0004), risk of relapse, and tumor progression.	('GI malignancies', 'Disease', (57, 72))	('higher', 'PosReg', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('mortality', 'Disease', (160, 169))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (74, 82))	('GI malignancies', 'Disease', 'MESH:D009369', (57, 72))	('MDSCs', 'Var', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (267, 272))	('relapse', 'CPA', (254, 261))	('tumor', 'Disease', (116, 121))	('mortality', 'Disease', 'MESH:D003643', (160, 169))
378933	33510845	Shibata et al evaluated 123 patients with advanced GI malignancy, including 62 with colorectal cancer (CRC), 43 with gastric cancer (GC), and 18 with esophageal malignancies, and found that overall survival (OS) was significantly shorter in stage IV GI cancer patients with high MDSC levels than in those with low MDSC levels (P < 0.05).	('GI cancer', 'Disease', (250, 259))	('malignancies', 'Disease', (161, 173))	('CRC', 'Disease', 'MESH:D015179', (103, 106))	('gastric cancer', 'Disease', (117, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('esophageal malignancies', 'Phenotype', 'HP:0100751', (150, 173))	('overall survival', 'MPA', (190, 206))	('GI cancer', 'Disease', 'MESH:D009369', (250, 259))	('patients', 'Species', '9606', (260, 268))	('GI cancer', 'Phenotype', 'HP:0007378', (250, 259))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('patients', 'Species', '9606', (28, 36))	('GI malignancy', 'Disease', (51, 64))	('GC', 'Phenotype', 'HP:0012126', (133, 135))	('high', 'Var', (274, 278))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('GI malignancy', 'Disease', 'MESH:D009369', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('stage IV', 'Disease', (241, 249))	('CRC', 'Disease', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('colorectal cancer', 'Disease', (84, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('shorter', 'NegReg', (230, 237))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
378934	33510845	Because MDSCs have a significant role in modulating cancer progression and metastasis by inhibiting the anti-tumor reactivity of T cells and natural killer (NK) cells, targeting MDSCs with immune checkpoint inhibitors (ICIs) can alleviate their pro-tumorigenic functions.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('inhibiting', 'NegReg', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('alleviate', 'NegReg', (229, 238))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('targeting', 'Var', (168, 177))	('metastasis', 'CPA', (75, 85))	('tumor', 'Disease', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', (109, 114))
378948	33510845	Moreover, MDSCs can stimulate and recruit regulatory T cells (Tregs) to the TME.	('MDSCs', 'Var', (10, 15))	('Tregs', 'Chemical', '-', (62, 67))	('recruit regulatory T cells', 'CPA', (34, 60))	('stimulate', 'PosReg', (20, 29))
378966	33510845	The authors concluded that cancer cell differentiation and lymph node metastasis are mostly related to the presence of M-MDSCs.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('presence', 'Var', (107, 115))	('related', 'Reg', (92, 99))	('M-MDSCs', 'Gene', (119, 126))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('lymph node metastasis', 'CPA', (59, 80))
378978	33510845	A high frequency of MDSCs in the PBMCs of patients with HCC has been linked to more aggressive forms of HCC and poor clinical outcomes following local ablation, hepatectomy, or hepatic arterial infusion chemotherapy.	('HCC', 'Phenotype', 'HP:0001402', (104, 107))	('MDSCs', 'Var', (20, 25))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('linked', 'Reg', (69, 75))	('HCC', 'Gene', (104, 107))	('HCC', 'Gene', (56, 59))	('patients', 'Species', '9606', (42, 50))	('HCC', 'Gene', '619501', (104, 107))	('HCC', 'Gene', '619501', (56, 59))
379016	33510845	In patients with GI cancer, MDSCs can lead to immunosuppression, and they play an important role in premalignant cell transformation, tumor growth, and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('MDSCs', 'Var', (28, 33))	('GI cancer', 'Disease', (17, 26))	('metastasis', 'CPA', (152, 162))	('play', 'Reg', (74, 78))	('premalignant cell transformation', 'CPA', (100, 132))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('role', 'Reg', (92, 96))	('patients', 'Species', '9606', (3, 11))	('lead to', 'Reg', (38, 45))	('GI cancer', 'Disease', 'MESH:D009369', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('GI cancer', 'Phenotype', 'HP:0007378', (17, 26))	('immunosuppression', 'MPA', (46, 63))	('tumor', 'Disease', (134, 139))
379017	33510845	A higher number of MDSCs at tumor sites and peripheral blood is correlated with higher mortality rates, risk of relapse, and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('tumor', 'Disease', (125, 130))	('MDSCs', 'Var', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('mortality', 'Disease', (87, 96))	('higher', 'PosReg', (80, 86))
379022	33113266	Using 2 human ESCC cell lines, we found that Eomes knockdown reduced esophageal cancer cell proliferation and that the esophageal cancer cell cycle was blocked in the G2/M phase.	('esophageal cancer', 'Disease', (69, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', (119, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('human', 'Species', '9606', (8, 13))	('Eomes', 'Protein', (45, 50))	('reduced', 'NegReg', (61, 68))	('knockdown', 'Var', (51, 60))
379023	33113266	Furthermore, we found that CCL20 could chemoregulate regulatory T cells (Tregs) through their specific receptor CCR6, then promoting the proliferation of esophageal cancer cells.	('promoting', 'PosReg', (123, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('CCL20', 'Var', (27, 32))	('CCR6', 'Gene', (112, 116))	('CCR6', 'Gene', '1235', (112, 116))	('proliferation', 'CPA', (137, 150))	('esophageal cancer', 'Disease', (154, 171))	('Tregs', 'Chemical', '-', (73, 78))
379024	33113266	Eomes knockdown also delayed the growth of human ESCC xenografts in BALB/c nude mice.	('delayed', 'NegReg', (21, 28))	('nude mice', 'Species', '10090', (75, 84))	('growth', 'CPA', (33, 39))	('Eomes', 'Protein', (0, 5))	('knockdown', 'Var', (6, 15))	('human', 'Species', '9606', (43, 48))
379028	33113266	Lian et al report that the Eomes-CCL20-CCR6 pathway plays a vital role in human ESCC progress and that high Eomes levels were associated with poor clinical prognosis.	('CCR6', 'Gene', '1235', (39, 43))	('CCR6', 'Gene', (39, 43))	('ESCC progress', 'Disease', (80, 93))	('Eomes levels', 'MPA', (108, 120))	('Lian', 'Species', '155640', (0, 4))	('high', 'Var', (103, 107))	('human', 'Species', '9606', (74, 79))
379029	33113266	They found that CCL20 could chemoregulate Tregs through their specific receptor CCR6 and then promote the proliferation of esophageal cancer cells.	('esophageal cancer', 'Disease', (123, 140))	('CCR6', 'Gene', (80, 84))	('CCR6', 'Gene', '1235', (80, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('Tregs', 'Chemical', '-', (42, 47))	('promote', 'PosReg', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('proliferation', 'CPA', (106, 119))	('CCL20', 'Var', (16, 21))
379044	33113266	Eomes expression is not only related to the early recurrence of gastric cancer after surgery, but also related to poor disease-free survival time.	('related', 'Reg', (29, 36))	('early recurrence of gastric cancer', 'Phenotype', 'HP:0006753', (44, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('related', 'Reg', (103, 110))	('gastric cancer', 'Disease', (64, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('Eomes expression', 'Var', (0, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))
379049	33113266	16  Moreover, in patients with ESCC, hypermethylation of Eomes may be an effective diagnostic method for ESCC.	('ESCC', 'Disease', (105, 109))	('Eomes', 'Protein', (57, 62))	('patients', 'Species', '9606', (17, 25))	('hypermethylation', 'Var', (37, 53))	('ESCC', 'Disease', (31, 35))
379050	33113266	17  Abnormal methylation of Eomes at the promoter region leads to its downregulation and results in the occurrence and development of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', (134, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('methylation', 'Var', (13, 24))	('results in', 'Reg', (89, 99))	('downregulation', 'NegReg', (70, 84))	('Eomes', 'Protein', (28, 33))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (134, 158))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (134, 158))
379103	33113266	We used CCK8 to test the effect of Eomes knockdown on the proliferation of esophageal cancer cells and found that proliferation decreased after Eomes knockdown (Figure 2F).	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Eomes knockdown', 'Var', (144, 159))	('knockdown', 'Var', (150, 159))	('decreased', 'NegReg', (128, 137))	('proliferation', 'CPA', (114, 127))	('esophageal cancer', 'Disease', (75, 92))
379104	33113266	Proliferation index of esophageal cancer cells after knocking down Eomes was assessed by CFSE assay, which verified that knocking down Eomes affected the proliferation index (Figure 2G).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('proliferation index', 'CPA', (154, 173))	('knocking down', 'Var', (121, 134))	('esophageal cancer', 'Disease', (23, 40))	('Eomes', 'Gene', (135, 140))	('affected', 'Reg', (141, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (23, 40))
379106	33113266	In order to investigate the mechanism by which Eomes regulated the proliferation of esophageal cancer cells, we used the KYSE450 line to establish an esophageal cancer cell line that stably knocked down Eomes.	('esophageal cancer', 'Disease', (150, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('knocked', 'Var', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Eomes', 'Gene', (203, 208))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
379108	33113266	We used a CCL20 recombinant protein to find if Eomes affected the proliferation of esophageal cancer cells through CCL20 (Figure 3H).	('affected', 'Reg', (53, 61))	('esophageal cancer', 'Disease', (83, 100))	('proliferation', 'CPA', (66, 79))	('CCL20', 'Var', (115, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))
379109	33113266	Using TCGA database, we found that ESCC patients with high CCL20 expression had a poor prognosis (Figure 3I).	('patients', 'Species', '9606', (40, 48))	('ESCC', 'Disease', (35, 39))	('CCL20', 'Gene', (59, 64))	('high', 'Var', (54, 58))
379113	33113266	To obtain PBMC, we collected peripheral blood from esophageal cancer patients, and found that in esophageal cancer patients the cell supernatant after knocking down Eomes had a reduced ability for chemotactic Tregs (Figure 4A).	('patients', 'Species', '9606', (115, 123))	('chemotactic Tregs', 'CPA', (197, 214))	('knocking down', 'Var', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancer', 'Disease', (51, 68))	('Eomes', 'Gene', (165, 170))	('reduced', 'NegReg', (177, 184))	('esophageal cancer', 'Disease', (97, 114))	('Tregs', 'Chemical', '-', (209, 214))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('patients', 'Species', '9606', (69, 77))
379117	33113266	To further verify that knocking down Eomes led to a reduction in CCL20 expression and thus reduced the chemotactic ability of Tregs, we collected peripheral blood from healthy donors and isolated PBMC.	('Eomes', 'Gene', (37, 42))	('chemotactic ability of Tregs', 'CPA', (103, 131))	('expression', 'MPA', (71, 81))	('Tregs', 'Chemical', '-', (126, 131))	('CCL20', 'Gene', (65, 70))	('knocking down', 'Var', (23, 36))	('reduced', 'NegReg', (91, 98))	('reduction', 'NegReg', (52, 61))
379118	33113266	We found that the ability to chemotactically attract Tregs was reduced in the supernatants of Eomes knockdown cells (Figure 4D), but there was no effect on the chemotaxis of PBMC (Figure 4E).	('knockdown', 'Var', (100, 109))	('Tregs', 'Chemical', '-', (53, 58))	('reduced', 'NegReg', (63, 70))	('ability', 'MPA', (18, 25))	('Eomes', 'Gene', (94, 99))
379125	33113266	We subcutaneously inoculated BALB/c nude mice with an esophageal cancer cell line KYSE450 that had stably knocked down Eomes.	('Eomes', 'Gene', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('nude mice', 'Species', '10090', (36, 45))	('knocked', 'Var', (106, 113))	('esophageal cancer', 'Disease', (54, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))
379126	33113266	We found that tumor proliferation was suppressed in the knockdown Eomes group and tumor proliferation rate became slower (Figure 5A).	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('suppressed', 'NegReg', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('slower', 'NegReg', (114, 120))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('knockdown', 'Var', (56, 65))
379128	33113266	We used qRT-PCR to analyze Eomes expression in tumor tissues and found that Eomes expression was reduced in the knockdown group (Figure 5C).	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('reduced', 'NegReg', (97, 104))	('knockdown', 'Var', (112, 121))	('Eomes expression', 'MPA', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
379134	33113266	23  Eomes expression can be found in almost all Th subtypes 24  and can induce IFN-gamma expression, 25  however the role of Eomes in tumors has been rarely reported and results in existing reports on tumor progression are not consistent.	('Eomes expression', 'Var', (4, 20))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('IFN-gamma', 'Gene', (79, 88))	('IFN-gamma', 'Gene', '3458', (79, 88))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('induce', 'Reg', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', (134, 139))
379139	33113266	Overexpression of Eomes in colorectal cancer resulted in a poor prognosis for colorectal cancer patients, and Eomes knockdown caused a reduction in colorectal cancer cell proliferation.	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('reduction', 'NegReg', (135, 144))	('Eomes', 'Protein', (110, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('knockdown', 'Var', (116, 125))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('colorectal cancer', 'Disease', (27, 44))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))	('colorectal cancer', 'Disease', (148, 165))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('colorectal cancer', 'Disease', (78, 95))
379140	33113266	13  This result was consistent with our findings, however in contrast Eomes expression in metastatic renal cell carcinoma patients was associated with a good prognosis.	('metastatic renal cell carcinoma', 'Disease', (90, 121))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (90, 121))	('Eomes expression', 'Var', (70, 86))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (101, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('patients', 'Species', '9606', (122, 130))
379143	33113266	In the current study, we found that Eomes knockdown could significantly inhibit CCL20 expression in ESCC, suggesting that Eomes plays a vital role in regulating the CCL20-CCR6 pathway.	('expression', 'MPA', (86, 96))	('CCR6', 'Gene', '1235', (171, 175))	('CCR6', 'Gene', (171, 175))	('inhibit', 'NegReg', (72, 79))	('CCL20', 'Gene', (80, 85))	('knockdown', 'Var', (42, 51))
379149	33113266	In vitro experiments also showed the effect of Eomes on esophageal cancer cell proliferation and that Eomes knockdown affected CCL20 secretion.	('knockdown', 'Var', (108, 117))	('esophageal cancer', 'Disease', (56, 73))	('CCL20 secretion', 'MPA', (127, 142))	('effect', 'Reg', (37, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('affected', 'Reg', (118, 126))
379150	33113266	However, it should be noted that CCL20 is an inflammatory chemokine and could also recruit suppressive immune cells to downregulate the antitumor response.	('downregulate', 'NegReg', (119, 131))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CCL20', 'Var', (33, 38))	('suppressive immune cells', 'Phenotype', 'HP:0002721', (91, 115))	('tumor', 'Disease', (140, 145))
379155	33113266	In our research, we found that in the esophageal cancer microenvironment, the supernatant from knocked down Eomes lines significantly reduced chemotaxis of Tregs.	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Tregs', 'Chemical', '-', (156, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('reduced', 'NegReg', (134, 141))	('Eomes', 'Gene', (108, 113))	('chemotaxis of Tregs', 'CPA', (142, 161))	('knocked down', 'Var', (95, 107))
379183	31577707	Meanwhile, Biopsy specimens were sent to 3D Medicines for next-generation sequencing (NGS) cancer gene panel (381 genes) test, with the results showing clinically significant mutations in NOTCH1 and TP53.	('TP53', 'Gene', (199, 203))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('NOTCH1', 'Gene', '4851', (188, 194))	('mutations', 'Var', (175, 184))	('NOTCH1', 'Gene', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TP53', 'Gene', '7157', (199, 203))
379198	31577707	It is hypothesized that highly mutated tumors are more likely to harbor neoantigens which make them targets of activated immune cells.	('harbor', 'Reg', (65, 71))	('tumors', 'Disease', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('highly mutated', 'Var', (24, 38))	('neoantigens', 'Protein', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (39, 45))
379203	31577707	According to a previous study, SHR-1210, a PD-1 inhibitor, when combined with the small molecule anti-angiogenesis inhibitor apatinib, can achieve an ORR of 50% in patients with advanced hepatocellular carcinoma.	('apatinib', 'Chemical', 'MESH:C553458', (125, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (187, 211))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (187, 211))	('hepatocellular carcinoma', 'Disease', (187, 211))	('SHR-1210', 'Var', (31, 39))	('patients', 'Species', '9606', (164, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
379205	31577707	Anlotinib can inhibit substrate phosphorylation and signal transduction by competing with ATP for the binding sites on VEGFR/PDGFR/FGFR/c-kit, therefore exhibits an effect of inhibiting tumor angiogenesis and tumor growth.	('binding', 'Interaction', (102, 109))	('c-kit', 'Gene', '3815', (136, 141))	('tumor', 'Disease', (186, 191))	('VEGFR', 'Gene', (119, 124))	('Anlotinib', 'Var', (0, 9))	('substrate phosphorylation', 'MPA', (22, 47))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (209, 214))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('inhibit', 'NegReg', (14, 21))	('c-kit', 'Gene', (136, 141))	('PDGFR', 'Gene', (125, 130))	('inhibiting', 'NegReg', (175, 185))	('PDGFR', 'Gene', '5159', (125, 130))	('signal transduction', 'MPA', (52, 71))	('Anlotinib', 'Chemical', 'None', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('VEGFR', 'Gene', '3791', (119, 124))
379279	31138245	also showed that perioperative complications and mortality were significantly lower with MIE versus open esophagectomy .	('perioperative complications', 'CPA', (17, 44))	('MIE', 'Chemical', '-', (89, 92))	('MIE', 'Var', (89, 92))	('lower', 'NegReg', (78, 83))	('mortality', 'CPA', (49, 58))
379306	30535493	Genetic, epigenetic and transcriptional comparison of esophagus tumor-associated and adjacent normal myofibroblasts Myofibroblasts (MFs) are present in healthy tissues and are also key components of the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', (64, 69))	('epigenetic', 'Var', (9, 19))	('esophagus tumor', 'Phenotype', 'HP:0100751', (54, 69))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('esophagus tumor', 'Disease', (54, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('esophagus tumor', 'Disease', 'MESH:D004938', (54, 69))
379314	30535493	The results imply that epigenetic rather than genetic alterations are associated with the development of the distinct expressional and functional features, which define this MF phenotype in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('associated', 'Reg', (70, 80))	('epigenetic', 'Var', (23, 33))	('tumor', 'Disease', (194, 199))
379322	30535493	In fact, several studies verified that the appearance of MMPs in the tumor microenvironment is associated with increased cancer aggressiveness and bad prognosis.	('aggressiveness', 'Phenotype', 'HP:0000718', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (69, 74))	('increased cancer aggressiveness', 'Disease', (111, 142))	('MMPs', 'Var', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('increased cancer aggressiveness', 'Disease', 'MESH:D009369', (111, 142))
379357	30535493	The TruSight Cancer panel targets 94 genes and sites of 284 single nucleotide polymorphisms (SNPs) associated with tumors.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('single nucleotide polymorphisms', 'Var', (60, 91))
379371	30535493	P0448; 1:2,000 for modified histones and anti-mouse IgG, cat.	('modified histones', 'Protein', (19, 36))	('anti-mouse', 'Var', (41, 51))	('mouse', 'Species', '10090', (46, 51))
379388	30535493	To identify genetic alterations in MF cells and possible somatic variants in esophagus tumor-derived MFs targeted genome analysis was performed.	('esophagus tumor', 'Disease', 'MESH:D004938', (77, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('variants', 'Var', (65, 73))	('esophagus tumor', 'Disease', (77, 92))	('esophagus tumor', 'Phenotype', 'HP:0100751', (77, 92))
379391	30535493	It was demonstrated that on the sequenced 255 kbp genomic region normal tissue-derived MFs of this patient carried 277 variants and identical number or variants were present in the tumor-associated MFs, while 282 variants were discovered in tumor tissue samples.	('patient', 'Species', '9606', (99, 106))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('MFs', 'Gene', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('variants', 'Var', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
379395	30535493	In the tumor-derived MF samples variants with 5-7% allele frequency in the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2; chr7: 148511066, C>A), TSC2 (chr16: 2120519, C>A) and folliculin (FLCN; chr17: 17119708, T>TG) genes were identified.	('FLCN', 'Gene', (206, 210))	('EZH2', 'Gene', '2146', (134, 138))	('2120519, C>A', 'Mutation', 'g.2120519C>A', (176, 188))	('tumor', 'Disease', (7, 12))	('EZH2', 'Gene', (134, 138))	('TSC2', 'Gene', '7249', (163, 167))	('C>A', 'Var', (157, 160))	('TSC2', 'Gene', (163, 167))	('folliculin', 'Gene', '201163', (194, 204))	('FLCN', 'Gene', '201163', (206, 210))	('148511066, C>A', 'Mutation', 'c.148511066C>A', (146, 160))	('C>A', 'Var', (185, 188))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('folliculin', 'Gene', (194, 204))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
379396	30535493	The SNPs affecting EZH2 and TSC2 caused missense mutations, the insertion in FLCN causes a frame-shift mutation and is described in the ClinVar and COSMIC database (id: COSM1381204) as a variant associated with the large intestine as primary tumor site.	('TSC2', 'Gene', '7249', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('TSC2', 'Gene', (28, 32))	('FLCN', 'Gene', '201163', (77, 81))	('frame-shift mutation', 'MPA', (91, 111))	('insertion', 'Var', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (242, 247))	('EZH2', 'Gene', '2146', (19, 23))	('missense', 'Var', (40, 48))	('FLCN', 'Gene', (77, 81))	('EZH2', 'Gene', (19, 23))
379397	30535493	In the tumor tissue variants of the FA complementation group D2 (FANCD2), XPC complex subunit, BRCA1 associated protein 1 and glypican 3 were demonstrated with 2-4% allele frequency and SNP of TP53 with allele frequency of 14.92%.	('BRCA1 associated protein 1', 'Gene', '8314', (95, 121))	('FANCD2', 'Gene', (65, 71))	('tumor', 'Disease', (7, 12))	('TP53', 'Gene', '7157', (193, 197))	('BRCA1 associated protein 1', 'Gene', (95, 121))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('SNP', 'Var', (186, 189))	('XPC', 'Gene', (74, 77))	('TP53', 'Gene', (193, 197))	('XPC', 'Gene', '7508', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('FANCD2', 'Gene', '2177', (65, 71))
379399	30535493	The de novo somatic nature of most of these variants is supported by the fact that all of the relevant variants, except for a FANCD2 variant in the tumor sample, have a 0% global allele frequency in the 1,000 Genomes Project database.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('variants', 'Var', (103, 111))	('FANCD2', 'Gene', '2177', (126, 132))	('FANCD2', 'Gene', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
379402	30535493	As no drastic difference in mutation frequency between tumor-derived MFs and MFs isolated from the normal tissue was detected, it was hypothesized that epigenetic modifications may be involved in the development of the observed morphological alterations, since epigenetic alterations can affect the expression profile and ultimately the morphology and the function of tumor-associated MFs.	('epigenetic alterations', 'Var', (261, 283))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('morphology', 'MPA', (337, 347))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('tumor', 'Disease', (368, 373))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('function', 'MPA', (356, 364))	('tumor', 'Disease', (55, 60))	('affect', 'Reg', (288, 294))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('expression profile', 'MPA', (299, 317))
379403	30535493	MFs were incubated with antibodies specific for pan-acetylated H3 and H4 as well as with antibodies recognizing specifically H3K9ac, H3K14ac, H3K18ac, H4K8ac, H4K12ac, H4K16ac, and di- and trimethylated H3K9.	('H3', 'Gene', '126961', (133, 135))	('H3', 'Gene', '126961', (203, 205))	('H3', 'Gene', '126961', (63, 65))	('H4K8ac', 'Var', (151, 157))	('H3', 'Gene', '126961', (125, 127))	('H4K12ac', 'Var', (159, 166))	('H3', 'Gene', '126961', (142, 144))	('H4K16ac', 'Var', (168, 175))
379440	30535493	To gain information on the genetic status of stromal MFs, next generation sequencing was performed to detect the occurrence of nucleotide variants in a set of most frequently mutated cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('nucleotide variants', 'Var', (127, 146))
379448	30535493	It is well-known, that in addition to DNA methylation, alterations in the acetylation or methylation level of specific lysine (K) side chains of histone proteins, established by histone modifying enzyme complexes, can lead to chromatin modifications, thereby to major variations in the gene expression pattern and consequently to morphological, and functional alterations of a given cell.	('lead to', 'Reg', (218, 225))	('alterations', 'Var', (55, 66))	('gene expression pattern', 'MPA', (286, 309))	('acetylation', 'MPA', (74, 85))	('chromatin modifications', 'MPA', (226, 249))	('lysine', 'Chemical', 'MESH:D008239', (119, 125))	('variations', 'Reg', (268, 278))	('methylation level', 'MPA', (89, 106))
379450	30535493	The observed alterations, including decreased levels of trimethylated H3K9 and acetylated H4K16 in tumor-associated MFs may affect chromatin structure, which can at least partly serve as the underlying cause of the altered morphology of tumor-derived MFs.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (237, 242))	('affect', 'Reg', (124, 130))	('H4K16', 'Protein', (90, 95))	('levels', 'MPA', (46, 52))	('trimethylated', 'Var', (56, 69))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('chromatin structure', 'MPA', (131, 150))	('acetylated', 'MPA', (79, 89))	('H3', 'Gene', '126961', (70, 72))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('decreased', 'NegReg', (36, 45))
379459	30535493	The increased expression of UCP2, a critical regulator of cellular metabolism, involved in the tumor-promoting metabolic shift during cell transformation, is also detectable in MFs.	('UCP2', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('expression', 'MPA', (14, 24))	('UCP2', 'Gene', '7351', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('MFs', 'Var', (177, 180))	('increased', 'PosReg', (4, 13))	('tumor', 'Disease', (95, 100))
379466	30535493	Decreased level of MSTN was also detectable in higher grade breast cancers and MSTN supplementation reduced the viability, and the migratory capacity of MCF-7 breast adenocarcinoma cell line.	('breast cancers', 'Disease', 'MESH:D001943', (60, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('breast cancers', 'Disease', (60, 74))	('MSTN', 'Gene', '2660', (79, 83))	('MSTN', 'Gene', (19, 23))	('reduced', 'NegReg', (100, 107))	('supplementation', 'Var', (84, 99))	('MCF-7 breast adenocarcinoma', 'Disease', (153, 180))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('breast cancers', 'Phenotype', 'HP:0003002', (60, 74))	('MCF-7 breast adenocarcinoma', 'Disease', 'MESH:D001943', (153, 180))	('MSTN', 'Gene', '2660', (19, 23))	('MSTN', 'Gene', (79, 83))	('migratory capacity', 'CPA', (131, 149))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (159, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('viability', 'CPA', (112, 121))
379468	30535493	This observation is also in agreement with previous results on the altered secretory profile of intestinal MFs of MAP3K8 mutant mice, developing increased numbers and sizes of tumors, associated with enhanced epithelial proliferation and decreased apoptosis (Table III).	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutant', 'Var', (121, 127))	('increased', 'PosReg', (145, 154))	('tumors', 'Disease', (176, 182))	('MAP3K8', 'Gene', (114, 120))	('mice', 'Species', '10090', (128, 132))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('decreased', 'NegReg', (238, 247))	('epithelial proliferation', 'CPA', (209, 233))	('enhanced', 'PosReg', (200, 208))	('apoptosis', 'CPA', (248, 257))
379510	29253179	Moreover, epigenetic reprogramming of histone modifications increases EZR expression through histone modification (i.e.	('EZR', 'Gene', (70, 73))	('histone', 'MPA', (93, 100))	('epigenetic reprogramming', 'Var', (10, 34))	('EZR', 'Gene', '7430', (70, 73))	('increases', 'PosReg', (60, 69))
379511	29253179	tri-methyl-histone 3-K4) within the promoter region for EZR, in part through the histone modifier SET and MYND domain-containing 3 (SMYD3).	('EZR', 'Gene', (56, 59))	('SET and MYND domain-containing 3', 'Gene', '64754', (98, 130))	('EZR', 'Gene', '7430', (56, 59))	('SMYD3', 'Gene', (132, 137))	('tri-methyl-histone', 'Var', (0, 18))	('tri-methyl-histone', 'Chemical', '-', (0, 18))	('SMYD3', 'Gene', '64754', (132, 137))
379520	29253179	pGLB-hE(-1324/+134), pGLB-hE(-697/+134) and pGLB-hE(-87/-134) luciferase reporter plasmids, and pCMV, pCMV-SP1 and pCMV-C-Jun plasmids were described in our previous work.	('-697/+134', 'Var', (29, 38))	('pGLB-hE', 'Chemical', '-', (44, 51))	('pGLB-hE', 'Chemical', '-', (21, 28))	('C-Jun', 'Gene', (120, 125))	('-1324/+134', 'Var', (8, 18))	('pGLB-hE', 'Chemical', '-', (0, 7))	('C-Jun', 'Gene', '3725', (120, 125))
379556	29253179	Briefly, KYSE 150 cells transfected with Flag-SMYD3 or truncated SMYD3 were fixed with 4% paraformaldehyde for 10 min at room temperature.	('SMYD3', 'Gene', (65, 70))	('SMYD3', 'Gene', '64754', (65, 70))	('SMYD3', 'Gene', (46, 51))	('truncated', 'Var', (55, 64))	('SMYD3', 'Gene', '64754', (46, 51))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (90, 106))
379578	29253179	The efficiency of transcribed biotinylated EZR-AS1 RNA and antisense EZR-AS1 RNA in vitro was detected by a Chemiluminescent Nucleic Acid Detection Module (Thermo, No.	('biotin', 'Chemical', 'MESH:D001710', (30, 36))	('EZR-AS1', 'Gene', '101409257', (43, 50))	('EZR-AS1', 'Gene', (69, 76))	('EZR-AS1', 'Gene', '101409257', (69, 76))	('antisense', 'Var', (59, 68))	('EZR-AS1', 'Gene', (43, 50))
379592	29253179	These results suggest that antisense lncRNA EZR-AS1 could modulate EZR gene expression in ESCC cells.	('EZR', 'Gene', (67, 70))	('EZR', 'Gene', (44, 47))	('EZR', 'Gene', '7430', (67, 70))	('expression', 'MPA', (76, 86))	('EZR-AS1', 'Gene', '101409257', (44, 51))	('EZR-AS1', 'Gene', (44, 51))	('antisense', 'Var', (27, 36))	('modulate', 'Reg', (58, 66))	('EZR', 'Gene', '7430', (44, 47))
379594	29253179	Compared with control, when the level of EZR-AS1 was decreased by 80%, the expression of EZR (variant 1), both at the mRNA and protein levels, was also reduced in both KYSE150 and KYSE510 cells (Figure 1D and F).	('KYSE150', 'CellLine', 'CVCL:1348', (168, 175))	('EZR', 'Gene', '7430', (41, 44))	('KYSE510', 'CellLine', 'CVCL:1354', (180, 187))	('EZR-AS1', 'Gene', (41, 48))	('reduced', 'NegReg', (152, 159))	('EZR-AS1', 'Gene', '101409257', (41, 48))	('EZR', 'Gene', '7430', (89, 92))	('KYSE510', 'Var', (180, 187))	('EZR', 'Gene', (89, 92))	('EZR', 'Gene', (41, 44))	('expression', 'MPA', (75, 85))	('KYSE150', 'Var', (168, 175))
379597	29253179	However, the expression of EZR (variant 2) was unaffected following either silencing or overexpression of EZR-AS1 (Figure 1D, E and H).	('EZR-AS1', 'Gene', (106, 113))	('EZR', 'Gene', '7430', (27, 30))	('overexpression', 'PosReg', (88, 102))	('EZR', 'Gene', '7430', (106, 109))	('EZR-AS1', 'Gene', '101409257', (106, 113))	('silencing', 'Var', (75, 84))	('EZR', 'Gene', (106, 109))	('EZR', 'Gene', (27, 30))
379599	29253179	As expected, EZR expression was significantly decreased following knockdown of EZR-AS1 and increased by the overexpression of EZR-AS1 (Supplementary Figure S3).	('EZR', 'Gene', (79, 82))	('EZR-AS1', 'Gene', (126, 133))	('EZR', 'Gene', '7430', (13, 16))	('EZR', 'Gene', '7430', (126, 129))	('EZR', 'Gene', '7430', (79, 82))	('EZR-AS1', 'Gene', (79, 86))	('EZR-AS1', 'Gene', '101409257', (126, 133))	('EZR-AS1', 'Gene', '101409257', (79, 86))	('EZR', 'Gene', (13, 16))	('decreased', 'NegReg', (46, 55))	('increased', 'PosReg', (91, 100))	('EZR', 'Gene', (126, 129))	('knockdown', 'Var', (66, 75))
379602	29253179	Real-time cell analysis (RTCA) showed that knockdown of EZR-AS1 did not affect cell proliferation compared with the control cells (Supplementary Figure S4), but cell migration was significantly repressed (Figure 2A).	('cell migration', 'CPA', (161, 175))	('knockdown', 'Var', (43, 52))	('EZR-AS1', 'Gene', (56, 63))	('EZR-AS1', 'Gene', '101409257', (56, 63))
379603	29253179	RTCA of KYSE150 cells, stably transfected with shEZR-AS1 to stably silence EZR-AS1 expression, showed that knockdown of EZR-AS1 expression significantly reduced ESCC cell migration compared with the control cells (Figure 2B).	('knockdown', 'Var', (107, 116))	('EZR-AS1', 'Gene', (120, 127))	('EZR-AS1', 'Gene', (49, 56))	('reduced', 'NegReg', (153, 160))	('EZR-AS1', 'Gene', '101409257', (120, 127))	('EZR-AS1', 'Gene', '101409257', (49, 56))	('KYSE150', 'CellLine', 'CVCL:1348', (8, 15))	('EZR-AS1', 'Gene', (75, 82))	('ESCC cell migration', 'CPA', (161, 180))	('silence', 'NegReg', (67, 74))	('EZR-AS1', 'Gene', '101409257', (75, 82))
379604	29253179	rescue of EZR expression in the RTCA assay showed that, though the migration was still less than the control, overexpression of EZR could significantly reverse EZR-AS1 knockdown-mediated suppression of ESCC cell migration (Figure 2C and D), similar to data from the transwell assay (Supplementary Figure S5B), further confirming the role of EZR-AS1 in cell migration.	('EZR', 'Gene', '7430', (160, 163))	('knockdown-mediated', 'Var', (168, 186))	('EZR', 'Gene', (128, 131))	('EZR', 'Gene', (341, 344))	('EZR', 'Gene', '7430', (10, 13))	('EZR-AS1', 'Gene', '101409257', (341, 348))	('suppression', 'NegReg', (187, 198))	('EZR', 'Gene', (160, 163))	('EZR-AS1', 'Gene', (341, 348))	('ESCC cell migration', 'CPA', (202, 221))	('EZR', 'Gene', '7430', (128, 131))	('EZR', 'Gene', '7430', (341, 344))	('EZR-AS1', 'Gene', (160, 167))	('EZR-AS1', 'Gene', '101409257', (160, 167))	('EZR', 'Gene', (10, 13))
379607	29253179	More than twenty days after the injection, silencing of EZR-AS1 decreased the tumor volume compared with the control group.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('EZR-AS1', 'Gene', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('silencing', 'Var', (43, 52))	('EZR-AS1', 'Gene', '101409257', (56, 63))	('tumor', 'Disease', (78, 83))	('decreased', 'NegReg', (64, 73))
379609	29253179	Moreover, overexpression of EZR reversed the EZR-AS1 knockdown-mediated reduction of tumor volume, tumor weight, and number of metastatic lymph nodules (Figure 3A-E and Supplementary Figure S6).	('reduction', 'NegReg', (72, 81))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (85, 90))	('EZR', 'Gene', (28, 31))	('EZR-AS1', 'Gene', (45, 52))	('EZR-AS1', 'Gene', '101409257', (45, 52))	('EZR', 'Gene', '7430', (28, 31))	('EZR', 'Gene', '7430', (45, 48))	('number of metastatic lymph nodules', 'CPA', (117, 151))	('knockdown-mediated', 'Var', (53, 71))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('EZR', 'Gene', (45, 48))
379614	29253179	the full-length cloned fragment (-1324/+134), a truncated cloned fragment (-697/+134) or an EZR promoter fragment (-87/+134)) with NC or siEZR-AS1 into ESCC cells.	('EZR-AS1', 'Gene', '101409257', (139, 146))	('-697/+134', 'Var', (75, 84))	('EZR', 'Gene', (139, 142))	('EZR-AS1', 'Gene', (139, 146))	('EZR', 'Gene', '7430', (139, 142))	('EZR', 'Gene', (92, 95))	('-1324/+134', 'Var', (33, 43))	('-87/+134', 'Var', (115, 123))	('EZR', 'Gene', '7430', (92, 95))
379616	29253179	Notably, the activity of the -87/+134 construct was significantly decreased following knockdown of EZR-AS1 (Figure 4B), whereas overexpression of EZR-AS1 enhanced the activity of the -87/+134 construct (Figure 4C).	('EZR-AS1', 'Gene', '101409257', (99, 106))	('knockdown', 'Var', (86, 95))	('decreased', 'NegReg', (66, 75))	('EZR-AS1', 'Gene', (146, 153))	('EZR-AS1', 'Gene', '101409257', (146, 153))	('activity', 'MPA', (13, 21))	('EZR-AS1', 'Gene', (99, 106))	('activity', 'MPA', (167, 175))
379620	29253179	However, luciferase reporter gene assays revealed that upon silencing of EZR-AS1 expression, SP1 and c-Jun continued to enhance the activity of -87/+134 construct, indicating that EZR-AS1 up-regulates EZR transcriptional expression, but did not affect the binding of SP1 and AP-1 transcription factors (Figure 4E).	('up-regulates', 'PosReg', (188, 200))	('enhance', 'PosReg', (120, 127))	('EZR', 'Gene', (201, 204))	('EZR', 'Gene', (73, 76))	('EZR', 'Gene', (180, 183))	('activity', 'MPA', (132, 140))	('c-Jun', 'Gene', (101, 106))	('EZR', 'Gene', '7430', (73, 76))	('AP-1', 'Gene', (275, 279))	('EZR-AS1', 'Gene', (73, 80))	('c-Jun', 'Gene', '3725', (101, 106))	('EZR-AS1', 'Gene', (180, 187))	('EZR-AS1', 'Gene', '101409257', (73, 80))	('AP-1', 'Gene', '3725', (275, 279))	('EZR', 'Gene', '7430', (201, 204))	('EZR', 'Gene', '7430', (180, 183))	('silencing', 'Var', (60, 69))	('EZR-AS1', 'Gene', '101409257', (180, 187))
379636	29253179	To test this prediction, we firstly knocked down SMYD3 using SMYD3 shRNA reported previously, and confirmed that endogenous EZR expression was reduced, at both the mRNA and protein levels, by at least 50% compared with the control group (Figure 5A, B and Supplementary Figure S8).	('EZR', 'Gene', (124, 127))	('knocked', 'Var', (36, 43))	('SMYD3', 'Gene', (49, 54))	('EZR', 'Gene', '7430', (124, 127))	('SMYD3', 'Gene', '64754', (61, 66))	('SMYD3', 'Gene', '64754', (49, 54))	('expression', 'MPA', (128, 138))	('SMYD3', 'Gene', (61, 66))	('reduced', 'NegReg', (143, 150))
379640	29253179	In addition, knockdown of SMYD3 decreased the enrichment of SMYD3 protein from SBS-1 to SBS-4 (Figure 5D).	('SMYD3', 'Gene', (60, 65))	('SMYD3', 'Gene', '64754', (26, 31))	('SMYD3', 'Gene', '64754', (60, 65))	('protein', 'Protein', (66, 73))	('enrichment of', 'MPA', (46, 59))	('knockdown', 'Var', (13, 22))	('decreased', 'NegReg', (32, 41))	('SMYD3', 'Gene', (26, 31))
379642	29253179	Next, to evaluate the role of EZR-AS1 in SMYD3-mediated EZR expression, we knocked down or overexpressed EZR-AS1, and then performed ChIP assays.	('EZR-AS1', 'Gene', '101409257', (105, 112))	('EZR', 'Gene', (56, 59))	('knocked', 'Var', (75, 82))	('SMYD3', 'Gene', (41, 46))	('EZR', 'Gene', (105, 108))	('EZR', 'Gene', (30, 33))	('SMYD3', 'Gene', '64754', (41, 46))	('EZR', 'Gene', '7430', (56, 59))	('EZR', 'Gene', '7430', (105, 108))	('EZR-AS1', 'Gene', (105, 112))	('EZR-AS1', 'Gene', (30, 37))	('EZR-AS1', 'Gene', '101409257', (30, 37))	('overexpressed', 'PosReg', (91, 104))	('EZR', 'Gene', '7430', (30, 33))
379650	29253179	Compared with the empty vector control, the activity of both pGLB-hE (-1324/+550) and pGLB-hE (-87/+550) promoters was more than 2-fold increased by overexpression of EZR-AS1, and the activity was reduced by ~50% upon silencing of EZR-AS1 (Figure 5G, right, Supplementary Figure S9).	('EZR-AS1', 'Gene', (167, 174))	('EZR-AS1', 'Gene', '101409257', (167, 174))	('pGLB-hE', 'Chemical', '-', (86, 93))	('pGLB-hE', 'Chemical', '-', (61, 68))	('activity', 'MPA', (184, 192))	('reduced', 'NegReg', (197, 204))	('silencing', 'Var', (218, 227))	('pGLB-hE', 'Gene', (86, 93))	('activity', 'MPA', (44, 52))	('increased', 'PosReg', (136, 145))	('EZR-AS1', 'Gene', (231, 238))	('EZR-AS1', 'Gene', '101409257', (231, 238))
379651	29253179	However, when the SBS-1 was mutated, overexpression of EZR-AS1 could not increase reporter gene activity; and mutation of SBS-2 had no effect on the increased activity following EZR-AS1 overexpression (Figure 5G, right).	('EZR-AS1', 'Gene', (178, 185))	('EZR-AS1', 'Gene', '101409257', (178, 185))	('activity', 'MPA', (159, 167))	('EZR-AS1', 'Gene', (55, 62))	('mutation', 'Var', (110, 118))	('EZR-AS1', 'Gene', '101409257', (55, 62))	('SBS-2', 'Gene', (122, 127))
379653	29253179	Whether SBS-2 was mutated or not, all reporter activity was decreased by about 50% after silencing EZR-AS1 and increased by more than 50% after overexpression of EZR-AS1 (Supplementary Figure S10).	('EZR-AS1', 'Gene', '101409257', (99, 106))	('decreased', 'NegReg', (60, 69))	('increased', 'PosReg', (111, 120))	('mutated', 'Var', (18, 25))	('EZR-AS1', 'Gene', (99, 106))	('EZR-AS1', 'Gene', (162, 169))	('EZR-AS1', 'Gene', '101409257', (162, 169))	('SBS-2', 'Gene', (8, 13))	('reporter activity', 'MPA', (38, 55))	('silencing', 'Var', (89, 98))
379661	29253179	To identify the functional domain within EZR-AS1 responsible for associating with SMYD3, we cloned a series of deletion constructs of EZR-AS1, and then performed an RNA pull-down assay.	('SMYD3', 'Gene', '64754', (82, 87))	('EZR-AS1', 'Gene', (41, 48))	('deletion constructs', 'Var', (111, 130))	('EZR-AS1', 'Gene', '101409257', (41, 48))	('SMYD3', 'Gene', (82, 87))	('EZR-AS1', 'Gene', (134, 141))	('EZR-AS1', 'Gene', '101409257', (134, 141))
379663	29253179	We also cloned a series of Flag-tagged SMYD3 deletion constructs to identify its EZR-AS1-binding domain.	('SMYD3', 'Gene', '64754', (39, 44))	('SMYD3', 'Gene', (39, 44))	('deletion', 'Var', (45, 53))	('EZR-AS1', 'Gene', (81, 88))	('EZR-AS1', 'Gene', '101409257', (81, 88))
379675	29253179	Rescue experiments show that overexpression of EZR does not lead to a complete rescue of the cell motility inhibited by EZR-AS1 silencing, which suggests that EZR-AS1 not only regulates EZR expression, but also affects other target genes as well (Figure 2C and D).	('EZR-AS1', 'Gene', (120, 127))	('affects', 'Reg', (211, 218))	('EZR', 'Gene', (159, 162))	('EZR', 'Gene', '7430', (120, 123))	('EZR-AS1', 'Gene', '101409257', (120, 127))	('EZR', 'Gene', '7430', (159, 162))	('silencing', 'Var', (128, 137))	('EZR-AS1', 'Gene', (159, 166))	('EZR', 'Gene', (186, 189))	('EZR-AS1', 'Gene', '101409257', (159, 166))	('cell motility', 'CPA', (93, 106))	('regulates', 'Reg', (176, 185))	('EZR', 'Gene', (47, 50))	('EZR', 'Gene', (120, 123))	('expression', 'MPA', (190, 200))	('EZR', 'Gene', '7430', (186, 189))	('EZR', 'Gene', '7430', (47, 50))
379676	29253179	When antisense lncRNA triggers DNA or chromatin modification, expansion of the modification may affect nearby promoters or enhancers, or may regulate a cluster of genes, an example being the Kcnq1 imprinted locus.	('affect', 'Reg', (96, 102))	('Kcnq1', 'Gene', '3784', (191, 196))	('regulate', 'Reg', (141, 149))	('modification', 'Var', (79, 91))	('chromatin modification', 'MPA', (38, 60))	('DNA', 'MPA', (31, 34))	('cluster of', 'MPA', (152, 162))	('Kcnq1', 'Gene', (191, 196))	('promoters', 'MPA', (110, 119))	('enhancers', 'MPA', (123, 132))
379677	29253179	In this study, ChIP assays show that silencing EZR-AS1 decreases SMYD3 binding on the EZR gene (Figure 5E).	('EZR-AS1', 'Gene', (47, 54))	('EZR-AS1', 'Gene', '101409257', (47, 54))	('SMYD3', 'Gene', (65, 70))	('EZR', 'Gene', '7430', (47, 50))	('SMYD3', 'Gene', '64754', (65, 70))	('EZR', 'Gene', '7430', (86, 89))	('decreases', 'NegReg', (55, 64))	('silencing', 'Var', (37, 46))	('binding', 'Interaction', (71, 78))	('EZR', 'Gene', (47, 50))	('EZR', 'Gene', (86, 89))
379679	29253179	In addition, we show that EZR-AS1 does not up-regulate EZR expression following SMYD3 knockdown (Figure 5H), and that the interaction between EZR-AS1 and SMYD3 depends on the full length of EZR-AS1 (Figure 6C), not the small regions comprising individual functional domains.	('knockdown', 'Var', (86, 95))	('EZR', 'Gene', '7430', (26, 29))	('EZR', 'Gene', (55, 58))	('EZR', 'Gene', (142, 145))	('up-regulate', 'PosReg', (43, 54))	('EZR', 'Gene', (190, 193))	('EZR-AS1', 'Gene', (26, 33))	('EZR-AS1', 'Gene', '101409257', (142, 149))	('EZR-AS1', 'Gene', '101409257', (190, 197))	('SMYD3', 'Gene', (154, 159))	('SMYD3', 'Gene', '64754', (154, 159))	('EZR', 'Gene', '7430', (55, 58))	('EZR', 'Gene', '7430', (142, 145))	('EZR', 'Gene', '7430', (190, 193))	('interaction', 'Interaction', (122, 133))	('EZR-AS1', 'Gene', (142, 149))	('SMYD3', 'Gene', (80, 85))	('EZR', 'Gene', (26, 29))	('EZR-AS1', 'Gene', (190, 197))	('SMYD3', 'Gene', '64754', (80, 85))	('EZR-AS1', 'Gene', '101409257', (26, 33))
379680	29253179	Importantly, ChIP assays show that degradation of EZR-AS1 RNA, by treatment with RNase A or RNase H, causes a total release of SMYD3 from SMYD3-binding site SBS-1, located in the GC-rich region downstream of the EZR promoter (Figure 6F).	('RNase A', 'Gene', '6035', (81, 88))	('EZR', 'Gene', '7430', (212, 215))	('SMYD3', 'Gene', (138, 143))	('SMYD3', 'Gene', (127, 132))	('SMYD3', 'Gene', '64754', (127, 132))	('degradation', 'Var', (35, 46))	('release', 'MPA', (116, 123))	('SMYD3', 'Gene', '64754', (138, 143))	('EZR', 'Gene', (50, 53))	('EZR-AS1', 'Gene', (50, 57))	('EZR', 'Gene', '7430', (50, 53))	('RNase A', 'Gene', (81, 88))	('EZR-AS1', 'Gene', '101409257', (50, 57))	('EZR', 'Gene', (212, 215))
379681	29253179	These results suggest that antisense lncRNA EZR-AS1 may provide a scaffold for SMYD3 recruitment, leading to redistribution and enrichment of SMYD3 along the EZR gene.	('EZR', 'Gene', '7430', (158, 161))	('SMYD3', 'Gene', (79, 84))	('SMYD3', 'Gene', '64754', (79, 84))	('SMYD3', 'Gene', (142, 147))	('EZR', 'Gene', (44, 47))	('SMYD3', 'Gene', '64754', (142, 147))	('EZR', 'Gene', (158, 161))	('enrichment', 'MPA', (128, 138))	('EZR-AS1', 'Gene', (44, 51))	('antisense', 'Var', (27, 36))	('EZR-AS1', 'Gene', '101409257', (44, 51))	('redistribution', 'MPA', (109, 123))	('EZR', 'Gene', '7430', (44, 47))
379690	29253179	In conclusion, we demonstrate that antisense RNA EZR-AS1 up-regulates EZR transcription and promotes ESCC cell migration through an interaction with both SMYD3 and RNA polymerase II.	('SMYD3', 'Gene', (154, 159))	('EZR', 'Gene', (49, 52))	('promotes', 'PosReg', (92, 100))	('EZR-AS1', 'Gene', (49, 56))	('EZR', 'Gene', (70, 73))	('antisense RNA', 'Var', (35, 48))	('SMYD3', 'Gene', '64754', (154, 159))	('EZR', 'Gene', '7430', (49, 52))	('EZR-AS1', 'Gene', '101409257', (49, 56))	('interaction', 'Interaction', (132, 143))	('EZR', 'Gene', '7430', (70, 73))	('up-regulates', 'PosReg', (57, 69))	('ESCC', 'Disease', (101, 105))
379724	24033341	Based on surface browning by pan-frying, frying chicken at higher frying degrees was more common in the high-risk vs. the low-risk controls (P < 0.05) and in ESCC patients vs. high-risk controls (P < 0.001).	('patients', 'Species', '9606', (163, 171))	('common', 'Reg', (90, 96))	('ESCC', 'Disease', (158, 162))	('chicken', 'Species', '9031', (48, 55))	('frying', 'Var', (41, 47))
379785	27401305	Since the R0-resection rate and long-term outcome of patients with T3/T4 tumors is poor with primary resection, multimodal therapeutic concepts with preoperative chemotherapy or combined radiochemotherapy or both are employed in these patients.	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (235, 243))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('T3/T4', 'Var', (67, 72))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
379796	27401305	Postoperative hospital stay in patients randomized to the FTS group was significantly shorter than in the conventional group (P < 0.05).	('shorter', 'NegReg', (86, 93))	('FTS', 'Chemical', '-', (58, 61))	('patients', 'Species', '9606', (31, 39))	('FTS', 'Var', (58, 61))
379798	27401305	Incision pain according to the Numeric Rating Scale was lower in patients of the FTS group than in those of the conventional group (P <0.05).	('FTS', 'Var', (81, 84))	('pain', 'Phenotype', 'HP:0012531', (9, 13))	('lower', 'NegReg', (56, 61))	('pain', 'Disease', 'MESH:D010146', (9, 13))	('pain', 'Disease', (9, 13))	('patients', 'Species', '9606', (65, 73))	('FTS', 'Chemical', '-', (81, 84))	('Incision pain', 'Phenotype', 'HP:0500005', (0, 13))
379809	27401305	On PODs 1 and 3, statistically significant differences were found in levels of IL-6 and CRP with the FTS group having lower levels than in the conventional group (P <0.05).	('levels', 'MPA', (69, 75))	('CRP', 'Gene', (88, 91))	('PODs 1 and 3', 'Gene', '79585', (3, 15))	('CRP', 'Gene', '1401', (88, 91))	('FTS', 'Chemical', '-', (101, 104))	('IL-6', 'Gene', (79, 83))	('FTS', 'Var', (101, 104))	('IL-6', 'Gene', '3569', (79, 83))
379810	27401305	On POD 7, the level of CRP was lower in the FTS group than that in the conventional group (P <0.05) (Table 5).	('level', 'MPA', (14, 19))	('CRP', 'Gene', (23, 26))	('lower', 'NegReg', (31, 36))	('CRP', 'Gene', '1401', (23, 26))	('FTS', 'Chemical', '-', (44, 47))	('FTS', 'Var', (44, 47))
379813	27401305	On POD 3, the level of serum globulin was higher in the FTS group than that in the conventional group (P <0.05) (Table 6).	('higher', 'PosReg', (42, 48))	('FTS', 'Var', (56, 59))	('level of serum globulin', 'MPA', (14, 37))	('FTS', 'Chemical', '-', (56, 59))
379824	27401305	A recent study verified that partial EN support during perioperation will not only improve the postoperative nutritional status and immune function, but also moderate the inflammatory response of gastric cancer patients after operative trauma.	('nutritional status', 'MPA', (109, 127))	('partial', 'Var', (29, 36))	('patients', 'Species', '9606', (211, 219))	('trauma', 'Disease', 'MESH:D014947', (236, 242))	('gastric cancer', 'Phenotype', 'HP:0012126', (196, 210))	('postoperative', 'MPA', (95, 108))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('immune function', 'CPA', (132, 147))	('trauma', 'Disease', (236, 242))	('moderate', 'NegReg', (158, 166))	('improve', 'PosReg', (83, 90))	('gastric cancer', 'Disease', 'MESH:D013274', (196, 210))	('gastric cancer', 'Disease', (196, 210))	('inflammatory response', 'CPA', (171, 192))
379837	27401305	Impairment of cellular and humoral immune system may lead to infections secondary to surgery, progression of malign tumors, and emergence of opportunistic infections.	('infection', 'Disease', 'MESH:D007239', (61, 70))	('opportunistic infections', 'Phenotype', 'HP:0031690', (141, 165))	('lead to', 'Reg', (53, 60))	('opportunistic infections', 'Disease', 'MESH:D009894', (141, 165))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('malign tumors', 'Disease', (109, 122))	('infection', 'Disease', (155, 164))	('malign tumors', 'Disease', 'MESH:D018198', (109, 122))	('infection', 'Disease', 'MESH:D007239', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Impairment', 'Var', (0, 10))	('infection', 'Disease', (61, 70))	('opportunistic infections', 'Disease', (141, 165))
379841	27401305	In the FTS group, the immune globulins (IgA and IgG) and T lymphocyte subsets (CD3, CD4 and CD4/CD8) were significantly higher than those in the conventional group (P < 0.05), whereas IL-6 and CRP were significantly lower (P < 0.05).	('IgA', 'Gene', (40, 43))	('T lymphocyte subsets', 'CPA', (57, 77))	('CD4', 'Gene', '920', (92, 95))	('IgA', 'Gene', '973', (40, 43))	('CRP', 'Gene', (193, 196))	('immune globulins', 'MPA', (22, 38))	('FTS', 'Chemical', '-', (7, 10))	('CRP', 'Gene', '1401', (193, 196))	('FTS', 'Var', (7, 10))	('higher', 'PosReg', (120, 126))	('CD8', 'Gene', (96, 99))	('IL-6', 'Gene', '3569', (184, 188))	('CD4', 'Gene', (84, 87))	('CD8', 'Gene', '925', (96, 99))	('CD4', 'Gene', (92, 95))	('CD4', 'Gene', '920', (84, 87))	('IL-6', 'Gene', (184, 188))
379865	25802497	A 55-year-old female was diagnosed with stage IIIa (cT2N0M0, uT2N1M0) rectal adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('uT2N1M0', 'Var', (61, 68))	('cT2N0M0', 'Var', (52, 59))	('adenocarcinoma', 'Disease', (77, 91))
379882	25802497	Severe gastrointestinal toxicities of 5-FU-based chemotherapy can be more pronounced in patients with evidence of polymorphisms in the thymidylate synthase (TS) or dihydropyrimidine dehydrogenase (DPD) genes.	('dihydropyrimidine dehydrogenase', 'Gene', (164, 195))	('DPD', 'Gene', (197, 200))	('5-FU', 'Chemical', 'MESH:D005472', (38, 42))	('Severe gastrointestinal toxicities', 'Disease', (0, 34))	('thymidylate synthase', 'Gene', '7298', (135, 155))	('patients', 'Species', '9606', (88, 96))	('dihydropyrimidine dehydrogenase', 'Gene', '1806', (164, 195))	('TS', 'Gene', '7298', (157, 159))	('Severe gastrointestinal toxicities', 'Disease', 'MESH:D005767', (0, 34))	('DPD', 'Gene', '1806', (197, 200))	('polymorphisms', 'Var', (114, 127))	('thymidylate synthase', 'Gene', (135, 155))
379920	20171523	1), however, have shown the strongest statistically significant correlations with esophagitis at lower doses (as low as V30), perhaps owing to technique differences.	('significant', 'Reg', (52, 63))	('esophagitis', 'Disease', 'MESH:D004941', (82, 93))	('correlations', 'Interaction', (64, 76))	('esophagitis', 'Phenotype', 'HP:0100633', (82, 93))	('esophagitis', 'Disease', (82, 93))	('V30', 'Var', (120, 123))
379923	20171523	Nevertheless, the data are somewhat consistent, with rates of acute Grade 2 or greater esophagitis increasing to >30% as V70 exceeds 20%, V50 exceeds 40%, and V35 exceeds 50%.	('V50', 'Var', (138, 141))	('esophagitis', 'Phenotype', 'HP:0100633', (87, 98))	('esophagitis', 'Disease', (87, 98))	('V35', 'Gene', '28474', (159, 162))	('V70', 'Var', (121, 124))	('esophagitis', 'Disease', 'MESH:D004941', (87, 98))	('V35', 'Gene', (159, 162))
379926	20171523	It is markedly increased with the addition of CCT (incidence, 6-24%) and is as great as 49% with concurrent gemcitabine.	('CCT', 'Chemical', '-', (46, 49))	('CCT', 'Var', (46, 49))	('gemcitabine', 'Chemical', 'MESH:C056507', (108, 119))	('increased', 'PosReg', (15, 24))
379936	20171523	The simplest models (probably too simple) use a single dose-volume variable (e.g., V35 [19], V20, or mean dose [22]).	('V35', 'Gene', (83, 86))	('mean dose', 'MPA', (101, 110))	('V35', 'Gene', '28474', (83, 86))	('V20', 'Var', (93, 96))
379940	20171523	Although a few reports have been published of serious esophageal toxicity from hypofractionation, no comprehensive dose-volume-based analyses have been published.	('esophageal toxicity', 'Disease', (54, 73))	('hypofractionation', 'Var', (79, 96))	('esophageal toxicity', 'Disease', 'MESH:D004935', (54, 73))
379971	20647397	Serum pepsinogens and Helicobacter pylori in relation to the risk of esophageal squamous cell carcinoma in the ATBC Study Helicobacter pylori (H. pylori) can induce gastric atrophy in humans, which in turn increases gastric cancer risk.	('humans', 'Species', '9606', (184, 190))	('ATBC', 'Chemical', '-', (111, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (69, 103))	('Helicobacter pylori', 'Species', '210', (122, 141))	('gastric atrophy', 'Disease', 'MESH:D013274', (165, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (216, 230))	('H. pylori', 'Species', '210', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('increases gastric cancer', 'Phenotype', 'HP:0006753', (206, 230))	('esophageal squamous cell carcinoma', 'Disease', (69, 103))	('turn increases gastric cancer', 'Disease', (201, 230))	('Helicobacter pylori', 'Species', '210', (22, 41))	('gastric atrophy', 'Disease', (165, 180))	('turn increases gastric cancer', 'Disease', 'MESH:D013274', (201, 230))	('Helicobacter pylori', 'Var', (122, 141))	('induce', 'Reg', (158, 164))
380034	20647397	Analysis of a combined, categorical variable of PGI and PGII, defined using the 50th percentiles of the control distributionsfound only the category of low PGI and low PGII was associated with risk of ESCC (OR=2.42, 95%CI:1.00-5.86), as may be expected given the previously discussed results.	('PGI', 'Gene', '633', (48, 51))	('low', 'Var', (152, 155))	('PGI', 'Gene', (168, 171))	('I', 'Chemical', 'MESH:D007455', (158, 159))	('I', 'Chemical', 'MESH:D007455', (220, 221))	('PGI', 'Gene', '633', (156, 159))	('PGI', 'Gene', '633', (56, 59))	('I', 'Chemical', 'MESH:D007455', (50, 51))	('PGI', 'Gene', '633', (168, 171))	('I', 'Chemical', 'MESH:D007455', (171, 172))	('I', 'Chemical', 'MESH:D007455', (58, 59))	('PGI', 'Gene', (48, 51))	('I', 'Chemical', 'MESH:D007455', (59, 60))	('low', 'Var', (164, 167))	('PGI', 'Gene', (156, 159))	('PGI', 'Gene', (56, 59))	('ESCC', 'Disease', (201, 205))	('I', 'Chemical', 'MESH:D007455', (170, 171))
380036	20647397	Similarly null estimates were obtained for whole cell positive/CagA negative, and CagA positive groups, compared with individuals negative for H. pylori (Table 2).	('H. pylori', 'Species', '210', (143, 152))	('positive', 'Var', (87, 95))	('negative', 'NegReg', (68, 76))
380037	20647397	Exploratory analyses of ESCC risk stratified by time between blood draw and cancer diagnosis suggested a stronger association between H. pylori seropositivity and ESCC in the longest time category (>13.24 years; OR=3.45, 95%CI:0.74-16.01) relative to estimates of the middle (>7.89 & <= 13.24 years; OR=1.07, 95%CI:0.37-3.07) or shortest (<= 7.89 years; OR=0.90, 95%CI:0.31-2.59) time categories (Supplementary Table 2).	('H. pylori', 'Species', '210', (134, 143))	('ESCC', 'Disease', (163, 167))	('I', 'Chemical', 'MESH:D007455', (225, 226))	('seropositivity', 'Var', (144, 158))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (137, 158))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('I', 'Chemical', 'MESH:D007455', (313, 314))	('ESCC', 'Disease', (24, 28))	('I', 'Chemical', 'MESH:D007455', (367, 368))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('H. pylori', 'Gene', (134, 143))
380065	20647397	First, by the age of entry into this study, H. pylori colonization may have burned itself out, by inducing gastric atrophy and thus destroying the environment in which it thrives, which could result in serologic amnesia.	('H. pylori', 'Species', '210', (44, 53))	('destroying', 'NegReg', (132, 142))	('gastric atrophy', 'Disease', 'MESH:D013274', (107, 122))	('inducing', 'Reg', (98, 106))	('serologic', 'Disease', (202, 211))	('result in', 'Reg', (192, 201))	('colonization', 'Var', (54, 66))	('amnesia', 'Disease', (212, 219))	('amnesia', 'Disease', 'MESH:D000647', (212, 219))	('environment in which', 'MPA', (147, 167))	('gastric atrophy', 'Disease', (107, 122))
380069	20647397	A subset of patients with atrophic gastritis are H. pylori-negative, and Acinetobacter lwoffii is known to cause gastric atrophy in mice.	('patients', 'Species', '9606', (12, 20))	('Acinetobacter lwoffii', 'Var', (73, 94))	('Acinetobacter lwoffii', 'Phenotype', 'HP:0032250', (73, 94))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (26, 44))	('gastric atrophy', 'Disease', (113, 128))	('Acinetobacter lwoffii', 'Species', '28090', (73, 94))	('cause', 'Reg', (107, 112))	('gastritis', 'Phenotype', 'HP:0005263', (35, 44))	('mice', 'Species', '10090', (132, 136))	('H. pylori', 'Species', '210', (49, 58))	('atrophic gastritis', 'Disease', 'MESH:D005757', (26, 44))	('gastric atrophy', 'Disease', 'MESH:D013274', (113, 128))	('atrophic gastritis', 'Disease', (26, 44))
380101	33329527	Echoing the above mentioned in vitro and in vivo preclinical experimental observations, lesion HLA-G expression was observed to be closely associated with tumor metastasis, poor tumor cell differentiation, advanced disease stage and worse survival in a variety of cancers in clinical settings.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('HLA-G', 'Gene', '3135', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('tumor', 'Disease', (178, 183))	('cancers', 'Disease', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor metastasis', 'Disease', 'MESH:D009362', (155, 171))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('tumor', 'Disease', (155, 160))	('tumor metastasis', 'Disease', (155, 171))	('associated', 'Reg', (139, 149))	('lesion', 'Var', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('HLA-G', 'Gene', (95, 100))
380121	33329527	b) Slides from three different zones within a same sample from another five CRC samples (#1022488, #1022363, #1020932, #1023081, and #444345), and c) slides from three case-matched blocks that each includes 36 esophageal cancer samples.	('#1020932', 'Var', (109, 117))	('esophageal cancer', 'Disease', (210, 227))	('#1023081', 'Var', (119, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (210, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('#444345', 'Var', (133, 140))	('#1022488', 'Var', (89, 97))	('#1022363', 'Var', (99, 107))
380126	33329527	Intratumor heterogeneous expression of HLA-G was observed among different sections and antibodies used in three CRC tissue samples (#598937, #624267, and #681878).	('#624267', 'Var', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('#598937', 'Var', (132, 139))	('tumor', 'Disease', (5, 10))	('HLA-G', 'Gene', (39, 44))	('HLA-G', 'Gene', '3135', (39, 44))	('#681878', 'Var', (154, 161))
380127	33329527	For the Group 1 antibodies (mAbs 4H84, MEM-G/1, and MEM-G/2), HLA-G expression was dramatically different in samples CRC#598937 (p<0.001) and CRC#681878 (p<0.001), while comparable degree of HLA-G expression was observed in sample CRC#624267 (p=0.453).	('MEM-G/2', 'Gene', (52, 59))	('different', 'Reg', (96, 105))	('CRC#681878', 'Var', (142, 152))	('expression', 'MPA', (68, 78))	('HLA-G', 'Gene', (62, 67))	('MEM-G/1', 'Gene', (39, 46))	('MEM-G/2', 'Gene', '17281', (52, 59))	('CRC#598937', 'Var', (117, 127))	('HLA-G', 'Gene', '3135', (62, 67))	('MEM-G/1', 'Gene', '382620', (39, 46))	('4H84', 'Chemical', '-', (33, 37))	('HLA-G', 'Gene', (191, 196))	('HLA-G', 'Gene', '3135', (191, 196))
380130	33329527	CRC#1022488 for an example, the percentage of HLA-G expression detected with mAbs 5A6G7 and 2A12 are much higher than that probed with mAbs 4H84, MEM-G/1 and MEM-G/2.	('MEM-G/2', 'Gene', '17281', (158, 165))	('MEM-G/1', 'Gene', (146, 153))	('mAbs 5A6G7', 'Var', (77, 87))	('4H84', 'Chemical', '-', (140, 144))	('5A6G7', 'Var', (82, 87))	('HLA-G', 'Gene', (46, 51))	('MEM-G/1', 'Gene', '382620', (146, 153))	('HLA-G', 'Gene', '3135', (46, 51))	('higher', 'PosReg', (106, 112))	('MEM-G/2', 'Gene', (158, 165))
380131	33329527	Zone 2 particularly, percentage of HLA-G expression detected by mAb 5A6G7 is 20.29% while HLA-G is nearly negative detected by mAb 4H84 (0.71%).	('HLA-G', 'Gene', '3135', (90, 95))	('HLA-G', 'Gene', (35, 40))	('HLA-G', 'Gene', '3135', (35, 40))	('HLA-G', 'Gene', (90, 95))	('mAb 5A6G7', 'Var', (64, 73))	('5A6G7', 'Var', (68, 73))	('4H84', 'Chemical', '-', (131, 135))
380132	33329527	In CRC#1022363, the degree of HLA-G detected by mAb 4H84 was 14.88%, 50.0% and 22.0% in zone 1, zone 2, and zone 3, respectively.	('4H84', 'Chemical', '-', (52, 56))	('HLA-G', 'Gene', '3135', (30, 35))	('HLA-G', 'Gene', (30, 35))	('CRC#1022363', 'Var', (3, 14))
380137	33329527	No significant variation of HLA-G expression was observed when detected by mAb 2A12 in CRC#598937 (p=0.1151), mAb 4H84 in CRC#681878 (p=0.154), and mAbs MEM-G/1 (p=0.203) and MEM-G/2 (p=0.386) in CRC#624267.	('MEM-G/1', 'Gene', (153, 160))	('HLA-G', 'Gene', (28, 33))	('HLA-G', 'Gene', '3135', (28, 33))	('MEM-G/2', 'Gene', '17281', (175, 182))	('MEM-G/1', 'Gene', '382620', (153, 160))	('CRC#681878', 'Var', (122, 132))	('MEM-G/2', 'Gene', (175, 182))	('4H84', 'Chemical', '-', (114, 118))
380144	33329527	Moreover, the staining pattern for mAbs 4H84 and 5A6G7 seems more consistent according to their recognizing epitope in the HLA-G heavy chain, that no mAbs 4H84neg5A6G7pos was observed ( Table 3 ).	('HLA-G', 'Gene', (123, 128))	('HLA-G', 'Gene', '3135', (123, 128))	('4H84', 'Chemical', '-', (155, 159))	('4H84', 'Chemical', '-', (40, 44))	('4H84neg', 'Chemical', '-', (155, 162))	('4H84', 'Var', (40, 44))	('5A6G7', 'Var', (49, 54))
380154	33329527	In addition to the HLA-G genetic variations both in 5'-upstream regulatory region and in 3'-untranslated region which comprise binding sites for transcription factor and microRNAs and epigenetic modifications, other environmental factor such as hypoxia, cytokines, hormones, and even immunotherapy chemicals and radiation have been acknowledged to be related to the regulation of HLA-G expression.	('hypoxia', 'Disease', 'MESH:D000860', (245, 252))	('HLA-G', 'Gene', (380, 385))	('HLA-G', 'Gene', '3135', (380, 385))	('hypoxia', 'Disease', (245, 252))	('HLA-G', 'Gene', (19, 24))	('HLA-G', 'Gene', '3135', (19, 24))	('variations', 'Var', (33, 43))
380162	33329527	In this context, in an our previous study, we found 44 out of 379 (11.6%) CRC patients were with the staining pattern of mAbs 4H84neg 5A6G7pos, and CRC patients with the patterns of mAbs 4H84neg 5A6G7pos had a longer survival time than those with the pattern of mAbs 4H84pos5A6G7neg.	('mAbs 4H84neg 5A6G7pos', 'Var', (182, 203))	('4H84neg', 'Chemical', '-', (187, 194))	('mAbs', 'Var', (121, 125))	('4H84pos5A6G7neg', 'Chemical', '-', (267, 282))	('patients', 'Species', '9606', (78, 86))	('survival time', 'CPA', (217, 230))	('CRC', 'Disease', (74, 77))	('4H84neg', 'Chemical', '-', (126, 133))	('longer', 'PosReg', (210, 216))	('4H84neg', 'Var', (126, 133))	('patients', 'Species', '9606', (152, 160))
380178	32591002	There was already a significant reduction of TPI in the acute phase up to POD 3 after ESCC surgery in comparison with the preoperative baseline TPI (P < 0.001).	('TPI', 'Gene', (144, 147))	('reduction', 'NegReg', (32, 41))	('TPI', 'Gene', '7167', (144, 147))	('surgery', 'Var', (91, 98))	('TPI', 'Gene', '7167', (45, 48))	('TPI', 'Gene', (45, 48))	('ESCC', 'Disease', (86, 90))
380240	32591002	TPI reduction rate was significantly milder in cases of less blood loss during surgery (P = 0.0087) and in cases of TEPP than in cases of OE (P = 0.0407) (Table 2).	('TPI', 'Gene', '7167', (0, 3))	('blood loss', 'Disease', 'MESH:D006473', (61, 71))	('blood loss during surgery', 'Phenotype', 'HP:0004846', (61, 86))	('TEPP', 'Var', (116, 120))	('milder', 'NegReg', (37, 43))	('blood loss', 'Disease', (61, 71))	('reduction', 'NegReg', (4, 13))	('TPI', 'Gene', (0, 3))	('TEPP', 'Chemical', '-', (116, 120))
380251	32591002	On the other hand, the TPI reduction rate was significantly milder after TEPP than after OE.	('TEPP', 'Var', (73, 77))	('TEPP', 'Chemical', '-', (73, 77))	('TPI', 'Gene', '7167', (23, 26))	('TPI', 'Gene', (23, 26))	('milder', 'NegReg', (60, 66))
380252	32591002	Although this might be one of the findings indicating the lesser invasiveness of TEPP, there was also another possibility: that TEPP as a painless procedure could maintain the postoperative patient's physical activity and prevent the disuse followed by skeletal muscle loss.	('TEPP', 'Var', (128, 132))	('disuse', 'CPA', (234, 240))	('patient', 'Species', '9606', (190, 197))	('prevent', 'NegReg', (222, 229))	('TEPP', 'Chemical', '-', (128, 132))	('muscle loss', 'Phenotype', 'HP:0003202', (262, 273))	('physical activity', 'CPA', (200, 217))	('skeletal muscle loss', 'Disease', (253, 273))	('skeletal muscle loss', 'Disease', 'MESH:D005207', (253, 273))	('TEPP', 'Chemical', '-', (81, 85))
380288	31637306	Moreover, transgenic thyroidal PBF in mice leads to hyperplasia and macrofollicular lesions by elevating AKT.	('transgenic', 'Var', (10, 20))	('hyperplasia', 'Disease', (52, 63))	('macrofollicular lesions', 'CPA', (68, 91))	('mice', 'Species', '10090', (38, 42))	('hyperplasia', 'Disease', 'MESH:D006965', (52, 63))	('elevating', 'PosReg', (95, 104))	('AKT', 'MPA', (105, 108))
380301	31637306	After transfection with shNC or sh2-PBF for 24 hours, ESCA cells were continually cultured in a serum-free medium for 24 h of starvation.	('sh2-PBF', 'Var', (32, 39))	('ESCA', 'Disease', 'MESH:D004938', (54, 58))	('transfection', 'Var', (6, 18))	('ESCA', 'Phenotype', 'HP:0011459', (54, 58))	('ESCA', 'Disease', (54, 58))	('shNC', 'Gene', (24, 28))
380314	31637306	The results indicated that PBF was highly expressed in Eca109, TE-1, EC9706, EC8712 and KYSE30 cells, compared with HEEC cells (Fig 1B).	('HEEC', 'CellLine', 'None', (116, 120))	('PBF', 'Gene', (27, 30))	('EC9706', 'Var', (69, 75))
380325	31637306	3B showed that the total apoptosis percentage of ESCA cells was significantly higher in the shPBF group than of that in the shNC group.	('higher', 'PosReg', (78, 84))	('ESCA', 'Phenotype', 'HP:0011459', (49, 53))	('ESCA', 'Disease', 'MESH:D004938', (49, 53))	('ESCA', 'Disease', (49, 53))	('apoptosis', 'CPA', (25, 34))	('shPBF', 'Var', (92, 97))
380328	31637306	In order to further determine the mechanism of the pro-apoptosis effect of PBF knockdown in ESCA cells, we investigated the status of apoptosis-related mitochondrial pathways, including Bcl2, Bax, cleaved-Caspase 9 and cleaved-Caspase 3, by using western blot.	('ESCA', 'Disease', 'MESH:D004938', (92, 96))	('PBF', 'Gene', (75, 78))	('Bax', 'Gene', '581', (192, 195))	('Caspase 9', 'Gene', (205, 214))	('Bax', 'Gene', (192, 195))	('Caspase 3', 'Gene', (227, 236))	('Bcl2', 'Gene', (186, 190))	('ESCA', 'Phenotype', 'HP:0011459', (92, 96))	('knockdown', 'Var', (79, 88))	('ESCA', 'Disease', (92, 96))	('Caspase 9', 'Gene', '842', (205, 214))	('Caspase 3', 'Gene', '836', (227, 236))	('Bcl2', 'Gene', '596', (186, 190))
380331	31637306	4C and D, Cyclin D1 and CDK4/6 were all down-regulated in ESCA cells transfected with shPBF, compared with shNC.	('CDK4/6', 'Gene', '1019;1021', (24, 30))	('ESCA', 'Phenotype', 'HP:0011459', (58, 62))	('ESCA', 'Disease', (58, 62))	('CDK4/6', 'Gene', (24, 30))	('shPBF', 'Var', (86, 91))	('Cyclin D1', 'Gene', '595', (10, 19))	('ESCA', 'Disease', 'MESH:D004938', (58, 62))	('Cyclin D1', 'Gene', (10, 19))	('down-regulated', 'NegReg', (40, 54))
380332	31637306	Taken together, these data suggest that PBF knockdown promotes ESCA cell apoptosis through the activation of mitochondrial pathways and induces cell cycle arrest by repressing Cyclin D1 and CDK4/6.	('Cyclin D1', 'Gene', (176, 185))	('CDK4/6', 'Gene', (190, 196))	('PBF', 'Gene', (40, 43))	('cell cycle arrest', 'CPA', (144, 161))	('ESCA', 'Disease', 'MESH:D004938', (63, 67))	('ESCA', 'Phenotype', 'HP:0011459', (63, 67))	('ESCA', 'Disease', (63, 67))	('activation', 'PosReg', (95, 105))	('Cyclin D1', 'Gene', '595', (176, 185))	('knockdown', 'Var', (44, 53))	('CDK4/6', 'Gene', '1019;1021', (190, 196))	('mitochondrial pathways', 'Pathway', (109, 131))	('induces', 'PosReg', (136, 143))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('repressing', 'NegReg', (165, 175))	('promotes', 'PosReg', (54, 62))
380340	31637306	Taken together, PBF knockdown-induced cell phenotypic changes, including inhibition of proliferation, mobility and so on, may be mediated by the inactivation of AKT/mTOR and Wnt3a/beta-catenin pathways.	('knockdown-induced', 'Var', (20, 37))	('inhibition', 'NegReg', (73, 83))	('proliferation', 'CPA', (87, 100))	('Wnt3a', 'Gene', '89780', (174, 179))	('Wnt3a', 'Gene', (174, 179))	('beta-catenin', 'Gene', (180, 192))	('inactivation', 'NegReg', (145, 157))	('beta-catenin', 'Gene', '1499', (180, 192))	('mTOR', 'Gene', '2475', (165, 169))	('mTOR', 'Gene', (165, 169))	('mobility', 'CPA', (102, 110))	('PBF', 'Gene', (16, 19))
380359	31637306	Interestingly, our results showed the dysregulation of AKT pathway happened after PBF knockdown, which might be the reason why the expression of Cyclin D1 and CDK4/6 changed.	('CDK4/6', 'Gene', (159, 165))	('knockdown', 'Var', (86, 95))	('Cyclin D1', 'Gene', (145, 154))	('changed', 'Reg', (166, 173))	('PBF', 'Gene', (82, 85))	('CDK4/6', 'Gene', '1019;1021', (159, 165))	('AKT pathway', 'Pathway', (55, 66))	('Cyclin D1', 'Gene', '595', (145, 154))
380373	31344989	And, the EC patients with decreased PNI held a worse OS and CSS compared with those who carried a higher PNI (HR = 1.29, 95% CI: 1.10-1.50; HR = 2.53, 95% CI: 1.15-5.57).	('patients', 'Species', '9606', (12, 20))	('EC', 'Disease', 'MESH:D004938', (9, 11))	('CSS', 'CPA', (60, 63))	('decreased', 'NegReg', (26, 35))	('PNI', 'Var', (36, 39))
380410	31344989	Low-PNI was confirmed as an independent poor predictive factor for OS when 10 studies whose HR of OS was calculated by multivariate analysis adjusting for TNM stage were synthesized (HR = 1.26, 95% CI: 1.08-1.48, I 2 = 70.6%, p = 000)(Figure 3c).	('Low-PNI', 'Var', (0, 7))	('TNM', 'Gene', (155, 158))	('TNM', 'Gene', '10178', (155, 158))
380416	31344989	Although NAC takes the advantage of shrinking the tumor bulk and reducing micrometastasis preoperatively, patients treated by intensive NAC are more likely to worsen nutritional status on account of side effects triggering by chemotherapy (Motoor, et al., 2012; Reisinger et al., 2015).	('NAC', 'Var', (136, 139))	('reducing', 'NegReg', (65, 73))	('micrometastasis', 'MPA', (74, 89))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('nutritional status', 'MPA', (166, 184))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('worsen', 'Reg', (159, 165))	('tumor', 'Disease', (50, 55))
380428	31344989	Particularly, low-PNI was confirmed as independent poor predictive factors for OS and CSS, when studies whose HR of OS/CSS was calculated by multivariate analysis adjusting for TNM stage were synthesized.	('TNM', 'Gene', (177, 180))	('TNM', 'Gene', '10178', (177, 180))	('CSS', 'Disease', (86, 89))	('low-PNI', 'Var', (14, 21))
380431	31344989	And, certain studies have shown that increased TILs are related to lower tumor stage and a better outcome than patients with few TILs (Gooden, De Bock, Leffers, Daemen, & Nijman, 2011; Ruiter, Ooft, Devriese, & Willems, 2017).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('TILs', 'Var', (47, 51))	('lower', 'NegReg', (67, 72))	('men', 'Species', '9606', (164, 167))	('patients', 'Species', '9606', (111, 119))
380432	31344989	So, PNI may affect the prognosis of EC patients by the tumor local immune response.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('affect', 'Reg', (12, 18))	('PNI', 'Var', (4, 7))	('EC', 'Disease', 'MESH:D004938', (36, 38))	('tumor', 'Disease', (55, 60))
380562	28913234	Among free flaps, anterolateral thigh free flap and jejunal free flap were associated with superior outcomes, when compared with radial forearm free flap.	('flap', 'Gene', (11, 15))	('flap', 'Gene', '241', (43, 47))	('flap', 'Gene', (149, 153))	('anterolateral', 'Var', (18, 31))	('flap', 'Gene', '241', (65, 69))	('flap', 'Gene', (43, 47))	('flap', 'Gene', '241', (11, 15))	('flap', 'Gene', '241', (149, 153))	('flap', 'Gene', (65, 69))
380634	28913234	In this review, fistula and stricture rates were higher for the RFFF than those of the ALT and jejunal free flap (Tables 3, 4, 5).	('fistula', 'Disease', 'MESH:D005402', (16, 23))	('flap', 'Gene', '241', (108, 112))	('stricture rates', 'CPA', (28, 43))	('fistula', 'Disease', (16, 23))	('higher', 'PosReg', (49, 55))	('RFFF', 'Var', (64, 68))	('flap', 'Gene', (108, 112))
380683	28913234	For circumferential esophagus reconstruction, fistula and stricture rates were higher for RFFF than for free flaps.	('fistula', 'Disease', (46, 53))	('flap', 'Gene', (109, 113))	('fistula', 'Disease', 'MESH:D005402', (46, 53))	('RFFF', 'Var', (90, 94))	('stricture', 'CPA', (58, 67))	('higher', 'PosReg', (79, 85))	('flap', 'Gene', '241', (109, 113))
380688	25890249	HAP emissions are an established lung carcinogen; however, associations with other cancer sites have not been fully explored.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('HAP emissions', 'Var', (0, 13))	('cancer', 'Disease', (83, 89))
380689	25890249	Using fixed-effects models, utilizing the adjusted odds ratios (OR) and 95% confidence intervals (95% CI) from each study, we evaluated the association between HAP and cervical neoplasia (663 cases and 1747 controls) and upper aero-digestive tract cancers (6022 cases and 15 325 controls).	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cervical neoplasia', 'Disease', 'MESH:D018290', (168, 186))	('HAP', 'Var', (160, 163))	('tract cancers', 'Disease', (242, 255))	('neoplasia', 'Phenotype', 'HP:0002664', (177, 186))	('tract cancers', 'Disease', 'MESH:D014571', (242, 255))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (168, 186))	('cervical neoplasia', 'Disease', (168, 186))
380690	25890249	We found that HAP was associated with cervical neoplasia (OR = 6.46; 95% CI = 3.12-13.36; 4 studies); oral (OR = 2.44; 95% CI = 1.87-3.19; 4 studies; 1000 cases/3450 controls); nasopharyngeal (OR = 1.80; 95% CI = 1.42-2.29; 6 studies; 2231 cases/2160 controls); pharyngeal (OR = 3.56; 95% CI = 2.22-5.70; 4 studies; 1036 cases/3746 controls); and laryngeal (OR = 2.35; 95% CI = 1.72- 3.21; 5 studies; 1416 cases/4514 controls) cancers.	('laryngeal', 'Disease', (347, 356))	('HAP', 'Var', (14, 17))	('pharyngeal', 'Disease', (262, 272))	('cancers', 'Disease', 'MESH:D009369', (427, 434))	('cancers', 'Phenotype', 'HP:0002664', (427, 434))	('cancers', 'Disease', (427, 434))	('cervical neoplasia', 'Disease', 'MESH:D018290', (38, 56))	('nasopharyngeal', 'Disease', (177, 191))	('oral', 'Disease', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('neoplasia', 'Phenotype', 'HP:0002664', (47, 56))	('associated', 'Reg', (22, 32))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (38, 56))	('cervical neoplasia', 'Disease', (38, 56))
380692	25890249	HAP was associated with cervical neoplasia among studies that accounted for HPV infection (OR = 9.60; 95% CI = 3.79-24.32) and smoking (OR = 4.72; 95% CI = 1.84-12.07).	('HAP', 'Var', (0, 3))	('HPV infection', 'Disease', 'MESH:D030361', (76, 89))	('cervical neoplasia', 'Disease', 'MESH:D018290', (24, 42))	('neoplasia', 'Phenotype', 'HP:0002664', (33, 42))	('associated with', 'Reg', (8, 23))	('HPV infection', 'Disease', (76, 89))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (24, 42))	('cervical neoplasia', 'Disease', (24, 42))
380693	25890249	Similarly, our observed associations between HAP and upper aero-digestive tract cancers remained significantly elevated when analyses were restricted to studies that controlled for smoking.	('elevated', 'PosReg', (111, 119))	('HAP', 'Var', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tract cancers', 'Disease', (74, 87))	('tract cancers', 'Disease', 'MESH:D014571', (74, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
380694	25890249	Our results suggest that the carcinogenic effect of HAP observed for lung cancer may extend to other cancers, including those of the cervix and the upper aero-digestive tract.	('carcinogenic', 'Disease', (29, 41))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('HAP', 'Var', (52, 55))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('carcinogenic', 'Disease', 'MESH:D063646', (29, 41))
380697	25890249	Based on animal and human studies, the World Health Organization's International Agency for Research on Cancer Working Group concluded that HAP from combustion of solid fuels, specifically coal, are carcinogenic to humans and particularly lung cancer.	('human', 'Species', '9606', (20, 25))	('lung cancer', 'Disease', (239, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('carcinogenic', 'Disease', 'MESH:D063646', (199, 211))	('carcinogenic', 'Disease', (199, 211))	('humans', 'Species', '9606', (215, 221))	('lung cancer', 'Disease', 'MESH:D008175', (239, 250))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('human', 'Species', '9606', (215, 220))	('HAP', 'Var', (140, 143))
380700	25890249	Studies have suggested that HAP may be associated with oral cancer and nasopharyngeal cancer.	('HAP', 'Var', (28, 31))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (71, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (71, 92))	('oral cancer', 'Disease', 'MESH:D009062', (55, 66))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (75, 92))	('nasopharyngeal cancer', 'Disease', (71, 92))	('associated', 'Reg', (39, 49))	('oral cancer', 'Disease', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
380724	25890249	Four studies (1036 cases/3746 controls) assessed the risk of pharyngeal cancer associated with HAP (Table 5).	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (61, 78))	('HAP', 'Var', (95, 98))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
380725	25890249	The risk of pharyngeal cancer associated with HAP in these four studies was 3.56 (95% CI = 2.22- 5.70) (Figure 2c) and there was no substantial heterogeneity (p = 0.99) (Table 4).	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (12, 29))	('HAP', 'Var', (46, 49))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
380727	25890249	Five studies (1416 cases / 4514 controls) evaluated the risk of laryngeal cancer associated with HAP (Table 5).	('HAP', 'Var', (97, 100))	('laryngeal cancer', 'Disease', 'MESH:D007822', (64, 80))	('laryngeal cancer', 'Disease', (64, 80))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (64, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
380731	25890249	With the existing evidence for the biological plausibility of HAP exposure potentially contributing to cervical neoplasia and upper aero-digestive cancers it is important to estimate this relationship.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (103, 121))	('cervical neoplasia', 'Disease', (103, 121))	('contributing', 'Reg', (87, 99))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cervical neoplasia', 'Disease', 'MESH:D018290', (103, 121))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('HAP exposure', 'Var', (62, 74))	('cancers', 'Disease', (147, 154))	('neoplasia', 'Phenotype', 'HP:0002664', (112, 121))
380733	25890249	Our meta-analysis observed that HAP is associated with increased risk for oral, nasopharyngeal, pharyngeal, and laryngeal cancers.	('nasopharyngeal', 'Disease', (80, 94))	('laryngeal cancers', 'Disease', 'MESH:D007822', (112, 129))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (112, 129))	('oral', 'Disease', (74, 78))	('pharyngeal', 'Disease', (96, 106))	('laryngeal cancers', 'Disease', (112, 129))	('HAP', 'Var', (32, 35))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (112, 128))
380736	25890249	HAP is known to cause an increase household air levels of sulfur dioxide, carbon monoxide, fluorine, and known carcinogens such as polycyclic aromatic hydrocarbons (PAHs), benzene, arsenic, 1,3-butadiene and formaldehyde,.	('PAHs', 'Chemical', 'MESH:D011084', (165, 169))	('HAP', 'Var', (0, 3))	('carbon monoxide', 'MPA', (74, 89))	('fluorine', 'Chemical', 'MESH:D005461', (91, 99))	('benzene', 'MPA', (172, 179))	('formaldehyde', 'Disease', (208, 220))	('arsenic', 'Chemical', 'MESH:D001151', (181, 188))	('fluorine', 'MPA', (91, 99))	('benzene', 'Chemical', 'MESH:D001554', (172, 179))	('carbon monoxide', 'Chemical', 'MESH:D002248', (74, 89))	('1,3-butadiene', 'Chemical', 'MESH:C031763', (190, 203))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (131, 163))	('increase', 'PosReg', (25, 33))	('sulfur dioxide', 'MPA', (58, 72))	('sulfur dioxide', 'Chemical', 'MESH:D013458', (58, 72))	('formaldehyde', 'Chemical', 'MESH:D005557', (208, 220))	('arsenic', 'Disease', (181, 188))
380737	25890249	Individual genetic variation and exposure to HAP is known to increase susceptibility to lung cancer.	('lung cancer', 'Disease', (88, 99))	('Individual genetic variation', 'Var', (0, 28))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
380740	25890249	IARC concluded that HAP from combustion of coal was carcinogenic to humans (group 1) and that from wood was a probable carcinogen (group 2A).	('humans', 'Species', '9606', (68, 74))	('carcinogenic', 'Disease', 'MESH:D063646', (52, 64))	('HAP', 'Var', (20, 23))	('carcinogenic', 'Disease', (52, 64))
380745	25890249	Interesting evidence also emerges from our study that HAP is associated with increased risk of cervical neoplasia despite controlling for the risk factors such as HPV and smoking status.	('cervical neoplasia', 'Disease', 'MESH:D018290', (95, 113))	('neoplasia', 'Phenotype', 'HP:0002664', (104, 113))	('HAP', 'Var', (54, 57))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (95, 113))	('cervical neoplasia', 'Disease', (95, 113))
380746	25890249	There is limited mechanistic data available on how HAP may cause cervical neoplasia.	('HAP', 'Var', (51, 54))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (65, 83))	('cervical neoplasia', 'Disease', (65, 83))	('cause', 'Reg', (59, 64))	('neoplasia', 'Phenotype', 'HP:0002664', (74, 83))	('cervical neoplasia', 'Disease', 'MESH:D018290', (65, 83))
380747	25890249	However, in support of the hypothesis that HAP exposures may increase risk of cervical cancer, studies on cigarette smoking suggest that airborne nitrosoamines can be transmitted through blood to organs including cervix, thereby leading to cancer.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cervical cancer', 'Disease', 'MESH:D002583', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('leading to', 'Reg', (229, 239))	('cervical cancer', 'Disease', (78, 93))	('nitrosoamines', 'Chemical', '-', (146, 159))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('HAP', 'Var', (43, 46))	('cancer', 'Disease', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
380750	25890249	This is the first meta-analysis to summarize the association between HAP and cancers other than lung.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('lung', 'Disease', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('HAP', 'Var', (69, 72))	('cancers', 'Disease', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
380754	25890249	Our results support the hypothesis that HAP is associated with the risk of cancers other than lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('lung cancer', 'Disease', (94, 105))	('HAP', 'Var', (40, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('associated', 'Reg', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
380755	25890249	95% CI 95% confidence intervals OR Adjusted odds ratios CIN Carcinoma in-situ OR Crude odds ratio HAP Household air pollution HPV Human papilloma virus PAHs Polycyclic aromatic hydrocarbons	('Carcinoma', 'Disease', (60, 69))	('Carcinoma', 'Disease', 'MESH:D002277', (60, 69))	('papilloma', 'Disease', 'MESH:D010212', (136, 145))	('Carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('papilloma', 'Phenotype', 'HP:0012740', (136, 145))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (157, 189))	('PAHs', 'Chemical', 'MESH:D011084', (152, 156))	('CIN', 'Disease', (56, 59))	('HAP', 'Var', (98, 101))	('papilloma', 'Disease', (136, 145))	('CIN', 'Disease', 'MESH:D007674', (56, 59))
380851	25364580	Only 17.1% of patients with Hb levels <=13 g/dL responded to treatment, whereas 48.8% of patients with a level of >13 (P=0.0002) responded.	('<=13', 'Var', (38, 42))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (89, 97))	('responded', 'Reg', (48, 57))
380858	25364580	MiR-192 and miR-194 in pre-therapeutic biopsies were considered indicators of major histopathologic regressions.	('MiR-192', 'Gene', (0, 7))	('miR-194', 'Var', (12, 19))	('MiR-192', 'Gene', '406967', (0, 7))
381042	24260060	The present study used two in vitro methods to re-express RIZ1 in the human ESCC TE13 cell line in order to induce apoptosis.	('RIZ1', 'Gene', (58, 62))	('human', 'Species', '9606', (70, 75))	('induce', 'Reg', (108, 114))	('re-express', 'Var', (47, 57))	('apoptosis', 'CPA', (115, 124))	('RIZ1', 'Gene', '7799', (58, 62))
381049	24260060	Treatment with 5-aza-CdR for 48 and 72 h resulted in increased RIZ1 protein expression and increased the rate of apoptosis in the TE13 cells (P<0.01).	('RIZ1', 'Gene', (63, 67))	('apoptosis', 'CPA', (113, 122))	('increased', 'PosReg', (53, 62))	('expression', 'MPA', (76, 86))	('5-aza-CdR', 'Var', (15, 24))	('RIZ1', 'Gene', '7799', (63, 67))
381051	24260060	Furthermore, the re-expression of RIZ1 led to an increased rate of apoptosis and this method may provide new therapeutic possibilities.	('re-expression', 'Var', (17, 30))	('apoptosis', 'CPA', (67, 76))	('RIZ1', 'Gene', (34, 38))	('RIZ1', 'Gene', '7799', (34, 38))
381059	24260060	Furthermore, the expression of RIZ1 may also be regulated by methylation of the gene promoter.	('RIZ1', 'Gene', (31, 35))	('methylation', 'Var', (61, 72))	('expression', 'MPA', (17, 27))	('regulated', 'Reg', (48, 57))	('RIZ1', 'Gene', '7799', (31, 35))
381060	24260060	The ESCC TE13 cell line was selected, which expresses low levels of RIZ1, to confirm the existence of methylation in the RIZ1 promoter in ESCC cells.	('RIZ1', 'Gene', (121, 125))	('methylation', 'Var', (102, 113))	('RIZ1', 'Gene', '7799', (68, 72))	('RIZ1', 'Gene', (68, 72))	('RIZ1', 'Gene', '7799', (121, 125))
381077	24260060	Due to the size of the amplicon, the open reading frame may be divided into five sections, designated A603, A1200, B, C and D. The primers were previously designed for the five amplicons of RIZ1 by Primer 5.0 software (Premier, Palo Alto, CA, USA) as follows: Forward: 5'-GTGGCTAGCATGAATCAGAACACTACTG-3' and reverse: 5'-TTGGCCAGAGGTGAAATCTGG CTC-3' for A603; forward: 5'-TGGCTGCGATATGTGA ATTG-3' and reverse: 5'-CTCTACGCTGATGCCGTCTC-3' for A1200; forward: 5'-GCTGATGGCAAAGCATCTG-3' and reverse: 5'-AATTCCTTGCCTTCAGAGTCAC-3' for B; forward: 5'-TCAAAGAAAGTCATTCAGTGC-3' and reverse: 5'-CGGTGATGGTACTGAAATG-3' for C; and forward: 5'-GCCTCAATCAGCATTACC-3' and reverse: 5'-GTCTACTCTTTGAAGAATGGTC-3' for D. PCR amplification for each amplicon (A603, A1200, B, C and D) of RIZ1 was also performed using cDNA from normal, control esophageal tissue.	('RIZ1', 'Gene', '7799', (766, 770))	('RIZ1', 'Gene', '7799', (190, 194))	('RIZ1', 'Gene', (766, 770))	('RIZ1', 'Gene', (190, 194))	('A603', 'Var', (738, 742))
381097	24260060	Due to the size of the protein coding region of the RIZ1 gene, the target was divided into five amplicons, A603, A1200, B, C and D. RNA was isolated, reverse transcribed into cDNA and amplified by PCR.	('RIZ1', 'Gene', (52, 56))	('RIZ1', 'Gene', '7799', (52, 56))	('A1200', 'Var', (113, 118))	('A603', 'Var', (107, 111))
381104	24260060	The loss of this methylation was hypothesized to result in the re-expression of RIZ1.	('RIZ1', 'Gene', (80, 84))	('RIZ1', 'Gene', '7799', (80, 84))	('methylation', 'Var', (17, 28))	('re-expression', 'MPA', (63, 76))	('loss', 'NegReg', (4, 8))
381106	24260060	qPCR and western blotting demonstrated that the mRNA and protein levels of RIZ1 were significantly higher in the 5-aza-CdR group compared with the control cells at every time point (Figs.	('5-aza-CdR', 'Var', (113, 122))	('RIZ1', 'Gene', '7799', (75, 79))	('RIZ1', 'Gene', (75, 79))	('higher', 'PosReg', (99, 105))
381118	24260060	From a genetic perspective, RIZ1 may be deactivated by chromosomal instability and microsatellite instability, as well as frameshift mutations, point mutations and heterozygote deficiency.	('frameshift mutations', 'Var', (122, 142))	('RIZ1', 'Gene', (28, 32))	('microsatellite instability', 'MPA', (83, 109))	('point mutations', 'Var', (144, 159))	('chromosomal instability', 'Var', (55, 78))	('chromosomal instability', 'Phenotype', 'HP:0040012', (55, 78))	('deactivated', 'NegReg', (40, 51))	('RIZ1', 'Gene', '7799', (28, 32))
381120	24260060	Changes to chromosome 1p36, on which RIZ1 is located, are also associated with numerous types of cancer, including breast cancer, ovarian cancer, liver cancer, colorectal cancer, chronic myeloid leukemia, melanoma, chromaffin tumor and neuroblastoma.	('cancer', 'Disease', (138, 144))	('ovarian cancer', 'Disease', 'MESH:D010051', (130, 144))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('chromaffin tumor', 'Phenotype', 'HP:0002666', (215, 231))	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('chronic myeloid leukemia', 'Disease', (179, 203))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('liver cancer', 'Disease', 'MESH:D006528', (146, 158))	('colorectal cancer', 'Disease', (160, 177))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', (97, 103))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Disease', (205, 213))	('associated', 'Reg', (63, 73))	('ovarian cancer', 'Disease', (130, 144))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('liver cancer', 'Phenotype', 'HP:0002896', (146, 158))	('RIZ1', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('liver cancer', 'Disease', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (187, 203))	('ovarian cancer', 'Phenotype', 'HP:0100615', (130, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('leukemia', 'Phenotype', 'HP:0001909', (195, 203))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (179, 203))	('RIZ1', 'Gene', '7799', (37, 41))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (179, 203))	('neuroblastoma', 'Disease', (236, 249))	('cancer', 'Disease', (171, 177))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('neuroblastoma', 'Phenotype', 'HP:0003006', (236, 249))	('breast cancer', 'Disease', (115, 128))	('chromaffin', 'Chemical', '-', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('neuroblastoma', 'Disease', 'MESH:D009447', (236, 249))	('cancer', 'Disease', (122, 128))	('Changes', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (226, 231))
381123	24260060	Taken together, this evidence indicates that the deactivation of the RIZ1 tumor suppressor gene may be significant in the progression of esophageal cancer.	('RIZ1', 'Gene', (69, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('deactivation', 'Var', (49, 61))	('RIZ1', 'Gene', '7799', (69, 73))	('esophageal cancer', 'Disease', (137, 154))
381126	24260060	The development of a malignant tumor is caused by the inactivation of tumor suppressor genes and the abnormal activation of oncogenes.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('oncogenes', 'Gene', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('activation', 'PosReg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (31, 36))	('caused by', 'Reg', (40, 49))	('malignant tumor', 'Disease', 'MESH:D018198', (21, 36))	('inactivation', 'Var', (54, 66))	('malignant tumor', 'Disease', (21, 36))
381137	24260060	This raises the possibility that the re-expression of RIZ1 may induce apoptosis in malignant esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('re-expression', 'Var', (37, 50))	('esophageal cancer', 'Disease', (93, 110))	('RIZ1', 'Gene', (54, 58))	('RIZ1', 'Gene', '7799', (54, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('induce', 'PosReg', (63, 69))	('apoptosis', 'CPA', (70, 79))
381249	33841514	According to the results of the analysis of malignant tumors, NCOA1, HERC1, HIPK3, MBNL1, hsa-let-7b-3p, hsa-miR-378a-5p, and hsa-miR-26a-5p were predictive or prognostic factors for malignant tumors.	('HERC1', 'Gene', '8925', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('hsa-let-7b-3p', 'Var', (90, 103))	('hsa-miR-378a', 'Gene', (105, 117))	('malignant tumors', 'Disease', (44, 60))	('malignant tumors', 'Disease', 'MESH:D009369', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('HERC1', 'Gene', (69, 74))	('HIPK3', 'Gene', '10114', (76, 81))	('MBNL1', 'Gene', (83, 88))	('NCOA1', 'Gene', (62, 67))	('hsa-miR-26a-5p', 'Var', (126, 140))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('HIPK3', 'Gene', (76, 81))	('malignant tumors', 'Disease', 'MESH:D009369', (183, 199))	('malignant tumors', 'Disease', (183, 199))	('NCOA1', 'Gene', '8648', (62, 67))	('MBNL1', 'Gene', '4154', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('hsa-miR-378a', 'Gene', '494327', (105, 117))
381270	33841514	A total of 766 DEmRNAs were primarily enriched in biological processes (BP) such as organic anion transport for colon cancer (GO:0015711) and cell components (CC) such as the apical part of the cell (GO:0045177) and the apical plasma membrane (GO:0016324) as well as ligand activity (GO:0048018) and signaling receptor activator activity (GO:0030546) of molecular function (MF) receptor for colon cancer (Figure 3).	('GO:0015711', 'Var', (126, 136))	('GO:0048018', 'Var', (284, 294))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('organic anion transport', 'MPA', (84, 107))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (391, 403))	('colon cancer', 'Disease', 'MESH:D015179', (391, 403))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('colon cancer', 'Disease', (112, 124))	('GO:0030546', 'Var', (339, 349))	('colon cancer', 'Disease', (391, 403))	('GO:0016324', 'Var', (244, 254))
381272	33841514	To investigate the enrichment in esophageal cancer, 448 DEmRNAs were used and enriched in muscle contraction (GO:0006936), the muscle system process (GO:0003012), digestion (GO:0007586), the presynaptic membrane (GO:0042734), the intrinsic component of the presynaptic membrane (GO:0098889) of biological processes (BP) and cell components (CC) (Figure 3).	('GO:0007586', 'Var', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GO:0042734', 'Var', (213, 223))	('GO:0006936', 'Var', (110, 120))	('GO:0003012', 'Var', (150, 160))	('men', 'Species', '9606', (25, 28))
381274	33841514	Rectosigmoid junction cancer was also analyzed by GO and KEGG enrichment; 623 DEmRNAs were screened out, and the top 5 GO enrichments were the regulation of membrane potential (GO:0042391), the transmembrane transporter complex (GO:1902495), the transporter complex (GO:1990351), muscle contraction (GO:0006936), and the ion channel complex (GO:0034702) of biological processes (BP) and cell components (CC) (Figure 3).	('GO:0034702', 'Var', (342, 352))	('GO:1990351', 'Var', (267, 277))	('GO:0006936', 'Var', (300, 310))	('Rectosigmoid junction cancer', 'Disease', 'MESH:D009369', (0, 28))	('men', 'Species', '9606', (128, 131))	('GO:0042391', 'Var', (177, 187))	('Rectosigmoid junction cancer', 'Disease', (0, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('men', 'Species', '9606', (68, 71))	('GO:1902495', 'Var', (229, 239))
381276	33841514	Rectal cancer was also analyzed by GO and KEGG enrichment; 691 DEmRNAs were screened out, and the top 5 GO enrichments were the regulation of membrane potential (GO:0042391), the regulation of transsynaptic signaling (GO:0099177), the synaptic membrane (GO:0097060), the modulation of chemical synaptic transmission (GO:0050804), and the muscle system process (GO:0003012) of biological processes (BP) and cell components (CC) (Figure 3).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('GO:0042391', 'Var', (162, 172))	('Rectal cancer', 'Phenotype', 'HP:0100743', (0, 13))	('GO:0097060', 'Var', (254, 264))	('men', 'Species', '9606', (113, 116))	('cancer', 'Disease', (7, 13))	('GO:0099177', 'Var', (218, 228))	('men', 'Species', '9606', (53, 56))	('GO:0050804', 'Var', (317, 327))	('GO:0003012', 'Var', (361, 371))
381279	33841514	A total of 637 DEmRNAs were screened out, and the top 5 GO enrichments were cornification (GO:0070268), digestion (GO:0007586), antimicrobial humoral response (GO:0019730), keratinocyte differentiation (GO:0030216), and skin development (GO:0043588) of biological processes (BP) (Figure 3).	('GO:0019730', 'Var', (160, 170))	('keratinocyte differentiation', 'CPA', (173, 201))	('GO:0043588', 'Var', (238, 248))	('men', 'Species', '9606', (65, 68))	('cornification', 'CPA', (76, 89))	('skin development', 'CPA', (220, 236))	('GO:0007586', 'Var', (115, 125))	('men', 'Species', '9606', (232, 235))	('GO:0070268', 'Var', (91, 101))	('GO:0030216', 'Var', (203, 213))
381313	33841514	The abnormal expression level of SRCs has triggered cancers, such as breast, endometrial and ovarian cancers.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Disease', (52, 59))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('triggered', 'Reg', (42, 51))	('abnormal', 'Var', (4, 12))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('SRCs', 'Gene', (33, 37))	('breast', 'Disease', (69, 75))	('endometrial and ovarian cancers', 'Disease', 'MESH:D004714', (77, 108))	('expression level', 'MPA', (13, 29))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('ovarian cancers', 'Phenotype', 'HP:0100615', (93, 108))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
381324	33841514	We eventually obtained 20 miRNAs associated with the staging of esophageal cancer and gastric cancer, including hsa-let-7b-3p, hsa-miR-378a-5p, hsa-miR-26a-5p, hsa-miR-382-5p, and hsa-miR-29b-2-5p.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('hsa-miR-382', 'Gene', '494331', (160, 171))	('hsa-miR-382', 'Gene', (160, 171))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('hsa-let-7b-3p', 'Var', (112, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('cancer', 'Disease', (75, 81))	('hsa-miR-378a', 'Gene', (127, 139))	('hsa-miR-26a-5p', 'Var', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('hsa-miR-29b-2', 'Gene', (180, 193))	('hsa-miR-29b-2', 'Gene', '407025', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('hsa-miR-378a', 'Gene', '494327', (127, 139))	('gastric cancer', 'Disease', (86, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
381325	33841514	Previous studies indicate that gastric cancer stem-like cells are derived from MKN-45- by the expression change of hsa-let-7b-3p.	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('gastric cancer', 'Disease', (31, 45))	('expression', 'MPA', (94, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (31, 45))	('hsa-let-7b-3p', 'Var', (115, 128))	('change', 'Reg', (105, 111))
381375	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
381389	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('malignant tumors', 'Disease', (55, 71))	('TRIM44', 'Gene', (245, 251))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
381397	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
381407	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('TRIM44', 'Gene', '54765', (18, 24))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('cancers', 'Disease', (111, 118))	('change', 'Reg', (60, 66))	('hallmark characteristics of', 'MPA', (70, 97))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))
381409	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (0, 6))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
381411	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))
381412	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('cyclin', 'Gene', (111, 117))	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', '5111', (125, 131))	('cyclin', 'Gene', '5111', (111, 117))	('knockdown', 'Var', (28, 37))	('accelerating', 'PosReg', (183, 195))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', (125, 131))
381414	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('p27', 'Gene', '10671', (64, 67))	('TRIM44', 'Gene', '54765', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('inhibited', 'NegReg', (91, 100))	('TRIM44', 'Gene', (14, 20))	('Knock-down', 'Var', (0, 10))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
381415	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('activated', 'PosReg', (99, 108))	('p21', 'Gene', (22, 25))	('glioma', 'Disease', (112, 118))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
381416	32503466	TRIM44 overexpression leads to high mTOR activity, which is consistent with observations of reduced mTOR signaling in cancer cell lines after siRNA knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('TRIM44', 'Gene', (0, 6))	('cancer', 'Disease', (118, 124))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduced', 'NegReg', (92, 99))	('TRIM44', 'Gene', '54765', (161, 167))	('TRIM44', 'Gene', '54765', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
381417	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('Akt', 'Gene', (63, 66))
381428	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('TNFSF10', 'Gene', (117, 124))	('apoptotic cell pathways', 'Pathway', (171, 194))	('INHBA', 'Gene', (110, 115))	('NUPR1', 'Gene', (89, 94))	('knockdown', 'Var', (39, 48))	('DDIT4', 'Gene', (130, 135))	('CADM1', 'Gene', (103, 108))	('activate', 'PosReg', (158, 166))	('CADM1', 'Gene', '23705', (103, 108))	('TNFSF10', 'Gene', '8743', (117, 124))	('TRIM44', 'Gene', '54765', (32, 38))	('TRIM44', 'Gene', (32, 38))	('CDK19', 'Gene', (96, 101))	('INHBA', 'Gene', '3624', (110, 115))	('NUPR1', 'Gene', '26471', (89, 94))	('DDIT4', 'Gene', '54541', (130, 135))	('CDK19', 'Gene', '23097', (96, 101))	('dysregulation', 'MPA', (72, 85))
381437	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('c-IAP2', 'Gene', (84, 90))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
381444	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
381460	32266120	The data of esophageal squamous cell carcinoma from the Gene Expression Omnibus (GEO) were selected as the research object, processed and analyzed to screen differentially expressed microRNAs (miRNAs) and differential methylation genes.	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('differential methylation', 'Var', (205, 229))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (12, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('esophageal squamous cell carcinoma', 'Disease', (12, 46))
381479	32266120	In addition to genetic characteristics, scientists have also found that esophageal cancer has a variety of epigenetic changes in recent years.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('epigenetic changes', 'Var', (107, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))
381481	32266120	Epigenetic abnormalities not only drive the occurrence and development of tumors, but also affect cell growth, invasion, metastasis, heterogeneity and drug resistance.	('heterogeneity', 'MPA', (133, 146))	('metastasis', 'CPA', (121, 131))	('Epigenetic abnormalities', 'Var', (0, 24))	('drug resistance', 'CPA', (151, 166))	('drug resistance', 'Phenotype', 'HP:0020174', (151, 166))	('drive', 'PosReg', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('affect', 'Reg', (91, 97))	('development', 'CPA', (59, 70))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('cell growth', 'CPA', (98, 109))	('invasion', 'CPA', (111, 119))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
381482	32266120	More importantly, epigenetic changes are often early events in the process of disease occurrence, which provides an opportunity to find tumor specific biomarkers.	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('epigenetic changes', 'Var', (18, 36))
381497	32266120	Finally, three differentially expressed down-regulated miRNAs were obtained, including hsa-mir- 139-5p, hsa-mir-1 and hsa-mir-133b.	('down-regulated', 'NegReg', (40, 54))	('hsa-mir-133b', 'Gene', (118, 130))	('hsa-mir-133b', 'Gene', '442890', (118, 130))	('hsa-mir-1', 'Var', (104, 113))
381498	32266120	There were nine up-regulated miRNAs, including hsa-mir-1246, hsa-mir-34c-5p, hsa-mir-455-5p, hsa-mir-455-3p, hsa-mir-146b-5p, hsa-mir-3651 and hsa-mir-429, as shown in Figs.	('hsa-mir-146b-5p', 'Var', (109, 124))	('hsa-mir-3651', 'Gene', (126, 138))	('hsa-mir-455', 'Gene', '619556', (77, 88))	('hsa-mir-429', 'Gene', '554210', (143, 154))	('hsa-mir-455', 'Gene', (93, 104))	('hsa-mir-34c-5p', 'Var', (61, 75))	('miRNAs', 'MPA', (29, 35))	('hsa-mir-429', 'Gene', (143, 154))	('up-regulated', 'PosReg', (16, 28))	('hsa-mir-455', 'Gene', '619556', (93, 104))	('hsa-mir-3651', 'Gene', '100500918', (126, 138))	('hsa-mir-1246', 'Gene', '100302142', (47, 59))	('hsa-mir-455', 'Gene', (77, 88))	('hsa-mir-1246', 'Gene', (47, 59))
381515	32266120	found that miRNA-338-3p, miRNA-218 and hsa-miRNA-139-5p were up-regulated in esophageal squamous cell carcinoma, while miRNA-183, miRNA-574-5p, miRNA-21 and miRNA-601 were down regulated.	('miRNA-21', 'Gene', (144, 152))	('miRNA-21', 'Gene', (25, 33))	('miRNA-338-3p', 'Var', (11, 23))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('miRNA-183', 'Gene', '406959', (119, 128))	('miRNA-183', 'Gene', (119, 128))	('miRNA-21', 'Gene', '406991', (144, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('miRNA-21', 'Gene', '406991', (25, 33))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('up-regulated', 'PosReg', (61, 73))
381516	32266120	Kano et al., found that 15 miRNAs were down regulated in esophageal squamous cell carcinoma compared with normal tissues, and 4 miRNAs were able to play an anti-cancer role (miRNA-145, miRNA-30a-3p, miRNA-133a and miRNA-133b), which was consistent with the differential expression miRNAs we analyzed, which proved that our screening method was feasible.	('esophageal squamous cell carcinoma', 'Disease', (57, 91))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('miRNA-133b', 'Gene', '442890', (214, 224))	('miRNA-145', 'Gene', '406937', (174, 183))	('miRNA-145', 'Gene', (174, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('miRNA-30a-3p', 'Var', (185, 197))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (57, 91))	('miRNA-133b', 'Gene', (214, 224))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('down regulated', 'NegReg', (39, 53))	('cancer', 'Disease', (161, 167))	('miRNA-133a', 'Var', (199, 209))
381524	32266120	The abnormal expression of lncRNAs may play an important role in the occurrence and development of esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (99, 119))	('abnormal', 'Var', (4, 12))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (99, 119))	('expression', 'MPA', (13, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('play', 'Reg', (39, 43))	('lncRNAs', 'Protein', (27, 34))	('esophageal carcinoma', 'Disease', (99, 119))
381528	32266120	FoxO gene changes have been described in a limited number of human cancers such as rhabdomyosarcoma, leukemia and lymphoma.	('FoxO', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (83, 99))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (83, 99))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lymphoma', 'Disease', (114, 122))	('leukemia', 'Disease', (101, 109))	('rhabdomyosarcoma', 'Disease', (83, 99))	('lymphoma', 'Disease', 'MESH:D008223', (114, 122))	('leukemia', 'Disease', 'MESH:D007938', (101, 109))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('changes', 'Var', (10, 17))	('human', 'Species', '9606', (61, 66))	('described', 'Reg', (28, 37))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))
381534	32266120	It can promote the phosphorylation of DNA protein kinase and repair the break of DNA double strand, thus affecting the radiosensitivity of tumor cells.	('DNA protein kinase', 'Enzyme', (38, 56))	('break', 'Var', (72, 77))	('phosphorylation', 'MPA', (19, 34))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('affecting', 'Reg', (105, 114))	('promote', 'PosReg', (7, 14))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
381584	30283226	Its neuroendocrine component presents positivity for synaptophysin in 75%-90%, chromogranin in 60-70%, CD56 in 50%, and for neuronal specific enolase in a variable percentage while the glandular exocrine component usually expresses specific nonneuroendocrine markers such as cytokeratins 7 and 20 and carcinoembryonic antigen.	('CD56', 'Gene', '4684', (103, 107))	('positivity', 'Var', (38, 48))	('synaptophysin', 'Gene', (53, 66))	('CD56', 'Gene', (103, 107))	('synaptophysin', 'Gene', '6855', (53, 66))	('carcinoembryonic antigen', 'Protein', (301, 325))	('cytokeratins', 'Protein', (275, 287))
381607	30275710	MIME was associated with higher incidence of pulmonary complications (OR =1.96, 95% CI =1.28-3.00) as well as total anastomotic leak (OR =2.55, 95% CI =1.40-4.63), stricture (OR =2.07, 95% CI =1.05-4.07), and vocal cord injury/palsy (OR =5.62, 95% CI =3.46-9.14).	('anastomotic leak', 'Disease', 'MESH:D057868', (116, 132))	('pulmonary complications', 'Disease', 'MESH:D008171', (45, 68))	('MIME', 'Var', (0, 4))	('MIME', 'Chemical', '-', (0, 4))	('anastomotic leak', 'Disease', (116, 132))	('stricture', 'Disease', (164, 173))	('pulmonary complications', 'Disease', (45, 68))	('vocal cord injury/palsy', 'Disease', 'MESH:D014826', (209, 232))	('pulmonary complications', 'Phenotype', 'HP:0006532', (45, 68))	('vocal cord injury/palsy', 'Disease', (209, 232))
381628	30275710	MIME was found to cause more intraoperative blood loss than MILE (WMD =16.9, 95% CI =3.22-30.58, P=0.02), but the difference of transfusion rate was of no statistical significance (OR =1.25, 95% CI =0.29-5.38, P=0.76).	('intraoperative blood loss', 'Disease', (29, 54))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (29, 54))	('MIME', 'Var', (0, 4))	('MIME', 'Chemical', '-', (0, 4))
381633	30275710	After pooled analysis, we found that MIME led to longer hospital stay (WMD =1.29, 95% CI =0.27-2.31, P=0.01).	('MIME', 'Var', (37, 41))	('MIME', 'Chemical', '-', (37, 41))	('longer', 'PosReg', (49, 55))	('hospital stay', 'CPA', (56, 69))
381641	30275710	It was also revealed that MIME was associated with higher incidence of vocal cord injury/palsy (OR =5.62, 95% CI =3.46-9.14, P=0.00), as shown in Figure 5, as well as a higher stricture rate (OR =2.07, 95% CI =1.05-4.07, P=0.04).	('MIME', 'Var', (26, 30))	('MIME', 'Chemical', '-', (26, 30))	('vocal cord injury/palsy', 'Disease', 'MESH:D014826', (71, 94))	('vocal cord injury/palsy', 'Disease', (71, 94))	('stricture', 'CPA', (176, 185))
381650	30275710	In the present study, we found that MIME was associated with higher rates of anastomotic leak, stricture, and pulmonary complication, and longer operating time than MILE, which were different from the findings of a previous meta-analysis.	('pulmonary complication', 'Disease', 'MESH:D008171', (110, 132))	('anastomotic leak', 'Disease', 'MESH:D057868', (77, 93))	('anastomotic leak', 'Disease', (77, 93))	('stricture', 'Disease', (95, 104))	('pulmonary complication', 'Disease', (110, 132))	('MIME', 'Var', (36, 40))	('MIME', 'Chemical', '-', (36, 40))
381669	30275710	Taken together, MIME was associated with higher incidence of total anastomotic leakage, stricture, vocal cord injury/palsy, and pulmonary complications, and as a result, MIME led to longer duration of hospital stay.	('pulmonary complications', 'Disease', (128, 151))	('anastomotic leak', 'Disease', (67, 83))	('stricture', 'Disease', (88, 97))	('pulmonary complications', 'Disease', 'MESH:D008171', (128, 151))	('longer', 'PosReg', (182, 188))	('MIME', 'Disease', (16, 20))	('MIME', 'Var', (170, 174))	('MIME', 'Chemical', '-', (170, 174))	('vocal cord injury/palsy', 'Disease', 'MESH:D014826', (99, 122))	('vocal cord injury/palsy', 'Disease', (99, 122))	('anastomotic leak', 'Disease', 'MESH:D057868', (67, 83))	('pulmonary complications', 'Phenotype', 'HP:0006532', (128, 151))	('MIME', 'Chemical', '-', (16, 20))
381684	29383093	In current study, we used a 4-nitroquinoline-1-oxide (4-NQO)-induced ESCC mouse model of test whether A-1210477, a Mcl-1 small molecular inhibitor, could repress ESCC development.	('A-1210477', 'Chemical', 'MESH:C000611392', (102, 111))	('4-nitroquinoline-1-oxide', 'Chemical', 'MESH:D015112', (28, 52))	('mouse', 'Species', '10090', (74, 79))	('4-NQO', 'Chemical', 'MESH:D015112', (54, 59))	('ESCC', 'Disease', (162, 166))	('A-1210477', 'Var', (102, 111))	('repress', 'NegReg', (154, 161))
381685	29383093	We showed that A-1210477 treatment decreased ESCC formation and animal weight loss in a dose dependent manner.	('decreased ESCC', 'Phenotype', 'HP:0025022', (35, 49))	('A-1210477', 'Chemical', 'MESH:C000611392', (15, 24))	('ESCC formation', 'CPA', (45, 59))	('decreased', 'NegReg', (35, 44))	('weight loss', 'Disease', 'MESH:D015431', (71, 82))	('A-1210477', 'Var', (15, 24))	('weight loss', 'Disease', (71, 82))	('weight loss', 'Phenotype', 'HP:0001824', (71, 82))
381687	29383093	Moreover, A-1210477 treatment increased the number of apoptotic cells in ESCC tissues.	('A-1210477', 'Var', (10, 19))	('increased', 'PosReg', (30, 39))	('A-1210477', 'Chemical', 'MESH:C000611392', (10, 19))
381694	29383093	In human ESCC, NF-kappaB subunits p50 and p65 can bind to Mcl-1 promoter and activate the expression of Mcl-1.	('activate', 'PosReg', (77, 85))	('bind', 'Interaction', (50, 54))	('p65', 'Var', (42, 45))	('NF-kappaB', 'Protein', (15, 24))	('human', 'Species', '9606', (3, 8))	('p50', 'Gene', (34, 37))	('expression', 'MPA', (90, 100))	('Mcl-1', 'Gene', (104, 109))	('p50', 'Gene', '4790', (34, 37))
381696	29383093	A-1210477 binds to MCL-1 with high affinity and induces MCL-1 protein elevation in cells.	('MCL-1', 'Gene', '4170', (56, 61))	('MCL-1', 'Gene', (56, 61))	('MCL-1', 'Gene', (19, 24))	('A-1210477', 'Chemical', 'MESH:C000611392', (0, 9))	('MCL-1', 'Gene', '4170', (19, 24))	('induces', 'Reg', (48, 55))	('elevation', 'PosReg', (70, 79))	('A-1210477', 'Var', (0, 9))
381698	29383093	We found that treatment of A-1210477 dramatically reduced ESCC tumor burden in a chemically induced mouse model.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('A-1210477', 'Var', (27, 36))	('mouse', 'Species', '10090', (100, 105))	('ESCC tumor', 'Disease', (58, 68))	('reduced', 'NegReg', (50, 57))	('A-1210477', 'Chemical', 'MESH:C000611392', (27, 36))	('ESCC tumor', 'Disease', 'MESH:D004938', (58, 68))
381705	29383093	Our results showed that A-1210477-treated mice had developed fewer tumors than the vehicle-treated mice did in a dose dependent manner (Figure 2A).	('mice', 'Species', '10090', (99, 103))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('A-1210477-treated', 'Var', (24, 41))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('fewer', 'NegReg', (61, 66))	('A-1210477', 'Chemical', 'MESH:C000611392', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
381706	29383093	Similarly, there was significant less body weight loss in the A-1210477-treatment group mice compared with the control ones (Figure 2B).	('weight loss', 'Disease', (43, 54))	('less', 'NegReg', (33, 37))	('weight loss', 'Phenotype', 'HP:0001824', (43, 54))	('A-1210477-treatment', 'Var', (62, 81))	('A-1210477', 'Chemical', 'MESH:C000611392', (62, 71))	('weight loss', 'Disease', 'MESH:D015431', (43, 54))	('mice', 'Species', '10090', (88, 92))
381707	29383093	Microscopically, we also noticed less malignancy formation in the esophagus following A-1210477-treatment (Figure 2C-2E).	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('less', 'NegReg', (33, 37))	('malignancy', 'Disease', (38, 48))	('A-1210477-treatment', 'Var', (86, 105))	('A-1210477', 'Chemical', 'MESH:C000611392', (86, 95))
381708	29383093	To understand how A-1210477 inhibited ESCC tumor progression, we examined the cell proliferation by Ki67 IHC staining.	('A-1210477', 'Chemical', 'MESH:C000611392', (18, 27))	('Ki67', 'Gene', '17345', (100, 104))	('A-1210477', 'Var', (18, 27))	('ESCC tumor', 'Disease', (38, 48))	('inhibited', 'NegReg', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Ki67', 'Gene', (100, 104))	('ESCC tumor', 'Disease', 'MESH:D004938', (38, 48))
381710	29383093	Thus, esophageal cell proliferation was reduced markedly following A-1210477 treatment.	('A-1210477', 'Chemical', 'MESH:C000611392', (67, 76))	('reduced', 'NegReg', (40, 47))	('A-1210477', 'Var', (67, 76))	('esophageal cell proliferation', 'CPA', (6, 35))
381711	29383093	To further probe how A-1210477 inhibited ESCC tumor progression, we evaluated the apoptotic cells of these ESCC after A-1210477 treatment by detecting cleaved caspase3 expression with quantitative IHC.	('caspase3', 'Gene', (159, 167))	('A-1210477', 'Chemical', 'MESH:C000611392', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('ESCC tumor', 'Disease', (41, 51))	('caspase3', 'Gene', '12367', (159, 167))	('ESCC tumor', 'Disease', 'MESH:D004938', (41, 51))	('A-1210477', 'Chemical', 'MESH:C000611392', (21, 30))	('A-1210477', 'Var', (118, 127))	('cleaved', 'MPA', (151, 158))	('inhibited', 'NegReg', (31, 40))	('A-1210477', 'Var', (21, 30))
381712	29383093	The percentage of TUNEL positive cells increased dose dependently from 1.9 % in DMSO mice to 8.9 % (p < 0.05) in low-dose A-1210477 mice and 19.0 % (p < 0.05) in high-dose A-1210477 mice (Figure 4E-4N).	('mice', 'Species', '10090', (85, 89))	('mice', 'Species', '10090', (182, 186))	('A-1210477', 'Chemical', 'MESH:C000611392', (122, 131))	('increased', 'PosReg', (39, 48))	('TUNEL', 'Gene', (18, 23))	('mice', 'Species', '10090', (132, 136))	('A-1210477', 'Chemical', 'MESH:C000611392', (172, 181))	('A-1210477', 'Var', (122, 131))	('DMSO', 'Chemical', 'MESH:D004121', (80, 84))
381713	29383093	Therefore, our data clearly demonstrated A-1210477 treatment led to increased cell death in mouse ESCC.	('mouse', 'Species', '10090', (92, 97))	('A-1210477', 'Chemical', 'MESH:C000611392', (41, 50))	('cell death', 'CPA', (78, 88))	('A-1210477', 'Var', (41, 50))
381716	29383093	Mcl-1 small molecular inhibitors, such as A-1210477 and S63845, have been proved to potently eliminate various kinds of Mcl1-dependent cancer cells.	('cancer', 'Disease', (135, 141))	('A-1210477', 'Var', (42, 51))	('Mcl-1', 'Gene', (0, 5))	('eliminate', 'NegReg', (93, 102))	('S63845', 'Var', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('A-1210477', 'Chemical', 'MESH:C000611392', (42, 51))	('Mcl1', 'Gene', (120, 124))	('Mcl1', 'Gene', '17210', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
381718	29383093	We showed that A-1210477 could release mouse tumor burden in a dose dependent manner.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('A-1210477', 'Chemical', 'MESH:C000611392', (15, 24))	('tumor', 'Disease', (45, 50))	('A-1210477', 'Var', (15, 24))	('mouse', 'Species', '10090', (39, 44))	('release', 'MPA', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
381719	29383093	Specifically, A-1210477 can repress the cell proliferation and increase cell death of ESCC in mouse.	('increase', 'PosReg', (63, 71))	('A-1210477', 'Var', (14, 23))	('repress', 'NegReg', (28, 35))	('mouse', 'Species', '10090', (94, 99))	('cell death', 'CPA', (72, 82))	('A-1210477', 'Chemical', 'MESH:C000611392', (14, 23))	('cell proliferation', 'CPA', (40, 58))
381725	29383093	Recently, a group showed a novel Mcl-1 inhibitor S63845, which inhibits Mcl-1 via binding to the BH3-binding groove of Mcl-1, was able to potently kill various cancer cells both in vitro and in vivo.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('inhibits', 'NegReg', (63, 71))	('S63845', 'Var', (49, 55))	('Mcl-1', 'Protein', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('BH3', 'Chemical', 'MESH:C006008', (97, 100))	('binding', 'Interaction', (82, 89))
381726	29383093	Mechanistically, S63845 can cause cell death through the BAX/BAK-dependent mitochondrial apoptotic pathway.	('S63845', 'Var', (17, 23))	('BAX', 'Gene', '12028', (57, 60))	('BAX', 'Gene', (57, 60))	('cell death', 'CPA', (34, 44))	('BAK', 'Gene', (61, 64))	('BAK', 'Gene', '12018', (61, 64))
381727	29383093	This study provides evidence that inhibition of Mcl-1 might be a common therapeutic method for treating cancers.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('inhibition', 'Var', (34, 44))	('Mcl-1', 'Gene', (48, 53))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
381728	29383093	We showed here that inhibition of Mcl-1 by A-1210477 caused ESCC repression.	('A-1210477', 'Var', (43, 52))	('inhibition', 'NegReg', (20, 30))	('ESCC repression', 'Disease', (60, 75))	('A-1210477', 'Chemical', 'MESH:C000611392', (43, 52))
381731	29383093	On the other hand, Bak or Bim results in apoptosis if release from Mcl-1.	('Bim', 'Chemical', '-', (26, 29))	('Bak', 'Gene', (19, 22))	('apoptosis', 'CPA', (41, 50))	('Bim', 'Var', (26, 29))	('Bak', 'Gene', '12018', (19, 22))
381734	29383093	The exact molecular mechanism how A-1210477 induces the apoptosis of ESCC cells needs further investigation.	('apoptosis', 'CPA', (56, 65))	('A-1210477', 'Var', (34, 43))	('A-1210477', 'Chemical', 'MESH:C000611392', (34, 43))
381735	29383093	In conclusion, our studies clearly demonstrate a role of A-1210477 in ESCC inhibition.	('A-1210477', 'Var', (57, 66))	('ESCC', 'Disease', (70, 74))	('inhibition', 'NegReg', (75, 85))	('A-1210477', 'Chemical', 'MESH:C000611392', (57, 66))
381761	29147064	Additionally, dysregulation of lncRNAs has been linked to the initiation and development of numerous tumors, including ESCC.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('ESCC', 'Disease', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('dysregulation', 'Var', (14, 27))	('numerous tumors', 'Disease', (92, 107))	('lncRNAs', 'Protein', (31, 38))	('numerous tumors', 'Disease', 'MESH:D009369', (92, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('linked', 'Reg', (48, 54))
381762	29147064	LncRNA HOTTIP was reported to be upregulated in ESCC, and knockdown of HOTTIP significantly inhibited ESCC cell proliferation and invasion.	('upregulated', 'PosReg', (33, 44))	('inhibited', 'NegReg', (92, 101))	('HOTTIP', 'Gene', (7, 13))	('ESCC', 'Disease', (102, 106))	('HOTTIP', 'Gene', '100316868', (71, 77))	('invasion', 'CPA', (130, 138))	('LncRNA', 'Protein', (0, 6))	('HOTTIP', 'Gene', (71, 77))	('HOTTIP', 'Gene', '100316868', (7, 13))	('ESCC', 'Disease', (48, 52))	('knockdown', 'Var', (58, 67))
381767	29147064	Moreover, NEAT1 displays carcinogenicity in multiple types of cancers, such as breast cancer and glioma.	('glioma', 'Disease', (97, 103))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('NEAT1', 'Var', (10, 15))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('carcinogenicity', 'MPA', (25, 40))	('cancers', 'Disease', (62, 69))
381768	29147064	It was previously reported that NEAT1 epigenetically silenced miR-129-5p expression by promoting DNA methylation of the CpG island in the miR-129 gene in breast tumorigenesis, thus resulting in an upregulation of WNT4 expression, a target of miR-129-5p.	('miR-129-5p', 'Gene', (62, 72))	('miR-129-5p', 'Gene', '100302178', (242, 252))	('promoting', 'PosReg', (87, 96))	('WNT4', 'Gene', '54361', (213, 217))	('upregulation', 'PosReg', (197, 209))	('miR-129-5p', 'Gene', (242, 252))	('epigenetically', 'Var', (38, 52))	('breast tumorigenesis', 'Disease', (154, 174))	('silenced', 'NegReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('miR-129', 'Gene', (138, 145))	('expression', 'MPA', (218, 228))	('miR-129-5p', 'Gene', '100302178', (62, 72))	('WNT4', 'Gene', (213, 217))	('DNA methylation', 'MPA', (97, 112))
381789	29147064	For instance, NETA1 functioned as a ceRNA for miR-377-3p, antagonized its function, and led to the derepression of its endogenous target E2F3, which was a core oncogene in promoting non-small-cell lung carcinoma progression.	('antagonized', 'NegReg', (58, 69))	('promoting', 'PosReg', (172, 181))	('miR-377', 'Gene', (46, 53))	('lung carcinoma', 'Disease', (197, 211))	('lung carcinoma', 'Disease', 'MESH:D008175', (197, 211))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (182, 211))	('NETA1', 'Var', (14, 19))	('E2F3', 'Gene', (137, 141))	('E2F3', 'Gene', '1871', (137, 141))	('derepression', 'MPA', (99, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('function', 'MPA', (74, 82))	('miR-377', 'Gene', '494326', (46, 53))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (186, 211))
381793	29147064	Furthermore, CTBP2 knockdown by lentiviral-mediated RNA interference resulted in inhibited cell growth, proliferation, migration, invasion, and cell cycle progression in neuroblastoma.	('CTBP2', 'Gene', (13, 18))	('neuroblastoma', 'Disease', (170, 183))	('knockdown', 'Var', (19, 28))	('cell growth', 'CPA', (91, 102))	('inhibited', 'NegReg', (81, 90))	('invasion', 'CPA', (130, 138))	('neuroblastoma', 'Phenotype', 'HP:0003006', (170, 183))	('neuroblastoma', 'Disease', 'MESH:D009447', (170, 183))	('RNA interference', 'MPA', (52, 68))	('cell cycle progression', 'CPA', (144, 166))	('migration', 'CPA', (119, 128))
381794	28755160	Successful video-assisted thoracoscopic surgery in prone position in patients with esophageal cancer and aberrant right subclavian artery: report of three cases An aberrant right subclavian artery (ARSA) with an associated nonrecurrent right inferior laryngeal nerve (NRILN) is a relatively rare anomaly that occurs at a frequency of 0.3 to 2.0% of the general population.	('ARSA', 'Phenotype', 'HP:0031014', (198, 202))	('rare anomaly', 'Disease', 'MESH:D035583', (291, 303))	('rare anomaly', 'Disease', (291, 303))	('esophageal cancer', 'Disease', (83, 100))	('aberrant right subclavian artery', 'Phenotype', 'HP:0031014', (105, 137))	('aberrant', 'Var', (164, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('aberrant right subclavian artery', 'Phenotype', 'HP:0031014', (164, 196))	('patients', 'Species', '9606', (69, 77))	('right inferior laryngeal nerve', 'Disease', (236, 266))
381803	28755160	Injury to this nerve may decrease the patient's quality of life because of the development of hoarseness and an increased risk of aspiration pneumonia.	('quality of life', 'CPA', (48, 63))	('increased risk of aspiration pneumonia', 'Phenotype', 'HP:0002100', (112, 150))	('Injury', 'Var', (0, 6))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (130, 150))	('decrease', 'NegReg', (25, 33))	('hoarseness', 'Disease', (94, 104))	('patient', 'Species', '9606', (38, 45))	('aspiration', 'Phenotype', 'HP:0002835', (130, 140))	('hoarseness', 'Phenotype', 'HP:0001609', (94, 104))	('aspiration pneumonia', 'Disease', (130, 150))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (130, 150))	('pneumonia', 'Phenotype', 'HP:0002090', (141, 150))
381804	28755160	A nonrecurrent right inferior laryngeal nerve (NRILN) is a relatively rare anomaly of the recurrent nerve that is associated with an aberrant right subclavian artery (ARSA).	('aberrant', 'Var', (133, 141))	('ARSA', 'Phenotype', 'HP:0031014', (167, 171))	('aberrant right subclavian artery', 'Phenotype', 'HP:0031014', (133, 165))	('rare anomaly', 'Disease', 'MESH:D035583', (70, 82))	('associated', 'Reg', (114, 124))	('rare anomaly', 'Disease', (70, 82))
381824	28755160	After pathologic examination, the esophageal cancer was diagnosed as squamous cell carcinoma (MtUt, Type 0-IIa, T1b(SM), N3, M0: ypStage III), or T1bN2M0, pStage IIIA in UICC.	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('T1bN2M0', 'Var', (146, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('squamous cell carcinoma', 'Disease', (69, 92))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
381828	28755160	After pathologic examination, the esophageal cancer was diagnosed as squamous cell carcinoma (Mt, Type 5, T3 (AD), N2, M0: ypStage III) or T3N2M0, pStageIIIB in UICC.	('AD', 'Disease', (110, 112))	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('squamous cell carcinoma', 'Disease', (69, 92))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('T3N2M0', 'Var', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('AD', 'Disease', 'MESH:D000544', (110, 112))
381913	28126011	Several preclinical studies have reported that metformin reduced cell proliferation, induced apoptosis, and caused cell cycle arrest in vitro and also reduced occurrence and growth of experimental tumors in vivo.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (115, 132))	('reduced', 'NegReg', (151, 158))	('metformin', 'Chemical', 'MESH:D008687', (47, 56))	('tumors', 'Disease', (197, 203))	('induced', 'Reg', (85, 92))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('cell cycle arrest', 'CPA', (115, 132))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cell proliferation', 'CPA', (65, 83))	('reduced', 'NegReg', (57, 64))	('apoptosis', 'CPA', (93, 102))	('metformin', 'Var', (47, 56))	('occurrence', 'CPA', (159, 169))
381920	28126011	Metformin has also been reported to exert its antineoplastic effects by stimulating AMPK through up-regulation of the p53-p21 axis and down-regulation of cyclin D1 levels.	('up-regulation', 'PosReg', (97, 110))	('p21', 'Gene', (122, 125))	('p21', 'Gene', '644914', (122, 125))	('antineoplastic effects', 'CPA', (46, 68))	('p53', 'Gene', (118, 121))	('down-regulation', 'NegReg', (135, 150))	('AMPK', 'Gene', (84, 88))	('Metformin', 'Var', (0, 9))	('p53', 'Gene', '7157', (118, 121))	('stimulating', 'PosReg', (72, 83))	('cyclin D1', 'Gene', '595', (154, 163))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('AMPK', 'Gene', '5563', (84, 88))	('cyclin D1', 'Gene', (154, 163))
381921	28126011	Metformin inhibits the corresponding cyclin-dependent kinases and then induces G1-phase arrest of the cell cycle.	('inhibits', 'NegReg', (10, 18))	('G1-phase arrest of the cell cycle', 'CPA', (79, 112))	('Metformin', 'Var', (0, 9))	('cyclin-dependent', 'Enzyme', (37, 53))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('induces', 'Reg', (71, 78))
381923	28126011	observed different results that AMPKalpha knockdown by small interfering RNA (siRNA) and compound C did not prevent the growth-inhibitory effects of metformin on medullary thyroid cancer cells.	('AMPK', 'Gene', (32, 36))	('thyroid cancer', 'Disease', (172, 186))	('thyroid cancer', 'Disease', 'MESH:D013964', (172, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('small interfering RNA', 'MPA', (55, 76))	('AMPK', 'Gene', '5563', (32, 36))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (162, 186))	('thyroid cancer', 'Phenotype', 'HP:0002890', (172, 186))	('knockdown', 'Var', (42, 51))	('metformin', 'Chemical', 'MESH:D008687', (149, 158))
381926	28126011	Moreover, in acute lymphoblastic leukemia (ALL), knockdown of AMPKalpha by short hairpin RNA (shRNA) rescued cells from metformin-induced apoptosis, which was associated with restoration of the unfolded protein response (UPR)/glucose-regulated protein 78 kDa (GRP78) function, down-regulation of UPR apoptotic markers inositol-requiring enzyme 1alpha (IRE1alpha) and C/EBP homologous protein (CHOP), and interruption of protein synthesis.	('CHOP', 'Gene', (393, 397))	('ALL', 'Phenotype', 'HP:0006721', (43, 46))	('protein synthesis', 'MPA', (420, 437))	('acute lymphoblastic leukemia', 'Disease', (13, 41))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (13, 41))	('inositol', 'Chemical', 'MESH:D007294', (318, 326))	('C/EBP homologous protein', 'Gene', '1649', (367, 391))	('GRP78', 'Gene', (260, 265))	('leukemia', 'Phenotype', 'HP:0001909', (33, 41))	('GRP78', 'Gene', '3309', (260, 265))	('IRE1alpha', 'Gene', (352, 361))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (13, 41))	('UPR', 'PosReg', (296, 299))	('interruption', 'NegReg', (404, 416))	('down-regulation', 'NegReg', (277, 292))	('metformin', 'Chemical', 'MESH:D008687', (120, 129))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (19, 41))	('AMPK', 'Gene', '5563', (62, 66))	('CHOP', 'Gene', '1649', (393, 397))	('glucose-regulated protein 78 kDa', 'Gene', '3309', (226, 258))	('IRE1alpha', 'Gene', '2081', (352, 361))	('function', 'MPA', (267, 275))	('glucose-regulated protein 78 kDa', 'Gene', (226, 258))	('knockdown', 'Var', (49, 58))	('C/EBP homologous protein', 'Gene', (367, 391))	('AMPK', 'Gene', (62, 66))
381927	28126011	Studies on breast cancer therapy have demonstrated that inhibition of AMPK with siRNA decreased the suppression of multidrug resistance 1 (MDR1) gene activation after exposure to metformin.	('MDR1', 'Gene', '5243', (139, 143))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('multidrug resistance 1', 'Gene', '5243', (115, 137))	('breast cancer', 'Disease', (11, 24))	('decreased', 'NegReg', (86, 95))	('suppression', 'MPA', (100, 111))	('AMPK', 'Gene', '5563', (70, 74))	('inhibition', 'Var', (56, 66))	('metformin', 'Chemical', 'MESH:D008687', (179, 188))	('multidrug resistance 1', 'Gene', (115, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('MDR1', 'Gene', (139, 143))	('AMPK', 'Gene', (70, 74))	('activation', 'MPA', (150, 160))
381928	28126011	Furthermore, overexpression of a dominant-negative mutant of AMPK attenuated the inhibitory effects of metformin on the phosphorylation of cAMP-responsive element-binding protein (CREB) and the expression of MDR1.	('MDR1', 'Gene', (208, 212))	('AMPK', 'Gene', '5563', (61, 65))	('attenuated', 'NegReg', (66, 76))	('phosphorylation', 'MPA', (120, 135))	('mutant', 'Var', (51, 57))	('MDR1', 'Gene', '5243', (208, 212))	('AMPK', 'Gene', (61, 65))	('inhibitory effects', 'MPA', (81, 99))	('cAMP-responsive element-binding protein', 'Gene', '1385', (139, 178))	('CREB', 'Gene', (180, 184))	('metformin', 'Chemical', 'MESH:D008687', (103, 112))	('expression', 'MPA', (194, 204))	('cAMP-responsive element-binding protein', 'Gene', (139, 178))	('CREB', 'Gene', '1385', (180, 184))
381951	28126011	In that report, REDD1 inactivation, using siRNA or REDD1-/- cells, abrogated cell cycle arrest independently of AMPK.	('inactivation', 'Var', (22, 34))	('REDD1', 'Gene', '54541', (51, 56))	('AMPK', 'Gene', (112, 116))	('REDD1', 'Gene', '54541', (16, 21))	('abrogated', 'NegReg', (67, 76))	('REDD1', 'Gene', (51, 56))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('REDD1', 'Gene', (16, 21))	('cell cycle arrest', 'CPA', (77, 94))	('AMPK', 'Gene', '5563', (112, 116))
381959	28126011	In addition, activation of IGF accelerated YYH1 tumor progression by promoting vascular smooth muscle cell proliferation, migration, and angiogenesis.	('vascular smooth muscle cell proliferation', 'CPA', (79, 120))	('promoting', 'PosReg', (69, 78))	('activation', 'Var', (13, 23))	('tumor', 'Disease', (48, 53))	('IGF', 'Gene', (27, 30))	('YYH1', 'Gene', (43, 47))	('angiogenesis', 'CPA', (137, 149))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('migration', 'CPA', (122, 131))	('accelerated', 'PosReg', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
381982	28126011	Inhibition of NF-kappaB can induce cancer cells to halt proliferation and die or can sensitize cells to chemotherapeutic reagents.	('halt proliferation', 'CPA', (51, 69))	('die', 'CPA', (74, 77))	('induce', 'Reg', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('NF-kappaB', 'Gene', '4790', (14, 23))	('NF-kappaB', 'Gene', (14, 23))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
381985	28126011	showed that metformin dampened NF-kappaB signaling by boosting NF-kappaB inhibitor alpha (IkappaBa) in hepatocellular carcinoma cell lines.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('metformin', 'Chemical', 'MESH:D008687', (12, 21))	('NF-kappaB inhibitor alpha', 'Gene', '4792', (63, 88))	('dampened', 'NegReg', (22, 30))	('boosting', 'PosReg', (54, 62))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('NF-kappaB', 'Gene', '4790', (63, 72))	('NF-kappaB', 'Gene', '4790', (31, 40))	('hepatocellular carcinoma', 'Disease', (103, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('NF-kappaB', 'Gene', (63, 72))	('metformin', 'Var', (12, 21))	('NF-kappaB', 'Gene', (31, 40))	('NF-kappaB inhibitor alpha', 'Gene', (63, 88))
381986	28126011	Moreover, forced expression of p65 or overexpression of an undegradable mutant form of IkappaBa was found to activate NF-kappaB signaling, thereby attenuating the antitumor effects of metformin.	('NF-kappaB', 'Gene', (118, 127))	('p65', 'Gene', '5970', (31, 34))	('IkappaBa', 'Gene', (87, 95))	('mutant', 'Var', (72, 78))	('metformin', 'Chemical', 'MESH:D008687', (184, 193))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('overexpression', 'PosReg', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('p65', 'Gene', (31, 34))	('activate', 'PosReg', (109, 117))	('attenuating', 'NegReg', (147, 158))	('NF-kappaB', 'Gene', '4790', (118, 127))	('tumor', 'Disease', (167, 172))
381993	28126011	In parallel, metformin down-regulates CSC marker genes in pancreatic cancer, esophageal cancer, and breast cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('pancreatic cancer', 'Disease', (58, 75))	('CSC marker genes', 'Gene', (38, 54))	('metformin', 'Var', (13, 22))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', (100, 113))	('esophageal cancer', 'Disease', (77, 94))	('down-regulates', 'NegReg', (23, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))
381994	28126011	In pancreatic cancer, metformin inhibits cell proliferation, migration, and invasion by weakening CSC function mediated by deregulating miRNAs.	('metformin', 'Var', (22, 31))	('pancreatic cancer', 'Disease', (3, 20))	('metformin', 'Chemical', 'MESH:D008687', (22, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('deregulating', 'PosReg', (123, 135))	('cell proliferation', 'CPA', (41, 59))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('weakening', 'NegReg', (88, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('migration', 'CPA', (61, 70))	('inhibits', 'NegReg', (32, 40))	('CSC function', 'CPA', (98, 110))	('invasion', 'CPA', (76, 84))	('miRNAs', 'MPA', (136, 142))
382004	28126011	Further studies are needed to improve our understanding of the pathways linking high metformin efficacy and cancer development.	('metformin', 'Chemical', 'MESH:D008687', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('high', 'Var', (80, 84))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
382006	28126011	Metformin also has indirect effects on the IGF and JNK/p38 MAPK pathways; other possible mechanisms include inhibition of the HER2 and NF-kappaB signaling pathways.	('NF-kappaB', 'Gene', (135, 144))	('MAPK', 'Gene', '5594', (59, 63))	('inhibition', 'NegReg', (108, 118))	('JNK', 'Gene', '5599', (51, 54))	('IGF', 'Pathway', (43, 46))	('MAPK', 'Gene', (59, 63))	('Metformin', 'Var', (0, 9))	('p38', 'Gene', '1432', (55, 58))	('HER2', 'Gene', '2064', (126, 130))	('HER2', 'Gene', (126, 130))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('NF-kappaB', 'Gene', '4790', (135, 144))	('JNK', 'Gene', (51, 54))	('p38', 'Gene', (55, 58))
382007	28126011	Further support for these observations is that metformin kills cancer stem cells and changes the properties of CSCs.	('metformin', 'Chemical', 'MESH:D008687', (47, 56))	('changes', 'Reg', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('properties of CSCs', 'CPA', (97, 115))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('metformin', 'Var', (47, 56))	('cancer', 'Disease', (63, 69))
382012	17384685	GAEC1 was ubiquitously expressed in normal tissues including esophageal and gastrointestinal organs; with amplification and overexpression in 6/10 (60%) ESCC cell lines and 34/99 (34%) primary tumors.	('GAEC1', 'Gene', '100126794', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('overexpression', 'PosReg', (124, 138))	('ESCC', 'Disease', (153, 157))	('amplification', 'Var', (106, 119))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('GAEC1', 'Gene', (0, 5))
382014	17384685	Although no significant correlation was observed between GAEC1 amplification and clinicopathological parameters and prognosis, our study demonstrated that overexpressed GAEC1 has tumorigenic potential and suggest that overexpressed GAEC1 may play an important role in ESCC pathogenesis.	('GAEC1', 'Gene', (57, 62))	('overexpressed', 'Var', (155, 168))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('GAEC1', 'Gene', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('GAEC1', 'Gene', '100126794', (169, 174))	('ESCC', 'Disease', (268, 272))	('GAEC1', 'Gene', (232, 237))	('GAEC1', 'Gene', '100126794', (232, 237))	('GAEC1', 'Gene', '100126794', (57, 62))	('tumor', 'Disease', (179, 184))
382015	17384685	Gene amplifications and overexpressions are among the major genomic aberrations involved in the esophageal squamous cell carcinomas (ESCC) pathogenesis (reviewed by).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('esophageal squamous cell carcinomas', 'Disease', (96, 131))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (96, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('overexpressions', 'PosReg', (24, 39))	('Gene amplifications', 'Var', (0, 19))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (107, 131))
382016	17384685	The amplification of 7q22 has been reported in ESCC and many other cancers, including breast cancer, choriocarcinoma, pancreatic carcinoma, non-papillary renal-cell carcinoma and T-cell leukemia.	('non-papillary renal-cell carcinoma and T-cell leukemia', 'Disease', 'MESH:C538614', (140, 194))	('reported', 'Reg', (35, 43))	('amplification', 'Var', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (101, 116))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('non-papillary renal-cell carcinoma', 'Phenotype', 'HP:0006770', (140, 174))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (118, 138))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Disease', (86, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('pancreatic carcinoma', 'Disease', (118, 138))	('renal-cell carcinoma', 'Phenotype', 'HP:0005584', (154, 174))	('leukemia', 'Phenotype', 'HP:0001909', (186, 194))	('7q22', 'Gene', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('choriocarcinoma', 'Disease', 'MESH:D002822', (101, 116))	('papillary renal-cell carcinoma', 'Phenotype', 'HP:0006766', (144, 174))	('ESCC', 'Disease', (47, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('choriocarcinoma', 'Disease', (101, 116))
382017	17384685	Thus, 7q22 is involved in the tumorigenesis of a range of cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('involved', 'Reg', (14, 22))	('cancers', 'Disease', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('7q22', 'Var', (6, 10))	('tumor', 'Disease', (30, 35))
382027	17384685	In addition, GAEC1 amplification was observed in 6/10 (60%) cell lines (HKESC1, HKESC2, HKESC3, EC109, KYSE 70, KYSE 410) when compared with NE1 (Figure 3B(a)).	('GAEC1', 'Gene', (13, 18))	('GAEC1', 'Gene', '100126794', (13, 18))	('HKESC1', 'CellLine', 'CVCL:D568', (72, 78))	('EC1', 'CellLine', 'CVCL:5V05', (96, 99))	('KYSE 70', 'Var', (103, 110))	('EC1', 'CellLine', 'CVCL:5V05', (15, 18))
382035	17384685	The sequencing results of the entire coding region of GAEC1 cDNA sequences from 99 paired (T and NT) specimens and 10 ESCC cell lines provided no evidence of alternatively spliced GAEC1 mRNAs, polymorphisms or somatic mutations of GAEC1 in ESCC.	('polymorphisms', 'Var', (193, 206))	('GAEC1', 'Gene', '100126794', (54, 59))	('GAEC1', 'Gene', '100126794', (231, 236))	('GAEC1', 'Gene', (180, 185))	('GAEC1', 'Gene', (231, 236))	('GAEC1', 'Gene', '100126794', (180, 185))	('GAEC1', 'Gene', (54, 59))
382036	17384685	Among the genetic changes detected (Ying and Tao, unpublished), an amplicon of ~1-2 Mb (defined by BAC clone RP11-401L13) was detected in 6/10 cell lines (HKESC1, HKESC2, HKESC3, EC109, KYSE70 and KYSE410) Figure 4(A and B).	('KYSE410', 'Var', (197, 204))	('RP11', 'Gene', '52528', (109, 113))	('HKESC1', 'CellLine', 'CVCL:D568', (155, 161))	('EC1', 'CellLine', 'CVCL:5V05', (179, 182))	('RP11', 'Gene', (109, 113))	('KYSE70', 'Var', (186, 192))
382072	17384685	Genomic amplification and overexpression of cancer-related genes contribute to tumor pathogenesis by activating protooncogenes.	('Genomic amplification', 'Var', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('overexpression', 'PosReg', (26, 40))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('protooncogenes', 'MPA', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('activating', 'PosReg', (101, 111))	('contribute', 'Reg', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
382080	17384685	One HPV16 E6E7 immortalized normal esophageal epithelial cell line (NE1) was used as a control.	('E6E7', 'Var', (10, 14))	('HPV16', 'Gene', (4, 9))	('HPV16', 'Species', '333760', (4, 9))
382091	17384685	To detect any polymorphisms or mutations in the GAEC1 coding sequence, cDNAs were synthesized using DNA-free RNAs and the entire coding region was amplified employing the Expand High FidelityPLUS Enzyme system (Roche, Mannheim, Germany) and primers GAEC1-F and GAEC1-R (Figure 1A; Supplementary Table 1).	('mutations', 'Var', (31, 40))	('GAEC1', 'Gene', (48, 53))	('GAEC1', 'Gene', '100126794', (48, 53))	('GAEC1', 'Gene', (261, 266))	('GAEC1', 'Gene', '100126794', (261, 266))	('GAEC1', 'Gene', (249, 254))	('GAEC1', 'Gene', '100126794', (249, 254))
382116	19604354	Although a total of 18 (25%) of 73 patients with esophageal SCC had s-MKRN1-Abs, none of the 43 healthy donors had a detectable level of s-MKRN1-Abs.	('s-MKRN1-Abs', 'Var', (68, 79))	('donor', 'Species', '9606', (104, 109))	('SCC', 'Gene', '6317', (60, 63))	('patients', 'Species', '9606', (35, 43))	('SCC', 'Gene', (60, 63))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))
382131	19604354	SEREX analysis has also led to the isolation of several antigens with known cancer relatedness, including a mutated version of the p53 tumor suppressor protein, while the presence of antibodies to p53 in serum was associated with poor prognosis in esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('p53', 'Gene', (131, 134))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('mutated', 'Var', (108, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (248, 265))	('p53', 'Gene', '7157', (197, 200))	('antibodies', 'Var', (183, 193))	('cancer', 'Disease', (259, 265))	('esophageal cancer', 'Disease', (248, 265))	('SEREX', 'Chemical', '-', (0, 5))	('tumor', 'Disease', (135, 140))	('p53', 'Gene', (197, 200))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('presence', 'Var', (171, 179))	('cancer', 'Disease', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('p53', 'Gene', '7157', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
382188	19604354	Nodal involvement was more frequently observed in the patients with s-MKRN1-Abs than in those without s-MKRN1-Abs, yet the difference was not statistically significant (P = 0.194).	('s-MKRN1-Abs', 'Var', (68, 79))	('patients', 'Species', '9606', (54, 62))	('Nodal involvement', 'CPA', (0, 17))	('observed', 'Reg', (38, 46))	('men', 'Species', '9606', (13, 16))
382191	19604354	Consequently, the sensitivity of serum markers to detect esophageal SCC was improved by using s-MKRN1-Abs in combination with conventional markers.	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (68, 71))	('improved', 'PosReg', (76, 84))	('s-MKRN1-Abs', 'Var', (94, 105))	('sensitivity', 'MPA', (18, 29))	('SCC', 'Gene', (68, 71))
382194	19604354	T.Tn esophageal SCC cells, as a positive control, showed higher MKRN1 mRNA levels than normal esophageal keratinocytes (Figure 3).	('higher', 'PosReg', (57, 63))	('T.Tn', 'Var', (0, 4))	('SCC', 'Gene', (16, 19))	('SCC', 'Phenotype', 'HP:0002860', (16, 19))	('SCC', 'Gene', '6317', (16, 19))	('MKRN1 mRNA levels', 'MPA', (64, 81))
382198	19604354	The protein (Figure 4a) and mRNA (Figure 4b) of transduced MKRN1 were observed in a stable transfected clone, Fmkrn-24, but not in the parental ras-NIH3T3 cells.	('transduced', 'Var', (48, 58))	('NIH3T3', 'CellLine', 'CVCL:0594', (148, 154))	('protein', 'MPA', (4, 11))	('MKRN1', 'Gene', (59, 64))	('mRNA', 'MPA', (28, 32))
382200	19604354	Two ubiquitinated proteins of 80 and 82 kDa were clearly observed in two MKRN1 transfectants but not in the parental ras-NIH3T3 cells (Figure 4a).	('NIH3T3', 'CellLine', 'CVCL:0594', (121, 127))	('MKRN1', 'Gene', (73, 78))	('transfectants', 'Var', (79, 92))	('observed', 'Reg', (57, 65))	('ubiquitinated proteins', 'MPA', (4, 26))
382207	19604354	have reported that a putative pseudogene-induced destabilization of MKRN1 led to defects of differentiation such as polycystic kidneys and bone deformity.	('polycystic kidneys', 'Disease', (116, 134))	('polycystic kidneys', 'Phenotype', 'HP:0000113', (116, 134))	('destabilization', 'NegReg', (49, 64))	('polycystic kidneys', 'Disease', 'MESH:D007690', (116, 134))	('bone deformity', 'Disease', 'MESH:D001847', (139, 153))	('MKRN1', 'Gene', (68, 73))	('pseudogene-induced', 'Var', (30, 48))	('bone deformity', 'Disease', (139, 153))
382212	19604354	Well-differentiated type tumors were observed more frequently in the patients with s-MKRN1-Abs than in the patients without s-MKRN1-Abs.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('type tumors', 'Disease', 'MESH:D009369', (20, 31))	('type tumors', 'Disease', (20, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('observed', 'Reg', (37, 45))	('s-MKRN1-Abs', 'Var', (83, 94))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (107, 115))
382226	19604354	The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/9/232/prepub This work was supported by 21st Century COE (Center of Excellence) Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grant-in-Aid for Scientific Research (#17591370 and #16390372) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.	('#16390372', 'Var', (329, 338))	('#17591370', 'Var', (315, 324))	('Aid', 'Gene', '57379', (286, 289))	('Aid', 'Gene', (286, 289))
382239	18700042	In contrast, in cancer cells multipolar mitotic spindles and various centrosomal anomalies, such as supernumerary centrosomes, centrosomes of abnormal size and shape, and prematurely split centrosomes are frequently observed It is conceivable that such abnormalities disrupt normal chromosomal segregation, producing aneuploid cells and causing chromosomal instability (CIN).	('normal chromosomal segregation', 'CPA', (275, 305))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('chromosomal instability', 'MPA', (345, 368))	('CIN', 'Disease', (370, 373))	('cancer', 'Disease', (16, 22))	('anomalies', 'Disease', 'MESH:D000014', (81, 90))	('causing', 'Reg', (337, 344))	('aneuploid cells', 'CPA', (317, 332))	('abnormalities', 'Var', (253, 266))	('CIN', 'Disease', 'MESH:D007674', (370, 373))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('producing', 'Reg', (307, 316))	('disrupt', 'NegReg', (267, 274))	('chromosomal instability', 'Phenotype', 'HP:0040012', (345, 368))	('CIN', 'Phenotype', 'HP:0040012', (370, 373))	('anomalies', 'Disease', (81, 90))
382304	18700042	The median survival of patients with high CENP-H expression was much shorter (19 months) than those with low CENP-H expression (33 months) (P < 0.001, Log-rank).	('patients', 'Species', '9606', (23, 31))	('high CENP-H expression', 'Var', (37, 59))	('shorter', 'NegReg', (69, 76))
382329	18700042	With regard to the correlation between immunohistochemical CENP-H staining and the prognosis of esophageal carcinoma, we have shown in univariate and multivariate analyses that high expression of CENP-H is an independent prognosticator for patient survival of esophageal cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (260, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('CENP-H', 'Gene', (196, 202))	('esophageal carcinoma', 'Disease', (96, 116))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (96, 116))	('patient', 'Species', '9606', (240, 247))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (96, 116))	('esophageal cancer', 'Disease', (260, 277))	('high expression', 'Var', (177, 192))
382334	18700042	In addition, we found that CENP-H might function as a new prognostic marker in ESCC for the N0 patient subgroups, because in these subgroups there is also a trend toward shorter overall survival times of patients with high expression of CENP-H.	('patients', 'Species', '9606', (204, 212))	('patient', 'Species', '9606', (95, 102))	('high', 'Var', (218, 222))	('CENP-H', 'Gene', (237, 243))	('ESCC', 'Disease', (79, 83))	('overall survival', 'MPA', (178, 194))	('shorter', 'NegReg', (170, 177))	('patient', 'Species', '9606', (204, 211))
382340	18700042	Inappropriate expression of CENP-H might deplete other centromere-kinetochore components and disrupt the kinetochore complex, or prevent normal kinetochore assembly and consequently cause aneuploidy and induce the development of cancer.	('deplete', 'NegReg', (41, 48))	('prevent', 'NegReg', (129, 136))	('CENP-H', 'Gene', (28, 34))	('cancer', 'Disease', (229, 235))	('aneuploidy', 'Disease', 'MESH:D000782', (188, 198))	('disrupt', 'NegReg', (93, 100))	('induce', 'PosReg', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('normal kinetochore assembly', 'CPA', (137, 164))	('cause', 'Reg', (182, 187))	('kinetochore complex', 'CPA', (105, 124))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('aneuploidy', 'Disease', (188, 198))	('Inappropriate', 'Var', (0, 13))
382341	18700042	Chromosomal abnormalities, including abnormal chromosome numbers, chromosome deletion, and amplification, are commonly found in ESCC.	('Chromosomal abnormalities', 'Disease', 'MESH:D002869', (0, 25))	('amplification', 'CPA', (91, 104))	('abnormal chromosome', 'Phenotype', 'HP:0031411', (37, 56))	('chromosome', 'CPA', (66, 76))	('abnormal chromosome', 'Var', (37, 56))	('Chromosomal abnormalities', 'Disease', (0, 25))	('ESCC', 'Disease', (128, 132))
382365	31056845	BE with low-grade or high-grade dysplasia alters the superficial tissue structure, typically within a few hundreds of microns of the esophagus surface.	('high-grade', 'Var', (21, 31))	('dysplasia', 'Disease', 'MESH:C536170', (32, 41))	('dysplasia', 'Disease', (32, 41))	('superficial tissue structure', 'CPA', (53, 81))	('alters', 'Reg', (42, 48))	('BE', 'Phenotype', 'HP:0100580', (0, 2))
382432	30093568	MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition.	('increased', 'PosReg', (21, 30))	('AXL', 'Gene', '558', (184, 187))	('AXL', 'Gene', '558', (89, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('expression', 'MPA', (6, 16))	('HNSCC', 'Phenotype', 'HP:0012288', (139, 144))	('AXL', 'Gene', (184, 187))	('patient', 'Species', '9606', (49, 56))	('AXL', 'Gene', (89, 92))	('NSCLC', 'Disease', (156, 161))	('MERTK', 'Gene', (122, 127))	('MERTK', 'Gene', (0, 5))	('inhibition', 'Var', (108, 118))	('inhibitors', 'Var', (93, 103))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))
382442	30093568	R428 has potent activity against AXL (IC50 = 14 nM) and fifty-fold selectivity for AXL relative to MERTK in cell-based assays.	('AXL', 'Gene', '558', (33, 36))	('AXL', 'Gene', (83, 86))	('R428', 'Var', (0, 4))	('AXL', 'Gene', (33, 36))	('AXL', 'Gene', '558', (83, 86))
382448	30093568	Targeting AXL with genetic silencing, a small molecule inhibitor, or an AXL-specific antibody increased MERTK protein expression in vitro and in vivo.	('AXL', 'Gene', (72, 75))	('increased', 'PosReg', (94, 103))	('genetic silencing', 'Var', (19, 36))	('AXL', 'Gene', '558', (10, 13))	('specific antibody increased', 'Phenotype', 'HP:0012475', (76, 103))	('MERTK protein', 'Protein', (104, 117))	('AXL', 'Gene', '558', (72, 75))	('AXL', 'Gene', (10, 13))
382449	30093568	Furthermore, combined targeting of MERTK and AXL inhibited tumor cell expansion in vitro and impacted tumor growth in vivo.	('MERTK', 'Gene', (35, 40))	('AXL', 'Gene', (45, 48))	('tumor', 'Disease', (59, 64))	('targeting', 'Var', (22, 31))	('impacted', 'Reg', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('AXL', 'Gene', '558', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('inhibited', 'NegReg', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
382458	30093568	Non-targeting control siRNA (Cat# D-001810-01-05) and siRNAs targeting AXL (Cat#J-003104-10-0005, #J-003104-12-0005) were purchased from Thermo Scientific and utilized for transfection of NSCLC cells with final concentrations of 25nM siRNA and 1muL/mL DharmaFECT1 Transfection Reagent (Cat#T-2001-02).	('Cat#J-003104-10-0005', 'Var', (76, 96))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('AXL', 'Gene', '558', (71, 74))	('AXL', 'Gene', (71, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('#J-003104-12-0005', 'Var', (98, 115))	('NSCLC', 'Disease', (188, 193))
382460	30093568	pcDNA3.1-TYRO3 was purchased from GenScript USA Inc. (#OHu23055D, Piscataway, NJ, USA).	('TYRO3', 'Gene', '7301', (9, 14))	('#OHu23055D', 'Var', (54, 64))	('TYRO3', 'Gene', (9, 14))
382467	30093568	H1299 NSCLC cells were cultured at low density in liquid medium containing R428, UNC2025, R428 and UNC2025, or vehicle.	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('R428', 'Var', (75, 79))	('UNC2025', 'Var', (81, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('R428', 'Var', (90, 94))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))	('UNC2025', 'Chemical', 'MESH:C000597431', (81, 88))	('NSCLC', 'Disease', (6, 11))	('UNC2025', 'Chemical', 'MESH:C000597431', (99, 106))
382471	30093568	R428, UNC2025, R428+UNC2025, or an equivalent volume of vehicle (0.5% hydroxypropylmethylcellulose + 0.1% Tween 80) were administered twice daily by oral gavage for 5 days/week.	('UNC2025', 'Chemical', 'MESH:C000597431', (6, 13))	('UNC2025', 'Chemical', 'MESH:C000597431', (20, 27))	('UNC2025', 'Var', (6, 13))	('Tween 80', 'Chemical', 'MESH:D011136', (106, 114))	('R428+UNC2025', 'Var', (15, 27))
382481	30093568	AXL, MERTK, and TYRO3 were differentially expressed in cancer cell lines and immunoblot analysis confirmed inhibition of AXL phosphorylation in response to treatment with R428 (Figure S1).	('AXL', 'Gene', (121, 124))	('R428', 'Var', (171, 175))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('AXL', 'Gene', '558', (0, 3))	('AXL', 'Gene', '558', (121, 124))	('TYRO3', 'Gene', (16, 21))	('AXL', 'Gene', (0, 3))	('inhibition', 'NegReg', (107, 117))	('TYRO3', 'Gene', '7301', (16, 21))	('cancer', 'Disease', (55, 61))
382482	30093568	Although all of the tumor cell lines expressed AXL to some degree, analysis of tumor cell expansion in culture revealed that only a subset of cell lines exhibited a statistically significant decrease in cell number in response to treatment with R428 and were scored as sensitive, while the majority were relatively resistant (Fig 1B, D and F).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('AXL', 'Gene', '558', (47, 50))	('AXL', 'Gene', (47, 50))	('response', 'MPA', (218, 226))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cell number', 'CPA', (203, 214))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (20, 25))	('decrease', 'NegReg', (191, 199))	('R428', 'Var', (245, 249))
382486	30093568	To determine whether alternative TAM family receptors are similarly upregulated in response to anti-AXL therapeutics, we analyzed the expression of MERTK and TYRO3 in HNSCC (UM-SCC47, HN30, UM-SCC4), TNBC (BT549, MDAMB231), NSCLC (H1299, H157), and esophageal cancer (KY270, KY410, SKGT4) cell lines after AXL inhibition mediated by genetic silencing (siAXL), small molecule inhibition (R428), or anti-AXL monoclonal antibody therapy (Mab173).	('inhibition', 'NegReg', (310, 320))	('BT549', 'CellLine', 'CVCL:1092', (206, 211))	('TYRO3', 'Gene', '7301', (158, 163))	('NSCLC', 'Disease', (224, 229))	('H157', 'CellLine', 'CVCL:2458', (238, 242))	('SCC4', 'Gene', '23383', (177, 181))	('esophageal cancer', 'Disease', 'MESH:D004938', (249, 266))	('AXL', 'Gene', '558', (306, 309))	('SCC4', 'Gene', (177, 181))	('AXL', 'Gene', (402, 405))	('NSCLC', 'Phenotype', 'HP:0030358', (224, 229))	('AXL', 'Gene', (100, 103))	('AXL', 'Gene', (354, 357))	('HNSCC', 'Phenotype', 'HP:0012288', (167, 172))	('SKGT4', 'CellLine', 'CVCL:2195', (282, 287))	('esophageal cancer', 'Disease', (249, 266))	('TAM', 'Chemical', 'MESH:C419191', (33, 36))	('MDAMB231', 'CellLine', 'CVCL:0062', (213, 221))	('AXL', 'Gene', (306, 309))	('UM-SCC47', 'CellLine', 'CVCL:7759', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('TYRO3', 'Gene', (158, 163))	('H1299', 'CellLine', 'CVCL:0060', (231, 236))	('HN30', 'Chemical', 'MESH:C009802', (184, 188))	('SCC4', 'Gene', '23383', (193, 197))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('AXL', 'Gene', '558', (402, 405))	('SCC4', 'Gene', (193, 197))	('AXL', 'Gene', '558', (100, 103))	('genetic silencing', 'Var', (333, 350))	('AXL', 'Gene', '558', (354, 357))
382487	30093568	First, cell lines were transfected with siAXL or a non-targeting siRNA control to examine the effects of genetic knockdown of AXL on MERTK and TYRO3 expression levels.	('AXL', 'Gene', (42, 45))	('TYRO3', 'Gene', (143, 148))	('TYRO3', 'Gene', '7301', (143, 148))	('AXL', 'Gene', '558', (126, 129))	('knockdown', 'Var', (113, 122))	('AXL', 'Gene', '558', (42, 45))	('AXL', 'Gene', (126, 129))
382493	30093568	TYRO3 protein levels were only slightly increased in a subset of cell lines treated with R428 (Fig 2) and high levels of TYRO3 did not correlate with resistance to AXL inhibition (Fig 1, 2).	('TYRO3', 'Gene', (0, 5))	('TYRO3', 'Gene', '7301', (0, 5))	('AXL', 'Gene', '558', (164, 167))	('TYRO3', 'Gene', (121, 126))	('R428', 'Var', (89, 93))	('increased', 'PosReg', (40, 49))	('TYRO3', 'Gene', '7301', (121, 126))	('AXL', 'Gene', (164, 167))
382496	30093568	To test this hypothesis, HNSCC (UM-SCC1, UM-SCC4, UM-SCC6, UM-SCC47, UM-SCC104), TNBC (SUM229, BT549, MDAMB231), and NSCLC (H1299 and H157) cell lines that co-expressed both AXL and MERTK were either treated with a combination of R428 and UNC2025 for 72 hours or transfected with siAXL and then treated with UNC2025 prior to determining relative cell numbers.	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('SCC1', 'Gene', '5795', (72, 76))	('AXL', 'Gene', '558', (282, 285))	('UM-SCC47', 'CellLine', 'CVCL:7759', (59, 67))	('H157', 'CellLine', 'CVCL:2458', (134, 138))	('UNC2025', 'Chemical', 'MESH:C000597431', (308, 315))	('NSCLC', 'Disease', (117, 122))	('UNC2025', 'Var', (239, 246))	('SCC1', 'Gene', (35, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('MDAMB231', 'CellLine', 'CVCL:0062', (102, 110))	('H1299', 'CellLine', 'CVCL:0060', (124, 129))	('SCC1', 'Gene', (72, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (25, 30))	('SCC4', 'Gene', '23383', (62, 66))	('AXL', 'Gene', (282, 285))	('AXL', 'Gene', '558', (174, 177))	('SCC4', 'Gene', (62, 66))	('SCC4', 'Gene', '23383', (44, 48))	('SCC4', 'Gene', (44, 48))	('R428', 'Var', (230, 234))	('SCC1', 'Gene', '5795', (35, 39))	('AXL', 'Gene', (174, 177))	('BT549', 'CellLine', 'CVCL:1092', (95, 100))	('UNC2025', 'Chemical', 'MESH:C000597431', (239, 246))
382498	30093568	AXL phosphorylation was not affected by treatment with UNC2025 at the doses used for these studies (Fig S3C).	('AXL', 'Gene', (0, 3))	('UNC2025', 'Chemical', 'MESH:C000597431', (55, 62))	('AXL', 'Gene', '558', (0, 3))	('UNC2025', 'Var', (55, 62))
382502	30093568	Similarly, reduced expansion was observed in esophageal cell lines expressing both AXL and MERTK after treatment with R428 and UNC2025 combination therapy (Fig S4C, D and E).	('UNC2025', 'Var', (127, 134))	('AXL', 'Gene', '558', (83, 86))	('AXL', 'Gene', (83, 86))	('UNC2025', 'Chemical', 'MESH:C000597431', (127, 134))
382504	30093568	To investigate potential mechanisms of synergistic anti-tumor activity mediated by the combination of R428 and UNC2025, we determined the status of downstream signaling pathways in the context of R428 and siAXL in combination with UNC2025.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('R428', 'Var', (196, 200))	('tumor', 'Disease', (56, 61))	('AXL', 'Gene', (207, 210))	('UNC2025', 'Chemical', 'MESH:C000597431', (111, 118))	('UNC2025', 'Chemical', 'MESH:C000597431', (231, 238))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('AXL', 'Gene', '558', (207, 210))
382505	30093568	In UM-SCC1 and MDAMB231 cells treated with R428 and UNC2025, there was a substantial decrease in expression of phospho-STAT6, phospho-AKT, phospho-P70S6K, phospho-S6rp, and phospho-C-RAF (Fig 4A and B).	('SCC1', 'Gene', (6, 10))	('R428', 'Var', (43, 47))	('AKT', 'Gene', (134, 137))	('STAT6', 'Gene', '6778', (119, 124))	('SCC1', 'Gene', '5795', (6, 10))	('C-RAF', 'Gene', (181, 186))	('phospho-S6rp', 'Var', (155, 167))	('P70S6K', 'Gene', '6198', (147, 153))	('decrease', 'NegReg', (85, 93))	('MDAMB231', 'CellLine', 'CVCL:0062', (15, 23))	('UNC2025', 'Chemical', 'MESH:C000597431', (52, 59))	('AKT', 'Gene', '207', (134, 137))	('UNC2025', 'Var', (52, 59))	('P70S6K', 'Gene', (147, 153))	('C-RAF', 'Gene', '5894', (181, 186))	('STAT6', 'Gene', (119, 124))	('expression', 'MPA', (97, 107))
382506	30093568	In both cases, signaling was decreased to a greater degree in cultures treated with R428 and UNC2025 as compared to cultures treated with either single agent.	('UNC2025', 'Chemical', 'MESH:C000597431', (93, 100))	('UNC2025', 'Var', (93, 100))	('decreased', 'NegReg', (29, 38))	('signaling', 'MPA', (15, 24))	('R428', 'Var', (84, 88))
382507	30093568	Similarly, in H1299 NSCLC cells treated with siAXL and UNC2025, combined inhibition of AXL and MERTK led to more potent decreases in phosphorylation of STAT6 and AKT (Fig 4C).	('H1299', 'CellLine', 'CVCL:0060', (14, 19))	('AXL', 'Gene', '558', (87, 90))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('AKT', 'Gene', '207', (162, 165))	('inhibition', 'NegReg', (73, 83))	('phosphorylation', 'MPA', (133, 148))	('AXL', 'Gene', (87, 90))	('STAT6', 'Gene', (152, 157))	('AXL', 'Gene', '558', (47, 50))	('UNC2025', 'Chemical', 'MESH:C000597431', (55, 62))	('AKT', 'Gene', (162, 165))	('STAT6', 'Gene', '6778', (152, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('UNC2025', 'Var', (55, 62))	('AXL', 'Gene', (47, 50))	('decreases', 'NegReg', (120, 129))	('NSCLC', 'Disease', (20, 25))
382512	30093568	Consistent with the biochemical effects of MERTK inhibition, ectopic expression of MERTK increased downstream signaling through phospho-P70S6K, phospho-S6rp, and phospho-C-RAF (Fig 5B and E).	('C-RAF', 'Gene', (170, 175))	('P70S6K', 'Gene', '6198', (136, 142))	('C-RAF', 'Gene', '5894', (170, 175))	('ectopic expression', 'Var', (61, 79))	('phospho-S6rp', 'Var', (144, 156))	('P70S6K', 'Gene', (136, 142))	('increased', 'PosReg', (89, 98))	('downstream signaling', 'MPA', (99, 119))	('MERTK', 'Gene', (83, 88))
382514	30093568	The observed upregulation of MERTK in tumor cell lines in response to AXL inhibition (Fig 2) and the potent anti-tumor responses mediated by combined targeting of MERTK and AXL in vitro (Fig 3) implicate co-inhibition as an effective therapeutic strategy.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', (113, 118))	('targeting', 'Var', (150, 159))	('MERTK', 'Gene', (163, 168))	('AXL', 'Gene', (173, 176))	('AXL', 'Gene', (70, 73))	('combined', 'Interaction', (141, 149))	('MERTK', 'Gene', (29, 34))	('inhibition', 'NegReg', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('upregulation', 'PosReg', (13, 25))	('AXL', 'Gene', '558', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('AXL', 'Gene', '558', (173, 176))
382519	30093568	Again, MERTK was prominently upregulated in tumors treated with R428 and this increase persisted during the extended treatment period (Fig 6B).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('MERTK', 'CPA', (7, 12))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('upregulated', 'PosReg', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('R428', 'Var', (64, 68))
382520	30093568	Consistent with this observation, tumor volume was not significantly different in mice treated with R428 relative to vehicle-treated mice.	('mice', 'Species', '10090', (82, 86))	('mice', 'Species', '10090', (133, 137))	('tumor', 'Disease', (34, 39))	('R428', 'Var', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
382524	30093568	Combined treatment with R428 and UNC2025 significantly decreased tumor volume compared to treatment with either inhibitor alone in both models (Fig 6C and D).	('tumor', 'Disease', (65, 70))	('R428', 'Var', (24, 28))	('decreased', 'NegReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('UNC2025', 'Chemical', 'MESH:C000597431', (33, 40))	('UNC2025', 'Var', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
382526	30093568	MERTK expression was also upregulated in R428-treated UM-SCC1 and MDAMB231 tumors after 28 days of treatment (Fig 6C and D), consistent with our previous results in cell culture (Fig 2) and animal models (Fig 6A and B).	('upregulated', 'PosReg', (26, 37))	('expression', 'MPA', (6, 16))	('MDAMB231 tumors', 'Disease', (66, 81))	('R428-treated', 'Var', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SCC1', 'Gene', (57, 61))	('MERTK', 'Gene', (0, 5))	('SCC1', 'Gene', '5795', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('MDAMB231 tumors', 'Disease', 'MESH:D009369', (66, 81))
382534	30093568	Moreover, ectopic expression of MERTK was sufficient to mediate resistance to AXL-targeting strategies and combined inhibition of both AXL and MERTK using a variety of different approaches provided potent anti-tumor activity in HNSCC, TNBC, and NSCLC cell culture and animal models.	('NSCLC', 'Phenotype', 'HP:0030358', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('AXL', 'Gene', '558', (78, 81))	('AXL', 'Gene', (135, 138))	('tumor', 'Disease', (210, 215))	('MERTK', 'Gene', (32, 37))	('NSCLC', 'Disease', (245, 250))	('inhibition', 'NegReg', (116, 126))	('HNSCC', 'Disease', (228, 233))	('HNSCC', 'Phenotype', 'HP:0012288', (228, 233))	('AXL', 'Gene', (78, 81))	('NSCLC', 'Disease', 'MESH:D002289', (245, 250))	('ectopic expression', 'Var', (10, 28))	('MERTK', 'Gene', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('AXL', 'Gene', '558', (135, 138))
382536	30093568	For example, HER2 and HER3 are upregulated in response to EGFR inhibition, and knockdown of the RTK RON results in upregulation of its close family member cMET.	('EGFR', 'Gene', '1956', (58, 62))	('cMET', 'Gene', '4233', (155, 159))	('upregulation', 'PosReg', (115, 127))	('cMET', 'Gene', (155, 159))	('RON', 'Gene', '4486', (100, 103))	('EGFR', 'Gene', (58, 62))	('HER3', 'Gene', (22, 26))	('upregulated', 'PosReg', (31, 42))	('HER2', 'Gene', (13, 17))	('HER2', 'Gene', '2064', (13, 17))	('knockdown', 'Var', (79, 88))	('RON', 'Gene', (100, 103))	('HER3', 'Gene', '2065', (22, 26))
382538	30093568	Additional studies have demonstrated activation of RTKs outside the immediate family of the targeted kinase, such as the induction of AXL expression in response to treatment with EGFR inhibitors.	('EGFR', 'Gene', (179, 183))	('activation', 'PosReg', (37, 47))	('AXL', 'Gene', '558', (134, 137))	('expression', 'MPA', (138, 148))	('inhibitors', 'Var', (184, 194))	('AXL', 'Gene', (134, 137))	('EGFR', 'Gene', '1956', (179, 183))
382545	30093568	Previous studies also associated P70S6K overexpression with increased risk of loco-regional recurrence in early breast cancer patients, and PF-4708671, a selective P70S6K inhibitor, has been utilized to reduce local relapse in breast cancer models and inhibit NSCLC tumorigenesis.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('breast cancer', 'Disease', (112, 125))	('patients', 'Species', '9606', (126, 134))	('tumor', 'Disease', (266, 271))	('NSCLC', 'Disease', 'MESH:D002289', (260, 265))	('inhibit', 'NegReg', (252, 259))	('loco-regional recurrence', 'CPA', (78, 102))	('reduce', 'NegReg', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('NSCLC', 'Disease', (260, 265))	('P70S6K', 'Gene', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('PF-4708671', 'Chemical', 'MESH:C552719', (140, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (260, 265))	('PF-4708671', 'Var', (140, 150))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('P70S6K', 'Gene', '6198', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('breast cancer', 'Disease', (227, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('P70S6K', 'Gene', (33, 39))	('overexpression', 'PosReg', (40, 54))	('P70S6K', 'Gene', '6198', (33, 39))	('local relapse', 'CPA', (210, 223))
382546	30093568	Thus, our observation that combined targeting of AXL and MERTK can synergistically inhibit these oncogenic signaling pathways suggests possible mechanisms for the synergistic anti-tumor activity described here.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('oncogenic signaling pathways', 'Pathway', (97, 125))	('targeting', 'Var', (36, 45))	('tumor', 'Disease', (180, 185))	('MERTK', 'Gene', (57, 62))	('AXL', 'Gene', '558', (49, 52))	('inhibit', 'NegReg', (83, 90))	('AXL', 'Gene', (49, 52))
382556	30093568	Indeed, inhibition of MERTK re-sensitized tumors to AXL inhibition mediated by R428 in preclinical models, providing strong rationale for clinical development of therapeutic strategies targeting both AXL and MERTK.	('inhibition', 'NegReg', (56, 66))	('AXL', 'Gene', '558', (200, 203))	('AXL', 'Gene', (52, 55))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('AXL', 'Gene', (200, 203))	('MERTK', 'Gene', (22, 27))	('inhibition', 'Var', (8, 18))	('AXL', 'Gene', '558', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
382673	24667581	2B) mRNA expression levels (P<0.05), while the BRB and PCA diets, but not the AC diet, decreased the total iNOS mRNA levels (P< 0.05) (Fig.	('AC', 'Chemical', 'MESH:D000872', (78, 80))	('BRB', 'Chemical', '-', (47, 50))	('iNOS', 'Gene', (107, 111))	('mRNA expression levels', 'MPA', (4, 26))	('iNOS', 'Gene', '24599', (107, 111))	('PCA', 'Var', (55, 58))	('PCA', 'Chemical', 'MESH:C009091', (55, 58))
382680	24667581	We presumed that PTX3 could be a new anti-inflammatory marker for esophageal tumors in rats because its expression was shown to be highly down-regulated in human ESCC cell lines and tissue through hypermethylation of the promoter region.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (156, 161))	('PTX3', 'Gene', (17, 21))	('SCC', 'Gene', (163, 166))	('hypermethylation', 'Var', (197, 213))	('rats', 'Species', '10116', (87, 91))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('esophageal tumor', 'Phenotype', 'HP:0100751', (66, 82))	('expression', 'MPA', (104, 114))	('down-regulated', 'NegReg', (138, 152))	('esophageal tumors', 'Disease', 'MESH:D004938', (66, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('SCC', 'Gene', '6317', (163, 166))	('esophageal tumors', 'Disease', (66, 83))	('esophageal tumors', 'Phenotype', 'HP:0100751', (66, 83))
382695	24667581	When compared to the NMBA control group, all three diets appeared to cause a delay in the formation of preneoplastic lesions in NMBA-treated esophagus as well as the progression of these lesions to papillomas.	('papilloma', 'Phenotype', 'HP:0012740', (198, 207))	('NMBA', 'Chemical', 'MESH:C014707', (21, 25))	('papillomas', 'Disease', 'MESH:D010212', (198, 208))	('papillomas', 'Disease', (198, 208))	('NMBA-treated', 'Var', (128, 140))	('NMBA', 'Chemical', 'MESH:C014707', (128, 132))	('papillomas', 'Phenotype', 'HP:0012740', (198, 208))	('delay', 'NegReg', (77, 82))
382714	24667581	In summary, results of the present study support the notion that while the AC in BRB are important for their chemopreventive activity, PCA, a major metabolite of BRB AC, is also effective in inhibiting tumorigenesis and inflammatory signaling.	('BRB', 'Chemical', '-', (81, 84))	('inhibiting', 'NegReg', (191, 201))	('PCA', 'Var', (135, 138))	('PCA', 'Chemical', 'MESH:C009091', (135, 138))	('tumor', 'Disease', (202, 207))	('BRB', 'Gene', (81, 84))	('inflammatory signaling', 'CPA', (220, 242))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('BRB', 'Chemical', '-', (162, 165))	('AC', 'Chemical', 'MESH:D000872', (166, 168))	('AC', 'Chemical', 'MESH:D000872', (75, 77))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
382723	28631378	Knockdown of RUNX2-I inhibits the cell-cell separation that is characteristic of initial activation of EMT.	('inhibits', 'NegReg', (21, 29))	('Knockdown', 'Var', (0, 9))	('EMT', 'Gene', (103, 106))	('cell-cell separation', 'CPA', (34, 54))	('EMT', 'Gene', '3702', (103, 106))	('RUNX2-I', 'Gene', (13, 20))
382724	28631378	Loss of RUNX2-I altered expression of EMT markers to a greater extent during activation than during subsequent cell invasion.	('expression', 'MPA', (24, 34))	('EMT', 'Gene', (38, 41))	('RUNX2-I', 'Gene', (8, 15))	('EMT', 'Gene', '3702', (38, 41))	('altered', 'Reg', (16, 23))	('Loss', 'Var', (0, 4))
382745	28631378	Inhibition of RUNX2 mRNA expression disrupts EMT at an early stage before loss of cell-cell adhesion.	('EMT', 'Gene', (45, 48))	('EMT', 'Gene', '3702', (45, 48))	('RUNX2', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('mRNA', 'MPA', (20, 24))	('disrupts', 'NegReg', (36, 44))
382777	28631378	Only anti-TGFbeta2 caused a significant effect on RUNX2 message (~40% decrease of RUNX2 mRNA, p < 0.001; anti-TGFbeta1, p=0.273; Noggin, p=0.837).	('anti-TGFbeta2', 'Var', (5, 18))	('RUNX2 message', 'MPA', (50, 63))	('RUNX2 mRNA', 'MPA', (82, 92))	('TGFbeta1', 'Gene', (110, 118))	('TGFbeta1', 'Gene', '100873157', (110, 118))	('decrease', 'NegReg', (70, 78))
382783	28631378	To confirm chicken AVC EMT is being disrupted after RUNX2 knock down, expression of smooth muscle alpha actin (alphaSMA), Collagen 1 (COL1) and Periostin (POSTN) messages were assessed by qPCR (Fig.	('POSTN', 'Gene', (155, 160))	('EMT', 'Gene', '3702', (23, 26))	('RUNX2', 'Gene', (52, 57))	('chicken', 'Species', '9031', (11, 18))	('POSTN', 'Gene', '395429', (155, 160))	('EMT', 'Gene', (23, 26))	('Periostin', 'Gene', (144, 153))	('Periostin', 'Gene', '395429', (144, 153))	('knock down', 'Var', (58, 68))
382789	28631378	Additionally, a significant decrease in endothelial VEGF receptors FLK-1(VEGFR2) (~70% decrease, p < 0.001) and FLT-1(VEGFR1) (~40% decrease, p < 0.001) was observed in transfected explants.	('FLT-1', 'Gene', (112, 117))	('FLK-1', 'Gene', '395323', (67, 72))	('transfected', 'Var', (169, 180))	('VEGFR1', 'Gene', (118, 124))	('FLK-1', 'Gene', (67, 72))	('decrease', 'NegReg', (28, 36))	('decrease', 'NegReg', (87, 95))	('VEGFR1', 'Gene', '374100', (118, 124))	('endothelial', 'Protein', (40, 51))	('VEGFR2', 'Gene', (73, 79))	('VEGFR2', 'Gene', '395323', (73, 79))	('FLT-1', 'Gene', '374100', (112, 117))
382792	28631378	Finally, FLK-1, but not FLT-1 (p=0.203), was affected (~27% decrease, p < 0.001) after RUNX2 knock down.	('decrease', 'NegReg', (60, 68))	('FLK-1', 'Gene', (9, 14))	('FLT-1', 'Gene', '374100', (24, 29))	('knock down', 'Var', (93, 103))	('RUNX2', 'Gene', (87, 92))	('FLT-1', 'Gene', (24, 29))	('FLK-1', 'Gene', '395323', (9, 14))
382799	28631378	SNAI2 knock down (~40% decrease, p < 0.001) in stage 16 transfected explants caused significant changes in ZEB2 (~30% decrease, p < 0.001), TWIST1 (~1.4-fold increase, p < 0.01) and FLK-1 (~1.5-fold increase, p < 0.001).	('decrease', 'NegReg', (23, 31))	('FLK-1', 'Gene', (182, 187))	('TWIST1', 'Gene', (140, 146))	('knock down', 'Var', (6, 16))	('TWIST1', 'Gene', '395491', (140, 146))	('SNAI2', 'Gene', (0, 5))	('SNAI2', 'Gene', '432368', (0, 5))	('FLK-1', 'Gene', '395323', (182, 187))	('changes', 'Reg', (96, 103))	('decrease', 'NegReg', (118, 126))	('ZEB2', 'Gene', '424306', (107, 111))	('increase', 'PosReg', (199, 207))	('increase', 'PosReg', (158, 166))	('ZEB2', 'Gene', (107, 111))
382820	28631378	Inhibition of TGFbeta3, TBRII, ADGRL2 (LPHN2,, and Olfactomedin-1 all show normal activation but a loss of cell invasion by explanted tissues in vitro.	('LPHN2', 'Gene', '424545', (39, 44))	('ADGRL2', 'Gene', (31, 37))	('Olfactomedin-1', 'Gene', '395535', (51, 65))	('Olfactomedin-1', 'Gene', (51, 65))	('cell invasion', 'CPA', (107, 120))	('TBRII', 'Gene', (24, 29))	('loss', 'NegReg', (99, 103))	('Inhibition', 'Var', (0, 10))	('LPHN2', 'Gene', (39, 44))	('TGFbeta3', 'Gene', (14, 22))
382824	28631378	The observation that RUNX2-I is significantly down-regulated when treated with anti-TGFbeta2, but not by anti-TGFbeta3, also supports that RUNX2-I expression is correlated with the activation step of EMT rather than the invasion step.	('down-regulated', 'NegReg', (46, 60))	('EMT', 'Gene', (200, 203))	('RUNX2-I', 'Gene', (139, 146))	('EMT', 'Gene', '3702', (200, 203))	('anti-TGFbeta2', 'Var', (79, 92))	('RUNX2-I', 'Gene', (21, 28))
382834	28631378	The finding RUNX2-I is induced by TGFbeta2 and therefore functions during EMT initiation led us to investigate changes of EMT markers after RUNX2-I knock down in cultured stage 14 (during EMT initiation) and stage 16 (EMT invasion) explants.	('RUNX2-I', 'Gene', (140, 147))	('EMT', 'Gene', (122, 125))	('EMT', 'Gene', '3702', (122, 125))	('knock down', 'Var', (148, 158))	('TGFbeta2', 'Gene', (34, 42))	('EMT', 'Gene', (74, 77))	('EMT', 'Gene', '3702', (74, 77))	('EMT', 'Gene', (218, 221))	('EMT', 'Gene', (188, 191))	('EMT', 'Gene', '3702', (218, 221))	('EMT', 'Gene', '3702', (188, 191))
382843	28631378	As expected, SNAI2 knockdown caused changes that were more correlated to EMT inhibition (ZEB1 and ZEB2 downregulation) in stage 14 explants (when activation is predominant) rather than in stage 16 explants (when invasion is predominant).	('changes', 'Reg', (36, 43))	('SNAI2', 'Gene', (13, 18))	('SNAI2', 'Gene', '432368', (13, 18))	('ZEB2', 'Gene', '424306', (98, 102))	('knockdown', 'Var', (19, 28))	('EMT', 'Gene', (73, 76))	('ZEB2', 'Gene', (98, 102))	('downregulation', 'NegReg', (103, 117))	('EMT', 'Gene', '3702', (73, 76))	('ZEB1', 'Gene', (89, 93))	('ZEB1', 'Gene', '396029', (89, 93))
382844	28631378	This is consistent with both the knockdown of RUNX2-I observed here and SNAI2's role in the activation step.	('knockdown', 'Var', (33, 42))	('SNAI2', 'Gene', (72, 77))	('SNAI2', 'Gene', '432368', (72, 77))	('RUNX2-I', 'Gene', (46, 53))
382846	28631378	Additionally, TWIST1 was downregulated after RUNX2-I inhibition in stage 14 explants but upregulated after both RUNX2-I and SNAI2 knockdown in stage 16 explants.	('inhibition', 'NegReg', (53, 63))	('upregulated', 'PosReg', (89, 100))	('TWIST1', 'Gene', (14, 20))	('knockdown', 'Var', (130, 139))	('SNAI2', 'Gene', (124, 129))	('downregulated', 'NegReg', (25, 38))	('TWIST1', 'Gene', '395491', (14, 20))	('SNAI2', 'Gene', '432368', (124, 129))
382851	28631378	FLK-1 downregulation continued in stage 16 explants after RUNX2 inhibition showing that RUNX2 is required for induction of this receptor during both activation and invasion steps of EMT.	('EMT', 'Gene', (182, 185))	('EMT', 'Gene', '3702', (182, 185))	('RUNX2', 'Gene', (58, 63))	('inhibition', 'Var', (64, 74))	('FLK-1', 'Gene', '395323', (0, 5))	('downregulation', 'NegReg', (6, 20))	('FLK-1', 'Gene', (0, 5))
382864	28631378	In summary, we find the 2-I isoform of RUNX2 to be specifically expressed in the developing heart and show that it has a role in the activation stage of endothelial EMT as loss of expression inhibits the cell separation characteristic of this stage.	('EMT', 'Gene', (165, 168))	('loss', 'Var', (172, 176))	('EMT', 'Gene', '3702', (165, 168))	('inhibits', 'NegReg', (191, 199))	('RUNX2', 'Gene', (39, 44))	('cell separation', 'CPA', (204, 219))
382866	28631378	Though it is not clear whether they are direct or indirect targets, loss of RUNX2-I inhibits the expression of the mesenchymal markers, POSTN and alpha-SMA.	('POSTN', 'Gene', '395429', (136, 141))	('RUNX2-I', 'Gene', (76, 83))	('POSTN', 'Gene', (136, 141))	('alpha-SMA', 'Protein', (146, 155))	('loss', 'Var', (68, 72))	('inhibits', 'NegReg', (84, 92))	('expression', 'MPA', (97, 107))
382901	27329034	We established the lentiviral system using short hairpin RNA to knockdown SALL4 in TE7 and EC109 cells.	('EC109', 'CellLine', 'CVCL:6898', (91, 96))	('SALL4', 'Gene', (74, 79))	('knockdown', 'Var', (64, 73))
382903	27329034	Xenograft tumor models showed that silencing of SALL4 decreased the ability to form tumors in vivo.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('silencing', 'Var', (35, 44))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('decreased', 'NegReg', (54, 63))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('SALL4', 'Gene', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
382928	27329034	Normal esophageal epithelium cell line Het-1a, human ESCC cell lines TE1, TE7, EC1, EC109, EC9706, KYSE70 and KYSE450 were preserved in our laboratory and maintained in RMPI 1640 (Hyclone, USA) supplemented with 10 % fetal bovine serum (FBS, Hyclone, USA), 100 units/mL of penicillin, and 100 mug/ml of streptomycin at 37  C, 5 % CO2 in a humidified incubator.	('Het-1a', 'CellLine', 'CVCL:3702', (39, 45))	('human', 'Species', '9606', (47, 52))	('streptomycin', 'Chemical', 'MESH:D013307', (303, 315))	('penicillin', 'Chemical', 'MESH:D010406', (273, 283))	('EC1', 'Gene', '4819', (79, 82))	('EC1', 'Gene', (79, 82))	('bovine', 'Species', '9913', (223, 229))	('EC109', 'CellLine', 'CVCL:6898', (84, 89))	('FBS', 'Disease', 'MESH:D005198', (237, 240))	('EC9706', 'Var', (91, 97))	('CO2', 'Chemical', '-', (330, 333))	('EC1', 'Gene', '4819', (84, 87))	('EC1', 'Gene', (84, 87))	('FBS', 'Disease', (237, 240))	('EC9706', 'CellLine', 'CVCL:E307', (91, 97))
382942	27329034	Thereafter, cells were incubated with AlexaFluor647 AnnexinV (Biolegend, USA) for 15 min at 4  C in the dark, and PI (Sigma, USA) was added.	('AlexaFluor647', 'Var', (38, 51))	('AlexaFluor647 AnnexinV', 'Chemical', '-', (38, 60))	('AnnexinV', 'Protein', (52, 60))
382975	27329034	The level of SALL4 mRNA expression was significantly reduced in shSALL4 cells compared to that in scramble cells (Fig.	('level', 'MPA', (4, 9))	('shSALL4', 'Var', (64, 71))	('shSALL4', 'Chemical', '-', (64, 71))	('reduced', 'NegReg', (53, 60))	('SALL4', 'Protein', (13, 18))
382980	27329034	The percentages of Annexin V-positive cells were much higher in shSALL4 groups than that in scrambled groups (Fig.	('higher', 'PosReg', (54, 60))	('shSALL4', 'Chemical', '-', (64, 71))	('Annexin V', 'Gene', '308', (19, 28))	('Annexin V', 'Gene', (19, 28))	('shSALL4 groups', 'Var', (64, 78))
382981	27329034	Cell cycle distribution analysis demonstrated that the number of cells was increased at G0/G1 phase and was decreased at S phase in shSALL4 cells, suggesting that knockdown of SALL4 induces typical cell cycle arrest at G0/G1 phase in ESCC cells (Fig.	('shSALL4', 'Chemical', '-', (132, 139))	('knockdown', 'Var', (163, 172))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (198, 215))	('cell cycle arrest', 'CPA', (198, 215))	('SALL4', 'Gene', (176, 181))
382982	27329034	Metastasis is a central problem during cancer therapeutics, as our result has indicated that the SALL4 expression was notably associated with lymph node metastasis, thereby we aimed to asses whether loss of SALL4 could affect tumor migration and invasion ability.	('lymph node metastasis', 'CPA', (142, 163))	('associated', 'Reg', (126, 136))	('cancer', 'Disease', (39, 45))	('loss', 'Var', (199, 203))	('Metastasis', 'Disease', (0, 10))	('Metastasis', 'Disease', 'MESH:D009362', (0, 10))	('expression', 'MPA', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('invasion ability', 'CPA', (246, 262))	('SALL4', 'Gene', (97, 102))	('affect', 'Reg', (219, 225))	('tumor', 'Disease', (226, 231))
382987	27329034	In addition, the mRNA expression level of the stemness marker Sox2, Oct4, Nanog were all down-regulated in shSALL4 group, which was confirmed by using RT-PCR (Fig.	('down-regulated', 'NegReg', (89, 103))	('Nanog', 'Gene', '79923', (74, 79))	('shSALL4', 'Var', (107, 114))	('shSALL4', 'Chemical', '-', (107, 114))	('mRNA expression level', 'MPA', (17, 38))	('Sox2', 'Gene', (62, 66))	('Oct4', 'Gene', '5460', (68, 72))	('Nanog', 'Gene', (74, 79))	('Sox2', 'Gene', '6657', (62, 66))	('Oct4', 'Gene', (68, 72))
382992	27329034	After 48 h, the CCK-8 assays showed that knockdown of SALL4 decreased cisplatin resistance and increased drug sensitivity in a dose-dependent manner (Fig.	('decreased', 'NegReg', (60, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('drug sensitivity', 'Phenotype', 'HP:0020174', (105, 121))	('drug sensitivity', 'MPA', (105, 121))	('SALL4', 'Gene', (54, 59))	('cisplatin resistance', 'MPA', (70, 90))	('increased', 'PosReg', (95, 104))	('knockdown', 'Var', (41, 50))
382993	27329034	To further investigate whether cisplatin could also induce apoptosis in TE7 cells, apoptosis assay was performed using Annexin-V by Flow Cytometry analysis, and the results showed that knockdown of SALL4 could significantly enhance the drug sensitivity to cisplatin treatment and induced cell apoptosis (Fig.	('drug sensitivity to cisplatin treatment', 'MPA', (236, 275))	('SALL4', 'Gene', (198, 203))	('induced', 'Reg', (280, 287))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('enhance', 'PosReg', (224, 231))	('cell apoptosis', 'CPA', (288, 302))	('drug sensitivity', 'Phenotype', 'HP:0020174', (236, 252))	('Annexin-V', 'Gene', (119, 128))	('knockdown', 'Var', (185, 194))	('Annexin-V', 'Gene', '11747', (119, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (256, 265))
382997	27329034	Conversely, the expression of mesenchymal cell marker (Vimentin) was decreased in shSALL4 group (Fig.	('Vimentin', 'Gene', (55, 63))	('Vimentin', 'Gene', '7431', (55, 63))	('decreased', 'NegReg', (69, 78))	('shSALL4', 'Var', (82, 89))	('shSALL4', 'Chemical', '-', (82, 89))	('expression', 'MPA', (16, 26))
383000	27329034	In summary, our results uncover that silencing of SALL4 promotes MET via Wnt/beta-catenin signaling pathway during ESCC tumorigenisis.	('ESCC', 'Disease', (115, 119))	('SALL4', 'Gene', (50, 55))	('silencing', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('MET via Wnt/beta-catenin signaling pathway', 'Pathway', (65, 107))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('promotes', 'PosReg', (56, 64))	('tumor', 'Disease', (120, 125))
383008	27329034	Taken together, these results suggest that knockdown of SALL4 reduces tumor burden and inhibits tumor formation in vivo.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('reduces', 'NegReg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (96, 101))	('inhibits', 'NegReg', (87, 95))	('knockdown', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('SALL4', 'Gene', (56, 61))
383022	27329034	Here, we found that knockdown of SALL4 in TE7 cells could increase the sensitivity to cisplatin in a dose-dependent manner.	('increase', 'PosReg', (58, 66))	('SALL4', 'Gene', (33, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('sensitivity to cisplatin', 'MPA', (71, 95))	('knockdown', 'Var', (20, 29))
383023	27329034	Inhibition of SALL4 may efficiently eradicate CSCs in ESCC, which benefit patients with chemorisistance and improve their prognosis.	('benefit', 'PosReg', (66, 73))	('eradicate', 'NegReg', (36, 45))	('CSCs', 'Disease', (46, 50))	('ESCC', 'Disease', (54, 58))	('patients', 'Species', '9606', (74, 82))	('prognosis', 'CPA', (122, 131))	('improve', 'PosReg', (108, 115))	('Inhibition', 'Var', (0, 10))	('SALL4', 'Gene', (14, 19))	('chemorisistance', 'CPA', (88, 103))
383035	27329034	In summary, our study shows that aberrantly activated SALL4 may contribute to esophageal tumorigenesis by promoting malignant proliferation and inhibiting cell apoptosis, regulating ESCC cell migration, invasion and cell cycle.	('regulating', 'Reg', (171, 181))	('aberrantly activated', 'Var', (33, 53))	('inhibiting', 'NegReg', (144, 154))	('cell cycle', 'CPA', (216, 226))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('contribute', 'Reg', (64, 74))	('malignant proliferation', 'CPA', (116, 139))	('SALL4', 'Gene', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('ESCC cell migration', 'CPA', (182, 201))	('invasion', 'CPA', (203, 211))	('promoting', 'PosReg', (106, 115))	('cell apoptosis', 'CPA', (155, 169))	('tumor', 'Disease', (89, 94))
383042	25834829	It was tested using an AKT shRNA knockdown of ESCC cell lines and the in vivo tumor suppressive effects of AKT knockdown were observed.	('knockdown', 'Var', (111, 120))	('AKT', 'Gene', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('AKT', 'Gene', '207', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('AKT', 'Gene', (23, 26))	('tumor', 'Disease', (78, 83))	('AKT', 'Gene', '207', (107, 110))
383051	25834829	Accumulation of genetic alterations leads to deregulation of the normal intracellular signaling network and interactions with the extracellular matrix environment, which are important factors associated with cancer development.	('cancer', 'Disease', (208, 214))	('genetic alterations', 'Var', (16, 35))	('deregulation', 'Reg', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('normal intracellular signaling network', 'MPA', (65, 103))	('interactions', 'Interaction', (108, 120))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
383063	25834829	We verified the practicality of this system by studying the changes in a molecular pathway utilizing an AKT (protein kinase B) shRNA knockdown approach in ESCC cell lines to knockdown AKT, which is frequently deregulated in cancers, to confirm its functionality in this in vivo animal model system.	('AKT', 'Gene', '207', (184, 187))	('AKT', 'Gene', (104, 107))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('knockdown', 'Var', (174, 183))	('AKT', 'Gene', (184, 187))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('cancers', 'Disease', (224, 231))	('AKT', 'Gene', '207', (104, 107))
383065	25834829	The 81-T, KYSE30, KYSE150, and SLMT-1 cells were labelled with luciferase and were cultured as previously described.	('KYSE30', 'Var', (10, 16))	('SLMT-1', 'CellLine', 'CVCL:E305', (31, 37))	('KYSE150', 'Var', (18, 25))
383082	25834829	The AKT knockdown oligonucleotide sequences were obtained from The RNAi Consortium/Public TRC portal (http://www.broadinstitute.org/rnai/public/), targeting sequence 984 (construct ID: TRCN0000288787) and sequence 1793 (TRCN0000199454) on AKT.	('AKT', 'Gene', (4, 7))	('oligonucleotide', 'Chemical', 'MESH:D009841', (18, 33))	('AKT', 'Gene', '207', (239, 242))	('AKT', 'Gene', '207', (4, 7))	('sequence 1793', 'Var', (205, 218))	('AKT', 'Gene', (239, 242))
383084	25834829	Western blot analysis was performed to verify efficient knockdown of AKT expression with AKT (Cat number 9272, Cell Signaling, Beverly, MA, USA) and p84 (Cat number GTX70220, Genetex, Irvine, CA, USA) was used as a loading control.	('AKT', 'Gene', (69, 72))	('p84', 'Gene', '9984', (149, 152))	('AKT', 'Gene', '207', (89, 92))	('p84', 'Gene', (149, 152))	('AKT', 'Gene', '207', (69, 72))	('AKT', 'Gene', (89, 92))	('knockdown', 'Var', (56, 65))
383093	25834829	The optimum cell concentrations for producing orthotopic tumors with consistent tumor sizes and survival times for mice, as well as being 100% tumorigenic for the tested ESCC cell lines, KYSE150 luc and SLMT-1 luc, are 1 x 105 cells and for KYSE30 luc and 81-T luc are 2 x 105 cells, each in a volume of 10 muL.	('KYSE150 luc', 'Var', (187, 198))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('orthotopic tumors', 'Disease', (46, 63))	('SLMT-1', 'CellLine', 'CVCL:E305', (203, 209))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (80, 85))	('orthotopic tumors', 'Disease', 'MESH:D009369', (46, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mice', 'Species', '10090', (115, 119))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
383098	25834829	Cross sections of the normal mouse esophagus (Figure 3(a)) and the esophagus after inoculation with KYSE150 showing luminal stricture due to the tumor growth (Figure 3(b)) are shown.	('KYSE150', 'Var', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('mouse', 'Species', '10090', (29, 34))
383102	25834829	Other common characteristics in ESCC, including squamous differentiation and focal keratinization are also observed in orthotopic tumors derived from KYSE150.	('ESCC', 'Disease', (32, 36))	('KYSE150', 'Var', (150, 157))	('focal keratinization', 'CPA', (77, 97))	('orthotopic tumors', 'Disease', (119, 136))	('squamous differentiation', 'Disease', (48, 72))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('orthotopic tumors', 'Disease', 'MESH:D009369', (119, 136))
383105	25834829	Demonstration of the usefulness of the current established ESCC orthotopic model for ESCC studies was shown by shRNA AKT knockdown of this well-known oncogenic signaling pathway for driving cancer.	('knockdown', 'Var', (121, 130))	('cancer', 'Disease', (190, 196))	('AKT', 'Gene', '207', (117, 120))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('AKT', 'Gene', (117, 120))	('oncogenic signaling pathway', 'Pathway', (150, 177))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
383109	25834829	Downregulation of well-studied AKT downstream invasion-associated markers including IL8 and VEGFA in the AKT knockdown cell lines was detected, as compared to the control (Figure 4(c)).	('AKT', 'Gene', '207', (105, 108))	('VEGFA', 'Gene', '7422', (92, 97))	('AKT', 'Gene', (31, 34))	('Downregulation', 'NegReg', (0, 14))	('IL8', 'Gene', (84, 87))	('IL8', 'Gene', '3576', (84, 87))	('VEGFA', 'Gene', (92, 97))	('AKT', 'Gene', (105, 108))	('knockdown', 'Var', (109, 118))	('AKT', 'Gene', '207', (31, 34))
383129	25834829	Notably, our previous studies indicated KYSE150 luc requires 1 x 106 cells for subcutaneous inoculation to obtain 100% tumorigenicity in nude mice.	('tumor', 'Disease', (119, 124))	('nude mice', 'Species', '10090', (137, 146))	('KYSE150', 'Var', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
383142	25834829	The usefulness of this current esophageal orthotopic model as a platform for molecular cancer studies was further demonstrated by silencing of the AKT gene, which is known to play a critical role in ESCC tumorigenesis by regulating invasion, angiogenesis, and metastasis.	('cancer', 'Disease', (87, 93))	('angiogenesis', 'CPA', (242, 254))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('regulating', 'PosReg', (221, 231))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('invasion', 'CPA', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', (204, 209))	('AKT', 'Gene', '207', (147, 150))	('metastasis', 'CPA', (260, 270))	('ESCC', 'Disease', (199, 203))	('silencing', 'Var', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('AKT', 'Gene', (147, 150))
383143	25834829	The in vivo orthotopic tumor growth, as monitored by bioluminescence, showed a statistically significant tumor growth inhibition after AKT knockdown.	('AKT', 'Gene', '207', (135, 138))	('knockdown', 'Var', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('AKT', 'Gene', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (105, 110))
383144	25834829	An in vitro inhibitory effect upon real-time invasion assay was also observed for AKT knockdown.	('inhibitory', 'NegReg', (12, 22))	('AKT', 'Gene', '207', (82, 85))	('knockdown', 'Var', (86, 95))	('AKT', 'Gene', (82, 85))
383147	25834829	These mutations may result in deregulation of signaling networks intracellularly and pathway activation disrupting the normal cell-cell and cell-matrix interaction in the tumor microenvironment that leads to ESCC tumorigenesis and metastasis.	('tumor', 'Disease', (213, 218))	('activation', 'PosReg', (93, 103))	('ESCC', 'Disease', (208, 212))	('result', 'Reg', (20, 26))	('signaling networks', 'Pathway', (46, 64))	('leads to', 'Reg', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('deregulation', 'MPA', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('disrupting', 'NegReg', (104, 114))	('mutations', 'Var', (6, 15))
383164	23525077	These studies have identified frequent mutations in TP53 and CDKN2A.	('TP53', 'Gene', '7157', (52, 56))	('CDKN2A', 'Gene', (61, 67))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (39, 48))	('CDKN2A', 'Gene', '1029', (61, 67))
383165	23525077	Beyond these two genes, small focused studies have noted sporadic mutations in APC, BRAF, CDH1, CTNNB1, EGFR, KRAS, PIK3CA, PTEN, and SMAD4.	('mutations', 'Var', (66, 75))	('PIK3CA', 'Gene', (116, 122))	('PTEN', 'Gene', (124, 128))	('APC', 'Disease', 'MESH:D011125', (79, 82))	('SMAD4', 'Gene', (134, 139))	('APC', 'Disease', (79, 82))	('CTNNB1', 'Gene', '1499', (96, 102))	('EGFR', 'Gene', (104, 108))	('PTEN', 'Gene', '5728', (124, 128))	('SMAD4', 'Gene', '4089', (134, 139))	('BRAF', 'Gene', '673', (84, 88))	('KRAS', 'Gene', '3845', (110, 114))	('PIK3CA', 'Gene', '5290', (116, 122))	('BRAF', 'Gene', (84, 88))	('CTNNB1', 'Gene', (96, 102))	('CDH1', 'Gene', '999', (90, 94))	('EGFR', 'Gene', '1956', (104, 108))	('KRAS', 'Gene', (110, 114))	('CDH1', 'Gene', (90, 94))
383170	23525077	These include ELMO1 and DOCK2, upstream modulators of the RAC1 GTPase, and characterize the presence of mutations impacting signal transduction pathways.	('impacting', 'Reg', (114, 123))	('mutations', 'Var', (104, 113))	('DOCK2', 'Gene', '1794', (24, 29))	('GTP', 'Chemical', 'MESH:D006160', (63, 66))	('signal transduction pathways', 'Pathway', (124, 152))	('DOCK2', 'Gene', (24, 29))	('RAC1', 'Gene', (58, 62))
383175	23525077	We identified a median of 26,161 genome-wide mutations per tumor (range 18,881-66,225) corresponding to a median mutation frequency of 9.9/Mb (range 7.1-25.2/Mb) relative to a haploid genome (Supplementary Table 3).	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))
383176	23525077	This step-wise decrease in mutation frequency was consistently seen in other cancers.	('decrease', 'NegReg', (15, 23))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Disease', (77, 84))	('mutation', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
383180	23525077	A total of 2,952 candidate rearrangements were identified with a median of 172 per tumor (range 77-402) (Supplementary Table 5).	('tumor', 'Disease', (83, 88))	('rearrangements', 'Var', (27, 41))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))
383183	23525077	To comprehensively characterize the mutation spectra, we measured the frequencies of base mutations at different trinucleotide contexts and observed a preponderance of C>T transitions (39.2/Mb) as seen in most epithelial cancers.	('trinucleotide', 'Chemical', '-', (113, 126))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('epithelial cancers', 'Disease', 'MESH:D000077216', (210, 228))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('C>T transitions', 'Var', (168, 183))	('epithelial cancers', 'Disease', (210, 228))
383187	23525077	The high frequency of AA transversions appears to be unique to EAC as equivalent events have not been identified in other cancer types.	('EAC', 'Disease', (63, 66))	('AA transversions', 'Var', (22, 38))	('AA transversion', 'Phenotype', 'HP:0011540', (22, 37))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('EAC', 'Phenotype', 'HP:0011459', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
383188	23525077	Within individual tumors, these AA transversions accounted for 5-48% of mutations (Supplementary Table 8), and the event number was correlated with overall mutation frequency (R2=0.92) (Supplementary Fig.	('mutations', 'Var', (72, 81))	('AA transversion', 'Phenotype', 'HP:0011540', (32, 47))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
383191	23525077	While A>C transversions remained notable at the AA sites, the percentage of all mutations consisting of these transversions was significantly lower in exons (16%) than seen across the entire genome (AAG, P=0.001; AAT, P=0.0006; AAC, P=0.0007; AAA, P=0.0006; two-tailed Student's t-test) (Fig.	('AAT', 'Gene', (213, 216))	('mutations', 'Var', (80, 89))	('AAG', 'Gene', (199, 202))	('AAC', 'Gene', (228, 231))	('AAC', 'Gene', '10249', (228, 231))	('lower', 'NegReg', (142, 147))	('AAG', 'Gene', '4350', (199, 202))	('AAT', 'Gene', '5265', (213, 216))	('exons', 'MPA', (151, 156))
383192	23525077	In contrast, the attenuation of C>T transitions at CG dinucleotides in coding regions (39.2/Mb vs. 25.4/Mb) was smaller than that seen for AA transversions.	('AA transversion', 'Phenotype', 'HP:0011540', (139, 154))	('CG dinucleotides', 'Chemical', 'MESH:C015772', (51, 67))	('C>T', 'Var', (32, 35))	('CG dinucleotides', 'Var', (51, 67))	('dinucleotides', 'Var', (54, 67))
383202	23525077	These four cases with the highest mutation rates were found to be MSI-positive with the highest mutation frequency tumor having mutations in two mismatch repair genes MSH6 and MSH3 (Supplementary Table 15).	('MSH3', 'Gene', (176, 180))	('MSH3', 'Gene', '4437', (176, 180))	('MSH6', 'Gene', '2956', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (128, 137))	('tumor', 'Disease', (115, 120))	('MSH6', 'Gene', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
383207	23525077	Among these, 199 genes were mutated in 5% or more of the tumors, including 33 genes mutated in over 10% of cases.	('mutated', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
383211	23525077	Because aberrant RAC1 activation has been implicated in malignant transformation of other cancer types, mainly by enhancing cellular motility, recurrent mutations in these genes may be functionally important.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('activation', 'PosReg', (22, 32))	('RAC1', 'Gene', (17, 21))	('aberrant', 'Var', (8, 16))	('cellular motility', 'CPA', (124, 141))	('enhancing', 'PosReg', (114, 123))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
383212	23525077	While no RAC1 or RAC2 mutations were identified, ELMO1 or DOCK2 are mutated in 25 (17%) EAC samples with two samples having mutations in both factors and two samples have two independent mutations in DOCK2 (Fig.	('EAC', 'Phenotype', 'HP:0011459', (88, 91))	('ELMO1', 'Gene', (49, 54))	('RAC2', 'Gene', (17, 21))	('DOCK2', 'Gene', (200, 205))	('DOCK2', 'Gene', '1794', (58, 63))	('EAC', 'Disease', (88, 91))	('DOCK2', 'Gene', '1794', (200, 205))	('mutated', 'Var', (68, 75))	('DOCK2', 'Gene', (58, 63))	('RAC2', 'Gene', '5880', (17, 21))
383213	23525077	Notably, a single amino acid, p.K312 of ELMO1, is mutated in three tumors, which suggests a gain of function phenotype.	('gain of function', 'PosReg', (92, 108))	('p.K312', 'Var', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('ELMO1', 'Gene', (40, 45))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
383217	23525077	Mutations were also present in other RAC1 GEFs (TRIO, TIAM1, VAV2, and ECT2) (Supplementary Fig.	('ECT2', 'Gene', (71, 75))	('VAV2', 'Gene', '7410', (61, 65))	('GEF', 'Gene', (42, 45))	('TIAM1', 'Gene', (54, 59))	('TIAM1', 'Gene', '7074', (54, 59))	('RAC1', 'Gene', (37, 41))	('TRIO', 'Gene', (48, 52))	('GEF', 'Gene', '9181', (42, 45))	('Mutations', 'Var', (0, 9))	('TRIO', 'Gene', '7204', (48, 52))	('VAV2', 'Gene', (61, 65))	('ECT2', 'Gene', '1894', (71, 75))
383218	23525077	Furthermore, we previously observed focal copy-number gain of the 11q13 locus containing the serine/threonine kinase, PAK1, a principal downstream effector of RAC1 that has been shown to be oncogenic in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('PAK1', 'Gene', (118, 122))	('copy-number', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Disease', (203, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('gain', 'PosReg', (54, 58))	('PAK1', 'Gene', '5058', (118, 122))
383219	23525077	To examine the significance of ELMO1 mutations, wild-type and mutant ELMO1 constructs were generated and introduced into NIH/3T3 cells.	('NIH/3T3', 'CellLine', 'CVCL:0594', (121, 128))	('mutant', 'Var', (62, 68))	('ELMO1', 'Gene', (69, 74))
383220	23525077	Based on studies in glioblastoma demonstrating correlative increase in cellular invasion with overexpression of wild-type ELMO1, we hypothesized that ELMO1 mutations would enhance cell invasion.	('cellular invasion', 'CPA', (71, 88))	('enhance', 'PosReg', (172, 179))	('mutations', 'Var', (156, 165))	('glioblastoma', 'Disease', (20, 32))	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('cell invasion', 'CPA', (180, 193))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('ELMO1', 'Gene', (150, 155))	('increase', 'PosReg', (59, 67))
383221	23525077	ELMO1 mutations (p.F59L, p.K312E, p.K312T, p.K349R, p.T421N) further resulted in a significant increase (2 to 7-fold) in invasion compared to wild-type ELMO1 (P-values in figure).	('p.K349R', 'Var', (43, 50))	('p.F59L', 'Mutation', 'rs1240982780', (17, 23))	('p.K312T', 'Mutation', 'p.K312T', (34, 41))	('p.T421N', 'Mutation', 'p.T421N', (52, 59))	('p.K312E', 'Mutation', 'rs767694297', (25, 32))	('increase', 'PosReg', (95, 103))	('p.F59L', 'Var', (17, 23))	('p.T421N', 'Var', (52, 59))	('p.K349R', 'Mutation', 'p.K349R', (43, 50))	('to 7', 'Species', '1214577', (107, 111))	('p.K312E', 'Var', (25, 32))	('ELMO1', 'Gene', (0, 5))	('invasion', 'CPA', (121, 129))	('p.K312T', 'Var', (34, 41))
383222	23525077	These results suggest that ELMO1 mutations can increase invasiveness and potentially contribute to tumorigenesis in EAC.	('tumor', 'Disease', (99, 104))	('ELMO1', 'Gene', (27, 32))	('invasiveness', 'CPA', (56, 68))	('EAC', 'Phenotype', 'HP:0011459', (116, 119))	('mutations', 'Var', (33, 42))	('contribute', 'Reg', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('increase', 'PosReg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('EAC', 'Disease', (116, 119))
383229	23525077	Mutations were also found in other chromatin modifying enzymes: PBRM1 and JARID2.	('JARID2', 'Gene', '3720', (74, 80))	('PBRM1', 'Gene', (64, 69))	('PBRM1', 'Gene', '55193', (64, 69))	('Mutations', 'Var', (0, 9))	('JARID2', 'Gene', (74, 80))
383231	23525077	Spartin, the gene product of SPG20, was reportedly mutated in Troyer syndrome, a genetic disorder characterized by progressive muscle stiffness and limb paralysis.	('muscle stiffness', 'Phenotype', 'HP:0003552', (127, 143))	('paralysis', 'Phenotype', 'HP:0003470', (153, 162))	('SPG20', 'Gene', (29, 34))	('limb paralysis', 'Disease', 'MESH:D010243', (148, 162))	('muscle stiffness', 'Disease', (127, 143))	('Troyer syndrome', 'Disease', (62, 77))	('Troyer syndrome', 'Disease', 'MESH:C536858', (62, 77))	('mutated', 'Var', (51, 58))	('SPG20', 'Gene', '23111', (29, 34))	('a genetic disorder', 'Disease', 'MESH:D030342', (79, 97))	('a genetic disorder', 'Disease', (79, 97))	('muscle stiffness', 'Disease', 'None', (127, 143))	('limb paralysis', 'Disease', (148, 162))	('Spartin', 'Gene', '23111', (0, 7))	('Spartin', 'Gene', (0, 7))
383233	23525077	More recently, SPG20 hypermethylation has been linked to colon cancer progression.	('hypermethylation', 'Var', (21, 37))	('SPG20', 'Gene', (15, 20))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('SPG20', 'Gene', '23111', (15, 20))	('colon cancer', 'Disease', (57, 69))	('linked', 'Reg', (47, 53))
383234	23525077	TLR4 was mutated in 6% of EACs.	('EAC', 'Phenotype', 'HP:0011459', (26, 29))	('mutated', 'Var', (9, 16))	('TLR4', 'Gene', '7099', (0, 4))	('TLR4', 'Gene', (0, 4))
383235	23525077	Germline polymorphisms in TLR4 correlate with risk of in Helicobacter pylori-mediated gastric carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (86, 103))	('TLR4', 'Gene', (26, 30))	('gastric carcinoma', 'Disease', 'MESH:D013274', (86, 103))	('Germline', 'Var', (0, 8))	('TLR4', 'Gene', '7099', (26, 30))	('Helicobacter pylori', 'Species', '210', (57, 76))	('gastric carcinoma', 'Disease', (86, 103))	('risk', 'Reg', (46, 50))
383238	23525077	Notably, the mutations in TLR4 fall between amino acids p.D379 and p.F487, a region critical for MD-2 interaction.	('p.F487', 'Var', (67, 73))	('MD-2', 'Gene', (97, 101))	('TLR4', 'Gene', '7099', (26, 30))	('MD-2', 'Gene', '23643', (97, 101))	('fall', 'Phenotype', 'HP:0002527', (31, 35))	('mutations', 'Var', (13, 22))	('TLR4', 'Gene', (26, 30))	('p.D379', 'Var', (56, 62))	('interaction', 'Interaction', (102, 113))
383239	23525077	One mutation impacts p.E439, a site essential for hydrogen bonding of TLR4 to MD-2 (Supplementary Fig.	('hydrogen', 'Chemical', 'MESH:D006859', (50, 58))	('p.E439', 'Var', (21, 27))	('TLR4', 'Gene', '7099', (70, 74))	('TLR4', 'Gene', (70, 74))	('impacts', 'Reg', (13, 20))	('MD-2', 'Gene', (78, 82))	('MD-2', 'Gene', '23643', (78, 82))
383240	23525077	These mutations suggest disruption of the TLR4/MD-2 complex as a potential driver of tumor progression in EAC.	('tumor', 'Disease', (85, 90))	('TLR4', 'Gene', (42, 46))	('EAC', 'Phenotype', 'HP:0011459', (106, 109))	('disruption', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('EAC', 'Disease', (106, 109))	('MD-2', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('TLR4', 'Gene', '7099', (42, 46))	('mutations', 'Var', (6, 15))	('MD-2', 'Gene', '23643', (47, 51))
383243	23525077	The lysine acetyltransferase MYST3, recurrently targeted for translocation in leukemia, was also mutated in seven specimens (5%) (Supplementary Fig.	('leukemia', 'Disease', (78, 86))	('leukemia', 'Phenotype', 'HP:0001909', (78, 86))	('leukemia', 'Disease', 'MESH:D007938', (78, 86))	('MYST3', 'Gene', '7994', (29, 34))	('mutated', 'Var', (97, 104))	('MYST3', 'Gene', (29, 34))
383245	23525077	We identified mutations in EAC that had been seen two or more times across all cancers in COSMIC database; we found 22 such genes (Supplementary Table 17).	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('EAC', 'Gene', (27, 30))	('EAC', 'Phenotype', 'HP:0011459', (27, 30))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('mutations', 'Var', (14, 23))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
383247	23525077	These results indicate that genes not reaching statistical significance in the cohort may harbor mutations of biologic relevance in individual tumors.	('mutations', 'Var', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
383248	23525077	Mutations in actionable genes were discovered in 23% of tumors with PIK3CA being the most frequently mutated (Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PIK3CA', 'Gene', (68, 74))	('tumors', 'Disease', (56, 62))	('PIK3CA', 'Gene', '5290', (68, 74))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('discovered', 'Reg', (35, 45))
383249	23525077	When also evaluating amplification status of genes, 48% of tumors in this cohort have a genomic alteration in a gene with a targeted agent.	('genomic alteration', 'Var', (88, 106))	('gene', 'Gene', (112, 116))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
383251	23525077	We also studied how cancer-associated pathways were disrupted by mutation in EAC.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('disrupted', 'Reg', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('EAC', 'Gene', (77, 80))	('mutation', 'Var', (65, 73))	('cancer', 'Disease', (20, 26))
383252	23525077	Cell-cycle control was altered by point mutation in 14% of EACs with most of the mutations occurring in CDKN2A (Fig.	('CDKN2A', 'Gene', '1029', (104, 110))	('point mutation', 'Var', (34, 48))	('occurring', 'Reg', (91, 100))	('EAC', 'Phenotype', 'HP:0011459', (59, 62))	('altered', 'Reg', (23, 30))	('mutations', 'Var', (81, 90))	('CDKN2A', 'Gene', (104, 110))	('Cell-cycle control', 'CPA', (0, 18))
383253	23525077	This process was also frequently affected by amplifications at the loci of CCND1, CCNE1, and CDK6.	('CCNE1', 'Gene', '898', (82, 87))	('CCNE1', 'Gene', (82, 87))	('affected', 'Reg', (33, 41))	('CCND1', 'Gene', (75, 80))	('amplifications', 'Var', (45, 59))	('CDK6', 'Gene', (93, 97))	('CCND1', 'Gene', '595', (75, 80))	('CDK6', 'Gene', '1021', (93, 97))
383254	23525077	Although activation of beta-catenin signaling is ubiquitous in CRC, mutations in this pathway were found in only 9% of EACs with two tumors having APC mutations that co-occur with either CDH1 or AXIN1 (Fig.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('EAC', 'Phenotype', 'HP:0011459', (119, 122))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('APC', 'Disease', 'MESH:D011125', (147, 150))	('CDH1', 'Gene', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('CDH1', 'Gene', '999', (187, 191))	('beta-catenin', 'Gene', (23, 35))	('APC', 'Disease', (147, 150))	('beta-catenin', 'Gene', '1499', (23, 35))	('mutations', 'Var', (68, 77))	('AXIN1', 'Gene', '8312', (195, 200))	('mutations', 'Var', (151, 160))	('AXIN1', 'Gene', (195, 200))
383255	23525077	Moreover, a potential AXIN1 fusion was identified by WGS in sample ESO-1060 spanning exon 5 of AXIN1 and exon 2 of GALNT7, which might alter normal gene function (Table 1).	('GALNT7', 'Gene', (115, 121))	('gene function', 'MPA', (148, 161))	('AXIN1', 'Gene', '8312', (22, 27))	('WGS', 'Var', (53, 56))	('AXIN1', 'Gene', '8312', (95, 100))	('AXIN1', 'Gene', (22, 27))	('alter', 'Reg', (135, 140))	('GALNT7', 'Gene', '51809', (115, 121))	('AXIN1', 'Gene', (95, 100))
383256	23525077	As in other cancer types, the TGFbeta/SMAD signaling pathway was mutated in 18% of EAC tumors.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TGFbeta', 'Gene', (30, 37))	('cancer', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('SMAD', 'Gene', (38, 42))	('TGFbeta', 'Gene', '7040', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', (87, 93))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))	('SMAD', 'Gene', '4089;4089', (38, 42))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('mutated', 'Var', (65, 72))
383257	23525077	The most recurrently altered gene in this pathway is SMAD4, which mutated in 10 samples and also subject to frequent copy-number loss (Fig.	('mutated', 'Var', (66, 73))	('SMAD4', 'Gene', (53, 58))	('copy-number loss', 'Var', (117, 133))	('SMAD4', 'Gene', '4089', (53, 58))	('altered', 'Reg', (21, 28))
383259	23525077	Unlike other epithelial tumor types, where such MAPK-pathway mutations are common, no BRAF mutations were observed, and NF1 and KRAS mutations were seen in only three (2%) and five tumors (3%), respectively.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('NF1', 'Gene', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('KRAS', 'Gene', '3845', (128, 132))	('mutations', 'Var', (133, 142))	('BRAF', 'Gene', '673', (86, 90))	('BRAF', 'Gene', (86, 90))	('KRAS', 'Gene', (128, 132))	('tumor', 'Disease', (24, 29))	('tumors', 'Disease', (181, 187))	('mutations', 'Var', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('epithelial tumor', 'Phenotype', 'HP:0031492', (13, 29))	('mutations', 'Var', (91, 100))	('NF1', 'Gene', '4763', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (181, 186))
383260	23525077	Three of the five KRAS mutations alter p.G12; however one EAC harbored a KRAS c.351A>C (p.K117N) event, a mutation caused by an AA transversion and previously observed in CRC.	('KRAS', 'Gene', (73, 77))	('AA transversion', 'Phenotype', 'HP:0011540', (128, 143))	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (73, 77))	('KRAS', 'Gene', '3845', (18, 22))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('p.G12', 'Var', (39, 44))	('mutations', 'Var', (23, 32))	('c.351A>C', 'Var', (78, 86))	('c.351A>C', 'Mutation', 'rs770248150', (78, 86))	('p.K117N', 'Mutation', 'rs770248150', (88, 95))
383261	23525077	PIK3CA was mutated in seven tumors, followed by PIK3R1 and PTEN in five and four tumors, respectively (Fig.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('PIK3R1', 'Gene', '5295', (48, 54))	('PIK3R1', 'Gene', (48, 54))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('PTEN', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('mutated', 'Var', (11, 18))	('PTEN', 'Gene', '5728', (59, 63))
383262	23525077	We explored mutations in the ErbB family of RTKs, which are important therapeutic targets in many cancer types.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ErbB', 'Gene', '1956', (29, 33))	('ErbB', 'Gene', (29, 33))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))
383263	23525077	Although three samples harbored EGFR mutations, these alterations were not previously annotated in other tumors.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('EGFR', 'Gene', '1956', (32, 36))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('EGFR', 'Gene', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
383264	23525077	Moreover, two of these alterations, p.S447Y and p.S1153I, were predicted by Polyphen-2 score to not be deleterious to normal function, and thus of questionable biologic significance.	('p.S447Y', 'Var', (36, 43))	('p.S1153I', 'Mutation', 'p.S1153I', (48, 56))	('p.S1153I', 'Var', (48, 56))	('p.S447Y', 'Mutation', 'rs1240947148', (36, 43))
383265	23525077	By contrast, ERBB2 mutations were present in five tumors.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('ERBB2', 'Gene', '2064', (13, 18))	('mutations', 'Var', (19, 28))	('ERBB2', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
383266	23525077	Three mutations were in the kinase domain including two c.351A>C (p.D769Y) mutations and one c.2327G>T (p.G776V).	('c.2327G>T', 'Var', (93, 102))	('c.351A>C', 'Var', (56, 64))	('p.G776V', 'Mutation', 'rs144434331', (104, 111))	('c.351A>C', 'Mutation', 'rs770248150', (56, 64))	('p.D769Y', 'Mutation', 'rs121913468', (66, 73))	('c.2327G>T', 'Mutation', 'rs144434331', (93, 102))
383268	23525077	Additionally, we demonstrate context specificity showing that A>C transversions are most common when the mutated adenine follows a 5' flanking adenine (AA) and especially at AAG trinucleotides.	('A>C transversions', 'Var', (62, 79))	('trinucleotides', 'Chemical', '-', (178, 192))	('AAG', 'Gene', (174, 177))	('flanking adenine', 'Chemical', '-', (134, 150))	('AAG', 'Gene', '4350', (174, 177))	('mutated', 'Var', (105, 112))	('transversions', 'Var', (66, 79))	('adenine', 'Chemical', 'MESH:D000225', (113, 120))	('common', 'Reg', (89, 95))	('adenine', 'Chemical', 'MESH:D000225', (143, 150))
383269	23525077	This mutational spectrum appears to be unique to EAC suggesting that these mutations are attributable to gastroesophageal reflux, where the gastric and duodenal contents travel into the lower esophagus creating an environment of inflammation.	('inflammation', 'Disease', 'MESH:D007249', (229, 241))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (105, 128))	('inflammation', 'Disease', (229, 241))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('mutations', 'Var', (75, 84))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (105, 128))	('gastroesophageal reflux', 'Disease', (105, 128))
383274	23525077	Statistical analysis also enabled a comprehensive assessment of mutated genes in EAC and identified mutations in cancer-related genes such as TP53, CDKN2A, SMAD4, and PIK3CA.	('EAC', 'Phenotype', 'HP:0011459', (81, 84))	('mutations', 'Var', (100, 109))	('CDKN2A', 'Gene', '1029', (148, 154))	('PIK3CA', 'Gene', '5290', (167, 173))	('SMAD4', 'Gene', (156, 161))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('EAC', 'Gene', (81, 84))	('PIK3CA', 'Gene', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('SMAD4', 'Gene', '4089', (156, 161))	('CDKN2A', 'Gene', (148, 154))
383275	23525077	It was notable that most well-annotated cancer genes were not affected by AA transversions.	('transversions', 'Var', (77, 90))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('AA transversion', 'Phenotype', 'HP:0011540', (74, 89))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
383276	23525077	In many cases, it is impossible to generate hotspot mutations such as KRAS p.G12 or PIK3CA p.E545 with an AA transversion.	('PIK3CA', 'Gene', '5290', (84, 90))	('KRAS', 'Gene', (70, 74))	('p.E545', 'Var', (91, 97))	('KRAS', 'Gene', '3845', (70, 74))	('PIK3CA', 'Gene', (84, 90))	('AA transversion', 'Phenotype', 'HP:0011540', (106, 121))
383278	23525077	Despite these caveats, it is likely that mutations caused by AA transversions do impact genes relevant for these tumors.	('mutations', 'Var', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('impact', 'Reg', (81, 87))	('AA transversion', 'Phenotype', 'HP:0011540', (61, 76))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('genes', 'MPA', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
383279	23525077	For example, a known transforming mutation in KRAS (c.351A>C; p.K117N) is created by an AA transversion.	('c.351A>C; p.K117N', 'Var', (52, 69))	('c.351A>C', 'Mutation', 'rs770248150', (52, 60))	('KRAS', 'Gene', (46, 50))	('AA transversion', 'Phenotype', 'HP:0011540', (88, 103))	('KRAS', 'Gene', '3845', (46, 50))	('p.K117N', 'Mutation', 'rs770248150', (62, 69))
383281	23525077	The data presented here verify the presence of frequent mutations in the PI3K cascade, but argue against wide-reaching mutations in these pathways, thus drawing contrasts between EAC and CRC, where beta-catenin activation and missense mutations of KRAS and BRAF are highly prevalent.	('KRAS', 'Gene', (248, 252))	('mutations', 'Var', (56, 65))	('missense mutations', 'Var', (226, 244))	('KRAS', 'Gene', '3845', (248, 252))	('activation', 'PosReg', (211, 221))	('EAC', 'Phenotype', 'HP:0011459', (179, 182))	('PI3K cascade', 'Pathway', (73, 85))	('beta-catenin', 'Gene', (198, 210))	('BRAF', 'Gene', (257, 261))	('BRAF', 'Gene', '673', (257, 261))	('beta-catenin', 'Gene', '1499', (198, 210))
383282	23525077	For the first time, we detected EAC mutations in regulators of invasion and motility including significantly recurrent mutations in DOCK2 and ELMO1.	('EAC', 'Phenotype', 'HP:0011459', (32, 35))	('ELMO1', 'Gene', (142, 147))	('DOCK2', 'Gene', (132, 137))	('mutations', 'Var', (36, 45))	('mutations', 'Var', (119, 128))	('DOCK2', 'Gene', '1794', (132, 137))
383283	23525077	These mutations may increase tumor fitness through alteration of cytoskeletal structure, increased invasive properties, or mitogenesis.	('tumor fitness', 'Disease', 'MESH:D012640', (29, 42))	('mitogenesis', 'CPA', (123, 134))	('invasive properties', 'CPA', (99, 118))	('alteration', 'Reg', (51, 61))	('tumor fitness', 'Disease', (29, 42))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cytoskeletal structure', 'CPA', (65, 87))	('increased', 'PosReg', (89, 98))	('mutations', 'Var', (6, 15))	('increase', 'PosReg', (20, 28))
383284	23525077	We demonstrate that ELMO1 mutations augment cellular invasiveness; thus, suggesting one mechanism by which these events contribute to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mutations', 'Var', (26, 35))	('cellular invasiveness', 'CPA', (44, 65))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('augment', 'PosReg', (36, 43))	('ELMO1', 'Gene', (20, 25))	('tumor', 'Disease', (134, 139))
383285	23525077	Given that EAC is a highly-invasive tumor prone to early metastasis, alterations in the RAC1 pathway may contribute to this phenotype.	('EAC', 'Disease', (11, 14))	('alterations', 'Var', (69, 80))	('contribute', 'Reg', (105, 115))	('EAC', 'Phenotype', 'HP:0011459', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('RAC1 pathway', 'Pathway', (88, 100))	('tumor', 'Disease', (36, 41))
383287	23525077	Currently, ERBB2 mutation assessment is not performed for EAC, despite ERBB2 being altered by both co-occurring amplification and mutation in 3% of samples.	('ERBB2', 'Gene', '2064', (71, 76))	('ERBB2', 'Gene', (71, 76))	('mutation', 'Var', (130, 138))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('altered', 'Reg', (83, 90))	('ERBB2', 'Gene', (11, 16))	('ERBB2', 'Gene', '2064', (11, 16))
383288	23525077	These data point to a potential role of mutation as an additional biomarker to guide use of ERBB2 (HER2)-targeting agents.	('mutation', 'Var', (40, 48))	('ERBB2', 'Gene', '2064', (92, 97))	('ERBB2', 'Gene', (92, 97))	('HER2', 'Gene', (99, 103))	('HER2', 'Gene', '2064', (99, 103))
383303	23525077	MuTect identifies candidate somatic mutations by Bayesian statistical analysis of bases and their qualities in the tumor and normal BAMs at a given genomic locus.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
383305	23525077	Small somatic insertions and deletions were detected using the Indelocator algorithm after local realignment of tumor and normal sequences.	('tumor', 'Disease', (112, 117))	('deletions', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))
383307	23525077	Somatic point, insertion, and deletion mutations were annotated using information from publicly available databases, including the UCSC Genome Browser's UCSC Genes track, miRBase release 15, dbSNP build 132, UCSC Genome Browser's ORegAnno track, UniProt release 2011_03, and COSMIC v51.	('deletion mutations', 'Var', (30, 48))	('v51', 'Gene', (282, 285))	('v51', 'Gene', '28786', (282, 285))
383311	23525077	Wild-type ELMO1, ELMO1 mutants, or GFP in the pBabe(puro) vector (1 mug) was co-transfected with 1 mug of pCL-Eco into 293 cells with Fugene HD (Roche, Indianapolis, IN) overnight.	('mutants', 'Var', (23, 30))	('ELMO1', 'Gene', (17, 22))	('HD', 'Disease', 'MESH:D006816', (141, 143))	('ELMO1', 'Gene', (10, 15))
383367	23280144	FXR expression was associated with higher tumor grade, larger tumor size, and lymph node metastasis (Table 1).	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('FXR expression', 'Var', (0, 14))	('lymph node metastasis', 'Disease', 'MESH:D009362', (78, 99))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('lymph node metastasis', 'Disease', (78, 99))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
383371	23280144	We then transiently transfected a FXR shRNA vector into esophageal cancer cells and stained for Ki-67 expression and found that Ki-67 expression was significantly lower in cells transfected with the FXR shRNA constructs than in those transfected with control shRNA (Figure 2b).	('expression', 'MPA', (134, 144))	('esophageal cancer', 'Disease', (56, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Ki-67', 'Chemical', '-', (96, 101))	('Ki-67', 'Gene', (128, 133))	('lower', 'NegReg', (163, 168))	('FXR', 'Var', (199, 202))	('Ki-67', 'Chemical', '-', (128, 133))
383372	23280144	Moreover, stably control shRNA or FXR shRNA-transfected SKGT-4 cells showed that FXR knockdown significantly reduced tumor cell growth compared with the controls (Figure 2c).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('SKGT-4', 'CellLine', 'CVCL:2195', (56, 62))	('tumor', 'Disease', (117, 122))	('knockdown', 'Var', (85, 94))	('reduced', 'NegReg', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
383373	23280144	In addition, we treated esophageal cancer cells with guggulsterone, a natural FXR inhibitor, for different durations at various concentrations and found that guggulsterone reduced tumor cell viability in a dose- and time-dependent manner (Figure 2e and f).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('reduced', 'NegReg', (172, 179))	('esophageal cancer', 'Disease', (24, 41))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (180, 185))	('guggulsterone', 'Chemical', 'MESH:C023617', (53, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('guggulsterone', 'Var', (158, 171))	('guggulsterone', 'Chemical', 'MESH:C023617', (158, 171))
383374	23280144	However, this effect of guggulsterone was diminished after knockdown of FXR expression (Figure 2d), indicating that the effects of guggulsterone were mediated via FXR inhibition.	('FXR expression', 'Gene', (72, 86))	('guggulsterone', 'Chemical', 'MESH:C023617', (24, 37))	('guggulsterone', 'Chemical', 'MESH:C023617', (131, 144))	('diminished', 'NegReg', (42, 52))	('knockdown', 'Var', (59, 68))
383377	23280144	Both tumor size and weight were significantly reduced by FXR shRNA (Table 3 and Figure 4a).	('weight', 'CPA', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('reduced', 'NegReg', (46, 53))	('FXR shRNA', 'Var', (57, 66))	('tumor', 'Disease', (5, 10))
383381	23280144	We found that the cells treated with a bile acid (chenodeoxycholic acid, deoxycholic acid, or lithocholic acid at a concentration of 200 muM) for 48 h had a decreased expression of RAR-beta2 mRNA but induced expression of COX-2 and FXR mRNAs (Figure 5a).	('deoxycholic acid', 'Var', (73, 89))	('muM', 'Gene', '56925', (137, 140))	('muM', 'Gene', (137, 140))	('chenodeoxycholic acid', 'Chemical', 'MESH:D002635', (50, 71))	('chenodeoxycholic acid', 'Var', (50, 71))	('lithocholic acid', 'Chemical', 'MESH:D008095', (94, 110))	('COX-2', 'Gene', (222, 227))	('COX-2', 'Gene', '5743', (222, 227))	('induced', 'PosReg', (200, 207))	('bile acid', 'Chemical', 'MESH:D001647', (39, 48))	('expression', 'MPA', (208, 218))	('RAR-beta', 'Gene', (181, 189))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (55, 71))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (73, 89))	('decreased', 'NegReg', (157, 166))	('expression', 'MPA', (167, 177))	('RAR-beta', 'Gene', '5915', (181, 189))
383383	23280144	Furthermore, the effects of chenodeoxycholic acid on RAR-beta2 and COX-2 expression were significantly antagonized in cells transiently transfected with FXR shRNA (Figure 5d and e).	('RAR-beta', 'Gene', (53, 61))	('antagonized', 'NegReg', (103, 114))	('chenodeoxycholic acid', 'Chemical', 'MESH:D002635', (28, 49))	('FXR', 'Var', (153, 156))	('COX-2', 'Gene', (67, 72))	('expression', 'MPA', (73, 83))	('COX-2', 'Gene', '5743', (67, 72))	('RAR-beta', 'Gene', '5915', (53, 61))
383384	23280144	Chenodeoxycholic acid acts at the transcriptional level through FXR to suppress RAR-beta2 expression because knockdown of FXR expression abolished the suppressive effect of chenodeoxycholic acid on RAR-beta2 promoter activity (Figure 5f).	('chenodeoxycholic acid', 'Chemical', 'MESH:D002635', (173, 194))	('RAR-beta', 'Gene', (80, 88))	('RAR-beta', 'Gene', (198, 206))	('knockdown', 'Var', (109, 118))	('RAR-beta', 'Gene', '5915', (80, 88))	('expression', 'MPA', (90, 100))	('RAR-beta', 'Gene', '5915', (198, 206))	('Chenodeoxycholic acid', 'Chemical', 'MESH:D002635', (0, 21))
383393	23280144	In vitro treatment with guggulsterone was associated with a significant increase in apoptosis and caspase-3 activity in Barrett esophagus-derived cells.	('increase', 'PosReg', (72, 80))	('activity', 'MPA', (108, 116))	('apoptosis', 'CPA', (84, 93))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (120, 137))	('caspase-3', 'Gene', (98, 107))	('caspase-3', 'Gene', '836', (98, 107))	('guggulsterone', 'Chemical', 'MESH:C023617', (24, 37))	('guggulsterone', 'Var', (24, 37))
383394	23280144	Bile acid-stimulated expression of FXR was shown to enhance the immune response in Barrett esophagus.	('immune response in', 'CPA', (64, 82))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (83, 100))	('enhance', 'PosReg', (52, 59))	('Bile acid', 'Chemical', 'MESH:D001647', (0, 9))	('expression', 'Var', (21, 31))	('FXR', 'Gene', (35, 38))
383404	23280144	Furthermore, a number of studies showed that guggulsterone has a suppressive effect on xenograft formation and growth of different cancers in vivo.	('suppressive', 'NegReg', (65, 76))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('guggulsterone', 'Chemical', 'MESH:C023617', (45, 58))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('growth', 'CPA', (111, 117))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('guggulsterone', 'Var', (45, 58))	('xenograft formation', 'CPA', (87, 106))
383407	23280144	Bile acid exposure causes phosphatidyl-inositol-3-kinase-mediated proliferation of Barrett adenocarcinoma cells, and deoxycholic acid at neutral pH activates NF-kappaB and induces interleukin-8 expression in esophageal cells in vitro.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('activates', 'PosReg', (148, 157))	('NF-kappaB', 'Gene', '4790', (158, 167))	('deoxycholic acid', 'Var', (117, 133))	('Barrett adenocarcinoma', 'Disease', (83, 105))	('phosphatidyl-inositol-3-kinase-mediated', 'MPA', (26, 65))	('Barrett adenocarcinoma', 'Disease', 'MESH:D001471', (83, 105))	('induces', 'Reg', (172, 179))	('interleukin-8', 'Gene', '3576', (180, 193))	('NF-kappaB', 'Gene', (158, 167))	('Bile acid', 'Chemical', 'MESH:D001647', (0, 9))	('expression', 'MPA', (194, 204))	('interleukin-8', 'Gene', (180, 193))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (117, 133))
383410	23280144	Our current study demonstrated that FXR mediated the effects of bile acids on gene expressions in esophageal cancer cells and that inhibition of FXR not only suppressed tumor cell viability via induction of apoptosis in vitro but also reduced formation and growth of nude mouse xenograft tumors.	('apoptosis', 'CPA', (207, 216))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('FXR', 'Gene', (145, 148))	('suppressed', 'NegReg', (158, 168))	('tumor', 'Disease', (169, 174))	('esophageal cancer', 'Disease', (98, 115))	('gene expressions', 'MPA', (78, 94))	('tumor', 'Disease', (288, 293))	('bile acids', 'Chemical', 'MESH:D001647', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('mouse', 'Species', '10090', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('reduced', 'NegReg', (235, 242))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('inhibition', 'Var', (131, 141))	('tumors', 'Disease', (288, 294))
383755	19403881	Many factors, including a poor intravenous injection, inaccurate dose calibration or camera calibration, or variable uptake times, can affect the SUL.	('inaccurate', 'Var', (54, 64))	('affect', 'Reg', (135, 141))	('SUL', 'MPA', (146, 149))	('SUL', 'Chemical', 'MESH:D013444', (146, 149))
383767	19403881	Remarkably, several studies have shown that changes in the SUVof primary tumors can quite accurately predict the outcomes in their nodal metastases.	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('changes', 'Var', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('metastases', 'Disease', (137, 147))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
383771	19403881	found that the accuracy of predicting event-free survival in lymphoma response assessment was slightly better using the change in SUV from the hottest lesion on study 1 to the hottest lesion on study 2 (which was a different lesion in 18% of cases) than using the change in the hottest lesion on the baseline study (76.1% accuracy vs. 73.9% accuracy in outcome prediction).	('change', 'Var', (120, 126))	('lymphoma', 'Disease', 'MESH:D008223', (61, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('better', 'PosReg', (103, 109))	('lymphoma', 'Disease', (61, 69))
383815	17144908	Previous studies identified associations between low social class and stomach, esophagus and pancreas cancers (both for incidence and mortality).	('stomach', 'Disease', (70, 77))	('associations', 'Interaction', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('low social class', 'Var', (49, 65))	('pancreas cancer', 'Phenotype', 'HP:0002894', (93, 108))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('esophagus and pancreas cancers', 'Disease', 'MESH:D004938', (79, 109))
383976	32102481	Detection of LINE-1 hypomethylation in cfDNA of Esophageal Adenocarcinoma Patients DNA methylation plays an important role in cancer development.	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (48, 73))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (48, 73))	('hypomethylation', 'Var', (20, 35))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('LINE-1', 'Gene', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('Esophageal Adenocarcinoma', 'Disease', (48, 73))
383977	32102481	Cancer cells exhibit two types of DNA methylation alteration: site-specific hypermethylation at promoter of oncosuppressor genes and global DNA hypomethylation.	('hypermethylation', 'Var', (76, 92))	('global', 'MPA', (133, 139))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('oncosuppressor genes', 'Gene', (108, 128))
383982	32102481	Results showed that hypomethylated LINE-1 sequences are present in EADC cfDNA.	('EADC', 'Disease', 'MESH:D004938', (67, 71))	('EADC', 'Phenotype', 'HP:0011459', (67, 71))	('hypomethylated', 'Var', (20, 34))	('EADC', 'Disease', (67, 71))
383983	32102481	Furthermore, longitudinal studies in BE suggested a correlation between methylation status of LINE-1 sequences in cfDNA and progression to EADC.	('LINE-1', 'Gene', (94, 100))	('methylation status', 'Var', (72, 90))	('BE', 'Phenotype', 'HP:0100580', (37, 39))	('EADC', 'Disease', 'MESH:D004938', (139, 143))	('EADC', 'Phenotype', 'HP:0011459', (139, 143))	('EADC', 'Disease', (139, 143))	('cfDNA', 'Disease', (114, 119))	('BE', 'Disease', 'MESH:D001471', (37, 39))
383988	32102481	Genome-wide methylation analysis conducted in a variety of neoplasias has revealed that, next to a selective hypermethylation at the CpG islands of specific tumor suppressor gene promoters, the dominant epigenetic change is global hypomethylation.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('neoplasias', 'Disease', 'MESH:D009369', (59, 69))	('global hypomethylation', 'Var', (224, 246))	('neoplasias', 'Phenotype', 'HP:0002664', (59, 69))	('neoplasias', 'Disease', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
383991	32102481	DNA methylation within the promoter region of human LINE-1 elements is important for maintaining transcriptional inactivation, for inhibiting transposition, and consequently for contributing to genome stability.	('contributing', 'Reg', (178, 190))	('inhibiting transposition', 'Phenotype', 'HP:0011540', (131, 155))	('genome stability', 'CPA', (194, 210))	('methylation', 'Var', (4, 15))	('human', 'Species', '9606', (46, 51))	('inhibiting', 'NegReg', (131, 141))	('transposition', 'MPA', (142, 155))	('transcriptional inactivation', 'MPA', (97, 125))
383992	32102481	In EADC, both the genetic and epigenetic alterations are probably the consequence of chronic inflammation associated with gastro-esophageal reflux, obesity, and smoking, which are important risk factors.	('obesity', 'Disease', (148, 155))	('esophageal reflux', 'Phenotype', 'HP:0002020', (129, 146))	('EADC', 'Phenotype', 'HP:0011459', (3, 7))	('EADC', 'Disease', (3, 7))	('inflammation', 'Disease', (93, 105))	('gastro-esophageal reflux', 'Disease', (122, 146))	('obesity', 'Phenotype', 'HP:0001513', (148, 155))	('epigenetic alterations', 'Var', (30, 52))	('obesity', 'Disease', 'MESH:D009765', (148, 155))	('inflammation', 'Disease', 'MESH:D007249', (93, 105))	('gastro-esophageal reflux', 'Disease', 'MESH:D005764', (122, 146))	('EADC', 'Disease', 'MESH:D004938', (3, 7))
383994	32102481	In previous studies, we showed that in the cfDNA of dysplastic Barrett's esophagus or EADC patients it was possible to detect tumor-related genetic alterations such as loss of heterozygosity (LOH), and that this alteration could be used to monitor patient outcomes.	('EADC', 'Disease', 'MESH:D004938', (86, 90))	('patients', 'Species', '9606', (91, 99))	('loss of heterozygosity', 'Var', (168, 190))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('EADC', 'Phenotype', 'HP:0011459', (86, 90))	('EADC', 'Disease', (86, 90))	("dysplastic Barrett's esophagus", 'Disease', (52, 82))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (63, 82))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (52, 82))	('patient', 'Species', '9606', (248, 255))	('patient', 'Species', '9606', (91, 98))	('tumor', 'Disease', (126, 131))
383998	32102481	These data suggest that the LINE-1 sequences could also be hypomethylated and contribute to genomic instability in EADC.	('genomic', 'MPA', (92, 99))	('hypomethylated', 'Var', (59, 73))	('EADC', 'Disease', 'MESH:D004938', (115, 119))	('contribute to', 'Reg', (78, 91))	('EADC', 'Phenotype', 'HP:0011459', (115, 119))	('EADC', 'Disease', (115, 119))
383999	32102481	In this study, we investigated the presence of hypomethylated LINE-1 sequences in the cfDNA of EADC patients.	('hypomethylated', 'Var', (47, 61))	('cfDNA', 'Disease', (86, 91))	('EADC', 'Disease', 'MESH:D004938', (95, 99))	('patients', 'Species', '9606', (100, 108))	('EADC', 'Phenotype', 'HP:0011459', (95, 99))	('EADC', 'Disease', (95, 99))
384000	32102481	LINE-1 sequences were chosen since their abundance and distribution throughout the genome indicate them as a good biomarker with which to detect hypomethylation of circulating tumor-derived DNA, usually present at low levels in the bloodstream.	('hypomethylation', 'Var', (145, 160))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))
384007	32102481	Using this approach, we were able to detect the presence of hypomethylated LINE-1 sequences in tumor FFPE-DNA.	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('hypomethylated', 'Var', (60, 74))	('LINE-1', 'Gene', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
384009	32102481	These data suggest that LINE-1 hypomethylation could be used as a surrogate marker in EADC samples, as suggested for ESCC subtype.	('EADC', 'Disease', 'MESH:D004938', (86, 90))	('hypomethylation', 'Var', (31, 46))	('EADC', 'Phenotype', 'HP:0011459', (86, 90))	('EADC', 'Disease', (86, 90))	('ESCC', 'Disease', (117, 121))
384013	32102481	Indeed, over 60% (11/18) of patients had a partial hypomethylation in their cfDNA, with a median methylation level of 67% vs. 100% of constitutive DNA (p = 0.0001) (Figure 5A).	('partial hypomethylation', 'Var', (43, 66))	('patients', 'Species', '9606', (28, 36))	('methylation level', 'MPA', (97, 114))
384016	32102481	These results showed that this approach, based on a restriction enzyme digestion and DNA amplification, allowed the detection of hypomethylated LINE-1 sequences in cfDNA of EADC patients.	('cfDNA', 'Disease', (164, 169))	('detection', 'Reg', (116, 125))	('patients', 'Species', '9606', (178, 186))	('EADC', 'Disease', 'MESH:D004938', (173, 177))	('hypomethylated', 'Var', (129, 143))	('EADC', 'Disease', (173, 177))	('EADC', 'Phenotype', 'HP:0011459', (173, 177))	('LINE-1', 'Gene', (144, 150))
384017	32102481	In several types of tumors, including ESCC, LINE-1 hypomethylation has been found to be associated with a poor prognosis.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('hypomethylation', 'Var', (51, 66))	('ESCC', 'Disease', (38, 42))	('LINE-1', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
384039	32102481	HpaII can cleave CCGG and, with less efficiency, mCCGG, and it is inhibited by the methylation of the internal cytosine (CmCGG).	('CCGG', 'Chemical', '-', (17, 21))	('cleave', 'Var', (10, 16))	('CCGG', 'Protein', (17, 21))	('CmCGG', 'Chemical', '-', (121, 126))	('cytosine', 'Chemical', 'MESH:D003596', (111, 119))	('CCGG', 'Chemical', '-', (50, 54))
384042	32102481	However, due to the rarity of 100% demethylation and to the possible existence of LINE-1 variants with mutations in the CCGG sequence, it was always possible to detect amplicons.	('mutations', 'Var', (103, 112))	('CCGG', 'Gene', (120, 124))	('CCGG', 'Chemical', '-', (120, 124))
384044	32102481	Results indicated that the hypomethylation status of LINE-1 could be used as a tumor surrogate marker not only to monitor EADC patients, but also as an additional tool in BE patient surveillance.	('BE', 'Disease', 'MESH:D001471', (171, 173))	('tumor', 'Disease', (79, 84))	('patient', 'Species', '9606', (174, 181))	('patient', 'Species', '9606', (127, 134))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('LINE-1', 'Gene', (53, 59))	('hypomethylation status', 'Var', (27, 49))	('patients', 'Species', '9606', (127, 135))	('EADC', 'Disease', 'MESH:D004938', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('EADC', 'Phenotype', 'HP:0011459', (122, 126))	('EADC', 'Disease', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
384046	29725336	Commonly, HER2 expression is associated with poor clinical outcome or chemoresistance in ovarian and breast cancer patients.	('patients', 'Species', '9606', (115, 123))	('expression', 'Var', (15, 25))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (89, 114))	('expression', 'Species', '29278', (15, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('HER2', 'Gene', (10, 14))	('HER2', 'Gene', '2064', (10, 14))	('chemoresistance', 'CPA', (70, 85))
384055	29725336	The human epidermal growth factor receptor 2 [(HER2), ErbB2] stimulates tumor cell proliferation via the Ras-MAP-kinase pathway and its expression is often associated with an aggressive tumor phenotype, advanced stage diseases, and poor clinical outcome.	('ErbB2', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (186, 191))	('human epidermal growth factor receptor 2', 'Gene', (4, 44))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('HER2', 'Gene', '2064', (47, 51))	('aggressive tumor', 'Disease', 'MESH:D001523', (175, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (72, 77))	('expression', 'Var', (136, 146))	('ErbB2', 'Gene', '2064', (54, 59))	('human epidermal growth factor receptor 2', 'Gene', '2064', (4, 44))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('expression', 'Species', '29278', (136, 146))	('stimulates', 'PosReg', (61, 71))	('HER2', 'Gene', (47, 51))	('aggressive tumor', 'Disease', (175, 191))	('Ras-MAP-kinase pathway', 'Pathway', (105, 127))	('associated with', 'Reg', (156, 171))
384065	29725336	Differential clinical responses toward therapeutic antibodies such as trastuzumab or rituximab related to polymorphisms in FCGRIIA and FCGRIIIA genes have promoted the development of Fc engineered antibodies, which improve cellular cytotoxicity against tumors.	('cytotoxicity', 'Disease', (232, 244))	('tumors', 'Disease', (253, 259))	('rituximab', 'Chemical', 'MESH:D000069283', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('polymorphisms', 'Var', (106, 119))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('trastuzumab', 'Chemical', 'MESH:D000068878', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('promoted', 'PosReg', (155, 163))	('cytotoxicity', 'Disease', 'MESH:D064420', (232, 244))	('FCGRIIA', 'Gene', (123, 130))	('improve', 'PosReg', (215, 222))
384069	29725336	For example, bispecific [HER2xCD16] antibodies retargeting NK cells to tumors have proven efficacy.	('2xCD16', 'Chemical', '-', (28, 34))	('tumors', 'Disease', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('HER2', 'Gene', (25, 29))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('bispecific', 'Var', (13, 23))	('HER2', 'Gene', '2064', (25, 29))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
384081	29725336	In accordance with the Declaration of Helsinki, written informed consent was obtained from all donors, and the research was approved by the relevant institutional review boards (ethic committee of the Medical Faculty of the CAU to Kiel, code number: D405/10, D403/14, D404/14).	('D405/10', 'Var', (250, 257))	('D403/14', 'Var', (259, 266))	('donor', 'Species', '9606', (95, 100))	('D404/14', 'Var', (268, 275))
384082	29725336	Twenty-four patients with histologically verified PDAC (10 females, age 67.2 +- 12.1 years; 14 males, age 66.6 +- 6.9 years, stage pT1-4, pN0-1, L0-1, V0-1Pn 0-1, R0-1) were enrolled.	('patients', 'Species', '9606', (12, 20))	('pN0-1', 'Var', (138, 143))	('PDAC', 'Disease', (50, 54))	('PDAC', 'Phenotype', 'HP:0006725', (50, 54))	('PDAC', 'Chemical', '-', (50, 54))
384100	29725336	Polyploidy was detected in 60-100% of cells in each investigated primary ovarian tumor sample which classified them together with a high expression of HER2 and epithelial cell adhesion molecule as cancer cells.	('ovarian tumor', 'Phenotype', 'HP:0100615', (73, 86))	('ovarian tumor', 'Disease', 'MESH:D010051', (73, 86))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('Polyploidy', 'Var', (0, 10))	('detected', 'Reg', (15, 23))	('HER2', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('ovarian tumor', 'Disease', (73, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('HER2', 'Gene', '2064', (151, 155))	('expression', 'Species', '29278', (137, 147))
384103	29725336	The genotype of tumor cell lines was recently confirmed by short tandem repeats analysis and mycoplasma negativity routinely once per month by RT-PCR.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('mycoplasma negativity', 'Disease', (93, 114))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('short tandem repeats analysis', 'Var', (59, 88))	('tumor', 'Disease', (16, 21))
384137	29725336	The co-culture of tumor cells with IL-2 stimulated allogeneic breast cancer, PDAC, or OC patients' PBL, respectively, in the absence of trastuzumab induced a delayed lysis of MCF-7 cells, a low lysis rate of PancTu-I cells and an obvious lysis of OC1 cells (Figure 1A) in comparison to the trastuzumab-mediated lysis suggesting an IL-2-mediated activation of PBL effector cells.	('MCF-7', 'CellLine', 'CVCL:0031', (175, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('delayed lysis', 'MPA', (158, 171))	('PDAC', 'Chemical', '-', (77, 81))	('allogeneic', 'Var', (51, 61))	('tumor', 'Disease', (18, 23))	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('IL-2', 'Gene', '3558', (331, 335))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Disease', (62, 75))	('IL-2', 'Gene', (35, 39))	('lysis', 'MPA', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('trastuzumab', 'Chemical', 'MESH:D000068878', (290, 301))	('OC', 'Phenotype', 'HP:0100615', (247, 249))	('PancTu-I', 'CellLine', 'CVCL:4012', (208, 216))	('trastuzumab', 'Chemical', 'MESH:D000068878', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('IL-2', 'Gene', '3558', (35, 39))	('IL-2', 'Gene', (331, 335))	('patients', 'Species', '9606', (89, 97))	('OC', 'Phenotype', 'HP:0100615', (86, 88))
384145	29725336	Besides varying direct effects of trastuzumab on the different tumor cells, one possible additional explanation for the weak lysis of PDAC cell lines by PBL from cancer patients is our observation of a significantly decreased CD16 expression on Vdelta2-positive gammadelta T cells within the PBL of PDAC patients (Figure 2A, right panel), in contrast to TCR gammadelta-negative NK cells (Figure 2A, left panel), which was not present in age-matched HDs or patients with other different (cancer) diseases (shortly before surgery, listed in Section "Materials and Methods") (Figure 2A).	('decreased', 'NegReg', (216, 225))	('PDAC', 'Chemical', '-', (134, 138))	('cancer', 'Disease', (162, 168))	('PDAC', 'Chemical', '-', (299, 303))	('HD', 'Disease', 'MESH:D006816', (449, 451))	('cancer', 'Disease', (487, 493))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PDAC', 'Phenotype', 'HP:0006725', (299, 303))	('PDAC', 'Phenotype', 'HP:0006725', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (487, 493))	('CD16', 'Gene', '2214', (226, 230))	('TCR', 'Gene', '6962', (354, 357))	('patients', 'Species', '9606', (456, 464))	('expression', 'MPA', (231, 241))	('trastuzumab', 'Chemical', 'MESH:D000068878', (34, 45))	('tumor', 'Disease', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('Vdelta2-positive', 'Var', (245, 261))	('patients', 'Species', '9606', (304, 312))	('cancer', 'Disease', 'MESH:D009369', (487, 493))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('CD16', 'Gene', (226, 230))	('PDAC', 'Disease', (299, 303))	('TCR', 'Gene', (354, 357))	('patients', 'Species', '9606', (169, 177))	('expression', 'Species', '29278', (231, 241))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
384159	29725336	Although the concentration of tribody [(HER2)2xCD16] was 10-fold lower than that of trastuzumab, the tribody significantly and more potently enhanced the PBL-mediated lysis of HER2-expressing tumor cells (Figure 4A).	('trastuzumab', 'Chemical', 'MESH:D000068878', (84, 95))	('HER2', 'Gene', (176, 180))	('tumor', 'Disease', (192, 197))	('HER2', 'Gene', (40, 44))	('tribody', 'Var', (101, 108))	('HER2', 'Gene', '2064', (176, 180))	('HER2', 'Gene', '2064', (40, 44))	('2xCD16', 'Chemical', '-', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('enhanced', 'PosReg', (141, 149))	('PBL-mediated lysis', 'MPA', (154, 172))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
384176	29725336	The limited cytotoxicity of short-term expanded gammadelta T cells was somewhat enhanced by the addition of their selective antigens such as PAg (Figure 6B, phosphoantigen, right two panels), whereas the addition of trastuzumab only weakly increased the cytotoxicity of these gammadelta T cells (Figure 6C, medium).	('PAg', 'Var', (141, 144))	('cytotoxicity', 'Disease', 'MESH:D064420', (254, 266))	('cytotoxicity', 'Disease', 'MESH:D064420', (12, 24))	('trastuzumab', 'Chemical', 'MESH:D000068878', (216, 227))	('PAg', 'Chemical', '-', (141, 144))	('cytotoxicity', 'Disease', (254, 266))	('enhanced', 'PosReg', (80, 88))	('cytotoxicity', 'Disease', (12, 24))
384187	29725336	Tribody [(HER2)2xCD16] triggered lysis of HER2-expressing tumor cells, but not of HER2-negative Raji cells, which, however, were efficiently killed in the presence of PAg BrHPP or tribody [(CD20)2xCD16] (Figure S4 in Supplementary Material).	('HER2', 'Gene', '2064', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('HER2', 'Gene', (42, 46))	('Raji cells', 'CellLine', 'CVCL:0511', (96, 106))	('2xCD16', 'Chemical', '-', (15, 21))	('PAg', 'Chemical', '-', (167, 170))	('HER2', 'Gene', (82, 86))	('BrHPP', 'Chemical', 'MESH:C429553', (171, 176))	('CD20', 'Gene', '54474', (190, 194))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PAg BrHPP', 'Var', (167, 176))	('lysis', 'MPA', (33, 38))	('HER2', 'Gene', (10, 14))	('HER2', 'Gene', '2064', (82, 86))	('CD20', 'Gene', (190, 194))	('2xCD16', 'Chemical', '-', (195, 201))	('HER2', 'Gene', '2064', (10, 14))
384215	29725336	treated OC patients with either trastuzumab combined with chemotherapy (NCT00433407) or HER2 cytotoxic T-cell (CTL) peptide-based vaccine (NCT00194714) or anti-CD3xanti-HER2/neu (HER2Bi) armed anti-CD3 activated T cells (aATC) plus low-dose aldesleukin and sargramostim (NCT02470559).	('OC', 'Phenotype', 'HP:0100615', (8, 10))	('HER2', 'Gene', (169, 173))	('HER2/neu', 'Gene', '2064', (169, 177))	('HER2', 'Gene', '2064', (169, 173))	('HER2', 'Gene', (88, 92))	('HER2/neu', 'Gene', (169, 177))	('HER2', 'Gene', '2064', (88, 92))	('NCT00194714', 'Var', (139, 150))	('HER2', 'Gene', (179, 183))	('patients', 'Species', '9606', (11, 19))	('HER2', 'Gene', '2064', (179, 183))	('trastuzumab', 'Chemical', 'MESH:D000068878', (32, 43))
384229	29725336	In addition, the anti-HER2 DC vaccination was combined with anti-estrogen therapy which improved regional nodal immune response and pCR rate in patients with estrogen receptor+/HER2+ early breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('regional nodal immune response', 'CPA', (97, 127))	('HER2', 'Gene', (177, 181))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('HER2', 'Gene', (22, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('HER2', 'Gene', '2064', (177, 181))	('breast cancer', 'Disease', (189, 202))	('HER2', 'Gene', '2064', (22, 26))	('patients', 'Species', '9606', (144, 152))	('pCR rate', 'CPA', (132, 140))	('improved', 'PosReg', (88, 96))	('estrogen', 'Var', (158, 166))
384245	29725336	In accordance with the Declaration of Helsinki, written informed consent was obtained from all donors, and the research was approved by the relevant institutional review boards (ethic committee of the Medical Faculty of the CAU to Kiel, code number: D405/10, D403/14, D404/14, AZ A157/11, AZ B3277/10).	('AZ A157/11', 'Var', (277, 287))	('donor', 'Species', '9606', (95, 100))	('D403/14', 'Var', (259, 266))	('D404/14', 'Var', (268, 275))	('D405/10', 'Var', (250, 257))
384248	28968424	miR-125b-5p functions as a tumor suppressor gene partially by regulating HMGA2 in esophageal squamous cell carcinoma MicroRNAs (miRNAs) play important roles in the progression of human cancer including esophageal squamous cell carcinoma (ESCC).	('HMGA2', 'Gene', (73, 78))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('miR-125b-5p', 'Var', (0, 11))	('esophageal squamous cell carcinoma', 'Disease', (202, 236))	('regulating', 'Reg', (62, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('cancer', 'Disease', (185, 191))	('tumor', 'Disease', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('HMGA2', 'Gene', '8091', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (202, 236))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('miR-125b-5p', 'Chemical', '-', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('human', 'Species', '9606', (179, 184))
384249	28968424	Although previous reports showed that miR-125b-5p was down-regulated in ESCC, the roles and mechanisms of loss of function of miR-125b-5p in ESCC were still unknown.	('miR-125b-5p', 'Var', (126, 137))	('miR-125b-5p', 'Chemical', '-', (38, 49))	('miR-125b-5p', 'Chemical', '-', (126, 137))	('down-regulated', 'NegReg', (54, 68))	('ESCC', 'Disease', (72, 76))	('miR-125b-5p', 'Gene', (38, 49))
384251	28968424	In-vitro assays showed that ectopic miR-125b-5p expression repressed cell proliferation, migration and invasion, and induced cell senescence.	('cell senescence', 'CPA', (125, 140))	('miR-125b-5p', 'Chemical', '-', (36, 47))	('induced', 'PosReg', (117, 124))	('cell proliferation', 'CPA', (69, 87))	('repressed', 'NegReg', (59, 68))	('migration', 'CPA', (89, 98))	('invasion', 'CPA', (103, 111))	('ectopic miR-125b-5p', 'Var', (28, 47))
384252	28968424	We also found that miR-125b-5p reduced the expressions of cell cycle regulatory genes including CCNA2, CCND1 and CCNE1, and regulated the markers of epithelial to mesenchymal transition (EMT) including E-cadherin, N-cadherin and EMT associated transcription factor Slug, and also decreased the MMPs including MMP2, MMP7 and MMP13.	('E-cadherin', 'Protein', (202, 212))	('regulated', 'Reg', (124, 133))	('CCNA2', 'Gene', (96, 101))	('MMPs', 'Gene', (294, 298))	('CCNE1', 'Gene', '898', (113, 118))	('epithelial to mesenchymal transition', 'CPA', (149, 185))	('MMP13', 'Gene', (324, 329))	('cell cycle regulatory genes', 'Gene', (58, 85))	('miR-125b-5p', 'Chemical', '-', (19, 30))	('CCND1', 'Gene', '595', (103, 108))	('MMP7', 'Gene', '4316', (315, 319))	('Slug', 'Gene', '6591', (265, 269))	('CCNA2', 'Gene', '890', (96, 101))	('CCND1', 'Gene', (103, 108))	('reduced', 'NegReg', (31, 38))	('MMP13', 'Gene', '4322', (324, 329))	('MMP2', 'Gene', (309, 313))	('MMPs', 'Gene', '4313;4316;4322', (294, 298))	('miR-125b-5p', 'Var', (19, 30))	('N-cadherin', 'Gene', (214, 224))	('expressions', 'MPA', (43, 54))	('MMP7', 'Gene', (315, 319))	('N-cadherin', 'Gene', '1000', (214, 224))	('CCNE1', 'Gene', (113, 118))	('decreased', 'NegReg', (280, 289))	('MMP2', 'Gene', '4313', (309, 313))	('Slug', 'Gene', (265, 269))
384253	28968424	Furthermore, the candidate target gene HMGA2 was negatively regulated by miR-125b-5p both in mRNA and protein levels.	('HMGA2', 'Gene', (39, 44))	('negatively', 'NegReg', (49, 59))	('miR-125b-5p', 'Var', (73, 84))	('HMGA2', 'Gene', '8091', (39, 44))	('miR-125b-5p', 'Chemical', '-', (73, 84))
384254	28968424	Importantly, knockdown of HMGA2 partially phenocopied the effects of miR-125b-5p overexpression on cell cycle regulators and EMT markers.	('HMGA2', 'Gene', '8091', (26, 31))	('cell', 'MPA', (99, 103))	('miR-125b-5p', 'Gene', (69, 80))	('HMGA2', 'Gene', (26, 31))	('EMT markers', 'CPA', (125, 136))	('miR-125b-5p', 'Chemical', '-', (69, 80))	('knockdown', 'Var', (13, 22))
384255	28968424	In conclusion, our results suggested that overexpression of miR-125b-5p inhibited cell proliferation, migration and invasion partially by down-regulating HMGA2 in ESCC.	('down-regulating', 'NegReg', (138, 153))	('ESCC', 'Disease', (163, 167))	('HMGA2', 'Gene', '8091', (154, 159))	('cell proliferation', 'CPA', (82, 100))	('miR-125b-5p', 'Chemical', '-', (60, 71))	('HMGA2', 'Gene', (154, 159))	('inhibited', 'NegReg', (72, 81))	('miR-125b-5p', 'Var', (60, 71))
384258	28968424	In anaplastic thyroid cancer, miR-125b-5p could inhibit the migration and invasion of tumor cells by targeting PIK3CD.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('thyroid cancer', 'Phenotype', 'HP:0002890', (14, 28))	('thyroid cancer', 'Disease', (14, 28))	('tumor', 'Disease', (86, 91))	('miR-125b-5p', 'Chemical', '-', (30, 41))	('thyroid cancer', 'Disease', 'MESH:D013964', (14, 28))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('PIK3CD', 'Gene', '5293', (111, 117))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (3, 28))	('PIK3CD', 'Gene', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('targeting', 'Reg', (101, 110))	('miR-125b-5p', 'Var', (30, 41))	('inhibit', 'NegReg', (48, 55))
384259	28968424	In triple-negative breast cancer, miR-125b-5p inhibited the epithelial-mesenchymal transition (EMT) by targeting MAP2K7.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('breast cancer', 'Disease', (19, 32))	('targeting', 'Reg', (103, 112))	('miR-125b-5p', 'Chemical', '-', (34, 45))	('MAP2K7', 'Gene', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('MAP2K7', 'Gene', '5609', (113, 119))	('inhibited', 'NegReg', (46, 55))	('epithelial-mesenchymal transition', 'CPA', (60, 93))	('miR-125b-5p', 'Var', (34, 45))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))
384260	28968424	In gastric cancer, miR-125b-5p suppressed the proliferation and invasion of tumor cells by targeting MCL1.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('miR-125b-5p', 'Chemical', '-', (19, 30))	('targeting', 'Reg', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('proliferation', 'CPA', (46, 59))	('MCL1', 'Gene', '4170', (101, 105))	('gastric cancer', 'Disease', (3, 17))	('MCL1', 'Gene', (101, 105))	('suppressed', 'NegReg', (31, 41))	('miR-125b-5p', 'Var', (19, 30))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
384261	28968424	In ESCC, miR-125b-5p was down-regulated, and its low expression was associated with HPV infection.	('associated', 'Reg', (68, 78))	('miR-125b-5p', 'Chemical', '-', (9, 20))	('HPV infection', 'Disease', 'MESH:D030361', (84, 97))	('down-regulated', 'NegReg', (25, 39))	('low', 'NegReg', (49, 52))	('miR-125b-5p', 'Var', (9, 20))	('expression', 'MPA', (53, 63))	('HPV infection', 'Disease', (84, 97))
384262	28968424	HPV-16 E6 transfection decreased the expression of miR-125b-5p in ESCC.	('miR-125b-5p', 'Var', (51, 62))	('expression', 'MPA', (37, 47))	('HPV-16', 'Species', '333760', (0, 6))	('decreased', 'NegReg', (23, 32))	('miR-125b-5p', 'Chemical', '-', (51, 62))
384264	28968424	The high mobility group protein A2 (HMGA2) was overexpressed in about 90% of ESCCs, and the high expression of HMGA2 was correlated with higher T stage, lower differentiation degree, lymph node metastasis, recurrence status, TNM stage and poor prognosis.	('TNM', 'Gene', (225, 228))	('HMGA2', 'Gene', '8091', (36, 41))	('high', 'Var', (92, 96))	('lymph node metastasis', 'CPA', (183, 204))	('high mobility group protein A2', 'Gene', (4, 34))	('higher', 'PosReg', (137, 143))	('HMGA2', 'Gene', (36, 41))	('high mobility group protein A2', 'Gene', '8091', (4, 34))	('lower differentiation degree', 'CPA', (153, 181))	('T stage', 'CPA', (144, 151))	('recurrence status', 'CPA', (206, 223))	('HMGA2', 'Gene', '8091', (111, 116))	('TNM', 'Gene', '10178', (225, 228))	('overexpressed', 'PosReg', (47, 60))	('HMGA2', 'Gene', (111, 116))
384266	28968424	In the present study, we revealed that overexpression of miR-125b-5p decreased the proliferation, migration and invasion and increased the senescence of esophageal cancer cells.	('overexpression', 'PosReg', (39, 53))	('increased', 'PosReg', (125, 134))	('senescence', 'CPA', (139, 149))	('miR-125b-5p', 'Chemical', '-', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('invasion', 'CPA', (112, 120))	('decreased', 'NegReg', (69, 78))	('miR-125b-5p', 'Var', (57, 68))	('esophageal cancer', 'Disease', (153, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
384267	28968424	Importantly, we further found that miR-125b-5p negatively regulated HMGA2, and knockdown of HMGA2 partially phenocopied the effects of miR-125b-5p overexpression on the tumor cell phenotype.	('HMGA2', 'Gene', '8091', (92, 97))	('miR-125b-5p', 'Chemical', '-', (135, 146))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('HMGA2', 'Gene', (92, 97))	('HMGA2', 'Gene', '8091', (68, 73))	('miR-125b-5p', 'Chemical', '-', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('HMGA2', 'Gene', (68, 73))	('negatively', 'NegReg', (47, 57))	('knockdown', 'Var', (79, 88))
384268	28968424	The human esophageal squamous cell carcinoma (ESCC) cell lines including KYSE30, KYSE150, KYSE180, KYSE410 and KYSE510 were provided by Dr Shimada (Kyoto University).	('KYSE180', 'Var', (90, 97))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (10, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('human', 'Species', '9606', (4, 9))	('KYSE510', 'CellLine', 'CVCL:1354', (111, 118))	('KYSE410', 'Var', (99, 106))	('esophageal squamous cell carcinoma', 'Disease', (10, 44))	('KYSE150', 'Var', (81, 88))	('KYSE510', 'Var', (111, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))
384271	28968424	The cells were seeded in six-well plates and transfected with miR-125b-5p mimics or HMGA2 siRNAs or negative control using lipofectamine 2000 transfection reagent (Invitrogen, Carlsbad, CA, USA) following the manufacture's protocol.	('miR-125b-5p', 'Var', (62, 73))	('HMGA2', 'Gene', (84, 89))	('lipofectamine 2000', 'Chemical', 'MESH:C086724', (123, 141))	('miR-125b-5p', 'Chemical', '-', (62, 73))	('HMGA2', 'Gene', '8091', (84, 89))
384296	28968424	We compared the miRNA expression profiles between ESCC tissues and paracancerous tissues using Agilent Human miRNA Microarray, and found that miR-125b-5p was down-regulated in ESCC tissues (Fig 1A).	('ESCC', 'Disease', (176, 180))	('miR-125b-5p', 'Chemical', '-', (142, 153))	('paracancerous', 'Disease', (67, 80))	('down-regulated', 'NegReg', (158, 172))	('Human', 'Species', '9606', (103, 108))	('miR-125b-5p', 'Var', (142, 153))	('paracancerous', 'Disease', 'None', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
384297	28968424	In the dataset of GSE66274, miR-125b-5p was significantly down-regulated in 14/30 ESCCs with fold change below 0.5 (Tumor/Normal, Fig 1D).	('Tumor', 'Phenotype', 'HP:0002664', (116, 121))	('ESCCs', 'Disease', (82, 87))	('down-regulated', 'NegReg', (58, 72))	('miR-125b-5p', 'Var', (28, 39))	('miR-125b-5p', 'Chemical', '-', (28, 39))
384298	28968424	To study the tumorigenic roles of miR-125b-5p in ESCC, we first evaluated the expression levels in four ESCC cell lines including KYSE30, KYSE180, KYSE150 and KYSE510 by Real-time PCR.	('tumor', 'Disease', (13, 18))	('KYSE180', 'Var', (138, 145))	('KYSE510', 'CellLine', 'CVCL:1354', (159, 166))	('KYSE30', 'Var', (130, 136))	('miR-125b-5p', 'Chemical', '-', (34, 45))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('KYSE510', 'Var', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('KYSE150', 'Var', (147, 154))
384299	28968424	KYSE150 and KYSE510 exhibited lower expression levels than other two cell lines (not shown).	('lower', 'NegReg', (30, 35))	('KYSE510', 'CellLine', 'CVCL:1354', (12, 19))	('KYSE510', 'Var', (12, 19))	('KYSE150', 'Var', (0, 7))	('expression levels', 'MPA', (36, 53))
384300	28968424	Transfection of miR-125b-5p mimics to KYSE150 and KYSE510 cell lines significantly enhanced the expression levels with fold change above 60 compared with negative control group (Fig 2A).	('expression levels', 'MPA', (96, 113))	('miR-125b-5p', 'Chemical', '-', (16, 27))	('KYSE510', 'CellLine', 'CVCL:1354', (50, 57))	('enhanced', 'PosReg', (83, 91))	('miR-125b-5p', 'Var', (16, 27))
384301	28968424	Overexpression of miR-125b-5p significantly inhibited cell proliferation of KYSE150 and KYSE510 cell lines (Fig 2B).	('inhibited', 'NegReg', (44, 53))	('miR-125b-5p', 'Var', (18, 29))	('KYSE510', 'CellLine', 'CVCL:1354', (88, 95))	('miR-125b-5p', 'Chemical', '-', (18, 29))
384303	28968424	miR-125b-5p also decreased the mRNA levels of cell cycle regulatory genes including CCNA2, CCND1 and CCNE1 in KYSE150 and KYSE510 (Fig 2C).	('mRNA levels', 'MPA', (31, 42))	('decreased', 'NegReg', (17, 26))	('miR-125b-5p', 'Var', (0, 11))	('CCND1', 'Gene', (91, 96))	('KYSE510', 'Var', (122, 129))	('CCNA2', 'Gene', (84, 89))	('KYSE510', 'CellLine', 'CVCL:1354', (122, 129))	('CCNE1', 'Gene', '898', (101, 106))	('CCND1', 'Gene', '595', (91, 96))	('cell cycle regulatory genes', 'Gene', (46, 73))	('miR-125b-5p', 'Chemical', '-', (0, 11))	('CCNE1', 'Gene', (101, 106))	('CCNA2', 'Gene', '890', (84, 89))
384304	28968424	Our results suggested that miR-125b-5p inhibited the proliferation of ESCC cells via down-regulating CCND1, CCNA2 and CCNE1.	('CCND1', 'Gene', (101, 106))	('CCNE1', 'Gene', (118, 123))	('inhibited', 'NegReg', (39, 48))	('miR-125b-5p', 'Var', (27, 38))	('CCNA2', 'Gene', (108, 113))	('CCND1', 'Gene', '595', (101, 106))	('proliferation', 'CPA', (53, 66))	('down-regulating', 'NegReg', (85, 100))	('ESCC', 'Disease', (70, 74))	('miR-125b-5p', 'Chemical', '-', (27, 38))	('CCNE1', 'Gene', '898', (118, 123))	('CCNA2', 'Gene', '890', (108, 113))
384305	28968424	Using Senescence beta-Galactosidase Staining Assay, we found that overexpression of miR-125b-5p significantly enhanced the senescence of ESCC cells (Fig 3A).	('beta-Galactosidase', 'Gene', (17, 35))	('miR-125b-5p', 'Chemical', '-', (84, 95))	('enhanced', 'PosReg', (110, 118))	('beta-Galactosidase', 'Gene', '2720', (17, 35))	('senescence', 'CPA', (123, 133))	('miR-125b-5p', 'Var', (84, 95))
384306	28968424	We also found that miR-125b-5p overerxpression significantly inhibited the migration and invasion of ESCC cells (Fig 3B).	('overerxpression', 'Var', (31, 46))	('inhibited', 'NegReg', (61, 70))	('miR-125b-5p overerxpression', 'Var', (19, 46))	('miR-125b-5p', 'Chemical', '-', (19, 30))
384308	28968424	Our study further found that overexpression of miR-125b-5p significantly increased the protein expression of E-cadherin, and reduced the expression of N-cadherin (Fig 3C).	('increased', 'PosReg', (73, 82))	('expression', 'MPA', (137, 147))	('N-cadherin', 'Gene', (151, 161))	('protein expression', 'MPA', (87, 105))	('reduced', 'NegReg', (125, 132))	('miR-125b-5p', 'Chemical', '-', (47, 58))	('N-cadherin', 'Gene', '1000', (151, 161))	('E-cadherin', 'Protein', (109, 119))	('miR-125b-5p', 'Var', (47, 58))
384310	28968424	Our findings indicated that miR-125b-5p significantly repressed the migration and invasion of ESCC cells, and regulated the markers of EMT.	('regulated', 'Reg', (110, 119))	('invasion of', 'CPA', (82, 93))	('miR-125b-5p', 'Var', (28, 39))	('repressed', 'NegReg', (54, 63))	('miR-125b-5p', 'Chemical', '-', (28, 39))	('migration', 'CPA', (68, 77))	('markers of', 'MPA', (124, 134))
384312	28968424	We also found that miR-125b-5p significantly decreased the expressions of MMP2, MMP7 and MMP13 using Real-time PCR assay (Fig 3E).	('miR-125b-5p', 'Chemical', '-', (19, 30))	('MMP2', 'Gene', '4313', (74, 78))	('expressions', 'MPA', (59, 70))	('decreased', 'NegReg', (45, 54))	('MMP13', 'Gene', (89, 94))	('MMP7', 'Gene', (80, 84))	('MMP13', 'Gene', '4322', (89, 94))	('MMP2', 'Gene', (74, 78))	('miR-125b-5p', 'Var', (19, 30))	('MMP7', 'Gene', '4316', (80, 84))
384314	28968424	HMGA2 was one of the candidate targets, and down-regulated by miR-125b-5p mimics both in mRNA and protein levels (Fig 4A and 4B).	('down-regulated', 'NegReg', (44, 58))	('miR-125b-5p', 'Var', (62, 73))	('HMGA2', 'Gene', '8091', (0, 5))	('mRNA and', 'MPA', (89, 97))	('HMGA2', 'Gene', (0, 5))	('miR-125b-5p', 'Chemical', '-', (62, 73))
384316	28968424	Very importantly, knockdown of HMGA2 partially phenocopied the effects of miR-125b-5p overexpression on cell cycle regulators and EMT markers.	('HMGA2', 'Gene', (31, 36))	('knockdown', 'Var', (18, 27))	('EMT markers', 'CPA', (130, 141))	('miR-125b-5p', 'Chemical', '-', (74, 85))	('cell', 'MPA', (104, 108))	('HMGA2', 'Gene', '8091', (31, 36))	('miR-125b-5p', 'Gene', (74, 85))
384319	28968424	In our results, the reduction of cell cycle regulatory genes and EMT markers when miR-125b-5p mimics were used was greater than that when HMGA2 was silenced.	('cell cycle regulatory genes', 'Gene', (33, 60))	('HMGA2', 'Gene', '8091', (138, 143))	('miR-125b-5p', 'Chemical', '-', (82, 93))	('reduction', 'NegReg', (20, 29))	('EMT markers', 'CPA', (65, 76))	('miR-125b-5p mimics', 'Var', (82, 100))	('HMGA2', 'Gene', (138, 143))
384320	28968424	Therefore, our findings suggested that low expression of miR-125b-5p in ESCC promoted the cell proliferation, migaration and invasion partially via targeting HMGA2.	('ESCC', 'Gene', (72, 76))	('migaration', 'CPA', (110, 120))	('miR-125b-5p', 'Chemical', '-', (57, 68))	('promoted', 'PosReg', (77, 85))	('cell proliferation', 'CPA', (90, 108))	('HMGA2', 'Gene', '8091', (158, 163))	('miR-125b-5p', 'Var', (57, 68))	('HMGA2', 'Gene', (158, 163))	('targeting', 'Reg', (148, 157))	('invasion', 'CPA', (125, 133))
384322	28968424	Knockdown of miR-125b-5p promoted the proliferation of KYSE30 cells, and also increased the expressions of CCNA2, CCND1 and CCNE1 (Fig 5A-5C).	('miR-125b-5p', 'Var', (13, 24))	('expressions', 'MPA', (92, 103))	('proliferation', 'CPA', (38, 51))	('CCNA2', 'Gene', (107, 112))	('CCND1', 'Gene', (114, 119))	('promoted', 'PosReg', (25, 33))	('CCND1', 'Gene', '595', (114, 119))	('increased', 'PosReg', (78, 87))	('miR-125b-5p', 'Chemical', '-', (13, 24))	('CCNE1', 'Gene', '898', (124, 129))	('CCNA2', 'Gene', '890', (107, 112))	('CCNE1', 'Gene', (124, 129))
384324	28968424	Knockdown of miR-125b-5p also increased the mRNA and protein expressions of Slug (Fig 5E and 5F).	('miR-125b-5p', 'Var', (13, 24))	('Slug', 'Gene', '6591', (76, 80))	('miR-125b-5p', 'Chemical', '-', (13, 24))	('increased', 'PosReg', (30, 39))	('Slug', 'Gene', (76, 80))
384325	28968424	Importantly, downregulation of miR-125b-5p increased the expression of HMGA2 both in mRNA and protein levels (Fig 5E and 5F).	('expression', 'MPA', (57, 67))	('HMGA2', 'Gene', (71, 76))	('miR-125b-5p', 'Var', (31, 42))	('downregulation', 'NegReg', (13, 27))	('increased', 'PosReg', (43, 52))	('miR-125b-5p', 'Chemical', '-', (31, 42))	('HMGA2', 'Gene', '8091', (71, 76))
384326	28968424	These results further confirmed that low expression of miR-125b-5p in ESCC promoted the cell proliferation, migaration and invasion partially via targeting HMGA2.	('HMGA2', 'Gene', '8091', (156, 161))	('migaration', 'CPA', (108, 118))	('invasion', 'CPA', (123, 131))	('promoted', 'PosReg', (75, 83))	('HMGA2', 'Gene', (156, 161))	('miR-125b-5p', 'Var', (55, 66))	('targeting', 'Reg', (146, 155))	('cell proliferation', 'CPA', (88, 106))	('miR-125b-5p', 'Chemical', '-', (55, 66))
384327	28968424	miR-125b-5p is down-regulated in many types of cancer including colorectal cancer and gallbladder cancer, and functions as tumor suppressor in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('miR-125b-5p', 'Var', (0, 11))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancer', 'Disease', (98, 104))	('down-regulated', 'NegReg', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gallbladder cancer', 'Disease', 'MESH:D005706', (86, 104))	('tumor', 'Disease', (123, 128))	('colorectal cancer', 'Disease', (64, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('miR-125b-5p', 'Chemical', '-', (0, 11))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('gallbladder cancer', 'Disease', (86, 104))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (75, 81))	('carcinogenesis', 'Disease', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
384328	28968424	miR-125b-5p is involved in the regulation of cell proferation, migration and invasion in tumors.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('miR-125b-5p', 'Var', (0, 11))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('invasion', 'CPA', (77, 85))	('miR-125b-5p', 'Chemical', '-', (0, 11))	('cell proferation', 'CPA', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('migration', 'CPA', (63, 72))
384329	28968424	In colorectal cancer, overexpression of miR-125b-5p using mimics in CRC cell lines significantly inhibited the proliferation, triggered G2/M cell cycle arrest, induced apoptosis, and promoted cell migration and invasion via direct targeting MCL1.	('invasion', 'CPA', (211, 219))	('overexpression', 'PosReg', (22, 36))	('G2/M cell cycle arrest', 'CPA', (136, 158))	('proliferation', 'CPA', (111, 124))	('colorectal cancer', 'Disease', (3, 20))	('induced', 'Reg', (160, 167))	('inhibited', 'NegReg', (97, 106))	('MCL1', 'Gene', (241, 245))	('triggered', 'Reg', (126, 135))	('cell migration', 'CPA', (192, 206))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('miR-125b-5p', 'Chemical', '-', (40, 51))	('MCL1', 'Gene', '4170', (241, 245))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('apoptosis', 'CPA', (168, 177))	('miR-125b-5p', 'Var', (40, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('promoted', 'PosReg', (183, 191))
384332	28968424	Although literatures showed that miR-125b-5p was down-regulated in ESCC, and was associated with HPV infection, the tumorigenic role and mechanism are still unknown.	('tumor', 'Disease', (116, 121))	('miR-125b-5p', 'Var', (33, 44))	('ESCC', 'Disease', (67, 71))	('miR-125b-5p', 'Chemical', '-', (33, 44))	('HPV infection', 'Disease', 'MESH:D030361', (97, 110))	('down-regulated', 'NegReg', (49, 63))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('HPV infection', 'Disease', (97, 110))	('associated', 'Reg', (81, 91))
384333	28968424	Our study found that in ESCC, overexpression of miR-125b-5p inhibited cell proliferation and decreased the expressions of CCNA2, CCND1 and CCNE1.	('CCNE1', 'Gene', (139, 144))	('CCND1', 'Gene', (129, 134))	('miR-125b-5p', 'Var', (48, 59))	('CCNA2', 'Gene', '890', (122, 127))	('cell proliferation', 'CPA', (70, 88))	('overexpression', 'PosReg', (30, 44))	('decreased', 'NegReg', (93, 102))	('inhibited', 'NegReg', (60, 69))	('expressions', 'MPA', (107, 118))	('CCND1', 'Gene', '595', (129, 134))	('ESCC', 'Disease', (24, 28))	('CCNA2', 'Gene', (122, 127))	('miR-125b-5p', 'Chemical', '-', (48, 59))	('CCNE1', 'Gene', '898', (139, 144))
384334	28968424	And we further found that overexpression of miR-125b-5p inhibited migration and invasion, and reduced the expressions of EMT markers, Slug and MMPs.	('expressions', 'MPA', (106, 117))	('Slug', 'Gene', '6591', (134, 138))	('MMPs', 'Gene', (143, 147))	('Slug', 'Gene', (134, 138))	('reduced', 'NegReg', (94, 101))	('EMT', 'CPA', (121, 124))	('miR-125b-5p', 'Chemical', '-', (44, 55))	('MMPs', 'Gene', '4313;4316;4322', (143, 147))	('inhibited', 'NegReg', (56, 65))	('miR-125b-5p', 'Var', (44, 55))
384335	28968424	Next we explored the mechanisms underlying the suppressive effects of miR-125b-5p on the cell proliferation, migration and invasion.	('cell proliferation', 'CPA', (89, 107))	('miR-125b-5p', 'Var', (70, 81))	('invasion', 'CPA', (123, 131))	('migration', 'CPA', (109, 118))	('miR-125b-5p', 'Chemical', '-', (70, 81))
384336	28968424	We found that miR-125b-5p could negatively regulated the expression of HMGA2, and knockdown of HMGA2 partially phenocopied the effects of miR-125b-5p overexpression on the tumor cell phenotypes.	('expression', 'MPA', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('HMGA2', 'Gene', (71, 76))	('tumor', 'Disease', (172, 177))	('HMGA2', 'Gene', '8091', (95, 100))	('knockdown', 'Var', (82, 91))	('HMGA2', 'Gene', (95, 100))	('negatively', 'NegReg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('miR-125b-5p', 'Chemical', '-', (14, 25))	('HMGA2', 'Gene', '8091', (71, 76))	('miR-125b-5p', 'Chemical', '-', (138, 149))
384339	28968424	In prostate cancer cells, silencing of HMGA2 could promote apoptosis, and inhibit migration, invasion and EMT.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('HMGA2', 'Gene', (39, 44))	('inhibit', 'NegReg', (74, 81))	('migration', 'CPA', (82, 91))	('prostate cancer', 'Disease', (3, 18))	('apoptosis', 'CPA', (59, 68))	('promote', 'PosReg', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('silencing', 'Var', (26, 35))	('HMGA2', 'Gene', '8091', (39, 44))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
384340	28968424	Importantly, our findings suggested that miR-125b-5p played vital roles in esophageal carcinogenesis partially through regulating the oncogene HMGA2.	('esophageal carcinogenesis', 'Disease', (75, 100))	('miR-125b-5p', 'Var', (41, 52))	('HMGA2', 'Gene', '8091', (143, 148))	('regulating', 'Reg', (119, 129))	('HMGA2', 'Gene', (143, 148))	('miR-125b-5p', 'Chemical', '-', (41, 52))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (75, 100))
384341	28968424	Dysregulation of miR-125b-5p was associated with many clinical parameters in several types of cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('miR-125b-5p', 'Gene', (17, 28))	('Dysregulation', 'Var', (0, 13))	('miR-125b-5p', 'Chemical', '-', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('associated', 'Reg', (33, 43))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
384342	28968424	In stage II/III breast cancer, low expression level of miR-125b-5p in serum was associated with good neoajuvant chemotherapy response and good prognosis.	('III breast cancer', 'Disease', (12, 29))	('expression level', 'MPA', (35, 51))	('III breast cancer', 'Disease', 'MESH:D001943', (12, 29))	('miR-125b-5p', 'Var', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('low', 'NegReg', (31, 34))	('miR-125b-5p', 'Chemical', '-', (55, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
384345	28968424	Further studies should examine the clinical value of miR-125b-5p as dianostic and prognostic markers in ESCC.	('miR-125b-5p', 'Chemical', '-', (53, 64))	('ESCC', 'Disease', (104, 108))	('miR-125b-5p', 'Var', (53, 64))
384347	28968424	Ectopic expression of miR-125b-5p using mimics significantly increased cisplatin induced cytotoxicity, apoptosis and chmosensitivity by down-regulating Bcl2 both in nasopharyngeal cancer and gallbladder cancer.	('gallbladder cancer', 'Disease', 'MESH:D005706', (191, 209))	('increased', 'PosReg', (61, 70))	('miR-125b-5p', 'Var', (22, 33))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (165, 186))	('cytotoxicity', 'Disease', (89, 101))	('down-regulating', 'NegReg', (136, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))	('cytotoxicity', 'Disease', 'MESH:D064420', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('gallbladder cancer', 'Disease', (191, 209))	('Bcl2', 'Gene', (152, 156))	('nasopharyngeal cancer', 'Disease', (165, 186))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('Bcl2', 'Gene', '596', (152, 156))	('cisplatin', 'MPA', (71, 80))	('chmosensitivity', 'CPA', (117, 132))	('miR-125b-5p', 'Chemical', '-', (22, 33))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (165, 186))	('apoptosis', 'CPA', (103, 112))
384349	28968424	Whether miR-125b-5p could inhibit the drug resistance in ESCC is needed to study.	('miR-125b-5p', 'Chemical', '-', (8, 19))	('drug resistance', 'Phenotype', 'HP:0020174', (38, 53))	('ESCC', 'Disease', (57, 61))	('inhibit', 'NegReg', (26, 33))	('miR-125b-5p', 'Var', (8, 19))	('drug resistance', 'MPA', (38, 53))
384350	28968424	Taken together, our findings revealed the suppressive effects of miR-125b-5p in esophageal carcinogenesis partially via negatively regulating HMGA2.	('miR-125b-5p', 'Var', (65, 76))	('miR-125b-5p', 'Chemical', '-', (65, 76))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (80, 105))	('negatively regulating', 'NegReg', (120, 141))	('esophageal carcinogenesis', 'Disease', (80, 105))	('HMGA2', 'Gene', '8091', (142, 147))	('suppressive', 'NegReg', (42, 53))	('HMGA2', 'Gene', (142, 147))
384356	28440057	And the downstream AKT/mTOR and ERK signaling pathways were inhibited by Linsitinib, while phosphorylation level of NF-kappaB p65 was obviously activated to reduce apoptosis effect in Linsitinib-resistant cell lines.	('Linsitinib', 'Var', (73, 83))	('ERK', 'Gene', '5594', (32, 35))	('phosphorylation level', 'MPA', (91, 112))	('Linsitinib', 'Chemical', 'MESH:C551528', (184, 194))	('NF-kappaB', 'Gene', '4790', (116, 125))	('apoptosis effect', 'CPA', (164, 180))	('ERK', 'Gene', (32, 35))	('NF-kappaB', 'Gene', (116, 125))	('AKT', 'Gene', '207', (19, 22))	('inhibited', 'NegReg', (60, 69))	('reduce', 'NegReg', (157, 163))	('p65', 'Gene', (126, 129))	('activated', 'PosReg', (144, 153))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (23, 27))	('AKT', 'Gene', (19, 22))	('Linsitinib', 'Chemical', 'MESH:C551528', (73, 83))	('p65', 'Gene', '5970', (126, 129))
384364	28440057	Studies of ESCC demonstrated that upon binding to its ligands IGF-1 or IGF-2, IGF-1R is autophosphorylated and the phosphorylation activates the downstream pathways of PI3K/AKT/mTOR and Ras/Raf/MEK/MAPK 9, 10, which promote tumor cell proliferation, invasion, metastasis, and evasion of apoptosis 10, 11.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('IGF-1', 'Gene', '3479', (78, 83))	('AKT', 'Gene', (173, 176))	('promote', 'PosReg', (216, 223))	('IGF-1', 'Gene', '3479', (62, 67))	('IGF-2', 'Gene', (71, 76))	('MAPK 9', 'Gene', '5601', (198, 204))	('IGF-2', 'Gene', '3481', (71, 76))	('invasion', 'CPA', (250, 258))	('phosphorylation', 'Var', (115, 130))	('mTOR', 'Gene', (177, 181))	('MAPK 9', 'Gene', (198, 204))	('metastasis', 'CPA', (260, 270))	('MEK', 'Gene', '5609', (194, 197))	('evasion of apoptosis', 'MPA', (276, 296))	('activates', 'PosReg', (131, 140))	('AKT', 'Gene', '207', (173, 176))	('Raf', 'Gene', (190, 193))	('tumor', 'Disease', (224, 229))	('IGF-1R', 'Gene', (78, 84))	('IGF-1R', 'Gene', '3480', (78, 84))	('mTOR', 'Gene', '2475', (177, 181))	('MEK', 'Gene', (194, 197))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('IGF-1', 'Gene', (78, 83))	('Raf', 'Gene', '22882', (190, 193))	('binding', 'Interaction', (39, 46))	('IGF-1', 'Gene', (62, 67))
384366	28440057	Thus, inhibition of the IGF-1R pathway may offer a promising strategy for ESCC treatment.	('ESCC', 'Disease', (74, 78))	('IGF-1R', 'Gene', (24, 30))	('IGF-1R', 'Gene', '3480', (24, 30))	('inhibition', 'Var', (6, 16))
384385	28440057	Stock solutions with a concentration of 10 mM were prepared and stored at -20 C. Antibodies against phospho-IGF1R (CST-3918), total-IGF1R (CST-9750), phospho-p65 (CST-3033), total-p65 (CST-8242), phospho-Akt308 (CST-2965), phospho-Akt473 (CST-9271), total-Akt (CST-1085), phospho-mTOR (CST-5536), total-mTOR (CST-2983), phospho-ERK1/2 (CST-9102), total-ERK1/2 (CST-4376), and PARP (CST-1078) were purchased from Cell Signaling Technology (Danvers, MA, USA).	('Akt', 'Gene', '207', (231, 234))	('IGF1R', 'Gene', (132, 137))	('mTOR', 'Gene', (280, 284))	('PARP', 'Gene', '1302', (376, 380))	('mTOR', 'Gene', (303, 307))	('mTOR', 'Gene', '2475', (280, 284))	('p65', 'Gene', '5970', (180, 183))	('Akt', 'Gene', (204, 207))	('PARP', 'Gene', (376, 380))	('CST-2983', 'Var', (309, 317))	('Akt', 'Gene', '207', (204, 207))	('mTOR', 'Gene', '2475', (303, 307))	('p65', 'Gene', (158, 161))	('Akt', 'Gene', (256, 259))	('Akt', 'Gene', '207', (256, 259))	('IGF1R', 'Gene', '3480', (108, 113))	('IGF1R', 'Gene', '3480', (132, 137))	('Akt', 'Gene', (231, 234))	('p65', 'Gene', '5970', (158, 161))	('IGF1R', 'Gene', (108, 113))	('p65', 'Gene', (180, 183))
384386	28440057	Cleaved Caspase-3 (25546-1-AP) were purchased from Protein Technology (Tucson, AZ) and Tubulin (ARH4207) were purchased from AR (San Diego, CA).	('Caspase-3', 'Gene', '836', (8, 17))	('25546-1-AP', 'Var', (19, 29))	('Caspase-3', 'Gene', (8, 17))
384403	28440057	In addition, we evaluated the sensitivity of Linsitinib with concentrations of 0.1-80 mumol/L in a panel of six commercially available ESCC cell lines (Eca-109, EC-9706, KYSE-510, KYSE-410, TE-1, and TE-13).	('KYSE-510', 'Var', (170, 178))	('Linsitinib', 'Chemical', 'MESH:C551528', (45, 55))	('EC-9706', 'CellLine', 'CVCL:E307', (161, 168))	('KYSE-410', 'Var', (180, 188))
384405	28440057	As shown in Figure 2, IGF-1R phosphorylation was inhibited after treatment of Linsitinib at 0.1 or 1.0 mumol/L for 72 h. Moreover, compared to the controls, phosphorylation of ERK1/2 was down-regulated by Linsitinib in both sensitive (TE-13) and resistant cell lines (TE-1, KYSE-510), and levels of phosphorylated AKT and mTOR were low in all three cell lines.	('ERK1/2', 'Protein', (176, 182))	('Linsitinib', 'Chemical', 'MESH:C551528', (205, 215))	('AKT', 'Gene', '207', (314, 317))	('Linsitinib', 'Var', (205, 215))	('IGF-1R', 'Gene', '3480', (22, 28))	('phosphorylation', 'MPA', (157, 172))	('Linsitinib', 'Chemical', 'MESH:C551528', (78, 88))	('mTOR', 'Gene', (322, 326))	('IGF-1R', 'Gene', (22, 28))	('mTOR', 'Gene', '2475', (322, 326))	('AKT', 'Gene', (314, 317))	('down-regulated', 'NegReg', (187, 201))
384424	28440057	Recent clinical trials of IGF-1R inhibitors have demonstrated variable antitumor effects 20, 23, which may reflect either the lack of patient selection strategies and/or little understanding of drug-resistant mechanisms.	('IGF-1R', 'Gene', (26, 32))	('IGF-1R', 'Gene', '3480', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('patient', 'Species', '9606', (134, 141))	('inhibitors', 'Var', (33, 43))
384432	28440057	As previously proposed, IGF-1R inhibitors could induce apoptosis, inhibit tumor growth, as well as sensitize cells to chemotherapy in esophageal carcinoma cells 29, 30.	('esophageal carcinoma', 'Disease', (134, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (134, 154))	('induce', 'PosReg', (48, 54))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (134, 154))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('IGF-1R', 'Gene', (24, 30))	('sensitize', 'Reg', (99, 108))	('tumor', 'Disease', (74, 79))	('inhibit', 'NegReg', (66, 73))	('IGF-1R', 'Gene', '3480', (24, 30))	('inhibitors', 'Var', (31, 41))	('apoptosis', 'CPA', (55, 64))
384504	27738344	Pre-treatment 5-FUDR and gene polymorphisms related to 5-FU metabolism (DPYDIVS14+1G>A, MTHFRA1298T or C677T, TMYS TSER) were characterized in gastro-esophageal cancer patients.	('gastro-esophageal cancer', 'Disease', 'MESH:D005764', (143, 167))	('MTHFRA1298T', 'Var', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('gastro-esophageal cancer', 'Disease', (143, 167))	('5-FU', 'Chemical', 'MESH:D005472', (14, 18))	('5-FU', 'Chemical', 'MESH:D005472', (55, 59))	('C677T', 'Var', (103, 108))	('patients', 'Species', '9606', (168, 176))	('C677T', 'Mutation', 'rs1801133', (103, 108))	('TMYS', 'Chemical', '-', (110, 114))	('DPYDIVS14+1G>A', 'Var', (72, 86))	('5-FUDR', 'Chemical', '-', (14, 20))	('TS', 'Gene', '7298', (115, 117))
384511	27738344	The most common side effects associated with 5-FU are diarrhea, mucositis, myelosuppression, hand foot syndrome and rarely cardiac toxicity.	('diarrhea', 'Disease', 'MESH:D003967', (54, 62))	('5-FU', 'Var', (45, 49))	('hand foot syndrome', 'Disease', (93, 111))	('mucositis', 'Disease', 'MESH:D052016', (64, 73))	('myelosuppression', 'Disease', 'MESH:D001855', (75, 91))	('5-FU', 'Chemical', 'MESH:D005472', (45, 49))	('hand foot syndrome', 'Disease', 'MESH:D060831', (93, 111))	('myelosuppression', 'Disease', (75, 91))	('diarrhea', 'Phenotype', 'HP:0002014', (54, 62))	('mucositis', 'Disease', (64, 73))	('cardiac toxicity', 'Disease', 'MESH:D066126', (123, 139))	('diarrhea', 'Disease', (54, 62))	('cardiac toxicity', 'Disease', (123, 139))
384518	27738344	The splice site variant IVS14+1G>A polymorphism in the DPYD gene (rs3918290; allele A also known as *2A allele) is the most consistent genetic marker for toxicity.	('DPYD', 'Gene', (55, 59))	('toxicity', 'Disease', 'MESH:D064420', (154, 162))	('toxicity', 'Disease', (154, 162))	('DPYD', 'Gene', '1806', (55, 59))	('IVS14+1G>A', 'Mutation', 'c.IVS14+1G>A', (24, 34))	('rs3918290;', 'Var', (66, 76))	('IVS14+1G>A polymorphism', 'Var', (24, 47))	('rs3918290', 'Mutation', 'rs3918290', (66, 75))
384523	27738344	DPYD polymorphism is frequently assessed in patients eligible for 5-FU treatment together with the C677T and the A1298T polymorphisms in the MTHFR gene and with the TSER polymorphism in the TS gene.	('A1298T', 'Var', (113, 119))	('DPYD', 'Gene', '1806', (0, 4))	('patients', 'Species', '9606', (44, 52))	('C677T', 'Mutation', 'rs1801133', (99, 104))	('C677T', 'Var', (99, 104))	('A1298T', 'Mutation', 'c.1298A>T', (113, 119))	('MTHFR', 'Gene', '4524', (141, 146))	('5-FU', 'Chemical', 'MESH:D005472', (66, 70))	('TS', 'Gene', '7298', (165, 167))	('MTHFR', 'Gene', (141, 146))	('TS', 'Gene', '7298', (190, 192))	('DPYD', 'Gene', (0, 4))
384526	27738344	As a consequence, polymorphisms affecting TS and MTHFR levels are presumed to be determinants of 5-FU clinical response, but indeed their clinical utility is still controversial.	('MTHFR', 'Gene', '4524', (49, 54))	('TS', 'Gene', '7298', (42, 44))	('polymorphisms', 'Var', (18, 31))	('5-FU', 'Chemical', 'MESH:D005472', (97, 101))	('MTHFR', 'Gene', (49, 54))
384537	27738344	The present study investigated the association between individual 5-FUDR, polymorphisms in DPYD, MTHFR,TSER and toxicity in a population of 107 gastric and gastro-esophageal junction cancer patients.	('polymorphisms', 'Var', (74, 87))	('investigated', 'Reg', (18, 30))	('toxicity', 'Disease', (112, 120))	('patients', 'Species', '9606', (190, 198))	('MTHFR', 'Gene', '4524', (97, 102))	('association', 'Interaction', (35, 46))	('5-FUDR', 'Gene', (66, 72))	('gastro-esophageal junction cancer', 'Disease', (156, 189))	('DPYD', 'Gene', (91, 95))	('gastro-esophageal junction cancer', 'Disease', 'MESH:D005764', (156, 189))	('TS', 'Gene', '7298', (103, 105))	('5-FUDR', 'Chemical', '-', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('DPYD', 'Gene', '1806', (91, 95))	('MTHFR', 'Gene', (97, 102))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))
384539	27738344	The inclusion criteria were: patients with measurable disease, adequate organ function and performance status of grade 0, 1 or 2 as defined by the Eastern Cooperative Oncology Group; patients who had undergone 5-FU based chemotherapy (DCF, EOX, FOLFOX, XELOX, FOLFIRI); patients who had undergone pre-treatment assay of 5-FUDR and characterization of polymorphisms of MTHFR, TSER and DPYD genes.	('patients', 'Species', '9606', (29, 37))	('patients', 'Species', '9606', (270, 278))	('MTHFR', 'Gene', '4524', (368, 373))	('5-FU', 'Chemical', 'MESH:D005472', (210, 214))	('XELOX', 'Chemical', 'MESH:C519688', (253, 258))	('TS', 'Gene', '7298', (375, 377))	('polymorphisms', 'Var', (351, 364))	('5-FU', 'Chemical', 'MESH:D005472', (320, 324))	('5-FUDR', 'Chemical', '-', (320, 326))	('Oncology', 'Phenotype', 'HP:0002664', (167, 175))	('MTHFR', 'Gene', (368, 373))	('DPYD', 'Gene', (384, 388))	('DPYD', 'Gene', '1806', (384, 388))	('patients', 'Species', '9606', (183, 191))	('DCF', 'Chemical', 'MESH:D015649', (235, 238))
384542	27738344	The commercial kit for fluoropyrimidine response (Diatech, Jesi, Italy) was used, according to the manufacturer's protocol, to analyze the following splice-site polymorphisms: IVS14+1G>A in the DPYD gene and C677T and A1298C SNPs in MTHFR gene.	('C677T', 'Mutation', 'rs1801133', (208, 213))	('C677T', 'Var', (208, 213))	('MTHFR', 'Gene', '4524', (233, 238))	('DPYD', 'Gene', (194, 198))	('A1298C', 'Mutation', 'rs1801131', (218, 224))	('A1298C SNPs', 'Var', (218, 229))	('IVS14+1G>A', 'Var', (176, 186))	('fluoropyrimidine', 'Chemical', '-', (23, 39))	('MTHFR', 'Gene', (233, 238))	('DPYD', 'Gene', '1806', (194, 198))	('IVS14+1G>A', 'Mutation', 'c.IVS14+1G>A', (176, 186))
384556	27738344	In the total samples analyzed, the 5-FUDR has a mean value of 1.61 +- 0.42 ng/ml/106 cells/min, and is not significantly affected by age, gender, MTHFR A1298T or C677T polymorphisms nor by the TSER polymorphism (Table 1).	('TS', 'Gene', '7298', (193, 195))	('MTHFR', 'Gene', '4524', (146, 151))	('A1298T', 'Mutation', 'c.1298A>T', (152, 158))	('C677T', 'Mutation', 'rs1801133', (162, 167))	('5-FUDR', 'Chemical', '-', (35, 41))	('MTHFR', 'Gene', (146, 151))	('C677T', 'Var', (162, 167))	('A1298T', 'Var', (152, 158))
384564	27738344	Against a 30% of grade 3-4 toxicities, the DPYD polymorphisms identify about 1-3% of patients at risk, because of the low frequencies of specific alleles in the general population.	('toxicities', 'Disease', (27, 37))	('patients', 'Species', '9606', (85, 93))	('toxicities', 'Disease', 'MESH:D064420', (27, 37))	('DPYD', 'Gene', (43, 47))	('polymorphisms', 'Var', (48, 61))	('DPYD', 'Gene', '1806', (43, 47))
384568	27738344	The underlying toxicity mechanism in poor 5-FU metabolizers could be explained by decreased drug clearance, as also suggested by the association between low 5-FUDR values and the presence of defective DPYD alleles, namely the *2A allele and the Hap7 haplotype.	('5-FUDR', 'MPA', (157, 163))	('low', 'NegReg', (153, 156))	('DPYD', 'Gene', (201, 205))	('5-FU', 'Chemical', 'MESH:D005472', (157, 161))	('*2A', 'Var', (226, 229))	('DPYD', 'Gene', '1806', (201, 205))	('5-FU', 'Chemical', 'MESH:D005472', (42, 46))	('decreased drug clearance', 'Phenotype', 'HP:0020171', (82, 106))	('5-FUDR', 'Chemical', '-', (157, 163))	('drug clearance', 'MPA', (92, 106))	('Hap7', 'Var', (245, 249))	('toxicity', 'Disease', 'MESH:D064420', (15, 23))	('toxicity', 'Disease', (15, 23))	('decreased', 'NegReg', (82, 91))
384574	27738344	Indeed, it has been demonstrated that the sensitivity to 5-FU is affected by polymorphisms in the orotate phosphoribosyltransferase gene (OPRT, transforming 5-FU in 5-fluorouridine monophosphate) and, in cancer tissues, by the level of activity of the OPRT enzyme and by the OPRT/DPD activities ratio.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('OPRT', 'Gene', '7372', (275, 279))	('OPRT', 'Gene', (275, 279))	('OPRT', 'Gene', '7372', (252, 256))	('OPRT', 'Gene', (252, 256))	('sensitivity', 'MPA', (42, 53))	('OPRT', 'Gene', '7372', (138, 142))	('OPRT', 'Gene', (138, 142))	('cancer', 'Disease', (204, 210))	('5-FU', 'Chemical', 'MESH:D005472', (57, 61))	('orotate phosphoribosyltransferase', 'Gene', (98, 131))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('DPD', 'Gene', '1806', (280, 283))	('activity', 'MPA', (236, 244))	('5-FU', 'Chemical', 'MESH:D005472', (157, 161))	('polymorphisms', 'Var', (77, 90))	('DPD', 'Gene', (280, 283))	('5-fluorouridine monophosphate', 'Chemical', 'MESH:C016462', (165, 194))	('affected', 'Reg', (65, 73))	('orotate phosphoribosyltransferase', 'Gene', '7372', (98, 131))
384576	27738344	A limitation of our study is the enrollment of patients treated with combination therapy, even though to date the studies of associations between DPYD polymorphisms and 5-FU toxicities were based on 5-FU based chemotherapy instead of only 5-FU monotherapy.	('DPYD', 'Gene', (146, 150))	('DPYD', 'Gene', '1806', (146, 150))	('toxicities', 'Disease', 'MESH:D064420', (174, 184))	('patients', 'Species', '9606', (47, 55))	('5-FU', 'Chemical', 'MESH:D005472', (199, 203))	('polymorphisms', 'Var', (151, 164))	('5-FU', 'Chemical', 'MESH:D005472', (169, 173))	('toxicities', 'Disease', (174, 184))	('5-FU', 'Chemical', 'MESH:D005472', (239, 243))
384590	27729036	LNM was found in 0.0, 2.7, 6.3, 18.2, 15.9, and 34.3 % of the m1, m2, m3, sm1, sm2, and sm3 lesions, respectively.	('sm2', 'Var', (79, 82))	('sm1', 'Gene', '7911', (74, 77))	('sm3', 'Var', (88, 91))	('sm1', 'Gene', (74, 77))
384635	27729036	And these results were also found in multivariate analysis which meant the tumor size was more than 2 cm (p = 0.003); the poor tumor differentiation (I + I-II vs II + II-III + III, p = 0.004), the depth of tumor invasion (m1 to m3 vs sm1 to sm3, p = 0.005), and angiolymphatic invasion (absent vs present, p < 0.05) were four independent predictors for LNM (Table 5).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('angiolymphatic invasion', 'CPA', (262, 285))	('sm1', 'Gene', (234, 237))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (206, 211))	('m1', 'Var', (222, 224))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('sm1', 'Gene', '7911', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('LNM', 'Disease', (353, 356))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', (75, 80))
384642	27729036	In our study, the incidence of LNM was 0.0 % of patients with m1 lesions, 2.7 % of patients with m2 lesions, 15.9 % of patients with sm2 lesions, and 34.3 % of patients with sm3 lesions.	('LNM', 'Disease', (31, 34))	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (119, 127))	('lesions', 'Var', (65, 72))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (48, 56))
384643	27729036	Furthermore, the involved lymph nodes were seen in more regions of sm2 to sm3 cancer cases than those of m1 to m2.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('sm2 to sm3', 'Var', (67, 77))
384682	26172299	We observed that MSLN amplification rate within esophageal cancer depends on the histotype (31% for adenocarcinomas versus 3% for squamous-cell carcinomas).	('esophageal cancer', 'Disease', (48, 65))	('squamous-cell carcinomas', 'Disease', 'MESH:D002294', (130, 154))	('adenocarcinomas', 'Disease', 'MESH:D000230', (100, 115))	('MSLN amplification', 'Var', (17, 35))	('squamous-cell carcinomas', 'Disease', (130, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('squamous-cell carcinomas', 'Phenotype', 'HP:0002860', (130, 154))	('adenocarcinomas', 'Disease', (100, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
384683	26172299	Subset analysis in breast cancer showed MSLN amplification rates of 28% in triple-negative breast cancer (TNBC) and 33% in basal-like breast cancer.	('MSLN amplification', 'Var', (40, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('breast cancer', 'Disease', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', (19, 32))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
384686	26172299	In mice inactivation of the MSLN gene produced physiologically normal, fertile offspring without any anatomical or histological abnormalities.	('mice', 'Species', '10090', (3, 7))	('inactivation', 'Var', (8, 20))	('MSLN', 'Gene', (28, 32))	('histological abnormalities', 'Phenotype', 'HP:0002664', (115, 141))
384701	26172299	Three clinical trials are ongoing (NCT01355965, NCT01583686, NCT02159716) and two partial responses (PR) were already reported; one in a patient with pancreatic cancer and one patient with malignant pleural mesothelioma.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('patient', 'Species', '9606', (137, 144))	('malignant pleural mesothelioma', 'Disease', (189, 219))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (189, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (199, 219))	('NCT02159716', 'Var', (61, 72))	('NCT01355965', 'Var', (35, 46))	('NCT01583686', 'Var', (48, 59))	('pancreatic cancer', 'Disease', (150, 167))	('patient', 'Species', '9606', (176, 183))
384707	26172299	The number of samples per tumor type in combination with the predicted percentage of samples with a MSLN amplification is shown in Fig.	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('MSLN', 'Var', (100, 104))
384708	26172299	Predicted amplification of MSLN was most frequently found in gynecological tumors, gastrointestinal tumors, NSCLC (21% of N = 612) and in synovial sarcoma (30% of N = 34).	('found', 'Reg', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('synovial sarcoma', 'Disease', 'MESH:D013584', (138, 154))	('gastrointestinal tumors', 'Disease', (83, 106))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (83, 106))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (138, 154))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('MSLN', 'Gene', (27, 31))	('amplification', 'Var', (10, 23))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (100, 106))	('NSCLC', 'Disease', (108, 113))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (83, 106))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('synovial sarcoma', 'Disease', (138, 154))
384709	26172299	In ovarian cancer 66% of 1,255 tumors had a predicted MSLN amplification and in cervical cancers (N = 114) this was 20%.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('MSLN amplification', 'Var', (54, 72))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('ovarian cancer', 'Disease', (3, 17))	('cervical cancers', 'Disease', (80, 96))	('cervical cancers', 'Disease', 'MESH:D002583', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
384710	26172299	Highest predicted MSLN amplification rate for gastrointestinal cancer was seen in pancreatic adenocarcinomas (36% of N = 121), followed by gastric cancers (24% of N = 212) and colorectal cancers (21% of N = 1,131).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colorectal cancers', 'Disease', 'MESH:D015179', (176, 194))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (82, 108))	('MSLN amplification', 'Var', (18, 36))	('gastric cancers', 'Disease', (139, 154))	('gastric cancers', 'Disease', 'MESH:D013274', (139, 154))	('gastric cancers', 'Phenotype', 'HP:0012126', (139, 154))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (46, 69))	('gastrointestinal cancer', 'Disease', (46, 69))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (46, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancers', 'Disease', (176, 194))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (82, 108))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('pancreatic adenocarcinomas', 'Disease', (82, 108))
384711	26172299	A predicted MSLN amplification rate of 13% was seen for esophageal cancer (N = 185), which was mainly driven by the subset of esophageal adenocarcinomas with an MSLN amplification rate of 31% (N = 64).	('esophageal cancer', 'Disease', (56, 73))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (126, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('esophageal adenocarcinomas', 'Disease', (126, 152))	('MSLN amplification', 'Var', (12, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
384713	26172299	Additionally, predicted MSLN amplifications were found in 9% of the renal cell carcinomas (N = 428 tumors), 5% of the thyroid cancers (N = 21 tumors), 5% of acute myeloid leukemias (N = 761 tumors) and 4% of the HNSCC (N = 356 tumors).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (68, 89))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (163, 180))	('renal cell carcinomas', 'Disease', (68, 89))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (68, 89))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('thyroid cancer', 'Phenotype', 'HP:0002890', (118, 132))	('thyroid cancers', 'Disease', (118, 133))	('tumors', 'Disease', (142, 148))	('leukemias', 'Phenotype', 'HP:0001909', (171, 180))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('found', 'Reg', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumors', 'Disease', (227, 233))	('MSLN amplifications', 'Var', (24, 43))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (157, 180))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (157, 180))	('thyroid cancers', 'Disease', 'MESH:D013964', (118, 133))	('acute myeloid leukemias', 'Disease', (157, 180))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
384714	26172299	We observed a predicted MSLN amplification rate of 10% in the total set of breast cancer samples (N = 7,270).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('MSLN amplification', 'Var', (24, 42))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
384715	26172299	Within the subset of estrogen receptor (ER) positive (N = 4,906) and within the subset of human epidermal growth factor 2 (HER2) positive (N = 1,580) breast cancer samples the MSLN amplification rate was 3% and 7%, respectively (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('estrogen receptor', 'Gene', (21, 38))	('breast cancer', 'Disease', (150, 163))	('ER', 'Gene', '2099', (124, 126))	('estrogen receptor', 'Gene', '2099', (21, 38))	('HER2', 'Gene', (123, 127))	('human', 'Species', '9606', (90, 95))	('MSLN amplification', 'Var', (176, 194))	('HER2', 'Gene', '2064', (123, 127))	('ER', 'Gene', '2099', (40, 42))	('positive', 'Reg', (44, 52))
384716	26172299	Within the subset of breast cancer samples for which we were informed on the molecular subtype classification, we observed a high MSLN amplification rate within the basal-like subtype (33% of N = 378).	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('MSLN', 'Var', (130, 134))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))
384725	26172299	The percentages of tumor samples that showed MSLN over-expression or predicted MSLN amplification differ between the two techniques, with on average higher percentages for the IHC data.	('MSLN amplification', 'MPA', (79, 97))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MSLN', 'Var', (45, 49))	('tumor', 'Disease', (19, 24))	('higher', 'PosReg', (149, 155))	('over-expression', 'PosReg', (50, 65))
384728	26172299	This does not account for all tumors, as 50-88% of ovarian cancers are considered MSLN positive based on IHC, while with our technique we find 66% of ovarian cancer samples having a predicted MSLN amplification.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('ovarian cancer', 'Disease', 'MESH:D010051', (150, 164))	('MSLN amplification', 'Var', (192, 210))	('ovarian cancer', 'Disease', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (51, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (150, 164))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('ovarian cancer', 'Disease', 'MESH:D010051', (51, 65))	('ovarian cancers', 'Phenotype', 'HP:0100615', (51, 66))	('ovarian cancers', 'Disease', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('ovarian cancers', 'Disease', 'MESH:D010051', (51, 66))
384731	26172299	We showed high percentages of predicted MSLN amplification in gynecological tumors, gastrointestinal tumors, NSCLC and synovial sarcomas.	('gastrointestinal tumors', 'Disease', (84, 107))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (84, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('MSLN amplification', 'Var', (40, 58))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('NSCLC', 'Disease', (109, 114))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (84, 107))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (119, 136))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('synovial sarcomas', 'Disease', (119, 136))	('tumors', 'Disease', (76, 82))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (119, 135))	('tumors', 'Disease', (101, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (128, 136))	('synovial sarcomas', 'Disease', 'MESH:D013584', (119, 136))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
384732	26172299	In addition, our technique revealed not yet reported predicted MSLN amplifications in 10% of renal cell cancers and 5% of thyroid cancers.	('renal cell cancers', 'Disease', (93, 111))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('thyroid cancers', 'Disease', (122, 137))	('MSLN amplifications', 'Var', (63, 82))	('thyroid cancers', 'Disease', 'MESH:D013964', (122, 137))	('renal cell cancers', 'Disease', 'MESH:C538614', (93, 111))	('thyroid cancer', 'Phenotype', 'HP:0002890', (122, 136))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
384733	26172299	In addition, we observed that MSLN amplification rate within esophageal cancer depends on the histotype (31% for adenocarcinomas versus 3% for squamous-cell carcinomas).	('adenocarcinomas', 'Disease', 'MESH:D000230', (113, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('adenocarcinomas', 'Disease', (113, 128))	('MSLN amplification', 'Var', (30, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('squamous-cell carcinomas', 'Disease', 'MESH:D002294', (143, 167))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('squamous-cell carcinomas', 'Disease', (143, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('squamous-cell carcinomas', 'Phenotype', 'HP:0002860', (143, 167))	('esophageal cancer', 'Disease', (61, 78))
384734	26172299	Subtype analysis in breast cancer showed MSLN amplification rates of 28% in triple-negative breast cancer (TNBC) and 33% in basal-like breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', (92, 105))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancer', 'Disease', (20, 33))	('MSLN amplification', 'Var', (41, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
384776	25447851	Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett's Esophagus Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC).	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (139, 164))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (72, 91))	("Barrett's Esophagus", 'Disease', (72, 91))	('GDF7', 'Gene', (28, 32))	('esophageal adenocarcinoma', 'Disease', (139, 164))	('TBX5', 'Gene', '6910', (19, 23))	('increases', 'PosReg', (117, 126))	('TBX5', 'Gene', (19, 23))	('Polymorphisms', 'Var', (0, 13))	('GDF7', 'Gene', '151449', (28, 32))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (139, 164))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (92, 111))	('Associated', 'Reg', (37, 47))	('BE', 'Phenotype', 'HP:0100580', (113, 115))	('Barrett', 'Disease', (92, 99))	('EAC', 'Phenotype', 'HP:0011459', (166, 169))
384777	25447851	We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1.	('FOXF1', 'Gene', '2294', (189, 194))	('single nucleotide polymorphisms', 'Var', (52, 83))	('FOXF1', 'Gene', (189, 194))	('BE', 'Phenotype', 'HP:0100580', (24, 26))
384779	25447851	We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.	('BE', 'Phenotype', 'HP:0100580', (146, 148))	('EAC', 'Phenotype', 'HP:0011459', (147, 150))	('associated', 'Reg', (73, 83))	('patients', 'Species', '9606', (174, 182))	('BE', 'Phenotype', 'HP:0100580', (188, 190))	('BE', 'Phenotype', 'HP:0100580', (89, 91))	('variants', 'Var', (64, 72))
384781	25447851	The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development.	('GDF7', 'Gene', (51, 55))	('rs3072', 'Var', (57, 63))	('rs2701108', 'Var', (142, 151))	('GDF7', 'Gene', '151449', (51, 55))	('rs3072', 'Mutation', 'rs3072', (57, 63))	('TBX5', 'Gene', '6910', (136, 140))	('TBX5', 'Gene', (136, 140))	('rs2701108', 'Mutation', 'rs2701108', (142, 151))
384782	25447851	Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674).	('BE', 'Phenotype', 'HP:0100580', (27, 29))	('rs2687201', 'Mutation', 'rs2687201', (70, 79))	('rs2687201', 'Var', (70, 79))	('EAC', 'Phenotype', 'HP:0011459', (63, 66))	('rs10423674', 'Var', (97, 107))	('rs10423674', 'Mutation', 'rs10423674', (97, 107))	('rs11789015', 'Var', (81, 91))	('rs11789015', 'Mutation', 'rs11789015', (81, 91))	('BE', 'Phenotype', 'HP:0100580', (62, 64))
384783	25447851	Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 x 10-9).	('esophageal adenocarcinoma', 'Disease', (72, 97))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (72, 97))	('rs3784262', 'Var', (99, 108))	('ALDH1A2', 'Gene', '8854', (117, 124))	('ALDH1A2', 'Gene', (117, 124))	('rs3784262', 'Mutation', 'rs3784262', (99, 108))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (72, 97))	('BE', 'Phenotype', 'HP:0100580', (65, 67))
384788	25447851	A role for genetics in the pathogenesis of gastroesophageal reflux disease, including BE and EAC, has been implicated on the basis of 3 observations: concordance in monozygous and dizygous twins; the increased risk of disease in those with a positive family history; and, recently, the identification of single nucleotide polymorphisms (SNPs) associated with BE in Genome-Wide Association Studies (GWAS).	('BE', 'Phenotype', 'HP:0100580', (86, 88))	('BE', 'Phenotype', 'HP:0100580', (359, 361))	('gastroesophageal reflux disease', 'Disease', (43, 74))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (43, 66))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (43, 74))	('EAC', 'Phenotype', 'HP:0011459', (93, 96))	('single nucleotide polymorphisms', 'Var', (304, 335))
384789	25447851	Our GWAS previously identified 2 SNPs, on chromosomes 6p21 (rs9257809; P = 4.1 x 10-9) and 16q24 (rs9936833; P = 2.7 x 10-10), that are associated with BE.	('associated', 'Reg', (136, 146))	('rs9257809;', 'Var', (60, 70))	('BE', 'Phenotype', 'HP:0100580', (152, 154))	('rs9936833;', 'Var', (98, 108))	('rs9257809', 'Mutation', 'rs9257809', (60, 69))	('rs9936833', 'Mutation', 'rs9936833', (98, 107))
384794	25447851	Replication Phase patients were diagnosed with BE with lengths of >=1 cm (C1M1) circumferential disease or >=2 cm tongue patterns (C0M2), according to the Prague criteria.	('circumferential disease', 'Disease', (80, 103))	('BE', 'Phenotype', 'HP:0100580', (47, 49))	('patients', 'Species', '9606', (18, 26))	('>=2 cm', 'Var', (107, 113))
384807	25447851	In Replication Phase 2, samples underwent custom genotyping for SNPs that met one of the following criteria: Passociation < 10-4 in combined Discovery and Replication Phase 1 analysis (n = 63); Passociation < 10-4 in Discovery Phase, but not included in Replication Phase 1 (n = 12); and Passociation < 10-4 in a sex-stratified analysis of the Discovery phase (n = 5); and candidate polymorphisms previously reported as associated with BE and not well tagged by the Discovery Phase or Immunochip arrays, specifically, MSR1 p.Arg293Gly, and variants in IGF1R and GHR (Supplementary Table 1).	('MSR1', 'Gene', '4481', (518, 522))	('GHR', 'Gene', '2690', (562, 565))	('p.Arg293Gly', 'Mutation', 'rs41341748', (523, 534))	('IGF1R', 'Gene', (552, 557))	('p.Arg293Gly', 'Var', (523, 534))	('MSR1', 'Gene', (518, 522))	('IGF1R', 'Gene', '3480', (552, 557))	('variants', 'Var', (540, 548))	('GHR', 'Gene', (562, 565))	('BE', 'Phenotype', 'HP:0100580', (436, 438))
384811	25447851	These SNPs were genotyped in an additional 1765 cases and 1586 controls from the UK and in an Irish cohort of 245 cases and 473 controls (Replication Phase 2, previously used to genotype rs9257809 and rs9936833 described in Su et al).	('rs9936833', 'Mutation', 'rs9936833', (201, 210))	('rs9257809', 'Mutation', 'rs9257809', (187, 196))	('rs9936833', 'Var', (201, 210))	('rs9257809', 'Var', (187, 196))
384812	25447851	After meta-analysis of these new data together with Discovery Phase and Replication Phase 1, seven SNPs showing evidence of associations with BE risk at Pmeta <5 x 10-6 were identified and genotyped in Replication Phase 3 samples (Table 1).	('Pmeta', 'Chemical', '-', (153, 158))	('BE', 'Phenotype', 'HP:0100580', (142, 144))	('Pmeta <', 'Var', (153, 160))	('associations', 'Interaction', (124, 136))
384813	25447851	After Replication Phase 3, two SNPs:rs3072 and rs2701108 on chromosome 2p24 and 12q24, respectively:reached the level of significance conventionally used for GWAS (P = 5 x 10-8) (Table 1).	('rs3072', 'Mutation', 'rs3072', (36, 42))	('rs3072', 'Var', (36, 42))	('rs2701108', 'Var', (47, 56))	('rs2701108', 'Mutation', 'rs2701108', (47, 56))
384814	25447851	Combined Pmeta values were 1.8 x 10-11 for rs3072 (OR = 1.14; 95% CI: 1.09-1.18) and 7.5 x 10-9 for rs2701108 (OR = 0.90; 95% CI: 0.86-0.93), derived from a total sample of 10,158 BE cases and 21,062 controls (Supplementary Table 3).	('rs2701108', 'Mutation', 'rs2701108', (100, 109))	('rs3072', 'Var', (43, 49))	('rs2701108', 'Var', (100, 109))	('rs3072', 'Mutation', 'rs3072', (43, 49))	('Pmeta', 'Chemical', '-', (9, 14))	('BE', 'Phenotype', 'HP:0100580', (180, 182))
384815	25447851	The associations remained at or near genome-wide significance upon restricting the analysis to the 8521 cases with histologically proven intestinal metaplasia (rs3072: P = 1.3 x 10-9; OR = 1.13; 95% CI: 1.09-1.17; rs2701108: P = 6.2 x 10-8; OR = 0.90; 95% CI: 0.86-0.94).	('rs2701108', 'Mutation', 'rs2701108', (214, 223))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (137, 158))	('rs3072', 'Mutation', 'rs3072', (160, 166))	('rs3072:', 'Var', (160, 167))	('rs2701108', 'Var', (214, 223))	('intestinal metaplasia', 'Disease', (137, 158))
384816	25447851	rs3072 lies between 2 genes, mapping 7.5 kb downstream of GDF7 (also known as BMP12) and 6.5 kb downstream of C2orf43 (Figure 2).	('C2orf43', 'Gene', (110, 117))	('GDF7', 'Gene', (58, 62))	('C2orf43', 'Gene', '60526', (110, 117))	('GDF7', 'Gene', '151449', (58, 62))	('BMP12', 'Gene', (78, 83))	('BMP12', 'Gene', '151449', (78, 83))	('rs3072', 'Mutation', 'rs3072', (0, 6))	('rs3072', 'Var', (0, 6))
384817	25447851	rs2701108 is 117 kb downstream of TBX5 and 270 kb upstream of RBM19.	('TBX5', 'Gene', (34, 38))	('rs2701108', 'Mutation', 'rs2701108', (0, 9))	('TBX5', 'Gene', '6910', (34, 38))	('RBM19', 'Gene', (62, 67))	('rs2701108', 'Var', (0, 9))	('RBM19', 'Gene', '9904', (62, 67))
384818	25447851	At chromosome 2p24, rs3072 remained the most strongly associated SNP, but at chromosome 12q24, rs1920562 was more strongly associated with disease risk (PDiscovery = 1.4 x 10-5; OR = 0.84) than the lead genotyped SNP (PDiscovery = 1.4 x 10-3; OR = 0.88).	('associated', 'Reg', (123, 133))	('rs1920562', 'Var', (95, 104))	('rs1920562', 'Mutation', 'rs1920562', (95, 104))	('rs3072', 'Var', (20, 26))	('disease', 'Disease', (139, 146))	('rs3072', 'Mutation', 'rs3072', (20, 26))
384819	25447851	rs1920562 (linkage disequilibrium [LD] with rs2701108; r2 = 0.6) lies 131 kb downstream of TBX5 and 256 kb upstream of RBM19.	('rs1920562', 'Var', (0, 9))	('rs1920562', 'Mutation', 'rs1920562', (0, 9))	('RBM19', 'Gene', (119, 124))	('TBX5', 'Gene', '6910', (91, 95))	('RBM19', 'Gene', '9904', (119, 124))	('TBX5', 'Gene', (91, 95))	('rs2701108', 'Mutation', 'rs2701108', (44, 53))	('rs2701108', 'Var', (44, 53))
384820	25447851	rs3072, which may alter a GATA binding motif, lies within a region of histone modifications, such as H3K4Me1, which mark enhancers (data from lymphoblastoid cell line (LCL) GM12878).	('rs3072', 'Mutation', 'rs3072', (0, 6))	('enhancers', 'PosReg', (121, 130))	('rs3072', 'Var', (0, 6))	('GATA', 'Chemical', '-', (26, 30))
384822	25447851	One of these, rs7255, maps to a site of high evolutionary conservation/constraint; another SNP, rs9306894, whilst not at a conserved site (Supplementary Table 5), is predicted as "likely to affect protein binding and linked to expression of a gene target" according to RegulomeDB.	('rs9306894', 'Var', (96, 105))	('rs7255', 'Mutation', 'rs7255', (14, 20))	('affect', 'Reg', (190, 196))	('expression', 'MPA', (227, 237))	('rs7255', 'Var', (14, 20))	('protein', 'Protein', (197, 204))	('binding', 'Interaction', (205, 212))	('linked', 'Reg', (217, 223))	('rs9306894', 'Mutation', 'rs9306894', (96, 105))
384825	25447851	After correcting for copy number, we determined associations between rs9306894 genotype and total RNA levels for expression quantitative trait locus (eQTL) analysis and bias in allelic expression of coding SNPs (allele-specific expression [ASE] analysis).	('rs9306894', 'Mutation', 'rs9306894', (69, 78))	('RNA levels', 'MPA', (98, 108))	('rs9306894', 'Var', (69, 78))
384827	25447851	In public data sets based on monocytes and on lymphoblastoid cell lines and adipose tissue, C2orf43 is the suggested target of rs9306894 following eQTL studies (GENevar; P = 7 x 10-4).	('rs9306894', 'Mutation', 'rs9306894', (127, 136))	('C2orf43', 'Gene', '60526', (92, 99))	('C2orf43', 'Gene', (92, 99))	('rs9306894', 'Var', (127, 136))
384828	25447851	rs9306894 genotype was not associated with GDF7 expression in these cell types.	('expression', 'MPA', (48, 58))	('rs9306894', 'Mutation', 'rs9306894', (0, 9))	('GDF7', 'Gene', (43, 47))	('rs9306894', 'Var', (0, 9))	('GDF7', 'Gene', '151449', (43, 47))
384831	25447851	rs1920562 and an additional SNP (rs1247938) in moderate LD (r2 = 0.52) with rs2701108, are highlighted by Regulome DB as being the most likely SNPs in this region to affect protein binding.	('rs2701108', 'Mutation', 'rs2701108', (76, 85))	('rs1920562', 'Var', (0, 9))	('rs1247938', 'Mutation', 'rs1247938', (33, 42))	('rs2701108', 'Var', (76, 85))	('rs1920562', 'Mutation', 'rs1920562', (0, 9))	('rs1247938', 'Var', (33, 42))	('protein', 'Protein', (173, 180))	('affect', 'Reg', (166, 172))
384832	25447851	CTCF and RAD21 binding are predicted to be affected by rs1247938 and the ability of IKZF1 to bind is predicted to be altered by rs1920562.	('affected', 'Reg', (43, 51))	('IKZF1', 'Gene', (84, 89))	('RAD21', 'Gene', (9, 14))	('rs1247938', 'Mutation', 'rs1247938', (55, 64))	('CTCF', 'Gene', (0, 4))	('rs1247938', 'Var', (55, 64))	('altered', 'Reg', (117, 124))	('bind', 'Interaction', (93, 97))	('RAD21', 'Gene', '5885', (9, 14))	('CTCF', 'Gene', '10664', (0, 4))	('IKZF1', 'Gene', '10320', (84, 89))	('rs1920562', 'Var', (128, 137))	('binding', 'Interaction', (15, 22))	('rs1920562', 'Mutation', 'rs1920562', (128, 137))
384834	25447851	However, none of the three rs2701108 region SNPs was associated with TBX5, TBX3 or RBM19 expression in the TCGA data (PeQTL > .39; PASE > .43; n = 62), was an eQTL in whole-transcriptome analysis, or was an eQTL in the public databases (details not shown).	('rs2701108', 'Mutation', 'rs2701108', (27, 36))	('expression', 'MPA', (89, 99))	('rs2701108', 'Var', (27, 36))	('TBX3', 'Gene', '6926', (75, 79))	('TBX3', 'Gene', (75, 79))	('RBM19', 'Gene', (83, 88))	('associated', 'Reg', (53, 63))	('RBM19', 'Gene', '9904', (83, 88))	('TBX5', 'Gene', '6910', (69, 73))	('TBX5', 'Gene', (69, 73))
384839	25447851	rs909253 maps to a highly conserved base (based on SiPhy score) in an intron of LTA (tumor necrosis factor-beta) where histone marks associated with both promoters and enhancers are present in lymphoblastoid cell lines (LCLs).	('tumor necrosis factor-beta', 'Gene', (85, 111))	('tumor necrosis factor-beta', 'Gene', '4049', (85, 111))	('rs909253', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('rs909253', 'Mutation', 'rs909253', (0, 8))
384841	25447851	We were able to genotype 3 other candidate SNPs previously reported for BE susceptibility (rs41341748, rs2715425, rs6898743) on the Sequenom iPLEX panel used to genotype UK Replication 2.	('rs41341748', 'Var', (91, 101))	('rs2715425', 'Var', (103, 112))	('rs2715425', 'Mutation', 'rs2715425', (103, 112))	('rs6898743', 'Mutation', 'rs6898743', (114, 123))	('rs6898743', 'Var', (114, 123))	('rs41341748', 'Mutation', 'rs41341748', (91, 101))	('BE', 'Phenotype', 'HP:0100580', (72, 74))
384842	25447851	Because rs41341748 (MSR1 p.Arg293Gly) has a low minor allele frequency (<5%) and consequently our power to detect an association was relatively low, we additionally genotyped it in UK Replication 3.	('MSR1', 'Gene', (20, 24))	('p.Arg293Gly', 'Mutation', 'rs41341748', (25, 36))	('MSR1', 'Gene', '4481', (20, 24))	('rs41341748', 'Mutation', 'rs41341748', (8, 18))	('rs41341748', 'Var', (8, 18))
384843	25447851	Three new genome-wide significant BE + EAC loci (4 SNPs) were recently identified by Levine et al in a combined analysis of EAC and BE: rs10419226 and rs10423674 in CRTC1, rs11789015 in BARX1 and rs2687201 within 100 kb of FOXP1.	('rs2687201', 'Var', (196, 205))	('BE', 'Phenotype', 'HP:0100580', (132, 134))	('rs2687201', 'Mutation', 'rs2687201', (196, 205))	('FOXP1', 'Gene', '27086', (223, 228))	('rs10423674', 'Var', (151, 161))	('BE', 'Phenotype', 'HP:0100580', (34, 36))	('CRTC1', 'Gene', (165, 170))	('rs10419226', 'Mutation', 'rs10419226', (136, 146))	('rs10423674', 'Mutation', 'rs10423674', (151, 161))	('EAC', 'Phenotype', 'HP:0011459', (39, 42))	('FOXP1', 'Gene', (223, 228))	('EAC', 'Phenotype', 'HP:0011459', (124, 127))	('rs10419226', 'Var', (136, 146))	('BARX1', 'Gene', '56033', (186, 191))	('rs11789015', 'Var', (172, 182))	('rs11789015', 'Mutation', 'rs11789015', (172, 182))	('CRTC1', 'Gene', '23373', (165, 170))	('BARX1', 'Gene', (186, 191))	('BE + EAC', 'Chemical', '-', (34, 42))
384844	25447851	None of these associations was genome-wide significant at P < 5 x 10-8 when Levine et al restricted their analysis to BE cases alone, although one SNP, rs10419226, within CRTC1, reached P = 5.5 x 10-8.	('BE', 'Phenotype', 'HP:0100580', (118, 120))	('CRTC1', 'Gene', (171, 176))	('CRTC1', 'Gene', '23373', (171, 176))	('rs10419226', 'Var', (152, 162))	('rs10419226', 'Mutation', 'rs10419226', (152, 162))
384846	25447851	Of the 4 Levine SNPs, rs10423674, 1 of 2 SNPs in CRTC1, and rs2687201, near FOXP1, were supported in this study (P = 0.02; OR = 1.14; 95% CI: 1.03-1.27 and P = 0.05; OR = 0.94; 95% CI: 0.88-1.00, respectively).	('rs2687201', 'Mutation', 'rs2687201', (60, 69))	('FOXP1', 'Gene', '27086', (76, 81))	('CRTC1', 'Gene', (49, 54))	('rs10423674', 'Mutation', 'rs10423674', (22, 32))	('CRTC1', 'Gene', '23373', (49, 54))	('rs10423674', 'Var', (22, 32))	('FOXP1', 'Gene', (76, 81))	('rs2687201', 'Var', (60, 69))
384847	25447851	There was also some support for rs11789015, near BARX1 (P = 0.07; OR = 0.90; 95% CI: 0.81-1.01).	('rs11789015', 'Mutation', 'rs11789015', (32, 42))	('rs11789015', 'Var', (32, 42))	('BARX1', 'Gene', '56033', (49, 54))	('BARX1', 'Gene', (49, 54))
384848	25447851	However, the association at rs10419226, within CRTC1, was not replicated in our data (P = 0.87; OR = 1.01; 95% CI: 0.91-1.11).	('rs10419226', 'Var', (28, 38))	('CRTC1', 'Gene', (47, 52))	('CRTC1', 'Gene', '23373', (47, 52))	('rs10419226', 'Mutation', 'rs10419226', (28, 38))
384850	25447851	In a BE-only meta-analysis, the associations improved with the inclusion of our data for 3 out of the 4 SNPs, with 1 (rs2687201, FOXP1) reaching genome-wide significance for BE (Table 2).	('FOXP1', 'Gene', (129, 134))	('associations', 'Interaction', (32, 44))	('BE', 'Phenotype', 'HP:0100580', (5, 7))	('rs2687201', 'Var', (118, 127))	('rs2687201', 'Mutation', 'rs2687201', (118, 127))	('BE', 'Phenotype', 'HP:0100580', (174, 176))	('FOXP1', 'Gene', '27086', (129, 134))
384852	25447851	On performing a meta-analysis of the Levine BE + EAC cases with our UK Discovery Phase, 4 SNPs (rs1497205, rs254348, rs3784262, and rs4523255) showed Pmeta < 10-5 and were not strongly correlated with 1 of the 4 BE + EAC SNPs reported previously.	('Pmeta', 'Chemical', '-', (150, 155))	('rs1497205', 'Var', (96, 105))	('BE + EAC', 'Chemical', '-', (44, 52))	('rs4523255', 'Var', (132, 141))	('BE + EAC', 'Chemical', '-', (212, 220))	('rs254348', 'Var', (107, 115))	('rs1497205', 'Mutation', 'rs1497205', (96, 105))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('rs4523255', 'Mutation', 'rs4523255', (132, 141))	('EAC', 'Phenotype', 'HP:0011459', (217, 220))	('Pmeta', 'MPA', (150, 155))	('BE', 'Phenotype', 'HP:0100580', (44, 46))	('rs3784262', 'Var', (117, 126))	('rs254348', 'Mutation', 'rs254348', (107, 115))	('BE', 'Phenotype', 'HP:0100580', (212, 214))	('rs3784262', 'Mutation', 'rs3784262', (117, 126))
384853	25447851	We therefore genotyped these 4 SNPs in our Replication Phase samples; rs3784262 (within ALDH1A2) was associated with BE + EAC (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 x 10-9).	('rs3784262', 'Mutation', 'rs3784262', (70, 79))	('ALDH1A2', 'Gene', (88, 95))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('BE + EAC', 'Disease', (117, 125))	('rs3784262', 'Var', (70, 79))	('ALDH1A2', 'Gene', '8854', (88, 95))	('BE + EAC', 'Chemical', '-', (117, 125))	('BE', 'Phenotype', 'HP:0100580', (117, 119))
384854	25447851	eQTL and ASE analysis (see Results - In Silico Fine Mapping and Annotation of the Chromosome 2p24 and 12q24 Loci) did not show associations for the rs3784262 proxy rs7165247 in TCGA data or other public data sets (details not shown).	('rs3784262', 'Var', (148, 157))	('rs7165247', 'Var', (164, 173))	('rs3784262', 'Mutation', 'rs3784262', (148, 157))	('rs7165247', 'Mutation', 'rs7165247', (164, 173))
384855	25447851	We have added 2 new BE predisposition SNPs, rs3072 on chromosome 2p24 and rs2701108 on chromosome 12q24, to the 2 BE SNPs on chromosome 6p21 (HLA region) and chromosome 16q23 (near FOXF1) that we reported previously.	('FOXF1', 'Gene', '2294', (181, 186))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('rs2701108', 'Mutation', 'rs2701108', (74, 83))	('rs3072', 'Var', (44, 50))	('rs2701108', 'Var', (74, 83))	('rs3072', 'Mutation', 'rs3072', (44, 50))	('BE', 'Phenotype', 'HP:0100580', (20, 22))	('FOXF1', 'Gene', (181, 186))
384861	25447851	In the chromosome 12q24 region, rs1920562 (the top imputed SNP) provided the strongest association signal and maps to a possible enhancer.	('rs1920562', 'Var', (32, 41))	('association', 'Interaction', (87, 98))	('rs1920562', 'Mutation', 'rs1920562', (32, 41))
384863	25447851	It is involved in cardiac development and its deficiency causes thoracic malformations and abnormalities of the diaphragmatic musculature, which could predispose patients to hiatus hernia and acid reflux, 2 subphenotypes of BE.	('acid reflux', 'Disease', (192, 203))	('hiatus hernia', 'Disease', (174, 187))	('patients', 'Species', '9606', (162, 170))	('acid reflux', 'Phenotype', 'HP:0002020', (192, 203))	('hiatus hernia', 'Disease', 'MESH:D006551', (174, 187))	('thoracic malformations and abnormalities', 'Disease', 'MESH:D000014', (64, 104))	('abnormalities of the diaphragmatic', 'Phenotype', 'HP:0000775', (91, 125))	('hernia', 'Phenotype', 'HP:0100790', (181, 187))	('deficiency', 'Var', (46, 56))	('hiatus hernia', 'Phenotype', 'HP:0002036', (174, 187))	('causes', 'Reg', (57, 63))	('BE', 'Phenotype', 'HP:0100580', (224, 226))
384864	25447851	Messenger RNA expression analysis using TCGA EAC data and public data from leukocytes and adipocytes provided little evidence that rs3072 or rs2701108 (or other SNPs in strong LD) were eQTLs or influenced ASE.	('rs3072', 'Mutation', 'rs3072', (131, 137))	('rs3072', 'Var', (131, 137))	('rs2701108', 'Var', (141, 150))	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('rs2701108', 'Mutation', 'rs2701108', (141, 150))
384866	25447851	Even for the "prototypic" multicancer SNP rs6983267, convincingly demonstrating the effects of SNP alleles on gene expression has required considerable additional work in a variety of systems, and even now, consistent eQTL and ASE associations have not been shown.	('rs6983267', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('rs6983267', 'Mutation', 'rs6983267', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
384868	25447851	We showed rs2687201 (FOXP1) to be associated with disease in a BE-only analysis.	('rs2687201', 'Mutation', 'rs2687201', (10, 19))	('associated', 'Reg', (34, 44))	('rs2687201', 'Var', (10, 19))	('FOXP1', 'Gene', '27086', (21, 26))	('disease', 'Disease', (50, 57))	('FOXP1', 'Gene', (21, 26))	('BE', 'Phenotype', 'HP:0100580', (63, 65))
384870	25447851	However, we were not able to replicate the association observed for another SNP (rs10419226) in CRTC1.	('rs10419226', 'Mutation', 'rs10419226', (81, 91))	('rs10419226', 'Var', (81, 91))	('CRTC1', 'Gene', (96, 101))	('CRTC1', 'Gene', '23373', (96, 101))
384871	25447851	We found another SNP, rs3784262 (ALDH1A2), to be formally associated with BE + EAC upon meta-analysis of our data with the Levine BE + EAC dataset.	('ALDH1A2', 'Gene', (33, 40))	('BE + EAC', 'Chemical', '-', (74, 82))	('associated', 'Reg', (58, 68))	('rs3784262', 'Var', (22, 31))	('BE + EAC', 'Chemical', '-', (130, 138))	('EAC', 'Phenotype', 'HP:0011459', (135, 138))	('BE', 'Phenotype', 'HP:0100580', (130, 132))	('rs3784262', 'Mutation', 'rs3784262', (22, 31))	('BE', 'Phenotype', 'HP:0100580', (74, 76))	('ALDH1A2', 'Gene', '8854', (33, 40))	('EAC', 'Phenotype', 'HP:0011459', (79, 82))	('BE + EAC', 'Disease', (74, 82))
384873	25447851	Of the candidate SNPs we assessed (Supplementary Table 8), we found supporting evidence, albeit short of genome-wide significance, for rs909253 (P = 3.1 x 10-4), mapping to an intronic region of LTA within the HLA region, but not in LD with rs9257809, the other HLA BE SNP.	('rs909253', 'Var', (135, 143))	('rs909253', 'Mutation', 'rs909253', (135, 143))	('BE', 'Phenotype', 'HP:0100580', (266, 268))	('mapping', 'Reg', (162, 169))	('rs9257809', 'Mutation', 'rs9257809', (241, 250))
384875	25447851	Second, the inflammatory response may be important: the SNPs within the HLA region (rs9257809 and, perhaps, rs909253) might act in this way and pathway analysis provided suggestive evidence of a role for type 1 diabetes genes in BE etiology.	('rs9257809', 'Mutation', 'rs9257809', (84, 93))	('rs909253', 'Var', (108, 116))	('rs9257809', 'Var', (84, 93))	('BE', 'Phenotype', 'HP:0100580', (229, 231))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (204, 219))	('diabetes', 'Disease', (211, 219))	('diabetes', 'Disease', 'MESH:D003920', (211, 219))	('rs909253', 'Mutation', 'rs909253', (108, 116))
385005	23878486	Aberrant methylation of CDKN2B and TIMP3 was most frequent and promoter hypermethylation of BRCA2, APC, CDKN2A, and CDKN2B was detected in two cases with subsequent progression to SCC.	('CDKN2A', 'Gene', '1029', (104, 110))	('TIMP3', 'Gene', (35, 40))	('APC', 'Disease', 'MESH:D011125', (99, 102))	('promoter', 'MPA', (63, 71))	('APC', 'Disease', (99, 102))	('CDKN2B', 'Gene', (116, 122))	('SCC', 'Gene', (180, 183))	('BRCA2', 'Gene', (92, 97))	('CDKN2B', 'Gene', '1030', (116, 122))	('CDKN2B', 'Gene', (24, 30))	('Aberrant methylation', 'Var', (0, 20))	('SCC', 'Phenotype', 'HP:0002860', (180, 183))	('SCC', 'Gene', '6317', (180, 183))	('CDKN2A', 'Gene', (104, 110))	('BRCA2', 'Gene', '675', (92, 97))	('CDKN2B', 'Gene', '1030', (24, 30))	('detected', 'Reg', (127, 135))	('TIMP3', 'Gene', '7078', (35, 40))
385026	23878486	The most common association of laryngeal papillomatosis and carcinoma has been correlated to the presence of HPV DNA synergistic with mucosal irritation, but in our patient HPV was negative.	('carcinoma', 'Disease', (60, 69))	('presence', 'Var', (97, 105))	('HPV', 'Species', '10566', (173, 176))	('patient', 'Species', '9606', (165, 172))	('laryngeal papillomatosis', 'Disease', 'MESH:C537876', (31, 55))	('mucosal irritation', 'Disease', (134, 152))	('carcinoma', 'Disease', 'MESH:D002277', (60, 69))	('laryngeal papillomatosis', 'Disease', (31, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('association', 'Interaction', (16, 27))	('HPV', 'Species', '10566', (109, 112))	('papilloma', 'Phenotype', 'HP:0012740', (41, 50))	('mucosal irritation', 'Disease', 'MESH:D052016', (134, 152))
385144	33605567	[26] found that the expression of lncRNA SBF2-AS1 was significantly up-regulated in ESCC cells, and the proliferation ability of ESCC was significantly reduced after silencing lncRNA SBF2-AS1.	('si', 'Chemical', 'MESH:D012825', (138, 140))	('expression', 'MPA', (20, 30))	('SBF2', 'Gene', (183, 187))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('AS1', 'Gene', (46, 49))	('silencing', 'Var', (166, 175))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('reduced', 'NegReg', (152, 159))	('proliferation ability', 'CPA', (104, 125))	('AS1', 'Gene', '5729', (188, 191))	('AS1', 'Gene', (188, 191))	('SBF2', 'Gene', '81846', (183, 187))	('SBF2', 'Gene', '81846', (41, 45))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('AS1', 'Gene', '5729', (46, 49))	('up-regulated', 'PosReg', (68, 80))	('SBF2', 'Gene', (41, 45))
385146	33605567	[27] found that lncRNA DUXAP8 can promote the proliferation of EC cells and may be an important regulator of EC.	('DUXAP8', 'Gene', (23, 29))	('DUXAP8', 'Gene', '503637', (23, 29))	('lncRNA', 'Var', (16, 22))	('proliferation', 'CPA', (46, 59))	('promote', 'PosReg', (34, 41))	('EC cells', 'CPA', (63, 71))
385148	33605567	The transfection of lncRNA DLX6-AS1 targeting oligonucleotides (si-dlx6-as1) was found to hinder the expression of lncRNA DLX6-AS1 in EC9706 and KYSE-520 cells Compared with negative control group, cell counting kit-8 (CCK-8) assay and colony formation analysis showed that the silencing of lncRNA DLX6-AS1 could significantly inhibit the proliferation of ESCC cells and reduce the number of colony formation, respectively.	('inhibit', 'NegReg', (327, 334))	('si', 'Chemical', 'MESH:D012825', (313, 315))	('DLX6-AS1', 'Gene', (298, 306))	('DLX6-AS1', 'Gene', (27, 35))	('si', 'Chemical', 'MESH:D012825', (278, 280))	('dlx6-as1', 'Gene', (67, 75))	('EC9706', 'CellLine', 'CVCL:E307', (134, 140))	('proliferation of ESCC cells', 'CPA', (339, 366))	('DLX6-AS1', 'Gene', '285987;1750;5729', (298, 306))	('DLX6-AS1', 'Gene', (122, 130))	('reduce', 'NegReg', (371, 377))	('hinder', 'NegReg', (90, 96))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('DLX6-AS1', 'Gene', '285987;1750;5729', (27, 35))	('KYSE-520', 'CellLine', 'CVCL:1355', (145, 153))	('DLX6-AS1', 'Gene', '285987;1750;5729', (122, 130))	('dlx6-as1', 'Gene', '285987', (67, 75))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('oligonucleotides', 'Chemical', 'MESH:D009841', (46, 62))	('expression', 'MPA', (101, 111))	('si', 'Chemical', 'MESH:D012825', (258, 260))	('silencing', 'Var', (278, 287))
385154	33605567	[31] investigated the expression, clinical significance and biological role of microRNAs-548k and lncRNA LET in ESCC.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('microRNAs-548k', 'Var', (79, 93))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('ESCC', 'Disease', (112, 116))	('lncRNA LET', 'Gene', '101241892', (98, 108))	('lncRNA LET', 'Gene', (98, 108))
385155	33605567	Bioinformatics analyses and cell experiments showed that lncRNA LET could inhibit the proliferation of ESCC cells, was a direct target of microRNA-548k, and mediated the carcinogenic effect of microRNA-548k in ESCC.	('microRNA-548k', 'Var', (193, 206))	('proliferation', 'CPA', (86, 99))	('microRNA-548k', 'Var', (138, 151))	('inhibit', 'NegReg', (74, 81))	('lncRNA LET', 'Gene', (57, 67))	('lncRNA LET', 'Gene', '101241892', (57, 67))	('carcinogenic', 'Disease', 'MESH:D063646', (170, 182))	('carcinogenic', 'Disease', (170, 182))
385161	33605567	[28], the authors examined the expression and biological role of lncRNA DLX6-AS1 in EC and found that the down-regulation of DLX6-AS1 could accelerate the apoptosis of ESCC cells and affect the expression of apoptosis-related protein B-cell lymphoma-2 (Bcl-2).	('down-regulation', 'Var', (106, 121))	('accelerate', 'PosReg', (140, 150))	('apoptosis-related', 'Protein', (208, 225))	('DLX6-AS1', 'Gene', '285987;1750;5729', (125, 133))	('si', 'Chemical', 'MESH:D012825', (214, 216))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (234, 249))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('affect', 'Reg', (183, 189))	('Bcl-2', 'Gene', (253, 258))	('Bcl-2', 'Gene', '596', (253, 258))	('expression', 'MPA', (194, 204))	('DLX6-AS1', 'Gene', (72, 80))	('si', 'Chemical', 'MESH:D012825', (200, 202))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('DLX6-AS1', 'Gene', (125, 133))	('apoptosis', 'CPA', (155, 164))	('lymphoma', 'Phenotype', 'HP:0002665', (241, 249))	('DLX6-AS1', 'Gene', '285987;1750;5729', (72, 80))
385173	33605567	[38] reported that the knockout of lncRNA BC032469 in TE13 and ECA109 cells could induce cell cycle arrest at the G0/G1 phase.	('induce', 'Reg', (82, 88))	('arrest', 'Disease', 'MESH:D006323', (100, 106))	('lncRNA BC032469', 'Gene', (35, 50))	('knockout', 'Var', (23, 31))	('arrest', 'Disease', (100, 106))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (89, 106))
385176	33605567	[39] confirmed that inhibiting lncRNA MALAT1 might activate ATM-CHK2 pathway in EC cells and ultimately led to G2/M stagnation in EC.	('inhibiting', 'Var', (20, 30))	('CHK2', 'Gene', (64, 68))	('G2/M stagnation', 'MPA', (111, 126))	('led to', 'Reg', (104, 110))	('ATM', 'Gene', (60, 63))	('MALAT1', 'Gene', (38, 44))	('activate', 'PosReg', (51, 59))	('CHK2', 'Gene', '11200', (64, 68))	('ATM', 'Gene', '472', (60, 63))	('MALAT1', 'Gene', '378938', (38, 44))
385180	33605567	[40] found that lncRNA AK001797 could regulate ESCC cell growth and cell cycle by activating murine double minute 2 (MDM2)/p53 signal, significantly increased the proportion of S-phase ESCC cells and reduced the proportion of G2/M phase ESCC cells.	('cell cycle', 'CPA', (68, 78))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('activating', 'PosReg', (82, 92))	('AK001797', 'Var', (23, 31))	('increased', 'PosReg', (149, 158))	('MDM2', 'Gene', '17246', (117, 121))	('ESCC', 'Disease', (47, 51))	('reduced', 'NegReg', (200, 207))	('murine double minute 2', 'Gene', '17246', (93, 115))	('regulate', 'Reg', (38, 46))	('G2/M phase ESCC cells', 'CPA', (226, 247))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('murine double minute 2', 'Gene', (93, 115))	('MDM2', 'Gene', (117, 121))	('S-phase ESCC cells', 'CPA', (177, 195))
385183	33605567	In addition, the knockout of lncRNA CASC9 significantly inhibited the migration and invasion of ESCC cells, suggesting that lncRNA CASC9 might be a new marker of poor prognosis of EC and a potential therapeutic target for intervention of EC.	('CASC9', 'Gene', (131, 136))	('si', 'Chemical', 'MESH:D012825', (173, 175))	('CASC9', 'Gene', '101805492', (131, 136))	('knockout', 'Var', (17, 25))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('CASC9', 'Gene', '101805492', (36, 41))	('CASC9', 'Gene', (36, 41))	('inhibited', 'NegReg', (56, 65))	('si', 'Chemical', 'MESH:D012825', (42, 44))
385185	33605567	Transwell invasion experiment showed that the number of invasive cells in the lncRNA DLX6-AS1 knockout group was lower than that in the control group in ESCC cell lines (EC9706 and KYSE-520).	('knockout', 'Var', (94, 102))	('si', 'Chemical', 'MESH:D012825', (14, 16))	('lower', 'NegReg', (113, 118))	('DLX6-AS1', 'Gene', (85, 93))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('DLX6-AS1', 'Gene', '285987;1750;5729', (85, 93))	('EC9706', 'CellLine', 'CVCL:E307', (170, 176))	('KYSE-520', 'CellLine', 'CVCL:1355', (181, 189))
385200	33605567	In conclusion, these results showed that lncRNA-BC032469 was a carcinogenic lncRNA that promoted cancer progression.	('promoted', 'PosReg', (88, 96))	('cancer', 'Disease', (97, 103))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('lncRNA-BC032469', 'Var', (41, 56))	('carcinogenic', 'Disease', 'MESH:D063646', (63, 75))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('carcinogenic', 'Disease', (63, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
385203	33605567	The invasion of KYSE-30 cells and HCE-4 cells was also significantly reduced by transfection with lncRNA LUCAT1 small interfering RNA (si-LUCAT1).	('HCE-4', 'CellLine', 'CVCL:1271', (34, 39))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('reduced', 'NegReg', (69, 76))	('LUCAT1', 'Gene', '100505994', (105, 111))	('LUCAT1', 'Gene', (105, 111))	('KYSE-30', 'CellLine', 'CVCL:1351', (16, 23))	('small', 'Var', (112, 117))	('LUCAT1', 'Gene', '100505994', (138, 144))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('LUCAT1', 'Gene', (138, 144))
385204	33605567	These effects of LUCAT1 siRNA were significantly blocked by pcDNA-LUCAT1 transfection.	('si', 'Chemical', 'MESH:D012825', (35, 37))	('LUCAT1', 'Gene', '100505994', (17, 23))	('LUCAT1', 'Gene', (17, 23))	('transfection', 'Var', (73, 85))	('LUCAT1', 'Gene', (66, 72))	('LUCAT1', 'Gene', '100505994', (66, 72))	('si', 'Chemical', 'MESH:D012825', (24, 26))
385214	33605567	[44] showed that antisense lncRNA EZR-AS1 was positively correlated with ezrin (EZR) expression in ESCC tissues and cell lines.	('expression', 'MPA', (85, 95))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('EZR', 'Gene', '7430', (34, 37))	('EZR-AS1', 'Gene', (34, 41))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('EZR-AS1', 'Gene', '101409257', (34, 41))	('correlated', 'Reg', (57, 67))	('EZR', 'Gene', (80, 83))	('antisense', 'Var', (17, 26))	('EZR', 'Gene', '7430', (80, 83))	('ezrin', 'Gene', '7430', (73, 78))	('ezrin', 'Gene', (73, 78))	('EZR', 'Gene', (34, 37))
385216	33605567	In mechanism, antisense lncRNA EZR-AS1 forms a complex with RNA polymerase II to activate EZR transcription.	('activate', 'PosReg', (81, 89))	('EZR', 'Gene', (90, 93))	('EZR-AS1', 'Gene', (31, 38))	('complex', 'Interaction', (47, 54))	('EZR-AS1', 'Gene', '101409257', (31, 38))	('EZR', 'Gene', '7430', (31, 34))	('EZR', 'Gene', '7430', (90, 93))	('antisense', 'Var', (14, 23))	('EZR', 'Gene', (31, 34))
385223	33605567	Knockout of lncRNA FAL1 inhibited cell invasion and EMT by affecting related genes, while overexpression of lncRNA FAL1 had the opposite effect, suggesting that lncRNA FAL1 could promote the invasion of EC cells [47].	('invasion', 'CPA', (191, 199))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('cell invasion', 'CPA', (34, 47))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('EMT', 'CPA', (52, 55))	('affecting', 'Reg', (59, 68))	('promote', 'PosReg', (179, 186))	('inhibited', 'NegReg', (24, 33))	('si', 'Chemical', 'MESH:D012825', (195, 197))	('Knockout', 'Var', (0, 8))	('lncRNA FAL1', 'Var', (161, 172))	('si', 'Chemical', 'MESH:D012825', (100, 102))
385236	33605567	Overexpression of lncRNA PCAT-1 could increase the proliferation rate and growth of EC cells, and reduce the chemical sensitivity of cells to cisplatin, which showed that lncRNA PCAT-1 promoted the development of EC and inhibited the sensitivity of EC to cisplatin [53].	('sensitivity', 'MPA', (234, 245))	('PCAT-1', 'Gene', '100750225', (178, 184))	('growth', 'CPA', (74, 80))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('PCAT-1', 'Gene', (178, 184))	('increase', 'PosReg', (38, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (255, 264))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('PCAT-1', 'Gene', '100750225', (25, 31))	('si', 'Chemical', 'MESH:D012825', (237, 239))	('development', 'CPA', (198, 209))	('PCAT-1', 'Gene', (25, 31))	('proliferation rate', 'CPA', (51, 69))	('reduce', 'NegReg', (98, 104))	('chemical sensitivity of cells to cisplatin', 'MPA', (109, 151))	('inhibited', 'NegReg', (220, 229))	('promoted', 'PosReg', (185, 193))	('lncRNA', 'Var', (171, 177))	('si', 'Chemical', 'MESH:D012825', (121, 123))
385238	33605567	Then, the relationship between the expression of lncRNA LOC285194 and clinicopathological features and prognosis was analyzed.	('lncRNA', 'Gene', (49, 55))	('LOC285194', 'Var', (56, 65))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('si', 'Chemical', 'MESH:D012825', (41, 43))
385239	33605567	The data showed that the expression of lncRNA LOC285194 in ESCC tumors was significantly lower than that in adjacent normal tissues.	('lower', 'NegReg', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('expression', 'MPA', (25, 35))	('ESCC tumors', 'Disease', (59, 70))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('ESCC tumors', 'Disease', 'MESH:D004938', (59, 70))	('LOC285194', 'Var', (46, 55))	('lncRNA', 'Gene', (39, 45))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
385240	33605567	The complete remission rate was 57% in the group with high expression of lncRNA LOC285194 and 15% in the group with low expression of lncRNA LOC285194.	('si', 'Chemical', 'MESH:D012825', (18, 20))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('lncRNA', 'Gene', (73, 79))	('LOC285194', 'Var', (80, 89))	('si', 'Chemical', 'MESH:D012825', (65, 67))
385242	33605567	In addition, Kaplan-Meier survival analysis showed that the disease-free survival rate and overall survival rate of patients with low expression of lncRNA LOC285194 decreased.	('decreased', 'NegReg', (165, 174))	('overall survival rate', 'CPA', (91, 112))	('patients', 'Species', '9606', (116, 124))	('low', 'NegReg', (130, 133))	('LOC285194', 'Var', (155, 164))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('lncRNA', 'Gene', (148, 154))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('disease-free survival rate', 'CPA', (60, 86))
385243	33605567	Multivariate analysis further confirmed that the low expression of lncRNA LOC285194 was an independent prognostic factor for chemoradiotherapy.	('si', 'Chemical', 'MESH:D012825', (18, 20))	('chemoradiotherapy', 'Disease', (125, 142))	('low', 'NegReg', (49, 52))	('expression', 'MPA', (53, 63))	('lncRNA', 'Gene', (67, 73))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('LOC285194', 'Var', (74, 83))
385250	33605567	Inhibition of lncRNA PART1 effectively promotes gefitinib-induced cell death, while increase of lncRNA PART1 promotes gefitinib resistance and Bcl-2 expression in EC cells by competitive binding to microRNA-129[57].	('promotes', 'PosReg', (39, 47))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('death', 'Disease', (71, 76))	('death', 'Disease', 'MESH:D003643', (71, 76))	('gefitinib', 'Chemical', 'MESH:D000077156', (48, 57))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('Bcl-2', 'Gene', '596', (143, 148))	('gefitinib', 'Chemical', 'MESH:D000077156', (118, 127))	('increase', 'PosReg', (84, 92))	('gefitinib resistance', 'MPA', (118, 138))	('lncRNA PART1', 'Gene', (96, 108))	('Inhibition', 'Var', (0, 10))	('binding', 'Interaction', (187, 194))	('expression', 'MPA', (149, 159))	('gefitinib-induced', 'MPA', (48, 65))	('Bcl-2', 'Gene', (143, 148))	('promotes', 'PosReg', (109, 117))
385254	33605567	These results suggested that the abnormal expression of lncRNAs was associated with chemosensitivity of EC and may be helpful to predict the poor prognosis of EC.	('si', 'Chemical', 'MESH:D012825', (152, 154))	('associated', 'Reg', (68, 78))	('expression', 'MPA', (42, 52))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('abnormal', 'Var', (33, 41))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('lncRNAs', 'Protein', (56, 63))
385255	33605567	In conclusion, the abnormal expressions of lncRNAs affect the proliferation, apoptosis, invasion, metastasis, and drug resistance of EC cells through related genes or signaling pathways, which provides new approaches for the diagnosis, targeted therapy and evaluation of therapeutic effect of EC (Table 1).	('abnormal expressions', 'Phenotype', 'HP:0100022', (19, 39))	('invasion', 'CPA', (88, 96))	('affect', 'Reg', (51, 57))	('apoptosis', 'CPA', (77, 86))	('proliferation', 'CPA', (62, 75))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('si', 'Chemical', 'MESH:D012825', (167, 169))	('metastasis', 'CPA', (98, 108))	('si', 'Chemical', 'MESH:D012825', (231, 233))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('drug resistance', 'CPA', (114, 129))	('drug resistance', 'Phenotype', 'HP:0020174', (114, 129))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('lncRNAs', 'Gene', (43, 50))	('abnormal expressions', 'Var', (19, 39))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('si', 'Chemical', 'MESH:D012825', (83, 85))
385275	28277193	In terms of esophageal cancer, dysregulation of miRNAs has been widely reported, including that of miR-21, miR-203, miR-205, miR-25, miR-93, miR-145, miR-27b, miR-100, and miR-125b, and is involved in the pathogenesis of esophageal cancer with a prognostic signature role.	('miR-27b', 'Gene', '407019', (150, 157))	('miR-21', 'Gene', '406991', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('miR-145', 'Gene', (141, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (12, 29))	('miR-203', 'Gene', (107, 114))	('miR-100', 'Gene', (159, 166))	('miR-205', 'Gene', '406988', (116, 123))	('esophageal cancer', 'Disease', (12, 29))	('miR-25', 'Gene', (125, 131))	('miR-21', 'Gene', (99, 105))	('miR-93', 'Gene', (133, 139))	('miR-203', 'Gene', '406986', (107, 114))	('involved', 'Reg', (189, 197))	('miR-125b', 'Var', (172, 180))	('miR-100', 'Gene', '406892', (159, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (221, 238))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('dysregulation', 'MPA', (31, 44))	('miR-93', 'Gene', '407051', (133, 139))	('miR-27b', 'Gene', (150, 157))	('miR-205', 'Gene', (116, 123))	('miR-25', 'Gene', '407014', (125, 131))	('esophageal cancer', 'Disease', (221, 238))	('miR-145', 'Gene', '406937', (141, 148))
385278	28277193	In human osteosarcoma, hepatocellular carcinoma, and colorectal carcinoma, aberrant regulation of miR-202 is involved in the modulation of cell growth and apoptosis through different pathways.	('human', 'Species', '9606', (3, 8))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (23, 47))	('cell growth', 'CPA', (139, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('miR-202', 'Gene', (98, 105))	('colorectal carcinoma', 'Disease', (53, 73))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (23, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('hepatocellular carcinoma', 'Disease', (23, 47))	('osteosarcoma', 'Disease', (9, 21))	('aberrant regulation', 'Var', (75, 94))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (53, 73))	('involved', 'Reg', (109, 117))	('apoptosis', 'CPA', (155, 164))	('modulation', 'Reg', (125, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('miR-202', 'Gene', '574448', (98, 105))
385286	28277193	Our results reveal a novel role of miR-202 dysregulation in ESCC pathogenesis, which might be a potential therapeutic target for ESCC.	('miR-202', 'Gene', '574448', (35, 42))	('ESCC', 'Disease', (60, 64))	('dysregulation', 'Var', (43, 56))	('miR-202', 'Gene', (35, 42))
385305	28277193	Recombinant pGL3 plasmid (200 ng) and miR-202 mimic (100 nM) were cotransfected into cultured cells (1 x 105 cells/well) in 96-well plates using Lipofectamine 2000.	('miR-202', 'Gene', '574448', (38, 45))	('miR-202', 'Gene', (38, 45))	('200', 'Var', (26, 29))	('pGL3', 'Gene', (12, 16))	('pGL3', 'Gene', '6391', (12, 16))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (145, 163))
385307	28277193	HSF2 gene expression analysis was performed on the basis of the GDS3838 profiles containing 17 ESCC cases and 17 adjacent noncancerous tissues.	('GDS3838', 'Var', (64, 71))	('HSF2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ESCC', 'Disease', (95, 99))	('HSF2', 'Gene', '3298', (0, 4))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
385313	28277193	These data suggest that miR-202 dysregulation might play a positive role in human ESCC tumorigenesis.	('ESCC tumor', 'Disease', (82, 92))	('dysregulation', 'Var', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('miR-202', 'Gene', '574448', (24, 31))	('miR-202', 'Gene', (24, 31))	('human', 'Species', '9606', (76, 81))	('ESCC tumor', 'Disease', 'MESH:D004938', (82, 92))	('positive', 'PosReg', (59, 67))
385324	28277193	As predicted, the protein level of HSF2 was significantly downregulated by miR-202 overexpression but upregulated by the miR-202 inhibitor in EC9706 and KYSE-510 cells (Fig.	('KYSE-510', 'CellLine', 'CVCL:1354', (153, 161))	('overexpression', 'Var', (83, 97))	('protein level', 'MPA', (18, 31))	('upregulated', 'PosReg', (102, 113))	('HSF2', 'Gene', (35, 39))	('downregulated', 'NegReg', (58, 71))	('miR-202', 'Gene', (121, 128))	('miR-202', 'Gene', (75, 82))	('miR-202', 'Gene', '574448', (121, 128))	('EC9706', 'CellLine', 'CVCL:E307', (142, 148))	('miR-202', 'Gene', '574448', (75, 82))	('HSF2', 'Gene', '3298', (35, 39))
385326	28277193	The wild and mutant 3'-UTRs of the HSF2 mRNA were cloned into the pGL3 luciferase vector (Fig.	('mutant', 'Var', (13, 19))	('pGL3', 'Gene', (66, 70))	('pGL3', 'Gene', '6391', (66, 70))	('HSF2', 'Gene', (35, 39))	('HSF2', 'Gene', '3298', (35, 39))
385332	28277193	Taken together, our data suggest that HSF2 mRNA is a direct target of miR-202 in ESCC cells and that the dysregulation of miR-202 and HSF2 expression is involved in ESCC carcinogenesis.	('miR-202', 'Gene', (122, 129))	('HSF2', 'Gene', (38, 42))	('miR-202', 'Gene', '574448', (122, 129))	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (165, 184))	('miR-202', 'Gene', '574448', (70, 77))	('miR-202', 'Gene', (70, 77))	('HSF2', 'Gene', '3298', (134, 138))	('ESCC carcinogenesis', 'Disease', (165, 184))	('HSF2', 'Gene', '3298', (38, 42))	('involved', 'Reg', (153, 161))	('HSF2', 'Gene', (134, 138))	('dysregulation', 'Var', (105, 118))
385335	28277193	The results showed that HSF2 silencing increased the rate of apoptosis of both EC9706 and KYSE-510 cells (Fig.	('KYSE-510', 'CellLine', 'CVCL:1354', (90, 98))	('HSF2', 'Gene', (24, 28))	('apoptosis', 'CPA', (61, 70))	('silencing', 'Var', (29, 38))	('EC9706', 'CellLine', 'CVCL:E307', (79, 85))	('HSF2', 'Gene', '3298', (24, 28))
385342	28277193	As shown in Figure 4D and E, gene expression of Hsp70 at both the mRNA and protein levels was strongly upregulated by HSF2 overexpression.	('Hsp70', 'Gene', (48, 53))	('overexpression', 'Var', (123, 137))	('HSF2', 'Gene', '3298', (118, 122))	('HSF2', 'Gene', (118, 122))	('Hsp70', 'Gene', '3308', (48, 53))	('upregulated', 'PosReg', (103, 114))	('gene expression', 'MPA', (29, 44))
385343	28277193	The above results indicate that miR-202 dysregulation-mediated upregulation of HSF2 contributes to the inhibition of oncogenic apoptosis of ESCC cells, in which Hsp70 is involved.	('HSF2', 'Gene', (79, 83))	('oncogenic apoptosis', 'CPA', (117, 136))	('Hsp70', 'Gene', '3308', (161, 166))	('miR-202', 'Gene', (32, 39))	('HSF2', 'Gene', '3298', (79, 83))	('miR-202', 'Gene', '574448', (32, 39))	('dysregulation-mediated', 'Var', (40, 62))	('Hsp70', 'Gene', (161, 166))	('upregulation', 'PosReg', (63, 75))	('inhibition', 'NegReg', (103, 113))
385346	28277193	Consistent with the results in Figure 2C, cleaved caspase 3 expression was downregulated by HSF2 overexpression and increased by HSF2 siRNA (Fig.	('increased', 'PosReg', (116, 125))	('expression', 'MPA', (60, 70))	('HSF2', 'Gene', '3298', (92, 96))	('downregulated', 'NegReg', (75, 88))	('HSF2', 'Gene', '3298', (129, 133))	('caspase 3', 'Gene', (50, 59))	('caspase 3', 'Gene', '836', (50, 59))	('HSF2', 'Gene', (129, 133))	('overexpression', 'Var', (97, 111))	('HSF2', 'Gene', (92, 96))	('cleaved', 'MPA', (42, 49))
385347	28277193	Further analysis confirmed that VER-155008, a specific molecular inhibitor of Hsp70, significantly increased the cleaved caspase 3 levels that were repressed by HSF2 overexpression (Fig.	('caspase 3', 'Gene', (121, 130))	('Hsp70', 'Gene', '3308', (78, 83))	('caspase 3', 'Gene', '836', (121, 130))	('HSF2', 'Gene', '3298', (161, 165))	('Hsp70', 'Gene', (78, 83))	('increased', 'PosReg', (99, 108))	('VER-155008', 'Var', (32, 42))	('HSF2', 'Gene', (161, 165))
385349	28277193	Aberrant expression of miRNAs has been reported in various human cancers and is associated with disease progression.	('human', 'Species', '9606', (59, 64))	('Aberrant', 'Var', (0, 8))	('miRNAs', 'Gene', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('expression', 'MPA', (9, 19))	('associated', 'Reg', (80, 90))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('reported', 'Reg', (39, 47))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))
385350	28277193	Dysregulation of miR-202 has also been identified in several carcinomas, where it exerts a tumor suppressor function or oncogenic function during carcinogenesis.	('miR-202', 'Gene', (17, 24))	('carcinogenesis', 'Disease', (146, 160))	('miR-202', 'Gene', '574448', (17, 24))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Disease', 'MESH:D009369', (61, 71))	('identified', 'Reg', (39, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('carcinomas', 'Disease', (61, 71))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))
385358	28277193	Further study found that ectopic expression of miR-202 promotes ESCC cell apoptosis, indicating that miR-202 dysregulation might play a positive role in human ESCC tumorigenesis.	('miR-202', 'Gene', (47, 54))	('ESCC tumor', 'Disease', 'MESH:D004938', (159, 169))	('miR-202', 'Gene', '574448', (47, 54))	('ESCC', 'Disease', (64, 68))	('promotes', 'PosReg', (55, 63))	('miR-202', 'Gene', (101, 108))	('miR-202', 'Gene', '574448', (101, 108))	('ESCC tumor', 'Disease', (159, 169))	('human', 'Species', '9606', (153, 158))	('ectopic expression', 'Var', (25, 43))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
385372	28277193	In the present study, we found that the apoptotic capacity of ESCC cells was significantly increased by miR-202 overexpression but decreased by miR-202 repression.	('miR-202', 'Gene', (144, 151))	('apoptotic capacity', 'CPA', (40, 58))	('miR-202', 'Gene', '574448', (144, 151))	('miR-202', 'Gene', (104, 111))	('decreased', 'NegReg', (131, 140))	('miR-202', 'Gene', '574448', (104, 111))	('overexpression', 'Var', (112, 126))	('increased', 'PosReg', (91, 100))
385380	28277193	In this study, we found that caspase 3 activation was significantly downregulated by HSF2 overexpression, but aberrantly increased by HSF2 siRNA in ESCC cells.	('activation', 'MPA', (39, 49))	('downregulated', 'NegReg', (68, 81))	('increased', 'PosReg', (121, 130))	('overexpression', 'Var', (90, 104))	('caspase 3', 'Gene', (29, 38))	('HSF2', 'Gene', '3298', (134, 138))	('HSF2', 'Gene', '3298', (85, 89))	('caspase 3', 'Gene', '836', (29, 38))	('HSF2', 'Gene', (85, 89))	('HSF2', 'Gene', (134, 138))
385455	31966072	The risk score calculated from the five expressed genes weighted by their coefficients was set as below: Risk score=(0.209095 x expression of PCNA) + (-0.023333 x expression of TNS4) + (-0.025136 x expression of SLC26A9) + (0.160318 x expression of ZFAS1) + (0.035372 x expression of AC104041.1).	('PCNA', 'Gene', '5111', (142, 146))	('0.209095', 'Var', (117, 125))	('SLC26A9', 'Gene', '115019', (212, 219))	('ZFAS1', 'Gene', (249, 254))	('TNS4', 'Gene', '84951', (177, 181))	('SLC26A9', 'Gene', (212, 219))	('PCNA', 'Gene', (142, 146))	('TNS4', 'Gene', (177, 181))	('ZFAS1', 'Gene', '441951', (249, 254))
385472	31966072	Additionally, a previous study reported that the dysregulated expression of certain micro (mi)RNAs (hsa-mir-425, hsa-let-7b, hsa-mir-23a, hsa-mir-3074, hsa-mir-424 and hsa-mir-505) could be used for the prognosis of esophageal adenocarcinoma.	('hsa-mir-505', 'Gene', '574508', (168, 179))	('dysregulated', 'Var', (49, 61))	('hsa-mir-425', 'Gene', '494337', (100, 111))	('hsa-mir-424', 'Gene', (152, 163))	('hsa-mir-23a', 'Gene', '407010', (125, 136))	('expression', 'MPA', (62, 72))	('hsa-let-7b', 'Gene', (113, 123))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (216, 241))	('esophageal adenocarcinoma', 'Disease', (216, 241))	('hsa-mir-3074', 'Gene', (138, 150))	('hsa-mir-424', 'Gene', '494336', (152, 163))	('hsa-mir-505', 'Gene', (168, 179))	('hsa-mir-23a', 'Gene', (125, 136))	('hsa-mir-425', 'Gene', (100, 111))	('hsa-let-7b', 'Gene', '406884', (113, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('hsa-mir-3074', 'Gene', '100422842', (138, 150))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (216, 241))
385479	31966072	Among them, the genes proliferating cell nuclear antigen (PCNA), ZNFX1 antisense RNA 1 (ZFAS1) and AC10401.1 were negatively associated with OS, whereas the two other genes tensin 4 (TNS4) and solute carrier family 26 member 9 (SLC26A9) were associated with an improved survival outcome.	('proliferating cell nuclear antigen', 'Gene', '5111', (22, 56))	('solute carrier family 26 member 9', 'Gene', '115019', (193, 226))	('proliferating cell nuclear antigen', 'Gene', (22, 56))	('solute carrier family 26 member 9', 'Gene', (193, 226))	('tensin 4', 'Gene', '84951', (173, 181))	('ZFAS1', 'Gene', '441951', (88, 93))	('PCNA', 'Gene', '5111', (58, 62))	('tensin 4', 'Gene', (173, 181))	('AC10401.1', 'Var', (99, 108))	('negatively', 'NegReg', (114, 124))	('TNS4', 'Gene', (183, 187))	('ZFAS1', 'Gene', (88, 93))	('ZNFX1 antisense RNA 1', 'Gene', '441951;57169', (65, 86))	('PCNA', 'Gene', (58, 62))	('TNS4', 'Gene', '84951', (183, 187))	('SLC26A9', 'Gene', (228, 235))	('SLC26A9', 'Gene', '115019', (228, 235))	('ZNFX1 antisense RNA 1', 'Gene', (65, 86))
385491	31966072	Regarding SLC26A9 and AC104041.1, there was no correlative literature in cancer.	('AC104041.1', 'Var', (22, 32))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('SLC26A9', 'Gene', '115019', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SLC26A9', 'Gene', (10, 17))
385507	30578870	Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease characterized by eosinophil infiltration of the esophageal epithelium, resulting in impairment of esophageal function and development of feeding intolerance, dysphagia, food impaction, or strictures.	('eosinophil infiltration', 'Phenotype', 'HP:0001880', (85, 108))	('food impaction', 'Phenotype', 'HP:0031984', (237, 251))	('Eosinophilic esophagitis', 'Phenotype', 'HP:0410151', (0, 24))	('eosinophil', 'Var', (85, 95))	('EoE', 'Phenotype', 'HP:0410151', (26, 29))	('feeding intolerance', 'Disease', (205, 224))	('dysphagia', 'Disease', 'MESH:D003680', (226, 235))	('esophageal function', 'CPA', (166, 185))	('eosinophil infiltration of the esophageal epithelium', 'Phenotype', 'HP:0410151', (85, 137))	('strictures', 'Disease', (256, 266))	('Eosinophilic esophagitis', 'Disease', 'MESH:D057765', (0, 24))	('impairment', 'NegReg', (152, 162))	('Eosinophilic esophagitis', 'Disease', (0, 24))	('food impaction', 'Disease', (237, 251))	('dysphagia', 'Disease', (226, 235))	('eosin', 'Chemical', 'MESH:D004801', (85, 90))	('dysphagia', 'Phenotype', 'HP:0002015', (226, 235))	('esophagitis', 'Phenotype', 'HP:0100633', (13, 24))
385521	30578870	Ligand binding and dimerization of ESRs leads to translocation of the ESR to the nucleus and induction of gene expression through binding DNA estrogen response elements or indirectly through interactions with other transcription factors in a concentration- and tissue-specific manner.	('ESR', 'Gene', (70, 73))	('binding', 'Interaction', (7, 14))	('ESR', 'Gene', '2099', (70, 73))	('dimerization', 'Var', (19, 31))	('gene expression', 'MPA', (106, 121))	('translocation', 'MPA', (49, 62))	('interactions', 'Interaction', (191, 203))	('ESR', 'Gene', '2099', (35, 38))	('induction', 'MPA', (93, 102))	('binding', 'Interaction', (130, 137))	('ESR', 'Gene', (35, 38))
385567	30578870	The bottom portion of the transwells were placed in chamber sliders (P2320T slider, 6.5 mm diameter, sized for a 0.33-cm2 growth area) inserted into the dual Ussing chambers (P2300 dual Ussing chamber; Physiologic Instruments, San Diego, Calif) containing Ringer buffer (pH 7.4) and mounted on an 8-chamber Ussing system (EM-CSYS-8 EasyMount Ussing Chamber System; Physiologic Instruments, San Diego, Calif).	('Calif', 'Gene', (238, 243))	('Calif', 'Gene', '9337', (238, 243))	('P2320T', 'Mutation', 'p.P2320T', (69, 75))	('Calif', 'Gene', (401, 406))	('Calif', 'Gene', '9337', (401, 406))	('P2320T', 'Var', (69, 75))
385618	30578870	IL-13 stimulation of EPC2 cells significantly decreased TER compared with control values (Fig 3, A), which is indicative of barrier dysfunction (2021 +- 516 vs 1258 +- 334 Omega   cm2, vehicle vs IL-13 [mean +- SD]; n = 10; P < .001).	('IL-13', 'Gene', '3596', (0, 5))	('IL-13', 'Gene', (196, 201))	('IL-13', 'Gene', '3596', (196, 201))	('EPC2', 'Gene', '26122', (21, 25))	('TER', 'MPA', (56, 59))	('decreased', 'NegReg', (46, 55))	('EPC2', 'Gene', (21, 25))	('IL-13', 'Gene', (0, 5))	('2021 +- 516', 'Var', (145, 156))
385647	30578870	Notably, IL-13 stimulation led to increased levels of pSTAT6 within 5 minutes, and maximal pSTAT6 was observed within 30 minutes (Fig 4, A).	('STAT6', 'Gene', (55, 60))	('stimulation', 'Var', (15, 26))	('IL-13', 'Gene', (9, 14))	('STAT6', 'Gene', (92, 97))	('STAT6', 'Gene', '6778', (55, 60))	('IL-13', 'Gene', '3596', (9, 14))	('STAT6', 'Gene', '6778', (92, 97))	('increased', 'PosReg', (34, 43))
385660	30578870	Recent studies have demonstrated that antagonism of the ESR pathway inhibits esophageal epithelial proliferation; therefore we generated mature EPC2-ALI monolayers and then pretreated the monolayers with MMP or PHTPP for 24 hours and subsequently examined the effect of E2 on IL-13-induced esophageal epithelial barrier dysfunction.	('E2', 'Chemical', 'MESH:D004958', (270, 272))	('esophageal epithelial proliferation', 'Phenotype', 'HP:0012859', (77, 112))	('ESR', 'Gene', (56, 59))	('PHTPP', 'Chemical', 'MESH:C556295', (211, 216))	('IL-13', 'Gene', (276, 281))	('antagonism', 'Var', (38, 48))	('EPC2', 'Gene', '26122', (144, 148))	('MMP', 'Gene', '4313;4323', (204, 207))	('IL-13', 'Gene', '3596', (276, 281))	('EPC2', 'Gene', (144, 148))	('MMP', 'Gene', (204, 207))	('esophageal epithelial proliferation', 'CPA', (77, 112))	('inhibits', 'NegReg', (68, 76))	('ESR', 'Gene', '2099', (56, 59))
385665	30578870	We reveal that that esophageal epithelium expresses both ESR1 and ESR2 and that 29.9% of the genes dysregulated in patients with EoE are estrogen-responsive genes involved in multiple pathways, including inflammation, membrane permeability, and cell-cell junctions.	('patients', 'Species', '9606', (115, 123))	('EoE', 'Disease', (129, 132))	('inflammation', 'Disease', 'MESH:D007249', (204, 216))	('EoE', 'Phenotype', 'HP:0410151', (129, 132))	('ESR2', 'Gene', '2100', (66, 70))	('inflammation', 'Disease', (204, 216))	('genes', 'Gene', (93, 98))	('dysregulated', 'Var', (99, 111))	('ESR1', 'Gene', (57, 61))	('ESR2', 'Gene', (66, 70))
385683	30578870	ESR2 has previously been reported to play a pivotal role in E2-mediated enhancement of intestinal epithelial barrier function.	('ESR2', 'Gene', '2100', (0, 4))	('enhancement', 'PosReg', (72, 83))	('E2', 'Chemical', 'MESH:D004958', (60, 62))	('intestinal epithelial barrier function', 'CPA', (87, 125))	('ESR2', 'Gene', (0, 4))	('E2-mediated', 'Var', (60, 71))
385717	30578870	Based on demographic, incidence, and RNA-seq analyses of patients with EoE in male and female subjects from single-center pediatric cohort, we revealed significant dysregulation of expression of the ESRs and estrogenresponsive gene network in patients with EoE.	('EoE', 'Phenotype', 'HP:0410151', (71, 74))	('expression', 'MPA', (181, 191))	('patients', 'Species', '9606', (243, 251))	('patients', 'Species', '9606', (57, 65))	('EoE', 'Disease', (257, 260))	('dysregulation', 'Var', (164, 177))	('EoE', 'Phenotype', 'HP:0410151', (257, 260))	('ESR', 'Gene', '2099', (199, 202))	('ESR', 'Gene', (199, 202))
385801	30588952	Thus, we diagnosed 121 of 127 lesions with PCS times less than 60 s as HGIN/invasive cancer, and 13 of 41 lesions with PCS times more than 60 s as LGIN/inflammation.	('inflammation', 'Disease', 'MESH:D007249', (152, 164))	('PCS', 'Chemical', '-', (43, 46))	('PCS', 'Chemical', '-', (119, 122))	('inflammation', 'Disease', (152, 164))	('HGIN/invasive cancer', 'Disease', (71, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('PCS', 'Var', (43, 46))	('HGIN/invasive cancer', 'Disease', 'MESH:D009362', (71, 91))
385901	30832605	We further categorized the patients into two groups based on whether their volume in the heart was higher (n = 5) or lower (n = 75) than 280 mL of V5000 cGy (mL).	('volume in the heart', 'MPA', (75, 94))	('higher', 'PosReg', (99, 105))	('V5000 cGy', 'Var', (147, 156))	('lower', 'NegReg', (117, 122))	('patients', 'Species', '9606', (27, 35))
385903	30832605	The occurrence rate of CEs after CRT was significantly higher in patients exposed to radiation with more than 280 mL of V5000 cGy (mL) than in those exposed to less than 280 mL of V5000 cGy (mL) (Fig.	('V5000 cGy', 'Var', (120, 129))	('CEs', 'Disease', (23, 26))	('patients', 'Species', '9606', (65, 73))	('CEs', 'Chemical', '-', (23, 26))	('higher', 'PosReg', (55, 61))
385944	29693138	miR-378a-3p exerts tumor suppressive function on the tumorigenesis of esophageal squamous cell carcinoma by targeting Rab10 Esophageal squamous cell carcinoma (ESCC) is a life-threatening cancer with increasing incidence worldwide.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (124, 158))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('miR', 'Gene', '220972', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Rab10', 'Gene', (118, 123))	('cancer', 'Disease', (188, 194))	('esophageal squamous cell carcinoma', 'Disease', (70, 104))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('miR', 'Gene', (0, 3))	('Esophageal squamous cell carcinoma', 'Disease', (124, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('tumor', 'Disease', (53, 58))	('targeting', 'Var', (108, 117))
385954	29693138	The silencing of Rab10 revealed antitumor effects in ESCC cell lines, and the expression of miR-378a-3p was negatively correlated with that of Rab10 in ESCC.	('Rab10', 'Gene', (17, 22))	('Rab10', 'Gene', (143, 148))	('expression', 'MPA', (78, 88))	('negatively', 'NegReg', (108, 118))	('Rab10', 'Gene', '10890', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('Rab10', 'Gene', '10890', (17, 22))	('miR-378a', 'Gene', (92, 100))	('miR-378a', 'Gene', '494327', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('silencing', 'Var', (4, 13))
385966	29693138	In addition, the aberrant expression of miRNAs has been closely associated with cancer, suggesting that they may act as novel oncogenes or tumor suppressor genes.	('expression', 'MPA', (26, 36))	('associated', 'Reg', (64, 74))	('aberrant', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
385967	29693138	It has been shown that the demethylation of miR-495 can suppress cell proliferation and migration, and promote breast cancer cell apoptosis by targeting signal transducer and activator of transcription-3.	('suppress', 'NegReg', (56, 64))	('miR-495', 'Gene', '574453', (44, 51))	('targeting', 'Reg', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('signal transducer and activator of transcription-3', 'Gene', '6774', (153, 203))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('cell proliferation', 'CPA', (65, 83))	('breast cancer', 'Disease', (111, 124))	('promote', 'PosReg', (103, 110))	('demethylation', 'Var', (27, 40))	('miR-495', 'Gene', (44, 51))
386014	29693138	The membrane was blocked using 5% non-fat milk at 25 C for 1 h, and then incubated with primary antibodies overnight at 4 C. The antibodies used were as follows: Anti-human GAPDH antibody (cat no.	('GAPDH', 'Gene', '2597', (173, 178))	('human', 'Species', '9606', (167, 172))	('GAPDH', 'Gene', (173, 178))	('Anti-human', 'Var', (162, 172))
386031	29693138	The results demonstrated that the overexpression of miR-378a-3p significantly decreased cell viability, whereas the knockout of miR-378a-3p promoted cell viability in the EC109 and KYSE150 cell lines (Fig.	('miR-378a', 'Gene', '494327', (52, 60))	('miR-378a', 'Gene', (52, 60))	('KYSE150', 'CellLine', 'CVCL:1348', (181, 188))	('knockout', 'Var', (116, 124))	('promoted', 'PosReg', (140, 148))	('cell viability', 'CPA', (149, 163))	('EC', 'Phenotype', 'HP:0011459', (171, 173))	('cell viability', 'CPA', (88, 102))	('decreased', 'NegReg', (78, 87))	('miR-378a', 'Gene', '494327', (128, 136))	('miR-378a', 'Gene', (128, 136))
386032	29693138	In addition, the results of the EdU experiment demonstrated that the overexpression of miR-378a-3p significantly decreased cell growth (P<0.01), whereas the knockout of miR-378a-3p promoted cell growth in the EC109 and KYSE150 cell lines (Fig.	('overexpression', 'PosReg', (69, 83))	('KYSE150', 'CellLine', 'CVCL:1348', (219, 226))	('men', 'Species', '9606', (42, 45))	('miR-378a', 'Gene', '494327', (169, 177))	('miR-378a', 'Gene', (169, 177))	('cell growth', 'CPA', (190, 201))	('EC', 'Phenotype', 'HP:0011459', (209, 211))	('EdU', 'Chemical', '-', (32, 35))	('knockout', 'Var', (157, 165))	('promoted', 'PosReg', (181, 189))	('cell growth', 'CPA', (123, 134))	('decreased', 'NegReg', (113, 122))	('miR-378a', 'Gene', '494327', (87, 95))	('miR-378a', 'Gene', (87, 95))
386058	29693138	9C, the MTT assay showed that silencing Rab10 in the ESCC cells markedly reduced the viability of EC109 and KYSE150 cells.	('viability', 'CPA', (85, 94))	('Rab10', 'Gene', '10890', (40, 45))	('MTT', 'Chemical', 'MESH:C070243', (8, 11))	('EC', 'Phenotype', 'HP:0011459', (98, 100))	('KYSE150', 'CellLine', 'CVCL:1348', (108, 115))	('reduced', 'NegReg', (73, 80))	('silencing', 'Var', (30, 39))	('Rab10', 'Gene', (40, 45))
386059	29693138	In addition, the knockdown of Rab10 suppressed ESCC cell migration and invasion (Fig.	('suppressed', 'NegReg', (36, 46))	('Rab10', 'Gene', '10890', (30, 35))	('invasion', 'CPA', (71, 79))	('ESCC cell migration', 'CPA', (47, 66))	('knockdown', 'Var', (17, 26))	('Rab10', 'Gene', (30, 35))
386060	29693138	The levels of caspase-3 and caspase-9 were enhanced by the knockdown of Rab10 in EC109 and KYSE150 cells, whereas those of MMP-2 and MMP-9 were significantly decreased in the cells transfected with siRab10 (Fig.	('levels', 'MPA', (4, 10))	('enhanced', 'PosReg', (43, 51))	('MMP-2', 'Gene', (123, 128))	('caspase-3', 'Gene', '836', (14, 23))	('EC', 'Phenotype', 'HP:0011459', (81, 83))	('Rab10', 'Gene', (200, 205))	('Rab10', 'Gene', (72, 77))	('caspase-9', 'Gene', '842', (28, 37))	('MMP-9', 'Gene', '4318', (133, 138))	('caspase-3', 'Gene', (14, 23))	('knockdown', 'Var', (59, 68))	('MMP-2', 'Gene', '4313', (123, 128))	('MMP-9', 'Gene', (133, 138))	('caspase-9', 'Gene', (28, 37))	('KYSE150', 'CellLine', 'CVCL:1348', (91, 98))	('Rab10', 'Gene', '10890', (72, 77))	('Rab10', 'Gene', '10890', (200, 205))
386088	29693138	In addition, the upregulation of miR-378a-3p decreased the level of Rab10, whereas the knockdown of Rab10 markedly reduced ESCC cell proliferation, migration and invasion.	('level', 'MPA', (59, 64))	('Rab10', 'Gene', (100, 105))	('migration', 'CPA', (148, 157))	('miR-378a', 'Gene', '494327', (33, 41))	('miR-378a', 'Gene', (33, 41))	('reduced', 'NegReg', (115, 122))	('Rab10', 'Gene', '10890', (68, 73))	('decreased', 'NegReg', (45, 54))	('ESCC', 'Disease', (123, 127))	('Rab10', 'Gene', '10890', (100, 105))	('upregulation', 'PosReg', (17, 29))	('invasion', 'CPA', (162, 170))	('Rab10', 'Gene', (68, 73))	('knockdown', 'Var', (87, 96))
386100	29805749	High IDO1 mRNA levels were associated with worse overall survival (OS) in both esophageal squamous cell carcinoma (SCC) (P = 0.02) and adenocarcinoma (AC) (P = 0.036).	('overall survival', 'MPA', (49, 65))	('adenocarcinoma', 'Disease', 'MESH:D000230', (135, 149))	('mRNA levels', 'MPA', (10, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('High', 'Var', (0, 4))	('IDO1', 'Gene', '3620', (5, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('OS', 'Chemical', '-', (67, 69))	('SCC', 'Gene', (115, 118))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('adenocarcinoma', 'Disease', (135, 149))	('IDO1', 'Gene', (5, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))	('SCC', 'Gene', '6317', (115, 118))	('worse', 'NegReg', (43, 48))
386101	29805749	High co-expression of IDO1 and programmed death ligand 1 (PD-L1) was associated with worse OS in SCC (P = 0.0031) and AC (P = 0.0186).	('PD-L1', 'Gene', '29126', (58, 63))	('High co-expression', 'Var', (0, 18))	('SCC', 'Gene', '6317', (97, 100))	('IDO1', 'Gene', '3620', (22, 26))	('SCC', 'Gene', (97, 100))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('OS', 'Chemical', '-', (91, 93))	('PD-L1', 'Gene', (58, 63))	('programmed death ligand 1', 'Gene', '29126', (31, 56))	('programmed death ligand 1', 'Gene', (31, 56))	('IDO1', 'Gene', (22, 26))
386103	29805749	EC with high IDO1 and PD-L1 expression is significantly correlated with decreased patient survival, and may correlate with increased T-cells.	('increased', 'PosReg', (123, 132))	('IDO1', 'Gene', (13, 17))	('high', 'Var', (8, 12))	('patient', 'Species', '9606', (82, 89))	('PD-L1', 'Gene', (22, 27))	('decreased', 'NegReg', (72, 81))	('expression', 'MPA', (28, 38))	('IDO1', 'Gene', '3620', (13, 17))	('increased T-cells', 'Phenotype', 'HP:0100828', (123, 140))	('PD-L1', 'Gene', '29126', (22, 27))	('T-cells', 'CPA', (133, 140))	('increased T-cell', 'Phenotype', 'HP:0100828', (123, 139))	('patient survival', 'CPA', (82, 98))
386130	29805749	Collectively, these findings support the hypothesis that the inhibition of IDO1 may increase intratumoral inflammation and increase tumor susceptibility to checkpoint inhibition, making it an ideal target for combining with the inhibition of PD-1 and/or CTLA-4.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('CTLA-4', 'Gene', (254, 260))	('inhibition', 'Var', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('CTLA-4', 'Gene', '1493', (254, 260))	('IDO1', 'Gene', '3620', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('increase tumor', 'Disease', (123, 137))	('increase', 'PosReg', (84, 92))	('tumor', 'Disease', (132, 137))	('inflammation', 'Disease', 'MESH:D007249', (106, 118))	('tumor', 'Disease', (98, 103))	('PD-1', 'Gene', (242, 246))	('inflammation', 'Disease', (106, 118))	('PD-1', 'Gene', '5133', (242, 246))	('IDO1', 'Gene', (75, 79))	('increase tumor', 'Disease', 'MESH:D009369', (123, 137))
386143	29805749	There was a significantly shorter patient survival in patients with high PD-L1 mRNA levels when compared with low PD-L1 expression in both the esophageal SCC and AC cohorts.	('patient', 'Species', '9606', (54, 61))	('mRNA levels', 'MPA', (79, 90))	('PD-L1', 'Gene', (114, 119))	('SCC', 'Gene', '6317', (154, 157))	('high', 'Var', (68, 72))	('patient survival', 'CPA', (34, 50))	('patients', 'Species', '9606', (54, 62))	('PD-L1', 'Gene', '29126', (73, 78))	('PD-L1', 'Gene', '29126', (114, 119))	('patient', 'Species', '9606', (34, 41))	('shorter', 'NegReg', (26, 33))	('SCC', 'Gene', (154, 157))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))	('PD-L1', 'Gene', (73, 78))
386144	29805749	In the SCC cohort, the overall survival for high versus low PD-L1 expression was 15.9 months compared with 28.1 months, respectively (Figure 1C; P = 0.0032).	('SCC', 'Gene', (7, 10))	('high', 'Var', (44, 48))	('SCC', 'Phenotype', 'HP:0002860', (7, 10))	('SCC', 'Gene', '6317', (7, 10))	('PD-L1', 'Gene', (60, 65))	('expression', 'MPA', (66, 76))	('PD-L1', 'Gene', '29126', (60, 65))	('low', 'NegReg', (56, 59))
386145	29805749	In the esophageal AC patient cohort, median OS was 22.8 months for high PD-L1 mRNA levels while median OS was not reached (NR) for low PD-L1 (Figure 2C; P = 0.025).	('PD-L1', 'Gene', (135, 140))	('OS', 'Chemical', '-', (103, 105))	('high', 'Var', (67, 71))	('patient', 'Species', '9606', (21, 28))	('PD-L1', 'Gene', '29126', (72, 77))	('PD-L1', 'Gene', '29126', (135, 140))	('esophageal AC', 'Disease', (7, 20))	('OS', 'Chemical', '-', (44, 46))	('PD-L1', 'Gene', (72, 77))
386153	29805749	In SCC, patients with high IDO1 and PD-1 expression compared with low expression for these markers, median overall survival was 15.1 months and 41.5 months, respectively.	('IDO1', 'Gene', (27, 31))	('SCC', 'Phenotype', 'HP:0002860', (3, 6))	('expression', 'MPA', (41, 51))	('SCC', 'Gene', '6317', (3, 6))	('high', 'Var', (22, 26))	('IDO1', 'Gene', '3620', (27, 31))	('PD-1', 'Gene', (36, 40))	('PD-1', 'Gene', '5133', (36, 40))	('SCC', 'Gene', (3, 6))	('patients', 'Species', '9606', (8, 16))
386172	29805749	It was further demonstrated that high PD-L1 mRNA expression, alone and in combination with high IDO1 expression, is associated with a worse overall patient survival.	('high', 'Var', (33, 37))	('patient', 'Species', '9606', (148, 155))	('IDO1', 'Gene', (96, 100))	('mRNA expression', 'MPA', (44, 59))	('PD-L1', 'Gene', (38, 43))	('IDO1', 'Gene', '3620', (96, 100))	('PD-L1', 'Gene', '29126', (38, 43))
386234	29396886	The mice were randomized into a control group and a treatment group (TE2-FUCCI: 7 mice per group, and TE14: 6 mice per group).	('mice', 'Species', '10090', (82, 86))	('mice', 'Species', '10090', (4, 8))	('mice', 'Species', '10090', (110, 114))	('TE2-FUCCI:', 'Var', (69, 79))	('TE14', 'Var', (102, 106))
386254	29396886	Metformin inhibited cell proliferation in all ESCC cell lines (TE1, TE2, TE4, TE5, TE6, TE8, TE10, TE11, TE14, TE15 and T.Tn) in a dose-dependent way.	('TE10', 'Var', (93, 97))	('TE4', 'Var', (73, 76))	('T.Tn', 'Var', (120, 124))	('cell proliferation', 'CPA', (20, 38))	('inhibited', 'NegReg', (10, 19))	('TE14', 'Var', (105, 109))	('TE15', 'Var', (111, 115))	('TE5', 'Var', (78, 81))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('TE1', 'Var', (63, 66))	('TE6', 'Var', (83, 86))	('TE8', 'Var', (88, 91))	('TE11', 'Var', (99, 103))
386257	29396886	Relative tumor volume was significantly smaller in the metformin-treated group than in the control group in both TE2-FUCCI (*P = .033) (Figure 3A) and TE14 cell lines (**P = .031) (Figure 3B).	('metformin', 'Chemical', 'MESH:D008687', (55, 64))	('metformin-treated', 'Var', (55, 72))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('smaller', 'NegReg', (40, 47))
386258	29396886	There was no marked difference in bodyweight change of the mice in the control group and in the metformin-treated group for both TE2-FUCCI (Figure 3C) and TE14 (Figure 3D).	('TE14', 'Var', (155, 159))	('mice', 'Species', '10090', (59, 63))	('metformin', 'Chemical', 'MESH:D008687', (96, 105))	('TE2-FUCCI', 'Var', (129, 138))
386263	29396886	Furthermore, a larger proportion of cells were in G0/G1 in the high-concentration metformin-treated group than in the control group.	('G0/G1', 'CPA', (50, 55))	('metformin', 'Chemical', 'MESH:D008687', (82, 91))	('high-concentration', 'Var', (63, 81))
386264	29396886	In the migration assay, the number of cells penetrating the membrane of TE2 cells was significantly and dose-dependently decreased by metformin (Figure 5A; *P = .01 for 0 vs 3 mmol/L and **P = .01 for 0 vs 5 mmol/L).	('metformin', 'Chemical', 'MESH:D008687', (134, 143))	('metformin', 'Var', (134, 143))	('migration assay', 'CPA', (7, 22))	('decreased', 'NegReg', (121, 130))
386280	29396886	It has been reported that tumor growth is inhibited and apoptosis is induced by metformin in vivo and, in our study, a similar tendency was shown.	('metformin', 'Chemical', 'MESH:D008687', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('inhibited', 'NegReg', (42, 51))	('metformin', 'Var', (80, 89))	('apoptosis', 'CPA', (56, 65))	('tumor', 'Disease', (26, 31))	('induced', 'Reg', (69, 76))
386281	29396886	Furthermore, TE14 cells were more sensitive to metformin than TE2 cells in vitro, and the tumor size of TE14 cells was smaller than that of TE2-FUCCI cells.	('TE14', 'Var', (104, 108))	('smaller', 'NegReg', (119, 126))	('metformin', 'Chemical', 'MESH:D008687', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('sensitive', 'MPA', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
386283	29396886	Based on these in vitro and in vivo results, metformin appears to affect tumor size by inhibiting cell proliferation and inducing apoptosis.	('cell proliferation', 'CPA', (98, 116))	('affect', 'Reg', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('inducing', 'NegReg', (121, 129))	('apoptosis', 'CPA', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('metformin', 'Var', (45, 54))	('tumor', 'Disease', (73, 78))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('inhibiting', 'NegReg', (87, 97))
386284	29396886	Expression of E-cadherin, the most important marker of epithelial cells, was induced by metformin in various ESCC lines, but sensitivity to metformin differed among those cell lines.	('E-cadherin', 'Gene', '999', (14, 24))	('metformin', 'Chemical', 'MESH:D008687', (88, 97))	('induced', 'Reg', (77, 84))	('Expression', 'MPA', (0, 10))	('metformin', 'Chemical', 'MESH:D008687', (140, 149))	('metformin', 'Var', (88, 97))	('E-cadherin', 'Gene', (14, 24))
386294	29396886	Change in intracellular localization of NF-kappaB by metformin may show that metformin exerts its antitumor effect by inhibiting EMT through NF-kappaB.	('metformin', 'Var', (77, 86))	('NF-kappaB', 'Gene', '4790', (40, 49))	('metformin', 'Chemical', 'MESH:D008687', (77, 86))	('NF-kappaB', 'Gene', (40, 49))	('metformin', 'Chemical', 'MESH:D008687', (53, 62))	('Change', 'Reg', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('NF-kappaB', 'Gene', '4790', (141, 150))	('EMT', 'CPA', (129, 132))	('inhibiting', 'NegReg', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('NF-kappaB', 'Gene', (141, 150))
386297	29396886	Differences in the metformin concentration can result in a high glucose concentration in the medium.	('Differences', 'Var', (0, 11))	('metformin', 'Chemical', 'MESH:D008687', (19, 28))	('high glucose', 'Phenotype', 'HP:0003074', (59, 71))	('result in', 'Reg', (47, 56))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('high glucose concentration in the medium', 'MPA', (59, 99))
386307	28603843	V-set and immunoglobulin domain containing 1 was downregulated in 60.5% of GC specimens, and high VSIG1 expression was identified as an independent favorable prognostic factor for overall survival in GC patients (hazard ratio, 0.58; 95% confidence interval, 0.35-0.96).	('V-set and immunoglobulin domain containing 1', 'Gene', '340547', (0, 44))	('GC', 'Phenotype', 'HP:0012126', (200, 202))	('patients', 'Species', '9606', (203, 211))	('expression', 'MPA', (104, 114))	('VSIG1', 'Gene', (98, 103))	('GC', 'Phenotype', 'HP:0012126', (75, 77))	('downregulated', 'NegReg', (49, 62))	('high', 'Var', (93, 97))
386310	28603843	The variant 2 VSIG1 transcript was the dominant form in these tissues and cancer cells.	('variant 2', 'Var', (4, 13))	('VSIG1', 'Gene', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
386312	28603843	Cell invasion of MKN1, MKN28, and KYSE150 cells was also reduced by VSIG1 introduction.	('VSIG1', 'Gene', (68, 73))	('KYSE150', 'CellLine', 'CVCL:1348', (34, 41))	('introduction', 'Var', (74, 86))	('Cell invasion', 'CPA', (0, 13))	('reduced', 'NegReg', (57, 64))
386318	28603843	In lung adenocarcinoma, one report indicated that the deletion of NKX2-1/TTF1 leads to conversion to a gastric lineage.6 This finding led us to test the hypothesis that VSIG1 is also expressed in a subset of lung adenocarcinomas and that VSIG1 may play a biological role in lung cancer as well.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('test', 'Reg', (144, 148))	('lung cancer', 'Disease', (274, 285))	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('deletion', 'Var', (54, 62))	('NKX2-1/TTF1', 'Gene', (66, 77))	('lung adenocarcinomas', 'Disease', (208, 228))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (208, 227))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (208, 228))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (208, 228))	('lung cancer', 'Disease', 'MESH:D008175', (274, 285))	('carcinomas', 'Phenotype', 'HP:0030731', (218, 228))	('play', 'Reg', (248, 252))	('lung adenocarcinoma', 'Disease', (3, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (208, 227))
386324	28603843	Human full-length VSIG1 variant 2 cDNA, reverse transcribed from the RNA obtained from human non-cancerous gastric tissue, was amplified by PCR using Phusion High-Fidelity DNA Polymerase (New England BioLabs, Ipswich, MA, USA) and cloned into a PiggyBac cumate switch inducible vector (System Biosciences, Mountain View, CA, USA).	('Human', 'Species', '9606', (0, 5))	('non-cancerous gastric', 'Disease', 'MESH:D013274', (93, 114))	('VSIG1', 'Gene', (18, 23))	('human', 'Species', '9606', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancerous gastric tissue', 'Phenotype', 'HP:0006753', (97, 121))	('variant', 'Var', (24, 31))	('non-cancerous gastric', 'Disease', (93, 114))
386332	28603843	KYSE150 cells stably transfected with VSIG1-HA or VSIG1-FLAG were suspended and mixed at a 1:1 ratio and incubated in 60-mm culture dishes to confluence.	('VSIG1-HA', 'Var', (38, 46))	('VSIG1-FLAG', 'Var', (50, 60))	('KYSE150', 'CellLine', 'CVCL:1348', (0, 7))
386341	28603843	As shown in Figure 1(f), there was a significant difference in OS between patients with GC showing high versus low VSIG1 expression (log-rank, P = 0.014).	('OS', 'Chemical', 'MESH:D009992', (63, 65))	('patients', 'Species', '9606', (74, 82))	('VSIG1', 'Gene', (115, 120))	('high', 'Var', (99, 103))	('GC', 'Phenotype', 'HP:0012126', (88, 90))
386342	28603843	Furthermore, high VSIG1 expression was confirmed to be an independent favorable prognostic indicator for GC patients by multivariate Cox regression analysis (hazard ratio, 0.58; 95% confidence interval, 0.35-0.96) (Table 2).	('Cox', 'Gene', '1351', (133, 136))	('Cox', 'Gene', (133, 136))	('high', 'Var', (13, 17))	('VSIG1', 'Gene', (18, 23))	('expression', 'MPA', (24, 34))	('patients', 'Species', '9606', (108, 116))	('GC', 'Phenotype', 'HP:0012126', (105, 107))
386343	28603843	As shown in Figure 1(g), GC patients with high VSIG1 expression showed better OS outcomes than those with low expression in another cohort, including 631 GC patients, with a Kaplan-Meier Plotter12 (P = 0.0081; hazard ratio, 0.75; 95% confidence interval, 0.60-0.93).	('GC', 'Phenotype', 'HP:0012126', (25, 27))	('patients', 'Species', '9606', (157, 165))	('high', 'Var', (42, 46))	('better', 'PosReg', (71, 77))	('OS', 'Chemical', 'MESH:D009992', (78, 80))	('patients', 'Species', '9606', (28, 36))	('GC', 'Phenotype', 'HP:0012126', (154, 156))	('VSIG1', 'Gene', (47, 52))
386363	28603843	Among the four mucins, MUC5AC expression was significantly and recurrently greater in the four types of tumors with high expression of VSIG1 compared to the respective counterparts (Fig.S3c-f).	('expression', 'MPA', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('MUC5AC', 'Gene', '4586', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('high expression', 'Var', (116, 131))	('VSIG1', 'Gene', (135, 140))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('mucin', 'Gene', '100508689', (15, 20))	('greater', 'PosReg', (75, 82))	('MUC5AC', 'Gene', (23, 29))	('mucin', 'Gene', (15, 20))
386365	28603843	In MKN45 cells, VSIG1 variant 2 mRNA expression was much greater than variant 1 expression, which aligned with the results from non-cancerous stomach and testicular tissues and lung cancers (Fig.	('mRNA expression', 'MPA', (32, 47))	('non-cancerous stomach', 'Disease', 'MESH:D013274', (128, 149))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('non-cancerous stomach', 'Disease', (128, 149))	('variant', 'Var', (22, 29))	('lung cancers', 'Disease', 'MESH:D008175', (177, 189))	('lung cancers', 'Phenotype', 'HP:0100526', (177, 189))	('cancerous stomach', 'Phenotype', 'HP:0006753', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('expression', 'MPA', (80, 90))	('VSIG1', 'Gene', (16, 21))	('lung cancers', 'Disease', (177, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('greater', 'PosReg', (57, 64))
386366	28603843	Based on these results, we established MKN1, MKN28, H1299, and KYSE150 cells, which could be induced to express VSIG1 variant 2.	('KYSE150', 'CellLine', 'CVCL:1348', (63, 70))	('VSIG1', 'Gene', (112, 117))	('variant 2', 'Var', (118, 127))	('H1299', 'CellLine', 'CVCL:0060', (52, 57))
386374	28603843	The Transwell migration assay showed a significant reduction in the number of migrated cells in VSIG1-overexpressing MKN1, MKN28, H1299, and KYSE150 cells compared to controls by 74%, 61%, 59%, and 64%, respectively (Fig.	('MKN1', 'Var', (117, 121))	('reduction', 'NegReg', (51, 60))	('VSIG1-overexpressing', 'Gene', (96, 116))	('KYSE150', 'CellLine', 'CVCL:1348', (141, 148))	('H1299', 'CellLine', 'CVCL:0060', (130, 135))
386380	28603843	As shown in Figure 7(a), five bands (arrowheads; bands 1-5) present in the lane for IP by anti-VSIG1 antibody and corresponding areas in the lane for IP by normal rabbit IgG were cut from the silver-stained gel after electrophoretic separation.	('rabbit', 'Species', '9986', (163, 169))	('anti-VSIG1 antibody', 'Var', (90, 109))	('antibody', 'Var', (101, 109))
386383	28603843	KYSE150 cells, stably transfected with VSIG1-HA or VSIG1-FLAG, were then established (Fig.	('VSIG1-HA', 'Var', (39, 47))	('KYSE150', 'CellLine', 'CVCL:1348', (0, 7))	('VSIG1-FLAG', 'Var', (51, 61))
386389	28603843	They found that VSIG1 protein expression was negative in 54.3% of specimens, and VISG1 positivity was identified as an independent favorable prognostic factor for both OS and disease-free survival.	('positivity', 'Var', (87, 97))	('OS', 'Chemical', 'MESH:D009992', (168, 170))	('VISG1', 'Gene', (81, 86))
386396	28603843	Specifically, TTF1 represses mucinous differentiation of the pulmonary epithelium,6 and NKX2-1 deletion combined with the oncogenic KRAS mutation causes mucinous adenocarcinoma of the lung in murine models.6, 17 Furthermore, loss of function mutations of NKX2-1 with concurrent KRAS mutations are recurrently identified in human mucinous lung adenocarcinomas.18 Indeed, VSIG1 expression in our lung adenocarcinoma cohort was inversely associated with TTF1 positivity, and invasive mucinous adenocarcinomas frequently expressed VSIG1.	('KRAS', 'Gene', '16653', (278, 282))	('KRAS', 'Gene', (132, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (495, 505))	('mucin', 'Gene', (329, 334))	('associated', 'Interaction', (435, 445))	('mucin', 'Gene', '100508689', (481, 486))	('inversely', 'NegReg', (425, 434))	('mucinous lung adenocarcinomas', 'Disease', (329, 358))	('expression', 'MPA', (376, 386))	('mucin', 'Gene', '100508689', (329, 334))	('mucinous lung adenocarcinomas', 'Disease', 'MESH:D002288', (329, 358))	('mucinous adenocarcinoma of the lung', 'Disease', 'MESH:D002288', (153, 188))	('VSIG1', 'Gene', (370, 375))	('mucin', 'Gene', (153, 158))	('KRAS', 'Gene', '16653', (132, 136))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (394, 413))	('mucin', 'Gene', '100508689', (153, 158))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (338, 357))	('VSIG1', 'Gene', (527, 532))	('invasive mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (472, 505))	('mucinous adenocarcinoma of the lung', 'Disease', (153, 188))	('lung adenocarcinoma cohort', 'Disease', 'MESH:D000077192', (394, 420))	('lung adenocarcinoma cohort', 'Disease', (394, 420))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (338, 358))	('carcinomas', 'Phenotype', 'HP:0030731', (348, 358))	('positivity', 'Var', (456, 466))	('human', 'Species', '9606', (323, 328))	('invasive mucinous adenocarcinomas', 'Disease', (472, 505))	('mucin', 'Gene', (29, 34))	('KRAS', 'Gene', (278, 282))	('mucin', 'Gene', '100508689', (29, 34))	('TTF1', 'Gene', (451, 455))	('murine', 'Species', '10090', (192, 198))	('mucin', 'Gene', (481, 486))
386406	28603843	Therefore, we explored whether VSIG1 dimerizes and, if so, in what manner, because other members of IgSF are known to mediate homophilic adhesion.26, 27 In addition, VSIG1 possessing two immunoglobulin folds in the extracellular domain was shown to mediate homophilic adhesion through the interactions of the same immunoglobulin-like domain, but not through the interactions of different immunoglobulin-like domains, in the mouse.24 It should be noted that the amino acid sequence similarities of the first and second immunoglobulin-like domains between mouse and human VSIG1 are 81.3% and 79.7%, respectively.24 Nevertheless, our results indicated that human VSIG1 also dimerized specifically through homophilic-cis-interaction but not through homophilic-trans-interaction.	('VSIG1', 'Gene', (660, 665))	('homophilic-cis-interaction', 'Var', (702, 728))	('dimerized', 'MPA', (671, 680))	('mouse', 'Species', '10090', (554, 559))	('mouse', 'Species', '10090', (424, 429))	('human', 'Species', '9606', (564, 569))	('human', 'Species', '9606', (654, 659))
386437	27387103	All of the patients received endoscopic examinations using narrow-band imaging (NBI) with magnifying endoscopy (ME) which has powerful 80 times optical magnification (Evis Lucera CLV-260NBI, GIF-H260Z endoscopy, Olympus Medical Systems Corp, Tokyo, Japan), and chromoendoscopy with 2% Lugol's solution (Sigma-Aldrich, St. Louis, Missouri, USA).	("Lugol's solution", 'Chemical', 'MESH:C010389', (285, 301))	('H260Z', 'Var', (195, 200))	('H260Z', 'SUBSTITUTION', 'None', (195, 200))	('ME', 'Chemical', '-', (112, 114))	('patients', 'Species', '9606', (11, 19))	('Missouri', 'Disease', (329, 337))
386471	27387103	Among those with synchronous esophageal invasive carcinoma, one (case 19) underwent esophagectomy, two (case 5, 12) with esophagectomy and CCRT, six (case 6, 11, 13, 16, 17, 18) with CCRT only, and three patients (case 14, 15, 20) with initial predicted invasiveness of lamina propria by IEE underwent ESD with pathological reporting microinvasion of superficial submucosa layer.	('esophageal invasive carcinoma', 'Phenotype', 'HP:0011459', (29, 58))	('patients', 'Species', '9606', (204, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('synchronous esophageal invasive carcinoma', 'Disease', 'MESH:D009378', (17, 58))	('synchronous esophageal invasive carcinoma', 'Disease', (17, 58))	('esophagectomy', 'Disease', (84, 97))	('microinvasion', 'Var', (334, 347))
386515	27387103	The survival was better for those who received screening than those who did not (HR 0.57, 95% CI 0.41-0.79) and the Cox regression model quantified a survival benefit of 29% by IEE screening.	('Cox', 'Gene', '1351', (116, 119))	('Cox', 'Gene', (116, 119))	('IEE screening', 'Var', (177, 190))	('better', 'PosReg', (17, 23))	('survival', 'MPA', (4, 12))
386588	25878483	PVS carries an increased risk of development of squamous cell carcinoma of esophagus and pharynx.	('squamous cell carcinoma of esophagus', 'Disease', (48, 84))	('squamous cell carcinoma of esophagus', 'Disease', 'MESH:D002294', (48, 84))	('PVS', 'Var', (0, 3))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (62, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
386632	25878483	PVS is associated with a high risk of development of squamous cell carcinoma of esophagus and pharynx.	('squamous cell carcinoma of esophagus', 'Disease', 'MESH:D002294', (53, 89))	('squamous cell carcinoma of esophagus', 'Disease', (53, 89))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (67, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('PVS', 'Var', (0, 3))
386701	32384472	Unadjusted Kaplan-Meier curve indicated that patients with T2 and T3 stage had longer median OS and CSS (3 months and 4 months, respectively) than with T1 stage in distantly metastatic esophageal cancer (M1 stage).	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('esophageal cancer', 'Disease', (185, 202))	('esophageal cancer', 'Disease', 'MESH:D004938', (185, 202))	('T3 stage', 'Var', (66, 74))	('longer', 'PosReg', (79, 85))	('patients', 'Species', '9606', (45, 53))	('distantly', 'Disease', (164, 173))	('CSS', 'MPA', (100, 103))
386703	32384472	Using T1M0 as a reference, patients with T1M1 had significantly worse OS and CSS than those with T2M1 and T3M1 stage (P < .001).	('patients', 'Species', '9606', (27, 35))	('CSS', 'CPA', (77, 80))	('T1M1', 'Var', (41, 45))	('worse', 'NegReg', (64, 69))
386724	32384472	In accordance with the STROBE statement, we performed a retrospective cohort study with eligible patients from this population-based database: those with pathologically confirmed esophageal cancer (site codes: C15.0-C15.5, C15.8, and C15.9), age >18 years, with esophageal cancer as the first and only primary cancer, and who were diagnosed between 2004 and 2014.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', (310, 316))	('esophageal cancer', 'Disease', (179, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('C15.0-C15.5', 'Var', (210, 221))	('cancer', 'Disease', (273, 279))	('esophageal cancer', 'Disease', (262, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('C15.9', 'Var', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('esophageal cancer', 'Disease', 'MESH:D004938', (262, 279))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('C15.8', 'Var', (223, 228))	('patients', 'Species', '9606', (97, 105))
386736	32384472	Tumor location was classified into 4 groups: upper esophageal cancer (cervical and upper third of the esophagus tumors; site codes, C15.0 and C15.3), middle esophageal cancer (thoracic and middle third of the esophagus tumors; site codes, C15.1 and C15.4), lower esophageal cancer (abdominal and lower third of the esophagus tumors; site codes, C15.2 and C15.5), and not reported (site codes, C15.8 and C15.9).	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('esophagus tumors', 'Phenotype', 'HP:0100751', (209, 225))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (325, 331))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('upper esophageal cancer', 'Disease', 'MESH:D004938', (45, 68))	('middle esophageal cancer', 'Disease', (150, 174))	('C15.0', 'Var', (132, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (263, 280))	('middle esophageal cancer', 'Disease', 'MESH:D004938', (150, 174))	('tumors', 'Disease', 'MESH:D009369', (325, 331))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('C15.2', 'Var', (345, 350))	('tumors', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophagus tumors', 'Phenotype', 'HP:0100751', (102, 118))	('esophageal cancer', 'Disease', (263, 280))	('upper esophageal cancer', 'Disease', (45, 68))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('esophagus tumors', 'Phenotype', 'HP:0100751', (315, 331))	('C15.5', 'Var', (355, 360))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('tumors', 'Disease', (112, 118))
386748	32384472	Among patients with M1 stage, those with T1 stage experienced significantly worse OS and CSS compared with those with T2 and T3 stage (P < .001, Tables 2 and 3).	('worse', 'NegReg', (76, 81))	('CSS', 'CPA', (89, 92))	('M1 stage', 'Var', (20, 28))	('patients', 'Species', '9606', (6, 14))
386749	32384472	Overall, patients with T2 and T3 stage had longer OS and CSS (3 months and 4 months, respectively) than those with T1 stage.	('longer', 'PosReg', (43, 49))	('patients', 'Species', '9606', (9, 17))	('T3 stage', 'Var', (30, 38))	('CSS', 'CPA', (57, 60))
386752	32384472	Among patients with M0 stage, those with T1 stage experienced significantly better OS and CSS than patients with T3 and T4 stages (P < .001, Tables 2 and 3).	('CSS', 'CPA', (90, 93))	('patients', 'Species', '9606', (99, 107))	('M0 stage', 'Var', (20, 28))	('better', 'PosReg', (76, 82))	('patients', 'Species', '9606', (6, 14))	('T1 stage', 'Var', (41, 49))
386756	32384472	Among patients with M1 stage, those with T1 stage also experienced significantly worse OS and CSS than those with T2 and T3 stages (P < .025, Tables 4 and 5) in 2 subgroups.	('M1 stage', 'Var', (20, 28))	('CSS', 'CPA', (94, 97))	('patients', 'Species', '9606', (6, 14))	('T1 stage', 'Var', (41, 49))	('worse', 'NegReg', (81, 86))
386760	32384472	Patients with T4 stage had significantly worse OS and CSS compared with those with T1 stage (P < .001, Tables 4 and 5).	('Patients', 'Species', '9606', (0, 8))	('worse', 'NegReg', (41, 46))	('T4 stage', 'Var', (14, 22))
386761	32384472	Among patients diagnosed with EAC with M0 stage, those with T1 stage had better OS and CSS than those with T3 and T4 stages (P < .001, Tables 4 and 5).	('EAC', 'Phenotype', 'HP:0011459', (30, 33))	('CSS', 'CPA', (87, 90))	('M0 stage', 'Var', (39, 47))	('EAC', 'Disease', (30, 33))	('T1 stage', 'Var', (60, 68))	('patients', 'Species', '9606', (6, 14))	('better', 'PosReg', (73, 79))
386766	32384472	Patients with T1 stage experienced significantly worse OS and CSS than those with T2 and T3 stage in metastatic esophageal cancer (P < .001).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('T1 stage', 'Var', (14, 22))	('CSS', 'CPA', (62, 65))	('worse', 'NegReg', (49, 54))	('Patients', 'Species', '9606', (0, 8))	('esophageal cancer', 'Disease', (112, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
386775	32384472	The conventional view about cancer spread is that cancer gains metastatic ability as a result of an accumulation of mutations as they grow, In most esophageal cancers, this process might happen when the cancer has invaded the deeper areas.	('cancer', 'Disease', (50, 56))	('esophageal cancer', 'Disease', (148, 165))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('metastatic ability', 'CPA', (63, 81))	('cancers', 'Disease', (159, 166))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Disease', (203, 209))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (28, 34))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('gains', 'PosReg', (57, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))
386779	32384472	In some patients with colon cancer, nearly all mutations required for metastasis were present within the primary tumor potentially at the time of cancer initiation.	('tumor', 'Disease', (113, 118))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('colon cancer', 'Disease', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Disease', (28, 34))	('patients', 'Species', '9606', (8, 16))
386780	32384472	Similarly, in ESCC, some of the missense mutations in the TP53 gene have contributed to the invasion and metastasis.	('missense mutations', 'Var', (32, 50))	('TP53', 'Gene', '7157', (58, 62))	('contributed', 'Reg', (73, 84))	('TP53', 'Gene', (58, 62))	('ESCC', 'Disease', (14, 18))
386781	32384472	A previous study revealed that TP53 mutations might occur very early in ESCC progression, even in squamous dysplasia, the precursor lesions of ESCC.	('squamous dysplasia', 'Disease', (98, 116))	('TP53', 'Gene', '7157', (31, 35))	('squamous dysplasia', 'Disease', 'MESH:D002294', (98, 116))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (98, 116))	('ESCC', 'Disease', (72, 76))
386782	32384472	These findings agree with our study that some esophageal cancers might have some distinct important molecular mutations that can result in early metastasis and biological aggressiveness in the early T stage of cancer development and lead to worse survival (this might be one of the mechanisms of our hypothesis).	('early metastasis', 'CPA', (139, 155))	('aggressiveness', 'Disease', 'MESH:D001523', (171, 185))	('worse survival', 'CPA', (241, 255))	('aggressiveness', 'Disease', (171, 185))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (57, 63))	('aggressiveness', 'Phenotype', 'HP:0000718', (171, 185))	('result in', 'Reg', (129, 138))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('esophageal cancer', 'Disease', (46, 63))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
386783	32384472	Hence, further studies are needed to uncover these molecular mutations that enable T1 stage tumors to distantly metastasize, which might aid in the discovery of new genomic changes in this subset of tumors or new prognostic markers or drug targets.	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('enable', 'Reg', (76, 82))
386787	32384472	Similarly, another previous study highlighted that the use of definitive radiotherapy dose (>=5040 cGy) in the treatment of primary tumor can improve the condition of patients with newly diagnosed metastatic esophageal cancer.	('>=5040 cGy', 'Var', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('patients', 'Species', '9606', (167, 175))	('esophageal cancer', 'Disease', (208, 225))	('tumor', 'Disease', (132, 137))	('improve', 'PosReg', (142, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))
386798	32384472	As only a few patients had T1a stage, it prevented us from exploring whether metastatic cancer patients with T1a stage had worse survival than those with T1b stage.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('T1a stage', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (14, 22))
386800	32384472	This prevented us from determining whether there is an intermediate effect of T stage on survival between T1M1a vs T2M1a and T3M1a, relative to the difference between the T1M1b vs T2M1b and T3M1b patients, and that of T1M0 vs T2M0 and T3M0 patients.	('patients', 'Species', '9606', (196, 204))	('T1M1a', 'Var', (106, 111))	('T1M1b', 'Var', (171, 176))	('patients', 'Species', '9606', (240, 248))
386918	30151003	Patients with EV and PHG in our study were found to have significantly higher serum bilirubin levels than either controls or patients with EV only (P = 0.007) indicating that the presence of PHG is related to severity of the hepatic disease.	('higher', 'PosReg', (71, 77))	('PHG', 'Phenotype', 'HP:0001409', (21, 24))	('related', 'Reg', (198, 205))	('higher serum bilirubin levels', 'Phenotype', 'HP:0002904', (71, 100))	('serum bilirubin levels', 'MPA', (78, 100))	('EV', 'Phenotype', 'HP:0002040', (14, 16))	('hepatic disease', 'Disease', 'MESH:D056486', (225, 240))	('PHG', 'Phenotype', 'HP:0001409', (191, 194))	('PHG', 'Var', (21, 24))	('EV', 'Phenotype', 'HP:0002040', (139, 141))	('hepatic disease', 'Phenotype', 'HP:0001392', (225, 240))	('hepatic disease', 'Disease', (225, 240))	('higher serum bilirubin', 'Phenotype', 'HP:0003573', (71, 93))
386969	28860804	Several studies have identified the blockage of VEGFR-2 as a promising therapy for inhibiting angiogenesis.	('angiogenesis', 'CPA', (94, 106))	('VEGFR-2', 'Gene', '3791', (48, 55))	('blockage', 'Var', (36, 44))	('inhibiting', 'NegReg', (83, 93))	('VEGFR-2', 'Gene', (48, 55))
386980	28860804	Although different daily apatinib doses were used for gastric carcinoma (850 mg) and breast carcinoma (500 mg), similar toxicities were observed.	('breast carcinoma', 'Phenotype', 'HP:0003002', (85, 101))	('gastric carcinoma', 'Disease', (54, 71))	('850 mg', 'Var', (73, 79))	('breast carcinoma', 'Disease', (85, 101))	('toxicities', 'Disease', 'MESH:D064420', (120, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('breast carcinoma', 'Disease', 'MESH:D001943', (85, 101))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (54, 71))	('500 mg', 'Var', (103, 109))	('toxicities', 'Disease', (120, 130))	('apatinib', 'Chemical', 'MESH:C553458', (25, 33))	('gastric carcinoma', 'Disease', 'MESH:D013274', (54, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
386986	26165988	Studies have shown that ECRG4 effectively inhibits the proliferation of tumor cells and induces apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('induces', 'Reg', (88, 95))	('inhibits', 'NegReg', (42, 50))	('tumor', 'Disease', (72, 77))	('apoptosis', 'CPA', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('ECRG4', 'Var', (24, 29))
386993	26165988	Flow cytometric analysis and Hoechst staining demonstrated that overexpres-sion of ECRG4 significantly induced apoptosis.	('ECRG4', 'Gene', (83, 88))	('Hoechst', 'Chemical', '-', (29, 36))	('apoptosis', 'CPA', (111, 120))	('overexpres-sion', 'Var', (64, 79))
387010	26165988	Knockout of the ECRG4 gene in zebrafish embryos using RNA interference technology results in an enhanced capacity for cell proliferation.	('enhanced', 'PosReg', (96, 104))	('Knockout', 'Var', (0, 8))	('zebrafish', 'Species', '7955', (30, 39))	('ECRG4', 'Gene', (16, 21))
387051	26165988	The results of the MTT assay showed that at day 2, day 3 and day 4, the proliferative capability was severely impaired in the pcDNA3.1-ECRG4 group compared with the pcDNA3.1 group (Fig.	('impaired', 'NegReg', (110, 118))	('proliferative capability', 'CPA', (72, 96))	('pcDNA3.1-ECRG4', 'Var', (126, 140))	('MTT', 'Chemical', 'MESH:C070243', (19, 22))
387053	26165988	The results indicated that ECRG4 significantly reduced the colony formation ability of laryngeal cancer cells (Fig.	('laryngeal cancer', 'Disease', (87, 103))	('ECRG4', 'Var', (27, 32))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('laryngeal cancer', 'Disease', 'MESH:D007822', (87, 103))	('reduced', 'NegReg', (47, 54))
387056	26165988	Hoechst staining showed that compared with cells in the parental group and the pcDNA3.1 group, cells in the pcDNA3.1-ECRG4 group exhibited significantly increased chromatin condensation and more densely stained nuclei (Fig.	('more', 'PosReg', (190, 194))	('increased', 'PosReg', (153, 162))	('Hoechst', 'Chemical', '-', (0, 7))	('pcDNA3.1-ECRG4', 'Var', (108, 122))	('chromatin condensation', 'CPA', (163, 185))	('densely stained nuclei', 'CPA', (195, 217))
387058	26165988	The results showed that the expression levels of cleaved-PARP, cleaved-caspase-3 and Bax were significantly elevated in cells from the pcDNA3.1-ECRG4 group compared with that from the pcDNA3.1 group (Fig.	('expression levels', 'MPA', (28, 45))	('PARP', 'Gene', (57, 61))	('caspase-3', 'Gene', (71, 80))	('Bax', 'Gene', (85, 88))	('PARP', 'Gene', '142', (57, 61))	('caspase-3', 'Gene', '836', (71, 80))	('elevated', 'PosReg', (108, 116))	('pcDNA3.1-ECRG4', 'Var', (135, 149))	('Bax', 'Gene', '581', (85, 88))
387073	26165988	ECRG4 induces cell cycle arrest at the G0/G1 phase, which is hypothesized to be the key determinant that leads to proliferation inhibition in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('inhibition', 'NegReg', (128, 138))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (14, 31))	('tumor', 'Disease', (142, 147))	('proliferation', 'CPA', (114, 127))	('cell cycle arrest at the G0/G1 phase', 'CPA', (14, 50))	('ECRG4', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
387076	26165988	The results demonstrated that ECRG4 inhibited the growth of laryngeal cancer cells through arresting cells in the G0/G1 phase and delaying cell cycle progression from the G0/G1 phase to the S phase and G2/M phase.	('inhibited', 'NegReg', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('delaying', 'NegReg', (130, 138))	('laryngeal cancer', 'Disease', 'MESH:D007822', (60, 76))	('cell cycle progression', 'CPA', (139, 161))	('growth', 'CPA', (50, 56))	('laryngeal cancer', 'Disease', (60, 76))	('arresting', 'NegReg', (91, 100))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (60, 76))	('ECRG4', 'Var', (30, 35))
387088	26165988	Studies have shown that ECRG4 effectively induces apoptosis in esophageal squamous cell carcinoma cells, head and neck squamous cell carcinoma cells and gastric cancer cells; accompanied by upregulation of Bax and downregulation of Bcl-2.	('downregulation', 'NegReg', (214, 228))	('gastric cancer', 'Disease', 'MESH:D013274', (153, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('upregulation', 'PosReg', (190, 202))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('gastric cancer', 'Phenotype', 'HP:0012126', (153, 167))	('Bax', 'Gene', (206, 209))	('ECRG4', 'Var', (24, 29))	('apoptosis', 'CPA', (50, 59))	('Bax', 'Gene', '581', (206, 209))	('Bcl-2', 'Gene', (232, 237))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('gastric cancer', 'Disease', (153, 167))	('neck squamous cell carcinoma', 'Disease', (114, 142))	('Bcl-2', 'Gene', '596', (232, 237))	('induces', 'Reg', (42, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (114, 142))
387090	26165988	The results of this study also demonstrated that overexpression of ECRG4 activated caspase-3 and PARP, and ultimately induced apoptosis through upregulating the expression of proapoptotic protein Bax and downregulating the expression of antiapoptotic protein Bcl-2.	('Bax', 'Gene', '581', (196, 199))	('PARP', 'Gene', '142', (97, 101))	('caspase-3', 'Gene', '836', (83, 92))	('downregulating', 'NegReg', (204, 218))	('upregulating', 'PosReg', (144, 156))	('expression', 'MPA', (223, 233))	('Bcl-2', 'Gene', (259, 264))	('apoptosis', 'CPA', (126, 135))	('expression', 'MPA', (161, 171))	('Bcl-2', 'Gene', '596', (259, 264))	('ECRG4', 'Var', (67, 72))	('PARP', 'Gene', (97, 101))	('Bax', 'Gene', (196, 199))	('overexpression', 'PosReg', (49, 63))	('activated', 'PosReg', (73, 82))	('caspase-3', 'Gene', (83, 92))	('induced', 'Reg', (118, 125))
387101	26130253	The model prediction performance was robust in two independent EA sets and outperformed TP53 mutation, flow cytometric DNA content and histopathologic diagnosis of dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (164, 173))	('mutation', 'Var', (93, 101))	('EA', 'Phenotype', 'HP:0011459', (63, 65))	('TP53', 'Gene', '7157', (88, 92))	('dysplasia', 'Disease', (164, 173))	('TP53', 'Gene', (88, 92))
387134	26130253	Some high frequency SCA such as frequent loss and homozygous deletion spanning CDKN2A, FHIT, and WWOX had a similar frequency in both nonprogressors and progressors and therefore conferred no or low risk (low HR) of progression to EA (Fig.	('CDKN2A', 'Gene', '1029', (79, 85))	('SCA', 'Disease', (20, 23))	('FHIT', 'Gene', (87, 91))	('WWOX', 'Gene', '51741', (97, 101))	('CDKN2A', 'Gene', (79, 85))	('EA', 'Phenotype', 'HP:0011459', (231, 233))	('FHIT', 'Gene', '2272', (87, 91))	('loss', 'NegReg', (41, 45))	('homozygous deletion', 'Var', (50, 69))	('WWOX', 'Gene', (97, 101))
387135	26130253	In contrast, progressors were characterized by many low to moderate frequency SCA segments with high HRs that were infrequent in nonprogressors such as loss and cnLOH on chromosome 17p linked to TP53 and amplification spanning ERBB2 (Fig.	('TP53', 'Gene', (195, 199))	('amplification', 'Var', (204, 217))	('SCA', 'Disease', (78, 81))	('ERBB2', 'Gene', '2064', (227, 232))	('ERBB2', 'Gene', (227, 232))	('TP53', 'Gene', '7157', (195, 199))
387140	26130253	However, the T1-model and T1T2-models generated high EA risk scores of >=0.96 in six advanced EAs from esophagectomy specimens (Supplementary Table S2) and risk scores of >0.99 in 39 of 47 EA samples from TCGA (downloaded September, 2014) from individuals who were not part of the case-cohort study (Supplementary methods).	('T1T2-models', 'Var', (26, 37))	('EAs', 'Chemical', '-', (94, 97))	('EA', 'Phenotype', 'HP:0011459', (94, 96))	('EA', 'Phenotype', 'HP:0011459', (189, 191))	('T1-model', 'Var', (13, 21))	('EA', 'Phenotype', 'HP:0011459', (53, 55))
387146	26130253	TP53 mutations status in exons 5-9 had been previously assessed in a longitudinal study in separate biopsies every two cm in the esophagus at a single time point before last endoscopy or EA diagnosis in 122 participants in this study, including 33 who subsequently progressed to EA.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('EA', 'Phenotype', 'HP:0011459', (279, 281))	('mutations', 'Var', (5, 14))	('EA', 'Phenotype', 'HP:0011459', (187, 189))	('participants', 'Species', '9606', (207, 219))
387147	26130253	In these 122 patients TP53 mutations had 42% sensitivity and 92% specificity for future progression to EA.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (13, 21))	('EA', 'Phenotype', 'HP:0011459', (103, 105))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
387157	26130253	EA has been shown to have a high overall frequency of point mutations, yet with the exception of TP53, few individual genes are recurrently mutated in more than 15% of EAs.	('EA', 'Phenotype', 'HP:0011459', (0, 2))	('point mutations', 'Var', (54, 69))	('TP53', 'Gene', '7157', (97, 101))	('EA', 'Phenotype', 'HP:0011459', (168, 170))	('TP53', 'Gene', (97, 101))	('EAs', 'Chemical', '-', (168, 171))
387169	26130253	TP53 mutations can be detected before development of EA in BE with TP53 mutations having 44.1% sensitivity and a 91.4% specificity for future progression to EA base on a previously published longitudinal study.	('mutations', 'Var', (72, 81))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('EA', 'Phenotype', 'HP:0011459', (157, 159))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('EA', 'Phenotype', 'HP:0011459', (53, 55))	('BE', 'Phenotype', 'HP:0100580', (59, 61))
387170	26130253	sequenced commonly mutated genes in EA and reported that only TP53 mutations could discriminate HGD from non-dysplastic BE and non-BE controls in a cross-sectional study.	('BE', 'Phenotype', 'HP:0100580', (131, 133))	('discriminate', 'Reg', (83, 95))	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('BE', 'Phenotype', 'HP:0100580', (120, 122))	('HGD', 'Disease', (96, 99))	('non-dysplastic', 'Disease', (105, 119))	('non-dysplastic', 'Disease', 'MESH:D004416', (105, 119))	('EA', 'Phenotype', 'HP:0011459', (36, 38))
387171	26130253	A recent study found TP53 mutations in 81% of EAs and an additional 9% of the remaining EAs harbored structural alterations inactivating TP53 or amplifying MDM2.	('TP53', 'Gene', (21, 25))	('MDM2', 'Gene', (156, 160))	('EA', 'Phenotype', 'HP:0011459', (88, 90))	('EAs', 'Chemical', '-', (46, 49))	('mutations', 'Var', (26, 35))	('amplifying', 'Var', (145, 155))	('EAs', 'Chemical', '-', (88, 91))	('MDM2', 'Gene', '4193', (156, 160))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', '7157', (21, 25))	('EA', 'Phenotype', 'HP:0011459', (46, 48))	('TP53', 'Gene', (137, 141))
387172	26130253	Our results suggest assessing the outcome of disruptions of the TP53 signaling pathway and resultant high-risk chromosomal instability using measures of cancer risk associated chromosomal alterations improves EA risk prediction over using TP53 mutation alone.	('improves', 'PosReg', (200, 208))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TP53', 'Gene', '7157', (239, 243))	('TP53', 'Gene', '7157', (64, 68))	('disruptions', 'Var', (45, 56))	('TP53', 'Gene', (64, 68))	('chromosomal instability', 'Phenotype', 'HP:0040012', (111, 134))	('TP53', 'Gene', (239, 243))	('EA', 'Phenotype', 'HP:0011459', (209, 211))
387209	25127029	Human bone marrow derived mesenchymal stem cells were used at passages 3-12 in their undifferentiated state; up to passage 12 they exhibited adipocyte, osteocyte and chondrocyte differentiation in adipocyte, osteocyte and chondrocyte differentiation media (Lonza, Cambridge, UK); the cells were CD105, CD166, CD29, CD44, alpha-SMA and vimentin positive and were CD14, CD34, CD45, cytokeratin and desmin negative.	('Human', 'Species', '9606', (0, 5))	('CD44', 'Gene', '960', (315, 319))	('CD166', 'Gene', '214', (302, 307))	('vimentin positive', 'Protein', (335, 352))	('exhibited', 'Reg', (131, 140))	('alpha-SMA', 'Protein', (321, 330))	('CD45', 'Gene', '5788', (374, 378))	('CD29', 'Gene', '3688', (309, 313))	('CD44', 'Gene', (315, 319))	('CD14', 'Gene', (362, 366))	('adipocyte', 'CPA', (141, 150))	('CD14', 'Gene', '929', (362, 366))	('CD29', 'Gene', (309, 313))	('CD45', 'Gene', (374, 378))	('CD166', 'Gene', (302, 307))	('CD105', 'Var', (295, 300))
387213	25127029	Cells were paraformaldehyde(PFA)-fixed (4% w/v), permeabilised with 0.2% Triton X-100 in PBS (PBS-T) for 30 min and processed for immunocytochemistry as previously described using primary antibodies to CD105, CD34, CD29 (Ancell Corporation, Bayport, MN), alpha-SMA, vimentin, desmin, pancytokeratin (Fitzgerald, NJ), ChemR23 (Millipore, MA,) or GPR1 (Abcam, Cambridge, UK) followed by incubation with the appropriate fluorescein or Texas Red labelled secondary antibodies raised in donkey (Jackson Immunoresearch, Soham, UK), and mounted with Vectashield  containing DAPI (Vector Laboratories, Peterborough, UK).	('PBS', 'Disease', 'MESH:D011535', (94, 97))	('PBS', 'Disease', (94, 97))	('PBS-T', 'Disease', 'MESH:D011535', (94, 99))	('CD29', 'Gene', (215, 219))	('CD105', 'Var', (202, 207))	('PBS-T', 'Disease', (94, 99))	('CD34', 'Var', (209, 213))	('PFA', 'Chemical', 'MESH:D017245', (28, 31))	('donkey', 'Species', '9793', (482, 488))	('MN', 'CellLine', 'CVCL:U508', (250, 252))	('PBS', 'Disease', 'MESH:D011535', (89, 92))	('PBS', 'Disease', (89, 92))	('CD29', 'Gene', '3688', (215, 219))
387216	25127029	The effects were studied of phorbol 12-myristate 13-acetate (PMA), Ro320432, SB202190, SP600125, U0126, ISO-1 (Calbiochem, Darmstadt, Germany), LY294002 (New England labs, Hertfordshire, UK), chemerin neutralising antibody (MAb2325, R&D Systems), CCX-832 and CCX826 (ChemoCentryx, Mountain View, CA).	('SP600125', 'Var', (87, 95))	('Ro320432', 'Chemical', '-', (67, 75))	('LY294002', 'Var', (144, 152))	('CCX826', 'Chemical', '-', (259, 265))	('U0126', 'Chemical', 'MESH:C113580', (97, 102))	('and', 'Var', (255, 258))	('phorbol 12-myristate 13-acetate', 'Chemical', 'MESH:D013755', (28, 59))	('LY294002', 'Chemical', 'MESH:C085911', (144, 152))	('PMA', 'Chemical', 'MESH:D013755', (61, 64))	('ISO-1', 'Gene', (104, 109))	('ISO-1', 'Gene', '63826', (104, 109))	('SB202190', 'Chemical', 'MESH:C090942', (77, 85))	('SP600125', 'Chemical', 'MESH:C432165', (87, 95))
387229	25127029	Direct evidence for a role of chemerin as an active component of CAM-CM was provided by the observation that immunoneutralisation of chemerin inhibited the effect of CAM-CM (Fig 1C, center); additionally, siRNA knockdown of chemerin expression decreased the activity of CM subsequently applied to MSCs in migration assays (Fig 1C, right; Fig S6 in File S2).	('CAM', 'Gene', (166, 169))	('decreased', 'NegReg', (244, 253))	('activity', 'MPA', (258, 266))	('CAM', 'Gene', '79823', (166, 169))	('knockdown', 'Var', (211, 220))	('CAM', 'Gene', '79823', (65, 68))	('CAM', 'Gene', (65, 68))
387235	25127029	The PKC inhibitor Ro320432 also inhibited migration, and the combination of Ro320432, U0126, SP600125 and SB202190 completely inhibited migratory responses (Fig 2C, right).	('migration', 'CPA', (42, 51))	('SP600125', 'Var', (93, 101))	('U0126', 'Chemical', 'MESH:C113580', (86, 91))	('inhibited', 'NegReg', (32, 41))	('SB202190', 'Var', (106, 114))	('Ro320432', 'Chemical', '-', (18, 26))	('migratory responses', 'CPA', (136, 155))	('inhibited', 'NegReg', (126, 135))	('SB202190', 'Chemical', 'MESH:C090942', (106, 114))	('Ro320432', 'Var', (18, 26))	('Ro320432', 'Var', (76, 84))	('U0126', 'Var', (86, 91))	('Ro320432', 'Chemical', '-', (76, 84))	('SP600125', 'Chemical', 'MESH:C432165', (93, 101))
387236	25127029	Evidence that PKC activation was upstream of MAP kinase stimulation is provided by the observation that PMA stimulated MSC migration and this was inhibited by U0126, SP600125 and SB202190; moreover, PMA stimulated phosphorylation of p42/44, p38 and JnkII kinases (Fig S8 in File S2).	('SP600125', 'Chemical', 'MESH:C432165', (166, 174))	('SB202190', 'Chemical', 'MESH:C090942', (179, 187))	('SP600125', 'Var', (166, 174))	('U0126', 'Chemical', 'MESH:C113580', (159, 164))	('SB202190', 'Var', (179, 187))	('p42', 'Gene', (233, 236))	('JnkII kinases', 'Enzyme', (249, 262))	('p38', 'Gene', '1432', (241, 244))	('p42', 'Gene', '2038', (233, 236))	('phosphorylation', 'MPA', (214, 229))	('MSC migration', 'CPA', (119, 132))	('U0126', 'Var', (159, 164))	('PMA', 'Chemical', 'MESH:D013755', (104, 107))	('PMA', 'Chemical', 'MESH:D013755', (199, 202))	('p38', 'Gene', (241, 244))
387237	25127029	There was a marked reduction in phosphorylation of p42/44, p38 and JnkII kinases after ChemR23 knockdown using siRNA consistent with the idea that these kinases are downstream of ChemR23 (Fig S8 in File S2).	('p38', 'Gene', (59, 62))	('reduction', 'NegReg', (19, 28))	('ChemR23', 'Gene', (87, 94))	('JnkII kinases', 'Enzyme', (67, 80))	('p38', 'Gene', '1432', (59, 62))	('knockdown', 'Var', (95, 104))	('p42', 'Gene', (51, 54))	('phosphorylation', 'MPA', (32, 47))	('p42', 'Gene', '2038', (51, 54))
387240	25127029	Following ChemR23 knockdown the MIF response to chemerin was profoundly inhibited (Fig 3A, center).	('knockdown', 'Var', (18, 27))	('ChemR23', 'Gene', (10, 17))	('MIF', 'Gene', (32, 35))	('inhibited', 'NegReg', (72, 81))	('MIF', 'Gene', '4282', (32, 35))
387243	25127029	Similarly, MIF knockdown (Fig S10 in File S2) increased MSC migration in response to low concentrations of chemerin (4 ng/ml), but interestingly the response to chemerin at higher concentrations (20 ng/ml) was not influenced by MIF knockdown (Fig 3C).	('MIF', 'Gene', (11, 14))	('knockdown', 'Var', (15, 24))	('MSC migration', 'CPA', (56, 69))	('increased', 'PosReg', (46, 55))	('MIF', 'Gene', (228, 231))	('MIF', 'Gene', '4282', (11, 14))	('low concentrations of chemerin', 'Phenotype', 'HP:0040209', (85, 115))	('MIF', 'Gene', '4282', (228, 231))
387245	25127029	MSCs labelled with PKH67 (Fig 4A, left) were identified as migrating in response to chemerin (Fig 4A, center) and CAM-CM (Fig 4A, right), and the migratory response was inhibited by CCX832 but not CCX826.	('migrating', 'CPA', (59, 68))	('migratory response', 'CPA', (146, 164))	('response to chemerin', 'MPA', (72, 92))	('CCX832', 'Chemical', '-', (182, 188))	('CCX826', 'Chemical', '-', (197, 203))	('CCX832', 'Var', (182, 188))	('PKH67', 'Var', (19, 24))	('CAM', 'Gene', '79823', (114, 117))	('inhibited', 'NegReg', (169, 178))	('CAM', 'Gene', (114, 117))
387250	25127029	Labelled cells in the xenografts were increased in tumors of OE21 and CAMs compared with OE21 cells alone (Fig 5A).	('CAMs', 'Disease', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CAMs', 'Chemical', '-', (70, 74))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('OE21', 'Var', (61, 65))	('increased', 'PosReg', (38, 47))
387267	25127029	Since chemerin is a chemoattractant for NK cells and dendritic cells it has been suggested that loss of chemerin allows tumors to evade the immune defense mechanisms that inhibit tumorigenesis.	('chemerin', 'Protein', (104, 112))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('loss', 'Var', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', (179, 184))
387271	25127029	Since receptor knockdown, immunoneutralisation and a ChemR23 receptor antagonist only partially inhibited the effects of CAM-CM, there are also likely to be other CAM chemoattractants.	('CAM', 'Gene', (121, 124))	('CAM', 'Gene', (163, 166))	('knockdown', 'Var', (15, 24))	('inhibited', 'NegReg', (96, 105))	('CAM', 'Gene', '79823', (121, 124))	('CAM', 'Gene', '79823', (163, 166))
387401	32089988	In the OCCM intermediate, MCM3 interacts with ORC Cdc6 at CTD and stimulates the ATPase activity.	('ATPase', 'Gene', (81, 87))	('Cdc6', 'Gene', '990', (50, 54))	('ATPase', 'Gene', '1769', (81, 87))	('CTD', 'Gene', (58, 61))	('activity', 'MPA', (88, 96))	('MCM3', 'Var', (26, 30))	('stimulates', 'PosReg', (66, 76))	('ORC', 'Gene', (46, 49))	('interacts', 'Interaction', (31, 40))	('CTD', 'Gene', '1283', (58, 61))	('Cdc6', 'Gene', (50, 54))
387420	32089988	Numerous rearrangements are one of the features of the aggressive cancer genome.	('rearrangements', 'Var', (9, 23))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('aggressive cancer', 'Disease', (55, 72))	('aggressive cancer', 'Disease', 'MESH:D009369', (55, 72))
387425	32089988	The diagnostic values of the individual MCM subunits were identified in various cancers including MCM2 in gastric cardiac cancer and salivary gland tumor, MCM5 in esophageal cancer, MCM7 in meningiomas, and MCM10 in breast cancer.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('MCM2', 'Var', (98, 102))	('meningiomas', 'Disease', (190, 201))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('cardiac cancer', 'Phenotype', 'HP:0100544', (114, 128))	('salivary gland tumor', 'Disease', (133, 153))	('MCM5', 'Gene', '4174', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('MCM7', 'Gene', (182, 186))	('esophageal cancer', 'Disease', (163, 180))	('MCM5', 'Gene', (155, 159))	('gastric cardiac cancer', 'Disease', (106, 128))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('salivary gland tumor', 'Disease', 'MESH:D008949', (133, 153))	('meningioma', 'Phenotype', 'HP:0002858', (190, 200))	('MCM7', 'Gene', '4176', (182, 186))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('salivary gland tumor', 'Phenotype', 'HP:0100684', (133, 153))	('cancers', 'Disease', (80, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('MCM10', 'Gene', (207, 212))	('meningiomas', 'Disease', 'MESH:D008579', (190, 201))	('gastric cardiac cancer', 'Disease', 'MESH:D006338', (106, 128))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('breast cancer', 'Disease', (216, 229))	('MCM10', 'Gene', '55388', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('meningiomas', 'Phenotype', 'HP:0002858', (190, 201))
387430	32089988	Besides, Genistein, BETi, and Breviscapine were reported to, respectively, downregulate MCM2, MCM5, and MCM7.	('MCM7', 'Gene', '4176', (104, 108))	('BETi', 'Chemical', '-', (20, 24))	('MCM5', 'Gene', '4174', (94, 98))	('downregulate', 'NegReg', (75, 87))	('MCM2', 'Gene', (88, 92))	('Breviscapine', 'Var', (30, 42))	('Breviscapine', 'Chemical', 'MESH:C061097', (30, 42))	('MCM7', 'Gene', (104, 108))	('Genistein', 'Chemical', 'MESH:D019833', (9, 18))	('MCM5', 'Gene', (94, 98))
387437	32089988	Univariate and multivariate survival analyses with Cox's regression model present evidence for independent prognostic roles of MCM2 in LUSC prognosis, MCM6 in glioma, MCM5 in lung squamous cell carcinoma, and MCM8 in pancreatic cancer.	('LUSC', 'Disease', (135, 139))	('MCM2', 'Gene', (127, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (217, 234))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (175, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('glioma', 'Disease', (159, 165))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (175, 203))	('pancreatic cancer', 'Disease', 'MESH:D010190', (217, 234))	('MCM8', 'Var', (209, 213))	('lung squamous cell carcinoma', 'Disease', (175, 203))	('MCM5', 'Gene', '4174', (167, 171))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('MCM6', 'Gene', '4175', (151, 155))	('MCM5', 'Gene', (167, 171))	('pancreatic cancer', 'Disease', (217, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('MCM6', 'Gene', (151, 155))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))
387443	32089988	Although initiation might be available at dormant origins, DNA damage would still accumulate because of fork progression obstacle, high frequency of chromosome recombination between nearby stalling forks, deletion of areas with tumor suppressor genes, and other genomic structural abnormalities.	('deletion', 'Var', (205, 213))	('fork', 'CPA', (104, 108))	('chromosome recombination', 'CPA', (149, 173))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('structural abnormalities', 'Disease', (270, 294))	('tumor', 'Disease', (228, 233))	('structural abnormalities', 'Disease', 'MESH:C536503', (270, 294))
387452	32089988	Cancer cells are produced by accumulated mutations in oncogenes and tumor suppressor genes.	('mutations', 'Var', (41, 50))	('oncogenes', 'Gene', (54, 63))	('tumor', 'Disease', (68, 73))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
387453	32089988	Genomic variations including mutation, extensive chromosome rearrangement, deletion, and excess amplification of genes are crucial in cancer prognosis.	('mutation', 'Var', (29, 37))	('deletion', 'Var', (75, 83))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('excess', 'PosReg', (89, 95))	('amplification', 'MPA', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
387455	32089988	Point mutations in MCM4 (F345I, G364R, and G486D) have been reported to cause dysfunction of MCM2-7 complex, unreplicated DNA in the S phase, and segregation of structurally altered genome to daughter cells, resulting in disrupted DNA replication in daughter cells, malignancy, and relapse of carcinomas.	('MCM4', 'Gene', '4173', (19, 23))	('G364R', 'Var', (32, 37))	('carcinomas', 'Disease', (293, 303))	('cause', 'Reg', (72, 77))	('G486D', 'Mutation', 'p.G486D', (43, 48))	('G364R', 'Mutation', 'rs1485929856', (32, 37))	('disrupted DNA replication', 'MPA', (221, 246))	('MCM4', 'Gene', (19, 23))	('malignancy', 'Disease', 'MESH:D009369', (266, 276))	('dysfunction', 'MPA', (78, 89))	('F345I', 'Mutation', 'p.F345I', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('carcinomas', 'Phenotype', 'HP:0030731', (293, 303))	('carcinomas', 'Disease', 'MESH:D002277', (293, 303))	('malignancy', 'Disease', (266, 276))	('MCM2-7', 'Gene', '4171;4172;4173;4174;4175;4176', (93, 99))	('MCM2-7', 'Gene', (93, 99))	('G486D', 'Var', (43, 48))	('F345I', 'Var', (25, 30))
387456	32089988	F345I mutation weakens the interaction with MCM6.	('MCM6', 'Gene', (44, 48))	('interaction', 'Interaction', (27, 38))	('MCM6', 'Gene', '4175', (44, 48))	('weakens', 'NegReg', (15, 22))	('F345I', 'Mutation', 'p.F345I', (0, 5))	('F345I mutation', 'Var', (0, 14))
387457	32089988	G364R mutation was detected in skin cancer cells, and G486D mutation was detected in endometrial cancer cells.	('endometrial cancer', 'Disease', 'MESH:D016889', (85, 103))	('detected', 'Reg', (73, 81))	('skin cancer', 'Disease', (31, 42))	('G364R', 'Mutation', 'rs1485929856', (0, 5))	('skin cancer', 'Phenotype', 'HP:0008069', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('G486D', 'Mutation', 'p.G486D', (54, 59))	('skin cancer', 'Disease', 'MESH:D012878', (31, 42))	('endometrial cancer', 'Disease', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('G364R', 'Var', (0, 5))	('endometrial cancer', 'Phenotype', 'HP:0012114', (85, 103))	('G486D', 'Var', (54, 59))
387458	32089988	Copy number variations (CNVs) of MCMs contribute to genomic instability and cancer progression.	('genomic instability', 'CPA', (52, 71))	('Copy number variations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('contribute', 'Reg', (38, 48))	('MCMs', 'Gene', (33, 37))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
387462	32089988	In the intronic region of MCM7, rs999885 controlled the expression level of miRNA (miR-106b-25) to decrease the death risk in intermediate or advanced HCC , while patients with homozygote genotype (CC) of rs1534309 showed a higher survival rate in acute myeloid leukemia than the patients with other genotypes (CG and GG).	('MCM7', 'Gene', (26, 30))	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (248, 270))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (254, 270))	('HCC', 'Gene', '619501', (151, 154))	('MCM7', 'Gene', '4176', (26, 30))	('rs1534309', 'Mutation', 'rs1534309', (205, 214))	('HCC', 'Phenotype', 'HP:0001402', (151, 154))	('CG', 'Chemical', 'MESH:C028505', (311, 313))	('HCC', 'Gene', (151, 154))	('expression level', 'MPA', (56, 72))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (280, 288))	('decrease', 'NegReg', (99, 107))	('acute myeloid leukemia', 'Disease', (248, 270))	('rs999885', 'Var', (32, 40))	('rs999885', 'Mutation', 'rs999885', (32, 40))	('rs1534309', 'Var', (205, 214))	('higher', 'PosReg', (224, 230))	('survival', 'CPA', (231, 239))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (248, 270))
387466	32089988	Survival analysis and joint effect analysis demonstrated that the combination of MCM2 and MCM6 could serve as HCC prognostic predictors.	('HCC', 'Phenotype', 'HP:0001402', (110, 113))	('MCM2', 'Var', (81, 85))	('MCM6', 'Gene', '4175', (90, 94))	('HCC', 'Gene', (110, 113))	('MCM6', 'Gene', (90, 94))	('HCC', 'Gene', '619501', (110, 113))
387495	32089988	IDH1 mutation, a classical biomarker in glioma, was reported to combinate MCM6 overexpressions to improve the prediction of the prognosis in glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (141, 154))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('improve', 'PosReg', (98, 105))	('MCM6', 'Gene', (74, 78))	('glioblastomas', 'Disease', (141, 154))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (40, 46))	('MCM6', 'Gene', '4175', (74, 78))	('IDH1', 'Gene', (0, 4))	('glioblastomas', 'Phenotype', 'HP:0012174', (141, 154))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
387503	32089988	Knockdown of MCM6 was related to a delay in S/G2-phase progression with downregulation of CDK2, CDK4, CyclinA, CyclinB1, CyclinD1, and CyclinE in HCC.	('MCM6', 'Gene', (13, 17))	('CyclinA', 'Gene', (102, 109))	('CDK2', 'Gene', '1017', (90, 94))	('CyclinD1', 'Gene', '595', (121, 129))	('CDK2', 'Gene', (90, 94))	('delay', 'NegReg', (35, 40))	('CDK4', 'Gene', (96, 100))	('CyclinD1', 'Gene', (121, 129))	('HCC', 'Gene', (146, 149))	('S/G2', 'Var', (44, 48))	('CyclinA', 'Gene', '890', (102, 109))	('S/G2', 'SUBSTITUTION', 'None', (44, 48))	('CyclinB1', 'Gene', '891', (111, 119))	('CDK4', 'Gene', '1019', (96, 100))	('CyclinB1', 'Gene', (111, 119))	('HCC', 'Gene', '619501', (146, 149))	('Knockdown', 'Var', (0, 9))	('HCC', 'Phenotype', 'HP:0001402', (146, 149))	('MCM6', 'Gene', '4175', (13, 17))	('downregulation', 'NegReg', (72, 86))
387504	32089988	Silencing of MCM7 reduced cyclinD1, cyclinE2, and CDK2, which triggered events in the G1 or G1/S phase.	('MCM7', 'Gene', (13, 17))	('cyclinD1', 'Gene', '595', (26, 34))	('triggered', 'Reg', (62, 71))	('reduced', 'NegReg', (18, 25))	('cyclinD1', 'Gene', (26, 34))	('cyclinE2', 'Gene', (36, 44))	('CDK2', 'Gene', (50, 54))	('MCM7', 'Gene', '4176', (13, 17))	('cyclinE2', 'Gene', '9134', (36, 44))	('Silencing', 'Var', (0, 9))	('CDK2', 'Gene', '1017', (50, 54))
387506	32089988	Besides, results of western blot analysis showed that beta-catenin and cyclin D1 were downregulated in MCM10 knockdown cells, suggesting that downregulated MCM10 suppressed metastasis in breast cancer via the Wnt/beta-catenin pathway.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('beta-catenin', 'Gene', '1499', (213, 225))	('MCM10', 'Gene', (103, 108))	('MCM10', 'Gene', '55388', (103, 108))	('cyclin D1', 'Gene', '595', (71, 80))	('beta-catenin', 'Gene', '1499', (54, 66))	('metastasis', 'CPA', (173, 183))	('cyclin D1', 'Gene', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('downregulated', 'NegReg', (86, 99))	('beta-catenin', 'Gene', (54, 66))	('MCM10', 'Gene', '55388', (156, 161))	('downregulated', 'Var', (142, 155))	('suppressed', 'NegReg', (162, 172))	('MCM10', 'Gene', (156, 161))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('beta-catenin', 'Gene', (213, 225))	('breast cancer', 'Disease', (187, 200))
387511	32089988	In this research, a protein-protein interaction between overexpressed mutant p53 and MCM2/4 was directly detected.	('MCM2/4', 'Gene', '4171;4173', (85, 91))	('MCM2/4', 'Gene', (85, 91))	('protein-protein', 'Protein', (20, 35))	('mutant', 'Var', (70, 76))	('overexpressed', 'PosReg', (56, 69))	('detected', 'Reg', (105, 113))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))
387512	32089988	Moreover, MCM2-7 was required for synergistic mutant p53-dependent induction of apoptosis by the combination of the poly ADP-ribose polymerase inhibitor talazoparib and the alkylating agent temozolomide, indicating a mutant p53-poly-ADP-ribose polymerase minichromosome maintenance functional axis.	('p53', 'Gene', (224, 227))	('p53', 'Gene', '7157', (224, 227))	('poly ADP-ribose polymerase', 'Gene', '142', (116, 142))	('talazoparib', 'Chemical', 'MESH:C586365', (153, 164))	('poly ADP-ribose polymerase', 'Gene', (116, 142))	('mutant', 'Var', (46, 52))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('temozolomide', 'Chemical', 'MESH:D000077204', (190, 202))	('MCM2-7', 'Gene', '4171;4172;4173;4174;4175;4176', (10, 16))	('MCM2-7', 'Gene', (10, 16))
387515	32089988	Silencing of MCM7 inhibited the phosphorylation of AKT1 and mTOR in both esophageal cancer cell lines, suggesting that MCM7 might promote cancer development and poor survival outcomes via activating the AKT1/mTOR signaling pathway.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (138, 144))	('MCM7', 'Gene', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mTOR', 'Gene', '2475', (60, 64))	('MCM7', 'Gene', '4176', (119, 123))	('phosphorylation', 'MPA', (32, 47))	('Silencing', 'Var', (0, 9))	('MCM7', 'Gene', (13, 17))	('AKT1', 'Gene', '207', (51, 55))	('AKT1', 'Gene', '207', (203, 207))	('mTOR', 'Gene', (208, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('inhibited', 'NegReg', (18, 27))	('poor survival outcomes', 'CPA', (161, 183))	('MCM7', 'Gene', '4176', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', (84, 90))	('AKT1', 'Gene', (51, 55))	('esophageal cancer', 'Disease', (73, 90))	('activating', 'PosReg', (188, 198))	('AKT1', 'Gene', (203, 207))	('mTOR', 'Gene', '2475', (208, 212))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('promote', 'PosReg', (130, 137))	('mTOR', 'Gene', (60, 64))
387518	32089988	Improper modifications might be mechanisms for cancer development and adverse prognosis.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Improper modifications', 'Var', (0, 22))	('mechanisms', 'Reg', (32, 42))	('cancer', 'Disease', (47, 53))	('modifications', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
387520	32089988	Dysfunctional phosphorylation of MCMs is suggested to be associated with oncogenesis and cancer development.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('MCMs', 'Gene', (33, 37))	('cancer', 'Disease', (89, 95))	('oncogenesis', 'CPA', (73, 84))	('Dysfunctional phosphorylation', 'Var', (0, 29))	('associated', 'Reg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
387532	32089988	A previous study indicated that MCM6 triggered the S/G2 phase transition.	('S/G2', 'Var', (51, 55))	('MCM6', 'Gene', (32, 36))	('S/G2', 'SUBSTITUTION', 'None', (51, 55))	('MCM6', 'Gene', '4175', (32, 36))
387546	32089988	Considering the cross-talk between phosphorylation and sumoylation, as well as the proliferation-promoting effect of restrained ubiquitylation, manipulation of sumoylation and ubiquitylation may be a potential method for MCM-targeted cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('restrained ubiquitylation', 'MPA', (117, 142))	('proliferation-promoting', 'CPA', (83, 106))	('talk', 'Gene', (22, 26))	('talk', 'Gene', '659', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('manipulation', 'Var', (144, 156))	('cancer', 'Disease', (234, 240))
387572	31007745	The raw data were downloaded as MINiML files and screened with the limma package in R (version 3.2.5; ) and subsequently, the log2 of the fold change (logFC) was calculated to screen DEGs between OSCC and normal oral mucosa tissues.	('SCC', 'Gene', '6317', (197, 200))	('DEGs', 'Var', (183, 187))	('SCC', 'Gene', (197, 200))
387586	31007745	CAL-27 cells with Lv-sh-SPP1, Lv-sh-ITGA3, Lv-sh-PLAU, LV-sh-NC or Cal-27 cells without transfection were seeded into 6-well plates at a density of 50,000 cells/well.	('Lv-sh-SPP1', 'Var', (18, 28))	('CAL-27', 'CellLine', 'CVCL:1107', (0, 6))	('ITGA3', 'Gene', '3675', (36, 41))	('ITGA3', 'Gene', (36, 41))
387592	31007745	For the Transwell cell migration assay, CAL-27 cells transfected with the Lv-sh-NC or CAL-27 cells with knockdown of SPP1, PLAU or ITGA3 were seeded at 1x104 cells/well in serum-free medium in the upper chambers of the Transwell plate, and the lower chamber contained the culture medium with 10% fetal bovine serum.	('CAL-27', 'CellLine', 'CVCL:1107', (40, 46))	('ITGA3', 'Gene', (131, 136))	('PLAU', 'Gene', (123, 127))	('bovine', 'Species', '9913', (302, 308))	('SPP1', 'Gene', (117, 121))	('CAL-27', 'CellLine', 'CVCL:1107', (86, 92))	('ITGA3', 'Gene', '3675', (131, 136))	('knockdown', 'Var', (104, 113))
387595	31007745	The 4 gene expression microarray datasets for OSCC, GSE37991, GSE23558, GSE30784 and GSE56532, were obtained from GEO.	('GSE23558', 'Var', (62, 70))	('SCC', 'Gene', '6317', (47, 50))	('GSE37991', 'Var', (52, 60))	('GSE30784', 'Var', (72, 80))	('SCC', 'Gene', (47, 50))
387597	31007745	3B, the KEGG pathways enriched by the DEGs were mainly associated with the cytokine-cytokine receptor interaction (hsa04060), Toll-like receptor (TLR) signaling pathway (hsa04620), chemokine signaling pathway (hsa04062), focal adhesion (hsa04510), extracellular matrix-receptor interaction (hsa04512) and phosphoinositide-3 kinase (PI3K)/Akt signaling pathway (hsa04151).	('phosphoinositide-3 kinase', 'Gene', (305, 330))	('chemokine signaling pathway', 'Pathway', (181, 208))	('hsa04151', 'Var', (361, 369))	('hsa04510', 'Var', (237, 245))	('Akt', 'Gene', (338, 341))	('phosphoinositide-3 kinase', 'Gene', '5295', (305, 330))	('associated', 'Reg', (55, 65))	('KEGG pathways', 'Pathway', (8, 21))	('hsa04512', 'Var', (291, 299))	('hsa', 'Species', '9606', (291, 294))	('Akt', 'Gene', '207', (338, 341))	('hsa', 'Species', '9606', (210, 213))	('cytokine-cytokine receptor interaction', 'Pathway', (75, 113))	('hsa', 'Species', '9606', (115, 118))	('hsa', 'Species', '9606', (361, 364))	('hsa', 'Species', '9606', (170, 173))	('TLR', 'Gene', '7099;51284', (146, 149))	('focal adhesion', 'Pathway', (221, 235))	('extracellular matrix-receptor interaction', 'Pathway', (248, 289))	('hsa04062', 'Var', (210, 218))	('hsa04620', 'Var', (170, 178))	('TLR', 'Gene', (146, 149))	('hsa04060', 'Var', (115, 123))	('hsa', 'Species', '9606', (237, 240))
387603	31007745	The survival analysis based on TCGA data revealed that OSCC patients with high SPP1, ITGA3 or PLAU expression had a shorter OS than those with low/intermediate expression of SPP1, ITGA3 or PLAU (P<0.05; Fig.	('shorter', 'NegReg', (116, 123))	('ITGA3', 'Gene', (180, 185))	('high', 'Var', (74, 78))	('ITGA3', 'Gene', '3675', (85, 90))	('SCC', 'Gene', (56, 59))	('patients', 'Species', '9606', (60, 68))	('SPP1', 'Gene', (79, 83))	('SCC', 'Gene', '6317', (56, 59))	('PLAU', 'Gene', (94, 98))	('ITGA3', 'Gene', '3675', (180, 185))	('ITGA3', 'Gene', (85, 90))
387612	31007745	The knockdown rates of SPP1, ITGA3 and PLAU were determined to be 44.78, 28.17 and 31.43%, respectively, indicating successful knockdown of the individual genes (Fig.	('SPP1', 'Gene', (23, 27))	('knockdown', 'Var', (127, 136))	('ITGA3', 'Gene', '3675', (29, 34))	('ITGA3', 'Gene', (29, 34))
387613	31007745	The CAL-27 cells transfected with Lv-sh-NC, as well as CAL-27 cells with SPP1, ITGA3 and PLAU knockdown were cultured in a 96-well plate for 0, 24, 48 and 72 h, and then subjected to a CCK-8 cell proliferation assay.	('ITGA3', 'Gene', (79, 84))	('knockdown', 'Var', (94, 103))	('CAL-27', 'CellLine', 'CVCL:1107', (55, 61))	('Lv-sh-NC', 'Var', (34, 42))	('ITGA3', 'Gene', '3675', (79, 84))	('CAL-27', 'CellLine', 'CVCL:1107', (4, 10))	('SPP1', 'Gene', (73, 77))
387614	31007745	6B, CAL-27 cells with knockdown of SPP1 or PLAU, but not ITGA3, possessed a lower capacity for cell proliferation.	('cell proliferation', 'CPA', (95, 113))	('PLAU', 'Gene', (43, 47))	('ITGA3', 'Gene', '3675', (57, 62))	('knockdown', 'Var', (22, 31))	('lower', 'NegReg', (76, 81))	('ITGA3', 'Gene', (57, 62))	('CAL-27', 'CellLine', 'CVCL:1107', (4, 10))	('SPP1', 'Gene', (35, 39))
387615	31007745	Furthermore, the migration and invasion ability of CAL-27 cells after knockdown of SPP1, ITGA3 or PLAU, was determined, as presented in Fig.	('migration', 'CPA', (17, 26))	('knockdown', 'Var', (70, 79))	('PLAU', 'Gene', (98, 102))	('ITGA3', 'Gene', '3675', (89, 94))	('invasion ability', 'CPA', (31, 47))	('SPP1', 'Gene', (83, 87))	('CAL-27', 'CellLine', 'CVCL:1107', (51, 57))	('ITGA3', 'Gene', (89, 94))
387616	31007745	The Transwell migration and invasion assays indicated that CAL-27 cells with knockdown of SPP1 or PLAU, but not ITGA3, possessed a decreased capacity for cell migration and invasion.	('ITGA3', 'Gene', '3675', (112, 117))	('invasion', 'CPA', (173, 181))	('PLAU', 'Gene', (98, 102))	('decreased', 'NegReg', (131, 140))	('knockdown', 'Var', (77, 86))	('ITGA3', 'Gene', (112, 117))	('CAL-27', 'CellLine', 'CVCL:1107', (59, 65))	('SPP1', 'Gene', (90, 94))	('cell migration', 'CPA', (154, 168))
387676	30510992	Frequent genetic alterations in ESCC include tumor suppressor p53 mutations, which may negate therapy-induced apoptotic cell death while promoting EMT, invasive growth, and metastasis.	('mutations', 'Var', (66, 75))	('SCC', 'Gene', '6317', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('death', 'Disease', (125, 130))	('tumor', 'Disease', (45, 50))	('negate', 'NegReg', (87, 93))	('metastasis', 'CPA', (173, 183))	('death', 'Disease', 'MESH:D003643', (125, 130))	('SCC', 'Gene', (33, 36))	('invasive growth', 'CPA', (152, 167))	('promoting', 'PosReg', (137, 146))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('EMT', 'CPA', (147, 150))
387697	30510992	A subset of patients displayed upregulation of the tumor suppressor p53 protein in SCC 3D organoids, indicating accumulation of dysfunctional mutant p53 protein, and thus recapitulating this aspect of the original tumors.	('protein', 'Protein', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('SCC', 'Gene', '6317', (83, 86))	('upregulation', 'PosReg', (31, 43))	('patients', 'Species', '9606', (12, 20))	('SCC', 'Gene', (83, 86))	('p53', 'Gene', '7157', (149, 152))	('tumor', 'Disease', (51, 56))	('original tumors', 'Disease', 'MESH:D009369', (205, 220))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('accumulation', 'PosReg', (112, 124))	('p53', 'Gene', (149, 152))	('mutant', 'Var', (142, 148))	('tumor', 'Disease', (214, 219))	('p53', 'Gene', '7157', (68, 71))	('dysfunctional', 'MPA', (128, 141))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('protein', 'Protein', (153, 160))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('p53', 'Gene', (68, 71))	('original tumors', 'Disease', (205, 220))
387711	30510992	Moreover, tumor cells with high CD44 expression (CD44H) contained more autophagic vesicles (AVs) (Figure 5A and B), suggesting that CD44H cells may have a higher autophagic capacity to cope with a variety of stressors present in the tumor microenvironment.	('autophagic capacity', 'CPA', (162, 181))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('autophagic vesicles', 'CPA', (71, 90))	('CD44', 'Gene', (32, 36))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', (10, 15))	('AV', 'Chemical', '-', (92, 94))	('CD44H', 'Var', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('higher', 'PosReg', (155, 161))
387718	30510992	Moreover, AV content was increased within CD44H cells and comparable between 3D organoids and xenograft tumors (Figure 5C).	('CD44H', 'Var', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('AV content', 'MPA', (10, 20))	('increased', 'PosReg', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('xenograft tumors', 'Disease', 'MESH:D009369', (94, 110))	('AV', 'Chemical', '-', (10, 12))	('xenograft tumors', 'Disease', (94, 110))
387724	30510992	The IC50 confirmed higher 5FU resistance of TE11R cells as compared with parental TE11 cells in both monolayer and 3D organoid culture conditions.	('TE11', 'Chemical', '-', (44, 48))	('TE11', 'Chemical', '-', (82, 86))	('higher', 'PosReg', (19, 25))	('TE11R', 'Chemical', '-', (44, 49))	('5FU resistance', 'MPA', (26, 40))	('5FU', 'Chemical', 'MESH:D005472', (26, 29))	('TE11R', 'Var', (44, 49))
387733	30510992	Since CD44H cells display a higher capacity of autophagy, we determined autophagic flux in TE11 3D organoids.	('TE11', 'Chemical', '-', (91, 95))	('autophagy', 'CPA', (47, 56))	('higher', 'PosReg', (28, 34))	('CD44H', 'Var', (6, 11))
387745	30510992	We analyzed the 5FU-surviving SCC cells in patient tumor-derived 3D organoids by flow cytometry, which revealed an enrichment of CD44H cells in 5FU-treated 3D organoids from patient 23, but not patient 26 (Figure 7D).	('SCC', 'Gene', '6317', (30, 33))	('patient', 'Species', '9606', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('patient', 'Species', '9606', (174, 181))	('patient', 'Species', '9606', (43, 50))	('5FU', 'Chemical', 'MESH:D005472', (16, 19))	('tumor', 'Disease', (51, 56))	('CD44H', 'Var', (129, 134))	('SCC', 'Gene', (30, 33))	('5FU', 'Chemical', 'MESH:D005472', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
387746	30510992	However, 5FU increased the overall AV contents in 3D organoids from both patients 23 and 26 (Figure 7E).	('AV contents', 'MPA', (35, 46))	('5FU', 'Chemical', 'MESH:D005472', (9, 12))	('5FU', 'Var', (9, 12))	('AV', 'Chemical', '-', (35, 37))	('patients', 'Species', '9606', (73, 81))	('increased', 'PosReg', (13, 22))
387748	30510992	We have previously demonstrated that poor prognosis in ESCC patients is associated with high ESCC cell expression of cleaved LC3, a marker of active autophagic flux.	('SCC', 'Gene', (94, 97))	('patients', 'Species', '9606', (60, 68))	('SCC', 'Gene', (56, 59))	('cleaved', 'Var', (117, 124))	('high ESCC', 'Phenotype', 'HP:0003565', (88, 97))	('LC3', 'Gene', '84557', (125, 128))	('SCC', 'Gene', '6317', (94, 97))	('SCC', 'Gene', '6317', (56, 59))	('LC3', 'Gene', (125, 128))
387766	30510992	Extensive studies with larger sample sizes are warranted as a future direction to compare patient-derived 3D organoids from therapy-responders and non-responders, and establish the relationship between autophagy activity or CD44H cell content in tumor biopsies and the organoid formation.	('autophagy activity', 'CPA', (202, 220))	('CD44H', 'Var', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('patient', 'Species', '9606', (90, 97))	('tumor', 'Disease', (246, 251))
387770	30510992	In addition, agents such as SB202190, a p38 MAPK inhibitor used in the aDMEM/F12+-based medium may be inhibitory for tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('+-based medium', 'Chemical', '-', (80, 94))	('inhibitory', 'NegReg', (102, 112))	('SB202190', 'Chemical', 'MESH:C090942', (28, 36))	('tumor', 'Disease', (117, 122))	('aDMEM', 'Chemical', '-', (71, 76))	('SB202190', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
387776	30510992	Patient-derived 3D organoids with evidence of 5FU resistance contained CD44H cells with increased autophagy capacity (Figure 7D and E).	('5FU', 'Chemical', 'MESH:D005472', (46, 49))	('increased', 'PosReg', (88, 97))	('CD44H', 'Var', (71, 76))	('autophagy capacity', 'CPA', (98, 116))	('Patient', 'Species', '9606', (0, 7))
387788	30510992	ESCC cell lines (TE series) were grown in RPMI1640 (11875093, Thermo Fisher Scientific, Waltham, MA) containing 10% fetal bovine serum (FBS) (SH3007103, Thermo Fisher Scientific) and 100-U/mL penicillin and 100-mug/mL streptomycin (15140122, Thermo Fisher Scientific), at 37 C in a humidified atmosphere of 5% CO2.	('RPMI1640', 'Chemical', '-', (42, 50))	('CO2', 'Chemical', '-', (310, 313))	('SH3007103', 'Var', (142, 151))	('15140122', 'Var', (232, 240))	('penicillin', 'Chemical', 'MESH:D010406', (192, 202))	('SCC', 'Gene', (1, 4))	('streptomycin', 'Chemical', 'MESH:D013307', (218, 230))	('11875093', 'Var', (52, 60))	('bovine', 'Species', '9913', (122, 128))	('SCC', 'Gene', '6317', (1, 4))
387790	30510992	To generate 3D organoids, each piece of the biopsies was rinsed in saline (0.9% NaCl) (S7653, Sigma-Aldrich, St. Louis, MO), and minced immediately with scissors and incubated for 45 minutes at 37 C in a 1-mL cocktail comprising 6.25-mg/mL dispase I (354235, BD Biosciences, San Jose, CA), 5-mg/mL collagenase (17018029, Thermo Fisher Scientific), 10-mM ROCK inhibitor Y27632 (1254, R&D Systems, Minneapolis, MN), and 0.5-mg/mL Fungizone (15290018, Thermo Fisher Scientific) with a periodical mixing (~once every 10 minutes) via Vortex-Genie 2 (Scientific Industries, Bohemia, NY).	('MN', 'CellLine', 'CVCL:U508', (409, 411))	('17018029', 'Var', (311, 319))	('354235', 'Var', (251, 257))	('Fungizone', 'Chemical', 'MESH:D000666', (428, 437))	('Bohemia', 'Disease', 'None', (568, 575))	('Bohemia', 'Disease', (568, 575))
387793	30510992	Cells were then resuspended in 1-mL advanced Dulbecco's modified Eagle medium (DMEM)/F12 (12491015, Thermo Fisher Scientific) containing 100-U/mL penicillin and 100-mug/mL streptomycin (15140122, Thermo Fisher Scientific), 1xGlutaMAX (35050061, Thermo Fisher Scientific), and 1xHEPES (15630080, Thermo Fisher Scientific) (aDMEM/F12+).	('15630080', 'Var', (285, 293))	('penicillin', 'Chemical', 'MESH:D010406', (146, 156))	('35050061', 'Var', (235, 243))	('15140122', 'Var', (186, 194))	('streptomycin', 'Chemical', 'MESH:D013307', (172, 184))	('12491015', 'Var', (90, 98))	('aDMEM', 'Chemical', '-', (322, 327))	("Dulbecco's modified Eagle medium", 'Chemical', '-', (45, 77))	('DMEM', 'Chemical', '-', (79, 83))	('DMEM', 'Chemical', '-', (323, 327))
387803	30510992	Alternatively, isolated organoids were dissociated by incubation with 0.25% Trypsin-EDTA, Y27632 and DNase I (1010415901, Sigma-Aldrich) into single cell suspensions and passaged.	('Y27632', 'Var', (90, 96))	('1010415901', 'Var', (110, 120))	('EDTA', 'Chemical', 'MESH:D004492', (84, 88))
387807	30510992	Established 3D organoids were untreated or treated with 5FU at a range of final concentrations (10-3-103 muM) for 72 hours, and further incubated with WST-1 reagent (11644807001, Sigma-Aldrich) (10 muL per well) for 2 hours before colorimetric cell proliferation assays, according to the manufacturer's instructions.	('5FU', 'Chemical', 'MESH:D005472', (56, 59))	('muM', 'Gene', (105, 108))	('11644807001', 'Var', (166, 177))	('muM', 'Gene', '56925', (105, 108))
387812	30510992	Tumors were harvested and minced into 1 mm3 pieces and incubated in Dulbecco's Modified Eagle Medium (DMEM, 11965, Thermo Fisher Scientific) containing 1 mg/mL collagenase I (C9263-1G, Sigma-Aldrich) at 37 C for 90 minutes.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('C9263-1G', 'Var', (175, 183))	('C9263-1G', 'SUBSTITUTION', 'None', (175, 183))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (68, 100))	('DMEM', 'Chemical', '-', (102, 106))
387823	30313107	Pathological stage was T1bN1M0 stage IIB according to the TNM Classification of Malignant Tumors-7th edition.	('Malignant Tumors-7th edition', 'Disease', 'MESH:D018198', (80, 108))	('Malignant Tumors-7th edition', 'Disease', (80, 108))	('Tumors', 'Phenotype', 'HP:0002664', (90, 96))	('T1bN1M0 stage', 'Var', (23, 36))
387873	30313107	Analysis of the expression pattern of p53 mutation revealed a common mutational pattern in both carcinoma and sarcoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('carcinoma and sarcoma', 'Disease', 'MESH:D012509', (96, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('mutation', 'Var', (42, 50))
387899	29440928	Early diagnostic potential of APC hypermethylation in esophageal cancer The hypermethylation of APC gene is observed in various cancers, including esophageal cancer (EC).	('esophageal cancer', 'Disease', (147, 164))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('APC', 'Disease', 'MESH:D011125', (30, 33))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('APC', 'Disease', (30, 33))	('cancers', 'Disease', (128, 135))	('APC', 'Phenotype', 'HP:0005227', (96, 99))	('hypermethylation', 'Var', (76, 92))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('APC', 'Disease', (96, 99))	('APC', 'Phenotype', 'HP:0005227', (30, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('observed', 'Reg', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
387901	29440928	The current study systematically reviewed studies on abnormal methylation of APC in EC and quantitatively synthesized 18 studies by meta-analysis involving 1008 ECs, 570 Barrett's esophagus (BE), and 782 controls.	('APC', 'Disease', (77, 80))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (170, 189))	('BE', 'Phenotype', 'HP:0100580', (191, 193))	('methylation', 'Var', (62, 73))	('APC', 'Phenotype', 'HP:0005227', (77, 80))	('APC', 'Disease', 'MESH:D011125', (77, 80))
387916	29440928	DNA methylation is one of the important epigenetic modifications involved in the inactivation of numerous tumor suppressor genes (TSGs).	('TSG', 'Gene', '57045', (130, 133))	('numerous tumor', 'Disease', 'MESH:D009369', (97, 111))	('methylation', 'Var', (4, 15))	('TSG', 'Gene', (130, 133))	('numerous tumor', 'Disease', (97, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
387917	29440928	It is well established that hypermethylation of multiple TSGs in association with the dysfunction of cellular biological pathways characterize human cancers.	('association', 'Reg', (65, 76))	('TSG', 'Gene', '57045', (57, 60))	('cancers', 'Disease', (149, 156))	('hypermethylation', 'Var', (28, 44))	('human', 'Species', '9606', (143, 148))	('cellular biological pathways', 'Pathway', (101, 129))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('TSG', 'Gene', (57, 60))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
387923	29440928	In the past decades, the downregulation of APC through promoter hypermethylation has frequently been observed in many cancers, including EC.	('APC', 'Disease', 'MESH:D011125', (43, 46))	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('APC', 'Disease', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('downregulation', 'NegReg', (25, 39))	('APC', 'Phenotype', 'HP:0005227', (43, 46))	('promoter hypermethylation', 'Var', (55, 80))
387925	29440928	The present study aimed at summarizing recent studies on aberrant methylation of APC in EC progression.	('aberrant methylation', 'Var', (57, 77))	('APC', 'Phenotype', 'HP:0005227', (81, 84))	('APC', 'Disease', 'MESH:D011125', (81, 84))	('APC', 'Disease', (81, 84))
387932	29440928	A total of 20 CpG sites (cg08636638, cg19115695, cg27062904, cg07661636, cg00190738, cg16110711, cg16451027, cg27379240, cg11057897, cg07003745, cg04011030, cg16481008, cg18315896, cg01528425, cg08934600, cg18536802, cg26660754, cg08512345, cg25922032, and cg04226363) in the promoter region of APC were included (Figure S1).	('APC', 'Disease', 'MESH:D011125', (295, 298))	('cg07661636', 'Var', (61, 71))	('APC', 'Disease', (295, 298))	('cg04226363', 'Var', (257, 267))	('cg00190738', 'Var', (73, 83))	('cg08636638', 'Var', (25, 35))	('cg11057897', 'Var', (121, 131))	('cg16481008', 'Var', (157, 167))	('cg25922032', 'Var', (241, 251))	('cg08512345', 'Var', (229, 239))	('cg07003745', 'Var', (133, 143))	('cg26660754', 'Var', (217, 227))	('cg16110711', 'Var', (85, 95))	('cg27379240', 'Var', (109, 119))	('cg08934600', 'Var', (193, 203))	('cg18315896', 'Var', (169, 179))	('cg04011030', 'Var', (145, 155))	('cg19115695', 'Var', (37, 47))	('cg16451027', 'Var', (97, 107))	('cg27062904', 'Var', (49, 59))	('cg01528425', 'Var', (181, 191))	('cg18536802', 'Var', (205, 215))	('APC', 'Phenotype', 'HP:0005227', (295, 298))
387942	29440928	Our results demonstrated that methylation of APC was associated with an increased risk for developing BE (OR =9.34; range, 2.92-29.82).	('developing BE', 'Disease', (91, 104))	('methylation', 'Var', (30, 41))	('APC', 'Phenotype', 'HP:0005227', (45, 48))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (45, 48))	('BE', 'Phenotype', 'HP:0100580', (102, 104))
387946	29440928	The summary specificity and sensitivity of methylated APC for distinguishing EC from controls were 0.96 (95% CI: 0.92-0.98) and 0.55 (95% CI: 0.39-0.69), respectively (Figure 3).	('APC', 'Disease', 'MESH:D011125', (54, 57))	('APC', 'Disease', (54, 57))	('APC', 'Phenotype', 'HP:0005227', (54, 57))	('methylated', 'Var', (43, 53))
387949	29440928	As shown in Figure 4, the Fagan plot analyses based on the PLR and NLR demonstrated that the probability of a patient being diagnosed with EC was, respectively, 82% and 93% following a positive methylated APC result, whereas the pretest probability of being diagnosed with EC was 25% and 50%, respectively.	('APC', 'Disease', (205, 208))	('patient', 'Species', '9606', (110, 117))	('APC', 'Phenotype', 'HP:0005227', (205, 208))	('methylated', 'Var', (194, 204))	('APC', 'Disease', 'MESH:D011125', (205, 208))
387952	29440928	As indicated by the PLR, BE patients had a ~13 times higher chance of having methylated APC than normal controls.	('APC', 'Disease', 'MESH:D011125', (88, 91))	('APC', 'Disease', (88, 91))	('patients', 'Species', '9606', (28, 36))	('BE', 'Phenotype', 'HP:0100580', (25, 27))	('APC', 'Phenotype', 'HP:0005227', (88, 91))	('methylated', 'Var', (77, 87))
387954	29440928	The Fagan plot analyses based on the PLR and NLR demonstrated that the probability of a patient being diagnosed with BE was, respectively, 81 and 93% following a positive methylated APC result, whereas the pretest probability of being diagnosed with BE was 25% and 50%, respectively (Figure 4).	('patient', 'Species', '9606', (88, 95))	('APC', 'Phenotype', 'HP:0005227', (182, 185))	('methylated', 'Var', (171, 181))	('APC', 'Disease', 'MESH:D011125', (182, 185))	('BE', 'Phenotype', 'HP:0100580', (250, 252))	('APC', 'Disease', (182, 185))	('BE', 'Phenotype', 'HP:0100580', (117, 119))
387960	29440928	Esophageal carcinoma is thought to develop from BE following accumulation of genetic and epigenetic abnormalities leading to the activation of oncogenes and/or inactivation of TSGs.	('Esophageal carcinoma', 'Disease', (0, 20))	('TSG', 'Gene', (176, 179))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (0, 20))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('activation', 'PosReg', (129, 139))	('TSG', 'Gene', '57045', (176, 179))	('BE', 'Phenotype', 'HP:0100580', (48, 50))	('inactivation', 'Var', (160, 172))	('oncogenes', 'Protein', (143, 152))
387962	29440928	Dysfunction of the Wnt/beta-catenin pathway components underlies multiple growth-related pathologies and human cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('Dysfunction', 'Var', (0, 11))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('beta-catenin', 'Gene', (23, 35))	('human', 'Species', '9606', (105, 110))	('beta-catenin', 'Gene', '1499', (23, 35))
387972	29440928	In particular, the APC methylation was 23 and 10 times more likely to predict EC and BE, respectively, although the effects came from heterogeneous sources.	('APC', 'Disease', 'MESH:D011125', (19, 22))	('APC', 'Disease', (19, 22))	('methylation', 'Var', (23, 34))	('BE', 'Phenotype', 'HP:0100580', (85, 87))	('APC', 'Phenotype', 'HP:0005227', (19, 22))
387974	29440928	Besides, our analysis of tumor stage appears consistent with a previous study in terms of the slight effect of APC methylation on EC progression.	('methylation', 'Var', (115, 126))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('APC', 'Phenotype', 'HP:0005227', (111, 114))	('APC', 'Disease', 'MESH:D011125', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('APC', 'Disease', (111, 114))
387977	29440928	These lesions can now be detected by molecular analyses for genetic or epigenetic alterations associated with tumorigenesis and could precede morphological tumor formation.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('epigenetic alterations', 'Var', (71, 93))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
387978	29440928	An emerging indication that alterations in epigenetic marks could be used as biomarkers (especially DNA methylation) was provided by analyses of hypermethylation of O-6-methyl-guanine-DNA methyltransferase (MGMT) in gliomas and glutathione S-transferase pi 1 (GSTP1) in prostate cancer.	('GSTP1', 'Gene', (260, 265))	('O-6-methyl-guanine-DNA methyltransferase', 'Gene', (165, 205))	('MGMT', 'Gene', (207, 211))	('prostate cancer', 'Phenotype', 'HP:0012125', (270, 285))	('prostate cancer', 'Disease', (270, 285))	('MGMT', 'Gene', '4255', (207, 211))	('O-6-methyl-guanine-DNA methyltransferase', 'Gene', '4255', (165, 205))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('hypermethylation', 'Var', (145, 161))	('GSTP1', 'Gene', '2950', (260, 265))	('glutathione S-transferase pi 1', 'Gene', (228, 258))	('glutathione S-transferase pi 1', 'Gene', '2950', (228, 258))	('prostate cancer', 'Disease', 'MESH:D011471', (270, 285))	('gliomas', 'Disease', 'MESH:D005910', (216, 223))	('gliomas', 'Phenotype', 'HP:0009733', (216, 223))	('gliomas', 'Disease', (216, 223))
387979	29440928	These hypermethylation events have been shown to be effective in the diagnosis of cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hypermethylation', 'Var', (6, 22))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))
387980	29440928	The detection of epigenetic alterations is therefore a promising auxiliary cancer diagnostic tool.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('epigenetic alterations', 'Var', (17, 39))	('auxiliary cancer', 'Disease', 'MESH:D009369', (65, 81))	('auxiliary cancer', 'Disease', (65, 81))
387983	29440928	Our results showed that the pooled AUC of APC methylation in distinguishing EC from normal control was 0.94, with 96% specificity and 55% sensitivity, and the pooled AUC for differentiating BE from normal controls was 0.88, with 96% specificity and 48% sensitivity.	('methylation', 'Var', (46, 57))	('BE', 'Phenotype', 'HP:0100580', (190, 192))	('APC', 'Phenotype', 'HP:0005227', (42, 45))	('APC', 'Disease', 'MESH:D011125', (42, 45))	('APC', 'Disease', (42, 45))
387986	29440928	These findings suggest that the hypermethylation of APC has a potential in the diagnosis of EC and BE.	('APC', 'Phenotype', 'HP:0005227', (52, 55))	('BE', 'Phenotype', 'HP:0100580', (99, 101))	('hypermethylation', 'Var', (32, 48))	('APC', 'Disease', 'MESH:D011125', (52, 55))	('APC', 'Disease', (52, 55))
387987	29440928	The notable findings of the current study are the significant association between APC methylation and increased risk of EC and BE and its potential role as an early diagnostic biomarker of EC.	('APC', 'Disease', 'MESH:D011125', (82, 85))	('APC', 'Disease', (82, 85))	('methylation', 'Var', (86, 97))	('BE', 'Phenotype', 'HP:0100580', (127, 129))	('APC', 'Phenotype', 'HP:0005227', (82, 85))
388000	28386210	Cox proportional hazards model, forward stepwise method by likelihood ratio with the condition of .05 for addition and .1 for deletion, was applied to investigate prognostic factors.	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('deletion', 'Var', (126, 134))
388020	28228658	In vitro, the expression levels of GRP78 were downregulated by small interfering RNA transfection in TE-1 and CaEs-17 ESCC lines.	('expression levels', 'MPA', (14, 31))	('small interfering RNA transfection', 'Var', (63, 97))	('GRP78', 'Protein', (35, 40))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('downregulated', 'NegReg', (46, 59))	('CaEs', 'Chemical', 'MESH:C042831', (110, 114))
388022	28228658	High GRP78 expression was significantly correlated with positive lymph node metastasis (P=0.035) and advanced tumor stage (P=0.017).	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('positive lymph node metastasis', 'CPA', (56, 86))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('GRP78', 'Protein', (5, 10))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
388023	28228658	Survival analysis revealed that high GRP78 expression was significantly associated with shorter overall survival (P=0.037).	('shorter', 'NegReg', (88, 95))	('high', 'Var', (32, 36))	('si', 'Chemical', 'MESH:D012825', (14, 16))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('overall survival', 'MPA', (96, 112))	('expression', 'MPA', (43, 53))	('GRP78', 'Protein', (37, 42))	('si', 'Chemical', 'MESH:D012825', (49, 51))
388025	28228658	si-GRP78 can significantly decrease the GRP78 expression level and reverse the invasion and migratory abilities of ESCC cells in TE-1 and CaEs-17 cell lines.	('GRP78', 'Protein', (40, 45))	('si-GRP78', 'Var', (0, 8))	('decrease', 'NegReg', (27, 35))	('expression level', 'MPA', (46, 62))	('reverse', 'NegReg', (67, 74))	('CaEs', 'Chemical', 'MESH:C042831', (138, 142))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('si', 'Chemical', 'MESH:D012825', (0, 2))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('si', 'Chemical', 'MESH:D012825', (83, 85))
388075	28228658	The invasion and migration abilities of TE-1 and CaEs-17 cells transfected with si-GRP78 and si-con were tested in Matrigel-coated cell culture chambers (Millipore).	('si-con', 'Chemical', '-', (93, 99))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('tested', 'Reg', (105, 111))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('si-con', 'Var', (93, 99))	('si-GRP78', 'Var', (80, 88))	('invasion', 'CPA', (4, 12))	('migration abilities', 'CPA', (17, 36))	('CaEs', 'Chemical', 'MESH:C042831', (49, 53))	('si', 'Chemical', 'MESH:D012825', (80, 82))
388099	28228658	In Table 1, high GRP78 expression was closely correlated with positive LN metastasis (P=0.035) and advanced tumor stage (P=0.017).	('positive LN metastasis', 'CPA', (62, 84))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('high', 'Var', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('GRP78', 'Protein', (17, 22))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('tumor', 'Disease', (108, 113))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('expression', 'MPA', (23, 33))
388104	28228658	The 5-year survival rate and the median survival time of the patients with high GRP78 expression were 26.0% and 28 months, respectively.	('high', 'Var', (75, 79))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('patients', 'Species', '9606', (61, 69))	('GRP78', 'Protein', (80, 85))
388109	28228658	TE-1 and CaEs-17 were transiently transfected with si-GRP78 or si-con for 48 h to explore the role of GRP78 in ESCC invasion and migration.	('CaEs', 'Chemical', 'MESH:C042831', (9, 13))	('si-con', 'Var', (63, 69))	('si-GRP78', 'Var', (51, 59))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('migration', 'CPA', (129, 138))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('si-con', 'Chemical', '-', (63, 69))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('ESCC', 'Disease', (111, 115))
388110	28228658	GRP78 expression levels in both cell lines were more effectively reduced by si-GRP78 than by si-con (P<0.05; Figure 4).	('si', 'Chemical', 'MESH:D012825', (76, 78))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('GRP78', 'Protein', (0, 5))	('reduced', 'NegReg', (65, 72))	('si-con', 'Chemical', '-', (93, 99))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('si-GRP78', 'Var', (76, 84))	('expression levels', 'MPA', (6, 23))
388112	28228658	The results revealed that the migratory activity of the si-GRP78-transfected TE-1 and CaEs-17 cells was remarkably reduced, GRP78 expression was suppressed in both cell lines, and si-GRP78 decreased their invasion into the Matrigel substrate.	('expression', 'MPA', (130, 140))	('invasion into the Matrigel substrate', 'CPA', (205, 241))	('decreased', 'NegReg', (189, 198))	('reduced', 'NegReg', (115, 122))	('migratory activity', 'CPA', (30, 48))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('si-GRP78', 'Var', (180, 188))	('si', 'Chemical', 'MESH:D012825', (209, 211))	('GRP78', 'Protein', (124, 129))	('suppressed', 'NegReg', (145, 155))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('si', 'Chemical', 'MESH:D012825', (180, 182))	('si-GRP78-transfected', 'Var', (56, 76))	('CaEs', 'Chemical', 'MESH:C042831', (86, 90))
388126	28228658	Further analysis showed that high GRP78 expression was associated with LN metastasis and advanced clinical stage.	('high', 'Var', (29, 33))	('expression', 'MPA', (40, 50))	('GRP78', 'Protein', (34, 39))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('associated', 'Reg', (55, 65))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('LN metastasis', 'CPA', (71, 84))
388127	28228658	Zhao et al performed a log-rank test and found that patients with high GRP78 expression exhibit poor prognosis.	('expression', 'MPA', (77, 87))	('patients', 'Species', '9606', (52, 60))	('high', 'Var', (66, 70))	('GRP78', 'Protein', (71, 76))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('si', 'Chemical', 'MESH:D012825', (83, 85))
388133	28228658	Our results showed that the invasion and migration capacities of these two cancer cell lines were lower in the GRP78 siRNA knockdown group than in the control group.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('GRP78', 'Gene', (111, 116))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('knockdown', 'Var', (123, 132))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('lower', 'NegReg', (98, 103))
388136	28228658	Dong et al explored the role of GRP78 in a tumor microenvironment and found that tumor growth and angiogenesis are suppressed in GRP78+/- mice in the early phase but not in the late phase.	('angiogenesis', 'CPA', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mice', 'Species', '10090', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('GRP78+/-', 'Var', (129, 137))	('suppressed', 'NegReg', (115, 125))	('tumor', 'Disease', (43, 48))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('tumor', 'Disease', (81, 86))
388149	28228658	High GRP78 expression was associated with LN metastasis and advanced clinical stage.	('High', 'Var', (0, 4))	('LN metastasis', 'CPA', (42, 55))	('expression', 'MPA', (11, 21))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('GRP78', 'Protein', (5, 10))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('associated', 'Reg', (26, 36))
388151	28228658	High GRP78 expression also enhanced the invasion and migration abilities of ESCC cells.	('High', 'Var', (0, 4))	('enhanced', 'PosReg', (27, 35))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('GRP78', 'Protein', (5, 10))
388179	27974927	The increased risk for breast cancer is associated, among others, with a personal or family history of the disease and inherited gene mutations in BRCA1 and BRCA2 breast cancer susceptibility genes.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('BRCA1', 'Gene', '672', (147, 152))	('BRCA1', 'Gene', (147, 152))	('BRCA2', 'Gene', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (134, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('BRCA2', 'Gene', '675', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
388208	27974927	Rindopepimut, a therapeutic vaccine targeting a mutant peptide called EGFRvIII, which is expressed in approximately one-third of the glioblastoma tumors, has a survival benefit among recurrent patients.	('mutant', 'Var', (48, 54))	('glioblastoma tumors', 'Disease', (133, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('survival benefit', 'CPA', (160, 176))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (133, 152))	('EGFRvIII', 'Gene', (70, 78))
388229	27974927	Some new monoclonal antibodies are tested in clinical trials: MM-111, a bispecific antibody that binds to HER2 and HER3, in patients with esophageal and gastroesophageal junction cancers; IMMU-132, an antibody-drug conjugate targeting Taurop-2, in patients with esophageal and other cancers; ontuxizumab (MORAb-004), an antibody targeting endosialin/ TEM1; OMP-52M51, anti-Notch1 monoclonal antibody, in patients with solid tumors; ABT-700, an anti-C-met antibody, in patients with solid tumors; MM-151, an antibody designed to bind and inhibit signaling from EGFR, in patients with solid tumors; CEP-37250/ KHK2804, an antibody targeting glycolipids, in patients with advanced solid tumors.	('OMP', 'Gene', (357, 360))	('tumor', 'Phenotype', 'HP:0002664', (684, 689))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('endosialin', 'Gene', '57124', (339, 349))	('HER3', 'Gene', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (488, 494))	('tumors', 'Phenotype', 'HP:0002664', (424, 430))	('CEP-37250/', 'Var', (597, 607))	('OMP', 'Gene', '4975', (357, 360))	('tumor', 'Phenotype', 'HP:0002664', (488, 493))	('inhibit', 'NegReg', (537, 544))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('endosialin', 'Gene', (339, 349))	('tumor', 'Phenotype', 'HP:0002664', (424, 429))	('esophageal and gastroesophageal junction cancers', 'Disease', 'MESH:D004938', (138, 186))	('tumors', 'Phenotype', 'HP:0002664', (589, 595))	('HER3', 'Gene', '2065', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('EGFR', 'Gene', (560, 564))	('tumor', 'Phenotype', 'HP:0002664', (589, 594))	('TEM1', 'Gene', '57124', (351, 355))	('tumors', 'Phenotype', 'HP:0002664', (684, 690))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('TEM1', 'Gene', (351, 355))
388259	26894650	High density genomic profiling arrays analyzing somatic copy-number alterations in 296 gastro-esophageal cancers have identified amplified genes in 37% of these cancers, most notably, amplifications of ERBB2, FGFR1, FGFR2, EGFR and MET.	('EGFR', 'Gene', '1956', (223, 227))	('gastro-esophageal cancers', 'Disease', (87, 112))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('ERBB2', 'Gene', '2064', (202, 207))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancers', 'Disease', (161, 168))	('FGFR2', 'Gene', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('FGFR1', 'Gene', '2260', (209, 214))	('FGFR2', 'Gene', '2263', (216, 221))	('gastro-esophageal cancers', 'Disease', 'MESH:D005764', (87, 112))	('EGFR', 'Gene', (223, 227))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('FGFR1', 'Gene', (209, 214))	('ERBB2', 'Gene', (202, 207))	('amplifications', 'Var', (184, 198))	('MET', 'Gene', (232, 235))
388331	26894650	Early phase clinical trials investigating immunotherapeutic agents have shown that targeting mesothelin is safe and does not result in enhanced toxicity to normal tissue.	('mesothelin', 'Gene', (93, 103))	('toxicity', 'Disease', 'MESH:D064420', (144, 152))	('toxicity', 'Disease', (144, 152))	('mesothelin', 'Gene', '10232', (93, 103))	('targeting', 'Var', (83, 92))
388347	26894650	In our study we found c-met positivity in 6.6% of carcinomas limiting the number of patients that could benefit from c-met targeted therapy.	('c-met', 'Gene', (117, 122))	('patients', 'Species', '9606', (84, 92))	('positivity', 'Var', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('c-met', 'Gene', '4233', (117, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('c-met', 'Gene', (22, 27))	('carcinomas', 'Disease', 'MESH:D002277', (50, 60))	('carcinomas', 'Disease', (50, 60))	('c-met', 'Gene', '4233', (22, 27))
388351	26894650	The Cancer Genome Atlas Research Network (TCGA) has recently comprehensively characterized gastric cancers and has proposed four subtypes (1) tumors positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hyper-methylation, and amplification of JAK2, PD-L1 and PD-L2; (2) microsatellite unstable tumors, which have rare mutations of HER2 and HER3, EGFR and PIK3CA; (3) genomically stable tumors, which are enriched for the diffuse histological variant and have newly described mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and (1) tumors with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases such as amplification of VEGFA and frequent amplifications of cell cycle mediators (CCNE1, CCND1 and CDK6).	('mutations', 'Var', (351, 360))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (594, 600))	('gastric cancers', 'Disease', (91, 106))	('aneuploidy', 'Disease', (649, 659))	('gastric cancers', 'Phenotype', 'HP:0012126', (91, 106))	('amplification', 'PosReg', (721, 734))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('VEGFA', 'Protein', (738, 743))	('tumors', 'Disease', (327, 333))	('tumor', 'Phenotype', 'HP:0002664', (594, 599))	('tumor', 'Phenotype', 'HP:0002664', (419, 424))	('tumors', 'Disease', (594, 600))	('tumors', 'Phenotype', 'HP:0002664', (419, 425))	('EGFR', 'Gene', '1956', (379, 383))	('Cancer', 'Disease', (4, 10))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (327, 333))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))	('CCNE1', 'Gene', (797, 802))	('unstable tumors', 'Disease', (318, 333))	('HER2', 'Gene', '2064', (364, 368))	('tumors', 'Disease', 'MESH:D009369', (594, 600))	('amplifications', 'MPA', (757, 771))	('amplification', 'PosReg', (670, 683))	('tumors', 'Disease', (419, 425))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('aneuploidy', 'Disease', 'MESH:D000782', (649, 659))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('unstable tumors', 'Disease', 'MESH:D000789', (318, 333))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('CDK6', 'Gene', (814, 818))	('EGFR', 'Gene', (379, 383))	('tumors', 'Disease', 'MESH:D009369', (419, 425))	('chromosomal instability', 'Phenotype', 'HP:0040012', (606, 629))	('HER2', 'Gene', (364, 368))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('gastric cancers', 'Disease', 'MESH:D013274', (91, 106))
388358	24722008	Excess body weight was responsible for 1,444 (1.5%) and 2,004 (2.2%) cancer cases among men and women, respectively, in 2009 in Korea.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('men', 'Species', '9606', (88, 91))	('women', 'Species', '9606', (96, 101))	('men', 'Species', '9606', (98, 101))	('Excess', 'Var', (0, 6))	('Excess body weight', 'Phenotype', 'HP:0004324', (0, 18))	('cancer', 'Disease', (69, 75))
388368	24722008	Beyond its effect on overall mortality and cardiovascular disease, excess body weight has been shown by prospective cohort studies and mortality data to contribute to an increased risk of several cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cardiovascular disease', 'Disease', 'MESH:D002318', (43, 65))	('excess body weight', 'Var', (67, 85))	('excess body weight', 'Phenotype', 'HP:0004324', (67, 85))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cardiovascular disease', 'Disease', (43, 65))	('cancers', 'Disease', (196, 203))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (43, 65))
388372	24722008	Physical inactivity is also closely linked to overweight and obesity and independently affects the risks of colon and breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('obesity', 'Phenotype', 'HP:0001513', (61, 68))	('Physical inactivity', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('overweight', 'Disease', (46, 56))	('obesity', 'Disease', 'MESH:D009765', (61, 68))	('overweight', 'Phenotype', 'HP:0025502', (46, 56))	('breast cancers', 'Phenotype', 'HP:0003002', (118, 132))	('obesity', 'Disease', (61, 68))	('linked', 'Reg', (36, 42))	('affects', 'Reg', (87, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('colon and breast cancers', 'Disease', 'MESH:D001943', (108, 132))
388404	24722008	The counterfactual exposure for excess body mass was BMI<23 kg/m2 while excess body weight groups included two separate categories of 23<=BMI<25 kg/m2 (overweight category) and BMI>=25 kg/m2 (obese category) and that for leisure-time physical activity was light to moderate (>=1 exercise session per week and >=15 minutes per session).	('overweight', 'Phenotype', 'HP:0025502', (152, 162))	('excess body weight', 'Phenotype', 'HP:0004324', (72, 90))	('23<=BMI<25 kg/m2', 'Var', (134, 150))	('BMI<23 kg/m2', 'Var', (53, 65))	('obese', 'Disease', 'MESH:D009765', (192, 197))	('obese', 'Disease', (192, 197))	('BMI>=25 kg/m2', 'Var', (177, 190))
388409	24722008	The prevalence of overweight (23 kg/m2<=BMI<25 kg/m2) was 28.5% among men and 23.2% among women, and the prevalence of obesity (BMI>=25 kg/m2) was 23.9% among men and 26.8% among women in 1992-1995.	('men', 'Species', '9606', (159, 162))	('overweight', 'Disease', (18, 28))	('women', 'Species', '9606', (90, 95))	('obesity', 'Disease', 'MESH:D009765', (119, 126))	('men', 'Species', '9606', (70, 73))	('obesity', 'Disease', (119, 126))	('23 kg/m2', 'Var', (30, 38))	('women', 'Species', '9606', (179, 184))	('men', 'Species', '9606', (92, 95))	('overweight', 'Phenotype', 'HP:0025502', (18, 28))	('obesity', 'Phenotype', 'HP:0001513', (119, 126))	('men', 'Species', '9606', (181, 184))
388415	24722008	Compared with light to moderateleisure-time physical activity, low physical activity increased the risk of breast cancer by 10%, but was not associated with colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal cancer', 'Disease', (157, 174))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('low physical activity increased', 'Phenotype', 'HP:0003546', (63, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('low physical activity', 'Var', (63, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))
388434	24722008	Sensitivity analysis showed that the PAF estimates were more sensitive to RR variation in women than in men, most likely due to the larger degree of uncertainty in the estimation of RRs for women (Figure 2).	('variation', 'Var', (77, 86))	('women', 'Species', '9606', (190, 195))	('men', 'Species', '9606', (104, 107))	('women', 'Species', '9606', (90, 95))	('men', 'Species', '9606', (92, 95))	('PAF', 'Chemical', '-', (37, 40))	('men', 'Species', '9606', (192, 195))	('PAF', 'Gene', (37, 40))	('sensitive', 'Reg', (61, 70))
388643	33505778	The results showed that miR-875-5p promoted the proliferation ESCC cells.	('miR-875-5p', 'Var', (24, 34))	('miR-875-5p', 'Chemical', '-', (24, 34))	('promoted', 'PosReg', (35, 43))	('proliferation ESCC cells', 'CPA', (48, 72))
388644	33505778	Subsequently, transwell results indicated that miR-875-5p promoted the invasion and migration of ESCC cells.	('miR-875-5p', 'Chemical', '-', (47, 57))	('invasion', 'CPA', (71, 79))	('miR-875-5p', 'Var', (47, 57))	('migration of', 'CPA', (84, 96))	('promoted', 'PosReg', (58, 66))	('ESCC', 'Disease', (97, 101))
388645	33505778	Furthermore, we showed that miR-875-5p was able to bind to CAPZA13'UTR, which contains the single nucleotide polymorphism (SNP), rs373245753, as reported in our previous study involving WGS and WES on ESCC.	('WGS', 'Disease', (186, 189))	('rs373245753', 'Var', (129, 140))	('CAPZA1', 'Gene', '829', (59, 65))	('CAPZA1', 'Gene', (59, 65))	('miR-875-5p', 'Chemical', '-', (28, 38))	('rs373245753', 'Mutation', 'rs373245753', (129, 140))	('miR-875-5p', 'Var', (28, 38))	('WGS', 'Disease', 'None', (186, 189))	('bind', 'Interaction', (51, 55))
388646	33505778	Subsequently, mRNA affinity pull-down assays verifiedthat the SNP disrupts miR-875-5p binding to CAPZA1.	('SNP', 'Var', (62, 65))	('miR-875-5p', 'Chemical', '-', (75, 85))	('miR-875-5p', 'MPA', (75, 85))	('binding', 'Interaction', (86, 93))	('disrupts', 'NegReg', (66, 74))	('CAPZA1', 'Gene', '829', (97, 103))	('CAPZA1', 'Gene', (97, 103))
388647	33505778	The current study is the first demonstration that miR-875-5p may function as an oncogene via down-regulation of CAPZA1 expression in ESCC.	('expression', 'MPA', (119, 129))	('down-regulation', 'NegReg', (93, 108))	('miR-875-5p', 'Chemical', '-', (50, 60))	('ESCC', 'Disease', (133, 137))	('miR-875-5p', 'Var', (50, 60))	('CAPZA1', 'Gene', '829', (112, 118))	('CAPZA1', 'Gene', (112, 118))
388654	33505778	It has also been reported that miR-223-3p has a tumor-promoting role in head and neck squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (72, 109))	('miR-223-3p', 'Var', (31, 41))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (81, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('tumor', 'Disease', (48, 53))	('miR-223-3p', 'Chemical', '-', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('neck squamous cell carcinoma', 'Disease', (81, 109))
388655	33505778	Indeed, miR-875-5p is amplified 6% and 5% in EAC and ESCC from the TCGA database, respectively.	('ESCC', 'Disease', (53, 57))	('miR-875-5p', 'Var', (8, 18))	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('miR-875-5p', 'Chemical', '-', (8, 18))	('amplified', 'PosReg', (22, 31))	('EAC', 'Disease', (45, 48))
388656	33505778	There are several studies that have reported that miR-875-5p has an important role in tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR-875-5p', 'Chemical', '-', (50, 60))	('tumor', 'Disease', (86, 91))	('miR-875-5p', 'Var', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
388657	33505778	Specifically, miR-875-5p promotes the invasion of lung cancer cells by inhibiting SATB2.	('inhibiting', 'NegReg', (71, 81))	('miR-875-5p', 'Var', (14, 24))	('lung cancer', 'Disease', (50, 61))	('SATB2', 'Gene', (82, 87))	('promotes', 'PosReg', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('SATB2', 'Gene', '23314', (82, 87))	('invasion', 'CPA', (38, 46))	('miR-875-5p', 'Chemical', '-', (14, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))
388659	33505778	We conducted a series of functional assays to assess the effects of miR-875-5p on ESCC cell lines.	('ESCC', 'Disease', (82, 86))	('miR-875-5p', 'Var', (68, 78))	('miR-875-5p', 'Chemical', '-', (68, 78))
388662	33505778	Interestingly, we found that miR-875-5p targeted the CAPZA1 3'UTR containing the single nucleotide polymorphism (SNP), rs373245753, which we identified in our previous study on WGS and WES in ESCC.	('rs373245753', 'Var', (119, 130))	('miR-875-5p', 'Var', (29, 39))	('single nucleotide polymorphism', 'Var', (81, 111))	('CAPZA1', 'Gene', '829', (53, 59))	('rs373245753', 'Mutation', 'rs373245753', (119, 130))	('CAPZA1', 'Gene', (53, 59))	('miR-875-5p', 'Chemical', '-', (29, 39))	('WGS', 'Disease', 'None', (177, 180))	('WGS', 'Disease', (177, 180))
388665	33505778	Therefore, the purpose of this study was to determine whether miR-875-5p has a tumor-promoting function via down-regulation of CAPZA1 and if the SNP has the potential disrupt the binding of miR-875-5p to CAPZA1 in ESCC.	('miR-875-5p', 'Var', (190, 200))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('ESCC', 'Disease', (214, 218))	('CAPZA1', 'Gene', '829', (127, 133))	('tumor', 'Disease', (79, 84))	('binding', 'Interaction', (179, 186))	('CAPZA1', 'Gene', (127, 133))	('CAPZA1', 'Gene', '829', (204, 210))	('CAPZA1', 'Gene', (204, 210))	('miR-875-5p', 'Chemical', '-', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('miR-875-5p', 'Chemical', '-', (190, 200))	('miR-875-5p', 'Var', (62, 72))	('down-regulation', 'NegReg', (108, 123))
388666	33505778	Human ESCC cell lines, YSE2, KYSE30, KYSE70, KYSE140, KYSE150, KYSE180, KYSE410, KYSE450, KYSE510, COLO680 were provided by Professor Y. Shimada of Kyoto University.	('Human', 'Species', '9606', (0, 5))	('KYSE70', 'Var', (37, 43))	('KYSE180', 'Var', (63, 70))	('KYSE450', 'Var', (81, 88))	('KYSE140', 'Var', (45, 52))	('KYSE510', 'Var', (90, 97))	('KYSE150', 'Var', (54, 61))	('KYSE410', 'Var', (72, 79))	('KYSE180', 'CellLine', 'CVCL:1349', (63, 70))	('KYSE30', 'Var', (29, 35))	('KYSE510', 'CellLine', 'CVCL:1354', (90, 97))
388691	33505778	Data of colony formation, cell invasion and migration numbers of miR-875-5p, luciferase activity and the enrichment of CAPZA1 mRNAs were analysed by Student's t-test (two-tailed).	('migration numbers', 'CPA', (44, 61))	('CAPZA1', 'Gene', (119, 125))	('colony formation', 'CPA', (8, 24))	('luciferase', 'Enzyme', (77, 87))	('activity', 'MPA', (88, 96))	('miR-875-5p', 'Chemical', '-', (65, 75))	('cell invasion', 'CPA', (26, 39))	('miR-875-5p', 'Var', (65, 75))	('CAPZA1', 'Gene', '829', (119, 125))
388692	33505778	Given that miRNAs can function as oncogenes or tumor suppressors in the progression of human cancers, we first assessed the functions of miR-875-5p in ESCC cells.	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (87, 92))	('miR-875-5p', 'Chemical', '-', (137, 147))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('miR-875-5p', 'Var', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
388693	33505778	According to the TCGA and cBioProtal for Cancer Genomics database, we found that the gene which miR-875-5p encodes was amplified 6% and 5% in EAC and ESCC, respectively, while approximately 1% were deleted in EAC and ESCC (Fig.	('EAC', 'Disease', (142, 145))	('EAC', 'Phenotype', 'HP:0011459', (209, 212))	('Cancer', 'Disease', (41, 47))	('miR-875-5p', 'Chemical', '-', (96, 106))	('ESCC', 'Disease', (150, 154))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))	('miR-875-5p', 'Var', (96, 106))
388695	33505778	1B to 1G, the expression of miR-875-5p significantly increased colony formation of ESCC cells compared with NC transfected cells, indicating that miR-875-5p promoted the proliferation ability of ESCC cells.	('miR-875-5p', 'Var', (146, 156))	('promoted', 'PosReg', (157, 165))	('miR-875-5p', 'Chemical', '-', (28, 38))	('miR-875-5p', 'Chemical', '-', (146, 156))	('increased', 'PosReg', (53, 62))	('miR-875-5p', 'Var', (28, 38))	('proliferation ability', 'CPA', (170, 191))	('colony formation', 'CPA', (63, 79))
388696	33505778	In transwell assays, miR-875-5p markedly enhanced the migration and invasion of ESCC cells compared with NC group in KYSE180 and KYSE510 cells (Figs.	('enhanced', 'PosReg', (41, 49))	('migration', 'CPA', (54, 63))	('KYSE510', 'CellLine', 'CVCL:1354', (129, 136))	('miR-875-5p', 'Chemical', '-', (21, 31))	('invasion of ESCC cells', 'CPA', (68, 90))	('KYSE180', 'CellLine', 'CVCL:1349', (117, 124))	('miR-875-5p', 'Var', (21, 31))
388697	33505778	1H to 1S), which indicated that miR-875-5p facilitated metastasis of ESCC cells.	('miR-875-5p', 'Chemical', '-', (32, 42))	('miR-875-5p', 'Var', (32, 42))	('metastasis of', 'CPA', (55, 68))	('facilitated', 'PosReg', (43, 54))	('ESCC', 'Disease', (69, 73))
388698	33505778	We used TargetScan database and predicted that miR-875-5p targeted the CAPZA1 3'UTR containing the T>G alteration at rs373245753 (Fig.	('miR-875-5p', 'Chemical', '-', (47, 57))	('miR-875-5p', 'Var', (47, 57))	('CAPZA1', 'Gene', '829', (71, 77))	('CAPZA1', 'Gene', (71, 77))	('rs373245753', 'Mutation', 'rs373245753', (117, 128))
388701	33505778	In addition, we employed a pair of PCR primers based on the 3'UTR and performed sequencing of the amplification products in 10 ESCC cell lines (YSE2, KYSE30, KYSE70, KYSE140, KYSE150, KYSE180, KYSE410, KYSE450, KYSE510, and COLO680).	('KYSE180', 'CellLine', 'CVCL:1349', (184, 191))	('KYSE450', 'Var', (202, 209))	('KYSE410', 'Var', (193, 200))	('KYSE30', 'Var', (150, 156))	('KYSE510', 'CellLine', 'CVCL:1354', (211, 218))	('KYSE70', 'Var', (158, 164))	('KYSE180', 'Var', (184, 191))	('KYSE140', 'Var', (166, 173))	('KYSE510', 'Var', (211, 218))	('KYSE150', 'Var', (175, 182))
388702	33505778	We showed that the T>G change at rs373245753 in the 3'UTR did not exist in these ESCC cell lines, indicating the need to heterogeneously-express the rs373245753 of 3'UTR in ESCC cells for further study (Fig.	('rs373245753', 'Mutation', 'rs373245753', (33, 44))	('rs373245753', 'Var', (33, 44))	('rs373245753', 'Mutation', 'rs373245753', (149, 160))	('rs373245753', 'Var', (149, 160))
388703	33505778	Then, the full length of CAPZA1 3'UTR fragments containing the rs373245753 T or G allele were cloned into the luciferase reporter vector, pGL3, to compare the luciferase activities between the two alleles (Fig.	('rs373245753', 'Mutation', 'rs373245753', (63, 74))	('pGL3', 'Gene', (138, 142))	('CAPZA1', 'Gene', '829', (25, 31))	('CAPZA1', 'Gene', (25, 31))	('pGL3', 'Gene', '6391', (138, 142))	('activities', 'MPA', (170, 180))	('rs373245753 T', 'Var', (63, 76))	('luciferase', 'Enzyme', (159, 169))
388704	33505778	The pGL3 vectors containing the rs373245753 T or G allele of the CAPZA1 3'UTR were co-transfected in parallel with NC and miR-875-5p mimic to KYSE180 cells and luciferase activity was assayed.	('miR-875-5p', 'Chemical', '-', (122, 132))	('CAPZA1', 'Gene', '829', (65, 71))	('pGL3', 'Gene', '6391', (4, 8))	('CAPZA1', 'Gene', (65, 71))	('rs373245753', 'Mutation', 'rs373245753', (32, 43))	('rs373245753 T', 'Var', (32, 45))	('KYSE180', 'CellLine', 'CVCL:1349', (142, 149))	('pGL3', 'Gene', (4, 8))
388706	33505778	These findings indicated that miR-875-5p directly targeted the CAPZA1 3'UTR(T), and negatively regulated CAPZA1 expression, while the variant allele attenuated these effects, thus allowing increased CAPZA1 expression in the presence of this variant allele.	('miR-875-5p', 'Chemical', '-', (30, 40))	('CAPZA1', 'Gene', (199, 205))	('variant', 'Var', (134, 141))	('expression', 'MPA', (206, 216))	('CAPZA1', 'Gene', '829', (63, 69))	('miR-875-5p', 'Var', (30, 40))	('CAPZA1', 'Gene', (63, 69))	('negatively regulated', 'NegReg', (84, 104))	('increased', 'PosReg', (189, 198))	('CAPZA1', 'Gene', '829', (105, 111))	('variant', 'Var', (241, 248))	('CAPZA1', 'Gene', (105, 111))	('CAPZA1', 'Gene', '829', (199, 205))	('expression', 'MPA', (112, 122))
388710	33505778	Colony formation abilities in both KYSE180 and KYSE510 cells were markedly suppressed by CAPZA1(T) overexpression, but substantially increased in the CAPZA1(G) overexpression cell lines (Figs.	('CAPZA1', 'Gene', '829', (89, 95))	('suppressed', 'NegReg', (75, 85))	('CAPZA1', 'Gene', (150, 156))	('Colony formation abilities', 'CPA', (0, 26))	('CAPZA1', 'Gene', (89, 95))	('KYSE510', 'Var', (47, 54))	('KYSE180', 'CellLine', 'CVCL:1349', (35, 42))	('KYSE510', 'CellLine', 'CVCL:1354', (47, 54))	('increased', 'PosReg', (133, 142))	('CAPZA1', 'Gene', '829', (150, 156))	('overexpression', 'Var', (99, 113))
388715	33505778	Cells were co-transfected with CAPZA1 CDS and miR-875-5p, then cell growth curves and colony formation assays showed that the function of CAPZA1 CDS was not reversed by miR-875-5p (Figs.	('CDS', 'Chemical', 'MESH:D002104', (38, 41))	('miR-875-5p', 'Var', (169, 179))	('CDS', 'Chemical', 'MESH:D002104', (145, 148))	('CAPZA1', 'Gene', '829', (31, 37))	('CAPZA1', 'Gene', '829', (138, 144))	('CAPZA1', 'Gene', (31, 37))	('CAPZA1', 'Gene', (138, 144))	('miR-875-5p', 'Chemical', '-', (46, 56))	('miR-875-5p', 'Chemical', '-', (169, 179))
388717	33505778	To determine whether miR-875-5p preferentially regulates CAPZA1 protein and mRNA levels of the CAPZA1 (T) and CAPZA1(G) transcripts, pGL3 vectors containing the rs373245753 T or G of the CAPZA1 3'UTR and miR-875-5p mimic were co-transfected into KYSE180 and KYSE510 cells.	('CAPZA1', 'Gene', '829', (95, 101))	('miR-875-5p', 'Chemical', '-', (21, 31))	('CAPZA1', 'Gene', '829', (110, 116))	('CAPZA1', 'Gene', (57, 63))	('protein', 'Protein', (64, 71))	('rs373245753', 'Var', (161, 172))	('CAPZA1', 'Gene', '829', (187, 193))	('CAPZA1', 'Gene', (95, 101))	('pGL3', 'Gene', (133, 137))	('CAPZA1', 'Gene', (110, 116))	('KYSE510', 'CellLine', 'CVCL:1354', (258, 265))	('CAPZA1', 'Gene', '829', (57, 63))	('rs373245753', 'Mutation', 'rs373245753', (161, 172))	('pGL3', 'Gene', '6391', (133, 137))	('mRNA levels', 'MPA', (76, 87))	('KYSE180', 'CellLine', 'CVCL:1349', (246, 253))	('regulates', 'Reg', (47, 56))	('CAPZA1', 'Gene', (187, 193))	('miR-875-5p', 'Chemical', '-', (204, 214))
388718	33505778	We found that the protein levels were markedly reduced in CAPZA1(T) cells compared to CAPZA1(G) and controls in KYSE180 and KYSE510 cells, which suggested that miR-875-5p might bind to CAPZA(T) and represses the protein expression of CAPZA1 (Figs.	('protein levels', 'MPA', (18, 32))	('miR-875-5p', 'Chemical', '-', (160, 170))	('protein expression', 'MPA', (212, 230))	('CAPZA1', 'Gene', '829', (86, 92))	('CAPZA1', 'Gene', '829', (58, 64))	('CAPZA1', 'Gene', (58, 64))	('CAPZA1', 'Gene', (234, 240))	('miR-875-5p', 'Var', (160, 170))	('KYSE180', 'CellLine', 'CVCL:1349', (112, 119))	('CAPZA1', 'Gene', '829', (234, 240))	('CAPZA1', 'Gene', (86, 92))	('represses', 'NegReg', (198, 207))	('bind', 'Interaction', (177, 181))	('reduced', 'NegReg', (47, 54))	('KYSE510', 'CellLine', 'CVCL:1354', (124, 131))
388719	33505778	In addition, qPCR assays showed that miR-875-5p could target CAPZA1(T) and suppressed CAPZA1 mRNA levels in KYSE180 and KYSE510 cells (Fig.	('suppressed', 'NegReg', (75, 85))	('CAPZA1', 'Gene', '829', (86, 92))	('miR-875-5p', 'Var', (37, 47))	('CAPZA1', 'Gene', (86, 92))	('KYSE180', 'CellLine', 'CVCL:1349', (108, 115))	('KYSE510', 'CellLine', 'CVCL:1354', (120, 127))	('CAPZA1', 'Gene', '829', (61, 67))	('miR-875-5p', 'Chemical', '-', (37, 47))	('CAPZA1', 'Gene', (61, 67))
388720	33505778	These observations indicated that miR-875-5p targets CAPZA1(T) and negatively regulates CAPZA1 mRNA expression.	('mRNA expression', 'MPA', (95, 110))	('miR-875-5p', 'Chemical', '-', (34, 44))	('negatively regulates', 'NegReg', (67, 87))	('miR-875-5p', 'Var', (34, 44))	('CAPZA1', 'Gene', '829', (88, 94))	('CAPZA1', 'Gene', (88, 94))	('CAPZA1', 'Gene', '829', (53, 59))	('CAPZA1', 'Gene', (53, 59))
388721	33505778	Increasing evidence has revealed that SNPs in the 3'UTRs of genes targeted by miRNAs can disturb or obstruct miRNA binding and consequently influence regulation of target genes, which might be associated with cancer.	('influence', 'Reg', (140, 149))	('disturb', 'Reg', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('regulation', 'MPA', (150, 160))	('cancer', 'Disease', (209, 215))	('miRNA', 'Protein', (109, 114))	('SNPs', 'Var', (38, 42))	('obstruct', 'NegReg', (100, 108))	('associated', 'Reg', (193, 203))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
388722	33505778	To determine whether the SNP, rs373245753 T>G, influences the binding of miR-875-5p and CAPZA1 mRNA, RNA affinity pull-down assays were performed.	('binding', 'Interaction', (62, 69))	('rs373245753 T>G', 'Var', (30, 45))	('miR-875-5p', 'Protein', (73, 83))	('CAPZA1', 'Gene', '829', (88, 94))	('CAPZA1', 'Gene', (88, 94))	('rs373245753', 'Mutation', 'rs373245753', (30, 41))	('miR-875-5p', 'Chemical', '-', (73, 83))	('influences', 'Reg', (47, 57))
388723	33505778	The pGL3 vectors containing the rs373245753 T or G allele of the CAPZA1 3'UTR were co-transfected with control or biotin-labeled miR-875-5p into KYSE180 and KYSE510 cells.	('miR-875-5p', 'Chemical', '-', (129, 139))	('CAPZA1', 'Gene', '829', (65, 71))	('pGL3', 'Gene', '6391', (4, 8))	('CAPZA1', 'Gene', (65, 71))	('rs373245753', 'Mutation', 'rs373245753', (32, 43))	('rs373245753 T', 'Var', (32, 45))	('KYSE510', 'CellLine', 'CVCL:1354', (157, 164))	('KYSE180', 'CellLine', 'CVCL:1349', (145, 152))	('biotin', 'Chemical', 'MESH:D001710', (114, 120))	('pGL3', 'Gene', (4, 8))
388727	33505778	We found that CAPZA1(T) was markedly elevated pulled down by biotin-miR-875-5p than CAPZA1(G) groups, which indicated that the SNP would disturbed the binding of miR-875-5p and CAPZA1 mRNA (Figs.	('miR-875-5p', 'Protein', (162, 172))	('binding', 'Interaction', (151, 158))	('elevated', 'PosReg', (37, 45))	('miR-875-5p', 'Chemical', '-', (68, 78))	('biotin-miR-875-5p', 'Var', (61, 78))	('CAPZA1', 'Gene', '829', (14, 20))	('CAPZA1', 'Gene', (14, 20))	('disturbed', 'Reg', (137, 146))	('CAPZA1', 'Gene', '829', (177, 183))	('CAPZA1', 'Gene', (177, 183))	('miR-875-5p', 'Chemical', '-', (162, 172))	('CAPZA1', 'Gene', '829', (84, 90))	('CAPZA1', 'Gene', (84, 90))	('biotin', 'Chemical', 'MESH:D001710', (61, 67))
388728	33505778	Subsequently, the levels of CAPZA1 mRNA were significantly enriched in the pull-down material isolated from KYSE180 and KYSE510 cells following co-transfection biotin-labeled miR-875-5p with CAPZA1(T) compared to CAPZA1(G).	('CAPZA1', 'Gene', '829', (28, 34))	('miR-875-5p', 'Chemical', '-', (175, 185))	('CAPZA1', 'Gene', (213, 219))	('CAPZA1', 'Gene', (28, 34))	('miR-875-5p', 'Var', (175, 185))	('CAPZA1', 'Gene', '829', (191, 197))	('KYSE180', 'CellLine', 'CVCL:1349', (108, 115))	('CAPZA1', 'Gene', (191, 197))	('KYSE510', 'CellLine', 'CVCL:1354', (120, 127))	('biotin', 'Chemical', 'MESH:D001710', (160, 166))	('CAPZA1', 'Gene', '829', (213, 219))
388730	33505778	Taken together, these results illustrated that the SNP, rs373245753 T>G, disturbed the binding of miR-875-5p and CAPZA1 mRNA.	('CAPZA1', 'Gene', (113, 119))	('miR-875-5p', 'Chemical', '-', (98, 108))	('rs373245753 T>G', 'Var', (56, 71))	('disturbed', 'Reg', (73, 82))	('rs373245753', 'Mutation', 'rs373245753', (56, 67))	('binding', 'Interaction', (87, 94))	('miR-875-5p', 'Protein', (98, 108))	('CAPZA1', 'Gene', '829', (113, 119))
388732	33505778	It has been reported that mutations or abnormal expression of miRNAs are associated with various cancers and miRNAs can function as tumor-promoting genes or tumor suppressors.	('tumor', 'Disease', (157, 162))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('expression', 'MPA', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('associated', 'Reg', (73, 83))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (132, 137))	('abnormal', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('miRNAs', 'Gene', (62, 68))
388733	33505778	According to the TCGA database, we found that miR-875-5p is amplified 6% with 1% deletion in ESCC.	('miR-875-5p', 'Chemical', '-', (46, 56))	('deletion', 'Var', (81, 89))	('ESCC', 'Gene', (93, 97))
388734	33505778	Although it has been confirmed that miR-875-5p exerts tumor suppressor function via down-regulation of EGFR in colorectal carcinoma (CRC), the specific functions and relevant machinery of miR-875-5p in ESCC have not been elucidated.	('colorectal carcinoma', 'Disease', (111, 131))	('CRC', 'Disease', 'MESH:D015179', (133, 136))	('EGFR', 'Gene', '1956', (103, 107))	('miR-875-5p', 'Chemical', '-', (36, 46))	('miR-875-5p', 'Chemical', '-', (188, 198))	('EGFR', 'Gene', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('down-regulation', 'NegReg', (84, 99))	('miR-875-5p', 'Var', (36, 46))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (111, 131))	('CRC', 'Disease', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CRC', 'Phenotype', 'HP:0030731', (133, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('tumor', 'Disease', (54, 59))
388735	33505778	This finding prompted us to conduct a series of functional assays to assess the effects of miR-875-5p in ESCC cells.	('ESCC', 'Disease', (105, 109))	('miR-875-5p', 'Var', (91, 101))	('miR-875-5p', 'Chemical', '-', (91, 101))
388736	33505778	We observed that miR-875-5p increased the ability of cells to proliferate, migrate, and invade.	('increased', 'PosReg', (28, 37))	('miR-875-5p', 'Chemical', '-', (17, 27))	('migrate', 'CPA', (75, 82))	('miR-875-5p', 'Var', (17, 27))	('invade', 'CPA', (88, 94))
388737	33505778	Then, we investigated the downstream gene of miR-875-5p using public databases, and unexpectedly found that miR-875-5p targeted CAPZA1 3'UTR containing the SNP, rs373245753, which was identified in our previous study involving WGS and WES in ESCC.	('rs373245753', 'Var', (161, 172))	('rs373245753', 'Mutation', 'rs373245753', (161, 172))	('CAPZA1', 'Gene', '829', (128, 134))	('CAPZA1', 'Gene', (128, 134))	('miR-875-5p', 'Chemical', '-', (45, 55))	('WGS', 'Disease', 'None', (227, 230))	('targeted', 'Reg', (119, 127))	('WGS', 'Disease', (227, 230))	('miR-875-5p', 'Chemical', '-', (108, 118))	('miR-875-5p', 'Var', (108, 118))
388738	33505778	There is mounting evidence that SNPs in miRNA-target gene interactions might affect miRNA-mediated gene regulation by disrupting the binding of miRNA to target mRNA, and even contribute to cancer development.	('SNPs', 'Var', (32, 36))	('disrupting', 'NegReg', (118, 128))	('miRNA', 'MPA', (144, 149))	('interactions', 'Interaction', (58, 70))	('contribute', 'Reg', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('affect', 'Reg', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('miRNA-mediated', 'MPA', (84, 98))	('binding', 'Interaction', (133, 140))	('cancer', 'Disease', (189, 195))
388739	33505778	For example, the SNP in the KIT 3'UTR disrupts a miR-221/222 binding site in gastrointestinal stromal tumors.	('SNP', 'Var', (17, 20))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (77, 108))	('KIT', 'Gene', (28, 31))	('miR-221', 'Gene', (49, 56))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (77, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('disrupts', 'NegReg', (38, 46))	('gastrointestinal stromal tumors', 'Disease', (77, 108))	('miR-221', 'Gene', '407006', (49, 56))	('KIT', 'Gene', '3815', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('binding', 'Interaction', (61, 68))
388740	33505778	The SNP in miR-146a is associated with decreased expression of ETS1.	('miR-146a', 'Gene', '406938', (11, 19))	('SNP', 'Var', (4, 7))	('expression', 'MPA', (49, 59))	('ETS1', 'Gene', (63, 67))	('ETS1', 'Gene', '2113', (63, 67))	('miR-146a', 'Gene', (11, 19))	('decreased', 'NegReg', (39, 48))
388741	33505778	The SNP in a miRNA-1827 binding site in MYCL1 alters MYCL1 expression, which is associated with small-cell lung cancer.	('SNP', 'Var', (4, 7))	('MYCL1', 'Gene', '4610', (40, 45))	('MYCL1', 'Gene', (53, 58))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (96, 118))	('expression', 'MPA', (59, 69))	('associated', 'Reg', (80, 90))	('small-cell lung cancer', 'Disease', (96, 118))	('MYCL1', 'Gene', (40, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('alters', 'Reg', (46, 52))	('MYCL1', 'Gene', '4610', (53, 58))
388743	33505778	In this study, we verified that miR-875-5p could directly target the CAPZA1 3'UTR, leading to decreased CAPZA1 expression, while the variant allele disturbed the binding of miR-875-5p to the CAPZA1 3'UTR.	('miR-875-5p', 'Chemical', '-', (32, 42))	('CAPZA1', 'Gene', '829', (104, 110))	('disturbed', 'Reg', (148, 157))	('CAPZA1', 'Gene', (104, 110))	('CAPZA1', 'Gene', '829', (69, 75))	('CAPZA1', 'Gene', (69, 75))	('expression', 'MPA', (111, 121))	('decreased', 'NegReg', (94, 103))	('CAPZA1', 'Gene', '829', (191, 197))	('variant', 'Var', (133, 140))	('CAPZA1', 'Gene', (191, 197))	('binding', 'Interaction', (162, 169))	('miR-875-5p', 'Chemical', '-', (173, 183))
388744	33505778	Furthermore, for the first time we showed that miR-875-5p functions as an oncogene by down-regulating CAPZA1 in ESCC.	('CAPZA1', 'Gene', (102, 108))	('miR-875-5p', 'Chemical', '-', (47, 57))	('miR-875-5p', 'Var', (47, 57))	('ESCC', 'Disease', (112, 116))	('down-regulating', 'NegReg', (86, 101))	('CAPZA1', 'Gene', '829', (102, 108))
388746	33505778	Additionally, we demonstrated that CAPZA1 CDS alone can directly inhibit the malignant phenotype of esophageal cancer, while miR-875-5p couldn't reverse the suppressive effect of CDS on malignant phenotype of esophageal cancer.	('miR-875-5p', 'Var', (125, 135))	('esophageal cancer', 'Disease', (209, 226))	('miR-875-5p', 'Chemical', '-', (125, 135))	('CDS', 'Chemical', 'MESH:D002104', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('esophageal cancer', 'Disease', (100, 117))	('CDS', 'Chemical', 'MESH:D002104', (42, 45))	('malignant phenotype of', 'CPA', (77, 99))	('esophageal cancer', 'Disease', 'MESH:D004938', (209, 226))	('CAPZA1', 'Gene', '829', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CAPZA1', 'Gene', (35, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('inhibit', 'NegReg', (65, 72))
388747	33505778	These results suggested that the miR-875-5p directly targeted CAPZA1 3'UTR(T), and consistently, the SNP rs373245753 T>G could influence the binding of miR-875-5p and CAPZA1 3'UTR(T), which indicated that miR-875-5p has a tumor-promoting function by down-regulation of CAPZA1 in ESCC.	('miR-875-5p', 'Chemical', '-', (205, 215))	('CAPZA1', 'Gene', '829', (62, 68))	('CAPZA1', 'Gene', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('rs373245753 T>G', 'Var', (105, 120))	('binding', 'Interaction', (141, 148))	('down-regulation', 'NegReg', (250, 265))	('CAPZA1', 'Gene', '829', (269, 275))	('miR-875-5p', 'Chemical', '-', (152, 162))	('CAPZA1', 'Gene', (269, 275))	('rs373245753', 'Mutation', 'rs373245753', (105, 116))	('ESCC', 'Disease', (279, 283))	('influence', 'Reg', (127, 136))	('tumor', 'Disease', (222, 227))	('CAPZA1', 'Gene', '829', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('CAPZA1', 'Gene', (167, 173))	('miR-875-5p', 'Chemical', '-', (33, 43))
388748	33505778	In above, the current study first demonstrated that miR-875-5p promoted the proliferation and metastasis of ESCC cells, probably through down-regulation of CAPZA1 expression.	('metastasis', 'CPA', (94, 104))	('proliferation', 'CPA', (76, 89))	('miR-875-5p', 'Chemical', '-', (52, 62))	('down-regulation', 'NegReg', (137, 152))	('expression', 'MPA', (163, 173))	('promoted', 'PosReg', (63, 71))	('CAPZA1', 'Gene', (156, 162))	('miR-875-5p', 'Var', (52, 62))	('CAPZA1', 'Gene', '829', (156, 162))	('ESCC', 'Disease', (108, 112))
388749	33505778	Moreover, the SNP, rs373245753, within the CAPZA1 3'UTR interfered with miR-875-5p binding to CAPZA1 mRNA.	('interfered', 'NegReg', (56, 66))	('binding', 'Interaction', (83, 90))	('CAPZA1', 'Gene', '829', (94, 100))	('CAPZA1', 'Gene', (94, 100))	('rs373245753', 'Mutation', 'rs373245753', (19, 30))	('miR-875-5p', 'Chemical', '-', (72, 82))	('CAPZA1', 'Gene', '829', (43, 49))	('CAPZA1', 'Gene', (43, 49))	('rs373245753', 'Var', (19, 30))	('miR-875-5p', 'MPA', (72, 82))
388750	33505778	Based on these findings, it is reasonable to propose that miR-875-5p has as a tumor-promoting gene in ESCC, which might highlight the potential of miRNA profiling in cancer diagnosis.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('ESCC', 'Disease', (102, 106))	('miR-875-5p', 'Chemical', '-', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', (78, 83))	('miR-875-5p', 'Var', (58, 68))
388752	33505778	In conclusion, we demonstrated that miR-875-5p functions as a tumor-promoting gene via down-regulation of CAPZA1 in ESCC cells.	('down-regulation', 'NegReg', (87, 102))	('CAPZA1', 'Gene', '829', (106, 112))	('CAPZA1', 'Gene', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('miR-875-5p', 'Chemical', '-', (36, 46))	('tumor', 'Disease', (62, 67))	('miR-875-5p', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
388772	33251986	promoting cancer progression by their aberrant expression in cancer cells for abnormal growth, survival and invasion.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', (61, 67))	('aberrant', 'Var', (38, 46))	('expression', 'MPA', (47, 57))	('abnormal growth', 'Phenotype', 'HP:0001507', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('promoting', 'PosReg', (0, 9))	('invasion', 'CPA', (108, 116))	('survival', 'CPA', (95, 103))
388779	33251986	In addition, in a sterile ear skin wound, a rapid neutrophil "swarming" was initiated by leukotriene B4 that activates its classical chemoattractant GPCR, followed by Fpr2 and CxcR2, a receptor for the mouse IL-8 (CXCL8) analogue CxcL2.	('mouse', 'Species', '10090', (202, 207))	('GPCR', 'MPA', (149, 153))	('leukotriene B4', 'Var', (89, 103))	('CxcL2', 'Gene', (230, 235))	('leukotriene B4', 'Chemical', 'MESH:D007975', (89, 103))	('CxcR2', 'Gene', '12765', (176, 181))	('CxcL2', 'Gene', '20310', (230, 235))	('activates', 'PosReg', (109, 118))	('CXCL8', 'Gene', '3576', (214, 219))	('CXCL8', 'Gene', (214, 219))	('CxcR2', 'Gene', (176, 181))
388785	33251986	A prominent feature of malignant transformation of DT epithelial cells is their acquirement of somatic gene mutations culminating in abnormal expression of proteins that enable unlimited cell proliferation, increased motility and invasiveness, many of which are directly mediated by GPCRs, including FPRs (Fprs) (Table 2).	('FPR', 'Gene', (300, 303))	('motility', 'CPA', (217, 225))	('Fpr', 'Gene', (306, 309))	('mutations', 'Var', (108, 117))	('proteins', 'Protein', (156, 164))	('enable', 'PosReg', (170, 176))	('increased', 'PosReg', (207, 216))	('FPR', 'Gene', '14293', (300, 303))	('unlimited cell proliferation', 'CPA', (177, 205))	('expression', 'MPA', (142, 152))	('invasiveness', 'CPA', (230, 242))	('Fpr', 'Gene', '14293', (306, 309))
388816	33251986	FPR1 silencing (shFPR1) significantly enhanced the growth of GC cell-derived xenograft tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('enhanced', 'PosReg', (38, 46))	('silencing', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('FPR1', 'Gene', (0, 4))
388821	33251986	GC patients with high FPR1 expression in tumors had lower overall survival rates than those with negative/low FPR1 expression.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('overall survival', 'MPA', (58, 74))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('high', 'Var', (17, 21))	('tumors', 'Disease', (41, 47))	('lower', 'NegReg', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('FPR1', 'Gene', (22, 26))	('patients', 'Species', '9606', (3, 11))
388843	33251986	Bleach of such a balance constitutes the cause of bacterial overexpansion and the consequent stomach inflammation-carcinogenesis.	('stomach inflammation', 'Phenotype', 'HP:0005263', (93, 113))	('inflammation-carcinogenesis', 'Disease', 'MESH:D063646', (101, 128))	('cause', 'Reg', (41, 46))	('bacterial overexpansion', 'Disease', (50, 73))	('Bleach', 'Var', (0, 6))	('inflammation-carcinogenesis', 'Disease', (101, 128))
388850	33251986	Given that HCC is typically an example of inflammation-associated cancer and FPR1 activation promotes the migration and ERK-dependent production of the neutrophil chemokine IL-8 (CXCL8) by HCC cells, FPR1 knockdown in HCC cells substantially reduced their tumorigenicity in nude mice, as an important piece of evidence that its presence in hepatic cells may act in a concerted inflammatory cycle in the liver to exacerbate the carcinoma development and progression.	('carcinoma', 'Disease', 'MESH:D009369', (427, 436))	('HCC', 'Gene', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('knockdown', 'Var', (205, 214))	('progression', 'CPA', (453, 464))	('HCC', 'Gene', '619501', (189, 192))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('inflammation', 'Disease', 'MESH:D007249', (42, 54))	('tumor', 'Disease', (256, 261))	('CXCL8', 'Gene', '3576', (179, 184))	('CXCL8', 'Gene', (179, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (427, 436))	('HCC', 'Gene', (189, 192))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('HCC', 'Gene', '619501', (11, 14))	('carcinoma', 'Disease', (427, 436))	('inflammation', 'Disease', (42, 54))	('FPR1', 'Gene', (200, 204))	('exacerbate', 'PosReg', (412, 422))	('HCC', 'Gene', (11, 14))	('HCC', 'Gene', '619501', (218, 221))	('reduced', 'NegReg', (242, 249))	('nude mice', 'Species', '10090', (274, 283))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('cancer', 'Disease', (66, 72))
388862	33251986	Absence of FPR1 increases the survival rate of colitis-associated CRC.	('survival rate', 'CPA', (30, 43))	('colitis', 'Phenotype', 'HP:0002583', (47, 54))	('CRC', 'Phenotype', 'HP:0003003', (66, 69))	('increases', 'PosReg', (16, 25))	('colitis', 'Disease', 'MESH:D003092', (47, 54))	('Absence', 'Var', (0, 7))	('colitis', 'Disease', (47, 54))	('FPR1', 'Gene', (11, 15))
388865	33251986	The ability of FPR2 to promote the malignancy of CRC cells was demonstrated by experiments, in which human CRC cell line SW1116, its proliferation, migration, invasion, anti-apoptosis and pro-angiogenesis properties were attenuated by silencing FPR2 with shRNA, resulting in reduced tumorigenicity in xenograft models.	('reduced', 'NegReg', (275, 282))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('migration', 'CPA', (148, 157))	('malignancy', 'Disease', 'MESH:D009369', (35, 45))	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('anti-apoptosis', 'CPA', (169, 183))	('pro-angiogenesis properties', 'CPA', (188, 215))	('malignancy', 'Disease', (35, 45))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('silencing', 'Var', (235, 244))	('human', 'Species', '9606', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('attenuated', 'NegReg', (221, 231))	('tumor', 'Disease', (283, 288))	('invasion', 'CPA', (159, 167))	('SW1116', 'CellLine', 'CVCL:0544', (121, 127))	('FPR2', 'Gene', (245, 249))
388866	33251986	Mechanistically, silencing FPR2 reduced the expression of proteins linked to EMT such as E-cadherin, N-cadherin, Snail, Slug and vimentin, indicating the capacity of FPR2 to support the malignant transformation of colon epithelial cells.	('N-cadherin', 'Gene', '1000', (101, 111))	('silencing', 'Var', (17, 26))	('malignant transformation of colon', 'Phenotype', 'HP:0100273', (186, 219))	('Slug', 'Gene', (120, 124))	('FPR2', 'Gene', (27, 31))	('Snail', 'Gene', '6615', (113, 118))	('Snail', 'Gene', (113, 118))	('up', 'Gene', '7378', (175, 177))	('reduced', 'NegReg', (32, 39))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('malignant transformation', 'CPA', (186, 210))	('expression of proteins', 'MPA', (44, 66))	('N-cadherin', 'Gene', (101, 111))	('Slug', 'Gene', '6591', (120, 124))
388873	33251986	In this respect, Fpr2 (FPR2) appears to be a double-edged sword in that if the receptor was aberrantly expressed by transformed human CRC cells, its capacity to mediate normal epithelial migration, proliferation and mucosal restitution is exploited by tumor cells to exacerbate the malignant behavior.	('CRC', 'Phenotype', 'HP:0003003', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('aberrantly', 'Var', (92, 102))	('exacerbate', 'PosReg', (267, 277))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('proliferation', 'CPA', (198, 211))	('human', 'Species', '9606', (128, 133))	('tumor', 'Disease', (252, 257))	('malignant behavior', 'CPA', (282, 300))
388876	33251986	Therefore, the absence of LL-37 is used as one of the biomarkers of human colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (74, 86))	('human', 'Species', '9606', (68, 73))	('LL-37', 'Gene', '820', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colon cancer', 'Disease', 'MESH:D015179', (74, 86))	('absence', 'Var', (15, 22))	('colon cancer', 'Disease', (74, 86))	('LL-37', 'Gene', (26, 31))
388910	33087752	Cancer cell lines represent pure populations of cancer cells, facilitating the detection of molecular genetic changes, in particular homozygous deletions.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('deletions', 'Var', (144, 153))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
388916	33087752	identified an overrepresentation of CTNNB1 mutations and microsatellite instability in established colon cancer cell lines compared to patient tumors.	('CTNNB1', 'Gene', (36, 42))	('patient', 'Species', '9606', (135, 142))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('CTNNB1', 'Gene', '1499', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('colon cancer', 'Disease', (99, 111))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('microsatellite instability', 'MPA', (57, 83))	('overrepresentation', 'PosReg', (14, 32))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
388942	33087752	Basal media were supplemented with fetal bovine serum (20% v/v; cat # F9665-500ML, Sigma), penicillin (100 U/ml; cat # 11074440001, Sigma) and gentamicin (2.5 mg/ml).	('cat # 11074440001', 'Var', (113, 130))	('cat # F9665-500ML', 'Var', (64, 81))	('penicillin', 'Chemical', 'MESH:D010406', (91, 101))	('gentamicin', 'Chemical', 'MESH:D005839', (143, 153))
388945	33087752	The following loci were used: amelogenin, CSF1PO, D5S818, D7S820, D13S317, D16S359, TH01, TPOX, and vWA.	('D16S359', 'Var', (75, 82))	('CSF1PO', 'Gene', (42, 48))	('D5S818', 'Var', (50, 56))	('CSF1PO', 'Gene', '1435', (42, 48))	('D7S820', 'Var', (58, 64))	('D13S317', 'Var', (66, 73))
388967	33087752	Annotation was done based on RefSeqGene (https://www.ncbi.nlm.nih.gov/refseq/rsg/) and variants were further evaluated based on dbSNP 147 (NCBI; https://www.ncbi.nlm.nih.gov/projects/SNP/), COSMIC database (Catalogue of Somatic Mutations in Cancer; https://cancer.sanger.ac.uk/cosmic) and ClinVar database.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('variants', 'Var', (87, 95))	('Cancer', 'Disease', (241, 247))	('Cancer', 'Disease', 'MESH:D009369', (241, 247))	('Cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', (257, 263))
388994	33087752	As expected, the microsatellite instable tumor from patient 3 harbored only very few copy number alterations, largely confined to a loss of chromosome arm 6p and a gain of chromosome 7.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('gain', 'PosReg', (164, 168))	('loss', 'NegReg', (132, 136))	('tumor', 'Disease', (41, 46))	('patient', 'Species', '9606', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('microsatellite', 'Var', (17, 31))
388996	33087752	For each patient, we analyzed mutations in two spatially distinct regions (two different FFPE blocks with tumor) to account for potential spatial heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('patient', 'Species', '9606', (9, 16))	('tumor', 'Disease', (106, 111))
388997	33087752	Mutations in key driver genes such as TP53 and KRAS were consistently present in both primary tumor samples and the derived cell line (Fig.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('TP53', 'Gene', (38, 42))	('tumor', 'Disease', (94, 99))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))	('TP53', 'Gene', '7157', (38, 42))
388999	33087752	Not surprisingly, the microsatellite instable tumor from patient 3 had the highest number of mutations.	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patient', 'Species', '9606', (57, 64))	('tumor', 'Disease', (46, 51))	('microsatellite', 'Var', (22, 36))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
389009	33087752	Features of intestinal differentiation as indicated by CDX2 and CK20 positivity were enhanced or re-acquired in the cell line while not or only weakly being expressed in the parental tumor (patients 2 and 3).	('parental tumor', 'Disease', (174, 188))	('parental tumor', 'Disease', 'MESH:D063129', (174, 188))	('CK20', 'Gene', '54474', (64, 68))	('CDX2', 'Gene', '1045', (55, 59))	('patients', 'Species', '9606', (190, 198))	('enhanced', 'PosReg', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('positivity', 'Var', (69, 79))	('CDX2', 'Gene', (55, 59))	('CK20', 'Gene', (64, 68))	('intestinal differentiation', 'CPA', (12, 38))
389024	33087752	A loss of 9p21.3 (CDKN2A locus) has also been described in the immortalization process of normal nasopharyngeal epithelial cells and may eventually confer a growth advantage in vitro under certain circumstances.	('CDKN2A', 'Gene', '1029', (18, 24))	('immortalization process', 'CPA', (63, 86))	('growth advantage', 'CPA', (157, 173))	('CDKN2A', 'Gene', (18, 24))	('loss', 'Var', (2, 6))
389027	33087752	As shown for colorectal cancer derived PDOs, mutations in known driver genes or genes of interest in the respective tumor entity (e.g., KRAS or BRAF in CRC) were invariably present in both primary tumor sample and derived cell line.	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('colorectal cancer', 'Disease', (13, 30))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('BRAF', 'Gene', '673', (144, 148))	('rectal cancer', 'Phenotype', 'HP:0100743', (17, 30))	('KRAS', 'Gene', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('BRAF', 'Gene', (144, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (197, 202))	('KRAS', 'Gene', '3845', (136, 140))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
389028	33087752	Only in the MSI cell line minor discrepancies for mutations in PTEN and TP53 could be observed, likely attributable to the increased mutation rate as a consequence of MSI.	('PTEN', 'Gene', '5728', (63, 67))	('MSI', 'Gene', (12, 15))	('TP53', 'Gene', '7157', (72, 76))	('mutations', 'Var', (50, 59))	('MSI', 'Gene', '5928', (12, 15))	('TP53', 'Gene', (72, 76))	('MSI', 'Gene', '5928', (167, 170))	('MSI', 'Gene', (167, 170))	('PTEN', 'Gene', (63, 67))
389030	33087752	This is in line with data from single cell subcloning of established CRC cell lines SW480 and HT29, which showed consistent mutations of KRAS and BRAF, respectively, across all established single cell clones:despite ongoing karyotype evolution/chromosomal instability.	('BRAF', 'Gene', (146, 150))	('HT29', 'CellLine', 'CVCL:0320', (94, 98))	('mutations', 'Var', (124, 133))	('BRAF', 'Gene', '673', (146, 150))	('chromosomal instability', 'Phenotype', 'HP:0040012', (244, 267))	('KRAS', 'Gene', (137, 141))	('SW480', 'CellLine', 'CVCL:0546', (84, 89))	('KRAS', 'Gene', '3845', (137, 141))
389031	33087752	In conclusion, our low-passage cell lines closely recapitulated tumor-characteristic immunophenotypic profiles and maintained treatment-relevant genomic features including MSI status, key mutations of driver genes and tumor-type specific copy number alterations.	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('copy number alterations', 'Var', (238, 261))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (218, 223))	('MSI', 'Gene', '5928', (172, 175))	('MSI', 'Gene', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
389036	32961992	We show here that DPT inhibited the kinase activity of epidermal growth factor receptor (EGFR) directly, as well as phosphorylation of its downstream signaling kinases, AKT, GSK-3beta, and ERK.	('DPT', 'Chemical', 'MESH:C014451', (18, 21))	('inhibited', 'NegReg', (22, 31))	('EGFR', 'Gene', (89, 93))	('DPT', 'Var', (18, 21))	('phosphorylation', 'MPA', (116, 131))	('epidermal growth factor receptor', 'Gene', (55, 87))	('kinase activity', 'MPA', (36, 51))	('AKT', 'Gene', (169, 172))	('ERK', 'Gene', '5594', (189, 192))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('GSK-3beta', 'Gene', '2931', (174, 183))	('AKT', 'Gene', '207', (169, 172))	('EGFR', 'Gene', '1956', (89, 93))	('GSK-3beta', 'Gene', (174, 183))	('ERK', 'Gene', (189, 192))
389051	32961992	EGFR phosphorylation specifically triggers the activation of PI3K/AKT and mitogen-activated protein kinase (MAPK) kinase/ERK signaling pathway.	('ERK', 'Gene', '5594', (121, 124))	('ERK', 'Gene', (121, 124))	('EGFR', 'Gene', (0, 4))	('AKT', 'Gene', (66, 69))	('phosphorylation', 'Var', (5, 20))	('activation', 'PosReg', (47, 57))	('AKT', 'Gene', '207', (66, 69))	('EGFR', 'Gene', '1956', (0, 4))
389070	32961992	As shown in Figure 1F, DPT not only inhibited EGFR kinase activity, but also suppressed EGFR and its downstream activation of AKT/GSK-3beta/ERK.	('suppressed', 'NegReg', (77, 87))	('AKT', 'Gene', (126, 129))	('activity', 'MPA', (58, 66))	('inhibited', 'NegReg', (36, 45))	('activation', 'PosReg', (112, 122))	('EGFR', 'Gene', '1956', (46, 50))	('GSK-3beta', 'Gene', '2931', (130, 139))	('ERK', 'Gene', '5594', (140, 143))	('EGFR', 'Gene', '1956', (88, 92))	('DPT', 'Chemical', 'MESH:C014451', (23, 26))	('EGFR', 'Gene', (46, 50))	('AKT', 'Gene', '207', (126, 129))	('DPT', 'Var', (23, 26))	('GSK-3beta', 'Gene', (130, 139))	('ERK', 'Gene', (140, 143))	('EGFR', 'Gene', (88, 92))
389075	32961992	IC50 values for DPT were approximately 7.64 nM (KYSE 30), 8.86 nM (KYSE 70), 8.92 nM (KYSE 410), 8.10 nM (KYSE 450), and 8.88 nM (KYSE 510) after 48 h of treatment, respectively.	('KYSE 450', 'Var', (106, 114))	('DPT', 'Chemical', 'MESH:C014451', (16, 19))	('KYSE 410', 'Var', (86, 94))	('KYSE 70', 'Var', (67, 74))
389078	32961992	Figure 2G,H shows that DPT prominently reduced the number of KYSE 30 and KYSE 450 cell colonies.	('KYSE 450 cell colonies', 'CPA', (73, 95))	('DPT', 'Chemical', 'MESH:C014451', (23, 26))	('reduced', 'NegReg', (39, 46))	('DPT', 'Var', (23, 26))	('KYSE 30', 'CPA', (61, 68))
389087	32961992	Multi-caspase activity in the control group was 5.4% and 3.8% in KYSE 30 and KYSE 450, respectively.	('KYSE', 'Var', (77, 81))	('caspase', 'Gene', (6, 13))	('activity', 'MPA', (14, 22))	('caspase', 'Gene', '834;835;837;838;839;841;842;843', (6, 13))
389102	32961992	The results demonstrated that DPT treatment (10 nM) led to depolarization of the MMP of 50.8 +- 2.7% and 49.2 +- 7.7% in the KYSE 30 and KYSE 450 ESCC cells, respectively (Figure 6A,B).	('depolarization', 'NegReg', (59, 73))	('MMP', 'MPA', (81, 84))	('DPT', 'Chemical', 'MESH:C014451', (30, 33))	('KYSE', 'Var', (137, 141))
389125	32961992	We found that DPT inhibited cell viability and elicited apoptosis in ESCC cells.	('elicited', 'Reg', (47, 55))	('DPT', 'Var', (14, 17))	('cell viability', 'CPA', (28, 42))	('DPT', 'Chemical', 'MESH:C014451', (14, 17))	('inhibited', 'NegReg', (18, 27))	('apoptosis', 'CPA', (56, 65))
389139	32961992	In our experiments, we found that DPT increases intracellular ROS levels in ESCC cells dose-dependently (Figure 5A,B).	('DPT', 'Chemical', 'MESH:C014451', (34, 37))	('increases intracellular ROS levels', 'Phenotype', 'HP:0025464', (38, 72))	('increases', 'PosReg', (38, 47))	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('DPT', 'Var', (34, 37))	('intracellular ROS levels', 'MPA', (48, 72))
389152	32961992	Based on our findings, DPT induces apoptosis by inhibiting the phosphorylation of EGFR directly in ESCC cells, and thus illustrates the mechanism behind its antitumor effects.	('EGFR', 'Gene', (82, 86))	('inhibiting', 'NegReg', (48, 58))	('DPT', 'Chemical', 'MESH:C014451', (23, 26))	('phosphorylation', 'MPA', (63, 78))	('DPT', 'Var', (23, 26))	('EGFR', 'Gene', '1956', (82, 86))
389161	32961992	Antibodies against p-EGFR (Tyr1068), EGFR, p-GSK-3beta (Ser9), GSK-3beta, p-ERK (Thr202/Tyr204), ERK, p-AKT (Ser473), and AKT were purchased from Cell Signaling Biotechnology (Beverly, MA, USA).	('Ser9', 'Chemical', '-', (56, 60))	('AKT', 'Gene', '207', (122, 125))	('Tyr1068', 'Chemical', '-', (27, 34))	('ERK', 'Gene', '5594', (97, 100))	('AKT', 'Gene', '207', (104, 107))	('EGFR', 'Gene', '1956', (21, 25))	('ERK', 'Gene', (76, 79))	('GSK-3beta', 'Gene', (45, 54))	('EGFR', 'Gene', '1956', (37, 41))	('GSK-3beta', 'Gene', '2931', (63, 72))	('ERK', 'Gene', (97, 100))	('Tyr204', 'Chemical', '-', (88, 94))	('AKT', 'Gene', (122, 125))	('Thr202', 'Chemical', '-', (81, 87))	('EGFR', 'Gene', (21, 25))	('GSK-3beta', 'Gene', (63, 72))	('AKT', 'Gene', (104, 107))	('Tyr1068', 'Var', (27, 34))	('Ser473', 'Chemical', '-', (109, 115))	('EGFR', 'Gene', (37, 41))	('GSK-3beta', 'Gene', '2931', (45, 54))	('ERK', 'Gene', '5594', (76, 79))
389167	32961992	ESCC cells (KYSE 30, KYSE 70, KYSE 410, KYSE 450, and KYSE 510) and JB6 cells were seeded in 96-well plates at 2.75 x 103, 10 x 103, 2.5 x 103, 3.5 x 103, 5.5 x 103, and 8 x 103 per 100 muL and incubated for 24 or 48 h after treatment with DPT (5, 7.5, and 10 nM).	('KYSE 70', 'Var', (21, 28))	('KYSE', 'Var', (12, 16))	('DPT', 'Chemical', 'MESH:C014451', (240, 243))	('KYSE 510', 'Var', (54, 62))	('JB6', 'CellLine', 'CVCL:H633', (68, 71))	('KYSE 450', 'Var', (40, 48))	('KYSE 410', 'Var', (30, 38))
389230	32503448	SM1; SM2; and SM3 involving <=1/3 of the superficial, middle, and deep layers of the resected specimen, respectively (Fig.	('SM', 'Chemical', '-', (5, 7))	('SM1', 'Gene', (0, 3))	('SM1', 'Gene', '7911', (0, 3))	('SM', 'Chemical', '-', (0, 2))	('SM2', 'Gene', '53366', (5, 8))	('SM', 'Chemical', '-', (14, 16))	('SM3', 'Var', (14, 17))	('SM2', 'Gene', (5, 8))
389261	32503448	3), in which the lymphatic endothelial cells were very thin near the tumor margin (site where LVI diagnosis is relatively easy), making recognition difficult, and in cases with SM3 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('SM', 'Chemical', '-', (177, 179))	('SM3', 'Var', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
389317	32251017	BE was associated with family histories of esophageal cancer (odds ratio = 2.63; 95% confidence interval = 1.07-6.47) and CRC in >=2 vs 0 FDRs (odds ratio = 3.73; 95% confidence interval = 0.898-15.4).	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('CRC', 'Phenotype', 'HP:0003003', (122, 125))	('CRC in >=2', 'Var', (122, 132))	('esophageal cancer', 'Disease', (43, 60))	('BE', 'Phenotype', 'HP:0100580', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
389318	32251017	DNA analysis of subjects with both BE and a family history of cancer identified one or more germline variants of interest in genes associated with cancer predisposition in 10 of 14 subjects, including the same novel variant in EPHA5 in 2 unrelated individuals.	('EPHA5', 'Gene', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('EPHA5', 'Gene', '2044', (227, 232))	('variants', 'Var', (101, 109))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (147, 153))	('BE', 'Phenotype', 'HP:0100580', (35, 37))
389334	32251017	Polyps at the splenic flexure or more distal were classified as in the left colon and more proximal polyps in the right colon.	('left colon', 'Disease', 'MESH:D003110', (71, 81))	('polyps', 'Disease', (100, 106))	('Polyps', 'Var', (0, 6))	('polyps', 'Disease', 'MESH:D011127', (100, 106))	('left colon', 'Disease', (71, 81))
389345	32251017	The median length by the Prague criteria was C0M2 (interquartile range = C0M1-C1M3), and dysplasia or adenocarcinoma was present in 5 (7.1%).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('C0M2', 'Var', (45, 49))	('adenocarcinoma', 'Disease', (102, 116))	('adenocarcinoma', 'Disease', 'MESH:D000230', (102, 116))	('dysplasia', 'Disease', 'MESH:C536170', (89, 98))	('dysplasia', 'Disease', (89, 98))
389357	32251017	The same missense VUS in EPHA5 (c.242A>C with minor allele frequency 0.04789) was identified in 2 unrelated subjects, one with a family history of CRC in 2 brothers and the other with a family history of both esophageal cancer and CRC diagnosed in his mother (subjects D and E in Table 4).	('esophageal cancer', 'Disease', (209, 226))	('CRC', 'Phenotype', 'HP:0003003', (147, 150))	('EPHA5', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('esophageal cancer', 'Disease', 'MESH:D004938', (209, 226))	('CRC', 'Disease', (231, 234))	('EPHA5', 'Gene', '2044', (25, 30))	('c.242A>C', 'Var', (32, 40))	('CRC', 'Phenotype', 'HP:0003003', (231, 234))	('c.242A>C', 'Mutation', 'rs33932471', (32, 40))
389359	32251017	In particular, we found the identical germline variant in EPHA5 in 2 cases of BE with family histories of esophageal cancer or at least 2 FDRs with CRC.	('EPHA5', 'Gene', '2044', (58, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('BE', 'Phenotype', 'HP:0100580', (78, 80))	('germline variant', 'Var', (38, 54))	('esophageal cancer', 'Disease', (106, 123))	('EPHA5', 'Gene', (58, 63))
389367	32251017	The same patient also had a germline variant in DNMT3A, which encodes DNA (cytosine-5)-methyltransferase 3A, and a variant in that gene has been associated with an increased risk of CRC.	('DNA (cytosine-5)-methyltransferase 3A', 'Gene', '1788', (70, 107))	('variant', 'Var', (115, 122))	('associated', 'Reg', (145, 155))	('DNMT3A', 'Gene', (48, 54))	('variant', 'Var', (37, 44))	('DNMT3A', 'Gene', '1788', (48, 54))	('CRC', 'Disease', (182, 185))	('patient', 'Species', '9606', (9, 16))	('CRC', 'Phenotype', 'HP:0003003', (182, 185))
389369	32251017	Another patient had a variant in PTCH1 that was predicted to be pathogenic.	('variant', 'Var', (22, 29))	('PTCH1', 'Gene', (33, 38))	('patient', 'Species', '9606', (8, 15))	('PTCH1', 'Gene', '5727', (33, 38))
389371	32251017	Variants in PTCH1 are associated with Gorlin (basal cell nevus) syndrome; however, these have also been found to be associated with microsatellite-unstable CRC, and hypermethylation of the PTCH1 promoter has been associated with aberrant crypt foci.	('aberrant', 'Disease', (229, 237))	('Variants', 'Var', (0, 8))	('associated', 'Reg', (213, 223))	('basal cell nevus', 'Phenotype', 'HP:0002671', (46, 62))	('PTCH1', 'Gene', '5727', (12, 17))	('nevus', 'Phenotype', 'HP:0003764', (57, 62))	('PTCH1', 'Gene', (189, 194))	('PTCH1', 'Gene', '5727', (189, 194))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('PTCH1', 'Gene', (12, 17))	('associated', 'Reg', (22, 32))	('Gorlin (basal cell nevus) syndrome', 'Disease', (38, 72))	('hypermethylation', 'Var', (165, 181))	('associated', 'Reg', (116, 126))
389372	32251017	Other variants in PTCH1 have been associated with esophageal squamous cell carcinoma, but PTCH1 is upregulated in BE.	('PTCH1', 'Gene', '5727', (18, 23))	('associated', 'Reg', (34, 44))	('variants', 'Var', (6, 14))	('PTCH1', 'Gene', '5727', (90, 95))	('upregulated', 'PosReg', (99, 110))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('PTCH1', 'Gene', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('PTCH1', 'Gene', (90, 95))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))
389373	32251017	Among individuals with BE and an FDR with esophageal cancer, we also found 8 suspicious germline variants, including a VUS in MSH6, a DNA mismatch repair gene known to be associated with Lynch syndrome.	('esophageal cancer', 'Disease', (42, 59))	('MSH6', 'Gene', '2956', (126, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('Lynch syndrome', 'Disease', (187, 201))	('variants', 'Var', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Lynch syndrome', 'Disease', 'MESH:D003123', (187, 201))	('BE', 'Phenotype', 'HP:0100580', (23, 25))	('associated', 'Reg', (171, 181))	('MSH6', 'Gene', (126, 130))
389375	32251017	FAP is caused by inherited inactivating variants in APC, leading to CRC at early ages, and associated with extracolonic malignancies, including gastric, duodenal, and biliary.	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('malignancies', 'Disease', 'MESH:D009369', (120, 132))	('APC', 'Disease', (52, 55))	('biliary', 'Disease', (167, 174))	('gastric', 'Disease', (144, 151))	('FAP', 'Disease', 'MESH:C567782', (0, 3))	('leading to', 'Reg', (57, 67))	('malignancies', 'Disease', (120, 132))	('CRC', 'Disease', (68, 71))	('duodenal', 'Disease', (153, 161))	('inactivating variants', 'Var', (27, 48))	('APC', 'Disease', 'MESH:D011125', (52, 55))	('caused by', 'Reg', (7, 16))	('FAP', 'Disease', (0, 3))	('associated with', 'Reg', (91, 106))
389377	32251017	A number of studies have implicated mutation or inactivation of APC by hypermethylation as an uncommon pathway for neoplastic progression of BE.	('APC', 'Disease', 'MESH:D011125', (64, 67))	('APC', 'Disease', (64, 67))	('inactivation', 'Var', (48, 60))	('hypermethylation', 'Var', (71, 87))	('mutation', 'Var', (36, 44))	('BE', 'Phenotype', 'HP:0100580', (141, 143))
389381	32251017	CRC tumors tend to have hypermethylation in the promoter region of EPHA5 or decreased expression of the protein, and decreased expression is associated with stage at presentation and prognosis of CRC.	('hypermethylation', 'Var', (24, 40))	('CRC tumors', 'Disease', 'MESH:D015179', (0, 10))	('expression of the', 'MPA', (86, 103))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('CRC', 'Phenotype', 'HP:0003003', (196, 199))	('expression', 'MPA', (127, 137))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('decreased', 'NegReg', (76, 85))	('EPHA5', 'Gene', (67, 72))	('CRC', 'Disease', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('EPHA5', 'Gene', '2044', (67, 72))	('CRC tumors', 'Disease', (0, 10))
389384	32251017	Although this rare EPHA5 missense variant is predicted to affect protein function by in silico models, it has not been reported in ClinVar, and thus, there is no additional information to assess its clinical significance.	('EPHA5', 'Gene', (19, 24))	('missense variant', 'Var', (25, 41))	('protein function', 'MPA', (65, 81))	('EPHA5', 'Gene', '2044', (19, 24))	('affect', 'Reg', (58, 64))
389400	32251017	: K23DK079291, U54CA163059, and U01CA199336), Department of Veterans Affairs (J.H.R.	('U54CA163059', 'Var', (15, 26))	('men', 'Species', '9606', (52, 55))	('K23DK079291', 'Var', (2, 13))	('U01CA199336', 'Var', (32, 43))	('U01', 'CellLine', 'CVCL:2220', (32, 35))
389426	31338250	Indeed, cyclin D1 amplification induces tumorigenesis as well as tumor growth.	('cyclin D1', 'Gene', '595', (8, 17))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('cyclin D1', 'Gene', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('induces', 'PosReg', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (40, 45))	('amplification', 'Var', (18, 31))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
389460	31338250	The cells were treated with NPs and free drugs at IC50 as follows: KYSE-30 + Dox (S1); KYSE-30 + Dox NPs (S2); KYSE-30 + HP (S3); KYSE-30 + HP NPs (S4); KYSE-30 + Dox + HP (S5); KYSE-30 + Dox + HP NPs (S6); KYSE-30 + HP + Dox NPs (S7); normal cells + Dox NPs (S8); normal cells + HP NPs (S9); KYSE-30 (S10).	('HP', 'Chemical', 'MESH:C035699', (194, 196))	('Dox', 'Chemical', 'MESH:D004317', (163, 166))	('KYSE-30', 'Var', (293, 300))	('HP', 'Chemical', 'MESH:C035699', (140, 142))	('Dox', 'Chemical', 'MESH:D004317', (97, 100))	('KYSE-30', 'Var', (111, 118))	('HP', 'Chemical', 'MESH:C035699', (217, 219))	('KYSE-30', 'Var', (207, 214))	('HP', 'Chemical', 'MESH:C035699', (121, 123))	('Dox', 'Chemical', 'MESH:D004317', (77, 80))	('Dox', 'Chemical', 'MESH:D004317', (222, 225))	('HP', 'Chemical', 'MESH:C035699', (169, 171))	('Dox', 'Chemical', 'MESH:D004317', (188, 191))	('HP', 'Chemical', 'MESH:C035699', (280, 282))	('Dox', 'Chemical', 'MESH:D004317', (251, 254))
389474	31338250	Significant reduction of cyclin D1 expression was observed after exposure of KYSE-30 cells to Dox NPs (S2) and HP NPs (S4) as respectively compared with Dox (S1; P = 0.012) and HP extract (S3; P = 0.033).	('HP NPs', 'Var', (111, 117))	('Dox', 'Chemical', 'MESH:D004317', (94, 97))	('reduction', 'NegReg', (12, 21))	('Dox', 'Chemical', 'MESH:D004317', (153, 156))	('expression', 'MPA', (35, 45))	('HP', 'Chemical', 'MESH:C035699', (111, 113))	('cyclin D1', 'Gene', '595', (25, 34))	('HP', 'Chemical', 'MESH:C035699', (177, 179))	('cyclin D1', 'Gene', (25, 34))
389492	31338250	Furthermore, nanoparticles caused a significant increase in cytotoxicity and yet decrease in the IC50 values in KYSE-30 cells.	('cytotoxicity', 'Disease', (60, 72))	('decrease', 'NegReg', (81, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (60, 72))	('nanoparticles', 'Var', (13, 26))	('IC50 values', 'MPA', (97, 108))	('increase', 'PosReg', (48, 56))
389519	31144617	Notably, we show that squamous tumors are dependent NRG1 signaling in vivo, in both genetically engineered mouse models and human xenograft models, and demonstrate that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells, blocking proliferation and inhibiting tumor growth.	('blocking', 'NegReg', (265, 273))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('NRG1', 'Gene', (183, 187))	('inhibition', 'Var', (169, 179))	('induces', 'Reg', (188, 195))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('keratinization', 'CPA', (196, 210))	('squamous tumors', 'Disease', (22, 37))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('squamous tumors', 'Disease', 'MESH:D002294', (22, 37))	('terminal squamous differentiation', 'CPA', (215, 248))	('mouse', 'Species', '10090', (107, 112))	('tumor', 'Disease', (303, 308))	('proliferation', 'CPA', (274, 287))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Disease', (31, 36))	('inhibiting', 'NegReg', (292, 302))	('human', 'Species', '9606', (124, 129))	('tumor', 'Disease', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
389522	31144617	Amplifications of master regulators act as oncogenic drivers in cancers arising in the tissues whose development they normally control.	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Disease', (64, 71))	('Amplifications', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
389526	31144617	Despite varied anatomic origins, squamous cell cancers (SCCs) share many common properties, including genetic and epigenetic alterations.	('epigenetic alterations', 'Var', (114, 136))	('SCC', 'Gene', (56, 59))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('squamous cell cancers', 'Disease', (33, 54))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (33, 54))	('SCC', 'Gene', '6317', (56, 59))	('squamous cell cancers', 'Disease', 'MESH:D002294', (33, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
389528	31144617	Amplification of TP63 is prevalent in SCCs, and TP63 expression is used to distinguish SCCs from other cancer subtypes in multiple tissues.	('prevalent', 'Reg', (25, 34))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('SCC', 'Gene', (38, 41))	('SCC', 'Gene', (87, 90))	('SCC', 'Gene', '6317', (38, 41))	('TP63', 'Gene', (17, 21))	('SCC', 'Gene', '6317', (87, 90))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
389530	31144617	Here we show that NRG1 expression is directly regulated by TP63 in SCCs of various organs, and that co-expression of NRG1 and its receptor ERBB3 is prevalent in SCCs.	('regulated', 'Reg', (46, 55))	('SCC', 'Gene', (161, 164))	('ERBB3', 'Gene', (139, 144))	('SCC', 'Gene', '6317', (161, 164))	('SCC', 'Gene', (67, 70))	('NRG1', 'Gene', (117, 121))	('ERBB3', 'Gene', '13867', (139, 144))	('NRG1', 'Gene', (18, 22))	('SCC', 'Gene', '6317', (67, 70))	('TP63', 'Var', (59, 63))	('expression', 'MPA', (23, 33))
389532	31144617	In addition, TP63 acts as a key survival factor and driver of SCCs.	('SCC', 'Gene', '6317', (62, 65))	('TP63', 'Var', (13, 17))	('SCC', 'Gene', (62, 65))
389535	31144617	Despite lacking this domain, deltaN-TP63, the major isoform expressed in SCCs, functions as both a positive and negative transcriptional regulator of different target gene subsets.	('SCC', 'Gene', '6317', (73, 76))	('deltaN-TP63', 'Var', (29, 40))	('SCC', 'Gene', (73, 76))	('lacking', 'NegReg', (8, 15))
389538	31144617	Together, these data suggest that deltaN-TP63 directly regulates NRG1 transcription in SCC.	('SCC', 'Gene', (87, 90))	('transcription', 'MPA', (70, 83))	('NRG1', 'Gene', (65, 69))	('deltaN-TP63', 'Var', (34, 45))	('SCC', 'Gene', '6317', (87, 90))	('regulates', 'Reg', (55, 64))
389539	31144617	Emerging evidence suggest that high ERBB3 or high NRG1 expression is associated with poor clinical outcome in SCCs.	('NRG1', 'Gene', (50, 54))	('ERBB3', 'Gene', (36, 41))	('SCC', 'Gene', '6317', (110, 113))	('SCC', 'Gene', (110, 113))	('expression', 'MPA', (55, 65))	('high', 'Protein', (45, 49))	('high', 'Var', (31, 35))	('ERBB3', 'Gene', '13867', (36, 41))
389541	31144617	Interestingly, NRG1/ERBB3 co-expression appeared prevalent in lung and head and neck SCCs, but was notably rare in lung adenocarcinoma across the various cancer datasets available in TCGA (Figure 2A).	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('co-expression', 'Var', (26, 39))	('prevalent', 'Reg', (49, 58))	('rare', 'Reg', (107, 111))	('ERBB3', 'Gene', (20, 25))	('SCC', 'Gene', '6317', (85, 88))	('ERBB3', 'Gene', '13867', (20, 25))	('lung', 'Disease', (62, 66))	('lung adenocarcinoma', 'Disease', (115, 134))	('cancer', 'Disease', (154, 160))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('SCC', 'Gene', (85, 88))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))
389546	31144617	Importantly, anti-NRG1 treatment markedly inhibited tumor growth in each of these models to an extent that far exceeded that observed in vitro.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('anti-NRG1', 'Var', (13, 22))	('inhibited', 'NegReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
389548	31144617	To further evaluate the NRG1-dependency in ERBB3/NRG1 co-expressing squamous cell cancers, we tested the efficacy of anti-NRG1 in lung SCC PDX models.	('tested', 'Reg', (94, 100))	('ERBB3', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('squamous cell cancers', 'Disease', (68, 89))	('SCC', 'Gene', (135, 138))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (68, 89))	('anti-NRG1', 'Var', (117, 126))	('ERBB3', 'Gene', '13867', (43, 48))	('squamous cell cancers', 'Disease', 'MESH:D002294', (68, 89))	('SCC', 'Gene', '6317', (135, 138))
389549	31144617	Again, anti-NRG1 significantly inhibited the tumor growth of three models that co-express NRG1 and ERBB3, resulting in tumor stasis (Figure 3B and Figure 3:figure supplement 1).	('ERBB3', 'Gene', '13867', (99, 104))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ERBB3', 'Gene', (99, 104))	('tumor', 'Disease', (45, 50))	('anti-NRG1', 'Var', (7, 16))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('inhibited', 'NegReg', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('NRG1', 'Gene', (90, 94))
389551	31144617	Furthermore, mice with Krt5-Cre-driven knockout of Erbb3 in basal progenitor cells are resistant to carcinogen-induced skin tumorigenesis and exhibit defective wound healing, while Krt5-driven overexpression of deltaN-TP63 enhances carcinogen-induced skin tumorigenesis.	('mice', 'Species', '10090', (13, 17))	('Krt5', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('defective wound healing', 'Phenotype', 'HP:0001058', (150, 173))	('knockout', 'Var', (39, 47))	('defective', 'NegReg', (150, 159))	('Krt5', 'Gene', '110308', (23, 27))	('tumor', 'Disease', (124, 129))	('Krt5', 'Gene', (181, 185))	('Erbb3', 'Gene', '13867', (51, 56))	('Krt5', 'Gene', '110308', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('wound healing', 'CPA', (160, 173))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('enhances', 'PosReg', (223, 231))	('Erbb3', 'Gene', (51, 56))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
389553	31144617	In this highly aggressive tumor model, anti-NRG1 dramatically increased the progression free survival (PFS) compared to control treatment, nearly doubling time to progression from 14 to 27 days (p<0.002) (Figure 3C-D).	('increased', 'PosReg', (62, 71))	('anti-NRG1', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('progression free survival', 'CPA', (76, 101))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
389557	31144617	We tested the effect of anti-NRG1 on a panel of ovarian cancer cell lines and indeed proliferation of cell lines expressing both NRG1 and ERBB3 was inhibited by anti-NRG1 in vitro (Figure 3:figure supplement 2A).	('NRG1', 'Gene', (129, 133))	('ERBB3', 'Gene', '13867', (138, 143))	('proliferation', 'CPA', (85, 98))	('anti-NRG1', 'Var', (161, 170))	('ERBB3', 'Gene', (138, 143))	('tested', 'Reg', (3, 9))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('inhibited', 'NegReg', (148, 157))	('ovarian cancer', 'Disease', (48, 62))
389562	31144617	Moreover, anti-NRG1-treated tumors showed a dramatic increase in the expression of KRT10, a differentiation-specific keratin normally restricted to the post-mitotic layers of stratified-keratinizing and cornifying epithelia (Figure 4A).	('anti-NRG1-treated', 'Var', (10, 27))	('KRT10', 'Gene', '16661', (83, 88))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('KRT10', 'Gene', (83, 88))	('expression', 'MPA', (69, 79))	('increase', 'PosReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
389563	31144617	Immunoblot analyses of treated tumors showed that anti-NRG1 inhibited ERBB3 activation and decreased the levels of multiple proliferation markers, consistent with a mechanism in which differentiation is induced at the expense of proliferation (Figure 4B and Figure 4:figure supplement 2).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('decreased', 'NegReg', (91, 100))	('tumors', 'Disease', (31, 37))	('ERBB3', 'Gene', '13867', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('activation', 'MPA', (76, 86))	('inhibited', 'NegReg', (60, 69))	('ERBB3', 'Gene', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('levels of multiple proliferation markers', 'MPA', (105, 145))	('anti-NRG1', 'Var', (50, 59))
389566	31144617	Treatment of SCC cell lines with anti-NRG1 in vitro also increased expression of the differentiation markers KRT1, KRT10, IVL and KRTDAP (Figure 4:figure supplement 3).	('KRT1', 'Gene', (109, 113))	('anti-NRG1', 'Var', (33, 42))	('KRTDAP', 'Gene', '64661', (130, 136))	('SCC', 'Gene', '6317', (13, 16))	('IVL', 'Gene', '16447', (122, 125))	('KRT10', 'Gene', '16661', (115, 120))	('KRTDAP', 'Gene', (130, 136))	('SCC', 'Gene', (13, 16))	('KRT10', 'Gene', (115, 120))	('IVL', 'Gene', (122, 125))	('KRT1', 'Gene', '16678', (115, 119))	('increased', 'PosReg', (57, 66))	('expression', 'MPA', (67, 77))	('KRT1', 'Gene', '16678', (109, 113))	('KRT1', 'Gene', (115, 119))
389571	31144617	In contrast, although NRG1 and ERBB3 co-expression is prevalent in ovarian tumors, ovarian cancer models did not respond to NRG1 inhibition in vivo.	('NRG1', 'Gene', (22, 26))	('ovarian tumors', 'Disease', (67, 81))	('prevalent', 'Reg', (54, 63))	('ERBB3', 'Gene', '13867', (31, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('ERBB3', 'Gene', (31, 36))	('ovarian tumors', 'Phenotype', 'HP:0100615', (67, 81))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('ovarian tumors', 'Disease', 'MESH:D010051', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ovarian cancer', 'Disease', (83, 97))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('co-expression', 'Var', (37, 50))
389594	31144617	72 hr after siRNA transfection, cells were washed twice with PBS and lysed in RIPA buffer containing protease/phosphatase inhibitors at 4 C. Protein concentrations were determined by BCA (Thermo Scientific).	('transfection', 'Var', (18, 30))	('PBS', 'Disease', 'MESH:D011535', (61, 64))	('PBS', 'Disease', (61, 64))	('RIPA buffer', 'Chemical', '-', (78, 89))
389597	31144617	Antibodies: TP63 alpha (Cell Signaling Technologies, CST 13109), deltaNTP63 (Biolegend 619001), actin (BD Bioscience 612656), p-ERBB3 (CST 4791), ERBB3 (CST 12708), PARP (CST 9542) and Cleaved caspase-3 (CST 9664).	('Cleaved', 'MPA', (185, 192))	('PARP', 'Gene', (165, 169))	('PARP', 'Gene', '11545', (165, 169))	('ERBB3', 'Gene', '13867', (146, 151))	('CST 4791', 'Var', (135, 143))	('ERBB3', 'Gene', (146, 151))	('caspase-3', 'Protein', (193, 202))	('CST 12708', 'Var', (153, 162))	('ERBB3', 'Gene', '13867', (128, 133))	('actin', 'Gene', (96, 101))	('actin', 'Gene', '100342017', (96, 101))	('ERBB3', 'Gene', (128, 133))	('deltaNTP63', 'Gene', (65, 75))
389606	31144617	Although NRG1 has already been established as a TP63 target in breast cells and NRG1/ERBB signaling has already been reported to play a role in squamous cell carcinoma biology, a strength of the work is the use of human material, murine models and cancer cell lines as well as an antibody to block NRG, which suggests that blocking NRG may affect tumor maintenance.	('cancer', 'Disease', (248, 254))	('affect', 'Reg', (340, 346))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('NRG', 'Gene', (298, 301))	('NRG', 'Gene', (332, 335))	('tumor', 'Disease', (347, 352))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('blocking', 'Var', (323, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('murine', 'Species', '10090', (230, 236))	('human', 'Species', '9606', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('squamous cell carcinoma', 'Disease', (144, 167))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))
389620	31144617	Reviewer #2:  The authors show that NRG1 is a transcriptional target of p63 and argue that anti-NRG1 could be an effective therapy for a wide variety of squamous cell carcinomas.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (153, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('anti-NRG1', 'Var', (91, 100))	('p63', 'Gene', '22061', (72, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('p63', 'Gene', (72, 75))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (153, 177))	('squamous cell carcinomas', 'Disease', (153, 177))
389623	31144617	In addition, they show that treatment with an anti-NRG1 antibody inhibits the growth of SCC xenograft models and provide evidence that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells.	('NRG1', 'Gene', (149, 153))	('terminal squamous differentiation', 'CPA', (181, 214))	('induces', 'Reg', (154, 161))	('inhibits', 'NegReg', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('keratinization', 'CPA', (162, 176))	('SCC', 'Gene', (88, 91))	('inhibition', 'Var', (135, 145))	('tumor', 'Disease', (218, 223))	('SCC', 'Gene', '6317', (88, 91))
389625	31144617	The authors provide some evidence that NRG1 inhibition decreases SCC cell proliferation and promotes cell differentiation.	('promotes', 'PosReg', (92, 100))	('SCC', 'Gene', (65, 68))	('inhibition', 'Var', (44, 54))	('NRG1', 'Gene', (39, 43))	('decreases', 'NegReg', (55, 64))	('SCC', 'Gene', '6317', (65, 68))	('cell differentiation', 'CPA', (101, 121))
389627	31144617	3) In Figure 1, it would be important to perform double IHC/IF to demonstrate co-localization of deltaN-TP63 and NRG1 at the protein level in tumor cells within human SCC tissue samples.	('human', 'Species', '9606', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('deltaN-TP63', 'Var', (97, 108))	('NRG1', 'Gene', (113, 117))	('SCC', 'Gene', '6317', (167, 170))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('SCC', 'Gene', (167, 170))
389635	31144617	As discussed in our final paragraph, EGFR and other signaling pathways also play an important role in driving these tumors and inhibition of NRG1 could drive deeper responses when combined with EGFR inhibition.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('EGFR', 'Gene', (37, 41))	('inhibition', 'Var', (127, 137))	('drive', 'Reg', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('EGFR', 'Gene', (194, 198))	('EGFR', 'Gene', '13649', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('NRG1', 'Gene', (141, 145))	('EGFR', 'Gene', '13649', (37, 41))
389636	31144617	We carried out qPCR analysis of four differentiation markers in three different squamous cell carcinoma lines treated with anti-NRG1 or control antibody in vitro.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('squamous cell carcinoma lines', 'Disease', 'MESH:D002294', (80, 109))	('anti-NRG1', 'Var', (123, 132))	('squamous cell carcinoma lines', 'Disease', (80, 109))
389647	30214089	The 5-year RFS for the enrolled patients was 57%, and the RFS of patients with SUVmax < 7.0 was better than that of patients with SUVmax >= 7.0, with a marginal difference (p = 0.0892).	('patients', 'Species', '9606', (32, 40))	('SUVmax < 7.0', 'Var', (79, 91))	('patients', 'Species', '9606', (116, 124))	('better', 'PosReg', (96, 102))	('patients', 'Species', '9606', (65, 73))	('RFS', 'MPA', (58, 61))
389648	30214089	Lymph node recurrences were significantly more common in patients with SUVmax >= 7.0, compared to patients with SUVmax < 7.0.	('patients', 'Species', '9606', (57, 65))	('SUVmax >= 7.0', 'Var', (71, 84))	('patients', 'Species', '9606', (98, 106))	('common', 'PosReg', (47, 53))	('Lymph node recurrences', 'CPA', (0, 22))
389682	30214089	This study evaluated the prognostic significance of SUVmax in patients who underwent R0-esophagectomy for EC and revealed that patients with a SUVmax >= 7.0 tended to have a lower RFS and a significantly higher risk of lymph node recurrence than patients with a SUVmax < 7.0.	('lower', 'NegReg', (174, 179))	('patients', 'Species', '9606', (246, 254))	('RFS', 'MPA', (180, 183))	('patients', 'Species', '9606', (127, 135))	('SUVmax >= 7.0', 'Var', (143, 156))	('lymph node recurrence', 'CPA', (219, 240))	('patients', 'Species', '9606', (62, 70))
389688	30214089	In addition, the RFS in patients with a SUVmax >= 7.0 tended to be lower than that in patients with a SUVmax < 7.0.	('SUVmax >= 7.0', 'Var', (40, 53))	('patients', 'Species', '9606', (24, 32))	('RFS', 'MPA', (17, 20))	('lower', 'NegReg', (67, 72))	('patients', 'Species', '9606', (86, 94))
389695	30214089	Our study showed that the risk of lymph node recurrence in patients with a SUVmax >= 7.0 was significantly higher than that in patients with a SUVmax < 7.0, although there were no significant associations between SUVmax and lymph node metastases in patients who did not receive preoperative treatment.	('men', 'Species', '9606', (296, 299))	('patients', 'Species', '9606', (249, 257))	('SUVmax >= 7.0', 'Var', (75, 88))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (59, 67))	('lymph node recurrence', 'CPA', (34, 55))	('lymph node metastases', 'Disease', 'MESH:D009362', (224, 245))	('higher', 'PosReg', (107, 113))	('lymph node metastases', 'Disease', (224, 245))
389708	28789358	Patients with PTPN9 positive expression had shorter survival time, compared with those that were PTPN9 negative.	('PTPN9', 'Gene', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('survival time', 'CPA', (52, 65))	('shorter', 'NegReg', (44, 51))	('positive expression', 'Var', (20, 39))
389710	28789358	Using RNA interference, the present study demonstrated that knockdown of PTPN9 significantly suppressed cell proliferation and invasion in Eca109.	('invasion', 'CPA', (127, 135))	('cell proliferation', 'CPA', (104, 122))	('PTPN9', 'Gene', (73, 78))	('knockdown', 'Var', (60, 69))	('rat', 'Species', '10116', (116, 119))	('suppressed', 'NegReg', (93, 103))	('rat', 'Species', '10116', (49, 52))
389711	28789358	Additionally, it was hypothesized that miR-126, described as a tumor suppressor in ESCC, may act at least in part via its inhibition of PTPN9 at the post-transcriptional level.	('PTPN9', 'Gene', (136, 141))	('tumor', 'Disease', (63, 68))	('miR-126', 'Var', (39, 46))	('inhibition', 'NegReg', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ESCC', 'Disease', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
389723	28789358	Located at chromosome 9q34.3, an intron of EGF-like domain-containing protein 7 (EGFL7), miRNA (miR)-126 is associated with various human tumors.	('EGFL7', 'Gene', (81, 86))	('tumors', 'Disease', (138, 144))	('associated', 'Reg', (108, 118))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('human', 'Species', '9606', (132, 137))	('miRNA', 'Var', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
389763	28789358	The results revealed that the knockdown of PTPN9 significantly inhibited cell proliferation at 48 (P<0.05), 72 (P<0.01) and 96 h (P<0.01) after transfection (Fig.	('rat', 'Species', '10116', (85, 88))	('cell proliferation at', 'CPA', (73, 94))	('inhibited', 'NegReg', (63, 72))	('knockdown', 'Var', (30, 39))	('PTPN9', 'Gene', (43, 48))
389768	28789358	In the last few years, a number of studies have revealed that a variety of human diseases are associated with aberrant expression of PTPN9.	('PTPN9', 'Gene', (133, 138))	('human', 'Species', '9606', (75, 80))	('associated', 'Reg', (94, 104))	('aberrant expression', 'Var', (110, 129))
389771	28789358	A previous study indicated that knockdown of PTPN9 in the liver of diabetic mice was able to lead to insulin sensitization and normalization of hyperglycemia.	('hyperglycemia', 'Phenotype', 'HP:0003074', (144, 157))	('diabetic', 'Disease', (67, 75))	('insulin sensitization', 'MPA', (101, 122))	('hyperglycemia', 'Disease', 'MESH:D006943', (144, 157))	('knockdown', 'Var', (32, 41))	('PTPN9', 'Gene', (45, 50))	('normalization', 'MPA', (127, 140))	('mice', 'Species', '10090', (76, 80))	('hyperglycemia', 'Disease', (144, 157))	('lead to', 'Reg', (93, 100))	('diabetic', 'Disease', 'MESH:D003920', (67, 75))
389772	28789358	In addition, it has been demonstrated that PTPN9 is able to negatively regulate the VEGF-induced cell signal through inhibition of the phosphorylation of VEGF receptor 2 on Tyr1175 in endothelial cells.	('rat', 'Species', '10116', (32, 35))	('Tyr1175', 'Var', (173, 180))	('PTPN9', 'Var', (43, 48))	('Tyr1175', 'Chemical', '-', (173, 180))	('VEGF-induced cell signal', 'MPA', (84, 108))	('negatively', 'NegReg', (60, 70))	('inhibition', 'NegReg', (117, 127))	('phosphorylation', 'MPA', (135, 150))
389773	28789358	Furthermore, it has been reported that PTPN9 is able to inhibit ErbB2 and epidermal growth factor receptor (EGFR) signaling by dephosphorylating ErbB2/EGFR to impair growth and invasiveness in breast cancer cells, supported by the results of Du et al.	('ErbB2', 'Gene', '2064', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('inhibit', 'NegReg', (56, 63))	('EGFR', 'Gene', '1956', (108, 112))	('ErbB2', 'Gene', '2064', (64, 69))	('ErbB2', 'Gene', (145, 150))	('invasiveness in breast cancer', 'Disease', 'MESH:D001943', (177, 206))	('EGFR', 'Gene', (151, 155))	('growth', 'CPA', (166, 172))	('dephosphorylating', 'Var', (127, 144))	('epidermal growth factor receptor', 'Gene', (74, 106))	('invasiveness in breast cancer', 'Disease', (177, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('EGFR', 'Gene', (108, 112))	('epidermal growth factor receptor', 'Gene', '1956', (74, 106))	('ErbB2', 'Gene', (64, 69))	('PTPN9', 'Var', (39, 44))	('impair', 'NegReg', (159, 165))	('EGFR', 'Gene', '1956', (151, 155))
389774	28789358	As expected, cell proliferation and invasion was significantly suppressed upon the knockdown of PTPN9.	('PTPN9', 'Gene', (96, 101))	('suppressed', 'NegReg', (63, 73))	('knockdown', 'Var', (83, 92))	('rat', 'Species', '10116', (25, 28))
389775	28789358	A number of previous studies have demonstrated that aberrant expression of miRNAs serves a key role in the tumorigenic process.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('miRNAs', 'Gene', (75, 81))	('aberrant expression', 'Var', (52, 71))	('rat', 'Species', '10116', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
389776	28789358	Therefore, an improved understanding of the underlying mechanisms of these non-coding RNAs may improve technologies for the diagnosis and treatment of human diseases.	('human', 'Species', '9606', (151, 156))	('improve', 'PosReg', (95, 102))	('non-coding RNAs', 'Var', (75, 90))
389786	26135649	There are many reports concerning the prevention of strictures after ESD for esophageal superficial squamous cell carcinoma (SCC), and preventive EBD is an example of one of the treatments; however even after six sessions of preventive EBD, strictures still frequently occur and preventive EBD sometimes causes perforation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('perforation', 'Disease', (311, 322))	('causes', 'Reg', (304, 310))	('preventive', 'Var', (279, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('SCC', 'Gene', (125, 128))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('occur', 'Reg', (269, 274))	('SCC', 'Gene', '6317', (125, 128))	('strictures', 'Disease', (241, 251))	('esophageal', 'Disease', (77, 87))
389821	26001209	Frequently observed alterations in BE include epigenetic silencing or loss of heterozygosity (LOH) of the P16INK4A and/or TP53 tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('TP53', 'Gene', (122, 126))	('loss of', 'NegReg', (70, 77))	('tumor', 'Disease', (127, 132))	('TP53', 'Gene', '7157', (122, 126))	('epigenetic silencing', 'Var', (46, 66))	('P16INK4A', 'Gene', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('P16INK4A', 'Gene', '1029', (106, 114))	('alterations', 'Reg', (20, 31))	('BE', 'Phenotype', 'HP:0100580', (35, 37))
389822	26001209	Whether these alterations necessarily lead to the clinical presentation of dysplasia and other cellular and architectural changes associated with this diagnosis is presently unknown.	('dysplasia', 'Disease', (75, 84))	('alterations', 'Var', (14, 25))	('lead', 'Reg', (38, 42))	('dysplasia', 'Disease', 'MESH:D004476', (75, 84))
389849	26001209	In the current formulation of the model, initiation occurs as a result of two rate-limiting events (e.g., bi-allelic inactivation of a tumor suppressor, such as TP53) due to previous likelihood-based model selection.	('bi-allelic inactivation', 'Var', (106, 129))	('TP53', 'Gene', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('TP53', 'Gene', '7157', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
389850	26001209	An initiated (dysplastic) cell may also undergo a transforming mutation with rate mu 2 that generates an initiated cell and a malignant cell.	('mu 2', 'Gene', (82, 86))	('dysplastic', 'Disease', (14, 24))	('mutation', 'Var', (63, 71))	('dysplastic', 'Disease', 'MESH:D004416', (14, 24))	('mu 2', 'Gene', '10053', (82, 86))
389870	26001209	Recent studies favor clonal expansion by crypt fission as the dominant mode of generating mutated crypts in the human colon that form adenomas.	('adenomas', 'Disease', (134, 142))	('human', 'Species', '9606', (112, 117))	('mutated', 'Var', (90, 97))	('adenomas', 'Disease', 'MESH:D000236', (134, 142))
389950	26001209	To explore the future influence of missed malignancies, the model predicted that if RFA removed all malignancies (omega = {1, 1, 1, 0}) but left behind the HGD tissue, then treatment would only moderately reduce future EAC cumulative incidence by an expected 15.7% before 2030.	('EAC', 'Gene', (219, 222))	('reduce', 'NegReg', (205, 211))	('malignancies', 'Disease', 'MESH:D009369', (100, 112))	('malignancies', 'Disease', 'MESH:D009369', (42, 54))	('removed', 'NegReg', (88, 95))	('EAC', 'Phenotype', 'HP:0011459', (219, 222))	('malignancies', 'Disease', (100, 112))	('malignancies', 'Disease', (42, 54))	('RFA', 'Var', (84, 87))	('EAC', 'Gene', '1540', (219, 222))	('men', 'Species', '9606', (178, 181))
389971	26001209	From the results derived from simulating an ablative treatment on a population of BE patients found to be positive for HGD during screening, we found that it was crucial to ablate dysplastic and not only preclinical malignant tissue to achieve the most significant impact on future EAC incidence.	('EAC', 'Gene', '1540', (282, 285))	('EAC', 'Gene', (282, 285))	('dysplastic', 'Disease', (180, 190))	('dysplastic', 'Disease', 'MESH:D004416', (180, 190))	('ablate', 'Var', (173, 179))	('patients', 'Species', '9606', (85, 93))	('BE', 'Phenotype', 'HP:0100580', (82, 84))	('EAC', 'Phenotype', 'HP:0011459', (282, 285))	('men', 'Species', '9606', (58, 61))
390009	20936529	Further, a recent study reported promotor hypermethylation of the gene coding for the selenoprotein GPx3 in Barrett's esophagus tissue, thereby epigenetically inactivating this gene.	('s', 'Chemical', 'MESH:D013455', (18, 19))	('s', 'Chemical', 'MESH:D013455', (86, 87))	('hypermethylation', 'Var', (42, 58))	('GPx3', 'Gene', (100, 104))	('s', 'Chemical', 'MESH:D013455', (131, 132))	('s', 'Chemical', 'MESH:D013455', (119, 120))	('s', 'Chemical', 'MESH:D013455', (116, 117))	('s', 'Chemical', 'MESH:D013455', (130, 131))	('s', 'Chemical', 'MESH:D013455', (175, 176))	('s', 'Chemical', 'MESH:D013455', (126, 127))	('epigenetically inactivating', 'Var', (144, 171))	('GPx3', 'Gene', '2878', (100, 104))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (108, 127))
390172	20562192	Another study in the same population showed that higher 25(OH)D concentrations were associated with higher risk of squamous dysplasia, the precursor lesion for ESCC.	('25(OH)D', 'Chemical', '-', (56, 63))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (115, 133))	('25(OH)D concentrations', 'Var', (56, 78))	('squamous dysplasia', 'Disease', (115, 133))	('squamous dysplasia', 'Disease', 'MESH:D002294', (115, 133))
390176	20562192	For the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, cases with epithelial tumors located in the esophagus (codes C152-159), gastric cardia (code C160), body of the stomach (codes C161-166), and overlapping and not otherwise specified locations (codes C168-169) were included.	('epithelial tumors located in the esophagus', 'Phenotype', 'HP:0100751', (117, 159))	('codes C152-159', 'Var', (161, 175))	('gastric cardia', 'Disease', (178, 192))	('code C160', 'Var', (194, 203))	('epithelial tumors', 'Disease', (117, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('codes C161-166', 'Var', (227, 241))	('gastric cardia', 'Disease', 'MESH:D004938', (178, 192))	('epithelial tumors', 'Disease', 'MESH:D002277', (117, 134))
390185	20562192	Conditional logistic regression models were used for the primary analyses of the association between circulating 25(OH)D and upper GI cancer risk, whereas unconditional models were used for stratified models.	('association', 'Interaction', (81, 92))	('GI cancer', 'Phenotype', 'HP:0007378', (131, 140))	('25(OH)D', 'Chemical', '-', (113, 120))	('upper GI cancer', 'Disease', (125, 140))	('circulating 25(OH)D', 'Var', (101, 120))	('upper GI cancer', 'Disease', 'MESH:D009369', (125, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
390199	20562192	The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study had the lowest median 25(OH)D concentration at 31.5 nmol/L among controls, whereas CLUE had the highest at 61.5 nmol/L.	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Alpha-Tocopherol', 'Chemical', 'MESH:D024502', (4, 20))	('Beta-Carotene', 'Chemical', 'MESH:D019207', (22, 35))	('lowest', 'NegReg', (68, 74))	('25(OH)D', 'Chemical', '-', (82, 89))	('Beta-Carotene', 'Var', (22, 35))
390209	20562192	Among never smokers, those in the lowest category of 25(OH)D concentrations were at lower risk of upper GI cancer compared with the reference group (OR = 0.55, 95% CI: 0.31, 0.96), with a statistically significant test for trend (P = 0.004).	('GI cancer', 'Phenotype', 'HP:0007378', (104, 113))	('upper GI cancer', 'Disease', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('25(OH)D', 'Chemical', '-', (53, 60))	('upper GI cancer', 'Disease', 'MESH:D009369', (98, 113))	('lower', 'NegReg', (84, 89))	('25(OH)D', 'Var', (53, 60))
390213	20562192	For example, subjects in the lowest category (<25 nmol/L) had a 47% (95% CI: 9, 69) lower risk of upper GI cancer than those in the referent group (50-<75 nmol/L).	('GI cancer', 'Phenotype', 'HP:0007378', (104, 113))	('upper GI cancer', 'Disease', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('<25 nmol/L', 'Var', (46, 56))	('upper GI cancer', 'Disease', 'MESH:D009369', (98, 113))	('lower', 'NegReg', (84, 89))
390216	20562192	Among Caucasians, no statistically significant associations were observed between circulating 25(OH)D and risk of upper GI cancer overall or in groups defined by sex or season.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('25(OH)D', 'Chemical', '-', (94, 101))	('circulating 25(OH)D', 'Var', (82, 101))	('upper GI cancer', 'Disease', (114, 129))	('GI cancer', 'Phenotype', 'HP:0007378', (120, 129))	('upper GI cancer', 'Disease', 'MESH:D009369', (114, 129))
390226	20562192	Among Asians, most of whom participated in the 2 Shanghai cohorts of Han Chinese, and among never smokers, the risk of cancer was statistically significantly lower for subjects with circulating concentrations of <50 nmol/L compared with those with higher concentrations.	('lower', 'NegReg', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('<50 nmol/L', 'Var', (212, 222))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
390258	28899457	Swainsonine Inhibits Invasion and the EMT Process in Esophageal Carcinoma Cells by Targeting Twist1 Esophageal cancer is a common gastrointestinal cancer, with a very high mortality rate in patients with metastasis.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('patients', 'Species', '9606', (190, 198))	('Carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('cancer', 'Disease', (111, 117))	('mortality', 'Disease', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Carcinoma', 'Disease', (64, 73))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (53, 73))	('Targeting', 'Var', (83, 92))	('Carcinoma', 'Disease', 'MESH:D009369', (64, 73))	('mortality', 'Disease', 'MESH:D003643', (172, 181))	('Swainsonine', 'Chemical', 'MESH:D017026', (0, 11))	('EMT Process', 'CPA', (38, 49))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (130, 153))	('Inhibits', 'NegReg', (12, 20))	('gastrointestinal cancer', 'Disease', (130, 153))	('Invasion', 'CPA', (21, 29))	('Twist1', 'Gene', (93, 99))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (130, 153))	('cancer', 'Disease', (147, 153))
390307	28899457	Because swainsonine inhibited cell invasion, we measured its effect on EMT using Western blot.	('swainsonine', 'Chemical', 'MESH:D017026', (8, 19))	('inhibited', 'NegReg', (20, 29))	('cell invasion', 'CPA', (30, 43))	('swainsonine', 'Var', (8, 19))
390310	28899457	As shown in Figure 3, swainsonine increased the expression of E-cadherin but decreased the expression of N-cadherin, vimentin, zinc finger E-box-binding homeobox 1 (ZEB1), and snail in a dose-dependent manner compared to the expressions of the same proteins in the control TGF-beta1-treated cells.	('expression', 'MPA', (91, 101))	('swainsonine', 'Var', (22, 33))	('TGF-beta1', 'Gene', '7040', (273, 282))	('ZEB1', 'Gene', (165, 169))	('expression', 'MPA', (48, 58))	('zinc finger E-box-binding homeobox 1', 'Gene', '6935', (127, 163))	('snail', 'Gene', '6615', (176, 181))	('increased', 'PosReg', (34, 43))	('N-cadherin', 'Gene', (105, 115))	('N-cadherin', 'Gene', '1000', (105, 115))	('zinc finger E-box-binding homeobox 1', 'Gene', (127, 163))	('swainsonine', 'Chemical', 'MESH:D017026', (22, 33))	('ZEB1', 'Gene', '6935', (165, 169))	('decreased', 'NegReg', (77, 86))	('vimentin', 'Gene', '7431', (117, 125))	('snail', 'Gene', (176, 181))	('vimentin', 'Gene', (117, 125))	('E-cadherin', 'Gene', (62, 72))	('TGF-beta1', 'Gene', (273, 282))	('E-cadherin', 'Gene', '999', (62, 72))
390315	28899457	Esophageal carcinoma cells were transfected with pEX or pEX-Twist1; untransfected cells served as control.	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (0, 20))	('Twist1', 'Gene', '7291', (60, 66))	('carcinoma', 'Disease', (11, 20))	('pEX', 'Var', (49, 52))	('carcinoma', 'Disease', 'MESH:D009369', (11, 20))	('Twist1', 'Gene', (60, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
390328	28899457	In the present study, we evaluated the effects of swainsonine on human esophageal carcinoma cell lines EC9706 and 293T in vitro and found that swainsonine inhibits invasion of these cells at 20, 50, and 100 mug/ml concentrations, with maximal effect at 50 mug/ml.	('human', 'Species', '9606', (65, 70))	('swainsonine', 'Var', (143, 154))	('inhibits', 'NegReg', (155, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('EC9706', 'CellLine', 'CVCL:E307', (103, 109))	('swainsonine', 'Chemical', 'MESH:D017026', (50, 61))	('invasion', 'CPA', (164, 172))	('293T', 'CellLine', 'CVCL:0063', (114, 118))	('esophageal carcinoma', 'Disease', (71, 91))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (71, 91))	('swainsonine', 'Chemical', 'MESH:D017026', (143, 154))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (71, 91))
390331	28899457	Apart from its effect on cell invasion, swainsonine has also been shown to decrease cancer cell growth and induce apoptosis via the mitochondrial pathway in lung cancer and esophageal cancer cells.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('esophageal cancer', 'Disease', (173, 190))	('lung cancer', 'Disease', (157, 168))	('swainsonine', 'Chemical', 'MESH:D017026', (40, 51))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('decrease', 'NegReg', (75, 83))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('apoptosis', 'CPA', (114, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('induce', 'PosReg', (107, 113))	('mitochondrial pathway', 'Pathway', (132, 153))	('swainsonine', 'Var', (40, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (173, 190))
390392	31897187	Elevated levels of serum SCC-Ag (>1.5 ng/ml), CEA (>5 ng/ml), CRP (>0.3 mg/dl), LDH (>250 U/l), and ALP (>350 U/l) at the time of BM diagnosis were observed in 68.8, 27.5, 75.4, 27.8, and 30.9% of patients, respectively.	('BM', 'Disease', 'MESH:D009362', (130, 132))	('ALP', 'Gene', '250', (100, 103))	('patients', 'Species', '9606', (197, 205))	('CRP', 'Gene', '1401', (62, 65))	('SCC', 'Disease', (25, 28))	('CEA', 'Gene', (46, 49))	('>250 U/l', 'Var', (85, 93))	('CEA', 'Gene', '1084', (46, 49))	('CRP', 'Gene', (62, 65))	('ALP', 'Gene', (100, 103))	('SCC', 'Disease', 'MESH:D002294', (25, 28))	('>350 U/l', 'Var', (105, 113))
390422	31897187	In turn, poor PS may prevent a patient from receiving further available treatment.	('patient', 'Species', '9606', (31, 38))	('poor PS', 'Var', (9, 16))	('prevent', 'NegReg', (21, 28))
390526	31428073	Body mass index (BMI) of DTC patients was significantly lower and the percentage of teeth with BOP was significantly higher than those in control subjects (P < 0.01).	('higher', 'PosReg', (117, 123))	('DTC', 'Phenotype', 'HP:0007378', (25, 28))	('patients', 'Species', '9606', (29, 37))	('BOP', 'Chemical', '-', (95, 98))	('teeth with BOP', 'Phenotype', 'HP:0000694', (84, 98))	('lower', 'NegReg', (56, 61))	('Body', 'MPA', (0, 4))	('DTC', 'Var', (25, 28))	('DTC', 'Chemical', '-', (25, 28))
390560	31428073	P. gingivalis, a periodontal pathogen included in these 11 species, plays a key role in the development of periodontitis by invasion of epithelial cells or by interfering with the host immunity.	('invasion', 'PosReg', (124, 132))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('interfering', 'NegReg', (159, 170))	('periodontitis', 'Phenotype', 'HP:0000704', (107, 120))	('periodontitis', 'Disease', 'MESH:D010518', (107, 120))	('men', 'Species', '9606', (99, 102))	('periodontitis', 'Disease', (107, 120))	('host immunity', 'CPA', (180, 193))
390612	28052030	The angiotensin II type 1 receptor antagonist telmisartan inhibits cell proliferation and tumor growth of esophageal adenocarcinoma via the AMPKa/mTOR pathway in vitro and in vivo Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB).	('mTOR', 'Gene', (146, 150))	('mTOR', 'Gene', '2475', (146, 150))	('esophageal adenocarcinoma via the AMPKa', 'Disease', (106, 145))	('telmisartan', 'Chemical', 'MESH:D000077333', (46, 57))	('tumor', 'Disease', (90, 95))	('hypertensive', 'Disease', 'MESH:D006973', (211, 223))	('angiotensin II type 1 receptor', 'Gene', '185', (4, 34))	('Telmisartan', 'Chemical', 'MESH:D000077333', (180, 191))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('angiotensin II type 1 (AT1) receptor', 'Gene', '185', (236, 272))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (106, 131))	('Telmisartan', 'Var', (180, 191))	('inhibits', 'NegReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('angiotensin II type 1 receptor', 'Gene', (4, 34))	('esophageal adenocarcinoma via the AMPKa', 'Disease', 'MESH:D004938', (106, 145))	('hypertensive', 'Disease', (211, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('cell proliferation', 'CPA', (67, 85))
390711	28052030	Activating AMPKalpha also suppressed cancer cell proliferation via increased expression of the cell cycle inhibitor p21.	('expression', 'MPA', (77, 87))	('p21', 'Gene', (116, 119))	('AMPKalpha', 'Chemical', '-', (11, 20))	('suppressed', 'NegReg', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('AMPKalpha', 'Gene', (11, 20))	('Activating', 'Var', (0, 10))	('increased', 'PosReg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('p21', 'Gene', '1026', (116, 119))
390723	28052030	The protein levels of p-p42/44 (Erk1/2) decreased in OE19 cells following telmisartan treatment, and these effects lasted for at least 48 h (Supplementary Figure 5B).	('protein levels', 'MPA', (4, 18))	('Erk1/2', 'Gene', (32, 38))	('telmisartan', 'Chemical', 'MESH:D000077333', (74, 85))	('Erk1/2', 'Gene', '5595;5594', (32, 38))	('p-p42/44', 'Var', (22, 30))	('decreased', 'NegReg', (40, 49))
390725	28052030	SCH772984 is a novel and selective inhibitor of ERK1/2 that displays characteristics of both type I and II kinase inhibitors.	('ERK1/2', 'Gene', '5595;5594', (48, 54))	('ERK1/2', 'Gene', (48, 54))	('SCH772984', 'Chemical', 'MESH:C587178', (0, 9))	('SCH772984', 'Var', (0, 9))
390727	28052030	In addition, SCH772984 did not affect telmisartan-induced down-regulation of cyclin D1 and cyclin E, even though the phosphorylation of Erk1/2 were obviously reduced by telmisartan.	('SCH772984', 'Var', (13, 22))	('Erk1/2', 'Gene', (136, 142))	('telmisartan', 'Chemical', 'MESH:D000077333', (169, 180))	('cyclin', 'Gene', '5111', (91, 97))	('cyclin', 'Gene', '5111', (77, 83))	('cyclin D1', 'Gene', '595', (77, 86))	('cyclin', 'Gene', (77, 83))	('cyclin', 'Gene', (91, 97))	('cyclin D1', 'Gene', (77, 86))	('phosphorylation', 'MPA', (117, 132))	('telmisartan', 'Chemical', 'MESH:D000077333', (38, 49))	('SCH772984', 'Chemical', 'MESH:C587178', (13, 22))	('down-regulation', 'NegReg', (58, 73))	('Erk1/2', 'Gene', '5595;5594', (136, 142))	('reduced', 'NegReg', (158, 165))
390731	28052030	Other PPAR-gamma partial agonists also inhibit cancer cell proliferation by inducing cell cycle arrest.	('cell cycle arrest', 'CPA', (85, 102))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('PPAR-gamma', 'Gene', (6, 16))	('inhibit', 'NegReg', (39, 46))	('cancer', 'Disease', (47, 53))	('PPAR-gamma', 'Gene', '5468', (6, 16))	('inducing', 'Reg', (76, 84))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('partial agonists', 'Var', (17, 33))
390765	28052030	However, the expression of p-AMPKalpha was induced by telmisartan, and this effect was slightly attenuated by miR-301a-3p (Supplementary Figure 6).	('p-AMPKalpha', 'Chemical', '-', (27, 38))	('miR-301a', 'Gene', (110, 118))	('expression', 'MPA', (13, 23))	('induced', 'Reg', (43, 50))	('telmisartan', 'Chemical', 'MESH:D000077333', (54, 65))	('miR-301a', 'Gene', '407027', (110, 118))	('p-AMPKalpha', 'Var', (27, 38))
390785	28052030	Primary antibodies used for western blot analyses were obtained from the following sources: beta-actin antibody was obtained from Sigma-Aldrich (St. Louis, MO, USA); cyclin D1 and cyclin E antibodies were obtained from Thermo Fisher Scientific (Waltham, MA, USA); Cdk6, Cdk2, and Cdk4 antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA); phosphorylated retinoblastoma protein and p27Kip1 antibodies were obtained from BD Biosciences Pharmingen (San Jose, CA, USA); PPAR-gamma (ab19481), E2F2 (ab65222), and AT1 receptor (ab9391) antibodies were purchased from Abcam (Abcam, USA); AMPKalpha (#5832), p-AMPKalpha Thr172 (#2535), LKB1 (#3047), p-LKB1 Ser428 (#3482), CaMKK (#4436), mTOR (#2983), p-mTOR Ser2448 (#5536), p70S6K (#2708), p-p70S6K Thr389 (#9205), Akt (#4685), p-Akt Ser473 (#4060), p21Waf1/Cip1 (#2947), p-Erk1/2 (#4370), and Erk1/2 (#4695) antibodies were purchased from Cell Signaling Technology (Boston, MA, USA).	('p-AMPKalpha', 'Chemical', '-', (624, 635))	('mTOR', 'Gene', '2475', (704, 708))	('Erk1/2', 'Gene', '5595;5594', (862, 868))	('LKB1', 'Gene', '6794', (652, 656))	('beta-actin', 'Gene', (92, 102))	('E2F2', 'Gene', '1870', (512, 516))	('p21', 'Gene', (818, 821))	('p27Kip1', 'Gene', (405, 412))	('cyclin', 'Gene', '5111', (180, 186))	('mTOR', 'Gene', '2475', (720, 724))	('p70S6K', 'Gene', '6198', (742, 748))	('PPAR-gamma', 'Gene', (490, 500))	('Erk1/2', 'Gene', (842, 848))	('#4685', 'Var', (788, 793))	('Cip1', 'Gene', '1026', (826, 830))	('#4060', 'Var', (810, 815))	('cyclin', 'Gene', '5111', (166, 172))	('LKB1', 'Gene', '6794', (668, 672))	('p27Kip1', 'Gene', '1027', (405, 412))	('Akt', 'Gene', (798, 801))	('cyclin D1', 'Gene', (166, 175))	('CaMKK', 'Gene', '10645', (689, 694))	('retinoblastoma', 'Phenotype', 'HP:0009919', (378, 392))	('AMPKalpha', 'Chemical', '-', (605, 614))	('AT1', 'Gene', (532, 535))	('Akt', 'Gene', '207', (798, 801))	('p70S6K', 'Gene', (760, 766))	('#2947', 'Var', (832, 837))	('retinoblastoma', 'Disease', (378, 392))	('Cdk6', 'Gene', (264, 268))	('cyclin', 'Gene', (180, 186))	('Cdk6', 'Gene', '1021', (264, 268))	('Cdk4', 'Gene', (280, 284))	('Akt', 'Gene', (783, 786))	('LKB1', 'Gene', (652, 656))	('cyclin D1', 'Gene', '595', (166, 175))	('p21', 'Gene', '1026', (818, 821))	('beta-actin', 'Gene', '728378', (92, 102))	('Cdk2', 'Gene', '1017', (270, 274))	('#4370', 'Var', (850, 855))	('cyclin', 'Gene', (166, 172))	('AMPKalpha', 'Chemical', '-', (626, 635))	('Thr172', 'Chemical', '-', (636, 642))	('Erk1/2', 'Gene', (862, 868))	('#5536', 'Var', (734, 739))	('Cdk2', 'Gene', (270, 274))	('Erk1/2', 'Gene', '5595;5594', (842, 848))	('p70S6K', 'Gene', (742, 748))	('CaMKK', 'Gene', (689, 694))	('LKB1', 'Gene', (668, 672))	('Akt', 'Gene', '207', (783, 786))	('AT1', 'Gene', '185', (532, 535))	('PPAR-gamma', 'Gene', '5468', (490, 500))	('mTOR', 'Gene', (704, 708))	('Cip1', 'Gene', (826, 830))	('Cdk4', 'Gene', '1019', (280, 284))	('p70S6K', 'Gene', '6198', (760, 766))	('retinoblastoma', 'Disease', 'MESH:D012175', (378, 392))	('E2F2', 'Gene', (512, 516))	('mTOR', 'Gene', (720, 724))
390992	33912449	Fourteen patients were excluded, and the exclusion criteria were as follows: the patients had contraindications to MRI, or patients had a greater area of internal necrosis caused by lesions, or the images had severe motion artifacts.	('patients', 'Species', '9606', (9, 17))	('lesions', 'Var', (182, 189))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (123, 131))	('necrosis', 'Disease', (163, 171))	('internal necrosis', 'Phenotype', 'HP:0010885', (154, 171))	('necrosis', 'Disease', 'MESH:D009336', (163, 171))
391060	31354293	Besides, co-transfection of FAK can attenuate the function of miR-4324 mimic.	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('attenuate', 'NegReg', (36, 45))	('function', 'MPA', (50, 58))	('co-transfection', 'Var', (9, 24))
391076	31354293	More than 30% of human genes can be regulated by various miRNAs, and it has been confirmed that abnormal miRNA expression is involved in the tumorigenesis and development of numerous malignancies.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('miR', 'Gene', (105, 108))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('abnormal', 'Var', (96, 104))	('human', 'Species', '9606', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('numerous malignancies', 'Disease', 'MESH:D009369', (174, 195))	('tumor', 'Disease', (141, 146))	('numerous malignancies', 'Disease', (174, 195))	('involved', 'Reg', (125, 133))	('miR', 'Gene', '220972', (105, 108))
391095	31354293	The 3'UTR of FAK gene that was wildtype (FAK-WT) and mutated at the miR-4324 binding-site (FAK-MT) was cloned into the pGL3-basic vector.	('pGL3', 'Gene', '6391', (119, 123))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', (68, 71))	('mutated', 'Var', (53, 60))	('pGL3', 'Gene', (119, 123))	('FAK gene', 'Gene', (13, 21))
391109	31354293	Bioinformatic analysis reveals one potential miR-4324 binding site in the 3' UTR (untranslated regions) of FAK mRNA (988-1008 amino acid, Figure 2A).	('miR', 'Gene', (45, 48))	('binding', 'Interaction', (54, 61))	('988-1008 amino acid', 'Var', (117, 136))	('miR', 'Gene', '220972', (45, 48))
391110	31354293	Dual-Luciferase reporter assay system with plasmids containing WT (pGL3-FAK-WT) or mutated (pGL3-FAK-MT) FAK mRNA 3'UTR was employed to validate the specific and direct binding between miR-4324 and FAK mRNA.	('mutated', 'Var', (83, 90))	('pGL3', 'Gene', '6391', (92, 96))	('binding', 'Interaction', (169, 176))	('miR', 'Gene', '220972', (185, 188))	('pGL3', 'Gene', (67, 71))	('pGL3', 'Gene', (92, 96))	('miR', 'Gene', (185, 188))	('pGL3', 'Gene', '6391', (67, 71))
391112	31354293	Besides, the intracellular FAK significantly decreased after miR-4324 mimic transfection in both mRNA (Figure 2C, **p<0.01) and protein levels (Figure 2D).	('mRNA', 'MPA', (97, 101))	('miR', 'Gene', '220972', (61, 64))	('intracellular FAK', 'MPA', (13, 30))	('miR', 'Gene', (61, 64))	('decreased', 'NegReg', (45, 54))	('transfection', 'Var', (76, 88))
391119	31354293	As the downregulation of E-cadherin and upregulation of N-cadherin & Vimentin are principal characterizations of cellular EMT, these results indicate that miR-4324 mimic can significantly prevent the EMT process in ESCC cells, and the downregulation of FAK is involved in this EMT preventing effect.	('the EMT process', 'CPA', (196, 211))	('N-cadherin', 'Gene', (56, 66))	('downregulation', 'NegReg', (7, 21))	('miR', 'Gene', '220972', (155, 158))	('E-cadherin', 'Gene', (25, 35))	('that', 'Var', (150, 154))	('miR', 'Gene', (155, 158))	('significantly', 'NegReg', (174, 187))	('N-cadherin', 'Gene', '1000', (56, 66))	('E-cadherin', 'Gene', '999', (25, 35))
391125	31354293	Presently, aberrant expression of FAK has been reported in a variety of malignancies.	('aberrant expression', 'Var', (11, 30))	('FAK', 'Gene', (34, 37))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('malignancies', 'Disease', (72, 84))	('reported', 'Reg', (47, 55))
391140	31354293	Besides, the vital functions of miR-4324/FAK axis were verified by statistically analyzing the relevance between their tumoral expression and patient-clinic-pathological characteristics, with the results demonstrating that low miR-4324 and high FAK expression are, respectively, associated with poor cell differentiation, tumor size and invasion, as well as numbers of metastatic lymph nodes.	('miR', 'Gene', (32, 35))	('expression', 'MPA', (249, 259))	('tumor', 'Disease', (119, 124))	('patient', 'Species', '9606', (142, 149))	('poor cell differentiation', 'CPA', (295, 320))	('high FAK', 'Var', (240, 248))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('associated', 'Reg', (279, 289))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('low', 'NegReg', (223, 226))	('miR', 'Gene', '220972', (227, 230))	('miR', 'Gene', (227, 230))	('tumor', 'Disease', (322, 327))	('invasion', 'CPA', (337, 345))	('miR', 'Gene', '220972', (32, 35))
391183	30680257	The case listing session of the SEER*Stat 8.2.1 software package was used to identify patients diagnosed with cancer of the esophagus and gastric cardia via "primary site" codes C15.0-C16.0 from 1973-2009 (SEER data entry starts in 1973).	('cancer', 'Disease', (110, 116))	('gastric cardia', 'Disease', (138, 152))	('C15.0-C16.0', 'Var', (178, 189))	('gastric cardia', 'Disease', 'MESH:D004938', (138, 152))	('cancer of the esophagus', 'Phenotype', 'HP:0100751', (110, 133))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('patients', 'Species', '9606', (86, 94))
391320	29844511	For gene GAPDH (35905_s_at), it was shown that the levels of GAPDH protein were significantly up-regulated in lung squamous cell carcinoma tissues by clinical tissue studies.	('levels', 'MPA', (51, 57))	('GAPDH', 'Gene', '2597', (9, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('up-regulated', 'PosReg', (94, 106))	('35905_s_at', 'Var', (16, 26))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 138))	('lung squamous cell carcinoma', 'Disease', (110, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('GAPDH', 'Gene', (9, 14))	('protein', 'Protein', (67, 74))	('GAPDH', 'Gene', '2597', (61, 66))	('GAPDH', 'Gene', (61, 66))
391322	29844511	IGHV4-31 (37864_s_at) has been detected as a candidate gene in peripheral blood mononuclear cells (PBMC) and tumor tissue groups of non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', (132, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('37864_s_at', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (132, 158))	('IGHV4-31', 'Gene', '28396', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('IGHV4-31', 'Gene', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (132, 158))	('tumor', 'Disease', (109, 114))
391323	29844511	CYAT1 (33273_f_at) is one of the most frequently ranked genes responsible for that clustering through the method proposed by Mondal et al.	('CYAT1', 'Gene', '100290481', (0, 5))	('33273_f_at', 'Var', (7, 17))	('CYAT1', 'Gene', (0, 5))
391324	29844511	reported perfect classification accuracy with only 3 genes: 37947_at, 33499_s_at (IGHA2) and 36528_at on the lung cancer dataset, indicating that these 3 genes are very crucial for lung cancer.	('36528_at', 'Var', (93, 101))	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('IGHA2', 'Gene', '3494', (82, 87))	('37947_at', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('IGHA2', 'Gene', (82, 87))	('33499_s_at', 'Var', (70, 80))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
391333	29844511	FOS (J04130_s_at) has a significant function in regulating cell proliferation, cell differentiation and cell transformation in leukemia and it was detected and validated in the paper.	('J04130_s_at', 'Var', (5, 16))	('FOS', 'Gene', (0, 3))	('leukemia', 'Disease', (127, 135))	('cell differentiation', 'CPA', (79, 99))	('leukemia', 'Disease', 'MESH:D007938', (127, 135))	('cell transformation', 'CPA', (104, 123))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('cell proliferation', 'CPA', (59, 77))	('FOS', 'Gene', '2353', (0, 3))
391334	29844511	Immune-related gene LYZ (U49835_s_at) were highly expressed in THP1 cells in leukemia.	('LYZ', 'Gene', (20, 23))	('leukemia', 'Disease', (77, 85))	('leukemia', 'Phenotype', 'HP:0001909', (77, 85))	('leukemia', 'Disease', 'MESH:D007938', (77, 85))	('LYZ', 'Gene', '4069', (20, 23))	('U49835_s_at', 'Var', (25, 36))	('THP1', 'CellLine', 'CVCL:0006', (63, 67))
391335	29844511	According to, as a direct target of activated NOTCH1, CCND3 (M21624_at) is up-regulated in T-cell acute lymphoblastic leukemia.	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (104, 126))	('NOTCH1', 'Gene', '4851', (46, 52))	('NOTCH1', 'Gene', (46, 52))	('CCND3', 'Gene', '896', (54, 59))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (91, 126))	('CCND3', 'Gene', (54, 59))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (91, 126))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('T-cell acute lymphoblastic leukemia', 'Disease', (91, 126))	('up-regulated', 'PosReg', (75, 87))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (98, 126))	('M21624_at', 'Var', (61, 70))
391336	29844511	By mediating JUNB (X60486_at), miRNA-149 promotes cell proliferation and inhibits apoptosis in T-cell acute lymphoblastic leukemia.	('JUNB', 'Gene', '3726', (13, 17))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (108, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('apoptosis', 'CPA', (82, 91))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (95, 130))	('promotes', 'PosReg', (41, 49))	('inhibits', 'NegReg', (73, 81))	('JUNB', 'Gene', (13, 17))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (95, 130))	('T-cell acute lymphoblastic leukemia', 'Disease', (95, 130))	('X60486_at', 'Var', (19, 28))	('miRNA-149', 'Gene', (31, 40))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (102, 130))	('cell proliferation', 'CPA', (50, 68))
391349	29844511	In GO:0007010 and GO:0034109, SLDSF has the best performance, same as PMD.	('PMD', 'Disease', 'MESH:D020371', (70, 73))	('GO:0007010', 'Var', (3, 13))	('GO:0034109', 'Var', (18, 28))	('PMD', 'Disease', (70, 73))
391352	29844511	In, MUC17, MUC5B and MUC6 gene mutations in tumor region T4A of esophageal squamous cell carcinoma predict the perturbation of O-glycan biosynthesis and processing.	('MUC6', 'Gene', (21, 25))	('MUC17', 'Gene', '140453', (4, 9))	('processing', 'MPA', (153, 163))	('mutations', 'Var', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal squamous cell carcinoma', 'Disease', (64, 98))	('O-glycan', 'Chemical', '-', (127, 135))	('MUC5B', 'Gene', '727897', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('MUC6', 'Gene', '4588', (21, 25))	('MUC5B', 'Gene', (11, 16))	('MUC17', 'Gene', (4, 9))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('O-glycan biosynthesis', 'MPA', (127, 148))	('T4A', 'Mutation', 'c.4T>A', (57, 60))	('tumor', 'Disease', (44, 49))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (64, 98))
391359	29844511	Furthermore, expression of certain CD44 variants may be important molecular markers for HNSC progression.	('CD44', 'Gene', (35, 39))	('expression', 'MPA', (13, 23))	('variants', 'Var', (40, 48))	('HNSC', 'Disease', (88, 92))	('CD44', 'Gene', '960', (35, 39))
391369	29844511	Variations in ferritin subunit composition may affect the rates of iron uptake and release in different tissues.	('rates', 'MPA', (58, 63))	('iron uptake', 'MPA', (67, 78))	('ferritin subunit', 'Protein', (14, 30))	('affect', 'Reg', (47, 53))	('Variations', 'Var', (0, 10))	('iron', 'Chemical', 'MESH:D007501', (67, 71))	('release', 'MPA', (83, 90))
391371	29844511	Defects in this light chain ferritin gene are associated with several neurodegenerative diseases and hyperferritinemia-cataract syndrome.	('neurodegenerative diseases', 'Disease', (70, 96))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (70, 96))	('cataract', 'Phenotype', 'HP:0000518', (119, 127))	('associated', 'Reg', (46, 56))	('Defects', 'Var', (0, 7))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (70, 96))	('hyperferritinemia', 'Phenotype', 'HP:0003281', (101, 118))	('hyperferritinemia-cataract syndrome', 'Disease', (101, 136))	('hyperferritinemia-cataract syndrome', 'Disease', 'MESH:C538137', (101, 136))
391376	29844511	Mutations in this gene cause Baraitser-Winter syndrome 1, which is characterized by intellectual disability with a distinctive facial appearance in human patients.	('Baraitser-Winter syndrome', 'Disease', 'OMIM:243310', (29, 54))	('patients', 'Species', '9606', (154, 162))	('human', 'Species', '9606', (148, 153))	('Mutations', 'Var', (0, 9))	('intellectual disability', 'Phenotype', 'HP:0001249', (84, 107))	('cause', 'Reg', (23, 28))	('Baraitser-Winter syndrome', 'Disease', (29, 54))
391378	29844511	Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis.	('Ehlers-Danlos syndrome type VIIA', 'Disease', (79, 111))	('osteogenesis imperfecta', 'Disease', 'MESH:D010013', (43, 66))	('Ehlers-Danlos syndrome Classical type', 'Disease', 'MESH:C536194', (113, 150))	('associated', 'Reg', (27, 37))	('idiopathic osteoporosis', 'Disease', 'MESH:C537700', (171, 194))	('Ehlers-Danlos syndrome Classical type', 'Disease', (113, 150))	('Ehlers-Danlos syndrome type VIIA', 'Disease', 'MESH:C562625', (79, 111))	('osteoporosis', 'Phenotype', 'HP:0000939', (182, 194))	('Mutations', 'Var', (0, 9))	('Caffey Disease', 'Disease', (152, 166))	('idiopathic osteoporosis', 'Disease', (171, 194))	('osteogenesis imperfecta', 'Disease', (43, 66))
391381	29844511	Mutations in this gene and keratin 4 have been associated with the autosomal dominant disorder White Sponge Nevus.	('keratin 4', 'Gene', (27, 36))	('autosomal dominant disorder White Sponge Nevus', 'Disease', (67, 113))	('autosomal dominant disorder White Sponge Nevus', 'Disease', 'MESH:D056784', (67, 113))	('Mutations', 'Var', (0, 9))	('Sponge Nevus', 'Phenotype', 'HP:0025510', (101, 113))	('associated', 'Reg', (47, 57))	('keratin 4', 'Gene', '3851', (27, 36))	('Nevus', 'Phenotype', 'HP:0003764', (108, 113))
391432	29207862	Type 1 g-NETs are associated with chronic atrophic gastritis (autoimmune destruction of gastric parietal cells) and auto-antibodies to either intrinsic factor or parietal cells (rarely both), also described as pernicious anaemia, leading to gastric achlorhydria and hypergastrinaemia (via loss of feedback mechanism).	('NETs', 'Phenotype', 'HP:0100634', (9, 13))	('chronic atrophic gastritis', 'Disease', 'MESH:D005757', (34, 60))	('anaemia', 'Phenotype', 'HP:0001903', (221, 228))	('chronic atrophic gastritis', 'Disease', (34, 60))	('gastritis', 'Phenotype', 'HP:0005263', (51, 60))	('associated', 'Reg', (18, 28))	('gastric achlorhydria and hypergastrinaemia', 'Disease', 'MESH:D000126', (241, 283))	('chronic atrophic gastritis', 'Phenotype', 'HP:0002582', (34, 60))	('leading to', 'Reg', (230, 240))	('anaemia', 'Disease', 'MESH:D000740', (221, 228))	('achlorhydria', 'Phenotype', 'HP:0032448', (249, 261))	('auto-antibodies', 'Var', (116, 131))	('anaemia', 'Disease', (221, 228))
391498	29207862	Germline testing allows confirmation of MEN-1 and enables family screening for a specific MEN-1 related mutation.	('MEN-1', 'Gene', '4221', (40, 45))	('MEN-1', 'Gene', (40, 45))	('mutation', 'Var', (104, 112))	('MEN-1', 'Gene', '4221', (90, 95))	('MEN-1', 'Gene', (90, 95))
391503	29207862	Surgery (local resection with lymphadenectomy or pancreaticoduodenectomy) is usually employed for patients with duodenal gastrinomas or large d-NETs (usually >2 cm); d-NETs invading beyond the submucosa; lymph node metastases; or d-NET in the peri-ampullary region.	('pancreatic', 'Disease', (49, 59))	('patients', 'Species', '9606', (98, 106))	('metastases', 'Disease', (215, 225))	('NETs', 'Phenotype', 'HP:0100634', (144, 148))	('gastrinomas', 'Disease', 'MESH:D015408', (121, 132))	('metastases', 'Disease', 'MESH:D009362', (215, 225))	('NETs', 'Phenotype', 'HP:0100634', (168, 172))	('gastrinomas', 'Disease', (121, 132))	('pancreatic', 'Disease', 'MESH:D010195', (49, 59))	('d-NETs', 'Var', (166, 172))
391508	29207862	For d-NETs associated with a functional syndrome (<10% of patients), appropriate specific therapy for control of hormone excess state should be commenced, such as: SSA therapy for carcinoid syndrome; and PPI treatment for Zollinger Ellison syndrome.	('functional syndrome', 'Disease', (29, 48))	('carcinoid syndrome', 'Disease', 'MESH:D002276', (180, 198))	('PPI', 'Var', (204, 207))	('associated', 'Reg', (11, 21))	('Zollinger Ellison syndrome', 'Disease', 'MESH:D015043', (222, 248))	('carcinoid syndrome', 'Disease', (180, 198))	('functional syndrome', 'Disease', 'MESH:D003109', (29, 48))	('Zollinger Ellison syndrome', 'Disease', (222, 248))	('carcinoid', 'Phenotype', 'HP:0100570', (180, 189))	('NETs', 'Phenotype', 'HP:0100634', (6, 10))	('Zollinger Ellison syndrome', 'Phenotype', 'HP:0002044', (222, 248))	('hormone excess', 'Phenotype', 'HP:0000845', (113, 127))	('patients', 'Species', '9606', (58, 66))
391513	26919254	Methylation of DACT2 accelerates esophageal cancer development by activating Wnt signaling Esophageal cancer is one of the most common malignancies worldwide.	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Wnt signaling', 'Pathway', (77, 90))	('Methylation', 'Var', (0, 11))	('DACT2', 'Gene', (15, 20))	('Esophageal cancer', 'Disease', (91, 108))	('activating', 'PosReg', (66, 76))	('accelerates', 'PosReg', (21, 32))	('esophageal cancer', 'Disease', (33, 50))	('malignancies', 'Disease', 'MESH:D009369', (135, 147))	('Esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('DACT2', 'Gene', '168002', (15, 20))	('malignancies', 'Disease', (135, 147))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
391517	26919254	The expression of DACT2 was detected in YES2 cells, while reduced DACT2 expression levels were found in TE8 and KYSE70 cells, and complete loss of DACT2 expression was found in KYSE30, KYSE140, KYSE150, KYSE410, KYSE450, TE3 and TE7 cells.	('YES2', 'Gene', '7526', (40, 44))	('YES2', 'Gene', (40, 44))	('KYSE140', 'Var', (185, 192))	('expression', 'Species', '29278', (4, 14))	('KYSE70', 'Var', (112, 118))	('KYSE450', 'Var', (212, 219))	('DACT2 expression levels', 'MPA', (66, 89))	('loss', 'NegReg', (139, 143))	('expression', 'Species', '29278', (72, 82))	('reduced', 'NegReg', (58, 65))	('expression', 'Species', '29278', (153, 163))	('KYSE150', 'Var', (194, 201))	('expression', 'MPA', (153, 163))	('DACT2', 'Gene', (147, 152))	('KYSE410', 'Var', (203, 210))	('KYSE30', 'Var', (177, 183))
391520	26919254	In human primary esophageal squamous carcinoma, 69% (87/126) of samples were methylated.	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (17, 46))	('esophageal squamous carcinoma', 'Disease', (17, 46))	('human', 'Species', '9606', (3, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (28, 46))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (17, 46))	('methylated', 'Var', (77, 87))
391521	26919254	Methylation of DACT2 was significantly associated with tumor stage and metastasis (P < 0.01, P < 0.05).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Methylation', 'Var', (0, 11))	('DACT2', 'Gene', (15, 20))	('tumor', 'Disease', (55, 60))	('metastasis', 'CPA', (71, 81))	('associated', 'Reg', (39, 49))
391536	26919254	Both genetic and epigenetic changes are involved in the development of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('epigenetic changes', 'Var', (17, 35))	('esophageal cancer', 'Disease', (71, 88))	('involved', 'Reg', (40, 48))
391541	26919254	DACT2 silencing by promoter region hypermethylation was detected in many tumor types including lung, gastric, hepatocellular and thyroid cancers.	('hypermethylation', 'Var', (35, 51))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('thyroid cancers', 'Disease', 'MESH:D013964', (129, 144))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('silencing', 'NegReg', (6, 15))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('tumor', 'Disease', (73, 78))	('hepatocellular', 'Disease', (110, 124))	('DACT2', 'Gene', (0, 5))	('gastric', 'Disease', (101, 108))	('lung', 'Disease', (95, 99))	('thyroid cancers', 'Disease', (129, 144))
391545	26919254	DACT2 expression was detected in YES2 cells, while expression of DACT2 was reduced in TE8 and KYSE70 cells, and no expression was detected in KYSE30, KYSE140, KYSE150, KYSE410, KYSE450, TE3 and TE7 cells (Figure 1A).	('KYSE150', 'Var', (159, 166))	('expression', 'Species', '29278', (6, 16))	('YES2', 'Gene', (33, 37))	('expression', 'MPA', (6, 16))	('expression', 'Species', '29278', (51, 61))	('expression', 'Species', '29278', (115, 125))	('reduced', 'NegReg', (75, 82))	('DACT2', 'Gene', (65, 70))	('expression', 'MPA', (51, 61))	('DACT2', 'Gene', (0, 5))	('KYSE30', 'Var', (142, 148))	('YES2', 'Gene', '7526', (33, 37))	('KYSE140', 'Var', (150, 157))	('KYSE70', 'Var', (94, 100))
391549	26919254	As expected, re-expression of DACT2 was found in KYSE30, KYSE140, KYSE150, KYSE410, KYSE450, TE3 and TE7 cells after 5-Aza treatment, and increased expression of DACT2 was detected in TE8 and KYSE70 cells (Figure 1A).	('KYSE150', 'Var', (66, 73))	('KYSE140', 'Var', (57, 64))	('KYSE410', 'Var', (75, 82))	('5-Aza', 'Chemical', '-', (117, 122))	('expression', 'Species', '29278', (148, 158))	('DACT2', 'Gene', (30, 35))	('re-expression', 'PosReg', (13, 26))	('KYSE30', 'Var', (49, 55))	('expression', 'Species', '29278', (16, 26))	('KYSE450', 'Var', (84, 91))
391550	26919254	These results demonstrated that DACT2 expression is regulated by promoter region methylation in human esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('expression', 'Species', '29278', (38, 48))	('methylation', 'Var', (81, 92))	('expression', 'MPA', (38, 48))	('human', 'Species', '9606', (96, 101))	('DACT2', 'Gene', (32, 37))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('regulated', 'Reg', (52, 61))
391552	26919254	Dense methylation was observed in the promoter region of DACT2 in KYSE150 and KYSE450 cells, while partial methylation was detected in KYSE70 cells and unmethylation was found in YES2 cells (Figure 1C).	('KYSE450', 'Var', (78, 85))	('YES2', 'Gene', '7526', (179, 183))	('methylation', 'MPA', (6, 17))	('YES2', 'Gene', (179, 183))	('DACT2', 'Gene', (57, 62))
391555	26919254	69% (87/126) of primary esophageal cancer samples, 35.7% (15/42) of dysplasia samples were methylated and no methylation (0/27) was found in normal esophageal mucosa.	('primary esophageal cancer', 'Disease', (16, 41))	('methylated', 'Var', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('primary esophageal cancer', 'Disease', 'MESH:D004938', (16, 41))	('dysplasia', 'Disease', (68, 77))	('dysplasia', 'Disease', 'MESH:D004476', (68, 77))
391556	26919254	Methylation of DACT2 was significantly associated with tumor stage and lymph node metastasis (Table 1, P < 0.01, P < 0.05), while no association was found between DACT2 methylation and gender, age, differentiation and tumor size (all P > 0.05).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('DACT2', 'Gene', (15, 20))	('tumor', 'Disease', (55, 60))	('lymph node metastasis', 'CPA', (71, 92))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('associated', 'Reg', (39, 49))	('tumor', 'Disease', (218, 223))
391561	26919254	These results indicate that the expression of DACT2 is regulated by promoter region methylation in primary esophageal cancer.	('regulated', 'Reg', (55, 64))	('primary esophageal cancer', 'Disease', (99, 124))	('DACT2', 'Gene', (46, 51))	('methylation', 'Var', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'Species', '29278', (32, 42))	('primary esophageal cancer', 'Disease', 'MESH:D004938', (99, 124))	('expression', 'MPA', (32, 42))
391565	26919254	The effect of DACT2 on cell growth was further validated by knocking down DACT2 in YES2 cells.	('YES2', 'Gene', (83, 87))	('DACT2', 'Gene', (74, 79))	('knocking down', 'Var', (60, 73))	('YES2', 'Gene', '7526', (83, 87))
391566	26919254	The OD values were 0.787 +- 0.022 vs. 0.876 +- 0.033 (P < 0.001) before and after knockdown DACT2 in YES2 cells (Figure 3A).	('DACT2', 'Gene', (92, 97))	('YES2', 'Gene', (101, 105))	('knockdown', 'Var', (82, 91))	('YES2', 'Gene', '7526', (101, 105))
391567	26919254	Cell viability was increased after knockdown of DACT2 in YES2 cells.	('knockdown', 'Var', (35, 44))	('YES2', 'Gene', (57, 61))	('Cell viability', 'CPA', (0, 14))	('increased', 'PosReg', (19, 28))	('YES2', 'Gene', '7526', (57, 61))	('DACT2', 'Gene', (48, 53))
391571	26919254	The effect of DACT2 on clonogenicity was further validated by knocking down DACT2 in YES2 cells.	('YES2', 'Gene', (85, 89))	('YES2', 'Gene', '7526', (85, 89))	('DACT2', 'Gene', (76, 81))	('knocking down', 'Var', (62, 75))
391572	26919254	The clone number was 129.3 +- 17.0 vs. 200.3 +- 4.5 (P < 0.01) before and after knockdown of DACT2 in YES2 cells (Figure 3B).	('knockdown', 'Var', (80, 89))	('YES2', 'Gene', (102, 106))	('YES2', 'Gene', '7526', (102, 106))	('DACT2', 'Gene', (93, 98))
391574	26919254	The G2/M phase was significantly different before and after re-expression of DACT2 in KYSE150 cells (P < 0.001).	('G2/M phase', 'CPA', (4, 14))	('expression', 'Species', '29278', (63, 73))	('re-expression', 'Var', (60, 73))	('DACT2', 'Gene', (77, 82))	('different', 'Reg', (33, 42))
391576	26919254	The G2/M phase was significantly different before and after re-expression of DACT2 in KYSE450 cells (P < 0.05).	('G2/M phase', 'CPA', (4, 14))	('expression', 'Species', '29278', (63, 73))	('re-expression', 'Var', (60, 73))	('DACT2', 'Gene', (77, 82))	('different', 'Reg', (33, 42))
391577	26919254	The effect of DACT2 on cell cycle was further validated by knocking down DACT2 in DACT2 highly expressed YES2 cells.	('YES2', 'Gene', (105, 109))	('DACT2', 'Gene', (73, 78))	('DACT2', 'Gene', (82, 87))	('YES2', 'Gene', '7526', (105, 109))	('knocking down', 'Var', (59, 72))
391578	26919254	The G2/M phase was significantly reduced by knocking down DACT2 in YES2 cells (P < 0.05, Figure 3C).	('G2/M phase', 'CPA', (4, 14))	('YES2', 'Gene', (67, 71))	('YES2', 'Gene', '7526', (67, 71))	('reduced', 'NegReg', (33, 40))	('DACT2', 'Gene', (58, 63))	('knocking down', 'Var', (44, 57))
391581	26919254	The levels of cyclinB1, CDC2 and p-CDC2 (Y15) were examined as well before and after knockdown of DACT2 in YES2 cells.	('CDC2', 'Gene', (24, 28))	('cyclinB1', 'Gene', (14, 22))	('cyclinB1', 'Gene', '891', (14, 22))	('CDC2', 'Gene', '983', (24, 28))	('CDC2', 'Gene', '983', (35, 39))	('DACT2', 'Gene', (98, 103))	('YES2', 'Gene', '7526', (107, 111))	('CDC2', 'Gene', (35, 39))	('knockdown', 'Var', (85, 94))	('YES2', 'Gene', (107, 111))
391582	26919254	The levels of cyclinB1 and CDC2 were increased, and the levels of p-CDC (Y15) were reduced after knockdown of DACT2 in YES2 cells.	('YES2', 'Gene', '7526', (119, 123))	('levels', 'MPA', (4, 10))	('knockdown', 'Var', (97, 106))	('CDC2', 'Gene', '983', (27, 31))	('DACT2', 'Gene', (110, 115))	('CDC2', 'Gene', (27, 31))	('reduced', 'NegReg', (83, 90))	('cyclinB1', 'Gene', (14, 22))	('cyclinB1', 'Gene', '891', (14, 22))	('YES2', 'Gene', (119, 123))	('increased', 'PosReg', (37, 46))
391586	26919254	The cell number was reduced significantly after re-expression of DACT2 in KYSE150 and KYSE450 cells (P < 0.001 for both, Figure 4A).	('reduced', 'NegReg', (20, 27))	('expression', 'Species', '29278', (51, 61))	('KYSE450', 'Var', (86, 93))	('cell number', 'CPA', (4, 15))	('re-expression', 'Var', (48, 61))	('DACT2', 'Gene', (65, 70))
391587	26919254	The number of migratory cells was 208.67 +- 16.29 vs. 350 +- 10 before and after knockdown of DACT2 in YES2 cells.	('DACT2', 'Gene', (94, 99))	('knockdown', 'Var', (81, 90))	('YES2', 'Gene', (103, 107))	('YES2', 'Gene', '7526', (103, 107))
391588	26919254	The cell number was increased significantly after knockdown of DACT2 in YES2 cells (P < 0.001, Figure 4A).	('YES2', 'Gene', (72, 76))	('increased', 'PosReg', (20, 29))	('knockdown', 'Var', (50, 59))	('cell number', 'CPA', (4, 15))	('YES2', 'Gene', '7526', (72, 76))	('DACT2', 'Gene', (63, 68))
391591	26919254	The invasive cell number was reduced significantly after re-expression of DACT2 in KYSE150 and KYSE450 cells (P < 0.001, P < 0.01, respectively, Figure 4A).	('re-expression', 'Var', (57, 70))	('DACT2', 'Gene', (74, 79))	('reduced', 'NegReg', (29, 36))	('expression', 'Species', '29278', (60, 70))	('KYSE450', 'Var', (95, 102))	('invasive cell number', 'CPA', (4, 24))
391592	26919254	The number of invasive cells was 198.33 +- 7.64 vs. 353.33 +- 12.58 before and after knockdown of DACT2 in YES2 cells.	('DACT2', 'Gene', (98, 103))	('YES2', 'Gene', '7526', (107, 111))	('knockdown', 'Var', (85, 94))	('YES2', 'Gene', (107, 111))
391593	26919254	The invasive cell number was increased significantly after knockdown of DACT2 in YES2 cells (P < 0.001, Figure 4A).	('DACT2', 'Gene', (72, 77))	('YES2', 'Gene', '7526', (81, 85))	('YES2', 'Gene', (81, 85))	('increased', 'PosReg', (29, 38))	('knockdown', 'Var', (59, 68))	('invasive cell number', 'CPA', (4, 24))
391595	26919254	As shown in Figure 4B, cell migration was sharply suppressed after re-expression of DACT2 in KYSE150 and KYSE450 cells.	('KYSE450', 'Var', (105, 112))	('suppressed', 'NegReg', (50, 60))	('re-expression', 'Var', (67, 80))	('DACT2', 'Gene', (84, 89))	('expression', 'Species', '29278', (70, 80))	('cell migration', 'CPA', (23, 37))
391596	26919254	While cell migration was promoted after knockdown of DACT2 in YES2 cells.	('cell migration', 'CPA', (6, 20))	('knockdown', 'Var', (40, 49))	('DACT2', 'Gene', (53, 58))	('promoted', 'PosReg', (25, 33))	('YES2', 'Gene', '7526', (62, 66))	('YES2', 'Gene', (62, 66))
391599	26919254	MMP-2 and MMP-9 expression was increased by knocking down DACT2 in YES2 cells.	('MMP-9', 'Gene', (10, 15))	('MMP-2', 'Gene', (0, 5))	('YES2', 'Gene', (67, 71))	('increased', 'PosReg', (31, 40))	('YES2', 'Gene', '7526', (67, 71))	('expression', 'Species', '29278', (16, 26))	('DACT2', 'Gene', (58, 63))	('expression', 'MPA', (16, 26))	('knocking down', 'Var', (44, 57))
391605	26919254	The levels of active-beta-catenin and c-Myc were increased and the level of p-beta-catenin was reduced by knocking down DACT2 in YES2 cells.	('levels', 'MPA', (4, 10))	('c-Myc', 'Gene', (38, 43))	('active-beta-catenin', 'MPA', (14, 33))	('c-Myc', 'Gene', '4609', (38, 43))	('YES2', 'Gene', (129, 133))	('increased', 'PosReg', (49, 58))	('reduced', 'NegReg', (95, 102))	('knocking down', 'Var', (106, 119))	('level of p-beta-catenin', 'MPA', (67, 90))	('DACT2', 'Gene', (120, 125))	('YES2', 'Gene', '7526', (129, 133))
391620	26919254	These data suggest that DACT2 methylation may serve as an esophageal cancer early detection marker, and methylation of DACT2 is involved in esophageal cancer development.	('methylation', 'Var', (30, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('methylation', 'Var', (104, 115))	('involved', 'Reg', (128, 136))	('DACT2', 'Gene', (119, 124))	('DACT2', 'Gene', (24, 29))	('esophageal cancer', 'Disease', (140, 157))
391621	26919254	The association of DACT2 methylation with tumor stage suggests that methylation of DACT2 is related to esophageal cancer progression.	('DACT2', 'Gene', (83, 88))	('tumor', 'Disease', (42, 47))	('esophageal cancer', 'Disease', (103, 120))	('methylation', 'Var', (68, 79))	('related', 'Reg', (92, 99))	('DACT2', 'Gene', (19, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('methylation', 'Var', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
391628	26919254	In contrast to T161, dual phosphorylation at T14 and Y15 results in inactivation of Cdk1.	('T14', 'Var', (45, 48))	('Y15', 'Var', (53, 56))	('Cdk1', 'Gene', (84, 88))	('inactivation', 'NegReg', (68, 80))	('Cdk1', 'Gene', '983', (84, 88))
391630	26919254	The levels of cyclin B1 and CDC2 were increased, and the levels of p-CDC (Y15) were reduced after knockdown of DACT2 in DACT2 highly expressed YES2 cells.	('DACT2', 'Gene', (111, 116))	('levels', 'MPA', (4, 10))	('YES2', 'Gene', '7526', (143, 147))	('cyclin B1', 'Gene', (14, 23))	('CDC2', 'Gene', (28, 32))	('YES2', 'Gene', (143, 147))	('knockdown', 'Var', (98, 107))	('CDC2', 'Gene', '983', (28, 32))	('reduced', 'NegReg', (84, 91))	('increased', 'PosReg', (38, 47))	('cyclin B1', 'Gene', '891', (14, 23))
391643	26919254	Methylation of DACT2 is significantly associated with tumor stage and metastasis.	('metastasis', 'CPA', (70, 80))	('associated', 'Reg', (38, 48))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('DACT2', 'Gene', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
391648	26919254	Ten esophageal cancer cell lines (KYSE30, KYSE70, KYSE140, KYSE150, KYSE450, KYSE140, TE3, TE7, TE8 and YES2) were included in this study.	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('KYSE30', 'Var', (34, 40))	('YES2', 'Gene', '7526', (104, 108))	('KYSE70', 'Var', (42, 48))	('YES2', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('KYSE140', 'Var', (77, 84))	('KYSE150', 'Var', (59, 66))	('esophageal cancer', 'Disease', (4, 21))	('KYSE450', 'Var', (68, 75))
391673	26919254	5 x 103 cells were plated into 96-well plates before and after knockdown of DACT2 in YES2 cells.	('YES2', 'Gene', (85, 89))	('YES2', 'Gene', '7526', (85, 89))	('knockdown', 'Var', (63, 72))	('DACT2', 'Gene', (76, 81))
391676	26919254	YES2 cells before and after knockdown of DACT2 were seeded in 6-well plates at a density of 1000 cells per well.	('YES2', 'Gene', '7526', (0, 4))	('DACT2', 'Gene', (41, 46))	('YES2', 'Gene', (0, 4))	('knockdown', 'Var', (28, 37))
391680	26919254	YES2 cells with or without knockdown of DACT2 were analyzed the cell cycle as well.	('knockdown', 'Var', (27, 36))	('YES2', 'Gene', '7526', (0, 4))	('DACT2', 'Gene', (40, 45))	('YES2', 'Gene', (0, 4))	('cell cycle', 'CPA', (64, 74))
391683	26919254	8 x 104 YES2 cells before and after knockdown of DACT2 were added to the upper chamber of 8.0 mum pore size transwell apparatus.	('DACT2', 'Gene', (49, 54))	('mum', 'Gene', (94, 97))	('YES2', 'Gene', (8, 12))	('knockdown', 'Var', (36, 45))	('mum', 'Gene', '56925', (94, 97))	('YES2', 'Gene', '7526', (8, 12))
391685	26919254	1 x 105 YES2 cells before and after knockdown of DACT2 were added to the upper chamber of a transwell apparatus coated with Matrigel.	('DACT2', 'Gene', (49, 54))	('YES2', 'Gene', '7526', (8, 12))	('YES2', 'Gene', (8, 12))	('knockdown', 'Var', (36, 45))
391742	24790804	Defects of the barrier function contribute to gastroesophageal reflux disease (GERD), which is manifested as damage to the esophageal epithelium due to exposure to the gastrointestinal refluxate.	('contribute', 'Reg', (32, 42))	('gastroesophageal reflux disease', 'Disease', (46, 77))	('gastrointestinal refluxate', 'Phenotype', 'HP:0002020', (168, 194))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (46, 69))	('GERD', 'Phenotype', 'HP:0002020', (79, 83))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (46, 77))	('Defects', 'Var', (0, 7))
391758	24790804	In the adherens junction, the major transmembrane adhesive protein is E-cadherin, and conditional knockout of E-cadherin in mouse esophageal epithelium significantly increased its permeability.	('permeability', 'MPA', (180, 192))	('increased', 'PosReg', (166, 175))	('mouse', 'Species', '10090', (124, 129))	('E-cadherin', 'Gene', '12550', (70, 80))	('conditional knockout', 'Var', (86, 106))	('E-cadherin', 'Gene', (70, 80))	('E-cadherin', 'Gene', (110, 120))	('E-cadherin', 'Gene', '12550', (110, 120))
391759	24790804	During gastresophageal reflux, luminal acid causes injury of the esophageal epithelium by altering the AJC and causes an early increase in paracellular permeability and dilated intercellular space (DIS).	('paracellular permeability', 'MPA', (139, 164))	('gastresophageal reflux', 'Phenotype', 'HP:0002020', (7, 29))	('dilated intercellular space', 'MPA', (169, 196))	('injury of the esophageal', 'Disease', 'MESH:D004941', (51, 75))	('altering', 'Reg', (90, 98))	('increase', 'PosReg', (127, 135))	('DIS', 'Chemical', '-', (198, 201))	('injury of the esophageal', 'Disease', (51, 75))	('luminal acid', 'Var', (31, 43))	('AJC', 'MPA', (103, 106))
391763	24790804	Oxidative stress may also induce DIS and impair the barrier function as well.	('barrier function', 'CPA', (52, 68))	('impair', 'NegReg', (41, 47))	('Oxidative', 'Var', (0, 9))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('DIS', 'Disease', (33, 36))	('DIS', 'Chemical', '-', (33, 36))	('induce', 'Reg', (26, 32))
391789	24790804	Using wild-type and knockout mice, we found that Nrf2 deficiency clearly reduced TEER in the absence of reflux.	('deficiency', 'Var', (54, 64))	('TEER', 'MPA', (81, 85))	('reduced', 'NegReg', (73, 80))	('Nrf2', 'Gene', (49, 53))	('mice', 'Species', '10090', (29, 33))
391791	24790804	Interestingly, both immunostaining and western blotting showed significant downregulation of Cldn4 in the esophageal epithelium of Nrf2 deficient mice.	('downregulation', 'NegReg', (75, 89))	('Cldn4', 'Gene', (93, 98))	('deficient', 'Var', (136, 145))	('mice', 'Species', '10090', (146, 150))	('Nrf2', 'Gene', (131, 135))
391803	24790804	Genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo.	('Genetic targeting', 'Var', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('G12D', 'Mutation', 'rs121913529', (52, 56))	('K-Ras', 'Gene', '16653', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('impairs', 'NegReg', (38, 45))	('Nrf2', 'Gene', (25, 29))	('tumor', 'Disease', (84, 89))	('rat', 'Species', '10116', (73, 76))	('K-Ras', 'Gene', (46, 51))
391804	24790804	This is probably why point mutations of Keap1 and Nrf2 have been frequently detected in human squamous cell carcinoma of the lung, head and neck, and the esophagus.	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (94, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('detected', 'Reg', (76, 84))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (94, 129))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (108, 129))	('point mutations', 'Var', (21, 36))	('human', 'Species', '9606', (88, 93))	('Keap1', 'Gene', (40, 45))	('Nrf2', 'Gene', (50, 54))	('squamous cell carcinoma of the lung', 'Disease', (94, 129))
391807	24790804	The consensus in this field is that activation of Nrf2 pathway by small-molecule inducers does not replicate the magnitude and duration of genetic perturbation, and thus will not promote carcinogenesis especially when used in a short-term.	('carcinogenesis', 'Disease', (187, 201))	('Nrf2 pathway', 'Pathway', (50, 62))	('rat', 'Species', '10116', (129, 132))	('promote', 'PosReg', (179, 186))	('activation', 'PosReg', (36, 46))	('small-molecule', 'Var', (66, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (187, 201))
391809	24790804	Genetic disruption of this complex has been shown to be a key mechanism of NFkB activation in human lung cancer.	('NFkB', 'Gene', (75, 79))	('Genetic disruption', 'Var', (0, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('human', 'Species', '9606', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('activation', 'PosReg', (80, 90))
391811	24790804	Deletion of Keap1 led to the accumulation and stabilization of IKKbeta and upregulation of NFkB-derived tumor angiogenic factors.	('stabilization', 'MPA', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('IKKbeta', 'Gene', (63, 70))	('IKKbeta', 'Gene', '16150', (63, 70))	('tumor', 'Disease', (104, 109))	('upregulation', 'PosReg', (75, 87))	('Keap1', 'Gene', (12, 17))	('accumulation', 'PosReg', (29, 41))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('Deletion', 'Var', (0, 8))
391812	24790804	Absence of Nrf2 induces more aggressive inflammation through activation of NFkB and downstream proinflammatory cytokines in astrocytes.	('aggressive inflammation', 'Disease', (29, 52))	('aggressive inflammation', 'Disease', 'MESH:D007249', (29, 52))	('activation', 'PosReg', (61, 71))	('NFkB', 'Gene', (75, 79))	('more', 'PosReg', (24, 28))	('Nrf2', 'Gene', (11, 15))	('Absence', 'Var', (0, 7))
391815	24790804	p65 also represses the Nrf2 pathway at the transcriptional level through HDAC3 and CBP.	('CBP', 'Gene', (83, 86))	('p65', 'Var', (0, 3))	('Nrf2 pathway', 'Pathway', (23, 35))	('represses', 'NegReg', (9, 18))	('HDAC3', 'Gene', (73, 78))	('CBP', 'Gene', '12914', (83, 86))	('HDAC3', 'Gene', '15183', (73, 78))
391817	24790804	NFkB subunits p50 and p65 induce transcription of Nrf2 in AML cells at a specific promoter kB site, and thus encourage resistance to chemotherapy-induced cytotoxicity.	('encourage', 'PosReg', (109, 118))	('AML', 'Disease', 'MESH:D015470', (58, 61))	('cytotoxicity', 'Disease', (154, 166))	('Nrf2', 'Gene', (50, 54))	('p50', 'Gene', '18033', (14, 17))	('p65', 'Var', (22, 25))	('transcription', 'MPA', (33, 46))	('p50', 'Gene', (14, 17))	('cytotoxicity', 'Disease', 'MESH:D064420', (154, 166))	('AML', 'Disease', (58, 61))	('induce', 'PosReg', (26, 32))
391818	24790804	For example, to determine whether NFkB and Nrf2 pathways impact barrier function through Cldn1 or Cldn4, gastresophageal reflux can be surgically produced in Cldn1 or Cldn4 conditional knockout mice, EDL2Cre;Cldn1loxP/loxP and EDL2Cre;Cldn4loxP/loxP, in which Cldn1 or Cldn4 is specifically deleted in esophageal squamous epithelium.	('deleted', 'Var', (291, 298))	('impact', 'Reg', (57, 63))	('Cldn1', 'Gene', '12737', (208, 213))	('Cldn1', 'Gene', '12737', (260, 265))	('Cldn1', 'Gene', (260, 265))	('Cldn1', 'Gene', (158, 163))	('Cldn1', 'Gene', '12737', (89, 94))	('Cldn1', 'Gene', (89, 94))	('gastresophageal', 'MPA', (105, 120))	('Cldn1', 'Gene', '12737', (158, 163))	('Cldn4', 'Gene', (269, 274))	('barrier function', 'MPA', (64, 80))	('gastresophageal reflux', 'Phenotype', 'HP:0002020', (105, 127))	('mice', 'Species', '10090', (194, 198))	('Cldn1', 'Gene', (208, 213))
391820	24790804	AJCs apical junction complexes Cldn claudin DIS dilated intercellular space GERD gastroesophageal reflux disease PPI proton pump inhibitors TJ tight junction TEER transepithelial electrical resistance	('gastroesophageal reflux disease', 'Disease', (81, 112))	('PPI', 'Var', (113, 116))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (81, 104))	('proton pump', 'Gene', (117, 128))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (81, 112))	('AJCs', 'Phenotype', 'HP:0032176', (0, 4))	('proton pump', 'Gene', '11944', (117, 128))	('GERD', 'Phenotype', 'HP:0002020', (76, 80))	('apical junction complexes', 'Phenotype', 'HP:0032176', (5, 30))	('DIS', 'Chemical', '-', (44, 47))	('dilated', 'Disease', (48, 55))
391821	22422400	Single nucleotide polymorphisms in the matrix metalloproteinase gene family and the frequency and duration of gastroesophageal reflux disease influence the risk of esophageal adenocarcinoma The matrix metalloproteinase (MMP) family of proteins mediates various cellular pathways, including apoptosis and angiogenesis.	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (110, 133))	('mediates', 'Reg', (244, 252))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (110, 141))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('angiogenesis', 'CPA', (304, 316))	('apoptosis', 'CPA', (290, 299))	('influence', 'Reg', (142, 151))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (164, 189))	('esophageal adenocarcinoma', 'Disease', (164, 189))	('gastroesophageal reflux disease', 'Disease', (110, 141))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (164, 189))
391822	22422400	Polymorphisms of MMP genes are associated with increased esophageal adenocarcinoma (EAC) risk.	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('MMP', 'Gene', (17, 20))	('Polymorphisms', 'Var', (0, 13))	('increased esophageal adenocarcinoma', 'Disease', (47, 82))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (57, 82))	('increased esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (47, 82))
391826	22422400	There were significant interactions between the MMP1 variants and the presence of GERD (p = 0.002) and between MMP3 variants and GERD (p = 0.04).	('MMP1', 'Gene', (48, 52))	('variants', 'Var', (116, 124))	('MMP3', 'Gene', '4314', (111, 115))	('GERD', 'Disease', (82, 86))	('MMP1', 'Gene', '4312', (48, 52))	('MMP3', 'Gene', (111, 115))	('GERD', 'Disease', (129, 133))	('variants', 'Var', (53, 61))
391828	22422400	In conclusion, MMP1 1G/2G (and possibly MMP3 6A/5A) polymorphisms alter EAC risk differentially for GERD and GERD-free individuals.	('MMP3', 'Gene', (40, 44))	('MMP1', 'Gene', (15, 19))	('EAC', 'Disease', (72, 75))	('MMP3', 'Gene', '4314', (40, 44))	('polymorphisms', 'Var', (52, 65))	('alter', 'Reg', (66, 71))	('EAC', 'Phenotype', 'HP:0011459', (72, 75))	('MMP1', 'Gene', '4312', (15, 19))
391836	22422400	Polymorphic variations in MMP12 have been correlated with breast cancer outcomes, and aberrant expression of several MMP genes has been associated with poorer esophageal cancer prognosis.	('associated', 'Reg', (136, 146))	('MMP12', 'Gene', '4321', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('esophageal cancer', 'Disease', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('aberrant expression', 'Var', (86, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('MMP12', 'Gene', (26, 31))	('correlated', 'Reg', (42, 52))	('MMP genes', 'Gene', (117, 126))	('poorer', 'NegReg', (152, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('Polymorphic variations', 'Var', (0, 22))
391838	22422400	Our recent case-control study of the MMP gene family found that the heterozygous (1G/2G) and homozygous (2G/2G) variant genotypes of MMP1 1G/2G (rs1799750) were independently associated with an approximately 1.5-fold to twofold greater risk of EAC.	('associated', 'Reg', (175, 185))	('EAC', 'Disease', (244, 247))	('MMP1', 'Gene', '4312', (133, 137))	('1G/2G (rs1799750', 'Var', (138, 154))	('rs1799750', 'Mutation', 'rs1799750', (145, 154))	('MMP1', 'Gene', (133, 137))	('EAC', 'Phenotype', 'HP:0011459', (244, 247))	('rs1799750', 'Var', (145, 154))
391839	22422400	Likewise, the homozygous (5A/5A) variant of MMP3 6A/5A (rs3025058) was associated with similar results (1.6 times greater risk).	('rs3025058', 'Mutation', 'rs3025058', (56, 65))	('rs3025058', 'Var', (56, 65))	('MMP3', 'Gene', (44, 48))	('MMP3', 'Gene', '4314', (44, 48))
391840	22422400	The same variants were also associated with higher risk of Barrett's esophagus, a potential outcome of chronic GERD, among tumor-free patients.	('tumor-free', 'Disease', 'MESH:D000072662', (123, 133))	('patients', 'Species', '9606', (134, 142))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (59, 78))	('tumor-free', 'Disease', (123, 133))	("Barrett's esophagus", 'Disease', (59, 78))	('variants', 'Var', (9, 17))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (59, 78))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
391841	22422400	Polymorphisms in MMP12 (-82A/G [rs2276109] and 1082A/G [rs652438]) were not associated with EAC risk.	('MMP12', 'Gene', (17, 22))	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('1082A/G [rs652438]', 'Var', (47, 65))	('rs652438', 'Mutation', 'rs652438', (56, 64))	('EAC', 'Disease', (92, 95))	('rs2276109', 'Mutation', 'rs2276109', (32, 41))	('1082A/G', 'Mutation', 'rs652438', (47, 54))	('-82A/G [rs2276109]', 'Var', (24, 42))	('MMP12', 'Gene', '4321', (17, 22))	('-82A/G', 'Mutation', 'rs2276109', (24, 30))
391843	22422400	For this reason, it was not possible to evaluate whether GERD modified the association between MMP1, MMP3 and MMP12 polymorphisms and EAC risk.	('polymorphisms', 'Var', (116, 129))	('MMP1', 'Gene', '4312', (95, 99))	('MMP3', 'Gene', '4314', (101, 105))	('MMP12', 'Gene', (110, 115))	('MMP1', 'Gene', '4312', (110, 114))	('EAC', 'Phenotype', 'HP:0011459', (134, 137))	('MMP1', 'Gene', (95, 99))	('MMP3', 'Gene', (101, 105))	('EAC', 'Disease', (134, 137))	('MMP1', 'Gene', (110, 114))	('MMP12', 'Gene', '4321', (110, 115))	('association', 'Interaction', (75, 86))
391845	22422400	In our study, we extend this work into a human setting and hypothesize that the relationship between MMP polymorphisms and EAC risk is modified by a history, severity, frequency and duration of GERD.	('EAC', 'Phenotype', 'HP:0011459', (123, 126))	('modified', 'Reg', (135, 143))	('human', 'Species', '9606', (41, 46))	('EAC', 'Disease', (123, 126))	('MMP', 'Gene', (101, 104))	('polymorphisms', 'Var', (105, 118))
391857	22422400	Single nucleotide polymorphisms of the MMP1, MMP3 and MMP12 genes were detected using modified polymerase chain reactions and the Taqman approach (Applied Biosystems, Foster City, CA) with commercial primer sequences.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('MMP1', 'Gene', (54, 58))	('MMP12', 'Gene', '4321', (54, 59))	('MMP1', 'Gene', (39, 43))	('MMP3', 'Gene', (45, 49))	('MMP12', 'Gene', (54, 59))	('MMP1', 'Gene', '4312', (54, 58))	('MMP1', 'Gene', '4312', (39, 43))	('MMP3', 'Gene', '4314', (45, 49))
391863	22422400	The homozygous 2G/2G variant for the MMP1 polymorphism was significantly more prevalent, whereas the wild-type 1G/1G genotypes were less common among cases than for controls (p = 0.01).	('MMP1', 'Gene', '4312', (37, 41))	('prevalent', 'Reg', (78, 87))	('2G/2G', 'Var', (15, 20))	('MMP1', 'Gene', (37, 41))
391866	22422400	In the crude analyses, the MMP1 polymorphism was associated with EAC risk (global Wald p = 0.009).	('MMP1', 'Gene', '4312', (27, 31))	('associated', 'Reg', (49, 59))	('polymorphism', 'Var', (32, 44))	('EAC', 'Phenotype', 'HP:0011459', (65, 68))	('MMP1', 'Gene', (27, 31))	('EAC', 'Disease', (65, 68))
391867	22422400	Specifically, the risk of EAC was significantly increased for patients carrying the MMP1 homozygous 2G/2G variant (OR 2.05, 95% CI 1.3-3.3, p = 0.002).	('EAC', 'Phenotype', 'HP:0011459', (26, 29))	('2G/2G', 'Var', (100, 105))	('EAC', 'Disease', (26, 29))	('MMP1', 'Gene', (84, 88))	('patients', 'Species', '9606', (62, 70))	('MMP1', 'Gene', '4312', (84, 88))
391868	22422400	Similarly, when compared to the wild-type MMP3 6A/6A genotype, the homozygous 5A/5A variant was marginally correlated with a greater EAC risk (AOR 1.70, 95% CI 1.0-2.8, p = 0.04), whereas the heterozygous 6A/5A variant did not (AOR 1.19, 95% CI 0.8-1.8, p = 0.42); global Wald p = 0.10.	('EAC', 'Phenotype', 'HP:0011459', (133, 136))	('variant', 'Var', (84, 91))	('MMP3', 'Gene', (42, 46))	('EAC', 'Disease', (133, 136))	('MMP3', 'Gene', '4314', (42, 46))
391871	22422400	In the subset of patients with self-reported GERD symptoms of more than once per month, a very strong, statistically significant association between the MMP1 polymorphism and EAC risk was observed, even after controlling for confounders (global Wald p < 0.001), which was driven by the increased risk of the 2G/2G genotype compared to wild type (AOR 10.87, 95% CI 4.0-29.2, p < 0.001) and also by the 1G/2G genotype (AOR 2.54, 95% CI 1.2-5.3, p = 0.01).	('polymorphism', 'Var', (158, 170))	('MMP1', 'Gene', (153, 157))	('EAC', 'Phenotype', 'HP:0011459', (175, 178))	('1G/2G', 'Var', (401, 406))	('EAC', 'Disease', (175, 178))	('2G/2G', 'Var', (308, 313))	('patients', 'Species', '9606', (17, 25))	('MMP1', 'Gene', '4312', (153, 157))
391874	22422400	A similar, albeit weaker, relationship was also observed for MMP3 where the 5A/5A homozygous variant was associated with a higher EAC risk only in the subset of patients with self-reported GERD (AOR 3.05, 95% CI 1.2-7.5, p = 0.01; global Wald p = 0.03) but not in the group without GERD (AOR 0.87, 95% CI 0.4-1.7, p = 0.69; global Wald p = 0.55).	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('MMP3', 'Gene', (61, 65))	('GERD', 'Disease', (189, 193))	('patients', 'Species', '9606', (161, 169))	('EAC', 'Disease', (130, 133))	('MMP3', 'Gene', '4314', (61, 65))	('variant', 'Var', (93, 100))
391878	22422400	This was due to a significant interaction term between the 2G/2G vs. wild-type 1G/1G and the presence or absence of GERD (p < 0.001) and a significant interaction term between the MMP1 heterozygote 1G/2G and GERD presence or absence (p = 0.03).	('MMP1', 'Gene', (180, 184))	('interaction', 'Interaction', (151, 162))	('GERD', 'Gene', (208, 212))	('MMP1', 'Gene', '4312', (180, 184))	('GERD', 'Gene', (116, 120))	('2G/2G', 'Var', (59, 64))
391882	22422400	Similarly, for GERD duration (global Wald p = 0.02), there was also a statistically significant interaction term between the MMP1 polymorphism and longstanding GERD of >15 years (p = 0.009), but not for the interaction term between MMP1 and GERD duration of 1-15 years (p = 0.13).	('polymorphism', 'Var', (130, 142))	('MMP1', 'Gene', (232, 236))	('MMP1', 'Gene', '4312', (125, 129))	('MMP1', 'Gene', (125, 129))	('MMP1', 'Gene', '4312', (232, 236))
391883	22422400	In contrast, our MMP3-GERD interaction analysis was entirely nonsignificant (global Wald p = 0.14) where only a trend in the interaction between the homozygous 5A/5A variant and GERD presence/absence (p = 0.08) was observed.	('MMP3', 'Gene', (17, 21))	('MMP3', 'Gene', '4314', (17, 21))	('variant', 'Var', (166, 173))
391885	22422400	Interaction analyses found a strong interaction (global Wald p = 0.002) between cumulative GERD severity and MMP1 polymorphism in an additive genetic model.	('polymorphism', 'Var', (114, 126))	('MMP1', 'Gene', (109, 113))	('MMP1', 'Gene', '4312', (109, 113))
391886	22422400	In our previous investigation of MMP genes and EAC risk, the variant 1G/2G and 2G/2G genotypes of MMP1 and the homozygous 5A/5A variant of MMP3 were individually found to be associated with an increased risk of EAC as well as Barrett's esophagus (a known outcome of chronic GERD) among cancer-free individuals.	('2G/2G', 'Var', (79, 84))	('EAC', 'Phenotype', 'HP:0011459', (211, 214))	('associated', 'Reg', (174, 184))	('EAC', 'Disease', (211, 214))	('MMP3', 'Gene', '4314', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('MMP genes', 'Gene', (33, 42))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (226, 245))	("Barrett's esophagus", 'Disease', (226, 245))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (226, 245))	('MMP1', 'Gene', (98, 102))	('MMP1', 'Gene', '4312', (98, 102))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('variant 1G/2G', 'Var', (61, 74))	('cancer', 'Disease', (286, 292))	('MMP3', 'Gene', (139, 143))
391888	22422400	To investigate the biological hypothesis that the MMP signaling pathway may also potentiate esophageal carcinogenesis more in the presence of GERD, we examined the relationships among MMP1, MMP3 and MMP12 polymorphisms, presence, frequency, duration and severity of GERD symptoms and EAC risk in a case-control analysis.	('MMP3', 'Gene', (190, 194))	('esophageal carcinogenesis', 'Disease', (92, 117))	('MMP1', 'Gene', (184, 188))	('MMP1', 'Gene', '4312', (199, 203))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (92, 117))	('MMP3', 'Gene', '4314', (190, 194))	('MMP12', 'Gene', (199, 204))	('EAC', 'Phenotype', 'HP:0011459', (284, 287))	('EAC', 'Disease', (284, 287))	('MMP12', 'Gene', '4321', (199, 204))	('MMP1', 'Gene', '4312', (184, 188))	('MMP1', 'Gene', (199, 203))	('polymorphisms', 'Var', (205, 218))	('potentiate', 'PosReg', (81, 91))
391889	22422400	We found statistically significant interactions between MMP1 1G/2G polymorphism and the presence, frequency, duration of GERD or cumulative GERD history.	('significant interactions', 'Reg', (23, 47))	('polymorphism', 'Var', (67, 79))	('MMP1', 'Gene', '4312', (56, 60))	('MMP1', 'Gene', (56, 60))
391891	22422400	We did not observe any interactions between MMP12 polymorphisms and GERD.	('MMP12', 'Gene', (44, 49))	('MMP12', 'Gene', '4321', (44, 49))	('polymorphisms', 'Var', (50, 63))
391892	22422400	Of great potential clinical importance, patients with frequent, longstanding or cumulative GERD who carried the MMP1 variant genotypes were found to have a much higher greater risk of EAC when compared to GERD-free individuals or those carrying the wild-type 1G/1G genotype.	('EAC', 'Phenotype', 'HP:0011459', (184, 187))	('patients', 'Species', '9606', (40, 48))	('EAC', 'Disease', (184, 187))	('MMP1', 'Gene', (112, 116))	('variant', 'Var', (117, 124))	('MMP1', 'Gene', '4312', (112, 116))
391894	22422400	Nonetheless, although a precise quantification of this risk is not possible, there was a clear synergistic effect of both longstanding and frequent GERD and MMP1 polymorphism on EAC risk.	('MMP1', 'Gene', '4312', (157, 161))	('GERD', 'Gene', (148, 152))	('polymorphism', 'Var', (162, 174))	('EAC', 'Phenotype', 'HP:0011459', (178, 181))	('MMP1', 'Gene', (157, 161))	('EAC', 'Disease', (178, 181))
391896	22422400	Genetic alterations in the MMP genes have already been linked to an increased risk of developing various malignancies, including nasopharyngeal, lung and colorectal cancers.	('Genetic alterations', 'Var', (0, 19))	('malignancies', 'Disease', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('linked to', 'Reg', (55, 64))	('colorectal cancers', 'Disease', (154, 172))	('MMP', 'Gene', (27, 30))	('lung', 'Disease', (145, 149))	('nasopharyngeal', 'Disease', (129, 143))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))	('colorectal cancers', 'Disease', 'MESH:D015179', (154, 172))
391898	22422400	Polymorphisms within members of the MMP family, including MMP1 and MMP3, are also associated with higher Barrett's esophagus and EAC risk.	('associated', 'Reg', (82, 92))	('MMP3', 'Gene', (67, 71))	("Barrett's esophagus", 'Disease', (105, 124))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (105, 124))	('EAC', 'Phenotype', 'HP:0011459', (129, 132))	('Polymorphisms', 'Var', (0, 13))	('MMP1', 'Gene', '4312', (58, 62))	('MMP3', 'Gene', '4314', (67, 71))	('EAC', 'Disease', (129, 132))	('higher', 'PosReg', (98, 104))	('MMP', 'Gene', (36, 39))	('MMP1', 'Gene', (58, 62))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (105, 124))
391899	22422400	Because only a minor subset of patients with polymorphisms, amplification or overexpression of MMP genes actually develops EAC, the potential significance of other parameters, such as gene-environmental interactions, needs to be considered to fully understand EAC carcinogenesis.	('EAC', 'Phenotype', 'HP:0011459', (260, 263))	('overexpression', 'PosReg', (77, 91))	('MMP genes', 'Gene', (95, 104))	('amplification', 'Var', (60, 73))	('EAC', 'Phenotype', 'HP:0011459', (123, 126))	('EAC', 'Disease', (123, 126))	('polymorphisms', 'Var', (45, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (264, 278))	('patients', 'Species', '9606', (31, 39))	('develops', 'Reg', (114, 122))	('carcinogenesis', 'Disease', (264, 278))
391901	22422400	In lung cancer development, for instance, gene-smoking interactions between various DNA repair gene (e.g., ERCC1, ERCC2 and XRCC1) polymorphisms and cigarette exposure are shown to be an important contributor to carcinogenesis.	('ERCC2', 'Gene', '2068', (114, 119))	('lung cancer', 'Disease', (3, 14))	('XRCC1', 'Gene', '7515', (124, 129))	('interactions', 'Interaction', (55, 67))	('ERCC1', 'Gene', (107, 112))	('ERCC1', 'Gene', '2067', (107, 112))	('carcinogenesis', 'Disease', 'MESH:D063646', (212, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('ERCC2', 'Gene', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('carcinogenesis', 'Disease', (212, 226))	('polymorphisms', 'Var', (131, 144))	('XRCC1', 'Gene', (124, 129))
391903	22422400	A similar relationship was also observed between polymorphisms of the vascular endothelial growth factor gene and cigarette smoking with EAC.	('vascular endothelial growth factor', 'Gene', (70, 104))	('vascular endothelial growth factor', 'Gene', '7422', (70, 104))	('polymorphisms', 'Var', (49, 62))	('EAC', 'Phenotype', 'HP:0011459', (137, 140))
391904	22422400	To our knowledge, this report is the first to describe a strong and consistent interaction between frequency, duration, severity or presence of GERD and the MMP1 polymorphism in their relationship with EAC risk.	('MMP1', 'Gene', '4312', (157, 161))	('polymorphism', 'Var', (162, 174))	('relationship', 'Interaction', (184, 196))	('EAC', 'Phenotype', 'HP:0011459', (202, 205))	('MMP1', 'Gene', (157, 161))	('EAC', 'Disease', (202, 205))	('GERD', 'Gene', (144, 148))
391910	22422400	However, these unmeasured confounding factors are unlikely to influence the results to any significant extent, considering the strong relationship observed between GERD and MMP1 polymorphism with EAC risk.	('GERD', 'Gene', (164, 168))	('MMP1', 'Gene', (173, 177))	('EAC', 'Phenotype', 'HP:0011459', (196, 199))	('EAC', 'Disease', (196, 199))	('polymorphism', 'Var', (178, 190))	('MMP1', 'Gene', '4312', (173, 177))
391911	22422400	In summary, our study represents the first report in humans that the MMP1 2G variant allele is associated with EAC risk in individuals with a history of GERD but not in GERD-free individuals.	('humans', 'Species', '9606', (53, 59))	('variant', 'Var', (77, 84))	('EAC', 'Disease', (111, 114))	('MMP1', 'Gene', '4312', (69, 73))	('associated with', 'Reg', (95, 110))	('MMP1', 'Gene', (69, 73))	('EAC', 'Phenotype', 'HP:0011459', (111, 114))
391990	33561950	Management of Non-Colorectal Digestive Cancers with Microsatellite Instability Microsatellite instability (MSI) is an established predictive biomarker for immune checkpoint inhibitors with potential prognostic value in different types of tumors.	('Cancers', 'Phenotype', 'HP:0002664', (39, 46))	('Non-Colorectal Digestive Cancers', 'Disease', 'MESH:D015179', (14, 46))	('Microsatellite instability', 'Disease', 'MESH:D053842', (79, 105))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('Non-Colorectal Digestive Cancers', 'Disease', (14, 46))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('Microsatellite instability', 'Disease', (79, 105))	('Microsatellite Instability', 'Var', (52, 78))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumors', 'Disease', (238, 244))
392002	33561950	For PCR-based testing, DNA is extracted from paired tumor and normal tissue and amplified at five chosen markers (BAT25, BAT26, D5S346, D2S123 and D17S250); alterations in the repeat length of each marker are compared between tumor and normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BAT25', 'Var', (114, 119))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (226, 231))	('D17S250)', 'Var', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('D2S123', 'Var', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('D5S346', 'Var', (128, 134))
392005	33561950	Deficient MMR (dMMR) entails a process whereby dysfunctional MMR proteins at the germline or somatic level lead to the MSI-H phenotype.	('lead to', 'Reg', (107, 114))	('dysfunctional MMR', 'Disease', 'MESH:C536143', (47, 64))	('Deficient', 'Var', (0, 9))	('MSI-H', 'Chemical', '-', (119, 124))	('dysfunctional MMR', 'Disease', (47, 64))	('MSI-H phenotype', 'Disease', (119, 134))
392031	33561950	Based on the phase 2 KEYNOTE-158 study, 29% of 102 patients with TMB-H (>=10 mut/Mb) tumors that had progressed on prior therapy responded to pembrolizumab monotherapy (median duration of response [DOR] not reached [NR]) and the FDA granted accelerated approval to its use for the treatment of solid tumors with TMB >=10 mut/Mb (determined by an FDA approved test) that is refractory to prior treatment.	('pembrolizumab', 'Chemical', 'MESH:C582435', (142, 155))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('TMB', 'Chemical', '-', (312, 315))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('TMB', 'Chemical', '-', (65, 68))	('TMB-H', 'Gene', (65, 70))	('tumors', 'Disease', (300, 306))	('TMB >=10', 'Var', (312, 320))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('TMB-H', 'Chemical', '-', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
392036	33561950	The presence of MSI-H/dMMR, TMB-H and PD-L1 overlap in solid tumors with different frequencies and their predictive power has not been compared in a systematic fashion (Table 3).	('MSI-H/dMMR', 'Var', (16, 26))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('TMB-H', 'Gene', (28, 33))	('PD-L1', 'Gene', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MSI-H', 'Chemical', '-', (16, 21))	('TMB-H', 'Chemical', '-', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('PD-L1', 'Gene', '29126', (38, 43))
392040	33561950	GC is commonly divided into four subtypes based on a molecular classification system: microsatellite unstable, Epstein-Barr virus (EBV) positive, genomically stable and chromosomal instable tumors.	('GC', 'Phenotype', 'HP:0012126', (0, 2))	('EBV', 'Species', '10376', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('microsatellite unstable', 'Var', (86, 109))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
392045	33561950	Data suggest that MSI-H GC is associated with improved survival, but these studies were retrospective in nature and confounded by inter-study heterogeneities.	('MSI-H', 'Chemical', '-', (18, 23))	('GC', 'Phenotype', 'HP:0012126', (24, 26))	('MSI-H GC', 'Var', (18, 26))	('improved', 'PosReg', (46, 54))	('survival', 'MPA', (55, 63))
392046	33561950	Based on a meta-analysis of four major randomized clinical trials, MSI-H GC was independently associated with improved disease-free survival (five-year DFS rates, 71.8% vs. 52.3%, p < 0.001) and overall survival (five-year OS rates, 77.5% vs. 59.3%, p < 0.001).	('improved', 'PosReg', (110, 118))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('MSI-H GC', 'Var', (67, 75))	('MSI-H', 'Chemical', '-', (67, 72))	('disease-free survival', 'CPA', (119, 140))	('OS', 'Gene', '17451', (223, 225))	('overall survival', 'CPA', (195, 211))
392056	33561950	For those with CPS >=10 irrespective of the MSI status, pembrolizumab improved median OS (mOS) versus chemotherapy (17.4 vs. 10.8 months, HR 0.69, 95% CI 0.49-0.97), but the difference was not statistically tested; pembrolizumab plus chemotherapy was not superior to chemotherapy (mOS 12.3 vs. 10.8 months, HR 0.85, 95% CI 0.62-1.17, p = 0.16).	('OS', 'Gene', '17451', (86, 88))	('mOS', 'Gene', (90, 93))	('mOS', 'Gene', '17451', (281, 284))	('pembrolizumab', 'Chemical', 'MESH:C582435', (56, 69))	('mOS', 'Gene', '17451', (90, 93))	('improved', 'PosReg', (70, 78))	('CPS', 'Chemical', '-', (15, 18))	('CPS >=10', 'Var', (15, 23))	('OS', 'Gene', '17451', (91, 93))	('pembrolizumab', 'Chemical', 'MESH:C582435', (215, 228))	('mOS', 'Gene', (281, 284))	('OS', 'Gene', '17451', (282, 284))
392094	33561950	In SBA, MSI-H was found to be associated with early-stage disease and lower rates of recurrence in a retrospective study of 74 patients.	('early-stage disease', 'CPA', (46, 65))	('lower', 'NegReg', (70, 75))	('patients', 'Species', '9606', (127, 135))	('MSI-H', 'Chemical', '-', (8, 13))	('MSI-H', 'Var', (8, 13))
392095	33561950	Additionally, dMMR/MSI-H was associated with improved cancer-specific survival in stage II SBA, improved postoperative cancer-specific survival and higher CPS, regardless of disease stage.	('postoperative', 'MPA', (105, 118))	('CPS', 'MPA', (155, 158))	('improved', 'PosReg', (96, 104))	('CPS', 'Chemical', '-', (155, 158))	('improved', 'PosReg', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (54, 60))	('dMMR/MSI-H', 'Var', (14, 24))	('cancer', 'Disease', (119, 125))	('MSI-H', 'Chemical', '-', (19, 24))	('stage II SBA', 'Disease', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('higher', 'PosReg', (148, 154))
392102	33561950	Both HPV positivity and increased TILs were associated with improved survival and treatment responses to chemoradiation in AC, indicating that HPV infection may trigger immune response and enhance the activity of ICIs, similar to what has been observed in clinical trials with ICIs in squamous cell carcinoma of the head and neck.	('HPV', 'Species', '10566', (143, 146))	('trigger', 'PosReg', (161, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (285, 308))	('activity', 'MPA', (201, 209))	('HPV infection', 'Disease', (143, 156))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (285, 308))	('squamous cell carcinoma', 'Disease', (285, 308))	('enhance', 'PosReg', (189, 196))	('positivity', 'Var', (9, 19))	('HPV', 'Species', '10566', (5, 8))	('improved', 'PosReg', (60, 68))	('ICIs', 'CPA', (213, 217))	('immune response', 'CPA', (169, 184))	('HPV infection', 'Disease', 'MESH:D030361', (143, 156))
392105	33561950	A combined analysis of the KEYNOTE-28 and KEYNOTE-158 study reported an RR of 10.9% in 137 patients with higher RRs in the PD-L1 positive group versus negative group (14.0% vs. 3.3%); median DOR was not reached after a median follow-up of 11.7 months.	('positive', 'Var', (129, 137))	('patients', 'Species', '9606', (91, 99))	('higher', 'PosReg', (105, 111))	('PD-L1', 'Gene', (123, 128))	('PD-L1', 'Gene', '29126', (123, 128))
392122	33561950	Tyrosine kinase inhibitors targeting NTRK, IDH1 and FGFR2 are efficacious in BTC with corresponding genetic alterations.	('genetic alterations', 'Var', (100, 119))	('FGFR2', 'Gene', '2263', (52, 57))	('FGFR2', 'Gene', (52, 57))	('BTC', 'Phenotype', 'HP:0100574', (77, 80))	('NTRK', 'Gene', (37, 41))	('IDH1', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (43, 47))
392129	33561950	A combined analysis of the KEYNOTE-28 and KEYNOTE-158 study reported an RR of 7.1% in 127 BTC patients with higher RRs in the PD-L1 positive group versus negative group.	('patients', 'Species', '9606', (94, 102))	('RRs', 'MPA', (115, 118))	('PD-L1', 'Gene', (126, 131))	('positive', 'Var', (132, 140))	('PD-L1', 'Gene', '29126', (126, 131))	('BTC', 'Phenotype', 'HP:0100574', (90, 93))	('higher', 'PosReg', (108, 114))
392145	33561950	Interestingly, MSI-H/dMMR was found in up to 18% of ampullary cancers and was associated with better survival, indicating a potential role of ICIs in the management of this malignancy.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('survival', 'MPA', (101, 109))	('malignancy', 'Disease', 'MESH:D009369', (173, 183))	('MSI-H', 'Chemical', '-', (15, 20))	('better', 'PosReg', (94, 100))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('malignancy', 'Disease', (173, 183))	('MSI-H/dMMR', 'Var', (15, 25))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
392170	33561950	Many of these pathways overlap with altered interferon-gamma signaling as a result of JAK1/2 mutation being a classical example.	('interferon-gamma', 'Gene', '3458', (44, 60))	('JAK1/2', 'Gene', '3716;3717', (86, 92))	('JAK1/2', 'Gene', (86, 92))	('interferon-gamma', 'Gene', (44, 60))	('mutation', 'Var', (93, 101))
392174	33561950	The mutation profile of metastatic lesions resembles that of primary lesions in each patient, but a new/second mutation in beta-2 microglobulin (B2M) gene was identified in the metastatic tumor of respective patients, suggesting that B2M mutations may contribute to secondary resistance to ICIs.	('tumor', 'Disease', (188, 193))	('secondary resistance', 'CPA', (266, 286))	('contribute', 'Reg', (252, 262))	('patient', 'Species', '9606', (208, 215))	('patients', 'Species', '9606', (208, 216))	('patient', 'Species', '9606', (85, 92))	('mutations', 'Var', (238, 247))	('B2M', 'Gene', (234, 237))	('B2M', 'Gene', '567', (234, 237))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('B2M', 'Gene', (145, 148))	('beta-2 microglobulin', 'Gene', '567', (123, 143))	('B2M', 'Gene', '567', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('beta-2 microglobulin', 'Gene', (123, 143))
392214	30855491	The report of IHC analysis was S100 (-), CK (focal+), Vim (+), EMA (+), DOG1 (-), SMA (focal+), CD65 (+), CD117(-), CD34 (-), P40 (-) and P63 (-).	('SMA', 'Gene', '6606', (82, 85))	('SMA', 'Gene', (82, 85))	('P63', 'Gene', (138, 141))	('CD65 (+', 'Var', (96, 103))	('DOG1', 'Gene', '55107', (72, 76))	('Vim', 'Gene', (54, 57))	('P40', 'Gene', (126, 129))	('CD34', 'Gene', (116, 120))	('CD34', 'Gene', '947', (116, 120))	('P63', 'Gene', '8626', (138, 141))	('Vim', 'Gene', '7431', (54, 57))	('P40', 'Gene', '8626', (126, 129))	('DOG1', 'Gene', (72, 76))	('CD117(-', 'Var', (106, 113))
392298	29770138	Although increasing number of studies are demonstrating CTA re-expression in cancer, their functional role in oncogenesis is largely unexplored.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('re-expression', 'Var', (60, 73))	('CTA', 'Protein', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
392350	29770138	Further, in colorectal cancer, the presence of NY-ESO-1 antibodies has been recently correlated with several prognostic clinicopathological parameters including depth of tumor invasion, clinical stage, lymph node, and distant metastasis.	('colorectal cancer', 'Disease', (12, 29))	('presence', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('distant metastasis', 'CPA', (218, 236))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('NY-ESO-1', 'Gene', '1485', (47, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('lymph node', 'CPA', (202, 212))	('tumor', 'Disease', (170, 175))	('correlated', 'Reg', (85, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('NY-ESO-1', 'Gene', (47, 55))
392371	29770138	Other modifications to the acellular vaccine approach currently in clinical trial are the use of a bacterial vector for NY-ESO-1 vaccine delivery (NCT01967758, Table 1); and combinatorial treatment of NY-ESO-1 vaccination with the mTOR inhibitor Sirolimus (NCT01536054, NCT02833506, Table 1) or with the demethylating agent Decitabine (NCT02750995, Table 1).	('Sirolimus', 'Chemical', 'MESH:D020123', (246, 255))	('NCT02833506', 'Var', (270, 281))	('NY-ESO-1', 'Gene', (201, 209))	('mTOR', 'Gene', '2475', (231, 235))	('NY-ESO-1', 'Gene', '1485', (120, 128))	('mTOR', 'Gene', (231, 235))	('Decitabine', 'Chemical', 'MESH:D000077209', (324, 334))	('NY-ESO-1', 'Gene', '1485', (201, 209))	('NY-ESO-1', 'Gene', (120, 128))	('NCT01536054', 'Var', (257, 268))
392373	29770138	The safety and efficacy of NY-ESO-1-pulsed DCs is currently under study in various clinical trials (Table 1), either alone (NCT02692976, NCT01883518, NCT02334735, NCT02224599) or in combination with a NY-ESO-1 protein vaccine and TLR4 agonist (NCT02387125).	('NY-ESO-1', 'Gene', (27, 35))	('TLR4', 'Gene', (230, 234))	('TLR4', 'Gene', '7099', (230, 234))	('NY-ESO-1', 'Gene', '1485', (201, 209))	('NY-ESO-1', 'Gene', (201, 209))	('NCT01883518', 'Var', (137, 148))	('NY-ESO-1', 'Gene', '1485', (27, 35))	('NCT02224599', 'Var', (163, 174))	('NCT02334735', 'Var', (150, 161))	('NCT02692976', 'Var', (124, 135))
392385	29770138	In a first cohort, approximately half of patients with metastatic melanoma or synovial cell sarcoma who received NY-ESO-1 transduced CD8+ T cells and IL-2 showed a clinical response.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('NY-ESO-1', 'Gene', '1485', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('synovial cell sarcoma', 'Phenotype', 'HP:0012570', (78, 99))	('transduced', 'Var', (122, 132))	('CD8', 'Gene', (133, 136))	('CD8', 'Gene', '925', (133, 136))	('synovial cell sarcoma', 'Disease', (78, 99))	('patients', 'Species', '9606', (41, 49))	('synovial cell sarcoma', 'Disease', 'MESH:D013584', (78, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('NY-ESO-1', 'Gene', (113, 121))
392392	29770138	While some current trials, summarized in Table 2, study NY-ESO-1 specific or multi-TAA TCR-transduced T cells in a range of advanced solid tumors (NCT03047811, NCT02457650, NCT02869217, NCT02366546), others focus on subgroups of patients with esophageal cancer (NCT01795976), breast cancer (NCT03093350), pancreatic cancer (NCT03192462), rhabdomyosarcoma (NCT02239861), hepatocellular carcinoma (NCT03175705), synovial sarcoma (NCT03250325), or hematological cancers (NCT02494167, NCT02291848).	('patients', 'Species', '9606', (229, 237))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (305, 322))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (338, 354))	('breast cancer', 'Disease', 'MESH:D001943', (276, 289))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (410, 426))	('esophageal cancer', 'Disease', (243, 260))	('breast cancer', 'Disease', (276, 289))	('NY-ESO-1', 'Gene', '1485', (56, 64))	('NCT03192462', 'Var', (324, 335))	('hematological cancers', 'Disease', (445, 466))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (370, 394))	('carcinoma', 'Phenotype', 'HP:0030731', (385, 394))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('NY-ESO-1', 'Gene', (56, 64))	('solid tumors', 'Disease', 'MESH:D009369', (133, 145))	('hematological cancers', 'Disease', 'MESH:D009369', (445, 466))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('NCT02494167', 'Var', (468, 479))	('NCT03047811', 'Var', (147, 158))	('NCT01795976', 'Var', (262, 273))	('pancreatic cancer', 'Disease', 'MESH:D010190', (305, 322))	('esophageal cancer', 'Disease', 'MESH:D004938', (243, 260))	('NCT03093350', 'Var', (291, 302))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (370, 394))	('cancers', 'Phenotype', 'HP:0002664', (459, 466))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('sarcoma', 'Phenotype', 'HP:0100242', (347, 354))	('sarcoma', 'Phenotype', 'HP:0100242', (419, 426))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('NCT03250325', 'Var', (428, 439))	('cancer', 'Phenotype', 'HP:0002664', (459, 465))	('pancreatic cancer', 'Disease', (305, 322))	('rhabdomyosarcoma', 'Disease', (338, 354))	('NCT02239861', 'Var', (356, 367))	('synovial sarcoma', 'Disease', (410, 426))	('hepatocellular carcinoma', 'Disease', (370, 394))	('NCT03175705', 'Var', (396, 407))	('synovial sarcoma', 'Disease', 'MESH:D013584', (410, 426))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('solid tumors', 'Disease', (133, 145))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (338, 354))
392395	29770138	Similarly, adoptive transfer of affinity-enhanced NY-ESO-1 transduced T cells is under evaluation (Table 2) in metastatic melanoma (NCT01350401), ovarian cancer (NCT01567891), synovial sarcoma (NCT01343043), myxoid/round cell liposarcoma (NCT02992743) and non-small cell lung cancer (NCT03029273, NCT02588612), and in a patient cohort with a variety of advanced solid cancers (NCT03159585).	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (256, 282))	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('liposarcoma', 'Disease', (226, 237))	('NCT02992743', 'Var', (239, 250))	('synovial sarcoma', 'Disease', (176, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (146, 160))	('NCT03029273', 'Var', (284, 295))	('myxoid/round cell liposarcoma', 'Phenotype', 'HP:0012268', (208, 237))	('NCT02588612', 'Var', (297, 308))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (271, 282))	('synovial sarcoma', 'Disease', 'MESH:D013584', (176, 192))	('non-small cell lung cancer', 'Disease', (256, 282))	('advanced solid cancers', 'Disease', 'MESH:D006223', (353, 375))	('liposarcoma', 'Phenotype', 'HP:0012034', (226, 237))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('ovarian cancer', 'Disease', (146, 160))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (176, 192))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('ovarian cancer', 'Phenotype', 'HP:0100615', (146, 160))	('liposarcoma', 'Disease', 'MESH:D008080', (226, 237))	('NY-ESO-1', 'Gene', '1485', (50, 58))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (256, 282))	('advanced solid cancers', 'Disease', (353, 375))	('NCT01343043', 'Var', (194, 205))	('NCT01350401', 'Var', (132, 143))	('patient', 'Species', '9606', (320, 327))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (260, 282))	('NY-ESO-1', 'Gene', (50, 58))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('NCT01567891', 'Var', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancers', 'Phenotype', 'HP:0002664', (368, 375))
392396	29770138	Furthermore, the safety, feasibility, and efficacy of NY-ESO-1 or multi TAA transduced T cell therapy in combination with other modalities is currently under review, including combination with treatment with the demethylating agent Decitabine (NCT03017131, NCT01333046, Table 3), NY-ESO-1157-165-pulsed DCs (NCT01697527, Table 3), transduced peripheral blood stem cells (NCT03240861, Table 3), or dominant-negative transforming growth factor-beta receptor II transduced TILs (NCT02650986, Table 3).	('NY-ESO-1', 'Gene', '1485', (54, 62))	('NY-ESO-1', 'Gene', '1485', (280, 288))	('NY-ESO-1', 'Gene', (54, 62))	('NY-ESO-1', 'Gene', (280, 288))	('NCT03240861', 'Var', (371, 382))	('NCT03017131', 'Var', (244, 255))	('Decitabine', 'Chemical', 'MESH:D000077209', (232, 242))
392419	29770138	Therefore, a pilot phase I trial has been designed to determine the safety and efficacy of combining CTLA-4 blockade with NY-ESO-1 adoptive T cell therapy and NY-ESO-1 vaccination in patients with locally advanced or metastatic malignancies (NCT02070406, Table 3).	('metastatic', 'CPA', (217, 227))	('NY-ESO-1', 'Gene', (159, 167))	('malignancies', 'Disease', (228, 240))	('NY-ESO-1', 'Gene', '1485', (122, 130))	('locally advanced', 'Disease', (197, 213))	('NY-ESO-1', 'Gene', '1485', (159, 167))	('CTLA-4', 'Gene', (101, 107))	('blockade', 'Var', (108, 116))	('malignancies', 'Disease', 'MESH:D009369', (228, 240))	('NY-ESO-1', 'Gene', (122, 130))	('patients', 'Species', '9606', (183, 191))
392420	29770138	Similarly to CTLA-4 inhibition, inhibition of the immune checkpoint molecule PD-1 induces a NY-ESO-1 specific CD8+ cytotoxic immune response.	('induces', 'Reg', (82, 89))	('inhibition', 'Var', (32, 42))	('NY-ESO-1', 'Gene', '1485', (92, 100))	('CD8', 'Gene', (110, 113))	('NY-ESO-1', 'Gene', (92, 100))	('CD8', 'Gene', '925', (110, 113))	('PD-1', 'Gene', (77, 81))
392422	29770138	In vitro blockade of both PD-1 and Tim-3 increased cytotoxic cell proliferation and cytokine secretion of NY-ESO-1157-165 CD8+ T cells.	('PD-1', 'Gene', (26, 30))	('increased', 'PosReg', (41, 50))	('Tim-3', 'Gene', (35, 40))	('cytokine secretion', 'MPA', (84, 102))	('NY-ESO-1', 'Gene', '1485', (106, 114))	('CD8', 'Gene', (122, 125))	('cytotoxic cell proliferation', 'CPA', (51, 79))	('Tim-3', 'Gene', '84868', (35, 40))	('CD8', 'Gene', '925', (122, 125))	('NY-ESO-1', 'Gene', (106, 114))	('blockade', 'Var', (9, 17))
392428	29770138	In this study, NY-ESO-1 transduced T cells could infiltrate tumors and reduce tumor growth by 50%; however, the cells could not reduce tumor burden and showed upregulation of PD-1, Tim-3, and LAG-3.	('reduce', 'NegReg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (60, 65))	('Tim-3', 'Gene', (181, 186))	('NY-ESO-1', 'Gene', '1485', (15, 23))	('transduced', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('NY-ESO-1', 'Gene', (15, 23))	('LAG-3', 'Gene', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('Tim-3', 'Gene', '84868', (181, 186))	('PD-1', 'Gene', (175, 179))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumors', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('LAG-3', 'Gene', '3902', (192, 197))	('upregulation', 'PosReg', (159, 171))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
392429	29770138	PD-1 blockade in addition to injection of transduced T cells reduced the tumor burden with an additional 35%.	('blockade', 'Var', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PD-1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('T cells reduced', 'Phenotype', 'HP:0005403', (53, 68))	('tumor', 'Disease', (73, 78))	('reduced', 'NegReg', (61, 68))
392430	29770138	Ongoing clinical trials are exploring the safety of combining NY-ESO-1 peptide vaccination with Nivolumab (NCT01176461, Table 3), or with both Nivolumab and Ipilimumab (NCT01176474, Table 3).	('NY-ESO-1', 'Gene', (62, 70))	('Nivolumab', 'Chemical', 'MESH:D000077594', (143, 152))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (157, 167))	('Nivolumab', 'Chemical', 'MESH:D000077594', (96, 105))	('NY-ESO-1', 'Gene', '1485', (62, 70))	('NCT01176461', 'Var', (107, 118))
392438	29770138	Since then, several preclinical studies have shown that demethylation not only increases expression of NY-ESO-1 specifically in tumor cells, but also induces specific CD8+ immune responses and tumor cell cytotoxicity; and when used in combination with NY-ESO-1 immunotherapy it reduced the tumor burden and prolonged the survival in several mouse models.	('CD8', 'Gene', '925', (167, 170))	('mouse', 'Species', '10090', (341, 346))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('NY-ESO-1', 'Gene', '1485', (103, 111))	('demethylation', 'Var', (56, 69))	('tumor', 'Disease', (290, 295))	('expression', 'MPA', (89, 99))	('NY-ESO-1', 'Gene', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('prolonged', 'PosReg', (307, 316))	('tumor', 'Disease', (193, 198))	('survival', 'CPA', (321, 329))	('increases', 'PosReg', (79, 88))	('reduced', 'NegReg', (278, 285))	('CD8', 'Gene', (167, 170))	('NY-ESO-1', 'Gene', '1485', (252, 260))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', (128, 133))	('NY-ESO-1', 'Gene', (252, 260))	('cytotoxicity', 'Disease', (204, 216))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cytotoxicity', 'Disease', 'MESH:D064420', (204, 216))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('induces', 'Reg', (150, 157))
392439	29770138	These experimental findings suggest that epigenetic modulation may enhance or even enable NY-ESO-1 adoptive immunotherapy in poorly immunogenic tumor types.	('enable', 'PosReg', (83, 89))	('immunogenic tumor', 'Disease', 'MESH:D009369', (132, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('NY-ESO-1', 'Gene', (90, 98))	('enhance', 'PosReg', (67, 74))	('immunogenic tumor', 'Disease', (132, 149))	('NY-ESO-1', 'Gene', '1485', (90, 98))	('epigenetic modulation', 'Var', (41, 62))
392539	27462775	An integrative framework to identify cell death-related microRNAs in esophageal squamous cell carcinoma Cell death is a critical biological process involved in many important functions, and defects in this system are usually linked with numerous human diseases including cancers.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (69, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('esophageal squamous cell carcinoma', 'Disease', (69, 103))	('defects', 'Var', (190, 197))	('numerous human diseases', 'Disease', (237, 260))	('numerous human diseases', 'Disease', 'MESH:D015658', (237, 260))	('linked', 'Reg', (225, 231))	('cancers', 'Disease', 'MESH:D009369', (271, 278))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('cancers', 'Disease', (271, 278))
392541	27462775	Follow-up experimental verification of 7 miRNAs indicated at least 3 miRNAs (MIR20b, MIR498 and MIR196) were involved in both apoptosis and autophagy processes.	('MIR20b', 'Gene', (77, 83))	('MIR20b', 'Gene', '574032', (77, 83))	('MIR498', 'Gene', '574460', (85, 91))	('MIR498', 'Gene', (85, 91))	('apoptosis', 'CPA', (126, 135))	('MIR196', 'Var', (96, 102))	('involved', 'Reg', (109, 117))	('autophagy processes', 'CPA', (140, 159))
392543	27462775	This integrative framework can also be easily extended to identify miRNAs in other key cellular signaling pathways or may find conditional specific miRNAs in other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('miRNAs', 'Var', (67, 73))
392567	27462775	In esophageal cancers cell line KYSE150, as shown in the up panel of Figure 2A, over-expression of MIR30e, MIR363, MIR498, MIR196, MIR422, MIR337 or MIR202 remarkably increase the LC3-I to LC3-II conversion whereas miR-20b modestly decrease.	('MIR202', 'Gene', (149, 155))	('esophageal cancers', 'Disease', (3, 21))	('MIR337', 'Gene', '442905', (139, 145))	('MIR363', 'Gene', (107, 113))	('MIR422', 'Var', (131, 137))	('miR-20b', 'Gene', '574032', (215, 222))	('LC3', 'Gene', (189, 192))	('esophageal cancers', 'Disease', 'MESH:D004938', (3, 21))	('LC3', 'Gene', (180, 183))	('MIR498', 'Gene', '574460', (115, 121))	('MIR498', 'Gene', (115, 121))	('MIR30e', 'Gene', (99, 105))	('MIR202', 'Gene', '574448', (149, 155))	('over-expression', 'PosReg', (80, 95))	('MIR196', 'Var', (123, 129))	('MIR337', 'Gene', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('MIR30e', 'Gene', '407034', (99, 105))	('LC3', 'Gene', '84557', (189, 192))	('MIR363', 'Gene', '574031', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('miR-20b', 'Gene', (215, 222))	('LC3', 'Gene', '84557', (180, 183))	('increase', 'PosReg', (167, 175))
392568	27462775	In addition to LC3, the sequestosome 1(SQSTM1/P62) protein were accumulated when MIR30e, MIR363, MIR498 or MIR196 were transfected whereas MIR20b significantly decreased (up panel of Figure 2B).	('SQSTM1', 'Gene', (39, 45))	('MIR498', 'Gene', (97, 103))	('P62', 'Gene', '8878', (46, 49))	('P62', 'Gene', (46, 49))	('MIR363', 'Gene', (89, 95))	('SQSTM1', 'Gene', '8878', (39, 45))	('MIR20b', 'Gene', (139, 145))	('MIR498', 'Gene', '574460', (97, 103))	('MIR363', 'Gene', '574031', (89, 95))	('decreased', 'NegReg', (160, 169))	('MIR196', 'Var', (107, 113))	('accumulated', 'PosReg', (64, 75))	('LC3', 'Gene', (15, 18))	('LC3', 'Gene', '84557', (15, 18))	('MIR30e', 'Gene', (81, 87))	('sequestosome', 'MPA', (24, 36))	('MIR20b', 'Gene', '574032', (139, 145))	('MIR30e', 'Gene', '407034', (81, 87))
392569	27462775	In another esophageal cancers cell line TE3, transfection of MIR20b, MIR363, MIR498 or MIR196 affected the autophagy when monitoring both LC3 and p62 (down panel of Figure 2A and Figure 2B).	('MIR196', 'Var', (87, 93))	('MIR20b', 'Gene', (61, 67))	('MIR363', 'Gene', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('esophageal cancers', 'Disease', (11, 29))	('autophagy', 'CPA', (107, 116))	('LC3', 'Gene', '84557', (138, 141))	('MIR20b', 'Gene', '574032', (61, 67))	('MIR498', 'Gene', (77, 83))	('LC3', 'Gene', (138, 141))	('MIR498', 'Gene', '574460', (77, 83))	('p62', 'Gene', '8878', (146, 149))	('MIR363', 'Gene', '574031', (69, 75))	('esophageal cancers', 'Disease', 'MESH:D004938', (11, 29))	('p62', 'Gene', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('affected', 'Reg', (94, 102))
392571	27462775	The cleaved PARP were modestly but significantly increased when transfection of MIR20b, MIR30e, MIR498 or MIR196 in both cell lines (Figure 2B).	('increased', 'PosReg', (49, 58))	('PARP', 'Gene', '142', (12, 16))	('MIR196', 'Var', (106, 112))	('MIR20b', 'Gene', (80, 86))	('MIR30e', 'Gene', (88, 94))	('cleaved', 'MPA', (4, 11))	('MIR30e', 'Gene', '407034', (88, 94))	('MIR20b', 'Gene', '574032', (80, 86))	('MIR498', 'Gene', '574460', (96, 102))	('PARP', 'Gene', (12, 16))	('MIR498', 'Gene', (96, 102))
392573	27462775	Collectively, above results suggested that the four predicted miRNAs, MIR20b, MIR30e, MIR498 and MIR196 may be involved in the apoptotic pathway in esophageal cancers cells.	('MIR196', 'Var', (97, 103))	('apoptotic pathway', 'Pathway', (127, 144))	('MIR30e', 'Gene', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('MIR20b', 'Gene', (70, 76))	('involved', 'Reg', (111, 119))	('esophageal cancers', 'Disease', (148, 166))	('MIR498', 'Gene', '574460', (86, 92))	('MIR20b', 'Gene', '574032', (70, 76))	('MIR498', 'Gene', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('esophageal cancers', 'Disease', 'MESH:D004938', (148, 166))	('MIR30e', 'Gene', '407034', (78, 84))
392575	27462775	At one hand, dysfunction in apoptotic machinery hampered damaged cells into apoptotic suicides; at the other hand, cytotoxic stress, for example chemotherapy, will elevate level of autophagy to protect cells from environmental stress or even promote the cancer cell proliferation.	('autophagy', 'CPA', (181, 190))	('elevate', 'PosReg', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (254, 260))	('cytotoxic', 'Var', (115, 124))	('promote', 'PosReg', (242, 249))
392579	27462775	In addition to genetic defects, alterations in genes in cell death pathways also contribute to the disease.	('genetic defects', 'Disease', 'MESH:D030342', (15, 30))	('genes', 'Gene', (47, 52))	('genetic defects', 'Disease', (15, 30))	('contribute', 'Reg', (81, 91))	('alterations', 'Var', (32, 43))	('disease', 'Disease', (99, 106))	('cell death pathways', 'Pathway', (56, 75))
392580	27462775	For example, pharmacological and genetic inhibition of autophagy enhanced the resveratrol-induced cytotoxicity to the ESCC cells.	('cytotoxicity', 'Disease', (98, 110))	('resveratrol', 'Chemical', 'MESH:D000077185', (78, 89))	('autophagy', 'CPA', (55, 64))	('enhanced', 'PosReg', (65, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (98, 110))	('resveratrol-induced', 'MPA', (78, 97))	('genetic inhibition', 'Var', (33, 51))
392581	27462775	A recent study also indicated that AZD2281, Novel poly (ADP-ribose) polymerase inhibitor enhances radio-sensitivity in esophageal squamous cancer cells.	('AZD2281', 'Chemical', 'MESH:C531550', (35, 42))	('AZD2281', 'Var', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('squamous cancer', 'Phenotype', 'HP:0002860', (130, 145))	('radio-sensitivity', 'CPA', (98, 115))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (119, 145))	('esophageal squamous cancer', 'Disease', (119, 145))	('enhances', 'PosReg', (89, 97))
392585	27462775	Follow-up experiments indicated transfection of MIR20b, MIR30e, MIR498 and MIR196 affected the apoptotic pathway in esophageal cancers cells.	('esophageal cancers', 'Disease', (116, 134))	('esophageal cancers', 'Disease', 'MESH:D004938', (116, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('MIR196', 'Var', (75, 81))	('affected', 'Reg', (82, 90))	('MIR20b', 'Gene', (48, 54))	('MIR498', 'Gene', '574460', (64, 70))	('MIR498', 'Gene', (64, 70))	('MIR30e', 'Gene', (56, 62))	('MIR30e', 'Gene', '407034', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('MIR20b', 'Gene', '574032', (48, 54))	('apoptotic pathway', 'Pathway', (95, 112))
392587	27462775	The results indicated at least 3 miRNAs (MIR20b, MIR498 and MIR196) were involved in cell death in two esophageal cancers cell lines.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cell death', 'CPA', (85, 95))	('MIR196', 'Var', (60, 66))	('esophageal cancers', 'Disease', (103, 121))	('MIR20b', 'Gene', (41, 47))	('esophageal cancers', 'Disease', 'MESH:D004938', (103, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('MIR20b', 'Gene', '574032', (41, 47))	('involved', 'Reg', (73, 81))	('MIR498', 'Gene', '574460', (49, 55))	('MIR498', 'Gene', (49, 55))
392588	27462775	Interestingly, three out of the four apoptotic related miRNAs (MIR20b, MIR498 and MIR196), can modulate both autophagy and apoptosis processes.	('MIR498', 'Gene', '574460', (71, 77))	('MIR498', 'Gene', (71, 77))	('modulate', 'Reg', (95, 103))	('apoptosis processes', 'CPA', (123, 142))	('MIR196', 'Var', (82, 88))	('MIR20b', 'Gene', (63, 69))	('MIR20b', 'Gene', '574032', (63, 69))	('autophagy', 'CPA', (109, 118))
392589	27462775	For example, MIR101 can modulate MCL1 (myeloid cell leukemia sequence 1) therefore promotes apoptosis.	('myeloid cell leukemia sequence 1', 'Gene', (39, 71))	('MCL1', 'Gene', (33, 37))	('myeloid cell leukemia sequence 1', 'Gene', '4170', (39, 71))	('apoptosis', 'CPA', (92, 101))	('promotes', 'PosReg', (83, 91))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (39, 60))	('MIR101', 'Var', (13, 19))	('MCL1', 'Gene', '4170', (33, 37))	('modulate', 'Reg', (24, 32))
392590	27462775	On the other hand, MIR101 can also negatively modulate the autophagy flux via inhibiting autophagy-related protein RAB5A.	('autophagy-related', 'Protein', (89, 106))	('modulate', 'Reg', (46, 54))	('negatively', 'NegReg', (35, 45))	('inhibiting', 'NegReg', (78, 88))	('MIR101', 'Var', (19, 25))	('autophagy flux', 'CPA', (59, 73))	('RAB5A', 'Gene', (115, 120))	('RAB5A', 'Gene', '5868', (115, 120))
392595	27462775	GSE13937 includes 76 US and Japanese patients enrolled in 3 distinct cohorts; GSE6188 for 104 normal and 151 disease samples; and GSE43732 for 119 normal and 119 cancer samples.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('GSE6188', 'Chemical', '-', (78, 85))	('cancer', 'Disease', (162, 168))	('patients', 'Species', '9606', (37, 45))	('GSE43732', 'Var', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('GSE6188', 'Gene', (78, 85))
392607	27462775	The membranes were blocked in 5% nonfat milk for 1 h, incubated with antibodies against PARP (1:1000, CST, USA), p62 and LC3 (1:1000, CST, USA) and beta-actin (1:1000, Santa Cruz Biotechnology, USA), respectively, according to the manufacturer's recommendations.	('beta-actin', 'Gene', '728378', (148, 158))	('p62', 'Gene', (113, 116))	('beta-actin', 'Gene', (148, 158))	('LC3', 'Gene', '84557', (121, 124))	('PARP', 'Gene', '142', (88, 92))	('LC3', 'Gene', (121, 124))	('1:1000', 'Var', (160, 166))	('1:1000', 'Var', (126, 132))	('p62', 'Gene', '8878', (113, 116))	('PARP', 'Gene', (88, 92))
392699	23805780	Levels of p53, Bax, Securin and p65 in esophageal and stomach cells were elevated during early days of RAN exposure while those of different mitotic checkpoint proteins were downregulated.	('p65', 'Gene', '19697', (32, 35))	('Securin', 'MPA', (20, 27))	('Bax', 'Gene', (15, 18))	('downregulated', 'NegReg', (174, 187))	('Bax', 'Gene', '12028', (15, 18))	('p53', 'Var', (10, 13))	('elevated', 'PosReg', (73, 81))	('p65', 'Gene', (32, 35))
392701	23805780	Present study suggested (a) RAN induces stomach cancer, however, presence of lime promoted higher cell transformation and thereby developed cancer earlier, (b) perturbations in components of the chromosome segregation machinery could be involved in the initial process of carcinogenicity and (c) the importance of precocious anaphase as a screening marker for identification of mitotic checkpoint defects during early days.	('higher cell transformation', 'CPA', (91, 117))	('perturbations', 'Var', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('stomach cancer', 'Disease', 'MESH:D013274', (40, 54))	('cancer', 'Disease', (140, 146))	('involved', 'Reg', (237, 245))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('stomach cancer', 'Phenotype', 'HP:0012126', (40, 54))	('lime', 'Species', '159033', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('stomach cancer', 'Disease', (40, 54))
392712	23805780	Recently, 40% esophageal cancer samples collected from patients of Meghalaya state having only RAN-chewing habit showed deletion of the microsatellite markers D9S1748 and D9S1749, located close to exon 1beta of CDKN2A/ARF gene at 9p21.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('D9S1748', 'Var', (159, 166))	('esophageal cancer', 'Disease', (14, 31))	('CDKN2A', 'Gene', (211, 217))	('ARF', 'Disease', 'MESH:D058186', (218, 221))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('CDKN2A', 'Gene', '1029', (211, 217))	('ARF', 'Disease', (218, 221))	('deletion', 'Var', (120, 128))	('patients', 'Species', '9606', (55, 63))	('-chewing habit', 'Phenotype', 'HP:0005216', (98, 112))	('D9S1749', 'Var', (171, 178))
392724	23805780	Moreover, genetic instability is also associated with chromosome instability (CIN) which leads to aneuploidy, a hallmark of cancer.	('chromosome instability', 'Disease', (54, 76))	('CIN', 'Disease', (78, 81))	('leads', 'Reg', (89, 94))	('associated', 'Reg', (38, 48))	('chromosome instability', 'Phenotype', 'HP:0040012', (54, 76))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CIN', 'Disease', 'MESH:D007674', (78, 81))	('hallmark of cancer', 'Disease', (112, 130))	('aneuploidy', 'Disease', (98, 108))	('CIN', 'Phenotype', 'HP:0040012', (78, 81))	('hallmark of cancer', 'Disease', 'MESH:D009369', (112, 130))	('aneuploidy', 'Disease', 'MESH:D000782', (98, 108))	('genetic instability', 'Var', (10, 29))
392782	23805780	The mean frequency (13.8%) of aneuploid cells was scored in both the stomach tumor bearing mice.	('mice', 'Species', '10090', (91, 95))	('stomach tumor', 'Phenotype', 'HP:0006753', (69, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('stomach tumor', 'Disease', 'MESH:D013274', (69, 82))	('aneuploid', 'Var', (30, 39))	('stomach tumor', 'Disease', (69, 82))
392783	23805780	Overall, the frequency of aneuploid cells was more following RAN + lime administeration than RAN alone (Table 1).	('RAN + lime', 'Var', (61, 71))	('lime', 'Species', '159033', (67, 71))	('aneuploid cells', 'Var', (26, 41))
392790	23805780	Levels of p53, p65, Bax and Securin in BMC from mice after administeration of RAN extract with or without lime for 60, 90 and 180 days, and those esophagus and stomach after 180 days of feeding were examined by immunoblotting.	('p65', 'Gene', '19697', (15, 18))	('lime', 'Species', '159033', (106, 110))	('p65', 'Gene', (15, 18))	('Bax', 'Gene', '12028', (20, 23))	('mice', 'Species', '10090', (48, 52))	('Bax', 'Gene', (20, 23))	('p53', 'Var', (10, 13))
392793	23805780	Such enhancement was significantly higher in RAN + lime than in only RAN administered mice (Figure 5).	('lime', 'Species', '159033', (51, 55))	('mice', 'Species', '10090', (86, 90))	('enhancement', 'PosReg', (5, 16))	('RAN + lime', 'Var', (45, 55))	('higher', 'PosReg', (35, 41))
392810	23805780	Such premature sister chromatids separation has been observed in yeast Mad2 mutants and Drosophila Bub1 mutants.	('Drosophila', 'Species', '7227', (88, 98))	('mutants', 'Var', (104, 111))	('Mad2', 'Gene', (71, 75))	('premature sister chromatids separation', 'Phenotype', 'HP:0200024', (5, 43))	('observed', 'Reg', (53, 61))	('yeast', 'Species', '4932', (65, 70))	('mutants', 'Var', (76, 83))
392812	23805780	Indeed, we observed aneuploid cells in BMC of mouse given RAN with and without lime, initially at low frequency and that was increased gradually irrespective of the development of stomach cancer.	('stomach cancer', 'Disease', 'MESH:D013274', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('aneuploid cells', 'Var', (20, 35))	('stomach cancer', 'Phenotype', 'HP:0012126', (180, 194))	('lime', 'Species', '159033', (79, 83))	('mouse', 'Species', '10090', (46, 51))	('stomach cancer', 'Disease', (180, 194))
392828	23805780	In view of the reports that defective mitotic checkpoint cause chromosomal instability and aneuploidy, we examined expression of Aurora kinases (Aurora-A and Aurora-B), Mad2 and Bub1 in bone marrow, esophagus and stomach cells of the mouse administered with RBN with or without lime for 260 days.	('aneuploidy', 'Disease', 'MESH:D000782', (91, 101))	('cause', 'Reg', (57, 62))	('mouse', 'Species', '10090', (234, 239))	('defective', 'Var', (28, 37))	('Aurora-B', 'Gene', '20871', (158, 166))	('Aurora-A', 'Gene', '20878', (145, 153))	('lime', 'Species', '159033', (278, 282))	('aneuploidy', 'Disease', (91, 101))	('BN', 'Chemical', 'MESH:C072598', (259, 261))	('chromosomal instability', 'Phenotype', 'HP:0040012', (63, 86))	('Aurora-B', 'Gene', (158, 166))	('Aurora-A', 'Gene', (145, 153))	('chromosomal instability', 'MPA', (63, 86))
392838	23805780	Over-expression of Securin has been shown to induce aneuploidy, arising from chromatid missegeration in human cell.	('Securin', 'Gene', (19, 26))	('aneuploidy', 'Disease', (52, 62))	('induce', 'Reg', (45, 51))	('human', 'Species', '9606', (104, 109))	('aneuploidy', 'Disease', 'MESH:D000782', (52, 62))	('Over-expression', 'Var', (0, 15))
392840	23805780	Besides Securin, we also observed increased expression of p53 and p65 (relA) in all the tissues of mice that were exposed to RAN-extract with or without lime.	('mice', 'Species', '10090', (99, 103))	('expression', 'MPA', (44, 54))	('p53', 'Var', (58, 61))	('p65', 'Gene', (66, 69))	('relA', 'Gene', (71, 75))	('p65', 'Gene', '19697', (66, 69))	('lime', 'Species', '159033', (153, 157))	('relA', 'Gene', '19697', (71, 75))	('increased', 'PosReg', (34, 43))
392841	23805780	Mutation in p53 gene is known to be associated with a variety of human and experimental animal cancers.	('human', 'Species', '9606', (65, 70))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('Mutation', 'Var', (0, 8))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('p53', 'Gene', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('associated', 'Reg', (36, 46))
392842	23805780	The accumulation of p53 protein or its stabilization in all the RAN treated (with or without lime) cells is an important indicator of the presence of mutant p53 protein as proposed earlier.	('stabilization', 'MPA', (39, 52))	('protein', 'Protein', (24, 31))	('protein', 'Protein', (161, 168))	('accumulation', 'PosReg', (4, 16))	('p53 protein', 'Protein', (20, 31))	('lime', 'Species', '159033', (93, 97))	('mutant', 'Var', (150, 156))	('p53', 'Gene', (157, 160))
392852	23805780	Present study suggested (a) RAN induces stomach cancer, however, presence of lime promoted higher cell transformation and thereby developed cancer earlier, (b) perturbations in components of the chromosome segregation machinery could be involved in the initial process of carcinogenicity and (c) the importance of precocious anaphase as a screening marker for identification of mitotic check point defects during early days.	('mitotic check point defects', 'Disease', (378, 405))	('higher cell transformation', 'CPA', (91, 117))	('perturbations', 'Var', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('stomach cancer', 'Disease', 'MESH:D013274', (40, 54))	('cancer', 'Disease', (140, 146))	('involved', 'Reg', (237, 245))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('mitotic check point defects', 'Disease', 'MESH:D016171', (378, 405))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('stomach cancer', 'Phenotype', 'HP:0012126', (40, 54))	('lime', 'Species', '159033', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('stomach cancer', 'Disease', (40, 54))
392930	32369505	We can speculate that the immune activity provoked by Leptotrichia, rather than Leptotrichia itself, may facilitate esophageal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('Leptotrichia', 'Var', (54, 66))	('Leptotrichia', 'Species', '109328', (80, 92))	('facilitate', 'PosReg', (105, 115))	('Leptotrichia', 'Species', '109328', (54, 66))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('esophageal', 'Disease', (116, 126))
393026	29695253	qRT-PCR analysis confirmed the microarray findings for hsa-miR-194* and hsa-miR-665 (p < 0.001 each) with AUC values of 0.811 (95% CI 0.694-0.927) and 0.817 (95% CI 0.704-0.930), respectively, in ROC analysis.	('hsa-miR-194*', 'Var', (55, 67))	('miR-665', 'Gene', (76, 83))	('miR-665', 'Gene', '100126315', (76, 83))	('0.817', 'Var', (151, 156))
393060	29695253	The following eight miRNAs were upregulated in non-responders: hsa-miR-1323, hsa-miR-3678-3p, hsv2-miR-H7-3p, hsa-miR-194*, hsa-miR-3152, kshv-miR-K12-4-3p, hsa-miR-665 and hsa-miR-3659.	('hsa-miR-3678-3p', 'Var', (77, 92))	('hsa-miR-194*', 'Var', (110, 122))	('hsa-miR-3152', 'Var', (124, 136))	('kshv', 'Species', '37296', (138, 142))	('kshv-miR-K12-4-3p', 'Var', (138, 155))	('miR-665', 'Gene', (161, 168))	('hsv2-miR-H7-3p', 'Var', (94, 108))	('hsv2', 'Species', '10310', (94, 98))	('miR-665', 'Gene', '100126315', (161, 168))	('upregulated', 'PosReg', (32, 43))
393061	29695253	By contrast, the four miRNAs hsa-miR-126*, hsa-miR-484, hsa-miR-330-3p and hsa-miR-3653 were downregulated in non-responders compared with that in responders (Table 2).	('miR-126', 'Gene', (33, 40))	('hsa-miR-3653', 'Gene', (75, 87))	('hsa-miR-484', 'Gene', '619553', (43, 54))	('hsa-miR-3653', 'Gene', '100500833', (75, 87))	('hsa-miR-330-3p', 'Var', (56, 70))	('downregulated', 'NegReg', (93, 106))	('hsa-miR-484', 'Gene', (43, 54))	('non-responders', 'Disease', (110, 124))	('miR-126', 'Gene', '406913', (33, 40))
393063	29695253	For miR-194* and miR-665 but not the remaining miRNAs, the microarray results could be confirmed with significantly higher miRNA levels in non-responders than in responders (median quantitative gene expression levels: 0.11 vs. 0.03, respectively, and 0.29 vs. 0.06, respectively; p < 0.001 each with a significance level of p < 0.006 after correction for multiple testing, Fig.	('miRNA levels', 'MPA', (123, 135))	('higher', 'PosReg', (116, 122))	('quantitative gene expression levels', 'MPA', (181, 216))	('miR-665', 'Gene', (17, 24))	('miR-194*', 'Var', (4, 12))	('miR-665', 'Gene', '100126315', (17, 24))
393064	29695253	ROC analysis showed AUC values of 0.811 (95% CI 0.694-0.927) for miR-194* and 0.817 (95% CI 0.704-0.930) for miR-665 for the non-response to RCTX.	('non-response', 'MPA', (125, 137))	('0.817', 'Var', (78, 83))	('miR-665', 'Gene', (109, 116))	('miR-665', 'Gene', '100126315', (109, 116))	('miR-194*', 'Var', (65, 73))
393065	29695253	The combination of miR-194* and miR-665 (sum of relative values in relation to the median expression level) had only a slightly better AUC value of 0.824 (95% CI 0.713-0.935).	('miR-194*', 'Var', (19, 27))	('miR-665', 'Gene', '100126315', (32, 39))	('miR-665', 'Gene', (32, 39))
393066	29695253	Crosstab analysis using the cut-offs defined by ROC analysis confirmed the association between high levels of miR-194* and miR-665 and non-response to neoadjuvant RCTX (p < 0.001 and p = 0.006; Table 3).	('miR-194*', 'Var', (110, 118))	('non-response', 'CPA', (135, 147))	('miR-665', 'Gene', '100126315', (123, 130))	('miR-665', 'Gene', (123, 130))
393068	29695253	Higher levels of miR-194* and miR-665 defined by ROC analysis were associated only in trend with a worse outcome of the patients in univariate analysis (p = 0.052 and p = 0.197, respectively; Fig.	('miR-194*', 'Var', (17, 25))	('patients', 'Species', '9606', (120, 128))	('miR-665', 'Gene', '100126315', (30, 37))	('miR-665', 'Gene', (30, 37))
393075	29695253	We could confirm the microarray results by single real-time RT-PCR for two miRNAs (miR-194* and miR-665) in an expanded case collection.	('miR-194*', 'Var', (83, 91))	('miR-665', 'Gene', '100126315', (96, 103))	('miR-665', 'Gene', (96, 103))
393079	29695253	Of note, one recent paper that also used the Agilent detection platform showed that a model encompassing upregulated miR-145-5p, upregulated miR-152, downregulated miR-193b-3p, and upregulated miR-376a-3p was highly accurate for the prediction of a nonresponse to neoadjuvant radiochemotherapy in an Asian cohort.	('upregulated', 'PosReg', (105, 116))	('downregulated', 'NegReg', (150, 163))	('upregulated', 'PosReg', (129, 140))	('miR-152', 'Gene', '406943', (141, 148))	('miR-376a-3p', 'Var', (193, 204))	('upregulated', 'PosReg', (181, 192))	('miR-193b-3p', 'Var', (164, 175))	('miR-152', 'Gene', (141, 148))	('miR-145-5p', 'Var', (117, 127))
393110	27857021	Accumulating evidence has shown that diabetic patients treated with metformin display a reduced incidence of neoplastic disease and might improve cancer prognosis, including that of human esophageal cancer cell (ESCC), in clinical trials.	('cancer', 'Disease', (146, 152))	('patients', 'Species', '9606', (46, 54))	('neoplastic disease', 'Phenotype', 'HP:0002664', (109, 127))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (199, 205))	('neoplastic disease', 'Disease', (109, 127))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('metformin', 'Var', (68, 77))	('metformin', 'Chemical', 'MESH:D008687', (68, 77))	('reduced', 'NegReg', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('human', 'Species', '9606', (182, 187))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('improve', 'PosReg', (138, 145))	('neoplastic disease', 'Disease', 'MESH:D009386', (109, 127))	('diabetic', 'Disease', 'MESH:D003920', (37, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (188, 205))	('diabetic', 'Disease', (37, 45))	('esophageal cancer', 'Disease', (188, 205))
393115	27857021	Furthermore, it has been argued that metformin affects the insulin/insulin-like growth factor (I/IGF) pathway and decreases the expression of insulin-like growth factor 1 receptor (IGF-1R).	('insulin', 'Gene', (67, 74))	('insulin', 'Gene', '3630', (142, 149))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (142, 179))	('metformin', 'Chemical', 'MESH:D008687', (37, 46))	('insulin', 'Gene', '3630', (67, 74))	('affects', 'Reg', (47, 54))	('decreases', 'NegReg', (114, 123))	('insulin-like growth factor 1 receptor', 'Gene', (142, 179))	('insulin', 'Gene', (59, 66))	('IGF-1R', 'Gene', '3480', (181, 187))	('expression', 'MPA', (128, 138))	('insulin', 'Gene', (142, 149))	('insulin', 'Gene', '3630', (59, 66))	('IGF-1R', 'Gene', (181, 187))	('metformin', 'Var', (37, 46))
393125	27857021	The results showed that metformin inhibited proliferation of ESCC cells, as well as induced cell cycle arrest and apoptosis.	('induced', 'Reg', (84, 91))	('metformin', 'Var', (24, 33))	('inhibited', 'NegReg', (34, 43))	('arrest', 'Disease', (103, 109))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (92, 109))	('metformin', 'Chemical', 'MESH:D008687', (24, 33))	('apoptosis', 'CPA', (114, 123))	('arrest', 'Disease', 'MESH:D006323', (103, 109))	('proliferation', 'CPA', (44, 57))
393132	27857021	In conclusion, our results supported that metformin has the ability to inhibit the proliferation of ESCCs, which may lead to suppression of the PI3K/AKT/mTOR signaling pathway.	('proliferation', 'CPA', (83, 96))	('inhibit', 'NegReg', (71, 78))	('AKT', 'Gene', (149, 152))	('metformin', 'Var', (42, 51))	('suppression', 'NegReg', (125, 136))	('mTOR', 'Gene', (153, 157))	('mTOR', 'Gene', '2475', (153, 157))	('ESCCs', 'CPA', (100, 105))	('metformin', 'Chemical', 'MESH:D008687', (42, 51))	('AKT', 'Gene', '207', (149, 152))
393167	27857021	To examine the potential molecular mechanisms for metformin antitumor effects, we detected the expression of IGF-IR, PI3K, AKT, pAKT, mTOR, p70S6K, and PKM2 by western blot.	('metformin', 'Chemical', 'MESH:D008687', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('IGF-IR', 'Gene', (109, 115))	('tumor', 'Disease', (64, 69))	('IGF-IR', 'Gene', '3480', (109, 115))	('AKT', 'Gene', '207', (129, 132))	('p70S6K', 'Gene', '6198', (140, 146))	('p70S6K', 'Gene', (140, 146))	('AKT', 'Gene', '207', (123, 126))	('PI3K', 'Var', (117, 121))	('PKM2', 'Gene', '5315', (152, 156))	('PKM2', 'Gene', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mTOR', 'Gene', (134, 138))	('mTOR', 'Gene', '2475', (134, 138))	('AKT', 'Gene', (123, 126))	('AKT', 'Gene', (129, 132))
393168	27857021	The results revealed that metformin reduced IGF-IR, PI3K, AKT, pAKT, mTOR, p70S6K, and PKM2 in EC109 and EC9706 cells (Fig.	('mTOR', 'Gene', (69, 73))	('p70S6K', 'Gene', (75, 81))	('IGF-IR', 'Gene', (44, 50))	('p70S6K', 'Gene', '6198', (75, 81))	('PKM2', 'Gene', (87, 91))	('EC9706', 'CellLine', 'CVCL:E307', (105, 111))	('metformin', 'Chemical', 'MESH:D008687', (26, 35))	('IGF-IR', 'Gene', '3480', (44, 50))	('PI3K', 'Var', (52, 56))	('AKT', 'Gene', '207', (64, 67))	('AKT', 'Gene', '207', (58, 61))	('reduced', 'NegReg', (36, 43))	('PKM2', 'Gene', '5315', (87, 91))	('AKT', 'Gene', (64, 67))	('mTOR', 'Gene', '2475', (69, 73))	('AKT', 'Gene', (58, 61))
393173	27857021	To explain the relationship between the PI3K/AKT/mTOR/PKM2 signaling pathway and apoptosis, we depleted PKM2 to detect the expression of apoptosis-related proteins in Eca109 and EC9706.	('depleted', 'NegReg', (95, 103))	('mTOR', 'Gene', (49, 53))	('mTOR', 'Gene', '2475', (49, 53))	('expression', 'MPA', (123, 133))	('PKM2', 'Gene', '5315', (54, 58))	('EC9706', 'CellLine', 'CVCL:E307', (178, 184))	('AKT', 'Gene', (45, 48))	('Eca109', 'Var', (167, 173))	('PKM2', 'Gene', (104, 108))	('PKM2', 'Gene', '5315', (104, 108))	('PKM2', 'Gene', (54, 58))	('EC9706', 'Var', (178, 184))	('AKT', 'Gene', '207', (45, 48))
393177	27857021	Based on our findings, metformin increased the expression of the pro-apoptosis protein Bim, partly due to the suppression of the PI3K/AKT/mTOR/PKM2 signaling pathway.	('mTOR', 'Gene', (138, 142))	('AKT', 'Gene', (134, 137))	('suppression', 'NegReg', (110, 121))	('mTOR', 'Gene', '2475', (138, 142))	('metformin', 'Chemical', 'MESH:D008687', (23, 32))	('PKM2', 'Gene', '5315', (143, 147))	('increased', 'PosReg', (33, 42))	('Bim', 'Gene', (87, 90))	('AKT', 'Gene', '207', (134, 137))	('Bim', 'Gene', '10018', (87, 90))	('expression', 'MPA', (47, 57))	('PKM2', 'Gene', (143, 147))	('metformin', 'Var', (23, 32))
393188	27857021	To explore the association between suppressing PI3K/AKT/mTOR/PKM2 and apoptosis, apoptosis-related proteins were detected after knockdown of PKM2 in Eca109 and EC9706 cells.	('PKM2', 'Gene', (61, 65))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', '2475', (56, 60))	('PKM2', 'Gene', '5315', (61, 65))	('knockdown', 'Var', (128, 137))	('AKT', 'Gene', (52, 55))	('PKM2', 'Gene', (141, 145))	('detected', 'Reg', (113, 121))	('PKM2', 'Gene', '5315', (141, 145))	('EC9706', 'CellLine', 'CVCL:E307', (160, 166))	('AKT', 'Gene', '207', (52, 55))
393203	27857021	Thus, inhibition of IGF-1R may be effectively block tumor growth in human ESCC.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('human', 'Species', '9606', (68, 73))	('tumor', 'Disease', (52, 57))	('ESCC', 'Disease', (74, 78))	('block', 'NegReg', (46, 51))	('IGF-1R', 'Gene', '3480', (20, 26))	('inhibition', 'Var', (6, 16))	('IGF-1R', 'Gene', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
393208	27857021	Inhibition of PI3K/AKT/mTOR down-regulates PKM2 expression and suppresses cancer metabolism, which has been confirmed in other various cancer cell lines.	('cancer', 'Disease', (135, 141))	('PKM2', 'Gene', '5315', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('down-regulates', 'NegReg', (28, 42))	('expression', 'MPA', (48, 58))	('AKT', 'Gene', '207', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', (74, 80))	('mTOR', 'Gene', (23, 27))	('cancer metabolism', 'Disease', 'MESH:D009369', (74, 91))	('Inhibition', 'Var', (0, 10))	('mTOR', 'Gene', '2475', (23, 27))	('AKT', 'Gene', (19, 22))	('suppresses', 'NegReg', (63, 73))	('cancer metabolism', 'Disease', (74, 91))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('PKM2', 'Gene', (43, 47))
393210	27857021	In order to explain the association between PKM2 and apoptosis, we found knockdown PKM2 activated caspase 3 and down-regulated caspase 9.	('PKM2', 'Gene', '5315', (44, 48))	('caspase 9', 'Gene', (127, 136))	('activated', 'PosReg', (88, 97))	('PKM2', 'Gene', (83, 87))	('caspase 3', 'Gene', (98, 107))	('caspase 9', 'Gene', '842', (127, 136))	('PKM2', 'Gene', '5315', (83, 87))	('caspase 3', 'Gene', '836', (98, 107))	('PKM2', 'Gene', (44, 48))	('down-regulated', 'NegReg', (112, 126))	('knockdown', 'Var', (73, 82))
393223	27857021	These effects may be attributed to metformin inducing cell cycle arrest and apoptosis.	('inducing', 'PosReg', (45, 53))	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('metformin', 'Var', (35, 44))	('arrest', 'Disease', (65, 71))	('metformin', 'Chemical', 'MESH:D008687', (35, 44))	('apoptosis', 'CPA', (76, 85))
393232	28487971	Cellular DNA damage was evaluated by a comet assay and an MTT assay demonstrated that AZT significantly inhibited the viability of TE-11 cells, in a time-and dose-dependent manner.	('viability of TE-11 cells', 'CPA', (118, 142))	('TE-11', 'Chemical', '-', (131, 136))	('MTT', 'Chemical', 'MESH:C070243', (58, 61))	('comet', 'Species', '302767', (39, 44))	('AZT', 'Chemical', 'MESH:D015215', (86, 89))	('AZT', 'Var', (86, 89))	('inhibited', 'NegReg', (104, 113))
393233	28487971	In addition, TE-11 cells treated with various concentrations of AZT exhibited a significant reduction in telomerase activity and percentage of cells in the G1/G0 phase, and an increase in the percentage of cells in the S phase.	('increase', 'PosReg', (176, 184))	('telomerase', 'CPA', (105, 115))	('AZT', 'Var', (64, 67))	('reduction', 'NegReg', (92, 101))	('AZT', 'Chemical', 'MESH:D015215', (64, 67))	('TE-11', 'Chemical', '-', (13, 18))	('activity', 'MPA', (116, 124))
393283	28487971	Treatment with 20, 100 and 200 microM AZT for 48 h resulted in a dose-dependent decrease in telomerase activity (Fig.	('AZT', 'Chemical', 'MESH:D015215', (38, 41))	('telomerase activity', 'MPA', (92, 111))	('decrease', 'NegReg', (80, 88))	('AZT', 'Var', (38, 41))
393291	28487971	In conclusion, AZT may induce DNA damage in TE-11 cells.	('AZT', 'Var', (15, 18))	('AZT', 'Chemical', 'MESH:D015215', (15, 18))	('TE-11', 'Chemical', '-', (44, 49))	('DNA damage', 'MPA', (30, 40))	('induce', 'Reg', (23, 29))
393304	28487971	The results of the MTT assay revealed that AZT inhibits the growth of cancer cells, which provides an experimental foundation for esophageal tumor therapy.	('esophageal tumor', 'Disease', 'MESH:D004938', (130, 146))	('MTT', 'Chemical', 'MESH:C070243', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal tumor', 'Disease', (130, 146))	('AZT', 'Var', (43, 46))	('AZT', 'Chemical', 'MESH:D015215', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('esophageal tumor', 'Phenotype', 'HP:0100751', (130, 146))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('inhibits', 'NegReg', (47, 55))
393313	28487971	Telomerase activity is directly associated with protection against cell death, and therefore the inhibition of telomerase in cancer cells leads to apoptosis.	('inhibition', 'Var', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('telomerase', 'Protein', (111, 121))	('apoptosis', 'CPA', (147, 156))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
393358	28348485	The primers for GAPDH were 5'-TCATGGGTGTGAACCATGAGAA-3' (forward) and 5'-GGCATGGACTGTGGTCATGAG-3' (reverse).	('GAPDH', 'Gene', '2597', (16, 21))	("5'-TCATGGGTGTGAACCATGAGAA-3", 'Var', (27, 54))	('GAPDH', 'Gene', (16, 21))
393364	28348485	After the EC9706 and EC9706/DDP cells were treated with DDP at various concentrations (1, 2, 4, 8, 16, 32 mug/mL) for 48 h, the cell viability rate was examined by MTT assay.	('DDP', 'Gene', '1678', (28, 31))	('MTT', 'Chemical', 'MESH:C070243', (164, 167))	('DDP', 'Gene', '1678', (56, 59))	('EC9706', 'CellLine', 'CVCL:E307', (21, 27))	('EC9706', 'CellLine', 'CVCL:E307', (10, 16))	('DDP', 'Gene', (28, 31))	('DDP', 'Gene', (56, 59))	('EC9706', 'Var', (10, 16))
393393	28348485	Here, we provided experimental evidence showing the combination of ECRG2 and DDP promoted the apoptosis of esophageal DDP-resistant cancer cells.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('ECRG2', 'Gene', '84651', (67, 72))	('ECRG2', 'Gene', (67, 72))	('DDP', 'Gene', '1678', (118, 121))	('DDP', 'Gene', '1678', (77, 80))	('promoted', 'PosReg', (81, 89))	('combination', 'Var', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('DDP', 'Gene', (118, 121))	('DDP', 'Gene', (77, 80))	('apoptosis', 'CPA', (94, 103))
393616	31920393	For example, knockdown of AK001796 led to an increase expression levels of p53 and p21, suggesting the role of AK001796 in regulating cell proliferation and cell cycle in ESCC cells.	('cell proliferation', 'CPA', (134, 152))	('ESCC', 'Disease', 'MESH:C562729', (171, 175))	('AK001796', 'Gene', (111, 119))	('cell cycle', 'CPA', (157, 167))	('p21', 'Gene', (83, 86))	('AK001796', 'Gene', '541471', (26, 34))	('ESCC', 'Disease', (171, 175))	('expression levels', 'MPA', (54, 71))	('p53', 'Gene', (75, 78))	('AK001796', 'Gene', (26, 34))	('p21', 'Gene', '644914', (83, 86))	('p53', 'Gene', '7157', (75, 78))	('knockdown', 'Var', (13, 22))	('AK001796', 'Gene', '541471', (111, 119))	('increase', 'PosReg', (45, 53))
393631	31920393	The plasmid containing the mutant seed region (PCAT-1-MUT and ANXA10 3'UTR-MUT) was obtained through site-specific mutagenesis on the base of the plasmid PCAT-1-WT.	('PCAT-1', 'Gene', '100750225', (47, 53))	('PCAT-1', 'Gene', '100750225', (154, 160))	('PCAT-1-MUT', 'Gene', '100750225;4594', (47, 57))	('PCAT-1-MUT', 'Gene', (47, 57))	('mutagenesis', 'Var', (115, 126))	('PCAT-1', 'Gene', (154, 160))	('ANXA10', 'Gene', '11199', (62, 68))	('PCAT-1', 'Gene', (47, 53))	('ANXA10', 'Gene', (62, 68))
393645	31920393	Figure 1B and C demonstrated the successful knockdown of PCAT-1 in KYSE150 and KYSE450 cells by two different PCAT-1 siRNAs (si-1 and si-2).	('PCAT-1', 'Gene', '100750225', (57, 63))	('PCAT-1', 'Gene', (110, 116))	('KYSE150', 'CellLine', 'CVCL:1348', (67, 74))	('knockdown', 'Var', (44, 53))	('PCAT-1', 'Gene', (57, 63))	('PCAT-1', 'Gene', '100750225', (110, 116))	('KYSE450', 'CellLine', 'CVCL:1353', (79, 86))
393647	31920393	As shown in Figure 1D and E, after PCAT-1 knockdown, the proliferative rates of these two cells lines were significantly decreased when compared with the siRNA control cells.	('PCAT-1', 'Gene', (35, 41))	('proliferative rates', 'CPA', (57, 76))	('decreased', 'NegReg', (121, 130))	('PCAT-1', 'Gene', '100750225', (35, 41))	('knockdown', 'Var', (42, 51))
393648	31920393	In addition, transwell invasion assay and wound healing assay showed that both invasion and migration of KYSE150 and KYSE450 cells were inhibited after PCAT-1 knockdown (Figure 1F-I).	('PCAT-1', 'Gene', '100750225', (152, 158))	('migration of KYSE150 and', 'CPA', (92, 116))	('knockdown', 'Var', (159, 168))	('inhibited', 'NegReg', (136, 145))	('PCAT-1', 'Gene', (152, 158))	('invasion', 'CPA', (79, 87))	('KYSE450', 'CellLine', 'CVCL:1353', (117, 124))	('KYSE150', 'CellLine', 'CVCL:1348', (105, 112))
393654	31920393	On the other hand, the relative expression levels of miR-508-3p was down-regulated and up-regulated by overexpression and knockdown of PCAT-1, respectively (Figure 2F-H).	('up-regulated', 'PosReg', (87, 99))	('down-regulated', 'NegReg', (68, 82))	('PCAT-1', 'Gene', (135, 141))	('miR-508', 'Gene', (53, 60))	('knockdown', 'Var', (122, 131))	('miR-508', 'Gene', '574513', (53, 60))	('overexpression', 'PosReg', (103, 117))	('expression levels', 'MPA', (32, 49))	('PCAT-1', 'Gene', '100750225', (135, 141))
393662	31920393	As shown in Figure 3F and G, after knockdown of PCAT-1 in KYSE150 cells, both mRNA and protein expression of ANXA10 were down-regulated.	('knockdown', 'Var', (35, 44))	('PCAT-1', 'Gene', (48, 54))	('KYSE150', 'CellLine', 'CVCL:1348', (58, 65))	('ANXA10', 'Gene', '11199', (109, 115))	('ANXA10', 'Gene', (109, 115))	('down-regulated', 'NegReg', (121, 135))	('PCAT-1', 'Gene', '100750225', (48, 54))
393666	31920393	In addition, the invasion and migration of KYSE150 cells were also stimulated by ANXA10 overexpression, knockdown of PCAT-1 reversed such effects of ANXA10.	('migration of KYSE150 cells', 'CPA', (30, 56))	('ANXA10', 'Gene', '11199', (149, 155))	('KYSE150', 'CellLine', 'CVCL:1348', (43, 50))	('ANXA10', 'Gene', (149, 155))	('PCAT-1', 'Gene', (117, 123))	('stimulated', 'PosReg', (67, 77))	('ANXA10', 'Gene', '11199', (81, 87))	('ANXA10', 'Gene', (81, 87))	('PCAT-1', 'Gene', '100750225', (117, 123))	('overexpression', 'Var', (88, 102))	('knockdown', 'Var', (104, 113))
393667	31920393	As indicated by the tumor growth curve in Figure 4A, the volume of PCAT-1 knockdown KYSE150 cells xenograft was much lower than that of control KYSE150 cells xenograft.	('PCAT-1', 'Gene', '100750225', (67, 73))	('KYSE150', 'CellLine', 'CVCL:1348', (144, 151))	('knockdown', 'Var', (74, 83))	('lower', 'NegReg', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('PCAT-1', 'Gene', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('KYSE150', 'CellLine', 'CVCL:1348', (84, 91))	('tumor', 'Disease', (20, 25))
393668	31920393	Accordingly, the tumor weight in PCAT-1 knockdown group was also significantly lower than that of control group (Figure 4B).	('tumor', 'Disease', (17, 22))	('lower', 'NegReg', (79, 84))	('knockdown', 'Var', (40, 49))	('PCAT-1', 'Gene', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('PCAT-1', 'Gene', '100750225', (33, 39))
393670	31920393	Besides, both mRNA and protein expression levels of ANXA10 were down-regulated in PCAT-1 knockdown KYSE150 cells xenograft, when compared with the control group (Figure 4E and F).	('down-regulated', 'NegReg', (64, 78))	('PCAT-1', 'Gene', '100750225', (82, 88))	('ANXA10', 'Gene', '11199', (52, 58))	('knockdown', 'Var', (89, 98))	('KYSE150', 'CellLine', 'CVCL:1348', (99, 106))	('PCAT-1', 'Gene', (82, 88))	('ANXA10', 'Gene', (52, 58))
393680	31920393	Interestingly, knockdown of PCAT-1 led to G0/G1 phase cell cycle arrest in colorectal cancer cells HT-29 and Caco-2.	('PCAT-1', 'Gene', (28, 34))	('colorectal cancer', 'Disease', (75, 92))	('knockdown', 'Var', (15, 24))	('G0/G1 phase cell cycle arrest', 'CPA', (42, 71))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('HT-29', 'CellLine', 'CVCL:0320', (99, 104))	('PCAT-1', 'Gene', '100750225', (28, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))
393681	31920393	The similar findings were also reported in osteosarcoma cells, where knockdown of PCAT-1 in U2OS cells caused an increase in the cell population at G0/G1 phase and a decrease in cell population at S phase.	('PCAT-1', 'Gene', (82, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (43, 55))	('osteosarcoma', 'Disease', 'MESH:D012516', (43, 55))	('cell population at G0/G1 phase', 'CPA', (129, 159))	('PCAT-1', 'Gene', '100750225', (82, 88))	('cell population at S phase', 'CPA', (178, 204))	('increase', 'PosReg', (113, 121))	('U2OS', 'CellLine', 'CVCL:0042', (92, 96))	('knockdown', 'Var', (69, 78))	('decrease', 'NegReg', (166, 174))	('osteosarcoma', 'Disease', (43, 55))
393682	31920393	In this regard, whether the cell cycle distribution in ESCC cells is changed or not after knockdown of PCAT-1 is also worthy of investigation.	('knockdown', 'Var', (90, 99))	('PCAT-1', 'Gene', (103, 109))	('changed', 'Reg', (69, 76))	('ESCC', 'Disease', 'MESH:C562729', (55, 59))	('PCAT-1', 'Gene', '100750225', (103, 109))	('ESCC', 'Disease', (55, 59))
393693	31920393	A number of studies also suggested that the alteration in the expression of ANXA10 is also related to the development of drug resistance in cancer cells.	('ANXA10', 'Gene', (76, 82))	('alteration', 'Var', (44, 54))	('related', 'Reg', (91, 98))	('drug resistance', 'Phenotype', 'HP:0020174', (121, 136))	('expression', 'MPA', (62, 72))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('ANXA10', 'Gene', '11199', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
393698	31114349	Prognostic significance of combined pretreatment body mass index (BMI) and BMI loss in patients with esophageal cancer Background: Body mass index (BMI) has been associated with a risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (188, 205))	('loss', 'NegReg', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Body mass index', 'Var', (131, 146))	('patients', 'Species', '9606', (87, 95))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', (188, 205))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('BMI', 'Gene', (75, 78))
393704	31114349	Subgroup analysis showed that patients with a high BMI were more likely to suffer hypertension (p<0.001) and receive only surgery (p<0.001), and they were less likely to be smokers (p=0.007) and anemic (p<0.001).	('high', 'Var', (46, 50))	('hypertension', 'Disease', 'MESH:D006973', (82, 94))	('hypertension', 'Disease', (82, 94))	('hypertension', 'Phenotype', 'HP:0000822', (82, 94))	('patients', 'Species', '9606', (30, 38))	('anemic', 'Disease', (195, 201))	('anemic', 'Disease', 'MESH:D000740', (195, 201))	('less', 'NegReg', (155, 159))
393705	31114349	Conversely, patients with high BMI loss were more likely to be anemic (p=0.001), to have advanced pathological stage (p=0.012), and to receive chemotherapy and radiotherapy (p=0.001).	('anemic', 'Disease', (63, 69))	('patients', 'Species', '9606', (12, 20))	('high', 'Var', (26, 30))	('BMI', 'Gene', (31, 34))	('loss', 'NegReg', (35, 39))	('anemic', 'Disease', 'MESH:D000740', (63, 69))	('receive', 'Reg', (135, 142))
393732	31114349	The three categories were as follows: underweight (<18.5 kg/m2), normal weight (18.5-22.9 kg/m2), and overweight and obese (>=23.0 kg/m2).	('<18.5 kg/m2', 'Var', (51, 62))	('18.5-22.9', 'Var', (80, 89))	('overweight', 'Phenotype', 'HP:0025502', (102, 112))	('obese', 'Disease', 'MESH:D009765', (117, 122))	('obese', 'Disease', (117, 122))
393757	31114349	The 10 year OS in patients with a high BMI was significantly longer than patients with a low BMI in both the whole cohort (p=0.004, Figure 1) and the ESCC cohort (p=0.003, Figure 2B).	('longer', 'PosReg', (61, 67))	('low BMI', 'Phenotype', 'HP:0045082', (89, 96))	('OS', 'Chemical', '-', (12, 14))	('high', 'Var', (34, 38))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (73, 81))
393759	31114349	Patients were divided into six groups: group 1 (BMI <18.5 kg/m2 and BMI loss =0), group 2 (18.5<= BMI <23.0 kg/m2 and BMI loss =0), group 3 (BMI >=23.0 kg/m2 and BMI loss =0), group 4 (BMI <18.5 kg/m2 and BMI loss >0), group 5 (18.5<= BMI <23.0 kg/m2 and BMI loss >0), group 6 (BMI >=23.0 kg/m2 and BMI loss >0).	('loss >0', 'NegReg', (259, 266))	('loss', 'NegReg', (72, 76))	('BMI', 'Var', (141, 144))	('Patients', 'Species', '9606', (0, 8))	('18.5<= BMI <23.0 kg/m2', 'Var', (228, 250))	('loss', 'NegReg', (122, 126))	('loss', 'NegReg', (209, 213))	('BMI <18.5 kg/m2', 'Var', (185, 200))	('BMI <18.5 kg/m2', 'Var', (48, 63))
393765	31114349	We found that the 10 year OS of patients with a high BMI were significantly longer than patients with a low BMI, which was true for both the entire cohort and the ESCC group.	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (88, 96))	('OS', 'Chemical', '-', (26, 28))	('longer', 'PosReg', (76, 82))	('high', 'Var', (48, 52))	('low BMI', 'Phenotype', 'HP:0045082', (104, 111))
393776	31114349	In this study, patients with a high BMI were less likely to be anemic (p<0.001), and this may imply better physical conditions.	('anemic', 'Disease', (63, 69))	('patients', 'Species', '9606', (15, 23))	('anemic', 'Disease', 'MESH:D000740', (63, 69))	('better', 'PosReg', (100, 106))	('less', 'NegReg', (45, 49))	('high', 'Var', (31, 35))
393790	31114349	Our study provides more concrete evidence that a high BMI is associated with favorable long-term survival in esophageal cancer patients treated with different therapies in China.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('BMI', 'MPA', (54, 57))	('patients', 'Species', '9606', (127, 135))	('esophageal cancer', 'Disease', (109, 126))	('high', 'Var', (49, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
393881	30046968	Post-ESD strictures seriously lower patients' quality of life, being associated with several symptoms, including dysphagia, nausea, vomiting, weight loss, and even cachexia.	('cachexia', 'Disease', (164, 172))	('lower', 'NegReg', (30, 35))	('nausea', 'Disease', 'MESH:D009325', (124, 130))	('vomiting', 'Disease', 'MESH:D014839', (132, 140))	('patients', 'Species', '9606', (36, 44))	('dysphagia', 'Disease', 'MESH:D003680', (113, 122))	('vomiting', 'Phenotype', 'HP:0002013', (132, 140))	('dysphagia', 'Disease', (113, 122))	('vomiting', 'Disease', (132, 140))	('weight loss', 'Disease', 'MESH:D015431', (142, 153))	('quality of life', 'CPA', (46, 61))	('associated', 'Reg', (69, 79))	('nausea', 'Phenotype', 'HP:0002018', (124, 130))	('cachexia', 'Disease', 'MESH:D002100', (164, 172))	('weight loss', 'Phenotype', 'HP:0001824', (142, 153))	('dysphagia', 'Phenotype', 'HP:0002015', (113, 122))	('cachexia', 'Phenotype', 'HP:0004326', (164, 172))	('nausea', 'Disease', (124, 130))	('weight loss', 'Disease', (142, 153))	('strictures', 'Var', (9, 19))
393911	30026856	Rac1 deletion in endothelial cells using a mouse model resulted in hemorrhage and edema due to a failure of lymphatic cell separated from vessels and lymphatic structures formation.	('edema', 'Disease', (82, 87))	('deletion', 'Var', (5, 13))	('edema', 'Disease', 'MESH:D004487', (82, 87))	('hemorrhage', 'Disease', (67, 77))	('Rac1', 'Gene', (0, 4))	('edema', 'Phenotype', 'HP:0000969', (82, 87))	('hemorrhage', 'Disease', 'MESH:D006470', (67, 77))	('edema due to a failure of lymphatic cell', 'Phenotype', 'HP:0001004', (82, 122))	('mouse', 'Species', '10090', (43, 48))
393912	30026856	A recent study showed that gastric cancer tissue with positive Rac1 expression had a higher microvessel density than that with negative expression, suggesting that Rac1 promoted the formation of cancer blood vessels and the growth of tumor.	('promoted', 'PosReg', (169, 177))	('tumor', 'Disease', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('higher', 'PosReg', (85, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (27, 41))	('expression', 'Var', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('positive', 'Var', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('microvessel density', 'CPA', (92, 111))	('Rac1', 'Var', (164, 168))	('cancer', 'Disease', (195, 201))	('gastric cancer', 'Disease', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('Rac1', 'Gene', (63, 67))	('cancer', 'Disease', (35, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (27, 41))
393914	30026856	Silencing Rac1 in human melanoma cells led to a weaken pattern of cell proliferation and invasion, while overexpression of Rac1 in mouse keratinocytes induced EMT and promoted cell migration and invasion.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('induced', 'PosReg', (151, 158))	('EMT', 'CPA', (159, 162))	('cell proliferation', 'CPA', (66, 84))	('cell migration', 'CPA', (176, 190))	('promoted', 'PosReg', (167, 175))	('overexpression', 'PosReg', (105, 119))	('mouse', 'Species', '10090', (131, 136))	('invasion', 'CPA', (195, 203))	('invasion', 'CPA', (89, 97))	('human', 'Species', '9606', (18, 23))	('Rac1', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))
393919	30026856	High level of Rac1 could predict a poor prognosis in different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Rac1', 'Gene', (14, 18))	('High level', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
393928	30026856	In this meta-analysis, the pooled hazard ratios (HRs) with their 95% confidence intervals (CIs) were used to evaluate the association between Rac1 expression and prognosis of cancer patients, and an HR >1 represented poor prognostic outcome for patients with elevated Rac1 expression.	('association', 'Interaction', (122, 133))	('patients', 'Species', '9606', (245, 253))	('elevated', 'PosReg', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('HR >1', 'Var', (199, 204))	('patients', 'Species', '9606', (182, 190))	('Rac1', 'Gene', (142, 146))	('expression', 'MPA', (273, 283))
393941	30026856	There were significant associations between high Rac1 expression and OS in subgroups including age, country of origin study, cancer type, cut-off value, follow-up time, sample size, multivariate/univariate analysis.	('expression', 'MPA', (54, 64))	('Rac1', 'Protein', (49, 53))	('high', 'Var', (44, 48))	('OS', 'Chemical', '-', (69, 71))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
393949	30026856	Both 1571 patients' pooled data for OS analysis and 815 patients' pooled data for DFS analysis showed that high Rac1 expression level was significantly correlated with poor survival in cancer patients.	('patients', 'Species', '9606', (56, 64))	('expression level', 'MPA', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (192, 200))	('Rac1', 'Protein', (112, 116))	('poor', 'NegReg', (168, 172))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('OS', 'Chemical', '-', (36, 38))	('high', 'Var', (107, 111))	('cancer', 'Disease', (185, 191))	('patients', 'Species', '9606', (10, 18))
393950	30026856	The probability of death in cancer patients with positive Rac1 expression was more than twice of that in patients with negative Rac1 expression.	('death', 'Disease', (19, 24))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('positive', 'Var', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('patients', 'Species', '9606', (35, 43))	('Rac1', 'Gene', (58, 62))	('cancer', 'Disease', (28, 34))	('expression', 'Var', (63, 73))	('death', 'Disease', 'MESH:D003643', (19, 24))
393956	30026856	A recent study showed high Rac1 expression led to polarity change in invasive ductal carcinoma of breast and was positively associated with lymph metastasis and poor prognosis.	('high', 'Var', (22, 26))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (78, 94))	('invasive ductal carcinoma of breast', 'Disease', 'MESH:D018270', (69, 104))	('associated', 'Reg', (124, 134))	('invasive ductal carcinoma of breast', 'Disease', (69, 104))	('Rac1', 'Gene', (27, 31))	('led to', 'Reg', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('lymph metastasis', 'CPA', (140, 156))	('polarity change', 'MPA', (50, 65))
393959	30026856	An included study revealed that down-regulation of Rac1 inhibited the proliferation and EMT capability in an ovarian epithelial cell line, and silencing Rac1 in xenograft tumor model presented a significant increase in E-cadherin and loss of vimentin.	('ovarian epithelial', 'Disease', (109, 127))	('increase', 'PosReg', (207, 215))	('vimentin', 'Gene', '7431', (242, 250))	('down-regulation', 'NegReg', (32, 47))	('Rac1', 'Gene', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('vimentin', 'Gene', (242, 250))	('tumor', 'Disease', (171, 176))	('E-cadherin', 'Gene', (219, 229))	('ovarian epithelial', 'Disease', 'MESH:D000077216', (109, 127))	('E-cadherin', 'Gene', '999', (219, 229))	('Rac1', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('inhibited', 'NegReg', (56, 65))	('silencing', 'Var', (143, 152))	('loss', 'NegReg', (234, 238))
393960	30026856	Overexpression of Rac1 was also reported to be associated with up-regulated N-cadherin and Vimentin level and negatively linked to E-cadherin level in lung cancer.	('E-cadherin', 'Gene', '999', (131, 141))	('Vimentin', 'Gene', '7431', (91, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('negatively linked', 'NegReg', (110, 127))	('N-cadherin', 'Gene', (76, 86))	('lung cancer', 'Disease', (151, 162))	('Vimentin', 'Gene', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Overexpression', 'Var', (0, 14))	('Rac1', 'Gene', (18, 22))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('E-cadherin', 'Gene', (131, 141))	('N-cadherin', 'Gene', '1000', (76, 86))	('up-regulated', 'PosReg', (63, 75))
393963	30026856	Early studies showed that treatment with NSC23766, a chemical inhibitor of Rac1, blocked the invasion and metastasis phenotype in multiple cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('blocked', 'NegReg', (81, 88))	('Rac1', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (139, 145))	('NSC23766', 'Var', (41, 49))
393964	30026856	It has also been shown that inhibition of Rac1 signaling in a murine lymphoma model abrogated tumor progression and metastasis in vivo .	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('lymphoma', 'Disease', (69, 77))	('inhibition', 'Var', (28, 38))	('tumor', 'Disease', (94, 99))	('abrogated', 'NegReg', (84, 93))	('lymphoma', 'Disease', 'MESH:D008223', (69, 77))	('murine', 'Species', '10090', (62, 68))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('Rac1', 'Protein', (42, 46))
393968	30026856	A plethora of biomarkers of interaction was found in the microenvironment of tumor cells, thus Rac1 combination of other biomarkers, instead of Rac1 alone, would be beneficial to improve the clinical stage.	('improve', 'PosReg', (179, 186))	('plethora', 'Phenotype', 'HP:0001050', (2, 10))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('combination', 'Var', (100, 111))	('clinical stage', 'CPA', (191, 205))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Rac1 combination', 'Var', (95, 111))	('tumor', 'Disease', (77, 82))
394012	29393484	Inhibition of the repair of radiation-induced DSBs has been demonstrated to increase the radiosensitivity of cancer cells.	('increase', 'PosReg', (76, 84))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('DSBs', 'Chemical', '-', (46, 50))	('cancer', 'Disease', (109, 115))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('DSBs', 'Var', (46, 50))	('increase the radiosensitivity of cancer cells', 'Phenotype', 'HP:0010997', (76, 121))
394039	29393484	Then incubated with secondary antibodies coupled with horseradish peroxidase at room temperature for 1.5 h, anti-mouse (#4410, 1:5,000) or anti-rabbit (#4414, 1:5,000) antibodies (Cell Signaling Technology, Inc.).	('#4414', 'Var', (152, 157))	('horseradish', 'Species', '3704', (54, 65))	('rabbit', 'Species', '9986', (144, 150))	('#4410', 'Var', (120, 125))	('mouse', 'Species', '10090', (113, 118))
394053	29393484	We selected the 48 h IC20 values (0.3 mM for Eca109 and 0.4 mM for EC9706) as a appropriate concentration for the subsequent experiments.	('EC9706', 'CellLine', 'CVCL:E307', (67, 73))	('EC9706', 'Var', (67, 73))	('Eca109', 'Var', (45, 51))
394073	29393484	The tumor volume was markedly smaller in the radiation + SH group than in the other three groups (P<0.05; Fig.	('tumor', 'Disease', (4, 9))	('radiation + SH', 'Var', (45, 59))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('SH', 'Chemical', 'MESH:C009271', (57, 59))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('smaller', 'NegReg', (30, 37))
394089	29393484	These findings suggest that aberrations in Bcl2 and Bax expression may determine the cell fate and the anticancer effect of radiation therapy.	('aberrations', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Bcl2', 'Gene', '596', (43, 47))	('Bax', 'Gene', (52, 55))	('cancer', 'Disease', (107, 113))	('Bax', 'Gene', '581', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Bcl2', 'Gene', (43, 47))	('determine', 'Reg', (71, 80))	('cell fate', 'CPA', (85, 94))
394100	29393484	For example, the inhibition of RAD51 enhanced the radiosensitivity of non-small cell lung cancer cells, and the siRNA-mediated downregulation of Ku80 expression can sensitize osteosarcoma cells to radiation probably via telomere length shortening.	('Ku80', 'Gene', '7520', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (70, 96))	('downregulation', 'NegReg', (127, 141))	('telomere length shortening', 'Phenotype', 'HP:0031413', (220, 246))	('lung cancer', 'Disease', (85, 96))	('osteosarcoma', 'Phenotype', 'HP:0002669', (175, 187))	('Ku80', 'Gene', (145, 149))	('inhibition', 'Var', (17, 27))	('expression', 'MPA', (150, 160))	('RAD51', 'Gene', (31, 36))	('RAD51', 'Gene', '5888', (31, 36))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('enhanced', 'PosReg', (37, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('osteosarcoma', 'Disease', (175, 187))	('osteosarcoma', 'Disease', 'MESH:D012516', (175, 187))	('radiosensitivity', 'CPA', (50, 66))
394303	27916803	Using MALDI-IMS they studied the changes in lipid composition in order to characterize the lipid profile following tumorigenesis in lung tumors with high MYC activity, and subsequent deactivation of MYC.	('high', 'Var', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('activity', 'MPA', (158, 166))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('deactivation', 'NegReg', (183, 195))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('MYC', 'Protein', (199, 202))	('lung tumors', 'Disease', 'MESH:D008175', (132, 143))	('lung tumor', 'Phenotype', 'HP:0100526', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('lung tumors', 'Phenotype', 'HP:0100526', (132, 143))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('lipid', 'Chemical', 'MESH:D008055', (91, 96))	('lung tumors', 'Disease', (132, 143))	('lipid', 'Chemical', 'MESH:D008055', (44, 49))
394305	27916803	PC 32:0, PC 32:1 and PGs increased in normal mouse lung tissue in comparison with tumor tissue.	('PG', 'Chemical', 'MESH:D010715', (21, 23))	('mouse', 'Species', '10090', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PC 32:0', 'Var', (0, 7))	('PC', 'Chemical', 'MESH:D010713', (9, 11))	('PGs', 'Gene', (21, 24))	('tumor', 'Disease', (82, 87))	('PC', 'Chemical', 'MESH:D010713', (0, 2))
394309	27916803	In this study, after MYC deactivation, there were decreases in both cPLA2 activity and specific metabolites as well as the mRNAs associated with COX and 5-LOX.	('cPLA2', 'Gene', (68, 73))	('cPLA2', 'Gene', '5321', (68, 73))	('mRNAs', 'MPA', (123, 128))	('activity', 'MPA', (74, 82))	('decreases', 'NegReg', (50, 59))	('deactivation', 'Var', (25, 37))	('specific metabolites', 'MPA', (87, 107))
394313	27916803	Results highlighted differential lipid profiles between tumor and adjacent normal tissue samples, with PC species PC 34:1, PC 36:2, and PC 36:3 significantly elevated in NSCLC tissues.	('SCLC', 'Phenotype', 'HP:0030357', (171, 175))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PC 36:2', 'Var', (123, 130))	('tumor', 'Disease', (56, 61))	('PC', 'Chemical', 'MESH:D010713', (114, 116))	('NSCLC', 'Disease', (170, 175))	('PC 36:3', 'Var', (136, 143))	('PC 34:1', 'Var', (114, 121))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('PC', 'Chemical', 'MESH:D010713', (136, 138))	('elevated', 'PosReg', (158, 166))	('PC', 'Chemical', 'MESH:D010713', (123, 125))	('lipid profiles', 'MPA', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('lipid', 'Chemical', 'MESH:D008055', (33, 38))	('PC', 'Chemical', 'MESH:D010713', (103, 105))
394321	27916803	In this study, MALDI-MS analysis showed that H596 cells incorporated four-fold higher levels of EPA into PLs than the A549 cells.	('PLs', 'Chemical', 'MESH:D010743', (105, 108))	('EPA', 'Chemical', 'MESH:D015118', (96, 99))	('EPA', 'MPA', (96, 99))	('H596', 'CellLine', 'CVCL:1571', (45, 49))	('A549', 'CellLine', 'CVCL:0023', (118, 122))	('higher', 'PosReg', (79, 85))	('H596', 'Var', (45, 49))
394328	27916803	In particular, this differential metabolite distribution mainly concerned PL species, such as SM 16:0/1, LPC 18:1, LPC 20:4, LPC 20:3, and LPC 22:6; these lipids were associated with lung cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('PL', 'Chemical', 'MESH:D010743', (74, 76))	('associated with', 'Reg', (167, 182))	('LPC 20:3', 'Var', (125, 133))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('lipids', 'Chemical', 'MESH:D008055', (155, 161))	('LPC', 'Chemical', 'MESH:D008244', (125, 128))	('LPC', 'Chemical', 'MESH:D008244', (115, 118))	('LPC', 'Chemical', 'MESH:D008244', (105, 108))	('LPC 22:6', 'Var', (139, 147))	('LPC', 'Chemical', 'MESH:D008244', (139, 142))	('lung cancer', 'Disease', (183, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('SM', 'Chemical', 'MESH:D013109', (94, 96))
394333	27916803	PI 38:3, PI 40:3, and PI 38:2 were higher in tumor samples, in comparison with the normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('PI 40:3', 'Var', (9, 16))	('PI 38:3', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('higher', 'PosReg', (35, 41))
394347	27916803	Results showed that several PIs were specifically localized into cancer cell clusters, with a heterogeneous distribution, which identified two different populations of cancer cells: the first predominantly expressed PI 18:0/18:1, the second PI 18:0/20:3.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('PIs', 'Chemical', 'MESH:D010716', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('PI 18:0/18:1', 'Var', (216, 228))
394350	27916803	In this study, the lipid class quantitation showed differences in lipidome of tumor and normal tissues: levels of PI, PE, PC, SM and LPC were significantly higher in tumor tissues than in healthy controls; PLs with the general formula C34:1 (mainly combination of C16:0 and C18:1) led to the association with tumor tissues for several lipid classes.	('association', 'Interaction', (292, 303))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('C34:1', 'Var', (235, 240))	('SM', 'Chemical', 'MESH:D013109', (126, 128))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('lipid', 'Chemical', 'MESH:D008055', (19, 24))	('PC', 'Chemical', 'MESH:D010713', (122, 124))	('lipid', 'Chemical', 'MESH:D008055', (66, 71))	('C16:0', 'Var', (264, 269))	('LPC', 'Chemical', 'MESH:D008244', (133, 136))	('lipid', 'Chemical', 'MESH:D008055', (335, 340))	('tumor', 'Disease', (309, 314))	('tumor', 'Disease', (166, 171))	('PLs', 'Chemical', 'MESH:D010743', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Disease', (78, 83))	('PC', 'Chemical', 'MESH:D010713', (134, 136))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('C18:1', 'Var', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('PE', 'Chemical', 'MESH:C483858', (118, 120))
394360	27916803	In addition, higher levels of PCs and PI 22:5/18:0 were found in migratory cells, with metastatic ability.	('migratory cells', 'CPA', (65, 80))	('PCs', 'Var', (30, 33))	('PC', 'Chemical', 'MESH:D010713', (30, 32))	('PI 22:5/18:0', 'Var', (38, 50))	('metastatic ability', 'CPA', (87, 105))
394362	27916803	They found that PS 18:0/20:4, PI 18:0/20:4, and PC 18:0/20:4 were markedly higher in the highly metastatic MDA-MB-231 cells than in slightly metastatic MCF-7 cells, (all p-values < 0.001).	('PC', 'Chemical', 'MESH:D010713', (48, 50))	('PS', 'Chemical', '-', (16, 18))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (107, 117))	('higher', 'PosReg', (75, 81))	('PC 18:0/20:4', 'Var', (48, 60))	('PI 18:0/20:4', 'Var', (30, 42))	('MCF-7', 'CellLine', 'CVCL:0031', (152, 157))	('highly metastatic', 'CPA', (89, 106))
394363	27916803	In contrast, the levels of PE 18:1/18:1 and PI 18:0/18:1 were markedly lower in cells with high metastatic potential than in slightly metastatic ones.	('PE', 'Chemical', 'MESH:C483858', (27, 29))	('PI 18:0/18:1', 'Var', (44, 56))	('levels', 'MPA', (17, 23))	('high metastatic potential', 'CPA', (91, 116))	('lower', 'NegReg', (71, 76))
394366	27916803	By using the MALDI-IMS approach, the lipid distributions into the tumor tissue were characterized by spatial heterogeneity: in particular PC 16:0/16:0, PC 16:0/18:1, PC 18:1/18:1 and PC 18:0/18:1 were localized in accessible tumor areas, whereas LPC 16:0/0:0 were localized in necrotic tumor regions.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('PC 16:0/16:0', 'Var', (138, 150))	('tumor', 'Disease', (225, 230))	('LPC', 'Chemical', 'MESH:D008244', (246, 249))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('PC 16:0/18:1', 'Var', (152, 164))	('tumor', 'Disease', (66, 71))	('PC', 'Chemical', 'MESH:D010713', (138, 140))	('PC 18:0/18:1', 'Var', (183, 195))	('necrotic tumor', 'Disease', 'MESH:D009369', (277, 291))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('PC', 'Chemical', 'MESH:D010713', (247, 249))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (286, 291))	('PC', 'Chemical', 'MESH:D010713', (183, 185))	('PC', 'Chemical', 'MESH:D010713', (152, 154))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('PC 18:1/18:1', 'Var', (166, 178))	('necrotic tumor', 'Disease', (277, 291))	('PC', 'Chemical', 'MESH:D010713', (166, 168))	('lipid', 'Chemical', 'MESH:D008055', (37, 42))
394367	27916803	The MALDI-IMS images revealed that palmitoylcarnitine, stearoylcarnitine, PC 16:0/22:1, and SM d18:1/16:0 are predominantly localized in the hypoxic tumor regions.	('hypoxic tumor', 'Disease', (141, 154))	('PC 16:0/22:1', 'Var', (74, 86))	('SM', 'Chemical', 'MESH:D013109', (92, 94))	('palmitoylcarnitine', 'Chemical', 'MESH:D010172', (35, 53))	('hypoxic tumor', 'Disease', 'MESH:D009369', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('SM d18:1/16:0', 'Var', (92, 105))	('PC', 'Chemical', 'MESH:D010713', (74, 76))	('stearoylcarnitine', 'MPA', (55, 72))	('palmitoylcarnitine', 'MPA', (35, 53))	('stearoylcarnitine', 'Chemical', '-', (55, 72))
394371	27916803	This study highlighted that serum triacylglycerol (TGs) containing C18:1 fatty acyl chains were at lower concentrations in patients with pCR.	('pCR', 'Disease', (137, 140))	('lower', 'NegReg', (99, 104))	('C18:1 fatty acyl chains', 'Var', (67, 90))	('TGs', 'Chemical', 'MESH:D014280', (51, 54))	('serum triacylglycerol', 'MPA', (28, 49))	('patients', 'Species', '9606', (123, 131))	('triacylglycerol', 'Chemical', 'MESH:D014280', (34, 49))
394379	27916803	They found that PS 18:0/18:1, PS 16:0/22:6 were significantly increased in patient samples, while PS 18:1/18:0, PS 18:0/20:5, had significantly decreased in comparison with healthy controls.	('increased', 'PosReg', (62, 71))	('decreased', 'NegReg', (144, 153))	('PS', 'Chemical', '-', (16, 18))	('PS', 'Chemical', '-', (30, 32))	('PS', 'Chemical', '-', (98, 100))	('PS', 'Chemical', '-', (112, 114))	('patient', 'Species', '9606', (75, 82))	('PS 16:0/22:6', 'Var', (30, 42))
394391	27916803	The HR-MALDI-IMS was employed on 38 human prostate tissue samples (14 in discovery set and 24 in the validation set): the expression of PI 18:0/18:1, PI 18:0/20:3 and PI 18:0/20:2 was significantly higher in cancer tissue than in benign epithelium.	('PI 18:0/18:1', 'Var', (136, 148))	('PI 18:0/20:3', 'Var', (150, 162))	('expression', 'MPA', (122, 132))	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('human', 'Species', '9606', (36, 41))	('higher', 'PosReg', (198, 204))
394393	27916803	Results showed five lipid species significantly lower in cancer than in benign tissues, specifically: LPC 16:0/OH + H+, LPC 16:0/OH + Na+, LPC 16:0/OH + K+, LPC 16:0/OH + matrix + H+, and SM d18:1/16:0 + H+.	('LPC', 'Chemical', 'MESH:D008244', (157, 160))	('LPC 16:0/OH + matrix + H+', 'Var', (157, 182))	('LPC', 'Chemical', 'MESH:D008244', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('LPC 16:0/OH + K+', 'Var', (139, 155))	('lipid', 'Chemical', 'MESH:D008055', (20, 25))	('cancer', 'Disease', (57, 63))	('lower', 'NegReg', (48, 53))	('SM d18:1/16:0 + H+', 'Var', (188, 206))	('LPC 16:0/OH + H+', 'Var', (102, 118))	('SM', 'Chemical', 'MESH:D013109', (188, 190))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('LPC', 'Chemical', 'MESH:D008244', (139, 142))	('LPC 16:0/OH + Na+', 'Var', (120, 137))	('LPC', 'Chemical', 'MESH:D008244', (102, 105))	('lipid species', 'MPA', (20, 33))
394394	27916803	A low level of LPC 16:0/OH in cancer tissue was associated with biochemical recurrence after radical prostatectomy.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('LPC 16:0/OH', 'Var', (15, 26))	('associated with', 'Reg', (48, 63))	('biochemical recurrence', 'Disease', (64, 86))	('LPC', 'Chemical', 'MESH:D008244', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
394398	27916803	The cut-off values derived in the tested serum (ePC 38:5 > 0.015 nmoles, PC 40:3 < 0.001 nmoles and PC 42:4 < 0.0001 nmoles) were associated with a predictability of 94% for the absence of prostate cancer; whereas for the cut-off value of ePC 38:5 < 0.015 nmoles, PC 40:3 > 0.001 nmoles, and PC 42:4 > 0.0001 nmoles, the predictability of prostate cancer disease was high.	('prostate cancer', 'Phenotype', 'HP:0012125', (339, 354))	('PC 40:3 > 0.001 nmoles', 'Var', (264, 286))	('PC', 'Chemical', 'MESH:D010713', (100, 102))	('PC', 'Chemical', 'MESH:D010713', (240, 242))	('PC', 'Chemical', 'MESH:D010713', (73, 75))	('PC', 'Chemical', 'MESH:D010713', (292, 294))	('PC', 'Chemical', 'MESH:D010713', (49, 51))	('PC', 'Chemical', 'MESH:D010713', (264, 266))	('prostate cancer', 'Phenotype', 'HP:0012125', (189, 204))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('prostate cancer disease', 'Disease', 'MESH:D011471', (339, 362))	('PC 42:4 > 0.0001 nmoles', 'Var', (292, 315))	('absence of prostate cancer', 'Disease', (178, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('absence of prostate cancer', 'Disease', 'MESH:D011471', (178, 204))	('prostate cancer disease', 'Disease', (339, 362))
394399	27916803	The authors concluded that a combination of serum ePC 38:5, PC 40:3 and PC 42:4 could be predictive for detecting prostate cancer, if confirmed in a larger dataset.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PC', 'Chemical', 'MESH:D010713', (72, 74))	('PC', 'Chemical', 'MESH:D010713', (51, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('PC 40:3', 'Var', (60, 67))	('PC 42:4', 'Var', (72, 79))	('PC', 'Chemical', 'MESH:D010713', (60, 62))	('prostate cancer', 'Disease', (114, 129))
394414	27916803	Since these changes in membrane PL levels can influence cell proliferation, motility and tumor progression, Kurabe and co-workers applied mass microscopy to human colorectal cancer tissues as a non-targeted screening for PC biomarkers for obtaining a lipid profile.	('influence', 'Reg', (46, 55))	('human', 'Species', '9606', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('membrane PL levels', 'MPA', (23, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (163, 180))	('lipid', 'Chemical', 'MESH:D008055', (251, 256))	('PC', 'Chemical', 'MESH:D010713', (221, 223))	('motility', 'CPA', (76, 84))	('PL', 'Chemical', 'MESH:D010743', (32, 34))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('cell proliferation', 'CPA', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('colorectal cancer', 'Disease', (163, 180))	('tumor', 'Disease', (89, 94))	('changes', 'Var', (12, 19))
394439	27916803	Authors suggested that deregulation of phospholipase A2 (PLA2) activity could produce a high level of LPC, providing a potential marker and therapeutic target.	('LPC', 'MPA', (102, 105))	('activity', 'MPA', (63, 71))	('phospholipase A2', 'Gene', '5319', (39, 55))	('PLA2', 'Gene', (57, 61))	('phospholipase A2', 'Gene', (39, 55))	('produce', 'Reg', (78, 85))	('PLA2', 'Gene', '5319', (57, 61))	('deregulation', 'Var', (23, 35))	('LPC', 'Chemical', 'MESH:D008244', (102, 105))
394442	27916803	Levels of PC 32:3, 34:1 and 36:2 were higher in ovarian cancers.	('PC', 'Chemical', 'MESH:D010713', (10, 12))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('PC 32:3', 'Var', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancers', 'Phenotype', 'HP:0100615', (48, 63))	('ovarian cancers', 'Disease', (48, 63))	('higher', 'Reg', (38, 44))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('ovarian cancers', 'Disease', 'MESH:D010051', (48, 63))
394459	27916803	The ovarian cancer patients presented both LPA and related LPLs, in particular LPA 16:0, LPA 18:0, 18:1, 18:2, LPI 16:0, LPI 18:0, LPI 20:4.	('LPI 18:0', 'Var', (121, 129))	('LPL', 'Gene', (59, 62))	('LPL', 'Gene', '4023', (59, 62))	('LPI', 'Chemical', 'MESH:C025449', (111, 114))	('LPI', 'Chemical', 'MESH:C025449', (131, 134))	('patients', 'Species', '9606', (19, 27))	('PLs', 'Chemical', 'MESH:D010743', (60, 63))	('ovarian cancer', 'Phenotype', 'HP:0100615', (4, 18))	('LPA', 'Chemical', 'MESH:C032881', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('LPA', 'Chemical', 'MESH:C032881', (89, 92))	('ovarian cancer', 'Disease', 'MESH:D010051', (4, 18))	('LPI', 'Var', (131, 134))	('LPI', 'Chemical', 'MESH:C025449', (121, 124))	('LPA', 'Chemical', 'MESH:C032881', (79, 82))	('ovarian cancer', 'Disease', (4, 18))
394476	27916803	In regards to pancreatic tissue, cerebrosides consisting of a C18:0, C20:0, C22:0, C24:0, or C24:1 FA demonstrated low levels regardless of metastasis status.	('C24:0', 'Var', (83, 88))	('pancreatic', 'Disease', (14, 24))	('C20:0', 'Var', (69, 74))	('C24:1 FA', 'Var', (93, 101))	('cerebrosides', 'Chemical', 'MESH:D002554', (33, 45))	('pancreatic', 'Disease', 'MESH:D010195', (14, 24))	('C18:0', 'Var', (62, 67))	('C22:0', 'Var', (76, 81))
394499	27916803	These changes in lipid content could compromise membrane fluidity and signal transduction in cancer cells, affecting tumorigenesis and gastric cancer progression.	('gastric cancer', 'Disease', (135, 149))	('changes', 'Var', (6, 13))	('signal transduction', 'MPA', (70, 89))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('affecting', 'Reg', (107, 116))	('cancer', 'Disease', (143, 149))	('lipid content', 'MPA', (17, 30))	('compromise', 'NegReg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('cancer', 'Disease', (93, 99))	('tumor', 'Disease', (117, 122))	('membrane fluidity', 'MPA', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
394506	27916803	S1P may be a potent stimulator of gastric cancer progression thanks to the activation of various RTK signaling pathways.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('activation', 'PosReg', (75, 85))	('gastric cancer', 'Disease', (34, 48))	('RTK signaling pathways', 'Pathway', (97, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('S1P', 'Var', (0, 3))	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))	('S1P', 'Chemical', 'MESH:C060506', (0, 3))
394517	27916803	In particular, the tumor tissue had increased absolute intensities for the signals relative to PS 18:0/18:1, PG 18:1/18:1, PI 16:0/18:1, PI 18:0/18:1, PS 18:1/18:1, PC 34:1 and PC 36:2 when compared with normal tissue.	('PC', 'Chemical', 'MESH:D010713', (165, 167))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('PS', 'Chemical', '-', (95, 97))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PC', 'Chemical', 'MESH:D010713', (177, 179))	('increased', 'PosReg', (36, 45))	('tumor', 'Disease', (19, 24))	('PS', 'Chemical', '-', (151, 153))	('PG', 'Chemical', 'MESH:D010715', (109, 111))	('PI 18:0/18:1', 'Var', (137, 149))
394551	27916803	In particular, there was an upregulation of PE 36:1, PC 38:4, PC 36:2 and PC 32:0, whereas PE 34:2, PE 36:4, PE 38:4, PC 34:1, PC 34:2, PC 36:4 and PI 36:4 were downregulated in tumor tissues when compared with normal ones.	('PE', 'Chemical', 'MESH:C483858', (109, 111))	('downregulated', 'NegReg', (161, 174))	('PC 32:0', 'Var', (74, 81))	('PC 34:1', 'Var', (118, 125))	('PE', 'Chemical', 'MESH:C483858', (100, 102))	('PE 34:2', 'Var', (91, 98))	('PE 36:4', 'Var', (100, 107))	('PC 34:2', 'Var', (127, 134))	('PE', 'Chemical', 'MESH:C483858', (91, 93))	('tumor', 'Disease', (178, 183))	('PE', 'Chemical', 'MESH:C483858', (44, 46))	('PC 38:4', 'Var', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('PC', 'Chemical', 'MESH:D010713', (74, 76))	('PC', 'Chemical', 'MESH:D010713', (136, 138))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('PE 38:4', 'Var', (109, 116))	('upregulation', 'PosReg', (28, 40))	('PC', 'Chemical', 'MESH:D010713', (127, 129))	('PC', 'Chemical', 'MESH:D010713', (62, 64))	('PC', 'Chemical', 'MESH:D010713', (118, 120))	('PC', 'Chemical', 'MESH:D010713', (53, 55))
394556	27916803	GPLs showed a different distribution in normal and cancerous tissues: the tumor tissue revealed higher absolute intensities for the lipid species PI 18:0/20:4, PS 18:0/18:1, PG 18:1/18:1 and PI 22:4/18:0; the FA 12:0 showed an increased absolute intensity in the normal tissue, correlating inversely with the cancerous ones.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('absolute intensities', 'MPA', (103, 123))	('cancerous', 'Disease', 'MESH:D009369', (309, 318))	('PS', 'Chemical', '-', (160, 162))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancerous', 'Disease', 'MESH:D009369', (51, 60))	('tumor', 'Disease', (74, 79))	('lipid', 'Chemical', 'MESH:D008055', (132, 137))	('GPLs', 'Chemical', 'MESH:D020404', (0, 4))	('PI 22:4/18:0', 'Var', (191, 203))	('PG 18:1/18:1', 'Var', (174, 186))	('higher', 'PosReg', (96, 102))	('PG', 'Chemical', 'MESH:D010715', (174, 176))	('PI 18:0/20:4', 'Var', (146, 158))	('cancerous', 'Disease', (309, 318))	('cancerous', 'Disease', (51, 60))
394563	27916803	They identified higher levels of PC 16:0/18:1 and PC 16:0/18:2 and SM d18:0/16:1 in thyroid papillary cancer compared to normal thyroid tissue.	('higher', 'PosReg', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('SM d18:0/16:1', 'Var', (67, 80))	('SM', 'Chemical', 'MESH:D013109', (67, 69))	('PC', 'Chemical', 'MESH:D010713', (33, 35))	('thyroid papillary cancer', 'Disease', (84, 108))	('PC', 'Chemical', 'MESH:D010713', (50, 52))	('thyroid papillary cancer', 'Disease', 'MESH:D000077273', (84, 108))	('thyroid papillary cancer', 'Phenotype', 'HP:0002895', (84, 108))
394564	27916803	Despite the intensities of most m/z values in neoplasm being higher than those in normal regions, the intensity of m/z 772.5, 782.5 and 848.5 in cancer regions was lower compared to healthy regions.	('cancer', 'Disease', (145, 151))	('lower', 'NegReg', (164, 169))	('higher', 'PosReg', (61, 67))	('neoplasm', 'Disease', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('intensities', 'MPA', (12, 23))	('neoplasm', 'Disease', 'MESH:D009369', (46, 54))	('neoplasm', 'Phenotype', 'HP:0002664', (46, 54))	('782.5', 'Var', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
394565	27916803	The m/z 798.5 peaks contained FA C18:1 that were expressed intensely in thyroid cancer regions.	('thyroid cancer', 'Phenotype', 'HP:0002890', (72, 86))	('FA C18:1', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('thyroid cancer', 'Disease', 'MESH:D013964', (72, 86))	('intensely', 'PosReg', (59, 68))	('thyroid cancer', 'Disease', (72, 86))
394568	27916803	Aiming to identify biomarkers able to differentiate among MTC patients, BTT patients and healthy individuals, the authors found changes in ten lipid levels: PC 34:1, PC 36:1, PC 38:6, PA 36:2, PA 36:3, PA 38:3, PA 38:4, PA 38:5, PA 40:5, and SM 34:1 in both tissues and sera.	('ten lipid levels', 'MPA', (139, 155))	('PA', 'Chemical', 'MESH:D010712', (229, 231))	('patients', 'Species', '9606', (62, 70))	('PC 34:1', 'Var', (157, 164))	('PC', 'Chemical', 'MESH:D010713', (157, 159))	('PA', 'Chemical', 'MESH:D010712', (220, 222))	('PA', 'Chemical', 'MESH:D010712', (211, 213))	('PA 36:3', 'Var', (193, 200))	('PC 38:6', 'Var', (175, 182))	('PC 36:1', 'Var', (166, 173))	('patients', 'Species', '9606', (76, 84))	('SM', 'Chemical', 'MESH:D013109', (242, 244))	('SM 34:1', 'Var', (242, 249))	('PA', 'Chemical', 'MESH:D010712', (202, 204))	('PA', 'Chemical', 'MESH:D010712', (184, 186))	('PA', 'Chemical', 'MESH:D010712', (193, 195))	('PC', 'Chemical', 'MESH:D010713', (175, 177))	('lipid', 'Chemical', 'MESH:D008055', (143, 148))	('MTC', 'Chemical', '-', (58, 61))	('PA 38:3', 'Var', (202, 209))	('PC', 'Chemical', 'MESH:D010713', (166, 168))	('PA 36:2', 'Var', (184, 191))	('changes', 'Reg', (128, 135))
394570	27916803	Serum level of PA 36:62, PA 36:3, PA 38:4, PA 38:5, and PA 40:5 decreased in BTT and MTC compared with normal.	('PA 40:5', 'Var', (56, 63))	('PA 38:4', 'Var', (34, 41))	('MTC', 'Chemical', '-', (85, 88))	('PA', 'Chemical', 'MESH:D010712', (34, 36))	('PA 36:62', 'Var', (15, 23))	('PA 36:3', 'Var', (25, 32))	('PA', 'Chemical', 'MESH:D010712', (25, 27))	('PA', 'Chemical', 'MESH:D010712', (56, 58))	('Serum level', 'MPA', (0, 11))	('PA', 'Chemical', 'MESH:D010712', (15, 17))	('PA', 'Chemical', 'MESH:D010712', (43, 45))	('decreased', 'NegReg', (64, 73))
394598	27729732	Core tip: Aberrant up- or downregulation of homeobox genes may play pivotal roles in the development and progression of gastrointestinal (GI) cancers.	('up-', 'PosReg', (19, 22))	('downregulation', 'NegReg', (26, 40))	('Aberrant', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gastrointestinal (GI) cancers', 'Disease', 'MESH:D004067', (120, 149))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('homeobox genes', 'Gene', (44, 58))
394601	27729732	Here, we review the major research data concerning the deregulation of homeobox genes in GI cancers and their underlying mechanisms.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('deregulation', 'Var', (55, 67))	('GI cancers', 'Disease', (89, 99))	('homeobox genes', 'Gene', (71, 85))	('GI cancer', 'Phenotype', 'HP:0007378', (89, 98))	('GI cancers', 'Disease', 'MESH:D009369', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
394602	27729732	The homeobox genes were first discovered in Drosophila melanogaster where their mutation led to malformations of body parts.	('homeobox genes', 'Gene', (4, 18))	('Drosophila melanogaster', 'Species', '7227', (44, 67))	('malformations', 'Disease', 'MESH:D000014', (96, 109))	('malformations', 'Disease', (96, 109))	('malformations of body', 'Phenotype', 'HP:0040064', (96, 117))	('led to', 'Reg', (89, 95))	('mutation', 'Var', (80, 88))
394609	27729732	This aberrant reduced or enhanced expression of homeobox genes is regulated by several mechanisms, such as loss of heterozygosity, gene amplification, CpG island promoter hypermethylation, or histone deacetylation, and consequently contributes to the development and progression of cancer.	('homeobox genes', 'Gene', (48, 62))	('reduced', 'NegReg', (14, 21))	('expression', 'MPA', (34, 44))	('enhanced', 'PosReg', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('loss', 'Var', (107, 111))	('contributes to', 'Reg', (232, 246))	('gene amplification', 'Var', (131, 149))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Disease', (282, 288))	('histone', 'MPA', (192, 199))
394611	27729732	For example, HOXA9 is downregulated in lung cancer tissues compared to that in surrounding non-cancerous tissues by an epigenetic silencing mechanism, whereas it is upregulated in acute lymphocystic leukemia.	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('non-cancerous', 'Disease', (91, 104))	('lung cancer', 'Disease', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('HOXA9', 'Gene', (13, 18))	('leukemia', 'Phenotype', 'HP:0001909', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('HOXA9', 'Gene', '3205', (13, 18))	('upregulated', 'PosReg', (165, 176))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('non-cancerous', 'Disease', 'MESH:D009369', (91, 104))	('acute lymphocystic leukemia', 'Phenotype', 'HP:0006721', (180, 207))	('acute lymphocystic leukemia', 'Disease', (180, 207))	('epigenetic silencing', 'Var', (119, 139))	('acute lymphocystic leukemia', 'Disease', 'MESH:D015470', (180, 207))	('downregulated', 'NegReg', (22, 35))
394613	27729732	For example, HOX transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA, is located in the HOXC locus near the 5' end, and recruits polycomb repressive complex 2 to lead epigenetic silencing of the HOXD locus.	('HOXD', 'Gene', (211, 215))	('HOXC', 'Gene', (104, 108))	('epigenetic silencing', 'Var', (183, 203))	('HOTAIR', 'Gene', (54, 60))	('HOX transcript antisense intergenic RNA', 'Gene', '100124700', (13, 52))	('HOXD', 'Gene', '3230', (211, 215))	('HOTAIR', 'Gene', '100124700', (54, 60))	('HOXC', 'Gene', '3220', (104, 108))	('HOX transcript antisense intergenic RNA', 'Gene', (13, 52))
394617	27729732	This article provides information on the underlying molecular mechanisms, aberrant expression in GI cancer tissues, and the potential value of various homeobox genes for early recognition or prediction of prognosis in GI cancers.	('GI cancer', 'Disease', 'MESH:D009369', (97, 106))	('GI cancers', 'Disease', (218, 228))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('GI cancer', 'Phenotype', 'HP:0007378', (97, 106))	('GI cancer', 'Disease', 'MESH:D009369', (218, 227))	('GI cancers', 'Disease', 'MESH:D009369', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('GI cancer', 'Phenotype', 'HP:0007378', (218, 227))	('GI cancer', 'Disease', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('aberrant', 'Var', (74, 82))
394625	27729732	A previous study using the reverse transcriptase-polymerase chain reaction (RT-PCR) showed that HOXA7, A9, and C6 mRNAs were overexpressed significantly in ESCC tissues compared to non-cancerous surrounding tissues.	('HOXA7', 'Gene', (96, 101))	('HOXA7', 'Gene', '3204', (96, 101))	('non-cancerous', 'Disease', (181, 194))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('C6 mRNAs', 'Var', (111, 119))	('overexpressed', 'PosReg', (125, 138))	('non-cancerous', 'Disease', 'MESH:D009369', (181, 194))	('ESCC', 'Disease', (156, 160))
394631	27729732	These researchers also used ESCC tissues to show that co-expression of HOXA13 with annexinA2 and SOD was significantly associated with poor prognosis.	('annexinA2 and SOD', 'Gene', '302;6647', (83, 100))	('HOXA13', 'Gene', (71, 77))	('HOXA13', 'Gene', '3209', (71, 77))	('co-expression', 'Var', (54, 67))	('associated', 'Reg', (119, 129))
394642	27729732	Another study showed that the expression of CDX2 in gastric cancer was governed mainly by promoter hypermethylation.	('promoter hypermethylation', 'Var', (90, 115))	('expression', 'MPA', (30, 40))	('CDX2', 'Gene', (44, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('governed', 'Reg', (71, 79))	('gastric cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))
394643	27729732	This suggested that aberrant downregulation of CDX2 might promote gastric carcinogenesis.	('downregulation', 'NegReg', (29, 43))	('aberrant', 'Var', (20, 28))	('promote', 'PosReg', (58, 65))	('CDX2', 'Gene', (47, 51))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (66, 88))	('gastric carcinogenesis', 'Disease', (66, 88))
394654	27729732	In contrast, several in vitro studies showed that the expression of IRX1 and PDX1 mRNA was downregulated in gastric cancer cells by an epigenetic silencing mechanism via promoter hypermethylation, suggesting their tumor-suppressive functions.	('expression', 'MPA', (54, 64))	('PDX1', 'Gene', (77, 81))	('downregulated', 'NegReg', (91, 104))	('promoter hypermethylation', 'Var', (170, 195))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('IRX1', 'Gene', (68, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (108, 122))	('IRX1', 'Gene', '79192', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('epigenetic silencing', 'Var', (135, 155))	('PDX1', 'Gene', '3651', (77, 81))	('tumor', 'Disease', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('gastric cancer', 'Disease', (108, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (108, 122))
394661	27729732	Furthermore, patient with positive HOXA13 expression had a lower overall survival and disease-free survival compared with patients with negative HOXA13 expression.	('overall survival', 'CPA', (65, 81))	('positive', 'Var', (26, 34))	('patient', 'Species', '9606', (13, 20))	('lower', 'NegReg', (59, 64))	('HOXA13', 'Gene', (35, 41))	('patient', 'Species', '9606', (122, 129))	('HOXA13', 'Gene', (145, 151))	('HOXA13', 'Gene', '3209', (35, 41))	('patients', 'Species', '9606', (122, 130))	('expression', 'Var', (42, 52))	('HOXA13', 'Gene', '3209', (145, 151))	('disease-free survival', 'CPA', (86, 107))
394669	27729732	This phenomenon has been validated by in vitro studies showing that overexpression of HOXB7 in gastric cancer cells promoted cellular invasion and migration, and inhibited apoptosis, whereas silencing HOXB7 showed the opposite effects.	('HOXB7', 'Gene', '3217', (86, 91))	('migration', 'CPA', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('promoted', 'PosReg', (116, 124))	('inhibited', 'NegReg', (162, 171))	('HOXB7', 'Gene', (86, 91))	('HOXB7', 'Gene', '3217', (201, 206))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('overexpression', 'PosReg', (68, 82))	('silencing', 'Var', (191, 200))	('gastric cancer', 'Disease', (95, 109))	('apoptosis', 'CPA', (172, 181))	('HOXB7', 'Gene', (201, 206))	('cellular invasion', 'CPA', (125, 142))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))
394680	27729732	Loss of CDX2 in colon cancer cells downregulated Mucdhl, thereby eliminating the latter's inhibition of Wnt/beta-catenin activity.	('eliminating', 'NegReg', (65, 76))	('beta-catenin', 'Gene', (108, 120))	('CDX2', 'Gene', (8, 12))	('colon cancer', 'Disease', (16, 28))	('beta-catenin', 'Gene', '1499', (108, 120))	('inhibition', 'MPA', (90, 100))	('downregulated', 'NegReg', (35, 48))	('Mucdhl', 'Protein', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('Loss', 'Var', (0, 4))	('colon cancer', 'Phenotype', 'HP:0003003', (16, 28))	('colon cancer', 'Disease', 'MESH:D015179', (16, 28))
394682	27729732	Furthermore, significant tumor formation was observed when heterozygous Cdx2+/-, but not wild-type mice, were treated with the DNA mutagen azosymethane.	('mice', 'Species', '10090', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('azosymethane', 'Chemical', '-', (139, 151))	('Cdx2+/-', 'Var', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
394684	27729732	At the tissue level, reduced expression of CDX2 in colorectal adenoma or cancer was associated significantly with right side tumors, poorly differentiated or high-grade carcinomas, advanced stage, poor prognosis, CpG island methylator phenotype, and mismatch repair-deficient tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('carcinomas', 'Disease', 'MESH:D002277', (169, 179))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('deficient tumors', 'Disease', (266, 282))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('CDX2', 'Gene', (43, 47))	('colorectal adenoma', 'Disease', (51, 69))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('poorly', 'Disease', (133, 139))	('right side tumors', 'Disease', (114, 131))	('high-grade', 'CPA', (158, 168))	('right side tumors', 'Disease', 'MESH:D000069584', (114, 131))	('poor prognosis', 'CPA', (197, 211))	('carcinomas', 'Disease', (169, 179))	('colorectal adenoma', 'Disease', 'MESH:D015179', (51, 69))	('expression', 'MPA', (29, 39))	('reduced', 'NegReg', (21, 28))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('advanced', 'Disease', (181, 189))	('deficient tumors', 'Disease', 'MESH:D009369', (266, 282))	('CpG island methylator', 'Var', (213, 234))
394688	27729732	The expression of the airstaless-like homeobox-4 gene (ALX4) was aberrantly reduced in colorectal dysplasia or adenocarcinoma compared with normal colonic mucosa, through DNA methylation.	('colorectal dysplasia', 'Disease', (87, 107))	('ALX4', 'Gene', (55, 59))	('colorectal dysplasia', 'Disease', 'MESH:D015179', (87, 107))	('expression', 'MPA', (4, 14))	('ALX4', 'Gene', '60529', (55, 59))	('adenocarcinoma', 'Disease', (111, 125))	('reduced', 'NegReg', (76, 83))	('DNA methylation', 'Var', (171, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('colonic mucosa', 'Disease', 'MESH:D015179', (147, 161))	('colonic mucosa', 'Disease', (147, 161))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))
394758	26496280	Patients with lymph node metastasis had significantly higher NLR than those without lymph node metastasis (P = 0.001).	('Patients', 'Species', '9606', (0, 8))	('lymph node metastasis', 'Var', (14, 35))	('higher', 'PosReg', (54, 60))	('NLR', 'MPA', (61, 64))
394763	26496280	Similarly, the 5-year survival rate was significantly lower in patients with high NLR values than in those with low NLR values (24.4% vs. 66.1%, P < 0.001; Figure 1B).	('high', 'Var', (77, 81))	('lower', 'NegReg', (54, 59))	('patients', 'Species', '9606', (63, 71))
394800	26496280	Furthermore, the 5-year survival rates of patients with high NLR and mGPS of 2 were 24.4% and 22.4%, respectively.	('patients', 'Species', '9606', (42, 50))	('mGPS', 'Var', (69, 73))	('NLR', 'Gene', (61, 64))	('high', 'Var', (56, 60))
394837	33151119	Next-generation sequencing (NGS) was then performed in this patient using both tissue and blood samples, which revealed EGFR amplification, TP53 missense mutation, and PIK3CA activating mutation (Table 1).	('patient', 'Species', '9606', (60, 67))	('amplification', 'Var', (125, 138))	('activating', 'PosReg', (175, 185))	('TP53', 'Gene', (140, 144))	('PIK3CA', 'Gene', (168, 174))	('missense mutation', 'Var', (145, 162))	('PIK3CA', 'Gene', '5290', (168, 174))	('TP53', 'Gene', '7157', (140, 144))	('EGFR', 'Gene', (120, 124))
394842	33151119	Multiple lung metastases have increased by more than 50% of baseline (the percentage of the tumor size enlargement compared with the status when immunotherapy initialed: lesion 1: 102%; lesion 2: 93%; and lesion 3: 215%).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('lung metastases', 'Disease', (9, 24))	('lesion', 'Var', (186, 192))	('enlargement', 'PosReg', (103, 114))	('lung metastases', 'Disease', 'MESH:D009362', (9, 24))	('tumor', 'Disease', (92, 97))	('increased', 'PosReg', (30, 39))
394851	33151119	Genome-wide sequencing of cell-free DNA has been reported to identify copy-number alterations that can be used for monitoring response to immunotherapy and identifying HPD in cancer patients.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('copy-number alterations', 'Var', (70, 93))	('HPD', 'Disease', (168, 171))	('patients', 'Species', '9606', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('HPD', 'Disease', 'MESH:D004421', (168, 171))
394859	33151119	The results from a recent study indicated a close association between MDM2/MDM4 amplification and HPD among stage IV cancer patients after anti-PD1 therapy.	('MDM4', 'Gene', (75, 79))	('amplification', 'Var', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('HPD', 'Disease', (98, 101))	('MDM4', 'Gene', '4194', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('MDM2', 'Gene', '4193', (70, 74))	('MDM2', 'Gene', (70, 74))	('patients', 'Species', '9606', (124, 132))	('HPD', 'Disease', 'MESH:D004421', (98, 101))
394874	33151119	demonstrated that non-small cell lung cancer (NSCLC) patients harboring EGFR mutations or ALK rearrangements displayed low objective response rate (ORR) to anti-PD1/PD-L1 therapy.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('objective response', 'MPA', (123, 141))	('patients', 'Species', '9606', (53, 61))	('low', 'NegReg', (119, 122))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (18, 44))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (22, 44))	('EGFR', 'Gene', (72, 76))	('rearrangements', 'Var', (94, 108))	('mutations', 'Var', (77, 86))	('ALK', 'Gene', (90, 93))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('lung cancer', 'Disease', (33, 44))
394875	33151119	In addition, the results from another study revealed a correlation between EGFR mutations and the low TTF (less than 2 months), and patients harboring EGFR mutations were more likely to experience HPD.	('low TTF', 'MPA', (98, 105))	('mutations', 'Var', (80, 89))	('HPD', 'Disease', (197, 200))	('mutations', 'Var', (156, 165))	('EGFR', 'Gene', (151, 155))	('HPD', 'Disease', 'MESH:D004421', (197, 200))	('patients', 'Species', '9606', (132, 140))	('EGFR', 'Gene', (75, 79))
394876	33151119	While EGFR mutations and ALK rearrangements are associated with the activation of corresponding signaling pathways, whether there exists a correlation between the mutation-driven signaling pathway and HPD remains to be identified.	('mutations', 'Var', (11, 20))	('HPD', 'Disease', (201, 204))	('EGFR', 'Gene', (6, 10))	('activation', 'PosReg', (68, 78))	('signaling pathways', 'Pathway', (96, 114))	('ALK', 'Gene', (25, 28))	('HPD', 'Disease', 'MESH:D004421', (201, 204))	('rearrangements', 'Var', (29, 43))
394970	32079295	In fact, it was observed that the activation of specific signaling pathways in tumors triggered by alterations in ECM stiffness, besides altering cell morphology and migration.	('EC', 'Disease', 'MESH:D004938', (114, 116))	('alterations', 'Var', (99, 110))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('activation', 'PosReg', (34, 44))	('altering', 'Reg', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
394974	32079295	Thus, once integrins represent the main class of receptors interacting with ECM, one could suggest that the activity of telomerase induced by the alterations in ECM stiffness, may be mediated, at least in part, by integrin receptors.	('stiffness', 'MPA', (165, 174))	('activity', 'MPA', (108, 116))	('EC', 'Disease', 'MESH:D004938', (76, 78))	('alterations', 'Var', (146, 157))	('telomerase', 'Enzyme', (120, 130))	('EC', 'Disease', 'MESH:D004938', (161, 163))
394978	32079295	Finally, because integrins represent a key element during mechanotransduction, one could say that the alterations in ECM stiffness might play a central role in the esophageal tissue transformation due to its involvement in telomere elongation.	('telomere elongation', 'CPA', (223, 242))	('involvement', 'Reg', (208, 219))	('men', 'Species', '9606', (46, 49))	('esophageal tissue', 'Disease', (164, 181))	('men', 'Species', '9606', (215, 218))	('alterations', 'Var', (102, 113))	('EC', 'Disease', 'MESH:D004938', (117, 119))
394995	32079295	Hence, because aberrant expression of MMP-2 and MMP-9 plays a key role along EC progression, different studies have shed some light on the mechanisms involved in the deregulation of MMP-2 and MMP-9 expression.	('MMP-9', 'Gene', '4318', (48, 53))	('MMP-9', 'Gene', (192, 197))	('MMP-9', 'Gene', (48, 53))	('MMP-2', 'Gene', (38, 43))	('expression', 'MPA', (24, 34))	('MMP-2', 'Gene', (182, 187))	('EC', 'Disease', 'MESH:D004938', (77, 79))	('aberrant', 'Var', (15, 23))	('MMP-2', 'Gene', '4313', (38, 43))	('MMP-2', 'Gene', '4313', (182, 187))	('MMP-9', 'Gene', '4318', (192, 197))
395000	32079295	Oppositely, the study performed by Garalla and colleagues showed that the blockage of the MAPK pathway was not able to interfere in MMP-7 expression, although MMP-7 aberrant levels had been previously related to EC progression.	('MMP-7', 'Gene', '4316', (159, 164))	('EC', 'Disease', 'MESH:D004938', (212, 214))	('MMP-7', 'Gene', '4316', (132, 137))	('aberrant', 'Var', (165, 173))	('MAPK', 'Gene', (90, 94))	('MAPK', 'Gene', '5595;5594;5595', (90, 94))	('MMP-7', 'Gene', (159, 164))	('related', 'Reg', (201, 208))	('MMP-7', 'Gene', (132, 137))
395001	32079295	Nonetheless, in the same study, the authors demonstrated that PI3K blockage, by using the chemical inhibitor LY294002, was able to strongly abolish MMP-7 secretion by EAC cells.	('LY294002', 'Chemical', 'MESH:C085911', (109, 117))	('EAC', 'Phenotype', 'HP:0011459', (167, 170))	('LY294002', 'Var', (109, 117))	('EAC', 'Disease', (167, 170))	('PI3K blockage', 'Var', (62, 75))	('MMP-7', 'Gene', (148, 153))	('EAC', 'Disease', 'MESH:D004938', (167, 170))	('MMP-7', 'Gene', '4316', (148, 153))	('abolish', 'NegReg', (140, 147))
395025	32079295	Of note, MMP-1 expression deregulation has been reported as a poor prognosis marker for EC development.	('deregulation', 'Var', (26, 38))	('expression', 'MPA', (15, 25))	('MMP-1', 'Gene', '4312', (9, 14))	('EC', 'Disease', 'MESH:D004938', (88, 90))	('MMP-1', 'Gene', (9, 14))	('men', 'Species', '9606', (98, 101))
395028	32079295	In addition, the relationship between GERD and MMPs along esophageal carcinogenesis seems to represent a wide event, and it has been reported that GERD condition is associated with the prevalence of polymorphisms in MMP-1 (*1G/2G) and MMP-3 (*6A/5A).	('MMP-1', 'Gene', '4312', (216, 221))	('MMPs', 'Gene', '4312;4313;4314;4316;4318;4321;4323', (47, 51))	('MMP-3', 'Gene', '4314', (235, 240))	('GERD', 'Disease', (147, 151))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (58, 83))	('GERD', 'Disease', 'MESH:D005764', (147, 151))	('associated', 'Reg', (165, 175))	('MMPs', 'Gene', (47, 51))	('GERD', 'Disease', (38, 42))	('esophageal carcinogenesis', 'Disease', (58, 83))	('MMP-1', 'Gene', (216, 221))	('MMP-3', 'Gene', (235, 240))	('polymorphisms', 'Var', (199, 212))	('GERD', 'Disease', 'MESH:D005764', (38, 42))
395029	32079295	Thus, because it is already known that polymorphisms in MMP-1 (*1G/2G) and MMP-3 (*6A/5A) are related to an enhanced risk for EAC development, these data suggest that the association between GERD and MMP polymorphisms is an early event during EAC development.	('polymorphisms', 'Var', (39, 52))	('men', 'Species', '9606', (254, 257))	('EAC', 'Phenotype', 'HP:0011459', (243, 246))	('MMP-3', 'Gene', '4314', (75, 80))	('MMP', 'Gene', (200, 203))	('MMP-1', 'Gene', '4312', (56, 61))	('EAC', 'Phenotype', 'HP:0011459', (126, 129))	('EAC', 'Disease', (243, 246))	('MMP-1', 'Gene', (56, 61))	('MMP-3', 'Gene', (75, 80))	('GERD', 'Disease', 'MESH:D005764', (191, 195))	('*1G/2G', 'Var', (63, 69))	('EAC', 'Disease', 'MESH:D004938', (243, 246))	('EAC', 'Disease', (126, 129))	('GERD', 'Disease', (191, 195))	('men', 'Species', '9606', (137, 140))	('EAC', 'Disease', 'MESH:D004938', (126, 129))	('related', 'Reg', (94, 101))
395031	32079295	In this way, a meta-analysis study conducted by Peng and colleagues revealed that the distinct polymorphisms present in MMP-7 and MMP-9 genes were not related to increased risk for EC development, and moreover, two polymorphisms found in MMP-2 gene were associated with a diminished susceptibility of EC development.	('EC', 'Disease', 'MESH:D004938', (181, 183))	('polymorphisms', 'Var', (215, 228))	('MMP-7', 'Gene', (120, 125))	('MMP-2', 'Gene', '4313', (238, 243))	('diminished', 'NegReg', (272, 282))	('MMP-7', 'Gene', '4316', (120, 125))	('men', 'Species', '9606', (191, 194))	('EC', 'Disease', 'MESH:D004938', (301, 303))	('MMP-9', 'Gene', '4318', (130, 135))	('men', 'Species', '9606', (311, 314))	('MMP-2', 'Gene', (238, 243))	('MMP-9', 'Gene', (130, 135))
395037	32079295	In this way, loss of E-cadherin, which plays a central role in cellular adhesion and communication by primarily mediating cell-cell adhesion, during tumor progression is directly associated with invasiveness and metastatic potential.	('associated', 'Reg', (179, 189))	('cell-cell adhesion', 'MPA', (122, 140))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('loss', 'Var', (13, 17))	('tumor', 'Disease', (149, 154))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('metastatic potential', 'CPA', (212, 232))	('invasiveness', 'CPA', (195, 207))
395045	32079295	Moreover, these data corroborate the previously reported association between aberrant expression of adhesion proteins, such as laminin and fibronectin, and EC progression.	('fibronectin', 'Gene', '2335', (139, 150))	('laminin', 'Protein', (127, 134))	('expression', 'MPA', (86, 96))	('EC', 'Disease', 'MESH:D004938', (156, 158))	('fibronectin', 'Gene', (139, 150))	('aberrant', 'Var', (77, 85))
395053	32079295	Indeed, co-expression of Lam5 (gamma2) chain and EGFR indicates a very poor prognosis of ESCC due to high metastatic potential.	('EGFR', 'Gene', '1956', (49, 53))	('Lam5', 'Gene', '3914', (25, 29))	('gamma2', 'Gene', '7453', (31, 37))	('EGFR', 'Gene', (49, 53))	('ESCC', 'Disease', (89, 93))	('ESCC', 'Disease', 'MESH:D000077277', (89, 93))	('gamma2', 'Gene', (31, 37))	('co-expression', 'Var', (8, 21))	('Lam5', 'Gene', (25, 29))
395055	32079295	In accordance with these data, when in contact with MMP-1, Lam5 (gamma2) cleavage enhances invasiveness and metastasis in ESCC patients, thus corroborating the biological consequences associated with Lam5 (gamma2) degradation during ESCC progression.	('Lam5', 'Gene', '3914', (59, 63))	('gamma2', 'Gene', '7453', (206, 212))	('ESCC', 'Disease', (122, 126))	('gamma2', 'Gene', '7453', (65, 71))	('MMP-1', 'Gene', '4312', (52, 57))	('enhances', 'PosReg', (82, 90))	('cleavage', 'Var', (73, 81))	('Lam5', 'Gene', (200, 204))	('ESCC', 'Disease', 'MESH:D000077277', (122, 126))	('patients', 'Species', '9606', (127, 135))	('Lam5', 'Gene', '3914', (200, 204))	('MMP-1', 'Gene', (52, 57))	('ESCC', 'Disease', (233, 237))	('ESCC', 'Disease', 'MESH:D000077277', (233, 237))	('gamma2', 'Gene', (206, 212))	('Lam5', 'Gene', (59, 63))	('gamma2', 'Gene', (65, 71))
395063	32079295	In EAC, high expression of laminin is associated with enhanced cell detachment, invasion, and dissemination in an osteopontin (OPN)-dependent manner.	('invasion', 'CPA', (80, 88))	('high', 'Var', (8, 12))	('OPN', 'Gene', (127, 130))	('expression', 'MPA', (13, 23))	('osteopontin', 'Gene', (114, 125))	('laminin', 'Protein', (27, 34))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('men', 'Species', '9606', (74, 77))	('EAC', 'Disease', (3, 6))	('OPN', 'Gene', '6696', (127, 130))	('EAC', 'Disease', 'MESH:D004938', (3, 6))	('enhanced', 'PosReg', (54, 62))	('cell detachment', 'CPA', (63, 78))	('dissemination', 'CPA', (94, 107))	('osteopontin', 'Gene', '6696', (114, 125))
395066	32079295	In other words, miRNA-202 is capable of suppressing tumor progression by targeting laminin alpha1 in ESCC, and high levels of laminin alpha1 have been associated with poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('laminin alpha1', 'Gene', (126, 140))	('tumor', 'Disease', (52, 57))	('laminin alpha1', 'Gene', (83, 97))	('laminin alpha1', 'Gene', '284217', (126, 140))	('ESCC', 'Disease', 'MESH:D000077277', (101, 105))	('targeting', 'Reg', (73, 82))	('miRNA-202', 'Var', (16, 25))	('laminin alpha1', 'Gene', '284217', (83, 97))	('ESCC', 'Disease', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('suppressing', 'NegReg', (40, 51))
395081	32079295	Additionally, fibronectin may also be regulated by long noncoding RNAs (lncRNAs).	('fibronectin', 'Gene', '2335', (14, 25))	('fibronectin', 'Gene', (14, 25))	('long noncoding RNAs', 'Var', (51, 70))
395082	32079295	It has been already reported that co-overexpression of fibronectin 1 and lncRNAs, such as lnc-ABCA12-3 (ATP Binding Cassette Subfamily A Member 12-3), in ESCC tissues is associated with tumor expansion, metastasis, and patients' poor prognosis.	('co-overexpression', 'Var', (34, 51))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('fibronectin 1', 'Gene', '2335', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('fibronectin 1', 'Gene', (55, 68))	('ESCC', 'Disease', (154, 158))	('ESCC', 'Disease', 'MESH:D000077277', (154, 158))	('tumor', 'Disease', (186, 191))	('ABCA12', 'Gene', (94, 100))	('ABCA12', 'Gene', '26154', (94, 100))	('patients', 'Species', '9606', (219, 227))	('associated with', 'Reg', (170, 185))	('metastasis', 'CPA', (203, 213))
395090	32079295	In EAC, upregulation and co-overexpression of tenascin-C and fibronectin have been directly associated with poor prognosis and metastasis of the patients.	('patients', 'Species', '9606', (145, 153))	('tenascin-C', 'Gene', (46, 56))	('upregulation', 'PosReg', (8, 20))	('poor prognosis', 'CPA', (108, 122))	('fibronectin', 'Gene', '2335', (61, 72))	('co-overexpression', 'Var', (25, 42))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('tenascin-C', 'Gene', '3371', (46, 56))	('fibronectin', 'Gene', (61, 72))	('EAC', 'Disease', (3, 6))	('EAC', 'Disease', 'MESH:D004938', (3, 6))	('metastasis', 'CPA', (127, 137))
395102	32079295	Additionally, Eca109 and EC9706 cells reduced the capacity of forming tubular networks upon galectin-3 knockdown in a phenomenon associated with MMP-2 downmodulation upon galectin-3 silencing.	('MMP-2', 'Gene', '4313', (145, 150))	('galectin-3', 'Gene', '3958', (92, 102))	('galectin-3', 'Gene', (92, 102))	('reduced', 'NegReg', (38, 45))	('galectin-3', 'Gene', (171, 181))	('men', 'Species', '9606', (123, 126))	('MMP-2', 'Gene', (145, 150))	('downmodulation', 'NegReg', (151, 165))	('EC9706', 'CellLine', 'CVCL:E307;0.19772709113114562', (25, 31))	('galectin-3', 'Gene', '3958', (171, 181))	('knockdown', 'Var', (103, 112))
395110	32079295	Finally, its deregulated expression is capable of altering not only the adhesion properties of EC cells, but also of improving EC cell migration and invasion abilities through the activation of phosphorylated extracellular signal-regulated kinases (pErk1/2) and FAK.	('extracellular signal-regulated kinases', 'Gene', '5594', (209, 247))	('adhesion properties', 'CPA', (72, 91))	('activation', 'PosReg', (180, 190))	('pErk', 'Gene', '9451', (249, 253))	('deregulated', 'Var', (13, 24))	('extracellular signal-regulated kinases', 'Gene', (209, 247))	('expression', 'MPA', (25, 35))	('invasion abilities', 'CPA', (149, 167))	('EC', 'Disease', 'MESH:D004938', (95, 97))	('EC', 'Disease', 'MESH:D004938', (127, 129))	('altering', 'Reg', (50, 58))	('pErk', 'Gene', (249, 253))	('improving', 'PosReg', (117, 126))
395173	30410394	The EC109 and EC9706 cells were trypsinized and suspended and cultured in culture plates (60 mm diameter) along with 10% FBS for 2 weeks.	('EC109', 'Var', (4, 9))	('EC109', 'CellLine', 'CVCL:6898', (4, 9))	('EC9706', 'CellLine', 'CVCL:E307', (14, 20))	('EC9706', 'Var', (14, 20))
395187	30410394	The miR-365 levels in ESCC cells, that is, EC109, EC1, and EC9706, were similar to those observed in tissue samples, and the levels of miR-365 were on the higher side when compared with the normal HEEC cell lines.	('miR', 'Gene', (135, 138))	('EC9706', 'Var', (59, 65))	('miR', 'Gene', (4, 7))	('EC9706', 'CellLine', 'CVCL:E307', (59, 65))	('miR', 'Gene', '220972', (4, 7))	('EC109', 'CellLine', 'CVCL:6898', (43, 48))	('EC1', 'Gene', '4819', (50, 53))	('EC1', 'Gene', (50, 53))	('EC1', 'Gene', '4819', (43, 46))	('miR', 'Gene', '220972', (135, 138))	('EC1', 'Gene', (43, 46))
395192	30410394	Tumor growth was evaluated in the xenografts mouse model, and the tumor weight reduced significantly (P<0.01) (Figure 3B) in mice receiving injection of EC9706 cells overexpressed for miR-365 compared with those receiving injection of vector control cells.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('reduced', 'NegReg', (79, 86))	('weight reduced', 'Phenotype', 'HP:0004325', (72, 86))	('tumor', 'Disease', (66, 71))	('overexpressed', 'Var', (166, 179))	('mouse', 'Species', '10090', (45, 50))	('mice', 'Species', '10090', (125, 129))	('EC9706', 'CellLine', 'CVCL:E307', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('miR', 'Gene', '220972', (184, 187))	('miR', 'Gene', (184, 187))
395198	30410394	The constructed luciferase reporter plasmids built by cloning the mutant 3'-UTR of PSAT1-expressing mutations in the miR-365 overexpression vector and the miR-365 seed region were used to co-transfect the HEK293 cells.	('mutations', 'Var', (100, 109))	('HEK293', 'CellLine', 'CVCL:0045', (205, 211))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', (155, 158))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', (117, 120))	('PSAT1', 'Gene', (83, 88))	('PSAT1', 'Gene', '29968', (83, 88))
395199	30410394	On assessing the luciferase activity, it was found that the overexpression of miR-365 did not suppress the reporter gene activity for mutations of PSAT 3'-UTR on two binding sites but significantly suppressed the activity of the wild-type PSAT1-UTR-MUT1 or MUT2 (P<0.01) (Figure 5A).	('activity', 'MPA', (213, 221))	('PSAT1', 'Gene', (239, 244))	('miR', 'Gene', '220972', (78, 81))	('PSAT1', 'Gene', '29968', (239, 244))	('miR', 'Gene', (78, 81))	('mutations', 'Var', (134, 143))	('suppressed', 'NegReg', (198, 208))	("PSAT 3'-UTR", 'Gene', (147, 158))
395200	30410394	The abnormal expression of miR-365 decreased the mRNA expression of PSAT1 significantly compared to the loading control, that is, GAPDH in both the ESCC cell lines (Figure 5B), confirming PSAT1 as a favorable target for miR-365.	('abnormal', 'Var', (4, 12))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('PSAT1', 'Gene', (68, 73))	('miR', 'Gene', (220, 223))	('decreased', 'NegReg', (35, 44))	('miR', 'Gene', '220972', (220, 223))	('PSAT1', 'Gene', '29968', (188, 193))	('mRNA expression', 'MPA', (49, 64))	('PSAT1', 'Gene', '29968', (68, 73))	('PSAT1', 'Gene', (188, 193))	('GAPDH', 'Gene', '2597', (130, 135))	('GAPDH', 'Gene', (130, 135))
395203	30410394	Reports have established that Ser/Thr kinase family protein GSK-3beta is deactivated as a result of phosphorylation at Ser9.	('deactivated', 'NegReg', (73, 84))	('Ser/Thr kinase family protein', 'Enzyme', (30, 59))	('Ser9', 'Chemical', '-', (119, 123))	('phosphorylation', 'MPA', (100, 115))	('GSK-3beta', 'Gene', '2932', (60, 69))	('GSK-3beta', 'Gene', (60, 69))	('Ser9', 'Var', (119, 123))
395204	30410394	GSK-3beta is found to regulate Snail activity; also, the epithelial phenol-typing is maintained by suppressing Snail, and hence, deactivation of GSK-3beta elevates EMT.	('EMT', 'Gene', '3702', (164, 167))	('suppressing', 'NegReg', (99, 110))	('elevates', 'PosReg', (155, 163))	('elevates EMT', 'Phenotype', 'HP:0008151', (155, 167))	('GSK-3beta', 'Gene', '2932', (145, 154))	('GSK-3beta', 'Gene', (145, 154))	('deactivation', 'Var', (129, 141))	('GSK-3beta', 'Gene', '2932', (0, 9))	('Snail', 'Gene', '6615', (31, 36))	('Snail', 'Gene', (31, 36))	('Snail', 'Gene', '6615', (111, 116))	('Snail', 'Gene', (111, 116))	('GSK-3beta', 'Gene', (0, 9))	('EMT', 'Gene', (164, 167))
395209	30410394	The study also showed that the ectopic expression of PSAT1 resulted in partial restoration of the E-cadherin and Snail levels, which were partially suppressed by miR-365, confirming the role of PSAT1 in reversing the consequences of miR-365 on EMT in selected esophageal cell lines (Figure 6C).	('PSAT1', 'Gene', '29968', (194, 199))	('PSAT1', 'Gene', (194, 199))	('PSAT1', 'Gene', (53, 58))	('E-cadherin', 'Gene', (98, 108))	('Snail', 'Gene', (113, 118))	('EMT', 'Gene', (244, 247))	('Snail', 'Gene', '6615', (113, 118))	('miR', 'Gene', '220972', (233, 236))	('miR', 'Gene', (233, 236))	('EMT', 'Gene', '3702', (244, 247))	('PSAT1', 'Gene', '29968', (53, 58))	('E-cadherin', 'Gene', '999', (98, 108))	('ectopic expression', 'Var', (31, 49))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))
395232	30410394	The outcome of experiments demonstrated that the overexpression of miR-365 resulted in the downregulation of PSAT1, and the abnormal expression of PSAT1 reversed the inhibitory activity of miR-365 on cell proliferation, invasion, and expression of EMT.	('downregulation', 'NegReg', (91, 105))	('abnormal', 'Var', (124, 132))	('EMT', 'Gene', (248, 251))	('invasion', 'CPA', (220, 228))	('miR', 'Gene', (189, 192))	('cell proliferation', 'CPA', (200, 218))	('PSAT1', 'Gene', (109, 114))	('EMT', 'Gene', '3702', (248, 251))	('miR', 'Gene', '220972', (189, 192))	('PSAT1', 'Gene', '29968', (147, 152))	('PSAT1', 'Gene', '29968', (109, 114))	('PSAT1', 'Gene', (147, 152))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))	('overexpression', 'PosReg', (49, 63))
395233	30410394	PHGDH and PSAT1 are the enzymes of serine pathway; literature suggest modifications in the levels of these two associated with progression of many cancers such as breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('modifications', 'Var', (70, 83))	('PHGDH', 'Gene', '26227', (0, 5))	('PHGDH', 'Gene', (0, 5))	('associated', 'Reg', (111, 121))	('serine', 'Chemical', 'MESH:D012694', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('PSAT1', 'Gene', '29968', (10, 15))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('PSAT1', 'Gene', (10, 15))	('cancers', 'Disease', (147, 154))	('breast cancer', 'Disease', (163, 176))
395240	30410394	The study confirmed that the effect of miR-365 on cell invasion and proliferation gets reversed after abnormal expression of PSAT1.	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('abnormal expression', 'Var', (102, 121))	('cell invasion', 'CPA', (50, 63))	('PSAT1', 'Gene', '29968', (125, 130))	('PSAT1', 'Gene', (125, 130))
395247	29328411	We found that RG108 increased the radiosensitivity of EC cells.	('increased', 'PosReg', (20, 29))	('RG108', 'Var', (14, 19))	('radiosensitivity', 'CPA', (34, 50))	('RG108', 'Chemical', 'MESH:C503639', (14, 19))
395248	29328411	Apoptosis and G2/M-phase arrest were induced by X-ray irradiation and were significantly enhanced by RG108.	('enhanced', 'PosReg', (89, 97))	('G2/M-phase arrest', 'CPA', (14, 31))	('RG108', 'Var', (101, 106))	('Apoptosis', 'CPA', (0, 9))	('RG108', 'Chemical', 'MESH:C503639', (101, 106))
395249	29328411	In addition, growth of tumor xenografts from the Eca-109 cells was significantly inhibited by irradiation in combination with RG108.	('RG108', 'Chemical', 'MESH:C503639', (126, 131))	('RG108', 'Var', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('inhibited', 'NegReg', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))
395256	29328411	Multiple genetic and epigenetic alterations are involved in the growth of ECs, including tumor suppressor gene (TSG) mutations, loss of heterozygosity and promoter methylation, as well as overexpression of oncogenes.	('mutations', 'Var', (117, 126))	('promoter', 'MPA', (155, 163))	('ECs', 'Disease', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('overexpression', 'PosReg', (188, 202))	('TSG', 'Gene', (112, 115))	('loss of heterozygosity', 'Var', (128, 150))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('TSG', 'Gene', '57045', (112, 115))
395258	29328411	Epigenetic events, such as aberrant de novo methylation of gene promoters, have recently been defined as markers of human cancers and therapeutic strategies targeting these mechanisms are currently being tested in several clinical trials.	('aberrant', 'Var', (27, 35))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('methylation', 'MPA', (44, 55))	('human', 'Species', '9606', (116, 121))
395277	29328411	For the cell cycle analysis, the cells were collected 24 h after treatment with RG108 or RG108 combined with 6 Gy of X-ray irradiation and fixed with 70% precooled ethanol overnight.	('RG108', 'Gene', (89, 94))	('RG108', 'Chemical', 'MESH:C503639', (89, 94))	('ethanol', 'Chemical', 'MESH:D000431', (164, 171))	('RG108', 'Var', (80, 85))	('RG108', 'Chemical', 'MESH:C503639', (80, 85))
395299	29328411	We selected 25 microM RG108, which resulted in ~90% cell viability, as the non-toxic dose for the subsequent experiments.	('cell viability', 'CPA', (52, 66))	('RG108', 'Chemical', 'MESH:C503639', (22, 27))	('RG108', 'Var', (22, 27))
395302	29328411	Given that 6 h of RG108 pretreatment before IR sensitized the EC cells to IR-induced cell death, this pretreatment time was used for further studies.	('pretreatment', 'Var', (24, 36))	('sensitized', 'Reg', (47, 57))	('RG108', 'Chemical', 'MESH:C503639', (18, 23))	('RG108', 'Gene', (18, 23))
395304	29328411	Firstly, we examined the clonogenicity of cells after treatment with 25 microM RG108 or an equivalent volume of DMSO (control) for 6 h with or without IR.	('RG108', 'Var', (79, 84))	('examined', 'Reg', (12, 20))	('DMSO', 'Chemical', 'MESH:D004121', (112, 116))	('RG108', 'Chemical', 'MESH:C503639', (79, 84))
395305	29328411	2A, the number of colonies after treatment with 25 microM RG108 and 6 Gy of X-ray irradiation was significantly decreased compared with the control (P<0.05) for both Eca-109 and TE-1 cells.	('decreased', 'NegReg', (112, 121))	('RG108', 'Var', (58, 63))	('TE-1', 'CellLine', 'CVCL:1759', (178, 182))	('RG108', 'Chemical', 'MESH:C503639', (58, 63))
395308	29328411	To investigate whether RG108 at a non-toxic dose could enhance radiation-induced apoptosis in EC cells, we performed Annexin V/7-AAD double-staining assays to analyze cellular apoptosis.	('radiation-induced apoptosis', 'CPA', (63, 90))	('Annexin V', 'Gene', '308', (117, 126))	('7-AAD', 'Chemical', '-', (127, 132))	('enhance', 'PosReg', (55, 62))	('Annexin V', 'Gene', (117, 126))	('RG108', 'Var', (23, 28))	('RG108', 'Chemical', 'MESH:C503639', (23, 28))
395309	29328411	3A and B, compared with control cells, apoptosis was modestly increased in both cell lines by treatment with RG108 or IR alone.	('RG108', 'Chemical', 'MESH:C503639', (109, 114))	('apoptosis', 'CPA', (39, 48))	('RG108', 'Var', (109, 114))
395310	29328411	However, apoptosis was significantly increased by treating cells with 25 microM RG108 for 6 h before exposure to IR in both cell lines.	('RG108', 'Var', (80, 85))	('RG108', 'Chemical', 'MESH:C503639', (80, 85))	('increased', 'PosReg', (37, 46))	('apoptosis', 'CPA', (9, 18))
395312	29328411	The results revealed that pretreatment with 25 microM RG108 for 6 h before 6 Gy irradiation significantly inhibited the expression of Bcl-2, while it upregulated the expression of Bax, in both Eca-109 and TE-1 cells (Fig.	('RG108', 'Var', (54, 59))	('Bax', 'Gene', (180, 183))	('expression', 'MPA', (120, 130))	('RG108', 'Chemical', 'MESH:C503639', (54, 59))	('upregulated', 'PosReg', (150, 161))	('inhibited', 'NegReg', (106, 115))	('TE-1', 'CellLine', 'CVCL:1759', (205, 209))	('Bcl-2', 'Gene', (134, 139))	('expression', 'MPA', (166, 176))
395316	29328411	While 6 Gy of X-ray irradiation alone induced a slight increase of Eca-109 and TE-1 cells in G2/M phase, pretreatment with 25 microM RG108 for 6 h in combination with IR significantly increased this radiation-induced arrest inthe G2/M phase by 9.77% in Eca-109 cells and 7.97% in TE-1 cells (both P<0.05).	('RG108', 'Chemical', 'MESH:C503639', (133, 138))	('G2/M phase', 'CPA', (230, 240))	('increase', 'PosReg', (55, 63))	('G2/M phase', 'CPA', (93, 103))	('TE-1', 'CellLine', 'CVCL:1759', (79, 83))	('increased', 'PosReg', (184, 193))	('TE-1', 'CellLine', 'CVCL:1759', (280, 284))	('RG108', 'Var', (133, 138))
395317	29328411	These results indicated that combined treatment with RG108 and IR increased the G2/M arrest of the EC cells induced by radiation.	('RG108', 'Var', (53, 58))	('M arrest', 'Disease', (83, 91))	('increased', 'PosReg', (66, 75))	('M arrest', 'Disease', 'MESH:D006323', (83, 91))	('RG108', 'Chemical', 'MESH:C503639', (53, 58))
395322	29328411	5A and B, treatment with RG108 or IR alone slightly decreased the xenograft size, whereas the combination of RG108 and IR significantly decreased the volume of tumors compared with the control treatment (57% reduction, P<0.05).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('RG108', 'Chemical', 'MESH:C503639', (109, 114))	('RG108', 'Var', (109, 114))	('decreased', 'NegReg', (52, 61))	('RG108', 'Chemical', 'MESH:C503639', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('xenograft size', 'CPA', (66, 80))	('tumors', 'Disease', (160, 166))	('decreased', 'NegReg', (136, 145))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
395324	29328411	6 (top), RG108 or IR alone modestly reduced the expression of Ki67, whereas the number of Ki67-positive cells was significantly decreased in Eca-109 tumors by combined treatment with both RG108 and IR (P<0.05).	('Ki67', 'Protein', (62, 66))	('RG108', 'Var', (188, 193))	('expression', 'MPA', (48, 58))	('RG108', 'Chemical', 'MESH:C503639', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('decreased', 'NegReg', (128, 137))	('Eca-109', 'Gene', (141, 148))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('reduced', 'NegReg', (36, 43))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('RG108', 'Chemical', 'MESH:C503639', (9, 14))
395326	29328411	6 (bottom), treatment with RG108 or IR alone modestly reduced the expression of CD31, but combined treatment with both RG108 and IR significantly decreased the expression of CD31.	('expression', 'MPA', (160, 170))	('CD31', 'Gene', (80, 84))	('RG108', 'Var', (119, 124))	('RG108', 'Chemical', 'MESH:C503639', (119, 124))	('CD31', 'Gene', '5175', (80, 84))	('RG108', 'Chemical', 'MESH:C503639', (27, 32))	('decreased', 'NegReg', (146, 155))	('expression', 'MPA', (66, 76))	('reduced', 'NegReg', (54, 61))	('CD31', 'Gene', (174, 178))	('CD31', 'Gene', '5175', (174, 178))
395332	29328411	Tumorigenesis and tumor progression are connected with genetic and epigenetic changes and one of these epigenetic factors is DNA methylation.	('epigenetic changes', 'Var', (67, 85))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DNA', 'Var', (125, 128))	('tumor', 'Disease', (18, 23))	('Tumorigenesis', 'CPA', (0, 13))	('genetic', 'Var', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
395333	29328411	Previous studies have revealed that the methylation statuses of specific genes may potentially be molecular markers of thyroid, breast, prostate, gastric and colon carcinomas.	('methylation statuses', 'Var', (40, 60))	('prostate', 'Disease', (136, 144))	('breast', 'Disease', (128, 134))	('markers', 'Reg', (108, 115))	('gastric and colon carcinomas', 'Disease', 'MESH:D013274', (146, 174))	('thyroid', 'Disease', (119, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
395334	29328411	The reversion of epigenetic mutations by DNMTIs, a promising class of novel drugs, represents an experimental strategy with great promise for epigenetic cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('epigenetic mutations', 'Var', (17, 37))	('DNMT', 'Gene', '1786', (41, 45))	('DNMT', 'Gene', (41, 45))
395336	29328411	Epigenetics and DNA methylation have recently become one of the most exciting frontiers for research on the radioresistance of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Epigenetics', 'Var', (0, 11))	('cancer', 'Disease', (127, 133))
395339	29328411	This leads to reactivation of tumor-suppressor genes and demethylation of genomic DNA, while exhibiting little toxicity in human cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('demethylation', 'Var', (57, 70))	('human', 'Species', '9606', (123, 128))	('cancer', 'Disease', (129, 135))	('toxicity', 'Disease', 'MESH:D064420', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('toxicity', 'Disease', (111, 119))	('tumor', 'Disease', (30, 35))	('reactivation', 'MPA', (14, 26))
395348	29328411	Zheng et al and Liu et al have reported that treatment with either miRNA-200c or MG132 promoted G2/M arrest in cancer cells, leading to the conclusion that strategies that target G2/M arrest may be effective for promoting radiosensitivity in cancer therapy.	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('MG132', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('M arrest', 'Disease', (99, 107))	('miRNA-200c', 'Var', (67, 77))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('M arrest', 'Disease', 'MESH:D006323', (99, 107))	('M arrest', 'Disease', 'MESH:D006323', (182, 190))	('cancer', 'Disease', (111, 117))	('promoted', 'PosReg', (87, 95))	('M arrest', 'Disease', (182, 190))	('MG132', 'Chemical', 'MESH:C072553', (81, 86))
395350	29328411	Analysis of mRNA expression indicated that RG108 combined with IR treatment increased the expression of EVA1A, which in most cancer tissues has reduced or undetectable expression compared to normal tissues.	('RG108', 'Chemical', 'MESH:C503639', (43, 48))	('reduced', 'NegReg', (144, 151))	('RG108', 'Var', (43, 48))	('expression', 'MPA', (168, 178))	('increased', 'PosReg', (76, 85))	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('EVA1A', 'Gene', '84141', (104, 109))	('expression', 'MPA', (90, 100))	('EVA1A', 'Gene', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
395351	29328411	The restoration of EVA1A expression induces death in some cancer cell lines through both autophagy and apoptosis, indicating that EVA1A is an effective tumor-suppressing molecule.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('EVA1A', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('EVA1A', 'Gene', (130, 135))	('expression', 'MPA', (25, 35))	('tumor', 'Disease', (152, 157))	('EVA1A', 'Gene', '84141', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('apoptosis', 'CPA', (103, 112))	('cancer', 'Disease', (58, 64))	('autophagy', 'CPA', (89, 98))	('EVA1A', 'Gene', '84141', (130, 135))	('restoration', 'Var', (4, 15))
395352	29328411	RG108 combined with radiotherapy increased the expression of EVA1A, which may be one of the reasons why RG108 inhibited tumor growth.	('EVA1A', 'Gene', (61, 66))	('RG108', 'Chemical', 'MESH:C503639', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('increased', 'PosReg', (33, 42))	('RG108', 'Var', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('EVA1A', 'Gene', '84141', (61, 66))	('RG108', 'Chemical', 'MESH:C503639', (104, 109))	('inhibited', 'NegReg', (110, 119))	('expression', 'MPA', (47, 57))	('tumor', 'Disease', (120, 125))
395353	29328411	The present study also revealed that RG108 modulated the radiosensitivity of Eca-109 cells via a complex mechanism by affecting multiple pathways, including the TGF-beta signaling pathway and Epstein-Barr virus infection pathway.	('affecting', 'Reg', (118, 127))	('TGF-beta signaling pathway', 'Pathway', (161, 187))	('modulated', 'Reg', (43, 52))	('Epstein-Barr virus infection', 'Disease', (192, 220))	('Epstein-Barr virus infection', 'Disease', 'MESH:D020031', (192, 220))	('RG108', 'Var', (37, 42))	('radiosensitivity', 'CPA', (57, 73))	('RG108', 'Chemical', 'MESH:C503639', (37, 42))
395356	29328411	The results of tumor xenograft experiments revealed that RG108, combined with IR, significantly inhibited the proliferation of Eca-109 cells in vivo.	('RG108', 'Chemical', 'MESH:C503639', (57, 62))	('RG108', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('proliferation', 'CPA', (110, 123))	('tumor', 'Disease', (15, 20))	('inhibited', 'NegReg', (96, 105))
395371	26880895	It has been reported that the deactivation of the CADM1/TSLC1 gene, partly through promoter hypermethylation, is associated with the occurrence and development of a wide variety of tumors, including non-small cell lung cancer, ovarian cancer, breast cancer, colon cancer, and laryngeal squamous cell carcinoma.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (199, 225))	('laryngeal squamous cell carcinoma', 'Disease', (276, 309))	('colon cancer', 'Disease', 'MESH:D015179', (258, 270))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('ovarian cancer', 'Disease', (227, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('ovarian cancer', 'Phenotype', 'HP:0100615', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))	('non-small cell lung cancer', 'Disease', (199, 225))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('colon cancer', 'Disease', (258, 270))	('CADM1/TSLC1', 'Gene', (50, 61))	('breast cancer', 'Disease', (243, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (276, 309))	('deactivation', 'Var', (30, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (199, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('colon cancer', 'Phenotype', 'HP:0003003', (258, 270))	('ovarian cancer', 'Disease', 'MESH:D010051', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('associated', 'Reg', (113, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (286, 309))
395372	26880895	Ito and colleagues reported that loss of CADM1/TSLC1 expression plays an important role in tumor growth, cell motility, and invasion and is associated with aggressive tumor behavior in ESCC.	('tumor growth', 'CPA', (91, 103))	('associated with', 'Reg', (140, 155))	('aggressive tumor behavior', 'Disease', (156, 181))	('CADM1/TSLC1', 'Gene', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('loss', 'Var', (33, 37))	('ESCC', 'Disease', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (156, 181))	('invasion', 'CPA', (124, 132))	('cell motility', 'CPA', (105, 118))
395386	26880895	Furthermore, Lee and colleagues reported that cohypermethylation of CADM1 in combination with p14 may be an independent prognostic factor for recurrence in patients with stage I ESCC.	('CADM1', 'Gene', (68, 73))	('cohypermethylation', 'Var', (46, 64))	('p14', 'Gene', (94, 97))	('stage I ESCC', 'Disease', (170, 182))	('p14', 'Gene', '1029', (94, 97))
395389	26880895	Our findings support the viewpoint of the study on lung adenocarcinoma that the prognostic impact of loss of CADM1/TSLC1 was significant for male patients but not for female patients, since it has been widely recognized that the prognosis of men and women with ESCC is distinct and TSLC1 might be one of the genes that play a different role in men and women with ESCC.	('women', 'Species', '9606', (352, 357))	('loss', 'Var', (101, 105))	('women', 'Species', '9606', (250, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('ESCC', 'Disease', (261, 265))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (51, 70))	('CADM1/TSLC1', 'Gene', (109, 120))
395531	26816502	However, in the longer term, brachytherapy was significantly better than stent with longer dysphagia relief (115 days vs. 82 days, difference of 33 days with p = 0.015).	('longer dysphagia', 'Disease', 'MESH:D003680', (84, 100))	('brachytherapy', 'Var', (29, 42))	('dysphagia', 'Phenotype', 'HP:0002015', (91, 100))	('longer dysphagia', 'Disease', (84, 100))
395540	26816502	However, dysphagia relief was more sustained in stent + EBRT arm than with stent alone (7 vs. 3 months, p = 0.002).	('dysphagia', 'Disease', 'MESH:D003680', (9, 18))	('dysphagia', 'Disease', (9, 18))	('dysphagia', 'Phenotype', 'HP:0002015', (9, 18))	('stent + EBRT arm', 'Var', (48, 64))	('EBRT', 'Chemical', '-', (56, 60))
395541	26816502	Overall median survival was significantly higher in stent + EBRT (180 vs. 120 days, p = 0.009).	('higher', 'PosReg', (42, 48))	('stent + EBRT', 'Var', (52, 64))	('EBRT', 'Chemical', '-', (60, 64))
395580	26208895	The differences between these two progression models have profound implications for cancer prevention and early detection: Linear models predict that inhibiting a single step will interrupt progression to cancer whereas branched evolution provides avenues for resistance to therapies that target only one branch (Figure 2).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('progression', 'MPA', (190, 201))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('interrupt', 'NegReg', (180, 189))	('inhibiting', 'Var', (150, 160))
395582	26208895	The theory of neoplastic evolution predicted that genomic instability would promote branched evolution of cancers, each with a unique somatic genome that might require individualized therapy and carry the potential for evolution of resistance to preventive and therapeutic interventions was proposed by Nowell in 1976 .	('promote', 'PosReg', (76, 83))	('genomic instability', 'Var', (50, 69))	('branched evolution', 'CPA', (84, 102))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
395586	26208895	Modern genome technologies have also provided evidence that neoplastic evolution may be accelerated by increased mutation rates and even more rapidly by punctuated or catastrophic chromosomal events that may occur in one or a few cell divisions (Figure 3) .	('mutation', 'Var', (113, 121))	('rat', 'Species', '10116', (94, 97))	('neoplastic evolution', 'CPA', (60, 80))	('increased', 'PosReg', (103, 112))	('accelerated', 'PosReg', (88, 99))	('rat', 'Species', '10116', (122, 125))
395587	26208895	This rapid evolution generates genetic and genomic variants (diversity) on which selection can act to promote progression to EA .	('promote', 'PosReg', (102, 109))	('variants', 'Var', (51, 59))	('rat', 'Species', '10116', (25, 28))	('progression', 'CPA', (110, 121))
395593	26208895	Recent studies indicate that the concept of gradual, linear progression with long time intervals for early detection may not apply to many EAs and other cancers that appear to arise by chromosome instability, which has historically been defined as an increased rate of gain or loss of whole chromosomes or large regions of chromosomes .	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('chromosome instability', 'Phenotype', 'HP:0040012', (185, 207))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('loss', 'NegReg', (277, 281))	('arise by', 'Reg', (176, 184))	('EAs', 'Disease', (139, 142))	('chromosome instability', 'Var', (185, 207))	('EAs', 'Chemical', '-', (139, 142))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('rat', 'Species', '10116', (261, 264))
395600	26208895	In a study evaluating a panel of tumor suppressor genes and DNA content abnormalities (tetraploidy, aneuploidy), only the chromosome instability markers, loss of heterozygosity (LOH), tetraploidy and aneuploidy, provided independent cancer risk assessment in multivariate analysis .	('tetraploidy', 'Disease', 'MESH:D057891', (184, 195))	('loss of heterozygosity', 'Var', (154, 176))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('aneuploidy', 'Disease', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tetraploidy', 'Disease', (87, 98))	('chromosome instability', 'Phenotype', 'HP:0040012', (122, 144))	('aneuploidy', 'Disease', (200, 210))	('tetraploidy', 'Disease', (184, 195))	('aneuploidy', 'Disease', 'MESH:D000782', (100, 110))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('aneuploidy', 'Disease', 'MESH:D000782', (200, 210))	('tumor', 'Disease', (33, 38))	('tetraploidy', 'Disease', 'MESH:D057891', (87, 98))
395601	26208895	Interestingly, use of aspirin or other NSAIDs was associated with reduced risk of progression to EA in patients with 17pLOH and DNA content tetraploidy and aneuploidy in this study.	('aspirin', 'Chemical', 'MESH:D001241', (22, 29))	('reduced', 'NegReg', (66, 73))	('17pLOH', 'Var', (117, 123))	('aneuploidy', 'Disease', (156, 166))	('tetraploidy', 'Disease', 'MESH:D057891', (140, 151))	('tetraploidy', 'Disease', (140, 151))	('patients', 'Species', '9606', (103, 111))	('aneuploidy', 'Disease', 'MESH:D000782', (156, 166))
395610	26208895	In the Dulak study, 8,331 genes had mutations in at least one EA, but only TP53 was mutated at high frequency (72%).	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('mutations', 'Var', (36, 45))
395618	26208895	The breakage-fusion-bridge cycle findings are consistent with findings of other investigators that short telomeres in (1) BE are associated with chromosome instability , (2) in the blood are a risk factor for progression from BE to EA  and (3) are found in EAs themselves .	('short telomeres', 'Var', (99, 114))	('associated', 'Reg', (129, 139))	('chromosome instability', 'MPA', (145, 167))	('short telomeres', 'Phenotype', 'HP:0031413', (99, 114))	('chromosome instability', 'Phenotype', 'HP:0040012', (145, 167))	('EAs', 'Chemical', '-', (257, 260))
395622	26208895	In the second patient, 31 of 39 mutations detected in EA were also found in adjacent BE .	('patient', 'Species', '9606', (14, 21))	('mutations', 'Var', (32, 41))	('found', 'Reg', (67, 72))
395627	26208895	Twenty-one of 40 patients whose biopsies were consistently non-dysplastic (53%) had mutations in the BE segment.	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (17, 25))	('non-dysplastic', 'Disease', (59, 73))	('non-dysplastic', 'Disease', 'MESH:D004416', (59, 73))
395629	26208895	Initial validation of a non-endoscopic screening device ("Cytosponge") to detect TP53 mutations in this study is a major step forward toward developing more effective screening strategies for high-risk BE and early EA .	('rat', 'Species', '10116', (179, 182))	('mutations', 'Var', (86, 95))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
395631	26208895	As the density of markers has increased, small localized regions of copy number alterations and LOH appear to be frequently found in fragile sites some of which contain genes such as CDKN2A, WWOX and FHIT that are deleted frequently .	('copy number alterations', 'Var', (68, 91))	('CDKN2A', 'Gene', (183, 189))	('WWOX', 'Gene', '51741', (191, 195))	('WWOX', 'Gene', (191, 195))	('CDKN2A', 'Gene', '1029', (183, 189))	('rat', 'Species', '10116', (84, 87))	('FHIT', 'Gene', (200, 204))	('FHIT', 'Gene', '2272', (200, 204))
395639	26208895	Non-progressors largely maintained stable genomes with only minor changes involving fragile sites and small genetic regions including 9p LOH and small deletions and homozygous deletion on 3p, 9p and 16q, the sites of FHIT, CDKN2A, and WWOX.	('WWOX', 'Gene', '51741', (235, 239))	('WWOX', 'Gene', (235, 239))	('FHIT', 'Gene', (217, 221))	('deletions', 'Var', (151, 160))	('CDKN2A', 'Gene', (223, 229))	('FHIT', 'Gene', '2272', (217, 221))	('CDKN2A', 'Gene', '1029', (223, 229))
395640	26208895	It has recently been proposed that everyone may develop similar genetic alterations during their lifetimes without progressing to clinically evident cancer .	('cancer', 'Disease', (149, 155))	('rat', 'Species', '10116', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('genetic alterations', 'Var', (64, 83))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
395641	26208895	In contrast, massive genomic alterations including widespread evidence of chromosome instability were detected beginning 48 months before the diagnosis of cancer, followed by catastrophic genome doublings and widespread aneuploidization in the 24 months before cancer .	('chromosome instability', 'CPA', (74, 96))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('aneuploidization', 'Var', (220, 236))	('rat', 'Species', '10116', (33, 36))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('chromosome instability', 'Phenotype', 'HP:0040012', (74, 96))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
395642	26208895	Strikingly, this pattern of chromosome instability followed by whole genome doublings has been observed in many types of cancer including esophageal, breast, colon, lung, and ovarian .	('lung', 'Disease', (165, 169))	('ovarian', 'Disease', (175, 182))	('colon', 'Disease', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('observed', 'Reg', (95, 103))	('esophageal', 'Disease', (138, 148))	('chromosome instability', 'Phenotype', 'HP:0040012', (28, 50))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('chromosome', 'Var', (28, 38))	('breast', 'Disease', (150, 156))	('cancer', 'Disease', (121, 127))
395649	26208895	One reported that variants at the MHC locus and at chromosome 16q24.1 predispose to development of BE .	('MHC', 'Gene', '3107', (34, 37))	('development of', 'CPA', (84, 98))	('predispose', 'Reg', (70, 80))	('variants', 'Var', (18, 26))	('MHC', 'Gene', (34, 37))
395654	26208895	This study also confirmed the previously reported association with BE near FOXF1 at 16q24, which was also associated with EA.	('associated', 'Reg', (106, 116))	('FOXF1', 'Gene', (75, 80))	('FOXF1', 'Gene', '2294', (75, 80))	('BE near', 'Var', (67, 74))
395655	26208895	One study reported that some CDKN2A polymorphisms were associated with reduced risk of EA .	('CDKN2A', 'Gene', (29, 35))	('reduced', 'NegReg', (71, 78))	('polymorphisms', 'Var', (36, 49))	('CDKN2A', 'Gene', '1029', (29, 35))
395656	26208895	This protective association is reminiscent of reports that CDKN2A abnormalities are associated with clonal expansions in BE but the chromosome instability leading to 17p LOH, tetraploidy and aneuploidy is required for progression to EA .	('tetraploidy', 'Disease', (175, 186))	('aneuploidy', 'Disease', 'MESH:D000782', (191, 201))	('chromosome instability', 'Phenotype', 'HP:0040012', (132, 154))	('abnormalities', 'Var', (66, 79))	('aneuploidy', 'Disease', (191, 201))	('17p', 'Disease', (166, 169))	('clonal', 'Var', (100, 106))	('tetraploidy', 'Disease', 'MESH:D057891', (175, 186))	('associated', 'Reg', (84, 94))	('CDKN2A', 'Gene', (59, 65))	('CDKN2A', 'Gene', '1029', (59, 65))
395662	26208895	Non-dysplastic BE epithelium was also found to contain mutant clones that were subsequently found in EA demonstrating a lineage that evolved and progressed over time.	('Non-dysplastic', 'Disease', (0, 14))	('rat', 'Species', '10116', (111, 114))	('Non-dysplastic', 'Disease', 'MESH:D004416', (0, 14))	('mutant', 'Var', (55, 61))
395709	23607896	However, some investigators urge caution based on the hypothesis that eradication of H. pylori may result in an increase in the incidence of gastroesophageal reflux disease, esophageal adenocarcinoma, and childhood asthma.	('H. pylori', 'Gene', (85, 94))	('asthma', 'Phenotype', 'HP:0002099', (215, 221))	('H. pylori', 'Species', '210', (85, 94))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (141, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('eradication', 'Var', (70, 81))	('esophageal adenocarcinoma', 'Disease', (174, 199))	('increase', 'PosReg', (112, 120))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (174, 199))	('asthma', 'Disease', (215, 221))	('asthma', 'Disease', 'MESH:D001249', (215, 221))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (141, 164))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (174, 199))	('gastroesophageal reflux disease', 'Disease', (141, 172))
395716	23607896	Based on evidence from this population, absence of H. pylori infection is more likely to be boon than a bane.	('infection', 'Disease', 'MESH:D007239', (61, 70))	('absence', 'Var', (40, 47))	('H. pylori infection', 'Phenotype', 'HP:0005202', (51, 70))	('H. pylori', 'Protein', (51, 60))	('H. pylori', 'Species', '210', (51, 60))	('infection', 'Disease', (61, 70))
395768	23607896	While eradication of H. pylori will likely increase the average acid secretion in areas where corpus gastritis is common, the ability to secrete acid is only one factor in the development of gastroesophageal reflux disease.	('gastroesophageal reflux disease', 'Disease', (191, 222))	('H. pylori', 'Gene', (21, 30))	('corpus gastritis', 'Disease', (94, 110))	('men', 'Species', '9606', (183, 186))	('H. pylori', 'Species', '210', (21, 30))	('eradication', 'Var', (6, 17))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (191, 222))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (191, 214))	('increase', 'PosReg', (43, 51))	('gastritis', 'Phenotype', 'HP:0005263', (101, 110))	('corpus gastritis', 'Disease', 'MESH:D005756', (94, 110))	('acid secretion', 'MPA', (64, 78))
395773	23607896	A recent meta-analysis also showed no convincing association between H. pylori eradication and the development of gastroesophageal reflux disease.	('gastroesophageal reflux disease', 'Disease', (114, 145))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (114, 137))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (114, 145))	('H. pylori', 'Species', '210', (69, 78))	('eradication', 'Var', (79, 90))	('men', 'Species', '9606', (106, 109))
395774	23607896	Some studies have suggested an inverse relationship exists between H. pylori seropositivity and asthma, while more recent meta-analyses have cast doubts regarding this claim.	('H. pylori', 'Species', '210', (67, 76))	('seropositivity', 'Var', (77, 91))	('asthma', 'Disease', 'MESH:D001249', (96, 102))	('asthma', 'Disease', (96, 102))	('asthma', 'Phenotype', 'HP:0002099', (96, 102))	('inverse', 'NegReg', (31, 38))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (70, 91))	('H. pylori', 'Protein', (67, 76))
395795	23607896	Recently, ATG16L1 (autophagy gene) polymorphism has been found to increase susceptibility to H. pylori infection in the European population.	('polymorphism', 'Var', (35, 47))	('ATG16L1', 'Gene', (10, 17))	('infection', 'Disease', (103, 112))	('infection', 'Disease', 'MESH:D007239', (103, 112))	('H. pylori infection', 'Phenotype', 'HP:0005202', (93, 112))	('H. pylori', 'Species', '210', (93, 102))	('susceptibility', 'Reg', (75, 89))
395796	23607896	Genetic polymorphism of NOD1 in H. pylori-infected individuals was found to be associated with gastritis in Koreans, gastric cancer in the Chinese, and erosive esophagitis in the Japanese.	('gastritis', 'Phenotype', 'HP:0005263', (95, 104))	('NOD1', 'Gene', (24, 28))	('H. pylori', 'Species', '210', (32, 41))	('gastritis', 'Disease', 'MESH:D005756', (95, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastritis', 'Disease', (95, 104))	('associated with', 'Reg', (79, 94))	('gastric cancer', 'Disease', (117, 131))	('esophagitis', 'Phenotype', 'HP:0100633', (160, 171))	('esophagitis', 'Disease', (160, 171))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('Genetic polymorphism', 'Var', (0, 20))	('esophagitis', 'Disease', 'MESH:D004941', (160, 171))
395797	23607896	In Malay population from the northeastern Peninsular Malaysia, polymorphism in the deleted in colorectal cancer (DCC) gene (rs10502974) had been associated with H. pylori infection in a case-control study.	('infection', 'Disease', (171, 180))	('infection', 'Disease', 'MESH:D007239', (171, 180))	('polymorphism', 'Var', (63, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('H. pylori', 'Species', '210', (161, 170))	('DCC', 'Gene', (113, 116))	('rs10502974', 'Mutation', 'rs10502974', (124, 134))	('H. pylori infection', 'Phenotype', 'HP:0005202', (161, 180))	('associated', 'Reg', (145, 155))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('Peninsular Malaysia', 'Disease', (42, 61))	('Peninsular Malaysia', 'Disease', 'None', (42, 61))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('rs10502974', 'Var', (124, 134))
395800	23607896	The host may also express protective gene variants against H. pylori infection resulting in reduced susceptibility to its disease phenotypes.	('susceptibility', 'MPA', (100, 114))	('infection', 'Disease', (69, 78))	('H. pylori', 'Disease', (59, 68))	('variants', 'Var', (42, 50))	('H. pylori', 'Species', '210', (59, 68))	('infection', 'Disease', 'MESH:D007239', (69, 78))	('H. pylori infection', 'Phenotype', 'HP:0005202', (59, 78))	('reduced', 'NegReg', (92, 99))
395801	23607896	Among the Chinese population, gene polymorphism of DNA methyltransferase-1 (DNMT-1), an enzyme important in genomic methylation patterns in mammalian cells, has been recently found to be associated with a reduced risk of H. pylori infection.	('infection', 'Disease', (231, 240))	('H. pylori infection', 'Phenotype', 'HP:0005202', (221, 240))	('reduced', 'NegReg', (205, 212))	('DNMT-1', 'Gene', '1786', (76, 82))	('H. pylori', 'Species', '210', (221, 230))	('DNA methyltransferase-1', 'Gene', (51, 74))	('infection', 'Disease', 'MESH:D007239', (231, 240))	('mammalian', 'Species', '9606', (140, 149))	('gene polymorphism', 'Var', (30, 47))	('DNMT-1', 'Gene', (76, 82))	('DNA methyltransferase-1', 'Gene', '1786', (51, 74))
395804	23607896	Using fixation index (FST) calculation and comparing highly differentiated SNPs between the Malays in Kelantan and Han Chinese and South Indians of the HUGO Pan-Asian SNP consortium study, the protective gene variants found among the Malays included C7orf10, TSTD2, SMG7, and XPA.	('Kelantan', 'Chemical', '-', (102, 110))	('TSTD2', 'Gene', (259, 264))	('variants', 'Var', (209, 217))	('C7orf10', 'Gene', (250, 257))
395830	19738454	Overexpression of Bcl-2 has been associated with resistance to cytotoxic chemotherapy in hematologic malignancies and solid tumors, including gastrointestinal cancer.	('Bcl-2', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('solid tumors', 'Disease', 'MESH:D009369', (118, 130))	('resistance to cytotoxic chemotherapy', 'MPA', (49, 85))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (142, 165))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('associated', 'Reg', (33, 43))	('hematologic malignancies', 'Disease', 'MESH:D019337', (89, 113))	('Overexpression', 'Var', (0, 14))	('solid tumors', 'Disease', (118, 130))	('hematologic malignancies', 'Disease', (89, 113))	('Bcl-2', 'Gene', '596', (18, 23))	('gastrointestinal cancer', 'Disease', (142, 165))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (142, 165))
395831	19738454	Kim et al evaluated an 18-mer phosphorothiated oligonucleotide antisense to Bcl-2 in the MKN-45 gastric carcinoma cell line in a mouse xenograft model alone or in combination with cytotoxic agents.	('oligonucleotide', 'Chemical', 'MESH:D009841', (47, 62))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('Bcl-2', 'Gene', (76, 81))	('Bcl-2', 'Gene', '596', (76, 81))	('mouse', 'Species', '10090', (129, 134))	('gastric carcinoma', 'Disease', 'MESH:D013274', (96, 113))	('gastric carcinoma', 'Disease', (96, 113))	('antisense', 'Var', (63, 72))
395832	19738454	Bcl-2 was down-regulated to 60% of its initial value after treatment with 1.0 muM of the anti-Bcl-2 antisense molecule compared with the controls of random and mismatched oligonucleotides, and enhanced the sensitivity of the xenograft to doxorubicin, cisplatin, and paclitaxel by 3-4-fold in vitro.	('antisense', 'Var', (100, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (251, 260))	('Bcl-2', 'Gene', (94, 99))	('Bcl-2', 'Gene', '596', (94, 99))	('sensitivity', 'MPA', (206, 217))	('oligonucleotides', 'Chemical', 'MESH:D009841', (171, 187))	('enhanced', 'PosReg', (193, 201))	('down-regulated', 'NegReg', (10, 24))	('paclitaxel', 'Chemical', 'MESH:D017239', (266, 276))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))	('doxorubicin', 'Chemical', 'MESH:D004317', (238, 249))
395886	19738454	A systematic analysis of randomized trials has also shown that combination chemotherapy regimens containing 5-FU was associated with improved survival compared with single agents (hazard ratio [HR] for death 0.83; 95% CI = 0.74 -0.93).	('survival', 'MPA', (142, 150))	('5-FU', 'Var', (108, 112))	('5-FU', 'Chemical', 'MESH:D005472', (108, 112))	('death', 'Disease', 'MESH:D003643', (202, 207))	('death', 'Disease', (202, 207))	('improved', 'PosReg', (133, 141))
395895	19738454	The expression of Bcl-2 was associated with poor prognosis in prostate cancer, higher tumor grade in breast cancer, and microsatellite instability in colorectal cancers but in gastric cancer Bcl-B expression correlated with a better outcome and more differentiated histology.	('colorectal cancers', 'Disease', (150, 168))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Bcl-B', 'Gene', (191, 196))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Bcl-B', 'Gene', '10017', (191, 196))	('breast cancer', 'Disease', (101, 114))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))	('colorectal cancers', 'Disease', 'MESH:D015179', (150, 168))	('Bcl-2', 'Gene', (18, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('prostate cancer', 'Disease', (62, 77))	('microsatellite instability', 'Var', (120, 146))	('Bcl-2', 'Gene', '596', (18, 23))	('gastric cancer', 'Disease', (176, 190))	('tumor', 'Disease', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
395922	22107166	Of the familial forms of CRC, (a) familial adenomatous polyposis (FAP; associated with germ line mutations in genes such as Adenomatous Polyposis Coli (APC) and, (b) hereditary non-polyposis colon cancer (HNPCC; associated with DNA mismatch repair enzymes) are the most common.	('FAP', 'Disease', (66, 69))	('mutations', 'Var', (97, 106))	('hereditary non-polyposis colon cancer', 'Phenotype', 'HP:0006716', (166, 203))	('P', 'Chemical', 'MESH:D010758', (136, 137))	('familial adenomatous polyposis', 'Disease', (34, 64))	('colon cancer', 'Disease', (191, 203))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('FAP', 'Disease', 'MESH:C567782', (66, 69))	('Adenomatous Polyposis Coli', 'Disease', (124, 150))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (34, 64))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (43, 64))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('colon cancer', 'Disease', 'MESH:D015179', (191, 203))	('P', 'Chemical', 'MESH:D010758', (153, 154))	('P', 'Chemical', 'MESH:D010758', (207, 208))	('Adenomatous Polyposis Coli', 'Phenotype', 'HP:0005227', (124, 150))	('colon cancer', 'Phenotype', 'HP:0003003', (191, 203))	('associated', 'Reg', (71, 81))
395927	22107166	Sporadic CRC has the same genetic etiology as FAP but the mutations in the APC gene are somatically acquired during the life of an individual.	('mutations', 'Var', (58, 67))	('FAP', 'Disease', (46, 49))	('P', 'Chemical', 'MESH:D010758', (48, 49))	('P', 'Chemical', 'MESH:D010758', (76, 77))	('FAP', 'Disease', 'MESH:C567782', (46, 49))	('APC', 'Gene', (75, 78))
395929	22107166	Dietary factors and environmental agents have been suspected of causing sporadic gene mutations and therefore involved in the induction of sporadic colon carcinomas.	('gene mutations', 'Var', (81, 95))	('carcinomas', 'Disease', (154, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('causing', 'Reg', (64, 71))	('carcinomas', 'Disease', 'MESH:D002277', (154, 164))
395986	22107166	The arylhydrocarbon receptor (Ahr), a transcription factor activated by ligands such as PAH whose signaling plays an important role in regulation and induction of several drug metabolizing enzymes such as CYP1A1, CYP1A2, CYP1B1, glutathione S-transferase, UDP-glucoronyltransferase, quinone oxidoreductase, etc..	('Ahr', 'Gene', '11622', (30, 33))	('CYP1A1', 'Var', (205, 211))	('CYP1A2', 'Gene', (213, 219))	('quinone oxidoreductase', 'Gene', '12972', (283, 305))	('P', 'Chemical', 'MESH:D010758', (215, 216))	('CYP1A2', 'Gene', '13077', (213, 219))	('quinone oxidoreductase', 'Gene', (283, 305))	('P', 'Chemical', 'MESH:D010758', (258, 259))	('UDP-glucoronyltransferase', 'Enzyme', (256, 281))	('P', 'Chemical', 'MESH:D010758', (223, 224))	('glutathione S-transferase', 'Gene', '54486', (229, 254))	('CYP1B1', 'Gene', '13078', (221, 227))	('Ahr', 'Gene', (30, 33))	('CYP1B1', 'Gene', (221, 227))	('P', 'Chemical', 'MESH:D010758', (207, 208))	('glutathione S-transferase', 'Gene', (229, 254))	('P', 'Chemical', 'MESH:D010758', (88, 89))
395990	22107166	showed induction of CYP1A1, CYP1A2, and CYP1B1 in Ahr (+/+) mice.	('CYP1B1', 'Gene', '13078', (40, 46))	('CYP1A2', 'Gene', (28, 34))	('CYP1A1', 'Var', (20, 26))	('Ahr', 'Gene', '11622', (50, 53))	('CYP1A2', 'Gene', '13077', (28, 34))	('Ahr', 'Gene', (50, 53))	('mice', 'Species', '10090', (60, 64))	('CYP1B1', 'Gene', (40, 46))
396006	22107166	Benzo(a)pyrene induces the expression of bioactivation enzymes in liver to a greater extent than detoxifying enzymes.	('induces', 'Reg', (15, 22))	('bioactivation enzymes', 'MPA', (41, 62))	('expression', 'MPA', (27, 37))	('Benzo', 'Var', (0, 5))	('Benzo(a)pyrene', 'Chemical', 'MESH:D001564', (0, 14))
396017	22107166	These studies informed that CYP1A1 is localized throughout the mice small intestine, and being in close proximity to lumen than CYP1B1, could effectively process B(a)P during its residence in intestine.	('CYP1B1', 'Gene', '13078', (128, 134))	('CYP1A1', 'Var', (28, 34))	('mice', 'Species', '10090', (63, 67))	('CYP1B1', 'Gene', (128, 134))
396026	22107166	PAHs were reported to activate src family-associated protein tyrosine kinases (PTKs) Lck and Fyn in T cells that initiate phospholipase Cgamma 1 activation, the production of 1,4,5-inositol triphosphate, and the release of Ca2+ from intracellular storage pools in the endoplasmic reticulum.	('phospholipase', 'Enzyme', (122, 135))	('Lck', 'Gene', (85, 88))	('activation', 'PosReg', (145, 155))	('release of Ca2+ from intracellular storage pools', 'MPA', (212, 260))	('PAHs', 'Var', (0, 4))	('Fyn', 'Gene', '14360', (93, 96))	('Lck', 'Gene', '16818', (85, 88))	('Ca2+', 'Chemical', 'MESH:D000069285', (223, 227))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('1,4,5-inositol triphosphate', 'Chemical', '-', (175, 202))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('PAHs', 'Chemical', 'MESH:D011084', (0, 4))	('Fyn', 'Gene', (93, 96))	('activate', 'PosReg', (22, 30))
396029	22107166	Recent studies have shown that DMBA-induced bone marrow toxicity is dependent on tumor necrosis factor alpha receptor (TNFR) and double-stranded RNA-dependent protein kinase (PKR).	('tumor necrosis factor alpha receptor', 'Gene', '21937', (81, 117))	('TNFR', 'Gene', '21937', (119, 123))	('PKR', 'Gene', (175, 178))	('TNFR', 'Gene', (119, 123))	('PKR', 'Gene', '19106', (175, 178))	('tumor necrosis factor alpha receptor', 'Gene', (81, 117))	('double-stranded RNA-dependent', 'Var', (129, 158))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('bone marrow toxicity', 'Disease', (44, 64))	('DMBA', 'Chemical', 'MESH:D015127', (31, 35))	('bone marrow toxicity', 'Disease', 'MESH:D001855', (44, 64))
396033	22107166	Spontaneous or environmentally-induced epigenetic changes become the centerpiece in the early molecular events in carcinogenesis.	('epigenetic changes', 'Var', (39, 57))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('carcinogenesis', 'Disease', (114, 128))
396034	22107166	Alterations in DNA methylation is one of the epigenetic changes that has been implicated in the malignant transformation and progression of several tumor types including colon tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('methylation', 'Var', (19, 30))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('colon tumors', 'Phenotype', 'HP:0100273', (170, 182))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (176, 181))	('colon tumors', 'Disease', 'MESH:D015179', (170, 182))	('colon tumor', 'Phenotype', 'HP:0100273', (170, 181))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('implicated', 'Reg', (78, 88))	('colon tumors', 'Disease', (170, 182))	('DNA', 'Gene', (15, 18))	('rat', 'Species', '10116', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
396049	22107166	In this mouse, the loss of a single copy of Apc gene predisposes the mice to the development of a large number of polyps, both in the small and large intestine.	('polyps', 'Disease', 'MESH:D011127', (114, 120))	('mice', 'Species', '10090', (69, 73))	('polyps', 'Disease', (114, 120))	('loss', 'Var', (19, 23))	('mouse', 'Species', '10090', (8, 13))	('Apc gene', 'Gene', (44, 52))
396064	22107166	showed that oral and intragastric administration of methylcholanthrene a PAH compound caused an increase in colorectal tumors in hamsters.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('colorectal tumors', 'Disease', 'MESH:D015179', (108, 125))	('colorectal tumors', 'Disease', (108, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('methylcholanthrene', 'Chemical', 'MESH:D008748', (52, 70))	('increase', 'PosReg', (96, 104))	('methylcholanthrene', 'Var', (52, 70))	('rat', 'Species', '10116', (42, 45))
396100	22107166	In another study, the Apc1638 mice when fed for about 32 weeks, with a Western-style diet that was high in fat, a significantly greater number of mice developed adenomas than mice fed with a standard diet (65% vs 13%).	('mice', 'Species', '10090', (175, 179))	('mice', 'Species', '10090', (30, 34))	('developed', 'PosReg', (151, 160))	('greater', 'PosReg', (128, 135))	('adenomas', 'Disease', 'MESH:D000236', (161, 169))	('Apc1638', 'Var', (22, 29))	('mice', 'Species', '10090', (146, 150))	('adenomas', 'Disease', (161, 169))
396110	22107166	In this context, the report of Khalil et al is worth mentioning as these studies have demonstrated that PAHs exacerbate the effects of high fat diets on intestinal inflammation.	('inflammation', 'Disease', (164, 176))	('high fat diets', 'MPA', (135, 149))	('PAHs', 'Var', (104, 108))	('PAHs', 'Chemical', 'MESH:D011084', (104, 108))	('effects', 'MPA', (124, 131))	('inflammation', 'Disease', 'MESH:D007249', (164, 176))	('exacerbate', 'PosReg', (109, 119))	('rat', 'Species', '10116', (93, 96))
396112	22107166	Two case-control studies of colon cancer and rectal cancer conducted in California and Utah revealed an association between people who smoked more than 20 pack-years and polymorphisms in the CYP1A1 gene.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('California', 'Disease', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('rectal cancer', 'Phenotype', 'HP:0100743', (45, 58))	('people', 'Species', '9606', (124, 130))	('CYP1A1', 'Gene', (191, 197))	('rectal cancer', 'Disease', 'MESH:D012004', (45, 58))	('colon cancer', 'Phenotype', 'HP:0003003', (28, 40))	('colon cancer', 'Disease', 'MESH:D015179', (28, 40))	('California', 'Disease', 'MESH:D004670', (72, 82))	('rectal cancer', 'Disease', (45, 58))	('polymorphisms', 'Var', (170, 183))	('colon cancer', 'Disease', (28, 40))
396144	22107166	As recent studies have shown that epigenetic alterations could be used as biomarkers in assessing the potential of environmental toxicants to contribute to carcinogenesis, additional information is warranted on the ability of PAHs to contribute to GI tract carcinogenesis through epigenetic mechanisms.	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('GI tract carcinogenesis', 'Disease', 'MESH:D063646', (248, 271))	('PAHs', 'Chemical', 'MESH:D011084', (226, 230))	('carcinogenesis', 'Disease', (156, 170))	('GI tract carcinogenesis', 'Disease', (248, 271))	('epigenetic', 'Var', (280, 290))	('carcinogenesis', 'Disease', 'MESH:D063646', (257, 271))	('contribute', 'Reg', (234, 244))	('rat', 'Species', '10116', (49, 52))	('carcinogenesis', 'Disease', (257, 271))
396152	16951537	Cigarette smoking, alcohol drinking and green tea consumption were significantly associated with an increased risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('alcohol', 'Chemical', 'MESH:D000438', (19, 26))	('alcohol drinking', 'Var', (19, 35))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('associated', 'Reg', (81, 91))	('alcohol drinking', 'Phenotype', 'HP:0030955', (19, 35))
396177	16951537	The end point in this study was the incidence of esophageal cancer defined as topography code C15.0-C15.9 according to the International Classification of Diseases for Oncology (2nd Ed.	('esophageal cancer', 'Disease', (49, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('C15.0-C15.9', 'Var', (94, 105))	('Oncology', 'Phenotype', 'HP:0002664', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
396217	16951537	In conclusion, we have found that smoking, alcohol drinking or green tea consumption is significantly associated with an increased incidence risk of esophageal cancer.	('alcohol drinking', 'Phenotype', 'HP:0030955', (43, 59))	('associated', 'Reg', (102, 112))	('alcohol', 'Chemical', 'MESH:D000438', (43, 50))	('esophageal cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('alcohol drinking', 'Var', (43, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))
396220	33112928	Loss of p120ctn causes EGFR-targeted therapy resistance and failure Epidermal growth factor receptor (EGFR) plays a vital role in cell division and survival signaling pathways.	('EGFR', 'Gene', '1956', (102, 106))	('Epidermal growth factor receptor', 'Gene', (68, 100))	('cell division', 'CPA', (130, 143))	('Epidermal growth factor receptor', 'Gene', '1956', (68, 100))	('p120ctn', 'Gene', '1500', (8, 15))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('Loss', 'Var', (0, 4))	('EGFR', 'Gene', (102, 106))	('p120ctn', 'Gene', (8, 15))
396223	33112928	p120-catenin (p120ctn) has recently been implicated as a biomarker for EGFR therapy.	('p120ctn', 'Var', (14, 21))	('p120-catenin', 'Gene', '1500', (0, 12))	('p120-catenin', 'Gene', (0, 12))
396224	33112928	In previous studies, we demonstrated that p120ctn is a tumor suppressor and its loss is capable of inducing cancer.	('inducing', 'Reg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('p120ctn', 'Var', (42, 49))	('loss', 'NegReg', (80, 84))	('tumor', 'Disease', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
396229	33112928	EGFR is over-activated by mutation, amplification, or overexpression, and high levels of EGFR in tumors and metastases is correlated with poorer patient outcome.	('metastases', 'Disease', (108, 118))	('EGFR', 'Gene', (0, 4))	('over-activated', 'PosReg', (8, 22))	('mutation', 'Var', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('metastases', 'Disease', 'MESH:D009362', (108, 118))	('overexpression', 'MPA', (54, 68))	('amplification', 'Var', (36, 49))	('patient', 'Species', '9606', (145, 152))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
396235	33112928	The molecular mechanisms by which EGFR-targeted therapies fail can vary from mutations that occur within EGFR, such as the T790M mutation, activation of pathways that circumvent the signaling cascade such as amplification of c-MET, and the blocking of other pathways necessary for EGFR-mediated apoptosis, like the suppression of BH3 through a deletion in BIM.	('c-MET', 'Gene', (225, 230))	('BH3', 'Chemical', 'MESH:C006008', (330, 333))	('T790M', 'Mutation', 'rs121434569', (123, 128))	('suppression', 'NegReg', (315, 326))	('BH3', 'Gene', (330, 333))	('EGFR', 'Gene', (105, 109))	('c-MET', 'Gene', '4233', (225, 230))	('BIM', 'Gene', (356, 359))	('T790M', 'Var', (123, 128))	('deletion', 'Var', (344, 352))
396237	33112928	Herein, we report that p120-catenin (p120ctn) regulates EGFR therapy effectiveness.	('p120ctn', 'Var', (37, 44))	('p120-catenin', 'Gene', (23, 35))	('p120-catenin', 'Gene', '1500', (23, 35))	('EGFR', 'Gene', (56, 60))	('regulates', 'Reg', (46, 55))
396238	33112928	p120ctn is a tumor suppressor gene that is down-regulated or lost in a vast array of epithelial cancers, including NSCLC, head and neck squamous cell carcinoma (HNSCC), esophageal and colon cancers, and is associated with advanced stage, metastasis and poor patient prognosis.	('tumor', 'Disease', (13, 18))	('colon cancers', 'Phenotype', 'HP:0003003', (184, 197))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('p120ctn', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('colon cancers', 'Disease', 'MESH:D015179', (184, 197))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (122, 159))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('colon cancers', 'Disease', (184, 197))	('lost', 'NegReg', (61, 65))	('epithelial cancers', 'Disease', 'MESH:D009369', (85, 103))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('NSCLC', 'Disease', (115, 120))	('epithelial cancers', 'Disease', (85, 103))	('esophageal', 'Disease', (169, 179))	('down-regulated', 'NegReg', (43, 57))	('patient', 'Species', '9606', (258, 265))	('neck squamous cell carcinoma', 'Disease', (131, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (131, 159))
396239	33112928	We were the first to show that loss of p120ctn in mice leads to cancer.	('loss', 'Var', (31, 35))	('cancer', 'Disease', (64, 70))	('leads to', 'Reg', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mice', 'Species', '10090', (50, 54))	('p120ctn', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
396240	33112928	We have previously shown that down-regulation of p120ctn in the presence of EGFR activation induces carcinogenesis and increases invasion.	('carcinogenesis', 'Disease', (100, 114))	('increases', 'PosReg', (119, 128))	('induces', 'Reg', (92, 99))	('p120ctn', 'Var', (49, 56))	('down-regulation', 'NegReg', (30, 45))	('invasion', 'CPA', (129, 137))	('activation', 'PosReg', (81, 91))	('carcinogenesis', 'Disease', 'MESH:D063646', (100, 114))	('EGFR', 'Gene', (76, 80))
396241	33112928	Specifically, this combination of decreased p120ctn and increased EGFR expression induces NFkB hyperactivation synergistically, leading to increased cellular invasion.	('expression', 'MPA', (71, 81))	('decreased', 'NegReg', (34, 43))	('increased', 'PosReg', (56, 65))	('EGFR', 'Gene', (66, 70))	('increased', 'PosReg', (139, 148))	('NFkB hyperactivation', 'Disease', 'MESH:D011504', (90, 110))	('p120ctn', 'Var', (44, 51))	('NFkB hyperactivation', 'Disease', (90, 110))	('cellular invasion', 'CPA', (149, 166))
396242	33112928	Using genetically modified human esophageal squamous keratinocytes (EPC cells), the data demonstrate that down-regulation/loss of p120ctn protein expression causes resistance to EGFR therapy.	('resistance', 'CPA', (164, 174))	('protein', 'Protein', (138, 145))	('human', 'Species', '9606', (27, 32))	('down-regulation/loss', 'NegReg', (106, 126))	('p120ctn', 'Var', (130, 137))
396243	33112928	Specifically, the data show that downregulation of p120ctn in cells with EGFR overexpression prevents cell death following treatment with gefitinib, erlotinib, or cetuximab.	('erlotinib', 'Chemical', 'MESH:D000069347', (149, 158))	('p120ctn', 'Var', (51, 58))	('gefitinib', 'Chemical', 'MESH:D000077156', (138, 147))	('EGFR', 'Gene', (73, 77))	('overexpression', 'PosReg', (78, 92))	('cetuximab', 'Chemical', 'MESH:D000068818', (163, 172))	('death', 'Disease', 'MESH:D003643', (107, 112))	('death', 'Disease', (107, 112))	('prevents', 'NegReg', (93, 101))	('downregulation', 'NegReg', (33, 47))
396247	33112928	Briefly, down-regulation of p120ctn in EPC1-hTERT and EPC2-hTERT cells was achieved via infection with TRIPZ inducible lentiviral p120ctn shRNA.	('EPC1', 'Gene', '80314', (39, 43))	('EPC1', 'Gene', (39, 43))	('hTERT', 'Gene', (59, 64))	('down-regulation', 'NegReg', (9, 24))	('p120ctn', 'Var', (28, 35))	('TRIPZ', 'Chemical', '-', (103, 108))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (54, 64))	('hTERT', 'Gene', '7015', (44, 49))	('hTERT', 'Gene', '7015', (59, 64))	('p120ctn', 'Var', (130, 137))	('infection', 'Disease', (88, 97))	('hTERT', 'Gene', (44, 49))	('infection', 'Disease', 'MESH:D007239', (88, 97))
396248	33112928	Treatment with 1 ug/mL doxycycline for 72 hours induces the down-regulation of p120ctn in the EPC1/EPC2-P and EPC1/EPC2-PE cells.	('EPC2', 'Gene', '26122', (115, 119))	('EPC2', 'Gene', (115, 119))	('p120ctn', 'Var', (79, 86))	('down-regulation', 'NegReg', (60, 75))	('EPC1', 'Gene', '80314', (110, 114))	('EPC1', 'Gene', (110, 114))	('doxycycline', 'Chemical', 'MESH:D004318', (23, 34))	('EPC2', 'Gene', '26122', (99, 103))	('EPC2', 'Gene', (99, 103))	('EPC1', 'Gene', '80314', (94, 98))	('EPC1', 'Gene', (94, 98))
396250	33112928	EPC1-PE and EPC2-PE cells were created by using both individual techniques for p120ctn down-regulation and EGFR overexpression in the same cell.	('down-regulation', 'NegReg', (87, 102))	('EPC2', 'Gene', '26122', (12, 16))	('overexpression', 'PosReg', (112, 126))	('p120ctn', 'Var', (79, 86))	('EGFR', 'Gene', (107, 111))	('EPC2', 'Gene', (12, 16))	('EPC1-P', 'CellLine', 'CVCL:4W34', (0, 6))
396252	33112928	HCC827 lung adenocarcinoma cells, with an acquired mutation in the EGFR tyrosine kinase domain, were used as a positive control for all experiments.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (7, 26))	('HCC827', 'CellLine', 'CVCL:2063', (0, 6))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (7, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('EGFR', 'Gene', (67, 71))	('lung adenocarcinoma', 'Disease', (7, 26))	('mutation in', 'Var', (51, 62))
396257	33112928	For viability testing, cells were treated with 5 muM gefitinib (#076091; Matrix Scientific, Columbia, SC), 10 muM erlotinib (#10483; Cayman Chemical; Ann Arbor, MI), or 10 nM cetuximab (#NBP2-75903; Novus Biologicals; Centennial, CO), with or without BAY 11-7085 (#B3033; ApexBio Technology; Houston, TX) at 2 muM or 3.3 muM for 48 hours.	('erlotinib', 'Chemical', 'MESH:D000069347', (114, 123))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (251, 262))	('#076091', 'Var', (64, 71))	('gefitinib', 'Chemical', 'MESH:D000077156', (53, 62))	('NBP2', 'Gene', (187, 191))	('NBP2', 'Gene', '10101', (187, 191))	('cetuximab', 'Chemical', 'MESH:D000068818', (175, 184))
396269	33112928	Human esophageal keratinocyte cell lines with p120ctn down-regulation and/or EGFR overexpression were generated in both EPC1-hTERT and EPC2-hTERT parental cells, outlined in Table 1.	('hTERT', 'Gene', (140, 145))	('Human', 'Species', '9606', (0, 5))	('hTERT', 'Gene', '7015', (125, 130))	('EPC1', 'Gene', (120, 124))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (135, 145))	('EPC1', 'Gene', '80314', (120, 124))	('down-regulation', 'NegReg', (54, 69))	('hTERT', 'Gene', (125, 130))	('p120ctn', 'Var', (46, 53))	('overexpression', 'PosReg', (82, 96))	('hTERT', 'Gene', '7015', (140, 145))	('EGFR', 'Gene', (77, 81))
396270	33112928	These modifications were done individually to create knockdown of p120ctn in EPC-P cells or overexpression of EGFR in EPC-E cells, respectively.	('overexpression', 'PosReg', (92, 106))	('p120ctn', 'Var', (66, 73))	('EPC-P', 'CellLine', 'CVCL:4361', (77, 82))	('EGFR', 'Gene', (110, 114))
396271	33112928	These modifications were also done in combination to create EPC-PE cells that have knockdown of p120ctn and overexpression of EGFR.	('p120ctn', 'Var', (96, 103))	('EPC-P', 'CellLine', 'CVCL:4361', (60, 65))	('EGFR', 'Gene', (126, 130))	('overexpression', 'PosReg', (108, 122))	('knockdown', 'Var', (83, 92))
396272	33112928	The control cells (EPC1/EPC2-C) contain empty vectors and express wild type levels of p120ctn and low levels of EGFR (Fig 1).	('EPC1', 'Gene', '80314', (19, 23))	('p120ctn', 'Var', (86, 93))	('EPC2', 'Gene', '26122', (24, 28))	('EPC1', 'Gene', (19, 23))	('EPC2', 'Gene', (24, 28))
396273	33112928	Western blot analysis demonstrates confirmation of p120ctn knockdown in EPC1/EPC2-P cells and overexpression of EGFR in EPC1/EPC2-E cells (Fig 1).	('EGFR', 'Gene', (112, 116))	('overexpression', 'PosReg', (94, 108))	('EPC2', 'Gene', '26122', (125, 129))	('EPC1', 'Gene', (120, 124))	('EPC2', 'Gene', (125, 129))	('EPC1', 'Gene', '80314', (120, 124))	('p120ctn', 'Var', (51, 58))	('EPC2', 'Gene', '26122', (77, 81))	('EPC2', 'Gene', (77, 81))	('EPC1', 'Gene', (72, 76))	('EPC1', 'Gene', '80314', (72, 76))
396274	33112928	EPC1/EPC2-PE cells have both down-regulation of p120ctn and overexpression of EGFR (Fig 1).	('down-regulation', 'NegReg', (29, 44))	('EPC2', 'Gene', '26122', (5, 9))	('EPC1', 'Gene', (0, 4))	('p120ctn', 'Var', (48, 55))	('EPC2', 'Gene', (5, 9))	('overexpression', 'PosReg', (60, 74))	('EPC1', 'Gene', '80314', (0, 4))	('EGFR', 'Gene', (78, 82))
396275	33112928	To determine whether decreased expression of p120ctn causes resistance in the engineered esophageal keratinocytes or is merely a potential biomarker for poor prognosis for patients treated with EGFR therapy as previously reported, we first tested the viability of EPC2-C, -P, -E, and -PE cells with varying concentrations of gefitinib to generate a dose response curve (Fig 2).	('p120ctn', 'Var', (45, 52))	('decreased', 'NegReg', (21, 30))	('EPC2', 'Gene', (264, 268))	('expression', 'MPA', (31, 41))	('patients', 'Species', '9606', (172, 180))	('EPC2', 'Gene', '26122', (264, 268))	('gefitinib', 'Chemical', 'MESH:D000077156', (325, 334))
396281	33112928	Gefitinib was able to effectively kill EPC2-E cells overexpressing mutant EGFR with an IC50 value of 5.8 uM.	('EPC2', 'Gene', '26122', (39, 43))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('EPC2', 'Gene', (39, 43))	('mutant', 'Var', (67, 73))	('EGFR', 'Gene', (74, 78))
396282	33112928	Interestingly, EPC2-PE cells, with the combination of decreased p120ctn expression and EGFR overexpression, were resistant to gefitinib treatment.	('gefitinib', 'Chemical', 'MESH:D000077156', (126, 135))	('EPC2', 'Gene', '26122', (15, 19))	('overexpression', 'PosReg', (92, 106))	('EPC2', 'Gene', (15, 19))	('EGFR', 'Gene', (87, 91))	('decreased', 'NegReg', (54, 63))	('p120ctn', 'Var', (64, 71))
396284	33112928	In fact, EPC2-PE cells have a toxicity profile that is indistinguishable from control EPC2-C and EPC2-P cells, suggesting a strong resistance to gefitinib induced by decreased p120ctn expression.	('toxicity', 'Disease', 'MESH:D064420', (30, 38))	('resistance', 'MPA', (131, 141))	('EPC2', 'Gene', '26122', (86, 90))	('EPC2', 'Gene', '26122', (97, 101))	('p120ctn expression', 'Var', (176, 194))	('EPC2', 'Gene', (86, 90))	('EPC2', 'Gene', (97, 101))	('EPC2', 'Gene', (9, 13))	('EPC2', 'Gene', '26122', (9, 13))	('toxicity', 'Disease', (30, 38))	('gefitinib', 'Chemical', 'MESH:D000077156', (145, 154))	('decreased', 'NegReg', (166, 175))
396285	33112928	These data establish that decreased p120ctn expression in human esophageal keratinocytes can cause gefitinib resistance.	('gefitinib resistance', 'MPA', (99, 119))	('human', 'Species', '9606', (58, 63))	('cause', 'Reg', (93, 98))	('p120ctn', 'Var', (36, 43))	('decreased', 'NegReg', (26, 35))	('gefitinib', 'Chemical', 'MESH:D000077156', (99, 108))
396287	33112928	After establishing that PE cells exhibited resistance to gefitinib, we assessed other EGFR-targeted therapies in the engineered cell lines to determine the effect of combining down-regulated p120ctn with overexpressed EGFR on cell viability.	('down-regulated', 'NegReg', (176, 190))	('p120ctn', 'Var', (191, 198))	('gefitinib', 'Chemical', 'MESH:D000077156', (57, 66))
396293	33112928	Importantly, EPC1-PE cells, expressing down-regulated p120ctn and upregulated EGFR, demonstrated resistance to all EGFR inhibitors tested, and that resistance was not statistically different than that found in EPC1-C and -P cells (Fig 3A).	('EPC1', 'Gene', '80314', (13, 17))	('resistance', 'MPA', (97, 107))	('EPC1', 'Gene', (13, 17))	('upregulated', 'PosReg', (66, 77))	('EPC1', 'Gene', (210, 214))	('EPC1-P', 'CellLine', 'CVCL:4W34', (13, 19))	('EPC1', 'Gene', '80314', (210, 214))	('EGFR', 'Gene', (78, 82))	('p120ctn', 'Var', (54, 61))	('down-regulated', 'NegReg', (39, 53))
396295	33112928	These data suggest that p120ctn confers resistance to not just gefitinib, but to multiple TKIs and other classes of EGFR-targeted therapies.	('resistance', 'MPA', (40, 50))	('gefitinib', 'Chemical', 'MESH:D000077156', (63, 72))	('p120ctn', 'Var', (24, 31))
396299	33112928	Results of this assay confirmed that EPC1-PE cells that have down-regulated p120ctn and overexpressed EGFR are resistant to cell death when treated with EGFR inhibitors (Fig 4D).	('death', 'Disease', 'MESH:D003643', (129, 134))	('death', 'Disease', (129, 134))	('EPC1-P', 'CellLine', 'CVCL:4W34', (37, 43))	('EGFR', 'Gene', (102, 106))	('p120ctn', 'Var', (76, 83))	('overexpressed', 'PosReg', (88, 101))	('down-regulated', 'NegReg', (61, 75))
396300	33112928	Having previously established that NFkB is hyperactivated by the cooperation between p120ctn down-regulation and EGFR overexpression, along with the known pro-survival effects of NFkB, we hypothesized that the combination of NFkB and EGFR inhibition may be able to induce EPC1-PE cell death.	('NFkB', 'Gene', (225, 229))	('EPC1-PE', 'Disease', (272, 279))	('down-regulation', 'NegReg', (93, 108))	('EGFR', 'Gene', (234, 238))	('inhibition', 'NegReg', (239, 249))	('hyperactivated', 'PosReg', (43, 57))	('EPC1-P', 'CellLine', 'CVCL:4W34', (272, 278))	('death', 'Disease', 'MESH:D003643', (285, 290))	('death', 'Disease', (285, 290))	('p120ctn', 'Var', (85, 92))
396309	33112928	The addition of BAY 11-7085 with EGFR inhibitors induced a significant amount of cell death in EPC1-E cells, 0.3-0.4 viability (Fig 5C) versus BAY 11-7085 and vehicle.	('BAY 11-7085', 'Chemical', 'MESH:C416282', (143, 154))	('inhibitors', 'Var', (38, 48))	('EPC1-E', 'CellLine', 'CVCL:4W34', (95, 101))	('death', 'Disease', 'MESH:D003643', (86, 91))	('death', 'Disease', (86, 91))	('EGFR', 'Gene', (33, 37))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (16, 27))
396311	33112928	The viability of EPC1-PE cells treated with BAY 11-7085 and EGFR inhibitors is significantly reduced, approximately 0.6, when compared to the BAY 11-7085 and vehicle control, 1.0, and to EPC1-C and EPC1-P cells, approximately 0.8 (Fig 5C).	('EPC1', 'Gene', '80314', (198, 202))	('EPC1', 'Gene', (17, 21))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (44, 55))	('EPC1', 'Gene', '80314', (17, 21))	('reduced', 'NegReg', (93, 100))	('EPC1-P', 'CellLine', 'CVCL:4W34', (17, 23))	('inhibitors', 'Var', (65, 75))	('EPC1', 'Gene', '80314', (187, 191))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (142, 153))	('EPC1', 'Gene', (187, 191))	('EGFR', 'Gene', (60, 64))	('EPC1-P', 'CellLine', 'CVCL:4W34', (198, 204))	('EPC1', 'Gene', (198, 202))
396312	33112928	While viability is reduced in EPC1-PE cells treated with BAY 11-7085 and EGFR inhibitors, they are not as severely affected as EPC1-E cells.	('viability', 'CPA', (6, 15))	('EPC1-P', 'CellLine', 'CVCL:4W34', (30, 36))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (57, 68))	('EGFR', 'Gene', (73, 77))	('EPC1-PE', 'Disease', (30, 37))	('inhibitors', 'Var', (78, 88))	('reduced', 'NegReg', (19, 26))	('EPC1-E', 'CellLine', 'CVCL:4W34', (127, 133))
396313	33112928	Unfortunately, treatment with higher BAY 11-7085 concentrations is prohibitive, this and other NFkB inhibitors have been well documented to cause problems in clinical trials by inducing unintended cytotoxicities and immune suppression.	('BAY 11-7085', 'Chemical', 'MESH:C416282', (37, 48))	('immune suppression', 'CPA', (216, 234))	('cytotoxicities', 'Disease', (197, 211))	('NFkB', 'Gene', (95, 99))	('cytotoxicities', 'Disease', 'MESH:D064420', (197, 211))	('inhibitors', 'Var', (100, 110))	('inducing', 'Reg', (177, 185))
396316	33112928	Tumors frequently develop acquired resistance due to secondary mutations in the targeted gene or other mutations contained within the tumor cell.	('mutations', 'Var', (63, 72))	('acquired resistance', 'MPA', (26, 45))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('develop', 'Reg', (18, 25))	('tumor', 'Disease', (134, 139))
396317	33112928	Our previous work identified p120ctn as a tumor suppressor and that its down-regulation/loss induces cancer in vivo.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('down-regulation/loss', 'NegReg', (72, 92))	('tumor', 'Disease', (42, 47))	('cancer', 'Disease', (101, 107))	('induces', 'Reg', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('p120ctn', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
396318	33112928	Moreover, we demonstrated that p120ctn down-regulation intersects and synergizes with EGFR overexpression to induce an aggressive and invasive cancer phenotype.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('invasive cancer', 'Disease', (134, 149))	('p120ctn', 'Var', (31, 38))	('down-regulation', 'NegReg', (39, 54))	('invasive cancer', 'Disease', 'MESH:D009362', (134, 149))	('EGFR', 'Gene', (86, 90))	('induce', 'PosReg', (109, 115))
396319	33112928	Even more recently it has been indicated that p120ctn may be a biomarker for EGFR therapy in NSCLC.	('p120ctn', 'Var', (46, 53))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('NSCLC', 'Disease', (93, 98))
396320	33112928	Specifically, lung cancer patients with low p120ctn protein expression had poorer outcomes when treated with gefitinib than those with normal p120ctn expression.	('low p120ctn', 'Var', (40, 51))	('lung cancer', 'Disease', (14, 25))	('patients', 'Species', '9606', (26, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('gefitinib', 'Chemical', 'MESH:D000077156', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('p120ctn', 'Var', (44, 51))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
396321	33112928	Given the transcriptional and carcinogenic interaction between p120ctn and EGFR, we hypothesized that p120ctn was more than a biomarker of EGFR therapy; rather, p120ctn could induce EGFR therapy resistance.	('p120ctn', 'Var', (161, 168))	('carcinogenic', 'Disease', 'MESH:D063646', (30, 42))	('carcinogenic', 'Disease', (30, 42))	('p120ctn', 'Var', (63, 70))	('EGFR therapy resistance', 'CPA', (182, 205))	('induce', 'Reg', (175, 181))
396322	33112928	In the present study, we show that the EGFR-targeted therapies, gefitinib, erlotinib, and cetuximab, are toxic to cells overexpressing EGFR alone but are not toxic at the same dose to cells with EGFR overexpression combined with p120ctn down-regulation.	('EGFR-targeted', 'Gene', (39, 52))	('gefitinib', 'Chemical', 'MESH:D000077156', (64, 73))	('cetuximab', 'Chemical', 'MESH:D000068818', (90, 99))	('erlotinib', 'Chemical', 'MESH:D000069347', (75, 84))	('p120ctn', 'Var', (229, 236))	('down-regulation', 'NegReg', (237, 252))
396323	33112928	We previously showed that down-regulation of p120ctn combined with overexpression of EGFR induces hyperactivation of NFkB p65 in human esophageal keratinocytes.	('EGFR', 'Gene', (85, 89))	('p120ctn', 'Var', (45, 52))	('overexpression', 'PosReg', (67, 81))	('NFkB p65', 'Gene', (117, 125))	('down-regulation', 'NegReg', (26, 41))	('human', 'Species', '9606', (129, 134))	('hyperactivation', 'PosReg', (98, 113))
396324	33112928	With this in mind, we hypothesized that a combination therapy of EGFR inhibitors and an NFkB inhibitor may induce cell death in cells with down-regulated p120ctn and overexpressing EGFR that were otherwise resistant to EGFR therapy.	('overexpressing', 'PosReg', (166, 180))	('EGFR', 'Gene', (181, 185))	('EGFR', 'Gene', (65, 69))	('death', 'Disease', 'MESH:D003643', (119, 124))	('induce', 'PosReg', (107, 113))	('death', 'Disease', (119, 124))	('inhibitors', 'Var', (70, 80))	('down-regulated', 'NegReg', (139, 153))	('p120ctn', 'Var', (154, 161))
396325	33112928	The initial data show that combined NFkB inhibitor with the EGFR therapies lead to an intermediate amount of cell death in cells with low p120ctn protein expression and EGFR overexpression, suggesting that an NFkB inhibitor may be useful in combination with an EGFR-targeted therapy to treat EGFR-positive tumors with decreased p120ctn.	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('p120ctn', 'Var', (138, 145))	('tumors', 'Disease', (306, 312))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('low', 'NegReg', (134, 137))	('death', 'Disease', 'MESH:D003643', (114, 119))	('p120ctn', 'Var', (328, 335))	('death', 'Disease', (114, 119))
396327	33112928	Decreased p120ctn has been identified as such a biomarker, and we have shown here that decreased p120ctn can indeed cause a tumor to be resistant to EGFR-targeted therapies.	('decreased p120ctn', 'Var', (87, 104))	('cause', 'Reg', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('p120ctn', 'Var', (97, 104))	('resistant', 'CPA', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
396328	33112928	Though further studies are required, these data suggest that stratifying patients with EGFR-activated tumors based on their p120ctn expression may aid in therapy effectiveness.	('tumors', 'Disease', (102, 108))	('p120ctn expression', 'Var', (124, 142))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('EGFR-activated', 'Gene', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('patients', 'Species', '9606', (73, 81))	('aid', 'Reg', (147, 150))
396329	33112928	Indeed, since decreased p120ctn protein expression significantly overlaps with EGFR overexpression in ESCC, it may be an explanation why cetuximab clinical trials failed in treating patients with ESCC.	('overexpression', 'PosReg', (84, 98))	('decreased', 'NegReg', (14, 23))	('p120ctn', 'Var', (24, 31))	('ESCC', 'Disease', (102, 106))	('patients', 'Species', '9606', (182, 190))	('cetuximab', 'Chemical', 'MESH:D000068818', (137, 146))
396330	33112928	Furthermore, inhibition of NFkB may be able to cooperate with EGFR therapy to eradicate tumors with EGFR activation and p120ctn down-regulation.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('p120ctn', 'Var', (120, 127))	('activation', 'PosReg', (105, 115))	('EGFR', 'Gene', (100, 104))	('NFkB', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('down-regulation', 'NegReg', (128, 143))
396363	32190688	EGFR knockdown with shRNA in ESCC cell significantly reduced the sensitivity of cancer cells to ILQ.	('EGFR', 'Gene', (0, 4))	('ILQ', 'Chemical', 'MESH:C040920', (96, 99))	('knockdown', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('reduced', 'NegReg', (53, 60))	('sensitivity', 'MPA', (65, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('EGFR', 'Gene', '1956', (0, 4))	('cancer', 'Disease', (80, 86))
396364	32190688	Moreover, it was found that ILQ had a significantly inhibitory effect on AP-1 family, the protein of Jun and Fos subfamilies was substantially downregulated, and the transcriptional activity of AP-1 family was dramatically suppressed by ILQ.	('AP-1', 'Gene', (194, 198))	('AP-1', 'Gene', '2353', (194, 198))	('ILQ', 'Chemical', 'MESH:C040920', (237, 240))	('AP-1', 'Gene', '2353', (73, 77))	('downregulated', 'NegReg', (143, 156))	('ILQ', 'Chemical', 'MESH:C040920', (28, 31))	('suppressed', 'NegReg', (223, 233))	('inhibitory effect', 'NegReg', (52, 69))	('transcriptional activity', 'MPA', (166, 190))	('ILQ', 'Var', (237, 240))	('Fos', 'Gene', '2353', (109, 112))	('AP-1', 'Gene', (73, 77))	('ILQ', 'Var', (28, 31))	('Fos', 'Gene', (109, 112))
396366	32190688	Finally, the antitumor potency of ILQ was validated in xenograft models and the tumor growth was prominently restrained by ILQ.	('ILQ', 'Chemical', 'MESH:C040920', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (17, 22))	('ILQ', 'Chemical', 'MESH:C040920', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ILQ', 'Var', (123, 126))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('restrained', 'NegReg', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
396376	32190688	Owing to its importance, in some tumor types such as lung adenocarcinoma, the somatic mutations of EGFR can act as a driver to accelerate tumor growth.	('EGFR', 'Gene', '1956', (99, 103))	('mutations', 'Var', (86, 95))	('EGFR', 'Gene', (99, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('lung adenocarcinoma', 'Disease', (53, 72))	('accelerate', 'PosReg', (127, 137))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (53, 72))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
396377	32190688	And the tumors with EGFR mutations have shown great response to EGFR inhibitors.	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('EGFR', 'Gene', '1956', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', '1956', (20, 24))	('response', 'MPA', (52, 60))
396380	32190688	In addition to overexpression, gene amplification of EGFR was also identified in ESCC tissue.	('EGFR', 'Gene', (53, 57))	('gene amplification', 'Var', (31, 49))	('ESCC', 'Disease', (81, 85))	('EGFR', 'Gene', '1956', (53, 57))
396381	32190688	The analysis of survival demonstrated that the patients with low copy number had longer survival in contrast with those of high EGFR amplification.	('longer', 'PosReg', (81, 87))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('patients', 'Species', '9606', (47, 55))	('survival', 'MPA', (88, 96))	('low copy number', 'Var', (61, 76))
396385	32190688	Recently, multiple studies had investigated the effect of ILQ on cancers, and ILQ has exhibited profound antitumor abilities against breast cancer, hepatocellular carcinoma, colon cancer, cervical cancer, prostate cancer, endometrial cancer, and so on.	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (148, 172))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('endometrial cancer', 'Disease', (222, 240))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('endometrial cancer', 'Disease', 'MESH:D016889', (222, 240))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('ILQ', 'Chemical', 'MESH:C040920', (78, 81))	('breast cancer', 'Disease', (133, 146))	('colon cancer', 'Phenotype', 'HP:0003003', (174, 186))	('cervical cancer', 'Disease', (188, 203))	('ILQ', 'Var', (78, 81))	('cervical cancer', 'Disease', 'MESH:D002583', (188, 203))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (148, 172))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ILQ', 'Chemical', 'MESH:C040920', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colon cancer', 'Disease', 'MESH:D015179', (174, 186))	('prostate cancer', 'Disease', 'MESH:D011471', (205, 220))	('hepatocellular carcinoma', 'Disease', (148, 172))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('prostate cancer', 'Phenotype', 'HP:0012125', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('prostate cancer', 'Disease', (205, 220))	('endometrial cancer', 'Phenotype', 'HP:0012114', (222, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('colon cancer', 'Disease', (174, 186))	('tumor', 'Disease', (109, 114))
396398	32190688	The primary antibodies used in this study including anti-p-EGFR (Tyr1068) (#3777), anti-EGFR (#4267), anti-p-Akt (S473) (#4060), anti-Akt (#4691), anti-p-ERK1/2 (Thr202/Tyr204) (#4370), anti-ERK1/2(#4695), anti-c-Jun (#9165), anti-JunB (#3746), anti-JunD (#5000), anti-FosB(#4691), anti-c-Fos (#2251), anti-Fra1(#5281), anti-Cyclin D1(#55506), anti-beta-actin (#3700), and anti-Histone H3 Ser10 (#53348) were products of Cell Signaling Technology (Danvers, MA).	('EGFR', 'Gene', (59, 63))	('FosB', 'Gene', (269, 273))	('Fra1', 'Gene', '8061', (307, 311))	('FosB', 'Gene', '2354', (269, 273))	('#4370', 'Var', (178, 183))	('Akt', 'Gene', (109, 112))	('Akt', 'Gene', (134, 137))	('#3746', 'Var', (237, 242))	('#2251', 'Var', (294, 299))	('JunD', 'Gene', (250, 254))	('Akt', 'Gene', '207', (109, 112))	('Cyclin D1', 'Gene', '595', (325, 334))	('Akt', 'Gene', '207', (134, 137))	('#3700', 'Var', (361, 366))	('ERK1/2', 'Gene', (191, 197))	('ERK1/2', 'Gene', '5595;5594', (191, 197))	('Cyclin D1', 'Gene', (325, 334))	('EGFR', 'Gene', (88, 92))	('EGFR', 'Gene', '1956', (59, 63))	('#53348', 'Var', (396, 402))	('c-Fos', 'Gene', (287, 292))	('JunB', 'Gene', (231, 235))	('#5000', 'Var', (256, 261))	('c-Fos', 'Gene', '2353', (287, 292))	('ERK1/2', 'Gene', '5595;5594', (154, 160))	('JunB', 'Gene', '3726', (231, 235))	('Fra1', 'Gene', (307, 311))	('c-Jun', 'Gene', '3725', (211, 216))	('JunD', 'Gene', '3727', (250, 254))	('c-Jun', 'Gene', (211, 216))	('EGFR', 'Gene', '1956', (88, 92))	('ERK1/2', 'Gene', (154, 160))
396415	32190688	To generate lentiviral particles, the plasmid pLKO.1-sh-EGFR, psPAX2 (#12260, Addgene), or pMD2.G (#12259, Addgene) was cotransfected into HEK-293T cells with PSPAX2 and PMD2.G.	('EGFR', 'Gene', '1956', (56, 60))	('#12260', 'Var', (70, 76))	('EGFR', 'Gene', (56, 60))	('HEK-293T', 'CellLine', 'CVCL:0063;0.1213289305524951', (139, 147))	('#12259', 'Var', (99, 105))
396429	32190688	As shown in Figures 1(b)-1(d), in three tested ESCC cells KYSE-140, KYSE-520, and TE-1, ILQ had demonstrated profound antitumor activity, and the cell viability was significantly decreased in a dose- and time-dependent manner.	('ILQ', 'Chemical', 'MESH:C040920', (88, 91))	('decreased', 'NegReg', (179, 188))	('KYSE-520', 'Var', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('KYSE-140', 'Var', (58, 66))	('cell viability', 'CPA', (146, 160))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
396434	32190688	Moreover, with EGFR inhibition, the phosphorylation of ERK and AKT, two major downstream signaling molecules, were both significantly reduced.	('AKT', 'Gene', (63, 66))	('ERK', 'Gene', '5594', (55, 58))	('inhibition', 'Var', (20, 30))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('reduced', 'NegReg', (134, 141))	('AKT', 'Gene', '207', (63, 66))	('phosphorylation', 'MPA', (36, 51))	('ERK', 'Gene', (55, 58))
396440	32190688	After transfection with EGFR-shRNA, the ability of colony formation had been affected in contrast with GFP-shRNA.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('colony formation', 'CPA', (51, 67))	('transfection', 'Var', (6, 18))
396445	32190688	Meanwhile, other proteins in the Fos subfamily, including FosB, c-Fos, and Fra1, were also substantially decreased after ILQ treatment (Figures 3(a) and 3(b)).	('Fos', 'Gene', (33, 36))	('FosB', 'Gene', (58, 62))	('Fra1', 'Gene', '8061', (75, 79))	('Fos', 'Gene', (58, 61))	('c-Fos', 'Gene', (64, 69))	('Fos', 'Gene', (66, 69))	('Fra1', 'Gene', (75, 79))	('FosB', 'Gene', '2354', (58, 62))	('Fos', 'Gene', '2353', (66, 69))	('Fos', 'Gene', '2353', (33, 36))	('ILQ', 'Chemical', 'MESH:C040920', (121, 124))	('Fos', 'Gene', '2353', (58, 61))	('c-Fos', 'Gene', '2353', (64, 69))	('ILQ', 'Var', (121, 124))	('decreased', 'NegReg', (105, 114))	('proteins', 'Protein', (17, 25))
396452	32190688	Next, we analyzed the cell phase distribution in ILQ-treated cells, as shown in Figure 4(b), after the treatment of ILQ, the proportion of cells in the G0/G1 phase increased in a dose-dependent manner, suggesting ILQ could cause cell cycle arrest.	('ILQ', 'Chemical', 'MESH:C040920', (213, 216))	('ILQ', 'Var', (213, 216))	('ILQ', 'Chemical', 'MESH:C040920', (116, 119))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (229, 246))	('ILQ', 'Chemical', 'MESH:C040920', (49, 52))	('cell cycle arrest', 'CPA', (229, 246))	('increased', 'PosReg', (164, 173))
396471	32190688	It is consolidated that the dysregulation of EGFR activity is closely associated with tumor development.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGFR', 'Gene', (45, 49))	('tumor', 'Disease', (86, 91))	('dysregulation', 'Var', (28, 41))	('associated', 'Reg', (70, 80))	('activity', 'MPA', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('EGFR', 'Gene', '1956', (45, 49))
396478	32190688	With the inactivation of EGFR, two key downstream molecules, ERK and Akt, were inhibited.	('Akt', 'Gene', (69, 72))	('EGFR', 'Gene', (25, 29))	('ERK', 'Gene', '5594', (61, 64))	('inhibited', 'NegReg', (79, 88))	('inactivation', 'Var', (9, 21))	('Akt', 'Gene', '207', (69, 72))	('ERK', 'Gene', (61, 64))	('EGFR', 'Gene', '1956', (25, 29))
396480	32190688	Moreover, in EGFR deficient cells, the sensitivities to ILQ were reduced significantly.	('sensitivities to ILQ', 'MPA', (39, 59))	('reduced', 'NegReg', (65, 72))	('ILQ', 'Chemical', 'MESH:C040920', (56, 59))	('deficient', 'Var', (18, 27))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
396485	32190688	Genomic profiling showed that CCND1 amplification was present in 57% tumor tissue and often coordinated with EGFR amplification to accelerate tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (142, 147))	('amplification', 'Var', (36, 49))	('EGFR', 'Gene', '1956', (109, 113))	('CCND1', 'Gene', (30, 35))	('accelerate', 'PosReg', (131, 141))	('EGFR', 'Gene', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('CCND1', 'Gene', '595', (30, 35))
396486	32190688	Some studies also indicated that dysregulated cyclin D1 expression is the reason for the reduced efficacy of EGFR inhibitors.	('cyclin D1', 'Gene', '595', (46, 55))	('cyclin D1', 'Gene', (46, 55))	('EGFR', 'Gene', '1956', (109, 113))	('dysregulated', 'Var', (33, 45))	('expression', 'MPA', (56, 66))	('reduced', 'NegReg', (89, 96))	('EGFR', 'Gene', (109, 113))	('efficacy', 'MPA', (97, 105))
396493	32190688	Western blotting also confirmed that the expression of proteins in Jun and Fos family was decreased after ILQ treatment.	('expression of proteins', 'MPA', (41, 63))	('ILQ', 'Chemical', 'MESH:C040920', (106, 109))	('decreased', 'NegReg', (90, 99))	('Fos', 'Gene', '2353', (75, 78))	('treatment', 'Var', (110, 119))	('Fos', 'Gene', (75, 78))	('Jun', 'Protein', (67, 70))
396520	31200527	Aberrant activation or mutation in the key members of the HH pathway is associated with the development of cancer and resistance to conventional anticancer therapy.	('activation', 'PosReg', (9, 19))	('cancer', 'Disease', (149, 155))	('Aberrant', 'Var', (0, 8))	('mutation', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('associated', 'Reg', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HH pathway', 'Pathway', (58, 68))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
396542	31200527	In OE33, fewer genes displayed >2-fold upregulation, among which was found to be again PTCH1 (Supplementary Table S1 and Figure 3B).	('PTCH1', 'Gene', (87, 92))	('upregulation', 'PosReg', (39, 51))	('PTCH1', 'Gene', '5727', (87, 92))	('OE33', 'Var', (3, 7))
396549	31200527	Therefore, modulation of the CSC population should illicit a change in radioresistance in OE-21 cells.	('change', 'Reg', (61, 67))	('modulation', 'Var', (11, 21))	('OE-21', 'CellLine', 'CVCL:2661', (90, 95))	('radioresistance', 'CPA', (71, 86))
396553	31200527	In this study, we demonstrated that the HH pathway is up-regulated in nCRT patients with Mandard 4 and 5 statuses after reviewing the resection material and moreover it may be a key player in the regulation of cancer stemness as shown by the change in the amount CD44+/CD24- CSC population upon HH pathway modulation.	('CD44', 'Gene', '960', (263, 267))	('CD24', 'Gene', (269, 273))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('modulation', 'Var', (306, 316))	('CD44', 'Gene', (263, 267))	('HH pathway', 'Pathway', (40, 50))	('patients', 'Species', '9606', (75, 83))	('CD24', 'Gene', '100133941', (269, 273))	('cancer stemness', 'Disease', 'MESH:D009369', (210, 225))	('up-regulated', 'PosReg', (54, 66))	('nCRT', 'Disease', (70, 74))	('change', 'Reg', (242, 248))	('cancer stemness', 'Disease', (210, 225))
396586	31200527	Two esophageal cancer cell lines were used, OE21 derived from ESCC of the upper esophagus and OE33 derived from a poorly differentiated Barrett's associated tumor of the distal esophagus.	('tumor', 'Disease', (157, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('ESCC of', 'Disease', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('OE33', 'Var', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal cancer', 'Disease', (4, 21))
396601	31200527	FACS analyses on LSRII (BD Biosciences) were performed on the expression of CD44+/CD24- and CD44+/CD24+ in OE21 and OE33 after 48 h 5 nM vismodegib treatment in RPMI media and their controls, which consisted of RPMI supplemented with DMSO.	('RPMI', 'Chemical', '-', (211, 215))	('CD44', 'Gene', (76, 80))	('OE33', 'Var', (116, 120))	('CD44', 'Gene', (92, 96))	('CD24', 'Gene', '100133941', (82, 86))	('OE21', 'Var', (107, 111))	('RPMI media', 'Chemical', '-', (161, 171))	('CD24', 'Gene', '100133941', (98, 102))	('CD24', 'Gene', (98, 102))	('RPMI', 'Chemical', '-', (161, 165))	('CD24', 'Gene', (82, 86))	('DMSO', 'Chemical', 'MESH:D004121', (234, 238))	('CD44', 'Gene', '960', (76, 80))	('CD44', 'Gene', '960', (92, 96))
396615	31200527	In vitro modulation of the HH pathway efficiently altered CSC populations, while inhibition of the pathway can be used to enhance sensitivity to common esophageal cancer treatments.	('CSC populations', 'CPA', (58, 73))	('enhance', 'PosReg', (122, 129))	('modulation', 'Var', (9, 19))	('esophageal cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('altered', 'Reg', (50, 57))	('HH pathway', 'Pathway', (27, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))
396621	30677088	Clinical significance of cancer specific methylation of the CDO1 gene in small bowel cancer Although small bowel cancer (SBC) is extremely rare, its prognosis is poor, and molecular mechanism of the SBC development remains unclear.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('small bowel cancer', 'Disease', 'MESH:D055752', (73, 91))	('small bowel cancer', 'Disease', 'MESH:D055752', (101, 119))	('small bowel cancer', 'Disease', (73, 91))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (113, 119))	('small bowel cancer', 'Disease', (101, 119))	('methylation', 'Var', (41, 52))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CDO1', 'Gene', '1036', (60, 64))	('CDO1', 'Gene', (60, 64))
396626	30677088	Among the various clinicopathological factors, positive correlation of CDO1 methylation with tumor diameter was observed (R = 0.31, p = 0.03), and the CDO1 methylation level was a possible prognostic factor for relapse-free survival (p = 0.09).	('relapse-free survival', 'CPA', (211, 232))	('CDO1', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('CDO1', 'Gene', '1036', (151, 155))	('tumor', 'Disease', (93, 98))	('methylation', 'Var', (76, 87))	('CDO1', 'Gene', '1036', (71, 75))	('CDO1', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
396629	30677088	Among small bowel tumors, CDO1 methylation in SBC was higher in order of malignant lymphoma, cancer, and leiomyosarcoma/GIST (p = 0.002) by ANOVA.	('methylation', 'Var', (31, 42))	('small bowel tumors', 'Disease', 'MESH:D015212', (6, 24))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('higher', 'PosReg', (54, 60))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (105, 119))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (105, 119))	('CDO1', 'Gene', (26, 30))	('malignant lymphoma', 'Disease', (73, 91))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('small bowel tumors', 'Disease', (6, 24))	('cancer', 'Disease', (93, 99))	('CDO1', 'Gene', '1036', (26, 30))	('small bowel tumors', 'Phenotype', 'HP:0100833', (6, 24))	('GIST', 'Phenotype', 'HP:0100723', (120, 124))	('leiomyosarcoma', 'Disease', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('malignant lymphoma', 'Disease', 'MESH:D008223', (73, 91))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('lymphoma', 'Phenotype', 'HP:0002665', (83, 91))
396642	30677088	Methylation of the promoter region of the CDO1 has been reported in a number of cancers including breast cancer, esophageal cancer, gastric cancer, and colon cancer, however there has no report with regard to SBC.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colon cancer', 'Phenotype', 'HP:0003003', (152, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CDO1', 'Gene', (42, 46))	('esophageal cancer', 'Disease', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colon cancer', 'Disease', 'MESH:D015179', (152, 164))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('gastric cancer', 'Disease', (132, 146))	('cancers', 'Disease', (80, 87))	('reported', 'Reg', (56, 64))	('CDO1', 'Gene', '1036', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Disease', (98, 111))	('colon cancer', 'Disease', (152, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
396707	30677088	However, in RFS, when the cutoff value of the TaqMeth V was 28.9, the high TaqMeth V group showed a tendency towards poor prognosis (p = 0.06, relative risk = 1.87).	('high', 'Var', (70, 74))	('TaqMeth V', 'Chemical', '-', (75, 84))	('RFS', 'Disease', (12, 15))	('TaqMeth V', 'Chemical', '-', (46, 55))
396726	30677088	This study is the first report regarding the relationship between methylation abnormality of the CDO1 gene and SBC.	('methylation abnormality', 'Var', (66, 89))	('CDO1', 'Gene', '1036', (97, 101))	('SBC', 'Disease', (111, 114))	('CDO1', 'Gene', (97, 101))
396728	30677088	We can infer from this result that methylation abnormality of the CDO1 is strongly involved in the carcinogenesis of SBC.	('CDO1', 'Gene', (66, 70))	('involved', 'Reg', (83, 91))	('methylation abnormality', 'Var', (35, 58))	('CDO1', 'Gene', '1036', (66, 70))	('carcinogenesis of SBC', 'Disease', (99, 120))	('carcinogenesis of SBC', 'Disease', 'MESH:D063646', (99, 120))
396729	30677088	There have been reports of cancer-specific CDO1 methylation abnormalities in the gastrointestinal tract in esophageal cancer, stomach cancer and CRC.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('stomach cancer', 'Disease', 'MESH:D013274', (126, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('methylation abnormalities', 'Var', (48, 73))	('stomach cancer', 'Phenotype', 'HP:0012126', (126, 140))	('CDO1', 'Gene', (43, 47))	('CRC', 'Disease', (145, 148))	('gastrointestinal tract', 'Disease', (81, 103))	('esophageal cancer', 'Disease', (107, 124))	('CRC', 'Phenotype', 'HP:0003003', (145, 148))	('cancer', 'Disease', (134, 140))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (81, 103))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('CDO1', 'Gene', '1036', (43, 47))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('abnormalities in the gastrointestinal tract', 'Phenotype', 'HP:0011024', (60, 103))	('stomach cancer', 'Disease', (126, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
396739	30677088	We next analyzed the clinicopathological features that might be associated with methylation abnormality of the CDO1.	('methylation abnormality', 'Var', (80, 103))	('CDO1', 'Gene', '1036', (111, 115))	('CDO1', 'Gene', (111, 115))
396740	30677088	There was little association between CDO1 methylation and the degree of progression of SBC or the site where the tumor existed.	('tumor', 'Disease', (113, 118))	('SBC', 'Disease', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('methylation', 'Var', (42, 53))	('CDO1', 'Gene', '1036', (37, 41))	('CDO1', 'Gene', (37, 41))
396743	30677088	This result was consistent with the characteristic of methylation abnormality of the CDO1 in Barrett's esophageal cancer that is clinically malignant.	('methylation abnormality', 'Var', (54, 77))	('CDO1', 'Gene', '1036', (85, 89))	('CDO1', 'Gene', (85, 89))	("Barrett's esophageal cancer", 'Phenotype', 'HP:0100580', (93, 120))	("Barrett's esophageal cancer", 'Disease', 'MESH:D004938', (93, 120))	("Barrett's esophageal cancer", 'Disease', (93, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))
396745	30677088	In this study, we can provide clinical evidence to support the possibility that methylation of CDO1 is involved in tumor cell proliferation.	('CDO1', 'Gene', '1036', (95, 99))	('CDO1', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('involved', 'Reg', (103, 111))	('methylation', 'Var', (80, 91))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
396746	30677088	Since there have also been some reports that CDO1 methylation is related to prognosis, the involvement of CDO1 methylation in the prognosis of SBC was also analyzed.	('CDO1', 'Gene', '1036', (106, 110))	('CDO1', 'Gene', (106, 110))	('SBC', 'Disease', (143, 146))	('CDO1', 'Gene', '1036', (45, 49))	('CDO1', 'Gene', (45, 49))	('related', 'Reg', (65, 72))	('methylation', 'Var', (50, 61))
396749	30677088	We showed the possibility that methylation abnormality of CDO1 could contribute to prognosis as a recurrence risk factor.	('methylation abnormality', 'Var', (31, 54))	('CDO1', 'Gene', '1036', (58, 62))	('CDO1', 'Gene', (58, 62))	('contribute', 'Reg', (69, 79))
396753	30677088	These findings indicated that methylation abnormality of CDO1 has high clinical significance as a useful biomarker of SBC.	('SBC', 'Disease', (118, 121))	('CDO1', 'Gene', '1036', (57, 61))	('methylation abnormality', 'Var', (30, 53))	('CDO1', 'Gene', (57, 61))
396756	30677088	In our previous reports, we also report the association between CDO1 methylation abnormality and atypia of CRC.	('CDO1', 'Gene', '1036', (64, 68))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('atypia', 'Disease', (97, 103))	('methylation abnormality', 'Var', (69, 92))	('CDO1', 'Gene', (64, 68))	('association', 'Interaction', (44, 55))
396758	30677088	As a result, utilization of CDO1 methylation abnormality can be expected as a biomarker for detection from adenoma to SBC.	('abnormality', 'Var', (45, 56))	('CDO1', 'Gene', '1036', (28, 32))	('CDO1', 'Gene', (28, 32))	('SBC', 'Disease', (118, 121))	('adenoma', 'Disease', 'MESH:D000236', (107, 114))	('methylation abnormality', 'Var', (33, 56))	('adenoma', 'Disease', (107, 114))
396764	30677088	Based on these results it can be said that clinical malignancy is indicated by methylation abnormality of the CDO1.	('CDO1', 'Gene', '1036', (110, 114))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('CDO1', 'Gene', (110, 114))	('malignancy', 'Disease', (52, 62))	('indicated by', 'Reg', (66, 78))	('methylation abnormality', 'Var', (79, 102))
396769	30677088	In this study, we showed cancer-specific methylation of CDO1 in SBC, its association with clinical malignancy, and its potential to function as a recurrence prediction marker.	('malignancy', 'Disease', (99, 109))	('SBC', 'Disease', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('association', 'Interaction', (73, 84))	('methylation', 'Var', (41, 52))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('CDO1', 'Gene', '1036', (56, 60))	('CDO1', 'Gene', (56, 60))	('cancer', 'Disease', (25, 31))	('malignancy', 'Disease', 'MESH:D009369', (99, 109))
396770	30677088	We plan to report biomarker research using methylation abnormality of the CDO1 to accumulate evidence that might lead towards better diagnosis of SBC.	('SBC', 'Disease', (146, 149))	('methylation abnormality', 'Var', (43, 66))	('CDO1', 'Gene', '1036', (74, 78))	('CDO1', 'Gene', (74, 78))
396794	30327727	Morbid obesity had a very similar age of onset reduction as ulcerative colitis (7.75 years versus 8.45 years) for colon cancer, suggesting that morbid obesity is a very strong risk factor for early onset of colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('obesity', 'Phenotype', 'HP:0001513', (7, 14))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Morbid obesity', 'Phenotype', 'HP:0012743', (0, 14))	('obesity', 'Phenotype', 'HP:0001513', (151, 158))	('colon cancer', 'Disease', (207, 219))	('ulcerative colitis', 'Disease', (60, 78))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (60, 78))	('morbid obesity', 'Phenotype', 'HP:0012743', (144, 158))	('morbid', 'Var', (144, 150))	('colon cancer', 'Phenotype', 'HP:0003003', (114, 126))	('colon cancer', 'Phenotype', 'HP:0003003', (207, 219))	('colitis', 'Phenotype', 'HP:0002583', (71, 78))	('ulcerative colitis', 'Disease', 'MESH:D003093', (60, 78))
396917	28932119	The elimination of Dox from blood was significantly prolonged upon administration as HCS-Dox compared to that with free Dox (Figure 8C; *p<0.05).	('elimination of Dox from blood', 'MPA', (4, 33))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('prolonged', 'PosReg', (52, 61))	('Dox', 'Chemical', 'MESH:D004317', (19, 22))	('Dox', 'Chemical', 'MESH:D004317', (89, 92))	('C', 'Chemical', 'MESH:D002244', (133, 134))	('Dox', 'Chemical', 'MESH:D004317', (120, 123))	('HCS-Dox', 'Var', (85, 92))
396919	28932119	These data suggested that HCS-Dox could reduce Dox toxicity toward the heart and kidney tissues, along with increasing its antitumor activities.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('reduce', 'NegReg', (40, 46))	('toxicity', 'Disease', 'MESH:D064420', (51, 59))	('toxicity', 'Disease', (51, 59))	('Dox', 'Chemical', 'MESH:D004317', (30, 33))	('HCS-Dox', 'Var', (26, 33))	('increasing', 'PosReg', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Dox', 'Chemical', 'MESH:D004317', (47, 50))
396930	28932119	Most importantly, HCS-Dox could significantly promote tumor suppression owing to its EPR effect and longer circulation time.	('promote', 'PosReg', (46, 53))	('HCS-Dox', 'Var', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Dox', 'Chemical', 'MESH:D004317', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
396933	27105523	We previously found that it is bound to hTERT, and UBE2D3 could attenuate radiosensitivity of human breast cancer cells.	('hTERT', 'Gene', (40, 45))	('attenuate', 'NegReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('UBE2D3', 'Var', (51, 57))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('hTERT', 'Gene', '7015', (40, 45))	('human', 'Species', '9606', (94, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('attenuate radiosensitivity', 'Phenotype', 'HP:0010997', (64, 90))
396938	27105523	MG132 treatment of UBE2D3 overexpressed cells caused a clear and dramatic increase in the amount of ubiquitinated hTERT species.	('MG132', 'Var', (0, 5))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('hTERT', 'Gene', '7015', (114, 119))	('increase', 'PosReg', (74, 82))	('hTERT', 'Gene', (114, 119))
396939	27105523	These findings indicate that UBE2D3 enhances radiosensitivity of EC109 cells by degradating hTERT through the ubiquitin proteolysis pathway.	('enhances', 'PosReg', (36, 44))	('radiosensitivity', 'MPA', (45, 61))	('UBE2D3', 'Var', (29, 35))	('hTERT', 'Gene', '7015', (92, 97))	('ubiquitin proteolysis pathway', 'Pathway', (110, 139))	('hTERT', 'Gene', (92, 97))	('degradating', 'NegReg', (80, 91))
396946	27105523	In this pathway, E2, which is including UBE2D3, together with ubiquitin ligase (E3), transfers ubiquitin to the specific substrate protein(s); Polyubiquitinated proteins are recognized by the 26S proteasome and rapidly degraded.	('ubiquitin ligase', 'Gene', '84585', (62, 78))	('Polyubiquitinated', 'Var', (143, 160))	('degraded', 'NegReg', (219, 227))	('ubiquitin ligase', 'Gene', (62, 78))	('transfers ubiquitin', 'MPA', (85, 104))
396948	27105523	We previously found that the inhibition of UBE2D3 could decrease radiosensitivity of MCF-7 cells by upregulating hTERT expression and activity.	('hTERT', 'Gene', (113, 118))	('MCF-7', 'CellLine', 'CVCL:0031', (85, 90))	('decrease radiosensitivity', 'Phenotype', 'HP:0010997', (56, 81))	('upregulating', 'PosReg', (100, 112))	('activity', 'MPA', (134, 142))	('hTERT', 'Gene', '7015', (113, 118))	('radiosensitivity of MCF-7 cells', 'CPA', (65, 96))	('decrease', 'NegReg', (56, 64))	('inhibition', 'Var', (29, 39))	('UBE2D3', 'Gene', (43, 49))
396949	27105523	In addition, we found that UBE2D3 was negatively correlated with hTERT expression and was a positive prognostic factor for EsC.	('UBE2D3', 'Var', (27, 33))	('hTERT', 'Gene', (65, 70))	('correlated', 'Interaction', (49, 59))	('hTERT', 'Gene', '7015', (65, 70))	('negatively', 'NegReg', (38, 48))	('EsC', 'Disease', (123, 126))
396960	27105523	There was no any ubiquitin change for those without using MG132 (Figure 7C, line 1 and 2); While two groups can be detected the existence of ubiquitin after MG132 deposed, and the content of ubquitin in UBE2D3 over-expressed cells was much higher than that in control group (Figure 7C, line 3 and 4).	('MG132', 'Chemical', 'MESH:C072553', (157, 162))	('content', 'MPA', (180, 187))	('MG132', 'Chemical', 'MESH:C072553', (58, 63))	('ubquitin', 'Chemical', '-', (191, 199))	('higher', 'PosReg', (240, 246))	('MG132 deposed', 'Var', (157, 170))	('ubiquitin', 'MPA', (141, 150))
396967	27105523	The inhibition of UBE2D3 could increase the expression of cell cycle checkpoint protein cyclinD1, which can promote the cell cycle from G1phase to S phase transformation.	('cell cycle', 'CPA', (120, 130))	('expression', 'MPA', (44, 54))	('cyclinD1', 'Gene', '12443', (88, 96))	('cyclinD1', 'Gene', (88, 96))	('inhibition', 'Var', (4, 14))	('promote', 'PosReg', (108, 115))	('UBE2D3', 'Gene', (18, 24))	('increase', 'PosReg', (31, 39))
396969	27105523	Cellular responses to DNA damage are coordinated primarily by the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively.	('single-stranded DNA', 'Var', (157, 176))	('Chk2', 'Gene', (70, 74))	('ATR', 'Gene', '245000', (79, 82))	('Chk1', 'Gene', '12649', (83, 87))	('DNA double-strand breaks', 'Var', (121, 145))	('ATM', 'Gene', '11920', (66, 69))	('Chk2', 'Gene', '50883', (70, 74))	('Chk1', 'Gene', (83, 87))	('DSBs', 'Chemical', '-', (147, 151))	('ATM', 'Gene', (66, 69))	('ATR', 'Gene', (79, 82))	('activated', 'PosReg', (108, 117))
396978	27105523	Therefore, we hypothesize that UBE2D3 can degraded hTERT through the ubiquitin pathway.	('UBE2D3', 'Var', (31, 37))	('hTERT', 'Gene', '7015', (51, 56))	('degraded', 'NegReg', (42, 50))	('hTERT', 'Gene', (51, 56))	('ubiquitin pathway', 'Pathway', (69, 86))
396981	27105523	This finding suggested that the UBE2D3 had the ability to stimulate hTERT degradation by ubiquitin-dependent proteolysis.	('hTERT', 'Gene', (68, 73))	('UBE2D3', 'Var', (32, 38))	('stimulate', 'PosReg', (58, 67))	('ubiquitin-dependent proteolysis', 'MPA', (89, 120))	('hTERT', 'Gene', '7015', (68, 73))
396982	27105523	There was no significant difference in hTERT expression level after MG132 interferation in the two cell lines, which proved that UBE2D3 was really involved in the process of hTERT ubiquitined degradation.	('MG132', 'Var', (68, 73))	('MG132', 'Chemical', 'MESH:C072553', (68, 73))	('hTERT', 'Gene', (174, 179))	('involved', 'Reg', (147, 155))	('hTERT', 'Gene', '7015', (39, 44))	('hTERT', 'Gene', (39, 44))	('hTERT', 'Gene', '7015', (174, 179))
396989	27105523	Immunohistochemical result showed that hTERT expression in tissues of OE mice was lower than that of NC mice, suggesting that UBE2D3 enhanced the in vivo radiosensitivity also through the hTERT degradation.	('radiosensitivity', 'CPA', (154, 170))	('UBE2D3', 'Var', (126, 132))	('hTERT', 'Gene', (188, 193))	('hTERT', 'Gene', '7015', (39, 44))	('mice', 'Species', '10090', (73, 77))	('mice', 'Species', '10090', (104, 108))	('vivo radiosensitivity', 'Phenotype', 'HP:0010997', (149, 170))	('hTERT', 'Gene', (39, 44))	('hTERT', 'Gene', '7015', (188, 193))	('enhanced', 'PosReg', (133, 141))
396993	27105523	UBE2D3 degraded hTERT and enhanced radiosensitivity of Esc cells through ubiquitin-proteasome pathway.	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (26, 51))	('enhanced', 'PosReg', (26, 34))	('ubiquitin-proteasome pathway', 'Pathway', (73, 101))	('UBE2D3', 'Var', (0, 6))	('radiosensitivity', 'CPA', (35, 51))	('degraded', 'NegReg', (7, 15))	('hTERT', 'Gene', '7015', (16, 21))	('hTERT', 'Gene', (16, 21))	('Esc', 'CellLine', 'CVCL:9108', (55, 58))
396994	27105523	These data are critical not only for our understanding of UBE2D3-mediated enhancement of radiosensitivity in cancer cells but also for the design and development of UBE2D3-based radiotherapy for EsC.	('radiosensitivity', 'MPA', (89, 105))	('EsC', 'Disease', (195, 198))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('enhancement', 'PosReg', (74, 85))	('UBE2D3-mediated', 'Var', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
397009	27105523	Briefly, EC109-pEGFP cells or EC109-pEGFP-UBE2D3 cells were subcutaneously injected into the right dorsal leg of BALB/c athymic nude mice (aged 4 to 6 weeks) which were named as NC and OE group respectively (Department of Laboratory Animals, Zhongnan Hospital of Wuhan University).	('nude mice', 'Species', '10090', (128, 137))	('EC109-pEGFP-UBE2D3', 'Var', (30, 48))	('EC109-pEGFP', 'Var', (9, 20))
397036	26318185	If employers allow adjustments in work requirements, utilizing occupational health services, partial RTW, etc., RTW may improve the quality of life for cancer survivors by providing social reintegration and increasing self-esteem .	('increasing', 'PosReg', (207, 217))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('RTW', 'Var', (112, 115))	('quality of life', 'CPA', (132, 147))	('improve', 'PosReg', (120, 127))	('social reintegration', 'CPA', (182, 202))	('providing', 'Reg', (172, 181))	('men', 'Species', '9606', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('self-esteem', 'CPA', (218, 229))	('men', 'Species', '9606', (25, 28))
397056	26318185	The sixth most prevalent was "blood" malignancies (C81-C96, n = 95), which included leukemia (n = 32), malignant lymphoma (n = 46), multiple myeloma (n = 8), and other related cancers (n = 9).	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('multiple myeloma', 'Disease', 'MESH:D009101', (132, 148))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('malignant lymphoma', 'Disease', 'MESH:D008223', (103, 121))	('multiple myeloma', 'Phenotype', 'HP:0006775', (132, 148))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('multiple myeloma', 'Disease', (132, 148))	('C81-C96', 'Var', (51, 58))	('leukemia', 'Phenotype', 'HP:0001909', (84, 92))	('malignant lymphoma', 'Disease', (103, 121))	('leukemia', 'Disease', (84, 92))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('leukemia', 'Disease', 'MESH:D007938', (84, 92))
397057	26318185	The seventh most prevalent was "male genital" cancers (C60-63, n = 78), which included prostatic cancer (n = 63) and testicular or penis cancer (n = 15).	('genital" cancer', 'Phenotype', 'HP:0010787', (37, 52))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('penis cancer', 'Phenotype', 'HP:0100850', (131, 143))	('penis cancer', 'Disease', (131, 143))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('genital" cancers', 'Disease', 'MESH:D009369', (37, 53))	('penis cancer', 'Disease', 'MESH:D010412', (131, 143))	('prostatic cancer', 'Disease', (87, 103))	('C60-63', 'Var', (55, 61))	('genital" cancers', 'Disease', (37, 53))	('prostatic cancer', 'Disease', 'MESH:D011471', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('prostatic cancer', 'Phenotype', 'HP:0012125', (87, 103))
397058	26318185	Tied for the eighth most prevalent were "esophageal" cancer (C15, n = 67) and "female genital" cancers (C51-C58, n = 67), which included cancer of the uterus (n = 47) and ovarian cancer (n = 20).	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('"esophageal" cancer', 'Disease', (40, 59))	('ovarian cancer', 'Disease', (171, 185))	('cancer', 'Disease', (137, 143))	('cancer of the uterus', 'Phenotype', 'HP:0010784', (137, 157))	('genital" cancers', 'Disease', 'MESH:D009369', (86, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('genital" cancers', 'Disease', (86, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('"esophageal" cancer', 'Disease', 'MESH:D004938', (40, 59))	('cancer', 'Disease', (95, 101))	('genital" cancer', 'Phenotype', 'HP:0010787', (86, 101))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('ovarian cancer', 'Disease', 'MESH:D010051', (171, 185))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('C51-C58', 'Var', (104, 111))	('cancer', 'Disease', (179, 185))
397059	26318185	The tenth most prevalent was "urinary" cancers (C64-C68, n = 53), which included renal cell carcinoma and ureter carcinoma (n = 30), and bladder cancer (n = 23).	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cancers', 'Disease', (39, 46))	('renal cell carcinoma and ureter carcinoma', 'Disease', 'MESH:C538614', (81, 122))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('C64-C68', 'Var', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (81, 101))	('bladder cancer', 'Disease', (137, 151))
397060	26318185	"Other" cancer (n = 133) included brain cancer (C71, n = 20), oral cancer (C00-C09, n = 20), pharyngo-laryngeal cancer (C10-C14, n = 27), thyroid cancer (C73, N = 19), and others (n = 47).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('thyroid cancer', 'Disease', (138, 152))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (8, 14))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (102, 118))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('brain cancer', 'Phenotype', 'HP:0030692', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('brain cancer', 'Disease', 'MESH:D001932', (34, 46))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('thyroid cancer', 'Disease', 'MESH:D013964', (138, 152))	('pharyngo-laryngeal cancer', 'Disease', 'MESH:D007822', (93, 118))	('C00-C09', 'Var', (75, 82))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('oral cancer', 'Disease', 'MESH:D009062', (62, 73))	('cancer', 'Disease', (67, 73))	('thyroid cancer', 'Phenotype', 'HP:0002890', (138, 152))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('oral cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('pharyngo-laryngeal cancer', 'Disease', (93, 118))	('brain cancer', 'Disease', (34, 46))	('C10-C14', 'Var', (120, 127))
397063	26318185	We used Fine-Gray proportional hazard regression for competing events in order to analyze whether age, gender, and cancer sites were statistically associated with partial/full RTW and full RTW.	('cancer', 'Disease', (115, 121))	('full RTW', 'Var', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('partial/full RTW', 'Var', (163, 179))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
397105	26318185	The ratio of partial RTW to full RTW among cancer site groups was highest in the "esophageal" cancer group, which may have possibly been due to a restriction in diet following esophageal surgery, leading to less physical strength and prevention of full-time work.	('less', 'NegReg', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('"esophageal" cancer', 'Disease', 'MESH:D004938', (81, 100))	('physical strength', 'CPA', (212, 229))	('"esophageal" cancer', 'Disease', (81, 100))	('partial RTW', 'Var', (13, 24))	('full-time work', 'CPA', (248, 262))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
397110	26318185	These results show that this is especially so for cancer sites with a high partial/full RTW ratio (e.g., gastric and esophageal cancers).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('partial/full', 'Var', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('gastric and esophageal cancers', 'Disease', 'MESH:D013274', (105, 135))	('cancer', 'Disease', (128, 134))
397165	23837094	The patients were subjected to a total of 37 procedures: 5 with HALO360 and 32 with HALO90.	('HALO360', 'Chemical', '-', (64, 71))	('HALO90', 'Var', (84, 90))	('HALO90', 'Chemical', '-', (84, 90))	('patients', 'Species', '9606', (4, 12))	('HALO360', 'Var', (64, 71))
397194	33432363	In the present study, reverse transcription-quantitative PCR was performed to investigate the levels of PART1, SRY-box transcription factor 6 (SOX6) and miR-18a-5p in ESCC tissues and cells.	('SOX6', 'Gene', '55553', (143, 147))	('miR-18a-5p', 'Chemical', '-', (153, 163))	('miR-18a-5p', 'Var', (153, 163))	('SRY-box transcription factor 6', 'Gene', (111, 141))	('SOX6', 'Gene', (143, 147))	('SRY-box transcription factor 6', 'Gene', '55553', (111, 141))
397198	33432363	Mechanistically, PART1 functions as a competing endogenous (ce)RNA by sponging miR-18a-5p, resulting in the upregulation of the downstream target gene, SOX6, coupled with the inactivation of the beta-catenin/c-myc signaling axis, to suppress ESCC cell proliferation and invasion.	('inactivation', 'NegReg', (175, 187))	('invasion', 'CPA', (270, 278))	('ESCC', 'Disease', (242, 246))	('miR-18a-5p', 'Chemical', '-', (79, 89))	('PART1', 'Gene', (17, 22))	('miR-18a-5p', 'Var', (79, 89))	('beta-catenin', 'Gene', '1499', (195, 207))	('SOX6', 'Gene', (152, 156))	('beta-catenin', 'Gene', (195, 207))	('c-myc', 'Gene', '4609', (208, 213))	('c-myc', 'Gene', (208, 213))	('SOX6', 'Gene', '55553', (152, 156))	('upregulation', 'PosReg', (108, 120))	('suppress', 'NegReg', (233, 241))
397199	33432363	In conclusion, data from the present study unveil a potential ceRNA regulatory pathway, in which PART1 affects SOX6 expression level by sponging miR-18a-5p, to ultimately suppress ESCC development and progression.	('SOX6', 'Gene', (111, 115))	('miR-18a-5p', 'Chemical', '-', (145, 155))	('SOX6', 'Gene', '55553', (111, 115))	('suppress', 'NegReg', (171, 179))	('miR-18a-5p', 'Gene', (145, 155))	('progression', 'CPA', (201, 212))	('ESCC', 'Disease', (180, 184))	('affects', 'Reg', (103, 110))	('sponging', 'Var', (136, 144))
397220	33432363	The StarBase online database v2.0 was also used to investigate the levels of PART1 and miR-18a-5p in patients with ESCA and in normal samples.	('ESCA', 'Disease', (115, 119))	('miR-18a-5p', 'Var', (87, 97))	('patients', 'Species', '9606', (101, 109))	('miR-18a-5p', 'Chemical', '-', (87, 97))
397236	33432363	The fragments, containing wild-type (WT) or mutant (MUT) binding sites of FOXP2 in the PART1 transcript were constructed using the pGL3-basic vector (Promega Corp.).	('FOXP2', 'Gene', '93986', (74, 79))	('pGL3', 'Gene', (131, 135))	('pGL3', 'Gene', '6391', (131, 135))	('FOXP2', 'Gene', (74, 79))	('mutant', 'Var', (44, 50))
397249	33432363	Furthermore, RT-qPCR demonstrated that the ESCC cell lines (Eca109, EC9706, TE1, KYSE70 and KYSE450) had significantly lower levels of PART1 and SOX6 compared with those in the Het-1A normal esophageal epithelial cell line (P<0.01) (Fig.	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('levels', 'MPA', (125, 131))	('lower', 'NegReg', (119, 124))	('KYSE70', 'Var', (81, 87))	('PART1', 'MPA', (135, 140))	('SOX6', 'Gene', (145, 149))	('EC9706', 'Var', (68, 74))	('SOX6', 'Gene', '55553', (145, 149))
397267	33432363	It was found that pcDNA3.1-PART1 significantly upregulated PART1 expression level in the Eca109 and EC9706 cell lines (P<0.0001) (Fig.	('upregulated', 'PosReg', (47, 58))	('pcDNA3.1-PART1', 'Var', (18, 32))	('PART1 expression level', 'MPA', (59, 81))	('EC9706', 'CellLine', 'CVCL:E307', (100, 106))
397272	33432363	Meanwhile, PART1 knockdown accelerated cell invasion in the Eca109 and EC9706 cell lines (Fig.	('cell invasion in', 'CPA', (39, 55))	('PART1', 'Gene', (11, 16))	('knockdown', 'Var', (17, 26))	('accelerated', 'PosReg', (27, 38))	('EC9706', 'CellLine', 'CVCL:E307', (71, 77))
397277	33432363	Notably, PART1 enrichment in the miR-18a-5p mimic group was significantly higher compared with that in the NC mimic group (P<0.0001) (Fig.	('PART1 enrichment', 'MPA', (9, 25))	('miR-18a-5p mimic', 'Var', (33, 49))	('miR-18a-5p', 'Chemical', '-', (33, 43))	('higher', 'PosReg', (74, 80))
397278	33432363	These findings suggested that PART1 and miR-18a-5p exhibited a direct interaction in the ESCC cell lines via the Ago2-dependent pathway.	('miR-18a-5p', 'Var', (40, 50))	('interaction', 'Interaction', (70, 81))	('Ago2', 'Gene', '27161', (113, 117))	('Ago2', 'Gene', (113, 117))	('miR-18a-5p', 'Chemical', '-', (40, 50))
397281	33432363	4H), whereas PART1 silencing significantly promoted miR-18a-5p expression in the Eca109 and EC9706 cell lines (Fig.	('PART1', 'Gene', (13, 18))	('promoted', 'PosReg', (43, 51))	('silencing', 'Var', (19, 28))	('miR-18a-5p', 'Chemical', '-', (52, 62))	('expression', 'MPA', (63, 73))	('miR-18a-5p', 'Gene', (52, 62))	('EC9706', 'CellLine', 'CVCL:E307', (92, 98))
397284	33432363	To further investigate the role of miR-18a-5p in ESCC progression, its expression level and downstream target genes were determined.	('miR-18a-5p', 'Chemical', '-', (35, 45))	('miR-18a-5p', 'Var', (35, 45))	('ESCC', 'Disease', (49, 53))
397287	33432363	It was found that 75 ESCC samples displayed higher expression level of miR-18a-5p compared with that in the paired adjacent normal samples (P<0.0001) (Fig.	('higher', 'PosReg', (44, 50))	('ESCC', 'Disease', (21, 25))	('miR-18a-5p', 'Chemical', '-', (71, 81))	('miR-18a-5p', 'Var', (71, 81))	('expression level', 'MPA', (51, 67))
397289	33432363	These findings suggested that miR-18a-5p may participate in ESCC development and progression.	('ESCC', 'Disease', (60, 64))	('miR-18a-5p', 'Chemical', '-', (30, 40))	('miR-18a-5p', 'Var', (30, 40))	('participate', 'Reg', (45, 56))
397296	33432363	5J), whereas miR-18a-5p mimic significantly suppressed the mRNA expression level of SOX6 in the Eca109 and EC9706 cell lines (Fig.	('suppressed', 'NegReg', (44, 54))	('miR-18a-5p', 'Var', (13, 23))	('EC9706', 'CellLine', 'CVCL:E307', (107, 113))	('SOX6', 'Gene', (84, 88))	('SOX6', 'Gene', '55553', (84, 88))	('miR-18a-5p', 'Chemical', '-', (13, 23))
397297	33432363	These findings indicated that miR-18a-5p directly affected the expression level of SOX6 in the ESCC cell lines.	('expression level', 'MPA', (63, 79))	('SOX6', 'Gene', (83, 87))	('SOX6', 'Gene', '55553', (83, 87))	('miR-18a-5p', 'Chemical', '-', (30, 40))	('miR-18a-5p', 'Var', (30, 40))	('affected', 'Reg', (50, 58))
397300	33432363	Notably, miR-18a-5p inhibitor triggered the upregulation of SOX6 proteins and the downregulation of beta-catenin and c-myc proteins, which was also partly reversed by PART1 and SOX6 siRNA (Fig.	('beta-catenin', 'Gene', (100, 112))	('beta-catenin', 'Gene', '1499', (100, 112))	('c-myc', 'Gene', '4609', (117, 122))	('c-myc', 'Gene', (117, 122))	('SOX6', 'Gene', '55553', (60, 64))	('downregulation', 'NegReg', (82, 96))	('upregulation', 'PosReg', (44, 56))	('miR-18a-5p', 'Chemical', '-', (9, 19))	('miR-18a-5p inhibitor', 'Var', (9, 29))	('SOX6', 'Gene', (177, 181))	('SOX6', 'Gene', (60, 64))	('SOX6', 'Gene', '55553', (177, 181))
397302	33432363	Notably, miR-18a-5p mimic triggered the downregulation of SOX6 proteins and the upregulation of beta-catenin and c-myc proteins, which was also partly reversed by pcDNA3.1-PART1 and pcDNA3.1-SOX6 (Fig.	('c-myc', 'Gene', (113, 118))	('SOX6', 'Gene', (58, 62))	('beta-catenin', 'Gene', '1499', (96, 108))	('downregulation', 'NegReg', (40, 54))	('upregulation', 'PosReg', (80, 92))	('SOX6', 'Gene', '55553', (58, 62))	('SOX6', 'Gene', (191, 195))	('miR-18a-5p', 'Chemical', '-', (9, 19))	('SOX6', 'Gene', '55553', (191, 195))	('miR-18a-5p mimic', 'Var', (9, 25))	('c-myc', 'Gene', '4609', (113, 118))	('beta-catenin', 'Gene', (96, 108))
397312	33432363	Notably, patients with ESCC and low PART1 expression level had poorer survival times compared with those with high PART1 expression levels.	('PART1', 'Protein', (36, 41))	('patients', 'Species', '9606', (9, 17))	('low', 'Var', (32, 35))	('ESCC', 'Disease', (23, 27))	('survival times', 'CPA', (70, 84))	('expression', 'MPA', (42, 52))	('poorer', 'NegReg', (63, 69))
397326	33432363	Furthermore, PART1 functions as a tumor suppressor by sponging miR-190a-3p to inactivate the PTEN/AKT signaling pathway in glioma.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('PTEN', 'Gene', (93, 97))	('tumor', 'Disease', (34, 39))	('PTEN', 'Gene', '5728', (93, 97))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('inactivate', 'NegReg', (78, 88))	('miR-190a-3p', 'Var', (63, 74))	('AKT', 'Gene', '207', (98, 101))	('glioma', 'Disease', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('AKT', 'Gene', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
397329	33432363	Further investigation revealed that miR-18a-5p and PART1 were both enriched using an anti-Ago2 antibody, and miR-18a-5p mimic significantly increased the accumulation of PART1 in the ESCC cell lines, suggesting that miR-18a-5p and PART1 both appear in the RNA-induced silencing complex.	('Ago2', 'Gene', '27161', (90, 94))	('miR-18a-5p', 'Chemical', '-', (216, 226))	('accumulation', 'MPA', (154, 166))	('miR-18a-5p', 'Chemical', '-', (36, 46))	('Ago2', 'Gene', (90, 94))	('increased', 'PosReg', (140, 149))	('miR-18a-5p', 'Chemical', '-', (109, 119))	('miR-18a-5p', 'Var', (109, 119))
397332	33432363	Recently, miR-18a-5p has been reported to participate in tumor progression, and may be a potential biomarker for the diagnosis and prognosis in a variety of different tumors.	('participate', 'Reg', (42, 53))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('miR-18a-5p', 'Chemical', '-', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('miR-18a-5p', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (57, 62))	('tumors', 'Disease', (167, 173))	('tumor', 'Disease', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
397335	33432363	In addition, miR-18a-5p inhibitor significantly promoted the expression level of SOX6, whereas miR-18a-5p mimic notably downregulated the expression level of SOX6.	('SOX6', 'Gene', '55553', (81, 85))	('downregulated', 'NegReg', (120, 133))	('expression level', 'MPA', (138, 154))	('SOX6', 'Gene', '55553', (158, 162))	('expression level', 'MPA', (61, 77))	('miR-18a-5p', 'Var', (95, 105))	('promoted', 'PosReg', (48, 56))	('SOX6', 'Gene', (158, 162))	('miR-18a-5p', 'Chemical', '-', (95, 105))	('SOX6', 'Gene', (81, 85))	('miR-18a-5p', 'Chemical', '-', (13, 23))
397336	33432363	These findings suggest that SOX6 is a direct target gene of miR-18a-5p in the ESCC cell lines.	('miR-18a-5p', 'Var', (60, 70))	('SOX6', 'Gene', '55553', (28, 32))	('SOX6', 'Gene', (28, 32))	('miR-18a-5p', 'Chemical', '-', (60, 70))
397347	33432363	PART1 overexpression and knockdown suppressed and promoted cell proliferation and invasion, respectively, in the Eca109 and EC9706 cell lines.	('promoted', 'PosReg', (50, 58))	('invasion', 'CPA', (82, 90))	('cell proliferation', 'CPA', (59, 77))	('EC9706', 'CellLine', 'CVCL:E307', (124, 130))	('suppressed', 'NegReg', (35, 45))	('knockdown', 'Var', (25, 34))	('PART1', 'Gene', (0, 5))
397348	33432363	PART1 was found to function as a ceRNA to sponge miR-18a-5p further resulting in the elevation of SOX6 expression levels, which triggered the downregulation of beta-catenin and c-myc proteins, and thus, suppressed ESCC progression.	('ESCC', 'Disease', (214, 218))	('beta-catenin', 'Gene', (160, 172))	('miR-18a-5p', 'Chemical', '-', (49, 59))	('miR-18a-5p', 'Var', (49, 59))	('elevation', 'PosReg', (85, 94))	('suppressed', 'NegReg', (203, 213))	('beta-catenin', 'Gene', '1499', (160, 172))	('c-myc', 'Gene', '4609', (177, 182))	('SOX6', 'Gene', (98, 102))	('c-myc', 'Gene', (177, 182))	('downregulation', 'NegReg', (142, 156))	('SOX6', 'Gene', '55553', (98, 102))
397461	31367271	Cisplatin induces severe nausea and vomiting, i.e., it is highly emetogenic, and it also has strong nephrotoxicity, in which a large amount infusion is necessary to prevent renal impairment.	('vomiting', 'Disease', 'MESH:D014839', (36, 44))	('renal impairment', 'Disease', (173, 189))	('nephrotoxicity', 'Disease', 'MESH:D007674', (100, 114))	('nephrotoxicity', 'Disease', (100, 114))	('renal impairment', 'Disease', 'MESH:D007674', (173, 189))	('nausea', 'Phenotype', 'HP:0002018', (25, 31))	('nausea', 'Disease', (25, 31))	('nausea', 'Disease', 'MESH:D009325', (25, 31))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('renal impairment', 'Phenotype', 'HP:0000083', (173, 189))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (25, 44))	('Cisplatin', 'Var', (0, 9))	('vomiting', 'Phenotype', 'HP:0002013', (36, 44))	('vomiting', 'Disease', (36, 44))
397462	31367271	In contrast, oxaliplatin is moderately emetogenic and less nephrotoxic than cisplatin.	('oxaliplatin', 'Var', (13, 24))	('emetogenic', 'MPA', (39, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('nephrotoxic', 'Disease', 'MESH:D007674', (59, 70))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (13, 24))	('nephrotoxic', 'Disease', (59, 70))
397478	31367271	In a study with docetaxel, cisplatin and S-1 (DCS) as neoadjuvant chemotherapy (JCOG1002), the response rate was 57.7%, and R0 resection was achieved in 84.6% of patients.	('patients', 'Species', '9606', (162, 170))	('S-1', 'Gene', '5707', (41, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('docetaxel', 'Chemical', 'MESH:D000077143', (16, 25))	('S-1', 'Gene', (41, 44))	('cisplatin', 'Var', (27, 36))	('DCS', 'Chemical', '-', (46, 49))
397495	31367271	Trifluridine/tipiracil improved the overall survival compared with the placebo in patients who had previously received two or more regimens.	('overall survival', 'MPA', (36, 52))	('patients', 'Species', '9606', (82, 90))	('Trifluridine/tipiracil', 'Var', (0, 22))	('improved', 'PosReg', (23, 31))	('tipiracil', 'Chemical', 'MESH:C000613754', (13, 22))	('Trifluridine', 'Chemical', 'MESH:D014271', (0, 12))
397502	31367271	Although pembrolizumab did not significantly improve overall survival compared with paclitaxel as a second-line therapy for advanced gastric or gastroesophageal junction cancer, pembrolizumab had a better safety profile than paclitaxel.	('pembrolizumab', 'Chemical', 'MESH:C582435', (178, 191))	('pembrolizumab', 'Chemical', 'MESH:C582435', (9, 22))	('gastric or gastroesophageal junction cancer', 'Disease', (133, 176))	('paclitaxel', 'Chemical', 'MESH:D017239', (84, 94))	('paclitaxel', 'Chemical', 'MESH:D017239', (225, 235))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('gastric or gastroesophageal junction cancer', 'Disease', 'MESH:D013274', (133, 176))	('pembrolizumab', 'Var', (178, 191))
397546	31367271	The Cancer Genome Atlas (TCGA) project proposes a molecular classification dividing gastric cancer into four subtypes: Tumors positive for Epstein-Barr virus, which display PIK3CA mutations, DNA hypermethylation, and an amplification of JAK2, PD-L1 and PD-L2; microsatellite unstable tumors, which show elevated mutation rates; genomically stable tumors, which are enriched for the diffuse histological variant and mutations of RhoA or fusions involving RHO-family GTPase-activating proteins; and tumors with chromosomal instability, which show aneuploidy and the focal amplification of receptor tyrosine kinases.	('Tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('mutation', 'MPA', (312, 320))	('unstable tumors', 'Disease', 'MESH:D000789', (275, 290))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('chromosomal instability', 'Phenotype', 'HP:0040012', (509, 532))	('tumors', 'Phenotype', 'HP:0002664', (497, 503))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('gastric cancer', 'Disease', (84, 98))	('Tumors', 'Disease', (119, 125))	('tumors', 'Disease', (347, 353))	('tumor', 'Phenotype', 'HP:0002664', (497, 502))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumors', 'Disease', (497, 503))	('receptor tyrosine kinases', 'Enzyme', (587, 612))	('tumors', 'Disease', (284, 290))	('aneuploidy', 'Disease', 'MESH:D000782', (545, 555))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('Tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('tumors', 'Disease', 'MESH:D009369', (497, 503))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('Cancer Genome Atlas', 'Disease', (4, 23))	('tumors', 'Disease', 'MESH:D009369', (284, 290))	('unstable tumors', 'Disease', (275, 290))	('PD-L1', 'Gene', (243, 248))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('aneuploidy', 'Disease', (545, 555))	('mutations', 'Var', (415, 424))	('PD-L1', 'Gene', '29126', (243, 248))
397553	31281468	Glutathione S-transferases genes variants and chemotherapy efficacy in gastrointestinal cancer patients: a meta-analysis based on 50 pharmacogenetic studies Background: The role of glutathione s-transferase genes (GSTP1, GSTM1 and GSTT1) variants and the GSTP1 expression level on chemotherapy efficacy of gastrointestinal cancer (GIC) patients were inconsistent.	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (71, 94))	('Glutathione S-transferases', 'Gene', '373156', (0, 26))	('GSTT1', 'Gene', '2952', (231, 236))	('GSTM1', 'Gene', '2944', (221, 226))	('gastrointestinal cancer', 'Disease', (71, 94))	('glutathione s-transferase', 'Gene', (181, 206))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (71, 94))	('variants', 'Var', (238, 246))	('variants', 'Var', (33, 41))	('GSTP1', 'Gene', '2950', (255, 260))	('GSTT1', 'Gene', (231, 236))	('glutathione s-transferase', 'Gene', '373156', (181, 206))	('GSTP1', 'Gene', '2950', (214, 219))	('GSTP1', 'Gene', (255, 260))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (306, 329))	('patients', 'Species', '9606', (336, 344))	('gastrointestinal cancer', 'Disease', (306, 329))	('GSTP1', 'Gene', (214, 219))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (306, 329))	('Glutathione S-transferases', 'Gene', (0, 26))	('patients', 'Species', '9606', (95, 103))	('GSTM1', 'Gene', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))
397554	31281468	Methods: A meta-analysis about GSTP1, GSTM1 and GSTT1 variants and the GSTP1 expression level on chemotherapy efficacy of GIC patients was performed using data from PubMed, PMC, EMBASE, Web of Science, and Wanfang database.	('GSTP1', 'Gene', (71, 76))	('GSTP1', 'Gene', '2950', (31, 36))	('GSTP1', 'Gene', '2950', (71, 76))	('GSTP1', 'Gene', (31, 36))	('GSTM1', 'Gene', '2944', (38, 43))	('GSTT1', 'Gene', '2952', (48, 53))	('GSTT1', 'Gene', (48, 53))	('patients', 'Species', '9606', (126, 134))	('variants', 'Var', (54, 62))	('GSTM1', 'Gene', (38, 43))
397557	31281468	Significant associations were found between the Ile105Val variant and overall survival of Caucasian GIC patients (IIe/Val vs. IIe/IIe: OR = 0.797 (0.674-0.944), P = 0.009).	('overall', 'MPA', (70, 77))	('Val', 'Chemical', 'MESH:D014633', (118, 121))	('Ile105Val', 'Mutation', 'rs1695', (48, 57))	('Val', 'Chemical', 'MESH:D014633', (54, 57))	('patients', 'Species', '9606', (104, 112))	('Ile105Val', 'Var', (48, 57))
397558	31281468	Caucasian GIC patients and gastric cancer patients with GSTT1 null genotype had worse response rates compared to GSTT1 present patients (OR = 0.530 (0.356-0.789), P = 0.002; OR = 0.643 (0.463-0.895), P = 0.009, respectively).	('gastric cancer', 'Disease', 'MESH:D013274', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('gastric cancer', 'Phenotype', 'HP:0012126', (27, 41))	('GSTT1', 'Gene', (113, 118))	('GSTT1', 'Gene', '2952', (113, 118))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (42, 50))	('null genotype', 'Var', (62, 75))	('GSTT1', 'Gene', (56, 61))	('GSTT1', 'Gene', '2952', (56, 61))	('patients', 'Species', '9606', (14, 22))	('gastric cancer', 'Disease', (27, 41))	('response', 'MPA', (86, 94))
397559	31281468	Conclusion: This meta-analysis illustrates that GSTP1 IIe105Val and GSTT1 null/present variants could be useful predictors of chemotherapy efficacy in patients with gastrointestinal cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (165, 188))	('GSTP1', 'Gene', (48, 53))	('GSTT1', 'Gene', '2952', (68, 73))	('patients', 'Species', '9606', (151, 159))	('GSTT1', 'Gene', (68, 73))	('gastrointestinal cancer', 'Disease', (165, 188))	('Val', 'Chemical', 'MESH:D014633', (60, 63))	('IIe105Val', 'Var', (54, 63))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (165, 188))	('GSTP1', 'Gene', '2950', (48, 53))
397567	31281468	The effects of GSTM1/GSTT1 (null/present) and GSTP1 (rs1695, Ile105Val) genetic polymorphisms on chemotherapy efficacy in GIC patients were not consistent in previous research.	('rs1695', 'Var', (53, 59))	('Ile105Val', 'Mutation', 'rs1695', (61, 70))	('GSTP1', 'Gene', '2950', (46, 51))	('chemotherapy', 'CPA', (97, 109))	('GSTM1', 'Gene', '2944', (15, 20))	('GSTM1', 'Gene', (15, 20))	('rs1695', 'Mutation', 'rs1695', (53, 59))	('GSTT1', 'Gene', (21, 26))	('GSTP1', 'Gene', (46, 51))	('GSTT1', 'Gene', '2952', (21, 26))	('patients', 'Species', '9606', (126, 134))
397568	31281468	There were four meta-analyses for the efficacy of glutathione S-transferases (GSTs) variants and chemotherapy in patients with GC or CRC.	('GSTs', 'Gene', '373156', (78, 82))	('patients', 'Species', '9606', (113, 121))	('GSTs', 'Gene', (78, 82))	('glutathione S-transferases', 'Gene', (50, 76))	('CRC', 'Disease', (133, 136))	('variants', 'Var', (84, 92))	('glutathione S-transferases', 'Gene', '373156', (50, 76))
397571	31281468	Therefore, we have updated new literatures to investigate the associations between GSTP1 (Ile105Val), GSTM1 (null/present), GSTT1 (null/present) variants and GSTP1 expression and clinical outcomes in GIC patients.	('patients', 'Species', '9606', (204, 212))	('GSTP1', 'Gene', (158, 163))	('associations', 'Interaction', (62, 74))	('GSTM1', 'Gene', '2944', (102, 107))	('variants', 'Var', (145, 153))	('GSTP1', 'Gene', (83, 88))	('GSTM1', 'Gene', (102, 107))	('GSTP1', 'Gene', '2950', (158, 163))	('Ile105Val', 'Mutation', 'rs1695', (90, 99))	('GSTP1', 'Gene', '2950', (83, 88))	('GSTT1', 'Gene', '2952', (124, 129))	('GSTT1', 'Gene', (124, 129))
397573	31281468	The inclusion criteria in our meta-analysis were as follows: (1) GIC patients including CRC, GC and EAC patients; (2) GSTP1 IIe105Val variant, GSTP1 expression condition (high and low), and GSTM1/GSTT1 (null /present) variants information; (3) at least having one clinical indicator (ORR, OS, TTP and PFS, ORs and HRs with corresponding to 95% CIs); (4) treatments with chemotherapy details.	('GSTM1', 'Gene', (190, 195))	('variant', 'Var', (134, 141))	('OS', 'Chemical', '-', (289, 291))	('GSTP1', 'Gene', '2950', (118, 123))	('GSTP1', 'Gene', (143, 148))	('CRC', 'Disease', (88, 91))	('GSTT1', 'Gene', '2952', (196, 201))	('GSTP1', 'Gene', '2950', (143, 148))	('GSTT1', 'Gene', (196, 201))	('patients', 'Species', '9606', (69, 77))	('GSTP1', 'Gene', (118, 123))	('patients', 'Species', '9606', (104, 112))	('Val', 'Chemical', 'MESH:D014633', (130, 133))	('GSTM1', 'Gene', '2944', (190, 195))	('variants', 'Var', (218, 226))
397576	31281468	Among them, there were four studies involving in the GSTP1 expression and the chemotherapy efficacy in 264 GIC patients; forty-six studies were enrolled in the meta-analysis of glutathione S-transferase variants (GSTP1 Ile105Val, GSTM1/ GSTT1 null/present) and chemotherapy efficacy in 6254 GIC patients.	('GSTP1', 'Gene', '2950', (213, 218))	('glutathione S-transferase', 'Gene', '373156', (177, 202))	('GSTP1', 'Gene', '2950', (53, 58))	('GSTP1', 'Gene', (213, 218))	('Ile105Val', 'Mutation', 'rs1695', (219, 228))	('GSTM1', 'Gene', '2944', (230, 235))	('patients', 'Species', '9606', (295, 303))	('patients', 'Species', '9606', (111, 119))	('null/present', 'NegReg', (243, 255))	('GSTT1', 'Gene', '2952', (237, 242))	('GSTT1', 'Gene', (237, 242))	('GSTM1', 'Gene', (230, 235))	('Ile105Val', 'Var', (219, 228))	('glutathione S-transferase', 'Gene', (177, 202))	('GSTP1', 'Gene', (53, 58))
397577	31281468	Forty-six studies including 6254 patients were selected in investigation about GSTP1 Ile105Val; 2408 patients in 17 studies were selected in meta-analysis about GSTM1 null/present variant; and meta-analysis about GSTT1 null/present variant has 17 studies, including 2414 patients.	('patients', 'Species', '9606', (101, 109))	('Ile105Val', 'Mutation', 'rs1695', (85, 94))	('patients', 'Species', '9606', (33, 41))	('GSTP1', 'Gene', (79, 84))	('GSTT1', 'Gene', '2952', (213, 218))	('GSTM1', 'Gene', '2944', (161, 166))	('GSTT1', 'Gene', (213, 218))	('GSTM1', 'Gene', (161, 166))	('Ile105Val', 'Var', (85, 94))	('patients', 'Species', '9606', (271, 279))	('GSTP1', 'Gene', '2950', (79, 84))
397582	31281468	ORR of GIC patients harboring GSTP1 Ile105Val variants was different (Val carriers vs. IIe/IIe: OR=1.58(1.159-2.154), P=0.004).	('Ile105Val', 'Mutation', 'rs1695', (36, 45))	('GSTP1', 'Gene', (30, 35))	('Val', 'Chemical', 'MESH:D014633', (42, 45))	('Val', 'Chemical', 'MESH:D014633', (70, 73))	('Ile105Val', 'Var', (36, 45))	('GSTP1', 'Gene', '2950', (30, 35))	('patients', 'Species', '9606', (11, 19))
397585	31281468	Compared with Asian GIC patients harboring GSTP1 Val105Val genotypic patients, IIe105IIe genotype or IIe carriers have lower ORR (OR=3.400(1.521-7.599), P=0.003; OR=3.466 (1.610-7.463), P=0.001, separately, Table 2).	('GSTP1', 'Gene', (43, 48))	('Val', 'Chemical', 'MESH:D014633', (49, 52))	('Val', 'Chemical', 'MESH:D014633', (55, 58))	('lower', 'NegReg', (119, 124))	('patients', 'Species', '9606', (69, 77))	('GSTP1', 'Gene', '2950', (43, 48))	('patients', 'Species', '9606', (24, 32))	('ORR', 'MPA', (125, 128))	('IIe105IIe', 'Var', (79, 88))
397591	31281468	The HRs of PFS in GC or CRC patients harboring different Ile105Val genotypes was different (Val carriers vs. IIe/IIe: HR= 1.509(1.059-2.150), P=0.023; HR= 0.420(0.247-0.715), P=0.001, respectively, Table 3, Figure 3b).	('Val', 'Chemical', 'MESH:D014633', (63, 66))	('Ile105Val', 'Var', (57, 66))	('Val', 'Chemical', 'MESH:D014633', (92, 95))	('patients', 'Species', '9606', (28, 36))	('CRC', 'Disease', (24, 27))	('Ile105Val', 'Mutation', 'rs1695', (57, 66))
397592	31281468	In order to compare TTP in GIC patients with different GSTP1 Ile105Val variants, four publications including 349 patients were enrolled and found no association between Val carriers and IIe/IIe patients (HR= 0.961(0.356-2.591), P=0.937).	('Ile105Val', 'Mutation', 'rs1695', (61, 70))	('patients', 'Species', '9606', (194, 202))	('Val', 'Chemical', 'MESH:D014633', (169, 172))	('patients', 'Species', '9606', (113, 121))	('Val', 'Chemical', 'MESH:D014633', (67, 70))	('Ile105Val', 'Var', (61, 70))	('GSTP1', 'Gene', (55, 60))	('patients', 'Species', '9606', (31, 39))	('GSTP1', 'Gene', '2950', (55, 60))
397594	31281468	For comparing ORR in GSTT1 null/present patients, 10 publications including 1104 patients' data showed positive result between GSTT1 null and present patients (OR= 0.657(0.489-0.883), P=0.005).	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (81, 89))	('GSTT1', 'Gene', (21, 26))	('GSTT1', 'Gene', (127, 132))	('patients', 'Species', '9606', (150, 158))	('GSTT1', 'Gene', '2952', (21, 26))	('GSTT1', 'Gene', '2952', (127, 132))	('null', 'Var', (133, 137))
397595	31281468	Ethnicity- and tumor type-subgroup analyses suggested that, for the Caucasian group, GSTT1 null/present was associated with ORR (OR= 0.530(0.356-0.789), P=0.002); for GC patients, GSTT1 null/present was associated with ORR (OR=0.643(0.463-0.895), P=0.009) (Table 2, Figure 3c, 3d).	('ORR', 'Disease', (124, 127))	('patients', 'Species', '9606', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('GSTT1', 'Gene', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('GSTT1', 'Gene', '2952', (85, 90))	('tumor', 'Disease', (15, 20))	('GSTT1', 'Gene', (180, 185))	('ORR', 'Disease', (219, 222))	('GSTT1', 'Gene', '2952', (180, 185))	('null/present', 'Var', (91, 103))	('null/present', 'Var', (186, 198))
397596	31281468	Our meta-analysis about comparing the ORRs in GSTM1 null/present patients included 10 literatures with 1102 patients.	('GSTM1', 'Gene', '2944', (46, 51))	('GSTM1', 'Gene', (46, 51))	('patients', 'Species', '9606', (65, 73))	('null/present', 'Var', (52, 64))	('patients', 'Species', '9606', (108, 116))
397597	31281468	No association was found between patients harboring GSTM1 null/present variant and ORRs in GIC patients (OR=1.120 (0.872-1.440), P= 0.375).	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (95, 103))	('ORRs', 'Disease', (83, 87))	('null/present', 'Var', (58, 70))	('GSTM1', 'Gene', '2944', (52, 57))	('GSTM1', 'Gene', (52, 57))
397599	31281468	We compared the pooling OS in GSTM1 null/present genotypic patients using 7 publications including 892 patients' data, no statistically significant associations were found in GSTM1 null/present genotypic patients (HR= 1.001(0.862-1.163), P=0.992).	('patients', 'Species', '9606', (204, 212))	('OS', 'Chemical', '-', (24, 26))	('null/present', 'Var', (181, 193))	('GSTM1', 'Gene', '2944', (30, 35))	('GSTM1', 'Gene', '2944', (175, 180))	('GSTM1', 'Gene', (30, 35))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (103, 111))	('GSTM1', 'Gene', (175, 180))
397600	31281468	No significant difference of OS was found between different GSTM1 null/present variant patients (Table 3).	('OS', 'Chemical', '-', (29, 31))	('GSTM1', 'Gene', '2944', (60, 65))	('GSTM1', 'Gene', (60, 65))	('null/present variant', 'Var', (66, 86))	('patients', 'Species', '9606', (87, 95))	('variant', 'Var', (79, 86))
397601	31281468	We compared the pooling PFS in GSTM1 null/present genotypic patients using five publications including 996 patients' data and found no significant association (HR= 0.957(0.823-1.114), P=0.572).	('null/present', 'Var', (37, 49))	('GSTM1', 'Gene', (31, 36))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (107, 115))	('GSTM1', 'Gene', '2944', (31, 36))
397603	31281468	We compared the pooled OS and PFS in GSTT1 null/present genotypic patients using 8 publications including 1366 patients' data and found no significant associations (null vs. present: HR= 1.104(0.889-1.370), P=0.371; HR= 1.102(0.918-1.322), P=0.299, respectively).	('GSTT1', 'Gene', '2952', (37, 42))	('GSTT1', 'Gene', (37, 42))	('null/present', 'Var', (43, 55))	('OS', 'Chemical', '-', (23, 25))	('patients', 'Species', '9606', (66, 74))	('patients', 'Species', '9606', (111, 119))
397606	31281468	Sensitivity analysis found that the OR and HR of every enrolled study didn't influence the final significant associations between GSTP1, GSTM1 and GSTT1 variants and chemotherapy efficacy in GIC patients (Figure S1), except the relationship between GSTP1 (IIe105Val) Val carriers vs. IIe/IIe model and the pooled HRs of PFS, which was just two literatures enrolled in tumor type-subgroup analysis.	('GSTP1', 'Gene', (130, 135))	('tumor', 'Disease', (368, 373))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('Val', 'Chemical', 'MESH:D014633', (262, 265))	('chemotherapy efficacy', 'CPA', (166, 187))	('GSTP1', 'Gene', '2950', (249, 254))	('GSTT1', 'Gene', '2952', (147, 152))	('GSTM1', 'Gene', '2944', (137, 142))	('Val', 'Chemical', 'MESH:D014633', (267, 270))	('GSTT1', 'Gene', (147, 152))	('GSTP1', 'Gene', '2950', (130, 135))	('patients', 'Species', '9606', (195, 203))	('variants', 'Var', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('GSTM1', 'Gene', (137, 142))	('GSTP1', 'Gene', (249, 254))
397608	31281468	It implies that the associations between GSTP1 Val/Val vs. IIe/IIe, Val/Val vs. IIe carriers and the ORR of GIC Asian patients were not robust.	('Val', 'Chemical', 'MESH:D014633', (51, 54))	('Val', 'Chemical', 'MESH:D014633', (72, 75))	('GSTP1', 'Gene', (41, 46))	('Val/Val', 'Var', (47, 54))	('Val', 'Chemical', 'MESH:D014633', (68, 71))	('Val', 'Chemical', 'MESH:D014633', (47, 50))	('patients', 'Species', '9606', (118, 126))	('GSTP1', 'Gene', '2950', (41, 46))
397609	31281468	As shown in Figure S3, Begg's and Egger's funnel plots found no publications bias under GSTP1 (IIe105Val) any genetic models (all P>0.05, Figure S4), and under GSTT1/GSTM1 (null/present) variants (GSTT1: P=0.788, P=0.247, GSTM1: P=0.421, P=0.272, respectively, Figure S5).	('GSTT1', 'Gene', (160, 165))	('GSTM1', 'Gene', (166, 171))	('GSTT1', 'Gene', (197, 202))	('GSTT1', 'Gene', '2952', (160, 165))	('GSTM1', 'Gene', '2944', (222, 227))	('GSTT1', 'Gene', '2952', (197, 202))	('GSTM1', 'Gene', (222, 227))	('GSTP1', 'Gene', '2950', (88, 93))	('Val', 'Chemical', 'MESH:D014633', (101, 104))	('variants', 'Var', (187, 195))	('GSTM1', 'Gene', '2944', (166, 171))	('GSTP1', 'Gene', (88, 93))
397611	31281468	We performed a meta-analysis to investigate the association between glutathione S-transferase gene (GSTP1 (Ile105Val), GSTM1/GSTT1 (null/present) variants and GSTP1 expression and clinical outcomes in patients with GIC.	('GSTP1', 'Gene', '2950', (100, 105))	('GSTP1', 'Gene', '2950', (159, 164))	('patients', 'Species', '9606', (201, 209))	('glutathione S-transferase', 'Gene', (68, 93))	('glutathione S-transferase', 'Gene', '373156', (68, 93))	('GSTM1', 'Gene', '2944', (119, 124))	('GSTP1', 'Gene', (100, 105))	('GSTP1', 'Gene', (159, 164))	('variants', 'Var', (146, 154))	('Ile105Val', 'Mutation', 'rs1695', (107, 116))	('GSTM1', 'Gene', (119, 124))	('GSTT1', 'Gene', (125, 130))	('GSTT1', 'Gene', '2952', (125, 130))
397613	31281468	Caucasian GIC patients carrying the GSTP1 Val/Val genotype, especially those with stomach disease, have better chemotherapy efficacy than patients with IIe carriers.	('chemotherapy efficacy', 'CPA', (111, 132))	('Val', 'Chemical', 'MESH:D014633', (42, 45))	('stomach disease', 'Disease', (82, 97))	('GSTP1', 'Gene', '2950', (36, 41))	('Val', 'Chemical', 'MESH:D014633', (46, 49))	('better', 'PosReg', (104, 110))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (138, 146))	('GSTP1', 'Gene', (36, 41))	('Val/Val', 'Var', (42, 49))
397614	31281468	Caucasian GIC patients bearing IIe/Val genotype have longer survival time than patients with IIe/IIe genotype.	('Val', 'Chemical', 'MESH:D014633', (35, 38))	('patients', 'Species', '9606', (79, 87))	('patients', 'Species', '9606', (14, 22))	('IIe/Val', 'Var', (31, 38))	('longer', 'PosReg', (53, 59))	('survival time', 'CPA', (60, 73))
397617	31281468	We found that GSTP1 IIe105Val and GSTT1 null/present polymorphisms could predict chemotherapy efficacy in GIC patients.	('predict', 'Reg', (73, 80))	('IIe105Val', 'Var', (20, 29))	('GSTP1', 'Gene', (14, 19))	('GSTT1', 'Gene', (34, 39))	('GSTT1', 'Gene', '2952', (34, 39))	('Val', 'Chemical', 'MESH:D014633', (26, 29))	('chemotherapy efficacy', 'CPA', (81, 102))	('GSTP1', 'Gene', '2950', (14, 19))	('patients', 'Species', '9606', (110, 118))
397621	31281468	Previous studies suggested that variants in GSTP1, GSTM1, GSTT1, XPCC1, MTHFR, TYMS and ABCC2 influence the chemotherapy efficacy in GC or/and CRC patients.	('ABCC2', 'Gene', (88, 93))	('GSTM1', 'Gene', (51, 56))	('GSTP1', 'Gene', (44, 49))	('TYMS', 'Gene', (79, 83))	('XPCC1', 'Gene', (65, 70))	('ABCC2', 'Gene', '1244', (88, 93))	('chemotherapy efficacy', 'CPA', (108, 129))	('MTHFR', 'Gene', '4524', (72, 77))	('GSTT1', 'Gene', '2952', (58, 63))	('patients', 'Species', '9606', (147, 155))	('GSTT1', 'Gene', (58, 63))	('CRC', 'Disease', (143, 146))	('variants', 'Var', (32, 40))	('GSTP1', 'Gene', '2950', (44, 49))	('TYMS', 'Gene', '7298', (79, 83))	('influence', 'Reg', (94, 103))	('MTHFR', 'Gene', (72, 77))	('GSTM1', 'Gene', '2944', (51, 56))
397623	31281468	GSTP1 IIe105Val and GSTM1/GSTT1 (null/present) polymorphisms decrease enzyme activity, resulting in the lower intracellular concentration of drugs such as cisplatin.	('enzyme activity', 'MPA', (70, 85))	('polymorphisms', 'Var', (47, 60))	('GSTP1', 'Gene', (0, 5))	('decrease', 'NegReg', (61, 69))	('GSTT1', 'Gene', '2952', (26, 31))	('GSTT1', 'Gene', (26, 31))	('IIe105Val', 'Var', (6, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('Val', 'Chemical', 'MESH:D014633', (12, 15))	('lower', 'NegReg', (104, 109))	('GSTM1', 'Gene', '2944', (20, 25))	('GSTM1', 'Gene', (20, 25))	('GSTP1', 'Gene', '2950', (0, 5))	('intracellular concentration of drugs', 'MPA', (110, 146))
397624	31281468	Therefore, patients harboring GSTP1 IIe105Val mutant variants may reduce the ability to detoxify drug metabolites, and then have better chemotherapy efficacy.	('GSTP1', 'Gene', (30, 35))	('IIe105Val mutant', 'Var', (36, 52))	('better', 'PosReg', (129, 135))	('Val', 'Chemical', 'MESH:D014633', (42, 45))	('ability to detoxify drug metabolites', 'MPA', (77, 113))	('GSTP1', 'Gene', '2950', (30, 35))	('chemotherapy efficacy', 'CPA', (136, 157))	('reduce', 'NegReg', (66, 72))	('patients', 'Species', '9606', (11, 19))
397625	31281468	Our meta-analysis showed that the GSTP1 IIe105Val variant was associated with ORR of GIC patients (Table 2, Figure 2a, 2b).	('associated', 'Reg', (62, 72))	('ORR of GIC patients', 'Disease', (78, 97))	('GSTP1', 'Gene', (34, 39))	('Val', 'Chemical', 'MESH:D014633', (46, 49))	('patients', 'Species', '9606', (89, 97))	('GSTP1', 'Gene', '2950', (34, 39))	('IIe105Val', 'Var', (40, 49))
397626	31281468	We also carried out heterogeneity analysis and we found significant heterogeneity when pooling the ORs of ORR in different GSTP1 IIe105Val variant patients, so we used the Mantel-Haenszel random model to analyze the associations.	('GSTP1', 'Gene', (123, 128))	('Val', 'Chemical', 'MESH:D014633', (135, 138))	('patients', 'Species', '9606', (147, 155))	('GSTP1', 'Gene', '2950', (123, 128))	('IIe105Val', 'Var', (129, 138))
397630	31281468	The subgroup-analysis also supported the significant association between GSTP1 IIe105Val and chemotherapy efficacy in GC and EC patients, or Caucasian GIC patients under dominant genetic model (Table 2, Table S3).	('chemotherapy efficacy', 'CPA', (93, 114))	('GSTP1', 'Gene', '2950', (73, 78))	('IIe105Val', 'Var', (79, 88))	('Val', 'Chemical', 'MESH:D014633', (85, 88))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (128, 136))	('GSTP1', 'Gene', (73, 78))
397632	31281468	The study-type subgroup analysis showed prospective study groups have no difference between GSTP1 Val carriers vs. IIe/IIe and ORR of chemotherapy in GIC patients.	('patients', 'Species', '9606', (154, 162))	('GSTP1', 'Gene', '2950', (92, 97))	('Val', 'Chemical', 'MESH:D014633', (98, 101))	('Val carriers', 'Var', (98, 110))	('GSTP1', 'Gene', (92, 97))
397634	31281468	Compared with Asian GIC patients harboring GSTP1 IIe105IIe genotypes, Val105Val genotypic patients have better response rates to chemotherapy under the fixed model (OR=3.400(1.521-7.599), P=0.003, Table 2).	('GSTP1', 'Gene', (43, 48))	('Val', 'Chemical', 'MESH:D014633', (70, 73))	('Val', 'Chemical', 'MESH:D014633', (76, 79))	('Val105Val', 'Var', (70, 79))	('response rates', 'CPA', (111, 125))	('better', 'PosReg', (104, 110))	('GSTP1', 'Gene', '2950', (43, 48))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (90, 98))
397635	31281468	Compared with GIC patients harboring GSTP1 IIe carriers, Val105Val genotypic patients have better chemotherapy efficacy (Figure 2).	('better', 'PosReg', (91, 97))	('Val', 'Chemical', 'MESH:D014633', (63, 66))	('GSTP1', 'Gene', '2950', (37, 42))	('patients', 'Species', '9606', (77, 85))	('chemotherapy efficacy', 'CPA', (98, 119))	('patients', 'Species', '9606', (18, 26))	('GSTP1', 'Gene', (37, 42))	('Val', 'Chemical', 'MESH:D014633', (57, 60))	('Val105Val', 'Var', (57, 66))
397636	31281468	While changing the analytical models could change the significant association of GSTP1 variants (Val/Val vs. IIe carriers) and ORR in Asian GIC patients (Figure S2).	('ORR', 'MPA', (127, 130))	('association', 'Interaction', (66, 77))	('variants', 'Var', (87, 95))	('Val', 'Chemical', 'MESH:D014633', (97, 100))	('Val', 'Chemical', 'MESH:D014633', (101, 104))	('GSTP1', 'Gene', '2950', (81, 86))	('patients', 'Species', '9606', (144, 152))	('change', 'Reg', (43, 49))	('GSTP1', 'Gene', (81, 86))
397637	31281468	Tumor type-subgroup analysis showed that, compared with IIe carriers variants, GC patients harboring Val/Val variant, not CRC patients, have better chemotherapy efficacy (Figure 2c, 2d).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('chemotherapy efficacy', 'CPA', (148, 169))	('variant', 'Var', (109, 116))	('patients', 'Species', '9606', (82, 90))	('Val/Val variant', 'Var', (101, 116))	('better', 'PosReg', (141, 147))	('Val', 'Chemical', 'MESH:D014633', (101, 104))	('Val', 'Chemical', 'MESH:D014633', (105, 108))	('patients', 'Species', '9606', (126, 134))
397638	31281468	Therefore, tumor types and ethnicity both influence the meta-analysis results about GSTP1 variants (Val/Val vs. IIe carriers) and ORR of GIC patients.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Val', 'Chemical', 'MESH:D014633', (104, 107))	('GSTP1', 'Gene', '2950', (84, 89))	('tumor', 'Disease', (11, 16))	('variants', 'Var', (90, 98))	('influence', 'Reg', (42, 51))	('GSTP1', 'Gene', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('patients', 'Species', '9606', (141, 149))	('Val', 'Chemical', 'MESH:D014633', (100, 103))
397644	31281468	Subgroup analysis with tumor types showed GSTT1 null/present variant associated with ORR in GC patients (OR= 0.643(0.463-0.895), P=0.009, Table 2, Figure 3c, 3d).	('patients', 'Species', '9606', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('associated', 'Reg', (69, 79))	('ORR', 'Disease', (85, 88))	('variant', 'Var', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('GSTT1', 'Gene', '2952', (42, 47))	('GSTT1', 'Gene', (42, 47))	('null/present variant', 'Var', (48, 68))	('tumor', 'Disease', (23, 28))
397646	31281468	Our results were consistent with previous meta-analyses, which was just enrolled seven literatures about the GSTT1 null/present variant and the ORs of ORR in GC patients.	('variant', 'Var', (128, 135))	('GSTT1', 'Gene', (109, 114))	('GSTT1', 'Gene', '2952', (109, 114))	('patients', 'Species', '9606', (161, 169))	('null/present variant', 'Var', (115, 135))
397647	31281468	There were heterogeneities when we pooled ORs or HRs of ORR, OS, PFS and TTP in patients harboring GSTP1 IIe105Val different variants (Table 2, Table 3).	('IIe105Val', 'Var', (105, 114))	('GSTP1', 'Gene', (99, 104))	('patients', 'Species', '9606', (80, 88))	('Val', 'Chemical', 'MESH:D014633', (111, 114))	('GSTP1', 'Gene', '2950', (99, 104))	('OS', 'Chemical', '-', (61, 63))
397648	31281468	Previously, there were four meta-analyses involved in Glutathione S-transferases genes' variants and chemotherapy efficacy in CRC or GC patients.	('CRC', 'Disease', (126, 129))	('patients', 'Species', '9606', (136, 144))	('Glutathione S-transferases', 'Gene', (54, 80))	('Glutathione S-transferases', 'Gene', '373156', (54, 80))	('variants', 'Var', (88, 96))
397651	31281468	Therefore, we systematically analyzed all available literatures related to GSTP1 expression levels and GSTP1 IIe105Val, GSTM1/GSTT1 deletion variants and chemotherapy efficacy in GIC patients.	('IIe105Val', 'Var', (109, 118))	('GSTT1', 'Gene', (126, 131))	('GSTM1', 'Gene', '2944', (120, 125))	('GSTT1', 'Gene', '2952', (126, 131))	('Val', 'Chemical', 'MESH:D014633', (115, 118))	('GSTP1', 'Gene', '2950', (75, 80))	('GSTP1', 'Gene', (103, 108))	('GSTM1', 'Gene', (120, 125))	('patients', 'Species', '9606', (183, 191))	('GSTP1', 'Gene', '2950', (103, 108))	('deletion variants', 'Var', (132, 149))	('GSTP1', 'Gene', (75, 80))
397655	31281468	We found that GSTP1 IIe105Val and GSTT1 deletion variants were associated with chemotherapy efficacy in gastrointestinal cancer patients.	('chemotherapy efficacy', 'CPA', (79, 100))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (104, 127))	('deletion', 'Var', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('IIe105Val', 'Var', (20, 29))	('associated', 'Reg', (63, 73))	('GSTP1', 'Gene', (14, 19))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (104, 127))	('GSTT1', 'Gene', (34, 39))	('GSTT1', 'Gene', '2952', (34, 39))	('Val', 'Chemical', 'MESH:D014633', (26, 29))	('patients', 'Species', '9606', (128, 136))	('gastrointestinal cancer', 'Disease', (104, 127))	('GSTP1', 'Gene', '2950', (14, 19))
397728	30479836	Esophageal carcinoma can metastasize to the brain, thus the absence of multifocal CNS involvement outside the eye may have been due to 5-FU and its ability to cross the blood-brain-barrier (BBB) yet it might not reach therapeutic levels in the retina.	('Esophageal carcinoma', 'Disease', (0, 20))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (0, 20))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (0, 20))	('5-FU', 'Var', (135, 139))	('5-FU', 'Chemical', 'MESH:D005472', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
397741	29375376	The overexpression or silencing of miR-203a-3p was performed to test its anti-proliferative effects.	('miR-203a', 'Gene', (35, 43))	('silencing', 'Var', (22, 31))	('miR-203a', 'Gene', '406986', (35, 43))
397747	29375376	Additionally, overexpression and silencing of miR-203a-3p in BE cells disrupted cell cycle progress, resulting in suppressing and accelerating cell proliferation, respectively.	('accelerating', 'PosReg', (130, 142))	('cell proliferation', 'CPA', (143, 161))	('silencing', 'Var', (33, 42))	('BE', 'Phenotype', 'HP:0100580', (61, 63))	('miR-203a', 'Gene', (46, 54))	('miR-203a', 'Gene', '406986', (46, 54))	('suppressing', 'NegReg', (114, 125))	('cell cycle progress', 'CPA', (80, 99))	('disrupted', 'NegReg', (70, 79))
397748	29375376	Taken together, these data provide a novel mechanism of potentially anti-neoplastic effects for omeprazole through modulation of miR-203a-3p expression and thus suppressing Hh/Gli1 signaling in BE cells.	('miR-203a', 'Gene', (129, 137))	('miR-203a', 'Gene', '406986', (129, 137))	('Hh/Gli1 signaling', 'MPA', (173, 190))	('omeprazole', 'Chemical', 'MESH:D009853', (96, 106))	('modulation', 'Var', (115, 125))	('suppressing', 'NegReg', (161, 172))	('BE', 'Phenotype', 'HP:0100580', (194, 196))	('expression', 'MPA', (141, 151))
397753	29375376	In addition to targeting the gastric acid pump, PPIs may inhibit vacuolar-type H+ ATPase (V-ATPase) activity to affect cancer cells homeostasis and counter the malignant behavior of cancer cells, including proliferation, migration, invasiveness and drug resistance.	('PPIs', 'Var', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('invasiveness', 'Disease', (232, 244))	('proliferation', 'CPA', (206, 219))	('migration', 'CPA', (221, 230))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('inhibit', 'NegReg', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (119, 125))	('affect', 'Reg', (112, 118))	('cancer', 'Disease', (182, 188))	('drug resistance', 'Phenotype', 'HP:0020174', (249, 264))	('vacuolar-type', 'MPA', (65, 78))	('activity', 'MPA', (100, 108))	('drug resistance', 'CPA', (249, 264))	('invasiveness', 'Disease', 'MESH:D009362', (232, 244))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gastric acid pump', 'MPA', (29, 46))
397754	29375376	Moreover, several lines of evidence suggest that inhibition of proton pumps activity could deprive cancer cells of the acidic microenvironment, which in turn leads to cancer cell death.	('cancer cell death', 'Disease', 'MESH:D003643', (167, 184))	('leads to', 'Reg', (158, 166))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (167, 173))	('deprive', 'NegReg', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (99, 105))	('proton pump', 'Gene', (63, 74))	('cancer cell death', 'Disease', (167, 184))	('inhibition', 'Var', (49, 59))	('proton pump', 'Gene', '495', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('acidic microenvironment', 'MPA', (119, 142))
397762	29375376	Expression profiles of miRNAs in many cancer tissues have been elaborated, and it has been shown that dysregulated miRNA expression is a hallmark for tumor evolution and progression by regulating the expression of cancer-related genes.	('miR', 'Gene', '220972', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (214, 220))	('miR', 'Gene', (23, 26))	('miR', 'Gene', '220972', (115, 118))	('regulating', 'Reg', (185, 195))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('expression', 'MPA', (200, 210))	('cancer', 'Disease', (38, 44))	('tumor', 'Disease', (150, 155))	('dysregulated', 'Var', (102, 114))	('miR', 'Gene', (115, 118))
397771	29375376	Moreover, we determined Gli1 as a target gene of miR-203a-3p, and miR-203a-3p knockdown partially reversed the inhibitory function of omeprazole through up-regulating Hh/Gli1 expression.	('expression', 'MPA', (175, 185))	('up-regulating', 'PosReg', (153, 166))	('miR-203a', 'Gene', (49, 57))	('knockdown', 'Var', (78, 87))	('miR-203a', 'Gene', '406986', (49, 57))	('miR-203a', 'Gene', (66, 74))	('miR-203a', 'Gene', '406986', (66, 74))	('omeprazole', 'Chemical', 'MESH:D009853', (134, 144))	('inhibitory function', 'MPA', (111, 130))	('Hh/Gli1', 'Gene', (167, 174))
397787	29375376	The membranes were blocked with 5% skim milk for 2 h and subsequently incubated overnight at 4 C with anti-Smo (1:1000, Rabbit, Abnova), anti-Gli1 (1:1000, Rabbit, Cell Signaling Technology), anti-Gli2 (1:500, Rabbit, Cell Signaling Technology), anti-Sufu (1:1000, Rabbit, Cell Signaling Technology), anti-Ptch2 (1:1000, Rabbit, Cell Signaling Technology), anti-Cyclin D1 (1:1000, Rabbit, Cell Signaling Technology), anti-Cyclin A2 (1:1000, Mouse, Cell Signaling Technology), anti-CDK2 (1:1000, Rabbit, Cell Signaling Technology), anti-CDK4 (1:1000, Rabbit, Cell Signaling Technology), anti-CDK6 (1:1000, Mouse, Cell Signaling Technology), anti-P18 (1:1000, Mouse, Cell Signaling Technology), anti-P21 Waf1/Cip (1:1000, Rabbit, Cell Signaling Technology), anti-P27 Kip1 (1:1000, Rabbit, Cell Signaling Technology), anti-GAPDH (1:3000, Mouse, Santa Cruz) and anti-Lamin A/C (1:1000, Mouse, Abcam).	('Mouse', 'Species', '10090', (882, 887))	('Rabbit', 'Species', '9986', (550, 556))	('Rabbit', 'Species', '9986', (495, 501))	('Cyclin A2', 'Gene', (422, 431))	('Mouse', 'Species', '10090', (658, 663))	('Rabbit', 'Species', '9986', (120, 126))	('Rabbit', 'Species', '9986', (779, 785))	('anti-Lamin', 'Var', (858, 868))	('P27', 'Gene', '3429', (761, 764))	('P21 Waf1/Cip', 'Gene', (698, 710))	('Cyclin A2', 'Gene', '100134866', (422, 431))	('anti-GAPDH', 'Var', (815, 825))	('Rabbit', 'Species', '9986', (381, 387))	('Mouse', 'Species', '10090', (441, 446))	('P27', 'Gene', (761, 764))	('Rabbit', 'Species', '9986', (720, 726))	('Mouse', 'Species', '10090', (835, 840))	('Mouse', 'Species', '10090', (605, 610))	('Rabbit', 'Species', '9986', (156, 162))	('anti-P18', 'Var', (640, 648))	('Rabbit', 'Species', '9986', (321, 327))	('Rabbit', 'Species', '9986', (210, 216))	('P21 Waf1/Cip', 'Gene', '69642', (698, 710))	('Rabbit', 'Species', '9986', (265, 271))
397813	29375376	To investigate the responsiveness of miRNAs to omeprazole, we detected the miR-203a-3p expression after different concentrations of omeprazole treated with 0, 40, and 80 muM for 48 h. As shown in (Figure 2B), omeprazole significantly increased miR-203a-3p in both CP-A and CP-B cells, when compared with solvent only (negative controls).	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', '220972', (37, 40))	('miR-203a', 'Gene', (244, 252))	('CP-A', 'Gene', (264, 268))	('miR-203a', 'Gene', '406986', (244, 252))	('muM', 'Gene', '56925', (170, 173))	('miR', 'Gene', (244, 247))	('muM', 'Gene', (170, 173))	('increased', 'PosReg', (234, 243))	('miR', 'Gene', (75, 78))	('miR', 'Gene', (37, 40))	('CP-A', 'Gene', '1357', (264, 268))	('omeprazole', 'Chemical', 'MESH:D009853', (132, 142))	('CP-B', 'Gene', (273, 277))	('miR-203a', 'Gene', '406986', (75, 83))	('omeprazole', 'Chemical', 'MESH:D009853', (209, 219))	('miR-203a', 'Gene', (75, 83))	('omeprazole', 'Var', (209, 219))	('CP-B', 'Gene', '1360', (273, 277))	('miR', 'Gene', '220972', (244, 247))	('omeprazole', 'Chemical', 'MESH:D009853', (47, 57))
397823	29375376	To demonstrate that Gli1 expression is regulated directly by miR-203a-3p, we sub-cloned the Gli1 3'-UTR containing the miR-203a-3p binding sequences [wild type (WT) or mutant (MT)] into a pmir-Glo vector.	('miR-203a', 'Gene', '406986', (61, 69))	('mutant', 'Var', (168, 174))	('miR-203a', 'Gene', (61, 69))	('Gli1', 'Gene', (92, 96))	('miR-203a', 'Gene', (119, 127))	('miR-203a', 'Gene', '406986', (119, 127))
397838	29375376	Furthermore, the expression of cell cycle-related proteins, including cyclin D1, CDK2, CDK4, CDK6, cyclin A2, P18, P21Waf1/Cip1(P21) and P27KIP1(P27), was changed after omeprazole treatment for 48 h (Figure 3G).	('changed', 'Reg', (155, 162))	('P27', 'Gene', (137, 140))	('P21', 'Gene', '644914', (128, 131))	('expression', 'MPA', (17, 27))	('P21', 'Gene', (115, 118))	('Cip1', 'Gene', (123, 127))	('cyclin A2', 'Gene', (99, 108))	('P27KIP1', 'Gene', (137, 144))	('CDK2', 'Gene', (81, 85))	('P21', 'Gene', (128, 131))	('cyclin D1', 'Gene', (70, 79))	('omeprazole', 'Chemical', 'MESH:D009853', (169, 179))	('P27', 'Gene', '3429', (145, 148))	('P27KIP1', 'Gene', '1027', (137, 144))	('CDK6', 'Gene', (93, 97))	('cyclin A2', 'Gene', '890', (99, 108))	('CDK4', 'Gene', (87, 91))	('P18', 'Var', (110, 113))	('cyclin D1', 'Gene', '595', (70, 79))	('Cip1', 'Gene', '1026', (123, 127))	('P27', 'Gene', '3429', (137, 140))	('P27', 'Gene', (145, 148))	('P21', 'Gene', '644914', (115, 118))
397842	29375376	On the contrary, silencing of miR-203a-3p generated a significantly higher proliferating rate than that of control transfected cells (Figures 3C,D).	('miR-203a', 'Gene', (30, 38))	('proliferating rate', 'CPA', (75, 93))	('miR-203a', 'Gene', '406986', (30, 38))	('higher', 'PosReg', (68, 74))	('silencing', 'Var', (17, 26))
397868	29375376	In addition, previous reports pointed out that Gli1 knockdown could suppress cancer cell growth, invasion, colony formation and induce cell cycle arrest, which further validates Gli1 as an oncogene.	('colony formation', 'CPA', (107, 123))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('knockdown', 'Var', (52, 61))	('induce', 'Reg', (128, 134))	('cell cycle arrest', 'CPA', (135, 152))	('suppress', 'NegReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Gli1', 'Gene', (47, 51))	('invasion', 'CPA', (97, 105))
397887	26380553	A classic use of a genetically engineered mouse in studying cancer is through the overexpression or deletion of a gene.	('mouse', 'Species', '10090', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('overexpression', 'PosReg', (82, 96))	('deletion', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
397896	26380553	A single genetic alteration may lead to a lower tumor penetrance in mice, lower metastatic rates in mice than is typically seen in humans, or no phenotype at all.	('humans', 'Species', '9606', (131, 137))	('mice', 'Species', '10090', (68, 72))	('tumor', 'Disease', (48, 53))	('rat', 'Species', '10116', (91, 94))	('lower', 'NegReg', (42, 47))	('mice', 'Species', '10090', (100, 104))	('alteration', 'Var', (17, 27))	('rat', 'Species', '10116', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('lower', 'NegReg', (74, 79))	('metastatic rates', 'CPA', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
397899	26380553	For example, CHD5 is a tumor suppressor gene at human 1p36, a common deletion in cancers of epithelial, neural, and hematopoietic origin.	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('human', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('deletion', 'Var', (69, 77))	('CHD5', 'Gene', (13, 17))	('tumor', 'Disease', (23, 28))
397916	26380553	Since c-myc and H-ras are both overexpressed in human breast cancer, the same group then went on to pair c-myc with H-ras; they demonstrated that, in comparison to mice expressing H-ras alone in which H-ras is not sufficient for full malignant transformation, the combination of c-myc and H-ras expression together in the same animals is highly carcinogenic.	('breast cancer', 'Disease', (54, 67))	('c-myc', 'Gene', '4609', (6, 11))	('c-myc', 'Gene', (6, 11))	('rat', 'Species', '10116', (135, 138))	('c-myc', 'Gene', '4609', (279, 284))	('mice', 'Species', '10090', (164, 168))	('human', 'Species', '9606', (48, 53))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('combination', 'Var', (264, 275))	('c-myc', 'Gene', (279, 284))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('c-myc', 'Gene', '4609', (105, 110))	('carcinogenic', 'Disease', 'MESH:D063646', (345, 357))	('c-myc', 'Gene', (105, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('carcinogenic', 'Disease', (345, 357))
397920	26380553	Many of these studies focus on gain-of-function mutations in oncogenes or loss-of-function mutations in tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('mutations', 'Var', (91, 100))	('oncogenes', 'Protein', (61, 70))	('gain-of-function', 'PosReg', (31, 47))	('loss-of-function', 'NegReg', (74, 90))	('mutations', 'Var', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
397933	26380553	The combination of ErbB2 and p53 mutation causes accelerated development of mammary tumors, occurring in the mice around 5 months of age.	('mammary tumors', 'Disease', 'MESH:D001943', (76, 90))	('mutation', 'Var', (33, 41))	('mammary tumors', 'Disease', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('p53', 'Gene', (29, 32))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mice', 'Species', '10090', (109, 113))	('rat', 'Species', '10116', (55, 58))	('accelerated', 'PosReg', (49, 60))	('ErbB2', 'Gene', (19, 24))
397937	26380553	In contrast to many single-gene mouse models of breast cancer, expression of PyMT resulted in transformation of the mammary epithelium.	('transformation', 'CPA', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('PyMT', 'Gene', (77, 81))	('resulted in', 'Reg', (82, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('mouse', 'Species', '10090', (32, 37))	('expression', 'Var', (63, 73))
397942	26380553	For example, loss of the type II transforming growth factor-beta receptor (Tgfbr2) in the context of PyMT expression (MMTV-PyVmT/Tgfbr2MGKO) results in a shortened median tumor latency and an increase in the number and size of lung metastases.	('lung metastases', 'Disease', 'MESH:D009362', (227, 242))	('Tgfbr2', 'Gene', '21813', (129, 135))	('shortened', 'NegReg', (154, 163))	('MMTV', 'Species', '11757', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('Tgfbr2', 'Gene', (75, 81))	('Tgfbr2', 'Gene', (129, 135))	('increase', 'PosReg', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('loss', 'Var', (13, 17))	('Tgfbr2', 'Gene', '21813', (75, 81))	('lung metastases', 'Disease', (227, 242))
397954	26380553	The occurrence of c-myc amplification and PI3K pathway alterations together have previously been implicated through examination of human prostate tumors.	('c-myc', 'Gene', '4609', (18, 23))	('alterations', 'Var', (55, 66))	('implicated', 'Reg', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('c-myc', 'Gene', (18, 23))	('prostate tumors', 'Disease', (137, 152))	('human', 'Species', '9606', (131, 136))	('rat', 'Species', '10116', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('prostate tumors', 'Disease', 'MESH:D011471', (137, 152))	('PI3K pathway', 'Pathway', (42, 54))
397956	26380553	Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deletion is one of the most frequent genetic alterations in human prostate cancer.	('human', 'Species', '9606', (123, 128))	('prostate cancer', 'Disease', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('PTEN', 'Gene', (57, 61))	('rat', 'Species', '10116', (112, 115))	('deletion', 'Var', (63, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (129, 144))	('prostate cancer', 'Phenotype', 'HP:0012125', (129, 144))
397959	26380553	In an effort to study PTEN, mutation of the gene has been combined with the manipulation of other tumor suppressors, including Ink4a/Arf.	('Ink4a/Arf', 'Gene', '12578', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('Ink4a/Arf', 'Gene', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutation', 'Var', (28, 36))	('tumor', 'Disease', (98, 103))
397965	26380553	Zhou et al (2006) created single gene transgenic models of either p53 or Rb inactivation in the prostate epithelium.	('inactivation', 'Var', (76, 88))	('transgenic', 'Species', '10090', (38, 48))	('Rb', 'Phenotype', 'HP:0009919', (73, 75))	('Rb', 'Gene', '5925', (73, 75))	('p53', 'Gene', (66, 69))
397977	26380553	K-ras and p53 mutations are less commonly found to be associated in lung cancer, though Ink4a/Arf methylation has been associated with K-ras mutations in human lung cancer.	('associated', 'Reg', (119, 129))	('lung cancer', 'Disease', (68, 79))	('human', 'Species', '9606', (154, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('mutations', 'Var', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('p53', 'Gene', (10, 13))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('Ink4a/Arf', 'Gene', '12578', (88, 97))	('lung cancer', 'Disease', (160, 171))	('Ink4a/Arf', 'Gene', (88, 97))
397988	26380553	Therefore, further development of lung cancer GEMMs manipulating these genes in combination is important in gaining a model that is histologically and molecularly similar to human disease.	('human', 'Species', '9606', (174, 179))	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('manipulating', 'Var', (52, 64))
397990	26380553	Studies comparing human tumor tissue and normal tissue have highlighted the various key mutations that are commonly involved in colorectal tumorigenesis; this has been the key in the development of genetically engineered mouse models of colorectal cancer.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('involved', 'Reg', (116, 124))	('tumor', 'Disease', (24, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (237, 254))	('human', 'Species', '9606', (18, 23))	('mutations', 'Var', (88, 97))	('mouse', 'Species', '10090', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('colorectal cancer', 'Disease', (237, 254))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (237, 254))
397992	26380553	Apc and Wnt signaling is aberrantly activated by mutation in 90% of human colorectal cancer.	('human', 'Species', '9606', (68, 73))	('Apc', 'Phenotype', 'HP:0005227', (0, 3))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('activated', 'PosReg', (36, 45))	('mutation', 'Var', (49, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colorectal cancer', 'Disease', (74, 91))
397993	26380553	The first Apc mouse developed and the most widely used of Apc mutant mice was the multiple intestinal neoplasia (Min) mouse (ApcMin/+).	('Min', 'Gene', (128, 131))	('Min', 'Phenotype', 'HP:0200008', (113, 116))	('mutant', 'Var', (62, 68))	('mouse', 'Species', '10090', (14, 19))	('Apc', 'Phenotype', 'HP:0005227', (58, 61))	('Min', 'Gene', (113, 116))	('multiple intestinal neoplasia', 'Gene', '11789', (82, 111))	('Apc', 'Phenotype', 'HP:0005227', (10, 13))	('Min', 'Gene', '11789', (128, 131))	('mice', 'Species', '10090', (69, 73))	('multiple intestinal neoplasia', 'Phenotype', 'HP:0200008', (82, 111))	('mouse', 'Species', '10090', (118, 123))	('multiple intestinal neoplasia', 'Gene', (82, 111))	('Apc', 'Phenotype', 'HP:0005227', (125, 128))	('neoplasia', 'Phenotype', 'HP:0002664', (102, 111))	('Min', 'Phenotype', 'HP:0200008', (128, 131))	('Min', 'Gene', '11789', (113, 116))
397995	26380553	Another disadvantage of the Apc mouse model is that the majority of the adenomas are benign, as deregulation of Wnt signaling is thought to be an important initiator of tumorigenesis but is not sufficient to drive tumor progression.	('adenomas', 'Disease', 'MESH:D000236', (72, 80))	('deregulation', 'Var', (96, 108))	('adenomas', 'Disease', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('Apc', 'Phenotype', 'HP:0005227', (28, 31))	('mouse', 'Species', '10090', (32, 37))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', (214, 219))	('Wnt signaling', 'MPA', (112, 125))
397996	26380553	It is thought that the sequential accumulation of mutations in specific genes, including Apc, K-ras, and p53, is necessary to drive the transition from normal epithelium to colorectal cancer, supporting the notion that malignant transformation may require the involvement of other genetic events or signaling pathways in cooperation with Apc.	('colorectal cancer', 'Disease', (173, 190))	('Apc', 'Phenotype', 'HP:0005227', (89, 92))	('mutations', 'Var', (50, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('rat', 'Species', '10116', (326, 329))	('Apc', 'Gene', (89, 92))	('p53', 'Gene', (105, 108))	('Apc', 'Phenotype', 'HP:0005227', (338, 341))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))
397997	26380553	More recently, various groups have undertaken the task of using the Apc mutation in mice with the Cre-Lox system to shift tumorigenesis away from the small intestine and into the large intestine using SRalpha, CDX2, and hCA1 promoters.	('Apc', 'Phenotype', 'HP:0005227', (68, 71))	('Lox', 'Gene', '16948', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Lox', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CDX2', 'Gene', (210, 214))	('mutation', 'Var', (72, 80))	('hCA1', 'Gene', '759', (220, 224))	('tumor', 'Disease', (122, 127))	('hCA1', 'Gene', (220, 224))	('mice', 'Species', '10090', (84, 88))	('CDX2', 'Gene', '12591', (210, 214))
397999	26380553	The authors found that normal intestinal epithelium appeared to be resistant to K-ras mutation, as expression of K-ras (V12) did not affect intestinal homeostasis in the mouse.	('K-ras', 'Gene', (80, 85))	('mouse', 'Species', '10090', (170, 175))	('intestinal homeostasis', 'MPA', (140, 162))	('mutation', 'Var', (86, 94))
398000	26380553	However, when they combined this K-ras mutation with Apc deficiency in the mice, there resulted accelerated intestinal tumorigenesis and increased invasion.	('tumor', 'Disease', (119, 124))	('mice', 'Species', '10090', (75, 79))	('Apc', 'Phenotype', 'HP:0005227', (53, 56))	('mutation', 'Var', (39, 47))	('K-ras', 'Gene', (33, 38))	('invasion', 'CPA', (147, 155))	('combined', 'Interaction', (19, 27))	('increased', 'PosReg', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('rat', 'Species', '10116', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('accelerated', 'PosReg', (96, 107))	('Apc deficiency', 'Disease', 'MESH:C566056', (53, 67))	('Apc deficiency', 'Disease', (53, 67))
398001	26380553	Byun et al (2014) also combined inactivation of Apc and activation of mutant K-ras, but used colon-specific expression of Cre recombinase (AKC mice).	('mutant', 'Var', (70, 76))	('Apc', 'Disease', (48, 51))	('Apc', 'Phenotype', 'HP:0005227', (48, 51))	('inactivation', 'NegReg', (32, 44))	('K-ras', 'Protein', (77, 82))	('activation', 'PosReg', (56, 66))	('mice', 'Species', '10090', (143, 147))
398002	26380553	The authors used mice with the Apc580S mutant allele, latent activated LSL-K-rasG12D mutation, and achieved inactivation of Apc and activation of K-ras through a cross with carbonic anhydrase 1 (CAC+) mice whereby Cre expression was tied to carbonic anhydrase 1, a gene expressed only in the large intestine.	('LSL-K-rasG12D', 'Gene', (71, 84))	('mice', 'Species', '10090', (17, 21))	('carbonic anhydrase 1', 'Gene', (173, 193))	('Apc580S mutant', 'Var', (31, 45))	('mutation', 'Var', (85, 93))	('carbonic anhydrase 1', 'Gene', '12346', (241, 261))	('mice', 'Species', '10090', (201, 205))	('Apc', 'Phenotype', 'HP:0005227', (124, 127))	('Apc', 'Phenotype', 'HP:0005227', (31, 34))	('mutant', 'Var', (39, 45))	('carbonic anhydrase 1', 'Gene', (241, 261))	('carbonic anhydrase 1', 'Gene', '12346', (173, 193))
398008	26380553	Aberrations in p53, BRCA1/2, and Rb1 are most common in SEOCs.	('Rb', 'Phenotype', 'HP:0009919', (33, 35))	('p53', 'Gene', (15, 18))	('Rb1', 'Gene', (33, 36))	('common', 'Reg', (46, 52))	('SEOCs', 'Disease', (56, 61))	('rat', 'Species', '10116', (4, 7))	('BRCA1/2', 'Gene', '12189;12190', (20, 27))	('Aberrations', 'Var', (0, 11))	('BRCA1/2', 'Gene', (20, 27))
398010	26380553	Since then, a more robust model of SEOC has been developed in which the mutation of p53 is combined with BRCA1/2 mutation and PTEN loss.	('mutation', 'Var', (113, 121))	('BRCA1/2', 'Gene', '12189;12190', (105, 112))	('loss', 'NegReg', (131, 135))	('BRCA1/2', 'Gene', (105, 112))	('p53', 'Gene', (84, 87))	('mutation', 'Var', (72, 80))	('PTEN', 'Gene', (126, 130))
398012	26380553	However, Perets et al (2013) demonstrated that the combination of mutant p53 and loss of BRCA2 results in SEOC in mice between 7 and 11 months of age.	('BRCA2', 'Gene', '12190', (89, 94))	('mutant', 'Var', (66, 72))	('p53', 'Gene', (73, 76))	('results in', 'Reg', (95, 105))	('rat', 'Species', '10116', (36, 39))	('SEOC', 'Disease', (106, 110))	('BRCA2', 'Gene', (89, 94))	('mice', 'Species', '10090', (114, 118))	('loss', 'NegReg', (81, 85))
398013	26380553	The combination of mutant p53 with PTEN loss results in oviductal lesions and endometrial tumors between 6 and 10 months of age.	('endometrial tumors', 'Disease', 'MESH:D016889', (78, 96))	('PTEN', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('loss', 'NegReg', (40, 44))	('p53', 'Gene', (26, 29))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('mutant', 'Var', (19, 25))	('endometrial tumors', 'Disease', (78, 96))	('oviductal lesions', 'Disease', (56, 73))	('oviductal lesions', 'Disease', 'MESH:C538511', (56, 73))	('results in', 'Reg', (45, 55))
398014	26380553	Furthermore, the combination of loss or mutation of p53, heterozygous or homozygous loss of BRCA1/2, and homozygous loss of PTEN results in reduced latency to SEOC and decreased survival of mice to 5 months.	('mutation', 'Var', (40, 48))	('PTEN', 'Gene', (124, 128))	('decreased', 'NegReg', (168, 177))	('loss', 'NegReg', (32, 36))	('survival', 'CPA', (178, 186))	('p53', 'Gene', (52, 55))	('loss', 'NegReg', (84, 88))	('BRCA1/2', 'Gene', '12189;12190', (92, 99))	('latency', 'MPA', (148, 155))	('BRCA1/2', 'Gene', (92, 99))	('mice', 'Species', '10090', (190, 194))	('reduced', 'NegReg', (140, 147))
398018	26380553	They also examined the effects of the mutation of the phosphoinositide 3-kinase catalytic subunit (PIK3CA).	('PIK3CA', 'Gene', '18706', (99, 105))	('mutation', 'Var', (38, 46))	('PIK3CA', 'Gene', (99, 105))
398019	26380553	Utilizing the H1047R PIK3CA mutation, they used a Cre-inducible (Gt)Rosa26Pik3caH1047R allele and observed hyperplasia but no tumor formation in the mice.	('H1047R', 'Var', (14, 20))	('PIK3CA', 'Gene', '18706', (21, 27))	('hyperplasia', 'Disease', (107, 118))	('PIK3CA', 'Gene', (21, 27))	('H1047R', 'Mutation', 'rs121913279', (80, 86))	('H1047R', 'Mutation', 'rs121913279', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('hyperplasia', 'Disease', 'MESH:D006965', (107, 118))	('mice', 'Species', '10090', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
398022	26380553	These data support the notion that cooperation between ARID1A and PIK3CA mutations is necessary to induce ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('PIK3CA', 'Gene', '18706', (66, 72))	('ARID1A', 'Gene', '93760', (55, 61))	('induce', 'Reg', (99, 105))	('PIK3CA', 'Gene', (66, 72))	('ovarian cancer', 'Disease', (106, 120))	('rat', 'Species', '10116', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('ARID1A', 'Gene', (55, 61))	('mutations', 'Var', (73, 82))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))
398030	26380553	Grippo et al (2003) overexpressed this common activating mutation in pancreatic acinar cells with resultant PanIN lesions in mice 18 to 24 months of age.	('mutation', 'Var', (57, 65))	('pancreatic', 'Disease', (69, 79))	('mice', 'Species', '10090', (125, 129))	('PanIN', 'Disease', (108, 113))	('pancreatic', 'Disease', 'MESH:D010195', (69, 79))	('activating', 'PosReg', (46, 56))
398035	26380553	Thus, the use of mouse models combining K-ras mutations with other genetic manipulations may be required to effectively study human pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (126, 131))	('mutations', 'Var', (46, 55))	('mouse', 'Species', '10090', (17, 22))	('pancreatic cancer', 'Disease', (132, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))	('K-ras', 'Protein', (40, 45))
398036	26380553	In addition to K-ras activating mutations, the most common genetic aberrations in human PDAC include inactivation of the tumor suppressor genes Ink4/Arf, p53, and SMAD4.	('Ink4', 'Gene', '1029', (144, 148))	('SMAD4', 'Gene', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('rat', 'Species', '10116', (71, 74))	('PDAC', 'Disease', (88, 92))	('PDAC', 'Phenotype', 'HP:0006725', (88, 92))	('Ink4', 'Gene', (144, 148))	('tumor', 'Disease', (121, 126))	('human', 'Species', '9606', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('p53', 'Gene', (154, 157))	('inactivation', 'Var', (101, 113))	('PDAC', 'Chemical', '-', (88, 92))	('Arf', 'Gene', '12578', (149, 152))	('Arf', 'Gene', (149, 152))
398037	26380553	Studies have shown that inactivation of each of these genes alone in the mouse pancreas results in no phenotype and must be combined with mutant K-ras to induce PDAC.	('induce', 'Reg', (154, 160))	('PDAC', 'Chemical', '-', (161, 165))	('inactivation', 'Var', (24, 36))	('mutant', 'Var', (138, 144))	('PDAC', 'Disease', (161, 165))	('PDAC', 'Phenotype', 'HP:0006725', (161, 165))	('mouse', 'Species', '10090', (73, 78))
398042	26380553	p53 mutations occur in 50%-75% of human PDAC, with a common mutation being Trp53R172H.	('p53', 'Gene', (0, 3))	('PDAC', 'Disease', (40, 44))	('human', 'Species', '9606', (34, 39))	('PDAC', 'Phenotype', 'HP:0006725', (40, 44))	('PDAC', 'Chemical', '-', (40, 44))	('mutations', 'Var', (4, 13))	('Trp53R172H', 'Var', (75, 85))
398044	26380553	Trp53R172H and K-rasG12D cooperate in these mice to promote the development of PanIN lesions as well as well-differentiated PDAC tumors with molecular heterogeneity and genomic instability.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('PanIN lesions', 'Disease', (79, 92))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('development', 'CPA', (64, 75))	('Trp53R172H', 'Var', (0, 10))	('PDAC', 'Chemical', '-', (124, 128))	('rat', 'Species', '10116', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PDAC', 'Phenotype', 'HP:0006725', (124, 128))	('mice', 'Species', '10090', (44, 48))	('promote', 'PosReg', (52, 59))
398046	26380553	Loss of SMAD4 was shown to promote the progression of K-rasG12D-initiated PDAC when crossed with LSL-K-rasG12D;Pdx1-Cre mice.	('Pdx1', 'Gene', (111, 115))	('K-rasG12D-initiated', 'Var', (54, 73))	('SMAD4', 'Gene', (8, 13))	('mice', 'Species', '10090', (120, 124))	('PDAC', 'Disease', (74, 78))	('PDAC', 'Phenotype', 'HP:0006725', (74, 78))	('Pdx1', 'Gene', '18609', (111, 115))	('promote', 'PosReg', (27, 34))	('PDAC', 'Chemical', '-', (74, 78))	('Loss', 'Var', (0, 4))
398047	26380553	SMAD4 depletion resulted in decreased survival of mice and formation of PanIN lesions.	('decreased', 'NegReg', (28, 37))	('survival', 'CPA', (38, 46))	('SMAD4', 'Gene', (0, 5))	('depletion', 'Var', (6, 15))	('mice', 'Species', '10090', (50, 54))
398048	26380553	Upon further examination of the implication of Smad4, Bardeesy et al (2006) looked at the effect that loss of SMAD4 had in mice harboring K-ras mutations as well as loss of p16Ink4a/p19Arf.	('p16Ink4a', 'Gene', '12578', (173, 181))	('K-ras', 'Protein', (138, 143))	('mice', 'Species', '10090', (123, 127))	('p19Arf', 'Gene', (182, 188))	('p16Ink4a', 'Gene', (173, 181))	('p19Arf', 'Gene', '12578', (182, 188))	('Smad4', 'Gene', '17128', (47, 52))	('Smad4', 'Gene', (47, 52))	('loss', 'Var', (165, 169))	('SMAD4', 'Gene', (110, 115))	('loss', 'Var', (102, 106))	('mutations', 'Var', (144, 153))
398049	26380553	These experiments showed that the loss of SMAD4 promotes the rapid formation of well-differentiated PDAC tumors with an increased expression of epithelial markers.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('expression', 'MPA', (130, 140))	('loss', 'Var', (34, 38))	('PDAC', 'Chemical', '-', (100, 104))	('promotes', 'PosReg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('SMAD4', 'Gene', (42, 47))	('PDAC', 'Phenotype', 'HP:0006725', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('increased', 'PosReg', (120, 129))
398051	26380553	Many models of pancreatic cancer have been developed that focus in some way on K-ras mutations and, when combined with other genetic mutations, accurately represent the histology of human disease.	('K-ras', 'Protein', (79, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (15, 32))	('rat', 'Species', '10116', (148, 151))	('human', 'Species', '9606', (182, 187))	('pancreatic cancer', 'Disease', 'MESH:D010190', (15, 32))	('mutations', 'Var', (85, 94))	('pancreatic cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
398055	26380553	These data led the authors to conclude that EGFR mutation alone is not sufficient to cause glioma and additional genetic events are necessary.	('cause', 'Reg', (85, 90))	('glioma', 'Disease', (91, 97))	('mutation', 'Var', (49, 57))	('EGFR', 'Gene', (44, 48))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
398056	26380553	Holland (2000) then went on to infect RCAS-EGFR into mice with INK4a-ARF deletion (RCAS-EGFR;tv-a-INK4a-AR-/-).	('INK4a', 'Gene', '12578', (98, 103))	('mice', 'Species', '10090', (53, 57))	('RCAS', 'Chemical', '-', (38, 42))	('INK4a', 'Gene', (63, 68))	('INK4a-ARF', 'Gene', (63, 72))	('RCAS', 'Chemical', '-', (83, 87))	('INK4a', 'Gene', '12578', (63, 68))	('INK4a-ARF', 'Gene', '12578', (63, 72))	('deletion', 'Var', (73, 81))	('INK4a', 'Gene', (98, 103))
398059	26380553	Fraser et al (2004) generated mice with expression of Cre recombinase and conditional deletion of PTEN under the control of the glial fibrillary acidic protein (GFAP) promoter (PTENloxP/loxP;GFAP-Cre).	('GFAP', 'Gene', (191, 195))	('mice', 'Species', '10090', (30, 34))	('glial fibrillary acidic protein', 'Gene', '14580', (128, 159))	('GFAP', 'Gene', '14580', (161, 165))	('GFAP', 'Gene', (161, 165))	('glial fibrillary acidic protein', 'Gene', (128, 159))	('PTEN', 'Gene', (98, 102))	('GFAP', 'Gene', '14580', (191, 195))	('rat', 'Species', '10116', (24, 27))	('deletion', 'Var', (86, 94))
398062	26380553	These data suggested to the authors that PTEN inactivation alone may contribute to gliomagenesis progression but needs additional events to initiate the process.	('glioma', 'Disease', (83, 89))	('contribute', 'Reg', (69, 79))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('PTEN', 'Protein', (41, 45))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('inactivation', 'Var', (46, 58))
398063	26380553	To address this issue, Zhu et al (2008) examined the effects of PTEN deletion with INK4a/ARF loss and constitutively active EGFRvIII.	('ARF loss', 'Disease', (89, 97))	('INK4a', 'Gene', (83, 88))	('INK4a', 'Gene', '12578', (83, 88))	('ARF loss', 'Disease', 'MESH:D015431', (89, 97))	('PTEN', 'Gene', (64, 68))	('deletion', 'Var', (69, 77))
398069	26380553	Further supporting this notion, Uziel et al (2005) showed that either homozygous or hemizygous deletion of Ink4c on a Ptc+/- background increased MB incidence to 30% with a tumor latency of 12 to 36 weeks.	('Ink4c', 'Gene', (107, 112))	('Ink4c', 'Gene', '12580', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('deletion', 'Var', (95, 103))	('Ptc', 'Gene', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('MB', 'Phenotype', 'HP:0002885', (146, 148))	('increased', 'PosReg', (136, 145))	('Ptc', 'Gene', '19713', (118, 121))
398071	26380553	Similar to the results seen with Ink4c, homozygous or hemizygous deletion of another cyclin-dependent kinase inhibitor, Kip1, in Ptc+/- mice increased MB tumor incidence to 60%-70%.	('mice', 'Species', '10090', (136, 140))	('MB', 'Phenotype', 'HP:0002885', (151, 153))	('increased', 'PosReg', (141, 150))	('Ink4c', 'Gene', '12580', (33, 38))	('Kip1', 'Gene', (120, 124))	('Ptc', 'Gene', '19713', (129, 132))	('Ink4c', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('Ptc', 'Gene', (129, 132))	('Kip1', 'Gene', '12576', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('deletion', 'Var', (65, 73))	('tumor', 'Disease', (154, 159))
398075	26380553	The development of retinoblastoma typically begins with an inherited germline mutation in the Rb1 gene of children.	('Rb1', 'Gene', (94, 97))	('retinoblastoma', 'Gene', '5925', (19, 33))	('Rb', 'Phenotype', 'HP:0009919', (94, 96))	('germline mutation', 'Var', (69, 86))	('retinoblastoma', 'Gene', (19, 33))	('children', 'Species', '9606', (106, 114))	('retinoblastoma', 'Phenotype', 'HP:0009919', (19, 33))
398077	26380553	Although children with heterozygous germline mutation of Rb develop retinoblastoma, these mice did not.	('Rb', 'Phenotype', 'HP:0009919', (57, 59))	('retinoblastoma', 'Gene', (68, 82))	('Rb', 'Gene', '5925', (57, 59))	('retinoblastoma', 'Gene', '5925', (68, 82))	('retinoblastoma', 'Phenotype', 'HP:0009919', (68, 82))	('children', 'Species', '9606', (9, 17))	('germline mutation', 'Var', (36, 53))	('mice', 'Species', '10090', (90, 94))	('develop', 'PosReg', (60, 67))
398078	26380553	It was later found that, in order to recapitulate the histopathological and molecular features of human neuroblastoma, more than one Rb family member needed to be inactivated since Rb1 mutation alone failed to cause retinoblastoma.	('retinoblastoma', 'Gene', '5925', (216, 230))	('neuroblastoma', 'Disease', (104, 117))	('neuroblastoma', 'Phenotype', 'HP:0003006', (104, 117))	('Rb', 'Phenotype', 'HP:0009919', (133, 135))	('retinoblastoma', 'Gene', (216, 230))	('mutation', 'Var', (185, 193))	('retinoblastoma', 'Phenotype', 'HP:0009919', (216, 230))	('Rb', 'Phenotype', 'HP:0009919', (181, 183))	('Rb', 'Gene', '5925', (133, 135))	('Rb', 'Gene', '5925', (181, 183))	('cause', 'Reg', (210, 215))	('human', 'Species', '9606', (98, 103))	('neuroblastoma', 'Disease', 'MESH:D009447', (104, 117))
398079	26380553	Donovan et al (2006) used Chx10-Cre to inactivate Rb and p107, a retinoblastoma-like gene that can function as a tumor suppressor.	('tumor', 'Disease', (113, 118))	('Chx10', 'Gene', '12677', (26, 31))	('Rb', 'Phenotype', 'HP:0009919', (50, 52))	('Rb', 'Gene', '5925', (50, 52))	('retinoblastoma', 'Gene', '5925', (65, 79))	('retinoblastoma', 'Gene', (65, 79))	('Chx10', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('retinoblastoma', 'Phenotype', 'HP:0009919', (65, 79))	('p107', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('p107', 'Gene', '19650', (57, 61))	('inactivate', 'Var', (39, 49))
398081	26380553	Inactivation of Rb was also combined with inactivation of another retinoblastoma-like gene, p130, using Chx10-Cre.	('Rb', 'Phenotype', 'HP:0009919', (16, 18))	('Chx10', 'Gene', (104, 109))	('Rb', 'Gene', '5925', (16, 18))	('retinoblastoma', 'Gene', '5925', (66, 80))	('retinoblastoma', 'Gene', (66, 80))	('p130', 'Gene', '12557', (92, 96))	('retinoblastoma', 'Phenotype', 'HP:0009919', (66, 80))	('Chx10', 'Gene', '12677', (104, 109))	('Inactivation', 'Var', (0, 12))	('p130', 'Gene', (92, 96))
398085	26380553	Urothelial cell carcinoma (UCC) is unique among epithelial carcinomas, as tumorigenesis occurs by two distinct pathways: low-grade, papillary tumors contain oncogenic mutations in Fgfr3 and H-ras, while high-grade, muscle-invasive tumors typically have defects in p53, Rb, and PTEN.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('Rb', 'Phenotype', 'HP:0009919', (269, 271))	('mutations', 'Var', (167, 176))	('tumor', 'Disease', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('H-ras', 'Protein', (190, 195))	('tumors', 'Disease', (231, 237))	('epithelial carcinomas', 'Disease', 'MESH:D002277', (48, 69))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('tumor', 'Disease', (231, 236))	('papillary tumors', 'Phenotype', 'HP:0007482', (132, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('papillary tumors', 'Disease', 'MESH:D002291', (132, 148))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('Fgfr3', 'Gene', (180, 185))	('papillary tumors', 'Disease', (132, 148))	('tumor', 'Disease', (142, 147))	('epithelial carcinomas', 'Disease', (48, 69))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('Rb', 'Gene', '5925', (269, 271))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('Urothelial cell carcinoma', 'Disease', 'MESH:C538614', (0, 25))	('Urothelial cell carcinoma', 'Disease', (0, 25))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('p53', 'Protein', (264, 267))
398086	26380553	Ahmad et al (2011) targeted the expression of mutated Fgfr3 to the mouse urothelium under the control of the UPII promoter, with resultant urothelial hyperplasia but no evidence of dysplasia or tumorigenesis in the mice.	('UPII', 'Gene', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('mice', 'Species', '10090', (215, 219))	('urothelial hyperplasia', 'Disease', (139, 161))	('mutated', 'Var', (46, 53))	('dysplasia', 'Disease', (181, 190))	('UPII', 'Gene', '22269', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('Fgfr3', 'Gene', (54, 59))	('mouse', 'Species', '10090', (67, 72))	('urothelial hyperplasia', 'Disease', 'MESH:D006965', (139, 161))	('dysplasia', 'Disease', 'MESH:D004476', (181, 190))
398087	26380553	Fgfr3 and K-ras mutations have been found to be mutually exclusive in human bladder cancer patients; however, when the authors paired the Fgfr3 mutation with K-ras (K-rasG12D) or beta-catenin (beta-cateninexon3/+) activating mutations, they found similar results to those described above, indicating Fgfr3 is not involved in initiating UCC tumorigenesis.	('bladder cancer', 'Disease', (76, 90))	('Fgfr3', 'Gene', (138, 143))	('beta-cateninexon3', 'Chemical', '-', (193, 210))	('patients', 'Species', '9606', (91, 99))	('UCC', 'Disease', (336, 339))	('human', 'Species', '9606', (70, 75))	('mutation', 'Var', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('tumor', 'Disease', (340, 345))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
398088	26380553	Mutations in the H-ras oncogene cause it to become constitutively expressed, and Zhang et al (2001) targeted expression of constitutively active H-ras to the urothelium, causing early onset hyperproliferation that progressed to low-grade, papillary, noninvasive tumors.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('low-grade', 'Disease', (228, 237))	('early onset hyperproliferation', 'Disease', (178, 208))	('tumors', 'Disease', (262, 268))	('causing', 'Reg', (170, 177))	('H-ras', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('rat', 'Species', '10116', (202, 205))
398089	26380553	Tumor latency depended on copy number of the H-ras transgene, though they demonstrated that low copy number mice develop tumors with a much longer latency of approximately 12 months.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('rat', 'Species', '10116', (81, 84))	('tumors', 'Disease', (121, 127))	('low copy', 'Var', (92, 100))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('mice', 'Species', '10090', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (121, 127))
398091	26380553	Mutation and/or deletion of p53 are common in human UCC and can occur with H-ras mutations.	('p53', 'Gene', (28, 31))	('occur', 'Reg', (64, 69))	('deletion', 'Var', (16, 24))	('Mutation', 'Var', (0, 8))	('human', 'Species', '9606', (46, 51))
398092	26380553	Gao et al (2004) used the UPII promoter to target mutated p53 to the urothelium of mice, with resultant urothelial hyperplasia and dysplasia but no UCC.	('UPII', 'Gene', (26, 30))	('urothelial hyperplasia and dysplasia', 'Disease', 'MESH:D006965', (104, 140))	('UPII', 'Gene', '22269', (26, 30))	('mice', 'Species', '10090', (83, 87))	('mutated', 'Var', (50, 57))	('p53', 'Gene', (58, 61))
398094	26380553	This suggests that loss of p53 is not enough to promote bladder tumorigenesis, but needs an event like H-ras activation with which to cooperate.	('tumor', 'Disease', (64, 69))	('rat', 'Species', '10116', (139, 142))	('loss', 'Var', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('p53', 'Gene', (27, 30))
398095	26380553	Deletion of PTEN occurs frequently in invasive UCC, with reports showing PTEN loss in up to 94% of advanced UCC.	('PTEN', 'Gene', (12, 16))	('loss', 'NegReg', (78, 82))	('invasive UCC', 'Disease', (38, 50))	('to 9', 'Species', '1214577', (89, 93))	('Deletion', 'Var', (0, 8))
398110	26380553	Since then, an inducible transgenic model of HNSCC has been developed using the progesterone receptor system in mice to induce expression of TGFbeta1, causing hyperproliferation in the buccal mucosa, tongue, and esophagus.	('TGFbeta1', 'Gene', '21803', (141, 149))	('causing', 'Reg', (151, 158))	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('rat', 'Species', '10116', (171, 174))	('hyperproliferation', 'Disease', (159, 177))	('expression', 'Var', (127, 137))	('transgenic', 'Species', '10090', (25, 35))	('TGFbeta1', 'Gene', (141, 149))	('mice', 'Species', '10090', (112, 116))
398111	26380553	The same group went on to use a similar technique to knock out TGFbetaRII in the buccal tissue, tongue, esophagus, and forestomach of mice; no phenotype or pathological changes were observed in comparison to controls.	('knock out', 'Var', (53, 62))	('mice', 'Species', '10090', (134, 138))	('TGFbetaRII', 'Gene', (63, 73))
398112	26380553	However, when TGFbetaRII deletion was combined with a K-ras mutation (K-rasG12D/+/TGFbetaRII-/-), mice developed primary tumors within 5 weeks.	('TGFbetaRII', 'Gene', (14, 24))	('primary tumors', 'Disease', 'MESH:D009369', (113, 127))	('developed', 'PosReg', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('deletion', 'Var', (25, 33))	('primary tumors', 'Disease', (113, 127))	('mice', 'Species', '10090', (98, 102))
398118	26380553	Many mouse models of gastric cancer involve the use of Helicobacter pylori infection and carcinogen treatments, though a variety of GEMMs have been established.	('infection', 'Disease', 'MESH:D007239', (75, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (21, 35))	('Helicobacter', 'Var', (55, 67))	('mouse', 'Species', '10090', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Helicobacter pylori', 'Species', '210', (55, 74))	('gastric cancer', 'Disease', (21, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (21, 35))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (55, 84))	('infection', 'Disease', (75, 84))
398121	26380553	K-ras transgenic mice are commonly used, and it has been shown that use of the K19 promoter to drive expression of the K-ras-V12 mutant results in recruitment of inflammatory cells and the development of dysplasia.	('mutant', 'Var', (129, 135))	('dysplasia', 'Disease', (204, 213))	('recruitment', 'PosReg', (147, 158))	('dysplasia', 'Disease', 'MESH:D004476', (204, 213))	('inflammatory cells', 'CPA', (162, 180))	('transgenic mice', 'Species', '10090', (6, 21))	('K-ras-V12', 'Gene', (119, 128))
398137	26380553	Defects in Mdr2 are associated with cholestasis, biliary fibrosis, or cirrhosis.	('associated', 'Reg', (20, 30))	('biliary fibrosis', 'Disease', 'MESH:D005355', (49, 65))	('Mdr2', 'Gene', '18670', (11, 15))	('cholestasis', 'Disease', (36, 47))	('cirrhosis', 'Disease', (70, 79))	('Defects', 'Var', (0, 7))	('cholestasis', 'Phenotype', 'HP:0001396', (36, 47))	('Mdr2', 'Gene', (11, 15))	('cirrhosis', 'Phenotype', 'HP:0001394', (70, 79))	('cholestasis', 'Disease', 'MESH:D002779', (36, 47))	('biliary fibrosis', 'Disease', (49, 65))	('cirrhosis', 'Disease', 'MESH:D005355', (70, 79))
398156	26380553	Esophageal keratinocytes with Klf5 knock down and p53R175H mutation, but not either alone, formed tumors in SCID/NCr mice, and these tumors were characteristic of invasive squamous cell carcinoma.	('tumors', 'Disease', (98, 104))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 195))	('p53R175H', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('p53R175H', 'Mutation', 'p.R53,175H', (50, 58))	('mice', 'Species', '10090', (117, 121))	('SCID', 'Disease', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('rat', 'Species', '10116', (13, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('Klf5', 'Gene', (30, 34))	('invasive squamous cell carcinoma', 'Disease', (163, 195))	('tumors', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Klf5', 'Gene', '12224', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('SCID', 'Disease', 'MESH:D053632', (108, 112))
398160	26380553	P120-catenin (p120ctn) is a tumor suppressor that is downregulated or lost in 35%-60% of ESCC patients.	('tumor', 'Disease', (28, 33))	('patients', 'Species', '9606', (94, 102))	('p120ctn', 'Var', (14, 21))	('P120-catenin', 'Gene', '1500', (0, 12))	('P120-catenin', 'Gene', (0, 12))	('ESCC', 'Disease', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('lost', 'NegReg', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('downregulated', 'NegReg', (53, 66))
398161	26380553	Stairs et al (2011) generated a conditional knock-out mouse model of p120ctn using the L2 promoter to delete p120ctn specifically in the squamous oral cavity, esophagus, and fore-stomach of mice (L2Cre;p120loxP/loxP).	('L2', 'Gene', '23960', (87, 89))	('p120ctn', 'Var', (69, 76))	('delete p120ctn', 'Var', (102, 116))	('mouse', 'Species', '10090', (54, 59))	('p120ctn', 'Var', (109, 116))	('L2', 'Gene', '23960', (196, 198))	('mice', 'Species', '10090', (190, 194))	('rat', 'Species', '10116', (24, 27))
398164	26380553	These data suggest that deletion of p120ctn creates a useful model in which to study ESCC, though it exhibits a long tumor latency period and is not highly invasive, indicating that further genetic events may be necessary to fully recapitulate human ESCC.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('human', 'Species', '9606', (244, 249))	('tumor', 'Disease', (117, 122))	('ESCC', 'Disease', (85, 89))	('p120ctn', 'Var', (36, 43))	('deletion', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
398170	26380553	Pollard et al (2007) inactivated mouse fumarate hydratase (Fh1) in the kidney to mimic hereditary leiomyomatosis and renal cell cancer (HLRCC) and found that Fh1 mutants developed renal cysts that overexpressed Hif1alpha and Hif2alpha at similar levels to renal carcinomas from HLRCC.	('renal cysts', 'Disease', (180, 191))	('renal cysts', 'Phenotype', 'HP:0000107', (180, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('carcinomas', 'Phenotype', 'HP:0030731', (262, 272))	('mutants', 'Var', (162, 169))	('Fh1', 'Species', '12583', (59, 62))	('renal carcinomas', 'Disease', (256, 272))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Hif1alpha', 'Protein', (211, 220))	('renal cysts', 'Disease', 'MESH:D007674', (180, 191))	('renal carcinomas', 'Phenotype', 'HP:0005584', (256, 272))	('hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (87, 134))	('renal carcinoma', 'Phenotype', 'HP:0005584', (256, 271))	('renal cell cancer', 'Phenotype', 'HP:0005584', (117, 134))	('Fh1', 'Gene', (158, 161))	('rat', 'Species', '10116', (51, 54))	('Fh1', 'Species', '12583', (158, 161))	('rat', 'Species', '10116', (43, 46))	('mouse', 'Species', '10090', (33, 38))	('renal carcinomas', 'Disease', 'MESH:C538614', (256, 272))	('overexpressed', 'PosReg', (197, 210))
398176	26380553	One of the points highlighted in this review, with regard to some of the GEMMs used in the study of human cancers, is that expression of a single activated oncogene or loss of a single tumor suppressor gene is sometimes not sufficient to convert an epithelial cell to a malignant phenotype.	('tumor', 'Disease', (185, 190))	('loss', 'Var', (168, 172))	('convert', 'Reg', (238, 245))	('human', 'Species', '9606', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
398185	26380553	Traditional pronuclear DNA injection results in transgene insertion into a single locus, which will pass to the next generation containing many copies of the transgene.	('transgene', 'Var', (48, 57))	('insertion', 'Reg', (58, 67))	('rat', 'Species', '10116', (121, 124))
398188	26380553	One further consideration in the development of GEMMs is that most human cancers are genetic mosaics since cancer cells harbor mutations that are absent in normal cells within the same body.	('cancer', 'Disease', (73, 79))	('cancers', 'Disease', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rat', 'Species', '10116', (19, 22))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('mutations', 'Var', (127, 136))	('human', 'Species', '9606', (67, 72))	('cancer', 'Disease', (107, 113))
398198	26380553	Whether a gene is an early initiating event or late event in the tumorigenic process is important, as the genes may differentially influence cancer development and progression.	('progression', 'CPA', (164, 175))	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('genes', 'Var', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('influence', 'Reg', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
398229	22837870	But, male sex, hiatus hernia and positivity for Helicobacter pylori infection were predictive of silent GERD.	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (48, 77))	('Helicobacter pylori infection', 'Disease', 'MESH:D016481', (48, 77))	('GERD', 'Disease', 'MESH:D005764', (104, 108))	('hiatus hernia', 'Phenotype', 'HP:0002036', (15, 28))	('GERD', 'Disease', (104, 108))	('hiatus hernia', 'Disease', (15, 28))	('positivity', 'Var', (33, 43))	('hiatus hernia', 'Disease', 'MESH:D006551', (15, 28))	('Helicobacter pylori infection', 'Disease', (48, 77))	('hernia', 'Phenotype', 'HP:0100790', (22, 28))
398233	22837870	Not surprisingly, the authors found that symptomatic GERD patients were more likely to have atypical symptoms, functional dyspepsia symptoms and higher scores on psychological symptoms (somatization, obsessive-compulsiveness and phobic anxiety) than those without.	('symptomatic', 'Var', (41, 52))	('GERD', 'Disease', (53, 57))	('higher scores', 'PosReg', (145, 158))	('dyspepsia', 'Phenotype', 'HP:0410281', (122, 131))	('obsessive-compulsiveness', 'Phenotype', 'HP:0000722', (200, 224))	('psychological symptoms', 'MPA', (162, 184))	('functional dyspepsia symptoms', 'Disease', 'MESH:D004415', (111, 140))	('atypical symptoms', 'Disease', (92, 109))	('functional dyspepsia symptoms', 'Disease', (111, 140))	('anxiety', 'Phenotype', 'HP:0000739', (236, 243))	('patients', 'Species', '9606', (58, 66))	('GERD', 'Disease', 'MESH:D005764', (53, 57))	('obsessive-compulsiveness and phobic anxiety', 'Disease', 'MESH:D009771', (200, 243))
398273	22291914	Another 1H NMR study investigated human plasma and identified variations in several metabolite concentrations associated with EAC that differed among ethnic groups.	('human', 'Species', '9606', (34, 39))	('several metabolite concentrations', 'MPA', (76, 109))	('variations', 'Var', (62, 72))	('EAC', 'Disease', (126, 129))	('EAC', 'Phenotype', 'HP:0011459', (126, 129))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('1H', 'Chemical', '-', (8, 10))
398387	18071283	On the other hand, elevation of portal venous pressure after performing BRTO implies that BRTO can aggravate a variety of portal hypertensive changes, including ascites, splenomegaly, the development of portosystemic collaterals and edema of the gall bladder (GB) or the intestinal wall.	('edema of the gall bladder', 'Disease', 'MESH:D005706', (233, 258))	('portal venous pressure', 'MPA', (32, 54))	('BRTO', 'Chemical', '-', (90, 94))	('hypertensive changes', 'Phenotype', 'HP:0000822', (129, 149))	('hypertensive', 'Disease', (129, 141))	('elevation', 'PosReg', (19, 28))	('ascites', 'Disease', (161, 168))	('BRTO', 'Chemical', '-', (72, 76))	('edema', 'Phenotype', 'HP:0000969', (233, 238))	('splenomegaly', 'Disease', (170, 182))	('portosystemic collaterals', 'Phenotype', 'HP:0025154', (203, 228))	('BRTO', 'Var', (90, 94))	('ascites', 'Disease', 'MESH:D001201', (161, 168))	('hypertensive', 'Disease', 'MESH:D006973', (129, 141))	('development of portosystemic collaterals', 'CPA', (188, 228))	('portal hypertensive changes', 'Phenotype', 'HP:0001409', (122, 149))	('ascites', 'Phenotype', 'HP:0001541', (161, 168))	('edema of the gall bladder', 'Disease', (233, 258))	('portosystemic collateral', 'Phenotype', 'HP:0025154', (203, 227))	('splenomegaly', 'Disease', 'MESH:D013163', (170, 182))	('splenomegaly', 'Phenotype', 'HP:0001744', (170, 182))	('aggravate', 'PosReg', (99, 108))	('men', 'Species', '9606', (195, 198))
398388	18071283	It has been well established that BRTO induces delayed or late worsening of esophageal varices; however, the effects of BRTO on the other portal hypertensive changes have not been established.	('esophageal varices', 'Phenotype', 'HP:0002040', (76, 94))	('BRTO', 'Chemical', '-', (34, 38))	('BRTO', 'Chemical', '-', (120, 124))	('esophageal varices', 'Disease', (76, 94))	('hypertensive changes', 'Phenotype', 'HP:0000822', (145, 165))	('hypertensive', 'Disease', 'MESH:D006973', (145, 157))	('hypertensive', 'Disease', (145, 157))	('portal hypertensive changes', 'Phenotype', 'HP:0001409', (138, 165))	('BRTO', 'Var', (34, 38))
398442	18071283	Thus, the spleens were found to be significantly enlarged after BRTO (p < 0.001) (Fig.	('enlarged', 'PosReg', (49, 57))	('BRTO', 'Var', (64, 68))	('spleens', 'CPA', (10, 17))	('BRTO', 'Chemical', '-', (64, 68))
398472	18071283	Thus, we evaluated whether BRTO aggravates a variety of portal hypertensive changes by comparing CT scans.	('hypertensive', 'Disease', 'MESH:D006973', (63, 75))	('hypertensive changes', 'Phenotype', 'HP:0000822', (63, 83))	('hypertensive', 'Disease', (63, 75))	('BRTO', 'Chemical', '-', (27, 31))	('portal hypertensive changes', 'Phenotype', 'HP:0001409', (56, 83))	('BRTO', 'Var', (27, 31))
398474	18071283	In terms of the concern that BRTO could aggravate ascites, a small number of studies have reported a very low incidence of developing ascites, i.e., ascites occurred in 0-10% of the patients after BRTO, but these studies did not describe how and when they evaluated this ascites.	('ascites', 'Disease', (134, 141))	('ascites', 'Phenotype', 'HP:0001541', (134, 141))	('ascites', 'Disease', 'MESH:D001201', (50, 57))	('ascites', 'Disease', 'MESH:D001201', (134, 141))	('ascites', 'Disease', (271, 278))	('ascites', 'Phenotype', 'HP:0001541', (271, 278))	('BRTO', 'Var', (197, 201))	('ascites', 'Disease', 'MESH:D001201', (271, 278))	('patients', 'Species', '9606', (182, 190))	('ascites', 'Disease', (149, 156))	('ascites', 'Phenotype', 'HP:0001541', (149, 156))	('ascites', 'Disease', 'MESH:D001201', (149, 156))	('ascites', 'Phenotype', 'HP:0001541', (50, 57))	('BRTO', 'Chemical', '-', (29, 33))	('BRTO', 'Chemical', '-', (197, 201))	('ascites', 'Disease', (50, 57))
398475	18071283	Yet in the present study, ascites developed or was aggravated in 82% (22 of 27 patients) after BRTO, and this was statistically significant (p = 0.001).	('ascites', 'Disease', 'MESH:D001201', (26, 33))	('ascites', 'Disease', (26, 33))	('ascites', 'Phenotype', 'HP:0001541', (26, 33))	('aggravated', 'PosReg', (51, 61))	('BRTO', 'Chemical', '-', (95, 99))	('BRTO', 'Var', (95, 99))	('patients', 'Species', '9606', (79, 87))
398479	18071283	Based on our results, where the ascites was evaluated on the post-procedural CT scans obtained within one week after BRTO, we believe that BRTO can induce aggravation or the development of ascites in the short term.	('ascites', 'Phenotype', 'HP:0001541', (32, 39))	('BRTO', 'Var', (139, 143))	('BRTO', 'Chemical', '-', (117, 121))	('ascites', 'Disease', (189, 196))	('ascites', 'Phenotype', 'HP:0001541', (189, 196))	('BRTO', 'Chemical', '-', (139, 143))	('ascites', 'Disease', 'MESH:D001201', (189, 196))	('ascites', 'Disease', 'MESH:D001201', (32, 39))	('ascites', 'Disease', (32, 39))	('men', 'Species', '9606', (181, 184))
398483	18071283	It is interesting that BRTO also seems to be able to induce splenic enlargement in a short time.	('BRTO', 'Chemical', '-', (23, 27))	('splenic enlargement', 'Phenotype', 'HP:0001744', (60, 79))	('splenic enlargement', 'Disease', (60, 79))	('splenic enlargement', 'Disease', 'MESH:D013158', (60, 79))	('BRTO', 'Var', (23, 27))
398523	33628843	In CRC, about 15% of the patients have the MSI phenotype with the mutations of MLH1, MLH3, MSH2, MSH3, MSH6, and PMS2 in DNA mismatch repair pathway.	('mutations', 'Var', (66, 75))	('MSH6', 'Gene', (103, 107))	('MSH3', 'Gene', '4437', (97, 101))	('MLH3', 'Gene', '27030', (85, 89))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('MSI', 'Disease', (43, 46))	('MSH2', 'Gene', (91, 95))	('MSH2', 'Gene', '4436', (91, 95))	('MLH3', 'Gene', (85, 89))	('PMS2', 'Gene', '5395', (113, 117))	('MLH1', 'Gene', '4292', (79, 83))	('MLH1', 'Gene', (79, 83))	('MSH6', 'Gene', '2956', (103, 107))	('patients', 'Species', '9606', (25, 33))	('PMS2', 'Gene', (113, 117))	('DNA mismatch repair pathway', 'Pathway', (121, 148))	('MSH3', 'Gene', (97, 101))
398530	33628843	Recent evidence indicates that TFs can directly regulate immune responses and then lead to immunosuppression in tumor.	('tumor', 'Disease', (112, 117))	('TFs', 'Var', (31, 34))	('immunosuppression', 'MPA', (91, 108))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('lead to', 'Reg', (83, 90))	('regulate', 'Reg', (48, 56))	('immune responses', 'CPA', (57, 73))
398590	33628843	Notably, H3K27Ac signals of ASCL2 were uniquely high in MSS CRC samples (Figure 4(d)).	('ASCL2', 'Gene', (28, 33))	('H3K27Ac', 'Var', (9, 16))	('ASCL2', 'Gene', '430', (28, 33))	('high', 'PosReg', (48, 52))	('CRC', 'Phenotype', 'HP:0003003', (60, 63))	('MSS CRC', 'Disease', (56, 63))
398605	33628843	Defects in the expression or nuclear localization of STAT2 can lessen the efficacy of IFN-related immunotherapies.	('lessen', 'NegReg', (63, 69))	('STAT2', 'Gene', (53, 58))	('Defects', 'Var', (0, 7))	('nuclear localization', 'MPA', (29, 49))	('IFN', 'Gene', '3439', (86, 89))	('expression', 'MPA', (15, 25))	('IFN', 'Gene', (86, 89))	('STAT2', 'Gene', '6773', (53, 58))
398606	33628843	Patients with mismatch repair-deficient (dMMR) or MSI status (accounts for ~15% in CRC) have benefit immune checkpoint therapy response.	('benefit', 'PosReg', (93, 100))	('mismatch repair-deficient', 'Var', (14, 39))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('Patients', 'Species', '9606', (0, 8))
398607	33628843	However, pMMR or MSS CRC patients (account for ~85% in CRC) have low tumor mutation burden and immune cell infiltration, which have been posited as mechanisms of immune resistance.	('pMMR', 'Var', (9, 13))	('CRC', 'Phenotype', 'HP:0003003', (21, 24))	('low tumor', 'Disease', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CRC', 'Phenotype', 'HP:0003003', (55, 58))	('immune cell infiltration', 'CPA', (95, 119))	('MSS', 'Disease', (17, 20))	('patients', 'Species', '9606', (25, 33))	('low tumor', 'Disease', 'MESH:D009800', (65, 74))
398630	33628843	Here, we infer that not only in CRC with MSS status but also in other cancer types, such as melanoma and other GI cancers, ETV4 may act as key functions (Figure 4(b) and Supplementary Figure 2).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('ETV4', 'Gene', (123, 127))	('GI cancers', 'Disease', 'MESH:D009369', (111, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('GI cancer', 'Phenotype', 'HP:0007378', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CRC', 'Disease', (32, 35))	('cancer', 'Disease', (114, 120))	('ETV4', 'Gene', '2118', (123, 127))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('melanoma', 'Disease', (92, 100))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('GI cancers', 'Disease', (111, 121))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('MSS status', 'Var', (41, 51))
398631	33628843	Moreover, H3K27Ac signal on ASCL2 also suggests the importance of ASCL2 in MSS CRC compared with other common GI cancers (Figure 4(d)).	('ASCL2', 'Gene', (28, 33))	('GI cancer', 'Phenotype', 'HP:0007378', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ASCL2', 'Gene', (66, 71))	('GI cancers', 'Disease', 'MESH:D009369', (110, 120))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('MSS CRC', 'Disease', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('ASCL2', 'Gene', '430', (28, 33))	('ASCL2', 'Gene', '430', (66, 71))	('H3K27Ac', 'Var', (10, 17))	('GI cancers', 'Disease', (110, 120))
398632	33628843	H3K27Ac signal on ETV4 indicates that ETV4 might be a common upregulated TF in other GI cancers (Supplementary Figure 2).	('upregulated', 'PosReg', (61, 72))	('ETV4', 'Gene', (38, 42))	('GI cancers', 'Disease', (85, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('ETV4', 'Gene', '2118', (38, 42))	('ETV4', 'Gene', (18, 22))	('H3K27Ac', 'Var', (0, 7))	('GI cancers', 'Disease', 'MESH:D009369', (85, 95))	('ETV4', 'Gene', '2118', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('GI cancer', 'Phenotype', 'HP:0007378', (85, 94))
398636	33628843	The findings of this study indicated that the expression of ASCL2 might influence the immune evasion in MSS patients, which may advance the understanding of poor ICB therapies to MSS CRC patients clinically.	('patients', 'Species', '9606', (187, 195))	('expression', 'Var', (46, 56))	('ICB', 'Chemical', '-', (162, 165))	('patients', 'Species', '9606', (108, 116))	('ASCL2', 'Gene', '430', (60, 65))	('CRC', 'Phenotype', 'HP:0003003', (183, 186))	('immune evasion', 'MPA', (86, 100))	('influence', 'Reg', (72, 81))	('ASCL2', 'Gene', (60, 65))	('MSS', 'Disease', (104, 107))	('advance', 'PosReg', (128, 135))
398649	33105560	More recent investigations into the distinct molecular composition of these tumors have uncovered key genetic and epigenetic alterations involved in tumorigenesis and progression.	('epigenetic', 'Var', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
398688	33105560	A six-year follow up of the OE02 patients demonstrated a preserved survival advantage in the perioperative chemotherapy group (HR 0.84) with an absolute five-year survival of 23% vs. 17.1%.	('OE02', 'Var', (28, 32))	('patients', 'Species', '9606', (33, 41))	('survival', 'MPA', (67, 75))
398701	33105560	Despite the various alterations present in cancer cells, inactivation of even a single oncogene can inhibit cellular growth and proliferation.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('inhibit', 'NegReg', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('inactivation', 'Var', (57, 69))
398704	33105560	This disease is driven by a chromosomal translocation resulting in the BCR-ABL mutant oncogene.	('ABL', 'Gene', '25', (75, 78))	('ABL', 'Gene', (75, 78))	('mutant', 'Var', (79, 85))
398706	33105560	It is important to understand the circumstances by which oncogene inactivation induces apoptosis, differentiation, and senescence in the context of heterogenous and complex activation of multiple signaling networks within a tumor.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('oncogene', 'Protein', (57, 65))	('tumor', 'Disease', (224, 229))	('senescence', 'CPA', (119, 129))	('apoptosis', 'CPA', (87, 96))	('inactivation', 'Var', (66, 78))	('induces', 'Reg', (79, 86))	('differentiation', 'CPA', (98, 113))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
398709	33105560	Overexpression and aberrant function of receptors belonging to this family have been frequently implicated in many human cancers.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (115, 120))	('aberrant function', 'Var', (19, 36))	('implicated', 'Reg', (96, 106))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
398715	33105560	Aberrant activation of EGFR via amplification, overexpression, or mutation has been demonstrated to induce tumor cell proliferation, migration, and metastasis.	('activation', 'PosReg', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('overexpression', 'PosReg', (47, 61))	('met', 'Gene', '79811', (148, 151))	('amplification', 'Var', (32, 45))	('induce', 'PosReg', (100, 106))	('migration', 'CPA', (133, 142))	('met', 'Gene', (148, 151))	('EGFR', 'Gene', '1956', (23, 27))	('mutation', 'Var', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('EGFR', 'Gene', (23, 27))
398717	33105560	The overall prevalence of EGFR amplification in EAC has been reported to be between 4 and 6%.	('EGFR', 'Gene', (26, 30))	('EAC', 'Phenotype', 'HP:0011459', (48, 51))	('EGFR', 'Gene', '1956', (26, 30))	('EAC', 'Disease', (48, 51))	('amplification', 'Var', (31, 44))
398732	33105560	Preclinical studies have demonstrated good antitumor activity of gefitinib in EAC cell lines, especially those with EGFR polysomy.	('gefitinib', 'Chemical', 'MESH:D000077156', (65, 74))	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('polysomy', 'Var', (121, 129))	('EAC', 'Disease', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('tumor', 'Disease', (47, 52))
398735	33105560	Subgroup analysis, however, demonstrated that, in the 20.2% of enrolled patients who had EGFR copy number gain (CNG) demonstrated by fluorescent in situ hybridization (FISH), there was significantly improved overall survival with gefitinib (HR 0.59, p = 0.05).	('improved', 'PosReg', (199, 207))	('EGFR', 'Gene', (89, 93))	('patients', 'Species', '9606', (72, 80))	('overall survival', 'MPA', (208, 224))	('copy number', 'Var', (94, 105))	('EGFR', 'Gene', '1956', (89, 93))	('gefitinib', 'Chemical', 'MESH:D000077156', (230, 239))	('gain', 'PosReg', (106, 110))
398736	33105560	Those patients with EGFR amplification (7.2%) benefited the most from gefitinib therapy (HR 0.21, p = 0.006).	('benefited', 'PosReg', (46, 55))	('EGFR', 'Gene', (20, 24))	('EGFR', 'Gene', '1956', (20, 24))	('gefitinib', 'Chemical', 'MESH:D000077156', (70, 79))	('patients', 'Species', '9606', (6, 14))	('amplification', 'Var', (25, 38))
398739	33105560	In a large single-intuition cohort of patients with metastatic gastroesophageal adenocarcinoma with EGFR amplification, anti-EGFR therapy was found to provide an excellent clinical response in a majority of patients.	('patients', 'Species', '9606', (207, 215))	('EGFR', 'Gene', '1956', (100, 104))	('amplification', 'Var', (105, 118))	('met', 'Gene', '79811', (52, 55))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (100, 104))	('met', 'Gene', (52, 55))	('EGFR', 'Gene', (125, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('gastroesophageal adenocarcinoma', 'Disease', (63, 94))	('patients', 'Species', '9606', (38, 46))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (69, 94))	('gastroesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (63, 94))
398743	33105560	Heterodimers that form with HER2 generate intracellular signals that are significantly more robust than other erbB receptors.	('HER2', 'Gene', '2064', (28, 32))	('erbB', 'Gene', (110, 114))	('Heterodimers', 'Var', (0, 12))	('erbB', 'Gene', '1956', (110, 114))	('more', 'PosReg', (87, 91))	('robust', 'MPA', (92, 98))	('intracellular signals', 'MPA', (42, 63))	('HER2', 'Gene', (28, 32))
398746	33105560	HER2 amplification has been demonstrated to be a poor prognostic indicator and oncogenic amplifications of HER2 have been reported in 20-30% of EAC cases as compared with just 3% in ESCC.	('HER2', 'Gene', '2064', (107, 111))	('amplifications', 'Var', (89, 103))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('EAC', 'Disease', (144, 147))	('HER2', 'Gene', (107, 111))
398764	33105560	Investigators uncovered an association between co-amplification of EGFR and HER2 and better clinical response to targeted HER2 therapy.	('HER2', 'Gene', (76, 80))	('HER2', 'Gene', '2064', (76, 80))	('co-amplification', 'Var', (47, 63))	('HER2', 'Gene', (122, 126))	('HER2', 'Gene', '2064', (122, 126))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))
398772	33105560	While VEGF expression has been associated with tumor progression and metastasis in ESCC, there has been little evidence of similar prognostic indication in EAC.	('met', 'Gene', '79811', (69, 72))	('met', 'Gene', (69, 72))	('VEGF', 'Gene', '7422', (6, 10))	('associated', 'Reg', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('VEGF', 'Gene', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ESCC', 'Disease', (83, 87))	('EAC', 'Phenotype', 'HP:0011459', (156, 159))	('expression', 'Var', (11, 21))	('tumor', 'Disease', (47, 52))
398790	33105560	Results demonstrated significantly prolonged median overall survival (6.5 vs 4.7 months, p = 0.0149) and progression-free survival (2.6 vs 1.8 months, p < 0.001) in patients receiving apatinib compared to placebo.	('apatinib', 'Var', (184, 192))	('overall', 'MPA', (52, 59))	('apatinib', 'Chemical', 'MESH:C553458', (184, 192))	('prolonged', 'PosReg', (35, 44))	('patients', 'Species', '9606', (165, 173))	('progression-free survival', 'CPA', (105, 130))
398799	33105560	Aberrant MET activation plays a critical role in tumor cell proliferation, invasion, and angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('invasion', 'CPA', (75, 83))	('tumor', 'Disease', (49, 54))	('MET', 'Gene', '79811', (9, 12))	('activation', 'PosReg', (13, 23))	('angiogenesis', 'CPA', (89, 101))	('MET', 'Gene', (9, 12))
398800	33105560	Genomic amplification of MET has been demonstrated to be a poor prognostic indicator in EAC.	('Genomic amplification', 'Var', (0, 21))	('MET', 'Gene', '79811', (25, 28))	('EAC', 'Phenotype', 'HP:0011459', (88, 91))	('EAC', 'Disease', (88, 91))	('MET', 'Gene', (25, 28))
398817	33105560	Genomic amplification of FGFR1 and FGFR2 has been reported in 3-4% of EAC samples and appeared to confer a poor prognostic in gastric adenocarcinoma.	('Genomic amplification', 'Var', (0, 21))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (126, 148))	('gastric adenocarcinoma', 'Disease', (126, 148))	('FGFR2', 'Gene', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('FGFR1', 'Gene', (25, 30))	('reported', 'Reg', (50, 58))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))	('FGFR1', 'Gene', '2260', (25, 30))
398821	33105560	Planned phase III trials are underway to evaluate if the addition of bemarituzumab to standard FOLFOX6 chemotherapy is beneficial in this subset of FGFR2b amplified tumors.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('amplified', 'Var', (155, 164))	('tumors', 'Disease', (165, 171))	('FOLFOX6', 'Chemical', '-', (95, 102))	('FGFR2b', 'Gene', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('bemarituzumab', 'Chemical', '-', (69, 82))
398822	33105560	AZD4547 is a highly selective small molecule tyrosine kinase inhibitor of FGFR1-3.	('FGFR1-3', 'Gene', '2260;2263;2261', (74, 81))	('AZD4547', 'Var', (0, 7))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR1-3', 'Gene', (74, 81))
398824	33105560	A recent phase II trial selected patients with advanced gastric adenocarcinoma and FGFR2 polysomy or gene amplification (via FISH) to receive AZD4547 or paclitaxel.	('polysomy', 'Var', (89, 97))	('FGFR2', 'Gene', (83, 88))	('patients', 'Species', '9606', (33, 41))	('paclitaxel', 'Chemical', 'MESH:D017239', (153, 163))	('gene amplification', 'Var', (101, 119))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (56, 78))	('AZD4547', 'Chemical', 'MESH:C572463', (142, 149))	('gastric adenocarcinoma', 'Disease', (56, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
398825	33105560	Exploratory biomarker analysis of FGFR2 amplification/polysomy demonstrated poor concordance with measured FGFR2 mRNA expression and significant intra-tumoral heterogeneity.	('intra-tumoral', 'Disease', 'MESH:D009369', (145, 158))	('FGFR2', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mRNA expression', 'MPA', (113, 128))	('intra-tumoral', 'Disease', (145, 158))	('amplification/polysomy', 'Var', (40, 62))
398830	33105560	Multiple studies have demonstrated enhanced anti-angiogenic effects with dual FGFR/VEGF therapy in solid tumors.	('VEGF', 'Gene', (83, 87))	('dual', 'Var', (73, 77))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('VEGF', 'Gene', '7422', (83, 87))	('enhanced', 'PosReg', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('anti-angiogenic effects', 'CPA', (44, 67))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('solid tumors', 'Disease', (99, 111))
398835	33105560	Aberrant regulation of mTOR has been proposed as a potential mechanism for the ineffectiveness of previously mentioned RTK-targeted therapies.	('RTK', 'Gene', '5979', (119, 122))	('regulation', 'MPA', (9, 19))	('Aberrant', 'Var', (0, 8))	('RTK', 'Gene', (119, 122))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (23, 27))
398847	33105560	In fact, some data suggest that dysregulated HSP90 expression may be responsible in potentiating the oncogenic effects of HER2, representing a potential mechanism of resistance to HER2-targeted therapies.	('oncogenic effects', 'CPA', (101, 118))	('HER2', 'Gene', (180, 184))	('potentiating', 'PosReg', (84, 96))	('HER2', 'Gene', '2064', (180, 184))	('dysregulated', 'Var', (32, 44))	('HER2', 'Gene', (122, 126))	('HSP90', 'Gene', (45, 50))	('HSP90', 'Gene', '3320', (45, 50))	('HER2', 'Gene', '2064', (122, 126))
398849	33105560	While clinical trials studying combined therapy in EAC are lacking, a published phase II trial found that a majority (69%) of patients with metastatic breast cancer, treated with the combination of the HSP90 inhibitor AUY992 and trastuzumab, achieved clinical response or stable disease.	('met', 'Gene', '79811', (140, 143))	('combination', 'Interaction', (183, 194))	('AUY992', 'Chemical', '-', (218, 224))	('stable disease', 'CPA', (272, 286))	('met', 'Gene', (140, 143))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('HSP90', 'Gene', (202, 207))	('AUY992', 'Var', (218, 224))	('HSP90', 'Gene', '3320', (202, 207))	('breast cancer', 'Disease', (151, 164))	('patients', 'Species', '9606', (126, 134))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('trastuzumab', 'Chemical', 'MESH:D000068878', (229, 240))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('clinical response', 'CPA', (251, 268))
398850	33105560	In EAC models, AUY992 has demonstrated robust antitumor activity when combined with 5-FU and cisplatin.	('AUY992', 'Chemical', '-', (15, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('AUY992', 'Var', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('5-FU', 'Chemical', 'MESH:D005472', (84, 88))
398851	33105560	An ongoing phase II clinical trial is evaluating the effects of AUY922 with docetaxel and irinotecan in patients with advanced gastroesophageal adenocarcinoma (NCT 01084330).	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('docetaxel', 'Chemical', 'MESH:D000077143', (76, 85))	('irinotecan', 'Chemical', 'MESH:D000077146', (90, 100))	('gastroesophageal adenocarcinoma', 'Disease', (127, 158))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (133, 158))	('AUY922', 'Var', (64, 70))	('gastroesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (127, 158))	('patients', 'Species', '9606', (104, 112))
398857	33105560	Preclinical studies have demonstrated AURKA overexpression to impair DNA damage repair through inhibition of RAD51, BRCA1, and BRCA2 (Figure 2).	('BRCA1', 'Gene', (116, 121))	('RAD51', 'Gene', '5888', (109, 114))	('AURKA', 'Gene', (38, 43))	('BRCA2', 'Gene', '675', (127, 132))	('AURKA', 'Gene', '6790', (38, 43))	('DNA damage repair', 'MPA', (69, 86))	('inhibition', 'NegReg', (95, 105))	('impair', 'NegReg', (62, 68))	('BRCA1', 'Gene', '672', (116, 121))	('BRCA2', 'Gene', (127, 132))	('overexpression', 'Var', (44, 58))	('RAD51', 'Gene', (109, 114))
398859	33105560	The inhibition of p53 occurs by the following two distinct mechanisms: MDM2-mediated degradation and direct phosphorylation at Ser315 and Ser215.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('Ser315', 'Chemical', '-', (127, 133))	('MDM2', 'Gene', '4193', (71, 75))	('MDM2', 'Gene', (71, 75))	('Ser215', 'Chemical', '-', (138, 144))	('degradation', 'MPA', (85, 96))	('phosphorylation', 'MPA', (108, 123))	('inhibition', 'NegReg', (4, 14))	('Ser215', 'Var', (138, 144))
398863	33105560	AURKA therapy in EAC is particularly interesting, due to the abundance of p53 mutations or deficiencies in human tumors.	('AURKA', 'Gene', (0, 5))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('human', 'Species', '9606', (107, 112))	('EAC', 'Phenotype', 'HP:0011459', (17, 20))	('mutations', 'Var', (78, 87))	('p53', 'Gene', (74, 77))	('EAC', 'Disease', (17, 20))	('AURKA', 'Gene', '6790', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('p53', 'Gene', '7157', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
398865	33105560	Alisertib (MLN8237) is a selective inhibitor of AURKA and has been shown in preclinical studies to induce mitotic spindle abnormalities, mitotic accumulation, and apoptosis.	('induce', 'PosReg', (99, 105))	('apoptosis', 'CPA', (163, 172))	('AURKA', 'Gene', (48, 53))	('mitotic accumulation', 'Disease', 'MESH:D004314', (137, 157))	('Alisertib', 'Chemical', 'MESH:C550258', (0, 9))	('mitotic spindle abnormalities', 'CPA', (106, 135))	('MLN8237', 'Chemical', 'MESH:C550258', (11, 18))	('MLN8237', 'Var', (11, 18))	('mitotic accumulation', 'Disease', (137, 157))	('AURKA', 'Gene', '6790', (48, 53))
398874	33105560	Preclinical studies have demonstrated that aberrant AXL expression was intimately involved in the resistance of EAC to standard chemotherapeutic regimens.	('involved', 'Reg', (82, 90))	('AXL', 'Gene', (52, 55))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('AXL', 'Gene', '558', (52, 55))	('aberrant', 'Var', (43, 51))
398877	33105560	In fact, AXL knockdown or pharmacologic AXL inhibition sensitizes resistant cells to epirubicin.	('AXL', 'Gene', '558', (40, 43))	('AXL', 'Gene', (9, 12))	('AXL', 'Gene', (40, 43))	('inhibition', 'NegReg', (44, 54))	('epirubicin', 'Chemical', 'MESH:D015251', (85, 95))	('knockdown', 'Var', (13, 22))	('AXL', 'Gene', '558', (9, 12))	('sensitizes', 'Reg', (55, 65))
398879	33105560	Subsequent studies have demonstrated that the AXL inhibitor NPS-1034 was effective in rendering these cells sensitive to EGFR-therapy.	('EGFR', 'Gene', '1956', (121, 125))	('AXL', 'Gene', (46, 49))	('NPS-1034', 'Chemical', 'MESH:C000588589', (60, 68))	('EGFR', 'Gene', (121, 125))	('AXL', 'Gene', '558', (46, 49))	('NPS-1034', 'Var', (60, 68))	('sensitive', 'MPA', (108, 117))
398889	33105560	In fact, high MSI was predictive of solid tumor response to PD-1 inhibition.	('tumor', 'Disease', (42, 47))	('MSI', 'MPA', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('high', 'Var', (9, 13))
398891	33105560	It was granted FDA approval as a third line therapy in advanced gastroesophageal adenocarcinoma expressing PD-L1 with high MSI or deficient mismatch repair (MMR).	('deficient', 'NegReg', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (70, 95))	('gastroesophageal adenocarcinoma', 'Disease', (64, 95))	('gastroesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (64, 95))	('PD-L1', 'Gene', (107, 112))	('high MSI', 'Var', (118, 126))
398895	33105560	Pembrolizumab monotherapy also improved median overall survival (17.4 vs. 10.8 months) in patients with high PD-L1 expression.	('improved', 'PosReg', (31, 39))	('PD-L1', 'Gene', (109, 114))	('expression', 'MPA', (115, 125))	('high', 'Var', (104, 108))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('overall survival', 'MPA', (47, 63))	('patients', 'Species', '9606', (90, 98))
398898	33105560	Recently reported results from the CheckMate 649 trial show significantly improved overall survival (14.4 vs. 11.1 months, p < 0.0001) and progression-free survival (7.7 vs. 6.1 months, p < 0.0001) when adding nivolumab to standard first line chemotherapy in patients with advanced gastroesophageal adenocarcinoma and high PD-L1 expression.	('expression', 'MPA', (329, 339))	('overall', 'MPA', (83, 90))	('high', 'Var', (318, 322))	('patients', 'Species', '9606', (259, 267))	('gastroesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (282, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (288, 313))	('progression-free survival', 'CPA', (139, 164))	('gastroesophageal adenocarcinoma', 'Disease', (282, 313))	('nivolumab', 'Chemical', 'MESH:D000077594', (210, 219))	('improved', 'PosReg', (74, 82))	('PD-L1', 'Gene', (323, 328))
398956	31614136	(Figure 2) Patients with locoregional recurrence had a significantly longer OS (median: 1.4 years, 95% CI 1.2-1.6) compared to patients with iBMEC (median: 1.0, 95%CI 0.6-1.5) or distant disease (median: 0.8, 95%CI 0.7-0.9) (p<0.001).	('patients', 'Species', '9606', (127, 135))	('longer', 'PosReg', (69, 75))	('locoregional', 'Var', (25, 37))	('iBMEC', 'Chemical', '-', (141, 146))	('Patients', 'Species', '9606', (11, 19))
398971	31614136	Median OS among patients with iBMEC with PCR was significantly longer than patients without PCR (1.56 years versus 0.66, p=0.019).	('iBMEC', 'Chemical', '-', (30, 35))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (75, 83))	('PCR', 'Var', (41, 44))	('iBMEC', 'Disease', (30, 35))
399029	31656898	Furthermore, the incorporation of the platinum(II) metal into their structure originated excellent theranostic agents for imaging, PDT, and molecular oxygen sensing.	('PDT', 'Disease', (131, 134))	('incorporation', 'Var', (17, 30))	('oxygen', 'Chemical', 'MESH:D010100', (150, 156))	('platinum(II)', 'Chemical', 'MESH:D010984', (38, 50))
399033	31656898	This can be explored to control the type of cell death in order to improve the effectiveness of PDT considering that an inflammatory response resulting from necrotic cell death after PDT can activate the antitumor immune response with implications also on vascular damage.	('necrotic cell death', 'Disease', 'MESH:D003643', (157, 176))	('vascular damage', 'Disease', 'MESH:D014652', (256, 271))	('necrotic cell death', 'Disease', (157, 176))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('vascular damage', 'Disease', (256, 271))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('PDT', 'Var', (183, 186))	('tumor', 'Disease', (208, 213))	('activate', 'PosReg', (191, 199))
399055	31656898	Also, regarding the protection of animals used for scientific purposes, the use of nonmammal embryos does not encompass any legal or ethical restrictions.- In a previous study, we demonstrated that chlorins 3 and 4 show a melanoma A375 cell uptake significantly higher than the ones observed for the corresponding diester derivatives 1 and 2.	('legal', 'Disease', 'MESH:D001766', (124, 129))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('chlorins', 'Chemical', 'MESH:C006969', (198, 206))	('chlorins', 'Var', (198, 206))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('legal', 'Disease', (124, 129))	('higher', 'PosReg', (262, 268))
399146	31404144	Beam geometry consisted of each treatment field with the following gantry angles: 0 /35 /70 /160 /200 /290 /325  (7 fields), 0 /35 /70 /160 /175 /200 /230 /290 /325  (9 fields), and 0 /35 /70 /160 /175 /200 /230 /290 /325  with an additional gantry angle based on individual irregular shape of tumor (10 fields).	('tumor', 'Disease', (294, 299))	('0 /35 /70 /160 /200 /290 /325', 'Var', (82, 111))	('0 /35 /70 /160 /175 /200 /230 /290 /325', 'Var', (182, 221))	('0 /35 /70 /160 /175 /200 /230 /290 /325', 'Var', (125, 164))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))
399157	31404144	For PTVs, D2, D98, D50, Dmean, conformity index (CI), and homogeneity index (HI) were analyzed.	('HI', 'Chemical', '-', (77, 79))	('D50', 'Var', (19, 22))	('D98', 'Var', (14, 17))	('PTV', 'Chemical', '-', (4, 7))
399159	31404144	The HI was defined as: HI = (D2-D98)/D50, where D2, D50, and D98 were the dose at 2, 50, and 98% of the PTV, respectively.	('HI', 'Chemical', '-', (4, 6))	('D98', 'Var', (61, 64))	('D50', 'Var', (52, 55))	('PTV', 'Chemical', '-', (104, 107))	('HI', 'Chemical', '-', (23, 25))
399170	31404144	The dose constraints were defined for OARs as follows: spinal cord < 50 Gy; total lungs: V5 < 60%, V20 < 30%, V30 < 20%, MLD < 20 Gy; heart: V30 <= 4 0%, V40 < 3 0%; liver: V20 <= 30%, V30 <= 20%.	('V30 < 20%', 'Var', (110, 119))	('MLD', 'Disease', (121, 124))	('V20 < 30%', 'Var', (99, 108))	('V20 <= 30%', 'Var', (173, 183))	('MLD', 'Disease', 'MESH:D007966', (121, 124))	('V40 < 3 0%', 'Var', (154, 164))	('V30 <=', 'Var', (185, 191))	('V30 <= 4 0%', 'Var', (141, 152))
399175	31404144	D2, D98, D50, and Dmean of PTVH as well as D98 of PTVL were significantly different in IMRT, VMAT, and HT (all p < 0.05).	('VMAT', 'Disease', 'None', (93, 97))	('D98', 'Var', (43, 46))	('VMAT', 'Disease', (93, 97))	('PTV', 'Chemical', '-', (27, 30))	('HT', 'Disease', 'MESH:D006973', (103, 105))	('D50', 'Var', (9, 12))	('IMRT', 'Disease', (87, 91))	('PTV', 'Chemical', '-', (50, 53))	('different', 'Reg', (74, 83))
399179	31404144	Besides, the three techniques generated different levels of D2 and D98 for PTVH and D2, D98, D50, and Dmean for PTVL (all p < 0.05).	('D98', 'Var', (88, 91))	('Dmean', 'MPA', (102, 107))	('D50', 'Var', (93, 96))	('PTV', 'Chemical', '-', (75, 78))	('D98', 'MPA', (67, 70))	('PTV', 'Chemical', '-', (112, 115))
399217	31404144	The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines suggested if limiting the risk of RP <= 20%, it was prudent to restrict V20 <= 30-35%, and MLD <= 20-23 Gy with conventional fractionation.	('MLD', 'Disease', 'MESH:D007966', (177, 180))	('MLD', 'Disease', (177, 180))	('V20 <=', 'Var', (158, 164))
399226	31404144	V30 and V50 of heart have also been regarded as vital predictors for cardiac toxicities.	('V50', 'Var', (8, 11))	('cardiac toxicities', 'Disease', 'MESH:D066126', (69, 87))	('cardiac toxicities', 'Disease', (69, 87))	('V30', 'Var', (0, 3))
399228	31404144	Although V30, V40, V50, and MHD of the heart were clinically acceptable in our study, it was really difficult to guarantee that heart V25 was <10% in particular for the middle and distal EC.	('MHD', 'Disease', 'None', (28, 31))	('MHD', 'Disease', (28, 31))	('V50', 'Var', (19, 22))	('V30', 'Var', (9, 12))	('V40', 'Var', (14, 17))
399295	30918589	The objective of our study is to evaluate the effectiveness of RFA and RFA+EMR in patients with BE with HGD and intramucosal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('patients', 'Species', '9606', (82, 90))	('intramucosal carcinoma', 'Disease', 'MESH:D002277', (112, 134))	('intramucosal carcinoma', 'Disease', (112, 134))	('RFA+EMR', 'Var', (71, 78))	('BE', 'Phenotype', 'HP:0100580', (96, 98))
399298	30918589	A higher eradication rate was observed in patients submitted to RFA + EMR compared to patients submitted to RFA isolated [RD 0.35 (0.15, 0.56)].	('eradication', 'MPA', (9, 20))	('patients', 'Species', '9606', (42, 50))	('RFA + EMR', 'Var', (64, 73))	('patients', 'Species', '9606', (86, 94))
399328	29190975	The pooled results showed DFS was significantly worse in EC patients with high plasma fibrinogen (HR = 1.21; 95% CI = 1.06-1.37; p < 0.001) (Figure 3).	('fibrinogen', 'Gene', '2244', (86, 96))	('DFS', 'MPA', (26, 29))	('fibrinogen', 'Gene', (86, 96))	('high plasma fibrinogen', 'Phenotype', 'HP:0011899', (74, 96))	('high', 'Var', (74, 78))	('worse', 'NegReg', (48, 53))	('patients', 'Species', '9606', (60, 68))
399378	27878270	Histone 3 lysine 9 (H3K9), H3K27 and H4K20 methylation are associated with transcriptional repression, whereas methylation of H3K4, H3K36 and H3K79 are associated with transcriptional activation.	('H3K79', 'Var', (142, 147))	('lysine', 'Chemical', 'MESH:D008239', (10, 16))	('methylation', 'Var', (111, 122))	('methylation', 'Var', (43, 54))	('transcriptional repression', 'MPA', (75, 101))	('associated', 'Reg', (59, 69))	('H3K4', 'Protein', (126, 130))	('transcriptional activation', 'MPA', (168, 194))	('H3K36', 'Var', (132, 137))	('H4K20', 'Protein', (37, 42))	('H3K27', 'Protein', (27, 32))
399379	27878270	Certain studies have revealed that the process of inflammation and infection in inflammatory cells is regulated by histone methylation, including H3K4, H3K9 and H3K27 methylation.	('infection', 'Disease', 'MESH:D007239', (67, 76))	('histone', 'Protein', (115, 122))	('inflammation', 'Disease', 'MESH:D007249', (50, 62))	('methylation', 'Var', (167, 178))	('inflammation', 'Disease', (50, 62))	('regulated', 'Reg', (102, 111))	('H3K9', 'Protein', (152, 156))	('H3K27', 'Protein', (161, 166))	('H3K4', 'Protein', (146, 150))	('infection', 'Disease', (67, 76))
399380	27878270	Specific HMTs or HDMs were revealed to link histone methylation to transcriptional genes of inflammation/infection, including nuclear factor kappaB (NF-kappaB), tumor necrosis factor-alpha and interleukin-6, when inflammatory cells, particularly Mon or macrophages, were investigated in vitro.	('transcriptional genes', 'Gene', (67, 88))	('NF-kappaB', 'Gene', (149, 158))	('interleukin-6', 'Gene', '3569', (193, 206))	('tumor necrosis factor-alpha', 'Gene', (161, 188))	('tumor necrosis factor-alpha', 'Gene', '7124', (161, 188))	('inflammation/infection', 'Disease', (92, 114))	('histone methylation', 'Var', (44, 63))	('link', 'Reg', (39, 43))	('inflammation/infection', 'Disease', 'MESH:D007249', (92, 114))	('kappaB', 'Gene', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('kappaB', 'Gene', '4790', (141, 147))	('NF-kappaB', 'Gene', '4790', (149, 158))	('kappaB', 'Gene', '4790', (152, 158))	('interleukin-6', 'Gene', (193, 206))	('kappaB', 'Gene', (152, 158))
399421	27878270	Notably, H3 from each sample contained three bands, with the largest band corresponding to the intact H3 probed with histone H3K9me2 antibody (data not shown), suggesting that the two smaller bands were derived from cleavage of histone H3 following K9 residues in WBCs.	('histone H3', 'Gene', '260423', (228, 238))	('histone H3', 'Gene', (228, 238))	('derived from', 'Reg', (203, 215))	('K9 residues', 'Var', (249, 260))	('H3K9me2', 'Chemical', '-', (125, 132))	('histone H3', 'Gene', '260423', (117, 127))	('histone H3', 'Gene', (117, 127))
399422	27878270	H3 cleavage following residues A21 to K27 in mouse embryonic stem cells has been reported previously, suggesting that the cleaved N-terminal fragments, including A1-A21, A1-A23 and A1-A27, containing the target K9 residue, escaped detection.	('A1-A21', 'Var', (162, 168))	('mouse', 'Species', '10090', (45, 50))	('A1-A27', 'Var', (181, 187))	('A1-A23', 'Var', (170, 176))
399441	27878270	By contrast, in cancer patients, the AUC values of H3K9me2 in the three WBCs were 0.88 for Neu, 0.84 for Lym and 0.80 for Mon, all greater than the 0.67 demonstrated by CRP (Fig.	('CRP', 'Gene', (169, 172))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('patients', 'Species', '9606', (23, 31))	('CRP', 'Gene', '1401', (169, 172))	('cancer', 'Disease', (16, 22))	('H3K9me2', 'Var', (51, 58))	('AUC', 'MPA', (37, 40))	('H3K9me2', 'Chemical', '-', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
399443	27878270	Considering the percentage of Neu of total WBCs, H3K9me2 in WBCs exhibited a unique diagnostic significance for the occurrence of sepsis in cancer patients compared with the commonly used indicator.	('sepsis', 'Phenotype', 'HP:0100806', (130, 136))	('sepsis', 'Disease', (130, 136))	('sepsis', 'Disease', 'MESH:D018805', (130, 136))	('H3K9me2', 'Chemical', '-', (49, 56))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (147, 155))	('H3K9me2', 'Var', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
399444	27878270	Previous studies have suggested that the inflammatory response in sepsis is regulated by histone methylation, including H3K4, H3K9 and H3K27 methylation.	('regulated', 'Reg', (76, 85))	('H3K4', 'Protein', (120, 124))	('H3K27 methylation', 'Var', (135, 152))	('histone', 'Protein', (89, 96))	('H3K9', 'Protein', (126, 130))	('sepsis', 'Disease', (66, 72))	('sepsis', 'Phenotype', 'HP:0100806', (66, 72))	('methylation', 'Var', (141, 152))	('sepsis', 'Disease', 'MESH:D018805', (66, 72))	('inflammatory response', 'CPA', (41, 62))
399461	27878270	The observation that the level of H3K9me2 is altered in sepsis is of interest, and other histone methylations, including H3K4, H3K27, H3K36, H3K79, H4K20 and arginine methylation, will be investigated in the future.	('altered', 'Reg', (45, 52))	('H3K36', 'Var', (134, 139))	('H3K9me2', 'Var', (34, 41))	('H3K9me2', 'Chemical', '-', (34, 41))	('arginine', 'Chemical', 'MESH:D001120', (158, 166))	('sepsis', 'Disease', (56, 62))	('sepsis', 'Phenotype', 'HP:0100806', (56, 62))	('H4K20', 'Var', (148, 153))	('H3K4', 'Var', (121, 125))	('H3K27', 'Var', (127, 132))	('sepsis', 'Disease', 'MESH:D018805', (56, 62))	('H3K79', 'Var', (141, 146))
399466	27878270	H3K9me2 histone 3 lysine 9 dimethylation WBCs white blood cells Neu neutrophils Lym lymphocytes Mon monocytes CRP C-reactive protein APACHE II Acute Physiology and Chronic Health Evaluation II SOFA Sequential Organ Failure Assessment AUC area under the curve	('CRP', 'Gene', (110, 113))	('CRP', 'Gene', '1401', (110, 113))	('C-reactive protein', 'Gene', (114, 132))	('C-reactive protein', 'Gene', '1401', (114, 132))	('H3K9me2', 'Chemical', '-', (0, 7))	('lysine', 'Chemical', 'MESH:D008239', (18, 24))	('H3K9me2', 'Var', (0, 7))
399534	27036540	Based on our data, the intraoperative blood loss in the group of TLTG was less than that in the group of LATG, but this value was not statistically significant.	('TLTG', 'Var', (65, 69))	('intraoperative blood loss', 'Disease', (23, 48))	('less', 'NegReg', (74, 78))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (23, 48))	('LTG', 'Chemical', '-', (66, 69))	('LATG', 'Chemical', '-', (105, 109))
399588	26252309	To produce DTA-expressing lentivirus in HEK293T cells, a modified HEK293T cell line that could express mutated elongation factor 2 (mEF-2) should be established.	('mutated', 'Var', (103, 110))	('HEK293T', 'CellLine', 'CVCL:0063', (40, 47))	('mEF-2', 'Gene', (132, 137))	('mEF-2', 'Gene', '13629', (132, 137))	('HEK293T', 'CellLine', 'CVCL:0063', (66, 73))	('DTA', 'Chemical', '-', (11, 14))	('elongation factor 2', 'Gene', '1938', (111, 130))	('elongation factor 2', 'Gene', (111, 130))
399590	26252309	The PCR products of EF-2 were extracted and then digested with EcoRI and BamHI enzymes; following the digestion, pCDH-CMV-EF-2-EF1-puro was obtained after the insertion of digested products of EF-2 into pCDH-CMV-MCS-EF1-puro, and the mutagenesis of human EF-2 was subsequently performed by the site-directed mutagenesis of codon 717(G717R, GGA to CGA) using a Site-Directed Mutagenesis Kit (Stratagene, San Diego, USA).	('EF-2', 'Gene', (122, 126))	('G717R', 'Var', (333, 338))	('EF-2', 'Gene', '1938', (193, 197))	('EF-2', 'Gene', (255, 259))	('EF-2-EF1', 'CellLine', 'CVCL:3569', (122, 130))	('CGA', 'Gene', (347, 350))	('EF-2', 'Gene', (20, 24))	('EF-2', 'Gene', '1938', (20, 24))	('human', 'Species', '9606', (249, 254))	('G717R', 'Mutation', 'rs757666325', (333, 338))	('EF-2', 'Gene', (193, 197))	('EF-2', 'Gene', '1938', (122, 126))	('mutagenesis', 'Var', (308, 319))	('CGA', 'Gene', '1113', (347, 350))	('EF-2', 'Gene', '1938', (255, 259))
399615	26252309	Moreover, the activities of these 2 promoters in different cancer cells, including HeLa, Eca109, and ZR-7530, were analyzed after the co-transfection of pGL3 and pRL-TK, and we found that Surp1430 has a stronger activity than does Surp269 in all of these cells (Figure 3C).	('Surp1430', 'Var', (188, 196))	('pGL3', 'Gene', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('stronger', 'PosReg', (203, 211))	('pGL3', 'Gene', '6391', (153, 157))	('activity', 'MPA', (212, 220))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('HeLa', 'CellLine', 'CVCL:0030', (83, 87))
399619	26252309	Therefore, we conclude that the Survivin promoter is a good driver for the expression of toxic genes, and Surp1430 is a better candidate than Surp269 in cancer gene therapy.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('Surp1430', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Survivin', 'Gene', '11799', (32, 40))	('Survivin', 'Gene', (32, 40))
399628	26252309	In addition, we induced a direct point mutation at the G717 residue of EF-2 with specific primers, thereby achieving the overexpression of mEF-2 in wild-type HEK293T after the establishment of a stable cell line named HEK293T[mEF-2(G717R)], which was infected with mEF-2-expressing lentivirus and selected with drugs.	('EF-2', 'Gene', '1938', (227, 231))	('G717R', 'Mutation', 'rs757666325', (232, 237))	('HEK293T', 'CellLine', 'CVCL:0063', (158, 165))	('mEF-2', 'Gene', (226, 231))	('mEF-2', 'Gene', '13629', (226, 231))	('EF-2', 'Gene', (71, 75))	('mEF-2', 'Gene', (139, 144))	('mEF-2', 'Gene', '13629', (139, 144))	('achieving', 'PosReg', (107, 116))	('overexpression', 'PosReg', (121, 135))	('EF-2', 'Gene', (266, 270))	('mEF-2', 'Gene', (265, 270))	('EF-2', 'Gene', (140, 144))	('mEF-2', 'Gene', '13629', (265, 270))	('point mutation at', 'Var', (33, 50))	('EF-2', 'Gene', '1938', (71, 75))	('EF-2', 'Gene', (227, 231))	('EF-2', 'Gene', '1938', (266, 270))	('HEK293T', 'CellLine', 'CVCL:0063', (218, 225))	('G717', 'Var', (55, 59))	('EF-2', 'Gene', '1938', (140, 144))
399630	26252309	After the co-transfection of the lentiviral vector with pMDLg/pRRE (RRK262263264AAH), pRSV-Rev and VSVG into HEK293T[mEF-2(G717R)], we obtained all of the IDLVs.	('HEK293T', 'CellLine', 'CVCL:0063', (109, 116))	('RRK262263264AAH', 'Var', (68, 83))	('G717R', 'Mutation', 'rs757666325', (123, 128))	('mEF-2', 'Gene', (117, 122))	('pRSV', 'Species', '12205', (86, 90))	('mEF-2', 'Gene', '13629', (117, 122))
399632	26252309	As shown in Figure 6, compared to pPRIME-CMV-GFP-FF3, a weaker fluorescence occurred after the transfection of pPRIME-CMV-GFP-2A-DTA-FF3 into HEK293T[mEF-2(G717R)]; however, the absence of fluorescence was found after the transfection of pPRIME-CMV-GFP-2A-DTA-FF3 into wild-type HEK293T (Figure S4 http://links.lww.com/MD/A359).	('HEK293T', 'CellLine', 'CVCL:0063', (142, 149))	('fluorescence', 'MPA', (63, 75))	('DTA', 'Chemical', '-', (256, 259))	('DTA', 'Chemical', '-', (129, 132))	('pPRIME-CMV-GFP-2A-DTA-FF3', 'Var', (111, 136))	('G717R', 'Mutation', 'rs757666325', (156, 161))	('mEF-2', 'Gene', (150, 155))	('HEK293T', 'CellLine', 'CVCL:0063', (279, 286))	('mEF-2', 'Gene', '13629', (150, 155))	('weaker', 'NegReg', (56, 62))
399633	26252309	Additionally, very weak fluorescence was observed after the transfection of pPRIME-Surp1430-GFP-FF3 into HEK293T.	('pPRIME-Surp1430-GFP-FF3', 'Var', (76, 99))	('fluorescence', 'MPA', (24, 36))	('weak', 'NegReg', (19, 23))	('HEK293T', 'CellLine', 'CVCL:0063', (105, 112))
399634	26252309	Moreover, almost no fluorescence was observed after the transfection of pPRIME-Surp1430-GFP-2A-DTA-FF3 into HEK293T[mEF-2(G717R)], indicating that HEK293T[mEF-2(G717R)] was successfully obtained and the DTA we used is effective for protein synthesis inhibition.	('protein', 'MPA', (232, 239))	('DTA', 'Chemical', '-', (95, 98))	('mEF-2', 'Gene', '13629', (155, 160))	('G717R', 'Mutation', 'rs757666325', (161, 166))	('mEF-2', 'Gene', (116, 121))	('G717R', 'Mutation', 'rs757666325', (122, 127))	('HEK293T', 'CellLine', 'CVCL:0063', (147, 154))	('pPRIME-Surp1430-GFP-2A-DTA-FF3', 'Var', (72, 102))	('mEF-2', 'Gene', '13629', (116, 121))	('HEK293T', 'CellLine', 'CVCL:0063', (108, 115))	('mEF-2', 'Gene', (155, 160))	('DTA', 'Chemical', '-', (203, 206))
399635	26252309	To validate the effect of DTA-expressing IDLV in cancer gene therapy, we established xenografts with ZR7530 in nude mice; these nude mice were randomly assigned into 4 different groups, and every group had 5 nude mice that were used in the experiment (n = 5).	('nude mice', 'Species', '10090', (111, 120))	('nude mice', 'Species', '10090', (128, 137))	('nude mice', 'Species', '10090', (208, 217))	('ZR7530', 'Var', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('DTA', 'Chemical', '-', (26, 29))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
399636	26252309	When tumors were produced in these nude mice and when the volume of these tumors grew to approximately 35 mm3, we injected concentrated DTA-expressing IDLVs into different groups; the first group received the pPRIME-CMV-GFP-FF3, the second group received the pPRIME-Surp1430-GFP-FF3, the third group received the pPRIME-CMV-GFP-2A-DTA-FF3, and the fourth group received the pPRIME-Surp1430-GFP-2A-DTA-FF3.	('nude mice', 'Species', '10090', (35, 44))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('DTA', 'Chemical', '-', (331, 334))	('pPRIME-Surp1430-GFP-2A-DTA-FF3', 'Var', (374, 404))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('DTA', 'Chemical', '-', (397, 400))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('DTA', 'Chemical', '-', (136, 139))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
399640	26252309	Although we observed tumor repression in the tested groups after repeated injection of DTA-expressing IDLVs, the tumors could not be completely eradicated, and a very small mass of tumors survived until mouse dissection.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (181, 186))	('mouse', 'Species', '10090', (203, 208))	('tumors', 'Disease', (113, 119))	('tumor', 'Disease', (21, 26))	('tumors', 'Disease', (181, 187))	('DTA-expressing', 'Var', (87, 101))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('DTA', 'Chemical', '-', (87, 90))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
399641	26252309	As expected, we found no potential toxicity on the whole body weight after dissection in the nude mice those were injected with pPRIME-CMV-GFP-FF3 or pPRIME-Surp1430-GFP-FF3, and no significant difference occurred between these 2 groups (P = 0.8119, P > 0.05); in addition, no adverse effect on whole body weight of nude mice injected with pPRIME-Surp1430-GFP-2A-DTA-FF3 when compared with pPRIME-CMV-GFP-FF3 (P = 0.3453, P > 0.05).	('pPRIME-Surp1430-GFP-2A-DTA-FF3', 'Var', (340, 370))	('DTA', 'Chemical', '-', (363, 366))	('toxicity', 'Disease', 'MESH:D064420', (35, 43))	('toxicity', 'Disease', (35, 43))	('nude mice', 'Species', '10090', (316, 325))	('nude mice', 'Species', '10090', (93, 102))
399645	26252309	Compared to the CMV promoter, the activity of Surp1430 is much lower than that of the CMV promoter in normal cells; however, the activity of Surp1430 is comparable to that of the CMV promoter in cancer cells, thereby guaranteeing the abundant and specific expression of DTA in cancer cells.	('DTA', 'Chemical', '-', (270, 273))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('Surp1430', 'Var', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('expression', 'MPA', (256, 266))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
399650	26252309	However, the activity of Surp1430 is very weak in HEK293T cells because the fluorescence that is driven by Surp1430 is much weaker than that is driven by CMV promoter.	('Surp1430', 'Var', (107, 115))	('fluorescence', 'MPA', (76, 88))	('weaker', 'NegReg', (124, 130))	('HEK293T', 'CellLine', 'CVCL:0063', (50, 57))
399651	26252309	In contrast, almost no fluorescence was observed after the transfection of pPRIME-Surp1430-GFP-2A-DTA-FF3 into HEK293T[mEF-2(G717R)] cells.	('HEK293T', 'CellLine', 'CVCL:0063', (111, 118))	('pPRIME-Surp1430-GFP-2A-DTA-FF3', 'Var', (75, 105))	('mEF-2', 'Gene', (119, 124))	('DTA', 'Chemical', '-', (98, 101))	('mEF-2', 'Gene', '13629', (119, 124))	('G717R', 'Mutation', 'rs757666325', (125, 130))
399654	26252309	As discussed in our previous study, many key amino acid residues in integrase have been modified for the generation of IDLVs, and these IDLVs have been used to infect mouse or human cells in vitro and in vivo.	('human', 'Species', '9606', (176, 181))	('infect', 'Reg', (160, 166))	('mouse', 'Species', '10090', (167, 172))	('modified', 'Var', (88, 96))
399659	26252309	Although we noted a very small mass of tumors in nude mice after the injection of DTA-expressing IDLVs, their killing effect on xenografts tumors is significant, and their failure in the penetration of IDLVs across tumor masses may be responsible for the survival of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('DTA', 'Chemical', '-', (82, 85))	('tumor', 'Disease', (273, 278))	('tumors', 'Disease', (39, 45))	('nude mice', 'Species', '10090', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('pen', 'Chemical', 'MESH:C058388', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (273, 279))	('tumor', 'Disease', (215, 220))	('tumors', 'Disease', (273, 279))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('DTA-expressing', 'Var', (82, 96))
399666	26252309	Meanwhile, we successfully obtained a modified HEK293T, HEK293T[mEF-2(G717R)], for use in DTA-expressing IDLVs production.	('HEK293T', 'Var', (56, 63))	('HEK293T', 'CellLine', 'CVCL:0063', (47, 54))	('mEF-2', 'Gene', (64, 69))	('mEF-2', 'Gene', '13629', (64, 69))	('G717R', 'Mutation', 'rs757666325', (70, 75))	('HEK293T', 'CellLine', 'CVCL:0063', (56, 63))	('DTA', 'Chemical', '-', (90, 93))
399671	26451118	Thus, we performed a meta-analysis by incorporating all available evidence to evaluate the rate of PD-L1 positivity and the overall survival (OS) according to PD-L1 status in patients with gastrointestinal tract cancer.	('gastrointestinal tract cancer', 'Disease', 'MESH:D004067', (189, 218))	('PD-L1', 'Gene', '29126', (159, 164))	('OS', 'Chemical', '-', (142, 144))	('gastrointestinal tract cancer', 'Disease', (189, 218))	('PD-L1', 'Gene', (99, 104))	('patients', 'Species', '9606', (175, 183))	('PD-L1', 'Gene', '29126', (99, 104))	('positivity', 'Var', (105, 115))	('gastrointestinal tract cancer', 'Phenotype', 'HP:0007378', (189, 218))	('PD-L1', 'Gene', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
399679	26451118	Additionally, positive PD-L1 expression status in tumor cells is a risk factor for prognosis of gastrointestinal tract cancer, especially esophageal cancer.	('gastrointestinal tract cancer', 'Disease', 'MESH:D004067', (96, 125))	('PD-L1', 'Gene', (23, 28))	('gastrointestinal tract cancer', 'Disease', (96, 125))	('especially esophageal cancer', 'Disease', (127, 155))	('especially esophageal cancer', 'Disease', 'MESH:D004938', (127, 155))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('PD-L1', 'Gene', '29126', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('positive', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('expression', 'MPA', (29, 39))	('gastrointestinal tract cancer', 'Phenotype', 'HP:0007378', (96, 125))	('tumor', 'Disease', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
399707	26451118	Overall, positive expression of PD-L1 in the tumor cells of gastrointestinal tract cancer patients was associated with a significantly poorer OS than negative expression (HR 1.61, 95% CI 1.10-2.35, P=0.014) (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('positive expression', 'Var', (9, 28))	('PD-L1', 'Gene', (32, 37))	('OS', 'Chemical', '-', (142, 144))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', (45, 50))	('gastrointestinal tract cancer', 'Disease', 'MESH:D004067', (60, 89))	('gastrointestinal tract cancer', 'Phenotype', 'HP:0007378', (60, 89))	('PD-L1', 'Gene', '29126', (32, 37))	('poorer', 'NegReg', (135, 141))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('gastrointestinal tract cancer', 'Disease', (60, 89))
399715	26451118	Furthermore, patients with positive expression of PD-L1 had significantly poorer survival than with those with negative expression.	('poorer', 'NegReg', (74, 80))	('PD-L1', 'Gene', (50, 55))	('patients', 'Species', '9606', (13, 21))	('survival', 'MPA', (81, 89))	('positive expression', 'Var', (27, 46))	('PD-L1', 'Gene', '29126', (50, 55))
399753	26248051	Lithium chloride L9650, lithium carbonate 255823, rapamycin R8781, 5-fluorouracil (5-FU) F6627, chloroquine C66288.	('lithium carbonate', 'Chemical', 'MESH:D016651', (24, 41))	('R8781', 'Var', (60, 65))	('5-FU', 'Chemical', 'MESH:D005472', (83, 87))	('Lithium chloride', 'Chemical', 'MESH:D018021', (0, 16))	('L9650', 'Var', (17, 22))
399781	26248051	Loss of LAMP1, an abundant lysosomal membrane protein is often associated with lysosome consumption.	('lysosome consumption', 'Disease', (79, 99))	('LAMP1', 'Gene', (8, 13))	('associated', 'Reg', (63, 73))	('LAMP1', 'Gene', '3916', (8, 13))	('Loss', 'Var', (0, 4))
399805	26248051	Impairment of autophagic flux by B10, a derivative of betulinic acid was also reported to convert autophagy in glioblastoma cells into a cell death process associated with lysosomal destabilization and the anti-tumour activity of recombinant Galectin 9 was also associated with impairment of lysosomal function and fatal frustration of autophagy.	('autophagic flux', 'CPA', (14, 29))	('convert', 'Reg', (90, 97))	('Galectin 9', 'Gene', '3965', (242, 252))	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('Galectin 9', 'Gene', (242, 252))	('B10', 'Var', (33, 36))	('tumour', 'Disease', (211, 217))	('betulinic acid', 'Chemical', 'MESH:C002070', (54, 68))	('autophagy', 'CPA', (98, 107))	('impairment of lysosomal function', 'Disease', (278, 310))	('impairment of lysosomal function', 'Disease', 'MESH:D003072', (278, 310))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))
399806	26248051	The causes of LMP include deficiencies in LAMP 1/2 proteins, increased cytosolic calcium, imbalance in specific membrane lipids (sphingolipids & cholesterol) and reactive oxygen species.	('cytosolic calcium', 'MPA', (71, 88))	('lipids', 'Chemical', 'MESH:D008055', (121, 127))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (162, 185))	('and reactive oxygen', 'MPA', (158, 177))	('lipids', 'Chemical', 'MESH:D008055', (136, 142))	('imbalance', 'Phenotype', 'HP:0002172', (90, 99))	('sphingolipids', 'Chemical', 'MESH:D013107', (129, 142))	('calcium', 'Chemical', 'MESH:D002118', (81, 88))	('LAMP 1/2 proteins', 'Protein', (42, 59))	('increased', 'PosReg', (61, 70))	('LMP', 'Disease', (14, 17))	('cholesterol', 'Chemical', 'MESH:D002784', (145, 156))	('deficiencies', 'Var', (26, 38))
399823	26227631	New strategies including monoclonal antibodies and tyrosine kinase inhibitors explore molecular targets that are normally deregulated in cancer cells, and represent a new hope for patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tyrosine', 'Var', (51, 59))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('patients', 'Species', '9606', (180, 188))
399840	26227631	The stromal phenotype change also induces ECM remodeling, resulting in the release of new growth factors and ECM molecules, such as collagen I and III, tenascin C and versican, besides matrix metalloproteinases (MMP) 2 and 9.	('change', 'Var', (22, 28))	('MMP', 'Gene', (212, 215))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('MMP', 'Gene', '4314;4318;4320;8510', (212, 215))	('induces', 'Reg', (34, 41))	('tenascin C', 'Gene', (152, 162))	('tenascin C', 'Gene', '3371', (152, 162))	('versican', 'Gene', (167, 175))	('ECM remodeling', 'CPA', (42, 56))	('release of new growth factors', 'MPA', (75, 104))	('versican', 'Gene', '1462', (167, 175))	('stromal phenotype', 'CPA', (4, 21))
399841	26227631	In addition, TGF-beta inhibition was demonstrated to decrease the formation of new blood vessels in xenograft prostate cancer model, as well as apoptosis rates of prostatic myofibroblasts.	('inhibition', 'Var', (22, 32))	('decrease', 'NegReg', (53, 61))	('formation of new blood vessels', 'CPA', (66, 96))	('xenograft prostate cancer', 'Disease', 'MESH:D011471', (100, 125))	('TGF-beta', 'Gene', '7040', (13, 21))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('TGF-beta', 'Gene', (13, 21))	('xenograft prostate cancer', 'Disease', (100, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('apoptosis rates', 'CPA', (144, 159))
399853	26227631	In a study using in vitro and in vivo approaches, these authors showed that transformation of human mammary epithelial cells mediated by transfection with HRAS and hTERT increased cell proliferation and survival in vitro.	('hTERT', 'Gene', (164, 169))	('HRAS', 'Gene', '3265', (155, 159))	('transfection', 'Var', (137, 149))	('increased', 'PosReg', (170, 179))	('HRAS', 'Gene', (155, 159))	('survival', 'CPA', (203, 211))	('cell proliferation', 'CPA', (180, 198))	('human', 'Species', '9606', (94, 99))	('hTERT', 'Gene', '7015', (164, 169))
399889	26227631	Inefficient lymph vessels drainage along with immaturity of tumor vessels creates a heterogeneous scenario mainly represented by hypoxia areas and variations in the interstitial pressure, that ultimately impacts in tumor progression and resistance to treatment.	('hypoxia', 'Disease', 'MESH:D000860', (129, 136))	('resistance to treatment', 'CPA', (237, 260))	('impacts', 'Reg', (204, 211))	('variations', 'Var', (147, 157))	('lymph vessels drainage', 'CPA', (12, 34))	('hypoxia', 'Disease', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Inefficient', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', (60, 65))
399894	26227631	The increment of Rac1b expression increases ROS level that, in turn, produces DNA damage and genomic instability, besides promoting EMT activation by stimulating the expression of the transcription factor Snail.	('Snail', 'Gene', '6615', (205, 210))	('stimulating', 'PosReg', (150, 161))	('ROS level', 'MPA', (44, 53))	('genomic instability', 'CPA', (93, 112))	('Rac1b', 'Gene', (17, 22))	('produces', 'Reg', (69, 77))	('EMT activation', 'CPA', (132, 146))	('increases ROS level', 'Phenotype', 'HP:0025464', (34, 53))	('expression', 'Var', (23, 33))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('DNA damage', 'MPA', (78, 88))	('increment', 'Var', (4, 13))	('promoting', 'PosReg', (122, 131))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('expression', 'MPA', (166, 176))	('Snail', 'Gene', (205, 210))	('increases', 'PosReg', (34, 43))
399905	26227631	On the other hand, DTF stromal gene expression correlated with better prognosis and overall survival not only for breast cancer, but also for ovarian, lung and colon tumors.	('lung', 'Disease', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('DTF', 'Var', (19, 22))	('ovarian', 'Disease', (142, 149))	('colon tumors', 'Phenotype', 'HP:0100273', (160, 172))	('colon tumors', 'Disease', 'MESH:D015179', (160, 172))	('better', 'PosReg', (63, 69))	('colon tumors', 'Disease', (160, 172))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))	('prognosis', 'CPA', (70, 79))
399931	26227631	Moreover, these alterations culminated in the transformation and invasion of epithelial cells from the ovaries and oral cavity.	('ovaries', 'Disease', 'MESH:D010051', (103, 110))	('alterations', 'Var', (16, 27))	('invasion of epithelial cells', 'CPA', (65, 93))	('transformation', 'CPA', (46, 60))	('culminated in', 'Reg', (28, 41))	('ovaries', 'Disease', (103, 110))
399933	26227631	Moreover, the importance of TP53 status in microenvironment was reinforced by the observation that the melanoma cell line B16F1 inoculated in p53-null mice produces tumors greatly faster than p53-wild type mice.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('mice', 'Species', '10090', (151, 155))	('tumors', 'Disease', (165, 171))	('mice', 'Species', '10090', (206, 210))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('faster', 'PosReg', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('p53-null', 'Var', (142, 150))	('B16F1', 'CellLine', 'CVCL:0158', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
399940	26227631	APC deletion was associated with the development of an advanced malignant phenotype represented by myofibroblast infiltration, release of angiogenic factor promoters, including VEGF and SDF, and a decrease in responsiveness to progesterone and estradiol via reduction of receptor expression.	('VEGF', 'Gene', '7422', (177, 181))	('estradiol', 'Chemical', 'MESH:D004958', (244, 253))	('APC', 'Gene', (0, 3))	('progesterone', 'Chemical', 'MESH:D011374', (227, 239))	('VEGF', 'Gene', (177, 181))	('release of', 'MPA', (127, 137))	('APC', 'Gene', '324', (0, 3))	('deletion', 'Var', (4, 12))	('myofibroblast infiltration', 'CPA', (99, 125))	('receptor', 'Protein', (271, 279))	('decrease', 'NegReg', (197, 205))	('reduction', 'NegReg', (258, 267))
399948	26227631	Particularly in esophageal squamous cell carcinoma, deletion of TGFBR2 in mouse fibroblasts in vivo resulted in extensive genetic and epigenetic alterations, such as loss of cyclin inhibitors p15 and p16, as well as hypermethylation of the p21WAF1 promoter in surrounding epithelial cells (Fig.	('esophageal squamous cell carcinoma', 'Disease', (16, 50))	('p15', 'Gene', (192, 195))	('p15', 'Gene', '12579', (192, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('loss', 'NegReg', (166, 170))	('cyclin', 'Gene', (174, 180))	('hypermethylation', 'MPA', (216, 232))	('p16', 'Gene', '12578', (200, 203))	('cyclin', 'Gene', '18538', (174, 180))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (16, 50))	('mouse', 'Species', '10090', (74, 79))	('TGFBR2', 'Gene', (64, 70))	('p16', 'Gene', (200, 203))	('deletion', 'Var', (52, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))
399951	26227631	For instance, some genetic deletions comprising regions bearing leucocyte stimulating factors can be deleted leading to poor local lymphocyte proliferation, as shown for the IL-15 deletion in colorectal tumors.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('deletion', 'Var', (180, 188))	('IL-15', 'Gene', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('poor', 'NegReg', (120, 124))	('colorectal tumors', 'Disease', 'MESH:D015179', (192, 209))	('deletions', 'Var', (27, 36))	('IL-15', 'Gene', '3600', (174, 179))	('local lymphocyte proliferation', 'CPA', (125, 155))	('colorectal tumors', 'Disease', (192, 209))
399953	26227631	Genetic deletions of regions including other immune mediator have been described in some tumors, such as IFNg locus deletions in melanomas, although the relevance of these events in terms of tumor immune architecture is still to be determined.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('deletions', 'Var', (116, 125))	('IFNg', 'Gene', (105, 109))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('melanomas', 'Disease', 'MESH:D008545', (129, 138))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('IFNg', 'Gene', '3458', (105, 109))	('described', 'Reg', (71, 80))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('melanomas', 'Disease', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
399956	26227631	This observation launched the discussion on whether the majority of the genetic alterations mapped in tumor microenvironment could be a result of the limitations of the techniques employed in the diverse studies.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('genetic', 'Var', (72, 79))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
399958	26227631	In fact, some studies reported a high frequency of genetic alterations in tumor microenvironment cells.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('genetic alterations', 'Var', (51, 70))
399961	26227631	Further, a similar study corroborated the results produced by Alinen and colleagues and reported that only one sample, out of 25 CAFs obtained from 25 fresh breast samples, exhibited a chromosomal aberration involving the chromosomes 4, 6 and 9 and another one a TP53 point mutation.	('CAFs', 'Gene', '6899', (129, 133))	('point mutation', 'Var', (268, 282))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (185, 207))	('TP53', 'Gene', (263, 267))	('CAFs', 'Gene', (129, 133))
399973	26227631	Therapeutic failure often relates to high mutation rates of tumor cells and the consequent intratumoral heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (96, 101))	('mutation', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
399978	26227631	In other way, some patients with non-small cell lung cancer become refractory to Epidermal Growth Factor Receptor (EGFR) inhibitors due to an EGFR mutation or MET amplification that arises after treatment with Getifinib and Erlotinib.	('patients', 'Species', '9606', (19, 27))	('non-small cell lung cancer', 'Disease', (33, 59))	('Erlotinib', 'Chemical', 'MESH:D000069347', (224, 233))	('EGFR', 'Gene', '1956', (142, 146))	('mutation', 'Var', (147, 155))	('EGFR', 'Gene', (142, 146))	('EGFR', 'Gene', '1956', (115, 119))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (37, 59))	('Getifinib', 'Chemical', '-', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MET amplification', 'Var', (159, 176))	('EGFR', 'Gene', (115, 119))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (81, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('due to', 'Reg', (132, 138))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (33, 59))	('Epidermal Growth Factor Receptor', 'Gene', (81, 113))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (33, 59))
399980	26227631	These patients relapse after the onset of secondary alterations, such as ALK fusion gene amplification or increased EGF phosphorylation.	('ALK', 'Gene', (73, 76))	('ALK', 'Gene', '238', (73, 76))	('EGF', 'Gene', (116, 119))	('patients', 'Species', '9606', (6, 14))	('EGF', 'Gene', '1950', (116, 119))	('amplification', 'Var', (89, 102))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('increased', 'PosReg', (106, 115))
399981	26227631	Nearly 60 % of melanoma patients harbor mutations in the BRAF gene.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('BRAF', 'Gene', '673', (57, 61))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAF', 'Gene', (57, 61))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (24, 32))
399982	26227631	However, BRAF pathway inhibitors often fail as a result of secondary mutations to the Platelet-Derived Growth Factor Receptor (PDGFRB) and NRAS.	('mutations', 'Var', (69, 78))	('PDGFRB', 'Gene', '5159', (127, 133))	('BRAF', 'Gene', (9, 13))	('PDGFRB', 'Gene', (127, 133))	('NRAS', 'Gene', (139, 143))	('NRAS', 'Gene', '4893', (139, 143))	('BRAF', 'Gene', '673', (9, 13))
399983	26227631	Moreover, despite the celebrated success of BCR/ABL fusion gene inhibition in chronic myeloid leukemia patients, continuous treatment occasionally produces drug resistance via acquisition of novel BCR/ABL mutations or alternative mechanisms, and the leukemia stem cells seem to be resistant to BCR/ABL inhibitors.	('leukemia', 'Disease', 'MESH:D007938', (250, 258))	('drug resistance', 'MPA', (156, 171))	('BCR/ABL', 'Gene', (44, 51))	('BCR/ABL', 'Gene', '25;613', (197, 204))	('drug resistance', 'Phenotype', 'HP:0020174', (156, 171))	('myeloid leukemia', 'Disease', 'MESH:D007951', (86, 102))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (86, 102))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (78, 102))	('produces', 'Reg', (147, 155))	('BCR/ABL', 'Gene', '25;613', (44, 51))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('BCR/ABL', 'Gene', (294, 301))	('mutations', 'Var', (205, 214))	('leukemia', 'Disease', (94, 102))	('leukemia', 'Disease', 'MESH:D007938', (94, 102))	('leukemia', 'Phenotype', 'HP:0001909', (250, 258))	('BCR/ABL', 'Gene', (197, 204))	('myeloid leukemia', 'Disease', (86, 102))	('patients', 'Species', '9606', (103, 111))	('BCR/ABL', 'Gene', '25;613', (294, 301))	('leukemia', 'Disease', (250, 258))
400007	25169763	Association of decreased expression of long non-coding RNA LOC285194 with chemoradiotherapy resistance and poor prognosis in esophageal squamous cell carcinoma Expression of the long non-coding RNA (lncRNA) LOC285194 was previously shown to be correlated with aggressive clinicopathological features and poor prognosis in several cancers.	('Expression', 'MPA', (160, 170))	('LOC285194', 'Gene', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (125, 159))	('expression', 'MPA', (25, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('decreased', 'NegReg', (15, 24))	('esophageal squamous cell carcinoma', 'Disease', (125, 159))	('cancers', 'Phenotype', 'HP:0002664', (330, 337))	('LOC285194', 'Var', (207, 216))	('cancers', 'Disease', (330, 337))	('cancers', 'Disease', 'MESH:D009369', (330, 337))
400008	25169763	The aim of the present study was to explore the relationship between LOC285194 expression and clinical outcomes in esophageal squamous cell carcinoma (ESCC), so as to assess whether it could be a novel biomarker for prognosis and prediction of response to therapy on ESCC patients.	('LOC285194', 'Var', (69, 78))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (115, 149))	('clinical', 'Species', '191496', (94, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('patients', 'Species', '9606', (272, 280))	('esophageal squamous cell carcinoma', 'Disease', (115, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))
400010	25169763	LOC285194 expression was significantly down-regulated in ESCC tumor tissues when compared with the adjacent normal tissues (p < 0.001).	('LOC285194', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('down-regulated', 'NegReg', (39, 53))	('ESCC tumor', 'Disease', 'MESH:D004938', (57, 67))	('expression', 'MPA', (10, 20))	('ESCC tumor', 'Disease', (57, 67))
400011	25169763	Low expression of LOC285194 was associated with larger tumor size (p = 0.002), advanced TNM stage (p = 0.018), more lymph node metastases (p = 0.013) and distant metastases (p = 0.015).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('metastases', 'Disease', (162, 172))	('metastases', 'Disease', 'MESH:D009362', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('expression', 'MPA', (4, 14))	('LOC285194', 'Var', (18, 27))	('tumor', 'Disease', (55, 60))	('more', 'PosReg', (111, 115))	('metastases', 'Disease', (127, 137))	('advanced TNM stage', 'CPA', (79, 97))	('Low', 'NegReg', (0, 3))	('larger', 'PosReg', (48, 54))
400013	25169763	Decreased expression of LOC285194 could serve as a molecular marker to predict the clinical outcome of ESCC patients after surgery, and select patients who would benefit from preoperative CRT.	('clinical', 'Species', '191496', (83, 91))	('patients', 'Species', '9606', (108, 116))	('LOC285194', 'Var', (24, 33))	('Decreased', 'NegReg', (0, 9))	('expression', 'MPA', (10, 20))	('patients', 'Species', '9606', (143, 151))	('ESCC', 'Disease', (103, 107))
400021	25169763	Additionally, multiple studies have indicated that the expression levels of lncRNAs are dysregulated in different kinds of tumors, including ESCC, and the aberrant expression of lncRNAs are correlated with metastasis, recurrence and prognosis.	('correlated with', 'Reg', (190, 205))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('expression', 'MPA', (164, 174))	('aberrant', 'Var', (155, 163))	('expression levels', 'MPA', (55, 72))	('ESCC', 'Disease', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('metastasis', 'CPA', (206, 216))
400026	25169763	It was first reported to be within a tumor suppressor unit in osteosarcoma and depletion of this lncRNA promoted proliferation of normal osteoblasts through regulation of apoptotic and cell cycle transcripts as well as VEGF receptor 1.	('regulation', 'Reg', (157, 167))	('VEGF', 'Gene', (219, 223))	('cell cycle', 'CPA', (185, 195))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('VEGF', 'Gene', '7422', (219, 223))	('osteosarcoma', 'Phenotype', 'HP:0002669', (62, 74))	('osteosarcoma', 'Disease', (62, 74))	('osteosarcoma', 'Disease', 'MESH:D012516', (62, 74))	('tumor', 'Disease', (37, 42))	('depletion', 'Var', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('apoptotic', 'Protein', (171, 180))	('promoted', 'PosReg', (104, 112))	('proliferation', 'CPA', (113, 126))
400029	25169763	In this study we examined the expression level of LOC285194 in ESCC tumors tissues and adjacent normal tissues.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('ESCC tumors', 'Disease', (63, 74))	('ESCC tumors', 'Disease', 'MESH:D004938', (63, 74))	('LOC285194', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
400030	25169763	The relationships between its expression and clinicopathological features were then analyzed so as to evaluate whether LOC285194 expression could be a useful biomarker for prognosis and prediction of response to therapy in ESCC patients.	('LOC285194', 'Var', (119, 128))	('ESCC', 'Disease', (223, 227))	('patients', 'Species', '9606', (228, 236))
400042	25169763	This study used five human ESCC cell lines (KYSE30, KYSE 70, KYSE 150, KYSE510 and Eca109) and one normal human esophageal epithelial cell (Het-1A).	('human', 'Species', '9606', (106, 111))	('KYSE30', 'Var', (44, 50))	('human', 'Species', '9606', (21, 26))	('KYSE 70', 'Var', (52, 59))	('KYSE510', 'Var', (71, 78))	('KYSE 150', 'Var', (61, 69))
400049	25169763	The DeltaCt method was used to calculate the relative expression of LOC285194 in ESCC tumor tissues or ESCC cell lines in comparison with paired normal tissues or cells, respectively.	('ESCC tumor', 'Disease', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('ESCC tumor', 'Disease', 'MESH:D004938', (81, 91))	('LOC285194', 'Var', (68, 77))
400050	25169763	The primers used in this study were synthesized by Invitrogen with the sequences as follows: 5'- TGTGCCTGTTTGACCTCTGA-3'(sense) and 5'-AGGAAGGATAAA AGACCGACCA -3'(antisense) for LOC285194; 5'-TGCACCACCAACTGCTTAGC-3'(sense) and 5'-GGCATGGACTGTGGTCATGAG -3' (antisense) for GAPDH.	('GAPDH', 'Gene', '2597', (272, 277))	('LOC285194', 'Var', (178, 187))	('GAPDH', 'Gene', (272, 277))
400058	25169763	To assess whether LOC285194 expression was associated with clinicopathologic characteristics in ESCC, we first measured its expression level by qRT-PCR in 142 paired tumor samples and adjacent non-tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', (166, 171))	('LOC285194', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('ESCC', 'Disease', (96, 100))	('tumor', 'Disease', (197, 202))
400059	25169763	We detected that LOC285194 expression was significantly down-regulated in tumor tissues when compared to the adjacent normal tissues (p < 0.001; Figure 1A).	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('LOC285194', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('expression', 'MPA', (27, 37))	('down-regulated', 'NegReg', (56, 70))	('tumor', 'Disease', (74, 79))
400061	25169763	Among the 5 tumor cell lines, the LOC285194 level was lower in 3(KYSE30, KYSE510, Eca109) as compared with the normal esophageal epithelial cell (p < 0.05; Figure 1B), but no statistical differences were observed for KYSE70 and KYSE150.	('LOC285194', 'Var', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('KYSE510', 'Var', (73, 80))	('KYSE30', 'Var', (65, 71))	('tumor', 'Disease', (12, 17))	('lower', 'NegReg', (54, 59))
400062	25169763	To further analyze whether there was an association between LOC285194 expression and specific clinicopathological parameters in patients with ESCC, we then used the median expression level of LOC285194 as a cutoff to divide the 142 patients into LOC285194-high (n = 71, with an average  Ct expression value of 8.29) and low groups (n = 71, with an average  Ct expression value of 11.96).	('patients', 'Species', '9606', (232, 240))	('LOC285194', 'Var', (192, 201))	('LOC285194-high', 'Var', (246, 260))	('ESCC', 'Disease', (142, 146))	('patients', 'Species', '9606', (128, 136))
400063	25169763	We found that the LOC285194-low group was significantly associated with larger tumor size, worse histologic grade, advanced TNM stage, and more lymph node metastasis and distant metastases (p < 0.05; Table 1).	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('larger', 'PosReg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('LOC285194-low', 'Var', (18, 31))	('metastases', 'Disease', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('more', 'PosReg', (139, 143))
400064	25169763	However, statistical association between LOC285194 expression and other clinicopathological data including gender, age, tumor location, smoking status, alcohol consumption and depth of invasion released no significant differences (p > 0.05; Table 1).	('LOC285194', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('expression', 'MPA', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('alcohol', 'Chemical', 'MESH:D000438', (152, 159))	('tumor', 'Disease', (120, 125))
400065	25169763	We next sought to explore whether LOC285194 expression could be a predictable molecular marker for CRT response on ESCC patients.	('ESCC', 'Disease', (115, 119))	('LOC285194 expression', 'Var', (34, 54))	('patients', 'Species', '9606', (120, 128))
400066	25169763	Of the 55 patients, the pathCR rate was 57% (16/28) in the LOC285194- high group, while it was only 15% (4/27) in the LOC285194-low group.	('LOC285194- high', 'Var', (59, 74))	('pathCR', 'CPA', (24, 30))	('patients', 'Species', '9606', (10, 18))
400067	25169763	In other words, patients with low expression of LOC285194 showed resistance to CRT.	('patients', 'Species', '9606', (16, 24))	('LOC285194', 'Var', (48, 57))	('resistance', 'MPA', (65, 75))
400068	25169763	These data suggested that LOC285194 could be a useful molecular maker for predicting the sensitivity to CRT on ESCC patients.	('LOC285194', 'Var', (26, 35))	('patients', 'Species', '9606', (116, 124))	('ESCC', 'Disease', (111, 115))
400069	25169763	Consequently, univariate analysis was then performed to determine whether LOC285194 was a feasible molecular maker for prediction of response to CRT, the results revealed that only LOC285194 expression was associated with tumor response to CRT (OR, 0.130; 95% CI, 0.036-0.478; p = 0.002; Table 2).	('LOC285194', 'Var', (181, 190))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('associated with', 'Reg', (206, 221))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))
400074	25169763	Moreover, multivariate analysis revealed that low expression of LOC285194 (HR, 0.341; 95% CI, 0.193-0.602; p < 0.001 and HR, 0.388; 95% CI, 0.210-0.715; p = 0.002 for DFS and OS, respectively) as well as distant metastasis (HR, 2.123; 95% CI, 1.063-4.240; p = 0.033 and HR, 2.389; 95% CI, 1.132-5.041; p = 0.022 for DFS and OS, respectively) were independent prognosis factors that affected the DFS and OS of ESCC patients after esophagectomy (Table 3).	('LOC285194', 'Var', (64, 73))	('low', 'Var', (46, 49))	('patients', 'Species', '9606', (414, 422))	('DFS', 'Disease', (395, 398))	('ESCC', 'Disease', (409, 413))	('affected', 'Reg', (382, 390))
400080	25169763	Here we reported lncRNA LOC285194, which was previously shown to function as a tumor suppressor in osteosarcoma and was significantly down-regulated in 43 osteosarcoma tumor samples and 5 osteosarcoma cell lines.	('osteosarcoma', 'Disease', (188, 200))	('osteosarcoma', 'Disease', 'MESH:D012516', (188, 200))	('osteosarcoma', 'Disease', (155, 167))	('osteosarcoma', 'Disease', 'MESH:D012516', (155, 167))	('osteosarcoma', 'Disease', (99, 111))	('osteosarcoma', 'Disease', 'MESH:D012516', (99, 111))	('lncRNA LOC285194', 'Var', (17, 33))	('down-regulated', 'NegReg', (134, 148))	('LOC285194', 'Var', (24, 33))	('osteosarcoma', 'Phenotype', 'HP:0002669', (188, 200))	('osteosarcoma tumor', 'Disease', 'MESH:D012516', (155, 173))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (168, 173))	('osteosarcoma', 'Phenotype', 'HP:0002669', (155, 167))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('osteosarcoma', 'Phenotype', 'HP:0002669', (99, 111))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('osteosarcoma tumor', 'Disease', (155, 173))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
400081	25169763	In addition, expression of LOC285194 deletion in tumor was found to be associated with poor prognosis of osteosarcoma patients.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('LOC285194 deletion', 'Var', (27, 45))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('patients', 'Species', '9606', (118, 126))
400082	25169763	The misexpression of this lncRNA was also discovered in colorectal cancer, and patients with low expression of LOC285194 had a shorter DFS.	('shorter', 'NegReg', (127, 134))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('LOC285194', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('patients', 'Species', '9606', (79, 87))	('DFS', 'MPA', (135, 138))
400083	25169763	This common characteristic thus strengthened the clinical application value of LOC285194.	('strengthened', 'PosReg', (32, 44))	('clinical', 'Species', '191496', (49, 57))	('LOC285194', 'Var', (79, 88))
400084	25169763	Therefore, we hypothesized that LOC285194 expression was also decreased in ESCC tumor tissues and decreased of this lncRNA may influence the treatment outcomes and could predict the prognosis of ESCC patients.	('ESCC tumor', 'Disease', (75, 85))	('LOC285194', 'Var', (32, 41))	('patients', 'Species', '9606', (200, 208))	('decreased', 'NegReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('expression', 'MPA', (42, 52))	('ESCC tumor', 'Disease', 'MESH:D004938', (75, 85))	('predict', 'Reg', (170, 177))	('lncRNA', 'MPA', (116, 122))	('ESCC', 'Disease', (195, 199))	('influence', 'Reg', (127, 136))	('treatment outcomes', 'CPA', (141, 159))	('decreased', 'NegReg', (98, 107))
400086	25169763	The qRT-PCR showed that LOC285194 was significantly down-regulated in ESCC tumor tissues compared to the adjacent nontumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('LOC285194', 'Var', (24, 33))	('tumor', 'Disease', (117, 122))	('down-regulated', 'NegReg', (52, 66))	('ESCC tumor', 'Disease', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ESCC tumor', 'Disease', 'MESH:D004938', (70, 80))	('tumor', 'Disease', (75, 80))
400088	25169763	Patients with low expression of LOC285194 showed larger tumor size, worse histologic grade, advanced TNM stage, more lymph node metastasis and distant metastases than the LOC285194-high group.	('larger', 'PosReg', (49, 55))	('LOC285194', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('more', 'PosReg', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('metastases', 'Disease', 'MESH:D009362', (151, 161))	('tumor', 'Disease', (56, 61))	('Patients', 'Species', '9606', (0, 8))	('low', 'NegReg', (14, 17))	('metastases', 'Disease', (151, 161))
400089	25169763	In the study by Liu Q et al, LOC285194 was found to be specifically induced by wild-type p53, p53 directly interacted with the p53 response element in the upstream of LOC285194 to induce its transcription.	('interacted', 'Interaction', (107, 117))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (89, 92))	('p53', 'Gene', '7157', (94, 97))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (89, 92))	('induce', 'PosReg', (180, 186))	('LOC285194', 'Var', (29, 38))	('transcription', 'MPA', (191, 204))	('LOC285194', 'Var', (167, 176))	('p53', 'Gene', (127, 130))
400090	25169763	Decreased expression of LOC285194 could be explained by p53 status, because p53 mutation or deletion could account for more than 50% of ESCC cases.	('p53', 'Gene', (56, 59))	('p53', 'Gene', (76, 79))	('LOC285194', 'Var', (24, 33))	('ESCC', 'Disease', (136, 140))	('Decreased', 'NegReg', (0, 9))	('deletion', 'Var', (92, 100))	('p53', 'Gene', '7157', (76, 79))	('expression', 'MPA', (10, 20))	('p53', 'Gene', '7157', (56, 59))	('mutation', 'Var', (80, 88))
400092	25169763	However, only 13-49% patients who have pathCR will benefit from the treatment, the remaining 50% patients present the CRT resistance.	('patients', 'Species', '9606', (21, 29))	('CRT resistance', 'MPA', (118, 132))	('pathCR', 'Var', (39, 45))	('patients', 'Species', '9606', (97, 105))
400094	25169763	In other words, patients with low expression of LOC285194 suggested resistance to CRT.	('resistance', 'MPA', (68, 78))	('patients', 'Species', '9606', (16, 24))	('LOC285194', 'Var', (48, 57))
400095	25169763	Therefore, our results indicated that low expression of LOC285194 could be a valuable molecular marker for personal treatment screening of ESCC patients before esophagectomy.	('LOC285194', 'Var', (56, 65))	('expression', 'MPA', (42, 52))	('patients', 'Species', '9606', (144, 152))	('low', 'NegReg', (38, 41))	('ESCC', 'Disease', (139, 143))
400096	25169763	In addition, rescuing the expression of LOC285194 may have a novel clinical application in the treatment of ESCC patients.	('LOC285194', 'Var', (40, 49))	('expression', 'MPA', (26, 36))	('patients', 'Species', '9606', (113, 121))	('clinical', 'Species', '191496', (67, 75))	('ESCC patients', 'Disease', (108, 121))
400097	25169763	It has been reported that LOC285194 is located at osteo3q13.31, which harbors frequent focal copy number alterations (CNAs) and loss of heterozygosity (LOH) in osteosarcoma.	('LOC285194', 'Var', (26, 35))	('loss of', 'NegReg', (128, 135))	('osteosarcoma', 'Phenotype', 'HP:0002669', (160, 172))	('osteosarcoma', 'Disease', (160, 172))	('osteosarcoma', 'Disease', 'MESH:D012516', (160, 172))
400098	25169763	And depletion of LOC285194 promotes osteoblast proliferation in vitro through regulation of cell cycle transcripts such as cyclin D1 and VEGF/VEGFR1.	('osteoblast proliferation', 'CPA', (36, 60))	('VEGF', 'Gene', (142, 146))	('cell', 'MPA', (92, 96))	('VEGF', 'Gene', '7422', (137, 141))	('LOC285194', 'Var', (17, 26))	('promotes', 'PosReg', (27, 35))	('VEGF', 'Gene', '7422', (142, 146))	('VEGF', 'Gene', (137, 141))	('VEGFR1', 'Gene', '2321', (142, 148))	('cyclin D1', 'Gene', '595', (123, 132))	('VEGFR1', 'Gene', (142, 148))	('osteoblast proliferation', 'Phenotype', 'HP:0011846', (36, 60))	('cyclin D1', 'Gene', (123, 132))
400099	25169763	Interestingly, focal osteo3q13.31 depletion and LOH are also found in various tumors including esophageal cancer.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('depletion', 'NegReg', (34, 43))	('LOH', 'Var', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('esophageal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
400101	25169763	Thus, we hypothesize that changes LOC285194 might be involved in the regulation of the expression of proliferation-associated genes that in turn may partly contribute to tumor resistance in preoperative CRT.	('involved', 'Reg', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('LOC285194', 'Var', (34, 43))	('contribute', 'Reg', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('expression', 'MPA', (87, 97))	('CRT', 'Disease', (203, 206))	('changes LOC285194', 'Var', (26, 43))
400102	25169763	Clearly, further cell experiments are needed to fully understand the oncogenic function of LOC285194 in human ESCC pathogenesis, including the elucidation of which signaling pathways are involved in resistance to CRT.	('human', 'Species', '9606', (104, 109))	('LOC285194', 'Var', (91, 100))	('ESCC', 'Disease', (110, 114))
400103	25169763	We observed a close association between low expression of LOC285194 and shorter DFS and OS in patients with ESCC.	('patients', 'Species', '9606', (94, 102))	('low', 'NegReg', (40, 43))	('shorter', 'NegReg', (72, 79))	('LOC285194', 'Var', (58, 67))	('ESCC', 'Disease', (108, 112))	('DFS', 'MPA', (80, 83))
400104	25169763	Furthermore, the multivariate analysis showed that low expression of LOC285194 was a powerful independent prognosis factor of poor DFS and OS, which was consistent with the previous reports in colorectal cancer and osteosarcoma.	('colorectal cancer', 'Disease', (193, 210))	('LOC285194', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('low expression', 'Var', (51, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (193, 210))	('osteosarcoma', 'Disease', (215, 227))	('colorectal cancer', 'Phenotype', 'HP:0003003', (193, 210))	('poor DFS', 'Disease', (126, 134))	('osteosarcoma', 'Phenotype', 'HP:0002669', (215, 227))	('osteosarcoma', 'Disease', 'MESH:D012516', (215, 227))
400105	25169763	These findings suggested that low expression of LOC285194 could signify a higher risk of disease recurrence and/or treatment failure, and, that postoperative ESCC patients should be closely monitored and receive effective adjuvant therapies.	('patients', 'Species', '9606', (163, 171))	('disease recurrence', 'CPA', (89, 107))	('expression', 'MPA', (34, 44))	('low', 'NegReg', (30, 33))	('LOC285194', 'Var', (48, 57))	('ESCC', 'Disease', (158, 162))
400106	25169763	Our study shown that LOC285194 expression was significantly down-regulated in ESCC tumor tissues and cell lines, and low expression of LOC285194 was associated with CRT resistance and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LOC285194', 'Gene', (21, 30))	('ESCC tumor', 'Disease', (78, 88))	('down-regulated', 'NegReg', (60, 74))	('CRT resistance', 'Disease', (165, 179))	('associated', 'Reg', (149, 159))	('expression', 'MPA', (31, 41))	('LOC285194', 'Var', (135, 144))	('ESCC tumor', 'Disease', 'MESH:D004938', (78, 88))	('low', 'NegReg', (117, 120))
400107	25169763	Furthermore, decreased expression of LOC285194 could potentially serve as a molecular marker to predict the clinical outcomes (shorter DFS and OS) of ESCC patients after surgery, and select patients who will benefit from the preoperative CRT.	('LOC285194', 'Var', (37, 46))	('clinical', 'Species', '191496', (108, 116))	('decreased', 'NegReg', (13, 22))	('patients', 'Species', '9606', (190, 198))	('ESCC', 'Disease', (150, 154))	('patients', 'Species', '9606', (155, 163))	('expression', 'MPA', (23, 33))
400133	21559197	Biopsies from the ulcer base are more likely to demonstrate characteristic CMV inclusions, which are usually seen in stromal and endothelial cells, as compared to HSV infection, which manifests in squamous cells.	('ulcer', 'Disease', 'MESH:D014456', (18, 23))	('ulcer', 'Disease', (18, 23))	('inclusions', 'Var', (79, 89))	('HSV infection', 'Disease', 'MESH:C536395', (163, 176))	('CMV', 'Disease', (75, 78))	('HSV infection', 'Disease', (163, 176))
400167	21559197	MAI leads to an exudative enteropathy and altered secretion of inflammatory mediators (e.g., interleukin-1).	('enteropathy', 'Disease', 'MESH:C538273', (26, 37))	('MAI', 'Var', (0, 3))	('enteropathy', 'Phenotype', 'HP:0002242', (26, 37))	('altered', 'Reg', (42, 49))	('secretion of inflammatory mediators', 'MPA', (50, 85))	('MAI', 'Species', '55883', (0, 3))	('enteropathy', 'Disease', (26, 37))
400174	21559197	As in gastric infection (see above), CMV causes intestinal inflammation, erosion, and ulceration, with characteristic CMV inclusions in stromal and endothelial cells.	('gastric infection', 'Disease', (6, 23))	('inclusions', 'Var', (122, 132))	('ulcer', 'Disease', 'MESH:D014456', (86, 91))	('ulcer', 'Disease', (86, 91))	('intestinal inflammation', 'Disease', 'MESH:D007249', (48, 71))	('causes', 'Reg', (41, 47))	('gastric infection', 'Disease', 'MESH:D013274', (6, 23))	('intestinal inflammation', 'Disease', (48, 71))	('erosion', 'Disease', (73, 80))	('CMV', 'Var', (37, 40))
400263	33050576	PTENP1 upregulates PTEN expression by sponging PTEN-targeting miRNAs (e.g., miR-17, miR-21, miR-214, miR-19, and miR-26), leading to tumor suppression.	('miR-17', 'Gene', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('miR-21', 'Gene', (84, 90))	('PTEN', 'Gene', '5728', (47, 51))	('miR-21', 'Gene', (92, 98))	('expression', 'MPA', (24, 34))	('PTEN', 'Gene', (19, 23))	('miR-214', 'Gene', (92, 99))	('upregulates', 'PosReg', (7, 18))	('miR-17', 'Gene', '406952', (76, 82))	('PTEN', 'Gene', '5728', (19, 23))	('miR-19', 'Var', (101, 107))	('tumor', 'Disease', (133, 138))	('PTEN', 'Gene', (0, 4))	('miR-26', 'Var', (113, 119))	('PTENP1', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('miR-21', 'Gene', '406991', (84, 90))	('miR-21', 'Gene', '406991', (92, 98))	('PTEN', 'Gene', (47, 51))	('miR-214', 'Gene', '406996', (92, 99))	('PTEN', 'Gene', '5728', (0, 4))	('PTENP1', 'Gene', '11191', (0, 6))
400265	33050576	It was shown that the 5'-domain of HOTAIR binds to PRC2 to promote gene repression, and the 3'-domain binds to the LSD1/coREST/REST complex, which demethylates lysine 4 of histone H3 (H3K4) to repress gene activation.	('PRC2', 'Gene', (51, 55))	('coREST', 'Gene', (120, 126))	('HOTAIR', 'Gene', (35, 41))	('HOTAIR', 'Gene', '100124700', (35, 41))	('demethylates', 'Var', (147, 159))	('LSD1', 'Gene', (115, 119))	('gene repression', 'MPA', (67, 82))	('coREST', 'Gene', '23186', (120, 126))	('LSD1', 'Gene', '23028', (115, 119))	('lysine', 'Chemical', 'MESH:D008239', (160, 166))	('promote', 'PosReg', (59, 66))	('gene activation', 'MPA', (201, 216))	('H3K4', 'Protein', (184, 188))	('repress', 'PosReg', (193, 200))
400267	33050576	Moreover, antisense non-coding RNA at the INK4 locus (ANRIL) is upregulated in adult T-cell leukemia and associates with EZH2 and the RelA/p65 subunit of NFkappaB, which enhances NFkappaB signaling and promotes cancer cell proliferation.	('enhances', 'PosReg', (170, 178))	('INK4', 'Gene', (42, 46))	('EZH2', 'Gene', '2146', (121, 125))	('adult T-cell leukemia', 'Disease', 'MESH:D015459', (79, 100))	('EZH2', 'Gene', (121, 125))	('NFkappaB', 'Gene', '4790', (179, 187))	('ANRIL', 'Gene', '100048912', (54, 59))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('NFkappaB', 'Gene', '4790', (154, 162))	('promotes', 'PosReg', (202, 210))	('NFkappaB', 'Gene', (179, 187))	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('antisense non-coding RNA', 'Var', (10, 34))	('NFkappaB', 'Gene', (154, 162))	('ANRIL', 'Gene', (54, 59))	('upregulated', 'PosReg', (64, 75))	('cancer', 'Disease', (211, 217))	('associates', 'Interaction', (105, 115))	('INK4', 'Gene', '1029', (42, 46))	('adult T-cell leukemia', 'Disease', (79, 100))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
400270	33050576	In mouse placenta, antisense of the IGF2R non-protein coding RNA (AIRN) has been shown to silence the transcription of cis-linked genes via chromatin interaction at their promoter regions.	('transcription', 'MPA', (102, 115))	('chromatin interaction', 'MPA', (140, 161))	('mouse', 'Species', '10090', (3, 8))	('antisense', 'Var', (19, 28))	('cis-linked genes', 'Gene', (119, 135))	('silence', 'NegReg', (90, 97))	('IGF2R', 'Gene', (36, 41))
400275	33050576	Quiescent fibroblasts can differentiate into CAFs upon stimulation by diverse external cues such as cytokines/chemokines, growth factors, reactive oxygen species, hypoxia, and non-coding RNAs.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (138, 161))	('non-coding RNAs', 'Var', (176, 191))	('CAF', 'Gene', '8850', (45, 48))	('CAF', 'Gene', (45, 48))	('hypoxia', 'Disease', 'MESH:D000860', (163, 170))	('hypoxia', 'Disease', (163, 170))
400311	33050576	Downregulation of focal adhesion kinase in CAFs increases CCL6 and CCL12 expression, leading to elevated glycolysis in cancer cells.	('CCL6', 'Gene', (58, 62))	('increases', 'PosReg', (48, 57))	('CAF', 'Gene', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('glycolysis', 'MPA', (105, 115))	('Downregulation', 'Var', (0, 14))	('cancer', 'Disease', (119, 125))	('expression', 'MPA', (73, 83))	('CCL12', 'Gene', (67, 72))	('CAF', 'Gene', '8850', (43, 46))	('elevated', 'PosReg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
400313	33050576	Epigenetic changes in prostate CAFs drive the synthesis of glutamine, which is then transported to adjacent cancer cells to promote energy production, differentiation, and the aggressiveness of prostate cancer cells.	('drive', 'Reg', (36, 41))	('synthesis', 'MPA', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('prostate cancer', 'Phenotype', 'HP:0012125', (194, 209))	('aggressiveness', 'Phenotype', 'HP:0000718', (176, 190))	('aggressiveness of prostate cancer', 'Disease', (176, 209))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('aggressiveness of prostate cancer', 'Disease', 'MESH:D011471', (176, 209))	('cancer', 'Disease', (203, 209))	('promote', 'PosReg', (124, 131))	('CAF', 'Gene', '8850', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Disease', (108, 114))	('prostate', 'Gene', (22, 30))	('differentiation', 'CPA', (151, 166))	('energy production', 'MPA', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CAF', 'Gene', (31, 34))	('glutamine', 'Chemical', 'MESH:D005973', (59, 68))	('Epigenetic changes', 'Var', (0, 18))
400337	33050576	Using microarrays and Kaplan-Meier survival analysis, they identified ten CAF-specific lncRNAs: nine lncRNAs (CRNDE, DANCR, LOC642852, MALAT1, MEG3, MGC2752, NEAT1, TP73-AS1, and XIST) were associated with shorter survival, and one (MIR155HG) was associated with longer survival.	('DANCR', 'Gene', (117, 122))	('NEAT1', 'Gene', '283131', (158, 163))	('AS1', 'Gene', '5729', (170, 173))	('MALAT1', 'Gene', (135, 141))	('MEG3', 'Gene', (143, 147))	('TP73', 'Gene', '7161', (165, 169))	('MALAT1', 'Gene', '378938', (135, 141))	('MIR155HG', 'Gene', '114614', (233, 241))	('DANCR', 'Gene', '57291', (117, 122))	('MIR155HG', 'Gene', (233, 241))	('CAF', 'Gene', '8850', (74, 77))	('XIST', 'Gene', (179, 183))	('MEG3', 'Gene', '55384', (143, 147))	('MGC2752', 'Var', (149, 156))	('TP73', 'Gene', (165, 169))	('CAF', 'Gene', (74, 77))	('AS1', 'Gene', (170, 173))	('XIST', 'Gene', '7503', (179, 183))	('NEAT1', 'Gene', (158, 163))	('LOC642852', 'Var', (124, 133))	('CRNDE', 'Gene', (110, 115))	('CRNDE', 'Gene', '643911', (110, 115))	('shorter', 'NegReg', (206, 213))
400339	33050576	Gene clusters involving DANCR, LOC642852, MALAT1, MEG3, MGC2752, TP73-AS1, and XIST are associated with metabolic processes and autophagy.	('AS1', 'Gene', '5729', (70, 73))	('DANCR', 'Gene', (24, 29))	('AS1', 'Gene', (70, 73))	('TP73', 'Gene', '7161', (65, 69))	('TP73', 'Gene', (65, 69))	('MALAT1', 'Gene', (42, 48))	('MEG3', 'Gene', (50, 54))	('MGC2752', 'Gene', (56, 63))	('DANCR', 'Gene', '57291', (24, 29))	('autophagy', 'CPA', (128, 137))	('MEG3', 'Gene', '55384', (50, 54))	('LOC642852', 'Var', (31, 40))	('XIST', 'Gene', '7503', (79, 83))	('XIST', 'Gene', (79, 83))	('associated', 'Reg', (88, 98))	('metabolic processes', 'CPA', (104, 123))	('MALAT1', 'Gene', '378938', (42, 48))
400346	33050576	In terms of clinical relevance, high FLJ22447 expression was associated with a high TNM stage and poor patient survival.	('TNM', 'Gene', '10178', (84, 87))	('high', 'Var', (32, 36))	('FLJ22447', 'Gene', (37, 45))	('FLJ22447', 'Gene', '400221', (37, 45))	('TNM', 'Gene', (84, 87))	('patient survival', 'CPA', (103, 119))	('poor', 'NegReg', (98, 102))	('patient', 'Species', '9606', (103, 110))	('expression', 'MPA', (46, 56))
400351	33050576	The shRNA-mediated knockdown of HIPK1-AS blocked the activation of CAFs by HeLa conditioned medium.	('CAF', 'Gene', (67, 70))	('knockdown', 'Var', (19, 28))	('CAF', 'Gene', '8850', (67, 70))	('HIPK1', 'Gene', '204851', (32, 37))	('HIPK1', 'Gene', (32, 37))	('HeLa', 'CellLine', 'CVCL:0030', (75, 79))	('blocked', 'NegReg', (41, 48))	('activation', 'MPA', (53, 63))
400359	33050576	Patients with high TIRY expression had poorer overall and progression-free survival than those with low TIRY expression.	('high TIRY expression', 'Var', (14, 34))	('overall', 'CPA', (46, 53))	('progression-free survival', 'CPA', (58, 83))	('Patients', 'Species', '9606', (0, 8))	('poorer', 'NegReg', (39, 45))
400361	33050576	Interestingly, TIRY in CAFs suppressed exosomal delivery of miR-14 to neighboring cancer cells, which caused the upregulation of WNT3A, a miR-14 target, and activation of Wnt/beta-catenin signaling in cancer cells.	('miR-14', 'Chemical', '-', (60, 66))	('cancer', 'Disease', (201, 207))	('CAF', 'Gene', (23, 26))	('cancer', 'Disease', (82, 88))	('miR-14', 'Chemical', '-', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('beta-catenin', 'Gene', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('beta-catenin', 'Gene', '1499', (175, 187))	('TIRY', 'Var', (15, 19))	('WNT3A', 'Gene', '89780', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('suppressed', 'NegReg', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('miR-14', 'Gene', (60, 66))	('WNT3A', 'Gene', (129, 134))	('upregulation', 'PosReg', (113, 125))	('CAF', 'Gene', '8850', (23, 26))	('exosomal delivery', 'MPA', (39, 56))	('activation', 'PosReg', (157, 167))
400378	33050576	LINC00092 knockdown also causes a reduction in glycolysis metabolites, such as lactate.	('lactate', 'MPA', (79, 86))	('glycolysis metabolites', 'MPA', (47, 69))	('LINC00092', 'Gene', '100188953', (0, 9))	('reduction', 'NegReg', (34, 43))	('lactate', 'Chemical', 'MESH:D019344', (79, 86))	('LINC00092', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))
400397	33050576	HOTAIR, in turn, activates the EMT, migration, and invasion of breast cancer cells by the epigenetic suppression of EGR1 and CDK5RAP1 promoters.	('EMT', 'CPA', (31, 34))	('HOTAIR', 'Gene', '100124700', (0, 6))	('EGR1', 'Gene', '1958', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CDK5RAP1', 'Gene', (125, 133))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('CDK5RAP1', 'Gene', '51654', (125, 133))	('breast cancer', 'Disease', (63, 76))	('HOTAIR', 'Gene', (0, 6))	('migration', 'CPA', (36, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('EGR1', 'Gene', (116, 120))	('invasion', 'CPA', (51, 59))	('epigenetic suppression', 'Var', (90, 112))	('activates', 'PosReg', (17, 26))
400405	33050576	Moreover, high ANRIL expression is associated with high TNM stage and lymph node metastasis in patients with oral squamous cell carcinoma.	('lymph node metastasis', 'CPA', (70, 91))	('oral squamous cell carcinoma', 'Disease', (109, 137))	('patients', 'Species', '9606', (95, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('ANRIL', 'Gene', (15, 20))	('associated', 'Reg', (35, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('expression', 'MPA', (21, 31))	('TNM', 'Gene', '10178', (56, 59))	('high', 'Var', (10, 14))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 137))	('ANRIL', 'Gene', '100048912', (15, 20))	('TNM', 'Gene', (56, 59))
400439	33050576	In melanoma-derived exosomes, the lncRNA Gm26809 was significantly enriched.	('Gm26809', 'Var', (41, 48))	('Gm26809', 'Chemical', '-', (41, 48))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
400442	33050576	Supplemented with further investigation on the exact working mechanisms, exosomal Gm26809 could be a good target for melanoma treatment.	('Gm26809', 'Var', (82, 89))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('Gm26809', 'Chemical', '-', (82, 89))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
400496	32748171	It is now widely recognized that microsatellite unstable (MSI-H) or mismatch repair protein deficient (dMMR) tumors and those high tumor mutational burden (TMB) are characterized by high numbers of mutations or 'neoantigens' and predict sensitivity to ICIs.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Disease', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('microsatellite', 'Var', (33, 47))	('mutations', 'Var', (198, 207))	('predict', 'Reg', (229, 236))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('MSI', 'Gene', (58, 61))	('TMB', 'Chemical', '-', (156, 159))	('dMMR', 'Chemical', '-', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MSI', 'Gene', '5928', (58, 61))	('deficient', 'NegReg', (92, 101))	('tumor', 'Disease', (109, 114))
400498	32748171	Among GI cancers, oesophagogastric cancer is reported to have the highest TMB at 5 mutations/megabase, whereas pancreatic cancer has the lowest at 1 mutation/megabase.	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('GI cancer', 'Phenotype', 'HP:0007378', (6, 15))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TMB', 'MPA', (74, 77))	('pancreatic cancer', 'Disease', (111, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))	('GI cancers', 'Disease', (6, 16))	('mutations/megabase', 'Var', (83, 101))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('TMB', 'Chemical', '-', (74, 77))	('gastric cancer', 'Disease', (27, 41))	('GI cancers', 'Disease', 'MESH:D009369', (6, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (27, 41))
400500	32748171	However, DCs in pancreatic cancer and cholangiocarcinoma (CCA) have been found to be limited in number or immature in advanced stages of disease, and mutations in the MHC I binding domain have been reported in colorectal cancer thus potentially representing less effective antigen presentation and recognition in these tumors.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('colorectal cancer', 'Disease', 'MESH:D015179', (210, 227))	('tumors', 'Disease', (319, 325))	('colorectal cancer', 'Disease', (210, 227))	('pancreatic cancer', 'Disease', (16, 33))	('tumors', 'Disease', 'MESH:D009369', (319, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('mutations', 'Var', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (16, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (210, 227))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('reported', 'Reg', (198, 206))	('tumors', 'Phenotype', 'HP:0002664', (319, 325))	('cholangiocarcinoma', 'Disease', (38, 56))	('CCA', 'Phenotype', 'HP:0030153', (58, 61))	('MHC I', 'Gene', (167, 172))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('binding', 'Interaction', (173, 180))	('pancreatic cancer', 'Disease', 'MESH:D010190', (16, 33))
400520	32748171	However pembrolizumab demonstrated benefit in those with CPS >= 10 in a post hoc analysis.	('CPS >= 10', 'Var', (57, 66))	('benefit', 'PosReg', (35, 42))	('CPS', 'Chemical', '-', (57, 60))	('pembrolizumab', 'Chemical', 'MESH:C582435', (8, 21))
400560	32748171	Nevertheless, in the ATTRACTION-02 study, the survival benefit from nivolumab in pre-treated patients with esophagastric cancer was observed in both PD-L1 positive and negative patients.	('PD-L1', 'Gene', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('survival', 'MPA', (46, 54))	('patients', 'Species', '9606', (177, 185))	('benefit', 'PosReg', (55, 62))	('gastric cancer', 'Disease', (113, 127))	('nivolumab', 'Chemical', 'MESH:D000077594', (68, 77))	('positive', 'Var', (155, 163))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('patients', 'Species', '9606', (93, 101))
400579	32748171	The ongoing phase II, single arm study evaluating trastuzumab, capectiabine and oxliaplatin in combination with pembrolizumab in the first-line setting of advanced HER2 amplified OGA which showed a high ORR (83%) with mPFS 11.4 months which showed a high ORR (83%) with mPFS 11.4 months and is currently still recruiting (Table 4).	('capectiabine', 'Chemical', '-', (63, 75))	('amplified', 'Var', (169, 178))	('HER2', 'Gene', (164, 168))	('OGA', 'Gene', '10724', (179, 182))	('pembrolizumab', 'Chemical', 'MESH:C582435', (112, 125))	('oxliaplatin', 'Chemical', '-', (80, 91))	('trastuzumab', 'Chemical', 'MESH:D000068878', (50, 61))	('OGA', 'Gene', (179, 182))	('HER2', 'Gene', '2064', (164, 168))
400598	32748171	Dual ICI therapy targeting CTLA-4 and PD-1 inhibition has established efficacy in malignancies such as melanoma and RCC.	('CTLA-4', 'Gene', (27, 33))	('inhibition', 'Var', (43, 53))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('malignancies', 'Disease', (82, 94))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('PD-1', 'Gene', (38, 42))	('PD-1', 'Chemical', '-', (38, 42))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))	('melanoma', 'Disease', (103, 111))
400607	32748171	Blockade of this inhibitory signal can promote T cell mediated tumor cell death and activate TILs in CRC typically express high levels of LAG3, which make this a promising therapeutic target.	('tumor cell death', 'Disease', (63, 79))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('promote', 'PosReg', (39, 46))	('Blockade', 'Var', (0, 8))	('tumor cell death', 'Disease', 'MESH:D003643', (63, 79))	('CRC', 'Gene', (101, 104))	('activate', 'PosReg', (84, 92))	('LAG3', 'Gene', (138, 142))	('LAG3', 'Gene', '3902', (138, 142))
400611	32748171	These modifications include DNA methylation, alterations to histone proteins and remodeling of chromatin and they are often aberrant in disease processes such as cancer.	('DNA', 'Var', (28, 31))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('histone proteins', 'Protein', (60, 76))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('remodeling of chromatin', 'CPA', (81, 104))	('alterations', 'Reg', (45, 56))
400612	32748171	Notably however, alterations in the epigenome rather than the core genetic material of cells have been shown to be reversible and hence a potential anti-cancer strategy.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('epigenome', 'MPA', (36, 45))	('alterations', 'Var', (17, 28))
400615	32748171	Furthermore, there is increasing evidence that epigenetic agents can promote the anti-cancer immune response via multiple mechanisms including increased antigen release and antigen presentation [steps 1 and 2 of the Cancer Immunity Cycle (Fig.	('antigen release', 'MPA', (153, 168))	('increased', 'PosReg', (143, 152))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Cancer', 'Disease', (216, 222))	('Cancer', 'Disease', 'MESH:D009369', (216, 222))	('Cancer', 'Phenotype', 'HP:0002664', (216, 222))	('promote', 'PosReg', (69, 76))	('antigen presentation', 'MPA', (173, 193))	('epigenetic agents', 'Var', (47, 64))	('cancer', 'Disease', (86, 92))
400617	32748171	Pre-clinical testing demonstrates that the DNMTi 5-azacitadine (5-AZA) upregulated 15 gene sets involved in the immune response such as antigen presentation, interferon signaling and chemokine and cytokine signaling in colorectal cancer cell lines.	('colorectal cancer', 'Disease', 'MESH:D015179', (219, 236))	('interferon', 'MPA', (158, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (219, 236))	('DNMTi', 'Var', (43, 48))	('antigen presentation', 'MPA', (136, 156))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('5-AZA', 'Chemical', '-', (64, 69))	('chemokine', 'MPA', (183, 192))	('colorectal cancer', 'Disease', (219, 236))	('DNMTi 5-azacitadine', 'Chemical', '-', (43, 62))	('upregulated', 'PosReg', (71, 82))
400626	32748171	Abberations in the Wnt/beta-catenin signaling pathway occur frequently in cancer and while the constituents of the pathway are known, the mechanisms underpinning how the proteins interact are yet to be fully elucidated.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('Wnt/beta-catenin signaling pathway', 'Pathway', (19, 53))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Abberations', 'Var', (0, 11))
400627	32748171	The role of Wnt signaling in development of colorectal cancer, most commonly via mutations of the APC gene, is particularly well-described however increasing evidence suggests that Wnt signaling also plays a key role in the pathogenesis of other GI cancers including PDAC, HCC, CCA and OG cancers, proposing a potential target for therapy.	('APC', 'Gene', (98, 101))	('colorectal cancer', 'Disease', (44, 61))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('mutations', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('PDAC', 'Chemical', '-', (267, 271))	('GI cancers', 'Disease', (246, 256))	('CCA', 'Phenotype', 'HP:0030153', (278, 281))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('CCA', 'Disease', (278, 281))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('GI cancers', 'Disease', 'MESH:D009369', (246, 256))	('APC', 'Gene', '324', (98, 101))	('HCC', 'Disease', (273, 276))	('PDAC', 'Disease', (267, 271))	('OG cancers', 'Disease', 'MESH:D009369', (286, 296))	('GI cancer', 'Phenotype', 'HP:0007378', (246, 255))	('OG cancers', 'Disease', (286, 296))	('colorectal cancer', 'Disease', 'MESH:D015179', (44, 61))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))
400632	32748171	By inactivating Wnt/beta-catenin signaling, presentation of cancer associated antigens and T cell priming appears to be restored.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('T cell priming', 'CPA', (91, 105))	('presentation', 'MPA', (44, 56))	('Wnt/beta-catenin signaling', 'Pathway', (16, 42))	('inactivating', 'Var', (3, 15))
400633	32748171	In addition to impairing the first 3 steps of the Cancer Immunity Cycle, aberrant Wnt/beta-catenin signaling also seems to deter T cells from entering the tumor and preferentially favors influx and survival of inhibitory Tregs while inactivating or stimulating apoptosis of effector T cells in the immune milieu.	('influx', 'CPA', (187, 193))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('preferentially', 'PosReg', (165, 179))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Tregs', 'Chemical', '-', (221, 226))	('stimulating', 'Reg', (249, 260))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('impairing', 'NegReg', (15, 24))	('tumor', 'Disease', (155, 160))	('aberrant', 'Var', (73, 81))	('entering', 'CPA', (142, 150))	('apoptosis', 'CPA', (261, 270))	('deter', 'NegReg', (123, 128))	('survival', 'CPA', (198, 206))	('favors', 'PosReg', (180, 186))
400636	32748171	In the clinic, the combination of DKN-01 and pembrolizumab has been shown to be safe and tolerable in patients with advanced MSS OG cancer with a hint of potential efficacy as a PR was observed in 1 patient and 5 patients had SD.	('SD', 'Disease', 'MESH:D029461', (226, 228))	('pembrolizumab', 'Chemical', 'MESH:C582435', (45, 58))	('MSS OG cancer', 'Disease', 'MESH:D013132', (125, 138))	('patient', 'Species', '9606', (213, 220))	('patient', 'Species', '9606', (102, 109))	('patients', 'Species', '9606', (102, 110))	('patient', 'Species', '9606', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('MSS OG cancer', 'Disease', (125, 138))	('patients', 'Species', '9606', (213, 221))	('DKN-01', 'Var', (34, 40))
400647	32748171	Supportively, the corresponding translational analyses indicated that BL-8040 reduced MDSC and Treg populations and increased tumor infiltration with CTLs.	('BL-8040', 'Var', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('reduced', 'NegReg', (78, 85))	('increased', 'PosReg', (116, 125))	('tumor', 'Disease', (126, 131))
400654	32748171	with chemotherapy and PD-1 blockade (Table 4) and use of the bispecific antibody, M7824, which blocks both immune-inhibitory TGFbeta and PD-L1 pathways and has demonstrated some efficacy signals in patients with PDAC and BTC.	('BTC', 'Disease', (221, 224))	('PD-L1 pathways', 'Pathway', (137, 151))	('M7824', 'Var', (82, 87))	('blocks', 'NegReg', (95, 101))	('patients', 'Species', '9606', (198, 206))	('efficacy', 'MPA', (178, 186))	('TGFbeta', 'Gene', '7039', (125, 132))	('PDAC', 'Disease', (212, 216))	('PD-1 blockade', 'Disease', (22, 35))	('PD-1 blockade', 'Disease', 'MESH:D010300', (22, 35))	('PDAC', 'Chemical', '-', (212, 216))	('TGFbeta', 'Gene', (125, 132))
400665	32886690	Furthermore, P. gingivalis augmented secretion and bioactivity of TGFbeta through glycoprotein A repetitions predominant (GARP) up-regulation.	('GARP', 'Gene', '2615', (122, 126))	('P. gingivalis', 'Var', (13, 26))	('bioactivity', 'MPA', (51, 62))	('up-regulation', 'PosReg', (128, 141))	('augmented', 'PosReg', (27, 36))	('P. gingivalis', 'Species', '837', (13, 26))	('GARP', 'Gene', (122, 126))	('TGFbeta', 'Gene', (66, 73))	('glycoprotein', 'MPA', (82, 94))	('secretion', 'MPA', (37, 46))
400666	32886690	Accordingly, disruption of either the GARP/TGFbeta axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis.	('Smad', 'Gene', (73, 77))	('YAP', 'Gene', (79, 82))	('GARP', 'Gene', '2615', (38, 42))	('Smad', 'Gene', '33529', (73, 77))	('disruption', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('GARP', 'Gene', (38, 42))	('abrogated', 'NegReg', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('YAP', 'Gene', '10413', (79, 82))	('tumor', 'Disease', (109, 114))	('P. gingivalis', 'Species', '837', (133, 146))
400669	32886690	Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC); this study shows that invasion of the bacterium Porphyromonas gingivalis enhances the aggressive progression of ESCC via the TGFbeta/Smad and TGFbeta/YAP/TAZ pathways.	('aggressive progression', 'CPA', (212, 234))	('ESCC', 'Disease', (238, 242))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (83, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('invasion', 'Var', (148, 156))	('YAP', 'Gene', '10413', (276, 279))	('Porphyromonas gingivalis', 'Species', '837', (174, 198))	('Smad', 'Gene', (259, 263))	('esophageal squamous cell carcinoma', 'Disease', (83, 117))	('YAP', 'Gene', (276, 279))	('enhances', 'PosReg', (199, 207))	('Microbial dysbiosis', 'Disease', (0, 19))	('Microbial dysbiosis', 'Disease', 'MESH:D064806', (0, 19))	('Smad', 'Gene', '33529', (259, 263))
400675	32886690	Previous studies reported that the amount of P. gingivalis in saliva was associated with the progression of oral cancer and ESCC.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('oral cancer', 'Disease', 'MESH:D009369', (108, 119))	('P. gingivalis', 'Species', '837', (45, 58))	('P. gingivalis', 'Var', (45, 58))	('associated with', 'Reg', (73, 88))	('oral cancer', 'Disease', (108, 119))	('ESCC', 'Disease', (124, 128))
400678	32886690	All of these findings support the notion that P. gingivalis is one of the key factors implicated in ESCC and may causatively influence the development, progression, and response to treatment of ESCC.	('ESCC', 'Disease', (194, 198))	('P. gingivalis', 'Var', (46, 59))	('ESCC', 'Disease', (100, 104))	('P. gingivalis', 'Species', '837', (46, 59))	('influence', 'Reg', (125, 134))
400682	32886690	Long-term infection by P. gingivalis has been shown to increase the invasiveness of oral cancer cells via induction of EMT-like changes and cell surface expression of cancer stem cell (CSC) markers cluster of differentiation (CD)44 and CD133.	('increase', 'PosReg', (55, 63))	('infection', 'Disease', (10, 19))	('infection', 'Disease', 'MESH:D007239', (10, 19))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (89, 95))	('CD', 'Chemical', 'MESH:D002104', (226, 228))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('P. gingivalis', 'Species', '837', (23, 36))	('invasiveness of oral cancer', 'Disease', (68, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cell surface', 'CPA', (140, 152))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('EMT-like changes', 'CPA', (119, 135))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('expression', 'Species', '29278', (153, 163))	('invasiveness of oral cancer', 'Disease', 'MESH:D009362', (68, 95))	('CD133', 'Gene', (236, 241))	('CD', 'Chemical', 'MESH:D002104', (236, 238))	('P. gingivalis', 'Var', (23, 36))
400684	32886690	In this study, we analyzed the influence of P. gingivalis on the prognosis of ESCC patients and revealed infection of P. gingivalis as a risk factor for the first time, to our knowledge.	('infection', 'Disease', (105, 114))	('infection', 'Disease', 'MESH:D007239', (105, 114))	('ESCC', 'Disease', (78, 82))	('P. gingivalis', 'Species', '837', (44, 57))	('P. gingivalis', 'Species', '837', (118, 131))	('P. gingivalis', 'Var', (118, 131))	('patients', 'Species', '9606', (83, 91))
400686	32886690	Up-regulation of glycoprotein A repetitions predominant (GARP) induced by intracellular colonization of P. gingivalis accelerates TGFbeta bioactivity, driving ESCC progression and metastasis.	('GARP', 'Gene', '2615', (57, 61))	('GARP', 'Gene', (57, 61))	('TGFbeta', 'Gene', (130, 137))	('metastasis', 'CPA', (180, 190))	('bioactivity', 'MPA', (138, 149))	('driving', 'PosReg', (151, 158))	('P. gingivalis', 'Var', (104, 117))	('P. gingivalis', 'Species', '837', (104, 117))	('Up-regulation', 'PosReg', (0, 13))	('glycoprotein A repetitions', 'Protein', (17, 43))	('accelerates', 'PosReg', (118, 129))	('ESCC', 'Disease', (159, 163))
400689	32886690	Both immunohistochemistry (IHC) and RNA in situ hybridization (RNAscope) detected P. gingivalis in the cytoplasm of cancer cells and stroma (Fig 1A).	('P. gingivalis', 'Species', '837', (82, 95))	('detected', 'Reg', (73, 81))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('P. gingivalis', 'Var', (82, 95))
400690	32886690	Consistent with our previous results, the amount of P. gingivalis in ESCC was positively associated with invasion depth, lymphatic metastasis, and tumor-node metastasis (TNM) stage (S1A Fig).	('associated', 'Reg', (89, 99))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('lymphatic metastasis', 'CPA', (121, 141))	('P. gingivalis', 'Var', (52, 65))	('P. gingivalis', 'Species', '837', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('invasion depth', 'CPA', (105, 119))	('ESCC', 'Disease', (69, 73))
400692	32886690	Univariate (S1B Fig) and multivariate (S1C Fig) Cox regression analysis revealed that the amount of P. gingivalis was an independent predictor of clinical outcome for ESCC patients.	('patients', 'Species', '9606', (172, 180))	('ESCC', 'Disease', (167, 171))	('P. gingivalis', 'Var', (100, 113))	('P. gingivalis', 'Species', '837', (100, 113))
400694	32886690	P. gingivalis treatment significantly increased the proliferation (Fig 1C), migration, and invasion (Fig 1D) of ESCC cells in vitro compared with treatments with heat-killed P. gingivalis, Lipopolysaccharide (LPS), and untreated controls.	('P. gingivalis', 'Species', '837', (174, 187))	('proliferation', 'CPA', (52, 65))	('Lipopolysaccharide', 'Chemical', 'MESH:D008070', (189, 207))	('invasion', 'CPA', (91, 99))	('P. gingivalis', 'Var', (0, 13))	('migration', 'CPA', (76, 85))	('P. gingivalis', 'Species', '837', (0, 13))	('increased', 'PosReg', (38, 47))
400698	32886690	Although E. coli DH5alpha had no enhancing effect on growth of NE6-T and KYSE30 cells, resembling the effect of E. coli DH5alpha on HCT-116 cells (S1E Fig), E. coli DH5alpha significantly augmented the abilities of migration and invasion in NE6-T and KYSE30 cells (S1F Fig).	('E. coli DH5alpha', 'Species', '668369', (9, 25))	('E. coli DH5alpha', 'Var', (157, 173))	('augmented', 'PosReg', (188, 197))	('invasion', 'CPA', (229, 237))	('HCT-116', 'CellLine', 'CVCL:0291', (132, 139))	('E. coli DH5alpha', 'Species', '668369', (112, 128))	('E. coli DH5alpha', 'Species', '668369', (157, 173))	('KYSE30', 'CellLine', 'CVCL:1351', (251, 257))	('migration', 'CPA', (215, 224))	('KYSE30', 'CellLine', 'CVCL:1351', (73, 79))
400702	32886690	Remarkably, NE6-T cells infected by P. gingivalis displayed an enhanced tumor growth in vivo compared with untreated controls (Fig 1F).	('P. gingivalis', 'Species', '837', (36, 49))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('infected', 'Disease', 'MESH:D007239', (24, 32))	('tumor', 'Disease', (72, 77))	('enhanced', 'PosReg', (63, 71))	('infected', 'Disease', (24, 32))	('P. gingivalis', 'Var', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
400704	32886690	In the mouse tail vein injection lung metastasis model, P. gingivalis significantly increased KYSE30 cell lung metastasis after 40 days compared with the control mice, evidenced by quantitative bioluminescence imaging and histological examination (Fig 1G).	('mouse', 'Species', '10090', (7, 12))	('P. gingivalis', 'Var', (56, 69))	('mice', 'Species', '10090', (162, 166))	('KYSE30', 'CellLine', 'CVCL:1351', (94, 100))	('increased', 'PosReg', (84, 93))	('P. gingivalis', 'Species', '837', (56, 69))	('KYSE30 cell lung metastasis', 'CPA', (94, 121))
400708	32886690	Together, these data demonstrate that P. gingivalis potentiates the aggressive progression of ESCC but has no malignant transformation potential.	('aggressive progression', 'CPA', (68, 90))	('potentiates', 'PosReg', (52, 63))	('P. gingivalis', 'Species', '837', (38, 51))	('P. gingivalis', 'Var', (38, 51))	('ESCC', 'Disease', (94, 98))
400714	32886690	Additionally, P. gingivalis increased the activation of a TGFbeta-responsive Smad-binding element (SBE) luciferase reporter in NE6-T and KYSE30 cells at 24 h postinfection.	('KYSE30', 'CellLine', 'CVCL:1351', (137, 143))	('gingivalis increased', 'Phenotype', 'HP:0000212', (17, 37))	('P. gingivalis', 'Var', (14, 27))	('infection', 'Disease', (162, 171))	('P. gingivalis', 'Species', '837', (14, 27))	('Smad', 'Gene', (77, 81))	('activation', 'PosReg', (42, 52))	('infection', 'Disease', 'MESH:D007239', (162, 171))	('Smad', 'Gene', '33529', (77, 81))	('SB', 'Chemical', 'MESH:D000965', (99, 101))
400721	32886690	Interestingly, P. gingivalis also induced up-regulation of cell-cycle inhibitors and apoptosis-related genes (S2C Fig), suggesting TGFbeta signaling as a mediator.	('apoptosis-related genes', 'Gene', (85, 108))	('P. gingivalis', 'Species', '837', (15, 28))	('P. gingivalis', 'Var', (15, 28))	('cell-cycle inhibitors', 'Gene', (59, 80))	('up-regulation', 'PosReg', (42, 55))
400724	32886690	The augmented xenograft tumor growth and weight of NE6-T (Fig 2H) and KYSE30 (S2H Fig) cells instigated by P. gingivalis treatment were significantly reduced by SB-431542 compared with P. gingivalis-treated NE6-T cells.	('SB-431542', 'Var', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('weight', 'CPA', (41, 47))	('tumor', 'Disease', (24, 29))	('P. gingivalis', 'Species', '837', (185, 198))	('KYSE30', 'CellLine', 'CVCL:1351', (70, 76))	('P. gingivalis', 'Species', '837', (107, 120))	('reduced', 'NegReg', (150, 157))	('SB-431542', 'Chemical', 'MESH:C459179', (161, 170))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
400726	32886690	Real-time PCR analyses showed that P. gingivalis induced increased mRNA levels of PAI-1, Smad7, Snail, and Oct4, which were rescued by SB-431542 or tinidazole in xenograft tumors, with the exception of Smad7 (S2I Fig).	('Smad', 'Gene', '33529', (89, 93))	('Oct4', 'Gene', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('Snail', 'MPA', (96, 101))	('Smad', 'Gene', '33529', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('Smad', 'Gene', (89, 93))	('tumors', 'Disease', (172, 178))	('SB-431542', 'Chemical', 'MESH:C459179', (135, 144))	('P. gingivalis', 'Var', (35, 48))	('PAI-1', 'Gene', '5054', (82, 87))	('tinidazole', 'Chemical', 'MESH:D014011', (148, 158))	('increased', 'PosReg', (57, 66))	('Oct4', 'Gene', '5460', (107, 111))	('PAI-1', 'Gene', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('mRNA levels', 'MPA', (67, 78))	('P. gingivalis', 'Species', '837', (35, 48))	('Smad', 'Gene', (202, 206))
400727	32886690	Again, IHC of pSmad2, PAI-1, Snail, and Oct4 showed significantly increased proteins induced by P. gingivalis (S2J Fig).	('increased', 'PosReg', (66, 75))	('Oct4', 'Gene', '5460', (40, 44))	('PAI-1', 'Gene', '5054', (22, 27))	('P. gingivalis', 'Species', '837', (96, 109))	('P. gingivalis', 'Var', (96, 109))	('Smad', 'Gene', (15, 19))	('Oct4', 'Gene', (40, 44))	('Smad', 'Gene', '33529', (15, 19))	('proteins induced', 'MPA', (76, 92))	('PAI-1', 'Gene', (22, 27))
400733	32886690	Immunofluorescence staining revealed that P. gingivalis exposure caused increased YAP/TAZ nuclear accumulation in NE6-T cells (Fig 3B) and KYSE30 cells (S3A Fig).	('increased', 'PosReg', (72, 81))	('P. gingivalis', 'Var', (42, 55))	('P. gingivalis', 'Species', '837', (42, 55))	('YAP', 'Gene', '10413', (82, 85))	('KYSE30', 'CellLine', 'CVCL:1351', (139, 145))	('YAP', 'Gene', (82, 85))
400734	32886690	Analysis of YAP/TAZ target genes further demonstrated that P. gingivalis-treated ESCC cells expressed significantly increased levels of mRNA and protein of connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61) (S3B Fig and Fig 3A).	('CTGF', 'Gene', '1490', (189, 193))	('cysteine', 'Chemical', 'MESH:D003545', (199, 207))	('CTGF', 'Gene', (189, 193))	('YAP', 'Gene', '10413', (12, 15))	('P. gingivalis-treated', 'Var', (59, 80))	('P. gingivalis', 'Species', '837', (59, 72))	('CYR61', 'Gene', (236, 241))	('YAP', 'Gene', (12, 15))	('connective tissue growth factor', 'Gene', '1490', (156, 187))	('CYR61', 'Gene', '3491', (236, 241))	('increased', 'PosReg', (116, 125))	('connective tissue growth factor', 'Gene', (156, 187))
400735	32886690	Pretreatment of ESCC cells with TGFbeta1-N, SB-431542, and tinidazole resulted in hyperphosphorylation of YAP/TAZ (Fig 3A) and YAP/TAZ cytoplasmic localization (Fig 3B and S3A Fig) and abolished the up-regulation of CTGF and CYR61 expression in response to P. gingivalis (Fig 3A and S3B Fig).	('YAP', 'Gene', (127, 130))	('abolished', 'NegReg', (185, 194))	('YAP', 'Gene', '10413', (106, 109))	('CTGF', 'Gene', '1490', (216, 220))	('SB-431542', 'Chemical', 'MESH:C459179', (44, 53))	('up-regulation', 'PosReg', (199, 212))	('hyperphosphorylation', 'MPA', (82, 102))	('CYR61', 'Gene', '3491', (225, 230))	('YAP', 'Gene', '10413', (127, 130))	('TGFbeta1', 'Gene', '7040', (32, 40))	('CTGF', 'Gene', (216, 220))	('tinidazole', 'Var', (59, 69))	('SB-431542', 'Var', (44, 53))	('TGFbeta1', 'Gene', (32, 40))	('YAP', 'Gene', (106, 109))	('CYR61', 'Gene', (225, 230))	('tinidazole', 'Chemical', 'MESH:D014011', (59, 69))	('P. gingivalis', 'Species', '837', (257, 270))	('expression', 'Species', '29278', (231, 241))
400737	32886690	To test the role of TGFbeta/Smad signaling in regulating YAP/TAZ activation, Smad2/3 was knocked down by short interfering RNA (siRNA) to block the propagation of canonical TGFbeta signaling.	('Smad', 'Gene', (28, 32))	('Smad2/3', 'Gene', '4088', (77, 84))	('Smad', 'Gene', '33529', (28, 32))	('Smad2/3', 'Gene', (77, 84))	('Smad', 'Gene', '33529', (77, 81))	('knocked', 'Var', (89, 96))	('YAP', 'Gene', '10413', (57, 60))	('Smad', 'Gene', (77, 81))	('YAP', 'Gene', (57, 60))
400741	32886690	Interestingly, P. gingivalis induced hyperphosphorylation of moesin-ezrin-radixin-like protein (Merlin), which is an upstream negative regulator of Hippo signaling (Fig 3D).	('moesin-ezrin-radixin-like protein', 'Gene', '32979', (61, 94))	('moesin-ezrin-radixin-like protein', 'Gene', (61, 94))	('P. gingivalis', 'Species', '837', (15, 28))	('P. gingivalis', 'Var', (15, 28))	('hyperphosphorylation', 'MPA', (37, 57))	('Merlin', 'Gene', '32979', (96, 102))	('Merlin', 'Gene', (96, 102))
400743	32886690	Overexpression of Lats1/2 or S518A Merlin in ESCC cells strongly and significantly inhibited the P. gingivalis-induced activation of YAP/TAZ (Fig 3E) and enhancement of migration and invasion (S3D Fig).	('Merlin', 'Gene', '32979', (35, 41))	('Lats1/2', 'Gene', (18, 25))	('expression', 'Species', '29278', (4, 14))	('YAP', 'Gene', '10413', (133, 136))	('S518A', 'Mutation', 'p.S518A', (29, 34))	('inhibited', 'NegReg', (83, 92))	('activation', 'PosReg', (119, 129))	('enhancement', 'PosReg', (154, 165))	('P. gingivalis', 'Species', '837', (97, 110))	('S518A', 'Var', (29, 34))	('Lats1/2', 'Gene', '8140', (18, 25))	('YAP', 'Gene', (133, 136))	('Merlin', 'Gene', (35, 41))
400744	32886690	Taken together, these results show that inactivation of Merlin and Lats1/2 by P. gingivalis is involved in the malignant progression of ESCC.	('Lats1/2', 'Gene', '8140', (67, 74))	('ESCC', 'Disease', (136, 140))	('Lats1/2', 'Gene', (67, 74))	('Merlin', 'Gene', (56, 62))	('P. gingivalis', 'Species', '837', (78, 91))	('involved', 'Reg', (95, 103))	('inactivation', 'Var', (40, 52))	('Merlin', 'Gene', '32979', (56, 62))	('malignant progression', 'CPA', (111, 132))
400746	32886690	Therefore, we tested whether P. gingivalis-induced activation of YAP/TAZ controls Smad2/3 nuclear accumulation by siRNA-mediated knocking down of YAP/TAZ in ESCC cells.	('YAP', 'Gene', '10413', (146, 149))	('YAP', 'Gene', (65, 68))	('YAP', 'Gene', (146, 149))	('Smad2/3', 'Gene', (82, 89))	('knocking down', 'Var', (129, 142))	('Smad2/3', 'Gene', '4088', (82, 89))	('P. gingivalis', 'Species', '837', (29, 42))	('tested', 'Reg', (14, 20))	('YAP', 'Gene', '10413', (65, 68))
400747	32886690	While phosphorylation of Smad2/3 was unaffected by deletion of YAP/TAZ (Fig 4A), YAP/TAZ knockdown abrogated the increase of transcriptional activity of Smad2/3 stimulated by P. gingivalis in an SBE luciferase reporter assay (Fig 4B).	('Smad2/3', 'Gene', (153, 160))	('Smad2/3', 'Gene', '4088', (153, 160))	('P. gingivalis', 'Species', '837', (175, 188))	('YAP', 'Gene', (63, 66))	('YAP', 'Gene', '10413', (81, 84))	('YAP', 'Gene', (81, 84))	('transcriptional activity', 'MPA', (125, 149))	('knockdown', 'Var', (89, 98))	('YAP', 'Gene', '10413', (63, 66))	('abrogated', 'NegReg', (99, 108))	('Smad2/3', 'Gene', (25, 32))	('deletion', 'Var', (51, 59))	('SB', 'Chemical', 'MESH:D000965', (195, 197))	('Smad2/3', 'Gene', '4088', (25, 32))
400749	32886690	In addition, knockdown of YAP/TAZ repressed the protein levels of Snail and Oct4 and caused a reversal of EMT markers (Fig 4A).	('Oct4', 'Gene', '5460', (76, 80))	('reversal', 'MPA', (94, 102))	('EMT', 'MPA', (106, 109))	('YAP', 'Gene', '10413', (26, 29))	('Oct4', 'Gene', (76, 80))	('knockdown', 'Var', (13, 22))	('YAP', 'Gene', (26, 29))	('Snail', 'MPA', (66, 71))	('protein levels', 'MPA', (48, 62))
400750	32886690	Furthermore, nuclear accumulation of Smad2/3 induced by P. gingivalis was markedly inhibited by YAP/TAZ knockdown (S4B Fig).	('YAP', 'Gene', (96, 99))	('P. gingivalis', 'Var', (56, 69))	('inhibited', 'NegReg', (83, 92))	('Smad2/3', 'Gene', (37, 44))	('Smad2/3', 'Gene', '4088', (37, 44))	('P. gingivalis', 'Species', '837', (56, 69))	('nuclear accumulation', 'MPA', (13, 33))	('YAP', 'Gene', '10413', (96, 99))	('knockdown', 'Var', (104, 113))
400754	32886690	After transfection with the pGL3-CTGF/CYR61 vectors, ESCC cells in the presence of P. gingivalis displayed an increase in CTGF or CYR61 promoter activities (Fig 4C).	('pGL3', 'Gene', (28, 32))	('increase', 'PosReg', (110, 118))	('CYR61', 'Gene', '3491', (38, 43))	('P. gingivalis', 'Species', '837', (83, 96))	('P. gingivalis', 'Var', (83, 96))	('CTGF', 'Gene', '1490', (33, 37))	('pGL3', 'Gene', '6391', (28, 32))	('CYR61', 'Gene', (130, 135))	('CYR61', 'Gene', '3491', (130, 135))	('CTGF', 'Gene', (33, 37))	('CYR61', 'Gene', (38, 43))	('CTGF', 'Gene', '1490', (122, 126))	('CTGF', 'Gene', (122, 126))
400755	32886690	Putative binding elements for TEAD1 (-1,794 to -1,781 nucleotides) and Smad (-1,745 to -1,732 nucleotides) were identified in the CYR61 promoter.	('TEAD', 'Disease', (30, 34))	('Smad', 'Gene', (71, 75))	('-1,745', 'Var', (77, 83))	('CYR61', 'Gene', (130, 135))	('CYR61', 'Gene', '3491', (130, 135))	('Smad', 'Gene', '33529', (71, 75))	('-1,794', 'Var', (37, 43))	('TEAD', 'Disease', 'None', (30, 34))
400758	32886690	P. gingivalis triggered stronger binding of YAP/TAZ, TEAD1, and Smad2/3 to CTGF (Fig 4D) and CYR61 (S4D Fig) promoters relative to control treatment in NE6-T cells.	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('CYR61', 'Gene', '3491', (93, 98))	('Smad2/3', 'Gene', (64, 71))	('YAP', 'Gene', '10413', (44, 47))	('CYR61', 'Gene', (93, 98))	('Smad2/3', 'Gene', '4088', (64, 71))	('stronger', 'PosReg', (24, 32))	('YAP', 'Gene', (44, 47))	('TEAD', 'Disease', (53, 57))	('binding', 'Interaction', (33, 40))	('TEAD', 'Disease', 'None', (53, 57))	('CTGF', 'Gene', (75, 79))	('CTGF', 'Gene', '1490', (75, 79))
400763	32886690	This assay demonstrated that Smad2/3 binding to the YAP/TAZ/TEAD1 complex was significantly increased following P. gingivalis challenge, and this was accompanied by decreased association with 14-3-3.	('decreased', 'NegReg', (165, 174))	('binding', 'Interaction', (37, 44))	('P. gingivalis', 'Species', '837', (112, 125))	('association', 'Interaction', (175, 186))	('Smad2/3', 'Gene', (29, 36))	('Smad2/3', 'Gene', '4088', (29, 36))	('YAP', 'Gene', (52, 55))	('increased', 'PosReg', (92, 101))	('TEAD', 'Disease', 'None', (60, 64))	('TEAD', 'Disease', (60, 64))	('P. gingivalis', 'Var', (112, 125))	('YAP', 'Gene', '10413', (52, 55))
400765	32886690	Because S94A YAP/S51A TAZ mutants lost the abilities to interact with TEAD, we transfected ESCC cells with S94A YAP/S51A TAZ mutants.	('abilities', 'MPA', (43, 52))	('S94A', 'Mutation', 'p.S94A', (107, 111))	('interact', 'Interaction', (56, 64))	('lost', 'NegReg', (34, 38))	('S51A', 'Mutation', 'p.S51A', (17, 21))	('S51A', 'Mutation', 'p.S51A', (116, 120))	('TEAD', 'Disease', 'None', (70, 74))	('YAP', 'Gene', '10413', (112, 115))	('S94A', 'Var', (107, 111))	('S94A', 'Mutation', 'p.S94A', (8, 12))	('TEAD', 'Disease', (70, 74))	('mutants', 'Var', (26, 33))	('YAP', 'Gene', '10413', (13, 16))	('S94A', 'Var', (8, 12))	('YAP', 'Gene', (13, 16))	('YAP', 'Gene', (112, 115))
400766	32886690	S94A YAP/S51A TAZ diminished migration and invasion in response to P. gingivalis (S4G Fig).	('S51A', 'Mutation', 'p.S51A', (9, 13))	('S94A', 'Var', (0, 4))	('YAP', 'Gene', '10413', (5, 8))	('migration', 'CPA', (29, 38))	('YAP', 'Gene', (5, 8))	('diminished', 'NegReg', (18, 28))	('P. gingivalis', 'Species', '837', (67, 80))	('S94A', 'Mutation', 'p.S94A', (0, 4))
400774	32886690	In line with this, we found that GARP protein levels were increased in NE6-T and KYSE30 cells in response to P. gingivalis (Fig 5A).	('P. gingivalis', 'Species', '837', (109, 122))	('P. gingivalis', 'Var', (109, 122))	('increased', 'PosReg', (58, 67))	('KYSE30', 'CellLine', 'CVCL:1351', (81, 87))	('GARP', 'Gene', '2615', (33, 37))	('GARP', 'Gene', (33, 37))
400776	32886690	Interestingly, P. gingivalis induced predominant membranous and paramembranous distributions of GARP in ESCC cells (Fig 5C).	('GARP', 'Gene', '2615', (96, 100))	('GARP', 'Gene', (96, 100))	('P. gingivalis', 'Species', '837', (15, 28))	('P. gingivalis', 'Var', (15, 28))	('membranous', 'CPA', (49, 59))
400778	32886690	GARP knockdown abrogated the P. gingivalis-induced increase of active TGFbeta in NE6-T and KYSE30 cells (S5A Fig).	('knockdown', 'Var', (5, 14))	('increase of active TGFbeta', 'Disease', 'MESH:D006940', (51, 77))	('abrogated', 'NegReg', (15, 24))	('GARP', 'Gene', '2615', (0, 4))	('GARP', 'Gene', (0, 4))	('P. gingivalis', 'Species', '837', (29, 42))	('increase of active TGFbeta', 'Disease', (51, 77))	('KYSE30', 'CellLine', 'CVCL:1351', (91, 97))
400780	32886690	Western blotting showed that GARP depletion abrogated the elevated levels of Smad2/3 phosphorylation, CTGF, PAI-1, Snail, and Oct4 induced by P. gingivalis treatment (Fig 5A).	('Oct4', 'Gene', (126, 130))	('PAI-1', 'Gene', '5054', (108, 113))	('Smad2/3', 'Gene', '4088', (77, 84))	('Smad2/3', 'Gene', (77, 84))	('levels', 'MPA', (67, 73))	('P. gingivalis', 'Species', '837', (142, 155))	('P. gingivalis', 'Var', (142, 155))	('CTGF', 'Gene', (102, 106))	('GARP', 'Gene', '2615', (29, 33))	('Oct4', 'Gene', '5460', (126, 130))	('PAI-1', 'Gene', (108, 113))	('CTGF', 'Gene', '1490', (102, 106))	('elevated', 'PosReg', (58, 66))	('abrogated', 'NegReg', (44, 53))	('GARP', 'Gene', (29, 33))	('Snail', 'MPA', (115, 120))
400781	32886690	In addition, knockdown of GARP expression also blocked P. gingivalis-induced ESCC cell migration and invasion (S5B Fig).	('GARP', 'Gene', (26, 30))	('ESCC', 'Disease', (77, 81))	('expression', 'Species', '29278', (31, 41))	('blocked', 'NegReg', (47, 54))	('P. gingivalis', 'Species', '837', (55, 68))	('knockdown', 'Var', (13, 22))	('invasion', 'CPA', (101, 109))	('GARP', 'Gene', '2615', (26, 30))
400784	32886690	Furthermore, knockdown of TLR4 or MYD88 markedly reduced the up-regulation of GARP and the enhanced activity of Smad2/3 induced by P. gingivalis (Fig 5E).	('GARP', 'Gene', (78, 82))	('reduced', 'NegReg', (49, 56))	('GARP', 'Gene', '2615', (78, 82))	('Smad2/3', 'Gene', (112, 119))	('TLR4', 'Gene', '34235', (26, 30))	('Smad2/3', 'Gene', '4088', (112, 119))	('P. gingivalis', 'Species', '837', (131, 144))	('MYD88', 'Gene', '35956', (34, 39))	('up-regulation', 'PosReg', (61, 74))	('TLR4', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('enhanced', 'PosReg', (91, 99))	('activity', 'MPA', (100, 108))	('MYD88', 'Gene', (34, 39))
400785	32886690	Although P. gingivalis induced activation of YAP/TAZ, as evidenced by decreased phosphorylation of S127YAP and S89TAZ and nuclear accumulation of YAP/TAZ, silencing of YAP/TAZ or overexpression of S127A mutant YAP had no effect on the expression of GARP (S5C and S5D Fig).	('YAP', 'Gene', '10413', (146, 149))	('YAP', 'Gene', (103, 106))	('YAP', 'Gene', '10413', (168, 171))	('phosphorylation', 'MPA', (80, 95))	('GARP', 'Gene', '2615', (249, 253))	('GARP', 'Gene', (249, 253))	('YAP', 'Gene', (45, 48))	('S127A', 'Var', (197, 202))	('expression', 'Species', '29278', (235, 245))	('YAP', 'Gene', '10413', (103, 106))	('silencing', 'Var', (155, 164))	('S89TAZ', 'Var', (111, 117))	('YAP', 'Gene', (210, 213))	('YAP', 'Gene', (146, 149))	('decreased', 'NegReg', (70, 79))	('YAP', 'Gene', '10413', (45, 48))	('YAP', 'Gene', (168, 171))	('S5C', 'Mutation', 'p.S5C', (255, 258))	('expression', 'Species', '29278', (183, 193))	('nuclear accumulation', 'CPA', (122, 142))	('P. gingivalis', 'Species', '837', (9, 22))	('YAP', 'Gene', '10413', (210, 213))	('S127A', 'Mutation', 'rs762471803', (197, 202))
400789	32886690	The protein levels of GARP, pSmad2, YAP/TAZ, Snail, and Oct4 were increased significantly in ESCC tissues with a high amount of P. gingivalis (Fig 6A).	('protein levels', 'MPA', (4, 18))	('increased', 'PosReg', (66, 75))	('GARP', 'Gene', '2615', (22, 26))	('GARP', 'Gene', (22, 26))	('YAP', 'Gene', '10413', (36, 39))	('YAP', 'Gene', (36, 39))	('Smad', 'Gene', (29, 33))	('Oct4', 'Gene', (56, 60))	('Smad', 'Gene', '33529', (29, 33))	('P. gingivalis', 'Var', (128, 141))	('P. gingivalis', 'Species', '837', (128, 141))	('Oct4', 'Gene', '5460', (56, 60))
400797	32886690	The risk score was calculated as follows: risk score = (-0.3918 x differential expression of E-cadherin + (-0.0443 x differential expression of Snail).	('expression', 'Species', '29278', (79, 89))	('E-cadherin', 'Gene', (93, 103))	('-0.0443', 'Var', (107, 114))	('E-cadherin', 'Gene', '999', (93, 103))	('-0.3918', 'Var', (56, 63))	('Snail', 'Protein', (144, 149))	('expression', 'Species', '29278', (130, 140))
400802	32886690	In addition, numerous studies have reported that P. gingivalis is an important risk factor for development and progression of a variety of cancers, including ESCC.	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('ESCC', 'Disease', (158, 162))	('P. gingivalis', 'Species', '837', (49, 62))	('P. gingivalis', 'Var', (49, 62))
400803	32886690	Here, we show that P. gingivalis exacerbates the aggressive progression of ESCC.	('P. gingivalis', 'Species', '837', (19, 32))	('ESCC', 'Disease', (75, 79))	('aggressive progression', 'CPA', (49, 71))	('exacerbates', 'PosReg', (33, 44))	('P. gingivalis', 'Var', (19, 32))
400806	32886690	Thus, ESCC patients with high levels of P. gingivalis and its downstream activated molecules have worse clinical outcomes.	('patients', 'Species', '9606', (11, 19))	('ESCC', 'Disease', (6, 10))	('P. gingivalis', 'Var', (40, 53))	('P. gingivalis', 'Species', '837', (40, 53))
400810	32886690	As a keystone periodontal pathogen, P. gingivalis enrichment in the oral cavity contributes to a dysbiotic microbial community, resulting in the onset of chronic periodontal disease and the possible subsequent development of oral cancer.	('P. gingivalis', 'Species', '837', (36, 49))	('oral cancer', 'Disease', (225, 236))	('chronic periodontal disease', 'Disease', (154, 181))	('dysbiotic microbial community', 'MPA', (97, 126))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('oral cancer', 'Disease', 'MESH:D009369', (225, 236))	('chronic periodontal disease', 'Disease', 'MESH:D055113', (154, 181))	('P. gingivalis', 'Var', (36, 49))	('periodontal disease', 'Phenotype', 'HP:0000704', (162, 181))
400811	32886690	Upon interaction with host cells, P. gingivalis induces cytoskeleton remodeling to allow its entry via activation of multiple signaling cascades and subsequently enhances invasiveness of oral cancer cells.	('P. gingivalis', 'Var', (34, 47))	('P. gingivalis', 'Species', '837', (34, 47))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('invasiveness of oral cancer', 'Disease', 'MESH:D009362', (171, 198))	('cytoskeleton', 'MPA', (56, 68))	('induces', 'Reg', (48, 55))	('invasiveness of oral cancer', 'Disease', (171, 198))	('activation', 'PosReg', (103, 113))	('enhances', 'PosReg', (162, 170))
400815	32886690	Fimbriae play a crucial role in mediating the attachment of P. gingivalis to tooth surface, other bacteria, and host cells for its internalization.	('P. gingivalis', 'Var', (60, 73))	('gingivalis to tooth surface', 'Phenotype', 'HP:0012292', (63, 90))	('P. gingivalis', 'Species', '837', (60, 73))	('attachment', 'Interaction', (46, 56))
400817	32886690	These data suggest that there are other mechanisms, such as LPS- or exosome-mediated signaling, imparting the oncogenic effect of P. gingivalis apart from intracellular invasion of P. gingivalis mediated by FimA.	('LPS-', 'MPA', (60, 64))	('P. gingivalis', 'Species', '837', (181, 194))	('oncogenic effect', 'MPA', (110, 126))	('P. gingivalis', 'Species', '837', (130, 143))	('P. gingivalis', 'Var', (130, 143))
400821	32886690	Deregulation of the TGFbeta signaling pathway has been demonstrated in multiple types of human cancers.	('human', 'Species', '9606', (89, 94))	('TGFbeta signaling pathway', 'Pathway', (20, 45))	('Deregulation', 'Var', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
400823	32886690	In line with this, we report that P. gingivalis induced increased secretion of TGFbeta1 and activation of TGFbeta1 and subsequently stimulated TGFbeta-dependent R-Smad phosphorylation.	('P. gingivalis', 'Var', (34, 47))	('stimulated', 'PosReg', (132, 142))	('activation', 'PosReg', (92, 102))	('TGFbeta-dependent', 'Protein', (143, 160))	('increased', 'PosReg', (56, 65))	('P. gingivalis', 'Species', '837', (34, 47))	('Smad', 'Gene', (163, 167))	('TGFbeta1', 'Gene', '7040', (106, 114))	('TGFbeta1', 'Gene', (106, 114))	('increased secretion of TGFbeta1', 'Phenotype', 'HP:0030269', (56, 87))	('Smad', 'Gene', '33529', (163, 167))	('TGFbeta1', 'Gene', '7040', (79, 87))	('secretion', 'MPA', (66, 75))	('TGFbeta1', 'Gene', (79, 87))
400825	32886690	Unexpectedly, downstream target genes of TGFbeta signaling involving cell-cycle suppression and apoptosis promotion were up-regulated in response to P. gingivalis.	('cell-cycle suppression', 'CPA', (69, 91))	('up-regulated', 'PosReg', (121, 133))	('apoptosis promotion', 'CPA', (96, 115))	('P. gingivalis', 'Var', (149, 162))	('TGFbeta signaling', 'Gene', (41, 58))	('P. gingivalis', 'Species', '837', (149, 162))
400828	32886690	We found that GARP, a TGFbeta-docking receptor on the cell surface, was markedly up-regulated in response to P. gingivalis and promoted TGFbeta bioactivity through the TLR4-MYD88 pathway.	('P. gingivalis', 'Species', '837', (109, 122))	('P. gingivalis', 'Var', (109, 122))	('TGFbeta', 'Gene', (136, 143))	('TLR4', 'Gene', (168, 172))	('MYD88', 'Gene', '35956', (173, 178))	('GARP', 'Gene', '2615', (14, 18))	('promoted', 'PosReg', (127, 135))	('MYD88', 'Gene', (173, 178))	('GARP', 'Gene', (14, 18))	('up-regulated', 'PosReg', (81, 93))	('TLR4', 'Gene', '34235', (168, 172))
400829	32886690	Chemical or genetic inhibition of GARP or TGFbeta blocked P. gingivalis-induced invasion and metastasis.	('inhibition', 'Var', (20, 30))	('blocked', 'NegReg', (50, 57))	('GARP', 'Gene', '2615', (34, 38))	('P. gingivalis', 'Species', '837', (58, 71))	('GARP', 'Gene', (34, 38))	('TGFbeta', 'Gene', (42, 49))	('genetic inhibition', 'Var', (12, 30))
400836	32886690	Furthermore, YAP/TAZ was required for P. gingivalis-associated oncogenic roles in ESCC because deletion of YAP/TAZ or overexpression of YAP S94A/TAZ S51A mutants abrogated the increased migration, invasion, and metastasis induced by P. gingivalis.	('invasion', 'CPA', (197, 205))	('S94A', 'Var', (140, 144))	('abrogated', 'NegReg', (162, 171))	('S51A', 'Var', (149, 153))	('YAP', 'Gene', (136, 139))	('deletion', 'Var', (95, 103))	('YAP', 'Gene', '10413', (107, 110))	('ESCC', 'Disease', (82, 86))	('migration', 'CPA', (186, 195))	('YAP', 'Gene', (107, 110))	('P. gingivalis', 'Species', '837', (233, 246))	('P. gingivalis', 'Species', '837', (38, 51))	('S94A', 'SUBSTITUTION', 'None', (140, 144))	('YAP', 'Gene', '10413', (13, 16))	('YAP', 'Gene', '10413', (136, 139))	('YAP', 'Gene', (13, 16))	('expression', 'Species', '29278', (122, 132))	('S51A', 'Mutation', 'p.S51A', (149, 153))
400842	32886690	We discovered that the mechanisms by which P. gingivalis induced suppression of Hippo signaling activity and YAP/TAZ activation involve inactivation of LATS1/2 and its upstream negative regulator Merlin.	('inactivation', 'NegReg', (136, 148))	('suppression', 'NegReg', (65, 76))	('Hippo signaling activity', 'MPA', (80, 104))	('YAP', 'Gene', '10413', (109, 112))	('Merlin', 'Gene', '32979', (196, 202))	('Merlin', 'Gene', (196, 202))	('YAP', 'Gene', (109, 112))	('LATS1/2', 'Gene', '8140', (152, 159))	('activation', 'PosReg', (117, 127))	('LATS1/2', 'Gene', (152, 159))	('P. gingivalis', 'Species', '837', (43, 56))	('P. gingivalis', 'Var', (43, 56))
400843	32886690	Upon exposure to P. gingivalis, Merlin was phosphorylated and thus inactivated, and this could be rescued by TGFbeta receptor inhibition.	('Merlin', 'Gene', '32979', (32, 38))	('P. gingivalis', 'Species', '837', (17, 30))	('Merlin', 'Gene', (32, 38))	('P. gingivalis', 'Var', (17, 30))	('inactivated', 'NegReg', (67, 78))
400844	32886690	Overexpression of S518A Merlin significantly reduced the invasive potential induced by P. gingivalis.	('reduced', 'NegReg', (45, 52))	('expression', 'Species', '29278', (4, 14))	('S518A', 'Var', (18, 23))	('Merlin', 'Gene', (24, 30))	('P. gingivalis', 'Species', '837', (87, 100))	('Merlin', 'Gene', '32979', (24, 30))	('S518A', 'Mutation', 'p.S518A', (18, 23))	('invasive potential', 'CPA', (57, 75))
400845	32886690	YAP/TAZ inactivation by Lats1/2 overexpression resembled the inhibitory effects of S518A Merlin.	('YAP', 'Gene', (0, 3))	('S518A', 'Mutation', 'p.S518A', (83, 88))	('Merlin', 'Gene', '32979', (89, 95))	('overexpression', 'Var', (32, 46))	('Merlin', 'Gene', (89, 95))	('Lats1/2', 'Gene', '8140', (24, 31))	('YAP', 'Gene', '10413', (0, 3))	('expression', 'Species', '29278', (36, 46))	('Lats1/2', 'Gene', (24, 31))
400851	32886690	It has been demonstrated that alterations in the oral microbiota or salivary composition represent promising noninvasive biomarkers for surveillance and early detection for high-risk subjects, as well as therapeutic response and prognosis for ESCC patients.	('patients', 'Species', '9606', (248, 256))	('alterations', 'Var', (30, 41))	('ESCC', 'Disease', (243, 247))
400859	32886690	In summary, the present study defines a complex circuitry underlying P. gingivalis-induced aggressive progression of ESCC, which orchestrates TGFbeta canonical and noncanonical signaling cascades.	('ESCC', 'Disease', (117, 121))	('P. gingivalis-induced', 'Var', (69, 90))	('P. gingivalis', 'Species', '837', (69, 82))
400910	32886690	Overexpression of Last1/2 or S518A Merlin in ESCC 209 cells affect the migration phenotypes.	('Merlin', 'Gene', '32979', (35, 41))	('expression', 'Species', '29278', (4, 14))	('S518A', 'Mutation', 'p.S518A', (29, 34))	('S518A', 'Var', (29, 34))	('affect', 'Reg', (60, 66))	('migration phenotypes', 'CPA', (71, 91))	('Merlin', 'Gene', (35, 41))
400915	32886690	A number of abbreviations are used in the manuscript, which should be explained, if they are used for the first time (especially if included in the abstract) Some minor things have been marked in the ms. Reviewer #3: In this manuscript, authors explore how P. gingivalis affects esophageal squamous cancer cells (ESCC).	('P. gingivalis', 'Var', (257, 270))	('squamous cancer', 'Phenotype', 'HP:0002860', (290, 305))	('P. gingivalis', 'Species', '837', (257, 270))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('affects', 'Reg', (271, 278))	('squamous cancer', 'Disease', 'MESH:D002294', (290, 305))	('squamous cancer', 'Disease', (290, 305))
400916	32886690	Results show that P. gingivalis promotes proliferation, migration and invasion.	('migration', 'CPA', (56, 65))	('P. gingivalis', 'Var', (18, 31))	('P. gingivalis', 'Species', '837', (18, 31))	('promotes', 'PosReg', (32, 40))	('invasion', 'CPA', (70, 78))	('proliferation', 'CPA', (41, 54))
400918	32886690	Authors provide evidence that P. gingivalis increases TGF-beta bioactivity in tumor cells, which results in activation of TGF-beta signaling pathway, ultimately leading to EMT activation.	('P. gingivalis', 'Var', (30, 43))	('EMT activation', 'CPA', (172, 186))	('P. gingivalis', 'Species', '837', (30, 43))	('bioactivity', 'MPA', (63, 74))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('TGF-beta', 'Gene', '7039', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('gingivalis increases', 'Phenotype', 'HP:0000212', (33, 53))	('TGF-beta', 'Gene', (54, 62))	('tumor', 'Disease', (78, 83))	('leading to', 'Reg', (161, 171))	('TGF-beta', 'Gene', '7039', (54, 62))	('increases', 'PosReg', (44, 53))	('TGF-beta', 'Gene', (122, 130))	('activation', 'PosReg', (108, 118))
400920	32886690	However, in figure 2 authors show that P. gingivalis indeed increases not only active TGF-beta but also total TGF-beta.	('increases', 'PosReg', (60, 69))	('active', 'MPA', (79, 85))	('TGF-beta', 'Gene', (110, 118))	('TGF-beta', 'Gene', (86, 94))	('TGF-beta', 'Gene', '7039', (110, 118))	('TGF-beta', 'Gene', '7039', (86, 94))	('P. gingivalis', 'Species', '837', (39, 52))	('P. gingivalis', 'Var', (39, 52))
400923	32886690	Authors show that infection with P. gingivalis in ESCC tumor cells promotes a more aggresive phenotype, and it is correlated with a poor prognosis, so P. gingivalis seems to be important for progression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('promotes', 'PosReg', (67, 75))	('more aggresive phenotype', 'MPA', (78, 102))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('infection', 'Disease', (18, 27))	('tumor', 'Disease', (55, 60))	('P. gingivalis', 'Species', '837', (151, 164))	('infection', 'Disease', 'MESH:D007239', (18, 27))	('P. gingivalis', 'Species', '837', (33, 46))	('P. gingivalis', 'Var', (33, 46))
400926	32886690	Authors claim that inactivation of Merlin is involved in the P. gingivalis-induced mechanism driving malignant progression of ESSC cells.	('ESSC', 'Disease', (126, 130))	('Merlin', 'Gene', '32979', (35, 41))	('P. gingivalis', 'Species', '837', (61, 74))	('involved', 'Reg', (45, 53))	('inactivation', 'Var', (19, 31))	('malignant progression', 'CPA', (101, 122))	('Merlin', 'Gene', (35, 41))
400927	32886690	However, the downregulation of Merlin provoked by P. gingivalis (fig.	('downregulation', 'NegReg', (13, 27))	('P. gingivalis', 'Var', (50, 63))	('Merlin', 'Gene', '32979', (31, 37))	('Merlin', 'Gene', (31, 37))	('P. gingivalis', 'Species', '837', (50, 63))
400936	32886690	4A (since it is not fully clear that phosphorylation is actually unaffected by deleting YAP/TAZ).	('YAP', 'Gene', (88, 91))	('deleting', 'Var', (79, 87))	('YAP', 'Gene', '10413', (88, 91))
400940	32886690	Figure S3: Controls for the overexpression of Lats1/2 and S518A Merlin should be included.	('Lats1/2', 'Gene', '8140', (46, 53))	('S518A', 'Var', (58, 63))	('Lats1/2', 'Gene', (46, 53))	('Merlin', 'Gene', (64, 70))	('Merlin', 'Gene', '32979', (64, 70))	('expression', 'Species', '29278', (32, 42))	('S518A', 'Mutation', 'p.S518A', (58, 63))
400945	32886690	Figure S3: revisit text (S518A Merlin) and figure (S51A Merlin).	('S518A', 'Mutation', 'p.S518A', (25, 30))	('S518A', 'Var', (25, 30))	('Merlin', 'Gene', (56, 62))	('S51A', 'Mutation', 'p.S51A', (51, 55))	('Merlin', 'Gene', '32979', (31, 37))	('Merlin', 'Gene', (31, 37))	('S51A', 'Var', (51, 55))	('Merlin', 'Gene', '32979', (56, 62))
400956	32886690	While fimA mutant P. gingivalis led to markedly decreased Smad2/3, this may be due to the simple reason of poor adherence.	('mutant P. gingivalis', 'Var', (11, 31))	('decreased', 'NegReg', (48, 57))	('P. gingivalis', 'Species', '837', (18, 31))	('Smad2/3', 'Gene', (58, 65))	('Smad2/3', 'Gene', '4088', (58, 65))
401032	32194797	In vitro, Stattic inhibited the viability of Eca-109 and Kyse-30 cells in a dose- and time- dependent manner, and significantly inhibited the expression of VEGF, Bcl-xl and CyclinD1 at mRNA and protein level.	('viability', 'CPA', (32, 41))	('Bcl-xl', 'Gene', (162, 168))	('VEGF', 'Gene', (156, 160))	('CyclinD1', 'Gene', (173, 181))	('Stattic', 'Var', (10, 17))	('Bcl-xl', 'Gene', '598', (162, 168))	('inhibited', 'NegReg', (18, 27))	('VEGF', 'Gene', '7422', (156, 160))	('expression', 'MPA', (142, 152))	('inhibited', 'NegReg', (128, 137))	('CyclinD1', 'Gene', '595', (173, 181))
401106	32194797	reported that STAT3 is a key regulator of VEGF, targeting STAT3 can decrease the expression of VEGF.	('STAT3', 'Gene', (14, 19))	('expression', 'MPA', (81, 91))	('VEGF', 'Gene', '7422', (95, 99))	('decrease', 'NegReg', (68, 76))	('VEGF', 'Gene', '7422', (42, 46))	('STAT3', 'Gene', '6774', (14, 19))	('VEGF', 'Gene', (95, 99))	('STAT3', 'Gene', '6774', (58, 63))	('targeting', 'Var', (48, 57))	('VEGF', 'Gene', (42, 46))	('STAT3', 'Gene', (58, 63))
401222	31966910	Conventionally, tissue biopsies have been used to access the molecular information of tumors, such as the histology and gene mutation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('gene mutation', 'Var', (120, 133))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))
401223	31966910	However, the practical use of consecutive tissue biopsies to monitor for mutations is limited due to patient discomfort, pain, and risks associated with repeat tissue biopsies, and difficulty in capturing intra-tumor heterogeneity.	('pain', 'Phenotype', 'HP:0012531', (121, 125))	('intra-tumor', 'Disease', 'MESH:D009369', (205, 216))	('pain', 'Disease', 'MESH:D010146', (121, 125))	('pain', 'Disease', (121, 125))	('intra-tumor', 'Disease', (205, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('patient', 'Species', '9606', (101, 108))	('mutations', 'Var', (73, 82))
401229	31966910	For example, an analysis of NSCLC patients' plasma for epidermal growth factor receptor (EGFR) to determine the existence of a T790M mutation is widely used.	('NSCLC', 'Disease', (28, 33))	('EGFR', 'Gene', (89, 93))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('epidermal growth factor receptor', 'Gene', (55, 87))	('T790M', 'Mutation', 'rs121434569', (127, 132))	('patients', 'Species', '9606', (34, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('T790M', 'Var', (127, 132))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('EGFR', 'Gene', '1956', (89, 93))
401239	31966910	A previous study showed a significantly broad range for ctDNA among patients with CRC (22-3922 ng/mL of blood) compared to healthy subjects (5-16 ng/mL of blood).	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('CRC', 'Disease', 'MESH:D015179', (82, 85))	('22-3922 ng/mL', 'Var', (87, 100))	('CRC', 'Disease', (82, 85))	('patients', 'Species', '9606', (68, 76))	('ctDNA', 'Disease', (56, 61))
401241	31966910	The OncoBEAM RAS CRC Assay identifies the cfDNA of the most frequent KRAS and NRAS mutations by using BEAMing technology.	('KRAS', 'Gene', (69, 73))	('mutations', 'Var', (83, 92))	('KRAS', 'Gene', '3845', (69, 73))	('CRC', 'Disease', 'MESH:D015179', (17, 20))	('CRC', 'Phenotype', 'HP:0003003', (17, 20))	('NRAS', 'Gene', (78, 82))	('NRAS', 'Gene', '4893', (78, 82))	('CRC', 'Disease', (17, 20))
401252	31966910	The Epi proColon  2.0 assay (also referred to as the mSEPT9 assay), which was FDA-approved for CRC screening in April 2016, is a qualitative in vitro diagnostic polymerase chain reaction (PCR) test for the detection of mutated methylated septin9 DNA in EDTA plasma derived from patient whole-blood specimens.	('septin9', 'Gene', '10801', (238, 245))	('CRC', 'Phenotype', 'HP:0003003', (95, 98))	('CRC', 'Disease', (95, 98))	('mSEPT9', 'Gene', '53860', (53, 59))	('EDTA', 'Chemical', 'MESH:D004492', (253, 257))	('CRC', 'Disease', 'MESH:D015179', (95, 98))	('septin9', 'Gene', (238, 245))	('patient', 'Species', '9606', (278, 285))	('mutated', 'Var', (219, 226))	('mSEPT9', 'Gene', (53, 59))
401258	31966910	For instance, emerging RAS mutations during therapy with anti-EGFR antibody revealed resistance in patients with metastatic CRC (mCRC).	('mutations', 'Var', (27, 36))	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('CRC', 'Disease', (124, 127))	('CRC', 'Disease', 'MESH:D015179', (130, 133))	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('CRC', 'Disease', 'MESH:D015179', (124, 127))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('patients', 'Species', '9606', (99, 107))	('CRC', 'Disease', (130, 133))	('RAS', 'Gene', (23, 26))
401279	31966910	Significant differences in ERBB2, APC, TP53, CDKN2A, and NRAS mutations were identified in the Japanese patients compared to United States patients.	('patients', 'Species', '9606', (139, 147))	('NRAS', 'Gene', (57, 61))	('APC', 'Disease', 'MESH:D011125', (34, 37))	('ERBB2', 'Gene', '2064', (27, 32))	('APC', 'Disease', (34, 37))	('TP53', 'Gene', '7157', (39, 43))	('ERBB2', 'Gene', (27, 32))	('CDKN2A', 'Gene', (45, 51))	('NRAS', 'Gene', '4893', (57, 61))	('patients', 'Species', '9606', (104, 112))	('mutations', 'Var', (62, 71))	('TP53', 'Gene', (39, 43))	('CDKN2A', 'Gene', '1029', (45, 51))
401281	31966910	A novel, positive correlation between APC and TP53 mutations with tumors that presented on the left side was reported.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (46, 50))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('APC', 'Disease', 'MESH:D011125', (38, 41))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('TP53', 'Gene', (46, 50))	('APC', 'Disease', (38, 41))
401282	31966910	A study through deep sequencing in patients with mCRC presented that mutations in TP53, KRAS, APC, KRAS, GNAS, and SMAD4 genes were detected in 69.3%, 39.6%, 23.7%, 16.8% and 13.8% patients, respectively.	('detected', 'Reg', (132, 140))	('patients', 'Species', '9606', (181, 189))	('APC', 'Disease', 'MESH:D011125', (94, 97))	('APC', 'Disease', (94, 97))	('KRAS', 'Gene', '3845', (99, 103))	('CRC', 'Disease', (50, 53))	('KRAS', 'Gene', '3845', (88, 92))	('CRC', 'Phenotype', 'HP:0003003', (50, 53))	('KRAS', 'Gene', (99, 103))	('patients', 'Species', '9606', (35, 43))	('SMAD4', 'Gene', (115, 120))	('TP53', 'Gene', (82, 86))	('mutations', 'Var', (69, 78))	('KRAS', 'Gene', (88, 92))	('CRC', 'Disease', 'MESH:D015179', (50, 53))	('GNAS', 'Gene', (105, 109))	('GNAS', 'Gene', '2778', (105, 109))	('SMAD4', 'Gene', '4089', (115, 120))	('TP53', 'Gene', '7157', (82, 86))
401283	31966910	The mutations in KRAS, GNAS, and SMAD4 were significantly associated with lung metastasis.	('GNAS', 'Gene', (23, 27))	('associated with', 'Reg', (58, 73))	('SMAD4', 'Gene', (33, 38))	('lung metastasis', 'Disease', 'MESH:D009362', (74, 89))	('lung metastasis', 'Disease', (74, 89))	('GNAS', 'Gene', '2778', (23, 27))	('KRAS', 'Gene', (17, 21))	('SMAD4', 'Gene', '4089', (33, 38))	('mutations', 'Var', (4, 13))	('KRAS', 'Gene', '3845', (17, 21))
401285	31966910	Specific subcategories of GCs harbor characteristic genetic aberrations, such as somatic mutations in RHOA and a chimeric gene fusion of CLDN18-ARHGAP26 in diffuse-type GCs.	('CLDN18', 'Gene', (137, 143))	('ARHGAP26', 'Gene', (144, 152))	('GC', 'Phenotype', 'HP:0012126', (26, 28))	('GCs', 'Phenotype', 'HP:0012126', (169, 172))	('CLDN18', 'Gene', '51208', (137, 143))	('GCs', 'Disease', 'MESH:D013274', (26, 29))	('GC', 'Phenotype', 'HP:0012126', (169, 171))	('RHOA', 'Gene', '387', (102, 106))	('GCs', 'Phenotype', 'HP:0012126', (26, 29))	('mutations', 'Var', (89, 98))	('GCs', 'Disease', (169, 172))	('RHOA', 'Gene', (102, 106))	('GCs', 'Disease', (26, 29))	('GCs', 'Disease', 'MESH:D013274', (169, 172))	('ARHGAP26', 'Gene', '23092', (144, 152))
401286	31966910	The landscape of esophageal cancer (EC)-related gene mutations that regulate the cell cycle (TP53, CCND1, CDKN2A, FBXW7), epigenetic processes (MLL2, EP300, CREBBP, TET2), and the signaling pathways involving NOTCH (NOTCH1, NOTCH3), WNT (FAT1, YAP1, AJUBA) and receptor-tyrosine kinase-phosphoinositide 3-kinase (PIK3CA, EGFR, ERBB2) has been described.	('AJUBA', 'Gene', '84962', (250, 255))	('NOTCH', 'Gene', (224, 229))	('MLL2', 'Gene', '8085', (144, 148))	('EP300', 'Gene', (150, 155))	('TP53', 'Gene', (93, 97))	('CCND1', 'Gene', (99, 104))	('NOTCH1', 'Gene', '4851', (216, 222))	('AJUBA', 'Gene', (250, 255))	('MLL2', 'Gene', (144, 148))	('ERBB2', 'Gene', '2064', (327, 332))	('NOTCH', 'Gene', '4851', (224, 229))	('NOTCH1', 'Gene', (216, 222))	('EGFR', 'Gene', (321, 325))	('CREBBP', 'Gene', '1387', (157, 163))	('regulate', 'Reg', (68, 76))	('FAT1', 'Gene', '2195', (238, 242))	('YAP1', 'Gene', '10413', (244, 248))	('EC', 'Disease', 'MESH:D004938', (36, 38))	('CDKN2A', 'Gene', (106, 112))	('PIK3CA', 'Gene', (313, 319))	('TET2', 'Gene', '54790', (165, 169))	('FBXW7', 'Gene', '55294', (114, 119))	('PIK3CA', 'Gene', '5290', (313, 319))	('YAP1', 'Gene', (244, 248))	('tyrosine', 'Chemical', 'None', (270, 278))	('esophageal cancer', 'Disease', 'MESH:D004938', (17, 34))	('TP53', 'Gene', '7157', (93, 97))	('CCND1', 'Gene', '595', (99, 104))	('mutations', 'Var', (53, 62))	('NOTCH', 'Gene', (209, 214))	('NOTCH3', 'Gene', '4854', (224, 230))	('EGFR', 'Gene', '1956', (321, 325))	('NOTCH', 'Gene', (216, 221))	('CDKN2A', 'Gene', '1029', (106, 112))	('EP300', 'Gene', '2033', (150, 155))	('cell', 'CPA', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('esophageal cancer', 'Disease', (17, 34))	('FAT1', 'Gene', (238, 242))	('NOTCH3', 'Gene', (224, 230))	('NOTCH', 'Gene', '4851', (209, 214))	('NOTCH', 'Gene', '4851', (216, 221))	('CREBBP', 'Gene', (157, 163))	('FBXW7', 'Gene', (114, 119))	('TET2', 'Gene', (165, 169))	('ERBB2', 'Gene', (327, 332))
401290	31966910	GI cancer patients with MMR deficiency and a subsequent hypermutated phenotype achieved outstanding outcomes after anti-PD-1 therapy.	('deficiency', 'Var', (28, 38))	('GI cancer', 'Phenotype', 'HP:0007378', (0, 9))	('patients', 'Species', '9606', (10, 18))	('MMR', 'Gene', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
401292	31966910	In CRC, mutations in transforming growth factor-beta (TGF-beta) signaling genes and BRAF were markedly increased in hypermutated tumors.	('transforming growth factor-beta', 'Gene', '7124', (21, 52))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('BRAF', 'Gene', '673', (84, 88))	('increased', 'PosReg', (103, 112))	('CRC', 'Disease', 'MESH:D015179', (3, 6))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('BRAF', 'Gene', (84, 88))	('mutations', 'Var', (8, 17))	('hypermutated tumors', 'Disease', 'MESH:D009369', (116, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('TGF-beta', 'Gene', (54, 62))	('hypermutated tumors', 'Disease', (116, 135))	('CRC', 'Disease', (3, 6))	('transforming growth factor-beta', 'Gene', (21, 52))	('TGF-beta', 'Gene', '7039', (54, 62))
401293	31966910	Mutations in DNA polymerase D1 (POLD1) and DNA polymerase E (POLE) genes have also been described as a cause of hypermutated CRC.	('CRC', 'Disease', (125, 128))	('polymerase D1', 'Gene', '5424', (17, 30))	('POLD1', 'Gene', (32, 37))	('POLD1', 'Gene', '5424', (32, 37))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('Mutations', 'Var', (0, 9))	('cause', 'Reg', (103, 108))	('polymerase D1', 'Gene', (17, 30))	('CRC', 'Disease', 'MESH:D015179', (125, 128))	('POLE', 'Gene', (61, 65))
401295	31966910	TGFBR2, ACVR2A, SMAD4, and ELF3 as well as the TGF-beta pathway are frequently mutated, suggesting a pivotal role in GC pathogenesis, including MSI.	('GC', 'Disease', 'MESH:D013274', (117, 119))	('GC', 'Phenotype', 'HP:0012126', (117, 119))	('ACVR2A', 'Gene', (8, 14))	('SMAD4', 'Gene', (16, 21))	('mutated', 'Var', (79, 86))	('TGF-beta', 'Gene', '7039', (47, 55))	('TGFBR2', 'Gene', (0, 6))	('ELF3', 'Gene', '1999', (27, 31))	('MSI', 'Disease', (144, 147))	('ACVR2A', 'Gene', '92', (8, 14))	('SMAD4', 'Gene', '4089', (16, 21))	('TGFBR2', 'Gene', '7048', (0, 6))	('TGF-beta', 'Gene', (47, 55))	('ELF3', 'Gene', (27, 31))
401298	31966910	A recent study using the Exiqon panel identified miR-20b-5p, miR-28-3p, miR-192-5p, miR-223-3p, and miR-296-5p as significantly upregulated in the serum of patients with EC, suggesting that these 5-miRNA signatures may serve as potential diagnostic biomarkers for ECs.	('miR-20b-5p', 'Var', (49, 59))	('patients', 'Species', '9606', (156, 164))	('miR-28-3p', 'Var', (61, 70))	('miR-223-3p', 'Var', (84, 94))	('EC', 'Disease', 'MESH:D004938', (264, 266))	('EC', 'Disease', 'MESH:D004938', (170, 172))	('miR-296-5p', 'Var', (100, 110))	('upregulated', 'PosReg', (128, 139))	('miR-192-5p', 'Var', (72, 82))
401299	31966910	Similarly, the expressions of seven miRNAs (miR-103a-3p, miR-127-3p, miR-151a-5p, miR-17-5p, miR-181a-5p, miR-18a-5p, and miR-18b-5p) were significantly higher in CRC compared to normal controls.	('expressions', 'MPA', (15, 26))	('miR-17-5p', 'Gene', (82, 91))	('CRC', 'Disease', (163, 166))	('higher', 'PosReg', (153, 159))	('miR-18a-5p', 'Var', (106, 116))	('miR-18b', 'Gene', (122, 129))	('miR-127-3p', 'Gene', (57, 67))	('CRC', 'Phenotype', 'HP:0003003', (163, 166))	('miR-103a-3p', 'Var', (44, 55))	('miR-151a-5p', 'Var', (69, 80))	('miR-181a-5p', 'Var', (93, 104))	('CRC', 'Disease', 'MESH:D015179', (163, 166))	('miR-18b', 'Gene', '574033', (122, 129))	('miR-127-3p', 'Gene', '100302165', (57, 67))	('miR-17-5p', 'Gene', '406952', (82, 91))
401303	31966910	Detection of BRAF mutation status was also recommended due to the ineffectiveness of anti-EGFR therapy for CRC patients with BRAF mutations.	('CRC', 'Disease', (107, 110))	('BRAF', 'Gene', '673', (13, 17))	('EGFR', 'Gene', '1956', (90, 94))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('BRAF', 'Gene', (13, 17))	('mutations', 'Var', (130, 139))	('EGFR', 'Gene', (90, 94))	('CRC', 'Disease', 'MESH:D015179', (107, 110))	('BRAF', 'Gene', '673', (125, 129))	('BRAF', 'Gene', (125, 129))	('patients', 'Species', '9606', (111, 119))
401304	31966910	A multicenter phase II study demonstrated antitumor activity of small-molecule MET inhibitor was shown in MRT-amplifier gastric/gastroesophageal/esophageal adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (145, 170))	('small-molecule', 'Var', (64, 78))	('tumor', 'Disease', (46, 51))	('gastroesophageal/esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (128, 170))	('gastroesophageal/esophageal adenocarcinoma', 'Disease', (128, 170))	('MET inhibitor', 'Gene', (79, 92))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
401305	31966910	A recent study using whole-exome sequencing characterized KDR/VEGFR2 somatic mutations as potential genetic biomarkers of patients' responses to antiangiogenic cancer therapies.	('VEGFR2', 'Gene', '3791', (62, 68))	('KDR', 'Gene', (58, 61))	('VEGFR2', 'Gene', (62, 68))	('KDR', 'Gene', '3791', (58, 61))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
401306	31966910	Interestingly, a recent cohort study presented that ALK, ROS1, and NTRK rearrangements classified a new subtype of mCRC with particularly poor outcome.	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('ROS1', 'Gene', '6098', (57, 61))	('NTRK', 'Gene', (67, 71))	('ALK', 'Gene', '238', (52, 55))	('rearrangements', 'Var', (72, 86))	('ALK', 'Gene', (52, 55))	('CRC', 'Disease', 'MESH:D015179', (116, 119))	('CRC', 'Disease', (116, 119))	('ROS1', 'Gene', (57, 61))
401307	31966910	Rearrangements of ALK, ROS1, and NTRK were more frequently observed in elderly patients with right-sided tumors and node-spreading, RAS wild-type, and MSI-high cancers.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('ALK', 'Gene', '238', (18, 21))	('ROS1', 'Gene', (23, 27))	('Rearrangements', 'Var', (0, 14))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('NTRK', 'Gene', (33, 37))	('cancers', 'Disease', (160, 167))	('ROS1', 'Gene', '6098', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('ALK', 'Gene', (18, 21))	('patients', 'Species', '9606', (79, 87))	('observed', 'Reg', (59, 67))	('node-spreading', 'CPA', (116, 130))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
401309	31966910	MMR deficiency has been shown to be positively prognostic for outcome in patients with GC and CRC.	('GC', 'Disease', 'MESH:D013274', (87, 89))	('GC', 'Phenotype', 'HP:0012126', (87, 89))	('prognostic', 'Reg', (47, 57))	('deficiency', 'Var', (4, 14))	('CRC', 'Disease', 'MESH:D015179', (94, 97))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('MMR', 'Gene', (0, 3))	('patients', 'Species', '9606', (73, 81))	('CRC', 'Disease', (94, 97))
401310	31966910	Notably, MMR deficiency is a variety of cancer predictor for response to anti-PD-1/PD-L1 blockade therapies.	('PD-L1', 'Gene', '29126', (83, 88))	('MMR', 'Gene', (9, 12))	('deficiency', 'Var', (13, 23))	('PD-L1', 'Gene', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
401336	31966910	Other study using patient-derived CRC organoids presented that of all RASGTPases activating proteins, only neurofibromin (NF1) deficiency facilitate cell survival and prompted EGF-independent tumor cell growth in human CRC samples, suggesting that NF1 protein levels should be measured in CRCs prior to initiate of targeted therapy against the MAPK pathway.	('deficiency', 'Var', (127, 137))	('patient', 'Species', '9606', (18, 25))	('CRC', 'Disease', (219, 222))	('CRC', 'Disease', (289, 292))	('neurofibromin', 'Gene', '4763', (107, 120))	('CRC', 'Phenotype', 'HP:0003003', (219, 222))	('facilitate', 'PosReg', (138, 148))	('CRC', 'Phenotype', 'HP:0003003', (289, 292))	('CRC', 'Disease', (34, 37))	('tumor', 'Disease', (192, 197))	('human', 'Species', '9606', (213, 218))	('CRC', 'Phenotype', 'HP:0003003', (34, 37))	('EGF', 'Gene', '1950', (176, 179))	('CRC', 'Disease', 'MESH:D015179', (219, 222))	('CRC', 'Disease', 'MESH:D015179', (289, 292))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('NF1', 'Gene', '4763', (122, 125))	('NF1', 'Gene', '4763', (248, 251))	('CRC', 'Disease', 'MESH:D015179', (34, 37))	('cell survival', 'CPA', (149, 162))	('neurofibromin', 'Gene', (107, 120))	('NF1', 'Gene', (122, 125))	('EGF', 'Gene', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('NF1', 'Gene', (248, 251))
401340	31966910	The principal gene alteration identified is NRF2 pathway disruption.	('NRF2', 'Gene', '4780', (44, 48))	('disruption', 'Reg', (57, 67))	('NRF2', 'Gene', (44, 48))	('alteration', 'Var', (19, 29))
401341	31966910	The second subgroup is ESCC2, characterized by the mutation of NOTCH1, ZNF750, KDM6A, KDM2D, PTEN, PIK3R1, and CDK6 amplification.	('PIK3R1', 'Gene', '5295', (99, 105))	('KDM6A', 'Gene', (79, 84))	('PTEN', 'Gene', (93, 97))	('NOTCH1', 'Gene', (63, 69))	('PTEN', 'Gene', '5728', (93, 97))	('KDM2D', 'Gene', (86, 91))	('ZNF750', 'Gene', '79755', (71, 77))	('KDM6A', 'Gene', '7403', (79, 84))	('mutation', 'Var', (51, 59))	('CDK6', 'Gene', (111, 115))	('NOTCH1', 'Gene', '4851', (63, 69))	('ZNF750', 'Gene', (71, 77))	('CDK6', 'Gene', '1021', (111, 115))	('PIK3R1', 'Gene', (99, 105))
401347	31966910	A study classifying CRC by both tumor side and location using NGS panel presented that RAS mutations are seen in 70% of cecal tumors but only 57% of ascending colon and 43% of hepatic flexure tumors.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('RAS', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CRC', 'Disease', (20, 23))	('CRC', 'Phenotype', 'HP:0003003', (20, 23))	('ascending colon', 'Disease', (149, 164))	('seen', 'Reg', (105, 109))	('tumor', 'Disease', (192, 197))	('CRC', 'Disease', 'MESH:D015179', (20, 23))	('hepatic flexure tumors', 'Disease', 'MESH:C566278', (176, 198))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cecal tumors', 'Disease', (120, 132))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (126, 131))	('hepatic flexure tumors', 'Disease', (176, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cecal tumors', 'Disease', 'MESH:D002430', (120, 132))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
401348	31966910	BRAFV600 mutations occur in 10% of cecal, 16% of ascending colon, and 22% of hepatic flexure tumors.	('ascending colon', 'Disease', (49, 64))	('cecal', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutations', 'Var', (9, 18))	('hepatic flexure tumors', 'Disease', (77, 99))	('BRAF', 'Gene', '673', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('hepatic flexure tumors', 'Disease', 'MESH:C566278', (77, 99))	('BRAF', 'Gene', (0, 4))	('occur', 'Reg', (19, 24))
401349	31966910	PIK3CA mutations are seen in 26% of descending colon but only 14% of sigmoid and 9% of rectosigmoid tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (7, 16))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('PIK3CA', 'Gene', (0, 6))	('descending colon', 'Disease', (36, 52))	('rectosigmoid tumors', 'Disease', 'MESH:D011350', (87, 106))	('PIK3CA', 'Gene', '5290', (0, 6))	('descending colon', 'Phenotype', 'HP:0012851', (36, 52))	('seen', 'Reg', (21, 25))	('rectosigmoid tumors', 'Disease', (87, 106))
401350	31966910	CTNNB1 mutations are almost absent in the sigmoid (1%), rectosigmoid junction (0%), and rectum (1%), but are still present in the descending colon (6%).	('absent', 'NegReg', (28, 34))	('descending colon', 'Phenotype', 'HP:0012851', (130, 146))	('CTNNB1', 'Gene', '1499', (0, 6))	('CTNNB1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
401409	31315281	Results showed that patients who received PBT had a significantly higher 5-year OS rate than those who did not (41.6% vs. 31.6%).	('OS', 'Chemical', '-', (80, 82))	('PBT', 'Var', (42, 45))	('patients', 'Species', '9606', (20, 28))	('higher', 'PosReg', (66, 72))
401411	31315281	Similarly, our findings showed an improvement in OS in patients with esophageal cancer receiving PBT.	('esophageal cancer', 'Disease', (69, 86))	('OS', 'Chemical', '-', (49, 51))	('PBT', 'Var', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('improvement', 'PosReg', (34, 45))	('patients', 'Species', '9606', (55, 63))	('men', 'Species', '9606', (41, 44))
401423	31315281	have investigated the actual incidence rate of heart toxicities and reported that a lower incidence rate of >=grade 2 heart toxicities was observed in patients who received PBT (4% vs. 53%).	('heart toxicities', 'Disease', 'MESH:D006331', (47, 63))	('PBT', 'Var', (173, 176))	('patients', 'Species', '9606', (151, 159))	('heart toxicities', 'Disease', (118, 134))	('heart toxicities', 'Disease', 'MESH:D006331', (118, 134))	('heart toxicities', 'Disease', (47, 63))
401436	31315281	Our results, in congruence with prior results, suggest that PBT can reduce pneumonitis after definitive radiotherapy.	('reduce', 'NegReg', (68, 74))	('pneumonitis', 'Disease', 'MESH:D011014', (75, 86))	('PBT', 'Var', (60, 63))	('pneumonitis', 'Disease', (75, 86))
401532	29117668	Among the 18 patients with endotracheal intubation before SB tube, four (22.2%) developed esophageal perforation due to misplaced SB tube.	('SB tube', 'Chemical', '-', (58, 65))	('esophageal perforation', 'Disease', (90, 112))	('patients', 'Species', '9606', (13, 21))	('SB tube', 'Chemical', '-', (130, 137))	('misplaced', 'Var', (120, 129))
401657	29333062	The primary pathogenic role of H. pylori in peptic ulcer formation is supported by robust evidence, and H. pylori was recognized as a true class I carcinogen for gastric cancer by the International Agency for Research on Cancer and the World Health Organization in 1994.	('gastric cancer', 'Disease', 'MESH:D013274', (162, 176))	('Cancer', 'Disease', 'MESH:D009369', (221, 227))	('H. pylori', 'Var', (104, 113))	('ulcer', 'Disease', 'MESH:D014456', (51, 56))	('ulcer', 'Disease', (51, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('peptic ulcer', 'Phenotype', 'HP:0004398', (44, 56))	('H. pylori', 'Species', '210', (31, 40))	('H. pylori', 'Species', '210', (104, 113))	('Cancer', 'Phenotype', 'HP:0002664', (221, 227))	('gastric cancer', 'Disease', (162, 176))	('Cancer', 'Disease', (221, 227))
401673	29333062	H. pylori CagA-negative individuals and controls (H. pylori-negative individuals) had similar EAC rates, as shown in one meta-analysis.	('H. pylori', 'Species', '210', (50, 59))	('EAC', 'CPA', (94, 97))	('H. pylori', 'Var', (0, 9))	('H. pylori', 'Species', '210', (0, 9))
401710	29069743	Determination of IL-1B (rs16944) and IL-6 (rs1800796) genetic polymorphisms in IgA nephropathy in a northwest Chinese Han population IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, but etiology and pathogenesis continue to be poorly understood.	('nephropathy', 'Disease', (137, 148))	('IgA', 'Gene', (133, 136))	('IgA nephropathy', 'Phenotype', 'HP:0000794', (79, 94))	('IL-6', 'Gene', '3569', (37, 41))	('nephropathy', 'Disease', 'MESH:D007674', (137, 148))	('rs16944', 'Var', (24, 31))	('IgAN', 'Phenotype', 'HP:0000794', (150, 154))	('IgA nephropathy', 'Phenotype', 'HP:0000794', (133, 148))	('IL-6', 'Gene', (37, 41))	('glomerulonephritis', 'Disease', 'MESH:D005921', (191, 209))	('IgAN', 'Gene', (150, 154))	('nephropathy', 'Phenotype', 'HP:0000112', (83, 94))	('IgA nephropathy', 'Gene', (79, 94))	('IgA', 'Gene', '973', (150, 153))	('nephropathy', 'Phenotype', 'HP:0000112', (137, 148))	('IgA nephropathy', 'Gene', '60498', (79, 94))	('rs16944', 'Mutation', 'rs16944', (24, 31))	('glomerulonephritis', 'Disease', (191, 209))	('IgA', 'Gene', '973', (79, 82))	('IgA nephropathy', 'Gene', (133, 148))	('IL-1B', 'Gene', (17, 22))	('IgA nephropathy', 'Gene', '60498', (133, 148))	('IgA', 'Gene', (150, 153))	('IgA', 'Gene', '973', (133, 136))	('IL-1B', 'Gene', '3553', (17, 22))	('glomerulonephritis', 'Phenotype', 'HP:0000099', (191, 209))	('rs1800796', 'Mutation', 'rs1800796', (43, 52))	('IgA', 'Gene', (79, 82))	('IgAN', 'Gene', '60498', (150, 154))	('nephropathy', 'Disease', (83, 94))	('rs1800796', 'Var', (43, 52))	('nephropathy', 'Disease', 'MESH:D007674', (83, 94))
401711	29069743	Polymorphisms in the cytokine genes may play a role in the etiology and pathogenesis of IgAN.	('play', 'Reg', (40, 44))	('cytokine genes', 'Gene', (21, 35))	('IgAN', 'Gene', '60498', (88, 92))	('Polymorphisms', 'Var', (0, 13))	('role', 'Reg', (47, 51))	('IgAN', 'Phenotype', 'HP:0000794', (88, 92))	('IgAN', 'Gene', (88, 92))
401712	29069743	We genotype 10 single nucleotide polymorphisms (SNPs) in IL-1B and IL-6 gene using Sequenom Mass-ARRAY technology from 417 IgAN patients and 463 healthy controls of the Chinese Han population.	('IgAN', 'Gene', (123, 127))	('IgAN', 'Gene', '60498', (123, 127))	('IL-6', 'Gene', (67, 71))	('IL-1B', 'Gene', (57, 62))	('IL-6', 'Gene', '3569', (67, 71))	('IL-1B', 'Gene', '3553', (57, 62))	('patients', 'Species', '9606', (128, 136))	('IgAN', 'Phenotype', 'HP:0000794', (123, 127))	('single nucleotide polymorphisms', 'Var', (15, 46))
401715	29069743	The rs16944 in IL-1B and rs1800796 in IL-6 were associated with 1.23-fold (95% CI, 1.02-1.48, P = 0.031) and 1.33-fold (95% CI, 1.11-1.66, P = 0.003) increases in the risk of developing IgAN, respectively.	('rs1800796', 'Var', (25, 34))	('IgAN', 'Gene', '60498', (186, 190))	('IL-1B', 'Gene', (15, 20))	('rs16944', 'Mutation', 'rs16944', (4, 11))	('IgAN', 'Phenotype', 'HP:0000794', (186, 190))	('IgAN', 'Gene', (186, 190))	('IL-1B', 'Gene', '3553', (15, 20))	('IL-6', 'Gene', (38, 42))	('rs16944', 'Var', (4, 11))	('IL-6', 'Gene', '3569', (38, 42))	('rs1800796', 'Mutation', 'rs1800796', (25, 34))	('increases', 'PosReg', (150, 159))
401716	29069743	There was only rs1800796 still correlated with IgAN in the allelic model after adjustment by age and gender and the Bonferroni correction.	('rs1800796', 'Mutation', 'rs1800796', (15, 24))	('IgAN', 'Gene', (47, 51))	('IgAN', 'Gene', '60498', (47, 51))	('rs1800796', 'Var', (15, 24))	('men', 'Species', '9606', (85, 88))	('IgAN', 'Phenotype', 'HP:0000794', (47, 51))	('correlated', 'Reg', (31, 41))
401717	29069743	In addition, Haplotype Grs1800796A rs2069837G rs2069840 (P = 0.037) and G rs1800796A rs2069837C rs2069840 (P = 0.042) in IL-6were considered to be associated with increased IgAN risk.	('IgAN', 'Gene', (173, 177))	('IgAN', 'Gene', '60498', (173, 177))	('IL-6', 'Gene', '3569', (121, 125))	('rs2069840', 'Mutation', 'rs2069840', (46, 55))	('G rs1800796A rs2069837C rs2069840', 'Var', (72, 105))	('rs2069840', 'Mutation', 'rs2069840', (96, 105))	('rs1800796', 'Mutation', 'rs1800796', (74, 83))	('rs2069837', 'Mutation', 'rs2069837', (85, 94))	('rs1800796', 'Mutation', 'rs1800796', (24, 33))	('IgAN', 'Phenotype', 'HP:0000794', (173, 177))	('Grs1800796A rs2069837G rs2069840', 'Var', (23, 55))	('IL-6', 'Gene', (121, 125))	('rs2069837', 'Mutation', 'rs2069837', (35, 44))
401718	29069743	This study verified the IL-6, IL-1B genetic variants polymorphisms contributed to IgAN susceptibility in a Chinese Han population.	('IgAN', 'Gene', (82, 86))	('IL-1B', 'Gene', '3553', (30, 35))	('contributed', 'Reg', (67, 78))	('IgAN', 'Gene', '60498', (82, 86))	('IL-1B', 'Gene', (30, 35))	('IL-6', 'Gene', (24, 28))	('IL-6', 'Gene', '3569', (24, 28))	('IgAN', 'Phenotype', 'HP:0000794', (82, 86))	('polymorphisms', 'Var', (53, 66))
401743	29069743	The rs2853550 and rs16944 in IL-1B, and rs1800796 in IL-6 were associated with 1.37-fold (95% CI, 1.00-1.87, P = 0.050), 1.23-fold (95% CI, 1.02-1.48, P = 0.031), and 1.33-fold (95% CI, 1.11-1.66, P = 0.003) increases in the risk of developing IgAN, respectively.	('IgAN', 'Phenotype', 'HP:0000794', (244, 248))	('IL-1B', 'Gene', (29, 34))	('rs1800796', 'Mutation', 'rs1800796', (40, 49))	('IL-6', 'Gene', (53, 57))	('rs2853550', 'Mutation', 'rs2853550', (4, 13))	('IL-6', 'Gene', '3569', (53, 57))	('IgAN', 'Gene', (244, 248))	('rs16944', 'Mutation', 'rs16944', (18, 25))	('rs2853550', 'Var', (4, 13))	('IL-1B', 'Gene', '3553', (29, 34))	('increases', 'PosReg', (208, 217))	('IgAN', 'Gene', '60498', (244, 248))	('rs1800796', 'Var', (40, 49))	('rs16944', 'Var', (18, 25))
401745	29069743	Only one (rs1800796) of the three SNPs was still correlated with IgAN in the allelic model after Bonferroni correction.	('rs1800796', 'Var', (10, 19))	('correlated', 'Reg', (49, 59))	('IgAN', 'Phenotype', 'HP:0000794', (65, 69))	('IgAN', 'Gene', (65, 69))	('IgAN', 'Gene', '60498', (65, 69))	('rs1800796', 'Mutation', 'rs1800796', (10, 19))
401747	29069743	The "A/G-A/A" genotype at the rs2853550 SNP increased the risk of IgAN in the dominant model (OR = 1.46; 95% CI, 1.04-2.05, P = 0.030), and "A/G" in the overdominant model with a P = 0.023 (OR = 1.151; 95%CI, 1.06 - 2.15).	('rs2853550', 'Mutation', 'rs2853550', (30, 39))	('IgAN', 'Phenotype', 'HP:0000794', (66, 70))	('rs2853550', 'Var', (30, 39))	('IgAN', 'Gene', (66, 70))	('IgAN', 'Gene', '60498', (66, 70))
401748	29069743	The "G" allele in rs16944 decreased the IgAN risk in the log-additive model (OR = 0.80; 95% CI, 0.66-0.97, P = 0.026).	('rs16944', 'Mutation', 'rs16944', (18, 25))	('rs16944', 'Var', (18, 25))	('IgAN', 'Phenotype', 'HP:0000794', (40, 44))	('decreased', 'NegReg', (26, 35))	('IgAN', 'Gene', (40, 44))	('IgAN', 'Gene', '60498', (40, 44))
401750	29069743	For the rs1800796 SNP, the "G" allele increased the risk 1.38-fold (95% CI, 1.04-1.83; P = 0.014) in the codominant model, the "C/G-G/G" genotype increased the risk of IgAN 1.45-fold (95% CI, 1.11-1.89; P = 0.006) in the dominant model, and the "G" allele increased the risk 1.34-fold (95% CI, 1.10-1.63; P = 0.004) in the log-additive model.	('C/G-G/G', 'Var', (128, 135))	('IgAN 1', 'Gene', '60498', (168, 174))	('rs1800796', 'Mutation', 'rs1800796', (8, 17))	('increased', 'PosReg', (146, 155))	('IgAN', 'Phenotype', 'HP:0000794', (168, 172))	('rs1800796', 'Var', (8, 17))	('IgAN 1', 'Gene', (168, 174))
401751	29069743	In addition, after adjustment for age and gender, the "G" allele increased the IgAN risk 1.70-fold (95% CI, 1.19-2.43; P = 0.003) in the codominant model, the "C/G-G/G" genotype increased the risk of IgAN more than 1.70-fold (95% CI, 1.26-2.48; P = 9.00E-04) in the dominant model, and the "G" allele increased the risk more than 1.50-fold (95% CI, 1.18-1.94; P = 0.001) in the log-additive model.	('IgAN', 'Gene', '60498', (200, 204))	('IgAN', 'Phenotype', 'HP:0000794', (79, 83))	('C/G-G/G', 'Var', (160, 167))	('IgAN', 'Gene', (79, 83))	('IgAN', 'Phenotype', 'HP:0000794', (200, 204))	('IgAN', 'Gene', (200, 204))	('IgAN', 'Gene', '60498', (79, 83))	('men', 'Species', '9606', (25, 28))	('increased', 'PosReg', (178, 187))
401752	29069743	According to the adjusted by Bonferroni correction, mutations at rs1800796 (codominant P = 0.012; dominant P = 3.2 E-03; additive P < 0.004) were still associated with an increased IgAN risk.	('mutations', 'Var', (52, 61))	('rs1800796', 'Mutation', 'rs1800796', (65, 74))	('IgAN', 'Gene', (181, 185))	('IgAN', 'Gene', '60498', (181, 185))	('associated', 'Reg', (152, 162))	('IgAN', 'Phenotype', 'HP:0000794', (181, 185))
401755	29069743	Finally, a haplotype-based association study was performed to examine associations between IL-1B and IL-6 haplotype and risk of IgAN (Table 4), and P-values were calculated using the Wald test.	('IL-6', 'Gene', (101, 105))	('IL-6', 'Gene', '3569', (101, 105))	('haplotype', 'Var', (106, 115))	('associations', 'Interaction', (70, 82))	('IgAN', 'Phenotype', 'HP:0000794', (128, 132))	('IL-1B', 'Gene', (91, 96))	('IgAN', 'Gene', '60498', (128, 132))	('IgAN', 'Gene', (128, 132))	('IL-1B', 'Gene', '3553', (91, 96))
401756	29069743	Altogether we detected that there were 11 haplotypes in the two genes and only two haplotypes (Grs1800796A rs2069837G rs2069840 and G rs1800796A rs2069837Crs2069840) were found to increase risk of suffering from IgAN by more than 1.40-fold (95 % CI, 1.02 - 1.95; P = 0.037) and 1.90-fold (95 % CI, 1.03 - 3.60; P = 0.042), respectively.	('IgAN', 'Phenotype', 'HP:0000794', (212, 216))	('rs2069837', 'Mutation', 'rs2069837', (107, 116))	('IgAN', 'Gene', (212, 216))	('rs2069837', 'Mutation', 'rs2069837', (145, 154))	('IgAN', 'Gene', '60498', (212, 216))	('rs2069840', 'Mutation', 'rs2069840', (118, 127))	('rs1800796', 'Mutation', 'rs1800796', (134, 143))	('rs2069840', 'Mutation', 'rs2069840', (155, 164))	('Grs1800796A rs2069837G rs2069840', 'Var', (95, 127))	('rs1800796', 'Mutation', 'rs1800796', (96, 105))
401757	29069743	After adjusting for age and gender, the "Grs1800796A rs2069837G rs2069840" (95% CI, 1.05 - 2.40; P = 0.027) and "Grs1800796Ars2069837Crs2069840" (95% CI, 1.09 - 5.02; P = 0.029) haplotypes increased the IgAN risk 1.59- fold and 2.34-fold, respectively.	('rs2069840', 'Mutation', 'rs2069840', (134, 143))	('rs2069837', 'Mutation', 'rs2069837', (124, 133))	('IgAN', 'Phenotype', 'HP:0000794', (203, 207))	('rs2069840', 'Mutation', 'rs2069840', (64, 73))	('rs1800796', 'Mutation', 'rs1800796', (114, 123))	('IgAN', 'Gene', (203, 207))	('rs2069837', 'Mutation', 'rs2069837', (53, 62))	('rs2069837G rs2069840', 'Var', (53, 73))	('Grs1800796Ars2069837Crs2069840', 'Var', (113, 143))	('IgAN', 'Gene', '60498', (203, 207))	('rs1800796', 'Mutation', 'rs1800796', (42, 51))	('increased', 'PosReg', (189, 198))
401763	29069743	Five novel variants were correlated with a protective effect against IgAN susceptibility were identified in a Genome-wide study.	('variants', 'Var', (11, 19))	('IgAN', 'Gene', (69, 73))	('IgAN', 'Phenotype', 'HP:0000794', (69, 73))	('IgAN', 'Gene', '60498', (69, 73))
401765	29069743	But in Asians, it was reported that people have fewer protective variants and have the highest prevalence.	('fewer', 'NegReg', (48, 53))	('people', 'Species', '9606', (36, 42))	('variants', 'Var', (65, 73))	('prevalence', 'MPA', (95, 105))
401770	29069743	We found that the rs2853550, rs16944 in IL-1B and rs1800796 in IL-6 genetic polymorphisms were correlated with an increased the IgAN risk in a northwestern Chinese Han patients population.	('IL-6', 'Gene', '3569', (63, 67))	('rs1800796', 'Mutation', 'rs1800796', (50, 59))	('rs16944', 'Var', (29, 36))	('IL-1B', 'Gene', (40, 45))	('IgAN', 'Phenotype', 'HP:0000794', (128, 132))	('rs1800796', 'Var', (50, 59))	('IgAN', 'Gene', (128, 132))	('rs2853550', 'Mutation', 'rs2853550', (18, 27))	('patients', 'Species', '9606', (168, 176))	('IL-6', 'Gene', (63, 67))	('IL-1B', 'Gene', '3553', (40, 45))	('rs2853550', 'Var', (18, 27))	('rs16944', 'Mutation', 'rs16944', (29, 36))	('IgAN', 'Gene', '60498', (128, 132))
401775	29069743	The polymorphism rs1143630 is located in intron four, a noncoding region of the IL1B gene.	('rs1143630', 'Mutation', 'rs1143630', (17, 26))	('rs1143630', 'Var', (17, 26))	('IL1B', 'Gene', '3553', (80, 84))	('IL1B', 'Gene', (80, 84))
401776	29069743	The SNP rs1143630 of IL1B in the additive model considering the "T" allele as risk showed association with the preeclamptic event.	('association', 'Reg', (90, 101))	('preeclamptic event', 'Disease', (111, 129))	('IL1B', 'Gene', (21, 25))	('SNP rs1143630', 'Var', (4, 17))	('rs1143630', 'Mutation', 'rs1143630', (8, 17))	('preeclamptic event', 'Phenotype', 'HP:0100602', (111, 129))	('IL1B', 'Gene', '3553', (21, 25))
401777	29069743	In our study, we detected that the SNP rs1143630 was not associated with IgAN risk.	('IgAN', 'Phenotype', 'HP:0000794', (73, 77))	('rs1143630', 'Mutation', 'rs1143630', (39, 48))	('rs1143630', 'Var', (39, 48))	('IgAN', 'Gene', (73, 77))	('IgAN', 'Gene', '60498', (73, 77))
401778	29069743	For rs1143633, there existed the significant difference between patients with schizophrenia and controls, and also found a association between rs16944 polymorphisms and female patients with schizophrenia in a Japanese population.	('association', 'Interaction', (123, 134))	('patients', 'Species', '9606', (176, 184))	('rs16944', 'Mutation', 'rs16944', (143, 150))	('schizophrenia', 'Disease', 'MESH:D012559', (190, 203))	('schizophrenia', 'Disease', (190, 203))	('patients', 'Species', '9606', (64, 72))	('schizophrenia', 'Disease', 'MESH:D012559', (78, 91))	('schizophrenia', 'Disease', (78, 91))	('schizophrenia', 'Phenotype', 'HP:0100753', (78, 91))	('schizophrenia', 'Phenotype', 'HP:0100753', (190, 203))	('rs1143633', 'Var', (4, 13))	('rs1143633', 'Mutation', 'rs1143633', (4, 13))	('rs16944', 'Gene', (143, 150))
401779	29069743	In this article, the results we get showed that rs16944 polymorphism increased in the risk of developing IgAN.	('IgAN', 'Gene', '60498', (105, 109))	('rs16944', 'Var', (48, 55))	('rs16944', 'Mutation', 'rs16944', (48, 55))	('IgAN', 'Phenotype', 'HP:0000794', (105, 109))	('IgAN', 'Gene', (105, 109))
401780	29069743	found that the IL-6 rs1800795 G>C polymorphisms presented an increased risk in dominant and recessive models, but they did not find that the IL-6 rs1800796 CC were correlated with an increased risk of coronary artery disease.	('rs1800795', 'Mutation', 'rs1800795', (20, 29))	('coronary artery disease', 'Disease', (201, 224))	('IL-6', 'Gene', '3569', (141, 145))	('IL-6', 'Gene', (15, 19))	('IL-6', 'Gene', '3569', (15, 19))	('coronary artery disease', 'Disease', 'MESH:D003324', (201, 224))	('rs1800795 G>C', 'Var', (20, 33))	('IL-6', 'Gene', (141, 145))	('rs1800796 CC', 'Var', (146, 158))	('rs1800796', 'Mutation', 'rs1800796', (146, 155))
401781	29069743	A study reported that the rs1800796 TT genotype was associated with increased the susceptibility of cerebral thrombosis in the Chinese population.	('cerebral thrombosis', 'Disease', (100, 119))	('cerebral thrombosis', 'Phenotype', 'HP:0005305', (100, 119))	('rs1800796', 'Mutation', 'rs1800796', (26, 35))	('cerebral thrombosis', 'Disease', 'MESH:D020767', (100, 119))	('rs1800796', 'Var', (26, 35))
401782	29069743	Previous meta-analysis demonstrated significant association between rs1800796 of IL6 and cancer risk, with the allele G as a risk allele.	('IL6', 'Gene', (81, 84))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('rs1800796', 'Mutation', 'rs1800796', (68, 77))	('cancer', 'Disease', (89, 95))	('IL6', 'Gene', '3569', (81, 84))	('rs1800796', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
401783	29069743	The frequency of GG genotype of rs2069837 was higher in hepatocellular carcinoma patients, compared with controls (P < 0.05).	('higher', 'PosReg', (46, 52))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (56, 80))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (56, 80))	('patients', 'Species', '9606', (81, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('hepatocellular carcinoma', 'Disease', (56, 80))	('rs2069837', 'Var', (32, 41))	('rs2069837', 'Mutation', 'rs2069837', (32, 41))
401784	29069743	In our current study, we for the first time studied the correlations between three SNPs (rs1800796, rs2069837 and rs2069840) in IL-6 gene and IgAN susceptibility in a Chinese population.	('rs2069840', 'Var', (114, 123))	('IL-6', 'Gene', '3569', (128, 132))	('rs2069837', 'Var', (100, 109))	('IgAN', 'Phenotype', 'HP:0000794', (142, 146))	('rs1800796', 'Mutation', 'rs1800796', (89, 98))	('IgAN', 'Gene', (142, 146))	('IgAN', 'Gene', '60498', (142, 146))	('rs2069837', 'Mutation', 'rs2069837', (100, 109))	('rs2069840', 'Mutation', 'rs2069840', (114, 123))	('rs1800796', 'Var', (89, 98))	('IL-6', 'Gene', (128, 132))
401785	29069743	Rs1800796 SNP was associated with IgAN risk, rs2069837 and rs2069840 showed no correlations with IgAN susceptibility.	('IgAN', 'Phenotype', 'HP:0000794', (34, 38))	('rs2069837', 'Var', (45, 54))	('rs2069837', 'Mutation', 'rs2069837', (45, 54))	('rs2069840', 'Mutation', 'rs2069840', (59, 68))	('IgAN', 'Phenotype', 'HP:0000794', (97, 101))	('Rs1800796', 'Mutation', 'Rs1800796', (0, 9))	('IgAN', 'Gene', (34, 38))	('associated', 'Reg', (18, 28))	('rs2069840', 'Var', (59, 68))	('IgAN', 'Gene', '60498', (34, 38))	('Rs1800796 SNP', 'Var', (0, 13))	('IgAN', 'Gene', (97, 101))	('IgAN', 'Gene', '60498', (97, 101))
401786	29069743	None of previous study found that IL-6 haplotype was directly associated with IgAN risk.	('IgAN', 'Gene', (78, 82))	('haplotype', 'Var', (39, 48))	('associated', 'Reg', (62, 72))	('IgAN', 'Gene', '60498', (78, 82))	('IL-6', 'Gene', (34, 38))	('IgAN', 'Phenotype', 'HP:0000794', (78, 82))	('IL-6', 'Gene', '3569', (34, 38))
401787	29069743	Our study detected that haplotype "Grs1800796Ars2069837Grs2069840" and "Grs1800796Ars2069837Crs2069840" are related with the IgAN increasing risk.	('rs2069837', 'Mutation', 'rs2069837', (46, 55))	('IgAN', 'Phenotype', 'HP:0000794', (125, 129))	('rs2069840', 'Mutation', 'rs2069840', (56, 65))	('rs1800796', 'Mutation', 'rs1800796', (36, 45))	('rs2069840', 'Mutation', 'rs2069840', (93, 102))	('Grs1800796Ars2069837Crs2069840', 'Var', (72, 102))	('rs2069837', 'Mutation', 'rs2069837', (83, 92))	('IgAN', 'Gene', (125, 129))	('IgAN', 'Gene', '60498', (125, 129))	('rs1800796', 'Mutation', 'rs1800796', (73, 82))
401790	29069743	Additional studies are needed to clarify the genetic mechanisms underlying IgAN by fine-mapping the susceptibility regions of the variants.	('variants', 'Var', (130, 138))	('IgAN', 'Phenotype', 'HP:0000794', (75, 79))	('IgAN', 'Gene', (75, 79))	('IgAN', 'Gene', '60498', (75, 79))
401792	29069743	This study offers new information on the relationship between two genes (IL-1B and IL-6) polymorphisms and IgAN susceptibility.	('IL-6', 'Gene', '3569', (83, 87))	('IL-1B', 'Gene', (73, 78))	('polymorphisms', 'Var', (89, 102))	('IgAN', 'Phenotype', 'HP:0000794', (107, 111))	('IL-1B', 'Gene', '3553', (73, 78))	('IgAN', 'Gene', (107, 111))	('IL-6', 'Gene', (83, 87))	('IgAN', 'Gene', '60498', (107, 111))
401806	22363450	It is becoming increasingly clear that aberrant activation of Notch signaling has been associated with the development of esophageal cancer.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('men', 'Species', '9606', (114, 117))	('associated', 'Reg', (87, 97))	('Notch', 'Protein', (62, 67))	('activation', 'PosReg', (48, 58))	('aberrant', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
401836	22363450	MicroRNAs (miRNAs) are short non-coding RNAs that bind to the 3' untranslated region (UTR) of cognate messenger RNAs (mRNAs) through fully complementary or imperfect base-pairing repressing the translation or decreasing the stability of the bound mRNAs.	('men', 'Species', '9606', (145, 148))	('imperfect base-pairing', 'Var', (156, 178))	('stability', 'MPA', (224, 233))	('bound', 'Interaction', (241, 246))	('translation', 'MPA', (194, 205))	('decreasing', 'NegReg', (209, 219))	('repressing', 'NegReg', (179, 189))
401844	22363450	Moreover, Notch signaling and its regulations are critically important at the level of post-transcriptional and/or translational regulation of genes by miRNAs in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('miRNAs', 'Var', (152, 158))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('glioblastoma', 'Disease', (162, 174))
401873	22363450	The cells were then incubated overnight with anti-Notch-1, anti-Jagged-1, anti-Hes-1, anti-Presenilin 1 and anti-Nicastrin antibody, respectively.	('Presenilin 1', 'Gene', (91, 103))	('anti-Hes-1', 'Var', (74, 84))	('anti-Jagged-1', 'Var', (59, 72))	('Nicastrin', 'Gene', (113, 122))	('Nicastrin', 'Gene', '23385', (113, 122))	('Presenilin 1', 'Gene', '5663', (91, 103))	('anti-Notch-1', 'Var', (45, 57))
401922	22363450	The data presented in this article show that curcumin selectively inhibits the proliferation of esophageal cancer cells, suppresses the formation of esophageal cancer cell colonies, promotes cell cycle arrest and apoptosis, inhibits esophagosphere formation, down regulates notch signaling and its gamma-secretase complex proteins, and also inhibits oncomir miRNA expression and induces tumor suppressor miRNA expression.	('proliferation', 'CPA', (79, 92))	('inhibits', 'NegReg', (341, 349))	('esophageal cancer', 'Disease', (149, 166))	('promotes', 'PosReg', (182, 190))	('apoptosis', 'CPA', (213, 222))	('tumor', 'Phenotype', 'HP:0002664', (387, 392))	('suppresses', 'NegReg', (121, 131))	('cell cycle arrest', 'CPA', (191, 208))	('down regulates', 'NegReg', (259, 273))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('induces', 'PosReg', (379, 386))	('formation of', 'CPA', (136, 148))	('tumor suppressor', 'Gene', (387, 403))	('curcumin', 'Var', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('notch signaling', 'MPA', (274, 289))	('gamma-secretase complex proteins', 'Protein', (298, 330))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (191, 208))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('tumor suppressor', 'Gene', '7248', (387, 403))	('esophagosphere formation', 'CPA', (233, 257))	('inhibits', 'NegReg', (224, 232))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('inhibits', 'NegReg', (66, 74))	('esophageal cancer', 'Disease', (96, 113))	('curcumin', 'Chemical', 'MESH:D003474', (45, 53))	('oncomir', 'Protein', (350, 357))
401936	22363450	In addition, it would be interesting to determine whether ectopic expression of Notch downstream target genes such as Hes-1 and c-myc in the condition of Notch knockdown or rescue protects from curcumin-mediated cell death.	('curcumin-mediated', 'MPA', (194, 211))	('curcumin', 'Chemical', 'MESH:D003474', (194, 202))	('knockdown', 'Var', (160, 169))	('Hes-1', 'Gene', (118, 123))	('c-myc', 'Gene', '4609', (128, 133))	('c-myc', 'Gene', (128, 133))
401952	22363450	However, esophageal cancer cells (and cell lines) are either p53 deficient (TE-7) or have mutations leading to accumulation of mutant, non-functional p53 protein (TE-10).	('mutant', 'Var', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (90, 99))	('deficient', 'NegReg', (65, 74))	('TE-7', 'CellLine', 'CVCL:9972', (76, 80))	('esophageal cancer', 'Disease', (9, 26))	('accumulation', 'PosReg', (111, 123))	('p53', 'Gene', (150, 153))	('p53', 'Gene', '7157', (150, 153))	('p53', 'Gene', '7157', (61, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (9, 26))	('p53', 'Gene', (61, 64))	('protein', 'Protein', (154, 161))
401962	22363450	Recent studies have also shown that treatment of PanC-1 or Colo-357 cells with genistein (isoflavone) showed decreased expression of the oncogenic miRNA such as miR-17, miR-20a, miR-106a, and increased the expression of the tumor suppressor miRNAs such as let-7, miR-16-1.	('decreased', 'NegReg', (109, 118))	('expression', 'MPA', (119, 129))	('isoflavone', 'Chemical', 'MESH:D007529', (90, 100))	('miR-106a', 'Var', (178, 186))	('Colo', 'Species', '307630', (59, 63))	('tumor suppressor', 'Gene', '7248', (224, 240))	('genistein', 'Chemical', 'MESH:D019833', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('expression', 'MPA', (206, 216))	('miR-20a', 'Var', (169, 176))	('miR-17', 'Var', (161, 167))	('miR-16', 'Gene', (263, 269))	('tumor suppressor', 'Gene', (224, 240))	('miR-16', 'Gene', '51573', (263, 269))	('men', 'Species', '9606', (41, 44))	('increased', 'PosReg', (192, 201))
401985	22220139	Recent studies have indicated that eosinophil infiltration at the invasion front of esophageal SCC may correlate with a less aggressive tumor.	('eosin', 'Chemical', 'MESH:D004801', (35, 40))	('esophageal SCC', 'Disease', (84, 98))	('aggressive tumor', 'Disease', 'MESH:D001523', (125, 141))	('eosinophil infiltration', 'Phenotype', 'HP:0001880', (35, 58))	('esophageal SCC', 'Disease', 'MESH:D004941', (84, 98))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('aggressive tumor', 'Disease', (125, 141))	('eosinophil infiltration', 'Var', (35, 58))
402041	20426865	We found that BPDE recruited DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A), but not beta (DNMT3B), in a time-dependent manner to methylate the RAR-beta2 gene promoter, which we confirmed by reverse transcription-polymerase chain reaction (RT-PCR) analysis of the reduced RAR-beta2 expression in these BPDE-treated esophageal cancer cell lines.	('expression', 'MPA', (288, 298))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('DNMT3B', 'Gene', (97, 103))	('DNMT3B', 'Gene', '1789', (97, 103))	('BPDE', 'Chemical', 'MESH:D015123', (14, 18))	('methylate', 'Var', (136, 145))	('DNMT3A', 'Gene', (74, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (321, 338))	('DNMT3A', 'Gene', '1788', (74, 80))	('reduced', 'NegReg', (270, 277))	('DNA (cytosine-5-)-methyltransferase 3 alpha', 'Gene', '1788', (29, 72))	('RAR-beta2', 'Gene', (278, 287))	('BPDE', 'Chemical', 'MESH:D015123', (308, 312))	('esophageal cancer', 'Disease', (321, 338))
402042	20426865	However, BPDE did not significantly change DNMT3A expression, but it slightly reduced DNMT3B expression.	('DNMT3A', 'Gene', (43, 49))	('DNMT3B', 'Gene', '1789', (86, 92))	('DNMT3A', 'Gene', '1788', (43, 49))	('BPDE', 'Var', (9, 13))	('BPDE', 'Chemical', 'MESH:D015123', (9, 13))	('reduced', 'NegReg', (78, 85))	('DNMT3B', 'Gene', (86, 92))
402052	20426865	Lost expression of RAR-beta2 in these various human cancers has been shown to be due to hypermethylation of its gene promoter.	('RAR-beta2', 'Gene', (19, 28))	('expression', 'MPA', (5, 15))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Lost', 'NegReg', (0, 4))	('human', 'Species', '9606', (46, 51))	('hypermethylation', 'Var', (88, 104))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
402053	20426865	However, it is still unknown if, and if so, how BPDE suppresses the expression of RAR-beta2 and induces methylation of its gene promoter.	('suppresses', 'NegReg', (53, 63))	('RAR-beta2', 'Gene', (82, 91))	('expression', 'MPA', (68, 78))	('methylation', 'MPA', (104, 115))	('induces', 'Reg', (96, 103))	('BPDE', 'Chemical', 'MESH:D015123', (48, 52))	('BPDE', 'Var', (48, 52))
402066	20426865	We therefore performed transient gene transfection experiments followed by reverse transcription-polymerase chain reaction (RT-PCR) analyses and found that the knockdown of DNMT3A expression antagonized the ability of BPDE to suppress RAR-beta2 expression (Figure 5B).	('RAR-beta2', 'Protein', (235, 244))	('DNMT3A', 'Gene', (173, 179))	('DNMT3A', 'Gene', '1788', (173, 179))	('knockdown', 'Var', (160, 169))	('antagonized', 'NegReg', (191, 202))	('expression', 'MPA', (245, 255))	('suppress', 'NegReg', (226, 234))	('BPDE', 'Chemical', 'MESH:D015123', (218, 222))
402067	20426865	Consequently, we sought to determine if knockdown of DNMT3A could antagonize the effect of BPDE on expression of these genes.	('DNMT3A', 'Gene', (53, 59))	('DNMT3A', 'Gene', '1788', (53, 59))	('knockdown', 'Var', (40, 49))	('BPDE', 'Chemical', 'MESH:D015123', (91, 95))
402071	20426865	RAR-beta2 gene promoter methylation is believed to be responsible for the lost expression of RAR-beta2 in various human cancers, including esophageal cancer.	('lost', 'NegReg', (74, 78))	('RAR-beta2', 'Gene', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('expression', 'MPA', (79, 89))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('methylation', 'Var', (24, 35))	('RAR-beta2', 'Gene', (0, 9))	('cancers', 'Disease', (120, 127))	('esophageal cancer', 'Disease', (139, 156))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('human', 'Species', '9606', (114, 119))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
402072	20426865	Lost expression of RAR-beta2 and methylation of the RAR-beta2 gene promoter have been used as diagnostic markers of tumorigenesis.	('RAR-beta2', 'Gene', (52, 61))	('RAR-beta2', 'Gene', (19, 28))	('expression', 'MPA', (5, 15))	('methylation', 'Var', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Lost', 'NegReg', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
402073	20426865	For example, methylation of the RAR-beta2 gene promoter has been found in early-stage breast cancer and has been detected in the bronchial aspirates of lung cancer patients at a much higher frequency than in patients with benign lung disease.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('patients', 'Species', '9606', (208, 216))	('methylation', 'Var', (13, 24))	('benign lung disease', 'Disease', (222, 241))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('RAR-beta2', 'Gene', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung disease', 'Phenotype', 'HP:0002088', (229, 241))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('patients', 'Species', '9606', (164, 172))	('found', 'Reg', (65, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('detected', 'Reg', (113, 121))	('breast cancer', 'Disease', (86, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('benign lung disease', 'Disease', 'MESH:D008171', (222, 241))	('lung cancer', 'Disease', (152, 163))
402074	20426865	Furthermore, the RAR-beta2 gene promoter has been detected at a high level of methylation in esophageal cancer and was found to be associated with RAR-beta2 gene silencing in this disease.	('RAR-beta2', 'Gene', (147, 156))	('gene', 'Var', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('associated', 'Reg', (131, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('RAR-beta2', 'Gene', (17, 26))	('methylation', 'MPA', (78, 89))
402081	20426865	In the current study, we found that BPDE recruited DNMT3A to methylate the RAR-beta2 gene promoter and thus silence its gene expression, which in turn, may contribute to the malignant transformation of esophageal epithelial cells.	('methylate', 'Var', (61, 70))	('esophageal epithelial', 'Disease', (202, 223))	('RAR-beta2', 'Gene', (75, 84))	('gene expression', 'MPA', (120, 135))	('silence', 'NegReg', (108, 115))	('BPDE', 'Chemical', 'MESH:D015123', (36, 40))	('DNMT3A', 'Gene', (51, 57))	('malignant transformation', 'CPA', (174, 198))	('DNMT3A', 'Gene', '1788', (51, 57))	('contribute to', 'Reg', (156, 169))
402254	33060568	We further demonstrated that the regulation of beta-catenin by DHODH was independent of DHODH catalyzing activity.	('beta-catenin', 'Gene', '1499', (47, 59))	('beta-catenin', 'Gene', (47, 59))	('DHODH', 'Var', (63, 68))
402261	33060568	Mutations of DHODH have been associated with various genetic diseases.	('genetic diseases', 'Disease', (53, 69))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (29, 39))	('genetic diseases', 'Disease', 'MESH:D030342', (53, 69))	('DHODH', 'Gene', (13, 18))
402262	33060568	For example, DHODH G202A, R346W causes deficient protein stability and R135C impairs the enzymatic activity, which are linked to Miller syndrome.	('enzymatic activity', 'MPA', (89, 107))	('Miller syndrome', 'Disease', 'MESH:C537680', (129, 144))	('protein stability', 'MPA', (49, 66))	('impairs', 'NegReg', (77, 84))	('deficient', 'NegReg', (39, 48))	('R346W', 'Var', (26, 31))	('G202A', 'Mutation', 'c.202G>A', (19, 24))	('R135C', 'Var', (71, 76))	('Miller syndrome', 'Disease', (129, 144))	('G202A', 'Var', (19, 24))	('R135C', 'Mutation', 'p.R135C', (71, 76))	('DHODH G202A', 'Var', (13, 24))	('linked', 'Reg', (119, 125))	('R346W', 'Mutation', 'p.R346W', (26, 31))
402263	33060568	DHODH polymorphism was reported to be linked with rheumatoid arthritis and lung cancer as well.	('lung cancer', 'Disease', (75, 86))	('DHODH', 'Gene', (0, 5))	('linked', 'Reg', (38, 44))	('polymorphism', 'Var', (6, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('rheumatoid arthritis', 'Disease', (50, 70))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (50, 70))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('arthritis', 'Phenotype', 'HP:0001369', (61, 70))
402266	33060568	Inhibition of DHODH leads to the starvation of pyrimidine pool and thereby decreases DNA and RNA synthesis and cell proliferation.	('pyrimidine pool', 'MPA', (47, 62))	('pyrimidine', 'Chemical', 'MESH:C030986', (47, 57))	('DHODH', 'Gene', (14, 19))	('starvation', 'MPA', (33, 43))	('cell proliferation', 'CPA', (111, 129))	('Inhibition', 'Var', (0, 10))	('decreases', 'NegReg', (75, 84))
402269	33060568	Furthermore, we demonstrated that DHODH was upregulated in ESCC samples compared with adjacent normal tissues and high expression of DHODH was significantly associated with early stages and shorter patient survival in ESCC.	('DHODH', 'Gene', (34, 39))	('high', 'Var', (114, 118))	('associated', 'Reg', (157, 167))	('patient', 'Species', '9606', (198, 205))	('ESCC', 'Disease', (218, 222))	('upregulated', 'PosReg', (44, 55))	('ESCC', 'Disease', (59, 63))	('shorter', 'NegReg', (190, 197))	('DHODH', 'Gene', (133, 138))	('patient survival', 'CPA', (198, 214))
402272	33060568	ESCC cell lines KYSE140, KYSE150, KYSE180, KYSE410, KYSE510, KYSE450, KYSE680, ECA109 and immortalized esophageal epithelial cell SHEE were generous gifts from Dr. Qimin Zhan (Key laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute) and stored at Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University.	('KYSE450', 'Var', (61, 68))	('KYSE510', 'Var', (52, 59))	('KYSE410', 'Var', (43, 50))	('Cancer', 'Disease', (255, 261))	('Carcinogenesis', 'Disease', (323, 337))	('KYSE180', 'Var', (34, 41))	('Carcinogenesis', 'Disease', 'MESH:D063646', (194, 208))	('Cancer', 'Disease', 'MESH:D009369', (255, 261))	('Cancer', 'Disease', (379, 385))	('Carcinogenesis', 'Disease', (194, 208))	('Carcinogenesis', 'Disease', 'MESH:D063646', (323, 337))	('Cancer', 'Phenotype', 'HP:0002664', (255, 261))	('KYSE150', 'Var', (25, 32))	('Cancer', 'Phenotype', 'HP:0002664', (379, 385))	('Cancer', 'Disease', 'MESH:D009369', (379, 385))	('KYSE680', 'Var', (70, 77))
402310	33060568	In particular, we noticed that patients with high DHODH expression exhibited a worse prognosis (Fig.	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('DHODH', 'Protein', (50, 55))
402317	33060568	On the contrary, efficient DHODH deletion significantly prevented tumor growth (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('DHODH', 'Gene', (27, 32))	('tumor', 'Disease', (66, 71))	('deletion', 'Var', (33, 41))	('prevented', 'NegReg', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
402319	33060568	Importantly, DHODH knockdown arrested cells in S phase and prolonged cell cycle as monitored by Live cell imaging (Supplementary Fig.	('cells', 'CPA', (38, 43))	('prolonged', 'PosReg', (59, 68))	('arrest', 'Disease', 'MESH:D006323', (29, 35))	('knockdown', 'Var', (19, 28))	('cell cycle', 'CPA', (69, 79))	('arrest', 'Disease', (29, 35))	('DHODH', 'Gene', (13, 18))
402320	33060568	Also, we found a remarkable decrease of cyclin A and cyclin B expression after DHODH knocking down (Supplementary Fig.	('cyclin A', 'Gene', '890', (40, 48))	('DHODH', 'Gene', (79, 84))	('expression', 'MPA', (62, 72))	('cyclin', 'Protein', (53, 59))	('decrease', 'NegReg', (28, 36))	('knocking down', 'Var', (85, 98))	('cyclin A', 'Gene', (40, 48))
402322	33060568	Consistently, knockdown of DHODH increased BAX, p53 and p21 expression, which linked with increased apoptosis and cell cycle arrest.	('p53', 'Gene', (48, 51))	('expression', 'MPA', (60, 70))	('BAX', 'Gene', '581', (43, 46))	('arrest', 'Disease', 'MESH:D006323', (125, 131))	('DHODH', 'Gene', (27, 32))	('increased', 'PosReg', (90, 99))	('p53', 'Gene', '7157', (48, 51))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (114, 131))	('p21', 'Gene', (56, 59))	('arrest', 'Disease', (125, 131))	('increased', 'PosReg', (33, 42))	('p21', 'Gene', '644914', (56, 59))	('knockdown', 'Var', (14, 23))	('apoptosis', 'CPA', (100, 109))	('BAX', 'Gene', (43, 46))
402325	33060568	We noticed that the expressions of Wnt/beta-catenin target genes, such as CCND1, Oct4, and Nanog, were dramatically decreased after DHODH knockdown (Fig.	('knockdown', 'Var', (138, 147))	('CCND1', 'Gene', (74, 79))	('expressions', 'MPA', (20, 31))	('Nanog', 'Gene', '79923', (91, 96))	('DHODH', 'Gene', (132, 137))	('Oct4', 'Gene', '5460', (81, 85))	('Wnt', 'Gene', (35, 38))	('beta-catenin', 'Gene', (39, 51))	('Nanog', 'Gene', (91, 96))	('CCND1', 'Gene', '595', (74, 79))	('beta-catenin', 'Gene', '1499', (39, 51))	('Wnt', 'Gene', '7471;89780;7474', (35, 38))	('decreased', 'NegReg', (116, 125))	('Oct4', 'Gene', (81, 85))
402326	33060568	Furthermore, we found DHODH knockdown reduced the transcriptional activity of beta-catenin (Fig.	('reduced', 'NegReg', (38, 45))	('transcriptional activity', 'MPA', (50, 74))	('beta-catenin', 'Gene', (78, 90))	('knockdown', 'Var', (28, 37))	('beta-catenin', 'Gene', '1499', (78, 90))	('DHODH', 'Gene', (22, 27))
402328	33060568	3f, knocking down of DHODH increased phospho-beta-catenin (p-beta-catenin) level but decreased beta-catenin as well as the downstream OCT4 and Nanog.	('knocking down', 'Var', (4, 17))	('Nanog', 'Gene', (143, 148))	('decreased', 'NegReg', (85, 94))	('increased', 'PosReg', (27, 36))	('DHODH', 'Gene', (21, 26))	('beta-catenin', 'Gene', '1499', (61, 73))	('beta-catenin', 'Gene', '1499', (45, 57))	('beta-catenin', 'Gene', (95, 107))	('OCT4', 'Gene', '5460', (134, 138))	('beta-catenin', 'Gene', (61, 73))	('Nanog', 'Gene', '79923', (143, 148))	('beta-catenin', 'Gene', '1499', (95, 107))	('beta-catenin', 'Gene', (45, 57))	('OCT4', 'Gene', (134, 138))
402333	33060568	We noticed that DHODH significantly stabilized beta-catenin protein level (Fig.	('beta-catenin', 'Gene', '1499', (47, 59))	('DHODH', 'Var', (16, 21))	('stabilized', 'PosReg', (36, 46))	('beta-catenin', 'Gene', (47, 59))
402335	33060568	Moreover, DHODH knockdown reduced the nuclear localization of beta-catenin (Fig.	('nuclear localization', 'MPA', (38, 58))	('beta-catenin', 'Gene', (62, 74))	('DHODH', 'Gene', (10, 15))	('knockdown', 'Var', (16, 25))	('beta-catenin', 'Gene', '1499', (62, 74))	('reduced', 'NegReg', (26, 33))
402340	33060568	This expression pattern was further confirmed in the slides of xenograft tumor sections derived from DHODH knockdown ECA109 cells and control cells (Supplementary Fig.	('knockdown', 'Var', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('DHODH', 'Gene', (101, 106))	('tumor', 'Disease', (73, 78))
402341	33060568	These data suggest that DHODH was positively correlated with beta-catenin at protein level in ESCC; and DHODH may involve in the regulation of beta-catenin phosphorylation, thus affecting the degradation of beta-catenin.	('beta-catenin', 'Gene', '1499', (61, 73))	('involve', 'Reg', (114, 121))	('beta-catenin', 'Gene', '1499', (143, 155))	('affecting', 'Reg', (178, 187))	('beta-catenin', 'Gene', (207, 219))	('DHODH', 'Var', (104, 109))	('beta-catenin', 'Gene', (61, 73))	('beta-catenin', 'Gene', '1499', (207, 219))	('beta-catenin', 'Gene', (143, 155))	('correlated', 'Reg', (45, 55))
402350	33060568	We found that the level of polyubiquitin beta-catenin complex was significantly increased in DHODH knockdown cells (Fig.	('beta-catenin', 'Gene', (41, 53))	('beta-catenin', 'Gene', '1499', (41, 53))	('increased', 'PosReg', (80, 89))	('DHODH', 'Gene', (93, 98))	('knockdown', 'Var', (99, 108))
402352	33060568	Conversely, ectopic expression of DHODH decreased the ubiquitin level of beta-catenin and GSK3beta level in a dose-dependent manner (Fig.	('GSK3beta', 'Gene', (90, 98))	('DHODH', 'Gene', (34, 39))	('beta-catenin', 'Gene', (73, 85))	('GSK3beta', 'Gene', '2931', (90, 98))	('ectopic expression', 'Var', (12, 30))	('beta-catenin', 'Gene', '1499', (73, 85))	('decreased', 'NegReg', (40, 49))
402353	33060568	Given the fact that phosphorylation by GSK3beta is critical for beta-catenin stability, we used GSK3beta inhibitor CHIR99021 and found that inhibition of GSK3beta elevated the expression of beta-catenin even DHODH was knocked down (Supplementary Fig.	('elevated', 'PosReg', (163, 171))	('inhibition', 'Var', (140, 150))	('GSK3beta', 'Gene', (39, 47))	('GSK3beta', 'Gene', '2931', (39, 47))	('beta-catenin', 'Gene', (190, 202))	('expression', 'MPA', (176, 186))	('GSK3beta', 'Gene', (154, 162))	('beta-catenin', 'Gene', (64, 76))	('beta-catenin', 'Gene', '1499', (190, 202))	('GSK3beta', 'Gene', '2931', (154, 162))	('beta-catenin', 'Gene', '1499', (64, 76))	('GSK3beta', 'Gene', (96, 104))	('GSK3beta', 'Gene', '2931', (96, 104))
402354	33060568	Furthermore, we detected the catalytic dysfunctional DHODH-mut (R135C) and found that DHODHm could restore beta-catenin expression, as well as wild-type DHODH (Supplementary Fig.	('beta-catenin', 'Gene', (107, 119))	('beta-catenin', 'Gene', '1499', (107, 119))	('DHODHm', 'Var', (86, 92))	('R135C', 'Mutation', 'p.R135C', (64, 69))	('restore', 'PosReg', (99, 106))
402362	33060568	Destruction complex containing Axin, APC, CK1alpha/delta, and GSK3alpha/beta couldnot phosphate beta-catenin at several Ser/Thr site, and beta-catenin will translocate into nuclear.	('Ser', 'Chemical', 'MESH:D012694', (120, 123))	('beta-catenin', 'Gene', '1499', (96, 108))	('beta-catenin', 'Gene', (138, 150))	('phosphate', 'Chemical', 'MESH:D010710', (86, 95))	('APC', 'Disease', (37, 40))	('beta-catenin', 'Gene', '1499', (138, 150))	('APC', 'Disease', 'MESH:D011125', (37, 40))	('CK1alpha/delta', 'Var', (42, 56))	('translocate', 'MPA', (156, 167))	('Thr', 'Chemical', 'MESH:D013912', (124, 127))	('beta-catenin', 'Gene', (96, 108))
402366	33060568	Therefore, our hypothesis would be activation of beta-catenin pathway by DHODH via the way of effectiveness on phosphorylation of beta-catenin state.	('beta-catenin', 'Gene', (49, 61))	('phosphorylation of', 'MPA', (111, 129))	('beta-catenin', 'Gene', '1499', (49, 61))	('DHODH', 'Var', (73, 78))	('beta-catenin', 'Gene', (130, 142))	('activation', 'PosReg', (35, 45))	('beta-catenin', 'Gene', '1499', (130, 142))
402371	33060568	Hence, inhibition of DHODH could impair beta-catenin mediated tumorigenesis.	('beta-catenin', 'Gene', '1499', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('inhibition', 'Var', (7, 17))	('beta-catenin', 'Gene', (40, 52))	('impair', 'NegReg', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('DHODH', 'Protein', (21, 26))
402372	33060568	Many DHODH inhibitors have shown potential anti-cancer effects, such as ML390, brequinar, and chiral tetrahydroindazole (HZ00).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('inhibitors', 'Var', (11, 21))	('DHODH', 'Gene', (5, 10))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tetrahydroindazole', 'Chemical', '-', (101, 119))
402374	33060568	Emerging evidence suggests that inhibition of DHODH impairs cancer cell proliferation, inducing differentiation.	('inhibition', 'Var', (32, 42))	('DHODH', 'Protein', (46, 51))	('differentiation', 'CPA', (96, 111))	('impairs cancer', 'Disease', 'MESH:D009369', (52, 66))	('inducing', 'Reg', (87, 95))	('impairs cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
402381	33060568	The clinical significance of our investigation revealed that patients with high expression of DHODH were predominant in early stage and had a much worse prognosis than ESCC patients with lower level.	('high expression', 'Var', (75, 90))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (173, 181))	('DHODH', 'Protein', (94, 99))
402416	32355175	OAGB rats were primarily compared to the gold standard RYGB and we hypothesized that OAGB rats were at a higher risk for post-operative precancerous or cancerous lesions.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('OAGB', 'Chemical', '-', (85, 89))	('rat', 'Species', '10116', (90, 93))	('OAGB', 'Var', (85, 89))	('cancer', 'Disease', (152, 158))	('OAGB', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancerous lesions', 'Disease', 'MESH:D009369', (152, 169))	('rat', 'Species', '10116', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancerous lesions', 'Disease', (152, 169))	('rat', 'Species', '10116', (5, 8))	('rats', 'Species', '10116', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('rats', 'Species', '10116', (5, 9))	('cancer', 'Disease', (139, 145))
402418	32355175	As previously observed, all bypass surgeries induced a rapid although transient weight loss, and maximal weight loss was observed between 10 and 14 days after surgery (Fig.	('weight loss', 'Disease', 'MESH:D015431', (80, 91))	('weight loss', 'Phenotype', 'HP:0001824', (105, 116))	('bypass', 'Var', (28, 34))	('weight loss', 'Disease', 'MESH:D015431', (105, 116))	('weight loss', 'Disease', (80, 91))	('weight loss', 'Phenotype', 'HP:0001824', (80, 91))	('weight loss', 'Disease', (105, 116))
402420	32355175	As a baseline control, we compared operated rats to unoperated control (CTRL) rats, and as expected, the CTRL group experienced the lowest observed weight loss (-4 +- 0.4%) (Fig.	('rats', 'Species', '10116', (78, 82))	('weight loss', 'Disease', 'MESH:D015431', (148, 159))	('rat', 'Species', '10116', (44, 47))	('rat', 'Species', '10116', (78, 81))	('weight loss', 'Disease', (148, 159))	('CTRL', 'Var', (105, 109))	('rat', 'Species', '10116', (57, 60))	('rat', 'Species', '10116', (38, 41))	('lowest', 'NegReg', (132, 138))	('weight loss', 'Phenotype', 'HP:0001824', (148, 159))	('rats', 'Species', '10116', (44, 48))
402426	32355175	Rats experienced almost 12% less weight gain post OAGB-35 than post OAGB-15 (P < 0.05).	('weight gain', 'Disease', 'MESH:D015430', (33, 44))	('Rats', 'Species', '10116', (0, 4))	('OAGB-35', 'Var', (50, 57))	('weight gain', 'Phenotype', 'HP:0004324', (33, 44))	('weight gain', 'Disease', (33, 44))	('OAGB', 'Chemical', '-', (50, 54))	('less', 'NegReg', (28, 32))	('OAGB', 'Chemical', '-', (68, 72))
402427	32355175	Although not statistically significant, OAGB-35 rats experienced almost 7% less weight gain than the RYGB rats.	('rats', 'Species', '10116', (106, 110))	('OAGB-35', 'Var', (40, 47))	('weight gain', 'Disease', (80, 91))	('rats', 'Species', '10116', (48, 52))	('less', 'NegReg', (75, 79))	('weight gain', 'Disease', 'MESH:D015430', (80, 91))	('OAGB', 'Chemical', '-', (40, 44))	('weight gain', 'Phenotype', 'HP:0004324', (80, 91))
402435	32355175	The OAGB-35 group had the highest percentage of esophagitis (50%; n = 5/10) and the lowest percentage of HEM (30%, n = 3/10) compared to the other groups.	('OAGB', 'Chemical', '-', (4, 8))	('esophagitis', 'Disease', 'MESH:D004938', (48, 59))	('HEM', 'Disease', 'MESH:C535858', (105, 108))	('esophagitis', 'Disease', (48, 59))	('esophagitis', 'Phenotype', 'HP:0100633', (48, 59))	('HEM', 'Disease', (105, 108))	('OAGB-35', 'Var', (4, 11))
402436	32355175	Rats that underwent RYGB displayed a lower percentage of esophageal lesions when compared to unoperated rats although the difference was not significant (P = 0.157).	('Rats', 'Species', '10116', (0, 4))	('rats', 'Species', '10116', (104, 108))	('rat', 'Species', '10116', (98, 101))	('RYGB', 'Var', (20, 24))	('lower', 'NegReg', (37, 42))	('esophageal', 'Disease', (57, 67))	('rat', 'Species', '10116', (104, 107))
402437	32355175	Most importantly, there was a prominent increase in the percentage of esophageal lesions present in OAGB-35 when compared to RYGB (P = 0.008).	('OAGB', 'Chemical', '-', (100, 104))	('OAGB-35', 'Var', (100, 107))	('increase', 'PosReg', (40, 48))	('esophageal lesions', 'Disease', (70, 88))
402450	32355175	In particular, concentrations of total and primary BA were about 2.3 fold higher in OAGB-15 animals compared to RYGB animals (OAGB-15 = 2,536 microM vs. RYGB = 1,114 microM, P = 0.0279 for total BA and OAGB-15 = 1,909 microM vs. RYGB = 822 microM, P = 0.0271 for primary BA).	('OAGB', 'Chemical', '-', (202, 206))	('BA', 'Chemical', 'MESH:D001647', (271, 273))	('higher', 'PosReg', (74, 80))	('rat', 'Species', '10116', (22, 25))	('BA', 'Chemical', 'MESH:D001647', (51, 53))	('OAGB', 'Chemical', '-', (84, 88))	('OAGB-15', 'Var', (84, 91))	('BA', 'Chemical', 'MESH:D001647', (195, 197))	('OAGB', 'Chemical', '-', (126, 130))
402460	32355175	Although OAGB-35 animals display abnormal values compared to unoperated CTRL rats for some of these markers (notably higher uremia and lower vitamin D) no association between anatomical lesions and biochemical parameters were discerned.	('uremia', 'Disease', 'MESH:D014511', (124, 130))	('OAGB-35', 'Var', (9, 16))	('rat', 'Species', '10116', (77, 80))	('vitamin D', 'Chemical', 'MESH:D014807', (141, 150))	('lower', 'NegReg', (135, 140))	('OAGB', 'Chemical', '-', (9, 13))	('higher', 'PosReg', (117, 123))	('uremia', 'Disease', (124, 130))	('rat', 'Species', '10116', (66, 69))	('rats', 'Species', '10116', (77, 81))
402462	32355175	We must note however that OAGB-35 rats experienced higher rates of esophagitis in addition to fundic and perianastomotic foveolar hyperplasia compared to the RYGB group.	('OAGB-35', 'Var', (26, 33))	('fundic', 'Disease', (94, 100))	('esophagitis', 'Disease', 'MESH:D004938', (67, 78))	('perianastomotic foveolar hyperplasia', 'Disease', (105, 141))	('rats', 'Species', '10116', (34, 38))	('esophagitis', 'Phenotype', 'HP:0100633', (67, 78))	('esophagitis', 'Disease', (67, 78))	('rat', 'Species', '10116', (58, 61))	('rat', 'Species', '10116', (34, 37))	('OAGB', 'Chemical', '-', (26, 30))	('perianastomotic foveolar hyperplasia', 'Disease', 'MESH:D006965', (105, 141))
402481	32355175	Undernutrition and micronutrient deficiencies could thus weaken the esophageal mucosa against aggressions secondary to biliary reflux, overpowering the beneficial features of OAGB and increasing the chances for carcinogenesis.	('overpowering', 'PosReg', (135, 147))	('aggressions', 'Phenotype', 'HP:0000718', (94, 105))	('carcinogenesis', 'Disease', (211, 225))	('weaken', 'NegReg', (57, 63))	('OAGB', 'Chemical', '-', (175, 179))	('increasing', 'PosReg', (184, 194))	('deficiencies', 'Var', (33, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (211, 225))
402485	32355175	Transposition of jejunum within the esophagus has been reported to induce hyperplasia of the transposed jejunum.	('hyperplasia', 'Disease', 'MESH:D006965', (74, 85))	('hyperplasia', 'Disease', (74, 85))	('induce', 'Reg', (67, 73))	('Transposition', 'Var', (0, 13))
402490	32355175	GER is a well-known risk factor of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('esophageal cancer', 'Disease', (35, 52))	('GER', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
402537	31444279	Among the down-regulated miRNAs in SCI, 21, 19 and 20 miRNAs were potentially associated with hematological, bladder and esophageal cancer, respectively, and three target genes (TP53, CCND1 and KRAS) were common to all three types of cancer.	('TP53', 'Gene', '7157', (178, 182))	('SCI', 'Disease', 'MESH:D013119', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('SCI', 'Phenotype', 'HP:0100561', (35, 38))	('CCND1', 'Gene', '595', (184, 189))	('down-regulated', 'NegReg', (10, 24))	('KRAS', 'Gene', '3845', (194, 198))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('bladder and esophageal cancer', 'Disease', 'MESH:D001749', (109, 138))	('SCI', 'Disease', (35, 38))	('CCND1', 'Gene', (184, 189))	('KRAS', 'Gene', (194, 198))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('miRNAs', 'Var', (25, 31))	('associated', 'Reg', (78, 88))	('TP53', 'Gene', (178, 182))	('hematological', 'Disease', (94, 107))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (234, 240))
402555	31444279	Potential target genes regulated by the differentially expressed miRNAs between SCI-S and healthy individuals were predicted using the miRWalk 2.0 online tool.	('miRNAs', 'Var', (65, 71))	('SCI', 'Disease', 'MESH:D013119', (80, 83))	('SCI', 'Phenotype', 'HP:0100561', (80, 83))	('SCI', 'Disease', (80, 83))
402560	31444279	Analysis of miRNAs up-regulated in SCI individuals (miR-125b-5p; miR-597-5p; miR-25-3p) resulted in 18 target genes associated with hematologic cancer, 10 with bladder cancer and 15 with esophageal cancer (Figure 3).	('miR-25', 'Gene', '407014', (77, 83))	('SCI', 'Disease', 'MESH:D013119', (35, 38))	('miRNAs', 'Gene', (12, 18))	('SCI', 'Phenotype', 'HP:0100561', (35, 38))	('hematologic cancer', 'Disease', (132, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('SCI', 'Disease', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('bladder cancer', 'Disease', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('esophageal cancer', 'Disease', (187, 204))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('associated', 'Reg', (116, 126))	('miR-25', 'Gene', (77, 83))	('miR-125b-5p', 'Var', (52, 63))	('up-regulated', 'PosReg', (19, 31))	('hematologic cancer', 'Phenotype', 'HP:0004377', (132, 150))	('25-3p', 'Chemical', 'MESH:C000863', (81, 86))	('hematologic cancer', 'Disease', 'MESH:D009369', (132, 150))
402563	31444279	For this purpose, we analyzed the differentially deregulated circulating miRNAs in individuals with SCI from a previous study of our group and showed that among the down-regulated miRNAs in SCI, 21, 19 and 20 miRNAs were potentially associated with hematological, bladder and esophageal cancer, respectively.	('associated', 'Reg', (233, 243))	('SCI', 'Disease', (190, 193))	('down-regulated', 'NegReg', (165, 179))	('SCI', 'Disease', 'MESH:D013119', (190, 193))	('bladder and esophageal cancer', 'Disease', 'MESH:D001749', (264, 293))	('SCI', 'Phenotype', 'HP:0100561', (100, 103))	('miRNAs', 'Var', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('SCI', 'Disease', (100, 103))	('hematological', 'Disease', (249, 262))	('SCI', 'Disease', 'MESH:D013119', (100, 103))	('SCI', 'Phenotype', 'HP:0100561', (190, 193))
402569	31444279	A former study has shown that miR-125a-5p have a reduced expression in patients with esophageal squamous cell carcinoma suggesting that this miRNA can function as a tumor suppressor in this type of cancer.	('expression', 'MPA', (57, 67))	('type of cancer', 'Disease', 'MESH:D009369', (190, 204))	('miR-125a-5p', 'Var', (30, 41))	('esophageal squamous cell carcinoma', 'Disease', (85, 119))	('reduced', 'NegReg', (49, 56))	('patients', 'Species', '9606', (71, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (85, 119))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('type of cancer', 'Disease', (190, 204))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('tumor', 'Disease', (165, 170))
402578	31444279	Our in silico analysis showed that down-regulation of miR-15b-5p, miR-30e-3p and miR-374b-5p in SCI individuals may have KRAS as one of the targets gene presents in the three most frequent types of cancer related to SCI.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('KRAS', 'Gene', (121, 125))	('miR-15b', 'Gene', '406949', (54, 61))	('cancer', 'Disease', (198, 204))	('KRAS', 'Gene', '3845', (121, 125))	('miR-30e-3p', 'Var', (66, 76))	('miR-374b', 'Gene', '100126317', (81, 89))	('SCI', 'Phenotype', 'HP:0100561', (96, 99))	('miR-15b', 'Gene', (54, 61))	('SCI', 'Phenotype', 'HP:0100561', (216, 219))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('SCI', 'Disease', (96, 99))	('SCI', 'Disease', (216, 219))	('SCI', 'Disease', 'MESH:D013119', (96, 99))	('SCI', 'Disease', 'MESH:D013119', (216, 219))	('down-regulation', 'NegReg', (35, 50))	('miR-374b', 'Gene', (81, 89))
402596	31452796	Notably, the mRNA and protein levels of Bcl-2 were downregulated, while p53 was upregulated in KYSE270 and KYSE150 cells following combined treatment.	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('KYSE150', 'CellLine', 'CVCL:1348', (107, 114))	('upregulated', 'PosReg', (80, 91))	('downregulated', 'NegReg', (51, 64))	('Bcl-2', 'Gene', (40, 45))	('Bcl-2', 'Gene', '596', (40, 45))	('KYSE270', 'Var', (95, 102))
402618	31452796	Following overnight culture, cells were treated with different treatments for four days, including DMSO, paclitaxel (10, 100 and 200 nM), shikonin (1 microM) and paclitaxel (100 nM) combined with shikonin (1 microM).	('paclitaxel', 'Chemical', 'MESH:D017239', (162, 172))	('shikonin', 'Chemical', 'MESH:C016101', (138, 146))	('10', 'Var', (117, 119))	('DMSO', 'Chemical', 'MESH:D004121', (99, 103))	('paclitaxel', 'Chemical', 'MESH:D017239', (105, 115))	('100 nM', 'Var', (174, 180))	('shikonin', 'Chemical', 'MESH:C016101', (196, 204))
402636	31452796	9664T; 1:1,000), anti-cleaved poly (ADP-ribose) polymerase (PARP; cat.	('poly (ADP-ribose) polymerase', 'Gene', '142', (30, 58))	('PARP', 'Gene', '142', (60, 64))	('anti-cleaved', 'Var', (17, 29))	('poly (ADP-ribose) polymerase', 'Gene', (30, 58))	('PARP', 'Gene', (60, 64))
402645	31452796	1B) alone did not significantly inhibit KYSE270 and KYSE150 cell growth.	('KYSE150', 'CellLine', 'CVCL:1348', (52, 59))	('KYSE270', 'Var', (40, 47))	('inhibit', 'NegReg', (32, 39))
402649	31452796	Between 24 and 96 h, cell survival rates were significantly reduced in the combined treatment group (100 nM paclitaxel and 1 microM shikonin) when compared with cell survival in all single agent treatment groups (P<0.001).	('paclitaxel', 'Chemical', 'MESH:D017239', (108, 118))	('100 nM', 'Var', (101, 107))	('cell survival rates', 'CPA', (21, 40))	('shikonin', 'Chemical', 'MESH:C016101', (132, 140))	('reduced', 'NegReg', (60, 67))
402662	31452796	To further confirm cell apoptosis was induced by various treatments, western blotting was performed to detect cleaved caspase-3 and cleaved PARP.	('caspase-3', 'Gene', (118, 127))	('PARP', 'Gene', (140, 144))	('caspase-3', 'Gene', '836', (118, 127))	('cleaved', 'Var', (132, 139))	('PARP', 'Gene', '142', (140, 144))
402680	31452796	Other studies have also reported that inhibiting or reducing Bcl-2 expression can sensitize cancer cells to chemotherapeutic agents.	('inhibiting', 'Var', (38, 48))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('sensitize', 'Reg', (82, 91))	('Bcl-2', 'Gene', (61, 66))	('reducing', 'NegReg', (52, 60))	('Bcl-2', 'Gene', '596', (61, 66))	('expression', 'MPA', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
402700	17373408	Similarly, tobacco use is associated with an elevated risk of lung cancer, as well as of cancers of the upper aero-digestive tract, bladder, kidney, pancreas, stomach, and cervix and a certain type of leukemia.	('stomach', 'Disease', (159, 166))	('pancreas', 'Disease', 'MESH:D010190', (149, 157))	('pancreas', 'Disease', (149, 157))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('lung cancer', 'Disease', (62, 73))	('kidney', 'Disease', (141, 147))	('tobacco', 'Species', '4097', (11, 18))	('cancers', 'Disease', (89, 96))	('leukemia', 'Disease', (201, 209))	('leukemia', 'Phenotype', 'HP:0001909', (201, 209))	('leukemia', 'Disease', 'MESH:D007938', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('tobacco use', 'Var', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
402719	17373408	Instead, the primary breakdown product of ethanol in the body, acetaldehyde, has been shown to cause damage to the organism's genetic material, the DNA, thereby contributing to cancer risk.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('contributing to', 'Reg', (161, 176))	('acetaldehyde', 'Chemical', 'MESH:D000079', (63, 75))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('acetaldehyde', 'Var', (63, 75))	('damage', 'MPA', (101, 107))	('ethanol', 'Chemical', 'MESH:D000431', (42, 49))
402742	17373408	These studies found that even in people who do not smoke, drinking is directly associated with the risk of laryngeal cancer, with risk increasing with the level of alcohol consumption.	('associated', 'Reg', (79, 89))	('drinking', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('laryngeal cancer', 'Disease', (107, 123))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('people', 'Species', '9606', (33, 39))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (107, 123))	('laryngeal cancer', 'Disease', 'MESH:D007822', (107, 123))
402865	30857144	It was reported that EGCG inhibited the proliferation and induced EC cells apoptosis (Ec9706 and Eca109) in a time- and dose-dependent manners by modulating the expression of telomerase activity, caspase-3 protein and membrane potential of mitochondrial or through p16 gene demethylation.	('EGCG', 'Gene', (21, 25))	('p16', 'Gene', (265, 268))	('modulating', 'Reg', (146, 156))	('proliferation', 'CPA', (40, 53))	('Ec9706', 'Var', (86, 92))	('telomerase', 'Protein', (175, 185))	('p16', 'Gene', '1029', (265, 268))	('expression', 'MPA', (161, 171))	('EGCG', 'Chemical', 'MESH:C045651', (21, 25))	('rat', 'Species', '10116', (47, 50))	('membrane potential', 'MPA', (218, 236))	('EC cells apoptosis', 'CPA', (66, 84))	('Eca109', 'Var', (97, 103))	('inhibited', 'NegReg', (26, 35))	('caspase-3', 'Gene', '836', (196, 205))	('caspase-3', 'Gene', (196, 205))	('Ec9706', 'CellLine', 'CVCL:E307', (86, 92))	('induced', 'PosReg', (58, 65))	('activity', 'MPA', (186, 194))	('demethylation', 'Var', (274, 287))
402877	30857144	EGCG also can suppress tumor metastasis through the regulation of related signaling pathways, such as the EGFR signaling pathway.	('suppress', 'NegReg', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('EGFR', 'Gene', '1956', (106, 110))	('EGCG', 'Var', (0, 4))	('tumor', 'Disease', (23, 28))	('EGFR', 'Gene', (106, 110))
402884	30857144	More and more studies have been focused on cancer epigenetics alterations in the last few years, including DNA methylation, gene silencing, genomic imprinting and microRNAs.	('DNA methylation', 'Var', (107, 122))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('gene silencing', 'Var', (124, 138))	('rat', 'Species', '10116', (66, 69))	('methylation', 'Var', (111, 122))
402886	30857144	Actually, DNA hyper-methylation is involved in various key events in cancer progression, for example, regulating the cell cycle, repairing of the DNA damage, and inducing cancer cell apoptosis.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('repairing', 'MPA', (129, 138))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('regulating', 'Reg', (102, 112))	('involved', 'Reg', (35, 43))	('cell cycle', 'CPA', (117, 127))	('cancer', 'Disease', (171, 177))	('inducing', 'Reg', (162, 170))	('hyper-methylation', 'Var', (14, 31))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (69, 75))
402893	30857144	EGCG also have been confirmed to induce ECa109 cell apoptosis and inhibit cell growth through p16 gene demethylation.	('demethylation', 'Var', (103, 116))	('p16', 'Gene', '1029', (94, 97))	('ECa109', 'CellLine', 'CVCL:6898', (40, 46))	('ECa109 cell apoptosis', 'CPA', (40, 61))	('cell growth', 'CPA', (74, 85))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('inhibit', 'NegReg', (66, 73))	('p16', 'Gene', (94, 97))	('EGCG', 'Var', (0, 4))	('induce', 'PosReg', (33, 39))
402906	30857144	These experiments indicated that EGCG may have a preventive effect on EC, and the related mechanism may be through downregulating the inflammatory-related factors, such as COX-2, ERK1/2, and c-Jun.	('ERK1/2', 'Gene', (179, 185))	('EGCG', 'Chemical', 'MESH:C045651', (33, 37))	('preventive', 'NegReg', (49, 59))	('ERK1/2', 'Gene', '5595;5594', (179, 185))	('c-Jun', 'MPA', (191, 196))	('downregulating', 'NegReg', (115, 129))	('EGCG', 'Var', (33, 37))	('men', 'Species', '9606', (12, 15))
402916	30857144	Pretreatment of ESCC cell line KYSE 150 with EGCG before the addition of EGF led to 32-85% reduction of phosphorylated EGFR and 80% decrease in EGFR protein expression.	('EGFR', 'Gene', (144, 148))	('EGF', 'Gene', '1950', (73, 76))	('phosphorylated', 'MPA', (104, 118))	('EGF', 'Gene', (119, 122))	('men', 'Species', '9606', (8, 11))	('EGF', 'Gene', '1950', (144, 147))	('EGF', 'Gene', (144, 147))	('EGF', 'Gene', '1950', (119, 122))	('reduction', 'NegReg', (91, 100))	('EGFR', 'Gene', '1956', (144, 148))	('EGFR', 'Gene', '1956', (119, 123))	('EGCG', 'Chemical', 'MESH:C045651', (45, 49))	('EGCG', 'Var', (45, 49))	('EGF', 'Gene', (73, 76))	('decrease', 'NegReg', (132, 140))	('EGFR', 'Gene', (119, 123))
402920	30857144	These studies indicate that the auto-oxidation of EGCG under cell culture conditions may result in the inactivation of EGFR-related signaling pathway.	('EGCG', 'Chemical', 'MESH:C045651', (50, 54))	('inactivation', 'NegReg', (103, 115))	('EGCG', 'Gene', (50, 54))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (119, 123))	('auto-oxidation', 'Var', (32, 46))
402958	30857144	found a significant correlation between the ECRG1 genetic polymorphism and ESCC in Kashmiri population.	('genetic polymorphism', 'Var', (50, 70))	('ESCC', 'Disease', (75, 79))	('ECRG1', 'Gene', '339967', (44, 49))	('ECRG1', 'Gene', (44, 49))
402966	30857144	It has been reported that EGCG acetylation can significantly improve the bioavailability in vivo and in vitro of colorectal cancer and EC.	('colorectal cancer', 'Disease', (113, 130))	('improve', 'PosReg', (61, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('EGCG', 'Chemical', 'MESH:C045651', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('bioavailability', 'MPA', (73, 88))	('acetylation', 'Var', (31, 42))
402978	30857144	P53 is the most common mutation gene in ESCC, and about half of EC patients have P53 gene mutation or overexpression, even in the early stage of cancer.	('cancer', 'Disease', (145, 151))	('P53', 'Gene', (81, 84))	('patients', 'Species', '9606', (67, 75))	('P53', 'Gene', '7157', (81, 84))	('overexpression', 'PosReg', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('mutation', 'Var', (90, 98))
402985	30857144	In their study, they found that after treatment with EGCG, the melanomas and various cancer cells have a significantly lower average value of Young's moduli, indicating that EGCG may inhibit cell migration and metastasis through increasing the stiffness of cancer cells.	('inhibit', 'NegReg', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('EGCG', 'Var', (174, 178))	('men', 'Species', '9606', (43, 46))	('rat', 'Species', '10116', (199, 202))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('increasing', 'PosReg', (229, 239))	('EGCG', 'Chemical', 'MESH:C045651', (174, 178))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('stiffness', 'MPA', (244, 253))	('EGCG', 'Chemical', 'MESH:C045651', (53, 57))	('cancer', 'Disease', (85, 91))	('melanomas', 'Disease', (63, 72))	('cell migration', 'CPA', (191, 205))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('lower', 'NegReg', (119, 124))	('average value', 'MPA', (125, 138))	("Young's moduli", 'MPA', (142, 156))	('cancer', 'Disease', (257, 263))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))
402995	30857144	Possible mechanisms of EGCG against EC included inhibition of EC cell proliferation, DNA methylation, angiogenesis, enhancement of apoptosis, anti-metastasis, antioxidant or pro-oxidant, synergistic effect in combination with other treatment methods as well as the modulation of multiple signal transduction and metabolic signaling pathways involved in carcinogenesis.	('EGCG', 'Chemical', 'MESH:C045651', (23, 27))	('rat', 'Species', '10116', (77, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (353, 367))	('EGCG', 'Var', (23, 27))	('carcinogenesis', 'Disease', (353, 367))	('angiogenesis', 'CPA', (102, 114))	('enhancement', 'PosReg', (116, 127))	('EC cell proliferation', 'CPA', (62, 83))	('apoptosis', 'CPA', (131, 140))	('modulation', 'Reg', (265, 275))	('men', 'Species', '9606', (123, 126))	('inhibition', 'NegReg', (48, 58))	('men', 'Species', '9606', (237, 240))
403026	29284434	Regarding pathologic disease stage of cervical lymph nodes, 12, 8, 2, 41, 25, and 5 patients were found to have stage N0, N1, N2a, N2b, N2c, and N3, respectively.	('N2a', 'Var', (126, 129))	('patients', 'Species', '9606', (84, 92))	('N2b', 'Var', (131, 134))	('N2c', 'Var', (136, 139))
403116	28418860	ROC1 knockdown significantly inhibited the growth of esophageal cancer cells in vitro and in vivo.	('inhibited', 'NegReg', (29, 38))	('ROC1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('esophageal cancer', 'Disease', (53, 70))	('ROC1', 'Gene', '9978', (0, 4))	('growth', 'CPA', (43, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
403117	28418860	Mechanistically, ROC1 silencing induced G2 cell cycle arrest and triggered apoptosis by accumulating the pro-apoptotic protein NOXA.	('arrest', 'Disease', (54, 60))	('apoptosis', 'CPA', (75, 84))	('ROC1', 'Gene', '9978', (17, 21))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('silencing', 'Var', (22, 31))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('accumulating', 'PosReg', (88, 100))	('NOXA', 'Gene', (127, 131))	('ROC1', 'Gene', (17, 21))	('NOXA', 'Gene', '5366', (127, 131))
403118	28418860	Consistently, the downregulation of NOXA expression via siRNA substantially attenuated apoptosis induced by ROC1 silencing.	('ROC1', 'Gene', (108, 112))	('expression', 'MPA', (41, 51))	('attenuated', 'NegReg', (76, 86))	('NOXA', 'Gene', (36, 40))	('apoptosis', 'CPA', (87, 96))	('NOXA', 'Gene', '5366', (36, 40))	('silencing', 'Var', (113, 122))	('ROC1', 'Gene', '9978', (108, 112))	('downregulation', 'NegReg', (18, 32))
403125	28418860	Dysfunction of ROC1 induced embryonic death and abnormal meiosis.	('abnormal meiosis', 'Disease', (48, 64))	('embryonic death', 'Disease', (28, 43))	('ROC1', 'Gene', '9978', (15, 19))	('Dysfunction', 'Var', (0, 11))	('ROC1', 'Gene', (15, 19))	('embryonic death', 'Disease', 'MESH:D003643', (28, 43))	('induced', 'Reg', (20, 27))	('abnormal meiosis', 'Disease', 'MESH:C536875', (48, 64))	('abnormal meiosis', 'Phenotype', 'HP:0031515', (48, 64))
403130	28418860	These findings revealed the detailed mechanism for proliferation-inhibition effect of ROC1 knockdown and suggested that ROC1 was an appealing drug target for esophageal cancer.	('ROC1', 'Gene', (86, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('knockdown', 'Var', (91, 100))	('proliferation-inhibition', 'CPA', (51, 75))	('ROC1', 'Gene', '9978', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ROC1', 'Gene', '9978', (86, 90))	('ROC1', 'Gene', (120, 124))	('esophageal cancer', 'Disease', (158, 175))
403134	28418860	To further assess the role of ROC1 on cell proliferation of esophageal cancer, ROC1 was knockdown by two specific siRNA oligoes, named siROC1-1 and siROC1-2.	('ROC1', 'Gene', (79, 83))	('ROC1', 'Gene', (150, 154))	('ROC1', 'Gene', '9978', (137, 141))	('ROC1', 'Gene', '9978', (30, 34))	('knockdown', 'Var', (88, 97))	('ROC1', 'Gene', '9978', (150, 154))	('esophageal cancer', 'Disease', (60, 77))	('ROC1', 'Gene', '9978', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ROC1', 'Gene', (137, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('ROC1', 'Gene', (30, 34))
403135	28418860	Results showed that ROC1 silencing significantly inhibited cell proliferation of both Kyse450 and TE1 cells (Figure 2A-2C).	('silencing', 'Var', (25, 34))	('inhibited', 'NegReg', (49, 58))	('cell proliferation', 'CPA', (59, 77))	('ROC1', 'Gene', '9978', (20, 24))	('ROC1', 'Gene', (20, 24))
403136	28418860	Besides, knockdown of ROC1 also effectively inhibited the cell colony formation in both cell lines (Figure 2D and 2E).	('knockdown', 'Var', (9, 18))	('ROC1', 'Gene', '9978', (22, 26))	('inhibited', 'NegReg', (44, 53))	('ROC1', 'Gene', (22, 26))	('cell colony formation in', 'CPA', (58, 82))
403139	28418860	As shown in Figure 3A, knockdown of ROC1 triggered G2/M cell cycle arrest in both Kyse450 and TE1 cells.	('ROC1', 'Gene', '9978', (36, 40))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('knockdown', 'Var', (23, 32))	('ROC1', 'Gene', (36, 40))	('arrest', 'Disease', (67, 73))
403140	28418860	Furthermore, ROC1 silencing induced significant accumulation of WEE1, an inhibitor of G2-M phase transition, while a decrease of p-H3, a hallmark of M phase cells, indicating that ROC1-silencing cells were arrested at the G2 phase (Figure 3B).	('silencing', 'Var', (18, 27))	('ROC1', 'Gene', (180, 184))	('accumulation', 'PosReg', (48, 60))	('arrest', 'Disease', (206, 212))	('ROC1', 'Gene', '9978', (13, 17))	('WEE1', 'Gene', (64, 68))	('WEE1', 'Gene', '7465', (64, 68))	('ROC1', 'Gene', (13, 17))	('decrease', 'NegReg', (117, 125))	('p-H3', 'MPA', (129, 133))	('arrest', 'Disease', 'MESH:D006323', (206, 212))	('ROC1', 'Gene', '9978', (180, 184))
403141	28418860	Next we examined whether apoptosis was also responsible for the anti-proliferative effects of ROC1 silencing.	('ROC1', 'Gene', '9978', (94, 98))	('ROC1', 'Gene', (94, 98))	('silencing', 'Var', (99, 108))
403142	28418860	Results showed that knockdown of ROC1 led to a significant increase in Annexin V-positive cells (Figure 4A) and caspase-3-actived cells (Figure 4B).	('ROC1', 'Gene', '9978', (33, 37))	('ROC1', 'Gene', (33, 37))	('caspase-3', 'Gene', (112, 121))	('knockdown', 'Var', (20, 29))	('Annexin V', 'Gene', (71, 80))	('Annexin V', 'Gene', '308', (71, 80))	('caspase-3', 'Gene', '836', (112, 121))	('increase', 'PosReg', (59, 67))
403144	28418860	Furthermore, we found that knockdown of ROC1 led to the loss of mitochondrial membrane potential (DeltaPsim) (Figure 5A), a classical marker of the activation of intrinsic apoptosis, which suggested that knockdown of ROC1 triggered mitochondrial apoptosis.	('ROC1', 'Gene', (217, 221))	('knockdown', 'Var', (27, 36))	('ROC1', 'Gene', '9978', (40, 44))	('knockdown', 'Var', (204, 213))	('loss', 'NegReg', (56, 60))	('ROC1', 'Gene', (40, 44))	('ROC1', 'Gene', '9978', (217, 221))	('mitochondrial apoptosis', 'CPA', (232, 255))
403145	28418860	To explore the potential mechanism of apoptosis, we investigated systematically the effect of ROC1 knockdown on the expression of the pro-apoptotic and anti-apoptotic proteins.	('ROC1', 'Gene', '9978', (94, 98))	('knockdown', 'Var', (99, 108))	('ROC1', 'Gene', (94, 98))
403148	28418860	NOXA knockdown significantly reduced the induction of apoptosis (Figure 6A) and the cleavage of PARP in ROC1-silencing cells (Figure 6B).	('apoptosis', 'CPA', (54, 63))	('NOXA', 'Gene', (0, 4))	('cleavage', 'MPA', (84, 92))	('NOXA', 'Gene', '5366', (0, 4))	('ROC1', 'Gene', (104, 108))	('knockdown', 'Var', (5, 14))	('PARP', 'Gene', (96, 100))	('reduced', 'NegReg', (29, 36))	('ROC1', 'Gene', '9978', (104, 108))	('PARP', 'Gene', '142', (96, 100))
403150	28418860	After demonstrating the inhibition efficacy of ROC1 silencing in vitro, we further investigated the growth-suppressive effect of ROC1 knockdown in subcutaneous-transplantation tumor model of human esophageal cancer in mice.	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('ROC1', 'Gene', '9978', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('silencing', 'Var', (52, 61))	('ROC1', 'Gene', '9978', (47, 51))	('tumor', 'Disease', (176, 181))	('ROC1', 'Gene', (129, 133))	('knockdown', 'Var', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('growth-suppressive', 'MPA', (100, 118))	('ROC1', 'Gene', (47, 51))	('human', 'Species', '9606', (191, 196))	('esophageal cancer', 'Disease', (197, 214))	('mice', 'Species', '10090', (218, 222))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
403151	28418860	Results showed that ROC1 silencing significantly suppressed tumor growth over time while control tumors grew rapidly, as revealed by the tumor growth curve (Figure 7A, **P<0.01), tumor size (Figure 7B, top panel) and tumor weight analysis (Figure 7B, bottom panel, **P<0.01).	('silencing', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('suppressed', 'NegReg', (49, 59))	('tumors', 'Disease', (97, 103))	('tumor', 'Disease', (60, 65))	('ROC1', 'Gene', (20, 24))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ROC1', 'Gene', '9978', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (179, 184))
403153	28418860	As shown in Figure 7C, ROC1 was effectively downregulated and the expression of NOXA and cleaved PARP were significantly induced upon ROC1 silencing.	('PARP', 'Gene', '142', (97, 101))	('downregulated', 'NegReg', (44, 57))	('ROC1', 'Gene', '9978', (23, 27))	('NOXA', 'Gene', (80, 84))	('silencing', 'Var', (139, 148))	('expression', 'MPA', (66, 76))	('ROC1', 'Gene', '9978', (134, 138))	('induced', 'PosReg', (121, 128))	('NOXA', 'Gene', '5366', (80, 84))	('PARP', 'Gene', (97, 101))	('ROC1', 'Gene', (23, 27))	('ROC1', 'Gene', (134, 138))
403154	28418860	These observations indicated that ROC1 silencing inhibited esophageal tumor growth both in vitro and in vivo by accumulating the expression of NOXA.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('expression', 'MPA', (129, 139))	('inhibited', 'NegReg', (49, 58))	('esophageal tumor', 'Disease', 'MESH:D004938', (59, 75))	('ROC1', 'Gene', '9978', (34, 38))	('esophageal tumor', 'Disease', (59, 75))	('silencing', 'Var', (39, 48))	('NOXA', 'Gene', (143, 147))	('esophageal tumor', 'Phenotype', 'HP:0100751', (59, 75))	('accumulating', 'PosReg', (112, 124))	('ROC1', 'Gene', (34, 38))	('NOXA', 'Gene', '5366', (143, 147))
403156	28418860	Results showed that ROC1 silencing significantly enhanced the cytotoxity of CDDP and inhibited cell viability (Figure 8A).	('silencing', 'Var', (25, 34))	('cytotoxity', 'Disease', 'MESH:D064420', (62, 72))	('inhibited', 'NegReg', (85, 94))	('enhanced', 'PosReg', (49, 57))	('CDDP', 'Chemical', 'MESH:D002945', (76, 80))	('cytotoxity', 'Disease', (62, 72))	('ROC1', 'Gene', '9978', (20, 24))	('ROC1', 'Gene', (20, 24))	('cell viability', 'CPA', (95, 109))
403157	28418860	Moreover, knockdown of ROC1 significantly enhanced CDDP-induced apoptosis, which is evident by the increased expression of cleaved-PARP (Figure 8B).	('CDDP', 'Chemical', 'MESH:D002945', (51, 55))	('expression', 'MPA', (109, 119))	('PARP', 'Gene', '142', (131, 135))	('ROC1', 'Gene', '9978', (23, 27))	('enhanced', 'PosReg', (42, 50))	('increased', 'PosReg', (99, 108))	('ROC1', 'Gene', (23, 27))	('knockdown', 'Var', (10, 19))	('PARP', 'Gene', (131, 135))	('CDDP-induced', 'Disease', (51, 63))
403159	28418860	RBX1/ROC1 disruption results in early embryonic lethality, cancer cell death or the inhibition of tumor cell migration.	('RBX1', 'Gene', '9978', (0, 4))	('tumor', 'Disease', (98, 103))	('inhibition', 'NegReg', (84, 94))	('ROC1', 'Gene', '9978', (5, 9))	('cancer cell death', 'Disease', 'MESH:D003643', (59, 76))	('embryonic lethality', 'Disease', 'MESH:D020964', (38, 57))	('embryonic lethality', 'Disease', (38, 57))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('RBX1', 'Gene', (0, 4))	('ROC1', 'Gene', (5, 9))	('disruption', 'Var', (10, 20))	('cancer cell death', 'Disease', (59, 76))
403161	28418860	Moreover, knockdown of ROC1 significantly inhibited cell proliferation in vitro and in vivo, and enhanced the cytotoxity of CDDP to ESCC cells.	('cytotoxity', 'Disease', 'MESH:D064420', (110, 120))	('cell proliferation', 'CPA', (52, 70))	('CDDP', 'Chemical', 'MESH:D002945', (124, 128))	('ROC1', 'Gene', '9978', (23, 27))	('enhanced', 'PosReg', (97, 105))	('inhibited', 'NegReg', (42, 51))	('ROC1', 'Gene', (23, 27))	('cytotoxity', 'Disease', (110, 120))	('knockdown', 'Var', (10, 19))
403163	28418860	Previous reports showed that knockdown of ROC1 destroy CRL/SCF complexes and thus disrupt CRL/SCF E3 ligase activity.	('SCF', 'Gene', (94, 97))	('CRL', 'Gene', '133396', (90, 93))	('ROC1', 'Gene', (42, 46))	('SCF', 'Gene', '4254', (59, 62))	('activity', 'MPA', (108, 116))	('knockdown', 'Var', (29, 38))	('SCF', 'Gene', '4254', (94, 97))	('CRL', 'Gene', (55, 58))	('CRL', 'Gene', (90, 93))	('ROC1', 'Gene', '9978', (42, 46))	('destroy', 'NegReg', (47, 54))	('CRL', 'Gene', '133396', (55, 58))	('SCF', 'Gene', (59, 62))	('disrupt', 'NegReg', (82, 89))
403165	28418860	In terms of apoptosis induction, Jia's finding showed that proapoptotic protein PUMA are involved in RBX1 (ROC1) silencing-induced apoptosis, whereas NOXA is associated with RBX2 silencing.	('NOXA', 'Gene', (150, 154))	('NOXA', 'Gene', '5366', (150, 154))	('RBX2', 'Gene', (174, 178))	('involved', 'Reg', (89, 97))	('RBX2', 'Gene', '9616', (174, 178))	('RBX1', 'Gene', '9978', (101, 105))	('ROC1', 'Gene', (107, 111))	('silencing-induced', 'Var', (113, 130))	('apoptosis', 'CPA', (131, 140))	('RBX1', 'Gene', (101, 105))	('ROC1', 'Gene', '9978', (107, 111))
403166	28418860	Here we found that knockdown of ROC1 led to the accumulation of NOXA and NOXA knockdown afforded significant protection against apoptosis, implying that NOXA also play an important role in ROC1 silencing-induced apoptosis for ESCC cells.	('ROC1', 'Gene', (189, 193))	('NOXA', 'Gene', (73, 77))	('knockdown', 'Var', (19, 28))	('knockdown', 'Var', (78, 87))	('silencing-induced', 'Var', (194, 211))	('ROC1', 'Gene', (32, 36))	('accumulation', 'PosReg', (48, 60))	('NOXA', 'Gene', (153, 157))	('NOXA', 'Gene', '5366', (73, 77))	('NOXA', 'Gene', (64, 68))	('ROC1', 'Gene', '9978', (189, 193))	('NOXA', 'Gene', '5366', (153, 157))	('NOXA', 'Gene', '5366', (64, 68))	('apoptosis', 'CPA', (128, 137))	('ROC1', 'Gene', '9978', (32, 36))
403171	28418860	Treatment ESCC or acute myelogenous leukemia cells with MLN4924, a neddylation inhibitor, lead to inactivation of CRL/SCF E3 ubiquitin ligase and transactivation of NOXA in a cell-type-specific manner to induce cell apoptosis.	('cell apoptosis', 'CPA', (211, 225))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (24, 44))	('SCF', 'Gene', '4254', (118, 121))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (18, 44))	('myelogenous leukemia', 'Disease', (24, 44))	('inactivation', 'NegReg', (98, 110))	('SCF', 'Gene', (118, 121))	('E3 ubiquitin ligase', 'Gene', '79594', (122, 141))	('CRL', 'Gene', (114, 117))	('leukemia', 'Phenotype', 'HP:0001909', (36, 44))	('MLN4924', 'Var', (56, 63))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (24, 44))	('induce', 'PosReg', (204, 210))	('CRL', 'Gene', '133396', (114, 117))	('E3 ubiquitin ligase', 'Gene', (122, 141))	('NOXA', 'Gene', '5366', (165, 169))	('transactivation', 'MPA', (146, 161))	('NOXA', 'Gene', (165, 169))	('MLN4924', 'Chemical', 'MESH:C539933', (56, 63))
403194	28418860	ROC1 regulator of Cullins-1 EC Esophageal cancer ESCC Esophageal squamous cell carcinoma RBX1 RING box protein-1 IHC immunohistochemistry CDDP cisplatin UPS ubiquitin proteasome system TNM tumor-node-metastasis MMP mitochondrial membrane potential S.D.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ROC1', 'Gene', '9978', (0, 4))	('CDDP', 'Var', (138, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('RING box protein-1', 'Gene', '9978', (94, 112))	('tumor-node-metastasis', 'Disease', (189, 210))	('regulator of Cullins-1', 'Gene', (5, 27))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (189, 210))	('Esophageal squamous cell carcinoma', 'Disease', (54, 88))	('cancer ESCC Esophageal squamous cell carcinoma', 'Phenotype', 'HP:0011459', (42, 88))	('regulator of Cullins-1', 'Gene', '9978', (5, 27))	('RBX1', 'Gene', '9978', (89, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('Esophageal cancer', 'Disease', (31, 48))	('CDDP', 'Chemical', 'MESH:D002945', (138, 142))	('RING box protein-1', 'Gene', (94, 112))	('UPS', 'Disease', (153, 156))	('ROC1', 'Gene', (0, 4))	('UPS', 'Disease', 'MESH:D017118', (153, 156))	('Esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('RBX1', 'Gene', (89, 93))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))
403262	28190989	Homocysteine induces inflammatory cytokine production in cultured human cells, and has been mechanistically linked to inflammatory bowel disease (IBD) and atherosclerosis.	('atherosclerosis', 'Disease', (155, 170))	('induces', 'Reg', (13, 20))	('linked', 'Reg', (108, 114))	('human', 'Species', '9606', (66, 71))	('Homocysteine', 'Chemical', 'MESH:D006710', (0, 12))	('inflammatory cytokine production', 'MPA', (21, 53))	('atherosclerosis', 'Phenotype', 'HP:0002621', (155, 170))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (118, 144))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (118, 144))	('atherosclerosis', 'Disease', 'MESH:D050197', (155, 170))	('Homocysteine', 'Var', (0, 12))	('inflammatory bowel disease', 'Disease', (118, 144))
403282	25914549	When the patients were segregated according to country, sample size, and pathological type, high NLR was also significantly correlated with OS.	('NLR', 'Gene', (97, 100))	('patients', 'Species', '9606', (9, 17))	('high', 'Var', (92, 96))	('correlated', 'Reg', (124, 134))
403283	25914549	High NLR is associated with poor prognosis in patients with EC.	('patients', 'Species', '9606', (46, 54))	('NLR', 'Gene', (5, 8))	('High', 'Var', (0, 4))
403300	25914549	In this meta-analysis, our pooled results demonstrated that high NLR was associated with poor OS (HR: 1.54, 95% CI: 1.32-1.80, I2=25.3%, P=0.245) and DFS (HR: 1.74, 95% CI: 1.25-2.43, I2=63.9%, P=0.096) in patients with EC.	('DFS', 'MPA', (150, 153))	('high', 'Var', (60, 64))	('NLR', 'Gene', (65, 68))	('patients', 'Species', '9606', (206, 214))	('poor OS', 'Disease', (89, 96))
403306	25914549	In conclusion, our meta-analysis demonstrated that high NLR was significantly associated with poor OS and DFS in patients with EC.	('associated', 'Reg', (78, 88))	('patients', 'Species', '9606', (113, 121))	('DFS', 'Disease', (106, 109))	('poor OS', 'Disease', (94, 101))	('NLR', 'Gene', (56, 59))	('high', 'Var', (51, 55))
403314	34022824	As early as the 1950s, blood type A was reported to be associated with an increased risk of gastric cancer.	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (55, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('blood type A', 'Var', (23, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (74, 106))
403319	34022824	One recent case-control study of 480 patients with esophageal squamous cell carcinoma (ESCC) and 480 controls suggested a higher frequency of blood type B in patients with ESCC.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('patients', 'Species', '9606', (37, 45))	('higher', 'PosReg', (122, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (51, 85))	('blood type B', 'Var', (142, 154))	('ESCC', 'Disease', (172, 176))	('patients', 'Species', '9606', (158, 166))	('esophageal squamous cell carcinoma', 'Disease', (51, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
403324	34022824	To determine blood type from the SNPs, we first used PHASE to infer haplotypes for rs505922, rs8176746, and rs574347, which provided two ABO alleles for each subject.	('ABO', 'Gene', '28', (137, 140))	('ABO', 'Gene', (137, 140))	('rs8176746', 'Mutation', 'rs8176746', (93, 102))	('rs8176746', 'Var', (93, 102))	('rs505922', 'Var', (83, 91))	('rs574347', 'Mutation', 'rs574347', (108, 116))	('rs505922', 'Mutation', 'rs505922', (83, 91))	('rs574347', 'Var', (108, 116))
403336	34022824	Compared to blood type O, blood type AB was associated with the highest risk of ESCC and gastric noncardia adenocarcinoma.	('gastric noncardia adenocarcinoma', 'Disease', (89, 121))	('gastric noncardia adenocarcinoma', 'Disease', 'MESH:D013274', (89, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('blood type AB', 'Var', (26, 39))	('ESCC', 'Disease', (80, 84))
403343	34022824	In addition, a Chinese case-control study and meta-analysis showed that gastric cancer patients with blood type A had a higher likelihood of Helicobacter pylori infections than patients with other blood types, suggesting more frequent infections or greater inflammations in response to infections related to blood type A.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('infections', 'Disease', (286, 296))	('infections', 'Disease', 'MESH:D007239', (235, 245))	('Helicobacter pylori', 'Species', '210', (141, 160))	('patients', 'Species', '9606', (177, 185))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Helicobacter pylori infections', 'Phenotype', 'HP:0005202', (141, 171))	('blood type A', 'Var', (101, 113))	('frequent infections', 'Phenotype', 'HP:0002719', (226, 245))	('infections', 'Disease', 'MESH:D007239', (161, 171))	('infections', 'Disease', (235, 245))	('infections', 'Disease', 'MESH:D007239', (286, 296))	('patients', 'Species', '9606', (87, 95))	('gastric cancer', 'Disease', (72, 86))	('infections', 'Disease', (161, 171))
403398	23101672	Adherent feed or fibrin to the mucosal surface is a strong indication of local necrosis and inflammation.	('necrosis', 'Disease', (79, 87))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('necrosis', 'Disease', 'MESH:D009336', (79, 87))	('inflammation', 'Disease', (92, 104))	('Adherent', 'Var', (0, 8))	('local necrosis', 'Phenotype', 'HP:0010885', (73, 87))
403441	23101672	Erosions can affect the esophagus with causes similar to those described for the oropharynx (BVD, MCF, BTV) (Fig.	('oropharynx', 'Disease', (81, 91))	('esophagus', 'Disease', (24, 33))	('MCF', 'CellLine', 'CVCL:E778', (98, 101))	('BTV', 'Species', '40051', (103, 106))	('Erosions', 'Var', (0, 8))	('affect', 'Reg', (13, 19))
403453	23101672	Alterations of this host-environment-microorganism homeostasis are what lead to lesions and disease.	('iron', 'Chemical', 'MESH:D007501', (28, 32))	('Alterations', 'Var', (0, 11))	('disease', 'Disease', (92, 99))	('lesions', 'Disease', (80, 87))	('lead to', 'Reg', (72, 79))
403521	30913304	The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial.	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (79, 103))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (31, 42))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (47, 61))	('lower', 'NegReg', (66, 71))	('mFOLFOX6/ziv-aflibercept', 'Var', (79, 103))
403527	30913304	Based in part on results from CALGB 80403 (Alliance)/E1206, modified FOLFOX6 (mFOLFOX6), a combination of oxaliplatin, leucovorin, and bolus plus infusional 5-fluorouracil, has become the most commonly used regimen in the United States for metastatic esophagogastric cancer.	('mFOLFOX6', 'Chemical', '-', (78, 86))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('modified', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (157, 171))	('FOLFOX6', 'Chemical', '-', (79, 86))	('leucovorin', 'Chemical', 'MESH:D002955', (119, 129))	('FOLFOX6', 'Chemical', '-', (69, 76))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (106, 117))
403535	30913304	We hypothesized that ziv-aflibercept would enhance the activity of first-line mFOLFOX6 in esophagogastric adenocarcinoma.	('mFOLFOX6', 'Chemical', '-', (78, 86))	('activity', 'MPA', (55, 63))	('ziv-aflibercept', 'Var', (21, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adenocarcinoma', 'Disease', (106, 120))	('adenocarcinoma', 'Disease', 'MESH:D000230', (106, 120))	('first-line mFOLFOX6', 'Enzyme', (67, 86))	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (90, 120))	('enhance', 'PosReg', (43, 50))
403564	30913304	The mFOLFOX6/ziv-aflibercept arm had a higher percentage of patients with esophageal cancer (37% vs 24%) and patients with an ECOG score of 0 (56% vs 38%), but neither of these differences was statistically significant (P = .40 and P = .29, respectively).	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (60, 68))	('mFOLFOX6/ziv-aflibercept', 'Var', (4, 28))	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (4, 28))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
403568	30913304	The 6-month PFS rate was 60.5% (95% confidence interval [CI], 44.3%-73.3%) for patients in the mFOLFOX6/ziv-aflibercept arm and 57.1% (95% CI, 33.8%-74.9%) for those in the mFOLFOX6/placebo arm.	('PFS', 'CPA', (12, 15))	('mFOLFOX6', 'Chemical', '-', (95, 103))	('mFOLFOX6/ziv-aflibercept', 'Var', (95, 119))	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (95, 119))	('patients', 'Species', '9606', (79, 87))	('mFOLFOX6', 'Chemical', '-', (173, 181))
403580	30913304	There also was no significant difference in subsequent treatment with ramucirumab (46% vs 57%; P = .59) or PD1-directed therapy (17% vs 24%; P = .52) between the mFOLFOX6/ziv-aflibercept arm and the mFOLFOX6/placebo arm.	('PD1', 'Gene', '5133', (107, 110))	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (162, 186))	('PD1', 'Gene', (107, 110))	('mFOLFOX6', 'Chemical', '-', (199, 207))	('ramucirumab', 'Chemical', 'MESH:C543333', (70, 81))	('mFOLFOX6', 'Chemical', '-', (162, 170))	('ramucirumab', 'Gene', (70, 81))	('mFOLFOX6/ziv-aflibercept', 'Var', (162, 186))
403581	30913304	Patients receiving mFOLFOX6/ziv-aflibercept tended to be more likely than mFOLFOX6/placebo patients to discontinue treatment for reasons other than progres-sive disease (44% vs 19%; P = .06).	('patients', 'Species', '9606', (91, 99))	('mFOLFOX6/ziv-aflibercept', 'Var', (19, 43))	('discontinue', 'NegReg', (103, 114))	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (19, 43))	('Patients', 'Species', '9606', (0, 8))	('mFOLFOX6', 'Chemical', '-', (74, 82))	('mFOLFOX6', 'Chemical', '-', (19, 27))	('progres-sive disease', 'Disease', (148, 168))
403584	30913304	Grade 3 or higher hypertension was observed more frequently in patients receiving mFOLFOX6/ziv-aflibercept than those in the mFOLFOX6/placebo arm (P = .0002).	('mFOLFOX6/ziv-aflibercept', 'Var', (82, 106))	('hypertension', 'Disease', 'MESH:D006973', (18, 30))	('Grade 3', 'Disease', (0, 7))	('patients', 'Species', '9606', (63, 71))	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (82, 106))	('mFOLFOX6', 'Chemical', '-', (125, 133))	('hypertension', 'Disease', (18, 30))	('hypertension', 'Phenotype', 'HP:0000822', (18, 30))	('mFOLFOX6', 'Chemical', '-', (82, 90))
403585	30913304	Rates of bleeding and thromboembolic events as well as episodes of heart failure and gastroin-testinal perforations were somewhat higher in patients receiving mFOLFOX6/ziv-aflibercept, but these differences were not statistically significant (Table 3).	('gastroin-testinal perforations', 'Disease', (85, 115))	('higher', 'PosReg', (130, 136))	('thromboembolic', 'Disease', (22, 36))	('bleeding', 'Disease', (9, 17))	('heart failure', 'Disease', 'MESH:D006333', (67, 80))	('heart failure', 'Phenotype', 'HP:0001635', (67, 80))	('patients', 'Species', '9606', (140, 148))	('thromboembolic events', 'Phenotype', 'HP:0001907', (22, 43))	('mFOLFOX6/ziv-aflibercept', 'Var', (159, 183))	('heart failure', 'Disease', (67, 80))	('thromboembolic', 'Disease', 'MESH:D013923', (22, 36))	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (159, 183))	('bleeding', 'Disease', 'MESH:D006470', (9, 17))
403587	30913304	In addition, there were 2 possibly treatment-related deaths, a suspected arrhythmia in the mFOLFOX6/ziv-aflibercept arm and a sudden death in the mFOLFOX6/placebo arm.	('arrhythmia', 'Disease', (73, 83))	('mFOLFOX6/ziv-aflibercept', 'Var', (91, 115))	('sudden death', 'Disease', (126, 138))	('deaths', 'Disease', (53, 59))	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (91, 115))	('deaths', 'Disease', 'MESH:D003643', (53, 59))	('mFOLFOX6', 'Chemical', '-', (146, 154))	('arrhythmia', 'Disease', 'MESH:D001145', (73, 83))	('arrhythmia', 'Phenotype', 'HP:0011675', (73, 83))	('mFOLFOX6', 'Chemical', '-', (91, 99))	('sudden death', 'Disease', 'MESH:D003645', (126, 138))
403589	30913304	The mean relative dose intensity, calculated as the ratio of the actual cumulative dose to the protocol-specified cumulative dose over the specified period, was lower in patients receiving mFOLFOX6/ziv-aflibercept for both 5-fluorouracil and oxaliplatin over the first 12 and 24 weeks of the trial (Fig.	('patients', 'Species', '9606', (170, 178))	('lower', 'NegReg', (161, 166))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (242, 253))	('relative dose intensity', 'MPA', (9, 32))	('mFOLFOX6/ziv-aflibercept', 'Var', (189, 213))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (223, 237))	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (189, 213))
403599	30913304	A subgroup analysis in the first-line FOLFOX/ramucirumab trial suggested an increased benefit of FOLFOX/ramucirumab for patients with gastric and gastroesophageal junctional cancer but not for patients with esophageal cancer.	('patients', 'Species', '9606', (193, 201))	('FOLFOX', 'Chemical', '-', (38, 44))	('ramucirumab', 'Chemical', 'MESH:C543333', (45, 56))	('ramucirumab', 'Chemical', 'MESH:C543333', (104, 115))	('esophageal cancer', 'Disease', (207, 224))	('FOLFOX/ramucirumab', 'Var', (97, 115))	('FOLFOX', 'Chemical', '-', (97, 103))	('gastric and gastroesophageal junctional cancer', 'Disease', 'MESH:D013274', (134, 180))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('esophageal cancer', 'Disease', 'MESH:D004938', (207, 224))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
403600	30913304	In our trial, an underpowered subgroup analysis suggested that ziv-aflibercept did not enhance the activity of first-line mFOLFOX6 in patients with gastric and gastroesophageal junctional cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('ziv-aflibercept', 'Var', (63, 78))	('mFOLFOX6', 'Chemical', '-', (122, 130))	('patients', 'Species', '9606', (134, 142))	('activity', 'MPA', (99, 107))	('gastric and gastroesophageal junctional cancer', 'Disease', 'MESH:D013274', (148, 194))
403602	30913304	Data from this trial suggest that there was increased toxicity in the mFOLFOX6/ziv-aflibercept arm.	('toxicity', 'Disease', 'MESH:D064420', (54, 62))	('mFOLFOX6/ziv-aflibercept', 'Var', (70, 94))	('toxicity', 'Disease', (54, 62))	('mFOLFOX6/ziv-aflibercept', 'Chemical', '-', (70, 94))
403609	30913304	Ziv-aflibercept has been associated with a clinically significant increase in toxicity in other cancers such as small cell lung cancer and prostate cancer.	('increase', 'PosReg', (66, 74))	('toxicity', 'Disease', 'MESH:D064420', (78, 86))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('toxicity', 'Disease', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('prostate cancer', 'Disease', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Ziv-aflibercept', 'Var', (0, 15))	('small cell lung cancer', 'Disease', 'MESH:D055752', (112, 134))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('prostate cancer', 'Disease', 'MESH:D011471', (139, 154))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (139, 154))	('cancers', 'Disease', (96, 103))	('small cell lung cancer', 'Disease', (112, 134))
403613	30913304	However, it is noteworthy that 44% of the patients in our trial received at least 3 lines of therapy, with 50% receiving ramucirumab and 19% receiving PD1-directed therapy.	('PD1', 'Gene', (151, 154))	('ramucirumab', 'Chemical', 'MESH:C543333', (121, 132))	('ramucirumab', 'Var', (121, 132))	('patients', 'Species', '9606', (42, 50))	('PD1', 'Gene', '5133', (151, 154))
403666	30527929	The EDP molecular signature of the EA1EoE1 and EA2EoE1 cohorts have comparable profiles relative to their EA+EoE- and NL control subjects, respectively (Fig 2, A and B).	('EA', 'Phenotype', 'HP:0002032', (106, 108))	('EoE', 'Phenotype', 'HP:0410151', (50, 53))	('EA', 'Phenotype', 'HP:0002032', (35, 37))	('EoE', 'Phenotype', 'HP:0410151', (109, 112))	('EA+EoE', 'Disease', (106, 112))	('EA2EoE1', 'Var', (47, 54))	('EA1EoE1', 'Var', (35, 42))	('EDP', 'Chemical', '-', (4, 7))	('EA+EoE', 'Disease', 'None', (106, 112))	('EDP', 'MPA', (4, 7))	('EoE', 'Phenotype', 'HP:0410151', (38, 41))	('EA', 'Phenotype', 'HP:0002032', (47, 49))
403673	30527929	A similar remission pattern in the EA+EoE+ and EA-EoE+ cohorts after treatment of EoE was observed; for instance, the mean posttreatment EoE scores were 662 (95% CI, 648-676) for EA+EoE+ versus 654 (95% CI, 631-671) for EA2EoE1, which were accompanied by a similar CCL26 mRNA level reduction of 85% 6 27% versus 91% 6 12% (mean 6 SD; Fig 3, B), respectively.	('EA-EoE', 'Disease', 'None', (47, 53))	('EoE', 'Phenotype', 'HP:0410151', (182, 185))	('EA', 'Phenotype', 'HP:0002032', (47, 49))	('reduction', 'NegReg', (282, 291))	('EA2EoE1', 'Var', (220, 227))	('EA', 'Phenotype', 'HP:0002032', (220, 222))	('EA+EoE+', 'Disease', 'None', (179, 186))	('EA+EoE+', 'Disease', 'None', (35, 42))	('EoE', 'Phenotype', 'HP:0410151', (38, 41))	('EA-EoE', 'Disease', (47, 53))	('EA', 'Phenotype', 'HP:0002032', (179, 181))	('EA', 'Phenotype', 'HP:0002032', (35, 37))	('EA+EoE+', 'Disease', (179, 186))	('EA+EoE+', 'Disease', (35, 42))	('CCL26', 'Gene', '10344', (265, 270))	('EoE', 'Phenotype', 'HP:0410151', (50, 53))	('EoE', 'Phenotype', 'HP:0410151', (82, 85))	('EoE', 'Phenotype', 'HP:0410151', (137, 140))	('CCL26', 'Gene', (265, 270))	('EoE', 'MPA', (137, 140))
403703	30527929	A plausible explanation for the high prevalence of EoE in the population with EA is the dysregulated expression of epithelial genes known to be involved in allergic inflammation in patients with EA at baseline, rendering the affected esophagus more prone to EoE development.	('EoE development', 'CPA', (258, 273))	('EA', 'Phenotype', 'HP:0002032', (78, 80))	('epithelial genes', 'Gene', (115, 131))	('allergic inflammation', 'Disease', (156, 177))	('EoE', 'Disease', (51, 54))	('patients', 'Species', '9606', (181, 189))	('EoE', 'Phenotype', 'HP:0410151', (51, 54))	('dysregulated', 'Var', (88, 100))	('EoE', 'Phenotype', 'HP:0410151', (258, 261))	('expression', 'MPA', (101, 111))	('EA', 'Phenotype', 'HP:0002032', (195, 197))	('more prone', 'PosReg', (244, 254))	('allergic inflammation', 'Disease', 'MESH:D007249', (156, 177))
403708	30527929	Microdeletions encompassing the forkhead box transcription factor gene cluster, specifically the FOXF1 gene, have recently been shown to be associated with EA.	('associated', 'Reg', (140, 150))	('FOXF1', 'Gene', (97, 102))	('FOXF1', 'Gene', '2294', (97, 102))	('Microdeletions', 'Var', (0, 14))	('EA', 'Phenotype', 'HP:0002032', (156, 158))
403711	30527929	It could be postulated that mutations in the FOX gene cluster not only lead to congenital malformations of both the lung and esophagus but also predispose toward EoE through transcriptional linkage to eotaxin.	('lead to', 'Reg', (71, 78))	('eotaxin', 'Gene', (201, 208))	('predispose', 'Reg', (144, 154))	('esophagus', 'Disease', (125, 134))	('congenital malformations', 'Disease', 'MESH:D000014', (79, 103))	('FOX', 'Gene', (45, 48))	('eotaxin', 'Gene', '6356', (201, 208))	('EoE', 'Phenotype', 'HP:0410151', (162, 165))	('mutations', 'Var', (28, 37))	('congenital malformations', 'Disease', (79, 103))	('EoE', 'Disease', (162, 165))
403714	30527929	Interestingly, a previous study had compared patients with EA with and without EoE (EA+EoE+ vs EA+EoE-) and found that patients with EA with EoE had significantly more reflux symptoms and dysphagia than those without.	('EA', 'Phenotype', 'HP:0002032', (84, 86))	('EoE', 'Phenotype', 'HP:0410151', (79, 82))	('patients', 'Species', '9606', (45, 53))	('EoE', 'Phenotype', 'HP:0410151', (141, 144))	('EoE', 'Phenotype', 'HP:0410151', (87, 90))	('reflux', 'MPA', (168, 174))	('EA', 'Phenotype', 'HP:0002032', (133, 135))	('reflux symptoms', 'Phenotype', 'HP:0002020', (168, 183))	('dysphagia', 'Phenotype', 'HP:0002015', (188, 197))	('EA', 'Phenotype', 'HP:0002032', (59, 61))	('EA+EoE+ vs EA+EoE', 'Disease', 'MESH:D015826', (84, 101))	('EoE', 'Var', (141, 144))	('EA+EoE+ vs EA+EoE', 'Disease', (84, 101))	('EoE', 'Phenotype', 'HP:0410151', (98, 101))	('patients', 'Species', '9606', (119, 127))	('dysphagia', 'Disease', 'MESH:D003680', (188, 197))	('dysphagia', 'Disease', (188, 197))	('more', 'PosReg', (163, 167))	('EA', 'Phenotype', 'HP:0002032', (95, 97))
403830	27734016	Additionally, L. delbrueckii and L. gasseri are herein implicated in the pathogenesis of a complicated lower respiratory tract infection.	('respiratory tract infection', 'Disease', (109, 136))	('respiratory tract infection', 'Disease', 'MESH:D012141', (109, 136))	('lower respiratory tract infection', 'Phenotype', 'HP:0002783', (103, 136))	('L. gasseri', 'Species', '1596', (33, 43))	('L. delbrueckii', 'Var', (14, 28))	('L. delbrueckii', 'Species', '1584', (14, 28))	('respiratory tract infection', 'Phenotype', 'HP:0011947', (109, 136))	('L. gasseri', 'Var', (33, 43))	('implicated', 'Reg', (55, 65))
403837	33671513	These findings have been strongly buttressed by demonstration of increased tumorigenesis in tissue-specific AEG-1 transgenic mouse models, and profound resistance of multiple types of cancer development and progression in total and conditional AEG-1 knockout mouse models.	('cancer', 'Disease', (184, 190))	('increased', 'PosReg', (65, 74))	('transgenic', 'Var', (114, 124))	('mouse', 'Species', '10090', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('AEG-1', 'Gene', (108, 113))	('mouse', 'Species', '10090', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('rat', 'Species', '10116', (55, 58))	('tumor', 'Disease', (75, 80))
403858	33671513	Indeed, overexpression of AEG-1 promotes all hallmarks of cancer and inhibition of AEG-1 reverses these phenotypes and tissue-specific AEG-1 transgenic mouse display augmented tumorigenesis and AEG-1 knockout mouse show resistance to the development and progression of multiple cancer types, such as those of liver, breast, prostate and colon, indicating that AEG-1 plays a pivotal role in regulating tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('AEG-1', 'Gene', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('cancer', 'Disease', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Disease', (176, 181))	('augmented', 'PosReg', (166, 175))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('AEG-1', 'Gene', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('mouse', 'Species', '10090', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('resistance', 'CPA', (220, 230))	('liver', 'Disease', (309, 314))	('mouse', 'Species', '10090', (152, 157))	('cancer', 'Disease', (58, 64))	('inhibition', 'Var', (69, 79))	('tumor', 'Disease', (401, 406))
403866	33671513	In both squamous cell carcinoma and adenocarcinoma, significant difference in survival time between low and high AEG-1 expression groups was observed in poorly differentiated cases (p < 0.001), but not in well-differentiated cases.	('expression', 'MPA', (119, 129))	('AEG-1', 'Gene', (113, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (36, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (8, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('squamous cell carcinoma', 'Disease', (8, 31))	('high', 'Var', (108, 112))	('adenocarcinoma', 'Disease', (36, 50))
403878	33671513	OS (p = 0.014) and DFS (p = 0.009) were longer in low AEG-1 expressing group versus high expressing group in patients who received postoperative chemotherapy.	('rat', 'Species', '10116', (138, 141))	('patients', 'Species', '9606', (109, 117))	('low', 'Var', (50, 53))	('DFS', 'CPA', (19, 22))	('AEG-1', 'Protein', (54, 59))
403879	33671513	Similarly, in patients receiving postoperative radiotherapy recurrence free survival was significantly shorter in high AEG-1 expressing group (p = 0.016).	('high', 'Var', (114, 118))	('rat', 'Species', '10116', (40, 43))	('shorter', 'NegReg', (103, 110))	('patients', 'Species', '9606', (14, 22))	('AEG-1', 'Protein', (119, 124))
403883	33671513	While 6.8% normal tissues showed AEG-1 expression, in NSCLC cases it was 61.3% (p < 0.001) which showed significant association with TNM stage (p = 0.021), dedifferentiation (p = 0.034), vascular invasion (p = 0.035), lymph node metastasis (p < 0.001) and poor overall survival (p = 0.024).	('TNM', 'Gene', (133, 136))	('AEG-1', 'Var', (33, 38))	('vascular invasion', 'CPA', (187, 204))	('lymph node metastasis', 'CPA', (218, 239))	('association', 'Reg', (116, 127))	('NSCLC', 'Disease', (54, 59))	('TNM', 'Gene', '10178', (133, 136))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('dedifferentiation', 'CPA', (156, 173))
403887	33671513	This analysis revealed that high AEG-1 expression significantly correlated with higher mortality and metastasis in breast, ovarian and cervical cancers.	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('AEG-1', 'Gene', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('expression', 'MPA', (39, 49))	('high', 'Var', (28, 32))	('mortality', 'Disease', (87, 96))	('higher', 'PosReg', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('metastasis in breast, ovarian and cervical cancers', 'Disease', 'MESH:D009362', (101, 151))
403888	33671513	In addition, polymorphisms in AEG-1 gene, such as a C/T variant in exon 11 or a G>A variant in exon 9, have been shown to confer susceptibility to breast and ovarian cancers in women from specific ethnic groups in China, which needs to be validated in more extensive studies in other patient cohorts.	('susceptibility', 'Reg', (129, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('C/T', 'Var', (52, 55))	('women', 'Species', '9606', (177, 182))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (147, 173))	('G>A', 'Var', (80, 83))	('ovarian cancers', 'Phenotype', 'HP:0100615', (158, 173))	('polymorphisms', 'Var', (13, 26))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patient', 'Species', '9606', (284, 291))	('AEG-1', 'Gene', (30, 35))
403902	33671513	These breast cancer patients also showed correlation between AEG-1 and proliferation marker Ki-67 (p = 0.003) in a subsequent study indicating that AEG-1 is associated with highly proliferative breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('rat', 'Species', '10116', (187, 190))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('AEG-1', 'Var', (148, 153))	('associated with', 'Reg', (157, 172))	('correlation', 'Interaction', (41, 52))	('breast cancer', 'Disease', (6, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('rat', 'Species', '10116', (78, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (194, 208))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('patients', 'Species', '9606', (20, 28))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancers', 'Disease', 'MESH:D001943', (194, 208))	('breast cancers', 'Disease', (194, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
403903	33671513	However, knocking down AEG-1 in breast cancer cells did not affect proliferation, although there was marked inhibition in migration, invasion and metastasis, arguing against the clinicopathologic study.	('breast cancer', 'Disease', (32, 45))	('rat', 'Species', '10116', (125, 128))	('inhibition', 'NegReg', (108, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('knocking down', 'Var', (9, 22))	('rat', 'Species', '10116', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('migration', 'CPA', (122, 131))	('AEG-1', 'Gene', (23, 28))
403904	33671513	Copy number alterations (CNA) of oncogenes is widely observed in human cancers.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('rat', 'Species', '10116', (16, 19))	('cancers', 'Disease', (71, 78))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
403907	33671513	Kaplan-Meier curves constructed to determine the effect of 8q22 gain on survival revealed significantly (p < 0.05) lower metastasis- and cancer-free survival in breast cancer patients with high 8q22 gain compared with low 8q22 gain, further validating the importance of AEG-1 expression in breast cancer prognosis.	('lower', 'NegReg', (115, 120))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (290, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('breast cancer', 'Disease', 'MESH:D001943', (290, 303))	('breast cancer', 'Disease', (290, 303))	('high 8q22', 'Var', (189, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('gain', 'PosReg', (199, 203))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (297, 303))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Disease', (161, 174))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))
403912	33671513	Microarray analysis of AEG-1-knockdown cells demonstrated that genes such as ALDH3A1 and MET contribute to the multidrug chemoresistance that is seen in AEG-1-positive specimens and it was hypothesized that AEG-1 may promote chemoresistance by improving survival of metastatic lesions.	('rat', 'Species', '10116', (52, 55))	('ALDH3A1', 'Gene', (77, 84))	('MET', 'Gene', (89, 92))	('chemoresistance', 'CPA', (225, 240))	('multidrug chemoresistance', 'MPA', (111, 136))	('survival of metastatic lesions', 'CPA', (254, 284))	('promote', 'PosReg', (217, 224))	('AEG-1', 'Var', (207, 212))	('MET', 'Gene', '79811', (89, 92))	('improving', 'PosReg', (244, 253))	('ALDH3A1', 'Gene', '218', (77, 84))
403913	33671513	In a subsequent study, it was documented that expression of AEG-1 was implicated in progression of precancerous breast lesions into cancerous ones.	('cancerous', 'Disease', 'MESH:D009369', (102, 111))	('precancerous breast lesions', 'Disease', (99, 126))	('expression', 'Var', (46, 56))	('precancerous breast lesions', 'Disease', 'MESH:D001943', (99, 126))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancerous', 'Disease', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancerous', 'Disease', (102, 111))	('cancerous', 'Disease', 'MESH:D009369', (132, 141))	('implicated', 'Reg', (70, 80))	('AEG-1', 'Gene', (60, 65))
403917	33671513	Additionally, AEG-1 overexpression was significantly associated with age (p = 0.042), Ki-67 status (p = 0.036), ER status (p = 0.018) and p53 status (p = 0.001) in invasive cancer patients, which was not observed in other previous studies.	('AEG-1', 'Protein', (14, 19))	('p53', 'Gene', (138, 141))	('ER', 'Gene', '2069', (112, 114))	('p53', 'Gene', '7157', (138, 141))	('invasive cancer', 'Disease', (164, 179))	('overexpression', 'PosReg', (20, 34))	('invasive cancer', 'Disease', 'MESH:D009362', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('associated', 'Reg', (53, 63))	('Ki-67 status', 'Var', (86, 98))	('patients', 'Species', '9606', (180, 188))
403920	33671513	High MVD was observed in 59 cases out of which 42 displayed high AEG-1 expression (p = 0.002) indicating that AEG-1 is associated with increased angiogenesis.	('expression', 'MPA', (71, 81))	('angiogenesis', 'CPA', (145, 157))	('High MVD', 'Disease', 'MESH:D052456', (0, 8))	('High MVD', 'Disease', (0, 8))	('AEG-1', 'Gene', (65, 70))	('AEG-1', 'Var', (110, 115))	('increased', 'PosReg', (135, 144))
403921	33671513	Poor disease-free and overall survivals were associated with high AEG-1 and VEGF levels in Kaplan-Meier 5-year survival analysis.	('AEG-1', 'Protein', (66, 71))	('VEGF', 'Gene', (76, 80))	('high', 'Var', (61, 65))	('Poor', 'NegReg', (0, 4))	('VEGF', 'Gene', '7422', (76, 80))	('overall survivals', 'CPA', (22, 39))	('disease-free', 'CPA', (5, 17))
403925	33671513	AEG-1 levels did not correlate with ER, PR or HER2 levels indicating that AEG-1 might promote all types of breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('HER2', 'Gene', (46, 50))	('ER', 'Gene', '2069', (36, 38))	('breast cancers', 'Phenotype', 'HP:0003002', (107, 121))	('AEG-1', 'Var', (74, 79))	('HER2', 'Gene', '2064', (46, 50))	('ER', 'Gene', '2069', (47, 49))	('PR', 'Gene', '140738', (40, 42))	('promote', 'PosReg', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancers', 'Disease', 'MESH:D001943', (107, 121))	('breast cancers', 'Disease', (107, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
403938	33671513	Overexpression of AEG-1 was found to be associated with poorer overall survival and lower 5-year survival in these patients.	('patients', 'Species', '9606', (115, 123))	('overall', 'MPA', (63, 70))	('AEG-1', 'Gene', (18, 23))	('poorer', 'NegReg', (56, 62))	('5-year survival', 'CPA', (90, 105))	('Overexpression', 'Var', (0, 14))	('lower', 'NegReg', (84, 89))
403944	33671513	Five-year survival curves demonstrated significantly shorter PFS (p < 0.001) as well as OS (p < 0.001) in patients with high expression of AEG-1, compared with those patients with low expression of AEG-1.	('PFS', 'MPA', (61, 64))	('high expression', 'Var', (120, 135))	('rat', 'Species', '10116', (33, 36))	('AEG-1', 'Gene', (139, 144))	('patients', 'Species', '9606', (106, 114))	('shorter', 'NegReg', (53, 60))	('patients', 'Species', '9606', (166, 174))
403945	33671513	In patients with high-expressing AEG-1 tumors, the median PFS was only 30.4 months, whereas PFS was 63.6 months for patients with low-expressing AEG-1 tumors.	('high-expressing', 'Var', (17, 32))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (151, 157))	('patients', 'Species', '9606', (116, 124))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (3, 11))	('AEG-1', 'Gene', (33, 38))	('tumors', 'Disease', (39, 45))
403946	33671513	Univariate analysis demonstrated that high AEG-1 expression was significantly associated with shorter OS (35.55 + 1.46 months, p < 0.0001) and shorter PFS (27.28 + 3.27 months, p < 0.0001).	('PFS', 'MPA', (151, 154))	('high', 'Var', (38, 42))	('expression', 'MPA', (49, 59))	('rat', 'Species', '10116', (27, 30))	('AEG-1', 'Gene', (43, 48))
403947	33671513	Notably, there was a 5-year OS of only 34.25% for patients with high AEG-1 expression.	('AEG-1', 'Gene', (69, 74))	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))
403951	33671513	Among 102 such patients, 77 were categorized as high AEG-1 expression, which was significantly associated with poor prognosis (p < 0.01).	('high', 'Var', (48, 52))	('patients', 'Species', '9606', (15, 23))	('AEG-1', 'Protein', (53, 58))
403952	33671513	Patients with high AEG-1 expression were significantly associated with shorter median survival time in years (1.13056 for high, 2.32156 for low AEG-1 expression) and 3-year survival rates (0.1436 for high, 0.3816 for low AEG-1 expression) when compared to those of low AEG-1 expression (p = 0.0028).	('high', 'Var', (14, 18))	('rat', 'Species', '10116', (182, 185))	('Patients', 'Species', '9606', (0, 8))	('AEG-1', 'Gene', (19, 24))	('0.1436', 'Var', (189, 195))	('shorter', 'NegReg', (71, 78))
403972	33671513	Tissue microarray of 90 cervical cancer samples, including 74 squamous cervical carcinoma and 16 adenocarcinoma) demonstrated that high AEG-1 expression was significantly associated with tumor size (>4 cm, p = 0.010) and metastasis to lymph nodes (p = 0.004).	('AEG-1', 'Protein', (136, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('squamous cervical carcinoma', 'Disease', (62, 89))	('squamous cervical carcinoma', 'Disease', 'MESH:D002294', (62, 89))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('metastasis to lymph nodes', 'CPA', (221, 246))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('rat', 'Species', '10116', (120, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('expression', 'MPA', (142, 152))	('adenocarcinoma', 'Disease', (97, 111))	('associated', 'Reg', (171, 181))	('high', 'Var', (131, 135))
403973	33671513	IHC staining of normal cervical squamous epithelium revealed absence of AEG-1, while AEG-1 staining was positive in cervical intraepithelial neoplasia (CIN) I, II and III samples, indicating AEG-1 expression may necessitate progression of CIN to cervical carcinoma.	('CIN', 'Disease', 'MESH:D007674', (152, 155))	('CIN', 'Disease', (239, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('necessitate', 'Reg', (212, 223))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (125, 150))	('CIN', 'Disease', 'MESH:D007674', (239, 242))	('CIN to cervical carcinoma', 'Disease', (239, 264))	('neoplasia', 'Phenotype', 'HP:0002664', (141, 150))	('neoplasia', 'Disease', 'MESH:D009369', (141, 150))	('AEG-1', 'Var', (191, 196))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (116, 150))	('CIN to cervical carcinoma', 'Disease', 'MESH:D002583', (239, 264))	('CIN', 'Disease', (152, 155))	('neoplasia', 'Disease', (141, 150))
403976	33671513	High AEG-1 expression was associated with tumor size (AUC = 0.826, p = 0.000) and lymph node metastasis (AUC = 0.745, p = 0.004) and showed significantly lower OS (p < 0.05) compared with low AEG-1 expression.	('lower', 'NegReg', (154, 159))	('tumor', 'Disease', (42, 47))	('High', 'Var', (0, 4))	('lymph node metastasis', 'CPA', (82, 103))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('AEG-1', 'Gene', (5, 10))	('expression', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('associated', 'Reg', (26, 36))
403977	33671513	High AEG-1 expression was identified as an independent prognostic factor for poor OS (hazard ratio = 4.021, p = 0.027).	('rat', 'Species', '10116', (93, 96))	('poor OS', 'Disease', (77, 84))	('High', 'Var', (0, 4))	('AEG-1 expression', 'Protein', (5, 21))
403985	33671513	A Pearson correlation found a significant positive association between AEG-1 levels and VEGF and NF-kappaB levels (p = 0) and MVD (p = 0) suggesting that AEG-1 as a potential inducer of angiogenesis which could potentially contribute to invasion and metastasis by cervical cancer.	('angiogenesis', 'CPA', (186, 198))	('inducer', 'PosReg', (175, 182))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('MVD', 'Gene', (126, 129))	('VEGF', 'Gene', (88, 92))	('metastasis', 'CPA', (250, 260))	('positive', 'PosReg', (42, 50))	('contribute', 'Reg', (223, 233))	('AEG-1', 'Var', (154, 159))	('NF-kappaB', 'Gene', '4790', (97, 106))	('invasion', 'CPA', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('VEGF', 'Gene', '7422', (88, 92))	('MVD', 'Gene', '4597', (126, 129))	('NF-kappaB', 'Gene', (97, 106))
403990	33671513	Although not statistically significant, AEG-1 expression showed a trend of higher level in patients with low Gleason score versus in patients with high Gleason score.	('level', 'MPA', (82, 87))	('patients', 'Species', '9606', (91, 99))	('low', 'Var', (105, 108))	('higher', 'PosReg', (75, 81))	('patients', 'Species', '9606', (133, 141))	('expression', 'MPA', (46, 56))	('AEG-1', 'Gene', (40, 45))
404001	33671513	Additionally, recurrence rate, determined by prostate-specific antigen (PSA) levels, was significantly higher in AEG-1-high patients compared to AEG-1-low patients.	('AEG-1-high', 'Var', (113, 123))	('recurrence', 'MPA', (14, 24))	('prostate-specific antigen', 'Gene', '354', (45, 70))	('PSA', 'Gene', (72, 75))	('PSA', 'Gene', '354', (72, 75))	('patients', 'Species', '9606', (155, 163))	('rat', 'Species', '10116', (25, 28))	('higher', 'PosReg', (103, 109))	('prostate-specific antigen', 'Gene', (45, 70))	('patients', 'Species', '9606', (124, 132))
404003	33671513	Interestingly, in this study, the authors showed that knocking out AEG-1 in the transgenic adenocarcinoma of mouse prostate (TRAMP) model prolonged tumor latency and abrogated tumor progression and metastasis further establishing the importance of AEG-1 in prostate cancer.	('abrogated', 'NegReg', (166, 175))	('prostate cancer', 'Phenotype', 'HP:0012125', (257, 272))	('prostate cancer', 'Disease', (257, 272))	('AEG-1', 'Gene', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('knocking out', 'Var', (54, 66))	('tumor', 'Disease', (176, 181))	('adenocarcinoma', 'Disease', (91, 105))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('mouse', 'Species', '10090', (109, 114))	('prolonged', 'PosReg', (138, 147))	('TRAMP', 'Gene', (125, 130))	('TRAMP', 'Gene', '85030', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('tumor', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('prostate cancer', 'Disease', 'MESH:D011471', (257, 272))
404006	33671513	It was identified that high AEG-1 staining index was associated with tumor progression and poor survival status in all types of GI cancers thus establishing the importance of AEG-1 as a prognostic marker for GI cancers.	('AEG-1', 'Protein', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('high', 'Var', (23, 27))	('GI cancers', 'Disease', 'MESH:D009369', (208, 218))	('GI cancer', 'Phenotype', 'HP:0007378', (128, 137))	('tumor', 'Disease', (69, 74))	('GI cancers', 'Disease', 'MESH:D009369', (128, 138))	('GI cancer', 'Phenotype', 'HP:0007378', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('GI cancers', 'Disease', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('GI cancers', 'Disease', (208, 218))
404050	33671513	Both nuclear and cytoplasmic AEG-1 expression significantly correlated with phosphorylated NF-kappaB (Ser 536), p73 and Rad50 in primary tumors.	('tumors', 'Disease', (137, 143))	('NF-kappaB', 'Gene', '4790', (91, 100))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('NF-kappaB', 'Gene', (91, 100))	('Ser 536', 'Var', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('Rad50', 'Gene', '10111', (120, 125))	('correlated', 'Reg', (60, 70))	('AEG-1', 'Gene', (29, 34))	('Rad50', 'Gene', (120, 125))	('p73', 'Gene', '7161', (112, 115))	('p73', 'Gene', (112, 115))	('Ser', 'Chemical', 'MESH:D012694', (102, 105))
404051	33671513	It was hypothesized that AEG-1 might be involved in p73-mediated DNA damage-induced apoptosis since cytoplasmic:but not nuclear:AEG-1 associated with increased apoptosis.	('apoptosis', 'CPA', (160, 169))	('DN', 'Chemical', '-', (65, 67))	('p73', 'Gene', '7161', (52, 55))	('AEG-1', 'Var', (128, 133))	('p73', 'Gene', (52, 55))	('increased', 'PosReg', (150, 159))
404053	33671513	Rectal cancer patients showed higher AEG-1 expression than colon cancer patients (p = 0.047) and in a follow-up study of 158 rectal cancer patients treated with radiotherapy (RT), the authors documented that high AEG-1 expression in primary tumors independently correlated with higher risk of distant recurrence (p = 0.009) and worse DFS (p = 0.007), indicating that AEG-1 might be a marker to identify patients who might develop distant relapse.	('high', 'Var', (208, 212))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('patients', 'Species', '9606', (14, 22))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('patients', 'Species', '9606', (403, 411))	('higher', 'PosReg', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (7, 13))	('AEG-1', 'Protein', (213, 218))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('Rectal cancer', 'Phenotype', 'HP:0100743', (0, 13))	('AEG-1 expression', 'MPA', (37, 53))	('colon cancer', 'Disease', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('patients', 'Species', '9606', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('cancer', 'Disease', (132, 138))	('expression', 'MPA', (219, 229))	('tumors', 'Disease', (241, 247))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('distant recurrence', 'CPA', (293, 311))	('patients', 'Species', '9606', (72, 80))
404061	33671513	AEG-1 and SND1 co-expression negatively correlated with postoperative overall survival and positively correlated with mortality (p = 0.009) in cox multivariate analysis, strongly indicating that AEG-1 and SND1 can serve as prognostic factors for colon cancer.	('SND1', 'Gene', (205, 209))	('colon cancer', 'Disease', 'MESH:D015179', (246, 258))	('colon cancer', 'Disease', (246, 258))	('mortality', 'Disease', (118, 127))	('SND1', 'Gene', '27044', (205, 209))	('negatively', 'NegReg', (29, 39))	('correlated', 'Reg', (102, 112))	('mortality', 'Disease', 'MESH:D003643', (118, 127))	('SND1', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('AEG-1', 'Var', (195, 200))	('rat', 'Species', '10116', (63, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (246, 258))	('SND1', 'Gene', '27044', (10, 14))	('co-expression', 'Var', (15, 28))	('AEG-1', 'Gene', (0, 5))
404069	33671513	This A>C SNP alters AP2 binding site in AEG-1 promoter and was suggested to be associated with HCC susceptibility in Iranian patients.	('A>C SNP', 'Var', (5, 12))	('AP2', 'Gene', '7020', (20, 23))	('associated', 'Reg', (79, 89))	('AP2', 'Gene', (20, 23))	('HCC', 'Disease', (95, 98))	('alters', 'Reg', (13, 19))	('patients', 'Species', '9606', (125, 133))
404074	33671513	Genomic amplification of AEG-1 in HCC patients was shown in additional studies.	('Genomic amplification', 'Var', (0, 21))	('AEG-1', 'Gene', (25, 30))	('HCC', 'Disease', (34, 37))	('patients', 'Species', '9606', (38, 46))
404078	33671513	Additionally, the 1-, 3- and 5-year OS in high AEG-1-expressing group were significantly lower than those in low AEG-1-expressing group (83.0% vs. 89.7%, 52.0% vs. 75.3%, 37.4% vs. 66.9%, respectively); and the 1-, 3- and 5-year cumulative recurrence rates were markedly higher in high AEG-1-expressing group than those in low AEG-1-expressing group (32.4% vs. 16.8%, 61.2% vs. 38.2%, 70.7% vs. 47.8%, respectively).	('lower', 'NegReg', (89, 94))	('high AEG-1-expressing', 'Var', (281, 302))	('high AEG-1-expressing', 'Var', (42, 63))	('higher', 'PosReg', (271, 277))	('rat', 'Species', '10116', (251, 254))
404091	33671513	High AEG-1 levels were associated with worse OS and RFS (p < 0.001 and p = 0.01, respectively) and cox regression analysis identified that TNM stage, surgery margin and high AEG-1 expression were independent factors for OS and RFS in PCCA.	('high', 'Var', (169, 173))	('TNM', 'Gene', (139, 142))	('PCCA', 'Disease', (234, 238))	('RFS', 'Disease', (227, 230))	('RFS', 'Disease', (52, 55))	('TNM', 'Gene', '10178', (139, 142))	('RFS', 'Disease', 'MESH:D005198', (227, 230))	('RFS', 'Disease', 'MESH:D005198', (52, 55))
404108	33671513	Average survival time in EphA7 and AEG-1 positive cases was 8.1 months versus 13.2 months in EphA7 and AEG-1 negative cases (p < 0.001).	('EphA7', 'Gene', (25, 30))	('EphA7', 'Gene', '2045', (25, 30))	('EphA7', 'Gene', '2045', (93, 98))	('positive', 'Var', (41, 49))	('AEG-1', 'Gene', (35, 40))	('EphA7', 'Gene', (93, 98))
404114	33671513	Additionally, in 105 PDAC patients, 98.09% showed AEG-1 expression by IHC which was associated with advanced clinical stage (p = 0.004), T (p = 0.006), N (p = 0.003) and M (p = 0.007) classifications, lymph node involvement (p = 0.003) and distant metastasis (p = 0.007).	('lymph node involvement', 'CPA', (201, 223))	('IHC', 'Gene', (70, 73))	('patients', 'Species', '9606', (26, 34))	('distant metastasis', 'CPA', (240, 258))	('associated', 'Reg', (84, 94))	('AEG-1 expression', 'Var', (50, 66))
404120	33671513	IHC analysis in 102 RCC patients that included 86 clear cell carcinomas, 10 papillary carcinomas, 3 chromophobe cell types and three cases of cancer of the collecting duct of Bellini as well as 6 matched lymph node metastases and seven cases of neoplastic embolus in the renal vein showed high AEG-1 expression in 96 cases, especially in lymph node metastases and neoplastic emboli with weak AEG-1 expression in normal tubular epithelium and no expression in normal glomeruli.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('carcinomas', 'Disease', (86, 96))	('carcinomas', 'Disease', (61, 71))	('RCC', 'Disease', (20, 23))	('neoplastic embolus', 'Disease', (245, 263))	('metastases', 'Disease', 'MESH:D009362', (215, 225))	('cell carcinoma', 'Disease', (56, 70))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('metastases', 'Disease', 'MESH:D009362', (349, 359))	('carcinomas', 'Disease', 'MESH:D009369', (86, 96))	('cancer', 'Disease', (142, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('metastases', 'Disease', (215, 225))	('metastases', 'Disease', (349, 359))	('carcinomas', 'Disease', 'MESH:D009369', (61, 71))	('neoplastic embolus', 'Disease', 'MESH:D004617', (245, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('papillary carcinomas', 'Disease', 'MESH:D002291', (76, 96))	('cell carcinoma', 'Disease', 'MESH:C538614', (56, 70))	('papillary carcinomas', 'Disease', (76, 96))	('patients', 'Species', '9606', (24, 32))	('AEG-1', 'Var', (294, 299))
404122	33671513	The cumulative 5-year survival rate was 91.3% and 52.4% in low and high AEG-1 expression groups, respectively.	('high', 'Var', (67, 71))	('AEG-1', 'Protein', (72, 77))	('rat', 'Species', '10116', (31, 34))
404123	33671513	The mean survival time was 76.98 and 60.94 months in low and high AEG-1 expression groups, respectively, indicating a potential role of AEG-1 in regulating advanced progression of RCC.	('high', 'Var', (61, 65))	('AEG-1', 'Gene', (66, 71))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))
404125	33671513	Similarly, p53 levels correlated with tumor diameter (p = 0.028), renal sinal invasion (p = 0.05) and Fuhrman grade (p = 0.026) indicating that AEG-1 and p53 might serve as prognostic markers for RCC.	('p53', 'Gene', (11, 14))	('tumor', 'Disease', (38, 43))	('p53', 'Gene', '7157', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Fuhrman grade', 'CPA', (102, 115))	('renal sinal invasion', 'CPA', (66, 86))	('correlated', 'Reg', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('AEG-1', 'Var', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RCC', 'Disease', (196, 199))
404132	33671513	In a multivariate survival analysis, patients with high SI (SI > 6) had a shorter OS compared to patients with low SI (SI < 6) (p < 0.001).	('shorter', 'NegReg', (74, 81))	('high SI (SI > 6', 'Var', (51, 66))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (97, 105))
404152	33671513	These patients were also classified into those who had either high- or low-AEG-1 expression.	('low-AEG-1', 'NegReg', (71, 80))	('patients', 'Species', '9606', (6, 14))	('high-', 'Var', (62, 67))
404155	33671513	IHC analysis of 204 tissues, including 32 normal brain tissues, 80 Low-malignant astrocytomas (LMAs) and 92 High-Malignant astrocytomas (HMAs) showed AEG-1 positivity in 74.4% tumor samples which significantly correlated with histological grades (p < 0.001).	('correlated', 'Reg', (210, 220))	('High-Malignant astrocytomas', 'Disease', (108, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('astrocytoma', 'Phenotype', 'HP:0009592', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('High-Malignant astrocytomas', 'Disease', 'MESH:D020339', (108, 135))	('tumor', 'Disease', (176, 181))	('Low-malignant astrocytomas', 'Disease', 'MESH:D020339', (67, 93))	('Low-malignant astrocytomas', 'Disease', (67, 93))	('AEG-1 positivity', 'Var', (150, 166))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
404160	33671513	IHC analysis of 75 oligodendroglioma patients, including 52 well-differentiated and 23 anaplatic tumors, showed AEG-1 expression in 68% cases with correlated with tumor grade and Ki-67 levels (p = 0) but not with age and sex.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('AEG-1', 'Var', (112, 117))	('tumor', 'Disease', (97, 102))	('oligodendroglioma', 'Disease', (19, 36))	('Ki-67 levels', 'MPA', (179, 191))	('tumor', 'Disease', (163, 168))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('oligodendroglioma', 'Disease', 'MESH:D009837', (19, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
404161	33671513	In high AEG-1 expressing patients, median survival time was 28 months (95% confidence interval, 25.54-30.46) and cumulative 3-year survival rate was 19.69%, while in low AEG-1 expressing patients these values were 57 months (95% confidence interval, 46.37-67.63) (p = 0) and 88.05%, respectively.	('patients', 'Species', '9606', (187, 195))	('high', 'Var', (3, 7))	('AEG-1', 'Protein', (8, 13))	('patients', 'Species', '9606', (25, 33))	('rat', 'Species', '10116', (140, 143))
404169	33671513	Although in clinical stage I-II no significant difference between low or high AEG-1 levels and OS was observed, in stages III-IV high AEG-1 levels correlated with poor survival and patients with distant metastasis and high AEG-1 levels showed shorter OS compared to patients without distant metastases.	('poor', 'NegReg', (163, 167))	('patients', 'Species', '9606', (266, 274))	('high', 'Var', (129, 133))	('high', 'Var', (218, 222))	('AEG-1', 'MPA', (134, 139))	('metastases', 'Disease', (291, 301))	('distant metastasis', 'CPA', (195, 213))	('patients', 'Species', '9606', (181, 189))	('metastases', 'Disease', 'MESH:D009362', (291, 301))	('shorter', 'NegReg', (243, 250))
404174	33671513	AEG-1 is also targeted by tumor suppressor miR-30e-5p, which is downregulated in HNSCC, and low levels of miR-30e-5p correlated with poor overall survival (p < 0.05).	('miR-30e-5p', 'Chemical', '-', (43, 53))	('poor', 'NegReg', (133, 137))	('overall', 'MPA', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('low', 'Var', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('miR-30e-5p', 'Chemical', '-', (106, 116))
404183	33671513	Additionally, 5-year survival rate in high AEG-1 expressing TSCC patients (16.98%, 95% CI: 32.04-50.13%) was significantly lower than low AEG-1 expressing patients (36.73%, 95% CI: 58.68-73.08%).	('high AEG-1 expressing', 'Var', (38, 59))	('lower', 'NegReg', (123, 128))	('rat', 'Species', '10116', (30, 33))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (155, 163))	('TSCC', 'Disease', (60, 64))
404186	33671513	IHC analysis of 62 osteosarcoma patients and 20 normal bone samples revealed 82.3% AEG-1 positivity in cancer samples out of which 32 cases showed high expression and barely detectable expression in normal bone.	('positivity', 'Var', (89, 99))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('AEG-1', 'Gene', (83, 88))	('osteosarcoma', 'Disease', 'MESH:D012516', (19, 31))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))	('cancer', 'Disease', (103, 109))	('osteosarcoma', 'Disease', (19, 31))	('expression', 'MPA', (152, 162))
404192	33671513	Additionally, IHC analysis of samples from 30 DLBCL patients and 15 reactive hyperplasia of the lymph nodes showed AEG-1 positivity with variable levels of expression in 76.67% DLBCL cases while little to no AEG-1 expression was detected in the controls.	('DLBCL', 'Disease', (177, 182))	('positivity', 'Var', (121, 131))	('AEG-1', 'Gene', (115, 120))	('hyperplasia', 'Disease', (77, 88))	('hyperplasia of the lymph', 'Phenotype', 'HP:0002716', (77, 101))	('hyperplasia', 'Disease', 'MESH:D006965', (77, 88))	('patients', 'Species', '9606', (52, 60))
404202	33671513	At titers of >=1:50 anti-AEG-1 antibody was detected in 49% of these patients, including 45% breast cancer, 50% HCC, 49% colorectal cancer, 45% lung cancer and 49% gastric cancer patients, with none of 230 normal individuals displaying positivity (p < 0.01).	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('anti-AEG-1', 'Var', (20, 30))	('HCC', 'Disease', (112, 115))	('detected', 'Reg', (44, 52))	('colorectal cancer', 'Disease', (121, 138))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('patients', 'Species', '9606', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('patients', 'Species', '9606', (179, 187))	('gastric cancer', 'Disease', (164, 178))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
404207	33671513	Even though AEG-1 is an established diagnostic/prognostic marker for cancer, its use is limited by the availability of tumor biopsy samples and as such anti-AEG-1 antibody might serve as an important surrogate for AEG-1.	('tumor', 'Disease', (119, 124))	('anti-AEG-1', 'Var', (152, 162))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Disease', (69, 75))
404219	33671513	The present study was supported in part by The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant 1R01DK107451-01A1, National Cancer Institute (NCI) Grants 1R01CA230561-01A1, 1R01CA240004-01 and 1R01CA244993-01, and Department of Defense (DOD) Grant CA170048.	('Diabetes', 'Disease', (69, 77))	('R01CA230561-01A1', 'CellLine', 'CVCL:X698', (185, 201))	('Cancer', 'Disease', (154, 160))	('1R01CA230561-01A1', 'Var', (184, 201))	('Cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('R01CA244993-01', 'CellLine', 'CVCL:9726', (224, 238))	('Kidney Diseases', 'Disease', 'MESH:D007674', (96, 111))	('1R01CA240004-01', 'Var', (203, 218))	('Diabetes', 'Disease', 'MESH:D003920', (69, 77))	('1R01CA244993-01', 'Var', (223, 238))	('Kidney Diseases', 'Phenotype', 'HP:0000112', (96, 111))	('Kidney Diseases', 'Disease', (96, 111))
404224	31367615	The simulation and inactivation of the central nervous, sympathetic, and parasympathetic nervous systems, or changes in the innervation of the GI tract might contribute to a higher incidence of GI cancers.	('changes', 'Reg', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('GI cancers', 'Disease', 'MESH:D009369', (194, 204))	('GI cancer', 'Phenotype', 'HP:0007378', (194, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('inactivation', 'Var', (19, 31))	('GI cancers', 'Disease', (194, 204))
404238	31367615	This neurobiological conclusion of cancer etiopathogenesis was based on several findings, including nerve infiltration of tumor tissues, the effects of stimulation or lesions of the CNS, and the effects of neurotransmitters or neuropep-tides on tumor incidence and progression.	('effects', 'Reg', (195, 202))	('lesions', 'Var', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (245, 250))	('lesions of the CNS', 'Phenotype', 'HP:0100006', (167, 185))	('tumor', 'Disease', (122, 127))	('cancer', 'Disease', (35, 41))
404251	31367615	Many studies have shown that several stimulations and lesions of the CNS can promote proliferation and metastasis of cancer cells by regulating specific immune functions and electrical activity.	('metastasis of cancer', 'Disease', (103, 123))	('promote', 'PosReg', (77, 84))	('metastasis of cancer', 'Disease', 'MESH:D009362', (103, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('regulating', 'Reg', (133, 143))	('electrical activity', 'MPA', (174, 193))	('specific immune functions', 'MPA', (144, 169))	('lesions of the CNS', 'Phenotype', 'HP:0100006', (54, 72))	('proliferation', 'CPA', (85, 98))	('lesions', 'Var', (54, 61))
404256	31367615	The inactivation of sensory neurons induced by capsaicin might promote the invasion and metastasis of tumor cells.	('inactivation', 'Var', (4, 16))	('sensory neurons', 'Gene', (20, 35))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('promote', 'PosReg', (63, 70))	('capsaicin', 'Chemical', 'MESH:D002211', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
404261	31367615	Age-related changes in brain innervation of the GI tract might increase inflammatory reaction in the gut and lead to a higher incidence of GI cancers.	('GI cancers', 'Disease', (139, 149))	('increase', 'PosReg', (63, 71))	('lead', 'Reg', (109, 113))	('GI cancer', 'Phenotype', 'HP:0007378', (139, 148))	('changes', 'Var', (12, 19))	('increase inflammatory reaction in the gut', 'Phenotype', 'HP:0002037', (63, 104))	('GI cancers', 'Disease', 'MESH:D009369', (139, 149))	('increase inflammatory reaction', 'Phenotype', 'HP:0012649', (63, 93))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('inflammatory reaction', 'CPA', (72, 93))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('brain innervation', 'CPA', (23, 40))
404267	31367615	Third, the adminis-tration of 6-OHDA could result in selective damage to catecholaminergic neurons in the periphe-ral nervous system and CNS.	('damage', 'NegReg', (63, 69))	('6-OHDA', 'Chemical', 'MESH:D016627', (30, 36))	('catecholamine', 'Chemical', 'MESH:D002395', (73, 86))	('catecholaminergic neurons', 'MPA', (73, 98))	('6-OHDA', 'Var', (30, 36))
404272	31367615	Several other studies revealed that the inactivation of the vagus nerve substantially promoted liver, kidney, and lung cancer metastasis by upregulating the levels of substance P (SP).	('substance P', 'Gene', '6863', (167, 178))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('kidney', 'CPA', (102, 108))	('upregulating', 'PosReg', (140, 152))	('liver', 'Disease', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('substance P', 'Gene', (167, 178))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('promoted', 'PosReg', (86, 94))	('inactivation', 'Var', (40, 52))	('SP', 'Gene', '6863', (180, 182))
404287	31367615	Inhibition of the postganglionic parasym-pathetic fiber can significantly decrease the proliferation and metastasis of HT-29 colon cancer cells.	('decrease', 'NegReg', (74, 82))	('proliferation', 'CPA', (87, 100))	('HT-29 colon cancer', 'Disease', (119, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('metastasis', 'CPA', (105, 115))	('Inhibition', 'Var', (0, 10))	('HT-29 colon cancer', 'Disease', 'MESH:D015179', (119, 137))	('colon cancer', 'Phenotype', 'HP:0003003', (125, 137))
404314	31367615	It has been demonstrated that mAChR can increase the migration and invasion of CRC cells by transactivation of the EGFR-ERK pathway.	('transactivation', 'Var', (92, 107))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('mAChR', 'Var', (30, 35))	('EGFR', 'Gene', '1956', (115, 119))	('increase', 'PosReg', (40, 48))	('ERK', 'Gene', '5594', (120, 123))	('migration', 'CPA', (53, 62))	('EGFR', 'Gene', (115, 119))	('ERK', 'Gene', (120, 123))	('invasion of CRC cells', 'CPA', (67, 88))
404315	31367615	The demon-stration that acetylcholine is involved in epithelial mesenchymal transition (EMT) and increases the expression of several markers via the M3 muscarinic receptor (M3R) has provided an insight into the mechanisms of gastric cancer growth and metastasis and will inform the discovery of new targets for gastric cancer treatment.	('M3R', 'Gene', '1131', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('acetylcholine', 'Chemical', 'MESH:D000109', (24, 37))	('gastric cancer', 'Disease', (225, 239))	('increases', 'PosReg', (97, 106))	('M3 muscarinic receptor', 'Gene', '1131', (149, 171))	('gastric cancer', 'Disease', 'MESH:D013274', (225, 239))	('involved', 'Reg', (41, 49))	('gastric cancer', 'Disease', (311, 325))	('expression', 'MPA', (111, 121))	('M3 muscarinic receptor', 'Gene', (149, 171))	('gastric cancer', 'Disease', 'MESH:D013274', (311, 325))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('gastric cancer', 'Phenotype', 'HP:0012126', (225, 239))	('M3R', 'Gene', (173, 176))	('epithelial mesenchymal transition', 'CPA', (53, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (311, 325))	('acetylcholine', 'Var', (24, 37))
404327	31367615	5-HT also promoted angiogenesis, but not proliferation, in a colorectal tumor animal model.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('angiogenesis', 'CPA', (19, 31))	('5-HT', 'Chemical', 'MESH:D012701', (0, 4))	('promoted', 'PosReg', (10, 18))	('colorectal tumor', 'Disease', (61, 77))	('5-HT', 'Var', (0, 4))	('colorectal tumor', 'Disease', 'MESH:D015179', (61, 77))
404330	31367615	Interestingly, Vicaut et al reported a direct mitogenic effect of high doses of 5-HT on tumor cells in athymic nude mice, whereas low doses of 5-HT inhibited tumor growth by decreasing the oxygen tension and blood supply to the tumors.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('5-HT', 'Chemical', 'MESH:D012701', (143, 147))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('5-HT', 'Chemical', 'MESH:D012701', (80, 84))	('5-HT', 'Var', (80, 84))	('nude mice', 'Species', '10090', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('oxygen', 'Chemical', 'MESH:D010100', (189, 195))	('tumors', 'Disease', (228, 234))	('blood', 'CPA', (208, 213))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mitogenic effect', 'MPA', (46, 62))	('oxygen tension', 'MPA', (189, 203))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('tumor', 'Disease', (158, 163))	('decreasing', 'NegReg', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (228, 233))	('inhibited', 'NegReg', (148, 157))
404387	31367615	BDNF and TrkB knockdown significantly decreased the rates of growth and proliferation, and increa-sed the apoptosis rate of colon cancer cells.	('colon cancer', 'Disease', (124, 136))	('decreased', 'NegReg', (38, 47))	('BDNF', 'Gene', '627', (0, 4))	('TrkB', 'Gene', (9, 13))	('apoptosis rate', 'CPA', (106, 120))	('BDNF', 'Gene', (0, 4))	('colon cancer', 'Phenotype', 'HP:0003003', (124, 136))	('knockdown', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colon cancer', 'Disease', 'MESH:D015179', (124, 136))	('TrkB', 'Gene', '4915', (9, 13))
404391	31367615	It was further observed that the use of antibodies blocking BDNF/TrkB resulted in tumor growth inhibition, characterized by an increase in cell apoptosis, suggesting that BDNF could contribute to cancer cell survival and serve as a prospective target mole-cule to inhibit tumor growth.	('BDNF', 'Gene', (60, 64))	('contribute', 'PosReg', (182, 192))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('TrkB', 'Gene', '4915', (65, 69))	('BDNF', 'Gene', (171, 175))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('BDNF', 'Gene', '627', (60, 64))	('TrkB', 'Gene', (65, 69))	('BDNF', 'Gene', '627', (171, 175))	('antibodies', 'Var', (40, 50))	('mole', 'Phenotype', 'HP:0003764', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Disease', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('increase', 'PosReg', (127, 135))	('cell apoptosis', 'CPA', (139, 153))
404410	31367615	However, some studies have shown that the precursor of NGF (proNGF) to p75NTR can decrease cell survival and promote apoptosis.	('promote', 'PosReg', (109, 116))	('decrease', 'NegReg', (82, 90))	('NGF', 'Var', (55, 58))	('p75NTR', 'Gene', (71, 77))	('p75NTR', 'Gene', '4804', (71, 77))	('apoptosis', 'CPA', (117, 126))	('cell survival', 'CPA', (91, 104))
404411	31367615	In one study, NGF significantly increased the anti-proliferative effect of 5-fluorouracil.	('NGF', 'Var', (14, 17))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (75, 89))	('anti-proliferative effect of 5-fluorouracil', 'MPA', (46, 89))	('increased', 'PosReg', (32, 41))
404416	31367615	Recently, mouse studies have demonstrated that NGF can significantly induce sprouting of sensory and sympathetic nerve fibers in bone metastases.	('NGF', 'Var', (47, 50))	('mouse', 'Species', '10090', (10, 15))	('bone metastases', 'Disease', (129, 144))	('induce', 'Reg', (69, 75))	('bone metastases', 'Disease', 'MESH:D009362', (129, 144))
404432	31367615	Phosphorylated IGF1R can stimulate the Ras-Raf-MEK-MAPK pathway, which regulates gene transcription and cellular metabolism, resulting in cell growth and survival.	('Phosphorylated', 'Var', (0, 14))	('MEK', 'Gene', (47, 50))	('MEK', 'Gene', '5609', (47, 50))	('cell growth', 'CPA', (138, 149))	('IGF1R', 'Gene', (15, 20))	('Raf', 'Gene', (43, 46))	('IGF1R', 'Gene', '3480', (15, 20))	('survival', 'CPA', (154, 162))	('cellular metabolism', 'MPA', (104, 123))	('stimulate', 'PosReg', (25, 34))	('Raf', 'Gene', '22882', (43, 46))	('regulates gene transcription', 'MPA', (71, 99))
404435	31367615	Dysregulation of the FGF/FGFR signaling pathway has been associated with many developmental disorders and with cancer.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('developmental disorders', 'Disease', (78, 101))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('developmental disorders', 'Disease', 'MESH:D002658', (78, 101))	('FGF/FGFR signaling pathway', 'Pathway', (21, 47))	('associated', 'Reg', (57, 67))
404436	31367615	Recent evidence suggests that any abnormalities in FGFs or FGFRs may promote multiple steps of cancer progression (proliferation, survival, tumor angiogenesis, and epithelial to mesenchymal transition) by gene amplification, chromosomal translocation, and mutations.	('FGFRs', 'Gene', (59, 64))	('survival', 'CPA', (130, 138))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Disease', (95, 101))	('FGFs', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('gene amplification', 'Var', (205, 223))	('mutations', 'Var', (256, 265))	('promote', 'PosReg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('abnormalities', 'Var', (34, 47))	('chromosomal translocation', 'Var', (225, 250))	('tumor', 'Disease', (140, 145))
404439	31367615	FGFR1/2 amplification remained a significant independent risk factor for poor disease-free survival and overall survival in poorly differentiated adenocarcinoma of the stomach.	('adenocarcinoma', 'Disease', 'MESH:D000230', (146, 160))	('amplification', 'Var', (8, 21))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('adenocarcinoma of the stomach', 'Phenotype', 'HP:0006753', (146, 175))	('poor', 'NegReg', (73, 77))	('adenocarcinoma', 'Disease', (146, 160))	('disease-free survival', 'CPA', (78, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
404441	31367615	High FGFR4 expression was positively correlated with the depth of invasion, lymph node metastasis, pathological stage, and distant metastasis in both DGC and IGC, while the elevated expression of FGFR1 and 2 was correlated with a poor outcome and survival in DGC.	('lymph node metastasis', 'CPA', (76, 97))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('FGFR1 and 2', 'Gene', '2260;2263', (196, 207))	('correlated', 'Reg', (37, 47))	('FGFR4', 'Gene', '2264', (5, 10))	('FGFR4', 'Gene', (5, 10))	('distant metastasis', 'CPA', (123, 141))	('elevated expression of FGFR1', 'Phenotype', 'HP:0030269', (173, 201))	('depth of invasion', 'CPA', (57, 74))
404444	31367615	The largest genomic analysis carried out to date revealed that FGFR2 amplification is always accompanied by deletion of the coding exon located proximal to the C-terminus.	('accompanied by', 'Reg', (93, 107))	('amplification', 'MPA', (69, 82))	('FGFR2', 'Gene', (63, 68))	('FGFR2', 'Gene', '2263', (63, 68))	('deletion', 'Var', (108, 116))
404447	31367615	FGFR2 silencing significantly inhibited the growth and survival of Snu-16 (gastric cancer cell line) and resulted in tumor growth regression in vivo.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('gastric cancer', 'Disease', (75, 89))	('inhibited', 'NegReg', (30, 39))	('tumor', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('survival', 'CPA', (55, 63))	('regression', 'NegReg', (130, 140))	('FGFR2', 'Gene', '2263', (0, 5))	('FGFR2', 'Gene', (0, 5))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('growth', 'CPA', (44, 50))	('silencing', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
404455	31367615	The simulation and inactivation of the CNS and the sympathetic and parasympathetic nervous systems, or changes in the innervation of the GI tract might alter the immunomodulatory influences of the vagal nerve, which could promote inflammatory processes and contribute to a higher incidence of cancers of the GI tract.	('cancers of the GI tract', 'Disease', (293, 316))	('inflammatory processes', 'CPA', (230, 252))	('promote', 'PosReg', (222, 229))	('cancers of the GI tract', 'Disease', 'MESH:D004067', (293, 316))	('cancers of the GI tract', 'Phenotype', 'HP:0007378', (293, 316))	('inactivation', 'Var', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('immunomodulatory influences of the vagal nerve', 'Phenotype', 'HP:0002886', (162, 208))	('immunomodulatory influences', 'MPA', (162, 189))	('alter', 'Reg', (152, 157))	('changes', 'Var', (103, 110))	('cancers', 'Phenotype', 'HP:0002664', (293, 300))
404456	31367615	Modulation of the neurotransmitters and the stimulation of signal transmission between nerves and tumor cells (e.g., electrical stimulation of nerves innervating tumors and beta-blockers) might promote or inhibit GI cancer progression.	('Modulation', 'Var', (0, 10))	('GI cancer', 'Phenotype', 'HP:0007378', (213, 222))	('promote', 'PosReg', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('inhibit', 'NegReg', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('GI cancer', 'Disease', (213, 222))	('electrical', 'Var', (117, 127))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('GI cancer', 'Disease', 'MESH:D009369', (213, 222))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Disease', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
404458	31367615	Therefore, a better understanding of neurotransmitter or neuropeptide receptor activators, inhibitors, or antagonists for the treatment of cancer, together with modifications of corresponding receptors, may represent a promising therapeutic strategy for cancer in the future.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (254, 260))	('modifications', 'Var', (161, 174))	('cancer', 'Disease', (139, 145))
404491	30867761	According to the stratification analysis based on difference factors, it was found that the pulmonary infection rate after minimally invasive esophagectomy was obviously higher in patients aged >=60 years, with a long-term smoking history and vital capacity <1100 ml, and complicated with coronary heart disease/diabetes mellitus/diseases of respiratory system than that in patients aged <60 years, without a long-term smoking history, with vital capacity >=1100 ml, and without coronary heart disease/diabetes mellitus/diseases of respiratory system (P<0.05) (Table III).	('diseases of respiratory system', 'Disease', 'MESH:D015619', (520, 550))	('diseases of respiratory system', 'Disease', 'MESH:D015619', (330, 360))	('pulmonary infection', 'Phenotype', 'HP:0006532', (92, 111))	('diabetes mellitus/diseases', 'Disease', 'MESH:D003920', (502, 528))	('patients', 'Species', '9606', (180, 188))	('coronary heart disease', 'Disease', (479, 501))	('coronary heart disease', 'Phenotype', 'HP:0001677', (479, 501))	('diabetes mellitus/diseases', 'Disease', (312, 338))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (312, 329))	('pulmonary infection', 'Disease', (92, 111))	('diabetes mellitus/diseases', 'Disease', (502, 528))	('coronary heart disease', 'Disease', (289, 311))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (502, 519))	('coronary heart disease', 'Phenotype', 'HP:0001677', (289, 311))	('coronary heart disease', 'Disease', 'MESH:D003324', (479, 501))	('diseases of respiratory system', 'Disease', (330, 360))	('diseases of respiratory system', 'Disease', (520, 550))	('higher', 'PosReg', (170, 176))	('coronary heart disease', 'Disease', 'MESH:D003324', (289, 311))	('<1100', 'Var', (258, 263))	('pulmonary infection', 'Disease', 'MESH:D008171', (92, 111))	('patients', 'Species', '9606', (374, 382))	('diabetes mellitus/diseases', 'Disease', 'MESH:D003920', (312, 338))
404535	29675094	Overexpression of eIF3e was associated with deep tumor depth, lymph nodes metastasis, and advanced TNM stage.	('advanced TNM stage', 'CPA', (90, 108))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('eIF3e', 'Gene', (18, 23))	('associated', 'Reg', (28, 38))	('deep tumor', 'Disease', 'MESH:D057887', (44, 54))	('deep tumor', 'Disease', (44, 54))	('Overexpression', 'Var', (0, 14))	('lymph nodes metastasis', 'CPA', (62, 84))
404536	29675094	Importantly, the patients with high eIF3e expression suffered shorter overall and disease-free survival.	('high', 'Var', (31, 35))	('patients', 'Species', '9606', (17, 25))	('shorter', 'NegReg', (62, 69))	('eIF3e', 'Protein', (36, 41))
404549	29675094	On the contrary, in glioblastoma and colon cancer, eIF3e was demonstrated to overexpress and facilitate the tumor progression.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('colon cancer', 'Phenotype', 'HP:0003003', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('colon cancer', 'Disease', 'MESH:D015179', (37, 49))	('glioblastoma', 'Disease', (20, 32))	('facilitate', 'PosReg', (93, 103))	('colon cancer', 'Disease', (37, 49))	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('tumor', 'Disease', (108, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('eIF3e', 'Var', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('overexpress', 'PosReg', (77, 88))
404551	29675094	We demonstrated that eIF3e was up-regulated in ESCC tissues and high level eIF3e negatively correlated with the survival of patients.	('up-regulated', 'PosReg', (31, 43))	('survival', 'CPA', (112, 120))	('patients', 'Species', '9606', (124, 132))	('eIF3e', 'Gene', (21, 26))	('correlated', 'Reg', (92, 102))	('ESCC', 'Disease', (47, 51))	('negatively', 'NegReg', (81, 91))	('high level', 'Var', (64, 74))	('eIF3e', 'Gene', (75, 80))
404567	29675094	As shown in Table 1, high eIF3e expression was correlated with deeper tumor depth (p=0.032), lymph nodes metastasis (p=0.023) and more advanced TNM stage (p=0.002), positively.	('eIF3e', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('high', 'Var', (21, 25))	('deeper tumor depth', 'Disease', 'MESH:D007222', (63, 81))	('deeper tumor depth', 'Disease', (63, 81))	('lymph nodes metastasis', 'CPA', (93, 115))	('expression', 'MPA', (32, 42))
404568	29675094	However, no significant difference was found in the correlation between eIF3e and other factors, such as sex, age, tumor size, etc.	('eIF3e', 'Var', (72, 77))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))
404574	29675094	Importantly, though not reaching statistical significant difference, the patients in eIF3ehigh group suffered lower survival and shorter median survival than the patients in eIF3elow group (5-year DFS: 39.5% vs. 55.7%, median 5-year DFS: 32 months vs. not reached.	('patients', 'Species', '9606', (162, 170))	('eIF3ehigh', 'Var', (85, 94))	('survival', 'MPA', (116, 124))	('lower', 'NegReg', (110, 115))	('median', 'MPA', (137, 143))	('patients', 'Species', '9606', (73, 81))	('shorter', 'NegReg', (129, 136))
404582	29675094	The efficiency of the transfection was high in both two cell lines, according to the Cy3-modified expression under light microscope and fluorescence microscope (Fig.	('Cy3-modified', 'Var', (85, 97))	('transfection', 'Var', (22, 34))	('Cy3', 'Chemical', '-', (85, 88))
404591	29675094	However, in the study of glioblastoma, Sesen and colleagues demonstrated that eIF3e expression was elevated and inhibition of eIF3e expression led into decreased proliferation by the ways of cell cycle arrest and increased apoptosis.	('inhibition', 'Var', (112, 122))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (191, 208))	('proliferation', 'CPA', (162, 175))	('decreased', 'NegReg', (152, 161))	('elevated', 'PosReg', (99, 107))	('apoptosis', 'CPA', (223, 232))	('glioblastoma', 'Disease', (25, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (25, 37))	('expression', 'MPA', (84, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (25, 37))	('expression', 'MPA', (132, 142))	('cell cycle arrest', 'CPA', (191, 208))	('eIF3e', 'Gene', (78, 83))	('eIF3e', 'Gene', (126, 131))
404598	29675094	Grzmil and colleagues created an in vivo model of eIF3e function in zebrafish and demonstrated that eIF3e could modulate MEK-ERK signaling pathway, of which disorder would lead into abnormal proliferation of cells and tumorigenesis.	('abnormal proliferation of cells', 'CPA', (182, 213))	('lead into', 'Reg', (172, 181))	('zebrafish', 'Species', '7955', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('modulate', 'Reg', (112, 120))	('eIF3e', 'Var', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('MEK-ERK signaling pathway', 'Pathway', (121, 146))	('tumor', 'Disease', (218, 223))
404599	29675094	Chen and colleagues found that eIF3e could down-regulated hypoxia inducible factor 2 alpha by hypoxia and pVHL independent regulation.	('down-regulated', 'NegReg', (43, 57))	('hypoxia', 'Disease', (58, 65))	('hypoxia inducible factor 2 alpha', 'Gene', (58, 90))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('hypoxia', 'Disease', 'MESH:D000860', (94, 101))	('eIF3e', 'Var', (31, 36))	('hypoxia inducible factor 2 alpha', 'Gene', '2034', (58, 90))	('hypoxia', 'Disease', (94, 101))	('pVHL', 'Gene', '7428', (106, 110))	('pVHL', 'Gene', (106, 110))
404600	29675094	In breast cancer, Morris and colleagues demonstrated eIF3e served as a regulator of DNA double-strand breaks through RNF8-dependent ubiquitylation pathway.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('DNA double-strand breaks', 'MPA', (84, 108))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('RNF8', 'Gene', '9025', (117, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('eIF3e', 'Var', (53, 58))	('RNF8', 'Gene', (117, 121))
404601	29675094	In the survival analysis, the patients in eIF3ehigh suffered lower survival and shorter median survival than the patients in eIF3elow group (5-year DFS: 39.5% vs. 55.7%, median 5-year DFS: 32 months vs. not reached.	('lower', 'NegReg', (61, 66))	('median survival', 'MPA', (88, 103))	('patients', 'Species', '9606', (113, 121))	('survival', 'MPA', (67, 75))	('eIF3ehigh', 'Var', (42, 51))	('patients', 'Species', '9606', (30, 38))	('shorter', 'NegReg', (80, 87))
404616	29319236	The group with NAC plus MIE had slightly longer operating time, more blood loss, higher morbidity, increased chance of surgical intensive care unit stay, and longer surgical intensive care unit stay time than the group with MIE alone.	('blood loss', 'Disease', 'MESH:D006473', (69, 79))	('MIE', 'Var', (24, 27))	('MIE', 'Chemical', '-', (224, 227))	('MIE', 'Chemical', '-', (24, 27))	('blood loss', 'Disease', (69, 79))	('longer', 'PosReg', (41, 47))	('morbidity', 'CPA', (88, 97))	('NAC', 'Var', (15, 18))	('NAC', 'Chemical', '-', (15, 18))
404650	29319236	NAC does not negatively impact the therapeutic outcome of MIE, instead, it may benefit long-term OS due to its downstaging effect.	('NAC', 'Var', (0, 3))	('NAC', 'Chemical', '-', (0, 3))	('benefit', 'PosReg', (79, 86))	('long-term OS', 'CPA', (87, 99))	('downstaging', 'NegReg', (111, 122))	('MIE', 'Chemical', '-', (58, 61))
404652	29319236	Although NAC may result in downstaging, which is beneficial, NAC may also lead to necrosis and fibrosis, especially around the tumor, and thus complicate the surgical procedure.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('necrosis', 'Disease', 'MESH:D009336', (82, 90))	('lead to', 'Reg', (74, 81))	('tumor', 'Disease', (127, 132))	('complicate', 'Reg', (143, 153))	('NAC', 'Var', (9, 12))	('downstaging', 'MPA', (27, 38))	('NAC', 'Chemical', '-', (9, 12))	('necrosis', 'Disease', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('NAC', 'Var', (61, 64))	('fibrosis', 'Disease', 'MESH:D005355', (95, 103))	('fibrosis', 'Disease', (95, 103))	('NAC', 'Chemical', '-', (61, 64))
404691	28626398	Polymerase chain reaction of the rectum samples revealed the presence of a Kirsten rat sarcoma viral oncogene homolog codon 12 mutation, limiting the use of anti-epidermal growth factor receptor antibodies as a treatment option.	('rat', 'Species', '10116', (83, 86))	('mutation', 'Var', (127, 135))	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('epidermal growth factor receptor', 'Gene', (162, 194))	('epidermal growth factor receptor', 'Gene', '24329', (162, 194))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))
404755	27920702	We diagnosed T1bN0M0 stage I esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('I esophageal cancer', 'Disease', 'MESH:D004938', (27, 46))	('T1bN0M0 stage', 'Var', (13, 26))	('I esophageal cancer', 'Disease', (27, 46))
404784	26898709	Modulation of E-cadherin expression promotes migration ability of esophageal cancer cells Losing the E-cadherin plays an important role in the metastasis of cancer.	('Modulation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('E-cadherin', 'Gene', (101, 111))	('E-cadherin', 'Gene', '999', (14, 24))	('migration ability', 'CPA', (45, 62))	('esophageal cancer', 'Disease', (66, 83))	('E-cadherin', 'Gene', '999', (101, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('metastasis of cancer', 'Disease', (143, 163))	('metastasis of cancer', 'Disease', 'MESH:D009362', (143, 163))	('E-cadherin', 'Gene', (14, 24))	('promotes', 'PosReg', (36, 44))
404829	26898709	The results implicate that Per2 may increase the levels of pHDAC1.	('levels', 'MPA', (49, 55))	('HDAC1', 'Gene', (60, 65))	('increase', 'PosReg', (36, 44))	('Per2', 'Var', (27, 31))	('HDAC1', 'Gene', '3065', (60, 65))
404833	26898709	We next took a further insight into the mechanism by which Per2 modulating the gene transcription of E-cadherin in esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('E-cadherin', 'Gene', (101, 111))	('gene transcription', 'MPA', (79, 97))	('Per2', 'Var', (59, 63))	('E-cadherin', 'Gene', '999', (101, 111))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('modulating', 'Reg', (64, 74))
404845	26898709	The results showed that the overexpression of Per2 markedly increased the migration of esophageal cancer cells, which was abolished by transfected with empty plasmids, or knockdown of the HDAC1 gene, of knockdown the E-cadherin gene, respectively (Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('esophageal cancer', 'Disease', (87, 104))	('HDAC1', 'Gene', (188, 193))	('migration', 'CPA', (74, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('E-cadherin', 'Gene', (217, 227))	('overexpression', 'PosReg', (28, 42))	('E-cadherin', 'Gene', '999', (217, 227))	('Per2', 'Gene', (46, 50))	('HDAC1', 'Gene', '3065', (188, 193))	('knockdown', 'Var', (203, 212))	('increased', 'PosReg', (60, 69))
404873	26898709	The information implies that the inhibition of HDAC1 may suppress cancer metastasis.	('inhibition', 'Var', (33, 43))	('HDAC1', 'Gene', (47, 52))	('cancer metastasis', 'Disease', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('suppress', 'NegReg', (57, 65))	('HDAC1', 'Gene', '3065', (47, 52))	('cancer metastasis', 'Disease', 'MESH:D009362', (66, 83))
404874	26898709	The inference is supported by our further experimental data; the presence of sodium butyrate (a HDAC1 inhibitor) markedly inhibits the migratory capacity of esophageal cancer cells.	('HDAC1', 'Gene', '3065', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('inhibits', 'NegReg', (122, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('sodium butyrate', 'Chemical', 'MESH:D020148', (77, 92))	('HDAC1', 'Gene', (96, 101))	('esophageal cancer', 'Disease', (157, 174))	('presence', 'Var', (65, 73))
404875	26898709	In summary, the present data show that human esophageal cancer cells with metastasis express high levels of Per2; Per2 suppresses the expression of E-cadherin in esophageal cancer cells.	('E-cadherin', 'Gene', (148, 158))	('esophageal cancer', 'Disease', (45, 62))	('expression', 'MPA', (134, 144))	('esophageal cancer', 'Disease', (162, 179))	('E-cadherin', 'Gene', '999', (148, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('suppresses', 'NegReg', (119, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('human', 'Species', '9606', (39, 44))	('Per2', 'Var', (114, 118))
404876	26898709	HDAC1 is involved in the inhibitory process of E-cadherin induced by Per2; blocking HDAC1 inhibits the migratory capacity of esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('blocking', 'Var', (75, 83))	('E-cadherin', 'Gene', (47, 57))	('HDAC1', 'Gene', (0, 5))	('HDAC1', 'Gene', '3065', (84, 89))	('esophageal cancer', 'Disease', (125, 142))	('inhibits', 'NegReg', (90, 98))	('E-cadherin', 'Gene', '999', (47, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('HDAC1', 'Gene', '3065', (0, 5))	('HDAC1', 'Gene', (84, 89))
404910	26898709	Modulation of E-cadherin expression promotes migration ability of esophageal cancer cells.	('Modulation', 'Var', (0, 10))	('E-cadherin', 'Gene', '999', (14, 24))	('migration ability', 'CPA', (45, 62))	('esophageal cancer', 'Disease', (66, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('E-cadherin', 'Gene', (14, 24))	('promotes', 'PosReg', (36, 44))
404914	25815591	The effect of silencing the ABCE1 gene on the proliferation, migration and invasive ability of the EC109 human esophageal cancer cells were assessed using a Cell counting kit-8 (CCK-8) and with proliferation, wound-healing and cell invasion assays.	('silencing', 'Var', (14, 23))	('CCK-8', 'Chemical', '-', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('esophageal cancer', 'Disease', (111, 128))	('migration', 'CPA', (61, 70))	('invasive ability', 'CPA', (75, 91))	('ABCE1', 'Gene', (28, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('human', 'Species', '9606', (105, 110))	('ABCE1', 'Gene', '6059', (28, 33))	('EC109', 'CellLine', 'CVCL:6898', (99, 104))
404918	25815591	These results revealed that ABCE1 is closely associated with cell proliferation, invasion and migration in esophageal cancer and silencing the ABCE1 gene by electroporation can significantly reduce the proliferation, invasion and migration capacity of EC109 cells in vitro.	('migration capacity', 'CPA', (230, 248))	('proliferation', 'CPA', (202, 215))	('ABCE1', 'Gene', '6059', (143, 148))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('silencing', 'Var', (129, 138))	('associated', 'Reg', (45, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('invasion', 'CPA', (217, 225))	('ABCE1', 'Gene', (28, 33))	('EC109', 'CellLine', 'CVCL:6898', (252, 257))	('ABCE1', 'Gene', (143, 148))	('ABCE1', 'Gene', '6059', (28, 33))	('reduce', 'NegReg', (191, 197))
404922	25815591	Previous studies have demonstrated that ATP-binding cassette protein E1 (ABCE1) is important in tumor development and abnormal expression may be associated with malignant tumor proliferation and migration.	('ABCE1', 'Gene', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ATP-binding cassette protein E1', 'Gene', '6059', (40, 71))	('expression', 'MPA', (127, 137))	('ABCE1', 'Gene', '6059', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('abnormal', 'Var', (118, 126))	('tumor', 'Disease', (96, 101))	('associated', 'Reg', (145, 155))	('malignant tumor', 'Disease', 'MESH:D018198', (161, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('migration', 'CPA', (195, 204))	('malignant tumor', 'Disease', (161, 176))	('ATP-binding cassette protein E1', 'Gene', (40, 71))
404923	25815591	In the present study, silencing the ABCE1 gene of EC109 human esophageal cancer cells by electroporation was performed to investigate the effect of the ABCE1 gene on the biological behavior of oesophageal cancer cells and to provide an experimental basis for ABCE1-targeted gene therapy in esophageal cancer.	('esophageal cancer', 'Disease', (62, 79))	('ABCE1', 'Gene', (259, 264))	('ABCE1', 'Gene', '6059', (36, 41))	('esophageal cancer', 'Disease', (290, 307))	('EC109', 'CellLine', 'CVCL:6898', (50, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))	('oesophageal cancer', 'Disease', 'MESH:D009369', (193, 211))	('ABCE1', 'Gene', '6059', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ABCE1', 'Gene', (36, 41))	('human', 'Species', '9606', (56, 61))	('silencing', 'Var', (22, 31))	('investigate', 'Reg', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('ABCE1', 'Gene', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('ABCE1', 'Gene', '6059', (259, 264))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('oesophageal cancer', 'Disease', (193, 211))	('esophageal cancer', 'Disease', 'MESH:D004938', (290, 307))
404977	25815591	In addition, nick wound-healing and Transwell chamber invasion assays revealed that, following ABCE1 gene silencing, the migration and invasive capacities of the EC109 esophageal cancer cells decreased, which was consistent with the results observed in 95-D/NCE-H466 lung cancer cells by Zhao et al.	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('migration', 'CPA', (121, 130))	('esophageal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('decreased', 'NegReg', (192, 201))	('lung cancer', 'Disease', (267, 278))	('EC109', 'CellLine', 'CVCL:6898', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('invasive capacities', 'CPA', (135, 154))	('silencing', 'NegReg', (106, 115))	('ABCE1', 'Gene', (95, 100))	('gene', 'Var', (101, 105))	('lung cancer', 'Disease', 'MESH:D008175', (267, 278))	('ABCE1', 'Gene', '6059', (95, 100))
404980	25815591	Therefore, the ABCE1 siRNA sequence may be an effective target site for esophageal cancer therapy and the inhibition of ABCE1 by electroporation may offer a novel therapeutic method in the treatment of malignant tumors, including esophageal cancer.	('ABCE1', 'Gene', (15, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (230, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('ABCE1', 'Gene', '6059', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('malignant tumors', 'Disease', (202, 218))	('esophageal cancer', 'Disease', (72, 89))	('inhibition', 'Var', (106, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('ABCE1', 'Gene', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('malignant tumors', 'Disease', 'MESH:D018198', (202, 218))	('ABCE1', 'Gene', '6059', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('esophageal cancer', 'Disease', (230, 247))
405027	24574946	If no treatment is given, a P-AVM will grow and cause portal hypertension, gastrointestinal bleeding or rupture of esophageal varices.	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (75, 100))	('esophageal varices', 'Phenotype', 'HP:0002040', (115, 133))	('P-AVM', 'Var', (28, 33))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (75, 100))	('gastrointestinal bleeding', 'Disease', (75, 100))	('rupture of esophageal', 'Disease', (104, 125))	('hypertension', 'Disease', (61, 73))	('portal hypertension', 'Phenotype', 'HP:0001409', (54, 73))	('cause', 'Reg', (48, 53))	('AVM', 'Phenotype', 'HP:0100026', (30, 33))	('hypertension', 'Phenotype', 'HP:0000822', (61, 73))	('rupture of esophageal', 'Disease', 'MESH:D004941', (104, 125))	('hypertension', 'Disease', 'MESH:D006973', (61, 73))
405040	24040621	For example, a loss- of-function mutation in PGRN has been associated with the onset of frontotemporal lobar degeneration.	('frontotemporal lobar degeneration', 'Disease', (88, 121))	('PGRN', 'Gene', '2896', (45, 49))	('mutation', 'Var', (33, 41))	('loss- of-function', 'NegReg', (15, 32))	('PGRN', 'Gene', (45, 49))	('frontotemporal lobar degeneration', 'Phenotype', 'HP:0006892', (88, 121))
405042	24040621	However, how the dysregulation of PGRN function leads to these pathogenic states is largely unknown.	('PGRN', 'Gene', (34, 38))	('PGRN', 'Gene', '2896', (34, 38))	('leads', 'Reg', (48, 53))	('dysregulation', 'Var', (17, 30))
405047	24040621	Complete cleavage of full length PGRN results in granulin peptides (GRN A-G and paragranulin) that are approximately 6 kDa in size, though intermediary cleavage products have also been identified.	('GRN', 'Gene', (34, 37))	('granulin', 'Gene', '2896', (84, 92))	('granulin', 'Gene', (49, 57))	('GRN', 'Gene', '2896', (68, 71))	('GRN', 'Gene', '2896', (34, 37))	('cleavage', 'Var', (9, 17))	('granulin', 'Gene', '2896', (49, 57))	('PGRN', 'Gene', '2896', (33, 37))	('granulin', 'Gene', (84, 92))	('GRN', 'Gene', (68, 71))	('PGRN', 'Gene', (33, 37))
405061	24040621	The malignancy of highly tumorigenic PGRN-expressing cell lines depends on the expression level, since attenuating PGRN mRNA levels greatly inhibits tumor progression.	('malignancy', 'Disease', 'MESH:D009369', (4, 14))	('inhibits', 'NegReg', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('PGRN', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('PGRN', 'Gene', (37, 41))	('tumor', 'Disease', (25, 30))	('malignancy', 'Disease', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('PGRN', 'Gene', '2896', (115, 119))	('mRNA levels', 'MPA', (120, 131))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('PGRN', 'Gene', '2896', (37, 41))	('attenuating', 'Var', (103, 114))
405106	24040621	To identify the soluble factors released from the chemoresistant CRCs, proteomic analysis of the conditioned media was performed, demonstrating that PGRN levels (among other factors) were significantly higher in the media from chemoresistant CRCs than the chemonaive cells.	('chemoresistant', 'Var', (227, 241))	('PGRN', 'Gene', '2896', (149, 153))	('higher', 'PosReg', (202, 208))	('levels', 'MPA', (154, 160))	('PGRN', 'Gene', (149, 153))
405115	23019392	At 4 weeks post-PDT, a significant improvement in the dysphagia score was observed in 90% of patients, from 2.75 +- 0.91 to 1.05 +- 0.83 (p < 0.05).	('dysphagia', 'Disease', 'MESH:D003680', (54, 63))	('improvement', 'PosReg', (35, 46))	('dysphagia', 'Disease', (54, 63))	('post-PDT', 'Var', (11, 19))	('dysphagia', 'Phenotype', 'HP:0002015', (54, 63))	('patients', 'Species', '9606', (93, 101))
405127	23019392	Early results of PDT in esophageal cancer are promising and PDT may help to lessen dysphagia, the symptom with the greatest impact on the quality of life of patients with an incurable disease.	('dysphagia', 'Disease', (83, 92))	('esophageal cancer', 'Disease', (24, 41))	('lessen', 'NegReg', (76, 82))	('dysphagia', 'Phenotype', 'HP:0002015', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('patients', 'Species', '9606', (157, 165))	('dysphagia', 'Disease', 'MESH:D003680', (83, 92))	('PDT', 'Var', (60, 63))
405179	23019392	At 4 weeks after PDT, a significant improvement was observed in dysphagia scores for 90% of the patients, from 2.75 +- 0.91 to 1.05 +- 0.83 (p < 0.05), with a dysphagia-free interval of 81 days.	('dysphagia', 'Phenotype', 'HP:0002015', (64, 73))	('PDT', 'Var', (17, 20))	('dysphagia', 'Disease', (159, 168))	('dysphagia', 'Disease', 'MESH:D003680', (64, 73))	('improvement', 'PosReg', (36, 47))	('dysphagia', 'Phenotype', 'HP:0002015', (159, 168))	('patients', 'Species', '9606', (96, 104))	('dysphagia-free interval', 'Disease', (159, 182))	('dysphagia', 'Disease', (64, 73))	('dysphagia-free interval', 'Disease', 'MESH:D003680', (159, 182))	('dysphagia', 'Disease', 'MESH:D003680', (159, 168))
405217	23019392	PDT was effective in palliating dysphagia in 90% of patients at four weeks following PDT with a dysphagia-free interval of 80 days.	('dysphagia', 'Disease', (96, 105))	('dysphagia', 'Disease', 'MESH:D003680', (32, 41))	('palliating', 'Disease', (21, 31))	('dysphagia', 'Phenotype', 'HP:0002015', (96, 105))	('dysphagia', 'Disease', (32, 41))	('dysphagia', 'Disease', 'MESH:D003680', (96, 105))	('dysphagia-free interval', 'Disease', (96, 119))	('dysphagia', 'Phenotype', 'HP:0002015', (32, 41))	('dysphagia-free interval', 'Disease', 'MESH:D003680', (96, 119))	('patients', 'Species', '9606', (52, 60))	('PDT', 'Var', (85, 88))
405219	23019392	In their series of 119 patients treated with PDT and RT, PDT improved the dysphagia score in all patients with a significant improvement in tumor stenosis when PDT was followed by RT.	('improved', 'PosReg', (61, 69))	('dysphagia', 'Disease', 'MESH:D003680', (74, 83))	('PDT', 'Var', (57, 60))	('tumor stenosis', 'Disease', 'MESH:D003251', (140, 154))	('improvement', 'PosReg', (125, 136))	('patients', 'Species', '9606', (23, 31))	('tumor stenosis', 'Disease', (140, 154))	('dysphagia', 'Disease', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('dysphagia', 'Phenotype', 'HP:0002015', (74, 83))	('patients', 'Species', '9606', (97, 105))
405220	23019392	In a multicenter study comparing PDT and Nd:YAG laser in obstructing esophageal cancer in 277 patients by Lightdale et al., the relief of dysphagia was equivalent between the two groups; however, PDT had a better objective tumor response rate.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('obstructing esophageal cancer', 'Disease', (57, 86))	('tumor', 'Disease', (223, 228))	('patients', 'Species', '9606', (94, 102))	('dysphagia', 'Disease', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PDT', 'Var', (196, 199))	('dysphagia', 'Phenotype', 'HP:0002015', (138, 147))	('obstructing esophageal cancer', 'Disease', 'MESH:D004938', (57, 86))	('dysphagia', 'Disease', 'MESH:D003680', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (223, 228))
405237	22876312	Low vegetable intake was responsible for 4.3% esophageal cancer deaths in men and 4.1% in women.	('esophageal cancer deaths', 'Disease', (46, 70))	('Low vegetable intake', 'Var', (0, 20))	('men', 'Species', '9606', (74, 77))	('esophageal cancer deaths', 'Disease', 'MESH:D004938', (46, 70))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('men', 'Species', '9606', (92, 95))	('women', 'Species', '9606', (90, 95))
405253	22876312	The objective of our study was to provide an evidence-based assessment of the proportion of esophageal cancer cases and deaths attributable to tobacco smoking, alcohol drinking, and low vegetable and fruit intake in China in 2005.	('men', 'Species', '9606', (66, 69))	('alcohol', 'Chemical', 'MESH:D000438', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('death', 'Disease', 'MESH:D003643', (120, 125))	('death', 'Disease', (120, 125))	('tobacco', 'Species', '4097', (143, 150))	('esophageal cancer', 'Disease', (92, 109))	('alcohol drinking', 'Phenotype', 'HP:0030955', (160, 176))	('low vegetable', 'Var', (182, 195))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
405290	22876312	In urban areas of China, the highest quintile level of vegetable intake was >=441.7 g/d among men and >=416.7 g/d among women, respectively, while the highest quintile of fruit intake was 150.0 g/d in both genders.	('men', 'Species', '9606', (94, 97))	('>=416.7', 'Var', (102, 109))	('women', 'Species', '9606', (120, 125))	('>=441.7', 'Var', (76, 83))	('men', 'Species', '9606', (122, 125))
405299	22876312	Our estimates showed that 4.3% of esophageal cancer deaths and cases among men (PAF = 4.1% for urban men and 4.4% for rural men) and 4.1% among women (PAF = 3.9% for urban women and 4.1% for rural women) were attributable to low vegetable intake, respectively.	('low vegetable', 'Var', (225, 238))	('men', 'Species', '9606', (199, 202))	('esophageal cancer deaths', 'Disease', (34, 58))	('esophageal cancer deaths', 'Disease', 'MESH:D004938', (34, 58))	('women', 'Species', '9606', (197, 202))	('men', 'Species', '9606', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('men', 'Species', '9606', (174, 177))	('men', 'Species', '9606', (101, 104))	('men', 'Species', '9606', (146, 149))	('PAF', 'Chemical', '-', (80, 83))	('men', 'Species', '9606', (75, 78))	('women', 'Species', '9606', (144, 149))	('PAF', 'Chemical', '-', (151, 154))	('women', 'Species', '9606', (172, 177))
405303	22876312	We estimate that 45.8% of esophageal cancer deaths were attributable to the combined effects of tobacco smoking, alcohol drinking, low vegetable intake and low fruit intake.	('alcohol drinking', 'Phenotype', 'HP:0030955', (113, 129))	('alcohol', 'Chemical', 'MESH:D000438', (113, 120))	('tobacco', 'Species', '4097', (96, 103))	('low fruit', 'Var', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('esophageal cancer deaths', 'Disease', (26, 50))	('esophageal cancer deaths', 'Disease', 'MESH:D004938', (26, 50))	('low', 'NegReg', (131, 134))
405380	19415743	This hypothesis is supported by high rates of somatic G > A transitions in CpG dinucleotides of the TP53 gene in ESCC tumor samples from areas in which drinking hot beverages is considered an important risk factor for ESCC; these mutations may indicate increased nitric oxide synthase activity in tumors.	('TP53', 'Gene', '7157', (100, 104))	('ESCC', 'Disease', (113, 117))	('tumors', 'Disease', 'MESH:D009369', (297, 303))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('ESCC', 'Disease', (218, 222))	('hot', 'Gene', '137872', (161, 164))	('TP53', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('increased', 'PosReg', (253, 262))	('hot', 'Gene', (161, 164))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('G > A transitions', 'Var', (54, 71))	('tumors', 'Disease', (297, 303))	('tumor', 'Disease', (297, 302))
405417	33650646	Additionally, lncRNA LOC100133669 facilitates ESCC cell proliferation by regulating Tim50.	('ESCC', 'Disease', (46, 50))	('Tim50', 'Gene', (84, 89))	('LOC100133669', 'Var', (21, 33))	('Tim50', 'Gene', '92609', (84, 89))	('regulating', 'Reg', (73, 83))	('facilitates', 'PosReg', (34, 45))
405421	33650646	N6-methyladenosine (m6A) modifications serve a vital role in cancer progression by controlling mRNA metabolism, including pre-mRNA splicing, mRNA transport, translation and stability.	('si', 'Chemical', 'MESH:D012825', (14, 16))	('m6A', 'Chemical', '-', (20, 23))	('modifications', 'Var', (25, 38))	('mRNA metabolism', 'MPA', (95, 110))	('mRNA transport', 'MPA', (141, 155))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('translation', 'MPA', (157, 168))	('controlling', 'Reg', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('stability', 'MPA', (173, 182))	('pre-mRNA splicing', 'MPA', (122, 139))
405423	33650646	Methyltransferase-like 3 promotes gastric cancer progression by enhancing heparin binding growth factor mRNA stability via m6A modification.	('enhancing', 'PosReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('heparin', 'Chemical', 'MESH:D006493', (74, 81))	('promotes', 'PosReg', (25, 33))	('heparin binding growth factor mRNA stability', 'MPA', (74, 118))	('gastric cancer', 'Disease', (34, 48))	('Methyltransferase-like 3', 'Gene', (0, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('m6A', 'Var', (123, 126))	('Methyltransferase-like 3', 'Gene', '56339', (0, 24))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('m6A', 'Chemical', '-', (123, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))
405424	33650646	Previous studies have demonstrated that lncRNAs regulate cell fates by affecting mRNA expression via m6A RNA modification.	('affecting', 'Reg', (71, 80))	('mRNA expression', 'MPA', (81, 96))	('m6A', 'Var', (101, 104))	('m6A', 'Chemical', '-', (101, 104))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('cell fates', 'CPA', (57, 67))
405426	33650646	FTO is highly expressed in patients with ESCC and FTO dysregulation is closely associated with the progression of ESCC.	('associated', 'Reg', (79, 89))	('ESCC', 'Disease', (114, 118))	('ESCC', 'Disease', (41, 45))	('patients', 'Species', '9606', (27, 35))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('dysregulation', 'Var', (54, 67))
405455	33650646	Apoptotic rate was determined from the ratio of APC+/7-AAD- (early apoptotic cells) and APC+/7-AAD+ cells (late apoptotic cells).	('7-AAD', 'Chemical', 'MESH:C025942', (53, 58))	('APC+/7-AAD+', 'Var', (88, 99))	('APC+/7-AAD-', 'Var', (48, 59))	('7-AAD', 'Chemical', 'MESH:C025942', (93, 98))
405487	33650646	Cell lysates (25 microl per IP reaction) were co-incubated with nucleic acid-compatible streptavidin magnetic beads (Pierce; Thermo Fisher Scientific, Inc.) combined with biotinylated sense or antisense CASC15 (Sangon Biotech Co., Ltd.).	('biotin', 'Chemical', 'MESH:D001710', (171, 177))	('antisense', 'Var', (193, 202))	('CASC15', 'Gene', (203, 209))	('CASC15', 'Gene', '401237', (203, 209))
405504	33650646	Patients with high CASC15 expression demonstrated lower overall survival rates compared with the low CASC15 expression group (P=0.0218; Fig.	('lower', 'NegReg', (50, 55))	('overall survival', 'MPA', (56, 72))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('CASC15', 'Gene', (101, 107))	('CASC15', 'Gene', '401237', (101, 107))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('CASC15', 'Gene', (19, 25))	('CASC15', 'Gene', '401237', (19, 25))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))
405515	33650646	The results indicated that CASC15 silencing repressed ESCC progression in vitro.	('ESCC', 'Disease', (54, 58))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('CASC15', 'Gene', (27, 33))	('CASC15', 'Gene', '401237', (27, 33))	('silencing', 'Var', (34, 43))
405521	33650646	These data indicated that CASC15 silencing hindered ESCC xenograft tumor growth.	('si', 'Chemical', 'MESH:D012825', (33, 35))	('CASC15', 'Gene', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('CASC15', 'Gene', '401237', (26, 32))	('silencing', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ESCC', 'Disease', (52, 56))	('tumor', 'Disease', (67, 72))	('hindered', 'NegReg', (43, 51))
405541	33650646	Additionally, a marked downregulation of FTO protein expression was observed in si-FTO-transfected Eca109 and KYSE450 cells compared with in si-NC-transfected cells (Fig.	('downregulation', 'NegReg', (23, 37))	('KYSE450', 'CellLine', 'CVCL:1353', (110, 117))	('FTO', 'Gene', (41, 44))	('expression', 'MPA', (53, 63))	('si-FTO-transfected', 'Var', (80, 98))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('si', 'Chemical', 'MESH:D012825', (80, 82))
405547	33650646	Additionally, cell apoptotic rates were decreased by ~0.5-fold in Eca-109 and KYSE450 cells transfected with CASC15 overexpression plasmid compared with in pcDNA-transfected cells (Fig.	('CASC15', 'Gene', (109, 115))	('CASC15', 'Gene', '401237', (109, 115))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('KYSE450', 'CellLine', 'CVCL:1353', (78, 85))	('cell apoptotic rates', 'CPA', (14, 34))	('overexpression', 'Var', (116, 130))	('decreased', 'NegReg', (40, 49))
405549	33650646	Furthermore, FTO-knockdown significantly weakened these CASC15-mediated pro-proliferative and anti-apoptotic effects (Fig.	('FTO-knockdown', 'Gene', (13, 26))	('weakened', 'NegReg', (41, 49))	('anti-apoptotic effects', 'CPA', (94, 116))	('CASC15', 'Gene', (56, 62))	('CASC15', 'Gene', '401237', (56, 62))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('FTO-knockdown', 'Var', (13, 26))
405553	33650646	Additionally, knockdown efficiency analysis revealed that SIM2 protein expression was significantly decreased in Eca109 and KYSE450 cells transfected with si-SIM2 compared with in cells transfected with si-NC (Fig.	('si', 'Chemical', 'MESH:D012825', (77, 79))	('protein', 'Protein', (63, 70))	('SIM2', 'Chemical', '-', (158, 162))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('decreased', 'NegReg', (100, 109))	('si-SIM2', 'Chemical', '-', (155, 162))	('SIM2', 'Chemical', '-', (58, 62))	('SIM2', 'Gene', (58, 62))	('si-SIM2', 'Var', (155, 162))	('si', 'Chemical', 'MESH:D012825', (203, 205))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('KYSE450', 'CellLine', 'CVCL:1353', (124, 131))	('si', 'Chemical', 'MESH:D012825', (86, 88))
405554	33650646	To further investigate whether SIM2 was associated with the regulatory effects exerted by CASC15 on ESCC progression in vitro, Eca109 and KYSE450 cells were transfected with si-NC, si-CASC15#1 or si-CASC15#1 + si-SIM2.	('CASC15', 'Gene', (184, 190))	('CASC15', 'Gene', '401237', (184, 190))	('si-NC', 'Var', (174, 179))	('SIM2', 'Chemical', '-', (213, 217))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('SIM2', 'Chemical', '-', (31, 35))	('CASC15', 'Gene', (199, 205))	('ESCC', 'Disease', (100, 104))	('si-SIM2', 'Chemical', '-', (210, 217))	('CASC15', 'Gene', '401237', (199, 205))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('si', 'Chemical', 'MESH:D012825', (196, 198))	('KYSE450', 'CellLine', 'CVCL:1353', (138, 145))	('si', 'Chemical', 'MESH:D012825', (210, 212))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('CASC15', 'Gene', (90, 96))	('CASC15', 'Gene', '401237', (90, 96))
405556	33650646	The introduction of si-SIM2 markedly attenuated the stimulatory effect of CASC15-knockdown on SIM2 protein expression in Eca109 and KYSE450 cells (Fig.	('stimulatory effect', 'MPA', (52, 70))	('SIM2', 'Chemical', '-', (23, 27))	('SIM2', 'Chemical', '-', (94, 98))	('CASC15', 'Gene', (74, 80))	('si-SIM2', 'Chemical', '-', (20, 27))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('si-SIM2', 'Var', (20, 27))	('attenuated', 'NegReg', (37, 47))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('CASC15', 'Gene', '401237', (74, 80))	('protein', 'Protein', (99, 106))	('SIM2', 'Gene', (94, 98))	('KYSE450', 'CellLine', 'CVCL:1353', (132, 139))
405559	33650646	Additionally, a ~0.4-fold (14.74 vs. 24.87%) decrease in cell apoptotic rate was observed in KYSE450 cells co-transfected with si-CASC15#1 and si-SIM2 compared with in cells co-transfected with si-CASC15#1 and si-NC (Fig.	('cell apoptotic rate', 'CPA', (57, 76))	('si-SIM2', 'Chemical', '-', (143, 150))	('CASC15', 'Gene', (130, 136))	('CASC15', 'Gene', (197, 203))	('si-SIM2', 'Var', (143, 150))	('CASC15', 'Gene', '401237', (197, 203))	('CASC15', 'Gene', '401237', (130, 136))	('si', 'Chemical', 'MESH:D012825', (194, 196))	('decrease', 'NegReg', (45, 53))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('si', 'Chemical', 'MESH:D012825', (210, 212))	('KYSE450', 'CellLine', 'CVCL:1353', (93, 100))
405560	33650646	6G and H), suggesting that SIM2 silencing weakened the CASC15-knockdown-induced apoptosis in Eca109 and KYSE450 cells SIM2 interference also attenuated the CASC15-knockdown-induced caspase-3 activity promotion in Eca109 and KYSE450 cells (Fig.	('CASC15', 'Gene', '401237', (55, 61))	('caspase-3', 'Gene', '836', (181, 190))	('CASC15', 'Gene', (156, 162))	('promotion', 'PosReg', (200, 209))	('attenuated', 'NegReg', (141, 151))	('CASC15', 'Gene', '401237', (156, 162))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('KYSE450', 'CellLine', 'CVCL:1353', (224, 231))	('interference', 'Var', (123, 135))	('SIM2', 'Chemical', '-', (27, 31))	('SIM2', 'Chemical', '-', (118, 122))	('SIM2', 'Var', (118, 122))	('weakened', 'NegReg', (42, 50))	('caspase-3', 'Gene', (181, 190))	('si', 'Chemical', 'MESH:D012825', (86, 88))	('apoptosis', 'CPA', (80, 89))	('KYSE450', 'CellLine', 'CVCL:1353', (104, 111))	('CASC15', 'Gene', (55, 61))
405566	33650646	Additionally, the present data demonstrated that high CASC15 expression was associated with poor survival outcomes in patients with ESCC, indicating that CASC15 had potential clinical diagnostic value in ESCC.	('ESCC', 'Disease', (204, 208))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('survival outcomes', 'CPA', (97, 114))	('CASC15', 'Gene', (54, 60))	('poor', 'NegReg', (92, 96))	('CASC15', 'Gene', (154, 160))	('CASC15', 'Gene', '401237', (154, 160))	('CASC15', 'Gene', '401237', (54, 60))	('high', 'Var', (49, 53))	('ESCC', 'Disease', (132, 136))	('patients', 'Species', '9606', (118, 126))	('expression', 'MPA', (61, 71))
405572	33650646	N-m6A modification is also involved in regulating mRNA stability.	('mRNA stability', 'MPA', (50, 64))	('N-m6A modification', 'Var', (0, 18))	('m6A', 'Chemical', '-', (2, 5))
405576	33650646	FTO-knockdown markedly weakened CASC15-mediated pro-proliferative and anti-apoptotic effects in ESCC cells.	('weakened', 'NegReg', (23, 31))	('FTO-knockdown', 'Gene', (0, 13))	('CASC15', 'Gene', (32, 38))	('CASC15', 'Gene', '401237', (32, 38))	('anti-apoptotic effects', 'CPA', (70, 92))	('FTO-knockdown', 'Var', (0, 13))
405603	33461529	The presence of AL, with the rates being shown to occur up to 50% in some studies, is a potentially serious adverse event for patients and it has previously been significantly associated with prolonged length of stay, the formation of strictures, and increased morbidity and mortality.	('strictures', 'MPA', (235, 245))	('associated', 'Reg', (176, 186))	('mortality', 'Disease', 'MESH:D003643', (275, 284))	('patients', 'Species', '9606', (126, 134))	('presence', 'Var', (4, 12))	('mortality', 'Disease', (275, 284))
405647	32708604	Additionally, the constitutive activation of cellular signaling by the overexpression and somatic mutation-mediated alterations conferred by the ErBb family on cholangiocarcinoma and other cancers enhances tumor aggressiveness and chemoresistance by contributing to the tumor microenvironment.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (206, 226))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('rat', 'Species', '10116', (120, 123))	('alterations', 'Var', (116, 127))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cellular signaling', 'MPA', (45, 63))	('ErBb', 'Gene', '1956', (145, 149))	('enhances', 'PosReg', (197, 205))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('ErBb', 'Gene', (145, 149))	('cholangiocarcinoma', 'Disease', (160, 178))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('activation', 'PosReg', (31, 41))	('tumor', 'Disease', (270, 275))	('cancers', 'Disease', (189, 196))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('overexpression', 'PosReg', (71, 85))	('tumor aggressiveness', 'Disease', (206, 226))	('chemoresistance', 'CPA', (231, 246))	('tumor', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('contributing', 'Reg', (250, 262))	('aggressiveness', 'Phenotype', 'HP:0000718', (212, 226))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
405648	32708604	This review summarizes the recent findings on the molecular functions of the ErBb family and their mutations during the progression of cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', (135, 153))	('ErBb', 'Gene', '1956', (77, 81))	('mutations', 'Var', (99, 108))	('ErBb', 'Gene', (77, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (135, 153))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (135, 153))
405658	32708604	EGF and its receptor EGFR are highly upregulated in 59.5% (22/37), and 32.4 (12/37) of patients with ICC, and these expressions showed no correlation with metastases of ICC.. Another report revealed that EGFR is highly expressed in 44.7% (17/38) of ICC patients, and its upregulation is closely correlated with poor differentiation, lymph node metastasis, and aberrant p53 expression.	('aberrant', 'Var', (360, 368))	('ICC', 'Disease', (249, 252))	('patients', 'Species', '9606', (253, 261))	('EGF', 'Gene', '1950', (204, 207))	('p53', 'Gene', (369, 372))	('poor differentiation', 'CPA', (311, 331))	('EGF', 'Gene', (0, 3))	('CC', 'Phenotype', 'HP:0030153', (102, 104))	('CC', 'Phenotype', 'HP:0030153', (250, 252))	('EGF', 'Gene', (21, 24))	('lymph node metastasis', 'CPA', (333, 354))	('EGF', 'Gene', (204, 207))	('expression', 'MPA', (373, 383))	('CC', 'Phenotype', 'HP:0030153', (170, 172))	('EGF', 'Gene', '1950', (0, 3))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('upregulation', 'PosReg', (271, 283))	('patients', 'Species', '9606', (87, 95))	('EGF', 'Gene', '1950', (21, 24))	('metastases', 'Disease', (155, 165))
405686	32708604	E-cadherin is preferentially localized in the cytoplasm of patients with CC relative to localization at the plasma membrane of bile duct epithelial cells, and its localization is significantly correlated with EGFR expression in patients with CC, such that loss of EGFR activity leads to restoration of membrane expression of E-cadherin.	('CC', 'Phenotype', 'HP:0030153', (73, 75))	('EGFR', 'Gene', (209, 213))	('preferentially', 'PosReg', (14, 28))	('restoration', 'MPA', (287, 298))	('activity', 'MPA', (269, 277))	('CC', 'Phenotype', 'HP:0030153', (242, 244))	('localization', 'MPA', (163, 175))	('correlated', 'Reg', (193, 203))	('patients', 'Species', '9606', (228, 236))	('rat', 'Species', '10116', (292, 295))	('patients', 'Species', '9606', (59, 67))	('E-cadherin', 'Protein', (325, 335))	('loss', 'Var', (256, 260))	('membrane expression', 'MPA', (302, 321))
405692	32708604	Tyrphostin AG1517 and tyrphostin AG879 as inhibitors of EGFR and ERBB2, respectively, effectively suppress the growth of CC cells, and combination treatment has shown a synergistic effect on the inhibition of CC cell growth by inhibiting cyclin D1 and activating caspase-3.	('caspase-3', 'Gene', (263, 272))	('growth', 'CPA', (111, 117))	('tyrphostin', 'Var', (22, 32))	('cyclin D1', 'Gene', '595', (238, 247))	('inhibiting', 'NegReg', (227, 237))	('cyclin D1', 'Gene', (238, 247))	('ERBB2', 'Gene', (65, 70))	('CC', 'Phenotype', 'HP:0030153', (209, 211))	('EGFR', 'Gene', (56, 60))	('suppress', 'NegReg', (98, 106))	('caspase-3', 'Gene', '836', (263, 272))	('activating', 'PosReg', (252, 262))	('CC', 'Phenotype', 'HP:0030153', (121, 123))
405696	32708604	Genome-wide microarray analysis revealed that the expression of EGFR and mitogen-activated protein kinase (MAPK) kinase 2 is regulated by IL-6 and 5-aza-CdR.	('IL-6', 'Gene', '3569', (138, 142))	('5-aza-CdR', 'Chemical', '-', (147, 156))	('mitogen-activated protein kinase (MAPK) kinase 2', 'Gene', '5605', (73, 121))	('5-aza-CdR', 'Var', (147, 156))	('EGFR', 'Gene', (64, 68))	('IL-6', 'Gene', (138, 142))	('regulated', 'Reg', (125, 134))
405700	32708604	High NTS expression was closely correlated with reduced progression-free survival (PFS) and OS of patients with CC, and loss of NTS led to suppression of CC cell invasion through inhibition of the EGFR/AKT signaling pathway by reducing EGFR expression.	('NTS', 'Gene', '4922', (5, 8))	('reduced', 'NegReg', (48, 55))	('progression-free survival', 'CPA', (56, 81))	('expression', 'MPA', (241, 251))	('patients', 'Species', '9606', (98, 106))	('CC', 'Phenotype', 'HP:0030153', (112, 114))	('reducing', 'NegReg', (227, 235))	('NTS', 'Gene', (128, 131))	('CC cell invasion', 'CPA', (154, 170))	('inhibition', 'NegReg', (179, 189))	('suppression', 'NegReg', (139, 150))	('expression', 'MPA', (9, 19))	('EGFR', 'Protein', (236, 240))	('CC', 'Phenotype', 'HP:0030153', (154, 156))	('EGFR/AKT signaling pathway', 'Pathway', (197, 223))	('loss', 'Var', (120, 124))	('NTS', 'Gene', (5, 8))	('NTS', 'Gene', '4922', (128, 131))
405706	32708604	ERBB2 expression significantly increased tumor formation in vivo by increasing bile duct obstruction and gross peritoneal metastases.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('increased', 'PosReg', (31, 40))	('tumor', 'Disease', (41, 46))	('ERBB2', 'Gene', (0, 5))	('increasing', 'PosReg', (68, 78))	('bile duct obstruction', 'Phenotype', 'HP:0005230', (79, 100))	('bile duct obstruction', 'Disease', (79, 100))	('metastases', 'Disease', (122, 132))	('bile duct obstruction', 'Disease', 'MESH:D002779', (79, 100))	('duct obstruction', 'Phenotype', 'HP:0000579', (84, 100))	('metastases', 'Disease', 'MESH:D009362', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('expression', 'Var', (6, 16))
405717	32708604	Furthermore, loss of NRP-1 induces cell cycle arrest at phase G1/S by suppressing cyclin E and cyclin-dependent kinase (CDK)2 and inducing p27, and it inhibits tumor metastasis and growth in vivo and in vitro by inhibiting activation of the VEGF/VEGFR, EGF/EGFR, and HGF/c-Met pathways.	('inhibits', 'NegReg', (151, 159))	('inducing', 'Reg', (130, 138))	('cyclin-dependent kinase (CDK)2', 'Gene', (95, 125))	('VEGFR', 'Gene', (246, 251))	('EGF', 'Gene', '1950', (242, 245))	('inhibiting', 'NegReg', (212, 222))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('arrest', 'Disease', (46, 52))	('loss', 'Var', (13, 17))	('EGF', 'Gene', '1950', (257, 260))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (35, 52))	('EGF', 'Gene', (253, 256))	('NRP-1', 'Gene', (21, 26))	('VEGF', 'Gene', '7422', (241, 245))	('EGF', 'Gene', '1950', (247, 250))	('EGF', 'Gene', (242, 245))	('VEGF', 'Gene', (241, 245))	('EGF', 'Gene', (257, 260))	('HGF/c-Met pathways', 'Pathway', (267, 285))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('induces', 'Reg', (27, 34))	('NRP-1', 'Gene', '8829', (21, 26))	('p27', 'Gene', '3429', (139, 142))	('tumor', 'Disease', (160, 165))	('VEGF', 'Gene', '7422', (246, 250))	('growth', 'CPA', (181, 187))	('p27', 'Gene', (139, 142))	('cyclin-dependent kinase (CDK)2', 'Gene', '1017', (95, 125))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('suppressing', 'NegReg', (70, 81))	('VEGF', 'Gene', (246, 250))	('EGF', 'Gene', (247, 250))	('EGF', 'Gene', '1950', (253, 256))	('VEGFR', 'Gene', '3791', (246, 251))
405719	32708604	L1CAM is a transmembrane glycoprotein that has been reported as highly expressed in 40.5% (17/42) of patients with poorly differentiated ICC, and loss of L1CAM markedly reduces the tumor growth and metastatic ability of CC cells in vivo and in vitro by inhibiting focal adhesion kinase (FAK) and AKT activation.	('inhibiting', 'NegReg', (253, 263))	('metastatic ability of', 'CPA', (198, 219))	('focal adhesion kinase', 'Gene', '5747', (264, 285))	('reduces', 'NegReg', (169, 176))	('L1CAM', 'Gene', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('CC', 'Phenotype', 'HP:0030153', (220, 222))	('patients', 'Species', '9606', (101, 109))	('L1CAM', 'Gene', (0, 5))	('focal adhesion kinase', 'Gene', (264, 285))	('CC', 'Phenotype', 'HP:0030153', (138, 140))	('FAK', 'Gene', (287, 290))	('loss', 'Var', (146, 150))	('AKT activation', 'Pathway', (296, 310))	('L1CAM', 'Gene', '3897', (154, 159))	('tumor', 'Disease', (181, 186))	('FAK', 'Gene', '5747', (287, 290))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('L1CAM', 'Gene', '3897', (0, 5))
405722	32708604	Inhibition of PGE2 synthesis or loss of the EP1 receptor suppresses EGFR activation.	('suppresses', 'NegReg', (57, 67))	('EP1 receptor', 'Protein', (44, 56))	('PGE2', 'Chemical', '-', (14, 18))	('loss', 'Var', (32, 36))	('activation', 'MPA', (73, 83))	('EGFR', 'Protein', (68, 72))	('Inhibition', 'Var', (0, 10))	('PGE2', 'Protein', (14, 18))
405745	32708604	Additionally, EP1 receptor-induced intracellular calcium concentration induces EGFR activation and subsequently leads to PGE2-mediated ERK activation.	('ERK', 'Gene', '5594', (135, 138))	('EGFR', 'Protein', (79, 83))	('activation', 'PosReg', (139, 149))	('activation', 'PosReg', (84, 94))	('ERK', 'Gene', (135, 138))	('rat', 'Species', '10116', (64, 67))	('EP1', 'Var', (14, 17))	('PGE2', 'Chemical', '-', (121, 125))	('leads to', 'Reg', (112, 120))	('calcium', 'Chemical', 'MESH:D002118', (49, 56))
405750	32708604	Fucosylation, which is the most common modification of glycoproteins and glycolipids, induces the biosynthesis of glycan branches of proteins via the addition of fucose to the reducing end of N- and O-linked glycan structures in glycoproteins and glycolipids by fucosyltransferases (FUTs).	('fucose', 'Chemical', 'MESH:D005643', (162, 168))	('induces', 'PosReg', (86, 93))	('glycan', 'Chemical', 'MESH:D011134', (208, 214))	('glycan', 'Chemical', 'MESH:D011134', (114, 120))	('biosynthesis of glycan branches of', 'MPA', (98, 132))	('N- and O-linked glycan', 'Chemical', '-', (192, 214))	('Fucosylation', 'Var', (0, 12))
405753	32708604	Loss of FUT1 reduces the metastatic ability of CC cells by inhibiting EMT through suppression of EGFR-mediated activation of the AKT/ERK pathway.	('reduces', 'NegReg', (13, 20))	('metastatic ability of CC cells', 'CPA', (25, 55))	('EMT', 'CPA', (70, 73))	('FUT1', 'Gene', (8, 12))	('FUT1', 'Gene', '2523', (8, 12))	('ERK', 'Gene', '5594', (133, 136))	('ERK', 'Gene', (133, 136))	('inhibiting', 'NegReg', (59, 69))	('CC', 'Phenotype', 'HP:0030153', (47, 49))	('EGFR-mediated', 'Protein', (97, 110))	('Loss', 'Var', (0, 4))	('suppression', 'NegReg', (82, 93))
405759	32708604	Loss of SOX4 in CC cells markedly reduced the migration and EMT of CC cells by suppressing EGFR expression.	('EGFR', 'Gene', (91, 95))	('reduced', 'NegReg', (34, 41))	('SOX4', 'Gene', (8, 12))	('migration', 'CPA', (46, 55))	('CC', 'Phenotype', 'HP:0030153', (16, 18))	('CC', 'Phenotype', 'HP:0030153', (67, 69))	('expression', 'MPA', (96, 106))	('SOX4', 'Gene', '6659', (8, 12))	('suppressing', 'NegReg', (79, 90))	('rat', 'Species', '10116', (49, 52))	('Loss', 'Var', (0, 4))
405768	32708604	Loss of EBP50 enhances cell motility and migration through induction CC cell EMT by increasing activation of EGFR and its signaling pathways such as ERK1/2 and STAT3.	('CC', 'Phenotype', 'HP:0030153', (69, 71))	('signaling pathways', 'Pathway', (122, 140))	('induction', 'PosReg', (59, 68))	('ERK1/2', 'Gene', (149, 155))	('EBP50', 'Gene', (8, 13))	('rat', 'Species', '10116', (44, 47))	('ERK1/2', 'Gene', '5595;5594', (149, 155))	('EBP50', 'Gene', '9368', (8, 13))	('enhances', 'PosReg', (14, 22))	('Loss', 'Var', (0, 4))	('EGFR', 'Pathway', (109, 113))	('increasing activation', 'PosReg', (84, 105))
405769	32708604	Identification of mutations in various types of cancers by next-generation sequencing technology has demonstrated that somatic mutations as activating mutations are significantly correlated with metastases and poor outcomes in targeted therapy via constitutive activation of downstream signaling pathways, eventually leading to new strategies for mutation-driven drug resistance.	('cancers', 'Disease', (48, 55))	('metastases', 'Disease', 'MESH:D009362', (195, 205))	('rat', 'Species', '10116', (108, 111))	('drug resistance', 'Phenotype', 'HP:0020174', (363, 378))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('rat', 'Species', '10116', (68, 71))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('metastases', 'Disease', (195, 205))	('leading to', 'Reg', (317, 327))	('downstream signaling pathways', 'Pathway', (275, 304))	('mutations', 'Var', (127, 136))	('rat', 'Species', '10116', (334, 337))	('activation', 'PosReg', (261, 271))
405771	32708604	All identified EGFR mutations were in-frame deletions in exon 19 (K745_E749 del) of patients with ICC and exon 19 (E746_A750 del) of one patient with ECC.	('E746_A750 del', 'Var', (115, 128))	('patient', 'Species', '9606', (137, 144))	('K745_E749 del', 'Mutation', 'p.745,749delE', (66, 79))	('patients', 'Species', '9606', (84, 92))	('K745_E749 del', 'Var', (66, 79))	('E746_A750 del', 'Mutation', 'p.746,750delA', (115, 128))	('CC', 'Phenotype', 'HP:0030153', (99, 101))	('ICC', 'Disease', (98, 101))	('EGFR', 'Gene', (15, 19))	('CC', 'Phenotype', 'HP:0030153', (151, 153))	('patient', 'Species', '9606', (84, 91))
405773	32708604	It was also shown that 15% (6/40) of patients with CC had point mutations in the tyrosine kinase domain of the EGFR of patients with ICC (K575R, E872K, T790M), ECC (C775Y, G882S, V843I, L858R), and GBC (A864T).	('V843I', 'Var', (179, 184))	('V843I', 'Mutation', 'rs146795390', (179, 184))	('K575R', 'Var', (138, 143))	('L858R', 'Mutation', 'rs121434568', (186, 191))	('patients', 'Species', '9606', (37, 45))	('T790M', 'Mutation', 'rs121434569', (152, 157))	('C775Y', 'Mutation', 'p.C775Y', (165, 170))	('CC', 'Phenotype', 'HP:0030153', (51, 53))	('K575R', 'Mutation', 'rs1282253805', (138, 143))	('G882S', 'Var', (172, 177))	('G882S', 'Mutation', 'p.G882S', (172, 177))	('EGFR', 'Gene', (111, 115))	('L858R', 'Var', (186, 191))	('CC', 'Phenotype', 'HP:0030153', (161, 163))	('E872K', 'Var', (145, 150))	('T790M', 'Var', (152, 157))	('patients', 'Species', '9606', (119, 127))	('CC', 'Phenotype', 'HP:0030153', (134, 136))	('C775Y', 'Var', (165, 170))	('E872K', 'Mutation', 'rs776347334', (145, 150))	('point mutations in', 'Var', (58, 76))	('A864T', 'Mutation', 'rs1171287261', (203, 208))
405774	32708604	Additionally, 90% (36/40) of CC patients showed a silent mutation at codon 787 in exon 20, and 83.3% of patients with EGFR mutations showed increased MAPK and AKT phosphorylation.	('patients', 'Species', '9606', (32, 40))	('CC', 'Phenotype', 'HP:0030153', (29, 31))	('MAPK', 'Protein', (150, 154))	('EGFR', 'Gene', (118, 122))	('AKT', 'Pathway', (159, 162))	('phosphorylation', 'MPA', (163, 178))	('increased', 'PosReg', (140, 149))	('patients', 'Species', '9606', (104, 112))	('mutations', 'Var', (123, 132))
405775	32708604	Another study demonstrated that 5% (1/20) of patients with CC had a mutation (E804K) in the tyrosine kinase domain located in exon 20 of EGFR, but its function is unknown.	('EGFR', 'Gene', (137, 141))	('E804K) in', 'Var', (78, 87))	('E804K', 'Mutation', 'rs552733360', (78, 83))	('rat', 'Species', '10116', (21, 24))	('patients', 'Species', '9606', (45, 53))	('CC', 'Phenotype', 'HP:0030153', (59, 61))
405777	32708604	The patient that harbored this mutation had pulmonary metastasis after undergoing curative surgical resection.	('pulmonary metastasis', 'Disease', 'MESH:D009362', (44, 64))	('rat', 'Species', '10116', (84, 87))	('mutation', 'Var', (31, 39))	('patient', 'Species', '9606', (4, 11))	('pulmonary metastasis', 'Disease', (44, 64))
405778	32708604	Moreover, EGFR mutations (E709K, L747-P753 delins, V786M) were identified in 7.4% (6/81) of patients with ICC, and a higher EGFR mutation rate (5/38, 13.2%) was detected in patients with ICC who had chronic advanced liver disease relative to those with normal livers (1/43, 2.3%).	('rat', 'Species', '10116', (138, 141))	('chronic advanced liver disease', 'Phenotype', 'HP:0100626', (199, 229))	('CC', 'Phenotype', 'HP:0030153', (107, 109))	('ICC', 'Disease', (187, 190))	('chronic advanced liver disease', 'Disease', 'MESH:D058625', (199, 229))	('patients', 'Species', '9606', (173, 181))	('liver disease', 'Phenotype', 'HP:0001392', (216, 229))	('EGFR', 'Gene', (10, 14))	('E709K', 'Var', (26, 31))	('L747-P753 delins', 'Mutation', 'p.747,753delinsP', (33, 49))	('patients', 'Species', '9606', (92, 100))	('V786M', 'Var', (51, 56))	('ICC', 'Disease', (106, 109))	('chronic advanced liver disease', 'Disease', (199, 229))	('CC', 'Phenotype', 'HP:0030153', (188, 190))	('V786M', 'Mutation', 'rs762672864', (51, 56))	('E709K', 'Mutation', 'rs727504256', (26, 31))	('L747-P753 delins', 'Var', (33, 49))
405779	32708604	Another report exhibits that mutations of EGFR (G719X, S768I, and L861Q) were identified in 21% (17/81) of patients with CC.	('identified', 'Reg', (78, 88))	('patients', 'Species', '9606', (107, 115))	('L861Q', 'Var', (66, 71))	('G719X', 'Mutation', 'p.G719X', (48, 53))	('EGFR', 'Gene', (42, 46))	('S768I', 'Var', (55, 60))	('G719X', 'Var', (48, 53))	('CC', 'Phenotype', 'HP:0030153', (121, 123))	('L861Q', 'Mutation', 'rs121913444', (66, 71))	('S768I', 'Mutation', 'rs121913465', (55, 60))
405780	32708604	Additionally, 9.5% (13/137) of biliary tract cancer (BTC) patients including those with CC have mutations in exon 20 and exon 21 in patients with ICC (T783I, S784F, D837N), ECC (D800G, C818R, V819M, Q820R, D837N, V851I, G873E, G874D), or GBC (A837N, T785I), which correspond with the kinase domain of EGFR.	('V819M', 'Var', (192, 197))	('G874D', 'Var', (227, 232))	('ICC', 'Disease', (146, 149))	('BTC', 'Phenotype', 'HP:0100574', (53, 56))	('S784F', 'Var', (158, 163))	('D800G', 'Var', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('V851I', 'Mutation', 'rs538497054', (213, 218))	('patients', 'Species', '9606', (132, 140))	('ECC', 'Disease', (173, 176))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (31, 51))	('T785I', 'Mutation', 'p.T785I', (250, 255))	('D837N', 'Var', (165, 170))	('Q820R', 'Mutation', 'rs1381875722', (199, 204))	('C818R', 'Mutation', 'p.C818R', (185, 190))	('D837N', 'Var', (206, 211))	('A837N', 'Mutation', 'p.A837N', (243, 248))	('G873E', 'Var', (220, 225))	('CC', 'Phenotype', 'HP:0030153', (147, 149))	('V819M', 'Mutation', 'p.V819M', (192, 197))	('mutations', 'Reg', (96, 105))	('Q820R', 'Var', (199, 204))	('C818R', 'Var', (185, 190))	('T783I', 'Var', (151, 156))	('G873E', 'Mutation', 'p.G873E', (220, 225))	('S784F', 'Mutation', 'rs1424329195', (158, 163))	('patients', 'Species', '9606', (58, 66))	('D800G', 'Mutation', 'p.D800G', (178, 183))	('cancer', 'Disease', (45, 51))	('D837N', 'Mutation', 'rs761920220', (165, 170))	('D837N', 'Mutation', 'rs761920220', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('G874D', 'Mutation', 'p.G874D', (227, 232))	('V851I', 'Var', (213, 218))	('CC', 'Phenotype', 'HP:0030153', (88, 90))	('T783I', 'Mutation', 'rs529174941', (151, 156))	('CC', 'Phenotype', 'HP:0030153', (174, 176))	('A837N', 'Var', (243, 248))
405781	32708604	Also, 10.5% (6/57) and 12.3% (7/57) of BTC patients have an identified mutation in the extracellular domain (ECD) of EGFR (L443Q, S464P, K467stop, N468D, G482E, G482R, L469S) as new mutations and in the tyrosine kinase domain (TKD) of EGFR (L707S, V786M, L788H, G810S, G824S, D837N T854I, D855N), respectively; 50%, 16.7%, and 33.3% of mutated BTC were detected in patients with ICC, ECC, and GBC, respectively.	('patients', 'Species', '9606', (365, 373))	('G482E', 'Var', (154, 159))	('V786M', 'Var', (248, 253))	('L707S', 'Var', (241, 246))	('N468D', 'Mutation', 'rs571837012', (147, 152))	('detected', 'Reg', (353, 361))	('BTC', 'Phenotype', 'HP:0100574', (344, 347))	('G824S', 'Var', (269, 274))	('L707S', 'Mutation', 'p.L707S', (241, 246))	('K467stop', 'Mutation', 'p.K467X', (137, 145))	('K467stop', 'Var', (137, 145))	('G482R', 'Var', (161, 166))	('D855N', 'Var', (289, 294))	('L443Q', 'Mutation', 'p.L443Q', (123, 128))	('CC', 'Phenotype', 'HP:0030153', (385, 387))	('T854I', 'Var', (282, 287))	('G482E', 'Mutation', 'p.G482E', (154, 159))	('ICC', 'Disease', (379, 382))	('L788H', 'Mutation', 'p.L788H', (255, 260))	('D837N', 'Mutation', 'rs761920220', (276, 281))	('patients', 'Species', '9606', (43, 51))	('L469S', 'Mutation', 'p.L469S', (168, 173))	('ECC', 'Disease', (384, 387))	('D855N', 'Mutation', 'p.D855N', (289, 294))	('S464P', 'Mutation', 'p.S464P', (130, 135))	('S464P', 'Var', (130, 135))	('BTC', 'Gene', (344, 347))	('L788H', 'Var', (255, 260))	('BTC', 'Phenotype', 'HP:0100574', (39, 42))	('T854I', 'SUBSTITUTION', 'None', (282, 287))	('EGFR', 'Gene', (117, 121))	('G824S', 'Mutation', 'p.G824S', (269, 274))	('L443Q', 'Var', (123, 128))	('CC', 'Phenotype', 'HP:0030153', (380, 382))	('G482R', 'Mutation', 'rs768627073', (161, 166))	('V786M', 'Mutation', 'rs762672864', (248, 253))	('N468D', 'Var', (147, 152))	('G810S', 'Mutation', 'rs121913230', (262, 267))
405782	32708604	Also, patients with a mutation of the ECD of EGFR revealed a worse OS, and those with maturation at the TKD of EGFR had shorter PFS and OS.	('shorter', 'NegReg', (120, 127))	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', (45, 49))	('patients', 'Species', '9606', (6, 14))	('PFS', 'CPA', (128, 131))	('rat', 'Species', '10116', (90, 93))
405783	32708604	Moreover, new mutations of EGFR were identified in patients with BTCs, including CC (E114K, Y1069C, I425L, C818F, G203R, R669Qfs*36, V524Sfs*44).	('E114K', 'Var', (85, 90))	('BTCs', 'Disease', (65, 69))	('EGFR', 'Gene', (27, 31))	('G203R', 'Var', (114, 119))	('I425L', 'Mutation', 'p.I425L', (100, 105))	('C818F', 'Var', (107, 112))	('R669Qfs*36', 'Mutation', 'p.R669QfsX36', (121, 131))	('Y1069C', 'Var', (92, 98))	('V524Sfs*44', 'Mutation', 'p.V524SfsX44', (133, 143))	('E114K', 'Mutation', 'rs1219568637', (85, 90))	('patients', 'Species', '9606', (51, 59))	('BTC', 'Phenotype', 'HP:0100574', (65, 68))	('V524Sfs*44', 'Var', (133, 143))	('G203R', 'Mutation', 'p.G203R', (114, 119))	('Y1069C', 'Mutation', 'p.Y1069C', (92, 98))	('CC', 'Phenotype', 'HP:0030153', (81, 83))	('I425L', 'Var', (100, 105))	('R669Qfs*36', 'Var', (121, 131))	('C818F', 'Mutation', 'p.C818F', (107, 112))
405784	32708604	ERBB2 mutations were identified in 25% (5/20) of patients with ECC, wherein ERBB2 was mutated in the kinase domain (V777L) and extracellular domain (S310F).	('S310F', 'Mutation', 'rs1057519816', (149, 154))	('ECC', 'Disease', (63, 66))	('V777L', 'Mutation', 'rs121913471', (116, 121))	('ERBB2', 'Gene', (0, 5))	('CC', 'Phenotype', 'HP:0030153', (64, 66))	('patients', 'Species', '9606', (49, 57))	('V777L', 'Var', (116, 121))	('S310F', 'Var', (149, 154))	('ERBB2', 'Gene', (76, 81))
405785	32708604	Also, ERBB2 activating mutations (S310F/Y, G292R, T862A, D769H, L869R, V842I, R678Q, G776V, S653C, R897W, and G660D) were detected in 2% (9/459) of patients with CC.	('G292R', 'Var', (43, 48))	('R678Q', 'Var', (78, 83))	('G660D', 'Mutation', 'rs1196929947', (110, 115))	('S653C', 'Var', (92, 97))	('L869R', 'Var', (64, 69))	('S653C', 'Mutation', 'p.S653C', (92, 97))	('D769H', 'Var', (57, 62))	('G660D', 'Var', (110, 115))	('patients', 'Species', '9606', (148, 156))	('T862A', 'Var', (50, 55))	('ERBB2', 'Gene', (6, 11))	('R897W', 'Var', (99, 104))	('G776V', 'Var', (85, 90))	('CC', 'Phenotype', 'HP:0030153', (162, 164))	('D769H', 'Mutation', 'rs121913468', (57, 62))	('S310F/Y', 'Var', (34, 41))	('activating', 'PosReg', (12, 22))	('G292R', 'Mutation', 'p.G292R', (43, 48))	('V842I', 'Mutation', 'rs1057519738', (71, 76))	('L869R', 'Mutation', 'rs1131692237', (64, 69))	('G776V', 'Mutation', 'rs144434331', (85, 90))	('V842I', 'Var', (71, 76))	('R897W', 'Mutation', 'rs375135008', (99, 104))	('S310F', 'Mutation', 'rs1057519816', (34, 39))	('T862A', 'Mutation', 'c.862T>A', (50, 55))	('R678Q', 'Mutation', 'rs1057519862', (78, 83))
405786	32708604	Although mutations of ERBB4 have been identified in patients with CC (S79Y, R106C, D376Y, C580*, K682N, F682L, E835D, R847C, R938C, Y950H, D960G, R992H, Y1066H, P1092S, Q1126K, Q1270K), its function remains unknown.	('R847C', 'Var', (118, 123))	('C580*', 'Var', (90, 95))	('R938C', 'Mutation', 'p.R938C', (125, 130))	('Q1126K', 'Var', (169, 175))	('R106C', 'Var', (76, 81))	('D376Y', 'Mutation', 'p.D376Y', (83, 88))	('F682L', 'Mutation', 'p.F682L', (104, 109))	('Y1066H', 'Mutation', 'rs878936823', (153, 159))	('K682N', 'Mutation', 'p.K682N', (97, 102))	('R106C', 'Mutation', 'rs751175543', (76, 81))	('D376Y', 'Var', (83, 88))	('ERBB4', 'Gene', '2066', (22, 27))	('R992H', 'Var', (146, 151))	('CC', 'Phenotype', 'HP:0030153', (66, 68))	('patients', 'Species', '9606', (52, 60))	('D960G', 'Mutation', 'p.D960G', (139, 144))	('identified', 'Reg', (38, 48))	('ERBB4', 'Gene', (22, 27))	('R847C', 'Mutation', 'rs754127388', (118, 123))	('C580*', 'SUBSTITUTION', 'None', (90, 95))	('R938C', 'Var', (125, 130))	('E835D', 'Mutation', 'p.E835D', (111, 116))	('Y950H', 'Mutation', 'p.Y950H', (132, 137))	('Q1270K', 'Var', (177, 183))	('Q1270K', 'Mutation', 'p.Q1270K', (177, 183))	('E835D', 'Var', (111, 116))	('F682L', 'Var', (104, 109))	('D960G', 'Var', (139, 144))	('Q1126K', 'Mutation', 'p.Q1126K', (169, 175))	('P1092S', 'Var', (161, 167))	('K682N', 'Var', (97, 102))	('Y1066H', 'Var', (153, 159))	('R992H', 'Mutation', 'rs1390491269', (146, 151))	('P1092S', 'Mutation', 'p.P1092S', (161, 167))	('Y950H', 'Var', (132, 137))	('S79Y', 'Mutation', 'p.S79Y', (70, 74))
405787	32708604	Moreover, new mutations of ERBB2 have been identified in patients with BTC, including CC (L755P/S, E265K, L994V, L1098M) (TCGA dataset).	('L994V', 'Mutation', 'p.L994V', (106, 111))	('E265K', 'Mutation', 'p.E265K', (99, 104))	('BTC', 'Phenotype', 'HP:0100574', (71, 74))	('BTC', 'Disease', (71, 74))	('patients', 'Species', '9606', (57, 65))	('L994V', 'Var', (106, 111))	('L755P', 'SUBSTITUTION', 'None', (90, 95))	('L1098M', 'Var', (113, 119))	('E265K', 'Var', (99, 104))	('L1098M', 'Mutation', 'p.L1098M', (113, 119))	('ERBB2', 'Gene', (27, 32))	('L755P', 'Var', (90, 95))	('CC', 'Phenotype', 'HP:0030153', (86, 88))
405788	32708604	ERBB3 mutations (G284R, V104M, A232V, E928G, G284R, V104L, D297Y, T355I) were detected in patients with BTC including CC, as activating mutants.	('G284R', 'Mutation', 'rs1057519803', (17, 22))	('A232V', 'Var', (31, 36))	('CC', 'Phenotype', 'HP:0030153', (118, 120))	('V104L', 'Mutation', 'rs1057519893', (52, 57))	('D297Y', 'Var', (59, 64))	('A232V', 'Mutation', 'p.A232V', (31, 36))	('G284R', 'Var', (17, 22))	('E928G', 'Var', (38, 43))	('ERBB3', 'Gene', (0, 5))	('T355I', 'Var', (66, 71))	('V104M', 'Mutation', 'rs1057519893', (24, 29))	('E928G', 'Mutation', 'p.E928G', (38, 43))	('BTC', 'Phenotype', 'HP:0100574', (104, 107))	('V104L', 'Var', (52, 57))	('V104M', 'Var', (24, 29))	('T355I', 'Mutation', 'rs993665271', (66, 71))	('G284R', 'Mutation', 'rs1057519803', (45, 50))	('patients', 'Species', '9606', (90, 98))	('ERBB3', 'Gene', '2065', (0, 5))	('G284R', 'Var', (45, 50))	('D297Y', 'Mutation', 'rs1057519891', (59, 64))	('BTC', 'Disease', (104, 107))
405789	32708604	Other mutants of EBBB3 (V1035D, G508R, G582W, A1252S, D581N, R444Q, V586M, G994D, N222Tfs*47, E230Dfs*39, D73Tfs*11, D296Ifs*16, D297Ifs*16) and ERBB4 (R103C, I68N, L432M, S602C, P1158H, T475A, S1286Lfs*5, F356Sfs*2) were identified in patients with BTC, including CC, but their function is unknown (TCGA dataset).	('E230Dfs*39', 'Mutation', 'p.E230DfsX39', (94, 104))	('BTC', 'Phenotype', 'HP:0100574', (250, 253))	('R444Q', 'Var', (61, 66))	('N222Tfs*47', 'Var', (82, 92))	('P1158H', 'Mutation', 'p.P1158H', (179, 185))	('G994D', 'Mutation', 'rs1195904336', (75, 80))	('D297Ifs*16', 'Mutation', 'p.D297IfsX16', (129, 139))	('V1035D', 'Mutation', 'p.V1035D', (24, 30))	('R103C', 'Mutation', 'rs201152419', (152, 157))	('L432M', 'Var', (165, 170))	('G582W', 'Var', (39, 44))	('D296Ifs*16', 'Var', (117, 127))	('T475A', 'Mutation', 'rs755541652', (187, 192))	('D581N', 'Mutation', 'p.D581N', (54, 59))	('G508R', 'Var', (32, 37))	('P1158H', 'Var', (179, 185))	('E230Dfs*39', 'Var', (94, 104))	('ERBB4', 'Gene', (145, 150))	('patients', 'Species', '9606', (236, 244))	('S602C', 'Var', (172, 177))	('G994D', 'Var', (75, 80))	('V586M', 'Var', (68, 73))	('CC', 'Phenotype', 'HP:0030153', (265, 267))	('F356Sfs*2', 'Var', (206, 215))	('N222Tfs*47', 'Mutation', 'p.N222TfsX47', (82, 92))	('D73Tfs*11', 'Mutation', 'p.D73TfsX11', (106, 115))	('D581N', 'Var', (54, 59))	('BTC', 'Disease', (250, 253))	('V586M', 'Mutation', 'p.V586M', (68, 73))	('G582W', 'Mutation', 'p.G582W', (39, 44))	('D73Tfs*11', 'Var', (106, 115))	('A1252S', 'Mutation', 'p.A1252S', (46, 52))	('V1035D', 'Var', (24, 30))	('D297Ifs*16', 'Var', (129, 139))	('A1252S', 'Var', (46, 52))	('EBBB3', 'Gene', (17, 22))	('D296Ifs*16', 'Mutation', 'p.D296IfsX16', (117, 127))	('G508R', 'Mutation', 'rs770129304', (32, 37))	('I68N', 'Mutation', 'p.I68N', (159, 163))	('ERBB4', 'Gene', '2066', (145, 150))	('S602C', 'Mutation', 'p.S602C', (172, 177))	('L432M', 'Mutation', 'p.L432M', (165, 170))	('R444Q', 'Mutation', 'rs777498890', (61, 66))	('S1286Lfs*5', 'Var', (194, 204))	('T475A', 'Var', (187, 192))
405790	32708604	EGFR inhibitors and their efficacy in cholangiocarcinoma summarized in Table 2.	('cholangiocarcinoma', 'Disease', (38, 56))	('EGFR', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('inhibitors', 'Var', (5, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))
405797	32708604	The FDA approved gefitinib is an EGFR inhibitor for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations, which has exon 19 deletions or exon 21 (L858R).	('lung cancer', 'Disease', (84, 95))	('gefitinib', 'Chemical', 'MESH:D000077156', (17, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (73, 95))	('mutations', 'Var', (114, 123))	('NSCLC', 'Disease', (97, 102))	('L858R', 'Mutation', 'rs121434568', (165, 170))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (69, 95))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('EGFR', 'Gene', (109, 113))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
405798	32708604	CC cells showed resistance to gefitinib or CI-1040, an inhibitor of MEK1/2, alone.	('gefitinib', 'Chemical', 'MESH:D000077156', (30, 39))	('resistance', 'MPA', (16, 26))	('CI-1040', 'Var', (43, 50))	('CI-1040', 'Chemical', 'MESH:C120227', (43, 50))	('CC', 'Phenotype', 'HP:0030153', (0, 2))	('MEK1/2', 'Gene', '5604;5605', (68, 74))	('MEK1/2', 'Gene', (68, 74))
405802	32708604	Gemcitabine, a pyrimidine analog, also inhibits the growth of CC cells in a concentration-dependent manner, and the combination of gefitinib and gemcitabine showed a synergistic effect in suppressing the tumor growth of CC cells in vivo and in vitro through significant inhibition of EGFR/ERK1/2 activation relative to treatment with either gefitinib or gemcitabine alone.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('suppressing', 'NegReg', (188, 199))	('gefitinib', 'Chemical', 'MESH:D000077156', (341, 350))	('ERK1/2', 'Gene', (289, 295))	('inhibition', 'NegReg', (270, 280))	('ERK1/2', 'Gene', '5595;5594', (289, 295))	('gemcitabine', 'Chemical', 'MESH:C056507', (145, 156))	('inhibits', 'NegReg', (39, 47))	('activation', 'PosReg', (296, 306))	('CC', 'Phenotype', 'HP:0030153', (220, 222))	('combination', 'Var', (116, 127))	('Gemcitabine', 'Chemical', 'MESH:C056507', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('gefitinib', 'Chemical', 'MESH:D000077156', (131, 140))	('pyrimidine', 'Chemical', 'MESH:C030986', (15, 25))	('rat', 'Species', '10116', (83, 86))	('growth', 'CPA', (52, 58))	('gemcitabine', 'Chemical', 'MESH:C056507', (354, 365))	('tumor', 'Disease', (204, 209))	('CC', 'Phenotype', 'HP:0030153', (62, 64))
405812	32708604	Cetuximab combined with target agents for the treatment of CC, and solid tumors are currently under evaluation in phase 1 or 2 clinical trials (ClinicalTrials.gov Identifier: NCT03829436, NCT03768375, NCT02836847, and NCT03693807).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('NCT03829436', 'Var', (175, 186))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('NCT03693807', 'Var', (218, 229))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Cetuximab', 'Chemical', 'MESH:D000068818', (0, 9))	('tumors', 'Disease', (73, 79))	('NCT02836847', 'Var', (201, 212))	('CC', 'Phenotype', 'HP:0030153', (59, 61))	('NCT03768375', 'Var', (188, 199))
405829	32708604	FDA-approved erlotinib is an EFGR inhibitor for first-line treatment of NSCLC patients with EGFR mutations.	('mutations', 'Var', (97, 106))	('NSCLC', 'Disease', (72, 77))	('patients', 'Species', '9606', (78, 86))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('EGFR', 'Gene', (92, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('erlotinib', 'Chemical', 'MESH:D000069347', (13, 22))
405835	32708604	The treatment of erlotinib for a patient with hepatocholangiocellular carcinoma with the EGFR R521K mutation had an SD with no metastases and showed a response duration of more than one year.	('patient', 'Species', '9606', (33, 40))	('rat', 'Species', '10116', (162, 165))	('EGFR', 'Gene', (89, 93))	('hepatocholangiocellular carcinoma', 'Disease', (46, 79))	('metastases', 'Disease', 'MESH:D009362', (127, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('R521K', 'Mutation', 'rs2227983', (94, 99))	('hepatocholangiocellular carcinoma', 'Disease', 'MESH:D009369', (46, 79))	('erlotinib', 'Chemical', 'MESH:D000069347', (17, 26))	('metastases', 'Disease', (127, 137))	('R521K', 'Var', (94, 99))
405844	32708604	T-DM1 treatment significantly increased invasive disease-free survival and showed a 50% lower risk of recurrence relative to the trastuzumab group (ClinicalTrials.gov Identifier: NCT01772472).	('trastuzumab', 'Chemical', 'MESH:D000068878', (129, 140))	('T-DM1', 'Var', (0, 5))	('T-DM1', 'Chemical', 'MESH:C550911', (0, 5))	('invasive disease-free survival', 'CPA', (40, 70))	('increased', 'PosReg', (30, 39))	('lower', 'NegReg', (88, 93))
405845	32708604	T-DM1 showed preclinical activity for inhibiting the progression of BTC, including CC.	('CC', 'Phenotype', 'HP:0030153', (83, 85))	('T-DM1', 'Var', (0, 5))	('T-DM1', 'Chemical', 'MESH:C550911', (0, 5))	('BTC', 'Phenotype', 'HP:0100574', (68, 71))	('inhibiting', 'NegReg', (38, 48))	('BTC', 'Disease', (68, 71))
405846	32708604	The growth inhibitory activity of BTC cells in vivo and in vitro by T-DM1 treatment was closely dependent on ERBB2 expression so that T-DM1 treatment has significant antitumor efficacy for ERBB2-expressing BTC cells but not for ERBB2-negative BTC cells in BTC xenograft models.	('T-DM1', 'Chemical', 'MESH:C550911', (134, 139))	('T-DM1', 'Chemical', 'MESH:C550911', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('T-DM1', 'Var', (134, 139))	('BTC', 'Phenotype', 'HP:0100574', (256, 259))	('BTC', 'Phenotype', 'HP:0100574', (243, 246))	('ERBB2-expressing', 'Var', (189, 205))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('BTC', 'Phenotype', 'HP:0100574', (206, 209))	('BTC', 'Phenotype', 'HP:0100574', (34, 37))	('growth inhibitory activity', 'MPA', (4, 30))
405847	32708604	Also, T-DM1 induces cell cycle arrest at the G2/M phase by inhibiting the activation of both ERBB2 and EGBB3.	('T-DM1', 'Var', (6, 11))	('arrest', 'Disease', (31, 37))	('T-DM1', 'Chemical', 'MESH:C550911', (6, 11))	('ERBB2', 'Protein', (93, 98))	('inhibiting', 'NegReg', (59, 69))	('EGBB3', 'Gene', (103, 108))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (20, 37))	('activation', 'MPA', (74, 84))	('arrest', 'Disease', 'MESH:D006323', (31, 37))
405848	32708604	Pertuzumab, in combination with trastuzumab for ERBB2 positive one CC patient, showed an excellent, ongoing, durable response by reduction of dominant TP53 mutation and significant tumor regression.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('TP53', 'Gene', (151, 155))	('reduction', 'NegReg', (129, 138))	('patient', 'Species', '9606', (70, 77))	('CC', 'Phenotype', 'HP:0030153', (67, 69))	('ERBB2', 'Gene', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('Pertuzumab', 'Chemical', 'MESH:C485206', (0, 10))	('trastuzumab', 'Chemical', 'MESH:D000068878', (32, 43))	('TP53', 'Gene', '7157', (151, 155))	('mutation', 'Var', (156, 164))
405857	32708604	Afatinib is an inhibitor for EGFR and ERBBs (HER2, HER4) and was approved by the FDA for metastatic NSCLC with non-resistant EGFR mutations (EGFR S768I, L861Q, and G719X).	('EGFR', 'Var', (141, 145))	('L861Q', 'Mutation', 'rs121913444', (153, 158))	('ERBB', 'Gene', '1956', (38, 42))	('NSCLC', 'Disease', (100, 105))	('G719X', 'Mutation', 'p.G719X', (164, 169))	('HER4', 'Gene', '2066', (51, 55))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('HER4', 'Gene', (51, 55))	('L861Q', 'Var', (153, 158))	('EGFR', 'Gene', (125, 129))	('ERBB', 'Gene', (38, 42))	('HER2', 'Gene', (45, 49))	('G719X', 'Var', (164, 169))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('HER2', 'Gene', '2064', (45, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('S768I', 'Mutation', 'rs121913465', (146, 151))
405865	32708604	Various EGFR-and ERBB2-CAR-T clinical trials are also under evaluation for patients with various cancer types (ClinicalTrials.gov Identifier: NCT03618381, NCT03638167, NCT03696030, NCT03198052, etc.).	('NCT03638167', 'Var', (155, 166))	('CAR-T', 'Gene', (23, 28))	('NCT03618381', 'Var', (142, 153))	('NCT03198052', 'Var', (181, 192))	('cancer', 'Disease', (97, 103))	('patients', 'Species', '9606', (75, 83))	('CAR-T', 'Gene', '9607', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('NCT03696030', 'Var', (168, 179))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
405884	32708604	Recently, tucatinib has been under evaluation for patients with breast cancer and CRC in combination with trastuzumab and capecitabine or palbociclib and letrozole (ClinicalTrials.gov Identifier: NCT03054363, NCT03501979, NCT03043313).	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('capecitabine', 'Chemical', 'MESH:D000069287', (122, 134))	('CRC', 'Disease', 'MESH:D015179', (82, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('patients', 'Species', '9606', (50, 58))	('letrozole', 'Chemical', 'MESH:D000077289', (154, 163))	('trastuzumab', 'Chemical', 'MESH:D000068878', (106, 117))	('palbociclib', 'Chemical', 'MESH:C500026', (138, 149))	('tucatinib', 'Chemical', '-', (10, 19))	('NCT03043313', 'Var', (222, 233))	('CRC', 'Disease', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
405890	32708604	Recently, mutations of EGFR and ERBBs were identified, but the functional role of the newly identified mutations of EGFR and ERBBs has remained unclear.	('ERBB', 'Gene', (32, 36))	('ERBB', 'Gene', (125, 129))	('ERBB', 'Gene', '1956', (125, 129))	('ERBB', 'Gene', '1956', (32, 36))	('mutations', 'Var', (10, 19))	('EGFR', 'Gene', (23, 27))	('EGFR', 'Gene', (116, 120))
405891	32708604	However, these mutations seem to affect the survival, invasion, metastasis, and chemoresistance of CC through changes in the expression or activation of EGFR and ERBBs.	('survival', 'CPA', (44, 52))	('chemoresistance', 'CPA', (80, 95))	('invasion', 'CPA', (54, 62))	('activation', 'PosReg', (139, 149))	('ERBB', 'Gene', '1956', (162, 166))	('affect', 'Reg', (33, 39))	('mutations', 'Var', (15, 24))	('CC', 'Phenotype', 'HP:0030153', (99, 101))	('expression', 'MPA', (125, 135))	('EGFR', 'Gene', (153, 157))	('metastasis', 'CPA', (64, 74))	('changes', 'Reg', (110, 117))	('ERBB', 'Gene', (162, 166))
405892	32708604	Overexpression and activation by mutation of EGFR and ERBBs have been linked to the development and progression of CC and acquisition of chemoresistance against chemotherapeutic agents.	('ERBB', 'Gene', (54, 58))	('mutation', 'Var', (33, 41))	('linked', 'Reg', (70, 76))	('EGFR', 'Gene', (45, 49))	('CC', 'Phenotype', 'HP:0030153', (115, 117))	('activation', 'PosReg', (19, 29))	('ERBB', 'Gene', '1956', (54, 58))
405914	31380271	Inhibition of this pathway can be achieved at different levels using various mechanisms; with monoclonal antibodies to VEGFA or its receptor, with recombinant fusion protein to VEGF and with various multi-targeted tyrosine kinase inhibitors (TKIs).	('VEGFA', 'Gene', (119, 124))	('monoclonal antibodies', 'Var', (94, 115))	('VEGFA', 'Gene', '7422', (119, 124))
405947	31380271	In gastric, junctional and cardia tumors, mPFS was 8.7 months for the ramucirumab arm vs. 7.1 months in the placebo arm (HR = 0.77) compared to patients with a primary esophageal tumor where mPFS was 5.6 vs. 6.1 months (HR = 1.30).	('gastric', 'Disease', (3, 10))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('junctional', 'Disease', (12, 22))	('esophageal tumor', 'Disease', 'MESH:D004938', (168, 184))	('ramucirumab', 'Chemical', 'MESH:C543333', (70, 81))	('patients', 'Species', '9606', (144, 152))	('esophageal tumor', 'Disease', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cardia tumors', 'Disease', 'MESH:D004938', (27, 40))	('ramucirumab', 'Var', (70, 81))	('cardia tumors', 'Disease', (27, 40))	('esophageal tumor', 'Phenotype', 'HP:0100751', (168, 184))
405964	31380271	A higher disease control rate with ramucirumab was found in patients with high EGFR expression tumors (2+/3+) compared with low expression tumors (0/1+) (87.5 vs. 50%, p = 0.02).	('higher', 'PosReg', (2, 8))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('high', 'Var', (74, 78))	('patients', 'Species', '9606', (60, 68))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ramucirumab', 'Chemical', 'MESH:C543333', (35, 46))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('disease control', 'CPA', (9, 24))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
405969	31380271	The RAISE study investigated the use of ramucirumab or placebo in combination with FOLFIRI in second line metastatic colorectal cancer and found a significant improvement in OS and PFS with the use of ramucirumab.	('ramucirumab', 'Var', (201, 212))	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('improvement', 'PosReg', (159, 170))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('colorectal cancer', 'Disease', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ramucirumab', 'Chemical', 'MESH:C543333', (201, 212))	('FOLFIRI', 'Chemical', '-', (83, 90))	('OS', 'Gene', '17451', (174, 176))	('ramucirumab', 'Chemical', 'MESH:C543333', (40, 51))	('PFS', 'Disease', (181, 184))
405970	31380271	A subsequent biomarker analysis identified VEGF-D as a potential marker, noting improved median OS in those patients with high levels of VEGF-D compared to low levels and investigators are currently developing an assay for further testing in clinical practice.	('high levels', 'Var', (122, 133))	('VEGF-D', 'Gene', (43, 49))	('VEGF-D', 'Gene', '2277', (43, 49))	('improved', 'PosReg', (80, 88))	('VEGF-D', 'Gene', '2277', (137, 143))	('VEGF-D', 'Gene', (137, 143))	('patients', 'Species', '9606', (108, 116))	('OS', 'Gene', '17451', (96, 98))
405996	31380271	Based on these results it is difficult to see a role for bevacizumab in OG cancer at present, although there are currently phase 1 trials investigating bevacizumab in combination with the anti PDL-1 monocolonal antibody atezolizumab in solid tumors, including esophageal, and gastric cancers (NCT02715531, NCT01633970).	('PDL-1', 'Gene', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal', 'Disease', (260, 270))	('solid tumors', 'Disease', (236, 248))	('OG cancer', 'Disease', (72, 81))	('NCT02715531', 'Var', (293, 304))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('PDL-1', 'Gene', '29126', (193, 198))	('bevacizumab', 'Chemical', 'MESH:D000068258', (57, 68))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('atezolizumab', 'Chemical', 'MESH:C000594389', (220, 232))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('solid tumors', 'Disease', 'MESH:D009369', (236, 248))	('NCT01633970', 'Var', (306, 317))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('gastric cancers', 'Disease', 'MESH:D013274', (276, 291))	('gastric cancers', 'Disease', (276, 291))	('OG cancer', 'Disease', 'MESH:D009369', (72, 81))	('gastric cancers', 'Phenotype', 'HP:0012126', (276, 291))	('bevacizumab', 'Chemical', 'MESH:D000068258', (152, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))
406006	31380271	As outlined in Table 4, the only TKI to be investigated in phase III trials is apatinib, where an Asian study of 267 patients with advanced gastric or GOJ adenocarcinoma demonstrated a significantly improved median OS with apatinib compared with placebo.	('apatinib', 'Chemical', 'MESH:C553458', (223, 231))	('improved', 'PosReg', (199, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('OS', 'Gene', '17451', (215, 217))	('apatinib', 'Var', (223, 231))	('patients', 'Species', '9606', (117, 125))	('gastric or GOJ adenocarcinoma', 'Disease', (140, 169))	('apatinib', 'Chemical', 'MESH:C553458', (79, 87))	('gastric or GOJ adenocarcinoma', 'Disease', 'MESH:D013274', (140, 169))
406036	31380271	Both ORR and duration of response were higher in the PD-L1 positive patients (15.5 vs. 6.4% and 16.3 and 6.9 months, respectively) as was OS, at 5.8 months (95% CI, 4.5-7.9) vs. 4.9 (95% CI, 3.4-6.5) months.	('PD-L1', 'Gene', (53, 58))	('higher', 'PosReg', (39, 45))	('OS', 'Gene', '17451', (138, 140))	('positive', 'Var', (59, 67))	('patients', 'Species', '9606', (68, 76))	('ORR', 'MPA', (5, 8))
406040	31380271	This extended the existing tumor agnostic license for pembrolizumab in patients with unresectable or metastatic, microsatellite-instability-high or mismatch-repair-deficient solid tumors, which would apply to ~4-5% gastric tumors.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('patients', 'Species', '9606', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('gastric tumors', 'Disease', 'MESH:D013274', (215, 229))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (27, 32))	('pembrolizumab', 'Chemical', 'MESH:C582435', (54, 67))	('deficient solid tumors', 'Disease', 'MESH:D009369', (164, 186))	('gastric tumors', 'Phenotype', 'HP:0006753', (215, 229))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('deficient solid tumors', 'Disease', (164, 186))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('microsatellite-instability-high', 'Var', (113, 144))	('gastric tumors', 'Disease', (215, 229))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Disease', (180, 185))
406055	31380271	For example a murine study using Colon-26 adenocarcinoma demonstrated that simultaneous treatment with anti-PD-1 and anti-VEGFR2 monoclonal antibodies resulted in a synergistically increased inhibition of tumor growth compared with either therapy alone without excess toxicity.	('murine', 'Species', '10090', (14, 20))	('anti-VEGFR2', 'Var', (117, 128))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('inhibition', 'NegReg', (191, 201))	('adenocarcinoma', 'Disease', (42, 56))	('anti-PD-1', 'Var', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('toxicity', 'Disease', 'MESH:D064420', (268, 276))	('adenocarcinoma', 'Disease', 'MESH:D000230', (42, 56))	('toxicity', 'Disease', (268, 276))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('increased', 'PosReg', (181, 190))
406057	31380271	A set of experiments with murine models of breast cancer, pancreatic neuroendocrine carcinoma and glioma demonstrated that anti-PD-L1 therapy can sensitize tumors to anti-angiogenic therapy and prolong its efficacy.	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (69, 93))	('anti-angiogenic therapy', 'CPA', (166, 189))	('sensitize', 'Reg', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('anti-PD-L1', 'Var', (123, 133))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('glioma', 'Disease', (98, 104))	('prolong', 'NegReg', (194, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('pancreatic neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (58, 93))	('efficacy', 'MPA', (206, 214))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('tumors', 'Disease', (156, 162))	('breast cancer', 'Disease', (43, 56))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('murine', 'Species', '10090', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('pancreatic neuroendocrine carcinoma', 'Disease', (58, 93))
406103	29384778	Hypomethylation of the recently identified tumor suppressor OR3A4 (probe cg09890332) validated in a separate cohort of samples (median methylation in progressors 67.8% vs 96.7% in nonprogressors; P = 0.0001, z = 3.85, Wilcoxon rank-sum test) and was associated with the progression to adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (285, 299))	('OR3A4', 'Gene', (60, 65))	('cg09890332', 'Chemical', '-', (73, 83))	('Hypomethylation', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('OR3A4', 'Gene', '390756', (60, 65))	('methylation', 'MPA', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('adenocarcinoma', 'Disease', (285, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('tumor', 'Disease', (43, 48))	('associated with', 'Reg', (250, 265))
406104	29384778	Hypomethylation of OR3A4 has the ability to risk stratify the patient with nondysplastic Barrett esophagus and may form the basis of a future surveillance program.	('OR3A4', 'Gene', (19, 24))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (89, 106))	('Hypomethylation', 'Var', (0, 15))	('patient', 'Species', '9606', (62, 69))	('OR3A4', 'Gene', '390756', (19, 24))	('nondysplastic Barrett esophagus', 'Disease', (75, 106))	('nondysplastic Barrett esophagus', 'Disease', 'MESH:D001471', (75, 106))
406116	29384778	Attempts at biomarker development for stratification of high-risk BE have focused on mutational change, specifically around the role of TP53 mutation in predicting "high-risk" disease, given its role as a driver in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('esophageal cancer', 'Disease', (215, 232))	('predicting "high-risk" disease', 'Disease', (153, 183))	('esophageal cancer', 'Disease', 'MESH:D004938', (215, 232))	('BE', 'Phenotype', 'HP:0100580', (66, 68))	('TP53', 'Gene', '7157', (136, 140))	('mutation', 'Var', (141, 149))	('TP53', 'Gene', (136, 140))
406117	29384778	However, Ross-Innes et al have convincingly demonstrated the presence of pathogenic TP53 mutations in apparently normal squamous esophageal mucosa, thus making its role in progression to invasive adenocarcinoma unclear.	('squamous esophageal mucosa', 'Disease', (120, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('pathogenic', 'Reg', (73, 83))	('invasive adenocarcinoma', 'Disease', (187, 210))	('TP53', 'Gene', '7157', (84, 88))	('mutations', 'Var', (89, 98))	('squamous esophageal mucosa', 'Disease', 'MESH:D000077277', (120, 146))	('TP53', 'Gene', (84, 88))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (187, 210))
406118	29384778	However, the role of epigenetic change in the pathogenesis of BE and esophageal cancer is less well-understood, but may well happen much earlier in the cancer development pathway, and, as a direct result, provide a more appropriate target for both predicting its development and potentially arresting tumorigenesis, should a suitable epigenetic modulator be identified.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('esophageal cancer', 'Disease', (69, 86))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', (301, 306))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('epigenetic', 'Var', (21, 31))	('BE', 'Phenotype', 'HP:0100580', (62, 64))	('cancer', 'Disease', (80, 86))
406152	29384778	For all patients in the progressor cohort (n = 30), the observed pathological disease stages at the time of resection were high-grade dysplasia (4/30, 13%), T1N0 (10/30, 33%), T1N1 (1/30, 3%), T2N0 (2/30, 7%), T2N1 (3/30,10%), T3N0 (6/30, 20%), and T3N1 (4/30, 13%).	('patients', 'Species', '9606', (8, 16))	('T2N0', 'Var', (193, 197))	('T3N1', 'Disease', (249, 253))	('dysplasia', 'Disease', 'MESH:D004476', (134, 143))	('dysplasia', 'Disease', (134, 143))	('T1N0', 'Disease', (157, 161))	('T1N1', 'Disease', (176, 180))	('T3N0', 'Disease', (227, 231))
406156	29384778	The top ranked differentially methylated probe was cg09890332 (chr17:3212495-3212495, hg19 coordinates), which tags a CpG dinucleotide -1044 bp upstream of the transcription start site of the long noncoding RNA, OR3A4 (NRR_024128.1).	('cg09890332', 'Chemical', '-', (51, 61))	('cg09890332', 'Var', (51, 61))	('OR3A4', 'Gene', (212, 217))	('OR3A4', 'Gene', '390756', (212, 217))	('chr17:3212495-3212495', 'STRUCTURAL_ABNORMALITY', 'None', (63, 84))
406159	29384778	The third highest ranked differentially methylated probe was cg17337672 (chr10:123354172-123354172), which tags a CpG dinucleotide within intron 2 of FGFR2 (fibroblast growth factor receptor 2, NM_000141.4).	('fibroblast growth factor receptor 2', 'Gene', '2263', (157, 192))	('fibroblast growth factor receptor 2', 'Gene', (157, 192))	('cg17337672', 'Var', (61, 71))	('FGFR2', 'Gene', '2263', (150, 155))	('FGFR2', 'Gene', (150, 155))	('chr10:123354172-123354172', 'STRUCTURAL_ABNORMALITY', 'None', (73, 98))
406161	29384778	Significant DMRs were found from chr2:503065-503193 (which tags an intragenic region, DMR P = 7.69 x 10-4), chr5:8217236-8217322 (which also tags an intragenic region, DMR P = 1.27 x 10-3), and chr10: 123353418-123355576, which spans a region from the 5'-UTR of FGFR2 to the first exon within FGFR2 (DMR P = 4.79 x 10-3).	('FGFR2', 'Gene', (262, 267))	('FGFR2', 'Gene', '2263', (262, 267))	('chr5:8217236-8217322', 'Var', (108, 128))	('FGFR2', 'Gene', '2263', (293, 298))	('FGFR2', 'Gene', (293, 298))	('chr5:8217236-8217322', 'STRUCTURAL_ABNORMALITY', 'None', (108, 128))	('chr2:503065-503193', 'STRUCTURAL_ABNORMALITY', 'None', (33, 51))
406164	29384778	For OR3A4 cg09890332, median methylation was 67.8% [interquartile range (IQR) 12.1] in progressors versus 96.7% (IQR 16.1) in nonprogressors (P = 0.0001, z = 5.158; Wilcoxon rank-sum test) (Fig.	('cg09890332', 'Chemical', '-', (10, 20))	('cg09890332', 'Var', (10, 20))	('OR3A4', 'Gene', (4, 9))	('OR3A4', 'Gene', '390756', (4, 9))	('methylation', 'MPA', (29, 40))
406166	29384778	To investigate whether this phenomenon was localized to this region or was a gene-wide phenomenon, an additional pyrosequencing assay was designed based on probe ID cg07863524 (chr17:3213471-3213471), which is +976 bp downstream from cg09890332 and -68 bp from the transcription start site of OR4A4.	('cg09890332', 'Var', (234, 244))	('OR4A4', 'Gene', (293, 298))	('OR4A4', 'Gene', '390134', (293, 298))	('chr17:3213471-3213471', 'STRUCTURAL_ABNORMALITY', 'None', (177, 198))	('cg09890332', 'Chemical', '-', (234, 244))
406171	29384778	Percentage methylation at OR3A4 and stromal expression was strongly negatively correlated (Pearson correlation coefficient -0.85, P = 0.014), and a similar, but nonsignificant correlation was observed with epithelial expression and methylation at OR3A4 (Pearson correlation coefficient -0.40, P = 0.373).	('methylation', 'Var', (232, 243))	('methylation', 'MPA', (11, 22))	('OR3A4', 'Gene', (26, 31))	('OR3A4', 'Gene', '390756', (26, 31))	('stromal expression', 'CPA', (36, 54))	('OR3A4', 'Gene', (247, 252))	('OR3A4', 'Gene', '390756', (247, 252))	('negatively', 'NegReg', (68, 78))
406172	29384778	To understand the accuracy of using methylation within cg09890332 of OR3A4 as a biomarker for high-risk BE, we carried out a multivariable reverse stepwise logistic regression analysis of methylation at the 3 tagged CpG dinucleotides within the pyrosequencing assay as the independent variables and progressor versus nonprogressor status as the dependent variables.	('cg09890332', 'Chemical', '-', (55, 65))	('BE', 'Phenotype', 'HP:0100580', (104, 106))	('cg09890332', 'Var', (55, 65))	('OR3A4', 'Gene', (69, 74))	('OR3A4', 'Gene', '390756', (69, 74))
406174	29384778	Modeling at a threshold of below 89% being significant showed that hypomethylation at OR3A4 can predict progression to invasive carcinoma with a sensitivity of 70.8%, specificity of 86%, positive predictive value of 85% and negative predictive value of 72.5%.	('invasive carcinoma', 'Disease', (119, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('invasive carcinoma', 'Disease', 'MESH:D009361', (119, 137))	('OR3A4', 'Gene', (86, 91))	('hypomethylation', 'Var', (67, 82))	('OR3A4', 'Gene', '390756', (86, 91))
406176	29384778	We have identified that hypomethylation at cg09890332 corresponding to the CG nucleotide at position (CHR) of OR3A4 can discriminate between patients who progress from nondysplastic BE and those who did not.	('OR3A4', 'Gene', '390756', (110, 115))	('nondysplastic BE', 'Disease', (168, 184))	('progress', 'PosReg', (154, 162))	('cg09890332', 'Var', (43, 53))	('hypomethylation', 'Var', (24, 39))	('cg09890332', 'Chemical', '-', (43, 53))	('BE', 'Phenotype', 'HP:0100580', (182, 184))	('OR3A4', 'Gene', (110, 115))	('CG', 'Chemical', 'MESH:C028505', (75, 77))	('patients', 'Species', '9606', (141, 149))	('discriminate', 'Reg', (120, 132))
406179	29384778	The effect of hypomethylation on the OR3A4 gene seems to be functional, in that immunohistochemistry reveals an increase in OR3A4 expression in samples with hypomethylation.	('expression', 'MPA', (130, 140))	('OR3A4', 'Gene', '390756', (124, 129))	('OR3A4', 'Gene', (37, 42))	('hypomethylation', 'Var', (157, 172))	('OR3A4', 'Gene', '390756', (37, 42))	('increase', 'PosReg', (112, 120))	('OR3A4', 'Gene', (124, 129))
406181	29384778	Our observed region coincides within 225 bp of a CTCF and RAD21 transcription factor binding site, further suggesting that methylation there has a functional effect to prevent transcription factor binding and alter gene expression.	('transcription', 'Protein', (176, 189))	('CTCF', 'Gene', (49, 53))	('prevent', 'NegReg', (168, 175))	('methylation', 'Var', (123, 134))	('alter', 'Reg', (209, 214))	('CTCF', 'Gene', '10664', (49, 53))	('binding', 'Interaction', (197, 204))	('RAD21', 'Gene', (58, 63))	('RAD21', 'Gene', '5885', (58, 63))	('gene expression', 'MPA', (215, 230))
406187	29384778	We found both at the individual probe level and as part of a DMR that there is hypomethylation in the CpG island associated with FGFR2; however, this did not validate at the single probe level when examined with bisulfite pyrosequencing.	('bisulfite pyrosequencing', 'Chemical', '-', (212, 236))	('hypomethylation', 'Var', (79, 94))	('FGFR2', 'Gene', (129, 134))	('FGFR2', 'Gene', '2263', (129, 134))
406195	29384778	Hypomethylation of OR3A4, although seemingly accurate for the detection of progression of Barrett to invasive adenocarcinoma, is likely to be of more utility as a multimodal stratifier in BE, taking account of previous findings at the mutational and copy number level, and also epigenetic change.	('OR3A4', 'Gene', (19, 24))	('Barrett', 'Disease', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('Hypomethylation', 'Var', (0, 15))	('OR3A4', 'Gene', '390756', (19, 24))	('epigenetic change', 'Var', (278, 295))	('invasive adenocarcinoma', 'Disease', (101, 124))	('BE', 'Phenotype', 'HP:0100580', (188, 190))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (101, 124))
406237	30662540	The meta-analysis data showed that higher incidences of grade3/4 bone marrow suppression and lymphatic fistula were observed in patients treated by neoadjuvant CRT plus surgery compared to neoadjuvant CT plus surgery or surgery alone.	('fistula', 'Disease', 'MESH:D005402', (103, 110))	('fistula', 'Disease', (103, 110))	('grade3/4', 'Var', (56, 64))	('patients', 'Species', '9606', (128, 136))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (65, 88))
406238	30662540	Neoadjuvant CRT plus surgery could increase the risk of cardiac complications and pulmonary embolism, even though there were no significant difference compared to neoadjuvant CT plus surgery or surgery alone(OR 1.09, 95% CI 0.82-1.45, P=0.57; OR 2.06, 95% CI 0.81-5.19, P=0.13).Oppositely, the patients conducted by neoadjuvant CRT plus surgery had higher incidences of bleed(OR 1.13, 95% CI 0.36-3.59, P=0.84), anastomotic fistula(OR 1.01, 95% CI 0.76-1.35, P=0.94), pulmonary(OR 2.06, 95% CI 0.81-5.19, P=0.13) and incision(OR 1.13, 95% CI 0.56-2.29, P=0.72) infection compared to neoadjuvant CT plus surgery or surgery alone, but no significant differences were shown between two arms.	('anastomotic fistula', 'Disease', (412, 431))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (82, 100))	('pulmonary', 'CPA', (468, 477))	('neoadjuvant CRT plus surgery', 'Var', (316, 344))	('patients', 'Species', '9606', (294, 302))	('pulmonary embolism', 'Disease', (82, 100))	('cardiac complications', 'Disease', 'MESH:D005117', (56, 77))	('incision', 'CPA', (517, 525))	('pulmonary embolism', 'Disease', 'MESH:D011655', (82, 100))	('anastomotic fistula', 'Disease', 'MESH:D005402', (412, 431))	('infection', 'Disease', (561, 570))	('infection', 'Disease', 'MESH:D007239', (561, 570))	('bleed', 'Disease', (370, 375))	('cardiac complications', 'Disease', (56, 77))
406268	30662540	Thus, superfluous dose radiation was positively related to high risk of anastomotic fistula or infection.	('anastomotic fistula or infection', 'Disease', 'MESH:D005402', (72, 104))	('superfluous dose', 'Var', (6, 22))	('anastomotic fistula or infection', 'Disease', (72, 104))	('related', 'Reg', (48, 55))
406325	29137320	Furthermore, Gimeracil, a component of S-1, has been found to enhance the efficacy of RT through the inhibition of the repair of radiation-induced DNA damage.	('repair of radiation-induced DNA damage', 'MPA', (119, 157))	('inhibition', 'NegReg', (101, 111))	('Gimeracil', 'Var', (13, 22))	('efficacy', 'MPA', (74, 82))	('S-1', 'Gene', (39, 42))	('enhance', 'PosReg', (62, 69))	('Gimeracil', 'Chemical', 'MESH:C104201', (13, 22))	('S-1', 'Gene', '5707', (39, 42))
406383	28706424	Sensitivity and specificity of type B1 for tumors limited to the epithelial layer (m1) or invading into the lamina propria (m2) were 71.4% and 100%, respectively.	('type', 'Var', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
406384	28706424	Sensitivity and specificity of type B2 for tumors invading into the muscularis mucosa (m3) or superficial submucosa (<= 200 mum, sm1) were 94.4% and 73.1%, respectively, while those of type B3 for tumors invading into the deep submucosa (> 200 mum, sm2) were 75.0% and 97.8%, respectively.	('type B2', 'Var', (31, 38))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('<= 200', 'Var', (117, 123))	('sm2', 'Gene', (249, 252))	('sm2', 'Gene', '53366', (249, 252))	('sm1', 'Gene', '7911', (129, 132))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (43, 49))	('tumors', 'Disease', (197, 203))	('sm1', 'Gene', (129, 132))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
406474	28393072	More interesting, the racial differences of COL11A1 were consistent across multiple molecular levels, with higher mutation frequency, higher methylation, and lower expression in White patients.	('methylation', 'MPA', (141, 152))	('lower', 'NegReg', (158, 163))	('patients', 'Species', '9606', (184, 192))	('expression', 'MPA', (164, 174))	('higher', 'PosReg', (134, 140))	('COL11A1', 'Gene', '1301', (44, 51))	('mutation', 'Var', (114, 122))	('higher', 'PosReg', (107, 113))	('COL11A1', 'Gene', (44, 51))
406488	28393072	Genome sequencing of liver cancer found that AXIN1 was more frequently mutated in patients with HBV infection, while mutations of its downstream gene CTNNB1 majorly occurred in HCV-associated cases.	('mutations', 'Var', (117, 126))	('AXIN1', 'Gene', '8312', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('liver cancer', 'Disease', 'MESH:D006528', (21, 33))	('CTNNB1', 'Gene', (150, 156))	('patients', 'Species', '9606', (82, 90))	('liver cancer', 'Disease', (21, 33))	('AXIN1', 'Gene', (45, 50))	('mutated', 'Var', (71, 78))	('CTNNB1', 'Gene', '1499', (150, 156))	('HBV infection', 'Disease', (96, 109))	('occurred', 'Reg', (165, 173))	('HBV infection', 'Disease', 'MESH:D006509', (96, 109))	('liver cancer', 'Phenotype', 'HP:0002896', (21, 33))
406491	28393072	Except cancer genomes, racial specificity was also observed in other molecular features, such as gene expression in pediatric B-Precursor acute lymphoblastic leukemia and methylation in prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('prostate cancer', 'Disease', (186, 201))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('methylation', 'Var', (171, 182))	('prostate cancer', 'Disease', 'MESH:D011471', (186, 201))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (138, 166))	('prostate cancer', 'Phenotype', 'HP:0012125', (186, 201))	('acute lymphoblastic leukemia', 'Disease', (138, 166))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('B-Precursor acute lymphoblastic leukemia', 'Phenotype', 'HP:0004812', (126, 166))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (138, 166))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (144, 166))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
406521	28393072	The majority of mutations were found in TP53 (80.1%); other SMGs included KMT2B (13.2%), NOTCH1 (12.8%), and PIK3CA (9.6%).	('PIK3CA', 'Gene', (109, 115))	('PIK3CA', 'Gene', '5290', (109, 115))	('KMT2B', 'Gene', (74, 79))	('mutations', 'Var', (16, 25))	('NOTCH1', 'Gene', '4851', (89, 95))	('NOTCH1', 'Gene', (89, 95))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('KMT2B', 'Gene', '9757', (74, 79))
406524	28393072	Tumors from White patients were more significantly associated with harboring a KEAP1 mutation (Figure 2(c)).	('KEAP1', 'Gene', (79, 84))	('harboring', 'Var', (67, 76))	('EA', 'Phenotype', 'HP:0011459', (80, 82))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (18, 26))	('KEAP1', 'Gene', '9817', (79, 84))
406527	28393072	For example, TP53 mutations were more frequent in White patients, while the mutation frequencies of its upstream genes EP300 and CDKN2A were higher in Asian patients.	('patients', 'Species', '9606', (56, 64))	('TP53', 'Gene', (13, 17))	('EP300', 'Gene', (119, 124))	('EP300', 'Gene', '2033', (119, 124))	('CDKN2A', 'Gene', (129, 135))	('patients', 'Species', '9606', (157, 165))	('CDKN2A', 'Gene', '1029', (129, 135))	('TP53', 'Gene', '7157', (13, 17))	('frequent', 'Reg', (38, 46))	('mutations', 'Var', (18, 27))
406528	28393072	Another example is the Keap1-Nrf2 pathway and White patients harbored more KEAP1 mutations, while Asian people had more NFE2L2 (also called NRF2) mutations.	('KEAP1', 'Gene', (75, 80))	('Nrf2', 'Gene', (29, 33))	('NFE2L2', 'Gene', '4780', (120, 126))	('people', 'Species', '9606', (104, 110))	('mutations', 'Var', (146, 155))	('NFE2L2', 'Gene', (120, 126))	('EA', 'Phenotype', 'HP:0011459', (76, 78))	('patients', 'Species', '9606', (52, 60))	('Keap1', 'Gene', (23, 28))	('mutations', 'Var', (81, 90))	('Nrf2', 'Gene', '4780', (29, 33))	('Keap1', 'Gene', '9817', (23, 28))	('KEAP1', 'Gene', '9817', (75, 80))	('NRF2', 'Gene', '4780', (140, 144))	('NRF2', 'Gene', (140, 144))
406530	28393072	Somatic mutations in NRF2 or KEAP1 disrupt the interaction of these two proteins and activate the NRF2 signaling.	('NRF2', 'Gene', (21, 25))	('interaction', 'Interaction', (47, 58))	('disrupt', 'NegReg', (35, 42))	('these two proteins', 'Protein', (62, 80))	('activate', 'PosReg', (85, 93))	('proteins', 'Protein', (72, 80))	('mutations', 'Var', (8, 17))	('KEAP1', 'Gene', '9817', (29, 34))	('NRF2', 'Gene', '4780', (98, 102))	('NRF2', 'Gene', '4780', (21, 25))	('EA', 'Phenotype', 'HP:0011459', (30, 32))	('KEAP1', 'Gene', (29, 34))	('NRF2', 'Gene', (98, 102))
406543	28393072	Mutated COL11A1 had higher expression than the wide-type gene (P = 0.03, Figure 5(d)).	('COL11A1', 'Gene', '1301', (8, 15))	('higher', 'PosReg', (20, 26))	('expression', 'MPA', (27, 37))	('COL11A1', 'Gene', (8, 15))	('Mutated', 'Var', (0, 7))
406544	28393072	In summary, COL11A1 had higher mutation frequency and higher methylation level in White people, which may decrease gene expression.	('COL11A1', 'Gene', '1301', (12, 19))	('higher', 'PosReg', (54, 60))	('mutation', 'Var', (31, 39))	('decrease', 'NegReg', (106, 114))	('higher', 'PosReg', (24, 30))	('people', 'Species', '9606', (88, 94))	('COL11A1', 'Gene', (12, 19))	('methylation level', 'MPA', (61, 78))	('gene expression', 'MPA', (115, 130))
406555	28393072	Taken the breast cancer-susceptible gene BRCA1 as an example, genetic BRCA1 mutations were significantly more common in Jewish (10.2%) versus non-Jewish (2.0%) cases.	('mutations', 'Var', (76, 85))	('BRCA1', 'Gene', '672', (41, 46))	('BRCA1', 'Gene', '672', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('common', 'Reg', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('BRCA1', 'Gene', (41, 46))	('breast cancer', 'Disease', (10, 23))	('BRCA1', 'Gene', (70, 75))	('Jewish', 'Disease', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
406556	28393072	Recently, the larger-scale tumor sequencing projects revealed that pattern and frequency of oncogene mutations might vary by race.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', (27, 32))	('oncogene', 'Gene', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
406557	28393072	For example, the mutation rate of EGFR in non-small-cell lung cancer is 16-18% in North Americans and Europeans, 19% in African-Americans, 22% in Indians, 29% in Koreans, 40% in Japanese, and around 50% in Chinese; such variability in EGFR mutation rate led to different effectiveness of tyrosine kinase inhibitors in the given population.	('EGFR', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (42, 68))	('mutation', 'Var', (17, 25))	('EGFR', 'Gene', '1956', (34, 38))	('effectiveness', 'MPA', (271, 284))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('EGFR', 'Gene', '1956', (235, 239))	('EGFR', 'Gene', (235, 239))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (46, 68))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
406562	28393072	Some differences might be important for tumorigenesis and personalized treatment, such as KEAP1 mutation, TFPI methylation, and COL11A1 expression.	('TFPI', 'Gene', (106, 110))	('COL11A1', 'Gene', '1301', (128, 135))	('TFPI', 'Gene', '7035', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('KEAP1', 'Gene', '9817', (90, 95))	('mutation', 'Var', (96, 104))	('COL11A1', 'Gene', (128, 135))	('KEAP1', 'Gene', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('EA', 'Phenotype', 'HP:0011459', (91, 93))
406604	27533454	Contrastingly in females, per unit increment in fasting blood glucose was significantly associated with ESCC mortality in patients with depth of invasion: T3-T4 (adjusted HR=1.07, 95% CI: 1.02-1.13, P=0.012) and negative embolus (adjusted HR=1.08, 95% CI: 1.02-1.15, P=0.005) after adjustment.	('T3-T4', 'Var', (155, 160))	('blood glucose', 'Chemical', 'MESH:D001786', (56, 69))	('ESCC mortality', 'Disease', (104, 118))	('patients', 'Species', '9606', (122, 130))	('associated', 'Reg', (88, 98))
406610	27533454	Especially in males with TNM stage II, ESCC patients with fasting blood glucose <= 6.16 mmol/L had significantly longer median follow-up time than patients with fasting blood glucose > 6.16 mmol/L (52.1 vs. 34.5 months, Log-rank test: P<0.001), as further confirmed by the Kaplan-Meier curves (Figure 2B).	('TNM', 'Gene', '10178', (25, 28))	('ESCC', 'Disease', (39, 43))	('<= 6.16 mmol/L', 'Var', (80, 94))	('patients', 'Species', '9606', (44, 52))	('longer', 'PosReg', (113, 119))	('blood glucose', 'Chemical', 'MESH:D001786', (66, 79))	('blood glucose', 'Chemical', 'MESH:D001786', (169, 182))	('TNM', 'Gene', (25, 28))	('patients', 'Species', '9606', (147, 155))
406611	27533454	In females with TNM stage: I-II and regional LNM: N1-N3, ESCC patients with fasting blood glucose <= 5.1 mmol/L had significantly longer median follow-up time than patients with fasting blood glucose > 5.1 mmol/L (58.8 vs. 31.3 months, Log-rank test: P<0.001), as further validated by the Kaplan-Meier curves (Figure 3B).	('longer', 'PosReg', (130, 136))	('TNM', 'Gene', (16, 19))	('blood glucose', 'Chemical', 'MESH:D001786', (186, 199))	('ESCC', 'Disease', (57, 61))	('N1-N3', 'Var', (50, 55))	('blood glucose', 'Chemical', 'MESH:D001786', (84, 97))	('TNM', 'Gene', '10178', (16, 19))	('<= 5.1 mmol/L', 'Var', (98, 111))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (62, 70))
406711	25605255	Molecular signatures are reported frequently and have proven to be prognostic in various tumors.	('Molecular signatures', 'Var', (0, 20))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
406749	25686822	Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1.	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('decreased', 'NegReg', (68, 77))	('silencing', 'Var', (9, 18))	('EGFR family', 'Gene', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('MUC4', 'Protein', (78, 82))	('expression', 'MPA', (83, 93))	('reduced', 'NegReg', (102, 109))	('pancreatic cancer', 'Disease', (44, 61))	('phospho-STAT1', 'MPA', (110, 123))
406750	25686822	Furthermore, canertinib and afatinib treatment also inhibited proliferation, migration and survival of pancreatic cancer cells by attenuation of signaling events including pERK1/2 (T202/Y204), cyclin D1, cyclin A, pFAK (Y925) and pAKT (Ser473).	('cyclin A', 'Gene', '890', (204, 212))	('pancreatic cancer', 'Disease', (103, 120))	('cyclin D1', 'Gene', (193, 202))	('T202/Y204', 'Var', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('inhibited', 'NegReg', (52, 61))	('signaling', 'MPA', (145, 154))	('canertinib', 'Chemical', 'MESH:C420268', (13, 23))	('cyclin A', 'Gene', (204, 212))	('attenuation', 'NegReg', (130, 141))	('AKT', 'Gene', '207', (231, 234))	('proliferation', 'CPA', (62, 75))	('cyclin D1', 'Gene', '595', (193, 202))	('migration', 'CPA', (77, 86))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('survival', 'CPA', (91, 99))	('FAK', 'Gene', (215, 218))	('afatinib', 'Chemical', 'MESH:D000077716', (28, 36))	('FAK', 'Gene', '5747', (215, 218))	('Ser473', 'Chemical', '-', (236, 242))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('AKT', 'Gene', (231, 234))
406759	25686822	Aberrant expression of cell surface mucins is a hallmark of epithelial cancers.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('mucin', 'Gene', (36, 41))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('hallmark of epithelial cancers', 'Disease', (48, 78))	('mucin', 'Gene', '100508689', (36, 41))	('hallmark of epithelial cancers', 'Disease', 'MESH:D000077216', (48, 78))
406763	25686822	Furthermore, earlier studies from our group have shown that MUC4 enhances invasion and metastasis of pancreatic cancer.	('MUC4', 'Var', (60, 64))	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (87, 118))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (101, 118))	('invasion', 'CPA', (74, 82))	('metastasis of pancreatic cancer', 'Disease', (87, 118))	('enhances', 'PosReg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
406765	25686822	Our earlier studies have shown that MUC4, a transmembrane mucin, interacts, stabilizes and activates HER2 mediated downstream signaling in pancreatic and ovarian cancer cells.	('ovarian cancer', 'Phenotype', 'HP:0100615', (154, 168))	('mucin', 'Gene', '100508689', (58, 63))	('HER2', 'Protein', (101, 105))	('stabilizes', 'MPA', (76, 86))	('mucin', 'Gene', (58, 63))	('activates', 'PosReg', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('MUC4', 'Var', (36, 40))	('pancreatic and ovarian cancer', 'Disease', 'MESH:D010190', (139, 168))	('interacts', 'Interaction', (65, 74))
406793	25686822	Also, earlier evidence indicates that MUC4 stabilizes HER2 thereby mediating cellular signaling for proliferation and metastasis and imparts resistance to gemcitabine in pancreatic cancer cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (170, 187))	('mediating', 'Reg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('MUC4', 'Var', (38, 42))	('metastasis', 'CPA', (118, 128))	('proliferation', 'CPA', (100, 113))	('gemcitabine', 'Chemical', 'MESH:C056507', (155, 166))	('pancreatic cancer', 'Disease', (170, 187))	('HER2', 'Protein', (54, 58))	('cellular signaling', 'MPA', (77, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (170, 187))	('resistance to gemcitabine', 'MPA', (141, 166))
406799	25686822	First, we aimed to identify the central mechanism through which pan-EGFR inhibitors inhibits MUC4 protein expression in pancreatic cancer cells.	('pan-EGFR', 'Gene', (64, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('MUC4 protein', 'Protein', (93, 105))	('inhibits', 'NegReg', (84, 92))	('inhibitors', 'Var', (73, 83))	('pancreatic cancer', 'Disease', (120, 137))
406848	25686822	Pancreatic cancer is the most lethal form of cancer with a very high incidence of distant metastasis due to aberrant expression of tumor antigens.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('aberrant', 'Var', (108, 116))	('tumor', 'Disease', (131, 136))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('distant metastasis', 'CPA', (82, 100))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', (45, 51))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
406849	25686822	We explored for the first time the novel role of pan-EGFR family inhibitors in reducing the metastatic potential of pancreatic cancer, with major emphasis on MUC4 inhibition using multiple cell lines and an orthotopic mouse model.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('reducing', 'NegReg', (79, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('metastatic potential', 'CPA', (92, 112))	('inhibitors', 'Var', (65, 75))	('mouse', 'Species', '10090', (218, 223))	('pancreatic cancer', 'Disease', (116, 133))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
406858	25686822	To prove this we transiently inhibited endogenous EGFR using siRNA in pancreatic cancer cells and, as expected, transient knockdown of EGFR expression led to inhibition of phospho-STAT1 thereby down regulating MUC4 mucin protein expression.	('mucin', 'Gene', (215, 220))	('inhibited', 'NegReg', (29, 38))	('pancreatic cancer', 'Disease', (70, 87))	('knockdown', 'Var', (122, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('mucin', 'Gene', '100508689', (215, 220))	('phospho-STAT1', 'MPA', (172, 185))	('EGFR', 'Gene', (135, 139))	('inhibition', 'NegReg', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))	('down regulating', 'NegReg', (194, 209))
406860	25686822	Down-regulation of MUC4 expression in canertinib and afatinib treated cells are further corroborated by down regulation of p-STAT1 (Ser727 and Y701), a transcriptional activator of MUC4.	('afatinib', 'Chemical', 'MESH:D000077716', (53, 61))	('expression', 'MPA', (24, 34))	('down regulation', 'NegReg', (104, 119))	('Y701', 'Var', (143, 147))	('p-STAT1', 'Gene', (123, 130))	('Down-regulation', 'NegReg', (0, 15))	('Ser727', 'Var', (132, 138))	('Ser727', 'Chemical', '-', (132, 138))	('MUC4', 'Gene', (19, 23))	('canertinib', 'Chemical', 'MESH:C420268', (38, 48))
406861	25686822	To further confirm the EGFR mediated MUC4 mucin down-regulation, confocal microscopy analysis of EGFR and MUC4 was also performed in EGFR knockdown CD18/HPAF cells, which showed similar observations as that of Western blot studies.	('knockdown', 'Var', (138, 147))	('down-regulation', 'NegReg', (48, 63))	('mucin', 'Gene', (42, 47))	('CD18', 'Gene', '3689', (148, 152))	('CD18', 'Gene', (148, 152))	('mucin', 'Gene', '100508689', (42, 47))
406862	25686822	Thus, confirming that inhibiting the EGFR mediated STAT pathway can block MUC4 mucin regulation.	('mucin', 'Gene', '100508689', (79, 84))	('EGFR mediated STAT pathway', 'Pathway', (37, 63))	('mucin', 'Gene', (79, 84))	('inhibiting', 'Var', (22, 32))	('block', 'NegReg', (68, 73))
406867	25686822	Our results show that there is a decrease in the number of colonies and consequently as significant reduction of phospho-ERK1/2, CyclinD1 and CyclinA protein levels in inhibitors treated cells.	('reduction', 'NegReg', (100, 109))	('CyclinA', 'Gene', (142, 149))	('decrease', 'NegReg', (33, 41))	('CyclinD1', 'Gene', '595', (129, 137))	('CyclinD1', 'Gene', (129, 137))	('inhibitors', 'Var', (168, 178))	('phospho-ERK1/2', 'MPA', (113, 127))	('CyclinA', 'Gene', '890', (142, 149))
406875	25686822	Notably, we were also able to show that these changes are also associated with a modest decrease in expression of endogenous MUC4 total RNA, which is sufficient to impair its downstream effectors such as FAK, AKT and ERK and result in impaired motility, proliferation and metastasis of pancreatic cancer cells.	('proliferation', 'CPA', (254, 267))	('decrease', 'NegReg', (88, 96))	('impaired motility', 'Disease', 'MESH:D015835', (235, 252))	('changes', 'Var', (46, 53))	('FAK', 'Gene', (204, 207))	('impair', 'NegReg', (164, 170))	('AKT', 'Gene', '207', (209, 212))	('expression', 'MPA', (100, 110))	('FAK', 'Gene', '5747', (204, 207))	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (272, 303))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('impaired motility', 'Disease', (235, 252))	('metastasis of pancreatic cancer', 'Disease', (272, 303))	('AKT', 'Gene', (209, 212))	('ERK', 'Gene', '5594', (217, 220))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (286, 303))	('ERK', 'Gene', (217, 220))
406879	25686822	Notably, in our study we have demonstrated the role of pan-EGFR inhibitors in limiting the migration of pancreatic cancer cells through FAK mediated pathway.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('pancreatic cancer', 'Disease', (104, 121))	('inhibitors', 'Var', (64, 74))	('pan-EGFR', 'Gene', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('FAK', 'Gene', (136, 139))	('FAK', 'Gene', '5747', (136, 139))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('migration', 'CPA', (91, 100))	('limiting', 'NegReg', (78, 86))
406885	25686822	In addition, we found that treatment with pan-EGFR inhibitors also resulted in down regulation of cell cycle key regulators such as Cyclin D1 and Cyclin A, implicating that down regulation of ERK1/2 and AKT pathways affects cell cycle progression.	('Cyclin D1', 'Gene', '595', (132, 141))	('down regulation', 'NegReg', (79, 94))	('Cyclin A', 'Gene', (146, 154))	('AKT', 'Gene', (203, 206))	('Cyclin D1', 'Gene', (132, 141))	('cell cycle progression', 'CPA', (224, 246))	('cell cycle key regulators', 'MPA', (98, 123))	('down regulation', 'NegReg', (173, 188))	('pan-EGFR', 'Gene', (42, 50))	('affects', 'Reg', (216, 223))	('Cyclin A', 'Gene', '890', (146, 154))	('AKT', 'Gene', '207', (203, 206))	('inhibitors', 'Var', (51, 61))
406894	25686822	Thus, these preclinical data suggests that partial abolishment of the MUC4 mucin mediated signaling axis along with inhibition of EGFR family members could be a more effective approach to combat pancreatic cancer as it inhibits the crosstalk between multiple pathways and could result in a highly efficient therapy when used in combination with primary care of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (195, 212))	('inhibits', 'NegReg', (219, 227))	('mucin', 'Gene', (75, 80))	('inhibition', 'Var', (116, 126))	('pancreatic cancer', 'Disease', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('pancreatic cancer', 'Disease', (361, 378))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (361, 378))	('pancreatic cancer', 'Disease', 'MESH:D010190', (361, 378))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (195, 212))	('mucin', 'Gene', '100508689', (75, 80))	('partial abolishment', 'Var', (43, 62))	('result in', 'Reg', (278, 287))	('EGFR', 'Gene', (130, 134))	('crosstalk', 'Interaction', (232, 241))
406976	24019132	In the esophagus, reliable detection of these field effect alterations could potentially be used for the risk stratification of patients with Barrett's esophagus without the need to identify and sample the specific area of neoplasia.	('alterations', 'Var', (59, 70))	('neoplasia', 'Disease', 'MESH:D009369', (223, 232))	('neoplasia', 'Phenotype', 'HP:0002664', (223, 232))	('patients', 'Species', '9606', (128, 136))	('neoplasia', 'Disease', (223, 232))	("Barrett's esophagus", 'Disease', (142, 161))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (142, 161))
407005	24019132	In addition, the area under the receiver operating characteristic (ROC) curve was calculated as a measure of the ability of disorder strength to differentiate between cancer and DBE vs. NDBE and control.	('DBE', 'Chemical', '-', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('NDBE', 'Chemical', '-', (186, 190))	('DBE', 'Chemical', '-', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('DBE', 'Var', (178, 181))
407019	24019132	Many bio-markers have been investigated in Barrett's-associated neoplasia, including the more promising markers with more evidence of aneuploidy, tetraploidy, and p53 LOH.	('aneuploidy', 'Disease', 'MESH:D000782', (134, 144))	('tetraploidy', 'Var', (146, 157))	('p53', 'Gene', (163, 166))	('p53', 'Gene', '7157', (163, 166))	('aneuploidy', 'Disease', (134, 144))	('neoplasia', 'Disease', (64, 73))	('neoplasia', 'Phenotype', 'HP:0002664', (64, 73))	('neoplasia', 'Disease', 'MESH:D009369', (64, 73))
407061	22489918	Based on the novel findings in the colon, we would like to determine whether mechanical stress-induced gene expression of COX-2 is a common mechanism throughout the GI tract and, if so, whether inhibition of COX-2 improves motility function in conditions with lumen dilation.	('lumen dilation', 'Phenotype', 'HP:0002617', (260, 274))	('improves', 'PosReg', (214, 222))	('COX-2', 'Gene', '29527', (208, 213))	('COX-2', 'Gene', (208, 213))	('COX-2', 'Gene', '29527', (122, 127))	('COX-2', 'Gene', (122, 127))	('motility function', 'CPA', (223, 240))	('inhibition', 'Var', (194, 204))
407137	22489918	Administration of COX-2 inhibitors in vivo in gastric outlet obstruction prevented impairments of smooth muscle contractility, and improved gastric emptying.	('rat', 'Species', '10116', (8, 11))	('improved gastric emptying', 'Phenotype', 'HP:0002578', (131, 156))	('smooth muscle contractility', 'CPA', (98, 125))	('inhibitors', 'Var', (24, 34))	('gastric outlet obstruction', 'Disease', (46, 72))	('gastric emptying', 'CPA', (140, 156))	('improved', 'PosReg', (131, 139))	('gastric outlet obstruction', 'Disease', 'MESH:D017219', (46, 72))	('COX-2', 'Gene', '29527', (18, 23))	('COX-2', 'Gene', (18, 23))	('gastric emptying', 'Phenotype', 'HP:0002578', (140, 156))
407155	22489918	This discrepancy may help to explain why NS-398 had a trend to slow gastric emptying in control rats, but significantly improved motility function in obstructed rats in our study.	('NS-398', 'Var', (41, 47))	('improved', 'PosReg', (120, 128))	('NS-398', 'Chemical', 'MESH:C080955', (41, 47))	('rats', 'Species', '10116', (161, 165))	('rats', 'Species', '10116', (96, 100))	('motility function', 'CPA', (129, 146))	('slow gastric emptying', 'MPA', (63, 84))	('gastric emptying', 'Phenotype', 'HP:0002578', (68, 84))
407162	22489918	Thus, inhibition of mechanical stress-induced COX-2 and other mechanically responsive genes may represent a novel therapeutic potential in patients with gastric dilation.	('COX-2', 'Gene', '29527', (46, 51))	('patients', 'Species', '9606', (139, 147))	('gastric dilation', 'Disease', 'MESH:D013271', (153, 169))	('COX-2', 'Gene', (46, 51))	('inhibition', 'Var', (6, 16))	('gastric dilation', 'Phenotype', 'HP:0005207', (153, 169))	('gastric dilation', 'Disease', (153, 169))
407183	21756922	Single-stranded breaks of                 telomeric DNA caused either directly by reactive oxygen species or indirectly as                 part of the DNA repair process are not as efficiently repaired.	('telomeric DNA', 'Protein', (42, 55))	('Single-stranded breaks', 'Var', (0, 22))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (82, 105))
407189	21756922	Replicative cellular senescence induced by telomere erosion has been                     proposed as a tumor suppressor mechanism.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor suppressor', 'Gene', '7248', (103, 119))	('telomere erosion', 'Var', (43, 59))	('Replicative', 'MPA', (0, 11))	('tumor suppressor', 'Gene', (103, 119))
407205	21756922	If telomere length is                         associated with risk of the ailments for which control patients were                         admitted to the hospital, and the direction of risk association is that same                         as that for the cancer of case patients, a true association may be masked.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('ailments', 'Disease', (74, 82))	('cancer', 'Disease', (256, 262))	('telomere length', 'Var', (3, 18))	('men', 'Species', '9606', (77, 80))	('patients', 'Species', '9606', (271, 279))	('associated', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))
407206	21756922	Furthermore, as telomere shortening has been associated with increased                         mortality, the                         recruitment of prevalent cases may produce invalid results due to survival                         bias where cancer patients that survive long enough to participate in the                         study may have longer telomere lengths than those who died.	('men', 'Species', '9606', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('associated', 'Reg', (45, 55))	('patients', 'Species', '9606', (251, 259))	('telomere', 'Var', (16, 24))	('telomere shortening', 'Phenotype', 'HP:0031413', (16, 35))	('telomere lengths', 'MPA', (353, 369))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('longer', 'PosReg', (346, 352))
407207	21756922	That is, rather being a causal factor in carcinogenesis, a                         biomarker such as short telomere length may occur as a result of the                         pathophysiological effects of the disease.	('occur', 'Reg', (127, 132))	('short telomere length', 'Phenotype', 'HP:0031413', (101, 122))	('short', 'Var', (101, 106))	('carcinogenesis', 'Disease', 'MESH:D063646', (41, 55))	('carcinogenesis', 'Disease', (41, 55))
407211	21756922	Such samples provide the means to establish a potential temporal                         relationship between a biomarker exposure such as short telomere length and                         subsequent cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('short telomere length', 'Phenotype', 'HP:0031413', (139, 160))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('short telomere length', 'Var', (139, 160))	('cancer', 'Disease', (200, 206))
407221	21756922	For individuals with the                         shortest telomere lengths compared to those with the longest, the Swedish                         study found a significant 4.5-fold increase in bladder cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('shortest telomere length', 'Phenotype', 'HP:0031413', (49, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (194, 208))	('bladder cancer', 'Disease', (194, 208))	('shortest', 'Var', (49, 57))	('shortest telomere lengths', 'Phenotype', 'HP:0031413', (49, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (194, 208))
407223	21756922	Among this combined group, short telomere length was                         associated with a statistically significant increased risk of developing 1                         of these 3 cancers (OR = 4.41, 95% CI = 2.10                         - 9.28; Ptrend = 0.001).	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('short telomere length', 'Phenotype', 'HP:0031413', (27, 48))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancers', 'Disease', (187, 194))	('short telomere length', 'Var', (27, 48))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
407225	21756922	Four studies found no                         statistically significant associations with overall breast cancer risk, 2                         observed significant increased risk among women with short telomere lengths, whereas 2 others found a significant                         increased risk among women with the longest telomere lengths.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('women', 'Species', '9606', (303, 308))	('women', 'Species', '9606', (186, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('short telomere lengths', 'Phenotype', 'HP:0031413', (197, 219))	('short telomere lengths', 'Var', (197, 219))	('short telomere length', 'Phenotype', 'HP:0031413', (197, 218))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
407227	21756922	Short telomere lengths were not associated with overall breast cancer risk.	('Short telomere lengths', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Short telomere length', 'Phenotype', 'HP:0031413', (0, 21))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('Short telomere lengths', 'Phenotype', 'HP:0031413', (0, 22))	('breast cancer', 'Disease', (56, 69))
407228	21756922	However, when stratified by menopausal status, premenopausal women with                         short telomere lengths were at a significantly increased risk of breast                         cancer (OR = 1.61, 95% CI = 1.05 - 2.45;                             Ptrend = 0.01; Pinteraction =                         0.004) compared to premenopausal women with the longest lengths.	('men', 'Species', '9606', (63, 66))	('breast                         cancer', 'Disease', 'MESH:D001943', (161, 198))	('men', 'Species', '9606', (28, 31))	('women', 'Species', '9606', (348, 353))	('breast                         cancer', 'Phenotype', 'HP:0003002', (161, 198))	('men', 'Species', '9606', (337, 340))	('women', 'Species', '9606', (61, 66))	('menopausal status', 'Phenotype', 'HP:0008209', (28, 45))	('men', 'Species', '9606', (50, 53))	('breast                         cancer', 'Disease', (161, 198))	('short telomere lengths', 'Phenotype', 'HP:0031413', (96, 118))	('short telomere length', 'Phenotype', 'HP:0031413', (96, 117))	('men', 'Species', '9606', (350, 353))	('short telomere lengths', 'Var', (96, 118))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
407234	21756922	Women with short telomeres were at a highly                         significant 15.5-fold increased risk of breast cancer (Ptrend                         = 2.1x10-80).	('Women', 'Species', '9606', (0, 5))	('short telomeres', 'Var', (11, 26))	('short telomeres', 'Phenotype', 'HP:0031413', (11, 26))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))
407240	21756922	Long telomere lengths were associated with a significantly                         increased risk of breast cancer (OR = 23.3, 95% CI =                         4.4 - 122.3; Ptrend < 0.0001).	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('Long telomere lengths', 'Var', (0, 21))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
407241	21756922	The large retrospective SEARCH Colorectal Study found a highly                         statistically significant association between telomere length and colorectal                         cancer risk.	('colorectal                         cancer', 'Phenotype', 'HP:0003003', (153, 194))	('significant association', 'Reg', (101, 124))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('colorectal                         cancer', 'Disease', (153, 194))	('colorectal                         cancer', 'Disease', 'MESH:D015179', (153, 194))	('telomere length', 'Var', (133, 148))
407245	21756922	In a hospital-based study of Chinese Han patients,                         short telomere lengths were associated with a statistically significant OR                         = 3.12 (95% CI = 2.01 - 4.79;                             Ptrend < 0.001) of gastric cancer risk.	('gastric cancer', 'Phenotype', 'HP:0012126', (251, 265))	('short telomere lengths', 'Phenotype', 'HP:0031413', (75, 97))	('short telomere lengths', 'Var', (75, 97))	('patients', 'Species', '9606', (41, 49))	('short telomere length', 'Phenotype', 'HP:0031413', (75, 96))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('gastric cancer', 'Disease', (251, 265))	('gastric cancer', 'Disease', 'MESH:D013274', (251, 265))
407251	21756922	Short telomeres have been associated with lung cancer risk in 3                         retrospective case-control studies.	('Short telomeres', 'Phenotype', 'HP:0031413', (0, 15))	('Short telomeres', 'Var', (0, 15))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('associated', 'Reg', (26, 36))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
407252	21756922	In the Korean study, short telomere                         length was associated with a statistically significant 8.7-fold increase in                         lung cancer risk (Ptrend < 0.0001).	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('short telomere                         length', 'Phenotype', 'HP:0031413', (21, 66))	('short telomere                         length', 'Var', (21, 66))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
407270	21756922	Short telomere length was associated with a non-significant                         elevation in breast cancer risk (OR = 1.58, 95% CI =                         0.75 - 3.31; Ptrend = 0.18).	('Short telomere length', 'Var', (0, 21))	('elevation', 'PosReg', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Short telomere length', 'Phenotype', 'HP:0031413', (0, 21))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
407272	21756922	Telomere length was not associated with colorectal                         cancer risk among men from the Physicians' Health Study (OR                         = 1.25, 95% CI = 0.86 - 1.81;                             Ptrend = 0.24), among women from the Women's                         Health Study (OR = 0.94, 95% CI = 0.65 -                         1.38; Ptrend = 0.76), or individuals within the EPIC                         cohort (OR = 1.13, 95% CI = 0.54 - 2.36;                             Ptrend = 0.82).	('men', 'Species', '9606', (241, 244))	('colorectal                         cancer', 'Phenotype', 'HP:0003003', (40, 81))	('Women', 'Species', '9606', (254, 259))	('men', 'Species', '9606', (93, 96))	('women', 'Species', '9606', (239, 244))	('colorectal                         cancer', 'Disease', (40, 81))	('colorectal                         cancer', 'Disease', 'MESH:D015179', (40, 81))	('men', 'Species', '9606', (256, 259))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Telomere', 'Var', (0, 8))
407275	21756922	Telomere length was a significant predictor of developing esophageal                         cancer in a cohort study of a high risk population of 300 patients with                         Barrett's esophagus.	('Telomere length', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (151, 159))	('esophageal                         cancer', 'Disease', 'MESH:D004938', (58, 99))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (189, 208))	('esophageal                         cancer', 'Disease', (58, 99))
407277	21756922	Patients with the shortest telomere lengths were at                         a statistically significantly increased risk of developing subsequent                         esophageal cancer (Hazard Ratio (HR) = 4.18, 95% CI                         = 1.60 - 10.94; Ptrend = 0.004).	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('shortest telomere length', 'Phenotype', 'HP:0031413', (18, 42))	('esophageal cancer', 'Disease', (170, 187))	('shortest telomere lengths', 'Phenotype', 'HP:0031413', (18, 43))	('Patients', 'Species', '9606', (0, 8))	('shortest', 'Var', (18, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))
407286	21756922	Consistent with these                         opposing telomere length associations, the C allele of rs401681 at the                         TERT-CLPTM1L locus has been statistically significantly associated with                         increased BCC risk and decreased melanoma risk.	('increased', 'PosReg', (237, 246))	('TERT', 'Gene', '7015', (141, 145))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('rs401681', 'Var', (101, 109))	('rs401681', 'Mutation', 'rs401681', (101, 109))	('BCC', 'Disease', (247, 250))	('CLPTM1L', 'Gene', '81037', (146, 153))	('BCC', 'Phenotype', 'HP:0002671', (247, 250))	('CLPTM1L', 'Gene', (146, 153))	('TERT', 'Gene', (141, 145))	('decreased melanoma', 'Disease', (260, 278))	('decreased melanoma', 'Disease', 'MESH:D008545', (260, 278))
407287	21756922	A longitudinal population-based study among residents of Bruneck,                         Italy observed a significant increase in overall cancer risk among                         individuals with short telomere lengths at baseline.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('overall', 'Disease', (131, 138))	('short telomere lengths', 'Phenotype', 'HP:0031413', (198, 220))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('short telomere lengths', 'Var', (198, 220))	('short telomere length', 'Phenotype', 'HP:0031413', (198, 219))	('increase', 'PosReg', (119, 127))	('cancer', 'Disease', (139, 145))
407291	21756922	Retrospective case-control studies of telomere length generally support an                 increased risk of cancer associated with short telomeres as measured in blood or                 buccal cell DNA (Figure 1).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('short telomeres', 'Phenotype', 'HP:0031413', (132, 147))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('short telomeres', 'Var', (132, 147))
407293	21756922	Reports                 on breast cancer range from a significant 96% reduction in breast cancer                 risk to a significant                 15-fold excess in breast cancer risk associated with the shortest quartile of telomere                 length.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('shortest', 'Var', (208, 216))	('reduction', 'NegReg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('breast cancer', 'Disease', (169, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
407300	21756922	Longer telomeres in cells such as                 melanocytes, which commonly acquire mutations in the BRAF oncogene, confer a higher proliferative capacity and                 therefore greater opportunity to acquire additional mutations for malignant                 transformation.	('mutations', 'Var', (86, 95))	('proliferative capacity', 'CPA', (134, 156))	('higher', 'PosReg', (127, 133))	('BRAF', 'Gene', '673', (103, 107))	('malignant                 transformation', 'CPA', (243, 283))	('BRAF', 'Gene', (103, 107))
407302	21756922	Although case numbers were small,                 when risk was examined by cancer type the authors noted the predictive value of                 telomere length appeared positively correlated with fatality rates.	('fatality rates', 'CPA', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('correlated', 'Reg', (182, 192))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('telomere length', 'Var', (146, 161))
407304	21756922	Likewise, in a longitudinal study                 of a high risk population of Barrett's esophagus patients, short telomere                 length was significantly associated with development of esophageal adenocarcinoma, which has an                 overall 5-year survival rate of 17%.	('short telomere                 length', 'Phenotype', 'HP:0031413', (109, 146))	('short telomere                 length', 'Var', (109, 146))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (196, 221))	('associated with', 'Reg', (165, 180))	('esophageal adenocarcinoma', 'Disease', (196, 221))	('patients', 'Species', '9606', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (196, 221))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (79, 98))	('men', 'Species', '9606', (188, 191))
407305	21756922	Given that chromosomal aberrations have been correlated                 with tumor aggressiveness, telomere shortening may be predictive of tumors displaying                 greater degrees of genomic instability.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('chromosomal aberrations', 'Var', (11, 34))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (77, 97))	('telomere shortening', 'Phenotype', 'HP:0031413', (99, 118))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (11, 34))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('telomere', 'MPA', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('aggressiveness', 'Phenotype', 'HP:0000718', (83, 97))	('tumor aggressiveness', 'Disease', (77, 97))	('correlated', 'Reg', (45, 55))
407306	21756922	Using the qPCR                 method to assay relative telomere length in all samples, the authors observed highly                 statistically significant increased cancer risk associated with short telomere                 length in the retrospective SEARCH breast and colorectal cancer studies, but null                 results in the prospective EPIC breast and colorectal studies.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal cancer', 'Disease', (273, 290))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('breast', 'Disease', (262, 268))	('cancer', 'Disease', (284, 290))	('colorectal cancer', 'Disease', 'MESH:D015179', (273, 290))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('short telomere                 length', 'Phenotype', 'HP:0031413', (196, 233))	('short telomere                 length', 'Var', (196, 233))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('colorectal cancer', 'Phenotype', 'HP:0003003', (273, 290))	('increased', 'PosReg', (158, 167))
407315	21756922	The risk associated with                 constitutional telomere length for a number of cancer types have yet to be defined.	('cancer', 'Disease', (88, 94))	('constitutional', 'Var', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))
407320	21375764	Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in association with the prognosis of esophageal squamous cell carcinoma Folic acid may affect the development of human cancers.	('Folic acid', 'Chemical', 'MESH:D005492', (142, 152))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('MTHFR', 'Gene', '4524', (58, 63))	('C677T', 'Mutation', 'rs1801133', (64, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('development', 'CPA', (168, 179))	('C677T', 'Var', (64, 69))	('folate', 'Chemical', 'MESH:D005492', (5, 11))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('human', 'Species', '9606', (183, 188))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))	('MTHFR', 'Gene', (58, 63))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('affect', 'Reg', (157, 163))	('cancers', 'Disease', (189, 196))
407323	21375764	The effects of diet folate, aberrant DNA methylation of selected genes and methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms on the prognosis of ESCC were evaluated by using Cox proportional hazard regression models.	('folate', 'Chemical', 'MESH:D005492', (20, 26))	('C677T', 'Mutation', 'rs1801133', (119, 124))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (75, 110))	('C677T', 'Var', (119, 124))	('MTHFR', 'Gene', (112, 117))	('ESCC', 'Disease', (167, 171))	('folate', 'Chemical', 'MESH:D005492', (94, 100))	('MTHFR', 'Gene', '4524', (112, 117))	('methylenetetrahydrofolate reductase', 'Gene', (75, 110))
407328	21375764	No significant relation was observed between aberrant DNA methylation of P16, MGMT and hMLH1 gene, as well as MTHFR C677T genetic polymorphisms and the prognosis of ESCC.	('MTHFR', 'Gene', (110, 115))	('C677T', 'Mutation', 'rs1801133', (116, 121))	('hMLH1', 'Gene', (87, 92))	('C677T', 'Var', (116, 121))	('ESCC', 'Disease', (165, 169))	('aberrant DNA', 'Var', (45, 57))	('MGMT', 'Gene', '4255', (78, 82))	('P16', 'Gene', (73, 76))	('MGMT', 'Gene', (78, 82))	('MTHFR', 'Gene', '4524', (110, 115))	('hMLH1', 'Gene', '4292', (87, 92))	('P16', 'Gene', '1029', (73, 76))
407339	21375764	More and more evidence has indicated the association of folate, as well as the aberrant DNA methylation with the risk of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('association', 'Interaction', (41, 52))	('aberrant', 'Var', (79, 87))	('folate', 'Chemical', 'MESH:D005492', (56, 62))	('DNA', 'Protein', (88, 91))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('human', 'Species', '9606', (121, 126))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('folate', 'MPA', (56, 62))
407342	21375764	High folate intake has been found to be significantly related with better survival of patients with advanced gastric cancer who were treated with first-line fluorouracil-based chemotherapy.	('survival', 'CPA', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('High', 'Var', (0, 4))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('High folate intake', 'Phenotype', 'HP:0032164', (0, 18))	('fluorouracil', 'Chemical', 'MESH:D005472', (157, 169))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('folate', 'Chemical', 'MESH:D005492', (5, 11))	('better', 'PosReg', (67, 73))	('patients', 'Species', '9606', (86, 94))
407343	21375764	Considering the folate pool imbalance and impaired repair mechanisms may result in DNA instability and strand breaks, we hypothesized that folate insufficiency disrupts global and specific gene methylation patterns may not only influence the susceptibility to, but also the progression of ESCC.	('imbalance', 'Phenotype', 'HP:0002172', (28, 37))	('influence', 'Reg', (228, 237))	('DNA instability', 'MPA', (83, 98))	('strand breaks', 'MPA', (103, 116))	('imbalance', 'Var', (28, 37))	('insufficiency', 'Disease', 'MESH:D000309', (146, 159))	('folate', 'Chemical', 'MESH:D005492', (139, 145))	('folate insufficiency', 'Phenotype', 'HP:0100507', (139, 159))	('ESCC', 'Disease', (289, 293))	('folate', 'Chemical', 'MESH:D005492', (16, 22))	('result', 'Reg', (73, 79))	('disrupts', 'NegReg', (160, 168))	('insufficiency', 'Disease', (146, 159))
407384	21375764	We further explored the role of aberrant DNA methylation of P16, MGMT and hMLH1 genes, as well as MTHFR C677T genetic polymorphisms in the prognosis of ESCC, but no significant association was observed (Table 3).	('P16', 'Gene', (60, 63))	('MGMT', 'Gene', (65, 69))	('MGMT', 'Gene', '4255', (65, 69))	('MTHFR', 'Gene', (98, 103))	('P16', 'Gene', '1029', (60, 63))	('hMLH1', 'Gene', '4292', (74, 79))	('C677T', 'Mutation', 'rs1801133', (104, 109))	('MTHFR', 'Gene', '4524', (98, 103))	('hMLH1', 'Gene', (74, 79))	('aberrant', 'Var', (32, 40))	('C677T', 'Var', (104, 109))	('ESCC', 'Disease', (152, 156))
407386	21375764	As shown in Figure 1 the median survival time were 3.06 years for low or moderate and more than 4.59 years for high folate consumption (log-rank test P = 0.063).	('high folate consumption', 'Phenotype', 'HP:0032164', (111, 134))	('folate', 'Chemical', 'MESH:D005492', (116, 122))	('low', 'NegReg', (66, 69))	('high', 'Var', (111, 115))
407389	21375764	The present study indicated that ESCC patients with high folate consumption may have better survival after surgery than individuals with low diet folate intake.	('better', 'PosReg', (85, 91))	('survival', 'CPA', (92, 100))	('ESCC', 'Disease', (33, 37))	('high folate consumption', 'Phenotype', 'HP:0032164', (52, 75))	('low diet folate intake', 'Phenotype', 'HP:0100507', (137, 159))	('folate', 'Chemical', 'MESH:D005492', (146, 152))	('high', 'Var', (52, 56))	('patients', 'Species', '9606', (38, 46))	('folate', 'Chemical', 'MESH:D005492', (57, 63))
407396	21375764	In some animal studies, dietary folate deficiency can inhibit rather than enhance the development of breast cancer, which is in contrast to the observation in epidemiological studies.	('deficiency', 'Var', (39, 49))	('inhibit', 'NegReg', (54, 61))	('folate deficiency', 'Phenotype', 'HP:0100507', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('folate', 'Chemical', 'MESH:D005492', (32, 38))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('enhance', 'PosReg', (74, 81))
407403	21375764	Loss of global DNA methylation may induce genomic instability and thereby promote carcinogenesis whereas promoter hypermethylation usually results in transcriptional gene inactivation.	('promote', 'PosReg', (74, 81))	('induce', 'Reg', (35, 41))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('genomic', 'MPA', (42, 49))	('carcinogenesis', 'Disease', (82, 96))	('global DNA', 'Protein', (8, 18))	('Loss', 'Var', (0, 4))
407404	21375764	In our previous study, we have reported that the aberrant CpG island hypermethylation of cancer related genes was associated with the clinical characteristics of ESCC and might be a promising biomarker for cancer diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('ESCC', 'Disease', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('associated', 'Reg', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('aberrant CpG island hypermethylation', 'Var', (49, 85))
407406	21375764	In the present study, we didn't observe a significant association between the methylation of selected genes and the survival of patients with ESCC.	('ESCC', 'Disease', (142, 146))	('patients', 'Species', '9606', (128, 136))	('methylation', 'Var', (78, 89))
407411	21375764	The MTHFR gene is highly polymorphic in the general population, with the most common functional variant of 677 C to T. This polymorphism results in an alanine to valine substitution, leading to a reduction in enzyme activity.	('alanine', 'Chemical', 'MESH:D000409', (151, 158))	('valine', 'Chemical', 'MESH:D014633', (162, 168))	('MTHFR', 'Gene', (4, 9))	('alanine to valine', 'Var', (151, 168))	('enzyme activity', 'MPA', (209, 224))	('results in', 'Reg', (137, 147))	('variant', 'Var', (96, 103))	('MTHFR', 'Gene', '4524', (4, 9))	('reduction', 'NegReg', (196, 205))	('677 C to T. This', 'Var', (107, 123))
407413	21375764	In the present study, we did not observe a significant independent effect of the MTHFR C677T polymorphism on patient's survival, which was consistent to the report by Sarbia.	('patient', 'Species', '9606', (109, 116))	('MTHFR', 'Gene', (81, 86))	('C677T', 'Mutation', 'rs1801133', (87, 92))	('C677T', 'Var', (87, 92))	('MTHFR', 'Gene', '4524', (81, 86))
407416	21375764	Interestingly, we found that diet folate intake had different effects on the prognosis of ESCC by different genotypes of MTHFR C677T.	('effects', 'Reg', (62, 69))	('folate', 'Chemical', 'MESH:D005492', (34, 40))	('MTHFR', 'Gene', '4524', (121, 126))	('C677T', 'Mutation', 'rs1801133', (127, 132))	('C677T', 'Var', (127, 132))	('MTHFR', 'Gene', (121, 126))	('ESCC', 'Disease', (90, 94))
407418	21375764	This finding indicates that ESCC prognosis might be influenced by folate intake in relation to MTHFR C677T genotypes.	('C677T', 'Var', (101, 106))	('MTHFR', 'Gene', (95, 100))	('folate', 'Chemical', 'MESH:D005492', (66, 72))	('C677T', 'Mutation', 'rs1801133', (101, 106))	('ESCC', 'Disease', (28, 32))	('influenced', 'Reg', (52, 62))	('MTHFR', 'Gene', '4524', (95, 100))
407462	20226080	In let-7 mutants, stem cells can fail to exit the cell cycle and terminally differentiate at the correct time, so that they continue to divide which is an indication of cancer.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('mutants', 'Var', (9, 16))	('let-7', 'Gene', '266952', (3, 8))	('let-7', 'Gene', (3, 8))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
407463	20226080	MiRNA genes are transcribed by RNA polymerase II (Pol II) in the nucleus to form large pri-miRNA transcripts which are capped (7MGpppG) and polyadenylated (AAAAA).	('polyadenylated', 'Var', (140, 154))	('miR', 'Gene', (91, 94))	('miR', 'Gene', '220972', (91, 94))
407473	20226080	Aberrant expression of miRNAs contributes to carcinogenesis by promoting the expression of proto oncogenes or by inhibiting the expression of tumor suppressor genes.	('expression', 'MPA', (77, 87))	('Aberrant expression', 'Var', (0, 19))	('promoting', 'PosReg', (63, 72))	('miR', 'Gene', (23, 26))	('miR', 'Gene', '220972', (23, 26))	('inhibiting', 'NegReg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('expression', 'MPA', (128, 138))	('carcinogenesis', 'Disease', (45, 59))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
407478	20226080	In fact these genes are found to be downregulated or deleted in a significant fraction of patients with B cell Chronic Lymphocytic Leukaemia (B-CLL), prostate cancer, mantle cell lymphoma and multiple myeloma.	('multiple myeloma', 'Disease', (192, 208))	('cell lymphoma', 'Phenotype', 'HP:0012191', (174, 187))	('B cell Chronic Lymphocytic Leukaemia', 'Disease', (104, 140))	('B cell Chronic Lymphocytic Leukaemia', 'Disease', 'MESH:D015451', (104, 140))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('prostate cancer', 'Disease', 'MESH:D011471', (150, 165))	('prostate cancer', 'Phenotype', 'HP:0012125', (150, 165))	('multiple myeloma', 'Phenotype', 'HP:0006775', (192, 208))	('mantle cell lymphoma', 'Disease', (167, 187))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (167, 187))	('prostate cancer', 'Disease', (150, 165))	('cell Chronic Lymphocytic Leukaemia', 'Phenotype', 'HP:0005539', (106, 140))	('deleted', 'Var', (53, 60))	('patients', 'Species', '9606', (90, 98))	('multiple myeloma', 'Disease', 'MESH:D009101', (192, 208))	('CLL', 'Phenotype', 'HP:0005550', (144, 147))	('lymphoma', 'Phenotype', 'HP:0002665', (179, 187))	('Chronic Lymphocytic Leukaemia', 'Phenotype', 'HP:0005550', (111, 140))	('downregulated', 'NegReg', (36, 49))
407483	20226080	Loss or amplification of a number of miRNAs have been found related to lung cancer.	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('related', 'Reg', (60, 67))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('amplification', 'Var', (8, 21))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Loss', 'NegReg', (0, 4))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
407516	20226080	In our present study we found that, 46 miRNAs are dysregulated in pancreatic cancer among which a significant number of miRNAs are overexpressed (P = 6.639 x 10-13, for details see Table 1) showing that miRNAs tend to be upregulated in pancreatic tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (236, 252))	('pancreatic cancer', 'Disease', (66, 83))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (120, 123))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('miR', 'Gene', '220972', (203, 206))	('pancreatic tumor', 'Disease', (236, 252))	('miR', 'Gene', (203, 206))	('dysregulated', 'Var', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('pancreatic tumor', 'Disease', 'MESH:D010190', (236, 252))	('upregulated', 'PosReg', (221, 232))
407551	20226080	Silencing of ADAM17 by miR-122 resulted in a dramatic reduction of in vitro migration, invasion, in vivo tumorigenesis, angiogenesis, and local invasion.	('in vitro migration', 'CPA', (67, 85))	('reduction', 'NegReg', (54, 63))	('ADAM17', 'Gene', '6868', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('miR-122', 'Gene', '406906', (23, 30))	('miR-122', 'Gene', (23, 30))	('angiogenesis', 'CPA', (120, 132))	('ADAM17', 'Gene', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('invasion', 'CPA', (87, 95))	('local invasion', 'CPA', (138, 152))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (105, 110))
407566	20226080	Downregulation of THBS1 can cause human cancer and may aid in immune evasion of KSHV infected cells.	('human', 'Species', '9606', (34, 39))	('aid', 'Reg', (55, 58))	('THBS1', 'Gene', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('KS', 'Phenotype', 'HP:0100726', (80, 82))	('KSHV', 'Species', '37296', (80, 84))	('Downregulation', 'Var', (0, 14))	('cause', 'Reg', (28, 33))	('cancer', 'Disease', (40, 46))	('THBS1', 'Gene', '7057', (18, 23))	('immune evasion of', 'MPA', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
407577	20226080	It has been observed in pancreatic cancer that high expression of miR-196a-2 and miR-219 can cause of a lower survival of the patients (14.3 months and 13.6 months) than the low expression (26.5 months and 23.8 months).	('pancreatic cancer', 'Disease', (24, 41))	('survival', 'MPA', (110, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('miR-219', 'Gene', (81, 88))	('high expression', 'Var', (47, 62))	('miR-196a-2', 'Gene', (66, 76))	('lower', 'NegReg', (104, 109))	('miR-196a-2', 'Gene', '406973', (66, 76))	('miR-219', 'Gene', '407002', (81, 88))	('patients', 'Species', '9606', (126, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (24, 41))
407590	20226080	As is evident, a particular type of cancer may be associated with the dysregulation of several distinct miRNAs and conversely dysregulation of one miRNA can be associated with several cancer types.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('associated', 'Reg', (160, 170))	('dysregulation', 'Var', (126, 139))	('cancer', 'Disease', (36, 42))	('miR', 'Gene', '220972', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('miR', 'Gene', (147, 150))	('particular type of cancer', 'Disease', (17, 42))	('particular type of cancer', 'Disease', 'MESH:D009369', (17, 42))	('miR', 'Gene', '220972', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('miR', 'Gene', (104, 107))	('associated', 'Reg', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('dysregulation', 'MPA', (70, 83))
407592	20226080	Other relevant parameters that have been considered are location of the miRNAs at fragile sites and cancer associated genomic regions, epigenetic alteration of miRNA expression and abnormalities in miRNA processing target genes and proteins.	('miR', 'Gene', (160, 163))	('miR', 'Gene', '220972', (198, 201))	('miR', 'Gene', (198, 201))	('epigenetic alteration', 'Var', (135, 156))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('miR', 'Gene', '220972', (72, 75))	('abnormalities', 'Var', (181, 194))	('miR', 'Gene', (72, 75))	('miR', 'Gene', '220972', (160, 163))
407681	20226080	The formal definitions of confidence and support are the following Find all association rules R in the cancer-miRNA network such that Supp(R) >= S (a minimal support threshold) and Conf(R) >= C (a minimal confidence threshold).	('Supp(R) >= S', 'Var', (134, 146))	('miR', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Conf(R) >= C', 'Var', (181, 193))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('miR', 'Gene', '220972', (110, 113))
407696	32675285	These results reveal an intracellular autocleavage mechanism in TMPRSS11A zymogen activation, which differs from the extracellular zymogen activation reported in other TTSPs.	('activation', 'PosReg', (82, 92))	('TMPRSS11A', 'Var', (64, 73))	('TTSPs', 'Chemical', '-', (168, 173))	('zymogen', 'Enzyme', (74, 81))
407711	32675285	There is a disulfide bond (Cys175-Cys292) linking the protease domain to the propepide region after the cleavage at the Arg186-Ile187 (Fig.	('disulfide', 'Chemical', 'MESH:D004220', (11, 20))	('Cys175', 'Chemical', '-', (27, 33))	('Cys292', 'Chemical', '-', (34, 40))	('Arg186', 'Chemical', '-', (120, 126))	('Ile187', 'Chemical', '-', (127, 133))	('Cys175-Cys292', 'Var', (27, 40))	('Arg186-Ile187', 'Var', (120, 133))	('propepide', 'Chemical', '-', (77, 86))
407720	32675285	To test this hypothesis, we made a plasmid expressing the mutant R265A, in which Arg265 in TMPRSS11A was replaced by Ala.	('Ala', 'Chemical', 'MESH:D000409', (117, 120))	('Arg265', 'Var', (81, 87))	('Arg265', 'Chemical', '-', (81, 87))	('R265A', 'Mutation', 'p.R265A', (65, 70))	('R265A', 'Var', (65, 70))
407725	32675285	To circumvent this problem, we made plasmids expressing mutants R186A and S368A, in which the activation cleavage site at Arg186 and the catalytic Ser368 were mutated to Ala, respectively (Fig.	('S368A', 'Var', (74, 79))	('Arg186', 'Chemical', '-', (122, 128))	('S368A', 'Mutation', 'p.S368A', (74, 79))	('Ser368 were mutated to Ala', 'Mutation', 'p.S368A', (147, 173))	('R186A', 'Var', (64, 69))	('R186A', 'Mutation', 'p.R186A', (64, 69))	('Arg186', 'Var', (122, 128))
407729	32675285	3 B), indicating that cleavages at Arg186 (generating the ~37-kDa band) and Arg265 (generating the ~28-kDa band) depended on the catalytic activity of TMPRSS11A.	('Arg186', 'Var', (35, 41))	('Arg265', 'Var', (76, 82))	('Arg265', 'Chemical', '-', (76, 82))	('Arg186', 'Chemical', '-', (35, 41))
407731	32675285	To verify our results, we expressed TMPRSS11A WT and mutants R186A and S368A in EC9706 cells, a human esophageal cancer cell line.	('S368A', 'Var', (71, 76))	('R186A', 'Var', (61, 66))	('human', 'Species', '9606', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('S368A', 'Mutation', 'p.S368A', (71, 76))	('cancer', 'Disease', (113, 119))	('EC9706', 'CellLine', 'CVCL:E307', (80, 86))	('R186A', 'Mutation', 'p.R186A', (61, 66))	('TMPRSS11A', 'Gene', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
407732	32675285	In Western blotting of lysates from transfected EC9706 cells, we detected three bands of ~57, ~37, and ~28 kDa, respectively, in TMPRSS11A WT, but a single ~57-kDa band in mutants R186A and S386A (Fig.	('R186A', 'Mutation', 'p.R186A', (180, 185))	('S386A', 'Mutation', 'p.S386A', (190, 195))	('EC9706', 'CellLine', 'CVCL:E307', (48, 54))	('S386A', 'Var', (190, 195))	('R186A', 'Var', (180, 185))
407734	32675285	These results are consistent, indicating that TMPRSS11A undergoes autoactivation at Arg186 and subsequent autocleavage at Arg265 in the protease domain.	('Arg186', 'Chemical', '-', (84, 90))	('Arg265', 'Var', (122, 128))	('Arg265', 'Chemical', '-', (122, 128))	('TMPRSS11A', 'Gene', (46, 55))	('autoactivation', 'MPA', (66, 80))	('autocleavage', 'MPA', (106, 118))	('Arg186', 'Var', (84, 90))
407737	32675285	We next treated HEK293 cells expressing TMPRSS11A with brefeldin A (BFA) and monensin, which inhibit protein trafficking in the endoplasmic reticulum (ER) and the Golgi.	('inhibit', 'NegReg', (93, 100))	('monensin', 'Chemical', 'MESH:D008985', (77, 85))	('BFA', 'Chemical', 'MESH:D020126', (68, 71))	('TMPRSS11A', 'Var', (40, 49))	('protein trafficking', 'MPA', (101, 120))	('ER', 'Gene', '2069', (151, 153))	('HEK293', 'CellLine', 'CVCL:0045', (16, 22))
407746	32675285	In Western blotting, we found all three bands of ~57/53, ~37, and ~28 kDa, respectively, in lysates from HEK293 cells expressing TMPRSS11A WT and s11A (Fig.	('TMPRSS11A WT', 'Var', (129, 141))	('s11A', 'Var', (146, 150))	('HEK293', 'CellLine', 'CVCL:0045', (105, 111))
407755	32675285	On Western blots, the sS368A fragment in the conditioned medium had a higher molecular mass than that in lysates (~57 versus ~53 kDa) (Fig.	('higher', 'PosReg', (70, 76))	('sS368A', 'Var', (22, 28))	('S368A', 'Mutation', 'p.S368A', (23, 28))	('molecular mass', 'MPA', (77, 91))
407756	32675285	When the samples were treated with PNGase F, the sS368A fragment from the conditioned medium and lysates migrated faster at ~53 and ~51 kDa, respectively (Fig.	('PNGase', 'Gene', '55768', (35, 41))	('PNGase', 'Gene', (35, 41))	('faster', 'PosReg', (114, 120))	('S368A', 'Mutation', 'p.S368A', (50, 55))	('sS368A', 'Var', (49, 55))	('migrated', 'CPA', (105, 113))
407757	32675285	The results suggest that other conformational changes or post-translational modifications may account for the higher molecular mass observed in the sS368A fragment from the conditioned medium.	('S368A', 'Mutation', 'p.S368A', (149, 154))	('higher', 'PosReg', (110, 116))	('sS368A', 'Var', (148, 154))
407758	32675285	We next transfected HEK293 cells with the plasmid expressing the sS368A mutant together with plasmids expressing TMPRSS11A WT and mutants R186A and S368A or a control vector.	('R186A', 'Mutation', 'p.R186A', (138, 143))	('S368A', 'Mutation', 'p.S368A', (66, 71))	('S368A', 'Mutation', 'p.S368A', (148, 153))	('HEK293', 'CellLine', 'CVCL:0045', (20, 26))	('R186A', 'Var', (138, 143))	('sS368A', 'Var', (65, 71))	('S368A', 'Var', (148, 153))
407759	32675285	In Western blotting, the ~37-kDa band derived from activation cleavage was observed in the conditioned medium from HEK293 cells co-expressing TMPRSS11A WT, but not mutants R186A and S368A (Fig.	('S368A', 'Mutation', 'p.S368A', (182, 187))	('R186A', 'Mutation', 'p.R186A', (172, 177))	('TMPRSS11A', 'Gene', (142, 151))	('S368A', 'Var', (182, 187))	('HEK293', 'CellLine', 'CVCL:0045', (115, 121))
407760	32675285	We then did another experiment, in which plasmid expressing the sS368A mutant was co-transfected with plasmids expressing TMPRSS11A, hepsin, TMPRSS2, and corin in HEK293 cells.	('sS368A', 'Var', (64, 70))	('TMPRSS2', 'Gene', (141, 148))	('corin', 'Gene', '10699', (154, 159))	('hepsin', 'Gene', '3249', (133, 139))	('hepsin', 'Gene', (133, 139))	('HEK293', 'CellLine', 'CVCL:0045', (163, 169))	('corin', 'Gene', (154, 159))	('S368A', 'Mutation', 'p.S368A', (65, 70))	('TMPRSS2', 'Gene', '7113', (141, 148))
407767	32675285	To examine the effect of HAI-1 and HAI-2 on TMPRSS11A activation cleavage, we co-transfected HEK293 cells with plasmids expressing TMPRSS11A WT and human HAI-1 or HAI-2.	('HAI-1', 'Gene', (25, 30))	('HAI-1', 'Gene', '6692', (154, 159))	('human', 'Species', '9606', (148, 153))	('HAI-2', 'Gene', (35, 40))	('HAI-2', 'Gene', '10653', (35, 40))	('HAI-1', 'Gene', '6692', (25, 30))	('HAI-2', 'Gene', (163, 168))	('HAI-2', 'Gene', '10653', (163, 168))	('HAI-1', 'Gene', (154, 159))	('HEK293', 'CellLine', 'CVCL:0045', (93, 99))	('TMPRSS11A', 'Var', (131, 140))
407769	32675285	In cells co-expressing TMPRSS11A and HAI-2, the ~37-kDa band was barely visible (Fig.	('HAI-2', 'Gene', '10653', (37, 42))	('TMPRSS11A', 'Var', (23, 32))	('HAI-2', 'Gene', (37, 42))
407775	32675285	This conclusion is supported by the findings that no activation cleavage was detected in catalytically inactive mutants R186A and S368A.	('S368A', 'Var', (130, 135))	('S368A', 'Mutation', 'p.S368A', (130, 135))	('R186A', 'Var', (120, 125))	('R186A', 'Mutation', 'p.R186A', (120, 125))
407776	32675285	In addition, TMPRSS11A WT, but not mutants R186A and S368A, cleaved the soluble TMPRSS11A mutant S368A, indicating that there were no other endogenous proteases capable of cleaving TMPRSS11A in the cells tested in our study.	('S368A', 'Mutation', 'p.S368A', (97, 102))	('S368A', 'Mutation', 'p.S368A', (53, 58))	('TMPRSS11A', 'Gene', (80, 89))	('R186A', 'Mutation', 'p.R186A', (43, 48))	('S368A', 'Var', (97, 102))
407786	32675285	TMPRSS11A variants are linked to the risk of oral and esophageal squamous cell carcinomas.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('variants', 'Var', (10, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (65, 89))	('linked', 'Reg', (23, 29))	('esophageal squamous cell carcinomas', 'Disease', (54, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (54, 89))	('TMPRSS11A', 'Gene', (0, 9))
407794	32675285	By cleaving CoV S proteins between the S1/S2 and the S2' sites, the proteases enhance viral entry and cell-cell fusion in airway tissues.	('cell-cell fusion', 'CPA', (102, 118))	('viral entry', 'CPA', (86, 97))	('enhance', 'PosReg', (78, 85))	('proteins', 'Protein', (18, 26))	('CoV', 'Gene', (12, 15))	('S', 'Gene', '43740568', (16, 17))	('S', 'Gene', '43740568', (53, 54))	('S', 'Gene', '43740568', (39, 40))	('cleaving', 'Var', (3, 11))	('CoV', 'Species', '11118', (12, 15))	('S', 'Gene', '43740568', (42, 43))
407804	32675285	Further studies are required to determine whether and how TMPRSS11A enhances CoV infectivity in host cells.	('TMPRSS11A', 'Var', (58, 67))	('CoV', 'Species', '11118', (77, 80))	('enhances', 'PosReg', (68, 76))	('CoV', 'CPA', (77, 80))
407806	32675285	Moreover, co-expression of TMPRSS11A and HAI-1 in 293T cells reduced, but did not abolish, the cleavage of TMPRSS11A.	('cleavage', 'MPA', (95, 103))	('HAI-1', 'Gene', (41, 46))	('TMPRSS11A', 'Gene', (107, 116))	('TMPRSS11A', 'Gene', (27, 36))	('co-expression', 'Var', (10, 23))	('HAI-1', 'Gene', '6692', (41, 46))	('293T', 'CellLine', 'CVCL:0063', (50, 54))	('reduced', 'NegReg', (61, 68))
407820	32675285	PCR-based site-directed mutagenesis (ClonExpress One Step Cloning kit) was carried out to make constructs expressing TMPRSS11A mutants R186A, R265A, and S368A.	('S', 'Gene', '43740568', (153, 154))	('S368A', 'Mutation', 'p.S368A', (153, 158))	('R186A', 'Mutation', 'p.R186A', (135, 140))	('S', 'Gene', '43740568', (53, 54))	('S', 'Gene', '43740568', (121, 122))	('S', 'Gene', '43740568', (122, 123))	('R265A', 'Mutation', 'p.R265A', (142, 147))	('R186A', 'Var', (135, 140))	('R265A', 'Var', (142, 147))
407822	32675285	Another pSecTag-based plasmid was made to express a soluble form of TMPRSS2 with the extracellular region (residues 106-492).	('S', 'Gene', '43740568', (72, 73))	('TMPRSS2', 'Gene', (68, 75))	('S', 'Gene', '43740568', (73, 74))	('S', 'Gene', '43740568', (9, 10))	('TMPRSS2', 'Gene', '7113', (68, 75))	('residues 106-492', 'Var', (107, 123))
407846	32675285	The concentrated media were incubated with a SARS-CoV-2 S protein extracellular domain (S-ECD) fragment (residues 16-1213) produced in insect cells and with a C-terminal FLAG tag (8 mug/ml, Bioword Technology, NCP0030P).	('SARS-CoV-2', 'Species', '2697049', (45, 55))	('S', 'Gene', '43740568', (45, 46))	('ECD', 'Gene', (90, 93))	('S', 'Gene', '43740568', (56, 57))	('S', 'Gene', '43740568', (88, 89))	('ECD', 'Gene', '11319', (90, 93))	('residues', 'Var', (105, 113))	('N', 'Chemical', 'MESH:D009584', (210, 211))	('S', 'Gene', '43740568', (48, 49))
407943	29792203	The average pulmonary function represented by FEV1% predicted was higher in RAMIE group than VAMIE group (P = 0.012).	('RAMIE', 'Species', '83906', (76, 81))	('pulmonary function', 'CPA', (12, 30))	('RAMIE', 'Var', (76, 81))	('higher', 'PosReg', (66, 72))
407952	29792203	In the recent years, multiple reports have demonstrated that MIE could decrease blood loss, the length of stay, and surgical complications.	('blood loss', 'Disease', 'MESH:D006473', (80, 90))	('decrease', 'NegReg', (71, 79))	('length of stay', 'CPA', (96, 110))	('blood loss', 'Disease', (80, 90))	('surgical complications', 'CPA', (116, 138))	('MIE', 'Var', (61, 64))
407995	28964637	Additionally, in adaptive immunity, VIP promotes T-helper (Th)2 type immune responses and reduces inflammatory Th1 type responses.	('reduces', 'NegReg', (90, 97))	('VIP', 'Var', (36, 39))	('Th1', 'Gene', (111, 114))	('promotes', 'PosReg', (40, 48))	('Th1', 'Gene', '51497', (111, 114))
408028	28964637	Several pieces of evidence indicate that CRTH2 receptor may play an important role in the allergic diseases, since the blockade of this receptor reduces the allergic airway inflammation.	('CRTH2', 'Gene', (41, 46))	('allergic airway inflammation', 'Disease', (157, 185))	('reduces', 'NegReg', (145, 152))	('allergic diseases', 'Disease', (90, 107))	('blockade', 'Var', (119, 127))	('allergic airway inflammation', 'Disease', 'MESH:D004342', (157, 185))	('allergic diseases', 'Disease', 'MESH:D004342', (90, 107))	('CRTH2', 'Gene', '11251', (41, 46))	('airway inflammation', 'Phenotype', 'HP:0002099', (166, 185))	('allergic airway inflammation', 'Phenotype', 'HP:0002099', (157, 185))
408031	28964637	In addition, several other studies implicate PGD2-induced inflammatory cells recruitment in allergic diseases that are mediated via CRTH2 receptor and blockage of this novel CRTH2 receptor attenuates the allergic manifestation in the patients.	('recruitment', 'PosReg', (77, 88))	('allergic manifestation', 'CPA', (204, 226))	('PGD2', 'Gene', (45, 49))	('CRTH2', 'Gene', '11251', (174, 179))	('inflammatory cells', 'CPA', (58, 76))	('CRTH2', 'Gene', (132, 137))	('attenuates', 'NegReg', (189, 199))	('allergic diseases', 'Disease', (92, 109))	('PGD2', 'Gene', '5730', (45, 49))	('patients', 'Species', '9606', (234, 242))	('CRTH2', 'Gene', (174, 179))	('allergic diseases', 'Disease', 'MESH:D004342', (92, 109))	('CRTH2', 'Gene', '11251', (132, 137))	('blockage', 'Var', (151, 159))
408068	28964637	Additionally, in nasal tissue of AR patients, ligation of PGD2 to CRTH2 receptor appears to be selectively involved in eosinophils recruitment.	('CRTH2', 'Gene', (66, 71))	('AR', 'Phenotype', 'HP:0003193', (33, 35))	('patients', 'Species', '9606', (36, 44))	('ligation', 'Var', (46, 54))	('PGD2', 'Gene', (58, 62))	('CRTH2', 'Gene', '11251', (66, 71))	('eosinophils recruitment', 'CPA', (119, 142))	('involved', 'Reg', (107, 115))	('PGD2', 'Gene', '5730', (58, 62))
408093	28964637	VIP has an excitatory effect on monocytes and macrophages but inhibits LPS-induced or IFN-gamma-induced inflammatory pathways in these cells.	('inhibits', 'NegReg', (62, 70))	('IFN-gamma', 'Gene', (86, 95))	('IFN-gamma', 'Gene', '3458', (86, 95))	('LPS-induced', 'Pathway', (71, 82))	('excitatory effect', 'MPA', (11, 28))	('LPS', 'Chemical', 'MESH:D008070', (71, 74))	('VIP', 'Var', (0, 3))
408120	28964637	Consistent with this study, VIP gene deficient (-/-) mice showed peribronchiolar airway inflammation along with the production of pro-inflammatory cytokines and airway hyper-responsiveness to inhaled cholinergic agonist methacholine.	('deficient', 'Var', (37, 46))	('mice', 'Species', '10090', (53, 57))	('inflammation', 'Disease', 'MESH:D007249', (88, 100))	('production of pro-inflammatory cytokines', 'MPA', (116, 156))	('VIP gene', 'Gene', (28, 36))	('methacholine', 'Chemical', 'MESH:D016210', (220, 232))	('inflammation', 'Disease', (88, 100))	('airway inflammation', 'Phenotype', 'HP:0002099', (81, 100))	('hyper-responsiveness', 'Disease', 'MESH:D012130', (168, 188))	('hyper-responsiveness', 'Disease', (168, 188))
408122	28964637	The wild-type mice with VIP gene have functional lung carbonyl reductase without any symptoms of asthma, whereas VIP-/- mice have abnormal carbonyl reductase and have spontaneous asthma suggesting that deficiency of VIP gene may cause a predisposition to asthma development.	('asthma', 'Disease', (255, 261))	('VIP gene', 'Gene', (216, 224))	('asthma', 'Disease', 'MESH:D001249', (179, 185))	('asthma', 'Disease', 'MESH:D001249', (255, 261))	('mice', 'Species', '10090', (120, 124))	('asthma', 'Disease', (179, 185))	('carbonyl reductase', 'MPA', (139, 157))	('mice', 'Species', '10090', (14, 18))	('asthma', 'Phenotype', 'HP:0002099', (255, 261))	('VIP', 'Gene', (24, 27))	('asthma', 'Disease', 'MESH:D001249', (97, 103))	('deficiency', 'Var', (202, 212))	('asthma', 'Phenotype', 'HP:0002099', (179, 185))	('asthma', 'Disease', (97, 103))	('asthma', 'Phenotype', 'HP:0002099', (97, 103))	('cause', 'Reg', (229, 234))	('lung', 'MPA', (49, 53))
408127	28964637	This effect is probably mediated by activation of other allergic mediators and cleavage of the bronchodilating peptides VIP and peptide histidine-methionine (PHM).	('histidine-methionine', 'Chemical', '-', (136, 156))	('activation', 'PosReg', (36, 46))	('cleavage', 'Var', (79, 87))
408128	28964637	Purified tryptase obtained from human lung extract has the ability to rapidly hydrolyze VIP at multiple sites at Arg12, Arg14, Lys20, and Lys21 and PHM at a single site Lys20 indicating tryptase-mediated degradation of the bronchodilators including VIP may be responsible for bronchial responsiveness in asthma.	('asthma', 'Phenotype', 'HP:0002099', (304, 310))	('Lys20', 'Var', (169, 174))	('Lys21', 'Var', (138, 143))	('Lys20', 'Chemical', '-', (127, 132))	('Lys21', 'Chemical', '-', (138, 143))	('Arg14', 'Chemical', '-', (120, 125))	('Arg14', 'Var', (120, 125))	('human', 'Species', '9606', (32, 37))	('Lys20', 'Var', (127, 132))	('Arg12', 'Chemical', '-', (113, 118))	('asthma', 'Disease', (304, 310))	('Lys20', 'Chemical', '-', (169, 174))	('asthma', 'Disease', 'MESH:D001249', (304, 310))	('Arg12', 'Var', (113, 118))
408152	28964637	Although these rats showed reduced nasal secretion, PNN did not affect eosinophils and mast cells infiltration, and other allergic symptoms (i.e.	('PNN', 'Var', (52, 55))	('reduced', 'NegReg', (27, 34))	('nasal secretion', 'MPA', (35, 50))	('rat', 'Species', '10116', (15, 18))	('allergic symptoms', 'Disease', (122, 139))	('allergic symptoms', 'Disease', 'MESH:D004342', (122, 139))	('rats', 'Species', '10116', (15, 19))	('rat', 'Species', '10116', (104, 107))
408169	28964637	VIP concentration is elevated in skin biopsies from patients with eczema, psoriasis and VIP may increase local blood flow in these patients.	('patients', 'Species', '9606', (131, 139))	('psoriasis', 'Disease', 'MESH:D011565', (74, 83))	('psoriasis', 'Disease', (74, 83))	('psoriasis', 'Phenotype', 'HP:0003765', (74, 83))	('elevated', 'PosReg', (21, 29))	('VIP concentration', 'MPA', (0, 17))	('VIP', 'Var', (88, 91))	('eczema', 'Disease', (66, 72))	('rat', 'Species', '10116', (11, 14))	('local blood flow', 'MPA', (105, 121))	('eczema', 'Disease', 'MESH:D004485', (66, 72))	('increase', 'PosReg', (96, 104))	('eczema', 'Phenotype', 'HP:0000964', (66, 72))	('patients', 'Species', '9606', (52, 60))
408188	28964637	GERD patients who have delayed gastric emptying, have the abnormalities in the peptide-immunoreactive fibers that innervate the gastric external muscle.	('abnormalities', 'Var', (58, 71))	('patients', 'Species', '9606', (5, 13))	('GERD', 'Disease', (0, 4))	('GERD', 'Disease', 'MESH:D005764', (0, 4))	('peptide-immunoreactive', 'Protein', (79, 101))	('gastric emptying', 'Phenotype', 'HP:0002578', (31, 47))
408196	28964637	Furthermore, we showed that inhibition of VIP-CRTH2 axis ameliorates eosinophils and mast cells inflammation in the esophagus.	('eosinophils', 'CPA', (69, 80))	('ameliorates', 'PosReg', (57, 68))	('CRTH2', 'Gene', (46, 51))	('inhibition', 'Var', (28, 38))	('CRTH2', 'Gene', '11251', (46, 51))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('rat', 'Species', '10116', (63, 66))	('inflammation', 'Disease', (96, 108))
408245	28434400	In the EBV subgroup, there was amplification of JAK2, CD274, and PDCD1LG2.	('CD274', 'Gene', '29126', (54, 59))	('PDCD1LG2', 'Gene', '80380', (65, 73))	('PDCD1LG2', 'Gene', (65, 73))	('CD274', 'Gene', (54, 59))	('JAK2', 'Gene', '3717', (48, 52))	('JAK2', 'Gene', (48, 52))	('amplification', 'Var', (31, 44))
408247	28434400	High expression of PD-L1 is associated with a poor prognosis in esophageal cancers.	('esophageal cancers', 'Disease', (64, 82))	('PD-L1', 'Gene', (19, 24))	('High', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('esophageal cancers', 'Disease', 'MESH:D004938', (64, 82))	('PD-L1', 'Gene', '29126', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
408248	28434400	studied the role of PD-L1 and PD-L2 expression in 41 human esophageal cancer resection specimens and demonstrated that expression of either PD-L1 or PD-L2 is a significant prognostic marker in patients with squamous cell carcinoma of the esophagus.	('PD-L2', 'Gene', (149, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (207, 230))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('PD-L2', 'Gene', (30, 35))	('squamous cell carcinoma of the esophagus', 'Disease', (207, 247))	('esophageal cancer', 'Disease', (59, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (221, 247))	('patients', 'Species', '9606', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('PD-L1', 'Gene', (20, 25))	('PD-L1', 'Gene', (140, 145))	('human', 'Species', '9606', (53, 58))	('PD-L1', 'Gene', '29126', (140, 145))	('PD-L1', 'Gene', '29126', (20, 25))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (207, 247))	('PD-L2', 'Gene', '80380', (149, 154))	('PD-L2', 'Gene', '80380', (30, 35))	('expression', 'Var', (119, 129))	('men', 'Species', '9606', (92, 95))
408309	28434400	The investigators demonstrated that tumors with high levels of CD3+ T cells in the core as well as at the invasive margin were associated with the best clinical outcome, independent of the TNM stage.	('CD3+ T cells', 'Var', (63, 75))	('TNM', 'Gene', '10178', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('TNM', 'Gene', (189, 192))	('tumors', 'Disease', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
408311	28434400	In this study, high TIL density in the metastatic sites conferred a greater response to chemotherapy treatment and was associated with a longer PFS.	('high', 'Var', (15, 19))	('response to chemotherapy treatment', 'MPA', (76, 110))	('men', 'Species', '9606', (106, 109))	('greater', 'PosReg', (68, 75))
408314	28434400	Microsatellite instability (MSI) in colorectal tumors occurs either due to a germline mutation in one of the four DNA MMR genes (MLH1, MSH2, MSH6, PMS2) or from epigenetic silencing of MLH1 caused by promoter region hypermethylation.	('epigenetic silencing', 'Var', (161, 181))	('PMS2', 'Gene', (147, 151))	('MLH1', 'Gene', '4292', (129, 133))	('MLH1', 'Gene', (129, 133))	('MSH6', 'Gene', (141, 145))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('PMS2', 'Gene', '5395', (147, 151))	('due', 'Reg', (68, 71))	('MLH1', 'Gene', '4292', (185, 189))	('Microsatellite instability', 'Disease', (0, 26))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('MLH1', 'Gene', (185, 189))	('colorectal tumors', 'Disease', 'MESH:D015179', (36, 53))	('MSH6', 'Gene', '2956', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MSH2', 'Gene', (135, 139))	('MSH2', 'Gene', '4436', (135, 139))	('colorectal tumors', 'Disease', (36, 53))
408315	28434400	This results in multiple frameshift and missense mutations of DNA coding sequences, which produce a large number of aberrant proteins that are recognized as "non-self" antigens and trigger an antitumor immune response.	('produce', 'Reg', (90, 97))	('missense mutations', 'Var', (40, 58))	('DNA', 'Gene', (62, 65))	('tumor', 'Disease', (196, 201))	('proteins', 'Protein', (125, 133))	('results in', 'Reg', (5, 15))	('trigger', 'Reg', (181, 188))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('frameshift', 'Var', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('aberrant', 'Var', (116, 124))
408316	28434400	In fact, the overall number of frameshift mutations in a microsatellite-unstable colorectal tumor has been shown to correlate with TIL density.	('frameshift mutations', 'Var', (31, 51))	('colorectal tumor', 'Disease', 'MESH:D015179', (81, 97))	('colorectal tumor', 'Disease', (81, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))
408338	28434400	A phase II study is evaluating the safety and abscopal effect of pembrolizumab when administered in combination with radiotherapy or tumor ablation, in patients with MMR-proficient metastatic CRC (NCT02437071).	('CRC', 'Phenotype', 'HP:0003003', (192, 195))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('metastatic CRC', 'Disease', (181, 195))	('tumor', 'Disease', (133, 138))	('NCT02437071', 'Var', (197, 208))	('pembrolizumab', 'Chemical', 'MESH:C582435', (65, 78))	('patients', 'Species', '9606', (152, 160))
408348	28434400	Moreover, many chemotherapeutic agents including taxanes, gemcitabine, doxorubicin, 5-azacitidine and 5-FU are known to have immunostimulatory effects in addition to their conventional cytotoxic activity.	('5-FU', 'Chemical', 'MESH:D005472', (102, 106))	('gemcitabine', 'Chemical', 'MESH:C056507', (58, 69))	('5-azacitidine', 'Var', (84, 97))	('5-azacitidine', 'Chemical', 'MESH:D001374', (84, 97))	('5-FU', 'Var', (102, 106))	('taxanes', 'Chemical', 'MESH:D043823', (49, 56))	('doxorubicin', 'Chemical', 'MESH:D004317', (71, 82))
408349	28434400	For example, 5-FU facilitates antigen expression by tumor cells, antigen uptake by dendritic cells, and subsequent cross-penetration of tumor antigens.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('antigen expression', 'MPA', (30, 48))	('5-FU', 'Chemical', 'MESH:D005472', (13, 17))	('tumor', 'Disease', (52, 57))	('cross-penetration', 'CPA', (115, 132))	('facilitates', 'PosReg', (18, 29))	('antigen uptake', 'CPA', (65, 79))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('5-FU', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (136, 141))
408350	28434400	Therefore, combining chemotherapy with an immune checkpoint inhibitor that can counteract the effects of PD-L1 is another potential therapeutic strategy that is being explored in clinical trials (NCT01633970, NCT02375672, NCT02291289).	('PD-L1', 'Gene', '29126', (105, 110))	('NCT01633970', 'Var', (196, 207))	('NCT02375672', 'Var', (209, 220))	('PD-L1', 'Gene', (105, 110))
408354	28434400	It is now well established that pancreatic cancer carcinogenesis is driven by alteration in multiple genes that regulate oncogenic pathways in the tumor cells and the neighboring microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('driven by', 'Reg', (68, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (32, 49))	('regulate', 'Reg', (112, 120))	('alteration', 'Var', (78, 88))	('men', 'Species', '9606', (191, 194))	('pancreatic cancer carcinogenesis', 'Disease', (32, 64))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('oncogenic pathways', 'Pathway', (121, 139))	('pancreatic cancer carcinogenesis', 'Disease', 'MESH:D010190', (32, 64))
408367	28434400	GV1001 is a telomerase peptide vaccine shown to prolong survival when combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) in a phase I/II study of unresectable pancreatic cancer patients.	('patients', 'Species', '9606', (198, 206))	('survival', 'MPA', (56, 64))	('prolong', 'PosReg', (48, 55))	('GM-CSF', 'Gene', (134, 140))	('GM-CSF', 'Gene', '1437', (134, 140))	('pancreatic cancer', 'Disease', 'MESH:D010190', (180, 197))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '1437', (84, 132))	('pancreatic cancer', 'Disease', (180, 197))	('GV1001', 'Chemical', '-', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('GV1001', 'Var', (0, 6))	('granulocyte-macrophage colony-stimulating factor', 'Gene', (84, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (180, 197))
408368	28434400	However, the phase III study comparing gemcitabine with or without GV1001 in advanced unresectable pancreatic cancer was terminated early due to lack of survival benefit in the GV1001 arm (NCT00358566).	('GV1001', 'Chemical', '-', (177, 183))	('pancreatic cancer', 'Disease', (99, 116))	('GV1001', 'Chemical', '-', (67, 73))	('GV1001', 'Var', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lack', 'NegReg', (145, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('gemcitabine', 'Chemical', 'MESH:C056507', (39, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))
408448	26895105	Multivariate and univariate regression analysis demonstrated that low/unchanged miR-486-5p predicted poor prognosis in ESCC (hazard ratio [HR], 4.32; 95% confidence interval [CI], 2.62-7.14; P < 0.001; HR, 3.88; 95% CI, 2.43-6.22; P < 0.001, respectively) and GC (HR, 2.46; 95% CI, 1.35-4.50; P = 0.003; HR, 2.55; 95% CI, 1.39-4.69; P = 0.002, respectively).	('miR-486', 'Gene', (80, 87))	('miR-486', 'Gene', '619554', (80, 87))	('ESCC', 'Disease', (119, 123))	('5p', 'Chemical', '-', (88, 90))	('low/unchanged', 'Var', (66, 79))	('GC', 'Phenotype', 'HP:0012126', (260, 262))
408455	26895105	It is accepted that gastric carcinogenesis, like that of other malignancies, involves the accumulation of genetic and epigenetic changes.	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (20, 42))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('malignancies', 'Disease', (63, 75))	('gastric carcinogenesis', 'Disease', (20, 42))	('epigenetic changes', 'Var', (118, 136))
408460	26895105	Aberrant expression of miR-486/miR-486-5p is associated with different types of disease.	('Aberrant expression', 'Var', (0, 19))	('5p', 'Chemical', '-', (39, 41))	('miR-486', 'Gene', (23, 30))	('types of disease', 'Disease', (71, 87))	('associated', 'Reg', (45, 55))	('miR-486', 'Gene', '619554', (23, 30))	('miR-486', 'Gene', (31, 38))	('miR-486', 'Gene', '619554', (31, 38))
408466	26895105	Deregulation of cancer-related miR-486-5p can also be a common event in both benign and malignant human breast tumors.	('breast tumors', 'Disease', (104, 117))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('5p', 'Chemical', '-', (39, 41))	('Deregulation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('benign', 'Disease', (77, 83))	('miR-486', 'Gene', (31, 38))	('breast tumors', 'Phenotype', 'HP:0100013', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast tumors', 'Disease', 'MESH:D001943', (104, 117))	('human', 'Species', '9606', (98, 103))	('miR-486', 'Gene', '619554', (31, 38))
408480	26895105	Kaplan-Meier analysis demonstrated that low or unchanged expression of miR-486-5p, stage of disease, tumor status, and node status were significant negative prognostic predictors for OS in patients with ESCC (P < 0.001, P < 0.001, P = 0.001, P < 0.001, respectively) and those with GC (P = 0.002, P < 0.001, P = 0.001, P = 0.005, respectively).	('expression', 'MPA', (57, 67))	('miR-486', 'Gene', (71, 78))	('5p', 'Chemical', '-', (79, 81))	('GC', 'Phenotype', 'HP:0012126', (282, 284))	('low', 'Var', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('miR-486', 'Gene', '619554', (71, 78))	('ESCC', 'Disease', (203, 207))	('negative', 'NegReg', (148, 156))	('patients', 'Species', '9606', (189, 197))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
408482	26895105	The prognosis of ESCC patients with low/unchanged miR-486-5p expression was significantly poorer than that of ESCC patients with high miR-486-5p expression (P < 0.001; Figure 2).	('patients', 'Species', '9606', (115, 123))	('miR-486', 'Gene', (50, 57))	('miR-486', 'Gene', (134, 141))	('low/unchanged', 'Var', (36, 49))	('5p', 'Chemical', '-', (142, 144))	('ESCC', 'Disease', (17, 21))	('poorer', 'NegReg', (90, 96))	('patients', 'Species', '9606', (22, 30))	('miR-486', 'Gene', '619554', (50, 57))	('miR-486', 'Gene', '619554', (134, 141))	('5p', 'Chemical', '-', (58, 60))
408484	26895105	After stratification of patients according to American Joint Committee on Cancer stage, low/unchanged miR-486-5p expression remained a significant predictor of poor survival in stage II (34.8 vs. 63.2 months; P < 0.001, n = 82) and stage III (15.2 vs. 50.0 months; P < 0.001, n = 78) ESCC.	('5p', 'Chemical', '-', (110, 112))	('poor', 'NegReg', (160, 164))	('low/unchanged', 'Var', (88, 101))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('miR-486', 'Gene', (102, 109))	('patients', 'Species', '9606', (24, 32))	('miR-486', 'Gene', '619554', (102, 109))
408486	26895105	The prognosis of GC patients with low/unchanged miR-486-5p expression was significantly poorer than that of GC patients with high miR-486-5p expression (P < 0.001; Figure 2).	('5p', 'Chemical', '-', (138, 140))	('miR-486', 'Gene', (130, 137))	('miR-486', 'Gene', '619554', (48, 55))	('GC', 'Phenotype', 'HP:0012126', (17, 19))	('miR-486', 'Gene', '619554', (130, 137))	('GC', 'Phenotype', 'HP:0012126', (108, 110))	('low/unchanged', 'Var', (34, 47))	('poorer', 'NegReg', (88, 94))	('patients', 'Species', '9606', (20, 28))	('5p', 'Chemical', '-', (56, 58))	('miR-486', 'Gene', (48, 55))	('patients', 'Species', '9606', (111, 119))
408491	26895105	Moreover, in multivariate analysis for GC, stage (HR, 2.72; 95% CI, 1.55-4.78; P < 0.001), low/unchanged miR-486-5p (HR, 2.55; 95% CI, 1.39-4.69; P = 0.002), and tumor size (HR, 2.09; 95% CI, 1.07-4.05; P = 0.03) predicted poor prognosis (Table 8).	('poor prognosis', 'CPA', (223, 237))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('miR-486', 'Gene', (105, 112))	('tumor', 'Disease', (162, 167))	('low/unchanged', 'Var', (91, 104))	('miR-486', 'Gene', '619554', (105, 112))	('5p', 'Chemical', '-', (113, 115))	('GC', 'Phenotype', 'HP:0012126', (39, 41))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
408509	26895105	A previous four-phase study detected increased miR-486-5p expression during the early stage of GC and identified five plasma miRNAs (miR-16, miR-25, miR-92a, miR-451, and miR-486-5p) that might serve as potential diagnostic markers for early-stage gastric non-cardia adenocarcinoma.	('5p', 'Chemical', '-', (55, 57))	('expression', 'MPA', (58, 68))	('miR-92a', 'Var', (149, 156))	('increased', 'PosReg', (37, 46))	('miR-451', 'Gene', (158, 165))	('gastric non-cardia adenocarcinoma', 'Disease', (248, 281))	('GC', 'Phenotype', 'HP:0012126', (95, 97))	('miR-16', 'Gene', (133, 139))	('miR-486', 'Gene', (47, 54))	('early-stage', 'Disease', (236, 247))	('gastric non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (248, 281))	('miR-25', 'Gene', (141, 147))	('5p', 'Chemical', '-', (179, 181))	('miR-16', 'Gene', '51573', (133, 139))	('miR-486', 'Gene', (171, 178))	('miR-486', 'Gene', '619554', (47, 54))	('miR-451', 'Gene', '574411', (158, 165))	('miR-25', 'Gene', '407014', (141, 147))	('miR-486', 'Gene', '619554', (171, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))
408512	26895105	Moreover, univariate and multivariate Cox regression analysis of potential prognostic factors for survival identified a significant relationship between low/unchanged miR-486-5p expression and poor prognosis of ESCC (P < 0.001, P < 0.001 respectively) and GC (P = 0.002, P = 0.003 respectively).	('low/unchanged', 'Var', (153, 166))	('ESCC', 'Disease', (211, 215))	('miR-486', 'Gene', (167, 174))	('Cox', 'Gene', '1351', (38, 41))	('Cox', 'Gene', (38, 41))	('miR-486', 'Gene', '619554', (167, 174))	('5p', 'Chemical', '-', (175, 177))	('GC', 'Phenotype', 'HP:0012126', (256, 258))
408561	26557905	If the pre-operative stage is T2N1 or greater in esophageal cancer, a neoadjuvant therapy is generally recommended before surgery.	('esophageal cancer', 'Disease', (49, 66))	('men', 'Species', '9606', (108, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('T2N1', 'Var', (30, 34))
408597	26557905	Tumor SUVmax in the subgroup with lymphatic invasion was higher than in the subgroup without lymphatic invasion in patients without neoadjuvant therapy (P = 0.007).	('patients', 'Species', '9606', (115, 123))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor SUVmax', 'CPA', (0, 12))	('higher', 'PosReg', (57, 63))	('lymphatic invasion', 'Var', (34, 52))
408624	26557905	A recent meta-analysis study showed a survival benefit of neoadjuvant therapy followed by surgery over surgery alone in patients with esophageal cancer; improved survival rates resulted from the addition of neoadjuvant therapy and not from further radical surgery.	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('neoadjuvant', 'Var', (207, 218))	('survival', 'MPA', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('improved', 'PosReg', (153, 161))	('patients', 'Species', '9606', (120, 128))	('esophageal cancer', 'Disease', (134, 151))
408639	20696410	In the first category, abnormal Hh signaling initiates growth of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Hh signaling', 'MPA', (32, 44))	('tumor', 'Disease', (69, 74))	('growth', 'CPA', (55, 61))	('abnormal', 'Var', (23, 31))	('abnormal Hh', 'Phenotype', 'HP:0011902', (23, 34))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
408653	20696410	These mechanisms include loss-of-function mutations in inhibitory proteins such as Patched1, gain-of-function mutations in positive regulators such as Smo, over-expression of the Hh ligands leading to activation of the pathway in an autocrine or paracrine fashion, and renewal of cancer stem cells (Figure C).	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('Patched1', 'Gene', (83, 91))	('mutations', 'Var', (110, 119))	('cancer', 'Disease', (280, 286))	('loss-of-function', 'NegReg', (25, 41))	('over-expression', 'PosReg', (156, 171))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('Smo', 'Gene', (151, 154))	('mutations', 'Var', (42, 51))	('gain-of-function', 'PosReg', (93, 109))
408654	20696410	Hh signaling was first linked to cancer when a mutation in the PTCH (human patched1 gene) was found to cause Gorlin syndrome, a rare genetic disorder characterized by tumor formation in the skin (Basal Cell Carcinoma, BCC), cerebellum (medulloblastoma, MB), and soft tissue (Rhabdomyosarcoma, RMS).	('Carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('cancer', 'Disease', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cause', 'Reg', (103, 108))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (109, 124))	('medulloblastoma', 'Phenotype', 'HP:0002885', (236, 251))	('medulloblastoma', 'Disease', 'MESH:D008527', (236, 251))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (275, 291))	('medulloblastoma', 'Disease', (236, 251))	('Gorlin syndrome', 'Disease', (109, 124))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (275, 291))	('PTCH', 'Gene', (63, 67))	('Basal Cell Carcinoma', 'Disease', 'MESH:D002280', (196, 216))	('genetic disorder', 'Disease', 'MESH:D030342', (133, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (284, 291))	('tumor', 'Disease', (167, 172))	('patched1', 'Gene', '5727', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('genetic disorder', 'Disease', (133, 149))	('human', 'Species', '9606', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('Basal Cell Carcinoma', 'Disease', (196, 216))	('patched1', 'Gene', (75, 83))	('Basal Cell Carcinoma', 'Phenotype', 'HP:0002671', (196, 216))	('Rhabdomyosarcoma', 'Disease', (275, 291))	('mutation', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
408655	20696410	Loss of one copy of PTCH is sufficient to cause the syndrome; germline mutation of both copies is presumably fatal as it is in mice.	('mice', 'Species', '10090', (127, 131))	('syndrome', 'Disease', (52, 60))	('cause', 'Reg', (42, 47))	('Loss', 'NegReg', (0, 4))	('PTCH', 'Gene', (20, 24))	('germline mutation', 'Var', (62, 79))
408656	20696410	Thus PTCH is a tumor suppressor gene; PTCH mutations are inherited as autosomal dominant causes of Gorlin syndrome.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Gorlin syndrome', 'Disease', (99, 114))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', (15, 20))	('PTCH', 'Gene', (38, 42))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (99, 114))
408658	20696410	Subsequently, mutations in other Hh pathway components, including hyper-activating mutations of SMO and loss-of-function mutations in Suppressor of fused (SUFU), were discovered in BCC.	('SMO', 'Gene', (96, 99))	('mutations', 'Var', (121, 130))	('hyper-activating', 'PosReg', (66, 82))	('loss-of-function', 'NegReg', (104, 120))	('SUFU', 'Gene', (155, 159))	('SUFU', 'Gene', '24069', (155, 159))	('SMO', 'Gene', '319757', (96, 99))
408663	20696410	Just as Hh signaling will play a different role in each tissue where it operates, the effect of damage to Hh signaling may have different implications for tumorigenesis in each type of developing cancer.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('damage', 'Var', (96, 102))	('tumor', 'Disease', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))
408666	20696410	The first category includes cancers in which a mutation in the Hh pathway plays an initiating role in tumorigenesis.	('cancers', 'Disease', (28, 35))	('tumor', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Hh pathway', 'Pathway', (63, 73))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
408675	20696410	Activating the Hh pathway at any of several levels of the signal transduction cascade, or in conjunction with inactivation of additional tumor suppressor genes, can lead to formation of these tumors.	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', (137, 142))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('Activating', 'Var', (0, 10))	('lead to', 'Reg', (165, 172))	('Hh pathway', 'Pathway', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
408676	20696410	These findings with sporadic BCC, MB, and RMS implicate activating Hh pathway mutations and the resultant Hh target gene over-activity as initiating events in tumorigenesis.	('BCC', 'Disease', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('activating', 'PosReg', (56, 66))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('over-activity', 'PosReg', (121, 134))
408686	20696410	More than 90% of sporadic BCCs have mutations in one allele of PTCH and an additional 10% have activating mutations in the gene SMOOTHENED (SMOH), a downstream component of the Hh pathway.	('BCCs', 'Disease', (26, 30))	('SMOOTHENED', 'Gene', (128, 138))	('mutations', 'Var', (36, 45))	('SMOH', 'Gene', '319757', (140, 144))	('SMOH', 'Gene', (140, 144))	('PTCH', 'Gene', (63, 67))	('mutations', 'Var', (106, 115))	('SMOOTHENED', 'Gene', '319757', (128, 138))	('activating', 'PosReg', (95, 105))
408687	20696410	Mutations identified in PTCH and SMOH presumably arise from UV radiation and result in Hh pathway over-activity.	('SMOH', 'Gene', '319757', (33, 37))	('SMOH', 'Gene', (33, 37))	('over-activity', 'PosReg', (98, 111))	('Mutations', 'Var', (0, 9))	('PTCH', 'Gene', (24, 28))	('Hh pathway', 'Pathway', (87, 97))
408688	20696410	Mice heterozygous for PTCH develop BCC after the deletion of the wildtype copy.	('Mice', 'Species', '10090', (0, 4))	('deletion', 'Var', (49, 57))	('BCC', 'Disease', (35, 38))
408708	20696410	Hyper=proliferative GNPs form patches of pre-neoplastic lesions, which appear on the surface of ptc1+/- mouse cerebellums, but not on the cerebellums of wild-type mice.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (45, 63))	('mouse', 'Species', '10090', (104, 109))	('mice', 'Species', '10090', (163, 167))	('pre-neoplastic lesions', 'CPA', (41, 63))	('ptc1+/-', 'Var', (96, 103))
408710	20696410	Although constitutive Hh pathway activation in Ptc1 heterozygous mouse MB lesions is well-documented, Ptc1 haploinsufficiency itself is not sufficient for neoplastic transformation given the low penetrance of MB in mice heterozygous for a mutation in the Ptc1 allele.	('haploinsufficiency', 'Disease', (107, 125))	('mutation', 'Var', (239, 247))	('activation', 'PosReg', (33, 43))	('mouse', 'Species', '10090', (65, 70))	('Ptc1', 'Gene', (255, 259))	('haploinsufficiency', 'Disease', 'MESH:D058495', (107, 125))	('mice', 'Species', '10090', (215, 219))
408711	20696410	Given that Ptc1 is a tumor suppressor gene, one clear candidate for a possible "second hit" to promote tumorigenesis was somatic mutation of the second copy of ptc1 leading to loss of heterozygosity, as in human basal cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('loss', 'NegReg', (176, 180))	('tumor', 'Disease', (21, 26))	('mutation', 'Var', (129, 137))	('human', 'Species', '9606', (206, 211))	('tumor', 'Disease', (103, 108))	('heterozygosity', 'MPA', (184, 198))	('ptc1', 'Gene', (160, 164))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (212, 232))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (212, 232))	('basal cell carcinoma', 'Disease', (212, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
408712	20696410	Data support inactivation of the second Ptc1 allele and ensuing loss of heterozygosity as a mechanism for MB tumorigenesis, but other mutations leading to neoplastic progression of early lesions may contribute instead or in addition.	('inactivation', 'Var', (13, 25))	('Ptc1', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('loss', 'NegReg', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
408714	20696410	Inhibiting Smo blocks proliferation in resected human MB tumors and prevents formation of MBs in mouse models of MB.	('MB tumors', 'Disease', (54, 63))	('Inhibiting', 'Var', (0, 10))	('MB tumors', 'Disease', 'OMIM:613675', (54, 63))	('human', 'Species', '9606', (48, 53))	('proliferation', 'CPA', (22, 35))	('prevents', 'NegReg', (68, 76))	('mouse', 'Species', '10090', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Smo', 'Gene', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('formation of MBs', 'MPA', (77, 93))
408718	20696410	Treatment with GDC-0449 resulted in rapid regression of the tumor and reduction of symptoms, but the effectiveness of the therapy was transient, due to quickly-acquired resistance due to mutation of SMO.	('SMO', 'Gene', (199, 202))	('reduction', 'NegReg', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('symptoms', 'MPA', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutation', 'Var', (187, 195))	('tumor', 'Disease', (60, 65))	('SMO', 'Gene', '319757', (199, 202))	('GDC-0449', 'Chemical', 'MESH:C538724', (15, 23))
408727	20696410	Most alveolar RMS tumors have translocations involving PAX3-FKHR or Pax7-FKHR fusion genes as well as PTCH imbalances.	('FKHR', 'Gene', '56458', (73, 77))	('Pax7', 'Gene', '18509', (68, 72))	('alveolar RMS tumors', 'Disease', (5, 24))	('FKHR', 'Gene', (60, 64))	('imbalances', 'Phenotype', 'HP:0002172', (107, 117))	('translocations', 'Var', (30, 44))	('FKHR', 'Gene', '56458', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('Pax7', 'Gene', (68, 72))	('alveolar RMS tumors', 'Disease', 'MESH:D002282', (5, 24))	('PAX3', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('PAX3', 'Gene', '18505', (55, 59))	('FKHR', 'Gene', (73, 77))
408728	20696410	In addition to the Gorlin syndrome model, manipulation of PAX and FOX genes, coupled with combinatorial activation of known oncogenes and inactivation of known tumor suppressor genes, leads to RMS in mouse models.	('PAX', 'Gene', (58, 61))	('activation', 'PosReg', (104, 114))	('FOX genes', 'Gene', (66, 75))	('inactivation', 'NegReg', (138, 150))	('PAX', 'Chemical', '-', (58, 61))	('Gorlin syndrome', 'Disease', (19, 34))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('RMS', 'Disease', (193, 196))	('mouse', 'Species', '10090', (200, 205))	('man', 'Species', '9606', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('leads to', 'Reg', (184, 192))	('manipulation', 'Var', (42, 54))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (19, 34))	('tumor', 'Disease', (160, 165))
408735	20696410	The restriction of Shh expression inhibits epithelial proliferation to allow normal crypt development by growth of the flanking epithelium.	('epithelia', 'Disease', 'None', (43, 52))	('inhibits', 'NegReg', (34, 42))	('Shh', 'Gene', (19, 22))	('restriction', 'Var', (4, 15))	('epithelia', 'Disease', (43, 52))
408740	20696410	The growth of colon cancer cell lines in vitro is inhibited by cyclopamine, an inhibitor of the Hh pathway.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('growth', 'CPA', (4, 10))	('cyclopamine', 'Var', (63, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (14, 26))	('cyclopamine', 'Chemical', 'MESH:C000541', (63, 74))	('colon cancer', 'Disease', 'MESH:D015179', (14, 26))	('inhibited', 'NegReg', (50, 59))	('colon cancer', 'Disease', (14, 26))
408745	20696410	Inhibiting the stroma's ability to activate the Hh pathway with an oral antagonist, an antibody, or genetic deletion inhibits the ability of human colon cancer xenografts to grow.	('colon cancer', 'Phenotype', 'HP:0003003', (147, 159))	('Hh pathway', 'Pathway', (48, 58))	('inhibits', 'NegReg', (117, 125))	('genetic deletion', 'Var', (100, 116))	('colon cancer', 'Disease', 'MESH:D015179', (147, 159))	('human', 'Species', '9606', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('colon cancer', 'Disease', (147, 159))
408748	20696410	Hh pathway mutations may drive colon cancer growth indirectly by allowing activation of the Wnt pathway (for a review see).	('colon cancer', 'Disease', (31, 43))	('mutations', 'Var', (11, 20))	('Wnt pathway', 'Pathway', (92, 103))	('Hh pathway', 'Gene', (0, 10))	('colon cancer', 'Phenotype', 'HP:0003003', (31, 43))	('colon cancer', 'Disease', 'MESH:D015179', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('drive', 'PosReg', (25, 30))
408751	20696410	Removal of Tcf4, an activator of Wnt target gene transcription, prevents development of intestinal crypt progenitor cells.	('Tcf4', 'Gene', (11, 15))	('prevents', 'NegReg', (64, 72))	('Removal', 'Var', (0, 7))	('Tcf4', 'Gene', '21413', (11, 15))
408752	20696410	Over-expression of oncogenic forms of ss-catenin, or mutations in a negative Wnt pathway component, Adenomatous polyposis coli (APC), results in hyper-proliferation of the epithelium.	('Over-expression', 'PosReg', (0, 15))	('ss-catenin', 'Protein', (38, 48))	('Adenomatous polyposis coli', 'Disease', (100, 126))	('Adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (100, 126))	('mutations', 'Var', (53, 62))	('APC', 'Disease', 'MESH:D011125', (128, 131))	('Adenomatous polyposis coli', 'Disease', 'MESH:D011125', (100, 126))	('ss-catenin', 'Chemical', '-', (38, 48))	('APC', 'Disease', (128, 131))	('hyper-proliferation', 'CPA', (145, 164))
408767	20696410	Absence of Shh allows formation of the dorsal pancreatic bud, and contributes to forming the ventral pancreatic bud.	('pancreatic', 'Disease', 'MESH:D010195', (101, 111))	('pancreatic', 'Disease', 'MESH:D010195', (46, 56))	('pancreatic', 'Disease', (101, 111))	('pancreatic', 'Disease', (46, 56))	('Shh', 'Gene', (11, 14))	('Absence', 'Var', (0, 7))
408769	20696410	Xenopus injected with mRNA encoding constitutively active Smoothened completely lack a pancreas.	('mRNA', 'Var', (22, 26))	('Xenopus', 'Species', '8355', (0, 7))	('lack a pancreas', 'Phenotype', 'HP:0100801', (80, 95))	('lack', 'NegReg', (80, 84))
408771	20696410	Thus loss of Shh promotes pancreatic development and over-expression of Shh prevents proper pancreatic development.	('prevents', 'NegReg', (76, 84))	('over-expression', 'Var', (53, 68))	('Shh', 'Gene', (72, 75))	('pancreatic', 'Disease', 'MESH:D010195', (92, 102))	('pancreatic', 'Disease', 'MESH:D010195', (26, 36))	('promotes', 'PosReg', (17, 25))	('Shh', 'Gene', (13, 16))	('pancreatic', 'Disease', (92, 102))	('pancreatic', 'Disease', (26, 36))	('loss', 'Var', (5, 9))
408773	20696410	Inhibiting Hh signal transduction in hamster pancreatic ductal cells reduces cell growth, suggesting that Hh is important for normal pancreatic regeneration.	('pancreatic', 'Disease', (45, 55))	('Inhibiting', 'Var', (0, 10))	('cell growth', 'CPA', (77, 88))	('pancreatic', 'Disease', 'MESH:D010195', (133, 143))	('reduces', 'NegReg', (69, 76))	('hamster', 'Species', '10034', (37, 44))	('pancreatic', 'Disease', (133, 143))	('pancreatic', 'Disease', 'MESH:D010195', (45, 55))
408780	20696410	Over-expression of Shh in the mouse pancreas causes "PanIN" lesions similar to early human pancreatic neoplasms in morphology and genetic changes (e.g.	('Shh', 'Gene', (19, 22))	('causes', 'Reg', (45, 51))	('pancreatic neoplasms', 'Disease', (91, 111))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (91, 111))	('neoplasms', 'Phenotype', 'HP:0002664', (102, 111))	('Over-expression', 'Var', (0, 15))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (91, 111))	('mouse', 'Species', '10090', (30, 35))	('human', 'Species', '9606', (85, 90))
408792	20696410	Inhibiting the stroma's ability to activate its Hh pathway with an oral antagonist, an antibody, or targeted genetic deletion inhibits the ability of human colon cancer xenografts to grow.	('human', 'Species', '9606', (150, 155))	('inhibits', 'NegReg', (126, 134))	('colon cancer', 'Disease', 'MESH:D015179', (156, 168))	('colon cancer', 'Phenotype', 'HP:0003003', (156, 168))	('Hh pathway', 'Pathway', (48, 58))	('colon cancer', 'Disease', (156, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('genetic deletion', 'Var', (109, 125))
408817	20696410	Reduction of Gli1 or Gli2 mRNA with antisense oligonucleotides decreased the viability of four cell lines and increased their susceptibility to chemotherapy (doxorubicin)-induced cell death, though the effect of the antisense oligonucleotides, with or without chemotherapy, was minimal.	('oligonucleotides', 'Chemical', 'MESH:D009841', (46, 62))	('viability of four cell lines', 'CPA', (77, 105))	('cell death', 'CPA', (179, 189))	('doxorubicin', 'Chemical', 'MESH:D004317', (158, 169))	('increased', 'PosReg', (110, 119))	('decreased', 'NegReg', (63, 72))	('oligonucleotides', 'Chemical', 'MESH:D009841', (226, 242))	('Gli2', 'Gene', (21, 25))	('antisense', 'Var', (36, 45))	('Reduction', 'NegReg', (0, 9))	('Gli1', 'Gene', (13, 17))	('susceptibility', 'MPA', (126, 140))
408822	20696410	Dysregulated Shh signaling may also be important for T-cell malignancies.	('T-cell malignancies', 'Disease', 'MESH:D009369', (53, 72))	('T-cell malignancies', 'Phenotype', 'HP:0005517', (53, 72))	('T-cell malignancies', 'Disease', (53, 72))	('Dysregulated', 'Var', (0, 12))	('Shh', 'Protein', (13, 16))
408843	20696410	When Gli2 and Gli3 are genetically deleted, the mice fail to form an esophagus.	('Gli2', 'Gene', (5, 9))	('Gli3', 'Gene', (14, 18))	('deleted', 'Var', (35, 42))	('mice', 'Species', '10090', (48, 52))	('fail to form an esophagus', 'Phenotype', 'HP:0002032', (53, 78))	('Gli3', 'Gene', '14634', (14, 18))	('fail', 'NegReg', (53, 57))
408844	20696410	In chronic gastric reflux disease in humans, acid from the stomach damages the mature esophagus and can lead to cellular metaplasia, a preneoplastic lesion, within the esophagus.	('gastric reflux disease', 'Disease', (11, 33))	('humans', 'Species', '9606', (37, 43))	('damages', 'NegReg', (67, 74))	('acid', 'Var', (45, 49))	('gastric reflux', 'Phenotype', 'HP:0002020', (11, 25))	('metaplasia', 'Disease', 'MESH:D008679', (121, 131))	('gastric reflux disease', 'Disease', 'MESH:D005764', (11, 33))	('lead to', 'Reg', (104, 111))	('metaplasia', 'Disease', (121, 131))
408858	20696410	In one study, detection of nuclear Gli1 protein was an independent predictor of early relapse and poor prognosis in esophageal squamous cell carcinoma after preoperative chemoradiation therapy but it will be important to perform more controls to ensure that the staining is specific.	('esophageal squamous cell carcinoma', 'Disease', (116, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('detection', 'Var', (14, 23))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (116, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('nuclear Gli1 protein', 'Protein', (27, 47))
408860	20696410	Further research will need to be conducted using mutations of the Hh pathway in a mouse model of esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (97, 117))	('mutations', 'Var', (49, 58))	('esophageal carcinoma', 'Disease', (97, 117))	('Hh pathway', 'Pathway', (66, 76))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (97, 117))	('mouse', 'Species', '10090', (82, 87))
408867	20696410	Heterozygous Ptc1 mutations, which allow over-activation of Hh target genes, cause ductal hyperplasias and dysplasias.	('cause', 'Reg', (77, 82))	('hyperplasias and dysplasias', 'Disease', 'MESH:D006965', (90, 117))	('over-activation', 'PosReg', (41, 56))	('Ptc1', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
408869	20696410	Gli2 homozygous null mutants, where target gene transcription is reduced, have epithelial hyperplasias and ductal outgrowths.	('mutants', 'Var', (21, 28))	('ductal outgrowths', 'CPA', (107, 124))	('reduced', 'NegReg', (65, 72))	('transcription', 'MPA', (48, 61))	('epithelial hyperplasias', 'Disease', (79, 102))	('Gli2', 'Gene', (0, 4))	('epithelial hyperplasias', 'Disease', 'MESH:D017573', (79, 102))
408872	20696410	Heterozygous PTCH mutations were identified in approximately a subset of human breast cancers, but their significance is unclear.	('breast cancers', 'Phenotype', 'HP:0003002', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancers', 'Disease', 'MESH:D001943', (79, 93))	('breast cancers', 'Disease', (79, 93))	('human', 'Species', '9606', (73, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('identified', 'Reg', (33, 43))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('Heterozygous PTCH mutations', 'Var', (0, 27))
408874	20696410	Deletion of the PTCH locus is the fourth most common change among tumor suppressor genes in breast cancer: 19% of human breast cancers and 33% of human breast cancer cell lines.	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('human', 'Species', '9606', (114, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('tumor', 'Disease', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('Deletion', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancers', 'Disease', 'MESH:D001943', (120, 134))	('breast cancer', 'Disease', (92, 105))	('breast cancers', 'Disease', (120, 134))	('PTCH', 'Gene', (16, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('breast cancers', 'Phenotype', 'HP:0003002', (120, 134))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('human', 'Species', '9606', (146, 151))	('breast cancer', 'Disease', (152, 165))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
408888	20696410	The Dhh homozygous null mutant mouse has no ovarian phenotype, indicating either redundancy between Ihh and Dhh, or Ihh as the main follicle development signal.	('mutant', 'Var', (24, 30))	('redundancy', 'MPA', (81, 91))	('Dhh', 'Chemical', '-', (108, 111))	('mouse', 'Species', '10090', (31, 36))	('Dhh', 'Gene', (4, 7))	('Dhh', 'Chemical', '-', (4, 7))
408893	20696410	Other groups have demonstrated epigenetic regulation of PTCH in ovarian carcinoma.	('epigenetic regulation', 'Var', (31, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (64, 81))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (64, 81))	('ovarian carcinoma', 'Disease', (64, 81))	('PTCH', 'Gene', (56, 60))
408894	20696410	We still lack a clear understanding of Hh pathway deregulation as an inciting or secondary event in ovarian carcinoma.	('ovarian carcinoma', 'Disease', (100, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('deregulation', 'Var', (50, 62))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (100, 117))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (100, 117))
408902	20696410	In the cell lines, inhibition of Smo with its antagonist cyclopamine reduces expression of Hh target genes and results in apoptosis.	('cyclopamine', 'Chemical', 'MESH:C000541', (57, 68))	('expression', 'MPA', (77, 87))	('results in', 'Reg', (111, 121))	('inhibition', 'Var', (19, 29))	('Smo', 'Gene', (33, 36))	('apoptosis', 'CPA', (122, 131))	('Hh target genes', 'Gene', (91, 106))	('reduces', 'NegReg', (69, 76))
408907	20696410	Disruption of Gli3 or Shh genes causes lung morphology abnormalities.	('lung morphology abnormalities', 'Disease', 'MESH:D000013', (39, 68))	('Gli3', 'Gene', (14, 18))	('Gli3', 'Gene', '14634', (14, 18))	('lung morphology abnormalities', 'Disease', (39, 68))	('Shh genes', 'Gene', (22, 31))	('causes', 'Reg', (32, 38))	('lung morphology abnormalities', 'Phenotype', 'HP:0002088', (39, 68))	('Disruption', 'Var', (0, 10))
408911	20696410	Because lung damage and consequential repair process lead to expansion of precursor populations, it is likely that repair processes induced by smoking-related damage, coupled with mutagenic effects of smoking, results in a predisposition to lung cancer.	('lung damage', 'Disease', 'MESH:D008171', (8, 19))	('lung cancer', 'Disease', (241, 252))	('lung cancer', 'Phenotype', 'HP:0100526', (241, 252))	('damage', 'Var', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('lung damage', 'Disease', (8, 19))	('results in', 'Reg', (210, 220))	('lung cancer', 'Disease', 'MESH:D008175', (241, 252))
408922	20696410	In these lines, inhibition of Smo with cyclopamine suppresses growth in vitro and in xenograft models.	('growth', 'CPA', (62, 68))	('cyclopamine', 'Chemical', 'MESH:C000541', (39, 50))	('Smo', 'Protein', (30, 33))	('suppresses', 'NegReg', (51, 61))	('inhibition', 'Var', (16, 26))
408927	20696410	In Category 2 cancers, mutations in the Hh pathway are not sufficient for tumorigenesis.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', (74, 79))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
408943	23472872	Stem/progenitor cells are important for maintaining tissue homeostasis, and their aberrant regulation contributes to tumor initiation and cancer progression.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancer', 'Disease', (138, 144))	('contributes', 'Reg', (102, 113))	('tumor initiation', 'Disease', 'MESH:D009369', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor initiation', 'Disease', (117, 133))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('aberrant', 'Var', (82, 90))
408948	23472872	Intriguingly, recent clinical studies have revealed that SOX2 gene amplification and protein overexpression frequently occur in SCC of human foregut-derived tissues including the lung and esophagus.	('SCC', 'Gene', (128, 131))	('amplification', 'Var', (67, 80))	('human', 'Species', '9606', (135, 140))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SOX2', 'Gene', (57, 61))	('SCC', 'Gene', '6317', (128, 131))	('protein', 'Protein', (85, 92))	('clinical', 'Species', '191496', (21, 29))	('overexpression', 'PosReg', (93, 107))
408957	23472872	In addition, deletion of the intercellular adhesion molecule p120-catenin disrupts epithelial integrity and leads to SCC in the forestomach.	('epithelial integrity', 'CPA', (83, 103))	('p120-catenin', 'Gene', (61, 73))	('SCC', 'Gene', (117, 120))	('leads to', 'Reg', (108, 116))	('deletion', 'Var', (13, 21))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('SCC', 'Gene', '6317', (117, 120))	('p120-catenin', 'Gene', '12388', (61, 73))	('disrupts', 'NegReg', (74, 82))
408976	23472872	To directly test the oncogenic potential of Sox2 in vivo, we generated KRT5-CreER; Rosa26 CAG-loxp-stop-loxp-Sox2-IRES-Egfp compound mutants (hereafter referred to as KRT5-CreER;Rosa26Sox2) in which Sox2 is overexpressed in basal progenitor cells and their derivatives following Tamoxifen injection (Figure 2A).	('Tamoxifen', 'Chemical', 'MESH:D013629', (279, 288))	('Rosa26', 'Gene', (83, 89))	('Rosa26', 'Gene', '14910', (178, 184))	('mutants', 'Var', (133, 140))	('Rosa26', 'Gene', '14910', (83, 89))	('Rosa26', 'Gene', (178, 184))	('rat', 'Species', '10116', (65, 68))
408978	23472872	While no apparent phenotypic changes were observed in Rosa26Sox2/Sox2 or KRT5-CreER;Rosa26Sox2/+ (heterozygous) compound mutants six months after three Tamoxifen injections (data not shown), Sox2 overexpression in KRT5-CreER;Rosa26Sox2/Sox2 (homozygous) mutants disrupts epithelial structure within six weeks (Figure 2C).	('mutants', 'Var', (254, 261))	('epithelial structure', 'CPA', (271, 291))	('disrupts', 'NegReg', (262, 270))	('overexpression', 'PosReg', (196, 210))	('Tamoxifen', 'Chemical', 'MESH:D013629', (152, 161))
408982	23472872	Severe skin lesions were also noticed in the KRT5-CreER;Rosa26Sox2/Sox2 mutants and necessitated euthanasia of the animals.	('mutants', 'Var', (72, 79))	('skin lesions', 'Disease', 'MESH:D012871', (7, 19))	('skin lesions', 'Disease', (7, 19))
408984	23472872	While no tumors were found in the esophagus over 30 weeks, multiple SCC nodules (n>=4) containing GFP+ve and p63+ve cells developed in the forestomach within 13 weeks (Figure 3A-H) (Table S1).	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('GFP+ve', 'Var', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('SCC', 'Gene', (68, 71))	('p63', 'Gene', (109, 112))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('p63', 'Gene', '22061', (109, 112))
408988	23472872	Significantly, Sox2 overexpression induces invasive SCC formation only in the forestomach, suggesting that either region-specific intrinsic differences in tumor susceptibility or microenvironmental factors are important for the malignant transformation of Sox2 overexpressing progenitor cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('overexpression', 'Var', (20, 34))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('SCC', 'Gene', (52, 55))	('Sox2', 'Gene', (15, 19))	('induces', 'Reg', (35, 42))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('SCC', 'Gene', '6317', (52, 55))
408993	23472872	Transcript levels of the endogenous Rosa26 gene in the mutants decreased 14.2 fold, as expected from recombination (Table S2).	('Rosa26', 'Gene', '14910', (36, 42))	('mutants', 'Var', (55, 62))	('decreased', 'NegReg', (63, 72))	('Rosa26', 'Gene', (36, 42))	('Transcript levels', 'MPA', (0, 17))
409001	23472872	Immunostaining further confirmed that p-Stat3 is enriched in the nuclei of hyperplastic forestomach epithelium (Figure 4C) and that this expression pattern is maintained in invasive SCC tumor cells (Figure 4C).	('SCC', 'Phenotype', 'HP:0002860', (182, 185))	('invasive SCC tumor', 'Disease', 'MESH:D009369', (173, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('invasive SCC tumor', 'Disease', (173, 191))	('hyperplastic forestomach epithelium', 'Disease', 'MESH:D013274', (75, 110))	('hyperplastic forestomach epithelium', 'Disease', (75, 110))	('p-Stat3', 'Var', (38, 45))
409022	23472872	EPC2 cells infected with lentivirus harboring Sox2-IRES-GFP and Stat3C have a higher sphere forming efficiency than control cells that overexpress either Sox2-IRES-GFP or Stat3C alone (9.2% for co-overexpression, 6.4% and 7.8% for Sox2 and Stat3C overexpression alone, respectively; Figure 5F, G).	('Stat3C', 'Gene', (240, 246))	('higher', 'PosReg', (78, 84))	('Stat3C', 'Gene', '20848', (171, 177))	('sphere forming efficiency', 'CPA', (85, 110))	('Stat3C', 'Gene', '20848', (64, 70))	('Stat3C', 'Gene', (64, 70))	('Stat3C', 'Gene', (171, 177))	('Stat3C', 'Gene', '20848', (240, 246))	('Sox2-IRES-GFP', 'Var', (46, 59))
409028	23472872	Moreover, the combination of these two transcription factors can also malignantly transform human esophageal progenitor-like cells, leading to squamous cell carcinoma when implanted into immunodeficient mice.	('squamous cell carcinoma', 'Disease', (143, 166))	('leading to', 'Reg', (132, 142))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (143, 166))	('combination', 'Var', (14, 25))	('mice', 'Species', '10090', (203, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('immunodeficient', 'Disease', 'MESH:D007153', (187, 202))	('immunodeficient', 'Disease', (187, 202))	('human', 'Species', '9606', (92, 97))
409031	23472872	Sox2 knockdown reduces the size of the tumor spheres formed in the 3D culture system and is accompanied by an increased number of apoptotic cells (Figure 6A, S4A).	('Sox2', 'Gene', (0, 4))	('increased number of apoptotic cells', 'Phenotype', 'HP:0030887', (110, 145))	('increased', 'PosReg', (110, 119))	('size', 'CPA', (27, 31))	('knockdown', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('reduces', 'NegReg', (15, 22))	('apoptotic cells', 'CPA', (130, 145))
409032	23472872	Similarly, Stat3 knockdown also reduces the size of the tumor spheres (Figure 6A, S4A).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('reduces', 'NegReg', (32, 39))	('knockdown', 'Var', (17, 26))	('Stat3', 'Gene', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
409033	23472872	When injected into NSG mice (1 x106 cells/injection), the tumors formed by the Sox2 or Stat3 knockdown cells are apparently smaller than those formed by the non-knockdown tumor cells [0.31+-0.078g (Sox2 knockdown), 0.24+-0.046g (Stat3 knockdown) and 0.66+-0.070g (non-knockdown control), n=6 for each group, Figure 6B].	('knockdown', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('0.24+-0.046g', 'Var', (215, 227))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('smaller', 'NegReg', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('mice', 'Species', '10090', (23, 27))
409034	23472872	A previous study has shown that SOX2 knockdown reduces the proliferation of the nontumorigenic esophageal SCC line TE10.	('proliferation', 'CPA', (59, 72))	('reduces', 'NegReg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('SCC', 'Gene', '6317', (106, 109))	('tumor', 'Disease', (83, 88))	('rat', 'Species', '10116', (66, 69))	('knockdown', 'Var', (37, 46))	('SOX2', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('SCC', 'Gene', (106, 109))
409035	23472872	SOX2 knockdown using the same system inhibits proliferation in the tumorigenic esophageal SCC line KYSE450 and leads to small esophageospheres (Figure 6C, D, S4B).	('tumor', 'Disease', (67, 72))	('SE', 'Disease', 'None', (101, 103))	('knockdown', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('SCC', 'Gene', '6317', (90, 93))	('leads to', 'Reg', (111, 119))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('proliferation', 'CPA', (46, 59))	('rat', 'Species', '10116', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('small esophageospheres', 'CPA', (120, 142))	('inhibits', 'NegReg', (37, 45))	('SOX2', 'Gene', (0, 4))
409036	23472872	Similarly, shRNA-mediated STAT3 knockdown also reduces the proliferation and increases the apoptosis of KYSE450 cells (Figure 6C, D, S4B) and combined knockdown of SOX2 and STAT3 leads to a further decrease in cell proliferation (Figure 6C, D).	('decrease', 'NegReg', (198, 206))	('proliferation', 'CPA', (59, 72))	('reduces', 'NegReg', (47, 54))	('apoptosis', 'CPA', (91, 100))	('knockdown', 'Var', (32, 41))	('rat', 'Species', '10116', (222, 225))	('cell proliferation', 'CPA', (210, 228))	('STAT3', 'Gene', (26, 31))	('increases', 'PosReg', (77, 86))	('SE', 'Disease', 'None', (106, 108))	('rat', 'Species', '10116', (66, 69))	('knockdown', 'Var', (151, 160))
409037	23472872	Moreover, individual knockdown of SOX2 and STAT3 in KYSE450 cells leads to smaller tumors than in mock controls (Figure 6E) and combined knockdown of SOX2 and STAT3 further reduces xenograft weight in NSG mice (Figure 6E).	('xenograft weight', 'CPA', (181, 197))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('STAT3', 'Gene', (159, 164))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('SE', 'Disease', 'None', (54, 56))	('reduces', 'NegReg', (173, 180))	('knockdown', 'Var', (137, 146))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('mice', 'Species', '10090', (205, 209))	('smaller', 'NegReg', (75, 82))	('SOX2', 'Gene', (150, 154))
409038	23472872	In aggregate, individual or combined knockdown of SOX2 and STAT3 in a tumorigenic esophageal SCC cell line reduces cell proliferation and tumor growth when injected into NSG mice.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (70, 75))	('knockdown', 'Var', (37, 46))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('SOX2', 'Gene', (50, 54))	('reduces', 'NegReg', (107, 114))	('rat', 'Species', '10116', (127, 130))	('cell proliferation', 'CPA', (115, 133))	('SCC', 'Gene', '6317', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('STAT3', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
409050	23472872	Purified p75+ve mouse basal progenitor cells form large colonies of cells in monolayer culture that continue to express the basal cell markers Sox2 and p63.	('p63', 'Gene', (152, 155))	('p63', 'Gene', '22061', (152, 155))	('p75+ve', 'Var', (9, 15))	('mouse', 'Species', '10090', (16, 21))
409055	23472872	Similar to the findings by Arnold et al., ablation of basal cells disrupts tissue integrity of the esophagus and forestomach in the Sox2-CreER;Rosa26DTA mice (Figure S1H), confirming that basal cells are stem/progenitor cells required for tissue maintenance.	('Rosa26', 'Gene', (143, 149))	('disrupts', 'NegReg', (66, 74))	('Rosa26', 'Gene', '14910', (143, 149))	('mice', 'Species', '10090', (153, 157))	('ablation', 'Var', (42, 50))	('tissue integrity', 'CPA', (75, 91))
409058	23472872	Notably, when Sox2 is overexpressed in the differentiated suprabasal cells of the esophagus and forestomach using the Krt10-Cre mouse line, the proliferation status in these cells remains unchanged and no tumor formation is observed (unpublished observations J.Q), suggesting that the ability to promote cell proliferation by Sox2 overexpression is specific to progenitor cells.	('cell proliferation', 'CPA', (304, 322))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('Krt10', 'Gene', '16661', (118, 123))	('mouse', 'Species', '10090', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('promote', 'PosReg', (296, 303))	('overexpression', 'Var', (331, 345))	('tumor', 'Disease', (205, 210))	('rat', 'Species', '10116', (151, 154))	('Krt10', 'Gene', (118, 123))	('rat', 'Species', '10116', (316, 319))	('Sox2', 'Gene', (326, 330))
409071	23472872	Our current study provides further evidence that inflammatory signaling is required for malignant transformation of basal progenitor cells and that inhibition of inflammation with Dexamethasone reduces tumor incidence.	('inflammation', 'Disease', 'MESH:D007249', (162, 174))	('inhibition', 'Var', (148, 158))	('tumor', 'Disease', (202, 207))	('inflammation', 'Disease', (162, 174))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('reduces', 'NegReg', (194, 201))	('Dexamethasone', 'Chemical', 'MESH:D003907', (180, 193))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
409079	23472872	Our data also suggest that Sox2 and Stat3 cooperate in the transformation of basal progenitor cells, and that disruption of this cooperation with a specific Stat3 inhibitor reduces tumor incidence.	('tumor', 'Disease', (181, 186))	('rat', 'Species', '10116', (47, 50))	('reduces', 'NegReg', (173, 180))	('transformation of basal progenitor cells', 'CPA', (59, 99))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('rat', 'Species', '10116', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('disruption', 'Var', (110, 120))
409080	23472872	In summary, we provide multiple lines of evidence supporting the idea that Sox2/Krt5/p75 positive basal progenitor cells in the esophagus and forestomach are able to self-renew and differentiate, and that ectopic Sox2 overexpression promotes the expansion of the progenitor pool.	('Krt5', 'Gene', '110308', (80, 84))	('Sox2', 'Gene', (213, 217))	('expansion', 'CPA', (246, 255))	('self-renew', 'CPA', (166, 176))	('differentiate', 'CPA', (181, 194))	('overexpression promotes', 'PosReg', (218, 241))	('Krt5', 'Gene', (80, 84))	('ectopic', 'Var', (205, 212))
409083	23472872	Perturbing SOX2 and STAT3 expression reduces the proliferation and survival of tumorigenic esophageal SCC cells both in vitro and in a xenograft model.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('survival', 'CPA', (67, 75))	('Perturbing', 'Var', (0, 10))	('SOX2', 'Gene', (11, 15))	('tumor', 'Disease', (79, 84))	('SCC', 'Gene', '6317', (102, 105))	('rat', 'Species', '10116', (56, 59))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('proliferation', 'CPA', (49, 62))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('STAT3', 'Gene', (20, 25))	('SCC', 'Gene', (102, 105))	('reduces', 'NegReg', (37, 44))
409084	23472872	Cooperative oncogenic lesions malignantly transform cells by modulating downstream gene expression and signaling circuitry.	('lesions', 'Var', (22, 29))	('rat', 'Species', '10116', (5, 8))	('modulating', 'Reg', (61, 71))
409147	33665167	Besides, the second mitochondria-derived activator of caspase (SMAC) mimetics can representatively cause the auto-degradation of cIAPs.	('cIAPs', 'Disease', (129, 134))	('mimetics', 'Var', (69, 77))	('auto-degradation', 'MPA', (109, 125))	('SMAC', 'Gene', (63, 67))	('cause', 'Reg', (99, 104))	('second mitochondria-derived activator of caspase', 'Gene', '56616', (13, 61))	('SMAC', 'Gene', '56616', (63, 67))	('second mitochondria-derived activator of caspase', 'Gene', (13, 61))
409148	33665167	In general, when the activity of caspase-8 is present, FLIPL and caspase-8 combine with each other to form a heterodimer to cleave RIPK1, RIPK3 and CYLD, which prevents the initiation of necroptosis.	('prevents', 'NegReg', (160, 168))	('cleave', 'Var', (124, 130))	('necroptosis', 'CPA', (187, 198))	('RIPK1', 'Gene', (131, 136))	('CYLD', 'Gene', (148, 152))	('CYLD', 'Gene', '1540', (148, 152))	('RIPK3', 'Gene', (138, 143))
409150	33665167	It has been reported that RIPK1 phosphorylates signal transducer and activator of transcription 3 (STAT3), which leads to the interaction of STAT3 with gene associated with retinoic and interferon-induced mortality 19 and subsequent translocation of STAT3 to the mitochondria to promote reactive oxygen species (ROS) generation and cell death.	('ROS', 'Chemical', 'MESH:D017382', (312, 315))	('RIPK1', 'Gene', (26, 31))	('interaction', 'Interaction', (126, 137))	('STAT3', 'Gene', '6774', (141, 146))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (287, 310))	('STAT3', 'Gene', '6774', (250, 255))	('STAT3', 'Gene', (141, 146))	('cell death', 'CPA', (332, 342))	('translocation', 'MPA', (233, 246))	('STAT3', 'Gene', '6774', (99, 104))	('signal transducer and activator of transcription 3', 'Gene', '6774', (47, 97))	('phosphorylates', 'Var', (32, 46))	('promote', 'PosReg', (279, 286))	('STAT3', 'Gene', (99, 104))	('STAT3', 'Gene', (250, 255))	('leads to', 'Reg', (113, 121))
409151	33665167	What's more, mitochondria may promote the translocation of necrosomes to mitochondria-associated membranes, which probably induces ROS generation and related necroptosis.	('promote', 'PosReg', (30, 37))	('induces', 'Reg', (123, 130))	('necroptosis', 'Disease', (158, 169))	('ROS', 'Chemical', 'MESH:D017382', (131, 134))	('ROS generation', 'MPA', (131, 145))	('mitochondria', 'Var', (13, 25))
409170	33665167	Moreover, ferroptosis is the exclusive mode of regulated necrosis that can be repressed by iron chelators (such as deferoxamine), lipophilic antioxidants (such as alpha-tocopherol and coenzyme Q10), and depletion of PUFA.	('coenzyme Q10', 'Chemical', 'MESH:C024989', (184, 196))	('depletion', 'Var', (203, 212))	('PUFA', 'Chemical', 'MESH:D005231', (216, 220))	('deferoxamine', 'Chemical', 'MESH:D003676', (115, 127))	('necrosis', 'Disease', (57, 65))	('ferroptosis', 'Disease', (10, 21))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (163, 179))	('lipophilic', 'MPA', (130, 140))	('iron', 'Chemical', 'MESH:D007501', (91, 95))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
409177	33665167	There are some conditions that can cause DNA damage and activate PARP1, such as ultraviolet light, alkylating agents, the Ca2+ signaling pathway, posttranslational modifications through acetylation, ROS, hypoxia, hypoglycemia.	('hypoxia', 'Disease', (204, 211))	('hypoxia', 'Disease', 'MESH:D000860', (204, 211))	('hypoglycemia', 'Disease', 'MESH:D007003', (213, 225))	('ROS', 'Chemical', 'MESH:D017382', (199, 202))	('ROS', 'Protein', (199, 202))	('acetylation', 'Var', (186, 197))	('posttranslational', 'Var', (146, 163))	('activate', 'PosReg', (56, 64))	('hypoglycemia', 'Disease', (213, 225))	('hypoglycemia', 'Phenotype', 'HP:0001943', (213, 225))	('PARP1', 'Gene', (65, 70))	('Ca2+', 'Chemical', 'MESH:D000069285', (122, 126))
409179	33665167	Then, NAD+ and ATP depletion cause energy depletion, which brings about cell death.	('energy depletion', 'MPA', (35, 51))	('NAD+', 'Var', (6, 10))	('NAD+', 'Chemical', 'MESH:D009243', (6, 10))	('cell death', 'CPA', (72, 82))	('brings about', 'Reg', (59, 71))	('ATP', 'Chemical', 'MESH:D000255', (15, 18))
409181	33665167	For instance, PAR polymer leads to the depolarization of the mitochondrial outer membrane and the release of active apoptosis-inducing factor (AIF) from the mitochondria into the nucleus, which results in chromatin condensation and large-scale (about 50 kb) DNA fragmentation, followed by regulated necrosis.	('results in', 'Reg', (194, 204))	('chromatin condensation', 'CPA', (205, 227))	('necrosis', 'Disease', (299, 307))	('PAR polymer', 'Var', (14, 25))	('apoptosis-inducing factor', 'Gene', '9131', (116, 141))	('apoptosis-inducing factor', 'Gene', (116, 141))	('release', 'MPA', (98, 105))	('depolarization', 'NegReg', (39, 53))	('necrosis', 'Disease', 'MESH:D009336', (299, 307))	('mitochondrial outer membrane', 'MPA', (61, 89))	('polymer', 'Chemical', 'MESH:D011108', (18, 25))	('DNA fragmentation', 'CPA', (258, 275))
409184	33665167	Notably, PAR glycohydrolase (PARG) can reverse all of the above processes and protect cells from PAR-mediated parthanatos via catalyzing the degradation of PAR, and knockout of PARG can markedly increase the toxicity of PAR and enhance the occurrence of parthanatos.	('occurrence', 'MPA', (240, 250))	('toxicity', 'Disease', 'MESH:D064420', (208, 216))	('PARG', 'Gene', (29, 33))	('PARG', 'Gene', (177, 181))	('enhance', 'PosReg', (228, 235))	('PAR glycohydrolase', 'Gene', '8505', (9, 27))	('knockout', 'Var', (165, 173))	('PARG', 'Gene', '8505', (177, 181))	('PAR glycohydrolase', 'Gene', (9, 27))	('toxicity', 'Disease', (208, 216))	('PARG', 'Gene', '8505', (29, 33))	('increase', 'PosReg', (195, 203))
409187	33665167	Thus far, a new definition of pyroptosis has been proposed as a type of regulated necrosis that mainly depends on the activation of caspase-1 and the cleavage of gasdermin D (GSDMD).	('activation', 'PosReg', (118, 128))	('cleavage', 'Var', (150, 158))	('GSDMD', 'Gene', '79792', (175, 180))	('caspase-1', 'Gene', (132, 141))	('necrosis', 'Disease', 'MESH:D009336', (82, 90))	('gasdermin D', 'Gene', '79792', (162, 173))	('GSDMD', 'Gene', (175, 180))	('necrosis', 'Disease', (82, 90))	('gasdermin D', 'Gene', (162, 173))	('caspase-1', 'Gene', '834', (132, 141))
409216	33665167	Accordingly, both loss of RIPK3 in the tumor microenvironment and loss of the kinase activity in RIPK1 have been reported to reduce tumor nodules in the lung in murine B16.F10 primary melanoma tumors, which further implies that RIPK3 and RIPK1 are fundamental for cancer growth and metastasis.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('reduce', 'NegReg', (125, 131))	('tumor', 'Disease', (132, 137))	('melanoma tumors', 'Disease', 'MESH:D008545', (184, 199))	('cancer', 'Disease', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('melanoma tumors', 'Disease', (184, 199))	('RIPK1', 'Gene', (97, 102))	('tumor', 'Disease', (193, 198))	('iron', 'Chemical', 'MESH:D007501', (53, 57))	('loss', 'NegReg', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('B16.F10', 'CellLine', 'CVCL:0159', (168, 175))	('tumor', 'Disease', (39, 44))	('RIPK3', 'Gene', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('loss', 'Var', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('murine', 'Species', '10090', (161, 167))
409239	33665167	Reportedly, the small-molecule SMAC mimetic BV6 could antagonize cIAPs to overcome apoptosis resistance by inducing necroptosis upon caspase inhibition and sensitize acute myeloid leukemia (AML) cells to cytarabine-induced cell death, which could be significantly inhibited by NEC1 or MLKL inhibitor necrosulfonamide but not by caspases inhibitor Z-VAD-FMK.	('cytarabine', 'Chemical', 'MESH:D003561', (204, 214))	('caspase', 'Gene', '834;837;838;841;12370', (133, 140))	('caspase', 'Gene', (328, 335))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (166, 188))	('SMAC', 'Gene', (31, 35))	('leukemia', 'Phenotype', 'HP:0001909', (180, 188))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (166, 188))	('cell death', 'CPA', (223, 233))	('AML', 'Disease', 'MESH:D015470', (190, 193))	('caspases', 'Gene', (328, 336))	('necrosulfonamide', 'Chemical', 'MESH:C570695', (300, 316))	('AML', 'Disease', (190, 193))	('caspases', 'Gene', '834;837;838;841;12370', (328, 336))	('AML', 'Phenotype', 'HP:0004808', (190, 193))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (172, 188))	('SMAC', 'Gene', '56616', (31, 35))	('caspase', 'Gene', '834;837;838;841;12370', (328, 335))	('sensitize', 'Reg', (156, 165))	('small-molecule', 'Var', (16, 30))	('BV6', 'Chemical', '-', (44, 47))	('necroptosis', 'MPA', (116, 127))	('inducing', 'Reg', (107, 115))	('caspase', 'Gene', (133, 140))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (347, 356))	('BV6', 'Var', (44, 47))	('acute myeloid leukemia', 'Disease', (166, 188))
409241	33665167	Besides, 1, 2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE) has been found to induce RIPK1-dependent necroptosis in malignant pleural mesothelioma cells, mainly in NCI-H28 cell line, in a concentration (1-100 muM)-dependent manner.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (135, 155))	('1, 2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine', 'Chemical', '-', (9, 61))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (125, 155))	('necroptosis', 'CPA', (110, 121))	('malignant pleural mesothelioma', 'Disease', (125, 155))	('RIPK1-dependent', 'Var', (94, 109))	('NCI-H28', 'CellLine', 'CVCL:1555', (173, 180))	('DAPE', 'Chemical', '-', (63, 67))
409242	33665167	What's more, BI2536, an inhibitor of serine/threonine protein kinase Polo-like Kinase 1 (PLK1), has been reported to induce necroptosis in androgen-insensitive prostate cancer cells (LNCaP-AI) to overcome castration-resistance.	('Polo-like Kinase 1', 'Gene', '5347', (69, 87))	('LNCaP', 'CellLine', 'CVCL:0395', (183, 188))	('BI2536', 'Var', (13, 19))	('prostate cancer', 'Disease', (160, 175))	('Polo-like Kinase 1', 'Gene', (69, 87))	('necroptosis', 'CPA', (124, 135))	('induce', 'PosReg', (117, 123))	('BI2536', 'Chemical', 'MESH:C518477', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('prostate cancer', 'Disease', 'MESH:D011471', (160, 175))	('PLK1', 'Gene', (89, 93))	('prostate cancer', 'Phenotype', 'HP:0012125', (160, 175))	('serine', 'Chemical', 'MESH:D012694', (37, 43))	('PLK1', 'Gene', '5347', (89, 93))
409243	33665167	Moreover, a multicentric parallel phase II trial has demonstrated that intravenous BI2536 has limited anti-cancer activity in five different cancer types, including advanced head and neck, breast, and ovarian cancer, soft tissue sarcoma and melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('melanoma', 'Disease', (241, 249))	('limited', 'NegReg', (94, 101))	('soft tissue sarcoma', 'Disease', (217, 236))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ovarian cancer', 'Disease', 'MESH:D010051', (201, 215))	('breast', 'Disease', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('cancer', 'Disease', (141, 147))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('ovarian cancer', 'Disease', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('BI2536', 'Var', (83, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (201, 215))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (209, 215))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (217, 236))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (217, 236))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('BI2536', 'Chemical', 'MESH:C518477', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
409244	33665167	In addition, intravenous BI2536 also exhibited modest efficacy in relapsed non-small-cell lung cancer in an open-label, randomized phase II clinical trial, while BI2536 failed to inhibit the progression of relapsed small-cell lung cancer.	('small-cell lung cancer', 'Disease', (215, 237))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (79, 101))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (79, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('BI2536', 'Var', (25, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (215, 237))	('BI2536', 'Chemical', 'MESH:C518477', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('non-small-cell lung cancer', 'Disease', (75, 101))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (75, 101))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (215, 237))	('BI2536', 'Chemical', 'MESH:C518477', (162, 168))
409246	33665167	Also, Compound C (also called dorsomorphin) has been found to induce glioma cell death via necroptosis.	('glioma cell death via necroptosis', 'Disease', 'MESH:D003643', (69, 102))	('dorsomorphin', 'Chemical', 'MESH:C516138', (30, 42))	('induce', 'PosReg', (62, 68))	('glioma cell death via necroptosis', 'Disease', (69, 102))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('Compound', 'Var', (6, 14))
409247	33665167	Last but not least, aurora kinase inhibitor CCT137690 can indirectly activate RIPK1, RIPK3, and MLKL in PDAC in vivo, which leads to the initiation of necroptosis and the inhibition of cancer growth and metastasis.	('RIPK1', 'Gene', (78, 83))	('initiation', 'PosReg', (137, 147))	('necroptosis', 'CPA', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('activate', 'PosReg', (69, 77))	('MLKL', 'Gene', (96, 100))	('leads to', 'Reg', (124, 132))	('CCT137690', 'Var', (44, 53))	('inhibition', 'NegReg', (171, 181))	('PDAC', 'Phenotype', 'HP:0006725', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('RIPK3', 'Gene', (85, 90))	('CCT137690', 'Chemical', 'MESH:C551619', (44, 53))	('cancer', 'Disease', (185, 191))
409266	33665167	The recognition that GPX4 plays such an important role in ferroptosis in various cancers suggests that the inhibitors of GPX4 could point the way for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('GPX4', 'Gene', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('GPX4', 'Gene', (121, 125))	('GPX4', 'Gene', '2879', (21, 25))	('cancer', 'Disease', (150, 156))	('GPX4', 'Gene', '2879', (121, 125))	('inhibitors', 'Var', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
409269	33665167	Accumulation of NRF2 inhibits ferroptosis by promoting the expression of antioxidant proteins, such as quinone oxidoreductase 1 and heme oxygenase-1, and ferritin heavy chain 1, while knockdown of NRF2 enhances ferroptosis in HCC cells.	('heme oxygenase-1', 'Gene', (132, 148))	('inhibits', 'NegReg', (21, 29))	('knockdown', 'Var', (184, 193))	('promoting', 'PosReg', (45, 54))	('HCC', 'Phenotype', 'HP:0001402', (226, 229))	('NRF2', 'Gene', '4780', (197, 201))	('NRF2', 'Gene', '4780', (16, 20))	('ferroptosis', 'CPA', (211, 222))	('expression', 'MPA', (59, 69))	('NRF2', 'Gene', (197, 201))	('enhances', 'PosReg', (202, 210))	('ferritin heavy chain 1', 'Gene', '2495', (154, 176))	('ferritin heavy chain 1', 'Gene', (154, 176))	('heme oxygenase-1', 'Gene', '3162', (132, 148))	('ferroptosis', 'CPA', (30, 41))	('NRF2', 'Gene', (16, 20))
409273	33665167	Thus, CD44v may be a biomarker for cancers that can be effectively treated with system  inhibitors.	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CD44v', 'Var', (6, 11))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
409284	33665167	The activation of p53, a common tumor suppressor gene, can trigger ferroptosis in certain cancer cells, as p53 directly inhibits the transcription of SLC7A11, an essential component of the system .	('inhibits', 'NegReg', (120, 128))	('ferroptosis', 'Disease', (67, 78))	('p53', 'Gene', (18, 21))	('SLC7A11', 'Gene', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('SLC7A11', 'Gene', '23657', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('transcription', 'MPA', (133, 146))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('trigger', 'Reg', (59, 66))	('tumor', 'Disease', (32, 37))	('cancer', 'Disease', (90, 96))	('p53', 'Var', (107, 110))	('activation', 'PosReg', (4, 14))
409285	33665167	P533KR, an acetylation-defective mutant, is a representative case because it specifically inhibits the expression of SLC7A11 rather than other target genes related to anti-proliferative and pro-apoptotic activity.	('expression', 'MPA', (103, 113))	('P533KR', 'Var', (0, 6))	('inhibits', 'NegReg', (90, 98))	('SLC7A11', 'Gene', (117, 124))	('SLC7A11', 'Gene', '23657', (117, 124))
409286	33665167	Moreover, p533KR fails to trigger cell-cycle arrest, senescence, and apoptosis but retains the tumor suppression function by inducing ferroptosis in vivo.	('arrest', 'Disease', (45, 51))	('inducing', 'Reg', (125, 133))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p533KR', 'Var', (10, 16))	('ferroptosis', 'CPA', (134, 145))	('tumor', 'Disease', (95, 100))	('arrest', 'Disease', 'MESH:D006323', (45, 51))
409287	33665167	However, p53 has been found to limit erastin-induced ferroptosis and protect CRC cells from cell death in a transcription-independent manner.	('p53', 'Var', (9, 12))	('erastin-induced ferroptosis', 'MPA', (37, 64))	('CRC', 'Disease', (77, 80))	('limit', 'NegReg', (31, 36))	('erastin', 'Chemical', 'MESH:C477224', (37, 44))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('CRC', 'Disease', 'MESH:D015179', (77, 80))	('cell death', 'CPA', (92, 102))
409288	33665167	Further research has indicated that p53 blocks dipeptidyl-peptidase-4 (DPP4) activity by inducing nuclear accumulation of DPP4, which inhibits DPP4-dependent lipid peroxidation and consequent ferroptosis.	('inhibits', 'NegReg', (134, 142))	('ferroptosis', 'CPA', (192, 203))	('blocks', 'NegReg', (40, 46))	('DPP4', 'Gene', (71, 75))	('lipid', 'Chemical', 'MESH:D008055', (158, 163))	('p53', 'Var', (36, 39))	('DPP4', 'Gene', (143, 147))	('DPP4', 'Gene', '1803', (122, 126))	('dipeptidyl-peptidase-4', 'Gene', '1803', (47, 69))	('DPP4', 'Gene', (122, 126))	('nuclear accumulation', 'MPA', (98, 118))	('activity', 'MPA', (77, 85))	('DPP4', 'Gene', '1803', (71, 75))	('dipeptidyl-peptidase-4', 'Gene', (47, 69))	('DPP4', 'Gene', '1803', (143, 147))	('inducing', 'PosReg', (89, 97))
409301	33665167	Similarly, artesunate-induced ferroptosis has been observed only in K-Ras-mutant PDAC cell lines, but not in human pancreatic ductal epithelial cells or wild-type K-Ras PDAC cells, which indicates that the anti-cancer activity of artesunate depends on K-Ras mutation.	('human', 'Species', '9606', (109, 114))	('PDAC', 'Phenotype', 'HP:0006725', (169, 173))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('K-Ras-mutant', 'Var', (68, 80))	('artesunate', 'Chemical', 'MESH:D000077332', (230, 240))	('cancer', 'Disease', (211, 217))	('artesunate', 'Chemical', 'MESH:D000077332', (11, 21))	('PDAC', 'Disease', (81, 85))	('PDAC', 'Phenotype', 'HP:0006725', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
409306	33665167	In addition, phenethyl isothiocyanate (PEITC) has been identified as a dietary anti-cancer compound by inducing ROS production.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('ROS', 'Chemical', 'MESH:D017382', (112, 115))	('phenethyl isothiocyanate', 'Chemical', 'MESH:C058305', (13, 37))	('inducing', 'PosReg', (103, 111))	('PEITC', 'Chemical', 'MESH:C058305', (39, 44))	('cancer', 'Disease', (84, 90))	('phenethyl', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ROS production', 'MPA', (112, 126))
409313	33665167	However, another study has found that erastin selectively targets certain genotypes in Ras-mutant cell lines, including H-Ras-mutant-engineered cells, N-Ras-mutant HT1080 human fibrosarcoma cells, and K-Ras-mutant Calu-1 non-small-cell lung cancer cells.	('Ras-mutant', 'Gene', (87, 97))	('erastin', 'Chemical', 'MESH:C477224', (38, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('N-Ras', 'Gene', (151, 156))	('fibrosarcoma', 'Disease', (177, 189))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (177, 189))	('non-small-cell lung cancer', 'Disease', (221, 247))	('HT1080', 'CellLine', 'CVCL:0317', (164, 170))	('H-Ras', 'Gene', '3265', (120, 125))	('H-Ras', 'Gene', (120, 125))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (221, 247))	('fibrosarcoma', 'Disease', 'MESH:D005354', (177, 189))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (225, 247))	('N-Ras', 'Gene', '4893', (151, 156))	('Ras-mutant', 'Var', (87, 97))	('human', 'Species', '9606', (171, 176))
409319	33665167	And it has been demonstrated that RSL3 can enhance the sensitivity of resistant cancer cells to chemotherapeutic drugs in certain types of cancers.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('enhance', 'PosReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('sensitivity', 'MPA', (55, 66))	('cancers', 'Disease', (139, 146))	('cancer', 'Disease', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('RSL3', 'Chemical', '-', (34, 38))	('cancer', 'Disease', (80, 86))	('RSL3', 'Var', (34, 38))
409320	33665167	Buthionine sulfoximine (BSO), an irreversible inhibitor of gamma-glutamyl cysteine synthetase, has been found to reduce GPX4 activity by inhibiting GSH synthesis, and subsequently increase ROS levels, which selectively triggers ferroptosis in BJ cells with oncogenic Ras mutation.	('GPX4', 'Gene', (120, 124))	('GPX4', 'Gene', '2879', (120, 124))	('Buthionine sulfoximine', 'Chemical', 'MESH:D019328', (0, 22))	('GSH synthesis', 'MPA', (148, 161))	('increase', 'PosReg', (180, 188))	('ROS levels', 'MPA', (189, 199))	('reduce', 'NegReg', (113, 119))	('inhibiting', 'NegReg', (137, 147))	('ROS', 'Chemical', 'MESH:D017382', (189, 192))	('mutation', 'Var', (271, 279))	('BJ', 'CellLine', 'CVCL:6573', (243, 245))	('increase ROS levels', 'Phenotype', 'HP:0025464', (180, 199))	('GSH', 'Chemical', 'MESH:D005978', (148, 151))	('cysteine', 'Chemical', 'MESH:D003545', (74, 82))	('Ras', 'Gene', (267, 270))	('BSO', 'Chemical', 'MESH:D019328', (24, 27))	('triggers', 'Reg', (219, 227))	('ferroptosis', 'Disease', (228, 239))
409325	33665167	APR246, a mutant-p53 reactivator, has been found to directly bind to and deplete GSH in oesophageal cancer cells, which results in the accumulation of lipid peroxidation and consequent ferroptosis.	('ferroptosis', 'CPA', (185, 196))	('deplete', 'NegReg', (73, 80))	('APR246', 'Var', (0, 6))	('APR246', 'Chemical', 'MESH:C533410', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lipid', 'Chemical', 'MESH:D008055', (151, 156))	('accumulation', 'PosReg', (135, 147))	('bind', 'Interaction', (61, 65))	('GSH', 'Chemical', 'MESH:D005978', (81, 84))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('GSH', 'MPA', (81, 84))	('lipid peroxidation', 'MPA', (151, 169))
409326	33665167	Lanperisone, which is commonly used as a muscle relaxant, can induce ROS generation to selectively kill K-Ras-mutant mouse embryonic fibroblasts via ferroptosis signaling in vitro, and it can also inhibit tumor growth through inducing ferroptosis in a K-Ras-driven mouse model of lung cancer in vivo.	('K-Ras-mutant', 'Gene', (104, 116))	('inducing', 'Reg', (226, 234))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('inhibit', 'NegReg', (197, 204))	('ferroptosis signaling', 'MPA', (149, 170))	('mouse', 'Species', '10090', (117, 122))	('mouse', 'Species', '10090', (265, 270))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('lung cancer', 'Disease', 'MESH:D008175', (280, 291))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('K-Ras-mutant', 'Var', (104, 116))	('ferroptosis', 'CPA', (235, 246))	('ROS generation', 'MPA', (69, 83))	('Lanperisone', 'Chemical', '-', (0, 11))	('lung cancer', 'Disease', (280, 291))	('lung cancer', 'Phenotype', 'HP:0100526', (280, 291))
409344	33665167	Compared with traditional administration methods, nano-DDS has the advantages of promoted drug availability and targeting ability, high solubility, and enhanced permeability and retention effect, especially in early-stage solid tumors.	('nano-DDS', 'Var', (50, 58))	('permeability', 'MPA', (161, 173))	('promoted', 'PosReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (228, 234))	('drug availability', 'CPA', (90, 107))	('enhanced', 'PosReg', (152, 160))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('retention', 'MPA', (178, 187))	('targeting ability', 'CPA', (112, 129))
409355	33665167	When inhibitions of PARP1 and BRCA1/2 coexist, the persistent DNA breaks can induce cell cycle arrest and apoptosis.	('BRCA1/2', 'Gene', '672;675', (30, 37))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('apoptosis', 'CPA', (106, 115))	('BRCA1/2', 'Gene', (30, 37))	('inhibitions', 'Var', (5, 16))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('arrest', 'Disease', (95, 101))	('persistent', 'Var', (51, 61))	('PARP1', 'Gene', (20, 25))	('induce', 'Reg', (77, 83))
409361	33665167	One of the views is that inhibitors of parthanatos, such as PARP1 inhibitors, could facilitate cancer cell death via inhibiting the DNA repair needed for cell survival, while other ideas are that inducers of parthanatos could directly promote cancer cell death ( Table 3 ).	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('promote', 'PosReg', (235, 242))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('DNA repair needed for cell survival', 'MPA', (132, 167))	('facilitate', 'PosReg', (84, 94))	('inhibiting', 'NegReg', (117, 127))	('inhibitors', 'Var', (25, 35))	('PARP1', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
409362	33665167	It has been found that inhibition of PARP1 and deficiency of BRCA1/2 synergistically kill BRCA1/2-deficient breast and other cancer cells via inhibiting DNA repair.	('DNA repair', 'MPA', (153, 163))	('BRCA1/2', 'Gene', '672;675', (61, 68))	('BRCA1/2', 'Gene', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('BRCA1/2', 'Gene', '672;675', (90, 97))	('breast', 'Disease', (108, 114))	('PARP1', 'Gene', (37, 42))	('BRCA1/2', 'Gene', (61, 68))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('deficient breast', 'Phenotype', 'HP:0003187', (98, 114))	('inhibiting', 'NegReg', (142, 152))	('deficiency', 'Var', (47, 57))
409364	33665167	What's more, as it is mentioned above that PARP1 can protect tumor cells from radiation and chemotherapeutic drugs, PARP1 inhibitors, such as 3-AB, GPI 15427, and nicotinamide, have been utilized as radiosensitizers or chemosensitizer.	('GPI 15427', 'Chemical', 'MESH:C502278', (148, 157))	('inhibitors', 'Var', (122, 132))	('nicotinamide', 'Chemical', 'MESH:D009536', (163, 175))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('3-AB', 'Chemical', 'MESH:C025160', (142, 146))	('PARP1', 'Gene', (116, 121))	('tumor', 'Disease', (61, 66))
409367	33665167	Sepantronium bromide (YM155), a survivin suppressant, has been found to induce parthanatos in cultured KYSE410 and KYSE150 esophageal carcinoma cell lines in vitro and relatedly inhibit esophageal squamous-cell carcinoma growth in mice, which can be abrogated by genetic knockdown of PARP1 or AIF.	('squamous-cell carcinoma growth', 'Disease', 'MESH:D002294', (197, 227))	('KYSE150', 'Var', (115, 122))	('survivin', 'Gene', (32, 40))	('survivin', 'Gene', '11799', (32, 40))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (123, 143))	('squamous-cell carcinoma growth', 'Disease', (197, 227))	('YM155', 'Chemical', 'MESH:C523798', (22, 27))	('induce', 'PosReg', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('Sepantronium bromide', 'Chemical', 'MESH:C523798', (0, 20))	('esophageal carcinoma', 'Disease', (123, 143))	('KYSE410', 'Var', (103, 110))	('YM155', 'Var', (22, 27))	('inhibit', 'NegReg', (178, 185))	('mice', 'Species', '10090', (231, 235))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (123, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('PARP1', 'Gene', (284, 289))	('parthanatos', 'MPA', (79, 90))
409382	33665167	Moreover, the combination of pyroptosis-targeted therapy and conventional remedies seems to enhance therapeutic efficacy, reduce off-target toxicity, and promote patient outcomes ( Table 4 ).	('toxicity', 'Disease', 'MESH:D064420', (140, 148))	('reduce', 'NegReg', (122, 128))	('toxicity', 'Disease', (140, 148))	('promote', 'PosReg', (154, 161))	('pyroptosis-targeted', 'Var', (29, 48))	('therapeutic efficacy', 'CPA', (100, 120))	('patient outcomes', 'CPA', (162, 178))	('patient', 'Species', '9606', (162, 169))	('enhance', 'PosReg', (92, 99))
409388	33665167	Furthermore, mechanistic studies have revealed that dioscin can induce pyroptosis through the caspase-3/GSDME pathway.	('caspase-3', 'Gene', (94, 103))	('induce', 'PosReg', (64, 70))	('pyroptosis', 'MPA', (71, 81))	('caspase-3', 'Gene', '836', (94, 103))	('dioscin', 'Var', (52, 59))	('GSDME', 'Chemical', '-', (104, 109))	('dioscin', 'Chemical', 'MESH:C019357', (52, 59))
409394	33665167	Compound L61H10, a heterocyclic ketone derivative, has been observed to kill cancer cells without apparent side effects in lung cancer cell lines and mice bearing lung cancer xenografts by inducing pyroptosis.	('mice', 'Species', '10090', (150, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', (163, 174))	('lung cancer', 'Disease', (123, 134))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('L61H10', 'Var', (9, 15))	('L61H10', 'Chemical', '-', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ketone', 'Chemical', 'MESH:D007659', (32, 38))	('inducing', 'PosReg', (189, 197))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('pyroptosis', 'MPA', (198, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))
409395	33665167	Further studies have revealed that compound L61H10 can arrest the cell cycle in the G2/M phase and switch apoptosis to caspase-3/GSDME-mediated pyroptosis.	('switch', 'Reg', (99, 105))	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('L61H10', 'Chemical', '-', (44, 50))	('caspase-3', 'Gene', '836', (119, 128))	('arrest', 'Disease', (55, 61))	('caspase-3', 'Gene', (119, 128))	('GSDME', 'Chemical', '-', (129, 134))	('L61H10', 'Var', (44, 50))	('cell cycle in the G2/M phase', 'CPA', (66, 94))
409398	33665167	In addition, a phase 1 dose-finding study of metformin has demonstrated that metformin can promote the efficiency of chemoradiotherapy and elevate the rates of overall survival and progression-free survival in patients with locally advanced head and neck squamous cell carcinoma.	('metformin', 'Var', (77, 86))	('elevate', 'Disease', (139, 146))	('promote', 'PosReg', (91, 98))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (241, 278))	('metformin', 'Chemical', 'MESH:D008687', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('overall survival', 'CPA', (160, 176))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (241, 278))	('elevate', 'Disease', 'MESH:D006973', (139, 146))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('patients', 'Species', '9606', (210, 218))	('chemoradiotherapy', 'CPA', (117, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))	('progression-free survival', 'CPA', (181, 206))
409404	33665167	Recent studies have found that small-molecule DPP8/9 inhibitors can induce pyroptosis in human AML cell lines and primary AML samples by activating the caspase-1/GSDMD pathway, which represents a brand-new therapeutic strategy for AML.	('activating', 'PosReg', (137, 147))	('induce', 'PosReg', (68, 74))	('AML', 'Disease', 'MESH:D015470', (122, 125))	('AML', 'Phenotype', 'HP:0004808', (122, 125))	('AML', 'Disease', (122, 125))	('AML', 'Disease', 'MESH:D015470', (231, 234))	('human', 'Species', '9606', (89, 94))	('AML', 'Disease', 'MESH:D015470', (95, 98))	('pyroptosis', 'MPA', (75, 85))	('DPP8/9', 'Gene', (46, 52))	('AML', 'Phenotype', 'HP:0004808', (95, 98))	('AML', 'Phenotype', 'HP:0004808', (231, 234))	('AML', 'Disease', (231, 234))	('AML', 'Disease', (95, 98))	('caspase-1', 'Gene', '834', (152, 161))	('inhibitors', 'Var', (53, 63))	('caspase-1', 'Gene', (152, 161))	('GSDMD', 'Gene', '79792', (162, 167))	('DPP8/9', 'Gene', '54878;91039', (46, 52))	('GSDMD', 'Gene', (162, 167))
409411	33665167	Recent studies have shown that, in addition to inducing necroptosis in prostate cancer cells, the PLK1 inhibitor BI2536 sensitizes esophageal squamous cell carcinoma cells to cisplatin in vivo and in vitro by inhibiting the DNA damage repair and promoting pyroptosis.	('BI2536', 'Chemical', 'MESH:C518477', (113, 119))	('DNA damage repair', 'MPA', (224, 241))	('PLK1', 'Gene', (98, 102))	('necroptosis in prostate cancer', 'Disease', 'MESH:D011471', (56, 86))	('sensitizes', 'Reg', (120, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('necroptosis in prostate cancer', 'Disease', (56, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('inhibiting', 'NegReg', (209, 219))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (131, 165))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('PLK1', 'Gene', '5347', (98, 102))	('inducing', 'Reg', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('pyroptosis', 'MPA', (256, 266))	('inhibitor BI2536', 'Var', (103, 119))	('BI2536', 'Var', (113, 119))	('promoting', 'PosReg', (246, 255))	('esophageal squamous cell carcinoma', 'Disease', (131, 165))
409412	33665167	Mechanistic studies have demonstrated that the combination of BI2536 and cisplatin can significantly increase the expression of caspase-3 and ensuing cleaved GSDME, which results in the pyroptosis of esophageal squamous cell carcinoma cells.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('GSDME', 'Chemical', '-', (158, 163))	('pyroptosis of esophageal squamous cell carcinoma', 'Disease', (186, 234))	('cleaved', 'MPA', (150, 157))	('BI2536', 'Var', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('caspase-3', 'Gene', (128, 137))	('results in', 'Reg', (171, 181))	('GSDME', 'Protein', (158, 163))	('increase', 'PosReg', (101, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('pyroptosis of esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (186, 234))	('BI2536', 'Chemical', 'MESH:C518477', (62, 68))	('caspase-3', 'Gene', '836', (128, 137))	('expression', 'MPA', (114, 124))
409418	33665167	In addition to the above various compounds, nano-DDS has also been applied to induce pyroptosis in cancer cells, which is similar to its application in ferroptosis mentioned above.	('induce', 'PosReg', (78, 84))	('nano-DDS', 'Var', (44, 52))	('pyroptosis', 'Disease', (85, 95))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
409434	33665167	Moreover, nano-DDS, an emerging administration method that can greatly enhance the drug targeting property and anti-cancer efficacy, has only been applied to deliver ferroptosis and pyroptosis inducers.	('drug', 'CPA', (83, 87))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('nano-DDS', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('enhance', 'PosReg', (71, 78))
409442	33553432	Postoperative Adjuvant Therapy for Patients with pN+ Esophageal Squamous Cell Carcinoma Esophageal squamous cell carcinoma (ESCC) is the most common pathological type of esophageal cancer in China.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (64, 87))	('Patients', 'Species', '9606', (35, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Squamous Cell Carcinoma', 'Disease', (64, 87))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('cancer', 'Disease', (181, 187))	('squamous cell carcinoma', 'Disease', (99, 122))	('pN+', 'Var', (49, 52))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('Carcinoma', 'Phenotype', 'HP:0030731', (78, 87))
409463	33553432	Each included patient had radical esophagectomy with two- or three-field lymphadenectomy between Jan 2009 and Dec 2011, pathologically confirmed ESCC, pathologically confirmed pN+ and pT2/4, no history of another tumor, Karnofsky performance status of 70 or more, survival time of 1 month or more, and received follow-up examinations in our previous studies.	('tumor', 'Disease', (213, 218))	('pN+', 'Var', (176, 179))	('patient', 'Species', '9606', (14, 21))	('pT2/4', 'Var', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('ESCC', 'Disease', (145, 149))
409492	33553432	Adjuvant therapy did not improve the OS of females, those with tumors in the upper or lower segment, those with stage pT2 or pT4, or those with TNM stage IIb (all p > 0.05).	('TNM', 'Gene', '10178', (144, 147))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('OS', 'Chemical', '-', (37, 39))	('tumors', 'Disease', (63, 69))	('pT4', 'Var', (125, 128))	('TNM', 'Gene', (144, 147))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
409498	33553432	Subgroup analysis (data not shown) indicated that adjuvant therapy significantly increased DFS in patients who had dissected LNs, tumor lesions less than 6 cm, upper- or middle-segment tumors, stage pT3, and TNM stage IIIa/b stage pN and in those who were male and younger than 60 years (all p < 0.05).	('tumor', 'Disease', (185, 190))	('TNM', 'Gene', (208, 211))	('less than', 'Var', (144, 153))	('middle-segment tumors', 'Disease', 'MESH:C537775', (170, 191))	('DFS', 'MPA', (91, 94))	('pT3', 'Gene', '7694', (199, 202))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('pT3', 'Gene', (199, 202))	('patients', 'Species', '9606', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('TNM', 'Gene', '10178', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('increased', 'PosReg', (81, 90))	('tumor', 'Disease', (130, 135))	('middle-segment tumors', 'Disease', (170, 191))
409509	33553432	One of our most notable findings was that POCT, relative to SA, significantly improved the 5-year OS from 15.2% to 28.0% and the 5-year DFS from 13.1% to 20.8%.	('POCT', 'Var', (42, 46))	('DFS', 'MPA', (136, 139))	('SA', 'Chemical', '-', (60, 62))	('OS', 'Chemical', '-', (98, 100))	('improved', 'PosReg', (78, 86))
409516	33553432	and our previous study also showed that POCT improved OS compared with SA.	('improved', 'PosReg', (45, 53))	('OS', 'Chemical', '-', (54, 56))	('POCT', 'Var', (40, 44))	('SA', 'Chemical', '-', (71, 73))
409527	33553432	reported that POCRT for patients with pN+ ESCC increased the 3-year DFS from 19.9% to 34.0% and the 3-year OS from 30.8% to 50.5%.	('OS', 'Chemical', '-', (107, 109))	('DFS', 'MPA', (68, 71))	('POCRT', 'Chemical', '-', (14, 19))	('increased', 'PosReg', (47, 56))	('patients', 'Species', '9606', (24, 32))	('pN+', 'Var', (38, 41))
409532	33553432	The present study also found that POCRT significantly improved OS (p = 0.034) and DFS (p = 0.009) compared with POCT.	('OS', 'Chemical', '-', (63, 65))	('POCRT', 'Chemical', '-', (34, 39))	('DFS', 'MPA', (82, 85))	('POCRT', 'Var', (34, 39))	('improved', 'PosReg', (54, 62))
409541	33553432	showed that POCRT for patients with pN+ ESCC significantly increased the median local recurrence-free survival from 21 to 42 months compared with SA.	('pN+ ESCC', 'Var', (36, 44))	('SA', 'Chemical', '-', (146, 148))	('local recurrence-free survival', 'CPA', (80, 110))	('patients', 'Species', '9606', (22, 30))	('increased', 'PosReg', (59, 68))	('POCRT', 'Chemical', '-', (12, 17))
409557	33553432	However, our multivariate Cox analysis indicated that adjuvant therapy was significantly and independently associated with improved OS, DFS, and LR.	('adjuvant', 'Var', (54, 62))	('improved', 'PosReg', (123, 131))	('OS', 'Chemical', '-', (132, 134))	('DFS', 'Disease', (136, 139))
409562	33553432	In conclusion, we found that the long-term survival of patients with pN+ ESCC after R0 resection remains poor.	('patients', 'Species', '9606', (55, 63))	('poor', 'NegReg', (105, 109))	('pN+', 'Var', (69, 72))
409571	32804918	Treatment with omipalisib decreased expression of p-AKT, p-4EBP1, p-p70S6K, p-S6, and p-ERK, therefore disrupting the activation of PI3K/AKT/mTOR and ERK signaling.	('4EBP1', 'Gene', (59, 64))	('mTOR', 'Gene', '2475', (141, 145))	('mTOR', 'Gene', (141, 145))	('ERK', 'Gene', '2048', (88, 91))	('AKT', 'Gene', (52, 55))	('ERK', 'Gene', '2048', (150, 153))	('p70S6K', 'Gene', (68, 74))	('p-S6', 'Var', (76, 80))	('AKT', 'Gene', '207', (137, 140))	('ERK', 'Gene', (88, 91))	('disrupting', 'NegReg', (103, 113))	('ERK', 'Gene', (150, 153))	('p70S6K', 'Gene', '6198', (68, 74))	('decreased', 'NegReg', (26, 35))	('4EBP1', 'Gene', '1978', (59, 64))	('AKT', 'Gene', (137, 140))	('expression', 'MPA', (36, 46))	('AKT', 'Gene', '207', (52, 55))
409583	32804918	Mounting evidence suggests that metformin exerts a suppressive effect on multiple types of tumors by suppressing oxidative phosphorylation and the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways.	('tumors', 'Disease', (91, 97))	('metformin', 'Var', (32, 41))	('mammalian target of rapamycin', 'Gene', (184, 213))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('phosphoinositide 3-kinase', 'Gene', '5290', (147, 172))	('phosphoinositide 3-kinase', 'Gene', (147, 172))	('metformin', 'Chemical', 'MESH:D008687', (32, 41))	('mTOR', 'Gene', (215, 219))	('mTOR', 'Gene', '2475', (215, 219))	('oxidative phosphorylation', 'MPA', (113, 138))	('AKT', 'Gene', (180, 183))	('AKT', 'Gene', '207', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mammalian target of rapamycin', 'Gene', '2475', (184, 213))	('suppressing', 'NegReg', (101, 112))
409589	32804918	Omipalisib is a selective and reversible ATP-competitive inhibitor with subnanomolar activity against p110alpha, p110beta, p110gamma, p110sigma, and the mTOR1 and mTOR2 complexes.	('p110sigma', 'Var', (134, 143))	('p110gamma', 'Gene', '5294', (123, 132))	('p110beta', 'Gene', '5291', (113, 121))	('Omipalisib', 'Chemical', 'MESH:C561454', (0, 10))	('mTOR', 'Gene', '2475', (163, 167))	('mTOR', 'Gene', (153, 157))	('ATP', 'Chemical', 'MESH:D000255', (41, 44))	('p110gamma', 'Gene', (123, 132))	('mTOR', 'Gene', '2475', (153, 157))	('mTOR', 'Gene', (163, 167))	('p110alpha', 'Gene', (102, 111))	('p110beta', 'Gene', (113, 121))	('p110alpha', 'Gene', '5290', (102, 111))
409594	32804918	Human ESCC cell lines KYSE150, KYSE70, KYSE180, and KYSE520 were obtained from CoBioer Biosciences Co, Ltd, (Nanjing, China) and authenticated by a third-party short tandem repeat analysis (Genetic Testing Biotechnology, Suzhou, China).	('Human', 'Species', '9606', (0, 5))	('KYSE180', 'Var', (39, 46))	('KYSE520', 'Var', (52, 59))	('KYSE70', 'Var', (31, 37))	('KYSE150', 'CellLine', 'CVCL:1348', (22, 29))
409615	32804918	Primary antibodies, AKT (#9272), ERK (#4695), P70S6K (#9202), S6 (#2217), 4EBP1 (#9644), p-AKT (Ser473, #4060), p-ERK (Thr202/Tyr204, #4376), p-P70S6K (Ser371, #9208), p-S6 (Ser235/236, #2211), p-4EBP1 (Thr37/46, #2855), and CDKN1B (#3688) were purchased from Cell Signaling Technology.	('P70S6K', 'Gene', '6198', (144, 150))	('#3688', 'Var', (233, 238))	('4EBP1', 'Gene', (196, 201))	('ERK', 'Gene', (114, 117))	('P70S6K', 'Gene', (46, 52))	('#9644', 'Var', (81, 86))	('AKT', 'Gene', (91, 94))	('4EBP1', 'Gene', (74, 79))	('CDKN1B', 'Gene', (225, 231))	('Ser473', 'Var', (96, 102))	('P70S6K', 'Gene', '6198', (46, 52))	('ERK', 'Gene', '2048', (114, 117))	('AKT', 'Gene', (20, 23))	('#9202', 'Var', (54, 59))	('ERK', 'Gene', (33, 36))	('4EBP1', 'Gene', '1978', (196, 201))	('AKT', 'Gene', '207', (91, 94))	('4EBP1', 'Gene', '1978', (74, 79))	('ERK', 'Gene', '2048', (33, 36))	('CDKN1B', 'Gene', '1027', (225, 231))	('P70S6K', 'Gene', (144, 150))	('AKT', 'Gene', '207', (20, 23))	('#9272', 'Var', (25, 30))
409621	32804918	A pilot screening of 1404 compounds from an FDA-approved compound library was conducted by MTT assay with 3 biological replicates using a panel of 4 ESCC cell lines: KYSE150, KYSE70, KYSE520, and KYSE180 (Figure 1A).	('KYSE150', 'Var', (166, 173))	('KYSE70', 'Var', (175, 181))	('KYSE150', 'CellLine', 'CVCL:1348', (166, 173))	('KYSE520', 'Var', (183, 190))	('MTT', 'Chemical', '-', (91, 94))	('KYSE180', 'Var', (196, 203))
409646	32804918	Further, the inactivation of the PI3K/AKT/mTOR signaling pathway is considered an effective therapeutic strategy for ESCC.	('mTOR', 'Gene', '2475', (42, 46))	('AKT', 'Gene', (38, 41))	('mTOR', 'Gene', (42, 46))	('inactivation', 'Var', (13, 25))	('AKT', 'Gene', '207', (38, 41))	('ESCC', 'Disease', (117, 121))
409656	32804918	showed that the cell death induced by omipalisib in NRAS mutant neurocutaneous melanocytosis cells occurs mainly via autophagy.	('NRAS', 'Gene', (52, 56))	('melanocytosis', 'Disease', 'MESH:C535835', (79, 92))	('autophagy', 'CPA', (117, 126))	('NRAS', 'Gene', '4893', (52, 56))	('mutant', 'Var', (57, 63))	('cell death', 'CPA', (16, 26))	('melanocytosis', 'Disease', (79, 92))
409657	32804918	There were negative feedback loops between the mTORC1 and MAPK signaling pathways, and LY294002, a PI3K inhibitor, could block feedback by reducing rapamycin-mediated MAPK/ERK activation.	('rapamycin', 'Chemical', 'MESH:D020123', (148, 157))	('LY294002', 'Var', (87, 95))	('mTORC1', 'Gene', (47, 53))	('rapamycin-mediated', 'MPA', (148, 166))	('MAPK signaling pathways', 'Pathway', (58, 81))	('ERK', 'Gene', '2048', (172, 175))	('reducing', 'NegReg', (139, 147))	('activation', 'PosReg', (176, 186))	('mTORC1', 'Gene', '382056', (47, 53))	('LY294002', 'Chemical', 'MESH:C085911', (87, 95))	('ERK', 'Gene', (172, 175))
409659	32804918	Consistent with our results, it was recently reported that BEZ235, another dual PI3K-mTOR inhibitor, has an inhibitory effect on ESCC, but its effect on feedback inhibition was not mentioned.	('inhibitory effect', 'MPA', (108, 125))	('ESCC', 'Disease', (129, 133))	('BEZ235', 'Var', (59, 65))	('BEZ235', 'Chemical', 'MESH:C531198', (59, 65))	('mTOR', 'Gene', '2475', (85, 89))	('mTOR', 'Gene', (85, 89))
409668	30542513	Of 7 patients receiving the 100 mug dose, 2 (29%) showed immune responses, compared with 3 of the 14 (21%) patients who received the 300 mug dose.	('patients', 'Species', '9606', (107, 115))	('immune', 'MPA', (57, 63))	('patients', 'Species', '9606', (5, 13))	('100 mug', 'Var', (28, 35))
409705	30542513	Six of the 22 (27%) patients had pre-existing antibodies to MAGE-A4, including 5 with high optical density (OD) (at least twice the cut-off level) and 1 with low OD (below twice the cut-off level) value.	('antibodies', 'Var', (46, 56))	('patients', 'Species', '9606', (20, 28))	('MAGE-A4', 'Gene', (60, 67))	('MAGE-A4', 'Gene', '4103', (60, 67))
409713	30542513	As shown in Tables 2 and 3, 11 of the 22 (50%) patients had pre-existing antibodies to NY-ESO-1, including 6 with high OD values.	('antibodies', 'Var', (73, 83))	('NY-ESO-1', 'Gene', (87, 95))	('patients', 'Species', '9606', (47, 55))	('NY-ESO-1', 'Gene', '246100', (87, 95))
409729	30542513	Survival time was significantly longer in NY-ESO-1 seronegative patients, including those with low titers of the antibody, than in those with high levels of pre-existing NY-ESO-1 antibodies (p = 0.0007) (Supplementary Figure 1, Figure 2B).	('longer', 'PosReg', (32, 38))	('NY-ESO-1', 'Gene', (42, 50))	('seronegative', 'Var', (51, 63))	('patients', 'Species', '9606', (64, 72))	('NY-ESO-1', 'Gene', '246100', (170, 178))	('Survival time', 'CPA', (0, 13))	('NY-ESO-1', 'Gene', (170, 178))	('NY-ESO-1', 'Gene', '246100', (42, 50))
409752	30542513	In the current trial, of the 16 patients with either refractory esophageal cancer (n = 14) or head/neck squamous cell carcinoma (n = 2), the 3 patients who demonstrated antigen spreading survived for a median of 7.5 months, while the 12 patients without spreading survived for 7.7 months.	('patients', 'Species', '9606', (32, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (99, 127))	('refractory esophageal cancer', 'Disease', (53, 81))	('head/neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (94, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('patients', 'Species', '9606', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('neck squamous cell carcinoma', 'Disease', (99, 127))	('antigen spreading', 'Var', (169, 186))	('refractory esophageal cancer', 'Disease', 'MESH:D004938', (53, 81))	('patients', 'Species', '9606', (237, 245))
409756	30542513	One study found that 31% of esophageal cancer patients had NY-ESO-1 auto-antibodies, and the positive rate increased with tumor stage progression.	('NY-ESO-1', 'Gene', '246100', (59, 67))	('esophageal cancer', 'Disease', (28, 45))	('patients', 'Species', '9606', (46, 54))	('NY-ESO-1', 'Gene', (59, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('auto-antibodies', 'Var', (68, 83))	('tumor', 'Disease', (122, 127))
409759	30542513	For the first time, we demonstrated that patients with refractory esophageal or head/neck squamous cell carcinoma that co-expressed MAGE-A4 and NY-ESO-1 had significantly worse prognosis than patients with tumors expressing MAGE-A4 alone.	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('head/neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (80, 113))	('MAGE-A4', 'Gene', '4103', (132, 139))	('MAGE-A4', 'Gene', (224, 231))	('NY-ESO-1', 'Gene', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('tumors', 'Disease', (206, 212))	('neck squamous cell carcinoma', 'Disease', (85, 113))	('NY-ESO-1', 'Gene', '246100', (144, 152))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (85, 113))	('MAGE-A4', 'Gene', '4103', (224, 231))	('esophageal', 'Disease', (66, 76))	('patients', 'Species', '9606', (192, 200))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('patients', 'Species', '9606', (41, 49))	('MAGE-A4', 'Gene', (132, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('co-expressed', 'Var', (119, 131))
409805	30542513	Clinical trials conducted at Mie University Hospital/Nagasaki Medical Center and Kitano Hospital were registered in the UMIN Clinical Trials Registry as UMIN000001599 and UMIN000002153, started on December 25, 2008 and July 2, 2009, and ended on November 23, 2012 and July 31, 2014, respectively.	('UMIN000001599', 'Disease', 'None', (153, 166))	('Clinical', 'Species', '191496', (0, 8))	('UMIN000001599', 'Disease', (153, 166))	('Clinical', 'Species', '191496', (125, 133))	('UMIN000002153', 'Var', (171, 184))
409828	30360388	Many congenital disorders associated with mutations of FOX transcription factors have been reported.	('congenital disorders', 'Disease', (5, 25))	('congenital disorders', 'Disease', 'MESH:D000013', (5, 25))	('mutations', 'Var', (42, 51))	('associated', 'Reg', (26, 36))
409833	30360388	The dysregulation of FOX proteins is associated with cancer initiation, invasion, progression, and drug resistance.	('drug resistance', 'CPA', (99, 114))	('cancer initiation', 'Disease', 'MESH:D009369', (53, 70))	('dysregulation', 'Var', (4, 17))	('progression', 'CPA', (82, 93))	('cancer initiation', 'Disease', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('associated', 'Reg', (37, 47))	('FOX proteins', 'Protein', (21, 33))	('invasion', 'CPA', (72, 80))	('drug resistance', 'Phenotype', 'HP:0020174', (99, 114))
409842	30360388	Somatic mutations of FOX transcription factors, such as amplification, point mutation, translocation, deletion and gene fusion, are commonly identified in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('translocation', 'Var', (87, 100))	('human', 'Species', '9606', (155, 160))	('gene fusion', 'Var', (115, 126))	('deletion', 'Var', (102, 110))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('point mutation', 'Var', (71, 85))	('amplification', 'Var', (56, 69))
409848	30360388	Indeed, FOXA1 and FOXA2 play important roles in tumorigenesis based on their multifaceted activities, mainly in terms of genome instability and mutation, activation of invasion and metastasis, and sustained proliferative signaling.	('tumor', 'Disease', (48, 53))	('FOXA2', 'Gene', (18, 23))	('FOXA1', 'Gene', '3169', (8, 13))	('FOXA2', 'Gene', '3170', (18, 23))	('activation', 'PosReg', (154, 164))	('mutation', 'Var', (144, 152))	('FOXA1', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('genome instability', 'CPA', (121, 139))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
409857	30360388	Dysregulation of cohesin has been associated with cancer.	('associated', 'Reg', (34, 44))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Dysregulation', 'Var', (0, 13))	('cohesin', 'Protein', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
409861	30360388	These observations support the hypothesis that FOXA factors have essential roles in the disruption of cancer metabolism, and the modulation of FOXAs may provide new opportunities for cancer treatment.	('disruption of cancer metabolism', 'Disease', (88, 119))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (183, 189))	('disruption of cancer metabolism', 'Disease', 'MESH:D015451', (88, 119))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('modulation', 'Var', (129, 139))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
409863	30360388	In cancer, FOXC1 and FOXC2 are involved mainly in inducing angiogenesis, invasion and metastasis, invading growth suppressors, genome instability and mutation, and sustaining proliferative signaling.	('FOXC1', 'Gene', (11, 16))	('growth suppressors', 'CPA', (107, 125))	('FOXC2', 'Gene', (21, 26))	('involved', 'Reg', (31, 39))	('mutation', 'Var', (150, 158))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('genome instability', 'CPA', (127, 145))	('invading', 'PosReg', (98, 106))	('cancer', 'Disease', (3, 9))	('inducing', 'PosReg', (50, 58))	('angiogenesis', 'CPA', (59, 71))	('proliferative', 'MPA', (175, 188))	('sustaining', 'PosReg', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
409886	30360388	Dysregulation of this axis, such as through inhibition of FOXO3a combined with overexpression of FOXM1, results in drug resistance to some standard therapies.	('FOXM1', 'Gene', (97, 102))	('drug resistance', 'MPA', (115, 130))	('FOXM1', 'Gene', '2305', (97, 102))	('Dysregulation', 'Var', (0, 13))	('FOXO3a', 'Gene', '2309', (58, 64))	('inhibition', 'NegReg', (44, 54))	('FOXO3a', 'Gene', (58, 64))	('drug resistance', 'Phenotype', 'HP:0020174', (115, 130))	('overexpression', 'PosReg', (79, 93))	('results in', 'Reg', (104, 114))
409887	30360388	Interestingly, the inhibition of FOXM1 alone is supposed to be adequate in targeting multifaceted mechanisms of tumorigenesis.	('inhibition', 'Var', (19, 29))	('FOXM1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('FOXM1', 'Gene', '2305', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))
409888	30360388	Interest in FOXM1 dysregulation and its impact on cancer management has been maintained in recent years.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('FOXM1', 'Gene', '2305', (12, 17))	('FOXM1', 'Gene', (12, 17))	('dysregulation', 'Var', (18, 31))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
409893	30360388	In contrast to the FOXC and FOXM subfamilies, which are genuine oncogenes, FOXO proteins negatively regulate various biological processes at multiple levels, and dysregulation of FOXOs may lead to cancer.	('FOXO', 'Gene', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('regulate', 'Reg', (100, 108))	('FOXOs', 'Gene', (179, 184))	('dysregulation', 'Var', (162, 175))	('lead to', 'Reg', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('negatively', 'NegReg', (89, 99))
409894	30360388	Indeed, FOXOs are part of a multitude of oncogenic pathways and cancer hallmarks, including resisting cell death, sustaining proliferative signaling, tumor-promoting inflammation, immune destruction, cellular energetics, replicative immortality, evading growth suppressors, genome instability and mutation, and inducing angiogenesis.	('FOXOs', 'Gene', (8, 13))	('inflammation', 'Disease', (166, 178))	('genome instability', 'CPA', (274, 292))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cellular energetics', 'CPA', (200, 219))	('mutation', 'Var', (297, 305))	('angiogenesis', 'CPA', (320, 332))	('evading', 'NegReg', (246, 253))	('inducing', 'PosReg', (311, 319))	('cancer hallmarks', 'Disease', (64, 80))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('proliferative signaling', 'MPA', (125, 148))	('tumor', 'Disease', (150, 155))	('inflammation', 'Disease', 'MESH:D007249', (166, 178))	('cancer hallmarks', 'Disease', 'MESH:D009369', (64, 80))	('cell death', 'CPA', (102, 112))	('replicative immortality', 'CPA', (221, 244))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('growth suppressors', 'CPA', (254, 272))
409903	30360388	A comprehensive review with regard to the roles of FOXO3a in carcinogenesis, e.g., the inactivation and the initiation and progression of cancer, has been recently documented.	('cancer', 'Disease', (138, 144))	('carcinogenesis', 'Disease', (61, 75))	('inactivation', 'Var', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('FOXO3a', 'Gene', '2309', (51, 57))	('FOXO3a', 'Gene', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
409908	30360388	In addition, FOXP3 and regulatory T cell (Treg) dysregulation result in autoimmune diseases.	('FOXP3', 'Gene', (13, 18))	('autoimmune diseases', 'Disease', 'MESH:D001327', (72, 91))	('autoimmune diseases', 'Disease', (72, 91))	('FOXP3', 'Gene', '50943', (13, 18))	('dysregulation', 'Var', (48, 61))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (72, 91))	('result in', 'Reg', (62, 71))
409911	30360388	FOXP-dependent cancer initiation and progression are generally associated with immune destruction, evading growth suppressors, genome instability and mutation, inducing angiogenesis, resisting cell death, sustaining proliferative signaling, and tumor-promoting inflammation.	('cell death', 'CPA', (193, 203))	('inflammation', 'Disease', 'MESH:D007249', (261, 273))	('cancer initiation', 'Disease', 'MESH:D009369', (15, 32))	('cancer initiation', 'Disease', (15, 32))	('angiogenesis', 'CPA', (169, 181))	('FOXP-dependent', 'Gene', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('mutation', 'Var', (150, 158))	('associated', 'Reg', (63, 73))	('inducing', 'PosReg', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('resisting', 'NegReg', (183, 192))	('tumor', 'Disease', (245, 250))	('proliferative', 'MPA', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('inflammation', 'Disease', (261, 273))
409923	30360388	Mutations and dysregulation of FOXP3 are linked to immune response abnormalities and carcinogenesis.	('linked', 'Reg', (41, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('immune response abnormalities', 'Phenotype', 'HP:0002715', (51, 80))	('FOXP3', 'Gene', (31, 36))	('dysregulation', 'Var', (14, 27))	('immune response abnormalities', 'CPA', (51, 80))	('carcinogenesis', 'Disease', (85, 99))	('Mutations', 'Var', (0, 9))	('FOXP3', 'Gene', '50943', (31, 36))
409929	30360388	However, dysregulation of FOXP4 has been associated with breast cancer, kidney cancer, prostate cancer, and NSCLC.	('breast cancer', 'Disease', (57, 70))	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('kidney cancer', 'Disease', 'MESH:D007680', (72, 85))	('FOXP4', 'Gene', '116113', (26, 31))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('dysregulation', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('NSCLC', 'Disease', (108, 113))	('kidney cancer', 'Phenotype', 'HP:0009726', (72, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('kidney cancer', 'Disease', (72, 85))	('FOXP4', 'Gene', (26, 31))	('prostate cancer', 'Disease', (87, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))
409930	30360388	FOXD3 can be considered a tumor suppressor since it inhibits tumor growth and angiogenesis of NSCLC and neuroblastoma, whereas its deficiency leads to the induction of EMT and increased invasiveness of breast cancer.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('neuroblastoma', 'Disease', (104, 117))	('FOXD3', 'Gene', (0, 5))	('neuroblastoma', 'Phenotype', 'HP:0003006', (104, 117))	('NSCLC', 'Disease', (94, 99))	('deficiency', 'Var', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (26, 31))	('invasiveness of breast cancer', 'Disease', 'MESH:D001943', (186, 215))	('neuroblastoma', 'Disease', 'MESH:D009447', (104, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('increased', 'PosReg', (176, 185))	('angiogenesis', 'CPA', (78, 90))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('inhibits', 'NegReg', (52, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('EMT', 'CPA', (168, 171))	('induction', 'PosReg', (155, 164))	('invasiveness of breast cancer', 'Disease', (186, 215))	('FOXD3', 'Gene', '27022', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
409936	30360388	However, FOXF1 may be also considered a tumor suppressor since the loss of FOXF1 is associated with poor prognosis in liver cancer patients.	('patients', 'Species', '9606', (131, 139))	('FOXF1', 'Gene', (9, 14))	('FOXF1', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('liver cancer', 'Phenotype', 'HP:0002896', (118, 130))	('FOXF1', 'Gene', '2294', (9, 14))	('liver cancer', 'Disease', 'MESH:D006528', (118, 130))	('loss', 'Var', (67, 71))	('liver cancer', 'Disease', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('FOXF1', 'Gene', '2294', (75, 80))
409937	30360388	FOXL1 is a novel tumor suppressor whose expression and co-expression with other regulators inhibit the aggressiveness of pancreatic cancer, kidney cancer, gallbladder cancer, and osteosarcoma and could be initially implicated in the modulation of the Wnt/APC (Adenomatous Polyposis Coli)/beta-catenin pathway.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('kidney cancer', 'Disease', (140, 153))	('gallbladder cancer', 'Disease', (155, 173))	('Adenomatous Polyposis Coli', 'Phenotype', 'HP:0005227', (260, 286))	('kidney cancer', 'Phenotype', 'HP:0009726', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('co-expression', 'Var', (55, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))	('Adenomatous Polyposis Coli', 'Disease', (260, 286))	('osteosarcoma', 'Disease', (179, 191))	('osteosarcoma', 'Disease', 'MESH:D012516', (179, 191))	('bladder cancer', 'Phenotype', 'HP:0009725', (159, 173))	('FOXL1', 'Gene', '2300', (0, 5))	('aggressiveness', 'Phenotype', 'HP:0000718', (103, 117))	('tumor', 'Disease', (17, 22))	('inhibit', 'NegReg', (91, 98))	('gallbladder cancer', 'Disease', 'MESH:D005706', (155, 173))	('implicated', 'Reg', (215, 225))	('FOXL1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('kidney cancer', 'Disease', 'MESH:D007680', (140, 153))	('APC', 'Disease', 'MESH:D011125', (255, 258))	('osteosarcoma', 'Phenotype', 'HP:0002669', (179, 191))	('expression', 'Var', (40, 50))	('aggressiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (103, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('APC', 'Disease', (255, 258))	('beta-catenin', 'Gene', (288, 300))	('Adenomatous Polyposis Coli', 'Disease', 'MESH:D011125', (260, 286))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('beta-catenin', 'Gene', '1499', (288, 300))	('aggressiveness of pancreatic cancer', 'Disease', (103, 138))
409948	30360388	For example, changes in the expression levels of FOXM1 or FOXOs are highly associated with chemoresistance and poor prognosis in cancer patients.	('FOXM1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('expression levels', 'MPA', (28, 45))	('FOXM1', 'Gene', '2305', (49, 54))	('changes', 'Var', (13, 20))	('cancer', 'Disease', (129, 135))	('chemoresistance', 'CPA', (91, 106))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('patients', 'Species', '9606', (136, 144))	('FOXOs', 'Gene', (58, 63))	('associated', 'Reg', (75, 85))
409949	30360388	Alternatively, aberrant activation of DNA damage repair may be associated not only with cancer initiation but also with cancer progression and genotoxic drug resistance.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer initiation', 'Disease', 'MESH:D009369', (88, 105))	('associated', 'Reg', (63, 73))	('cancer', 'Disease', (120, 126))	('cancer initiation', 'Disease', (88, 105))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('DNA', 'MPA', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('aberrant', 'Var', (15, 23))
409951	30360388	The expression of FOXM1 may confer genotoxic agent resistance, and its overexpression in DNA-damaging cancer drug-resistant cells has been commonly observed (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('overexpression', 'PosReg', (71, 85))	('confer', 'Reg', (28, 34))	('genotoxic agent resistance', 'MPA', (35, 61))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('expression', 'Var', (4, 14))	('FOXM1', 'Gene', (18, 23))	('FOXM1', 'Gene', '2305', (18, 23))
409957	30360388	MK-2206, another Akt inhibitor, can also lead to FOXO3a activation and dephosphorylation and potentially synergize with conventional genotoxic drugs such as doxorubicin in liver cancer treatment.	('MK-2206', 'Chemical', 'MESH:C548887', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Akt', 'Gene', '207', (17, 20))	('FOXO3a', 'Gene', '2309', (49, 55))	('liver cancer', 'Disease', 'MESH:D006528', (172, 184))	('liver cancer', 'Phenotype', 'HP:0002896', (172, 184))	('synergize', 'Reg', (105, 114))	('doxorubicin', 'Chemical', 'MESH:D004317', (157, 168))	('liver cancer', 'Disease', (172, 184))	('lead to', 'Reg', (41, 48))	('FOXO3a', 'Gene', (49, 55))	('activation', 'PosReg', (56, 66))	('Akt', 'Gene', (17, 20))	('dephosphorylation', 'MPA', (71, 88))	('MK-2206', 'Var', (0, 7))
409959	30360388	Human cancers occur in a multi-step manner as a result of the accumulation of genetic alterations and epigenetic changes.	('Human', 'Species', '9606', (0, 5))	('epigenetic changes', 'Var', (102, 120))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('genetic alterations', 'Var', (78, 97))	('cancers', 'Disease', (6, 13))
409960	30360388	Numerous studies have indicated the roles of somatic mutations of FOX family genes in various types of human cancers in relation to transcriptional modulation as well as DNA repair or histone modification.	('human', 'Species', '9606', (103, 108))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('transcriptional', 'MPA', (132, 147))	('mutations', 'Var', (53, 62))	('FOX family genes', 'Gene', (66, 82))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
409961	30360388	The FOXM1 gene on human chromosome 12p13.33 is suggested to be amplified in 5.6% of breast cancer and 58% of malignant peripheral nerve sheath tumors and is frequently upregulated in human cancer.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (18, 23))	('FOXM1', 'Gene', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('human', 'Species', '9606', (183, 188))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (109, 149))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))	('amplified', 'Var', (63, 72))	('upregulated', 'PosReg', (168, 179))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (109, 149))	('FOXM1', 'Gene', '2305', (4, 9))	('cancer', 'Disease', (189, 195))	('malignant peripheral nerve sheath tumors', 'Disease', (109, 149))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
409967	30360388	This may also explain why mutated p53 and deregulated FOXM1 are both frequently selected in cancer.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('FOXM1', 'Gene', '2305', (54, 59))	('mutated', 'Var', (26, 33))	('FOXM1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('deregulated', 'Var', (42, 53))
409972	30360388	By contrast, co-depletion of FBXO31 and FOXM1 can restore the genomic instability phenotype but not the delay in mitosis, indicating that FBXO31 probably has additional mitotic substrates.	('FBXO31', 'Gene', '79791', (138, 144))	('co-depletion', 'Var', (13, 25))	('FBXO31', 'Gene', '79791', (29, 35))	('mitosis', 'Disease', (113, 120))	('FOXM1', 'Gene', '2305', (40, 45))	('FOXM1', 'Gene', (40, 45))	('mitosis', 'Disease', 'None', (113, 120))	('FBXO31', 'Gene', (138, 144))	('genomic instability phenotype', 'MPA', (62, 91))	('restore', 'PosReg', (50, 57))	('FBXO31', 'Gene', (29, 35))
409976	30360388	The tumor suppressor functions of FOXO transcription factors are lost in cancer cells as a result of chromosomal translocations or deletions of FOXO genes or Akt-mediated cytoplasmic sequestration of FOXO proteins.	('tumor', 'Disease', (4, 9))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('chromosomal translocations', 'Var', (101, 127))	('FOXO', 'Gene', (144, 148))	('Akt', 'Gene', '207', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lost', 'NegReg', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('deletions', 'Var', (131, 140))	('Akt', 'Gene', (158, 161))
409979	30360388	Genome doubling and ongoing dynamic CIN are related to intratumor heterogeneity and lead the parallel evolution of driver somatic copy-number alterations, including amplifications of FOXA1, CDK4 and BCL11A.	('BCL11A', 'Gene', (199, 205))	('CIN', 'Disease', 'MESH:D007674', (36, 39))	('CDK4', 'Gene', (190, 194))	('CDK4', 'Gene', '1019', (190, 194))	('amplifications', 'Var', (165, 179))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('CIN', 'Phenotype', 'HP:0040012', (36, 39))	('FOXA1', 'Gene', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('CIN', 'Disease', (36, 39))	('BCL11A', 'Gene', '53335', (199, 205))	('FOXA1', 'Gene', '3169', (183, 188))
409983	30360388	Studies in the past decade have revealed that miRNAs are involved in various biological processes such as cell differentiation, stress resistance or tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('as c', 'Gene', (103, 107))	('miRNAs', 'Var', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('as c', 'Gene', '29108', (103, 107))	('tumor', 'Disease', (149, 154))	('stress resistance', 'CPA', (128, 145))	('involved', 'Reg', (57, 65))
409985	30360388	Recently, several studies have indicated the specific modulation of FOX genes by miRNAs in various different cancers such as colorectal cancer, esophageal cancer, triple-negative breast cancer and hepatocellular carcinoma.	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (197, 221))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('as c', 'Gene', '29108', (122, 126))	('modulation', 'Reg', (54, 64))	('miRNAs', 'Var', (81, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('hepatocellular carcinoma', 'Disease', (197, 221))	('as c', 'Gene', (122, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('breast cancer', 'Disease', (179, 192))	('cancers', 'Disease', (109, 116))	('colorectal cancer', 'Disease', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('FOX genes', 'Gene', (68, 77))	('esophageal cancer', 'Disease', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (197, 221))
409989	30360388	By contrast, the restoration of miR-422a expression significantly suppressed tumor growth and liver metastasis in xenograft tumor models by modulating its direct targets, such as FOXG1, FOXQ1 and FOXE1.	('miR-422a', 'Gene', (32, 40))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('FOXE1', 'Gene', '2304', (196, 201))	('liver metastasis', 'Disease', (94, 110))	('miR-422a', 'Gene', '494334', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('expression', 'MPA', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('restoration', 'Var', (17, 28))	('FOXQ1', 'Gene', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('FOXG1', 'Gene', (179, 184))	('liver metastasis', 'Disease', 'MESH:D009362', (94, 110))	('FOXQ1', 'Gene', '94234', (186, 191))	('xenograft tumor', 'Disease', (114, 129))	('modulating', 'Reg', (140, 150))	('xenograft tumor', 'Disease', 'MESH:D009369', (114, 129))	('FOXE1', 'Gene', (196, 201))	('suppressed', 'NegReg', (66, 76))	('tumor', 'Disease', (77, 82))	('FOXG1', 'Gene', '2290', (179, 184))
409993	30360388	FOX proteins are involved in various cellular processes, such as the DNA damage response, differentiation, proliferation and drug resistance, and consequently, targeting FOX proteins can significantly contribute to tumorigenesis and tumor progression.	('targeting', 'Var', (160, 169))	('contribute', 'Reg', (201, 211))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('drug resistance', 'Phenotype', 'HP:0020174', (125, 140))	('FOX proteins', 'Protein', (170, 182))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
409996	30360388	For example, depletion of FOXM1 expression by small interfering RNA transfection of lung adenocarcinoma cells can significantly decrease DNA replication and mitosis and reduce anchorage-independent growth of cell colonies on soft agar.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('DNA replication', 'CPA', (137, 152))	('FOXM1', 'Gene', '2305', (26, 31))	('lung adenocarcinoma', 'Disease', (84, 103))	('FOXM1', 'Gene', (26, 31))	('small interfering RNA', 'Var', (46, 67))	('mitosis', 'Disease', (157, 164))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('depletion', 'MPA', (13, 22))	('mitosis', 'Disease', 'None', (157, 164))	('decrease', 'NegReg', (128, 136))	('reduce', 'NegReg', (169, 175))
409997	30360388	Silencing of FOXM1 by RNAi also abolished estrogen-stimulated breast cancer cell proliferation and overcame acquired tamoxifen resistance.	('estrogen-stimulated', 'CPA', (42, 61))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('acquired tamoxifen resistance', 'MPA', (108, 137))	('overcame', 'PosReg', (99, 107))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('FOXM1', 'Gene', (13, 18))	('FOXM1', 'Gene', '2305', (13, 18))	('tamoxifen', 'Chemical', 'MESH:D013629', (117, 126))	('Silencing', 'Var', (0, 9))	('abolished', 'NegReg', (32, 41))
410006	30360388	Alternatively, the suppression of the proteasome causes regression of leukemia and abrogates BCR-ABL-stimulated evasion of apoptosis in part through modulation of forkhead tumor suppressors.	('BCR-ABL', 'Gene', (93, 100))	('BCR-ABL', 'Gene', '25', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('evasion of apoptosis', 'MPA', (112, 132))	('tumor', 'Disease', (172, 177))	('modulation', 'Var', (149, 159))	('suppression', 'NegReg', (19, 30))	('leukemia', 'Disease', (70, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('proteasome', 'Protein', (38, 48))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('abrogates', 'NegReg', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('regression', 'NegReg', (56, 66))
410016	30360388	In addition, better drug-delivery strategies for not only small-molecule drugs but also RNAi may help improve the effectiveness of cancer treatment.	('cancer', 'Disease', (131, 137))	('RNAi', 'Gene', (88, 92))	('improve', 'PosReg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('small-molecule', 'Var', (58, 72))	('drug-delivery', 'MPA', (20, 33))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
410032	27579613	Further study showed that tumor size and T stage were independent predictors of the prognosis of node-negative patients, and the combination of tumor size and T stage improved the predictive accuracy by 3.7%.	('improved', 'PosReg', (167, 175))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('combination', 'Var', (129, 140))	('patients', 'Species', '9606', (111, 119))
410174	27256629	We also performed a dose-response meta-analysis to evaluate the dose-response associations between dietary fruit and vegetable, saturated fat, monounsaturated fat and polyunsaturated fat intakes and BE risk.	('monounsaturated fat', 'Chemical', '-', (143, 162))	('saturated fat', 'Chemical', '-', (149, 162))	('saturated fat', 'Chemical', '-', (128, 141))	('saturated fat', 'Chemical', '-', (173, 186))	('polyunsaturated fat', 'Chemical', '-', (167, 186))	('BE', 'Phenotype', 'HP:0100580', (199, 201))	('monounsaturated fat', 'MPA', (143, 162))	('polyunsaturated', 'Var', (167, 182))
410176	27256629	There were no significant changes of BE risk per unit increase (serving/day) with fruit intake (OR = 0.66, 95% CI = 0.39-1.14) and per unit increase (gram/day) with saturated fat intake (OR: 1.03, 95% CI 0.99-1.07), monounsaturated fat intake (OR: 1.15, 95% CI 0.63-2.09) or polyunsaturated fat intake (OR: 0.70, 95% CI 0.40-1.25).	('polyunsaturated fat', 'Var', (275, 294))	('BE', 'Phenotype', 'HP:0100580', (37, 39))	('increase', 'PosReg', (54, 62))	('monounsaturated fat', 'Chemical', '-', (216, 235))	('monounsaturated fat', 'Var', (216, 235))	('saturated fat', 'Chemical', '-', (165, 178))	('saturated fat', 'Chemical', '-', (222, 235))	('saturated fat', 'Chemical', '-', (281, 294))	('polyunsaturated fat', 'Chemical', '-', (275, 294))
410184	27256629	Figures 4a-d indicated that fats, including saturated fat, monounsaturated fat, polyunsaturated fat and cholesterol intakes, were not associated with BE risk.	('fats', 'Gene', (28, 32))	('saturated fat', 'Chemical', '-', (65, 78))	('polyunsaturated fat', 'Chemical', '-', (80, 99))	('saturated fat', 'Chemical', '-', (86, 99))	('fats', 'Gene', '118611', (28, 32))	('polyunsaturated', 'Var', (80, 95))	('monounsaturated fat', 'Chemical', '-', (59, 78))	('BE', 'Phenotype', 'HP:0100580', (150, 152))	('cholesterol', 'Chemical', 'MESH:D002784', (104, 115))	('saturated fat', 'Chemical', '-', (44, 57))	('monounsaturated', 'Var', (59, 74))
410199	24130695	In CE81T tumor-bearing mice, 1BB1 reduced tumor growth and downregulated TGF-beta, cyclin B1, MMP-1, and CXCR4 expression in tumors.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('BB1', 'Gene', (30, 33))	('cyclin B1', 'MPA', (83, 92))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('CE81T', 'Var', (3, 8))	('reduced', 'NegReg', (34, 41))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CXCR4 expression', 'MPA', (105, 121))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('TGF-beta', 'Gene', (73, 81))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('MMP-1', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('BB1', 'Gene', '941', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('downregulated', 'NegReg', (59, 72))	('tumor', 'Disease', (125, 130))	('mice', 'Species', '10090', (23, 27))
410220	24130695	We also determined the effect of anti-IL-19 monoclonal antibody (mAb) on reducing esophageal carcinoma tumor growth in a mouse model.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('esophageal carcinoma tumor', 'Disease', (82, 108))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (82, 102))	('mouse', 'Species', '10090', (121, 126))	('reducing', 'NegReg', (73, 81))	('anti-IL-19', 'Var', (33, 43))	('esophageal carcinoma tumor', 'Disease', 'MESH:D009369', (82, 108))
410233	24130695	We previously reported that 1BB1 neutralized hIL-19.	('hIL-19', 'Gene', (45, 51))	('BB1', 'Gene', '941', (29, 32))	('BB1', 'Gene', (29, 32))	('neutralized', 'Var', (33, 44))	('hIL-19', 'Gene', '29949', (45, 51))
410265	24130695	High IL-19 expression was associated with advanced tumor stage and a high incidence of lymph-node metastasis and distant metastasis (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('High', 'Var', (0, 4))	('lymph-node metastasis', 'Disease', 'MESH:D009362', (87, 108))	('expression', 'MPA', (11, 21))	('tumor', 'Disease', (51, 56))	('lymph-node metastasis', 'Disease', (87, 108))	('distant metastasis', 'CPA', (113, 131))	('IL-19', 'Gene', (5, 10))	('associated', 'Reg', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
410273	24130695	2D), indicated that endogenous IL-19-induced STAT-3 phosphorylation was attenuated by 1BB1 and 51D.	('51D', 'Var', (95, 98))	('attenuated', 'NegReg', (72, 82))	('STAT-3', 'Gene', '6774', (45, 51))	('BB1', 'Gene', '941', (87, 90))	('STAT-3', 'Gene', (45, 51))	('BB1', 'Gene', (87, 90))	('endogenous', 'MPA', (20, 30))
410278	24130695	IL-19 significantly promoted CE81T cell migration and anti-IL-19 mAb (1BB1) and anti-IL-20R1 mAb (51D) specifically inhibited the activity (Fig.	('CE81T cell migration', 'CPA', (29, 49))	('BB1', 'Gene', (71, 74))	('IL-20R1', 'Gene', '53832', (85, 92))	('inhibited', 'NegReg', (116, 125))	('BB1', 'Gene', '941', (71, 74))	('promoted', 'PosReg', (20, 28))	('IL-20R1', 'Gene', (85, 92))	('anti-IL-19', 'Var', (54, 64))	('activity', 'MPA', (130, 138))
410280	24130695	The colony formation was significantly higher in IL-19 treated CE81T cells than in untreated control, the activity of which was attenuated by 1BB1 and 51D mAbs (Fig.	('CE81T', 'Var', (63, 68))	('higher', 'PosReg', (39, 45))	('BB1', 'Gene', '941', (143, 146))	('BB1', 'Gene', (143, 146))	('attenuated', 'NegReg', (128, 138))	('IL-19', 'Gene', (49, 54))	('colony formation', 'CPA', (4, 20))
410288	24130695	We subcutaneously (s.c.) injected CE81T cells into BALB/C SCID mice, treated the mice with a 1BB1 injection (15 mg/kg, s.c.) every 3 days, and then determined tumor growth for 32 days.	('mice', 'Species', '10090', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Disease', (159, 164))	('BB1', 'Gene', '941', (94, 97))	('SCID', 'Disease', 'MESH:D053632', (58, 62))	('BB1', 'Gene', (94, 97))	('SCID', 'Disease', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('CE81T', 'Var', (34, 39))
410316	24130695	However, we did find the clinicopathological variables correlated to IL-19 expression; high IL-19 expression associated with advanced tumor stages.	('associated', 'Reg', (109, 119))	('IL-19', 'Gene', (92, 97))	('IL-19', 'Gene', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('high', 'Var', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('expression', 'MPA', (98, 108))
410323	24130695	Our in vivo experiment showed that anti-IL-19 monoclonal antibody inhibited CE81T tumor growth.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('anti-IL-19', 'Var', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibited', 'NegReg', (66, 75))	('tumor', 'Disease', (82, 87))
410330	24130695	Antagonizing IL-19 may have therapeutic potential in esophageal cancer.	('IL-19', 'Gene', (13, 18))	('esophageal cancer', 'Disease', (53, 70))	('Antagonizing', 'Var', (0, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
410382	23691473	Therefore, the action of CVPs-B on the accessibility of the chemotactic factor may be considered as one of the mechanisms in which CVPs-B inhibits the proliferation of EsCa cells and modulates their cell cycle.	('EsCa cells', 'CPA', (168, 178))	('cell cycle', 'CPA', (199, 209))	('accessibility of', 'MPA', (39, 55))	('proliferation', 'CPA', (151, 164))	('inhibits', 'NegReg', (138, 146))	('CVPs-B', 'Var', (131, 137))	('modulates', 'Reg', (183, 192))	('EsCa', 'Phenotype', 'HP:0011459', (168, 172))	('EsCa', 'CellLine', 'CVCL:2401', (168, 172))
410383	23691473	In this study, the cell cycle rate in EG increased after incubation with CVPs-B compared with the CG.	('EG', 'Chemical', '-', (38, 40))	('increased', 'PosReg', (41, 50))	('CVPs-B', 'Var', (73, 79))	('cell cycle rate', 'CPA', (19, 34))
410446	22200953	Patients with STC1-positive tumors had significantly poorer overall survival (OS) and disease-free survival (DFS) than those with STC1-negative tumors (5-year OS, 36.4 vs. 64.7%, P=0.0006; 5-year DFS, 35.0 vs. 61.0%, P=0.0001, Fig.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumors', 'Disease', (28, 34))	('STC1-positive', 'Var', (14, 27))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'CPA', (60, 76))	('poorer', 'NegReg', (53, 59))	('disease-free survival', 'CPA', (86, 107))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
410492	20196733	Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as the most frequent mechanism for gene inactivation in cancers.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('tumor', 'Disease', (67, 72))	('cancers', 'Disease', (172, 179))
410497	20196733	Presence of methylated DNA sequences in clinical specimens and potential of using them as biomarkers have been recognized.	('clinical', 'Species', '191496', (40, 48))	('DNA', 'Gene', (23, 26))	('methylated', 'Var', (12, 22))
410500	20196733	While the field of cancer genetics has enjoyed a great deal of attention among cancer researchers in the last few decades, the appreciation of cancer epigenetics is more recent, owing to the fact that epigenetic mechanisms have emerged as key mechanisms in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('epigenetic', 'Var', (201, 211))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (257, 263))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
410505	20196733	During cancer development, two distinct changes in DNA methylation occur: genome-wide hypomethylation and locus-specific gain or loss of cytosine methylation in promoter-associated CpG islands.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('hypomethylation', 'Var', (86, 101))	('cytosine', 'Chemical', 'MESH:D003596', (137, 145))	('loss', 'NegReg', (129, 133))	('gain', 'PosReg', (121, 125))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cytosine methylation', 'MPA', (137, 157))
410506	20196733	It is likely that genome-wide changes in methylation substantially alter overall chromatin architecture, chromosome segregation in mitosis, and ultimately cell ploidy, all of which augment cellular transformation.	('cellular transformation', 'CPA', (189, 212))	('alter', 'Reg', (67, 72))	('augment', 'PosReg', (181, 188))	('mitosis', 'Disease', (131, 138))	('changes', 'Var', (30, 37))	('chromatin', 'MPA', (81, 90))	('mitosis', 'Disease', 'None', (131, 138))	('methylation', 'Var', (41, 52))	('cell ploidy', 'CPA', (155, 166))
410524	20196733	Considerable amounts of work have been done which shows numerous methylated genes are useful as prognostic or diagnostic biomarkers based on analysis of cancer biopsies.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('methylated genes', 'Var', (65, 81))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (153, 159))
410530	20196733	Dramatic progress has been made over last few years in identifying genes that are found methylated in cancer tissue but not in corresponding non-cancer tissues.	('cancer', 'Disease', (145, 151))	('non-cancer', 'Disease', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('genes', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('methylated', 'Var', (88, 98))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('non-cancer', 'Disease', 'MESH:D009369', (141, 151))
410535	20196733	Genes that are found to be methylated at higher frequency/higher prevalence in cancer tissue and at very lower frequency/lower prevalence in normal tissue may have potential as biomarkers.	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Disease', (79, 85))	('methylated', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
410538	20196733	Table 1 summarizes a list of studies that have used aberrant methylation of a gene or a panel of genes based on the analysis of body fluids from cancer patients for non-invasive detection of multiple types of cancers.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancers', 'Disease', (209, 216))	('cancer', 'Disease', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('patients', 'Species', '9606', (152, 160))	('aberrant methylation', 'Var', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
410546	20196733	have tested methylation of multiple genes in sputum samples from cancer and non-cancer patients.	('non-cancer', 'Disease', 'MESH:D009369', (76, 86))	('tested', 'Reg', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('methylation', 'Var', (12, 23))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', (80, 86))	('non-cancer', 'Disease', (76, 86))
410547	20196733	Based on their studies, methylation of P16INK4A in sputum DNA may have significant potential as a biomarker of lung cancer risk.	('P16INK4A', 'Gene', (39, 47))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('methylation', 'Var', (24, 35))	('P16INK4A', 'Gene', '1029', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
410548	20196733	Recent studies from our laboratory identified a methylated panel of genes that appear to be more promising than those previously reported as potential lung cancer biomarkers based on analyses of biopsies as well as sputum samples from cancer patients.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', (235, 241))	('methylated', 'Var', (48, 58))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('lung cancer', 'Disease', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('patients', 'Species', '9606', (242, 250))
410550	20196733	Table 1 further summarizes a list of studies that have used aberrant methylation of a gene or a panel of genes in detection of breast cancer based on analysis of body fluids from breast cancer patients.	('patients', 'Species', '9606', (193, 201))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('aberrant methylation', 'Var', (60, 80))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('breast cancer', 'Disease', (179, 192))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
410553	20196733	Table 1 further summarizes a list of studies that have used aberrant methylation of a gene or a panel of genes in detection of multiple cancer types such as prostate ovarian cancer, hepatocellular cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, esophageal cancer, cervical cancer and hematologic cancers.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('hematologic cancers', 'Disease', 'MESH:D009369', (314, 333))	('cancer', 'Disease', (232, 238))	('cervical cancer', 'Disease', (294, 309))	('cervical cancer', 'Disease', 'MESH:D002583', (294, 309))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Disease', (286, 292))	('bladder cancer', 'Disease', (240, 254))	('cancer', 'Disease', (248, 254))	('bladder cancer', 'Disease', 'MESH:D001749', (240, 254))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('cancer', 'Disease', (303, 309))	('prostate ovarian cancer', 'Phenotype', 'HP:0012125', (157, 180))	('gastric cancer', 'Disease', (205, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (256, 273))	('bladder cancer', 'Phenotype', 'HP:0009725', (240, 254))	('cancers', 'Phenotype', 'HP:0002664', (326, 333))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', (326, 332))	('cancer', 'Disease', (213, 219))	('hepatocellular cancer', 'Disease', (182, 203))	('colorectal cancer', 'Disease', (221, 238))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('prostate ovarian cancer', 'Disease', (157, 180))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (182, 203))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', (267, 273))	('prostate ovarian cancer', 'Disease', 'MESH:D010051', (157, 180))	('cancer', 'Disease', (197, 203))	('gastric cancer', 'Disease', 'MESH:D013274', (205, 219))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (182, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('hematologic cancers', 'Disease', (314, 333))	('aberrant', 'Var', (60, 68))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('pancreatic cancer', 'Disease', 'MESH:D010190', (256, 273))	('esophageal cancer', 'Disease', 'MESH:D004938', (275, 292))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('gastric cancer', 'Phenotype', 'HP:0012126', (205, 219))	('pancreatic cancer', 'Disease', (256, 273))	('esophageal cancer', 'Disease', (275, 292))
410557	20196733	Multiple genes have been found to be ethylated in prostatic tumors and PINs and thus they may be good candidates for early detection of prostatic cancer in high-risk populations.	('prostatic tumors', 'Disease', 'MESH:D011471', (50, 66))	('prostatic cancer', 'Disease', (136, 152))	('prostatic cancer', 'Disease', 'MESH:D011471', (136, 152))	('prostatic cancer', 'Phenotype', 'HP:0012125', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('PINs', 'Disease', (71, 75))	('prostatic tumors', 'Disease', (50, 66))	('ethylated', 'Var', (37, 46))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
410559	20196733	GSTP1 methylation was also found in ejaculates.	('found', 'Reg', (27, 32))	('methylation', 'Var', (6, 17))	('GSTP1', 'Gene', '2950', (0, 5))	('GSTP1', 'Gene', (0, 5))
410566	20196733	Similarly, as reported in the same study, detection of tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma and peritoneal fluid from early stage ovarian cancer patient should enhance early detection of ovarian cancer.	('RASSF1A', 'Gene', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('stage ovarian cancer', 'Disease', 'MESH:D010051', (159, 179))	('BRCA1', 'Gene', '672', (75, 80))	('BRCA1', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('peritoneal fluid', 'Phenotype', 'HP:0030995', (131, 147))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('stage ovarian cancer', 'Disease', (159, 179))	('ovarian cancer', 'Disease', 'MESH:D010051', (222, 236))	('enhance', 'PosReg', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('hypermethylation', 'Var', (93, 109))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('patient', 'Species', '9606', (180, 187))	('RASSF1A', 'Gene', '11186', (85, 92))	('ovarian cancer', 'Disease', (222, 236))	('tumor', 'Disease', (55, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (165, 179))	('ovarian cancer', 'Phenotype', 'HP:0100615', (222, 236))
410574	20196733	Specifically, p16INK4A methylation appears to be at very high frequency>50% in plasma of cancer patients with no false positive in plasma samples from non-hepatocellular cancer patients.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('p16INK4A', 'Gene', '1029', (14, 22))	('cancer', 'Disease', (170, 176))	('methylation', 'Var', (23, 34))	('patients', 'Species', '9606', (177, 185))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (155, 176))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (89, 95))	('p16INK4A', 'Gene', (14, 22))	('patients', 'Species', '9606', (96, 104))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (155, 176))	('hepatocellular cancer', 'Disease', (155, 176))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
410576	20196733	Of the paired plasma from the HCC patients, aberrant methylation was detected in 43% of the patients.	('detected', 'Reg', (69, 77))	('patients', 'Species', '9606', (34, 42))	('aberrant methylation', 'Var', (44, 64))	('patients', 'Species', '9606', (92, 100))
410587	20196733	Although, frequency of methylation of these genes in plasma samples of primary cancer patients did not appear to be high, it is substantially higher in recurrent cancers.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancer', 'Disease', (162, 168))	('methylation', 'Var', (23, 34))	('cancers', 'Disease', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('higher', 'PosReg', (142, 148))	('patients', 'Species', '9606', (86, 94))
410588	20196733	The feasibility of amplification of ethylated DNA from stool samples of patients with CRC has been reported.	('ethylated', 'Var', (36, 45))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('CRC', 'Disease', (86, 89))	('patients', 'Species', '9606', (72, 80))
410591	20196733	However, specificity of SFRP2 methylation was quite poor, at 77%.	('SFRP2', 'Gene', (24, 29))	('methylation', 'Var', (30, 41))	('SFRP2', 'Gene', '6423', (24, 29))
410594	20196733	The combination of HIC1 methylation analysis with fecal occult blood test allowed for the detection of two thirds of CRCs.	('CRCs', 'Disease', (117, 121))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('HIC1', 'Gene', '3090', (19, 23))	('HIC1', 'Gene', (19, 23))	('methylation analysis', 'Var', (24, 44))
410597	20196733	With MBD enrichment, methylated vimentin was detected in stools enriched with >=10 ng of cancer cell DNA in stool from CRC patients.	('detected', 'Reg', (45, 53))	('MBD', 'Disease', 'MESH:D012080', (5, 8))	('vimentin', 'Gene', '7431', (32, 40))	('methylated', 'Var', (21, 31))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('MBD', 'Disease', (5, 8))	('patients', 'Species', '9606', (123, 131))	('vimentin', 'Gene', (32, 40))	('cancer', 'Disease', (89, 95))	('CRC', 'Phenotype', 'HP:0003003', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
410603	20196733	Multiple genes have been found to be ethylated in bladder cancer with high specificity and sensitivity.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('bladder cancer', 'Disease', (50, 64))	('ethylated', 'Var', (37, 46))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))
410604	20196733	Methylation of p14ARF, P16INK4A has been reported in bladder cancers as well as plasma from the cancer patients.	('p14ARF', 'Gene', (15, 21))	('reported', 'Reg', (41, 49))	('bladder cancers', 'Disease', (53, 68))	('P16INK4A', 'Gene', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('P16INK4A', 'Gene', '1029', (23, 31))	('bladder cancers', 'Phenotype', 'HP:0009725', (53, 68))	('p14ARF', 'Gene', '1029', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('bladder cancers', 'Disease', 'MESH:D001749', (53, 68))	('patients', 'Species', '9606', (103, 111))	('cancer', 'Disease', (96, 102))	('bladder cancer', 'Phenotype', 'HP:0009725', (53, 67))
410608	20196733	2003 have shown that methylation of p16INK4A and CDKN2B in plasma might be potential useful biomarkers in screening high-risk populations for early HNSCC and monitoring their to response to treatment.	('p16INK4A', 'Gene', (36, 44))	('CDKN2B', 'Gene', '1030', (49, 55))	('p16INK4A', 'Gene', '1029', (36, 44))	('methylation', 'Var', (21, 32))	('early HNSCC', 'Disease', (142, 153))	('CDKN2B', 'Gene', (49, 55))
410609	20196733	Although, significant amounts of work has been done in identifying genes that are methylated in head and neck cancer specimens, only few reports exist that describe application of these methylation based biomarkers to body fluids from cancer patients.	('cancer', 'Disease', (110, 116))	('methylated', 'Var', (82, 92))	('head and neck cancer', 'Phenotype', 'HP:0012288', (96, 116))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('head and neck cancer', 'Disease', 'MESH:D006258', (96, 116))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('patients', 'Species', '9606', (242, 250))
410612	20196733	Hypermethylation of 16INK4A and ppENK genes was detected in 60% and 80% of the plasma samples taken from patients whose tumors harbored the same methylation, respectively.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('patients', 'Species', '9606', (105, 113))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('detected', 'Reg', (48, 56))	('INK4A', 'Gene', '1029', (22, 27))	('Hypermethylation', 'Var', (0, 16))	('INK4A', 'Gene', (22, 27))	('ppENK', 'Gene', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
410621	20196733	reported TAC-1 promoter methylation in plasma samples from >50% of the esophageal cancer patients but at significantly less frequency and levels in plasma samples from non-cancer patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TAC-1', 'Gene', (9, 14))	('TAC-1', 'Gene', '6863', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('methylation', 'Var', (24, 35))	('promoter', 'MPA', (15, 23))	('non-cancer', 'Disease', (168, 178))	('patients', 'Species', '9606', (89, 97))	('non-cancer', 'Disease', 'MESH:D009369', (168, 178))	('patients', 'Species', '9606', (179, 187))	('esophageal cancer', 'Disease', (71, 88))
410625	20196733	Aberrant methylation of CpG islands within the promoter regions of several genes such as p16INK4A, DAPK, MGMT, CDH-1 and RAR-beta has been identified in cervical cancer.	('cervical cancer', 'Disease', 'MESH:D002583', (153, 168))	('CDH-1', 'Gene', '999', (111, 116))	('cervical cancer', 'Disease', (153, 168))	('DAPK', 'Gene', (99, 103))	('Aberrant', 'Var', (0, 8))	('DAPK', 'Gene', '1612', (99, 103))	('RAR-beta', 'Gene', '5915', (121, 129))	('CDH-1', 'Gene', (111, 116))	('p16INK4A', 'Gene', (89, 97))	('MGMT', 'Gene', '4255', (105, 109))	('MGMT', 'Gene', (105, 109))	('identified', 'Reg', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('methylation', 'MPA', (9, 20))	('p16INK4A', 'Gene', '1029', (89, 97))	('RAR-beta', 'Gene', (121, 129))
410626	20196733	Recently, Widshwendel 2004 identified five additional genes, namely CALCA, hTERT, MYOD1, PGR and TIMP3, as being methylated significantly more frequently in cervical cancer than in normal cervical tissue.	('TIMP3', 'Gene', '7078', (97, 102))	('TIMP3', 'Gene', (97, 102))	('methylated', 'Var', (113, 123))	('CALCA', 'Gene', '796', (68, 73))	('MYOD1', 'Gene', '4654', (82, 87))	('cervical cancer', 'Disease', 'MESH:D002583', (157, 172))	('hTERT', 'Gene', '7015', (75, 80))	('cervical cancer', 'Disease', (157, 172))	('PGR', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('MYOD1', 'Gene', (82, 87))	('CALCA', 'Gene', (68, 73))	('PGR', 'Gene', '5241', (89, 92))	('hTERT', 'Gene', (75, 80))
410629	20196733	At least one of the tree genes was found to be methylated in 75% tumors and 55% plasma samples.	('methylated', 'Var', (47, 57))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Disease', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
410632	20196733	In one study, 39 of 43 blood samples (91%) sequentially collected from 12 patients with AML, ALL, or ABL showed CDKN2B methylation status in excellent concordance with morphologic disease stage.	('AML', 'Disease', 'MESH:D015470', (88, 91))	('CDKN2B', 'Gene', (112, 118))	('methylation', 'Var', (119, 130))	('patients', 'Species', '9606', (74, 82))	('ABL', 'Gene', '25', (101, 104))	('ABL', 'Gene', (101, 104))	('AML', 'Disease', (88, 91))	('CDKN2B', 'Gene', '1030', (112, 118))
410633	20196733	Early detection of CDKN2B methylation at apparent remission or its acquisition during follow-up may prove valuable for predicting relapse.	('CDKN2B', 'Gene', '1030', (19, 25))	('methylation', 'Var', (26, 37))	('relapse', 'Disease', (130, 137))	('CDKN2B', 'Gene', (19, 25))
410634	20196733	Overall survival of patients with CDKN2B methylation was notably shortened among 38 adults with AML and 12 adults with ALL.	('AML', 'Disease', (96, 99))	('shortened', 'NegReg', (65, 74))	('methylation', 'Var', (41, 52))	('CDKN2B', 'Gene', (34, 40))	('patients', 'Species', '9606', (20, 28))	('AML', 'Disease', 'MESH:D015470', (96, 99))	('Overall survival', 'MPA', (0, 16))	('CDKN2B', 'Gene', '1030', (34, 40))
410635	20196733	Aberrant p15 methylation may have important prognostic implications for clinical monitoring and risk assessment.	('methylation', 'MPA', (13, 24))	('clinical', 'Species', '191496', (72, 80))	('Aberrant', 'Var', (0, 8))	('p15', 'Protein', (9, 12))
410638	20196733	Each gene (DLC-1, PCDHGB7, CYP27B1, EFNA5, CCND1 and RAR-beta) was frequently hypermethylated in these NHLs (87, 78, 61, 53, 40 and 38%, respectively), but not in benign follicular hyperplasia.	('PCDHGB7', 'Gene', (18, 25))	('benign follicular hyperplasia', 'Disease', (163, 192))	('EFNA5', 'Gene', '1946', (36, 41))	('DLC-1', 'Gene', '10395', (11, 16))	('PCDHGB7', 'Gene', '56099', (18, 25))	('RAR-beta', 'Gene', (53, 61))	('hypermethylated', 'Var', (78, 93))	('CCND1', 'Gene', (43, 48))	('DLC-1', 'Gene', (11, 16))	('CYP27B1', 'Gene', '1594', (27, 34))	('RAR-beta', 'Gene', '5915', (53, 61))	('benign follicular hyperplasia', 'Disease', 'MESH:D011470', (163, 192))	('EFNA5', 'Gene', (36, 41))	('CCND1', 'Gene', '595', (43, 48))	('CYP27B1', 'Gene', (27, 34))	('follicular hyperplasia', 'Phenotype', 'HP:0002729', (170, 192))
410639	20196733	Although some genes such as DLC-1 and PCDHGB7 were methylated in the vast majority of NHLs, others were differentially methylated in specific subtypes.	('DLC-1', 'Gene', (28, 33))	('methylated', 'Var', (51, 61))	('NHLs', 'Disease', (86, 90))	('PCDHGB7', 'Gene', (38, 45))	('PCDHGB7', 'Gene', '56099', (38, 45))	('DLC-1', 'Gene', '10395', (28, 33))
410640	20196733	The methylation of the candidate tumor suppressor gene DLC-1 was detected in a high proportion of primary tumor and plasma DNA samples by using quantitative methylation-specific PCR analysis.	('detected', 'Reg', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('DLC-1', 'Gene', '10395', (55, 60))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (33, 38))	('DLC-1', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
410641	20196733	This promoter hypermethylation inversely correlated with DLC-1 gene expression in primary NHL samples.	('DLC-1', 'Gene', (57, 62))	('hypermethylation', 'Var', (14, 30))	('expression', 'MPA', (68, 78))	('DLC-1', 'Gene', '10395', (57, 62))	('correlated', 'Reg', (41, 51))
410643	20196733	p16INK4A methylation was found to occur in 73% of patients but in none of the healthy controls.	('methylation', 'Var', (9, 20))	('p16INK4A', 'Gene', '1029', (0, 8))	('patients', 'Species', '9606', (50, 58))	('p16INK4A', 'Gene', (0, 8))
410646	20196733	The results suggest that presence of methylated and apoptotic DNA in plasma of patients with lymphoproliferative diseases is a frequent event and may be used as a marker for early diagnosis and during the follow-up of the disease.	('DNA', 'Gene', (62, 65))	('lymphoproliferative diseases', 'Phenotype', 'HP:0005523', (93, 121))	('lymphoproliferative diseases', 'Disease', 'MESH:D008232', (93, 121))	('presence', 'Reg', (25, 33))	('lymphoproliferative diseases', 'Disease', (93, 121))	('apoptotic', 'Var', (52, 61))	('patients', 'Species', '9606', (79, 87))	('methylated', 'Var', (37, 47))
410651	32199129	Silencing lncRNA AGAP2-AS1 Upregulates miR-195-5p to Repress Migration and Invasion of EC Cells via the Decrease of FOSL1 Expression The interaction of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs has been implicated in various types of cancers, including esophageal cancer (EC).	('Expression', 'MPA', (122, 132))	('Repress', 'NegReg', (53, 60))	('AS1', 'Gene', (23, 26))	('Decrease', 'NegReg', (104, 112))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('AGAP2', 'Gene', (17, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (273, 290))	('Invasion', 'CPA', (75, 83))	('lncRNA', 'Gene', (10, 16))	('Migration', 'CPA', (61, 70))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('FOSL1', 'Gene', (116, 121))	('cancers', 'Disease', (254, 261))	('implicated', 'Reg', (223, 233))	('esophageal cancer', 'Disease', (273, 290))	('AS1', 'Gene', '5729', (23, 26))	('AGAP2', 'Gene', '116986', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('interaction', 'Interaction', (137, 148))	('FOSL1', 'Gene', '8061', (116, 121))	('miR-195', 'Gene', '406971', (39, 46))	('miR-195', 'Gene', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (254, 261))
410655	32199129	Knockdown of AGAP2-AS1 or overexpression of miR-195-5p reduced EC cell proliferation, migration, and invasion, blocked cell cycle entry, and elevated apoptosis.	('blocked', 'NegReg', (111, 118))	('elevated', 'PosReg', (141, 149))	('migration', 'CPA', (86, 95))	('reduced', 'NegReg', (55, 62))	('apoptosis', 'CPA', (150, 159))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (13, 22))	('miR-195-5p', 'Chemical', '-', (44, 54))	('miR-195-5p', 'Var', (44, 54))	('cell cycle entry', 'CPA', (119, 135))	('AGAP2-AS1', 'Gene', (13, 22))	('invasion', 'CPA', (101, 109))
410656	32199129	FOSL1 was found to be specifically targeted by miR-195-5p.	('miR-195-5p', 'Var', (47, 57))	('FOSL1', 'Gene', (0, 5))	('miR-195-5p', 'Chemical', '-', (47, 57))
410657	32199129	AGAP2-AS1 was observed to upregulate FOSL1 by binding to miR-195-5p.	('miR-195-5p', 'Chemical', '-', (57, 67))	('upregulate', 'PosReg', (26, 36))	('miR-195-5p', 'Var', (57, 67))	('FOSL1', 'Gene', (37, 42))	('binding', 'Interaction', (46, 53))	('AGAP2-AS1', 'Gene', (0, 9))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (0, 9))
410658	32199129	Silencing of AGAP2-AS1 was observed to restrain the development of EC both in vitro and in vivo through upregulating miR-195-5p and downregulating FOSL1.	('FOSL1', 'Gene', (147, 152))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (13, 22))	('upregulating', 'PosReg', (104, 116))	('downregulating', 'NegReg', (132, 146))	('restrain', 'NegReg', (39, 47))	('miR-195-5p', 'Chemical', '-', (117, 127))	('Silencing', 'Var', (0, 9))	('development of', 'CPA', (52, 66))	('AGAP2-AS1', 'Gene', (13, 22))	('miR-195-5p', 'Var', (117, 127))
410659	32199129	Taken together, AGAP2-AS1 knockdown exercises suppressive effects on the development of EC through miR-195-5p-dependent downregulation of FOSL1.	('miR-195-5p-dependent', 'Var', (99, 119))	('downregulation', 'NegReg', (120, 134))	('FOSL1', 'Gene', (138, 143))	('suppressive', 'NegReg', (46, 57))	('miR-195-5p', 'Chemical', '-', (99, 109))	('AGAP2-AS1', 'Gene', (16, 25))	('knockdown', 'Var', (26, 35))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (16, 25))	('development of', 'CPA', (73, 87))
410665	32199129	High expression of AGAP2-AS1 has been identified in gastric cancer and non-small-cell lung cancer, suggesting that knockdown of AGAP2-AS1 leads to a decrease in cell proliferation and migration, along with the repression of invasion and tumorigenesis.	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('decrease', 'NegReg', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('knockdown', 'Var', (115, 124))	('AGAP2-AS1', 'Gene', (19, 28))	('cell proliferation', 'CPA', (161, 179))	('invasion', 'CPA', (224, 232))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (128, 137))	('non-small-cell lung cancer', 'Disease', (71, 97))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (71, 97))	('gastric cancer', 'Disease', (52, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))	('tumor', 'Disease', (237, 242))	('AGAP2-AS1', 'Gene', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (19, 28))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
410669	32199129	The association between increased FOSL1 expression and ESCC has been investigated, and the silencing of FOSL1 has been reported to have inhibitory effects on cell proliferation and invasion and confer protection against the cytotoxicity of cisplatin in ESCC cells.	('cisplatin', 'Chemical', 'MESH:D002945', (240, 249))	('inhibitory', 'NegReg', (136, 146))	('cytotoxicity', 'Disease', 'MESH:D064420', (224, 236))	('cell proliferation', 'CPA', (158, 176))	('FOSL1', 'Gene', (104, 109))	('cytotoxicity', 'Disease', (224, 236))	('invasion', 'CPA', (181, 189))	('ESCC', 'Disease', (55, 59))	('silencing', 'Var', (91, 100))	('protection', 'NegReg', (201, 211))
410670	32199129	It was presumed that there were putative binding sites between miR-195-5p and FOSL1 based on the miRNA-mRNA interaction analysis from the StarBase website, as well as putative binding sites between miR-195-5p and AGAP2-AS1 through lncRNA-miRNA interaction prediction by the StarBase and RAID databases.	('miR-195-5p', 'Chemical', '-', (198, 208))	('miR-195-5p', 'Chemical', '-', (63, 73))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (213, 222))	('binding', 'Interaction', (41, 48))	('miR-195-5p', 'Var', (198, 208))	('RAID', 'Disease', '-', (287, 291))	('RAID', 'Disease', (287, 291))	('binding', 'Interaction', (176, 183))	('FOSL1', 'Gene', (78, 83))	('miR-195-5p', 'Gene', (63, 73))	('AGAP2-AS1', 'Gene', (213, 222))
410671	32199129	As discussed above, we hypothesized that AGAP2-AS1 plays a critical role in EC development with the implication of miR-195-5p and FOSL1.	('miR-195-5p', 'Var', (115, 125))	('AGAP2-AS1', 'Gene', (41, 50))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (41, 50))	('FOSL1', 'Gene', (130, 135))	('miR-195-5p', 'Chemical', '-', (115, 125))
410674	32199129	The existing literature has suggested that miR-195-5p plays an anti-oncogenic role in a variety of cancers, including non-small-cell lung cancer, colorectal cancer, and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('miR-195-5p', 'Chemical', '-', (43, 53))	('miR-195-5p', 'Var', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('non-small-cell lung cancer', 'Disease', (118, 144))	('gastric cancer', 'Disease', (169, 183))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('colorectal cancer', 'Disease', (146, 163))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
410680	32199129	Next, in order to evaluate the detailed effects associated with miR-195-5p on EC cells, the expression of miR-195-5p was altered in KYSE70 cells.	('altered', 'Reg', (121, 128))	('miR-195-5p', 'Chemical', '-', (64, 74))	('miR-195-5p', 'Chemical', '-', (106, 116))	('miR-195-5p', 'Var', (106, 116))	('expression', 'MPA', (92, 102))
410682	32199129	The proliferation (Figure 2B), migration, and invasion (Figure 2C) along with cell cycle and apoptosis (Figures 2D and 2E) of the KYSE70 cells were also examined in response to transfection with miR-195-5p mimic or inhibitor.	('miR-195-5p', 'Chemical', '-', (195, 205))	('miR-195-5p mimic', 'Var', (195, 211))	('invasion', 'CPA', (46, 54))
410683	32199129	When miR-195-5p expression was restored in the KYSE70 cells, cell proliferation, migration, and invasion were reduced.	('reduced', 'NegReg', (110, 117))	('miR-195-5p', 'Chemical', '-', (5, 15))	('invasion', 'CPA', (96, 104))	('miR-195-5p expression', 'Var', (5, 26))	('migration', 'CPA', (81, 90))	('cell proliferation', 'CPA', (61, 79))
410684	32199129	In contrast, inhibition of miR-195-5p elevated KYSE70 cell proliferation, migration, and invasion.	('inhibition', 'Var', (13, 23))	('invasion', 'CPA', (89, 97))	('migration', 'CPA', (74, 83))	('miR-195-5p', 'Chemical', '-', (27, 37))	('KYSE70 cell proliferation', 'CPA', (47, 72))	('miR-195-5p', 'Protein', (27, 37))	('elevated', 'PosReg', (38, 46))
410685	32199129	Following overexpression of miR-195-5p, the proportion of KYSE70 cells at the G0/G1 phase was elevated while the proportion at the S phase was reduced, suggesting an inhibited cell cycle progression, while an opposite trend was observed whereby the cell cycle progression was enhanced after inhibition of miR-195-5p.	('elevated', 'PosReg', (94, 102))	('cell cycle progression', 'CPA', (176, 198))	('miR-195-5p', 'Chemical', '-', (305, 315))	('KYSE70', 'Var', (58, 64))	('cell cycle progression', 'CPA', (249, 271))	('miR-195-5p', 'Chemical', '-', (28, 38))	('miR-195-5p', 'Var', (28, 38))	('enhanced', 'PosReg', (276, 284))	('inhibited', 'NegReg', (166, 175))	('reduced', 'NegReg', (143, 150))
410686	32199129	Additionally, upregulation of miR-195-5p was found to notably enhance KYSE70 cell apoptosis, while the miR-195-5p inhibitor decreased KYSE70 cell apoptosis.	('enhance', 'PosReg', (62, 69))	('KYSE70 cell apoptosis', 'CPA', (70, 91))	('decreased', 'NegReg', (124, 133))	('miR-195-5p', 'Var', (30, 40))	('miR-195-5p', 'Chemical', '-', (30, 40))	('miR-195-5p', 'Chemical', '-', (103, 113))	('upregulation', 'PosReg', (14, 26))
410687	32199129	Taken together, these results indicate that miR-195-5p inhibits the proliferation and migration of EC cells, while enhancing the apoptosis of EC cells.	('proliferation', 'CPA', (68, 81))	('migration', 'CPA', (86, 95))	('apoptosis', 'CPA', (129, 138))	('inhibits', 'NegReg', (55, 63))	('miR-195-5p', 'Chemical', '-', (44, 54))	('miR-195-5p', 'Var', (44, 54))	('enhancing', 'PosReg', (115, 124))
410689	32199129	The target genes were intersected with EC-related genes in GEO: GSE45670, which identified 18 intersection genes (FOSL1, CHEK1, E2F7, BCL11B, SALL1, CCNE1, SALL4, CDC25A, ATP13A3, TENM2, HOXA10, ANLN, EN2, PLAG1, EPB41L4B, CASK, AMMECR1, APLN) that were overexpressed in EC and could potentially be regulated by miR-195-5p (Figure 3A).	('HOXA10', 'Gene', (187, 193))	('EPB41L4B', 'Gene', (213, 221))	('ANLN', 'Gene', '54443', (195, 199))	('PLAG1', 'Gene', (206, 211))	('E2F7', 'Gene', '144455', (128, 132))	('APLN', 'Gene', (238, 242))	('CHEK1', 'Gene', (121, 126))	('EN2', 'Gene', (201, 204))	('BCL11B', 'Gene', '64919', (134, 140))	('CCNE1', 'Gene', (149, 154))	('BCL11B', 'Gene', (134, 140))	('SALL4', 'Gene', '57167', (156, 161))	('ANLN', 'Gene', (195, 199))	('TENM2', 'Gene', '57451', (180, 185))	('SALL1', 'Gene', '6299', (142, 147))	('miR-195-5p', 'Chemical', '-', (312, 322))	('miR-195-5p', 'Var', (312, 322))	('HOXA10', 'Gene', '3206', (187, 193))	('PLAG1', 'Gene', '5324', (206, 211))	('CCNE1', 'Gene', '898', (149, 154))	('CASK', 'Gene', '8573', (223, 227))	('SALL1', 'Gene', (142, 147))	('CASK', 'Gene', (223, 227))	('EN2', 'Gene', '2020', (201, 204))	('SALL4', 'Gene', (156, 161))	('E2F7', 'Gene', (128, 132))	('ATP13A3', 'Gene', (171, 178))	('CDC25A', 'Gene', '993', (163, 169))	('APLN', 'Gene', '8862', (238, 242))	('AMMECR1', 'Gene', '9949', (229, 236))	('CHEK1', 'Gene', '1111', (121, 126))	('ATP13A3', 'Gene', '79572', (171, 178))	('AMMECR1', 'Gene', (229, 236))	('TENM2', 'Gene', (180, 185))	('EPB41L4B', 'Gene', '54566', (213, 221))	('CDC25A', 'Gene', (163, 169))
410692	32199129	Based on the miR-195-5p binding sites on FOSL1 predicted by StarBase, we mutated the binding sites for miR-195-5p on FOSL1 3' untranslated region (UTR) and constructed wild-type (pGL3-FOSL1-3' UTR) and mutant (pGL3-FOSL1-3' UTR-MUT) luciferase reporter gene plasmids.	('pGL3', 'Gene', '6391', (179, 183))	('pGL3', 'Gene', '6391', (210, 214))	('miR-195-5p', 'Chemical', '-', (13, 23))	('miR-195-5p', 'Chemical', '-', (103, 113))	('pGL3', 'Gene', (179, 183))	('pGL3', 'Gene', (210, 214))	('mutant', 'Var', (202, 208))
410693	32199129	The luciferase activity of pGL3-FOSL1-3' UTR was significantly decreased in the cells co-transfected with miR-195-5p mimic (p < 0.05), while the luciferase activity of pGL3-FOSL1-3' UTR-MUT exhibited no significant change between co-transfection with miR-195-5p mimic and negative control (NC)-mimic (p > 0.05; Figure 3G), indicating that FOSL1 was indeed a target gene of miR-195-5p.	('pGL3', 'Gene', (168, 172))	('pGL3', 'Gene', '6391', (27, 31))	('decreased', 'NegReg', (63, 72))	('pGL3', 'Gene', '6391', (168, 172))	('activity', 'MPA', (15, 23))	('miR-195-5p', 'Chemical', '-', (373, 383))	('miR-195-5p', 'Chemical', '-', (251, 261))	('miR-195-5p', 'Var', (106, 116))	('miR-195-5p', 'Chemical', '-', (106, 116))	('luciferase', 'Enzyme', (4, 14))	('pGL3', 'Gene', (27, 31))
410694	32199129	Next, the expression of FOSL1 was determined in the KYSE70 cells transfected with miR-195-5p mimic or miR-195-5p inhibitor.	('FOSL1', 'Gene', (24, 29))	('miR-195-5p mimic', 'Var', (82, 98))	('miR-195-5p inhibitor', 'Var', (102, 122))	('miR-195-5p', 'Chemical', '-', (82, 92))	('miR-195-5p', 'Chemical', '-', (102, 112))
410695	32199129	The results illustrated that the expression of FOSL1 was significantly decreased in the EC cells transfected with miR-195-5p mimic, but increased in EC cells transfected with miR-195-5p inhibitor (Figure 3H).	('miR-195-5p', 'Chemical', '-', (114, 124))	('miR-195-5p', 'Chemical', '-', (175, 185))	('expression', 'MPA', (33, 43))	('increased', 'PosReg', (136, 145))	('miR-195-5p mimic', 'Var', (114, 130))	('FOSL1', 'Gene', (47, 52))	('decreased', 'NegReg', (71, 80))
410696	32199129	Hence, we concluded that FOSL1 was a target gene of miR-195-5p and was an upregulated gene in EC.	('FOSL1', 'Gene', (25, 30))	('miR-195-5p', 'Chemical', '-', (52, 62))	('miR-195-5p', 'Var', (52, 62))	('upregulated', 'PosReg', (74, 85))
410699	32199129	The proliferation, migration, and invasion of EC cells co-transfected with miR-195-5p mimic and oe-FOSL1 were decreased when compared with those co-transfected with NC-mimic and oe-FOSL1 (p < 0.05).	('proliferation', 'CPA', (4, 17))	('miR-195-5p', 'Chemical', '-', (75, 85))	('miR-195-5p mimic', 'Var', (75, 91))	('migration', 'CPA', (19, 28))	('decreased', 'NegReg', (110, 119))	('invasion', 'CPA', (34, 42))	('oe-FOSL1', 'Var', (96, 104))
410700	32199129	The proportion of G0/G1 phase cells co-transfected with miR-195-5p mimic and oe-FOSL1 was significantly increased but that at the S phase was reduced when compared with that of cells co-transfected with NC-mimic and oe-FOSL1 (p < 0.05).	('increased', 'PosReg', (104, 113))	('reduced', 'NegReg', (142, 149))	('oe-FOSL1', 'Var', (77, 85))	('miR-195-5p', 'Chemical', '-', (56, 66))	('miR-195-5p mimic', 'Var', (56, 72))	('G0/G1 phase cells', 'CPA', (18, 35))
410701	32199129	The apoptosis ability of EC cells co-transfected with miR-195-5p mimic and oe-FOSL1 was higher than that for EC cells co-transfected with NC-mimic and oe-FOSL1 (p < 0.05).	('higher', 'PosReg', (88, 94))	('miR-195-5p mimic', 'Var', (54, 70))	('miR-195-5p', 'Chemical', '-', (54, 64))	('oe-FOSL1', 'Var', (75, 83))	('apoptosis ability', 'CPA', (4, 21))
410702	32199129	Therefore, miR-195-5p inhibited proliferation, migration, and invasion and promoted apoptosis of EC cells through targeting FOSL1.	('inhibited', 'NegReg', (22, 31))	('apoptosis', 'CPA', (84, 93))	('promoted', 'PosReg', (75, 83))	('FOSL1', 'Gene', (124, 129))	('migration', 'CPA', (47, 56))	('proliferation', 'CPA', (32, 45))	('invasion', 'CPA', (62, 70))	('miR-195-5p', 'Chemical', '-', (11, 21))	('targeting', 'Reg', (114, 123))	('miR-195-5p', 'Var', (11, 21))
410703	32199129	lncRNAs that possess the potential of binding to miR-195-5p were predicted based on the databases RAID and StarBase.	('RAID', 'Disease', (98, 102))	('miR-195-5p', 'Var', (49, 59))	('binding', 'Interaction', (38, 45))	('RAID', 'Disease', '-', (98, 102))	('miR-195-5p', 'Chemical', '-', (49, 59))
410710	32199129	As shown in Figure 5G, the luciferase activity of pGL3-AGAP2-AS1 was obviously decreased in the cells co-transfected with miR-195-5p mimic when compared with the cells co-transfected with NC-mimic (p < 0.05), while the luciferase activity of pGL3-AGAP2-AS1-MUT exhibited no significant change (p > 0.05).	('activity', 'MPA', (38, 46))	('decreased', 'NegReg', (79, 88))	('miR-195-5p mimic', 'Var', (122, 138))	('AGAP2-AS1', 'Gene', (55, 64))	('pGL3', 'Gene', (50, 54))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (247, 256))	('miR-195-5p', 'Chemical', '-', (122, 132))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (55, 64))	('pGL3', 'Gene', (242, 246))	('pGL3', 'Gene', '6391', (50, 54))	('luciferase', 'Enzyme', (27, 37))	('pGL3', 'Gene', '6391', (242, 246))	('AGAP2-AS1', 'Gene', (247, 256))
410711	32199129	An RNA immunoprecipitation (RIP) assay was then performed, which illustrated that the levels of AGAP2-AS1 and miR-195-5p were significantly higher when precipitated with Ago2 than with immunoglobulin G (IgG) (p < 0.05; Figure 5H).	('miR-195-5p', 'Chemical', '-', (110, 120))	('AGAP2-AS1', 'Gene', (96, 105))	('miR-195-5p', 'Var', (110, 120))	('levels', 'MPA', (86, 92))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (96, 105))	('higher', 'PosReg', (140, 146))
410717	32199129	The expression of miR-195-5p was significantly increased, while FOSL1 expression was significantly decreased in the EC cells following the silencing of AGAP2-AS1, which was reversed by co-transfection with miR-195-5p mimic (Figures 5K and 5L).	('miR-195-5p', 'Gene', (18, 28))	('miR-195-5p', 'Chemical', '-', (18, 28))	('AGAP2-AS1', 'Gene', (152, 161))	('FOSL1', 'Gene', (64, 69))	('decreased', 'NegReg', (99, 108))	('expression', 'MPA', (4, 14))	('silencing', 'Var', (139, 148))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (152, 161))	('increased', 'PosReg', (47, 56))	('expression', 'MPA', (70, 80))	('miR-195-5p', 'Chemical', '-', (206, 216))
410720	32199129	After AGAP2-AS1 was silenced, the proliferation, migration, and invasion of KYSE70 cells were significantly decreased, which could be rescued by inhibition of miR-195-5p or overexpression of FOSL1.	('silenced', 'Var', (20, 28))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (6, 15))	('migration', 'CPA', (49, 58))	('decreased', 'NegReg', (108, 117))	('AGAP2-AS1', 'Gene', (6, 15))	('invasion of KYSE70 cells', 'CPA', (64, 88))	('miR-195-5p', 'Chemical', '-', (159, 169))
410721	32199129	The proportion of cells at the G0/G1 phase was significantly elevated, while the proportion of cells at the S phase was decreased along with promoted apoptosis after sh-AGAP2-AS1 transfection, all of which was reversed by the co-transfection with either miR-195-5p inhibitor or oe-FOSL1.	('decreased', 'NegReg', (120, 129))	('AGAP2-AS1', 'Gene', (169, 178))	('apoptosis', 'CPA', (150, 159))	('transfection', 'Var', (179, 191))	('elevated', 'PosReg', (61, 69))	('miR-195-5p', 'Chemical', '-', (254, 264))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (169, 178))	('G0/G1 phase', 'CPA', (31, 42))
410724	32199129	The results revealed that the tumor volume and weight were reduced in mice after silencing AGAP2-AS1.	('reduced', 'NegReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mice', 'Species', '10090', (70, 74))	('silencing', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('AGAP2-AS1', 'Gene', (91, 100))	('tumor', 'Disease', (30, 35))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (91, 100))
410725	32199129	In contrast, the reduced tumor volume and weight induced by AGAP2-AS1 silencing was counteracted following overexpression of FOSL1 (Figures 7A-7C).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (60, 69))	('silencing', 'Var', (70, 79))	('tumor', 'Disease', (25, 30))	('AGAP2-AS1', 'Gene', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('reduced', 'NegReg', (17, 24))
410726	32199129	Hence, silencing of AGAP2-AS1 suppressed in vivo tumorigenesis through downregulating FOSL1.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('FOSL1', 'Gene', (86, 91))	('suppressed', 'NegReg', (30, 40))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (20, 29))	('tumor', 'Disease', (49, 54))	('downregulating', 'NegReg', (71, 85))	('AGAP2-AS1', 'Gene', (20, 29))	('silencing', 'Var', (7, 16))
410729	32199129	Alteration of lncRNAs has been implicated in multiple malignant tumors, including EC.	('implicated', 'Reg', (31, 41))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Alteration', 'Var', (0, 10))	('malignant tumors', 'Disease', 'MESH:D018198', (54, 70))	('malignant tumors', 'Disease', (54, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('lncRNAs', 'Gene', (14, 21))
410731	32199129	Our findings identified that AGAP2-AS1 binds to miR-195-5p to induce cell proliferation, invasion, and migration and suppress cell cycle arrest as well as apoptosis in EC via upregulation of FOSL1, providing a novel insight into the molecular mechanism by which AGAP2-AS1 influences EC progression.	('arrest', 'Disease', (137, 143))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (126, 143))	('AGAP2-AS1', 'Gene', (29, 38))	('influences', 'Reg', (272, 282))	('induce', 'PosReg', (62, 68))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (262, 271))	('AGAP2-AS1', 'Gene', (262, 271))	('invasion', 'CPA', (89, 97))	('cell proliferation', 'CPA', (69, 87))	('FOSL1', 'Gene', (191, 196))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (29, 38))	('upregulation', 'PosReg', (175, 187))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('miR-195-5p', 'Chemical', '-', (48, 58))	('miR-195-5p', 'Var', (48, 58))	('apoptosis', 'CPA', (155, 164))	('suppress', 'NegReg', (117, 125))	('migration', 'CPA', (103, 112))
410737	32199129	In glioblastoma multiforme, cell proliferation, migration, and invasion are also decreased and cell apoptosis is increased following silencing of AGAP2-AS1.	('decreased', 'NegReg', (81, 90))	('migration', 'CPA', (48, 57))	('AGAP2-AS1', 'Gene', (146, 155))	('cell apoptosis', 'CPA', (95, 109))	('cell proliferation', 'CPA', (28, 46))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (146, 155))	('silencing', 'Var', (133, 142))	('invasion', 'CPA', (63, 71))	('glioblastoma multiforme', 'Disease', (3, 26))	('increased', 'PosReg', (113, 122))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (3, 26))
410738	32199129	The literature has highlighted the critical role of the balance of the lncRNA-miRNA-mRNA regulatory network in many biological processes, and any disturbance of the ceRNA network may lead to different diseases, including cancers.	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancers', 'Disease', (221, 228))	('lncRNA-miRNA-mRNA regulatory network', 'MPA', (71, 107))	('disturbance', 'Var', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('lead to', 'Reg', (183, 190))	('diseases', 'Disease', (201, 209))
410740	32199129	Our current results further demonstrated that AGAP2-AS1 could bind to miR-195-5p in EC.	('bind', 'Interaction', (62, 66))	('AGAP2-AS1', 'Gene', (46, 55))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (46, 55))	('miR-195-5p', 'Chemical', '-', (70, 80))	('miR-195-5p', 'Var', (70, 80))
410741	32199129	A previous report clarified the binding relationship between lncRNA XIST and miR-195-5p, which promotes cell proliferation and invasion in osteosarcoma cancer.	('XIST', 'Gene', '7503', (68, 72))	('miR-195-5p', 'Chemical', '-', (77, 87))	('osteosarcoma cancer', 'Disease', (139, 158))	('XIST', 'Gene', (68, 72))	('invasion', 'CPA', (127, 135))	('cell proliferation', 'CPA', (104, 122))	('miR-195-5p', 'Var', (77, 87))	('binding', 'Interaction', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('osteosarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('osteosarcoma cancer', 'Disease', 'MESH:D012516', (139, 158))	('promotes', 'PosReg', (95, 103))
410742	32199129	In addition, we found the aberrant downregulation of miR-195-5p in EC cells.	('miR-195-5p', 'Chemical', '-', (53, 63))	('miR-195-5p', 'Var', (53, 63))	('downregulation', 'NegReg', (35, 49))
410743	32199129	Also, repression of EC cell proliferation, migration, and invasion along with promoted apoptosis were all triggered by the overexpression of miR-195-5p.	('miR-195-5p', 'Var', (141, 151))	('EC cell proliferation', 'CPA', (20, 41))	('overexpression', 'PosReg', (123, 137))	('apoptosis', 'CPA', (87, 96))	('invasion', 'CPA', (58, 66))	('migration', 'CPA', (43, 52))	('repression', 'NegReg', (6, 16))	('miR-195-5p', 'Chemical', '-', (141, 151))
410746	32199129	The repressive role of miR-195-5p in cell proliferation, invasion, and migration has been consistently documented in oral squamous cell carcinoma.	('invasion', 'CPA', (57, 65))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 145))	('miR-195-5p', 'Chemical', '-', (23, 33))	('migration', 'CPA', (71, 80))	('miR-195-5p', 'Var', (23, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('oral squamous cell carcinoma', 'Disease', (117, 145))	('cell proliferation', 'CPA', (37, 55))
410747	32199129	Our data further provided evidence indicating that AGAP2-AS1 exerted a tumor promotive role by binding to miR-195-5p.	('AGAP2-AS1', 'Gene', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('binding', 'Interaction', (95, 102))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('miR-195-5p', 'Chemical', '-', (106, 116))	('miR-195-5p', 'Var', (106, 116))	('tumor', 'Disease', (71, 76))
410748	32199129	Through a similar mechanism, lncRNA SNHG1 binds to miR-195-5p to enhance the proliferative and migratory capabilities of hepatocellular carcinoma cells.	('miR-195-5p', 'Var', (51, 61))	('binds', 'Interaction', (42, 47))	('enhance', 'PosReg', (65, 72))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (121, 145))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('hepatocellular carcinoma', 'Disease', (121, 145))	('SNHG1', 'Gene', '23642', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('SNHG1', 'Gene', (36, 41))	('miR-195-5p', 'Chemical', '-', (51, 61))
410749	32199129	In our study, we identified that FOSL1 was a target gene of miR-195-5p and was negatively regulated by miR-195-5p, which was similarly reported by a prior study that concluded that miR-195-5p directly targets FOSL1 to inhibit cell migration and invasion in prostate cancer.	('FOSL1', 'Gene', (209, 214))	('prostate cancer', 'Phenotype', 'HP:0012125', (257, 272))	('inhibit', 'NegReg', (218, 225))	('miR-195-5p', 'Chemical', '-', (60, 70))	('miR-195-5p', 'Var', (60, 70))	('miR-195-5p', 'Chemical', '-', (181, 191))	('prostate cancer', 'Disease', (257, 272))	('FOSL1', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('miR-195-5p', 'Chemical', '-', (103, 113))	('miR-195-5p', 'Var', (103, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (257, 272))
410752	32199129	As suggested in vitro, miR-195-5p directly targeted FOSL1 to inhibit EC progression.	('FOSL1', 'Gene', (52, 57))	('miR-195-5p', 'Chemical', '-', (23, 33))	('EC progression', 'CPA', (69, 83))	('inhibit', 'NegReg', (61, 68))	('miR-195-5p', 'Var', (23, 33))
410753	32199129	Moreover, the in vivo experiments confirmed that silencing AGAP2-AS1 functioned to suppress tumor growth through inhibition of FOSL1.	('silencing', 'Var', (49, 58))	('FOSL1', 'Gene', (127, 132))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('inhibition', 'NegReg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('AGAP2-AS1', 'Gene', (59, 68))	('suppress', 'NegReg', (83, 91))
410755	32199129	Silencing of AGAP2-AS1 increased miR-195-5p expression to downregulate FOSL1, ultimately suppressing cell proliferation, migration, and invasion while inducing cell cycle arrest and apoptosis in EC (Figure 8).	('migration', 'CPA', (121, 130))	('miR-195-5p', 'Chemical', '-', (33, 43))	('inducing', 'Reg', (151, 159))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (160, 177))	('suppressing', 'NegReg', (89, 100))	('miR-195-5p expression', 'MPA', (33, 54))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (13, 22))	('invasion', 'CPA', (136, 144))	('apoptosis', 'CPA', (182, 191))	('arrest', 'Disease', 'MESH:D006323', (171, 177))	('increased', 'PosReg', (23, 32))	('downregulate', 'NegReg', (58, 70))	('FOSL1', 'Gene', (71, 76))	('AGAP2-AS1', 'Gene', (13, 22))	('Silencing', 'Var', (0, 9))	('cell proliferation', 'CPA', (101, 119))	('arrest', 'Disease', (171, 177))
410768	32199129	The EC cells were transfected with the following sequences or plasmids: shRNA against AGAP2-AS1 (sh-AGAP2-AS1), miR-195-5p mimic, miR-195-5p inhibitor, and FOSL1 overexpression plasmid (oe-FOSL1) as well as corresponding negative controls (sh-NC, oe-NC, NC-mimic, and NC-inhibitor).	('AGAP2-AS1', 'Gene', (86, 95))	('AGAP2-AS1', 'Gene', (100, 109))	('miR-195-5p', 'Chemical', '-', (112, 122))	('miR-195-5p', 'Var', (112, 122))	('miR-195-5p', 'Chemical', '-', (130, 140))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (100, 109))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (86, 95))	('overexpression', 'PosReg', (162, 176))
410771	32199129	The expression of miR-195-5p was normalized to the housekeeping gene U6, while the expression of other genes was normalized to housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH).	('miR-195-5p', 'Chemical', '-', (18, 28))	('miR-195-5p', 'Var', (18, 28))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (145, 185))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (145, 185))
410775	32199129	The membrane was then blocked using 5% skimmed milk at 37 C for 1 h, followed by membrane incubation at 4 C overnight with the primary rabbit polyclonal antibodies to FOSL1 (ab232745, 1:1,000) or GAPDH (ab9485, 1:2,500).	('rabbit', 'Species', '9986', (135, 141))	('GAPDH', 'Gene', (196, 201))	('ab232745', 'Var', (174, 182))	('FOSL1', 'Gene', (167, 172))	('ab9485', 'Var', (203, 209))
410782	32199129	Using the liposome transfection method, recombinant plasmids (pGL3-AGAP2-AS1, pGL3-AGAP2-AS1-MUT, pGL3-FOSL1-3' UTR, pGL3-FOSL1-3' UTR-MUT) and Renilla reference plasmid were respectively co-transfected with miR-195-5p mimic or NC-mimic into HEK293T cells.	('pGL3', 'Gene', (62, 66))	('miR-195-5p', 'Chemical', '-', (208, 218))	('miR-195-5p mimic', 'Var', (208, 224))	('pGL3', 'Gene', '6391', (98, 102))	('HEK293T', 'CellLine', 'CVCL:0063;0.13669791703184006', (242, 249))	('pGL3', 'Gene', (117, 121))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (83, 92))	('pGL3', 'Gene', '6391', (117, 121))	('pGL3', 'Gene', '6391', (62, 66))	('AGAP2-AS1', 'Gene', (67, 76))	('pGL3', 'Gene', (78, 82))	('pGL3', 'Gene', (98, 102))	('AGAP2-AS1', 'Gene', '100130776;116986;5729', (67, 76))	('pGL3', 'Gene', '6391', (78, 82))	('AGAP2-AS1', 'Gene', (83, 92))
410835	31912332	As for cT stage, the proportion of patients with cT1a, cT2, cT3 and cT4a was larger in the 50.4 Gy group, whereas the proportion of patients with cT1b and cT4b was larger in the 60 Gy group (p = 0.0001).	('cT2', 'Gene', (55, 58))	('50.4 Gy', 'Var', (91, 98))	('cT3', 'Gene', '285782', (60, 63))	('patients', 'Species', '9606', (35, 43))	('cT3', 'Gene', (60, 63))	('patients', 'Species', '9606', (132, 140))	('cT2', 'Gene', '386757', (55, 58))
410836	31912332	The numbers of patients with T1aN0M0 and T1bN0M0 in cStage I were 7 (4.1%) and 15 (8.8%) in the 50.4 Gy group and 29 (3.5%) and 134 (16.2%) in the 60 Gy group, respectively.	('T1aN0M0', 'Var', (29, 36))	('patients', 'Species', '9606', (15, 23))	('T1bN0M0', 'Var', (41, 48))
410847	31912332	With regard to the reason why there was no statistically significant difference in OS between the two dose groups, it is possible that patients in the 50.4 Gy group had less treatment-related toxicities, which could not be confirmed precisely in the registry that we used for analysis.	('patients', 'Species', '9606', (135, 143))	('less', 'NegReg', (169, 173))	('OS', 'Chemical', '-', (83, 85))	('toxicities', 'Disease', 'MESH:D064420', (192, 202))	('50.4 Gy', 'Var', (151, 158))	('toxicities', 'Disease', (192, 202))
410869	31380608	Additionally, our recent study of two U.S. cohort studies reported that overweight in early adulthood and weight gain in later life were associated with increased EA and GCA risks.	('overweight', 'Var', (72, 82))	('weight gain', 'Disease', 'MESH:D015430', (106, 117))	('weight gain', 'Phenotype', 'HP:0004324', (106, 117))	('overweight', 'Phenotype', 'HP:0025502', (72, 82))	('GCA', 'Gene', '25801', (170, 173))	('GCA', 'Gene', (170, 173))	('weight gain', 'Disease', (106, 117))
410889	31380608	As there were suggestions of non-linearity of the association between BMI z-score and EA/GCA, men were categorized as having a normal weight or overweight at 7 and 13 years and in early adulthood (i.e., conscription).	('men', 'Species', '9606', (94, 97))	('overweight', 'Phenotype', 'HP:0025502', (144, 154))	('BMI', 'Gene', (70, 73))	('z-score', 'Var', (74, 81))	('EA/GCA', 'Gene', (86, 92))	('EA/GCA', 'Gene', '25801', (86, 92))
410907	31380608	Overweight in childhood was associated with a 2-times increased risk of EA/GCA at both ages 7 (HR=2.36, 95% CI: 1.42-3.92) and 13 years (HR=1.77, 95% CI: 1.15-2.71; Table 2).	('Overweight', 'Var', (0, 10))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('child', 'Species', '9606', (14, 19))	('EA/GCA', 'Gene', (72, 78))	('EA/GCA', 'Gene', '25801', (72, 78))
410908	31380608	In early adulthood, overweight was associated with a 2-times increased risk of EA (HR=2.11, 95% CI: 1.33-3.33) but not GCA (HR=0.91, 95% CI: 0.46-1.79), resulting in a 50% increased risk of EA/GCA combined (HR=1.52, 95% CI: 1.05-2.22).	('EA/GCA', 'Gene', (190, 196))	('overweight', 'Var', (20, 30))	('overweight', 'Phenotype', 'HP:0025502', (20, 30))	('GCA', 'Gene', '25801', (193, 196))	('GCA', 'Gene', (193, 196))	('GCA', 'Gene', '25801', (119, 122))	('GCA', 'Gene', (119, 122))	('EA/GCA', 'Gene', '25801', (190, 196))
410911	31380608	Similar results were observed when we examined the associations between a one-unit increase in BMI z-score and EA/GCA (Supplemental Table S3).	('increase', 'PosReg', (83, 91))	('men', 'Species', '9606', (125, 128))	('z-score', 'Var', (99, 106))	('EA/GCA', 'Gene', '25801', (111, 117))	('EA/GCA', 'Gene', (111, 117))	('increase in BMI', 'Phenotype', 'HP:0031418', (83, 98))	('BMI', 'Gene', (95, 98))
410939	31380608	Another hypothesis is that dysfunctional adipose tissue may lead to metabolic sequelae, such as glucose intolerance, hypertension, metabolic syndrome, or chronic, low-grade inflammation.	('inflammation', 'Disease', 'MESH:D007249', (173, 185))	('lead to', 'Reg', (60, 67))	('metabolic syndrome', 'Disease', 'MESH:D008659', (131, 149))	('glucose intolerance', 'Phenotype', 'HP:0001952', (96, 115))	('metabolic syndrome', 'Disease', (131, 149))	('inflammation', 'Disease', (173, 185))	('dysfunctional', 'Var', (27, 40))	('hypertension', 'Disease', 'MESH:D006973', (117, 129))	('metabolic', 'MPA', (68, 77))	('glucose intolerance', 'Disease', 'MESH:D018149', (96, 115))	('glucose intolerance', 'Disease', (96, 115))	('hypertension', 'Disease', (117, 129))	('hypertension', 'Phenotype', 'HP:0000822', (117, 129))
410949	31380608	However, in early adulthood, overweight was associated with a 2-times increased risk of EA but not GCA.	('GCA', 'Gene', '25801', (99, 102))	('overweight', 'Var', (29, 39))	('GCA', 'Gene', (99, 102))	('overweight', 'Phenotype', 'HP:0025502', (29, 39))
410984	30228821	In addition, 39 individual DEGs demonstrated a minimum 2-fold copy number-associated expression change (median: 5.35, 95% CI: 4.53-16.98) and Pearson's correlation coefficient >= 0.6 (p < 0.05), of which PTP4A3 showed the highest correlation (CNV-FC = 21362.13; Pearson's correlation coefficient = 0.9983; p = 0.037).	('PTP4A3', 'Gene', (204, 210))	('expression', 'MPA', (85, 95))	('copy number-associated', 'Var', (62, 84))	('PTP4A3', 'Gene', '11156', (204, 210))
411009	30228821	There appears to be a higher occurrence of mutations in the PTEN gene (36.84%) in patients of Chinese ethnicity with SCEC in contrast to EGFR, KARS, or PIK3CA mutations.	('EGFR', 'Gene', (137, 141))	('PIK3CA', 'Gene', '5290', (152, 158))	('KARS', 'Gene', (143, 147))	('PTEN', 'Gene', (60, 64))	('mutations', 'Var', (43, 52))	('KARS', 'Gene', '3735', (143, 147))	('EGFR', 'Gene', '1956', (137, 141))	('PIK3CA', 'Gene', (152, 158))	('SCEC', 'Disease', (117, 121))
411020	30018747	However, recent progress in next-generation sequencing has enabled non-small cell lung cancer (NSCLC) patients with specific genomic alterations to benefit from molecular targeted therapies.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('cell lung cancer', 'Disease', (77, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('patients', 'Species', '9606', (102, 110))	('cell lung cancer', 'Disease', 'MESH:D008175', (77, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('benefit', 'PosReg', (148, 155))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (71, 93))	('alterations', 'Var', (133, 144))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (67, 93))	('NSCLC', 'Disease', (95, 100))
411022	30018747	Molecularly targeted drugs for EGFR mutation or ALK fusion genes have led to remarkable improvement in personal therapies, especially in pulmonary adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('EGFR', 'Gene', '1956', (31, 35))	('ALK', 'Gene', '238', (48, 51))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (137, 161))	('EGFR', 'Gene', (31, 35))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (137, 161))	('ALK', 'Gene', (48, 51))	('improvement', 'PosReg', (88, 99))	('personal therapies', 'CPA', (103, 121))	('pulmonary adenocarcinoma', 'Disease', (137, 161))	('mutation', 'Var', (36, 44))
411023	30018747	Several driver mutation candidates have also been identified in lung squamous cell carcinoma (SCC), though effective targeted therapies have not yet been established.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 92))	('mutation', 'Var', (15, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('lung squamous cell carcinoma', 'Disease', (64, 92))	('SCC', 'Gene', (94, 97))	('SCC', 'Gene', '6317', (94, 97))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (64, 92))	('identified', 'Reg', (50, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
411027	30018747	As a result of gene amplification, DeltaNp63alpha is the more abundantly detected isoform in human squamous cell carcinomas, including those in the lung, and silencing DeltaNp63 using siRNA suppresses growth of DeltaNp63-expressing cancer cells.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('p63', 'Gene', (174, 177))	('p63', 'Gene', (41, 44))	('cancer', 'Disease', (232, 238))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (99, 123))	('human', 'Species', '9606', (93, 98))	('p63', 'Gene', '8626', (174, 177))	('p63', 'Gene', (217, 220))	('growth', 'CPA', (201, 207))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('p63', 'Gene', '8626', (41, 44))	('p63', 'Gene', '8626', (217, 220))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('silencing', 'Var', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (99, 123))	('squamous cell carcinomas', 'Disease', (99, 123))
411061	30018747	Although use of RNAi may be the simplest approach to knocking down expression of a target gene, it sometimes exhibits marked off-target effects and unpredictable knockdown efficiencies.	('knocking', 'Var', (53, 61))	('expression', 'Species', '29278', (67, 77))	('expression', 'MPA', (67, 77))
411128	30003189	Based on the genetic alteration of esophageal SCC, p53 is reportedly one of the key molecules in the diagnosis and in the treatment of esophageal SCC.7 The most frequently mutated gene identified in esophageal SCC is the p53 gene, and its mutation and/or protein overexpression are observed in 40%-60% of patients with esophageal cancer:even in the early phase of carcinogenesis.8, 9 Because p53 alteration was a good predictor for treatment response and survival in esophageal SCC, the 5-year survival rate in the p53-normal group was significantly higher than that in the p53-alteration group.10, 11, 12 The overexpression of p53 protein usually results from genetic alterations modifying protein conformation and stability.7, 8 Such p53 protein alteration frequently induces p53 autoantibodies (s-p53 Abs) in esophageal SCC.	('esophageal SCC', 'Disease', (35, 49))	('p53', 'Gene', (51, 54))	('p53', 'Gene', (574, 577))	('p53', 'Gene', (392, 395))	('carcinogenesis', 'Disease', 'MESH:D063646', (364, 378))	('esophageal SCC', 'Disease', (812, 826))	('esophageal SCC', 'Disease', 'MESH:D004941', (35, 49))	('SCC', 'Phenotype', 'HP:0002860', (478, 481))	('esophageal SCC', 'Disease', 'MESH:D004941', (812, 826))	('esophageal SCC', 'Disease', (199, 213))	('induces', 'Reg', (770, 777))	('p53', 'Gene', '7157', (778, 781))	('p53', 'Gene', (628, 631))	('esophageal SCC', 'Disease', 'MESH:D004941', (199, 213))	('p53', 'Gene', '7157', (515, 518))	('esophageal SCC', 'Disease', (135, 149))	('p53', 'Gene', '7157', (221, 224))	('esophageal SCC', 'Disease', 'MESH:D004941', (135, 149))	('p53', 'Gene', (778, 781))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('esophageal SCC', 'Disease', (467, 481))	('p53', 'Gene', '7157', (800, 803))	('SCC', 'Phenotype', 'HP:0002860', (823, 826))	('p53', 'Gene', (515, 518))	('esophageal cancer', 'Disease', 'MESH:D004938', (319, 336))	('p53', 'Gene', '7157', (736, 739))	('esophageal SCC', 'Disease', 'MESH:D004941', (467, 481))	('alteration', 'Var', (748, 758))	('p53', 'Gene', (221, 224))	('patients', 'Species', '9606', (305, 313))	('p53', 'Gene', (800, 803))	('esophageal cancer', 'Disease', (319, 336))	('p53', 'Gene', '7157', (51, 54))	('p53', 'Gene', '7157', (574, 577))	('p53', 'Gene', (736, 739))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('SCC', 'Phenotype', 'HP:0002860', (210, 213))	('p53', 'Gene', '7157', (392, 395))	('carcinogenesis', 'Disease', (364, 378))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('protein', 'Protein', (740, 747))	('p53', 'Gene', '7157', (628, 631))
411139	30003189	Clinical impact of s-p53 Abs in surveillance of high-risk patients was reported.18 Cawley et al detected s-p53 Abs in four patients with Barrett's esophagus, including one with dysplasia that later progressed to adenocarcinoma.	('Abs', 'Var', (111, 114))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (137, 156))	('p53', 'Gene', (107, 110))	('progressed', 'Reg', (198, 208))	('p53', 'Gene', '7157', (21, 24))	('p53', 'Gene', '7157', (107, 110))	('adenocarcinoma', 'Disease', (212, 226))	('dysplasia', 'Disease', (177, 186))	('patients', 'Species', '9606', (123, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	("Barrett's esophagus", 'Disease', (137, 156))	('adenocarcinoma', 'Disease', 'MESH:D000230', (212, 226))	('dysplasia', 'Disease', 'MESH:D004476', (177, 186))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (137, 156))	('patients', 'Species', '9606', (58, 66))	('p53', 'Gene', (21, 24))
411157	30003189	Generally, the genetic alteration of p53 could induce s-p53 Abs in patients with other gastroenterological cancers.	('gastroenterological cancers', 'Disease', (87, 114))	('patients', 'Species', '9606', (67, 75))	('p53', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p53', 'Gene', '7157', (56, 59))	('gastroenterological cancers', 'Disease', 'MESH:D009369', (87, 114))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('induce', 'Reg', (47, 53))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('genetic alteration', 'Var', (15, 33))
411162	30003189	Further analysis on such patients with very high titers should be carried out to evaluate the anti-tumoral effects of the presence of s-p53 Abs.	('tumor', 'Disease', (99, 104))	('p53', 'Gene', '7157', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('patients', 'Species', '9606', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('presence', 'Var', (122, 130))	('p53', 'Gene', (136, 139))
411168	30003189	Eight patients had tumors with p53 mutations among exons 5 to 8.	('p53', 'Gene', (31, 34))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('p53', 'Gene', '7157', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (35, 44))
411201	28947992	It was further verified that Thsd7a had obvious effect on proliferation in naked mice with xenograft of Eca109 cells.	('Thsd7a', 'Var', (29, 35))	('mice', 'Species', '10090', (81, 85))	('proliferation', 'CPA', (58, 71))
411203	28947992	Together, it was demonstrated that Thsd7a might have a certain degree of carcinogenesis in ESCC.	('ESCC', 'Disease', (91, 95))	('carcinogenesis', 'Disease', (73, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (73, 87))	('Thsd7a', 'Var', (35, 41))
411222	28947992	We then inhibited Thsd7a expression in ECa 109 and EC 9706 cells using small interfering RNA (siRNA) and the result uncovered that the knocking down of Thsd7a damaged the process of cell proliferating, reduced migratory and invasive ability, resulted in block of Cell Cycle, and increased apoptosis rate in Eca 109 and EC 9706 cells.	('Thsd7a', 'Gene', (152, 158))	('apoptosis rate', 'CPA', (289, 303))	('cell proliferating', 'CPA', (182, 200))	('block', 'NegReg', (254, 259))	('inhibited', 'NegReg', (8, 17))	('reduced', 'NegReg', (202, 209))	('Cell Cycle', 'CPA', (263, 273))	('increased', 'PosReg', (279, 288))	('knocking down', 'Var', (135, 148))	('EC 9706', 'CellLine', 'CVCL:E307', (319, 326))	('EC 9706', 'CellLine', 'CVCL:E307', (51, 58))
411224	28947992	In addition, it was uncovered by microarray analyses that multiple pathways essential to cancerous occurrence and development were mediated by the knocking down of Thsd7a, which provided a valuable insight into the principle of Thsd7a mediating ESCC occurrence and progression.	('cancerous', 'Disease', 'MESH:D009369', (89, 98))	('ESCC', 'Disease', (245, 249))	('mediated by', 'Reg', (131, 142))	('Thsd7a', 'Gene', (164, 170))	('cancerous', 'Disease', (89, 98))	('knocking', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
411293	28947992	The effect of Thsd7a on cells in vitro was explored by means of transiently knocking out Thsd7a through transfecting Eca 109 and EC 9706 cells with anti-Thsd7a siRNA.	('Thsd7a', 'Gene', (89, 95))	('EC 9706', 'CellLine', 'CVCL:E307', (129, 136))	('knocking', 'Var', (76, 84))
411297	28947992	Nevertheless, the proliferating activity of Eca109 was notably inhibited after which was transfected with siRNA for 48 hours (siRNA1 for 72 hours) in comparison to control group (P < 0.05), although the proliferating activity of EC 9706 was under significant inhibition after which was transfected with siRNA1 for 48 hours (siRNA2 for 72 hours) compared with the Normal control group (P < 0.05), which indicated that the proliferating activity of EC 9706 and Eca109 cell lines was under the suppression of knocking out Thsd7a (Figure 4A).	('knocking out', 'Var', (506, 518))	('EC 9706', 'CellLine', 'CVCL:E307', (229, 236))	('proliferating activity', 'CPA', (18, 40))	('inhibited', 'NegReg', (63, 72))	('EC 9706', 'CellLine', 'CVCL:E307', (447, 454))	('Thsd7a', 'Gene', (519, 525))
411299	28947992	After 48 hours of transfection using anti-Thsd7a siRNA2, the scrapes of experimental groups including EC 9706 and Eca 109 cell lines were remarkably broader than those of control groups (siRNA-control and Normal control).	('scrapes', 'CPA', (61, 68))	('anti-Thsd7a', 'Var', (37, 48))	('EC 9706', 'CellLine', 'CVCL:E307', (102, 109))
411300	28947992	The relative migration of the group transfected with anti-Thsd7a siRNA were significantly different in statistics from that of control group, which also suggested that the migrating activities of EC 9706 and Eca 109 cell lines were remarkably inhibited by knocking out Thsd7a (Figure 4C).	('inhibited', 'NegReg', (243, 252))	('migrating activities', 'CPA', (172, 192))	('different', 'Reg', (90, 99))	('knocking out', 'Var', (256, 268))	('EC 9706', 'CellLine', 'CVCL:E307', (196, 203))	('Thsd7a', 'Gene', (269, 275))
411301	28947992	It was revealed that the quantities of normal and siRNA control groups were notably superior to those of experimental groups which contained EC 9706 and Eca 109 cell lines transfected with siRNA (P < 0.05, Figure 4D), which indicated that the invading activities of EC 9706 and Eca 109 cell lines were suppressed by knocking out Thsd7a.	('EC 9706', 'CellLine', 'CVCL:E307', (141, 148))	('knocking out', 'Var', (316, 328))	('Thsd7a', 'Gene', (329, 335))	('invading activities', 'CPA', (243, 262))	('EC 9706', 'CellLine', 'CVCL:E307', (266, 273))	('suppressed', 'NegReg', (302, 312))
411302	28947992	According to Figure 5A, the ratio values of EC 9706 and Eca 109 cells stuck in G0/G1 phase in the experimental groups transfected with anti-Thsd7a siRNA (siRNA1 and siRNA2) were remarkably higher than those in control groups (P < 0.05), which indicated that knocking out Thsd7a could induce the arresting of cell cycles in G0/G1 phase.	('knocking out', 'Var', (258, 270))	('cell cycles in G0/G1 phase', 'CPA', (308, 334))	('EC 9706', 'CellLine', 'CVCL:E307', (44, 51))	('Thsd7a', 'Gene', (271, 277))	('arresting', 'CPA', (295, 304))	('higher', 'PosReg', (189, 195))	('induce', 'Reg', (284, 290))
411303	28947992	It was revealed in Figure 5B that the apoptotic rates of EC 9706 and Eca 109 cell lines for the siRNA-Thsd7a groups (siRNA1 and siRNA2) were significantly increased compared with the control group (P < 0.05), suggesting that silencing of Thsd7a promotes apoptosis of Eca 109 and EC 9706 cells.	('silencing', 'Var', (225, 234))	('apoptotic', 'CPA', (38, 47))	('apoptosis', 'CPA', (254, 263))	('EC 9706', 'CellLine', 'CVCL:E307', (57, 64))	('promotes', 'PosReg', (245, 253))	('EC 9706', 'CellLine', 'CVCL:E307', (279, 286))	('Thsd7a', 'Gene', (238, 244))
411311	28947992	It was found that knockdown of Thsd7a could suppress the oncogenesis in athymic naked mice with exnografts induced by Eca 109 cell lines (Figure 6F, 6G), which casually confirmed the oncogenic effect of Thsd7a on Eca 109 cell lines in vitro.	('knockdown', 'Var', (18, 27))	('mice', 'Species', '10090', (86, 90))	('Thsd7a', 'Gene', (31, 37))	('suppress', 'NegReg', (44, 52))	('oncogenesis', 'CPA', (57, 68))
411329	28947992	The proliferating, migrating as well as invading capacities of EC 9706 and Eca 109 cell lines of ESCC were prohibited by knocking out Thsd7a using particular siRNA1 and siRNA2.	('invading capacities', 'CPA', (40, 59))	('EC 9706', 'CellLine', 'CVCL:E307', (63, 70))	('proliferating', 'CPA', (4, 17))	('knocking out', 'Var', (121, 133))	('Thsd7a', 'Gene', (134, 140))	('migrating', 'CPA', (19, 28))	('prohibited', 'NegReg', (107, 117))
411334	28947992	However, according to the results of correlation assays in which Thsd7a of Eca 109 and EC 9706 cell lines were knocked out using siRNA1 and siRNA2, Thsd7a was capable of promoting cell invasion and migration, indicating the essentiality of Thsd7a to motion capacity in vitro, which agrees with previous non-tumor study of Eichmann A's.	('non-tumor', 'Disease', (303, 312))	('knocked out', 'Var', (111, 122))	('EC 9706', 'CellLine', 'CVCL:E307', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('promoting', 'PosReg', (170, 179))	('migration', 'CPA', (198, 207))	('non-tumor', 'Disease', 'MESH:D009369', (303, 312))	('cell invasion', 'CPA', (180, 193))	('Thsd7a', 'Gene', (148, 154))
411340	28947992	The second significantly enriched pathway, mTOR signaling, the remarkable enriched pathways after Thsd7a was knocked down, was essential to the proliferating, migrating, and invading activity of tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('Thsd7a', 'Gene', (98, 104))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('knocked down', 'Var', (109, 121))
411347	28947992	In sum, the essentiality of Thsd7a in ESCC, especially for Kazakh patients was verified in this study which indicated that Thsd7a might be used as a biomarker for diagnosing ESCC and a target for treating ESCC of Kazakh patients, Xinjiang.	('Thsd7a', 'Var', (123, 129))	('ESCC', 'Disease', (174, 178))	('patients', 'Species', '9606', (220, 228))	('ESCC', 'Disease', (205, 209))	('patients', 'Species', '9606', (66, 74))
411353	26633576	We found statistically significant, but modest, synergistic enhancement of levels of O6-POB-dGuo in the esophagus but not the oral cavity of rats treated with racemic NNN (low and median doses only) compared to the sum of the amounts formed in these tissues of rats treated with (S)-NNN or (R)-NNN.	('(S)-NNN', 'Chemical', 'MESH:C008655', (279, 286))	('(R)-NNN', 'Chemical', '-', (290, 297))	('rats', 'Species', '10116', (141, 145))	('rats', 'Species', '10116', (261, 265))	('O6-POB-dGuo', 'Var', (85, 96))	('NNN', 'Chemical', 'MESH:C008655', (283, 286))	('enhancement', 'PosReg', (60, 71))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (85, 96))	('NNN', 'Chemical', 'MESH:C008655', (294, 297))	('NNN', 'Chemical', 'MESH:C008655', (167, 170))
411355	26633576	Our results provide the first quantitation of O6-POB-dGuo in DNA from tissues of rats treated with NNN, and evidence for synergy in DNA adduct formation as one possible mechanism by which (R)-NNN enhances the carcinogenicity of (S)-NNN in rats.	('R)-NNN', 'Var', (189, 195))	('synergy', 'Disease', 'None', (121, 128))	('rats', 'Species', '10116', (81, 85))	('NNN', 'Chemical', 'MESH:C008655', (232, 235))	('synergy', 'Disease', (121, 128))	('enhances', 'PosReg', (196, 204))	('carcinogenic', 'Disease', 'MESH:D063646', (209, 221))	('(S)-NNN', 'Chemical', 'MESH:C008655', (228, 235))	('(R)-NNN', 'Chemical', '-', (188, 195))	('carcinogenic', 'Disease', (209, 221))	('NNN', 'Chemical', 'MESH:C008655', (99, 102))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (46, 57))	('NNN', 'Chemical', 'MESH:C008655', (192, 195))	('rats', 'Species', '10116', (239, 243))
411361	26633576	We hypothesized that metabolites of (R)-NNN could enhance the levels of DNA adducts produced in the metabolism of (S)-NNN.	('(S)-NNN', 'Chemical', 'MESH:C008655', (114, 121))	('(R)-NNN', 'Chemical', '-', (36, 43))	('metabolites', 'Var', (21, 32))	('levels of DNA adducts produced', 'MPA', (62, 92))	('enhance', 'PosReg', (50, 57))
411369	26633576	Albeit present in low levels, O6-POB-dGuo has the greatest mutagenicity among the four identified POB-DNA adducts.	('O6-POB-dGuo', 'Var', (30, 41))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (30, 41))	('mutagenicity', 'MPA', (59, 71))
411370	26633576	O6-Substituted guanine adducts lead to misincorporation of thymine thus inducing GC to AT transitions.	('O6', 'Chemical', '-', (0, 2))	('misincorporation of thymine', 'MPA', (39, 66))	('adducts', 'Var', (23, 30))	('inducing', 'Reg', (72, 80))	('lead to', 'Reg', (31, 38))	('thymine', 'Chemical', 'MESH:D013941', (59, 66))	('guanine', 'Chemical', 'MESH:D006147', (15, 22))	('rat', 'Species', '10116', (49, 52))	('O6-Substituted', 'Var', (0, 14))	('AT', 'Disease', 'None', (87, 89))
411371	26633576	O6-POB-dGuo induces G to A transitions in bacteria; in human HEK-293 cells, O6-POB-dGuo induces mainly G to A transitions, as well as a small number of G to T transversions, more complex multiple mutations and remote mutations together with deletions.	('induces', 'Reg', (88, 95))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (0, 11))	('O6-POB-dGuo', 'Var', (76, 87))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (76, 87))	('human', 'Species', '9606', (55, 60))	('HEK-293', 'CellLine', 'CVCL:0045', (61, 68))
411373	26633576	In the study described here, we report the first quantitation of O6-POB-dGuo in tissues of NNN-treated rats, using liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry with accurate mass detection (LC-NSI-HRMS/MS).	('rat', 'Species', '10116', (103, 106))	('LC-NSI-HRMS/MS', 'Disease', 'MESH:D009103', (236, 250))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (65, 76))	('O6-POB-dGuo', 'Var', (65, 76))	('rat', 'Species', '10116', (215, 218))	('rats', 'Species', '10116', (103, 107))	('NNN', 'Chemical', 'MESH:C008655', (91, 94))	('LC-NSI-HRMS/MS', 'Disease', (236, 250))
411375	26633576	(R)-NNN, (S)-NNN and racemic NNN are carcinogenic.	('carcinogenic', 'Disease', (37, 49))	('racemic', 'Var', (21, 28))	('(S)-NNN', 'Chemical', 'MESH:C008655', (9, 16))	('NNN', 'Chemical', 'MESH:C008655', (29, 32))	('R)-NNN', 'Var', (1, 7))	('NNN', 'Chemical', 'MESH:C008655', (13, 16))	('(R)-NNN', 'Chemical', '-', (0, 7))	('carcinogenic', 'Disease', 'MESH:D063646', (37, 49))	('S)-NNN', 'Var', (10, 16))	('NNN', 'Chemical', 'MESH:C008655', (4, 7))
411409	26633576	The remaining sample after LC-ESI-MS/MS quantitation of POB-DNA adducts was subjected to further column purification for quantitation of O6-POB-dGuo using LC-NSI-HRMS/MS.	('LC-NSI-HRMS/MS', 'Disease', (155, 169))	('LC-NSI-HRMS/MS', 'Disease', 'MESH:D009103', (155, 169))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (137, 148))	('O6-POB-dGuo', 'Var', (137, 148))
411419	26633576	The following ion transitions were monitored with accurate mass extracted: m/z 415.2 [M+H]+ to m/z 148.0757 [POB]+ and 152.0567 [Gua+H]+ for O6-POB-dGuo, and m/z 419.2 [M+H]+ to m/z 152.1008 [[pyridine-D4]POB]+ and 152.0567 [Gua+H]+ for [pyridine-D4]O6-POB-dGuo.	('Gua', 'Chemical', 'MESH:D006147', (129, 132))	('pyridine-D4', 'Chemical', '-', (193, 204))	('152.0567 [Gua+H]+ for [pyridine-D4]O6-POB-dGuo', 'Var', (215, 261))	('m/z 419.2 [M+H]+ to', 'Var', (158, 177))	('152.0567 [Gua+H', 'Var', (119, 134))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (141, 152))	('[pyridine-D4]O6-POB-dGuo', 'Chemical', '-', (237, 261))	('rat', 'Species', '10116', (54, 57))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (250, 261))	('m/z', 'Var', (75, 78))	('Gua', 'Chemical', 'MESH:D006147', (225, 228))	('pyridine-D4', 'Chemical', '-', (238, 249))
411421	26633576	The ion source was operated in positive ion mode with a spray voltage of 2200 V and the ion transfer tube at 300  C. Peak integration was performed at 15 ppm mass tolerance due to the coalescence effect caused by the close masses of [Gua + H]+ and [[pyridine-D4]POB]+ and the relatively high internal standard signal.	('[[pyridine-D4]POB]+', 'Var', (248, 267))	('pyridine-D4', 'Chemical', '-', (250, 261))	('rat', 'Species', '10116', (22, 25))	('[Gua + H]+', 'Var', (233, 243))	('Gua', 'Chemical', 'MESH:D006147', (234, 237))	('rat', 'Species', '10116', (127, 130))	('coalescence', 'MPA', (184, 195))
411447	26633576	For the high dosage level, the adduct level from (S)-NNN was also higher than (R)-NNN but the difference was not significant (p = 0.103).	('(S)-NNN', 'Chemical', 'MESH:C008655', (49, 56))	('S)-NNN', 'Var', (50, 56))	('adduct level', 'MPA', (31, 43))	('higher', 'PosReg', (66, 72))	('(R)-NNN', 'Chemical', '-', (78, 85))
411469	26633576	In a previous attempt using NSI and a high resolution orbital trap (Orbitrap Velos) mass spectrometer, O6-POB-dGuo was detected in 14 ppm (R)-NNN and (S)-NNN-treated rat nasal respiratory mucosa and 14 ppm (S)-NNN-treated rat esophageal mucosa.	('(S)-NNN', 'Chemical', 'MESH:C008655', (206, 213))	('esophageal mucosa', 'Disease', 'MESH:D004941', (226, 243))	('rat', 'Species', '10116', (166, 169))	('O6-POB-dGuo', 'Var', (103, 114))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (103, 114))	('rat', 'Species', '10116', (222, 225))	('(S)-NNN', 'Chemical', 'MESH:C008655', (150, 157))	('rat', 'Species', '10116', (181, 184))	('esophageal mucosa', 'Disease', (226, 243))	('(R)-NNN', 'Chemical', '-', (138, 145))
411472	26633576	Overall, the newly developed LC-NSI-HRMS/MS method allowed the quantitation of ultra trace levels of O6-POB-dGuo from low-dosage NNN-treated rats with a LOD of 6.5 amol for diluted standard and 100 amol for spiked calf thymus DNA samples, which is about a 100-fold improvement over the LC-ESI-MS/MS method.	('calf', 'Species', '9913', (214, 218))	('O6-POB-dGuo', 'Var', (101, 112))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (101, 112))	('amol', 'Phenotype', 'HP:0004845', (164, 168))	('rats', 'Species', '10116', (141, 145))	('LC-NSI-HRMS/MS', 'Disease', (29, 43))	('NNN', 'Chemical', 'MESH:C008655', (129, 132))	('amol', 'Phenotype', 'HP:0004845', (198, 202))	('LC-NSI-HRMS/MS', 'Disease', 'MESH:D009103', (29, 43))
411475	26633576	Besides the low yield, O6-POB-dGuo is also a substrate for O6-alkylguanine-DNA alkyltransferase (AGT), which repairs this modification by transferring the O6-alkyl group to its cysteine residue resulting in inactivation and degradation of the protein.	('O6-alkyl', 'Var', (155, 163))	('degradation', 'MPA', (224, 235))	('O6', 'Chemical', '-', (59, 61))	('O6', 'Chemical', '-', (155, 157))	('O6-alkylguanine', 'Chemical', '-', (59, 74))	('rat', 'Species', '10116', (50, 53))	('inactivation', 'MPA', (207, 219))	('cysteine', 'Chemical', 'MESH:D003545', (177, 185))	('O6', 'Chemical', '-', (23, 25))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (23, 34))	('protein', 'Protein', (243, 250))
411477	26633576	O6-POB-dGuo induces G to A transition mutations in E. coli, and G to A transitions, G to T transversions, base deletion and remote mutations in human HEK-293 cells.	('O6-POB-dGuo', 'Var', (0, 11))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (0, 11))	('human', 'Species', '9606', (144, 149))	('G to T transversions', 'Var', (84, 104))	('HEK-293', 'CellLine', 'CVCL:0045', (150, 157))	('base deletion', 'Var', (106, 119))	('E. coli', 'Species', '562', (51, 58))
411478	26633576	In addition, multiple studies have shown that O6-alkylguanine lesions formed from both endogenous and exogenous sources can induce mainly G to A mutations and are believed to be highly mutagenic.	('induce', 'Reg', (124, 130))	('O6-alkylguanine', 'Chemical', '-', (46, 61))	('O6-alkylguanine lesions', 'Var', (46, 69))
411486	26633576	One possible hypothesis for the observed synergistic effect in O6-POB-dGuo formation involves the repair efficiency of O6-POB-dGuo by AGTs.	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (63, 74))	('AGTs', 'Chemical', 'MESH:D000616', (134, 138))	('O6-POB-dGuo', 'Disease', (63, 74))	('O6-POB-dGuo', 'Var', (119, 130))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (119, 130))
411509	26633576	In summary, we have developed a novel LC-NSI-HRMS/MS method for quantitation of ultra-trace levels of O6-POB-dGuo from low-dose NNN-treated rats with 100-fold improvement in sensitivity compared to the low-resolution LC-ESI-MS/MS method.	('LC-NSI-HRMS/MS', 'Disease', (38, 52))	('improvement', 'PosReg', (159, 170))	('rats', 'Species', '10116', (140, 144))	('NNN', 'Chemical', 'MESH:C008655', (128, 131))	('LC-NSI-HRMS/MS', 'Disease', 'MESH:D009103', (38, 52))	('O6-POB-dGuo', 'Var', (102, 113))	('O6-POB-dGuo', 'Chemical', 'MESH:C000612303', (102, 113))
411534	26205191	Head and neck cancers are frequently driven by EGFR signaling and high expression of EGFR is associated with a poor prognosis and radioresistance.	('EGFR', 'Gene', (85, 89))	('radioresistance', 'CPA', (130, 145))	('Head and neck cancers', 'Phenotype', 'HP:0012288', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('high expression', 'Var', (66, 81))	('neck cancers', 'Disease', (9, 21))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', '1956', (85, 89))	('neck cancers', 'Disease', 'MESH:D006258', (9, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('EGFR', 'Gene', (47, 51))
411559	26205191	Additional studies with cetuximab and radiation therapy include RTOG 0920, a phase III study of post-operative radiation with or without cetuximab in locally advanced head and neck cancer patients, and RTOG 1216, (NCT01810913) a three arm phase II/III study of radiation with either docetaxel, docetaxel with cetuximab, or cisplatin in high risk post-operative patients.	('cetuximab', 'Chemical', 'MESH:D000068818', (24, 33))	('cetuximab', 'Chemical', 'MESH:D000068818', (309, 318))	('patients', 'Species', '9606', (361, 369))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (323, 332))	('neck cancer', 'Disease', 'MESH:D006258', (176, 187))	('neck cancer', 'Disease', (176, 187))	('head and neck cancer', 'Phenotype', 'HP:0012288', (167, 187))	('RTOG', 'Var', (64, 68))	('patients', 'Species', '9606', (188, 196))	('docetaxel', 'Chemical', 'MESH:D000077143', (283, 292))	('cetuximab', 'Chemical', 'MESH:D000068818', (137, 146))	('docetaxel', 'Chemical', 'MESH:D000077143', (294, 303))
411570	26205191	EGFR targeted therapies have become standard of care in a subset of patients with advanced stage nonsmall cell lung cancer.	('EGFR', 'Gene', (0, 4))	('nonsmall cell lung cancer', 'Disease', (97, 122))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (97, 122))	('targeted therapies', 'Var', (5, 23))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (97, 122))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('EGFR', 'Gene', '1956', (0, 4))
411573	26205191	Subset analyses from several studies demonstrate the benefit of small molecule EGFR inhibitors is limited to patients with tumors harboring specific EGFR mutations and wild type KRAS.	('KRAS', 'Gene', (178, 182))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('KRAS', 'Gene', '3845', (178, 182))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('patients', 'Species', '9606', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'Gene', (149, 153))	('mutations', 'Var', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
411574	26205191	Interestingly, specific acquired EGFR mutations (T790M) also lead to erlotinib resistance.	('erlotinib resistance', 'MPA', (69, 89))	('erlotinib', 'Chemical', 'MESH:D000069347', (69, 78))	('lead to', 'Reg', (61, 68))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))	('T790M', 'Mutation', 'rs121434569', (49, 54))	('T790M', 'Var', (49, 54))	('mutations (T790M', 'Var', (38, 54))
411589	26205191	Massachusetts General Hospital is running a phase II study of afatinib followed by concurrent chemoradiation in EGFR mutant nonsmall cell lung cancer (NCT01553942).	('EGFR', 'Gene', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (124, 149))	('afatinib', 'Chemical', 'MESH:D000077716', (62, 70))	('mutant', 'Var', (117, 123))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (124, 149))	('EGFR', 'Gene', '1956', (112, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('nonsmall cell lung cancer', 'Disease', (124, 149))
411590	26205191	An ongoing phase II study from Beijing Cancer Hospital (NCT01391260) is studying the combination of gefitinib with radiation alone in patients with specific EGFR activating mutations.	('EGFR', 'Gene', (157, 161))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patients', 'Species', '9606', (134, 142))	('gefitinib', 'Chemical', 'MESH:D000077156', (100, 109))	('mutations', 'Var', (173, 182))	('activating', 'PosReg', (162, 172))	('Beijing Cancer', 'Disease', (31, 45))	('Beijing Cancer', 'Disease', 'MESH:D009369', (31, 45))	('EGFR', 'Gene', '1956', (157, 161))
411591	26205191	Another phase II study from China randomizes patients with exon 19 or 21 EGFR mutations to cisplatin and etoposide or erlotinib with radiation therapy (NCT01714908).	('EGFR', 'Gene', '1956', (73, 77))	('erlotinib', 'Chemical', 'MESH:D000069347', (118, 127))	('EGFR', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('etoposide', 'Chemical', 'MESH:D005047', (105, 114))	('patients', 'Species', '9606', (45, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))
411595	26205191	Interestingly, unlike nonsmall cell lung cancer, in colorectal cancer EGFR overexpression or specific EGFR activating mutations have not been found to be predictive of response to anti-EGFR therapies.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('overexpression', 'PosReg', (75, 89))	('EGFR', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('EGFR', 'Gene', '1956', (70, 74))	('mutations', 'Var', (118, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('EGFR', 'Gene', '1956', (185, 189))	('EGFR', 'Gene', (70, 74))	('rectal cancer', 'Phenotype', 'HP:0100743', (56, 69))	('nonsmall cell lung cancer', 'Disease', (22, 47))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (22, 47))	('colorectal cancer', 'Disease', (52, 69))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (22, 47))	('EGFR', 'Gene', '1956', (102, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('EGFR', 'Gene', (102, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
411663	26205191	Thus, EGFR inhibition during the first few hours after radiation may actually protect cells, whereas 24 hours after inhibition, the combined effects of G1 arrest and inhibition of DNA repair might produce sensitization.	('inhibition', 'NegReg', (166, 176))	('inhibition', 'Var', (11, 21))	('EGFR', 'Gene', '1956', (6, 10))	('EGFR', 'Gene', (6, 10))
411677	26205191	Interestingly, inhibition of EGFR with cetuximab attenuates EGFR nuclear import and suppresses DNA-PK activity.	('DNA-PK', 'Gene', '5591', (95, 101))	('suppresses', 'NegReg', (84, 94))	('attenuates', 'NegReg', (49, 59))	('cetuximab', 'Chemical', 'MESH:D000068818', (39, 48))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (29, 33))	('DNA-PK', 'Gene', (95, 101))	('EGFR', 'Gene', (60, 64))	('inhibition', 'Var', (15, 25))
411688	26205191	For example, cisplatin induces nuclear translocation of EGFR.	('EGFR', 'Gene', '1956', (56, 60))	('nuclear translocation', 'MPA', (31, 52))	('cisplatin', 'Var', (13, 22))	('EGFR', 'Gene', (56, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
411696	26205191	Given these results, it is perplexing why the combination of EGFR inhibitors with chemoradiation has been a failure so far.	('inhibitors', 'Var', (66, 76))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
411698	26205191	Given the G1 arrest seen after EGFR inhibition, it is possible EGFR inhibitors are antagonizing the effects of chemotherapy when administered simultaneously.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', '1956', (31, 35))	('inhibition', 'Var', (36, 46))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', (31, 35))	('inhibitors', 'Var', (68, 78))	('G1 arrest', 'MPA', (10, 19))
411703	26205191	As discussed above, preclinical studies demonstrate that the sequencing of EGFR inhibitors with chemotherapy and with radiation therapy affect sensitivity and synergy.	('sensitivity', 'MPA', (143, 154))	('EGFR', 'Gene', '1956', (75, 79))	('synergy', 'MPA', (159, 166))	('sequencing', 'Var', (61, 71))	('affect', 'Reg', (136, 142))	('EGFR', 'Gene', (75, 79))	('inhibitors', 'Var', (80, 90))
411717	26205191	In lung cancer, specific EGFR mutations determine sensitivity and resistance to small molecule inhibitors.	('EGFR', 'Gene', (25, 29))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (30, 39))	('resistance', 'MPA', (66, 76))	('sensitivity', 'MPA', (50, 61))	('determine', 'Reg', (40, 49))	('EGFR', 'Gene', '1956', (25, 29))
411719	26205191	Interestingly, increased gene copy number does not correlate with overexpression and neither EGFR mutations nor EGFR overexpression are predictive of response.	('EGFR', 'Gene', (112, 116))	('EGFR', 'Gene', '1956', (93, 97))	('EGFR', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('EGFR', 'Gene', '1956', (112, 116))
411720	26205191	In colorectal cancer and other malignancies, alterations of several downstream proteins are predictive of resistance to EGFR directed therapies.	('alterations', 'Var', (45, 56))	('malignancies', 'Disease', 'MESH:D009369', (31, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('malignancies', 'Disease', (31, 43))	('rectal cancer', 'Phenotype', 'HP:0100743', (7, 20))	('EGFR', 'Gene', '1956', (120, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('EGFR', 'Gene', (120, 124))
411721	26205191	The most robust is KRAS mutational status; however, BRAF, PI3K, or PTEN mutations and c-Met or Her2 overexpression are also associated with anti-EGFR therapy resistance (reviewed in).	('mutations', 'Var', (72, 81))	('c-Met', 'Gene', (86, 91))	('PI3K', 'Var', (58, 62))	('EGFR', 'Gene', '1956', (145, 149))	('KRAS', 'Gene', (19, 23))	('c-Met', 'Gene', '4233', (86, 91))	('associated', 'Reg', (124, 134))	('Her2', 'Gene', (95, 99))	('EGFR', 'Gene', (145, 149))	('PTEN', 'Gene', (67, 71))	('Her2', 'Gene', '2064', (95, 99))	('KRAS', 'Gene', '3845', (19, 23))	('PTEN', 'Gene', '5728', (67, 71))	('BRAF', 'Gene', '673', (52, 56))	('overexpression', 'PosReg', (100, 114))	('BRAF', 'Gene', (52, 56))
411725	26205191	In nonsmall cell lung cancer, treatment with erlotinib is associated with the development of/selection for cells with a resistant T790M EGFR mutation.	('erlotinib', 'Chemical', 'MESH:D000069347', (45, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (3, 28))	('T790M', 'Mutation', 'rs121434569', (130, 135))	('T790M', 'Var', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('EGFR', 'Gene', '1956', (136, 140))	('nonsmall cell lung cancer', 'Disease', (3, 28))	('EGFR', 'Gene', (136, 140))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (3, 28))
411726	26205191	Recently, drugs have been developed to target cells harboring a T790M EGFR mutation.	('EGFR', 'Gene', '1956', (70, 74))	('T790M', 'Var', (64, 69))	('T790M', 'Mutation', 'rs121434569', (64, 69))	('EGFR', 'Gene', (70, 74))
411727	26205191	AZD9291 is an irreversible tyrosine kinase inhibitor with selectivity against mutant forms of EGFR.	('AZD9291', 'Var', (0, 7))	('EGFR', 'Gene', '1956', (94, 98))	('AZD9291', 'Chemical', 'MESH:C000596361', (0, 7))	('EGFR', 'Gene', (94, 98))	('mutant', 'Var', (78, 84))	('tyrosine', 'Chemical', 'MESH:D014443', (27, 35))
411728	26205191	This drug was found to be effective in patients with nonsmall cell lung cancer harboring the T790M EGFR mutation who had progressed on treatment with EGFR small molecule inhibitors.	('EGFR', 'Gene', (99, 103))	('EGFR', 'Gene', (150, 154))	('patients', 'Species', '9606', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('nonsmall cell lung cancer', 'Disease', (53, 78))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (53, 78))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (53, 78))	('T790M', 'Mutation', 'rs121434569', (93, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', '1956', (150, 154))	('T790M', 'Var', (93, 98))
411729	26205191	Interestingly, resistance to AZD9291 develops through another acquired EGFR mutation (C797S), illustrating the complexity and challenges associated with anti-EGFR therapy.	('EGFR', 'Gene', (158, 162))	('C797S', 'Mutation', 'rs1057519861', (86, 91))	('EGFR', 'Gene', '1956', (71, 75))	('AZD9291', 'Chemical', 'MESH:C000596361', (29, 36))	('AZD9291', 'Var', (29, 36))	('EGFR', 'Gene', '1956', (158, 162))	('EGFR', 'Gene', (71, 75))	('C797S', 'Var', (86, 91))
411732	26205191	Additionally, combinations of EGFR targeted therapies with other novel agents, such as drugs targeting hsp90, may improve the efficacy of these therapies.	('EGFR', 'Gene', (30, 34))	('combinations', 'Interaction', (14, 26))	('targeted', 'Var', (35, 43))	('hsp90', 'Gene', (103, 108))	('improve', 'PosReg', (114, 121))	('EGFR', 'Gene', '1956', (30, 34))	('hsp90', 'Gene', '3320', (103, 108))
411749	32035486	FOXM1 silencing led to a loss of cell growth and suppressed cell migration and invasion in ESCC cells.	('invasion in', 'CPA', (79, 90))	('cell migration', 'CPA', (60, 74))	('ESCC', 'Disease', (91, 95))	('cell growth', 'CPA', (33, 44))	('suppressed', 'NegReg', (49, 59))	('FOXM1', 'Gene', (0, 5))	('loss', 'NegReg', (25, 29))	('silencing', 'Var', (6, 15))	('ESCC', 'Disease', 'MESH:C562729', (91, 95))
411768	32035486	indicated that the silencing of FOXM1 inhibits epithelial-mesenchymal transformation (EMT) in colon cancer cells and acts as a molecular marker for the prediction of invasion, metastasis and prognosis in colorectal cancer.	('epithelial-mesenchymal transformation', 'CPA', (47, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (204, 221))	('colon cancer', 'Disease', (94, 106))	('inhibits', 'NegReg', (38, 46))	('silencing', 'Var', (19, 28))	('FOXM1', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('colorectal cancer', 'Disease', (204, 221))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
411770	32035486	Approximately 90% of ESCC cases show dysregulated Wnt signaling, leading to the nuclear translocation and aggregation of beta-catenin through inactivating APC mutations or activating beta-catenin mutations, followed by the combination of T-cell factor (TCF) and lymphoid enhancing factor transcription factors (LEF) to activate the transcription of downstream genes, including c-Myc and cyclin D1.	('T-cell factor', 'Gene', (238, 251))	('c-Myc', 'Gene', (377, 382))	('TCF', 'Gene', '3172', (253, 256))	('c-Myc', 'Gene', '4609', (377, 382))	('inactivating', 'NegReg', (142, 154))	('transcription', 'MPA', (332, 345))	('mutations', 'Var', (159, 168))	('APC', 'Disease', 'MESH:D011125', (155, 158))	('cyclin D1', 'Gene', (387, 396))	('T-cell factor', 'Gene', '3172', (238, 251))	('APC', 'Disease', (155, 158))	('ESCC', 'Disease', 'MESH:C562729', (21, 25))	('activating', 'PosReg', (172, 182))	('cyclin D1', 'Gene', '595', (387, 396))	('aggregation', 'MPA', (106, 117))	('TCF', 'Gene', (253, 256))	('mutations', 'Var', (196, 205))	('beta-catenin', 'Protein', (183, 195))	('activate', 'PosReg', (319, 327))	('ESCC', 'Disease', (21, 25))	('nuclear translocation', 'MPA', (80, 101))
411774	32035486	found that the deletion of FOXM1 in mice prevented colorectal tumorigenesis through the regulation of beta-catenin/TCF4/E-cad signaling and the suppression of EMT.	('TCF4/E', 'Gene', '21416;21413', (115, 121))	('E-cad', 'Gene', '999', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('EMT', 'CPA', (159, 162))	('deletion', 'Var', (15, 23))	('TCF4/E', 'Gene', (115, 121))	('tumor', 'Disease', (62, 67))	('E-cad', 'Gene', (120, 125))	('prevented', 'NegReg', (41, 50))	('mice', 'Species', '10090', (36, 40))	('suppression', 'NegReg', (144, 155))	('FOXM1', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
411796	32035486	Sections were probed with rabbit monoclonal anti-Foxm1(1:250, ab207298, Abcam, USA), anti-beta-catenin (1:100, ab32572, Abcam, USA), anti-Tcf4 (1:150, ab217668, Abcam, USA), anti-E -cadherin (1:200, ab1416, Abcam, USA), and anti-CD34 (1:200, ab762, Abcam, USA) primary antibodies overnight at 4  C, followed by the appropriate secondary antibodies for 30 min.	('Foxm1', 'Gene', '2305', (49, 54))	('1:200', 'Var', (235, 240))	('CD34', 'Gene', (229, 233))	('CD34', 'Gene', '947', (229, 233))	('E -cadherin', 'Gene', (179, 190))	('1:200', 'Var', (192, 197))	('Foxm1', 'Gene', (49, 54))	('E -cadherin', 'Gene', '999', (179, 190))	('Tcf4', 'Gene', (138, 142))	('1:100', 'Var', (104, 109))	('Tcf4', 'Gene', '6925', (138, 142))
411841	32035486	5) suggesting that FoxM1 silencing inhibited cell proliferation.	('silencing', 'Var', (25, 34))	('FoxM1', 'Gene', '2305', (19, 24))	('FoxM1', 'Gene', (19, 24))	('cell proliferation', 'CPA', (45, 63))	('inhibited', 'NegReg', (35, 44))
411843	32035486	Wound healing assays showed that FoxM1 silencing led to slower wound closure rates compared to the control group (P < 0.05, Fig.	('FoxM1', 'Gene', '2305', (33, 38))	('wound closure rates', 'CPA', (63, 82))	('FoxM1', 'Gene', (33, 38))	('slower', 'NegReg', (56, 62))	('silencing', 'Var', (39, 48))
411845	32035486	The results showed that the expression FoxM1 and Tcf4 in FoxM1 silenced groups were significantly lower than blank- and negative control groups (P < 0.05, Fig.	('FoxM1', 'Gene', '2305', (39, 44))	('FoxM1', 'Gene', '2305', (57, 62))	('FoxM1', 'Gene', (39, 44))	('FoxM1', 'Gene', (57, 62))	('silenced', 'Var', (63, 71))	('expression', 'MPA', (28, 38))	('Tcf4', 'Gene', (49, 53))	('Tcf4', 'Gene', '6925', (49, 53))	('lower', 'NegReg', (98, 103))
411848	32035486	These findings confirmed that FoxM1 silencing prevent the EMT of tumor cells.	('prevent', 'NegReg', (46, 53))	('tumor', 'Disease', (65, 70))	('FoxM1', 'Gene', '2305', (30, 35))	('FoxM1', 'Gene', (30, 35))	('silencing', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
411879	32035486	Here, we found that the FoxM1 silencing inhibited cell growth and invasion, indicating that FoxM1 functions as a tumor promoter in ESCC.	('tumor', 'Disease', (113, 118))	('FoxM1', 'Gene', '2305', (92, 97))	('FoxM1', 'Gene', (92, 97))	('inhibited', 'NegReg', (40, 49))	('FoxM1', 'Gene', '2305', (24, 29))	('ESCC', 'Disease', 'MESH:C562729', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('FoxM1', 'Gene', (24, 29))	('silencing', 'Var', (30, 39))	('ESCC', 'Disease', (131, 135))
411883	32035486	The dysregulation of Wnt signaling is closely related to the biological behavior of various tumors.	('related', 'Reg', (46, 53))	('dysregulation', 'Var', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Wnt signaling', 'Pathway', (21, 34))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
411936	31416240	Because exosomes contain the same overall structure and macromolecules (lipids, proteins, nucleic acids and so on), almost all of the Exo-SERS spectra showed common Raman peaks near 628, 730, 963, 999, 1127, 1318, 1370 and 1453 cm-1, which corresponding to deformation vibration of adenine ring, adenine vibration, adenine C-N deformed vibration, symmetric respiratory vibration of phenylalanine, C-C skeletal stretching, amide III vibration, CH deformation and CH3CH2 wagging (e.g., nucleic acids, collagen), nucleotide (adenine, guanine, thymine), and CH2CH3 deformation vibration, respectively.	('adenine C-N', 'Chemical', 'MESH:D000225', (315, 326))	('adenine', 'Chemical', 'MESH:D000225', (296, 303))	('adenine', 'Chemical', 'MESH:D000225', (522, 529))	('CH deformation', 'Disease', (443, 457))	('CH deformation', 'Disease', 'MESH:D009140', (443, 457))	('adenine', 'Chemical', 'MESH:D000225', (282, 289))	('amide III', 'MPA', (422, 431))	('C-C skeletal stretching', 'MPA', (397, 420))	('wagging', 'NegReg', (469, 476))	('phenylalanine', 'Chemical', 'MESH:C119108', (382, 395))	('deformation', 'Var', (257, 268))	('guanine', 'Chemical', 'MESH:D006147', (531, 538))	('adenine', 'Chemical', 'MESH:D000225', (315, 322))	('amide III', 'Chemical', 'MESH:D000577', (422, 431))	('CH2CH3', 'Chemical', 'MESH:C103208', (554, 560))	('thymine', 'Chemical', 'MESH:D013941', (540, 547))	('CH3CH2', 'Chemical', 'MESH:C103208', (462, 468))
411943	31416240	This showed three specific Raman peaks at 963-967, 998 and 1032 cm-1, which were assigned to the C-N deformed vibration, symmetric respiratory vibration of phenylalanine, CH2CH3 bending (e.g., phospholipid) and C-C vibration (e.g., polysaccharide).	('CH2CH3', 'Var', (171, 177))	('CH2CH3', 'Chemical', 'MESH:C103208', (171, 177))	('C-N', 'Chemical', 'MESH:C521609', (97, 100))	('phenylalanine', 'Chemical', 'MESH:C119108', (156, 169))	('deformed', 'Var', (101, 109))
411948	31416240	Additionally, the peak intensity ratio of I1221/I735 and I998/I735 were above 1 in the M10A-exosome; in cancerous exosomes, by contrast, this is below 1 (Figure 4a,b).	('I998/I735', 'Var', (57, 66))	('cancerous', 'Disease', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('M10A', 'Mutation', 'p.M10A', (87, 91))	('cancerous', 'Disease', 'MESH:D009369', (104, 113))	('I1221/I735', 'Var', (42, 52))
411951	31416240	It has been proved that diploid, triploid, binuclear, or multinuclear cells may appear in the process of cancer cell proliferation.	('diploid', 'CPA', (24, 31))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('multinuclear cells', 'CPA', (57, 75))	('triploid', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('binuclear', 'CPA', (43, 52))
411960	31416240	For example, the vibration contributed to amino acid/proteins (919, 998, 1067, 1221, 1264, 1453, 1562 cm-1), carbohydrates (1374, 1532 cm-1) and lipids (1067, 1264, 1532 cm-1) on the membranes were stronger in M10A-exosomes than that of M231- and MCF7-exosomes.	('vibration contributed', 'MPA', (17, 38))	('stronger', 'PosReg', (198, 206))	('carbohydrates', 'Chemical', 'MESH:D002241', (109, 122))	('M10A', 'Mutation', 'p.M10A', (210, 214))	('M10A-exosomes', 'Var', (210, 223))
411961	31416240	For example, in normal exosome of L02 and M10A, the intensity of 1374 cm-1 (carbohydrate, A, T, G) was stronger than 1318 cm-1 (amide III); however, the cancerous exosomes were the opposite.	('amide III', 'Chemical', 'MESH:D000577', (128, 137))	('cancerous', 'Disease', (153, 162))	('M10A', 'Mutation', 'p.M10A', (42, 46))	('intensity', 'MPA', (52, 61))	('carbohydrate', 'Chemical', 'MESH:D002241', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('L02', 'Var', (34, 37))	('stronger', 'PosReg', (103, 111))	('cancerous', 'Disease', 'MESH:D009369', (153, 162))	('1374 cm-1', 'Var', (65, 74))	('M10A', 'Var', (42, 46))
411967	31416240	As for EC109 and EC9706, these two cell lines are both human esophageal squamous cell carcinoma and have many common characteristics, thus they showed the same Raman phenotypes and some of the samples mixed together in the PCA model.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('esophageal squamous cell carcinoma', 'Disease', (61, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (61, 95))	('PCA', 'Disease', (223, 226))	('human', 'Species', '9606', (55, 60))	('EC109', 'Var', (7, 12))	('EC9706', 'Var', (17, 23))
411997	29865880	We hypothesize that a moderate CAIX expression facilitates metastases and thereby worsens prognosis.	('prognosis', 'CPA', (90, 99))	('facilitates', 'PosReg', (47, 58))	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('CAIX', 'Protein', (31, 35))	('worsens', 'NegReg', (82, 89))	('expression', 'Var', (36, 46))	('metastases', 'Disease', (59, 69))
412012	29865880	Cell lines PT1590, LN1590, PT6216, LN6216c, LN6216gc, and LN6216o were acquired from primary tumour and lymph nodes of patients with esophageal adenocarcinoma at the University Medical Center Hamburg-Eppendorf as described previously.	('PT6216', 'CellLine', 'CVCL:0C59', (27, 33))	('LN6216o', 'Var', (58, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('LN6216gc', 'Var', (44, 52))	('esophageal adenocarcinoma', 'Disease', (133, 158))	('LN6216', 'CellLine', 'CVCL:0C58', (44, 50))	('LN6216', 'CellLine', 'CVCL:0C58', (58, 64))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (133, 158))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('LN6216c', 'Var', (35, 42))	('LN6216', 'CellLine', 'CVCL:0C58', (35, 41))	('PT6216', 'Var', (27, 33))	('LN1590', 'Var', (19, 25))
412064	29865880	In two further studies, a high CAIX expression was associated with shorter survival in both adeno and squamous cell esophageal carcinoma.	('high', 'Var', (26, 30))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (116, 136))	('adeno', 'Disease', (92, 97))	('CAIX', 'Protein', (31, 35))	('survival', 'MPA', (75, 83))	('shorter', 'NegReg', (67, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell esophageal carcinoma', 'Disease', (102, 136))	('expression', 'MPA', (36, 46))	('squamous cell esophageal carcinoma', 'Disease', 'MESH:D000077277', (102, 136))
412139	28977943	One large well-designed, comprehensive population-based study analyzed cancers associated with the ten leading causes of cancer-related death, including EC, and found that unmarried status contributed to poor survival rates in all ten cancers.	('death', 'Disease', (136, 141))	('poor', 'NegReg', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Disease', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('unmarried', 'Var', (172, 181))	('death', 'Disease', 'MESH:D003643', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancer', 'Disease', (235, 241))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancers', 'Disease', (235, 242))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Disease', (121, 127))
412206	28232848	EE was performed in standard manner with Olympus gastroduodenoscopes (GIF 1T160, GIFH180) and Pentax colonoscopes (FC-38M) in the case of acute GIB (hematemesis, hematochezia, and melena) and/or suspected GIB because of anemia and hypovolemic shock or deterioration of physical status in patients with known underlying GIB source.	('GIB', 'Disease', (205, 208))	('hematochezia', 'Phenotype', 'HP:0002573', (162, 174))	('GIB', 'Phenotype', 'HP:0002239', (205, 208))	('melena', 'Phenotype', 'HP:0002249', (180, 186))	('GIFH180', 'Var', (81, 88))	('anemia', 'Phenotype', 'HP:0001903', (220, 226))	('hematochezia', 'Disease', (162, 174))	('hematochezia', 'Disease', 'MESH:D006471', (162, 174))	('hematemesis', 'Disease', 'MESH:D006396', (149, 160))	('shock', 'Phenotype', 'HP:0031273', (243, 248))	('acute GIB', 'Disease', (138, 147))	('GIB', 'Phenotype', 'HP:0002239', (319, 322))	('hematemesis', 'Phenotype', 'HP:0002248', (149, 160))	('hematemesis', 'Disease', (149, 160))	('GIB', 'Phenotype', 'HP:0002239', (144, 147))	('hypovolemic shock', 'Phenotype', 'HP:0031274', (231, 248))	('hypovolemic shock', 'Disease', 'MESH:D012769', (231, 248))	('hypovolemic shock', 'Disease', (231, 248))
412231	28232848	In these situations, injection therapy or the application of clips can cause mucosal damage or may increase vessel lesions accidentally, resulting in further increasing the likelihood of severe or recurrent GIB.	('mucosal damage', 'Disease', (77, 91))	('cause', 'Reg', (71, 76))	('GIB', 'Disease', (207, 210))	('injection therapy', 'Var', (21, 38))	('GIB', 'Phenotype', 'HP:0002239', (207, 210))	('vessel lesions accidentally', 'Disease', 'MESH:D000081084', (108, 135))	('mucosal damage', 'Disease', 'MESH:D009059', (77, 91))	('increasing', 'PosReg', (158, 168))	('vessel lesions accidentally', 'Disease', (108, 135))	('increase', 'PosReg', (99, 107))
412299	27957305	Kaplan-Meier survivals estimation of the overall survival for definitive chemo-radiation with cisplatin, cisplatin+5-FU, cisplatin+irinotecan, and cisplatin+paclitaxel are shown in Figure 1 and for definitive chemo-radiation with old regimens and new regimens are shown in Figure 2.	('paclitaxel', 'Chemical', 'MESH:D017239', (157, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('men', 'Species', '9606', (238, 241))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('cisplatin+irinotecan', 'Var', (121, 141))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('cisplatin+5-FU', 'Var', (105, 119))	('5-FU', 'Chemical', 'MESH:D005472', (115, 119))	('men', 'Species', '9606', (255, 258))	('irinotecan', 'Chemical', 'MESH:D000077146', (131, 141))
412323	27957305	We also proved that cisplatin with the 5-FU scheme was statistically significant better than the cisplatin with paclitaxel scheme (p = 0.028).	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('better', 'PosReg', (81, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('paclitaxel', 'Chemical', 'MESH:D017239', (112, 122))	('5-FU', 'Var', (39, 43))	('5-FU', 'Chemical', 'MESH:D005472', (39, 43))
412357	24369500	There were 10-11.9% mismatched cases shown to have a pathological complete response despite being diagnosed with residual tumors.	('mismatched', 'Var', (20, 30))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Disease', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
412361	23466817	Known oncomirs, such as miR-21, miR-25 and miR-223, and tumor suppressor miRNAs, including miR-205, miR-203, let-7c, and miR-133a, showed progressively altered expression from BE to EA.	('miR-223', 'Gene', (43, 50))	('miR-203', 'Gene', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('let-7c', 'Gene', (109, 115))	('altered', 'Reg', (152, 159))	('BE', 'Phenotype', 'HP:0100580', (176, 178))	('miR-203', 'Gene', '406986', (100, 107))	('miR-25', 'Gene', (32, 38))	('EA', 'Phenotype', 'HP:0011459', (182, 184))	('miR-205', 'Gene', '406988', (91, 98))	('miR-223', 'Gene', '407008', (43, 50))	('miR-21', 'Gene', '406991', (24, 30))	('let-7c', 'Gene', '406885', (109, 115))	('miR-133a', 'Var', (121, 129))	('expression', 'MPA', (160, 170))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('miR-25', 'Gene', '407014', (32, 38))	('miR-21', 'Gene', (24, 30))	('miR-205', 'Gene', (91, 98))
412376	23466817	Aberrant miRNA expressions have been observed in almost all solid tumors and hematological malignancies studied.	('miRNA expressions', 'MPA', (9, 26))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Aberrant', 'Var', (0, 8))	('hematological malignancies', 'Disease', 'MESH:D019337', (77, 103))	('observed', 'Reg', (37, 45))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('hematological malignancies', 'Phenotype', 'HP:0004377', (77, 103))	('hematological malignancies', 'Disease', (77, 103))
412391	23466817	There were only a few miRNAs that were significantly different in EA but not in BE tissues compared to NE, including miR-375 (down-regulated in EA only, not in BE) and miR-106-3b, miR-18, miR-18-3p, miR-20b, and miR-92a-1-3p (up-regulated in EA only, not in BE) (Supplemental Table 1).	('miR-18-3p', 'Gene', (188, 197))	('EA', 'Phenotype', 'HP:0011459', (144, 146))	('miR-106-3b', 'Var', (168, 178))	('miR-18', 'Gene', '406953', (180, 186))	('miR-18-3p', 'Gene', '406959', (188, 197))	('BE', 'Phenotype', 'HP:0100580', (258, 260))	('down-regulated', 'NegReg', (126, 140))	('miR-92a-1', 'Gene', (212, 221))	('miR-20b', 'Gene', '574032', (199, 206))	('miR-375', 'Gene', '494324', (117, 124))	('miR-18', 'Gene', '406953', (188, 194))	('miR-92a-1', 'Gene', '407048', (212, 221))	('up-regulated', 'PosReg', (226, 238))	('BE', 'Phenotype', 'HP:0100580', (80, 82))	('miR-18', 'Gene', (180, 186))	('miR-375', 'Gene', (117, 124))	('BE', 'Phenotype', 'HP:0100580', (160, 162))	('EA', 'Phenotype', 'HP:0011459', (242, 244))	('miR-18', 'Gene', (188, 194))	('EA', 'Phenotype', 'HP:0011459', (66, 68))	('miR-20b', 'Gene', (199, 206))
412421	23466817	Loss of miR-23b may therefore confer proliferative advantage and promote esophageal carcinogenesis.	('proliferative advantage', 'CPA', (37, 60))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (73, 98))	('esophageal carcinogenesis', 'Disease', (73, 98))	('miR-23b', 'Gene', '407011', (8, 15))	('promote', 'PosReg', (65, 72))	('miR-23b', 'Gene', (8, 15))	('Loss', 'Var', (0, 4))
412426	23466817	Paradoxically, we found miR-133a and miR-1, two putative tumor-suppressing miRNAs, having the largest fold increase in expression in BE patients.	('expression', 'MPA', (119, 129))	('increase', 'PosReg', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('miR-1', 'Gene', (37, 42))	('patients', 'Species', '9606', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('BE', 'Phenotype', 'HP:0100580', (133, 135))	('tumor', 'Disease', (57, 62))	('miR-133a', 'Var', (24, 32))
412429	23466817	MiR-133a and miR-1 have been shown to suppress tumorigenic property, mediate apoptosis and cell cycle arrest, and inhibit proliferation and invasion in bladder, esophageal, lung, and head and neck cancer cells.	('tumor', 'Disease', (47, 52))	('inhibit', 'NegReg', (114, 121))	('bladder', 'Disease', (152, 159))	('MiR-133a', 'Var', (0, 8))	('apoptosis', 'CPA', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('esophageal', 'Disease', (161, 171))	('head and neck cancer', 'Phenotype', 'HP:0012288', (183, 203))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('invasion', 'CPA', (140, 148))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('lung', 'Disease', (173, 177))	('neck cancer', 'Disease', 'MESH:D006258', (192, 203))	('miR-1', 'Gene', (13, 18))	('neck cancer', 'Disease', (192, 203))	('cell cycle arrest', 'CPA', (91, 108))	('suppress', 'NegReg', (38, 46))
412435	23466817	The miRNAs encoded by these three clusters can be categorized into four separate miRNA families according to their seed sequences, including the miR-17 family (miR-17, miR-20a, miR-20b, miR-106a, miR-106b, and miR-93), the miR-18 family (miR-18a and miR-18b), the miR-19 family (miR-19a, miR-19b-1, and miR-19b-2) and the miR-92 family (miR-92a-1, miR-92a-2, miR-383, and miR-25).	('miR-20b', 'Gene', '574032', (177, 184))	('miR-18', 'Gene', '406953', (238, 244))	('miR-93', 'Gene', '407051', (210, 216))	('miR-18b', 'Gene', '574033', (250, 257))	('miR-106b', 'Gene', '406900', (196, 204))	('miR-17', 'Gene', '406952', (160, 166))	('miR-18', 'Gene', (223, 229))	('miR-19b-1', 'Gene', (288, 297))	('miR-106b', 'Gene', (196, 204))	('miR-106a', 'Gene', (186, 194))	('miR-17', 'Gene', (145, 151))	('miR-20a', 'Gene', (168, 175))	('miR-383', 'Gene', '494332', (359, 366))	('miR-20a', 'Gene', '406982', (168, 175))	('miR-18', 'Gene', (238, 244))	('miR-92a-2', 'Gene', '407049', (348, 357))	('miR-19b-2', 'Gene', '406981', (303, 312))	('miR-383', 'Gene', (359, 366))	('miR-19b-1', 'Gene', '406980', (288, 297))	('miR-25', 'Gene', (372, 378))	('miR-92a-2', 'Gene', (348, 357))	('miR-92', 'Gene', '407047', (348, 354))	('miR-92', 'Gene', '407047', (322, 328))	('miR-19b-2', 'Gene', (303, 312))	('miR-20b', 'Gene', (177, 184))	('miR-18a', 'Gene', (238, 245))	('miR-17', 'Gene', (160, 166))	('miR-18', 'Gene', '406953', (250, 256))	('miR-92a-1', 'Gene', (337, 346))	('miR-106a', 'Gene', '406899', (186, 194))	('miR-19a', 'Var', (279, 286))	('miR-92', 'Gene', '407047', (337, 343))	('miR-92', 'Gene', (348, 354))	('miR-92', 'Gene', (322, 328))	('miR-92a-1', 'Gene', '407048', (337, 346))	('miR-18', 'Gene', (250, 256))	('miR-93', 'Gene', (210, 216))	('miR-17', 'Gene', '406952', (145, 151))	('miR-92', 'Gene', (337, 343))	('miR-25', 'Gene', '407014', (372, 378))	('miR-18a', 'Gene', '406953', (238, 245))	('miR-18', 'Gene', '406953', (223, 229))	('miR-18b', 'Gene', (250, 257))
412473	33552060	Rat GAL2 transfected into Chinese hamster ovary (CHO) cells and human embryonic kidney 293 (HEK-293) cells did not alter forskolin-stimulated cAMP accumulation after galanin activity.	('human', 'Species', '9606', (64, 69))	('Rat', 'Species', '10116', (0, 3))	('galanin', 'Gene', (166, 173))	('CHO', 'CellLine', 'CVCL:0213', (49, 52))	('embryonic kidney', 'Disease', (70, 86))	('forskolin-stimulated cAMP accumulation', 'MPA', (121, 159))	('forskolin', 'Chemical', 'MESH:D005576', (121, 130))	('293 (HEK-293)', 'CellLine', 'CVCL:0045', (87, 100))	('embryonic kidney', 'Disease', 'MESH:D007674', (70, 86))	('cAMP', 'Chemical', 'MESH:D000242', (142, 146))	('transfected', 'Var', (9, 20))	('galanin', 'Gene', '51083', (166, 173))	('Chinese hamster', 'Species', '10029', (26, 41))
412505	33552060	In porcine diabetes models, an increase in GAL-positive cells was observed after streptozotocin supplementation in antrum and pylorus but only in the myenteric plexus.	('streptozotocin', 'Chemical', 'MESH:D013311', (81, 95))	('diabetes', 'Disease', (11, 19))	('diabetes', 'Disease', 'MESH:D003920', (11, 19))	('GAL-positive cells', 'CPA', (43, 61))	('supplementation', 'Var', (96, 111))	('increase', 'PosReg', (31, 39))
412512	33552060	In the case of intragastric administration of Brachyspira hyodysenteriae, an increase in the number of enteric GAL-IR nerve fibers and neurons in the examined porcine stomach was noted.	('enteric GAL-IR nerve fibers', 'CPA', (103, 130))	('rat', 'Species', '10116', (36, 39))	('increase', 'PosReg', (77, 85))	('Brachyspira hyodysenteriae', 'Species', '159', (46, 72))	('Brachyspira hyodysenteriae', 'Var', (46, 72))
412532	33552060	According to research by Zacharko-Siembida et al., supplementation with red kidney bean (Phaseolus vulgaris) lectins resulted in a statistically significant increase in GAL distribution in submucosal neurons (79.1 +- 5.3% in experimental vs. 56.8 +- 6.4% in control) in porcine jejunum.	('GAL distribution', 'MPA', (169, 185))	('increase', 'PosReg', (157, 165))	('kidney bean', 'Species', '3885', (76, 87))	('supplementation', 'Var', (51, 66))	('Phaseolus vulgaris', 'Species', '3885', (89, 107))
412652	32850412	Dose constraints applied were as follows: spinal cord, V28 < 0.03 cm3, V22 < 0.35 cm3, and V15.6 < 1.2 cm3; trachea and ipsilateral bronchus, V40 < 0.03 cm3, V32 < 5 cm3; heart, V38 < 0.3 cm3, and V32 < 15 cm3); and gastric pull-up area, V35 < 0.05 cm3, V26.5 < 5 cm3.	('trachea', 'Disease', (108, 115))	('V15.6', 'Var', (91, 96))	('V35 < 0.05 cm3', 'Var', (238, 252))	('trachea', 'Disease', 'MESH:C557675', (108, 115))	('V40 < 0.03 cm3', 'Var', (142, 156))	('V38 < 0.3', 'Var', (178, 187))	('V32 < 15 cm3', 'Var', (197, 209))	('V32 < 5 cm3', 'Var', (158, 169))	('V26.5 <', 'Var', (254, 261))
412731	31671695	The Oncogene AF1Q is Associated with WNT and STAT Signaling and Offers a Novel Independent Prognostic Marker in Patients with Resectable Esophageal Cancer AF1q impairs survival in hematologic and solid malignancies.	('impairs', 'NegReg', (160, 167))	('malignancies', 'Disease', 'MESH:D009369', (202, 214))	('AF1q', 'Chemical', '-', (155, 159))	('Associated', 'Reg', (21, 31))	('Cancer', 'Phenotype', 'HP:0002664', (148, 154))	('malignancies', 'Disease', (202, 214))	('AF1q', 'Var', (155, 159))	('survival', 'CPA', (168, 176))	('hematologic', 'Disease', (180, 191))	('Cancer', 'Disease', (148, 154))	('Cancer', 'Disease', 'MESH:D009369', (148, 154))
412738	31671695	Patients with AF1q-positive EC relapsed and died earlier compared to patients with AF1q-negative EC (disease-free survival (DFS), p = 0.0005; disease-specific survival (DSS), p = 0.003); in the multivariable Cox regression model, AF1q proved to be an independent prognostic marker (DFS, p = 0.01; DSS, p = 0.03).	('AF1q', 'Chemical', '-', (83, 87))	('AF1q', 'Chemical', '-', (14, 18))	('AF1q', 'Var', (230, 234))	('DSS', 'Chemical', '-', (169, 172))	('died', 'Disease', (44, 48))	('died', 'Disease', 'MESH:D003643', (44, 48))	('DSS', 'Chemical', '-', (297, 300))	('AF1q', 'Chemical', '-', (230, 234))
412750	31671695	However, the exact mechanisms that AF1q involves to promote cancer are largely unidentified.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('AF1q', 'Chemical', '-', (35, 39))	('AF1q', 'Var', (35, 39))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('promote', 'PosReg', (52, 59))
412767	31671695	The following antibodies were used: CD44 (Santa Cruz, sc-9960) in a 1:200 dilution and AF1q (Abcam, ab109016) in a 1:200 dilution.	('CD44', 'Var', (36, 40))	('AF1q', 'Var', (87, 91))	('AF1q', 'Chemical', '-', (87, 91))
412779	31671695	Patient and tumor characteristics compared between AF1q-positive and AF1q-negative tumors are compiled in Table 1.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('AF1q', 'Chemical', '-', (69, 73))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('AF1q-positive', 'Var', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('AF1q', 'Chemical', '-', (51, 55))
412781	31671695	Patients with AF1q-positive tumors suffered from a higher rate of positive resection margins (R1) compared to patients with AF1q-negative tumors (p = 0.004).	('AF1q', 'Chemical', '-', (14, 18))	('AF1q', 'Chemical', '-', (124, 128))	('AF1q-positive', 'Var', (14, 27))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('positive', 'CPA', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
412791	31671695	In a multivariable Cox regression model, AF1q proved to be an independent factor for survival (DFS p = 0.01; DSS p = 0.03) next to the local tumor stage in regard to DSS (p = 0.007, respectively), regional lymph node metastases (DFS, p < 0.0001 and DSS, p < 0.0001, respectively), and histological tumor subtype (DFS p = 0.0004 and DSS, p = 0.003) as well as neoadjuvant therapy in regard to DFS (p = 0.005).	('AF1q', 'Chemical', '-', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('DSS', 'Chemical', '-', (332, 335))	('DSS', 'Chemical', '-', (109, 112))	('tumor', 'Disease', (298, 303))	('AF1q', 'Var', (41, 45))	('metastases', 'Disease', 'MESH:D009362', (217, 227))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('DSS', 'Chemical', '-', (249, 252))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('DSS', 'Chemical', '-', (166, 169))	('metastases', 'Disease', (217, 227))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
412797	31671695	We previously reported that AF1q physically binds TCF/LEF and STAT3 and boosts their target gene transcription.	('STAT3', 'Gene', (62, 67))	('AF1q', 'Chemical', '-', (28, 32))	('TCF/LEF', 'Gene', (50, 57))	('AF1q', 'Var', (28, 32))	('boosts', 'PosReg', (72, 78))	('binds', 'Interaction', (44, 49))
412798	31671695	In breast cancer patients, the cooperation of AF1q with TCF7 led to the transcription of CD44, which is a WNT target gene that is essentially involved in tumor progression and epithelial-to-mesenchymal transition.	('TCF7', 'Gene', (56, 60))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('AF1q', 'Chemical', '-', (46, 50))	('cooperation', 'Var', (31, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('transcription', 'MPA', (72, 85))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CD44', 'Gene', (89, 93))	('AF1q', 'Var', (46, 50))	('led to', 'Reg', (61, 67))	('tumor', 'Disease', (154, 159))
412799	31671695	In invasive breast cancer cells, AF1q further induced pYSTAT3 levels through the Src kinase-driven PDGFB/PDGFRB cascade.	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('pYSTAT3 levels', 'MPA', (54, 68))	('invasive breast cancer', 'Disease', (3, 25))	('AF1q', 'Chemical', '-', (33, 37))	('invasive breast cancer', 'Disease', 'MESH:D001943', (3, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('AF1q', 'Var', (33, 37))	('induced', 'PosReg', (46, 53))
412800	31671695	Similarily to the findings in breast cancer, we here demonstrate an association of AF1q with both WNT and STAT signaling in the sense that the patients with AF1q-positive EC show enhanced tumoral levels of both proposed downstream targets CD44 and pYSTAT3.	('AF1q', 'Chemical', '-', (83, 87))	('association', 'Interaction', (68, 79))	('AF1q-positive', 'Var', (157, 170))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('enhanced', 'PosReg', (179, 187))	('STAT signaling', 'MPA', (106, 120))	('breast cancer', 'Disease', (30, 43))	('tumoral', 'Disease', (188, 195))	('tumoral', 'Disease', 'MESH:D009369', (188, 195))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('CD44', 'MPA', (239, 243))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('pYSTAT3', 'MPA', (248, 255))	('AF1q', 'Gene', (83, 87))	('AF1q', 'Chemical', '-', (157, 161))
412804	31671695	In addition, AF1q-positive ECs show higher rates of positive resection margins compared to AF1q-negative ECs.	('AF1q', 'Chemical', '-', (13, 17))	('higher', 'PosReg', (36, 42))	('AF1q-positive', 'Var', (13, 26))	('AF1q', 'Chemical', '-', (91, 95))	('positive resection margins', 'CPA', (52, 78))
412805	31671695	We believe that the AF1q-induced co-activation of WNT and STAT signaling plays a key role in EC initiation, proliferation, and dissemination.	('WNT', 'Pathway', (50, 53))	('AF1q-induced', 'Var', (20, 32))	('AF1q', 'Chemical', '-', (20, 24))
412814	31671695	In this cohort of patients, AF1q proved to have a highly significant prognostic impact on both DFS and DSS in the univariate analysis.	('DFS', 'Disease', (95, 98))	('AF1q', 'Chemical', '-', (28, 32))	('AF1q', 'Var', (28, 32))	('DSS', 'Chemical', '-', (103, 106))	('DSS', 'Disease', (103, 106))
412818	31671695	We demonstrate here for the first time a positive correlation between the expression of AF1q and the WNT and the STAT3 target genes CD44 and pYSTAT3 in EC, suggesting that AF1q may act as a cofactor for boosting the transcription of CD44 and pYSTAT3 in EC.	('expression', 'MPA', (74, 84))	('AF1q', 'Gene', (88, 92))	('AF1q', 'Chemical', '-', (172, 176))	('transcription', 'MPA', (216, 229))	('pYSTAT3', 'Gene', (141, 148))	('AF1q', 'Var', (172, 176))	('pYSTAT3', 'Gene', (242, 249))	('AF1q', 'Chemical', '-', (88, 92))	('boosting', 'PosReg', (203, 211))	('CD44', 'Gene', (233, 237))	('CD44', 'Gene', (132, 136))
412820	31671695	The association of AF1q with WNT and STAT3 signaling implicates various (combinatorial) targeting options such as CD44 and STAT3, JAK, and Src, as well as tyrosine kinases.	('implicates', 'Reg', (53, 63))	('tyrosine', 'Chemical', 'MESH:D014443', (155, 163))	('AF1q', 'Gene', (19, 23))	('association', 'Interaction', (4, 15))	('AF1q', 'Chemical', '-', (19, 23))	('CD44', 'Var', (114, 118))
412851	29901650	According to the esophageal cancer TNM (tumor, node, metastasis) staging system (American Joint Committee on Cancer/International Union for Cancer Control staging system, 2010), the pathological stage was IIIb: T3N1bM0.	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Cancer', 'Disease', (109, 115))	('Cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('TNM', 'Gene', '10178', (35, 38))	('esophageal cancer', 'Disease', (17, 34))	('Cancer', 'Disease', 'MESH:D009369', (109, 115))	('Cancer', 'Disease', 'MESH:D009369', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (17, 34))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Cancer', 'Phenotype', 'HP:0002664', (140, 146))	('TNM', 'Gene', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('T3N1bM0', 'Var', (211, 218))
412881	29901650	Tyrosine kinase inhibitor (TKI) therapy was reported with partial response in cases both with and without EGFR mutation for pulmonary MEC.	('pulmonary MEC', 'Disease', (124, 137))	('EGFR', 'Gene', (106, 110))	('EGFR', 'Gene', '1956', (106, 110))	('mutation', 'Var', (111, 119))
412924	27088503	Kaplan-Meier univariate analysis, showed that patients with ETL < 3 cm have a 5-year survival rate significantly better compared to those with ETL >= 3 cm (47% versus 29.1%, log-rank P<0.0001, respectively); this result is confirmed also in the SCC and AC groups (SCC: 41.6% versus 24.9%, log-rank P<0.0001, respectively; AC: 54.1% versus 33.9%, log-rank P = 0.0030, respectively).	('SCC', 'Gene', '6317', (245, 248))	('patients', 'Species', '9606', (46, 54))	('better', 'PosReg', (113, 119))	('SCC', 'Gene', (264, 267))	('SCC', 'Phenotype', 'HP:0002860', (264, 267))	('survival', 'CPA', (85, 93))	('SCC', 'Gene', '6317', (264, 267))	('ETL < 3 cm', 'Var', (60, 70))	('SCC', 'Gene', (245, 248))	('SCC', 'Phenotype', 'HP:0002860', (245, 248))
412977	23710306	The majority of luminal GI cancers follow an adenoma-carcinoma sequence with sequential and progressive genomic instability, loss of heterozygosity, up-regulation of oncogenes and down-regulation of tumor suppressor genes.	('down-regulation', 'NegReg', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (45, 62))	('up-regulation', 'PosReg', (149, 162))	('tumor suppressor', 'Gene', '7248', (199, 215))	('oncogenes', 'Protein', (166, 175))	('adenoma-carcinoma', 'Disease', (45, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('loss of heterozygosity', 'Var', (125, 147))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('luminal GI cancers', 'Disease', (16, 34))	('tumor suppressor', 'Gene', (199, 215))	('luminal GI cancers', 'Disease', 'MESH:D009369', (16, 34))	('GI cancer', 'Phenotype', 'HP:0007378', (24, 33))
413006	23710306	Phosphorylation of H2Ax to form gammaH2Ax in chromatin around DNA breaks is an early event in the induction of cellular senescence and serves as a landing pad for the accumulation and retention of the central components of the signaling cascade in senescence.	('cellular', 'CPA', (111, 119))	('gammaH2Ax', 'Chemical', '-', (32, 41))	('H2Ax', 'Gene', (19, 23))	('Phosphorylation', 'Var', (0, 15))	('H2Ax', 'Gene', (37, 41))	('H2Ax', 'Gene', '3014', (19, 23))	('H2Ax', 'Gene', '3014', (37, 41))
413012	23710306	Other studies involving mouse models and prostate cancer found that inactivation of p53 led to decreased numbers of senescent cells as well as aggressive growth of cancer cells.	('decreased', 'NegReg', (95, 104))	('mouse', 'Species', '10090', (24, 29))	('prostate cancer', 'Disease', 'MESH:D011471', (41, 56))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('p53', 'Gene', (84, 87))	('prostate cancer', 'Disease', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('inactivation', 'Var', (68, 80))
413031	23710306	Senescence increased the susceptibility of pancreatic stellate cells to immune-mediated cell destruction.	('susceptibility', 'MPA', (25, 39))	('pancreatic stellate', 'Disease', (43, 62))	('Senescence', 'Var', (0, 10))	('pancreatic stellate', 'Disease', 'MESH:D010195', (43, 62))
413036	23710306	Similar data from human thyroid anaplastic carcinoma cells also supports the inhibition of proliferation and cell growth following p53 re-expression.	('re-expression', 'Var', (135, 148))	('thyroid anaplastic carcinoma', 'Phenotype', 'HP:0011779', (24, 52))	('human', 'Species', '9606', (18, 23))	('p53', 'Gene', (131, 134))	('cell growth', 'CPA', (109, 120))	('thyroid anaplastic carcinoma', 'Disease', 'MESH:D065646', (24, 52))	('inhibition', 'NegReg', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('proliferation', 'CPA', (91, 104))	('thyroid anaplastic carcinoma', 'Disease', (24, 52))
413037	23710306	Human studies with hepatocellular carcinoma have found that p53 mutations are commonly associated with poorly differentiated tumors and appear to be an early molecular event.	('Human', 'Species', '9606', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('associated', 'Reg', (87, 97))	('p53', 'Gene', (60, 63))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (19, 43))	('mutations', 'Var', (64, 73))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (19, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('hepatocellular carcinoma', 'Disease', (19, 43))
413051	23710306	Identifying senescent cells, DNA damage response and loss of p16 in both the Barrett's epithelium and underlying esophageal stroma may have a role in predicting whether patients with high-grade dysplasia will respond to endoscopic therapy and radiofrequency ablation.	('respond', 'Reg', (209, 216))	('patients', 'Species', '9606', (169, 177))	('p16', 'Protein', (61, 64))	('dysplasia', 'Disease', (194, 203))	('esophageal stroma', 'Disease', 'MESH:D004941', (113, 130))	('dysplasia', 'Disease', 'MESH:D004476', (194, 203))	('loss', 'Var', (53, 57))	('esophageal stroma', 'Disease', (113, 130))
413062	23710306	They postulated that sustained inactivation of p53, a master cell cycle protein that is needed to trigger the senescence pathway, may be required for continued tumor maintenance and survival.	('inactivation', 'Var', (31, 43))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('p53', 'Gene', (47, 50))	('tumor', 'Disease', (160, 165))
413070	23710306	Pharmacologic reactivation of p53 may then be a promising target for the treatment of human cancers.	('Pharmacologic', 'Var', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('p53', 'Gene', (30, 33))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
413115	21305538	Impaired TGF-beta and Smad4 signaling prevents cell cycle arrest and promotes invasion in esophageal adenocarcinoma cells by increased expression of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1(PAI-1) through MAPK pathways.	('esophageal adenocarcinoma', 'Disease', (90, 115))	('increased', 'PosReg', (125, 134))	('PAI-1', 'Gene', (230, 235))	('plasminogen activator inhibitor 1', 'Gene', '5054', (196, 229))	('promotes', 'PosReg', (69, 77))	('prevents', 'NegReg', (38, 46))	('Impaired', 'Var', (0, 8))	('expression', 'MPA', (135, 145))	('uPA', 'Gene', (187, 190))	('plasminogen activator inhibitor 1', 'Gene', (196, 229))	('uPA', 'Gene', '5328', (187, 190))	('arrest', 'Disease', (58, 64))	('TGF-beta', 'Gene', (9, 17))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (90, 115))	('urokinase-type plasminogen activator', 'Gene', (149, 185))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (90, 115))	('invasion', 'CPA', (78, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('PAI-1', 'Gene', '5054', (230, 235))	('arrest', 'Disease', 'MESH:D006323', (58, 64))	('urokinase-type plasminogen activator', 'Gene', '5328', (149, 185))
413117	21305538	In addition, we have found that deletion of beta-2 spectrin, the crucial adaptor for Smad2/3 and Smad4 resulted in a dramatic and spontaneous formation of liver and gastrointestinal cancers including esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('deletion', 'Var', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('beta-2', 'Gene', '10242', (44, 50))	('liver and gastrointestinal cancers', 'Disease', 'MESH:D006528', (155, 189))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('Smad2/3', 'Gene', (85, 92))	('esophageal cancer', 'Disease', (200, 217))	('beta-2', 'Gene', (44, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (200, 217))	('Smad2/3', 'Gene', '4087;4088', (85, 92))
413120	21305538	Aberrant activation of Notch signaling has been reported in some hematologic malignancies and multiple solid tumors.	('activation', 'PosReg', (9, 19))	('hematologic malignancies', 'Disease', (65, 89))	('Aberrant', 'Var', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('Notch signaling', 'Pathway', (23, 38))	('reported', 'Reg', (48, 56))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))	('solid tumors', 'Disease', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('hematologic malignancies', 'Disease', 'MESH:D019337', (65, 89))
413125	21305538	We and others have recently observed multiple gastrointestinal cancers including gastric and esophageal in mouse mutants of the TGF-beta pathway; the tumors potentially arise from a clonal population of dysfunctional stem cells with activation of oncogenic events.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('mouse', 'Species', '10090', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('TGF-beta pathway', 'Gene', (128, 144))	('multiple gastrointestinal cancers', 'Disease', 'MESH:D004067', (37, 70))	('mutants', 'Var', (113, 120))	('gastric', 'Disease', (81, 88))	('esophageal', 'Disease', (93, 103))	('multiple gastrointestinal cancers', 'Disease', (37, 70))
413126	21305538	In this study, we provide evidence that Barrett's-related adenocarcinoma could result from a dysfunctional population of stem cells arising from disrupted TGF-beta and subsequent activation of Notch signaling.	('disrupted', 'Var', (145, 154))	('Notch signaling', 'MPA', (193, 208))	('dysfunctional population', 'MPA', (93, 117))	('adenocarcinoma', 'Disease', (58, 72))	('TGF-beta', 'Protein', (155, 163))	('adenocarcinoma', 'Disease', 'MESH:D000230', (58, 72))	('result from', 'Reg', (79, 90))	('activation', 'PosReg', (179, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
413182	21305538	Given the tumor suppressor activity of TGF-beta signaling, we decided to evaluate the functional consequence of its disruption and evaluate RUNX3 and CDK4 expression.	('RUNX3', 'Gene', '864', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('disruption', 'Var', (116, 126))	('expression', 'MPA', (155, 165))	('CDK4', 'Gene', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('RUNX3', 'Gene', (140, 145))	('CDK4', 'Gene', '1019', (150, 154))
413193	21305538	Disruption of TGF-beta signaling is an important factor in Barrett's esophagus and esophageal adenocarcinoma.	('TGF-beta', 'Protein', (14, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (83, 108))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (59, 78))	('esophageal adenocarcinoma', 'Disease', (83, 108))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (83, 108))	('Disruption', 'Var', (0, 10))
413194	21305538	Loss of the tumor suppressor function of TGF-beta signaling through Smad4 in esophageal cancer has been previously described as a cause of tumor progression due to the loss of the transcription factor RUNX3, loss of p16, p21 and gain of CDK4.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('tumor', 'Disease', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('tumor', 'Disease', (12, 17))	('CDK4', 'Gene', '1019', (237, 241))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('p16', 'Gene', (216, 219))	('Loss', 'NegReg', (0, 4))	('p21', 'Gene', (221, 224))	('RUNX3', 'Gene', '864', (201, 206))	('p16', 'Gene', '1029', (216, 219))	('Smad4', 'Gene', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('gain', 'PosReg', (229, 233))	('loss', 'NegReg', (168, 172))	('p21', 'Gene', '1026', (221, 224))	('loss', 'Var', (208, 212))	('RUNX3', 'Gene', (201, 206))	('CDK4', 'Gene', (237, 241))
413199	21305538	Aberrant activation of Notch signaling has been reported in gastrointestinal cancers including colon cancer and pancreatic cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('activation', 'PosReg', (9, 19))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('Aberrant', 'Var', (0, 8))	('gastrointestinal cancers', 'Disease', (60, 84))	('pancreatic cancers', 'Disease', (112, 130))	('colon cancer', 'Disease', 'MESH:D015179', (95, 107))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (60, 84))	('Notch signaling', 'Pathway', (23, 38))	('colon cancer', 'Phenotype', 'HP:0003003', (95, 107))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('pancreatic cancers', 'Disease', 'MESH:D010190', (112, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('colon cancer', 'Disease', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (112, 130))
413208	21305538	gamma-secretase inhibitor GSI XXI inhibits cell proliferation only in BE3 with dysfunction of TGF-beta and high notch signaling but not in SKGT-4 cells and FLO-1 and OE33 other esophageal adenocarcinoma cell lines with lower Notch signaling.	('GSI', 'Chemical', '-', (26, 29))	('inhibits', 'NegReg', (34, 42))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (177, 202))	('dysfunction', 'Var', (79, 90))	('esophageal adenocarcinoma', 'Disease', (177, 202))	('SKGT-4', 'CellLine', 'CVCL:2195', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (177, 202))	('TGF-beta', 'Gene', (94, 102))	('high notch signaling', 'MPA', (107, 127))	('cell proliferation', 'CPA', (43, 61))
413216	21305538	Meanwhile, RUNX3 expression has been evaluated in esophageal adenocarcinoma cell lines and it was found that the restoration of RUNX3 expression via transfection was able to produce robust inhibition of cell growth.	('transfection', 'Var', (149, 161))	('cell growth', 'CPA', (203, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (50, 75))	('RUNX3', 'Gene', '864', (11, 16))	('expression', 'MPA', (134, 144))	('esophageal adenocarcinoma', 'Disease', (50, 75))	('RUNX3', 'Gene', (11, 16))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (50, 75))	('RUNX3', 'Gene', '864', (128, 133))	('RUNX3', 'Gene', (128, 133))	('restoration', 'Var', (113, 124))	('inhibition', 'NegReg', (189, 199))
413217	21305538	Moreover, beta2SP/Smad4 double heterozygous mice develop multiple gastric tumors with E-Cadeherin/beta-catenin complexes in gastric epithelial cells of these mutant mice.	('mice', 'Species', '10090', (165, 169))	('develop', 'PosReg', (49, 56))	('beta2SP', 'Chemical', '-', (10, 17))	('gastric tumors', 'Disease', 'MESH:D013274', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('gastric tumors', 'Disease', (66, 80))	('gastric tumors', 'Phenotype', 'HP:0006753', (66, 80))	('mutant', 'Var', (158, 164))	('mice', 'Species', '10090', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
413227	21305538	Loss of beta2SP/Smad4, resulting in the disruption of TGF-beta signaling, could contribute to the activation of Notch signaling via Hes-1, a Notch signaling molecule (Figure 6).	('activation', 'PosReg', (98, 108))	('Hes-1', 'Gene', (132, 137))	('Hes-1', 'Gene', '3280', (132, 137))	('Notch signaling', 'MPA', (112, 127))	('beta2SP', 'Chemical', '-', (8, 15))	('TGF-beta', 'Gene', (54, 62))	('beta2SP/Smad4', 'Protein', (8, 21))	('disruption', 'MPA', (40, 50))	('Loss', 'Var', (0, 4))
413228	21305538	Moreover, rescue of TGF-beta signaling by restoration of beta2SP-Smad4 or Notch inhibition by gamma-secretase inhibitors in the setting of dysfunctional of TGF-beta signaling could hold promise for new personalized therapeutic approaches in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (241, 266))	('beta2SP-Smad4', 'Gene', (57, 70))	('beta2SP-Smad4', 'Gene', '4089', (57, 70))	('dysfunctional', 'Var', (139, 152))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (241, 266))	('esophageal adenocarcinoma', 'Disease', (241, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
413235	27296953	In the subgroup analysis, median PFS was 4.0 +- 0.2 months (95% CI, 3.6-4.3) in patients with high expression of miRNA-214, while it was 4.6 +- 0.3 months (95% CI, 4.1-5.1) in patients with low expression of miRNA-214 (log rank = 0.023).	('patients', 'Species', '9606', (176, 184))	('miRNA-214', 'Gene', (113, 122))	('patients', 'Species', '9606', (80, 88))	('miRNA-214', 'Gene', '406996', (208, 217))	('miRNA-214', 'Gene', '406996', (113, 122))	('high expression', 'Var', (94, 109))	('miRNA-214', 'Gene', (208, 217))
413257	27296953	Recent evidence demonstrates that miRNAs may function similarly to oncogenes or tumor suppressors, suggesting that they may play an important role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', (80, 85))	('miRNAs', 'Var', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('play', 'Reg', (124, 128))
413258	27296953	confirmed that pri-miR-124-1 rs531564 and pri-miR-34 rs4938723 were associated with an increased risk of ESCC in Chinese patients.	('rs4938723', 'Mutation', 'rs4938723', (53, 62))	('rs531564', 'Var', (29, 37))	('ESCC', 'Disease', (105, 109))	('miR-124-1', 'Gene', '406907', (19, 28))	('rs531564', 'Mutation', 'rs531564', (29, 37))	('miR-34', 'Gene', (46, 52))	('miR-124-1', 'Gene', (19, 28))	('miR-34', 'Gene', '407040', (46, 52))	('rs4938723', 'Var', (53, 62))	('patients', 'Species', '9606', (121, 129))
413278	27296953	In the subgroup analysis, the PFS was significantly different in patients with high expression of miRNA-214 when compared to low expression.	('PFS', 'MPA', (30, 33))	('miRNA-214', 'Gene', (98, 107))	('different', 'Reg', (52, 61))	('miRNA-214', 'Gene', '406996', (98, 107))	('patients', 'Species', '9606', (65, 73))	('high expression', 'Var', (79, 94))
413302	27296953	In one study, the miRNA expression level was compared in matched ESCC tissues and normal tissues by quantitative polymerase chain reaction, and it was determined that expression levels of miR-98, miR-101, and miR-214 were significantly lower in tumor than in normal tissues.	('miR-101', 'Var', (196, 203))	('lower', 'NegReg', (236, 241))	('tumor', 'Disease', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('miR-98', 'Gene', '407054', (188, 194))	('miR-214', 'Gene', (209, 216))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('miR-98', 'Gene', (188, 194))	('miR-214', 'Gene', '406996', (209, 216))	('expression levels', 'MPA', (167, 184))
413317	29727831	Significantly better 3-year DFS and OS rates among patients who received right thoracic esophagectomy were found, as compared with left thoracic esophagectomy.	('better', 'PosReg', (14, 20))	('DFS', 'CPA', (28, 31))	('patients', 'Species', '9606', (51, 59))	('right', 'Var', (73, 78))
413393	28053055	Codes for a diagnosis of Barrett's esophagus include: the International Classification of Disease 9th revision (ICD-9) code 530.2 "Barrett's ulcer", which on KPNC endoscopy reporting sheets was specified as "Barrett's esophagitis"; ICD-9 code 530.85 "Barrett's esophagus", which was introduced in 2003 and replaced 530.2; and the Systematized Nomenclature of Medicine (SNOMED) code M73330 (Barrett's esophagus).	('esophagitis', 'Disease', 'MESH:D004941', (218, 229))	("Barrett's esophagitis", 'Phenotype', 'HP:0100580', (208, 229))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (390, 409))	('M73330', 'Var', (382, 388))	('ulcer', 'Disease', 'MESH:D014456', (141, 146))	('ulcer', 'Disease', (141, 146))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (251, 270))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (25, 44))	('esophagitis', 'Phenotype', 'HP:0100633', (218, 229))	('esophagitis', 'Disease', (218, 229))
413494	28035369	miRNA-196a negatively regulates the expression of ANXA1, thereby inhibiting the proliferation, invasion and metastasis of ESCC cells.	('invasion', 'CPA', (95, 103))	('metastasis', 'CPA', (108, 118))	('negatively', 'NegReg', (11, 21))	('regulates', 'Reg', (22, 31))	('ESCC', 'Disease', (122, 126))	('proliferation', 'CPA', (80, 93))	('inhibiting', 'NegReg', (65, 75))	('ANXA1', 'Gene', (50, 55))	('expression', 'Species', '120120', (36, 46))	('miRNA-196a', 'Var', (0, 10))	('expression', 'MPA', (36, 46))	('ANXA1', 'Gene', '301', (50, 55))
413501	28035369	In addition, microRNAs (miRNAs or miRs) can bind with messenger RNAs (mRNAs) of target gene, thus negatively regulating gene expression and affecting the occurrence and progression of a variety of tumors, Luthra et al reported that miR-196a negatively regulates the expression of the ANXA1 gene, thus affecting the prognosis of esophageal adenocarcinoma.	('expression', 'MPA', (266, 276))	('regulates', 'Reg', (252, 261))	('affecting', 'Reg', (301, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('gene expression', 'MPA', (120, 135))	('negatively', 'NegReg', (98, 108))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('expression', 'Species', '120120', (266, 276))	('ANXA1', 'Gene', '301', (284, 289))	('negatively', 'NegReg', (241, 251))	('regulating', 'Reg', (109, 119))	('affecting', 'Reg', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (328, 353))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (328, 353))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('miR-196a', 'Var', (232, 240))	('expression', 'Species', '120120', (125, 135))	('esophageal adenocarcinoma', 'Disease', (328, 353))	('miR-196a', 'Chemical', '-', (232, 240))	('ANXA1', 'Gene', (284, 289))
413503	28035369	Therefore, the question of whether the expression of ANXA1 in ESCC affects the proliferation, invasion and metastasis of ESCC cells, as well as the prognosis of ESCC, and whether it is also negatively regulated by miR-196a, is still worthy of investigation.	('invasion', 'CPA', (94, 102))	('proliferation', 'CPA', (79, 92))	('metastasis', 'CPA', (107, 117))	('affects', 'Reg', (67, 74))	('expression', 'Var', (39, 49))	('ANXA1', 'Gene', (53, 58))	('ESCC', 'Disease', (161, 165))	('expression', 'Species', '120120', (39, 49))	('miR-196a', 'Chemical', '-', (214, 222))	('ANXA1', 'Gene', '301', (53, 58))
413519	28035369	SAB1405457, 1:1,000; anti-Snail, WH0006591M5, 1:2,000; anti-E-cadherin, WH0000999M1, 1:2,000; and the internal control beta-actin, A1978, 1:3,000) (all from Sigma-Aldrich, St. Louis, MO, USA) for overnight culture at 4 C with mild shaking.	('Snail', 'Gene', (26, 31))	('Snail', 'Gene', '6615', (26, 31))	('beta-actin', 'Gene', '728378', (119, 129))	('WH0000999M1', 'Var', (72, 83))	('beta-actin', 'Gene', (119, 129))	('WH0006591M5', 'Var', (33, 44))
413539	28035369	The results of RT-PCR indicated that following transfection of the cells with miR-196a mimic, the expression of miR-196a in the cells was significantly increased (relative expression level, 1.1 vs. 43, p<0.001; Fig.	('increased', 'PosReg', (152, 161))	('miR-196a', 'Var', (112, 120))	('expression', 'Species', '120120', (172, 182))	('miR-196a', 'Chemical', '-', (78, 86))	('miR-196a', 'Chemical', '-', (112, 120))	('expression', 'Species', '120120', (98, 108))	('expression', 'MPA', (98, 108))
413540	28035369	The results of western blot analysis revealed that ANXA1 protein expression was significantly downregulated in the cells transfected with miR-196a mimic, with a significantly lighter electrophoretic band (Fig.	('miR-196a mimic', 'Var', (138, 152))	('miR-196a', 'Chemical', '-', (138, 146))	('ANXA1', 'Gene', (51, 56))	('ANXA1', 'Gene', '301', (51, 56))	('expression', 'Species', '120120', (65, 75))	('lighter', 'NegReg', (175, 182))	('electrophoretic band', 'MPA', (183, 203))	('expression', 'MPA', (65, 75))	('downregulated', 'NegReg', (94, 107))	('protein', 'Protein', (57, 64))
413541	28035369	4B), indicating that the overexpression of miR-196a significantly decreased the expression of ANXA1, thus confirming that miR-196a negatively regulates the expression of ANXA1 in ESCC cells.	('miR-196a', 'Chemical', '-', (122, 130))	('miR-196a', 'Var', (43, 51))	('ANXA1', 'Gene', (94, 99))	('decreased', 'NegReg', (66, 75))	('ANXA1', 'Gene', (170, 175))	('negatively', 'NegReg', (131, 141))	('miR-196a', 'Var', (122, 130))	('ANXA1', 'Gene', '301', (94, 99))	('expression', 'Species', '120120', (80, 90))	('ANXA1', 'Gene', '301', (170, 175))	('expression', 'Species', '120120', (156, 166))	('regulates', 'Reg', (142, 151))	('expression', 'Species', '120120', (29, 39))	('expression', 'MPA', (80, 90))	('expression', 'MPA', (156, 166))	('miR-196a', 'Chemical', '-', (43, 51))
413542	28035369	The results of MTT assay revealed that the survival rate of the cells transfected with the miR-196a mimic was significantly lower than that of the cells in the control group (Pre-NC group; 57 vs. 100%, p=0.027) (Fig.	('miR-196a mimic', 'Var', (91, 105))	('MTT', 'Chemical', '-', (15, 18))	('miR-196a', 'Chemical', '-', (91, 99))	('lower', 'NegReg', (124, 129))	('survival rate', 'CPA', (43, 56))
413543	28035369	However, co-transfection of the cells with the miR-196a mimic and the ANXA1 overexpression plasmid reversed the inhibitory effects of miR-196a on cell proliferation (90 vs. 57%, p=0.034) (Fig.	('ANXA1', 'Gene', (70, 75))	('ANXA1', 'Gene', '301', (70, 75))	('miR-196a', 'Var', (134, 142))	('expression', 'Species', '120120', (80, 90))	('miR-196a', 'Chemical', '-', (47, 55))	('miR-196a', 'Chemical', '-', (134, 142))	('cell proliferation', 'CPA', (146, 164))
413545	28035369	However, co-transfection of the cells with miR-196a mimic and the ANXA1 overexpression plasmid reversed the inhibitory effects of miR-196a on cell migration and invasion (99 vs. 56, p=0.015; 38 vs. 24, p=0.04, respectively) (Fig.	('ANXA1', 'Gene', (66, 71))	('miR-196a', 'Var', (130, 138))	('invasion', 'CPA', (161, 169))	('expression', 'Species', '120120', (76, 86))	('cell migration', 'CPA', (142, 156))	('ANXA1', 'Gene', '301', (66, 71))	('miR-196a', 'Chemical', '-', (43, 51))	('miR-196a', 'Chemical', '-', (130, 138))
413546	28035369	These results confirmed that miR-196a decreases ANXA1 expression, thereby inhibiting the proliferation, migration and invasion of Eca109 cells.	('expression', 'MPA', (54, 64))	('decreases', 'NegReg', (38, 47))	('inhibiting', 'NegReg', (74, 84))	('proliferation', 'CPA', (89, 102))	('ANXA1', 'Gene', '301', (48, 53))	('miR-196a', 'Chemical', '-', (29, 37))	('invasion of Eca109 cells', 'CPA', (118, 142))	('expression', 'Species', '120120', (54, 64))	('miR-196a', 'Var', (29, 37))	('ANXA1', 'Gene', (48, 53))
413548	28035369	However, following the overexpression of miR-196a, the expression of E-cadherin was upregulated, while that of Snail was downregulated (Fig.	('E-cadherin', 'Protein', (69, 79))	('upregulated', 'PosReg', (84, 95))	('overexpression', 'PosReg', (23, 37))	('expression', 'Species', '120120', (27, 37))	('expression', 'Species', '120120', (55, 65))	('miR-196a', 'Var', (41, 49))	('expression', 'MPA', (55, 65))	('downregulated', 'NegReg', (121, 134))	('Snail', 'Gene', '6615', (111, 116))	('Snail', 'Gene', (111, 116))	('miR-196a', 'Chemical', '-', (41, 49))
413560	28035369	Hu et al analyzed the mutations in the promoter region and the coding region of the whole ANXA1 gene, and did not find any mutation or polymorphism so as to support this hypothesis.	('ANXA1', 'Gene', '301', (90, 95))	('mutations', 'Var', (22, 31))	('ANXA1', 'Gene', (90, 95))
413564	28035369	However, other studies have found opposite results, demonstrating that ANXA1 inhibits the growth, invasion and metastasis of nasopharyngeal carcinoma, and that the knockdown of ANXA1 promoted cell proliferation and invasion.	('invasion', 'CPA', (215, 223))	('cell proliferation', 'CPA', (192, 210))	('ANXA1', 'Gene', '301', (177, 182))	('growth', 'CPA', (90, 96))	('ANXA1', 'Gene', (71, 76))	('ANXA1', 'Gene', (177, 182))	('knockdown', 'Var', (164, 173))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (125, 149))	('metastasis of nasopharyngeal carcinoma', 'Disease', (111, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('metastasis of nasopharyngeal carcinoma', 'Disease', 'MESH:D009362', (111, 149))	('ANXA1', 'Gene', '301', (71, 76))	('promoted', 'PosReg', (183, 191))	('inhibits', 'NegReg', (77, 85))
413571	28035369	When ANXA1 mRNA and miR-196a are combined with each other, this can lead to the formation of a gene-silencing complex, thus blocking the protein translation of ANXA1.	('miR-196a', 'Chemical', '-', (20, 28))	('lead to', 'Reg', (68, 75))	('blocking', 'NegReg', (124, 132))	('protein translation', 'MPA', (137, 156))	('miR-196a', 'Var', (20, 28))	('ANXA1', 'Gene', (5, 10))	('ANXA1', 'Gene', (160, 165))	('ANXA1', 'Gene', '301', (5, 10))	('ANXA1', 'Gene', '301', (160, 165))
413572	28035369	This study found that miR-196a downregulated the expression of ANXA1, thus inhibiting the expression of Snail, while promoting the expression of E-cadherin, as well as inhibiting the proliferation, invasion and metastasis of ESCC cells, consistent with the findings of other studies.	('E-cadherin', 'Protein', (145, 155))	('promoting', 'PosReg', (117, 126))	('expression', 'Species', '120120', (131, 141))	('proliferation', 'CPA', (183, 196))	('expression', 'MPA', (90, 100))	('Snail', 'Gene', '6615', (104, 109))	('inhibiting', 'NegReg', (75, 85))	('ESCC', 'Disease', (225, 229))	('miR-196a', 'Var', (22, 30))	('expression', 'MPA', (49, 59))	('expression', 'Species', '120120', (90, 100))	('miR-196a', 'Chemical', '-', (22, 30))	('ANXA1', 'Gene', (63, 68))	('expression', 'Species', '120120', (49, 59))	('inhibiting', 'NegReg', (168, 178))	('metastasis', 'CPA', (211, 221))	('downregulated', 'NegReg', (31, 44))	('Snail', 'Gene', (104, 109))	('invasion', 'CPA', (198, 206))	('ANXA1', 'Gene', '301', (63, 68))	('expression', 'MPA', (131, 141))
413575	28035369	The use of miR-196a may thus be a promising new approach for the treatment of ESCC.	('ESCC', 'Disease', (78, 82))	('miR-196a', 'Var', (11, 19))	('miR-196a', 'Chemical', '-', (11, 19))
413577	28035369	miR-196a may downregulate ANXA1, thus negatively regulating ANXA1 and inhibiting the Snail/E-cadherin pathway, followed by the inhibition of EMT, and ultimately the inhibition of the proliferation, invasion and metastasis of ESCC cells.	('ANXA1', 'Gene', '301', (26, 31))	('ANXA1', 'Gene', '301', (60, 65))	('invasion', 'CPA', (198, 206))	('EMT', 'CPA', (141, 144))	('ESCC', 'Disease', (225, 229))	('miR-196a', 'Chemical', '-', (0, 8))	('Snail', 'Gene', '6615', (85, 90))	('Snail', 'Gene', (85, 90))	('downregulate', 'NegReg', (13, 25))	('miR-196a', 'Var', (0, 8))	('proliferation', 'CPA', (183, 196))	('metastasis', 'CPA', (211, 221))	('inhibiting', 'NegReg', (70, 80))	('negatively regulating', 'NegReg', (38, 59))	('ANXA1', 'Gene', (26, 31))	('inhibition', 'NegReg', (127, 137))	('ANXA1', 'Gene', (60, 65))	('inhibition', 'NegReg', (165, 175))
413581	27594985	We performed high coverage, paired end whole genome sequencing on eight EAC cell lines:ESO26, ESO51, FLO-1, JH-EsoAd1, OACM5.1 C, OACP4 C, OE33, SK-GT-4:all verified against original patient material, and one esophageal high grade dysplasia cell line, CP-D. We have made available the aligned sequence data and report single nucleotide variants (SNVs), small insertions and deletions (indels), and copy number alterations, identified by comparison with the human reference genome and known single nucleotide polymorphisms (SNPs).	('esophageal high grade dysplasia', 'Disease', 'MESH:D008228', (209, 240))	('human', 'Species', '9606', (457, 462))	('CP-D', 'Gene', (252, 256))	('single nucleotide variants', 'Var', (318, 344))	('SK-GT', 'Chemical', '-', (145, 150))	('esophageal high grade dysplasia', 'Disease', (209, 240))	('patient', 'Species', '9606', (183, 190))	('CP-D', 'Gene', '1362', (252, 256))
413584	27594985	In addition to point mutations there are also widespread copy number alterations with evidence of catastrophic events such as chromothripsis and bridge fusion breakages in about one-third of cases .	('bridge', 'Disease', (145, 151))	('chromothripsis', 'Disease', 'MESH:D000072837', (126, 140))	('copy number alterations', 'Var', (57, 80))	('chromothripsis', 'Disease', (126, 140))
413585	27594985	We selected eight EAC cell lines:ESO26, ESO51, FLO-1, JH-EsoAd1, OACM5.1 C, OACP4 C, OE33, SK-GT-4:the identities of which have been verified by short tandem repeat (STR) analysis, p53 mutation and xenograft histology against the original tumors , and one esophageal high grade dysplasia (CP-D) cell line.	('p53', 'Gene', (181, 184))	('p53', 'Gene', '7157', (181, 184))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('original tumors', 'Disease', 'MESH:D009369', (230, 245))	('CP-D', 'Gene', '1362', (289, 293))	('esophageal high grade dysplasia', 'Disease', 'MESH:D008228', (256, 287))	('esophageal high grade dysplasia', 'Disease', (256, 287))	('mutation', 'Var', (185, 193))	('original tumors', 'Disease', (230, 245))	('CP-D', 'Gene', (289, 293))	('SK-GT', 'Chemical', '-', (91, 96))
413586	27594985	We performed high-coverage paired-end whole genome sequencing and aligned the sequence data to the human reference genome in order to detect single nucleotide variants, indels and copy number alterations.	('human', 'Species', '9606', (99, 104))	('indels', 'Var', (169, 175))	('single nucleotide variants', 'Var', (141, 167))	('copy number alterations', 'Var', (180, 203))
413588	27594985	The number of variations identified in the high-grade dysplasia CP-D line was not significantly lower to the median of other EAC cell lines, consistent with the finding that such pre-malignant lesions have already accumulated many SNVs .	('dysplasia', 'Disease', (54, 63))	('CP-D', 'Gene', (64, 68))	('variations', 'Var', (14, 24))	('CP-D', 'Gene', '1362', (64, 68))	('dysplasia', 'Disease', 'MESH:D004476', (54, 63))
413590	27594985	Yet, the abundance of called variants compared to a range of 4,8x10 3-6x10 4 reported in human EAC , may indicate that a proportion of the variants called in our final annotation are of germline origin.	('human', 'Species', '9606', (89, 94))	('variants', 'Var', (29, 37))	('variants', 'Var', (139, 147))
413592	27594985	69% of EACs have TP53 mutations , while all cell lines carried at least one deleterious TP53 mutation.	('TP53', 'Gene', '7157', (88, 92))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (88, 92))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
413593	27594985	A SMAD4 mutation was present in 2 of 9 cell lines, ESO26 and JH-EsoAd, consistent with the 13% observed in EAC .	('SMAD4', 'Gene', '4089', (2, 7))	('SMAD4', 'Gene', (2, 7))	('mutation', 'Var', (8, 16))
413594	27594985	We were not able to identify mutations in ARID1A (affected by UTR variants in 1 of 9 cell lines) that is reportedly mutated in about 10% of cases of EAC specimens.	('ARID1A', 'Gene', '8289', (42, 48))	('ARID1A', 'Gene', (42, 48))	('variants', 'Var', (66, 74))	('EAC', 'Disease', (149, 152))
413597	27594985	We identified a pathogenic KRAS mutation in SKGT4, and a missense mutation of uncertain significance in MET (OE33), EGFR (CP-D, ESO26, IH-EsoAd1).	('SKGT4', 'CellLine', 'CVCL:2195', (44, 49))	('KRAS', 'Gene', '3845', (27, 31))	('EGFR', 'Gene', '1956', (116, 120))	('pathogenic', 'Reg', (16, 26))	('CP-D', 'Gene', (122, 126))	('CP-D', 'Gene', '1362', (122, 126))	('KRAS', 'Gene', (27, 31))	('SKGT4', 'Gene', (44, 49))	('mutation', 'Var', (32, 40))	('EGFR', 'Gene', (116, 120))
413598	27594985	Among DNA repair genes all cell lines carry benign missense variants of ATM and missense variants of uncertain significance in BRCA2.	('missense variants', 'Var', (80, 97))	('BRCA2', 'Gene', '675', (127, 132))	('BRCA2', 'Gene', (127, 132))	('ATM', 'Gene', (72, 75))	('missense variants', 'Var', (51, 68))
413599	27594985	MSH2 is affected by a missense variant in SKGT4, splice site variants in CP-D, JH-EsoAd1, and UTR variants in ESO51 and OACP4 C ( Supplementary material 3, Supplementary material 4, Supplementary material 6).	('CP-D', 'Gene', '1362', (73, 77))	('SKGT4', 'Gene', (42, 47))	('MSH2', 'Gene', (0, 4))	('affected by', 'Reg', (8, 19))	('SKGT4', 'CellLine', 'CVCL:2195', (42, 47))	('ESO51', 'Gene', (110, 115))	('MSH2', 'Gene', '4436', (0, 4))	('CP-D', 'Gene', (73, 77))	('missense variant', 'Var', (22, 38))	('variants', 'Var', (98, 106))
413600	27594985	Copy number analysis ( Supplementary material 1, Supplementary material 2) identified recurrent amplifications in ERBB2, MYC, MET and SEMA5A, and deletions in SMAD4, CDKN2A, CCDC102B and SMARCA4.	('CCDC102B', 'Gene', (174, 182))	('CDKN2A', 'Gene', (166, 172))	('SMAD4', 'Gene', (159, 164))	('MET', 'Gene', (126, 129))	('CDKN2A', 'Gene', '1029', (166, 172))	('MYC', 'Gene', (121, 124))	('CCDC102B', 'Gene', '79839', (174, 182))	('MYC', 'Gene', '4609', (121, 124))	('SMAD4', 'Gene', '4089', (159, 164))	('deletions', 'Var', (146, 155))	('SEMA5A', 'Gene', (134, 140))	('SMARCA4', 'Gene', (187, 194))	('SMARCA4', 'Gene', '6597', (187, 194))	('ERBB2', 'Gene', '2064', (114, 119))	('SEMA5A', 'Gene', '9037', (134, 140))	('ERBB2', 'Gene', (114, 119))
413602	27594985	Accession numbers: CP-D ERS1158083; SK-GT-4 ERS1158082; OE33 ERS1158081; OACP4 C ERS1158080; OACM5.1 ERS1158079; JH-EsoAd1 ERS1158078; FLO-1 ERS1158077; ES051 ERS1158076; ES026 ERS1158075.	('ERS1158078', 'Var', (123, 133))	('ERS1158079', 'Var', (101, 111))	('CP-D', 'Gene', (19, 23))	('ERS1158081', 'Var', (61, 71))	('ERS1158080', 'Var', (81, 91))	('CP-D', 'Gene', '1362', (19, 23))	('ES051 ERS1158076; ES026 ERS1158075', 'Var', (153, 187))	('ERS1158077', 'Var', (141, 151))	('ERS1158083', 'Var', (24, 34))	('SK-GT', 'Chemical', '-', (36, 41))	('ERS1158082', 'Var', (44, 54))
413604	27594985	Effect Predictor Analysis annotated VCF files of GAKT called variants for CP-D, ESO26, ESO51, FLO-1, JH-EsoAd1, OACM5.1 C, OACP4 C, OE33, SK-GT-4 are available for download at the EMBL-EBI European Variation Archive (EVA, http://www.ebi.ac.uk/eva/) under the study PRJEB14018).	('CP-D', 'Gene', '1362', (74, 78))	('variants', 'Var', (61, 69))	('SK-GT', 'Chemical', '-', (138, 143))	('CP-D', 'Gene', (74, 78))
413605	27594985	Filtered variants: 1) CP-D, 2) ESO26, 3) ESO51, 4) FLO-1, 5) JH-EsoAd1, 6) OACM5.1 C, 7) OACP4 C, 8) OE33, 9) SK-GT-4.	('OACP4 C', 'Var', (89, 96))	('CP-D', 'Gene', (22, 26))	('ESO51', 'Var', (41, 46))	('SK-GT', 'Chemical', '-', (110, 115))	('CP-D', 'Gene', '1362', (22, 26))	('OE33', 'Var', (101, 105))
413613	27594985	Dataset validation WGS section:   There isn't an ARID1A UTR variant shown for any of the cell lines in Figure 2b yet the authors mention 1 of the 9 cell lines has such a variant in the text.	('UTR', 'Gene', (56, 59))	('variant', 'Var', (60, 67))	('ARID1A', 'Gene', (49, 55))	('ARID1A', 'Gene', '8289', (49, 55))
413614	27594985	Presumably missense mutations were found in MET and EGFR?	('EGFR', 'Gene', (52, 56))	('EGFR', 'Gene', '1956', (52, 56))	('MET', 'Gene', (44, 47))	('missense mutations', 'Var', (11, 29))
413615	27594985	Both classes of variants will be of interest to researchers working on understanding the genetics of oesophageal adenocarcinoma and wishing to identify appropriate cell models to work with.	('oesophageal adenocarcinoma', 'Disease', (101, 127))	('variants', 'Var', (16, 24))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (101, 127))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))
413617	27594985	As the authors state, oesophageal adenocarcinoma seems to be one of the cancers carrying the most mutations, and although several cell lines, including those utilized in this study are commonly used for laboratory studies, there has never been a systemic study of the genetic abnormalities in these cells lines.	('oesophageal adenocarcinoma', 'Disease', (22, 48))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (22, 48))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (23, 48))	('mutations', 'Var', (98, 107))	('genetic abnormalities', 'Disease', 'MESH:D030342', (268, 289))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic abnormalities', 'Disease', (268, 289))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
413647	25133481	Nearly half of subjects enrolled in the Registry (48%) had non-dysplastic BE (NDBE) at baseline, while another 48% had dysplasia (21% low-grade (LGD), 19% high-grade (HGD), and 8% indefinite (IND)).	('BE', 'Phenotype', 'HP:0100580', (80, 82))	('dysplasia', 'Disease', 'MESH:D004476', (119, 128))	('non-dysplastic', 'Disease', (59, 73))	('low-grade', 'Var', (134, 143))	('IND', 'Chemical', '-', (192, 195))	('NDBE', 'Chemical', '-', (78, 82))	('high-grade', 'Var', (155, 165))	('BE', 'Phenotype', 'HP:0100580', (74, 76))	('dysplasia', 'Disease', (119, 128))	('non-dysplastic', 'Disease', 'MESH:D004416', (59, 73))
413711	23495056	Additionally, aberrant glycosylation of proteins has been implicated in many diseases, including cancer.	('glycosylation', 'MPA', (23, 36))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (14, 36))	('cancer', 'Disease', (97, 103))	('aberrant', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('proteins', 'Protein', (40, 48))	('implicated', 'Reg', (58, 68))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
413720	23495056	Reductive amination reagents suitable for stable-isotopic labeling have been developed to modify the reduced end of N-glycans and allow for relative quantification.	('modify', 'Var', (90, 96))	('N-glycans', 'Chemical', '-', (116, 125))	('reduced end of', 'MPA', (101, 115))
413724	23495056	Stable isotopic labeling of N-glycans through permethylation is an alternative to reductive amination and offers many advantages, including enhanced ionization efficiency, enhanced hydrophobicity, and simplified tandem MS interpretation.	('ionization', 'Disease', (149, 159))	('N-glycans', 'Chemical', '-', (28, 37))	('enhanced', 'PosReg', (140, 148))	('enhanced', 'PosReg', (172, 180))	('permethylation', 'Var', (46, 60))	('hydrophobicity', 'MPA', (181, 195))	('ionization', 'Disease', 'MESH:D004194', (149, 159))
413725	23495056	The enhanced hydrophobicity as a result of permethylation allows separation on a C18 column.	('enhanced', 'PosReg', (4, 12))	('C18', 'Gene', (81, 84))	('permethylation', 'Var', (43, 57))	('C18', 'Gene', '27241', (81, 84))	('hydrophobicity', 'MPA', (13, 27))
413726	23495056	Also, permethylation permits the simultaneous detection of both neutral and acidic glycans in positive ion mode mass spectrometry.	('mul', 'Gene', (35, 38))	('mul', 'Gene', '4591', (35, 38))	('permethylation', 'Var', (6, 20))	('glycans', 'Chemical', 'MESH:D011134', (83, 90))
413801	23495056	The retention times of CH2DI or CD3I permethylated glycans are lower than that of CH3I permethylated counterparts.	('CH2DI', 'Chemical', '-', (23, 28))	('CD3I', 'Chemical', '-', (32, 36))	('lower', 'NegReg', (63, 68))	('CH2DI', 'Var', (23, 28))	('CH3I', 'Chemical', 'MESH:C014055', (82, 86))	('retention times', 'MPA', (4, 19))	('CD3I permethylated', 'Var', (32, 50))	('glycans', 'Chemical', 'MESH:D011134', (51, 58))
413802	23495056	Moreover, the retention times of CD3I permethylated glycans are less than that of CH2DI permethylated counterparts.	('CH2DI', 'Chemical', '-', (82, 87))	('CD3I', 'Chemical', '-', (33, 37))	('glycans', 'Chemical', 'MESH:D011134', (52, 59))	('less', 'NegReg', (64, 68))	('CD3I permethylated', 'Var', (33, 51))	('retention times', 'MPA', (14, 29))
413811	23495056	The most intense ions of these glycan structures were [M+3H]3+ or [M+2H+NH4]3+.	('glycan', 'Chemical', 'MESH:D011134', (31, 37))	('[M+3H]3+', 'Var', (54, 62))	('[M+2H+NH4]3+', 'Var', (66, 78))	('3H', 'Chemical', 'MESH:D014316', (57, 59))	('2H', 'Chemical', 'MESH:D003903', (69, 71))	('NH4', 'Chemical', '-', (72, 75))
413812	23495056	The extracted ion chromatograms and mass spectra of H4N5S1 glycan with 809.0916 m/z values ("light" permethylated) and 844.3113 ("heavy" permethylated) are depicted in Figure 3a.	('809.0916', 'Var', (71, 79))	('glycan', 'Chemical', 'MESH:D011134', (59, 65))	('844.3113', 'Var', (119, 127))	('H4N5S1', 'Gene', (52, 58))	('H4N5', 'Species', '309406', (52, 56))
413813	23495056	The peak heights of the "heavy" permethylated glycans relative to that of "light" permethylated ones (H/L) for H4N5S1 (Figure 3a), N4H5S2 (Figure 3b), N5H6S3 (Figure 3c), and N5H6S4 (Figure 3d) were 1.07, 1.11, 0.99, and 1.10, respectively.	('H4N5', 'Species', '309406', (111, 115))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('N4H5S2', 'Var', (131, 137))	('N', 'Chemical', 'MESH:D009584', (175, 176))	('glycans', 'Chemical', 'MESH:D011134', (46, 53))	('H4N5S1', 'Var', (111, 117))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('N5H6S4', 'Var', (175, 181))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('N5H6S3', 'Var', (151, 157))
413823	23495056	The H/L ratios of N-glycan pairs for the same blood serum samples, but "light" and "heavy" permethylated were 1.05, 0.858 and 1.11 for H5N2 (Figure 4a), F1H3N5 (Figure 4b) and F1H4N5 (Figure 4c), respectively.	('H5N2', 'Species', '119220', (135, 139))	('H3N5', 'Species', '136481', (155, 159))	('F1H4N5', 'Var', (176, 182))	('N-glycan', 'Chemical', '-', (18, 26))	('F1H3N5', 'Var', (153, 159))	('H4N5', 'Species', '309406', (178, 182))	('H5N2', 'Var', (135, 139))
413826	23495056	The peak area ratios of H/L for the same glycans derived from cancer samples ("heavy" permethylated) and DF samples ("light" permethylated) were 1.52, 0.85, and 0.70 for H5N2 (Figure 4d), F1H3N5 (Figure 4e), and F1H4N5 (Figure 4f), respectively.	('glycans', 'Chemical', 'MESH:D011134', (41, 48))	('H5N2', 'Species', '119220', (170, 174))	('H5N2', 'Var', (170, 174))	('F1H4N5', 'Var', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('H4N5', 'Species', '309406', (214, 218))	('H3N5', 'Species', '136481', (190, 194))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('F1H3N5', 'Var', (188, 194))
413830	23495056	The ratios were 4.14 for H5N2 (Figure 5a), 0.63 for F1H3N5 (Figure 5b) and 0.80 for F1H4N5 (Figure 5c).	('H4N5', 'Species', '309406', (86, 90))	('F1H3N5', 'Var', (52, 58))	('F1H4N5', 'Var', (84, 90))	('H3N5', 'Species', '136481', (54, 58))	('H5N2', 'Species', '119220', (25, 29))
413831	23495056	The H/L peak area ratios of the same glycans derived from HGD and DF were 3.25 for H5N2 (Figure 6a), 0.63 for F1H3N5 (Figure 6b) and 0.69 for F1H4N5 (Figure 6c).	('F1H3N5', 'Var', (110, 116))	('glycans', 'Chemical', 'MESH:D011134', (37, 44))	('H5N2', 'Gene', (83, 87))	('H4N5', 'Species', '309406', (144, 148))	('H3N5', 'Species', '136481', (112, 116))	('H5N2', 'Species', '119220', (83, 87))
413840	33525727	Aberrant Left Subclavian Artery-Esophageal Fistula in a Patient with a Prolonged Use of Nasogastric Tube: A Case Report and Literature Review Arterial-esophageal fistula is a rare but potentially fatal complication.	('Patient', 'Species', '9606', (56, 63))	('Aberrant', 'Var', (0, 8))	('Nasogastric Tube', 'Phenotype', 'HP:0040288', (88, 104))	('fistula', 'Disease', 'MESH:D005402', (162, 169))	('fistula', 'Disease', (162, 169))	('Aberrant Left Subclavian Artery', 'Phenotype', 'HP:0031014', (0, 31))
413841	33525727	Right aortic arch with aberrant left subclavian artery is a rare congenital vascular anomaly that can cause esophageal compression, particularly when the proximal portion of the aberrant subclavian artery forms a Kommerell's diverticulum.	('congenital vascular anomaly', 'Disease', 'MESH:D000783', (65, 92))	('esophageal compression', 'Disease', (108, 130))	('cause', 'Reg', (102, 107))	("Kommerell's diverticulum", 'Phenotype', 'HP:0011593', (213, 237))	('Right aortic arch', 'Disease', (0, 17))	('Right aortic arch', 'Phenotype', 'HP:0012020', (0, 17))	('aberrant left subclavian artery', 'Phenotype', 'HP:0031014', (23, 54))	('aberrant subclavian artery', 'Phenotype', 'HP:0031014', (178, 204))	('aberrant', 'Var', (23, 31))	('Right aortic arch with aberrant left subclavian artery', 'Phenotype', 'HP:0011598', (0, 54))	('congenital vascular anomaly', 'Disease', (65, 92))
413843	33525727	We report a patient with massive gastrointestinal bleeding secondary to aberrant left subclavian artery-esophageal fistula after a prolonged use of nasogastric tube.	('artery-esophageal fistula', 'Disease', (97, 122))	('aberrant left subclavian artery', 'Phenotype', 'HP:0031014', (72, 103))	('artery-esophageal fistula', 'Disease', 'MESH:D004937', (97, 122))	('gastrointestinal bleeding', 'Disease', (33, 58))	('aberrant left', 'Var', (72, 85))	('nasogastric tube', 'Phenotype', 'HP:0040288', (148, 164))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (33, 58))	('patient', 'Species', '9606', (12, 19))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (33, 58))
413880	33525727	A literature search showed a total of 40 documented cases of aberrant subclavian artery and esophageal fistulae (Table 1).	('aberrant subclavian artery', 'Phenotype', 'HP:0031014', (61, 87))	('fistula', 'Disease', (103, 110))	('fistula', 'Disease', 'MESH:D005402', (103, 110))	('aberrant subclavian', 'Var', (61, 80))
413888	33525727	According to our review of documented cases of aberrant subclavian artery and esophageal fistulae so far, 24 of 40 patients (60%) eventually died of massive bleeding or associated complications.	('massive bleeding', 'Disease', (149, 165))	('aberrant', 'Var', (47, 55))	('patients', 'Species', '9606', (115, 123))	('aberrant subclavian artery', 'Phenotype', 'HP:0031014', (47, 73))	('fistula', 'Disease', 'MESH:D005402', (89, 96))	('fistula', 'Disease', (89, 96))	('massive bleeding', 'Disease', 'MESH:D014202', (149, 165))
413892	33525727	Our report aims to raise awareness to the fact that the presence of an arch anomaly is potentially responsible for fatal hemorrhage associated with a simple medical device such as an NG tube in a chronically ill patient.	('presence', 'Var', (56, 64))	('hemorrhage', 'Disease', (121, 131))	('arch anomaly', 'Disease', (71, 83))	('responsible', 'Reg', (99, 110))	('patient', 'Species', '9606', (212, 219))	('hemorrhage', 'Disease', 'MESH:D006470', (121, 131))	('arch anomaly', 'Phenotype', 'HP:0009794', (71, 83))	('arch anomaly', 'Disease', 'MESH:D001015', (71, 83))
413944	31450627	In studies analyzing clinical specimens, patients with high expression levels of CTR2 in ovarian tumors had poor survival outcomes from CDDP treatment compared with those with low expression levels.	('CDDP', 'Chemical', 'MESH:D002945', (136, 140))	('CTR2', 'Gene', '1318', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CTR2', 'Gene', (81, 85))	('patients', 'Species', '9606', (41, 49))	('high expression levels', 'Var', (55, 77))	('ovarian tumors', 'Disease', (89, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('ovarian tumors', 'Phenotype', 'HP:0100615', (89, 103))	('ovarian tumors', 'Disease', 'MESH:D010051', (89, 103))	('poor', 'NegReg', (108, 112))
413946	31450627	Naka and colleagues demonstrated that patients with gastric cancer and high expression levels of OCT2 are significantly correlated with positive responders to CDDP-based therapy.	('high', 'Var', (71, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('CDDP', 'Chemical', 'MESH:D002945', (159, 163))	('OCT2', 'Gene', '6582', (97, 101))	('patients', 'Species', '9606', (38, 46))	('OCT2', 'Gene', (97, 101))	('gastric cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))
413965	31450627	Some clinical studies analyzing tumor specimens have reported that high expression levels of Nrf2 correlate to inferior benefit from CDDP-containing therapies in patients with bladder and lung cancer.	('patients', 'Species', '9606', (162, 170))	('high', 'Var', (67, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('expression levels', 'MPA', (72, 89))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Nrf2', 'Gene', '4780', (93, 97))	('bladder and lung cancer', 'Disease', 'MESH:D001749', (176, 199))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('CDDP', 'Chemical', 'MESH:D002945', (133, 137))	('inferior', 'NegReg', (111, 119))	('tumor', 'Disease', (32, 37))	('Nrf2', 'Gene', (93, 97))	('S', 'Chemical', 'MESH:D013455', (0, 1))
413978	31450627	A study analyzing clinical specimens revealed that high expression levels of XPF are associated with inferior clinical response to CDDP in patients with head and neck cancer.	('XPF', 'Gene', (77, 80))	('clinical response', 'MPA', (110, 127))	('patients', 'Species', '9606', (139, 147))	('head and neck cancer', 'Disease', 'MESH:D006258', (153, 173))	('expression levels', 'MPA', (56, 73))	('CDDP', 'Chemical', 'MESH:D002945', (131, 135))	('high', 'Var', (51, 55))	('head and neck cancer', 'Phenotype', 'HP:0012288', (153, 173))	('XPF', 'Gene', '2072', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('inferior', 'NegReg', (101, 109))
413980	31450627	CDDP-induced DNA adducts without sufficient repair by the NER system can generate double-strand breaks, the most lethal DNA damage lesion.	('CDDP', 'Chemical', 'MESH:D002945', (0, 4))	('damage lesion', 'Disease', (124, 137))	('adducts', 'Var', (17, 24))	('damage lesion', 'Disease', 'MESH:D007674', (124, 137))	('double-strand breaks', 'MPA', (82, 102))	('generate', 'Reg', (73, 81))
413981	31450627	Breast cancer type 1 and 2 susceptibility protein (BRCA1 and 2) are two vital components of this system, and genetic alterations of their encoded genes are commonly found in patients with hereditary breast and ovarian cancer syndromes.	('BRCA1 and 2', 'Gene', '672;675', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('hereditary breast and ovarian cancer syndromes', 'Disease', 'MESH:D061325', (188, 234))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer type 1 and 2 susceptibility protein', 'Gene', '672;675', (0, 49))	('ovarian cancer', 'Phenotype', 'HP:0100615', (210, 224))	('patients', 'Species', '9606', (174, 182))	('genetic alterations', 'Var', (109, 128))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('found', 'Reg', (165, 170))
413983	31450627	For example, a study enrolling patients with BRCA1/2-defective ovarian cancer demonstrated that patients with these mutations respond positively to platinum-based drug therapies.	('platinum', 'Chemical', 'MESH:D010984', (148, 156))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('mutations', 'Var', (116, 125))	('patients', 'Species', '9606', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('patients', 'Species', '9606', (96, 104))	('BRCA1/2-defective ovarian cancer', 'Disease', (45, 77))	('BRCA1/2-defective ovarian cancer', 'Disease', 'MESH:D010051', (45, 77))
413984	31450627	In particular, the National Comprehensive Cancer Network Guideline states that CDDP-based regimens are preferential in the treatment of patients with pancreatic cancer and known BRCA1/2 mutations.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('CDDP', 'Chemical', 'MESH:D002945', (79, 83))	('BRCA1/2', 'Gene', '672;675', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutations', 'Var', (186, 195))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('patients', 'Species', '9606', (136, 144))	('BRCA1/2', 'Gene', (178, 185))	('pancreatic cancer', 'Disease', (150, 167))
413985	31450627	Although there were only a few enrolled subjects, a study from an eminent cancer research center demonstrated that patients with pancreatic cancer carrying these mutations had favorable responses to platinum-based treatments.	('patients', 'Species', '9606', (115, 123))	('mutations', 'Var', (162, 171))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', (74, 80))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('platinum', 'Chemical', 'MESH:D010984', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
413988	31450627	Thus, the MMR defect is now thought to engender the development of DNA damage tolerance and subsequent CDDP resistance.	('defect', 'Var', (14, 20))	('MMR', 'Gene', (10, 13))	('CDDP', 'Chemical', 'MESH:D002945', (103, 107))
414008	31450627	Alterations in ECM stiffness and elasticity can establish a physical barrier hindering drug delivery to cancer cells.	('drug delivery', 'MPA', (87, 100))	('elasticity', 'MPA', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Alterations', 'Var', (0, 11))	('hindering', 'NegReg', (77, 86))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
414035	31450627	In a recent study using a transgenic mouse model with breast cancer cells, Salvagno and colleagues showed that CSF-1R blockade is an effective way to enhance CDDP-induced anticancer activity, which is stimulated by an intratumoral type I IFN response.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (175, 181))	('IFN', 'Gene', '3439', (238, 241))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('CDDP', 'Chemical', 'MESH:D002945', (158, 162))	('breast cancer', 'Disease', (54, 67))	('mouse', 'Species', '10090', (37, 42))	('CDDP-induced', 'Gene', (158, 170))	('S', 'Chemical', 'MESH:D013455', (75, 76))	('IFN', 'Gene', (238, 241))	('tumor', 'Disease', (223, 228))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('CSF-1R', 'Gene', (111, 117))	('S', 'Chemical', 'MESH:D013455', (112, 113))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('blockade', 'Var', (118, 126))	('enhance', 'PosReg', (150, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
414039	31450627	Furthermore, Samuel and colleagues demonstrated that secreted EVs from ovarian cancer cells during CDDP treatment can lead to invasiveness and drug resistance in bystander cells.	('lead to', 'Reg', (118, 125))	('drug resistance', 'Phenotype', 'HP:0020174', (143, 158))	('ovarian cancer', 'Disease', 'MESH:D010051', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))	('drug resistance in bystander', 'CPA', (143, 171))	('ovarian cancer', 'Disease', (71, 85))	('EVs', 'Var', (62, 65))	('S', 'Chemical', 'MESH:D013455', (13, 14))	('invasiveness', 'CPA', (126, 138))	('CDDP', 'Chemical', 'MESH:D002945', (99, 103))
414042	31450627	Qix and colleagues showed that miR-196a wrapping in CAF-derived exosomes can enhance CDDP resistance in head and neck cancer cells.	('head and neck cancer', 'Phenotype', 'HP:0012288', (104, 124))	('enhance', 'PosReg', (77, 84))	('CDDP resistance', 'CPA', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('miR-196a wrapping', 'Var', (31, 48))	('head and neck cancer', 'Disease', 'MESH:D006258', (104, 124))	('CAF', 'Chemical', 'MESH:C035000', (52, 55))	('CDDP', 'Chemical', 'MESH:D002945', (85, 89))
414052	31450627	Results from this study suggested that CTLs can abrogate CAF-mediated GSH metabolism and platinum resistance through the immunogenic action of IFN-beta.	('CAF', 'Chemical', 'MESH:C035000', (57, 60))	('GSH', 'Chemical', 'MESH:D005978', (70, 73))	('IFN-beta', 'Gene', '3456', (143, 151))	('platinum resistance', 'CPA', (89, 108))	('IFN-beta', 'Gene', (143, 151))	('CAF-mediated GSH metabolism', 'MPA', (57, 84))	('platinum', 'Chemical', 'MESH:D010984', (89, 97))	('CTLs', 'Var', (39, 43))	('abrogate', 'NegReg', (48, 56))
414073	31450627	In this study, we found that the CSF1R c.1085A>G genetic variant, which is present in approximately 40% of the East Asian population, can regulate the polarization status and function of macrophages.	('polarization', 'CPA', (151, 163))	('CSF1R', 'Gene', (33, 38))	('c.1085A>G', 'Mutation', 'c.1085A>G', (39, 48))	('regulate', 'Reg', (138, 146))	('CSF1R', 'Gene', '1436', (33, 38))	('c.1085A>G', 'Var', (39, 48))	('function of macrophages', 'CPA', (175, 198))
414074	31450627	Macrophages with this CSF1R genetic variant are resistant to CSF-1 stimulation but sensitive to CSF-1R inhibitors.	('CSF-1', 'Gene', '1435', (61, 66))	('variant', 'Var', (36, 43))	('CSF1R', 'Gene', (22, 27))	('CSF-1', 'Gene', '1435', (96, 101))	('CSF-1', 'Gene', (61, 66))	('CSF-1', 'Gene', (96, 101))	('CSF1R', 'Gene', '1436', (22, 27))
414075	31450627	These results suggest that the CSF1R c.1085A>G genetic variant might be a potential biomarker that can be used in targeting CSF-1R signaling for cancer treatments.	('cancer', 'Disease', (145, 151))	('c.1085A>G', 'Mutation', 'c.1085A>G', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('CSF-1R signaling', 'MPA', (124, 140))	('CSF1R', 'Gene', '1436', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('c.1085A>G', 'Var', (37, 46))	('CSF1R', 'Gene', (31, 36))
414095	31450627	Preclinical and clinical studies have showed that CDDP resistance is a complex biological phenomenon mediated by inner adaptive mechanisms of tumor cells responsive to not only CDDP stimulation but also the interaction from any TME component.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CDDP', 'Var', (177, 181))	('tumor', 'Disease', (142, 147))	('CDDP', 'Chemical', 'MESH:D002945', (50, 54))	('CDDP', 'Chemical', 'MESH:D002945', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
414101	31450627	The study was supported by a research grant from the Ministry of Health and Welfare (MOHW107-TDU-B-211-123003 and MOHW108-TDU-B-211-133003), National Health Research Institutes (CA-108-PP-24), and Ministry of Science and Technology (MOST104-2314-B-400-026 and MOST107-2314-B-400-014).	('MOST104-2314-B-400-026', 'Var', (233, 255))	('MOHW108-TDU-B-211-133003', 'Chemical', 'MESH:C072528', (114, 138))	('CA-108-PP-24', 'Chemical', 'MESH:C541976', (178, 190))	('S', 'Chemical', 'MESH:D013455', (209, 210))	('MOHW107-TDU-B-211-123003', 'Chemical', 'MESH:C415942', (85, 109))	('MOHW108-TDU-B-211-133003', 'Var', (114, 138))	('MOST107-2314-B-400-014', 'Var', (260, 282))	('MOST104-2314-B-400-026 and MOST107-2314-B-400-014', 'Chemical', 'MESH:C095293', (233, 282))	('MOHW107-TDU-B-211-123003', 'Var', (85, 109))	('S', 'Chemical', 'MESH:D013455', (235, 236))	('S', 'Chemical', 'MESH:D013455', (262, 263))
414111	30268789	Dysplastic BE tissues also had significantly increased levels of ZEB1 and significantly decreased levels of CDH1 compared with non-dysplastic BE tissues.	('levels', 'MPA', (55, 61))	('increased', 'PosReg', (45, 54))	('BE', 'Phenotype', 'HP:0100580', (142, 144))	('BE', 'Disease', 'MESH:D001471', (11, 13))	('Dysplastic', 'Var', (0, 10))	('CDH1', 'MPA', (108, 112))	('decreased', 'NegReg', (88, 97))	('BE', 'Disease', 'MESH:D001471', (142, 144))	('ZEB1', 'Protein', (65, 69))	('levels', 'MPA', (98, 104))	('BE', 'Phenotype', 'HP:0100580', (11, 13))
414113	30268789	These observations suggest that reflux induces EMT in metaplastic BE tissues, which promotes development of SSIM.	('development of SSIM', 'CPA', (93, 112))	('BE', 'Phenotype', 'HP:0100580', (66, 68))	('BE', 'Disease', 'MESH:D001471', (66, 68))	('reflux', 'Var', (32, 38))	('EMT', 'CPA', (47, 50))	('promotes', 'PosReg', (84, 92))	('induces', 'Reg', (39, 46))
414133	30268789	We used two non-neoplastic, telomerase-immortalized Barrett's epithelial cell lines (BAR-T, BAR-10T), and two non-neoplastic, telomerase-immortalized squamous epithelial cell lines from GERD patients with (NES-B10T) and without (NES-G2T) Barrett's esophagus; all of these cell lines were developed in our laboratory.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (238, 257))	('patients', 'Species', '9606', (191, 199))	('B10T', 'Var', (210, 214))	('GERD', 'Disease', 'MESH:D005764', (186, 190))	('B10T', 'SUBSTITUTION', 'None', (210, 214))	('GERD', 'Disease', (186, 190))	('rat', 'Species', '10116', (309, 312))	('G2T', 'Mutation', 'rs786203656', (233, 236))
414169	30268789	In contrast, acidic bile salt treatment had no apparent effect on CDH1 levels or cell migration in human esophageal squamous cells (NES-B10T and NES-G4T) (Figure 2F).	('B10T', 'SUBSTITUTION', 'None', (136, 140))	('B10T', 'Var', (136, 140))	('G4T', 'Mutation', 'c.4G>T', (149, 152))	('rat', 'Species', '10116', (89, 92))	('human', 'Species', '9606', (99, 104))	('bile salt', 'Chemical', 'MESH:D001647', (20, 29))	('CDH1 levels', 'MPA', (66, 77))	('cell migration', 'CPA', (81, 95))
414173	30268789	To determine which transcription factors mediate loss of CDH1 expression in BAR-T cells, we knocked down or overexpressed ZEB1, ZEB2, SNAIL, and SLUG using siRNAs or cDNAs, respectively.	('knocked', 'Var', (92, 99))	('overexpressed', 'PosReg', (108, 121))	('SNAIL', 'Gene', '6615', (134, 139))	('SNAIL', 'Gene', (134, 139))	('CDH1', 'Gene', (57, 61))	('SLUG', 'Gene', '6591', (145, 149))	('SLUG', 'Gene', (145, 149))
414174	30268789	Furthermore, knockdown of ZEB1 or ZEB2 reduced cell migration (Figure 3B), whereas stable overexpression of ZEB1 or ZEB2 (Supplemental Figure 3D) increased cell migration (Figure 3B).	('rat', 'Species', '10116', (55, 58))	('increased', 'PosReg', (146, 155))	('ZEB1', 'Gene', (26, 30))	('reduced', 'NegReg', (39, 46))	('ZEB2', 'Gene', (34, 38))	('cell migration', 'CPA', (47, 61))	('rat', 'Species', '10116', (164, 167))	('knockdown', 'Var', (13, 22))	('cell migration', 'CPA', (156, 170))
414199	30268789	VEGFR2 inhibition with a specific shRNA (Figure 7D) prevented the acidic bile salt-induced increases in ZEB1 and ZEB2 expression and the decrease in CDH1 protein.	('VEGFR2', 'Gene', '3791', (0, 6))	('ZEB2', 'Gene', (113, 117))	('decrease', 'NegReg', (137, 145))	('CDH1 protein', 'Protein', (149, 161))	('bile salt', 'Chemical', 'MESH:D001647', (73, 82))	('inhibition', 'Var', (7, 17))	('acidic bile salt-induced', 'MPA', (66, 90))	('VEGFR2', 'Gene', (0, 6))	('expression', 'MPA', (118, 128))	('increases', 'PosReg', (91, 100))	('protein', 'Protein', (154, 161))	('ZEB1', 'Gene', (104, 108))
414205	30268789	Finally, in non-neoplastic Barrett's cells, we have found that acidic bile salts activate VEGF/VEGFR2 signaling to induce ZEB upregulation with reciprocal CDH1 downregulation, and that inhibition of the VEGF/VEGFR2 axis abolishes these acidic bile salt effects on gene expression.	('downregulation', 'NegReg', (160, 174))	('VEGF', 'Gene', '7422', (203, 207))	('inhibition', 'Var', (185, 195))	('ZEB', 'MPA', (122, 125))	('VEGF', 'Gene', (203, 207))	('VEGFR2', 'Gene', (208, 214))	('VEGFR2', 'Gene', '3791', (208, 214))	('VEGF', 'Gene', '7422', (90, 94))	('upregulation', 'PosReg', (126, 138))	('VEGF', 'Gene', '7422', (208, 212))	('bile salt', 'Chemical', 'MESH:D001647', (70, 79))	('VEGF', 'Gene', (90, 94))	('VEGFR2', 'Gene', (95, 101))	('bile salts', 'Chemical', 'MESH:D001647', (70, 80))	('CDH1', 'Gene', (155, 159))	('VEGF', 'Gene', (208, 212))	('bile salt', 'Chemical', 'MESH:D001647', (243, 252))	('VEGFR2', 'Gene', '3791', (95, 101))	('VEGF', 'Gene', '7422', (95, 99))	('VEGF', 'Gene', (95, 99))
414208	30268789	In a mouse model of pancreatic cancer that used a Cre-lox based system to generate pancreas-specific mutations in Kras and p53 genes, Rhim et al.	('p53', 'Gene', '22060', (123, 126))	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('mutations', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Kras', 'Gene', (114, 118))	('Kras', 'Gene', '16653', (114, 118))	('lox', 'Gene', '16948', (54, 57))	('rat', 'Species', '10116', (78, 81))	('p53', 'Gene', (123, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('mouse', 'Species', '10090', (5, 10))	('lox', 'Gene', (54, 57))	('pancreatic cancer', 'Disease', (20, 37))
414229	30268789	Inhibition of VEGF/VEGFR2 signaling (by VEGF blocking antibody, VEGF-A genetic deletion, pharmacologic VEGFR2 inhibition, or VEGFR2 shRNA) eliminated these EMT features.	('VEGF', 'Gene', (125, 129))	('VEGF', 'Gene', '7422', (19, 23))	('VEGFR2', 'Gene', (19, 25))	('VEGF', 'Gene', (19, 23))	('VEGFR2', 'Gene', (103, 109))	('VEGFR2', 'Gene', '3791', (19, 25))	('VEGF', 'Gene', '7422', (40, 44))	('VEGF', 'Gene', '7422', (64, 68))	('genetic deletion', 'Var', (71, 87))	('VEGF-A', 'Gene', (64, 70))	('VEGFR2', 'Gene', '3791', (103, 109))	('VEGF', 'Gene', (40, 44))	('VEGF', 'Gene', (64, 68))	('VEGFR2', 'Gene', (125, 131))	('VEGF', 'Gene', '7422', (103, 107))	('VEGF', 'Gene', (103, 107))	('VEGFR2', 'Gene', '3791', (125, 131))	('VEGF', 'Gene', '7422', (14, 18))	('VEGF', 'Gene', '7422', (125, 129))	('VEGF', 'Gene', (14, 18))	('VEGF-A', 'Gene', '7422', (64, 70))
414264	30283599	CE-IM was seen in 77.4% in the RFA group compared to 2.3% in sham group (P < 0.001).	('RFA', 'Var', (31, 34))	('CE-IM', 'Chemical', '-', (0, 5))	('CE-IM', 'Disease', (0, 5))
414270	30283599	In the ablation group, patients were less likely to progress to HGD/EAC compared to surveillance group (1.5% vs 26.5% respectively, P < 0.001) or to EAC (1.5% vs 8.8% respectively, P = 0.03).	('patients', 'Species', '9606', (23, 31))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('less', 'NegReg', (37, 41))	('EAC', 'Phenotype', 'HP:0011459', (149, 152))	('HGD/EAC', 'Disease', (64, 71))	('ablation', 'Var', (7, 15))
414281	30283599	After RFA, patients have reported significant improvement in quality of life, less stress about esophageal cancer or esophagectomy.	('RFA', 'Var', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('improvement', 'PosReg', (46, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('patients', 'Species', '9606', (11, 19))	('quality', 'MPA', (61, 68))
414297	30283599	CE-D rate was significantly lower (67%) in those with ultra-long BE compared with those with < 8 cm (100%, P = 0.02).	('lower', 'NegReg', (28, 33))	('CE-D', 'Chemical', '-', (0, 4))	('CE-D rate', 'CPA', (0, 9))	('ultra-long BE', 'Var', (54, 67))	('BE', 'Phenotype', 'HP:0100580', (65, 67))
414331	30283599	Photosensitivity is the commonest side effect being reported in up to 69% patients after PDT treatment using porfimer sodium because of absorption of porfimer sodium by the skin from the systemic circulation which is then activated by light.	('patients', 'Species', '9606', (74, 82))	('Photosensitivity', 'Phenotype', 'HP:0000992', (0, 16))	('absorption', 'MPA', (136, 146))	('Photosensitivity', 'Disease', (0, 16))	('porfimer', 'Var', (150, 158))
414335	30283599	Treatment with 5-aminolevulinic acid is associated with lower incidence of photosensitivity reactions and stricture formation but it is not commonly used in the United States.	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (15, 36))	('5-aminolevulinic', 'Var', (15, 31))	('lower', 'NegReg', (56, 61))	('stricture formation', 'CPA', (106, 125))	('photosensitivity', 'Phenotype', 'HP:0000992', (75, 91))
414397	29945563	These patients also had the highest cost for hospital admissions of all cancers ($27,506) due to the performance of resource intensive procedures, such as post-surgery esophageal dilation and biopsies to the esophagus or other parts of the gastrointestinal tract (through endoscopies).	('biopsies', 'Var', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('esophageal dilation', 'Disease', 'MESH:D002311', (168, 187))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('patients', 'Species', '9606', (6, 14))	('gastrointestinal tract', 'Disease', (240, 262))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (240, 262))	('esophageal dilation', 'Disease', (168, 187))
414446	29945563	The mean net costs per 30 patient-days of patients receiving radiotherapy alone was highest in the initial phase ($1330; 95% CI, $1187-$1474) followed by surgery plus chemotherapy plus radiotherapy ($1323; 95% CI, $757-$1890), chemotherapy plus radiotherapy ($1129; 95% CI, ($909-$1350), chemotherapy alone ($1109; 95% CI, $935-$1282), surgery plus chemotherapy ($1089; 95% CI, $862-$1316), surgery plus radiotherapy ($1080; 95% CI, $494-$1667), and surgery alone ($996; 95% CI, $856-$1135).	('patient', 'Species', '9606', (26, 33))	('$1089', 'Var', (363, 368))	('patient', 'Species', '9606', (42, 49))	('$1080', 'Var', (418, 423))	('patients', 'Species', '9606', (42, 50))
414555	29531462	Dysregulation of PARP1 is involved in development of Barrett's esophagus To investigate the potential role of poly(ADP-ribose) polymerase 1 (PARP1) in the development of Barrett's esophagus (BE).	("Barrett's esophagus", 'Disease', (170, 189))	('poly(ADP-ribose) polymerase 1', 'Gene', (110, 139))	("Barrett's esophagus", 'Disease', (53, 72))	('PARP1', 'Gene', (141, 146))	('involved', 'Reg', (26, 34))	('Dysregulation', 'Var', (0, 13))	('PARP1', 'Gene', (17, 22))	('PARP1', 'Gene', '142', (141, 146))	('poly(ADP-ribose) polymerase 1', 'Gene', '142', (110, 139))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (170, 189))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (53, 72))	('PARP1', 'Gene', '142', (17, 22))
414561	29531462	In the mouse model of BE, positive staining for NF-kappaB, gammaH2AX, and poly(ADP-ribose) (PAR) was observed.	('mouse', 'Species', '10090', (7, 12))	('poly(ADP-ribose)', 'Chemical', 'MESH:D011064', (74, 90))	('gammaH2AX', 'Gene', '15270', (59, 68))	('NF-kappaB', 'Protein', (48, 57))	('poly', 'Var', (74, 78))	('gammaH2AX', 'Gene', (59, 68))
414562	29531462	H2O2 and bile acids (pH 4) increased the PARP1 mRNA expression level in normal esophageal epithelial cells.	('increased', 'PosReg', (27, 36))	('PARP1', 'Gene', (41, 46))	('esophageal epithelia', 'Disease', (79, 99))	('esophageal epithelia', 'Disease', 'MESH:D004941', (79, 99))	('bile acids', 'Chemical', 'MESH:D001647', (9, 19))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (79, 99))
414564	29531462	The dysfunction of PARP1 in esophageal epithelial cells increases the levels of ROS and oxidative DNA damage, which could be common risk factors for BE and esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (156, 181))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (28, 48))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (156, 181))	('increases', 'PosReg', (56, 65))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (156, 181))	('esophageal epithelia', 'Disease', 'MESH:D004941', (28, 48))	('dysfunction', 'Var', (4, 15))	('esophageal epithelia', 'Disease', (28, 48))	('PARP1', 'Gene', (19, 24))	('oxidative DNA damage', 'MPA', (88, 108))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('levels of ROS', 'MPA', (70, 83))
414567	29531462	PARP1 inhibition could decrease the cell viability after bile acids treatment, and increased the oxidative damage, double-strand breaks, and apoptosis.	('decrease', 'NegReg', (23, 31))	('increased', 'PosReg', (83, 92))	('oxidative damage', 'MPA', (97, 113))	('double-strand breaks', 'MPA', (115, 135))	('inhibition', 'Var', (6, 16))	('cell viability', 'CPA', (36, 50))	('bile acids', 'Chemical', 'MESH:D001647', (57, 67))	('apoptosis', 'CPA', (141, 150))	('PARP1', 'Gene', (0, 5))
414576	29531462	These active free radicals attack double-strand DNA, inducing various types of DNA lesions, including DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs), which may lead to genomic instability.	('genomic', 'MPA', (189, 196))	('lead to', 'Reg', (181, 188))	('double-strand breaks', 'Var', (142, 162))	('DSBs', 'Chemical', '-', (164, 168))	('inducing', 'Reg', (53, 61))	('single-strand', 'Var', (106, 119))
414627	29531462	In response to this treatment, significant upregulation of the mRNA levels of PARP1 was observed at 2 h for H2O2 and at 4 h and 8 h for both H2O2 and bile acids (Figure 2C).	('H2O2', 'Var', (108, 112))	('mRNA levels', 'MPA', (63, 74))	('H2O2', 'Chemical', 'MESH:D006861', (141, 145))	('H2O2', 'Chemical', 'MESH:D006861', (108, 112))	('upregulation', 'PosReg', (43, 55))	('PARP1', 'Gene', (78, 83))	('bile acids', 'Chemical', 'MESH:D001647', (150, 160))
414629	29531462	The knockdown of PARP1 in BAR-T cells (Figure 3A) led to a significantly lower cell viability following exposure to H2O2, compared with controls (P < 0.01 for 100 mumol/L, 200 mumol/L, and 400 mumol/L H2O2; Figure 3B), suggesting that the downregulation of endogenous PARP1 sensitized the BAR-T cells to H2O2-induced oxidative stress.	('BAR-T', 'CellLine', 'CVCL:4M95', (289, 294))	('PARP1', 'Gene', (17, 22))	('PARP1', 'Gene', (268, 273))	('cell viability', 'CPA', (79, 93))	('H2O2', 'Chemical', 'MESH:D006861', (201, 205))	('downregulation', 'NegReg', (239, 253))	('H2O2', 'Chemical', 'MESH:D006861', (304, 308))	('BAR-T', 'CellLine', 'CVCL:4M95', (26, 31))	('oxidative stress', 'Phenotype', 'HP:0025464', (317, 333))	('lower', 'NegReg', (73, 78))	('H2O2', 'Chemical', 'MESH:D006861', (116, 120))	('knockdown', 'Var', (4, 13))	('sensitized', 'Reg', (274, 284))
414631	29531462	As shown in Figure 3C, BAR-T cells with PARP1 knockdown displayed a significantly severe DNA damage signal upon exposure to 200 mumol/L H2O2 for 2 h (4.3 +- 0.8 vs 8.6 +- 1.4, P < 0.01).	('severe', 'PosReg', (82, 88))	('knockdown', 'Var', (46, 55))	('BAR-T', 'CellLine', 'CVCL:4M95', (23, 28))	('H2O2', 'Chemical', 'MESH:D006861', (136, 140))	('DNA damage signal', 'MPA', (89, 106))	('PARP1', 'Gene', (40, 45))
414633	29531462	BAR-T cells with knockdown of endogenous PARP1 displayed higher H2O2 levels than control cells transfected with scrambled shRNA (Figure 4A).	('endogenous', 'Var', (30, 40))	('higher', 'PosReg', (57, 63))	('PARP1', 'Gene', (41, 46))	('H2O2 levels', 'MPA', (64, 75))	('H2O2', 'Chemical', 'MESH:D006861', (64, 68))	('BAR-T', 'CellLine', 'CVCL:4M95', (0, 5))	('knockdown', 'Var', (17, 26))
414635	29531462	On exposure of BAR-T cells with PARP1 knockdown to bile acids (pH 4), more oxidative DNA damage was observed than control cells exposed to acidic bile acids (Figure 4B).	('BAR-T', 'CellLine', 'CVCL:4M95', (15, 20))	('bile acids', 'Chemical', 'MESH:D001647', (51, 61))	('PARP1', 'Gene', (32, 37))	('bile acids', 'Chemical', 'MESH:D001647', (146, 156))	('oxidative DNA damage', 'MPA', (75, 95))	('knockdown', 'Var', (38, 47))
414637	29531462	The immunocytochemical staining for gammaH2AX, a reliable marker for DSBs, demonstrated significantly high levels of positive gammaH2AX sites following knockdown of PARP1 in BAR-T cells (19.8% +- 0.3% vs 42.6% +- 7.2%, P < 0.01, Figure 4C) than in control cells.	('knockdown', 'Var', (152, 161))	('gammaH2AX', 'Gene', '15270', (36, 45))	('gammaH2AX', 'Gene', '15270', (126, 135))	('BAR-T', 'CellLine', 'CVCL:4M95', (174, 179))	('gammaH2AX', 'Gene', (36, 45))	('DSBs', 'Chemical', '-', (69, 73))	('PARP1', 'Gene', (165, 170))	('gammaH2AX', 'Gene', (126, 135))
414641	29531462	Consistent with this finding, the cells with PARP1 knockdown displayed significantly more apoptosis after acidic bile acid exposure as indicated by annexin V assay (P < 0.05, 10 min: 2.1 +- 0.2 vs 6.3 +- 0.8; 30 min: 2.3 +- 0.1 vs 8.5 +- 1.2, Figure 4E).	('annexin V', 'Gene', '308', (148, 157))	('more', 'PosReg', (85, 89))	('PARP1', 'Gene', (45, 50))	('annexin V', 'Gene', (148, 157))	('bile acid', 'Chemical', 'MESH:D001647', (113, 122))	('apoptosis', 'CPA', (90, 99))	('knockdown', 'Var', (51, 60))
414643	29531462	Our results showed that excessive PARP1 expression may probably a resistance factor of BE epithelial cells to H2O2 or bile acid-induced oxidative damage and cell death.	('expression', 'MPA', (40, 50))	('bile acid-induced oxidative damage', 'MPA', (118, 152))	('bile acid', 'Chemical', 'MESH:D001647', (118, 127))	('excessive', 'Var', (24, 33))	('PARP1', 'Gene', (34, 39))	('H2O2', 'Chemical', 'MESH:D006861', (110, 114))
414644	29531462	In recent years, PARP1 inhibitors have shown promising therapeutic effects on ovarian cancer, breast cancer, and neurological diseases, and this effect is mainly associated with the induction of DSBs.	('PARP1', 'Gene', (17, 22))	('neurological diseases', 'Disease', (113, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (78, 92))	('inhibitors', 'Var', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('DSBs', 'Disease', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Disease', (78, 92))	('DSBs', 'Chemical', '-', (195, 199))	('neurological diseases', 'Disease', 'MESH:D019636', (113, 134))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))
414645	29531462	Interestingly, pharmacological inhibition of PARP1 provides significant benefits in animal models of cardiovascular disorders.	('pharmacological', 'Var', (15, 30))	('cardiovascular disorders', 'Phenotype', 'HP:0001626', (101, 125))	('PARP1', 'Gene', (45, 50))	('cardiovascular disorders', 'Disease', (101, 125))	('cardiovascular disorders', 'Disease', 'MESH:D002318', (101, 125))	('benefits', 'PosReg', (72, 80))
414659	29531462	Further, NF-kappaB activity was greatly abrogated independent of upstream activation of NF-kappaB in PARP-/- mice and cell lines, and PARP1 inhibition reduced the extent of inflammation by modulating oxidative stress and impairing the activation of NF-kappaB and activator protein-1 in an inflammation model.	('activation', 'MPA', (235, 245))	('reduced', 'NegReg', (151, 158))	('inflammation', 'Disease', (289, 301))	('inflammation', 'Disease', 'MESH:D007249', (173, 185))	('NF-kappaB', 'Protein', (9, 18))	('inhibition', 'Var', (140, 150))	('impairing', 'NegReg', (221, 230))	('modulating', 'Reg', (189, 199))	('oxidative stress', 'MPA', (200, 216))	('inflammation', 'Disease', (173, 185))	('abrogated', 'NegReg', (40, 49))	('activity', 'MPA', (19, 27))	('activator protein-1', 'MPA', (263, 282))	('PARP1', 'Gene', (134, 139))	('mice', 'Species', '10090', (109, 113))	('oxidative stress', 'Phenotype', 'HP:0025464', (200, 216))	('inflammation', 'Disease', 'MESH:D007249', (289, 301))
414663	29531462	Thus, PARP1 acts as a mediator of esophageal disease, and PARylation may play a pivotal protective role as an antioxidant defense mechanism by maintaining esophageal epithelial cell function under pathological conditions of oxidative stress.	('esophageal disease', 'Disease', (34, 52))	('esophageal disease', 'Disease', 'MESH:D004935', (34, 52))	('esophageal epithelia', 'Disease', (155, 175))	('esophageal epithelia', 'Disease', 'MESH:D004941', (155, 175))	('oxidative stress', 'Phenotype', 'HP:0025464', (224, 240))	('maintaining', 'PosReg', (143, 154))	('PARylation', 'Var', (58, 68))	('PARP1', 'Gene', (6, 11))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (155, 175))
414673	29531462	We further demonstrated that PARP1 inhibition could increase the oxidative damage as demonstrated by an increase in the levels of H2O2, intracellular reactive oxygen species, oxidative DNA damage, double-strand breaks, and apoptosis.	('oxidative DNA damage', 'MPA', (175, 195))	('increase', 'PosReg', (104, 112))	('oxidative damage', 'MPA', (65, 81))	('increase', 'PosReg', (52, 60))	('intracellular reactive oxygen species', 'MPA', (136, 173))	('double-strand breaks', 'MPA', (197, 217))	('apoptosis', 'CPA', (223, 232))	('PARP1', 'Gene', (29, 34))	('levels of H2O2', 'MPA', (120, 134))	('H2O2', 'Chemical', 'MESH:D006861', (130, 134))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (150, 173))	('inhibition', 'Var', (35, 45))
414674	29531462	The dysfunction of PARP1 in esophageal epithelial cells increases the levels of reactive oxygen species and oxidative DNA damage, and downregulation of PARP1 or PARP1 inhibitor may be a potential therapeutic strategy for Barrett's esophagus.	('esophageal epithelia', 'Phenotype', 'HP:0012859', (28, 48))	('downregulation', 'NegReg', (134, 148))	('increases', 'PosReg', (56, 65))	('PARP1', 'Gene', (152, 157))	('esophageal epithelia', 'Disease', 'MESH:D004941', (28, 48))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (221, 240))	('dysfunction', 'Var', (4, 15))	('esophageal epithelia', 'Disease', (28, 48))	('PARP1', 'Gene', (19, 24))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (80, 103))	("Barrett's esophagus", 'Disease', (221, 240))
414777	28765338	Porphyromonas gingivalis also preferentially activates Th2-mediated immune responses, inducing polarization to M2 macrophages which are less efficient at eliminating engulfed bacterial pathogens and their lipopolysaccharide (LPS) products.	('activates', 'PosReg', (45, 54))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (205, 223))	('Porphyromonas', 'Var', (0, 13))	('LPS', 'Disease', (225, 228))	('inducing', 'Reg', (86, 94))	('Porphyromonas gingivalis', 'Species', '837', (0, 24))	('preferentially', 'PosReg', (30, 44))	('Th2-mediated', 'CPA', (55, 67))	('polarization', 'MPA', (95, 107))	('LPS', 'Disease', 'MESH:C536528', (225, 228))
414793	26716642	The identification of two regulatory ESCC susceptibility genetic variants in the TERT-CLPTM1L loci The chromosome 5p15.33 TERT-CLPTM1L region has been identified by genome-wide association studies as a susceptibility locus of multiple malignancies.	('TERT', 'Gene', (122, 126))	('CLPTM1L', 'Gene', '81037', (127, 134))	('TERT', 'Gene', (81, 85))	('TERT', 'Gene', '7015', (122, 126))	('CLPTM1L', 'Gene', (127, 134))	('variants', 'Var', (65, 73))	('TERT', 'Gene', '7015', (81, 85))	('CLPTM1L', 'Gene', '81037', (86, 93))	('multiple malignancies', 'Disease', 'MESH:D009369', (226, 247))	('CLPTM1L', 'Gene', (86, 93))	('multiple malignancies', 'Disease', (226, 247))
414796	26716642	After analyzing 2098 ESCC patients and frequency-matched 2150 unaffected controls, we found that rs2853691, rs2736100 and rs451360 genetic polymorphisms are significantly associated with ESCC risk in Chinese (all P<0.05).	('ESCC', 'Disease', (187, 191))	('rs451360', 'Mutation', 'rs451360', (122, 130))	('rs2853691', 'Mutation', 'rs2853691', (97, 106))	('rs451360', 'Var', (122, 130))	('associated with', 'Reg', (171, 186))	('rs2736100', 'Var', (108, 117))	('patients', 'Species', '9606', (26, 34))	('rs2853691', 'Var', (97, 106))	('rs2736100', 'Mutation', 'rs2736100', (108, 117))
414797	26716642	Reporter gene assays indicated that the ESCC susceptibility SNP rs2736100 locating in a potential TERT intronic promoter has a genotype-specific effect on TERT expression.	('rs2736100', 'Var', (64, 73))	('ESCC', 'Disease', (40, 44))	('TERT', 'Gene', (98, 102))	('effect', 'Reg', (145, 151))	('rs2736100', 'Mutation', 'rs2736100', (64, 73))	('TERT', 'Gene', '7015', (98, 102))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', '7015', (155, 159))
414798	26716642	Similarly, the CLPTM1L rs451360 SNP also showed allelic impacts on gene expression.	('rs451360', 'Mutation', 'rs451360', (23, 31))	('CLPTM1L', 'Gene', (15, 22))	('rs451360 SNP', 'Var', (23, 35))	('impacts', 'Reg', (56, 63))	('gene expression', 'MPA', (67, 82))	('CLPTM1L', 'Gene', '81037', (15, 22))
414799	26716642	After measuring TERT and CLPTM1L expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2736100 G risk allele carriers showed elevated oncogene TERT expression.	('TERT', 'Gene', (16, 20))	('TERT', 'Gene', '7015', (16, 20))	('CLPTM1L', 'Gene', '81037', (25, 32))	('esophageal cancer', 'Disease', (66, 83))	('CLPTM1L', 'Gene', (25, 32))	('rs2736100 G', 'Var', (125, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('TERT', 'Gene', (183, 187))	('elevated', 'PosReg', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rs2736100', 'Mutation', 'rs2736100', (125, 134))	('TERT', 'Gene', '7015', (183, 187))
414800	26716642	Also, subjects with the rs451360 protective T allele had much lower oncogene CLPTM1L expression than those with G allele in tissue specimens.	('expression', 'MPA', (85, 95))	('rs451360', 'Mutation', 'rs451360', (24, 32))	('lower', 'NegReg', (62, 67))	('rs451360 protective', 'Var', (24, 43))	('CLPTM1L', 'Gene', '81037', (77, 84))	('CLPTM1L', 'Gene', (77, 84))
414804	26716642	Independent susceptibility single nucleotide polymorphisms (SNPs) in this region were identified in lung cancer, melanoma, nonmelanoma skin cancer, glioma, bladder cancer, pancreatic cancer, testicular germ cell cancer, estrogen-negative breast cancer, ovarian cancer and prostate cancer, suggesting that the region harbors several essential elements associating etiology of multiple cancers.	('prostate cancer', 'Disease', 'MESH:D011471', (272, 287))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('prostate cancer', 'Phenotype', 'HP:0012125', (272, 287))	('glioma', 'Disease', (148, 154))	('cancer', 'Disease', (105, 111))	('prostate cancer', 'Disease', (272, 287))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('multiple cancers', 'Disease', 'MESH:D009369', (375, 391))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancer', 'Disease', (238, 251))	('cancer', 'Disease', (183, 189))	('single nucleotide polymorphisms', 'Var', (27, 58))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (384, 390))	('pancreatic cancer', 'Disease', 'MESH:D010190', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lung cancer', 'Disease', (100, 111))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('cancer', 'Disease', (261, 267))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('nonmelanoma skin cancer', 'Disease', 'MESH:D012878', (123, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (253, 267))	('pancreatic cancer', 'Disease', (172, 189))	('multiple cancers', 'Disease', (375, 391))	('cancer', 'Disease', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('bladder cancer', 'Disease', 'MESH:D001749', (156, 170))	('bladder cancer', 'Disease', (156, 170))	('cancer', 'Disease', (281, 287))	('cancers', 'Phenotype', 'HP:0002664', (384, 391))	('ovarian cancer', 'Disease', (253, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('cancer', 'Disease', (384, 390))	('nonmelanoma skin cancer', 'Disease', (123, 146))	('skin cancer', 'Phenotype', 'HP:0008069', (135, 146))	('ovarian cancer', 'Phenotype', 'HP:0100615', (253, 267))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('germ cell cancer', 'Phenotype', 'HP:0100728', (202, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))	('bladder cancer', 'Phenotype', 'HP:0009725', (156, 170))
414807	26716642	Activated TERT transcription in many cancers leads to increased telomerase activity to counteract telomere shortening and promotes malignant transformation of normal cells.	('promotes', 'PosReg', (122, 130))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('telomere shortening', 'Phenotype', 'HP:0031413', (98, 117))	('TERT', 'Gene', (10, 14))	('cancers', 'Disease', (37, 44))	('malignant transformation', 'CPA', (131, 155))	('increased', 'PosReg', (54, 63))	('Activated', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('telomerase', 'Enzyme', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('TERT', 'Gene', '7015', (10, 14))	('activity', 'MPA', (75, 83))
414814	26716642	Genotype distributions of fifteen TERT-CLPTM1L genetic variants in the Jiangsu discovery set are showed in Table 1.	('CLPTM1L', 'Gene', (39, 46))	('variants', 'Var', (55, 63))	('TERT', 'Gene', (34, 38))	('TERT', 'Gene', '7015', (34, 38))	('CLPTM1L', 'Gene', '81037', (39, 46))
414816	26716642	Frequencies of rs2853691, rs2736100 or rs45136 genotypes among patients differed significantly from those among controls (all P < 0.05).	('rs2853691', 'Var', (15, 24))	('rs2736100', 'Mutation', 'rs2736100', (26, 35))	('rs2853691', 'Mutation', 'rs2853691', (15, 24))	('patients', 'Species', '9606', (63, 71))	('rs2736100', 'Var', (26, 35))	('rs45136', 'Mutation', 'rs45136', (39, 46))	('rs45136', 'Var', (39, 46))
414817	26716642	Logistic regression analyses revealed that rs2853691, rs2736100 and rs451360 SNPs were significantly associated with ESCC risk (rs2853691: allelic OR = 1.50, 95% CI = 1.25-1.80, P = 7.0 x 10-6; rs2736100: allelic OR = 1.39, 95% CI = 1.17-1.64, P = 7.8 x 10-5; rs45136: allelic OR = 0.69, 95% CI = 0.52-0.91, P = 0.007) (Table 1).	('rs45136', 'Mutation', 'rs45136', (260, 267))	('rs45136', 'Mutation', 'rs45136', (68, 75))	('rs451360 SNPs', 'Var', (68, 81))	('rs451360', 'Mutation', 'rs451360', (68, 76))	('rs2853691', 'Var', (43, 52))	('rs2853691', 'Mutation', 'rs2853691', (128, 137))	('rs2736100', 'Var', (54, 63))	('rs2736100', 'Var', (194, 203))	('rs2853691', 'Mutation', 'rs2853691', (43, 52))	('associated', 'Reg', (101, 111))	('ESCC', 'Disease', (117, 121))	('rs2736100', 'Mutation', 'rs2736100', (54, 63))	('rs2736100', 'Mutation', 'rs2736100', (194, 203))
414818	26716642	Associations between genotypes of rs2853691, rs2736100 and rs45136 genetic variants and ESCC risk were calculated using unconditional logistic regression analyses in Jiangsu set (Table 2).	('ESCC', 'Disease', (88, 92))	('rs45136', 'Var', (59, 66))	('rs2736100', 'Var', (45, 54))	('rs45136', 'Mutation', 'rs45136', (59, 66))	('rs2853691', 'Var', (34, 43))	('rs2736100', 'Mutation', 'rs2736100', (45, 54))	('rs2853691', 'Mutation', 'rs2853691', (34, 43))
414819	26716642	The rs2853691 G allele was showed to be risk allele; subjects having the AG or GG genotype had an OR of 1.19(95% CI = 0.88-1.60, P = 0.214) or 1.40(95% CI = 1.10-1.77, P = 0.006) for developing ESCC, respectively, compared with subjects having the AA genotype.	('ESCC', 'Disease', (194, 198))	('rs2853691 G', 'Var', (4, 15))	('rs2853691', 'Mutation', 'rs2853691', (4, 13))
414821	26716642	Moreover, a significantly decreased OR was associated with the rs451360 GT genotype (OR = 0.67, 95% CI = 0.48-0.93, P = 0.018) but not the TT genotype (OR = 0.72, 95% CI = 0.41-1.29, P = 0.275).	('rs451360', 'Mutation', 'rs451360', (63, 71))	('rs451360', 'Var', (63, 71))	('decreased', 'NegReg', (26, 35))
414823	26716642	In two validation sets (Shandong set and Hebei set), the significant associations between rs2853691, rs2736100 and rs45136 SNPs and ESCC risk were also observed (Table 2).	('rs2853691', 'Mutation', 'rs2853691', (90, 99))	('rs45136 SNPs', 'Var', (115, 127))	('rs2736100', 'Var', (101, 110))	('rs2736100', 'Mutation', 'rs2736100', (101, 110))	('rs45136', 'Mutation', 'rs45136', (115, 122))	('rs2853691', 'Var', (90, 99))	('ESCC', 'Disease', (132, 136))
414824	26716642	Individuals with rs2853691 GG genotype showed significantly increased ESCC risk compared with those with rs2853691 AA genotype in both validation sets (ORShandong = 1.30, 95% CI = 1.07-1.59, P = 0.010; ORHebei = 1.29, 95% CI = 1.01-1.64, P = 0.048).	('rs2853691 GG', 'Var', (17, 29))	('rs2853691', 'Mutation', 'rs2853691', (105, 114))	('ESCC', 'Disease', (70, 74))	('increased ESCC', 'Phenotype', 'HP:0003565', (60, 74))	('increased', 'PosReg', (60, 69))	('rs2853691', 'Mutation', 'rs2853691', (17, 26))
414825	26716642	Carriers of rs2736100 GG genotype showed significantly elevated risks developing ESCC compared with rs2736100 TT carriers (ORBeijing = 1.48, 95% CI = 1.29-1.70, P = 2.2 x 10-6; ORHebei = 1.32, 95% CI = 1.10-1.59, P = 3.2 x 10-4).	('rs2736100', 'Mutation', 'rs2736100', (12, 21))	('rs2736100', 'Mutation', 'rs2736100', (100, 109))	('ESCC', 'Disease', (81, 85))	('rs2736100 GG', 'Var', (12, 24))
414827	26716642	However, only rs451360 GT genotype was significantly associated with ESCC risk (OR = 0.68, 95% CI = 0.49-0.93, P = 0.017) in Hebei validation set.	('rs451360 GT', 'Var', (14, 25))	('rs451360', 'Mutation', 'rs451360', (14, 22))	('associated', 'Reg', (53, 63))	('ESCC', 'Disease', (69, 73))
414828	26716642	In the pooled analyses, we found that the rs2853691 AG or GG genotype carriers had a 1.16-fold or 1.32-fold increased risk to develop ESCC compared to the AA genotype carriers (95% CI = 1.01-1.32, P = 0.036 or 95% CI = 1.16-1.50, P = 2.2 x 10-5) (Table 2).	('rs2853691', 'Var', (42, 51))	('ESCC', 'Disease', (134, 138))	('rs2853691', 'Mutation', 'rs2853691', (42, 51))
414829	26716642	Intriguingly, either rs2736100 TG or GG genotype was significantly associated with ESCC risk (OR = 1.32, 95% CI = 1.44-1.53, P = 2.1 x 10-4; OR = 1.41, 95% CI = 1.29-1.55, P = 4.0 x 10-8) compared to the TT genotype.	('rs2736100', 'Mutation', 'rs2736100', (21, 30))	('associated', 'Reg', (67, 77))	('rs2736100 TG', 'Var', (21, 33))	('ESCC', 'Disease', (83, 87))
414830	26716642	Similarly, subjects having the rs451360 GT or TT genotype had an OR of 0.68 (95%CI = 0.58-0.81, P = 6.3 x 10-6) or 0.61 (95%CI = 0.44-0.85, P = 0.003) for developing ESCC compared with individual having the GG genotype.	('developing', 'PosReg', (155, 165))	('ESCC', 'Disease', (166, 170))	('rs451360', 'Mutation', 'rs451360', (31, 39))	('rs451360 GT', 'Var', (31, 42))
414831	26716642	The risk of ESCC associated with the rs2853691, rs2736100 or rs451360 SNP was further investigated by stratifying for age, sex, smoking and alcohol drinking status using the combined data of three case-control sets (Table 3).	('rs451360', 'Mutation', 'rs451360', (61, 69))	('rs2853691', 'Var', (37, 46))	('rs2736100', 'Var', (48, 57))	('ESCC', 'Disease', (12, 16))	('alcohol', 'Chemical', 'MESH:D000438', (140, 147))	('alcohol drinking', 'Phenotype', 'HP:0030955', (140, 156))	('rs2853691', 'Mutation', 'rs2853691', (37, 46))	('rs2736100', 'Mutation', 'rs2736100', (48, 57))	('rs451360 SNP', 'Var', (61, 73))
414832	26716642	For rs2853691, a significantly increased risk of ESCC associated with the rs2853691 GG genotype compared with the AA genotype was observed for both groups stratified by sex, smoking and drinking status (all P < 0.05) or the group aged 58 years or younger (P = 5.4 x 10-5).	('rs2853691', 'Var', (4, 13))	('rs2853691', 'Mutation', 'rs2853691', (74, 83))	('ESCC', 'Disease', (49, 53))	('rs2853691', 'Mutation', 'rs2853691', (4, 13))	('rs2853691 GG', 'Var', (74, 86))
414833	26716642	Additionally, the rs2853691 AG genotype was only associated with ESCC risk in the male group (P = 0.026), the smoking group (P = 0.008) or the drinking group (P = 0.013).	('rs2853691 AG', 'Var', (18, 30))	('rs2853691', 'Mutation', 'rs2853691', (18, 27))	('ESCC', 'Disease', (65, 69))
414834	26716642	For rs2736100, significant associations between TG or GG genotype and ESCC risk were observed in all stratified groups (all P < 0.05), but not in the drinking group (P = 0.974).	('ESCC', 'Disease', (70, 74))	('rs2736100', 'Mutation', 'rs2736100', (4, 13))	('rs2736100', 'Var', (4, 13))
414835	26716642	For rs451360, the TT genotype was only associated with ESCC risk in the male group (P = 0.006), the group aged 58 years or younger (P = 0.016), the non-smoking group (P = 0.025) or the drinking group (P = 0.005).	('rs451360', 'Mutation', 'rs451360', (4, 12))	('rs451360', 'Var', (4, 12))	('ESCC', 'Disease', (55, 59))
414836	26716642	However, significant associations between the rs451360 GT genotype and ESCC risk were observed in all stratified groups (all P < 0.05), but not in the female group (P = 0.326).	('ESCC', 'Disease', (71, 75))	('rs451360', 'Mutation', 'rs451360', (46, 54))	('rs451360', 'Var', (46, 54))
414837	26716642	Considering the chromosome location of the three ESCC susceptibility SNPs, we only investigated the impacts of TERT rs2736100 and CLPTM1L rs451360 SNPs on gene expression.	('CLPTM1L', 'Gene', (130, 137))	('rs2736100', 'Mutation', 'rs2736100', (116, 125))	('rs451360', 'Var', (138, 146))	('rs451360', 'Mutation', 'rs451360', (138, 146))	('TERT', 'Gene', (111, 115))	('CLPTM1L', 'Gene', '81037', (130, 137))	('TERT', 'Gene', '7015', (111, 115))
414838	26716642	The rs2736100 variant locates in the intron 2 region of TERT.	('rs2736100', 'Mutation', 'rs2736100', (4, 13))	('rs2736100', 'Var', (4, 13))	('TERT', 'Gene', (56, 60))	('TERT', 'Gene', '7015', (56, 60))
414839	26716642	As shown in Figure 1A, reporter gene assays demonstrated that the intron 2 segment containing the rs2736100 flanking sequence showed promoter activities in KYSE30 and KYSE150 ESCC cells.	('rs2736100', 'Mutation', 'rs2736100', (98, 107))	('rs2736100', 'Var', (98, 107))	('KYSE150', 'CellLine', 'CVCL:1348', (167, 174))	('promoter activities', 'MPA', (133, 152))
414841	26716642	We next examined whether the ESCC susceptibility SNP rs451360 has an allele-specific effect on the intronic enhancer activity on CLPTM1L expression in ESCC.	('ESCC', 'Disease', (29, 33))	('CLPTM1L', 'Gene', (129, 136))	('expression', 'MPA', (137, 147))	('enhancer', 'PosReg', (108, 116))	('rs451360', 'Var', (53, 61))	('CLPTM1L', 'Gene', '81037', (129, 136))	('rs451360', 'Mutation', 'rs451360', (53, 61))
414843	26716642	As shown in Figure 2A, we found that subjects with the rs920778 TT genotype had significantly lower TERT mRNA levels (mean +- SE) than those with the GG genotypes in normal esophagus tissues (0.128 +- 0.047 [n=18] vs. 0.493 +- 0.078 [n=17], P<0.01) or ESCC tissues (0.030 +- 0.006 [n=18] vs. 0.847 +- 0.120 [n=17], P<0.01).	('rs920778', 'Mutation', 'rs920778', (55, 63))	('TERT', 'Gene', (100, 104))	('rs920778', 'Var', (55, 63))	('lower', 'NegReg', (94, 99))	('TERT', 'Gene', '7015', (100, 104))
414844	26716642	Similar results were observed when the CLPTM1L mRNA levels were compared between rs451360 GT+TT and GG genotypes in both normal tissues (0.713 +- 0.266 [n=17] vs. 4.810 +- 0.810 [n=49], P<0.01) and ESCC specimens (1.059 +- 0.346 [n=17] vs. 10.650 +- 1.922 [n=49], P<0.01).	('rs451360', 'Var', (81, 89))	('CLPTM1L', 'Gene', '81037', (39, 46))	('rs451360', 'Mutation', 'rs451360', (81, 89))	('CLPTM1L', 'Gene', (39, 46))
414845	26716642	In the current study, we systematically examined the impacts of SNPs in the TERT-CLPTM1L loci on ESCC susceptibility via a case-control design as well as gene expression of TERT or CLPTM1L in vitro and in vivo.	('TERT', 'Gene', '7015', (76, 80))	('TERT', 'Gene', (173, 177))	('TERT', 'Gene', '7015', (173, 177))	('CLPTM1L', 'Gene', (81, 88))	('CLPTM1L', 'Gene', '81037', (181, 188))	('SNPs', 'Var', (64, 68))	('CLPTM1L', 'Gene', (181, 188))	('TERT', 'Gene', (76, 80))	('CLPTM1L', 'Gene', '81037', (81, 88))	('ESCC', 'Disease', (97, 101))
414846	26716642	After genotyping 15 htSNPs in the discovery stage, we identified three ESCC susceptibility genetic polymorphisms (rs2853691, rs2736100 and rs451360) which were validated in two validation case-control sets.	('ESCC', 'Disease', (71, 75))	('rs2853691', 'Mutation', 'rs2853691', (114, 123))	('rs2736100', 'Var', (125, 134))	('rs2736100', 'Mutation', 'rs2736100', (125, 134))	('rs451360', 'Var', (139, 147))	('rs2853691', 'Var', (114, 123))	('rs451360', 'Mutation', 'rs451360', (139, 147))
414847	26716642	Similarly, the CLPTM1L rs451360 polymorphism also showed allelic effects on gene expression.	('rs451360', 'Mutation', 'rs451360', (23, 31))	('effects', 'Reg', (65, 72))	('CLPTM1L', 'Gene', (15, 22))	('gene expression', 'MPA', (76, 91))	('rs451360', 'Var', (23, 31))	('CLPTM1L', 'Gene', '81037', (15, 22))
414853	26716642	Since rs2736100 G allele is associated with elevated TERT expression, the associations between the polymorphism and increased cancer risk are biologically plausible.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TERT', 'Gene', (53, 57))	('rs2736100 G', 'Var', (6, 17))	('TERT', 'Gene', '7015', (53, 57))	('elevated', 'PosReg', (44, 52))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('rs2736100', 'Mutation', 'rs2736100', (6, 15))
414856	26716642	The CLPTM1L rs451360 polymorphism has been associated with decreased risk of lung cancer among different ethnic populations, with T allele as a protective allele.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('decreased', 'NegReg', (59, 68))	('CLPTM1L', 'Gene', '81037', (4, 11))	('CLPTM1L', 'Gene', (4, 11))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('rs451360', 'Mutation', 'rs451360', (12, 20))	('rs451360', 'Var', (12, 20))	('lung cancer', 'Disease', (77, 88))
414857	26716642	Here, we provided first evidences that rs451360 SNP also play a part in ESCC susceptibility, which are unlikely to be attributable to unknown confounding factors due to having relatively large sample sizes, significantly increased odd ratios with small P values.	('increased', 'PosReg', (221, 230))	('play', 'Reg', (57, 61))	('rs451360 SNP', 'Var', (39, 51))	('ESCC', 'Disease', (72, 76))	('rs451360', 'Mutation', 'rs451360', (39, 47))
414858	26716642	Additionally, our genotype-phenotype correlation data between the rs451360 genetic variant and gene expression supports the case-control study since the protective T allele carriers showing less oncogene CLPTM1L expression.	('CLPTM1L', 'Gene', (204, 211))	('less', 'NegReg', (190, 194))	('expression', 'MPA', (212, 222))	('rs451360', 'Mutation', 'rs451360', (66, 74))	('rs451360', 'Var', (66, 74))	('CLPTM1L', 'Gene', '81037', (204, 211))
414860	26716642	In conclusion, we demonstrated that there are three genetic polymorphisms (rs2853691, rs2736100 and rs451360) in the TERT-CLPTM1L loci are significantly associated with ESCC risk in Chinese populations.	('ESCC', 'Disease', (169, 173))	('rs451360', 'Var', (100, 108))	('CLPTM1L', 'Gene', '81037', (122, 129))	('rs2853691', 'Var', (75, 84))	('CLPTM1L', 'Gene', (122, 129))	('rs2736100', 'Var', (86, 95))	('rs451360', 'Mutation', 'rs451360', (100, 108))	('associated with', 'Reg', (153, 168))	('TERT', 'Gene', (117, 121))	('TERT', 'Gene', '7015', (117, 121))	('rs2853691', 'Mutation', 'rs2853691', (75, 84))	('rs2736100', 'Mutation', 'rs2736100', (86, 95))
414869	26716642	To reduce the costs of the study, we genotyped the TERT-CLPTM1L rs2853691 A>G, rs2736100 T>G and rs451360 G>T SNPs in two validation sets using the PCR-based restriction fragment length polymorphism (RFLP) as described in Supplementary Table S3.	('rs2853691 A>G', 'Var', (64, 77))	('rs2736100 T>G', 'Var', (79, 92))	('TERT', 'Gene', (51, 55))	('rs2736100', 'Mutation', 'rs2736100', (79, 88))	('rs451360', 'Mutation', 'rs451360', (97, 105))	('rs451360 G>T', 'Var', (97, 109))	('TERT', 'Gene', '7015', (51, 55))	('CLPTM1L', 'Gene', '81037', (56, 63))	('rs2853691', 'Mutation', 'rs2853691', (64, 73))	('CLPTM1L', 'Gene', (56, 63))
414871	26716642	Similarly, the intron 16 segment of CLPTM1L (chr.5: 1285954~1286844 bp [GRCh38.p2] including the rs451360 flanking region) was amplified with human genomic DNA carrying CLPTM1L rs451360 GG genotype or TT genotype.	('CLPTM1L', 'Gene', (36, 43))	('CLPTM1L', 'Gene', '81037', (36, 43))	('human', 'Species', '9606', (142, 147))	('rs451360', 'Mutation', 'rs451360', (97, 105))	('CLPTM1L', 'Gene', '81037', (169, 176))	('rs451360 GG', 'Var', (177, 188))	('CLPTM1L', 'Gene', (169, 176))	('rs451360', 'Mutation', 'rs451360', (177, 185))
414879	26716642	Pearson's chi2 test was used to examine the differences in demographic variables, smoking status, drinking status, and genotype distributions of rs2853691, rs2736100 or rs451360 SNP between ESCC cases and healthy controls.	('ESCC', 'Disease', (190, 194))	('rs2853691', 'Mutation', 'rs2853691', (145, 154))	('rs2736100', 'Var', (156, 165))	('rs451360 SNP', 'Var', (169, 181))	('rs2736100', 'Mutation', 'rs2736100', (156, 165))	('rs451360', 'Mutation', 'rs451360', (169, 177))	('rs2853691', 'Var', (145, 154))
414880	26716642	The associations between rs2853691, rs2736100 or rs451360 genotypes and ESCC risk were estimated by odds ratios and their 95% confidence intervals computed by logistic regression models.	('associations', 'Interaction', (4, 16))	('rs2853691', 'Mutation', 'rs2853691', (25, 34))	('rs2736100', 'Mutation', 'rs2736100', (36, 45))	('rs451360', 'Mutation', 'rs451360', (49, 57))	('rs451360', 'Var', (49, 57))	('rs2853691', 'Var', (25, 34))	('rs2736100', 'Var', (36, 45))	('ESCC', 'Disease', (72, 76))
414904	26314958	The patients were included if their pathological stage was T3-4N0-3M0 according to the AJCC/UICC TNM staging system (Version 7.0, 2009) and if they did not receive neoadjuvant therapy.	('T3-4N0-3M0', 'Var', (59, 69))	('TNM', 'Gene', (97, 100))	('patients', 'Species', '9606', (4, 12))	('TNM', 'Gene', '10178', (97, 100))
414930	26314958	Among the 51 patients in the small-field group, the Dmean and Dmax of PTVsto were 2062 cGy and 6374cGy, respectively, compared with 2813 cGy and 6657 cGy, respectively among the 54 patients in the large-field group (both p < 0.001, respectively).	('6374cGy', 'Var', (95, 102))	('patients', 'Species', '9606', (13, 21))	('2062 cGy', 'Var', (82, 90))	('PTV', 'Chemical', '-', (70, 73))	('patients', 'Species', '9606', (181, 189))	('PTVsto', 'Gene', (70, 76))
414940	26314958	Moreover, the incidences of acute (35.2% vs. 29.4%, p = 0.527) and late gastric toxicities (18.5% vs. 9.8%, p = 0.202) in the large-field group were a little higher than those in the small-field group, but no statistically significant difference was found.	('large-field', 'Var', (126, 137))	('late gastric toxicities', 'Disease', (67, 90))	('late gastric toxicities', 'Disease', 'MESH:D013274', (67, 90))
414941	26314958	By multiple logistic regression analysis, V50 was the only predictive factor for Grade 2 and above gastric toxicity (p = 0.024, Table 3).	('gastric toxicity', 'Disease', 'MESH:D013274', (99, 115))	('gastric toxicity', 'Disease', (99, 115))	('V50', 'Var', (42, 45))
414942	26314958	ROC curve analysis showed that the cut-off value of V50 was 14.05% (0.815, 95% CI:0.685-0.946; the sensitivity and specificity were 82.4%, and 61.3%, respectively) and that the rates of Grade 2 and above acute and late toxicities were 19.1% for V50 < 14.05% and 34.5% for V50 > 14.05%.	('V50 < 14.05', 'Var', (245, 256))	('V50', 'Var', (272, 275))	('late toxicities', 'Disease', (214, 229))	('V50', 'Var', (52, 55))	('late toxicities', 'Disease', 'MESH:D064420', (214, 229))
414944	26314958	V50 was the most predictive factor for >= grade 2 toxicity for the stomach.	('toxicity', 'Disease', 'MESH:D064420', (50, 58))	('toxicity', 'Disease', (50, 58))	('V50', 'Var', (0, 3))
414948	26314958	In two retrospective studies for esophageal cancer, the risk of acute toxicity in the upper aerodigestive tract and stomach was 2.3%-11.9% for the small T portal group and 12%-18.6% for the large T portal group, which was similar to our results.	('small', 'Var', (147, 152))	('toxicity', 'Disease', 'MESH:D064420', (70, 78))	('toxicity', 'Disease', (70, 78))	('esophageal cancer', 'Disease', (33, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
414965	26314958	We found that V50 for the intrathoracic stomach was the most predictive factor for >= grade 2 gastric toxicity.	('gastric toxicity', 'Disease', 'MESH:D013274', (94, 110))	('V50', 'Var', (14, 17))	('gastric toxicity', 'Disease', (94, 110))
415081	26841926	Three mechanisms have been suggested for the role of E .coli in tumor promotion: (a) the bacteria increase the carcinogenic potential of nitrosamine precursors, (b) accelerate urothelial proliferation, and (c) expose the host tissue to free radicals which results in DNA damage.	('nitrosamine', 'Chemical', 'MESH:D009602', (137, 148))	('tumor', 'Disease', (64, 69))	('bacteria', 'Var', (89, 97))	('rat', 'Species', '10116', (194, 197))	('E .coli', 'Species', '562', (53, 60))	('accelerate', 'PosReg', (165, 175))	('increase', 'PosReg', (98, 106))	('rat', 'Species', '10116', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('expose', 'Reg', (210, 216))	('urothelial proliferation', 'CPA', (176, 200))	('carcinogenic', 'Disease', 'MESH:D063646', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('carcinogenic', 'Disease', (111, 123))
415131	25742648	In addition, studies have shown chronic exposure of lung alveolar epithelial type II cells to NNK results in malignant transformation and combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells.	('lung alveolar epithelial type II', 'Disease', 'MESH:D002277', (52, 84))	('breast cell carcinogenesis chronically', 'Disease', (170, 208))	('enhanced', 'PosReg', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancerous', 'Disease', 'MESH:D009369', (251, 260))	('cancerous', 'Disease', 'MESH:D009369', (237, 246))	('B[a]P', 'Var', (155, 160))	('non-cancerous', 'Disease', (233, 246))	('breast cell carcinogenesis chronically', 'Disease', 'MESH:D063646', (170, 208))	('NNK', 'Gene', (94, 97))	('lung alveolar epithelial type II', 'Disease', (52, 84))	('malignant transformation', 'CPA', (109, 133))	('cancerous', 'Disease', (237, 246))	('NNK', 'Var', (147, 150))	('cancerous', 'Disease', (251, 260))	('non-cancerous', 'Disease', 'MESH:D009369', (233, 246))
415176	22069487	Other reports have indicated the importance of CD44 in esophageal squamous carcinoma demonstrating a higher expression of CD44v6, but its impact on tumor invasion remains controversial.	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (55, 84))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('higher', 'PosReg', (101, 107))	('esophageal squamous carcinoma', 'Disease', (55, 84))	('tumor', 'Disease', (148, 153))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (55, 84))	('CD44', 'Gene', (47, 51))	('CD44v6', 'Var', (122, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('expression', 'MPA', (108, 118))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (66, 84))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
415183	22069487	Additionally, a dominant-negative mutant of TGFbetaRII (a gift of Dr. H. Moses, Vanderbilt University, Nashville, TN), subcloned into pBABE puro, was used to generate ECdnT cells and empty pBABE puro as a control.	('TGFbetaRII', 'Gene', '7048', (44, 54))	('TGFbetaRII', 'Gene', (44, 54))	('mutant', 'Var', (34, 40))
415222	22069487	We previously established a model to analyze the effects of E-cadherin loss on esophageal keratinocytes by retroviral expression of dominant-negative E-cadherin (EC) or dominant-negative E-cadherin in combination with dominant-negative TGFbetaRII (ECdnT).	('TGFbetaRII', 'Gene', '7048', (236, 246))	('E-cadherin', 'Protein', (187, 197))	('TGFbetaRII', 'Gene', (236, 246))	('dominant-negative', 'Var', (132, 149))	('E-cadherin', 'Protein', (150, 160))	('dominant-negative', 'Var', (169, 186))
415232	22069487	Activin A treatment increased CD44 variant expression in TE-11 in the absence of E-cadherin (Fig.	('increased', 'PosReg', (20, 29))	('Activin', 'Gene', (0, 7))	('TE-11', 'Chemical', '-', (57, 62))	('CD44', 'Gene', (30, 34))	('Activin', 'Gene', '83729', (0, 7))	('variant', 'Var', (35, 42))	('expression', 'MPA', (43, 53))
415236	22069487	Overexpression of Activin A has been described in esophageal squamous cell carcinoma and is associated with poor prognosis.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('Activin', 'Gene', (18, 25))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('described', 'Reg', (37, 46))	('Overexpression', 'Var', (0, 14))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))	('Activin', 'Gene', '83729', (18, 25))
415243	22069487	Interestingly, silencing of ESPR1/2 in epithelial cells induced expression of the mesenchymal cadherin, N-cadherin, without changes in E-cadherin expression.	('expression', 'MPA', (64, 74))	('silencing', 'Var', (15, 24))	('N-cadherin', 'Gene', (104, 114))	('ESPR1/2', 'Gene', (28, 35))	('N-cadherin', 'Gene', '1000', (104, 114))	('induced', 'Reg', (56, 63))
415244	22069487	Conversely, expression of ESPR1 can reverse Twist-induced EMT in mammary epithelial cells.	('Twist', 'Gene', (44, 49))	('expression', 'Var', (12, 22))	('Twist', 'Gene', '7291', (44, 49))	('ESPR1', 'Gene', (26, 31))
415253	22069487	In conclusion, we show that CD44 upregulation is associated with the loss of E-cadherin in esophageal carcinoma and that CD44 promotes MMP-9 mediated tumor invasion.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (91, 111))	('esophageal carcinoma', 'Disease', (91, 111))	('loss', 'NegReg', (69, 73))	('MMP-9', 'Gene', '4318', (135, 140))	('promotes', 'PosReg', (126, 134))	('E-cadherin', 'Protein', (77, 87))	('MMP-9', 'Gene', (135, 140))	('upregulation', 'PosReg', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('CD44', 'Gene', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('CD44', 'Var', (121, 125))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (91, 111))	('tumor', 'Disease', (150, 155))
415287	32055782	AI assisted colonoscopy improved adenoma detection rates (ADR) from 20.3% to 29.1%, and the mean number of adenomas per patient from 0.31 to 0.53.	('adenomas', 'Disease', (107, 115))	('improved', 'PosReg', (24, 32))	('adenoma', 'Disease', (33, 40))	('patient', 'Species', '9606', (120, 127))	('colon', 'Disease', 'MESH:D015179', (12, 17))	('adenoma', 'Disease', 'MESH:D000236', (107, 114))	('adenoma', 'Disease', 'MESH:D000236', (33, 40))	('AI assisted', 'Var', (0, 11))	('adenoma', 'Disease', (107, 114))	('adenomas', 'Disease', 'MESH:D000236', (107, 115))	('colon', 'Disease', (12, 17))
415322	32055782	Liu et al found that the combined diagnosis with CA724, CEA, CA199, and AFP for esophageal cancer reached 93.85% sensitivity and 83.71% specificity.	('AFP', 'Gene', '174', (72, 75))	('CEA', 'Gene', (56, 59))	('CA724', 'Var', (49, 54))	('CA199', 'Var', (61, 66))	('CEA', 'Gene', '1084', (56, 59))	('esophageal cancer', 'Disease', (80, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('AFP', 'Gene', (72, 75))
415323	32055782	Another study demonstrated that the combined diagnosis with CYFRA21-1, CEA, and NSE for older esophageal cancer reached 84% sensitivity and 86% specificity.	('CYFRA21-1', 'Var', (60, 69))	('NSE', 'Gene', (80, 83))	('CEA', 'Gene', (71, 74))	('esophageal cancer', 'Disease', (94, 111))	('CEA', 'Gene', '1084', (71, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('NSE', 'Gene', '2026', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
415331	32055782	However, a phase II/III randomized controlled trial of concurrent chemoradiotherapy combined with cetuximab in the treatment of esophageal cancer showed that cetuximab treatment reduced median overall survival (mOS) and increased incidence of non-hematologic adverse events.	('overall survival', 'MPA', (193, 209))	('esophageal cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cetuximab', 'Var', (158, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('reduced', 'NegReg', (178, 185))
415336	32055782	By analyzing the serological markers (CEA, CA199, CA724, and CA242) and lymph node metastasis of 584 patients with gastric cancer, Bai et al reported the combined sensitivity reached 96.3%, the specificity was 69.8%, and the AUC was 0.899.	('CEA', 'Gene', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('patients', 'Species', '9606', (101, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('CEA', 'Gene', '1084', (38, 41))	('CA199', 'Var', (43, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('CA242', 'Var', (61, 66))	('CA724', 'Var', (50, 55))	('gastric cancer', 'Disease', (115, 129))
415349	32055782	In a randomized phase III clinical trial of cetuximab plus FOLFIRI (folinic acid + fluorouracil + irinotecan) for the treatment of metastatic colorectal cancer, cetuximab increased overall survival by 8.2 months compared with FOLFIRI treatment alone.	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('folinic acid', 'Chemical', 'MESH:D002955', (68, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('irinotecan', 'Chemical', 'MESH:C051890', (98, 108))	('cetuximab', 'Var', (161, 170))	('colorectal cancer', 'Disease', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('clinical', 'Species', '191496', (26, 34))	('fluorouracil', 'Chemical', 'MESH:D005472', (83, 95))	('increased', 'PosReg', (171, 180))	('overall survival', 'MPA', (181, 197))
415353	32055782	This suggests that bevacizumab is more suitable for advanced colorectal cancer patients with RAS mutations.	('mutations', 'Var', (97, 106))	('colorectal cancer', 'Disease', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('RAS', 'Gene', (93, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('patients', 'Species', '9606', (79, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))
415363	32055782	In recent years, there have been many reports that demonstrate the clearance of helicobacter pylori can cause an increase in the incidence of IBD, which may be related to the long-term "immune escape" caused by chronic helicobacter pylori infection.	('helicobacter pylori', 'Species', '210', (219, 238))	('IBD', 'Disease', (142, 145))	('helicobacter pylori', 'Var', (80, 99))	('clearance', 'Var', (67, 76))	('helicobacter pylori infection', 'Disease', 'MESH:D016481', (219, 248))	('IBD', 'Disease', 'MESH:D043183', (142, 145))	('helicobacter pylori infection', 'Phenotype', 'HP:0005202', (219, 248))	('helicobacter pylori', 'Species', '210', (80, 99))	('helicobacter pylori infection', 'Disease', (219, 248))
415369	32055782	Moreover, reports show gene epigenetic modification, microsatellite instability (MSl) play an important role in the development of serrated adenoma.	('adenoma', 'Disease', 'MESH:D000236', (140, 147))	('serrated adenoma', 'Phenotype', 'HP:0032222', (131, 147))	('adenoma', 'Disease', (140, 147))	('epigenetic modification', 'Var', (28, 51))	('microsatellite', 'MPA', (53, 67))
415370	32055782	In colorectal cancer with SA, the hypermethylation of the mismatch repair gene hMLH1 and MGMT promoter region is closely related to the occurrence of MSI and plays an extremely important role in this pathway.	('MGMT', 'Gene', (89, 93))	('related', 'Reg', (121, 128))	('hypermethylation', 'Var', (34, 50))	('SA', 'Phenotype', 'HP:0032222', (26, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('hMLH1', 'Gene', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('MSI', 'Gene', (150, 153))	('hMLH1', 'Gene', '4292', (79, 84))	('colorectal cancer', 'Disease', (3, 20))	('MSI', 'Gene', '5928', (150, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('MGMT', 'Gene', '4255', (89, 93))
415376	32055782	The researchers further screened 4 colorectal cancer candidate miRNA markers: let-7b-3p, miR-150-3p, miR-145-3p, and miR-139-3p and tested 134 samples in biobank for diagnostic verification.	('miR-139-3p', 'Gene', (117, 127))	('colorectal cancer', 'Disease', 'MESH:D015179', (35, 52))	('miR-150-3p', 'Var', (89, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (35, 52))	('miR-145-3p', 'Var', (101, 111))	('let-7b-3p', 'Var', (78, 87))	('miR-139-3p', 'Gene', '406931', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('colorectal cancer', 'Disease', (35, 52))
415377	32055782	Logistic regression model analysis showed that the combined AUC of let-7b-3p, miR-145-3p, and miR-139-3p was as high as 0.927 and significantly higher than plasma miRNA.	('miR-139-3p', 'Gene', (94, 104))	('higher', 'PosReg', (144, 150))	('let-7b-3p', 'Var', (67, 76))	('miR-145-3p', 'Var', (78, 88))	('miR-139-3p', 'Gene', '406931', (94, 104))
415379	32055782	Moreover, they found exosomes treatment inhibited tumors in a variety of pancreatic cancer mouse models and significantly improve their overall survival.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('pancreatic cancer', 'Disease', (73, 90))	('improve', 'PosReg', (122, 129))	('inhibited', 'NegReg', (40, 49))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('exosomes', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('mouse', 'Species', '10090', (91, 96))	('overall survival', 'CPA', (136, 152))
415397	28002078	Although a recent meta-analysis of observational studies shows that physical activity is associated with a reduced risk of esophageal cancer, the literature regarding physical activity in patients with esophageal cancer after esophagectomy is sparse.	('esophageal cancer', 'Disease', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('esophageal cancer', 'Disease', (202, 219))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('reduced', 'NegReg', (107, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (202, 219))	('patients', 'Species', '9606', (188, 196))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('physical activity', 'Var', (68, 85))
415414	28002078	According to the World Health Organization (WHO) guidelines, both male and female patients with BMI 30 kg/m2 or more were classified as obese, those with BMI of 25 kg/m2 or more as overweight, those with BMI of less than 18.5 kg/m2 as underweight, and those with BMI between 18.5 and 24.9 kg/m2 as a normal population.	('patients', 'Species', '9606', (82, 90))	('obese', 'Disease', 'MESH:D009765', (136, 141))	('BMI', 'Var', (96, 99))	('obese', 'Disease', (136, 141))	('overweight', 'Phenotype', 'HP:0025502', (181, 191))
415443	29207660	Genetic polymorphisms of ATG5 predict survival and recurrence in patients with early-stage esophageal squamous cell carcinoma Esophageal squamous cell carcinoma (ESCC) is a deadly disease with high risk of tumor recurrence even among patients with an early pathologic stage of tumor.	('esophageal squamous cell carcinoma', 'Disease', (91, 125))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('ATG5', 'Gene', (25, 29))	('patients', 'Species', '9606', (234, 242))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (91, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('polymorphisms', 'Var', (8, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('Esophageal squamous cell carcinoma', 'Disease', (126, 160))	('patients', 'Species', '9606', (65, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('ATG5', 'Gene', '9474', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (126, 160))
415447	29207660	We repeatedly demonstrated that 3 SNPs in ATG5, rs1322178, rs3804329, and rs671116, were significantly correlated with the prognosis of patients with early-stage ESCC (HR[95 % CI]=2.01[1.19-3.40], p=0.009 for ATG5: rs1322178; HR[95 % CI]=1.88 [1.08-3.26], p=0.025 for ATG5:rs3804329; HR[95 % CI]=1.73[1.24-2.42], p=0.001 for ATG5:rs671116, in combined group).	('ATG5', 'Gene', '9474', (42, 46))	('rs3804329', 'Mutation', 'rs3804329', (273, 282))	('rs671116', 'Mutation', 'rs671116', (330, 338))	('rs1322178', 'Mutation', 'rs1322178', (48, 57))	('ESCC', 'Disease', (162, 166))	('ATG5', 'Gene', (209, 213))	('ATG5', 'Gene', (42, 46))	('rs1322178', 'Mutation', 'rs1322178', (215, 224))	('rs1322178', 'Var', (48, 57))	('rs671116', 'Var', (74, 82))	('ATG5', 'Gene', '9474', (325, 329))	('rs671116', 'Mutation', 'rs671116', (74, 82))	('correlated', 'Reg', (103, 113))	('ATG5', 'Gene', '9474', (268, 272))	('rs3804329', 'Var', (59, 68))	('ATG5', 'Gene', (325, 329))	('rs3804329', 'Mutation', 'rs3804329', (59, 68))	('ATG5', 'Gene', (268, 272))	('patients', 'Species', '9606', (136, 144))	('ATG5', 'Gene', '9474', (209, 213))
415448	29207660	Both rs1322178 and rs3804329 can predict early distant metastasis of patients.	('rs3804329', 'Mutation', 'rs3804329', (19, 28))	('rs3804329', 'Var', (19, 28))	('rs1322178', 'Mutation', 'rs1322178', (5, 14))	('rs1322178', 'Var', (5, 14))	('early distant metastasis', 'CPA', (41, 65))	('patients', 'Species', '9606', (69, 77))
415471	29207660	We thus set out to investigate the association of ATG SNPs (single nucleotide polymorphisms) with the prognosis of early-stage ESCC and found that SNPs at ATG5 gene are significantly associated with the prognosis of early-stage ESCC (Supplementary Table 1).	('ATG5', 'Gene', '9474', (155, 159))	('early-stage ESCC', 'Disease', (216, 232))	('SNPs', 'Var', (147, 151))	('ATG5', 'Gene', (155, 159))	('associated with', 'Reg', (183, 198))
415479	29207660	Three ATG5 SNPs, rs1322178, rs3804329 and rs671116, were found to be significantly or borderline associated with overall survival of patients by either the dominant, the recessive or the additive model (Supplementary Table 1).	('rs671116', 'Mutation', 'rs671116', (42, 50))	('ATG5', 'Gene', (6, 10))	('patients', 'Species', '9606', (133, 141))	('rs671116', 'Var', (42, 50))	('rs3804329', 'Mutation', 'rs3804329', (28, 37))	('rs3804329', 'Var', (28, 37))	('rs1322178', 'Mutation', 'rs1322178', (17, 26))	('rs1322178', 'Var', (17, 26))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('overall', 'MPA', (113, 120))	('associated', 'Reg', (97, 107))	('ATG5', 'Gene', '9474', (6, 10))
415481	29207660	Significant association of ATG5: rs1322178 and ATG5: rs671116 with risk of death was further confirmed in the replication group (HR[95 % CI]=1.99[1.02-3.90], p=0.045 and HR[95 % CI]=1.59 [1.06-2.41], p=0.027 for ATG5: rs1322178 and ATG5: rs671116, respectively, Table 2).	('ATG5', 'Gene', (212, 216))	('rs1322178', 'Var', (33, 42))	('rs1322178', 'Mutation', 'rs1322178', (33, 42))	('rs1322178', 'Mutation', 'rs1322178', (218, 227))	('ATG5', 'Gene', (27, 31))	('death', 'Disease', (75, 80))	('rs671116', 'Mutation', 'rs671116', (238, 246))	('ATG5', 'Gene', '9474', (232, 236))	('ATG5', 'Gene', '9474', (47, 51))	('rs671116', 'Mutation', 'rs671116', (53, 61))	('ATG5', 'Gene', '9474', (212, 216))	('ATG5', 'Gene', '9474', (27, 31))	('rs671116', 'Var', (53, 61))	('ATG5', 'Gene', (47, 51))	('ATG5', 'Gene', (232, 236))	('death', 'Disease', 'MESH:D003643', (75, 80))
415482	29207660	The genotypes of ATG5:rs3804329 displayed borderline association with overall survival in the replication group (p=0.064, Table 2).	('rs3804329', 'Var', (22, 31))	('ATG5', 'Gene', (17, 21))	('overall survival', 'MPA', (70, 86))	('rs3804329', 'Mutation', 'rs3804329', (22, 31))	('ATG5', 'Gene', '9474', (17, 21))
415483	29207660	All of these SNPs were significantly correlated with hazard of death in the combined group (HR[95 % CI]=2.01[1.19-3.40], p=0.009 for ATG5:rs1322178; HR[95 % CI]=1.88[1.08-3.26], p=0.025 for ATG5:rs3804329; HR[95 % CI]=1.73[1.24-2.42], p=0.001 for ATG5:rs671116, Table 2).	('ATG5', 'Gene', (247, 251))	('ATG5', 'Gene', (133, 137))	('rs671116', 'Mutation', 'rs671116', (252, 260))	('rs3804329', 'Mutation', 'rs3804329', (195, 204))	('ATG5', 'Gene', '9474', (190, 194))	('death', 'Disease', 'MESH:D003643', (63, 68))	('death', 'Disease', (63, 68))	('correlated', 'Reg', (37, 47))	('ATG5', 'Gene', '9474', (133, 137))	('rs1322178', 'Var', (138, 147))	('ATG5', 'Gene', (190, 194))	('ATG5', 'Gene', '9474', (247, 251))	('rs1322178', 'Mutation', 'rs1322178', (138, 147))
415486	29207660	Patients carrying the AG genotype of ATG5:rs3804329 also had a 4.5-fold increased hazard of early distant metastasis (OR [95 % CI]= 4.50 [1.19-17.01], P=0.027, Table 3) compared to patients with the AA genotype.	('early distant metastasis', 'CPA', (92, 116))	('rs3804329', 'Mutation', 'rs3804329', (42, 51))	('rs3804329', 'Var', (42, 51))	('Patients', 'Species', '9606', (0, 8))	('ATG5', 'Gene', '9474', (37, 41))	('patients', 'Species', '9606', (181, 189))	('ATG5', 'Gene', (37, 41))
415488	29207660	Patients carrying variant genotype CT exhibited decreases in both OS and PFS (mean survival time [MST] 33.54 vs. 12.69 months for OS; MST 17.80 vs. 7.74 months for PFS, Figure 1A and 1B).	('Patients', 'Species', '9606', (0, 8))	('decreases', 'NegReg', (48, 57))	('PFS', 'Disease', (73, 76))	('variant', 'Var', (18, 25))
415489	29207660	Both OS and PFS were significantly shorter in patients with the variant allele of ATG5:rs3804329 (MST 31.71 vs. 17.47 months, P=0.029 for OS; MST 17.74 vs. 9.25 months, P= 0.037 for PFS, Figure 1C and 1D).	('PFS', 'CPA', (12, 15))	('patients', 'Species', '9606', (46, 54))	('shorter', 'NegReg', (35, 42))	('rs3804329', 'Mutation', 'rs3804329', (87, 96))	('rs3804329', 'Var', (87, 96))	('ATG5', 'Gene', '9474', (82, 86))	('ATG5', 'Gene', (82, 86))
415490	29207660	Patients carrying the TT genotype of ATG5:rs671116 also had significantly shorter OS and PFS compared to patients with the CC or CT genotypes (MST 34.16 vs. 26.43 months, P=0.023 for OS; MST 19.87 vs. 12.26 months, P= 0.008 for PFS, Figure 1E and 1F).	('shorter', 'NegReg', (74, 81))	('PFS', 'CPA', (89, 92))	('patients', 'Species', '9606', (105, 113))	('rs671116', 'Mutation', 'rs671116', (42, 50))	('rs671116', 'Var', (42, 50))	('ATG5', 'Gene', '9474', (37, 41))	('Patients', 'Species', '9606', (0, 8))	('ATG5', 'Gene', (37, 41))
415496	29207660	High expression of ATG5 in normal tissue was significantly correlated with increased risk of tumor progression compared to low expression (HR [95 % CI]=1.82 [0.99-3.35], P=0.033, Table 4).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('High', 'Var', (0, 4))	('ATG5', 'Gene', '9474', (19, 23))	('tumor', 'Disease', (93, 98))	('ATG5', 'Gene', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
415498	29207660	Re-classifying the groups into low (scoring 0), middle (scoring 1 or 2), and high (scoring 3), high ATG5 expression in tumor tissue had a 2.23-fold higher hazard of death compared to low expression (HR [95 % CI]=2.23 [1.06-4.68], P=0.035, Table 4).	('ATG5', 'Gene', '9474', (100, 104))	('tumor', 'Disease', (119, 124))	('ATG5', 'Gene', (100, 104))	('death', 'Disease', 'MESH:D003643', (165, 170))	('death', 'Disease', (165, 170))	('high', 'Var', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
415503	29207660	Unexpectedly, the expression level of ATG5 in both normal and tumor tissue did not exhibit significant correlation with the genotypes of ATG5:rs1322178, ATG5:rs3804329, or ATG5:rs671116 (Supplementary Table 3).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('ATG5', 'Gene', (38, 42))	('rs671116', 'Mutation', 'rs671116', (177, 185))	('tumor', 'Disease', (62, 67))	('ATG5', 'Gene', '9474', (153, 157))	('ATG5', 'Gene', (172, 176))	('rs3804329', 'Mutation', 'rs3804329', (158, 167))	('ATG5', 'Gene', (153, 157))	('ATG5', 'Gene', '9474', (137, 141))	('rs1322178', 'Mutation', 'rs1322178', (142, 151))	('rs1322178', 'Var', (142, 151))	('ATG5', 'Gene', '9474', (172, 176))	('ATG5', 'Gene', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('ATG5', 'Gene', '9474', (38, 42))
415504	29207660	In the current study, we demonstrated that 3 SNPs in ATG5, rs1322178, rs3804329, and rs671116, significantly correlated with the prognosis of patients with early-stage ESCC (Table 2 and Figure 1).	('rs671116', 'Var', (85, 93))	('rs1322178', 'Var', (59, 68))	('rs1322178', 'Mutation', 'rs1322178', (59, 68))	('ATG5', 'Gene', '9474', (53, 57))	('rs3804329', 'Mutation', 'rs3804329', (70, 79))	('early-stage ESCC', 'Disease', (156, 172))	('rs3804329', 'Var', (70, 79))	('patients', 'Species', '9606', (142, 150))	('ATG5', 'Gene', (53, 57))	('rs671116', 'Mutation', 'rs671116', (85, 93))	('correlated with', 'Reg', (109, 124))
415505	29207660	Both ATG5:rs1322178 and ATG5: rs3804329 can predict early distant metastasis of early-stage ESCC (Table 3).	('ATG5', 'Gene', (24, 28))	('rs3804329', 'Mutation', 'rs3804329', (30, 39))	('rs3804329', 'Var', (30, 39))	('ATG5', 'Gene', '9474', (5, 9))	('rs1322178', 'Var', (10, 19))	('predict', 'Reg', (44, 51))	('rs1322178', 'Mutation', 'rs1322178', (10, 19))	('early distant metastasis', 'CPA', (52, 76))	('ATG5', 'Gene', (5, 9))	('early-stage ESCC', 'Disease', (80, 96))	('ATG5', 'Gene', '9474', (24, 28))
415509	29207660	ATG5: rs1322178 is located within the 3' untranslated region (3'-UTR), whereas rs3804329 and rs671116 are in the intron region of the ATG5 gene.	('ATG5', 'Gene', (134, 138))	('ATG5', 'Gene', (0, 4))	('rs671116', 'Mutation', 'rs671116', (93, 101))	('rs671116', 'Var', (93, 101))	('rs3804329', 'Mutation', 'rs3804329', (79, 88))	('rs3804329', 'Var', (79, 88))	('rs1322178', 'Var', (6, 15))	('rs1322178', 'Mutation', 'rs1322178', (6, 15))	('ATG5', 'Gene', '9474', (0, 4))	('ATG5', 'Gene', '9474', (134, 138))
415512	29207660	We observed alteration of the nucleotide from wildtype C to variant T of ATG5: rs1322175, supporting the notion that these nucleotides might be targeted by different mature microRNAs by sequence alignment.	('ATG5', 'Gene', '9474', (73, 77))	('rs1322175', 'Var', (79, 88))	('ATG5', 'Gene', (73, 77))	('variant', 'Var', (60, 67))	('rs1322175', 'Mutation', 'rs1322175', (79, 88))
415513	29207660	We thus hypothesized thatrs1322178 may regulate ATG5 expression by modulating RNA stability in ESCC.	('ATG5', 'Gene', '9474', (48, 52))	('regulate', 'Reg', (39, 47))	('thatrs1322178', 'Var', (21, 34))	('rs1322178', 'Mutation', 'rs1322178', (25, 34))	('ATG5', 'Gene', (48, 52))	('RNA stability', 'MPA', (78, 91))	('ESCC', 'Disease', (95, 99))	('expression', 'MPA', (53, 63))	('modulating', 'Reg', (67, 77))
415519	29207660	ATG5 gene knockdown by small interference RNA (siRNA) has also been reported to enhance starvation-induced cell death.	('death', 'Disease', 'MESH:D003643', (112, 117))	('death', 'Disease', (112, 117))	('ATG5', 'Gene', (0, 4))	('enhance', 'PosReg', (80, 87))	('ATG5', 'Gene', '9474', (0, 4))	('knockdown', 'Var', (10, 19))	('small interference', 'MPA', (23, 41))
415551	29207660	Based on the results of previous studies, 20 candidate SNPs were selected, which consisted of 1 SNP at autophagy related 3 (ATG3), 6 SNPs at autophagy related 5 (ATG5), 9 SNPs at autophagy related 7 (ATG7), 3 SNPs at autophagy related 16-like 1 (ATG16L1), and 1 SNP at beclin 1 (BECN1) (Supplementary Table 1).	('beclin 1', 'Gene', '8678', (269, 277))	('beclin 1', 'Gene', (269, 277))	('ATG5', 'Gene', (162, 166))	('autophagy related 5', 'Gene', (141, 160))	('autophagy related 16-like 1', 'Gene', (217, 244))	('ATG7', 'Gene', (200, 204))	('SNPs', 'Var', (171, 175))	('ATG3', 'Gene', (124, 128))	('ATG3', 'Gene', '64422', (124, 128))	('BECN1', 'Gene', '8678', (279, 284))	('autophagy related 7', 'Gene', (179, 198))	('autophagy related 3', 'Gene', (103, 122))	('autophagy related 16-like 1', 'Gene', '55054', (217, 244))	('BECN1', 'Gene', (279, 284))	('autophagy related 7', 'Gene', '10533', (179, 198))	('ATG5', 'Gene', '9474', (162, 166))	('ATG16L1', 'Gene', '55054', (246, 253))	('autophagy related 5', 'Gene', '9474', (141, 160))	('ATG7', 'Gene', '10533', (200, 204))	('ATG16L1', 'Gene', (246, 253))	('autophagy related 3', 'Gene', '64422', (103, 122))
415562	27203740	This receptor tyrosine kinase is upregulated in 10-20% of esophageal squamous cell carcinoma (ESCC) tissues, and amplification of ERBB2 has been correlated with poor prognosis in esophageal cancer.	('upregulated', 'PosReg', (33, 44))	('tyrosine kinase', 'Enzyme', (14, 29))	('esophageal cancer', 'Disease', (179, 196))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (58, 92))	('ERBB2', 'Gene', '2064', (130, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('ERBB2', 'Gene', (130, 135))	('esophageal squamous cell carcinoma', 'Disease', (58, 92))	('amplification', 'Var', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
415565	27203740	Furthermore, miR-193a-5p reduced ERBB2 expression by directly targeting the 3'UTR.	('ERBB2', 'Gene', '2064', (33, 38))	('reduced', 'NegReg', (25, 32))	('193a', 'Chemical', '-', (17, 21))	('targeting', 'Reg', (62, 71))	('expression', 'MPA', (39, 49))	('miR-193a-5p', 'Var', (13, 24))	('ERBB2', 'Gene', (33, 38))
415566	27203740	Increased miR-193a-5p enhanced radiosensitivity and inhibited tumorigenesis in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('miR-193a-5p', 'Var', (10, 21))	('radiosensitivity', 'MPA', (31, 47))	('tumor', 'Disease', (62, 67))	('193a', 'Chemical', '-', (14, 18))	('inhibited', 'NegReg', (52, 61))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (22, 47))	('enhanced', 'PosReg', (22, 30))
415568	27203740	Our data suggest that patients with high miR-193a-5p will likely benefit from CCRT treatment alone, however a combination of CCRT with Herceptin may be beneficial for patients with low miR-193a-5p expression.	('miR-193a-5p', 'Var', (41, 52))	('benefit', 'PosReg', (65, 72))	('patients', 'Species', '9606', (22, 30))	('high miR-193a-5p', 'Var', (36, 52))	('patients', 'Species', '9606', (167, 175))	('Herceptin', 'Chemical', 'MESH:D000068878', (135, 144))	('193a', 'Chemical', '-', (189, 193))	('193a', 'Chemical', '-', (45, 49))
415590	27203740	In ESCC, 10-20% of tumors show ERBB2 up-regulation, and amplification of ERBB2 is correlated with poor prognosis.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ESCC', 'Disease', (3, 7))	('up-regulation', 'PosReg', (37, 50))	('ERBB2', 'Gene', '2064', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('ERBB2', 'Gene', (31, 36))	('ERBB2', 'Gene', (73, 78))	('ERBB2', 'Gene', '2064', (73, 78))	('amplification', 'Var', (56, 69))
415592	27203740	In this study, we found that down-regulation of ERBB2 enhanced radiosensitivity.	('radiosensitivity', 'CPA', (63, 79))	('ERBB2', 'Gene', '2064', (48, 53))	('ERBB2', 'Gene', (48, 53))	('down-regulation', 'Var', (29, 44))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (54, 79))	('enhanced', 'PosReg', (54, 62))
415593	27203740	MiR-193a-5p regulated ERBB2 expression by directly targeting to the ERBB2-3'UTR, and was found to enhance radiosensitivity and inhibit tumorigenesis in vitro and in vivo.	('ERBB2', 'Gene', '2064', (22, 27))	('enhance', 'PosReg', (98, 105))	('ERBB2', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('ERBB2', 'Gene', '2064', (68, 73))	('expression', 'MPA', (28, 38))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('ERBB2', 'Gene', (68, 73))	('MiR-193a-5p', 'Var', (0, 11))	('193a', 'Chemical', '-', (4, 8))	('inhibit', 'NegReg', (127, 134))	('targeting', 'Interaction', (51, 60))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (98, 122))	('radiosensitivity', 'CPA', (106, 122))
415596	27203740	Overexpression of miR-193a-5p enhanced CCRT response in KYSE cells.	('enhanced', 'PosReg', (30, 38))	('miR-193a-5p', 'Var', (18, 29))	('CCRT response', 'MPA', (39, 52))	('193a', 'Chemical', '-', (22, 26))
415598	27203740	Finally, overexpression of miR-193a-5p disrupted Herceptin dependent growth inhibition through ERBB2 down-regulation.	('miR-193a-5p', 'Var', (27, 38))	('disrupted', 'NegReg', (39, 48))	('down-regulation', 'NegReg', (101, 116))	('ERBB2', 'Gene', '2064', (95, 100))	('ERBB2', 'Gene', (95, 100))	('Herceptin', 'Chemical', 'MESH:D000068878', (49, 58))	('Herceptin dependent growth inhibition', 'MPA', (49, 86))	('193a', 'Chemical', '-', (31, 35))
415603	27203740	The results showed that high ERBB2 expression was correlated with poor prognosis for ESCC patients (Figure 1A).	('ERBB2', 'Gene', (29, 34))	('expression', 'MPA', (35, 45))	('ESCC', 'Disease', (85, 89))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (90, 98))	('ERBB2', 'Gene', '2064', (29, 34))
415611	27203740	These results indicated that modulation of ERBB2 levels in stable cell lines can produce the expected ERBB2-dependent signaling processes in KYSE cells (Supplementary Figure S1).	('ERBB2', 'Gene', '2064', (43, 48))	('ERBB2', 'Gene', '2064', (102, 107))	('ERBB2', 'Gene', (43, 48))	('ERBB2', 'Gene', (102, 107))	('produce', 'Reg', (81, 88))	('modulation', 'Var', (29, 39))
415620	27203740	The above results indicated that high ERBB2 is a potential prognosis marker in ESCC patients.	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (84, 92))	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', '2064', (38, 43))	('ESCC', 'Disease', (79, 83))
415627	27203740	To verify whether ERBB2 expression was suppressed by miR-193a-5p in KYSE cells, miR-193a-5p precursors and inhibitors were transiently transfected into KYSE cells.	('expression', 'MPA', (24, 34))	('193a', 'Chemical', '-', (84, 88))	('193a', 'Chemical', '-', (57, 61))	('miR-193a-5p', 'Var', (53, 64))	('ERBB2', 'Gene', '2064', (18, 23))	('ERBB2', 'Gene', (18, 23))	('suppressed', 'NegReg', (39, 49))
415629	27203740	MiR-193a-5p overexpression caused ERBB2 to decrease to 70% and 60% of control levels in KYSE70 and KYSE510 cells, respectively.	('decrease', 'NegReg', (43, 51))	('overexpression', 'PosReg', (12, 26))	('KYSE510', 'CellLine', 'CVCL:1354', (99, 106))	('ERBB2', 'Gene', (34, 39))	('ERBB2', 'Gene', '2064', (34, 39))	('MiR-193a-5p', 'Var', (0, 11))	('193a', 'Chemical', '-', (4, 8))
415633	27203740	The results showed that ERBB2 was the only target protein repressed by miR-193a-5p (Figure 2B and Supplementary Figure S3).	('ERBB2', 'Gene', (24, 29))	('ERBB2', 'Gene', '2064', (24, 29))	('miR-193a-5p', 'Var', (71, 82))	('193a', 'Chemical', '-', (75, 79))
415634	27203740	To study whether miR-193a-5p suppressed ERBB2 expression by directly binding to the ERBB2 3'UTR, a luciferase reporter assay was used in KYSE cells.	('ERBB2', 'Gene', (84, 89))	('ERBB2', 'Gene', '2064', (40, 45))	('ERBB2', 'Gene', (40, 45))	('binding', 'Interaction', (69, 76))	('193a', 'Chemical', '-', (21, 25))	('expression', 'MPA', (46, 56))	('ERBB2', 'Gene', '2064', (84, 89))	('miR-193a-5p', 'Var', (17, 28))	('suppressed', 'NegReg', (29, 39))
415635	27203740	According to a sequence alignment, the seed region of human miR-193a-5p formed a complimentary match with the ERBB2 3'UTR target sequence in different mammals (Supplementary Figure S4).	('193a', 'Chemical', '-', (64, 68))	('ERBB2', 'Gene', '2064', (110, 115))	('miR-193a-5p', 'Var', (60, 71))	('ERBB2', 'Gene', (110, 115))	('human', 'Species', '9606', (54, 59))
415636	27203740	One construct linked luciferase with the wild type ERBB2 3'UTR target sequence (ERBB2-3'UTR), and the other construct contained a mutation in the ERBB2 3'UTR target sequence (CCC to GGG, ERBB2-Mut-3'UTR; Figure 2C).	('ERBB2', 'Gene', (187, 192))	('CCC', 'Gene', (175, 178))	('mutation', 'Var', (130, 138))	('ERBB2', 'Gene', '2064', (187, 192))	('ERBB2', 'Gene', '2064', (146, 151))	('luciferase', 'Enzyme', (21, 31))	('ERBB2', 'Gene', (146, 151))	('ERBB2', 'Gene', '2064', (51, 56))	('ERBB2', 'Gene', '2064', (80, 85))	('ERBB2', 'Gene', (51, 56))	('ERBB2', 'Gene', (80, 85))
415637	27203740	The results of the reporter assay showed that miR-193a-5p overexpression reduced luciferase activity approximately 35 to 60%, whereas miR-193a-5p down-regulation increased luciferase activity by 2.3-fold in the ERBB2-3'UTR group.	('193a', 'Chemical', '-', (50, 54))	('down-regulation', 'NegReg', (146, 161))	('ERBB2', 'Gene', (211, 216))	('ERBB2', 'Gene', '2064', (211, 216))	('increased', 'PosReg', (162, 171))	('activity', 'MPA', (183, 191))	('reduced', 'NegReg', (73, 80))	('luciferase', 'Enzyme', (81, 91))	('miR-193a-5p', 'Var', (46, 57))	('miR-193a-5p', 'Var', (134, 145))	('193a', 'Chemical', '-', (138, 142))	('activity', 'MPA', (92, 100))
415638	27203740	In the ERBB2-Mut-3'UTR group, luciferase activity was unaffected by miR-193a-5p manipulation (Figure 2D).	('193a', 'Chemical', '-', (72, 76))	('luciferase', 'Enzyme', (30, 40))	('ERBB2', 'Gene', '2064', (7, 12))	('miR-193a-5p manipulation', 'Var', (68, 92))	('ERBB2', 'Gene', (7, 12))	('activity', 'MPA', (41, 49))
415639	27203740	These results suggest that miR-193a-5p represses ERBB2 expression by directly binding to the ERBB2 3'UTR.	('binding', 'Interaction', (78, 85))	('miR-193a-5p', 'Var', (27, 38))	('expression', 'MPA', (55, 65))	('ERBB2', 'Gene', (93, 98))	('represses', 'NegReg', (39, 48))	('ERBB2', 'Gene', (49, 54))	('ERBB2', 'Gene', '2064', (49, 54))	('193a', 'Chemical', '-', (31, 35))	('ERBB2', 'Gene', '2064', (93, 98))
415643	27203740	Figure 2E showed that in the control group, miR-193a-5p overexpression decreased ERBB2 expression and inhibited tumorigenesis in vitro.	('ERBB2', 'Gene', (81, 86))	('ERBB2', 'Gene', '2064', (81, 86))	('inhibited', 'NegReg', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('expression', 'MPA', (87, 97))	('193a', 'Chemical', '-', (48, 52))	('tumor', 'Disease', (112, 117))	('miR-193a-5p', 'Var', (44, 55))	('decreased', 'NegReg', (71, 80))
415644	27203740	In ERBB2-overexpressing cells, the regulatory ability of miR-193a-5p was abolished because the ERBB2-overexpressing plasmid did not include the ERBB2 3'UTR (Figure 2E).	('abolished', 'NegReg', (73, 82))	('ERBB2', 'Gene', '2064', (95, 100))	('ERBB2', 'Gene', '2064', (144, 149))	('ERBB2', 'Gene', (95, 100))	('ERBB2', 'Gene', '2064', (3, 8))	('193a', 'Chemical', '-', (61, 65))	('ERBB2', 'Gene', (144, 149))	('miR-193a-5p', 'Var', (57, 68))	('ERBB2', 'Gene', (3, 8))	('regulatory', 'MPA', (35, 45))
415645	27203740	These results demonstrated that ERBB2-dependent tumorigenesis is regulated by miR-193a-5p.	('ERBB2', 'Gene', (32, 37))	('ERBB2', 'Gene', '2064', (32, 37))	('tumor', 'Disease', (48, 53))	('193a', 'Chemical', '-', (82, 86))	('miR-193a-5p', 'Var', (78, 89))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('regulated', 'Reg', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
415646	27203740	Transient expression of miR-193a-5p successfully decreased ERBB2 expression in KYSE70 and KYSE510 cells (Figure 2B).	('miR-193a-5p', 'Var', (24, 35))	('ERBB2', 'Gene', (59, 64))	('ERBB2', 'Gene', '2064', (59, 64))	('decreased', 'NegReg', (49, 58))	('expression', 'MPA', (65, 75))	('193a', 'Chemical', '-', (28, 32))	('KYSE510', 'CellLine', 'CVCL:1354', (90, 97))
415650	27203740	The cisplatin IC50 in miR-193a-5p-overexpressing cells was decreased compared with vector control group, and the cisplatin IC50 in ERBB2 and miR-193a-5p co-expressing cells was increased compared with miR-193a-5p-overexpressing or vector control group (control IC50/193a-5p IC50/193a-5p + ERBB2 IC50: 27.1 muM/12.0 muM/42.3 muM; Supplementary Figure S6).	('miR-193a-5p', 'Var', (141, 152))	('muM', 'Gene', '56925', (306, 309))	('miR-193a-5p-overexpressing', 'Var', (22, 48))	('muM', 'Gene', (306, 309))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('ERBB2', 'Gene', '2064', (289, 294))	('193a', 'Chemical', '-', (266, 270))	('muM', 'Gene', '56925', (324, 327))	('increased', 'PosReg', (177, 186))	('muM', 'Gene', (324, 327))	('193a', 'Chemical', '-', (279, 283))	('ERBB2', 'Gene', (131, 136))	('muM', 'Gene', '56925', (315, 318))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('cisplatin IC50', 'MPA', (4, 18))	('193a', 'Chemical', '-', (145, 149))	('muM', 'Gene', (315, 318))	('decreased', 'NegReg', (59, 68))	('193a', 'Chemical', '-', (26, 30))	('cisplatin IC50', 'MPA', (113, 127))	('ERBB2', 'Gene', '2064', (131, 136))	('ERBB2', 'Gene', (289, 294))	('193a', 'Chemical', '-', (205, 209))
415653	27203740	The results showed lower miR-193a-5p expression in KYSE50, KYSE70, KYSE150, and KYSE510 cells compared to HET-1A cells.	('193a', 'Chemical', '-', (29, 33))	('KYSE510', 'CellLine', 'CVCL:1354', (80, 87))	('miR-193a-5p', 'Gene', (25, 36))	('KYSE150', 'Var', (67, 74))	('KYSE70', 'Var', (59, 65))	('KYSE50', 'Var', (51, 57))	('KYSE510', 'Var', (80, 87))	('expression', 'MPA', (37, 47))	('lower', 'NegReg', (19, 24))
415654	27203740	MiR-193a-5p expression was higher in KYSE170 than HET-1A cells (Figure 3A).	('MiR-193a-5p', 'Gene', (0, 11))	('193a', 'Chemical', '-', (4, 8))	('KYSE170', 'Var', (37, 44))	('higher', 'PosReg', (27, 33))	('KYSE170', 'CellLine', 'CVCL:1358', (37, 44))	('expression', 'MPA', (12, 22))
415655	27203740	Combining the results from Figure 1B and Figure 3A, we found that expression of ERBB2 was inversely correlated with miR-193a-5p in KYSE cells.	('correlated', 'Interaction', (100, 110))	('expression', 'MPA', (66, 76))	('193a', 'Chemical', '-', (120, 124))	('miR-193a-5p', 'Var', (116, 127))	('ERBB2', 'Gene', '2064', (80, 85))	('ERBB2', 'Gene', (80, 85))
415659	27203740	The results showed that miR-193a-5p overexpression reduced the colony formation ability by approximately 88% and 41% in KYSE70 and KYSE510 cells, respectively.	('KYSE510', 'CellLine', 'CVCL:1354', (131, 138))	('reduced', 'NegReg', (51, 58))	('miR-193a-5p', 'Var', (24, 35))	('overexpression', 'PosReg', (36, 50))	('colony formation ability', 'CPA', (63, 87))	('193a', 'Chemical', '-', (28, 32))
415661	27203740	The soft agar assay represents anchorage-independent growth in in vitro tumorigenesis and showed a 62% and 47% decrease in miR-193a-5p-overexpressing KYSE70 and KYSE510 cells, respectively.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('193a', 'Chemical', '-', (127, 131))	('agar', 'Chemical', 'MESH:D000362', (9, 13))	('decrease', 'NegReg', (111, 119))	('KYSE510', 'CellLine', 'CVCL:1354', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('miR-193a-5p-overexpressing', 'Var', (123, 149))
415666	27203740	Tumors with miR-193a-5p overexpression were significantly smaller than the control groups (Figure 3E).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('smaller', 'NegReg', (58, 65))	('miR-193a-5p overexpression', 'Var', (12, 38))	('193a', 'Chemical', '-', (16, 20))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('overexpression', 'Var', (24, 38))
415668	27203740	Indeed, the expression of ERBB2 was significantly decreased in miR-193a-5p-overexpressing tumors (Figure 3F).	('ERBB2', 'Gene', (26, 31))	('193a', 'Chemical', '-', (67, 71))	('ERBB2', 'Gene', '2064', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('decreased', 'NegReg', (50, 59))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('expression', 'MPA', (12, 22))	('miR-193a-5p-overexpressing', 'Var', (63, 89))
415669	27203740	These results indicated that miR-193a-5p inhibited tumor growth by decreasing ERBB2 expression in vitro and in vivo.	('decreasing', 'NegReg', (67, 77))	('ERBB2', 'Gene', '2064', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ERBB2', 'Gene', (78, 83))	('193a', 'Chemical', '-', (33, 37))	('tumor', 'Disease', (51, 56))	('miR-193a-5p', 'Var', (29, 40))	('inhibited', 'NegReg', (41, 50))	('expression', 'MPA', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
415670	27203740	To verify the correlation of ERBB2 and miR-193a-5p in ESCC patients, immunohistochemistry and in situ hybridization were performed to examine both ERBB2 and miR-193a-5p expression in clinical tissues (Figure 4A).	('ERBB2', 'Gene', (29, 34))	('ESCC', 'Disease', (54, 58))	('193a', 'Chemical', '-', (43, 47))	('193a', 'Chemical', '-', (161, 165))	('ERBB2', 'Gene', (147, 152))	('ERBB2', 'Gene', '2064', (147, 152))	('patients', 'Species', '9606', (59, 67))	('ERBB2', 'Gene', '2064', (29, 34))	('miR-193a-5p', 'Var', (157, 168))
415671	27203740	In patients with high miR-193a-5p, the expression of ERBB2 was lower compared with patients with low miR-193a-5p (Figure 4A).	('ERBB2', 'Gene', '2064', (53, 58))	('lower', 'NegReg', (63, 68))	('193a', 'Chemical', '-', (105, 109))	('193a', 'Chemical', '-', (26, 30))	('patients', 'Species', '9606', (3, 11))	('miR-193a-5p', 'Var', (22, 33))	('expression', 'MPA', (39, 49))	('patients', 'Species', '9606', (83, 91))	('high miR-193a-5p', 'Var', (17, 33))	('ERBB2', 'Gene', (53, 58))
415673	27203740	In situ hybridization showed that miR-193a-5p was decreased in tumor tissue compared with adjacent normal tissue (purple color indicates miR-193a-5p and red color indicates nucleus, Figure 4B).	('tumor', 'Disease', (63, 68))	('miR-193a-5p', 'Gene', (34, 45))	('193a', 'Chemical', '-', (38, 42))	('decreased', 'NegReg', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('miR-193a-5p', 'Var', (137, 148))	('193a', 'Chemical', '-', (141, 145))
415674	27203740	In NT paired analysis, the tissues were collected from the same patient, or non-NT paired analysis, all collected tissues form patients, miR-193a-5p was significantly decreased in tumor tissue (Figure 4C-4D).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('patient', 'Species', '9606', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('patient', 'Species', '9606', (127, 134))	('tumor', 'Disease', (180, 185))	('patients', 'Species', '9606', (127, 135))	('decreased', 'NegReg', (167, 176))	('miR-193a-5p', 'Var', (137, 148))	('193a', 'Chemical', '-', (141, 145))
415675	27203740	To evaluate whether miR-193a-5p was a good prognostic marker in ESCC patients, in situ hybridization was used to detect the expression of miR-193a-5p in 131 ESCC patients.	('patients', 'Species', '9606', (162, 170))	('ESCC', 'Disease', (64, 68))	('miR-193a-5p', 'Var', (138, 149))	('193a', 'Chemical', '-', (24, 28))	('patients', 'Species', '9606', (69, 77))	('193a', 'Chemical', '-', (142, 146))
415679	27203740	To further investigate the correlation between miR-193a-5p and ERBB2, the percentage of high/med/low ERBB2 was analyzed in low/med/high miR-193a5p groups.	('ERBB2', 'Gene', '2064', (63, 68))	('ERBB2', 'Gene', (63, 68))	('miR-193a5p', 'Var', (136, 146))	('193a', 'Chemical', '-', (140, 144))	('ERBB2', 'Gene', '2064', (101, 106))	('193a', 'Chemical', '-', (51, 55))	('ERBB2', 'Gene', (101, 106))
415680	27203740	In low miR-193a-5p group, 54.9% were high ERBB2, 35.3% were medium ERBB2, and 9.8% were in the low ERBB2 group.	('ERBB2', 'Gene', '2064', (67, 72))	('ERBB2', 'Gene', (67, 72))	('ERBB2', 'Gene', (99, 104))	('ERBB2', 'Gene', '2064', (99, 104))	('low miR-193a-5p', 'Var', (3, 18))	('ERBB2', 'Gene', '2064', (42, 47))	('ERBB2', 'Gene', (42, 47))	('193a', 'Chemical', '-', (11, 15))	('miR-193a-5p', 'Var', (7, 18))
415681	27203740	In the medium miR-193a-5p group, 38.3% showed high ERBB2, 44.7% exhibited medium ERBB2, and 17% were in the low ERBB2 group.	('medium miR-193a-5p', 'Var', (7, 25))	('ERBB2', 'Gene', '2064', (112, 117))	('ERBB2', 'Gene', (81, 86))	('ERBB2', 'Gene', (112, 117))	('ERBB2', 'Gene', '2064', (81, 86))	('ERBB2', 'Gene', '2064', (51, 56))	('193a', 'Chemical', '-', (18, 22))	('ERBB2', 'Gene', (51, 56))
415682	27203740	In the high miR-193a-5p group, 27.3% were high ERBB2, 39.4% were medium ERBB2, and 33.3% were low ERBB2 (Figure 4F).	('ERBB2', 'Gene', '2064', (98, 103))	('ERBB2', 'Gene', (47, 52))	('ERBB2', 'Gene', '2064', (47, 52))	('ERBB2', 'Gene', (98, 103))	('193a', 'Chemical', '-', (16, 20))	('ERBB2', 'Gene', '2064', (72, 77))	('high miR-193a-5p', 'Var', (7, 23))	('ERBB2', 'Gene', (72, 77))
415684	27203740	The results showed that ERBB2 expression was inversely correlated with miR-193a-5p in these groups (correlation coefficient = -0.213, P = 0.015).	('expression', 'MPA', (30, 40))	('correlated', 'Interaction', (55, 65))	('193a', 'Chemical', '-', (75, 79))	('ERBB2', 'Gene', (24, 29))	('miR-193a-5p', 'Var', (71, 82))	('ERBB2', 'Gene', '2064', (24, 29))	('inversely', 'NegReg', (45, 54))
415685	27203740	These results suggested that miR-193a-5p is a potential diagnostic and prognostic marker in ESCC.	('miR-193a-5p', 'Var', (29, 40))	('ESCC', 'Disease', (92, 96))	('193a', 'Chemical', '-', (33, 37))
415698	27203740	The expression of ERBB2 and miR-193a-5p was evaluated by western blotting and real-time PCR, respectively.	('miR-193a-5p', 'Var', (28, 39))	('ERBB2', 'Gene', '2064', (18, 23))	('193a', 'Chemical', '-', (32, 36))	('ERBB2', 'Gene', (18, 23))
415700	27203740	The results showed that the up-regulation of ERBB2 occurred in an irradiation dosage-dependent manner, and miR-193a-5p expression was inversely correlated with ERBB2 (Figure 5B).	('ERBB2', 'Gene', '2064', (160, 165))	('ERBB2', 'Gene', (160, 165))	('miR-193a-5p', 'Var', (107, 118))	('ERBB2', 'Gene', '2064', (45, 50))	('ERBB2', 'Gene', (45, 50))	('193a', 'Chemical', '-', (111, 115))	('up-regulation', 'PosReg', (28, 41))
415702	27203740	The results showed higher cisplatin resistance in KYSE170 cells treated with miR-193a-5p inhibitors than control cells (Figure 5C).	('miR-193a-5p', 'Gene', (77, 88))	('higher', 'PosReg', (19, 25))	('inhibitors', 'Var', (89, 99))	('KYSE170', 'CellLine', 'CVCL:1358', (50, 57))	('193a', 'Chemical', '-', (81, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('cisplatin resistance', 'MPA', (26, 46))
415703	27203740	The cisplatin resistance was lower in stable miR-193a-5p-overexpressing KYSE70 cells than control cells (Figure 5C).	('miR-193a-5p-overexpressing', 'Var', (45, 71))	('cisplatin resistance', 'MPA', (4, 24))	('lower', 'NegReg', (29, 34))	('193a', 'Chemical', '-', (49, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))
415704	27203740	Two independent miR-193a-5p-overexpressing KYSE70 cells were further used to investigate whether miR-193a-5p enhanced CCRT response in a dose dependent manner.	('miR-193a-5p', 'Var', (97, 108))	('CCRT response', 'MPA', (118, 131))	('193a', 'Chemical', '-', (20, 24))	('enhanced', 'PosReg', (109, 117))	('193a', 'Chemical', '-', (101, 105))
415705	27203740	The cisplatin resistance was lower in high miR-193a-5p-overexpressing than low miR-193a-5p-overexpressing KYSE70 cells (Supplementary Figure S7).	('193a', 'Chemical', '-', (47, 51))	('cisplatin resistance', 'MPA', (4, 24))	('lower', 'NegReg', (29, 34))	('193a', 'Chemical', '-', (83, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('high miR-193a-5p-overexpressing', 'Var', (38, 69))
415706	27203740	The results indicated that high miR-193a-5p was correlated with a good CCRT response in KYSE170 and KYSE70 cells.	('193a', 'Chemical', '-', (36, 40))	('CCRT response', 'CPA', (71, 84))	('KYSE170', 'CellLine', 'CVCL:1358', (88, 95))	('miR-193a-5p', 'Var', (32, 43))	('high miR-193a-5p', 'Var', (27, 43))
415708	27203740	To verify whether miR-193a-5p is a potential biomarker for the CCRT response, five CCRT good response and four CCRT poor response patient RNA samples were used to evaluate miR-193a-5p expression by real-time PCR.	('miR-193a-5p', 'Var', (172, 183))	('patient', 'Species', '9606', (130, 137))	('CCRT', 'Disease', (63, 67))	('193a', 'Chemical', '-', (22, 26))	('193a', 'Chemical', '-', (176, 180))
415709	27203740	The results showed that miR-193a-5p was significantly higher in the CCRT good response than poor response patients (Figure 5D).	('higher', 'PosReg', (54, 60))	('miR-193a-5p', 'Var', (24, 35))	('patients', 'Species', '9606', (106, 114))	('193a', 'Chemical', '-', (28, 32))	('CCRT', 'Disease', (68, 72))
415710	27203740	Since ERBB2 was highly expressed in CCRTR cells (Figure 5B), we utilized these cells to investigate whether miR-193a-5p enhance CCRT response through ERBB2 dependent pathway.	('enhance', 'PosReg', (120, 127))	('ERBB2', 'Gene', '2064', (150, 155))	('miR-193a-5p', 'Var', (108, 119))	('ERBB2', 'Gene', '2064', (6, 11))	('193a', 'Chemical', '-', (112, 116))	('ERBB2', 'Gene', (150, 155))	('ERBB2', 'Gene', (6, 11))	('CCRT response', 'MPA', (128, 141))
415713	27203740	8% / 100 mug/ml: 64.7 +- 7.0% / 300 mug/ml: 41.1 +- 19.5%; Two-way ANOVA), however, in miR-193a-5p group, the growth inhibition of Herceptin was eliminated (0 mug/ml: 100 +- 21.6% / 50 mug/ml: 87.1 +- 16.5% / 100 mug/ml: 99.3 +- 10.8% / 300 mug/ml: 124.7 +- 18.1%; Figure 5E).	('miR-193a-5p', 'Var', (87, 98))	('193a', 'Chemical', '-', (91, 95))	('Herceptin', 'Chemical', 'MESH:D000068878', (131, 140))	('eliminated', 'NegReg', (145, 155))	('growth', 'MPA', (110, 116))
415719	27203740	Parental or miR-193a-5p overexpressing KYSE70 cells were subcutaneously injected into immunodeficient mice.	('mice', 'Species', '10090', (102, 106))	('193a', 'Chemical', '-', (16, 20))	('miR-193a-5p', 'Var', (12, 23))	('immunodeficient', 'Disease', 'MESH:D007153', (86, 101))	('immunodeficient', 'Disease', (86, 101))
415725	27203740	Herceptin did not enhance CCRT response in mice injected with miR-193a-5p-ovexpresing KYSE70 cells (Supplementary Figure S9).	('mice', 'Species', '10090', (43, 47))	('CCRT response', 'CPA', (26, 39))	('miR-193a-5p-ovexpresing', 'Var', (62, 85))	('193a', 'Chemical', '-', (66, 70))	('Herceptin', 'Chemical', 'MESH:D000068878', (0, 9))
415726	27203740	These results suggest that high expression of miR-193a-5p decreases the ERBB2 expression level, and thereby enhances the CCRT response in ESCC patients.	('193a', 'Chemical', '-', (50, 54))	('decreases', 'NegReg', (58, 67))	('CCRT response', 'MPA', (121, 134))	('enhances', 'PosReg', (108, 116))	('expression level', 'MPA', (78, 94))	('patients', 'Species', '9606', (143, 151))	('miR-193a-5p', 'Var', (46, 57))	('ERBB2', 'Gene', '2064', (72, 77))	('ERBB2', 'Gene', (72, 77))	('ESCC', 'Disease', (138, 142))
415731	27203740	Furthermore, miR-193a-5p, a miRNA that regulates ERBB2 expression by directly targeting to ERBB2-3'UTR, enhanced radiosensitivity and inhibited tumorigenesis in vitro and in vivo.	('tumor', 'Disease', (144, 149))	('ERBB2', 'Gene', '2064', (91, 96))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (104, 129))	('ERBB2', 'Gene', (91, 96))	('inhibited', 'NegReg', (134, 143))	('enhanced', 'PosReg', (104, 112))	('193a', 'Chemical', '-', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('radiosensitivity', 'CPA', (113, 129))	('ERBB2', 'Gene', (49, 54))	('ERBB2', 'Gene', '2064', (49, 54))	('miR-193a-5p', 'Var', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
415734	27203740	Moreover, overexpression of miR-193a-5p enhanced CCRT response in KYSE cells.	('CCRT response in KYSE cells', 'CPA', (49, 76))	('enhanced', 'PosReg', (40, 48))	('miR-193a-5p', 'Var', (28, 39))	('193a', 'Chemical', '-', (32, 36))
415736	27203740	Overexpression of miR-193a-5p disrupted Herceptin dependent growth inhibition through ERBB2 down-regulation.	('miR-193a-5p', 'Var', (18, 29))	('193a', 'Chemical', '-', (22, 26))	('disrupted', 'NegReg', (30, 39))	('down-regulation', 'NegReg', (92, 107))	('ERBB2', 'Gene', '2064', (86, 91))	('ERBB2', 'Gene', (86, 91))	('Herceptin', 'Chemical', 'MESH:D000068878', (40, 49))	('Herceptin dependent growth inhibition', 'MPA', (40, 77))
415737	27203740	According to our results, ERBB2 and miR-193a-5p were potential prognostic and CCRT response biomarkers in ESCC.	('193a', 'Chemical', '-', (40, 44))	('ERBB2', 'Gene', (26, 31))	('ERBB2', 'Gene', '2064', (26, 31))	('ESCC', 'Disease', (106, 110))	('miR-193a-5p', 'Var', (36, 47))
415738	27203740	Our data suggest that patients with high miR-193a-5p will likely benefit from CCRT treatment alone.	('miR-193a-5p', 'Var', (41, 52))	('benefit', 'PosReg', (65, 72))	('patients', 'Species', '9606', (22, 30))	('high miR-193a-5p', 'Var', (36, 52))	('193a', 'Chemical', '-', (45, 49))
415742	27203740	Additionally, we found that miR-193a-5p regulates ERBB2 expression by directly targeting the 3'UTR of ERBB2 (Figure 2).	('regulates', 'Reg', (40, 49))	('ERBB2', 'Gene', (50, 55))	('ERBB2', 'Gene', '2064', (102, 107))	('ERBB2', 'Gene', '2064', (50, 55))	('193a', 'Chemical', '-', (32, 36))	('miR-193a-5p', 'Var', (28, 39))	('ERBB2', 'Gene', (102, 107))	("3'UTR", 'MPA', (93, 98))	('expression', 'MPA', (56, 66))	('targeting', 'Reg', (79, 88))
415745	27203740	Because reduction of ERBB2 promoted tumor apoptosis in gastrointestinal adenocarcinomas, we hypothesized that miR-193a-5p may also induce tumor apoptosis.	('193a', 'Chemical', '-', (114, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('miR-193a-5p', 'Var', (110, 121))	('reduction', 'NegReg', (8, 17))	('tumor', 'Disease', (138, 143))	('gastrointestinal adenocarcinomas', 'Disease', (55, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('promoted', 'PosReg', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ERBB2', 'Gene', '2064', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('ERBB2', 'Gene', (21, 26))	('induce', 'PosReg', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (36, 41))	('gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (55, 87))
415746	27203740	Hence, we examined apoptosis rates after overexpressing miR-193a-5p in an ESCC cell line.	('examined', 'Reg', (10, 18))	('miR-193a-5p', 'Var', (56, 67))	('193a', 'Chemical', '-', (60, 64))	('overexpressing', 'PosReg', (41, 55))
415747	27203740	Western blotting showed an increase in cleaved PARP, and flow cytometry revealed a 6-fold increase in the sub-G1 population in miR-193a-5p-overexpressing KYSE70 cells (Supplementary Figure S10).	('PARP', 'Gene', (47, 51))	('193a', 'Chemical', '-', (131, 135))	('sub-G1 population', 'CPA', (106, 123))	('increase', 'PosReg', (90, 98))	('increase', 'PosReg', (27, 35))	('PARP', 'Gene', '1302', (47, 51))	('miR-193a-5p-overexpressing', 'Var', (127, 153))
415752	27203740	After evaluation by Q-PCR, miR-455-3p, miR-200b-3p, let-7e-5p, miR-181b-5p, miR-125a-5p, miR-181a-5p, miR-200b-5p, miR-31-5p, and miR-200a-3p were significantly down-regulated in cisplatin resistant EAC cells.	('miR-181a-5p', 'Var', (89, 100))	('miR-200b-3p', 'Var', (39, 50))	('miR-200a', 'Gene', (130, 138))	('cisplatin resistant EAC', 'Disease', (179, 202))	('miR-200a', 'Gene', '406983', (130, 138))	('let-7e-5p', 'Var', (52, 61))	('miR-31', 'Gene', (115, 121))	('down-regulated', 'NegReg', (161, 175))	('miR-200b-5p', 'Var', (102, 113))	('EAC', 'Phenotype', 'HP:0011459', (199, 202))	('miR-455-3p', 'Var', (27, 37))	('miR-125a-5p', 'Var', (76, 87))	('miR-181b-5p', 'Var', (63, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('miR-31', 'Gene', '407035', (115, 121))
415754	27203740	In cisplatin resistant ESCC cells, miR-130a-3p was increased, and in 5-FU (5-fluorouracil) resistant esophageal cancer cells, miR-378a-3p, miR-192-5p, miR-210-3p, miR-194-5p, miR-17-3p, miR-935, miR-125a-5p, miR-1226-3p, miR-99b-5p, and miR-18a-3p were significantly down-regulated, while miR-222-3p, miR193b-3p, miR-31-5p, miR-27b-3p, and miR-550a-3p were increased.	('miR-935', 'Gene', '100126325', (186, 193))	('cisplatin', 'Chemical', 'MESH:D002945', (3, 12))	('miR-99b', 'Gene', (221, 228))	('miR-17-3p', 'Gene', (175, 184))	('miR-1226-3p', 'Var', (208, 219))	('esophageal cancer', 'Disease', (101, 118))	('miR-27b', 'Gene', '407019', (324, 331))	('miR-550a-3p', 'Gene', (340, 351))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('miR-31', 'Gene', '407035', (313, 319))	('miR-222-3p', 'Var', (289, 299))	('miR-550a-3p', 'Gene', '100616354', (340, 351))	('miR-192-5p', 'Var', (139, 149))	('miR-378a-3p', 'Var', (126, 137))	('miR193b-3p', 'Var', (301, 311))	('down-regulated', 'NegReg', (267, 281))	('increased', 'PosReg', (51, 60))	('miR-99b', 'Gene', '407056', (221, 228))	('miR-17-3p', 'Gene', '406952', (175, 184))	('miR-130a-3p', 'Var', (35, 46))	('miR-210-3p', 'Var', (151, 161))	('miR-31', 'Gene', (313, 319))	('miR-935', 'Gene', (186, 193))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('miR-27b', 'Gene', (324, 331))
415756	27203740	We found that miR193a-5p down-regulation was significantly associated with poor prognosis in ESCC patients (Figure 4).	('patients', 'Species', '9606', (98, 106))	('193a', 'Chemical', '-', (17, 21))	('miR193a-5p', 'Var', (14, 24))	('down-regulation', 'NegReg', (25, 40))	('ESCC', 'Disease', (93, 97))
415758	27203740	Combined with our findings, these reports indicate that miR-193a-5p functions as a tumor suppressor in a variety of cancers.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('193a', 'Chemical', '-', (60, 64))	('tumor', 'Disease', (83, 88))	('miR-193a-5p', 'Var', (56, 67))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
415759	27203740	MiR-193a-5p overexpression, or ERBB2 disruption, significantly enhanced radiosensitivity of KYSE cells (Figure 1F and Figure 2F).	('radiosensitivity of KYSE cells', 'CPA', (72, 102))	('overexpression', 'PosReg', (12, 26))	('disruption', 'Var', (37, 47))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (63, 88))	('enhanced', 'PosReg', (63, 71))	('MiR-193a-5p', 'Var', (0, 11))	('193a', 'Chemical', '-', (4, 8))	('ERBB2', 'Gene', '2064', (31, 36))	('ERBB2', 'Gene', (31, 36))
415762	27203740	Further, miR-193a-5p overexpression diminished ERBB2 levels and was related to a good CCRT response in KYSE cells.	('ERBB2', 'Gene', (47, 52))	('ERBB2', 'Gene', '2064', (47, 52))	('diminished', 'NegReg', (36, 46))	('193a', 'Chemical', '-', (13, 17))	('CCRT response', 'MPA', (86, 99))	('miR-193a-5p', 'Var', (9, 20))	('overexpression', 'PosReg', (21, 35))
415766	27203740	Importantly, both miR-193a-5p and Herceptin treatments were effective at reducing either the cisplatin concentration or radiation dosage necessary to induce cell death.	('Herceptin', 'Chemical', 'MESH:D000068878', (34, 43))	('cisplatin concentration', 'MPA', (93, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('miR-193a-5p', 'Var', (18, 29))	('193a', 'Chemical', '-', (22, 26))	('reducing', 'NegReg', (73, 81))	('radiation dosage', 'MPA', (120, 136))
415768	27203740	In addition, our findings suggest that miR-193a-5p might be a valuable predictive biomarker of the CCRT response in ESCC patients.	('ESCC', 'Disease', (116, 120))	('193a', 'Chemical', '-', (43, 47))	('miR-193a-5p', 'Var', (39, 50))	('patients', 'Species', '9606', (121, 129))
415798	27203740	KYSE70 and CE48T CCRT-resistant cells were generated through a stepwise increase in cisplatin and irradiation.	('increase', 'PosReg', (72, 80))	('cisplatin', 'MPA', (84, 93))	('CE48T', 'CellLine', 'CVCL:Y009', (11, 16))	('CE48T', 'Var', (11, 16))	('KYSE70', 'Var', (0, 6))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))
415807	27203740	Mutant ERBB2-3'UTR was constructed by two-step site directed mutagenesis with the primers ERBB2 3'UTR mutant F (5'-AAATAAAGAGGGAGGGGGA GAATGGGTGTT-3') and ERBB2 3'UTR mutant R (5'- CTCCCCCTCCCTCTTTATTTCATCTTTAAA-3').	('mutant', 'Var', (102, 108))	('ERBB2', 'Gene', '2064', (155, 160))	('ERBB2', 'Gene', '2064', (7, 12))	('ERBB2', 'Gene', '2064', (90, 95))	('ERBB2', 'Gene', (7, 12))	('ERBB2', 'Gene', (155, 160))	('ERBB2', 'Gene', (90, 95))
415812	27203740	The correlation of the intensity of miR-193a-5p and ERBB2 was determined using Spearman's test.	('ERBB2', 'Gene', '2064', (52, 57))	('193a', 'Chemical', '-', (40, 44))	('miR-193a-5p', 'Var', (36, 47))	('ERBB2', 'Gene', (52, 57))
415818	25678848	Results showed that 17/20 (85%) gastroesophageal tissues from carcinogen MNNG-treated rats developed dysplasia and cancer, as compared to 8/20 (40%) rats treated with MNNG plus MRN-100.	('cancer', 'Disease', (115, 121))	('dysplasia', 'Disease', (101, 110))	('MNNG', 'Chemical', 'MESH:D008769', (73, 77))	('dysplasia', 'Disease', 'MESH:D004476', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rats', 'Species', '10116', (86, 90))	('rats', 'Species', '10116', (149, 153))	('MNNG', 'Chemical', 'MESH:D008769', (167, 171))	('MRN-100', 'Chemical', '-', (177, 184))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('developed', 'PosReg', (91, 100))	('carcinogen MNNG-treated', 'Var', (62, 85))
415904	25678848	In contrast, rats with MRN-100 showed organ weight similar to control rats.	('MRN-100', 'Chemical', '-', (23, 30))	('rats', 'Species', '10116', (13, 17))	('MRN-100', 'Var', (23, 30))	('organ weight', 'CPA', (38, 50))	('rats', 'Species', '10116', (70, 74))
415908	25678848	Data show that rats treated with MNNG displayed a significant decrease in the levels of blood GSH (-30.1%) and gastric GSH (-39.9%) (p<0.01) when compared with control group.	('MNNG', 'Var', (33, 37))	('GSH', 'Chemical', '-', (94, 97))	('gastric GSH', 'MPA', (111, 122))	('MNNG', 'Chemical', 'MESH:D008769', (33, 37))	('decrease', 'NegReg', (62, 70))	('GSH', 'Chemical', '-', (119, 122))	('blood GSH', 'MPA', (88, 97))	('rats', 'Species', '10116', (15, 19))
415910	25678848	Carcinogen MNNG depleted the levels of antioxidant enzymes in the blood (SOD: -45.1%, CAT:- 34.0%, and GPx: -48.1%), and gastric tissues (SOD: -69.8%, CAT:-34.0%, and GPx: -36.2%) (p<0.01), as compared to control untreated rats.	('depleted', 'NegReg', (16, 24))	('MNNG', 'Chemical', 'MESH:D008769', (11, 15))	('rats', 'Species', '10116', (223, 227))	('CAT', 'Gene', '24248', (151, 154))	('CAT', 'Gene', '24248', (86, 89))	('MNNG', 'Var', (11, 15))	('CAT', 'Gene', (151, 154))	('levels of antioxidant enzymes', 'MPA', (29, 58))	('CAT', 'Gene', (86, 89))
415911	25678848	In contrast, MRN-100 supplementation markedly enhanced the levels of antioxidant enzymes of blood and gastric tissues within reach of normal values (Figure 5).	('levels of antioxidant enzymes', 'MPA', (59, 88))	('MRN-100', 'Chemical', '-', (13, 20))	('MRN-100', 'Gene', (13, 20))	('supplementation', 'Var', (21, 36))	('enhanced', 'PosReg', (46, 54))
415913	25678848	Treatment with MNNG resulted in a decrease in the TAC level in the blood (-70.4%-p<0.01) and in the gastric tissues (-70.7%) (p<0.01) as compared to control rats.	('MNNG', 'Var', (15, 19))	('rats', 'Species', '10116', (157, 161))	('decrease', 'NegReg', (34, 42))	('MNNG', 'Chemical', 'MESH:D008769', (15, 19))	('TAC level', 'MPA', (50, 59))
415917	25678848	MNNG-treated rats demonstrated a remarkable increase in TFR as compared to control untreated rats.	('rats', 'Species', '10116', (13, 17))	('TFR', 'MPA', (56, 59))	('MNNG-treated', 'Var', (0, 12))	('increase', 'PosReg', (44, 52))	('rat', 'Species', '10116', (13, 16))	('rat', 'Species', '10116', (25, 28))	('rats', 'Species', '10116', (93, 97))	('MNNG', 'Chemical', 'MESH:D008769', (0, 4))	('rat', 'Species', '10116', (93, 96))
415925	25678848	It is of interest to note that supplementation with MRN-100 provided significant protection against the body-weight loss in carcinogen-treated animals.	('weight loss', 'Phenotype', 'HP:0001824', (109, 120))	('weight loss', 'Disease', 'MESH:D015431', (109, 120))	('MRN-100', 'Chemical', '-', (52, 59))	('MRN-100', 'Gene', (52, 59))	('supplementation', 'Var', (31, 46))	('weight loss', 'Disease', (109, 120))
415955	24137396	Older patients who decline to have surgery and patients with post-operative stenosis comprise ~50% of all patients with advanced esophageal cancer.	('patients', 'Species', '9606', (47, 55))	('stenosis', 'Var', (76, 84))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (106, 114))	('esophageal cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
416032	23626476	Phospholipase C (PLC) inhibitors U73122 and neomycin, and protein kinase C (PKC) inhibitor GF109203X also reduced the contraction.	('neomycin', 'Chemical', 'MESH:D009355', (44, 52))	('protein kinase C', 'Gene', '112476', (58, 74))	('contraction', 'MPA', (118, 129))	('GF109203X', 'Var', (91, 100))	('GF109203X', 'Chemical', 'MESH:C070515', (91, 100))	('PKC', 'Gene', (76, 79))	('PKC', 'Gene', '112476', (76, 79))	('U73122', 'Chemical', 'MESH:C060229', (33, 39))	('protein kinase C', 'Gene', (58, 74))	('Phospholipase C', 'Enzyme', (0, 15))	('U73122', 'Var', (33, 39))	('reduced', 'NegReg', (106, 113))
416034	23626476	MEK inhibitor PD98059 and JNK inhibitor SP600125 blocked the contraction.	('SP600125', 'Chemical', 'MESH:C432165', (40, 48))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('SP600125', 'Var', (40, 48))	('JNK', 'Gene', (26, 29))	('PD98059', 'Var', (14, 21))	('JNK', 'Gene', '5599', (26, 29))	('PD98059', 'Chemical', 'MESH:C093973', (14, 21))
416083	23626476	Smooth muscle cells were permeabilized to diffuse the agents such as C3 exoenzyme, Y27632 or PKC antibody, which do not diffuse across the intact cell membrane.	('PKC', 'Gene', '112476', (93, 96))	('PKC', 'Gene', (93, 96))	('Y27632', 'Var', (83, 89))	('Y27632', 'Chemical', 'MESH:C108830', (83, 89))
416090	23626476	Y27632 (10-5) or PKC antibody was added to the smooth muscle cell for 10 min.	('Y27632', 'Chemical', 'MESH:C108830', (0, 6))	('PKC', 'Gene', (17, 20))	('PKC', 'Gene', '112476', (17, 20))	('Y27632', 'Var', (0, 6))
416108	23626476	LPA-induced contraction was almost completely blocked by Ki16425.	('LPA', 'Chemical', 'MESH:C032881', (0, 3))	('LPA-induced', 'CPA', (0, 11))	('Ki16425', 'Var', (57, 64))	('Ki16425', 'Chemical', 'MESH:C477898', (57, 64))
416109	23626476	2B shows that LPA-induced contraction of ESMCs was significantly inhibited by Ki16425, from 20.24+-0.51 to 1.70+-1.38.	('Ki16425', 'Var', (78, 85))	('LPA', 'Chemical', 'MESH:C032881', (14, 17))	('Ki16425', 'Chemical', 'MESH:C477898', (78, 85))	('ESMCs', 'Chemical', '-', (41, 46))	('inhibited', 'NegReg', (65, 74))
416114	23626476	LPA-induced contraction of ESMCs was not affected by PLA2 inhibitor DEDA (10-5 M) and PLD inhibitor rhoCMB (10-5 M), but significantly abolished by PLC inhibitor Neomycin and U73122 (10-6 M).	('U73122', 'Var', (175, 181))	('PLD', 'Gene', '2822', (86, 89))	('PLD', 'Gene', (86, 89))	('PLA2', 'Gene', '5319', (53, 57))	('DEDA', 'Chemical', '-', (68, 72))	('rhoCMB', 'Chemical', '-', (100, 106))	('ESMCs', 'Chemical', '-', (27, 32))	('PLA2', 'Gene', (53, 57))	('Neomycin', 'Chemical', 'MESH:D009355', (162, 170))	('abolished', 'NegReg', (135, 144))	('U73122', 'Chemical', 'MESH:C060229', (175, 181))	('LPA', 'Chemical', 'MESH:C032881', (0, 3))
416115	23626476	Percent decrease in cell length was as follows: 20.24+-0.51 vs. 7.30+-1.23, 8.61+-1.08, 18.04+-1.26 or 19.04+-1.17 in the cells preincubated with Neomycin, U73122, rhoCMB or DEDA, respectively (Fig.	('rhoCMB', 'Chemical', '-', (164, 170))	('cell length', 'CPA', (20, 31))	('DEDA', 'Chemical', '-', (174, 178))	('U73122', 'Chemical', 'MESH:C060229', (156, 162))	('Neomycin', 'Chemical', 'MESH:D009355', (146, 154))	('decrease', 'NegReg', (8, 16))	('U73122', 'Var', (156, 162))
416117	23626476	Cells were preincubated with PKC inhibitor GF109203X (3x10-6 M) for 10 min before the addition of LPA.	('GF109203X', 'Chemical', 'MESH:C070515', (43, 52))	('GF109203X', 'Var', (43, 52))	('PKC', 'Gene', (29, 32))	('LPA', 'Chemical', 'MESH:C032881', (98, 101))	('PKC', 'Gene', '112476', (29, 32))
416122	23626476	Figure 4B shows that LPA-induced contraction of permeabilized esophageal smooth muscle cells was significantly inhibited by antibodies raised against PKC-epsilon (1+-200), from 20.24+-0.51 to 11.94+-1.37, but not by antibodies raised against the PKC-betaII or -gamma isozyme (18.79+-1.61 or 18.76+-1.44).	('PKC-betaII or -gamma', 'Gene', '5582', (246, 266))	('PKC-betaII or -gamma', 'Gene', (246, 266))	('PKC-epsilon', 'Gene', '5581', (150, 161))	('inhibited', 'NegReg', (111, 120))	('LPA', 'Chemical', 'MESH:C032881', (21, 24))	('antibodies', 'Var', (124, 134))	('PKC-epsilon', 'Gene', (150, 161))
416124	23626476	Preincubation of cells with ERK1/2 inhibitor PD98059 for 30 min blocked the contraction induced by LPA.	('ERK1/2', 'Gene', (28, 34))	('ERK1/2', 'Gene', '5595;5594', (28, 34))	('PD98059', 'Var', (45, 52))	('blocked', 'NegReg', (64, 71))	('LPA', 'Chemical', 'MESH:C032881', (99, 102))	('PD98059', 'Chemical', 'MESH:C093973', (45, 52))
416125	23626476	The selective inhibitor of JNK, SP600125, inhibited the contraction too.	('JNK', 'Gene', '5599', (27, 30))	('SP600125', 'Chemical', 'MESH:C432165', (32, 40))	('SP600125', 'Var', (32, 40))	('inhibited', 'NegReg', (42, 51))	('JNK', 'Gene', (27, 30))
416127	23626476	Percent decrease in cell length was as follows: 20.24+-0.51 vs. 9.30+-1.27, 11.60+-1.15 or 16.78+-1.00 in the cells preincubated with PD98059, SP600125 or SB202190, respectively (Fig.	('SB202190', 'Chemical', 'MESH:C090942', (155, 163))	('PD98059', 'Chemical', 'MESH:C093973', (134, 141))	('cell length', 'CPA', (20, 31))	('SP600125', 'Chemical', 'MESH:C432165', (143, 151))	('SB202190', 'Var', (155, 163))	('decrease', 'NegReg', (8, 16))	('SP600125', 'Var', (143, 151))	('PD98059', 'Var', (134, 141))
416130	23626476	Percent decrease in cell length was as follows: 20.24+-0.51 vs. 6.5+-1.43, 6.83+-1.88 or 7.03+-1.76 in the cells preincubated with GF109203X only, GF109203X with PD98059, or GF109203X with SP600125, respectively (Fig.	('cell length', 'CPA', (20, 31))	('PD98059', 'Chemical', 'MESH:C093973', (162, 169))	('GF109203X', 'Var', (174, 183))	('GF109203X', 'Chemical', 'MESH:C070515', (147, 156))	('GF109203X', 'Chemical', 'MESH:C070515', (131, 140))	('GF109203X', 'Chemical', 'MESH:C070515', (174, 183))	('SP600125', 'Chemical', 'MESH:C432165', (189, 197))	('decrease', 'NegReg', (8, 16))	('GF109203X', 'Var', (147, 156))	('GF109203X', 'Var', (131, 140))	('SP600125', 'Var', (189, 197))
416135	23626476	LPA-induced contraction of permeabilized ESMCs was reduced by C3 exoenzyme and by Y27632, from 20.24+-0.51 to 10.02+-1.44 and from 20.24+-0.51 to 10.97+-1.13 (Fig.	('reduced', 'NegReg', (51, 58))	('ESMCs', 'Chemical', '-', (41, 46))	('Y27632', 'Var', (82, 88))	('C3 exoenzyme', 'Enzyme', (62, 74))	('LPA', 'Chemical', 'MESH:C032881', (0, 3))	('Y27632', 'Chemical', 'MESH:C108830', (82, 88))
416167	23626476	The compounds of PD98059, SP600125, and SB202190 have been identified as highly selective, potent and cell permeable inhibitors of ERK1/2, JNK, and p38 MAP kinase, respectively.	('PD98059', 'Var', (17, 24))	('JNK', 'Gene', (139, 142))	('ERK1/2', 'Gene', (131, 137))	('p38 MAP kinase', 'Gene', '1432', (148, 162))	('PD98059', 'Chemical', 'MESH:C093973', (17, 24))	('ERK1/2', 'Gene', '5595;5594', (131, 137))	('SB202190', 'Chemical', 'MESH:C090942', (40, 48))	('SP600125', 'Chemical', 'MESH:C432165', (26, 34))	('JNK', 'Gene', '5599', (139, 142))	('SP600125', 'Var', (26, 34))	('p38 MAP kinase', 'Gene', (148, 162))	('SB202190', 'Var', (40, 48))
416176	23626476	LPA increase the intracellular free calcium concentration.	('LPA', 'Var', (0, 3))	('intracellular free calcium concentration', 'MPA', (17, 57))	('calcium', 'Chemical', 'MESH:D002118', (36, 43))	('increase', 'PosReg', (4, 12))	('LPA', 'Chemical', 'MESH:C032881', (0, 3))
416194	33033560	Given the oropharyngeal structures' location and vital function in promoting a patent airway, speech articulation, and deglutition, damage to these structures and resulting dysphagia leads to significantly increased risk for malnutrition, aspiration pneumonia, and death.	('deglutition', 'Disease', 'MESH:D003680', (119, 130))	('speech articulation', 'Phenotype', 'HP:0009088', (94, 113))	('malnutrition', 'Phenotype', 'HP:0004395', (225, 237))	('pneumonia', 'Phenotype', 'HP:0002090', (250, 259))	('damage', 'Var', (132, 138))	('deglutition', 'Disease', (119, 130))	('promoting', 'PosReg', (67, 76))	('dysphagia', 'Disease', (173, 182))	('aspiration pneumonia', 'Disease', (239, 259))	('death', 'Disease', 'MESH:D003643', (265, 270))	('death', 'Disease', (265, 270))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (239, 259))	('aspiration', 'Phenotype', 'HP:0002835', (239, 249))	('dysphagia', 'Phenotype', 'HP:0002015', (173, 182))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (239, 259))	('malnutrition', 'Disease', (225, 237))	('dysphagia', 'Disease', 'MESH:D003680', (173, 182))
416208	33033560	Given the enormous complexity and coordination required in swallowing, it is unsurprising that dysfunction of involved structures along any of these steps can result in dysphagia.	('result in', 'Reg', (159, 168))	('dysphagia', 'Disease', (169, 178))	('dysphagia', 'Phenotype', 'HP:0002015', (169, 178))	('dysphagia', 'Disease', 'MESH:D003680', (169, 178))	('dysfunction', 'Var', (95, 106))
416256	33033560	They also noted increased muscle fiber diameter in GFP+ fibers suggesting reduced atrophy and even increased diameter compared to pre-injury, suggesting new muscle growth.	('diameter', 'MPA', (109, 117))	('atrophy', 'Disease', 'MESH:D001284', (82, 89))	('GFP+ fibers', 'Var', (51, 62))	('increased muscle fiber diameter', 'Phenotype', 'HP:0003557', (16, 47))	('increased muscle', 'Phenotype', 'HP:0003712', (16, 32))	('increased', 'PosReg', (16, 25))	('atrophy', 'Disease', (82, 89))	('increased', 'PosReg', (99, 108))	('muscle fiber diameter', 'CPA', (26, 47))
416270	33033560	Notably, at passages 20, 50 and even 80, their cells did not form aggregates and salivary spheres, implying lack of cellular transformation and maintenance of a basal ductal cell phenotype which expressed keratin 14, 18 and p63, markers for basal, ductal and basal duct cells respectively.	('keratin 14', 'Gene', (205, 215))	('p63', 'Var', (224, 227))	('keratin 14', 'Gene', '3861', (205, 215))
416338	32154652	All cases of esophageal cancer were selected from the SEER database using tumor site codes ranging from C15.0 to C15.9.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (13, 30))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('C15.0', 'Var', (104, 109))	('tumor', 'Disease', (74, 79))	('esophageal cancer', 'Disease', (13, 30))
416399	31823231	Although 18F-FDG PET/CT features of tumors aid in predicting patient prognosis, there is increasing interest in mining additional quantitative body composition data that could improve the prognostic power of 18F-FDG PET/CT, without additional examination costs or radiation exposure.	('patient', 'Species', '9606', (61, 68))	('18F-FDG', 'Chemical', 'MESH:D019788', (208, 215))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('18F-FDG', 'Var', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('18F-FDG', 'Chemical', 'MESH:D019788', (9, 16))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
416483	31823231	reported that low SMI on CT was associated with decreased survival, but only in patients age 65 years and older.	('patients', 'Species', '9606', (80, 88))	('SMI', 'MPA', (18, 21))	('decreased', 'NegReg', (48, 57))	('low', 'Var', (14, 17))	('survival', 'MPA', (58, 66))
416514	29682564	Similar to miRNAs, circRNAs are thought to be crucial to cancer development and have thus been widely studied: a series of dysregulated circRNAs have been identified as important to the development of radiation resistance, circ_002059 is significantly downregulated in gastric carcinoma and may be a stable and novel biomarker, and circRNA_001569 may target miR-145 and thus contribute to colorectal cancer cell proliferation and invasion.	('miR-145', 'Gene', (358, 365))	('miR', 'Gene', '22877', (358, 361))	('cancer', 'Disease', (400, 406))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (400, 406))	('colorectal cancer', 'Disease', 'MESH:D015179', (389, 406))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('gastric carcinoma', 'Disease', 'MESH:D013274', (269, 286))	('miR', 'Gene', (11, 14))	('invasion', 'CPA', (430, 438))	('colorectal cancer', 'Disease', (389, 406))	('contribute', 'Reg', (375, 385))	('gastric carcinoma', 'Disease', (269, 286))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (400, 406))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (269, 286))	('circRNA_001569', 'Var', (332, 346))	('target', 'Reg', (351, 357))	('miR', 'Gene', '22877', (11, 14))	('miR', 'Gene', (358, 361))	('downregulated', 'NegReg', (252, 265))	('miR-145', 'Gene', '406937', (358, 365))	('circ_002059', 'Var', (223, 234))	('colorectal cancer', 'Phenotype', 'HP:0003003', (389, 406))
416586	29682564	For example, ciRS-7 abrogates miR-7, circRNA_010567 suppress miR-141, and circRNA_100290 may act as a sponge for the miR-29 gene family.	('miR', 'Gene', (30, 33))	('suppress', 'NegReg', (52, 60))	('miR', 'Gene', '22877', (117, 120))	('miR', 'Gene', (61, 64))	('ciRS-7', 'Gene', (13, 19))	('miR-141', 'Gene', (61, 68))	('miR', 'Gene', '22877', (30, 33))	('miR-7', 'Gene', (30, 35))	('circRNA_100290', 'Var', (74, 88))	('miR', 'Gene', (117, 120))	('miR', 'Gene', '22877', (61, 64))	('ciRS-7', 'Gene', '103611090', (13, 19))	('miR-141', 'Gene', '406933', (61, 68))	('miR-7', 'Gene', '10859', (30, 35))
416609	29186164	However, PEG esophageal carcinoma has statistically significant inferior OS compared with non-PEG esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (13, 33))	('PEG', 'Chemical', '-', (9, 12))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (98, 118))	('inferior', 'NegReg', (64, 72))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (13, 33))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (98, 118))	('OS', 'Chemical', '-', (73, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('PEG', 'Chemical', '-', (94, 97))	('esophageal carcinoma', 'Disease', (98, 118))	('PEG', 'Var', (9, 12))	('esophageal carcinoma', 'Disease', (13, 33))
416637	29186164	PEG patients were significantly less likely to be treatment-naive (p = 0.019) and had a higher prevalence of esophageal cancer (p = 0.023).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('less', 'NegReg', (32, 36))	('PEG', 'Var', (0, 3))	('PEG', 'Chemical', '-', (0, 3))	('esophageal cancer', 'Disease', (109, 126))	('patients', 'Species', '9606', (4, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
416643	29186164	The survival difference is significantly more pronounced between PEG tube and non-PEG esophageal carcinoma patients (p = 0.0090), favoring non-PEG (Fig 4).	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('esophageal carcinoma', 'Disease', (86, 106))	('PEG', 'Chemical', '-', (82, 85))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (86, 106))	('PEG', 'Chemical', '-', (143, 146))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (86, 106))	('non-PEG', 'Var', (139, 146))	('PEG', 'Chemical', '-', (65, 68))	('patients', 'Species', '9606', (107, 115))
416670	27907911	In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in ZNF208 and the risk of esophageal cancer in a Chinese Han population.	('ZNF208', 'Gene', '7757', (97, 103))	('ZNF208', 'Gene', (97, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('single nucleotide polymorphisms', 'Var', (55, 86))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('esophageal cancer', 'Disease', (120, 137))
416672	27907911	Logistic regressionl analysis showed that two SNPs (rs8103163 and rs7248488) were associated with an increased risk of esophageal cancer under different inheritance models after Bonferroni correction.	('rs8103163', 'Var', (52, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('rs7248488', 'Mutation', 'rs7248488', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('rs7248488', 'Var', (66, 75))	('rs8103163', 'Mutation', 'rs8103163', (52, 61))	('esophageal cancer', 'Disease', (119, 136))
416673	27907911	Haplotype analysis suggested that the four variants comprised one block, and that the Grs2188972Crs2188971Crs8103163Crs7248488 haplotype was significantly correlated with an increased risk of esophageal cancer.	('correlated', 'Reg', (155, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (192, 209))	('Grs2188972Crs2188971Crs8103163Crs7248488', 'Var', (86, 126))	('esophageal cancer', 'Disease', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
416674	27907911	Our data indicate that variants in ZNF208 are contribute to the susceptibility to esophageal cancer in a Chinese Han population.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('ZNF208', 'Gene', (35, 41))	('susceptibility', 'Reg', (64, 78))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('esophageal cancer', 'Disease', (82, 99))	('variants', 'Var', (23, 31))	('ZNF208', 'Gene', '7757', (35, 41))
416680	27907911	Single nucleotide polymorphisms (SNPs) that are correlated with an increased risk of esophageal cancer have been identified previously.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('esophageal cancer', 'Disease', (85, 102))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))
416683	27907911	Mutations in ZNF208 have been observed in gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (42, 56))	('Mutations', 'Var', (0, 9))	('gastric cancer', 'Disease', 'MESH:D013274', (42, 56))	('ZNF208', 'Gene', (13, 19))	('observed', 'Reg', (30, 38))	('gastric cancer', 'Disease', (42, 56))	('ZNF208', 'Gene', '7757', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
416686	27907911	Recently, an association between one variant (rs8105767) within the ZNF208 gene and telomere length was identified in a genome-wide association study.	('rs8105767', 'Mutation', 'rs8105767', (46, 55))	('ZNF208', 'Gene', (68, 74))	('ZNF208', 'Gene', '7757', (68, 74))	('telomere length', 'MPA', (84, 99))	('rs8105767', 'Var', (46, 55))
416687	27907911	Interestingly, r s8105767 was associated with the risk of neuroblastoma, but not osteosarcoma or leukemia.	('associated', 'Reg', (30, 40))	('osteosarcoma or leukemia', 'Disease', (81, 105))	('neuroblastoma', 'Phenotype', 'HP:0003006', (58, 71))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))	('osteosarcoma or leukemia', 'Disease', 'MESH:D012516', (81, 105))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('neuroblastoma', 'Disease', 'MESH:D009447', (58, 71))	('neuroblastoma', 'Disease', (58, 71))	('r s8105767', 'Var', (15, 25))
416692	27907911	We performed a case-control study to evaluate the association between SNPs/haplotypes in the ZNF208 gene and esophageal cancer susceptibility in a Chinese Han population.	('ZNF208', 'Gene', '7757', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('ZNF208', 'Gene', (93, 99))	('esophageal cancer', 'Disease', (109, 126))	('association', 'Interaction', (50, 61))	('SNPs/haplotypes', 'Var', (70, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
416693	27907911	Fivevariants (rs2188972, rs2188971, rs8103163, rs7248488 and rs8105767) were included in the analysis.	('rs7248488', 'Mutation', 'rs7248488', (47, 56))	('rs2188972', 'Mutation', 'rs2188972', (14, 23))	('rs2188971', 'Mutation', 'rs2188971', (25, 34))	('rs8105767', 'Var', (61, 70))	('rs8103163', 'Mutation', 'rs8103163', (36, 45))	('rs2188971', 'Var', (25, 34))	('rs7248488', 'Var', (47, 56))	('rs8103163', 'Var', (36, 45))	('rs2188972', 'Var', (14, 23))	('rs8105767', 'Mutation', 'rs8105767', (61, 70))
416694	27907911	provide evidence for a correlation between SNPs in the ZNF208 gene and esophageal cancer in the Chinese Han population.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('correlation', 'Interaction', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('SNPs', 'Var', (43, 47))	('ZNF208', 'Gene', '7757', (55, 61))	('esophageal cancer', 'Disease', (71, 88))	('ZNF208', 'Gene', (55, 61))
416697	27907911	We identified associations between four SNPs in ZNF208 and esophageal cancer using a logistic regression model after adjustment for age and gender.	('associations', 'Interaction', (14, 26))	('esophageal cancer', 'Disease', (59, 76))	('SNPs', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('men', 'Species', '9606', (123, 126))	('ZNF208', 'Gene', (48, 54))	('ZNF208', 'Gene', '7757', (48, 54))
416698	27907911	Interestingly, rs2188972 was associated with an increased risk of esophageal cancer in homozygote (p = 0.046) and additive (p = 0.046) models.	('rs2188972', 'Var', (15, 24))	('esophageal cancer', 'Disease', (66, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('rs2188972', 'Mutation', 'rs2188972', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
416701	27907911	A significant association was also detected between rs7248488 and the risk of esophageal cancer in dominant (p = 0.017) and additive (p = 0.01) models, as well as in the co-dominant model for the homozygous genotype (p = 0.028).	('rs7248488', 'Var', (52, 61))	('rs7248488', 'Mutation', 'rs7248488', (52, 61))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
416702	27907911	We did not observe any association between rs8105767 and esophageal cancer risk in any of the models.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs8105767', 'Var', (43, 52))	('esophageal cancer', 'Disease', (57, 74))	('rs8105767', 'Mutation', 'rs8105767', (43, 52))
416703	27907911	Only two mutations, rs8103163 (dominant p = 0.045; additive p = 0.040) and rs7248488 (additive p = 0.050), were associated with an increased risk of esophageal cancer after Bonferroni correction.	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('rs7248488', 'Mutation', 'rs7248488', (75, 84))	('rs7248488', 'Var', (75, 84))	('rs8103163', 'Mutation', 'rs8103163', (20, 29))	('esophageal cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rs8103163', 'Var', (20, 29))	('associated', 'Reg', (112, 122))
416707	27907911	We assessed the relationship between SNPs in the ZNF208 gene and esophageal cancer in a Chinese Han population.	('esophageal cancer', 'Disease', (65, 82))	('SNPs', 'Var', (37, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ZNF208', 'Gene', (49, 55))	('ZNF208', 'Gene', '7757', (49, 55))
416708	27907911	Our results indicate that four SNPs (rs2188972, rs2188971, rs8103163, and rs7248488) are associated with an increased risk of esophageal cancer after adjustment for age and gender.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('associated', 'Reg', (89, 99))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('rs2188971', 'Var', (48, 57))	('rs2188971', 'Mutation', 'rs2188971', (48, 57))	('men', 'Species', '9606', (156, 159))	('rs7248488', 'Var', (74, 83))	('rs2188972', 'Var', (37, 46))	('rs8103163', 'Mutation', 'rs8103163', (59, 68))	('rs2188972', 'Mutation', 'rs2188972', (37, 46))	('rs8103163', 'Var', (59, 68))	('esophageal cancer', 'Disease', (126, 143))	('rs7248488', 'Mutation', 'rs7248488', (74, 83))
416709	27907911	However, we did not detect an association between rs8105767 and esophageal cancer susceptibility.	('rs8105767', 'Var', (50, 59))	('rs8105767', 'Mutation', 'rs8105767', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
416711	27907911	However, rs8105767 showed no significant association with telomere length or gastric cancer in a Chinese population, and it was not associated with esophageal cancer in our study.	('rs8105767', 'Var', (9, 18))	('gastric cancer', 'Disease', (77, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', (148, 165))	('rs8105767', 'Mutation', 'rs8105767', (9, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('telomere', 'MPA', (58, 66))
416716	27907911	Another study demonstrated that ZNF280B promotes prostate cancer cell growth and survival through down-regulation of p53.	('survival', 'CPA', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('p53', 'Gene', (117, 120))	('ZNF280B', 'Chemical', '-', (32, 39))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('ZNF280B', 'Var', (32, 39))	('down-regulation', 'NegReg', (98, 113))	('p53', 'Gene', '22060', (117, 120))	('prostate cancer', 'Disease', (49, 64))	('promotes', 'PosReg', (40, 48))
416717	27907911	determined that the ZNF motif (Cys2-His2) in ZNF425 was the main region responsible for the transcriptional repression activity of this protein.	('ZNF425', 'Gene', (45, 51))	('ZNF425', 'Gene', '155054', (45, 51))	('Cys2-His2', 'Var', (31, 40))	('ZNF', 'Chemical', '-', (20, 23))	('Cys2-His2', 'Chemical', '-', (31, 40))	('ZNF', 'Chemical', '-', (45, 48))	('transcriptional repression activity', 'MPA', (92, 127))
416720	27907911	Depletion of any of the genes could alter treatment response.	('alter', 'Reg', (36, 41))	('treatment response', 'CPA', (42, 60))	('men', 'Species', '9606', (47, 50))	('Depletion', 'Var', (0, 9))
416722	27907911	In our study, rs2188972, rs2188971, rs8103163, and rs7248488 were associated with the risk of esophageal cancer.	('rs2188972', 'Mutation', 'rs2188972', (14, 23))	('rs2188971', 'Mutation', 'rs2188971', (25, 34))	('rs8103163', 'Mutation', 'rs8103163', (36, 45))	('associated', 'Reg', (66, 76))	('rs2188971', 'Var', (25, 34))	('esophageal cancer', 'Disease', (94, 111))	('rs8103163', 'Var', (36, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('rs7248488', 'Mutation', 'rs7248488', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rs2188972', 'Var', (14, 23))	('rs7248488', 'Var', (51, 60))
416723	27907911	Given the limited value of analysis of a single SNP, we evaluated the association between haplotypes in the ZNF208 gene and esophageal cancer susceptibility.	('ZNF208', 'Gene', '7757', (108, 114))	('ZNF208', 'Gene', (108, 114))	('esophageal cancer', 'Disease', (124, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('haplotypes', 'Var', (90, 100))
416724	27907911	After adjustment for gender and age, the results showed that the ATAA haplotype was associated with a significantly increased risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('men', 'Species', '9606', (12, 15))	('esophageal cancer', 'Disease', (134, 151))	('ATAA', 'Var', (65, 69))
416725	27907911	Although our study has provided evidence for an association between genetic variants in ZNF208 and esophageal cancer, the results should be interpreted with caution.	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('ZNF208', 'Gene', (88, 94))	('genetic variants', 'Var', (68, 84))	('ZNF208', 'Gene', '7757', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('esophageal cancer', 'Disease', (99, 116))
416727	27907911	In conclusion, our data indicate that rs2188972, rs2188971, rs8103163, and rs7248488 in the ZNF208 gene as well as the ATAA haplotype are associated with an increased risk of esophageal cancer in a Chinese Han population.	('esophageal cancer', 'Disease', (175, 192))	('rs2188972', 'Mutation', 'rs2188972', (38, 47))	('rs7248488', 'Mutation', 'rs7248488', (75, 84))	('rs2188971', 'Mutation', 'rs2188971', (49, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('ZNF208', 'Gene', (92, 98))	('ZNF208', 'Gene', '7757', (92, 98))	('rs8103163', 'Mutation', 'rs8103163', (60, 69))	('rs7248488', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('rs2188971', 'Var', (49, 58))	('rs2188972', 'Var', (38, 47))	('rs8103163', 'Var', (60, 69))
416736	27907911	Venous blood samples (5 mL) were collected from each subject into tubes containing EDTA, centrifuged, and stored at -80 C. Few studies have investigatedinvestigate the associations between SNPs in the ZNF208 and esophageal cancer.	('associations', 'Interaction', (168, 180))	('ZNF208', 'Gene', (201, 207))	('Venous blood', 'Disease', (0, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (212, 229))	('ZNF208', 'Gene', '7757', (201, 207))	('EDTA', 'Chemical', 'MESH:D004492', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('Venous blood', 'Disease', 'MESH:D006402', (0, 12))	('SNPs', 'Var', (189, 193))	('esophageal cancer', 'Disease', (212, 229))
416738	27907911	Five SNPs (rs2188972, rs2188971, rs8103163, rs7248488, and rs8105767) were selected for our study.	('rs8103163', 'Mutation', 'rs8103163', (33, 42))	('rs8105767', 'Mutation', 'rs8105767', (59, 68))	('rs7248488', 'Mutation', 'rs7248488', (44, 53))	('rs2188972', 'Mutation', 'rs2188972', (11, 20))	('rs8103163', 'Var', (33, 42))	('rs8105767', 'Var', (59, 68))	('rs7248488', 'Var', (44, 53))	('rs2188971', 'Mutation', 'rs2188971', (22, 31))	('rs2188971', 'Var', (22, 31))	('rs2188972', 'Var', (11, 20))
416811	33980247	Further, we demonstrated that silencing ATF5 phenocopies HIF1alpha knockdown in tumorigenic properties in vitro and inhibited ESCA tumor angiogenesis and proliferation in vivo.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('ESCA', 'Disease', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('inhibited', 'NegReg', (116, 125))	('HIF1alpha', 'Gene', '3091', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (131, 136))	('silencing', 'Var', (30, 39))	('HIF1alpha', 'Gene', (57, 66))
416831	33980247	Antibodies for ATF5 (ab184923), VEGFA (ab52917), TIMP1 (ab61224), TWIST1 (ab175430), EGF (ab206423), CD31 (ab134168) and POL II (ab264350) were bought from Abcam (Cambridge, MA, USA).	('VEGFA', 'Gene', '7422', (32, 37))	('EGF', 'Gene', (33, 36))	('TIMP1', 'Gene', '7076', (49, 54))	('ab206423', 'Var', (90, 98))	('EGF', 'Gene', (85, 88))	('TWIST1', 'Gene', (66, 72))	('TWIST1', 'Gene', '7291', (66, 72))	('EGF', 'Gene', '1950', (85, 88))	('EGF', 'Gene', '1950', (33, 36))	('VEGFA', 'Gene', (32, 37))	('ab264350', 'Var', (129, 137))	('ab134168', 'Var', (107, 115))	('TIMP1', 'Gene', (49, 54))
416832	33980247	Antibodies for PDK1 (13037), PGK1 (68540), CA9 (5649), CBP (7389), P300 (54062), HIF1alpha (14179), HIF1beta (5537) and flag-tag (2368) were procured from Cell Signaling Technology.	('5537', 'Var', (110, 114))	('PDK1', 'Gene', (15, 19))	('54062', 'Var', (73, 78))	('CA9', 'Gene', '768', (43, 46))	('HIF1alpha', 'Gene', '3091', (81, 90))	('P300', 'Gene', (67, 71))	('68540', 'Var', (35, 40))	('7389', 'Var', (60, 64))	('HIF1beta', 'Gene', (100, 108))	('PDK1', 'Gene', '5163', (15, 19))	('P300', 'Gene', '2033', (67, 71))	('HIF1alpha', 'Gene', (81, 90))	('CBP', 'Gene', '1387', (55, 58))	('14179', 'Var', (92, 97))	('PGK1', 'Gene', '5230', (29, 33))	('13037', 'Var', (21, 26))	('CBP', 'Gene', (55, 58))	('PGK1', 'Gene', (29, 33))	('HIF1beta', 'Gene', '3091', (100, 108))	('5649', 'Var', (48, 52))	('CA9', 'Gene', (43, 46))
416854	33980247	Patients with a high level of ATF5 expression had a shorter overall survival time than those with low expression level (Fig.	('ATF5', 'Gene', (30, 34))	('high', 'Var', (16, 20))	('shorter', 'NegReg', (52, 59))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (60, 76))
416857	33980247	Colony formation assay indicated that ATF5 knock-down suppressed the tumorigenicity of ESCA cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('suppressed', 'NegReg', (54, 64))	('ATF5', 'Gene', (38, 42))	('tumor', 'Disease', (69, 74))	('ESCA', 'Disease', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('knock-down', 'Var', (43, 53))
416859	33980247	Interestingly, six proteins (PDK1, CA9, PAI1, VEGFA, TWIST1, PGK1), belonging to the HIF1 signaling pathway, were downregulated in the shATF5 group and could be transcriptionally activated by HIF1 transcriptional complex.	('HIF1', 'Gene', '3091', (192, 196))	('PDK1', 'Gene', (29, 33))	('HIF1', 'Gene', '3091', (85, 89))	('shATF5', 'Var', (135, 141))	('CA9', 'Gene', '768', (35, 38))	('CA9', 'Gene', (35, 38))	('VEGFA', 'Gene', (46, 51))	('PAI1', 'Gene', (40, 44))	('HIF1', 'Gene', (192, 196))	('PGK1', 'Gene', (61, 65))	('TWIST1', 'Gene', (53, 59))	('HIF1', 'Gene', (85, 89))	('PGK1', 'Gene', '5230', (61, 65))	('downregulated', 'NegReg', (114, 127))	('PAI1', 'Gene', '5054', (40, 44))	('PDK1', 'Gene', '5163', (29, 33))	('TWIST1', 'Gene', '7291', (53, 59))	('VEGFA', 'Gene', '7422', (46, 51))
416863	33980247	RT-PCR analysis further revealed that ATF5 silencing reduced the mRNAs expression of the identified proteins in hypoxia (Fig.	('hypoxia', 'Disease', (112, 119))	('ATF5', 'Gene', (38, 42))	('hypoxia', 'Disease', 'MESH:D000860', (112, 119))	('mRNAs expression of the identified proteins', 'MPA', (65, 108))	('silencing', 'Var', (43, 52))	('reduced', 'NegReg', (53, 60))
416864	33980247	Moreover, Results from dual-luciferase assays showed that loss of ATF5 dramatically decreased the luciferase activation of identified genes in ESCA cells in hypoxia (Fig.	('luciferase', 'Enzyme', (98, 108))	('loss', 'Var', (58, 62))	('ATF5', 'Gene', (66, 70))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('activation of', 'MPA', (109, 122))	('hypoxia', 'Disease', (157, 164))	('decreased', 'NegReg', (84, 93))
416866	33980247	According to the results, silencing of ATF5 significantly inhibited VEGFA secretion in the ESCA cells in hypoxia (Fig.	('VEGFA', 'Gene', (68, 73))	('hypoxia', 'Disease', (105, 112))	('hypoxia', 'Disease', 'MESH:D000860', (105, 112))	('VEGFA', 'Gene', '7422', (68, 73))	('silencing', 'Var', (26, 35))	('ATF5', 'Gene', (39, 43))	('inhibited', 'NegReg', (58, 67))
416874	33980247	We first knocked-down the ATF5 gene in ESCA cell lines and performed ChIP assays to examine the interaction between HIF1 transcriptional complex and HIF1 target gene promoters.	('ATF5', 'Gene', (26, 30))	('HIF1', 'Gene', (149, 153))	('interaction', 'Interaction', (96, 107))	('HIF1', 'Gene', (116, 120))	('HIF1', 'Gene', '3091', (149, 153))	('HIF1', 'Gene', '3091', (116, 120))	('knocked-down', 'Var', (9, 21))
416875	33980247	Silencing of ATF5 reduced the binding between HIF1 transcriptional complex and HIF1 target gene promoters in hypoxia (Fig.	('binding', 'Interaction', (30, 37))	('HIF1', 'Gene', (46, 50))	('hypoxia', 'Disease', (109, 116))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('HIF1', 'Gene', '3091', (79, 83))	('reduced', 'NegReg', (18, 25))	('HIF1', 'Gene', '3091', (46, 50))	('HIF1', 'Gene', (79, 83))	('Silencing', 'Var', (0, 9))	('ATF5', 'Gene', (13, 17))
416882	33980247	Silencing of HIF1alpha dramatically decrease the physical interaction between ATF5 and HIF1beta, P300 or Pol II in hypoxia (Fig.	('P300', 'Gene', (97, 101))	('HIF1beta', 'Gene', (87, 95))	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('Silencing', 'Var', (0, 9))	('HIF1alpha', 'Gene', (13, 22))	('HIF1beta', 'Gene', '3091', (87, 95))	('HIF1alpha', 'Gene', '3091', (13, 22))	('P300', 'Gene', '2033', (97, 101))	('physical interaction', 'MPA', (49, 69))	('hypoxia', 'Disease', (115, 122))	('decrease', 'NegReg', (36, 44))
416883	33980247	5h) and loss of ATF5 had no visual effect in HIF1alpha expression and stabilization in normoxia (Additional file 2: Figure S1E-F).	('expression', 'MPA', (55, 65))	('HIF1alpha', 'Gene', (45, 54))	('loss', 'Var', (8, 12))	('stabilization', 'MPA', (70, 83))	('HIF1alpha', 'Gene', '3091', (45, 54))	('ATF5', 'Gene', (16, 20))
416884	33980247	Next, we conducted a functional assay to examine whether ATF5 inhibition could phenocopy HIF1 inhibition.	('HIF1', 'Gene', '3091', (89, 93))	('inhibition', 'Var', (62, 72))	('ATF5', 'Protein', (57, 61))	('HIF1', 'Gene', (89, 93))
416885	33980247	First, we constructed KYSE30 cells stably expressing vector + shnc, D/N-ATF5 + shnc, and vector + shHIF1alpha.	('HIF1alpha', 'Gene', (100, 109))	('vector + shnc', 'Var', (53, 66))	('HIF1alpha', 'Gene', '3091', (100, 109))	('D/N-ATF5 + shnc', 'Var', (68, 83))
416886	33980247	Western blot assay indicated that the expression of the identified proteins was inhibited in cells expressing D/N-ATF5 and shHIF1alpha in hypoxia (Fig.	('expression', 'MPA', (38, 48))	('HIF1alpha', 'Gene', (125, 134))	('D/N-ATF5', 'Var', (110, 118))	('hypoxia', 'Disease', 'MESH:D000860', (138, 145))	('hypoxia', 'Disease', (138, 145))	('HIF1alpha', 'Gene', '3091', (125, 134))	('inhibited', 'NegReg', (80, 89))
416887	33980247	In addition, dual-luciferase assay showed that cells expressing D/N-ATF5 and shHIF1alpha had similarly lower ability to activate the HIF1 target gene promoters compared with negative control cells in hypoxia (Fig.	('HIF1', 'Gene', '3091', (133, 137))	('hypoxia', 'Disease', 'MESH:D000860', (200, 207))	('activate', 'PosReg', (120, 128))	('D/N-ATF5', 'Var', (64, 72))	('HIF1alpha', 'Gene', (79, 88))	('HIF1', 'Gene', '3091', (79, 83))	('HIF1', 'Gene', (133, 137))	('lower', 'NegReg', (103, 108))	('HIF1alpha', 'Gene', '3091', (79, 88))	('HIF1', 'Gene', (79, 83))	('hypoxia', 'Disease', (200, 207))
416888	33980247	Furthermore, CCK8 and Transwell assays showed that cells expressing D/N-ATF5 and shHIF1alpha presented similarly lower proliferation, invasion, and migration ability relative to negative control cells in hypoxia (Fig.	('hypoxia', 'Disease', (204, 211))	('hypoxia', 'Disease', 'MESH:D000860', (204, 211))	('HIF1alpha', 'Gene', '3091', (83, 92))	('lower', 'NegReg', (113, 118))	('D/N-ATF5', 'Var', (68, 76))	('HIF1alpha', 'Gene', (83, 92))	('invasion', 'CPA', (134, 142))	('migration ability', 'CPA', (148, 165))	('proliferation', 'CPA', (119, 132))
416889	33980247	Consistently, tube formation assay showed that the medium from inhibition ATF5 and silencing HIF1alpha cells similarly inhibited tube formation ability of HUVECs in hypoxia (Fig.	('tube formation ability', 'CPA', (129, 151))	('hypoxia', 'Disease', 'MESH:D000860', (165, 172))	('inhibited', 'NegReg', (119, 128))	('HIF1alpha', 'Gene', (93, 102))	('hypoxia', 'Disease', (165, 172))	('inhibition', 'Var', (63, 73))	('HIF1alpha', 'Gene', '3091', (93, 102))	('silencing', 'Var', (83, 92))
416891	33980247	KYSE30 cells stably expressing vector + shnc, D/N-ATF5 + shnc, vector + shATF5#1, and vector + shATF5#2 were subcutaneously injected into nude mice (1 x 106 cells per mouse).	('nude mice', 'Species', '10090', (138, 147))	('D/N-ATF5 + shnc', 'Var', (46, 61))	('vector + shnc', 'Var', (31, 44))	('mouse', 'Species', '10090', (167, 172))
416893	33980247	Tumors volume of D/N-ATF5 and shATF5 groups grew significantly slower compared with the negative control group (Fig.	('shATF5', 'Var', (30, 36))	('D/N-ATF5', 'Var', (17, 25))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('slower', 'NegReg', (63, 69))
416895	33980247	As expected, tumor weight and volume from the D/N-ATF5 and shATF5 groups were significantly smaller than those from the negative control group (Fig.	('tumor', 'Disease', (13, 18))	('shATF5', 'Var', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('D/N-ATF5', 'Var', (46, 54))	('smaller', 'NegReg', (92, 99))
416896	33980247	The expression of VEGFA and CD31 was investigated by IHC, and the results showed that VEGFA and CD31 was significantly lower in the D/N-ATF5 and shATF5 groups (Fig.	('VEGFA', 'Gene', (18, 23))	('lower', 'NegReg', (119, 124))	('VEGFA', 'Gene', (86, 91))	('CD31', 'Protein', (96, 100))	('VEGFA', 'Gene', '7422', (18, 23))	('shATF5', 'Var', (145, 151))	('VEGFA', 'Gene', '7422', (86, 91))	('D/N-ATF5', 'Var', (132, 140))
416897	33980247	Similarly, analysis of tumor micro-vessel density indicated that tumor micro-vessel was downregulated in D/N-ATF5 and shATF5 groups (Fig.	('D/N-ATF5', 'Var', (105, 113))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('shATF5', 'Var', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (23, 28))	('downregulated', 'NegReg', (88, 101))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
416899	33980247	Based on the results, the expression of VEGFA, PDK1, CA9, and PGK1 was significantly reduced in the D/N-ATF5 and shATF5 groups (Fig.	('expression', 'MPA', (26, 36))	('PGK1', 'Gene', (62, 66))	('CA9', 'Gene', '768', (53, 56))	('PDK1', 'Gene', '5163', (47, 51))	('shATF5', 'Var', (113, 119))	('PDK1', 'Gene', (47, 51))	('VEGFA', 'Gene', '7422', (40, 45))	('D/N-ATF5', 'Var', (100, 108))	('VEGFA', 'Gene', (40, 45))	('reduced', 'NegReg', (85, 92))	('CA9', 'Gene', (53, 56))	('PGK1', 'Gene', '5230', (62, 66))
416910	33980247	Studies have shown that transfection of D/N-ATF5 transgene can trigger massive apoptosis in various cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('D/N-ATF5', 'Gene', (40, 48))	('apoptosis', 'CPA', (79, 88))	('transfection', 'Var', (24, 36))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('trigger', 'Reg', (63, 70))
416911	33980247	Also, the use of D/N-ATF5 can significantly reduce the growth of various tumors in in vivo xenograft models by promoting apoptosis of cancer cells.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('reduce', 'NegReg', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('promoting', 'PosReg', (111, 120))	('D/N-ATF5', 'Var', (17, 25))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
416912	33980247	Here, we demonstrated a novel mechanism of D/N-ATF5 against tumor progression.	('D/N-ATF5', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))
416913	33980247	D/N-ATF5 suppressed the activation of the HIF1 signaling pathway, and further inhibited tumor angiogenesis in in-vivo xenograft models (Figs.	('inhibited', 'NegReg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('HIF1', 'Gene', '3091', (42, 46))	('D/N-ATF5', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('HIF1', 'Gene', (42, 46))	('suppressed', 'NegReg', (9, 19))	('tumor', 'Disease', (88, 93))
416916	33980247	Our findings suggest that inhibition of ATF5 activity can be anti-tumorigenic and especially in certain HIF1-mediated tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('ATF5 activity', 'Protein', (40, 53))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (66, 71))	('inhibition', 'Var', (26, 36))	('HIF1', 'Gene', '3091', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('HIF1', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
416921	33341917	Salvage Robot-Assisted Minimally Invasive Esophagectomy (RAMIE) for T4b Esophageal Cancer After Definitive Chemoradiotherapy Patients  with esophageal cancer  that invades adjacent structures (cT4b) are precluded from surgery and usually treated with definitive chemoradiotherapy (dCRT).	('dCRT', 'Gene', '45841', (281, 285))	('Patients', 'Species', '9606', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('dCRT', 'Gene', (281, 285))	('T4b', 'Var', (68, 71))	('RAMIE', 'Species', '83906', (57, 62))	('cancer', 'Disease', (151, 157))	('Cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))
416923	33341917	This study aimed to assess the perioperative and oncologic outcomes of a salvage robot-assisted minimally invasive esophagectomy (RAMIE) in patients with cT4b esophageal cancer after dCRT.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('dCRT', 'Gene', '45841', (183, 187))	('RAMIE', 'Species', '83906', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('dCRT', 'Gene', (183, 187))	('cT4b', 'Var', (154, 158))	('patients', 'Species', '9606', (140, 148))
416924	33341917	Between June 2012 and November 2019, patients who underwent a RAMIE with a gastric conduit reconstruction after completion of dCRT for cT4b esophageal carcinoma were identified from a prospectively maintained surgical database at the University Medical Center Utrecht.	('cT4b', 'Var', (135, 139))	('esophageal carcinoma', 'Disease', (140, 160))	('dCRT', 'Gene', '45841', (126, 130))	('patients', 'Species', '9606', (37, 45))	('dCRT', 'Gene', (126, 130))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (140, 160))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (140, 160))	('RAMIE', 'Species', '83906', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
416930	33341917	In patients with cT4b esophageal cancer treated with dCRT followed by a salvage RAMIE, a radical resection rate of 92% was achieved, with acceptable complications and promising survival rates.	('dCRT', 'Gene', (53, 57))	('RAMIE', 'Species', '83906', (80, 85))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cT4b', 'Var', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('patients', 'Species', '9606', (3, 11))	('dCRT', 'Gene', '45841', (53, 57))
416967	33341917	The primary tumor in the RAMIE group was located mainly in the upper one-third of the esophagus, whereas the primary tumor in the non-RAMIE group was located in the middle one-third of the esophagus.	('RAMIE', 'Var', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('RAMIE', 'Species', '83906', (134, 139))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('RAMIE', 'Species', '83906', (25, 30))
417006	33341917	This is the first study to assess the perioperative and oncologic outcomes of a salvage RAMIE after dCRT for patients with a cT4b esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (130, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (130, 150))	('patients', 'Species', '9606', (109, 117))	('RAMIE', 'Species', '83906', (88, 93))	('dCRT', 'Gene', '45841', (100, 104))	('dCRT', 'Gene', (100, 104))	('cT4b', 'Var', (125, 129))	('esophageal carcinoma', 'Disease', (130, 150))
417016	33341917	The observed morbidity and mortality rates are comparable with those of previous reports on the surgical management of T4b esophageal cancer despite widely varying definitions and classifications of complications.	('T4b', 'Var', (119, 122))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mortality', 'Disease', 'MESH:D003643', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mortality', 'Disease', (27, 36))
417042	33036415	Therefore, this study aims to characterize the alteration patterns of mothers against decapentaplegic homolog 3 (SMAD3) in patients with CRC and its applications in early detection by using a genome-wide methylation array to identify an aberrant hypomethylation site in the intron position of the SMAD3 gene.	('CRC', 'Phenotype', 'HP:0003003', (137, 140))	('mothers against decapentaplegic homolog 3', 'Gene', (70, 111))	('SMAD3', 'Gene', (113, 118))	('patients', 'Species', '9606', (123, 131))	('aberrant', 'Var', (237, 245))	('CRC', 'Disease', (137, 140))	('mothers against decapentaplegic homolog 3', 'Gene', '4088', (70, 111))	('hypomethylation site', 'Var', (246, 266))	('SMAD3', 'Gene', (297, 302))
417043	33036415	Quantitative methylation-specific polymerase chain reaction showed that hypomethylated SMAD3 occurred in 91.4% (501/548) of Taiwanese CRC tissues and 66.6% of benign tubular adenoma polyps.	('hypomethylated', 'Var', (72, 86))	('CRC', 'Phenotype', 'HP:0003003', (134, 137))	('benign tubular adenoma polyps', 'Disease', 'MESH:D011127', (159, 188))	('benign tubular adenoma polyps', 'Disease', (159, 188))	('SMAD3', 'Gene', (87, 92))
417044	33036415	In addition, SMAD3 hypomethylation was observed in 94.7% of patients with CRC from The Cancer Genome Atlas dataset.	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('observed', 'Reg', (39, 47))	('patients', 'Species', '9606', (60, 68))	('CRC', 'Disease', (74, 77))	('Cancer', 'Disease', (87, 93))	('CRC', 'Phenotype', 'HP:0003003', (74, 77))	('hypomethylation', 'Var', (19, 34))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))
417047	33036415	Hypomethylated SMAD3 was found in cancers of the digestive system, such as liver cancer, gastric cancer, and colorectal cancer, but not in breast cancer, endometrial cancer, and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('rectal cancer', 'Phenotype', 'HP:0100743', (113, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Disease', (34, 41))	('liver cancer', 'Disease', 'MESH:D006528', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('found', 'Reg', (25, 30))	('liver cancer', 'Phenotype', 'HP:0002896', (75, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))	('colorectal cancer', 'Disease', (109, 126))	('endometrial cancer', 'Phenotype', 'HP:0012114', (154, 172))	('Hypomethylated', 'Var', (0, 14))	('lung cancer', 'Disease', (178, 189))	('liver cancer', 'Disease', (75, 87))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('endometrial cancer', 'Disease', (154, 172))	('breast cancer', 'Disease', (139, 152))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('SMAD3', 'Gene', (15, 20))	('endometrial cancer', 'Disease', 'MESH:D016889', (154, 172))	('gastric cancer', 'Disease', (89, 103))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))
417058	33036415	As described previously, 86.1% of the CRC patients in Taiwan showed BEN Domain Containing 5 (BEND5) hypermethylation.	('hypermethylation', 'Var', (100, 116))	('CRC', 'Phenotype', 'HP:0003003', (38, 41))	('BEND5', 'Gene', (93, 98))	('patients', 'Species', '9606', (42, 50))	('CRC', 'Disease', (38, 41))
417064	33036415	We set three criteria to classify potential CRC genes: (1) hypomethylation in Taiwanese patients with CRC, (2) a methylation level close to 0.2 in CRC tissues, and (3) hypomethylation in Western patients with CRC (Figure 1).	('CRC', 'Phenotype', 'HP:0003003', (102, 105))	('CRC', 'Phenotype', 'HP:0003003', (147, 150))	('hypomethylation', 'Var', (168, 183))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (195, 203))	('hypomethylation', 'MPA', (59, 74))	('methylation level', 'MPA', (113, 130))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))	('CRC', 'Phenotype', 'HP:0003003', (209, 212))
417070	33036415	According to the datasets from TCGA, SMAD3 was hypomethylated in cancers of the digestive system, such as liver cancer, gastric cancer, colon cancer, and rectal cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', (112, 118))	('hypomethylated', 'Var', (47, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Disease', (65, 72))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', (128, 134))	('liver cancer', 'Disease', 'MESH:D006528', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('colon cancer', 'Phenotype', 'HP:0003003', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))	('cancer', 'Disease', (142, 148))	('liver cancer', 'Phenotype', 'HP:0002896', (106, 118))	('liver cancer', 'Disease', (106, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('colon cancer', 'Disease', 'MESH:D015179', (136, 148))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('gastric cancer', 'Disease', (120, 134))	('rectal cancer', 'Phenotype', 'HP:0100743', (154, 167))	('colon cancer', 'Disease', (136, 148))	('SMAD3', 'Gene', (37, 42))
417077	33036415	However, a specific methylated primer design and sequencing revealed that several CpG sites near region +12535 showed decreased methylation in CRC tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('CRC tumor', 'Disease', (143, 152))	('CRC tumor', 'Disease', 'MESH:D015179', (143, 152))	('region +12535', 'Var', (97, 110))	('methylation', 'MPA', (128, 139))	('decreased', 'NegReg', (118, 127))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))
417078	33036415	In total, 45 CpG sites were verified in SMAD3, but only cg24032190 showed a significant hypomethylation difference between cancerous and noncancerous tissues (p  0.001).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('hypomethylation', 'MPA', (88, 103))	('cg24032190', 'Var', (56, 66))	('cancerous', 'Disease', 'MESH:D009369', (140, 149))	('cancerous', 'Disease', 'MESH:D009369', (123, 132))	('cancerous', 'Disease', (123, 132))	('cancerous', 'Disease', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cg24032190', 'Chemical', '-', (56, 66))
417081	33036415	Hypomethylated SMAD3 was observed in 66.6% (6/9) polyps obtained from Taipei Veterans General Hospital.	('polyps', 'Disease', 'MESH:D011127', (49, 55))	('Hypomethylated', 'Var', (0, 14))	('polyps', 'Disease', (49, 55))	('observed', 'Reg', (25, 33))	('SMAD3', 'Gene', (15, 20))
417085	33036415	cg24032190, which is located on the gene body of SMAD3, showing that they were hypomethylated in 94.7% (36/38) of CRC paired tissues and 92.0% (289/314) of nonpaired colorectal tumor tissues (Figure 3A,B).	('colorectal tumor', 'Disease', (166, 182))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('colorectal tumor', 'Disease', 'MESH:D015179', (166, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cg24032190', 'Chemical', '-', (0, 10))	('hypomethylated', 'Var', (79, 93))
417098	33036415	By contrast, the correlation was positive in the SMAD3 hypomethylation cg24032190 gene body region +12535 region (array probe 6, p = 0.036) and cg25547520 gene body region +927 (array probe 7, p = 0.036) (Figure 6).	('SMAD3', 'Gene', (49, 54))	('cg25547520', 'Var', (144, 154))	('cg24032190', 'Chemical', '-', (71, 81))	('cg24032190', 'Gene', (71, 81))
417100	33036415	SMAD3 hypomethylation is commonly observed in several clinical parameters, such as age, ethnicity, sex, tumor type, tumor stage, tumor size, regional lymph node metastasis, distant metastasis, differentiation grade, vascular invasion, location, microsatellite instability (MSI), and kirsten rat sarcoma viral oncogene homologue (KRAS) mutation.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('differentiation grade', 'CPA', (193, 214))	('tumor', 'Disease', (129, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (295, 302))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('KRAS', 'Gene', (329, 333))	('vascular invasion', 'CPA', (216, 233))	('distant metastasis', 'CPA', (173, 191))	('tumor', 'Disease', (104, 109))	('mutation', 'Var', (335, 343))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('regional lymph node metastasis', 'CPA', (141, 171))	('sarcoma', 'Disease', 'MESH:D012509', (295, 302))	('observed', 'Reg', (34, 42))	('KRAS', 'Gene', '24525', (329, 333))	('sarcoma', 'Disease', (295, 302))
417103	33036415	According to the results, 62.5% (10/15) of patients with esophageal cancer had SMAD3 hypomethylation.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('hypomethylation', 'Var', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('SMAD3', 'Gene', (79, 84))	('patients', 'Species', '9606', (43, 51))	('esophageal cancer', 'Disease', (57, 74))
417104	33036415	However, the result was the opposite in endometrial cancer, where 60% (9/15) of patients showed SMAD3 hypermethylation.	('endometrial cancer', 'Disease', 'MESH:D016889', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('patients', 'Species', '9606', (80, 88))	('endometrial cancer', 'Disease', (40, 58))	('SMAD3', 'Gene', (96, 101))	('hypermethylation', 'Var', (102, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (40, 58))
417107	33036415	Hypomethylated SMAD3 was found in cancers of the digestive system, such as liver cancer (8/12, 66.6%), gastric cancer (1/2, 50%), colon cancer (36/38, 94.7%), and rectal cancer (7/7, 100%) (Figure 7).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', (170, 176))	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancer', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('liver cancer', 'Disease', 'MESH:D006528', (75, 87))	('cancers', 'Disease', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('liver cancer', 'Phenotype', 'HP:0002896', (75, 87))	('found', 'Reg', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('Hypomethylated', 'Var', (0, 14))	('liver cancer', 'Disease', (75, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('colon cancer', 'Disease', (130, 142))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('SMAD3', 'Gene', (15, 20))	('rectal cancer', 'Phenotype', 'HP:0100743', (163, 176))	('cancer', 'Disease', (34, 40))	('gastric cancer', 'Disease', (103, 117))
417109	33036415	We stratified the overall survival of Taiwanese patients with CRC and patients in TCGA datasets into two subsets on the basis of SMAD3 methylation: low hypomethylation and no-hypomethylation groups.	('patients', 'Species', '9606', (70, 78))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('low hypomethylation', 'Var', (148, 167))	('no-hypomethylation', 'Var', (172, 190))	('patients', 'Species', '9606', (48, 56))
417110	33036415	The results indicated that the survival rate of the no-hypomethylation group was higher than that of the hypomethylation group, especially among Taiwanese male, elderly, and late-stage CRC patients (Figure 8).	('CRC', 'Phenotype', 'HP:0003003', (185, 188))	('survival rate', 'CPA', (31, 44))	('higher', 'PosReg', (81, 87))	('patients', 'Species', '9606', (189, 197))	('no-hypomethylation', 'Var', (52, 70))
417111	33036415	Both hypermethylation and hypomethylation are independent processes critical to colorectal tumor formation.	('colorectal tumor', 'Disease', (80, 96))	('colorectal tumor', 'Disease', 'MESH:D015179', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('hypermethylation', 'Var', (5, 21))	('hypomethylation', 'Var', (26, 41))
417115	33036415	According to previous studies, a high expression of ACOT7 is related to poor prognosis in acute myeloid leukemia.	('high', 'Var', (33, 37))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (90, 112))	('ACOT7', 'Gene', (52, 57))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (90, 112))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (96, 112))	('acute myeloid leukemia', 'Disease', (90, 112))
417116	33036415	RASA3 hypomethylation is a frequent characteristic of hepatocellular carcinoma, and serves as a potential biomarker in early detection.	('hypomethylation', 'Var', (6, 21))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 78))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (54, 78))	('hepatocellular carcinoma', 'Disease', (54, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('RASA3', 'Protein', (0, 5))
417117	33036415	The CpG site cg13482620, which is located in B3GNTL1, was strongly associated with lung cancer in Norwegian women.	('women', 'Species', '9606', (108, 113))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('cg13482620', 'Chemical', '-', (13, 23))	('cg13482620', 'Var', (13, 23))	('B3GNTL1', 'Gene', '146712', (45, 52))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('B3GNTL1', 'Gene', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('associated with', 'Reg', (67, 82))
417118	33036415	A PIGB mutation may lead to development and neurogenesis problems.	('PIGB', 'Gene', (2, 6))	('lead to', 'Reg', (20, 27))	('PIGB', 'Gene', '9488', (2, 6))	('mutation', 'Var', (7, 15))
417119	33036415	A MAP3K5 mutation is related to malignant stages of prostate cancer.	('mutation', 'Var', (9, 17))	('MAP3K5', 'Gene', '4217', (2, 8))	('MAP3K5', 'Gene', (2, 8))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('related', 'Reg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('prostate cancer', 'Disease', (52, 67))
417120	33036415	A LPIN1 mutation causes rhabdomyolysis.	('rhabdomyolysis', 'Disease', 'MESH:D012206', (24, 38))	('LPIN1', 'Gene', '23175', (2, 7))	('causes', 'Reg', (17, 23))	('LPIN1', 'Gene', (2, 7))	('rhabdomyolysis', 'Disease', (24, 38))	('mutation', 'Var', (8, 16))	('rhabdomyolysis', 'Phenotype', 'HP:0003201', (24, 38))
417121	33036415	A MYBPC3 mutation was noted in patients with inherited hypertrophic cardiomyopathy.	('mutation', 'Var', (9, 17))	('hypertrophic cardiomyopathy', 'Phenotype', 'HP:0001639', (55, 82))	('inherited hypertrophic cardiomyopathy', 'Disease', 'MESH:D002312', (45, 82))	('inherited hypertrophic cardiomyopathy', 'Disease', (45, 82))	('patients', 'Species', '9606', (31, 39))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (68, 82))	('MYBPC3', 'Gene', (2, 8))
417122	33036415	Single-nucleotide polymorphisms (SNPs), such as rs36221701, which are located upstream of SMAD3, are significantly related to gene expression in inflammatory bowel disease (IBD), which may increase CRC risk by 3- to 5-fold.	('IBD', 'Phenotype', 'HP:0002037', (173, 176))	('rs36221701', 'Mutation', 'rs36221701', (48, 58))	('CRC', 'Disease', (198, 201))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('IBD', 'Disease', (173, 176))	('rs36221701', 'Var', (48, 58))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (145, 171))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (145, 171))	('gene expression', 'MPA', (126, 141))	('IBD', 'Disease', 'MESH:D015212', (173, 176))	('SMAD3', 'Gene', (90, 95))	('inflammatory bowel disease', 'Disease', (145, 171))	('increase', 'PosReg', (189, 197))	('CRC', 'Phenotype', 'HP:0003003', (198, 201))	('related', 'Reg', (115, 122))
417124	33036415	SNP rs36221701 is considered a susceptibility locus in Crohn's disease and is strongly associated with repeat operations.	('SNP rs36221701', 'Var', (0, 14))	("Crohn's disease", 'Phenotype', 'HP:0100280', (55, 70))	("Crohn's disease", 'Disease', 'MESH:D003424', (55, 70))	("Crohn's disease", 'Disease', (55, 70))	('rs36221701', 'Mutation', 'rs36221701', (4, 14))	('associated with', 'Reg', (87, 102))
417125	33036415	Even among Western patients, SMAD3 rs17293632 is a susceptibility locus in Crohn's disease.	('rs17293632', 'Var', (35, 45))	('patients', 'Species', '9606', (19, 27))	('rs17293632', 'Mutation', 'rs17293632', (35, 45))	("Crohn's disease", 'Phenotype', 'HP:0100280', (75, 90))	('susceptibility', 'Reg', (51, 65))	("Crohn's disease", 'Disease', 'MESH:D003424', (75, 90))	("Crohn's disease", 'Disease', (75, 90))	('SMAD3', 'Gene', (29, 34))
417129	33036415	Results showed that significant hypomethylation occurs in tumor tissues on cg24032190 in SMAD3.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('SMAD3', 'Gene', (89, 94))	('cg24032190', 'Chemical', '-', (75, 85))	('cg24032190', 'Var', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('hypomethylation', 'MPA', (32, 47))
417133	33036415	Moreover, SMAD3 hypomethylation was observed in 66.6% (6/9) of polyps, and the methylation level in polyps was between that of normal and tumor tissues (Figure 2B).	('observed', 'Reg', (36, 44))	('tumor', 'Disease', (138, 143))	('SMAD3', 'Gene', (10, 15))	('polyps', 'Disease', (100, 106))	('polyps', 'Disease', (63, 69))	('hypomethylation', 'Var', (16, 31))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('polyps', 'Disease', 'MESH:D011127', (63, 69))	('polyps', 'Disease', 'MESH:D011127', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
417135	33036415	On the basis of the outcome, SMAD3 hypomethylation could be a superior early predictive biomarker in Asian patients with CRC.	('CRC', 'Disease', (121, 124))	('CRC', 'Phenotype', 'HP:0003003', (121, 124))	('hypomethylation', 'Var', (35, 50))	('patients', 'Species', '9606', (107, 115))	('SMAD3', 'Gene', (29, 34))
417138	33036415	Consequently, our target CpG site cg24032190, which is located on the gene body, showed hypomethylation but low expression (Figure 6).	('cg24032190', 'Chemical', '-', (34, 44))	('low', 'NegReg', (108, 111))	('cg24032190', 'Var', (34, 44))	('hypomethylation', 'Var', (88, 103))	('expression', 'MPA', (112, 122))
417139	33036415	Moreover, SMAD3 deficiency promotes tumorigenesis in the distal colon of carrying an inactivated allele of the adenomatous polyposis coli gene (ApcMin/+) mice.	('mice', 'Species', '10090', (154, 158))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (111, 137))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (111, 132))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (111, 137))	('SMAD3', 'Gene', (10, 15))	('promotes', 'PosReg', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('adenomatous polyposis coli', 'Disease', (111, 137))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('deficiency', 'Var', (16, 26))
417140	33036415	Deficient SMAD3 expression is related to human gastric cancer.	('Deficient', 'Var', (0, 9))	('related', 'Reg', (30, 37))	('gastric cancer', 'Disease', (47, 61))	('SMAD3', 'Gene', (10, 15))	('human', 'Species', '9606', (41, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('expression', 'MPA', (16, 26))
417151	33036415	We analyzed the methylation level of cg24032190 in SMAD3 in different cancer types.	('cg24032190', 'Chemical', '-', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cg24032190', 'Var', (37, 47))	('SMAD3', 'Gene', (51, 56))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
417153	33036415	Esophageal cancer is the only cancer that showed hypomethylation in Taiwanese patients (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('patients', 'Species', '9606', (78, 86))	('hypomethylation', 'Var', (49, 64))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
417154	33036415	By contrast, based on the TCGA data, cg24032190 SMAD3 caused no significant difference in the methylation pattern in esophageal cancer (Figure 7 and Table 2).	('cg24032190', 'Chemical', '-', (37, 47))	('methylation', 'MPA', (94, 105))	('esophageal cancer', 'Disease', (117, 134))	('cg24032190', 'Var', (37, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
417158	33036415	Furthermore, we observed that cg24032190 of SMAD3 is 60% hypermethylated in endometrial cancer in both Taiwanese patients and TCGA datasets (Table 2).	('SMAD3', 'Gene', (44, 49))	('endometrial cancer', 'Disease', (76, 94))	('patients', 'Species', '9606', (113, 121))	('endometrial cancer', 'Phenotype', 'HP:0012114', (76, 94))	('cg24032190', 'Chemical', '-', (30, 40))	('endometrial cancer', 'Disease', 'MESH:D016889', (76, 94))	('cg24032190', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
417236	32332598	The univariate analysis showed that postoperative T stage (chi2 = 2; P = .04), lymph node metastasis (chi2 = 12.132; P = .000), postoperative staging (chi2 = 16.528; P = .000), KPS <80 (chi2 = 4.715; P = .03) were the main prognostic factor for overall survival.	('postoperative T', 'Disease', (36, 51))	('postoperative T', 'Disease', 'MESH:D010149', (36, 51))	('lymph node metastasis', 'CPA', (79, 100))	('KPS <80', 'Var', (177, 184))
417360	31290583	It is also theoretically possible that the liquids include N-nitroso-bile acids, which may play a role in the initiation of carcinogenesis.	('initiation of carcinogenesis', 'Disease', 'MESH:D063646', (110, 138))	('N-nitroso-bile acids', 'Var', (59, 79))	('N-nitroso-bile acids', 'Chemical', 'MESH:D001647', (59, 79))	('initiation of carcinogenesis', 'Disease', (110, 138))
417366	31290583	This carcinogenic process is likely initiated by the production of N-nitroso-bile acids, which is mutagenic and promoted by sustained chronic inflammation.	('carcinogenic', 'Disease', 'MESH:D063646', (5, 17))	('carcinogenic', 'Disease', (5, 17))	('inflammation', 'Disease', (142, 154))	('N-nitroso-bile', 'Var', (67, 81))	('N-nitroso-bile acids', 'Chemical', 'MESH:D001647', (67, 87))	('inflammation', 'Disease', 'MESH:D007249', (142, 154))
417408	30783157	Compared with evaluable patients who had a median follow-up with cross-sectional imaging of 15 months, no significant differences were seen regarding MLD, V5, V10, V20, V30 (Data not shown).	('V10', 'Var', (159, 162))	('MLD', 'Disease', 'MESH:D007966', (150, 153))	('MLD', 'Disease', (150, 153))	('V30', 'Var', (169, 172))	('V20', 'Var', (164, 167))	('patients', 'Species', '9606', (24, 32))
417416	30783157	Patients with grade II or higher RP did not have higher lung DVH parameters compared with patients who developed no more than grade I RP (V5 51.8% vs. 57.1%, V10 34.7% vs 39.4%, V20 18.6% vs. 18.8%, MLD 11.0% vs. 11.2%, p > 0.05 in all cases).	('Patients', 'Species', '9606', (0, 8))	('MLD', 'Disease', 'MESH:D007966', (199, 202))	('V10', 'Var', (158, 161))	('patients', 'Species', '9606', (90, 98))	('MLD', 'Disease', (199, 202))
417454	30783157	: pulmologist participating in scoring of radiation pneumonitis L.H.B., S.B., K.Z., S.W., J.T., C.G.	('pneumonitis', 'Disease', (52, 63))	('S.B.', 'Var', (72, 76))	('K.Z.', 'Var', (78, 82))	('pneumonitis', 'Disease', 'MESH:D011014', (52, 63))	('J.T.', 'Var', (90, 94))
417600	29245248	Besides, the positive rates of SCC-Ag and CYFR21-1 in the patients were 67.7% and 69.4%, which were higher than that of the CEA (16.1%), respectively (P < .05, Table 2).	('CEA', 'Gene', '1084', (124, 127))	('SCC', 'Gene', (31, 34))	('SCC', 'Gene', '6317', (31, 34))	('patients', 'Species', '9606', (58, 66))	('CYFR21-1', 'Var', (42, 50))	('CEA', 'Gene', (124, 127))
417612	29245248	Our results indicated that patients with metastasis showed higher serum IL-6 than those without.	('metastasis', 'Var', (41, 51))	('IL-6', 'Gene', '3569', (72, 76))	('higher serum IL-6', 'Phenotype', 'HP:0030783', (59, 76))	('patients', 'Species', '9606', (27, 35))	('higher', 'PosReg', (59, 65))	('IL-6', 'Gene', (72, 76))
417632	29245248	In addition, the positive rate of CYFR21-1 increased with the progression of esophageal cancer with a ratio of 22.2% of pTNM stage 0-IIA and 77.8% pTNM stage IIB/III; however, SCC-Ag and CEA rates were not correlated to the pTNM stages.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('TNM', 'Gene', (225, 228))	('CEA', 'Gene', (187, 190))	('CEA', 'Gene', '1084', (187, 190))	('TNM', 'Gene', '10178', (121, 124))	('TNM', 'Gene', '10178', (148, 151))	('SCC', 'Gene', (176, 179))	('CYFR21-1', 'Var', (34, 42))	('increased', 'PosReg', (43, 52))	('TNM', 'Gene', '10178', (225, 228))	('esophageal cancer', 'Disease', (77, 94))	('TNM', 'Gene', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('SCC', 'Gene', '6317', (176, 179))	('TNM', 'Gene', (148, 151))
417658	29181149	reported that 10 out of 48 patients with molecular targeted therapy such as Bevacizumab and sunitinib had PI; two patients had abdominal pain and eight patients had no clinical symptoms.	('Bevacizumab', 'Chemical', 'MESH:D000068258', (76, 87))	('PI', 'Disease', (106, 108))	('abdominal pain', 'Phenotype', 'HP:0002027', (127, 141))	('abdominal', 'Disease', (127, 136))	('patients', 'Species', '9606', (27, 35))	('sunitinib', 'Chemical', 'MESH:D000077210', (92, 101))	('pain', 'Phenotype', 'HP:0012531', (137, 141))	('molecular targeted therapy', 'Var', (41, 67))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (152, 160))
417661	29181149	Thus, a potential mechanism of PI induced by CF therapy may be a mucosal disorder caused by 5-fluorouracil, which was exacerbated by cisplatin.	('mucosal disorder', 'Disease', (65, 81))	('5-fluorouracil', 'Var', (92, 106))	('mucosal disorder', 'Disease', 'MESH:D052016', (65, 81))	('caused', 'Reg', (82, 88))
417674	28874135	In contrast, replication-competent Ad produced greater cytotoxicity in p53 mutated than in wild-type esophageal carcinoma cells, suggesting a possible association between the cytotoxicity and the p53 genotype.	('greater', 'PosReg', (47, 54))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (101, 121))	('Ad', 'Gene', '8081', (35, 37))	('cytotoxicity', 'Disease', (175, 187))	('mutated', 'Var', (75, 82))	('p53', 'Gene', (71, 74))	('cytotoxicity', 'Disease', (55, 67))	('p53', 'Gene', '7157', (71, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('esophageal carcinoma', 'Disease', (101, 121))	('cytotoxicity', 'Disease', 'MESH:D064420', (175, 187))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (101, 121))	('p53', 'Gene', '7157', (196, 199))	('p53', 'Gene', (196, 199))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))
417684	28874135	Consequently, substituting the fiber-knob region can convert the infectivity based on the Ad subtypes.	('substituting', 'Var', (14, 26))	('infectivity', 'MPA', (65, 76))	('Ad', 'Gene', '8081', (90, 92))	('convert', 'Reg', (53, 60))
417693	28874135	Replacement of the fiber-knob region with the Ad35-derived one can widen the target tumor scopes and furthermore produce better cytotoxicity.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('widen', 'PosReg', (67, 72))	('Replacement', 'Var', (0, 11))	('cytotoxicity', 'Disease', (128, 140))	('Ad', 'Gene', '8081', (46, 48))
417697	28874135	Human pancreatic carcinoma, PANC-1 (TKG 0606, p53 genotype: mutated), AsPC-1 (JCRB1454, null), MIA-PaCa-2 (TKG 0227, mutated) and BxPC-3 (JCRB1448, mutated) cells, and human esophageal carcinoma, TE-1 (TGK 0252, mutated at codon 272 Val to Met), TE-2 (TGK 0253, wild-type), TE-10 (TKG 0261, mutated at codon 242 Cys to Tyr), TE-11 (TKG 0262, wild-type), YES-2 (mutated at codon 236 Tyr to Asn), YES-4 (wild-type), YES-5 (mutated at codon 280 Arg to Gly), YES-6 (wild-type) and T.Tn (JCRB 0261, mutated at codon 214 His to Arg and 258 Glu to stop) cells were from Cell Resource Center for Biomedical Research (TKG number; Sendai, Japan), National Institutes of Biomedical Innovation, Health and Nutrition (JCRB number; Tokyo, Japan) or Dr. Yutaka Shimada (YES-2, YES-4, YES-5 and YES-6; Kyoto University, Kyoto, Japan).	('Human', 'Species', '9606', (0, 5))	('242 Cys to Tyr', 'Mutation', 'p.C242Y', (308, 322))	('280 Arg to Gly', 'Mutation', 'p.R280G', (438, 452))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('TGK', 'Gene', '7051', (252, 255))	('YES-2', 'Gene', (354, 359))	('AsPC-1', 'CellLine', 'CVCL:0152', (70, 76))	('258 Glu to stop', 'SUBSTITUTION', 'None', (530, 545))	('TGK', 'Gene', (252, 255))	('human', 'Species', '9606', (168, 173))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (174, 194))	('214 His to Arg', 'Mutation', 'p.H214R', (511, 525))	('p53', 'Gene', '7157', (46, 49))	('272 Val to Met', 'Mutation', 'p.V272M', (229, 243))	('258 Glu to stop', 'Var', (530, 545))	('YES-2', 'Gene', '7526', (354, 359))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (6, 26))	('p53', 'Gene', (46, 49))	('YES-2', 'Gene', (755, 760))	('TGK', 'Gene', '7051', (202, 205))	('MIA-PaCa-2', 'CellLine', 'CVCL:0428', (95, 105))	('TGK', 'Gene', (202, 205))	('TE-2', 'Gene', '8260', (246, 250))	('BxPC-3', 'CellLine', 'CVCL:0186', (130, 136))	('pancreatic carcinoma', 'Disease', (6, 26))	('TE-2', 'Gene', (246, 250))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (174, 194))	('236 Tyr to Asn', 'Mutation', 'p.Y236N', (378, 392))	('PANC-1', 'CellLine', 'CVCL:0480', (28, 34))	('YES-2', 'Gene', '7526', (755, 760))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('esophageal carcinoma', 'Disease', (174, 194))
417698	28874135	HEK293 cells (CRL-1573) and human mesothelioma, NCI-H2452 (CRL-5946, wild-type but truncated p53 protein), NCI-H2052 (CRL-5915, wild-type), NCI-H226 (CRL-5826, wild-type), NCI-H28 (CRL-5820, wild-type) and MSTO-211H (CRL-2081, wild-type) cells, were from ATCC (CRL number; Manassas, VA, USA).	('NCI-H2452', 'CellLine', 'CVCL:1553', (48, 57))	('human', 'Species', '9606', (28, 33))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('mesothelioma', 'Disease', (34, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('CRL-5946', 'Var', (59, 67))	('NCI-H226', 'CellLine', 'CVCL:1544', (140, 148))
417703	28874135	Replication-competent Ad5 or AdF35 in which the E1 gene was activated by an exogenous regulatory element, Ad5/Sur, Ad5/MK, Ad5/COX-2, AdF35/Sur, AdF35/MK and AdF35/COX-2, were prepared by replacing the authentic E1 promoter region with 5' upstream regulatory sequences of the MK (0.6 kb, D10604) the Sur (0.5 kb, U75285), or COX-2 (0.3 kb, U04636) gene.	('Ad', 'Gene', '8081', (106, 108))	('COX-2', 'Gene', (325, 330))	('COX-2', 'Gene', (127, 132))	('Ad', 'Gene', '8081', (134, 136))	('Ad5', 'Gene', '8081', (123, 126))	('Ad', 'Gene', '8081', (158, 160))	('Ad5', 'Gene', (22, 25))	('Ad5', 'Gene', '8081', (115, 118))	('Ad', 'Gene', '8081', (29, 31))	('Ad', 'Gene', '8081', (22, 24))	('COX-2', 'Gene', '5743', (325, 330))	('COX-2', 'Gene', (164, 169))	('COX-2', 'Gene', '5743', (127, 132))	('D10604', 'Var', (288, 294))	('Ad5', 'Gene', '8081', (106, 109))	('Ad5/Sur', 'Gene', '8081;6833', (106, 113))	('Ad5', 'Gene', (123, 126))	('MK', 'Gene', '4192', (119, 121))	('MK', 'Gene', '4192', (151, 153))	('COX-2', 'Gene', '5743', (164, 169))	('Ad', 'Gene', '8081', (123, 125))	('Ad5', 'Gene', (115, 118))	('MK', 'Gene', '4192', (276, 278))	('Ad', 'Gene', '8081', (145, 147))	('U04636', 'Var', (340, 346))	('Ad5', 'Gene', (106, 109))	('Ad', 'Gene', '8081', (115, 117))	('Ad5', 'Gene', '8081', (22, 25))	('Ad5/Sur', 'Gene', (106, 113))
417708	28874135	Cells were stained with either anti-CAR antibody (Ab) (#05-644, Upstate, Charlottesville, VA, USA) followed by fluorescein isothiocyanate (FITC)-conjugated anti-mouse IgG Ab or with FITC-conjugated anti-human CD46 Ab (#555949, BD Pharmingen, San Jose, CA, USA).	('CD46', 'Gene', (209, 213))	('#05-644', 'Var', (55, 62))	('human', 'Species', '9606', (203, 208))	('mouse', 'Species', '10090', (161, 166))	('FITC', 'Chemical', 'MESH:D016650', (139, 143))	('fluorescein isothiocyanate', 'Chemical', 'MESH:D016650', (111, 137))	('CAR', 'Gene', '1525', (36, 39))	('CAR', 'Gene', (36, 39))	('#555949', 'Var', (218, 225))	('FITC', 'Chemical', 'MESH:D016650', (182, 186))	('CD46', 'Gene', '4179', (209, 213))
417713	28874135	The protein was transferred to a nylon filter and was hybridized with Ab against gamma-H2A histone family member X (gamma-H2AX) (#613401, BioLegend, San Diego, CA, USA), p53 (DO-10 MS-187-P, Thermo Fisher Scientific, Fremont, CA, USA), p21 (#2947, Cell Signaling, Danvers, MA, USA) or beta-actin (#4970, Cell Signaling) as a control.	('beta-actin', 'Gene', (285, 295))	('gamma-H2AX', 'Chemical', '-', (116, 126))	('#613401', 'Var', (129, 136))	('p53', 'Gene', (170, 173))	('p53', 'Gene', '7157', (170, 173))	('#4970', 'Var', (297, 302))	('p21', 'Gene', (236, 239))	('p21', 'Gene', '644914', (236, 239))	('beta-actin', 'Gene', '728378', (285, 295))
417751	28874135	The p53 genotype of all the pancreatic carcinoma was either mutated (PANC-1, BxPC-3 and MIA-PaCa-2) or deleted (AsPC-1), and that of all the mesothelioma was wild-type except NCI-H2452 cells which had truncated p53 protein despite the wild-type p53 gene.	('pancreatic carcinoma', 'Disease', (28, 48))	('PANC-1', 'CellLine', 'CVCL:0480', (69, 75))	('p53', 'Gene', '7157', (4, 7))	('MIA-PaCa-2', 'CellLine', 'CVCL:0428', (88, 98))	('p53', 'Gene', (211, 214))	('p53', 'Gene', (245, 248))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (28, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('p53', 'Gene', '7157', (211, 214))	('mutated', 'Var', (60, 67))	('mesothelioma', 'Disease', (141, 153))	('protein', 'Protein', (215, 222))	('BxPC-3', 'CellLine', 'CVCL:0186', (77, 83))	('p53', 'Gene', '7157', (245, 248))	('AsPC-1', 'CellLine', 'CVCL:0152', (112, 118))	('NCI-H2452', 'CellLine', 'CVCL:1553', (175, 184))	('p53', 'Gene', (4, 7))
417753	28874135	We then investigated cytotoxicity of esophageal carcinoma, which included 5 cells with mutated (TE-1, TE-10, YES-2, YES-5 and T.Tn) and 4 cells with wild-type p53 gene (TE-2, TE-11, YES-4 and YES-6).	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (37, 57))	('mutated', 'Var', (87, 94))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('cytotoxicity', 'Disease', (21, 33))	('YES-2', 'Gene', (109, 114))	('TE-2', 'Gene', '8260', (169, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('YES-2', 'Gene', '7526', (109, 114))	('TE-2', 'Gene', (169, 173))	('esophageal carcinoma', 'Disease', (37, 57))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (37, 57))
417757	28874135	In contrast, Ad5 vectors did not show the statistical difference (P = 0.21) with those in the wild-type (103.0 +- 39.2, n = 12) and in mutant p53 gene (49.4 +- 20.0, n = 15), but Ad5 tended to be more effective to p53-mutant than the wild-type cells.	('Ad5', 'Gene', '8081', (13, 16))	('p53', 'Gene', (142, 145))	('Ad5', 'Gene', '8081', (179, 182))	('p53', 'Gene', '7157', (142, 145))	('mutant', 'Var', (135, 141))	('Ad5', 'Gene', (13, 16))	('p53', 'Gene', (214, 217))	('p53', 'Gene', '7157', (214, 217))	('Ad5', 'Gene', (179, 182))
417762	28874135	Cells with mutated p53 gene showed various responses, decreased in TE-1, increased in YES-2 and T.Tn, and unchanged p53 in TE-10 cells.	('TE-1', 'CPA', (67, 71))	('increased', 'PosReg', (73, 82))	('YES-2', 'Gene', '7526', (86, 91))	('p53', 'Gene', '7157', (116, 119))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('decreased', 'NegReg', (54, 63))	('T.Tn', 'CPA', (96, 100))	('YES-2', 'Gene', (86, 91))	('mutated', 'Var', (11, 18))	('p53', 'Gene', (116, 119))
417781	28874135	The fiber-knob region of Ad5 and Ad35 is responsible for binding with CAR and CD46 molecules, respectively, and replacement of the Ad5-derived region with the Ad35 region ablated the CAR binding ability and enabled AdF35 bind to CD46 molecules.	('Ad', 'Gene', '8081', (25, 27))	('Ad', 'Gene', '8081', (159, 161))	('CAR', 'Gene', '1525', (183, 186))	('Ad', 'Gene', '8081', (215, 217))	('ablated', 'NegReg', (171, 178))	('CD46', 'Gene', (78, 82))	('CAR', 'Gene', (183, 186))	('CD46', 'Gene', (229, 233))	('Ad5', 'Gene', '8081', (131, 134))	('bind', 'Interaction', (221, 225))	('Ad5', 'Gene', '8081', (25, 28))	('Ad', 'Gene', '8081', (131, 133))	('enabled', 'PosReg', (207, 214))	('CAR', 'Gene', '1525', (70, 73))	('CD46', 'Gene', '4179', (229, 233))	('CD46', 'Gene', '4179', (78, 82))	('replacement', 'Var', (112, 123))	('binding', 'Interaction', (57, 64))	('Ad5', 'Gene', (131, 134))	('Ad', 'Gene', '8081', (33, 35))	('CAR', 'Gene', (70, 73))	('Ad5', 'Gene', (25, 28))
417799	28874135	We examined a correlation between the p53 genotype and the cytotoxic activity with esophageal carcinoma and demonstrated that cells with wild-type p53 gene were resistant to Ad replication-induced cytotoxicity compared with those with mutant p53 in particular with the AdF35 vectors.	('Ad', 'Gene', '8081', (174, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (197, 209))	('p53', 'Gene', (242, 245))	('esophageal carcinoma', 'Disease', (83, 103))	('Ad', 'Gene', '8081', (269, 271))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('p53', 'Gene', '7157', (242, 245))	('p53', 'Gene', '7157', (147, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('mutant', 'Var', (235, 241))	('resistant', 'NegReg', (161, 170))	('cytotoxicity', 'Disease', (197, 209))	('p53', 'Gene', (147, 150))
417800	28874135	Previous studies showed that transduction with the wild-type p53 enhanced cytotoxicity produced by replication-competent Ad and that the Ad-mediated cytotoxicity, which was further augmented by co-expressed p53, was independent of the p53 status of target cells.	('cytotoxicity', 'Disease', (149, 161))	('cytotoxicity', 'Disease', (74, 86))	('Ad', 'Gene', '8081', (121, 123))	('enhanced', 'PosReg', (65, 73))	('p53', 'Gene', (207, 210))	('cytotoxicity', 'Disease', 'MESH:D064420', (149, 161))	('p53', 'Gene', '7157', (207, 210))	('cytotoxicity', 'Disease', 'MESH:D064420', (74, 86))	('p53', 'Gene', (235, 238))	('p53', 'Gene', '7157', (235, 238))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('transduction', 'Var', (29, 41))	('Ad', 'Gene', '8081', (137, 139))
417801	28874135	Expression of E1A accompanied by the viral replications enhanced expression of p53 and the phosphorylation, which contributed to augmentation of cell death.	('phosphorylation', 'MPA', (91, 106))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('E1A', 'Var', (14, 17))	('enhanced', 'PosReg', (56, 64))	('expression', 'MPA', (65, 75))	('cell death', 'CPA', (145, 155))	('augmentation', 'PosReg', (129, 141))
417802	28874135	In contrast, the E1A-induced phosphorylation of mutated p53, functioned as a dominant-negative form, increased the resistance to cell death, which consequently augmented viral replications and production of viral progenies.	('viral replications', 'CPA', (170, 188))	('mutated', 'Var', (48, 55))	('p53', 'Gene', (56, 59))	('increased', 'PosReg', (101, 110))	('resistance to cell death', 'CPA', (115, 139))	('p53', 'Gene', '7157', (56, 59))	('augmented', 'PosReg', (160, 169))	('phosphorylation', 'MPA', (29, 44))
417815	28874135	We noticed that the mutated p53 esophageal carcinoma tended to decreased p21 expression, and consequently mutated p53 genotype and decreased p21 levels could be relevant to each other regarding the Ad-mediated cytotoxicity.	('p53', 'Gene', (28, 31))	('cytotoxicity', 'Disease', 'MESH:D064420', (210, 222))	('p53', 'Gene', (114, 117))	('p21', 'Gene', (73, 76))	('p21', 'Gene', '644914', (73, 76))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (32, 52))	('p21', 'Gene', (141, 144))	('decreased', 'NegReg', (63, 72))	('p21', 'Gene', '644914', (141, 144))	('Ad', 'Gene', '8081', (198, 200))	('mutated', 'Var', (20, 27))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (32, 52))	('mutated', 'Var', (106, 113))	('p53', 'Gene', '7157', (114, 117))	('p53', 'Gene', '7157', (28, 31))	('decreased', 'NegReg', (131, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cytotoxicity', 'Disease', (210, 222))	('esophageal carcinoma', 'Disease', (32, 52))
417821	28874135	Prediction of Ad-mediated cytotoxicity is important from the standpoint of the possible clinical application, and further investigations are required to establish such predictive markers because genetic and epigenetic alterations in target cells are involved in the Ad-mediated cytotoxicity.	('involved', 'Reg', (250, 258))	('cytotoxicity', 'Disease', 'MESH:D064420', (278, 290))	('cytotoxicity', 'Disease', (26, 38))	('epigenetic alterations', 'Var', (207, 229))	('Ad', 'Gene', '8081', (14, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))	('cytotoxicity', 'Disease', (278, 290))	('Ad', 'Gene', '8081', (266, 268))
417824	28874135	We however demonstrated that the cytotoxicity was greater in p53 mutated than in wild-type esophageal carcinoma cells and perhaps was associated decreased p21 levels.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (91, 111))	('cytotoxicity', 'Disease', (33, 45))	('p21', 'Gene', (155, 158))	('p21', 'Gene', '644914', (155, 158))	('cytotoxicity', 'Disease', 'MESH:D064420', (33, 45))	('decreased', 'NegReg', (145, 154))	('p53', 'Gene', '7157', (61, 64))	('greater', 'PosReg', (50, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('esophageal carcinoma', 'Disease', (91, 111))	('p53', 'Gene', (61, 64))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (91, 111))	('mutated', 'Var', (65, 72))
417847	26124180	Of note, significantly better overall survival was observed in patients with coexistence of high EGFR expression and low p-Akt expression (p = 0.030).	('high', 'Var', (92, 96))	('better', 'PosReg', (23, 29))	('expression', 'MPA', (102, 112))	('EGFR', 'Gene', '1956', (97, 101))	('Akt', 'Gene', '207', (123, 126))	('EGFR', 'Gene', (97, 101))	('patients', 'Species', '9606', (63, 71))	('Akt', 'Gene', (123, 126))	('low', 'NegReg', (117, 120))	('overall survival', 'MPA', (30, 46))
417858	26124180	In a previously published retrospective study, we found that combining h-R3 with radiotherapy (RT) or chemoradiotherapy (CRT) resulted in moderate benefit on OS in patients with advanced ESCC.	('ESCC', 'Disease', (187, 191))	('h-R3', 'Var', (71, 75))	('patients', 'Species', '9606', (164, 172))	('OS', 'Chemical', '-', (158, 160))	('benefit', 'PosReg', (147, 154))
417860	26124180	We hypothesized that patients with high EGFR expression would have a better overall survival with the EGFR inhibitor h-R3 antibody, compared with the patients with low expression.	('overall survival', 'MPA', (76, 92))	('patients', 'Species', '9606', (21, 29))	('EGFR', 'Gene', '1956', (40, 44))	('patients', 'Species', '9606', (150, 158))	('EGFR', 'Gene', (40, 44))	('better', 'PosReg', (69, 75))	('EGFR', 'Gene', '1956', (102, 106))	('high', 'Var', (35, 39))	('EGFR', 'Gene', (102, 106))
417881	26124180	As shown in Figure 2A, there was a trend (p = 0.289) that patients expressing high EGFR had better OS compared with patients with low expression.	('EGFR', 'Gene', '1956', (83, 87))	('high', 'Var', (78, 82))	('EGFR', 'Gene', (83, 87))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (58, 66))	('OS', 'Chemical', '-', (99, 101))	('better', 'PosReg', (92, 98))
417887	26124180	As shown in Figure 3A and 3B, the patients with high EGFR and low p-Akt had significantly better survival (p = 0.030) compared with other sub-groups; this was not the case for patients EGFR high/p-Akt high (p = 0.463).	('patients', 'Species', '9606', (176, 184))	('Akt', 'Gene', '207', (197, 200))	('survival', 'MPA', (97, 105))	('Akt', 'Gene', '207', (68, 71))	('EGFR', 'Gene', (185, 189))	('Akt', 'Gene', (197, 200))	('better', 'PosReg', (90, 96))	('Akt', 'Gene', (68, 71))	('patients', 'Species', '9606', (34, 42))	('low', 'Var', (62, 65))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('high', 'Var', (48, 52))	('EGFR', 'Gene', '1956', (185, 189))
417891	26124180	Overexpression of EGFR has been reported to be associated with poor prognosis in experimental and clinical settings.	('Overexpression', 'Var', (0, 14))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))
417894	26124180	Although no improvement in OS was found for the entire population investigated, results of these trials suggest that patients with certain clinical and/or biological characteristics may do better with EGFR inhibitors and these characteristics especially certain molecular biomarkers may be useful for stratification and outcome prediction.	('OS', 'Chemical', '-', (27, 29))	('EGFR', 'Gene', '1956', (201, 205))	('better', 'PosReg', (189, 195))	('EGFR', 'Gene', (201, 205))	('inhibitors', 'Var', (206, 216))	('patients', 'Species', '9606', (117, 125))
417895	26124180	Given that predictive markers for other epithelial cancers such as mutations in KRAS, EGFR or BRAF are rarely detected in esophageal cancers, EGFR expression has been predominantly investigated for its potentiality of predicting treatment outcome for esophageal cancers.	('esophageal cancers', 'Disease', (122, 140))	('EGFR', 'Gene', '1956', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('esophageal cancers', 'Disease', 'MESH:D004938', (251, 269))	('esophageal cancers', 'Disease', 'MESH:D004938', (122, 140))	('EGFR', 'Gene', '1956', (86, 90))	('epithelial cancers', 'Disease', (40, 58))	('epithelial cancers', 'Disease', 'MESH:D000077216', (40, 58))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('BRAF', 'Gene', '673', (94, 98))	('BRAF', 'Gene', (94, 98))	('EGFR', 'Gene', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('KRAS', 'Gene', '3845', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('KRAS', 'Gene', (80, 84))	('esophageal cancers', 'Disease', (251, 269))	('mutations', 'Var', (67, 76))	('EGFR', 'Gene', (86, 90))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))
417900	26124180	In experimental models, Fichter et al reported in OE21 cells (ESCC cell line overexpressing EGFR), a significant reduction of cell viability up to about 50% occurred upon treatment with erlotinib, gefitinib or lapatinib.	('cell viability', 'CPA', (126, 140))	('erlotinib', 'Chemical', 'MESH:D000069347', (186, 195))	('lapatinib', 'Chemical', 'MESH:D000077341', (210, 219))	('reduction', 'NegReg', (113, 122))	('OE21', 'CellLine', 'CVCL:2661', (50, 54))	('EGFR', 'Gene', '1956', (92, 96))	('erlotinib', 'Var', (186, 195))	('EGFR', 'Gene', (92, 96))	('gefitinib', 'Chemical', 'MESH:D000077156', (197, 206))
417902	26124180	Mimura et al also demonstrated p-Akt expression was enhanced to a large extent by EGF, whereas p-Erk expression was marginally increased in response to EGF when the EGFR-overexpressing ESCC cell line KYSE30 was treated with EGF.	('EGFR', 'Gene', (165, 169))	('Akt', 'Gene', '207', (33, 36))	('p-Erk', 'Gene', (95, 100))	('p-Erk', 'Gene', '9451', (95, 100))	('enhanced', 'PosReg', (52, 60))	('Akt', 'Gene', (33, 36))	('expression', 'MPA', (37, 47))	('EGF', 'Var', (82, 85))	('EGFR', 'Gene', '1956', (165, 169))
417998	21768433	The association between the number of severe typical and/or atypical GERD symptoms and esophageal adenocarcinogenesis was then determined while controlling for duration of symptoms and PPI use.	('esophageal adenocarcinogenesis', 'Disease', 'MESH:D004941', (87, 117))	('esophageal adenocarcinogenesis', 'Disease', (87, 117))	('atypical', 'Var', (60, 68))
418002	21768433	The results demonstrate that patients with minimal or no GERD symptoms who are using PPIs have increased odds of esophageal adenocarcinogenesis compared with those with severe symptoms, especially when GERD symptoms have been present for more than 10 years.	('patients', 'Species', '9606', (29, 37))	('esophageal adenocarcinogenesis', 'Disease', (113, 143))	('esophageal adenocarcinogenesis', 'Disease', 'MESH:D004941', (113, 143))	('PPIs', 'Var', (85, 89))
418009	21768433	Vela and colleagues demonstrated that acid suppression in GERD patients did not result in a decrease in the total number of reflux episodes but rather in a shift from acidic to nonacidic reflux coupled with symptom resolution.	('reflux episodes', 'Phenotype', 'HP:0002020', (124, 139))	('reflux episodes', 'MPA', (124, 139))	('shift', 'Reg', (156, 161))	('acidic to nonacidic reflux', 'MPA', (167, 193))	('acid', 'Var', (38, 42))	('patients', 'Species', '9606', (63, 71))
418041	32377706	The results also revealed increased expression levels of WAVE3 and decreased expression levels of miRNA200b in the serum of patients with ESCC, compared with healthy volunteers.	('WAVE3', 'Gene', (57, 62))	('patients', 'Species', '9606', (124, 132))	('WAVE3', 'Gene', '10810', (57, 62))	('increased', 'PosReg', (26, 35))	('miRNA200b', 'Chemical', '-', (98, 107))	('miRNA200b', 'Var', (98, 107))	('decreased', 'NegReg', (67, 76))	('expression levels', 'MPA', (77, 94))	('ESCC', 'Disease', (138, 142))	('expression levels', 'MPA', (36, 53))
418042	32377706	High expression of WAVE3 was significantly associated with tumor TNM stage, invasion depth and lymphatic invasion of ESCC.	('WAVE3', 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('High', 'Var', (0, 4))	('invasion depth', 'CPA', (76, 90))	('TNM', 'Gene', '10178', (65, 68))	('WAVE3', 'Gene', '10810', (19, 24))	('lymphatic invasion', 'CPA', (95, 113))	('associated', 'Reg', (43, 53))	('ESCC', 'Disease', (117, 121))	('TNM', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
418043	32377706	In cells transfected with miRNA200b mimic, the miRNA200b was overexpressed, WAVE3 protein was downregulated and cell migration ability was decreased.	('WAVE3', 'Gene', '10810', (76, 81))	('cell migration ability', 'CPA', (112, 134))	('downregulated', 'NegReg', (94, 107))	('decreased', 'NegReg', (139, 148))	('miRNA200b', 'Chemical', '-', (47, 56))	('miRNA200b', 'Var', (47, 56))	('WAVE3', 'Gene', (76, 81))	('miRNA200b', 'Chemical', '-', (26, 35))	('overexpressed', 'PosReg', (61, 74))
418044	32377706	The results of the present study suggest that WAVE3 may serve as an oncogene in ESCC, and its inhibition via miRNA200b decreased tumor cell migration.	('decreased tumor', 'Disease', 'MESH:D002303', (119, 134))	('WAVE3', 'Gene', '10810', (46, 51))	('inhibition', 'NegReg', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('miRNA200b', 'Chemical', '-', (109, 118))	('WAVE3', 'Gene', (46, 51))	('decreased tumor', 'Disease', (119, 134))	('ESCC', 'Disease', (80, 84))	('miRNA200b', 'Var', (109, 118))
418053	32377706	Previous studies have indicated that WASP deficiencies can result in abnormal maintenance of morphological structure and cell migration.	('deficiencies', 'Var', (42, 54))	('cell migration', 'CPA', (121, 135))	('WASP', 'Gene', (37, 41))	('WASP', 'Gene', '7454', (37, 41))	('result', 'Reg', (59, 65))
418063	32377706	Sossey-Alaoui et al demonstrated that miRNA200 binds to the 3'-UTR of WAVE3 to inhibit WAVE3 protein expression and influence the progression of tumors, with miRNA200b being identified as the representative member.	('inhibit', 'NegReg', (79, 86))	('WAVE3', 'Gene', '10810', (70, 75))	('miRNA200b', 'Var', (158, 167))	('WAVE3', 'Gene', '10810', (87, 92))	('influence', 'Reg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('miRNA200', 'Var', (38, 46))	('WAVE3', 'Gene', (87, 92))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('WAVE3', 'Gene', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('miRNA200b', 'Chemical', '-', (158, 167))
418064	32377706	The present study aimed to regulate the expression of WAVE3 using miRNA200b, and to further explore the effect of WAVE3 on cell migration ability in ESCC.	('ESCC', 'Disease', (149, 153))	('WAVE3', 'Gene', (54, 59))	('WAVE3', 'Gene', '10810', (114, 119))	('miRNA200b', 'Chemical', '-', (66, 75))	('miRNA200b', 'Var', (66, 75))	('regulate', 'Reg', (27, 35))	('WAVE3', 'Gene', '10810', (54, 59))	('WAVE3', 'Gene', (114, 119))
418066	32377706	A number of studies have also demonstrated that miRNA200 is associated with the regulation of EMT, via the regulation of WAVE3 protein.	('WAVE3', 'Gene', '10810', (121, 126))	('EMT', 'CPA', (94, 97))	('miRNA200', 'Var', (48, 56))	('WAVE3', 'Gene', (121, 126))	('regulation', 'MPA', (107, 117))	('associated', 'Reg', (60, 70))
418069	32377706	miRNA200b mimics were transfected into ESCC cell lines (EC109 and EC1), and the negative regulation of WAVE3 expression via miRNA200b was investigated.	('WAVE3', 'Gene', '10810', (103, 108))	('EC109', 'CellLine', 'CVCL:6898', (56, 61))	('EC1', 'Gene', (66, 69))	('EC1', 'Gene', '4819', (66, 69))	('miRNA200b', 'Chemical', '-', (124, 133))	('miRNA200b', 'Var', (124, 133))	('EC1', 'Gene', (56, 59))	('WAVE3', 'Gene', (103, 108))	('EC1', 'Gene', '4819', (56, 59))	('miRNA200b', 'Chemical', '-', (0, 9))
418083	32377706	Sections with scores >1.5 were considered as WAVE3-positive and sections were scores <=1.5 were considered as WAVE3-negative.	('WAVE3', 'Gene', '10810', (45, 50))	('WAVE3', 'Gene', '10810', (110, 115))	('scores', 'Var', (14, 20))	('WAVE3', 'Gene', (45, 50))	('WAVE3', 'Gene', (110, 115))
418090	32377706	Subsequently, qPCR was performed using the TB Green Premix Taq II reagent kit according to the manufacturer's protocol (Takara Biotechnology Co., Ltd.) to quantify WAVE3 mRNA in serum and miRNA200b in serum and RNA extracted from transfected cells on a LightCycler 480 II Real-Time PCR System (Roche Diagnostics).	('miRNA200b', 'Var', (188, 197))	('TB', 'Chemical', 'MESH:D013725', (43, 45))	('WAVE3', 'Gene', (164, 169))	('WAVE3', 'Gene', '10810', (164, 169))	('miRNA200b', 'Chemical', '-', (188, 197))
418114	32377706	2B, the AUC of WAVE3 was 0.8325 [95% confidence interval (CI); 0.7249-3.9401], which indicated that WAVE3 exhibited a good diagnostic performance.	('WAVE3', 'Gene', '10810', (15, 20))	('WAVE3', 'Gene', (100, 105))	('0.8325', 'Var', (25, 31))	('WAVE3', 'Gene', (15, 20))	('WAVE3', 'Gene', '10810', (100, 105))
418118	32377706	MiRBase was also used to search the putative miRNAs that target WAVE3, and it was indicated that miRNA200b had three potential binding sites in the 3'-UTR of WAVE mRNA (Fig.	('binding', 'Interaction', (127, 134))	('WAVE3', 'Gene', (64, 69))	('miRNA200b', 'Chemical', '-', (97, 106))	('miRNA200b', 'Var', (97, 106))	('WAVE3', 'Gene', '10810', (64, 69))
418119	32377706	miRNA200b expression levels were examined via RT-qPCR and the results suggested that the expression of miRNA200b in ESCC serum was significantly decreased compared with normal serum (P<0.0001; Fig.	('miRNA200b', 'Chemical', '-', (103, 112))	('miRNA200b', 'Var', (103, 112))	('expression', 'MPA', (89, 99))	('ESCC', 'Disease', (116, 120))	('decreased', 'NegReg', (145, 154))	('miRNA200b', 'Chemical', '-', (0, 9))
418120	32377706	Together with the increased level of WAVE3 in ESCC serum compared with the normal group, it was hypothesized that miRNA200b expression is negatively associated with WAVE3 expression.	('expression', 'MPA', (171, 181))	('negatively', 'NegReg', (138, 148))	('WAVE3', 'Gene', (165, 170))	('WAVE3', 'Gene', '10810', (165, 170))	('WAVE3', 'Gene', '10810', (37, 42))	('miRNA200b', 'Var', (114, 123))	('WAVE3', 'Gene', (37, 42))	('miRNA200b', 'Chemical', '-', (114, 123))	('associated', 'Interaction', (149, 159))
418121	32377706	To investigate whether miRNA200b alters the expression of WAVE3, EC109 and EC1 cell lines were transfected with miRNA200b mimics.	('alters', 'Reg', (33, 39))	('EC109', 'CellLine', 'CVCL:6898', (65, 70))	('EC1', 'Gene', (65, 68))	('WAVE3', 'Gene', (58, 63))	('EC1', 'Gene', '4819', (65, 68))	('EC1', 'Gene', '4819', (75, 78))	('miRNA200b', 'Chemical', '-', (112, 121))	('miRNA200b', 'Chemical', '-', (23, 32))	('miRNA200b', 'Var', (23, 32))	('EC1', 'Gene', (75, 78))	('WAVE3', 'Gene', '10810', (58, 63))
418122	32377706	Subsequently, RT-qPCR was performed to analyze the expression of miRNA200b and western blot analysis was used to detect the expression of WAVE3 protein.	('WAVE3', 'Gene', (138, 143))	('miRNA200b', 'Chemical', '-', (65, 74))	('miRNA200b', 'Var', (65, 74))	('WAVE3', 'Gene', '10810', (138, 143))
418123	32377706	Compared with the blank control group and the mimic negative control group, the expression of miRNA200b in the miRNA200b mimic group was increased (Fig.	('miRNA200b', 'Chemical', '-', (111, 120))	('miRNA200b', 'Var', (111, 120))	('miRNA200b', 'Chemical', '-', (94, 103))	('miRNA200b', 'Var', (94, 103))	('increased', 'PosReg', (137, 146))	('expression', 'MPA', (80, 90))
418125	32377706	The results suggested that WAVE3 expression may be inhibited by miRNA200b.	('WAVE3', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))	('inhibited', 'NegReg', (51, 60))	('miRNA200b', 'Chemical', '-', (64, 73))	('miRNA200b', 'Var', (64, 73))	('WAVE3', 'Gene', '10810', (27, 32))
418127	32377706	Therefore, it was hypothesized that high levels of miRNA200b expression may inhibit cell migration.	('miRNA200b', 'Chemical', '-', (51, 60))	('cell migration', 'CPA', (84, 98))	('miRNA200b', 'Var', (51, 60))	('inhibit', 'NegReg', (76, 83))
418128	32377706	Compared with the blank control group and the mimic negative control group, cell migration was decreased in the miRNA200b mimic group (Fig.	('decreased', 'NegReg', (95, 104))	('miRNA200b mimic', 'Var', (112, 127))	('cell migration', 'CPA', (76, 90))	('miRNA200b', 'Chemical', '-', (112, 121))
418129	32377706	Therefore, the results suggest that miRNA200b inhibition of WAVE3 expression decreases ESCC cell migration.	('WAVE3', 'Gene', (60, 65))	('miRNA200b inhibition', 'Var', (36, 56))	('expression', 'MPA', (66, 76))	('decreases ESCC', 'Phenotype', 'HP:0025022', (77, 91))	('ESCC', 'Disease', (87, 91))	('miRNA200b', 'Chemical', '-', (36, 45))	('WAVE3', 'Gene', '10810', (60, 65))	('decreases', 'NegReg', (77, 86))
418139	32377706	Further investigation indicated that the expression of WAVE3 is closely associated with overall survival, survival rate after recurrence, mortality of patients with breast cancer, metastasis and progression.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('WAVE3', 'Gene', '10810', (55, 60))	('breast cancer', 'Disease', (165, 178))	('metastasis', 'Disease', (180, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('survival', 'CPA', (106, 114))	('associated', 'Reg', (72, 82))	('patients', 'Species', '9606', (151, 159))	('mortality', 'Disease', 'MESH:D003643', (138, 147))	('overall survival', 'CPA', (88, 104))	('expression', 'Var', (41, 51))	('WAVE3', 'Gene', (55, 60))	('mortality', 'Disease', (138, 147))
418146	32377706	The results of the present study indicated that the abnormal expression of WAVE3 was associated with tumor stage, infiltration depth and lymphatic invasion.	('WAVE3', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('abnormal', 'Var', (52, 60))	('infiltration depth', 'CPA', (114, 132))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('WAVE3', 'Gene', '10810', (75, 80))	('lymphatic invasion', 'CPA', (137, 155))	('expression', 'MPA', (61, 71))	('associated', 'Reg', (85, 95))
418147	32377706	Yue et al reported high expression of WAVE3 mRNA in the serum of patients with gastric cancer, and revealed that high WAVE3 expression was closely associated with lymph node metastasis, depth of tumor invasion and TNM stage of gastric cancer.	('tumor', 'Disease', (195, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (227, 241))	('TNM', 'Gene', (214, 217))	('WAVE3', 'Gene', (38, 43))	('WAVE3', 'Gene', '10810', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))	('WAVE3', 'Gene', (118, 123))	('expression', 'MPA', (24, 34))	('gastric cancer', 'Disease', (227, 241))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patients', 'Species', '9606', (65, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (227, 241))	('high', 'Var', (113, 117))	('associated', 'Reg', (147, 157))	('lymph node metastasis', 'CPA', (163, 184))	('expression', 'MPA', (124, 134))	('gastric cancer', 'Disease', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('TNM', 'Gene', '10178', (214, 217))	('WAVE3', 'Gene', '10810', (38, 43))
418153	32377706	The present study indicated that miRNA200b was downregulated in the serum of patients with ESCC compared with healthy subjects.	('downregulated', 'NegReg', (47, 60))	('ESCC', 'Disease', (91, 95))	('miRNA200b', 'Chemical', '-', (33, 42))	('miRNA200b', 'Var', (33, 42))	('patients', 'Species', '9606', (77, 85))
418154	32377706	Considering the higher serum level of WAVE3 in patients with ESCC compared with healthy controls, it was hypothesized that miRNA200 expression was negatively associated with WAVE3 expression in patients with ESCC.	('higher', 'PosReg', (16, 22))	('ESCC', 'Disease', (208, 212))	('negatively', 'NegReg', (147, 157))	('serum level', 'MPA', (23, 34))	('patients', 'Species', '9606', (194, 202))	('WAVE3', 'Gene', (174, 179))	('WAVE3', 'Gene', (38, 43))	('patients', 'Species', '9606', (47, 55))	('expression', 'MPA', (180, 190))	('associated', 'Interaction', (158, 168))	('miRNA200', 'Var', (123, 131))	('WAVE3', 'Gene', '10810', (174, 179))	('WAVE3', 'Gene', '10810', (38, 43))
418155	32377706	The results are consistent with a previous study that indicated that WAVE3 is a direct target of miRNA200b, using a luciferase reporter assay.	('miRNA200b', 'Chemical', '-', (97, 106))	('miRNA200b', 'Var', (97, 106))	('WAVE3', 'Gene', (69, 74))	('WAVE3', 'Gene', '10810', (69, 74))
418156	32377706	The ESCC cell lines EC109 and EC1 were transfected with a miRNA200b mimic, and the expression of WAVE3 protein and miRNA200b were determined.	('miRNA200b', 'Chemical', '-', (58, 67))	('WAVE3', 'Gene', '10810', (97, 102))	('EC1', 'Gene', '4819', (20, 23))	('EC1', 'Gene', (20, 23))	('miRNA200b', 'Chemical', '-', (115, 124))	('miRNA200b', 'Var', (115, 124))	('EC1', 'Gene', (30, 33))	('EC109', 'CellLine', 'CVCL:6898', (20, 25))	('WAVE3', 'Gene', (97, 102))	('EC1', 'Gene', '4819', (30, 33))
418157	32377706	The results suggested that higher levels of miRNA200b and lower levels of WAVE3 protein were observed in the miRNA200b mimic group compared with the negative control group, which indicated that exogenous miRNA200b inhibits the expression of WAVE3 protein in ESCC cells.	('lower', 'NegReg', (58, 63))	('miRNA200b', 'Chemical', '-', (204, 213))	('miRNA200b', 'Var', (204, 213))	('WAVE3', 'Gene', '10810', (74, 79))	('expression', 'MPA', (227, 237))	('WAVE3', 'Gene', (241, 246))	('miRNA200b', 'Chemical', '-', (109, 118))	('inhibits', 'NegReg', (214, 222))	('miRNA200b', 'Chemical', '-', (44, 53))	('WAVE3', 'Gene', '10810', (241, 246))	('WAVE3', 'Gene', (74, 79))
418158	32377706	Therefore, it was hypothesized that miRNA200b downregulation may contribute to the upregulation of WAVE3 in ESCC cells; however, the underlying mechanisms require further investigation.	('downregulation', 'NegReg', (46, 60))	('upregulation', 'PosReg', (83, 95))	('WAVE3', 'Gene', (99, 104))	('miRNA200b', 'Chemical', '-', (36, 45))	('miRNA200b', 'Var', (36, 45))	('WAVE3', 'Gene', '10810', (99, 104))
418159	32377706	Previous studies have demonstrated that the expression of WAVE3 is positively correlated with tumor metastasis, such as breast, pancreatic, prostate and colon cancer, and that miRNA200b may inhibit the expression of WAVE3.	('expression', 'MPA', (44, 54))	('inhibit', 'NegReg', (190, 197))	('pancreatic, prostate and colon cancer', 'Disease', 'MESH:D011471', (128, 165))	('colon cancer', 'Phenotype', 'HP:0003003', (153, 165))	('WAVE3', 'Gene', '10810', (216, 221))	('miRNA200b', 'Chemical', '-', (176, 185))	('WAVE3', 'Gene', (216, 221))	('WAVE3', 'Gene', (58, 63))	('miRNA200b', 'Var', (176, 185))	('expression', 'MPA', (202, 212))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('correlated', 'Reg', (78, 88))	('tumor metastasis', 'Disease', 'MESH:D009362', (94, 110))	('tumor metastasis', 'Disease', (94, 110))	('breast', 'Disease', (120, 126))	('WAVE3', 'Gene', '10810', (58, 63))
418160	32377706	In the present study, cells transfected with miRNA200b mimic were used to analyze cell migration.	('cell migration', 'CPA', (82, 96))	('miRNA200b', 'Chemical', '-', (45, 54))	('miRNA200b mimic', 'Var', (45, 60))
418161	32377706	According to the Transwell assay, the number of migratory cells was significantly reduced at 48 h in the miRNA200b mimic group compared with the negative control group, which indicated that cell migration decreased when WAVE3 expression was downregulated.	('WAVE3', 'Gene', '10810', (220, 225))	('number of migratory cells', 'CPA', (38, 63))	('downregulated', 'NegReg', (241, 254))	('cell migration', 'CPA', (190, 204))	('WAVE3', 'Gene', (220, 225))	('decreased', 'NegReg', (205, 214))	('miRNA200b mimic', 'Var', (105, 120))	('reduced', 'NegReg', (82, 89))	('miRNA200b', 'Chemical', '-', (105, 114))
418171	32377706	Furthermore, the expression of WAVE3 was negatively associated with miRNA200b expression.	('miRNA200b', 'Var', (68, 77))	('WAVE3', 'Gene', '10810', (31, 36))	('negatively', 'NegReg', (41, 51))	('expression', 'MPA', (17, 27))	('WAVE3', 'Gene', (31, 36))	('miRNA200b', 'Chemical', '-', (68, 77))
418172	32377706	miRNA200b overexpression decreased the expression of WAVE3 protein, thereby inhibiting the migration of ESCC.	('migration of ESCC', 'CPA', (91, 108))	('WAVE3', 'Gene', (53, 58))	('decreased', 'NegReg', (25, 34))	('WAVE3', 'Gene', '10810', (53, 58))	('inhibiting', 'NegReg', (76, 86))	('expression', 'MPA', (39, 49))	('overexpression', 'PosReg', (10, 24))	('miRNA200b', 'Chemical', '-', (0, 9))	('miRNA200b', 'Var', (0, 9))
418227	31522214	In addition, photons-CSA was associated with significantly higher rates of grade 2 emesis, dysphagia, and myelo-suppression.	('CSA', 'Chemical', '-', (21, 24))	('myelo-suppression', 'Disease', 'MESH:D011596', (106, 123))	('dysphagia', 'Phenotype', 'HP:0002015', (91, 100))	('dysphagia', 'Disease', 'MESH:D003680', (91, 100))	('emesis', 'Phenotype', 'HP:0002013', (83, 89))	('dysphagia', 'Disease', (91, 100))	('photons-CSA', 'Var', (13, 24))	('myelo-suppression', 'Disease', (106, 123))	('higher', 'PosReg', (59, 65))	('grade', 'Disease', (75, 80))
418287	31522214	A small study from Sweden, compromising seven patients with locally advanced rectal cancers (sacrum or pelvic sidewall invasion) with IMRT and PBT (45 Gy to elective lymph nodes, 50 Gy to the primary tumor and 62.5 Gy to boost areas in 25 fractions).	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('patients', 'Species', '9606', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('rectal cancer', 'Phenotype', 'HP:0100743', (77, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('compromising', 'NegReg', (27, 39))	('tumor', 'Disease', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('45 Gy', 'Var', (148, 153))
418333	31000935	High-grade injuries are more likely to develop chronic complications, such as esophageal strictures and gastric outlet obstruction.	('gastric outlet obstruction', 'Disease', (104, 130))	('gastric outlet obstruction', 'Disease', 'MESH:D017219', (104, 130))	('esophageal strictures', 'Phenotype', 'HP:0002043', (78, 99))	('High-grade injuries', 'Var', (0, 19))	('esophageal strictures', 'Disease', (78, 99))	('esophageal stricture', 'Phenotype', 'HP:0002043', (78, 98))
418360	31000935	On the other hand, drugs including quinidine, alendronate, potassium chloride, aspirin, and nonsteroidal anti-inflammatory agents may result in larger areas of ulceration and the development of strictures.	('potassium chloride', 'Chemical', 'MESH:D011189', (59, 77))	('result', 'Reg', (134, 140))	('ulceration', 'MPA', (160, 170))	('quinidine', 'Chemical', 'MESH:D011802', (35, 44))	('strictures', 'MPA', (194, 204))	('aspirin', 'Chemical', 'MESH:D001241', (79, 86))	('quinidine', 'Var', (35, 44))	('alendronate', 'Chemical', 'MESH:D019386', (46, 57))
418377	30774375	In vivo, CTS inhibited tumor growth of EC109 cell in xenograft mice without any obvious effect on body weight.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('mice', 'Species', '10090', (63, 67))	('inhibited', 'NegReg', (13, 22))	('CTS', 'Chemical', 'MESH:C037886', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('EC109', 'CellLine', 'CVCL:6898', (39, 44))	('CTS', 'Var', (9, 12))	('tumor', 'Disease', (23, 28))
418385	30774375	It has been reported that abnormal expression of STAT3 is correlated with the occurrence and development of many cancer types, such as breast cancer, ovarian cancer and colorectal cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('STAT3', 'Gene', (49, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (169, 186))	('expression', 'MPA', (35, 45))	('cancer', 'Disease', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('STAT3', 'Gene', '6774', (49, 54))	('breast cancer', 'Disease', (135, 148))	('colorectal cancer', 'Disease', (169, 186))	('correlated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', (142, 148))	('ovarian cancer', 'Disease', 'MESH:D010051', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (169, 186))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('ovarian cancer', 'Disease', (150, 164))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('ovarian cancer', 'Phenotype', 'HP:0100615', (150, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('abnormal', 'Var', (26, 34))
418390	30774375	These findings indicated that the dysfunction of STAT3 signaling also participated in the modulation of aggravation of esophageal cancer.	('STAT3', 'Gene', (49, 54))	('dysfunction', 'Var', (34, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('STAT3', 'Gene', '6774', (49, 54))	('esophageal cancer', 'Disease', (119, 136))
418431	30774375	As shown in Figure 1A, compared with pancreatic cancer cell lines SW1990 and BXPC3, which are reported as STAT3 signaling overactivated cells, esophageal carcinoma cells exhibited significantly higher levels of p-STAT3 at Tyr705, especially in EC109 cells.	('higher', 'PosReg', (194, 200))	('esophageal carcinoma', 'Disease', (143, 163))	('EC109', 'CellLine', 'CVCL:6898', (244, 249))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (143, 163))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (143, 163))	('BXPC3', 'CellLine', 'CVCL:0186', (77, 82))	('Tyr705', 'Var', (222, 228))	('pancreatic cancer', 'Disease', (37, 54))	('STAT3', 'Gene', '6774', (106, 111))	('SW1990', 'CellLine', 'CVCL:1723', (66, 72))	('STAT3', 'Gene', '6774', (213, 218))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))	('Tyr705', 'Chemical', '-', (222, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('STAT3', 'Gene', (106, 111))	('STAT3', 'Gene', (213, 218))
418446	30774375	As shown in Figure 3, CTS significantly diminishes proliferative activities of both esophageal cancer cell lines in a time- and dose-dependent manner.	('proliferative activities', 'CPA', (51, 75))	('esophageal cancer', 'Disease', (84, 101))	('CTS', 'Chemical', 'MESH:C037886', (22, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('diminishes', 'NegReg', (40, 50))	('CTS', 'Var', (22, 25))
418450	30774375	As described in Figure S2A, CTS dose-dependently increased the proportion of apoptotic cells, which increased from 14.38% in the untreated group to 54.10% in the treated group (20 micromol/L) in EC109 cells, and from 7.33% to 18.14% in CAES17 cells over 24 hours.	('CAES17', 'Chemical', '-', (236, 242))	('CTS', 'Chemical', 'MESH:C037886', (28, 31))	('increased', 'PosReg', (49, 58))	('CTS', 'Var', (28, 31))	('apoptotic cells', 'CPA', (77, 92))	('EC109', 'CellLine', 'CVCL:6898', (195, 200))
418479	30774375	There is growing evidence that CTS inhibits proliferation and growth via the STAT3 signaling pathway in human glioma cells, cholangiocarcinoma cells and gastric cancer cells, among others.	('CTS', 'Chemical', 'MESH:C037886', (31, 34))	('gastric cancer', 'Disease', 'MESH:D013274', (153, 167))	('cholangiocarcinoma', 'Disease', (124, 142))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (124, 142))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('human', 'Species', '9606', (104, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (153, 167))	('STAT3', 'Gene', (77, 82))	('growth', 'CPA', (62, 68))	('inhibits', 'NegReg', (35, 43))	('STAT3', 'Gene', '6774', (77, 82))	('proliferation', 'CPA', (44, 57))	('gastric cancer', 'Disease', (153, 167))	('glioma', 'Disease', (110, 116))	('CTS', 'Var', (31, 34))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (124, 142))
418488	30774375	Our study showed that CTS not only directly inhibits the p-STAT3 level, but also inhibits JAK2-mediated STAT3 phosphorylation during IL-6 stimulation.	('inhibits', 'NegReg', (81, 89))	('STAT3', 'Gene', '6774', (104, 109))	('JAK2', 'Gene', (90, 94))	('STAT3', 'Gene', (104, 109))	('IL-6', 'Gene', (133, 137))	('STAT3', 'Gene', '6774', (59, 64))	('CTS', 'Chemical', 'MESH:C037886', (22, 25))	('IL-6', 'Gene', '3569', (133, 137))	('inhibits', 'NegReg', (44, 52))	('JAK2', 'Gene', '3717', (90, 94))	('STAT3', 'Gene', (59, 64))	('CTS', 'Var', (22, 25))
418494	30774375	In HepG2 cells, CTS inhibits cell proliferation by inducing G1 cell arrest.	('arrest', 'Disease', (68, 74))	('inhibits', 'NegReg', (20, 28))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('inducing', 'Reg', (51, 59))	('CTS', 'Chemical', 'MESH:C037886', (16, 19))	('cell proliferation', 'CPA', (29, 47))	('HepG2', 'CellLine', 'CVCL:0027', (3, 8))	('CTS', 'Var', (16, 19))
418496	30774375	Our study suggests that in ESCC, CTS inhibits cell proliferation by inducing apoptosis and shows no effects on the cell cycle.	('CTS', 'Var', (33, 36))	('apoptosis', 'CPA', (77, 86))	('inducing', 'NegReg', (68, 76))	('CTS', 'Chemical', 'MESH:C037886', (33, 36))	('inhibits', 'NegReg', (37, 45))	('cell proliferation', 'CPA', (46, 64))
418531	30719423	By controlling the FDR and FWER at 0.05, we identified seven significantly differentially expressed miRNAs, including miR-16-5a, miR-92-3a, miR-107, miR-320C, miR-451a, miR-486, and miR-574 (Table 2).	('miR-92-3a', 'Var', (129, 138))	('miR-486', 'Gene', '619554', (169, 176))	('miR-451a', 'Gene', '574411', (159, 167))	('miR-451a', 'Gene', (159, 167))	('miR-107', 'Gene', '406901', (140, 147))	('miR-574', 'Gene', '693159', (182, 189))	('miR-16', 'Gene', (118, 124))	('miR-107', 'Gene', (140, 147))	('miR-16', 'Gene', '51573', (118, 124))	('miR-320C', 'Var', (149, 157))	('miR-486', 'Gene', (169, 176))	('miR-574', 'Gene', (182, 189))
418534	30719423	To obtain a more manageable set of miRNAs, we sacrificed one more cross-validation error and finally identified six miRNAs, including miR-7b-5p, miR-107, miR-16-5p, miR-191-3p, miR-451a, and miR-574-5p, which all had a selection frequency higher than 90%.	('miR-16', 'Gene', (154, 160))	('miR-7b-5p', 'Var', (134, 143))	('miR-107', 'Gene', (145, 152))	('miR-574', 'Gene', '693159', (191, 198))	('miR-191-3p', 'Gene', '100302141', (165, 175))	('cross-validation error', 'Disease', 'MESH:C537866', (66, 88))	('miR-16', 'Gene', '51573', (154, 160))	('miR-574', 'Gene', (191, 198))	('cross-validation error', 'Disease', (66, 88))	('miR-191-3p', 'Gene', (165, 175))	('miR-107', 'Gene', '406901', (145, 152))	('miR-451a', 'Gene', '574411', (177, 185))	('miR-451a', 'Gene', (177, 185))
418536	30719423	The HHSVM and the SESVM identified the same set of six miRNAs as Lasso logistic regression, including miR-7b-5p, miR-107, miR-16-5p, miR-191-3p, miR-451a, and miR-574-5p.	('miR-7b-5p', 'Var', (102, 111))	('miR-574', 'Gene', '693159', (159, 166))	('miR-16', 'Gene', '51573', (122, 128))	('miR-574', 'Gene', (159, 166))	('miR-107', 'Gene', '406901', (113, 120))	('miR-191-3p', 'Gene', (133, 143))	('miR-451a', 'Gene', '574411', (145, 153))	('miR-451a', 'Gene', (145, 153))	('miR-107', 'Gene', (113, 120))	('miR-191-3p', 'Gene', '100302141', (133, 143))	('miR-16', 'Gene', (122, 128))
418570	29152066	Molecular changes associated with gene alterations precede histopathological abnormalities, and may be developed for imaging as an adjunct to endoscopy for early cancer detection.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('gene alterations', 'Var', (34, 50))	('cancer', 'Disease', (162, 168))
418604	29152066	We confirmed these findings using anti-FGFR2 antibody labeled with AF488, Figure 2G-2I.	('AF488', 'Var', (67, 72))	('FGFR2', 'Gene', (39, 44))	('AF488', 'Chemical', '-', (67, 72))	('FGFR2', 'Gene', '2263', (39, 44))
418605	29152066	We quantified our results, and found a significantly greater mean fluorescence intensity for SRR*-Cy5.5 than for control with QhTERT cells that express either FGFR2b or FGFR2c compared with wild-type, Figure 2J.	('FGFR2', 'Gene', (159, 164))	('fluorescence intensity', 'MPA', (66, 88))	('FGFR2', 'Gene', '2263', (159, 164))	('FGFR2', 'Gene', (169, 174))	('FGFR2', 'Gene', '2263', (169, 174))	('QhTERT', 'CellLine', 'CVCL:C451', (126, 132))	('greater', 'PosReg', (53, 60))	('SRR*-Cy5.5', 'Var', (93, 103))	('Cy5.5', 'Chemical', 'MESH:C098793', (98, 103))
418610	29152066	Using flow cytometry, we measured an apparent dissociation constant of kd = 68 nM for binding of SRR*-Cy5.5 to QhTERT cells that express FGFR2c, Figure 3N.	('SRR*-Cy5.5', 'Var', (97, 107))	('FGFR2', 'Gene', (137, 142))	('Cy5.5', 'Chemical', 'MESH:C098793', (102, 107))	('FGFR2', 'Gene', '2263', (137, 142))	('binding', 'Interaction', (86, 93))	('QhTERT', 'CellLine', 'CVCL:C451', (111, 117))
418615	29152066	The mean (+-std) T/B ratio for SRR*-Cy5.5 was significantly higher for HGD and EAC than that for BE and SQ, Figure 4I.	('Cy5.5', 'Chemical', 'MESH:C098793', (36, 41))	('higher', 'PosReg', (60, 66))	('HGD', 'Disease', (71, 74))	('T/B ratio', 'MPA', (17, 26))	('SRR*-Cy5.5', 'Var', (31, 41))	('EAC', 'Disease', (79, 82))
418646	29152066	GP369 is an antibody specific for FGFR2b that exhibits potent anti-tumor activity.	('FGFR2', 'Gene', (34, 39))	('FGFR2', 'Gene', '2263', (34, 39))	('GP369', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('GP369', 'Chemical', '-', (0, 5))
418648	29152066	Tyrosine kinase inhibitors have been shown to decrease survival of gastric cancer cells with FGFR2 amplifications in vitro.	('amplifications', 'Var', (99, 113))	('FGFR2', 'Gene', (93, 98))	('decrease survival of gastric cancer', 'Phenotype', 'HP:0006753', (46, 81))	('FGFR2', 'Gene', '2263', (93, 98))	('gastric cancer', 'Disease', (67, 81))	('survival', 'CPA', (55, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('decrease', 'NegReg', (46, 54))	('Tyrosine kinase inhibitors', 'MPA', (0, 26))
418805	33937056	Opportunities exist for vaccination programs for cervical and liver cancer, genetic testing and use of new targeted therapies for breast and prostate cancer, and positive changes in lifestyle for lung, colorectal and bladder cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))	('bladder cancers', 'Phenotype', 'HP:0009725', (217, 232))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (130, 156))	('liver cancer', 'Phenotype', 'HP:0002896', (62, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (217, 231))	('colorectal and bladder cancers', 'Disease', 'MESH:D001749', (202, 232))	('prostate cancer', 'Phenotype', 'HP:0012125', (141, 156))	('cervical', 'Disease', (49, 57))	('liver cancer', 'Disease', 'MESH:D006528', (62, 74))	('liver cancer', 'Disease', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('genetic', 'Var', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('lung', 'Disease', (196, 200))
418872	33937056	Moreover, several studies have shown that high rates and long histories of consanguinity, observed in some upper income countries in Asia and elsewhere, decrease incidences of breast cancer by decreasing the frequency of mutations on the two major susceptibility genes BRCA1 and BRCA2.	('decreasing', 'NegReg', (193, 203))	('mutations', 'Var', (221, 230))	('BRCA2', 'Gene', (279, 284))	('incidences', 'MPA', (162, 172))	('BRCA1', 'Gene', '672', (269, 274))	('BRCA2', 'Gene', '675', (279, 284))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('BRCA1', 'Gene', (269, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('breast cancer', 'Disease', (176, 189))	('decrease', 'NegReg', (153, 161))
418884	33937056	Medical and biological advances have led to new promising treatments for this cancer that include Radium-223 for bone metastases, pembrolizumab as immunotherapy (PDL1 blocker) for microsatellite instability (MSI) disease, and poly ADP ribose polymerase (PARP) inhibitors for those with mutations in homologous recombination genes, most commonly BRCA2.	('BRCA2', 'Gene', (345, 350))	('men', 'Species', '9606', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('bone metastases', 'Disease', (113, 128))	('mutations', 'Var', (286, 295))	('microsatellite instability (MSI) disease', 'Disease', 'MESH:D053842', (180, 220))	('PARP', 'Gene', (254, 258))	('cancer', 'Disease', (78, 84))	('BRCA2', 'Gene', '675', (345, 350))	('poly ADP ribose polymerase', 'Gene', '142', (226, 252))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('PDL1', 'Gene', '29126', (162, 166))	('pembrolizumab', 'Chemical', 'MESH:C582435', (130, 143))	('poly ADP ribose polymerase', 'Gene', (226, 252))	('PDL1', 'Gene', (162, 166))	('PARP', 'Gene', '142', (254, 258))	('bone metastases', 'Disease', 'MESH:D009362', (113, 128))
418886	33937056	The most common mutations involved in prostate cancer include BRCA1/2; ATM (odds ratio (OR) = 2.18), HoxB13 (OR = 3.23), genes involved in repairing mismatched genes and genes associated with Lynch Syndrome (OR = 4.87), and CHEK2 (OR = 1.98).	('Lynch Syndrome', 'Disease', 'MESH:D003123', (192, 206))	('HoxB13', 'Gene', (101, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('involved', 'Reg', (26, 34))	('BRCA1/2', 'Gene', '672;675', (62, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('ATM', 'Gene', (71, 74))	('CHEK2', 'Gene', '11200', (224, 229))	('Lynch Syndrome', 'Disease', (192, 206))	('mutations', 'Var', (16, 25))	('HoxB13', 'Gene', '10481', (101, 107))	('prostate cancer', 'Disease', (38, 53))	('CHEK2', 'Gene', (224, 229))	('ATM', 'Gene', '472', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mismatched genes', 'Var', (149, 165))	('BRCA1/2', 'Gene', (62, 69))
418949	33937056	Moreover, a family history of gastric cancer, of Lynch syndrome and of familial adenomatous polyposis, and genetic mutations mainly on the CDH1 gene are strong risk factors known to be associated with hereditary stomach cancer.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('associated', 'Reg', (185, 195))	('Lynch syndrome', 'Disease', (49, 63))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (71, 101))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (80, 101))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('Lynch syndrome', 'Disease', 'MESH:D003123', (49, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (30, 44))	('gastric cancer', 'Disease', (30, 44))	('CDH1', 'Gene', (139, 143))	('CDH1', 'Gene', '999', (139, 143))	('hereditary stomach cancer', 'Disease', 'MESH:D013274', (201, 226))	('genetic mutations', 'Var', (107, 124))	('hereditary stomach cancer', 'Disease', (201, 226))	('familial adenomatous polyposis', 'Disease', (71, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (30, 44))	('stomach cancer', 'Phenotype', 'HP:0012126', (212, 226))
418961	33937056	In addition, 5% of colorectal cancer cases may include underlying genetic predispositions from germline disorders such as Lynch syndrome, familial adenomatous polyposis, and mutations on genes involved in the mismatch repair pathway.	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (19, 36))	('familial adenomatous polyposis', 'Disease', (138, 168))	('Lynch syndrome', 'Disease', (122, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (19, 36))	('mutations', 'Var', (174, 183))	('Lynch syndrome', 'Disease', 'MESH:D003123', (122, 136))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (138, 168))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (147, 168))	('colorectal cancer', 'Disease', (19, 36))
418990	33937056	Genetic risk factors associated with bladder cancer include mutations of the retinoblastoma, RB1, gene as well as mutations in PTEN that are also associated with breast and thyroid cancers and Cowden disease.	('mutations', 'Var', (114, 123))	('retinoblastoma', 'Gene', '5925', (77, 91))	('Cowden disease', 'Disease', 'MESH:D006223', (193, 207))	('retinoblastoma', 'Phenotype', 'HP:0009919', (77, 91))	('RB1', 'Gene', (93, 96))	('thyroid cancer', 'Phenotype', 'HP:0002890', (173, 187))	('breast and thyroid cancers', 'Disease', 'MESH:D001943', (162, 188))	('bladder cancer', 'Disease', 'MESH:D001749', (37, 51))	('bladder cancer', 'Disease', (37, 51))	('RB1', 'Gene', '5925', (93, 96))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('PTEN', 'Gene', (127, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))	('retinoblastoma', 'Gene', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('associated', 'Reg', (146, 156))	('mutations', 'Var', (60, 69))	('PTEN', 'Gene', '5728', (127, 131))	('Cowden disease', 'Disease', (193, 207))
419007	33937056	FMTC can occur alone, or it can be seen along with other tumors caused by mutations in the RET gene.	('RET', 'Gene', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (74, 83))	('RET', 'Gene', '5979', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('FMTC', 'Disease', (0, 4))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
419011	33937056	This syndrome is most often caused by mutations in the PTEN gene.	('PTEN', 'Gene', '5728', (55, 59))	('mutations', 'Var', (38, 47))	('PTEN', 'Gene', (55, 59))	('caused by', 'Reg', (28, 37))
419014	33937056	This syndrome is caused by mutations in the PRKAR1A gene.	('mutations', 'Var', (27, 36))	('PRKAR1A', 'Gene', '5573', (44, 51))	('PRKAR1A', 'Gene', (44, 51))	('caused by', 'Reg', (17, 26))
419015	33937056	Familial non medullary thyroid carcinoma: genes on chromosome 19 and chromosome 1 are suspected of causing these familial cancers.	('thyroid carcinoma', 'Disease', 'MESH:D013964', (23, 40))	('non medullary thyroid carcinoma', 'Phenotype', 'HP:0040198', (9, 40))	('familial cancers', 'Disease', (113, 129))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (23, 40))	('thyroid carcinoma', 'Disease', (23, 40))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (13, 40))	('genes', 'Var', (42, 47))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('causing', 'Reg', (99, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('familial cancers', 'Disease', 'MESH:D009369', (113, 129))
419068	33937056	showed that a subset of X-chromosome tumor suppressor genes can escape from X-inactivation that might occur from a gene mutation on one of the X-chromosomes.	('X-chromosome tumor', 'Disease', (24, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutation', 'Var', (120, 128))	('X-chromosome tumor', 'Disease', 'MESH:D009369', (24, 42))
419069	33937056	The authors conclude that biallelic expression of these genes in females explains a portion of the reduced cancer incidence compared to males across a variety of cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('biallelic expression', 'Var', (26, 46))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('reduced', 'NegReg', (99, 106))	('cancer', 'Disease', (107, 113))
419117	33801652	The pre-treatment clinical diagnosis based on TNM staging was cT4aN2M0.	('TNM', 'Gene', (46, 49))	('TNM', 'Gene', '10178', (46, 49))	('cT4aN2M0', 'Var', (62, 70))
419184	33801652	This concern resulted in a delay in the time of NG tube removal and oral intake introduction; (2) increased pleural fluid collection also delayed the chest tube removal; (3) impaired respiratory function hindered proper post-operative physical therapy and recovery; (4) in consequence, the length of hospital stay was prolonged compared to non-complicated cases.	('recovery', 'CPA', (256, 264))	('chest tube removal', 'Disease', 'MESH:D002637', (150, 168))	('prolonged', 'PosReg', (318, 327))	('pleural fluid', 'Phenotype', 'HP:0002202', (108, 121))	('impaired respiratory function', 'Phenotype', 'HP:0002093', (174, 203))	('chest tube removal', 'Disease', (150, 168))	('impaired', 'Var', (174, 182))	('delay', 'NegReg', (27, 32))	('delayed', 'NegReg', (138, 145))	('increased', 'PosReg', (98, 107))	('respiratory function hindered', 'Phenotype', 'HP:0002093', (183, 212))	('hindered', 'NegReg', (204, 212))	('pleural fluid collection', 'MPA', (108, 132))	('respiratory function', 'MPA', (183, 203))
419236	30202417	There was a significant correlation between EGFR/MSI1 mRNA expression, in which mean fold of MSI1 mRNA expression in EGFR underexpressed cases was significantly higher than that in the EGFR overexpressed cases (1.47 +- 0.48 vs. 1.31 +- 0.42, fold changes) (p = 0.05).	('MSI1', 'Gene', (49, 53))	('underexpressed', 'Var', (122, 136))	('MSI1', 'Gene', (93, 97))	('EGFR', 'Gene', (185, 189))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('MSI1', 'Gene', '4440', (49, 53))	('MSI1', 'Gene', '4440', (93, 97))	('EGFR', 'Gene', '1956', (44, 48))	('higher', 'PosReg', (161, 167))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (185, 189))
419242	30202417	In the case of tumor size, the biggest and smallest tumors were observed among patients with EGFR underexpression or MSI1 overexpression and patients with EGFR/MSI1 overexpression, respectively (5.67 +- 3.18 and 3.5 +- 0.58 cm).	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('EGFR', 'Gene', (155, 159))	('MSI1', 'Gene', '4440', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('patients', 'Species', '9606', (141, 149))	('MSI1', 'Gene', (117, 121))	('EGFR', 'Gene', '1956', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('overexpression', 'PosReg', (122, 136))	('smallest tumors', 'Disease', (43, 58))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('EGFR', 'Gene', '1956', (155, 159))	('underexpression', 'Var', (98, 113))	('tumor', 'Disease', (15, 20))	('MSI1', 'Gene', '4440', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('smallest tumors', 'Disease', 'MESH:D009369', (43, 58))	('EGFR', 'Gene', (93, 97))	('MSI1', 'Gene', (160, 164))	('patients', 'Species', '9606', (79, 87))
419253	30202417	Most EGFR alterations in ESCC can be observed by EGFR gene amplification and protein overexpression.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('overexpression', 'PosReg', (85, 99))	('EGFR', 'Gene', '1956', (5, 9))	('protein', 'Protein', (77, 84))	('ESCC', 'Disease', (25, 29))	('EGFR', 'Gene', (5, 9))	('gene amplification', 'Var', (54, 72))	('alterations', 'Reg', (10, 21))
419255	30202417	Deregulation of EGFR plays an important role in tumor progression of lung, breast, gastrointestinal, and liver carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('liver carcinoma', 'Phenotype', 'HP:0001402', (105, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('tumor', 'Disease', (48, 53))	('Deregulation', 'Var', (0, 12))	('lung', 'Disease', (69, 73))	('liver carcinoma', 'Disease', 'MESH:D006528', (105, 120))	('EGFR', 'Gene', '1956', (16, 20))	('liver carcinoma', 'Disease', (105, 120))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('gastrointestinal', 'Disease', (83, 99))	('breast', 'Disease', (75, 81))	('EGFR', 'Gene', (16, 20))
419258	30202417	The promoter sequence of EGFR has several binding sites for NFKB1, which is one of the target genes in the NOTCH pathway; therefore activation of MSI1 may activate the NOTCH pathway via suppression of NUMB and subsequently result in activation of EGFR.	('NFKB1', 'Gene', (60, 65))	('NOTCH pathway', 'Pathway', (168, 181))	('EGFR', 'Gene', (25, 29))	('NUMB', 'Gene', (201, 205))	('MSI1', 'Gene', (146, 150))	('activate', 'PosReg', (155, 163))	('NUMB', 'Gene', '8650', (201, 205))	('suppression', 'NegReg', (186, 197))	('MSI1', 'Gene', '4440', (146, 150))	('NFKB1', 'Gene', '4790', (60, 65))	('activation', 'Var', (132, 142))	('activation', 'PosReg', (233, 243))	('EGFR', 'Gene', '1956', (247, 251))	('EGFR', 'Gene', (247, 251))	('EGFR', 'Gene', '1956', (25, 29))
419306	27172793	Knockdown of AXL expression was shown to inhibit cell proliferation, survival, migration and invasion both in vitro and in vivo.	('migration', 'CPA', (79, 88))	('invasion', 'CPA', (93, 101))	('Knockdown', 'Var', (0, 9))	('AXL', 'Gene', '558', (13, 16))	('survival', 'CPA', (69, 77))	('cell proliferation', 'CPA', (49, 67))	('inhibit', 'NegReg', (41, 48))	('AXL', 'Gene', (13, 16))
419314	27172793	Meanwhile, the AXL inhibitor BMS777607 and HER2 inhibitor lapatinib exhibit a synergistic cytotoxic effect in breast and ovarian cancer cells.	('BMS777607', 'Var', (29, 38))	('BMS777607', 'Chemical', 'MESH:C550356', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lapatinib', 'Chemical', 'MESH:D000077341', (58, 67))	('HER2', 'Gene', (43, 47))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (110, 135))	('HER2', 'Gene', '2064', (43, 47))	('AXL', 'Gene', (15, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('AXL', 'Gene', '558', (15, 18))
419330	27172793	Faint expression of AXL in non-cancerous (normal, 1+, 5.6 % [5/89]) esophageal tissue also significantly correlated with increased risks of death and disease recurrence (HR [95 % CI]=3.63 [1.29-10.29], P=0.015 for OS; HR [95 % CI]=2.72 [1.01-7.33], P=0.048 for PFS, Table 2).	('death and disease', 'Disease', 'MESH:D003643', (140, 157))	('Faint expression', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('AXL', 'Gene', '558', (20, 23))	('non-cancerous', 'Disease', (27, 40))	('AXL', 'Gene', (20, 23))	('non-cancerous', 'Disease', 'MESH:D009369', (27, 40))
419335	27172793	Cumulative analysis of the effects of expression of AXL and HER2 on prognosis revealed that co-expression of AXL and HER2 notably increased the hazards of both death and recurrence by more than 3-fold (HR [95 % CI]=3.43 [1.40-8.42], P=0.007 for OS; HR [95 % CI]=3.19[1.37-7.45], P=0.007 for PFS, Table 2).	('HER2', 'Gene', (117, 121))	('co-expression', 'Var', (92, 105))	('AXL', 'Gene', '558', (109, 112))	('death', 'Disease', 'MESH:D003643', (160, 165))	('AXL', 'Gene', (52, 55))	('death', 'Disease', (160, 165))	('HER2', 'Gene', '2064', (117, 121))	('HER2', 'Gene', (60, 64))	('HER2', 'Gene', '2064', (60, 64))	('AXL', 'Gene', (109, 112))	('increased', 'PosReg', (130, 139))	('AXL', 'Gene', '558', (52, 55))
419337	27172793	Both OS and PFS differed significantly between patients with different levels of AXL expression (median survival time [MST] = 47.8 vs. 13.4 vs. 12.3 vs. 7.7 months in tissues expressing levels 0, 1+, 2+, 3+ of AXL, log-rank P=0.008 for OS, Figure 2A; MST= 33.0 vs. 8.6 vs. 7.5 vs. 7.7 months in tissues expressing levels 0, 1+, 2+, 3+ of AXL, log-rank P=0.040 for PFS, Figure 2B).	('levels 0', 'Var', (186, 194))	('AXL', 'Gene', (338, 341))	('AXL', 'Gene', '558', (81, 84))	('patients', 'Species', '9606', (47, 55))	('AXL', 'Gene', (81, 84))	('AXL', 'Gene', '558', (210, 213))	('AXL', 'Gene', '558', (338, 341))	('AXL', 'Gene', (210, 213))
419340	27172793	Co-expression of AXL and HER2 also increased the risk of recurrence compared to patients with neither AXL nor HER2 expression, however, without reaching statistical significance (OR [95 % CI]=4.11(0.59-28.46), P=0.152, Table 3).	('patients', 'Species', '9606', (80, 88))	('AXL', 'Gene', '558', (102, 105))	('recurrence', 'CPA', (57, 67))	('AXL', 'Gene', '558', (17, 20))	('HER2', 'Gene', (25, 29))	('Co-expression', 'Var', (0, 13))	('HER2', 'Gene', (110, 114))	('AXL', 'Gene', (102, 105))	('HER2', 'Gene', '2064', (25, 29))	('AXL', 'Gene', (17, 20))	('HER2', 'Gene', '2064', (110, 114))
419344	27172793	Co-expression of AXL and HER2 were also associated with an increased incidence of distant metastasis compared to patients with neither AXL nor HER expression (the proportion with no recurrence, local recurrence, and distant metastasis were 1.7 % vs. 16.7 % vs. 41.7% in the AXL (-) and HER2 (-) group and 0 % vs. 25 % vs. 75 % in the AXL (+) and HER2 (+) group, respectively, P=0.012, Table 4).	('HER2', 'Gene', '2064', (286, 290))	('AXL', 'Gene', '558', (274, 277))	('AXL', 'Gene', (334, 337))	('AXL', 'Gene', (135, 138))	('patients', 'Species', '9606', (113, 121))	('HER2', 'Gene', (346, 350))	('AXL', 'Gene', (274, 277))	('AXL', 'Gene', '558', (17, 20))	('Co-expression', 'Var', (0, 13))	('HER2', 'Gene', (25, 29))	('distant metastasis', 'CPA', (82, 100))	('HER2', 'Gene', '2064', (346, 350))	('AXL', 'Gene', '558', (334, 337))	('HER2', 'Gene', '2064', (25, 29))	('AXL', 'Gene', (17, 20))	('AXL', 'Gene', '558', (135, 138))	('HER2', 'Gene', (286, 290))
419374	27172793	Over-expression of AXL increased risk of death (Table 2 and Figure 2), and distant metastasis of ESCC (Table 3 and 4).	('AXL', 'Gene', '558', (19, 22))	('distant metastasis', 'CPA', (75, 93))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('AXL', 'Gene', (19, 22))	('Over-expression', 'Var', (0, 15))	('ESCC', 'Disease', (97, 101))
419394	27172793	The activity of foretinib was demonstrated in a phase II trial in patients with advanced papillary renal cell carcinoma (PRCC), especially in those with germline MET mutations.	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (89, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('PRCC', 'Gene', '5546', (121, 125))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (89, 119))	('PRCC', 'Gene', (121, 125))	('papillary renal cell carcinoma', 'Disease', (89, 119))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (99, 119))	('germline MET mutations', 'Var', (153, 175))	('foretinib', 'Chemical', 'MESH:C544831', (16, 25))	('activity', 'MPA', (4, 12))	('patients', 'Species', '9606', (66, 74))
419414	27172793	Het-1A, a non-tumorigenic primary esophageal squamous cell line, was transformed by SV40 T antigen and was cultured on CellBind dishes (Corning) in BEGM medium (Lonza).	('SV40 T', 'Var', (84, 90))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
419420	27172793	The CE48T/VGH cells, lapatinib-resistant sub-cells and Het-1A cells were plated on 96-well plates (8000 cells/well) and treated with the indicated amounts of AXL inhibitor, foretinib (GSK1363089, provided by Santa Cruz Biotechnology, Inc. SC-364492) or HER2 inhibitors.	('lapatinib', 'Chemical', 'MESH:D000077341', (21, 30))	('AXL', 'Gene', '558', (158, 161))	('HER2', 'Gene', (253, 257))	('GSK1363089', 'Chemical', 'MESH:C544831', (184, 194))	('HER2', 'Gene', '2064', (253, 257))	('foretinib', 'Chemical', 'MESH:C544831', (173, 182))	('CE48T/VGH', 'Var', (4, 13))	('AXL', 'Gene', (158, 161))
419575	26103161	Inhibition of MDM2 expression results in p53 accumulation and activation.	('p53', 'Gene', '7157', (41, 44))	('accumulation', 'PosReg', (45, 57))	('MDM2', 'Gene', '4193', (14, 18))	('Inhibition', 'Var', (0, 10))	('MDM2', 'Gene', (14, 18))	('activation', 'PosReg', (62, 72))	('p53', 'Gene', (41, 44))
419577	26103161	However, when we silenced p53, there were no significant changes in JD-induced apoptosis (S1 Fig).	('silenced', 'Var', (17, 25))	('JD-induced apoptosis', 'CPA', (68, 88))	('p53', 'Gene', (26, 29))	('JD', 'Chemical', 'MESH:C000606573', (68, 70))	('p53', 'Gene', '7157', (26, 29))
419612	25277672	However, three times more people needed to be treated to prevent one death (24 vs. 8) in the 0.12% regression model compared to the 0.42% progression model.	('0.12%', 'Var', (93, 98))	('death', 'Disease', 'MESH:D003643', (69, 74))	('death', 'Disease', (69, 74))	('people', 'Species', '9606', (26, 32))
419648	25277672	Furthermore, the resources required to gain that effectiveness vary considerably when treating all BE: screening and treating of all BE requires up to 3 times more patients to be treated per death prevented in a situation with regression compared to a situation with high progression.	('death', 'Disease', (191, 196))	('regression', 'Var', (227, 237))	('BE', 'Phenotype', 'HP:0100580', (99, 101))	('BE', 'Phenotype', 'HP:0100580', (133, 135))	('patients', 'Species', '9606', (164, 172))	('death', 'Disease', 'MESH:D003643', (191, 196))
419721	25627444	In addition, repairing GT defect after wedge resection with sufficient surgical margin is difficult and complicated; suturing in the direction of the long axis may lead to stenosis of the GT, and suturing in the direction of the short axis may fail to repair with tension of the GT.	('GT', 'Chemical', '-', (188, 190))	('GT defect', 'Disease', 'MESH:D013915', (23, 32))	('lead to', 'Reg', (164, 171))	('GT', 'Chemical', '-', (279, 281))	('suturing', 'Var', (117, 125))	('GT defect', 'Disease', (23, 32))	('stenosis', 'MPA', (172, 180))	('GT', 'Chemical', '-', (23, 25))
419761	25627444	The 2010 Japanese Gastric Cancer Association guidelines for the treatment of submucosal gastric cancer specify the following as extended criteria for curative endoscopic resection: size <=30 mm; differentiated-dominant histology; lack of vessel involvement; and submucosal invasion of <500 mum.	('submucosal gastric cancer', 'Disease', 'MESH:D013274', (77, 102))	('Cancer', 'Disease', 'MESH:D009369', (26, 32))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('differentiated-dominant histology', 'CPA', (195, 228))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('submucosal gastric cancer', 'Phenotype', 'HP:0031498', (77, 102))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (18, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('submucosal gastric cancer', 'Disease', (77, 102))	('submucosal invasion', 'CPA', (262, 281))	('<=30', 'Var', (186, 190))	('Cancer', 'Disease', (26, 32))
419767	25627444	Therefore, even in cT2N0 GTC, a negative SN would reliably indicate the absence of nodal metastases with a high degree of accuracy.	('nodal metastases', 'Disease', (83, 99))	('GT', 'Chemical', '-', (25, 27))	('absence', 'NegReg', (72, 79))	('nodal metastases', 'Disease', 'MESH:D009362', (83, 99))	('cT2N0', 'Var', (19, 24))	('negative', 'NegReg', (32, 40))
419803	19190333	Individuals with deficiencies in telomere maintenance are susceptible to enhanced telomere loss during cell proliferation; such deficiencies could result in telomere dysfunction and genomic instability.	('genomic instability', 'CPA', (182, 201))	('deficiencies', 'Var', (17, 29))	('telomere loss', 'MPA', (82, 95))	('telomere dysfunction', 'Disease', 'MESH:C536801', (157, 177))	('telomere dysfunction', 'Disease', (157, 177))	('deficiencies', 'Var', (128, 140))	('enhanced', 'PosReg', (73, 81))	('result in', 'Reg', (147, 156))
419807	19190333	Shortened telomeres were observed in cancer cells in 44 out 47 (94%) of the tumors examined.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Shortened telomeres', 'Phenotype', 'HP:0031413', (0, 19))	('observed', 'Reg', (25, 33))	('Shortened', 'Var', (0, 9))
419808	19190333	Telomere length in CAFs was significantly associated with chromosomal instability on 4q and 13q, and lymphocytes telomere length was significantly associated with instability on chromosomal arms 15q.	('Telomere length', 'Var', (0, 15))	('associated', 'Reg', (147, 157))	('associated', 'Reg', (42, 52))	('chromosomal instability', 'Phenotype', 'HP:0040012', (58, 81))	('chromosomal instability', 'MPA', (58, 81))	('CAFs', 'Chemical', '-', (19, 23))
419819	19190333	Chromosomal instability caused by dysfunctional telomeres could drive the tumorigenic process by increasing genomic instability, thus resulting in increased mutation rates for oncogenes and tumor suppressor genes.	('oncogenes', 'Gene', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('increased', 'PosReg', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('drive', 'PosReg', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('dysfunctional', 'Var', (34, 47))	('increasing', 'PosReg', (97, 107))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (74, 79))	('genomic instability', 'MPA', (108, 127))	('Chromosomal', 'MPA', (0, 11))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('mutation rates', 'MPA', (157, 171))
419821	19190333	Short telomeres have also been detected in tissue samples taken from patients with Barrett's esophagus (BE), which is associated with an increased risk of esophageal adenocarcinoma.	('detected', 'Reg', (31, 39))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (155, 180))	('Short telomeres', 'Phenotype', 'HP:0031413', (0, 15))	('BE', 'Phenotype', 'HP:0100580', (104, 106))	('Short telomeres', 'Var', (0, 15))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (155, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('patients', 'Species', '9606', (69, 77))	("Barrett's esophagus", 'Disease', (83, 102))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (83, 102))	('esophageal adenocarcinoma', 'Disease', (155, 180))
419824	19190333	Recently, short telomeres in blood leucocytes were reported to predict cancer risk in patients who were diagnosed with Barrett's esophagus.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('predict', 'Reg', (63, 70))	("Barrett's esophagus", 'Disease', (119, 138))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (119, 138))	('cancer', 'Disease', (71, 77))	('short telomeres', 'Var', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('short telomeres', 'Phenotype', 'HP:0031413', (10, 25))	('patients', 'Species', '9606', (86, 94))
419851	19190333	Linear regression was used to analyze the relationship between the LOH frequency on chromosome arms and telomere length, while controlling for age, gender, smoking status, family history of cancer and tumor grade.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('LOH frequency', 'Var', (67, 80))	('telomere', 'MPA', (104, 112))
419868	19190333	Telomere attrition in cancer cells (defined as telomere length in CAFs minus the telomere length in cancer cells) was significantly correlated with LOH frequency on chromosome arms 1p, 6q, 13q and 15q.	('correlated', 'Reg', (132, 142))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('Telomere attrition', 'Disease', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (22, 28))	('CAFs', 'Chemical', '-', (66, 70))	('LOH', 'Var', (148, 151))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
419871	19190333	Telomere attrition in cancer cells was significantly associated with LOH frequency on chromosome arms 5p, 5q, 6q, 15q, 16p, and 16q.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('LOH', 'Var', (69, 72))	('Telomere', 'MPA', (0, 8))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
419872	19190333	These data indicate that significantly longer median telomere length was observed: (i) in CAFs from patients with chromosome instability on 3q, 4p, 4q, 5q, 6q, 10q, 12p, 12q, 13q, 15q, 16q, and 20q; and (ii) in infiltrative lymphocytes from patients with chromosome instability on 4q, 6p, 10q, 12q, 15q, 16p, and 16q.	('chromosome', 'Var', (114, 124))	('chromosome instability', 'Phenotype', 'HP:0040012', (255, 277))	('patients', 'Species', '9606', (100, 108))	('CAFs', 'Chemical', '-', (90, 94))	('chromosome instability', 'Phenotype', 'HP:0040012', (114, 136))	('patients', 'Species', '9606', (241, 249))	('longer', 'PosReg', (39, 45))
419873	19190333	In addition, patients with chromosome instability on 15q, 16p, and 16q showed significantly higher levels of telomere attrition in their tumor cells than in patients without such chromosome arm instability (Table 4).	('higher', 'PosReg', (92, 98))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('patients', 'Species', '9606', (13, 21))	('telomere attrition', 'MPA', (109, 127))	('patients', 'Species', '9606', (157, 165))	('chromosome instability', 'Phenotype', 'HP:0040012', (27, 49))	('levels', 'MPA', (99, 105))	('chromosome instability', 'Var', (27, 49))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
419875	19190333	While multivariate logistic regression found no association between telomere length in cancer cells and chromosomal instability, telomere attrition in cancer cells was found significantly associated with instability for chromosomes 13q and 15q, with adjusted ORs of 6.0 (P = 0.038) and 14.3 (P = 0.025), respectively.	('cancer', 'Disease', (87, 93))	('associated', 'Reg', (188, 198))	('instability', 'MPA', (204, 215))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('chromosomal instability', 'Phenotype', 'HP:0040012', (104, 127))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('telomere attrition', 'Var', (129, 147))
419878	19190333	In the present study, we demonstrated that high level of telomere attrition in cancer cells was significantly associated with specific chromosome arm instabilities in ESCC.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ESCC', 'Disease', (167, 171))	('associated', 'Reg', (110, 120))	('telomere attrition', 'Var', (57, 75))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
419879	19190333	Our findings here are consistent with previous reports that telomere shortening is associated with chromosome instability in ESCC tumors, in Barrett's esophagus, and in tissues taken from patients with ulcerative colitis, which is associated with increased risk of colon cancer.	('chromosome instability', 'Disease', (99, 121))	('patients', 'Species', '9606', (188, 196))	('ulcerative colitis', 'Disease', (202, 220))	('telomere shortening', 'Var', (60, 79))	('colon cancer', 'Disease', 'MESH:D015179', (265, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('chromosome instability', 'Phenotype', 'HP:0040012', (99, 121))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('ESCC tumors', 'Disease', 'MESH:D004938', (125, 136))	('colon cancer', 'Disease', (265, 277))	('ulcerative colitis', 'Disease', 'MESH:D003093', (202, 220))	('telomere shortening', 'Phenotype', 'HP:0031413', (60, 79))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('colitis', 'Phenotype', 'HP:0002583', (213, 220))	('associated', 'Reg', (83, 93))	('colon cancer', 'Phenotype', 'HP:0003003', (265, 277))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (202, 220))	('ESCC tumors', 'Disease', (125, 136))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (141, 160))
419882	19190333	Using a genome-wide scan approach, we discovered that high level telomere attrition in cancer cells was significantly associated with instability on chromosomes 13q and 15q in ESCC.	('ESCC', 'Disease', (176, 180))	('cancer', 'Disease', (87, 93))	('telomere attrition', 'Var', (65, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('associated', 'Reg', (118, 128))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
419883	19190333	Surprisingly, we also found that long telomeres in tumor stroma cells (carcinoma-associated fibroblasts and infiltrative lymphocytes) were significantly associated with instability on chromosomes 4q, 13q and 15q.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('carcinoma', 'Disease', (71, 80))	('tumor stroma', 'Disease', 'MESH:D009369', (51, 63))	('carcinoma', 'Disease', 'MESH:D002277', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('tumor stroma', 'Disease', (51, 63))	('associated', 'Reg', (153, 163))	('long telomeres', 'Var', (33, 47))
419884	19190333	This finding is not entirely consistent with previous reports that short telomeres in epithelial cells/cancer cells are associated with chromosome abnormalities in human cancers.	('chromosome abnormalities in human cancers', 'Disease', 'MESH:D009369', (136, 177))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('associated', 'Reg', (120, 130))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (136, 160))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('short telomeres', 'Phenotype', 'HP:0031413', (67, 82))	('chromosome abnormalities in human cancers', 'Disease', (136, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('short telomeres', 'Var', (67, 82))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
419899	19190333	A recent study compared telomere length between normal breast epithelium, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) from 18 patients and found that the shortening of telomeres on chromosome 17q is greater than the average shortening of all telomeres.	('shortening of telomeres', 'Phenotype', 'HP:0031413', (179, 202))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (74, 98))	('ductal carcinoma in situ', 'Disease', (74, 98))	('shortening', 'NegReg', (179, 189))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (74, 90))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (120, 136))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (74, 98))	('invasive ductal carcinoma', 'Disease', (111, 136))	('patients', 'Species', '9606', (151, 159))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('telomeres', 'Var', (193, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (111, 136))
420082	10036123	In nine of the 13 patients with esophageal cancer, the number of positive lymph nodes detected was increased by RT-PCR compared to histology.	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('RT-PCR', 'Var', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('increased', 'PosReg', (99, 108))	('patients', 'Species', '9606', (18, 26))	('esophageal cancer', 'Disease', (32, 49))
420106	20809956	Bmi-1 overexpression leads to activation of human telomerase reverse transcriptase transcription and induction of telomerase activity in immortalized mammary epithelial cells.	('human', 'Species', '9606', (44, 49))	('telomerase activity', 'MPA', (114, 133))	('overexpression', 'Var', (6, 20))	('activation', 'PosReg', (30, 40))	('Bmi-1', 'Gene', '648', (0, 5))	('human', 'MPA', (44, 49))	('Bmi-1', 'Gene', (0, 5))
420108	20809956	A recent report has shown that Bmi-1 autoantibodies were newly potential biomarkers of nasopharyngeal cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (87, 108))	('autoantibodies', 'Var', (37, 51))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (87, 108))	('Bmi-1', 'Gene', (31, 36))	('Bmi-1', 'Gene', '648', (31, 36))	('nasopharyngeal cancer', 'Disease', (87, 108))
420188	20809956	Patients with tumors exhibiting high Bmi-1 expression had significantly shorter overall survival compared with patients with low expression of Bmi-1 in the T3-T4 subgroup (n = 112; log-rank, P = 0.015; Fig.	('high', 'Var', (32, 36))	('Bmi-1', 'Gene', '648', (37, 42))	('shorter', 'NegReg', (72, 79))	('overall survival', 'MPA', (80, 96))	('Bmi-1', 'Gene', (37, 42))	('expression', 'Var', (43, 53))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Bmi-1', 'Gene', '648', (143, 148))	('Patients', 'Species', '9606', (0, 8))	('Bmi-1', 'Gene', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('patients', 'Species', '9606', (111, 119))
420192	20809956	The mean (SD) absorbance ratio was 0.128 (0.060) in sera from control (n = 102) and 0.228 (0.085) in sera from esophageal cancer patients (n = 159) (Fig.	('patients', 'Species', '9606', (129, 137))	('esophageal cancer', 'Disease', (111, 128))	('0.228', 'Var', (84, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
420194	20809956	The cutoff for positive antibody reactivity against Bmi-1 was 0.248, which was defined as an absorbance greater than 2 SDs above the mean value of the control.	('Bmi-1', 'Gene', '648', (52, 57))	('SDs', 'Chemical', 'MESH:D012967', (119, 122))	('Bmi-1', 'Gene', (52, 57))	('0.248', 'Var', (62, 67))
420200	20809956	Bmi-1 antibodies were also significantly much prevalent in patients with lymph node metastasis than those in patients without lymph node metastasis.	('patients', 'Species', '9606', (109, 117))	('prevalent', 'Reg', (46, 55))	('lymph node metastasis', 'Disease', (73, 94))	('Bmi-1', 'Gene', '648', (0, 5))	('antibodies', 'Var', (6, 16))	('Bmi-1', 'Gene', (0, 5))	('patients', 'Species', '9606', (59, 67))
420222	20809956	In addition, we found that in subgroup of patient with T classification as T3-T4 or N classification as N1, higher Bmi-1 expression also indicated a shorter overall survival time.	('Bmi-1', 'Gene', (115, 120))	('overall survival time', 'CPA', (157, 178))	('expression', 'MPA', (121, 131))	('patient', 'Species', '9606', (42, 49))	('shorter', 'NegReg', (149, 156))	('T3-T4', 'Var', (75, 80))	('higher', 'PosReg', (108, 114))	('Bmi-1', 'Gene', '648', (115, 120))
420227	20809956	It indicates that Bmi-1 antibodies are more prevalent in sera from patients with later stage tumor than in sera from patients with early stage tumor.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (143, 148))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Disease', (93, 98))	('antibodies', 'Var', (24, 34))	('patients', 'Species', '9606', (117, 125))	('Bmi-1', 'Gene', '648', (18, 23))	('Bmi-1', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('prevalent', 'Reg', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
420239	32922554	Long non-coding RNAs (lncRNAs) have increasingly been associated with tumor biomarkers for diagnosis and prognosis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('Long non-coding RNAs', 'Var', (0, 20))	('associated', 'Reg', (54, 64))
420265	32922554	DUXAP8, a pseudogene derived from lncRNA, promotes growth of pancreatic carcinoma cells by epigenetically silencing CDKN1A and KLF2.	('CDKN1A', 'Gene', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('DUXAP8', 'Gene', (0, 6))	('CDKN1A', 'Gene', '1026', (116, 122))	('growth', 'CPA', (51, 57))	('DUXAP8', 'Gene', '503637', (0, 6))	('promotes', 'PosReg', (42, 50))	('KLF2', 'Gene', '10365', (127, 131))	('pancreatic carcinoma', 'Disease', (61, 81))	('KLF2', 'Gene', (127, 131))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (61, 81))	('epigenetically silencing', 'Var', (91, 115))
420270	32922554	DUXAP8 knockdown resulted in clear cell cycle arrest at the G0/G1 phase.	('DUXAP8', 'Gene', (0, 6))	('DUXAP8', 'Gene', '503637', (0, 6))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('arrest', 'Disease', (46, 52))	('knockdown', 'Var', (7, 16))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (35, 52))
420308	32922554	Also, combination of DUXAP8 and RNF2 showed better prognostic value than individual effects (crude p<0.0001; adjusted p=0.001; Figure 5L, Table 3).	('RNF2', 'Gene', '6045', (32, 36))	('DUXAP8', 'Gene', (21, 27))	('combination', 'Var', (6, 17))	('DUXAP8', 'Gene', '503637', (21, 27))	('prognostic', 'MPA', (51, 61))	('RNF2', 'Gene', (32, 36))
420322	32922554	Then, we further validated the potential significance of PCGs in HCC using HCCDB and oncomine databases.	('PCGs', 'Chemical', '-', (57, 61))	('HCCDB', 'Chemical', '-', (75, 80))	('PCGs', 'Var', (57, 61))	('oncomine', 'Chemical', '-', (85, 93))	('HCC', 'Disease', (65, 68))
420332	32922554	Dysregulation of lncRNAs may alter development of tumors.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('Dysregulation', 'Var', (0, 13))	('lncRNAs', 'Protein', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('alter', 'Reg', (29, 34))
420339	32922554	It has been reported that DUXAP8 enhances GC cell proliferation and tumorigenesis, partly by epigenetically silencing PLEKHO1 expression through binding to PRC2, making it a potential biomarker for GC diagnosis and therapy.	('tumor', 'Disease', (68, 73))	('GC cell proliferation', 'CPA', (42, 63))	('expression', 'MPA', (126, 136))	('PLEKHO1', 'Gene', '51177', (118, 125))	('enhances', 'PosReg', (33, 41))	('binding', 'Interaction', (145, 152))	('DUXAP8', 'Gene', '503637', (26, 32))	('PRC2', 'Gene', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('PLEKHO1', 'Gene', (118, 125))	('epigenetically silencing', 'Var', (93, 117))	('rat', 'Species', '10116', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('DUXAP8', 'Gene', (26, 32))
420342	32922554	This accelerates cell proliferation and tumorigenesis, partly by epigenetically silencing transcription of CDKN1A and KLF2, and by binding to EZH2 and LSD1 .	('LSD1', 'Gene', '23028', (151, 155))	('accelerates', 'PosReg', (5, 16))	('cell proliferation', 'CPA', (17, 35))	('KLF2', 'Gene', '10365', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('rat', 'Species', '10116', (29, 32))	('epigenetically silencing', 'Var', (65, 89))	('EZH2', 'Gene', (142, 146))	('EZH2', 'Gene', '2146', (142, 146))	('KLF2', 'Gene', (118, 122))	('CDKN1A', 'Gene', (107, 113))	('transcription', 'MPA', (90, 103))	('binding', 'Interaction', (131, 138))	('rat', 'Species', '10116', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('CDKN1A', 'Gene', '1026', (107, 113))	('LSD1', 'Gene', (151, 155))
420353	32922554	It has been reported that knockdown of DUXAP8 resulted in clear cell cycle arrest in the G0/G1 phase ini non-small lung cancer cell lines, H1299, and H1975, which further decreased cyclin D1, CDK2, CDK4 and CDK6 expression in cell cycle process.	('CDK2', 'Gene', '1017', (192, 196))	('DUXAP8', 'Gene', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('CDK4', 'Gene', '1019', (198, 202))	('small lung', 'Phenotype', 'HP:0002089', (109, 119))	('CDK6', 'Gene', (207, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cell cycle process', 'CPA', (226, 244))	('CDK2', 'Gene', (192, 196))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('cyclin D1', 'Gene', (181, 190))	('arrest', 'Disease', (75, 81))	('H1299', 'CellLine', 'CVCL:0060', (139, 144))	('cyclin D1', 'Gene', '595', (181, 190))	('knockdown', 'Var', (26, 35))	('lung cancer', 'Disease', (115, 126))	('decreased', 'NegReg', (171, 180))	('H1975', 'Var', (150, 155))	('CDK4', 'Gene', (198, 202))	('expression', 'MPA', (212, 222))	('arrest', 'Disease', 'MESH:D006323', (75, 81))	('DUXAP8', 'Gene', '503637', (39, 45))	('H1975', 'CellLine', 'CVCL:1511', (150, 155))	('CDK6', 'Gene', '1021', (207, 211))
420365	32922554	The study also suggested that bumetanide slows down tumor growth by interfering with the cell cycle rather than by inducing cytotoxicity.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cytotoxicity', 'Disease', 'MESH:D064420', (124, 136))	('tumor', 'Disease', (52, 57))	('bumetanide', 'Chemical', 'MESH:D002034', (30, 40))	('cytotoxicity', 'Disease', (124, 136))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('interfering', 'NegReg', (68, 79))	('slows down', 'NegReg', (41, 51))	('bumetanide', 'Var', (30, 40))	('rat', 'Species', '10116', (100, 103))	('cell cycle', 'CPA', (89, 99))
420380	32922554	Therefore, we speculate that SNF2 is an oncogene in HCC A recent study showed that downregulation of SNF2, a co-expression-related gene of DUXAP8, decreases cell growth and metastases of HCC cells..	('decreases', 'NegReg', (147, 156))	('metastases', 'Disease', (173, 183))	('SNF2', 'Gene', (101, 105))	('downregulation', 'Var', (83, 97))	('SNF2', 'Gene', '6597', (101, 105))	('SNF2', 'Gene', (29, 33))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('DUXAP8', 'Gene', (139, 145))	('DUXAP8', 'Gene', '503637', (139, 145))	('SNF2', 'Gene', '6597', (29, 33))
420408	32158268	Previous studies have shown that high levels of FFA can promote the occurrence and development of a variety of tumors.	('men', 'Species', '9606', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('FFA', 'Protein', (48, 51))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('occurrence', 'CPA', (68, 78))	('high levels', 'Var', (33, 44))	('promote', 'PosReg', (56, 63))	('FFA', 'Chemical', 'MESH:D005230', (48, 51))
420438	32158268	Triglycerides Assay Kit (F001-1-1)/Total cholesterol Assay Kit (F002-1-1)/High density lipoprotein cholesterol Assay Kit (F003-1-1) from Nanjing Jiancheng Bioengineering Institute, China, was used to detect the concentration of TG/TC/HDL in the PCa cells.	('PCa', 'Phenotype', 'HP:0012125', (245, 248))	('cholesterol', 'Chemical', 'MESH:D002784', (99, 110))	('TC', 'Chemical', 'MESH:D013667', (231, 233))	('TG/TC/HDL', 'Var', (228, 237))	('TG', 'Chemical', '-', (228, 230))	('cholesterol', 'Chemical', 'MESH:D002784', (41, 52))	('PCa', 'Disease', (245, 248))	('Triglycerides', 'Chemical', 'MESH:D014280', (0, 13))	('PCa', 'Disease', 'MESH:D011471', (245, 248))
420448	32158268	Membranes were incubated at 4 C overnight with antibodies to beta-actin (36 kDa; Zhongshan Jinqiao, China) and PPARgamma (58kDa; Abcam), at a working ratio of 1:1000.	('beta-actin', 'Gene', (61, 71))	('beta-actin', 'Gene', '728378', (61, 71))	('36 kDa', 'Var', (73, 79))
420479	32158268	The tumor volume and weight in HFD group (n = 9) are higher than the NC group (n = 3).	('tumor', 'Disease', (4, 9))	('HFD', 'Var', (31, 34))	('higher', 'PosReg', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
420487	32158268	Moreover, Omega-3 polyunsaturated fatty acids can induce apoptosis of breast cancer cells, and eicosapentaenoic acid can inhibit metastasis of colorectal cancer cells by inhibiting PGE-dependent cell movement.	('inhibit', 'NegReg', (121, 128))	('eicosapentaenoic acid', 'Chemical', 'MESH:D015118', (95, 116))	('Omega-3 polyunsaturated fatty acids', 'Chemical', '-', (10, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('induce', 'PosReg', (50, 56))	('colorectal cancer', 'Disease', (143, 160))	('eicosapentaenoic acid', 'Var', (95, 116))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('inhibiting', 'NegReg', (170, 180))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))	('apoptosis', 'CPA', (57, 66))	('PGE', 'Chemical', 'MESH:D011458', (181, 184))	('men', 'Species', '9606', (204, 207))	('metastasis', 'CPA', (129, 139))	('PGE-dependent cell movement', 'CPA', (181, 208))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
420504	32158268	After treatment of esophageal cancer cells with PPAR-gamma antagonist GW9662, the cell proliferation ability is significantly enhanced Similarly, Srivastava et al found that patients with high expression of PPARgamma in lung cancer have higher survival rates, suggesting that PPARgamma has an antitumor effect in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (313, 324))	('cell proliferation ability', 'CPA', (82, 108))	('higher', 'PosReg', (237, 243))	('lung cancer', 'Phenotype', 'HP:0100526', (313, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Disease', (297, 302))	('esophageal cancer', 'Disease', 'MESH:D004938', (19, 36))	('PPAR-gamma', 'Gene', '5468', (48, 58))	('high', 'Var', (188, 192))	('lung cancer', 'Disease', (220, 231))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('esophageal cancer', 'Disease', (19, 36))	('survival rates', 'CPA', (244, 258))	('PPARgamma', 'Gene', (207, 216))	('lung cancer', 'Disease', (313, 324))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('PPAR-gamma', 'Gene', (48, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('patients', 'Species', '9606', (174, 182))	('men', 'Species', '9606', (11, 14))
420507	32158268	It is worth noting that although some literatures have suggested that PPARgamma has potential to modulate NF-kappaB activity and oxidative stress in E2-deprived breast cancer cell lines and anti-PPARgamma therapy is a novel strategy to improve the therapeutic effects of E2-induced apoptosis in E2-deprived breast cancer.	('modulate', 'Reg', (97, 105))	('E2-deprived breast cancer', 'Disease', 'MESH:D001943', (149, 174))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('oxidative stress', 'Phenotype', 'HP:0025464', (129, 145))	('E2-deprived breast cancer', 'Disease', (295, 320))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('E2-deprived breast cancer', 'Disease', 'MESH:D001943', (295, 320))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('anti-PPARgamma', 'Var', (190, 204))	('NF-kappaB', 'Protein', (106, 115))	('E2-deprived breast cancer', 'Disease', (149, 174))	('activity', 'MPA', (116, 124))	('oxidative', 'MPA', (129, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (307, 320))
420508	32158268	However, most studies have pointed out that PPARgamma has an antitumor effect in breast cancer.	('PPARgamma', 'Var', (44, 53))	('breast cancer', 'Disease', (81, 94))	('tumor', 'Disease', (65, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
420520	32158268	Consequently, our results showed that PPARgamma could promote the mRNA expression level of vimentin, while it could be reversed by the downregulation of PPARgamma.	('promote', 'PosReg', (54, 61))	('PPARgamma', 'Var', (38, 47))	('vimentin', 'Gene', '7431', (91, 99))	('mRNA expression level', 'MPA', (66, 87))	('vimentin', 'Gene', (91, 99))
420524	32158268	Previous literature has shown that PPARgamma can promote the ability of proliferation and invasion by upregulating VEGF-A expression in PCa cells.	('upregulating', 'PosReg', (102, 114))	('expression', 'MPA', (122, 132))	('PCa', 'Disease', (136, 139))	('PCa', 'Disease', 'MESH:D011471', (136, 139))	('proliferation', 'CPA', (72, 85))	('PPARgamma', 'Var', (35, 44))	('PCa', 'Phenotype', 'HP:0012125', (136, 139))	('VEGF-A', 'Gene', (115, 121))	('promote', 'PosReg', (49, 56))	('invasion', 'CPA', (90, 98))
420583	31633107	Despite the controversy and lack of consensus about the role of GV primary prophylaxis, Mishra and colleagues described a 2-year probability of bleeding of 13% in those patients with IGV1 and GOV2 treated with endoscopic injection of cyanoacrylate compared with 45% in those patients in whom no intervention was instituted and 28% in those taking beta-blockers.	('GOV', 'Phenotype', 'HP:0002040', (192, 195))	('patients', 'Species', '9606', (169, 177))	('GOV2', 'Var', (192, 196))	('GV', 'Phenotype', 'HP:0030169', (64, 66))	('GV', 'Phenotype', 'HP:0030169', (184, 186))	('IGV1', 'Gene', (183, 187))	('bleeding', 'Disease', 'MESH:D006470', (144, 152))	('cyanoacrylate', 'Chemical', 'MESH:D003487', (234, 247))	('patients', 'Species', '9606', (275, 283))	('bleeding', 'Disease', (144, 152))
420609	31097977	Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('associated to', 'Reg', (146, 159))	('malignant progression', 'CPA', (160, 181))	('aberrant', 'Var', (17, 25))	('lignan', 'Chemical', 'MESH:D017705', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('advantage', 'PosReg', (113, 122))	('NRF2', 'Gene', (56, 60))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('activation', 'PosReg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('accumulation', 'PosReg', (40, 52))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
420614	31097977	In this regard, not only fluctuations in the nutrient/oxygen availability but also the presence of electrophiles or xenobiotics can induce alterations in the redox balance and promote cell death by damaging essential macromolecules such as lipids, proteins, and DNA, particularly susceptible to reactive oxygen species (ROS).	('essential macromolecules', 'MPA', (207, 231))	('oxygen', 'Chemical', 'MESH:D010100', (304, 310))	('induce alterations', 'Reg', (132, 150))	('oxygen', 'Chemical', 'MESH:D010100', (54, 60))	('proteins', 'Protein', (248, 256))	('promote', 'PosReg', (176, 183))	('presence', 'Var', (87, 95))	('lipids', 'Chemical', 'MESH:D008055', (240, 246))	('damaging', 'Reg', (198, 206))	('redox balance', 'MPA', (158, 171))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (295, 318))	('ROS', 'Chemical', 'MESH:D017382', (320, 323))	('lipids', 'MPA', (240, 246))	('rat', 'Species', '10116', (143, 146))	('cell death', 'CPA', (184, 194))
420628	31097977	Among them, Cys151, located within the BTB domain, was found to facilitate NRF2 activation, while Cys273, 288, and 297, located in the IVR, were found to suppress NRF2 activity facilitating its interaction with KEAP1 (see Figure 1(b)).	('activity', 'MPA', (168, 176))	('NRF2', 'Enzyme', (75, 79))	('Cys273', 'Chemical', '-', (98, 104))	('Cys151', 'Var', (12, 18))	('BTB', 'Chemical', '-', (39, 42))	('Cys151', 'Chemical', '-', (12, 18))	('interaction', 'Interaction', (194, 205))	('NRF2', 'Enzyme', (163, 167))	('suppress', 'NegReg', (154, 162))	('Cys273', 'Var', (98, 104))	('facilitate', 'PosReg', (64, 74))	('activation', 'PosReg', (80, 90))
420629	31097977	Similarly, seven highly conserved and redox-sensitive cysteines (Cys119, 235, 311, 316, 414, and 516) have been identified in NRF2 and their oxidative modification was found to prevent KEAP1 recognition and binding.	('cysteines', 'Chemical', 'MESH:D003545', (54, 63))	('Cys119', 'Chemical', '-', (65, 71))	('Cys119', 'Var', (65, 71))	('KEAP1', 'Protein', (185, 190))	('recognition', 'Interaction', (191, 202))	('binding', 'Interaction', (207, 214))	('oxidative modification', 'MPA', (141, 163))	('prevent', 'NegReg', (177, 184))	('NRF2', 'Gene', (126, 130))
420637	31097977	In the following sections, we will discuss the oncogenic alterations in the NRF2/KEAP1 pathway that confer a selective advantage to malignant cells and their relevance as therapeutic targets in the treatment of cancer.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('lignan', 'Chemical', 'MESH:D017705', (134, 140))	('alterations', 'Var', (57, 68))	('rat', 'Species', '10116', (61, 64))	('NRF2/KEAP1', 'Gene', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
420638	31097977	The molecular events that lead to cancer initiation, promotion, and progression are characterized by genetic and epigenetic changes in oncogenes and tumor suppressors that control key biological events related to cell proliferation, survival, and metabolism.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('oncogenes', 'Gene', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('rat', 'Species', '10116', (225, 228))	('epigenetic changes', 'Var', (113, 131))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer initiation', 'Disease', 'MESH:D009369', (34, 51))	('tumor', 'Disease', (149, 154))	('cancer initiation', 'Disease', (34, 51))	('changes', 'Var', (124, 131))
420641	31097977	In this regard, despite that initial studies recognized its chemopreventive function in carcinogenesis and its cytoprotective role in many human pathologies, growing evidence also indicates that aberrant activation of the NRF2/KEAP1 pathway is frequently found in many tumors, promoting cancer growth, survival, metastasis formation, and therapy resistance.	('activation', 'PosReg', (204, 214))	('carcinogenesis', 'Disease', (88, 102))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('aberrant', 'Var', (195, 203))	('metastasis formation', 'CPA', (312, 332))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('therapy resistance', 'CPA', (338, 356))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('NRF2/KEAP1 pathway', 'Pathway', (222, 240))	('tumors', 'Disease', (269, 275))	('promoting', 'PosReg', (277, 286))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('human', 'Species', '9606', (139, 144))	('survival', 'CPA', (302, 310))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))
420642	31097977	The occurrence of genetic mutations in the NRF2, KEAP1, or CUL3 genes represents the most frequent and well-characterized mechanism of sustained NRF2 activation in cancer (see Figure 3(a)).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('activation', 'PosReg', (150, 160))	('CUL3', 'Gene', '8452', (59, 63))	('CUL3', 'Gene', (59, 63))	('NRF2', 'Gene', (145, 149))	('KEAP1', 'Gene', (49, 54))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('NRF2', 'Gene', (43, 47))	('genetic mutations', 'Var', (18, 35))
420643	31097977	In this regard, loss-of-function (LOF) mutations in the KEAP1 gene, targeting the Kelch/DGR domain, normally required for NRF2 interaction and degradation, were initially identified in tissues or cell lines derived from lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('patients', 'Species', '9606', (232, 240))	('lung cancer', 'Disease', (220, 231))	('mutations', 'Var', (39, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('KEAP1', 'Gene', (56, 61))	('loss-of-function', 'NegReg', (16, 32))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
420644	31097977	These observations were confirmed in subsequent studies reporting that the biallelic inactivation of KEAP1 caused by somatic mutations in the Kelch domain or in the IVR region was a frequent event in non-small-cell lung carcinoma (NSCLC).	('mutations in', 'Var', (125, 137))	('small-cell lung carcinoma', 'Disease', (204, 229))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (204, 229))	('NSCLC', 'Phenotype', 'HP:0030358', (231, 236))	('biallelic', 'Var', (75, 84))	('NSCLC', 'Disease', (231, 236))	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (204, 229))	('NSCLC', 'Disease', 'MESH:D002289', (231, 236))	('KEAP1', 'Gene', (101, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (200, 229))
420645	31097977	Indeed, LOF mutations in KEAP1 gene were, respectively, found in 50% (6/12) or 19% (10/54) of the cancer cell lines or cancer samples analyzed, while loss of heterozygosity at 19p13.2, the genetic locus of KEAP1, occurred at frequencies of 61% and 41% in NSCLC-derived cell lines and tumor tissues, respectively.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('NSCLC', 'Disease', (255, 260))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('NSCLC', 'Disease', 'MESH:D002289', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (98, 104))	('KEAP1', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))	('tumor', 'Disease', (284, 289))	('LOF', 'NegReg', (8, 11))
420647	31097977	Additional research further expanded the list of KEAP1 mutations in several cohorts of patients with different subtypes of lung cancer, pointing out the existence of widely distributed alterations beyond the DGR and the IVR motifs of the KEAP1 protein.	('mutations', 'Var', (55, 64))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('KEAP1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('patients', 'Species', '9606', (87, 95))	('rat', 'Species', '10116', (189, 192))	('alterations', 'Reg', (185, 196))
420648	31097977	Consistently, all these alterations produced typical clinicopathological features associated with increased NRF2 activity, therapy resistance, and poor prognosis, suggesting that the genetic status of KEAP1 might be used to stratify NSCLC patients and select personalized therapeutic options.	('NSCLC', 'Disease', (233, 238))	('alterations', 'Var', (24, 35))	('NSCLC', 'Disease', 'MESH:D002289', (233, 238))	('patients', 'Species', '9606', (239, 247))	('NRF2', 'Protein', (108, 112))	('therapy resistance', 'CPA', (123, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (233, 238))	('increased', 'PosReg', (98, 107))	('activity', 'MPA', (113, 121))	('rat', 'Species', '10116', (226, 229))	('KEAP1', 'Gene', (201, 206))	('rat', 'Species', '10116', (28, 31))
420652	31097977	Notably, KEAP1 missense or nonsense mutations have also been reported in malignant melanoma and hepatocellular, papillary thyroid, and endometrial carcinomas as well as gall bladder, breast, cervical, and ovarian cancers.	('KEAP1', 'Gene', (9, 14))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (135, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (205, 219))	('ovarian cancers', 'Disease', (205, 220))	('nonsense mutations', 'Var', (27, 45))	('ovarian cancers', 'Disease', 'MESH:D010051', (205, 220))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (135, 157))	('papillary thyroid', 'Disease', (112, 129))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('malignant melanoma', 'Phenotype', 'HP:0002861', (73, 91))	('malignant melanoma', 'Disease', 'MESH:D008545', (73, 91))	('cervical', 'Disease', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('gall bladder', 'Disease', 'MESH:D005705', (169, 181))	('hepatocellular', 'Disease', (96, 110))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('ovarian cancers', 'Phenotype', 'HP:0100615', (205, 220))	('endometrial carcinomas', 'Disease', (135, 157))	('breast', 'Disease', (183, 189))	('malignant melanoma', 'Disease', (73, 91))	('gall bladder', 'Disease', (169, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('reported', 'Reg', (61, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
420653	31097977	As concerning the NRF2 gene, mutations in the DLG/ETGE motifs of the Neh2 domain resulting in decreased KEAP1 binding were also initially identified in biopsies and cell lines from lung cancer.	('NRF2', 'Gene', (18, 22))	('Neh2', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mutations', 'Var', (29, 38))	('lung cancer', 'Disease', (181, 192))	('KEAP1', 'MPA', (104, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('decreased', 'NegReg', (94, 103))	('Neh2', 'Gene', '252969', (69, 73))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
420654	31097977	A similar pattern of NRF2 mutations was also observed in head and neck carcinoma, hepatocellular carcinoma, and papillary renal cell carcinoma (PRCC) as well as esophageal and skin cancers, resulting in increased malignant potential and chemoresistance.	('NRF2', 'Gene', (21, 25))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('papillary renal cell carcinoma', 'Disease', (112, 142))	('mutations', 'Var', (26, 35))	('skin cancers', 'Disease', (176, 188))	('PRCC', 'Gene', '5546', (144, 148))	('increased', 'PosReg', (203, 212))	('skin cancers', 'Disease', 'MESH:D012878', (176, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (122, 142))	('observed', 'Reg', (45, 53))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (112, 142))	('lignan', 'Chemical', 'MESH:D017705', (215, 221))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('neck carcinoma', 'Disease', (66, 80))	('neck carcinoma', 'Disease', 'MESH:D006258', (66, 80))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (112, 142))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PRCC', 'Gene', (144, 148))	('malignant potential', 'CPA', (213, 232))	('esophageal', 'Disease', (161, 171))	('PRCC', 'Phenotype', 'HP:0006766', (144, 148))	('chemoresistance', 'CPA', (237, 252))	('skin cancers', 'Phenotype', 'HP:0008069', (176, 188))	('hepatocellular carcinoma', 'Disease', (82, 106))
420655	31097977	In a recent study, Kerins and Ooi provided a comprehensive dataset of NRF2 gain-of-function mutations in The Cancer Genome Atlas (TCGA), identifying 226 NRF2-mutant tumors from 10364 cases.	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('NRF2-mutant', 'Gene', (153, 164))	('tumors', 'Disease', (165, 171))	('NRF2', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('gain-of-function', 'PosReg', (75, 91))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
420657	31097977	reported the first example of increased NRF2 signaling being not caused by somatic mutations, since the genetic deletion of NRF2 exon 2 (see Figure 3(b)) was found to promote elevated NRF2 activity and stability in head-neck squamous carcinoma (HNSC) and NSCLC, by removing the KEAP1-interacting domain in the absence of other genetic changes.	('head-neck squamous carcinoma', 'Phenotype', 'HP:0012288', (215, 243))	('HNSC', 'Phenotype', 'HP:0012288', (245, 249))	('stability', 'MPA', (202, 211))	('promote elevated', 'PosReg', (167, 183))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (225, 243))	('deletion', 'Var', (112, 120))	('NRF2', 'Gene', (124, 128))	('KEAP1-interacting domain', 'MPA', (278, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('NRF2', 'Enzyme', (184, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))	('head-neck squamous carcinoma (HNSC) and NSCLC', 'Disease', 'MESH:C535575', (215, 260))	('activity', 'MPA', (189, 197))
420658	31097977	Last but not least, inactivating mutations or copy number loss of the CUL3 or RBX1 genes that control NRF2 ubiquitylation/degradation has also been described in PRCC and papillary thyroid, esophageal, and serous ovarian cancers.	('described', 'Reg', (148, 157))	('RBX1', 'Gene', (78, 82))	('papillary thyroid', 'Disease', (170, 187))	('serous ovarian cancers', 'Disease', (205, 227))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (205, 227))	('ubiquitylation/degradation', 'MPA', (107, 133))	('esophageal', 'Disease', (189, 199))	('CUL3', 'Gene', '8452', (70, 74))	('copy number loss', 'Var', (46, 62))	('PRCC', 'Gene', (161, 165))	('PRCC', 'Phenotype', 'HP:0006766', (161, 165))	('RBX1', 'Gene', '9978', (78, 82))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('ovarian cancers', 'Phenotype', 'HP:0100615', (212, 227))	('NRF2', 'Gene', (102, 106))	('CUL3', 'Gene', (70, 74))	('inactivating mutations', 'Var', (20, 42))	('PRCC', 'Gene', '5546', (161, 165))
420659	31097977	In summary, genetic alterations in the NRF2/KEAP1 pathway are one of the leading causes of its prooncogenic activation.	('causes', 'Reg', (81, 87))	('genetic alterations', 'Var', (12, 31))	('NRF2/KEAP1 pathway', 'Pathway', (39, 57))	('prooncogenic activation', 'MPA', (95, 118))	('rat', 'Species', '10116', (24, 27))
420662	31097977	On the other hand, the mutation status of KEAP1 and NRF2 genes in NSCLC patients might have a clinical relevance and represent not only a valid predictive biomarker but also a molecular indication for the choice of a personalized therapy.	('NRF2', 'Gene', (52, 56))	('mutation', 'Var', (23, 31))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('KEAP1', 'Gene', (42, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('patients', 'Species', '9606', (72, 80))
420663	31097977	Modifications of the epigenetic status in the NRF2 or KEAP1 genes have been shown to induce NRF2 stabilization and increased target gene expression in many tumors.	('induce', 'PosReg', (85, 91))	('KEAP1', 'Gene', (54, 59))	('expression', 'MPA', (137, 147))	('epigenetic status', 'Var', (21, 38))	('increased', 'PosReg', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('NRF2', 'Gene', (46, 50))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('Modifications', 'Var', (0, 13))	('tumors', 'Disease', (156, 162))	('stabilization', 'MPA', (97, 110))	('NRF2', 'Protein', (92, 96))
420664	31097977	For example, the hypermethylation of CpG islands within the KEAP1 promoter region (see Figure 3(c)) has been reported to induce chemoresistance in malignant glioma and breast, prostate, colorectal, thyroid renal, and lung cancers, due to a marked decrease in the KEAP1 mRNA levels and an augmented expression of NRF2 target genes.	('expression', 'MPA', (298, 308))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('induce', 'PosReg', (121, 127))	('CpG', 'Gene', (37, 40))	('lung cancers', 'Disease', 'MESH:D008175', (217, 229))	('thyroid renal', 'Disease', 'MESH:D013959', (198, 211))	('colorectal', 'Disease', 'MESH:D015179', (186, 196))	('augmented', 'PosReg', (288, 297))	('lung cancers', 'Disease', (217, 229))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('KEAP1 mRNA levels', 'MPA', (263, 280))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancers', 'Phenotype', 'HP:0100526', (217, 229))	('decrease', 'NegReg', (247, 255))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('malignant glioma', 'Disease', 'MESH:D005910', (147, 163))	('malignant glioma', 'Disease', (147, 163))	('colorectal', 'Disease', (186, 196))	('chemoresistance', 'CPA', (128, 143))	('breast', 'Disease', (168, 174))	('hypermethylation', 'Var', (17, 33))	('prostate', 'Disease', (176, 184))	('thyroid renal', 'Disease', (198, 211))
420668	31097977	While decreased NRF2 activity due to hypermethylation of the NRF2 promoter has been observed in prostate cancers, its hypomethylation was recently reported in colorectal cancer, an event associated to NRF2 overexpression and augmented chemoresistance.	('prostate cancers', 'Disease', 'MESH:D011471', (96, 112))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NRF2', 'Gene', (61, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('hypermethylation', 'MPA', (37, 53))	('NRF2', 'Gene', (201, 205))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('prostate cancers', 'Phenotype', 'HP:0012125', (96, 112))	('prostate cancers', 'Disease', (96, 112))	('chemoresistance', 'CPA', (235, 250))	('colorectal cancer', 'Disease', (159, 176))	('activity', 'MPA', (21, 29))	('decreased', 'NegReg', (6, 15))	('NRF2', 'Enzyme', (16, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('hypomethylation', 'Var', (118, 133))	('overexpression', 'PosReg', (206, 220))
420674	31097977	Importantly, an emerging mechanism of NRF2/KEAP1 epigenetic deregulation in cancer is represented by microRNAs (miRNAs), small noncoding molecules that recognize the 3'-untranslated regions (UTRs) of specific mRNAs and negatively regulate their abundance by translation blocking or forced degradation (see Figure 3(e)).	('NRF2/KEAP1', 'Gene', (38, 48))	('regulate', 'Reg', (230, 238))	('abundance', 'MPA', (245, 254))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('epigenetic deregulation', 'Var', (49, 72))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('negatively', 'NegReg', (219, 229))
420676	31097977	Similarly, miR-507, miR-634, miR-450a, and miR-129-5p were found to directly inhibit NRF2 expression while their low levels were associated with poor outcome in esophageal carcinoma.	('NRF2', 'Gene', (85, 89))	('miR-507', 'Gene', '574512', (11, 18))	('associated', 'Reg', (129, 139))	('inhibit', 'NegReg', (77, 84))	('miR-634', 'Gene', (20, 27))	('miR-450a', 'Var', (29, 37))	('miR-129-5p', 'Gene', '100302178', (43, 53))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (161, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (161, 181))	('miR-129-5p', 'Gene', (43, 53))	('miR-634', 'Gene', '693219', (20, 27))	('expression', 'MPA', (90, 100))	('miR-507', 'Gene', (11, 18))	('esophageal carcinoma', 'Disease', (161, 181))
420681	31097977	In the same cell line, miR-153, miR27a, and miR-142-5p were also found to repress NRF2-dependent transactivation of cytoprotective genes while the forced expression of each miRNA was sufficient to markedly decrease the levels of GCLC and GSR.	('NRF2-dependent', 'Gene', (82, 96))	('GSR', 'MPA', (238, 241))	('GCLC', 'Gene', (229, 233))	('GCLC', 'Gene', '2729', (229, 233))	('decrease', 'NegReg', (206, 214))	('miR27a', 'Gene', (32, 38))	('repress', 'NegReg', (74, 81))	('miR-153', 'Var', (23, 30))	('miR27a', 'Gene', '407018', (32, 38))	('cytoprotective genes', 'Gene', (116, 136))	('miR-142-5p', 'Var', (44, 54))
420682	31097977	Recently, miR-155 inhibition was found to attenuate the malignancy and promote apoptosis in arsenic-transformed bronchial epithelial cells by repressing NRF2, suggesting that miR-155 might promote malignant transformation of lung cells exposed to arsenite.	('miR-155', 'Gene', '406947', (175, 182))	('promote', 'PosReg', (71, 78))	('repressing', 'PosReg', (142, 152))	('malignancy', 'Disease', 'MESH:D009369', (56, 66))	('miR-155', 'Gene', '406947', (10, 17))	('attenuate', 'NegReg', (42, 51))	('miR-155', 'Gene', (175, 182))	('arsenite', 'Chemical', 'MESH:C015001', (247, 255))	('NRF2', 'Gene', (153, 157))	('miR-155', 'Gene', (10, 17))	('malignancy', 'Disease', (56, 66))	('lignan', 'Chemical', 'MESH:D017705', (199, 205))	('malignant transformation', 'CPA', (197, 221))	('apoptosis', 'CPA', (79, 88))	('inhibition', 'Var', (18, 28))	('promote', 'PosReg', (189, 196))	('lignan', 'Chemical', 'MESH:D017705', (58, 64))	('arsenic', 'Chemical', 'MESH:D001151', (92, 99))
420683	31097977	Similarly, miR-153 and miR-93a were also proposed to drive breast carcinogenesis, since their increased expression was paralleled by reduced NRF2 protein content in mammary tumors and breast cancer cell lines treated with 17beta-estradiol.	('miR-93a', 'Var', (23, 30))	('increased', 'PosReg', (94, 103))	('NRF2 protein', 'Protein', (141, 153))	('breast carcinogenesis', 'Disease', (59, 80))	('tumors and breast cancer', 'Disease', 'MESH:D001943', (173, 197))	('protein', 'Protein', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('expression', 'MPA', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (222, 238))	('drive', 'Reg', (53, 58))	('miR-153', 'Var', (11, 18))	('reduced', 'NegReg', (133, 140))	('breast carcinogenesis', 'Disease', 'MESH:D061325', (59, 80))
420689	31097977	In another context, increased expression of miR-200a was shown to negatively modulate KEAP1 levels in response to methylseleninic acid (MSA), while the use of antagomir-200a attenuated the KEAP1 downregulation induced by MSA in ESCC cells.	('miR-200a', 'Gene', (44, 52))	('attenuated', 'NegReg', (174, 184))	('increased', 'PosReg', (20, 29))	('negatively', 'NegReg', (66, 76))	('response to methylseleninic acid', 'MPA', (102, 134))	('downregulation', 'NegReg', (195, 209))	('expression', 'Var', (30, 40))	('KEAP1', 'MPA', (86, 91))	('MSA', 'Chemical', 'MESH:C008493', (221, 224))	('modulate', 'Reg', (77, 85))	('methylseleninic acid', 'Chemical', 'MESH:C008493', (114, 134))	('MSA', 'Chemical', 'MESH:C008493', (136, 139))	('miR-200a', 'Gene', '406983', (44, 52))
420702	31097977	Indeed, an earlier study reported that high levels of p62 were significantly correlated with HER2 overexpression in human breast cancers, while a role for p62 in breast carcinogenesis was further evidenced in a recent study wherein p62 was shown to facilitate HER2-dependent mammary tumorigenesis in MMTV-Neu transgenic mice by the activation of multiple pathways, including the NRF2/KEAP1.	('MMTV', 'Species', '11757', (300, 304))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('breast carcinogenesis', 'Disease', 'MESH:D061325', (162, 183))	('HER2', 'Gene', (260, 264))	('transgenic mice', 'Species', '10090', (309, 324))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('breast cancers', 'Disease', (122, 136))	('overexpression', 'PosReg', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('facilitate', 'PosReg', (249, 259))	('HER2', 'Gene', '2064', (93, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('breast carcinogenesis', 'Disease', (162, 183))	('HER2', 'Gene', '2064', (260, 264))	('p62', 'Var', (232, 235))	('human', 'Species', '9606', (116, 121))	('tumor', 'Disease', (283, 288))	('HER2', 'Gene', (93, 97))
420703	31097977	Also, altered p62 expression was associated to increased NRF2 activation and enhanced chemoresistance in cancer stem cell- (CSC-) enriched mammospheres derived from MCF-7 breast cancer cells, compared to monolayer cultured cells.	('enhanced', 'PosReg', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('p62', 'Gene', (14, 17))	('increased', 'PosReg', (47, 56))	('cancer', 'Disease', (178, 184))	('expression', 'MPA', (18, 28))	('MCF-7 breast cancer', 'Disease', (165, 184))	('activation', 'PosReg', (62, 72))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('NRF2', 'Gene', (57, 61))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (165, 184))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('chemoresistance', 'CPA', (86, 101))	('altered', 'Var', (6, 13))
420705	31097977	In another context, it has been proposed that p62 might serve as a prognostic marker in patients with glioma, being its content positively correlated to the NRF2 levels and a poor prognosis.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('positively', 'PosReg', (128, 138))	('correlated', 'Reg', (139, 149))	('content', 'MPA', (120, 127))	('patients', 'Species', '9606', (88, 96))	('NRF2 levels', 'MPA', (157, 168))	('glioma', 'Disease', (102, 108))	('p62', 'Var', (46, 49))
420706	31097977	From a clinical perspective, p62 was also found to decrease arsenic sensitivity in human transformed lung bronchial epithelial BEAS-2B cells, by noncanonical stimulation of the NRF2/KEAP1 pathway, presumably due to its constitutive activation after carcinogenesis induction.	('p62', 'Var', (29, 32))	('carcinogenesis', 'Disease', (249, 263))	('stimulation', 'PosReg', (158, 169))	('BEAS-2B', 'CellLine', 'CVCL:0168', (127, 134))	('human', 'Species', '9606', (83, 88))	('NRF2/KEAP1 pathway', 'Pathway', (177, 195))	('arsenic sensitivity', 'MPA', (60, 79))	('decrease', 'NegReg', (51, 59))	('arsenic', 'Chemical', 'MESH:D001151', (60, 67))	('carcinogenesis', 'Disease', 'MESH:D063646', (249, 263))
420710	31097977	Also, since amplification of the p62 gene or aberrant accumulation of its phosphorylated form is frequently found in many cancers, either inhibitors of p62 phosphorylation or antagonists of p62/NRF2 interaction might restore the route of NRF2 proteasomal degradation in the context of a functional KEAP1 expression.	('restore', 'PosReg', (217, 224))	('p62', 'Gene', (33, 36))	('amplification', 'Var', (12, 25))	('route', 'MPA', (229, 234))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('NRF2 proteasomal degradation', 'MPA', (238, 266))
420714	31097977	Collectively, these data suggest that the overexpression of different types of ETGE-containing proteins in cancer cells might sustain NRF2 activity even in the absence of activating mutations in the NRF2 or inactivating mutations in the KEAP1 genes.	('NRF2', 'Protein', (134, 138))	('NRF2', 'Gene', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('KEAP1', 'Gene', (237, 242))	('inactivating mutations', 'Var', (207, 229))	('activity', 'MPA', (139, 147))	('overexpression', 'PosReg', (42, 56))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
420715	31097977	With this respect, the lack of fumarate hydratase (FH), an enzyme that converts fumarate to malate in the TCA (tricarboxylic acid) cycle, was found to promote fumarate accumulation and lead to succinylation of KEAP1 cysteines, NRF2 stabilization, and subsequent transactivation of stress-related genes (see Figure 3(g)) in PRCC.	('malate', 'Chemical', 'MESH:C030298', (92, 98))	('stabilization', 'MPA', (232, 245))	('fumarate', 'Chemical', 'MESH:D005650', (31, 39))	('stress-related genes', 'Gene', (281, 301))	('PRCC', 'Gene', (323, 327))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (111, 129))	('fumarate', 'Chemical', 'MESH:D005650', (80, 88))	('PRCC', 'Phenotype', 'HP:0006766', (323, 327))	('fumarate accumulation', 'MPA', (159, 180))	('lack', 'Var', (23, 27))	('TCA', 'Chemical', 'MESH:D014233', (106, 109))	('NRF2', 'Gene', (227, 231))	('fumarate hydratase', 'Gene', '2271', (31, 49))	('succinylation', 'MPA', (193, 206))	('promote', 'PosReg', (151, 158))	('lack of fumarate hydratase', 'Phenotype', 'HP:0003536', (23, 49))	('FH', 'Gene', '2271', (51, 53))	('PRCC', 'Gene', '5546', (323, 327))	('cysteines', 'Chemical', 'MESH:D003545', (216, 225))	('fumarate', 'Chemical', 'MESH:D005650', (159, 167))	('transactivation', 'PosReg', (262, 277))	('fumarate hydratase', 'Gene', (31, 49))
420716	31097977	Accumulating evidence suggests that other cancer-specific alterations, particularly those related to oncogenic signaling can strongly influence the activity of NRF2 without affecting its protein stability but rather increasing its mRNA levels (see Figure 3).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('influence', 'Reg', (134, 143))	('activity', 'MPA', (148, 156))	('rat', 'Species', '10116', (209, 212))	('mRNA levels', 'MPA', (231, 242))	('cancer', 'Disease', (42, 48))	('protein stability', 'MPA', (187, 204))	('NRF2', 'Gene', (160, 164))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('rat', 'Species', '10116', (62, 65))	('increasing', 'Reg', (216, 226))	('alterations', 'Var', (58, 69))
420722	31097977	Importantly, increased expression of the antioxidant genes NQO1 and HMOX1 was found to promote an aggressive phenotype associated to chemoresistance, while the genetic ablation of NRF2 by CRISPR/Cas9 was able to impair the malignant progression and restore the sensitivity to several anticancer drugs.	('impair', 'NegReg', (212, 218))	('lignan', 'Chemical', 'MESH:D017705', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('NRF2', 'Gene', (180, 184))	('aggressive phenotype', 'MPA', (98, 118))	('cancer', 'Disease', (288, 294))	('HMOX1', 'Gene', (68, 73))	('malignant progression', 'CPA', (223, 244))	('genetic ablation', 'Var', (160, 176))	('restore', 'PosReg', (249, 256))	('NQO1', 'Gene', (59, 63))	('chemoresistance', 'Disease', (133, 148))	('promote', 'PosReg', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('increased', 'PosReg', (13, 22))	('expression', 'MPA', (23, 33))
420724	31097977	Importantly, strong evidence also indicates that aberrant activation of the PI3K/AKT pathway, a master regulator of cancer cell growth, survival, and metabolism can act upstream NRF2 signaling in different types of tumors (see Figure 3(h)).	('act', 'Reg', (165, 168))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('AKT', 'Gene', '207', (81, 84))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('aberrant', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('AKT', 'Gene', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('activation', 'PosReg', (58, 68))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))
420725	31097977	Initial studies provided indirect evidence of a functional interaction between the PI3K/AKT and NRF2/KEAP1 pathways since the pharmacologic inhibition of the former was able to prevent NRF2 nuclear accumulation in renal adenocarcinoma cells and auditory cells.	('inhibition', 'Var', (140, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('AKT', 'Gene', '207', (88, 91))	('nuclear accumulation', 'MPA', (190, 210))	('AKT', 'Gene', (88, 91))	('NRF2', 'Protein', (185, 189))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (214, 234))	('renal adenocarcinoma', 'Disease', 'MESH:D002292', (214, 234))	('renal adenocarcinoma', 'Disease', (214, 234))	('prevent', 'NegReg', (177, 184))
420726	31097977	Later studies conducted on lung cancer cell lines with KEAP1 (A549 and H2126) or NRF2 (EBC1 and LK2) mutations demonstrated that the sustained activation of the PI3K/AKT pathway was accompanied by increased NRF2 mRNA levels and NRF2 nuclear accumulation leading to metabolic reprogramming, enhanced cell proliferation, and apoptosis evasion.	('apoptosis evasion', 'CPA', (323, 340))	('H2126', 'CellLine', 'CVCL:1532', (71, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('AKT', 'Gene', (166, 169))	('increased', 'PosReg', (197, 206))	('NRF2', 'Protein', (207, 211))	('metabolic reprogramming', 'CPA', (265, 288))	('NRF2', 'Gene', (228, 232))	('rat', 'Species', '10116', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (101, 110))	('AKT', 'Gene', '207', (166, 169))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('lung cancer', 'Disease', (27, 38))	('nuclear accumulation', 'CPA', (233, 253))	('activation', 'PosReg', (143, 153))	('enhanced', 'PosReg', (290, 298))	('mRNA levels', 'MPA', (212, 223))	('NRF2', 'Gene', (81, 85))	('rat', 'Species', '10116', (311, 314))	('cell proliferation', 'CPA', (299, 317))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))
420742	31097977	Importantly, disruption of the PERK/NRF2 axis was able to reverse both the resistance to ER stress and to anticancer drugs.	('resistance to ER stress', 'MPA', (75, 98))	('cancer', 'Disease', (110, 116))	('PERK', 'Gene', (31, 35))	('disruption', 'Var', (13, 23))	('PERK', 'Gene', '9451', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('reverse', 'NegReg', (58, 65))
420748	31097977	Taken together, these data highlight the existence of a complex interrelation between the NRF2/KEAP1 pathway and stress-related responses commonly found in the microenvironment of malignant tumors, confirming that aberrant NRF2 activation can represent a common feature of cancer cells, even in the absence of alterations of the redox status or prooncogenic mutations in NRF2/KEAP1 genes.	('malignant tumors', 'Disease', 'MESH:D009369', (180, 196))	('NRF2', 'Gene', (223, 227))	('cancer', 'Disease', (273, 279))	('activation', 'PosReg', (228, 238))	('rat', 'Species', '10116', (314, 317))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('iron', 'Chemical', 'MESH:D007501', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('malignant tumors', 'Disease', (180, 196))	('aberrant', 'Var', (214, 222))
420754	31097977	For example, aberrant NRF2 activation has been shown to induce overexpression of the MDR1 (multidrug resistance protein 1), MRP1-5 (multi-drug resistance-associated protein 1-5), and BCRP (breast cancer resistance protein) genes or to increase the activity of their corresponding proteins, leading to widespread chemoresistance.	('MRP1', 'Gene', '4363', (124, 128))	('activity', 'MPA', (248, 256))	('MDR1', 'Gene', (85, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('breast cancer resistance protein', 'Gene', (189, 221))	('activation', 'PosReg', (27, 37))	('NRF2', 'Gene', (22, 26))	('widespread chemoresistance', 'CPA', (301, 327))	('drug resistance', 'Phenotype', 'HP:0020174', (138, 153))	('increase', 'PosReg', (235, 243))	('MRP1', 'Gene', (124, 128))	('proteins', 'Protein', (280, 288))	('multidrug resistance protein 1', 'Gene', '5243', (91, 121))	('aberrant', 'Var', (13, 21))	('overexpression', 'MPA', (63, 77))	('drug resistance', 'Phenotype', 'HP:0020174', (96, 111))	('multidrug resistance protein 1', 'Gene', (91, 121))	('MDR1', 'Gene', '5243', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('leading to', 'Reg', (290, 300))	('breast cancer resistance protein', 'Gene', '9429', (189, 221))	('BCRP', 'Gene', (183, 187))	('BCRP', 'Gene', '9429', (183, 187))
420758	31097977	For example, by using high-throughput screening to identify small molecule inhibitors of the NRF2 transcriptional activity at ARE sites, AEM1 was found to broadly impair the expression of NRF2 target genes, leading to growth inhibition and increased chemosensitivity of A549 NSCLC cells in vitro and in vivo (see Table 1).	('increased', 'PosReg', (240, 249))	('expression', 'MPA', (174, 184))	('NSCLC', 'Disease', (275, 280))	('growth inhibition', 'CPA', (218, 235))	('NRF2', 'Gene', (93, 97))	('NSCLC', 'Disease', 'MESH:D002289', (275, 280))	('AEM1', 'Var', (137, 141))	('A549', 'CellLine', 'CVCL:0023', (270, 274))	('impair', 'NegReg', (163, 169))	('chemosensitivity', 'CPA', (250, 266))	('NSCLC', 'Phenotype', 'HP:0030358', (275, 280))
420759	31097977	Also, a quantitative high-throughput screening on ~400 000 small molecules made by Singh and coworkers led to the identification of ML385, a compound with high specificity and selectivity for NSCLC with constitutive NRF2 activation caused by inactivating mutations of KEAP1 (see Table 1).	('NRF2', 'Gene', (216, 220))	('NSCLC', 'Disease', (192, 197))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('activation', 'PosReg', (221, 231))	('KEAP1', 'Gene', (268, 273))	('ML385', 'Var', (132, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('inactivating mutations', 'Var', (242, 264))
420760	31097977	In preclinical models of NSCLC, the combined use of ML385 with Carboplatin was associated to significant antitumor activity, confirming that NRF2 targeting is a promising strategy for the treatment of advanced NSCLC.	('rat', 'Species', '10116', (173, 176))	('Carboplatin', 'Chemical', 'MESH:D016190', (63, 74))	('NSCLC', 'Disease', (25, 30))	('NSCLC', 'Disease', (210, 215))	('ML385', 'Var', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('tumor', 'Disease', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (210, 215))
420784	31097977	Later studies conducted on mouse Hepa-1c1c7 hepatoma cells and primary human hepatocytes consistently reported that Brusatol could transiently and rapidly deplete the NRF2 protein levels in a KEAP1-independent way through a posttranscriptional mechanism, strongly increasing the cell sensitivity to electrophilic stress inducers (see Table 1).	('deplete', 'NegReg', (155, 162))	('Hepa-1c1c7 hepatoma', 'Disease', (33, 52))	('Brusatol', 'Var', (116, 124))	('mouse', 'Species', '10090', (27, 32))	('NRF2 protein levels', 'MPA', (167, 186))	('increasing', 'PosReg', (264, 274))	('cell sensitivity to electrophilic stress inducers', 'MPA', (279, 328))	('Brusatol', 'Chemical', 'MESH:C020237', (116, 124))	('human', 'Species', '9606', (71, 76))	('Hepa-1c1c7 hepatoma', 'Disease', 'MESH:D006528', (33, 52))
420823	31097977	Mechanistically, Honokiol markedly activated the JNK pathway while in contrast, it strongly reduced both NF-kappaB activity and NRF2 protein levels, leading to increased ROS production and apoptosis, as further confirmed in BALB/C nude mice injected with Raji cells.	('Raji', 'CellLine', 'CVCL:0511', (255, 259))	('NRF2 protein levels', 'MPA', (128, 147))	('increased', 'PosReg', (160, 169))	('NF-kappaB activity', 'MPA', (105, 123))	('nude mice', 'Species', '10090', (231, 240))	('JNK pathway', 'Pathway', (49, 60))	('Honokiol', 'Var', (17, 25))	('apoptosis', 'CPA', (189, 198))	('Honokiol', 'Chemical', 'MESH:C005499', (17, 25))	('increased ROS production', 'Phenotype', 'HP:0025464', (160, 184))	('reduced', 'NegReg', (92, 99))	('ROS production', 'MPA', (170, 184))	('ROS', 'Chemical', 'MESH:D017382', (170, 173))	('activated', 'PosReg', (35, 44))
420837	31097977	Known for its anti-inflammatory, antimicrobial, and antihelminthic effects, Berberine was recently found to exert also antineoplastic activity in breast cancer by inducing oxidative stress.	('Berberine', 'Chemical', 'MESH:D001599', (76, 85))	('inducing', 'PosReg', (163, 171))	('antineoplastic activity', 'CPA', (119, 142))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('oxidative stress', 'Phenotype', 'HP:0025464', (172, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('oxidative stress', 'MPA', (172, 188))	('Berberine', 'Var', (76, 85))
420874	31097977	Importantly, when used as an adjuvant, PIK-75 was able to counteract the increase in NRF2 induced by Gemcitabine and to significantly potentiate its antitumor effects both in vitro and in vivo.	('NRF2', 'Gene', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('potentiate', 'PosReg', (134, 144))	('increase', 'PosReg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('Gemcitabine', 'Chemical', 'MESH:C056507', (101, 112))	('PIK-75', 'Var', (39, 45))
420876	31097977	In another study conducted on U251 human glioblastoma cells, the ERK and PI3K signaling cascades were found to regulate the expression and activation of NRF2, while the cotreatment with pharmacologic inhibitors (PD98059 for ERK and LY292004 for PI3K) was able to revert these changes and trigger cell death.	('human glioblastoma', 'Disease', (35, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (41, 53))	('PD98059', 'Var', (212, 219))	('trigger', 'Reg', (288, 295))	('human glioblastoma', 'Disease', 'MESH:D005909', (35, 53))	('PD98059', 'Chemical', 'MESH:C093973', (212, 219))	('NRF2', 'Gene', (153, 157))	('LY292004', 'Var', (232, 240))	('expression', 'MPA', (124, 134))	('cell death', 'CPA', (296, 306))	('LY292004', 'Chemical', '-', (232, 240))	('activation', 'MPA', (139, 149))	('regulate', 'Reg', (111, 119))	('U251', 'CellLine', 'CVCL:0021', (30, 34))
420877	31097977	Interestingly, LGB-321 and AZD1208, two inhibitors of PIM kinase, a protein frequently overexpressed in many tumors exposed to hypoxia, were found to impair tumor growth and selectively kill different types of hypoxic cancer cells in vitro and in vivo, preventing NRF2 nuclear accumulation and leading to the buildup of ROS, suggesting that this strategy might overcome the hypoxia-mediated therapy resistance frequently encountered in the treatment of many tumors.	('hypoxic cancer', 'Disease', 'MESH:D009369', (210, 224))	('impair', 'NegReg', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (458, 463))	('hypoxic cancer', 'Disease', (210, 224))	('buildup', 'MPA', (309, 316))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('NRF2', 'Protein', (264, 268))	('preventing', 'NegReg', (253, 263))	('AZD1208', 'Chemical', 'MESH:C587575', (27, 34))	('LGB-321', 'Gene', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (458, 464))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('rat', 'Species', '10116', (348, 351))	('hypoxia', 'Disease', (127, 134))	('leading to', 'Reg', (294, 304))	('tumor', 'Phenotype', 'HP:0002664', (458, 463))	('hypoxia', 'Disease', (374, 381))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (458, 464))	('tumors', 'Disease', (109, 115))	('hypoxia', 'Disease', 'MESH:D000860', (127, 134))	('hypoxia', 'Disease', 'MESH:D000860', (374, 381))	('tumors', 'Disease', 'MESH:D009369', (458, 464))	('tumor', 'Disease', (157, 162))	('ROS', 'MPA', (320, 323))	('nuclear accumulation', 'MPA', (269, 289))	('AZD1208', 'Var', (27, 34))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('ROS', 'Chemical', 'MESH:D017382', (320, 323))	('tumor', 'Disease', (458, 463))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Disease', (109, 114))
420880	31097977	With this respect, by establishing Gefitinib-resistant (GR) NSCLC cells, it has been shown that the increased overexpression of several NRF2-dependent target genes was due to an acquired KEAP1 mutation, an event promoting a malignant phenotype and cross-resistance to the EGFR-TKIs Afatinib and Osimertinib both in vitro and in vivo.	('EGFR', 'Gene', '1956', (272, 276))	('Afatinib', 'Chemical', 'MESH:D000077716', (282, 290))	('Osimertinib', 'Chemical', 'MESH:C000603933', (295, 306))	('EGFR', 'Gene', (272, 276))	('increased overexpression', 'PosReg', (100, 124))	('NSCLC', 'Disease', (60, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('malignant phenotype', 'CPA', (224, 243))	('lignan', 'Chemical', 'MESH:D017705', (226, 232))	('Gefitinib', 'Chemical', 'MESH:D000077156', (35, 44))	('promoting', 'PosReg', (212, 221))	('mutation', 'Var', (193, 201))	('KEAP1', 'Gene', (187, 192))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
420881	31097977	Here, the inhibition of NRF2, either by treatment with Brusatol or by restored expression of wild-type KEAP1, suppressed tumor cell proliferation and tumorigenicity in vitro and in vivo, confirming that deregulation of the NRF2/KEAP1 pathway can be responsible for the acquired resistance to EGFR-TKIs observed in many NSCLC patients, while its pharmacologic ablation might represent a valid option to overcome this phenomenon.	('NSCLC', 'Disease', (319, 324))	('EGFR', 'Gene', '1956', (292, 296))	('inhibition', 'NegReg', (10, 20))	('Brusatol', 'Chemical', 'MESH:C020237', (55, 63))	('patients', 'Species', '9606', (325, 333))	('NSCLC', 'Disease', 'MESH:D002289', (319, 324))	('NRF2', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('rat', 'Species', '10116', (139, 142))	('EGFR', 'Gene', (292, 296))	('deregulation', 'Var', (203, 215))	('NSCLC', 'Phenotype', 'HP:0030358', (319, 324))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('suppressed', 'NegReg', (110, 120))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
420883	31097977	Here, the authors demonstrated that Icotinib and Gefitinib triggered apoptosis in EGFR mutant HCC827 but not in EGFR wild-type A549 NSCLC cells without inducing protective autophagy.	('EGFR', 'Gene', (112, 116))	('triggered', 'Reg', (59, 68))	('EGFR', 'Gene', (82, 86))	('Icotinib', 'Chemical', 'MESH:C531470', (36, 44))	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('HCC827', 'Gene', (94, 100))	('mutant', 'Var', (87, 93))	('NSCLC', 'Disease', (132, 137))	('EGFR', 'Gene', '1956', (112, 116))	('apoptosis', 'CPA', (69, 78))	('rat', 'Species', '10116', (25, 28))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('EGFR', 'Gene', '1956', (82, 86))	('A549', 'CellLine', 'CVCL:0023', (127, 131))	('Gefitinib', 'Chemical', 'MESH:D000077156', (49, 58))
420884	31097977	Moreover, suppression of the NRF2 activity with the inhibitor Brusatol significantly reduced the cell survival of A549 cells, without further sensitizing them to EGFR TKI-induced cell death, suggesting that suppression of NRF2 can be used to induce autophagy-independent cell death in NSCLC tumors.	('activity', 'MPA', (34, 42))	('NSCLC tumors', 'Disease', 'MESH:D009369', (285, 297))	('suppression', 'NegReg', (10, 21))	('suppression', 'Var', (207, 218))	('NRF2', 'Protein', (29, 33))	('NSCLC tumors', 'Disease', (285, 297))	('Brusatol', 'Chemical', 'MESH:C020237', (62, 70))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('cell survival', 'CPA', (97, 110))	('autophagy-independent cell', 'CPA', (249, 275))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('reduced', 'NegReg', (85, 92))	('NRF2', 'Gene', (222, 226))	('induce', 'PosReg', (242, 248))	('NSCLC', 'Phenotype', 'HP:0030358', (285, 290))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))
420888	31097977	Surprisingly, the synergistic combination of the drugs was found to decrease the transcriptional activity of NRF2, inducing oxidative stress-dependent cell death in MDA-MB-231 and MDA-MB-436 breast cancer cells by strongly depleting the intracellular levels of GSH and NADPH, observations further confirmed in human xenograft tumors.	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('GSH', 'Chemical', 'MESH:D005978', (261, 264))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (165, 175))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (180, 190))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('intracellular levels of GSH', 'MPA', (237, 264))	('decrease', 'NegReg', (68, 76))	('human', 'Species', '9606', (310, 315))	('oxidative stress', 'Phenotype', 'HP:0025464', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('transcriptional activity', 'MPA', (81, 105))	('drugs', 'Var', (49, 54))	('oxidative stress-dependent', 'MPA', (124, 150))	('xenograft tumors', 'Disease', (316, 332))	('NADPH', 'Chemical', 'MESH:D009249', (269, 274))	('depleting', 'NegReg', (223, 232))	('xenograft tumors', 'Disease', 'MESH:D009369', (316, 332))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('inducing', 'Reg', (115, 123))	('NRF2', 'Gene', (109, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
420891	31097977	Another recent study investigated the anticancer effects of CP-673451, a selective PDGFRbeta inhibitor, in models of NSCLC.	('NSCLC', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('PDGFRbeta', 'Gene', '5156', (83, 92))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('CP-673451', 'Chemical', '-', (60, 69))	('PDGFRbeta', 'Gene', (83, 92))	('CP-673451', 'Var', (60, 69))
420892	31097977	Here, CP-673451 was found to suppress NRF2 expression and promote a significant increase in cell apoptosis, accompanied by ROS accumulation in A549 and H358 NSCLC cell lines that was further exacerbated by the coadministration of Cisplatin.	('NRF2', 'Gene', (38, 42))	('ROS', 'Chemical', 'MESH:D017382', (123, 126))	('CP-673451', 'Var', (6, 15))	('accumulation', 'PosReg', (127, 139))	('cell apoptosis', 'CPA', (92, 106))	('suppress', 'NegReg', (29, 37))	('increase', 'PosReg', (80, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('H358', 'CellLine', 'CVCL:1559', (152, 156))	('Cisplatin', 'Chemical', 'MESH:D002945', (230, 239))	('ROS', 'MPA', (123, 126))	('rat', 'Species', '10116', (220, 223))	('NSCLC', 'Disease', (157, 162))	('expression', 'MPA', (43, 53))	('CP-673451', 'Chemical', '-', (6, 15))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))	('A549', 'CellLine', 'CVCL:0023', (143, 147))
420901	31097977	Apart from the use of chemical compounds with inhibitory effects, genetic inactivation of NRF2 by RNA interference is also a promising strategy to selectively impair NRF2 activity and overcome chemoresistance.	('chemoresistance', 'CPA', (193, 208))	('NRF2', 'Gene', (90, 94))	('overcome', 'PosReg', (184, 192))	('rat', 'Species', '10116', (137, 140))	('RNA interference', 'MPA', (98, 114))	('impair', 'NegReg', (159, 165))	('NRF2', 'Protein', (166, 170))	('genetic inactivation', 'Var', (66, 86))	('activity', 'MPA', (171, 179))
420905	31097977	In another study, MDA-MB-231 breast carcinoma cells with stable NRF2 knockdown displayed enhanced sensitivity to photodynamic therapy (PDT) due to increased ROS levels.	('sensitivity', 'MPA', (98, 109))	('ROS', 'Chemical', 'MESH:D017382', (157, 160))	('enhanced', 'PosReg', (89, 97))	('increased', 'PosReg', (147, 156))	('breast carcinoma', 'Phenotype', 'HP:0003002', (29, 45))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (18, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('NRF2', 'Gene', (64, 68))	('increased ROS levels', 'Phenotype', 'HP:0025464', (147, 167))	('knockdown', 'Var', (69, 78))	('breast carcinoma', 'Disease', 'MESH:D001943', (29, 45))	('breast carcinoma', 'Disease', (29, 45))	('ROS levels', 'MPA', (157, 167))
420906	31097977	Importantly, these observations were also confirmed in breast MCF-7, colon HCT116, renal A498 carcinoma, and glioblastoma A172 cells, indicating that genetic ablation of NRF2 might potentially increase the efficacy of PDT in malignant tumors of different origin by altered redox homeostasis and cytotoxic ROS accumulation.	('malignant tumors', 'Disease', (225, 241))	('genetic ablation', 'Var', (150, 166))	('malignant tumors', 'Disease', 'MESH:D009369', (225, 241))	('glioblastoma', 'Disease', (109, 121))	('PDT', 'CPA', (218, 221))	('increase', 'PosReg', (193, 201))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('redox homeostasis', 'MPA', (273, 290))	('altered', 'Reg', (265, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('NRF2', 'Gene', (170, 174))	('breast MCF-7, colon HCT116, renal A498 carcinoma', 'Disease', 'MESH:D001943', (55, 103))	('efficacy', 'MPA', (206, 214))	('ROS', 'Chemical', 'MESH:D017382', (305, 308))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))
420908	31097977	Interestingly, knockdown of AATBCC by siRNAs was able to downregulate NRF2 protein levels and increase the sensitivity of UM-UC-3 and EJ bladder cancer cells to Cisplatin.	('AATBC', 'Gene', (28, 33))	('downregulate', 'NegReg', (57, 69))	('knockdown', 'Var', (15, 24))	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('increase', 'PosReg', (94, 102))	('protein levels', 'MPA', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('EJ', 'CellLine', 'CVCL:7039', (134, 136))	('sensitivity', 'MPA', (107, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('NRF2', 'Protein', (70, 74))	('Cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('bladder cancer', 'Disease', (137, 151))	('AATBC', 'Gene', '284837', (28, 33))
420909	31097977	Also, it has been proposed that the use of NRF2 siRNAs might have a therapeutic relevance in the treatment of laryngeal squamous cancer, since Hep-2 cells refractory to Cisplatin due to high levels of the antioxidant enzyme HO-1 were found to be strongly sensitized by NRF2 knockdown and subsequent ROS elevation.	('HO-1', 'Gene', (224, 228))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('laryngeal squamous cancer', 'Phenotype', 'HP:0012118', (110, 135))	('laryngeal squamous cancer', 'Disease', 'MESH:D007822', (110, 135))	('HO-1', 'Gene', '3162', (224, 228))	('Cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('ROS', 'Chemical', 'MESH:D017382', (299, 302))	('NRF2', 'Gene', (269, 273))	('ROS', 'Gene', (299, 302))	('Hep-2', 'CellLine', 'CVCL:1906', (143, 148))	('knockdown', 'Var', (274, 283))	('squamous cancer', 'Phenotype', 'HP:0002860', (120, 135))	('elevation', 'PosReg', (303, 312))	('laryngeal squamous cancer', 'Disease', (110, 135))	('ROS elevation', 'Phenotype', 'HP:0025464', (299, 312))	('sensitized', 'PosReg', (255, 265))
420910	31097977	Lastly, siRNAs against NRF2 were found to enhance the cytotoxicity of Cisplatin in human cholangiocarcinoma KKU-100 cells, further elevating the production of ROS normally induced by the single administration of various anticancer drugs.	('ROS', 'MPA', (159, 162))	('ROS', 'Chemical', 'MESH:D017382', (159, 162))	('siRNAs', 'Var', (8, 14))	('cancer', 'Disease', (224, 230))	('Cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('elevating', 'PosReg', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('cholangiocarcinoma KKU-100', 'Disease', 'MESH:D018281', (89, 115))	('cytotoxicity', 'Disease', (54, 66))	('cholangiocarcinoma KKU-100', 'Disease', (89, 115))	('cytotoxicity', 'Disease', 'MESH:D064420', (54, 66))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('rat', 'Species', '10116', (202, 205))	('enhance', 'PosReg', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('human', 'Species', '9606', (83, 88))	('production', 'MPA', (145, 155))	('NRF2', 'Gene', (23, 27))
420913	31097977	In this regard, an earlier study reported that high levels of NRF2 were associated to Cisplatin and Paclitaxel resistance in endometrial serous carcinoma (ESC).	('Cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('endometrial serous carcinoma', 'Disease', (125, 153))	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (125, 153))	('NRF2', 'Gene', (62, 66))	('Paclitaxel', 'Chemical', 'MESH:D017239', (100, 110))	('associated', 'Reg', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('high levels', 'Var', (47, 58))
420917	31097977	identified K67, a small noncovalent inhibitor of phospho-p62/KEAP1 interaction, as a molecule capable of restoring the main route of NRF2 degradation in human HCC lines.	('K67', 'Var', (11, 14))	('K67', 'Chemical', '-', (11, 14))	('restoring', 'PosReg', (105, 114))	('human', 'Species', '9606', (153, 158))	('main route of NRF2 degradation', 'MPA', (119, 149))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
420918	31097977	Importantly, K67 exerted also antineoplastic effects in several HCC cell lines by decreasing proliferation and enhancing the cytotoxicity of either Sorafenib or Cisplatin, confirming that this inhibitor might be exploited to treat HCC cancers with p62-dependent NRF2 hyperactivation.	('Sorafenib', 'Chemical', 'MESH:D000077157', (148, 157))	('K67', 'Var', (13, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('HCC', 'Disease', (231, 234))	('K67', 'Chemical', '-', (13, 16))	('proliferation', 'CPA', (93, 106))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('HCC', 'Phenotype', 'HP:0001402', (231, 234))	('cancers', 'Disease', (235, 242))	('decreasing', 'NegReg', (82, 92))	('enhancing', 'PosReg', (111, 120))	('HCC', 'Phenotype', 'HP:0001402', (64, 67))	('Cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('cytotoxicity', 'Disease', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('rat', 'Species', '10116', (100, 103))
420919	31097977	However, due to K67 low solubility, the authors proposed that changes in its chemical structure would have been required before performing any clinical study.	('K67', 'Var', (16, 19))	('K67', 'Chemical', '-', (16, 19))	('solubility', 'MPA', (24, 34))
420922	31097977	Here, by using therapy-resistant HCC BEL-7402/5-FU cells, the authors showed that DMC promoted a significant increase in the KEAP1 protein levels, preventing NRF2 nuclear translocation and subsequent target gene transactivation.	('BEL-7402', 'CellLine', 'CVCL:5492', (37, 45))	('KEAP1 protein levels', 'MPA', (125, 145))	('NRF2', 'Protein', (158, 162))	('increase', 'PosReg', (109, 117))	('DMC', 'Chemical', 'MESH:C501649', (82, 85))	('nuclear translocation', 'MPA', (163, 184))	('HCC', 'Phenotype', 'HP:0001402', (33, 36))	('5-FU', 'Chemical', 'MESH:D005472', (46, 50))	('transactivation', 'MPA', (212, 227))	('preventing', 'NegReg', (147, 157))	('DMC', 'Var', (82, 85))
420931	31097977	Other experimental work from the group of Furfaro focused on malignant neuroblastoma, wherein the activation of NRF2 has been proposed to promote resistance to proteasome inhibitors such as Bortezomib (BTZ).	('neuroblastoma', 'Disease', 'MESH:D009447', (71, 84))	('BTZ', 'Chemical', 'MESH:D000069286', (202, 205))	('resistance to', 'MPA', (146, 159))	('neuroblastoma', 'Disease', (71, 84))	('malignant neuroblastoma', 'Phenotype', 'HP:0100697', (61, 84))	('Furfaro', 'Chemical', '-', (42, 49))	('promote', 'PosReg', (138, 145))	('neuroblastoma', 'Phenotype', 'HP:0003006', (71, 84))	('Bortezomib', 'Chemical', 'MESH:D000069286', (190, 200))	('activation', 'Var', (98, 108))	('NRF2', 'Gene', (112, 116))	('lignan', 'Chemical', 'MESH:D017705', (63, 69))
420936	31097977	investigated the potential role of NRF2 signaling in CSC-like properties of ovarian CSCs exhibiting high enzymatic activity of aldehyde dehydrogenase1 (ALDH1) and high expression levels of p62, a hallmark associated also to aggressive behavior and drug resistance.	('expression levels', 'MPA', (168, 185))	('ALDH1', 'Gene', (152, 157))	('ALDH1', 'Gene', '216', (152, 157))	('p62', 'Var', (189, 192))	('drug resistance', 'Phenotype', 'HP:0020174', (248, 263))	('ovarian', 'Disease', (76, 83))	('ovarian', 'Disease', 'MESH:D010049', (76, 83))	('aggressive behavior', 'Phenotype', 'HP:0000718', (224, 243))
420938	31097977	Among these features, chemoresistance, colony/sphere formation, tumor growth, and the expression of CSC markers were strongly abrogated, an effect that was also produced by NRF2 silencing (see Table 2).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('colony/sphere formation', 'CPA', (39, 62))	('tumor', 'Disease', (64, 69))	('chemoresistance', 'CPA', (22, 37))	('NRF2', 'Gene', (173, 177))	('expression', 'MPA', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('abrogated', 'NegReg', (126, 135))	('silencing', 'Var', (178, 187))	('CSC markers', 'Gene', (100, 111))
420941	31097977	In another context, by screening a collection of 5879 known bioactive compounds and FDA-approved drugs in HepG2, Liu and coworkers demonstrated that the CDC7/CDK9 inhibitor PHA-767491 was also a potent suppressor of NRF2 transcriptional activity.	('NRF2', 'Gene', (216, 220))	('rat', 'Species', '10116', (138, 141))	('PHA-767491', 'Var', (173, 183))	('CDC7', 'Gene', (153, 157))	('suppressor', 'NegReg', (202, 212))	('HepG2', 'CellLine', 'CVCL:0027', (106, 111))	('CDC7', 'Gene', '8317', (153, 157))	('CDK9', 'Gene', (158, 162))	('transcriptional activity', 'MPA', (221, 245))	('CDK9', 'Gene', '1025', (158, 162))
420942	31097977	Validation assays performed in MM cells confirmed that PHA-767491 prevented NRF2 nuclear translocation, increased the mitochondrial superoxide generation, and suppressed cell growth (see Table 2).	('PHA-767491', 'Var', (55, 65))	('cell growth', 'CPA', (170, 181))	('increased', 'PosReg', (104, 113))	('superoxide', 'Chemical', 'MESH:D013481', (132, 142))	('NRF2', 'Gene', (76, 80))	('nuclear translocation', 'CPA', (81, 102))	('prevented', 'NegReg', (66, 75))	('mitochondrial superoxide generation', 'MPA', (118, 153))	('rat', 'Species', '10116', (147, 150))	('suppressed', 'NegReg', (159, 169))
420947	31097977	However, this indicates that NRF2 inhibitors might effectively increase the efficacy of many chemotherapeutics in HCC patients (see Table 2).	('increase', 'PosReg', (63, 71))	('efficacy', 'MPA', (76, 84))	('HCC', 'Phenotype', 'HP:0001402', (114, 117))	('inhibitors', 'Var', (34, 44))	('NRF2', 'Gene', (29, 33))	('HCC', 'Disease', (114, 117))	('patients', 'Species', '9606', (118, 126))
420953	31097977	Mechanistically, CP was found to prevent NRF2 nuclear accumulation and promote its degradation through the beta-TrCP-dependent pathway, leading to ROS accumulation and marked suppression of anchorage-independent growth in several NSCLC cell lines with mutant KEAP1.	('NRF2', 'Gene', (41, 45))	('prevent', 'NegReg', (33, 40))	('promote', 'PosReg', (71, 78))	('degradation', 'MPA', (83, 94))	('ROS', 'Chemical', 'MESH:D017382', (147, 150))	('accumulation', 'PosReg', (151, 163))	('nuclear accumulation', 'MPA', (46, 66))	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('anchorage-independent growth', 'CPA', (190, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (230, 235))	('beta-TrCP', 'Gene', (107, 116))	('beta-TrCP', 'Gene', '8945', (107, 116))	('mutant', 'Var', (252, 258))	('ROS', 'MPA', (147, 150))	('NSCLC', 'Disease', (230, 235))	('suppression', 'NegReg', (175, 186))
420954	31097977	Moreover, when used alone or in combination with Rapamycin in vitro or in vivo, CP impaired the growth of tumors harboring KEAP1 or both KEAP1/LKB1 mutations, a frequent event in lung cancer.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('mutations', 'Var', (148, 157))	('LKB1', 'Gene', '6794', (143, 147))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('CP impaired the growth of tumors', 'Disease', (80, 112))	('CP impaired the growth of tumors', 'Disease', 'MESH:D006130', (80, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('Rapamycin', 'Chemical', 'MESH:D020123', (49, 58))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))	('LKB1', 'Gene', (143, 147))
420955	31097977	Therefore, CP could be a repurposed therapeutic agent for tumors with high NRF2 activity while the combined use of CP and Rapamycin might be a valid clinical approach in tumors with KEAP1 and LKB1 mutations (see Table 2).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('LKB1', 'Gene', (192, 196))	('Rapamycin', 'Chemical', 'MESH:D020123', (122, 131))	('tumors', 'Disease', (58, 64))	('LKB1', 'Gene', '6794', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('NRF2', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutations', 'Var', (197, 206))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('activity', 'MPA', (80, 88))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (170, 176))
420967	31097977	In this regard, earlier studies reported that Metformin inhibited proliferation in several cancer cell lines by suppressing HO-1 expression through the inhibition of a RAF/ERK/NRF2 signaling and AMPK-independent pathways that promoted a marked decrease in the NRF2 protein content.	('inhibition', 'NegReg', (152, 162))	('decrease', 'NegReg', (244, 252))	('AMPK', 'Gene', (195, 199))	('NRF2 protein content', 'MPA', (260, 280))	('RAF', 'Gene', (168, 171))	('expression', 'MPA', (129, 139))	('Metformin', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Metformin', 'Chemical', 'MESH:D008687', (46, 55))	('HO-1', 'Gene', '3162', (124, 128))	('AMPK', 'Gene', '5562', (195, 199))	('inhibited', 'NegReg', (56, 65))	('HO-1', 'Gene', (124, 128))	('suppressing', 'NegReg', (112, 123))	('proliferation', 'CPA', (66, 79))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('RAF', 'Gene', '22882', (168, 171))	('rat', 'Species', '10116', (73, 76))
420976	31097977	Here, Metformin was shown to exert antineoplastic effects by inhibiting cell proliferation and enhancing apoptotic cell death in HT29 CRC cell lines, as a consequence of the transcriptional inactivation produced on NRF2 and NF-kappaB (see Table 2).	('HT29 CRC', 'CellLine', 'CVCL:8478', (129, 137))	('apoptotic cell death', 'CPA', (105, 125))	('inhibiting', 'NegReg', (61, 71))	('CRC', 'Phenotype', 'HP:0003003', (134, 137))	('enhancing', 'PosReg', (95, 104))	('rat', 'Species', '10116', (84, 87))	('NRF2', 'Gene', (215, 219))	('cell proliferation', 'CPA', (72, 90))	('NF-kappaB', 'Protein', (224, 233))	('Metformin', 'Var', (6, 15))	('transcriptional', 'MPA', (174, 189))	('CRC', 'Phenotype', 'HP:0030731', (134, 137))	('Metformin', 'Chemical', 'MESH:D008687', (6, 15))
420977	31097977	Also, additional research from Yu and coworkers demonstrated that Metformin was able to sensitize A549 NSCLC cells but not normal lung epithelial BEAS-2B cells, to the natural compound EGCG by inducing ROS-dependent apoptosis.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('rat', 'Species', '10116', (55, 58))	('Metformin', 'Chemical', 'MESH:D008687', (66, 75))	('inducing', 'PosReg', (193, 201))	('NSCLC', 'Disease', (103, 108))	('ROS', 'Chemical', 'MESH:D017382', (202, 205))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('EGCG', 'Chemical', 'MESH:C045651', (185, 189))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('BEAS-2B', 'CellLine', 'CVCL:0168', (146, 153))	('Metformin', 'Var', (66, 75))	('ROS-dependent apoptosis', 'CPA', (202, 225))
420982	31097977	Interestingly, the antitubercular agent Isoniazid (INH) known to induce hepatotoxicity in patients subdued to long-term treatment was found to induce ROS accumulation and apoptosis in HepG2 HCC and in transformed human liver THLE-2 cells, by preventing NRF2 nuclear translocation due to the inhibition of its importer Karyopherin beta1 (see Table 2).	('hepatotoxicity', 'Disease', (72, 86))	('THLE-2', 'CellLine', 'CVCL:3803', (225, 231))	('ROS', 'MPA', (150, 153))	('importer', 'MPA', (309, 317))	('ROS', 'Chemical', 'MESH:D017382', (150, 153))	('nuclear translocation', 'MPA', (258, 279))	('accumulation', 'PosReg', (154, 166))	('preventing', 'NegReg', (242, 252))	('apoptosis', 'CPA', (171, 180))	('HCC', 'Phenotype', 'HP:0001402', (190, 193))	('inhibition', 'NegReg', (291, 301))	('Isoniazid', 'Var', (40, 49))	('hepatotoxicity', 'Disease', 'MESH:D056486', (72, 86))	('Isoniazid', 'Chemical', 'MESH:D007538', (40, 49))	('NRF2', 'Protein', (253, 257))	('human', 'Species', '9606', (213, 218))	('induce', 'PosReg', (143, 149))	('patients', 'Species', '9606', (90, 98))	('HepG2 HCC', 'CellLine', 'CVCL:0027', (184, 193))
420987	31097977	Of note, given the functional location of NRF2 at the crossroad of multiple pathways, pharmacologic manipulations of upstream regulators or downstream effectors of NRF2 signaling might also produce remarkable anticancer effects and synergize with already established drugs through mechanisms that almost invariantly converge on the disruption of the intracellular redox homeostasis.	('NRF2', 'Gene', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('NRF2', 'Gene', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('pharmacologic', 'Var', (86, 99))	('cancer', 'Disease', (213, 219))
421008	29567990	In this present study, we found that the Wnt signaling activity was higher in the radioresistant cell lines compared with parental esophageal squamous cell lines and inhibition of Wnt signaling could reverse the resistance to IR in the radioresistant cell lines.	('parental esophageal squamous cell lines', 'Disease', (122, 161))	('resistance to IR', 'MPA', (212, 228))	('higher', 'PosReg', (68, 74))	('Wnt signaling activity', 'MPA', (41, 63))	('parental esophageal squamous cell lines', 'Disease', 'MESH:D000077277', (122, 161))	('inhibition', 'Var', (166, 176))
421014	29567990	From the tumor growth curves, we could see that rECA109 and rKyse150 were more resistant to IR compared with parental ECA109 and Kyse150, respectively (Fig.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('resistant to IR', 'MPA', (79, 94))	('tumor', 'Disease', (9, 14))	('rKyse150', 'Var', (60, 68))	('rECA109', 'Var', (48, 55))
421015	29567990	The tumor growth delays of rECA109 and rKyse150 (50% and 47%) were significantly lower than ECA109 and Kyse150, respectively (81% and 83%) (Supplementary Table S1).	('lower', 'NegReg', (81, 86))	('tumor growth delay', 'Disease', 'MESH:D006130', (4, 22))	('growth delay', 'Phenotype', 'HP:0001510', (10, 22))	('tumor growth delay', 'Disease', (4, 22))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('growth delays', 'Phenotype', 'HP:0001510', (10, 23))	('rKyse150', 'Var', (39, 47))
421017	29567990	2b, E-cadherin was decreased while Slug and Vimentin were increased in rECA109 and rKyse150 compared with ECA109 and Kyse150.	('E-cadherin', 'Gene', '999', (4, 14))	('rECA109', 'Var', (71, 78))	('increased', 'PosReg', (58, 67))	('rKyse150', 'Var', (83, 91))	('Vimentin', 'Gene', (44, 52))	('Slug', 'Gene', '6591', (35, 39))	('Slug', 'Gene', (35, 39))	('decreased', 'NegReg', (19, 28))	('E-cadherin', 'Gene', (4, 14))	('Vimentin', 'Gene', '7431', (44, 52))
421019	29567990	Western blotting analysis indicated that beta-catenin and Wnt target genes c-myc were upregulated in rECA109 and rKyse150 (Fig.	('rKyse150', 'Var', (113, 121))	('beta-catenin', 'Gene', (41, 53))	('rECA109', 'Gene', (101, 108))	('beta-catenin', 'Gene', '1499', (41, 53))	('upregulated', 'PosReg', (86, 97))	('c-myc', 'Gene', '4609', (75, 80))	('c-myc', 'Gene', (75, 80))
421027	29567990	In addition, we tested another DSB biomarker, mediator of DNA damage checkpoint protein 1 (MDC1) whose change was consistent with gammaH2AX foci (Suppl.	('tested', 'Reg', (16, 22))	('mediator of DNA damage checkpoint protein 1', 'Gene', '9656', (46, 89))	('gammaH2AX', 'Var', (130, 139))	('MDC1', 'Gene', (91, 95))	('MDC1', 'Gene', '9656', (91, 95))	('mediator of DNA damage checkpoint protein 1', 'Gene', (46, 89))
421043	29567990	ChIP assay indicated that the HMGB1 genomic DNA promoter fragment (-4146 to -3801; -3099 to -2793) could be amplified by in groups using TCF4 or beta-catenin antibody to immunoprecipitate chromatin, which indicated that beta-catenin/TCF4 heterodimer could directly bind to the promoter of HMGB1 (Fig.	('TCF4', 'Gene', (233, 237))	('TCF4', 'Gene', '6925', (233, 237))	('HMGB1', 'Gene', (30, 35))	('HMGB1', 'Gene', '3146', (30, 35))	('beta-catenin', 'Gene', '1499', (220, 232))	('beta-catenin', 'Gene', (145, 157))	('bind', 'Interaction', (265, 269))	('-4146', 'Var', (67, 72))	('HMGB1', 'Gene', '3146', (289, 294))	('beta-catenin', 'Gene', '1499', (145, 157))	('HMGB1', 'Gene', (289, 294))	('TCF4', 'Gene', (137, 141))	('TCF4', 'Gene', '6925', (137, 141))	('beta-catenin', 'Gene', (220, 232))
421087	29567990	Upon inhibition of Wnt signaling, HMGB1 was downregulated and WNT1 upregulated HMGB1.	('WNT1', 'Gene', (62, 66))	('downregulated', 'NegReg', (44, 57))	('inhibition', 'Var', (5, 15))	('WNT1', 'Gene', '7471', (62, 66))	('HMGB1', 'Gene', (34, 39))	('HMGB1', 'Gene', (79, 84))	('HMGB1', 'Gene', '3146', (34, 39))	('HMGB1', 'Gene', '3146', (79, 84))	('upregulated', 'PosReg', (67, 78))
421090	29567990	Furthermore, blocking HMGB1 sensitized radioresistant cells to IR with the inhibition of DNA damage repair while overexpressing HMGB1 promoted parental cells radioresisance with the enhancement of DNA damage repair.	('HMGB1', 'Gene', (22, 27))	('HMGB1', 'Gene', '3146', (22, 27))	('blocking', 'Var', (13, 21))	('radioresisance', 'CPA', (158, 172))	('inhibition', 'NegReg', (75, 85))	('HMGB1', 'Gene', '3146', (128, 133))	('HMGB1', 'Gene', (128, 133))	('enhancement', 'PosReg', (182, 193))
421091	29567990	Moreover, blocking HMGB1 partly attenuated WNT1-induced radioresistance and DNA damage repair.	('HMGB1', 'Gene', '3146', (19, 24))	('DNA damage repair', 'CPA', (76, 93))	('blocking', 'Var', (10, 18))	('attenuated', 'NegReg', (32, 42))	('WNT1', 'Gene', (43, 47))	('HMGB1', 'Gene', (19, 24))	('WNT1', 'Gene', '7471', (43, 47))	('radioresistance', 'CPA', (56, 71))
421101	29567990	Briefly, before IR exposure, cells were subjected to different stimulation including recombinant WNT1 treatment (abcam; UK), iCRT14 treatment (MCE; USA), plenti-HMGB1 or SiHMGB1 transfection.	('WNT1', 'Gene', (97, 101))	('HMGB1', 'Gene', (161, 166))	('HMGB1', 'Gene', '3146', (161, 166))	('transfection', 'Var', (178, 190))	('WNT1', 'Gene', '7471', (97, 101))	('HMGB1', 'Gene', (172, 177))	('HMGB1', 'Gene', '3146', (172, 177))
421126	29552622	The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes Aberrations in the esophageal proliferation-differentiation gradient are histologic hallmarks in eosinophilic esophagitis (EoE) and gastroesophageal reflux disease.	('eosinophilic esophagitis', 'Disease', 'MESH:D004802', (216, 240))	('gastroesophageal reflux disease', 'Disease', (251, 282))	('esophagitis', 'Phenotype', 'HP:0100633', (229, 240))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (251, 274))	('Aberrations', 'Var', (119, 130))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (251, 282))	('eosinophilic esophagitis', 'Phenotype', 'HP:0410151', (216, 240))	('eosinophilic esophagitis', 'Disease', (216, 240))	('EoE', 'Phenotype', 'HP:0410151', (242, 245))
421132	29552622	Genetic and pharmacologic manipulations establish proof of concept for the utility of organoids for future studies and personalized medicine in EoE and other esophageal diseases.	('esophageal diseases', 'Disease', 'MESH:D004935', (158, 177))	('EoE', 'Phenotype', 'HP:0410151', (144, 147))	('manipulations', 'Var', (26, 39))	('EoE', 'Disease', (144, 147))	('esophageal diseases', 'Disease', (158, 177))
421133	29552622	We optimized culture conditions for 3-dimensional mouse and human esophageal organoids and used this experimental platform with potential applications toward personalized medicine to identify disruption of notch3-mediated squamous cell differentiation as a mechanism contributing to reactive epithelial changes under inflammatory conditions.	('squamous cell differentiation', 'CPA', (222, 251))	('notch3', 'Gene', '4854', (206, 212))	('notch3', 'Gene', (206, 212))	('disruption', 'Var', (192, 202))	('mouse', 'Species', '10090', (50, 55))	('contributing', 'Reg', (267, 279))	('human', 'Species', '9606', (60, 65))
421159	29552622	Murine esophageal epithelial sheets were prepared as described from wild-type C57BL/6J mice and Notch1loxP/loxP mice (Jackson Laboratory, Bar Harbor, ME).	('esophageal epithelia', 'Disease', (7, 27))	('esophageal epithelia', 'Disease', 'MESH:D004941', (7, 27))	('mice', 'Species', '10090', (87, 91))	('Murine', 'Species', '10090', (0, 6))	('Notch1loxP/loxP', 'Var', (96, 111))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (7, 27))	('mice', 'Species', '10090', (112, 116))
421160	29552622	Telomerase-immortalized normal human esophageal epithelial cell line EPC2-hTERT and derivatives carrying GFP, DNMAML1, or DNMAML1Tet-Off  were grown in keratinocyte-SFM (KSFM) medium containing 0.09 mM Ca2+ as described previously.	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (69, 79))	('DNMAML1', 'Chemical', '-', (122, 129))	('Ca2+', 'Chemical', 'MESH:D000069285', (202, 206))	('DNMAML1', 'Chemical', '-', (110, 117))	('human', 'Species', '9606', (31, 36))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (37, 57))	('esophageal epithelia', 'Disease', 'MESH:D004941', (37, 57))	('KSFM', 'Chemical', '-', (170, 174))	('DNMAML1Tet-Off', 'Var', (122, 136))	('esophageal epithelia', 'Disease', (37, 57))
421162	29552622	For ex vivo Notch1 deletion in 3D esophageal organoids generated from Notch1loxP/loxP mice, organoids were incubated with Adenovirus expressing Cre recombinase or green fluorescent protein (GFP, control) (University of Iowa Gene Transfer Vector Core).	('mice', 'Species', '10090', (86, 90))	('deletion', 'Var', (19, 27))	('Notch1', 'Gene', (12, 18))
421187	29552622	Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was done with TaqMan Gene Expression Assays (Applied Biosystems, Foster City, CA) for NOTCH1 (Hs01062014_m1), NOTCH2 (Hs00225747_m1), NOTCH3 (Hs00166432_m1), NOTCH4 (Hs00270200_m1), JAG2 (Hs00171432_m1), DLL1 (Hs00194509_m1), HES5 (Hs01387463_g1), IVL (Hs00846307_s1), FLG (Hs00863478_g1),and GAPDH (Hs99999905_m1), using the StepOnePlus Real-Time PCR System (Applied Biosystems).	('FLG', 'Gene', (340, 343))	('NOTCH3', 'Gene', '4854', (205, 211))	('Hs00171432_m1', 'Var', (259, 272))	('JAG2', 'Gene', '3714', (253, 257))	('NOTCH3', 'Gene', (205, 211))	('Hs00863478_g1', 'Var', (345, 358))	('Hs01062014_m1', 'Var', (165, 178))	('NOTCH2', 'Gene', (181, 187))	('DLL1', 'Gene', (275, 279))	('FLG', 'Gene', '2312', (340, 343))	('Hs00270200_m1', 'Var', (237, 250))	('NOTCH1', 'Gene', (157, 163))	('HES5', 'Gene', (297, 301))	('GAPDH', 'Gene', '2597', (364, 369))	('NOTCH4', 'Gene', (229, 235))	('NOTCH4', 'Gene', '4855', (229, 235))	('NOTCH1', 'Gene', '4851', (157, 163))	('DLL1', 'Gene', '28514', (275, 279))	('Hs00225747_m1', 'Var', (189, 202))	('IVL', 'Gene', '3713', (319, 322))	('Hs00166432_m1', 'Var', (213, 226))	('Hs01387463_g1', 'Var', (303, 316))	('GAPDH', 'Gene', (364, 369))	('JAG2', 'Gene', (253, 257))	('IVL', 'Gene', (319, 322))	('HES5', 'Gene', '388585', (297, 301))	('NOTCH2', 'Gene', '4853', (181, 187))	('Hs00194509_m1', 'Var', (281, 294))	('Hs00846307_s1', 'Var', (324, 337))
421204	29552622	Additionally, although organoid formation efficiency was comparable between KSFMC and aDMEM/F12, the latter supplemented either fully or partially (with EGF, R-Spondin1, and Noggin only) (Figure 2E and F, and data not shown); OFR was impaired on culture in KFSM as compared to KSFMC (Figure 2F).	('KSFMC', 'Chemical', '-', (76, 81))	('EGF', 'Gene', (153, 156))	('EGF', 'Gene', '1950', (153, 156))	('KSFMC', 'Chemical', '-', (277, 282))	('KFSM', 'Var', (257, 261))	('impaired', 'NegReg', (234, 242))
421222	29552622	Notch inhibition is expected to perturb squamous cell differentiation, resulting in accumulation of undifferentiated basal keratinocytes and hyperkeratosis.	('squamous cell differentiation', 'CPA', (40, 69))	('undifferentiated basal keratinocytes', 'CPA', (100, 136))	('hyperkeratosis', 'Disease', 'MESH:D017488', (141, 155))	('Notch inhibition', 'Var', (0, 16))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (141, 155))	('perturb', 'Reg', (32, 39))	('accumulation', 'PosReg', (84, 96))	('hyperkeratosis', 'Disease', (141, 155))
421229	29552622	Finally, these findings were recapitulated in murine esophageal organoids on GSI treatment or adenoviral Cre-mediated Notch1 deletion ex vivo (Figure 5D-F).	('GSI', 'Chemical', '-', (77, 80))	('Notch1', 'Gene', (118, 124))	('murine', 'Species', '10090', (46, 52))	('deletion', 'Var', (125, 133))
421237	29552622	Moreover, Notch inhibition suppressed OFR in mice, but not human (Figure 7), in agreement with our recent findings in neoplastic murine esophageal 3D organoids, suggesting a potential species difference in the role of Notch signaling in esophageal epithelial cells.	('esophageal epithelia', 'Disease', 'MESH:D004941', (237, 257))	('Notch', 'Var', (10, 15))	('human', 'Species', '9606', (59, 64))	('mice', 'Species', '10090', (45, 49))	('OFR', 'MPA', (38, 41))	('esophageal epithelia', 'Disease', (237, 257))	('inhibition suppressed', 'NegReg', (16, 37))	('murine', 'Species', '10090', (129, 135))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (237, 257))
421242	29552622	Although NOTCH3 protein was not detectable, our preliminary IHC analysis suggested that esophageal biopsies from active EoE patients (n = 5) display downregulation of ICN1Val1744, the activated form of NOTCH1 that is expressed in the basal compartment of normal squamous epithelia in non-EoE normal biopsies (n = 4) (Figure 8B and data not shown).	('NOTCH3', 'Gene', '4854', (9, 15))	('EoE', 'Phenotype', 'HP:0410151', (288, 291))	('squamous epithelia', 'Disease', (262, 280))	('EoE', 'Phenotype', 'HP:0410151', (120, 123))	('ICN1Val1744', 'Var', (167, 178))	('NOTCH3', 'Gene', (9, 15))	('NOTCH1', 'Gene', (202, 208))	('NOTCH1', 'Gene', '4851', (202, 208))	('squamous epithelia', 'Disease', 'MESH:D002294', (262, 280))	('squamous epithelia', 'Phenotype', 'HP:0002860', (262, 280))	('downregulation', 'NegReg', (149, 163))	('patients', 'Species', '9606', (124, 132))
421256	29552622	Among factors and agents originally used for murine esophageal 3D organoids, R-Spondin1 and Noggin, Wnt3A, or A83-01 improved OFR in passaged organoids in KSFMC; however, SB202190, a p38 mitogen-activated protein kinase inhibitor, impaired organoid formation by human cells.	('organoid formation by human cells', 'CPA', (240, 273))	('SB202190', 'Var', (171, 179))	('OFR', 'MPA', (126, 129))	('human', 'Species', '9606', (262, 267))	('impaired', 'NegReg', (231, 239))	('murine', 'Species', '10090', (45, 51))	('KSFMC', 'Chemical', '-', (155, 160))	('SB202190', 'Chemical', 'MESH:C090942', (171, 179))
421258	29552622	Given the inhibitory effect of SB202190, human esophageal cells may be sensitive to p38 mitogen-activated protein kinase-mediated processes, raising the possibility that antioxidants may alleviate cellular stress and improve cell survival.	('SB202190', 'Chemical', 'MESH:C090942', (31, 39))	('cellular stress', 'MPA', (197, 212))	('improve', 'PosReg', (217, 224))	('SB202190', 'Var', (31, 39))	('human', 'Species', '9606', (41, 46))	('alleviate', 'PosReg', (187, 196))	('cell survival', 'CPA', (225, 238))
421264	29552622	Added into KSFM via CaCl2, Ca2+ may facilitate cell-cell contact via adhesion molecules, such as E-cadherin, to activate Notch signaling and squamous cell differentiation.	('Ca2+', 'Var', (27, 31))	('cell-cell contact', 'CPA', (47, 64))	('Ca2+', 'Chemical', 'MESH:D000069285', (27, 31))	('E-cadherin', 'Gene', (97, 107))	('E-cadherin', 'Gene', '999', (97, 107))	('CaCl2', 'Chemical', 'MESH:D002122', (20, 25))	('Notch signaling', 'Pathway', (121, 136))	('facilitate', 'PosReg', (36, 46))	('KSFM', 'Chemical', '-', (11, 15))	('squamous cell differentiation', 'CPA', (141, 170))	('activate', 'PosReg', (112, 120))
421273	29552622	It should be noted that Notch3 may limit EMT in normal esophageal epithelial cells.	('esophageal epithelia', 'Phenotype', 'HP:0012859', (55, 75))	('esophageal epithelia', 'Disease', 'MESH:D004941', (55, 75))	('Notch3', 'Var', (24, 30))	('esophageal epithelia', 'Disease', (55, 75))	('limit', 'NegReg', (35, 40))
421275	29552622	Interestingly, Notch-mutant mice display atopic dermatitis-like disease in the skin with epithelial induction of Tslp expression, BCH, spongiosis, hyperkeratosis, and dermal eosinophilia with concurrent upregulation of IL4 and IL13, all relevant to EoE.	('eosinophilia', 'Phenotype', 'HP:0001880', (174, 186))	('Tslp expression', 'Gene', (113, 128))	('hyperkeratosis', 'Disease', (147, 161))	('hyperkeratosis', 'Disease', 'MESH:D017488', (147, 161))	('IL4', 'Gene', (219, 222))	('dermal eosinophilia', 'Phenotype', 'HP:0032022', (167, 186))	('mice', 'Species', '10090', (28, 32))	('dermatitis', 'Phenotype', 'HP:0011123', (48, 58))	('BCH', 'Disease', (130, 133))	('dermal eosinophilia', 'Disease', 'MESH:D004802', (167, 186))	('display atopic dermatitis', 'Phenotype', 'HP:0001047', (33, 58))	('spongiosis', 'Disease', (135, 145))	('IL13', 'Gene', (227, 231))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (147, 161))	('upregulation', 'PosReg', (203, 215))	('dermal eosinophilia', 'Disease', (167, 186))	('EoE', 'Phenotype', 'HP:0410151', (249, 252))	('IL4', 'Gene', '16189', (219, 222))	('atopic dermatitis-like disease', 'Disease', 'MESH:D003876', (41, 71))	('atopic dermatitis-like disease', 'Disease', (41, 71))	('Notch-mutant', 'Var', (15, 27))
421295	26622820	It has been demonstrated that CKI suppresses tumor cell growth by inducing apoptosis and inhibits the migration, invasion and adhesion capacity of tumor cells by downregulating the protein expression of CD44v6.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('CD44v6', 'Gene', (203, 209))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('inhibits', 'NegReg', (89, 97))	('inducing', 'NegReg', (66, 74))	('apoptosis', 'CPA', (75, 84))	('suppresses', 'NegReg', (34, 44))	('tumor', 'Disease', (45, 50))	('downregulating', 'NegReg', (162, 176))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('CKI', 'Var', (30, 33))	('migration', 'CPA', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('protein expression', 'MPA', (181, 199))
421307	26622820	The following day, the adherent cells (60-70% adherence) were placed in RPMI-1640 medium supplemented with 0.2% FBS, and the supernatant was extracted after 24 h. The compound Radix Sophorae Flavescentis injection was then added to the medium at various concentrations (final concentrations: 0, 0.0125, 0.025, 0.05, 0.1, 0.2, 0.4 and 0.8 mg/ml) with a total of 8 gradients, followed by culture for 24 h. There were 4 different treatment groups: the control group (untreated cells), the low-dose group (0.05 mg/ml of the compound), the medium-dose group (0.2 mg/ml of the compound) and the high-dose group (0.8 ng/ml) of the compound.	('FBS', 'Disease', (112, 115))	('FBS', 'Disease', 'MESH:D005198', (112, 115))	('RPMI-1640 medium', 'Chemical', '-', (72, 88))	('0.05 mg/ml', 'Var', (502, 512))
421358	22622863	Hyperinsulinemia acting through aberrations in the insulin-like growth factor pathways and steroid hormone metabolism, but also through independent mitogenic actions, is the main mechanism suggested to explain the association between diabetes and cancer.	('diabetes', 'Disease', (234, 242))	('steroid hormone', 'Chemical', 'MESH:D013256', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('insulin', 'Gene', (5, 12))	('diabetes', 'Disease', 'MESH:D003920', (234, 242))	('Hyperinsulinemia', 'Disease', (0, 16))	('insulin', 'Gene', '3630', (5, 12))	('cancer', 'Disease', (247, 253))	('aberrations', 'Var', (32, 43))	('steroid hormone metabolism', 'MPA', (91, 117))	('Hyperinsulinemia', 'Disease', 'MESH:D006946', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('insulin', 'Gene', (51, 58))	('Hyperinsulinemia', 'Phenotype', 'HP:0000842', (0, 16))	('insulin', 'Gene', '3630', (51, 58))
421412	22622863	However, when diabetes treatment was separated into metformin or non-metformin, only pancreatic cancer was significantly associated with metformin treatment, while all listed cancers were significantly associated with diabetes with non-metformin treatment.	('men', 'Species', '9606', (28, 31))	('metformin', 'Chemical', 'MESH:D008687', (236, 245))	('diabetes', 'Disease', 'MESH:D003920', (14, 22))	('metformin', 'Chemical', 'MESH:D008687', (52, 61))	('metformin', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('metformin', 'Chemical', 'MESH:D008687', (137, 146))	('men', 'Species', '9606', (152, 155))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('pancreatic cancer', 'Disease', (85, 102))	('diabetes', 'Disease', 'MESH:D003920', (218, 226))	('diabetes', 'Disease', (14, 22))	('men', 'Species', '9606', (251, 254))	('associated', 'Reg', (121, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('metformin', 'Chemical', 'MESH:D008687', (69, 78))	('diabetes', 'Disease', (218, 226))
421454	22622863	For example, studies observed that patients with type 2 diabetes exposed to sulfonylureas and exogenous insulin had a significantly increased risk of cancer-related mortality compared with patients exposed to metformin.	('type 2 diabetes', 'Phenotype', 'HP:0005978', (49, 64))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('diabetes', 'Disease', (56, 64))	('metformin', 'Chemical', 'MESH:D008687', (209, 218))	('cancer', 'Disease', (150, 156))	('diabetes', 'Disease', 'MESH:D003920', (56, 64))	('sulfonylureas', 'Chemical', 'MESH:D013453', (76, 89))	('insulin', 'Gene', (104, 111))	('patients', 'Species', '9606', (35, 43))	('patients', 'Species', '9606', (189, 197))	('insulin', 'Gene', '3630', (104, 111))	('sulfonylureas', 'Var', (76, 89))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
421456	22622863	An increased risk of GI cancer was noted in patients with non-metformin treatment but not in patients with metformin treatment with an exception for pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('patients', 'Species', '9606', (44, 52))	('GI cancer', 'Disease', (21, 30))	('GI cancer', 'Phenotype', 'HP:0007378', (21, 30))	('men', 'Species', '9606', (77, 80))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('pancreatic cancer', 'Disease', (149, 166))	('non-metformin treatment', 'Var', (58, 81))	('metformin', 'Chemical', 'MESH:D008687', (62, 71))	('metformin', 'Chemical', 'MESH:D008687', (107, 116))	('GI cancer', 'Disease', 'MESH:D009369', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('patients', 'Species', '9606', (93, 101))	('men', 'Species', '9606', (122, 125))
421489	24003404	Moreover, in our institution, patients who have received radiation in the mediastinum are also contraindicated for minimally invasive esophagectomy because the radiation might have destroyed the layered structure and have caused tissue adhesions such that the layers cannot be recognized to cut and divide.	('tin', 'Chemical', 'MESH:D014001', (80, 83))	('tissue adhesions', 'CPA', (229, 245))	('layered structure', 'CPA', (195, 212))	('destroyed', 'NegReg', (181, 190))	('patients', 'Species', '9606', (30, 38))	('caused', 'Reg', (222, 228))	('radiation', 'Var', (160, 169))
421528	24003404	Furthermore, secondary endpoints, including pain score, intraoperative blood loss, duration of hospitalization, and quality of life at 6 weeks after surgery, were significantly better following the minimally invasive procedure than in the open group.	('minimally invasive procedure', 'Var', (198, 226))	('quality of life', 'CPA', (116, 131))	('pain', 'Phenotype', 'HP:0012531', (44, 48))	('pain', 'Disease', 'MESH:D010146', (44, 48))	('pain', 'Disease', (44, 48))	('intraoperative blood loss', 'Disease', (56, 81))	('better', 'PosReg', (177, 183))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (56, 81))
421536	24003404	We have performed radio-guided SLN mapping for cT1aN0 or cT2N0 esophageal cancer to verify the feasibility of SLN mapping.	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('cT1aN0', 'Var', (47, 53))	('cT2N0', 'Var', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
421540	24003404	We developed a radio-guided method to detect SLN in esophageal cancer rather than the conventional blue-dye method.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('SLN', 'Var', (45, 48))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))
421543	24003404	reported our results of a radio-guided SLN navigation validation study of esophageal cancer; 75 consecutive patients who were diagnosed preoperatively with T1N0M0 or T2N0M0 primary esophageal cancer were enrolled.	('esophageal cancer', 'Disease', (181, 198))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('T1N0M0', 'Var', (156, 162))	('esophageal cancer', 'Disease', (74, 91))	('T2N0M0', 'Var', (166, 172))	('patients', 'Species', '9606', (108, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
421699	33470377	However, in a different analysis, with the same objective but in T2N0M0 patients, tumor grade shows to be an independent factor, whereas localization wasn t 23.	('T2N0M0', 'Var', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('patients', 'Species', '9606', (72, 80))
421719	33469362	In addition, sarcopenia (P = 0.002, HR = 3.991, 95% CI: 1.653-9.638) and LMR < 2.67 (P < 0.001, HR = 2.665, 95% CI: 1.563-4.543) were independent predictors of OS.	('sarcopenia', 'Disease', 'MESH:D055948', (13, 23))	('sarcopenia', 'Disease', (13, 23))	('LMR < 2.67', 'Var', (73, 83))
421768	33469362	In the sarcopenia group, patients with LMR>=2.67 had significantly longer median OS compared to those with LMR<2.67 (19 months vs 9 months, P<0.001, Figure 2B).	('sarcopenia', 'Disease', (7, 17))	('LMR<2', 'Gene', (107, 112))	('LMR>=2.67', 'Var', (39, 48))	('patients', 'Species', '9606', (25, 33))	('sarcopenia', 'Disease', 'MESH:D055948', (7, 17))	('LMR<2', 'Gene', '22853', (107, 112))	('longer', 'PosReg', (67, 73))
421769	33469362	To assess the combined prognostic value of sarcopenia and LMR, we stratified the patients based on the SLMR score as defined by Lin et al: 0 - no sarcopenia and LMR <2.67 (N=17), 1 - sarcopenia or LMR <2.67 (N=57), 2 - sarcopenia and LMR <2.67 (N=26).	('sarcopenia', 'Disease', 'MESH:D055948', (146, 156))	('sarcopenia', 'Disease', 'MESH:D055948', (183, 193))	('sarcopenia', 'Disease', 'MESH:D055948', (43, 53))	('sarcopenia', 'Disease', (43, 53))	('sarcopenia', 'Disease', (146, 156))	('sarcopenia', 'Disease', (183, 193))	('sarcopenia', 'Disease', 'MESH:D055948', (219, 229))	('patients', 'Species', '9606', (81, 89))	('LMR', 'Var', (197, 200))	('sarcopenia', 'Disease', (219, 229))
421771	33469362	In addition, CCRT significantly prolonged the median OS of patients with sarcopenia (14 months vs 8 months, P=0.025, Figure 3).	('prolonged', 'PosReg', (32, 41))	('CCRT', 'Var', (13, 17))	('sarcopenia', 'Disease', (73, 83))	('patients', 'Species', '9606', (59, 67))	('sarcopenia', 'Disease', 'MESH:D055948', (73, 83))
421778	33469362	We found that sarcopenia and LMR are independent prognostic factors for esophageal cancer patients undergoing definitive radiotherapy, and lower LMR indicates a higher risk of pre-treatment sarcopenia.	('lower', 'Var', (139, 144))	('sarcopenia', 'Disease', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('sarcopenia', 'Disease', (190, 200))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('patients', 'Species', '9606', (90, 98))	('sarcopenia', 'Disease', 'MESH:D055948', (14, 24))	('sarcopenia', 'Disease', 'MESH:D055948', (190, 200))
421809	33469362	Another study showed that high LMR was predictive of better clinical response and prognosis for patients with locally advanced esophageal cancer receiving definitive CCRT.	('esophageal cancer', 'Disease', (127, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('patients', 'Species', '9606', (96, 104))	('high LMR', 'Var', (26, 34))	('better', 'PosReg', (53, 59))
421865	31557242	The average gross changes of two groups of patients (CR/SD) in coarseness, STD, entropy, and strength between patients with good response and poor response were 0.00047/0.00106(P < 0.0001), 1.11/1.13HU (P = 0.0007), 0.05/0.10 (P = 0.0003), and 1.29/3.42 (P < 0.0001) from the beginning to the end of radiation treatment.	('coarseness', 'MPA', (63, 73))	('patients', 'Species', '9606', (43, 51))	('0.00047/0.00106', 'Var', (161, 176))	('patients', 'Species', '9606', (110, 118))	('entropy', 'MPA', (80, 87))
421877	31557242	As shown in Fig 4, the survival time of patients with lower MCTN changes (less than 3.43HU) was greater than that of larger HU changes (greater than 3.43HU), which was statistically significant by Log-rank tests (P = 0.0208).	('less', 'Var', (74, 78))	('greater', 'PosReg', (96, 103))	('patients', 'Species', '9606', (40, 48))	('MCTN changes', 'MPA', (60, 72))	('survival time', 'CPA', (23, 36))	('lower', 'NegReg', (54, 59))
421899	31557242	Chen et al argued that different structural regions in the tissue respond differently to radiation, and these differences inevitably lead to changes in the shape of the histogram, usually a spread of the peak as indicated by the changes of STD, skewness and kurtosis.	('changes', 'Reg', (229, 236))	('shape', 'MPA', (156, 161))	('lead', 'Reg', (133, 137))	('differences', 'Var', (110, 121))	('peak', 'MPA', (204, 208))	('changes', 'Reg', (141, 148))	('spread', 'MPA', (190, 196))	('skewness and kurtosis', 'Disease', 'MESH:D015835', (245, 266))
421920	28243118	Besides, it has been reported that the loss of stromal Cav-1 might predict poor prognosis in breast cancer, gastric cancer, pancreas cancer, prostate cancer, oral SCC and esophageal SCC.	('gastric cancer', 'Phenotype', 'HP:0012126', (108, 122))	('loss', 'Var', (39, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('SCC', 'Phenotype', 'HP:0002860', (182, 185))	('oral SCC and esophageal SCC', 'Disease', 'MESH:D004938', (158, 185))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('gastric cancer', 'Disease', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('prostate cancer', 'Disease', 'MESH:D011471', (141, 156))	('prostate cancer', 'Phenotype', 'HP:0012125', (141, 156))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Cav-1', 'Gene', (55, 60))	('prostate cancer', 'Disease', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('gastric cancer', 'Disease', 'MESH:D013274', (108, 122))	('pancreas cancer', 'Disease', 'MESH:D010190', (124, 139))	('Cav-1', 'Gene', '857', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreas cancer', 'Phenotype', 'HP:0002894', (124, 139))	('pancreas cancer', 'Disease', (124, 139))
421952	28243118	In conclusion, a loss of stromal Cav-1 can promote cancer cell survival and resist to apoptosis.	('Cav-1', 'Gene', (33, 38))	('promote', 'PosReg', (43, 50))	('resist to apoptosis', 'CPA', (76, 95))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Cav-1', 'Gene', '857', (33, 38))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('loss', 'Var', (17, 21))
421953	28243118	Thus, the absence of stromal Cav-1 is one of the powerful predictor about oxidative stress, autophagic CAFs and reverse Warburg effect.	('Cav-1', 'Gene', (29, 34))	('Cav-1', 'Gene', '857', (29, 34))	('autophagic CAFs', 'CPA', (92, 107))	('CAFs', 'Chemical', '-', (103, 107))	('reverse Warburg effect', 'Disease', (112, 134))	('oxidative', 'MPA', (74, 83))	('absence', 'Var', (10, 17))	('oxidative stress', 'Phenotype', 'HP:0025464', (74, 90))
421954	28243118	Downregulation of stromal Cav-1 can promote cancer survival and predict a poor prognosis.	('promote', 'PosReg', (36, 43))	('Cav-1', 'Gene', (26, 31))	('stromal', 'Protein', (18, 25))	('cancer', 'Disease', (44, 50))	('Downregulation', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Cav-1', 'Gene', '857', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
421955	28243118	Recently, some reporters suggested that the absence of the stromal Cav-1 can cause a "lethal" breast cancer microenvironment and associated with cancer recurrence, metastasis and poor clinical outcome.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('associated', 'Reg', (129, 139))	('Cav-1', 'Gene', (67, 72))	('cause', 'Reg', (77, 82))	('absence', 'Var', (44, 51))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Cav-1', 'Gene', '857', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('metastasis', 'CPA', (164, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('breast cancer', 'Disease', (94, 107))
421964	28243118	Cav-1 is a 21-24 kDa integral membrane protein, consisting of two isoforms, alpha-isoform with a slower migration (containing residues 1-178) and beta-isoform with a faster migration (containing residues 32-178).	('containing residues 1-178', 'Var', (115, 140))	('migration', 'MPA', (104, 113))	('Cav-1', 'Gene', (0, 5))	('Cav-1', 'Gene', '857', (0, 5))	('slower', 'NegReg', (97, 103))
421965	28243118	It was reported that Cav-1 has a central hydrophobic domain (residues 102-134), which are considered to form an unusual hairpin loop structure in the membrane, thus leading to both the amino-terminal domain (residues 1-101) and the carboxyl-terminal domain (residues 135-178) of Cav-1 face with the cytoplasm.	('Cav-1', 'Gene', '857', (21, 26))	('Cav-1', 'Gene', '857', (279, 284))	('face', 'Reg', (285, 289))	('residues 1-101', 'Var', (208, 222))	('Cav-1', 'Gene', (21, 26))	('Cav-1', 'Gene', (279, 284))	('residues 135-178', 'Var', (258, 274))
421971	28243118	The cooperation between Cav-1 and Rho-GTPases promotes tumor metastasis, which mainly depend on the elevated expression of alpha5-integrin and the enhanced activation of Src, Ras and Erk.	('alpha5-integrin', 'Protein', (123, 138))	('Cav-1', 'Gene', '857', (24, 29))	('expression', 'MPA', (109, 119))	('Ras', 'Protein', (175, 178))	('Erk', 'Gene', (183, 186))	('enhanced activation', 'PosReg', (147, 166))	('cooperation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Cav-1', 'Gene', (24, 29))	('tumor metastasis', 'Disease', 'MESH:D009362', (55, 71))	('tumor metastasis', 'Disease', (55, 71))	('Erk', 'Gene', '5594', (183, 186))	('Src', 'Gene', '6714', (170, 173))	('promotes', 'PosReg', (46, 54))	('elevated', 'PosReg', (100, 108))	('Src', 'Gene', (170, 173))
421974	28243118	These phenomena are not in accordance with the study reported by Lin et al who indicated that Cav-1 expression inhibits RhoC GTPase activation and subsequently activates the p38 mitogen-activated protein kinase (MAPK) pathway, thus restricting migration and invasion of primary pancreatic cancer cells.	('RhoC GTPase', 'Gene', '389', (120, 131))	('pancreatic cancer', 'Disease', (278, 295))	('activates', 'PosReg', (160, 169))	('pancreatic cancer', 'Disease', 'MESH:D010190', (278, 295))	('Cav-1', 'Gene', '857', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('inhibits', 'NegReg', (111, 119))	('p38 mitogen-activated protein kinase', 'Gene', (174, 210))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (278, 295))	('restricting', 'NegReg', (232, 243))	('activation', 'MPA', (132, 142))	('RhoC GTPase', 'Gene', (120, 131))	('p38 mitogen-activated protein kinase', 'Gene', '1432', (174, 210))	('expression', 'Var', (100, 110))	('Cav-1', 'Gene', (94, 99))
421991	28243118	Moreover, the decreased expression of Cav-1 by small interfering RNA significantly reduces the expression of phospho-AKT, cyclinD1 and CDK4, downstream transducers phosphorylated ERK and STAT3, thus leading to the inhibition of the metastatic lung cancer cells proliferation.	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('inhibition', 'NegReg', (214, 224))	('CDK4', 'Gene', '1019', (135, 139))	('reduces', 'NegReg', (83, 90))	('ERK', 'Gene', (179, 182))	('cyclinD1', 'Gene', (122, 130))	('small interfering', 'Var', (47, 64))	('expression', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('AKT', 'Gene', (117, 120))	('expression', 'MPA', (95, 105))	('lung cancer', 'Disease', (243, 254))	('decreased', 'NegReg', (14, 23))	('STAT3', 'Gene', (187, 192))	('Cav-1', 'Gene', (38, 43))	('Cav-1', 'Gene', '857', (38, 43))	('cyclinD1', 'Gene', '595', (122, 130))	('AKT', 'Gene', '207', (117, 120))	('CDK4', 'Gene', (135, 139))	('STAT3', 'Gene', '6774', (187, 192))	('ERK', 'Gene', '5594', (179, 182))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))
421992	28243118	In addition, Cav-1 expression negatively regulates cell cycle progression by inducing G0/G1 arrest via a p53/p21WAF1/Cip1-dependent pathway.	('Cip1', 'Gene', (117, 121))	('inducing', 'Reg', (77, 85))	('G0/G1 arrest', 'CPA', (86, 98))	('cell cycle progression', 'CPA', (51, 73))	('expression', 'Var', (19, 29))	('Cav-1', 'Gene', (13, 18))	('p53', 'Gene', (105, 108))	('regulates', 'Reg', (41, 50))	('p53', 'Gene', '7157', (105, 108))	('Cip1', 'Gene', '1026', (117, 121))	('negatively', 'NegReg', (30, 40))	('Cav-1', 'Gene', '857', (13, 18))
421999	28243118	It has been shown that the absence of Cav-1 significantly reduces the activation of the AKT pathway mediated by TGF-beta, thus contributing to the increased expression of proapoptotic proteins BIM.	('reduces', 'NegReg', (58, 65))	('Cav-1', 'Gene', '857', (38, 43))	('increased', 'PosReg', (147, 156))	('expression', 'MPA', (157, 167))	('AKT', 'Gene', '207', (88, 91))	('activation', 'MPA', (70, 80))	('Cav-1', 'Gene', (38, 43))	('TGF-beta', 'Gene', '7040', (112, 120))	('absence', 'Var', (27, 34))	('BIM', 'MPA', (193, 196))	('AKT', 'Gene', (88, 91))	('TGF-beta', 'Gene', (112, 120))
422001	28243118	Furthermore, the expression of Cav-1 in human breast cancer cells is able to inhibit anoikis and enhances matrix-independent survival by a mechanism, which involves upregulation of insulin-like growth factor (IGF)-insulin receptor (IR) expression and IGF-I-induced PI3K/AKT signaling pathway.	('insulin receptor', 'Gene', (214, 230))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Disease', (46, 59))	('enhances', 'PosReg', (97, 105))	('AKT', 'Gene', '207', (270, 273))	('inhibit', 'NegReg', (77, 84))	('matrix-independent survival', 'CPA', (106, 133))	('upregulation', 'PosReg', (165, 177))	('human', 'Species', '9606', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('expression', 'Var', (17, 27))	('IGF-I', 'Gene', (251, 256))	('Cav-1', 'Gene', (31, 36))	('expression', 'MPA', (236, 246))	('anoikis', 'CPA', (85, 92))	('Cav-1', 'Gene', '857', (31, 36))	('IGF-I', 'Gene', '3479', (251, 256))	('AKT', 'Gene', (270, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('insulin receptor', 'Gene', '3643', (214, 230))
422009	28243118	In contrast, stromal Cav-1 expression is stronger in the follicular, solid and trabecular PTC variants than in classical PTC.	('Cav-1', 'Gene', '857', (21, 26))	('PTC', 'Phenotype', 'HP:0002895', (90, 93))	('PTC', 'Phenotype', 'HP:0002895', (121, 124))	('solid', 'Disease', (69, 74))	('stronger', 'PosReg', (41, 49))	('expression', 'MPA', (27, 37))	('trabecular', 'CPA', (79, 89))	('Cav-1', 'Gene', (21, 26))	('variants', 'Var', (94, 102))	('trabecular PTC', 'Phenotype', 'HP:0032465', (79, 93))	('follicular', 'Disease', (57, 67))
422011	28243118	The study first reported that downregulation of Cav-1 in epithelia and stroma is coincided with BRAF mutation of PTC.	('PTC', 'Gene', (113, 116))	('downregulation', 'NegReg', (30, 44))	('PTC', 'Phenotype', 'HP:0002895', (113, 116))	('Cav-1', 'Gene', (48, 53))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('epithelia and stroma', 'Disease', 'None', (57, 77))	('mutation', 'Var', (101, 109))	('Cav-1', 'Gene', '857', (48, 53))
422016	28243118	Thus, loss of Cav-1 may activate EGFR signaling and destabilize cell-cell and cell-matrix contacts, contributing to the onset of Barrett esophagus metaplasia and progression to Barrett adenocarcinoma of the esophagus.	('Barrett esophagus metaplasia', 'Disease', (129, 157))	('loss', 'Var', (6, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('Barrett adenocarcinoma of the esophagus', 'Disease', (177, 216))	('EGFR', 'Gene', '1956', (33, 37))	('activate', 'PosReg', (24, 32))	('contributing to', 'Reg', (100, 115))	('Cav-1', 'Gene', (14, 19))	('Barrett esophagus metaplasia', 'Disease', 'MESH:D001471', (129, 157))	('EGFR', 'Gene', (33, 37))	('Barrett adenocarcinoma of the esophagus', 'Disease', 'MESH:D001471', (177, 216))	('destabilize', 'NegReg', (52, 63))	('Cav-1', 'Gene', '857', (14, 19))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (129, 146))
422018	28243118	Whereas OE33 cells are subjected to demethylation by 5-AzadC treatment and could increase Cav-1 mRNA expression, which interpreted that DNA hypermethylation could make Cav-1 gene silencing, and hypermethylation of Cav-1 promoter is a common event in human EAC and occurs early during Barrett's-associated EAC.	('Cav-1', 'Gene', (214, 219))	('EAC', 'Phenotype', 'HP:0011459', (305, 308))	('Cav-1', 'Gene', '857', (90, 95))	('Cav-1', 'Gene', '857', (168, 173))	('demethylation', 'Var', (36, 49))	('human', 'Species', '9606', (250, 255))	("Barrett's-associated EAC", 'Disease', (284, 308))	('EAC', 'Disease', (305, 308))	('EAC', 'Disease', (256, 259))	('Cav-1', 'Gene', '857', (214, 219))	('silencing', 'NegReg', (179, 188))	('Cav-1', 'Gene', (168, 173))	('hypermethylation', 'Var', (194, 210))	('increase', 'PosReg', (81, 89))	('Cav-1', 'Gene', (90, 95))	('hypermethylation', 'Var', (140, 156))	('EAC', 'Phenotype', 'HP:0011459', (256, 259))
422020	28243118	It was reported that the positive staining of Cav-1 is downregulated in lung adenocarcinomas and loss of Cav-1 may be a critical step for tumor extension and dedifferentiation.	('Cav-1', 'Gene', '857', (46, 51))	('tumor', 'Disease', (138, 143))	('loss', 'Var', (97, 101))	('lung adenocarcinomas', 'Disease', (72, 92))	('positive staining', 'MPA', (25, 42))	('Cav-1', 'Gene', (105, 110))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (72, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('Cav-1', 'Gene', '857', (105, 110))	('downregulated', 'NegReg', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Cav-1', 'Gene', (46, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
422027	28243118	More importantly, A549 cell lines transduced with the Cav-1 K176R mutant would enhance drug resistance of doxorubicin and cisplatin through the influence of interaction between Cav-1 and P-glycoprotein.	('Cav-1', 'Gene', (177, 182))	('interaction', 'Interaction', (157, 168))	('Cav-1', 'Gene', (54, 59))	('A549', 'CellLine', 'CVCL:0023', (18, 22))	('P-glycoprotein', 'Gene', '5243', (187, 201))	('P-glycoprotein', 'Gene', (187, 201))	('Cav-1', 'Gene', '857', (177, 182))	('drug resistance', 'Phenotype', 'HP:0020174', (87, 102))	('doxorubicin', 'Chemical', 'MESH:D004317', (106, 117))	('enhance', 'PosReg', (79, 86))	('Cav-1', 'Gene', '857', (54, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('K176R', 'Var', (60, 65))	('K176R', 'Mutation', 'rs768455935', (60, 65))
422044	28243118	Cav-1 knockdown could significantly reduce the tumorigenicity and chemoresistance of breast cancer stem cells by downregulating the beta-catenin/ABCG2 pathway.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('reduce', 'NegReg', (36, 42))	('breast cancer', 'Disease', (85, 98))	('Cav-1', 'Gene', (0, 5))	('chemoresistance of', 'CPA', (66, 84))	('beta-catenin', 'Gene', (132, 144))	('ABCG2', 'Gene', (145, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('ABCG2', 'Gene', '9429', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('beta-catenin', 'Gene', '1499', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Cav-1', 'Gene', '857', (0, 5))	('knockdown', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (47, 52))	('downregulating', 'NegReg', (113, 127))
422046	28243118	An interesting study revealed that 19% estrogen receptor-positive breast cancers involve Cav-1 P132L mutation.	('breast cancers', 'Phenotype', 'HP:0003002', (66, 80))	('P132L', 'Var', (95, 100))	('Cav-1', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancers', 'Disease', 'MESH:D001943', (66, 80))	('breast cancers', 'Disease', (66, 80))	('P132L', 'Mutation', 'rs1213469537', (95, 100))	('Cav-1', 'Gene', '857', (89, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))
422048	28243118	However, another study reported that Cav-1 P132L mutation has not found in breast cancer.	('P132L', 'Var', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('Cav-1', 'Gene', '857', (37, 42))	('P132L', 'Mutation', 'rs1213469537', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('Cav-1', 'Gene', (37, 42))
422049	28243118	Therefore, further studies are needed to explore the possible mechanism of the Cav-1 P132L mutation on tumorigenicity of breast cancer.	('P132L', 'Var', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('Cav-1', 'Gene', (79, 84))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('Cav-1', 'Gene', '857', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('P132L', 'Mutation', 'rs1213469537', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
422059	28243118	In the stromal of gastric adenocarcinoma, our group previously showed that low stromal Cav-1 levels and high autophagy levels may cooperatively promote GC development, and downregulation of stromal Cav-1 is a novel predictor of poor GC prognosis.	('GC', 'Phenotype', 'HP:0012126', (233, 235))	('low', 'NegReg', (75, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('Cav-1', 'Gene', (198, 203))	('downregulation', 'Var', (172, 186))	('autophagy levels', 'CPA', (109, 125))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (18, 40))	('promote', 'PosReg', (144, 151))	('gastric adenocarcinoma', 'Disease', (18, 40))	('Cav-1', 'Gene', (87, 92))	('Cav-1', 'Gene', '857', (198, 203))	('GC', 'Phenotype', 'HP:0012126', (152, 154))	('GC development', 'CPA', (152, 166))	('Cav-1', 'Gene', '857', (87, 92))
422060	28243118	Consistent with our results, loss of stromal Cav-1 can significantly activate fibroblasts in GC microenvironment, and it may function as a potential biomarker for GC progression.	('Cav-1', 'Gene', '857', (45, 50))	('activate', 'PosReg', (69, 77))	('GC', 'Phenotype', 'HP:0012126', (163, 165))	('loss', 'Var', (29, 33))	('GC', 'Phenotype', 'HP:0012126', (93, 95))	('fibroblasts in GC microenvironment', 'CPA', (78, 112))	('Cav-1', 'Gene', (45, 50))
422067	28243118	Together with Cav-1, expression in pancreatic carcinoma induces an epithelial phenotype and promotes cell-cell contact, with increased expression of plasma membrane bound E-cadherin and beta-catenin, resulting in reducing cell migration and invasion.	('increased', 'PosReg', (125, 134))	('E-cadherin', 'Gene', (171, 181))	('E-cadherin', 'Gene', '999', (171, 181))	('cell-cell contact', 'CPA', (101, 118))	('induces', 'Reg', (56, 63))	('expression', 'Var', (21, 31))	('promotes', 'PosReg', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('expression', 'MPA', (135, 145))	('invasion', 'CPA', (241, 249))	('reducing', 'NegReg', (213, 221))	('Cav-1', 'Gene', (14, 19))	('cell migration', 'CPA', (222, 236))	('Cav-1', 'Gene', '857', (14, 19))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (35, 55))	('beta-catenin', 'Gene', (186, 198))	('beta-catenin', 'Gene', '1499', (186, 198))	('epithelial phenotype', 'CPA', (67, 87))	('pancreatic carcinoma', 'Disease', (35, 55))
422075	28243118	Stromal Cav-1 expression in CAFs is lower than that in paracancerous associated and normal fibroblasts, and its absence is closely related to TNM stage, lymph node metastasis, distant metastasis and HER-2/neu amplification, they also indicated that the loss of stromal Cav-1 is an independent prognostic indicator in pancreatic carcinoma.	('CAFs', 'Chemical', '-', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('loss', 'Var', (253, 257))	('lower', 'NegReg', (36, 41))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (317, 337))	('Cav-1', 'Gene', (8, 13))	('related', 'Reg', (131, 138))	('pancreatic carcinoma', 'Disease', (317, 337))	('Cav-1', 'Gene', '857', (8, 13))	('paracancerous', 'Disease', (55, 68))	('Cav-1', 'Gene', (269, 274))	('Cav-1', 'Gene', '857', (269, 274))	('TNM', 'Gene', '10178', (142, 145))	('paracancerous', 'Disease', 'None', (55, 68))	('HER-2', 'Gene', '2064', (199, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('expression', 'MPA', (14, 24))	('HER-2', 'Gene', (199, 204))	('TNM', 'Gene', (142, 145))
422083	28243118	However, Cav-1 has been reported to function as a tumor suppressor role through its modulation of eNOS in HCC and Cav-1 overexpression means a better overall survival.	('Cav-1', 'Gene', '857', (9, 14))	('HCC', 'Gene', (106, 109))	('Cav-1', 'Gene', '857', (114, 119))	('better', 'PosReg', (143, 149))	('eNOS', 'Protein', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('overall survival', 'CPA', (150, 166))	('modulation', 'Var', (84, 94))	('HCC', 'Gene', '619501', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('Cav-1', 'Gene', (9, 14))	('HCC', 'Phenotype', 'HP:0001402', (106, 109))	('Cav-1', 'Gene', (114, 119))
422091	28243118	In addition, the coexpression of Cav-1 and activated AKT/mTOR pathway can predict a poor disease-free survival, contributing to disease progression and metastasis in RCC.	('Cav-1', 'Gene', (33, 38))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('metastasis', 'CPA', (152, 162))	('disease progression', 'CPA', (128, 147))	('coexpression', 'Var', (17, 29))	('AKT', 'Gene', '207', (53, 56))	('Cav-1', 'Gene', '857', (33, 38))	('mTOR', 'Gene', (57, 61))	('mTOR', 'Gene', '2475', (57, 61))	('AKT', 'Gene', (53, 56))	('contributing', 'Reg', (112, 124))
422093	28243118	Furthermore, Cav-1 may boost the angiogenesis, associating with microvessel density (MVD), and the coexpression of Cav-1 and MVD is significantly correlated with metastasis and a worse prognosis in clear cell RCC.	('metastasis', 'CPA', (162, 172))	('coexpression', 'Var', (99, 111))	('Cav-1', 'Gene', '857', (115, 120))	('angiogenesis', 'CPA', (33, 45))	('Cav-1', 'Gene', (13, 18))	('boost', 'PosReg', (23, 28))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('RCC', 'Disease', (209, 212))	('Cav-1', 'Gene', (115, 120))	('Cav-1', 'Gene', '857', (13, 18))	('correlated with', 'Reg', (146, 161))	('microvessel density', 'CPA', (64, 83))
422096	28243118	High expression of Cav-1 has a significant positive association with higher stage and grade tumor.	('Cav-1', 'Gene', (19, 24))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Cav-1', 'Gene', '857', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('higher stage', 'CPA', (69, 81))
422101	28243118	Furthermore, Cav-1 mediates angiogenesis via cooperating with VEGFR2 during prostate cancer progression.	('VEGFR2', 'Gene', '3791', (62, 68))	('Cav-1', 'Gene', '857', (13, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cooperating', 'Var', (45, 56))	('VEGFR2', 'Gene', (62, 68))	('Cav-1', 'Gene', (13, 18))	('mediates', 'Reg', (19, 27))	('angiogenesis', 'CPA', (28, 40))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
422104	28243118	Compared to stromal Cav-1 expression in patients with benign prostatic hypertrophy, primary prostate cancers and prostate cancer metastases, the results indicated that the loss of stromal Cav-1 is associated with advanced prostate cancer and metastatic disease, and it could be a powerful prognostic marker for patients with prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('metastatic disease', 'Disease', (242, 260))	('prostate cancers', 'Phenotype', 'HP:0012125', (92, 108))	('primary prostate cancers', 'Disease', (84, 108))	('advanced prostate cancer', 'Disease', (213, 237))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (325, 340))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('associated', 'Reg', (197, 207))	('benign prostatic hypertrophy', 'Phenotype', 'HP:0008711', (54, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (325, 340))	('prostate cancer metastases', 'Disease', 'MESH:D009362', (113, 139))	('loss', 'Var', (172, 176))	('prostate cancer', 'Disease', (325, 340))	('prostate cancer metastases', 'Disease', (113, 139))	('metastatic disease', 'Disease', 'MESH:C538445', (242, 260))	('benign prostatic hypertrophy', 'Disease', (54, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (222, 237))	('primary prostate cancers', 'Disease', 'MESH:D011471', (84, 108))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (222, 237))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('patients', 'Species', '9606', (40, 48))	('Cav-1', 'Gene', (20, 25))	('Cav-1', 'Gene', (188, 193))	('patients', 'Species', '9606', (311, 319))	('benign prostatic hypertrophy', 'Disease', 'MESH:D011470', (54, 82))	('advanced prostate cancer', 'Disease', 'MESH:D011471', (213, 237))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cav-1', 'Gene', '857', (20, 25))	('stromal', 'Gene', (180, 187))	('Cav-1', 'Gene', '857', (188, 193))
422108	28243118	Furthermore, Cav-1 overexpression has the ability to suppress cutaneous SCC progression by decreasing cell proliferation, migration and invasion capabilities.	('decreasing', 'NegReg', (91, 101))	('SCC', 'Gene', '6317', (72, 75))	('invasion capabilities', 'CPA', (136, 157))	('Cav-1', 'Gene', (13, 18))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('suppress', 'NegReg', (53, 61))	('overexpression', 'Var', (19, 33))	('Cav-1', 'Gene', '857', (13, 18))	('cell proliferation', 'CPA', (102, 120))
422109	28243118	Whereas Cav-1 knockdown occurs the opposite results, simultaneously, increases the invasive ability and incidence of spontaneous lymph node metastasis.	('increases', 'PosReg', (69, 78))	('Cav-1', 'Gene', (8, 13))	('Cav-1', 'Gene', '857', (8, 13))	('knockdown', 'Var', (14, 23))	('invasive ability', 'CPA', (83, 99))
422114	28243118	The opposite results are found in other studies, and genetic evidence showed the inactivation of Cav-1 by a mutation or reduced expression may take effect in the pathogenesis of OSCC.	('Cav-1', 'Gene', '857', (97, 102))	('SCC', 'Gene', (179, 182))	('inactivation', 'NegReg', (81, 93))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('SCC', 'Gene', '6317', (179, 182))	('Cav-1', 'Gene', (97, 102))	('mutation', 'Var', (108, 116))	('expression', 'MPA', (128, 138))	('reduced', 'NegReg', (120, 127))
422125	28243118	However, these clinical findings appear to conflict with those reports from prostate cancer, breast cancer, pancreatic cancer and esophageal SCC patients, where the loss of stromal Cav-1 expression is associated with recurrent disease, advanced stage, metastatic spread and poor survival.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('recurrent disease', 'CPA', (217, 234))	('loss', 'Var', (165, 169))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('breast cancer', 'Disease', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('metastatic spread', 'CPA', (252, 269))	('Cav-1', 'Gene', (181, 186))	('pancreatic cancer', 'Disease', (108, 125))	('advanced stage', 'CPA', (236, 250))	('stromal', 'Gene', (173, 180))	('Cav-1', 'Gene', '857', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('patients', 'Species', '9606', (145, 153))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('esophageal SCC', 'Disease', (130, 144))	('associated', 'Reg', (201, 211))	('prostate cancer', 'Disease', (76, 91))	('esophageal SCC', 'Disease', 'MESH:D004941', (130, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
422140	28243118	Downregulation of miR-138 promotes lipid raft formation via upregulating multiple components of lipid rafts, including flotillin-1 (FLOT1) and FLOT2, and then Cav-1 facilitates the recruitment of the tumor necrosis factor receptor and inhibitor of NF-kappaB kinase signalosome into lipid rafts and activates the NF-kappaB signaling pathway, consequently leading to the progression of aggressiveness and poorer clinical outcomes in human esophageal SCCs.	('NF-kappaB', 'Gene', '4790', (312, 321))	('facilitates', 'PosReg', (165, 176))	('flotillin-1', 'Gene', (119, 130))	('FLOT2', 'Gene', '2319', (143, 148))	('aggressiveness', 'Disease', (384, 398))	('NF-kappaB', 'Gene', '4790', (248, 257))	('lipid', 'Chemical', 'MESH:D008055', (282, 287))	('aggressiveness', 'Phenotype', 'HP:0000718', (384, 398))	('human', 'Species', '9606', (431, 436))	('esophageal SCCs', 'Disease', 'MESH:D004941', (437, 452))	('recruitment', 'MPA', (181, 192))	('aggressiveness', 'Disease', 'MESH:D001523', (384, 398))	('Downregulation', 'Var', (0, 14))	('lipid', 'Chemical', 'MESH:D008055', (35, 40))	('FLOT1', 'Gene', '10211', (132, 137))	('Cav-1', 'Gene', (159, 164))	('FLOT1', 'Gene', (132, 137))	('miR-138', 'Chemical', '-', (18, 25))	('Cav-1', 'Gene', '857', (159, 164))	('tumor necrosis', 'Disease', 'MESH:D009336', (200, 214))	('lipid raft', 'MPA', (35, 45))	('lipid', 'Chemical', 'MESH:D008055', (96, 101))	('esophageal SCCs', 'Disease', (437, 452))	('activates', 'PosReg', (298, 307))	('tumor necrosis', 'Disease', (200, 214))	('flotillin-1', 'Gene', '10211', (119, 130))	('leading to', 'Reg', (354, 364))	('promotes', 'PosReg', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('NF-kappaB', 'Gene', (312, 321))	('FLOT2', 'Gene', (143, 148))	('miR-138', 'Gene', (18, 25))	('NF-kappaB', 'Gene', (248, 257))	('upregulating', 'PosReg', (60, 72))	('SCC', 'Phenotype', 'HP:0002860', (448, 451))
422145	28243118	Overexpression of Cav-1 may be correlated with tumor extension, advanced pathologic stage, pT and poor prognosis in lung SCC.	('Cav-1', 'Gene', '857', (18, 23))	('SCC', 'Gene', (121, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Cav-1', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('SCC', 'Gene', '6317', (121, 124))	('tumor', 'Disease', (47, 52))
422149	28243118	Hypermethylation of the Cav-1 promoter is found in bladder SCC (25.9%) by comparison with adenocarcinomas (0%), nonneoplastic urothelium (0%) via methylation-specific PCR.	('Hypermethylation', 'Var', (0, 16))	('adenocarcinomas', 'Disease', 'MESH:D000230', (90, 105))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('Cav-1', 'Gene', (24, 29))	('adenocarcinomas', 'Disease', (90, 105))	('bladder SCC', 'Disease', 'MESH:D001745', (51, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('Cav-1', 'Gene', '857', (24, 29))	('bladder SCC', 'Disease', (51, 62))
422150	28243118	However, a strong diffuse immunostaining of Cav-1 protein is detected in all the specimens of bladder SCC, suggesting that aberrant methylation and protein expression of the Cav-1 are related to bladder SCC.	('bladder SCC', 'Disease', (94, 105))	('aberrant', 'Var', (123, 131))	('related', 'Reg', (184, 191))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('bladder SCC', 'Disease', 'MESH:D001745', (195, 206))	('Cav-1', 'Gene', (44, 49))	('methylation', 'MPA', (132, 143))	('bladder SCC', 'Disease', 'MESH:D001745', (94, 105))	('Cav-1', 'Gene', (174, 179))	('SCC', 'Phenotype', 'HP:0002860', (203, 206))	('protein expression', 'MPA', (148, 166))	('Cav-1', 'Gene', '857', (44, 49))	('detected', 'Reg', (61, 69))	('Cav-1', 'Gene', '857', (174, 179))	('bladder SCC', 'Disease', (195, 206))
422168	28243118	Taken together, the multifunction of Cav-1 can regulate cell proliferation, migration, apoptosis, autophagy and cell cycle in cancer by various pathways.	('multifunction', 'Var', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('migration', 'CPA', (76, 85))	('regulate', 'Reg', (47, 55))	('Cav-1', 'Gene', '857', (37, 42))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('apoptosis', 'CPA', (87, 96))	('autophagy', 'CPA', (98, 107))	('cell proliferation', 'CPA', (56, 74))	('cell cycle', 'CPA', (112, 122))	('Cav-1', 'Gene', (37, 42))
422179	25784817	In patients with ESCC, HPV16 E6 and PI3K expression were negatively correlated with the 3-year OS (P<0.05), 5-year OS (P<0.05), and progression-free survival (P<0.05).	('PI3K expression', 'Var', (36, 51))	('HPV16', 'Gene', (23, 28))	('HPV16', 'Species', '333760', (23, 28))	('ESCC', 'Disease', (17, 21))	('progression-free survival', 'CPA', (132, 157))	('patients', 'Species', '9606', (3, 11))	('negatively', 'NegReg', (57, 67))
422188	25784817	It was postulated that high-risk HPV was involved in the very early stage of the classical dysplasia-carcinoma sequence of ESCC because of the presence of HPV DNA in normal esophageal epithelium and cancer precursor lesions.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('HPV', 'Species', '10566', (155, 158))	('HPV', 'Gene', (155, 158))	('dysplasia-carcinoma', 'Disease', (91, 110))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('dysplasia-carcinoma', 'Disease', 'MESH:D002277', (91, 110))	('cancer', 'Disease', (199, 205))	('HPV', 'Species', '10566', (33, 36))	('presence', 'Var', (143, 151))
422208	25784817	The Mann-Whitney U-test was performed to compute the differences in p75NTR and PI3K expression between HPV16 E6-positive and HPV16 E6-negative cases.	('p75NTR', 'Gene', '4804', (68, 74))	('PI3K', 'Protein', (79, 83))	('HPV16', 'Gene', (103, 108))	('p75NTR', 'Gene', (68, 74))	('E6-positive', 'Var', (109, 120))	('HPV16', 'Species', '333760', (103, 108))	('HPV16', 'Species', '333760', (125, 130))
422215	25784817	Correlations between expression levels of HPV16 E6, p75NTR, and PI3K with clinical features such as patient age, sex, and histology are shown in Table 2.	('p75NTR', 'Gene', '4804', (52, 58))	('HPV16', 'Species', '333760', (42, 47))	('patient', 'Species', '9606', (100, 107))	('HPV16', 'Gene', (42, 47))	('PI3K', 'Var', (64, 68))	('p75NTR', 'Gene', (52, 58))
422217	25784817	The expression of p75NTR and PI3K was significantly different between different tumor node metastasis (TNM) stage groups of patients with ESCC (P<0.05), while there was no significant difference in HPV16 E6 expression between different TNM stage groups in control patients.	('p75NTR', 'Gene', (18, 24))	('HPV16', 'Species', '333760', (198, 203))	('patients', 'Species', '9606', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('different', 'Reg', (52, 61))	('expression', 'MPA', (4, 14))	('p75NTR', 'Gene', '4804', (18, 24))	('tumor node metastasis', 'Disease', 'MESH:D009362', (80, 101))	('patients', 'Species', '9606', (264, 272))	('tumor node metastasis', 'Disease', (80, 101))	('ESCC', 'Disease', (138, 142))	('PI3K', 'Var', (29, 33))
422220	25784817	There was also a positive correlation between p75NTR and PI3K expression in ESCC tumors (r=0.364, P<0.001).	('ESCC tumors', 'Disease', (76, 87))	('p75NTR', 'Gene', (46, 52))	('p75NTR', 'Gene', '4804', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ESCC tumors', 'Disease', 'MESH:D004938', (76, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('PI3K expression', 'Var', (57, 72))
422225	25784817	Furthermore, as shown in Table 4 and Figure 2, multivariate analysis revealed that HPV16 E6-positive or PI3K-positive patients had significantly worse 5-year OS compared with HPV16 E6-negative or PI3K-negative patients (HR =1.874, P=0.021; HR =1.961, P=0.011, respectively).	('PI3K-positive', 'Var', (104, 117))	('worse', 'NegReg', (145, 150))	('HPV16', 'Species', '333760', (175, 180))	('HPV16', 'Gene', (83, 88))	('patients', 'Species', '9606', (210, 218))	('HPV16', 'Species', '333760', (83, 88))	('patients', 'Species', '9606', (118, 126))	('E6-positive', 'Var', (89, 100))
422228	25784817	The 3-year OS was also taken into consideration, as shown in Table 4 and Figure 2; HPV16 E6-positive patients with ESCC had significantly worse 3-year OS compared with HPV16 E6-negative patients with ESCC (HR =2.118, P<0.05).	('ESCC', 'Disease', (115, 119))	('patients', 'Species', '9606', (101, 109))	('E6-positive', 'Var', (89, 100))	('worse', 'NegReg', (138, 143))	('HPV16', 'Species', '333760', (168, 173))	('HPV16', 'Gene', (83, 88))	('HPV16', 'Species', '333760', (83, 88))	('patients', 'Species', '9606', (186, 194))
422234	25784817	Here, the incidence of HPV16 E6-positivity was significantly higher in patients with ESCC compared with controls, suggesting that, in Shaan Xi Province, the prevalence of HPV16 among patients with ESCC is considerably high, and that high-risk HPV infection may be a carcinogenic factor underlying the etiology of ESCC.	('HPV infection', 'Disease', (243, 256))	('E6-positivity', 'Var', (29, 42))	('carcinogenic', 'Disease', (266, 278))	('HPV16', 'Gene', (23, 28))	('HPV16', 'Species', '333760', (23, 28))	('HPV16', 'Species', '333760', (171, 176))	('patients', 'Species', '9606', (71, 79))	('HPV16', 'Gene', (171, 176))	('ESCC', 'Disease', (313, 317))	('HPV infection', 'Disease', 'MESH:D030361', (243, 256))	('patients', 'Species', '9606', (183, 191))	('carcinogenic', 'Disease', 'MESH:D063646', (266, 278))
422253	25784817	LY294002, a specific PI3K inhibitor, causes prominent cell differentiation in human embryonic stem cells.	('LY294002', 'Var', (0, 8))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('cell differentiation', 'CPA', (54, 74))	('causes', 'Reg', (37, 43))	('human', 'Species', '9606', (78, 83))
422262	25784817	HPV16 infection or high PI3K expression in patients with ESCC were independently associated with poor OS and PFS, whereas p75NTR expression was not correlated with clinical prognosis.	('high', 'Var', (19, 23))	('infection', 'Disease', (6, 15))	('ESCC', 'Disease', (57, 61))	('infection', 'Disease', 'MESH:D007239', (6, 15))	('HPV16', 'Species', '333760', (0, 5))	('patients', 'Species', '9606', (43, 51))	('PI3K', 'Protein', (24, 28))	('poor OS', 'Disease', (97, 104))	('PFS', 'Disease', (109, 112))	('HPV16', 'Gene', (0, 5))	('p75NTR', 'Gene', (122, 128))	('p75NTR', 'Gene', '4804', (122, 128))	('associated', 'Reg', (81, 91))
422307	24516584	The protection against cancer provided by physical activity might be mediated by insulin or adipocytokines: (1) Physical activity reduces insulin resistance and lowers fasting insulin levels.	('insulin', 'Gene', '3630', (176, 183))	('insulin resistance', 'Phenotype', 'HP:0000855', (138, 156))	('insulin', 'Gene', (81, 88))	('lowers', 'NegReg', (161, 167))	('Physical activity', 'Var', (112, 129))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('insulin', 'Gene', '3630', (81, 88))	('insulin', 'Gene', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('insulin', 'Gene', (138, 145))	('reduces', 'NegReg', (130, 137))	('insulin', 'Gene', '3630', (138, 145))
422344	21820109	Resection of at least 50% of the esophageal mucosal circumference is strongly associated with stricture formation.	('associated with', 'Reg', (78, 93))	('Resection', 'Var', (0, 9))	('esophageal mucosal', 'Disease', (33, 51))	('esophageal mucosal', 'Disease', 'MESH:D052016', (33, 51))	('stricture formation', 'Disease', (94, 113))
422398	21820109	However, tobacco use was associated with stricture formation, with a threshold effect identified at 25 pack-years.	('tobacco use', 'Var', (9, 20))	('stricture formation', 'Disease', (41, 60))	('tobacco', 'Species', '4097', (9, 16))	('associated', 'Reg', (25, 35))
422425	21820109	In summary, we have demonstrated that resecting greater than 50% of the esophageal lumen and heavy tobacco use are associated with the risk of symptomatic post-EMR stricture formation.	('associated', 'Reg', (115, 125))	('tobacco', 'Species', '4097', (99, 106))	('stricture', 'Disease', (164, 173))	('resecting', 'Var', (38, 47))
422507	30854333	HP viability may be impaired by ascorbic acid, as its growth in the stomach is increased in patients with low ascorbic acid, while the disappearance of the bacterium increases stomach ascorbic acid.	('increased', 'PosReg', (79, 88))	('ascorbic acid', 'Chemical', 'MESH:D001205', (32, 45))	('growth', 'MPA', (54, 60))	('patients', 'Species', '9606', (92, 100))	('increases', 'PosReg', (166, 175))	('stomach ascorbic acid', 'MPA', (176, 197))	('HP', 'Species', '210', (0, 2))	('low', 'Var', (106, 109))	('disappearance', 'Var', (135, 148))	('increases stomach', 'Phenotype', 'HP:0005207', (166, 183))	('ascorbic acid', 'Chemical', 'MESH:D001205', (184, 197))	('ascorbic acid', 'Chemical', 'MESH:D001205', (110, 123))	('ascorbic acid', 'MPA', (110, 123))
422518	30854333	The eradication of HP not only results in an increased incidence of developing esophageal adenocarcinoma but also appears to decrease its ability to delay or prevent gastric cancer.	('gastric cancer', 'Disease', (166, 180))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('eradication', 'Var', (4, 15))	('HP', 'Species', '210', (19, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('esophageal adenocarcinoma', 'Disease', (79, 104))	('decrease', 'NegReg', (125, 133))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
422542	30854333	Possessing of Lex and Ley leads to higher HP internalization rates by gastric epithelium as compared to Lea and Leb or non-expressing Lewis antigen.	('Ley', 'Var', (22, 25))	('HP', 'Species', '210', (42, 44))	('HP internalization rates', 'MPA', (42, 66))	('Lex', 'Var', (14, 17))	('higher', 'PosReg', (35, 41))
422543	30854333	Lewis antigen and urease are inversely related because urease promotes HP survival and colonization while inhibiting internalization.	('HP', 'Species', '210', (71, 73))	('HP survival', 'CPA', (71, 82))	('inhibiting', 'NegReg', (106, 116))	('internalization', 'MPA', (117, 132))	('colonization', 'CPA', (87, 99))	('promotes', 'PosReg', (62, 70))	('urease', 'Var', (55, 61))	('urea', 'Chemical', 'MESH:D014508', (55, 59))	('urea', 'Chemical', 'MESH:D014508', (18, 22))
422556	30854333	In summary, eradication of HP might represent a potential strategy for treating these tumors, either low-grade beta-cell lymphoma and to some extent higher grades of this tumor.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumors', 'Disease', (86, 92))	('lymphoma', 'Disease', (121, 129))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('lymphoma', 'Disease', 'MESH:D008223', (121, 129))	('tumor', 'Disease', (171, 176))	('HP', 'Species', '210', (27, 29))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('eradication', 'Var', (12, 23))	('cell lymphoma', 'Phenotype', 'HP:0012191', (116, 129))
422559	30854333	Hence, cagA+ might be considered to be a hallmark of HP carcinogenicity.	('cagA+', 'Var', (7, 12))	('hallmark of HP carcinogenicity', 'Disease', (41, 71))	('hallmark of HP carcinogenicity', 'Disease', 'MESH:C537262', (41, 71))	('cagA+', 'Chemical', '-', (7, 12))
422560	30854333	Some studies have shown that the cagA+ strain significantly increases epithelial proliferation rate either directly or through the induction of hypergastrinemia (increased gastrin level) while another study shows that cagA+ apoptosis indices are increased.	('epithelial proliferation rate', 'CPA', (70, 99))	('increased', 'PosReg', (162, 171))	('cagA+', 'Chemical', '-', (33, 38))	('cagA+', 'Chemical', '-', (218, 223))	('hypergastrinemia', 'Disease', (144, 160))	('cagA+', 'Var', (33, 38))	('increases', 'PosReg', (60, 69))	('increased gastrin', 'Phenotype', 'HP:0500167', (162, 179))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (144, 160))	('hypergastrinemia', 'Disease', 'None', (144, 160))
422612	30854333	- Levofloxacin is a suggestive substitue for Clarithromycin resistant strains, although Levofloxacin might induce localized inflammation in the form of tendinitis or tendon rupture.	('Clarithromycin', 'Chemical', 'MESH:D017291', (45, 59))	('tendon rupture', 'Phenotype', 'HP:0100550', (166, 180))	('inflammation', 'Disease', (124, 136))	('induce', 'Reg', (107, 113))	('Levofloxacin', 'Var', (88, 100))	('Levofloxacin', 'Chemical', 'MESH:D064704', (88, 100))	('Levofloxacin', 'Chemical', 'MESH:D064704', (2, 14))	('inflammation', 'Disease', 'MESH:D007249', (124, 136))	('tendinitis or tendon rupture', 'Disease', 'MESH:D052256', (152, 180))	('tendinitis or tendon rupture', 'Disease', (152, 180))
422618	30854333	PFO leads to activation of Metronidazole, and the product of this reaction leads to the destruction of the helical structure of the DNA of the microorganism.	('destruction', 'NegReg', (88, 99))	('helical structure of the', 'MPA', (107, 131))	('activation', 'PosReg', (13, 23))	('PFO', 'Var', (0, 3))	('Metronidazole', 'MPA', (27, 40))	('Metronidazole', 'Chemical', 'MESH:D008795', (27, 40))
422626	30854333	Moreover, PPI has been shown to be effective against a series of protozoa, yeasts, and amoebas, including Giardia lamblia, Trichomonas vaginalis, Plasmodium falciparum.	('Giardia lamblia', 'Disease', (106, 121))	('yeasts', 'Species', '4932', (75, 81))	('Trichomonas vaginalis', 'Species', '5722', (123, 144))	('Giardia lamblia', 'Species', '5741', (106, 121))	('Plasmodium falciparum', 'Species', '5833', (146, 167))	('PPI', 'Var', (10, 13))	('Trichomonas vaginalis', 'Disease', (123, 144))
422653	30854333	In fact, the bactericidal activity specifically against both resting (in the buffer) and growing (in broth) HP was significantly higher at pH 5 as compared to that at pH 7.	('higher', 'PosReg', (129, 135))	('HP', 'Species', '210', (108, 110))	('pH 5', 'Var', (139, 143))	('bactericidal activity', 'MPA', (13, 34))
422689	26402664	Furthermore, to explore the structure-activity relationships of the isolated compounds, the cytotoxic activities of the isolated diterpenoids were tested against five human cancer cell lines: HCT-116, A2780, NCI-H1650, BGC-823, and HepG2.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('C', 'Chemical', 'MESH:D002244', (221, 222))	('NCI-H1650', 'CellLine', 'CVCL:1483', (208, 217))	('HepG2', 'CellLine', 'CVCL:0027', (232, 237))	('C', 'Chemical', 'MESH:D002244', (193, 194))	('A2780', 'CellLine', 'CVCL:0134', (201, 206))	('tested', 'Reg', (147, 153))	('HCT-116', 'CellLine', 'CVCL:0291', (192, 199))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('human', 'Species', '9606', (167, 172))	('C', 'Chemical', 'MESH:D002244', (209, 210))	('A2780', 'Var', (201, 206))	('diterpenoids', 'Chemical', 'MESH:D004224', (129, 141))
422691	26402664	The molecular formula of 1 was determined to be C22H34O6 on the basis of positive HR-ESI-MS at m/z 417.22367 [M + Na]+ (calcd for C22H34O6Na+, 417.22467).	('C22H34O6', 'Var', (48, 56))	('C22H34O6', 'Chemical', '-', (130, 138))	('C22H34O6Na', 'Chemical', '-', (130, 140))	('C22H34O6', 'Chemical', '-', (48, 56))	('C22H34O6Na+', 'Var', (130, 141))
422692	26402664	Its IR spectrum displayed the absorption bands of hydroxyl group (3422 cm-1) and free carbonyl group (1731 cm-1).	('1731 cm-1', 'Var', (102, 111))	('3422 cm-1', 'Var', (66, 75))	('carbon', 'Chemical', 'MESH:D002244', (86, 92))	('hydroxyl', 'Chemical', 'MESH:D017665', (50, 58))
422693	26402664	The NMR spectra revealed three methyls (deltaC 9.2, 33.3, 21.5(each q); deltaH 1.12 (3H, d, 7.1 Hz), 0.91 (3H, s), 0.85 (3H, s)), one acetoxyl group (deltaC 170.8(s), 21.5(q); deltaH 2.13(3H, s)), one ketone carbonyl group (deltaC 222.8), three oxy-methines (deltaC 81.6, 76.1, 75.4) and one oxy-methylene (deltaC 63.7).	('deltaC', 'Chemical', '-', (224, 230))	('deltaH 1.12', 'Var', (72, 83))	('deltaC', 'Chemical', '-', (259, 265))	('3H', 'Chemical', 'MESH:D014316', (107, 109))	('3H', 'Chemical', 'MESH:D014316', (121, 123))	('3H', 'Chemical', 'MESH:D014316', (85, 87))	('deltaC', 'Chemical', '-', (307, 313))	('deltaH', 'Chemical', '-', (176, 182))	('carbon', 'Chemical', 'MESH:D002244', (208, 214))	('deltaC', 'Chemical', '-', (150, 156))	('acetoxyl', 'Chemical', 'MESH:D001585', (134, 142))	('deltaH', 'Chemical', '-', (72, 78))	('deltaC', 'Chemical', '-', (40, 46))	('3H', 'Chemical', 'MESH:D014316', (188, 190))	('0.91', 'Var', (101, 105))	('deltaC', 'Var', (40, 46))
422706	26402664	Comparison of the NMR spectral data of 2 with those of 1 indicated that one angular methyl (deltaC 33.3, deltaH 0.91 (3H, s)) at C-4 in 1 had been replaced by one hydroxymethyl (deltaC 69.5, deltaH 3.19 (1H, d, J = 10.6) and 2.82 (1H, d, J = 10.6)) in 2.	('deltaH', 'Chemical', '-', (105, 111))	('C-4', 'Gene', (129, 132))	('C', 'Chemical', 'MESH:D002244', (97, 98))	('C', 'Chemical', 'MESH:D002244', (183, 184))	('deltaH', 'Var', (191, 197))	('deltaC', 'Chemical', '-', (92, 98))	('3H', 'Chemical', 'MESH:D014316', (118, 120))	('1H', 'Chemical', '-', (204, 206))	('C-4', 'Gene', '720', (129, 132))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('deltaC', 'Chemical', '-', (178, 184))	('deltaH', 'Chemical', '-', (191, 197))	('C', 'Chemical', 'MESH:D002244', (129, 130))	('1H', 'Chemical', '-', (231, 233))
422709	26402664	In the HMBC spectrum, correlations were observed for deltaH 3.19 (H-18) with deltaC 32.9 (C-3) and 17.3 (C-19) also confirmed that a hydroxymethyl group was linked to C-4.	('C-4', 'Gene', (167, 170))	('H-18', 'Gene', (66, 70))	('C', 'Chemical', 'MESH:D002244', (90, 91))	('H-18', 'Gene', '132243', (66, 70))	('C-4', 'Gene', '720', (167, 170))	('deltaC', 'Chemical', '-', (77, 83))	('C', 'Chemical', 'MESH:D002244', (82, 83))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('deltaH 3.19', 'Var', (53, 64))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('deltaH', 'Chemical', '-', (53, 59))	('C', 'Chemical', 'MESH:D002244', (10, 11))
422714	26402664	The molecular formula of 3 was deduced to be C22H30O5 by positive HR-ESI-MS at m/z 397.1992 [M + Na]+ (calcd for C22H30O5Na+, 397.19855).	('C22H30O5', 'Var', (45, 53))	('C22H30O5Na', 'Chemical', '-', (113, 123))	('C22H30O5', 'Chemical', '-', (113, 121))	('C22H30O5Na+', 'Var', (113, 124))	('C22H30O5', 'Chemical', '-', (45, 53))
422716	26402664	The IR spectrum of 3 showed the presence of hydroxyl (3418 cm-1), carbonyl (1732 cm-1), and double bond (1647 cm-1) groups.	('carbonyl', 'MPA', (66, 74))	('1647 cm-1', 'Var', (105, 114))	('carbon', 'Chemical', 'MESH:D002244', (66, 72))	('3418 cm-1', 'Var', (54, 63))	('hydroxyl', 'MPA', (44, 52))	('double bond', 'MPA', (92, 103))	('1732 cm-1', 'Var', (76, 85))	('hydroxyl', 'Chemical', 'MESH:D017665', (44, 52))
422717	26402664	The 1H- and 13C-NMR spectra of 3, together with the results from a HSQC experiment showed the presence of one exocyclic double bond (deltaH 6.00, 5.38 (each 1H, brs); deltaC 117.5, 151.1), one acetoxyl group (deltaH 1.95 (3H, s); deltaC 170.1 (s), 21.5 (q)), one ketone carbonyl (deltaC 204.6), and two angular methyl groups (deltaH 0.88 and 1.08 (each 3H, s); deltaC 31.4 (q) and 21.3 (q)).	('C', 'Chemical', 'MESH:D002244', (235, 236))	('3H', 'Chemical', 'MESH:D014316', (353, 355))	('deltaC', 'Chemical', '-', (361, 367))	('deltaH', 'Chemical', '-', (326, 332))	('deltaC', 'Var', (230, 236))	('C', 'Chemical', 'MESH:D002244', (366, 367))	('deltaC 117.5', 'Var', (167, 179))	('acetoxyl', 'Chemical', 'MESH:D001585', (193, 201))	('1H', 'Chemical', '-', (157, 159))	('deltaH', 'Chemical', '-', (133, 139))	('deltaC', 'Chemical', '-', (167, 173))	('deltaC', 'Chemical', '-', (280, 286))	('13C', 'Chemical', '-', (12, 15))	('deltaC', 'Var', (361, 367))	('3H', 'Chemical', 'MESH:D014316', (222, 224))	('deltaH', 'Var', (326, 332))	('C', 'Chemical', 'MESH:D002244', (14, 15))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('C', 'Chemical', 'MESH:D002244', (285, 286))	('deltaH', 'Chemical', '-', (209, 215))	('1H', 'Chemical', '-', (4, 6))	('carbon', 'Chemical', 'MESH:D002244', (270, 276))	('deltaC', 'Chemical', '-', (230, 236))	('C', 'Chemical', 'MESH:D002244', (172, 173))
422720	26402664	The 1H- and 13C-NMR spectra of 3 were very similar to those of kamebacetal A (7), except for the absence of a dioxygenated methine (deltaH 5.51 (1H, d, J = 1.1 Hz, H-20); deltaC 101.9) and a methoxyl group (deltaH 3.38 (3H, s); deltaC 54.9) as well as the presence of an acetoxyl group (deltaH 1.95 (s, 3H); deltaC170.1 (s), 21.5 (q)) and an oxygenated methylene (deltaH 4.09 (1H, dd, J = 10.3, 1.5 Hz, H-20) and 4.03 (1H, dd, J = 10.3, 1.6 Hz, H-20); deltaC 61.0) in 3.	('3H', 'Chemical', 'MESH:D014316', (220, 222))	('deltaC', 'Chemical', '-', (228, 234))	('kamebacetal A', 'Chemical', '-', (63, 76))	('deltaC', 'Chemical', '-', (171, 177))	('deltaC', 'Chemical', '-', (308, 314))	('deltaC', 'Var', (452, 458))	('deltaH', 'Chemical', '-', (207, 213))	('deltaC170', 'Var', (308, 317))	('deltaH', 'Chemical', '-', (364, 370))	('3H', 'Chemical', 'MESH:D014316', (303, 305))	('1H', 'Chemical', '-', (419, 421))	('13C', 'Chemical', '-', (12, 15))	('acetoxyl', 'Chemical', 'MESH:D001585', (271, 279))	('deltaH', 'Var', (364, 370))	('deltaH', 'Chemical', '-', (132, 138))	('oxygen', 'Chemical', 'MESH:D010100', (112, 118))	('oxygen', 'Chemical', 'MESH:D010100', (342, 348))	('1H', 'Chemical', '-', (377, 379))	('1H', 'Chemical', '-', (4, 6))	('deltaC', 'Chemical', '-', (452, 458))	('1H', 'Chemical', '-', (145, 147))	('deltaC170', 'DELETION', 'None', (308, 317))	('deltaH', 'Chemical', '-', (287, 293))
422721	26402664	Meanwhile, the following cross-peaks were observed in the HMBC spectrum: deltaH 3.95 (H-7beta) with deltaC 61.0 (C-20), deltaH 4.57 (H-1) with deltaC 170.1 (OAc), and deltaH 4.61 (H-14) with deltaC 30.9 (C-12), 204.5 (C-15) and 151.1 (C-16).	('deltaH', 'Chemical', '-', (167, 173))	('deltaH', 'Chemical', '-', (120, 126))	('H-7beta', 'Disease', 'MESH:D000848', (86, 93))	('H-14', 'Gene', '3008', (180, 184))	('C', 'Chemical', 'MESH:D002244', (148, 149))	('C', 'Chemical', 'MESH:D002244', (218, 219))	('C', 'Chemical', 'MESH:D002244', (235, 236))	('deltaH', 'Chemical', '-', (73, 79))	('deltaC', 'Chemical', '-', (100, 106))	('deltaC', 'Var', (143, 149))	('deltaH', 'Var', (167, 173))	('C-15', 'Gene', (218, 222))	('deltaH', 'Var', (120, 126))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('deltaH', 'Var', (73, 79))	('deltaC', 'Var', (100, 106))	('H-14', 'Gene', (180, 184))	('H-7beta', 'Disease', (86, 93))	('deltaC', 'Chemical', '-', (191, 197))	('C', 'Chemical', 'MESH:D002244', (204, 205))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('C-15', 'Gene', '51316', (218, 222))	('C', 'Chemical', 'MESH:D002244', (196, 197))	('deltaC', 'Chemical', '-', (143, 149))	('OAc', 'Chemical', '-', (157, 160))
422741	26402664	Compound 8 exhibited significant cytotoxic effects on both NCI-H1650 and HepG2 cells (IC50: 1.09-2.58 muM), whereas compounds 6 and 7 had an insignificant effect on the NCI-H1650 cell line (IC50 > 10 muM), suggesting that the relative configuration of the C-20 chiral carbon affected the cytotoxic effect of the tested diterpenoids on some of the tumor cell lines (NCI-H1650 and HepG2), whereas the beta-configuration enhanced their cytotoxic activity.	('NCI-H1650', 'CellLine', 'CVCL:1483', (169, 178))	('C', 'Chemical', 'MESH:D002244', (170, 171))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('cytotoxic activity', 'MPA', (433, 451))	('HepG2', 'CellLine', 'CVCL:0027', (73, 78))	('NCI-H1650', 'CellLine', 'CVCL:1483', (365, 374))	('carbon', 'Chemical', 'MESH:D002244', (268, 274))	('affected', 'Reg', (275, 283))	('muM', 'Gene', '56925', (200, 203))	('C', 'Chemical', 'MESH:D002244', (366, 367))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('beta-configuration', 'Var', (399, 417))	('C', 'Chemical', 'MESH:D002244', (256, 257))	('muM', 'Gene', (200, 203))	('enhanced', 'PosReg', (418, 426))	('C', 'Chemical', 'MESH:D002244', (87, 88))	('HepG2', 'CellLine', 'CVCL:0027', (379, 384))	('diterpenoids', 'Chemical', 'MESH:D004224', (319, 331))	('C', 'Chemical', 'MESH:D002244', (191, 192))	('NCI-H1650', 'CellLine', 'CVCL:1483', (59, 68))	('muM', 'Gene', '56925', (102, 105))	('tumor', 'Disease', (347, 352))	('muM', 'Gene', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('cytotoxic effect', 'CPA', (288, 304))
422787	26402664	The presence of the 20-OAc group has a positive effect on the cytotoxic activity (compounds 1, 2, and 4), and the mechanism underlying their cytotoxic activity requires further investigation.	('cytotoxic activity', 'CPA', (62, 80))	('presence', 'Var', (4, 12))	('positive', 'PosReg', (39, 47))	('20-OAc', 'Chemical', '-', (20, 26))
422795	30353671	Data from a tumor xenograft mouse model indicated that inhibition of AXL with R428 in combination with epirubicin synergistically suppresses tumor growth and proliferation.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('mouse', 'Species', '10090', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('suppresses', 'NegReg', (130, 140))	('AXL', 'Protein', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('R428', 'Chemical', '-', (78, 82))	('tumor', 'Disease', (12, 17))	('inhibition', 'NegReg', (55, 65))	('R428', 'Var', (78, 82))
422796	30353671	Our findings support future clinical trials to assess the therapeutic potential of R428 in epirubicin-resistant tumors with overexpression of AXL and activation of c-MYC.	('AXL', 'Protein', (142, 145))	('activation', 'PosReg', (150, 160))	('R428', 'Var', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('c-MYC', 'Protein', (164, 169))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))	('overexpression', 'PosReg', (124, 138))
422809	30353671	Frequent gene amplification and overexpression of c-MYC have been found in invasive EAC (Miller et al., 2003; von Rahden et al., 2006; Sarbia et al., 2001).	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('von', 'Disease', 'MESH:D014842', (110, 113))	('overexpression', 'PosReg', (32, 46))	('gene amplification', 'Var', (9, 27))	('c-MYC', 'Protein', (50, 55))	('von', 'Disease', (110, 113))	('invasive EAC', 'Disease', (75, 87))
422825	30353671	For stable AXL expression silencing, control shRNA or a pool of five validated AXL shRNA lentivirus particles (Sigma-Aldrich) were used to transduce FLO-1 and SK-GT-4 cells, followed by selection with 1 mug mL-1 puromycin (Invitrogen) for 10 days.	('AXL', 'Protein', (11, 14))	('silencing', 'Var', (26, 35))	('puromycin', 'Chemical', 'MESH:D011691', (212, 221))
422854	30353671	Additionally, we showed that pharmacologic inhibition of AKT by MK-2206 (5 mum) led to a marked decrease in p-GSK3beta (S9), beta-catenin, and c-MYC protein levels in FLO-1 cells (Fig.	('AKT', 'Enzyme', (57, 60))	('decrease', 'NegReg', (96, 104))	('beta-catenin', 'MPA', (125, 137))	('MK-2206', 'Var', (64, 71))	('MK-2206', 'Chemical', 'MESH:C548887', (64, 71))	('c-MYC protein levels', 'MPA', (143, 163))
422959	30122990	In the case of hematologic inflammation markers, a high CNP score was significantly associated with poor PFS and OS in our ESCC patients receiving curative esophagectomy with R0 resection.	('hematologic inflammation', 'Disease', 'MESH:D007249', (15, 39))	('hematologic inflammation', 'Disease', (15, 39))	('CNP', 'Gene', (56, 59))	('PFS', 'Disease', (105, 108))	('high', 'Var', (51, 55))	('poor', 'NegReg', (100, 104))	('OS', 'Chemical', '-', (113, 115))	('patients', 'Species', '9606', (128, 136))
423063	29114596	Retrospective data reported acute grade >=2 nausea rates of 29% to 34% in patients with EC who were treated with PSPT versus similar or slightly lower (21%) rates in our study, despite a similar chemotherapy regimen.	('nausea', 'Disease', 'MESH:D009325', (44, 50))	('PSPT', 'Chemical', '-', (113, 117))	('PSPT', 'Var', (113, 117))	('patients', 'Species', '9606', (74, 82))	('EC', 'Phenotype', 'HP:0011459', (88, 90))	('nausea', 'Phenotype', 'HP:0002018', (44, 50))	('nausea', 'Disease', (44, 50))
423092	28462368	Sunday, May 7, 2017: "Basic Mechanisms of Injury and Repair", "In Vivo Models of Gastrointestinal Disorders," "Transcriptional and Epigenetic Regulation of GI Function and Disease."	('Gastrointestinal Disorders', 'Disease', (81, 107))	('Gastrointestinal Disorders', 'Phenotype', 'HP:0011024', (81, 107))	('Gastrointestinal Disorders', 'Disease', 'MESH:D005767', (81, 107))	('Epigenetic Regulation', 'Var', (131, 152))
423112	28462368	GIONC 2017 Distinguished Mentor Award Recipient: Dr. Jun Yu, The Chinese University of Hong Kong Her award will be presented at the start of the GIONC Distinguished Abstract Plenary Session on Monday, May 8, 2017.	('art', 'Gene', '181', (134, 137))	('art', 'Gene', (134, 137))	('Dr. Jun Yu', 'Var', (49, 59))
423130	28462368	The award will be presented to Kenneth K. Wang, MD, AGAF during Advanced Technology for the Diagnosis of Gastrointestinal Disease: Sniff, Scope, Stain or Stiffness?, Saturday, May 6, 4-5:30 p.m., 4:00-4:06 PM, S105a (RF).	('Gastrointestinal Disease', 'Phenotype', 'HP:0011024', (105, 129))	('AGA', 'Gene', '175', (52, 55))	('S105a', 'Var', (210, 215))	('AGA', 'Gene', (52, 55))	('Gastrointestinal Disease', 'Disease', (105, 129))	('Gastrointestinal Disease', 'Disease', 'MESH:D005767', (105, 129))
423153	28462368	The award will be presented to Arun J. Sanyal, MD during The Dr. Charles S. Lieber Lecture : Mechanisms of Liver Injury in NAFLD and NASH, Sunday, May 7, 2-3 p.m., 2:00-2:06 PM, S403b (SOA) Eugene B. Chang, MD, AGAF and Tor Christopher Savidge, PhD DDW 2017 is the inaugural event for members interested in this new section of the council.	('NASH', 'Gene', (133, 137))	('S403b', 'Var', (178, 183))	('AGA', 'Gene', '175', (211, 214))	('Liver Injury', 'Disease', (107, 119))	('NASH', 'Gene', '64092', (133, 137))	('AGA', 'Gene', (211, 214))	('Liver Injury', 'Disease', 'MESH:D056486', (107, 119))
423159	28462368	The award will be presented to John F. Cryan, PhD during Gut Microbiota in Disease; Identifying Personalized Approaches in Management of Disease and Section Business Meeting, Sunday, May 7, 2-3:30 p.m. 2:00-2:06 PM, S102abc (TS) Satish S.C. Rao, MD, PhD, AGAF and John Wiley, MD To attract the best science and cutting-edge research in neurogastroenterology and GI motility for presentation at Digestive Disease Week  (DDW).	('AGA', 'Gene', (255, 258))	('Digestive Disease', 'Phenotype', 'HP:0011024', (394, 411))	('AGA', 'Gene', '175', (255, 258))	('S102abc', 'Var', (216, 223))	('Digestive Disease Week', 'Disease', (394, 416))
423292	28344602	We also found that, firstly, NBT + EBRT is safe and beneficial in terms of local control in the radical treatment of elderly patients with ESCC, and secondly, the OS rate was significantly increased, and the late complication rate was significantly decreased in patients aged 70-74 years compared to that of patients aged > 74 years.	('patients', 'Species', '9606', (125, 133))	('patients', 'Species', '9606', (262, 270))	('NBT', 'Chemical', '-', (29, 32))	('patients', 'Species', '9606', (308, 316))	('NBT + EBRT', 'Var', (29, 39))	('decreased', 'NegReg', (249, 258))	('local', 'CPA', (75, 80))	('EBRT', 'Chemical', '-', (35, 39))	('ESCC', 'Disease', (139, 143))	('increased', 'PosReg', (189, 198))
423302	28344602	Our results suggest that elderly patients with ESCC could benefit from NBT + EBRT without major toxicities.	('toxicities', 'Disease', (96, 106))	('patients', 'Species', '9606', (33, 41))	('EBRT', 'Chemical', '-', (77, 81))	('NBT', 'Chemical', '-', (71, 74))	('ESCC', 'Disease', (47, 51))	('toxicities', 'Disease', 'MESH:D064420', (96, 106))	('NBT', 'Var', (71, 74))
423313	25608466	Plasma POU3F3 could serve as a potential biomarker for diagnosis of ESCC, and the combination of POU3F3 and SCCA was more efficient for ESCC detection, in particular for early tumor screening.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('POU3F3', 'Gene', (97, 103))	('ESCC', 'Disease', (68, 72))	('POU3F3', 'Gene', '5455', (97, 103))	('ESCC', 'Disease', (136, 140))	('tumor', 'Disease', (176, 181))	('POU3F3', 'Gene', (7, 13))	('POU3F3', 'Gene', '5455', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('combination', 'Var', (82, 93))
423321	25608466	The aberrant expression of lncRNAs have been reported to serve as potential diagnostic or prognostic biomarkers for many human malignancies such as breast, lung, liver, and colon cancers.	('malignancies', 'Disease', 'MESH:D009369', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colon cancers', 'Disease', (173, 186))	('malignancies', 'Disease', (127, 139))	('lung', 'Disease', (156, 160))	('breast', 'Disease', (148, 154))	('aberrant expression', 'Var', (4, 23))	('human', 'Species', '9606', (121, 126))	('colon cancers', 'Phenotype', 'HP:0003003', (173, 186))	('liver', 'Disease', (162, 167))	('lncRNAs', 'Protein', (27, 34))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('colon cancers', 'Disease', 'MESH:D015179', (173, 186))
423327	25608466	In gastric cancer patients, plasma AA174084 levels dropped markedly on day 15 after surgery compared with preoperative levels and were associated with invasion and lymphatic metastasis.	('AA174084', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('lymphatic metastasis', 'CPA', (164, 184))	('gastric cancer', 'Disease', (3, 17))	('associated with', 'Reg', (135, 150))	('dropped', 'NegReg', (51, 58))	('patients', 'Species', '9606', (18, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
423337	25608466	On the basis of previous study, 10 lncRNAs (HOTAIR, AFAP1-AS1, POU3F3, HNF1A-AS1, PlncRNA1, SPRY4-IT1, ENST00000435885.1, ENST00000547963.1, 91H and XLOC_013104) which have been reported to be differently expressed in esophageal cancer were selected in the present study.	('POU3F3', 'Gene', '5455', (63, 69))	('PlncRNA1', 'Gene', (82, 90))	('HOTAIR', 'Gene', (44, 50))	('HNF1A-AS1', 'Gene', '283460', (71, 80))	('XLOC_013104', 'Var', (149, 160))	('ENST00000435885.1', 'Var', (103, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))	('POU3F3', 'Gene', (63, 69))	('AFAP1-AS1', 'Gene', (52, 61))	('PlncRNA1', 'Gene', '100506428', (82, 90))	('esophageal cancer', 'Disease', (218, 235))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('91H', 'Var', (141, 144))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (92, 101))	('ENST00000547963.1', 'Var', (122, 139))	('HNF1A-AS1', 'Gene', (71, 80))	('HOTAIR', 'Gene', '100124700', (44, 50))	('SPRY4-IT1', 'Gene', (92, 101))
423339	25608466	Among them, HOTAIR, AFAP1-AS1, POU3F3, HNF1A-AS1, PlncRNA1, SPRY4-IT1, ENST00000435885.1 and ENST00000547963.1 were significantly higher in most of ESCC tumor tissues compared with paired adjacent normal tissues (Figure 1).	('ENST00000547963.1', 'Var', (93, 110))	('PlncRNA1', 'Gene', (50, 58))	('HOTAIR', 'Gene', (12, 18))	('SPRY4-IT1', 'Gene', (60, 69))	('higher', 'PosReg', (130, 136))	('ENST00000435885.1', 'Var', (71, 88))	('PlncRNA1', 'Gene', '100506428', (50, 58))	('ESCC tumor', 'Disease', 'MESH:D004938', (148, 158))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (20, 29))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('HOTAIR', 'Gene', '100124700', (12, 18))	('HNF1A-AS1', 'Gene', (39, 48))	('AFAP1-AS1', 'Gene', (20, 29))	('HNF1A-AS1', 'Gene', '283460', (39, 48))	('ESCC tumor', 'Disease', (148, 158))	('POU3F3', 'Gene', (31, 37))	('POU3F3', 'Gene', '5455', (31, 37))
423408	25608466	provided the pioneering evidence that blood cells were the major contributor to the circulating miRNAs and that perturbations in blood cell counts and hemolysis could alter plasma miRNAs levels by up to 50-fold.	('hemolysis', 'Disease', (151, 160))	('hemolysis', 'Disease', 'MESH:D006461', (151, 160))	('alter', 'Reg', (167, 172))	('perturbations', 'Var', (112, 125))	('circulating miRNAs', 'MPA', (84, 102))	('plasma miRNAs levels', 'MPA', (173, 193))
423492	26064090	Modifications in the structure of lncRNAs, which are induced by large- or small-scale mutations, as well as their abnormal expression, have been linked with the onset of several pathological conditions and, most importantly, cancer.	('mutations', 'Var', (86, 95))	('ncRNA', 'Gene', '220202', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('expression', 'MPA', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('structure', 'MPA', (21, 30))	('cancer', 'Disease', (225, 231))	('linked', 'Reg', (145, 151))	('Modifications', 'Reg', (0, 13))	('ncRNA', 'Gene', (35, 40))
423493	26064090	The aberrant expression of lncRNAs, across both solid and human hematological malignancies, brought these molecules to the forefront of cancer research and accelerated the investigation of their mechanistic roles in these multifactorial disorders.	('accelerated', 'PosReg', (156, 167))	('hematological malignancies', 'Disease', (64, 90))	('human', 'Species', '9606', (58, 63))	('hematological malignancies', 'Disease', 'MESH:D019337', (64, 90))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('aberrant expression', 'Var', (4, 23))	('cancer', 'Disease', (136, 142))	('ncRNA', 'Gene', (28, 33))	('hematological malignancies', 'Phenotype', 'HP:0004377', (64, 90))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('ncRNA', 'Gene', '220202', (28, 33))
423494	26064090	Dysregulated lncRNAs promote neoplastic transformation through the malfunction of common biological procedures such as epigenetic and transcriptional regulation, apoptosis, and epithelial-mesenchymal-transition (EMT).	('epithelial-mesenchymal-transition', 'CPA', (177, 210))	('neoplastic transformation', 'CPA', (29, 54))	('promote', 'PosReg', (21, 28))	('ncRNA', 'Gene', (14, 19))	('Dysregulated', 'Var', (0, 12))	('epigenetic', 'Var', (119, 129))	('apoptosis', 'CPA', (162, 171))	('ncRNA', 'Gene', '220202', (14, 19))
423502	26064090	MALAT1 is also implicated in metastasis; chromosomal translocation is the main mechanism behind its marked upregulation in cancer.	('upregulation', 'PosReg', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('chromosomal translocation', 'Var', (41, 66))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
423503	26064090	Malfunction of MALAT1 affects cancer cells' mobility, invasiveness, and survival through the abnormal splicing of genes that are involved in oncogenesis- and metastasis-related procedures (e.g., WNT and MAPK signaling, cytoskeletal organization and cell cycle, EMT).	('MAPK', 'Gene', '5594', (203, 207))	('affects', 'Reg', (22, 29))	('MAPK', 'Gene', (203, 207))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('Malfunction', 'Var', (0, 11))	('invasiveness', 'CPA', (54, 66))	('cytoskeletal', 'CPA', (219, 231))	('survival', 'CPA', (72, 80))	('mobility', 'CPA', (44, 52))	('abnormal splicing', 'Var', (93, 110))	('cell cycle', 'CPA', (249, 259))	('MALAT1', 'Gene', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
423512	26064090	Indeed, a bulk of experimental data denotes not only the dysregulation of lncRNAs in various cancers but also their association with patients' prognosis and response to treatment, rendering lncRNAs as an untapped source of diagnostic, prognostic, and predictive markers as well as a novel class of therapeutic targets.	('cancers', 'Disease', (93, 100))	('association', 'Interaction', (116, 127))	('ncRNA', 'Gene', (191, 196))	('dysregulation', 'Var', (57, 70))	('ncRNA', 'Gene', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ncRNA', 'Gene', '220202', (191, 196))	('ncRNA', 'Gene', '220202', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
423518	26064090	Moreover, H19 is a potent predictor of early recurrence in bladder cancer patients.	('recurrence in bladder', 'Phenotype', 'HP:0012786', (45, 66))	('H19', 'Var', (10, 13))	('patients', 'Species', '9606', (74, 82))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('bladder cancer', 'Disease', (59, 73))
423523	26064090	Antisense oligonucleotides represent an alternative option to achieve lncRNA targeting and recent studies demonstrated that this strategy can result in inhibition of MALAT1 and arrest of metastasis in mouse models.	('inhibition', 'NegReg', (152, 162))	('ncRNA', 'Gene', (71, 76))	('metastasis', 'CPA', (187, 197))	('ncRNA', 'Gene', '220202', (71, 76))	('mouse', 'Species', '10090', (201, 206))	('oligonucleotides', 'Chemical', 'MESH:D009841', (10, 26))	('Antisense', 'Var', (0, 9))	('MALAT1', 'Protein', (166, 172))
423525	26064090	Analyses of aberrantly expressed lncRNAs, though mechanistic studies, provide new insights into their ubiquitous implication in pathways that govern hallmark processes of cancer, including cell proliferation, evasion of apoptosis, tumor invasion, and metastasis.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('aberrantly expressed', 'Var', (12, 32))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('ncRNA', 'Gene', '220202', (34, 39))	('cell proliferation', 'CPA', (189, 207))	('ncRNA', 'Gene', (34, 39))	('cancer', 'Disease', (171, 177))	('evasion', 'MPA', (209, 216))	('tumor', 'Disease', (231, 236))	('metastasis', 'CPA', (251, 261))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
423536	26064090	Similarly to H19, c-Myc can also induce the transcription of CCAT1, also known as CARLo-5 (cancer-associated region long noncoding RNA), transcription and its ectopic expression was able to promote CRC cell proliferation in vitro.	('promote', 'PosReg', (190, 197))	('ectopic expression', 'Var', (159, 177))	('transcription', 'MPA', (44, 57))	('c-Myc', 'Gene', (18, 23))	('cancer', 'Disease', (91, 97))	('CARLo-5', 'Gene', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('CARLo-5', 'Gene', '100507056', (82, 89))	('CCAT1', 'Gene', '100507056', (61, 66))	('CRC cell proliferation', 'CPA', (198, 220))	('CCAT1', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('c-Myc', 'Gene', '4609', (18, 23))	('induce', 'PosReg', (33, 39))
423541	26064090	Briefly, it was found that knockdown of CARLo-5 resulted in decreased expression of PCNA (proliferating cell nuclear antigen), which is essential for DNA replication and increased synthesis of the cell-cycle regulators p16, p21, and p27.	('knockdown', 'Var', (27, 36))	('decreased', 'NegReg', (60, 69))	('PCNA', 'Gene', (84, 88))	('CARLo-5', 'Gene', (40, 47))	('CARLo-5', 'Gene', '100507056', (40, 47))	('p21', 'Gene', (224, 227))	('p27', 'Gene', '3429', (233, 236))	('p16', 'Gene', '1029', (219, 222))	('p27', 'Gene', (233, 236))	('proliferating cell nuclear antigen', 'Gene', (90, 124))	('increased', 'PosReg', (170, 179))	('p16', 'Gene', (219, 222))	('PCNA', 'Gene', '5111', (84, 88))	('expression', 'MPA', (70, 80))	('proliferating cell nuclear antigen', 'Gene', '5111', (90, 124))	('p21', 'Gene', '1026', (224, 227))
423544	26064090	In HCC cells, depletion of HEIH resulted in reduced cell proliferation and contributed to cell-cycle arrest mainly by p16, p27, and p21 protein upregulation.	('cell-cycle arrest', 'CPA', (90, 107))	('p27', 'Gene', '3429', (123, 126))	('p27', 'Gene', (123, 126))	('p16', 'Gene', '1029', (118, 121))	('cell proliferation', 'CPA', (52, 70))	('p21', 'Gene', '1026', (132, 135))	('p21', 'Gene', (132, 135))	('HEIH', 'Gene', (27, 31))	('depletion', 'Var', (14, 23))	('reduced', 'NegReg', (44, 51))	('HEIH', 'Gene', '100859930', (27, 31))	('p16', 'Gene', (118, 121))	('upregulation', 'PosReg', (144, 156))
423550	26064090	Additionally, knockdown of PVT-1 inhibits cell proliferation in vitro and promotes apoptosis through the activation of TGF-beta signalling pathway-related genes such as SMAD4.	('promotes', 'PosReg', (74, 82))	('SMAD4', 'Gene', (169, 174))	('cell proliferation in vitro', 'CPA', (42, 69))	('activation', 'PosReg', (105, 115))	('TGF-beta', 'Gene', '7040', (119, 127))	('SMAD4', 'Gene', '4089', (169, 174))	('TGF-beta', 'Gene', (119, 127))	('knockdown', 'Var', (14, 23))	('inhibits', 'NegReg', (33, 41))	('apoptosis', 'CPA', (83, 92))	('PVT-1', 'Gene', '5820', (27, 32))	('PVT-1', 'Gene', (27, 32))
423552	26064090	This observation, in addition to the fact that MALAT1 is localized in nuclear speckles, implies that it may affect the alternative splicing of pre-mRNAs, through the modulation of SR factors.	('MALAT1', 'Var', (47, 53))	('modulation', 'Reg', (166, 176))	('SR factors', 'Protein', (180, 190))	('affect', 'Reg', (108, 114))	('alternative splicing', 'MPA', (119, 139))	('SR', 'Chemical', '-', (180, 182))
423554	26064090	Interestingly, inhibition of GAS5 expression resulted in increased protein levels of E2F1 and Cyclin D1, which are two major players in the retinoblastoma protein (pRB) pathway, as well as in decreased P21 levels which has a critical role in cell cycle arrest.	('retinoblastoma', 'Gene', (140, 154))	('retinoblastoma', 'Gene', '5925', (140, 154))	('Cyclin D1', 'Gene', (94, 103))	('decreased', 'NegReg', (192, 201))	('pRB', 'Gene', (164, 167))	('retinoblastoma', 'Phenotype', 'HP:0009919', (140, 154))	('P21', 'Gene', '1026', (202, 205))	('pRB', 'Gene', '5925', (164, 167))	('protein levels', 'MPA', (67, 81))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (242, 259))	('GAS5', 'Gene', '60674', (29, 33))	('Cyclin D1', 'Gene', '595', (94, 103))	('E2F1', 'Gene', '1869', (85, 89))	('E2F1', 'Gene', (85, 89))	('increased', 'PosReg', (57, 66))	('P21', 'Gene', (202, 205))	('inhibition', 'Var', (15, 25))	('GAS5', 'Gene', (29, 33))
423555	26064090	In pancreatic cancer cells, inhibition of GAS5 expression increases CDK6 protein levels thereby facilitating cell cycle progression.	('facilitating', 'Reg', (96, 108))	('increases', 'PosReg', (58, 67))	('pancreatic cancer', 'Disease', (3, 20))	('CDK6', 'Gene', (68, 72))	('CDK6', 'Gene', '1021', (68, 72))	('GAS5', 'Gene', '60674', (42, 46))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('inhibition', 'Var', (28, 38))	('GAS5', 'Gene', (42, 46))	('cell cycle progression', 'CPA', (109, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))
423561	26064090	Moreover, loc285194 which is a p53-regulated tumor suppressor lncRNA was found to inhibit CRC cell growth both in vitro and in vivo.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('loc285194', 'Var', (10, 19))	('tumor', 'Disease', (45, 50))	('inhibit', 'NegReg', (82, 89))	('CRC cell growth', 'CPA', (90, 105))	('ncRNA', 'Gene', (63, 68))	('ncRNA', 'Gene', '220202', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
423563	26064090	HOTAIR epigenetically regulates the expression of essential metastasis-suppressor genes through the coordination of histone modification complexes, PRC2 and LSD1.	('HOTAIR', 'Gene', '100124700', (0, 6))	('regulates', 'Reg', (22, 31))	('PRC2', 'Gene', (148, 152))	('epigenetically', 'Var', (7, 21))	('essential metastasis-suppressor genes', 'Gene', (50, 87))	('LSD1', 'Gene', (157, 161))	('HOTAIR', 'Gene', (0, 6))	('LSD1', 'Gene', '23028', (157, 161))	('expression', 'MPA', (36, 46))
423567	26064090	Silencing of HOTAIR expression reduced HCC cell proliferation and negatively regulated the expression levels of matrix metalloproteinase-9 (MMP9) and angiogenic factor VEGF, which are known to be involved in metastasis and angiogenesis, respectively.	('matrix metalloproteinase-9', 'Gene', (112, 138))	('MMP9', 'Gene', '4318', (140, 144))	('reduced', 'NegReg', (31, 38))	('negatively regulated', 'NegReg', (66, 86))	('VEGF', 'Gene', '7422', (168, 172))	('matrix metalloproteinase-9', 'Gene', '4318', (112, 138))	('HOTAIR', 'Gene', (13, 19))	('HCC cell proliferation', 'CPA', (39, 61))	('Silencing', 'Var', (0, 9))	('expression levels', 'MPA', (91, 108))	('MMP9', 'Gene', (140, 144))	('VEGF', 'Gene', (168, 172))	('HOTAIR', 'Gene', '100124700', (13, 19))
423568	26064090	Likewise, in GC cell lines, knock-down of HOTAIR, reduced invasiveness and the expression of MMP1 and MMP3.	('invasiveness', 'CPA', (58, 70))	('MMP1', 'Gene', (93, 97))	('HOTAIR', 'Gene', '100124700', (42, 48))	('expression', 'MPA', (79, 89))	('MMP3', 'Gene', (102, 106))	('knock-down', 'Var', (28, 38))	('MMP1', 'Gene', '4312', (93, 97))	('MMP3', 'Gene', '4314', (102, 106))	('reduced', 'NegReg', (50, 57))	('HOTAIR', 'Gene', (42, 48))
423569	26064090	Another interesting finding was that HOTAIR silencing reversed EMT through regulation of Snail, which is one of the main transcription factors that controls EMT and cell motility.	('EMT', 'CPA', (63, 66))	('Snail', 'Gene', (89, 94))	('HOTAIR', 'Gene', (37, 43))	('Snail', 'Gene', '6615', (89, 94))	('HOTAIR', 'Gene', '100124700', (37, 43))	('regulation', 'Reg', (75, 85))	('silencing', 'Var', (44, 53))
423573	26064090	A number of studies provided evidence that ectopic expression of MALAT1 promotes proliferation and migration of cell lines in vitro and enhances tumor growth and metastasis in vivo.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ectopic expression', 'Var', (43, 61))	('MALAT1', 'Gene', (65, 71))	('enhances', 'PosReg', (136, 144))	('tumor', 'Disease', (145, 150))	('promotes', 'PosReg', (72, 80))	('proliferation', 'CPA', (81, 94))	('migration of cell lines', 'CPA', (99, 122))
423584	26064090	demonstrated that H19 may activate miR-200 family members, resulting in subsequent suppression of their target genes, E-cadherin transcriptional repressors (ZEB1/2).	('E-cadherin', 'Gene', (118, 128))	('suppression', 'NegReg', (83, 94))	('ZEB1/2', 'Gene', '6935;9839', (157, 163))	('activate', 'PosReg', (26, 34))	('E-cadherin', 'Gene', '999', (118, 128))	('H19', 'Var', (18, 21))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('ZEB1/2', 'Gene', (157, 163))
423598	26064090	showed that CRNDE splice variants are upregulated in early stage neoplastic colorectal tissues including adenomas and adenocarcinomas.	('CRNDE', 'Gene', (12, 17))	('adenomas', 'Disease', 'MESH:D000236', (105, 113))	('CRNDE', 'Gene', '643911', (12, 17))	('adenomas', 'Disease', (105, 113))	('splice variants', 'Var', (18, 33))	('upregulated', 'PosReg', (38, 49))	('colorectal', 'Disease', 'MESH:D015179', (76, 86))	('adenocarcinomas', 'Disease', 'MESH:D000230', (118, 133))	('adenocarcinomas', 'Disease', (118, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('colorectal', 'Disease', (76, 86))
423607	26064090	Single nucleotide polymorphisms (SNP) in lncRNA genes are associated with CRC susceptibility.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('associated', 'Reg', (58, 68))	('CRC susceptibility', 'Disease', (74, 92))	('ncRNA', 'Gene', (42, 47))	('ncRNA', 'Gene', '220202', (42, 47))
423608	26064090	In particular, two SNPs located in the lncRNA PRNCR1 gene (rs13252298 and rs1456315) are connected with decreased risk for CRC, while patients harboring two different SNPs, namely, rs7007694C and rs16901946G, have low risk to develop poorly differentiated CRC.	('rs1456315', 'Var', (74, 83))	('poorly differentiated CRC', 'Disease', (234, 259))	('rs13252298', 'Var', (59, 69))	('PRNCR1', 'Gene', '101867536', (46, 52))	('ncRNA', 'Gene', (40, 45))	('rs16901946G', 'Var', (196, 207))	('rs1456315', 'Mutation', 'rs1456315', (74, 83))	('patients', 'Species', '9606', (134, 142))	('PRNCR1', 'Gene', (46, 52))	('decreased', 'NegReg', (104, 113))	('rs7007694C', 'Var', (181, 191))	('CRC', 'Disease', (123, 126))	('ncRNA', 'Gene', '220202', (40, 45))	('rs13252298', 'Mutation', 'rs13252298', (59, 69))	('rs7007694', 'Mutation', 'rs7007694', (181, 190))
423609	26064090	On the contrary, the rs1456315G SNP is linked to increased risk for the development of CRC with poor differentiated status.	('CRC', 'Disease', (87, 90))	('rs1456315G', 'Var', (21, 31))	('rs1456315', 'Mutation', 'rs1456315', (21, 30))
423611	26064090	Briefly, the rs7958904 CC genotype is related with decreased risk of CRC compared to the rs7958904 GG genotype.	('decreased', 'NegReg', (51, 60))	('rs7958904 CC', 'Var', (13, 25))	('rs7958904', 'Mutation', 'rs7958904', (89, 98))	('rs7958904', 'Mutation', 'rs7958904', (13, 22))	('CRC', 'Disease', (69, 72))
423617	26064090	Patients with high PVT1 expression levels present a more adverse outcome as indicated by shorter OS periods, compared to those with low PVT1 expression.	('PVT1', 'Gene', (19, 23))	('PVT1', 'Gene', (136, 140))	('expression', 'MPA', (24, 34))	('PVT1', 'Gene', '5820', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('PVT1', 'Gene', '5820', (136, 140))	('OS periods', 'MPA', (97, 107))	('shorter', 'NegReg', (89, 96))
423618	26064090	Moreover, multivariate analysis revealed that PVT1 expression in CRC predicts an increased risk of death, independently of important clinicopathological factors.	('PVT1', 'Gene', '5820', (46, 50))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('PVT1', 'Gene', (46, 50))	('expression', 'Var', (51, 61))
423621	26064090	The levels of lncRNA 91H expression are significantly upregulated in CRC compared to noncancerous tissues, and 91H constitutes an independent predictor of poor prognosis in CRC.	('91H', 'Var', (111, 114))	('levels', 'MPA', (4, 10))	('ncRNA', 'Gene', (15, 20))	('upregulated', 'PosReg', (54, 65))	('CRC', 'Disease', (173, 176))	('cancerous', 'Disease', (88, 97))	('ncRNA', 'Gene', '220202', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancerous', 'Disease', 'MESH:D009369', (88, 97))	('CRC', 'Disease', (69, 72))
423625	26064090	Reduced expression levels of LOC285194 are associated with more aggressive features of tumors and correlate significantly with shorter DFS.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('more', 'PosReg', (59, 63))	('Reduced', 'NegReg', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('expression levels', 'MPA', (8, 25))	('tumors', 'Disease', (87, 93))	('LOC285194', 'Var', (29, 38))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
423628	26064090	The expression of a novel class of lncRNAs, transcribed ultraconserved regions (T-UCRs), namely, uc.73 and uc.388, is reported to decrease in CRC and uc.73 is found to be associated with OS of CRC patients.	('uc.73', 'Gene', (97, 102))	('ncRNA', 'Gene', (36, 41))	('CRC', 'Disease', (193, 196))	('patients', 'Species', '9606', (197, 205))	('decrease', 'NegReg', (130, 138))	('expression', 'MPA', (4, 14))	('ncRNA', 'Gene', '220202', (36, 41))	('uc.73', 'Var', (150, 155))	('associated', 'Reg', (171, 181))	('CRC', 'Disease', (142, 145))
423629	26064090	Additionally, patients with low GAS5 expression had significantly shorter OS than those with high GAS5 expression and GAS5 expression was identified as an independent indicator of CRC prognosis.	('GAS5', 'Gene', (32, 36))	('CRC', 'Disease', (180, 183))	('shorter', 'NegReg', (66, 73))	('GAS5', 'Gene', (98, 102))	('GAS5', 'Gene', '60674', (118, 122))	('GAS5', 'Gene', '60674', (32, 36))	('GAS5', 'Gene', '60674', (98, 102))	('patients', 'Species', '9606', (14, 22))	('low', 'Var', (28, 31))	('GAS5', 'Gene', (118, 122))
423637	26064090	AA174084 is another lncRNA with possible diagnostic value in GC, as it was significantly upregulated in gastric juice from GC patients compared to the gastric juice derived from patients with other gastric disorders or to normal mucosa.	('AA174084', 'Var', (0, 8))	('gastric disorders', 'Disease', (198, 215))	('upregulated', 'PosReg', (89, 100))	('gastric disorders', 'Disease', 'MESH:D013274', (198, 215))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (126, 134))	('ncRNA', 'Gene', (21, 26))	('ncRNA', 'Gene', '220202', (21, 26))
423648	26064090	On the other hand, lncRNAs such as FENDRR, MEG3, LET, GAS5, BM742401, and GACAT1 were found to represent indicators of favorable prognosis.	('GAS5', 'Gene', (54, 58))	('FENDRR', 'Gene', '400550', (35, 41))	('GACAT1', 'Gene', (74, 80))	('GACAT1', 'Gene', '104326057', (74, 80))	('BM742401', 'Var', (60, 68))	('ncRNA', 'Gene', (20, 25))	('GAS5', 'Gene', '60674', (54, 58))	('FENDRR', 'Gene', (35, 41))	('ncRNA', 'Gene', '220202', (20, 25))
423652	26064090	GAS5 and BM742401 are additional markers of favorable GC patients' prognosis since decreased expression levels were associated with poorer survival.	('GAS5', 'Gene', '60674', (0, 4))	('patients', 'Species', '9606', (57, 65))	('decreased', 'NegReg', (83, 92))	('BM742401', 'Var', (9, 17))	('expression levels', 'MPA', (93, 110))	('GAS5', 'Gene', (0, 4))	('poorer', 'NegReg', (132, 138))
423679	26064090	Patients with high expression levels had significantly better OS, suggesting that BC008363 is a biomarker of favorable prognosis in PDAC.	('PDAC', 'Chemical', '-', (132, 136))	('high expression levels', 'Var', (14, 36))	('BC008363', 'Var', (82, 90))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (55, 61))	('PDAC', 'Disease', (132, 136))	('PDAC', 'Phenotype', 'HP:0006725', (132, 136))
423689	26064090	In particular, patients with rs11752942AG and GG genotypes have lower risk for ESCC compared to rs11752942AA, revealing their value as markers for screening high-risk populations.	('rs11752942AG', 'Var', (29, 41))	('lower', 'NegReg', (64, 69))	('patients', 'Species', '9606', (15, 23))	('ESCC', 'Disease', (79, 83))
423691	26064090	The expression of AFAP1-AS1 is markedly increased in EAC compared to normal esophageal tissues and hypomethylation is responsible for the observed upregulation.	('AFAP1-AS1', 'Gene', (18, 27))	('hypomethylation', 'Var', (99, 114))	('EAC', 'Phenotype', 'HP:0011459', (53, 56))	('expression', 'MPA', (4, 14))	('EAC', 'Disease', (53, 56))	('increased', 'PosReg', (40, 49))	('upregulation', 'PosReg', (147, 159))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (18, 27))
423704	26064090	Interestingly, low LOC285194 expression was associated with adverse clinicopathological characteristics of the tumors such as TNM stage and distant metastasis.	('TNM', 'Gene', '10178', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('TNM', 'Gene', (126, 129))	('distant metastasis', 'CPA', (140, 158))	('low LOC285194', 'Var', (15, 28))	('LOC285194', 'Var', (19, 28))	('expression', 'MPA', (29, 39))
423705	26064090	In the group of patients who received CRT, the expression of LOC285194 was found to be an independent predictor of patients' response to therapy, and in the subgroup patients after esophagectomy the LOC285194 levels were found to significantly correlate with their improved DFS and OS probabilities (Table 3).	('patients', 'Species', '9606', (115, 123))	('DFS', 'Disease', (274, 277))	('LOC285194', 'Var', (199, 208))	('improved', 'PosReg', (265, 273))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (166, 174))	('LOC285194', 'Var', (61, 70))
423710	26064090	In liver cancer cell lines, HOTAIR silencing inhibited cell proliferation and increased the cells sensitivity to Cisplatin and Doxorubicin.	('HOTAIR', 'Gene', '100124700', (28, 34))	('silencing', 'Var', (35, 44))	('liver cancer', 'Phenotype', 'HP:0002896', (3, 15))	('liver cancer', 'Disease', 'MESH:D006528', (3, 15))	('Doxorubicin', 'Chemical', 'MESH:D004317', (127, 138))	('liver cancer', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cell proliferation', 'CPA', (55, 73))	('Cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('increased', 'PosReg', (78, 87))	('inhibited', 'NegReg', (45, 54))	('HOTAIR', 'Gene', (28, 34))
423711	26064090	MRUL (multidrug resistant-related and upregulated lncRNA) is overexpressed in two MDR GC cell sublines, and depletion of MRUL expression via siRNA, increased chemosensitivity of GC cells to Adriamycin and Vincristine.	('ncRNA', 'Gene', (51, 56))	('increased', 'PosReg', (148, 157))	('ncRNA', 'Gene', '220202', (51, 56))	('Vincristine', 'Chemical', 'MESH:D014750', (205, 216))	('chemosensitivity', 'MPA', (158, 174))	('Adriamycin', 'Chemical', 'MESH:D004317', (190, 200))	('depletion', 'Var', (108, 117))	('MRUL', 'Gene', (121, 125))
423713	26064090	Modulation of the expression of certain tumor-suppressor lncRNAs can be used as an alternative therapeutic approach in GI cancers.	('Modulation', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('GI cancers', 'Disease', (119, 129))	('ncRNA', 'Gene', (58, 63))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('expression', 'MPA', (18, 28))	('GI cancers', 'Disease', 'MESH:D009369', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('GI cancer', 'Phenotype', 'HP:0007378', (119, 128))	('tumor', 'Disease', (40, 45))	('ncRNA', 'Gene', '220202', (58, 63))
423722	26064090	Regarding the clinical management of GI cancers (Tables 1-3) some of the most promising lncRNA-oriented studies include: (i) the development of a CCAT1-specific peptide nucleic acid based molecular beacon for both imaging and in situ detection of CRC, (ii) the diagnostic value of HULC serum levels in HCC, (iii) the prognostic potential of HOTAIR for all GI cancers, and (iv) the predictive role of LOC285194 regarding chemoradiotherapy response in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('HULC', 'Gene', (281, 285))	('GI cancer', 'Phenotype', 'HP:0007378', (37, 46))	('cancers', 'Phenotype', 'HP:0002664', (359, 366))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('HOTAIR', 'Gene', '100124700', (341, 347))	('cancer', 'Phenotype', 'HP:0002664', (461, 467))	('GI cancers', 'Disease', (356, 366))	('HOTAIR', 'Gene', (341, 347))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('HULC', 'Gene', '728655', (281, 285))	('GI cancers', 'Disease', (37, 47))	('ncRNA', 'Gene', (89, 94))	('GI cancers', 'Disease', 'MESH:D009369', (356, 366))	('ncRNA', 'Gene', '220202', (89, 94))	('CCAT1', 'Gene', '100507056', (146, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (450, 467))	('CCAT1', 'Gene', (146, 151))	('GI cancers', 'Disease', 'MESH:D009369', (37, 47))	('LOC285194', 'Var', (400, 409))	('GI cancer', 'Phenotype', 'HP:0007378', (356, 365))	('esophageal cancer', 'Disease', (450, 467))
423847	19491834	Our prior study that measured the prevalence of FBE raised the possibility that FBE probands with cancer may be less obese than non-FBE probands with cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('less', 'NegReg', (112, 116))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('BE', 'Phenotype', 'HP:0100580', (81, 83))	('FBE', 'Var', (80, 83))	('obese', 'Disease', 'MESH:D009765', (117, 122))	('cancer', 'Disease', (150, 156))	('BE', 'Phenotype', 'HP:0100580', (133, 135))	('cancer', 'Disease', (98, 104))	('obese', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('BE', 'Phenotype', 'HP:0100580', (49, 51))
423873	19491834	The trait is proposed to be a manifestation of genetic variant(s) that confer a susceptibility to metaplastic transformation of the esophageal epithelium perhaps in the presence of inflammation caused by gastro-esophageal reflux and/or obesity.	('variant', 'Var', (55, 62))	('metaplastic transformation', 'CPA', (98, 124))	('gastro-esophageal reflux', 'Disease', (204, 228))	('obesity', 'Disease', 'MESH:D009765', (236, 243))	('obesity', 'Disease', (236, 243))	('gastro-esophageal reflux', 'Disease', 'MESH:D005764', (204, 228))	('obesity', 'Phenotype', 'HP:0001513', (236, 243))	('esophageal reflux', 'Phenotype', 'HP:0002020', (211, 228))	('susceptibility', 'Reg', (80, 94))	('inflammation', 'Disease', 'MESH:D007249', (181, 193))	('inflammation', 'Disease', (181, 193))
423894	19065486	Perforations only occurred 1% of the patients who received photodynamic therapy versus 7% of those who received laser therapy.	('patients', 'Species', '9606', (37, 45))	('photodynamic therapy', 'Var', (59, 79))	('Perforations', 'CPA', (0, 12))
423909	19065486	The rate of progression to cancer was significantly reduced in those who received photodynamic therapy, and it decreased to 15% versus 29% of those who received omeprazole.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('omeprazole', 'Chemical', 'MESH:D009853', (161, 171))	('reduced', 'NegReg', (52, 59))	('photodynamic therapy', 'Var', (82, 102))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
423919	19065486	A small series recently reported, though, that very high light dosages of up to l000J/cm fiber might be needed to eliminate dysplasia, although even at this dosage the group only found a 75% response rate.	('l000J/cm', 'Var', (80, 88))	('dysplasia', 'Disease', 'MESH:D004476', (124, 133))	('dysplasia', 'Disease', (124, 133))
423925	19065486	However, those patients who had photodynamic therapy generally had a significantly worse performance status, which made them less likely to be surgical candidates.	('performance status', 'MPA', (89, 107))	('photodynamic therapy', 'Var', (32, 52))	('patients', 'Species', '9606', (15, 23))
423944	19065486	Photodynamic therapy can cause fairly severe chest pain and nausea.	('pain', 'Phenotype', 'HP:0012531', (51, 55))	('nausea', 'Phenotype', 'HP:0002018', (60, 66))	('nausea', 'Disease', 'MESH:D009325', (60, 66))	('chest pain', 'Phenotype', 'HP:0100749', (45, 55))	('Photodynamic therapy', 'Var', (0, 20))	('cause', 'Reg', (25, 30))	('chest pain', 'Disease', 'MESH:D002637', (45, 55))	('nausea', 'Disease', (60, 66))	('chest pain', 'Disease', (45, 55))
423955	33498997	Nonetheless, guidelines recommend assessing nutritional deficiencies in all such patients because, regardless of whether they are still on anticancer treatments or not, malnutrition leads to low performance status, impaired quality of life (QoL), unplanned hospitalizations, and reduced survival.	('low', 'NegReg', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('survival', 'CPA', (287, 295))	('reduced', 'NegReg', (279, 286))	('quality', 'MPA', (224, 231))	('impaired', 'NegReg', (215, 223))	('performance status', 'MPA', (195, 213))	('malnutrition', 'Var', (169, 181))	('malnutrition', 'Phenotype', 'HP:0004395', (169, 181))	('patients', 'Species', '9606', (81, 89))	('nutritional deficiencies', 'Disease', (44, 68))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('nutritional deficiencies', 'Disease', 'MESH:D044342', (44, 68))
423998	33498997	In later stages, a negative protein and energy balance derived from metabolic derangements results in progressive functional impairment with clinical manifestations characterized by hypophagia, early satiety, fatigue, and wasting.	('early satiety', 'Disease', (194, 207))	('fatigue', 'Phenotype', 'HP:0012378', (209, 216))	('metabolic derangements', 'Phenotype', 'HP:0001939', (68, 90))	('hypophagia', 'Disease', 'None', (182, 192))	('wasting', 'Disease', (222, 229))	('derangements', 'Var', (78, 90))	('fatigue', 'Disease', 'MESH:D005221', (209, 216))	('hypophagia', 'Disease', (182, 192))	('negative', 'NegReg', (19, 27))	('fatigue', 'Disease', (209, 216))
424048	33498997	In esophageal cancer patients, PEG tends to grant a better nutritional status than self-expandable metal stent, and it is an independent factor associated with overall survival.	('cancer', 'Disease', (14, 20))	('associated', 'Reg', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('nutritional status', 'MPA', (59, 77))	('better', 'PosReg', (52, 58))	('PEG', 'Var', (31, 34))	('patients', 'Species', '9606', (21, 29))	('PEG', 'Chemical', '-', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
424050	33498997	indicate a slightly worse QoL in esophageal cancer patients using NGT feeding compared with the percutaneous route during chemoradiation therapy.	('QoL', 'MPA', (26, 29))	('NGT feeding', 'Var', (66, 77))	('worse', 'NegReg', (20, 25))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('patients', 'Species', '9606', (51, 59))	('NGT', 'Phenotype', 'HP:0040288', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
424075	33498997	Regarding clinical appropriateness, HPN is not recommended in patients with worsening clinical conditions (severe organ dysfunction or uncontrolled symptoms), low KPS (<50) or poor ECOG score (>=3), short estimated life expectancy, and patient refusal.	('organ dysfunction', 'Disease', 'MESH:D009102', (114, 131))	('PN', 'Gene', '79650', (37, 39))	('patient', 'Species', '9606', (62, 69))	('patients', 'Species', '9606', (62, 70))	('organ dysfunction', 'Disease', (114, 131))	('low', 'Var', (159, 162))	('patient', 'Species', '9606', (236, 243))
424126	33482859	Patients with low GSTM3 expression tended to exhibit an increased rate of poor differentiation in both the mRNA cohort (p = 0.024) and protein cohort (p = 0.004).	('GSTM3', 'Gene', '2947', (18, 23))	('expression', 'MPA', (24, 34))	('poor differentiation', 'CPA', (74, 94))	('Patients', 'Species', '9606', (0, 8))	('GSTM3', 'Gene', (18, 23))	('low', 'Var', (14, 17))
424141	33482859	At least five mammalian GST gene families have been identified as polymorphic, and mutations or deletions of these genes contribute to the predisposition of several diseases, including cancer.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('deletions', 'Var', (96, 105))	('contribute', 'Reg', (121, 131))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('diseases', 'Disease', (165, 173))	('cancer', 'Disease', (185, 191))	('mammalian', 'Species', '9606', (14, 23))
424146	33482859	GSTM3 polymorphisms may increase lung cancer and esophageal cancer susceptibility.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('increase', 'PosReg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('polymorphisms', 'Var', (6, 19))	('GSTM3', 'Gene', (0, 5))	('cancer', 'Disease', (60, 66))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('GSTM3', 'Gene', '2947', (0, 5))	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('lung cancer', 'Disease', (33, 44))
424181	33482859	Then, GSTM3 mRNA expression in the mRNA cohort was divided into two groups: the low-expression group (<= 0.662, n = 91) and the high-expression group (>0.662, n = 93).	('<= 0.662', 'Var', (102, 110))	('GSTM3', 'Gene', '2947', (6, 11))	('GSTM3', 'Gene', (6, 11))
424195	33482859	Cox's proportional hazards regression confirmed that high GSTM3 expression was significantly associated with lower risk of disease recurrence in the mRNA cohort (hazard ratio, HR: 0.635, 95 % confidence interval, CI: 0.435-0.927, p = 0.019) and protein cohort (HR: 0.659, 95 % CI: 0.484-0.898, p = 0.008) (Tables 5 and 6).	('lower', 'NegReg', (109, 114))	('high', 'Var', (53, 57))	('disease recurrence', 'CPA', (123, 141))	('GSTM3', 'Gene', (58, 63))	('GSTM3', 'Gene', '2947', (58, 63))
424201	33482859	High GSTM3 expression levels indeed decreased the risk of disease recurrence for patients with resected ESCC compared with those with low GSTM3 expression levels.	('High', 'Var', (0, 4))	('GSTM3', 'Gene', (5, 10))	('GSTM3', 'Gene', '2947', (5, 10))	('patients', 'Species', '9606', (81, 89))	('GSTM3', 'Gene', '2947', (138, 143))	('ESCC', 'Disease', (104, 108))	('disease', 'Disease', (58, 65))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('GSTM3', 'Gene', (138, 143))	('decreased', 'NegReg', (36, 45))
424206	33482859	Epigenetic inactivation of GSTM3 has been reported in Barrett's adenocarcinoma.	('adenocarcinoma', 'Disease', (64, 78))	('reported', 'Reg', (42, 50))	('GSTM3', 'Gene', '2947', (27, 32))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('GSTM3', 'Gene', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Epigenetic inactivation', 'Var', (0, 23))
424212	33482859	Some studies have noted that high GSTM3 expression is a poor prognostic factor, whereas others have noted that low GSTM3 expression is a poor prognostic factor.	('high', 'Var', (29, 33))	('GSTM3', 'Gene', '2947', (115, 120))	('GSTM3', 'Gene', '2947', (34, 39))	('GSTM3', 'Gene', (34, 39))	('GSTM3', 'Gene', (115, 120))
424214	33482859	Meding S reported that high GSTM3 expression correlated with lymph node metastasis and advanced stage of colon cancer, and low GSTM3 expression was associated with better survival.	('expression', 'MPA', (34, 44))	('high', 'Var', (23, 27))	('colon cancer', 'Disease', 'MESH:D015179', (105, 117))	('better', 'PosReg', (164, 170))	('colon cancer', 'Disease', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lymph node metastasis', 'CPA', (61, 82))	('low', 'Var', (123, 126))	('GSTM3', 'Gene', (127, 132))	('correlated with', 'Reg', (45, 60))	('GSTM3', 'Gene', (28, 33))	('GSTM3', 'Gene', '2947', (127, 132))	('GSTM3', 'Gene', '2947', (28, 33))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))
424222	33482859	Univariate analysis demonstrated that patients with high GSTM3 expression tended to have better 3- and 5-year DSS compared with those with low-expression in the mRNA cohort (64.6 % vs. 56.2 % and 52.8 % vs. 46.0 %, p = 0.132) and the protein cohort (42.4 % vs. 31.0 % and 37.1 % vs. 22.3 %, p = 0.070); however, the difference was not statistically significant.	('DSS', 'Gene', '5376', (110, 113))	('better', 'PosReg', (89, 95))	('GSTM3', 'Gene', (57, 62))	('GSTM3', 'Gene', '2947', (57, 62))	('high', 'Var', (52, 56))	('patients', 'Species', '9606', (38, 46))	('DSS', 'Gene', (110, 113))
424227	33482859	Our present study showed that the difference of DFS between low and high expression of GSTM3 was statistically significant, but the difference in DSS did not reach statistical significance.	('DSS', 'Gene', '5376', (146, 149))	('high expression', 'Var', (68, 83))	('low', 'Var', (60, 63))	('GSTM3', 'Gene', (87, 92))	('DSS', 'Gene', (146, 149))	('GSTM3', 'Gene', '2947', (87, 92))
424232	33482859	Both low- and high-expression of GSTM3 cohorts received no neoadjuvant or adjuvant treatment until disease recurrence.	('low-', 'NegReg', (5, 9))	('GSTM3', 'Gene', '2947', (33, 38))	('high-expression', 'Var', (14, 29))	('GSTM3', 'Gene', (33, 38))
424240	33482859	Patients with low GSTM3 expression tended to exhibit an increased rate of poor differentiation in patients with resectable ESCC.	('GSTM3', 'Gene', '2947', (18, 23))	('poor differentiation', 'CPA', (74, 94))	('ESCC', 'Disease', (123, 127))	('patients', 'Species', '9606', (98, 106))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('Patients', 'Species', '9606', (0, 8))	('GSTM3', 'Gene', (18, 23))	('low', 'Var', (14, 17))
424254	32509787	Anti-proliferative activity of xanthohumol was abrogated or enhanced according to the knockdown or overexpression of KRT18 protein, respectively.	('knockdown', 'Var', (86, 95))	('overexpression', 'PosReg', (99, 113))	('xanthohumol', 'Chemical', 'MESH:C104536', (31, 42))	('Anti-proliferative activity', 'CPA', (0, 27))	('abrogated', 'NegReg', (47, 56))	('enhanced', 'PosReg', (60, 68))	('KRT18 protein', 'Protein', (117, 130))
424255	32509787	Xanthohumol also induced apoptosis and cell cycle arrest at G1 phase which was associated with the modulation of expression of related makers including cyclin D1, cyclin D3, and cleaved-PARP, Bcl-2, cytochrome c and Bax.	('Bcl-2', 'Gene', '596', (192, 197))	('cyclin D1', 'Gene', (152, 161))	('cyclin D3', 'Gene', (163, 172))	('cytochrome c', 'Gene', '54205', (199, 211))	('cyclin D1', 'Gene', '595', (152, 161))	('cyclin D3', 'Gene', '896', (163, 172))	('PARP', 'Gene', '142', (186, 190))	('Bax', 'Gene', '581', (216, 219))	('Xanthohumol', 'Chemical', 'MESH:C104536', (0, 11))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (39, 56))	('arrest', 'Disease', 'MESH:D006323', (50, 56))	('Bax', 'Gene', (216, 219))	('apoptosis', 'CPA', (25, 34))	('arrest', 'Disease', (50, 56))	('PARP', 'Gene', (186, 190))	('cytochrome c', 'Gene', (199, 211))	('Xanthohumol', 'Var', (0, 11))	('Bcl-2', 'Gene', (192, 197))
424287	32509787	Antibodies to examine Bcl-2 (CST 15071), Bax (CST 5023), cyclin D1 (CST 2922), cyclin D3 (CST 2936), COX IV (CST 4850), alpha-tubulin (CST 3873), and beta-tubulin (CST 5346) expression was from Cell Signaling Technology (Beverly, MA, United States).	('CST 2936', 'Var', (90, 98))	('Bax', 'Gene', '581', (41, 44))	('CST', 'Var', (68, 71))	('cyclin D1', 'Gene', '595', (57, 66))	('alpha-tubulin', 'Gene', '10376', (120, 133))	('cyclin D1', 'Gene', (57, 66))	('Bcl-2', 'Gene', (22, 27))	('cyclin D3', 'Gene', '896', (79, 88))	('cyclin D3', 'Gene', (79, 88))	('COX IV', 'Gene', (101, 107))	('Bax', 'Gene', (41, 44))	('Bcl-2', 'Gene', '596', (22, 27))	('CST 5346', 'Var', (164, 172))	('alpha-tubulin', 'Gene', (120, 133))	('COX IV', 'Gene', '1327', (101, 107))
424290	32509787	The human EC cell line KYSE30, KYSE70, KYSE410, KYSE450, and KYSE510 was purchased from the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China).	('KYSE410', 'Var', (39, 46))	('KYSE70', 'Var', (31, 37))	('human', 'Species', '9606', (4, 9))	('KYSE510', 'Var', (61, 68))
424350	32509787	Results indicated that xanthohumol significantly decreased the tumor growth relative to the control group without causing any change in mouse body weight (Figures 6A-D).	('tumor', 'Disease', (63, 68))	('mouse', 'Species', '10090', (136, 141))	('xanthohumol', 'Chemical', 'MESH:C104536', (23, 34))	('decreased', 'NegReg', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('xanthohumol', 'Var', (23, 34))
424357	32509787	It has been reported that xanthohumol inhibits colorectal cancer cells via downregulation of Hexokinases II-mediated glycolysis, exhibits anti-myeloma activity in vitro through inhibition of cell proliferation via the ERK and JNK-dependent mechanism and exerts anticancer effects against gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('ERK', 'Gene', '5594', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('gastric cancer', 'Disease', 'MESH:D013274', (288, 302))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('xanthohumol', 'Chemical', 'MESH:C104536', (26, 37))	('inhibits', 'NegReg', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('ERK', 'Gene', (218, 221))	('cell proliferation', 'CPA', (191, 209))	('xanthohumol', 'Var', (26, 37))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('gastric cancer', 'Phenotype', 'HP:0012126', (288, 302))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('myeloma', 'Disease', 'MESH:D009101', (143, 150))	('Hexokinases II-mediated glycolysis', 'MPA', (93, 127))	('downregulation', 'NegReg', (75, 89))	('colorectal cancer', 'Disease', (47, 64))	('JNK', 'Gene', (226, 229))	('JNK', 'Gene', '5599', (226, 229))	('inhibition', 'NegReg', (177, 187))	('gastric cancer', 'Disease', (288, 302))	('myeloma', 'Disease', (143, 150))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', (296, 302))
424364	32509787	Moreover, shRNA-mediated knock down of KRT18 in KYSE30 cells reduced the colony formation and treatment of these cells with xanthohumol failed to further suppress the growth of KYSE30 cells.	('knock down', 'Var', (25, 35))	('colony formation', 'CPA', (73, 89))	('KRT18', 'Gene', (39, 44))	('men', 'Species', '9606', (99, 102))	('xanthohumol', 'Chemical', 'MESH:C104536', (124, 135))	('reduced', 'NegReg', (61, 68))
424368	32509787	It has been reported that high Keratin18 predicts aggressive hepatocellular cancer phenotype and serves as a diagnostic and prognostic factor for acute alcoholic hepatitis.	('hepatitis', 'Phenotype', 'HP:0012115', (162, 171))	('acute alcoholic hepatitis', 'Disease', (146, 171))	('high', 'Var', (26, 30))	('Keratin18', 'Gene', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Keratin18', 'Gene', '3875', (31, 40))	('acute alcoholic hepatitis', 'Disease', 'MESH:D006519', (146, 171))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (61, 82))	('predicts', 'Reg', (41, 49))	('aggressive hepatocellular cancer', 'Disease', 'MESH:D006528', (50, 82))	('aggressive hepatocellular cancer', 'Disease', (50, 82))
424411	32321970	The depth of invasion was subclassified as HGIN/intraepithelial cancer (m1), cancer invading the lamina propria (m2), muscularis mucosae (m3), superficial portion of the submucosa ( 200 mum, sm1), and deep submucosa (>sm1).	('intraepithelial cancer', 'Phenotype', 'HP:0032187', (48, 70))	(' 200', 'Var', (181, 185))	('sm1', 'Gene', '7911', (191, 194))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('sm1', 'Gene', '7911', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('sm1', 'Gene', (191, 194))	('sm1', 'Gene', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
424454	32321970	W.-L. Wang, C.-T. Lee, T.-H. Chen, M.-H. Hsu, C.-M. Tseng, C.-H. Tseng, C.-M. Tai and H.-P. Wang enrolled the study subjects and followed up the endoscopies for all patients.	('C.-M. Tseng', 'Var', (46, 57))	('patients', 'Species', '9606', (165, 173))	('C.-H. Tseng', 'Var', (59, 70))
424509	31991604	By providing an escape route for cancers from the immune response, the expression of Treg cells is significantly correlated with worse overall survival (OS) in the majority of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (176, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('OS', 'Chemical', '-', (153, 155))	('expression', 'Var', (71, 81))	('cancers', 'Disease', (33, 40))	('overall survival', 'MPA', (135, 151))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('solid tumors', 'Disease', (176, 188))	('worse', 'NegReg', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
424521	31991604	Immature DCs (iDCs) present antigens to T cells, and then induce immune tolerance including the generation of inducible Treg cells, T cell anergy and deletion.	('induce', 'PosReg', (58, 64))	('DC', 'Gene', '20299', (9, 11))	('DC', 'Gene', '20299', (15, 17))	('deletion', 'Var', (150, 158))	('T cell anergy', 'CPA', (132, 145))	('immune tolerance', 'CPA', (65, 81))
424539	31991604	Tumor tissues contain MDSCs, which can suppress innate and adaptive antitumor immunity and contribute to tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (72, 77))	('contribute', 'Reg', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('suppress', 'NegReg', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('MDSCs', 'Var', (22, 27))	('tumor', 'Disease', (105, 110))
424542	31991604	Moreover, MDSCs can endow cancer cells with stem cell-like properties and are linked with cancer stemness.	('cancer stemness', 'Disease', (90, 105))	('stem cell-like properties', 'CPA', (44, 69))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (26, 32))	('MDSCs', 'Var', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer stemness', 'Disease', 'MESH:D009369', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('linked', 'Reg', (78, 84))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
424590	31991604	CTCs are disseminated along chemotactic gradients and induce extravasation at non-random and organ-specific sites, followed by tumor growth and proliferation at the new sites.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('CTCs', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('induce', 'Reg', (54, 60))	('proliferation', 'CPA', (144, 157))	('extravasation', 'MPA', (61, 74))
424624	31991604	The dual roles of the CCL2/CCR2 axis in cancer development can lead to opposite results, as patients with higher CCL2 or CCR2 expression had significantly better OS in NSCLC but shorter OS and progression-free survival in diffuse large B cell lymphoma (DLBCL), although evidence about the roles of CCL2/CCR2 in DLBCL is limited.	('B cell lymphoma', 'Disease', (236, 251))	('OS', 'Chemical', '-', (162, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('better', 'PosReg', (155, 161))	('CCR2', 'Gene', (27, 31))	('BC', 'Disease', 'MESH:D001943', (255, 257))	('BC', 'Phenotype', 'HP:0003002', (313, 315))	('CCL2', 'Gene', (22, 26))	('CCL2', 'Gene', (298, 302))	('shorter', 'NegReg', (178, 185))	('CCR2', 'Gene', '729230', (27, 31))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Disease', (40, 46))	('CCR2', 'Gene', (303, 307))	('BC', 'Phenotype', 'HP:0003002', (255, 257))	('CCR2', 'Gene', (121, 125))	('CCL2', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('LC', 'Phenotype', 'HP:0100526', (171, 173))	('B cell lymphoma', 'Disease', 'MESH:D016393', (236, 251))	('CCR2', 'Gene', '729230', (303, 307))	('CCR2', 'Gene', '729230', (121, 125))	('CCL2', 'Gene', '6347', (22, 26))	('CCL2', 'Gene', '6347', (298, 302))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (236, 251))	('lymphoma', 'Phenotype', 'HP:0002665', (243, 251))	('OS', 'Chemical', '-', (186, 188))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('expression', 'Var', (126, 136))	('CCL2', 'Gene', '6347', (113, 117))	('higher', 'PosReg', (106, 112))	('large B cell', 'Phenotype', 'HP:0005404', (230, 242))	('BC', 'Disease', 'MESH:D001943', (313, 315))	('NSCLC', 'Disease', (168, 173))
424645	31991604	With the strong protumor functions, the expression of CCR7 or CCL21 has been reported to be strongly correlated with poor survival.	('CCL21', 'Gene', '6366', (62, 67))	('CCL21', 'Gene', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('expression', 'Var', (40, 50))	('correlated', 'Reg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('poor survival', 'CPA', (117, 130))	('tumor', 'Disease', (19, 24))	('CCR7', 'Gene', '1236', (54, 58))	('CCR7', 'Gene', (54, 58))
424651	31991604	Consistently, due to the tumor-promoting effects, high CXCL1 expression has been shown to be a risk factor for cancer prognosis, with poor OS, advanced tumor, node, and metastasis stage, and lymph node metastasis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('OS', 'Chemical', '-', (139, 141))	('tumor', 'Disease', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (152, 157))	('CXCL1', 'Gene', '2919', (55, 60))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('high', 'Var', (50, 54))	('CXCL1', 'Gene', (55, 60))
424726	29713984	In 2000, Hanahan and Weinberg proposed the concept that several distinct physiologic properties distinguish the behavior of cancer cells from that of normal cells, and that genetic alterations within several key molecular pathways allow normal cells to acquire these essential cancer properties (i.e.	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('genetic alterations', 'Var', (173, 192))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('behavior', 'MPA', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
424729	29713984	Moreover, the acquisition of these cancer hallmarks can be accelerated by: 1) genome instability (which can reflected by aneuploidy or whole genome doubling) and mutation, and 2) a cancer-promoting microenvironment.	('men', 'Species', '9606', (210, 213))	('aneuploidy', 'Disease', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer hallmarks', 'Disease', (35, 51))	('genome instability', 'CPA', (78, 96))	('cancer hallmarks', 'Disease', 'MESH:D009369', (35, 51))	('mutation', 'Var', (162, 170))	('aneuploidy', 'Disease', 'MESH:D000782', (121, 131))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (181, 187))	('accelerated', 'PosReg', (59, 70))	('cancer', 'Disease', (35, 41))
424730	29713984	In metaplastic Barrett's tissue specimens, genetic alterations in genes that facilitate the acquisition of these cancer hallmarks have been described even before the tissues exhibit any histological features of dysplasia (Reviewed in), suggesting that a biomarker(s) is out there that could be used in clinical management strategies for patients with non-dysplastic Barrett's esophagus.	('cancer hallmarks', 'Disease', 'MESH:D009369', (113, 129))	("non-dysplastic Barrett's esophagus", 'Disease', (351, 385))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (366, 385))	('men', 'Species', '9606', (317, 320))	('dysplasia', 'Disease', (211, 220))	('men', 'Species', '9606', (37, 40))	('dysplasia', 'Disease', 'MESH:D004476', (211, 220))	('cancer hallmarks', 'Disease', (113, 129))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (351, 385))	('patients', 'Species', '9606', (337, 345))	('genetic alterations', 'Var', (43, 62))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
424733	29713984	Using complex bioinformatics analyses, the investigators found that non-dysplastic Barrett's esophagus has a high frequency of somatic mutations ranging from 1.3 to 5.4 mutations per megabase of DNA, rates higher than those found in cancers of the prostate and breast.	("non-dysplastic Barrett's esophagus", 'Disease', (68, 102))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('mutations', 'Var', (169, 178))	('cancers of the prostate', 'Disease', (233, 256))	('cancers of the prostate', 'Disease', 'MESH:D011471', (233, 256))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (68, 102))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (83, 102))
424736	29713984	They found that p53 mutations were the earliest shared somatic mutations, often preceding inactivation of p16, in non-dysplastic Barrett's metaplasia and its matching esophageal adenocarcinoma.	("non-dysplastic Barrett's metaplasia", 'Disease', (114, 149))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (167, 192))	('p16', 'Gene', (106, 109))	('p53', 'Gene', (16, 19))	('esophageal adenocarcinoma', 'Disease', (167, 192))	('p53', 'Gene', '7157', (16, 19))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (167, 192))	("non-dysplastic Barrett's metaplasia", 'Disease', 'MESH:D001471', (114, 149))	('p16', 'Gene', '1029', (106, 109))	('mutations', 'Var', (20, 29))
424737	29713984	Although inactivation of the tumor suppressor genes p53 and p16 were early alterations found in non-dysplastic Barrett's tissues, activation of oncogenes such as ERBB2 occurred in the later dysplastic stage suggesting a role in neoplastic transformation.	('p16', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('dysplastic', 'Disease', 'MESH:D004416', (100, 110))	('activation', 'PosReg', (130, 140))	('p53', 'Gene', (52, 55))	('dysplastic', 'Disease', (100, 110))	('non-dysplastic Barrett', 'Disease', (96, 118))	('dysplastic', 'Disease', (190, 200))	('p53', 'Gene', '7157', (52, 55))	('p16', 'Gene', '1029', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('dysplastic', 'Disease', 'MESH:D004416', (190, 200))	('inactivation', 'Var', (9, 21))	('ERBB2', 'Gene', '2064', (162, 167))	("non-dysplastic Barrett's", 'Disease', 'MESH:D001471', (96, 120))	('ERBB2', 'Gene', (162, 167))
424739	29713984	Interestingly, however, this study found that only a minority of tumors progressed along this traditional pathway, which involves the step-wise accumulation of alterations in the p53 and p16 tumor suppressor genes, followed by oncogene activation, and then development of genomic instability.	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('men', 'Species', '9606', (264, 267))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('p16', 'Gene', '1029', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('activation', 'PosReg', (236, 246))	('alterations', 'Var', (160, 171))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('p16', 'Gene', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
424741	29713984	In this genome-doubled pathway, p53 mutation was acquired first, followed by whole genome doubling, an alteration primarily detected in areas of dysplasia.	('dysplasia', 'Disease', (145, 154))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('dysplasia', 'Disease', 'MESH:D004476', (145, 154))	('mutation', 'Var', (36, 44))
424742	29713984	Genomic instability and oncogene amplification developed after whole genome doubling, followed by malignancy (Figure 2).	('Genomic instability', 'CPA', (0, 19))	('amplification', 'Var', (33, 46))	('malignancy', 'Disease', 'MESH:D009369', (98, 108))	('oncogene', 'Gene', (24, 32))	('malignancy', 'Disease', (98, 108))
424753	29713984	A polygenic trait is defined as a trait influenced by many genes and, indeed, this study found that many common variant SNPs (any one of which did not increase risk of disease) together accounted for the increased risk of Barrett's esophagus and esophageal adenocarcinoma.	("Barrett's esophagus", 'Disease', (222, 241))	('esophageal adenocarcinoma', 'Disease', (246, 271))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (222, 241))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (246, 271))	('variant', 'Var', (112, 119))	('accounted', 'Reg', (186, 195))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (246, 271))
424760	29713984	They found a significant association for germline variations only in the COX pathway (specifically in the antioxidant microsomal glutathione S-transferase 1 [MGST1] gene), with risk for Barrett's esophagus and the combined outcome of Barrett's esophagus and esophageal adenocarcinoma; none of the pathways were associated with risk of esophageal adenocarcinoma alone.	("Barrett's esophagus", 'Disease', (186, 205))	('microsomal glutathione S-transferase 1', 'Gene', '4257', (118, 156))	('MGST1', 'Gene', '4257', (158, 163))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (186, 205))	('microsomal glutathione S-transferase 1', 'Gene', (118, 156))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (258, 283))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (234, 253))	('MGST1', 'Gene', (158, 163))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (335, 360))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (335, 360))	('esophageal adenocarcinoma', 'Disease', (258, 283))	("Barrett's esophagus", 'Disease', (234, 253))	('esophageal adenocarcinoma', 'Disease', (335, 360))	('COX pathway', 'Pathway', (73, 84))	('variations', 'Var', (50, 60))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (258, 283))
424765	29713984	Therefore, germline mutations in genes that modify inflammatory responses to oxidative stress, such as MGST1, might help to explain differences in intensity of NF-kappaB activation in esophageal squamous cells from GERD with and without Barrett's esophagus, and perhaps why Barrett's esophagus develops in only some GERD patients.	('oxidative stress', 'Phenotype', 'HP:0025464', (77, 93))	('activation', 'PosReg', (170, 180))	('patients', 'Species', '9606', (321, 329))	('MGST1', 'Gene', '4257', (103, 108))	('NF-kappaB', 'Protein', (160, 169))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (274, 293))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (237, 256))	('MGST1', 'Gene', (103, 108))	('mutations', 'Var', (20, 29))
424767	29713984	They found having a SNP in the FOXP1 gene in the absence of reflux symptoms had an odds ratio (OR) of developing Barrett's esophagus of 1.5; the highest OR of 6.0 was found for patients with reflux symptoms who had no SNP in their FOXP1 gene.	('SNP', 'Var', (20, 23))	('FOXP1', 'Gene', (231, 236))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (113, 132))	('patients', 'Species', '9606', (177, 185))	('reflux symptoms', 'Phenotype', 'HP:0002020', (191, 206))	('FOXP1', 'Gene', '27086', (31, 36))	('FOXP1', 'Gene', '27086', (231, 236))	('reflux symptoms', 'Disease', (191, 206))	('FOXP1', 'Gene', (31, 36))	('reflux symptoms', 'Phenotype', 'HP:0002020', (60, 75))	("developing Barrett's esophagus", 'Disease', (102, 132))
424768	29713984	The presence of a SNP in the FOXP1 gene combined with at least weekly reflux symptoms significantly decreased the risk of Barrett's esophagus from an OR of 6.0 to 5.44.	('FOXP1', 'Gene', (29, 34))	('reflux symptoms', 'Phenotype', 'HP:0002020', (70, 85))	('SNP', 'Var', (18, 21))	("Barrett's esophagus", 'Disease', (122, 141))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (122, 141))	('decreased', 'NegReg', (100, 109))	('presence', 'Var', (4, 12))	('FOXP1', 'Gene', '27086', (29, 34))
424774	29713984	As noted in the studies discussed above, modern "omics" technologies have provided insights into pathways of neoplastic progression in Barrett's esophagus through acquired somatic mutations and genome wide doubling, and have increased our understanding of the contribution that inherited, genetic variation may play in modifying susceptibility to Barrett's esophagus and esophageal adenocarcinoma.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (135, 154))	('mutations', 'Var', (180, 189))	('genetic variation', 'Var', (289, 306))	('esophageal adenocarcinoma', 'Disease', (371, 396))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (371, 396))	("Barrett's esophagus", 'Disease', (347, 366))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (347, 366))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (371, 396))
424790	29713984	Therefore, inactivation of p53 allows cells to acquire two essential cancer hallmarks - the ability to resist growth-inhibitory signals such as DNA damage and the avoidance of apoptosis.	('p53', 'Gene', '7157', (27, 30))	('ability', 'MPA', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer hallmarks', 'Disease', (69, 85))	('inactivation', 'Var', (11, 23))	('cancer hallmarks', 'Disease', 'MESH:D009369', (69, 85))	('apoptosis', 'CPA', (176, 185))	('resist growth-inhibitory signals', 'MPA', (103, 135))	('p53', 'Gene', (27, 30))
424791	29713984	Moreover, inactivation of p53 is one of the earliest somatic events in the neoplastic progression of Barrett's esophagus (Reviewed in).	('inactivation', 'Var', (10, 22))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	("Barrett's esophagus", 'Disease', (101, 120))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (101, 120))
424792	29713984	In general, p53 inactivation occurs by mutation in one allele of the gene accompanied by genomic loss of the other copy (i.e.	('loss', 'NegReg', (97, 101))	('mutation', 'Var', (39, 47))	('inactivation', 'NegReg', (16, 28))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))
424793	29713984	Wild-type p53 protein is rapidly degraded, but some p53 mutations render the protein stable so that it accumulates and becomes easily detectable in tissue samples by immunostaining.	('mutations', 'Var', (56, 65))	('accumulates', 'PosReg', (103, 114))	('p53', 'Gene', '7157', (10, 13))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('render', 'Reg', (66, 72))	('p53', 'Gene', (10, 13))
424794	29713984	In contrast, other mutations in p53 lead to loss of its expression in tissue samples, resulting in loss of immunostaining.	('immunostaining', 'MPA', (107, 121))	('mutations', 'Var', (19, 28))	('p53', 'Gene', (32, 35))	('loss', 'NegReg', (44, 48))	('expression', 'MPA', (56, 66))	('p53', 'Gene', '7157', (32, 35))	('loss', 'NegReg', (99, 103))
424795	29713984	Aberrant p53 expression (overexpression or loss of expression) has been shown in recent studies to be a useful indicator of neoplastic progression in Barrett's esophagus.	('Aberrant', 'Var', (0, 8))	("Barrett's esophagus", 'Disease', (150, 169))	('expression', 'MPA', (13, 23))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (150, 169))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('loss of expression', 'NegReg', (43, 61))
424797	29713984	Aberrant p53 expression was detected in 14% of biopsies from controls, and in 49% of biopsies from the cases with neoplastic progression.	('expression', 'MPA', (13, 23))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('Aberrant', 'Var', (0, 8))
424798	29713984	In the cases, aberrant p53 expression was associated with an overall relative risk (RR) of 6.4 for neoplastic progression after adjusting for age, gender, length of Barrett's esophagus, and esophagitis.	('associated', 'Reg', (42, 52))	('aberrant', 'Var', (14, 22))	('expression', 'MPA', (27, 37))	('neoplastic progression', 'CPA', (99, 121))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (165, 184))	('esophagitis', 'Phenotype', 'HP:0100633', (190, 201))	('p53', 'Gene', (23, 26))	('esophagitis', 'Disease', (190, 201))	('p53', 'Gene', '7157', (23, 26))	('esophagitis', 'Disease', 'MESH:D004941', (190, 201))
424799	29713984	In patients with non-dysplastic Barrett's esophagus at baseline, aberrant p53 expression was associated with an adjusted RR of 4.3 for neoplastic progression, whereas the adjusted RR for neoplastic progression in those with low grade dysplasia at baseline was 12.2.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (32, 51))	('dysplasia', 'Disease', 'MESH:D004476', (234, 243))	('expression', 'MPA', (78, 88))	('neoplastic progression', 'CPA', (135, 157))	("non-dysplastic Barrett's esophagus", 'Disease', (17, 51))	('aberrant', 'Var', (65, 73))	('p53', 'Gene', (74, 77))	('associated', 'Reg', (93, 103))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (17, 51))	('patients', 'Species', '9606', (3, 11))	('dysplasia', 'Disease', (234, 243))	('p53', 'Gene', '7157', (74, 77))
424800	29713984	More recently, aberrant p53 expression was prospectively evaluated in patients with Barrett's esophagus enrolled in a surveillance program as a predictor of progression to high grade dysplasia (HGD) or esophageal adenocarcinoma.	('patients', 'Species', '9606', (70, 78))	("Barrett's esophagus", 'Disease', (84, 103))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('HGD', 'Disease', 'None', (194, 197))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (84, 103))	('dysplasia', 'Disease', (183, 192))	('HGD', 'Disease', (194, 197))	('dysplasia', 'Disease', 'MESH:D004476', (183, 192))	('esophageal adenocarcinoma', 'Disease', (202, 227))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (202, 227))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (202, 227))	('aberrant', 'Var', (15, 23))
424803	29713984	Aberrant p53 expression was found significantly more often in the patients who progressed to HGD or cancer (63.6%) than in patients who did not progress (7.5%).	('HGD', 'Disease', (93, 96))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('p53', 'Gene', (9, 12))	('patients', 'Species', '9606', (123, 131))	('p53', 'Gene', '7157', (9, 12))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('HGD', 'Disease', 'None', (93, 96))	('patients', 'Species', '9606', (66, 74))
424804	29713984	Multivariate analysis demonstrated that aberrant p53 expression detected by immunostaining was a significant (hazard ratio, HR 17) and independent predictor of neoplastic progression.	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (49, 52))	('neoplastic progression', 'CPA', (160, 182))	('expression', 'MPA', (53, 63))	('aberrant', 'Var', (40, 48))
424805	29713984	Recent studies such as these suggest that detecting aberrant p53 expression by immunohistochemistry on non-dysplastic and low-grade dysplastic biopsies of Barrett's esophagus may be a clinically useful predictor of neoplastic progression.	('non-dysplastic', 'Disease', (103, 117))	('Barrett', 'Disease', (155, 162))	('dysplastic', 'Disease', (107, 117))	('dysplastic', 'Disease', 'MESH:D004416', (107, 117))	('expression', 'MPA', (65, 75))	('aberrant', 'Var', (52, 60))	('dysplastic', 'Disease', 'MESH:D004416', (132, 142))	('dysplastic', 'Disease', (132, 142))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (155, 174))	('non-dysplastic', 'Disease', 'MESH:D004416', (103, 117))
424810	29713984	A more recent study explored using clinical and demographic data along with Cytosponge tissue samples analyzed for a molecular biomarker panel including protein biomarkers (P53, c-Myc, Aurora kinase A), methylation markers (MYOD1, RUNX3), glandular atypia, and TP53 mutation to classify patients with Barrett's esophagus into low-, moderate-, or high-risk categories.	('MYOD1', 'Gene', '4654', (224, 229))	("Barrett's esophagus", 'Disease', (301, 320))	('P53', 'Gene', '7157', (173, 176))	('c-Myc', 'Gene', (178, 183))	('Aurora kinase A', 'Gene', (185, 200))	('TP53', 'Gene', '7157', (261, 265))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (301, 320))	('MYOD1', 'Gene', (224, 229))	('patients', 'Species', '9606', (287, 295))	('TP53', 'Gene', (261, 265))	('RUNX3', 'Gene', (231, 236))	('Aurora kinase A', 'Gene', '6790', (185, 200))	('P53', 'Gene', (262, 265))	('RUNX3', 'Gene', '864', (231, 236))	('c-Myc', 'Gene', '4609', (178, 183))	('P53', 'Gene', (173, 176))	('mutation', 'Var', (266, 274))	('P53', 'Gene', '7157', (262, 265))
424832	29713984	Immunostaining for p53 is recommended by the British Society of Gastroenterology as an adjunct to histological assessment of dysplasia in patients with Barrett's esophagus, essentially meaning that aberrant p53 expression can be used as a biomarker for neoplasia.	("Barrett's esophagus", 'Disease', (152, 171))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (152, 171))	('dysplasia', 'Disease', (125, 134))	('men', 'Species', '9606', (31, 34))	('dysplasia', 'Disease', 'MESH:D004476', (125, 134))	('men', 'Species', '9606', (117, 120))	('neoplasia', 'Disease', (253, 262))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '7157', (207, 210))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('neoplasia', 'Phenotype', 'HP:0002664', (253, 262))	('neoplasia', 'Disease', 'MESH:D009369', (253, 262))	('expression', 'MPA', (211, 221))	('patients', 'Species', '9606', (138, 146))	('aberrant', 'Var', (198, 206))
424835	28915630	CASP8 -652 6N insertion/deletion polymorphism and overall cancer risk: evidence from 49 studies The CASP8 -652 6N insertion/deletion (I/D) polymorphism reduces expression of caspase 8.	('expression', 'MPA', (160, 170))	('CASP8', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CASP8', 'Gene', '841', (0, 5))	('CASP8', 'Gene', (100, 105))	('CASP8', 'Gene', '841', (100, 105))	('reduces', 'NegReg', (152, 159))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('polymorphism', 'Var', (139, 151))	('caspase 8', 'Gene', '841', (174, 183))	('cancer', 'Disease', (58, 64))	('caspase 8', 'Gene', (174, 183))
424838	28915630	Stratified analyses showed that the polymorphism was associated with decreased risk of colorectal, breast, esophageal, renal cell, lung, cervical, bladder, gastric, and other cancers.	('colorectal', 'Disease', (87, 97))	('decreased', 'NegReg', (69, 78))	('renal cell', 'Disease', (119, 129))	('colorectal', 'Disease', 'MESH:D015179', (87, 97))	('lung', 'Disease', (131, 135))	('esophageal', 'Disease', (107, 117))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('bladder', 'Disease', (147, 154))	('gastric', 'Disease', (156, 163))	('polymorphism', 'Var', (36, 48))	('cancers', 'Disease', (175, 182))	('breast', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cervical', 'Disease', (137, 145))
424840	28915630	Our results highlight the role of the CASP8 -652 6N ins/del polymorphism in decreasing cancer risk.	('cancer', 'Disease', (87, 93))	('CASP8', 'Gene', (38, 43))	('CASP8', 'Gene', '841', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('decreasing', 'NegReg', (76, 86))	('-652 6N ins/del', 'Mutation', 'rs3834129', (44, 59))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('6N ins/del polymorphism', 'Var', (49, 72))
424846	28915630	Apoptosis is a control mechanism to prevent over-proliferation in normal cells, and apoptosis pathway aberrations are implicated in cancer development.	('cancer', 'Disease', (132, 138))	('implicated', 'Reg', (118, 128))	('apoptosis pathway', 'Pathway', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('aberrations', 'Var', (102, 113))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
424850	28915630	The CASP8 -652 6N ins/del polymorphism (rs3834129) is a six-nucleotide insertion/deletion variant located in the CASP8 promoter region, and leads to decreased CASP8 expression.	('CASP8', 'Gene', '841', (113, 118))	('-652 6N ins/del', 'Mutation', 'rs3834129', (10, 25))	('CASP8', 'Gene', (4, 9))	('CASP8', 'Gene', (113, 118))	('CASP8', 'Gene', '841', (4, 9))	('rs3834129', 'Mutation', 'rs3834129', (40, 49))	('expression', 'MPA', (165, 175))	('rs3834129', 'Var', (40, 49))	('CASP8', 'Gene', (159, 164))	('CASP8', 'Gene', '841', (159, 164))	('decreased', 'NegReg', (149, 158))
424852	28915630	Extensive epidemiological studies have assessed the association between the CASP8 -652 6N ins/del polymorphism and cancer risk.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('CASP8', 'Gene', (76, 81))	('CASP8', 'Gene', '841', (76, 81))	('6N ins/del polymorphism', 'Var', (87, 110))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('-652 6N ins/del', 'Mutation', 'rs3834129', (82, 97))
424858	28915630	We observed no correlations between the CASP8 -652 6N ins/del polymorphism and prostate cancer or lymphoma.	('CASP8', 'Gene', (40, 45))	('lymphoma', 'Disease', (98, 106))	('CASP8', 'Gene', '841', (40, 45))	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('lymphoma', 'Disease', 'MESH:D008223', (98, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('-652 6N ins/del', 'Mutation', 'rs3834129', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('prostate cancer', 'Disease', (79, 94))	('6N ins/del polymorphism', 'Var', (51, 74))
424860	28915630	We also found that the CASP8 -652 6N ins/del polymorphism decreased cancer risk in population-based (DD vs. II: OR=0.83, 95% CI=0.75-0.92) and hospital-based groups (DD vs. II: OR=0.61, 95% CI=0.49-0.75).	('CASP8', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('decreased cancer', 'Disease', 'MESH:D009369', (58, 74))	('6N ins/del polymorphism', 'Var', (34, 57))	('-652 6N ins/del', 'Mutation', 'rs3834129', (29, 44))	('decreased cancer', 'Disease', (58, 74))	('CASP8', 'Gene', '841', (23, 28))
424862	28915630	The present meta-analysis comprehensively evaluated the relationship between the CASP8 -652 6N ins/del polymorphism and cancer risk across 49 studies (33,494 cases and 36,397 controls).	('CASP8', 'Gene', '841', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('CASP8', 'Gene', (81, 86))	('-652 6N ins/del', 'Mutation', 'rs3834129', (87, 102))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('6N ins/del polymorphism', 'Var', (92, 115))
424863	28915630	The CASP8 -652 6N ins/del polymorphism was associated with decreased cancer risk in all five genetic models, and in the following subgroups: colorectal cancer, breast cancer, esophageal cancer, renal cell carcinoma, lung cancer, cervical cancer, bladder cancer, gastric cancer, other cancers, Asian, Caucasian, mixed population, population-based controls, hospital-based controls, high quality score, and low quality score.	('cancers', 'Disease', 'MESH:D009369', (284, 291))	('6N ins/del polymorphism', 'Var', (15, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('gastric cancer', 'Disease', 'MESH:D013274', (262, 276))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('cervical cancer', 'Disease', (229, 244))	('cervical cancer', 'Disease', 'MESH:D002583', (229, 244))	('renal cell carcinoma', 'Disease', (194, 214))	('bladder cancer', 'Disease', 'MESH:D001749', (246, 260))	('bladder cancer', 'Disease', (246, 260))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (194, 214))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (246, 260))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('gastric cancer', 'Phenotype', 'HP:0012126', (262, 276))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('CASP8', 'Gene', '841', (4, 9))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('cancers', 'Disease', (284, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('decreased cancer', 'Disease', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('colorectal cancer', 'Disease', (141, 158))	('decreased cancer', 'Disease', 'MESH:D009369', (59, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('esophageal cancer', 'Disease', (175, 192))	('-652 6N ins/del', 'Mutation', 'rs3834129', (10, 25))	('CASP8', 'Gene', (4, 9))	('lung cancer', 'Disease', (216, 227))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (194, 214))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('gastric cancer', 'Disease', (262, 276))	('breast cancer', 'Disease', (160, 173))
424867	28915630	The CASP8 -652 6N del variant inactivates the transcription factor stimulatory protein 1 binding site, decreasing CASP8 transcription.	('transcription', 'MPA', (120, 133))	('CASP8', 'Gene', (4, 9))	('variant', 'Var', (22, 29))	('CASP8', 'Gene', '841', (4, 9))	('CASP8', 'Gene', '841', (114, 119))	('inactivates', 'NegReg', (30, 41))	('decreasing', 'NegReg', (103, 113))	('CASP8', 'Gene', (114, 119))	('-652 6N del', 'Mutation', 'rs3834129', (10, 21))
424868	28915630	Thus, this variant may affect cancer susceptibility by influencing immune surveillance.	('cancer', 'Disease', (30, 36))	('influencing', 'Reg', (55, 66))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('affect', 'Reg', (23, 29))	('immune surveillance', 'CPA', (67, 86))	('variant', 'Var', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
424871	28915630	Biochemical assays illustrated that this variant might decrease apoptotic reactivity in cancer cell-stimulated T lymphocytes.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('decrease', 'NegReg', (55, 63))	('apoptotic reactivity', 'CPA', (64, 84))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('variant', 'Var', (41, 48))
424873	28915630	A 2012 meta-analysis by Chen, et al., including 19 case-control studies with 23,172 cases and 26,532 controls, associated the del allele, ins/del genotype, and del allele carriers with reduced overall cancer risk.	('del allele', 'Var', (126, 136))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('del allele', 'Var', (160, 170))	('ins/del', 'Var', (138, 145))	('reduced', 'NegReg', (185, 192))
424875	28915630	In 2014, breast cancer- and colorectal cancer-specific meta-analyses concluded that the CASP8 -652 6N del polymorphism reduced cancer risk.	('CASP8', 'Gene', (88, 93))	('6N del polymorphism', 'Var', (99, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', (127, 133))	('reduced', 'NegReg', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('colorectal cancer', 'Disease', (28, 45))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('breast cancer', 'Disease', (9, 22))	('-652 6N del', 'Mutation', 'rs3834129', (94, 105))	('CASP8', 'Gene', '841', (88, 93))
424878	28915630	In subgroup analyses, the polymorphism was associated with reduced risk of colorectal cancer, breast cancer, esophageal cancer, renal cell carcinoma, lung cancer, cervical cancer, bladder cancer, gastric cancer, and other cancers, but not prostate cancer or lymphoma.	('reduced', 'NegReg', (59, 66))	('colorectal cancer', 'Disease', (75, 92))	('lung cancer', 'Disease', (150, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (196, 210))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (128, 148))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lymphoma', 'Disease', (258, 266))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('lymphoma', 'Disease', 'MESH:D008223', (258, 266))	('prostate cancer', 'Disease', 'MESH:D011471', (239, 254))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('gastric cancer', 'Disease', (196, 210))	('prostate cancer', 'Phenotype', 'HP:0012125', (239, 254))	('cervical cancer', 'Disease', 'MESH:D002583', (163, 178))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('breast cancer', 'Disease', (94, 107))	('renal cell carcinoma', 'Disease', (128, 148))	('cervical cancer', 'Disease', (163, 178))	('bladder cancer', 'Disease', (180, 194))	('bladder cancer', 'Disease', 'MESH:D001749', (180, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (128, 148))	('prostate cancer', 'Disease', (239, 254))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('bladder cancer', 'Phenotype', 'HP:0009725', (180, 194))	('cancers', 'Disease', (222, 229))	('gastric cancer', 'Disease', 'MESH:D013274', (196, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))	('polymorphism', 'Var', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('esophageal cancer', 'Disease', (109, 126))	('lymphoma', 'Phenotype', 'HP:0002665', (258, 266))
424882	28915630	However, the limited number of studies in Africans and mixed ethnicity population may account for this finding, and CASP8 -652 6N ins/del polymorphism allelic distributions might vary geographically and ethnically.	('6N ins/del polymorphism', 'Var', (127, 150))	('CASP8', 'Gene', (116, 121))	('CASP8', 'Gene', '841', (116, 121))	('-652 6N ins/del', 'Mutation', 'rs3834129', (122, 137))
424883	28915630	Our meta-analysis of the association between the CASP8 -652 6N ins/del polymorphism and cancer risk is by far the largest such meta-analysis with the greatest statistical power published thus far.	('cancer', 'Disease', (88, 94))	('6N ins/del', 'Var', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('-652 6N ins/del', 'Mutation', 'rs3834129', (55, 70))	('CASP8', 'Gene', '841', (49, 54))	('CASP8', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
424891	28915630	Studies included in our analysis met the following criteria: (1) evaluated CASP8 -652 6N ins/del polymorphism with respect to cancer risk; (2) case-control design; (3) sufficient information to extract genotype frequencies for all subjects; (4) genotype frequency of controls consistent with Hardy-Weinberg equilibrium (HWE); (5) publication language was English or Chinese.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('CASP8', 'Gene', (75, 80))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('-652 6N ins/del', 'Mutation', 'rs3834129', (81, 96))	('6N ins/del polymorphism', 'Var', (86, 109))	('CASP8', 'Gene', '841', (75, 80))
424896	28915630	Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) obtained from case and control genotype frequencies were used to assess the strength of association between the CASP8 -652 6N ins/del polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('6N ins/del polymorphism', 'Var', (191, 214))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('-652 6N ins/del', 'Mutation', 'rs3834129', (186, 201))	('CASP8', 'Gene', (180, 185))	('cancer', 'Disease', (219, 225))	('CASP8', 'Gene', '841', (180, 185))
424914	26943380	A 68-year-old asymptomatic man was referred to our hospital for evaluation because of an irregularity in the gastric body, which was detected during a medical examination.	('man', 'Species', '9606', (27, 30))	('irregularity', 'Var', (89, 101))	('gastric body', 'Disease', 'MESH:D013274', (109, 121))	('gastric body', 'Disease', (109, 121))
424949	25580077	As hypermethylation at the c2orf40 locus inhibits ECRG4 gene expression in many epithelial cancers, several investigators have speculated that ECRG4 is a candidate tumor suppressor.	('epithelial cancers', 'Disease', (80, 98))	('epithelial cancer', 'Phenotype', 'HP:0031492', (80, 97))	('tumor', 'Disease', (164, 169))	('inhibits', 'NegReg', (41, 49))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('c2orf40', 'Gene', '84417', (27, 34))	('c2orf40', 'Gene', (27, 34))	('epithelial cancers', 'Disease', 'MESH:D000077216', (80, 98))	('ECRG4 gene', 'Gene', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('hypermethylation', 'Var', (3, 19))	('expression', 'MPA', (61, 71))
424958	25580077	Because ECRG4 expression is significantly downregulated by hypermethylation in human cancers, there are compelling reasons to believe that its basic biology might be directly tied to the onset, development, and progression of human cancer.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('human', 'Species', '9606', (226, 231))	('hypermethylation', 'Var', (59, 75))	('human', 'Species', '9606', (79, 84))	('cancer', 'Disease', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('downregulated', 'NegReg', (42, 55))	('cancer', 'Disease', (85, 91))	('expression', 'MPA', (14, 24))	('human cancers', 'Disease', 'MESH:D009369', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('ECRG4', 'Gene', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('human cancers', 'Disease', (79, 92))
424975	25580077	By 2007, the detection of ECRG4 had gained value as an independent prognostic factor of poor survival in patients with esophageal cancer and implicated in tissue regeneration after injury.	('ECRG4', 'Gene', (26, 31))	('patients', 'Species', '9606', (105, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('detection', 'Var', (13, 22))	('esophageal cancer', 'Disease', (119, 136))
424982	25580077	It is further supported by the fact that methylation inhibitors like the drug 5-AZA-C, can increase ECRG4 expression in vivo and in vitro, presumably by inhibiting deoxyribonucleic acid (DNA) methylation.	('ECRG4', 'Protein', (100, 105))	('5-AZA-C', 'Chemical', 'MESH:D001374', (78, 85))	('expression', 'MPA', (106, 116))	('deoxyribonucleic acid', 'MPA', (164, 185))	('5-AZA-C', 'Var', (78, 85))	('increase', 'PosReg', (91, 99))	('inhibiting', 'NegReg', (153, 163))
424987	25580077	In contrast to the wide distribution of ECRG4 gene expression in normal tissues, the epigenetic silencing of ECRG4 expression by methylation of its promoter downregulates constitutive human ECRG4 gene expression in a wide variety of human cancers.	('ECRG4', 'Gene', (109, 114))	('constitutive human ECRG4 gene expression', 'MPA', (171, 211))	('human', 'Species', '9606', (233, 238))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('methylation', 'Var', (129, 140))	('downregulates', 'NegReg', (157, 170))	('human cancers', 'Disease', 'MESH:D009369', (233, 246))	('human', 'Species', '9606', (184, 189))	('human cancers', 'Disease', (233, 246))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('epigenetic silencing', 'Var', (85, 105))
424991	25580077	To this end, it is important to note that ECRG4 expression confers increased cell sensitivity to antitumor drugs like 5-fluorouracil, presumably by virtue of its ability to increase apoptosis.	('5-fluorouracil', 'Chemical', 'MESH:D005472', (118, 132))	('ECRG4', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('increase', 'PosReg', (173, 181))	('increased', 'PosReg', (67, 76))	('apoptosis', 'CPA', (182, 191))	('expression', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
425008	25580077	In addition to being secreted, encoding a ligand, and being processed differently in different cell types, there are also no reports of genetic mutations in the c2orf40 locus that are associated with human cancers.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('human cancers', 'Disease', (200, 213))	('c2orf40', 'Gene', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('associated', 'Reg', (184, 194))	('mutations', 'Var', (144, 153))	('human cancers', 'Disease', 'MESH:D009369', (200, 213))	('c2orf40', 'Gene', '84417', (161, 168))
425011	25580077	Overexpression of ECRG4 in vivo has significant effects on cell growth and function in several preclinical models of human disease (see "Infection, inflammation, and injury").	('inflammation', 'Disease', 'MESH:D007249', (148, 160))	('function', 'MPA', (75, 83))	('human', 'Species', '9606', (117, 122))	('inflammation', 'Disease', (148, 160))	('ECRG4', 'Gene', (18, 23))	('effects', 'Reg', (48, 55))	('Overexpression', 'Var', (0, 14))	('cell growth', 'CPA', (59, 70))
425013	25580077	In our laboratories, we have had significant difficulty establishing a direct antimitogenic effect of ECRG4 overexpression when transfecting tumor cells in vitro.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('ECRG4', 'Gene', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('overexpression', 'Var', (108, 122))	('tumor', 'Disease', (141, 146))	('antimitogenic effect', 'MPA', (78, 98))
425041	25580077	On one hand, Li et al reported ECRG4 transfection inhibits proinflammatory NF-kappaB activation, its nuclear translocation, and the activation of cyclooxygenase-2 as a mechanism to inhibit cell proliferation, colony formation, anchorage-independent cell growth, and cell cycle progression.	('cyclooxygenase-2', 'Gene', (146, 162))	('activation', 'MPA', (85, 95))	('cyclooxygenase-2', 'Gene', '5743', (146, 162))	('NF-kappaB', 'Gene', (75, 84))	('cell proliferation', 'CPA', (189, 207))	('ECRG4', 'Gene', (31, 36))	('nuclear translocation', 'MPA', (101, 122))	('anchorage-independent cell growth', 'CPA', (227, 260))	('cell cycle progression', 'CPA', (266, 288))	('inhibit', 'NegReg', (181, 188))	('colony formation', 'CPA', (209, 225))	('inhibits', 'NegReg', (50, 58))	('transfection', 'Var', (37, 49))	('NF-kappaB', 'Gene', '4790', (75, 84))
425051	25580077	In cancer, the continuous downregulation of ECRG4 through hypermethylation blocks the restoration of ECRG4 to the cell surface and as such compromises normal immune cell surveillance (Figure 4A), resulting in the display of a continuous reactive phenotype (Figure 4B) that enables constitutive reactivity (Figure 4C) and responsiveness (Figure 4D) to growth promoting agents.	('enables', 'PosReg', (273, 280))	('continuous reactive phenotype', 'MPA', (226, 255))	('blocks', 'NegReg', (75, 81))	('compromises', 'NegReg', (139, 150))	('ECRG4 to the cell surface', 'MPA', (101, 126))	('downregulation', 'NegReg', (26, 40))	('constitutive reactivity', 'MPA', (281, 304))	('hypermethylation', 'Var', (58, 74))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('normal immune cell surveillance', 'MPA', (151, 182))	('responsiveness', 'MPA', (321, 335))	('restoration', 'MPA', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
425052	25580077	In this model, the hypermethylation in the c2orf40 locus prevents an ultimate return of ECRG4 to the cell surface, thereby interfering with normal immunosurveillance and proinflammatory signaling.	('interfering', 'NegReg', (123, 134))	('c2orf40', 'Gene', (43, 50))	('prevents', 'NegReg', (57, 65))	('normal immunosurveillance', 'MPA', (140, 165))	('c2orf40', 'Gene', '84417', (43, 50))	('hypermethylation', 'Var', (19, 35))
425056	25580077	It is interesting to speculate that the loss of ECRG4 will increase susceptibility to spontaneous cancers and increase aberrant inflammatory responses to injury.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('increase', 'PosReg', (110, 118))	('ECRG4', 'Gene', (48, 53))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('loss', 'Var', (40, 44))	('cancers', 'Disease', (98, 105))
425057	25580077	If such links are identified, the findings would support a causative link between the naturally occurring downregulation of ECRG4 expression that is observed after hypermethylation and the development, progression, and metastasis of epithelial and hematopoietic cancers.	('expression', 'MPA', (130, 140))	('hypermethylation', 'Var', (164, 180))	('metastasis of epithelial and hematopoietic cancers', 'Disease', 'MESH:D009362', (219, 269))	('downregulation', 'NegReg', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('progression', 'CPA', (202, 213))	('ECRG4', 'Gene', (124, 129))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))
425062	24953013	Immunofluorescence analysis showed that AURKA overexpression enhanced STAT3 nuclear translocation while AURKA genetic knockdown reduced the nuclear translocation of STAT3 in AGS and FLO-1 cells, respectively.	('nuclear translocation of STAT3', 'MPA', (140, 170))	('enhanced', 'PosReg', (61, 69))	('knockdown', 'Var', (118, 127))	('AURKA', 'Gene', '6790', (104, 109))	('reduced', 'NegReg', (128, 135))	('AURKA', 'Gene', (104, 109))	('AURKA', 'Gene', '6790', (40, 45))	('AURKA', 'Gene', (40, 45))	('STAT3 nuclear translocation', 'MPA', (70, 97))
425063	24953013	Using a luciferase reporter assay, we demonstrated that AURKA expression induces transcriptional activity of STAT3.	('AURKA', 'Gene', '6790', (56, 61))	('induces', 'PosReg', (73, 80))	('AURKA', 'Gene', (56, 61))	('transcriptional activity', 'MPA', (81, 105))	('STAT3', 'Gene', (109, 114))	('expression', 'Var', (62, 72))
425064	24953013	Pharmacological inhibition of AURKA by MLN8237 reduced STAT3 phosphorylation along with down-regulation of STAT3 pro-survival targets, BCL2 and MCL1.	('MLN8237', 'Var', (39, 46))	('STAT3 phosphorylation', 'MPA', (55, 76))	('MCL1', 'Gene', (144, 148))	('MCL1', 'Gene', '4170', (144, 148))	('down-regulation', 'NegReg', (88, 103))	('BCL2', 'Gene', '596', (135, 139))	('AURKA', 'Gene', '6790', (30, 35))	('reduced', 'NegReg', (47, 54))	('BCL2', 'Gene', (135, 139))	('AURKA', 'Gene', (30, 35))
425066	24953013	The inhibition of JAK2 using JAK2-specific inhibitor AZD1480 or siRNA knockdown, in presence of AURKA overexpression, abrogated the AURKA-mediated STAT3 activation.	('knockdown', 'Var', (70, 79))	('AZD1480', 'Chemical', 'MESH:C545606', (53, 60))	('JAK2', 'Gene', (29, 33))	('AURKA', 'Gene', (96, 101))	('abrogated', 'NegReg', (118, 127))	('siRNA', 'Gene', (64, 69))	('AURKA', 'Gene', '6790', (132, 137))	('JAK2', 'Gene', '3717', (18, 22))	('AURKA', 'Gene', (132, 137))	('JAK2', 'Gene', '3717', (29, 33))	('inhibition', 'NegReg', (4, 14))	('JAK2', 'Gene', (18, 22))	('AURKA', 'Gene', '6790', (96, 101))
425073	24953013	Aurora kinase A (AURKA) amplification and overexpression are frequent findings in UGCs as well as several other malignancies.	('AURKA', 'Gene', (17, 22))	('malignancies', 'Disease', (112, 124))	('Aurora kinase A', 'Gene', '6790', (0, 15))	('UGCs', 'Disease', (82, 86))	('amplification', 'Var', (24, 37))	('overexpression', 'PosReg', (42, 56))	('malignancies', 'Disease', 'MESH:D009369', (112, 124))	('AURKA', 'Gene', '6790', (17, 22))	('Aurora kinase A', 'Gene', (0, 15))
425079	24953013	The pharmacological inhibition of AURKA using small molecule inhibitor MLN8237, also known as alisertib, has shown significant inhibition of tumor growth in pre-clinical xenograft tumor models with promising results in phase II clinical trials.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('AURKA', 'Gene', (34, 39))	('MLN8237', 'Var', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('alisertib', 'Chemical', 'MESH:C550258', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (180, 185))	('inhibition', 'NegReg', (127, 137))	('AURKA', 'Gene', '6790', (34, 39))
425086	24953013	AURKA knockdown or pharmacological inhibition reversed these pro-survival effects.	('AURKA', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('AURKA', 'Gene', '6790', (0, 5))
425113	24953013	In a separate experiment, and in order to check whether AURKA reconstitution, after its knockdown, would restore STAT3 phosphorylation, we transfected the FLO-1 cells with siScramble or siAURKA for 24h.	('AURKA', 'Gene', (188, 193))	('AURKA', 'Gene', '6790', (56, 61))	('AURKA', 'Gene', (56, 61))	('knockdown', 'Var', (88, 97))	('AURKA', 'Gene', '6790', (188, 193))	('STAT3 phosphorylation', 'MPA', (113, 134))	('restore', 'PosReg', (105, 112))
425120	24953013	In order to investigate whether changes in AURKA levels would affect phosphorylation of STAT3, we modulated AURKA levels in FLO-1, AGS, and MKN45 cell lines and assessed the changes in STAT3 phosphorylation by Western blotting.	('affect', 'Reg', (62, 68))	('STAT3', 'MPA', (185, 190))	('AURKA', 'Gene', '6790', (108, 113))	('modulated', 'Var', (98, 107))	('AURKA', 'Gene', (108, 113))	('AURKA', 'Gene', '6790', (43, 48))	('phosphorylation', 'MPA', (69, 84))	('AURKA', 'Gene', (43, 48))	('changes', 'Var', (32, 39))
425121	24953013	Our data indicated that in FLO-1 cells, and after knocking down AURKA, p-STAT3 (Tyr705) levels were decreased (Figure 1A, left panel).	('AURKA', 'Gene', (64, 69))	('Tyr705', 'Chemical', '-', (80, 86))	('knocking down', 'Var', (50, 63))	('decreased', 'NegReg', (100, 109))	('AURKA', 'Gene', '6790', (64, 69))
425124	24953013	To confirm these observations, we aslo knocked down endogenous AURKA in MKN45 cells and examined STAT3 phosphorylation.	('examined', 'Reg', (88, 96))	('AURKA', 'Gene', (63, 68))	('knocked', 'Var', (39, 46))	('STAT3 phosphorylation', 'MPA', (97, 118))	('AURKA', 'Gene', '6790', (63, 68))
425125	24953013	Indeed, Western blot analysis data showed a decrease in p-STAT3 levels (Tyr705), as compared to scramble control transfected cells (Figure 1C).	('p-STAT3 levels', 'MPA', (56, 70))	('decrease', 'NegReg', (44, 52))	('Tyr705', 'Var', (72, 78))	('Tyr705', 'Chemical', '-', (72, 78))
425129	24953013	For a rescue experiment, we knocked down the endogenous AURKA for 24h followed by its reconstitution using exogenous AURKA transfection.	('AURKA', 'Gene', '6790', (56, 61))	('AURKA', 'Gene', (117, 122))	('AURKA', 'Gene', (56, 61))	('AURKA', 'Gene', '6790', (117, 122))	('knocked', 'Var', (28, 35))
425130	24953013	The STAT3 transcriptional activity was measured and demonstrated that knockdown of endogenous AURKA reduced the STAT3 reporter activity whereas overexpression of AURKA restored the activity of the STAT3 reporter (Figure 2B).	('AURKA', 'Gene', '6790', (162, 167))	('knockdown', 'Var', (70, 79))	('AURKA', 'Gene', '6790', (94, 99))	('reduced', 'NegReg', (100, 107))	('AURKA', 'Gene', (162, 167))	('AURKA', 'Gene', (94, 99))	('STAT3 reporter activity', 'MPA', (112, 135))
425135	24953013	Our data clearly indicated that AURKA knockdown in FLO-1 cells led to a significant (p<0.01) decrease of cells showing positive nuclear staining of STAT3 relative to control cells (Figure 3A).	('AURKA', 'Gene', '6790', (32, 37))	('cells', 'MPA', (105, 110))	('decrease', 'NegReg', (93, 101))	('AURKA', 'Gene', (32, 37))	('knockdown', 'Var', (38, 47))
425141	24953013	Next, we treated FLO-1 and AGS cells for 72h with MLN8237 (0.5 microM) and examined the expression levels of pro-survival proteins, BCL2 and MCL1, known protein targets of STAT3 with anti-apoptotic functions.	('MLN8237', 'Var', (50, 57))	('2h', 'Chemical', 'MESH:D003903', (42, 44))	('BCL2', 'Gene', '596', (132, 136))	('MCL1', 'Gene', '4170', (141, 145))	('BCL2', 'Gene', (132, 136))	('MCL1', 'Gene', (141, 145))	('expression', 'MPA', (88, 98))
425142	24953013	Indeed, our data indicated that MLN8237 treatment led to a decrease in STAT3 phosphorylation and BCL2 and MCL1 expression levels (Figure 4 A&B).	('MCL1', 'Gene', '4170', (106, 110))	('MCL1', 'Gene', (106, 110))	('BCL2', 'Gene', '596', (97, 101))	('decrease', 'NegReg', (59, 67))	('BCL2', 'Gene', (97, 101))	('STAT3 phosphorylation', 'MPA', (71, 92))	('MLN8237 treatment', 'Var', (32, 49))
425143	24953013	The detected transient increase of total unphosphorylated AURKA protein level following MLN8237 treatment could be a cellular response to inhibition of its activity and function, which has been reported previously by others.	('AURKA', 'Gene', (58, 63))	('unphosphorylated', 'MPA', (41, 57))	('activity', 'MPA', (156, 164))	('increase', 'PosReg', (23, 31))	('AURKA', 'Gene', '6790', (58, 63))	('MLN8237 treatment', 'Var', (88, 105))
425145	24953013	Collectively, these data suggest that AURKA inhibition suppresses the STAT3 pathway leading to decreased survival of cancer cells.	('decreased', 'NegReg', (95, 104))	('STAT3 pathway', 'Pathway', (70, 83))	('AURKA', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('inhibition', 'Var', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('AURKA', 'Gene', '6790', (38, 43))	('suppresses', 'NegReg', (55, 65))
425147	24953013	Our results indicated for the first time that knockdown of AURKA by siRNA resulted in a significant decrease in phosphorylation and expression of JAK2 in FLO-1 (Figure 5A, left panel) and MKN45 (Supplemental Figure 2).	('AURKA', 'Gene', (59, 64))	('phosphorylation', 'MPA', (112, 127))	('knockdown', 'Var', (46, 55))	('decrease', 'NegReg', (100, 108))	('JAK2', 'Gene', '3717', (146, 150))	('AURKA', 'Gene', '6790', (59, 64))	('expression', 'MPA', (132, 142))	('JAK2', 'Gene', (146, 150))
425149	24953013	Our data showed that AURKA knockdown resulted in decreased JAK2 mRNA levels (Figure 5A, right panel).	('knockdown', 'Var', (27, 36))	('AURKA', 'Gene', (21, 26))	('JAK2', 'Gene', '3717', (59, 63))	('decreased', 'NegReg', (49, 58))	('JAK2', 'Gene', (59, 63))	('AURKA', 'Gene', '6790', (21, 26))
425150	24953013	Conversely, AURKA overexpression led to an increase in JAK2 phosphorylation at Y221 and JAK2 protein and mRNA levels (Figure 5B).	('JAK2', 'Gene', '3717', (88, 92))	('JAK2', 'Gene', (88, 92))	('AURKA', 'Gene', '6790', (12, 17))	('JAK2', 'Gene', '3717', (55, 59))	('increase', 'PosReg', (43, 51))	('AURKA', 'Gene', (12, 17))	('JAK2', 'Gene', (55, 59))	('Y221', 'Var', (79, 83))	('overexpression', 'PosReg', (18, 32))
425153	24953013	Western blot analysis indicated that inhibition of JAK2 abrogated AURKA-induced phosphorylation of STAT3 (Figure 5C).	('AURKA', 'Gene', '6790', (66, 71))	('inhibition', 'Var', (37, 47))	('abrogated', 'NegReg', (56, 65))	('AURKA', 'Gene', (66, 71))	('JAK2', 'Gene', '3717', (51, 55))	('phosphorylation', 'MPA', (80, 95))	('JAK2', 'Gene', (51, 55))
425154	24953013	Consistent with these results, knockdown of JAK2 in FLO-1 cells stably overexpressing AURKA significantly reduced the AURKA-induced STAT3 phosphorylation (Figure 5D).	('AURKA', 'Gene', '6790', (86, 91))	('AURKA', 'Gene', (86, 91))	('JAK2', 'Gene', (44, 48))	('AURKA', 'Gene', '6790', (118, 123))	('AURKA', 'Gene', (118, 123))	('JAK2', 'Gene', '3717', (44, 48))	('reduced', 'NegReg', (106, 113))	('knockdown', 'Var', (31, 40))
425158	24953013	Importantly, our data suggest that pharmacological inhibition of AURKA could be a plausible approach to suppress the AURKA-STAT3 oncogenic axis.	('AURKA', 'Gene', (65, 70))	('suppress', 'NegReg', (104, 112))	('AURKA', 'Gene', (117, 122))	('AURKA-STAT3', 'Gene', (117, 128))	('pharmacological', 'Var', (35, 50))	('AURKA-STAT3', 'Gene', '6790;6774', (117, 128))	('AURKA', 'Gene', '6790', (65, 70))	('AURKA', 'Gene', '6790', (117, 122))
425163	24953013	In our current report, we show that AURKA knockdown or pharmacological inhibition can significantly decrease STAT3 phosphorylation/activity and expression of STAT3 downstream targets, BCL2 and MCL1.	('BCL2', 'Gene', (184, 188))	('STAT3 phosphorylation/activity', 'MPA', (109, 139))	('expression', 'MPA', (144, 154))	('BCL2', 'Gene', '596', (184, 188))	('AURKA', 'Gene', '6790', (36, 41))	('MCL1', 'Gene', '4170', (193, 197))	('decrease', 'NegReg', (100, 108))	('AURKA', 'Gene', (36, 41))	('knockdown', 'Var', (42, 51))	('MCL1', 'Gene', (193, 197))
425175	24953013	Therefore, targeted inhibition of AURKA, which is capable of regulating several important pathways in cancer cells, could be a novel therapeutic approach to target multiple oncogenic signaling pathways.	('AURKA', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('targeted inhibition', 'Var', (11, 30))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('AURKA', 'Gene', '6790', (34, 39))
425248	19597950	Cell culture studies have shown that oxidized EGCG inactivates epidermal growth factor receptor, which might subsequently reduce cancer development.	('EGCG', 'Chemical', 'MESH:C045651', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('inactivates', 'NegReg', (51, 62))	('reduce', 'NegReg', (122, 128))	('oxidized', 'Var', (37, 45))	('epidermal growth factor receptor', 'Gene', (63, 95))	('EGCG', 'Gene', (46, 50))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('epidermal growth factor receptor', 'Gene', '1956', (63, 95))	('men', 'Species', '9606', (143, 146))
425306	19597950	Notably, polycyclic aromatic hydrocarbons (PAHs), known esophageal carcinogens in animals and suspected carcinogens in humans, have also been detected in teas.	('esophageal carcinogens', 'Disease', 'MESH:D004941', (56, 78))	('polycyclic', 'Var', (9, 19))	('humans', 'Species', '9606', (119, 125))	('esophageal carcinogens', 'Disease', (56, 78))	('PAHs', 'Chemical', 'MESH:D011084', (43, 47))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (9, 41))
425331	18722278	found that radiaton was associated with a high prevalence inferior left ventricular ischemia detected by myocardial perfusion abnormalities on cardiac gated myocardial perfusion imaging (GMPI).	('myocardial perfusion abnormalities', 'Disease', 'MESH:D009202', (105, 139))	('myocardial perfusion abnormalities', 'Disease', (105, 139))	('ventricular ischemia', 'Disease', (72, 92))	('GMPI', 'Chemical', '-', (187, 191))	('ventricular ischemia', 'Disease', 'MESH:D007511', (72, 92))	('radiaton', 'Var', (11, 19))
425370	18722278	In our experience, the time and effort spent in treatment planning for patients with lung cancer are less for proton therapy than for IMRT.	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('patients', 'Species', '9606', (71, 79))	('proton', 'Var', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))
425455	33731170	In addition to histology, several other tools including genomic markers, gene expression and epigenetic modifications are also used to predict outcome in cancer patients.	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('patients', 'Species', '9606', (161, 169))	('epigenetic modifications', 'Var', (93, 117))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
425479	33731170	The authors noted that patients with triple negative breast cancer have fewer treatment options compared to those with HER 2/neu negative breast cancer.	('HER 2', 'Gene', '2064', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('neu', 'Gene', '2064', (125, 128))	('triple negative', 'Var', (37, 52))	('HER 2', 'Gene', (119, 124))	('neu', 'Gene', (125, 128))	('patients', 'Species', '9606', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
425570	33731170	This study once again showed that AI algorithms may improve the pathologist's productivity and reduce the number of false negatives associated with morphologic detection of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('reduce', 'NegReg', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('improve', 'PosReg', (52, 59))	('AI algorithms', 'Var', (34, 47))	('productivity', 'CPA', (78, 90))
425604	33718226	Meanwhile, activated caspase-1 also cleaves GSDMD into the C-terminal domain and N-terminal domain.	('caspase-1', 'Gene', '834', (21, 30))	('GSDMD', 'Gene', (44, 49))	('GSDMD', 'Gene', '79792', (44, 49))	('caspase-1', 'Gene', (21, 30))	('cleaves', 'Var', (36, 43))
425608	33718226	On the other hand, inducing pyroptosis directly suppresses tumor proliferation.	('tumor', 'Disease', (59, 64))	('suppresses', 'NegReg', (48, 58))	('pyroptosis', 'MPA', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('inducing', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
425616	33718226	NLRC4 is responded to bacterial protein, while AIM2 is mainly activated by bacteria or double-stranded DNA in cells infected by viruses.	('responded to bacterial protein', 'MPA', (9, 39))	('NLRC4', 'Gene', (0, 5))	('AIM2', 'Gene', '9447', (47, 51))	('infected', 'Disease', (116, 124))	('double-stranded DNA', 'Var', (87, 106))	('AIM2', 'Gene', (47, 51))	('infected', 'Disease', 'MESH:D007239', (116, 124))	('NLRC4', 'Gene', '58484', (0, 5))
425621	33718226	In 2015, Feng Shao and colleagues found GSDMD knockdown in iBMDM cells reversed caspase-1-dependent pyroptosis, which demonstrated the crucial role of GSDMD in pyroptosis.	('GSDMD', 'Gene', '79792', (151, 156))	('caspase-1', 'Gene', (80, 89))	('reversed', 'NegReg', (71, 79))	('knockdown', 'Var', (46, 55))	('GSDMD', 'Gene', '79792', (40, 45))	('GSDMD', 'Gene', (40, 45))	('caspase-1', 'Gene', '834', (80, 89))	('GSDMD', 'Gene', (151, 156))
425633	33718226	Knocking down caspase-3 switched pyroptosis to apoptosis through inactivating GSDME.	('GSDME', 'Chemical', '-', (78, 83))	('caspase-3', 'Gene', '836', (14, 23))	('GSDME', 'Gene', (78, 83))	('caspase-3', 'Gene', (14, 23))	('inactivating', 'NegReg', (65, 77))	('Knocking', 'Var', (0, 8))
425635	33718226	Subsequent studies confirmed that caspase-3 triggered GSDME-dependent pyroptosis in high GSDME expression cells in contrast to apoptosis in cells with low GSDME expression.	('GSDME', 'Chemical', '-', (54, 59))	('caspase-3', 'Gene', '836', (34, 43))	('GSDME', 'Chemical', '-', (89, 94))	('GSDME-dependent', 'MPA', (54, 69))	('GSDME', 'Chemical', '-', (155, 160))	('caspase-3', 'Gene', (34, 43))	('high GSDME expression', 'Var', (84, 105))
425649	33718226	Mutations in mice GSDMA3 exhibit hair-loss phenotypes.	('mice', 'Species', '10090', (13, 17))	('GSDMA3', 'Gene', '450219', (18, 24))	('hair-loss', 'Phenotype', 'HP:0001596', (33, 42))	('Mutations', 'Var', (0, 9))	('GSDMA3', 'Gene', (18, 24))	('hair-loss', 'CPA', (33, 42))
425650	33718226	Specific GSDMA3 mutations (T278P, L343P, Y344C, A348T, and 412EA) were found to interfere with the combination of GSDMA3-CT and GSDMA3-NT.	('GSDMA3', 'Gene', '450219', (128, 134))	('T278P', 'Var', (27, 32))	('L343P', 'Var', (34, 39))	('GSDMA3', 'Gene', '450219', (114, 120))	('GSDMA3', 'Gene', '450219', (9, 15))	('Y344C', 'Var', (41, 46))	('T278P', 'Mutation', 'rs17849781', (27, 32))	('Y344C', 'Mutation', 'p.Y344C', (41, 46))	('GSDMA3', 'Gene', (9, 15))	('A348T', 'Var', (48, 53))	('A348T', 'Mutation', 'rs1718119', (48, 53))	('L343P', 'Mutation', 'rs370978892', (34, 39))	('GSDMA3', 'Gene', (128, 134))	('GSDMA3', 'Gene', (114, 120))	('interfere', 'NegReg', (80, 89))
425657	33718226	Similar to other gasdermins, the N-terminal of GSDMC can lead to pore formation.	('GSDMC', 'Gene', (47, 52))	('N-terminal', 'Var', (33, 43))	('lead to', 'Reg', (57, 64))	('GSDMC', 'Gene', '56169', (47, 52))	('pore', 'MPA', (65, 69))
425689	33718226	In recent years, several substances, including 4-hydroxybenacid, Simvastatin, huaier extract, polyphyllin VI, Resibufogenin, have been proved to kill NSCLC via caspase-1-dependent pyroptosis.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('4-hydroxybenacid', 'Chemical', '-', (47, 63))	('caspase-1', 'Gene', (160, 169))	('kill', 'PosReg', (145, 149))	('Simvastatin', 'Chemical', 'MESH:D019821', (65, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('polyphyllin', 'Var', (94, 105))	('polyphyllin VI', 'Chemical', '-', (94, 108))	('Resibufogenin', 'Chemical', 'MESH:C005734', (110, 123))	('caspase-1', 'Gene', '834', (160, 169))	('NSCLC', 'Disease', (150, 155))
425690	33718226	Polyphyllin VI could elevate ROS/NF-kappaB signaling to activate canonical pyroptosis in A549 and H1299 cell lines.	('Polyphyllin', 'Var', (0, 11))	('NF-kappaB', 'Gene', (33, 42))	('elevate', 'PosReg', (21, 28))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('H1299', 'CellLine', 'CVCL:0060', (98, 103))	('activate', 'PosReg', (56, 64))	('Polyphyllin VI', 'Chemical', '-', (0, 14))	('NF-kappaB', 'Gene', '4790', (33, 42))	('canonical pyroptosis', 'MPA', (65, 85))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))
425691	33718226	NAC, a ROS scavenger, could reverse Polyphyllin VI-induced pyroptosis accompanied by suppression of NF-kappaB, NLRP3, and caspase-1.	('ROS', 'Chemical', 'MESH:D017382', (7, 10))	('NLRP3', 'Gene', '114548', (111, 116))	('NAC', 'Gene', (0, 3))	('caspase-1', 'Gene', '834', (122, 131))	('NAC', 'Gene', '6622', (0, 3))	('suppression', 'NegReg', (85, 96))	('Polyphyllin VI', 'Chemical', '-', (36, 50))	('NF-kappaB', 'Gene', '4790', (100, 109))	('Polyphyllin', 'Var', (36, 47))	('NLRP3', 'Gene', (111, 116))	('caspase-1', 'Gene', (122, 131))	('NF-kappaB', 'Gene', (100, 109))
425697	33718226	Overexpression or silencing of P53 in A549 cells elicited or suppressed pyroptosis respectively.	('suppressed', 'NegReg', (61, 71))	('A549', 'CellLine', 'CVCL:0023', (38, 42))	('silencing', 'Var', (18, 27))	('elicited', 'Reg', (49, 57))	('pyroptosis', 'CPA', (72, 82))	('P53', 'Gene', (31, 34))	('P53', 'Gene', '7157', (31, 34))
425701	33718226	Non-coding RNA also participates in the canonical pyroptosis of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('Non-coding', 'Var', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('RNA', 'Gene', (11, 14))	('participates', 'Reg', (20, 32))	('NSCLC', 'Disease', (64, 69))
425704	33718226	Subsequent experiments found that knocking down LncRNA-XIST led to pyroptosis by activating the miR-335/SOD2/ROS/NLRP3 signal pathway.	('SOD2', 'Gene', (104, 108))	('SOD2', 'Gene', '6648', (104, 108))	('NLRP3', 'Gene', (113, 118))	('miR-335', 'Gene', '442904', (96, 103))	('NLRP3', 'Gene', '114548', (113, 118))	('XIST', 'Gene', '7503', (55, 59))	('ROS', 'Chemical', 'MESH:D017382', (109, 112))	('XIST', 'Gene', (55, 59))	('pyroptosis', 'Disease', (67, 77))	('miR-335', 'Gene', (96, 103))	('activating', 'PosReg', (81, 91))	('knocking down', 'Var', (34, 47))
425707	33718226	In addition to NLRP3/caspase-1/GSDMD pathway, the induction of GSDME cleavage in NSCLC causes pyroptosis and inhibits proliferation as well.	('NLRP3', 'Gene', (15, 20))	('GSDME', 'Chemical', '-', (63, 68))	('NLRP3', 'Gene', '114548', (15, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('caspase-1', 'Gene', '834', (21, 30))	('proliferation', 'CPA', (118, 131))	('inhibits', 'NegReg', (109, 117))	('induction', 'Var', (50, 59))	('pyroptosis', 'CPA', (94, 104))	('NSCLC', 'Disease', (81, 86))	('GSDME', 'Gene', (63, 68))	('caspase-1', 'Gene', (21, 30))	('causes', 'Reg', (87, 93))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('GSDMD', 'Gene', (31, 36))	('GSDMD', 'Gene', '79792', (31, 36))
425711	33718226	L61H10, a thiopyran derivative, induced an apoptosis-to-pyroptosis switch through inhibiting NF-kappaB.	('apoptosis-to-pyroptosis', 'MPA', (43, 66))	('inhibiting', 'NegReg', (82, 92))	('L61H10', 'Var', (0, 6))	('L61H10', 'Chemical', '-', (0, 6))	('NF-kappaB', 'Gene', '4790', (93, 102))	('thiopyran', 'Chemical', 'MESH:C522033', (10, 19))	('NF-kappaB', 'Gene', (93, 102))	('induced', 'Reg', (32, 39))
425723	33718226	Relevant studies have shown that berberine, euxanthone, alpinumisoflavone and other drugs could activate caspase-1-dependent pyroptosis and kill HCC cells.	('berberine', 'Chemical', 'MESH:D001599', (33, 42))	('activate', 'PosReg', (96, 104))	('caspase-1', 'Gene', '834', (105, 114))	('euxanthone', 'Var', (44, 54))	('alpinumisoflavone', 'Chemical', 'MESH:C000154', (56, 73))	('euxanthone', 'Chemical', 'MESH:C404221', (44, 54))	('caspase-1', 'Gene', (105, 114))	('HCC', 'Disease', (145, 148))	('HCC', 'Phenotype', 'HP:0001402', (145, 148))
425724	33718226	Inhibiting autophagy by chloroquine or ATG5 siRNA enhanced alpinumisoflavone induced pyroptosis.	('alpinumisoflavone induced pyroptosis', 'MPA', (59, 95))	('Inhibiting', 'Var', (0, 10))	('autophagy', 'CPA', (11, 20))	('alpinumisoflavone', 'Chemical', 'MESH:C000154', (59, 76))	('chloroquine', 'Chemical', 'MESH:D002738', (24, 35))	('ATG5', 'Gene', '9474', (39, 43))	('enhanced', 'PosReg', (50, 58))	('ATG5', 'Gene', (39, 43))
425729	33718226	The results showed that As2O3 and As2O3-NPs induced pyroptosis differently in diverse cell lines.	('As2O3', 'Var', (24, 29))	('induced', 'Reg', (44, 51))	('pyroptosis differently', 'Disease', 'MESH:D007674', (52, 74))	('pyroptosis differently', 'Disease', (52, 74))	('As2O3-NPs', 'Var', (34, 43))	('As2O3', 'Chemical', 'MESH:D000077237', (24, 29))	('As2O3', 'Chemical', 'MESH:D000077237', (34, 39))
425731	33718226	Besides, nanoparticles improved the efficacy of As2O3 by enhancing the endocytosis of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('enhancing', 'PosReg', (57, 66))	('efficacy', 'MPA', (36, 44))	('As2O3', 'Protein', (48, 53))	('nanoparticles', 'Var', (9, 22))	('tumor', 'Disease', (86, 91))	('improved', 'PosReg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('As2O3', 'Chemical', 'MESH:D000077237', (48, 53))
425733	33718226	Then IL-18 and CCL5 released from pyroptotic MPhi enhanced the chemotaxis and cytotoxicity of NK cells and eliminated HCC via activating antitumor immunity.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('CCL5', 'Gene', '6352', (15, 19))	('HCC', 'Disease', (118, 121))	('chemotaxis', 'CPA', (63, 73))	('cytotoxicity', 'Disease', (78, 90))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('IL-18', 'Gene', '3606', (5, 10))	('tumor', 'Disease', (141, 146))	('CCL5', 'Gene', (15, 19))	('eliminated', 'NegReg', (107, 117))	('IL-18', 'Gene', (5, 10))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('enhanced', 'PosReg', (50, 58))	('pyroptotic', 'Var', (34, 44))	('activating', 'PosReg', (126, 136))
425734	33718226	Blockage of IL-1beta or IL-18 could terminate Sorafenib's antitumor effect.	('Sorafenib', 'Gene', (46, 55))	('IL-1beta', 'Gene', (12, 20))	('IL-18', 'Gene', (24, 29))	('Blockage', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('terminate', 'NegReg', (36, 45))	('Sorafenib', 'Chemical', 'MESH:D000077157', (46, 55))	('tumor', 'Disease', (62, 67))	('IL-1beta', 'Gene', '3552', (12, 20))	('IL-18', 'Gene', '3606', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
425736	33718226	FL118, a camptothecin analog, inhibited proliferation, invasion and metastasis in SW480 and HT129 cells via caspase-1-dependent pyroptosis.	('FL118', 'Chemical', 'MESH:C578515', (0, 5))	('caspase-1', 'Gene', (108, 117))	('SW480', 'CellLine', 'CVCL:0546', (82, 87))	('HT129', 'CellLine', 'CVCL:K126', (92, 97))	('inhibited', 'NegReg', (30, 39))	('camptothecin', 'Chemical', 'MESH:D002166', (9, 21))	('invasion', 'CPA', (55, 63))	('metastasis', 'CPA', (68, 78))	('caspase-1', 'Gene', '834', (108, 117))	('proliferation', 'CPA', (40, 53))	('FL118', 'Var', (0, 5))
425738	33718226	c9, t11, c15-CLNA (CLNA1), and t9, t11, c15-CLNA (CLNA2) all belong to conjugated alpha-linolenic acid isomers, and both of them showed a potent anti-cancer effect through activating canonical and noncanonical pyroptosis respectively.	('canonical', 'Pathway', (183, 192))	('activating', 'PosReg', (172, 182))	('alpha-linolenic acid', 'Chemical', 'MESH:D017962', (82, 102))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('c15-CLNA', 'Var', (9, 17))	('noncanonical pyroptosis', 'Pathway', (197, 220))	('cancer', 'Disease', (150, 156))	('t11', 'Var', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
425741	33718226	Knocking down RP1-85F18.6 cleaved GSDMD to trigger pyroptosis.	('Knocking down', 'Var', (0, 13))	('RP1', 'Gene', '6101', (14, 17))	('RP1', 'Gene', (14, 17))	('trigger', 'Reg', (43, 50))	('GSDMD', 'Gene', (34, 39))	('GSDMD', 'Gene', '79792', (34, 39))	('pyroptosis', 'MPA', (51, 61))
425748	33718226	In gastric cancer, chemotherapeutic drugs such as cisplatin and 5-Fu were found to induce GSDME-dependent pyroptosis, which could be transformed into apoptosis via GSDME knockout.	('GSDME', 'Chemical', '-', (164, 169))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('GSDME-dependent pyroptosis', 'MPA', (90, 116))	('induce', 'PosReg', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('GSDME', 'Chemical', '-', (90, 95))	('gastric cancer', 'Disease', (3, 17))	('5-Fu', 'Chemical', 'MESH:D005472', (64, 68))	('5-Fu', 'Var', (64, 68))
425749	33718226	BIX-01294 is a newly discovered autophagy inducer that, when combined with cisplatin, enhances the sensitivity of gastric cancer to cisplatin by activating autophagy.	('gastric cancer', 'Disease', (114, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('autophagy', 'CPA', (156, 165))	('BIX-01294', 'Var', (0, 9))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('activating', 'PosReg', (145, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('enhances', 'PosReg', (86, 94))	('sensitivity', 'MPA', (99, 110))
425754	33718226	Due to the high expression of GSDME in esophageal cancer, some researchers have found that activation of GSDME also led to esophageal cancer pyroptosis.	('GSDME', 'Chemical', '-', (30, 35))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('GSDME', 'Gene', (105, 110))	('cancer pyroptosis', 'Disease', 'MESH:D009369', (134, 151))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('led to', 'Reg', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer pyroptosis', 'Disease', (134, 151))	('GSDME', 'Chemical', '-', (105, 110))	('activation', 'Var', (91, 101))
425756	33718226	Knocking out of GSDME could convert the pyroptosis into apoptosis.	('GSDME', 'Gene', (16, 21))	('pyroptosis', 'MPA', (40, 50))	('GSDME', 'Chemical', '-', (16, 21))	('Knocking out', 'Var', (0, 12))	('convert', 'Reg', (28, 35))
425757	33718226	PLK1 inhibitor BI2536 could enhance the sensitivity of esophageal squamous cell carcinoma to cisplatin by inhibiting DNA damage repair and inducing pyroptosis.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('BI2536', 'Chemical', 'MESH:C518477', (15, 21))	('pyroptosis', 'MPA', (148, 158))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (55, 89))	('inhibiting', 'NegReg', (106, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('enhance', 'PosReg', (28, 35))	('DNA damage repair', 'MPA', (117, 134))	('esophageal squamous cell carcinoma', 'Disease', (55, 89))	('inducing', 'Reg', (139, 147))	('PLK1', 'Gene', (0, 4))	('BI2536', 'Var', (15, 21))	('sensitivity', 'MPA', (40, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('PLK1', 'Gene', '5347', (0, 4))
425758	33718226	Cisplatin combined with BI2536 triggered esophageal cancer cell death through caspase-3/GSDME pathway, while BI2536 or cisplatin alone did not exhibit morphological changes of pyroptosis.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('BI2536', 'Var', (24, 30))	('BI2536', 'Chemical', 'MESH:C518477', (109, 115))	('caspase-3', 'Gene', (78, 87))	('GSDME', 'Chemical', '-', (88, 93))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('BI2536', 'Chemical', 'MESH:C518477', (24, 30))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('caspase-3', 'Gene', '836', (78, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
425760	33718226	Overexpression of MST1 could increase cellular ROS, activating caspase-1 to elicit pyroptosis.	('MST1', 'Gene', (18, 22))	('increase cellular ROS', 'Phenotype', 'HP:0025464', (29, 50))	('activating', 'Reg', (52, 62))	('increase', 'PosReg', (29, 37))	('caspase-1', 'Gene', '834', (63, 72))	('ROS', 'Chemical', 'MESH:D017382', (47, 50))	('elicit', 'Reg', (76, 82))	('Overexpression', 'Var', (0, 14))	('cellular ROS', 'MPA', (38, 50))	('caspase-1', 'Gene', (63, 72))	('MST1', 'Gene', '4485', (18, 22))	('pyroptosis', 'MPA', (83, 93))
425765	33718226	Further mechanisms studies showed that MTX - TMPs induced pyroptosis of cholangiocarcinoma through the GSDME pathway.	('MTX', 'Var', (39, 42))	('GSDME', 'Chemical', '-', (103, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('MTX - TMPs', 'Chemical', '-', (39, 49))	('pyroptosis of cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 90))	('pyroptosis of cholangiocarcinoma', 'Disease', (58, 90))
425781	33718226	Silencing eEF-2K could enhance doxorubicin-induced pyroptosis by decreasing autophagy, suggested that doxorubicin induced protective autophagy by activating eEF-2K in melanoma cells during pyroptosis.	('eEF-2K', 'Gene', '29904', (157, 163))	('eEF-2K', 'Gene', '29904', (10, 16))	('eEF-2K', 'Gene', (157, 163))	('eEF-2K', 'Gene', (10, 16))	('doxorubicin-induced', 'MPA', (31, 50))	('autophagy', 'CPA', (76, 85))	('Silencing', 'Var', (0, 9))	('doxorubicin', 'Chemical', 'MESH:D004317', (102, 113))	('doxorubicin', 'Chemical', 'MESH:D004317', (31, 42))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('decreasing', 'NegReg', (65, 75))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('activating', 'PosReg', (146, 156))	('enhance', 'PosReg', (23, 30))
425786	33718226	The combination of BRAF inhibitors and MEK inhibitors is recommended by the FDA for the treatment of BRAF V600E/K mutant melanoma.	('BRAF', 'Gene', (101, 105))	('V600E', 'SUBSTITUTION', 'None', (106, 111))	('melanoma', 'Disease', (121, 129))	('BRAF', 'Gene', '673', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('BRAF', 'Gene', (19, 23))	('BRAF', 'Gene', '673', (101, 105))	('MEK', 'Gene', (39, 42))	('MEK', 'Gene', '5609', (39, 42))	('V600E', 'Var', (106, 111))
425796	33718226	In the tumor-bearing mice model, pyroptosis of less than 15% of tumor cells led to the elimination of the entire 4T1 mammary tumor graft, which was not observed in immunodeficient mice.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (64, 69))	('immunodeficient', 'Disease', 'MESH:D007153', (164, 179))	('pyroptosis', 'Var', (33, 43))	('tumor', 'Disease', (7, 12))	('elimination', 'NegReg', (87, 98))	('immunodeficient', 'Disease', (164, 179))	('mice', 'Species', '10090', (21, 25))	('4T1', 'CellLine', 'CVCL:0125', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('mice', 'Species', '10090', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
425797	33718226	Further study showed that pyroptosis induced tumor tissue clearance by activating cytotoxic T cells and CD4+ T helper cells in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('CD4', 'Gene', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('pyroptosis', 'Var', (26, 36))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (131, 136))	('CD4', 'Gene', '920', (104, 107))	('iron', 'Chemical', 'MESH:D007501', (145, 149))	('activating', 'PosReg', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
425799	33718226	Combination of NP-GSDMA3, Phe-BF3 and anti-PD1 notably inhibited tumor growth, which indicated that the pyroptosis associated inflammatory response enhanced the antitumor immunity of checkpoint blockade.	('GSDMA3', 'Gene', '450219', (18, 24))	('pyroptosis associated', 'MPA', (104, 125))	('tumor', 'Disease', (65, 70))	('anti-PD1', 'Gene', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Phe-BF3', 'Chemical', '-', (26, 33))	('enhanced', 'PosReg', (148, 156))	('GSDMA3', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Phe-BF3', 'Var', (26, 33))	('inhibited', 'NegReg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (165, 170))
425803	33718226	Inhibiting miRNA145 reversed tanshinone II A induced pyroptosis.	('Inhibiting', 'Var', (0, 10))	('pyroptosis', 'MPA', (53, 63))	('tanshinone II A', 'Chemical', 'MESH:C021751', (29, 44))	('miRNA145', 'Gene', (11, 19))	('miRNA145', 'Gene', '406937', (11, 19))
425805	33718226	Knocking down Sirt1 activated AIM2 and caspase-1 to elicit pyroptosis.	('Sirt1', 'Gene', '23411', (14, 19))	('caspase-1', 'Gene', '834', (39, 48))	('Knocking down', 'Var', (0, 13))	('AIM2', 'Gene', '9447', (30, 34))	('elicit', 'Reg', (52, 58))	('caspase-1', 'Gene', (39, 48))	('AIM2', 'Gene', (30, 34))	('Sirt1', 'Gene', (14, 19))	('pyroptosis', 'MPA', (59, 69))
425816	33718226	Inhibition of autophagy could improve Taxol's cytotoxicity.	('autophagy', 'CPA', (14, 23))	('improve', 'PosReg', (30, 37))	('cytotoxicity', 'Disease', 'MESH:D064420', (46, 58))	('Taxol', 'Chemical', 'MESH:D017239', (38, 43))	('Inhibition', 'Var', (0, 10))	('cytotoxicity', 'Disease', (46, 58))
425821	33718226	In osteosarcoma, Dioscin inhibited tumor proliferation by inducing G2/M-phase arrest, apoptosis and GSDME-dependent pyroptosis.	('arrest', 'Disease', (78, 84))	('GSDME-dependent pyroptosis', 'CPA', (100, 126))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('Dioscin', 'Chemical', 'MESH:C019357', (17, 24))	('inducing', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('tumor', 'Disease', (35, 40))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('GSDME', 'Chemical', '-', (100, 105))	('Dioscin', 'Var', (17, 24))	('inhibited', 'NegReg', (25, 34))	('apoptosis', 'CPA', (86, 95))
425829	33718226	On the one hand, ROS activates canonical inflammasome pathway to elicit pyroptosis.	('pyroptosis', 'MPA', (72, 82))	('canonical inflammasome pathway', 'Pathway', (31, 61))	('ROS', 'Var', (17, 20))	('ROS', 'Chemical', 'MESH:D017382', (17, 20))	('elicit', 'Reg', (65, 71))	('activates', 'PosReg', (21, 30))
425830	33718226	On the other hand, ROS triggers apoptosis and secondary GSDME-dependent pyroptosis.	('apoptosis', 'CPA', (32, 41))	('triggers', 'Reg', (23, 31))	('GSDME', 'Chemical', '-', (56, 61))	('ROS', 'Var', (19, 22))	('ROS', 'Chemical', 'MESH:D017382', (19, 22))
425833	33718226	Resibufogenin, L61H10, JQ1 and other drugs can activate pyroptosis via inhibiting NF-kappaB.	('inhibiting', 'NegReg', (71, 81))	('L61H10', 'Chemical', '-', (15, 21))	('activate', 'PosReg', (47, 55))	('Resibufogenin', 'Chemical', 'MESH:C005734', (0, 13))	('NF-kappaB', 'Gene', (82, 91))	('pyroptosis', 'CPA', (56, 66))	('L61H10', 'Var', (15, 21))	('NF-kappaB', 'Gene', '4790', (82, 91))
425841	33718226	In recent years, more and more researchers focus their attention on the regulatory role of non-coding RNAs in tumorigenesis and development.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('non-coding', 'Var', (91, 101))	('development', 'CPA', (128, 139))	('RNAs', 'Gene', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
425843	33718226	Depending on the downstream target, specific miRNAs can act as either oncogenes or tumor suppressor genes.	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miRNAs', 'Var', (45, 51))
425858	33718226	Autophagy inducer BIX-01294 was reported to enhance pyroptosis induced by cisplatin, although the specific mechanisms of autophagy activation were unclear.	('BIX-01294', 'Var', (18, 27))	('enhance', 'PosReg', (44, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('pyroptosis', 'CPA', (52, 62))
425866	33718226	All the above results suggested that pyroptosis could play an antitumor role by activating the immune response.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('pyroptosis', 'Var', (37, 47))	('immune response', 'CPA', (95, 110))	('tumor', 'Disease', (66, 71))	('activating', 'PosReg', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
425870	33718226	Granzyme A was also proved to induce tumor cell pyroptosis via the cleavage of GSDMB in another recent study.	('induce', 'PosReg', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('GSDMB', 'Gene', '55876', (79, 84))	('Granzyme A', 'Gene', (0, 10))	('tumor', 'Disease', (37, 42))	('Granzyme A', 'Gene', '3001', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('GSDMB', 'Gene', (79, 84))	('cleavage', 'Var', (67, 75))
425880	33718226	As2O3-NPs enhanced endocytosis of tumor cells to increase the cellular As2O3 content.	('increase', 'PosReg', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('enhanced', 'PosReg', (10, 18))	('As2O3-NPs', 'Var', (0, 9))	('As2O3', 'Chemical', 'MESH:D000077237', (71, 76))	('As2O3', 'Chemical', 'MESH:D000077237', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
425881	33718226	Then As2O3 exerted antitumor effects via inducing pyroptosis.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('pyroptosis', 'MPA', (50, 60))	('As2O3', 'Var', (5, 10))	('As2O3', 'Chemical', 'MESH:D000077237', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('inducing', 'PosReg', (41, 49))
425895	33718226	Besides, the cellular contents released from pyroptotic tumor cells can promote infiltration of inflammatory cells in the tumor microenvironment and improve antitumor immunity.	('pyroptotic', 'Var', (45, 55))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('infiltration', 'CPA', (80, 92))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('promote', 'PosReg', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('improve', 'PosReg', (149, 156))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('iron', 'Chemical', 'MESH:D007501', (136, 140))
425910	33295697	In de novo metastatic GE adenocarcinoma patients, ECOG, pretreatment NRI and change in NRI were significant prognostic factors for OS while sarcopenia was not.	('NRI', 'Disease', (69, 72))	('change', 'Var', (77, 83))	('patients', 'Species', '9606', (40, 48))	('sarcopenia', 'Disease', 'MESH:D055948', (140, 150))	('adenocarcinoma', 'Disease', 'MESH:D000230', (25, 39))	('adenocarcinoma', 'Disease', (25, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('men', 'Species', '9606', (64, 67))	('sarcopenia', 'Disease', (140, 150))
426006	33335861	MRI can yield a superior soft-tissue contrast when compared with CBCT, which not only means that both the tumor and surrounding organs at risk (OARs) can be recognized more clearly, but also make it possible for soft tissue based set-up correction.	('MRI', 'Var', (0, 3))	('OAR', 'Gene', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('soft-tissue', 'MPA', (25, 36))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('OAR', 'Gene', '4936', (144, 147))	('tumor', 'Disease', (106, 111))
426035	33335861	According to previous studies, ESE mainly affects the out-of-field in-air dose distribution in CC direction.	('ESE', 'Var', (31, 34))	('out-of-field in-air dose distribution', 'MPA', (54, 91))	('ESE', 'Chemical', '-', (31, 34))	('affects', 'Reg', (42, 49))
426042	33335861	Out-of-field doses were considerably increased due to the presence of ESE under 1.5 T magnetic field.	('Out-of-field doses', 'CPA', (0, 18))	('presence', 'Var', (58, 66))	('ESE', 'Chemical', '-', (70, 73))	('increased', 'PosReg', (37, 46))
426085	33335861	Out-of-field dose escalation induced by ESE is also a significant issue for MRI guided esophageal cancer radiotherapy, even more protruding than previous studies about breast cases.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('esophageal cancer', 'Disease', (87, 104))	('ESE', 'Var', (40, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('ESE', 'Chemical', '-', (40, 43))
426093	31939620	miRNA (miR)-542-3p is a tumor suppressor in multiple types of cancer.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('miRNA', 'Var', (0, 5))
426094	31939620	However, whether and how miR-542-3p contributes to the progression of esophageal cancer remains unknown, and this is the aim of the present study.	('contributes', 'Reg', (36, 47))	('miR-542-3p', 'Var', (25, 35))	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
426095	31939620	In the current study, decreased expression of miR-542-3p was detected in tumor tissues compared with normal tissues from patients with esophageal cancer, and miR-542-3p expression was negatively correlated with mRNA expression levels of ovarian tumor domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) in tumor tissues from patients with esophageal cancer.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian tumor', 'Phenotype', 'HP:0100615', (237, 250))	('aldehyde', 'Chemical', 'MESH:D000447', (279, 287))	('OTUB1', 'Gene', '55611', (307, 312))	('negatively', 'NegReg', (184, 194))	('expression', 'MPA', (32, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (350, 367))	('tumor', 'Disease', (317, 322))	('patients', 'Species', '9606', (336, 344))	('tumor', 'Disease', (73, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('tumor', 'Disease', (245, 250))	('ovarian tumor', 'Disease', (237, 250))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('patients', 'Species', '9606', (121, 129))	('miR-542-3p', 'Var', (158, 168))	('OTUB1', 'Gene', (307, 312))	('decreased', 'NegReg', (22, 31))	('esophageal cancer', 'Disease', (350, 367))	('ovarian tumor', 'Disease', 'MESH:D010051', (237, 250))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('mRNA expression levels', 'MPA', (211, 233))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('esophageal cancer', 'Disease', (135, 152))
426096	31939620	In KYSE150 human esophageal squamous cell carcinoma cells, overexpression of miR-542-3p significantly decreased OTUB1 at mRNA and protein levels, whereas downregulation of miR-542-3p significantly increased OTUB1 expression.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (28, 51))	('OTUB1', 'Gene', (112, 117))	('OTUB1', 'Gene', (207, 212))	('KYSE150', 'CellLine', 'CVCL:1348', (3, 10))	('expression', 'MPA', (213, 223))	('human', 'Species', '9606', (11, 16))	('downregulation', 'NegReg', (154, 168))	('OTUB1', 'Gene', '55611', (207, 212))	('increased', 'PosReg', (197, 206))	('esophageal squamous cell carcinoma', 'Disease', (17, 51))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (17, 51))	('miR-542-3p', 'Var', (77, 87))	('OTUB1', 'Gene', '55611', (112, 117))	('decreased', 'NegReg', (102, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
426097	31939620	Using a dual-luciferase assay, OTUB1 was validated to be a target gene of miR-542-3p in KYSE150 cells.	('OTUB1', 'Gene', '55611', (31, 36))	('miR-542-3p', 'Var', (74, 84))	('KYSE150', 'CellLine', 'CVCL:1348', (88, 95))	('OTUB1', 'Gene', (31, 36))
426098	31939620	Functionally, miR-542-3p significantly inhibited the migration and invasion of KYSE150 cells by repression of OTUB1 expression.	('inhibited', 'NegReg', (39, 48))	('miR-542-3p', 'Var', (14, 24))	('OTUB1', 'Gene', '55611', (110, 115))	('KYSE150', 'CellLine', 'CVCL:1348', (79, 86))	('repression', 'NegReg', (96, 106))	('OTUB1', 'Gene', (110, 115))
426099	31939620	These results demonstrated that miR-542-3p may promote the metastasis of esophageal cancer cells, and indicated that miR-542-3p may be a treatment target for esophageal cancer.	('metastasis of esophageal cancer', 'Disease', (59, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('promote', 'PosReg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('miR-542-3p', 'Var', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('metastasis of esophageal cancer', 'Disease', 'MESH:D004938', (59, 90))	('esophageal cancer', 'Disease', (158, 175))
426106	31939620	Dysregulation of miRNA expression contributes to a number of human diseases such as cancer.	('miRNA expression', 'Protein', (17, 33))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('contributes', 'Reg', (34, 45))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('human', 'Species', '9606', (61, 66))
426113	31939620	A negative correlation was observed between miR-542-3p and OTUB1 mRNA expression in tumor tissues.	('negative', 'NegReg', (2, 10))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('OTUB1', 'Gene', (59, 64))	('tumor', 'Disease', (84, 89))	('miR-542-3p', 'Var', (44, 54))	('mRNA expression', 'MPA', (65, 80))	('OTUB1', 'Gene', '55611', (59, 64))
426114	31939620	Western blotting and reverse transcription-quantitative PCR (RT-qPCR) data indicated that OTUB1 was negatively regulated by miR-542-3p in esophageal cancer cells.	('esophageal cancer', 'Disease', (138, 155))	('negatively', 'NegReg', (100, 110))	('OTUB1', 'Gene', '55611', (90, 95))	('miR-542-3p', 'Var', (124, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('OTUB1', 'Gene', (90, 95))
426115	31939620	A dual-luciferase assay validated OTUB1 as a target gene for miR-542-3p.	('OTUB1', 'Gene', '55611', (34, 39))	('miR-542-3p', 'Var', (61, 71))	('OTUB1', 'Gene', (34, 39))
426116	31939620	Furthermore, function assays demonstrated that miR-542-3p inhibited the migration and invasion of KYSE150 human esophageal squamous cell carcinoma cells through repression of OTUB1 expression.	('KYSE150', 'CellLine', 'CVCL:1348', (98, 105))	('human', 'Species', '9606', (106, 111))	('esophageal squamous cell carcinoma', 'Disease', (112, 146))	('migration', 'CPA', (72, 81))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (112, 146))	('OTUB1', 'Gene', (175, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('repression', 'NegReg', (161, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('miR-542-3p', 'Var', (47, 57))	('inhibited', 'NegReg', (58, 67))	('OTUB1', 'Gene', '55611', (175, 180))	('invasion', 'CPA', (86, 94))
426117	31939620	The data from the present study suggested a potential tumor suppressor role for miR-542-3p in esophageal cancer.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('esophageal cancer', 'Disease', (94, 111))	('miR-542-3p', 'Var', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (54, 59))
426135	31939620	pGL3-OTUB1-3'UTR-mutant (Mut, 5'...UUCACCCCCUUCUUCCUGGAACA...) was created by introducing two site mutations into miR-542-3p potential target sites using QuickChangeSite-Directed Mutagenesis kits (Agilent Technologies, Inc.).	('OTUB1', 'Gene', (5, 10))	('pGL3', 'Gene', '6391', (0, 4))	('OTUB1', 'Gene', '55611', (5, 10))	('mutations', 'Var', (99, 108))	('pGL3', 'Gene', (0, 4))
426140	31939620	In brief, KYSE150 cells (1x105) transfected with miR-NC mimic + pcDNA3.1, miR-542-3p mimic + pcDNA3.1 or miR-542-3p mimic + pcDNA3.1-OTUB1 were cultured in the upper chamber in serum-free DMEM at 37 C. Following 72 h of invasion, cells on the upper side of the filter were removed and cells that invaded to the underside of the membranes were fixed using 8% formaldehyde at room temperature for 15 min, followed by staining with crystal violet at room temperature for 30 min.	('OTUB1', 'Gene', (133, 138))	('miR-542-3p mimic + pcDNA3.1', 'Var', (74, 101))	('KYSE150', 'CellLine', 'CVCL:1348', (10, 17))	('formaldehyde', 'Chemical', 'MESH:D005557', (358, 370))	('OTUB1', 'Gene', '55611', (133, 138))	('miR-NC mimic + pcDNA3.1', 'Var', (49, 72))
426144	31939620	The results demonstrated that the expression of miR-542-3p was significantly downregulated in tumor tissues compared with adjacent normal tissues (Fig.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('downregulated', 'NegReg', (77, 90))	('expression', 'MPA', (34, 44))	('miR-542-3p', 'Var', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))
426145	31939620	OTUB1 is a newly identified oncogene in esophageal cancer and has been reported to be regulated by miR-542-3p in colorectal cancer.	('colorectal cancer', 'Disease', (113, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('OTUB1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('OTUB1', 'Gene', '55611', (0, 5))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('miR-542-3p', 'Var', (99, 109))	('esophageal cancer', 'Disease', (40, 57))	('regulated', 'Reg', (86, 95))
426148	31939620	In addition, Pearson's correlation analysis indicated that expression of miR-542-3p was significantly negatively correlated with OTUB1 mRNA expression levels in esophageal tumor tissues (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('OTUB1', 'Gene', (129, 134))	('miR-542-3p', 'Var', (73, 83))	('OTUB1', 'Gene', '55611', (129, 134))	('esophageal tumor', 'Disease', (161, 177))	('esophageal tumor', 'Phenotype', 'HP:0100751', (161, 177))	('esophageal tumor', 'Disease', 'MESH:D004941', (161, 177))	('negatively', 'NegReg', (102, 112))
426149	31939620	These results suggested that miR-542-3p may inhibit esophageal cancer progression and act as a tumor suppressor.	('inhibit', 'NegReg', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('miR-542-3p', 'Var', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
426152	31939620	Overexpression of miR-542-3p significantly decreased OTUB1 mRNA levels and OTUB1 protein levels in cells (Fig.	('OTUB1', 'Gene', (53, 58))	('OTUB1', 'Gene', (75, 80))	('miR-542-3p', 'Var', (18, 28))	('OTUB1', 'Gene', '55611', (53, 58))	('OTUB1', 'Gene', '55611', (75, 80))	('decreased', 'NegReg', (43, 52))
426154	31939620	These data demonstrated that miR-542-3p may negatively regulate OTUB1 in esophageal cancer cells.	('esophageal cancer', 'Disease', (73, 90))	('OTUB1', 'Gene', (64, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('miR-542-3p', 'Var', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('negatively regulate', 'NegReg', (44, 63))	('OTUB1', 'Gene', '55611', (64, 69))
426156	31939620	Transfection of miR-542-3p mimic significantly reduced luciferase activity of OTUB1 3'UTR-WT compared with cells transfected with miR-NC mimic (Fig.	('OTUB1', 'Gene', (78, 83))	('activity', 'MPA', (66, 74))	('OTUB1', 'Gene', '55611', (78, 83))	('miR-542-3p', 'Var', (16, 26))	('reduced', 'NegReg', (47, 54))	('luciferase', 'Enzyme', (55, 65))
426158	31939620	These data suggested that miR-542-3p may bind directly to the putative binding site in 3'UTR of OTUB1 to repress its expression.	('OTUB1', 'Gene', '55611', (96, 101))	('repress', 'NegReg', (105, 112))	('expression', 'MPA', (117, 127))	('OTUB1', 'Gene', (96, 101))	('miR-542-3p', 'Var', (26, 36))
426159	31939620	To study the biological function of miR-542-3p in esophageal cancer cells, wound healing and cell invasion assays were performed to detect cell migratory and invasive ability of cells transfected with the miR-542-3p mimic either with or without overexpression of OTUB1.	('OTUB1', 'Gene', (263, 268))	('OTUB1', 'Gene', '55611', (263, 268))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', (50, 67))	('miR-542-3p', 'Var', (205, 215))	('cell migratory', 'CPA', (139, 153))	('invasive ability', 'CPA', (158, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
426160	31939620	Transfection of miR-542-3p mimic reduced OTUB1 protein expression whereas co-transfection of miR-542-3p mimic and recombinant OTUB1 reversed the downregulation of OTUB1 in KYSE150 cells (Fig.	('KYSE150', 'CellLine', 'CVCL:1348', (172, 179))	('OTUB1', 'Gene', '55611', (41, 46))	('OTUB1', 'Gene', (126, 131))	('OTUB1', 'Gene', '55611', (163, 168))	('reduced', 'NegReg', (33, 40))	('miR-542-3p', 'Var', (16, 26))	('OTUB1', 'Gene', '55611', (126, 131))	('OTUB1', 'Gene', (41, 46))	('OTUB1', 'Gene', (163, 168))
426161	31939620	In addition, overexpression of OTUB1 reversed migration inhibition induced by miR-542-3p mimic (Fig.	('OTUB1', 'Gene', '55611', (31, 36))	('miR-542-3p mimic', 'Var', (78, 94))	('migration inhibition', 'CPA', (46, 66))	('OTUB1', 'Gene', (31, 36))
426162	31939620	Similarly, overexpression of miR-542-3p significantly inhibited the invasive ability of the cells, which was reversed by overexpression of OTUB1 (Fig.	('inhibited', 'NegReg', (54, 63))	('OTUB1', 'Gene', (139, 144))	('OTUB1', 'Gene', '55611', (139, 144))	('invasive ability of the cells', 'CPA', (68, 97))	('miR-542-3p', 'Var', (29, 39))
426163	31939620	The results demonstrated that miR-542-3p may inhibit the migratory and invasive abilities of esophageal cancer cells through repression of OTUB1.	('OTUB1', 'Gene', (139, 144))	('invasive abilities of esophageal cancer', 'Disease', (71, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('invasive abilities of esophageal cancer', 'Disease', 'MESH:D004938', (71, 110))	('OTUB1', 'Gene', '55611', (139, 144))	('miR-542-3p', 'Var', (30, 40))	('inhibit', 'NegReg', (45, 52))	('repression', 'NegReg', (125, 135))
426166	31939620	Decreased expression of miR-542-3p has been observed in certain types of cancers, including hepatocellular carcinoma, osteosarcoma, colorectal cancer and melanoma.	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', (73, 80))	('Decreased', 'NegReg', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('expression', 'MPA', (10, 20))	('osteosarcoma', 'Phenotype', 'HP:0002669', (118, 130))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('miR-542-3p', 'Var', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('colorectal cancer', 'Disease', (132, 149))	('hepatocellular carcinoma', 'Disease', (92, 116))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('osteosarcoma', 'Disease', (118, 130))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('osteosarcoma', 'Disease', 'MESH:D012516', (118, 130))
426168	31939620	RT-qPCR revealed that miR-542-3p expression was decreased in tumor tissues compared with adjacent normal tissues from patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('esophageal cancer', 'Disease', (132, 149))	('decreased', 'NegReg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-542-3p', 'Var', (22, 32))	('patients', 'Species', '9606', (118, 126))	('tumor', 'Disease', (61, 66))
426169	31939620	In KYSE150 cells, overexpression of miR-542-3p markedly reduced cell migratory and invasive abilities.	('KYSE150', 'CellLine', 'CVCL:1348', (3, 10))	('overexpression', 'PosReg', (18, 32))	('reduced', 'NegReg', (56, 63))	('miR-542-3p', 'Var', (36, 46))
426170	31939620	Thus, consistent with its tumor suppressor role in other cancer types, miR-542-3p may also function as a tumor suppressor in esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('esophageal cancer', 'Disease', (125, 142))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Disease', (136, 142))	('miR-542-3p', 'Var', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
426174	31939620	miR-542-3p has been demonstrated to bind to 3'UTR of OTUB1 mRNA to downregulate OTUB1 in colorectal cancer cells.	('OTUB1', 'Gene', (53, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('miR-542-3p', 'Var', (0, 10))	('bind', 'Interaction', (36, 40))	('downregulate', 'NegReg', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('OTUB1', 'Gene', '55611', (80, 85))	('OTUB1', 'Gene', '55611', (53, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('OTUB1', 'Gene', (80, 85))
426176	31939620	Additionally, OTUB1 expression levels were inversely correlated with miR-542-3p expression levels in tumor tissues, and in KYSE150 cells, overexpression of miR-542-3p decreased OTUB1 expression.	('KYSE150', 'CellLine', 'CVCL:1348', (123, 130))	('OTUB1', 'Gene', '55611', (14, 19))	('OTUB1', 'Gene', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('miR-542-3p', 'Var', (156, 166))	('OTUB1', 'Gene', '55611', (177, 182))	('expression', 'MPA', (183, 193))	('OTUB1', 'Gene', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('expression levels', 'MPA', (20, 37))	('decreased', 'NegReg', (167, 176))
426180	31939620	Notably, in KYSE150 cells, overexpression of miR-542-3p decreased Snail expression.	('miR-542-3p', 'Var', (45, 55))	('decreased', 'NegReg', (56, 65))	('Snail', 'Gene', (66, 71))	('KYSE150', 'CellLine', 'CVCL:1348', (12, 19))	('Snail', 'Gene', '6615', (66, 71))
426181	31939620	Finally, cell migration and invasion inhibition induced by miR-542-3p overexpression was partially attenuated by co-transfection of recombinant OTUB1 in KYSE150 cells.	('miR-542-3p', 'Var', (59, 69))	('OTUB1', 'Gene', (144, 149))	('cell migration', 'CPA', (9, 23))	('KYSE150', 'CellLine', 'CVCL:1348', (153, 160))	('attenuated', 'NegReg', (99, 109))	('overexpression', 'PosReg', (70, 84))	('invasion inhibition', 'CPA', (28, 47))	('OTUB1', 'Gene', '55611', (144, 149))
426182	31939620	These results demonstrated that miR-542-3p may regulate OTUB1 to inhibit cell metastasis of esophageal cancer, which were consistent with a previous study about the role of OTUB1 in esophageal cancer.	('OTUB1', 'Gene', '55611', (56, 61))	('OTUB1', 'Gene', (173, 178))	('esophageal cancer', 'Disease', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('OTUB1', 'Gene', '55611', (173, 178))	('metastasis of esophageal cancer', 'Disease', 'MESH:D004938', (78, 109))	('miR-542-3p', 'Var', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('OTUB1', 'Gene', (56, 61))	('metastasis of esophageal cancer', 'Disease', (78, 109))	('inhibit', 'NegReg', (65, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
426183	31939620	Future studies are needed to determine whether the expression of miR-542-3p may be used as a biomarker to predict distant metastasis and overall survival of patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('miR-542-3p', 'Var', (65, 75))	('distant metastasis', 'CPA', (114, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('patients', 'Species', '9606', (157, 165))	('esophageal cancer', 'Disease', (171, 188))
426184	31939620	The results of the present study indicated a potential tumor suppressor role for miR-542-3p in esophageal cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('miR-542-3p', 'Var', (81, 91))	('esophageal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
426185	31939620	Overexpression of miR-542-3p inhibited migration and invasion of esophageal cancer cells.	('inhibited', 'NegReg', (29, 38))	('esophageal cancer', 'Disease', (65, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('miR-542-3p', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('invasion of', 'CPA', (53, 64))
426186	31939620	Therefore, upregulation of miR-542-3p may be a potential treatment approach for patients with esophageal cancer.	('miR-542-3p', 'Var', (27, 37))	('patients', 'Species', '9606', (80, 88))	('esophageal cancer', 'Disease', (94, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('upregulation', 'PosReg', (11, 23))
426209	31519770	Cytological experiments suggest that TRPM1 might be a tumor suppressor because of the anti-tumor role of microRNA-211 which is located in TRPM1 gene.	('TRPM1', 'Gene', (37, 42))	('TRPM1', 'Gene', '4308', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('microRNA-211', 'Var', (105, 117))	('TRPM1', 'Gene', (138, 143))	('TRPM1', 'Gene', '4308', (37, 42))	('tumor', 'Disease', (91, 96))
426212	31519770	A recent research has revealed that TRPM7 displays a significantly higher level in esophageal cancer tissues and cell lines, but TRPM7 knockdown facilitates migration and invasion of esophageal cancer cells.	('TRPM7', 'Gene', '54822', (36, 41))	('esophageal cancer', 'Disease', (83, 100))	('knockdown', 'Var', (135, 144))	('invasion', 'CPA', (171, 179))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('TRPM7', 'Gene', (129, 134))	('facilitates', 'PosReg', (145, 156))	('esophageal cancer', 'Disease', (183, 200))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TRPM7', 'Gene', (36, 41))	('migration', 'CPA', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('esophageal cancer', 'Disease', 'MESH:D004938', (183, 200))	('TRPM7', 'Gene', '54822', (129, 134))
426216	31519770	The cytological experiments showed that both TRPM8 knockdown and TRPM8 antagonist inhibited proliferation of esophageal cancer cells, and TRPM8 overexpression and TRPM8 agonist exerted the opposite role.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('TRPM8', 'Gene', (138, 143))	('TRPM8', 'Gene', (45, 50))	('TRPM8', 'Gene', (163, 168))	('inhibited', 'NegReg', (82, 91))	('TRPM8', 'Gene', '79054', (163, 168))	('TRPM8', 'Gene', '79054', (45, 50))	('overexpression', 'PosReg', (144, 158))	('esophageal cancer', 'Disease', (109, 126))	('TRPM8', 'Gene', '79054', (65, 70))	('TRPM8', 'Gene', (65, 70))	('proliferation', 'CPA', (92, 105))	('TRPM8', 'Gene', '79054', (138, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))	('knockdown', 'Var', (51, 60))
426248	31519770	However, RQ-00203078, a potent antagonist of TRPM8 to reduce Ca2+ influx, had no effect on TRPM8 expression (Figure 1G).	('RQ-00203078', 'Chemical', 'MESH:C043461', (9, 20))	('TRPM8', 'Gene', (45, 50))	('Ca2+', 'Chemical', 'MESH:D002118', (61, 65))	('reduce', 'NegReg', (54, 60))	('Ca2+ influx', 'MPA', (61, 72))	('TRPM8', 'Gene', '79054', (91, 96))	('TRPM8', 'Gene', (91, 96))	('TRPM8', 'Gene', '79054', (45, 50))	('expression', 'MPA', (97, 107))	('RQ-00203078', 'Var', (9, 20))
426249	31519770	The CCK-8 assay showed that TRPM8 knockdown and blocking reduced cell viability (Figure 1H,I).	('cell viability', 'CPA', (65, 79))	('blocking reduced', 'NegReg', (48, 64))	('knockdown', 'Var', (34, 43))	('TRPM8', 'Gene', '79054', (28, 33))	('TRPM8', 'Gene', (28, 33))
426254	31519770	Moreover, RQ-00203078 restrained the colony formation (Figure 2B).	('restrained', 'NegReg', (22, 32))	('RQ-00203078', 'Chemical', 'MESH:C043461', (10, 21))	('colony formation', 'CPA', (37, 53))	('RQ-00203078', 'Var', (10, 21))
426258	31519770	In addition, TRPM8 antagonist resulted in a significantly higher apoptotic rate in esophageal cancer cells (Figure 2F).	('esophageal cancer', 'Disease', (83, 100))	('apoptotic rate', 'CPA', (65, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('antagonist', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TRPM8', 'Gene', '79054', (13, 18))	('higher', 'PosReg', (58, 64))	('TRPM8', 'Gene', (13, 18))
426262	31519770	We found that the value of OD 450 decreased significantly in the co-incubation system for 24 h, and both TRPM8 siRNA and RQ-00203078 further weakened cell viability in the co-incubation system (Figure 3A,B).	('weakened', 'NegReg', (141, 149))	('decreased', 'NegReg', (34, 43))	('TRPM8', 'Gene', (105, 110))	('TRPM8', 'Gene', '79054', (105, 110))	('RQ-00203078', 'Var', (121, 132))	('RQ-00203078', 'Chemical', 'MESH:C043461', (121, 132))	('cell viability', 'CPA', (150, 164))
426265	31519770	Western blot analysis revealed that both TRPM8 knockdown and TRPM8 antagonist induced down-regulation of PD-L1 (Figure 3E).	('TRPM8', 'Gene', (41, 46))	('PD-L1', 'Gene', (105, 110))	('knockdown', 'Var', (47, 56))	('TRPM8', 'Gene', (61, 66))	('TRPM8', 'Gene', '79054', (61, 66))	('PD-L1', 'Gene', '29126', (105, 110))	('TRPM8', 'Gene', '79054', (41, 46))	('down-regulation', 'NegReg', (86, 101))
426269	31519770	First, we found TRPM8 inhibition could dramatically reduce the calcineurin activity of EC109 cells (Figure 4A,B).	('inhibition', 'Var', (22, 32))	('EC109', 'CellLine', 'CVCL:6898', (87, 92))	('TRPM8', 'Gene', '79054', (16, 21))	('calcineurin activity', 'MPA', (63, 83))	('TRPM8', 'Gene', (16, 21))	('reduce', 'NegReg', (52, 58))
426272	31519770	The Western blot analysis showed that both TRPM8 knockdown and TRPM8 antagonist promoted the expression of inactive form of NFATc3, that was phosphorylated NFATc3 (p-NFATc3) (Figure 4E).	('knockdown', 'Var', (49, 58))	('promoted', 'PosReg', (80, 88))	('NFATc3', 'Gene', '4775', (124, 130))	('NFATc3', 'Gene', '4775', (166, 172))	('NFATc3', 'Gene', (124, 130))	('TRPM8', 'Gene', '79054', (43, 48))	('NFATc3', 'Gene', '4775', (156, 162))	('expression', 'MPA', (93, 103))	('NFATc3', 'Gene', (166, 172))	('TRPM8', 'Gene', (43, 48))	('TRPM8', 'Gene', '79054', (63, 68))	('NFATc3', 'Gene', (156, 162))	('TRPM8', 'Gene', (63, 68))
426275	31519770	It has been widely reported that FK506 is a potent inhibitor of calcineurin activity.	('calcineurin activity', 'MPA', (64, 84))	('FK506', 'Chemical', 'MESH:D016559', (33, 38))	('FK506', 'Var', (33, 38))
426276	31519770	In FK506-treated EC109 cells, the calcineurin activity was significantly lower (Figure 4G).	('calcineurin activity', 'MPA', (34, 54))	('FK506', 'Chemical', 'MESH:D016559', (3, 8))	('lower', 'NegReg', (73, 78))	('FK506-treated', 'Var', (3, 16))	('EC109', 'CellLine', 'CVCL:6898', (17, 22))
426278	31519770	The expression of NFATc3 was down-regulated by FK506, accompanied by the reduced expression of PD-L1 (Figure 4H).	('FK506', 'Var', (47, 52))	('NFATc3', 'Gene', '4775', (18, 24))	('reduced', 'NegReg', (73, 80))	('FK506', 'Chemical', 'MESH:D016559', (47, 52))	('expression', 'MPA', (4, 14))	('NFATc3', 'Gene', (18, 24))	('PD-L1', 'Gene', (95, 100))	('down-regulated', 'NegReg', (29, 43))	('PD-L1', 'Gene', '29126', (95, 100))	('expression', 'MPA', (81, 91))
426280	31519770	In addition, FK506 displayed the similar effect as PD-L1 neutralizing antibody did in the cell viability of EC109 cells with TRPM8 overexpression (Figure 5B).	('TRPM8', 'Gene', (125, 130))	('EC109', 'CellLine', 'CVCL:6898', (108, 113))	('PD-L1', 'Gene', '29126', (51, 56))	('cell viability', 'CPA', (90, 104))	('FK506', 'Var', (13, 18))	('FK506', 'Chemical', 'MESH:D016559', (13, 18))	('overexpression', 'PosReg', (131, 145))	('TRPM8', 'Gene', '79054', (125, 130))	('PD-L1', 'Gene', (51, 56))
426283	31519770	The results showed that both calcineurin B overexpression and NFATc3 overexpression could increase cell viability of the co-incubation system, and RQ-00203078 could partially counteract the protective role of calcineurin B overexpression and NFATc3 overexpression in the co-incubation system (Figure 5E,F).	('NFATc3', 'Gene', (62, 68))	('increase', 'PosReg', (90, 98))	('calcineurin B', 'Gene', '5534', (29, 42))	('overexpression', 'PosReg', (43, 57))	('calcineurin B', 'Gene', (29, 42))	('NFATc3', 'Gene', '4775', (242, 248))	('calcineurin B', 'Gene', '5534', (209, 222))	('RQ-00203078', 'Var', (147, 158))	('RQ-00203078', 'Chemical', 'MESH:C043461', (147, 158))	('NFATc3', 'Gene', (242, 248))	('cell viability', 'CPA', (99, 113))	('NFATc3', 'Gene', '4775', (62, 68))	('calcineurin B', 'Gene', (209, 222))
426296	31519770	Subsequent study confirms that loss of TRPM1 predicts the poor prognosis of patients with melanoma.	('melanoma', 'Disease', (90, 98))	('patients', 'Species', '9606', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('TRPM1', 'Gene', (39, 44))	('loss', 'Var', (31, 35))	('TRPM1', 'Gene', '4308', (39, 44))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
426302	31519770	revealed that the expression of TRPM8 was higher in oral squamous carcinoma cells, and TRPM8 antagonist RQ-00203078 deceased intracellular calcium concentration and limited migration ability and invasion ability of oral squamous carcinoma cells.	('antagonist', 'Var', (93, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (220, 238))	('limited', 'NegReg', (165, 172))	('squamous carcinoma', 'Disease', (57, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('calcium', 'Chemical', 'MESH:D002118', (139, 146))	('squamous carcinoma', 'Disease', 'MESH:D002294', (220, 238))	('expression', 'MPA', (18, 28))	('RQ-00203078', 'Chemical', 'MESH:C043461', (104, 115))	('TRPM8', 'Gene', '79054', (87, 92))	('TRPM8', 'Gene', (87, 92))	('TRPM8', 'Gene', '79054', (32, 37))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (57, 75))	('TRPM8', 'Gene', (32, 37))	('higher', 'PosReg', (42, 48))	('squamous carcinoma', 'Disease', 'MESH:D002294', (57, 75))	('intracellular calcium concentration', 'MPA', (125, 160))	('migration ability', 'CPA', (173, 190))	('invasion ability', 'CPA', (195, 211))	('squamous carcinoma', 'Disease', (220, 238))	('deceased', 'NegReg', (116, 124))
426305	31519770	demonstrated that TRPM8 agonist menthol-boosted calcium influx in melanoma cells, and led to the decreased cell viability.	('TRPM8', 'Gene', (18, 23))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('calcium', 'Chemical', 'MESH:D002118', (48, 55))	('melanoma', 'Disease', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('menthol-boosted', 'PosReg', (32, 47))	('cell viability', 'CPA', (107, 121))	('agonist', 'Var', (24, 31))	('calcium influx', 'MPA', (48, 62))	('decreased', 'NegReg', (97, 106))	('menthol', 'Chemical', 'MESH:D008610', (32, 39))	('TRPM8', 'Gene', '79054', (18, 23))
426308	31519770	We found that TRPM8 inhibition by siRNA transfection and RQ-00203078 treatment impaired the calcineurin activity.	('RQ-00203078', 'Var', (57, 68))	('calcineurin activity', 'MPA', (92, 112))	('RQ-00203078', 'Chemical', 'MESH:C043461', (57, 68))	('inhibition', 'NegReg', (20, 30))	('TRPM8', 'Gene', '79054', (14, 19))	('impaired', 'NegReg', (79, 87))	('TRPM8', 'Gene', (14, 19))
426312	31519770	It has been revealed that dysfunction of cytochrome c oxidase complex-mediated calcium-calcineurin activation is positively related to the progression of esophageal cancer, which displays the similar results as we did.	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('cytochrome c oxidase complex-mediated', 'Enzyme', (41, 78))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('calcium', 'Chemical', 'MESH:D002118', (79, 86))	('dysfunction', 'Var', (26, 37))	('related', 'Reg', (124, 131))	('esophageal cancer', 'Disease', (154, 171))
426333	30763293	Compared with HEEPIC, the level of POU5F1B was upregulated in ECA109 (p<0.01), ECA9706 (p<0.01), KYSE410 (p<0.01), and KYSE510 (p=0.036).	('KYSE410', 'Var', (97, 104))	('ECA9706', 'Var', (79, 86))	('POU5F1B', 'Gene', (35, 42))	('KYSE510', 'Var', (119, 126))	('ECA109', 'Var', (62, 68))	('upregulated', 'PosReg', (47, 58))	('ECA9706', 'CellLine', 'CVCL:E307', (79, 86))	('POU5F1B', 'Gene', '5462', (35, 42))
426334	30763293	The silencing of POU5F1B played a role in inhibiting colony formation.	('POU5F1B', 'Gene', (17, 24))	('inhibiting', 'NegReg', (42, 52))	('colony formation', 'CPA', (53, 69))	('POU5F1B', 'Gene', '5462', (17, 24))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('silencing', 'Var', (4, 13))
426336	30763293	The rate was 21.00+-0.1 and 29.1+-0.1% (p<0.0072) in the si-NC group and si-POU5F1B group, respectively.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('POU5F1B', 'Gene', '5462', (76, 83))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('POU5F1B', 'Gene', (76, 83))	('si-NC', 'Var', (57, 62))
426338	30763293	Radiotherapy contributed to the decline in the expression level of POU5F1B in plasma, which was upregulated in ECA109, ECA9706, KYSE410, and KYSE510, but not in HEEPIC.	('POU5F1B', 'Gene', '5462', (67, 74))	('ECA9706', 'CellLine', 'CVCL:E307', (119, 126))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('ECA109', 'Var', (111, 117))	('decline', 'NegReg', (32, 39))	('KYSE510', 'Var', (141, 148))	('ECA9706', 'Var', (119, 126))	('upregulated', 'PosReg', (96, 107))	('POU5F1B', 'Gene', (67, 74))	('expression level', 'MPA', (47, 63))	('KYSE410', 'Var', (128, 135))
426339	30763293	The knockdown of POU5F1B increased the radiosensitivity of esophageal cancer cell lines.	('POU5F1B', 'Gene', (17, 24))	('esophageal cancer', 'Disease', (59, 76))	('increased', 'PosReg', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('POU5F1B', 'Gene', '5462', (17, 24))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('increased the radiosensitivity of esophageal cancer', 'Phenotype', 'HP:0010997', (25, 76))	('knockdown', 'Var', (4, 13))	('radiosensitivity of', 'CPA', (39, 58))
426393	30763293	Knocking down MEG3 plays a role in promoting the expression of angiogenesis-relevant genes.	('MEG3', 'Gene', '55384', (14, 18))	('Knocking down', 'Var', (0, 13))	('promoting', 'PosReg', (35, 44))	('expression', 'MPA', (49, 59))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('angiogenesis-relevant genes', 'Gene', (63, 90))	('MEG3', 'Gene', (14, 18))	('si', 'Chemical', 'MESH:D012825', (55, 57))
426394	30763293	Silencing H19 in gynecologic malignant cancers helps to enhance the ability of cells to take up glucose.	('H19', 'Gene', '283120', (10, 13))	('malignant cancers', 'Disease', (29, 46))	('H19', 'Gene', (10, 13))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('malignant cancers', 'Disease', 'MESH:D009369', (29, 46))	('enhance', 'PosReg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('glucose', 'Chemical', 'MESH:D005947', (96, 103))	('Silencing', 'Var', (0, 9))
426399	30763293	In prostate cancer, inhibition of lncRNAROR expression can lead to increased expression of mir-145, thus reducing the expression of OCT4 and inhibiting cell proliferation.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('lncRNAROR expression', 'Protein', (34, 54))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('prostate cancer', 'Disease', (3, 18))	('OCT4', 'Gene', '5460', (132, 136))	('increased', 'PosReg', (67, 76))	('cell proliferation', 'CPA', (152, 170))	('OCT4', 'Gene', (132, 136))	('mir-145', 'Gene', (91, 98))	('expression', 'MPA', (118, 128))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('expression', 'MPA', (77, 87))	('inhibition', 'Var', (20, 30))	('mir-145', 'Gene', '406937', (91, 98))	('inhibiting', 'NegReg', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('reducing', 'NegReg', (105, 113))	('si', 'Chemical', 'MESH:D012825', (83, 85))
426403	30763293	In esophageal cancer, the expression of lncRNA LOC285194 is related to the radiochemotherapy resistance and prognosis of esophageal cancer patients.	('patients', 'Species', '9606', (139, 147))	('related', 'Reg', (60, 67))	('esophageal cancer', 'Disease', (3, 20))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('esophageal cancer', 'Disease', (121, 138))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('lncRNA LOC285194', 'Var', (40, 56))
426406	30763293	Our results demonstrated that radiotherapy downregulated the expression of POU5F1B in plasma, and the knockdown of POU5F1B enhanced radiosensitivity, partly through inhibiting proliferation and inducing apoptosis.	('enhanced', 'PosReg', (123, 131))	('downregulated', 'NegReg', (43, 56))	('POU5F1B', 'Gene', '5462', (115, 122))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('POU5F1B', 'Gene', '5462', (75, 82))	('knockdown', 'Var', (102, 111))	('radiosensitivity', 'CPA', (132, 148))	('apoptosis', 'CPA', (203, 212))	('proliferation', 'CPA', (176, 189))	('inhibiting', 'NegReg', (165, 175))	('POU5F1B', 'Gene', (75, 82))	('POU5F1B', 'Gene', (115, 122))	('si', 'Chemical', 'MESH:D012825', (209, 211))	('inducing', 'NegReg', (194, 202))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('expression', 'MPA', (61, 71))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (123, 148))
426453	30342494	In order to be eligible to participate in this study, a patient must be scheduled to receive nCRT for a potentially resectable, locally advanced (cT1b-4aN0-3 M0) esophageal or gastroesophageal junction tumor, either squamous cell carcinoma or adenocarcinoma.	('cT1b-4aN0-3', 'Var', (146, 157))	('esophageal', 'Disease', 'MESH:D004941', (162, 172))	('esophageal', 'Disease', (182, 192))	('esophageal', 'Disease', (162, 172))	('gastroesophageal junction tumor', 'Disease', 'MESH:D008309', (176, 207))	('gastroesophageal junction tumor', 'Disease', (176, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('squamous cell carcinoma or adenocarcinoma', 'Disease', (216, 257))	('esophageal', 'Disease', 'MESH:D004941', (182, 192))	('patient', 'Species', '9606', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('squamous cell carcinoma or adenocarcinoma', 'Disease', 'MESH:D002294', (216, 257))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (216, 239))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
426532	29699062	Early identification of poor responders may prompt consideration of other treatment modalities including TIPS, balloon-occluded retrograde transvenous obliteration (BRTO), splenectomy and devascularization, or partial splenic embolization (PSE).	('splenic embolization', 'Disease', 'MESH:D013158', (218, 238))	('splenic embolization', 'Phenotype', 'HP:0012223', (218, 238))	('splenic embolization', 'Disease', (218, 238))	('partial', 'Var', (210, 217))
426599	29270023	Deletion and downregulation of MTAP contribute to the motility of esophageal squamous carcinoma cells Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, with a low 5-year overall survival rate.	('Esophageal squamous cell carcinoma', 'Disease', (102, 136))	('MTAP', 'Gene', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('malignancies', 'Disease', (169, 181))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (66, 95))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (77, 95))	('MTAP', 'Gene', '4507', (31, 35))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (66, 95))	('downregulation', 'NegReg', (13, 27))	('esophageal squamous carcinoma', 'Disease', (66, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('malignancies', 'Disease', 'MESH:D009369', (169, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('Deletion', 'Var', (0, 8))
426603	29270023	Further statistical analysis showed a positive correlation between deletion and decreased mRNA expression of MTAP in the ESCC tissues tested (coefficient: 0.826; P=1.17x10-23).	('MTAP', 'Gene', (109, 113))	('deletion', 'Var', (67, 75))	('decreased', 'NegReg', (80, 89))	('MTAP', 'Gene', '4507', (109, 113))	('mRNA expression', 'MPA', (90, 105))
426606	29270023	At the molecular level, MTAP knockdown downregulated E-cadherin and p-GSK3beta but upregulated Slug expression.	('GSK3beta', 'Gene', (70, 78))	('MTAP', 'Gene', '4507', (24, 28))	('knockdown', 'Var', (29, 38))	('Slug', 'Gene', (95, 99))	('E-cadherin', 'Gene', (53, 63))	('E-cadherin', 'Gene', '999', (53, 63))	('GSK3beta', 'Gene', '2932', (70, 78))	('upregulated', 'PosReg', (83, 94))	('MTAP', 'Gene', (24, 28))	('Slug', 'Gene', '6591', (95, 99))	('downregulated', 'NegReg', (39, 52))
426607	29270023	Our results indicated that MTAP deletion results in the decreased expression in ESCCs and that it plays a role in promoting the mobility and inducing the epithelial-to-mesenchymal transition of ESCC cells via the GSK3beta/Slug/E-cadherin axis.	('GSK3beta', 'Gene', '2932', (213, 221))	('deletion', 'Var', (32, 40))	('MTAP', 'Gene', '4507', (27, 31))	('Slug', 'Gene', (222, 226))	('mobility', 'CPA', (128, 136))	('ESCCs', 'Protein', (80, 85))	('decreased', 'NegReg', (56, 65))	('expression', 'MPA', (66, 76))	('epithelial-to-mesenchymal transition', 'CPA', (154, 190))	('promoting', 'PosReg', (114, 123))	('inducing', 'Reg', (141, 149))	('GSK3beta', 'Gene', (213, 221))	('E-cadherin', 'Gene', '999', (227, 237))	('E-cadherin', 'Gene', (227, 237))	('MTAP', 'Gene', (27, 31))	('Slug', 'Gene', '6591', (222, 226))
426613	29270023	Identification and investigation of genetic deletions might not only help reveal the mechanisms that underlie the tumorigenesis and development of ESCC but also provide potential biomarkers for the detection and therapy of the disease.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('deletions', 'Var', (44, 53))	('tumor', 'Disease', (114, 119))	('ESCC', 'Disease', (147, 151))
426620	29270023	The human ESCC cell lines KYSE30, KYSE150, KYSE180, KYSE410, KYSE450, and KYSE510 were generously provided by Dr Y Shimada (Kyoto University, Kyoto, Japan).	('KYSE450', 'Var', (61, 68))	('human', 'Species', '9606', (4, 9))	('KYSE180', 'Var', (43, 50))	('KYSE410', 'Var', (52, 59))	('KYSE150', 'Var', (34, 41))
426641	29270023	Mann-Whitney test or Kruskal-Wallis test was performed for the evaluation of the association between MTAP deletion and clinicopathological parameters.	('deletion', 'Var', (106, 114))	('MTAP', 'Gene', '4507', (101, 105))	('MTAP', 'Gene', (101, 105))
426642	29270023	The correlation between MTAP deletion and mRNA downregulation was analyzed using Spearman's relative analysis.	('deletion', 'Var', (29, 37))	('MTAP', 'Gene', '4507', (24, 28))	('downregulation', 'NegReg', (47, 61))	('MTAP', 'Gene', (24, 28))	('mRNA', 'MPA', (42, 46))
426645	29270023	We then analyzed the relationship between MTAP deletion and the clinicopathological parameters (Table 2).	('deletion', 'Var', (47, 55))	('MTAP', 'Gene', (42, 46))	('MTAP', 'Gene', '4507', (42, 46))
426647	29270023	To determine whether the genomic deletion of MTAP results in the downregulation of its expression, we analyzed the relationship between the copy number and mRNA expression of MTAP in 90 ESCC cases using the online data in which both copy number alterations and mRNA expression were detected in each case.	('deletion', 'Var', (33, 41))	('expression', 'MPA', (87, 97))	('downregulation', 'NegReg', (65, 79))	('MTAP', 'Gene', (175, 179))	('MTAP', 'Gene', (45, 49))	('MTAP', 'Gene', '4507', (175, 179))	('ESCC', 'Disease', (186, 190))	('MTAP', 'Gene', '4507', (45, 49))
426649	29270023	Reduced MTAP mRNA expression was present in 90.9% (20/22) of the cases with deletions compared with 5.9% (4/68) of the cases without deletions (Figure 2A).	('deletions', 'Var', (76, 85))	('Reduced', 'NegReg', (0, 7))	('MTAP', 'Gene', (8, 12))	('MTAP', 'Gene', '4507', (8, 12))
426651	29270023	Further statistical analysis showed a positive correlation between deletion and decreased mRNA expression of MTAP in the ESCC tissues tested (coefficient: 0.826; P=1.17x10-23; Table 3).	('MTAP', 'Gene', (109, 113))	('deletion', 'Var', (67, 75))	('decreased', 'NegReg', (80, 89))	('MTAP', 'Gene', '4507', (109, 113))	('mRNA expression', 'MPA', (90, 105))
426654	29270023	The levels of MTAP protein are relatively higher in KYSE30, KYSE150, KYSE410, and KYSE450 than those in KYSE180, KYSE510, and EC109 (Figure 3A).	('levels', 'MPA', (4, 10))	('MTAP', 'Gene', '4507', (14, 18))	('MTAP', 'Gene', (14, 18))	('higher', 'PosReg', (42, 48))	('KYSE150', 'Var', (60, 67))	('KYSE30', 'Var', (52, 58))	('EC109', 'CellLine', 'CVCL:6898', (126, 131))	('KYSE410', 'Var', (69, 76))	('KYSE450', 'Var', (82, 89))
426656	29270023	The transwell assays showed that knockdown of MTAP enhanced the invasion and migration of KYSE150 and KYSE450 cells (Figure 3B), and that overexpression of MTAP decreased the invasion and migration in KYSE510 cells (Figure 3C).	('MTAP', 'Gene', (46, 50))	('decreased', 'NegReg', (161, 170))	('MTAP', 'Gene', (156, 160))	('knockdown', 'Var', (33, 42))	('invasion', 'CPA', (64, 72))	('MTAP', 'Gene', '4507', (46, 50))	('enhanced', 'PosReg', (51, 59))	('MTAP', 'Gene', '4507', (156, 160))
426658	29270023	After MTAP knockdown, both E-cadherin and p-GSK3beta were downregulated, whereas Slug was upregulated in the KYSE150 cells (Figure 4).	('Slug', 'Gene', (81, 85))	('Slug', 'Gene', '6591', (81, 85))	('GSK3beta', 'Gene', (44, 52))	('downregulated', 'NegReg', (58, 71))	('MTAP', 'Gene', (6, 10))	('GSK3beta', 'Gene', '2932', (44, 52))	('upregulated', 'PosReg', (90, 101))	('E-cadherin', 'Gene', (27, 37))	('E-cadherin', 'Gene', '999', (27, 37))	('knockdown', 'Var', (11, 20))	('MTAP', 'Gene', '4507', (6, 10))
426659	29270023	Genomic deletion is one of the major processes that causes tumorigenesis and the development of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('Genomic deletion', 'Var', (0, 16))	('human', 'Species', '9606', (96, 101))	('causes', 'Reg', (52, 58))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
426660	29270023	The common deletion peaks are at CDKN2A/B genes, inactivation of which are associated with tumorigenesis and cancer development.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('CDKN2A/B', 'Gene', '1029;1030', (33, 41))	('inactivation', 'Var', (49, 61))	('cancer', 'Disease', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CDKN2A/B', 'Gene', (33, 41))	('deletion', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('associated', 'Reg', (75, 85))	('tumor', 'Disease', (91, 96))
426662	29270023	By analyzing the copy number alterations using high-throughput array-based genomic data from several studies, we found that MTAP deletion occurred in 19.1% of ESCCs.	('MTAP', 'Gene', '4507', (124, 128))	('deletion', 'Var', (129, 137))	('ESCCs', 'Disease', (159, 164))	('occurred', 'Reg', (138, 146))	('MTAP', 'Gene', (124, 128))
426663	29270023	No significant correlation was observed between MTAP deletion and gender, pT, LNM, and grade, except for age.	('deletion', 'Var', (53, 61))	('MTAP', 'Gene', (48, 52))	('MTAP', 'Gene', '4507', (48, 52))
426665	29270023	The correlation between MTAP deletion and loss of expression has been found in multiple types of cancers, including gastrointestinal stromal tumors, laryngeal squamous cell carcinoma, and glioblastoma multiforme.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('loss of', 'NegReg', (42, 49))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('expression', 'MPA', (50, 60))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('glioblastoma multiforme', 'Disease', (188, 211))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('laryngeal squamous cell carcinoma', 'Disease', (149, 182))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (188, 211))	('MTAP', 'Gene', (24, 28))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (116, 147))	('deletion', 'Var', (29, 37))	('MTAP', 'Gene', '4507', (24, 28))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (116, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (149, 182))	('gastrointestinal stromal tumors', 'Disease', (116, 147))
426666	29270023	In the present study, we established a significantly positive correlation between copy number and mRNA level of MTAP in ESCC.	('positive', 'PosReg', (53, 61))	('ESCC', 'Disease', (120, 124))	('copy number', 'Var', (82, 93))	('MTAP', 'Gene', (112, 116))	('mRNA level', 'MPA', (98, 108))	('MTAP', 'Gene', '4507', (112, 116))
426668	29270023	It has been observed that deletion and loss of MTAP expression are associated with poor outcomes for several human cancers, and MTAP inactivation contributes to cell proliferation and invasion of cancer cells.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('deletion', 'Var', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('contributes', 'Reg', (146, 157))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('MTAP', 'Gene', (128, 132))	('MTAP', 'Gene', '4507', (128, 132))	('cell proliferation', 'CPA', (161, 179))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('MTAP', 'Gene', (47, 51))	('cancer', 'Disease', (196, 202))	('MTAP', 'Gene', '4507', (47, 51))	('inactivation', 'NegReg', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('expression', 'MPA', (52, 62))	('loss', 'NegReg', (39, 43))
426670	29270023	In this study, our data indicate that the loss of MTAP expression enhanced the invasion and migration of ESCC cells, and overexpression of MTAP decreased the cell invasion and migration, which suggested that MTAP expression might play a role in the inhibition of cell motility.	('loss', 'Var', (42, 46))	('decreased', 'NegReg', (144, 153))	('MTAP', 'Gene', (50, 54))	('MTAP', 'Gene', (139, 143))	('MTAP', 'Gene', (208, 212))	('enhanced', 'PosReg', (66, 74))	('MTAP', 'Gene', '4507', (139, 143))	('MTAP', 'Gene', '4507', (50, 54))	('MTAP', 'Gene', '4507', (208, 212))	('invasion', 'CPA', (79, 87))
426672	29270023	Our data showed that MTAP knockdown in ESCC cells led to a downregulation of E-cadherin expression, which has been well established as a hallmark of the EMT process in human cancers.	('MTAP', 'Gene', '4507', (21, 25))	('human', 'Species', '9606', (168, 173))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('downregulation', 'NegReg', (59, 73))	('knockdown', 'Var', (26, 35))	('MTAP', 'Gene', (21, 25))	('expression', 'MPA', (88, 98))
426674	29270023	It has been reported that Slug expression is stabilized by the inactivation of GSK3beta in epithelial cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Slug', 'Gene', '6591', (26, 30))	('GSK3beta', 'Gene', '2932', (79, 87))	('Slug', 'Gene', (26, 30))	('inactivation', 'Var', (63, 75))	('epithelial cancers', 'Disease', (91, 109))	('expression', 'MPA', (31, 41))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('epithelial cancers', 'Disease', 'MESH:D000077216', (91, 109))	('GSK3beta', 'Gene', (79, 87))	('stabilized', 'Reg', (45, 55))
426675	29270023	In this study, we also detected the decreased phosphorylation of GSK3beta at Ser9 after knockdown of MTAP.	('MTAP', 'Gene', (101, 105))	('GSK3beta', 'Gene', '2932', (65, 73))	('Ser9', 'Chemical', '-', (77, 81))	('MTAP', 'Gene', '4507', (101, 105))	('knockdown', 'Var', (88, 97))	('phosphorylation', 'MPA', (46, 61))	('GSK3beta', 'Gene', (65, 73))	('decreased', 'NegReg', (36, 45))
426677	29270023	Further investigation should be performed to determine whether deletion of MTAP plays a role in the tumorigenesis or progressions of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('ESCC', 'Disease', (133, 137))	('progressions', 'CPA', (117, 129))	('MTAP', 'Gene', (75, 79))	('deletion', 'Var', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('MTAP', 'Gene', '4507', (75, 79))
426678	29270023	In summary, our data show that frequent deletion and decreased expression of MTAP occur in primary ESCC tumors and that decreased expression of MTAP enhances the motility and EMT of ESCC cells through the GSK3beta/Slug/E-cadherin axis.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('deletion', 'Var', (40, 48))	('GSK3beta', 'Gene', '2932', (205, 213))	('E-cadherin', 'Gene', (219, 229))	('E-cadherin', 'Gene', '999', (219, 229))	('Slug', 'Gene', (214, 218))	('decreased', 'NegReg', (120, 129))	('expression', 'Var', (130, 140))	('MTAP', 'Gene', (144, 148))	('MTAP', 'Gene', '4507', (144, 148))	('GSK3beta', 'Gene', (205, 213))	('ESCC tumors', 'Disease', 'MESH:D004938', (99, 110))	('EMT of', 'CPA', (175, 181))	('expression', 'MPA', (63, 73))	('Slug', 'Gene', '6591', (214, 218))	('decreased', 'NegReg', (53, 62))	('enhances', 'PosReg', (149, 157))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('MTAP', 'Gene', (77, 81))	('motility', 'CPA', (162, 170))	('ESCC', 'Disease', (182, 186))	('MTAP', 'Gene', '4507', (77, 81))	('ESCC tumors', 'Disease', (99, 110))
426692	27925455	In addition, the acute toxicities associated with CDDP and 5-Fu significantly increased and restricted the application of CCRT.	('5-Fu', 'Chemical', 'MESH:D005472', (59, 63))	('CDDP', 'Var', (50, 54))	('toxicities', 'Disease', 'MESH:D064420', (23, 33))	('CDDP', 'Chemical', '-', (50, 54))	('increased', 'PosReg', (78, 87))	('toxicities', 'Disease', (23, 33))	('CR', 'Chemical', 'MESH:D002857', (123, 125))
426704	27925455	Patients were regarded eligible according to the following criteria: (1) histological diagnosis of esophageal cancer; (2) clinical stages II to IV disease according to the International Union Against Cancer (UICC, 2002) TNM stage criteria; (3) Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1; (4) no evidence of severe organ dysfunction; (5) adequate bone marrow, renal, hepatic, cardiac, and respiratory function (hemoglobulin >=9 g/dL, white blood cell >=3000/muL, neutrophil >=1.5 x 109/L, platelet counts >=10 x 104/muL, serum creatinine < 1.5 mg/dL); and (6) no cancer treatments prior to enrollment.	('cancer', 'Disease', (574, 580))	('hepatic', 'CPA', (378, 385))	('muL', 'Gene', '4591', (527, 530))	('neutrophil', 'CPA', (474, 484))	('cancer', 'Phenotype', 'HP:0002664', (574, 580))	('organ dysfunction', 'Disease', 'MESH:D019965', (326, 343))	('IV disease', 'Disease', 'MESH:D020432', (144, 154))	('Cancer', 'Phenotype', 'HP:0002664', (200, 206))	('organ dysfunction', 'Disease', (326, 343))	('muL', 'Gene', '4591', (469, 472))	('creatinine', 'Chemical', 'MESH:D003404', (538, 548))	('white blood cell', 'CPA', (445, 461))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('hemoglobulin', 'Var', (422, 434))	('>=10', 'Var', (516, 520))	('Patients', 'Species', '9606', (0, 8))	('Cancer', 'Disease', (200, 206))	('renal', 'CPA', (371, 376))	('esophageal cancer', 'Disease', (99, 116))	('cancer', 'Disease', 'MESH:D009369', (574, 580))	('cancer', 'Disease', (110, 116))	('platelet counts', 'CPA', (500, 515))	('muL', 'Gene', (527, 530))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('respiratory function', 'CPA', (400, 420))	('Cancer', 'Disease', 'MESH:D009369', (200, 206))	('IV disease', 'Disease', (144, 154))	('men', 'Species', '9606', (586, 589))	('muL', 'Gene', (469, 472))	('Oncology', 'Phenotype', 'HP:0002664', (264, 272))	('>=1.5', 'Var', (485, 490))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('men', 'Species', '9606', (607, 610))
426783	27925455	Compared with CDDP-based chemotherapy plus 60 Gy radiotherapy, our recent systemic review and pooled analysis which enrolled 1915 patients from 26 clinical studies also showed that the most common acute toxicities of grade 3 or higher for CDDP-based CCRT were hematologic toxicities, the most severe grade 3 or higher radiation-related acute toxicity was esophagitis, and the pooled incidence of esophagitis was 12.8% which was in line with this cohort 17.	('CR', 'Chemical', 'MESH:D002857', (251, 253))	('toxicity', 'Disease', 'MESH:D064420', (342, 350))	('toxicities', 'Disease', 'MESH:D064420', (272, 282))	('CDDP', 'Chemical', '-', (239, 243))	('toxicities', 'Disease', (272, 282))	('toxicity', 'Disease', (342, 350))	('CDDP-based', 'Var', (239, 249))	('hematologic toxicities', 'Disease', 'MESH:D006402', (260, 282))	('esophagitis', 'Disease', (396, 407))	('esophagitis', 'Disease', 'MESH:D004941', (396, 407))	('CDDP', 'Chemical', '-', (14, 18))	('hematologic toxicities', 'Disease', (260, 282))	('esophagitis', 'Disease', (355, 366))	('patients', 'Species', '9606', (130, 138))	('esophagitis', 'Phenotype', 'HP:0100633', (396, 407))	('esophagitis', 'Disease', 'MESH:D004941', (355, 366))	('toxicities', 'Disease', 'MESH:D064420', (203, 213))	('esophagitis', 'Phenotype', 'HP:0100633', (355, 366))	('toxicities', 'Disease', (203, 213))
426800	27245877	After analyzing 1588 ESCC patients and frequency-matched 1600 unaffected controls, we found that MMP13 rs2252070 G > A genetic polymorphism is significantly associated with ESCC risk in Chinese Han populations (GA: OR = 0.63, 95% CI = 0.54-0.74, P = 1.7 x 10-6, AA: OR = 0.73, 95% CI = 0.66-0.81, P = 1.8 x 10-6).	('MMP13', 'Gene', '4322', (97, 102))	('MMP13', 'Gene', (97, 102))	('rs2252070', 'Mutation', 'rs2252070', (103, 112))	('associated', 'Reg', (157, 167))	('ESCC', 'Disease', (173, 177))	('patients', 'Species', '9606', (26, 34))	('rs2252070 G > A', 'Var', (103, 118))
426801	27245877	Interestingly, the rs2252070 G-to-A change was shown to diminish a Sp1-binding site in ESCC cells.	('Sp1-binding site', 'MPA', (67, 83))	('diminish', 'NegReg', (56, 64))	('rs2252070 G-to-A', 'Var', (19, 35))	('rs2252070', 'Mutation', 'rs2252070', (19, 28))
426802	27245877	Reporter gene assays indicated that the rs2252070 A allele locating in a potential MMP13 promoter has low promoter activities.	('MMP13', 'Gene', '4322', (83, 88))	('rs2252070 A', 'Var', (40, 51))	('rs2252070', 'Mutation', 'rs2252070', (40, 49))	('promoter activities', 'MPA', (106, 125))	('MMP13', 'Gene', (83, 88))
426803	27245877	After measuring MMP13 gene expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2252070 A protective allele carriers showed decreased oncogene MMP13 expression.	('decreased', 'NegReg', (165, 174))	('oncogene', 'MPA', (175, 183))	('MMP13', 'Gene', (184, 189))	('MMP13', 'Gene', (16, 21))	('MMP13', 'Gene', '4322', (184, 189))	('rs2252070 A', 'Var', (119, 130))	('MMP13', 'Gene', '4322', (16, 21))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('expression', 'MPA', (190, 200))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('rs2252070', 'Mutation', 'rs2252070', (119, 128))
426812	27245877	Deregulated MMP13 expression might impact prognosis of ESCC patients through tumor invasion, vascular permeation, and lymph node metastasis.	('Deregulated', 'Var', (0, 11))	('vascular permeation', 'CPA', (93, 112))	('lymph node metastasis', 'CPA', (118, 139))	('MMP13', 'Gene', '4322', (12, 17))	('patients', 'Species', '9606', (60, 68))	('MMP13', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('expression', 'MPA', (18, 28))	('ESCC', 'Disease', (55, 59))	('prognosis', 'CPA', (42, 51))	('tumor', 'Disease', (77, 82))	('impact', 'Reg', (35, 41))
426817	27245877	One of the most studied SNPs is the MMP13 rs2252070 polymorphism.	('rs2252070', 'Var', (42, 51))	('MMP13', 'Gene', (36, 41))	('rs2252070', 'Mutation', 'rs2252070', (42, 51))	('MMP13', 'Gene', '4322', (36, 41))
426818	27245877	In HepG2 cells, the MMP13 promoter with the rs2252070 A allele had approximately twice as much transcriptional activity as that with the G allele in the same position (P = 0.0037).	('rs2252070 A', 'Var', (44, 55))	('MMP13', 'Gene', (20, 25))	('rs2252070', 'Mutation', 'rs2252070', (44, 53))	('HepG2', 'CellLine', 'CVCL:0027', (3, 8))	('MMP13', 'Gene', '4322', (20, 25))	('transcriptional activity', 'MPA', (95, 119))
426821	27245877	However, the details on how this genetic variant impacts MMP13 expression is still largely unknown.	('MMP13', 'Gene', (57, 62))	('expression', 'MPA', (63, 73))	('MMP13', 'Gene', '4322', (57, 62))	('impacts', 'Reg', (49, 56))	('variant', 'Var', (41, 48))
426823	27245877	In addition, to the best of our knowledge, we firstly examined the fine-regulation of MMP13 expression by rs2252070-mediaed allelic binding of Sp1 and its involvement in ESCC.	('MMP13', 'Gene', '4322', (86, 91))	('rs2252070-mediaed', 'Var', (106, 123))	('binding', 'Interaction', (132, 139))	('rs2252070', 'Mutation', 'rs2252070', (106, 115))	('MMP13', 'Gene', (86, 91))	('expression', 'MPA', (92, 102))	('ESCC', 'Disease', (170, 174))
426824	27245877	To validate the biological function of MMP13 rs2252070 genetic variant in vivo, we detected the association between its genotypes and MMP13 mRNA expression levels in normal and cancerous esophagus tissues.	('rs2252070', 'Mutation', 'rs2252070', (45, 54))	('rs2252070', 'Var', (45, 54))	('MMP13', 'Gene', (39, 44))	('mRNA expression levels', 'MPA', (140, 162))	('cancerous esophagus', 'Disease', (177, 196))	('MMP13', 'Gene', (134, 139))	('association', 'Interaction', (96, 107))	('MMP13', 'Gene', '4322', (39, 44))	('MMP13', 'Gene', '4322', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancerous esophagus', 'Phenotype', 'HP:0100751', (177, 196))	('cancerous esophagus', 'Disease', 'MESH:D004938', (177, 196))
426827	27245877	There are multiple SNPs in MMP13 covering a ~13 kb region of chromosome 11q22.3.	('MMP13', 'Gene', '4322', (27, 32))	('SNPs', 'Var', (19, 23))	('MMP13', 'Gene', (27, 32))
426830	27245877	MMP13 htSNPs (rs11225490, rs2252070, rs17099788 and rs3758854) were analyzed by the MassArray system (Sequenom Inc., San Diego, California, USA).	('rs11225490', 'Mutation', 'rs11225490', (14, 24))	('rs11225490', 'Var', (14, 24))	('rs17099788', 'Mutation', 'rs17099788', (37, 47))	('MMP13', 'Gene', (0, 5))	('rs2252070', 'Mutation', 'rs2252070', (26, 35))	('rs3758854', 'Mutation', 'rs3758854', (52, 61))	('rs2252070', 'Var', (26, 35))	('MMP13', 'Gene', '4322', (0, 5))	('rs3758854', 'Var', (52, 61))	('rs17099788', 'Var', (37, 47))
426831	27245877	Synthetic double-stranded and 3' biotin-labeled oligonucleotides corresponding to the Sp1 consensus binding sequence, MMP13 rs2252070G or rs2252070A sequences (Supplementary Table 3) and pure recombinant Sp1 protein (E639A, Promega) were incubated at 25  C for 20 min using the Light Shift Chemiluminescent EMSA Kit (Pierce, Rockford, IL).	('rs2252070', 'Mutation', 'rs2252070', (138, 147))	('MMP13', 'Gene', (118, 123))	('rs2252070', 'Mutation', 'rs2252070', (124, 133))	('oligonucleotide', 'Chemical', 'MESH:D009841', (48, 63))	('MMP13', 'Gene', '4322', (118, 123))	('rs2252070A', 'Var', (138, 148))	('rs2252070G', 'Var', (124, 134))	('biotin', 'Chemical', 'MESH:D001710', (33, 39))	('E639A', 'Mutation', 'p.E639A', (217, 222))
426834	27245877	Specific primer pairs (Supplementary Table 4) with XhoI and KpnI restriction sites were used to amplify multiple deletion fragments spanning 5'-region of MMP13 (from -186 bp to -41 bp, relative to the transcription start site) from human genomic DNA carrying MMP13 rs2252070GG or rs2252070AA genotype.	('MMP13', 'Gene', (259, 264))	('rs2252070', 'Mutation', 'rs2252070', (265, 274))	('MMP13', 'Gene', '4322', (259, 264))	('rs2252070', 'Mutation', 'rs2252070', (280, 289))	('rs2252070GG', 'Var', (265, 276))	('MMP13', 'Gene', (154, 159))	('rs2252070AA', 'Var', (280, 291))	('human', 'Species', '9606', (232, 237))	('MMP13', 'Gene', '4322', (154, 159))
426846	27245877	The genotype frequencies of MMP13 candidate SNPs (rs11225490 T > C, rs2252070 G > A, rs17099788 A > G and rs3758854 G > A) are summarized in Table 1.	('rs2252070 G > A', 'Var', (68, 83))	('rs3758854', 'Mutation', 'rs3758854', (106, 115))	('rs11225490', 'Mutation', 'rs11225490', (50, 60))	('rs11225490 T > C', 'Var', (50, 66))	('rs17099788 A > G', 'Var', (85, 101))	('rs3758854 G > A', 'Var', (106, 121))	('rs17099788', 'Mutation', 'rs17099788', (85, 95))	('MMP13', 'Gene', (28, 33))	('rs2252070', 'Mutation', 'rs2252070', (68, 77))	('MMP13', 'Gene', '4322', (28, 33))
426848	27245877	Logistic regression analyses revealed that rs2252070 SNP was significantly associated with ESCC risk (allelic OR = 0.70, 95% CI = 0.60-0.83, P = 2.1 x 10-5) (Table 1).	('ESCC', 'Disease', (91, 95))	('associated', 'Reg', (75, 85))	('rs2252070 SNP', 'Var', (43, 56))	('rs2252070', 'Mutation', 'rs2252070', (43, 52))
426849	27245877	Associations between genotypes of MMP13 rs2252070 G > A SNP and ESCC risk were calculated using unconditional logistic regression analyses (Table 2).	('rs2252070 G > A', 'Var', (40, 55))	('ESCC', 'Disease', (64, 68))	('rs2252070', 'Mutation', 'rs2252070', (40, 49))	('MMP13', 'Gene', '4322', (34, 39))	('MMP13', 'Gene', (34, 39))
426850	27245877	The MMP13 rs2252070 A allele was found to be a protective allele.	('MMP13', 'Gene', '4322', (4, 9))	('MMP13', 'Gene', (4, 9))	('rs2252070', 'Mutation', 'rs2252070', (10, 19))	('rs2252070 A', 'Var', (10, 21))
426851	27245877	Individuals with the rs2252070 GA genotype had an OR of 0.65 (95% CI = 0.49-0.88, P = 0.004) for developing ESCC in Jiangsu Set, compared with individual having the rs2252070 GG genotype.	('rs2252070', 'Mutation', 'rs2252070', (165, 174))	('rs2252070', 'Mutation', 'rs2252070', (21, 30))	('rs2252070', 'Var', (21, 30))	('ESCC', 'Disease', (108, 112))
426852	27245877	Similarly, the rs2252070 AA genotypes had a significantly decreased risk for ESCC compared with the rs2252070 GG genotype (OR = 0.79, 95% CI = 0.65-0.95, P = 0.011).	('ESCC', 'Disease', (77, 81))	('rs2252070', 'Mutation', 'rs2252070', (100, 109))	('decreased', 'NegReg', (58, 67))	('rs2252070', 'Mutation', 'rs2252070', (15, 24))	('rs2252070 AA', 'Var', (15, 27))
426853	27245877	In Shandong Set, carriers of the rs2252070 GA or AA genotypes were significantly associated with decreased ESCC risk (OR = 0.65, 95% CI = 0.53-0.81, P = 8.8 x 10-5, or OR = 0.75, 95% CI = 0.65-0.86, P = 4.9 x 10-5) (Table 3).	('decreased ESCC', 'Phenotype', 'HP:0025022', (97, 111))	('rs2252070', 'Mutation', 'rs2252070', (33, 42))	('decreased', 'NegReg', (97, 106))	('rs2252070 GA', 'Var', (33, 45))	('ESCC', 'Disease', (107, 111))
426855	27245877	The risk of ESCC associated with the rs2252070 SNP was further investigated by stratifying for age, sex, smoking and alcohol drinking status using the combined data of two case-control sets (Table 3).	('ESCC', 'Disease', (12, 16))	('rs2252070', 'Var', (37, 46))	('rs2252070', 'Mutation', 'rs2252070', (37, 46))	('alcohol', 'Chemical', 'MESH:D000438', (117, 124))	('alcohol drinking', 'Phenotype', 'HP:0030955', (117, 133))
426856	27245877	The variant genotypes of MMP13 rs2252070 (GA or AA) were consistently associated with a significantly decreased risk of ESCC in all subgroups.	('MMP13', 'Gene', '4322', (25, 30))	('rs2252070', 'Mutation', 'rs2252070', (31, 40))	('rs2252070', 'Var', (31, 40))	('ESCC', 'Disease', (120, 124))	('MMP13', 'Gene', (25, 30))	('decreased', 'NegReg', (102, 111))
426857	27245877	Since rs2252070 SNP is located a potential Sp1 binding sequence of the MMP13 5'-region (Fig.	('Sp1', 'Protein', (43, 46))	('MMP13', 'Gene', (71, 76))	('MMP13', 'Gene', '4322', (71, 76))	('rs2252070 SNP', 'Var', (6, 19))	('rs2252070', 'Mutation', 'rs2252070', (6, 15))
426858	27245877	1A), we then conducted EMSA to distinguish the differences in binding capacity between the rs2252070G and A alleles to Sp1 (Fig.	('binding', 'Interaction', (62, 69))	('Sp1', 'Gene', (119, 122))	('rs2252070', 'Mutation', 'rs2252070', (91, 100))	('rs2252070G', 'Var', (91, 101))
426859	27245877	1B, we found that Sp1 protein bound only to the biotin-labeled oligonucleotide probe with the G allele but not the A allele probe.	('Sp1', 'Gene', (18, 21))	('biotin', 'Chemical', 'MESH:D001710', (48, 54))	('oligonucleotide', 'Chemical', 'MESH:D009841', (63, 78))	('G allele', 'Var', (94, 102))	('bound', 'Interaction', (30, 35))
426861	27245877	Because the rs2252070 SNP is located in the Sp1 binding sit of MMP13 promoter, we speculated that this polymorphism will influence gene expression of MMP13.	('rs2252070 SNP', 'Var', (12, 25))	('rs2252070', 'Mutation', 'rs2252070', (12, 21))	('MMP13', 'Gene', (150, 155))	('MMP13', 'Gene', (63, 68))	('MMP13', 'Gene', '4322', (150, 155))	('gene expression', 'MPA', (131, 146))	('influence', 'Reg', (121, 130))	('MMP13', 'Gene', '4322', (63, 68))
426863	27245877	Interestingly, the MMP13 rs2252070G allelic reporter construct (pMMP-G) showed significantly higher luciferase activities compared to the rs2252070A allelic reporter construct (pMMP-A) in KYSE30 cells (P < 0.01) (Fig.	('higher', 'PosReg', (93, 99))	('rs2252070', 'Mutation', 'rs2252070', (138, 147))	('rs2252070', 'Mutation', 'rs2252070', (25, 34))	('MMP13', 'Gene', (19, 24))	('activities', 'MPA', (111, 121))	('MMP13', 'Gene', '4322', (19, 24))	('pMMP-A', 'Chemical', '-', (177, 183))	('rs2252070G', 'Var', (25, 35))	('luciferase', 'Enzyme', (100, 110))	('pMMP-G', 'Chemical', '-', (64, 70))
426864	27245877	Moreover, KYSE150 cells transfected with pMMP-G showed significantly higher luciferase activities compared to cells expressing pMMP-A (P < 0.05) (Fig.	('KYSE150', 'CellLine', 'CVCL:1348', (10, 17))	('pMMP-G', 'Chemical', '-', (41, 47))	('activities', 'MPA', (87, 97))	('pMMP-G', 'Var', (41, 47))	('luciferase', 'Enzyme', (76, 86))	('higher', 'PosReg', (69, 75))	('pMMP-A', 'Chemical', '-', (127, 133))
426865	27245877	This indicates that Sp1 could bind the rs2252070G allelic MMP13 promoter and prompt increased MMP13 expression.	('MMP13', 'Gene', (94, 99))	('rs2252070G', 'Var', (39, 49))	('MMP13', 'Gene', '4322', (94, 99))	('expression', 'MPA', (100, 110))	('rs2252070', 'Mutation', 'rs2252070', (39, 48))	('increased', 'PosReg', (84, 93))	('MMP13', 'Gene', (58, 63))	('MMP13', 'Gene', '4322', (58, 63))	('bind', 'Interaction', (30, 34))
426866	27245877	Considering rs2252070 G-to-A change could impact MMP13 promoter activity in cancer cells, we investigated whether there is an allele-specific effect of rs2252070 SNP on MMP13 expression in esophagus tissue specimens (Fig.	('MMP13', 'Gene', (49, 54))	('rs2252070 G-to-A', 'Var', (12, 28))	('rs2252070 SNP', 'Var', (152, 165))	('MMP13', 'Gene', '4322', (169, 174))	('MMP13', 'Gene', (169, 174))	('rs2252070', 'Mutation', 'rs2252070', (152, 161))	('rs2252070', 'Mutation', 'rs2252070', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('impact', 'Reg', (42, 48))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('MMP13', 'Gene', '4322', (49, 54))
426867	27245877	We found that there were significantly lower MMP13 mRNA levels (mean +- SD) among carriers of the rs2252070 AA genotype compared to carriers of the GG genotype in ESCC tissues (0.014 +- 0.026 [n = 12] vs. 0.119 +- 0.074 [n = 24], P < 0.01) or normal esophagus tissues (0.024 +- 0.034 [n = 12] vs. 0.088 +- 0.050 [n = 24], P < 0.01).	('rs2252070 AA', 'Var', (98, 110))	('ESCC', 'Disease', (163, 167))	('MMP13', 'Gene', '4322', (45, 50))	('rs2252070', 'Mutation', 'rs2252070', (98, 107))	('lower', 'NegReg', (39, 44))	('MMP13', 'Gene', (45, 50))
426868	27245877	To further verify if Sp1 indeed promotes MMP13 expression, we knocked-down endogenous Sp1 with siRNAs and examine the expression of MMP13 in two ESCC cell lines.	('MMP13', 'Gene', '4322', (41, 46))	('MMP13', 'Gene', (132, 137))	('Sp1', 'Gene', (86, 89))	('MMP13', 'Gene', '4322', (132, 137))	('knocked-down', 'Var', (62, 74))	('MMP13', 'Gene', (41, 46))	('expression', 'MPA', (47, 57))
426869	27245877	Decreased MMP13 expression was observed after Sp1 silencing (Fig.	('Sp1', 'Var', (46, 49))	('Decreased', 'NegReg', (0, 9))	('MMP13', 'Gene', '4322', (10, 15))	('MMP13', 'Gene', (10, 15))	('expression', 'MPA', (16, 26))
426870	27245877	4), suggesting that Sp1 enhance endogenous MMP13 expression in ESCC cells.	('enhance', 'PosReg', (24, 31))	('MMP13', 'Gene', (43, 48))	('expression', 'MPA', (49, 59))	('MMP13', 'Gene', '4322', (43, 48))	('endogenous', 'MPA', (32, 42))	('Sp1', 'Var', (20, 23))
426871	27245877	In the current study, we systematically examined the impacts of SNPs in the MMP13 locus on ESCC susceptibility via a case-control design as well as gene expression of MMP13 in vitro and in vivo.	('MMP13', 'Gene', '4322', (76, 81))	('ESCC', 'Disease', (91, 95))	('SNPs', 'Var', (64, 68))	('MMP13', 'Gene', '4322', (167, 172))	('MMP13', 'Gene', (167, 172))	('MMP13', 'Gene', (76, 81))
426872	27245877	After genotyping 4 htSNPs at the discovery stage, we identified one ESCC susceptibility genetic polymorphism (rs2252070) which were validated in another case-control sets.	('ESCC', 'Disease', (68, 72))	('rs2252070', 'Var', (110, 119))	('rs2252070', 'Mutation', 'rs2252070', (110, 119))
426873	27245877	Reporter gene assays indicated that the ESCC susceptibility SNP rs2252070 a potential MMP13 promoter has a genotype-specific effect on MMP13 expression.	('MMP13', 'Gene', (135, 140))	('MMP13', 'Gene', '4322', (86, 91))	('MMP13', 'Gene', '4322', (135, 140))	('effect', 'Reg', (125, 131))	('expression', 'MPA', (141, 151))	('rs2252070', 'Mutation', 'rs2252070', (64, 73))	('rs2252070', 'Var', (64, 73))	('MMP13', 'Gene', (86, 91))
426879	27245877	Accumulated evidences demonstrated that the MMP13 rs2252070 polymorphism is a regulatory polymorphism in cells, but the detailed mechanisms are far from clear.	('MMP13', 'Gene', '4322', (44, 49))	('rs2252070', 'Mutation', 'rs2252070', (50, 59))	('rs2252070', 'Var', (50, 59))	('MMP13', 'Gene', (44, 49))
426880	27245877	Here, for the first time, we found that the rs2252070 G allele but not A allele could bind Sp1 and promote MMP13 expression in ESCC.	('expression', 'MPA', (113, 123))	('bind', 'Interaction', (86, 90))	('promote', 'PosReg', (99, 106))	('rs2252070 G', 'Var', (44, 55))	('rs2252070', 'Mutation', 'rs2252070', (44, 53))	('MMP13', 'Gene', (107, 112))	('Sp1', 'Protein', (91, 94))	('MMP13', 'Gene', '4322', (107, 112))
426881	27245877	This is consistent with our molecular epidemiology studies showing that MMP13 rs2252070 A allele is a protecting allele of ESCC in Chinese.	('MMP13', 'Gene', '4322', (72, 77))	('rs2252070 A', 'Var', (78, 89))	('ESCC', 'Disease', (123, 127))	('rs2252070', 'Mutation', 'rs2252070', (78, 87))	('MMP13', 'Gene', (72, 77))
426882	27245877	That is, subjects carrying the MMP13 rs2252070 A allele without Sp1 binding have less oncogene MMP13 expression; therefore, these carriers show decreased risk to develop ESCC.	('MMP13', 'Gene', '4322', (31, 36))	('decreased', 'NegReg', (144, 153))	('rs2252070 A', 'Var', (37, 48))	('MMP13', 'Gene', (95, 100))	('less', 'NegReg', (81, 85))	('rs2252070', 'Mutation', 'rs2252070', (37, 46))	('MMP13', 'Gene', '4322', (95, 100))	('expression', 'MPA', (101, 111))	('MMP13', 'Gene', (31, 36))	('ESCC', 'Disease', (170, 174))
426883	27245877	In all, we demonstrated that functional MMP13 rs2252070 SNP was associated with a significantly decreased risk of ESCC in Chinese Han populations.	('ESCC', 'Disease', (114, 118))	('rs2252070 SNP', 'Var', (46, 59))	('decreased', 'NegReg', (96, 105))	('MMP13', 'Gene', (40, 45))	('rs2252070', 'Mutation', 'rs2252070', (46, 55))	('MMP13', 'Gene', '4322', (40, 45))
426884	27245877	Functional analysis showed that the rs2252070A allele contributes to significantly decreased expression of MMP13 in vitro and in vivo in the target tissues, which is most likely due to a diminished Sp1 regulation.	('decreased', 'NegReg', (83, 92))	('expression', 'MPA', (93, 103))	('rs2252070A', 'Var', (36, 46))	('Sp1', 'MPA', (198, 201))	('rs2252070', 'Mutation', 'rs2252070', (36, 45))	('MMP13', 'Gene', (107, 112))	('diminished', 'NegReg', (187, 197))	('MMP13', 'Gene', '4322', (107, 112))
426886	27245877	The Sp1-mediaded allelic regulation of MMP13 expression by an ESCC susceptibility SNP rs2252070.	('rs2252070', 'Var', (86, 95))	('rs2252070', 'Mutation', 'rs2252070', (86, 95))	('MMP13', 'Gene', (39, 44))	('MMP13', 'Gene', '4322', (39, 44))	('expression', 'MPA', (45, 55))	('ESCC', 'Disease', (62, 66))
426959	20507631	The most noteworthy one, EBS-Dowling Meara (DM), is frequently associated with marked morbidity and, in a minority of patients, may result in death during early infancy.	('result in', 'Reg', (132, 141))	('EBS-Dowling Meara', 'Var', (25, 42))	('death', 'Disease', 'MESH:D003643', (142, 147))	('death', 'Disease', (142, 147))	('patients', 'Species', '9606', (118, 126))
427025	20507631	Of importance, spontaneous mutations for autosomal dominant disease are not uncommon in EBS but account for only the minority of cases of DEB lacking a known family history for the disease.	('mutations', 'Var', (27, 36))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (41, 67))	('autosomal dominant disease', 'Disease', (41, 67))
427026	20507631	Localized EBS, EBS-DM, and EBS generalized other (EBS-Koebner) result from dominant negative mutations within either the keratin 5 or keratin 14 gene.	('EBS', 'Disease', (10, 13))	('keratin 14', 'Gene', (134, 144))	('mutations', 'Var', (93, 102))	('keratin 14', 'Gene', '3861', (134, 144))	('keratin 5', 'Gene', '3852', (121, 130))	('keratin 5', 'Gene', (121, 130))	('EBS-Koebner', 'Disease', 'MESH:D016110', (50, 61))	('negative', 'NegReg', (84, 92))	('EBS-Koebner', 'Disease', (50, 61))	('EBS-DM', 'Disease', (15, 21))	('EBS-DM', 'Disease', 'MESH:D016110', (15, 21))
427027	20507631	The site of mutation -- i.e., the location within the individual keratin filament -- is strongly correlated with EBS subtype, with EBS-DM patients having mutations within particularly structurally sensitive portions of the molecule.	('correlated', 'Reg', (97, 107))	('EBS-DM', 'Disease', 'MESH:D016110', (131, 137))	('EBS', 'Disease', (113, 116))	('EBS-DM', 'Disease', (131, 137))	('mutations', 'Var', (154, 163))	('patients', 'Species', '9606', (138, 146))
427028	20507631	EBS with mottled pigmentation results from mutations within the keratin 5 gene, and EBS with muscular dystrophy is caused by mutations within the gene for plectin.	('mottled pigmentation', 'Phenotype', 'HP:0001070', (9, 29))	('mutations', 'Var', (125, 134))	('keratin 5', 'Gene', '3852', (64, 73))	('keratin 5', 'Gene', (64, 73))	('plectin', 'Gene', (155, 162))	('results from', 'Reg', (30, 42))	('mottled pigmentation', 'Disease', (9, 29))	('muscular dystrophy', 'Disease', 'MESH:D009136', (93, 111))	('mutations', 'Var', (43, 52))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (93, 111))	('plectin', 'Gene', '5339', (155, 162))	('muscular dystrophy', 'Disease', (93, 111))	('EBS', 'Disease', (0, 3))	('caused by', 'Reg', (115, 124))
427029	20507631	A rare autosomal recessive form of EBS is known to result from mutations in the keratin 14 gene.	('mutations', 'Var', (63, 72))	('EBS', 'Disease', (35, 38))	('autosomal recessive form', 'Disease', (7, 31))	('keratin 14', 'Gene', (80, 90))	('result from', 'Reg', (51, 62))	('keratin 14', 'Gene', '3861', (80, 90))
427030	20507631	EBS with pyloric atresia is caused by mutations either within the gene for plectin or the genes for the heterodimeric transmembrane protein, alpha6beta4 integrin.	('plectin', 'Gene', '5339', (75, 82))	('pyloric atresia', 'Phenotype', 'HP:0004399', (9, 24))	('pyloric atresia', 'Disease', (9, 24))	('plectin', 'Gene', (75, 82))	('pyloric atresia', 'Disease', 'MESH:C562561', (9, 24))	('caused by', 'Reg', (28, 37))	('mutations', 'Var', (38, 47))
427031	20507631	Two suprabasal subtypes of EBS -- plakophilin deficiency and lethal acantholytic EB -- are known to arise as the result of mutations in the genes for plakophilin-1 and desmoplakin, respectively.	('EBS -- plakophilin deficiency', 'Disease', 'MESH:D016110', (27, 56))	('result', 'Reg', (113, 119))	('EBS -- plakophilin deficiency', 'Disease', (27, 56))	('plakophilin-1', 'Gene', '5317', (150, 163))	('mutations', 'Var', (123, 132))	('plakophilin-1', 'Gene', (150, 163))
427032	20507631	The presence of mutational hotspots with this disease facilitates rapid DNA screening in many patients.	('facilitates', 'PosReg', (54, 65))	('mutational', 'Var', (16, 26))	('patients', 'Species', '9606', (94, 102))	('rapid DNA screening', 'MPA', (66, 85))
427033	20507631	The majority of JEB-nH patients have less severe mutations within the same targeted genes, although a minority have mutations instead within the gene encoding for type XVII collagen (formerly known as bullous pemphigoid antigen 2 or BP-180).	('JEB-nH', 'Disease', (16, 22))	('patients', 'Species', '9606', (23, 31))	('BP-180', 'Gene', '1308', (233, 239))	('mutations', 'Var', (116, 125))	('BP-180', 'Gene', (233, 239))
427034	20507631	JEB with pyloric atresia is caused by mutations in either of the genes encoding for the two subunits of alpha6beta4 integrin.	('pyloric atresia', 'Phenotype', 'HP:0004399', (9, 24))	('pyloric atresia', 'Disease', (9, 24))	('pyloric atresia', 'Disease', 'MESH:C562561', (9, 24))	('caused by', 'Reg', (28, 37))	('mutations', 'Var', (38, 47))
427035	20507631	All types of DEB result from mutations within the type VII collagen gene (COL7A1).	('COL7A1', 'Gene', (74, 80))	('COL7A1', 'Gene', '1294', (74, 80))	('mutations', 'Var', (29, 38))	('result from', 'Reg', (17, 28))	('DEB', 'Disease', (13, 16))
427036	20507631	Of note, those with DDEB tend to have missense mutations resulting in glycine substitutions within the triple helical domain of type VII collagen.	('missense mutations', 'Var', (38, 56))	('DDEB', 'Disease', (20, 24))	('glycine substitutions', 'MPA', (70, 91))	('glycine', 'Chemical', 'MESH:D005998', (70, 77))
427037	20507631	Analogous to what is seen in JEB-H and JEB-nH, patients with severe generalized RDEB may be either homozygous for their COL7A1 mutation or have two different mutations (i.e., "compound heterozygosity"), resulting in premature termination codons.	('COL7A1', 'Gene', '1294', (120, 126))	('COL7A1', 'Gene', (120, 126))	('mutation', 'Var', (127, 135))	('patients', 'Species', '9606', (47, 55))	('premature termination codons', 'MPA', (216, 244))	('generalized RDEB', 'Disease', (68, 84))
427038	20507631	In contrast, less severe types of mutations within the type VII collagen gene occur in patients with RDEB generalized other.	('type VII collagen gene', 'Gene', (55, 77))	('RDEB', 'Disease', (101, 105))	('patients', 'Species', '9606', (87, 95))	('occur', 'Reg', (78, 83))	('mutations', 'Var', (34, 43))
427040	20507631	Kindler syndrome, a rare autosomal recessive genodermatosis, is caused by mutations in the gene for kindlin-1, a recently discovered component of focal contacts in basal keratinocytes.	('Kindler syndrome', 'Disease', 'MESH:C536321', (0, 16))	('kindlin-1', 'Gene', '55612', (100, 109))	('autosomal recessive genodermatosis', 'Disease', (25, 59))	('mutations', 'Var', (74, 83))	('caused by', 'Reg', (64, 73))	('kindlin-1', 'Gene', (100, 109))	('Kindler syndrome', 'Disease', (0, 16))	('autosomal recessive genodermatosis', 'Disease', 'MESH:D030342', (25, 59))
427049	20507631	These include determination of the mode of transmission in patients suspected of having spontaneous mutations for DDEB (since the majority of these have been shown to have RDEB instead) or in patients involved in specific research projects which might benefit from full genotypic determination.	('DDEB', 'Gene', (114, 118))	('patients', 'Species', '9606', (192, 200))	('mutations', 'Var', (100, 109))	('patients', 'Species', '9606', (59, 67))
427050	20507631	Some families having one or more severely affected family members with autosomal recessive disease may also desire to screen clinically unaffected siblings for possible silent mutations, as well as their genetically unrelated spouses, prior to their pursuing pregnancy.	('silent mutations', 'Var', (169, 185))	('autosomal recessive disease', 'Disease', (71, 98))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (71, 98))
427078	34012270	In addition, the high expression of MFSD4 was significantly correlated with patient survival.	('high', 'Var', (17, 21))	('patient survival', 'CPA', (76, 92))	('MFSD4', 'Gene', (36, 41))	('MFSD4', 'Gene', '148808', (36, 41))	('correlated', 'Reg', (60, 70))	('patient', 'Species', '9606', (76, 83))
427091	34012270	Epigenetic modifications, such as DNA methylation, can change gene expression patterns and play an important role in cancer formation.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('role', 'Reg', (109, 113))	('play', 'Reg', (91, 95))	('change', 'Reg', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Epigenetic modifications', 'Var', (0, 24))	('cancer', 'Disease', (117, 123))	('DNA', 'Var', (34, 37))	('gene expression patterns', 'MPA', (62, 86))
427095	34012270	In the case analysis based on p16 methylation, the mutation/polymorphism of p53 was found to be significantly associated with the risk of esophageal carcinoma.	('p16', 'Gene', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('esophageal carcinoma', 'Disease', (138, 158))	('associated', 'Reg', (110, 120))	('mutation/polymorphism', 'Var', (51, 72))	('p16', 'Gene', '1029', (30, 33))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (138, 158))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (138, 158))
427152	34012270	A homozygous missense mutation in the 14th exon of the ATP4A gene triggers changes in the transmembrane region and prevents the release of protons from cells to the stomach, causing a lack of stomach acid.	('prevents', 'NegReg', (115, 123))	('changes', 'Reg', (75, 82))	('missense mutation in', 'Var', (13, 33))	('release of protons from cells to the stomach', 'MPA', (128, 172))	('ATP4A', 'Gene', (55, 60))	('lack', 'NegReg', (184, 188))	('ATP4A', 'Gene', '495', (55, 60))	('stomach acid', 'MPA', (192, 204))
427157	34012270	A notable consistency was identified between the downregulated and methylated states of ATP4B and ATP4A in gastric cancer tissues.	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('ATP4B', 'Gene', (88, 93))	('ATP4B', 'Gene', '496', (88, 93))	('ATP4A', 'Gene', '495', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('downregulated', 'NegReg', (49, 62))	('ATP4A', 'Gene', (98, 103))	('gastric cancer', 'Disease', (107, 121))	('methylated', 'Var', (67, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))
427159	34012270	In the present study, ATP4A and ATP4B were down-regulated and hypomethylated in esophageal carcinoma tissues.	('down-regulated', 'NegReg', (43, 57))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (80, 100))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (80, 100))	('ATP4B', 'Gene', (32, 37))	('ATP4B', 'Gene', '496', (32, 37))	('esophageal carcinoma', 'Disease', (80, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('ATP4A', 'Gene', (22, 27))	('ATP4A', 'Gene', '495', (22, 27))	('hypomethylated', 'Var', (62, 76))
427161	34012270	This further suggested that epigenetic changes of ATP4A and ATP4B may play an essential role in esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('play', 'Reg', (70, 74))	('ATP4A', 'Gene', '495', (50, 55))	('esophageal carcinoma', 'Disease', (96, 116))	('epigenetic changes', 'Var', (28, 46))	('role', 'Reg', (88, 92))	('ATP4B', 'Gene', (60, 65))	('ATP4B', 'Gene', '496', (60, 65))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (96, 116))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (96, 116))	('ATP4A', 'Gene', (50, 55))
427162	34012270	Cholecystokinin A receptor (CCKAR) is a G protein-coupled receptor that can be activated by cholecystokinin (CCK), whose mutation can affect the risk of gallbladder cancer in women.	('CCKAR', 'Gene', '886', (28, 33))	('Cholecystokinin A receptor', 'Gene', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('gallbladder cancer', 'Disease', (153, 171))	('gallbladder cancer', 'Disease', 'MESH:D005706', (153, 171))	('CCK', 'Gene', '885', (109, 112))	('CCK', 'Gene', '885', (28, 31))	('CCK', 'Gene', (109, 112))	('affect', 'Reg', (134, 140))	('mutation', 'Var', (121, 129))	('cholecystokinin', 'Gene', (92, 107))	('cholecystokinin', 'Gene', '885', (92, 107))	('women', 'Species', '9606', (175, 180))	('Cholecystokinin A receptor', 'Gene', '886', (0, 26))	('CCK', 'Gene', (28, 31))	('CCKAR', 'Gene', (28, 33))
427171	34012270	This further suggested that epigenetic changes in CCKAR and CCKBR may play an essential role in esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('play', 'Reg', (70, 74))	('CCKBR', 'Gene', '887', (60, 65))	('esophageal carcinoma', 'Disease', (96, 116))	('epigenetic changes', 'Var', (28, 46))	('role', 'Reg', (88, 92))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (96, 116))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (96, 116))	('CCKAR', 'Gene', '886', (50, 55))	('CCKAR', 'Gene', (50, 55))	('CCKBR', 'Gene', (60, 65))
427174	34012270	In the present study, MFSD4 was down-regulated and hypermethylated, which suggested that the down-regulation of MFSD4 may be associated with hypermethylation.	('down-regulation', 'NegReg', (93, 108))	('MFSD4', 'Gene', (22, 27))	('MFSD4', 'Gene', '148808', (22, 27))	('MFSD4', 'Gene', (112, 117))	('hypermethylation', 'Var', (141, 157))	('MFSD4', 'Gene', '148808', (112, 117))	('down-regulated', 'NegReg', (32, 46))
427179	34012270	In the present study, B3GAT1 was down-regulated and hypomethylated in esophageal carcinoma tissues.	('esophageal carcinoma', 'Disease', (70, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (70, 90))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (70, 90))	('B3GAT1', 'Gene', '27087', (22, 28))	('down-regulated', 'NegReg', (33, 47))	('B3GAT1', 'Gene', (22, 28))	('hypomethylated', 'Var', (52, 66))
427181	34012270	In conclusion, we proposed that epigenetic modifications of MFSD4 and B3GAT1 play an important role in the pathology of esophageal carcinoma.	('esophageal carcinoma', 'Disease', (120, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (120, 140))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (120, 140))	('B3GAT1', 'Gene', (70, 76))	('MFSD4', 'Gene', (60, 65))	('MFSD4', 'Gene', '148808', (60, 65))	('B3GAT1', 'Gene', '27087', (70, 76))	('role', 'Reg', (95, 99))	('epigenetic modifications', 'Var', (32, 56))
427186	34012270	In addition, the analysis of exon data from esophagogastric junctional adenocarcinoma revealed mutations in ESRRB, suggesting that ESRRB may be a potential therapeutic target.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('ESRRB', 'Gene', (108, 113))	('adenocarcinoma', 'Disease', 'MESH:D000230', (71, 85))	('esophagogastric junctional adenocarcinoma', 'Phenotype', 'HP:0011459', (44, 85))	('mutations', 'Var', (95, 104))	('adenocarcinoma', 'Disease', (71, 85))
427189	34012270	A recent study showed that ESRRG promoter hypermethylation was associated with the occurrence of laryngeal squamous cell carcinoma (LSCC), which suggested that ESRRG can serve as a biomarker for the diagnosis and prognosis of LSCC.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('ESRRG', 'Gene', (27, 32))	('promoter hypermethylation', 'Var', (33, 58))	('associated', 'Reg', (63, 73))	('ESRRG', 'Gene', '2104', (160, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('squamous cell carcinoma', 'Disease', (107, 130))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 130))	('ESRRG', 'Gene', (160, 165))	('ESRRG', 'Gene', '2104', (27, 32))
427193	34012270	Furthermore, ESRRB and ESRRG were hypomethylated and hypermethylated, respectively.	('hypermethylated', 'Var', (53, 68))	('ESRRG', 'Gene', '2104', (23, 28))	('ESRRG', 'Gene', (23, 28))	('hypomethylated', 'Var', (34, 48))	('ESRRB', 'Gene', (13, 18))
427209	34012270	Therefore, it was suggested that epigenetic changes of hub genes may play an essential role in esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (95, 115))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (95, 115))	('epigenetic changes', 'Var', (33, 51))	('hub', 'Gene', '1993', (55, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('play', 'Reg', (69, 73))	('esophageal carcinoma', 'Disease', (95, 115))	('hub', 'Gene', (55, 58))	('role', 'Reg', (87, 91))
427260	33311557	No immunoreactivity for normal rabbit IgG (sc-20271; Santa Cruz Biotechnology) was observed under the conditions used for the anti-PAI-1 and anti-LRP1 antibodies in human placental tissue (Fig.	('human', 'Species', '9606', (165, 170))	('LRP1', 'Gene', (146, 150))	('anti-PAI-1', 'Gene', (126, 136))	('anti-PAI-1', 'Var', (126, 136))	('LRP1', 'Gene', '4035', (146, 150))
427281	33311557	The PI3K inhibitor LY294002 and MEK1/2 inhibitor PD98059 suppressed the induction of both migration and invasion in rhPAI-1-treated ESCC cells (Fig.	('LY294002', 'Chemical', 'MESH:C085911', (19, 27))	('migration', 'CPA', (90, 99))	('PD98059', 'Chemical', 'MESH:C093973', (49, 56))	('invasion', 'CPA', (104, 112))	('rhPAI-1', 'Chemical', '-', (116, 123))	('MEK1/2', 'Gene', '5604;5605', (32, 38))	('MEK1/2', 'Gene', (32, 38))	('LY294002', 'Var', (19, 27))	('suppressed', 'NegReg', (57, 67))
427284	33311557	The knockdown of LRP1 in ESCC cells significantly suppressed the rhPAI-1-induced migration and invasion (Fig.	('suppressed', 'NegReg', (50, 60))	('invasion', 'CPA', (95, 103))	('knockdown', 'Var', (4, 13))	('rhPAI-1-induced', 'Gene', (65, 80))	('LRP1', 'Gene', '4035', (17, 21))	('rhPAI-1', 'Chemical', '-', (65, 72))	('migration', 'CPA', (81, 90))	('LRP1', 'Gene', (17, 21))
427285	33311557	The p-Akt and p-Erk1/2 levels decreased following LRP1 knockdown in ESCC cells (Figs.	('knockdown', 'Var', (55, 64))	('LRP1', 'Gene', '4035', (50, 54))	('LRP1', 'Gene', (50, 54))	('Akt', 'Gene', '207', (6, 9))	('Erk1/2', 'Gene', '5595;5594', (16, 22))	('Akt', 'Gene', (6, 9))	('Erk1/2', 'Gene', (16, 22))	('decreased', 'NegReg', (30, 39))
427290	33311557	LY294002 and PD98059 suppressed the abilities of migration and invasion in macrophages induced by rhPAI-1 (Fig.	('LY294002', 'Var', (0, 8))	('PD98059', 'Var', (13, 20))	('rhPAI-1', 'Gene', (98, 105))	('rhPAI-1', 'Chemical', '-', (98, 105))	('suppressed', 'NegReg', (21, 31))	('PD98059', 'Chemical', 'MESH:C093973', (13, 20))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('invasion in macrophages', 'CPA', (63, 86))
427293	33311557	5l, m), and knockdown of LRP1 in macrophages suppressed the rhPAI-1-induced migration and invasion (Fig.	('LRP1', 'Gene', (25, 29))	('rhPAI-1', 'Chemical', '-', (60, 67))	('LRP1', 'Gene', '4035', (25, 29))	('knockdown', 'Var', (12, 21))	('suppressed', 'NegReg', (45, 55))	('rhPAI-1-induced', 'Gene', (60, 75))
427294	33311557	The levels of PAI-1-induced p-Akt and p-Erk1/2 were also reduced by the knockdown of LRP1 in macrophages (Fig.	('LRP1', 'Gene', (85, 89))	('Erk1/2', 'Gene', (40, 46))	('Akt', 'Gene', '207', (30, 33))	('LRP1', 'Gene', '4035', (85, 89))	('Akt', 'Gene', (30, 33))	('Erk1/2', 'Gene', '5595;5594', (40, 46))	('reduced', 'NegReg', (57, 64))	('knockdown', 'Var', (72, 81))
427302	33311557	Kaplan-Meier analysis showed that patients with high expression levels of PAI-1 and LRP1 (ST) had significantly shorter disease-free survival (DFS) (p = 0.016 and p = 0.013, respectively) (Fig.	('disease-free survival', 'CPA', (120, 141))	('LRP1', 'Gene', '4035', (84, 88))	('high expression levels', 'Var', (48, 70))	('patients', 'Species', '9606', (34, 42))	('LRP1', 'Gene', (84, 88))	('PAI-1', 'Gene', (74, 79))	('shorter', 'NegReg', (112, 119))
427303	33311557	7a, c), and patients with high expression levels of LRP1 (CA) had significantly shorter CSS (p = 0.041) (Fig.	('patients', 'Species', '9606', (12, 20))	('high expression levels', 'Var', (26, 48))	('LRP1', 'Gene', (52, 56))	('shorter', 'NegReg', (80, 87))	('LRP1', 'Gene', '4035', (52, 56))	('CSS', 'CPA', (88, 91))
427310	33311557	In addition, the patients with high expression levels of both PAI-1 and LRP1 (ST) had significantly shorter DFS (p = 0.027) compared to those with high expression levels of either PAI-1 or LRP1 (ST) (Fig.	('LRP1', 'Gene', (189, 193))	('LRP1', 'Gene', (72, 76))	('shorter', 'NegReg', (100, 107))	('LRP1', 'Gene', '4035', (189, 193))	('PAI-1', 'Gene', (62, 67))	('high expression levels', 'Var', (31, 53))	('patients', 'Species', '9606', (17, 25))	('DFS', 'MPA', (108, 111))	('LRP1', 'Gene', '4035', (72, 76))
427324	33311557	Recent in vivo studies have noted that PAI-1 inhibitors suppress tumor growth, angiogenesis, and metastasis of some cancers (e.g., ovarian cancer, lung carcinoma, urothelial carcinoma, and fibrosarcoma).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('metastasis', 'CPA', (97, 107))	('PAI-1', 'Gene', (39, 44))	('ovarian cancer', 'Disease', (131, 145))	('tumor', 'Disease', (65, 70))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (163, 183))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('ovarian cancer', 'Phenotype', 'HP:0100615', (131, 145))	('lung carcinoma', 'Disease', (147, 161))	('angiogenesis', 'CPA', (79, 91))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (189, 201))	('urothelial carcinoma', 'Disease', (163, 183))	('suppress', 'NegReg', (56, 64))	('inhibitors', 'Var', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('fibrosarcoma', 'Disease', 'MESH:D005354', (189, 201))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('fibrosarcoma', 'Disease', (189, 201))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('ovarian cancer', 'Disease', 'MESH:D010051', (131, 145))	('cancers', 'Disease', (116, 123))	('lung carcinoma', 'Disease', 'MESH:D008175', (147, 161))
427397	32556644	The primary antibodies were rabbit anti-SOX2 (ab97959; abcam), rabbit anti-CK13 (ab92551, dilution 1:200; abcam), goat anti-p63 (BAF1916, dilution 1:200; R&D Systems), rat anti-PAX9 (ab28538, dilution 1:200; abcam), goat anti-E-cadherin (AF648, dilution 1:200; R&D Systems), rabbit anti-CK5 (GTX113219, dilution 1:200; GeneTex, Irvine, CA, USA), rabbit anti-Claudin4 (ab210796, dilution 1:200; abcam) and rabbit anti-Involucrin (ab53112, dilution 1:200; abcam).	('Claudin4', 'Gene', (358, 366))	('anti-PAX9', 'Var', (172, 181))	('R', 'Chemical', 'MESH:D001120', (154, 155))	('D', 'Chemical', 'MESH:D003903', (156, 157))	('D', 'Chemical', 'MESH:D003903', (263, 264))	('R', 'Chemical', 'MESH:D001120', (261, 262))	('Claudin4', 'Gene', '1364', (358, 366))
427412	32556644	We then differentiated DE into FG with a combination of LDN193189 (hereafter LDN) and SB431542 with CHIR.	('SB431542', 'Chemical', 'MESH:C459179', (86, 94))	('D', 'Chemical', 'MESH:D003903', (23, 24))	('D', 'Chemical', 'MESH:D003903', (57, 58))	('R', 'Chemical', 'MESH:D001120', (103, 104))	('D', 'Chemical', 'MESH:D003903', (78, 79))	('LDN193189', 'Var', (56, 65))	('SB431542', 'Var', (86, 94))
427418	32556644	At Day 13, (2) resulted in an enhanced expression of p63, which is a marker for dAFG (esophageal progenitor) and is expressed in basal cells of the esophageal epithelium, at the mRNA level (Fig.	('D', 'Chemical', 'MESH:D003903', (3, 4))	('enhanced', 'PosReg', (30, 38))	('R', 'Chemical', 'MESH:D001120', (179, 180))	('dAFG', 'Chemical', '-', (80, 84))	('p63', 'Var', (53, 56))	('expression', 'MPA', (39, 49))
427453	32556644	To identify which subtype of RARs is important for esophageal differentiation, we used the small molecules AM580 (RARalpha-specific agonist), CD2314 (RARbeta-specific agonist) and BMS961 (RARgamma-specific agonist) instead of ATRA (Fig.	('RARbeta', 'Gene', (150, 157))	('RARbeta', 'Gene', '5914', (150, 157))	('CD2314', 'Chemical', 'MESH:C000624245', (142, 148))	('RARs', 'Gene', (29, 33))	('ATRA', 'Chemical', 'MESH:D014212', (226, 230))	('CD2314', 'Var', (142, 148))	('RARalpha', 'Gene', (114, 122))	('RARs', 'Gene', '5917', (29, 33))	('AM580', 'Chemical', 'MESH:C068073', (107, 112))	('RARalpha', 'Gene', '5914', (114, 122))
427455	32556644	RT-PCR showed that AM580 and CD2314 treatment resulted in a non-significant increasing trend in the expression of FABP5, which is a retinoid target gene and whose expression is highest in the esophagus among human organ tissues, and SOX2, a general FG marker, but not the EEC-specific markers CK13, PAX9 and S100A14 (Fig.	('AM580', 'Chemical', 'MESH:C068073', (19, 24))	('retinoid', 'Chemical', 'MESH:D012176', (132, 140))	('CD2314', 'Chemical', 'MESH:C000624245', (29, 35))	('S100A14', 'Gene', (308, 315))	('CD2314', 'Var', (29, 35))	('R', 'Chemical', 'MESH:D001120', (5, 6))	('AM580', 'Var', (19, 24))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('expression', 'MPA', (100, 110))	('EEC', 'Chemical', '-', (272, 275))	('FABP5', 'Gene', (114, 119))	('FABP5', 'Gene', '2171', (114, 119))	('S100A14', 'Gene', '57402', (308, 315))	('human', 'Species', '9606', (208, 213))
427456	32556644	In contrast, BMS961 treatment significantly enhanced the expression of FABP5, CK13 and S100A14, similarly to ATRA treatment (Fig.	('expression', 'MPA', (57, 67))	('ATRA', 'Chemical', 'MESH:D014212', (109, 113))	('CK13', 'Gene', (78, 82))	('S100A14', 'Gene', '57402', (87, 94))	('FABP5', 'Gene', '2171', (71, 76))	('S100A14', 'Gene', (87, 94))	('FABP5', 'Gene', (71, 76))	('enhanced', 'PosReg', (44, 52))	('BMS961', 'Var', (13, 19))
427479	32556644	reported that ATRA treatment for 1 day during FG induction from DE at Day 5 in their protocol resulted in the increased expression of p63 and GATA4 at Day 9. p63 is expressed in not only dAFG but vAFG as well, which is a progenitor of lung cells.	('D', 'Chemical', 'MESH:D003903', (151, 152))	('GATA4', 'Gene', (142, 147))	('D', 'Chemical', 'MESH:D003903', (70, 71))	('vAFG', 'Chemical', '-', (196, 200))	('dAFG', 'Chemical', '-', (187, 191))	('ATRA', 'Chemical', 'MESH:D014212', (14, 18))	('p63', 'Var', (158, 161))	('D', 'Chemical', 'MESH:D003903', (64, 65))	('GATA4', 'Gene', '2626', (142, 147))
427485	32556644	In the present study, we demonstrated that treatment of FG with ATRA from Day 6 to Day 13 resulted in the enhanced expression of SOX2 and p63 (S-Fig.	('p63', 'Var', (138, 141))	('D', 'Chemical', 'MESH:D003903', (83, 84))	('enhanced', 'PosReg', (106, 114))	('ATRA', 'Chemical', 'MESH:D014212', (64, 68))	('SOX2', 'Protein', (129, 133))	('D', 'Chemical', 'MESH:D003903', (74, 75))	('expression', 'MPA', (115, 125))
427501	32556644	ATRA may, therefore, have activated neither RARalpha nor RARbeta in the current experiments, while the agonists AM580 and CD2314 activated RARalpha and RARbeta, respectively, and enhanced the expression of SOX2.	('RARbeta', 'Gene', '5914', (152, 159))	('RARalpha', 'Gene', (139, 147))	('RARbeta', 'Gene', (57, 64))	('enhanced', 'PosReg', (179, 187))	('activated', 'PosReg', (129, 138))	('RARalpha', 'Gene', '5914', (44, 52))	('expression', 'MPA', (192, 202))	('RARalpha', 'Gene', '5914', (139, 147))	('ATRA', 'Chemical', 'MESH:D014212', (0, 4))	('CD2314', 'Chemical', 'MESH:C000624245', (122, 128))	('RARbeta', 'Gene', '5914', (57, 64))	('AM580', 'Chemical', 'MESH:C068073', (112, 117))	('SOX2', 'Protein', (206, 210))	('RARbeta', 'Gene', (152, 159))	('CD2314', 'Var', (122, 128))	('RARalpha', 'Gene', (44, 52))
427505	32556644	However, no report has clarified the relationship between the prognosis and expression or mutation of RARgamma in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('RARgamma', 'Gene', (102, 110))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('mutation', 'Var', (90, 98))
427513	30618491	High ESPN expression was an independent prognosticator in multivariate analysis for overall survival (P = 0.009, hazard ratio = 1.688) and disease-free survival (P = 0.049, hazard ratio = 1.451).	('High ESPN', 'Phenotype', 'HP:0003565', (0, 9))	('High', 'Var', (0, 4))	('rat', 'Species', '10116', (180, 183))	('ESPN', 'Gene', (5, 9))	('rat', 'Species', '10116', (120, 123))	('disease-free', 'CPA', (139, 151))
427515	30618491	Inhibition of endogenous ESPN in ESCC cells decreased ESCC growth by reducing cell proliferating rates.	('cell proliferating rates', 'CPA', (78, 102))	('rat', 'Species', '10116', (97, 100))	('ESCC', 'Disease', (54, 58))	('reducing', 'NegReg', (69, 77))	('decreased ESCC', 'Phenotype', 'HP:0025022', (44, 58))	('Inhibition', 'Var', (0, 10))	('decreased', 'NegReg', (44, 53))	('rat', 'Species', '10116', (90, 93))
427525	30618491	ESPN gene mutation causes hereditary deafness and vestibular dysfunction accompanied by stereociliary shortening in jerker mice and humans.	('vestibular dysfunction', 'Phenotype', 'HP:0001751', (50, 72))	('humans', 'Species', '9606', (132, 138))	('causes', 'Reg', (19, 25))	('hereditary deafness and vestibular dysfunction', 'Disease', 'MESH:D000160', (26, 72))	('mutation', 'Var', (10, 18))	('ESPN', 'Gene', (0, 4))	('stereociliary shortening', 'Disease', (88, 112))	('deafness', 'Phenotype', 'HP:0000365', (37, 45))	('mice', 'Species', '10090', (123, 127))
427556	30618491	siESPN transfectants in KYSE270 and TE10 were harvested, fixed in 1% paraformaldehyde, and stained with PI (5 mg/ml) in PBS supplemented with RNase A for 30 min at room temperature.	('RNase A', 'Gene', (142, 149))	('KYSE270', 'Var', (24, 31))	('rat', 'Species', '10116', (174, 177))	('RNase A', 'Gene', '6035', (142, 149))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (69, 85))	('men', 'Species', '9606', (130, 133))
427575	30618491	In multivariate analysis, high ESPN expression (P = 0.009, hazard ratio = 1.688, 95% confidence interval 1.141-2.498) remained independently associated with inferior OS, together with T classification, T3/4 (P = 0.005, hazard ratio = 2.033, 95% confidence interval 1.242-3.327) and N classification, N1/2/3 (P = 0.005, hazard ratio = 2.261, 95% confidence interval 1.281-3.992).	('high', 'Var', (26, 30))	('inferior OS', 'Disease', (157, 168))	('ESPN expression', 'MPA', (31, 46))	('rat', 'Species', '10116', (326, 329))	('rat', 'Species', '10116', (226, 229))	('rat', 'Species', '10116', (66, 69))	('high ESPN', 'Phenotype', 'HP:0003565', (26, 35))
427577	30618491	The 5-year OS and DFS rates were 30% and 29% in patients with high ESPN expression, and 54% and 43% in patients with low ESPN expression.	('low ESPN', 'Phenotype', 'HP:0025022', (117, 125))	('DFS', 'CPA', (18, 21))	('rat', 'Species', '10116', (22, 25))	('high ESPN', 'Phenotype', 'HP:0003565', (62, 71))	('high ESPN expression', 'Var', (62, 82))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (48, 56))
427578	30618491	The MTT assays indicated that knockdown endogenous ESPN expression impaired cell proliferation in both ESCC cell lines (Fig.	('impaired', 'NegReg', (67, 75))	('rat', 'Species', '10116', (88, 91))	('cell proliferation', 'CPA', (76, 94))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('ESPN', 'Gene', (51, 55))	('knockdown endogenous', 'Var', (30, 50))
427579	30618491	Furthermore, as demonstrated by the colony formation assay, the knockdown of ESPN in both ESCC cell lines decreased the colony numbers of cells, compared to the corresponding negative control group (Fig.	('decreased', 'NegReg', (106, 115))	('rat', 'Species', '10116', (23, 26))	('ESPN', 'Gene', (77, 81))	('knockdown', 'Var', (64, 73))	('colony numbers of cells', 'CPA', (120, 143))
427582	30618491	Furthermore, using the same panels, the endogenous protein expression levels of p21 and p27 in siESPN-KYSE270 and siESPN-TE10 cells were not significantly higher than that of corresponding negative control cells (Fig.	('p21', 'Gene', (80, 83))	('p27', 'Gene', '10671', (88, 91))	('siESPN-KYSE270', 'Var', (95, 109))	('higher', 'PosReg', (155, 161))	('p21', 'Gene', '644914', (80, 83))	('p27', 'Gene', (88, 91))
427588	30618491	In the present study, high ESPN expression was highly representative of biological aggressiveness and independently associated with poor disease-free survival.	('aggressiveness', 'Disease', 'MESH:D001523', (83, 97))	('disease-free survival', 'CPA', (137, 158))	('ESPN expression', 'MPA', (27, 42))	('high', 'Var', (22, 26))	('high ESPN', 'Phenotype', 'HP:0003565', (22, 31))	('aggressiveness', 'Disease', (83, 97))	('aggressiveness', 'Phenotype', 'HP:0000718', (83, 97))	('poor', 'NegReg', (132, 136))	('associated', 'Reg', (116, 126))
427589	30618491	The 5-year disease-free survival rate was only 30% in patients with high ESPN expression, implying that ESPN status might be employed to select certain patients for adjuvant therapy after esophagectomy.	('high', 'Var', (68, 72))	('patients', 'Species', '9606', (54, 62))	('rat', 'Species', '10116', (33, 36))	('ESPN', 'Gene', (73, 77))	('patients', 'Species', '9606', (152, 160))	('high ESPN', 'Phenotype', 'HP:0003565', (68, 77))
427591	30618491	Although there were more early stage diseases (69% versus 77%) in patients with low ESPN expression compared to patients with high ESPN expression, it did not reach significance (P = 0.21, Table 2).	('low ESPN', 'Phenotype', 'HP:0025022', (80, 88))	('low', 'Var', (80, 83))	('high ESPN', 'Phenotype', 'HP:0003565', (126, 135))	('ESPN', 'Gene', (84, 88))	('early', 'Disease', (25, 30))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (66, 74))
427601	30618491	ESPN mutation lost association with other actin-binding proteins or stereocilia-related proteins, such as, myosin XVa, myosin IIIa, Eps8, and whirlin results in abnormally short, long or fused stereocilia.	('whirlin', 'Gene', '25861', (142, 149))	('lost', 'NegReg', (14, 18))	('myosin XVa', 'Gene', (107, 117))	('results in', 'Reg', (150, 160))	('myosin XVa', 'Gene', '51168', (107, 117))	('mutation', 'Var', (5, 13))	('Eps8', 'Gene', (132, 136))	('ESPN', 'Gene', (0, 4))	('myosin IIIa', 'Gene', (119, 130))	('Eps8', 'Gene', '2059', (132, 136))	('myosin IIIa', 'Gene', '53904', (119, 130))	('whirlin', 'Gene', (142, 149))	('association', 'Interaction', (19, 30))
427616	30618491	To the best of our knowledge, this is the first study to illustrate that ESPN inhibition prevented the ESCC cell proliferation.	('ESPN', 'Gene', (73, 77))	('prevented', 'NegReg', (89, 98))	('inhibition', 'Var', (78, 88))	('rat', 'Species', '10116', (120, 123))	('ESCC', 'Disease', (103, 107))	('rat', 'Species', '10116', (63, 66))
427619	28487609	Cox regression analysis revealed that vigorous venous invasion (v2, v3) (HR = 5.99; 95%CI: 1.71-24.90) and LNR of > 0.16 (HR = 4.29, 95%CI: 1.79-10.89) were independent poor prognostic factors for OS.	('vigorous venous invasion', 'Disease', (38, 62))	('v2, v3', 'Gene', (64, 70))	('v2, v3)', 'Gene', '6983', (64, 71))	('vigorous venous invasion', 'Disease', 'MESH:D054556', (38, 62))	('LNR', 'Var', (107, 110))
427657	28487609	Tumor size was significantly larger and esophageal invasion significantly shorter in type III than in type II tumors (Table 1).	('shorter', 'NegReg', (74, 81))	('type II tumors', 'Disease', (102, 116))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('larger', 'PosReg', (29, 35))	('type II tumors', 'Disease', 'MESH:D009369', (102, 116))	('type III', 'Var', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('esophageal invasion', 'CPA', (40, 59))
427665	28487609	According to Cox's regression analysis, vigorous venous invasion (v2 or v3) (HR = 5.99, 95%CI: 1.71-24.90, P = 0.004) and LNR of > 0.16 (HR = 4.29, 95%CI: 1.79-10.89, P = 0.001) were independent prognostic factors for poor OS (Table 4).	('LNR of > 0.16', 'Var', (122, 135))	('poor OS', 'Disease', (218, 225))	('vigorous venous invasion', 'Disease', (40, 64))	('vigorous venous invasion', 'Disease', 'MESH:D054556', (40, 64))
427695	28487609	LNR is reportedly an independent prognostic factor for esophagogastric cancer.	('gastric cancer', 'Disease', (63, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('LNR', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
427769	27548236	In comparison, a significant reduction in viability of esophageal adenocarcinoma and ovarian cancer cells is observed with 25.0-50.0 microg/mL and 50.0-200.0 microg/mL cranberry proanthocyanidins, respectively.	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('viability of esophageal adenocarcinoma and ovarian cancer', 'Disease', 'MESH:D010051', (42, 99))	('50.0-200.0 microg/mL', 'Var', (147, 167))	('reduction', 'NegReg', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('proanthocyanidins', 'Chemical', 'MESH:D044945', (178, 195))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (55, 80))
427801	27548236	Specifically, treatment with an equimolar concentration of five bile salts (taurocholic, glycocholic, glycodeoxycholic, glycochenodeoxycholic and deoxycholic acids) in acidified medium (pH 4.0) induces rapid apoptosis of esophageal adenocarcinoma cells except in the case of constitutively resistant OE19 cells were exposure to an acidified bile salt mixture has little impact on cell viability.	('glycochenodeoxycholic', 'Disease', 'None', (120, 141))	('apoptosis', 'CPA', (208, 217))	('induces', 'Reg', (194, 201))	('rat', 'Species', '10116', (49, 52))	('esophageal adenocarcinoma cells', 'Disease', 'MESH:D004938', (221, 252))	('glycocholic', 'Var', (89, 100))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (221, 246))	('esophageal adenocarcinoma cells', 'Disease', (221, 252))	('bile salt', 'Chemical', 'MESH:D001647', (64, 73))	('glycochenodeoxycholic', 'Disease', (120, 141))	('men', 'Species', '9606', (19, 22))	('bile salts', 'Chemical', 'MESH:D001647', (64, 74))	('deoxycholic acids', 'Var', (146, 163))	('bile salt', 'Chemical', 'MESH:D001647', (341, 350))	('glycodeoxycholic', 'Var', (102, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
427847	27548236	Finally, in esophageal adenocarcinoma JHEsoAD1 cells, pharmacologic inhibition of mTOR using cranberry proanthocyanidins or rapamycin induces autophagy resulting in cell death and survival, respectively.	('proanthocyanidins', 'Chemical', 'MESH:D044945', (103, 120))	('rapamycin', 'Chemical', 'MESH:D020123', (124, 133))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (12, 37))	('autophagy', 'CPA', (142, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('esophageal adenocarcinoma', 'Disease', (12, 37))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (12, 37))	('cell death', 'CPA', (165, 175))	('mTOR', 'Gene', (82, 86))	('induces', 'Reg', (134, 141))	('survival', 'CPA', (180, 188))	('pharmacologic', 'Var', (54, 67))
427923	27548236	A recent study published by The Cancer Genome Atlas Network showed that a large number of genetic alterations were shared across 279 patients with head and neck squamous cell carcinomas including activating mutations in PIK3CA, the gene encoding the catalytic subunit of phosphatidylinositol 3-kinase (PI3K).	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (156, 185))	('patients', 'Species', '9606', (133, 141))	('activating', 'PosReg', (196, 206))	('neck squamous cell carcinomas', 'Disease', (156, 185))	('PIK3CA', 'Gene', (220, 226))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (161, 185))	('mutations', 'Var', (207, 216))	('PIK3CA', 'Gene', '5290', (220, 226))	('rat', 'Species', '10116', (102, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
427936	27624872	Multivariate analysis revealed that patients identified as having poor-response, poor-survival and recurrence spectral signatures were correlated with increased risk of poor response to CCRT (P = 0.012), increased risk of death (P = 0.111) and increased risk of recurrence (P = 0.030) respectively.	('death', 'Disease', (222, 227))	('patients', 'Species', '9606', (36, 44))	('poor-survival', 'Var', (81, 94))	('poor-response', 'Var', (66, 79))	('poor response', 'MPA', (169, 182))	('death', 'Disease', 'MESH:D003643', (222, 227))
427982	27624872	Patients identified as having a poor-response spectra showed a significant, more than 11-fold increased risk of poor response compared with patients identified as having a good-response spectra (Logistics regression model, OR [95% CI] = 11.69 (1.73-79.20), P = 0.012, Table 2).	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (140, 148))	('poor-response', 'Var', (32, 45))	('poor response', 'MPA', (112, 125))
427994	27624872	Cancer formation is usually triggered by accumulating genetic or epigenetic mutations, which result in great changes in the biochemical compounds in cells.	('changes', 'Reg', (109, 116))	('triggered', 'Reg', (28, 37))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('biochemical compounds in', 'MPA', (124, 148))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('epigenetic mutations', 'Var', (65, 85))	('genetic', 'Var', (54, 61))
428019	27624872	There was an 11-fold increased risk of poor response for the patients with poor-response spectra compared to patients with good-response spectra (Table 2).	('poor-response', 'Var', (75, 88))	('patients', 'Species', '9606', (61, 69))	('poor response', 'MPA', (39, 52))	('patients', 'Species', '9606', (109, 117))
428024	27624872	We previously reported that the single nucleotide polymorphisms (SNPs) at the genes involved in the nucleotide excision repair and growth factor-related pathway can be prognostic biomarkers of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('single nucleotide polymorphisms', 'Var', (32, 63))	('esophageal cancer', 'Disease', (193, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))
428052	27624872	In the current study, patients with a complete pathological response or microscopic residual disease after CCRT were classified as "good responders" to CCRT, whereas those with macroscopic residual disease or progressive disease after treatment were classified as "poor responders" to CCRT.	('microscopic', 'Var', (72, 83))	('progressive disease', 'Disease', (209, 228))	('patients', 'Species', '9606', (22, 30))	('progressive disease', 'Disease', 'MESH:D018450', (209, 228))
428069	24486052	Eosinophil binding to HEF and HEMC increased following incubation of mesenchymal cells with eosinophil-derived products, and decreased following blockade of TGFbeta1 and p38MAPK blockade.	('p38', 'Gene', '1432', (170, 173))	('increased', 'PosReg', (35, 44))	('HEMC', 'Chemical', '-', (30, 34))	('binding', 'Interaction', (11, 18))	('HEMC increased', 'Phenotype', 'HP:0001899', (30, 44))	('Eosinophil', 'MPA', (0, 10))	('decreased', 'NegReg', (125, 134))	('TGFbeta1', 'Gene', '7040', (157, 165))	('p38', 'Gene', (170, 173))	('TGFbeta1', 'Gene', (157, 165))	('eosin', 'Chemical', 'MESH:D004801', (92, 97))	('HEF', 'Chemical', '-', (22, 25))	('blockade', 'Var', (145, 153))	('HEF', 'Protein', (22, 25))
428132	24486052	To further implicate TGF-beta1 in the pro-fibrogenic response of EoE, we neutralized TGF-beta1 activity in eosinophil sonicates prior to co-culture with HEF and observed a significant reduction of the eosinophil sonicate-induced FN secretion by HEF (Fig.	('reduction', 'NegReg', (184, 193))	('TGF-beta1', 'Gene', (21, 30))	('eosin', 'Chemical', 'MESH:D004801', (107, 112))	('neutralized', 'Var', (73, 84))	('HEF', 'Chemical', '-', (245, 248))	('HEF', 'Chemical', '-', (153, 156))	('eosin', 'Chemical', 'MESH:D004801', (201, 206))	('implicate', 'Reg', (11, 20))	('activity', 'MPA', (95, 103))	('TGF-beta1', 'Gene', '7040', (21, 30))	('TGF-beta1', 'Gene', '7040', (85, 94))	('TGF-beta1', 'Gene', (85, 94))	('eosinophil sonicate-induced FN secretion', 'MPA', (201, 241))
428175	24486052	In fact, blocking TGF-beta1 signaling or p38MAPK signaling, or neutralizing biologically active TGF-beta1 greatly reduced, but not completely eliminated, the increase in ECM production induced by TGF-beta1 and eosinophil sonicates.	('TGF-beta1', 'Gene', '7040', (96, 105))	('eosin', 'Chemical', 'MESH:D004801', (210, 215))	('TGF-beta1', 'Gene', '7040', (196, 205))	('TGF-beta1', 'Gene', (196, 205))	('TGF-beta1', 'Gene', (18, 27))	('reduced', 'NegReg', (114, 121))	('TGF-beta1', 'Gene', (96, 105))	('blocking', 'NegReg', (9, 17))	('p38', 'Gene', '1432', (41, 44))	('TGF-beta1', 'Gene', '7040', (18, 27))	('ECM production', 'MPA', (170, 184))	('neutralizing', 'Var', (63, 75))	('increase', 'PosReg', (158, 166))	('p38', 'Gene', (41, 44))
428183	24486052	Although TGF-beta1 failed to upregulated VCAM-1 expression, blocking TGF-beta1 or p38MAPK signaling markedly reduced the adhesion increased by TGF-beta1 or eosinophil sonicates.	('TGF-beta1', 'Gene', (143, 152))	('TGF-beta1', 'Gene', '7040', (69, 78))	('TGF-beta1', 'Gene', (69, 78))	('reduced', 'NegReg', (109, 116))	('VCAM-1', 'Gene', (41, 47))	('p38', 'Gene', '1432', (82, 85))	('adhesion', 'MPA', (121, 129))	('VCAM-1', 'Gene', '7412', (41, 47))	('TGF-beta1', 'Gene', '7040', (9, 18))	('TGF-beta1', 'Gene', (9, 18))	('eosin', 'Chemical', 'MESH:D004801', (156, 161))	('p38', 'Gene', (82, 85))	('blocking', 'Var', (60, 68))	('TGF-beta1', 'Gene', '7040', (143, 152))
428188	24486052	Mice deficient in the IL-13 decoy receptor IL-13alpha2, and therefore highly susceptible to IL-13-mediated responses, have hypercontractile responses to acetylcholine .	('hypercontractile responses to acetylcholine', 'MPA', (123, 166))	('acetylcholine', 'Chemical', 'MESH:D000109', (153, 166))	('IL-13', 'Gene', (22, 27))	('Mice', 'Species', '10090', (0, 4))	('deficient', 'Var', (5, 14))
428210	24122254	The overall survival rate was better in patients with high LC3 expression compared to patients with low LC3 expression.	('better', 'PosReg', (30, 36))	('high', 'Var', (54, 58))	('LC3', 'Gene', '84557', (59, 62))	('LC3', 'Gene', '84557', (104, 107))	('patients', 'Species', '9606', (40, 48))	('LC3', 'Gene', (59, 62))	('LC3', 'Gene', (104, 107))	('patients', 'Species', '9606', (86, 94))
428267	24122254	The median MVD was 19.1 +- 10.3 in tumors with high LC3 expression, 40.9 +- 20.1 in tumors with moderate expression, and 54.0 +- 15.2 in low LC3 expression tumor.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('LC3', 'Gene', '84557', (52, 55))	('LC3', 'Gene', (141, 144))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('high', 'Var', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (35, 40))	('tumors', 'Disease', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('LC3', 'Gene', '84557', (141, 144))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('LC3', 'Gene', (52, 55))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (84, 89))	('tumors', 'Disease', (35, 41))
428274	24122254	Patients with high LC3 expression had longer overall survival than those with low LC3 expression (p = 0.04).	('LC3', 'Gene', (82, 85))	('longer', 'PosReg', (38, 44))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('LC3', 'Gene', '84557', (19, 22))	('LC3', 'Gene', (19, 22))	('LC3', 'Gene', '84557', (82, 85))	('overall survival', 'MPA', (45, 61))
428384	30210237	With regard to survival, we found that ESCC patients with high SOX2 expression had significantly better survival time than those with low SOX2 expression (p=0.021).	('SOX2', 'Gene', (63, 67))	('SOX2', 'Gene', '6657', (138, 142))	('SOX2', 'Gene', '6657', (63, 67))	('ESCC', 'Disease', (39, 43))	('patients', 'Species', '9606', (44, 52))	('SOX2', 'Gene', (138, 142))	('better', 'PosReg', (97, 103))	('high', 'Var', (58, 62))	('survival time', 'CPA', (104, 117))
428386	30210237	Furthermore, higher T stage, clinical stage (pTNM), venous invasion, and high p53 expression were independent predictors of a worse progression-free survival.	('venous invasion', 'CPA', (52, 67))	('expression', 'MPA', (82, 92))	('pTNM', 'Chemical', '-', (45, 49))	('clinical stage', 'CPA', (29, 43))	('T stage', 'CPA', (20, 27))	('p53', 'Gene', (78, 81))	('high', 'Var', (73, 77))	('p53', 'Gene', '7157', (78, 81))
428405	30210237	Ki-67 labeling index was found to be significantly associated with poor prognosis in many malignancies, such as lymphoma, neuroendocrine tumors, and bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (149, 163))	('lymphoma', 'Disease', (112, 120))	('malignancies', 'Disease', (90, 102))	('Ki-67', 'Var', (0, 5))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (122, 143))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (122, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('bladder cancer', 'Disease', (149, 163))	('lymphoma', 'Disease', 'MESH:D008223', (112, 120))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('neuroendocrine tumors', 'Disease', (122, 143))	('associated', 'Reg', (51, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (149, 163))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
428407	30210237	Yao et al reported that high expression of p53 was associated with poor prognosis in patients with early-stage ESCC.	('early-stage ESCC', 'Disease', (99, 115))	('patients', 'Species', '9606', (85, 93))	('high', 'Var', (24, 28))	('p53', 'Gene', '7157', (43, 46))	('p53', 'Gene', (43, 46))
428441	30210237	Notably, high Cyclin D1 was correlated with increased p53 expression (p=0.015).	('expression', 'MPA', (58, 68))	('p53', 'Gene', (54, 57))	('Cyclin D1', 'Gene', '595', (14, 23))	('p53', 'Gene', '7157', (54, 57))	('increased', 'PosReg', (44, 53))	('Cyclin D1', 'Gene', (14, 23))	('high', 'Var', (9, 13))
428447	30210237	Univariate analysis showed that N stage (p=0.014), higher pTNM (p=0.006), adjuvant therapy (p=0.044), presence of venous invasion (p=0.015), lymph node metastasis (p=0.007), and high expression of P53 (p=0.018) were associated with OS (Table 3).	('lymph node metastasis', 'CPA', (141, 162))	('P53', 'Gene', '7157', (197, 200))	('high expression', 'Var', (178, 193))	('pTNM', 'Chemical', '-', (58, 62))	('P53', 'Gene', (197, 200))
428451	30210237	We found that therapy (hazard ratio [HR]: 0.490, 95% confidence interval [CI]: 0.249-0.964, p=0.039), high expression of p53 (HR: 2.697, 95% CI: 1.373-5.299, p=0.004), and venous invasion (HR: 2.373, 95% CI: 1.129-4.987, p=0.023) were significant independent predictors of OS.	('high', 'Var', (102, 106))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('venous invasion', 'CPA', (172, 187))
428453	30210237	In the multivariate analysis, higher T stage, pTNM stage, venous invasion, and high p53 expression were also found to be independent factors affecting PFS (Table 4).	('high', 'Var', (79, 83))	('p53', 'Gene', '7157', (84, 87))	('p53', 'Gene', (84, 87))	('expression', 'MPA', (88, 98))	('pTNM', 'Chemical', '-', (46, 50))	('PFS', 'Disease', (151, 154))
428458	30210237	SOX2 expression was significantly correlated with favorable prognosis in the group with age <65 years (p=0.020), tumor size <4 cm (p=0.031), moderate differentiation (p=0.018), T2 pathological stage (p=0.032), no lymph node metastasis (p=0.017), the combination of radical surgery and chemotherapy (p=0.017), LNR >0.2 (p=0.026), lower p53 expression (p=0.029), and higher Cyclin D1 expression (p=0.031).	('SOX2', 'Gene', '6657', (0, 4))	('tumor', 'Disease', (113, 118))	('Cyclin D1', 'Gene', (372, 381))	('lower', 'NegReg', (329, 334))	('expression', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('p53', 'Gene', (335, 338))	('p53', 'Gene', '7157', (335, 338))	('Cyclin D1', 'Gene', '595', (372, 381))	('expression', 'MPA', (382, 392))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LNR', 'Var', (309, 312))	('moderate differentiation', 'CPA', (141, 165))	('SOX2', 'Gene', (0, 4))	('higher', 'PosReg', (365, 371))
428460	30210237	The Kaplan-Meier survival analysis with log-rank test showed that high p53 expression was associated with shorter OS and PFS (p=0.018 and p=0.006, respectively) in ESCC.	('shorter', 'NegReg', (106, 113))	('p53', 'Gene', (71, 74))	('ESCC', 'Disease', (164, 168))	('p53', 'Gene', '7157', (71, 74))	('high', 'Var', (66, 70))	('PFS', 'CPA', (121, 124))	('expression', 'MPA', (75, 85))
428464	30210237	Next, we found that the combination of p53 and Cyclin D1 was significantly correlated with poor prognosis in radical surgery (p=0.020) and in the chemotherapy (p=0.020) after stratification.	('radical', 'Disease', (109, 116))	('Cyclin D1', 'Gene', '595', (47, 56))	('combination', 'Var', (24, 35))	('Cyclin D1', 'Gene', (47, 56))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))
428470	30210237	As previously described, high level of SOX2 is associated with poor prognosis in human oral squamous cell carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('oral squamous cell carcinomas', 'Disease', (87, 116))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (92, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('SOX2', 'Gene', '6657', (39, 43))	('human', 'Species', '9606', (81, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('SOX2', 'Gene', (39, 43))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (87, 116))	('high level', 'Var', (25, 35))
428476	30210237	With regard to survival, we found that ESCC patients with high SOX2 expression had significantly better survival time than those with low SOX2 expression (p=0.021) by Kaplan-Meier analysis.	('SOX2', 'Gene', (63, 67))	('SOX2', 'Gene', '6657', (138, 142))	('SOX2', 'Gene', '6657', (63, 67))	('ESCC', 'Disease', (39, 43))	('patients', 'Species', '9606', (44, 52))	('SOX2', 'Gene', (138, 142))	('better', 'PosReg', (97, 103))	('high', 'Var', (58, 62))	('survival time', 'CPA', (104, 117))
428477	30210237	Subgroup analysis found that in the low SOX2 expression group, receiving both radical surgery and chemotherapy did not lead to any significant survival benefit.	('SOX2', 'Gene', '6657', (40, 44))	('SOX2', 'Gene', (40, 44))	('low', 'Var', (36, 39))
428489	30210237	With regard to survival, our study revealed that ESCC patients with p53 overexpression had lower OS and PFS rates than patient without p53 expression.	('lower', 'NegReg', (91, 96))	('patient', 'Species', '9606', (54, 61))	('patient', 'Species', '9606', (119, 126))	('overexpression', 'Var', (72, 86))	('patients', 'Species', '9606', (54, 62))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('PFS rates', 'CPA', (104, 113))	('p53', 'Gene', (68, 71))	('ESCC', 'Disease', (49, 53))	('p53', 'Gene', '7157', (68, 71))
428498	30210237	In conclusion, our study found that treatment modality, high expression of p53, and venous invasion were significant independent predictors of OS.	('p53', 'Gene', (75, 78))	('high expression', 'Var', (56, 71))	('venous invasion', 'CPA', (84, 99))	('p53', 'Gene', '7157', (75, 78))
428499	30210237	We also found that higher T stage, pTNM, venous invasion, and high p53 expression were significantly associated with worse PFS.	('expression', 'MPA', (71, 81))	('T stage', 'CPA', (26, 33))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('pTNM', 'Chemical', '-', (35, 39))	('high', 'Var', (62, 66))	('venous invasion', 'CPA', (41, 56))
428500	30210237	Notably, high expression level of SOX2 was associated with favorable prognosis in ESCC.	('ESCC', 'Disease', (82, 86))	('SOX2', 'Gene', '6657', (34, 38))	('SOX2', 'Gene', (34, 38))	('high', 'Var', (9, 13))
428501	30210237	The combination of p53 and Cyclin D1 was significantly correlated with poor prognosis in OS and PFS (p=0.047 and p=0.001, respectively).	('PFS', 'Disease', (96, 99))	('correlated', 'Reg', (55, 65))	('Cyclin D1', 'Gene', (27, 36))	('combination', 'Var', (4, 15))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('Cyclin D1', 'Gene', '595', (27, 36))
428506	29767234	Importantly, miR-125a-5p enhanced the cytotoxic effects of cisplatin on EC1 and TE1 cells, and co-treatment with miR-125a-5p and cisplatin significantly induced cell apoptosis and reduced the cell migratory and invasive abilities of EC1 and TE1 cells, coupled with an increase in the E-cadherin level and a decrease in the N-cadherin and Vimentin levels.	('cytotoxic effects', 'CPA', (38, 55))	('EC1', 'Gene', (233, 236))	('5p', 'Chemical', '-', (22, 24))	('E-cadherin', 'Gene', (284, 294))	('E-cadherin', 'Gene', '999', (284, 294))	('decrease', 'NegReg', (307, 315))	('N-cadherin', 'Gene', (323, 333))	('miR-125a', 'Gene', '406910', (113, 121))	('increase', 'PosReg', (268, 276))	('N-cadherin', 'Gene', '1000', (323, 333))	('EC1', 'Gene', '4819', (233, 236))	('miR-125a', 'Gene', (113, 121))	('Vimentin', 'Gene', '7431', (338, 346))	('5p', 'Chemical', '-', (122, 124))	('EC', 'Phenotype', 'HP:0011459', (233, 235))	('cell apoptosis', 'CPA', (161, 175))	('Vimentin', 'Gene', (338, 346))	('EC1', 'Gene', (72, 75))	('EC', 'Phenotype', 'HP:0011459', (72, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('miR-125a', 'Gene', '406910', (13, 21))	('cisplatin', 'Var', (129, 138))	('reduced', 'NegReg', (180, 187))	('induced', 'PosReg', (153, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('miR-125a', 'Gene', (13, 21))	('EC1', 'Gene', '4819', (72, 75))	('co-treatment', 'Var', (95, 107))
428523	29767234	In the current study, we examined miRNA-125a-5p expression in ESCC tissues and cell lines, and verified its role in the regulation of the proliferation, the cell cycle, apoptosis, and in the migratory and invasive abilities of ESCC cells.	('apoptosis', 'CPA', (169, 178))	('invasive abilities', 'CPA', (205, 223))	('cell cycle', 'CPA', (157, 167))	('5p', 'Chemical', '-', (45, 47))	('miRNA-125a-5p', 'Var', (34, 47))
428526	29767234	Taken together, the data from the current study suggest that the manipulation of miR-125a-5p may be used as a strategy with which to enhance the cytotoxic effects of cisplatin on ESCC via the suppression of the activation of the STAT3 signaling pathway.	('suppression', 'NegReg', (192, 203))	('enhance', 'PosReg', (133, 140))	('5p', 'Chemical', '-', (90, 92))	('STAT3', 'Gene', '6774', (229, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('cytotoxic effects', 'CPA', (145, 162))	('miR-125a', 'Gene', (81, 89))	('STAT3', 'Gene', (229, 234))	('manipulation', 'Var', (65, 77))	('miR-125a', 'Gene', '406910', (81, 89))
428530	29767234	The human ESCC cell lines, including Eca109, EC9706, EC1, TE1, KYSE450 and KYSE70, as well as normal esophageal epithelial cells, Het-1A, were maintained in liquid nitrogen in our laboratory.	('EC1', 'Gene', '4819', (53, 56))	('EC', 'Phenotype', 'HP:0011459', (53, 55))	('human', 'Species', '9606', (4, 9))	('KYSE70', 'Var', (75, 81))	('KYSE450', 'Var', (63, 70))	('EC9706', 'CellLine', 'CVCL:E307', (45, 51))	('nitrogen', 'Chemical', 'MESH:D009584', (164, 172))	('EC', 'Phenotype', 'HP:0011459', (45, 47))	('EC1', 'Gene', (53, 56))	('EC9706', 'Var', (45, 51))
428533	29767234	The human STAT3 3'-UTR-wild-type (STAT3-3'-UTR-WT) region containing the miR-125a-5p binding sequence was amplified by PCR, and the STAT3-3'-UTR-mutation (STAT3-3'-UTR-MUT) region with a substitution of 8 bp in the miR-125a-5p binding region was generated using a QuikChange Site-Directed Mutagenesis kit (Stratagene, La Jolla, CA, USA).	('substitution', 'Var', (187, 199))	('STAT3-3', 'Gene', (34, 41))	('miR-125a', 'Gene', '406910', (73, 81))	('miR-125a', 'Gene', '406910', (215, 223))	('STAT3-3', 'Gene', '6774', (155, 162))	('miR-125a', 'Gene', (73, 81))	('STAT3-3', 'Gene', '6774', (132, 139))	('miR-125a', 'Gene', (215, 223))	('STAT3', 'Gene', (155, 160))	('STAT3', 'Gene', (132, 137))	('5p', 'Chemical', '-', (82, 84))	('5p', 'Chemical', '-', (224, 226))	('STAT3', 'Gene', '6774', (155, 160))	('STAT3', 'Gene', (10, 15))	('STAT3', 'Gene', (34, 39))	('human', 'Species', '9606', (4, 9))	('STAT3', 'Gene', '6774', (132, 137))	('STAT3-3', 'Gene', (155, 162))	('STAT3', 'Gene', '6774', (34, 39))	('STAT3-3', 'Gene', '6774', (34, 41))	('STAT3', 'Gene', '6774', (10, 15))	('STAT3-3', 'Gene', (132, 139))
428566	29767234	Furthermore, an in vitro analysis demonstrated that the relative level of miR-125a-5p in ESCC cells (Eca109, EC9706, EC1, TE1, KYSE450 and KYSE70) was evidently lower than that in the normal esophageal epithelial cell line, Het-1A (P<0.01) (Fig.	('lower', 'NegReg', (161, 166))	('EC9706', 'CellLine', 'CVCL:E307', (109, 115))	('Eca109', 'Var', (101, 107))	('EC', 'Phenotype', 'HP:0011459', (109, 111))	('miR-125a', 'Gene', (74, 82))	('EC9706', 'Var', (109, 115))	('EC1', 'Gene', (117, 120))	('EC1', 'Gene', '4819', (117, 120))	('miR-125a', 'Gene', '406910', (74, 82))	('EC', 'Phenotype', 'HP:0011459', (117, 119))	('5p', 'Chemical', '-', (83, 85))
428584	29767234	Chemoresistance is the main cause of tumor treatment failure, and aberrant miRNA levels are closely linked to chemosensitivity and chemoresistance in a wide range of tumors.	('miRNA levels', 'MPA', (75, 87))	('tumor treatment failure', 'Disease', 'MESH:D016609', (37, 60))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('linked', 'Reg', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('aberrant', 'Var', (66, 74))	('tumor treatment failure', 'Disease', (37, 60))	('Chemoresistance', 'CPA', (0, 15))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
428627	29767234	These findings suggest that miR-125a-5p may be an important regulator of cell proliferation, cell cycle and apoptosis in ESCC, and thus the manipulation of miR-125a-5p may be a novel molecular target for ESCC.	('ESCC', 'Disease', (204, 208))	('miR-125a', 'Gene', (156, 164))	('5p', 'Chemical', '-', (37, 39))	('miR-125a', 'Gene', '406910', (28, 36))	('miR-125a', 'Gene', '406910', (156, 164))	('manipulation', 'Var', (140, 152))	('miR-125a', 'Gene', (28, 36))	('ESCC', 'Disease', (121, 125))	('5p', 'Chemical', '-', (165, 167))
428632	29767234	To further interpret the possible role of miR-125a-5p in invasion and metastasis of ESCC, we further examined the alterations in the migratory and invasive abilities of ESCC cells triggered by miRNA-125a-5p.	('5p', 'Chemical', '-', (204, 206))	('miR-125a', 'Gene', '406910', (42, 50))	('5p', 'Chemical', '-', (51, 53))	('migratory', 'CPA', (133, 142))	('miRNA-125a-5p', 'Var', (193, 206))	('invasive abilities', 'CPA', (147, 165))	('miR-125a', 'Gene', (42, 50))
428637	29767234	Recent studies have revealed that aberrant miRNA levels are tightly implicated in chemoresistance or chemosensitivity in a host of tumors, suggesting that targeting miRNAs to eradicate chemoresistance or improve chemosensitivity may be a novel therapeutic strategy for the therapy of tumor patients.	('chemoresistance', 'CPA', (185, 200))	('tumor', 'Disease', (284, 289))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('host of tumors', 'Disease', (123, 137))	('patients', 'Species', '9606', (290, 298))	('aberrant', 'Var', (34, 42))	('chemosensitivity', 'CPA', (212, 228))	('eradicate', 'NegReg', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (131, 136))	('host of tumors', 'Disease', 'MESH:D006086', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('implicated', 'Reg', (68, 78))	('miRNA levels', 'MPA', (43, 55))	('improve', 'PosReg', (204, 211))
428648	29767234	In this study, we determined whether the involvement of miRNA-125a-5p in the sensitivity of ESCC cells to cisplatin may be tightly associated with the activated status of the STAT3 signaling pathway.	('miRNA-125a-5p', 'Var', (56, 69))	('5p', 'Chemical', '-', (67, 69))	('associated', 'Reg', (131, 141))	('STAT3', 'Gene', '6774', (175, 180))	('involvement', 'Reg', (41, 52))	('STAT3', 'Gene', (175, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('sensitivity', 'MPA', (77, 88))
428758	29463006	In general, curative resection is recommended for both limited (T1-2, N0-1, M0) and advanced (T3-4, N0-1, M0) esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal cancer', 'Disease', (110, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('T3-4', 'Var', (94, 98))
428798	29463006	In terms of the Clavien-Dindo classification, the HR (2.336) (95% CI 1.096-3.984, p = 0.028) of RFS was significantly higher in patients with class 1-2 complications compared to those patients without complications, but the HR of patients with class 3a-5 complications was not significantly different from those without complications (p = 0.052).	('higher', 'PosReg', (118, 124))	('RFS', 'Gene', (96, 99))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (230, 238))	('RFS', 'Chemical', '-', (96, 99))	('complications', 'Var', (152, 165))	('patients', 'Species', '9606', (128, 136))
428820	29463006	First, BMI had a significant HR for OS (0.864) and RFS (0.862), suggesting that underweight status or malnutrition may have an adverse effect on OS and RFS.	('underweight', 'Var', (80, 91))	('malnutrition', 'Disease', (102, 114))	('malnutrition', 'Disease', 'MESH:D044342', (102, 114))	('OS', 'Chemical', '-', (145, 147))	('RFS', 'Chemical', '-', (51, 54))	('malnutrition', 'Phenotype', 'HP:0004395', (102, 114))	('OS', 'Chemical', '-', (36, 38))	('RFS', 'Chemical', '-', (152, 155))
428849	28816160	However, the RTOG-0617 phase 3 trial of dose escalation has reported a significantly lower OS for 74 Gy than for 60 Gy in daily 2-Gy fractions, triggering efforts to identify reasons for the reduced survival.	('OS', 'Chemical', '-', (91, 93))	('lower', 'NegReg', (85, 90))	('74 Gy', 'Var', (98, 103))
428916	28816160	In another study, 14% of esophageal cancer patients had symptomatic cardiac disease 5 years after radiation therapy, the risk varying with the fractions of whole-heart volumes receiving >=45 Gy, 50 Gy, and 55 Gy.	('cardiac disease', 'Disease', 'MESH:D006331', (68, 83))	('esophageal cancer', 'Disease', (25, 42))	('patients', 'Species', '9606', (43, 51))	('50 Gy', 'Var', (195, 200))	('esophageal cancer', 'Disease', 'MESH:D004938', (25, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cardiac disease', 'Disease', (68, 83))	('symptomatic', 'Disease', (56, 67))
428984	28770168	In this era of molecular oncology, it is disconcerting that such a small proportion of patients received targeted therapy which has been associated with improved outcomes in a myriad of solid tumor indications.	('solid tumor', 'Disease', (186, 197))	('solid tumor', 'Disease', 'MESH:D009369', (186, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('oncology', 'Phenotype', 'HP:0002664', (25, 33))	('targeted', 'Var', (105, 113))	('patients', 'Species', '9606', (87, 95))
428988	28770168	The ToGA trial also demonstrated an improved response rate and survival outcomes utilizing HER2 targeted therapy in gastroesophageal cancers.	('response rate', 'CPA', (45, 58))	('gastroesophageal cancers', 'Disease', (116, 140))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('HER2', 'Gene', (91, 95))	('improved', 'PosReg', (36, 44))	('HER2', 'Gene', '2064', (91, 95))	('survival outcomes', 'CPA', (63, 80))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (116, 140))	('targeted therapy', 'Var', (96, 112))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
429007	28770168	This protein can recognize and excise a wide scope of DNA damage, including damage resulting from the cross-linking of platinum-based anti-cancer drugs.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cross-linking', 'Var', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('platinum', 'Chemical', 'MESH:D010984', (119, 127))	('cancer', 'Disease', (139, 145))
429009	28770168	A clear linkage between high expression levels of ERCC1 and decreased patient response to the platinum-based therapy has been shown.	('ERCC1', 'Gene', '2067', (50, 55))	('decreased', 'NegReg', (60, 69))	('platinum', 'Chemical', 'MESH:D010984', (94, 102))	('patient', 'Species', '9606', (70, 77))	('expression', 'MPA', (29, 39))	('patient response to the platinum-based therapy', 'CPA', (70, 116))	('high', 'Var', (24, 28))	('ERCC1', 'Gene', (50, 55))
429010	28770168	Patients who had tumors with high levels of ERCC1 experienced significantly shorter OS (11.1 months) compared to patients with no or low ERCC1 (33.7 months) when treated with platinum-based regimens.	('ERCC1', 'Gene', (44, 49))	('ERCC1', 'Gene', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('ERCC1', 'Gene', '2067', (137, 142))	('tumors', 'Disease', (17, 23))	('patients', 'Species', '9606', (113, 121))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('Patients', 'Species', '9606', (0, 8))	('platinum', 'Chemical', 'MESH:D010984', (175, 183))	('shorter', 'NegReg', (76, 83))	('high levels', 'Var', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('ERCC1', 'Gene', '2067', (44, 49))
429019	28770168	It is because of this relationship that high expression of TUBB3 has been shown to inhibit taxane-based therapies in a number of cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('high expression', 'Var', (40, 55))	('TUBB3', 'Gene', '10381', (59, 64))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('taxane-based', 'CPA', (91, 103))	('taxane', 'Chemical', 'MESH:C080625', (91, 97))	('inhibit', 'NegReg', (83, 90))	('TUBB3', 'Gene', (59, 64))
429020	28770168	In gastric tumors, high TUBB3 expression had a significantly lower response rate (16.7%) to docetaxel then tumors with low TUBB3 expression (64.3%).	('TUBB3', 'Gene', '10381', (24, 29))	('lower', 'NegReg', (61, 66))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('gastric tumors', 'Disease', (3, 17))	('response rate', 'MPA', (67, 80))	('TUBB3', 'Gene', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (107, 113))	('docetaxel', 'Chemical', 'MESH:D000077143', (92, 101))	('TUBB3', 'Gene', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('high', 'Var', (19, 23))	('TUBB3', 'Gene', '10381', (123, 128))	('gastric tumors', 'Disease', 'MESH:D013274', (3, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('gastric tumors', 'Phenotype', 'HP:0006753', (3, 17))
429021	28770168	Another study which quantified TUBB3 via mass spectrometry, compared gastroesophageal cancer patients with high or low TUBB3 expression in a cohort treated with taxanes.	('gastroesophageal cancer', 'Disease', (69, 92))	('TUBB3', 'Gene', '10381', (119, 124))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (69, 92))	('TUBB3', 'Gene', (31, 36))	('TUBB3', 'Gene', '10381', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('expression', 'MPA', (125, 135))	('high', 'Var', (107, 111))	('TUBB3', 'Gene', (119, 124))	('patients', 'Species', '9606', (93, 101))	('taxanes', 'Chemical', 'MESH:D043823', (161, 168))	('low', 'NegReg', (115, 118))
429022	28770168	Patients with low TUBB3 (<700 amol/microg) had nearly double the survival duration (1,566 days) compared to patients with high expression of TUBB3 (801 days).	('TUBB3', 'Gene', (18, 23))	('TUBB3', 'Gene', '10381', (18, 23))	('amol', 'Phenotype', 'HP:0004845', (30, 34))	('survival duration', 'CPA', (65, 82))	('TUBB3', 'Gene', (141, 146))	('TUBB3', 'Gene', '10381', (141, 146))	('<700 amol/microg', 'Var', (25, 41))	('Patients', 'Species', '9606', (0, 8))	('low', 'NegReg', (14, 17))	('patients', 'Species', '9606', (108, 116))
429030	28770168	Prognostically, the presence of TS in esophageal tumors was found to have a twofold greater chance of cancer recurrence, regardless of the first-line regimen.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('esophageal tumors', 'Disease', 'MESH:D004938', (38, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('esophageal tumors', 'Disease', (38, 55))	('esophageal tumors', 'Phenotype', 'HP:0100751', (38, 55))	('presence', 'Var', (20, 28))
429033	28770168	Tumoral PD-L1 expression has also been associated with improved response to a number of immunotherapies targeting various immune system-affiliated ligands.	('expression', 'Var', (14, 24))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('improved', 'PosReg', (55, 63))	('PD-L1', 'Gene', (8, 13))	('response', 'CPA', (64, 72))	('PD-L1', 'Gene', '29126', (8, 13))
429172	30717809	Using the calculated threshold of 1.14, the DeltaMTV yielded a sensitivity of 60%, specificity of 94%, accuracy of 86%, PPV of 75%, and NPV of 88% for predicting locoregional recurrence.	('DeltaMTV', 'Chemical', '-', (44, 52))	('locoregional recurrence', 'CPA', (162, 185))	('DeltaMTV', 'Var', (44, 52))
429202	29296124	TFF1 hypermethylation and decreased expression in esophageal squamous cell carcinoma and histologically normal tumor surrounding esophageal cells Esophageal squamous cell carcinoma (ESCC) is one of the 10 most incident cancer types in the world, and it is mainly associated with tobacco and alcohol consumption.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('decreased', 'NegReg', (26, 35))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (146, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))	('alcohol', 'Chemical', 'MESH:D000438', (291, 298))	('tumor', 'Disease', (111, 116))	('tobacco', 'Species', '4097', (279, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('hypermethylation', 'Var', (5, 21))	('cancer', 'Disease', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('TFF1', 'Gene', '7031', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Esophageal squamous cell carcinoma', 'Disease', (146, 180))	('TFF1', 'Gene', (0, 4))	('expression', 'MPA', (36, 46))
429256	29296124	TFF1 promoter was hypermethylated in tumor and histologically normal tumor surrounding tissue in comparison with healthy esophagus (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('TFF1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('hypermethylated', 'Var', (18, 33))
429259	29296124	Taken together, our results suggest that a TFF1 promoter methylation increase of less than 20% can result in a reduction of gene expression greater than 80% and total absence of protein expression, as observed when comparing healthy esophagus and non-tumor adjacent mucosa from ESCC patients.	('reduction', 'NegReg', (111, 120))	('methylation', 'Var', (57, 68))	('increase', 'PosReg', (69, 77))	('promoter', 'MPA', (48, 56))	('protein expression', 'MPA', (178, 196))	('absence', 'NegReg', (167, 174))	('TFF1', 'Gene', (43, 47))	('non-tumor', 'Disease', 'MESH:D009369', (247, 256))	('patients', 'Species', '9606', (283, 291))	('gene expression greater', 'MPA', (124, 147))	('ESCC', 'Disease', (278, 282))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('non-tumor', 'Disease', (247, 256))
429261	29296124	These findings are consistent with the hypothesis that methylation-dependent silencing of TFF1 may occur in both ESCC and tumor adjacent normal-appearing mucosa.	('ESCC', 'Disease', (113, 117))	('silencing', 'NegReg', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('methylation-dependent', 'Var', (55, 76))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('TFF1', 'Gene', (90, 94))
429262	29296124	However, we found no association between TFF1 expression levels or promoter methylation rate in normal esophageal cells and tobacco smoking or alcohol drinking, two well-recognized risk factors for this cancer type (Additional file 1: Table S1), suggesting that methylation-mediated silencing of TFF1 is independent of these risk factors.	('alcohol drinking', 'Phenotype', 'HP:0030955', (143, 159))	('alcohol', 'Chemical', 'MESH:D000438', (143, 150))	('methylation-mediated', 'Var', (262, 282))	('cancer', 'Disease', (203, 209))	('TFF1', 'Gene', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('TFF1', 'Gene', (296, 300))	('tobacco', 'Species', '4097', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
429274	29296124	Finally, we show that silencing of TFF1 expression by promoter hypermethylation is a specific feature of ESCC, since the same profile was not observed in esophageal adenocarcinoma.	('expression', 'MPA', (40, 50))	('ESCC', 'Disease', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('promoter hypermethylation', 'Var', (54, 79))	('silencing', 'NegReg', (22, 31))	('esophageal adenocarcinoma', 'Disease', (154, 179))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (154, 179))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (154, 179))	('TFF1', 'Gene', (35, 39))
429281	29296124	In gastric cancer, the loss of TFF1 can contribute to the induction of pro-inflammatory and anti-apoptotic genes through activation of NF-kappaB pathway.	('NF-kappaB', 'Gene', (135, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('pro-inflammatory and', 'MPA', (71, 91))	('induction', 'MPA', (58, 67))	('gastric cancer', 'Disease', (3, 17))	('anti-apoptotic genes', 'Gene', (92, 112))	('loss', 'Var', (23, 27))	('NF-kappaB', 'Gene', '4790', (135, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('TFF1', 'Gene', (31, 35))	('activation', 'PosReg', (121, 131))
429283	29296124	For example, the absence of TFF1 enhances the tumorigenic abilities of MCF7, a breast cancer cell line, in vitro and in vivo.	('MCF7', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('enhances', 'PosReg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (46, 51))	('breast cancer', 'Disease', (79, 92))	('absence', 'Var', (17, 24))	('MCF7', 'CellLine', 'CVCL:0031', (71, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('TFF1', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
429284	29296124	Similarly, TFF1-KO also enhances tumor formation in ovary and lung using a 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis model.	('anthracene', 'Chemical', 'MESH:C034020', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('ovary', 'Disease', (52, 57))	('ovary', 'Disease', 'MESH:D010051', (52, 57))	('tumor', 'Disease', (33, 38))	('DMBA', 'Chemical', 'MESH:D015127', (107, 111))	('enhances', 'PosReg', (24, 32))	('7,12-dimethylbenz', 'Chemical', '-', (75, 92))	('TFF1-KO', 'Var', (11, 18))
429288	29296124	However, it is important to mention that EAC is closely related to gastric cancers with chromosomal instability and these two tumors clearly differ from gastric adenocarcinoma related to Epstein-Barr infection, microsatellite instability, and genomic stability.	('related', 'Reg', (56, 63))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('men', 'Species', '9606', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('EAC', 'Disease', (41, 44))	('chromosomal instability', 'Var', (88, 111))	('chromosomal instability', 'Phenotype', 'HP:0040012', (88, 111))	('tumors', 'Disease', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('Epstein-Barr infection', 'Disease', (187, 209))	('gastric adenocarcinoma', 'Disease', (153, 175))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('Epstein-Barr infection', 'Disease', 'MESH:D020031', (187, 209))	('gastric cancers', 'Phenotype', 'HP:0012126', (67, 82))	('differ', 'Reg', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('gastric cancers', 'Disease', (67, 82))	('gastric cancers', 'Disease', 'MESH:D013274', (67, 82))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (153, 175))
429308	26077392	Nonacid pepsin increases metrics of tumorigenicity in esophageal epithelial cells in vitro.	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('increases', 'PosReg', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Nonacid', 'Var', (0, 7))	('metrics', 'MPA', (25, 32))	('tumor', 'Disease', (36, 41))
429358	26077392	However, in the context of weak or non- acid reflux that afflicts the proximal airways, nonacid pepsin has been shown to activate inflammatory and carcinogenic signaling pathways, promote hyperproliferation, cell migration and anchorage-independent growth, and increase tumor volume in a hamster buccal pouch model.	('increase tumor', 'Disease', 'MESH:D009369', (261, 275))	('carcinogenic', 'Disease', 'MESH:D063646', (147, 159))	('carcinogenic', 'Disease', (147, 159))	('activate', 'PosReg', (121, 129))	('hamster', 'Species', '10034', (288, 295))	('increase tumor', 'Disease', (261, 275))	('cell migration', 'CPA', (208, 222))	('hyperproliferation', 'CPA', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('- acid reflux', 'Phenotype', 'HP:0002020', (38, 51))	('anchorage-independent growth', 'CPA', (227, 255))	('promote', 'PosReg', (180, 187))	('nonacid pepsin', 'Var', (88, 102))
429367	26077392	COX-2 inhibitors have been shown to abrogate cell proliferation in EAC cells in vitro, reduce tumor incidence in animal models of EAC, and slow Barrett's epithelium cell proliferation in a clinical trial.	('slow', 'NegReg', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('abrogate', 'NegReg', (36, 44))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('cell proliferation', 'CPA', (45, 63))	('tumor', 'Disease', (94, 99))	('COX-2', 'Gene', '4513', (0, 5))	('inhibitors', 'Var', (6, 16))	('COX-2', 'Gene', (0, 5))	('EAC', 'Phenotype', 'HP:0011459', (67, 70))	('reduce', 'NegReg', (87, 93))
429376	26077392	The rapid and concomitant rise of EAC with PPI usage over the last 40 years clearly illustrates the failure of the current acid-targeting treatment paradigm to prevent reflux-attributed carcinogenesis and implicates nonacid reflux in development and progression of EAC.	('PPI', 'Var', (43, 46))	('EAC', 'Phenotype', 'HP:0011459', (34, 37))	('EAC', 'Disease', (34, 37))	('EAC', 'Phenotype', 'HP:0011459', (265, 268))	('carcinogenesis', 'Disease', 'MESH:D063646', (186, 200))	('EAC', 'Disease', (265, 268))	('carcinogenesis', 'Disease', (186, 200))
429407	11855155	The ratios of the adenocarcinoma group to the SCCA group among the three groups were 0.0375, 0.0241 and 0.0292 for group 1, 2 and 3, respectively (p=0.811).	('0.0241', 'Var', (93, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (18, 32))	('0.0292', 'Var', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('adenocarcinoma', 'Disease', (18, 32))
429469	22162921	When compared with H2RA, PPI therapy has been shown to be more efficacious in preventing the progression of Barrett's esophagus to both dysplasia and esophageal adenocarcinoma.	("Barrett's esophagus", 'Disease', (108, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('dysplasia and esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (136, 175))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (150, 175))	('PPI therapy', 'Var', (25, 36))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (108, 127))	('H2RA', 'Chemical', '-', (19, 23))
429470	22162921	In observational studies, PPI therapy has been shown to be associated with a lower risk of developing low-grade dysplasia, high-grade dysplasia, and esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (149, 174))	('esophageal adenocarcinoma', 'Disease', (149, 174))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (149, 174))	('PPI therapy', 'Var', (26, 37))	('dysplasia', 'Disease', (134, 143))	('dysplasia', 'Disease', (112, 121))	('dysplasia', 'Disease', 'MESH:D004476', (112, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('dysplasia', 'Disease', 'MESH:D004476', (134, 143))
429471	22162921	A study by El Serag et al found the incidence of any grade dysplasia to be significantly lower amongst those receiving PPIs after a diagnosis of Barrett's esophagus compared with those not treated by PPIs.	('lower', 'NegReg', (89, 94))	('any', 'Disease', (49, 52))	('PPIs', 'Var', (119, 123))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (145, 164))	('dysplasia', 'Disease', (59, 68))	('dysplasia', 'Disease', 'MESH:D004476', (59, 68))
429477	22162921	COX-2 inhibition has been shown to suppress cell growth and increase apoptosis in Barrett's esophagus-associated esophageal adenocarcinoma cell lines.	('esophageal adenocarcinoma', 'Disease', (113, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (82, 101))	('increase', 'PosReg', (60, 68))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (113, 138))	('COX-2', 'Gene', '4513', (0, 5))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (113, 138))	('cell growth', 'CPA', (44, 55))	('inhibition', 'Var', (6, 16))	('apoptosis', 'CPA', (69, 78))	('COX-2', 'Gene', (0, 5))	('suppress', 'NegReg', (35, 43))
429525	22162921	Endoscopic therapy for high-grade dysplasia or intramucosal carcinoma is performed with the goal of preserving the esophagus while ablating all Barrett's esophagus epithelium to prevent neoplastic progression.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (144, 163))	('dysplasia or intramucosal carcinoma', 'Disease', 'MESH:D002277', (34, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('ablating', 'Var', (131, 139))	('dysplasia or intramucosal carcinoma', 'Disease', (34, 69))
429544	22162921	Disease progression was lower in the ablation group (3.6% versus 16.3%) and fewer cancers were noted (1.2% versus 9.3%).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Disease progression', 'CPA', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('ablation', 'Var', (37, 45))	('lower', 'NegReg', (24, 29))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))
429611	22162921	For patients with nondysplastic Barrett's esophagus, treatment with a PPI may decrease acid exposure and delay the progression to dysplasia.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (32, 51))	("nondysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (18, 51))	('decrease', 'NegReg', (78, 86))	("nondysplastic Barrett's esophagus", 'Disease', (18, 51))	('acid exposure', 'MPA', (87, 100))	('dysplasia', 'Disease', (130, 139))	('patients', 'Species', '9606', (4, 12))	('dysplasia', 'Disease', 'MESH:D004476', (130, 139))	('PPI', 'Var', (70, 73))	('delay', 'NegReg', (105, 110))
429745	33628778	In conclusion, the modified target volume definition and increased dose of definitive chemoradiotherapy in patients with ESCC had low toxicity and might improve survival, but additional trials are necessary to prove the superiority of this strategy.	('toxicity', 'Disease', 'MESH:D064420', (134, 142))	('toxicity', 'Disease', (134, 142))	('modified', 'Var', (19, 27))	('improve', 'PosReg', (153, 160))	('survival', 'MPA', (161, 169))	('ESCC', 'Disease', (121, 125))	('patients', 'Species', '9606', (107, 115))
429794	32686281	In an ESCC rat model, the authors observed that CCL2 was associated with TAM accumulation in esophageal carcinogenesis induced by nitrosamine.	('CCL2', 'Var', (48, 52))	('esophageal carcinogenesis', 'Disease', (93, 118))	('rat', 'Species', '10116', (11, 14))	('nitrosamine', 'Chemical', 'MESH:D009602', (130, 141))	('TAM', 'Chemical', '-', (73, 76))
429804	32686281	They found that M2 polarization of TAMs could upregulate PD-L2 expression to enhance immunosuppression in ESCC.	('PD-L2', 'Gene', '58205', (57, 62))	('upregulate', 'PosReg', (46, 56))	('ESCC', 'Disease', (106, 110))	('PD-L2', 'Gene', (57, 62))	('expression', 'MPA', (63, 73))	('M2 polarization', 'Var', (16, 31))	('immunosuppression', 'MPA', (85, 102))	('TAMs', 'Chemical', '-', (35, 39))	('enhance', 'PosReg', (77, 84))
429826	30062088	With the development of sensitive techniques that can detect rare mutations, the heterogeneous landscape of tumors can be determined using blood samples.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
429831	30062088	In addition, importantly, amplification in ctDNA can be depend on both the amount of ctDNA in the plasma due to high tumor burden and high copy number of specific gene.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('depend', 'Reg', (56, 62))	('high copy number', 'Var', (134, 150))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
429837	30062088	The use of several biomarkers in ctDNA including the levels of overall ctDNA, ALU247 fragment concentration, KRAS mutations, TP53 mutations, BRAF mutations, and septin 9 (SEPT9) methylation have been demonstrated for the diagnosis of CRC.	('BRAF', 'Gene', (141, 145))	('CRC', 'Phenotype', 'HP:0003003', (234, 237))	('ALU247 fragment concentration', 'MPA', (78, 107))	('mutations', 'Var', (146, 155))	('SEPT9', 'Gene', '10801', (171, 176))	('TP53', 'Gene', '7157', (125, 129))	('SEPT9', 'Gene', (171, 176))	('KRAS', 'Gene', (109, 113))	('TP53', 'Gene', (125, 129))	('mutations', 'Var', (130, 139))	('septin 9', 'Gene', '10801', (161, 169))	('KRAS', 'Gene', '3845', (109, 113))	('CRC', 'Disease', (234, 237))	('BRAF', 'Gene', '673', (141, 145))	('septin 9', 'Gene', (161, 169))
429838	30062088	Also, detection of methylated SEPT9 DNA in plasma is US FDA approved as a blood test for CRC screening.	('methylated', 'Var', (19, 29))	('SEPT9', 'Gene', '10801', (30, 35))	('SEPT9', 'Gene', (30, 35))	('CRC', 'Disease', (89, 92))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))
429843	30062088	In addition, because many cancers share common gene mutations such as TP53 mutations and KRAS mutations, ctDNA presents challenges in the detection of the specific organ sites of malignancies.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('mutations', 'Var', (94, 103))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('TP53', 'Gene', '7157', (70, 74))	('malignancies', 'Disease', (179, 191))	('cancers', 'Disease', (26, 33))	('TP53', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (75, 84))	('KRAS', 'Gene', (89, 93))	('KRAS', 'Gene', '3845', (89, 93))
429845	30062088	Methylation haplotyping in plasma is a promising strategy for the early detection of a tumor and its primary growth site.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('Methylation haplotyping', 'Var', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
429846	30062088	Studies have reported the utility of methylation scores from over 9,000 CpG sites in cfDNA for cancer detection, with 76.3% accuracy for the prediction of cancer type.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('methylation', 'Var', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
429852	30062088	In addition, methylated BCAT1/IKZF1 have been evaluated as biomarkers for CRC.	('IKZF1', 'Gene', '10320', (30, 35))	('methylated', 'Var', (13, 23))	('IKZF1', 'Gene', (30, 35))	('CRC', 'Disease', (74, 77))	('BCAT1', 'Gene', (24, 29))	('CRC', 'Phenotype', 'HP:0003003', (74, 77))	('BCAT1', 'Gene', '586', (24, 29))
429854	30062088	In a meta-analysis of 16 studies including 1,193 patients with GC, the presence of ctDNA was significantly associated with the shorter disease-free survival (HR 4.36, 95% CI 3.08-6.16, p < 0.001) and overall survival (HR 1.77, 95% CI 1.38-2.28, p < 0.001) of GC patients, with high specificity (0.95, 95% CI 0.93-0.96) and relatively moderate sensitivity (0.62, 95% CI 0.59-0.65).	('shorter', 'NegReg', (127, 134))	('GC', 'Phenotype', 'HP:0012126', (63, 65))	('GC', 'Phenotype', 'HP:0012126', (259, 261))	('overall survival', 'CPA', (200, 216))	('presence', 'Var', (71, 79))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (262, 270))	('disease-free survival', 'CPA', (135, 156))	('ctDNA', 'Gene', (83, 88))
429856	30062088	Similarly, several studies have reported the tumor-associated mutations in ctDNA and the prognosis of patients with esophageal cancer; however, these studies included a limited number of patients, and further investigations are warranted.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('patients', 'Species', '9606', (187, 195))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Disease', (45, 50))	('ctDNA', 'Gene', (75, 80))	('mutations', 'Var', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('esophageal cancer', 'Disease', (116, 133))
429867	30062088	In addition, the retrospective exploratory analysis in a biomarker subgroup of the CORRECT trial, which was a phase III trial investigating the efficacy and safety of regorafenib in patients with mCRC, confirmed the utility of detecting KRAS, BRAF, and PIK3CA mutations in ctDNA.	('PIK3CA', 'Gene', (253, 259))	('KRAS', 'Gene', (237, 241))	('regorafenib', 'Chemical', 'MESH:C559147', (167, 178))	('KRAS', 'Gene', '3845', (237, 241))	('BRAF', 'Gene', '673', (243, 247))	('PIK3CA', 'Gene', '5290', (253, 259))	('BRAF', 'Gene', (243, 247))	('patients', 'Species', '9606', (182, 190))	('CRC', 'Phenotype', 'HP:0003003', (197, 200))	('detecting', 'Reg', (227, 236))	('mutations', 'Var', (260, 269))
429868	30062088	Plasma DNA detected with BEAMing in 503 patients demonstrated that mutation status in ctDNA changed dynamically during chemotherapy and differed from that in pretreatment archival tissue.	('mutation', 'Var', (67, 75))	('patients', 'Species', '9606', (40, 48))	('differed', 'Reg', (136, 144))	('changed', 'Reg', (92, 99))	('ctDNA', 'Gene', (86, 91))
429869	30062088	This assay is a qualitative PCR-based test and allows for the detection of 34 mutations within exons 2, 3, and 4 of KRAS and NRAS genes from a single blood sample.	('NRAS', 'Gene', (125, 129))	('NRAS', 'Gene', '4893', (125, 129))	('mutations', 'Var', (78, 87))	('KRAS', 'Gene', (116, 120))	('KRAS', 'Gene', '3845', (116, 120))
429873	30062088	This study suggested that the emergence of KRAS mutations is a mechanism of resistance to anti-EGFR therapy and that these mutations may be detected in ctDNA as a more sensitive monitoring tool than radiological imaging.	('KRAS', 'Gene', (43, 47))	('EGFR', 'Gene', '1956', (95, 99))	('KRAS', 'Gene', '3845', (43, 47))	('mutations', 'Var', (48, 57))	('EGFR', 'Gene', (95, 99))
429874	30062088	More recently, other studies have also demonstrated mutations associated with the resistance and decline of mutant KRAS clones after the withdrawal of anti-EGFR therapy.	('EGFR', 'Gene', '1956', (156, 160))	('KRAS', 'Gene', (115, 119))	('decline', 'NegReg', (97, 104))	('mutant', 'Var', (108, 114))	('KRAS', 'Gene', '3845', (115, 119))	('EGFR', 'Gene', (156, 160))
429875	30062088	BRAF mutations have been confirmed to be associated with poor prognosis in patients with metastatic CRC; moreover, the limited efficacy of anti-EGFR therapy in patients with BRAF-mutant metastatic CRC has been shown in several studies.	('EGFR', 'Gene', (144, 148))	('patients', 'Species', '9606', (160, 168))	('metastatic CRC', 'Disease', (186, 200))	('CRC', 'Phenotype', 'HP:0003003', (100, 103))	('patients', 'Species', '9606', (75, 83))	('BRAF', 'Gene', '673', (174, 178))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (174, 178))	('metastatic CRC', 'Disease', (89, 103))	('CRC', 'Phenotype', 'HP:0003003', (197, 200))	('BRAF', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (144, 148))
429876	30062088	The analysis of BRAF mutations in ctDNA by using qPCR-based methods has shown specificity and sensitivity of 100%.	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('mutations', 'Var', (21, 30))
429879	30062088	This exploratory analysis suggested that the monitoring of BRAF V600E mutant fraction in ctDNA could effectively predict response to combination therapy including a BRAF inhibitor and that overcoming the emergence of RAS-mutant subclones is important in combating resistance to this combination therapy.	('BRAF', 'Gene', '673', (165, 169))	('BRAF', 'Gene', (59, 63))	('predict', 'Reg', (113, 120))	('BRAF', 'Gene', (165, 169))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('BRAF', 'Gene', '673', (59, 63))	('V600E', 'Var', (64, 69))
429880	30062088	HER2 or MET amplification is also known as a mechanism of resistance to anti-EGFR therapy in patients with metastatic CRC.	('metastatic CRC', 'Disease', (107, 121))	('patients', 'Species', '9606', (93, 101))	('EGFR', 'Gene', '1956', (77, 81))	('HER2', 'Gene', (0, 4))	('CRC', 'Phenotype', 'HP:0003003', (118, 121))	('HER2', 'Gene', '2064', (0, 4))	('EGFR', 'Gene', (77, 81))	('MET amplification', 'Var', (8, 25))
429882	30062088	In addition, the frequency of HER2 amplifications increased from approximately 3% in treatment-naive patients to over 10% in patients who were administered anti-EGFR therapy.	('patients', 'Species', '9606', (101, 109))	('EGFR', 'Gene', (161, 165))	('increased', 'PosReg', (50, 59))	('amplifications', 'Var', (35, 49))	('HER2', 'Gene', (30, 34))	('HER2', 'Gene', '2064', (30, 34))	('EGFR', 'Gene', '1956', (161, 165))	('patients', 'Species', '9606', (125, 133))
429888	30062088	Furthermore, MET amplification in ctDNA was not detected in patients with RAS mutations after cetuximab therapy, thus suggesting that MET amplification is one of the mechanisms (other than RAS mutations) that cause resistance to anti-EGFR therapy.	('MET', 'Var', (134, 137))	('EGFR', 'Gene', (234, 238))	('cause', 'Reg', (209, 214))	('cetuximab', 'Chemical', 'MESH:D000068818', (94, 103))	('resistance', 'MPA', (215, 225))	('patients', 'Species', '9606', (60, 68))	('EGFR', 'Gene', '1956', (234, 238))
429889	30062088	In a phase Ib trial of cabozantinib and panitumumab combination therapy, the preliminary evidence of efficacy in patients with MET-amplified metastatic CRC was reported.	('panitumumab', 'Chemical', 'MESH:D000077544', (40, 51))	('metastatic CRC', 'Disease', (141, 155))	('patients', 'Species', '9606', (113, 121))	('CRC', 'Phenotype', 'HP:0003003', (152, 155))	('cabozantinib', 'Chemical', 'MESH:C558660', (23, 35))	('MET-amplified', 'Var', (127, 140))
429890	30062088	The amplification of the HER2 gene or overexpression of the HER2 protein, which contributes to cancer progression, has been reported in approximately 20% of patients with advanced GC.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('protein', 'Protein', (65, 72))	('HER2', 'Gene', (60, 64))	('cancer', 'Disease', (95, 101))	('reported', 'Reg', (124, 132))	('patients', 'Species', '9606', (157, 165))	('HER2', 'Gene', '2064', (60, 64))	('GC', 'Phenotype', 'HP:0012126', (180, 182))	('overexpression', 'PosReg', (38, 52))	('amplification', 'Var', (4, 17))	('HER2', 'Gene', (25, 29))	('HER2', 'Gene', '2064', (25, 29))
429892	30062088	The gold-standard diagnostic method for detecting HER2 positivity and suitability for trastuzumab therapy is an immunohistochemistry score of 3+ or 2+ with a positive result in fluorescence in situ hybridization.	('trastuzumab', 'Chemical', 'MESH:D000068878', (86, 97))	('HER2', 'Gene', '2064', (50, 54))	('positivity', 'Var', (55, 65))	('HER2', 'Gene', (50, 54))
429894	30062088	More recently, the droplet digital PCR of HER2 copy number in ctDNA has been reported.	('HER2', 'Gene', '2064', (42, 46))	('ctDNA', 'Disease', (62, 67))	('copy number', 'Var', (47, 58))	('HER2', 'Gene', (42, 46))
429896	30062088	Considering that HER2 status may be altered after recurrence, the HER2 copy number analysis in ctDNA enables the real-time evaluation of HER2 status and leads to more effective treatment choices with HER2-targeted agents.	('copy number', 'Var', (71, 82))	('HER2', 'Gene', '2064', (66, 70))	('HER2', 'Gene', (200, 204))	('HER2', 'Gene', '2064', (200, 204))	('HER2', 'Gene', (17, 21))	('HER2', 'Gene', (137, 141))	('HER2', 'Gene', '2064', (17, 21))	('HER2', 'Gene', '2064', (137, 141))	('HER2', 'Gene', (66, 70))
429901	30062088	In addition, an umbrella trial in patients with mCRC based on the molecular profiling of ctDNA, including the status of HER2, BRAF V600E, BRAF non-V600E, MET, or high tumor mutation burden, is ongoing in Japan.	('V600E', 'Mutation', 'rs113488022', (131, 136))	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('BRAF', 'Gene', '673', (138, 142))	('V600E', 'Var', (131, 136))	('HER2', 'Gene', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('BRAF', 'Gene', (126, 130))	('MET', 'Var', (154, 157))	('HER2', 'Gene', '2064', (120, 124))	('BRAF', 'Gene', '673', (126, 130))	('patients', 'Species', '9606', (34, 42))	('V600E', 'Mutation', 'rs113488022', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('BRAF', 'Gene', (138, 142))	('tumor', 'Disease', (167, 172))
429907	28491151	Methylation of DIRAS1 promotes colorectal cancer progression and may serve as a marker for poor prognosis DIRAS1 is a new member of the Ras gene family.	('DIRAS1', 'Gene', '148252', (106, 112))	('promotes', 'PosReg', (22, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Methylation', 'Var', (0, 11))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('DIRAS1', 'Gene', (15, 21))	('colorectal cancer', 'Disease', (31, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('DIRAS1', 'Gene', '148252', (15, 21))	('DIRAS1', 'Gene', (106, 112))
429912	28491151	DIRAS1 was methylated in 47.3% (69/146) of primary colorectal cancer samples, no methylation was found in non-cancerous colonic tissue samples.	('non-cancerous colonic', 'Disease', 'MESH:D015179', (106, 127))	('DIRAS1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('methylated', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('non-cancerous colonic', 'Disease', (106, 127))
429913	28491151	Methylation of DIRAS1 was significantly associated with TNM stage (P < 0.05) and short survival time (P = 0.0121).	('Methylation', 'Var', (0, 11))	('DIRAS1', 'Gene', (15, 21))	('TNM', 'Gene', '10178', (56, 59))	('associated', 'Reg', (40, 50))	('TNM', 'Gene', (56, 59))	('short survival time', 'CPA', (81, 100))
429916	28491151	Inactivation of gene function by germline mutations within at least one of four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) can be found in approximately 70% of cases, and 95% of the mutations occur in hMSH2 or hMLH1.	('PMS2', 'Gene', (125, 129))	('hMSH2', 'Gene', (209, 214))	('MLH1', 'Gene', '4292', (103, 107))	('Inactivation', 'NegReg', (0, 12))	('MSH2', 'Gene', (109, 113))	('mutations', 'Var', (190, 199))	('MLH1', 'Gene', (219, 223))	('gene function', 'MPA', (16, 29))	('hMLH1', 'Gene', (218, 223))	('MSH2', 'Gene', '4436', (109, 113))	('hMLH1', 'Gene', '4292', (218, 223))	('MSH2', 'Gene', (210, 214))	('MSH6', 'Gene', (115, 119))	('MLH1', 'Gene', '4292', (219, 223))	('PMS2', 'Gene', '5395', (125, 129))	('MSH6', 'Gene', '2956', (115, 119))	('germline mutations', 'Var', (33, 51))	('hMSH2', 'Gene', '4436', (209, 214))	('MSH2', 'Gene', '4436', (210, 214))	('MLH1', 'Gene', (103, 107))
429941	28491151	The association of DIRAS1 methylation and overall survival rate of patients were calculated by the Kaplan-Meier method, and differences in survival curve were evaluated using the log-rank test.	('methylation', 'Var', (26, 37))	('DIRAS1', 'Gene', (19, 25))	('patients', 'Species', '9606', (67, 75))
429942	28491151	Methylation of DIRAS1 was detected in 47.3% (69/146) of primary colorectal cancers, and no methylation was found in 50 cases of non-cancerous colonic tissue samples (Fig.	('colorectal cancers', 'Disease', 'MESH:D015179', (64, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('colorectal cancers', 'Disease', (64, 82))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('DIRAS1', 'Gene', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('detected', 'Reg', (26, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))
429949	28491151	Methylation of DIRAS1 may promote colorectal carcinogenesis and progression.	('promote', 'PosReg', (26, 33))	('progression', 'CPA', (64, 75))	('Methylation', 'Var', (0, 11))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (34, 59))	('DIRAS1', 'Gene', (15, 21))	('colorectal carcinogenesis', 'Disease', (34, 59))
430084	26275293	Whole exome sequencing of this tumor revealed mutations in many cancer-associated genes including ARID1A, PIK3CA, and TP53, and focal amplifications of HMGA2 and MET.	('ARID1A', 'Gene', '8289', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mutations', 'Var', (46, 55))	('ARID1A', 'Gene', (98, 104))	('PIK3CA', 'Gene', (106, 112))	('tumor', 'Disease', (31, 36))	('cancer', 'Disease', (64, 70))	('PIK3CA', 'Gene', '5290', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('HMGA2', 'Gene', '8091', (152, 157))	('MET', 'Gene', (162, 165))	('HMGA2', 'Gene', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
430088	26275293	Aberrant activation of receptor tyrosine kinases (RTKs) through oncogene amplifications or mutations are particularly prevalent in gastroesophageal (GE) junction tumors, and it is likely that combinations of alterations in multiple oncogenic pathways drive EG cancer growth.	('activation', 'PosReg', (9, 19))	('gastroesophageal (GE) junction tumors', 'Disease', 'MESH:D008309', (131, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('prevalent', 'Reg', (118, 127))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('oncogene', 'Gene', (64, 72))	('cancer', 'Disease', (260, 266))	('amplifications', 'Var', (73, 87))	('mutations', 'Var', (91, 100))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
430128	26275293	Esophageal adenocarcinoma from the complete responder harbored 18 mutations including mutations in p53, AIRD1A, PIK3CA and MET gene.	('MET', 'Gene', (123, 126))	('mutations', 'Var', (86, 95))	('Esophageal adenocarcinoma', 'Disease', (0, 25))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (0, 25))	('PIK3CA', 'Gene', '5290', (112, 118))	('AIRD1A', 'Gene', (104, 110))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('PIK3CA', 'Gene', (112, 118))
430129	26275293	In addition, this tumor had focal amplification of HMGA2 and MET genes.	('HMGA2', 'Gene', (51, 56))	('HMGA2', 'Gene', '8091', (51, 56))	('MET', 'Gene', (61, 64))	('tumor', 'Disease', (18, 23))	('amplification', 'Var', (34, 47))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
430130	26275293	Adenocarcinoma from the patient with 9 months disease stabilization harbored 21 mutations, including p53, ERBB2 and ERCC1 mutations as well as focal amplifications involving ERBB2 and CCND1.	('Adenocarcinoma', 'Disease', (0, 14))	('CCND1', 'Gene', (184, 189))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('ERBB2', 'Gene', '2064', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('ERBB2', 'Gene', '2064', (174, 179))	('ERBB2', 'Gene', (106, 111))	('patient', 'Species', '9606', (24, 31))	('p53', 'Gene', (101, 104))	('ERBB2', 'Gene', (174, 179))	('p53', 'Gene', '7157', (101, 104))	('CCND1', 'Gene', '595', (184, 189))	('mutations', 'Var', (122, 131))	('ERCC1', 'Gene', '2067', (116, 121))	('ERCC1', 'Gene', (116, 121))
430131	26275293	Lastly, a tumor from a patient with metastatic esophageal squamous cell with 5 months stable disease revealed 8 mutations, including p53 mutation and focal amplifications of PIK3CA, SOX2, NOTCH2, and IGF1R.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('IGF1R', 'Gene', (200, 205))	('NOTCH2', 'Gene', (188, 194))	('SOX2', 'Gene', '6657', (182, 186))	('PIK3CA', 'Gene', (174, 180))	('mutation', 'Var', (137, 145))	('IGF1R', 'Gene', '3480', (200, 205))	('tumor', 'Disease', (10, 15))	('p53', 'Gene', '7157', (133, 136))	('patient', 'Species', '9606', (23, 30))	('NOTCH2', 'Gene', '4853', (188, 194))	('PIK3CA', 'Gene', '5290', (174, 180))	('p53', 'Gene', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('SOX2', 'Gene', (182, 186))
430147	26275293	Such analysis identified oncogenic ARAF mutations in a lung adenocarcinoma patient with near complete radiographic response for 5 years to single agent sorafenib.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('ARAF', 'Gene', (35, 39))	('patient', 'Species', '9606', (75, 82))	('lung adenocarcinoma', 'Disease', (55, 74))	('sorafenib', 'Chemical', 'MESH:D000077157', (152, 161))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('mutations', 'Var', (40, 49))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('ARAF', 'Gene', '369', (35, 39))
430174	26134607	Preoperative endoscopy was performed by using an Evis Lucera Spectrum system (Olympus, Tokyo, Japan) with a magnifying upper gastrointestinal endoscope (GIF-H260Z; Olympus).	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (119, 151))	('H260Z', 'Var', (157, 162))	('H260Z', 'SUBSTITUTION', 'None', (157, 162))	('GIF', 'Gene', (153, 156))	('GIF', 'Gene', '2694', (153, 156))	('upper gastrointestinal endoscope', 'Disease', (119, 151))
430181	26134607	Barrett's adenocarcinoma was defined as cancer arising from Barrett's esophagus, which was defined by the presence of esophageal glands, duplication of the muscularis mucosae under the lesions, or a squamous island within the lesions, in accordance with the Japanese Classification of Esophageal Cancer.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (60, 79))	('duplication', 'Var', (137, 148))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (285, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Cancer', 'Phenotype', 'HP:0002664', (296, 302))	("Barrett's adenocarcinoma", 'Disease', (0, 24))	('Esophageal Cancer', 'Disease', (285, 302))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
430201	25710005	Association of Polymorphisms in X-Ray Repair Cross Complementing 1 Gene and Risk of Esophageal Squamous Cell Carcinoma in a Chinese Population Objectives.	('Esophageal Squamous Cell Carcinoma', 'Disease', (84, 118))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (84, 118))	('Carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('X-Ray Repair Cross Complementing 1', 'Gene', '7515', (32, 66))	('X-Ray Repair Cross Complementing 1', 'Gene', (32, 66))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('Association', 'Interaction', (0, 11))	('Polymorphisms', 'Var', (15, 28))
430202	25710005	To investigate the association between three single nucleotide polymorphisms (SNPs) in the X-ray repair cross complementing 1 gene (XRCC1) and the risk of esophageal squamous cell carcinoma (ESCC) in Chinese population.	('X-ray repair cross complementing 1', 'Gene', (91, 125))	('single nucleotide polymorphisms', 'Var', (45, 76))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (155, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('XRCC1', 'Gene', '7515', (132, 137))	('X-ray repair cross complementing 1', 'Gene', '7515', (91, 125))	('esophageal squamous cell carcinoma', 'Disease', (155, 189))	('XRCC1', 'Gene', (132, 137))
430204	25710005	The genotypes of three XRCC1 polymorphisms at -77T>C (T-77C), codon 194 (Arg194Trp), and codon 399 (Arg399Gln) were studied by means of polymerase chain reaction-restriction fragment length polymorphism techniques (PCR-RFLP).	('-77T>C', 'Mutation', 'rs3213245', (46, 52))	('Arg194Trp', 'Var', (73, 82))	('Arg399Gln', 'Var', (100, 109))	('Arg399Gln', 'SUBSTITUTION', 'None', (100, 109))	('T-77C', 'Mutation', 'rs3213245', (54, 59))	('Arg194Trp', 'SUBSTITUTION', 'None', (73, 82))	('XRCC1', 'Gene', (23, 28))
430205	25710005	These results suggested that the gene-gene interactions might play vital roles in the progression on esophageal cancer in Chinese Han population and it would be necessary to confirm these findings in a large and multiethnic population.	('roles', 'Reg', (73, 78))	('interactions', 'Var', (43, 55))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
430210	25710005	Oxidative damage to DNA may lead to mutations that activate oncogenes or inactivate tumor suppressor genes and may eventually increase the probability of genetic alterations developing into neoplastic events.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('genetic alterations', 'MPA', (154, 173))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('activate', 'PosReg', (51, 59))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (84, 89))	('lead', 'Reg', (28, 32))	('oncogenes', 'Protein', (60, 69))	('increase', 'PosReg', (126, 134))	('inactivate', 'NegReg', (73, 83))
430212	25710005	There are more than 60 validated single nucleotide polymorphisms (SNPs) in the XRCC1 gene containing 17 exons and 16 introns on chromosome 19q13.2-13.3, among which three polymorphisms in the XRCC1 gene at the -77T>C (5' end, T to C), codon 194 (exon 6, Arg to Trp), and codon 399 (exon 10, Arg to Gln) have been studied.	('-77T>C', 'Var', (210, 216))	('XRCC1', 'Gene', (79, 84))	('XRCC1', 'Gene', (192, 197))	('Arg to Trp', 'Var', (254, 264))	('-77T>C', 'SUBSTITUTION', 'None', (210, 216))
430213	25710005	The genetic polymorphism of XRCC1 codon 194 results in an arginine to tryptophan amino acid substitution and occurs at a conserved residue in humans, hamsters, and mice, and this evolutionary conservation suggests that this site is functionally important.	('mice', 'Species', '10090', (164, 168))	('results in', 'Reg', (44, 54))	('tryptophan amino acid', 'Chemical', '-', (70, 91))	('XRCC1', 'Gene', (28, 33))	('polymorphism', 'Var', (12, 24))	('arginine', 'Chemical', 'MESH:D001120', (58, 66))	('arginine to tryptophan', 'MPA', (58, 80))	('humans', 'Species', '9606', (142, 148))
430214	25710005	The genetic polymorphism in the XRCC1 gene at codon 399 results in an arginine to glutamine amino acid substitution.	('arginine to', 'Var', (70, 81))	('results in', 'Reg', (56, 66))	('glutamine amino acid', 'Chemical', '-', (82, 102))	('XRCC1', 'Gene', (32, 37))
430215	25710005	A report of Lunn and colleagues measured the prevalence of aflatoxin B1 adducts in placental DNA from 120 Taiwanese women and suggested that the XRCC1 codon 399 polymorphism may result in deficient DNA repair capacity.	('DNA repair', 'MPA', (198, 208))	('deficient', 'NegReg', (188, 197))	('women', 'Species', '9606', (116, 121))	('XRCC1', 'Gene', (145, 150))	('polymorphism', 'Var', (161, 173))	('codon 399 polymorphism', 'Var', (151, 173))
430216	25710005	showed that -77T>C can increase the combination of XRCC1 promoter and a transcription inhibitory factor, thus reducing the promoter activity and protein expression.	('combination', 'Interaction', (36, 47))	('-77T>C', 'SUBSTITUTION', 'None', (12, 18))	('reducing', 'NegReg', (110, 118))	('increase', 'PosReg', (23, 31))	('protein expression', 'MPA', (145, 163))	('promoter activity', 'MPA', (123, 140))	('XRCC1', 'Gene', (51, 56))	('-77T>C', 'Var', (12, 18))
430217	25710005	Thus, we conducted this case-control study to comprehensively investigate the role of the polymorphisms (codon 194, codon 399, and -77T>C) in XRCC1 gene in the development of ESCC in a Chinese Han population.	('-77T>C', 'SUBSTITUTION', 'None', (131, 137))	('codon 194', 'Var', (105, 114))	('codon 399', 'Var', (116, 125))	('ESCC', 'Disease', (175, 179))	('-77T>C', 'Var', (131, 137))	('XRCC1', 'Gene', (142, 147))
430226	25710005	The genotype distributions of the three studied SNPs in controls were all in accordance with Hardy-Weinberg equilibrium; the P value was 0.28, 0.79, and 0.09 for codon 194, codon 399, and -77T>C, respectively.	('-77T>C', 'SUBSTITUTION', 'None', (188, 194))	('-77T>C', 'Var', (188, 194))	('codon 399', 'Var', (173, 182))	('codon 194', 'Var', (162, 171))
430227	25710005	The heterozygous genotype TC, combined genotype TC or CC, and allele C of XRCC1 -77T>C may decrease risk of ESCC; however, there was no significantly statistical association after adjusting age, gender, smoking, drinking, and family history of cancer.	('XRCC1', 'Gene', (74, 79))	('-77T>C', 'SUBSTITUTION', 'None', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('-77T>C', 'Var', (80, 86))	('ESCC', 'Disease', (108, 112))	('decrease', 'NegReg', (91, 99))
430228	25710005	In order to study the haplotypes for XRCC1 codon 194, codon 399, and -77T>C, SNPHAP 2.0 software was applied, showing a total of eight built haplotypes.	('-77T>C', 'SUBSTITUTION', 'None', (69, 75))	('-77T>C', 'Var', (69, 75))	('XRCC1', 'Gene', (37, 42))
430229	25710005	For every susceptibility analysis of a haplotype, the haplotype CGT (codon 194, codon 399, and -77T>C) containing major allele was taken as control.	('CGT', 'Gene', '7368', (64, 67))	('codon 399', 'Var', (80, 89))	('CGT', 'Gene', (64, 67))	('-77T>C', 'SUBSTITUTION', 'None', (95, 101))	('codon 194', 'Var', (69, 78))	('-77T>C', 'Var', (95, 101))
430230	25710005	The data of Table 4 indicated that only haplotype CGC (codon 194, codon 399, and -77T>C) may decrease risk for developing ESCC compared to the control after adjusting age, gender, smoking, drinking, and family history of cancer (OR: 0.62, 95% CI: 0.40-0.96).	('-77T>C', 'Var', (81, 87))	('haplotype', 'Var', (40, 49))	('ESCC', 'Disease', (122, 126))	('-77T>C', 'SUBSTITUTION', 'None', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('decrease', 'NegReg', (93, 101))	('codon 194', 'Var', (55, 64))	('codon 399', 'Var', (66, 75))
430232	25710005	XRCC1 polymorphisms have been reported to be associated with the risk of different kinds of cancers, including gastric cancer, colorectal cancer, lung cancer, and breast cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('polymorphisms', 'Var', (6, 19))	('associated', 'Reg', (45, 55))	('colorectal cancer', 'Disease', (127, 144))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('lung cancer', 'Disease', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('breast cancer', 'Disease', (163, 176))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('XRCC1', 'Gene', (0, 5))	('cancers', 'Disease', (92, 99))	('gastric cancer', 'Disease', (111, 125))
430233	25710005	founded that there was no relationship between polymorphism of XRCC1 codon 194 and esophageal adenocarcinoma (EA) susceptibility in Canada population.	('XRCC1', 'Gene', (63, 68))	('EA', 'Phenotype', 'HP:0011459', (110, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (83, 108))	('esophageal adenocarcinoma', 'Disease', (83, 108))	('polymorphism', 'Var', (47, 59))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (83, 108))
430234	25710005	In this study we did not observe significant association between polymorphism of XRCC1 -77T>C and EC susceptibility.	('-77T>C', 'SUBSTITUTION', 'None', (87, 93))	('polymorphism', 'Var', (65, 77))	('-77T>C', 'Var', (87, 93))
430235	25710005	firstly reported the XRCC1 -77T>C polymorphism in 5' noncoding region in 2004, the results found that XRCC1 -77T>C can increase the combination of XRCC1 promoter and a transcription inhibitory factor, thus reducing the promoter activity and protein expression.	('combination', 'Interaction', (132, 143))	('-77T>C', 'SUBSTITUTION', 'None', (108, 114))	('reducing', 'NegReg', (206, 214))	('protein expression', 'MPA', (241, 259))	('-77T>C', 'Var', (27, 33))	('-77T>C', 'Var', (108, 114))	('increase', 'PosReg', (119, 127))	('promoter activity', 'MPA', (219, 236))	('-77T>C', 'SUBSTITUTION', 'None', (27, 33))
430236	25710005	However, they did not find the association of XRCC1 -77T>C polymorphism with ESCC susceptibility.	('ESCC', 'Disease', (77, 81))	('-77T>C', 'Var', (52, 58))	('-77T>C', 'SUBSTITUTION', 'None', (52, 58))
430237	25710005	The relationship between XRCC1 -77T>C and EC susceptibility needs to be clarified by more large size studies.	('-77T>C', 'SUBSTITUTION', 'None', (31, 37))	('XRCC1', 'Gene', (25, 30))	('-77T>C', 'Var', (31, 37))
430238	25710005	In conclusion, the present study suggested that the single polymorphism in the DNA repair gene XRCC1 was not statistically associated with risk of ESCC; however, haplotype CGC (codon 194, codon 399 and -77T>C) of three SNPs in XRCC1 gene may decrease risk for ESCC susceptibility.	('-77T>C', 'Var', (202, 208))	('XRCC1', 'Gene', (95, 100))	('ESCC', 'Disease', (260, 264))	('ESCC', 'Disease', (147, 151))	('XRCC1', 'Gene', (227, 232))	('-77T>C', 'SUBSTITUTION', 'None', (202, 208))	('decrease', 'NegReg', (242, 250))
430290	19139719	FISH analysis revealed no translocations of PAX5 gene, but polyploidy in some SCLC tumor tissues (6 /37).	('PAX5', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SCLC tumor', 'Disease', 'MESH:D018288', (78, 88))	('SCLC tumor', 'Disease', (78, 88))	('polyploidy', 'Var', (59, 69))
430294	19139719	Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274 and maximum effect was seen when both inhibitors were used.	('decreased', 'NegReg', (38, 47))	('SCLC', 'Gene', '7864', (65, 69))	('SCLC', 'Gene', (65, 69))	('SU11274', 'Chemical', 'MESH:C478479', (115, 122))	('PAX5', 'Protein', (19, 23))	('combined', 'Interaction', (93, 101))	('SN38', 'Var', (107, 111))	('Loss', 'NegReg', (0, 4))	('SU11274', 'Var', (115, 122))	('SN38', 'Chemical', 'MESH:D000077146', (107, 111))
430316	19139719	Since enforced expression of PAX5 in neuroblastoma S-type cells confers on them a more oncogenic phenotype and since PAX5 knockdown results in significant loss in cell viability, PAX5 is believed to not only support cancer cell survival but also contribute to metastasis.	('contribute', 'Reg', (246, 256))	('loss', 'NegReg', (155, 159))	('oncogenic', 'CPA', (87, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('support', 'PosReg', (208, 215))	('neuroblastoma', 'Disease', (37, 50))	('cell viability', 'CPA', (163, 177))	('knockdown', 'Var', (122, 131))	('PAX5', 'Gene', (117, 121))	('metastasis', 'CPA', (260, 270))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('neuroblastoma', 'Phenotype', 'HP:0003006', (37, 50))	('PAX5', 'Var', (179, 183))	('PAX5', 'Gene', (29, 33))
430329	19139719	The phospho specific (pY1230/1234/1235 anti-c-Met rabbit polyclonal was from Biosource (Carlsbad, CA) and the rabbit polyclonal against Ron-beta and the mouse monoclonal against Topoisomerase 1 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).	('pY1230/1234/1235', 'Var', (22, 38))	('rabbit', 'Species', '9986', (110, 116))	('Ron', 'Gene', '4486', (136, 139))	('Ron', 'Gene', (136, 139))	('rabbit', 'Species', '9986', (50, 56))	('mouse', 'Species', '10090', (153, 158))	('c-Met', 'Gene', (44, 49))	('c-Met', 'Gene', '4233', (44, 49))
430351	19139719	Further incubation with the appropriate secondary antibodies conjugated with fluorescein (CY3 and CY5) followed.	('CY5', 'Chemical', 'MESH:C085321', (98, 101))	('CY5', 'Var', (98, 101))	('CY3', 'Chemical', '-', (90, 93))	('fluorescein', 'Chemical', 'MESH:D019793', (77, 88))	('CY3', 'Var', (90, 93))
430369	19139719	SU11274 was used to inhibit c-Met at 2.5 microM, whereas SN38 was used at 2.5 nM.	('c-Met', 'Gene', '4233', (28, 33))	('SN38', 'Chemical', 'MESH:D000077146', (57, 61))	('SU11274', 'Var', (0, 7))	('SU11274', 'Chemical', 'MESH:C478479', (0, 7))	('inhibit', 'NegReg', (20, 27))	('c-Met', 'Gene', (28, 33))
430399	19139719	Fifteen (50%) SCLC exhibited increased PAX5 copy number (N3, N4 and/or N5), whereas one (3%) additional small cell carcinoma contained PAX5 tetraploid (N4) and octaploid (N8) cells.	('SCLC', 'Gene', '7864', (14, 18))	('SCLC', 'Gene', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('PAX5 tetraploid', 'Var', (135, 150))	('PAX5', 'Protein', (39, 43))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (104, 124))	('carcinoma', 'Disease', (115, 124))	('increased', 'PosReg', (29, 38))	('carcinoma', 'Disease', 'MESH:D002277', (115, 124))
430403	19139719	One non-synonymous heterozygous mutation 964G>AG leading to amino acid change A322S in the PAX5 gene was detected in cell line H146.	('964G>AG', 'Mutation', 'c.964G>AG', (41, 48))	('PAX5', 'Gene', (91, 95))	('A322S', 'SUBSTITUTION', 'None', (78, 83))	('A322S', 'Var', (78, 83))	('H146', 'CellLine', 'CVCL:1473', (127, 131))
430413	19139719	To demonstrate the endogenous relationship between PAX5 activity and c-Met protein levels, we knocked down PAX5 in H526 SCLC cells and determined the intracellular levels of c-Met.	('c-Met', 'Gene', (174, 179))	('c-Met', 'Gene', (69, 74))	('c-Met', 'Gene', '4233', (174, 179))	('c-Met', 'Gene', '4233', (69, 74))	('H526 SCLC', 'CellLine', 'CVCL:1569', (115, 124))	('PAX5', 'Gene', (107, 111))	('knocked', 'Var', (94, 101))
430424	19139719	In order to test the translational potential of PAX5 as an adjuvant chemotherapeutic target in SCLC therapy, as an initial step, we determined the effects of knockdown of PAX5 in H69 cells, individually and in combination with SU11274 (a specific c-Met inhibitor currently in clinical trials) and SN38 (a potent Topoisomerase 1 inhibitor and the active metabolite of irinotecan); a drug used in the treatment of SCLC.	('SCLC', 'Gene', '7864', (412, 416))	('SCLC', 'Gene', (412, 416))	('c-Met', 'Gene', (247, 252))	('c-Met', 'Gene', '4233', (247, 252))	('PAX5', 'Gene', (171, 175))	('H69', 'CellLine', 'CVCL:8121', (179, 182))	('SN38', 'Chemical', 'MESH:D000077146', (297, 301))	('irinotecan', 'Chemical', 'MESH:D000077146', (367, 377))	('knockdown', 'Var', (158, 167))	('SU11274', 'Chemical', 'MESH:C478479', (227, 234))	('SCLC', 'Gene', '7864', (95, 99))	('SCLC', 'Gene', (95, 99))
430427	19139719	The cell viability in the above knockdown cells further decreased when treated with either SU11274 or SN38, however the loss in viability was significantly higher in those cells treated with the Topo1 inhibitor SN38.	('SU11274', 'Chemical', 'MESH:C478479', (91, 98))	('SN38', 'Var', (102, 106))	('SU11274', 'Var', (91, 98))	('cell viability', 'CPA', (4, 18))	('SN38', 'Chemical', 'MESH:D000077146', (211, 215))	('decreased', 'NegReg', (56, 65))	('SN38', 'Chemical', 'MESH:D000077146', (102, 106))
430428	19139719	Finally, treatment of PAX5 knockdown cells with both SN38 and SU11274 compounds resulted in maximum loss in viability.	('viability', 'CPA', (108, 117))	('SN38', 'Chemical', 'MESH:D000077146', (53, 57))	('SU11274', 'Chemical', 'MESH:C478479', (62, 69))	('SU11274 compounds', 'Var', (62, 79))	('SN38', 'Var', (53, 57))	('loss', 'NegReg', (100, 104))
430464	19139719	In diffuse large B cell lymphomas and lymphoplasmacytoid lymphoma, a sub-type of B-cell non-Hodgkin's lymphoma, frequent translocation of the PAX5 gene to the IgH chain gene locus [t (9; 14) (p13; q32)] was reported most likely due to aberrant somatic hypermutation events.	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (92, 110))	('p13', 'Gene', (192, 195))	('lymphomas', 'Disease', 'MESH:D008223', (24, 33))	("Hodgkin's lymphoma", 'Disease', (92, 110))	('lymphoplasmacytoid lymphoma', 'Disease', (38, 65))	('lymphomas', 'Phenotype', 'HP:0002665', (24, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (57, 65))	('translocation', 'Var', (121, 134))	('p13', 'Gene', '440926', (192, 195))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (92, 110))	('IgH', 'Gene', '3492', (159, 162))	('IgH', 'Gene', (159, 162))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (17, 33))	('PAX5', 'Gene', (142, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))	('lymphoplasmacytoid lymphoma', 'Disease', 'MESH:D008258', (38, 65))	('lymphomas', 'Disease', (24, 33))
430466	19139719	We have used the FISH method that previously identified reproducibly PAX and non-PAX gene rearrangements in other cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('rearrangements', 'Var', (90, 104))	('PAX', 'Chemical', '-', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('PAX', 'Chemical', '-', (69, 72))
430473	19139719	The physiological relevance can be appreciated by the fact that knockdown of PAX5 in SCLC cells resulted in a substantial loss in c-Met protein expression, thereby linking directly expression of c-Met to PAX5.	('c-Met', 'Gene', '4233', (195, 200))	('PAX5', 'Gene', (77, 81))	('linking', 'Reg', (164, 171))	('SCLC', 'Gene', '7864', (85, 89))	('loss', 'NegReg', (122, 126))	('c-Met', 'Gene', (130, 135))	('knockdown', 'Var', (64, 73))	('SCLC', 'Gene', (85, 89))	('c-Met', 'Gene', (195, 200))	('c-Met', 'Gene', '4233', (130, 135))
430480	19139719	Since most of the SCLC has mutated p53 that makes it nonfunctional, the above role of PAX5 may not be relevant, however in those tumors that harbor wt p53, depending on the expression, PAX5 (or PAX2 and PAX8) is very likely to interfere with p53 transcription and thereby contribute to the tumor development.	('PAX5', 'Var', (185, 189))	('tumors', 'Disease', (129, 135))	('p53', 'Gene', (35, 38))	('PAX8', 'Gene', (203, 207))	('tumor', 'Disease', (129, 134))	('transcription', 'MPA', (246, 259))	('p53', 'Gene', '7157', (151, 154))	('PAX2', 'Gene', '5076', (194, 198))	('tumor', 'Disease', (290, 295))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('PAX8', 'Gene', '7849', (203, 207))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('contribute', 'Reg', (272, 282))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('interfere', 'NegReg', (227, 236))	('p53', 'Gene', (151, 154))	('mutated', 'Var', (27, 34))	('p53', 'Gene', '7157', (242, 245))	('PAX2', 'Gene', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('SCLC', 'Gene', '7864', (18, 22))	('p53', 'Gene', '7157', (35, 38))	('SCLC', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('p53', 'Gene', (242, 245))
430491	19139719	It is possible that in normal cells, nuclear c-Met binds to PAX5 and acts as a feedback inhibitor of PAX5 transcriptional activity, however in SCLC cells, although the mutated c-Met is translocated into the nucleus in HGF treated cells, its ability to inhibit PAX5 function may be lost and therefore led to the elevated levels of c-Met in SCLC.	('mutated', 'Var', (168, 175))	('SCLC', 'Gene', (339, 343))	('HGF', 'Gene', (218, 221))	('c-Met', 'Gene', (176, 181))	('c-Met', 'Gene', (45, 50))	('inhibit', 'NegReg', (252, 259))	('c-Met', 'Gene', (330, 335))	('lost', 'NegReg', (281, 285))	('PAX5', 'Gene', (260, 264))	('HGF', 'Gene', '3082', (218, 221))	('function', 'MPA', (265, 273))	('c-Met', 'Gene', '4233', (176, 181))	('c-Met', 'Gene', '4233', (45, 50))	('c-Met', 'Gene', '4233', (330, 335))	('elevated', 'PosReg', (311, 319))	('SCLC', 'Gene', '7864', (143, 147))	('SCLC', 'Gene', (143, 147))	('SCLC', 'Gene', '7864', (339, 343))
430492	19139719	Abrogation of PAX5 is known to decrease viability of cancer cells thereby suggesting that PAX5 is required for survival and proliferation.	('viability', 'CPA', (40, 49))	('Abrogation', 'Var', (0, 10))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('decrease', 'NegReg', (31, 39))	('PAX5', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
430498	19139719	Loss of PAX5 clearly decreases the viability of SCLC cells, however the decrease is much greater when combined with c-Met or Topo1 inhibitor; and the maximum effect is seen when all the three conditions are combined.	('PAX5', 'Gene', (8, 12))	('SCLC', 'Gene', (48, 52))	('decreases', 'NegReg', (21, 30))	('SCLC', 'Gene', '7864', (48, 52))	('viability', 'CPA', (35, 44))	('Loss', 'Var', (0, 4))	('c-Met', 'Gene', (116, 121))	('c-Met', 'Gene', '4233', (116, 121))
430595	18843013	In a mouse model, deletion of hypoxia-inducible transcription factor 1 (HIF-1), which regulates VEGF and CA IX expression, resulted in decreased pulmonary metastasis from breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('decreased pulmonary metastasis', 'Disease', (135, 165))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('hypoxia', 'Disease', (30, 37))	('HIF-1', 'Gene', (72, 77))	('breast cancer', 'Disease', (171, 184))	('hypoxia', 'Disease', 'MESH:D000860', (30, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('mouse', 'Species', '10090', (5, 10))	('decreased pulmonary metastasis', 'Disease', 'MESH:D009362', (135, 165))	('deletion', 'Var', (18, 26))
430705	31865635	In the univariate analysis, patients with high serum PD-L1 levels showed significantly worse overall survival than those with low serum PD-L1 levels (Table 3, left panel).	('PD-L1', 'Gene', (53, 58))	('low serum PD', 'Phenotype', 'HP:0031817', (126, 138))	('overall survival', 'CPA', (93, 109))	('high serum PD', 'Phenotype', 'HP:0003165', (42, 55))	('worse', 'NegReg', (87, 92))	('PD-L1', 'Gene', '29126', (53, 58))	('PD-L1', 'Gene', (136, 141))	('PD-L1', 'Gene', '29126', (136, 141))	('high', 'Var', (42, 46))	('patients', 'Species', '9606', (28, 36))
430722	31865178	PIK3CA and KRAS Amplification in Esophageal Adenocarcinoma and their Impact on the Inflammatory Tumor Microenvironment and Prognosis Gene amplifications of PIK3CA or KRAS induce a downstream activation of the AKT-mTOR or RAF-ERK-pathways.	('ERK', 'Gene', '5594', (225, 228))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (44, 58))	('Tumor', 'Phenotype', 'HP:0002664', (96, 101))	('PIK3CA', 'Gene', (156, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('ERK', 'Gene', (225, 228))	('KRAS', 'Gene', '3845', (11, 15))	('RAF', 'Gene', '22882', (221, 224))	('PIK3CA', 'Gene', '5290', (0, 6))	('AKT', 'Gene', (209, 212))	('Adenocarcinoma', 'Disease', (44, 58))	('KRAS', 'Gene', (11, 15))	('activation', 'PosReg', (191, 201))	('KRAS', 'Gene', '3845', (166, 170))	('RAF', 'Gene', (221, 224))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (33, 58))	('induce', 'Reg', (171, 177))	('mTOR', 'Gene', (213, 217))	('PIK3CA', 'Gene', '5290', (156, 162))	('KRAS', 'Gene', (166, 170))	('AKT', 'Gene', '207', (209, 212))	('PIK3CA', 'Gene', (0, 6))	('amplifications', 'Var', (138, 152))	('mTOR', 'Gene', '2475', (213, 217))
430727	31865178	Amplifications of KRAS were seen in 94 patients (17.1%), PIK3CA amplifications in 23 patients (5.0%).	('PIK3CA', 'Gene', '5290', (57, 63))	('KRAS', 'Gene', (18, 22))	('patients', 'Species', '9606', (39, 47))	('KRAS', 'Gene', '3845', (18, 22))	('patients', 'Species', '9606', (85, 93))	('Amplifications', 'Var', (0, 14))	('PIK3CA', 'Gene', (57, 63))
430728	31865178	KRAS amplifications significantly correlated with nodal positive patients and poorer overall survival (OS) in the subgroup without neoadjuvant treatment (p = 0.004), coamplifications of Her2 (p = 0.027), and TP53 mutations (p = 0.016).	('amplifications', 'Var', (5, 19))	('Her2', 'Gene', (186, 190))	('correlated', 'Reg', (34, 44))	('Her2', 'Gene', '2064', (186, 190))	('nodal', 'Gene', (50, 55))	('TP53', 'Gene', '7157', (208, 212))	('TP53', 'Gene', (208, 212))	('patients', 'Species', '9606', (65, 73))	('nodal', 'Gene', '4838', (50, 55))	('overall', 'MPA', (85, 92))	('KRAS', 'Gene', (0, 4))	('coamplifications', 'Var', (166, 182))	('poorer', 'NegReg', (78, 84))	('mutations', 'Var', (213, 222))	('KRAS', 'Gene', '3845', (0, 4))
430729	31865178	PIK3CA amplifications significantly correlated with a high amount of tumor infiltrating T cells (p = 0.003) and showed a tendency to better OS (p = 0.068).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('amplifications', 'Var', (7, 21))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
430735	31865178	Most of the adenocarcinomas arise from Barrett metaplasia due to chronic reflux disease followed by an accumulation of different mutations, copy-number variations, and chromothripsis causing genetic instability.	('Barrett metaplasia', 'Disease', (39, 57))	('chronic reflux disease', 'Disease', (65, 87))	('chronic reflux disease', 'Disease', 'MESH:D002908', (65, 87))	('chromothripsis', 'Disease', 'MESH:D000072837', (168, 182))	('copy-number variations', 'Var', (140, 162))	('mutations', 'Var', (129, 138))	('reflux disease', 'Phenotype', 'HP:0002020', (73, 87))	('arise', 'Reg', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('adenocarcinomas', 'Disease', 'MESH:D000230', (12, 27))	('adenocarcinomas', 'Disease', (12, 27))	('chromothripsis', 'Disease', (168, 182))
430738	31865178	Interestingly, these and other mutations can already be detected in histologically inconspicuous Barrett's mucosa without dysplasia.	('Barrett', 'Disease', (97, 104))	('mutations', 'Var', (31, 40))	('dysplasia', 'Disease', (122, 131))	('dysplasia', 'Disease', 'MESH:C536170', (122, 131))
430740	31865178	Another example for very early occurring mutations can be seen for TP53 and NOTCH1, as such mutations are found in normal esophageal squamous cell epithelium in healthy volunteers.	('mutations', 'Var', (41, 50))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('NOTCH1', 'Gene', '4851', (76, 82))	('NOTCH1', 'Gene', (76, 82))
430741	31865178	The probability of mutation increases with age and the extent of NOTCH1-mutations is greater than the expected rate of invasive esophageal squamous cell carcinoma.	('mutation', 'Var', (19, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('invasive esophageal squamous cell carcinoma', 'Disease', (119, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('invasive esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (119, 162))	('NOTCH1', 'Gene', '4851', (65, 71))	('NOTCH1', 'Gene', (65, 71))
430742	31865178	There is growing evidence that copy-number alterations (CNAs) of the genome are the major pathophysiological differences between Barrett's mucosa and invasive adenocarcinoma of the esophagus.	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (150, 173))	('copy-number alterations', 'Var', (31, 54))	("Barrett's mucosa", 'Disease', (129, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('invasive adenocarcinoma', 'Disease', (150, 173))
430745	31865178	Various studies have shown that CNG/amplification of KRAS and PIK3CA lead to an activation of these pathways even without additional activating mutations in the genes themselves.	('PIK3CA', 'Gene', (62, 68))	('KRAS', 'Gene', (53, 57))	('PIK3CA', 'Gene', '5290', (62, 68))	('CNG/amplification', 'Var', (32, 49))	('KRAS', 'Gene', '3845', (53, 57))	('activation', 'PosReg', (80, 90))
430747	31865178	Therapeutic interventions of the activated PIK-AKT pathway have been discussed as well and resistance to cisplatin-containing cytostatic therapy is described in ovarian cancer with amplification of PIK3CA mRNA.	('AKT', 'Gene', (47, 50))	('PIK3CA', 'Gene', '5290', (198, 204))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('AKT', 'Gene', '207', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ovarian cancer', 'Disease', 'MESH:D010051', (161, 175))	('PIK3CA', 'Gene', (198, 204))	('amplification', 'Var', (181, 194))	('ovarian cancer', 'Disease', (161, 175))
430749	31865178	In colon carcinoma and non-small-cell lung carcinoma, a relationship to mutations and CNA and specific reactions of the (inflammatory) tumor microenvironment was shown.	('mutations', 'Var', (72, 81))	('colon carcinoma', 'Disease', (3, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('lung carcinoma', 'Disease', (38, 52))	('tumor', 'Disease', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (23, 52))	('colon carcinoma', 'Disease', 'MESH:D003110', (3, 18))	('lung carcinoma', 'Disease', 'MESH:D008175', (38, 52))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (27, 52))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
430785	31865178	KRAS amplifications were seen in 94 patients (17.1%).	('amplifications', 'Var', (5, 19))	('KRAS', 'Gene', (0, 4))	('patients', 'Species', '9606', (36, 44))	('KRAS', 'Gene', '3845', (0, 4))
430787	31865178	KRAS amplifications were not associated with sex (p = 0.719), patient's age (p = 0.416), and tumor stage (p = 0.880).	('KRAS', 'Gene', '3845', (0, 4))	('amplifications', 'Var', (5, 19))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('patient', 'Species', '9606', (62, 69))	('tumor', 'Disease', (93, 98))	('KRAS', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
430789	31865178	We found a correlation between KRAS amplification and Her2 amplifications (p = 0.027) and TP53 mutations (p = 0.016), respectively.	('amplifications', 'MPA', (59, 73))	('KRAS', 'Gene', (31, 35))	('Her2', 'Gene', (54, 58))	('TP53', 'Gene', '7157', (90, 94))	('KRAS', 'Gene', '3845', (31, 35))	('Her2', 'Gene', '2064', (54, 58))	('TP53', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))
430791	31865178	PIK3CA amplifications were seen in 23 patients (5.0%).	('PIK3CA', 'Gene', '5290', (0, 6))	('patients', 'Species', '9606', (38, 46))	('amplifications', 'Var', (7, 21))	('PIK3CA', 'Gene', (0, 6))
430792	31865178	PIK3CA amplifications showed no correlation with sex (p = 0.501), patient's age (p = 0.673), tumor stage (p = 0.155), lymph node metastasis (p = 0.669), Her2 amplifications (p = 0.488), or TP53 mutations (p = 0.132).	('TP53', 'Gene', '7157', (189, 193))	('Her2', 'Gene', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('amplifications', 'Var', (158, 172))	('lymph node metastasis', 'CPA', (118, 139))	('TP53', 'Gene', (189, 193))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (194, 203))	('PIK3CA', 'Gene', (0, 6))	('Her2', 'Gene', '2064', (153, 157))	('patient', 'Species', '9606', (66, 73))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
430793	31865178	In tumors with a high amount of tumor infiltrating T cells (CD3 high), the frequency of PIK3CA amplifications was significantly higher (11.9%) compared with T-cell low tumors (3.0%, p = 0.003) (compare Figure 1).	('PIK3CA', 'Gene', '5290', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumors', 'Disease', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (3, 8))	('amplifications', 'Var', (95, 109))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('T-cell low', 'Phenotype', 'HP:0005403', (157, 167))	('PIK3CA', 'Gene', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('higher', 'PosReg', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
430805	31865178	All tumors that harbored KRAS and PIK3CA amplifications also expressed KRAS and PIK3CA protein visualized by immunohistochemistry (Figure 3).	('PIK3CA', 'Gene', (34, 40))	('protein', 'Protein', (87, 94))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('amplifications', 'Var', (41, 55))	('PIK3CA', 'Gene', '5290', (34, 40))	('KRAS', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('PIK3CA', 'Gene', (80, 86))	('KRAS', 'Gene', '3845', (71, 75))	('PIK3CA', 'Gene', '5290', (80, 86))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
430818	31865178	Primary resected patients with PIK3CA amplifications show a favorable prognosis; however, statistical significance is not achieved (p = 0.068).	('PIK3CA', 'Gene', (31, 37))	('patients', 'Species', '9606', (17, 25))	('PIK3CA', 'Gene', '5290', (31, 37))	('amplifications', 'Var', (38, 52))
430820	31865178	One work finds an unfavorable prognosis in PIK3CA amplifications, another study shows a favorable prognosis in activating PIK3CA mutations.	('PIK3CA', 'Gene', (122, 128))	('PIK3CA', 'Gene', '5290', (43, 49))	('mutations', 'Var', (129, 138))	('PIK3CA', 'Gene', '5290', (122, 128))	('activating', 'MPA', (111, 121))	('amplifications', 'Var', (50, 64))	('PIK3CA', 'Gene', (43, 49))
430826	31865178	This interesting relationship between gene amplification, tumor cell-associated cancer pathway activation, and effect on the inflammatory tumor microenvironment could be explained by the PIK-AKT pathway-mediated activation of the NF-kappaB pathway, as previously described on colitis-associated colon carcinoma or on ovarian carcinoma.	('colitis', 'Phenotype', 'HP:0002583', (276, 283))	('tumor', 'Disease', (138, 143))	('NF-kappaB', 'Gene', (230, 239))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('cancer', 'Disease', (80, 86))	('gene amplification', 'Var', (38, 56))	('tumor', 'Disease', (58, 63))	('NF-kappaB', 'Gene', '4790', (230, 239))	('AKT', 'Gene', '207', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('colitis-associated colon carcinoma', 'Disease', (276, 310))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (317, 334))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('ovarian carcinoma', 'Disease', (317, 334))	('activation', 'PosReg', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (317, 334))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('colitis-associated colon carcinoma', 'Disease', 'MESH:D003110', (276, 310))	('AKT', 'Gene', (191, 194))	('activation', 'PosReg', (212, 222))
430830	31865178	Therefore, we examined these checkpoint markers in our tumor population, but see no relation of an accumulation of these checkpoint markers and T cell-rich tumors with amplification of PIK3CA.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('PIK3CA', 'Gene', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('PIK3CA', 'Gene', '5290', (185, 191))	('tumor', 'Disease', (156, 161))	('amplification', 'Var', (168, 181))	('tumors', 'Disease', (156, 162))
430832	31865178	Further studies need to clarify the interactions of copy-number variations and the tumor microenvironment.	('tumor', 'Disease', (83, 88))	('copy-number variations', 'Var', (52, 74))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))
430835	31865178	In conclusion, this work on a very large collection of EAC shows that KRAS amplification is prognostically unfavorable in primary resected EACs, whereas the PIK3CA-amplified genotype with T cell-rich inflammatory tumor microenvironment shows a tendency to a better OS.	('EACs', 'Disease', (139, 143))	('tumor', 'Disease', (213, 218))	('KRAS', 'Gene', (70, 74))	('PIK3CA', 'Gene', (157, 163))	('KRAS', 'Gene', '3845', (70, 74))	('amplification', 'Var', (75, 88))	('EAC', 'Phenotype', 'HP:0011459', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('PIK3CA', 'Gene', '5290', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('EAC', 'Phenotype', 'HP:0011459', (139, 142))
430860	29339095	For example, the columnar-type cytokeratin CK18 could not fully compensate for loss of the stratified-type cytokeratin CK14 in CK14 mutant skin.	('mutant', 'Var', (132, 138))	('CK18', 'Gene', '16668', (43, 47))	('CK14', 'Gene', (127, 131))	('CK14', 'Gene', (119, 123))	('CK14', 'Gene', '16664', (119, 123))	('CK14', 'Gene', '16664', (127, 131))	('CK18', 'Gene', (43, 47))
430862	29339095	Further emphasizing the crucial role of p63 in stratified epithelium development, ectopic p63 expression in the simple epithelium of the lung is sufficient to convert it to stratified.	('p63', 'Gene', '22061', (90, 93))	('ectopic', 'Var', (82, 89))	('p63', 'Gene', (90, 93))	('p63', 'Gene', '22061', (40, 43))	('p63', 'Gene', (40, 43))	('convert', 'Reg', (159, 166))
430863	29339095	While SOX2 hypomorphic mutant embryos with the most severe reduction of SOX2 (~5% normal SOX2 level) develop esophageal atresia (EA) and tracheoesophageal fistula (TEF) due to defects in tube separation, those retaining slightly higher SOX2 levels (~18% normal SOX2 level) instead have defects in stratification and development of the esophageal epithelium.	('esophageal atresia', 'Disease', 'MESH:D004933', (109, 127))	('defects', 'NegReg', (176, 183))	('TEF', 'Disease', 'None', (164, 167))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (137, 162))	('reduction', 'NegReg', (59, 68))	('tracheoesophageal fistula', 'Disease', (137, 162))	('esophageal atresia', 'Disease', (109, 127))	('development of the esophageal epithelium', 'CPA', (316, 356))	('tube separation', 'CPA', (187, 202))	('TEF', 'Phenotype', 'HP:0002575', (164, 167))	('TEF', 'Disease', (164, 167))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (137, 162))	('SOX2', 'Gene', (72, 76))	('develop', 'PosReg', (101, 108))	('esophageal atresia', 'Phenotype', 'HP:0002032', (109, 127))	('EA', 'Phenotype', 'HP:0002032', (129, 131))	('mutant', 'Var', (23, 29))	('SOX2', 'Gene', (6, 10))	('defects', 'Reg', (286, 293))	('stratification', 'CPA', (297, 311))
430872	29339095	This study was performed using an in vitro deletion of SOX15 in an esophageal cell culture model, and so it will be important to assess the role of SOX15 in GI epithelial regionalization using in vivo mouse models or esophageal organoid models.	('SOX15', 'Gene', (55, 60))	('mouse', 'Species', '10090', (201, 206))	('deletion', 'Var', (43, 51))
430878	29339095	During mouse development, CDX2 expression is prominent in the developing hindgut by E8.5, becomes restricted to the intestine at the foregut/midgut boundary by E12.5, and is maintained in this pattern throughout adulthood.	('mouse', 'Species', '10090', (7, 12))	('E8.5', 'Var', (84, 88))	('CDX2', 'Gene', (26, 30))	('CDX2', 'Gene', '12591', (26, 30))	('E12.5', 'Var', (160, 165))
430880	29339095	Studies of SOX2 and CDX2 mutants demonstrate that establishing a balance between SOX2 and CDX2 is essential for proper regional patterning at this junction.	('SOX2', 'Gene', (11, 15))	('mutants', 'Var', (25, 32))	('CDX2', 'Gene', '12591', (90, 94))	('CDX2', 'Gene', (20, 24))	('CDX2', 'Gene', '12591', (20, 24))	('CDX2', 'Gene', (90, 94))
430881	29339095	Ectopic CDX2 expression in the mouse glandular gastric mucosa induces the expression of intestinal genes, and intestine-like goblet cells emerge.	('expression', 'MPA', (74, 84))	('induces', 'PosReg', (62, 69))	('CDX2', 'Gene', (8, 12))	('mouse', 'Species', '10090', (31, 36))	('CDX2', 'Gene', '12591', (8, 12))	('intestinal genes', 'Gene', (88, 104))	('Ectopic', 'Var', (0, 7))
430882	29339095	report that ectopic CDX2 expression in a transitional zone of cells at the SCJ induces intestinal metaplasia in vivo, mimicking the metaplasia characteristic of Barrett's esophagus.	('intestinal metaplasia', 'Disease', (87, 108))	('CDX2', 'Gene', (20, 24))	('induces', 'Reg', (79, 86))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (87, 108))	('CDX2', 'Gene', '12591', (20, 24))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (161, 180))	('expression', 'Var', (25, 35))	('ectopic', 'Var', (12, 19))
430883	29339095	On the other hand, ectopic SOX2 expression in the intestine inhibits the ability of CDX2 to bind to its target genes resulting in a foregut-like phenotype or anteriorization of the intestine.	('anteriorization of the intestine', 'CPA', (158, 190))	('ectopic', 'Var', (19, 26))	('foregut-like phenotype', 'CPA', (132, 154))	('CDX2', 'Gene', (84, 88))	('CDX2', 'Gene', '12591', (84, 88))	('bind', 'Interaction', (92, 96))	('inhibits', 'NegReg', (60, 68))	('ability', 'MPA', (73, 80))	('SOX2', 'Gene', (27, 31))
430884	29339095	Further consistent with the idea that the developing gut must have appropriately balanced SOX2-CDX2 expression, elimination of CDX2 from the early developing midgut via conditional knockout induces SOX2 expression.	('elimination', 'Var', (112, 123))	('CDX2', 'Gene', (127, 131))	('expression', 'MPA', (203, 213))	('CDX2', 'Gene', (95, 99))	('SOX2', 'Gene', (198, 202))	('CDX2', 'Gene', '12591', (127, 131))	('CDX2', 'Gene', '12591', (95, 99))	('induces', 'Reg', (190, 197))
430886	29339095	Coincident with p63 and SOX2 expression, CDX2 mutant intestinal epithelium loses columnar characteristics and is instead flattened with stratified-like characteristics.	('p63', 'Gene', '22061', (16, 19))	('columnar characteristics', 'CPA', (81, 105))	('CDX2', 'Gene', (41, 45))	('p63', 'Gene', (16, 19))	('mutant', 'Var', (46, 52))	('loses', 'NegReg', (75, 80))	('CDX2', 'Gene', '12591', (41, 45))
430889	29339095	The role of CDX2 in later stages of intestinal epithelium development is generally conserved as loss of CDX2 from the mouse intestine beginning at ~E13.5 also anteriorizes the epithelium, albeit partially.	('anteriorizes', 'Reg', (159, 171))	('loss', 'Var', (96, 100))	('CDX2', 'Gene', (12, 16))	('CDX2', 'Gene', '12591', (12, 16))	('mouse', 'Species', '10090', (118, 123))	('CDX2', 'Gene', (104, 108))	('CDX2', 'Gene', '12591', (104, 108))
430891	29339095	Similarly, inducible knockout of Cdx2 from the adult intestinal epithelium induces gastric epithelial cell marker expression and reduces intestinal epithelial cell marker expression.	('Cdx2', 'Gene', (33, 37))	('intestinal epithelial cell marker expression', 'MPA', (137, 181))	('knockout', 'Var', (21, 29))	('induces', 'PosReg', (75, 82))	('gastric epithelial cell marker expression', 'MPA', (83, 124))	('Cdx2', 'Gene', '12591', (33, 37))	('reduces', 'NegReg', (129, 136))
430892	29339095	It may be that the failure to induce p63 underlies the differences between the degree of anterior transformation observed in early versus late CDX2 mutants.	('mutants', 'Var', (148, 155))	('anterior transformation', 'CPA', (89, 112))	('CDX2', 'Gene', (143, 147))	('p63', 'Gene', '22061', (37, 40))	('CDX2', 'Gene', '12591', (143, 147))	('p63', 'Gene', (37, 40))
430899	29339095	For example, the foregut-associated factors SOX2, PAX9, and WNT10A are highly induced in the distal midgut/hindgut of CDX2 mutants, and the columnar factor Indian Hedgehog (discussed below) is only severely diminished in the distal midgut/hindgut domain of mutants.	('CDX2', 'Gene', (118, 122))	('CDX2', 'Gene', '12591', (118, 122))	('PAX9', 'Gene', '18511', (50, 54))	('WNT10A', 'Gene', (60, 66))	('WNT10A', 'Gene', '22409', (60, 66))	('PAX9', 'Gene', (50, 54))	('induced', 'PosReg', (78, 85))	('mutants', 'Var', (123, 130))
430903	29339095	Because this model also deletes HNF4A in the liver causing a lethal phenotype, the colon phenotype could only be studied in embryos.	('lethal phenotype', 'MPA', (61, 77))	('causing', 'Reg', (51, 58))	('deletes', 'Var', (24, 31))	('HNF4A', 'Gene', (32, 37))	('HNF4A', 'Gene', '15378', (32, 37))
430904	29339095	Elimination of HNF4A within the embryonic colon epithelium severely disrupts colon architecture with defects in both epithelial morphogenesis and epithelial cell cytodifferentiation.	('colon', 'Disease', (77, 82))	('disrupts', 'NegReg', (68, 76))	('embryonic colon', 'Disease', (32, 47))	('defects', 'NegReg', (101, 108))	('Elimination', 'Var', (0, 11))	('HNF4A', 'Gene', '15378', (15, 20))	('HNF4A', 'Gene', (15, 20))	('embryonic colon', 'Disease', 'MESH:D015179', (32, 47))	('epithelial morphogenesis', 'CPA', (117, 141))
430906	29339095	It is possible that deletion of HNF4A earlier in the course of small intestinal development would illuminate a new role for HNF4A in this process.	('HNF4A', 'Gene', '15378', (124, 129))	('HNF4A', 'Gene', (124, 129))	('deletion', 'Var', (20, 28))	('HNF4A', 'Gene', (32, 37))	('HNF4A', 'Gene', '15378', (32, 37))
430907	29339095	It is also possible that HNF4G, which is absent in the colon epithelium but present in the small intestinal epithelium, compensates for HNF4A function in mutants.	('HNF4G', 'Gene', '30942', (25, 30))	('mutants', 'Var', (154, 161))	('HNF4A', 'Gene', '15378', (136, 141))	('HNF4G', 'Gene', (25, 30))	('HNF4A', 'Gene', (136, 141))
430927	29339095	By E18.5, after GI epithelial domains have undergone significant morphogenetic remodeling, SHH expression decreases in the bulk of the stratified squamous epithelium of the esophagus, becoming limited to the distal esophageal epithelium, yet it increases in the epithelium of the hindstomach and intestines.	('SHH', 'Gene', '20423', (91, 94))	('SHH', 'Gene', (91, 94))	('E18.5', 'Var', (3, 8))	('decreases', 'NegReg', (106, 115))	('expression', 'MPA', (95, 105))
430930	29339095	A more recent examination of any remaining esophageal cells in SHH mutants shows that elimination of SHH in the esophageal domain results in premature expression of stratified epithelial cell markers.	('SHH', 'Gene', '20423', (101, 104))	('SHH', 'Gene', (63, 66))	('expression', 'MPA', (151, 161))	('mutants', 'Var', (67, 74))	('SHH', 'Gene', (101, 104))	('SHH', 'Gene', '20423', (63, 66))
430935	29339095	Moreover, the glandular stomach of SHH mutants is also posteriorized, expressing some intestinal markers.	('SHH', 'Gene', (35, 38))	('expressing', 'Reg', (70, 80))	('mutants', 'Var', (39, 46))	('SHH', 'Gene', '20423', (35, 38))
430936	29339095	Likewise, loss of HOXA5 from the underlying gastric mesenchyme disrupts epithelial HH signaling in the developing stomach.	('loss', 'Var', (10, 14))	('HOXA5', 'Gene', (18, 23))	('epithelial HH signaling', 'MPA', (72, 95))	('disrupts', 'NegReg', (63, 71))	('HOXA5', 'Gene', '15402', (18, 23))
430937	29339095	IHH expression expands into the forestomach domain at the expense of SHH expression in HOXA5 mutants and mutant stomachs are posteriorized, expressing the intestinal marker alkaline phosphatase even into the presumptive forestomach domain (Figure 3).	('IHH', 'Gene', '16147', (0, 3))	('HOXA5', 'Gene', (87, 92))	('SHH', 'Gene', (69, 72))	('mutant', 'Var', (105, 111))	('expressing', 'MPA', (140, 150))	('mutants', 'Var', (93, 100))	('SHH', 'Gene', '20423', (69, 72))	('HOXA5', 'Gene', '15402', (87, 92))	('IHH', 'Gene', (0, 3))
430938	29339095	On the other hand, induced expression of SHH in the hindstomach as a consequence of Hnf1b knockout, Fgf10 knockout, Fgfr2 knockout, or the expression of mutant Activin receptors compromises the IHH domain within the hindstomach and anteriorizes the epithelium (Figure 3).	('anteriorizes the epithelium', 'CPA', (232, 259))	('SHH', 'Gene', (41, 44))	('Fgf10', 'Gene', (100, 105))	('Fgfr2', 'Gene', '14183', (116, 121))	('IHH', 'Gene', (194, 197))	('knockout', 'Var', (106, 114))	('mutant', 'Var', (153, 159))	('IHH', 'Gene', '16147', (194, 197))	('Hnf1b', 'Gene', '21410', (84, 89))	('SHH', 'Gene', '20423', (41, 44))	('knockout', 'Var', (122, 130))	('compromises', 'NegReg', (178, 189))	('Fgf10', 'Gene', '14165', (100, 105))	('Fgfr2', 'Gene', (116, 121))	('Hnf1b', 'Gene', (84, 89))	('knockout', 'Var', (90, 98))
430944	29339095	Loss of mesenchymal BARX1 reduces the expression of the WNT signaling inhibitors secreted frizzled-related proteins 1 and 2 (SFRP1/2).	('SFRP1/2', 'Gene', '20377;20319', (125, 132))	('SFRP1/2', 'Gene', (125, 132))	('BARX1', 'Gene', '12022', (20, 25))	('expression', 'MPA', (38, 48))	('mesenchymal', 'Gene', (8, 19))	('secreted frizzled-related proteins 1 and 2', 'Gene', '20377;20319', (81, 123))	('reduces', 'NegReg', (26, 33))	('Loss', 'Var', (0, 4))	('BARX1', 'Gene', (20, 25))
430946	29339095	The entire BARX1 mutant foregut is posteriorized, with anterior (esophagus/forestomach) regions containing a mixed "squamo-glandular" type epithelium with reduced levels of SOX2.	('BARX1', 'Gene', (11, 16))	('mutant', 'Var', (17, 23))	('BARX1', 'Gene', '12022', (11, 16))
430947	29339095	Perhaps most striking is the intestinal villus-like epithelium present in BARX1 mutant hindstomachs.	('intestinal villus', 'Phenotype', 'HP:0011473', (29, 46))	('BARX1', 'Gene', (74, 79))	('BARX1', 'Gene', '12022', (74, 79))	('mutant', 'Var', (80, 86))
430948	29339095	In this region, aberrant WNT signaling induces CDX2 expression to shift the global gene expression profile in the developing stomach toward a more posterior midgut/intestinal endoderm program.	('aberrant', 'Var', (16, 24))	('CDX2', 'Gene', (47, 51))	('CDX2', 'Gene', '12591', (47, 51))	('shift', 'Reg', (66, 71))	('induces', 'Reg', (39, 46))
430961	29339095	While deletion of BMP receptors in the epithelium fails to disrupt villus formation, modulation of BMP signaling within the mesenchyme:either increased or decreased mesenchymal BMP:disrupts villus morphogenesis by altering the pattering of mesenchymal PDGFRA+ cell clusters (Figure 5B).	('BMP', 'Gene', '649', (18, 21))	('BMP', 'Gene', '649', (177, 180))	('pattering of mesenchymal PDGFRA+ cell clusters', 'CPA', (227, 273))	('BMP', 'Gene', (18, 21))	('BMP', 'Gene', (177, 180))	('altering', 'Reg', (214, 222))	('disrupts', 'NegReg', (181, 189))	('decreased', 'NegReg', (155, 164))	('BMP', 'Gene', '649', (99, 102))	('deletion', 'Var', (6, 14))	('BMP', 'Gene', (99, 102))	('villus morphogenesis', 'CPA', (190, 210))
430969	29339095	When WNT signaling is blocked early in the developing proximal hindstomach epithelium by elimination of B-catenin using Shh-Cre, proximal gland marker expression is replaced by distal gland marker expression by E10.5, including the induction of PDX1.	('E10.5', 'Var', (211, 216))	('PDX1', 'Gene', '18609', (245, 249))	('Shh', 'Gene', (120, 123))	('B-catenin', 'Chemical', '-', (104, 113))	('Shh', 'Gene', '20423', (120, 123))	('PDX1', 'Gene', (245, 249))
430979	29339095	Finally, loss of gastric BMP signaling disrupts parietal cell development in the proximal (fundic) glands.	('disrupts', 'NegReg', (39, 47))	('BMP', 'Gene', (25, 28))	('loss', 'Var', (9, 13))	('BMP', 'Gene', '649', (25, 28))	('gastric', 'Protein', (17, 24))
430981	29339095	Overall, BMP signaling seems to have a vital role in maintenance of the gastric epithelium because loss of BMP signaling resulting in metaplasia and dysplasia.	('BMP', 'Gene', '649', (107, 110))	('BMP', 'Gene', '649', (9, 12))	('BMP', 'Gene', (107, 110))	('BMP', 'Gene', (9, 12))	('metaplasia and dysplasia', 'Disease', 'MESH:D008679', (134, 158))	('loss', 'Var', (99, 103))
430990	29339095	Early (E11.5) conditional knockout of Gata4 in the intestine results in an epithelial cell proliferation defect via transcriptional regulation of cell cycle proteins and Frizzled class receptor 5 (Fzd5).	('Gata4', 'Gene', (38, 43))	('epithelial cell proliferation', 'CPA', (75, 104))	('Gata4', 'Gene', '14463', (38, 43))	('transcriptional regulation', 'MPA', (116, 142))	('knockout', 'Var', (26, 34))	('Fzd5', 'Gene', '14367', (197, 201))	('defect', 'NegReg', (105, 111))	('Fzd5', 'Gene', (197, 201))
430994	29339095	Ectopic expression of GATA4 in the mouse ileum results in a loss of the ileal gene expression program and a gain in the jejunal program.	('ileal', 'Pathway', (72, 77))	('gain', 'PosReg', (108, 112))	('Ectopic expression', 'Var', (0, 18))	('loss', 'NegReg', (60, 64))	('mouse', 'Species', '10090', (35, 40))	('GATA4', 'Gene', (22, 27))	('jejunal program', 'MPA', (120, 135))
430995	29339095	It is important to note that GATA6 is present throughout the intestinal epithelium and that the presence of GATA6 in GATA4-deficient jejunum or GATA4-expressing ileum does not compensate for loss or gain of GATA4 function in these tissues.	('presence', 'Var', (96, 104))	('GATA6', 'Gene', (29, 34))	('GATA6', 'Gene', '14465', (29, 34))	('gain', 'PosReg', (199, 203))	('GATA6', 'Gene', (108, 113))	('GATA6', 'Gene', '14465', (108, 113))
430996	29339095	Furthermore, inducible deletion of GATA6 from the adult intestinal epithelium does not alter jejunal enterocyte identity.	('GATA6', 'Gene', '14465', (35, 40))	('GATA6', 'Gene', (35, 40))	('jejunal enterocyte identity', 'CPA', (93, 120))	('deletion', 'Var', (23, 31))
430998	29339095	Loss of GATA6 from the embryonic ileal intestinal epithelium also reduces expression of ileal enterocyte markers and induces expression of the colon epithelial cell marker Car1.	('expression', 'MPA', (74, 84))	('GATA6', 'Gene', (8, 13))	('GATA6', 'Gene', '14465', (8, 13))	('reduces', 'NegReg', (66, 73))	('Car1', 'Gene', '12346', (172, 176))	('Car1', 'Gene', (172, 176))	('ileal enterocyte markers', 'MPA', (88, 112))	('induces', 'Reg', (117, 124))	('embryonic ileal intestinal', 'Disease', (23, 49))	('expression', 'MPA', (125, 135))	('Loss', 'Var', (0, 4))	('embryonic ileal intestinal', 'Disease', 'MESH:D007077', (23, 49))
430999	29339095	Simultaneous inducible deletion of both GATA4 and GATA6 from the adult intestinal epithelium results in duodenal and jejunal epithelial cells displaying a phenotype similar to the GATA6-deficient ileum.	('results in', 'Reg', (93, 103))	('GATA6', 'Gene', '14465', (50, 55))	('deletion', 'Var', (23, 31))	('GATA6', 'Gene', (50, 55))	('GATA6', 'Gene', '14465', (180, 185))	('duodenal', 'MPA', (104, 112))	('GATA4', 'Gene', (40, 45))	('GATA6', 'Gene', (180, 185))
431004	29339095	While ATOH1, NGN3, and NEUROD1 seem to regulate global development of enteroendocrine cells in the intestine, PDX1, PAX4, and PAX6 control enteroendocrine differentiation within the proximal intestine with enteroendocrine cells virtually eliminated from the duodenum and jejunum of mutants (Figure 6B).	('PAX4', 'Gene', (116, 120))	('regulate', 'Reg', (39, 47))	('PDX1', 'Gene', '18609', (110, 114))	('control', 'Reg', (131, 138))	('NEUROD1', 'Gene', '18012', (23, 30))	('NEUROD1', 'Gene', (23, 30))	('PAX6', 'Gene', '18508', (126, 130))	('mutants', 'Var', (282, 289))	('PAX6', 'Gene', (126, 130))	('PDX1', 'Gene', (110, 114))	('ATOH1', 'Gene', '11921', (6, 11))	('NGN3', 'Gene', (13, 17))	('ATOH1', 'Gene', (6, 11))	('PAX4', 'Gene', '18506', (116, 120))	('NGN3', 'Gene', '11925', (13, 17))	('enteroendocrine differentiation', 'CPA', (139, 170))
431005	29339095	Differences in regionally-enriched enteroendocrine cell populations also occur in the small intestine of GATA4 and GATA6 conditional knockout embryos.	('GATA4', 'Gene', (105, 110))	('conditional knockout', 'Var', (121, 141))	('GATA6', 'Gene', '14465', (115, 120))	('GATA6', 'Gene', (115, 120))
431066	29362648	identified poorer pulmonary function and limited functional reserve as a risk factor for higher mortality and morbidity after OE.	('pulmonary function', 'CPA', (18, 36))	('poorer pulmonary function', 'Phenotype', 'HP:0005952', (11, 36))	('higher', 'PosReg', (89, 95))	('OE', 'Chemical', '-', (126, 128))	('poorer', 'Var', (11, 17))
431084	29362648	reported a significantly lower rate of overall complications in the MIE group than in the OE group (37.9 vs. 60.3, p = 0.016).	('MIE', 'Chemical', '-', (68, 71))	('MIE', 'Var', (68, 71))	('OE', 'Chemical', '-', (90, 92))	('lower', 'NegReg', (25, 30))
431185	27526295	We then applied this data to identify LE in patients with PEMD and found that nearly half of the patients with PMED had high IEL in comparison to only 10% of patients with dysmotility-negative GERD.	('high IEL', 'MPA', (120, 128))	('patients', 'Species', '9606', (44, 52))	('PEMD', 'Disease', 'None', (58, 62))	('dysmotility', 'Disease', 'MESH:D015154', (172, 183))	('LE', 'Phenotype', 'HP:0006527', (38, 40))	('dysmotility', 'Disease', (172, 183))	('LE', 'Chemical', '-', (38, 40))	('patients', 'Species', '9606', (158, 166))	('PMED', 'Var', (111, 115))	('PEMD', 'Disease', (58, 62))	('patients', 'Species', '9606', (97, 105))
431282	28336766	In the present study, inflammatory cells were detected at the gastric cardia in all participants, but those with large WC and higher total abdominal fat were found to exhibit greater cardiac mucosal lengthening and had more proximal acid reflux.	('gastric cardia', 'Disease', 'MESH:D004938', (62, 76))	('participants', 'Species', '9606', (84, 96))	('acid reflux', 'Phenotype', 'HP:0002020', (233, 244))	('cardia', 'Disease', 'MESH:D004938', (70, 76))	('large WC', 'Var', (113, 121))	('cardia', 'Disease', (70, 76))	('greater', 'PosReg', (175, 182))	('higher', 'Var', (126, 132))	('cardia', 'Disease', (183, 189))	('more', 'PosReg', (219, 223))	('cardia', 'Disease', 'MESH:D004938', (183, 189))	('gastric cardia', 'Disease', (62, 76))	('proximal acid reflux', 'MPA', (224, 244))
431295	28336766	Fourth, although our analysis suggest that both high WC and WHR increase gastric and esophageal cancers risk, few studies have conducted further adjustments between these measures and BMI to try to clarify their independent role.	('high WC', 'Var', (48, 55))	('increase gastric and esophageal cancers', 'Disease', 'MESH:D013274', (64, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('WHR', 'Var', (60, 63))	('WHR increase', 'Phenotype', 'HP:0031819', (60, 72))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('increase gastric', 'Phenotype', 'HP:0005207', (64, 80))
431297	28336766	In the present study, high WC was positively associated with risk of EAC but not with esophageal squamous cell carcinoma.	('EAC', 'Disease', (69, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (86, 120))	('high WC', 'Var', (22, 29))	('EAC', 'Phenotype', 'HP:0011459', (69, 72))	('esophageal squamous cell carcinoma', 'Disease', (86, 120))
431334	26557916	BMI was found to be a significantly independent prognostic factor for poor OS (hazard ratio, 0.698; 95% confidence interval [CI], 0.573-0.581; P < 0.001; Table 3).	('BMI', 'Var', (0, 3))	('poor OS', 'Disease', (70, 77))	('OS', 'Chemical', '-', (75, 77))
431374	25789002	Furthermore, UBE2D3, lymph node status and tumor location were independent prognostic factors for esophageal cancer in multivariate analysis.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('esophageal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (43, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))	('UBE2D3', 'Var', (13, 19))
431376	25789002	In conclusion, the findings of the present study indicated that hTERT and UBE2D3 proteins appear to be involved in the development of esophageal cancer, that UBE2D3 may a positive prognostic factor for esophageal cancer, and that UBE2D3 and hTERT expression levels are inversely correlated.	('hTERT', 'Gene', '7015', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('esophageal cancer', 'Disease', (202, 219))	('UBE2D3', 'Gene', (74, 80))	('hTERT', 'Gene', (64, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('hTERT', 'Gene', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (202, 219))	('involved', 'Reg', (103, 111))	('hTERT', 'Gene', '7015', (64, 69))	('UBE2D3', 'Var', (158, 164))	('esophageal cancer', 'Disease', (134, 151))
431385	25789002	Although previous studies have demonstrated that high hTERT expression is a predictive and prognostic biomarker of a poor outcome in a range of malignancies, including Ewing's sarcoma, and colorectal, gastric and breast carcinoma, studies regarding the role of hTERT expression in esophageal cancer are sparse and thus warrant further investigation.	('breast carcinoma', 'Disease', (213, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('gastric', 'Disease', (201, 208))	('hTERT', 'Gene', '7015', (261, 266))	('esophageal cancer', 'Disease', 'MESH:D004938', (281, 298))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (168, 183))	('malignancies', 'Disease', 'MESH:D009369', (144, 156))	('malignancies', 'Disease', (144, 156))	('hTERT', 'Gene', '7015', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (168, 183))	('esophageal cancer', 'Disease', (281, 298))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('hTERT', 'Gene', (261, 266))	('breast carcinoma', 'Disease', 'MESH:D001943', (213, 229))	('colorectal', 'Disease', (189, 199))	('hTERT', 'Gene', (54, 59))	("Ewing's sarcoma", 'Disease', (168, 183))	('high', 'Var', (49, 53))	('breast carcinoma', 'Phenotype', 'HP:0003002', (213, 229))
431423	25789002	Yang et al demonstrated that the tumor location did not impact the survival rate of esophageal cancer; however, in the seventh edition of the UICC TNM system, tumor location (upper and middle thoracic versus lower thoracic) was important for grouping T2-3N0M0 squamous cell cancers.	('squamous cell cancers', 'Phenotype', 'HP:0002860', (260, 281))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('squamous cell cancers', 'Disease', 'MESH:D002294', (260, 281))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('T2-3N0M0', 'Var', (251, 259))	('tumor', 'Disease', (159, 164))	('esophageal cancer', 'Disease', (84, 101))	('tumor', 'Disease', (33, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (260, 280))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('squamous cell cancers', 'Disease', (260, 281))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
431435	25789002	Mittal et al reported that knocking down UBE2D3 in human breast cancer cells resulted in elevated cyclin D1 levels, and that a low level of UBE2D3 expression was a determinant factor in the progression of metastatic breast cancer.	('breast cancer', 'Disease', (57, 70))	('cyclin D1 levels', 'MPA', (98, 114))	('UBE2D3', 'Gene', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Disease', (216, 229))	('knocking down', 'Var', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('UBE2D3', 'Gene', (41, 47))	('human', 'Species', '9606', (51, 56))	('elevated', 'PosReg', (89, 97))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
431438	25789002	In addition, UBE2D3 appeared to be an independent prognostic factor for esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('UBE2D3', 'Var', (13, 19))
431441	25789002	These results indicate that hTERT and UBE2D3 may interact with each other, validating the proposal that UBE2D3 potentially has a role in the hTERT signaling pathway.	('hTERT', 'Gene', (28, 33))	('hTERT', 'Gene', '7015', (141, 146))	('UBE2D3', 'Var', (104, 110))	('role', 'Reg', (129, 133))	('hTERT', 'Gene', (141, 146))	('interact', 'Reg', (49, 57))	('hTERT', 'Gene', '7015', (28, 33))
431444	25789002	Furthermore, the expression of UBE2D3, lymph node involvement and tumor location were independent predictive prognostic factors; thus, UBE2D3 expression may be a promising prognostic biomarker in esophageal cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('tumor', 'Disease', (66, 71))	('UBE2D3', 'Var', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('esophageal cancer', 'Disease', (196, 213))
431453	25333941	Inhibition of H2S synthesis resulted in significant exacerbation of inflammation and injury.	('exacerbation', 'PosReg', (52, 64))	('H2S', 'Chemical', 'MESH:D006862', (14, 17))	('inflammation and injury', 'Disease', 'MESH:D007249', (68, 91))	('Inhibition', 'Var', (0, 10))	('H2S synthesis', 'Protein', (14, 27))
431472	25333941	In recent years, H2S has been shown to exhibit a number of beneficial effects in the GI tract, including increasing mucosal resistance to damage induced by nonsteroidal anti-inflammatory drugs and ischemia-reperfusion, and acceleration of healing of mucosal ulcers.	('increasing', 'PosReg', (105, 115))	('acceleration', 'PosReg', (223, 235))	('beneficial effects', 'PosReg', (59, 77))	('ischemia', 'Disease', 'MESH:D007511', (197, 205))	('mucosal', 'MPA', (116, 123))	('healing', 'CPA', (239, 246))	('rat', 'Species', '10116', (229, 232))	('mucosal ulcers', 'Disease', (250, 264))	('H2S', 'Chemical', 'MESH:D006862', (17, 20))	('H2S', 'Var', (17, 20))	('mucosal ulcers', 'Disease', 'MESH:D019226', (250, 264))	('ischemia', 'Disease', (197, 205))
431493	25333941	These doses of PAG and CHH have been shown to significantly inhibit CSE and CBS activities in rats.	('CBS', 'Gene', (76, 79))	('CHH', 'Disease', 'MESH:C535916', (23, 26))	('inhibit', 'NegReg', (60, 67))	('CSE', 'Gene', (68, 71))	('CSE', 'Gene', '24962', (68, 71))	('CHH', 'Disease', (23, 26))	('rats', 'Species', '10116', (94, 98))	('PAG', 'Var', (15, 18))	('PAG', 'Chemical', 'MESH:C022050', (15, 18))	('CBS', 'Gene', '24250', (76, 79))
431504	25333941	L-tryptophan, L-PAG, CHH and NaHS were from Sigma-Aldrich (St. Louis, MO, USA).	('L-tryptophan', 'Chemical', 'MESH:D014364', (0, 12))	('CHH', 'Disease', 'MESH:C535916', (21, 24))	('NaHS', 'Chemical', 'MESH:C025451', (29, 33))	('CHH', 'Disease', (21, 24))	('L-tryptophan', 'Var', (0, 12))	('L-PAG', 'Chemical', '-', (14, 19))
431516	25333941	Administration of L-PAG, but not CHH, resulted in a significant worsening of esophagitis in the hyperglycemic rats.	('rat', 'Species', '10116', (110, 113))	('rat', 'Species', '10116', (8, 11))	('L-PAG', 'Chemical', '-', (18, 23))	('worsening', 'NegReg', (64, 73))	('esophagitis', 'Disease', 'MESH:D004941', (77, 88))	('CHH', 'Disease', 'MESH:C535916', (33, 36))	('rats', 'Species', '10116', (110, 114))	('CHH', 'Disease', (33, 36))	('esophagitis', 'Phenotype', 'HP:0100633', (77, 88))	('esophagitis', 'Disease', (77, 88))	('L-PAG', 'Var', (18, 23))
431519	25333941	The exacerbation of esophagitis by PAG was completely reversed by co-administration L-Trp.	('rat', 'Species', '10116', (77, 80))	('L-Trp', 'Chemical', 'MESH:D014364', (84, 89))	('esophagitis', 'Disease', (20, 31))	('esophagitis', 'Phenotype', 'HP:0100633', (20, 31))	('esophagitis', 'Disease', 'MESH:D004941', (20, 31))	('PAG', 'Var', (35, 38))	('PAG', 'Chemical', 'MESH:C022050', (35, 38))	('exacerbation', 'PosReg', (4, 16))
431522	25333941	Treatment with L-Trp, which attenuated the detrimental effects of PAG in the esophagitis model, modestly increased serum IL-10 levels but did not affect serum IL-17 levels (Fig.	('esophagitis', 'Phenotype', 'HP:0100633', (77, 88))	('PAG', 'Chemical', 'MESH:C022050', (66, 69))	('L-Trp', 'Chemical', 'MESH:D014364', (15, 20))	('serum IL-10 levels', 'MPA', (115, 133))	('PAG', 'Gene', (66, 69))	('L-Trp', 'Var', (15, 20))	('increased', 'PosReg', (105, 114))	('esophagitis', 'Disease', (77, 88))	('esophagitis', 'Disease', 'MESH:D004941', (77, 88))
431524	25333941	Pre-treatment with PAG, but not CHH, significantly increased the severity of the esophagitis (Fig.	('esophagitis', 'Disease', 'MESH:D004941', (81, 92))	('CHH', 'Disease', 'MESH:C535916', (32, 35))	('esophagitis', 'Disease', (81, 92))	('CHH', 'Disease', (32, 35))	('esophagitis', 'Phenotype', 'HP:0100633', (81, 92))	('PAG', 'Var', (19, 22))	('PAG', 'Chemical', 'MESH:C022050', (19, 22))
431528	25333941	The combination of NaHS and L-Trp reduced histological changes in the esophageal mucosa of rats dramatically, with sharply decreased inflammation, subepithelial edema, and less epithelial disorganization.	('histological changes', 'CPA', (42, 62))	('reduced', 'NegReg', (34, 41))	('rats', 'Species', '10116', (91, 95))	('L-Trp', 'Var', (28, 33))	('decreased', 'NegReg', (123, 132))	('inflammation', 'Disease', 'MESH:D007249', (133, 145))	('inflammation', 'Disease', (133, 145))	('subepithelial edema', 'Disease', (147, 166))	('NaHS', 'Chemical', 'MESH:C025451', (19, 23))	('subepithelial edema', 'Disease', 'MESH:D004487', (147, 166))	('edema', 'Phenotype', 'HP:0000969', (161, 166))	('L-Trp', 'Chemical', 'MESH:D014364', (28, 33))
431543	25333941	Inhibition of H2S synthesis was also associated with marked increases in serum levels of IL-10 (an anti-inflammatory cytokine) and decreased serum levels of IL-17 (a pro-inflammatory cytokine), while the H2S donor had the opposite effect.	('H2S', 'Chemical', 'MESH:D006862', (14, 17))	('H2S', 'Protein', (14, 17))	('donor', 'Species', '9606', (208, 213))	('H2S', 'Chemical', 'MESH:D006862', (204, 207))	('decreased', 'NegReg', (131, 140))	('synthesis', 'MPA', (18, 27))	('serum levels of IL-10', 'MPA', (73, 94))	('Inhibition', 'Var', (0, 10))	('serum levels of IL-17', 'MPA', (141, 162))	('increases', 'PosReg', (60, 69))
431599	34011038	Cytological examination of the pancreatic mass was highlighted by immunohistochemical staining for PCK, P63, P40, and CK7, and it was presumed to be derived from primary ESCC (Fig.	('CK7', 'Gene', (118, 121))	('CK7', 'Gene', '3855', (118, 121))	('PCK', 'Var', (99, 102))	('pancreatic mass', 'Disease', (31, 46))	('P63', 'Var', (104, 107))	('P40', 'Var', (109, 112))
431602	34011038	The TMB was determined to be 5.26 mutations/Mb, and a total of 20 nonsynonymous mutations were detected in the whole genome, including 6 insertion-deletion mutations, 9 single-nucleotide variants, and 5 copy number variations.	('copy number variations', 'Var', (203, 225))	('TMB', 'Chemical', '-', (4, 7))	('insertion-deletion mutations', 'Var', (137, 165))	('single-nucleotide variants', 'Var', (169, 195))
431603	34011038	The tumor harbored clinically relevant mutations in CDKN2A, CCND1, and FGF19.	('tumor', 'Disease', (4, 9))	('FGF19', 'Gene', '9965', (71, 76))	('mutations', 'Var', (39, 48))	('CCND1', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CDKN2A', 'Gene', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CCND1', 'Gene', '595', (60, 65))	('CDKN2A', 'Gene', '1029', (52, 58))	('FGF19', 'Gene', (71, 76))
431663	33670049	STAT3beta Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma The prognosis of esophageal squamous cell carcinoma (ESCC) patients is poor, with a five-year survival of 15-34%.	('patients', 'Species', '9606', (193, 201))	('Cellular Necroptosis', 'MPA', (75, 95))	('STAT3beta', 'Chemical', '-', (0, 9))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (151, 185))	('Squamous Cell Carcinoma', 'Disease', (110, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('STAT3beta', 'Var', (0, 9))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('esophageal squamous cell carcinoma', 'Disease', (151, 185))	('Carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (110, 133))	('Enhances', 'PosReg', (10, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('Inducing', 'Reg', (66, 74))
431665	33670049	The data showed that ESCC patients who demonstrate both high STAT3alpha expression and high STAT3beta expression in the cytoplasm have a significantly better survival rate.	('survival rate', 'CPA', (158, 171))	('better', 'PosReg', (151, 157))	('patients', 'Species', '9606', (26, 34))	('STAT3beta', 'Chemical', '-', (92, 101))	('high STAT3beta', 'Var', (87, 101))
431666	33670049	Moreover, the ESCC patients with high STAT3beta expression have a complete response to concurrent chemoradiotherapy.	('high STAT3beta expression', 'Var', (33, 58))	('ESCC', 'Disease', (14, 18))	('patients', 'Species', '9606', (19, 27))	('STAT3beta', 'Chemical', '-', (38, 47))
431674	33670049	The data showed that ESCC patients who demonstrate both high STAT3alpha expression and high STAT3beta expression in the cytoplasm have a significantly better survival rate, and STAT3beta expression is an independent protective factor (HR = 0.424, p = 0.003).	('survival rate', 'CPA', (158, 171))	('high STAT3alpha expression', 'Var', (56, 82))	('better', 'PosReg', (151, 157))	('patients', 'Species', '9606', (26, 34))	('STAT3beta', 'Chemical', '-', (177, 186))	('STAT3beta', 'Chemical', '-', (92, 101))	('high STAT3beta', 'Var', (87, 101))
431676	33670049	In ESCC cells, high STAT3beta expression significantly inhibits the ability of colony formation and cell proliferation, suggesting that STAT3beta enhances sensitivity to CCRT (platinum plus radiation therapy).	('enhances', 'PosReg', (146, 154))	('sensitivity to CCRT', 'MPA', (155, 174))	('STAT3beta', 'Chemical', '-', (136, 145))	('platinum', 'Chemical', 'MESH:D010984', (176, 184))	('inhibits', 'NegReg', (55, 63))	('STAT3beta', 'Var', (136, 145))	('STAT3beta', 'Chemical', '-', (20, 29))	('cell proliferation', 'CPA', (100, 118))
431686	33670049	Despite STAT3 being most commonly presented as an oncogene, its opposing role as a tumor suppressor also depends on its different isoforms, i.e., full-length STAT3alpha and truncated STAT3beta, which are generated by alternative splicing of exon 23.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('STAT3beta', 'Gene', (183, 192))	('STAT3alpha', 'Gene', (158, 168))	('truncated', 'Var', (173, 182))	('STAT3beta', 'Chemical', '-', (183, 192))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
431699	33670049	Enforcing STAT3beta expression decreased the clonogenic ability of ESCC and enhanced the sensitivity to cisplatin and 5-fluorouracil.	('5-fluorouracil', 'Chemical', 'MESH:D005472', (118, 132))	('STAT3beta', 'Chemical', '-', (10, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('decreased', 'NegReg', (31, 40))	('clonogenic ability', 'CPA', (45, 63))	('enhanced', 'PosReg', (76, 84))	('STAT3beta expression', 'Var', (10, 30))
431701	33670049	In the current investigation, we show that STAT3beta increases sensitivity to CCRT (platinum plus radiation therapy).	('STAT3beta', 'Chemical', '-', (43, 52))	('STAT3beta', 'Var', (43, 52))	('sensitivity', 'MPA', (63, 74))	('platinum', 'Chemical', 'MESH:D010984', (84, 92))	('increases', 'PosReg', (53, 62))
431702	33670049	Our data confirm that STAT3beta induces cellular necroptosis upon exposure to platinum plus radiation therapy via activating the TNF signaling pathway and transcriptionally activating cell necrosis-related genes such as RIPK1 and MLKL.	('cell', 'CPA', (184, 188))	('RIPK1', 'Gene', '8737', (220, 225))	('MLKL', 'Gene', (230, 234))	('STAT3beta', 'Var', (22, 31))	('necrosis', 'Disease', (189, 197))	('cellular necroptosis', 'CPA', (40, 60))	('MLKL', 'Gene', '197259', (230, 234))	('STAT3beta', 'Chemical', '-', (22, 31))	('transcriptionally', 'MPA', (155, 172))	('RIPK1', 'Gene', (220, 225))	('necrosis', 'Disease', 'MESH:D009336', (189, 197))	('platinum', 'Chemical', 'MESH:D010984', (78, 86))	('activating', 'PosReg', (114, 124))	('activating', 'PosReg', (173, 183))	('TNF', 'Gene', (129, 132))	('induces', 'Reg', (32, 39))	('TNF', 'Gene', '7124', (129, 132))
431705	33670049	Our previous study also showed that moderate/strong STAT3beta significantly prolongs both overall survival and recurrence-free survival in patients who received adjuvant chemoradiotherapy (ACRT), but the model of STAT3alpha and STAT3beta in terms of prognosis is incomplete.	('STAT3beta', 'Chemical', '-', (228, 237))	('patients', 'Species', '9606', (139, 147))	('overall survival', 'CPA', (90, 106))	('STAT3beta', 'Chemical', '-', (52, 61))	('STAT3beta', 'Var', (52, 61))	('recurrence-free survival', 'CPA', (111, 135))	('prolongs', 'NegReg', (76, 84))	('moderate/strong STAT3beta', 'Var', (36, 61))
431709	33670049	Our data highlighted that high-expression cytoplasmic STAT3beta was significantly associated with longer overall survival (p = 0.005; Figure 1E).	('cytoplasmic', 'Protein', (42, 53))	('STAT3beta', 'Gene', (54, 63))	('longer', 'PosReg', (98, 104))	('high-expression', 'Var', (26, 41))	('overall', 'MPA', (105, 112))	('STAT3beta', 'Chemical', '-', (54, 63))
431710	33670049	Strikingly, high-expression cytoplasmic STAT3beta was a protective factor for overall survival based on univariant analysis (HR = 0.458, 95% CI = 0.261-0.802, p = 0.006) and multivariant analysis (HR = 0.424, 95% CI = 0.241-0.748, p = 0.003).	('STAT3beta', 'Chemical', '-', (40, 49))	('high-expression cytoplasmic', 'Var', (12, 39))	('STAT3beta', 'Gene', (40, 49))	('overall survival', 'CPA', (78, 94))	('cytoplasmic', 'Var', (28, 39))
431711	33670049	Moreover, we evaluated which model of STAT3beta and STAT3alpha was correlated with a favorable prognosis.	('STAT3beta', 'Var', (38, 47))	('STAT3alpha', 'Var', (52, 62))	('STAT3beta', 'Chemical', '-', (38, 47))
431712	33670049	Combining cytoplasmic STAT3beta and nuclear STAT3alpha for assessing the correlation with overall survival, high-expression cytoplasmic STAT3beta and low-expression nuclear STAT3alpha is the best combination to indicate prolonged overall survival (p = 0.001, Figure 1F).	('overall survival', 'CPA', (230, 246))	('STAT3beta', 'Chemical', '-', (136, 145))	('STAT3beta', 'Chemical', '-', (22, 31))	('prolonged', 'PosReg', (220, 229))	('low-expression', 'Var', (150, 164))	('high-expression', 'Var', (108, 123))
431713	33670049	Furthermore, high-expression cytoplasmic STAT3beta and high-expression cytoplasmic STAT3alpha also indicated prolonged overall survival (p = 0.008, Figure 1G).	('high-expression', 'Var', (13, 28))	('STAT3beta', 'Chemical', '-', (41, 50))	('overall survival', 'CPA', (119, 135))	('high-expression', 'Var', (55, 70))	('prolonged', 'PosReg', (109, 118))
431714	33670049	Taken together, high-expression cytoplasmic STAT3beta and low-expression nuclear STAT3alpha correlated with favorable clinical prognoses and prolonged survival in ESCC patients alone or in combination.	('ESCC', 'Disease', (163, 167))	('STAT3beta', 'Chemical', '-', (44, 53))	('high-expression', 'Var', (16, 31))	('prolonged', 'PosReg', (141, 150))	('patients', 'Species', '9606', (168, 176))	('low-expression', 'NegReg', (58, 72))
431715	33670049	We found that high-expression STAT3beta was moderately associated with ESCC patient's response to CCRT (ratio of complete response (CR) = 31.4%, p = 0.043), especially with a platinum plus ionizing radiation therapeutic regime (ratio of CR = 40.6%, p = 0.014) (Figure 2A).	('STAT3beta', 'Chemical', '-', (30, 39))	('platinum plus ionizing radiation', 'Disease', 'MESH:D004194', (175, 207))	('ESCC', 'Disease', (71, 75))	('STAT3beta', 'Protein', (30, 39))	('patient', 'Species', '9606', (76, 83))	('platinum plus ionizing radiation', 'Disease', (175, 207))	('high-expression', 'Var', (14, 29))	('response', 'MPA', (86, 94))
431716	33670049	The correlation between STAT3beta and clinical parameters also demonstrated that high-express cytoplasmic STAT3beta had a better response to CCRT (p = 0.008; Table 2).	('better', 'PosReg', (122, 128))	('STAT3beta', 'Chemical', '-', (106, 115))	('STAT3beta', 'Chemical', '-', (24, 33))	('response', 'MPA', (129, 137))	('STAT3beta', 'Gene', (106, 115))	('high-express', 'Var', (81, 93))
431717	33670049	These results suggested that ESCC patients with high expression levels of STAT3beta who were receiving concurrent radiotherapy and chemotherapy tended to complete remission and had a favorable prognosis.	('STAT3beta', 'Gene', (74, 83))	('STAT3beta', 'Chemical', '-', (74, 83))	('patients', 'Species', '9606', (34, 42))	('high expression levels', 'Var', (48, 70))
431721	33670049	Regarding treatment with cisplatin for 24 h, KYSE150 was more resistant than the others with a half-maximal inhibitory concentration (IC50) of 44.6 muM, while TE3 was the most sensitive cells with IC50 5.49 muM (Figure 3B and Table S3).	('resistant', 'MPA', (62, 71))	('KYSE150', 'Var', (45, 52))	('TE3', 'Chemical', '-', (159, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (25, 34))
431727	33670049	We established stably expressing STAT3beta ESCC cell lines, KYSE30 and KYSE150, which were labeled KYSE30-STAT3beta and KYSE150- STAT3beta (Figure 4A).	('STAT3beta', 'Chemical', '-', (129, 138))	('KYSE30-STAT3beta', 'Var', (99, 115))	('STAT3beta', 'Chemical', '-', (106, 115))	('KYSE150-', 'Var', (120, 128))	('STAT3beta', 'Chemical', '-', (33, 42))
431734	33670049	A cell proliferation assay was used for validation, in which the proliferation of cells was confirmed by EdU staining, both in the KYSE30, KYSE150-Vector, and -STAT3beta groups.	('KYSE30', 'Var', (131, 137))	('STAT3beta', 'Chemical', '-', (160, 169))	('EdU', 'Chemical', '-', (105, 108))	('KYSE150-Vector', 'Var', (139, 153))
431735	33670049	The EdU-positive cells were dramatically decreased after cisplatin, ionizing radiation, and CCRT treatment (Figure 4E,F).	('EdU-positive cells', 'CPA', (4, 22))	('cisplatin', 'Var', (57, 66))	('decreased', 'NegReg', (41, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('EdU', 'Chemical', '-', (4, 7))
431736	33670049	Thus, these data indicate that high STAT3beta expression likely contributed to enhance the ESCC cells' sensitivity to chemoradiotherapy.	('STAT3beta', 'Chemical', '-', (36, 45))	('STAT3beta', 'Protein', (36, 45))	('enhance', 'PosReg', (79, 86))	('high', 'Var', (31, 35))	('sensitivity to chemoradiotherapy', 'CPA', (103, 135))
431746	33670049	These results emphasized that STAT3beta inhibited cell proliferation and induced cell death and were consistent with the results of clonogenicity and cell proliferation assays as previous demonstrated.	('STAT3beta', 'Chemical', '-', (30, 39))	('cell death', 'CPA', (81, 91))	('inhibited', 'NegReg', (40, 49))	('STAT3beta', 'Var', (30, 39))	('cell proliferation', 'CPA', (50, 68))
431755	33670049	STAT3beta significantly increased cell death under cisplatin or IR alone and combined (Figure 5F).	('STAT3beta', 'Chemical', '-', (0, 9))	('cell death', 'CPA', (34, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('STAT3beta', 'Var', (0, 9))	('increased', 'PosReg', (24, 33))
431756	33670049	To confirm this result, RIPK1 and MLKL protein levels were increased and the phosphorylation of MLKL was clearly enhanced in STAT3beta high-expression KYSE30 and KYSE150 cells after CCRT (Figure 5G-I).	('phosphorylation', 'MPA', (77, 92))	('MLKL', 'Gene', '197259', (34, 38))	('MLKL', 'Gene', '197259', (96, 100))	('MLKL', 'Gene', (34, 38))	('KYSE150', 'Var', (162, 169))	('RIPK1', 'Gene', (24, 29))	('MLKL', 'Gene', (96, 100))	('KYSE30', 'Var', (151, 157))	('STAT3beta', 'Chemical', '-', (125, 134))	('increased', 'PosReg', (59, 68))	('enhanced', 'PosReg', (113, 121))	('RIPK1', 'Gene', '8737', (24, 29))
431757	33670049	The phosphorylation of STAT3alpha was decreased and there were fewer STAT3alpha in the nucleus after CCRT in KYSE30 and KYSE150 Vector expressing cells, and STAT3beta induced an increase in the expression of pSTAT3alpha and nuclear retention (Figure S3).	('KYSE30', 'Var', (109, 115))	('STAT3beta', 'Chemical', '-', (157, 166))	('decreased', 'NegReg', (38, 47))	('STAT3alpha', 'Protein', (69, 79))	('phosphorylation', 'MPA', (4, 19))	('nuclear retention', 'CPA', (224, 241))	('STAT3alpha', 'Protein', (23, 33))	('expression', 'MPA', (194, 204))	('increase', 'PosReg', (178, 186))	('pSTAT3alpha', 'Protein', (208, 219))	('fewer', 'NegReg', (63, 68))
431760	33670049	These results demonstrate that STAT3beta enhances ESCC cell necroptosis in response to CCRT by upregulating TNF and necroptosis signaling pathway-related proteins.	('upregulating', 'PosReg', (95, 107))	('necroptosis signaling pathway-related proteins', 'Pathway', (116, 162))	('TNF', 'Gene', (108, 111))	('TNF', 'Gene', '7124', (108, 111))	('ESCC cell necroptosis', 'CPA', (50, 71))	('STAT3beta', 'Chemical', '-', (31, 40))	('enhances', 'PosReg', (41, 49))	('STAT3beta', 'Var', (31, 40))
431775	33670049	It has been demonstrated that a high ratio of STAT3beta/STAT3alpha correlates with favorable clinical prognoses in acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (115, 137))	('STAT3beta', 'Chemical', '-', (46, 55))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (115, 137))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (121, 137))	('leukemia', 'Phenotype', 'HP:0001909', (129, 137))	('acute myeloid leukemia', 'Disease', (115, 137))	('STAT3beta/STAT3alpha', 'Var', (46, 66))
431777	33670049	The reason for the combined prognostic model may be the inhibition of the transcriptional ability of STAT3alpha via STAT3beta.	('inhibition', 'NegReg', (56, 66))	('STAT3beta', 'Chemical', '-', (116, 125))	('transcriptional ability', 'MPA', (74, 97))	('STAT3beta', 'Var', (116, 125))	('STAT3alpha', 'Protein', (101, 111))
431785	33670049	Taken together, our data suggest that STAT3beta is a tumor suppressor and enhances sensitivity to CCRT.	('enhances', 'PosReg', (74, 82))	('STAT3beta', 'Chemical', '-', (38, 47))	('sensitivity to CCRT', 'MPA', (83, 102))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('STAT3beta', 'Var', (38, 47))	('tumor', 'Disease', (53, 58))
431789	33670049	STAT3beta has been shown to prolong the phosphorylation of STAT3alpha Y705 and nuclear retention.	('STAT3alpha', 'Protein', (59, 69))	('prolong', 'PosReg', (28, 35))	('STAT3beta', 'Chemical', '-', (0, 9))	('Y705', 'Var', (70, 74))	('nuclear retention', 'CPA', (79, 96))	('phosphorylation', 'MPA', (40, 55))
431793	33670049	We found the phosphorylation of Y705 of STAT3 was decreased after cisplatin and ionizing radiation treatment in our KYSE150 and KYSE510 cell lines (Figure 3C).	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('phosphorylation', 'MPA', (13, 28))	('Y705', 'Var', (32, 36))	('decreased', 'NegReg', (50, 59))	('STAT3', 'Gene', (40, 45))
431805	33670049	DNMT1 and NDMT3b are transcriptionally regulated by STAT3, and activated STAT3 induced DNMT1 expression and hypermethylated TNFalpha in MDSCs.	('DNMT1', 'Gene', '1786', (87, 92))	('TNFalpha', 'Gene', (124, 132))	('STAT3', 'Gene', (73, 78))	('expression', 'MPA', (93, 103))	('DNMT1', 'Gene', (0, 5))	('TNFalpha', 'Gene', '7124', (124, 132))	('activated', 'PosReg', (63, 72))	('DNMT1', 'Gene', '1786', (0, 5))	('hypermethylated', 'Var', (108, 123))	('DNMT1', 'Gene', (87, 92))
431806	33670049	In the ESCC chemoradiotherapy model, STAT3beta upregulated the TNF signaling pathway and necroptosis, which may be a negative factor of STAT3alpha.	('STAT3beta', 'Chemical', '-', (37, 46))	('STAT3beta', 'Var', (37, 46))	('TNF', 'Gene', (63, 66))	('upregulated', 'PosReg', (47, 58))	('TNF', 'Gene', '7124', (63, 66))	('necroptosis', 'CPA', (89, 100))
431834	33670049	Cell deaths were assessed using an Annexin V-FITC apoptosis detection kit (#C1062M, Beyotime, Shanghai, China).	('Annexin V', 'Gene', '308', (35, 44))	('Annexin V', 'Gene', (35, 44))	('deaths', 'Disease', (5, 11))	('deaths', 'Disease', 'MESH:D003643', (5, 11))	('#C1062M', 'Var', (75, 82))
431841	33670049	KYSE150 STAT3-KO cells were seeded onto coverslips for 24 h. Cells were transfected with Flag-STAT3alpha, STAT3beta-HA, or a combination of both.	('STAT3beta-HA', 'Var', (106, 118))	('Flag-STAT3alpha', 'Var', (89, 104))	('STAT3beta', 'Chemical', '-', (106, 115))
431848	33670049	Our study provides novel evidence that STAT3beta induces cellular necroptosis upon CCRT exposure and specifically regulates gene expression, including the TNF signaling pathway and necroptosis-associated genes.	('regulates', 'Reg', (114, 123))	('cellular necroptosis', 'CPA', (57, 77))	('STAT3beta', 'Var', (39, 48))	('TNF', 'Gene', (155, 158))	('necroptosis-associated genes', 'Gene', (181, 209))	('TNF', 'Gene', '7124', (155, 158))	('induces', 'Reg', (49, 56))	('gene expression', 'MPA', (124, 139))	('STAT3beta', 'Chemical', '-', (39, 48))
431855	31237106	Prognostic impact of examined lymph node count in pT1N0M0 esophageal cancer: A population-based study Research on the impact of examined lymph node (ELN) count on node-negative esophageal cancer (EC) especially pT1N0M0 EC is inadequate.	('pT1N0M0', 'Var', (211, 218))	('esophageal cancer', 'Disease', 'MESH:D004938', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('esophageal cancer', 'Disease', (177, 194))
431867	31237106	Endoscopic therapy could just be therapeutic when a lesion <=2 cm in diameter is fully removed with clear lateral and deep margins and histopathologic assessment demonstrates well or moderate differentiation, invasion no deeper than the superficial submucosa, and no lymphovascular invasion (LVI).9, 10 Esophagectomy should continue to remain the standard treatment in patients with T1N0M0 EC.10  Surgery may not only resect the lesion and potential precancerous lesions to the maximum extent, but also dissect the potential metastatic lymph nodes (LN) to help accurate staging and improve the prognosis.	('patients', 'Species', '9606', (369, 377))	('prognosis', 'MPA', (594, 603))	('cancer', 'Phenotype', 'HP:0002664', (453, 459))	('precancerous lesions', 'Disease', 'MESH:D011230', (450, 470))	('T1N0M0 EC.10', 'Var', (383, 395))	('precancerous lesions', 'Disease', (450, 470))	('improve', 'PosReg', (582, 589))
431868	31237106	In the past decade, many studies have examined the impact of examined lymph node (ELN) count on the survival of patients with cancer, and a higher number of ELNs is associated with a better prognosis.11, 12, 13, 14 However, few studies have considered the relationship between the ELN count and survival in patients with pT1N0M0 EC.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pT1N0M0 EC', 'Var', (321, 331))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('patients', 'Species', '9606', (307, 315))
431870	31237106	Hence, in this report, we performed a population-based retrospective analysis of the United States Surveillance, Epidemiology, and End Results (SEER) database to investigate whether the ELN count in resected pT1N0M0 EC patients acts as a prognostic factor for the OS and esophageal cancer-specific survival (ECSS).	('CS', 'Chemical', 'MESH:D002586', (309, 311))	('esophageal cancer', 'Disease', (271, 288))	('pT1N0M0', 'Var', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('OS', 'Chemical', '-', (264, 266))	('esophageal cancer', 'Disease', 'MESH:D004938', (271, 288))	('patients', 'Species', '9606', (219, 227))
431881	31237106	Histologic codes 8140, 8144, 8210, 8211, 8255, 8260, 8263, 8310, 8480, and 8481 were used to define adenocarcinomas; codes 8052, 8070, 8071, 8072, 8074, and 8083 for squamous cell carcinomas; and all other remaining codes as other histology.	('8072', 'Var', (141, 145))	('adenocarcinomas', 'Disease', 'MESH:D000230', (100, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('codes 8052', 'Var', (117, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (166, 190))	('adenocarcinomas', 'Disease', (100, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('squamous cell carcinomas', 'Disease', (166, 190))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (166, 190))	('8071', 'Var', (135, 139))
431912	31237106	Greater extent of lymphadenectomy was associated with increased survival for patients with pT1N0M0 EC and optimum lymphadenectomy was 10 to 12 nodes.	('pT1N0M0 EC', 'Var', (91, 101))	('patients', 'Species', '9606', (77, 85))	('survival', 'MPA', (64, 72))	('increased', 'PosReg', (54, 63))
431937	29891973	Among these genes, four lncRNAs (RP5-1172N10.2, RP11-579D7.4, RP11-89N17.4, LA16c-325D7.2) had positive coefficients which suggested that higher expression level was associated with shorter survival and three (RP1-251M9.2, RP11-259O2.2, LINC00173) had negative coefficients suggested that higher levels of expression were related with longer survival.	('RP11', 'Gene', (62, 66))	('RP1', 'Gene', '6101', (223, 226))	('expression level', 'MPA', (145, 161))	('LINC00173', 'Gene', (237, 246))	('RP5-1172N10.2', 'Var', (33, 46))	('RP1', 'Gene', (210, 213))	('RP11', 'Gene', '26121', (223, 227))	('RP11', 'Gene', '26121', (48, 52))	('RP1', 'Gene', '6101', (48, 51))	('RP1', 'Gene', '6101', (210, 213))	('RP11', 'Gene', '26121', (62, 66))	('higher', 'PosReg', (138, 144))	('RP11', 'Gene', (223, 227))	('RP11', 'Gene', (48, 52))	('RP1', 'Gene', (62, 65))	('shorter', 'NegReg', (182, 189))	('RP1', 'Gene', (223, 226))	('RP1', 'Gene', (48, 51))	('RP1', 'Gene', '6101', (62, 65))	('LINC00173', 'Gene', '100287569', (237, 246))
431944	29891973	Patients with higher-risk scores tended to have higher expression level of risky lncRNAs (RP5-1172N10.2, RP11-89N17.4, LA16c-325D7.2, RP11-579D7.4).	('expression level', 'MPA', (55, 71))	('RP11', 'Gene', '26121', (134, 138))	('RP11', 'Gene', (105, 109))	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (48, 54))	('RP5-1172N10.2', 'Var', (90, 103))	('LA16c-325D7.2', 'Var', (119, 132))	('RP11', 'Gene', (134, 138))	('RP11', 'Gene', '26121', (105, 109))
431959	29891973	Here, we further explored its role in ESCC cell lines by transfecting sh-LINC00173 to knock down LINC00173 expression.	('LINC00173', 'Gene', '100287569', (73, 82))	('LINC00173', 'Gene', '100287569', (97, 106))	('expression', 'MPA', (107, 117))	('LINC00173', 'Gene', (73, 82))	('knock', 'Var', (86, 91))	('LINC00173', 'Gene', (97, 106))
431960	29891973	Colony formation assays showed that the knockdown of LINC00173 boosted the colony number (Fig.	('LINC00173', 'Gene', (53, 62))	('knockdown', 'Var', (40, 49))	('boosted', 'PosReg', (63, 70))	('LINC00173', 'Gene', '100287569', (53, 62))	('colony number', 'CPA', (75, 88))
431961	29891973	Cell cycle analysis demonstrated that LINC00173 knockdown led to a decreased G1/G0 population (Fig.	('G1/G0 population', 'CPA', (77, 93))	('LINC00173', 'Gene', (38, 47))	('decreased', 'NegReg', (67, 76))	('LINC00173', 'Gene', '100287569', (38, 47))	('knockdown', 'Var', (48, 57))
431967	29891973	Growing evidence suggests that the aberrant expression of specific lncRNAs may acts as major contributor to tumorigenesis and intimately correlated with tumor progression.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('expression', 'MPA', (44, 54))	('lncRNAs', 'Protein', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('aberrant', 'Var', (35, 43))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('correlated', 'Reg', (137, 147))
432010	29033590	Physical activity has also been reported to be associated with decreased incidence and mortality of various cancers.	('decreased', 'NegReg', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('Physical activity', 'Var', (0, 17))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancers', 'Disease', (108, 115))
432048	29033590	In the group with no RAT, moderate/long sitting time and moderate/long OAT (all P<0.05) were significantly associated with higher ESCC risk, especially long sitting time (AOR 6.92, 95% CI 2.42-19.80).	('OAT', 'Disease', (71, 74))	('ESCC', 'Disease', (130, 134))	('higher', 'PosReg', (123, 129))	('OAT', 'Disease', 'MESH:D015799', (71, 74))	('moderate/long sitting time', 'Var', (26, 52))	('long sitting time', 'Disease', (152, 169))	('RAT', 'Species', '10116', (21, 24))
432092	28687822	Furthermore, a stricture rate of 6% was reported among RFA-treated patients, which is notably lower than alternative treatment methods for dysplasia in BE.	('stricture', 'MPA', (15, 24))	('BE', 'Phenotype', 'HP:0100580', (152, 154))	('patients', 'Species', '9606', (67, 75))	('RFA-treated', 'Var', (55, 66))	('dysplasia', 'Disease', (139, 148))	('dysplasia', 'Disease', 'MESH:D004476', (139, 148))
432134	27326259	This study shows that UBE2D3 knockdown was associated with significant increases in radioresistance to X-rays, telomerase activity, telomere length, and telomere shelterins.	('UBE2D3', 'Gene', (22, 28))	('knockdown', 'Var', (29, 38))	('telomerase activity', 'CPA', (111, 130))	('telomere length', 'CPA', (132, 147))	('increases', 'PosReg', (71, 80))	('telomere shelterins', 'CPA', (153, 172))	('rays', 'Species', '255564', (105, 109))	('radioresistance to X-rays', 'CPA', (84, 109))
432135	27326259	UBE2D3 knockdown-mediated radioresistance was related to a decrease in the spontaneous and ionizing radiation-induced apoptosis, resulting from a decrease in the Bax/Bcl-2 ratio.	('Bax', 'Gene', (162, 165))	('Bcl-2', 'Gene', (166, 171))	('knockdown-mediated', 'Var', (7, 25))	('radioresistance', 'CPA', (26, 41))	('Bcl-2', 'Gene', '596', (166, 171))	('UBE2D3', 'Gene', (0, 6))	('Bax', 'Gene', '581', (162, 165))	('decrease', 'NegReg', (59, 67))	('decrease', 'NegReg', (146, 154))
432147	27326259	Moreover, UBE2D3 increases the function of BRCA1, which not only acts as a tumor suppressor gene but also takes part in DNA damage repair by ubiquitin in a variety of downstream molecules.	('BRCA1', 'Gene', (43, 48))	('UBE2D3', 'Var', (10, 16))	('increases', 'PosReg', (17, 26))	('function', 'MPA', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('BRCA1', 'Gene', '672', (43, 48))	('tumor', 'Disease', (75, 80))
432149	27326259	UBE2D3 suppresses UBE2N via monoubiquitination of Otub1 at lysine 59 and 109 residues.	('Otub1', 'Gene', (50, 55))	('UBE2D3', 'Var', (0, 6))	('Otub1', 'Gene', '55611', (50, 55))	('suppresses', 'NegReg', (7, 17))	('monoubiquitination', 'MPA', (28, 46))	('UBE2N', 'Gene', (18, 23))	('UBE2N', 'Gene', '7334', (18, 23))	('lysine', 'Chemical', 'MESH:D008239', (59, 65))
432164	27326259	The following protocol was used for GAPDH and UBE2D3: preincubated at 95C for 30 sec followed by 40 cycles of 95C for 5 sec, 60C for 15 sec and 72C for 30 sec.	('95C', 'Var', (110, 113))	('GAPDH', 'Gene', '2597', (36, 41))	('GAPDH', 'Gene', (36, 41))
432177	27326259	Cells grown on coverslips (Fisher Scientific, USA) were divided into 4 groups: Eca-109-NC, Eca-109-sh, IR+Eca-109-NC, IR+Eca-109-sh.	('Eca', 'Chemical', '-', (106, 109))	('Eca', 'Chemical', '-', (79, 82))	('Eca', 'Chemical', '-', (121, 124))	('IR+Eca-109-sh', 'Var', (118, 131))	('Eca', 'Chemical', '-', (91, 94))	('IR+Eca-109-NC', 'Var', (103, 116))	('Eca-109-NC', 'Var', (79, 89))	('Eca-109-sh', 'Var', (91, 101))
432181	27326259	A comparison of Eca-109-NC and Eca-109-sh cells showed that the expression of UBE2D3 was reduced in Eca-109-sh cells both at the mRNA (Figure 1A) and protein levels (Figure 1B, 1C) (P < 0.05).	('UBE2D3', 'Gene', (78, 84))	('expression', 'MPA', (64, 74))	('Eca', 'Chemical', '-', (100, 103))	('Eca', 'Chemical', '-', (31, 34))	('Eca-109-sh', 'Var', (100, 110))	('Eca', 'Chemical', '-', (16, 19))	('reduced', 'NegReg', (89, 96))
432186	27326259	D0, Dq and SF2 values in the Eca-109-sh group were significantly lower than those of the Eca-109-NC groups (P < 0.05).	('SF2', 'Gene', '6426', (11, 14))	('lower', 'NegReg', (65, 70))	('SF2', 'Gene', (11, 14))	('Eca', 'Chemical', '-', (29, 32))	('Eca-109-sh', 'Var', (29, 39))	('Eca', 'Chemical', '-', (89, 92))
432192	27326259	However, telomerase activity in the Eca-109-sh group was significantly higher than that in the Eca-109-NC group (Figure 3A, P < 0.5).	('higher', 'PosReg', (71, 77))	('telomerase activity', 'MPA', (9, 28))	('Eca', 'Chemical', '-', (36, 39))	('Eca', 'Chemical', '-', (95, 98))	('Eca-109-sh', 'Var', (36, 46))
432198	27326259	Additionally, after exposure to 2 Gy IR, the proliferation of Eca-109-sh cells was significantly higher than that of Eca-109-NC cells (Figure 5B) (P < 0.05).	('higher', 'PosReg', (97, 103))	('Eca', 'Chemical', '-', (62, 65))	('proliferation', 'CPA', (45, 58))	('Eca', 'Chemical', '-', (117, 120))	('Eca-109-sh', 'Var', (62, 72))
432202	27326259	The percentage of apoptotic cells for each group was as follows: Eca-109-NC: 6.08 +- 1.15%, Eca-109-sh: 2.00 +- 0.72%, Eca-109-NC + IR: 14.3 +- 0.95%, and Eca-109-sh + IR: 3.77 +- 1.56%.	('Eca-109-NC', 'Var', (65, 75))	('Eca-109-sh', 'Var', (92, 102))	('Eca', 'Chemical', '-', (65, 68))	('Eca', 'Chemical', '-', (155, 158))	('Eca-109-NC + IR', 'Var', (119, 134))	('Eca', 'Chemical', '-', (119, 122))	('Eca', 'Chemical', '-', (92, 95))
432203	27326259	The percentage of cells undergoing spontaneous or ionizing radiation-induced apoptosis was significantly decreased in Eca-109-sh cells compared to that in Eca-109-NC cells (Figure 6, P < 0.05).	('Eca', 'Chemical', '-', (155, 158))	('cells', 'CPA', (18, 23))	('Eca', 'Chemical', '-', (118, 121))	('spontaneous', 'CPA', (35, 46))	('Eca-109-sh', 'Var', (118, 128))	('decreased', 'NegReg', (105, 114))
432204	27326259	These results suggest that UBE2D3 knockdown reduces spontaneous and ionizing radiation-induced apoptosis in Eca-109 cells.	('knockdown', 'Var', (34, 43))	('reduces', 'NegReg', (44, 51))	('UBE2D3', 'Gene', (27, 33))	('Eca', 'Chemical', '-', (108, 111))
432205	27326259	To investigate the effect of UBE2D3 on DNA damage repair, immunofluorescence was used to assess the changes in phospho-gammaH2AX after UBE2D3 knockdown.	('UBE2D3', 'Gene', (135, 141))	('gammaH2AX', 'Chemical', '-', (119, 128))	('knockdown', 'Var', (142, 151))
432206	27326259	As shown in Figure 7, gammaH2AX foci significantly decreased in Eca-109-sh cells when compared with those in Eca-109-NC cells (P < 0.05).	('Eca-109-sh', 'Var', (64, 74))	('gammaH2AX', 'Protein', (22, 31))	('decreased', 'NegReg', (51, 60))	('gammaH2AX', 'Chemical', '-', (22, 31))	('Eca', 'Chemical', '-', (109, 112))	('Eca', 'Chemical', '-', (64, 67))
432209	27326259	UBE2D3 knockdown significantly increased protein levels of hTERT, TRF1, TRF2, POT1, and RAP1, but had no effect on TPP1 and TIN2 protein levels (Figure 8A).	('RAP1', 'Gene', '5906', (88, 92))	('TRF1', 'Gene', (66, 70))	('TPP1', 'Gene', (115, 119))	('hTERT', 'Gene', (59, 64))	('increased', 'PosReg', (31, 40))	('TRF1', 'Gene', '7013', (66, 70))	('RAP1', 'Gene', (88, 92))	('POT1', 'Gene', (78, 82))	('TIN2', 'Gene', '26277', (124, 128))	('POT1', 'Gene', '25913', (78, 82))	('TRF2', 'Gene', '7014', (72, 76))	('UBE2D3', 'Gene', (0, 6))	('TRF2', 'Gene', (72, 76))	('TPP1', 'Gene', '1200', (115, 119))	('TIN2', 'Gene', (124, 128))	('hTERT', 'Gene', '7015', (59, 64))	('knockdown', 'Var', (7, 16))	('protein levels', 'MPA', (41, 55))
432213	27326259	The proportion of Bax/Bcl-2 was reduced in the absence of UBE2D3 (Figure 8B).	('Bax', 'Gene', '581', (18, 21))	('reduced', 'NegReg', (32, 39))	('UBE2D3', 'Gene', (58, 64))	('absence', 'Var', (47, 54))	('Bcl-2', 'Gene', (22, 27))	('Bcl-2', 'Gene', '596', (22, 27))	('Bax', 'Gene', (18, 21))
432214	27326259	To determine the mechanisms involved in the DNA damage repair and cell cycle changes induced by UBE2D3 knockdown, the expression of DNA damage repair proteins (ataxia telangiectasia mutated, ATM; ataxia telangiectasia rad3-related, ATR; p-ATM; p-ATR; and gammaH2AX) and cell cycle check point proteins (cyclin D1, CDC25A, CDC25C, and Chk1) were assessed by western blot.	('ataxia', 'Phenotype', 'HP:0001251', (196, 202))	('telangiectasia', 'Phenotype', 'HP:0001009', (167, 181))	('cyclin D1', 'Gene', '595', (303, 312))	('gammaH2AX', 'Chemical', '-', (255, 264))	('CDC25C', 'Gene', (322, 328))	('ATR', 'Gene', '545', (232, 235))	('ATM', 'Gene', (191, 194))	('ataxia telangiectasia', 'Disease', (196, 217))	('ATM', 'Gene', (239, 242))	('CDC25C', 'Gene', '995', (322, 328))	('UBE2D3', 'Gene', (96, 102))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (160, 181))	('ATR', 'Gene', '545', (246, 249))	('Chk1', 'Gene', (334, 338))	('telangiectasia', 'Phenotype', 'HP:0001009', (203, 217))	('ataxia', 'Phenotype', 'HP:0001251', (160, 166))	('Chk1', 'Gene', '1111', (334, 338))	('knockdown', 'Var', (103, 112))	('ATR', 'Gene', (232, 235))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (196, 217))	('CDC25A', 'Gene', '993', (314, 320))	('ATM', 'Gene', '472', (191, 194))	('ATM', 'Gene', '472', (239, 242))	('ataxia telangiectasia', 'Disease', (160, 181))	('cyclin D1', 'Gene', (303, 312))	('ATR', 'Gene', (246, 249))	('CDC25A', 'Gene', (314, 320))
432215	27326259	UBE2D3 knockdown induced a significant increase in ATM, ATR, p-ATM, cyclin D1, and Chk1 expression, while it significantly reduced gammaH2AX, CDC25A, and CDC25C protein expression (Figure 8B).	('ATM', 'Gene', '472', (63, 66))	('increase', 'PosReg', (39, 47))	('cyclin D1', 'Gene', '595', (68, 77))	('gammaH2AX', 'Protein', (131, 140))	('expression', 'MPA', (88, 98))	('ATR', 'Gene', (56, 59))	('Chk1', 'Gene', (83, 87))	('ATM', 'Gene', (63, 66))	('Chk1', 'Gene', '1111', (83, 87))	('CDC25A', 'Gene', '993', (142, 148))	('CDC25C', 'Gene', (154, 160))	('ATM', 'Gene', '472', (51, 54))	('UBE2D3', 'Gene', (0, 6))	('CDC25C', 'Gene', '995', (154, 160))	('CDC25A', 'Gene', (142, 148))	('ATR', 'Gene', '545', (56, 59))	('knockdown', 'Var', (7, 16))	('gammaH2AX', 'Chemical', '-', (131, 140))	('ATM', 'Gene', (51, 54))	('cyclin D1', 'Gene', (68, 77))	('reduced', 'NegReg', (123, 130))
432221	27326259	Ubiquitylation modification, which is mediated by the ubiquitin/proteasome system (UPS), plays an important role in DNA damage response activated by DNA DSBs as well as some other posttranslational protein modifications such as phosphorylation, acetylation and methylation.	('Ubiquitylation modification', 'MPA', (0, 27))	('acetylation', 'MPA', (245, 256))	('DSBs', 'Chemical', '-', (153, 157))	('methylation', 'Var', (261, 272))	('phosphorylation', 'MPA', (228, 243))	('DSBs', 'Var', (153, 157))
432224	27326259	In this study, we used the clonogenic assay to assess the radioresistance in an esophageal cancer cell line, Eca-109, after UBE2D3 knockdown, and demonstrated that UBE2D3 knockdown induced radioresistance.	('knockdown', 'Var', (131, 140))	('esophageal cancer', 'Disease', (80, 97))	('radioresistance', 'CPA', (58, 73))	('knockdown', 'Var', (171, 180))	('radioresistance', 'CPA', (189, 204))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('Eca', 'Chemical', '-', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('UBE2D3 knockdown', 'Var', (164, 180))
432228	27326259	The results showed that UBE2D3 knockdown raised hTERT protein expression, enhanced telomerase activity, and increased telomere length.	('increased telomere length', 'Phenotype', 'HP:0031413', (108, 133))	('telomerase', 'Enzyme', (83, 93))	('UBE2D3', 'Gene', (24, 30))	('hTERT', 'Gene', (48, 53))	('increased', 'PosReg', (108, 117))	('activity', 'MPA', (94, 102))	('telomere length', 'CPA', (118, 133))	('enhanced', 'PosReg', (74, 82))	('raised', 'PosReg', (41, 47))	('knockdown', 'Var', (31, 40))	('hTERT', 'Gene', '7015', (48, 53))
432229	27326259	To verify this hypothesis, we assessed the expression of telomere shelterin proteins which play a protective role and are positively associated with the state of telomere homeostasis, and found that UBE2D3 knockdown increased the expressions of TRF1, TRF2, POT1 and RAP1, but did not affect the expressions of TPP1 and TIN2.	('TRF2', 'Gene', '7014', (251, 255))	('RAP1', 'Gene', (266, 270))	('TRF2', 'Gene', (251, 255))	('TIN2', 'Gene', '26277', (319, 323))	('TPP1', 'Gene', (310, 314))	('UBE2D3', 'Gene', (199, 205))	('TRF1', 'Gene', '7013', (245, 249))	('expressions', 'MPA', (230, 241))	('TIN2', 'Gene', (319, 323))	('TPP1', 'Gene', '1200', (310, 314))	('TRF1', 'Gene', (245, 249))	('POT1', 'Gene', '25913', (257, 261))	('increased', 'PosReg', (216, 225))	('POT1', 'Gene', (257, 261))	('RAP1', 'Gene', '5906', (266, 270))	('knockdown', 'Var', (206, 215))
432230	27326259	As TRF2 is a key protein that binds to the double strand of the telomere, we chose it for further study of telomere homeostasis after 2 Gy or 4 Gy irradiation and determined that UBE2D3 knockdown increased TRF2 expression in a dose dependent manner.	('increased', 'PosReg', (196, 205))	('TRF2', 'Gene', (206, 210))	('knockdown', 'Var', (186, 195))	('TRF2', 'Gene', (3, 7))	('expression', 'MPA', (211, 221))	('TRF2', 'Gene', '7014', (3, 7))	('TRF2', 'Gene', '7014', (206, 210))
432232	27326259	Cyclin D1 was overexpressed, and CDC25A expression was reduced after UBE2D3 knockdown.	('expression', 'MPA', (40, 50))	('overexpressed', 'PosReg', (14, 27))	('knockdown', 'Var', (76, 85))	('CDC25A', 'Gene', '993', (33, 39))	('reduced', 'NegReg', (55, 62))	('UBE2D3', 'Gene', (69, 75))	('CDC25A', 'Gene', (33, 39))
432234	27326259	Phosphorylation of ATM can activate Chk1 by phosphorylation on S345.	('Chk1', 'Gene', (36, 40))	('Chk1', 'Gene', '1111', (36, 40))	('activate', 'PosReg', (27, 35))	('Phosphorylation', 'Var', (0, 15))	('phosphorylation', 'Var', (44, 59))	('ATM', 'Gene', (19, 22))	('ATM', 'Gene', '472', (19, 22))
432236	27326259	Chk1 phosphorylation inhibits CDC25C activity and leads to G2/M arrest.	('G2/M arrest', 'CPA', (59, 70))	('inhibits', 'NegReg', (21, 29))	('CDC25C', 'Gene', (30, 36))	('phosphorylation', 'Var', (5, 20))	('Chk1', 'Gene', (0, 4))	('CDC25C', 'Gene', '995', (30, 36))	('Chk1', 'Gene', '1111', (0, 4))	('leads to', 'Reg', (50, 58))
432237	27326259	In addition, UBE2D3 knockdown increased the expressions of shelterins, ATM and ATR, but reduced the expressions of Chk1 and CDC25C in cells treated with or without radiation exposure.	('expressions', 'MPA', (44, 55))	('Chk1', 'Gene', '1111', (115, 119))	('CDC25C', 'Gene', '995', (124, 130))	('ATM', 'Gene', (71, 74))	('UBE2D3', 'Gene', (13, 19))	('ATM', 'Gene', '472', (71, 74))	('expressions', 'MPA', (100, 111))	('increased', 'PosReg', (30, 39))	('knockdown', 'Var', (20, 29))	('ATR', 'Gene', '545', (79, 82))	('CDC25C', 'Gene', (124, 130))	('ATR', 'Gene', (79, 82))	('shelterins', 'Protein', (59, 69))	('reduced', 'NegReg', (88, 95))	('Chk1', 'Gene', (115, 119))
432238	27326259	Therefore, this study indicates that UBE2D3 knockdown combined with radiation could promote the transformation of Chk1 into phosphorylation of Chk1 via increasing the activation of ATM and ATR.	('Chk1', 'Gene', (114, 118))	('increasing', 'PosReg', (152, 162))	('promote', 'PosReg', (84, 91))	('Chk1', 'Gene', '1111', (114, 118))	('Chk1', 'Gene', (143, 147))	('activation', 'PosReg', (167, 177))	('Chk1', 'Gene', '1111', (143, 147))	('phosphorylation', 'MPA', (124, 139))	('ATR', 'Gene', '545', (189, 192))	('transformation', 'MPA', (96, 110))	('knockdown', 'Var', (44, 53))	('ATR', 'Gene', (189, 192))	('ATM', 'Gene', (181, 184))	('ATM', 'Gene', '472', (181, 184))
432240	27326259	Thus, prolonged G2/M arrest induced by knockdown of UBE2D3 may be mediated via the ATM/ATR-Chk1-CDC25C signaling pathway.	('Chk1', 'Gene', (91, 95))	('knockdown', 'Var', (39, 48))	('ATM', 'Gene', '472', (83, 86))	('UBE2D3', 'Gene', (52, 58))	('CDC25C', 'Gene', (96, 102))	('G2/M arrest', 'CPA', (16, 27))	('Chk1', 'Gene', '1111', (91, 95))	('ATR', 'Gene', '545', (87, 90))	('ATR', 'Gene', (87, 90))	('mediated', 'Reg', (66, 74))	('CDC25C', 'Gene', '995', (96, 102))	('ATM', 'Gene', (83, 86))
432246	27326259	As a histone H2A variant, H2AX plays an essential role in the cellular response to DNA DSBs.	('H2AX', 'Gene', '3014', (26, 30))	('H2AX', 'Gene', (26, 30))	('DSBs', 'Chemical', '-', (87, 91))	('variant', 'Var', (17, 24))
432250	27326259	In this study, the number of DNA damage foci decreased and the repair kinetics of total DSB increased after UBE2D3 knockdown, indicating that UBE2D3 knockdown enhanced DNA damage repair ability in esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('damage foci decreased', 'Disease', 'MESH:C565785', (33, 54))	('repair kinetics', 'MPA', (63, 78))	('enhanced', 'PosReg', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('increased', 'PosReg', (92, 101))	('UBE2D3', 'Gene', (108, 114))	('damage foci decreased', 'Disease', (33, 54))	('esophageal cancer', 'Disease', (197, 214))	('knockdown', 'Var', (115, 124))
432254	24995146	XB130 (AFAP1L2) is an adaptor protein involved in many cellular functions, such as cell survival, cell proliferation, migration, and gene and miRNA expression.	('rat', 'Species', '10116', (110, 113))	('XB130', 'Gene', (0, 5))	('AFAP1L2', 'Gene', (7, 14))	('miRNA', 'Var', (142, 147))	('XB130', 'Gene', '84632', (0, 5))	('AFAP1L2', 'Gene', '84632', (7, 14))	('rat', 'Species', '10116', (121, 124))
432256	24995146	As a tyrosine kinase substrate, tyrosine phosphorylated XB130 associates with the p85alpha regulatory subunit of phosphoinositol-3-kinase (PI3K) and subsequently affects Akt activity and its downstream signalling.	('phosphoinositol-3-kinase', 'Gene', (113, 137))	('p85alpha', 'Gene', (82, 90))	('phosphoinositol-3-kinase', 'Gene', '5295', (113, 137))	('Akt', 'Gene', '207', (170, 173))	('rat', 'Species', '10116', (26, 29))	('Akt', 'Gene', (170, 173))	('XB130', 'Gene', (56, 61))	('p85alpha', 'Gene', '5295', (82, 90))	('tyrosine', 'Chemical', 'MESH:D014443', (32, 40))	('tyrosine', 'Chemical', 'MESH:D014443', (5, 13))	('tyrosine', 'Var', (32, 40))	('XB130', 'Gene', '84632', (56, 61))	('activity', 'MPA', (174, 182))	('associates', 'Interaction', (62, 72))	('affects', 'Reg', (162, 169))
432316	24995146	In normal rat thyroid FRTL-5 cells, cyclic adenosine monophosphate (cAMP) treatment increased tyrosine phosphorylation of a 125 kDa protein (p125) and its association with the p85alpha subunit of PI3K.	('increased tyrosine phosphorylation', 'Phenotype', 'HP:0003231', (84, 118))	('p85alpha', 'Gene', '5295', (176, 184))	('cAMP', 'Chemical', 'MESH:D000242', (68, 72))	('association', 'Interaction', (155, 166))	('tyrosine phosphorylation', 'MPA', (94, 118))	('p125', 'Var', (141, 145))	('cyclic adenosine monophosphate', 'Chemical', 'MESH:D000242', (36, 66))	('tyrosine', 'Chemical', 'MESH:D014443', (94, 102))	('rat', 'Species', '10116', (10, 13))	('increased', 'PosReg', (84, 93))	('p85alpha', 'Gene', (176, 184))
432317	24995146	Matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry identified p125 as a rat ortholog of human XB130 (which was labeled as PI3K-associated protein or PI3KAP).	('rat', 'Species', '10116', (110, 113))	('XB130', 'Gene', '84632', (132, 137))	('human', 'Species', '9606', (126, 131))	('p125', 'Var', (100, 104))	('XB130', 'Gene', (132, 137))
432319	24995146	Inhibition or knockdown of Src kinase abolished cAMP-induced tyrosine phosphorylation of XB130, XB130 interaction with the p85alpha subunit of PI3K, and decreased PI3K activity.	('XB130', 'Gene', (89, 94))	('abolished', 'NegReg', (38, 47))	('PI3K activity', 'CPA', (163, 176))	('p85alpha', 'Gene', (123, 131))	('Src', 'Gene', (27, 30))	('Src', 'Gene', '6714', (27, 30))	('XB130', 'Gene', (96, 101))	('decreased', 'NegReg', (153, 162))	('XB130', 'Gene', '84632', (89, 94))	('p85alpha', 'Gene', '5295', (123, 131))	('knockdown', 'Var', (14, 23))	('tyrosine', 'Chemical', 'MESH:D014443', (61, 69))	('cAMP', 'Chemical', 'MESH:D000242', (48, 52))	('XB130', 'Gene', '84632', (96, 101))	('tyrosine phosphorylation', 'MPA', (61, 85))	('interaction', 'Interaction', (102, 113))
432320	24995146	In addition, knockdown of XB130 was associated with reduced potentiation of cell synthesis and reduced cyclin D1 protein expression.	('XB130', 'Gene', (26, 31))	('potentiation', 'MPA', (60, 72))	('cell synthesis', 'MPA', (76, 90))	('reduced', 'NegReg', (52, 59))	('XB130', 'Gene', '84632', (26, 31))	('reduced', 'NegReg', (95, 102))	('cyclin D1', 'Gene', '595', (103, 112))	('knockdown', 'Var', (13, 22))	('cyclin D1', 'Gene', (103, 112))
432323	24995146	The association of XB130 with PI3K is important in the regulation of cell proliferation, cell cycle progression, and cell survival of both normal and cancer cells.	('PI3K', 'Var', (30, 34))	('XB130', 'Gene', '84632', (19, 24))	('association', 'Interaction', (4, 15))	('rat', 'Species', '10116', (81, 84))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('XB130', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cell cycle', 'CPA', (89, 99))
432326	24995146	In human thyroid cancer cells, phosphorylated XB130 controls PI3K/Akt activity and subsequently regulates cell proliferation and survival.	('cell proliferation', 'CPA', (106, 124))	('Akt', 'Gene', (66, 69))	('survival', 'CPA', (129, 137))	('thyroid cancer', 'Disease', (9, 23))	('rat', 'Species', '10116', (118, 121))	('human', 'Species', '9606', (3, 8))	('thyroid cancer', 'Phenotype', 'HP:0002890', (9, 23))	('controls', 'Reg', (52, 60))	('Akt', 'Gene', '207', (66, 69))	('phosphorylated', 'Var', (31, 45))	('XB130', 'Gene', (46, 51))	('thyroid cancer', 'Disease', 'MESH:D013964', (9, 23))	('regulates', 'Reg', (96, 105))	('XB130', 'Gene', '84632', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
432331	24995146	Downregulation of XB130 reduced phosphorylation of Akt and the Akt substrate, glycogen synthase kinase beta (GSK3beta), which is a serine-threonine kinase that inhibits glycogen synthase assisting in energy metabolism and cell cycle progression.	('rat', 'Species', '10116', (72, 75))	('Akt', 'Gene', (51, 54))	('reduced', 'NegReg', (24, 31))	('GSK3beta', 'Gene', (109, 117))	('XB130', 'Gene', (18, 23))	('Downregulation', 'Var', (0, 14))	('GSK3beta', 'Gene', '2932', (109, 117))	('glycogen synthase', 'Enzyme', (169, 186))	('Akt', 'Gene', '207', (51, 54))	('XB130', 'Gene', '84632', (18, 23))	('inhibits', 'NegReg', (160, 168))	('cell cycle progression', 'CPA', (222, 244))	('Akt', 'Gene', '207', (63, 66))	('phosphorylation', 'MPA', (32, 47))	('serine', 'Chemical', 'MESH:D012694', (131, 137))	('Akt', 'Gene', (63, 66))
432334	24995146	In addition, measurement of the cell proliferation markers, Ki67 and proliferating cell nuclear antigen (PCNA), showed that knockdown of XB130 reduces cell proliferation.	('knockdown', 'Var', (124, 133))	('PCNA', 'Gene', (105, 109))	('rat', 'Species', '10116', (163, 166))	('proliferating cell nuclear antigen', 'Gene', (69, 103))	('rat', 'Species', '10116', (76, 79))	('XB130', 'Gene', (137, 142))	('PCNA', 'Gene', '5111', (105, 109))	('cell proliferation', 'CPA', (151, 169))	('rat', 'Species', '10116', (44, 47))	('proliferating cell nuclear antigen', 'Gene', '5111', (69, 103))	('XB130', 'Gene', '84632', (137, 142))	('reduces', 'NegReg', (143, 150))
432337	24995146	RNAi silencing of XB130 reduced phosphorylation of p27 Kip1, p21 Cip/WAF1, and FOXO3a and inhibited cell survival in WRO and A549 cells.	('p27 Kip1', 'Gene', '1027', (51, 59))	('WAF1', 'Gene', '1026', (69, 73))	('reduced', 'NegReg', (24, 31))	('A549', 'CellLine', 'CVCL:0023', (125, 129))	('XB130', 'Gene', (18, 23))	('silencing', 'Var', (5, 14))	('FOXO3a', 'Gene', '2309', (79, 85))	('p21', 'Gene', '1026', (61, 64))	('FOXO3a', 'Gene', (79, 85))	('WAF1', 'Gene', (69, 73))	('XB130', 'Gene', '84632', (18, 23))	('phosphorylation', 'MPA', (32, 47))	('inhibited', 'NegReg', (90, 99))	('p21', 'Gene', (61, 64))	('p27 Kip1', 'Gene', (51, 59))
432345	24995146	Microarray analysis of XB130 shRNA transfected WRO cells compared to vector transfected control cells demonstrated that XB130 knockdown has a significant effect on gene expression profiles.	('XB130', 'Gene', (120, 125))	('XB130', 'Gene', '84632', (23, 28))	('gene expression profiles', 'MPA', (164, 188))	('XB130', 'Gene', '84632', (120, 125))	('rat', 'Species', '10116', (109, 112))	('effect', 'Reg', (154, 160))	('knockdown', 'Var', (126, 135))	('XB130', 'Gene', (23, 28))
432346	24995146	In total, 57 genes with cell proliferation or survival related function showed a downregulated change in XB130 knockdown cells.	('knockdown', 'Var', (111, 120))	('downregulated', 'NegReg', (81, 94))	('XB130', 'Gene', '84632', (105, 110))	('cell proliferation', 'CPA', (24, 42))	('rat', 'Species', '10116', (36, 39))	('XB130', 'Gene', (105, 110))
432347	24995146	Ingenuity pathway analysis listed the top molecular and cellular functions related to XB130 knockdown as cellular growth, proliferation, and cell cycle.	('cellular growth', 'CPA', (105, 120))	('knockdown', 'Var', (92, 101))	('rat', 'Species', '10116', (129, 132))	('XB130', 'Gene', (86, 91))	('cell cycle', 'CPA', (141, 151))	('XB130', 'Gene', '84632', (86, 91))	('proliferation', 'CPA', (122, 135))
432348	24995146	The expression levels of multiple miRNAs were altered in XB130 knockdown WRO cells.	('expression levels', 'MPA', (4, 21))	('XB130', 'Gene', '84632', (57, 62))	('altered', 'Reg', (46, 53))	('knockdown', 'Var', (63, 72))	('XB130', 'Gene', (57, 62))
432349	24995146	The three miRNAs miR-33a, 149a, and 193a-3p, which showed changes in expression level after XB130 downregulation, exhibit tumor suppressive function in thyroid cancer cells.	('expression level', 'MPA', (69, 85))	('XB130', 'Gene', '84632', (92, 97))	('193a-3p', 'Var', (36, 43))	('downregulation', 'NegReg', (98, 112))	('thyroid cancer', 'Disease', (152, 166))	('thyroid cancer', 'Phenotype', 'HP:0002890', (152, 166))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('changes', 'Reg', (58, 65))	('miR-33a', 'Gene', '407039', (17, 24))	('thyroid cancer', 'Disease', 'MESH:D013964', (152, 166))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('miR-33a', 'Gene', (17, 24))	('XB130', 'Gene', (92, 97))	('tumor', 'Disease', (122, 127))
432350	24995146	The expression of both the pri-miRNA and mature miRNA of miR-33a, 149a, and 193a-3p was increased in XB130 knockdown WRO cells.	('knockdown', 'Var', (107, 116))	('XB130', 'Gene', '84632', (101, 106))	('expression', 'MPA', (4, 14))	('XB130', 'Gene', (101, 106))	('increased', 'PosReg', (88, 97))	('miR-33a', 'Gene', (57, 64))	('miR-33a', 'Gene', '407039', (57, 64))
432361	24995146	Moreover, when TPC1 cells were transfected with constitutively activated (CA) forms of Rho GTPase, RhoA (Q63L) or Rac1 (Q61L), only the CA-Rac1 expressing cells showed translocation of XB130 to the cell periphery.	('Rac1', 'Gene', '5879', (114, 118))	('Rac1', 'Gene', '5879', (139, 143))	('Q61L', 'Mutation', 'p.Q61L', (120, 124))	('TPC1', 'Gene', (15, 19))	('XB130', 'Gene', (185, 190))	('Q63L', 'Mutation', 'p.Q63L', (105, 109))	('Rac1', 'Gene', (114, 118))	('translocation', 'MPA', (168, 181))	('RhoA', 'Gene', (99, 103))	('XB130', 'Gene', '84632', (185, 190))	('Q61L', 'Var', (120, 124))	('Q63L', 'Var', (105, 109))	('RhoA', 'Gene', '387', (99, 103))	('TPC1', 'Gene', '53373', (15, 19))	('Rac1', 'Gene', (139, 143))
432364	24995146	Immunofluorescence (IF) confocal microscopy analysis using cells transfected with different XB130 deletion constructs indicates that both the N-terminus (containing 167aa) and C-terminus (containing 63aa) are required for XB130 movement to the cell periphery.	('containing 167aa', 'Var', (154, 170))	('XB130', 'Gene', '84632', (92, 97))	('containing', 'Var', (188, 198))	('XB130', 'Gene', '84632', (222, 227))	('deletion', 'Var', (98, 106))	('XB130', 'Gene', (222, 227))	('XB130', 'Gene', (92, 97))
432369	24995146	Deregulation of adaptor proteins is highly related to the abnormality of cellular functions and leads to a spectrum of diseases, including cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('Deregulation', 'Var', (0, 12))	('cellular functions', 'MPA', (73, 91))	('leads to', 'Reg', (96, 104))	('related', 'Reg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('adaptor', 'Protein', (16, 23))	('spectrum of diseases', 'Disease', (107, 127))	('cancer', 'Disease', (139, 145))
432382	24995146	Furthermore, the localization of XB130 in the nucleus of human esophageal squamous carcinoma cells was associated with a shorter 5-year survival rate.	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (63, 92))	('XB130', 'Gene', '84632', (33, 38))	('esophageal squamous carcinoma', 'Disease', (63, 92))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (74, 92))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (63, 92))	('5-year survival rate', 'CPA', (129, 149))	('shorter', 'NegReg', (121, 128))	('localization', 'Var', (17, 29))	('XB130', 'Gene', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('rat', 'Species', '10116', (145, 148))	('human', 'Species', '9606', (57, 62))
432387	24995146	The volume of tumors formed from XB130 knockdown WRO cells was significantly smaller than those formed from WRO cells transfected with a control vector.	('XB130', 'Gene', '84632', (33, 38))	('knockdown', 'Var', (39, 48))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('XB130', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('smaller', 'NegReg', (77, 84))
432388	24995146	The absence of XB130 led to a reduction in tumor growth accompanied with reduced cell proliferation and enhanced apoptosis.	('cell proliferation', 'CPA', (81, 99))	('XB130', 'Gene', '84632', (15, 20))	('apoptosis', 'CPA', (113, 122))	('reduced', 'NegReg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('enhanced', 'PosReg', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('reduction', 'NegReg', (30, 39))	('XB130', 'Gene', (15, 20))	('absence', 'Var', (4, 11))	('tumor', 'Disease', (43, 48))	('rat', 'Species', '10116', (93, 96))
432399	24995146	Among these tumors, 70% of the identified cases are caused by substitution missense mutations in the XB130 gene.	('XB130', 'Gene', '84632', (101, 106))	('substitution missense mutations', 'Var', (62, 93))	('XB130', 'Gene', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('caused by', 'Reg', (52, 61))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
432413	24995146	Dysregulation of XB130 expression in thyroid tissue may result in the dysfunction of the thyroid leading to developmental retardation and hormone disorders.	('hormone disorders', 'Disease', 'MESH:D009384', (138, 155))	('XB130', 'Gene', (17, 22))	('Dysregulation', 'Var', (0, 13))	('developmental retardation', 'Phenotype', 'HP:0001263', (108, 133))	('dysfunction', 'MPA', (70, 81))	('XB130', 'Gene', '84632', (17, 22))	('developmental retardation', 'Disease', 'MESH:C563867', (108, 133))	('hormone disorders', 'Disease', (138, 155))	('developmental retardation', 'Disease', (108, 133))	('result in', 'Reg', (56, 65))
432451	24498351	In addition, HAT can uncoat reovirus virions to promote infection in cell culture and cleaves the surface glycoprotein, hemagglutinin (HA), of the influenza virus   .	('reovirus', 'Species', '10891', (28, 36))	('cleaves', 'Var', (86, 93))	('infection', 'Disease', (56, 65))	('infection', 'Disease', 'MESH:D007239', (56, 65))	('influenza virus', 'Species', '11309', (147, 162))	('promote', 'PosReg', (48, 55))
432452	24498351	Recently, a study employing genetic ablation of TMPRSS11A and HAT in mice demonstrated that the two proteases are dispensable for development, general health, and long-term survival in the absence of external challenges or additional genetic deficits.	('ablation', 'Var', (36, 44))	('TMPRSS11A', 'Gene', (48, 57))	('genetic deficits', 'Disease', (234, 250))	('rat', 'Species', '10116', (81, 84))	('genetic deficits', 'Disease', 'MESH:D030342', (234, 250))	('mice', 'Species', '10090', (69, 73))	('genetic ablation', 'Var', (28, 44))
432474	24498351	For cloning into the pPIC9 vector, HATL5 serine protease sequence from the pcDNA 3.1 V5/HIS/TOPO human-HATL5 plasmid was mutated to remove an XhoI site using the Agilent Quick-Change II  site directed mutagenesis kit (Agilent Technologies, Inc. Santa Clara, CA).	('human', 'Species', '9606', (97, 102))	('mutated', 'Var', (121, 128))	('remove', 'NegReg', (132, 138))	('N', 'Chemical', 'MESH:D009584', (78, 79))
432477	24498351	The Leu-Glu-Lys-Arg-Ile-Val-Asn is cleaved between Arg and Ile by the yeast protease KEX2 which is a transmembrane protease located in the Golgi, rendering a secreted activated HATL5 serine protease domain.	('Arg', 'Chemical', 'MESH:D001120', (51, 54))	('KEX2', 'Gene', (85, 89))	('Ile-Val-Asn', 'Chemical', '-', (20, 31))	('Ile', 'Chemical', 'MESH:D007532', (20, 23))	('Leu-Glu-Lys-Arg-Ile-Val-Asn', 'Var', (4, 31))	('Ile', 'Chemical', 'MESH:D007532', (59, 62))	('Arg', 'Chemical', 'MESH:D001120', (16, 19))	('KEX2', 'Gene', '855483', (85, 89))	('yeast', 'Species', '4932', (70, 75))	('Leu-Glu-Lys-Arg', 'Chemical', '-', (4, 19))
432480	24498351	For transformation of Pichia pastoris, 40 microg of pPIC9-human-HATL5, pPIC9-matriptase, pPIC9 empty vector was digested with SalI, and purified by phenol-chloroform extraction.	('pPIC9-human-HATL5', 'Var', (52, 69))	('chloroform', 'Chemical', 'MESH:D002725', (155, 165))	('human', 'Species', '9606', (58, 63))	('phenol', 'Chemical', 'MESH:D019800', (148, 154))	('matriptase', 'Gene', (77, 87))	('matriptase', 'Gene', '19143', (77, 87))	('Pichia pastoris', 'Species', '4922', (22, 37))
432491	24498351	The "CR802", "ES482", and "T271" cervical, esophageal, and oral cancer tissue arrays, including normal or cancer adjacent normal tissue, were obtained from US Biomax, Inc. (Rockville, MD).	('ES482', 'Var', (14, 19))	('oral cancer', 'Disease', 'MESH:D009062', (59, 70))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('oral cancer', 'Disease', (59, 70))	('cancer', 'Disease', (106, 112))	('T271', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
432499	24498351	The catalytic domain of mouse HATL5 contains the essential serine protease catalytic triad residues, H225, D270, S366, and the substrate binding pocket residues, D360, S386 and G388.	('G388', 'Var', (177, 181))	('S386', 'Var', (168, 172))	('mouse', 'Species', '10090', (24, 29))	('D270', 'Var', (107, 111))	('rat', 'Species', '10116', (132, 135))	('HATL5', 'Gene', (30, 35))	('D360', 'Var', (162, 166))	('S366', 'Var', (113, 117))	('H225', 'Var', (101, 105))
432500	24498351	The SWG motif in the catalytic domain is conserved in all members of the HAT/DESC subfamily and is predicted to be located at the top of the substrate binding pocket, positioning the scissile bond of the substrate in the correct orientation (S386WG in HATL5).	('positioning', 'PosReg', (167, 178))	('rat', 'Species', '10116', (146, 149))	('HATL5', 'Gene', (252, 257))	('rat', 'Species', '10116', (209, 212))	('S386WG', 'Var', (242, 248))	('scissile bond', 'MPA', (183, 196))
432501	24498351	Proteolytic activation of HATL5 is predicted to occur within a motif (K184IVNG) at the junction of the pro- and catalytic domains.	('K184IVNG', 'Var', (70, 78))	('N', 'Chemical', 'MESH:D009584', (76, 77))	('Proteolytic activation', 'MPA', (0, 22))	('HATL5', 'Gene', (26, 31))
432587	24498351	Given the expression of HATL5 in the non-proliferating suprabasal/apical layers coupled with the observation that HATL5 is lost during the dedifferentiation of epithelial cells, a hallmark of squamous cell carcinogenesis, it will be important to explore whether the observed link between loss of HATL5 and squamous cell carcinoma progression is correlational or causal.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (306, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (320, 329))	('lost', 'NegReg', (123, 127))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (306, 329))	('squamous cell carcinoma', 'Disease', (306, 329))	('hallmark of squamous cell carcinogenesis', 'Disease', (180, 220))	('loss', 'Var', (288, 292))	('HATL5', 'Gene', (24, 29))	('HATL5', 'Gene', (296, 301))	('hallmark of squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (180, 220))	('HATL5', 'Gene', (114, 119))	('rat', 'Species', '10116', (48, 51))
432625	22500262	However, there were significant differences in age, the histologic grade, the tumor size, and the T stage between the two groups: an older age, more histologic grade G1/2 tumors, a smaller tumor size, and more pT1/2 stage tumors were the specific features of the type II tumors.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (271, 277))	('pT1/2', 'Gene', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('G1/2', 'Var', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Disease', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('smaller', 'NegReg', (181, 188))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('type II tumors', 'Disease', (263, 277))	('tumors', 'Disease', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('tumor', 'Disease', (271, 276))	('pT1/2', 'Gene', '58492', (210, 215))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumor', 'Disease', (189, 194))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('type II tumors', 'Disease', 'MESH:D009369', (263, 277))
432639	22500262	On the univariate analysis, the T stage (T1-2 vs. T3-4), N stage (N0 vs. N+) and R0 resection were significantly associated with survival, while the Siewert type or the transhiatal approach was not.	('T1-2', 'Gene', (41, 45))	('associated with', 'Reg', (113, 128))	('survival', 'MPA', (129, 137))	('T1-2', 'Gene', '923;9173;292', (41, 45))	('R0 resection', 'Var', (81, 93))
432827	33290281	A loss of IL-18 could decrease the ability of effector cells to secrete IFN-gamma and promote tumor cell survival.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('decrease the ability of effector cells', 'Phenotype', 'HP:0040218', (22, 60))	('IL-18', 'Gene', (10, 15))	('decrease', 'NegReg', (22, 30))	('IFN-gamma', 'Gene', '3458', (72, 81))	('IFN-gamma', 'Gene', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('promote', 'PosReg', (86, 93))	('ability', 'MPA', (35, 42))	('IL-18', 'Gene', '3606', (10, 15))	('loss', 'Var', (2, 6))
432856	33290281	Our previous work on GRAIL has demonstrated the presence of 2 isoforms, one of which has been shown to stabilize mutant p53.	('p53', 'Gene', '7157', (120, 123))	('GRAIL', 'Gene', '79589', (21, 26))	('GRAIL', 'Gene', (21, 26))	('mutant', 'Var', (113, 119))	('p53', 'Gene', (120, 123))
432897	33290281	Filters for DAPI, CY3, CY5, CY7, Texas Red, and Qdot were applied to each image set for each core.	('CY7', 'Var', (28, 31))	('CY5', 'Var', (23, 26))	('CY7', 'Chemical', '-', (28, 31))	('DAPI', 'Chemical', 'MESH:C007293', (12, 16))	('CY3', 'Chemical', '-', (18, 21))	('Texas Red', 'Chemical', 'MESH:C034657', (33, 42))	('CY5', 'Chemical', 'MESH:C085321', (23, 26))
433047	25957003	PCS decreased the mean PV-IVC gradient to 22 mm saline in the patients treated emergently and 20 mm saline in the patients treated electively.	('decreased', 'NegReg', (4, 13))	('PCS', 'Var', (0, 3))	('saline', 'Chemical', 'MESH:D012965', (48, 54))	('saline', 'Chemical', 'MESH:D012965', (100, 106))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (62, 70))	('PV-IVC gradient', 'MPA', (23, 38))
433054	25957003	Similarly, elective PCS prevented recurrent variceal bleeding for <=25 years in all but 1 of 144 patients.	('bleeding', 'Disease', 'MESH:D006470', (53, 61))	('elective', 'Var', (11, 19))	('prevented', 'NegReg', (24, 33))	('bleeding', 'Disease', (53, 61))	('patients', 'Species', '9606', (97, 105))
433068	25957003	Survival of patients who required emergency treatment for active bleeding was greater at all time points after EPCS than after emergency then repetitive ET (P < .001).	('EPCS', 'Var', (111, 115))	('patients', 'Species', '9606', (12, 20))	('active bleeding', 'Disease', 'MESH:D006470', (58, 73))	('active bleeding', 'Disease', (58, 73))	('ET', 'Chemical', '-', (153, 155))	('greater', 'PosReg', (78, 85))
433070	25957003	Five and 10 years after entry in the study, survival of patients treated by EPCS was 3-fold greater than that of patients treated by emergency ET.	('ET', 'Chemical', '-', (143, 145))	('patients', 'Species', '9606', (56, 64))	('EPCS', 'Var', (76, 80))	('patients', 'Species', '9606', (113, 121))	('survival', 'MPA', (44, 52))	('greater', 'PosReg', (92, 99))
433071	25957003	The initial survival rates of patients treated electively by ET and PCS were similar, at 93% and 99%, respectively; however, within 1 year and thereafter, there was a greater survival rate in the PCS group than in the ET or TIPS groups (P < .001), largely because of recurrent variceal hemorrhage in patients who received ET or TIPS.	('PCS', 'Var', (196, 199))	('greater', 'PosReg', (167, 174))	('hemorrhage', 'Disease', (286, 296))	('hemorrhage', 'Disease', 'MESH:D006470', (286, 296))	('patients', 'Species', '9606', (30, 38))	('ET', 'Chemical', '-', (218, 220))	('ET', 'Chemical', '-', (61, 63))	('survival', 'MPA', (175, 183))	('ET', 'Chemical', '-', (322, 324))	('patients', 'Species', '9606', (300, 308))
433098	25957003	In patients treated by PCS, results of liver function tests showed improvement in 75% who survived 1 year and 78-80% who survived 5 years.	('improvement', 'PosReg', (67, 78))	('patients', 'Species', '9606', (3, 11))	('PCS', 'Var', (23, 26))
433103	25957003	In contrast, patients treated by PCS had a marked improvement in hepatic function throughout the 5 years post-operatively, related likely to freedom from recurrent hemorrhage.	('hepatic function', 'MPA', (65, 81))	('hemorrhage', 'Disease', 'MESH:D006470', (164, 174))	('patients', 'Species', '9606', (13, 21))	('improvement', 'PosReg', (50, 61))	('PCS', 'Var', (33, 36))	('hemorrhage', 'Disease', (164, 174))
433115	25957003	As we have observed in our recent reports, compared with emergency EST and TIPS, EPCS produced a significantly greater survival rate, was much more effective in controlling bleeding, and was followed by less than one-half the incidence of PSE.	('PSE', 'Disease', (239, 242))	('bleeding', 'Disease', 'MESH:D006470', (173, 181))	('survival rate', 'CPA', (119, 132))	('bleeding', 'Disease', (173, 181))	('greater', 'PosReg', (111, 118))	('EPCS', 'Var', (81, 85))
433155	25957003	Permanent control of bleeding was achieved in 97% of patients treated by EPCS but in only 22% treated by TIPS.	('patients', 'Species', '9606', (53, 61))	('bleeding', 'Disease', (21, 29))	('EPCS', 'Var', (73, 77))	('bleeding', 'Disease', 'MESH:D006470', (21, 29))
433171	25957003	Permanent control of bleeding in the entire group of 518 patients was achieved by PCS in 98%, but by ET in only 28%.	('patients', 'Species', '9606', (57, 65))	('bleeding', 'Disease', 'MESH:D006470', (21, 29))	('ET', 'Chemical', '-', (101, 103))	('bleeding', 'Disease', (21, 29))	('PCS', 'Var', (82, 85))
433177	25957003	QOL was significantly better in patients treated by PCS than in those treated by ET, in large part owing to freedom from recurrent bleeding.	('patients', 'Species', '9606', (32, 40))	('bleeding', 'Disease', (131, 139))	('PCS', 'Var', (52, 55))	('QOL', 'MPA', (0, 3))	('better', 'PosReg', (22, 28))	('bleeding', 'Disease', 'MESH:D006470', (131, 139))	('ET', 'Chemical', '-', (81, 83))
433192	25957003	In the 5-year survivors, 68% of patients treated by PCS and 23% of patients who underwent ET improved their Child risk class.	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (67, 75))	('improved', 'PosReg', (93, 101))	('PCS', 'Var', (52, 55))	('ET', 'Chemical', '-', (90, 92))	('Child', 'Species', '9606', (108, 113))	('Child risk class', 'MPA', (108, 124))
433202	25957003	Furthermore, PCS had a 99% permanent patency rate, led to 5-and 10-year survival rates of 70 and 65%, respectively, had a low incidence of recurrent PSE, and in many patients led to an acceptable QOL with improvement in liver function in 79% and in quantitative Child risk class in 68%.	('liver function', 'MPA', (220, 234))	('QOL', 'MPA', (196, 199))	('improvement', 'PosReg', (205, 216))	('Child', 'Species', '9606', (262, 267))	('patients', 'Species', '9606', (166, 174))	('improvement in liver function', 'Phenotype', 'HP:0001410', (205, 234))	('led to', 'Reg', (175, 181))	('PSE', 'Disease', (149, 152))	('PCS', 'Var', (13, 16))
433227	30680196	MPBC features an immunohistochemical profile similar as the one described in conventional UBC, exhibiting cytokeratin (CK)7 expression in all cases, as well as reactivity for uroplakin III, CK34betaE12, CK20, p63, thrombomodulin and high-molecular-weight CK, with decreasing frequency.	('UBC', 'Chemical', '-', (90, 93))	('p63', 'Gene', (209, 212))	('MPBC', 'Chemical', '-', (0, 4))	('CK20', 'Gene', (203, 207))	('CK20', 'Gene', '54474', (203, 207))	('p63', 'Gene', '8626', (209, 212))	('uroplakin III', 'Gene', (175, 188))	('thrombomodulin', 'Gene', '7056', (214, 228))	('thrombomodulin', 'Gene', (214, 228))	('high-molecular-weight CK', 'Protein', (233, 257))	('CK34betaE12', 'Var', (190, 201))	('uroplakin III', 'Gene', '7380', (175, 188))
433234	30680196	When MPBC grows under normal mucosa, routine follow-up cystoscopy and urine cytology are unable to detect neoplastic cells, and cold cup biopsy may miss an MPBC invading the muscle layer under the benign surface epithelium; thus, deep biopsies are recommended.	('MPBC', 'Var', (156, 160))	('miss', 'NegReg', (148, 152))	('MPBC', 'Chemical', '-', (156, 160))	('MPBC', 'Chemical', '-', (5, 9))	('men', 'Species', '9606', (253, 256))
433252	30680196	HER2-targeted therapy in combination with standard chemotherapy has resulted in a significantly increased survival rate in patients with HER2 amplification in breast and gastro-esophageal cancer.	('increased', 'PosReg', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast', 'Disease', (159, 165))	('survival', 'CPA', (106, 114))	('patients', 'Species', '9606', (123, 131))	('HER2', 'Gene', (137, 141))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (137, 141))	('gastro-esophageal cancer', 'Disease', (170, 194))	('HER2', 'Gene', '2064', (0, 4))	('gastro-esophageal cancer', 'Disease', 'MESH:D005764', (170, 194))	('amplification', 'Var', (142, 155))
433257	30680196	Skagias et al, also identified that HER2 expression was correlated with decreased disease-specific survival (P=0.002) and overall survival rates (P=0.025).	('overall survival rates', 'CPA', (122, 144))	('disease-specific survival', 'CPA', (82, 107))	('HER2', 'Gene', (36, 40))	('decreased', 'NegReg', (72, 81))	('HER2', 'Gene', '2064', (36, 40))	('expression', 'Var', (41, 51))
433258	30680196	Previous studies have highlighted the apparent lack of a marked association between HER2 protein expression and gene amplification in BC, with the latter being characterized by extreme heterogeneity within the same tumor.	('HER2', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', (215, 220))	('HER2', 'Gene', '2064', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('gene amplification', 'Var', (112, 130))
433264	30680196	Conversely, Sangoi et al reported specificity as high as 92% for HER2 positivity by immunohistochemistry (IHC) (comprising 2+ and 3+ staining) in MPBC compared with conventional UBC with retraction artifacts; furthermore, in the same study, a very low sensitivity (25%) was achieved and statistical significance was lacking.	('HER2', 'Gene', '2064', (65, 69))	('MPBC', 'Chemical', '-', (146, 150))	('positivity', 'Var', (70, 80))	('UBC', 'Chemical', '-', (178, 181))	('HER2', 'Gene', (65, 69))
433266	30680196	In a recent series of MPBC only, the frequency of HER2 positivity was as high as 74%.	('MPBC', 'Chemical', '-', (22, 26))	('HER2', 'Gene', '2064', (50, 54))	('positivity', 'Var', (55, 65))	('HER2', 'Gene', (50, 54))
433273	30680196	As a prognostic factor, HER2 amplification (but not overexpression) exhibits a significant association with a significant increase in cancer-specific mortality, whereas another study failed to identify such an association in a smaller case series, possibly due to differences in patient selection criteria and methods, as well as the proportion of the MP component in the tumor and on the sample selected.	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('amplification', 'Var', (29, 42))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('cancer', 'Disease', (134, 140))	('tumor', 'Disease', (372, 377))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('patient', 'Species', '9606', (279, 286))	('HER2', 'Gene', '2064', (24, 28))	('HER2', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('increase', 'PosReg', (122, 130))
433275	30680196	Previous studies identified a significant association between protein expression and gene amplification in MPBC, supporting the hypothesis that IHC may also provide reliable results in this setting.	('MPBC', 'Chemical', '-', (107, 111))	('gene amplification', 'Var', (85, 103))	('MPBC', 'Gene', (107, 111))	('protein expression', 'MPA', (62, 80))
433278	30680196	Genomic analyses identified that MPBC carries a significant high frequency of unique activating mutations in the extracellular domain of HER2 in comparison with conventional BC (34 vs 5%, respectively).	('activating', 'PosReg', (85, 95))	('MPBC', 'Var', (33, 37))	('HER2', 'Gene', (137, 141))	('MPBC', 'Chemical', '-', (33, 37))	('HER2', 'Gene', '2064', (137, 141))
433279	30680196	The point-mutated MPBC are not amplified nor overexpress HER2, thus being de facto undetectable using standard techniques (ISH and IHC).	('HER2', 'Gene', (57, 61))	('MPBC', 'Chemical', '-', (18, 22))	('point-mutated', 'Var', (4, 17))	('HER2', 'Gene', '2064', (57, 61))
433280	30680196	In their series, Tschui et al detected a novel D769N mutation in one case in association with HER2 amplification.	('D769N', 'Var', (47, 52))	('HER2', 'Gene', '2064', (94, 98))	('D769N', 'Mutation', 'rs121913468', (47, 52))	('HER2', 'Gene', (94, 98))
433285	30680196	In the breast, MP histology was described as a predictor of lower response to standard adjuvant anti-HER2 targeted therapy (trastuzumab) and chemotherapy.	('HER2', 'Gene', (101, 105))	('HER2', 'Gene', '2064', (101, 105))	('trastuzumab', 'Chemical', 'MESH:D000068878', (124, 135))	('MP histology', 'Var', (15, 27))	('response', 'MPA', (66, 74))	('lower', 'NegReg', (60, 65))
433316	30143023	Association between cyclooxygenase-2 (COX-2) 8473 T > C polymorphism and cancer risk: a meta-analysis and trial sequential analysis Numerous studies have investigated the relationship between COX-2 8473 T > C polymorphism and cancer susceptibility, however, the results remain controversial.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('8473 T > C polymorphism', 'Var', (198, 221))	('8473 T > C', 'Mutation', 'rs5275', (198, 208))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('8473 T > C', 'Mutation', 'rs5275', (45, 55))	('cancer', 'Disease', (226, 232))	('COX-2', 'Gene', '5743', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('COX-2', 'Gene', (192, 197))	('Association', 'Interaction', (0, 11))	('cyclooxygenase-2', 'Gene', (20, 36))	('COX-2', 'Gene', (38, 43))	('cyclooxygenase-2', 'Gene', '5743', (20, 36))	('COX-2', 'Gene', '5743', (192, 197))
433320	30143023	Overall, our results indicated that 8473 T > C polymorphism was not associated with cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('8473 T > C polymorphism', 'Var', (36, 59))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('8473 T > C', 'Mutation', 'rs5275', (36, 46))
433321	30143023	However, stratified analysis showed that the polymorphism was associated with a statistically significant decreased risk for nasopharyngeal cancer and bladder cancer, but an increased risk for esophageal cancer and skin cancer.	('bladder cancer', 'Disease', (151, 165))	('skin cancer', 'Disease', (215, 226))	('nasopharyngeal cancer', 'Disease', (125, 146))	('polymorphism', 'Var', (45, 57))	('decreased', 'NegReg', (106, 115))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (125, 146))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('skin cancer', 'Disease', 'MESH:D012878', (215, 226))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('skin cancer', 'Phenotype', 'HP:0008069', (215, 226))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (125, 146))	('esophageal cancer', 'Disease', (193, 210))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))
433323	30143023	No significant association between COX-2 8473 T > C polymorphism and cancer risk was detected.	('COX-2', 'Gene', (35, 40))	('8473 T > C polymorphism', 'Var', (41, 64))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('8473 T > C', 'Mutation', 'rs5275', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
433332	30143023	One of these functional polymorphisms, the 8473 T > C polymorphism in the 3'-untranslated region (3'UTR) of COX-2 gene is the most widely investigated polymorphism.	('8473 T > C', 'Var', (43, 53))	('COX-2', 'Gene', (108, 113))	('8473 T > C', 'Mutation', 'rs5275', (43, 53))
433333	30143023	Previous functional researches have indicated that 8473 T > C polymorphism is related to the alteration of the mRNA level of COX-2 gene via playing an important role in message stability and translational efficiency.	('translational', 'MPA', (191, 204))	('COX-2', 'Gene', (125, 130))	('alteration', 'Reg', (93, 103))	('mRNA level', 'MPA', (111, 121))	('8473 T > C', 'Mutation', 'rs5275', (51, 61))	('8473 T > C', 'Var', (51, 61))
433334	30143023	There are numerous case-control studies that have investigated the role of 8473 T > C polymorphism in cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('8473 T > C', 'Var', (75, 85))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('8473 T > C', 'Mutation', 'rs5275', (75, 85))
433335	30143023	Therefore, to draw a more precise conclusion, we conduct the present meta-analysis to evaluate the association of 8473 T > C polymorphism in COX-2 gene with cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('COX-2', 'Gene', (141, 146))	('8473 T > C polymorphism', 'Var', (114, 137))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('8473 T > C', 'Mutation', 'rs5275', (114, 124))	('cancer', 'Disease', (157, 163))	('association', 'Interaction', (99, 110))
433336	30143023	Literature in electronic databases, including PubMed, EMBASE, OVID and Web of Science, were systematically searched using the following terms: "cyclooxygenase-2 or COX-2 or PTGS2" and "polymorphism or variant or genotype" and "cancer or carcinoma or neoplasm".	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('carcinoma or neoplasm', 'Disease', (237, 258))	('variant', 'Var', (201, 208))	('carcinoma or neoplasm', 'Disease', 'MESH:D009369', (237, 258))	('polymorphism', 'Var', (185, 197))	('OVID', 'Disease', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('PTGS2', 'Gene', '5743', (173, 178))	('cancer', 'Disease', (227, 233))	('COX-2', 'Gene', (164, 169))	('PTGS2', 'Gene', (173, 178))	('cyclooxygenase-2', 'Gene', '5743', (144, 160))	('neoplasm', 'Phenotype', 'HP:0002664', (250, 258))	('cyclooxygenase-2', 'Gene', (144, 160))	('OVID', 'Disease', 'None', (62, 66))
433337	30143023	The inclusion criteria were as follows: studies investigating the association of COX-2 8473 T > C polymorphism with cancer risk; studies with essential information on genotype or allele frequencies to estimate ORs and 95% CIs; studies with human subjects; and case-controlled studies.	('8473 T > C polymorphism', 'Var', (87, 110))	('human', 'Species', '9606', (240, 245))	('association', 'Interaction', (66, 77))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('8473 T > C', 'Mutation', 'rs5275', (87, 97))	('COX-2', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
433339	30143023	From all eligible publications, the following data, including the first author, year of publication, population ethnicity, country, source of controls, cancer type, detection genotype methods of COX-2 8473 T > C polymorphism, and number of cases and controls, were carefully extracted by two authors (Qiuping Li and Chao Ma) independently.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('8473 T > C polymorphism', 'Var', (201, 224))	('8473 T > C', 'Mutation', 'rs5275', (201, 211))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('COX-2', 'Gene', (195, 200))
433340	30143023	We analyzed the association of COX-2 8473 T > C polymorphism with cancer risk using Stata software (Version 11.0; StataCorp, College Station, TX).	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('8473 T > C polymorphism', 'Var', (37, 60))	('8473 T > C', 'Mutation', 'rs5275', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))	('COX-2', 'Gene', (31, 36))
433347	30143023	In our included studies, 38,634 cases and 55,206 controls surveyed the association between COX-2 8473 T > C polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('COX-2', 'Gene', (91, 96))	('8473 T > C polymorphism', 'Var', (97, 120))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('8473 T > C', 'Mutation', 'rs5275', (97, 107))
433351	30143023	The COX2 8473 T > C polymorphism was primarily detected by genotyping methods including TaqMan, PCR-RFLP and PCR-PIRA, in addition to the methods of SNPlex, SNP-IT, PCR-KASP, Invader, Illumina GoldenGate, Pyrosequencing and MassARRAY.	('polymorphism', 'Var', (20, 32))	('COX2', 'Gene', (4, 8))	('8473 T > C', 'Mutation', 'rs5275', (9, 19))	('8473 T > C polymorphism', 'Var', (9, 32))	('COX2', 'Gene', '4513', (4, 8))
433352	30143023	We used subgroup analysis to search the effects of ethnicity, study design, genotype method and cancer type for the relationship of COX2 8473 T > C polymorphism with cancer risk.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('8473 T > C', 'Mutation', 'rs5275', (137, 147))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('8473 T > C polymorphism', 'Var', (137, 160))	('COX2', 'Gene', (132, 136))	('cancer', 'Disease', (96, 102))	('COX2', 'Gene', '4513', (132, 136))
433353	30143023	The association between COX2 8473 T > C polymorphism and cancer risk was evaluated in five comparison models: homozygote comparison, heterozygote comparison, dominant model, recessive model and allele analysis.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('8473 T > C polymorphism', 'Var', (29, 52))	('COX2', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('8473 T > C', 'Mutation', 'rs5275', (29, 39))	('COX2', 'Gene', '4513', (24, 28))
433355	30143023	Furthermore, neither dominant nor recessive model discovered significant associations of 8473 T > C polymorphism with cancer risk ((CC + TC) vs. TT: OR = 0.99, 95% CI = 0.95-1.04, p = 0.644; CC vs. (TC + TT): OR = 1.01, 95%CI = 0.94-1.09, p = 0.779).	('8473 T > C', 'Mutation', 'rs5275', (89, 99))	('cancer', 'Disease', (118, 124))	('associations', 'Interaction', (73, 85))	('8473 T > C', 'Var', (89, 99))	('TC', 'Chemical', 'MESH:D013667', (137, 139))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TC', 'Chemical', 'MESH:D013667', (199, 201))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
433356	30143023	Overall, the results of this meta-analysis showed no significant association between COX-2 8473 T > C polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('COX-2', 'Gene', (85, 90))	('8473 T > C polymorphism', 'Var', (91, 114))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('8473 T > C', 'Mutation', 'rs5275', (91, 101))
433357	30143023	In order to estimate the effects of specific study characteristics on the relationship between COX-2 8473 T > C polymorphism and cancer risk, we carried out subgroup analysis in control source, ethnicity, genotyping method and type of cancer under a variety of genetic models.	('8473 T > C', 'Var', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (235, 241))	('type of cancer', 'Disease', (227, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('COX-2', 'Gene', (95, 100))	('8473 T > C', 'Mutation', 'rs5275', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('type of cancer', 'Disease', 'MESH:D009369', (227, 241))
433359	30143023	However, by comparison, we discovered statistically significant decreased cancer risk in PCR-PIRA (TC vs. TT: OR = 0.78, 95% CI: 0.61-0.99, p = 0.037; (CC + TC) vs. TT: OR = 0.79, 95% CI: 0.63-0.78, P = 0.035; C allele vs. T allele: OR = 0.84, 95% CI: 0.74-0.96, P = 0.010).	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('TC', 'Chemical', 'MESH:D013667', (99, 101))	('TC', 'Chemical', 'MESH:D013667', (157, 159))	('cancer', 'Disease', (74, 80))	('PCR-PIRA', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('decreased', 'NegReg', (64, 73))
433360	30143023	According to cancer type, 8473 T > C polymorphism was associated with a statistically significant decreased risk for nasopharyngeal cancer except for heterozygote comparison (CC vs. TT: OR = 0.59, 95% CI: 0.40-0.86, P = 0.007; (CC + TC) vs. TT: OR = 0.79, 95% CI: 0.64-0.98, P = 0.030; CC vs. (TC + TT): OR = 0.65, 95%CI: 0.46-0.94, P = 0.020; C allele vs. T allele: OR = 0.80, 95% CI: 0.68-0.94, P = 0.007).	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TC', 'Chemical', 'MESH:D013667', (294, 296))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('TC', 'Chemical', 'MESH:D013667', (233, 235))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (117, 138))	('8473 T > C polymorphism', 'Var', (26, 49))	('polymorphism', 'Var', (37, 49))	('decreased', 'NegReg', (98, 107))	('nasopharyngeal cancer', 'Disease', (117, 138))	('8473 T > C', 'Mutation', 'rs5275', (26, 36))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (117, 138))
433361	30143023	In the group with bladder cancer, we also found a decreased risk in the homozygote comparison, heterozygote comparison and allele analysis (CC vs. TT: OR = 0.74, 95% CI = 0.55-0.99, P = 0.040; TC vs. TT: OR = 0.75, 95% CI = 0.62-0.90, P = 0.002; C allele vs. T allele: OR = 0.76, 95% CI = 0.60-0.96, P = 0.020), but not in the dominant model and recessive model.	('bladder cancer', 'Disease', 'MESH:D001749', (18, 32))	('TC', 'Chemical', 'MESH:D013667', (193, 195))	('bladder cancer', 'Disease', (18, 32))	('C allele', 'Var', (246, 254))	('decreased', 'NegReg', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('bladder cancer', 'Phenotype', 'HP:0009725', (18, 32))
433362	30143023	However, for the esophageal cancer group, the COX-2 8473 T > C polymorphism was significantly associated with an increased risk in the heterozygote comparison and dominant model (TC vs. TT: OR = 1.35, 95% CI = 1.10-1.66, P = 0.004; (CC + TC) vs. TT: OR = 1.33, 95% CI = 1.10-1.63, P = 0.004), but not in the homozygote comparison, recessive model and allele analysis.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('COX-2', 'Gene', (46, 51))	('esophageal cancer', 'Disease', (17, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (17, 34))	('8473 T > C', 'Mutation', 'rs5275', (52, 62))	('TC', 'Chemical', 'MESH:D013667', (179, 181))	('associated', 'Reg', (94, 104))	('8473 T > C', 'Var', (52, 62))	('TC', 'Chemical', 'MESH:D013667', (238, 240))
433363	30143023	For the group of skin cancer, we also observed the association of a significantly increased risk in the homozygote comparison and allele analysis (CC vs. TT: OR = 1.51, 95% CI = 1.02-2.25, P = 0.041; C allele vs. T allele: OR = 1.21, 95% CI = 1.02-1.45, P = 0.031, respectively), but not in heterozygote comparison, dominant model and recessive model.	('skin cancer', 'Phenotype', 'HP:0008069', (17, 28))	('C allele', 'Var', (200, 208))	('skin cancer', 'Disease', (17, 28))	('skin cancer', 'Disease', 'MESH:D012878', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
433365	30143023	Similarly, we also observed no significant association of 8473 T > C polymorphism with other cancers, including cervical cancer, colorectal cancer, gallbladder cancer, gastric cancer, HCC, lung cancer, oral cancer, ovarian cancer and prostate cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (215, 229))	('colorectal cancer', 'Disease', (129, 146))	('prostate cancer', 'Disease', 'MESH:D011471', (234, 249))	('HCC', 'Disease', (184, 187))	('prostate cancer', 'Phenotype', 'HP:0012125', (234, 249))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cervical cancer', 'Disease', (112, 127))	('gallbladder cancer', 'Disease', (148, 166))	('cervical cancer', 'Disease', 'MESH:D002583', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('HCC', 'Phenotype', 'HP:0001402', (184, 187))	('prostate cancer', 'Disease', (234, 249))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (168, 182))	('8473 T > C', 'Mutation', 'rs5275', (58, 68))	('oral cancer', 'Disease', 'MESH:D009062', (202, 213))	('oral cancer', 'Disease', (202, 213))	('lung cancer', 'Disease', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (152, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (215, 229))	('8473 T > C polymorphism', 'Var', (58, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('gallbladder cancer', 'Disease', 'MESH:D005706', (148, 166))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('cancers', 'Disease', (93, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ovarian cancer', 'Disease', (215, 229))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('gastric cancer', 'Disease', (168, 182))
433366	30143023	Significant heterogeneity was obvious in all the comparisons of COX-2 8473 T > C polymorphism (Table 2).	('COX-2', 'Gene', (64, 69))	('8473 T > C', 'Mutation', 'rs5275', (70, 80))	('8473 T > C polymorphism', 'Var', (70, 93))
433372	30143023	According to the above studies, many researchers hypothesized that polymorphism sites in 3'UTR of COX-2 gene, with 8473 T > C polymorphism included, might increase the expression of COX-2 and affect the susceptibility of cancer.	('COX-2', 'Gene', (182, 187))	('increase', 'PosReg', (155, 163))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('polymorphism sites', 'Var', (67, 85))	('expression', 'MPA', (168, 178))	('cancer', 'Disease', (221, 227))	('8473 T > C', 'Mutation', 'rs5275', (115, 125))	('COX-2', 'Gene', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('affect', 'Reg', (192, 198))	('8473 T > C', 'Var', (115, 125))
433373	30143023	Therefore, the correlation between 8473 T > C polymorphism in 3'UTR of COX-2 gene and cancer susceptibility has been of great interest in polymorphism research.	('8473 T > C polymorphism', 'Var', (35, 58))	('8473 T > C', 'Mutation', 'rs5275', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
433374	30143023	In this meta-analysis, not only did we try to make sure whether 8473 T > C polymorphism has any relationship with the susceptibility of overall cancer, but we also performed TSA to efficiently decrease the risk of type I error and evaluate whether our results were stable.	('8473 T > C', 'Mutation', 'rs5275', (64, 74))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('decrease', 'NegReg', (193, 201))	('TSA', 'Chemical', '-', (174, 177))	('cancer', 'Disease', (144, 150))	('8473 T > C polymorphism', 'Var', (64, 87))	('polymorphism', 'Var', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
433375	30143023	In the present meta-analysis, we comprehensively researched the association of the 8473 T > C polymorphism in the 3'UTR region of COX-2 with cancer risk in all population through 79 studies.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('the 8473 T > C', 'Var', (79, 93))	('8473 T > C', 'Mutation', 'rs5275', (83, 93))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('association', 'Interaction', (64, 75))
433376	30143023	The results showed that no significant association between 8473 T > C polymorphism we studied and overall cancer risk was detected under all five genetic comparisons.	('8473 T > C polymorphism', 'Var', (59, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('8473 T > C', 'Mutation', 'rs5275', (59, 69))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
433382	30143023	In the stratification analysis by type of cancer, the results indicated that the 8473 T > C polymorphism was associated with a statistically significant decreased risk for nasopharyngeal cancer in other four models except for heterozygote comparison, and bladder cancer in the homozygote comparison, heterozygote comparison and allele analysis.	('nasopharyngeal cancer', 'Disease', (172, 193))	('8473 T > C', 'Var', (81, 91))	('type of cancer', 'Disease', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('8473 T > C', 'Mutation', 'rs5275', (81, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (255, 269))	('decreased', 'NegReg', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (172, 193))	('type of cancer', 'Disease', 'MESH:D009369', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('bladder cancer', 'Disease', 'MESH:D001749', (255, 269))	('bladder cancer', 'Disease', (255, 269))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (172, 193))
433385	30143023	Secondly, 8473 T > C polymorphism might play different roles in different cancers.	('8473 T > C polymorphism', 'Var', (10, 33))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('8473 T > C', 'Mutation', 'rs5275', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
433386	30143023	Most importantly, the influence of COX-2 gene 8473 T > C polymorphism on cancer risk might be affected by complex interactions between gene and environment.	('cancer', 'Disease', (73, 79))	('COX-2', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('interactions', 'Interaction', (114, 126))	('8473 T > C polymorphism', 'Var', (46, 69))	('8473 T > C', 'Mutation', 'rs5275', (46, 56))	('affected', 'Reg', (94, 102))
433388	30143023	Currently, some meta-analysis have investigated the relationship of 8473 T > C polymorphism with susceptibility to some types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('8473 T > C', 'Mutation', 'rs5275', (68, 78))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('8473 T > C polymorphism', 'Var', (68, 91))
433389	30143023	indicated that COX-2 gene 8473 T > C polymorphism was a factor for suffering from lung cancer, and Zhu et al.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('COX-2', 'Gene', (15, 20))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('8473 T > C polymorphism', 'Var', (26, 49))	('8473 T > C', 'Mutation', 'rs5275', (26, 36))
433390	30143023	suggested that 8473 T > C polymorphism might cause a decreased risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('8473 T > C', 'Mutation', 'rs5275', (15, 25))	('8473 T > C polymorphism', 'Var', (15, 38))	('decreased', 'NegReg', (53, 62))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
433391	30143023	Like Pan et al., the current study supports the view that no significant association between 8473 T > C polymorphism and lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('8473 T > C polymorphism', 'Var', (93, 116))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('8473 T > C', 'Mutation', 'rs5275', (93, 103))
433393	30143023	Secondly, the studies with the most recent or larger sample size were included, we therefore carried out a more systematic review of all eligible studies on the COX-2 8473 T > C polymorphisms and risk of lung cancer.	('8473 T > C', 'Mutation', 'rs5275', (167, 177))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('COX-2', 'Gene', (161, 166))	('lung cancer', 'Disease', (204, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('8473 T > C polymorphisms', 'Var', (167, 191))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
433394	30143023	Thirdly, the result of this polymorphism on cancer susceptibility might be influenced by some environmental factors or other polymorphisms, such as smoking.	('polymorphism', 'Var', (28, 40))	('influenced', 'Reg', (75, 85))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
433395	30143023	For example, 8473 T > C polymorphism was associated with a decreased risk in nasopharyngeal cancer.	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (77, 98))	('8473 T > C', 'Mutation', 'rs5275', (13, 23))	('decreased', 'NegReg', (59, 68))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (77, 98))	('nasopharyngeal cancer', 'Disease', (77, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('8473 T > C polymorphism', 'Var', (13, 36))
433396	30143023	Besides, it is the first TSA that comprehensively elaborated the influence of COX-2 8473 T > C polymorphism in response to cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TSA', 'Chemical', '-', (25, 28))	('COX-2', 'Gene', (78, 83))	('cancer', 'Disease', (123, 129))	('8473 T > C', 'Mutation', 'rs5275', (84, 94))	('8473 T > C polymorphism', 'Var', (84, 107))
433397	30143023	Secondly, there was significant heterogeneity in this meta-analysis between the polymorphism and cancer under all five genetic models.	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('polymorphism', 'Var', (80, 92))	('cancer', 'Disease', (97, 103))
433399	30143023	The results of this meta-analysis manifested that the association between COX-2 8473 T > C polymorphism and overall cancer was not detected under all five genetic comparisons.	('COX-2', 'Gene', (74, 79))	('cancer', 'Disease', (116, 122))	('8473 T > C polymorphism', 'Var', (80, 103))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('8473 T > C', 'Mutation', 'rs5275', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
433400	30143023	In the stratification analysis of cancer type, 8473 T > C polymorphism might be associated with a statistically significant decreased risk for nasopharyngeal cancer and bladder cancer, but an increased risk for esophageal cancer and skin cancer.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('bladder cancer', 'Disease', 'MESH:D001749', (169, 183))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (143, 164))	('cancer', 'Disease', (177, 183))	('bladder cancer', 'Disease', (169, 183))	('skin cancer', 'Disease', (233, 244))	('esophageal cancer', 'Disease', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('bladder cancer', 'Phenotype', 'HP:0009725', (169, 183))	('cancer', 'Disease', (238, 244))	('skin cancer', 'Phenotype', 'HP:0008069', (233, 244))	('cancer', 'Disease', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancer', 'Disease', (158, 164))	('nasopharyngeal cancer', 'Disease', (143, 164))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('8473 T > C', 'Var', (47, 57))	('skin cancer', 'Disease', 'MESH:D012878', (233, 244))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (143, 164))	('8473 T > C', 'Mutation', 'rs5275', (47, 57))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('decreased', 'NegReg', (124, 133))	('cancer', 'Disease', (34, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (211, 228))
433407	29632807	By contrast, increased expression of p-mTORSer2448 and p-p70S6KThr421/Ser424 was discovered upon PSMD7 overexpression in Het-1A cells.	('Het-1A', 'CellLine', 'CVCL:3702', (121, 127))	('p-mTORSer2448', 'Var', (37, 50))	('Ser424', 'Chemical', '-', (70, 76))	('PSMD7', 'Gene', (97, 102))	('overexpression', 'PosReg', (103, 117))	('p-p70S6KThr421/Ser424', 'Var', (55, 76))	('increased', 'PosReg', (13, 22))	('expression', 'MPA', (23, 33))
433418	29632807	It has been reported that four deubiquitinases (USP14, UCHL5/Uch37, PSMD7/RPN8, and PSMD14/RPN11) are related to proteasome function of removing or editing the ubiquitinated proteasome substrates 11.	('USP14', 'Gene', (48, 53))	('UCHL5', 'Gene', '51377', (55, 60))	('RPN11', 'Gene', '10213', (91, 96))	('RPN8', 'Gene', (74, 78))	('Uch37', 'Gene', '51377', (61, 66))	('RPN8', 'Gene', '5713', (74, 78))	('related', 'Reg', (102, 109))	('PSMD14', 'Gene', (84, 90))	('ubiquitinated proteasome substrates 11', 'MPA', (160, 198))	('USP14', 'Gene', '9097', (48, 53))	('RPN11', 'Gene', (91, 96))	('UCHL5', 'Gene', (55, 60))	('Uch37', 'Gene', (61, 66))	('PSMD14', 'Gene', '10213', (84, 90))	('editing', 'Var', (148, 155))
433431	29632807	Furthermore, we also found that PSMD7 knockdown in vivo suppressed the tumor growth using ESCC tumor models.	('PSMD7', 'Gene', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('suppressed', 'NegReg', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ESCC', 'Disease', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (71, 76))	('knockdown', 'Var', (38, 47))	('tumor', 'Disease', (95, 100))
433445	29632807	Lentivirus supernatant was collected 48 h later and used to infect EC9706 cells with polybrene (Sigma-Aldrich, USA), followed by selection by puromycin (Thermo Scientific, USA).	('puromycin', 'Chemical', 'MESH:D011691', (142, 151))	('infect', 'Reg', (60, 66))	('polybrene', 'Chemical', 'MESH:D006583', (85, 94))	('polybrene', 'Var', (85, 94))	('EC9706', 'CellLine', 'CVCL:E307', (67, 73))
433474	29632807	Together, we obtained transient and stable PSMD7 knockdown EC9706 cells.	('knockdown', 'Var', (49, 58))	('PSMD7', 'Gene', (43, 48))	('EC9706', 'CellLine', 'CVCL:E307', (59, 65))
433476	29632807	2A), suggesting that inhibition of PSMD7 decreased the survival of EC9706 cells.	('decreased', 'NegReg', (41, 50))	('survival', 'CPA', (55, 63))	('PSMD7', 'Gene', (35, 40))	('inhibition', 'Var', (21, 31))	('EC9706', 'CellLine', 'CVCL:E307', (67, 73))
433477	29632807	Whether PSMD7 knockdown in EC9706 cells had impacts on apoptosis and cell cycle distribution was investigated by flow cytometry.	('impacts', 'Reg', (44, 51))	('EC9706', 'CellLine', 'CVCL:E307', (27, 33))	('knockdown', 'Var', (14, 23))	('PSMD7', 'Gene', (8, 13))	('apoptosis', 'CPA', (55, 64))
433478	29632807	Results showed that inhibition of PSMD7 in EC9706 cells caused cell apoptosis with significantly increased numbers of early apoptosis cells and late apoptosis cells (P < 0.05) (Fig.	('increased', 'PosReg', (97, 106))	('PSMD7', 'Gene', (34, 39))	('EC9706', 'Var', (43, 49))	('inhibition', 'NegReg', (20, 30))	('cell apoptosis', 'CPA', (63, 77))	('EC9706', 'CellLine', 'CVCL:E307', (43, 49))
433480	29632807	PSMD7 knockdown raised caspase-3 activity compared with the control (P < 0.05), which was further confirmed by the increased cleavage of caspase-3 in shPSMD7 group (Fig.	('PSMD7', 'Gene', (0, 5))	('increased', 'PosReg', (115, 124))	('raised', 'PosReg', (16, 22))	('caspase-3', 'Gene', (23, 32))	('caspase-3', 'Gene', '836', (137, 146))	('activity', 'MPA', (33, 41))	('caspase-3', 'Gene', (137, 146))	('knockdown', 'Var', (6, 15))	('cleavage', 'MPA', (125, 133))	('shPSMD7', 'Gene', (150, 157))	('caspase-3', 'Gene', '836', (23, 32))
433485	29632807	Moreover, the protein level of p-mTORSer2448 and p-p70S6KThr421/Ser424 was reduced by ~ 60.0% (P < 0.05) and ~ 73.7% (P < 0.05), respectively (Fig.	('protein level', 'MPA', (14, 27))	('p-p70S6KThr421/Ser424', 'Var', (49, 70))	('reduced', 'NegReg', (75, 82))	('p-mTORSer2448', 'Var', (31, 44))	('Ser424', 'Chemical', '-', (64, 70))
433488	29632807	The protein level of p-mTORSer2448 and p-p70S6KThr421/Ser424 in PSMD7 overexpressing Het-1A cells was raised to ~ 1.26 times (P < 0.05) and ~ 1.84 times (P < 0.05), respectively, compared with controls (Fig.	('Ser424', 'Chemical', '-', (54, 60))	('protein level', 'MPA', (4, 17))	('PSMD7', 'Gene', (64, 69))	('p-p70S6KThr421/Ser424', 'Var', (39, 60))	('Het-1A', 'CellLine', 'CVCL:3702', (85, 91))	('raised', 'PosReg', (102, 108))	('p-mTORSer2448', 'Var', (21, 34))
433489	29632807	As the apoptosis was enhanced and the proteasomal activity was inhibited in the in vitro experiments, the potential effect of PSMD7 knockdown on the inhibition of ESCC tumorigenesis in vivo was subsequently tested.	('PSMD7', 'Gene', (126, 131))	('ESCC', 'Disease', (163, 167))	('tumor', 'Disease', (168, 173))	('knockdown', 'Var', (132, 141))	('enhanced', 'PosReg', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('apoptosis', 'CPA', (7, 16))	('inhibited', 'NegReg', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('proteasomal', 'MPA', (38, 49))
433493	29632807	Summary, PSMD7 knockdown induces impaired tumor growth in vivo.	('knockdown', 'Var', (15, 24))	('impaired tumor', 'Disease', (33, 47))	('PSMD7', 'Gene', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('impaired tumor', 'Disease', 'MESH:D015417', (33, 47))
433494	29632807	5C, the activity of caspase-3 in shPSMD7 group was higher than that in control groups (P < 0.05).	('caspase-3', 'Gene', '836', (20, 29))	('activity', 'MPA', (8, 16))	('shPSMD7', 'Var', (33, 40))	('caspase-3', 'Gene', (20, 29))	('higher', 'PosReg', (51, 57))
433499	29632807	PSMD7 knockdown blocked the expression levels of mTOR and p70S6K in vivo, reduced by 33% and 37%, respectively (P < 0.05) (Fig.	('mTOR', 'Gene', (49, 53))	('blocked', 'NegReg', (16, 23))	('expression levels', 'MPA', (28, 45))	('PSMD7', 'Gene', (0, 5))	('mTOR', 'Gene', '2475', (49, 53))	('p70S6K', 'Gene', (58, 64))	('p70S6K', 'Gene', '6198', (58, 64))	('knockdown', 'Var', (6, 15))	('reduced', 'NegReg', (74, 81))
433500	29632807	The protein levels of p-mTORSer2448 and p-p70S6KThr421/Ser424 were also decreased by 18% (P < 0.05) and 36% (P < 0.05), respectively (Fig.	('protein levels', 'MPA', (4, 18))	('decreased', 'NegReg', (72, 81))	('p-mTORSer2448', 'Var', (22, 35))	('Ser424', 'Chemical', '-', (55, 61))	('p-p70S6KThr421/Ser424', 'Var', (40, 61))
433501	29632807	These data suggest that inhibition of PSMD7 suppressed the activity of mTOR/p70S6K in vivo.	('activity', 'MPA', (59, 67))	('suppressed', 'NegReg', (44, 54))	('PSMD7', 'Gene', (38, 43))	('mTOR', 'Gene', '2475', (71, 75))	('inhibition', 'Var', (24, 34))	('mTOR', 'Gene', (71, 75))	('p70S6K', 'Gene', '6198', (76, 82))	('p70S6K', 'Gene', (76, 82))
433503	29632807	Moreover, PSMD7 knockdown cells had higher caspase-3 activity and strengthened the cleavage of caspase-3 compared with control cells (ineffective shRNA).	('caspase-3', 'Gene', '836', (95, 104))	('higher', 'PosReg', (36, 42))	('PSMD7', 'Gene', (10, 15))	('strengthened', 'PosReg', (66, 78))	('caspase-3', 'Gene', (43, 52))	('knockdown', 'Var', (16, 25))	('caspase-3', 'Gene', (95, 104))	('activity', 'MPA', (53, 61))	('cleavage', 'MPA', (83, 91))	('caspase-3', 'Gene', '836', (43, 52))
433508	29632807	MG132 has been shown to cause the dephosphorylation of p70S6K/mTOR and induce cell autophagy 22.	('MG132', 'Var', (0, 5))	('dephosphorylation', 'MPA', (34, 51))	('mTOR', 'Gene', '2475', (62, 66))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('mTOR', 'Gene', (62, 66))	('cause', 'Reg', (24, 29))	('cell autophagy 22', 'CPA', (78, 95))	('p70S6K', 'Gene', (55, 61))	('induce', 'PosReg', (71, 77))	('p70S6K', 'Gene', '6198', (55, 61))
433510	29632807	Our results showed that the effect of PSMD7 depletion in ESCC cell lines was similar to MG132 treatment, but the decreased phosphorylation residue of p70S6K was different, which are Thr421/Ser424 in PSMD7 knockdown and Thr389 in MG132 treatment.	('p70S6K', 'Gene', (150, 156))	('Ser424', 'Chemical', '-', (189, 195))	('p70S6K', 'Gene', '6198', (150, 156))	('phosphorylation residue', 'MPA', (123, 146))	('Thr421/Ser424', 'Var', (182, 195))	('Thr421', 'Chemical', '-', (182, 188))	('Thr389', 'Chemical', '-', (219, 225))	('Thr389', 'Var', (219, 225))	('MG132', 'Chemical', 'MESH:C072553', (229, 234))	('MG132', 'Chemical', 'MESH:C072553', (88, 93))	('decreased', 'NegReg', (113, 122))
433514	29632807	The in vivo experimental results were consistent with those of the in vitro experiments, as the caspase activity and the level of cleaved PARP and ubiquitinated protein were significantly elevated after PSMD7 inhibition.	('activity', 'MPA', (104, 112))	('PARP', 'Gene', '1302', (138, 142))	('PSMD7', 'Gene', (203, 208))	('inhibition', 'Var', (209, 219))	('elevated', 'PosReg', (188, 196))	('PARP', 'Gene', (138, 142))	('caspase', 'Enzyme', (96, 103))
433678	26188709	For example, gene-expression profiles and copy number, mucin core proteins, angiogenic and growth factor levels, inhibitors of apoptosis, tumor cell expression of erythropoietin-receptor (EPO-R), preoperative plasma fibrinogen and serum albumin level (FA score), and cell signaling pathways have all been shown to predict prognosis in esophageal cancer, and may serve as potential biomarkers in future editions of staging system.	('fibrinogen', 'Gene', (216, 226))	('albumin', 'Gene', '213', (237, 244))	('esophageal cancer', 'Disease', 'MESH:D004938', (335, 352))	('tumor', 'Disease', (138, 143))	('albumin', 'Gene', (237, 244))	('predict', 'Reg', (314, 321))	('erythropoietin-receptor', 'Gene', '2057', (163, 186))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('erythropoietin-receptor', 'Gene', (163, 186))	('EPO-R', 'Gene', (188, 193))	('copy number', 'Var', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('EPO-R', 'Gene', '2057', (188, 193))	('angiogenic', 'MPA', (76, 86))	('esophageal cancer', 'Disease', (335, 352))	('fibrinogen', 'Gene', '2244', (216, 226))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
433681	26273410	Micro ribonucleic acid-93 promotes proliferation and migration of esophageal squamous cell carcinoma by targeting disabled 2 Accumulated evidence has revealed that the dysregulation of micro ribonucleic acids (miRNAs) may contribute to esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', (236, 270))	('ribonucleic', 'Chemical', '-', (191, 202))	('contribute', 'Reg', (222, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (66, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('dysregulation', 'Var', (168, 181))	('ribonucleic', 'Chemical', '-', (6, 17))	('esophageal squamous cell carcinoma', 'Disease', (66, 100))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (236, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (247, 270))
433688	26273410	The introduction of miR-93 significantly promotes cell proliferation, cell cycle progression, and the metastatic capability of EC109 cells.	('miR-93', 'Gene', (20, 26))	('EC109', 'CellLine', 'CVCL:6898', (127, 132))	('metastatic capability of EC109 cells', 'CPA', (102, 138))	('cell cycle progression', 'CPA', (70, 92))	('promotes', 'PosReg', (41, 49))	('introduction', 'Var', (4, 16))	('miR-93', 'Gene', '407051', (20, 26))	('cell proliferation', 'CPA', (50, 68))
433690	26273410	In addition, the knockdown of DAB2 by small interfering RNA displayed a consentaneous phenocopy with miR-93 overexpression in EC109 cells.	('neo', 'Chemical', '-', (80, 83))	('small interfering', 'Var', (38, 55))	('knockdown', 'Var', (17, 26))	('miR-93', 'Gene', '407051', (101, 107))	('DAB2', 'Gene', (30, 34))	('EC109', 'CellLine', 'CVCL:6898', (126, 131))	('miR-93', 'Gene', (101, 107))	('DAB2', 'Gene', '1601', (30, 34))
433698	26273410	In the past few years, several possible mechanisms have been proposed to explain the downregulation of DAB2 expression in different cancers, most of them concerning epigenetic regulation.	('DAB2', 'Gene', (103, 107))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('DAB2', 'Gene', '1601', (103, 107))	('downregulation', 'NegReg', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'MPA', (108, 118))	('epigenetic regulation', 'Var', (165, 186))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
433699	26273410	Aberrant gene methylation was reported to contribute to the loss of DAB2 protein in lung and nasopharyngeal cancers, while micro ribonucleic acid (miRNA) regulation played an important role at post-transcription level in ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (221, 236))	('ovarian cancers', 'Disease', (221, 236))	('Aberrant', 'Var', (0, 8))	('ovarian cancers', 'Disease', 'MESH:D010051', (221, 236))	('protein', 'Protein', (73, 80))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('nasopharyngeal cancers', 'Disease', 'MESH:D009303', (93, 115))	('loss', 'NegReg', (60, 64))	('DAB2', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('nasopharyngeal cancers', 'Disease', (93, 115))	('DAB2', 'Gene', '1601', (68, 72))	('lung', 'Disease', (84, 88))	('micro ribonucleic acid ', 'Gene', (123, 146))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('ovarian cancer', 'Phenotype', 'HP:0100615', (221, 235))	('micro ribonucleic acid ', 'Gene', '407051', (123, 146))
433739	26273410	Results of CCK-8 assay showed that ectopic miR-93 expression significantly stimulated EC109 cell growth compared with the control (P < 0.01), while transfection of the miR-93 inhibitor showed significant growth retardation in EC109 cells (P < 0.05) (Fig.	('growth retardation', 'Disease', 'MESH:D006130', (204, 222))	('EC109', 'CellLine', 'CVCL:6898', (86, 91))	('miR-93', 'Gene', '407051', (168, 174))	('stimulated', 'PosReg', (75, 85))	('miR-93', 'Gene', (168, 174))	('growth retardation', 'Phenotype', 'HP:0001510', (204, 222))	('miR-93', 'Gene', '407051', (43, 49))	('miR-93', 'Gene', (43, 49))	('ectopic', 'Var', (35, 42))	('EC109', 'CellLine', 'CVCL:6898', (226, 231))	('EC109 cell growth', 'CPA', (86, 103))	('growth retardation', 'Disease', (204, 222))
433744	26273410	The results of flow cytometry assay showed that compared with the control, the cell percentage in the G0-G1 stages significantly decreased in miR-93 transfected EC109 cells, while the percentage in S stage increased markedly (P < 0.01).	('cell percentage in the G0-G1 stages', 'CPA', (79, 114))	('transfected', 'Var', (149, 160))	('miR-93', 'Gene', '407051', (142, 148))	('miR-93', 'Gene', (142, 148))	('EC109', 'CellLine', 'CVCL:6898', (161, 166))	('decreased', 'NegReg', (129, 138))
433747	26273410	The results showed that the number of migration cells in the miR-93 transfected group was significantly higher than the control (P < 0.05, Fig.	('miR-93', 'Gene', (61, 67))	('higher', 'PosReg', (104, 110))	('miR-93', 'Gene', '407051', (61, 67))	('transfected', 'Var', (68, 79))
433756	26273410	Accordingly, the knockdown of miR-93 expression by transfection of the miR-93 inhibitor (Fig.	('miR-93', 'Gene', '407051', (71, 77))	('miR-93', 'Gene', (71, 77))	('knockdown', 'Var', (17, 26))	('expression', 'MPA', (37, 47))	('miR-93', 'Gene', '407051', (30, 36))	('miR-93', 'Gene', (30, 36))
433760	26273410	Using TargetScan software, we found the predicted miR-93 target site (positions 1690-1696), which is highly conserved across species (Fig.	('positions 1690-1696', 'Var', (70, 89))	('miR-93', 'Gene', (50, 56))	('miR-93', 'Gene', '407051', (50, 56))
433761	26273410	The synthesized DAB2 3'-UTR segments containing the target site (wild type/mutant) were subcloned to psiCHECK-2 dual luciferase vector (Fig.	('DAB2', 'Gene', (16, 20))	('type/mutant', 'Var', (70, 81))	('DAB2', 'Gene', '1601', (16, 20))
433767	26273410	CCK-8 and EdU incorporation assays were performed to examine the effects of DAB2 knockdown on cell proliferation.	('knockdown', 'Var', (81, 90))	('DAB2', 'Gene', (76, 80))	('EdU', 'Chemical', 'MESH:C031086', (10, 13))	('DAB2', 'Gene', '1601', (76, 80))
433770	26273410	The effect of DAB2 knockdown on ESCC cell cycles was evaluated by flow cytometry assay, and the results showed a significant decline in percentage of G0/G1 cells (P < 0.05) when DAB2 was knocked down by RNA interference, and an elevation in the percentage of S stage cells was also determined (P < 0.05) (Fig.	('DAB2', 'Gene', (178, 182))	('DAB2', 'Gene', (14, 18))	('knocked', 'Var', (187, 194))	('decline', 'NegReg', (125, 132))	('G0/G1 cells', 'CPA', (150, 161))	('RNA interference', 'MPA', (203, 219))	('DAB2', 'Gene', '1601', (178, 182))	('DAB2', 'Gene', '1601', (14, 18))
433773	26273410	The results of transwell migration assay showed an enhanced capability in si-DAB2 transfected EC109 cells compared with the control (P < 0.05) (Fig.	('transfected', 'Var', (82, 93))	('transwell migration assay', 'CPA', (15, 40))	('EC109', 'CellLine', 'CVCL:6898', (94, 99))	('enhanced', 'PosReg', (51, 59))	('DAB2', 'Gene', (77, 81))	('DAB2', 'Gene', '1601', (77, 81))
433775	26273410	MiRNAs have been estimated to control the expression of more than 30% of all protein coding genes and have been proven to play pivotal roles in tumorigenesis.24, As to esophageal cancer, miRNA dysregulation has also been reported to act as a tumor promoter and is closely associated to patient prognosis.	('tumor', 'Disease', (144, 149))	('esophageal cancer', 'Disease', (168, 185))	('dysregulation', 'Var', (193, 206))	('associated', 'Reg', (272, 282))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('patient', 'Species', '9606', (286, 293))	('tumor', 'Disease', (242, 247))	('miRNA', 'MPA', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
433784	26273410	Studies have shown that DAB2 could inhibit the growth of several cancer cells and the inhibitory effects could partly attribute to Wnt signaling restraint.33, On the other hand, a loss of DAB2 has been reported to increase the propensity for metastasis by facilitating TGF-beta-stimulated epithelial-to-mesenchymal transition.	('TGF-beta', 'Gene', '7040', (269, 277))	('metastasis', 'CPA', (242, 252))	('loss', 'Var', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('increase', 'PosReg', (214, 222))	('DAB2', 'Gene', (188, 192))	('TGF-beta', 'Gene', (269, 277))	('facilitating', 'PosReg', (256, 268))	('DAB2', 'Gene', '1601', (188, 192))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('DAB2', 'Gene', '1601', (24, 28))	('DAB2', 'Gene', (24, 28))
433787	26273410	In our study, a significant promotion of proliferation and corresponding change in EC109 cell cycles was observed either by miR-93 transfection or DAB2 knockdown, thus leading to the conclusion that miR-93 could inhibit ESCC cell proliferation by targeting DAB2.	('knockdown', 'Var', (152, 161))	('miR-93', 'Gene', (199, 205))	('EC109 cell cycles', 'CPA', (83, 100))	('EC109', 'CellLine', 'CVCL:6898', (83, 88))	('promotion', 'PosReg', (28, 37))	('miR-93', 'Gene', '407051', (124, 130))	('miR-93', 'Gene', (124, 130))	('DAB2', 'Gene', '1601', (147, 151))	('ESCC', 'Disease', (220, 224))	('change', 'Reg', (73, 79))	('inhibit', 'NegReg', (212, 219))	('DAB2', 'Gene', (147, 151))	('DAB2', 'Gene', '1601', (257, 261))	('DAB2', 'Gene', (257, 261))	('transfection', 'Var', (131, 143))	('proliferation', 'CPA', (41, 54))	('miR-93', 'Gene', '407051', (199, 205))
433788	26273410	Aside from the promotion of cell proliferation, we also identified an increase in the migration ability of miR-93 transfected EC109 cells, while a decreased number of migration cells were observed with miR-93 depletion.	('increase', 'PosReg', (70, 78))	('miR-93', 'Gene', '407051', (202, 208))	('miR-93', 'Gene', '407051', (107, 113))	('miR-93', 'Gene', (202, 208))	('cell proliferation', 'CPA', (28, 46))	('miR-93', 'Gene', (107, 113))	('transfected', 'Var', (114, 125))	('migration ability', 'CPA', (86, 103))	('EC109', 'CellLine', 'CVCL:6898', (126, 131))
433789	26273410	Interestingly, the knockdown of DAB2 in EC109 cells by RNA interference brought nearly identical results to miR-93 overexpression in transwell migration assay.	('knockdown', 'Var', (19, 28))	('DAB2', 'Gene', (32, 36))	('miR-93', 'Gene', '407051', (108, 114))	('DAB2', 'Gene', '1601', (32, 36))	('miR-93', 'Gene', (108, 114))	('EC109', 'CellLine', 'CVCL:6898', (40, 45))	('RNA interference', 'MPA', (55, 71))
433834	26131602	The three most enriched entries in Gene Ontology (GO) molecular function were "GO:0008289~lipid binding," "GO:0005501~retinoid binding," and "GO:0019840~isoprenoid binding," which are associated with the three most well-known lipocalin ligands.	('isoprenoid', 'Chemical', 'MESH:D013729', (153, 163))	('GO:0005501~retinoid', 'Var', (107, 126))	('GO:0019840~isoprenoid', 'Var', (142, 163))	('GO:0008289~lipid', 'MPA', (79, 95))	('lipid', 'Chemical', 'MESH:D008055', (90, 95))	('GO:0019840~isoprenoid', 'MPA', (142, 163))	('GO:0005501~retinoid', 'MPA', (107, 126))	('retinoid', 'Chemical', 'MESH:D012176', (118, 126))
433869	26131602	Our previous study has identified a novel splicing variant of LCN2 receptor in ESCC.	('LCN2', 'Gene', '3934', (62, 66))	('splicing variant', 'Var', (42, 58))	('LCN2', 'Gene', (62, 66))	('ESCC', 'Disease', (79, 83))
433875	26131602	FABP5 is related to radiosensitivity of ESCC cell line TE-11, with a high degree of DNA methylation within its promoter region in three ESCC cell lines (TE-1, TE-2 and TE-10).	('methylation', 'Var', (88, 99))	('FABP5', 'Gene', (0, 5))	('related', 'Reg', (9, 16))	('TE-2', 'Gene', '8260', (159, 163))	('TE-2', 'Gene', (159, 163))	('FABP5', 'Gene', '2171', (0, 5))
433876	26131602	The expression of LCN2 was visibly decreased in the GSE26886 esophageal carcinoma expression data, which contradicts previous results.	('esophageal carcinoma', 'Disease', (61, 81))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (61, 81))	('GSE26886', 'Var', (52, 60))	('expression', 'MPA', (4, 14))	('decreased', 'NegReg', (35, 44))	('LCN2', 'Gene', '3934', (18, 22))	('LCN2', 'Gene', (18, 22))
433878	26131602	This difference might be attributable to the different sources of esophageal carcinoma clinical samples; the clinical samples of GSE26886 came from Germany.	('clinical samples', 'Species', '88229', (109, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('esophageal carcinoma', 'Disease', (66, 86))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (66, 86))	('clinical samples', 'Species', '88229', (87, 103))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (66, 86))	('GSE26886', 'Var', (129, 137))
433916	25620904	Histopathological examination revealed clear cell carcinoma (G2 > G3, pT3a, pN0, M0, and pStage III).	('pT3a', 'Disease', (70, 74))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (39, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('pN0', 'Disease', (76, 79))	('G2 > G3', 'Var', (61, 68))	('clear cell carcinoma', 'Disease', (39, 59))
433971	25337715	Alteration of expression level, molecular weight, subcellular localization, and post-translational modifications of proteins have been implicated in the tumorigenesis and development processes of ESCC.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('implicated', 'Reg', (135, 145))	('Alteration', 'Var', (0, 10))	('post-translational', 'MPA', (80, 98))	('development processes', 'CPA', (171, 192))	('ESCC', 'Disease', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('subcellular', 'MPA', (50, 61))	('tumor', 'Disease', (153, 158))	('molecular weight', 'MPA', (32, 48))	('proteins', 'Protein', (116, 124))	('expression level', 'MPA', (14, 30))
433972	25337715	Researches on protein alterations in ESCC, especially those highly overexpressed, may have potentials to divide patients into different prognostic groups.	('protein', 'Protein', (14, 21))	('ESCC', 'Gene', (37, 41))	('alterations', 'Var', (22, 33))	('patients', 'Species', '9606', (112, 120))
433973	25337715	P53 was the most common protein with abnormality found in ESCC, and mutated p53 protein functionally promoted cell invasion and metastasis.	('promoted', 'PosReg', (101, 109))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('P53', 'Gene', (0, 3))	('protein', 'Protein', (80, 87))	('P53', 'Gene', '7157', (0, 3))	('mutated', 'Var', (68, 75))
434009	25337715	There was a significant correlation between high expression of PI3K-p85alpha, EGFR and p53 and the overall survival (P = 0.00111, 0.00001, 0.00426, Figure 3C).	('high expression', 'Var', (44, 59))	('p53', 'Gene', (87, 90))	('p85alpha', 'Gene', (68, 76))	('p53', 'Gene', '7157', (87, 90))	('p85alpha', 'Gene', '5295', (68, 76))	('overall survival', 'CPA', (99, 115))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))
434010	25337715	Stratified analysis indicated that high expression of p53 was correlated with short overall survival in pN0 (P = 0.010) and stage I/IIA (P = 0.005), EGFR in pN0 (P = 0.003), pN1 (P = 0.002) and stage IIB/III (P = 0.00005) and PI3K-p85alpha in pN1 (P = 0.00007) and stage IIB/III (P = 0.001).	('expression', 'MPA', (40, 50))	('pN1', 'Gene', '5270', (243, 246))	('pN1', 'Gene', '5270', (174, 177))	('pN1', 'Gene', (243, 246))	('EGFR', 'Gene', '1956', (149, 153))	('p85alpha', 'Gene', '5295', (231, 239))	('p53', 'Gene', (54, 57))	('pN1', 'Gene', (174, 177))	('EGFR', 'Gene', (149, 153))	('p53', 'Gene', '7157', (54, 57))	('high', 'Var', (35, 39))	('short', 'NegReg', (78, 83))	('p85alpha', 'Gene', (231, 239))
434013	25337715	Patients with high expression of two or three proteins had a much poorer prognosis compared with those with zero or one high marker (P = 0.00001, Figure 5D).	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('poorer', 'NegReg', (66, 72))
434042	24319345	Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated.	('adenocarcinoma', 'Disease', 'MESH:D000230', (12, 26))	('hypermethylated', 'Var', (85, 100))	('SCC', 'Gene', (36, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('SCC', 'Phenotype', 'HP:0002860', (36, 39))	('SCC', 'Gene', '6317', (36, 39))	('adenocarcinoma', 'Disease', (12, 26))
434046	24319345	MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.	('MGMT', 'Gene', (0, 4))	('patients', 'Species', '9606', (145, 153))	('esophageal cancers', 'Disease', 'MESH:D004938', (61, 79))	('methylation', 'Var', (5, 16))	('TMZ', 'Chemical', 'MESH:D000077204', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('esophageal cancers', 'Disease', (61, 79))	('MGMT', 'Gene', '4255', (0, 4))
434058	24319345	Even though a large number of laboratories are investigating the role of RTKs in esophageal cancers, epigenetic changes can occur in preneoplastic and neoplastic lesions, particularly, the hypermethylation of O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT).	('RTK', 'Gene', (73, 76))	('hypermethylation', 'Var', (189, 205))	('esophageal cancers', 'Disease', 'MESH:D004938', (81, 99))	('O-6-methylguanine-deoxyribonucleic acid', 'Chemical', '-', (209, 248))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (151, 169))	('neoplastic lesions', 'Disease', 'MESH:D051437', (151, 169))	('MGMT', 'Gene', (274, 278))	('RTK', 'Gene', '5979', (73, 76))	('occur', 'Reg', (124, 129))	('MGMT', 'Gene', '4255', (274, 278))	('neoplastic lesions', 'Disease', (151, 169))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancers', 'Disease', (81, 99))
434062	24319345	However, such genetic silencing is also associated with improved overall survival in patients receiving alkylating agents.	('patients', 'Species', '9606', (85, 93))	('genetic silencing', 'Var', (14, 31))	('improved', 'PosReg', (56, 64))	('overall survival', 'MPA', (65, 81))
434066	24319345	Given that MGMT hypermethylation has been demonstrated in esophageal pre-malignant and malignant lesions, we investigated the role of TMZ in the treatment of esophageal cancer.	('MGMT', 'Gene', '4255', (11, 15))	('MGMT', 'Gene', (11, 15))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('esophageal', 'Disease', (58, 68))	('hypermethylation', 'Var', (16, 32))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('TMZ', 'Chemical', 'MESH:D000077204', (134, 137))	('esophageal cancer', 'Disease', (158, 175))
434067	24319345	Our recent experience with a patient with esophageal cancer whose tumor expressed methylated MGMT and had a durable response to TMZ stimulated us to explore the relative frequency of MGMT methylation in esophageal tumors.	('TMZ', 'Chemical', 'MESH:D000077204', (128, 131))	('methylated', 'Var', (82, 92))	('MGMT', 'Gene', '4255', (183, 187))	('MGMT', 'Gene', (93, 97))	('esophageal tumors', 'Disease', 'MESH:D004938', (203, 220))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (66, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('esophageal tumors', 'Phenotype', 'HP:0100751', (203, 220))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('esophageal cancer', 'Disease', (42, 59))	('MGMT', 'Gene', (183, 187))	('MGMT', 'Gene', '4255', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (214, 219))	('patient', 'Species', '9606', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('esophageal tumors', 'Disease', (203, 220))
434070	24319345	Esophageal cancer cell lines (BE-3, FLO, SKGT-4, SKGT-5, Kyse-110, Kyse-140, Kyse-220, Kyse-410, Kyse-520, Kyse-850, TE-1, TE-8 and TE-12) were cultured in Dulbecco's Modified Eagle's Medium (DMEM) or DMEM+Hank's F12 media supplemented with 10% fetal bovine serum and penicillin in a 37 C, 5% CO2 environment.	('DMEM', 'Chemical', '-', (192, 196))	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('CO2', 'Chemical', '-', (293, 296))	('SKGT-4', 'CellLine', 'CVCL:2195', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Kyse-220', 'Var', (77, 85))	('bovine', 'Species', '9913', (251, 257))	('Kyse-140', 'Var', (67, 75))	('DMEM', 'Chemical', '-', (201, 205))	('penicillin', 'Chemical', 'MESH:D010406', (268, 278))	('Esophageal cancer', 'Disease', (0, 17))	('Kyse-110', 'Var', (57, 65))	('Kyse-410', 'Var', (87, 95))
434105	24319345	This phase 2 study, IRB approved, targeted individuals with advanced aerodigestive tract cancers whose tumors display methylation of their MGMT promoters.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tract cancers', 'Disease', 'MESH:D014571', (83, 96))	('MGMT', 'Gene', (139, 143))	('tumors', 'Disease', (103, 109))	('MGMT', 'Gene', '4255', (139, 143))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('methylation', 'Var', (118, 129))	('tract cancers', 'Disease', (83, 96))
434122	24319345	The MGMT methylation status is summarized as: for adenocarcinoma, 12/17 (70.5%) cases were methylated and the remaining 5/17 (29.4%) cases were unmethylated.	('MGMT', 'Gene', '4255', (4, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('adenocarcinoma', 'Disease', (50, 64))	('adenocarcinoma', 'Disease', 'MESH:D000230', (50, 64))	('MGMT', 'Gene', (4, 8))	('methylated', 'Var', (91, 101))
434123	24319345	In addition, four adjacent normal tissue samples from the adenocarcinoma-methylated group were also found to be methylated.	('adenocarcinoma', 'Disease', 'MESH:D000230', (58, 72))	('adenocarcinoma', 'Disease', (58, 72))	('methylated', 'Var', (112, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
434124	24319345	In SCC, 3/8 (37.5%) samples were methylated and 5/8 (62.5%) were unmethylated [Table 2].	('SCC', 'Gene', '6317', (3, 6))	('methylated', 'Var', (33, 43))	('SCC', 'Gene', (3, 6))	('SCC', 'Phenotype', 'HP:0002860', (3, 6))
434126	24319345	Of these, 1/4 (25%) adenocarcinoma cells were methylated and 1/9 (11%) SCC cells were methylated.	('adenocarcinoma', 'Disease', (20, 34))	('adenocarcinoma', 'Disease', 'MESH:D000230', (20, 34))	('SCC', 'Gene', (71, 74))	('methylated', 'Var', (46, 56))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('SCC', 'Gene', '6317', (71, 74))
434145	24319345	In an analysis of archived tissues samples, 71% of esophageal adenocarcinoma and 38% of SCC patient samples were positive for MGMT methylation.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (51, 76))	('patient', 'Species', '9606', (92, 99))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('SCC', 'Gene', (88, 91))	('esophageal adenocarcinoma', 'Disease', (51, 76))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (51, 76))	('MGMT', 'Gene', (126, 130))	('MGMT', 'Gene', '4255', (126, 130))	('positive', 'Reg', (113, 121))	('SCC', 'Gene', '6317', (88, 91))	('methylation', 'Var', (131, 142))
434153	24319345	Patients with GBM containing a methylated MGMT promoter benefited from TMZ, whereas those who did not have a methylated MGMT promoter did not have such a benefit.	('MGMT', 'Gene', (42, 46))	('MGMT', 'Gene', '4255', (42, 46))	('TMZ', 'MPA', (71, 74))	('TMZ', 'Chemical', 'MESH:D000077204', (71, 74))	('methylated', 'Var', (31, 41))	('Patients', 'Species', '9606', (0, 8))	('MGMT', 'Gene', '4255', (120, 124))	('benefited', 'PosReg', (56, 65))	('MGMT', 'Gene', (120, 124))
434156	24319345	Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor; among patients whose tumor contained a methylated MGMT promoter, survival benefit was observed in those treated with TMZ and radiotherapy.	('patients', 'Species', '9606', (107, 115))	('methylated', 'Var', (140, 150))	('benefit', 'PosReg', (175, 182))	('MGMT', 'Gene', '4255', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('TMZ', 'Chemical', 'MESH:D000077204', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('MGMT', 'Gene', (151, 155))	('tumor', 'Disease', (122, 127))	('MGMT', 'Gene', (27, 31))	('MGMT', 'Gene', '4255', (151, 155))
434159	24319345	Opportunities for improving esophageal cancer therapy include targeting epigenetic changes that occur with MGMT methylation.	('esophageal cancer', 'Disease', (28, 45))	('MGMT', 'Gene', '4255', (107, 111))	('MGMT', 'Gene', (107, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('epigenetic changes', 'Var', (72, 90))
434160	24319345	Such methylation may represent an early event in tumorigenesis, particularly in the setting of esophageal adenocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('methylation', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('esophageal adenocarcinoma', 'Disease', (95, 120))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (95, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (95, 120))
434162	24319345	These changes may result in development of intestinal metaplasia with progression to intraepithelial neoplasia, and subsequently invasive adenocarcinoma.	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (129, 152))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (43, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (85, 110))	('neoplasia', 'Phenotype', 'HP:0002664', (101, 110))	('changes', 'Var', (6, 13))	('intraepithelial neoplasia', 'Disease', (85, 110))	('invasive adenocarcinoma', 'Disease', (129, 152))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (85, 110))	('result in', 'Reg', (18, 27))	('intestinal metaplasia', 'Disease', (43, 64))
434168	24319345	Reduced MGMT expression is seen in the setting of methylation of the MGMT promoter, which has been seen in 45% of cases.	('MGMT', 'Gene', '4255', (69, 73))	('MGMT', 'Gene', (69, 73))	('Reduced', 'NegReg', (0, 7))	('MGMT', 'Gene', '4255', (8, 12))	('MGMT', 'Gene', (8, 12))	('methylation', 'Var', (50, 61))
434173	24319345	Furthermore, there was improved survival in mice treated with TMZ compared with cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('TMZ', 'Var', (62, 65))	('improved', 'PosReg', (23, 31))	('TMZ', 'Chemical', 'MESH:D000077204', (62, 65))	('survival', 'CPA', (32, 40))	('mice', 'Species', '10090', (44, 48))
434182	24319345	We present a unique case of an esophageal cancer patient with MGMT methylation who responded dramatically to TMZ.	('MGMT', 'Gene', (62, 66))	('responded', 'MPA', (83, 92))	('MGMT', 'Gene', '4255', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('esophageal cancer', 'Disease', (31, 48))	('patient', 'Species', '9606', (49, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (109, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('methylation', 'Var', (67, 78))
434183	24319345	In light of this, a retrospective analysis was carried out on the frequency of MGMT methylation in squamous cell and adenocarcinoma of the esophagus.	('MGMT', 'Gene', (79, 83))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (117, 148))	('methylation', 'Var', (84, 95))	('adenocarcinoma of the esophagus', 'Disease', (117, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('MGMT', 'Gene', '4255', (79, 83))
434187	23586049	The Role of MicroRNAs in Cancer Susceptibility Single nucleotide polymorphisms (SNPs) are germline variations interspersed in the human genome.	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Cancer', 'Disease', (25, 31))	('Cancer', 'Disease', 'MESH:D009369', (25, 31))	('Single nucleotide polymorphisms', 'Var', (47, 78))	('human', 'Species', '9606', (130, 135))
434191	23586049	Hereditary cancer comes up from mutations that occur in high-penetrant predisposing tumor genes.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Hereditary cancer', 'Disease', 'MESH:D009369', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('mutations', 'Var', (32, 41))	('Hereditary cancer', 'Disease', (0, 17))
434192	23586049	However, a considerable part of inherited cancers arises from multiple low-penetrant predisposing gene variants that influence the behavior of cancer insurgence.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('inherited cancers', 'Disease', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('arises from', 'Reg', (50, 61))	('inherited cancers', 'Disease', 'MESH:D009386', (32, 49))	('behavior', 'MPA', (131, 139))	('variants', 'Var', (103, 111))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (143, 149))	('influence', 'Reg', (117, 126))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))
434193	23586049	Despite the established significance of such polymorphic variants in cancer predisposition, sometimes their functional role remains unknown.	('polymorphic variants', 'Var', (45, 65))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
434199	23586049	The presence of SNPs either in the genomic miRNA sequences or in the 3'UTR of cancer-related genes could influence miRNA-dependent regulation altering consequently tumor susceptibility (Figure 1).	('tumor', 'Disease', (164, 169))	('influence', 'Reg', (105, 114))	('SNPs', 'Var', (16, 20))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('miRNA-dependent regulation', 'MPA', (115, 141))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('presence', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
434202	23586049	The SNP rs2910164 is located in the pri-miRNA sequence of miR-146a and has C and G allelic forms.	('rs2910164', 'Mutation', 'rs2910164', (8, 17))	('miR-146a', 'Gene', '406938', (58, 66))	('rs2910164', 'Var', (8, 17))	('miR-146a', 'Gene', (58, 66))
434205	23586049	showed that the C allele of SNP rs2910164 is associated with significantly decreased risk of bladder cancer (OR = 0.80; 95% CI: 0.71-0.90), and GC/CC genotypes confer a significantly reduced risk of recurrence, compared with the GG genotype.	('GC', 'Phenotype', 'HP:0012126', (144, 146))	('bladder cancer', 'Disease', (93, 107))	('rs2910164', 'Mutation', 'rs2910164', (32, 41))	('reduced', 'NegReg', (183, 190))	('decreased', 'NegReg', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('SNP rs2910164', 'Var', (28, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))
434206	23586049	The same authors demonstrated by functional studies that the miR-146a rs2910164 C allele inhibits proliferation in bladder cancer cells.	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('rs2910164', 'Mutation', 'rs2910164', (70, 79))	('inhibits', 'NegReg', (89, 97))	('miR-146a', 'Gene', (61, 69))	('rs2910164 C', 'Var', (70, 81))	('miR-146a', 'Gene', '406938', (61, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('proliferation', 'CPA', (98, 111))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))
434207	23586049	showed that CC genotype of rs2910164 was associated with an increased risk of nasopharyngeal carcinoma (NPC) (GC + GG versus CC, OR = 0.49; 95% CI: 0.35-0.69).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('rs2910164', 'Mutation', 'rs2910164', (27, 36))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (78, 102))	('NPC', 'Phenotype', 'HP:0100630', (104, 107))	('nasopharyngeal carcinoma', 'Disease', (78, 102))	('GC', 'Phenotype', 'HP:0012126', (110, 112))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (78, 102))	('rs2910164', 'Var', (27, 36))
434209	23586049	The allelic variants of rs2910164 were evaluated in familial breast and ovarian cancers in BRCA1/BRCA2-negative patients in a study which suggested that the polymorphism may impact on the age of cancer onset.	('BRCA2', 'Gene', (97, 102))	('BRCA1', 'Gene', (91, 96))	('impact', 'Reg', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (195, 201))	('BRCA2', 'Gene', '675', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('patients', 'Species', '9606', (112, 120))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('familial breast and ovarian cancers', 'Disease', 'MESH:D061325', (52, 87))	('ovarian cancers', 'Phenotype', 'HP:0100615', (72, 87))	('rs2910164', 'Var', (24, 33))	('BRCA1', 'Gene', '672', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('rs2910164', 'Mutation', 'rs2910164', (24, 33))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
434211	23586049	However, a large study of breast cancer cases negative for disease-causing mutations or unclassified variants in BRCA1 and BRCA2 showed no associations between rs2910164 genotype and breast cancer susceptibility.	('breast cancer', 'Disease', (26, 39))	('BRCA2', 'Gene', '675', (123, 128))	('rs2910164', 'Var', (160, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('rs2910164', 'Mutation', 'rs2910164', (160, 169))	('BRCA1', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('associations', 'Interaction', (139, 151))	('BRCA2', 'Gene', (123, 128))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('breast cancer', 'Disease', (183, 196))	('BRCA1', 'Gene', '672', (113, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
434212	23586049	Another study showed also lack of association of the rs2910164 SNP with breast cancer risk in a series of BRCA1 and BRCA2 mutation carriers.	('association', 'Interaction', (34, 45))	('BRCA1', 'Gene', (106, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('rs2910164', 'Mutation', 'rs2910164', (53, 62))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('BRCA2', 'Gene', (116, 121))	('breast cancer', 'Disease', (72, 85))	('BRCA1', 'Gene', '672', (106, 111))	('rs2910164 SNP', 'Var', (53, 66))	('BRCA2', 'Gene', '675', (116, 121))
434213	23586049	In a meth-analysis study, a stratified analysis by ethnicity showed that the rs2910164 polymorphism is associated with increased breast cancer risk among Europeans in a recessive model (CC versus GC + GG: OR = 1.31; 95% CI: 1.05-1.65).	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('GC', 'Phenotype', 'HP:0012126', (196, 198))	('meth', 'Chemical', '-', (5, 9))	('rs2910164', 'Mutation', 'rs2910164', (77, 86))	('rs2910164', 'Var', (77, 86))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('increased', 'PosReg', (119, 128))
434214	23586049	In another meta-analysis was shown that SNP rs2910164 is not associated with the risk of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', (89, 113))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('SNP rs2910164', 'Var', (40, 53))	('rs2910164', 'Mutation', 'rs2910164', (44, 53))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (89, 113))
434215	23586049	Thus, the C allele of rs2910164 seems to be associated with cancer risk in a cancer type specific manner, but further studies are required to better clarify this matter.	('associated', 'Reg', (44, 54))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('rs2910164', 'Mutation', 'rs2910164', (22, 31))	('cancer', 'Disease', (60, 66))	('rs2910164', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
434217	23586049	The SNP rs11614913 is located in the pre-miRNA region of miR-196a2 and has two allelic forms, T and C. Hu et al.	('rs11614913', 'Mutation', 'rs11614913', (8, 18))	('miR-196a2', 'Gene', '406973', (57, 66))	('rs11614913', 'Var', (8, 18))	('miR-196a2', 'Gene', (57, 66))
434218	23586049	found that in nonsmall cell lung cancer patients who were homozygous CC at SNP rs11614913, risk of death significantly increased (hazard ratio HR = 1.76; 95% CI: 1.34-2.32).	('nonsmall cell lung cancer', 'Disease', (14, 39))	('rs11614913', 'Var', (79, 89))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (14, 39))	('patients', 'Species', '9606', (40, 48))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('rs11614913', 'Mutation', 'rs11614913', (79, 89))	('SNP', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('increased', 'PosReg', (119, 128))
434219	23586049	The genotype rs11614913 CC was associated with a significant increase in mature hsa-mir-196a expression without changes in levels of the precursor, suggesting an enhanced processing of the pre-miRNA.	('rs11614913', 'Mutation', 'rs11614913', (13, 23))	('processing', 'MPA', (171, 181))	('expression', 'MPA', (93, 103))	('rs11614913 CC', 'Var', (13, 26))	('enhanced', 'PosReg', (162, 170))	('increase', 'PosReg', (61, 69))	('mature hsa-mir-196a', 'Protein', (73, 92))
434223	23586049	A meta-analysis of 15 studies showed that individuals with the TC/CC genotypes are associated with higher cancer risk than those with the TT genotype (OR = 1.18; 95% CI: 1.03-1.34; P < 0.001) supporting the hypothesis that hsa-miR-196a2 rs11614913 polymorphism may contribute to cancer susceptibility.	('contribute', 'Reg', (265, 275))	('miR-196a2', 'Gene', (227, 236))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('TC/CC', 'Var', (63, 68))	('cancer', 'Disease', (106, 112))	('rs11614913', 'Mutation', 'rs11614913', (237, 247))	('rs11614913 polymorphism', 'Var', (237, 260))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('miR-196a2', 'Gene', '406973', (227, 236))
434224	23586049	The SNP rs6505162 is an A/C polymorphism located in the pre-miRNA region of miR-423.	('miR-423', 'Gene', '494335', (76, 83))	('rs6505162', 'Mutation', 'rs6505162', (8, 17))	('miR-423', 'Gene', (76, 83))	('rs6505162', 'Var', (8, 17))
434226	23586049	The most relevant finding was the association of rs6505162 SNP with reduced esophageal cancer risk, following an additive model (OR = 0.64; 95% CI: 0.51-0.80, P < 0.0001), being the C allele less represented in cases than in controls.	('rs6505162', 'Mutation', 'rs6505162', (49, 58))	('esophageal cancer', 'Disease', (76, 93))	('rs6505162', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('reduced', 'NegReg', (68, 75))
434228	23586049	In a sample of Chinese patients with surgically resected colorectal adenocarcinoma, homozygous CC genotypes of SNP rs6505162 were significantly associated with both the overall survival (HR = 2.12; 95% CI: 1.34-3.34, P = 0.001) and the recurrence-free survival (HR = 1.59; 95% CI: 1.08-2.36).	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (57, 82))	('associated', 'Reg', (144, 154))	('recurrence-free survival', 'CPA', (236, 260))	('overall survival', 'CPA', (169, 185))	('patients', 'Species', '9606', (23, 31))	('rs6505162', 'Var', (115, 124))	('rs6505162', 'Mutation', 'rs6505162', (115, 124))	('SNP', 'Gene', (111, 114))	('colorectal adenocarcinoma', 'Disease', (57, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
434229	23586049	The SNP rs3746444, having the two alleles A and G, is located in the pre-miR region of miR-499.	('rs3746444', 'Var', (8, 17))	('miR-499', 'Gene', '574501', (87, 94))	('rs3746444', 'Mutation', 'rs3746444', (8, 17))	('miR-499', 'Gene', (87, 94))
434230	23586049	In a case-control study on a Chinese population, the variant G was associated with a significant increased risks of breast cancer (OR = 1.25; 95% CI: 1.02-1.51) in a dominant genetic model.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('variant', 'Var', (53, 60))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
434231	23586049	In a meta-analysis study the rs3746444 polymorphism was significantly associated with breast cancer risk in Asian population, being the G allele responsible for the increased risk (OR = 1.10; 95% CI: 1.01-1.20).	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('associated', 'Reg', (70, 80))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('rs3746444', 'Mutation', 'rs3746444', (29, 38))	('rs3746444', 'Var', (29, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))
434232	23586049	Moreover, the rs3746444 polymorphism was associated with a significant increased risk (OR = 1.98; 95% CI: 1.36-2.98; P = 0.0004) of cervical squamous cell carcinoma, following an overdominant model.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('rs3746444', 'Var', (14, 23))	('squamous cell carcinoma', 'Disease', (141, 164))	('rs3746444', 'Mutation', 'rs3746444', (14, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))
434233	23586049	SNP rs4919510 is located in pre-miRNA region of miR-608 and has C and G alleles.	('rs4919510', 'Mutation', 'rs4919510', (4, 13))	('miR-608', 'Gene', (48, 55))	('miR-608', 'Gene', '693193', (48, 55))	('SNP', 'Var', (0, 3))
434235	23586049	In CRC patients receiving first-line fluoropyrimidine-based chemotherapy several SNPs located in miRNA regions were genotyped, the rs4919510 resulted associated with increased risk for both recurrence and death (HR = 2.72; 95% CI: 1.38-5.33 and HR = 3.53; 95% CI: 1.42-8.73).	('recurrence', 'CPA', (190, 200))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('death', 'Disease', 'MESH:D003643', (205, 210))	('rs4919510', 'Var', (131, 140))	('fluoropyrimidine', 'Chemical', '-', (37, 53))	('rs4919510', 'Mutation', 'rs4919510', (131, 140))	('patients', 'Species', '9606', (7, 15))	('death', 'Disease', (205, 210))
434236	23586049	These findings were confirmed by an independent study, in which rs4919510 was associated with altered recurrence-free survival only in patients receiving chemotherapy but not in those without chemotherapy.	('patients', 'Species', '9606', (135, 143))	('rs4919510', 'Mutation', 'rs4919510', (64, 73))	('rs4919510', 'Var', (64, 73))	('recurrence-free survival', 'CPA', (102, 126))
434238	23586049	Recently, rs4919510 was studied in breast cancer patients, and the G-allele was specifically associated with an increased risk of HER2-positive subtype (OR = 1.62; 95% CI: 1.23-2.15).	('rs4919510', 'Var', (10, 19))	('G-allele', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('associated', 'Reg', (93, 103))	('rs4919510', 'Mutation', 'rs4919510', (10, 19))	('HER2', 'Gene', (130, 134))	('breast cancer', 'Disease', (35, 48))	('patients', 'Species', '9606', (49, 57))	('HER2', 'Gene', '2064', (130, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
434241	23586049	The G allele of SNP rs895819 resulted significantly less frequent in cases than in controls, indicating a lower familial breast cancer risk for patients carrying this variant (OR = 0.88; 95% CI: 0.78-0.99).	('lower', 'NegReg', (106, 111))	('SNP rs895819', 'Var', (16, 28))	('familial breast cancer', 'Disease', 'MESH:D001943', (112, 134))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('familial breast cancer', 'Disease', (112, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('rs895819', 'Mutation', 'rs895819', (20, 28))
434244	23586049	In a case-control study on renal carcinoma, individuals carrying AG/GG genotypes of SNP rs895819 had a statistically significant lower susceptibility in the development of renal cancer (OR = 0.71; 95% CI: 0.56-0.90) than individuals with AA genotype.	('AG/GG', 'Var', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('renal carcinoma', 'Disease', 'MESH:C538614', (27, 42))	('renal cancer', 'Disease', (172, 184))	('rs895819', 'Mutation', 'rs895819', (88, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('SNP', 'Gene', (84, 87))	('renal cancer', 'Disease', 'MESH:D007680', (172, 184))	('renal cancer', 'Phenotype', 'HP:0009726', (172, 184))	('renal carcinoma', 'Disease', (27, 42))	('renal carcinoma', 'Phenotype', 'HP:0005584', (27, 42))	('lower', 'NegReg', (129, 134))
434245	23586049	In another case-control study which was performed to investigate the role of SNP rs895819 in gastric cancer susceptibility, subjects with the variant genotypes (AG + GG) showed an increased risk of gastric cancer relative to AA carriers (OR = 1.48; 95% CI: 1.06-2.05).	('variant', 'Var', (142, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('gastric cancer', 'Disease', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('rs895819', 'Mutation', 'rs895819', (81, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Disease', (93, 107))
434248	23586049	This polymorphisms was associated with increased risk in esophageal cancer with a dominant model (OR = 1.75; 95% CI: 1.10-2.80) and increased risk of death in patients with colorectal cancer receiving first-line fluoropyrimidine-based chemotherapy (HR = 3.22; 95% CI: 1.70-6.10).	('colorectal cancer', 'Disease', (173, 190))	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('death', 'Disease', 'MESH:D003643', (150, 155))	('death', 'Disease', (150, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('esophageal cancer', 'Disease', (57, 74))	('fluoropyrimidine', 'Chemical', '-', (212, 228))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))	('patients', 'Species', '9606', (159, 167))	('polymorphisms', 'Var', (5, 18))
434249	23586049	SNP variants located in 3'UTRs can destroy or create miRNA binding sites influencing tumor susceptibility.	('tumor', 'Disease', (85, 90))	('destroy', 'NegReg', (35, 42))	('variants', 'Var', (4, 12))	('miRNA', 'MPA', (53, 58))	('influencing', 'Reg', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('SNP', 'Gene', (0, 3))
434252	23586049	Among the SNPs located in the 3'UTRs, the most studied is the rs61764370, which is located in the KRAS gene.	('rs61764370', 'Mutation', 'rs61764370', (62, 72))	('rs61764370', 'Var', (62, 72))	('KRAS', 'Gene', '3845', (98, 102))	('KRAS', 'Gene', (98, 102))
434255	23586049	Therefore, the rs61764370 polymorphism fulfills the criteria of relevance in cancer predisposition.	('rs61764370', 'Mutation', 'rs61764370', (15, 25))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('rs61764370', 'Var', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
434257	23586049	These authors showed that the less common G variant of rs61764370 disrupts significantly the binding of microRNA let-7 to the 3'UTR of KRAS, increasing KRAS expression.	('microRNA let-7', 'Protein', (104, 118))	('expression', 'MPA', (157, 167))	('KRAS', 'Gene', (135, 139))	('KRAS', 'Gene', (152, 156))	('rs61764370', 'Var', (55, 65))	('binding', 'Interaction', (93, 100))	('KRAS', 'Gene', '3845', (135, 139))	('KRAS', 'Gene', '3845', (152, 156))	('disrupts', 'NegReg', (66, 74))	('increasing', 'PosReg', (141, 151))	('rs61764370', 'Mutation', 'rs61764370', (55, 65))
434258	23586049	In addition, in that study was found that subjects (smoking < 40 pack/year) with the GG + GT genotypes have an increased risk (OR = 1.36; 95% CI: 1.07-1.73; P = 0.01) of nonsmall lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('GG + GT', 'Var', (85, 92))	('nonsmall lung cancer', 'Disease', 'MESH:D002289', (170, 190))	('nonsmall lung cancer', 'Disease', (170, 190))
434259	23586049	After this first study, G variant of rs61764370 was found associated with higher risk in breast cancer, colorectal cancer, melanoma, oral cancers, and ovarian cancer.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', (89, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('rs61764370', 'Var', (37, 47))	('colorectal cancer', 'Disease', (104, 121))	('ovarian cancer', 'Disease', 'MESH:D010051', (151, 165))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('rs61764370', 'Mutation', 'rs61764370', (37, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('oral cancers', 'Disease', 'MESH:D009062', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('oral cancers', 'Disease', (133, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('ovarian cancer', 'Disease', (151, 165))
434260	23586049	Conversely, other authors did not find significant association of rs61764370 with cancer risk in colorectal cancer, nonsmall lung cancer, and ovarian cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('ovarian cancer', 'Disease', (142, 156))	('cancer', 'Disease', (82, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (142, 156))	('rs61764370', 'Mutation', 'rs61764370', (66, 76))	('colorectal cancer', 'Disease', (97, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('nonsmall lung cancer', 'Disease', (116, 136))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ovarian cancer', 'Disease', 'MESH:D010051', (142, 156))	('cancer', 'Disease', (108, 114))	('nonsmall lung cancer', 'Disease', 'MESH:D002289', (116, 136))	('rs61764370', 'Var', (66, 76))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
434261	23586049	Thus, the relevance of rs61764370 in cancer predisposition is still debated and deserves further investigations.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('rs61764370', 'Mutation', 'rs61764370', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('rs61764370', 'Var', (23, 33))
434262	23586049	The SNP rs334348 is located in the 3'UTR of TGFBR1 gene and has A and G variants.	('rs334348', 'Var', (8, 16))	('TGFBR1', 'Gene', '7046', (44, 50))	('rs334348', 'Mutation', 'rs334348', (8, 16))	('TGFBR1', 'Gene', (44, 50))
434264	23586049	Functionally, it was shown that the G allele of rs334348 is targeted with higher efficiency by miR-628-5p than the A allele.	('rs334348', 'Mutation', 'rs334348', (48, 56))	('rs334348', 'Var', (48, 56))	('miR-628-5p', 'Var', (95, 105))
434267	23586049	The SNP rs3134615 is in the 3'-UTR of MYCL1, within a miR-1827 binding site, and has G and T alleles.	('rs3134615', 'Mutation', 'rs3134615', (8, 17))	('MYCL1', 'Gene', '4610', (38, 43))	('miR-1827', 'Gene', (54, 62))	('rs3134615', 'Var', (8, 17))	('miR-1827', 'Gene', '100302217', (54, 62))	('MYCL1', 'Gene', (38, 43))
434269	23586049	Moreover, the same authors demonstrated that the T allele significantly impairs the interaction of miR-1827 with the 3'UTR of MYCL1, reducing miR-1827 dependent inhibition of MYCL1 expression.	('MYCL1', 'Gene', (175, 180))	('miR-1827', 'Gene', '100302217', (99, 107))	('inhibition', 'MPA', (161, 171))	('miR-1827', 'Gene', (99, 107))	('miR-1827', 'Gene', (142, 150))	('miR-1827', 'Gene', '100302217', (142, 150))	('MYCL1', 'Gene', '4610', (175, 180))	('MYCL1', 'Gene', '4610', (126, 131))	('impairs', 'NegReg', (72, 79))	('MYCL1', 'Gene', (126, 131))	('T allele', 'Var', (49, 57))	('interaction', 'Interaction', (84, 95))	('reducing', 'NegReg', (133, 141))
434270	23586049	The SNP rs7963551 is located in the 3'UTR of RAD52 and has C and A variants.	('RAD52', 'Gene', '5893', (45, 50))	('rs7963551', 'Mutation', 'rs7963551', (8, 17))	('rs7963551', 'Var', (8, 17))	('RAD52', 'Gene', (45, 50))
434272	23586049	In a study performed to evaluate the relevance of rs7963551 on breast cancer susceptibility, the C allele was associated with reduced cancer risk (OR = 0.84; 95% CI: 0.75-0.95).	('C allele', 'Var', (97, 105))	('rs7963551', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('rs7963551', 'Mutation', 'rs7963551', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('reduced', 'NegReg', (126, 133))
434274	23586049	The rs16917496 is a C/T variation located in the 3'UTR of SET8 within the miR-502 binding site, having the C allele a perfect match in the seed region of miR-502.	('rs16917496', 'Mutation', 'rs16917496', (4, 14))	('miR-502', 'Gene', '574504', (74, 81))	('miR-502', 'Gene', '574504', (154, 161))	('SET8', 'Gene', (58, 62))	('SET8', 'Gene', '387893', (58, 62))	('rs16917496', 'Var', (4, 14))	('miR-502', 'Gene', (74, 81))	('miR-502', 'Gene', (154, 161))
434275	23586049	The expression of SET8 in breast tumor tissues of patients with a CC genotype is significantly lower than in patients with TT genotype, and, importantly, the age of breast cancer onset depends on the number of C alleles, being significantly lower in C allele carriers (P = 0.022).	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('lower', 'NegReg', (95, 100))	('SET8', 'Gene', (18, 22))	('SET8', 'Gene', '387893', (18, 22))	('breast cancer', 'Disease', (165, 178))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (109, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast tumor', 'Phenotype', 'HP:0100013', (26, 38))	('lower', 'NegReg', (241, 246))	('expression', 'MPA', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('breast tumor', 'Disease', 'MESH:D001943', (26, 38))	('C allele carriers', 'Var', (250, 267))	('breast tumor', 'Disease', (26, 38))
434278	23586049	The rs1049253 is a C/T variation located in the 3'UTR of CASP3 gene within the binding site of miR-885-5p.	('rs1049253', 'Mutation', 'rs1049253', (4, 13))	('CASP3', 'Gene', (57, 62))	('CASP3', 'Gene', '836', (57, 62))	('rs1049253', 'Var', (4, 13))
434282	23586049	The genotypes CC/CT rs1049253 resulted associated with significantly increased cancer risk (OR = 1.29; 95% CI: 1.07-1.56), but no associations were found for the other 6 SNPs.	('increased', 'PosReg', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('rs1049253', 'Mutation', 'rs1049253', (20, 29))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('rs1049253', 'Var', (20, 29))
434283	23586049	Moreover, the rs1049253 CC genotype was associated with reduced levels of CASP3 mRNA compared with the TT genotype, and C allele resulted in stronger down-regulation than T allele of the CASP3 expression determined with miR-885-5p mimic transfection and luciferase assay.	('levels of', 'MPA', (64, 73))	('reduced', 'NegReg', (56, 63))	('CASP3', 'Gene', '836', (187, 192))	('down-regulation', 'NegReg', (150, 165))	('rs1049253 CC', 'Var', (14, 26))	('CASP3', 'Gene', '836', (74, 79))	('CASP3', 'Gene', (187, 192))	('expression', 'MPA', (193, 203))	('CASP3', 'Gene', (74, 79))	('rs1049253', 'Mutation', 'rs1049253', (14, 23))
434284	23586049	In a study of Landi et al., SNPs located in the miRNA binding sites of 3'UTR of genes relevant in the pathogenesis of colorectal cancer (CRC) were computationally tested for their ability to affect the binding of the miRNA with its target.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('affect', 'Reg', (191, 197))	('binding', 'Interaction', (202, 209))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('SNPs', 'Var', (28, 32))	('miRNA', 'Protein', (217, 222))	('colorectal cancer', 'Disease', (118, 135))	('CRC', 'Phenotype', 'HP:0003003', (137, 140))
434285	23586049	Eight polymorphisms were further studied by case-control studies and two of them, rs17281995 and rs1051690, located in the CD86 and INSR genes respectively, resulted significantly associated with CRC risk.	('rs17281995', 'Mutation', 'rs17281995', (82, 92))	('CD86', 'Gene', '942', (123, 127))	('CD86', 'Gene', (123, 127))	('CRC', 'Phenotype', 'HP:0003003', (196, 199))	('rs1051690', 'Mutation', 'rs1051690', (97, 106))	('associated', 'Reg', (180, 190))	('INSR', 'Gene', '3643', (132, 136))	('rs1051690', 'Var', (97, 106))	('CRC', 'Disease', (196, 199))	('rs17281995', 'Var', (82, 92))	('INSR', 'Gene', (132, 136))
434286	23586049	In a subsequent paper, the same authors extended the study of rs17281995 and rs1051690 polymorphisms in CRC risk, analyzing an additional population (OR = 2.93; 95% CI: 1.29-6.67, for rs17281995 and OR = 2.06; 95% CI: 1.19-3.56, for rs1051690, in the pooled samples, following a codominant model).	('CRC', 'Disease', (104, 107))	('rs1051690', 'Var', (233, 242))	('rs1051690', 'Mutation', 'rs1051690', (233, 242))	('rs17281995', 'Var', (184, 194))	('rs17281995', 'Mutation', 'rs17281995', (62, 72))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('rs17281995', 'Mutation', 'rs17281995', (184, 194))	('rs1051690', 'Mutation', 'rs1051690', (77, 86))	('rs17281995', 'Var', (62, 72))	('rs1051690', 'Var', (77, 86))
434287	23586049	The SNP rs1044129 is a G/A variation located in the 3'UTR of RYR3 gene in the miR-367 binding site.	('rs1044129', 'Var', (8, 17))	('RYR3', 'Gene', (61, 65))	('RYR3', 'Gene', '6263', (61, 65))	('miR-367', 'Gene', '442912', (78, 85))	('rs1044129', 'Mutation', 'rs1044129', (8, 17))	('miR-367', 'Gene', (78, 85))
434292	23586049	HOXB5, a member of the HOX gene family, has a SNP (1010A/G) in its 3'UTR in the binding site of miR-7.	('miR-7', 'Gene', (96, 101))	('miR-7', 'Gene', '10859', (96, 101))	('HOXB5', 'Gene', '3215', (0, 5))	('SNP (1010A/G', 'Var', (46, 58))	('1010A/G', 'Mutation', 'rs762486367', (51, 58))	('binding', 'Interaction', (80, 87))	('HOXB5', 'Gene', (0, 5))
434293	23586049	first showed the importance of HOXB5 in the pathogenesis of bladder cancer demonstrating that inhibition of its expression decreases bladder cell proliferation and tumorigenicity.	('decreases bladder', 'Phenotype', 'HP:0005343', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (164, 169))	('decreases', 'NegReg', (123, 132))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('HOXB5', 'Gene', '3215', (31, 36))	('HOXB5', 'Gene', (31, 36))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('bladder cell proliferation', 'CPA', (133, 159))	('bladder cancer', 'Disease', (60, 74))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('inhibition', 'Var', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
434295	23586049	In agreement with the above results, the authors showed by luciferase assay that the 1010A allele is repressed with higher efficiency by miR-7 than the 1010G allele.	('miR-7', 'Gene', '10859', (137, 142))	('1010A', 'Var', (85, 90))	('miR-7', 'Gene', (137, 142))
434296	23586049	The rs4245739 is an A/C variation located in the 3'UTR of MDM4 in an miR-191 binding site.	('MDM4', 'Gene', '4194', (58, 62))	('miR-191', 'Gene', '406966', (69, 76))	('MDM4', 'Gene', (58, 62))	('miR-191', 'Gene', (69, 76))	('rs4245739', 'Var', (4, 13))	('rs4245739', 'Mutation', 'rs4245739', (4, 13))
434301	23586049	A Korean study of 2010 evaluated AGO1, AGO2, TNRC6A, TNRC6C, TARBP2 and XPO5 mutations in colorectal (CRC) and gastric cancers (GC), with or without microsatellite instability.	('CRC', 'Phenotype', 'HP:0003003', (102, 105))	('TNRC6C', 'Gene', '57690', (53, 59))	('AGO1', 'Gene', (33, 37))	('GC', 'Phenotype', 'HP:0012126', (128, 130))	('TARBP2', 'Gene', (61, 67))	('TARBP2', 'Gene', '6895', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('AGO2', 'Gene', '27161', (39, 43))	('TNRC6A', 'Gene', '27327', (45, 51))	('colorectal', 'Disease', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('XPO5', 'Gene', '57510', (72, 76))	('TNRC6A', 'Gene', (45, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('mutations', 'Var', (77, 86))	('gastric cancers', 'Disease', 'MESH:D013274', (111, 126))	('TNRC6C', 'Gene', (53, 59))	('gastric cancers', 'Disease', (111, 126))	('gastric cancers', 'Phenotype', 'HP:0012126', (111, 126))	('AGO2', 'Gene', (39, 43))	('XPO5', 'Gene', (72, 76))	('AGO1', 'Gene', '26523', (33, 37))
434302	23586049	Data of this study indicate that frameshift mutations in AGO2 and TNRC6A and their losses of expression are common in GCs and CRCs with microsatellite instability and suggest that these alterations may contribute to the cancer development by deregulating miRNAs.	('CRCs', 'Disease', (126, 130))	('CRC', 'Phenotype', 'HP:0003003', (126, 129))	('AGO2', 'Gene', '27161', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('GCs', 'Disease', (118, 121))	('microsatellite instability', 'MPA', (136, 162))	('miRNAs', 'MPA', (255, 261))	('losses', 'NegReg', (83, 89))	('common', 'Reg', (108, 114))	('GC', 'Phenotype', 'HP:0012126', (118, 120))	('contribute', 'Reg', (202, 212))	('AGO2', 'Gene', (57, 61))	('deregulating', 'NegReg', (242, 254))	('TNRC6A', 'Gene', '27327', (66, 72))	('cancer', 'Disease', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TNRC6A', 'Gene', (66, 72))	('frameshift mutations', 'Var', (33, 53))	('expression', 'MPA', (93, 103))
434305	23586049	The variant-containing genotypes of Asn929Asp and Cys1033Arg significantly reduced risk, with odds ratios of 0.67 (95% CI: 0.47-0.96) and 0.68 (95% CI = 0.47-0.98), respectively.	('Cys1033Arg', 'Var', (50, 60))	('reduced', 'NegReg', (75, 82))	('Asn929Asp', 'SUBSTITUTION', 'None', (36, 45))	('Asn929Asp', 'Var', (36, 45))	('Cys1033Arg', 'SUBSTITUTION', 'None', (50, 60))
434306	23586049	Haplotype analysis showed that a common haplotype of GEMIN4 was associated with a significant reduction in the risk of renal cell carcinoma (OR = 0.66; 95% CI: 0.45-0.97).	('reduction', 'NegReg', (94, 103))	('haplotype', 'Var', (40, 49))	('GEMIN4', 'Gene', (53, 59))	('renal cell carcinoma', 'Disease', (119, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('GEMIN4', 'Gene', '50628', (53, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (119, 139))
434307	23586049	The same research group, in a successive study, took a polygenic approach to evaluate the effects of 41 potentially functional SNPs in miRNAs-related genes on survival and recurrence among renal cell carcinoma (RCC) patients.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (189, 209))	('RCC', 'Disease', (211, 214))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('SNPs', 'Var', (127, 131))	('patients', 'Species', '9606', (216, 224))	('renal cell carcinoma', 'Disease', (189, 209))	('miRNAs-related genes', 'Gene', (135, 155))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))
434309	23586049	The most significant associations were SNPs in GEMIN4 with the variant alleles of both rs7813 and rs910925 associated with 1.74-fold (95% CI: 1.15-2.62) increased risk of death, whereas the variant allele of rs3744741 conferred a decreased risk of death (HR = 0.39; 95% CI: 0.19-0.77).	('rs7813', 'Var', (87, 93))	('GEMIN4', 'Gene', '50628', (47, 53))	('death', 'Disease', 'MESH:D003643', (171, 176))	('rs3744741', 'Mutation', 'rs3744741', (208, 217))	('rs7813', 'Mutation', 'rs7813', (87, 93))	('SNPs', 'Var', (39, 43))	('death', 'Disease', (171, 176))	('associated', 'Reg', (107, 117))	('death', 'Disease', 'MESH:D003643', (248, 253))	('death', 'Disease', (248, 253))	('GEMIN4', 'Gene', (47, 53))	('rs910925', 'Mutation', 'rs910925', (98, 106))	('rs3744741', 'Var', (208, 217))	('rs910925', 'Var', (98, 106))	('associations', 'Interaction', (21, 33))
434310	23586049	Haplotypes of DICER and DROSHA were also associated with altered patient survival and recurrence.	('DICER', 'Gene', (14, 19))	('associated', 'Reg', (41, 51))	('DROSHA', 'Gene', '29102', (24, 30))	('DROSHA', 'Gene', (24, 30))	('patient survival', 'CPA', (65, 81))	('patient', 'Species', '9606', (65, 72))	('recurrence', 'CPA', (86, 96))	('Haplotypes', 'Var', (0, 10))	('DICER', 'Gene', '23405', (14, 19))	('altered', 'Reg', (57, 64))
434312	23586049	A common haplotype of the GEMIN4 gene was associated with a significantly reduced risk of esophageal cancer (OR = 0.65; 95% CI: 0.42-0.99).	('haplotype', 'Var', (9, 18))	('GEMIN4', 'Gene', (26, 32))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('GEMIN4', 'Gene', '50628', (26, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('reduced', 'NegReg', (74, 81))
434315	23586049	Two SNPs in AGO2 (rs11786030 and rs2292779) and DICER1 rs1057035 were associated with both DFS and OS.	('AGO2', 'Gene', (12, 16))	('DICER1', 'Gene', (48, 54))	('DICER1', 'Gene', '23405', (48, 54))	('rs2292779', 'Mutation', 'rs2292779', (33, 42))	('rs11786030', 'Var', (18, 28))	('associated', 'Reg', (70, 80))	('AGO2', 'Gene', '27161', (12, 16))	('rs1057035', 'Mutation', 'rs1057035', (55, 64))	('rs11786030', 'Mutation', 'rs11786030', (18, 28))	('rs2292779', 'Var', (33, 42))	('rs1057035', 'Var', (55, 64))	('DFS', 'Disease', (91, 94))
434316	23586049	Two SNPs in HIWI (rs4759659 and rs11060845), and DGCR8 rs9606250 were associated with DFS, while DROSHA rs874332 and GEMIN4 rs4968104 were associated with OS only.	('GEMIN4', 'Gene', '50628', (117, 123))	('DFS', 'Disease', (86, 89))	('rs11060845', 'Var', (32, 42))	('rs4968104', 'Var', (124, 133))	('associated', 'Reg', (70, 80))	('HIWI', 'Gene', '9271', (12, 16))	('rs4968104', 'Mutation', 'rs4968104', (124, 133))	('rs9606250', 'Mutation', 'rs9606250', (55, 64))	('rs9606250', 'Var', (55, 64))	('rs4759659', 'Mutation', 'rs4759659', (18, 27))	('DGCR8', 'Gene', (49, 54))	('DROSHA', 'Gene', '29102', (97, 103))	('DROSHA', 'Gene', (97, 103))	('GEMIN4', 'Gene', (117, 123))	('rs11060845', 'Mutation', 'rs11060845', (32, 42))	('rs4759659', 'Var', (18, 27))	('rs874332', 'Mutation', 'rs874332', (104, 112))	('DGCR8', 'Gene', '54487', (49, 54))	('HIWI', 'Gene', (12, 16))	('GC', 'Phenotype', 'HP:0012126', (50, 52))
434317	23586049	The most significant associations were observed in variant allele of AGO2 rs11786030 with 2.62-fold increased risk of disease progression (95% CI: 1.41-4.88) and in minor allele homozygote of AGO2 rs2292779 with 2.94-fold increased risk of death (95% CI: 1.52-5.69).	('rs11786030', 'Mutation', 'rs11786030', (74, 84))	('disease progression', 'CPA', (118, 137))	('rs2292779', 'Mutation', 'rs2292779', (197, 206))	('AGO2', 'Gene', '27161', (69, 73))	('AGO2', 'Gene', (192, 196))	('death', 'Disease', 'MESH:D003643', (240, 245))	('death', 'Disease', (240, 245))	('AGO2', 'Gene', (69, 73))	('AGO2', 'Gene', '27161', (192, 196))	('rs11786030', 'Var', (74, 84))	('rs2292779', 'Var', (197, 206))
434318	23586049	A recent study was performed in order to evaluate the role of miR-SNPs of GEMIN4 in prostate cancer.	('GEMIN4', 'Gene', '50628', (74, 80))	('miR-SNPs', 'Var', (62, 70))	('prostate cancer', 'Disease', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('GEMIN4', 'Gene', (74, 80))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))
434319	23586049	The high-resolution melting method was used to genotype seven polymorphisms (rs7813, rs4968104, rs3744741, rs2740348, rs1062923, rs910925, and rs910924) in the GEMIN4 gene.	('meth', 'Chemical', '-', (28, 32))	('rs1062923', 'Var', (118, 127))	('rs910924', 'Mutation', 'rs910924', (143, 151))	('rs2740348', 'Mutation', 'rs2740348', (107, 116))	('rs910924', 'Var', (143, 151))	('GEMIN4', 'Gene', '50628', (160, 166))	('GEMIN4', 'Gene', (160, 166))	('rs7813', 'Var', (77, 83))	('rs4968104', 'Mutation', 'rs4968104', (85, 94))	('rs1062923', 'Mutation', 'rs1062923', (118, 127))	('rs7813', 'Mutation', 'rs7813', (77, 83))	('rs3744741', 'Var', (96, 105))	('rs910925', 'Mutation', 'rs910925', (129, 137))	('rs4968104', 'Var', (85, 94))	('rs2740348', 'Var', (107, 116))	('rs910925', 'Var', (129, 137))	('rs3744741', 'Mutation', 'rs3744741', (96, 105))
434320	23586049	Patients carrying the variant heterozygote GC genotype in the rs2740348 were at a 36% decreased risk of prostate cancer (OR = 0.64; 95% CI: 0.42-0.99).	('rs2740348', 'Mutation', 'rs2740348', (62, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('decreased risk of prostate', 'Phenotype', 'HP:0008687', (86, 112))	('rs2740348', 'Var', (62, 71))	('decreased', 'NegReg', (86, 95))	('Patients', 'Species', '9606', (0, 8))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('GC', 'Phenotype', 'HP:0012126', (43, 45))	('prostate cancer', 'Disease', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
434322	23586049	Two common haplotypes were found to be associated with decreased risk of prostate cancer.	('prostate cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('decreased risk of prostate', 'Phenotype', 'HP:0008687', (55, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('decreased', 'NegReg', (55, 64))	('haplotypes', 'Var', (11, 21))
434323	23586049	In the subgroup analysis, higher risk of more severity of prostate cancer (clinical stage III and IV) was observed in individuals with the rs7813 TT genotype (OR = 2.64; 95% CI: 1.02-7.64), while lower risk of more severity of prostate cancer was observed in individuals with the rs3744741 T allele (OR = 0.69; 95% CI: 0.50-0.96).	('prostate cancer', 'Disease', 'MESH:D011471', (227, 242))	('prostate cancer', 'Phenotype', 'HP:0012125', (227, 242))	('rs3744741', 'Mutation', 'rs3744741', (280, 289))	('rs7813', 'Mutation', 'rs7813', (139, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (58, 73))	('rs7813 TT', 'Var', (139, 148))	('prostate cancer', 'Disease', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('prostate cancer', 'Disease', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('prostate cancer', 'Disease', 'MESH:D011471', (58, 73))
434325	23586049	Significant differences in TTR were found for XPO5 rs11077 (median TTR: 24.7 months for the AA genotype versus 73.1 months for the AC or CC genotypes; P = 0.029).	('rs11077', 'Mutation', 'rs11077', (51, 58))	('XPO5', 'Gene', '57510', (46, 50))	('XPO5', 'Gene', (46, 50))	('rs11077', 'Var', (51, 58))
434326	23586049	In multivariate analyses, the XPO5 rs11077 AA genotype (OR = 1.77; 95% CI: 1.07-2.91) emerged as independent variable influencing TTR.	('rs11077 AA', 'Var', (35, 45))	('TTR', 'Disease', (130, 133))	('XPO5', 'Gene', (30, 34))	('XPO5', 'Gene', '57510', (30, 34))	('rs11077', 'Mutation', 'rs11077', (35, 42))
434327	23586049	In a recent case-control study on head and neck cancer (HNC), three SNPs at miRNA binding sites of miRNA processing genes were genotyped (rs1057035 in 3'UTR of DICER, rs3803012 in 3'UTR of RAN, and rs10773771 in 3'UTR of HIWI).	('HNC', 'Phenotype', 'HP:0012288', (56, 59))	('head and neck cancer', 'Phenotype', 'HP:0012288', (34, 54))	('HIWI', 'Gene', (221, 225))	('rs3803012', 'Mutation', 'rs3803012', (167, 176))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('rs10773771', 'Mutation', 'rs10773771', (198, 208))	('HIWI', 'Gene', '9271', (221, 225))	('rs1057035', 'Mutation', 'rs1057035', (138, 147))	('RAN', 'Gene', '5901', (189, 192))	('neck cancer', 'Disease', 'MESH:D006258', (43, 54))	('rs10773771', 'Var', (198, 208))	('DICER', 'Gene', '23405', (160, 165))	('rs1057035', 'Var', (138, 147))	('rs3803012', 'Var', (167, 176))	('neck cancer', 'Disease', (43, 54))	('DICER', 'Gene', (160, 165))	('RAN', 'Gene', (189, 192))
434328	23586049	Although none of the SNPs was significantly associated with overall risk of HNC, rs1057035 in 3'UTR of DICER was associated with a significantly decreased risk of oral cancer (TC/CC versus TT, OR = 0.65; 95% CI: 0.46-0.92).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('rs1057035', 'Mutation', 'rs1057035', (81, 90))	('HNC', 'Phenotype', 'HP:0012288', (76, 79))	('rs1057035', 'Var', (81, 90))	('DICER', 'Gene', (103, 108))	('oral cancer', 'Disease', 'MESH:D009062', (163, 174))	('decreased', 'NegReg', (145, 154))	('oral cancer', 'Disease', (163, 174))	('DICER', 'Gene', '23405', (103, 108))
434329	23586049	Furthermore, luciferase activity assay showed that rs1057035 variant C allele led to significantly lower expression levels of DICER as compared to the T allele, which may be due to the higher inhibition of hsa-miR-574-3p on DICER mRNA.	('DICER', 'Gene', '23405', (224, 229))	('lower', 'NegReg', (99, 104))	('DICER', 'Gene', (224, 229))	('rs1057035', 'Mutation', 'rs1057035', (51, 60))	('rs1057035', 'Var', (51, 60))	('expression levels', 'MPA', (105, 122))	('DICER', 'Gene', '23405', (126, 131))	('DICER', 'Gene', (126, 131))
434330	23586049	These findings indicated that rs1057035 located at 3'UTR of DICER may contribute to the risk of oral cancer by affecting the binding of miRNAs to DICER.	('rs1057035', 'Mutation', 'rs1057035', (30, 39))	('rs1057035', 'Var', (30, 39))	('miRNAs', 'Protein', (136, 142))	('DICER', 'Gene', (146, 151))	('oral cancer', 'Disease', 'MESH:D009062', (96, 107))	('DICER', 'Gene', '23405', (60, 65))	('binding', 'Interaction', (125, 132))	('oral cancer', 'Disease', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('affecting', 'Reg', (111, 120))	('DICER', 'Gene', (60, 65))	('DICER', 'Gene', '23405', (146, 151))
434332	23586049	The SNP of miRNA biogenesis pathway evaluated was the rs11077 of XPO5.	('rs11077', 'Mutation', 'rs11077', (54, 61))	('XPO5', 'Gene', (65, 69))	('rs11077', 'Var', (54, 61))	('miRNA biogenesis pathway', 'Pathway', (11, 35))	('XPO5', 'Gene', '57510', (65, 69))
434333	23586049	Overall survival was significantly longer in patients with C/C or A/C variant in XPO5 rs11077 (P = 0.012).	('A/C', 'Var', (66, 69))	('C/C or A/C', 'Var', (59, 69))	('XPO5', 'Gene', (81, 85))	('XPO5', 'Gene', '57510', (81, 85))	('longer', 'PosReg', (35, 41))	('rs11077', 'Var', (86, 93))	('rs11077', 'Mutation', 'rs11077', (86, 93))	('Overall survival', 'MPA', (0, 16))	('patients', 'Species', '9606', (45, 53))
434334	23586049	The study of polymorphisms, affecting miRNA-dependent pathways and involved in cancer susceptibility, is rapidly growing, and in the near future probably other SNPs will be investigated, and the SNPs mentioned in this paper will be further evaluated.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miRNA-dependent pathways', 'Pathway', (38, 62))	('polymorphisms', 'Var', (13, 26))	('affecting', 'Reg', (28, 37))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
434342	32819319	Retroviral knockdown of MEIS1 in KYSE-30 cells caused a noteworthy underexpression of both MEIS1 and major involved markers in stemness state of the cells including SALL4, OCT4, BMI-1, HIWI and KLF4.	('HIWI', 'Gene', (185, 189))	('KYSE', 'Chemical', '-', (33, 37))	('OCT4', 'Gene', (172, 176))	('BMI-1', 'Gene', '648', (178, 183))	('HIWI', 'Gene', '9271', (185, 189))	('MEIS1', 'Gene', (91, 96))	('MEIS1', 'Gene', (24, 29))	('underexpression', 'NegReg', (67, 82))	('BMI-1', 'Gene', (178, 183))	('knockdown', 'Var', (11, 20))	('OCT4', 'Gene', '5460', (172, 176))
434350	32819319	Deregulated MEIS1 mRNA and protein expression can lead to tumorigenesis in a number of tumor types such as acute myeloid leukemia, lung adenocarcinoma tumors, neuroblastomas, ovarian carcinomas and ESCC.	('neuroblastomas, ovarian carcinomas', 'Disease', 'MESH:D010051', (159, 193))	('lung adenocarcinoma tumors', 'Disease', 'MESH:D000077192', (131, 157))	('MEIS1', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('expression', 'MPA', (35, 45))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Deregulated', 'Var', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('neuroblastoma', 'Phenotype', 'HP:0003006', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('acute myeloid leukemia', 'Disease', (107, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (131, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('lead to', 'Reg', (50, 57))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (175, 193))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (107, 129))	('lung adenocarcinoma tumors', 'Disease', (131, 157))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (113, 129))	('ESCC', 'Disease', (198, 202))	('tumor', 'Disease', (151, 156))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('mRNA and', 'MPA', (18, 26))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (107, 129))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
434374	32819319	To deliver shRNA into the esophageal cancer cell line KYSE30, we used a lentiviral-based vector that expressed MEIS1 shRNA.	('KYSE', 'Chemical', '-', (54, 58))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('MEIS1', 'Var', (111, 116))
434380	32819319	Furthermore, the level of HIWI mRNA expression was significantly reduced about - 14.28 in MEIS1 silenced cells in comparison with control.	('reduced', 'NegReg', (65, 72))	('silenced', 'Var', (96, 104))	('HIWI', 'Gene', (26, 30))	('HIWI', 'Gene', '9271', (26, 30))	('MEIS1', 'Gene', (90, 95))
434381	32819319	These data clearly showed the significant decrease in expression of the majority of selected stemness genes in KYSE-30 cells after MEIS1 silencing.	('expression', 'MPA', (54, 64))	('stemness genes', 'Gene', (93, 107))	('decrease', 'NegReg', (42, 50))	('silencing', 'Var', (137, 146))	('KYSE', 'Chemical', '-', (111, 115))	('MEIS1', 'Gene', (131, 136))
434382	32819319	No changes were observed in mRNA expression of NANOG and PLK1 following silencing of MEIS1 in KYSE-30 cells.	('NANOG', 'Gene', (47, 52))	('silencing', 'Var', (72, 81))	('MEIS1', 'Gene', (85, 90))	('PLK1', 'Gene', (57, 61))	('PLK1', 'Gene', '5347', (57, 61))	('mRNA expression', 'MPA', (28, 43))	('KYSE', 'Chemical', '-', (94, 98))	('NANOG', 'Gene', '79923', (47, 52))
434386	32819319	The present study demonstrated the impact of MEIS1 on expression of stem cell markers in ESCC and found that mRNA expression of major stem cell markers including SALL4, OCT4, BMI-1, HIWI and KLF4 was significantly decreased in MEIS1 silenced cells compared to control.	('expression', 'MPA', (54, 64))	('BMI-1', 'Gene', '648', (175, 180))	('HIWI', 'Gene', '9271', (182, 186))	('mRNA expression', 'MPA', (109, 124))	('silenced', 'Var', (233, 241))	('OCT4', 'Gene', '5460', (169, 173))	('OCT4', 'Gene', (169, 173))	('MEIS1', 'Gene', (227, 232))	('BMI-1', 'Gene', (175, 180))	('decreased', 'NegReg', (214, 223))	('SALL4', 'Gene', (162, 167))	('HIWI', 'Gene', (182, 186))
434394	32819319	In other cancers including neuroblastoma, high level expression of MEIS1 and MEIS2 genes was demonstrated, and defective MEIS1 cells showed impaired proliferation leading to cell death.	('neuroblastoma', 'Disease', (27, 40))	('MEIS1', 'Gene', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('MEIS2', 'Gene', '4212', (77, 82))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('death', 'Disease', 'MESH:D003643', (179, 184))	('neuroblastoma', 'Phenotype', 'HP:0003006', (27, 40))	('death', 'Disease', (179, 184))	('MEIS2', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('proliferation', 'CPA', (149, 162))	('defective', 'Var', (111, 120))	('impaired', 'NegReg', (140, 148))	('expression', 'MPA', (53, 63))	('MEIS1', 'Gene', (121, 126))	('neuroblastoma', 'Disease', 'MESH:D009447', (27, 40))
434395	32819319	We have recently reported that MEIS1 knockdown in KYSE-30 cells can induce expression of epithelial differentiation markers CDX2, and KRT4, while it can suppress the involved genes in EMT process including TWIST1, EGF.	('CDX2', 'Gene', '1045', (124, 128))	('EGF', 'Gene', (214, 217))	('TWIST1', 'Gene', (206, 212))	('induce', 'PosReg', (68, 74))	('expression', 'MPA', (75, 85))	('suppress', 'NegReg', (153, 161))	('knockdown', 'Var', (37, 46))	('KRT4', 'Gene', (134, 138))	('KRT4', 'Gene', '3851', (134, 138))	('TWIST1', 'Gene', '7291', (206, 212))	('EGF', 'Gene', '1950', (214, 217))	('EMT', 'Gene', (184, 187))	('EMT', 'Gene', '3702', (184, 187))	('MEIS1', 'Gene', (31, 36))	('epithelial', 'CPA', (89, 99))	('KYSE', 'Chemical', '-', (50, 54))	('CDX2', 'Gene', (124, 128))
434409	32819319	Aberrant expression of SALL4 observed in different types of cancers and disruption of multiple cellular tumorigenesis processes suggested a key stemness regulatory effect for SALL4.	('disruption', 'Reg', (72, 82))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('SALL4', 'Gene', (23, 28))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('tumor', 'Disease', (104, 109))	('expression', 'MPA', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
434419	32819319	Furthermore, expression of BMI-1 was also decreased after MEIS1 knockdown in KYSE-30 cells.	('decreased', 'NegReg', (42, 51))	('BMI-1', 'Gene', '648', (27, 32))	('expression', 'MPA', (13, 23))	('KYSE', 'Chemical', '-', (77, 81))	('MEIS1', 'Gene', (58, 63))	('knockdown', 'Var', (64, 73))	('BMI-1', 'Gene', (27, 32))
434425	32819319	Similar to OCT4 and SALL4, the expression of HIWI was reduced after silencing of MEIS1 in ESCC line KYSE-30.	('OCT4', 'Gene', '5460', (11, 15))	('HIWI', 'Gene', '9271', (45, 49))	('OCT4', 'Gene', (11, 15))	('MEIS1', 'Gene', (81, 86))	('KYSE', 'Chemical', '-', (100, 104))	('expression', 'MPA', (31, 41))	('reduced', 'NegReg', (54, 61))	('silencing', 'Var', (68, 77))	('HIWI', 'Gene', (45, 49))
434428	32819319	Our study revealed that the level of HIWI mRNA expression was significantly decreased in MESI1 silenced cells in comparison with control cells.	('MESI1', 'Gene', (89, 94))	('decreased', 'NegReg', (76, 85))	('HIWI', 'Gene', (37, 41))	('HIWI', 'Gene', '9271', (37, 41))	('silenced', 'Var', (95, 103))
434432	32819319	Furthermore, we demonstrated that expression of certain stemness factors including SALL4, OCT4, BMI-1, HIWI and KLF4 genes were significantly decreased after MEIS1 silencing in ESCC line KYSE-30.	('OCT4', 'Gene', '5460', (90, 94))	('HIWI', 'Gene', (103, 107))	('KLF4 genes', 'Gene', (112, 122))	('expression', 'MPA', (34, 44))	('HIWI', 'Gene', '9271', (103, 107))	('BMI-1', 'Gene', '648', (96, 101))	('decreased', 'NegReg', (142, 151))	('OCT4', 'Gene', (90, 94))	('MEIS1', 'Gene', (158, 163))	('KYSE', 'Chemical', '-', (187, 191))	('silencing', 'Var', (164, 173))	('SALL4', 'Gene', (83, 88))	('BMI-1', 'Gene', (96, 101))
434489	29928189	Thus, although the combination of radiotherapy and CPT-11 increases the risk of radiation pneumonitis, concurrent radiotherapy and chemotherapy with CDDP and CPT-11 may be a better choice in managing both primary and metastatic esophageal NEC.	('pneumonitis', 'Disease', (90, 101))	('CPT-11', 'Chemical', 'MESH:D000077146', (51, 57))	('CPT-11', 'Gene', (51, 57))	('primary', 'Disease', (205, 212))	('NEC', 'Phenotype', 'HP:0100634', (239, 242))	('CPT-11', 'Gene', (158, 164))	('pneumonitis', 'Disease', 'MESH:D011014', (90, 101))	('CPT-11', 'Chemical', 'MESH:D000077146', (158, 164))	('CDDP', 'Chemical', 'MESH:D002945', (149, 153))	('combination', 'Var', (19, 30))	('man', 'Species', '9606', (191, 194))
434497	29499515	To characterize the adrenal lesion, a PET scan was obtained which showed high uptake of 18F-fluoro-2-deoxy-d-glucose (FDG), consistent with a metastasis, suggesting T3N2M1, clinical stage IV esophageal cancer.	('adrenal lesion', 'Disease', 'MESH:D000307', (20, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('FDG', 'Chemical', '-', (118, 121))	('T3N2M1', 'Var', (165, 171))	('18F-fluoro-2-deoxy-d-glucose', 'Chemical', '-', (88, 116))	('uptake', 'MPA', (78, 84))	('esophageal cancer', 'Disease', (191, 208))	('adrenal lesion', 'Disease', (20, 34))
434499	29499515	The pathologic stage of the esophageal cancer was T3N0M0, Stage II.	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('esophageal cancer', 'Disease', (28, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('T3N0M0', 'Var', (50, 56))
434554	29642773	The 5-year survival rate of patients with esophageal cancer having high ADCmin, ADCmean, and ADCmax and volume transfer constant before chemoradiotherapy was greater than those with respectively lower values.	('esophageal cancer', 'Disease', (42, 59))	('greater', 'PosReg', (158, 165))	('high', 'Var', (67, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('ADCmax', 'MPA', (93, 99))	('ADCmin', 'MPA', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('patients', 'Species', '9606', (28, 36))
434616	29642773	Both groups displayed a positive correlation between Ktrans and the tumor size reduction rate before and after chemoradiotherapy (all P < .05; Table 2).	('tumor', 'Disease', (68, 73))	('Ktrans', 'Var', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Ktrans', 'Chemical', '-', (53, 59))
434619	29642773	In the sensitive and resistant groups, patients with EC having high ADCmin (>=1.155 x 10-3 mm2/s), ADCmean (>=1.525 x 10-3 mm2/s), ADCmax (>=1.565 x 10-3 mm2/s), and Ktrans (>=0.505 min-1) had a greater 5-year survival rate than those with low ADCmin (<1.155 x 10-3 mm2/s), ADCmean (<1.525 x 10-3 mm2/s), ADCmax (<1.565 x 10-3 mm2/s), and Ktrans (<0.505 min-1; all P < .05; Figure 3).	('Ktrans', 'Chemical', '-', (339, 345))	('patients', 'Species', '9606', (39, 47))	('greater', 'PosReg', (195, 202))	('min-1', 'Gene', (182, 187))	('>=1.525 x 10-3 mm2/s', 'Var', (108, 128))	('min-1', 'Gene', '966', (182, 187))	('Ktrans', 'Chemical', '-', (166, 172))	('min-1', 'Gene', '966', (354, 359))	('min-1', 'Gene', (354, 359))	('5-year survival rate', 'CPA', (203, 223))	('>=1.155 x 10-3 mm2/s', 'Var', (76, 96))
434707	29510754	ROC curve analysis also identified the following cut-off values for CRP and CPK at 1POD: 9.6 x 10^4 mug/L and 1164 IU/L, respectively (Fig.	('CRP', 'Gene', '1401', (68, 71))	('CRP', 'Gene', (68, 71))	('1164 IU/L', 'Var', (110, 119))
434709	29510754	In a univariate analysis, the predictive factors for developing anastomotic leakage related to gastric conduit included levels of CRP and CPK at 1POD.	('anastomotic leakage', 'MPA', (64, 83))	('CRP', 'Gene', '1401', (130, 133))	('CRP', 'Gene', (130, 133))	('CPK', 'Var', (138, 141))
434710	29510754	When a multiple logistic regression analysis was performed to evaluate confounding factors, 3FLND and the levels of CPK and CRP at 1POD were found to be significantly associated with developing major complications related to gastric conduit (Table 5).	('CRP', 'Gene', '1401', (124, 127))	('CRP', 'Gene', (124, 127))	('gastric conduit', 'Disease', (225, 240))	('3FLND', 'Var', (92, 97))	('associated', 'Reg', (167, 177))
434743	28528706	As anticipated, alterations in this large control system can contribute to disease pathogenesis and carcinogenesis.	('carcinogenesis', 'Disease', (100, 114))	('contribute', 'Reg', (61, 71))	('alterations', 'Var', (16, 27))	('carcinogenesis', 'Disease', 'MESH:D063646', (100, 114))	('rat', 'Species', '10116', (20, 23))
434757	28528706	In fact, some miRNAs are actually derived from lncRNAs, such as miRNA-675-3p and miRNA-675-5p, which come from the lncRNA H19.	('H19', 'Gene', (122, 125))	('ncRNA', 'Gene', '220202', (48, 53))	('ncRNA', 'Gene', (116, 121))	('ncRNA', 'Gene', (48, 53))	('ncRNA', 'Gene', '220202', (116, 121))	('miRNA-675-5p', 'Var', (81, 93))	('H19', 'Gene', '283120', (122, 125))
434771	28528706	In general, methylation of a lncRNA gene prevents its transcription, which in turn allows the expression of nearby mRNA-encoding genes.	('ncRNA', 'Gene', (30, 35))	('transcription', 'MPA', (54, 67))	('prevents', 'NegReg', (41, 49))	('expression', 'MPA', (94, 104))	('ncRNA', 'Gene', '220202', (30, 35))	('methylation', 'Var', (12, 23))	('allows', 'Reg', (83, 89))
434772	28528706	Conversely, the absence of methylation of a lncRNA gene is thought to allow its expression, which in turn blocks expression of nearby mRNA genes, in cis .	('absence', 'Var', (16, 23))	('expression', 'MPA', (113, 123))	('allow', 'PosReg', (70, 75))	('ncRNA', 'Gene', '220202', (45, 50))	('blocks', 'NegReg', (106, 112))	('methylation', 'Var', (27, 38))	('expression', 'MPA', (80, 90))	('ncRNA', 'Gene', (45, 50))
434775	28528706	This hybrid then represses transcription; individuals with expanded CGG repeats at this promoter region have fragile X mental retardation.	('represses', 'NegReg', (17, 26))	('transcription', 'MPA', (27, 40))	('fragile X mental retardation', 'Disease', (109, 137))	('fragile X mental retardation', 'Disease', 'MESH:D005600', (109, 137))	('mental retardation', 'Phenotype', 'HP:0001249', (119, 137))	('expanded CGG repeats', 'Var', (59, 79))
434802	28528706	This finding suggests that the phenotypic changes induced by siRNA transfection were mediated directly by AFAP1-AS1, rather than indirectly, via AFAP1.	('transfection', 'Var', (67, 79))	('rat', 'Species', '10116', (117, 120))	('AFAP1', 'Gene', '60312', (106, 111))	('mediated', 'Reg', (85, 93))	('AS1', 'Gene', (112, 115))	('AFAP1', 'Gene', (106, 111))	('AS1', 'Gene', '5729', (112, 115))	('AFAP1', 'Gene', (145, 150))	('AFAP1', 'Gene', '60312', (145, 150))
434805	28528706	Silencing of this lncRNA in ESCC cells inhibited proliferation and reduced colony-forming capacity, so AFAP1-AS1 appears to function as an oncogene that promotes ESCC development or progression.	('colony-forming capacity', 'CPA', (75, 98))	('rat', 'Species', '10116', (56, 59))	('inhibited', 'NegReg', (39, 48))	('ncRNA', 'Gene', (19, 24))	('proliferation', 'CPA', (49, 62))	('ncRNA', 'Gene', '220202', (19, 24))	('AS1', 'Gene', '5729', (109, 112))	('AS1', 'Gene', (109, 112))	('reduced', 'NegReg', (67, 74))	('progression', 'CPA', (182, 193))	('AFAP1', 'Gene', (103, 108))	('AFAP1', 'Gene', '60312', (103, 108))	('ESCC', 'Disease', (162, 166))	('Silencing', 'Var', (0, 9))	('promotes', 'PosReg', (153, 161))
434817	28528706	siRNA-mediated knockdown of HNF1A-AS1 reduced EAC cell proliferation and decreased anchorage-independent growth, measured by colony-formation assays, compared with a scrambled siRNA control.	('knockdown', 'Var', (15, 24))	('decreased', 'NegReg', (73, 82))	('reduced', 'NegReg', (38, 45))	('HNF1A-AS1', 'Gene', '283460', (28, 37))	('anchorage-independent growth', 'CPA', (83, 111))	('rat', 'Species', '10116', (62, 65))	('EAC cell proliferation', 'CPA', (46, 68))	('EAC', 'Phenotype', 'HP:0011459', (46, 49))	('HNF1A-AS1', 'Gene', (28, 37))
434818	28528706	These experiments also showed reduced cell migration and invasion in EAC cell lines after siRNA knockdown of HNF1A-AS1.	('knockdown', 'Var', (96, 105))	('cell migration', 'CPA', (38, 52))	('rat', 'Species', '10116', (46, 49))	('EAC', 'Phenotype', 'HP:0011459', (69, 72))	('reduced', 'NegReg', (30, 37))	('invasion in EAC cell lines', 'CPA', (57, 83))	('HNF1A-AS1', 'Gene', (109, 118))	('HNF1A-AS1', 'Gene', '283460', (109, 118))
434820	28528706	Interestingly, lncRNA H19 was the gene most markedly dysregulated by knockdown of HNF1A-AS1; the correlation between these lncRNAs was verified in primary EACs.	('ncRNA', 'Gene', (16, 21))	('ncRNA', 'Gene', '220202', (124, 129))	('H19', 'Gene', '283120', (22, 25))	('ncRNA', 'Gene', '220202', (16, 21))	('EAC', 'Phenotype', 'HP:0011459', (155, 158))	('H19', 'Gene', (22, 25))	('HNF1A-AS1', 'Gene', (82, 91))	('HNF1A-AS1', 'Gene', '283460', (82, 91))	('knockdown', 'Var', (69, 78))	('ncRNA', 'Gene', (124, 129))
434841	26456456	MTHFR C677T Polymorphism is Associated with Tumor Response to Preoperative Chemoradiotherapy: A Result Based on Previous Reports Preoperative chemoradiotherapy (pRCT) followed by surgery has been widely practiced in locally advanced rectal cancer, esophageal cancer, gastric cancer and other cancers.	('MTHFR', 'Gene', (0, 5))	('Associated', 'Reg', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('gastric cancer', 'Disease', (267, 281))	('esophageal cancer', 'Disease', 'MESH:D004938', (248, 265))	('rectal cancer', 'Disease', 'MESH:D012004', (233, 246))	('C677T', 'Mutation', 'rs1801133', (6, 11))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('cancers', 'Disease', (292, 299))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('esophageal cancer', 'Disease', (248, 265))	('gastric cancer', 'Disease', 'MESH:D013274', (267, 281))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('Tumor', 'Phenotype', 'HP:0002664', (44, 49))	('MTHFR', 'Gene', '4524', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('C677T', 'Var', (6, 11))	('rectal cancer', 'Disease', (233, 246))	('cancers', 'Disease', 'MESH:D009369', (292, 299))	('CT', 'Chemical', 'MESH:D002251', (163, 165))	('rectal cancer', 'Phenotype', 'HP:0100743', (233, 246))	('gastric cancer', 'Phenotype', 'HP:0012126', (267, 281))
434844	26456456	Recently, a series of reports have investigated the association of the genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and epidermal growth factor receptor (EGFR) genes with the tumor response to pRCT; however, the results were inconsistent and inconclusive.	('tumor', 'Disease', (199, 204))	('EGFR', 'Gene', '1956', (178, 182))	('investigated', 'Reg', (35, 47))	('MTHFR', 'Gene', (133, 138))	('CT', 'Chemical', 'MESH:D002251', (219, 221))	('epidermal growth factor receptor', 'Gene', (144, 176))	('methylenetetrahydrofolate reductase', 'Gene', (96, 131))	('EGFR', 'Gene', (178, 182))	('polymorphisms', 'Var', (79, 92))	('association', 'Interaction', (52, 63))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (96, 131))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('epidermal growth factor receptor', 'Gene', '1956', (144, 176))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('MTHFR', 'Gene', '4524', (133, 138))
434845	26456456	A systematic review and meta-analysis was performed by searching relevant studies about the association of MTHFR and EGFR polymorphisms with the tumor regression grade (TRG) in response to pRCT in databases of PubMed, EMBAS, Web of science, Chinese National Knowledge Infrastructure, and Wanfang database up to March 30, 2015.	('polymorphisms', 'Var', (122, 135))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('EGFR', 'Gene', '1956', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('EGFR', 'Gene', (117, 121))	('MTHFR', 'Gene', '4524', (107, 112))	('tumor', 'Disease', (145, 150))	('MTHFR', 'Gene', (107, 112))	('CT', 'Chemical', 'MESH:D002251', (191, 193))	('association', 'Interaction', (92, 103))
434848	26456456	The pooled analysis results indicated that MTHFR C677T might be correlated with the tumor response to pRCT under the recessive model (CC vs. CTTT) in overall analysis (OR=1.426(1.074-1.894), P=0.014), rectal cancer (OR=1.483(1.102-1.996), P=0.009), and TRG 1-2 vs. 3-5 group (OR=1.423(1.046-1.936), P=0.025), while other polymorphism including MTHFR A1298C, EGFR G497A, and EGFR CA repeat polymorphisms exerted significant association under all genetic models in overall analysis or subgroup analysis.	('MTHFR', 'Gene', (344, 349))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('G497A', 'Var', (363, 368))	('rectal cancer', 'Disease', 'MESH:D012004', (201, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('C677T', 'Mutation', 'rs1801133', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('EGFR', 'Gene', (358, 362))	('CT', 'Chemical', 'MESH:D002251', (104, 106))	('MTHFR', 'Gene', '4524', (43, 48))	('G497A', 'Mutation', 'rs750713244', (363, 368))	('TRG 1', 'Gene', '7195', (253, 258))	('TRG 1', 'Gene', (253, 258))	('EGFR', 'Gene', (374, 378))	('CT', 'Chemical', 'MESH:D002251', (141, 143))	('A1298C', 'Var', (350, 356))	('MTHFR', 'Gene', '4524', (344, 349))	('rectal cancer', 'Disease', (201, 214))	('rectal cancer', 'Phenotype', 'HP:0100743', (201, 214))	('MTHFR', 'Gene', (43, 48))	('EGFR', 'Gene', '1956', (358, 362))	('A1298C', 'Mutation', 'rs1801131', (350, 356))	('tumor', 'Disease', (84, 89))	('EGFR', 'Gene', '1956', (374, 378))
434849	26456456	MTHFR C677T might be correlated with the tumor response to pRCT.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MTHFR', 'Gene', '4524', (0, 5))	('tumor', 'Disease', (41, 46))	('C677T', 'Mutation', 'rs1801133', (6, 11))	('C677T', 'Var', (6, 11))	('MTHFR', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('correlated', 'Reg', (21, 31))	('CT', 'Chemical', 'MESH:D002251', (61, 63))
434857	26456456	There are 2 common polymorphisms in MTHFR - C677T (rs1801133) and A1298C (rs1801131) - that are widely investigated.	('rs1801133', 'Mutation', 'rs1801133', (51, 60))	('C677T', 'Mutation', 'rs1801133', (44, 49))	('MTHFR', 'Gene', (36, 41))	('A1298C (rs1801131) -', 'Var', (66, 86))	('rs1801131', 'Mutation', 'rs1801131', (74, 83))	('rs1801133', 'Var', (51, 60))	('MTHFR', 'Gene', '4524', (36, 41))	('A1298C', 'Mutation', 'rs1801131', (66, 72))
434860	26456456	A polymorphism in the EGFR gene has been reported to lead the substitution of an arginine (Arg) residue by a lysine (Lys) in codon 497 (G497A).	('Lys', 'Chemical', 'MESH:D008239', (117, 120))	('arginine', 'Chemical', 'MESH:D001120', (81, 89))	('lysine', 'Chemical', 'MESH:D008239', (109, 115))	('Arg', 'Chemical', 'MESH:D001120', (91, 94))	('EGFR', 'Gene', '1956', (22, 26))	('substitution', 'Var', (62, 74))	('polymorphism', 'Var', (2, 14))	('G497A', 'Mutation', 'rs750713244', (136, 141))	('EGFR', 'Gene', (22, 26))
434861	26456456	Another polymorphism variant in EGFR is the CA repeats in intron 1 (rs11568315).	('EGFR', 'Gene', '1956', (32, 36))	('rs11568315', 'Mutation', 'rs11568315', (68, 78))	('rs11568315', 'Var', (68, 78))	('EGFR', 'Gene', (32, 36))
434863	26456456	Although a series of studies have been performed to examine the association of MTHFR and EGFR polymorphisms with the tumor response to pRCT, the results were inconsistent and inconclusive.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (89, 93))	('CT', 'Chemical', 'MESH:D002251', (137, 139))	('MTHFR', 'Gene', '4524', (79, 84))	('tumor', 'Disease', (117, 122))	('MTHFR', 'Gene', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('polymorphisms', 'Var', (94, 107))	('association', 'Interaction', (64, 75))
434864	26456456	In the present study, we conducted a meta-analysis to evaluate the association of MTHFR and EGFR polymorphisms with the tumor response to pRCT.	('MTHFR', 'Gene', (82, 87))	('CT', 'Chemical', 'MESH:D002251', (140, 142))	('MTHFR', 'Gene', '4524', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('EGFR', 'Gene', '1956', (92, 96))	('polymorphisms', 'Var', (97, 110))	('EGFR', 'Gene', (92, 96))	('association', 'Interaction', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
434865	26456456	We performed a systematic search for published articles in the database of PubMed, EMBASW, Web of Science, Chinese National Knowledge Infrastructure, and Wanfang on the association of MTHFR or EGFR polymorphisms and the response to preoperative chemoradiotherapy up to March 30, 2015.	('EGFR', 'Gene', '1956', (193, 197))	('association', 'Interaction', (169, 180))	('MTHFR', 'Gene', '4524', (184, 189))	('EGFR', 'Gene', (193, 197))	('MTHFR', 'Gene', (184, 189))	('polymorphisms', 'Var', (198, 211))
434866	26456456	The following keywords and subject terms were used: "the methylenetetrahydrofolate reductase gene OR MTHFR", "Epidermal growth factor receptor OR EGFR", "polymorphism OR polymorphisms", and "Chemoradiation OR chemoradiotherapy OR chemo-radiotherapy OR radio-chemotherapy".	('MTHFR"', 'Gene', (101, 107))	('polymorphisms', 'Var', (170, 183))	('polymorphism', 'Var', (154, 166))	('EGFR', 'Gene', '1956', (146, 150))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (57, 92))	('EGFR', 'Gene', (146, 150))	('Epidermal growth factor receptor', 'Gene', (110, 142))	('methylenetetrahydrofolate reductase', 'Gene', (57, 92))	('Epidermal growth factor receptor', 'Gene', '1956', (110, 142))	('MTHFR"', 'Gene', '4524', (101, 107))
434867	26456456	Inclusion criteria: (1) evaluation of the association between MTHFR C677T, MTHFR A1298C, EGFR G497A, and EGFR CA repeat polymorphisms and response to preoperative chemoradiotherapy; (2) response to chemoradiotherapy was evaluated by tumor regression grade (TRG); (3) genotype frequency data could be obtained to estimate the odds ratio (OR) and 95% confidence interval (CI).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (89, 93))	('tumor', 'Disease', (233, 238))	('MTHFR', 'Gene', (75, 80))	('C677T', 'Mutation', 'rs1801133', (68, 73))	('association', 'Interaction', (42, 53))	('A1298C', 'Mutation', 'rs1801131', (81, 87))	('EGFR', 'Gene', '1956', (105, 109))	('C677T', 'Var', (68, 73))	('MTHFR', 'Gene', '4524', (62, 67))	('G497A', 'Mutation', 'rs750713244', (94, 99))	('EGFR', 'Gene', (105, 109))	('MTHFR', 'Gene', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('MTHFR', 'Gene', '4524', (75, 80))
434869	26456456	Based on the inclusion and exclusion criteria, 2 investigators extracted the following information from all eligible studies: name of first author, year of publication, country of origin, ethnicity, age, sex ratio, cancer type, disease stage, chemotherapy drugs, radiation dose, and genotype frequency in responders and non-responders of MTHFR C677T, MTHFR A1298C, EGFR G497A, and EGFR CA repeat polymorphisms.	('EGFR', 'Gene', (381, 385))	('cancer', 'Disease', (215, 221))	('G497A', 'Mutation', 'rs750713244', (370, 375))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('MTHFR', 'Gene', '4524', (351, 356))	('G497A', 'Var', (370, 375))	('EGFR', 'Gene', (365, 369))	('MTHFR', 'Gene', '4524', (338, 343))	('EGFR', 'Gene', '1956', (365, 369))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('C677T', 'Mutation', 'rs1801133', (344, 349))	('A1298C', 'Mutation', 'rs1801131', (357, 363))	('EGFR', 'Gene', '1956', (381, 385))	('C677T', 'Var', (344, 349))	('MTHFR', 'Gene', (351, 356))	('MTHFR', 'Gene', (338, 343))
434873	26456456	The pooled odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were calculated to assess the strength of the association between MTHFR C677T, MTHFR A1298C, EGFR G497A, and EGFR CA repeat polymorphisms and the response to preoperative chemoradiotherapy.	('MTHFR', 'Gene', (149, 154))	('association', 'Interaction', (129, 140))	('G497A', 'Mutation', 'rs750713244', (181, 186))	('MTHFR', 'Gene', '4524', (162, 167))	('EGFR', 'Gene', '1956', (176, 180))	('G497A', 'Var', (181, 186))	('EGFR', 'Gene', (176, 180))	('A1298C', 'Mutation', 'rs1801131', (168, 174))	('MTHFR', 'Gene', '4524', (149, 154))	('C677T', 'Var', (155, 160))	('C677T', 'Mutation', 'rs1801133', (155, 160))	('EGFR', 'Gene', '1956', (192, 196))	('MTHFR', 'Gene', (162, 167))	('EGFR', 'Gene', (192, 196))
434878	26456456	In the present study we finally analyzed 8 included studies containing 839 cases for MTHFR C677T, 5 studies involving 634 cases for MTHFR A1298C, 3 studies containing 340 cases for EGFR G497A, and 4 studies containing 396 cases for EGFR CA repeat.	('MTHFR', 'Gene', '4524', (85, 90))	('A1298C', 'Mutation', 'rs1801131', (138, 144))	('C677T', 'Var', (91, 96))	('EGFR', 'Gene', (181, 185))	('MTHFR', 'Gene', (132, 137))	('C677T', 'Mutation', 'rs1801133', (91, 96))	('MTHFR', 'Gene', (85, 90))	('G497A', 'Mutation', 'rs750713244', (186, 191))	('MTHFR', 'Gene', '4524', (132, 137))	('EGFR', 'Gene', '1956', (232, 236))	('EGFR', 'Gene', (232, 236))	('EGFR', 'Gene', '1956', (181, 185))
434879	26456456	We firstly analyzed the association of MTHFR C677T with the response to pRCT under 5 genetic models.	('CT', 'Chemical', 'MESH:D002251', (74, 76))	('MTHFR', 'Gene', (39, 44))	('response to pRCT', 'MPA', (60, 76))	('association', 'Interaction', (24, 35))	('MTHFR', 'Gene', '4524', (39, 44))	('C677T', 'Mutation', 'rs1801133', (45, 50))	('C677T', 'Var', (45, 50))
434880	26456456	Overall, the C677T polymorphism was correlated with the response to pRCT in recessive model (CC vs. CTTT, OR=1.426(1.074-1.894), P=0.014, Table 2), but not in allele model, homozygote model, heterozygote model, or dominant model.	('response to', 'MPA', (56, 67))	('C677T', 'Mutation', 'rs1801133', (13, 18))	('correlated', 'Reg', (36, 46))	('C677T', 'Var', (13, 18))	('CT', 'Chemical', 'MESH:D002251', (100, 102))	('CT', 'Chemical', 'MESH:D002251', (70, 72))
434885	26456456	For MTHFR C677T polymorphism, we arrived at almost the same results in all genetic models.	('C677T', 'Var', (10, 15))	('C677T', 'Mutation', 'rs1801133', (10, 15))	('MTHFR', 'Gene', (4, 9))	('MTHFR', 'Gene', '4524', (4, 9))
434887	26456456	was deleted, a significant association was identified between the polymorphism and the response to pRCT under heterozygote model (AC vs. CC).	('response to pRCT', 'MPA', (87, 103))	('CT', 'Chemical', 'MESH:D002251', (101, 103))	('polymorphism', 'Var', (66, 78))
434889	26456456	To evaluate the publication bias among the selected studies, Begg's funnel plot was used for polymorphisms of MTHFR C677T, MTHFR A1298C, and EGFR CA repeat, and symmetrical funnel plots were obtained in all genetic models (and data not shown), indicating lack of publication bias.	('MTHFR', 'Gene', (110, 115))	('MTHFR', 'Gene', '4524', (123, 128))	('EGFR', 'Gene', '1956', (141, 145))	('C677T', 'Mutation', 'rs1801133', (116, 121))	('C677T', 'Var', (116, 121))	('EGFR', 'Gene', (141, 145))	('MTHFR', 'Gene', (123, 128))	('MTHFR', 'Gene', '4524', (110, 115))	('A1298C', 'Mutation', 'rs1801131', (129, 135))	('A1298C', 'Var', (129, 135))
434890	26456456	In the present study, we performed a meta-analysis by pooling 20 studies to investigate the association of MTHFR and EGFR polymorphisms with the tumor response to pRCT in cancers.	('polymorphisms', 'Var', (122, 135))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('EGFR', 'Gene', '1956', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('EGFR', 'Gene', (117, 121))	('MTHFR', 'Gene', '4524', (107, 112))	('CT', 'Chemical', 'MESH:D002251', (165, 167))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('tumor', 'Disease', (145, 150))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('MTHFR', 'Gene', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('association', 'Interaction', (92, 103))
434891	26456456	The results suggested that MTHFR C677T might be correlated with the tumor response, while the polymorphisms of A1298C in MTHFR and G497A and CA repeat in EGFR were not associated with the response.	('tumor', 'Disease', (68, 73))	('EGFR', 'Gene', (154, 158))	('C677T', 'Mutation', 'rs1801133', (33, 38))	('MTHFR', 'Gene', '4524', (27, 32))	('EGFR', 'Gene', '1956', (154, 158))	('MTHFR', 'Gene', '4524', (121, 126))	('A1298C', 'Mutation', 'rs1801131', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('G497A', 'Mutation', 'rs750713244', (131, 136))	('MTHFR', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('correlated', 'Reg', (48, 58))	('MTHFR', 'Gene', (121, 126))	('C677T', 'Var', (33, 38))	('G497A', 'Var', (131, 136))
434897	26456456	Because many studies have determined the association of MTHFR polymorphisms with the tumor response to pRCT, we performed a systematic search in literature databases for related studies and conducted a meta-analysis to investigate the association between MTHFR polymorphisms and the response to pRCT, also including the EGFR polymorphisms.	('tumor', 'Disease', (85, 90))	('CT', 'Chemical', 'MESH:D002251', (105, 107))	('response to pRCT', 'MPA', (283, 299))	('EGFR', 'Gene', '1956', (320, 324))	('association', 'Interaction', (41, 52))	('MTHFR', 'Gene', '4524', (56, 61))	('MTHFR', 'Gene', '4524', (255, 260))	('EGFR', 'Gene', (320, 324))	('polymorphisms', 'Var', (62, 75))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('polymorphisms', 'Var', (261, 274))	('MTHFR', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('MTHFR', 'Gene', (255, 260))	('association', 'Interaction', (235, 246))	('CT', 'Chemical', 'MESH:D002251', (297, 299))
434898	26456456	The results suggested that MTHFR C677T might be correlated with the tumor response to pRCT under the recessive model in overall analysis, rectal cancer, and TRG 1-2 vs. 3-5 group, while other polymorphism exert significant association under all genetic models in overall analysis or subgroup analyses.	('tumor', 'Disease', (68, 73))	('C677T', 'Mutation', 'rs1801133', (33, 38))	('CT', 'Chemical', 'MESH:D002251', (88, 90))	('MTHFR', 'Gene', '4524', (27, 32))	('TRG 1', 'Gene', '7195', (157, 162))	('TRG 1', 'Gene', (157, 162))	('rectal cancer', 'Disease', 'MESH:D012004', (138, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('rectal cancer', 'Disease', (138, 151))	('MTHFR', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('correlated', 'Reg', (48, 58))	('rectal cancer', 'Phenotype', 'HP:0100743', (138, 151))	('C677T', 'Var', (33, 38))
434900	26456456	To the best of our knowledge, this is the first meta-analysis to address the association between MTHFR and EGFR polymorphisms and the response to pRCT, in which we tried to pool all the potential related studies regardless of cancer type.	('EGFR', 'Gene', '1956', (107, 111))	('polymorphisms', 'Var', (112, 125))	('response to pRCT', 'MPA', (134, 150))	('EGFR', 'Gene', (107, 111))	('MTHFR', 'Gene', '4524', (97, 102))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('CT', 'Chemical', 'MESH:D002251', (148, 150))	('MTHFR', 'Gene', (97, 102))	('association', 'Interaction', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
434901	26456456	Firstly, the study number and the sample size were very small, especially for EGFR polymorphisms and esophageal cancer, which also led to the lack of stability of the results for MTHFR A1298C polymorphism.	('esophageal cancer', 'Disease', (101, 118))	('polymorphisms', 'Var', (83, 96))	('MTHFR', 'Gene', (179, 184))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('A1298C', 'Mutation', 'rs1801131', (185, 191))	('MTHFR', 'Gene', '4524', (179, 184))
434902	26456456	In summary, we obtained a comprehensive result from the current meta-analysis that MTHFR C677T polymorphism was correlated with the response to pRCT in overall and in rectal cancer, while MTHFR A1298C and EGFR G497A and CA repeat polymorphisms showed no significant association with the tumor response to pRCT.	('rectal cancer', 'Disease', (167, 180))	('C677T', 'Mutation', 'rs1801133', (89, 94))	('rectal cancer', 'Phenotype', 'HP:0100743', (167, 180))	('EGFR', 'Gene', '1956', (205, 209))	('G497A', 'Mutation', 'rs750713244', (210, 215))	('response to pRCT', 'MPA', (132, 148))	('CT', 'Chemical', 'MESH:D002251', (146, 148))	('MTHFR', 'Gene', '4524', (188, 193))	('correlated with', 'Reg', (112, 127))	('MTHFR', 'Gene', '4524', (83, 88))	('tumor', 'Disease', (287, 292))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('rectal cancer', 'Disease', 'MESH:D012004', (167, 180))	('A1298C', 'Mutation', 'rs1801131', (194, 200))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('C677T', 'Var', (89, 94))	('EGFR', 'Gene', (205, 209))	('MTHFR', 'Gene', (188, 193))	('MTHFR', 'Gene', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('CT', 'Chemical', 'MESH:D002251', (307, 309))
434913	25997063	Among all these extrapulmonary carcinomas, 93.7% of adenocarcinomas exhibited TFF3 positivity, whereas only 2.9% of squamous cell carcinomas were TFF3-positive.	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (116, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('adenocarcinomas', 'Disease', 'MESH:D000230', (52, 67))	('extrapulmonary carcinomas', 'Disease', (16, 41))	('adenocarcinomas', 'Disease', (52, 67))	('extrapulmonary carcinomas', 'Phenotype', 'HP:0032271', (16, 41))	('TFF3', 'Gene', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (116, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('TFF3', 'Gene', '7033', (78, 82))	('positivity', 'Var', (83, 93))	('squamous cell carcinomas', 'Disease', (116, 140))	('extrapulmonary carcinomas', 'Disease', 'MESH:D002277', (16, 41))	('TFF3', 'Gene', (146, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('TFF3', 'Gene', '7033', (146, 150))
434914	25997063	Totally, 92.9% of both pulmonary and extrapulmonary adenocarcinomas exhibited TFF3 positivity, whereas only 1.5% of squamous cell carcinomas were TFF3-positive.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (116, 140))	('squamous cell carcinomas', 'Disease', (116, 140))	('TFF3', 'Gene', '7033', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (116, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('TFF3', 'Gene', (146, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('adenocarcinomas', 'Disease', 'MESH:D000230', (52, 67))	('positivity', 'Var', (83, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('adenocarcinomas', 'Disease', (52, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('exhibited', 'Reg', (68, 77))	('TFF3', 'Gene', (78, 82))	('TFF3', 'Gene', '7033', (146, 150))
434980	25997063	We next examined the mRNA levels of TFF3 by qPCR in 16 NSCLC cell lines, 11 of which have been reported to be derived from lung ADC, 4 of which have been reported to be derived from lung SCC and 1 of which has been reported to be derived from lung ASC.	('TFF3', 'Gene', '7033', (36, 40))	('NSCLC', 'Disease', (55, 60))	('SCC', 'Gene', (187, 190))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('SCC', 'Phenotype', 'HP:0002860', (187, 190))	('SCC', 'Gene', '6317', (187, 190))	('qPCR', 'Var', (44, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('TFF3', 'Gene', (36, 40))
434983	25997063	The mRNAs of the 4 markers of the squamous lineage (KRT5, KRT6A, KRT6B, and TP63) were all highly expressed in the NSCLC lines identified to be of squamous origin (H697, H1270, LC-1/sq, and LC-1F) and adenosquamous origin (H596) (Figure 2A, Supplemental Digital Content 3, http://links.lww.com/MD/A268).	('H697', 'Var', (164, 168))	('TP63', 'Gene', (76, 80))	('TP63', 'Gene', '8626', (76, 80))	('KRT5', 'Gene', '3852', (52, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))	('KRT6B', 'Gene', '3854', (65, 70))	('NSCLC', 'Disease', (115, 120))	('KRT6A', 'Gene', '3853', (58, 63))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('KRT5', 'Gene', (52, 56))	('H697', 'CellLine', 'CVCL:0079', (164, 168))	('H1270', 'CellLine', 'CVCL:9E87', (170, 175))	('KRT6B', 'Gene', (65, 70))	('H1270', 'Var', (170, 175))	('KRT6A', 'Gene', (58, 63))
434990	25997063	siRNA-mediated depletion of TFF3 expression in NCI-H1975 or HCC-2935 cells resulted in decreased mRNA levels of TTF-1 relative to their vector control cells.	('depletion', 'Var', (15, 24))	('decreased', 'NegReg', (87, 96))	('NCI-H1975', 'CellLine', 'CVCL:1511', (47, 56))	('TFF3', 'Gene', (28, 32))	('TTF-1', 'Gene', '7080', (112, 117))	('TTF-1', 'Gene', (112, 117))	('HCC-2935', 'CellLine', 'CVCL:1265', (60, 68))	('TFF3', 'Gene', '7033', (28, 32))
434991	25997063	mRNA levels of KRT7 were slightly increased in NCI-H1975 and slightly decreased in HCC-2935 cells upon siRNA-mediated depletion of TFF3 (Figure 3A).	('TFF3', 'Gene', '7033', (131, 135))	('NCI-H1975', 'CellLine', 'CVCL:1511', (47, 56))	('depletion', 'MPA', (118, 127))	('decreased', 'NegReg', (70, 79))	('HCC-2935', 'CellLine', 'CVCL:1265', (83, 91))	('NCI-H1975', 'Var', (47, 56))	('TFF3', 'Gene', (131, 135))	('mRNA levels of', 'MPA', (0, 14))	('KRT7', 'Gene', '3855', (15, 19))	('increased', 'PosReg', (34, 43))	('KRT7', 'Gene', (15, 19))
435026	25997063	We observed a high frequency of TFF3 positivity in cervical ADC (31/35, 88.6%), esophageal ADC (19/20, 95%), colorectal ADC (29/29, 100%), and gastric ADC (25/27, 92.6%).	('TFF3', 'Gene', '7033', (32, 36))	('cervical ADC', 'Disease', (51, 63))	('esophageal ADC', 'Disease', (80, 94))	('gastric ADC', 'Disease', (143, 154))	('positivity', 'Var', (37, 47))	('TFF3', 'Gene', (32, 36))	('colorectal ADC', 'Disease', (109, 123))
435060	20095993	demonstrated increased postoperative pulmonary complications in patients receiving preoperative chemoradiation for esophageal cancer when the V10 was >=40% and when the V15 was >=30% of lung volume.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('V10', 'Var', (142, 145))	('patients', 'Species', '9606', (64, 72))	('pulmonary complications', 'Phenotype', 'HP:0006532', (37, 60))	('increased postoperative pulmonary complications', 'Disease', 'MESH:D011183', (13, 60))	('esophageal cancer', 'Disease', (115, 132))	('increased postoperative pulmonary complications', 'Disease', (13, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('>=40%', 'Var', (150, 155))
435105	19463183	Polymorphism in COX-2 modifies the inverse association between Helicobacter pylori seropositivity and esophageal squamous cell carcinoma risk in Taiwan: a case control study Overexpression of Cyclooxygenase-2 (COX-2) was observed in many types of cancers, including esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', (266, 300))	('Cyclooxygenase-2', 'Gene', '5743', (192, 208))	('Helicobacter pylori', 'Species', '210', (63, 82))	('COX-2', 'Gene', '5743', (210, 215))	('COX-2', 'Gene', (16, 21))	('Cyclooxygenase-2', 'Gene', (192, 208))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (76, 97))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('COX-2', 'Gene', '5743', (16, 21))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (266, 300))	('inverse', 'NegReg', (35, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (277, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('COX-2', 'Gene', (210, 215))	('Polymorphism', 'Var', (0, 12))	('Helicobacter pylori seropositivity', 'Phenotype', 'HP:0005202', (63, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))
435109	19463183	The purpose of this study was to evaluate the association and interaction between COX-2 single nucleotide polymorphism (SNP), H. pylori infection and the risk of developing ESCC.	('interaction', 'Interaction', (62, 73))	('infection', 'Disease', (136, 145))	('ESCC', 'Disease', (173, 177))	('infection', 'Disease', 'MESH:D007239', (136, 145))	('H. pylori infection', 'Phenotype', 'HP:0005202', (126, 145))	('H. pylori', 'Species', '210', (126, 135))	('COX-2', 'Gene', (82, 87))	('association', 'Interaction', (46, 57))	('COX-2', 'Gene', '5743', (82, 87))	('single nucleotide polymorphism', 'Var', (88, 118))
435114	19463183	In analysis adjusting for the covariates and confounders, H. pylori seropositivity was found to be inversely association with the ESCC development (adjusted OR: 0.5, 95% CI: 0.3 - 0.9).	('H. pylori', 'Gene', (58, 67))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (61, 82))	('H. pylori', 'Species', '210', (58, 67))	('inversely', 'NegReg', (99, 108))	('seropositivity', 'Var', (68, 82))	('association', 'Interaction', (109, 120))	('ESCC development', 'Disease', (130, 146))
435128	19463183	Several naturally occurring single nucleotide polymorphism (SNP) in the COX-2 promoter region were observed and its distribution varied in different ethnics.	('single nucleotide polymorphism', 'Var', (28, 58))	('COX-2', 'Gene', (72, 77))	('COX-2', 'Gene', '5743', (72, 77))
435159	19463183	The Hardy-Weinberg equilibrium test was used to assess the discrepancies between the observed and the expected COX-2 1195G   A genotype frequencies among control subjects.	('COX-2', 'Gene', '5743', (111, 116))	('COX-2', 'Gene', (111, 116))	('1195G   A', 'Var', (117, 126))
435169	19463183	After controlling for the covariates, H. pylori seropositivity was found to confer a 0.5-fold risk (95% CI: 0.3 - 0.9) of developing ESCC.	('H. pylori', 'Gene', (38, 47))	('ESCC', 'Disease', (133, 137))	('H. pylori', 'Species', '210', (38, 47))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (41, 62))	('seropositivity', 'Var', (48, 62))
435172	19463183	The distribution of COX-2 -1195 polymorphism both for the cases and controls was shown in Table 3.	('COX-2', 'Gene', (20, 25))	('polymorphism', 'Var', (32, 44))	('COX-2', 'Gene', '5743', (20, 25))
435181	19463183	Alternatively, H. pylori seropositivity conveyed a notably inverse effect among patients with COX-2 AA polymorphism (AOR ratio: 0.3, 95% CI: 0.1 - 0.9).	('COX-2', 'Gene', (94, 99))	('patients', 'Species', '9606', (80, 88))	('COX-2', 'Gene', '5743', (94, 99))	('AA polymorphism', 'Var', (100, 115))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (18, 39))	('inverse', 'NegReg', (59, 66))	('H. pylori', 'Species', '210', (15, 24))	('H. pylori', 'Disease', (15, 24))
435184	19463183	Several studies have suggested the association between overexpression of COX-2 and ESCC.	('COX-2', 'Gene', '5743', (73, 78))	('overexpression', 'Var', (55, 69))	('COX-2', 'Gene', (73, 78))	('ESCC', 'Disease', (83, 87))
435185	19463183	According the previous study, COX-2 -1195G/A polymorphism, a functional SNP disclosed in Chinese populations, could modified not only COX-2 mRNA level, but the risk of ESCC.	('-1195G/A', 'Mutation', 'rs689466', (36, 44))	('polymorphism', 'Var', (45, 57))	('COX-2', 'Gene', (30, 35))	('COX-2', 'Gene', (134, 139))	('ESCC', 'Disease', (168, 172))	('modified', 'Reg', (116, 124))	('COX-2', 'Gene', '5743', (30, 35))	('COX-2', 'Gene', '5743', (134, 139))
435195	19463183	This observation suggests that COX-2 expression in low esophageal region is lower under H. pylori seropositive status.	('H. pylori', 'Disease', (88, 97))	('COX-2', 'Gene', '5743', (31, 36))	('lower', 'NegReg', (76, 81))	('seropositive status', 'Var', (98, 117))	('expression', 'MPA', (37, 47))	('H. pylori', 'Species', '210', (88, 97))	('COX-2', 'Gene', (31, 36))
435200	19463183	These findings suggest that the protective effect to lower third ESCC risk provided by H. pylori seropositivity may be mediated by influencing COX-2 AA genotype expression.	('COX-2', 'Gene', '5743', (143, 148))	('lower third ESCC', 'Disease', (53, 69))	('H. pylori', 'Gene', (87, 96))	('H. pylori', 'Species', '210', (87, 96))	('influencing', 'Reg', (131, 142))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (90, 111))	('COX-2', 'Gene', (143, 148))	('seropositivity', 'Var', (97, 111))
435208	19463183	This study provided evidence that both COX-2 -1195G/A polymorphism and H. pylori infection had influence in risk of ESCC in Taiwanese population.	('infection', 'Disease', 'MESH:D007239', (81, 90))	('ESCC', 'Disease', (116, 120))	('influence', 'Reg', (95, 104))	('COX-2', 'Gene', (39, 44))	('-1195G/A', 'Mutation', 'rs689466', (45, 53))	('polymorphism', 'Var', (54, 66))	('COX-2', 'Gene', '5743', (39, 44))	('H. pylori infection', 'Phenotype', 'HP:0005202', (71, 90))	('risk', 'Reg', (108, 112))	('H. pylori', 'Species', '210', (71, 80))	('infection', 'Disease', (81, 90))
435211	19463183	These findings suggest that COX-2 -1195 polymorphism plays a role in modifying the inverse association between H. pylori infection and risk of ESCC.	('COX-2', 'Gene', '5743', (28, 33))	('infection', 'Disease', (121, 130))	('ESCC', 'Disease', (143, 147))	('infection', 'Disease', 'MESH:D007239', (121, 130))	('polymorphism', 'Var', (40, 52))	('H. pylori', 'Species', '210', (111, 120))	('H. pylori', 'Disease', (111, 120))	('H. pylori infection', 'Phenotype', 'HP:0005202', (111, 130))	('COX-2', 'Gene', (28, 33))
435263	31442498	The first is a 65-year-old man with cG2T4N1M0 adenocarcinoma (Table 3, Patient 2).	('adenocarcinoma', 'Disease', (46, 60))	('cG2T4N1M0', 'Var', (36, 45))	('adenocarcinoma', 'Disease', 'MESH:D000230', (46, 60))	('Patient', 'Species', '9606', (71, 78))	('man', 'Species', '9606', (27, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
435264	31442498	The second was a 60-year-old man (Table 3, Patient 3) with cG3T2N1M0 adenocarcinoma.	('man', 'Species', '9606', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('Patient', 'Species', '9606', (43, 50))	('cG3T2N1M0', 'Var', (59, 68))	('adenocarcinoma', 'Disease', (69, 83))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))
435266	31442498	The first is a 74-year-old man with diabetes who had cG3T2N0M0 adenocarcinoma (Table 3, Patient 4).	('man', 'Species', '9606', (27, 30))	('cG3T2N0M0', 'Var', (53, 62))	('diabetes', 'Disease', (36, 44))	('Patient', 'Species', '9606', (88, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('adenocarcinoma', 'Disease', (63, 77))	('diabetes', 'Disease', 'MESH:D003920', (36, 44))	('adenocarcinoma', 'Disease', 'MESH:D000230', (63, 77))
435267	31442498	The second patient, a 44-year-old woman with a history of smoking, had a cG2T2N0M0 adenocarcinoma (Table 3, Patient 5).	('Patient', 'Species', '9606', (108, 115))	('adenocarcinoma', 'Disease', (83, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('patient', 'Species', '9606', (11, 18))	('woman', 'Species', '9606', (34, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('cG2T2N0M0', 'Var', (73, 82))
435394	31385574	As the only member of the CX3C family, CX3CL1 can increase the adhesion between tumor cells and supply the immune cells [T cells and natural killer (NK) cells] to local tumor, thus reducing infiltration and metastasis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('adhesion', 'CPA', (63, 71))	('reducing', 'NegReg', (181, 189))	('infiltration', 'CPA', (190, 202))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (80, 85))	('increase', 'PosReg', (50, 58))	('tumor', 'Disease', (169, 174))	('CX3CL1', 'Var', (39, 45))
435395	31385574	Meanwhile, CX3CL1 is able to enhance the adhesion between tumor cells and vascular endothelial cells, induce tumor vascularization and mediate the infiltration and metastasis of tumor.	('adhesion', 'CPA', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (178, 183))	('metastasis of tumor', 'Disease', 'MESH:D009362', (164, 183))	('induce', 'PosReg', (102, 108))	('CX3CL1', 'Var', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('infiltration', 'CPA', (147, 159))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('enhance', 'PosReg', (29, 36))	('metastasis of tumor', 'Disease', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mediate', 'Reg', (135, 142))	('tumor', 'Disease', (109, 114))
435396	31385574	reported that the CX3CL1 expression in breast cancer cells can strengthen the chemotaxis on T cells, NK cells and dendritic cells (DCs), so it can serve as a prognostic marker and novel therapeutic target of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('strengthen', 'PosReg', (63, 73))	('chemotaxis on T cells', 'CPA', (78, 99))	('CX3CL1 expression', 'Var', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', (208, 221))	('breast cancer', 'Disease', (39, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))
435421	31385574	In conclusion, CX3CL1, CXCL-12, CCL20, and other chemokines may be applied to assess the conditions of EC and predict the recurrence risk and blocking or eliminating these highly expressed chemokines may prevent the metastasis of EC, providing new approaches for treatment.	('CCL20', 'Gene', (32, 37))	('CCL20', 'Gene', '6364', (32, 37))	('men', 'Species', '9606', (268, 271))	('CXCL-12', 'Gene', '6387', (23, 30))	('blocking', 'Var', (142, 150))	('eliminating', 'NegReg', (154, 165))	('CXCL-12', 'Gene', (23, 30))	('metastasis', 'CPA', (216, 226))	('prevent', 'NegReg', (204, 211))
435423	31164636	Potent and specific MTH1 inhibitors targeting gastric cancer Human mutT homolog 1(MTH1), the oxidized dNTP pool sanitizer enzyme, has been reported to be highly expressed in various malignant tumors.	('mutT homolog 1', 'Gene', '4521', (67, 81))	('Human', 'Species', '9606', (61, 66))	('MTH1', 'Gene', '4521', (82, 86))	('gastric cancer', 'Disease', (46, 60))	('MTH1', 'Gene', '4521', (20, 24))	('MTH1', 'Gene', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('mutT homolog 1', 'Gene', (67, 81))	('malignant tumors', 'Disease', (182, 198))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('malignant tumors', 'Disease', 'MESH:D018198', (182, 198))	('inhibitors', 'Var', (25, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('dNTP', 'Chemical', 'MESH:D010278', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('MTH1', 'Gene', (82, 86))
435426	31164636	Using an in vitro MTH1 inhibitor screening system, the compounds available in our laboratory were screened and the small molecules containing 5-cyano-6-phenylpyrimidine structure were firstly found to show potently and specifically inhibitory effect on MTH1, especially compound MI-743 with IC50 = 91.44 +- 1.45 nM.	('5-cyano-6-phenylpyrimidine', 'Chemical', '-', (142, 168))	('inhibitory effect', 'NegReg', (232, 249))	('MTH1', 'Gene', (18, 22))	('5-cyano-6-phenylpyrimidine', 'Var', (142, 168))	('MTH1', 'Gene', '4521', (18, 22))	('MI-743', 'Chemical', '-', (279, 285))	('MTH1', 'Gene', (253, 257))	('MTH1', 'Gene', '4521', (253, 257))
435428	31164636	Moreover, MI-743 could not only inhibit cell proliferation in up to 16 cancer cell lines, especially gastric cancer cells HGC-27 and MGC-803, but also significantly induce MTH1-related 8-oxo-dG accumulation and DNA damage.	('inhibit', 'NegReg', (32, 39))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('DNA damage', 'MPA', (211, 221))	('MI-743', 'Var', (10, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cell proliferation', 'CPA', (40, 58))	('8-oxo-dG', 'Chemical', 'MESH:C067134', (185, 193))	('gastric cancer', 'Disease', (101, 115))	('HGC-27', 'CellLine', 'CVCL:1279', (122, 128))	('MTH1', 'Gene', '4521', (172, 176))	('MTH1', 'Gene', (172, 176))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('induce', 'PosReg', (165, 171))	('MI-743', 'Chemical', '-', (10, 16))
435429	31164636	Furthermore, the growth of xenograft tumours derived by injection of MGC-803 cells in nude mice was also significantly inhibited by MI-743 treatment.	('nude mice', 'Species', '10090', (86, 95))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('inhibited', 'NegReg', (119, 128))	('atm', 'Gene', '472', (142, 145))	('MI-743', 'Var', (132, 138))	('atm', 'Gene', (142, 145))	('xenograft tumours', 'Disease', (27, 44))	('MI-743', 'Chemical', '-', (132, 138))	('xenograft tumours', 'Disease', 'MESH:D009369', (27, 44))
435430	31164636	Importantly, MTH1 knockdown by siRNA in those two gastric cancer cells exhibited the similar findings.	('knockdown', 'Var', (18, 27))	('MTH1', 'Gene', '4521', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('MTH1', 'Gene', (13, 17))
435432	31164636	Small molecule MI-743 with 5-cyano-6-phenylpyrimidine structure may serve as a novel lead compound targeting the overexpressed MTH1 for gastric cancer treatment.	('atm', 'Gene', '472', (154, 157))	('MI-743', 'Var', (15, 21))	('MTH1', 'Gene', '4521', (127, 131))	('atm', 'Gene', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('gastric cancer', 'Disease', (136, 150))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('5-cyano-6-phenylpyrimidine', 'Chemical', '-', (27, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('MTH1', 'Gene', (127, 131))	('MI-743', 'Chemical', '-', (15, 21))
435442	31164636	A following article reported that the cytoxicity of TH588 may be related to its off-target effects to tubulin rather than MTH1.	('toxicity', 'Disease', (40, 48))	('MTH1', 'Gene', '4521', (122, 126))	('TH588', 'Var', (52, 57))	('tubulin', 'Protein', (102, 109))	('toxicity', 'Disease', 'MESH:D064420', (40, 48))	('TH588', 'Chemical', '-', (52, 57))	('MTH1', 'Gene', (122, 126))
435455	31164636	Moreover, a novel potent and specific MTH1 inhibitor MI-743 with 5-cyano-6-phenylpyrimidine structure was firstly found and it could obviously induce the MTH1-related 8-oxo-dG accumulation, DNA damage and proliferation inhibition in two MTH1 highly expressed gastric cancer cell lines.	('MI-743', 'Var', (53, 59))	('MTH1', 'Gene', (154, 158))	('gastric cancer', 'Disease', (259, 273))	('MTH1', 'Gene', (38, 42))	('proliferation inhibition', 'CPA', (205, 229))	('DNA damage', 'MPA', (190, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (259, 273))	('MTH1', 'Gene', '4521', (154, 158))	('MTH1', 'Gene', '4521', (38, 42))	('induce', 'PosReg', (143, 149))	('MTH1', 'Gene', '4521', (237, 241))	('MTH1', 'Gene', (237, 241))	('gastric cancer', 'Phenotype', 'HP:0012126', (259, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('8-oxo-dG', 'Chemical', 'MESH:C067134', (167, 175))	('5-cyano-6-phenylpyrimidine', 'Chemical', '-', (65, 91))	('MI-743', 'Chemical', '-', (53, 59))
435471	31164636	Considering the elevated levels of MTH1 in our tested human tumor tissues and cancer cell lines, as well as the reported significance of this protein in cancer development, small molecule inhibitors targeting MTH1 has been recognized as a novel target-based anti-cancer strategy.	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (263, 269))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Disease', (78, 84))	('inhibitors', 'Var', (188, 198))	('small molecule inhibitors', 'Var', (173, 198))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('human', 'Species', '9606', (54, 59))	('MTH1', 'Gene', (209, 213))	('MTH1', 'Gene', '4521', (209, 213))	('MTH1', 'Gene', (35, 39))	('MTH1', 'Gene', '4521', (35, 39))
435473	31164636	MTH1 recombinant protein and its mutant E56A were expressed and purified (Supplementary Fig.	('E56A', 'Var', (40, 44))	('E56A', 'Mutation', 'p.E56A', (40, 44))	('MTH1', 'Gene', '4521', (0, 4))	('MTH1', 'Gene', (0, 4))
435477	31164636	After further optimizing and screening, two potent compounds MI-743 (IC50 = 91.44 +- 1.45 nM) and MI-401 (IC50 = 461.32 +- 2.67 nM) were selected for the following experiments, with compound MI-929 (IC50 > 50 microM) as a negative control (Fig.	('MI', 'Chemical', 'MESH:C011506', (191, 193))	('MI-743', 'Chemical', '-', (61, 67))	('MI', 'Chemical', 'MESH:C011506', (61, 63))	('MI', 'Chemical', 'MESH:C011506', (98, 100))	('MI-401', 'Var', (98, 104))	('MI-743', 'Var', (61, 67))
435480	31164636	Thus, type A pose with the highest score (-10.495) was selected as the best docking conformation, which included some reported critical residues (Asp119, Asp120 and Asn33) in MTH1 active binding pocket.	('Asp120', 'Chemical', '-', (154, 160))	('MTH1', 'Gene', '4521', (175, 179))	('Asp119', 'Var', (146, 152))	('Asp120', 'Var', (154, 160))	('Asn33', 'Chemical', '-', (165, 170))	('Asp119', 'Chemical', '-', (146, 152))	('Asn33', 'Var', (165, 170))	('MTH1', 'Gene', (175, 179))
435485	31164636	The propargyl group occupies a hydrophobic cavity surrounded by Phe74, Phe139, Phe72, Phe27, Met81 and Gly141 residues.	('Phe74', 'Chemical', '-', (64, 69))	('Phe72', 'Chemical', '-', (79, 84))	('Phe72', 'Var', (79, 84))	('Met81', 'Var', (93, 98))	('Gly141 residues', 'Var', (103, 118))	('Phe27', 'Var', (86, 91))	('Gly141', 'Chemical', '-', (103, 109))	('Phe139', 'Var', (71, 77))	('Phe139', 'Chemical', '-', (71, 77))	('Phe74', 'Var', (64, 69))	('Met81', 'Chemical', '-', (93, 98))	('Phe27', 'Chemical', '-', (86, 91))
435488	31164636	To further determine the key residues of compound MI-743 binding in the active site of MTH1, the mutations of MTH1 (Asp119 to Ala119, Asp120 to Ala120, Asn33 to Ala33 and Trp117 to Ala117) were carried out before molecular docking study, respectively.	('mutations', 'Var', (97, 106))	('Ala117', 'Chemical', '-', (181, 187))	('MTH1', 'Gene', (87, 91))	('MTH1', 'Gene', (110, 114))	('MTH1', 'Gene', '4521', (87, 91))	('Asp119 to', 'Var', (116, 125))	('Trp117', 'Chemical', '-', (171, 177))	('MTH1', 'Gene', '4521', (110, 114))	('Asp120 to', 'Var', (134, 143))	('Trp117 to', 'Var', (171, 180))	('Ala33', 'Chemical', '-', (161, 166))	('Asn33', 'Chemical', '-', (152, 157))	('Ala119', 'Chemical', '-', (126, 132))	('Asp119', 'Chemical', '-', (116, 122))	('Asn33 to', 'Var', (152, 160))	('Ala120', 'Chemical', '-', (144, 150))	('MI-743', 'Chemical', '-', (50, 56))	('Asp120', 'Chemical', '-', (134, 140))
435490	31164636	2e, f, the root mean square deviation (RMSD) results of protein (MTH1) from the wild-type and mutant systems and ligand (MI-743) tend to be stable after 30 ns, which suggested that the systems were equilibrated.	('MTH1', 'Gene', (65, 69))	('MTH1', 'Gene', '4521', (65, 69))	('mutant', 'Var', (94, 100))	('RMSD', 'Disease', 'None', (39, 43))	('RMSD', 'Disease', (39, 43))	('MI-743', 'Chemical', '-', (121, 127))
435491	31164636	In the modeled compound MI-743-MTH1 D119A, D120A, N33A and W117A complexes, the number of the hydrogen bonds are decreased, when compared with the wild-type model.	('W117A', 'SUBSTITUTION', 'None', (59, 64))	('W117A', 'Var', (59, 64))	('hydrogen bonds', 'MPA', (94, 108))	('N33A', 'Var', (50, 54))	('MI-743', 'Chemical', '-', (24, 30))	('D120A', 'Mutation', 'p.D120A', (43, 48))	('hydrogen', 'Chemical', 'MESH:D006859', (94, 102))	('MTH1', 'Gene', (31, 35))	('MTH1', 'Gene', '4521', (31, 35))	('D119A', 'Mutation', 'p.D119A', (36, 41))	('N33A', 'Mutation', 'p.N33A', (50, 54))	('decreased', 'NegReg', (113, 122))	('D120A', 'Var', (43, 48))
435492	31164636	These findings indicate that the residues of Asp119, Asp120, Asn33 and Trp117 of MTH1 may be crucial for binding with compound MI-743.	('MTH1', 'Gene', (81, 85))	('Asn33', 'Chemical', '-', (61, 66))	('Asp120', 'Var', (53, 59))	('MTH1', 'Gene', '4521', (81, 85))	('Asp119', 'Chemical', '-', (45, 51))	('Asn33', 'Var', (61, 66))	('Trp117', 'Chemical', '-', (71, 77))	('MI-743', 'Chemical', '-', (127, 133))	('Trp117', 'Var', (71, 77))	('Asp120', 'Chemical', '-', (53, 59))	('Asp119', 'Var', (45, 51))	('binding', 'Interaction', (105, 112))
435493	31164636	Furthermore, the binding free energies of wild-type and D119A, D120A, N33A, W117A mutations on structure of compound MI-743-MTH1 complexes were calculated by MM/PBSA module in AmberTools14 package.	('N33A', 'Var', (70, 74))	('D120A', 'Var', (63, 68))	('binding', 'Interaction', (17, 24))	('D119A', 'Mutation', 'p.D119A', (56, 61))	('MTH1', 'Gene', (124, 128))	('D119A', 'Var', (56, 61))	('W117A', 'SUBSTITUTION', 'None', (76, 81))	('MTH1', 'Gene', '4521', (124, 128))	('MI-743', 'Chemical', '-', (117, 123))	('W117A', 'Var', (76, 81))	('N33A', 'Mutation', 'p.N33A', (70, 74))	('D120A', 'Mutation', 'p.D120A', (63, 68))	('PBSA', 'Chemical', 'MESH:C437084', (161, 165))	('complexes', 'Interaction', (129, 138))
435495	31164636	2k), the affinities of MI-743 binding with the D119A, D120A, and N33A mutated MTH1 were decreased to 89.75, 68.48 and 96.25%, this value was increased to 1.24 folds in the W117A mutated MTH1 system, which suggested that Asp119, Asp120 and Asn33 of MTH1 were crucial residues when binding to compound MI-743.	('N33A', 'Mutation', 'p.N33A', (65, 69))	('MI-743', 'Chemical', '-', (300, 306))	('decreased', 'NegReg', (88, 97))	('Asp120', 'Chemical', '-', (228, 234))	('MTH1', 'Gene', (78, 82))	('Asn33', 'Chemical', '-', (239, 244))	('D119A', 'Var', (47, 52))	('affinities', 'MPA', (9, 19))	('MTH1', 'Gene', '4521', (78, 82))	('W117A', 'SUBSTITUTION', 'None', (172, 177))	('MI-743', 'Chemical', '-', (23, 29))	('N33A mutated', 'Var', (65, 77))	('MI-743', 'Gene', (23, 29))	('D119A', 'Mutation', 'p.D119A', (47, 52))	('Asp119', 'Chemical', '-', (220, 226))	('W117A', 'Var', (172, 177))	('D120A', 'Mutation', 'p.D120A', (54, 59))	('MTH1', 'Gene', (186, 190))	('MTH1', 'Gene', '4521', (186, 190))	('MTH1', 'Gene', '4521', (248, 252))	('MTH1', 'Gene', (248, 252))	('binding', 'Interaction', (30, 37))	('D120A', 'Var', (54, 59))
435497	31164636	Similar to MI-743, MI-401 can form hydrogen bonds and pi-pi stacking interaction with MTH1 (Supplementary Fig.	('form', 'Reg', (30, 34))	('MI-401', 'Var', (19, 25))	('MI', 'Chemical', 'MESH:C011506', (19, 21))	('pi-pi stacking', 'CPA', (54, 68))	('hydrogen', 'Chemical', 'MESH:D006859', (35, 43))	('hydrogen bonds', 'CPA', (35, 49))	('MTH1', 'Gene', (86, 90))	('MI-743', 'Chemical', '-', (11, 17))	('MTH1', 'Gene', '4521', (86, 90))	('MI', 'Chemical', 'MESH:C011506', (11, 13))
435499	31164636	Therefore, MI-401 shows moderate activity when compared with MI-743.	('MI-401', 'Var', (11, 17))	('MI', 'Chemical', 'MESH:C011506', (61, 63))	('MI-743', 'Chemical', '-', (61, 67))	('activity', 'MPA', (33, 41))	('MI', 'Chemical', 'MESH:C011506', (11, 13))
435501	31164636	5D), compared with those values in MI-743-MTH1, further indicating the different binding activity between compounds MI-743 or MI-401 and MTH1.	('MTH1', 'Gene', '4521', (137, 141))	('MI-743', 'Chemical', '-', (116, 122))	('MI-743', 'Var', (116, 122))	('MI', 'Chemical', 'MESH:C011506', (126, 128))	('MTH1', 'Gene', (42, 46))	('MI', 'Chemical', 'MESH:C011506', (116, 118))	('MI-401', 'Var', (126, 132))	('MTH1', 'Gene', '4521', (42, 46))	('MI', 'Chemical', 'MESH:C011506', (35, 37))	('MI-743', 'Chemical', '-', (35, 41))	('binding', 'Interaction', (81, 88))	('MTH1', 'Gene', (137, 141))
435502	31164636	In order to further testify the specificity of compounds MI-743 and MI-401 on MTH1 rather than other 8-oxo-dGTP scavengers: human mutT homolog 2 (MTH2), human 8-oxoguanine glycosylase 1 (OGG1) and human mutY homolog (MUTYH) at cellular level, the cellular thermal shift assay (CETSA) was performed.	('OGG1', 'Gene', (187, 191))	('OGG1', 'Gene', '4968', (187, 191))	('MTH2', 'Gene', (146, 150))	('MI', 'Chemical', 'MESH:C011506', (68, 70))	('MUTYH', 'Gene', '4595', (217, 222))	('human', 'Species', '9606', (153, 158))	('MTH1', 'Gene', (78, 82))	('MTH1', 'Gene', '4521', (78, 82))	('MI', 'Chemical', 'MESH:C011506', (57, 59))	('8-oxoguanine glycosylase 1', 'Gene', (159, 185))	('8-oxo-dGTP', 'Chemical', 'MESH:C078206', (101, 111))	('MTH2', 'Gene', '55270', (146, 150))	('mutT homolog 2', 'Gene', '55270', (130, 144))	('MI-401', 'Var', (68, 74))	('human', 'Species', '9606', (197, 202))	('8-oxoguanine glycosylase 1', 'Gene', '4968', (159, 185))	('MI-743', 'Chemical', '-', (57, 63))	('MUTYH', 'Gene', (217, 222))	('human', 'Species', '9606', (124, 129))	('mutT homolog 2', 'Gene', (130, 144))	('MI-743', 'Var', (57, 63))
435503	31164636	2c, after compound MI-743 treatment, MTH1 was particularly stable until the incubation temperature was increased to 61  C, similar to that of the positive compound TH588 or (S)-crizotinib treatment.	('atm', 'Gene', (191, 194))	('MI-743', 'Chemical', '-', (19, 25))	('atm', 'Gene', '472', (29, 32))	('atm', 'Gene', (29, 32))	('atm', 'Gene', '472', (191, 194))	('(S)-crizotinib', 'Chemical', 'MESH:D000077547', (173, 187))	('compound MI-743', 'Var', (10, 25))	('TH588', 'Chemical', '-', (164, 169))	('MTH1', 'Gene', '4521', (37, 41))	('MTH1', 'Gene', (37, 41))
435504	31164636	However, after compound MI-401 or MI-929 treatment, the temperature of MTH1 degradation was significantly decreased to 49  C, similar to the negative control (Fig.	('decreased', 'NegReg', (106, 115))	('atm', 'Gene', (44, 47))	('atm', 'Gene', '472', (44, 47))	('MI', 'Chemical', 'MESH:C011506', (34, 36))	('MI', 'Chemical', 'MESH:C011506', (24, 26))	('compound MI-401', 'Var', (15, 30))	('MTH1', 'Gene', '4521', (71, 75))	('MTH1', 'Gene', (71, 75))	('MI-929', 'Var', (34, 40))	('temperature', 'MPA', (56, 67))
435509	31164636	Given that compound MI-743 can specifically target MTH1 at cellular level and in vitro, the cytotoxicity of MI-743 on cancer cells was measured, accompanied by compounds MI-929, TH588 and (S)-crizotinib.	('cancer', 'Disease', (118, 124))	('MI', 'Chemical', 'MESH:C011506', (170, 172))	('cytotoxicity', 'Disease', (92, 104))	('MTH1', 'Gene', '4521', (51, 55))	('MTH1', 'Gene', (51, 55))	('MI', 'Chemical', 'MESH:C011506', (20, 22))	('MI-743', 'Chemical', '-', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (92, 104))	('TH588', 'Chemical', '-', (178, 183))	('MI', 'Chemical', 'MESH:C011506', (108, 110))	('MI-743', 'Chemical', '-', (108, 114))	('MI-743', 'Var', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('(S)-crizotinib', 'Chemical', 'MESH:D000077547', (188, 202))
435510	31164636	3a, after treatment with these four compounds for 72 h, contrary to MI-929 but similar to TH588 and (S)-crizotinib, the cell viabilities of 16 cancer cell lines treated with MI-743 were sharply decreased, particularly human gastric cancer cell lines MGC-803 (IC50 = 2.91 +- 0.46 microM) and HGC-27 (IC50 = 1.14 +- 0.16 microM).	('TH588', 'Chemical', '-', (90, 95))	('MI-743', 'Chemical', '-', (174, 180))	('cancer', 'Disease', (232, 238))	('MI', 'Chemical', 'MESH:C011506', (68, 70))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('gastric cancer', 'Disease', 'MESH:D013274', (224, 238))	('atm', 'Gene', '472', (13, 16))	('atm', 'Gene', (13, 16))	('HGC-27', 'CellLine', 'CVCL:1279', (291, 297))	('MI-743', 'Var', (174, 180))	('cell viabilities', 'CPA', (120, 136))	('cancer', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('gastric cancer', 'Phenotype', 'HP:0012126', (224, 238))	('MI', 'Chemical', 'MESH:C011506', (174, 176))	('(S)-crizotinib', 'Chemical', 'MESH:D000077547', (100, 114))	('human', 'Species', '9606', (218, 223))	('decreased', 'NegReg', (194, 203))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('gastric cancer', 'Disease', (224, 238))
435511	31164636	Furthermore, colony formation assays were also performed, MGC-803 and HGC-27 cells, which were treated with MI-743, TH588 or (S)-crizotinib, formed smaller and fewer colonies, compared with those cells treated with DMSO or MI-929 (Fig.	('HGC-27', 'CellLine', 'CVCL:1279', (70, 76))	('DMSO', 'Chemical', 'MESH:D004121', (215, 219))	('(S)-crizotinib', 'Chemical', 'MESH:D000077547', (125, 139))	('TH588', 'Chemical', '-', (116, 121))	('MI', 'Chemical', 'MESH:C011506', (223, 225))	('smaller', 'NegReg', (148, 155))	('colonies', 'CPA', (166, 174))	('fewer', 'NegReg', (160, 165))	('MI', 'Chemical', 'MESH:C011506', (108, 110))	('MI-743', 'Var', (108, 114))	('MI-743', 'Chemical', '-', (108, 114))	('TH588', 'Var', (116, 121))
435512	31164636	In addition, MI-743 had no obviously inhibitory effect on gastric normal cells (GES-1, Fig.	('GES-1', 'CellLine', 'CVCL:Z677', (80, 85))	('MI-743', 'Var', (13, 19))	('MI-743', 'Chemical', '-', (13, 19))	('gastric normal cells', 'CPA', (58, 78))
435514	31164636	Previously, it has been reported that inhibiting MTH1 can increase the content of genomic 8-oxo-dG, aggravate the incorporation of oxidized nucleotides into DNA, further induce DNA damage and apoptosis.	('inhibiting', 'Var', (38, 48))	('incorporation of oxidized nucleotides into DNA', 'MPA', (114, 160))	('increase', 'PosReg', (58, 66))	('8-oxo-dG', 'Chemical', 'MESH:C067134', (90, 98))	('DNA damage', 'MPA', (177, 187))	('MTH1', 'Gene', '4521', (49, 53))	('MTH1', 'Gene', (49, 53))	('aggravate', 'PosReg', (100, 109))	('apoptosis', 'CPA', (192, 201))	('induce', 'Reg', (170, 176))	('content of genomic 8-oxo-dG', 'MPA', (71, 98))
435516	31164636	We found that the levels of 8-oxo-dG in MGC-803 and HGC-27 cells were sharply increased after being dealt with MI-743 for 48 h, compared with those in DMSO treatment (Fig.	('8-oxo-dG', 'Chemical', 'MESH:C067134', (28, 36))	('levels', 'MPA', (18, 24))	('MI-743', 'Chemical', '-', (111, 117))	('MI-743', 'Var', (111, 117))	('increased', 'PosReg', (78, 87))	('DMSO', 'Chemical', 'MESH:D004121', (151, 155))	('HGC-27', 'CellLine', 'CVCL:1279', (52, 58))	('atm', 'Gene', '472', (159, 162))	('atm', 'Gene', (159, 162))	('8-oxo-dG', 'MPA', (28, 36))
435519	31164636	These findings indicate that the obvious DNA damage responses are induced by compound MI-743.	('compound MI-743', 'Var', (77, 92))	('DNA damage responses', 'CPA', (41, 61))	('MI-743', 'Chemical', '-', (86, 92))
435522	31164636	In addition, MGC-803 and HGC-27 cells, which were treated with MI-743, exhibited significant apoptosis-related morphologies, such as cell shrinkage, nuclear fragmentation and condensation, in a dose-dependent manner (Fig.	('nuclear fragmentation', 'CPA', (149, 170))	('apoptosis-related', 'CPA', (93, 110))	('HGC-27', 'CellLine', 'CVCL:1279', (25, 31))	('MI-743', 'Var', (63, 69))	('MI-743', 'Chemical', '-', (63, 69))	('condensation', 'CPA', (175, 187))	('cell shrinkage', 'CPA', (133, 147))
435524	31164636	These results suggest that compound MI-743 could markedly induce cellular DDR and apoptosis, which may be related to its specific inhibition to MTH1 activity.	('MTH1', 'Gene', (144, 148))	('apoptosis', 'CPA', (82, 91))	('induce', 'PosReg', (58, 64))	('MTH1', 'Gene', '4521', (144, 148))	('compound MI-743', 'Var', (27, 42))	('MI-743', 'Chemical', '-', (36, 42))	('cellular', 'CPA', (65, 73))
435525	31164636	On the basis of the cellular effects of compound MI-743, its in vivo role on gastric cancer was further determined, using the MGC-803 cells-derived xenograft model in BALB/c nude mice.	('compound MI-743', 'Var', (40, 55))	('gastric cancer', 'Disease', (77, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('nude mice', 'Species', '10090', (174, 183))	('MI-743', 'Chemical', '-', (49, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
435529	31164636	In addition, after MI-743 treatment, the expression levels of ATMpS1981 and 8-oxo-dG, were sharply increased (Fig.	('ATM', 'Gene', '472', (62, 65))	('atm', 'Gene', '472', (29, 32))	('expression levels', 'MPA', (41, 58))	('8-oxo-dG', 'Chemical', 'MESH:C067134', (76, 84))	('MI-743', 'Chemical', '-', (19, 25))	('atm', 'Gene', (29, 32))	('ATM', 'Gene', (62, 65))	('increased', 'PosReg', (99, 108))	('MI-743', 'Var', (19, 25))	('8-oxo-dG', 'MPA', (76, 84))
435530	31164636	Moreover, massive area of cell destruction, cell death and significantly increased apoptotic cells were observed in the MI-743 treatment group, compared with those in the oil treatment group (Fig.	('increased', 'PosReg', (73, 82))	('atm', 'Gene', '472', (178, 181))	('MI-743', 'Chemical', '-', (120, 126))	('MI-743', 'Var', (120, 126))	('apoptotic cells', 'CPA', (83, 98))	('atm', 'Gene', (178, 181))	('atm', 'Gene', '472', (130, 133))	('atm', 'Gene', (130, 133))	('oil', 'Chemical', 'MESH:D009821', (171, 174))
435535	31164636	6A, B, MTH1 depletion resulted in significantly decreased cell viability in most of the cancer cells, and DNA damage response (Fig.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('MTH1', 'Gene', '4521', (7, 11))	('MTH1', 'Gene', (7, 11))	('decreased', 'NegReg', (48, 57))	('DNA', 'Reg', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('depletion', 'Var', (12, 21))
435540	31164636	7i), indicating that the expression of MTH1 or its activity plays a key role in these two gastric cancer cells' survival, and the cellular effects of MI-743 are indeed dependent on MTH1 in these two cancer cell lines.	('MTH1', 'Gene', (181, 185))	('activity', 'MPA', (51, 59))	('MI-743', 'Chemical', '-', (150, 156))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MI-743', 'Var', (150, 156))	('MTH1', 'Gene', '4521', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (98, 104))	('MTH1', 'Gene', '4521', (39, 43))	('cancer', 'Disease', (199, 205))	('MTH1', 'Gene', (39, 43))	('gastric cancer', 'Disease', (90, 104))
435543	31164636	Our findings strongly suggest that targeting inhibition of the highly activated MTH1 and the resulting downstream 8-oxo-dG gathering play a crucial role in mediating MI-743-induced gastric cancer cell apoptosis.	('inhibition', 'NegReg', (45, 55))	('8-oxo-dG', 'Chemical', 'MESH:C067134', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('gastric cancer', 'Disease', (181, 195))	('MTH1', 'Gene', (80, 84))	('8-oxo-dG gathering', 'MPA', (114, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (181, 195))	('MTH1', 'Gene', '4521', (80, 84))	('MI-743', 'Chemical', '-', (166, 172))	('MI-743-induced', 'Var', (166, 180))	('gastric cancer', 'Phenotype', 'HP:0012126', (181, 195))
435544	31164636	MI-743 and its scaffold may serve as a lead compound for the MTH1-related gastric cancer treatment (Fig.	('MTH1', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MTH1', 'Gene', '4521', (61, 65))	('atm', 'Gene', '472', (92, 95))	('atm', 'Gene', (92, 95))	('MI-743', 'Var', (0, 6))	('gastric cancer', 'Disease', (74, 88))	('MI-743', 'Chemical', '-', (0, 6))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))
435551	31164636	Furthermore, knocking down MTH1 in these cell lines is associated with significantly decreased cell proliferation and DNA damage.	('cell proliferation', 'CPA', (95, 113))	('knocking down', 'Var', (13, 26))	('decreased', 'NegReg', (85, 94))	('MTH1', 'Gene', (27, 31))	('MTH1', 'Gene', '4521', (27, 31))	('DNA damage', 'CPA', (118, 128))
435556	31164636	Furthermore, the cytotoxicity of MTH1 inhibitors TH588 and TH1579 may be more efficient than siRNA-induced MTH1 protein loss, which may be related to the compensatory mechanism through MTH1's gradual exhaustion.	('TH1579', 'Chemical', '-', (59, 65))	('TH1579', 'Var', (59, 65))	('TH588', 'Chemical', '-', (49, 54))	('MTH1', 'Gene', '4521', (185, 189))	('MTH1', 'Gene', (185, 189))	('cytotoxicity', 'Disease', (17, 29))	('MTH1', 'Gene', '4521', (107, 111))	('MTH1', 'Gene', (107, 111))	('TH588', 'Var', (49, 54))	('MTH1', 'Gene', '4521', (33, 37))	('MTH1', 'Gene', (33, 37))	('cytotoxicity', 'Disease', 'MESH:D064420', (17, 29))
435557	31164636	However, compared to the effects of TH588 and TH1579, it is hard to explain that the reported potent MTH1 inhibitors could not incorporate the 8-oxodG into DNA and induce cancer cell death, even though they can engage in MTH1 at cellular level.	('TH1579', 'Chemical', '-', (46, 52))	('cancer cell death', 'Disease', 'MESH:D003643', (171, 188))	('incorporate', 'MPA', (127, 138))	('induce', 'Reg', (164, 170))	('8-oxodG', 'MPA', (143, 150))	('8-oxodG', 'Chemical', 'MESH:C067134', (143, 150))	('MTH1', 'Gene', (101, 105))	('MTH1', 'Gene', (221, 225))	('TH588', 'Chemical', '-', (36, 41))	('inhibitors', 'Var', (106, 116))	('MTH1', 'Gene', '4521', (221, 225))	('MTH1', 'Gene', '4521', (101, 105))	('cancer cell death', 'Disease', (171, 188))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('not', 'NegReg', (123, 126))
435560	31164636	The results suggest that MI-743 is highly selective in binding and inhibiting MTH1.	('MI-743', 'Var', (25, 31))	('MI-743', 'Chemical', '-', (25, 31))	('binding', 'Interaction', (55, 62))	('MTH1', 'Gene', (78, 82))	('inhibiting', 'NegReg', (67, 77))	('MTH1', 'Gene', '4521', (78, 82))
435562	31164636	Small molecule MI-743 with 5-cyano-6-phenylpyrimidine structure can specifically target MTH1 and inhibit the two gastric cancer cells growth both in vitro and in vivo.	('MI-743', 'Var', (15, 21))	('inhibit', 'NegReg', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('MTH1', 'Gene', (88, 92))	('5-cyano-6-phenylpyrimidine', 'Chemical', '-', (27, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('MTH1', 'Gene', '4521', (88, 92))	('MI-743', 'Chemical', '-', (15, 21))
435563	31164636	MI-743 may serve as a novel lead compound targeting the overexpressed MTH1 for gastric cancer treatment.	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('MI-743', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MTH1', 'Gene', (70, 74))	('MI-743', 'Chemical', '-', (0, 6))	('MTH1', 'Gene', '4521', (70, 74))	('atm', 'Gene', '472', (97, 100))	('gastric cancer', 'Disease', (79, 93))	('atm', 'Gene', (97, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
435567	31164636	Rabbit polyclonal antibodies against MUTYH(19650-1-AP), OGG1(15125-1-AP), p21(10355-1-AP), PARP(13371-1-AP), and caspase 3(19677-1-AP) were purchased from Proteintech (Wuhan, China).	('OGG1', 'Gene', (56, 60))	('MUTYH', 'Gene', '4595', (37, 42))	('OGG1', 'Gene', '4968', (56, 60))	('p21', 'Gene', '644914', (74, 77))	('PARP', 'Gene', (91, 95))	('19677-1-AP', 'Var', (123, 133))	('p21', 'Gene', (74, 77))	('PARP', 'Gene', '1302', (91, 95))	('Rabbit', 'Species', '9986', (0, 6))	('MUTYH', 'Gene', (37, 42))
435574	31164636	Malachite green (M110699), ammonium molybdate (A116378) and crystal violet solution (C110702) were purchased from Aladdin(China).	('C110702', 'Var', (85, 92))	('Ala', 'Chemical', 'MESH:D000409', (114, 117))	('crystal violet', 'Chemical', 'MESH:D005840', (60, 74))	('A116378', 'Chemical', '-', (47, 54))	('M110699', 'Var', (17, 24))	('ammonium molybdate', 'Chemical', 'MESH:C022175', (27, 45))	('Malachite', 'Species', '64457', (0, 9))	('M110699', 'Chemical', '-', (17, 24))
435576	31164636	Enhanced chemiluminescence(QL228436) and Lipofectamine  RNAiMAX Reagent(13778030) were purchased from Thermo Fisher Scientific.	('QL228436', 'Var', (27, 35))	('13778030', 'Var', (72, 80))	('chemiluminescence', 'MPA', (9, 26))	('Lipofectamine', 'Chemical', 'MESH:C086724', (41, 54))	('Enhanced', 'PosReg', (0, 8))
435596	31164636	The plasmids pET28a-MTH1 and its mutant pET28a-E56A, the gifts from Dr. Thomas Helleday group in Karolinska Institute were transformed into E. coli BL21(DE3).	('pET28a-E56A', 'Var', (40, 51))	('MTH1', 'Gene', '4521', (20, 24))	('MTH1', 'Gene', (20, 24))	('E56A', 'Mutation', 'p.E56A', (47, 51))	('BL21', 'CellLine', 'CVCL:M639', (148, 152))	('E. coli', 'Species', '562', (140, 147))
435607	31164636	The preparation of the protein structure was performed under Amber 10: EHT force field using the Quickprep module with the default parameters, which included adding hydrogen atoms, repairing the missing residues and setting up the protonation states of the ionizable residues with pKa = 7.	('ionizable', 'Disease', 'MESH:D004194', (257, 266))	('hydrogen atoms', 'MPA', (165, 179))	('ionizable', 'Disease', (257, 266))	('adding', 'PosReg', (158, 164))	('hydrogen', 'Chemical', 'MESH:D006859', (165, 173))	('repairing', 'Var', (181, 190))	('protonation states', 'MPA', (231, 249))
435609	31164636	The four residues Asp119, Asp120, Asn33 and Trp117 were manually mutated to Ala by the protein builder module in MOE 2015.10 package.	('Trp117', 'Gene', (44, 50))	('Asp119', 'Var', (18, 24))	('Asp120', 'Var', (26, 32))	('Asp119', 'Chemical', '-', (18, 24))	('Ala', 'Chemical', 'MESH:D000409', (76, 79))	('Trp117', 'Chemical', '-', (44, 50))	('Asn33', 'Chemical', '-', (34, 39))	('Asn33', 'Var', (34, 39))	('Asp120', 'Chemical', '-', (26, 32))
435610	31164636	Then, the mutations systems of D119A, D120A, N33A, W117A were balanced by 30 ns molecular dynamic (MD) simulations, using AmberTools14 and NAMD packages.	('N33A', 'Mutation', 'p.N33A', (45, 49))	('D120A', 'Var', (38, 43))	('W117A', 'SUBSTITUTION', 'None', (51, 56))	('D119A', 'Mutation', 'p.D119A', (31, 36))	('D119A', 'Var', (31, 36))	('W117A', 'Var', (51, 56))	('N33A', 'Var', (45, 49))	('D120A', 'Mutation', 'p.D120A', (38, 43))
435614	31164636	After the MD simulations of mutation systems, the obtained stable MD trajectory for each wild-type and mutation systems were used to assess the binding free energy (DeltaGbind) using the MM/PBSA module in AmberTools14 package.	('mutation', 'Var', (103, 111))	('PBSA', 'Chemical', 'MESH:C437084', (190, 194))	('binding', 'Interaction', (144, 151))
435626	31164636	MGC-803, HGC-27 and GES-1 cells were seeded into 100mm2 plastic dishes(1 x 105 cells/well) and incubated overnight prior to the addition of compound MI-743 at 1, 2, 4, 8 and 12 microM for 48 h or compound MI-743 at 12 microM for 12, 24, 36 and 48 h, respectively.	('MI-743', 'Chemical', '-', (205, 211))	('compound MI-743', 'Var', (196, 211))	('compound MI-743', 'Var', (140, 155))	('GES-1', 'CellLine', 'CVCL:Z677', (20, 25))	('MI-743', 'Chemical', '-', (149, 155))	('HGC-27', 'CellLine', 'CVCL:1279', (9, 15))
435664	31118488	Recently, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has produced remarkably durable clinical responses in HNSCC, with an objective response rate (ORR) of 13.3%, median progression-free survival (PFS) of 2.0 months, and median overall survival (OS) of 7.5 months.	('PD-1', 'Gene', (30, 34))	('PD-1', 'Gene', '5133', (30, 34))	('programmed death-ligand 1', 'Gene', (36, 61))	('programmed death-ligand 1', 'Gene', '29126', (36, 61))	('HNSCC', 'Disease', (133, 138))	('programmed death-1', 'Gene', (10, 28))	('HNSCC', 'Phenotype', 'HP:0012288', (133, 138))	('PD-L1', 'Gene', (63, 68))	('programmed death-1', 'Gene', '5133', (10, 28))	('blockade', 'Var', (70, 78))	('OS', 'Gene', '17451', (271, 273))	('PD-L1', 'Gene', '29126', (63, 68))
435674	31118488	Defects in MHC class I molecules lead to impaired T-cell mediated cytotoxicity against tumor cells.	('MHC class I molecule', 'Gene', (11, 31))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('MHC class I molecule', 'Gene', '3106', (11, 31))	('Defects', 'Var', (0, 7))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('impaired', 'NegReg', (41, 49))	('cytotoxicity', 'Disease', (66, 78))
435675	31118488	The deregulated expression of MHC class I genes has been demonstrated in various tumor types.	('MHC class I genes', 'Gene', (30, 47))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('deregulated', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('expression', 'MPA', (16, 26))	('tumor', 'Disease', (81, 86))
435702	31118488	In multivariate analysis, MHC class I loss in the PD-L1-positive setting retain prognostic significance (HR = 3.84, 95% CI 1.43-10.35; P = 0.008), as well as loss of p16 expression was associated with a worse survival (HR = 3.12, 95% CI 1.12-8.68; P = 0.029).	('loss', 'Var', (158, 162))	('PD-L1', 'Gene', (50, 55))	('MHC class I', 'Gene', (26, 37))	('p16', 'Gene', '1029', (166, 169))	('PD-L1', 'Gene', '29126', (50, 55))	('p16', 'Gene', (166, 169))	('loss', 'NegReg', (38, 42))	('expression', 'MPA', (170, 180))
435713	31118488	According to Perea et al., non-small cell lung cancer patients with decreased MHC class I and high PD-L1 expression have larger tumor sizes that show a more aggressive phenotype, similar to esophageal cancer patients.	('decreased', 'NegReg', (68, 77))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('decreased MHC', 'Phenotype', 'HP:0025547', (68, 81))	('non-small cell lung cancer', 'Disease', (27, 53))	('expression', 'MPA', (105, 115))	('MHC class', 'Gene', (78, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('high', 'Var', (94, 98))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (27, 53))	('tumor', 'Disease', (128, 133))	('esophageal cancer', 'Disease', 'MESH:D004938', (190, 207))	('larger', 'PosReg', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (31, 53))	('patients', 'Species', '9606', (208, 216))	('PD-L1', 'Gene', (99, 104))	('esophageal cancer', 'Disease', (190, 207))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (27, 53))	('PD-L1', 'Gene', '29126', (99, 104))
435716	31118488	is that the proportion of CD8-positive T cell infiltration was 100% in PD-L1-positive patients with high MHC class I expression compared to 37% in PD-L1-positive patients with MHC class I loss, which indicates that T-cell-mediated adaptive immune response could not be activated without the presence of MHC class I expression.	('PD-L1', 'Gene', '29126', (147, 152))	('patients', 'Species', '9606', (162, 170))	('T cell infiltration', 'CPA', (39, 58))	('high MHC', 'Phenotype', 'HP:0025548', (100, 108))	('CD8', 'Gene', '925', (26, 29))	('MHC class I', 'Gene', (105, 116))	('PD-L1', 'Gene', (71, 76))	('high', 'Var', (100, 104))	('PD-L1', 'Gene', '29126', (71, 76))	('PD-L1', 'Gene', (147, 152))	('CD8', 'Gene', (26, 29))	('patients', 'Species', '9606', (86, 94))
435725	31118488	According to Ito et al., esophageal cancer patients with both high expression of PD-L1 and MHC class I seem to have a worse prognosis than patients with high expression of PD-L1 and decreased MHC class I expression.	('PD-L1', 'Gene', '29126', (172, 177))	('patients', 'Species', '9606', (139, 147))	('esophageal cancer', 'Disease', (25, 42))	('patients', 'Species', '9606', (43, 51))	('PD-L1', 'Gene', (81, 86))	('MHC class I', 'Gene', (91, 102))	('high expression', 'Var', (62, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (25, 42))	('MHC class I', 'Gene', (192, 203))	('PD-L1', 'Gene', '29126', (81, 86))	('decreased MHC', 'Phenotype', 'HP:0025547', (182, 195))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('expression', 'MPA', (204, 214))	('PD-L1', 'Gene', (172, 177))
435726	31118488	On the other hand, in patients with hepatocellular carcinoma, MHC class I downregulation appears to be associated with poor prognosis among the low PD-L1 group, whereas no significant difference in survival is observed according to MHC class I expression among the high PD-L1 group.	('downregulation', 'NegReg', (74, 88))	('PD-L1', 'Gene', (270, 275))	('PD-L1', 'Gene', '29126', (148, 153))	('patients', 'Species', '9606', (22, 30))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (36, 60))	('hepatocellular carcinoma', 'Disease', (36, 60))	('PD-L1', 'Gene', '29126', (270, 275))	('MHC class I', 'Gene', (62, 73))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (36, 60))	('low', 'Var', (144, 147))	('PD-L1', 'Gene', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
435732	31118488	Two study groups reported that PD-L1 positivity is a poor prognostic factor with a shortened OS in HNSCC.	('PD-L1', 'Gene', '29126', (31, 36))	('OS', 'Gene', '17451', (93, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (99, 104))	('positivity', 'Var', (37, 47))	('HNSCC', 'Disease', (99, 104))	('PD-L1', 'Gene', (31, 36))
435737	31118488	Besides, metabolic reprogramming by tumor microenvironment and regulation of other anabolic and catabolic pathway by mitochondria also influences tumor-immune response as well as epigenetic modification of T cells.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('epigenetic modification', 'Var', (179, 202))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('influences', 'Reg', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
435743	31118488	LOH in chromosome 6 (human leukocyte antigen) or 15 (beta-2-microglobulin) is the most commonly found mechanism of MHC class I alteration.	('alteration', 'Var', (127, 137))	('MHC class I', 'Gene', (115, 126))	('human', 'Species', '9606', (21, 26))	('LOH', 'Var', (0, 3))
435749	31118488	We used E1L3N, the rabbit monoclonal antibody for PD-L1 expression, which has been regarded as having relatively lower concordance rate than other antibodies for PD-L1 such as SP142 or SP263.	('SP142', 'Chemical', '-', (176, 181))	('PD-L1', 'Gene', (50, 55))	('PD-L1', 'Gene', '29126', (162, 167))	('rabbit', 'Species', '9986', (19, 25))	('PD-L1', 'Gene', '29126', (50, 55))	('E1L3N', 'Var', (8, 13))	('SP263', 'Chemical', '-', (185, 190))	('PD-L1', 'Gene', (162, 167))
435751	31118488	Furthermore, E1L3N showed good agreement rate with other antibodies in some studies performed in head and neck cancer patients.	('E1L3N', 'Var', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('head and neck cancer', 'Phenotype', 'HP:0012288', (97, 117))	('agreement', 'Interaction', (31, 40))	('neck cancer', 'Disease', 'MESH:D006258', (106, 117))	('neck cancer', 'Disease', (106, 117))	('patients', 'Species', '9606', (118, 126))
435776	31118488	The association of PD-L1 positivity and MHC class I loss with demographic and clinico-pathological variables was analyzed using Student's t-test or chi-square tests, where appropriate.	('PD-L1', 'Gene', (19, 24))	('loss', 'NegReg', (52, 56))	('positivity', 'Var', (25, 35))	('MHC class I', 'Gene', (40, 51))	('PD-L1', 'Gene', '29126', (19, 24))
435848	27957439	Although, no clear evidence has been reported on the relationship between opium and opioids with colorectal cancers and little evidence exists in this field; opium and opioids can increase the risk of cancers such as gastric, larynx, bladder, lung, esophagus, oral cavity and also the risk of death from these gastrointestinal cancers.	('gastric', 'Disease', (217, 224))	('colorectal cancers', 'Disease', (97, 115))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Phenotype', 'HP:0002664', (327, 334))	('increase', 'PosReg', (180, 188))	('cancers', 'Disease', (327, 334))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('colorectal cancers', 'Disease', 'MESH:D015179', (97, 115))	('bladder', 'Disease', (234, 241))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (310, 334))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('oral cavity', 'Disease', (260, 271))	('lung', 'Disease', (243, 247))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancers', 'Disease', (108, 115))	('cancers', 'Disease', 'MESH:D009369', (327, 334))	('gastrointestinal cancers', 'Disease', (310, 334))	('opium', 'Var', (158, 163))	('esophagus', 'Disease', (249, 258))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('larynx', 'Disease', (226, 232))
435852	27957439	In addition, pyrolysis and alkaloids of morphine lead to sister chromatic exchange in human lymphocytes and morphological changes in cultured Syrian hamster embryo cells.	('sister chromatic exchange', 'MPA', (57, 82))	('Syrian hamster', 'Species', '10036', (142, 156))	('alkaloids', 'Chemical', 'MESH:D000470', (27, 36))	('human', 'Species', '9606', (86, 91))	('morphine', 'Gene', (40, 48))	('lead to', 'Reg', (49, 56))	('pyrolysis', 'Var', (13, 22))	('morphine', 'Chemical', 'MESH:D009020', (40, 48))	('morphological changes', 'CPA', (108, 129))
435873	27927246	MIO also had reduced incidence of total complications; (OR = 0.700, 95% CI = 0.626 ~ 0.781, P V < 0.05), pulmonary complications (OR = 0.527, 95% CI = 0431 ~ 0.645, P V < 0.05), cardiovascular complications (OR = 0.770, 95% CI = 0.681 ~ 0.872, P V < 0.05), and surgical technology related (STR) complications (OR = 0.639, 95% CI = 0.522 ~ 0.781, P V < 0.05), as well as lower in-hospital mortality (OR = 0.668, 95% CI = 0.539 ~ 0.827, P V < 0.05).	('lower', 'NegReg', (370, 375))	('surgical technology related', 'CPA', (261, 288))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (178, 206))	('pulmonary complications', 'Phenotype', 'HP:0006532', (105, 128))	('cardiovascular complications', 'Disease', 'MESH:D002318', (178, 206))	('MIO', 'Chemical', '-', (0, 3))	('pulmonary complications', 'CPA', (105, 128))	('cardiovascular complications', 'Disease', (178, 206))	('reduced', 'NegReg', (13, 20))	('MIO', 'Var', (0, 3))
435900	27927246	Thirty-three studies (5243 cases) reported that the patients in MIE group received more neoadjuvant therapy (Table 3, pooled OR = 1.364, 95% CI = 1.042 ~ 1.785, P V = 0.024).	('more', 'PosReg', (83, 87))	('neoadjuvant therapy', 'CPA', (88, 107))	('MIE', 'Var', (64, 67))	('MIE', 'Chemical', '-', (64, 67))	('patients', 'Species', '9606', (52, 60))
435903	27927246	Duration of hospital stay (13,899 cases), including ICU stay (10,761 cases), were found to be significantly lower in MIO group (WMD = -1.599, 95% CI = (-2.680 ~ -0.518,P V < 0.05 and WMD = -3.66, 95% CI = -4.891 ~ -2.428, P V < 0.05).	('MIO', 'Chemical', '-', (117, 120))	('MIO', 'Var', (117, 120))	('lower', 'NegReg', (108, 113))	('ICU stay', 'MPA', (52, 60))
435908	27927246	There was very strong evidence of reduced risk of pulmonary complications in the MIO group (OR = 0.527, 95%CI = 0.431 ~ 0.645, P V < 0.05), with statistical heterogeneity (I 2 of 60.3%, P Q = 0.012) (Fig.	('reduced', 'NegReg', (34, 41))	('pulmonary complications', 'Phenotype', 'HP:0006532', (50, 73))	('MIO', 'Chemical', '-', (81, 84))	('MIO', 'Var', (81, 84))	('pulmonary complications', 'CPA', (50, 73))
435913	27927246	Thirty-six studies reported cardiovascular complications (MIO 3745 vs OE 9138).	('MIO 3745', 'Var', (58, 66))	('cardiovascular complications', 'Disease', 'MESH:D002318', (28, 56))	('cardiovascular complications', 'Disease', (28, 56))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (28, 56))	('OE', 'Chemical', '-', (70, 72))	('MIO', 'Chemical', '-', (58, 61))	('reported', 'Reg', (19, 27))
435914	27927246	There was very strong evidence of reduced cardiovascular complications in MIO group (OR = 0.770, 95% CI = 0.681 ~ 0.872, P V < 0.05), with statistical homogeneity (I 2 of 2.4%, P Q = 0.427) (Fig.	('reduced', 'NegReg', (34, 41))	('cardiovascular complications', 'Disease', (42, 70))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (42, 70))	('cardiovascular complications', 'Disease', 'MESH:D002318', (42, 70))	('MIO', 'Chemical', '-', (74, 77))	('MIO', 'Var', (74, 77))
435915	27927246	Thirty-nine studies reported STR complications (MIO2933 vs OE 3058).	('MIO2933', 'Var', (48, 55))	('OE', 'Chemical', '-', (59, 61))	('MIO2933', 'CellLine', 'CVCL:0433', (48, 55))	('STR complications', 'Disease', (29, 46))
435916	27927246	There was very strong evidence of reduced STR complications in MIO group (OR = 0.770, 95% CI = 0.681 ~ 0.872, P V < 0.05), with statistical homogeneity (I 2 of 2.4%, P Q = 0.918) (Fig.	('MIO', 'Chemical', '-', (63, 66))	('MIO', 'Var', (63, 66))	('STR complications', 'MPA', (42, 59))	('reduced', 'NegReg', (34, 41))
435918	27927246	There was no evidence of reduced gastrointestinal complications in MIO group (OR = 1.097, 95% CI = 0.835 ~ 1.442, P V = 0.507), with statistical homogeneity (I 2 of 31.7%, P Q = 0.083) (Table 3).	('MIO', 'Chemical', '-', (67, 70))	('reduced', 'NegReg', (25, 32))	('MIO', 'Var', (67, 70))	('gastrointestinal complications', 'Phenotype', 'HP:0004798', (33, 63))	('gastrointestinal complications', 'Disease', (33, 63))	('gastrointestinal complications', 'Disease', 'MESH:D005767', (33, 63))
435920	27927246	There was no evidence of reduced anastomotic leak in MIO group (OR = 1.023, 95% CI = 0.870 ~ 1.202, P V = 0.785), with statistical homogeneity (I 2 of 8.5%, P Q = 0.304) (Table 3).	('reduced', 'NegReg', (25, 32))	('anastomotic leak', 'Disease', (33, 49))	('MIO', 'Chemical', '-', (53, 56))	('MIO', 'Var', (53, 56))	('anastomotic leak', 'Disease', 'MESH:D057868', (33, 49))
435927	27927246	We found higher operative duration in the MIO group, consistent with Kunisaki's, Shiraishi's, and randomized controlled trials reported, perhaps due to surgeons' familiarization with a new and complex techniques.	('MIO', 'Chemical', '-', (42, 45))	('MIO', 'Var', (42, 45))	('operative duration', 'MPA', (16, 34))	('higher', 'PosReg', (9, 15))
435933	27927246	However, a number of studies have reported significantly lower pulmonary complications for those who underwent MIO 17.1% (813/4761) versus OE 22.6% (2264/10,020), with overall morbidity of 20.8% (3077/14,781), consistent with the result of 3.1-37.0% from other studies.	('MIO', 'Chemical', '-', (111, 114))	('MIO', 'Var', (111, 114))	('pulmonary complications', 'CPA', (63, 86))	('OE', 'Chemical', '-', (139, 141))	('pulmonary complications', 'Phenotype', 'HP:0006532', (63, 86))	('lower', 'NegReg', (57, 62))
435942	27927246	reported significant decrease in the morbidity of arrhythmia and pulmonary embolism in MIO group.	('arrhythmia', 'Disease', 'MESH:D001145', (50, 60))	('arrhythmia', 'Phenotype', 'HP:0011675', (50, 60))	('MIO', 'Var', (87, 90))	('decrease', 'NegReg', (21, 29))	('arrhythmia', 'Disease', (50, 60))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (65, 83))	('pulmonary embolism', 'Disease', (65, 83))	('pulmonary embolism', 'Disease', 'MESH:D011655', (65, 83))	('MIO', 'Chemical', '-', (87, 90))
435944	27927246	also indicated that the perforation from minimally invasive surgery as such could decrease the risks leading to arrhythmia.	('arrhythmia', 'Phenotype', 'HP:0011675', (112, 122))	('arrhythmia', 'Disease', (112, 122))	('decrease', 'NegReg', (82, 90))	('perforation', 'Var', (24, 35))	('arrhythmia', 'Disease', 'MESH:D001145', (112, 122))
435947	27927246	In accordance with Zhou et al's conclusion, we also did not find the evidence of reduced risk of anastomotic leak in the MIO group.	('anastomotic leak', 'Disease', 'MESH:D057868', (97, 113))	('anastomotic leak', 'Disease', (97, 113))	('MIO', 'Chemical', '-', (121, 124))	('MIO', 'Var', (121, 124))
436083	33882958	The standardized mean difference (SMD) in post-operative hospitalization duration in SLET group compared with that in the control group comprised the secondary outcome.	('SMD', 'Disease', 'MESH:C537501', (34, 37))	('SMD', 'Disease', (34, 37))	('SLET', 'Var', (85, 89))
436185	29938465	Their study showed that the risk of suffering from another serious disease among cancer patients with low SES was 1.5 times greater than those with high SES levels.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', (81, 87))	('low', 'Var', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
436206	29721055	Genetic Variants Within MTORC1 Genes Predict Gastric Cancer Prognosis in Chinese Populations Objective: Mammalian target of rapamycin complex 1 (mTORC1) plays an important role in maintaining proper cellular functions in gastric cancer (GC).	('mTORC1', 'Gene', (145, 151))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Gastric Cancer', 'Disease', 'MESH:D013274', (45, 59))	('gastric cancer', 'Disease', (221, 235))	('MTORC1', 'Gene', (24, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (221, 235))	('Variants', 'Var', (8, 16))	('MTORC1', 'Gene', '382056', (24, 30))	('mTORC1', 'Gene', '382056', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('gastric cancer', 'Phenotype', 'HP:0012126', (221, 235))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (45, 59))	('Mammalian target of rapamycin', 'Gene', '2475', (104, 133))	('Gastric Cancer', 'Disease', (45, 59))	('Mammalian target of rapamycin', 'Gene', (104, 133))
436207	29721055	Previous studies demonstrated genetic variants within mTORC1 genes were associated with GC risk.	('genetic variants', 'Var', (30, 46))	('mTORC1', 'Gene', '382056', (54, 60))	('associated', 'Reg', (72, 82))	('mTORC1', 'Gene', (54, 60))
436208	29721055	However, no studies reported the associations between genetic variants within mTORC1 genes and GC prognosis.	('mTORC1', 'Gene', '382056', (78, 84))	('variants', 'Var', (62, 70))	('mTORC1', 'Gene', (78, 84))
436209	29721055	Herein, we firstly assessed the associations of genetic variants of mTORC1 genes with overall survival (OS) of GC in Chinese populations.	('OS', 'Chemical', '-', (104, 106))	('mTORC1', 'Gene', '382056', (68, 74))	('associations', 'Interaction', (32, 44))	('variants', 'Var', (56, 64))	('mTORC1', 'Gene', (68, 74))	('overall survival', 'MPA', (86, 102))
436210	29721055	Methods: We genotyped eight single nucleotide polymorphisms (SNPs) in mTORC1 genes (i.e., rs2536 T>C and rs1883965 G>A for mTOR, rs3160 T>C and rs26865 A>G for MLST8, rs3751934 C>A, rs1062935 T>C, rs3751932 T>C and rs12602885 G>A for RPTOR) by the TaqMan method in 197 Chinese GC patients who had surgical resection in Xinhua Hospital.	('mTOR', 'Gene', '2475', (70, 74))	('rs1062935', 'Mutation', 'rs1062935', (182, 191))	('mTOR', 'Gene', '2475', (123, 127))	('rs26865 A>G', 'Var', (144, 155))	('rs1883965 G>A', 'Var', (105, 118))	('rs3751934', 'Mutation', 'rs3751934', (167, 176))	('rs3160', 'Mutation', 'rs3160', (129, 135))	('rs3160 T>C', 'Var', (129, 139))	('patients', 'Species', '9606', (280, 288))	('rs12602885 G>A', 'Var', (215, 229))	('rs1062935 T>C', 'Var', (182, 195))	('rs2536 T>C', 'Var', (90, 100))	('mTORC1', 'Gene', (70, 76))	('rs1883965', 'Mutation', 'rs1883965', (105, 114))	('rs2536', 'Mutation', 'rs2536', (90, 96))	('mTOR', 'Gene', (123, 127))	('MLST8', 'Gene', '64223', (160, 165))	('mTOR', 'Gene', (70, 74))	('MLST8', 'Gene', (160, 165))	('rs26865', 'Mutation', 'rs26865', (144, 151))	('mTORC1', 'Gene', '382056', (70, 76))	('rs3751932', 'Mutation', 'rs3751932', (197, 206))	('rs3751932 T>C', 'Var', (197, 210))	('Xin', 'Gene', '165904', (319, 322))	('rs3751934 C>A', 'Var', (167, 180))	('rs12602885', 'Mutation', 'rs12602885', (215, 225))	('Xin', 'Gene', (319, 322))
436214	29721055	Conclusions: Our findings indicated that genetic variants within mTORC1 genes may predict GC prognosis in Chinese populations.	('predict', 'Reg', (82, 89))	('mTORC1', 'Gene', '382056', (65, 71))	('genetic variants', 'Var', (41, 57))	('mTORC1', 'Gene', (65, 71))
436220	29721055	Deregulation of the pathway commonly exists in most of human cancers.	('Deregulation', 'Var', (0, 12))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
436227	29721055	In addition, it was demonstrated that genetic variants within mTORC1 genes were associated with esophageal cancer and GC risk.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('mTORC1', 'Gene', '382056', (62, 68))	('genetic variants', 'Var', (38, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('associated', 'Reg', (80, 90))	('mTORC1', 'Gene', (62, 68))
436228	29721055	There are few published studies that have addressed the role of genetic variants in mTORC1 genes in GC prognosis.	('mTORC1', 'Gene', '382056', (84, 90))	('genetic variants', 'Var', (64, 80))	('mTORC1', 'Gene', (84, 90))
436240	29721055	Finally, we identified eight SNPs (rs2536 T>C and rs1883965 G>A for mTOR, rs3160 T>C and rs26865 A>G for MLST8, rs3751934 C>A, rs1062935 T>C, rs3751932 T>C and rs12602885 G>A for RPTOR) for the study.	('rs1062935', 'Mutation', 'rs1062935', (127, 136))	('mTOR', 'Gene', '2475', (68, 72))	('rs26865 A>G', 'Var', (89, 100))	('rs1883965 G>A', 'Var', (50, 63))	('rs3160', 'Mutation', 'rs3160', (74, 80))	('rs3751934', 'Mutation', 'rs3751934', (112, 121))	('rs1883965', 'Mutation', 'rs1883965', (50, 59))	('rs26865', 'Mutation', 'rs26865', (89, 96))	('rs3160 T>C', 'Var', (74, 84))	('rs3751932 T>C', 'Var', (142, 155))	('MLST8', 'Gene', '64223', (105, 110))	('MLST8', 'Gene', (105, 110))	('rs3751932', 'Mutation', 'rs3751932', (142, 151))	('rs12602885 G>A', 'Var', (160, 174))	('rs2536 T>C', 'Var', (35, 45))	('rs1062935 T>C', 'Var', (127, 140))	('rs2536', 'Mutation', 'rs2536', (35, 41))	('mTOR', 'Gene', (68, 72))	('rs3751934 C>A', 'Var', (112, 125))	('rs12602885', 'Mutation', 'rs12602885', (160, 170))
436241	29721055	Among them, five SNPs (rs2536 T>C, rs3160 T>C, rs1062935 T>C, rs3751934 C>A, rs3751932 T>C) located in the 3'-untranslated region (3'UTR) may affect the miRNA binding site function.	('rs2536 T>C', 'Var', (23, 33))	('rs3160', 'Mutation', 'rs3160', (35, 41))	('rs1062935', 'Mutation', 'rs1062935', (47, 56))	('rs3751934', 'Mutation', 'rs3751934', (62, 71))	('affect', 'Reg', (142, 148))	('rs3751934 C>A', 'Var', (62, 75))	('rs3160 T>C', 'Var', (35, 45))	('rs1062935 T>C', 'Var', (47, 60))	('rs2536', 'Mutation', 'rs2536', (23, 29))	('rs3751932 T>C', 'Var', (77, 90))	('miRNA', 'MPA', (153, 158))	('rs3751932', 'Mutation', 'rs3751932', (77, 86))
436242	29721055	For the remaining three SNPs, rs1883965 G>A located in the intron region, rs26865 A>G located in the 5' near gene, rs12602885 G>A located in the 5'-untranslated region (5'UTR) and all of them may affect the TFBS function.	('rs1883965', 'Mutation', 'rs1883965', (30, 39))	('TFBS', 'Chemical', '-', (207, 211))	('rs12602885', 'Mutation', 'rs12602885', (115, 125))	('rs1883965 G>A', 'Var', (30, 43))	('rs26865 A>G', 'Var', (74, 85))	('TFBS function', 'CPA', (207, 220))	('affect', 'Reg', (196, 202))	('rs26865', 'Mutation', 'rs26865', (74, 81))	('rs12602885 G>A', 'Var', (115, 129))
436251	29721055	As shown in Table 1, patients with tumor size > 4cm, T3 or T4 invasion, Stage III/IV, vascular, lymphatic vessel and perineural invasion, chemotherapy were obviously at higher risk of death compared with those with tumor size <= 4cm, T1/T2 invasion, Stage I or II, without vascular, lymphatic vessel and perineural invasion, non-chemotherapy (adjusted P = 0.029, 0.017, < 0.001, < 0.001, 0.036, respectively).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('T4 invasion', 'Var', (59, 70))	('tumor', 'Disease', (35, 40))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('death', 'Disease', 'MESH:D003643', (184, 189))	('death', 'Disease', (184, 189))
436256	29721055	As shown in Figure 1 and 2, Kaplan-Meier survival plots indicated cumulative risks for GC death associated with the presence of more than one through five risk genotypes (Log-rank P = 0.033, 0.015, respectively).	('presence', 'Var', (116, 124))	('death', 'Disease', 'MESH:D003643', (90, 95))	('death', 'Disease', (90, 95))
436258	29721055	We found that RPTOR rs1062935 CC variant increased risk of GC death, as well as patients with more than three risk genotypes, when compared to those with three or less risk genotypes.	('patients', 'Species', '9606', (80, 88))	('rs1062935', 'Mutation', 'rs1062935', (20, 29))	('death', 'Disease', 'MESH:D003643', (62, 67))	('rs1062935 CC', 'Var', (20, 32))	('death', 'Disease', (62, 67))
436266	29721055	The deletion of RPTOR remarkably impaired acute myeloid leukemia (AML) progression through analyzing AML mouse models.	('AML', 'Disease', (66, 69))	('AML', 'Disease', 'MESH:D015470', (101, 104))	('AML', 'Disease', (101, 104))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (42, 64))	('impaired acute myeloid leukemia', 'Disease', 'MESH:D015470', (33, 64))	('impaired acute myeloid leukemia', 'Disease', (33, 64))	('AML', 'Disease', 'MESH:D015470', (66, 69))	('leukemia', 'Phenotype', 'HP:0001909', (56, 64))	('deletion', 'Var', (4, 12))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (48, 64))	('mouse', 'Species', '10090', (105, 110))	('RPTOR', 'Gene', (16, 21))
436268	29721055	Some studies investigated the associations of genetic variants in mTORC1 pathway genes with susceptibility and survival of different cancers.	('investigated', 'Reg', (13, 25))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('mTORC1', 'Gene', '382056', (66, 72))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('associations', 'Interaction', (30, 42))	('genetic variants', 'Var', (46, 62))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mTORC1', 'Gene', (66, 72))
436269	29721055	identified that four SNPs (rs11653499, rs7211818, rs7212142 and rs9674559) in RPTOR were associated with an increased risk of bladder cancer, and He J et al.	('associated with', 'Reg', (89, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('rs11653499', 'Mutation', 'rs11653499', (27, 37))	('rs7212142', 'Mutation', 'rs7212142', (50, 59))	('rs11653499', 'Var', (27, 37))	('rs9674559', 'Var', (64, 73))	('bladder cancer', 'Disease', (126, 140))	('rs7211818', 'Mutation', 'rs7211818', (39, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (126, 140))	('rs7211818', 'Var', (39, 48))	('rs7212142', 'Var', (50, 59))	('rs9674559', 'Mutation', 'rs9674559', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
436270	29721055	found that mTOR rs1883965 A variant genotypes were associated with an increased GC risk.	('rs1883965', 'Mutation', 'rs1883965', (16, 25))	('mTOR', 'Gene', (11, 15))	('rs1883965 A', 'Var', (16, 27))	('mTOR', 'Gene', '2475', (11, 15))
436271	29721055	did not find main effects of five SNPs located in PIK3R1 and mTOR with esophageal cancer risk using their own data, meta-analysis identified mTOR rs2295080 associated with cancer risk and the same effect occurred among subjects with one-to-three risk genotypes in further combined analysis.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mTOR', 'Gene', '2475', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mTOR', 'Gene', (141, 145))	('mTOR', 'Gene', '2475', (61, 65))	('rs2295080', 'Mutation', 'rs2295080', (146, 155))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('esophageal cancer', 'Disease', (71, 88))	('associated', 'Reg', (156, 166))	('PIK3R1', 'Gene', '5295', (50, 56))	('mTOR', 'Gene', (61, 65))	('cancer', 'Disease', (172, 178))	('PIK3R1', 'Gene', (50, 56))	('rs2295080', 'Var', (146, 155))
436273	29721055	Similar to our results, their findings further validated the importance of genetic variations as well as mTOR signaling pathway on the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('genetic variations', 'Var', (75, 93))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (105, 109))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
436274	29721055	A meta-analysis revealed mTOR rs11121704 TT was associated with poor clinical outcome, including death, metastasis and resistance to chemotherapy in patients with lung and esophageal cancer.	('resistance', 'CPA', (119, 129))	('patients', 'Species', '9606', (149, 157))	('esophageal cancer', 'Disease', (172, 189))	('metastasis', 'CPA', (104, 114))	('rs11121704', 'Mutation', 'rs11121704', (30, 40))	('rs11121704 TT', 'Var', (30, 43))	('death', 'Disease', 'MESH:D003643', (97, 102))	('lung', 'Disease', 'MESH:D008171', (163, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lung', 'Disease', (163, 167))	('mTOR', 'Gene', '2475', (25, 29))	('death', 'Disease', (97, 102))	('mTOR', 'Gene', (25, 29))
436275	29721055	found two SNPs in mTOR and AKT genes increased GC susceptibility in the subgroups of man, H. pylori-negative individuals, and one SNP in AKT gene associated with lymph node metastasis but not with the survival in 203 cases.	('mTOR', 'Gene', (18, 22))	('mTOR', 'Gene', '2475', (18, 22))	('AKT', 'Gene', (27, 30))	('man', 'Species', '9606', (85, 88))	('lymph node metastasis', 'Disease', (162, 183))	('AKT', 'Gene', '207', (137, 140))	('AKT', 'Gene', '207', (27, 30))	('SNPs', 'Var', (10, 14))	('increased', 'PosReg', (37, 46))	('associated with', 'Reg', (146, 161))	('H. pylori', 'Species', '210', (90, 99))	('AKT', 'Gene', (137, 140))
436276	29721055	Although researchers investigated different SNPs in different genes from different perspectives, and produced the final results differently, published results and ours both supported the hypothesis that SNPs in mTOR signaling pathway have positive effects on GC risk and prognosis.	('positive', 'PosReg', (239, 247))	('mTOR', 'Gene', '2475', (211, 215))	('mTOR', 'Gene', (211, 215))	('SNPs', 'Var', (203, 207))	('prognosis', 'CPA', (271, 280))
436277	29721055	Some studies have indicated that clinical pathological characteristics and adjuvant therapy would affect overall survival, however, the phenomenon that not all patients with the same situations have the same survival time suggests genetic variations may also insert one foot.	('patients', 'Species', '9606', (160, 168))	('overall survival', 'MPA', (105, 121))	('genetic variations', 'Var', (231, 249))	('affect', 'Reg', (98, 104))	('insert', 'Reg', (259, 265))
436279	29721055	Even if no genetic main effects existed for bulks of SNPs, according to several studies, we believed SNPs of interest might collectively confer and modulate cancer outcome.	('SNPs', 'Var', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('modulate', 'Reg', (148, 156))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('confer', 'Reg', (137, 143))
436280	29721055	We observed that the combined effect of genetic variants in mTORC1 genes on a poorer survival of GC.	('mTORC1', 'Gene', (60, 66))	('variants', 'Var', (48, 56))	('poorer', 'NegReg', (78, 84))	('mTORC1', 'Gene', '382056', (60, 66))
436282	29721055	Firstly, the sample size was relatively small, especially for the low MAF of two SNPs (rs1882965 and rs2536), so we could not have enough power to calculate weak effects of genetic variants on clinical outcomes.	('rs1882965', 'Mutation', 'rs1882965', (87, 96))	('rs1882965', 'Var', (87, 96))	('rs2536', 'Mutation', 'rs2536', (101, 107))	('rs2536', 'Var', (101, 107))
436284	29721055	In conclusion, our findings demonstrate that genetic variants in mTORC1 genes may influence GC prognosis in Chinese populations.	('mTORC1', 'Gene', '382056', (65, 71))	('mTORC1', 'Gene', (65, 71))	('genetic variants', 'Var', (45, 61))	('influence', 'Reg', (82, 91))
436325	28212604	Kaplan-Meier survival estimator with log-rank test was used to analyze the patient survival rates in the Claudin-2 high expression group versus the non-high expression group.	('patient', 'Species', '9606', (75, 82))	('Claudin-2', 'Gene', (105, 114))	('rat', 'Species', '10116', (92, 95))	('Claudin-2', 'Gene', '9075', (105, 114))	('high expression', 'Var', (115, 130))
436335	28212604	The Claudin-2 non-high expression group had a median survival time of 20 months with a mean survival time of 33 months (censoring rate = 22%).	('Claudin-2', 'Gene', '9075', (4, 13))	('non-high expression', 'Var', (14, 33))	('rat', 'Species', '10116', (130, 133))	('Claudin-2', 'Gene', (4, 13))
436338	28212604	None of the clinicopathologic characteristics including age, sex, TNM staging and differentiation were found to be significantly associated with Claudin-2 high expression (Table 2).	('TNM', 'Gene', '10178', (66, 69))	('Claudin-2', 'Gene', '9075', (145, 154))	('high expression', 'Var', (155, 170))	('TNM', 'Gene', (66, 69))	('Claudin-2', 'Gene', (145, 154))
436352	28212604	VDR was also found to directly enhance Claudin-2 expression in intestinal epithelium.	('VDR', 'Var', (0, 3))	('enhance', 'PosReg', (31, 38))	('Claudin-2', 'Gene', (39, 48))	('expression', 'MPA', (49, 59))	('Claudin-2', 'Gene', '9075', (39, 48))
436358	28212604	Claudin-2 is a unique protein in the Claudin family and forms a cation and water selective paracellular channel in tight junctions, and its expression increases intercellular permeability which opens the gate to change the microenvironment of the esophageal epithelium and may eventually lead to columnar cell metaplasia and BE.	('intercellular permeability', 'MPA', (161, 187))	('columnar cell metaplasia', 'Disease', 'MESH:D008679', (296, 320))	('increases', 'PosReg', (151, 160))	('lead to', 'Reg', (288, 295))	('change', 'Reg', (212, 218))	('water', 'Chemical', 'MESH:D014867', (75, 80))	('Claudin-2', 'Gene', '9075', (0, 9))	('expression', 'Var', (140, 150))	('microenvironment', 'MPA', (223, 239))	('Claudin-2', 'Gene', (0, 9))	('BE', 'Phenotype', 'HP:0100580', (325, 327))	('columnar cell metaplasia', 'Disease', (296, 320))
436443	25395880	Since adenocarcinoma is known to primarily affect patients with GERD resulting in intestinal metaplasia and squamous cell carcinoma (SCC) is known to primarily affect patients with achalasia, victims of caustic ingestion, diet rich in processed foods, and smokers especially in the setting of alcohol consumption, it may indeed be prudent to target this cohort of patients and subject them to undergo routine surveillance endoscopies.	('GERD', 'Var', (64, 68))	('achalasia', 'Disease', (181, 190))	('squamous cell carcinoma', 'Disease', (108, 131))	('patients', 'Species', '9606', (364, 372))	('alcohol', 'Chemical', 'MESH:D000438', (293, 300))	('intestinal metaplasia', 'Disease', (82, 103))	('achalasia', 'Phenotype', 'HP:0002571', (181, 190))	('adenocarcinoma', 'Disease', (6, 20))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))	('patients', 'Species', '9606', (50, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('adenocarcinoma', 'Disease', 'MESH:D000230', (6, 20))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (82, 103))	('SCC', 'Gene', '6317', (133, 136))	('patients', 'Species', '9606', (167, 175))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('affect', 'Reg', (160, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('achalasia', 'Disease', 'MESH:D004931', (181, 190))	('SCC', 'Gene', (133, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
436476	25395880	Ground-breaking research at MD Anderson has now demonstrated how inhibition of anticytotoxic T-lymphocyte antigen 4 receptor can allow the immune system to evade cancer, thus resulting in establishing a "vaccine against melanoma".	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('inhibition', 'Var', (65, 75))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanoma', 'Disease', (220, 228))	('melanoma', 'Disease', 'MESH:D008545', (220, 228))
436480	25395880	Targeted therapy against CSCs can inhibit tumor proliferation, migration and therefore development of metastases (EMT pathway).	('tumor', 'Disease', (42, 47))	('CSCs', 'Gene', (25, 29))	('Targeted', 'Var', (0, 8))	('metastases', 'Disease', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('inhibit', 'NegReg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('migration', 'CPA', (63, 72))	('metastases', 'Disease', 'MESH:D009362', (102, 112))
436495	25395880	Perforations, subsequent stricture development, risk of tumor recurrence, and the establishment of surveillance protocols are some of the issues that have risen from these lesser interventional procedures.	('Perforations', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('stricture development', 'CPA', (25, 46))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
436502	23409141	Notch1 Is a 5-Fluorouracil Resistant and Poor Survival Marker in Human Esophagus Squamous Cell Carcinomas Notch signaling involves the processes that govern cell proliferation, cell fate decision, cell differentiation and stem cell maintenance.	('Notch1', 'Gene', (0, 6))	('Notch1', 'Gene', '4851', (0, 6))	('Human', 'Species', '9606', (65, 70))	('Carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('Esophagus Squamous Cell Carcinomas', 'Disease', (71, 105))	('Esophagus Squamous Cell Carcinomas', 'Disease', 'MESH:D002294', (71, 105))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (12, 26))	('Squamous Cell Carcinomas', 'Phenotype', 'HP:0002860', (81, 105))	('Notch signaling', 'Var', (106, 121))	('involves', 'Reg', (122, 130))
436510	23409141	We conclude that Notch1 expression is associated with cell aggressiveness and 5-FU drug resistance in human esophageal squamous cell carcinoma cell lines in vitro and is significantly associated with a poor survival in human esophageal squamous cell carcinomas.	('squamous cell carcinoma cell lines', 'Disease', (119, 153))	('poor', 'NegReg', (202, 206))	('aggressiveness', 'Disease', (59, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('aggressiveness', 'Phenotype', 'HP:0000718', (59, 73))	('Notch1', 'Gene', (17, 23))	('associated', 'Reg', (38, 48))	('squamous cell carcinoma cell lines', 'Disease', 'MESH:D002294', (119, 153))	('aggressiveness', 'Disease', 'MESH:D001523', (59, 73))	('drug resistance', 'Phenotype', 'HP:0020174', (83, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (236, 259))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (225, 259))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (108, 142))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (236, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('esophageal squamous cell carcinomas', 'Disease', (225, 260))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (225, 260))	('associated with', 'Reg', (184, 199))	('human', 'Species', '9606', (102, 107))	('5-FU drug resistance', 'MPA', (78, 98))	('expression', 'Var', (24, 34))	('5-FU', 'Chemical', 'MESH:D005472', (78, 82))	('human', 'Species', '9606', (219, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('carcinomas', 'Phenotype', 'HP:0030731', (250, 260))	('esophageal squamous cell carcinoma', 'Disease', (108, 142))
436513	23409141	Altered Notch signaling has been associated with different malignancies including pancreatic, breast and colon carcinomas, in addition to glioma, leukemia and lymphoma.	('Notch signaling', 'MPA', (8, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('glioma', 'Disease', (138, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('breast and colon carcinomas', 'Disease', 'MESH:D015179', (94, 121))	('malignancies', 'Disease', 'MESH:D009369', (59, 71))	('Altered', 'Var', (0, 7))	('leukemia and lymphoma', 'Disease', 'MESH:D007938', (146, 167))	('pancreatic', 'Disease', 'MESH:D010195', (82, 92))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('associated', 'Reg', (33, 43))	('malignancies', 'Disease', (59, 71))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (159, 167))	('pancreatic', 'Disease', (82, 92))
436517	23409141	Hes-1, the downstream molecule of the Notch pathway, has been associated with invasive and metastatic potential of osteosarcomas, and inhibition of Notch pathway by gamma-secretase inhibitors could eliminate invasion in Matrigel without affecting cell proliferation, survival or anchorage-independent growth.	('Hes-1', 'Gene', '3280', (0, 5))	('inhibition', 'Var', (134, 144))	('associated', 'Reg', (62, 72))	('eliminate', 'NegReg', (198, 207))	('invasion in Matrigel', 'CPA', (208, 228))	('metastatic potential', 'CPA', (91, 111))	('osteosarcomas', 'Disease', (115, 128))	('osteosarcomas', 'Phenotype', 'HP:0002669', (115, 128))	('Hes-1', 'Gene', (0, 5))	('osteosarcomas', 'Disease', 'MESH:D012516', (115, 128))
436521	23409141	Inhibition of Notch signaling abrogates hypoxia-induced EMT and invasion, and, conversely, an activated form of Notch can substitute for hypoxia to induce these processes.	('hypoxia', 'Disease', (40, 47))	('hypoxia', 'Disease', 'MESH:D000860', (40, 47))	('hypoxia', 'Disease', 'MESH:D000860', (137, 144))	('hypoxia', 'Disease', (137, 144))	('abrogates', 'NegReg', (30, 39))	('Inhibition', 'Var', (0, 10))
436524	23409141	Further study shows that the expression of activated Notch1 causes strong growth inhibition of HPV-positive, but not HPV-negative, cervical carcinoma cells.	('carcinoma', 'Disease', (140, 149))	('expression', 'Var', (29, 39))	('growth inhibition', 'CPA', (74, 91))	('Notch1', 'Gene', (53, 59))	('carcinoma', 'Disease', 'MESH:D002277', (140, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
436525	23409141	In addition, aberrant notch expressions were also reported in human lung squamous cell carcinomas.	('notch expressions', 'MPA', (22, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (68, 97))	('reported', 'Reg', (50, 58))	('human', 'Species', '9606', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('lung squamous cell carcinomas', 'Disease', (68, 97))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (73, 97))	('aberrant', 'Var', (13, 21))
436566	23409141	Higher levels of both Notch1 and Notch3 RNA expression in the cancer cell lines than that in the Het-1A cell line were repeatedly verified (Figure 1A).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Notch3 RNA', 'Var', (33, 43))	('Notch1', 'Var', (22, 28))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
436568	23409141	Western blotting revealed that KYSE70 expressed high level Notch1, KYSE140 and Het-1A were weakly positive for Notch1 while KYSE450 was negative for Notch1 (Figure 1B).	('Notch1', 'Var', (111, 117))	('Notch1', 'Var', (59, 65))	('KYSE450', 'CellLine', 'CVCL:1353', (124, 131))
436572	23409141	As shown in Figure 2A and B, KYSE450 cells grow faster than KYSE70 cells under normoxia condition.	('KYSE450', 'CellLine', 'CVCL:1353', (29, 36))	('faster', 'PosReg', (48, 54))	('grow', 'CPA', (43, 47))	('KYSE450', 'Var', (29, 36))
436586	23409141	Figure 4D shows significantly less 5-FU growth inhibition in KYSE70 cells than in KYSE450 cells under hypoxia condition (P<0.001).	('KYSE70', 'Var', (61, 67))	('hypoxia condition', 'Disease', 'MESH:D000860', (102, 119))	('KYSE450', 'CellLine', 'CVCL:1353', (82, 89))	('hypoxia condition', 'Disease', (102, 119))	('5-FU growth inhibition', 'MPA', (35, 57))	('less', 'NegReg', (30, 34))	('5-FU', 'Chemical', 'MESH:D005472', (35, 39))
436589	23409141	In normoxia condition elevated levels of 5-FU sensitivity were repeatedly shown in the Notch1 specific siRNA treated cells (Figure 5B), compared to the Notch1 non-specific siRNA treated control cells (p = 0.004).	('levels', 'MPA', (31, 37))	('Notch1 specific siRNA', 'Var', (87, 108))	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('elevated', 'PosReg', (22, 30))	('5-FU sensitivity', 'MPA', (41, 57))
436590	23409141	Similarly cultivated in 1% O2 significantly higher levels of 5-FU sensitivity were observed in the Notch1 specific siRNA treated cells (Figure 5C, p = 0.004).	('levels', 'MPA', (51, 57))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('higher', 'PosReg', (44, 50))	('5-FU sensitivity', 'MPA', (61, 77))	('Notch1', 'Var', (99, 105))	('O2', 'Chemical', 'MESH:D010100', (27, 29))
436591	23409141	Immunohistochemical screening of the tissue microarray sections revealed variable Notch1 (Figure 6, upper panel) and Her-1 expressions (Figure 6, lower panel).	('Notch1', 'Var', (82, 88))	('Her-1', 'Gene', (117, 122))	('Her-1', 'Gene', '1956', (117, 122))	('expressions', 'MPA', (123, 134))
436605	23409141	In consistent with our previous study in prostate cancer cells with greater stemness in response to hypoxia, both KYSE70 and KYSE450 esophagus cancer cell lines were responding to hypoxia by upregulation of the stemness factors Oct3/4 and Sox2.	('upregulation', 'PosReg', (191, 203))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (41, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('Sox2', 'Gene', '6657', (239, 243))	('Oct3/4', 'Gene', '5460', (228, 234))	('Oct3/4', 'Gene', (228, 234))	('prostate cancer', 'Disease', (41, 56))	('responding', 'MPA', (166, 176))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('stemness factors', 'CPA', (211, 227))	('esophagus cancer', 'Disease', (133, 149))	('hypoxia', 'Disease', (100, 107))	('hypoxia', 'Disease', (180, 187))	('KYSE450', 'CellLine', 'CVCL:1353', (125, 132))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('KYSE450', 'Var', (125, 132))	('Sox2', 'Gene', (239, 243))	('esophagus cancer', 'Disease', 'MESH:D004938', (133, 149))	('hypoxia', 'Disease', 'MESH:D000860', (180, 187))
436608	23409141	However, we discovered that the KYSE70 cells showed significantly higher 5-FU resistance under both normoxia and hypoxia than the KYSE450 cells did.	('KYSE70', 'Var', (32, 38))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('KYSE450', 'CellLine', 'CVCL:1353', (130, 137))	('hypoxia', 'Disease', (113, 120))	('5-FU', 'Chemical', 'MESH:D005472', (73, 77))	('higher', 'PosReg', (66, 72))	('5-FU resistance', 'MPA', (73, 88))
436630	23409141	Agrawal et al discovered in a whole exome sequencing study of a series 32 primary head and neck squamous cell tumors that nearly 40% of the 28 mutations identified in Notch1 were predicted to truncate the gene product, and they suggest that Notch1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.	('truncate', 'NegReg', (192, 200))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', (110, 115))	('neck squamous cell tumors', 'Disease', 'MESH:D000077195', (91, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (320, 325))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('Notch1', 'Gene', (167, 173))	('neck squamous cell tumors', 'Disease', (91, 116))	('gene product', 'MPA', (205, 217))	('tumor', 'Disease', (266, 271))	('mutations', 'Var', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
436631	23409141	Using a tissue-specific Notch1 knockout approach in a mouse model Nicolas et al found that ablation of Notch1 resulted in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis.	('corneal hyperplasia', 'Disease', (136, 155))	('men', 'Species', '9606', (179, 182))	('skin tumors', 'Phenotype', 'HP:0008069', (187, 198))	('Notch1', 'Gene', (103, 109))	('ablation', 'Var', (91, 99))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('skin tumors', 'Disease', (187, 198))	('corneal hyperplasia', 'Phenotype', 'HP:0000485', (136, 155))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (232, 251))	('skin carcinogenesis', 'Disease', (232, 251))	('skin tumors', 'Disease', 'MESH:D012878', (187, 198))	('facilitated', 'PosReg', (203, 214))	('mouse', 'Species', '10090', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('corneal hyperplasia', 'Disease', 'MESH:D006965', (136, 155))
436635	23409141	However, double edge function of Notch1 do exist, not only because there are strong lines of evidence as suppressor, but also because about one fourth of the tumors in our study were negative for Notch1 expression; Functional mutation of Notch1 may trigger Notch1 overexpression in the rest cells of tumor by a till now unexplored mechanism, so that both functional mutation and overexpression of Notch1 may exist in the same tumors in different phases of tumor development.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('Notch1', 'Gene', (257, 263))	('tumor', 'Disease', (426, 431))	('tumor', 'Disease', 'MESH:D009369', (426, 431))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Functional mutation', 'Var', (215, 234))	('tumors', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumors', 'Phenotype', 'HP:0002664', (426, 432))	('tumor', 'Disease', (456, 461))	('Notch1', 'Gene', (238, 244))	('men', 'Species', '9606', (469, 472))	('tumor', 'Disease', 'MESH:D009369', (456, 461))	('tumor', 'Phenotype', 'HP:0002664', (426, 431))	('trigger', 'Reg', (249, 256))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', (426, 432))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (456, 461))	('tumor', 'Disease', (300, 305))	('tumors', 'Disease', 'MESH:D009369', (426, 432))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('overexpression', 'MPA', (264, 278))
436672	19336548	Thus began a series of interdisciplinary exchanges that resulted in our working together to conduct and publish a study showing that menthol, especially in the presence of ethanol (remember that these exposures, which often occur together, seem to act synergistically to increase cancer risk), increases permeation and reservoir formation of two known tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo(a)pyrene.	('tobacco', 'Species', '4097', (352, 359))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('permeation', 'MPA', (304, 314))	('benzo(a)pyrene', 'Chemical', 'MESH:D001564', (424, 438))	('menthol', 'Chemical', 'MESH:D008610', (133, 140))	('menthol', 'Var', (133, 140))	('cancer', 'Disease', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone', 'Chemical', 'MESH:C016583', (373, 419))	('increase', 'PosReg', (271, 279))	('reservoir formation', 'MPA', (319, 338))	('increases', 'PosReg', (294, 303))	('ethanol', 'Chemical', 'MESH:D000431', (172, 179))
436726	33933129	The total RPA score was calculated for each patient using the following factors: gender (female = 0, male = 1), site of the lesion (lower or middle segment = 0, upper segment = 1), SLNs in CT (no = 0, yes = 1), dissected LNs (<= 12 = 0, > 12 = 1) and pT stage (pT1 = 0, pT2 = 1, pT3 = 2).	('patient', 'Species', '9606', (44, 51))	('pT1', 'Gene', (261, 264))	('pT3', 'Gene', '7694', (279, 282))	('<=', 'Var', (226, 228))	('pT3', 'Gene', (279, 282))	('pT1', 'Gene', '58492', (261, 264))
436730	33933129	The optimal surgical technique for the curative treatment of patients with pN0 esophageal cancer has remained controversial.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('patients', 'Species', '9606', (61, 69))	('pN0', 'Var', (75, 78))	('pN0 esophageal cancer', 'Phenotype', 'HP:0011459', (75, 96))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
436748	33933129	reported that the five- and 10-year OS rates were 83.8 and 71.9% for pT1N0M0, 78.8 and 67.4% for pT2N0M0, 67.8 and 51.1% for pT3N0M0 ESCC patients after three-field surgery, respectively.	('pT1', 'Gene', (69, 72))	('pT3', 'Gene', (125, 128))	('pT2N0M0', 'Var', (97, 104))	('pT3', 'Gene', '7694', (125, 128))	('pT1', 'Gene', '58492', (69, 72))	('patients', 'Species', '9606', (138, 146))
436830	31901859	The expression levels of ATP6V1C1, ATP6V1C2 variant 1 (v1) and ATP6V1C2 variants 1 and 2 (v1,2) were analyzed using the oligonucleotides shown in Table S2.	('variant', 'Var', (44, 51))	('ATP6V1C1', 'Gene', (25, 33))	('ATP6V1C2', 'Gene', '245973', (63, 71))	('ATP6V1C1', 'Gene', '528', (25, 33))	('ATP6V1C2', 'Gene', '245973', (35, 43))	('ATP6V1C2', 'Gene', (35, 43))	('ATP6V1C2', 'Gene', (63, 71))
436834	31901859	The prediction of 3D models for hC1 (NP_001686.1), hC2b (NP_653184.2) and hC2a (NP_001034451.1) isoforms was performed by homology and ab initio modeling by four distinct programs: Modeller 9.19, Swiss-Model, RaptorX and I-Tasser.	('NP_001034451.1', 'Var', (80, 94))	('hC1', 'Gene', '3217', (32, 35))	('NP_001686.1', 'Var', (37, 48))	('hC1', 'Gene', (32, 35))	('hC2b', 'Gene', (51, 55))	('hC2b', 'Gene', '100130342', (51, 55))
436853	31901859	For ATP6V1C2-v1 and ATP6V1C2-v1,2 the mRNA levels were significantly lower in the ESCC group than those in the normal surrounding tissues group, with the median values of -4.3 and -9.6-fold, respectively (v1: median of 0.000489 in ESCC and 0.00241074 normal surrounding; v1,2: median of in 0.000629 ESCC and 0.006044 normal surrounding) (Fig.	('ESCC', 'Disease', (231, 235))	('ESCC', 'Disease', (82, 86))	('ESCC', 'Disease', 'MESH:C562729', (299, 303))	('ATP6V1C2', 'Gene', '245973', (20, 28))	('ATP6V1C2', 'Gene', '245973', (4, 12))	('lower', 'NegReg', (69, 74))	('ATP6V1C2', 'Gene', (4, 12))	('ESCC', 'Disease', 'MESH:C562729', (231, 235))	('ATP6V1C2', 'Gene', (20, 28))	('ESCC', 'Disease', (299, 303))	('mRNA levels', 'MPA', (38, 49))	('0.00241074', 'Var', (240, 250))	('0.006044', 'Var', (308, 316))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))
436860	31901859	These results suggest that the expression levels of the different C isoforms are carefully guarded to achieve a proportional balance in normal tissues, which dysregulation towards the C1 prevalence over the C2 is an intrinsic characteristic of ESCC.	('C1', 'Gene', '3217', (184, 186))	('ESCC', 'Disease', 'MESH:C562729', (244, 248))	('dysregulation', 'Var', (158, 171))	('ESCC', 'Disease', (244, 248))
436866	31901859	In addition, we performed the analysis of conserved domains among the human V-ATPase subunits C1 (NP_001686.1) (hC1), C2a (NP_001034451.1) (hC2a) and C2b (NP_653184.2) (hC2b) using the program BLASTP 2.8.0 in the mammalian taxon of the database NCBI Protein Reference Sequences.	('hC1', 'Gene', (112, 115))	('C1', 'Gene', '3217', (113, 115))	('C2b', 'Gene', (170, 173))	('hC2b', 'Gene', '100130342', (169, 173))	('C2b', 'Gene', (150, 153))	('NP_001686.1', 'Var', (98, 109))	('human', 'Species', '9606', (70, 75))	('hC1', 'Gene', '3217', (112, 115))	('C2b', 'Gene', '100130342', (170, 173))	('V-ATPase', 'Gene', '1769', (76, 84))	('V-ATPase', 'Gene', (76, 84))	('NP_001034451.1', 'Var', (123, 137))	('C1', 'Gene', '3217', (94, 96))	('mammalian', 'Species', '9606', (213, 222))	('hC2b', 'Gene', (169, 173))	('C2b', 'Gene', '100130342', (150, 153))
436898	31901859	Moreover, a knockdown of a4 did not affect invasion of breast cancer cells, but resulted in a 2-fold increase in the a3 mRNA levels, which is in line with our results suggesting a tightly regulated balance among the isoforms of these V-ATPase subunits.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('V-ATPase', 'Gene', (234, 242))	('knockdown', 'Var', (12, 21))	('increase', 'PosReg', (101, 109))	('a3 mRNA levels', 'MPA', (117, 131))	('V-ATPase', 'Gene', '1769', (234, 242))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
436903	31901859	This model provides new insights on previous reports, where V-ATPase containing C2a or C2b isoforms exhibited lower coupling efficiency between ATP hydrolysis and proton transport than V-ATPase containing C1 or Vma5p (yeast C subunit).	('V-ATPase', 'Gene', '1769', (60, 68))	('yeast', 'Species', '4932', (218, 223))	('Vma5p', 'Gene', '853782', (211, 216))	('C2a', 'Var', (80, 83))	('V-ATPase', 'Gene', (185, 193))	('C2b', 'Gene', '100130342', (87, 90))	('ATP', 'Chemical', 'MESH:D000255', (62, 65))	('ATP', 'Chemical', 'MESH:D000255', (144, 147))	('lower', 'NegReg', (110, 115))	('V-ATPase', 'Gene', '1769', (185, 193))	('V-ATPase', 'Gene', (60, 68))	('ATP', 'Chemical', 'MESH:D000255', (187, 190))	('C2b', 'Gene', (87, 90))	('C1', 'Gene', '3217', (205, 207))	('Vma5p', 'Gene', (211, 216))	('coupling efficiency', 'MPA', (116, 135))
436951	31600976	The CAIX inhibitor FC12-520A gave the strongest heat decrease response.	('heat', 'MPA', (48, 52))	('heat decrease response', 'Phenotype', 'HP:0002046', (48, 70))	('CAIX', 'Gene', (4, 8))	('FC12-520A', 'Var', (19, 28))	('CAIX', 'Gene', '768', (4, 8))
436955	31600976	Although FC12-520A leads to the strongest response amongst the CAIX inhibitors all CAIX inhibitors show a heat flow reduction in a similar range, demonstrating consistency of CAIX inhibition.	('CAIX', 'Gene', '768', (63, 67))	('CAIX', 'Gene', '768', (83, 87))	('CAIX', 'Gene', (175, 179))	('response', 'MPA', (42, 50))	('reduction', 'NegReg', (116, 125))	('FC12-520A', 'Var', (9, 18))	('CAIX', 'Gene', '768', (175, 179))	('CAIX', 'Gene', (63, 67))	('CAIX', 'Gene', (83, 87))	('heat flow', 'MPA', (106, 115))
436982	31600976	Tissue slices were cultured in TUM medium at 37  C for 24 h. Following this initial incubation period the medium was changed and specific experimental inhibitors (CAIX inhibitors: FC8-325A, FC8-207A, FC12-520A and AQP1 inhibitor TEA (Merck, Sigma-Aldrich Chemie GmbH Buchs, Switzerland) added to final concentrations of 500 muM.	('TEA', 'Chemical', 'MESH:C488288', (229, 232))	('AQP1', 'Gene', (214, 218))	('CAIX', 'Gene', '768', (163, 167))	('AQP1', 'Gene', '358', (214, 218))	('FC12-520A', 'Var', (200, 209))	('CAIX', 'Gene', (163, 167))
437036	29029539	The embolic agent, microspheres (Embosphere Microspheres, BioSphere Medical, diameters ranging from 500 to 1200 mum) and irregular PVA particles (500-1000 mum, multiple vendors), multiple Tornado embolization microcoils (Cook, Bloomington, IN, USA), N-butyl-2-cyanoacrylate (Compont Medical Adhesive; Beijing Compont Medical Devices Co., Ltd., Beijing, China, 0.5ml), or gelatin sponge particles (100-1400mum) were selected by the velocity of the flow of fistula-feeding artery(s) and the size and location of the fistula.	('embolic agent', 'Phenotype', 'HP:0001907', (4, 17))	('100-1400mum', 'Var', (397, 408))	('N-butyl-2-cyanoacrylate', 'Chemical', 'MESH:D004659', (250, 273))	('fistula', 'Disease', 'MESH:D005402', (514, 521))	('embolic', 'Disease', (4, 11))	('fistula-feeding artery', 'Phenotype', 'HP:0025154', (455, 477))	('fistula', 'Disease', 'MESH:D005402', (455, 462))	('fistula', 'Disease', (455, 462))	('fistula', 'Disease', (514, 521))	('embolic', 'Disease', 'MESH:D004617', (4, 11))
437107	29029539	In patients with mild-severity IAPF, the outcome of endoscopic treatment was slightly better than that of TAE procedures because these patients were similar to other patients with cirrhotic variceal bleeding.	('cirrhotic variceal bleeding', 'Disease', (180, 207))	('patients', 'Species', '9606', (135, 143))	('mild-severity', 'Var', (17, 30))	('IAPF', 'Disease', 'None', (31, 35))	('IAPF', 'Disease', (31, 35))	('patients', 'Species', '9606', (3, 11))	('TAE', 'Chemical', '-', (106, 109))	('cirrhotic variceal bleeding', 'Disease', 'MESH:D014648', (180, 207))	('patients', 'Species', '9606', (166, 174))
437141	28947442	A number of studies have shown that changes of chemical elements levels might be linked to the risk of some cancers, including EC.	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('changes', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('linked', 'Reg', (81, 87))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('chemical elements levels', 'MPA', (47, 71))	('cancers', 'Disease', (108, 115))
437173	28947442	For two-class problems, a detailed report of classification results is the confusion matrix consisting of four numbers: true positive (TP), false positive (FP), true negative (TN) and false negative (FN).	('P', 'Chemical', 'MESH:D010758', (157, 158))	('P', 'Chemical', 'MESH:D010758', (136, 137))	('confusion', 'Phenotype', 'HP:0001289', (75, 84))	('false positive', 'Var', (140, 154))	('false negative', 'Var', (184, 198))
437263	27900728	reported that 5-year metastasis rates for EP/LPM, MM, SM1, and SM2 ESCC were 0.4, 8.7, 7.7, and 36.2%, respectively and for mucosal cancer with and without lymphovascular permeation, 46.7 and 0.7%, respectively.	('mucosal cancer', 'Disease', (124, 138))	('SM1', 'Gene', '7911', (54, 57))	('SM2', 'Gene', (63, 66))	('metastasis', 'CPA', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mucosal cancer', 'Disease', 'MESH:D009062', (124, 138))	('EP/LPM', 'Var', (42, 48))	('SM1', 'Gene', (54, 57))	('SM2', 'Gene', '53366', (63, 66))
437282	27900728	reported that chemoradiotherapy after ESD was an effective and safe approach for T1a-MM or T1b ESCCs.	('T1a', 'Gene', (81, 84))	('T1a', 'Gene', '10630', (81, 84))	('T1b', 'Var', (91, 94))
437320	26571024	Dysregulation of membrane proteins has been linked to a variety of human cancers.	('cancers', 'Disease', (73, 80))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('membrane proteins', 'Protein', (17, 34))	('linked', 'Reg', (44, 50))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
437335	26571024	Various doses of CE146T cells (102, 103, and 104) were injected subcutaneously into both flanks of 5-week-old male NOD-SCID mice to generate tumors.	('NOD', 'Gene', '1822', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('mice', 'Species', '10090', (124, 128))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('CE146', 'Chemical', '-', (17, 22))	('NOD', 'Gene', (115, 118))	('CE146T', 'Var', (17, 23))
437342	26571024	The results showed that CE146T has remarkably higher migration and invasion abilities than CE81T (Fig 1A and 1B), which was identified as a well differentiated cancer cell.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('higher', 'PosReg', (46, 52))	('cancer', 'Disease', (160, 166))	('CE146', 'Chemical', '-', (24, 29))	('migration', 'CPA', (53, 62))	('invasion abilities', 'CPA', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CE146T', 'Var', (24, 30))
437343	26571024	In addition, CE146T also has higher sphere formation ability than CE81T (Fig 1C).	('higher', 'PosReg', (29, 35))	('CE146', 'Chemical', '-', (13, 18))	('CE146T', 'Var', (13, 19))	('sphere formation ability', 'CPA', (36, 60))
437345	26571024	Accordingly, we used flow cytometry to analyze the expression of CD44 in CE146T and CE81T.	('CE146T', 'Var', (73, 79))	('CE81T', 'Var', (84, 89))	('CD44', 'Gene', '960', (65, 69))	('CE146', 'Chemical', '-', (73, 78))	('CD44', 'Gene', (65, 69))
437346	26571024	The result showed that CE146T has higher levels of CD44 than CE81T (Fig 1D).	('CE146', 'Chemical', '-', (23, 28))	('higher', 'PosReg', (34, 40))	('CD44', 'Gene', '960', (51, 55))	('CE146T', 'Var', (23, 29))	('CD44', 'Gene', (51, 55))	('levels', 'MPA', (41, 47))
437347	26571024	Taken together, these data indicated that CE146T has more CSC population and exhibits more CSC properties than CE81T, implying that we are able to identify CSC markers by comparing the proteomic changes of CE146T and CE81T.	('CE146T', 'Var', (42, 48))	('CE81T', 'Var', (217, 222))	('more', 'PosReg', (53, 57))	('CSC population', 'CPA', (58, 72))	('CE146', 'Chemical', '-', (42, 47))	('CSC properties', 'CPA', (91, 105))	('CE146', 'Chemical', '-', (206, 211))	('CE146T', 'Var', (206, 212))
437348	26571024	Thus, we used a comparative membrane proteomic analysis to identify the novel CSC markers from CE146T and CE81T.	('CE81T', 'Var', (106, 111))	('CE146T', 'Var', (95, 101))	('CE146', 'Chemical', '-', (95, 100))	('CSC', 'Disease', (78, 81))
437349	26571024	Although CE146T and CE81T are not isogenic, CE146T may express higher levels of proteins associated with CSC properties than CE81T based on above observations.	('CE146', 'Chemical', '-', (44, 49))	('levels of proteins', 'MPA', (70, 88))	('CSC', 'Disease', (105, 108))	('CE146T', 'Var', (44, 50))	('CE146', 'Chemical', '-', (9, 14))	('higher', 'PosReg', (63, 69))
437350	26571024	Among membrane proteins, total 13 proteins showed specific expression or more than a 50-fold increase of expression in CE146T compared with CE81T (Table 1).	('increase', 'PosReg', (93, 101))	('CE146', 'Chemical', '-', (119, 124))	('expression', 'MPA', (59, 69))	('CE146T', 'Var', (119, 125))	('expression', 'MPA', (105, 115))
437351	26571024	RT-PCR and qPCR results showed that intercellular adhesion molecule 1 (ICAM1) and prominin-2 (PROM2) have higher gene expression in CE146T than in CE81T, which is consistent with the proteomic finding (Fig 2A and 2B).	('gene expression', 'MPA', (113, 128))	('CE146T', 'Var', (132, 138))	('PROM2', 'Gene', '150696', (94, 99))	('prominin-2', 'Gene', '150696', (82, 92))	('CE146', 'Chemical', '-', (132, 137))	('PROM2', 'Gene', (94, 99))	('intercellular adhesion molecule 1', 'Gene', (36, 69))	('higher', 'PosReg', (106, 112))	('intercellular adhesion molecule 1', 'Gene', '3383', (36, 69))	('prominin-2', 'Gene', (82, 92))
437352	26571024	Western blot showed that ICAM1 has a high expression in CE146T, but not PROM2 (Fig 2C).	('CE146T', 'Var', (56, 62))	('PROM2', 'Gene', '150696', (72, 77))	('PROM2', 'Gene', (72, 77))	('expression', 'MPA', (42, 52))	('CE146', 'Chemical', '-', (56, 61))	('ICAM1', 'Gene', (25, 30))
437353	26571024	Two kinds of ICAM1 shRNA were transfected into CE146T (labeled as shICAM1#1 and shICAM1#2), both transfected cells showed obvious knockdown of ICAM1 in western blot assay (Fig 3A).	('CE146', 'Chemical', '-', (47, 52))	('ICAM1', 'Gene', (143, 148))	('knockdown', 'Var', (130, 139))
437354	26571024	ICAM1 knockdown did not affect cell growth of CE146T (Fig 3B), but it significantly reduced cell migration and invasion abilities of CE146T in wound-healing and transwell assays, respectively (Fig 3C and 3D).	('wound-healing', 'CPA', (143, 156))	('CE146', 'Chemical', '-', (133, 138))	('invasion abilities', 'CPA', (111, 129))	('reduced', 'NegReg', (84, 91))	('transwell assays', 'CPA', (161, 177))	('cell migration', 'CPA', (92, 106))	('ICAM1', 'Gene', (0, 5))	('CE146T', 'Var', (133, 139))	('knockdown', 'Var', (6, 15))	('CE146', 'Chemical', '-', (46, 51))
437355	26571024	In addition, two pharmacological ICAM1 inhibitors, silibinin and 18 beta-glycyrrhetinic acid (18beta-GA), displayed similar effect on reducing the migration and invasion abilities of CE146T (Fig 3C and 3D).	('ICAM1', 'Gene', (33, 38))	('migration', 'CPA', (147, 156))	('invasion abilities', 'CPA', (161, 179))	('reducing', 'NegReg', (134, 142))	('CE146T', 'Var', (183, 189))	('18beta-GA', 'Chemical', 'MESH:C119129', (94, 103))	('beta-glycyrrhetinic acid', 'Chemical', '-', (68, 92))	('silibinin', 'Chemical', 'MESH:D000077385', (51, 60))	('CE146', 'Chemical', '-', (183, 188))
437356	26571024	The results indicated that ICAM1 contributes to CE146T metastatic properties in vitro.	('CE146T', 'Var', (48, 54))	('CE146', 'Chemical', '-', (48, 53))	('ICAM1', 'Gene', (27, 32))
437359	26571024	The result indicated that ICAM1 knockdown significantly reduces the sphere formation ability of CE146Y, no matter in sphere number or in sphere size (Fig 4A).	('sphere formation ability', 'CPA', (68, 92))	('knockdown', 'Var', (32, 41))	('ICAM1', 'Gene', (26, 31))	('reduces', 'NegReg', (56, 63))	('CE146Y', 'Var', (96, 102))	('CE146', 'Chemical', '-', (96, 101))
437360	26571024	In addition, it also significantly reduced the secondary sphere formation of CE146T (Fig 4B).	('CE146T', 'Var', (77, 83))	('secondary sphere formation', 'CPA', (47, 73))	('CE146', 'Chemical', '-', (77, 82))	('reduced', 'NegReg', (35, 42))
437363	26571024	The result showed that ICAM1 knockdown reduces the ability of cisplatin resistance of CE146T, and the IC50 of CE146T in control group (shGFP) and ICAM1 knockdown group (shICA1#1) are 5 muM and 3.5 muM of cisplatin, respectively (Fig 4C).	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('knockdown', 'Var', (29, 38))	('ICAM1', 'Gene', (23, 28))	('CE146T', 'Var', (110, 116))	('cisplatin resistance', 'MPA', (62, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (204, 213))	('CE146', 'Chemical', '-', (86, 91))	('CE146', 'Chemical', '-', (110, 115))	('reduces', 'NegReg', (39, 46))
437364	26571024	To study the functions of ICAM1 on tumorigenesis in vivo, we injected subcutaneously into both flanks of NOD-SCID mice with 102, 103, or 104 of CE146T cells.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CE146', 'Chemical', '-', (144, 149))	('NOD', 'Gene', '1822', (105, 108))	('tumor', 'Disease', (35, 40))	('NOD', 'Gene', (105, 108))	('CE146T', 'Var', (144, 150))	('mice', 'Species', '10090', (114, 118))
437366	26571024	The results showed that even low dose of CE146T cells (102) without subpopulation enrichment is able to induce tumorigenesis in NOD-SCID mice, suggesting that CE146T indeed has high population of CSC (Fig 5B and 5C).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('CE146T', 'Var', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('NOD', 'Gene', (128, 131))	('tumor', 'Disease', (111, 116))	('CE146', 'Chemical', '-', (41, 46))	('CE146', 'Chemical', '-', (159, 164))	('mice', 'Species', '10090', (137, 141))	('NOD', 'Gene', '1822', (128, 131))
437367	26571024	In addition, higher dose of ICAM1 knockdown CE146T cells (104) are needed to induce tumor formation, revealing that ICAM1 knockdown reduces in vivo tumorigenic potential, one of the important properties of CSC (Fig 5B and 5C).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('CE146', 'Chemical', '-', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (148, 153))	('knockdown', 'Var', (122, 131))	('tumor', 'Disease', (84, 89))	('reduces', 'NegReg', (132, 139))	('ICAM1', 'Gene', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
437372	26571024	Therefore, we examined p53 protein levels of CE146T in shGFP control and under the treatment of shRNA or pharmacological ICAM1 inhibitor condition.	('CE146T', 'Var', (45, 51))	('CE146', 'Chemical', '-', (45, 50))	('examined', 'Reg', (14, 22))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))
437373	26571024	Western blot revealed that ICAM1 knockdown and pharmacological inhibitors are able to increase p53 levels of CE146T (Fig 6A), implying that ICAM1 may regulate esophageal CSC characters, at least partly, by reducing p53 levels and its related signaling pathways.	('signaling pathways', 'Pathway', (242, 260))	('increase', 'PosReg', (86, 94))	('CE146', 'Chemical', '-', (109, 114))	('reducing', 'NegReg', (206, 214))	('knockdown', 'Var', (33, 42))	('inhibitors', 'Var', (63, 73))	('esophageal CSC', 'Disease', (159, 173))	('p53', 'Gene', (215, 218))	('ICAM1', 'Var', (140, 145))	('regulate', 'Reg', (150, 158))	('p53', 'Gene', '7157', (215, 218))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('ICAM1', 'Gene', (27, 32))
437375	26571024	The result showed that mRNA levels of pituitary tumor-transforming gene 1 protein-interacting protein (PTTG1IP) and DNA (cytosine-5)-methyltransferase 1 (DNMT1) are obviously reduced under ICAM1 knockdown condition, which is consistent with the proteomic result (Fig 6B).	('reduced', 'NegReg', (175, 182))	('PTTG1IP', 'Gene', '102723899', (103, 110))	('PTTG1IP', 'Gene', (103, 110))	('DNMT1', 'Gene', (154, 159))	('ICAM1', 'Gene', (189, 194))	('DNA (cytosine-5)-methyltransferase 1', 'Gene', '1786', (116, 152))	('mRNA levels', 'MPA', (23, 34))	('pituitary tumor-transforming gene 1 protein-interacting protein', 'Gene', '102723899', (38, 101))	('knockdown', 'Var', (195, 204))	('DNMT1', 'Gene', '1786', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
437376	26571024	In the xenotransplantation experiment, ICAM1 knockdown loses its inhibition power on tumorigenesis at high cell number (104) injection condition (Fig 5B).	('tumor', 'Disease', (85, 90))	('inhibition', 'NegReg', (65, 75))	('ICAM1', 'Gene', (39, 44))	('loses', 'NegReg', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('knockdown', 'Var', (45, 54))
437379	26571024	The result revealed that ICAM1 knockdown using both shRNA and pharmacological inhibition efficiently reduces ICAM1 expression and simultaneously increases CD44 expression in a reverse correlation manner (Fig 7A).	('expression', 'MPA', (160, 170))	('ICAM1', 'Gene', (109, 114))	('reduces', 'NegReg', (101, 108))	('increases', 'PosReg', (145, 154))	('expression', 'MPA', (115, 125))	('CD44', 'Gene', '960', (155, 159))	('ICAM1', 'Gene', (25, 30))	('knockdown', 'Var', (31, 40))	('CD44', 'Gene', (155, 159))
437380	26571024	In addition, CD44 knockdown is also able to increase ICAM1 by reverse correlation in a similar manner (Fig 7B).	('knockdown', 'Var', (18, 27))	('ICAM1', 'Gene', (53, 58))	('CD44', 'Gene', '960', (13, 17))	('increase', 'PosReg', (44, 52))	('CD44', 'Gene', (13, 17))
437385	26571024	Our investigation showed the presence of ICAM1 contributes to cancer cell sphere formation, drug resistance, and tumorigenesis in mouse xenotransplantation model, indicating that ICAM1 can be used as a potential CSC marker of ESCC and therefore serve as a therapeutic target for drug design and development.	('tumor', 'Disease', (113, 118))	('contributes', 'Reg', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('presence', 'Var', (29, 37))	('ICAM1', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Disease', (62, 68))	('ICAM1', 'Gene', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mouse', 'Species', '10090', (130, 135))	('drug resistance', 'CPA', (92, 107))	('drug resistance', 'Phenotype', 'HP:0020174', (92, 107))
437387	26571024	Our study observed that the expression of ICAM1 reversely correlates with p53 levels, suggesting that the high expression of ICAM1 could lead to cancer malignancy.	('ICAM1', 'Gene', (125, 130))	('lead to', 'Reg', (137, 144))	('high', 'Var', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('p53', 'Gene', (74, 77))	('cancer malignancy', 'Disease', 'MESH:D009369', (145, 162))	('p53', 'Gene', '7157', (74, 77))	('cancer malignancy', 'Disease', (145, 162))
437392	26571024	This result gives an explanation to our study that ICAM1 knockdown decreases PTTG1IP levels leading to stabilize p53, and thereby increasing p53 levels.	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('increasing', 'PosReg', (130, 140))	('knockdown', 'Var', (57, 66))	('PTTG1IP', 'Gene', '102723899', (77, 84))	('p53', 'Gene', '7157', (113, 116))	('decreases', 'NegReg', (67, 76))	('p53', 'Gene', (113, 116))	('PTTG1IP', 'Gene', (77, 84))	('ICAM1', 'Gene', (51, 56))
437394	26571024	DNMT1 overexpression was identified in various cancers and it could result in epigenetic alteration of multiple tumor suppressor genes and ultimately lead to tumorigenesis and poor prognosis.	('poor prognosis', 'CPA', (176, 190))	('tumor', 'Disease', (158, 163))	('lead to', 'Reg', (150, 157))	('epigenetic alteration', 'Var', (78, 99))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancers', 'Disease', (47, 54))	('result in', 'Reg', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('overexpression', 'PosReg', (6, 20))	('DNMT1', 'Gene', (0, 5))	('DNMT1', 'Gene', '1786', (0, 5))	('tumor', 'Disease', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
437397	26571024	Signaling pathway cross-talk, for instance mTOR/S6K1 and Hedgehog pathways or EGFR and VEGF pathways, is well recognized to provide complex interaction and extensive communication in response to cellular stimulation, and lead to synergistic or antagonistic effects and eventually desirable biological outcomes.	('VEGF', 'Gene', (87, 91))	('Hedgehog pathways', 'Pathway', (57, 74))	('lead to', 'Reg', (221, 228))	('S6K1', 'Gene', (48, 52))	('S6K1', 'Gene', '6198', (48, 52))	('VEGF', 'Gene', '7422', (87, 91))	('mTOR', 'Gene', (43, 47))	('interaction', 'Interaction', (140, 151))	('mTOR', 'Gene', '2475', (43, 47))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (78, 82))	('cross-talk', 'Var', (18, 28))	('synergistic', 'Interaction', (229, 240))
437407	20587703	An increase in IL-2 tertile from baseline to t10 was also non-significantly associated with worsening dysplasia for all participants (OR=1.32 p=0.098), and significantly associated with worsening dysplasia among those with mild dysplasia at baseline (OR=2.0 p=0.01).	('dysplasia', 'Disease', (196, 205))	('t10', 'Var', (45, 48))	('dysplasia', 'Disease', 'MESH:D004476', (196, 205))	('dysplasia', 'Disease', (228, 237))	('dysplasia', 'Disease', 'MESH:D004476', (102, 111))	('participants', 'Species', '9606', (120, 132))	('associated with', 'Reg', (170, 185))	('mild dysplasia', 'Disease', 'MESH:D010661', (223, 237))	('IL-2', 'Gene', '3558', (15, 19))	('dysplasia', 'Disease', (102, 111))	('mild dysplasia', 'Disease', (223, 237))	('dysplasia', 'Disease', 'MESH:D004476', (228, 237))	('IL-2', 'Gene', (15, 19))	('increase', 'PosReg', (3, 11))
437411	20587703	The favorable effect of selenomethionine on esophageal dysplasia in the original trial may have been mediated in part by its effect on reducing levels of IL-2.	('IL-2', 'Gene', '3558', (154, 158))	('IL-2', 'Gene', (154, 158))	('selenomethionine', 'Chemical', 'MESH:D012645', (24, 40))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (44, 64))	('selenomethionine', 'Var', (24, 40))	('reducing', 'NegReg', (135, 143))	('esophageal dysplasia', 'Disease', (44, 64))
437418	20587703	It found that subjects supplemented with selenium, beta-carotene, and alpha-tocopherol had a statistically significant reduction in all-cause mortality (9%) and in total cancer mortality (13%).	('alpha-tocopherol', 'Var', (70, 86))	('reduction', 'NegReg', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('beta-carotene', 'Var', (51, 64))	('selenium', 'Chemical', 'MESH:D012643', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('all-cause', 'CPA', (132, 141))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (70, 86))	('beta-carotene', 'Chemical', 'MESH:D019207', (51, 64))
437420	20587703	We subsequently conducted a randomized, controlled 10 month intervention of selenomethionine 200ug QD and/or celecoxib 200mg BID (2 x 2 factorial design) that included 238 residents of Linxian with biopsy-proven mild or moderate squamous dysplasia.	('selenomethionine', 'Var', (76, 92))	('squamous dysplasia', 'Disease', (229, 247))	('celecoxib', 'Chemical', 'MESH:D000068579', (109, 118))	('squamous dysplasia', 'Disease', 'MESH:D002294', (229, 247))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (229, 247))	('selenomethionine', 'Chemical', 'MESH:D012645', (76, 92))
437440	20587703	The statistical analysis explored 3 objectives: whether selenium or celecoxib treatments altered cytokine levels; whether baseline cytokine levels were associated with baseline dysplasia, dysplasia at t10, or change in dysplasia, after controlling for treatment effects; and whether the effect of treatment on dysplasia (regression, stable disease, progression) may have been mediated by cytokine levels.	('dysplasia', 'Disease', 'MESH:D004476', (219, 228))	('cytokine levels', 'MPA', (97, 112))	('selenium', 'Chemical', 'MESH:D012643', (56, 64))	('dysplasia', 'Disease', (310, 319))	('celecoxib', 'Chemical', 'MESH:D000068579', (68, 77))	('treatments', 'Var', (78, 88))	('dysplasia', 'Disease', 'MESH:D004476', (310, 319))	('dysplasia', 'Disease', (188, 197))	('dysplasia', 'Disease', (177, 186))	('dysplasia', 'Disease', 'MESH:D004476', (177, 186))	('associated', 'Reg', (152, 162))	('altered', 'Reg', (89, 96))	('dysplasia', 'Disease', (219, 228))	('dysplasia', 'Disease', 'MESH:D004476', (188, 197))
437446	20587703	If an individual cytokine's t10-t0 change was associated with a change in dysplasia and that cytokine's level was also associated with a treatment that changed dysplasia in the same direction (in objective 1), then we considered this to be evidence that this cytokine may have mediated the treatment effect.	('change', 'Reg', (64, 70))	('t10-t0', 'Var', (28, 34))	('dysplasia', 'Disease', (160, 169))	('dysplasia', 'Disease', 'MESH:D004476', (160, 169))	('dysplasia', 'Disease', (74, 83))	('dysplasia', 'Disease', 'MESH:D004476', (74, 83))	('associated', 'Reg', (46, 56))
437454	20587703	Selenomethionine treatment was associated with a lower t10-t0 difference in IL-2 (a median effect (IQR) of -1.0 (7.4) MFI, a -9.0% change, p=0.04) (Table 3).	('t10-t0 difference', 'MPA', (55, 72))	('Selenomethionine', 'Chemical', 'MESH:D012645', (0, 16))	('IL-2', 'Gene', '3558', (76, 80))	('lower', 'NegReg', (49, 54))	('IL-2', 'Gene', (76, 80))	('Selenomethionine', 'Var', (0, 16))
437464	20587703	There were no statistically significant associations between change in cytokine tertiles and change in dysplasia status among subjects on selenomethionine who began the trial with moderate dysplasia or among subjects on celecoxib treatment.	('dysplasia', 'Disease', 'MESH:D004476', (189, 198))	('dysplasia', 'Disease', (103, 112))	('dysplasia', 'Disease', 'MESH:D004476', (103, 112))	('celecoxib', 'Chemical', 'MESH:D000068579', (220, 229))	('dysplasia status', 'Disease', 'MESH:D013226', (103, 119))	('selenomethionine', 'Chemical', 'MESH:D012645', (138, 154))	('dysplasia status', 'Disease', (103, 119))	('selenomethionine', 'Var', (138, 154))	('dysplasia', 'Disease', (189, 198))
437467	20587703	We measured 22 cytokines simultaneously in each serum sample, and found that selenomethionine supplementation was associated with lower IL-2 levels and celecoxib treatment was associated with lower IL-7 levels and higher IL-13 levels.	('supplementation', 'Var', (94, 109))	('lower', 'NegReg', (130, 135))	('IL-2', 'Gene', (136, 140))	('higher', 'PosReg', (214, 220))	('lower', 'NegReg', (192, 197))	('IL-7', 'Gene', '3574', (198, 202))	('selenomethionine', 'Chemical', 'MESH:D012645', (77, 93))	('selenomethionine supplementation', 'Var', (77, 109))	('IL-13', 'Gene', (221, 226))	('celecoxib', 'Chemical', 'MESH:D000068579', (152, 161))	('IL-7', 'Gene', (198, 202))	('IL-13', 'Gene', '3596', (221, 226))	('IL-2', 'Gene', '3558', (136, 140))
437477	20587703	Of particular relevance to the current findings are several possible mechanisms by which a selenium-induced reduction in IL-2 might protect against tumor development.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('selenium-induced', 'Var', (91, 107))	('IL-2', 'Gene', (121, 125))	('selenium', 'Chemical', 'MESH:D012643', (91, 99))	('IL-2', 'Gene', '3558', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('reduction', 'NegReg', (108, 117))
437482	20587703	Selenium-induced reduction in IL-2 might also protect against tumor development by reducing the activity of regulator T-cells (Tregs), which are T-lymphocytes that can impair cancer immunosurveillance.	('cancer immunosurveillance', 'Disease', (175, 200))	('IL-2', 'Gene', (30, 34))	('activity', 'MPA', (96, 104))	('Selenium', 'Chemical', 'MESH:D012643', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('impair', 'NegReg', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', (62, 67))	('reducing', 'NegReg', (83, 91))	('cancer immunosurveillance', 'Disease', 'MESH:D009369', (175, 200))	('regulator T-cells', 'CPA', (108, 125))	('Selenium-induced', 'Var', (0, 16))	('reduction', 'NegReg', (17, 26))	('IL-2', 'Gene', '3558', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
437484	20587703	Thus, the reduction in IL-2 seen with selenomethionine treatment could lead to reduced Treg activity and enhanced tumor immune surveillance.	('IL-2', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('reduced', 'NegReg', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('selenomethionine', 'Chemical', 'MESH:D012645', (38, 54))	('tumor', 'Disease', (114, 119))	('selenomethionine', 'Var', (38, 54))	('IL-2', 'Gene', '3558', (23, 27))	('reduction', 'NegReg', (10, 19))	('Treg activity', 'CPA', (87, 100))	('enhanced', 'PosReg', (105, 113))
437486	20587703	It is interesting to note that PAHs can also have harmful effects on immunologic function.	('PAHs', 'Var', (31, 35))	('PAHs', 'Chemical', 'MESH:D011084', (31, 35))	('immunologic function', 'CPA', (69, 89))
437489	20587703	Thus PAH exposure and selenium exposure are probably both impacting cancer immunosurveillance in Linxian (in opposite directions) via their effects on Tregs.	('cancer immunosurveillance', 'Disease', (68, 93))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('selenium', 'Chemical', 'MESH:D012643', (22, 30))	('Tregs', 'CPA', (151, 156))	('cancer immunosurveillance', 'Disease', 'MESH:D009369', (68, 93))	('selenium', 'Var', (22, 30))	('impacting', 'Reg', (58, 67))	('PAH', 'Chemical', 'MESH:D011084', (5, 8))	('effects', 'Reg', (140, 147))
437493	20587703	Thus, the decrease in IL-7 seen with celecoxib supplementation could serve to lessen a potentially adverse chronic inflammatory response that might potentiate cancer formation.	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('supplementation', 'Var', (47, 62))	('IL-7', 'Gene', '3574', (22, 26))	('lessen', 'NegReg', (78, 84))	('decrease', 'NegReg', (10, 18))	('potentiate', 'PosReg', (148, 158))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('IL-7', 'Gene', (22, 26))	('celecoxib', 'Chemical', 'MESH:D000068579', (37, 46))
437501	17166268	Mitochondrial DNA mutations in preneoplastic lesions of the gastrointestinal tract: A biomarker for the early detection of cancer Somatic mutations of mitochondrial DNA (mtDNA) are common in many human cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lesions of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (45, 82))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('mutations', 'Var', (18, 27))	('mitochondrial DNA', 'Gene', (151, 168))	('human', 'Species', '9606', (196, 201))	('Mitochondrial DNA', 'Gene', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancer', 'Disease', (123, 129))	('cancers', 'Disease', (202, 209))	('cancer', 'Disease', (202, 208))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('preneoplastic lesions of the gastrointestinal tract', 'Disease', 'MESH:D011230', (31, 82))	('mutations', 'Var', (138, 147))
437502	17166268	We have described an oligonucleotide microarray ("MitoChip") for rapid sequencing of the entire mitochondrial genome (Zhou et al, J Mol Diagn 2006), facilitating the analysis of mtDNA mutations in preneoplastic lesions.	('lesion', 'Disease', (211, 217))	('lesion', 'Disease', 'MESH:D051437', (211, 217))	('oligonucleotide', 'Chemical', 'MESH:D009841', (21, 36))	('mutations', 'Var', (184, 193))	('mtDNA', 'Gene', (178, 183))
437509	17166268	Although the functional significance of these mutations has been debated vis-a-vis their "cause and effect" relationship in cancer cells, there is little doubt that mtDNA mutations can serve an important role as a biomarker for human cancers.	('cancer', 'Disease', (124, 130))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancers', 'Disease', 'MESH:D009369', (234, 241))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('cancers', 'Disease', (234, 241))	('human', 'Species', '9606', (228, 233))	('mtDNA', 'Gene', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
437510	17166268	Nevertheless, despite the frequency and widespread nature of mtDNA alterations in human cancers, the ability to use this property for biomarker development has been stymied due to the absence of high-throughput platforms for mutation detection.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('alterations', 'Var', (67, 78))	('cancers', 'Disease', (88, 95))	('mtDNA', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('human', 'Species', '9606', (82, 87))
437513	17166268	Moreover, mtDNA mutations in cancer are often heteroplasmic, and therefore, an added caveat over throughput and scale of the assay is its sensitivity for detecting aberrant clones within heterogenous templates.	('cancer', 'Disease', (29, 35))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('mtDNA', 'Gene', (10, 15))
437516	17166268	In this study, we utilize the MitoChip v2.0 arrays for detecting somatic mtDNA alterations in preneoplastic lesions of the gastrointestinal tract (Barrett esophagus, colorectal adenomas, and colitis-associated dysplasia).	('Barrett esophagus', 'Phenotype', 'HP:0100580', (147, 164))	('alterations', 'Var', (79, 90))	('lesions of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (108, 145))	('mtDNA', 'Gene', (73, 78))	('preneoplastic lesions of the gastrointestinal tract', 'Disease', 'MESH:D011230', (94, 145))	('colitis-associated dysplasia', 'Disease', (191, 219))	('colorectal adenomas', 'Disease', (166, 185))	('colorectal adenomas', 'Disease', 'MESH:D015179', (166, 185))	('Barrett esophagus', 'Disease', (147, 164))	('colitis-associated dysplasia', 'Disease', 'MESH:D003092', (191, 219))	('colitis', 'Phenotype', 'HP:0002583', (191, 198))
437517	17166268	To our knowledge, this is the first report of complete mitochondrial genome sequencing in preneoplastic lesions of the GI tract, and provides unequivocal, albeit preliminary, evidence that mtDNA alterations are a frequent and early event in the multistep progression model of gastrointestinal neoplasia.	('alterations', 'Var', (195, 206))	('lesion', 'Disease', (104, 110))	('gastrointestinal neoplasia', 'Phenotype', 'HP:0007378', (276, 302))	('lesion', 'Disease', 'MESH:D051437', (104, 110))	('lesions of the GI tract', 'Phenotype', 'HP:0007378', (104, 127))	('neoplasia', 'Phenotype', 'HP:0002664', (293, 302))	('gastrointestinal neoplasia', 'Disease', 'MESH:D009369', (276, 302))	('mtDNA', 'Gene', (189, 194))	('gastrointestinal neoplasia', 'Disease', (276, 302))
437518	17166268	These findings lay the groundwork for exploring mtDNA mutations as a biomarker for early detection of cancer utilizing high-throughput, array-based sequencing technologies.	('mtDNA', 'Gene', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
437534	17166268	As seen in Figure 1, the COI, ND4 and ND5 genes were the ones most commonly affected by sequence alterations, once the non-coding region was excluded.	('COI', 'Gene', (25, 28))	('ND4', 'Gene', '4538', (30, 33))	('ND5', 'Gene', '4540', (38, 41))	('COI', 'Gene', '4512', (25, 28))	('ND5', 'Gene', (38, 41))	('ND4', 'Gene', (30, 33))	('sequence alterations', 'Var', (88, 108))	('affected', 'Reg', (76, 84))
437538	17166268	In the seven Barrett esophagus samples, we found no significant differences in the overall frequency of alterations between samples with no dysplasia and those with dysplastic epithelium; nevertheless, there was a trend towards higher rate of non-synonymous mutations in samples with dysplasia (9/23 or 39%) versus those without dysplasia (2/15 or 13%).	('higher', 'PosReg', (228, 234))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (13, 30))	('dysplastic', 'Disease', (165, 175))	('dysplasia', 'Disease', (284, 293))	('dysplastic', 'Disease', 'MESH:D004416', (165, 175))	('dysplasia', 'Disease', 'MESH:D004476', (140, 149))	('dysplasia', 'Disease', 'MESH:D004476', (284, 293))	('dysplasia', 'Disease', (329, 338))	('dysplasia', 'Disease', (140, 149))	('dysplasia', 'Disease', 'MESH:D004476', (329, 338))	('non-synonymous mutations', 'Var', (243, 267))
437539	17166268	Several recurrent (i.e., in more than one specimen) sequence alterations were seen in the four adenoma samples [see Additional file 1], but one non-synonymous mutation in particular, Thr415Ala in the COI gene was observed in 3 of 4 adenomas, suggesting a putative pathogenic role.	('COI', 'Gene', '4512', (200, 203))	('adenoma', 'Disease', (232, 239))	('adenoma', 'Disease', (95, 102))	('adenomas', 'Disease', 'MESH:D000236', (232, 240))	('adenomas', 'Disease', (232, 240))	('Thr415Ala', 'Var', (183, 192))	('Thr415Ala', 'SUBSTITUTION', 'None', (183, 192))	('COI', 'Gene', (200, 203))	('adenoma', 'Disease', 'MESH:D000236', (232, 239))	('adenoma', 'Disease', 'MESH:D000236', (95, 102))
437544	17166268	Of note, the two associated carcinomas shared a subset of genetic alterations with the synchronous, albeit topographically distinct, dysplastic lesions, arguing for a potential field defect shared across the colonic epithelium.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('dysplastic lesions', 'Disease', 'MESH:D021782', (133, 151))	('carcinomas', 'Disease', (28, 38))	('carcinomas', 'Disease', 'MESH:D002277', (28, 38))	('dysplastic lesions', 'Disease', (133, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('genetic alterations', 'Var', (58, 77))
437547	17166268	For example, a poly-C tract known as D310 in the non-coding D-loop is commonly mutated in many cancers, and was recently been shown to be mutated in precursor lesions of head and neck cancer, esophageal adenocarcinoma, and gallbladder adenocarcinoma.	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (223, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('lesion', 'Disease', 'MESH:D051437', (159, 165))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('head and neck cancer', 'Phenotype', 'HP:0012288', (170, 190))	('lesion', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('neck cancer', 'Disease', 'MESH:D006258', (179, 190))	('neck cancer', 'Disease', (179, 190))	('poly-C', 'Chemical', 'MESH:D011066', (15, 21))	('gallbladder adenocarcinoma', 'Disease', (223, 249))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (192, 217))	('D310', 'Chemical', '-', (37, 41))	('D310', 'Var', (37, 41))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (192, 217))	('esophageal adenocarcinoma', 'Disease', (192, 217))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))
437553	17166268	It is important to stress that chip-based chemistry is best suited for detection of single base pair alterations, and it is likely that we are missing insertions/deletions, frameshift mutations, and large deletions, all of which have been reported in cancer samples.	('insertions/deletions', 'Var', (151, 171))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('frameshift mutations', 'Var', (173, 193))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (251, 257))
437554	17166268	In addition, because we are not using lymphocyte DNA as a germline control, there is a potential for underestimating the true frequency of somatic alterations, since some mtDNA alterations will be common in both histologically "normal" tissue and preneoplasia, as a result of a field defect.	('alterations', 'Var', (177, 188))	('preneoplasia', 'Disease', 'None', (247, 259))	('mtDNA', 'Gene', (171, 176))	('neoplasia', 'Phenotype', 'HP:0002664', (250, 259))	('preneoplasia', 'Disease', (247, 259))
437561	17166268	Of note, we detect mtDNA alterations even at the earliest histologic stages of the multistep progression model of esophageal adenocarcinoma, namely, in Barrett mucosa without evidence of dysplasia, and find no significant differences in the overall frequency of sequence variations between Barrett mucosa with or without dysplasia.	('alterations', 'Var', (25, 36))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (114, 139))	('esophageal adenocarcinoma', 'Disease', (114, 139))	('dysplasia', 'Disease', (187, 196))	('mtDNA', 'Gene', (19, 24))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (114, 139))	('dysplasia', 'Disease', (321, 330))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('dysplasia', 'Disease', 'MESH:D004476', (187, 196))	('dysplasia', 'Disease', 'MESH:D004476', (321, 330))
437562	17166268	On the contrary, there is a trend towards higher rate of non-synonymous mutations in samples with dysplasia (9/23 or 39%) versus those without dysplasia (2/15 or 13%).	('dysplasia', 'Disease', 'MESH:D004476', (143, 152))	('higher', 'PosReg', (42, 48))	('dysplasia', 'Disease', (98, 107))	('dysplasia', 'Disease', 'MESH:D004476', (98, 107))	('dysplasia', 'Disease', (143, 152))	('non-synonymous mutations', 'Var', (57, 81))
437563	17166268	The significance of this latter difference is uncertain and will need to be confirmed in larger series; however, one can speculate that the increased prevalence of non-synonymous changes, with the potential effect on mitochondrial protein function, might provide a selective advantage in the advanced histologic lesions.	('lesion', 'Disease', (312, 318))	('mitochondrial protein function', 'MPA', (217, 247))	('effect', 'Reg', (207, 213))	('lesion', 'Disease', 'MESH:D051437', (312, 318))	('changes', 'Var', (179, 186))
437564	17166268	The presence of clonal genetic alterations in non-dysplastic Barrett epithelium is not unexpected; for example, we have reported the occurrence of homozygous chromosome 9p21 deletions, encompassing the CDKN2A/p16 gene, in 16% of Barrett epithelia even in the absence of dysplasia.	('Barrett epithelia', 'Disease', 'MESH:D001471', (229, 246))	('p16', 'Gene', (209, 212))	('absence of dysplasia', 'Disease', (259, 279))	('deletions', 'Var', (174, 183))	('absence of dysplasia', 'Disease', 'MESH:D004832', (259, 279))	('p16', 'Gene', '1029', (209, 212))	('CDKN2A', 'Gene', (202, 208))	('Barrett epithelia', 'Disease', (229, 246))	('dysplastic', 'Disease', (50, 60))	('CDKN2A', 'Gene', '1029', (202, 208))	('dysplastic', 'Disease', 'MESH:D004416', (50, 60))
437569	17166268	For example, the adenoma-carcinoma sequence is characterized by nearly ubiquitous aberrations in the wnt signaling pathway, such as APC or beta-catenin gene mutations.	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (17, 34))	('beta-catenin', 'Gene', (139, 151))	('wnt signaling pathway', 'Pathway', (101, 122))	('mutations', 'Var', (157, 166))	('adenoma-carcinoma', 'Disease', (17, 34))	('APC', 'Disease', 'MESH:D011125', (132, 135))	('beta-catenin', 'Gene', '1499', (139, 151))	('APC', 'Disease', (132, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
437570	17166268	In contrast, colitis-associated dysplasia and carcinomas commonly demonstrate abnormalities of p53 gene function as an early event.	('colitis-associated dysplasia', 'Disease', 'MESH:D003092', (13, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('colitis', 'Phenotype', 'HP:0002583', (13, 20))	('function', 'MPA', (104, 112))	('abnormalities', 'Var', (78, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('carcinomas', 'Disease', 'MESH:D002277', (46, 56))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('colitis-associated dysplasia', 'Disease', (13, 41))	('carcinomas', 'Disease', (46, 56))
437572	17166268	Of note, we detected multiple somatic alterations that were present in more than 1 adenoma; in particular a Thr415Ala mutation in the COI gene (RCRS position 7146) was present in 3 of 4 adenomas.	('adenomas', 'Disease', (186, 194))	('adenoma', 'Disease', 'MESH:D000236', (83, 90))	('COI', 'Gene', '4512', (134, 137))	('Thr415Ala', 'Var', (108, 117))	('Thr415Ala', 'SUBSTITUTION', 'None', (108, 117))	('adenoma', 'Disease', (83, 90))	('adenoma', 'Disease', 'MESH:D000236', (186, 193))	('COI', 'Gene', (134, 137))	('adenoma', 'Disease', (186, 193))	('adenomas', 'Disease', 'MESH:D000236', (186, 194))
437573	17166268	Curiously, this identical mutation has been previously reported in association with Alzheimer disease, but we could not determine a reported association with cancer.	('association', 'Reg', (67, 78))	('mutation', 'Var', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('Alzheimer disease', 'Disease', 'MESH:D000544', (84, 101))	('Alzheimer disease', 'Disease', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Alzheimer disease', 'Phenotype', 'HP:0002511', (84, 101))
437575	17166268	Mutations of the cytochrome oxidase gene family with corresponding biochemical defects have been reported not only in colorectal carcinomas, but also in isolated colonic crypts.	('colorectal carcinomas', 'Disease', 'MESH:D015179', (118, 139))	('colorectal carcinomas', 'Disease', (118, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('reported', 'Reg', (97, 105))	('Mutations', 'Var', (0, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))
437577	17166268	The absence of the Thr415Ala mutation, or other adenoma-associated sequence alterations, in the three colitis-associated dysplasia cases also reiterates what is known from the study of nuclear genes; i.e., the genetic pathways in the two precursor lesions of colorectal cancer are distinct.	('colitis-associated dysplasia', 'Disease', 'MESH:D003092', (102, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (259, 276))	('colitis', 'Phenotype', 'HP:0002583', (102, 109))	('adenoma', 'Disease', 'MESH:D000236', (48, 55))	('absence', 'NegReg', (4, 11))	('colorectal cancer', 'Phenotype', 'HP:0003003', (259, 276))	('lesion', 'Disease', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('colitis-associated dysplasia', 'Disease', (102, 130))	('Thr415Ala', 'Var', (19, 28))	('adenoma', 'Disease', (48, 55))	('Thr415Ala', 'SUBSTITUTION', 'None', (19, 28))	('lesion', 'Disease', 'MESH:D051437', (248, 254))	('colorectal cancer', 'Disease', (259, 276))
437578	17166268	In our series, we also had the opportunity to examine a sessile serrated adenoma (SSA), which harbored a striking number (N = 35) of somatic mtDNA alterations, all but one of which were transition mutations.	('serrated adenoma', 'Phenotype', 'HP:0032222', (64, 80))	('adenoma', 'Disease', (73, 80))	('adenoma', 'Disease', 'MESH:D000236', (73, 80))	('alterations', 'Var', (147, 158))
437579	17166268	Given the established association between SSAs and nuclear mismatch repair (MMR) deficiency, which likely accounts for the increased predisposition of these lesions to progress to invasive adenocarcinomas, we assessed MMR status in the SSA.	('deficiency', 'Var', (81, 91))	('SSAs', 'Disease', (42, 46))	('adenocarcinomas', 'Disease', 'MESH:D000230', (189, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('invasive adenocarcinoma', 'Disease', (180, 203))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (180, 203))	('lesion', 'Disease', (157, 163))	('adenocarcinomas', 'Disease', (189, 204))	('lesion', 'Disease', 'MESH:D051437', (157, 163))
437581	17166268	The underlying basis for the exceptionally large number of mtDNA alterations in this "mitochondrial mutator" adenoma remains unknown, and a larger series of colorectal adenomas of the serrated and non-serrated subtypes would have to be examined in order to determine whether our rudimentary observation in a single SSA bears out in other specimens of this nature.	('alterations', 'Var', (65, 76))	('adenoma', 'Disease', 'MESH:D000236', (168, 175))	('colorectal adenomas', 'Disease', 'MESH:D015179', (157, 176))	('adenoma', 'Disease', (109, 116))	('adenoma', 'Disease', (168, 175))	('colorectal adenomas of the serrated', 'Phenotype', 'HP:0032222', (157, 192))	('adenoma', 'Disease', 'MESH:D000236', (109, 116))	('colorectal adenomas', 'Disease', (157, 176))
437582	17166268	In summary, our preliminary study confirms that mtDNA alterations are highly prevalent in preneoplastic lesions of the gastrointestinal tract.	('lesions of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (104, 141))	('mtDNA', 'Gene', (48, 53))	('preneoplastic lesions of the gastrointestinal tract', 'Disease', 'MESH:D011230', (90, 141))	('prevalent', 'Reg', (77, 86))	('alterations', 'Var', (54, 65))
437604	34046362	In addition, tumor occurs by acquiring a series of mutations over time, and genomic instability and mutation are hallmarks of tumors.	('tumor', 'Disease', (13, 18))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('mutation', 'Var', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('genomic', 'MPA', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', (126, 131))
437606	34046362	Single cell DNA sequencing can be used to reveal ITH and phylogeny at the copy number variation (CNV) and single nucleotide variation (SNV) level, and it has been widely used in cancer study.	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (178, 184))	('single nucleotide variation', 'Var', (106, 133))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))
437638	34046362	As was known, mutations accumulated as age increased and Pt.1 was the oldest among the four patients.	('mutations', 'Var', (14, 23))	('patients', 'Species', '9606', (92, 100))	('accumulated', 'Reg', (24, 35))
437641	34046362	Whether in the primary or lymph node sites, the C > T mutation was significantly enriched, consistent with the results of a relatively large set of Chinese GEJ cancer patients.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('C > T mutation', 'Var', (48, 62))
437647	34046362	Most of the mutation sites of TTN occurred in the immunoglobulin I-set domain.	('TTN', 'Gene', '7273', (30, 33))	('mutation', 'Var', (12, 20))	('occurred', 'Reg', (34, 42))	('TTN', 'Gene', (30, 33))
437658	34046362	Mutation of TP53 was trunk mutation in both Pt.3 and Pt.4, indicating that TP53 mutations occurred earlier and played an important role in tumor progression and lymph node metastasis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutations', 'Var', (80, 89))	('TP53', 'Gene', (12, 16))	('role', 'Reg', (131, 135))	('Mutation', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('TP53', 'Gene', '7157', (12, 16))	('lymph node metastasis', 'CPA', (161, 182))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
437660	34046362	While in Pt.4, the two lymph nodes were separated from the same branches, simultaneously showing the mutation of POTEF, OSBPL7 and CHRFAM7A.	('CHRFAM7A', 'Gene', (131, 139))	('showing', 'Reg', (89, 96))	('POTEF', 'Gene', '728378', (113, 118))	('OSBPL7', 'Gene', (120, 126))	('POTEF', 'Gene', (113, 118))	('mutation', 'Var', (101, 109))	('OSBPL7', 'Gene', '114881', (120, 126))	('CHRFAM7A', 'Gene', '89832', (131, 139))
437684	34046362	The mutation spectra in our study revealed that C > T mutations were significantly enriched in the patients whether in the primary site or lymph node site, indicating that C > T mutation played a crucial role in GEJ tumorigenesis and progression.	('tumor', 'Disease', (216, 221))	('C > T mutations', 'Var', (48, 63))	('patients', 'Species', '9606', (99, 107))	('C > T mutation', 'Var', (172, 186))	('progression', 'CPA', (234, 245))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
437685	34046362	Our study identified the recurrent mutations happened in TTN, TP53, AAR2, CCDC108, CACNA1E, RYR3, LRP1B etc.	('TTN', 'Gene', (57, 60))	('RYR3', 'Gene', (92, 96))	('LRP1B', 'Gene', (98, 103))	('AAR2', 'Gene', (68, 72))	('CACNA1E', 'Gene', (83, 90))	('RYR3', 'Gene', '6263', (92, 96))	('TP53', 'Gene', '7157', (62, 66))	('AAR2', 'Gene', '25980', (68, 72))	('CACNA1E', 'Gene', '777', (83, 90))	('TP53', 'Gene', (62, 66))	('TTN', 'Gene', '7273', (57, 60))	('LRP1B', 'Gene', '53353', (98, 103))	('CCDC108', 'Gene', '255101', (74, 81))	('CCDC108', 'Gene', (74, 81))	('mutations', 'Var', (35, 44))
437687	34046362	Another study focusing on 12 cases of synchronous GEJ cancer and distal gastric cancer revealed the predominance of TP53 mutation.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('TP53', 'Gene', (116, 120))	('synchronous GEJ cancer', 'Disease', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('mutation', 'Var', (121, 129))	('TP53', 'Gene', '7157', (116, 120))	('synchronous GEJ cancer', 'Disease', 'MESH:D009369', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('gastric cancer', 'Disease', (72, 86))
437691	34046362	Compared with TCGA data in gastric and esophagus cancers, similarities were observed among GEJ cancer and EAC (esophagus adenocarcinoma) or GA-CIN (gastric adenocarcinoma-chromosomal instability), such as high frequencies of copy number gains in Chr7, 8, 20 and losses in Chr4, 5, 18, 21.	('esophagus adenocarcinoma', 'Phenotype', 'HP:0011459', (111, 135))	('copy number', 'Var', (225, 236))	('gastric adenocarcinoma-chromosomal instability', 'Disease', (148, 194))	('GA-CIN', 'Disease', (140, 146))	('esophagus cancers', 'Disease', (39, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancer', 'Disease', (49, 55))	('gains', 'PosReg', (237, 242))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (95, 101))	('gastric adenocarcinoma-chromosomal instability', 'Disease', 'MESH:D043171', (148, 194))	('esophagus cancers', 'Disease', 'MESH:D004938', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('adenocarcinoma', 'Disease', (156, 170))	('Chr7', 'Gene', (246, 250))	('adenocarcinoma', 'Disease', (121, 135))	('Chr4', 'Gene', (272, 276))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('losses', 'NegReg', (262, 268))	('adenocarcinoma', 'Disease', 'MESH:D000230', (156, 170))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('chromosomal instability', 'Phenotype', 'HP:0040012', (171, 194))	('GA-CIN', 'Disease', 'MESH:C536833', (140, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('adenocarcinoma', 'Disease', 'MESH:D000230', (121, 135))
437694	34046362	And the mutation frequency of TP53 in our GEJ cancer patients was 50%, much lower than that in EC [71% in EAC and 91% in ESCC (esophagus squamous cell carcinoma)], but close to that in GC (50% in non-hypermutated gastric cancer and 35% in hypermutated gastric cancer).	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('GC', 'Phenotype', 'HP:0012126', (185, 187))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('lower', 'NegReg', (76, 81))	('gastric cancer', 'Disease', (213, 227))	('TP53', 'Gene', (30, 34))	('esophagus squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 160))	('patients', 'Species', '9606', (53, 61))	('gastric cancer', 'Disease', (252, 266))	('gastric cancer', 'Disease', 'MESH:D013274', (213, 227))	('mutation', 'Var', (8, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', (46, 52))	('esophagus squamous cell carcinoma', 'Disease', (127, 160))	('cancer', 'Disease', (260, 266))	('gastric cancer', 'Disease', 'MESH:D013274', (252, 266))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('TP53', 'Gene', '7157', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('gastric cancer', 'Phenotype', 'HP:0012126', (213, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (252, 266))
437697	34046362	There were also reports that TTN was at the top ranking of mutated genes in multiple solid tumors, including the gastric adenocarcinoma, small cell lung cancer and colorectal adenocarcinoma.	('TTN', 'Gene', (29, 32))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('small cell lung cancer', 'Disease', (137, 159))	('TTN', 'Gene', '7273', (29, 32))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (113, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('colorectal adenocarcinoma', 'Disease', (164, 189))	('gastric adenocarcinoma', 'Disease', (113, 135))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (164, 189))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('small cell lung cancer', 'Disease', 'MESH:D055752', (137, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (137, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('mutated', 'Var', (59, 66))
437698	34046362	The average mutation frequency of TTN in solid tumors was 29.68% and the mutation frequency in gastric adenocarcinoma was as high as 60%~70%.	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (95, 117))	('gastric adenocarcinoma', 'Disease', (95, 117))	('TTN', 'Gene', (34, 37))	('TTN', 'Gene', '7273', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutation', 'Var', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
437700	34046362	In a study of 12 patients with synchronous GEJ cancer and GC, the TTN mutation were found in 7 of 24 tumor tissues.	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('synchronous GEJ cancer', 'Disease', (31, 53))	('TTN', 'Gene', (66, 69))	('patients', 'Species', '9606', (17, 25))	('TTN', 'Gene', '7273', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutation', 'Var', (70, 78))	('synchronous GEJ cancer', 'Disease', 'MESH:D009369', (31, 53))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
437702	34046362	Among them were mutations in ARID1A, ATM, BRCA1 and TP53 genes, amplifications in CCND1, ERBB2 and MYC genes, deletions in PTEN and RB1 genes etc.	('CCND1', 'Gene', (82, 87))	('ERBB2', 'Gene', (89, 94))	('PTEN', 'Gene', (123, 127))	('BRCA1', 'Gene', '672', (42, 47))	('amplifications', 'Var', (64, 78))	('BRCA1', 'Gene', (42, 47))	('RB1', 'Gene', (132, 135))	('mutations', 'Var', (16, 25))	('ERBB2', 'Gene', '2064', (89, 94))	('TP53', 'Gene', (52, 56))	('MYC', 'Gene', '4609', (99, 102))	('ATM', 'Gene', '472', (37, 40))	('PTEN', 'Gene', '5728', (123, 127))	('RB1', 'Gene', '5925', (132, 135))	('deletions', 'Var', (110, 119))	('ARID1A', 'Gene', (29, 35))	('ATM', 'Gene', (37, 40))	('TP53', 'Gene', '7157', (52, 56))	('ARID1A', 'Gene', '8289', (29, 35))	('MYC', 'Gene', (99, 102))	('CCND1', 'Gene', '595', (82, 87))
437724	33714953	The results indicated that miR-20b-5p was increased in radioresistant KYSE-150R cells compared with KYSE-150 cells, whereas miR-125a-5p was downregulated.	('increased', 'PosReg', (42, 51))	('radioresistant', 'CPA', (55, 69))	('miR-20b-5p', 'Chemical', '-', (27, 37))	('miR-20b-5p', 'Var', (27, 37))	('miR-125a-5p', 'Chemical', '-', (124, 135))
437727	33714953	These data indicate that miR-20b-5p and miR-125a-5p promote tumorigenesis in radioresistant KYSE-150R cells and have the potential to be used as novel therapeutic targets for the treatment of esophageal cancer.	('miR-125a-5p', 'Var', (40, 51))	('miR-125a-5p', 'Chemical', '-', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('miR-20b-5p', 'Chemical', '-', (25, 35))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('miR-20b-5p', 'Var', (25, 35))	('promote', 'PosReg', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
437731	33714953	Previous studies indicated it may be caused by microenvironmental hypoxia, abnormal intrinsic DNA damage response activity, mutations of oncogenes or tumor suppressors or the altering of signaling pathways.	('altering', 'Reg', (175, 183))	('mutations', 'Var', (124, 133))	('caused by', 'Reg', (37, 46))	('oncogenes', 'Gene', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('intrinsic DNA damage response activity', 'MPA', (84, 122))	('hypoxia', 'Disease', (66, 73))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('signaling pathways', 'Pathway', (187, 205))	('tumor', 'Disease', (150, 155))	('abnormal intrinsic DNA damage response', 'Phenotype', 'HP:0003254', (75, 113))
437736	33714953	However, whether miR-20b and miR-125a affect tumorigenesis in radioresistant EC cells remains unknown.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('miR-20b', 'Var', (17, 24))	('miR-125a', 'Var', (29, 37))	('affect', 'Reg', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
437739	33714953	While the expression of miR-125a-5p was declined in KYSE-150R cells (Figure 1B).	('miR-125a-5p', 'Chemical', '-', (24, 35))	('declined', 'NegReg', (40, 48))	('expression', 'MPA', (10, 20))	('miR-125a-5p', 'Var', (24, 35))
437740	33714953	To dissect the biological function of miRNA, we planned to alter the expression of miR-20b-5p and miR-125a-5p in KYSE-150R cells and then investigate the cellular process after the change.	('investigate', 'Reg', (138, 149))	('miR-125a-5p', 'Var', (98, 109))	('miR-20b-5p', 'Gene', (83, 93))	('miR-125a-5p', 'Chemical', '-', (98, 109))	('alter', 'Reg', (59, 64))	('miR-20b-5p', 'Chemical', '-', (83, 93))
437742	33714953	The results showed that overexpression of miR-20b-5p promoted cell proliferation, migration, and invasion.	('promoted', 'PosReg', (53, 61))	('cell proliferation', 'CPA', (62, 80))	('migration', 'CPA', (82, 91))	('miR-20b-5p', 'Chemical', '-', (42, 52))	('overexpression', 'PosReg', (24, 38))	('miR-20b-5p', 'Var', (42, 52))	('invasion', 'CPA', (97, 105))
437743	33714953	In contrast, downregulation of miR-20b-5p suppressed these cell activities in both KYSE-150 and KYSE-150R cells (Figure 2A-2C).	('downregulation', 'NegReg', (13, 27))	('suppressed', 'NegReg', (42, 52))	('cell activities', 'CPA', (59, 74))	('miR-20b-5p', 'Chemical', '-', (31, 41))	('miR-20b-5p', 'Var', (31, 41))
437744	33714953	In both cell lines, a reduction of apoptosis was found in miR-20b-5p overexpressing cells, whereas an enhancement of apoptosis was found in cells transfected with miR-20b-5p inhibitors (Figure 2D).	('overexpressing', 'Var', (69, 83))	('reduction', 'NegReg', (22, 31))	('miR-20b-5p', 'Chemical', '-', (58, 68))	('enhancement', 'PosReg', (102, 113))	('miR-20b-5p overexpressing', 'Var', (58, 83))	('miR-20b-5p', 'Chemical', '-', (163, 173))	('apoptosis', 'CPA', (35, 44))
437745	33714953	In this study, we found that in both cell lines, overexpression of miR-20b-5p downregulated the E-cadherin protein, an epithelial marker, and upregulated N-cadherin and Vimentin proteins, which are mesenchymal markers (Figure 2E).	('N-cadherin', 'Gene', (154, 164))	('N-cadherin', 'Gene', '1000', (154, 164))	('miR-20b-5p', 'Var', (67, 77))	('Vimentin', 'Gene', (169, 177))	('E-cadherin', 'Gene', '999', (96, 106))	('E-cadherin', 'Gene', (96, 106))	('overexpression', 'PosReg', (49, 63))	('Vimentin', 'Gene', '7431', (169, 177))	('upregulated', 'PosReg', (142, 153))	('miR-20b-5p', 'Chemical', '-', (67, 77))	('downregulated', 'NegReg', (78, 91))
437746	33714953	These data indicated that miR-20b-5p promoted the EMT process in EC cells.	('EMT process', 'CPA', (50, 61))	('miR-20b-5p', 'Var', (26, 36))	('promoted', 'PosReg', (37, 45))	('miR-20b-5p', 'Chemical', '-', (26, 36))
437748	33714953	We found that overexpression of miR-125a-5p inhibited cell proliferation, migration and invasion, whereas miR-125a-5p inhibitor exhibited a reverse effect in both KYSE-150 and KYSE-150R cells (Figure 3A-3C).	('cell proliferation', 'CPA', (54, 72))	('miR-125a-5p', 'Var', (32, 43))	('miR-125a-5p', 'Chemical', '-', (32, 43))	('invasion', 'CPA', (88, 96))	('inhibited', 'NegReg', (44, 53))	('miR-125a-5p', 'Chemical', '-', (106, 117))	('migration', 'CPA', (74, 83))	('overexpression', 'PosReg', (14, 28))
437749	33714953	The results of TUNEL assays demonstrated that cell apoptosis was accelerated by transfection with miR-125a-5p mimics and suppressed by transfection with miR-125a-5p inhibitors (Figure 3D).	('cell apoptosis', 'CPA', (46, 60))	('miR-125a-5p', 'Chemical', '-', (153, 164))	('miR-125a-5p', 'Chemical', '-', (98, 109))	('suppressed', 'NegReg', (121, 131))	('accelerated', 'PosReg', (65, 76))	('transfection', 'Var', (80, 92))	('miR-125a-5p', 'Gene', (98, 109))
437750	33714953	As for EMT process, in both cell lines, overexpression of miR-125a-5p increased E-cadherin protein expression levels, and reduced N-cadherin and Vimentin protein expression levels compared to those in the control group (Figure 3E).	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '999', (80, 90))	('N-cadherin', 'Gene', (130, 140))	('increased', 'PosReg', (70, 79))	('miR-125a-5p', 'Var', (58, 69))	('overexpression', 'PosReg', (40, 54))	('Vimentin', 'Gene', (145, 153))	('N-cadherin', 'Gene', '1000', (130, 140))	('miR-125a-5p', 'Chemical', '-', (58, 69))	('Vimentin', 'Gene', '7431', (145, 153))	('reduced', 'NegReg', (122, 129))
437751	33714953	These results suggested that miR-125a-5p inhibited EMT in EC cells.	('EMT in', 'CPA', (51, 57))	('miR-125a-5p', 'Var', (29, 40))	('miR-125a-5p', 'Chemical', '-', (29, 40))	('inhibited', 'NegReg', (41, 50))
437752	33714953	Based on the miRNA database TargetScan and miRanda, the predicted targets of miR-20b and miR-125a are PTEN and IL6R, respectively (Supporting Information Supplementary Figure 2A, 2B).	('PTEN', 'Gene', (102, 106))	('IL6R', 'Gene', '3570', (111, 115))	('miR-125a', 'Var', (89, 97))	('miR-20b', 'Gene', (77, 84))	('IL6R', 'Gene', (111, 115))	('PTEN', 'Gene', '5728', (102, 106))
437754	33714953	In KYSE-150R cells, miR-20b-5p mimics significantly inhibited PTEN luciferase activity (Figure 4A).	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('miR-20b-5p', 'Chemical', '-', (20, 30))	('miR-20b-5p', 'Var', (20, 30))	('inhibited', 'NegReg', (52, 61))	('activity', 'MPA', (78, 86))
437755	33714953	However, a mutation in the binding site of miR-20b-5p in PTEN 3'-UTR abrogated the effects of miR-20b-5p on the luciferase activity.	('miR-20b-5p', 'Chemical', '-', (43, 53))	('abrogated', 'NegReg', (69, 78))	('luciferase', 'Enzyme', (112, 122))	('binding', 'Interaction', (27, 34))	('PTEN', 'Gene', (57, 61))	('miR-20b-5p', 'Gene', (43, 53))	('PTEN', 'Gene', '5728', (57, 61))	('effects', 'MPA', (83, 90))	('mutation', 'Var', (11, 19))	('activity', 'MPA', (123, 131))	('miR-20b-5p', 'Chemical', '-', (94, 104))
437756	33714953	The co-transfection of miR-125a-5p mimic and IL6R WT 3'-UTR remarkably reduced the luciferase activity in KYSE-150R cells.	('WT', 'Disease', 'MESH:C536751', (50, 52))	('miR-125a-5p', 'Chemical', '-', (23, 34))	('IL6R', 'Gene', (45, 49))	('activity', 'MPA', (94, 102))	('reduced', 'NegReg', (71, 78))	('miR-125a-5p mimic', 'Var', (23, 40))	('IL6R', 'Gene', '3570', (45, 49))	('luciferase', 'Enzyme', (83, 93))
437758	33714953	Western blot as well as RT-PCR analysis proved that overexpression of miR-20b-5p and miR-125a-5p could negatively regulate the expression of PTEN and IL6R at both mRNA and protein levels (Figure 4C-4F), respectively.	('miR-125a-5p', 'Var', (85, 96))	('PTEN', 'Gene', (141, 145))	('negatively', 'NegReg', (103, 113))	('PTEN', 'Gene', '5728', (141, 145))	('expression', 'MPA', (127, 137))	('IL6R', 'Gene', (150, 154))	('miR-125a-5p', 'Chemical', '-', (85, 96))	('regulate', 'Reg', (114, 122))	('IL6R', 'Gene', '3570', (150, 154))	('miR-20b-5p', 'Chemical', '-', (70, 80))	('miR-20b-5p', 'Var', (70, 80))
437760	33714953	Our results showed that miR-20b-5p mimics did not change the protein level of Akt and ERK in KYSE-150 cells, but remarkably increased p-Akt and p-ERK expression compared with miR-20b mimics-NC (Supporting Information Supplementary Figure 3).	('ERK', 'Gene', '5594', (146, 149))	('expression', 'MPA', (150, 160))	('increased', 'PosReg', (124, 133))	('ERK', 'Gene', (146, 149))	('Akt', 'Gene', '207', (78, 81))	('Akt', 'Gene', (136, 139))	('miR-20b-5p', 'Chemical', '-', (24, 34))	('Akt', 'Gene', '207', (136, 139))	('Akt', 'Gene', (78, 81))	('ERK', 'Gene', '5594', (86, 89))	('miR-20b-5p', 'Var', (24, 34))	('ERK', 'Gene', (86, 89))
437762	33714953	These data verified that miR-20b-5p and miR-125a-5p directly target PTEN and IL6R in EC, respectively.	('miR-125a-5p', 'Var', (40, 51))	('IL6R', 'Gene', (77, 81))	('miR-125a-5p', 'Chemical', '-', (40, 51))	('target', 'Reg', (61, 67))	('IL6R', 'Gene', '3570', (77, 81))	('PTEN', 'Gene', (68, 72))	('miR-20b-5p', 'Chemical', '-', (25, 35))	('PTEN', 'Gene', '5728', (68, 72))	('miR-20b-5p', 'Var', (25, 35))
437763	33714953	To clarify whether miR-20b-5p increased cellular growth and migration controlled by PTEN, both cell lines were co-transfected with miR-20b-5p mimics and PTEN.	('cellular growth', 'CPA', (40, 55))	('miR-20b-5p', 'Chemical', '-', (19, 29))	('PTEN', 'Gene', (153, 157))	('PTEN', 'Gene', (84, 88))	('miR-20b-5p', 'Var', (19, 29))	('PTEN', 'Gene', '5728', (153, 157))	('PTEN', 'Gene', '5728', (84, 88))	('migration', 'CPA', (60, 69))	('miR-20b-5p', 'Chemical', '-', (131, 141))
437766	33714953	Western blot analysis showed that in KYSE-150R cells, transfection of PTEN decreased the EMT process (Figure 5E).	('EMT process', 'CPA', (89, 100))	('PTEN', 'Gene', (70, 74))	('PTEN', 'Gene', '5728', (70, 74))	('decreased', 'NegReg', (75, 84))	('transfection', 'Var', (54, 66))
437767	33714953	Based on these data, we proved that miR-20b-5p increased KYSE-150R cell growth and metastasis by targeting PTEN.	('PTEN', 'Gene', (107, 111))	('metastasis', 'CPA', (83, 93))	('miR-20b-5p', 'Chemical', '-', (36, 46))	('PTEN', 'Gene', '5728', (107, 111))	('KYSE-150R cell growth', 'CPA', (57, 78))	('miR-20b-5p', 'Var', (36, 46))	('increased', 'PosReg', (47, 56))
437770	33714953	Western blot analysis showed that transfection of KYSE-150R cells with IL6R, promoted the EMT process (Figure 6E).	('IL6R', 'Gene', (71, 75))	('promoted', 'PosReg', (77, 85))	('IL6R', 'Gene', '3570', (71, 75))	('EMT process', 'CPA', (90, 101))	('transfection', 'Var', (34, 46))
437771	33714953	Thus, our results suggested that miR-125a-5p decreased KYSE-150R cell growth and metastasis by targeting the IL6R.	('IL6R', 'Gene', (109, 113))	('miR-125a-5p', 'Var', (33, 44))	('miR-125a-5p', 'Chemical', '-', (33, 44))	('targeting', 'Reg', (95, 104))	('IL6R', 'Gene', '3570', (109, 113))	('decreased', 'NegReg', (45, 54))	('metastasis', 'CPA', (81, 91))	('KYSE-150R cell growth', 'CPA', (55, 76))
437775	33714953	In current study, we firstly verified that the expression level of miR-20b-5p was markedly elevated in KYSE-150R cells compared to that in KYSE-150 cells.	('elevated', 'PosReg', (91, 99))	('miR-20b-5p', 'Var', (67, 77))	('KYSE-150R', 'Var', (103, 112))	('expression level', 'MPA', (47, 63))	('miR-20b-5p', 'Chemical', '-', (67, 77))
437777	33714953	Consistent with these studies, we observed increased cell proliferation, invasion, and migration in cells overexpressing miR-20b-5p.	('migration', 'CPA', (87, 96))	('miR-20b-5p', 'Chemical', '-', (121, 131))	('increased', 'PosReg', (43, 52))	('invasion', 'CPA', (73, 81))	('cell proliferation', 'CPA', (53, 71))	('miR-20b-5p', 'Var', (121, 131))
437783	33714953	Our findings suggested that miR-20b-5p inhibited cell apoptosis and promoted EMT process in EC cells.	('inhibited', 'NegReg', (39, 48))	('EMT process', 'CPA', (77, 88))	('promoted', 'PosReg', (68, 76))	('miR-20b-5p', 'Chemical', '-', (28, 38))	('cell apoptosis', 'CPA', (49, 63))	('miR-20b-5p', 'Var', (28, 38))
437784	33714953	Moreover, we found miR-20b-5p exerted its function on KYSE-150R cells by targeting PTEN, which is among the most frequently transformed tumor-suppressor genes in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('PTEN', 'Gene', '5728', (83, 87))	('miR-20b-5p', 'Chemical', '-', (19, 29))	('miR-20b-5p', 'Var', (19, 29))	('human', 'Species', '9606', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('targeting', 'Reg', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('tumor', 'Disease', (136, 141))	('PTEN', 'Gene', (83, 87))
437787	33714953	Loss of PTEN leads to a continuous activation of the signal pathway, and therefore, fail to control cell growth.	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('signal pathway', 'Pathway', (53, 67))	('Loss', 'Var', (0, 4))	('activation', 'PosReg', (35, 45))
437793	33714953	Results of current study indicate miR-20b-5p exerts its function partly through PTEN /PI3K/Akt signaling pathway.	('Akt', 'Gene', '207', (91, 94))	('PTEN', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (80, 84))	('miR-20b-5p', 'Chemical', '-', (34, 44))	('Akt', 'Gene', (91, 94))	('miR-20b-5p', 'Var', (34, 44))
437794	33714953	Our study also found that there was a low expression level of miR-125a-5p in radioresistant KYSE-150R cells.	('expression level', 'MPA', (42, 58))	('miR-125a-5p', 'Var', (62, 73))	('miR-125a-5p', 'Chemical', '-', (62, 73))
437795	33714953	reported that miR-125a suppressed bladder cancer cell proliferation by inducing cell cycle arrest and cell apoptosis.	('suppressed', 'NegReg', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('cell apoptosis', 'CPA', (102, 116))	('miR-125a', 'Var', (14, 22))	('arrest', 'Disease', 'MESH:D006323', (91, 97))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('inducing', 'PosReg', (71, 79))	('bladder cancer', 'Disease', (34, 48))	('arrest', 'Disease', (91, 97))
437796	33714953	Cell cycle became stagnant at the G0/G1 phase when miR-125a-5p was overexpressed.	('Cell cycle', 'CPA', (0, 10))	('miR-125a-5p', 'Var', (51, 62))	('miR-125a-5p', 'Chemical', '-', (51, 62))
437797	33714953	In cervical cancer, cell invasion and tumor metastasis has been reported to be regulated by miR-125a-5p as it targets STAT3.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('miR-125a-5p', 'Var', (92, 103))	('cell invasion', 'CPA', (20, 33))	('miR-125a-5p', 'Chemical', '-', (92, 103))	('cancer', 'Disease', (12, 18))	('STAT3', 'Gene', '6774', (118, 123))	('tumor metastasis', 'Disease', 'MESH:D009362', (38, 54))	('STAT3', 'Gene', (118, 123))	('tumor metastasis', 'Disease', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
437798	33714953	Current study results showed that miR-125a-5p weakened cell proliferation, migration, invasion, and the EMT process.	('miR-125a-5p', 'Var', (34, 45))	('EMT process', 'CPA', (104, 115))	('miR-125a-5p', 'Chemical', '-', (34, 45))	('cell proliferation', 'CPA', (55, 73))	('migration', 'CPA', (75, 84))	('invasion', 'CPA', (86, 94))	('weakened', 'NegReg', (46, 54))
437799	33714953	In addition, miR-125a-5p also increased apoptosis via IL6R, an oncogene which encodes a subunit of the interleukin 6 (IL6) receptor complex.	('IL6R', 'Gene', (54, 58))	('apoptosis', 'CPA', (40, 49))	('miR-125a-5p', 'Var', (13, 24))	('IL6R', 'Gene', '3570', (54, 58))	('miR-125a-5p', 'Chemical', '-', (13, 24))	('IL6', 'Gene', '3569', (118, 121))	('IL6', 'Gene', (118, 121))	('increased', 'PosReg', (30, 39))	('IL6', 'Gene', '3569', (54, 57))	('IL6', 'Gene', (54, 57))
437802	33714953	Overexpression of IL6R has been demonstrated to correlate with the increase in proliferative activity and the inhibition of apoptosis.	('inhibition', 'NegReg', (110, 120))	('IL6R', 'Gene', '3570', (18, 22))	('proliferative activity', 'CPA', (79, 101))	('increase', 'PosReg', (67, 75))	('Overexpression', 'Var', (0, 14))	('IL6R', 'Gene', (18, 22))	('apoptosis', 'CPA', (124, 133))
437804	33714953	Silencing IL6R expression suppressed tumor growth, migration and angiogenesis, as well as enhanced the antitumor activity in several cancer cells.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('suppressed', 'NegReg', (26, 36))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('IL6R', 'Gene', (10, 14))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('enhanced', 'PosReg', (90, 98))	('angiogenesis', 'CPA', (65, 77))	('Silencing', 'Var', (0, 9))	('IL6R', 'Gene', '3570', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
437806	33714953	Results of current study indicate that miR-125a-5p exerts its function via IL6R to activate JAK-STAT3 signaling pathway.	('STAT3', 'Gene', (96, 101))	('miR-125a-5p', 'Var', (39, 50))	('activate', 'PosReg', (83, 91))	('IL6R', 'Gene', (75, 79))	('miR-125a-5p', 'Chemical', '-', (39, 50))	('IL6R', 'Gene', '3570', (75, 79))	('STAT3', 'Gene', '6774', (96, 101))
437807	33714953	Combined with the previous study, our data suggested that miR-125a-5p served as an important tumor suppressor gene in EC cells.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('miR-125a-5p', 'Var', (58, 69))	('tumor', 'Disease', (93, 98))	('miR-125a-5p', 'Chemical', '-', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
437813	33714953	GenePharma provided (Shanghai, China) miR-20b-5p mimic, miR-125a-5p mimic, miR-20b-5p inhibitor, miR-125a-5p inhibitor and their corresponding negative controls.	('miR-125a-5p', 'Chemical', '-', (97, 108))	('miR-125a-5p', 'Chemical', '-', (56, 67))	('miR-20b-5p', 'Chemical', '-', (75, 85))	('miR-20b-5p', 'Chemical', '-', (38, 48))	('miR-20b-5p', 'Var', (75, 85))	('miR-125a-5p', 'Var', (56, 67))
437828	33714953	A wild-type 3'-UTR and a mutant 3'-UTR of PTEN and IL6R were amplified from KYSE-150 cells using PCR, and cloned into a pGL3-Basic vector.	('PTEN', 'Gene', (42, 46))	('mutant', 'Var', (25, 31))	('pGL3', 'Gene', '6391', (120, 124))	('PTEN', 'Gene', '5728', (42, 46))	('IL6R', 'Gene', (51, 55))	('pGL3', 'Gene', (120, 124))	('IL6R', 'Gene', '3570', (51, 55))
437840	28637795	There is growing evidence of population-specific variation that may contribute to racial/ethnic differences in the risk of cancer and cancer-related phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('contribute', 'Reg', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (123, 129))	('variation', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
437841	28637795	This is seen with the risk alleles at 8q24 and the higher burden of prostate cancer in African Americans and the missense variant in CREBRF and high prevalence of obesity in Samoans.	('obesity', 'Disease', (163, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))	('CREBRF', 'Gene', (133, 139))	('CREBRF', 'Gene', '153222', (133, 139))	('prostate cancer', 'Disease', (68, 83))	('obesity', 'Phenotype', 'HP:0001513', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('obesity', 'Disease', 'MESH:D009765', (163, 170))	('missense variant', 'Var', (113, 129))
437855	28637795	Genetic studies in the African Ancestry Prostate Cancer (AAPC) Consortium (>4,853 prostate cancer cases and 4,678 controls) identified two African-specific variants at 8q24 as well as one at 17q21.33/ZNF365 in a region that a later GWAS in men of European ancestry found evidence of association with a separate variant.	('ZNF365', 'Gene', (200, 206))	('AAPC', 'Disease', 'MESH:D011125', (57, 61))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (40, 55))	('Prostate Cancer', 'Disease', (40, 55))	('Prostate Cancer', 'Disease', 'MESH:D011471', (40, 55))	('men', 'Species', '9606', (240, 243))	('AAPC', 'Disease', (57, 61))	('ZNF365', 'Gene', '22891', (200, 206))	('prostate cancer', 'Disease', (82, 97))	('variants', 'Var', (156, 164))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('association', 'Interaction', (283, 294))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (82, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))
437856	28637795	The only GWAS in exclusively African men was in a small sample of Ghanaians (474 prostate cancer cases and 458 controls) that reported loci specific for high and low risk prostate cancer that were not replicated in AAPC.	('prostate cancer', 'Disease', 'MESH:D011471', (171, 186))	('prostate cancer', 'Phenotype', 'HP:0012125', (171, 186))	('prostate cancer', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AAPC', 'Disease', (215, 219))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('low risk prostate', 'Phenotype', 'HP:0008687', (162, 179))	('men', 'Species', '9606', (37, 40))	('prostate cancer', 'Disease', (171, 186))	('loci', 'Var', (135, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('AAPC', 'Disease', 'MESH:D011125', (215, 219))
437862	28637795	More than 170 breast cancer risk loci have been identified in GWAS of overall breast cancer, or estrogen receptor-positive (ER+) and ER- disease, with the most recent scan in the Breast Cancer Association Consortium (BCAC)/Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium discovering ~40% (n=71) of these loci (OncoArray, personal communication, D. Easton).	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('Breast Cancer', 'Phenotype', 'HP:0003002', (179, 192))	('Variants', 'Var', (265, 273))	('Cancer', 'Phenotype', 'HP:0002664', (284, 290))	('Breast Cancer', 'Disease', (277, 290))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('Breast Cancer', 'Disease', (179, 192))	('Breast Cancer', 'Disease', 'MESH:D001943', (277, 290))	('Breast Cancer', 'Phenotype', 'HP:0003002', (277, 290))	('breast cancer', 'Disease', (14, 27))	('Breast Cancer', 'Disease', 'MESH:D001943', (179, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('person', 'Species', '9606', (360, 366))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
437863	28637795	GWAS of breast cancer in East Asians (Japanese, Chinese and Koreans) have reported 11 novel loci, including a common deletion in the APOBEC3 gene, with the largest meta-analysis from the Asian Breast Cancer Consortium (7,619 breast cancer cases and 6,286 controls), reporting the two latest discoveries at 1p22.3 and 21q22.12.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('Breast Cancer', 'Disease', (193, 206))	('breast cancer', 'Disease', (225, 238))	('Breast Cancer', 'Disease', 'MESH:D001943', (193, 206))	('Cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('Breast Cancer', 'Phenotype', 'HP:0003002', (193, 206))	('APOBEC3', 'Gene', (133, 140))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))	('deletion', 'Var', (117, 125))
437866	28637795	In the only scan of Hispanic/Latinas (3,140 breast cancer cases and 8,184 controls), a novel protective variant that originates from Native Americans was identified at 6q25.1, near the Estrogen Receptor 1 gene (ESR1) in a region previously discovered in Chinese.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('ESR1', 'Gene', '2099', (211, 215))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Estrogen Receptor 1', 'Gene', (185, 204))	('ESR1', 'Gene', (211, 215))	('variant', 'Var', (104, 111))	('Estrogen Receptor 1', 'Gene', '2099', (185, 204))
437879	28637795	In the only African American GWAS (1,737 lung cancer cases and 3,602 controls), one loci at 15q25.1, that encodes for the alpha-nicotinic acetylcholine receptor (CHRNA3-CHRNB4-CHRNA5) (rs2036527) and one at 5p15.33, that encodes for telomerase reverse transcriptase (TERT)rs2853677), confirmed these discoveries from previous GWAS of European and East Asian ancestry populations.	('TERT', 'Gene', (267, 271))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))	('rs2036527', 'Mutation', 'rs2036527', (185, 194))	('TERT', 'Gene', '7015', (267, 271))	('lung cancer', 'Disease', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('rs2036527', 'Var', (185, 194))	('CHRNA3-CHRNB4-CHRNA5', 'Disease', 'None', (162, 182))	('rs2853677', 'Mutation', 'rs2853677', (272, 281))	('CHRNA3-CHRNB4-CHRNA5', 'Disease', (162, 182))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('telomerase reverse transcriptase', 'Gene', (233, 265))	('telomerase reverse transcriptase', 'Gene', '7015', (233, 265))
437880	28637795	In East Asians, variants in the 15q25.1 CHRNA3-CHRNB4-CHRNA5 region were not associated with lung cancer at a genome-wide significance level.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('CHRNA3-CHRNB4-CHRNA5', 'Disease', 'None', (40, 60))	('variants', 'Var', (16, 24))	('CHRNA3-CHRNB4-CHRNA5', 'Disease', (40, 60))	('associated', 'Reg', (77, 87))
437881	28637795	However, variant rs2736100 at 5p15.33 TERT, which was previously found to be a suggestive association in European ancestry populations (correlated with rs2853677 in East Asians; p>10-7), reached genome-wide significance in a Japanese study with 1,026 adenocarcinoma cases.	('TERT', 'Gene', (38, 42))	('adenocarcinoma', 'Disease', (251, 265))	('rs2736100', 'Mutation', 'rs2736100', (17, 26))	('variant rs2736100', 'Var', (9, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('adenocarcinoma', 'Disease', 'MESH:D000230', (251, 265))	('TERT', 'Gene', '7015', (38, 42))	('rs2853677', 'Mutation', 'rs2853677', (152, 161))
437882	28637795	An additional novel independent signal at 5p15.33 TERT, rs465498, has also been identified for overall lung cancer in East Asian populations.	('TERT', 'Gene', '7015', (50, 54))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('rs465498', 'Mutation', 'rs465498', (56, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('TERT', 'Gene', (50, 54))	('rs465498', 'Var', (56, 64))
437895	28637795	In a Japanese study, with a discovery set of 431 bladder cancer cases and 5,581 controls, a novel risk variant at the 15q25 risk locus was identified.	('bladder cancer', 'Disease', (49, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('variant', 'Var', (103, 110))
437896	28637795	In a Chinese study, with a discovery set of 599 bladder cancer cases and 4,645 controls, a novel risk variant at 5q12.3 was reported that did not replicate in European ancestry populations.	('bladder cancer', 'Disease', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('variant', 'Var', (102, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))
437898	28637795	In the only GWAS conducted in a non-European ancestry population, of 225 African American renal cell carcinoma cases and 375 controls, a signal was detected at 12p11.23, 77 kb from a previously reported European-ancestry renal cell carcinoma marker; however, the association did not reach genome-wide significance (p = 1.2 x 10-7).	('renal cell carcinoma', 'Disease', 'MESH:C538614', (90, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('renal cell carcinoma', 'Disease', (221, 241))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (221, 241))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (221, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('12p11.23', 'Var', (160, 168))	('renal cell carcinoma', 'Disease', (90, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))
437909	28637795	Sublocation analyses suggests that the variants identified at 1q22, 5p13.1, 5q14.3, and 6p21.10 may be specifically associated with non-cardia gastric adenocarcinoma, although further work by sublocations is required to confirm these findings.	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('non-cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (132, 165))	('non-cardia gastric adenocarcinoma', 'Disease', (132, 165))	('variants', 'Var', (39, 47))	('associated', 'Reg', (116, 126))
437917	28637795	Variants at 12q24.12 (rs671) and 12q24.13 (rs2074356), which are in or near the ALDH2 gene, have been reported to have a potential multiplicative interaction with alcohol drinking, a major risk factor for esophageal cancer.	('rs2074356', 'Mutation', 'rs2074356', (43, 52))	('rs671', 'Mutation', 'rs671', (22, 27))	('Variants', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('esophageal cancer', 'Disease', (205, 222))	('ALDH2', 'Gene', '217', (80, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (205, 222))	('alcohol drinking', 'Phenotype', 'HP:0030955', (163, 179))	('rs671', 'Var', (22, 27))	('alcohol drinking', 'Disease', (163, 179))	('ALDH2', 'Gene', (80, 85))	('alcohol', 'Chemical', 'MESH:D000438', (163, 170))
437919	28637795	The ALDH2 rs671 A allele, which is common in East Asian populations (30-50% frequency) and almost nonexistent in European ancestry populations, has been associated with a reduction in the enzyme's ability to metabolize acetaldehyde, the primary metabolite of alcohol and an established carcinogen.	('ability', 'MPA', (197, 204))	('ALDH2', 'Gene', '217', (4, 9))	('metabolize acetaldehyde', 'MPA', (208, 231))	('alcohol', 'Chemical', 'MESH:D000438', (259, 266))	('rs671', 'Mutation', 'rs671', (10, 15))	('ALDH2', 'Gene', (4, 9))	('reduction', 'NegReg', (171, 180))	('rs671 A', 'Var', (10, 17))	('acetaldehyde', 'Chemical', 'MESH:D000079', (219, 231))
437922	28637795	The variants at 4q23 and 6p21.32 were also found associated at a genome-wide association level with the sublocation of oropharyngeal cancer.	('oropharyngeal cancer', 'Disease', (119, 139))	('variants', 'Var', (4, 12))	('associated', 'Reg', (49, 59))	('sublocation', 'Disease', (104, 115))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
437926	28637795	In spite of the small discovery sample for two of the GWAS studies, with less than 300 nasopharyngeal cancer cases, these studies were able to detect large effects for variants in HLA-A at 6p22.1, with odds ratios ranging from 1.86-2.57.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('variants', 'Var', (168, 176))	('effects', 'Reg', (156, 163))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (87, 108))	('HLA-A', 'Gene', '3105', (180, 185))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (87, 108))	('HLA-A', 'Gene', (180, 185))	('nasopharyngeal cancer', 'Disease', (87, 108))
437927	28637795	The risk variant in this HLA region is common in Chinese populations.	('HLA', 'Gene', '3115', (25, 28))	('variant', 'Var', (9, 16))	('HLA', 'Gene', (25, 28))
437928	28637795	In a recent meta-analysis of four GWAS of nasopharyngeal cancer that included 2,152 Chinese nasopharyngeal cancer cases and 3,740 controls, a novel risk variant was identified within the CLPTM1L/TERT region at 5p15.33, and a suggestive association at 9p21.3 from an early study was confirmed, reaching a GWAS significance threshold in this larger study.	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (92, 113))	('variant', 'Var', (153, 160))	('TERT', 'Gene', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (92, 113))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (42, 63))	('nasopharyngeal cancer', 'Disease', (92, 113))	('TERT', 'Gene', '7015', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('CLPTM1L', 'Gene', '81037', (187, 194))	('CLPTM1L', 'Gene', (187, 194))	('nasopharyngeal cancer', 'Disease', (42, 63))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (42, 63))
437960	28637795	A GWAS of lung cancer in non-smoking East Asian women identified three novel loci at 10q25.2/VTI1A, 16p22.1/DCBLD and 6p21.32/HLA-DRA.	('VTI1A', 'Gene', '143187', (93, 98))	('HLA-DRA', 'Gene', '3122', (126, 133))	('HLA-DRA', 'Gene', (126, 133))	('16p22.1/DCBLD', 'Var', (100, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (10, 21))	('GWAS of lung cancer', 'Disease', (2, 21))	('women', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('VTI1A', 'Gene', (93, 98))	('GWAS of lung cancer', 'Disease', 'MESH:D008175', (2, 21))
438121	25106743	Diagnostic application of PIK3CA mutation analysis in Chinese esophageal cancer patients The PIK3CA gene mutation was found to associate with prognosis and might affect molecular targeted therapy in esophageal carcinoma (EC).	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('mutation', 'Var', (105, 113))	('PIK3CA', 'Gene', '5290', (93, 99))	('esophageal cancer', 'Disease', (62, 79))	('esophageal carcinoma', 'Disease', (199, 219))	('PIK3CA', 'Gene', '5290', (26, 32))	('affect', 'Reg', (162, 168))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (199, 219))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (199, 219))	('PIK3CA', 'Gene', (26, 32))	('PIK3CA', 'Gene', (93, 99))	('associate', 'Reg', (127, 136))
438126	25106743	10 mutations occurred in exon 9 and 2 in exon 20, including G1624A:E542K (n = 4), G1633A:E545K (n = 6) and A3140G:H1047R (n = 2).	('G1633A', 'Mutation', 'rs104886003', (82, 88))	('E545K', 'Mutation', 'rs104886003', (89, 94))	('G1624A', 'Mutation', 'rs121913273', (60, 66))	('H1047R', 'Mutation', 'rs121913279', (114, 120))	('G1633A:E545K', 'Var', (82, 94))	('G1624A:E542K', 'Var', (60, 72))	('E542K', 'Mutation', 'rs121913273', (67, 72))	('A3140G', 'Mutation', 'g.3140A>G', (107, 113))	('A3140G:H1047R', 'Var', (107, 120))
438127	25106743	Among these 12 cases characterized for PIK3CA mutation, however, only 7 and 6 cases were identified by Sanger sequencing (6.6%,7/106) and pyrosequencing (5.7%,6/106), respectively.	('mutation', 'Var', (46, 54))	('PIK3CA', 'Gene', (39, 45))	('PIK3CA', 'Gene', '5290', (39, 45))
438131	25106743	More than 30% of various solid tumor types were found to contain the mutations, and it was frequently mutated in cancers of the colon, breast, brain, liver, stomach and lung.	('mutations', 'Var', (69, 78))	('cancers of the colon', 'Disease', 'MESH:D015179', (113, 133))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('stomach', 'Disease', (157, 164))	('tumor', 'Disease', (31, 36))	('breast', 'Disease', (135, 141))	('liver', 'Disease', (150, 155))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('lung', 'Disease', (169, 173))	('brain', 'Disease', (143, 148))	('cancers of the colon', 'Disease', (113, 133))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
438132	25106743	Mutations in the three mutation hotspots in PIK3CA (G1624A:E542K, G1633A:E545K, and A3140G:H1047R) have been shown to elevate the lipid kinase activity and thereby leading to the activation of the downstream Akt signaling pathway.	('PIK3CA', 'Gene', (44, 50))	('A3140G', 'Mutation', 'g.3140A>G', (84, 90))	('E542K', 'Mutation', 'rs121913273', (59, 64))	('G1624A:E542K', 'Var', (52, 64))	('A3140G:H1047R', 'Var', (84, 97))	('G1633A', 'Mutation', 'rs104886003', (66, 72))	('PIK3CA', 'Gene', '5290', (44, 50))	('G1624A', 'Mutation', 'rs121913273', (52, 58))	('downstream Akt signaling pathway', 'Pathway', (197, 229))	('E545K', 'Mutation', 'rs104886003', (73, 78))	('activation', 'PosReg', (179, 189))	('H1047R', 'Mutation', 'rs121913279', (91, 97))	('elevate', 'PosReg', (118, 125))	('G1633A:E545K', 'Var', (66, 78))	('lipid', 'MPA', (130, 135))
438133	25106743	Targeted therapies such as Imatinib mesylate (anti-BCR/ABL and c-kit), Gefitinib and Erlotinib (anti-EGFR) that appear to impart a high degree of specificity for translocated/mutated oncogenesis give hope that therapies targeted specifically against mutant PIK3CA can be developed.	('Erlotinib', 'Chemical', 'MESH:D000069347', (85, 94))	('Gefitinib', 'Chemical', 'MESH:D000077156', (71, 80))	('c-kit', 'Gene', (63, 68))	('BCR/ABL', 'Gene', '25;613', (51, 58))	('c-kit', 'Gene', '3815', (63, 68))	('PIK3CA', 'Gene', (257, 263))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('BCR/ABL', 'Gene', (51, 58))	('mutant', 'Var', (250, 256))	('Imatinib mesylate', 'Chemical', 'MESH:D000068877', (27, 44))	('PIK3CA', 'Gene', '5290', (257, 263))
438134	25106743	A recent report extends previous studies suggesting that the acquisition of PIK3CA mutations may be an important molecular event in the etiology of esophageal cancer (EC) and the mutations are associated with their clinical outcome.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', (148, 165))	('PIK3CA', 'Gene', (76, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('PIK3CA', 'Gene', '5290', (76, 82))	('associated', 'Reg', (193, 203))
438135	25106743	The frequency of PIK3CA mutation in EC varied from 0% to 21%, which could likely introduce some bias in the statistical analyses of their clinical significance.	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('mutation', 'Var', (24, 32))
438136	25106743	The difference might be due to a difference in the patient cohorts or the methods used to assess PIK3CA mutation.	('PIK3CA', 'Gene', (97, 103))	('mutation', 'Var', (104, 112))	('PIK3CA', 'Gene', '5290', (97, 103))	('patient', 'Species', '9606', (51, 58))
438137	25106743	What's more, somatic mutations of PIK3CA in EC samples are less than that observed in colorectal (18.8-32.0%) and breast (8.3-40%) tumors.	('PIK3CA', 'Gene', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('PIK3CA', 'Gene', '5290', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('less', 'NegReg', (59, 63))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('colorectal', 'Disease', (86, 96))	('mutations', 'Var', (21, 30))
438138	25106743	Therefore, standard methods with high sensitivity and speciality will be conductive to examine the predictive and prognostic significance of PIK3CA mutations in EC.	('mutations', 'Var', (148, 157))	('PIK3CA', 'Gene', (141, 147))	('PIK3CA', 'Gene', '5290', (141, 147))
438141	25106743	In previous studies, researchers compared the detection rate of PIK3CA, EGFR, KRAS and BRAF mutation in colorectal or lung cancers by different methods.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colorectal or lung cancers', 'Disease', 'MESH:D015179', (104, 130))	('PIK3CA', 'Gene', (64, 70))	('lung cancers', 'Phenotype', 'HP:0100526', (118, 130))	('mutation', 'Var', (92, 100))	('BRAF', 'Gene', '673', (87, 91))	('EGFR', 'Gene', '1956', (72, 76))	('PIK3CA', 'Gene', '5290', (64, 70))	('KRAS', 'Gene', (78, 82))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('EGFR', 'Gene', (72, 76))	('KRAS', 'Gene', '3845', (78, 82))	('BRAF', 'Gene', (87, 91))	('colorectal or lung cancers', 'Disease', (104, 130))
438157	25106743	Following PCR amplification, 3 uL of PCR product was transferred to 96-well plates for Hybridization, which contained 37 uL of the hybridization solution (SurExam, China) and a mixture of 1000 probe-coated beads of each type of mutation (H1047L, H1047R, E542K, E545K, E545D).	('E542K', 'Mutation', 'rs121913273', (254, 259))	('E545D', 'Var', (268, 273))	('H1047R', 'Var', (246, 252))	('H1047L', 'Mutation', 'rs121913279', (238, 244))	('E545K', 'Mutation', 'rs104886003', (261, 266))	('H1047L', 'Var', (238, 244))	('E545K', 'Var', (261, 266))	('H1047R', 'Mutation', 'rs121913279', (246, 252))	('E542K', 'Var', (254, 259))	('E545D', 'Mutation', 'rs121913275', (268, 273))
438158	25106743	DNA samples from the same preparation for PCR direct sequencing analysis were subjected to PIK3CA mutant analysis using AmoyDx (r) PIK3CA Five Mutations Detection Kit (Amoy Diagnostics Co.Ltd).	('PIK3CA', 'Gene', (91, 97))	('PIK3CA', 'Gene', '5290', (91, 97))	('PIK3CA', 'Gene', (131, 137))	('PIK3CA', 'Gene', '5290', (131, 137))	('mutant', 'Var', (98, 104))
438159	25106743	The kit contains primers designed for detection of 5 common PIK3CA mutations based on ARMS PCR (amplification refractory mutation specific PCR) and double circular probe detection technology.	('PIK3CA', 'Gene', '5290', (60, 66))	('PIK3CA', 'Gene', (60, 66))	('mutations', 'Var', (67, 76))
438160	25106743	The agreement for genotype PIK3CA mutational was measured by the index kappa calculated using SPSS software version 15, and Statistical differences were analyzed by the McNemar test and p value less than 0.05 was recorded as significant.	('PIK3CA', 'Gene', '5290', (27, 33))	('mutational', 'Var', (34, 44))	('PIK3CA', 'Gene', (27, 33))
438167	25106743	PIK3CA mutations on exons 9 and 20 were analyzed in 106 esophageal carcinoma patients by Sanger sequencing, pyrosequencing, ME-Liquidchip.	('esophageal carcinoma', 'Disease', (56, 76))	('PIK3CA', 'Gene', (0, 6))	('patients', 'Species', '9606', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('PIK3CA', 'Gene', '5290', (0, 6))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (56, 76))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (56, 76))	('mutations', 'Var', (7, 16))
438168	25106743	PIK3CA mutations rates were 5.7% (6/106), 6.6% (7/106) and 11.3% (12/106) by Sanger sequencing, pyrosequencing, and ME-Liquidchip respectively.	('mutations', 'Reg', (7, 16))	('PIK3CA', 'Gene', '5290', (0, 6))	('pyrosequencing', 'Var', (96, 110))	('PIK3CA', 'Gene', (0, 6))
438169	25106743	PIK3CA mutation spectrum was similar in all 4 approaches with the exception that exon 20 mutation (representing approximately 16.7% of the mutations according to ME-Liquidchip and ARMS) were not detected by pyrosequencing.	('exon', 'Var', (81, 85))	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))
438170	25106743	The detection percentage of PIK3CA mutation by ME-Liquidchip was higher than that of Sanger sequencing and pyrosequencing, this difference was statistically significant (p < 0.05, respectively).	('higher', 'PosReg', (65, 71))	('PIK3CA', 'Gene', (28, 34))	('PIK3CA', 'Gene', '5290', (28, 34))	('mutation', 'Var', (35, 43))
438171	25106743	Two samples (EC037 and EC058) carried mutations according to Sanger sequencing, but were negative according to pyrosequencing.	('mutations', 'Var', (38, 47))	('EC037', 'CellLine', 'CVCL:9046', (13, 18))	('carried', 'Reg', (30, 37))
438175	25106743	In most tissue types, mutations predominantly cluster within the helical and kinase domains of the PIK3CA subunit.	('PIK3CA', 'Gene', '5290', (99, 105))	('mutations', 'Var', (22, 31))	('PIK3CA', 'Gene', (99, 105))
438176	25106743	Exon 9 mutations are located in the helical domain of p110a and are considered to abrogate inhibitory intermolecular interaction between p85 and p110.	('inhibitory intermolecular interaction', 'MPA', (91, 128))	('p85', 'Gene', (137, 140))	('p110a', 'Gene', (54, 59))	('p110', 'Gene', '100616443', (145, 149))	('p110', 'Gene', '100616443', (54, 58))	('abrogate', 'NegReg', (82, 90))	('p110', 'Gene', (145, 149))	('p110', 'Gene', (54, 58))	('p85', 'Gene', '5295', (137, 140))	('p110a', 'Gene', '5290', (54, 59))	('mutations', 'Var', (7, 16))
438177	25106743	Many researchers suggested that these genetic alterations may be kinase activating and oncogenic in different human malignant tumors, including colon, breast cancer, endometrial, lung, and brain tumors.	('brain tumors', 'Disease', (189, 201))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('malignant tumors', 'Disease', 'MESH:D018198', (116, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('malignant tumors', 'Disease', (116, 132))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Disease', (151, 164))	('endometrial', 'Disease', 'MESH:D014591', (166, 177))	('genetic alterations', 'Var', (38, 57))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colon', 'Disease', (144, 149))	('endometrial', 'Disease', (166, 177))	('human', 'Species', '9606', (110, 115))	('brain tumors', 'Disease', 'MESH:D001932', (189, 201))	('brain tumors', 'Phenotype', 'HP:0030692', (189, 201))	('lung', 'Disease', (179, 183))
438178	25106743	Recently, Song and Lin identified PIK3CA mutations in EC with whole-genome sequencing, whole-exome sequencing or array comparative genomic hybridization analysis, and suggested their functional relevance in EC.	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', (34, 40))	('PIK3CA', 'Gene', '5290', (34, 40))
438180	25106743	Therefore, PIK3CA mutation screening would greatly improve therapeutic strategies for EC in the future.	('PIK3CA', 'Gene', '5290', (11, 17))	('mutation', 'Var', (18, 26))	('PIK3CA', 'Gene', (11, 17))
438182	25106743	Several methods have been applied to detection of PIK3CA gene mutation in EC, it is necessary to compare the assays.	('PIK3CA', 'Gene', (50, 56))	('PIK3CA', 'Gene', '5290', (50, 56))	('mutation', 'Var', (62, 70))
438184	25106743	So pyrosequencing assay for PIK3CA mutation detection is certainly useful, because most activating PIK3CA mutations cluster in the hotspots of exons 9 and 20.	('PIK3CA', 'Gene', (28, 34))	('PIK3CA', 'Gene', '5290', (99, 105))	('PIK3CA', 'Gene', '5290', (28, 34))	('activating', 'PosReg', (88, 98))	('mutations', 'Var', (106, 115))	('PIK3CA', 'Gene', (99, 105))
438185	25106743	ME-Liquidchip is a novel technology, which integrates the sensitive mutant enriched PCR and quantitative high-throughput liquidchip (suspension array) to detect DNA somatic mutations in EGFR, KRAS, BRAF, and PIK3CA genes from tissues or serum samples.	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (198, 202))	('EGFR', 'Gene', '1956', (186, 190))	('mutations', 'Var', (173, 182))	('EGFR', 'Gene', (186, 190))	('KRAS', 'Gene', (192, 196))	('PIK3CA', 'Gene', (208, 214))	('PIK3CA', 'Gene', '5290', (208, 214))	('KRAS', 'Gene', '3845', (192, 196))
438186	25106743	Here, we report our study of PIK3CA mutations by Sanger sequencing, pyrosequencing, ME-Liquidchip and ARMS in a clinical setting.	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('mutations', 'Var', (36, 45))
438187	25106743	With 106 EC samples, a total of 12 PIK3CA mutations were identified.	('PIK3CA', 'Gene', (35, 41))	('mutations', 'Var', (42, 51))	('PIK3CA', 'Gene', '5290', (35, 41))
438188	25106743	The prevalence and distribution of PIK3CA mutations found in our study by ME-Liquidchip (11.3%) were in agreement with previous data reported in esophageal cancer.	('esophageal cancer', 'Disease', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('PIK3CA', 'Gene', (35, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('PIK3CA', 'Gene', '5290', (35, 41))	('mutations', 'Var', (42, 51))
438189	25106743	As to Sanger sequencing and pyrosequencing, the detected rate of PIK3CA mutation was 6.6% and 5.7%, respectively.	('PIK3CA', 'Gene', (65, 71))	('PIK3CA', 'Gene', '5290', (65, 71))	('mutation', 'Var', (72, 80))
438190	25106743	Sanger sequencing detected two tumors harboring E545K and H1047R mutation, but the same samples were considered wt according to pyrosequencing.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('H1047R', 'Mutation', 'rs121913279', (58, 64))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('E545K', 'Mutation', 'rs104886003', (48, 53))	('E545K', 'Var', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('H1047R', 'Var', (58, 64))
438191	25106743	On the contrary, a tumor harboring a E545K mutation in terms of pyrosequencing was not detected by Sanger sequencing.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('E545K', 'Mutation', 'rs104886003', (37, 42))	('E545K', 'Var', (37, 42))
438194	25106743	It's reported there was an different distribution of PIK3CA mutations between adenocarcinoma and SCC histological subtypes of EC.	('adenocarcinoma', 'Disease', (78, 92))	('PIK3CA', 'Gene', '5290', (53, 59))	('adenocarcinoma', 'Disease', 'MESH:D000230', (78, 92))	('SCC', 'Gene', (97, 100))	('mutations', 'Var', (60, 69))	('SCC', 'Gene', '6317', (97, 100))	('PIK3CA', 'Gene', (53, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
438195	25106743	However, all our detected mutant samples were esophageal SCC.	('mutant', 'Var', (26, 32))	('SCC', 'Gene', (57, 60))	('SCC', 'Gene', '6317', (57, 60))
438197	25106743	We have demonstrated that ME-Liquidchip and ARMS is highly sensitive for clinical diagnosis of PIK3CA mutation in EC.	('mutation', 'Var', (102, 110))	('PIK3CA', 'Gene', (95, 101))	('PIK3CA', 'Gene', '5290', (95, 101))
438198	23560067	Investigation of Tumor Suppressing Function of CACNA2D3 in Esophageal Squamous Cell Carcinoma Deletion of 3p is one of the most frequent genetic alterations in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes (TSGs) within these regions.	('Carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('TSG', 'Gene', '65960', (267, 270))	('Tumor', 'Phenotype', 'HP:0002664', (17, 22))	('CACNA2D3', 'Gene', '12294', (47, 55))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (160, 194))	('CACNA2D3', 'Gene', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('TSG', 'Gene', (267, 270))	('Esophageal Squamous Cell Carcinoma', 'Disease', (59, 93))	('Tumor Suppressing', 'CPA', (17, 34))	('Deletion of 3p', 'Var', (94, 108))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (59, 93))	('esophageal squamous cell carcinoma', 'Disease', (160, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
438202	23560067	Functional studies demonstrated that CACNA2D3 could inhibit tumorigenicity, cell motility and induce apoptosis.	('inhibit', 'NegReg', (52, 59))	('CACNA2D3', 'Var', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cell motility', 'CPA', (76, 89))	('induce', 'PosReg', (94, 100))	('apoptosis', 'CPA', (101, 110))	('tumor', 'Disease', (60, 65))
438208	23560067	Comparative genomic hybridization and loss of heterozygosity studies found that deletion of 3p was one of the most frequent genetic alterations in ESCC, suggesting the existence of one or more tumor suppressor genes within these frequently deleted regions.	('deletion', 'Var', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('ESCC', 'Gene', (147, 151))	('tumor', 'Disease', (193, 198))
438214	23560067	Frequent allele loss of CACNA2D2 has been reported in lung, breast and other cancers.	('breast', 'Disease', (60, 66))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('reported', 'Reg', (42, 50))	('CACNA2D2', 'Gene', (24, 32))	('allele loss', 'Var', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung', 'Disease', (54, 58))	('CACNA2D2', 'Gene', '56808', (24, 32))
438231	23560067	SNP site (rs589281) within CACNA2D3 gene was PCR amplified and sequencing analyzed with primers (CAC-SNP-F1:5' TGTTGTGAT GATTAGGTGAG-3'; CAC-SNP-R1:5' CTGTGGAGAATCACCTAATTC-3').	('CACNA2D3', 'Gene', (27, 35))	('rs589281', 'Mutation', 'rs589281', (10, 18))	('rs589281', 'Var', (10, 18))
438255	23560067	Downregulation of CACNA2D3 was also detected in 4 ESCC cell lines KYSE30, KYSE510, KYSE410 and HKESC1 (Fig.	('KYSE510', 'Var', (74, 81))	('Downregulation', 'NegReg', (0, 14))	('HKESC1', 'CellLine', 'CVCL:D568', (95, 101))	('KYSE410', 'Var', (83, 90))	('CACNA2D3', 'Gene', (18, 26))
438264	23560067	In our previous study, LOH at the SNP site rs589281 within CACNA2D3 gene was detected in about 50% of primary ESCC cases.	('primary ESCC', 'Disease', (102, 114))	('rs589281', 'Mutation', 'rs589281', (43, 51))	('rs589281', 'Var', (43, 51))	('CACNA2D3', 'Gene', (59, 67))
438266	23560067	Loss of CACNA2D3 allele could be observed in 2 cell lines (KYSE410 and KYSE510) and 1 primary ESCC tumor with the downregulation of CACNA2D3.	('ESCC tumor', 'Disease', 'MESH:D004938', (94, 104))	('CACNA2D3', 'Gene', (132, 140))	('ESCC tumor', 'Disease', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('KYSE510', 'Var', (71, 78))	('downregulation', 'NegReg', (114, 128))
438267	23560067	To characterize its tumor suppressive function, CACNA2D3 was stably transfected into KYSE30 (30-CAC) and KYSE510 (510-CAC).	('KYSE510', 'Var', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('CACNA2D3', 'Gene', (48, 56))	('tumor', 'Disease', (20, 25))
438273	23560067	The average weight of tumors induced by 30-CAC cells (0.168+-0.080 g) was significantly decreased compared to the tumors induced by 30-Vec cells (0.825+-0.072 g) (P<0.01, Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Vec', 'Gene', (135, 138))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Vec', 'Gene', '12562', (135, 138))	('tumors', 'Disease', (114, 120))	('decreased', 'NegReg', (88, 97))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', (22, 28))	('30-CAC cells', 'Var', (40, 52))
438274	23560067	Cell invasion assay found that cells invaded through Matrigel were also significantly decreased in 30-CAC (91.03%) and 510-CAC (75.07%) cells, compared with that in 30-Vec and 510-Vec cells, respectively (Fig.	('30-CAC', 'Var', (99, 105))	('Vec', 'Gene', '12562', (180, 183))	('Vec', 'Gene', (180, 183))	('cells invaded through Matrigel', 'CPA', (31, 61))	('decreased', 'NegReg', (86, 95))	('510-CAC', 'Var', (119, 126))	('Vec', 'Gene', '12562', (168, 171))	('Vec', 'Gene', (168, 171))
438280	23560067	In the present study, intracellular Ca2+ level in the KYSE30 cells after CACNA2D3 transfection was measured by FACS.	('transfection', 'Var', (82, 94))	('FACS', 'Gene', (111, 115))	('FACS', 'Gene', '14081', (111, 115))	('intracellular Ca2+ level', 'MPA', (22, 46))	('CACNA2D3', 'Gene', (73, 81))
438285	23560067	After STS treatment, the apoptotic index, defined as the percentage of apoptotic cells (F2+F4), was significantly higher in CACNA2D3 transfectants (P<0.05) compared with empty vector-transfected cells (Fig.	('transfectants', 'Var', (133, 146))	('apoptotic index', 'CPA', (25, 40))	('STS', 'Chemical', 'MESH:D019311', (6, 9))	('higher', 'PosReg', (114, 120))	('CACNA2D3', 'Gene', (124, 132))
438293	23560067	We also noted that the promoter hypermethylation could be detected in 12/28 (42.8%) of methylation-positive ESCCs matched non-tumor tissues, which might be promoted by local environment.	('non-tumor', 'Disease', 'MESH:D009369', (122, 131))	('methylation-positive', 'Var', (87, 107))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('non-tumor', 'Disease', (122, 131))	('ESCCs', 'Disease', (108, 113))
438294	23560067	found that patients with gastroesophageal reflux disease showed a high degree of hMLH1 hypermethylation, suggesting that local environment due to reflux might promote hypermethylation.	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (25, 56))	('hypermethylation', 'Var', (87, 103))	('hMLH1', 'Gene', '4292', (81, 86))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (25, 48))	('patients', 'Species', '9606', (11, 19))	('promote', 'PosReg', (159, 166))	('gastroesophageal reflux disease', 'Disease', (25, 56))	('hMLH1', 'Gene', (81, 86))
438300	23560067	Further study showed that CACNA2D3 could arrest cell cycle at G1/S checkpoint by upregulating p53 and p21 expression and downregulating CDK2 expression.	('CDK2', 'Gene', (136, 140))	('downregulating', 'NegReg', (121, 135))	('cell cycle at G1/S checkpoint', 'CPA', (48, 77))	('upregulating', 'PosReg', (81, 93))	('expression', 'MPA', (106, 116))	('CACNA2D3', 'Var', (26, 34))	('p21', 'Protein', (102, 105))	('expression', 'MPA', (141, 151))	('CDK2', 'Gene', '12566', (136, 140))	('p53', 'Protein', (94, 97))
438304	23560067	In this study, we found that CACNA2D3 could significantly increase apoptotic index after STS treatment (P<0.05).	('increase apoptotic index', 'Phenotype', 'HP:0030887', (58, 82))	('increase', 'PosReg', (58, 66))	('STS', 'Chemical', 'MESH:D019311', (89, 92))	('apoptotic index', 'CPA', (67, 82))	('CACNA2D3', 'Var', (29, 37))
438306	23560067	In diffuse gastric cancer, E-cadherin is inactivated mainly through LOH, somatic mutations and promoter hypermethylation.	('LOH', 'Var', (68, 71))	('inactivated', 'NegReg', (41, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (11, 25))	('promoter hypermethylation', 'Var', (95, 120))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (11, 25))	('E-cadherin', 'Protein', (27, 37))	('gastric cancer', 'Disease', (11, 25))
438427	31221127	Comparison of larynx SCC high TrkB-T1 RNA expressers to low expressers (n = 96) revealed gene expression differences consistent with the high TrkB-T1 tumors being more neural-like.	('SCC', 'Gene', (21, 24))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('TrkB', 'Gene', (142, 146))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('SCC', 'Gene', '6317', (21, 24))	('high', 'Var', (137, 141))	('TrkB', 'Gene', '4915', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('TrkB', 'Gene', (30, 34))	('TrkB', 'Gene', '4915', (142, 146))
438460	31221127	The ease of reproducible measurement of TrkB-T1 mRNA, via detection of the terminal exon using DNA microarrays or RNASeq, was used to determine if tumors highly enriched for TrkB-T1 mRNA make up a separate subtype of head and neck SCC and to discern pathways that are enriched in this subset of SCCs.	('TrkB', 'Gene', '4915', (40, 44))	('SCC', 'Gene', '6317', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('SCCs', 'Phenotype', 'HP:0002860', (295, 299))	('SCC', 'Phenotype', 'HP:0002860', (295, 298))	('tumors', 'Disease', (147, 153))	('SCC', 'Gene', '6317', (295, 298))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('TrkB', 'Gene', (40, 44))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('TrkB', 'Gene', '4915', (174, 178))	('SCC', 'Gene', (231, 234))	('SCC', 'Phenotype', 'HP:0002860', (231, 234))	('TrkB', 'Gene', (174, 178))	('mRNA', 'Var', (182, 186))	('SCC', 'Gene', (295, 298))
438471	31221127	All genes were considered in determining gene sets differentially represented in the high and low TrkB-T1 mRNA groups for Larynx + Oral, ESSC, LUSC, and LUAD.	('Larynx + Oral', 'Disease', (122, 135))	('TrkB', 'Gene', '4915', (98, 102))	('high', 'Var', (85, 89))	('LUAD', 'Disease', (153, 157))	('TrkB', 'Gene', (98, 102))	('LUAD', 'Phenotype', 'HP:0030078', (153, 157))	('low', 'NegReg', (94, 97))	('ESSC', 'Disease', (137, 141))	('LUSC', 'Disease', (143, 147))
438476	31221127	Logistic regression was used to determine the relation between the presence of CASP8, PIK3CA mutations and NTRK2 expression (Statistical Analysis Software, Cary, NC, USA).	('expression', 'MPA', (113, 123))	('NTRK2', 'Gene', '4915', (107, 112))	('mutations', 'Var', (93, 102))	('CASP8', 'Gene', '841', (79, 84))	('CASP8', 'Gene', (79, 84))	('PIK3CA', 'Gene', (86, 92))	('NTRK2', 'Gene', (107, 112))	('PIK3CA', 'Gene', '5290', (86, 92))
438477	31221127	For clinical parameters of high and low TrkB-T1 RNA tumor patients, either Chi Squared or Fisher Exact test when appropriate or in the case of age, the Student t test was used to determine statistical significance.	('TrkB', 'Gene', '4915', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('low', 'NegReg', (36, 39))	('tumor', 'Disease', (52, 57))	('TrkB', 'Gene', (40, 44))	('high', 'Var', (27, 31))	('patients', 'Species', '9606', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
438485	31221127	High TrkB-T1 expressers comprised 30% of tumors for LASC (vs. 0% of normal controls), 20% of tumors for OSCC (vs 21% of normal controls), 35% for LUSC (vs. 0% of normal controls), and 36% for ESSC (vs. 0% for normal controls).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TrkB', 'Gene', '4915', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('High', 'Var', (0, 4))	('LASC', 'Disease', (52, 56))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('LASC', 'Chemical', '-', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('TrkB', 'Gene', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('SCC', 'Gene', (105, 108))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('tumors', 'Disease', (93, 99))	('SCC', 'Gene', '6317', (105, 108))
438486	31221127	For adenocarcinomas, the fractions of tumors with TrkB-T1 expression over the average were 13% for LUAD (vs. 24% of normal controls) and 10% for ESAD (vs. 54% of normal controls) (Additional file 2: Table S1).	('ESAD', 'Disease', (145, 149))	('LUAD', 'Disease', (99, 103))	('over', 'PosReg', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('TrkB', 'Gene', '4915', (50, 54))	('adenocarcinomas', 'Disease', 'MESH:D000230', (4, 19))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('ESAD', 'Phenotype', 'HP:0011459', (145, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('TrkB', 'Gene', (50, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (9, 19))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('adenocarcinomas', 'Disease', (4, 19))	('expression', 'Var', (58, 68))	('LUAD', 'Phenotype', 'HP:0030078', (99, 103))
438492	31221127	When this analysis was done for high TrkB-T1 RNA expresser LUSCs, the similarity to brain tissue was seen, and for ESSC the top nine out of ten matches were brain tissue samples.	('high', 'Var', (32, 36))	('TrkB', 'Gene', (37, 41))	('TrkB', 'Gene', '4915', (37, 41))
438498	31221127	The next step was to determine if transcriptome patterns associated with high TrkB expression indicated similar pathways were enriched in tumor sites distinct from the head and neck.	('TrkB', 'Gene', '4915', (78, 82))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('TrkB', 'Gene', (78, 82))	('expression', 'MPA', (83, 93))	('high', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
438499	31221127	Again, the same pathways were seen to be enriched in high TrkB-T1 expressers versus low expresser ESSCs and LUSCs (Fig.	('TrkB', 'Gene', (58, 62))	('high', 'Var', (53, 57))	('TrkB', 'Gene', '4915', (58, 62))	('expressers', 'Var', (66, 76))
438500	31221127	A second gene set analysis tool was used to verify common differences in biological pathways seen in high versus low TrkB-T1 expressers in SCCs.	('SCC', 'Gene', '6317', (139, 142))	('TrkB', 'Gene', (117, 121))	('low', 'NegReg', (113, 116))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('TrkB', 'Gene', '4915', (117, 121))	('SCC', 'Gene', (139, 142))	('SCCs', 'Phenotype', 'HP:0002860', (139, 143))	('high', 'Var', (101, 105))
438505	31221127	That and the retinol metabolism pathway were included among pathways enriched in TrkB-T1 SCC high expressers, though the statistical significance of the enrichment was much weaker.	('SCC', 'Gene', '6317', (89, 92))	('TrkB', 'Gene', '4915', (81, 85))	('retinol', 'Chemical', 'MESH:D014801', (13, 20))	('TrkB', 'Gene', (81, 85))	('high expressers', 'Var', (93, 108))	('retinol metabolism pathway', 'Pathway', (13, 39))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
438516	31221127	cBioPortal was used to examine genes whose mutation, amplification and mRNA level are associated with head and neck SCC and are suspect drivers of SCC at that site.	('SCC', 'Gene', (116, 119))	('SCC', 'Gene', (147, 150))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('mutation', 'Var', (43, 51))	('amplification', 'Var', (53, 66))	('SCC', 'Gene', '6317', (116, 119))	('associated', 'Reg', (86, 96))	('SCC', 'Gene', '6317', (147, 150))	('mRNA level', 'MPA', (71, 81))
438524	31221127	An examination of patient outcomes revealed that high expressers of TrkB-T1 had reduced overall survival (p < 0.04, Fig.	('TrkB', 'Gene', '4915', (68, 72))	('overall survival', 'MPA', (88, 104))	('reduced', 'NegReg', (80, 87))	('TrkB', 'Gene', (68, 72))	('patient', 'Species', '9606', (18, 25))	('high expressers', 'Var', (49, 64))
438526	31221127	In the first 1000 days, high levels of TrkB-T1 mRNA trended toward predicting better outcomes in that time period but not after that.	('TrkB', 'Gene', (39, 43))	('better', 'PosReg', (78, 84))	('TrkB', 'Gene', '4915', (39, 43))	('high levels', 'Var', (24, 35))
438527	31221127	In the TCGA data set more of the high TrkB-T1 expresser tumors were advanced stage tumors (Additional file 2: Table S1).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('high', 'Var', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('stage tumors', 'Disease', (77, 89))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('stage tumors', 'Disease', 'MESH:D062706', (77, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('TrkB', 'Gene', '4915', (38, 42))	('TrkB', 'Gene', (38, 42))
438530	31221127	An examination of two additional LUSC datasets revealed, in one, a similar pattern with TrkB high expressers showing better outcomes (GSE457) while the other, with only 56 patients, showed no difference (GSE17710).	('TrkB', 'Gene', '4915', (88, 92))	('GSE457', 'Chemical', '-', (134, 140))	('TrkB', 'Gene', (88, 92))	('better', 'PosReg', (117, 123))	('patients', 'Species', '9606', (172, 180))	('high expressers', 'Var', (93, 108))
438547	31221127	These high TrkB-T1 SCCs would likely be a subset of the neuroendocrine-like tumors or C4 classification of Chen et al.	('SCC', 'Gene', '6317', (19, 22))	('TrkB', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('neuroendocrine-like tumors', 'Disease', (56, 82))	('high', 'Var', (6, 10))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('SCC', 'Gene', (19, 22))	('TrkB', 'Gene', '4915', (11, 15))	('SCCs', 'Phenotype', 'HP:0002860', (19, 23))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))	('neuroendocrine-like tumors', 'Disease', 'MESH:D018358', (56, 82))
438552	31221127	The Tcfap2a transcription factor binding site sequence was overrepresented in the promoters of DE genes in high TrkB-T1 mRNA expressers versus low expressers in all 4 SCCs studied.	('Tcfap2a', 'Gene', (4, 11))	('SCCs', 'Phenotype', 'HP:0002860', (167, 171))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('SCC', 'Gene', '6317', (167, 170))	('TrkB', 'Gene', '4915', (112, 116))	('overrepresented', 'PosReg', (59, 74))	('TrkB', 'Gene', (112, 116))	('high', 'Var', (107, 111))	('SCC', 'Gene', (167, 170))
438566	31221127	These include glutathione metabolism and xenobiotic/drug metabolism by cyp450, two KEGG pathways associated with high TrkB-T1 mRNA levels in SCC.	('xenobiotic/drug metabolism', 'Enzyme', (41, 67))	('high', 'Var', (113, 117))	('TrkB', 'Gene', '4915', (118, 122))	('SCC', 'Gene', (141, 144))	('KEGG', 'Enzyme', (83, 87))	('TrkB', 'Gene', (118, 122))	('glutathione', 'Chemical', 'MESH:D005978', (14, 25))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('cyp450', 'Enzyme', (71, 77))	('SCC', 'Gene', '6317', (141, 144))	('mRNA levels', 'MPA', (126, 137))	('glutathione metabolism', 'Enzyme', (14, 36))
438567	31221127	In non-SCC breast cancer, TrkB kinase activity has been shown to reduce levels of the Keap inhibitor, which increases Nfe2l2 directed transcription.	('SCC', 'Gene', (7, 10))	('levels of the', 'MPA', (72, 85))	('increases', 'PosReg', (108, 117))	('SCC', 'Phenotype', 'HP:0002860', (7, 10))	('SCC', 'Gene', '6317', (7, 10))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('TrkB', 'Gene', '4915', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Disease', (11, 24))	('TrkB', 'Gene', (26, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('reduce', 'NegReg', (65, 71))	('kinase activity', 'Var', (31, 46))	('Nfe2l2', 'Gene', (118, 124))	('Nfe2l2', 'Gene', '4780', (118, 124))
438572	31221127	While the correlation between TrkB-T1 mRNA level and PIK3CA copy number was marginal in the SCCs (Additional file 8: Table S4), the functional interaction of these genes in these tumors was further supported by the increase in mutagenic PIK3CA activation in high TrkB expressers in LASC for example (Fig.	('SCC', 'Gene', '6317', (92, 95))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('LASC', 'Chemical', '-', (282, 286))	('TrkB', 'Gene', (30, 34))	('SCC', 'Gene', (92, 95))	('TrkB', 'Gene', '4915', (263, 267))	('PIK3CA', 'Gene', '5290', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('SCCs', 'Phenotype', 'HP:0002860', (92, 96))	('PIK3CA', 'Gene', '5290', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('TrkB', 'Gene', (263, 267))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))	('mutagenic', 'Var', (227, 236))	('tumors', 'Disease', (179, 185))	('increase', 'PosReg', (215, 223))	('PIK3CA', 'Gene', (237, 243))	('TrkB', 'Gene', '4915', (30, 34))	('PIK3CA', 'Gene', (53, 59))	('activation', 'PosReg', (244, 254))
438575	31221127	These and other findings allow speculation that PI3K activation and increased transcription of TrkB-FL and TrkB-T1 are mutually stimulatory.	('TrkB', 'Gene', (107, 111))	('PI3K', 'Var', (48, 52))	('TrkB', 'Gene', '4915', (95, 99))	('TrkB', 'Gene', (95, 99))	('TrkB', 'Gene', '4915', (107, 111))	('increased', 'PosReg', (68, 77))	('transcription', 'MPA', (78, 91))
438582	31221127	Pik3ca enrichment in head and neck SCC predicts poorer outcomes while amplified PIKC3A in LUSC may have the opposite effect (Fig.	('SCC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('amplified', 'Var', (70, 79))	('PIKC3A', 'Gene', (80, 86))	('poorer', 'NegReg', (48, 54))	('SCC', 'Gene', '6317', (35, 38))	('Pik3ca', 'Gene', (0, 6))	('Pik3ca', 'Gene', '5290', (0, 6))
438625	30808911	Dosimetric parameters tested for cutaneous toxicity were mean dose received (Dmean) and dose (Gy) received by 2, 50, 95, 98% of the volume (D2%, D50%, D95%, D98%) for the target volumes (breast, susclavian and subclavian), skin, susclavian and subclavian skin areas; volume (cc) of the target and skin areas, volume (cc) of the breast target volume receiving 95% of the dose (V95%).	('D95%', 'Var', (151, 155))	('cutaneous toxicity', 'Disease', (33, 51))	('Dmean', 'Chemical', '-', (77, 82))	('D98%', 'Var', (157, 161))	('cutaneous toxicity', 'Disease', 'MESH:D013262', (33, 51))
438627	30808911	Dosimetric parameters tested for toxicity to the esophagus were volume of the esophagus, Dmean, D2%, D50%, D95%, D98%, volume (cc) of the esophagus that received a dose of 30 or 45 Gray (V30 Gy, V45 Gy).	('D98', 'Var', (113, 116))	('Dmean', 'Chemical', '-', (89, 94))	('V45 Gy', 'Var', (195, 201))	('V30 Gy', 'Var', (187, 193))	('toxicity', 'Disease', 'MESH:D064420', (33, 41))	('toxicity', 'Disease', (33, 41))
438651	30808911	In the total mastectomy sub-group analysis, a higher D98% susclavian skin value was associated with a higher risk of developing skin grade >=2 acute toxicity (p = 0.013; OR = 1.07, 95% CI [1.016-1.135]).	('acute toxicity', 'Disease', (143, 157))	('acute toxicity', 'Disease', 'MESH:D000208', (143, 157))	('skin grade >=2', 'Disease', (128, 142))	('D98%', 'Var', (53, 57))
438657	30808911	The exploratory analysis for the association between acute esophageal toxicity and the dose received by percentage of the esophageal volume ranging from 1 to 100% (Gy) revealed a significant association between acute grade >=2 esophageal toxicity and dose ranging from D7% to D36%, and between acute grade >=1 esophageal toxicity and dose ranging from D1% to D30%.	('esophageal toxicity', 'Disease', (227, 246))	('D1%', 'Var', (352, 355))	('esophageal toxicity', 'Disease', (59, 78))	('D7%', 'Var', (269, 272))	('esophageal toxicity', 'Disease', 'MESH:D004935', (227, 246))	('esophageal toxicity', 'Disease', (310, 329))	('esophageal toxicity', 'Disease', 'MESH:D004935', (59, 78))	('D30%', 'Var', (359, 363))	('esophageal toxicity', 'Disease', 'MESH:D004935', (310, 329))	('D36%', 'Var', (276, 280))
438673	30808911	In univariate analysis, acute grade >=1 esophageal toxicity was significantly associated to esophageal D2% (p = 0.0004), Dmean (p = 0.009), V30 (p = 0.016) and V45 (p = 0.006).	('V30', 'Var', (140, 143))	('associated', 'Reg', (78, 88))	('Dmean', 'Var', (121, 126))	('esophageal toxicity', 'Disease', 'MESH:D004935', (40, 59))	('esophageal toxicity', 'Disease', (40, 59))	('Dmean', 'Chemical', '-', (121, 126))	('esophageal D2%', 'Disease', (92, 106))	('V45', 'Var', (160, 163))
438687	30808911	In this series, BMI (p = 0.003), skin D95% (p = 0.033) and susclavian skin D98% (p = 0.034) were associated with skin grade >=2 acute toxicity.	('acute toxicity', 'Disease', (128, 142))	('skin D95%', 'Var', (33, 42))	('BMI', 'Disease', (16, 19))	('acute toxicity', 'Disease', 'MESH:D000208', (128, 142))
438689	30808911	reported that bra cup size >= D, BMI, smoking during RT, and the use of concomitant hormone therapy were associated with acute grade >=2 dermatitis in multivariate analysis.	('dermatitis', 'Phenotype', 'HP:0011123', (137, 147))	('bra cup size', 'Phenotype', 'HP:0000378', (14, 26))	('dermatitis', 'Disease', 'MESH:D003872', (137, 147))	('associated', 'Reg', (105, 115))	('BMI', 'Var', (33, 36))	('dermatitis', 'Disease', (137, 147))
438740	29507707	In the NeusoftPacs 3.0 software, the reconstructed image was measured along CT mediastinal window according to the following standards and procedures: 1) Standards for defining presence of lesions were esophageal wall thickness > 5mm and esophageal diameter (without gas) > 10mm accompanied by local irregular luminal narrowing.	('gas', 'Gene', (267, 270))	('> 10mm', 'Var', (272, 278))	('gas', 'Gene', '2588', (267, 270))	('esophageal diameter', 'CPA', (238, 257))	('esophageal wall thickness', 'CPA', (202, 227))
438781	29507707	In postoperative adjuvant chemotherapy, patient survival in the iT4 group of the largest long diameter was superior to those without adjuvant chemotherapy (X2 = 6.003, P = 0.014).	('patient', 'Species', '9606', (40, 47))	('iT4', 'Var', (64, 67))	('patient survival', 'CPA', (40, 56))
438904	26099724	Based on the studies of the population in these areas, it was found that ESCC is related with genetic factors: genetic polymorphisms can increase an individual's susceptibility to cancer.	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('susceptibility', 'MPA', (162, 176))	('increase', 'PosReg', (137, 145))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))	('genetic polymorphisms', 'Var', (111, 132))
438918	26099724	results, while the expressions of VEGF mRNA of different ethnic groups in Xinjiang were different: the expression levels of the Han ESCC patients were significantly higher than those of Uyghur and Kazakh patients.	('patients', 'Species', '9606', (204, 212))	('Han ESCC', 'Var', (128, 136))	('expression levels', 'MPA', (103, 120))	('VEGF', 'Gene', '7422', (34, 38))	('patients', 'Species', '9606', (137, 145))	('higher', 'PosReg', (165, 171))	('VEGF', 'Gene', (34, 38))
438934	26099724	That means the amplification or overexpression of HER-2 gene in ESCC can be used as an independent prognostic factor.	('HER-2', 'Gene', (50, 55))	('HER-2', 'Gene', '2064', (50, 55))	('overexpression', 'PosReg', (32, 46))	('amplification', 'Var', (15, 28))
438937	26099724	The ESCC HER-2 expression levels of Han ESCC patients were significantly higher than those of Uyghur and Kazakh patients.	('HER-2', 'Gene', '2064', (9, 14))	('HER-2', 'Gene', (9, 14))	('Han', 'Var', (36, 39))	('patients', 'Species', '9606', (112, 120))	('expression levels', 'MPA', (15, 32))	('patients', 'Species', '9606', (45, 53))	('ESCC', 'Gene', (4, 8))	('higher', 'PosReg', (73, 79))
438949	26419362	Mutations in RHBDF2 located on 17q25.1 have recently been found to be causative.	('RHBDF2', 'Gene', (13, 19))	('RHBDF2', 'Gene', '79651', (13, 19))	('Mutations', 'Var', (0, 9))
438950	26419362	A diagnosis of tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2.	('tylosis', 'Disease', (15, 22))	('tylosis', 'Disease', 'MESH:D053546', (15, 22))	('RHBDF2', 'Gene', (215, 221))	('oesophageal lesions', 'Disease', (156, 175))	('oesophageal lesions', 'Disease', 'MESH:D005764', (156, 175))	('oesophageal cancer', 'Disease', (28, 46))	('oesophageal cancer', 'Disease', 'MESH:D009369', (28, 46))	('RHBDF2', 'Gene', '79651', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cutaneous', 'Disease', (142, 151))	('mutations', 'Var', (202, 211))
438983	26419362	Following linkage mapping and targeted next generation sequencing, missense mutations have been described in RHBDF2 located on 17q25.1, which encodes an inactive rhomboid protein, iRhom2, that plays a role in EGFR shedding.	('EGFR', 'Gene', (209, 213))	('RHBDF2', 'Gene', (109, 115))	('RHBDF2', 'Gene', '79651', (109, 115))	('iRhom2', 'Gene', (180, 186))	('iRhom2', 'Gene', '79651', (180, 186))	('EGFR', 'Gene', '1956', (209, 213))	('missense mutations', 'Var', (67, 85))
438984	26419362	It is likely that aberrant EGFR signalling underlies the propensity for oesophageal carcinoma.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (72, 93))	('aberrant', 'Var', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (73, 93))	('oesophageal carcinoma', 'Disease', (72, 93))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (72, 93))
438985	26419362	A diagnosis of tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including focal palmar and plantar hyperkeratosis and oesophageal lesions, and mutations in RHBDF2.	('hyperkeratosis', 'Phenotype', 'HP:0000962', (167, 181))	('tylosis', 'Disease', 'MESH:D053546', (15, 22))	('oesophageal cancer', 'Disease', (28, 46))	('mutations', 'Var', (211, 220))	('oesophageal cancer', 'Disease', 'MESH:D009369', (28, 46))	('RHBDF2', 'Gene', '79651', (224, 230))	('RHBDF2', 'Gene', (224, 230))	('plantar hyperkeratosis', 'Phenotype', 'HP:0007556', (159, 181))	('plantar hyperkeratosis and oesophageal lesions', 'Disease', 'MESH:D005764', (159, 205))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tylosis', 'Disease', (15, 22))
438988	26419362	To date, three disease-associated missense mutations in RHBDF2 have been identified:c.557 T   C (p.Ile186Thr), c.566C   T (p.Pro189Leu) and c.562 G   A (p.Asp188Asn).	('RHBDF2', 'Gene', '79651', (56, 62))	('c.562', 'CellLine', 'CVCL:X233', (140, 145))	('c.562 G   A', 'Var', (140, 151))	('RHBDF2', 'Gene', (56, 62))	('p.Ile186Thr', 'Mutation', 'rs387907129', (97, 108))	('c.557 T   C', 'Var', (84, 95))	('p.Asp188Asn', 'Mutation', 'rs387907130', (153, 164))	('p.Pro189Leu', 'Mutation', 'rs387907130', (123, 134))	('c.566C   T', 'Var', (111, 121))
438994	26419362	substantially after birth but before puberty) and, more recently, the demonstration of mutation in RHBDF2 that enable differential diagnosis.	('RHBDF2', 'Gene', '79651', (99, 105))	('RHBDF2', 'Gene', (99, 105))	('mutation', 'Var', (87, 95))
438998	26419362	Diffuse epidermolytic PPK (EPPK) has been shown to be due to mutations in the gene encoding the palmoplantar specific keratin, KRT9, and in some cases KRT1 (16) whilst diffuse, non-epidermolytic PPK (NEPPK) has recently been associated with mutations in the gene encoding the water channel protein, Aquaporin 5.	('EPPK', 'Gene', '3857', (27, 31))	('NEPPK', 'Gene', '3848', (200, 205))	('EPPK', 'Gene', (201, 205))	('Aquaporin 5', 'Gene', (299, 310))	('palmoplantar', 'Disease', (96, 108))	('EPPK', 'Gene', '3857', (201, 205))	('non-epidermolytic PPK', 'Gene', '3848', (177, 198))	('KRT9', 'Gene', '3857', (127, 131))	('due', 'Reg', (54, 57))	('KRT9', 'Gene', (127, 131))	('mutations', 'Var', (61, 70))	('palmoplantar', 'Disease', 'MESH:D007645', (96, 108))	('Diffuse epidermolytic PPK', 'Disease', (0, 25))	('NEPPK', 'Gene', (200, 205))	('Aquaporin 5', 'Gene', '362', (299, 310))	('KRT1', 'Gene', (151, 155))	('non-epidermolytic PPK', 'Gene', (177, 198))	('KRT1', 'Gene', '3848', (151, 155))	('associated', 'Reg', (225, 235))	('EPPK', 'Gene', (27, 31))	('mutations', 'Var', (241, 250))
439002	26419362	To date, three disease-associated missense mutations in RHBDF2 have been identified: c.557 T   C (p.Ile186Thr), c.566C   T (p.Pro189Leu) and c.562 G   A (p.Asp188Asn) and form part of genetic counselling for the Liverpool family.	('c.562', 'CellLine', 'CVCL:X233', (141, 146))	('p.Ile186Thr', 'Mutation', 'rs387907129', (98, 109))	('RHBDF2', 'Gene', '79651', (56, 62))	('c.566C   T', 'Var', (112, 122))	('c.557 T   C', 'Var', (85, 96))	('p.Asp188Asn', 'Mutation', 'rs387907130', (154, 165))	('p.Pro189Leu', 'Mutation', 'rs387907130', (124, 135))	('RHBDF2', 'Gene', (56, 62))	('c.562 G   A', 'Var', (141, 152))
439026	26419362	Tylosis with oesophageal cancer is associated with gain-of-function mutations in the highly conserved cytoplasmic N-terminus of iRhom2.	('Tylosis', 'Disease', 'MESH:D053546', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('oesophageal cancer', 'Disease', (13, 31))	('Tylosis', 'Disease', (0, 7))	('oesophageal cancer', 'Disease', 'MESH:D009369', (13, 31))	('gain-of-function', 'PosReg', (51, 67))	('iRhom2', 'Gene', (128, 134))	('iRhom2', 'Gene', '79651', (128, 134))	('mutations', 'Var', (68, 77))
439028	26419362	EGFR pathway dysregulation has been implicated in several epithelial malignancies including sporadic squamous cell carcinoma of the oesophagus and head and neck cancers.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('EGFR', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('dysregulation', 'Var', (13, 26))	('implicated', 'Reg', (36, 46))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (58, 81))	('head and neck cancers', 'Phenotype', 'HP:0012288', (147, 168))	('squamous cell carcinoma of the oesophagus', 'Disease', 'MESH:D002294', (101, 142))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('neck cancers', 'Disease', (156, 168))	('squamous cell carcinoma of the oesophagus', 'Disease', (101, 142))	('malignancies', 'Disease', (69, 81))	('neck cancers', 'Disease', 'MESH:D006258', (156, 168))	('EGFR', 'Gene', '1956', (0, 4))
439058	25546281	Based on the county-level CMs as illustrated in Figure 2a-c, the 14 counties were divided into three groups (outlined by a purple separator curve in Figure 2a): XP-LS-XY-JH-SY (Group I), YD-SX-MC-YQ-LB-WS-JY (Group II), and FG-SQ (Group III).	('LS-XY-JH-SY', 'CellLine', 'CVCL:7028', (164, 175))	('YD-SX-MC-YQ-LB-WS-JY', 'Var', (187, 207))	('XP-LS-XY-JH-SY', 'Var', (161, 175))	('YD-SX-MC-YQ-LB-WS', 'Chemical', '-', (187, 204))
439164	25132090	Oral leukoplakia has been reported to have associations with genetic variants of the phase ?	('genetic variants', 'Var', (61, 77))	('Oral leukoplakia', 'Phenotype', 'HP:0002745', (0, 16))	('Oral leukoplakia', 'Disease', (0, 16))	('associations', 'Interaction', (43, 55))	('Oral leukoplakia', 'Disease', 'MESH:D007972', (0, 16))
439165	25132090	xenobiotic metabolism enzyme GSTT, p53 overexpression, and with variants of DNA repair genes, and these variants have also shown associations with risk of UGI cancers.	('overexpression', 'PosReg', (39, 53))	('UGI cancers', 'Disease', (155, 166))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('variants', 'Var', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('xenobiotic', 'Enzyme', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('GSTT', 'Gene', (29, 33))	('DNA repair genes', 'Gene', (76, 92))	('UGI cancers', 'Disease', 'MESH:D009369', (155, 166))	('associations', 'Reg', (129, 141))	('variants', 'Var', (64, 72))
439169	25132090	Smoking and alcohol drinking have all been related to increased risk of oral leukoplakia, as have deficiencies of beta-carotene.	('beta-carotene', 'Chemical', 'MESH:D019207', (114, 127))	('beta-carotene', 'Protein', (114, 127))	('oral leukoplakia', 'Disease', (72, 88))	('oral leukoplakia', 'Disease', 'MESH:D007972', (72, 88))	('oral leukoplakia', 'Phenotype', 'HP:0002745', (72, 88))	('alcohol', 'Chemical', 'MESH:D000438', (12, 19))	('alcohol drinking', 'Phenotype', 'HP:0030955', (12, 28))	('deficiencies', 'Var', (98, 110))
439170	25132090	Further, supplementation with vitamin A and beta-carotene and consumption of fresh vegetables have been associated with reduced risk of oral leukoplakia.	('supplementation', 'Var', (9, 24))	('vitamin A', 'Chemical', 'MESH:D014801', (30, 39))	('oral leukoplakia', 'Phenotype', 'HP:0002745', (136, 152))	('oral leukoplakia', 'Disease', 'MESH:D007972', (136, 152))	('men', 'Species', '9606', (15, 18))	('beta-carotene', 'Chemical', 'MESH:D019207', (44, 57))	('oral leukoplakia', 'Disease', (136, 152))	('reduced', 'NegReg', (120, 127))
439248	25162035	No matter in esophagus or stomach, patients with grade 3 injury had a higher risk to develop lumen stricture than those with grade 2b injury.	('develop', 'PosReg', (85, 92))	('lumen stricture', 'Disease', (93, 108))	('grade 3 injury', 'Var', (49, 63))	('patients', 'Species', '9606', (35, 43))
439249	25162035	Alkalis cause liquefaction necrosis, and as they are more viscous, most of the liquid adheres to the esophageal mucosa, with only a relatively small amount reaching the stomach.	('esophageal mucosa', 'Disease', (101, 118))	('necrosis', 'Disease', 'MESH:D009336', (27, 35))	('esophageal mucosa', 'Disease', 'MESH:D004941', (101, 118))	('Alkalis', 'Var', (0, 7))	('necrosis', 'Disease', (27, 35))	('liquefaction necrosis', 'Phenotype', 'HP:0010885', (14, 35))
439250	25162035	Therefore, the extent of esophageal damage is greater with alkalis than with acids.	('esophageal damage', 'Disease', 'MESH:D004935', (25, 42))	('esophageal damage', 'Disease', (25, 42))	('alkalis', 'Var', (59, 66))
439316	23660276	PTV coverage was assessed numerically by calculating the V95 and V105 from the DVHs, which represent the percentage volume of the PTV that receives at least 95% and 105% of the prescribed dose, respectively.	('V95', 'Var', (57, 60))	('PTV', 'Chemical', '-', (130, 133))	('PTV', 'Chemical', '-', (0, 3))	('V105', 'Var', (65, 69))
439328	23660276	For both doses, the results showed that the V5 and V10 values were significantly associated with RPG>=2 (P < 0.05) but the V15-V40, and MLD values were not.	('V15', 'Gene', '28814', (123, 126))	('MLD', 'Disease', (136, 139))	('RPG>=2', 'Disease', (97, 103))	('MLD', 'Disease', 'MESH:D007966', (136, 139))	('V15', 'Gene', (123, 126))	('V10 values', 'Var', (51, 61))	('associated', 'Reg', (81, 91))
439333	23660276	With respect to the coverage of the PTV, the V95 and V105 values in the E-plan were significantly higher than those in the conventional plan (P < 0.001).	('higher', 'PosReg', (98, 104))	('E-plan', 'Var', (72, 78))	('PTV', 'Chemical', '-', (36, 39))	('V95', 'MPA', (45, 48))	('V105', 'Var', (53, 57))
439337	23660276	However, the E-plan was disadvantageous with respect to the values of V30, V35 and V40.	('V35', 'Gene', '28474', (75, 78))	('V30', 'Var', (70, 73))	('V40', 'Var', (83, 86))	('V35', 'Gene', (75, 78))
439340	23660276	From Table 2 and Table 3, the V5 and V10 values were found to be associated with RPG>=2 at either 50.4 Gy or 59.4 Gy, but the MLD value was not associated with RPG>=2 at 50.4 Gy EFRT.	('associated', 'Reg', (65, 75))	('V10', 'Var', (37, 40))	('MLD', 'Disease', (126, 129))	('MLD', 'Disease', 'MESH:D007966', (126, 129))	('RPG>=2', 'Disease', (81, 87))	('EFRT', 'Chemical', '-', (178, 182))
439348	23660276	V5-V50 and MLD values) were significantly associated with RPG>=2.	('V5-V50', 'Var', (0, 6))	('associated', 'Reg', (42, 52))	('MLD', 'Disease', 'MESH:D007966', (11, 14))	('RPG>', 'Disease', (58, 62))	('MLD', 'Disease', (11, 14))
439349	23660276	published their results for 56 patients with or without CRT and found that the V30 value was predictive of late lung toxicity.	('V30 value', 'Var', (79, 88))	('late lung toxicity', 'Disease', (107, 125))	('patients', 'Species', '9606', (31, 39))	('late lung toxicity', 'Disease', 'MESH:D008171', (107, 125))
439350	23660276	In that report, they also found that V5-V40 and MLD values were significantly associated with the occurrence of late lung injury.	('associated with', 'Reg', (78, 93))	('V5-V40', 'Var', (37, 43))	('MLD', 'Disease', 'MESH:D007966', (48, 51))	('MLD', 'Disease', (48, 51))	('late lung injury', 'Disease', (112, 128))	('late lung injury', 'Disease', 'MESH:D055370', (112, 128))
439360	23660276	The first is that the dose conformity, such as V95 and V105 for PTV, is improved in the E-plan.	('dose conformity', 'CPA', (22, 37))	('V105', 'Var', (55, 59))	('improved', 'PosReg', (72, 80))	('V95', 'Var', (47, 50))	('PTV', 'Chemical', '-', (64, 67))
439366	22807904	Complete and Sustained Objective Response per RECIST to Irvalec (PM02734) in Undifferentiated Large Cell Esophageal Adenocarcinoma: A Case Report and a Review of the Literature Undifferentiated large cell carcinoma is a rare entity in esophageal cancer and very few data are available in the literature on this uncommon histological subtype.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (235, 252))	('cell carcinoma', 'Disease', 'MESH:C538614', (200, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('PM02734', 'Var', (65, 72))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (105, 130))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (194, 214))	('esophageal cancer', 'Disease', (235, 252))	('Cell Esophageal Adenocarcinoma', 'Disease', (100, 130))	('cell carcinoma', 'Disease', (200, 214))	('Cell Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (100, 130))
439541	31728180	Mechanistically, Linc02023 specifically binds to PTEN and blocks its interaction with WWP2, thus suppressing the degradation of PTEN and its downstream expression.	('Linc02023', 'Var', (17, 26))	('PTEN', 'Gene', '5728', (49, 53))	('PTEN', 'Gene', (128, 132))	('blocks', 'NegReg', (58, 64))	('PTEN', 'Gene', '5728', (128, 132))	('WWP2', 'Gene', (86, 90))	('interaction', 'Interaction', (69, 80))	('WWP2', 'Gene', '11060', (86, 90))	('suppressing', 'NegReg', (97, 108))	('binds', 'Interaction', (40, 45))	('degradation', 'MPA', (113, 124))	('expression', 'MPA', (152, 162))	('PTEN', 'Gene', (49, 53))
439543	31728180	Recent studies have shown that the restoration of CASC2 expression significantly suppresses growth and metastasis in breast cancer cells via regulation of the miR-96-5p/SYVN1 pathway and inactivation of the TGF-beta signaling pathway.	('miR-96', 'Gene', '407053', (159, 165))	('miR-96', 'Gene', (159, 165))	('restoration', 'Var', (35, 46))	('inactivation', 'NegReg', (187, 199))	('suppresses', 'NegReg', (81, 91))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('CASC2', 'Gene', '255082', (50, 55))	('CASC2', 'Gene', (50, 55))	('breast cancer', 'Disease', (117, 130))	('expression', 'MPA', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('SYVN1', 'Gene', (169, 174))	('TGF-beta signaling pathway', 'Pathway', (207, 233))	('SYVN1', 'Gene', '84447', (169, 174))
439554	31728180	ESCC cell lines, KYSE30, KYSE70, KYSE150, KYSE180, KYSE410 and EC109, were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (Hyclone) at 37  C in a 5% CO2 humidified incubator.	('ESCC', 'Disease', 'MESH:C562729', (0, 4))	('CO2', 'Chemical', 'MESH:D002245', (188, 191))	('KYSE150', 'Var', (33, 40))	('calf', 'Species', '9913', (150, 154))	('ESCC', 'Disease', (0, 4))	('KYSE70', 'Var', (25, 31))	('KYSE150', 'CellLine', 'CVCL:1348', (33, 40))	('KYSE410', 'Var', (51, 58))	('KYSE180', 'Var', (42, 49))
439583	31728180	The pSPT19 plasmid containing sense or antisense CASC2 were constructed and purchased from GenePharma Company.	('sense', 'Var', (30, 35))	('antisense', 'Var', (39, 48))	('CASC2', 'Gene', '255082', (49, 54))	('CASC2', 'Gene', (49, 54))
439587	31728180	Cells were co-transfected with luciferase reporter vector comprising the wild type or mutant CASC2 fragment (CASC2-WT or CASC2-MUT) and miR-NC or miR-155.	('CASC2', 'Gene', (93, 98))	('CASC2', 'Gene', (121, 126))	('CASC2', 'Gene', '255082', (121, 126))	('mutant', 'Var', (86, 92))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('miR', 'Gene', '220972', (146, 149))	('CASC2', 'Gene', (109, 114))	('CASC2', 'Gene', '255082', (109, 114))	('miR', 'Gene', (146, 149))	('CASC2-MUT', 'Gene', (121, 130))	('CASC2-MUT', 'Gene', '255082', (121, 130))	('CASC2', 'Gene', '255082', (93, 98))
439599	31728180	Expression of CASC2 was detected in six ESCC cell lines (KYSE30, KYSE70, KYSE150, KYSE180, KYSE410 and EC109).	('ESCC', 'Disease', (40, 44))	('detected', 'Reg', (24, 32))	('KYSE150', 'Var', (73, 80))	('KYSE410', 'Var', (91, 98))	('KYSE150', 'CellLine', 'CVCL:1348', (73, 80))	('KYSE180', 'Var', (82, 89))	('KYSE70', 'Var', (65, 71))	('ESCC', 'Disease', 'MESH:C562729', (40, 44))	('CASC2', 'Gene', (14, 19))	('KYSE30', 'Var', (57, 63))	('CASC2', 'Gene', '255082', (14, 19))
439607	31728180	The results indicated that CASC2 overexpression reduced the cell migration and invasion, while knockdown of CASC2 enhanced the migration and invasion capacity in KYSE30 and KYSE150 cells (Fig.	('cell migration', 'CPA', (60, 74))	('CASC2', 'Gene', (108, 113))	('CASC2', 'Gene', '255082', (27, 32))	('CASC2', 'Gene', '255082', (108, 113))	('reduced', 'NegReg', (48, 55))	('invasion capacity', 'CPA', (141, 158))	('knockdown', 'Var', (95, 104))	('enhanced', 'PosReg', (114, 122))	('KYSE150', 'CellLine', 'CVCL:1348', (173, 180))	('invasion', 'CPA', (79, 87))	('CASC2', 'Gene', (27, 32))	('migration', 'CPA', (127, 136))
439611	31728180	Conversely, cell apoptosis rate of KYSE30 and KYSE150 cells treated with cisplatin or capecitabine were notably inhibited by CASC2 knockdown compared to control groups (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('CASC2', 'Gene', '255082', (125, 130))	('CASC2', 'Gene', (125, 130))	('knockdown', 'Var', (131, 140))	('inhibited', 'NegReg', (112, 121))	('KYSE150', 'CellLine', 'CVCL:1348', (46, 53))	('capecitabine', 'Chemical', 'MESH:C110904', (86, 98))	('cell apoptosis rate', 'CPA', (12, 31))
439612	31728180	Moreover, we detected the IC50 (half maximal inhibitory concentration) changes to cisplatin or capecitabine after CASC2 alteration in ESCC cells.	('changes', 'Reg', (71, 78))	('ESCC', 'Disease', 'MESH:C562729', (134, 138))	('CASC2', 'Gene', (114, 119))	('capecitabine', 'Chemical', 'MESH:C110904', (95, 107))	('alteration', 'Var', (120, 130))	('cisplatin', 'MPA', (82, 91))	('CASC2', 'Gene', '255082', (114, 119))	('ESCC', 'Disease', (134, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))
439615	31728180	3e, f, Additional file 2: Figure S2E and F), while knockdown of CASC2 significantly increased the IC50 of cisplatin or capecitabine (Fig.	('capecitabine', 'Chemical', 'MESH:C110904', (119, 131))	('increased', 'PosReg', (84, 93))	('CASC2', 'Gene', '255082', (64, 69))	('CASC2', 'Gene', (64, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('IC50 of cisplatin', 'MPA', (98, 115))	('knockdown', 'Var', (51, 60))
439618	31728180	Among these genes, we found that the tumor suppressor Suppressors of Cytokine Signaling 1 (SOCS1) was one of the most elevated genes regulated by CASC2 overexpression (Additional file 3: Figure S3).	('CASC2', 'Gene', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('CASC2', 'Gene', '255082', (146, 151))	('SOCS1', 'Gene', '8651', (91, 96))	('overexpression', 'Var', (152, 166))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('SOCS1', 'Gene', (91, 96))	('elevated', 'PosReg', (118, 126))
439619	31728180	For validation of these results, qRT-PCR and western blot was conducted in ESCC cells with CASC2 alteration.	('alteration', 'Var', (97, 107))	('ESCC', 'Disease', (75, 79))	('CASC2', 'Gene', (91, 96))	('CASC2', 'Gene', '255082', (91, 96))	('ESCC', 'Disease', 'MESH:C562729', (75, 79))
439634	31728180	Of note, the CASC2 RIP in both KYSE30 and KYSE150 cells was significantly enriched for miR-155 compared to the empty vector (MS2) and CASC2 with mutations in miR-155 targeting sites (CASC2-MUT) (Fig.	('MS2', 'Gene', '100271694', (125, 128))	('CASC2-MUT', 'Gene', (183, 192))	('miR-155', 'Gene', (158, 165))	('CASC2-MUT', 'Gene', '255082', (183, 192))	('CASC2', 'Gene', '255082', (183, 188))	('CASC2', 'Gene', (183, 188))	('mutations', 'Var', (145, 154))	('KYSE150', 'CellLine', 'CVCL:1348', (42, 49))	('MS2', 'Gene', (125, 128))	('CASC2', 'Gene', (134, 139))	('CASC2', 'Gene', (13, 18))	('CASC2', 'Gene', '255082', (134, 139))	('CASC2', 'Gene', '255082', (13, 18))
439637	31728180	The results showed that endogenous CASC2 pull-down by AGO2 was specifically enriched in miR-155-transfected cells (Fig.	('CASC2', 'Gene', '255082', (35, 40))	('CASC2', 'Gene', (35, 40))	('AGO2', 'Gene', (54, 58))	('miR-155-transfected', 'Var', (88, 107))	('pull-down', 'NegReg', (41, 50))	('AGO2', 'Gene', '27161', (54, 58))
439644	31728180	Overexpression of wild-type CASC2, but not the mutant, upregulated SOCS1 expression, while miR-155 transfection abrogated this increase (Fig.	('SOCS1', 'Gene', '8651', (67, 72))	('expression', 'MPA', (73, 83))	('upregulated', 'PosReg', (55, 66))	('miR-155', 'Var', (91, 98))	('CASC2', 'Gene', (28, 33))	('SOCS1', 'Gene', (67, 72))	('abrogated', 'NegReg', (112, 121))	('CASC2', 'Gene', '255082', (28, 33))
439646	31728180	The SOCS1 downregulation mediated by CASC2 knockdown was abolished by inhibition of miR-155 (Fig.	('miR-155', 'Gene', (84, 91))	('SOCS1', 'Gene', (4, 9))	('CASC2', 'Gene', (37, 42))	('CASC2', 'Gene', '255082', (37, 42))	('knockdown', 'Var', (43, 52))	('downregulation', 'NegReg', (10, 24))	('SOCS1', 'Gene', '8651', (4, 9))	('abolished', 'NegReg', (57, 66))
439650	31728180	In contrast, CASC2 knockdown decreased the luciferase activity of pmirGLO-SOCS1, which was attenuated by inhibition of miR-155 (Fig.	('miR-155', 'Gene', (119, 126))	('luciferase', 'Enzyme', (43, 53))	('knockdown', 'Var', (19, 28))	('SOCS1', 'Gene', '8651', (74, 79))	('CASC2', 'Gene', (13, 18))	('activity', 'MPA', (54, 62))	('decreased', 'NegReg', (29, 38))	('SOCS1', 'Gene', (74, 79))	('attenuated', 'NegReg', (91, 101))	('CASC2', 'Gene', '255082', (13, 18))
439656	31728180	Furthermore, using a series of deletion-mapping analyses, we identified that a 1300 nt region in the middle of the CASC2 transcript (1300-2600 nt) is required for CASC2-SOCS1 association (Fig.	('association', 'Interaction', (175, 186))	('CASC2', 'Gene', '255082', (115, 120))	('CASC2', 'Gene', '255082', (163, 168))	('CASC2', 'Gene', (163, 168))	('SOCS1', 'Gene', '8651', (169, 174))	('1300-2600 nt', 'Var', (133, 145))	('SOCS1', 'Gene', (169, 174))	('CASC2', 'Gene', (115, 120))
439660	31728180	In contrast, knockdown of CASC2 dramatically promoted the degradation of SOCS1 in KYSE150 cells (Fig.	('SOCS1', 'Gene', '8651', (73, 78))	('CASC2', 'Gene', (26, 31))	('SOCS1', 'Gene', (73, 78))	('promoted', 'PosReg', (45, 53))	('KYSE150', 'CellLine', 'CVCL:1348', (82, 89))	('CASC2', 'Gene', '255082', (26, 31))	('knockdown', 'Var', (13, 22))	('degradation', 'MPA', (58, 69))
439662	31728180	7f), while CASC2 knockdown increased the level of SOCS1 ubiquitination in KYSE150 cells (Fig.	('increased', 'PosReg', (27, 36))	('SOCS1', 'Gene', '8651', (50, 55))	('CASC2', 'Gene', '255082', (11, 16))	('knockdown', 'Var', (17, 26))	('SOCS1', 'Gene', (50, 55))	('KYSE150', 'CellLine', 'CVCL:1348', (74, 81))	('CASC2', 'Gene', (11, 16))
439667	31728180	Moreover, silence of SOCS1 attenuated the CASC2-mediated sensitivity of KYSE30 cell to cisplatin or capecitabine (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('SOCS1', 'Gene', (21, 26))	('attenuated', 'NegReg', (27, 37))	('silence', 'Var', (10, 17))	('CASC2', 'Gene', '255082', (42, 47))	('capecitabine', 'Chemical', 'MESH:C110904', (100, 112))	('sensitivity', 'MPA', (57, 68))	('CASC2', 'Gene', (42, 47))	('SOCS1', 'Gene', '8651', (21, 26))
439680	31728180	CASC2 overexpression inhibites the viability, migration and invasion, and elevates apoptosis of breast cancer cells through acting as a ceRNA for miR-96 and upregulating synoviolin (SYVN1) expression.	('miR-96', 'Gene', (146, 152))	('invasion', 'CPA', (60, 68))	('overexpression', 'Var', (6, 20))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('elevates', 'PosReg', (74, 82))	('breast cancer', 'Disease', (96, 109))	('synoviolin', 'Chemical', 'None', (170, 180))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR-96', 'Gene', '407053', (146, 152))	('CASC2', 'Gene', (0, 5))	('SYVN1', 'Gene', '84447', (182, 187))	('apoptosis', 'CPA', (83, 92))	('inhibites', 'NegReg', (21, 30))	('CASC2', 'Gene', '255082', (0, 5))	('upregulating', 'PosReg', (157, 169))	('SYVN1', 'Gene', (182, 187))	('viability', 'CPA', (35, 44))	('expression', 'MPA', (189, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
439687	31728180	Several studies found that the promoters of SOCS1 gene were often hypermethylation in some human cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('hypermethylation', 'Var', (66, 82))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SOCS1', 'Gene', '8651', (44, 49))	('SOCS1', 'Gene', (44, 49))	('human', 'Species', '9606', (91, 96))
439691	31728180	Here, we showed that lncRNA CASC2 was involved in the dysregulation of SOCS1 in ESCC cells.	('SOCS1', 'Gene', '8651', (71, 76))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('dysregulation', 'Var', (54, 67))	('SOCS1', 'Gene', (71, 76))	('CASC2', 'Gene', (28, 33))	('CASC2', 'Gene', '255082', (28, 33))	('ESCC', 'Disease', (80, 84))
439727	31407608	Findings from the current study suggested that cholesterol intake significantly increases the risk of developing esophageal cancer in both American and European populations.	('cholesterol', 'Var', (47, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('cholesterol', 'Chemical', 'MESH:D002784', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal cancer', 'Disease', (113, 130))
439745	30782182	Univariate survival analysis showed that SUVmax2 MTV1  MTV TLG1 TLG2 and  TLG were associated with OS.	('MTV', 'Chemical', '-', (49, 52))	('MTV', 'Chemical', '-', (55, 58))	('TLG1 TLG2', 'Gene', (59, 68))	('TLG', 'Chemical', '-', (74, 77))	('TLG', 'Chemical', '-', (64, 67))	('associated with', 'Reg', (83, 98))	('TLG', 'Chemical', '-', (59, 62))	('SUVmax2 MTV1  MTV', 'Var', (41, 58))	('TLG2', 'Gene', (64, 68))	('OS', 'Chemical', '-', (99, 101))
439746	30782182	Based on the largest Youden index of ROC curves, patients with SUVmax2 < 7.8, MTV1 < 10.5,  MTV < 0.075, TLG1 < 59.8, TLG2 < 44.3 and  TLG < 0.27 tended to live longer.	('MTV', 'Chemical', '-', (78, 81))	('TLG', 'Chemical', '-', (135, 138))	('TLG', 'Chemical', '-', (105, 108))	('TLG', 'Chemical', '-', (118, 121))	('MTV1', 'Var', (78, 82))	('live longer', 'CPA', (156, 167))	('patients', 'Species', '9606', (49, 57))	('MTV', 'Chemical', '-', (92, 95))	('TLG1 < 59.8', 'Var', (105, 116))
439799	30782182	1b show Kaplan-Meier plots for both parameters.. Log-Rank test of Kaplan-Meier survival analysis showed that MTV1 < 10.5 mL and TLG1 < 59.8 were associated with improved OS, with an estimated median survival of 36.9 months (95% CI: 26.4-47.5, p < 0.0001) and 48.9 months (95% CI: 25-72.7, p < 0.0001), respectively.	('OS', 'Chemical', '-', (170, 172))	('TLG1 < 59.8', 'Var', (128, 139))	('TLG', 'Chemical', '-', (128, 131))	('MTV1 < 10.5 mL', 'Var', (109, 123))	('MTV', 'Chemical', '-', (109, 112))	('improved', 'PosReg', (161, 169))
439803	30782182	Log-Rank test of Kaplan-Meier survival analysis showed that SUVmax2 < 7.8 and TLG2 < 44.3 were associated with improved OS, with an estimated median survival of 27.9 months (p < 0.001) and 32.6 months (p < 0.001), respectively.	('TLG', 'Chemical', '-', (78, 81))	('improved', 'PosReg', (111, 119))	('SUVmax2', 'Var', (60, 67))	('OS', 'Chemical', '-', (120, 122))
439804	30782182	Mean DeltaSUVmax was 0.46 +- 0.34, mean DeltaMTV was - 0.25 +- 1.42, and mean DeltaTLG was 0.38 +- 0.92.Univariate survival analysis showed that DeltaSUVmax was not significantly associated with OS, while DeltaMTV and DeltaTLG both showed a significant association with OS (Table 2).	('MTV', 'Chemical', '-', (210, 213))	('associated', 'Reg', (179, 189))	('MTV', 'Chemical', '-', (45, 48))	('OS', 'Chemical', '-', (270, 272))	('DeltaSUVmax', 'Var', (145, 156))	('TLG', 'Chemical', '-', (83, 86))	('TLG', 'Chemical', '-', (223, 226))	('OS', 'Chemical', '-', (195, 197))	('association', 'Interaction', (253, 264))
439806	30782182	Kaplan-Meier survival analysis showed that DeltaMTV < 0.075 and DeltaTLG < 0.27 were associated with improved OS, with an estimated median survival of 41.6 months for both parameters (p < 0.001, p < 0.014) (Fig.	('OS', 'Chemical', '-', (110, 112))	('MTV', 'Chemical', '-', (48, 51))	('improved', 'PosReg', (101, 109))	('DeltaMTV < 0.075', 'Var', (43, 59))	('DeltaTLG < 0.27', 'Var', (64, 79))	('TLG', 'Chemical', '-', (69, 72))
439808	30782182	ROC analysis showed that Stage I-II and a lesion length (Length_T) <= 3.5 cm was associated with improved median survival, which was 67.8 months (p < 0.001) in stage I-II patients and was not reached in the group with a tumor length_T <= 3.5 cm (p < 0.001), respectively (Fig.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('improved', 'PosReg', (97, 105))	('<= 3.5', 'Var', (67, 73))	('patients', 'Species', '9606', (171, 179))	('median survival', 'MPA', (106, 121))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
439929	24066061	Increasing studies investigating the association between IL-18 gene promoter polymorphisms (-607 C>A and -137G>C) and cancer risk have yielded conflicting results.	('-607 C>A', 'Mutation', 'rs1946518', (92, 100))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('IL-18', 'Gene', '3606', (57, 62))	('-137G>C', 'Mutation', 'rs187238', (105, 112))	('IL-18', 'Gene', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('-607 C>A', 'Var', (92, 100))
439930	24066061	We assessed the strength of the association of IL-18 gene promoter -607 C>A and -137G>C polymorphisms with cancer risk and performed sub-group analyses by cancer types, ethnicities, source of controls and sample size.	('-607 C>A', 'Mutation', 'rs1946518', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('-137G>C', 'Mutation', 'rs187238', (80, 87))	('promoter -607 C>A', 'Var', (58, 75))	('association', 'Interaction', (32, 43))	('IL-18', 'Gene', '3606', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('IL-18', 'Gene', (47, 52))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
439934	24066061	As for gastrointestinal cancer, we also found that -607 C>A polymorphism was significantly associated with increased cancer risk (CA/AA vs. CC: OR = 1.25, 95% CI: 1.05, 1.50, Pheterogeneity = 0.458).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('-607 C>A', 'Var', (51, 59))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (7, 30))	('gastrointestinal cancer', 'Disease', (7, 30))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('-607 C>A', 'Mutation', 'rs1946518', (51, 59))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (7, 30))	('cancer', 'Disease', (117, 123))
439936	24066061	The meta-analysis results suggest that IL-18 gene promoter -607 C>A polymorphism is significantly associated with overall cancer risk, especially in nasopharyngeal carcinoma and gastrointestinal cancer; and the -137 G>C polymorphism is associated with increased overall cancer risk in Asian populations and also significantly increases the risk of nasopharyngeal carcinoma.	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('-607 C>A', 'Mutation', 'rs1946518', (59, 67))	('IL-18', 'Gene', (39, 44))	('increased', 'PosReg', (252, 261))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (149, 173))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('nasopharyngeal carcinoma', 'Disease', (348, 372))	('carcinoma', 'Phenotype', 'HP:0030731', (363, 372))	('increases', 'Reg', (326, 335))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('promoter -607 C>A', 'Var', (50, 67))	('-137 G>C', 'Mutation', 'rs187238', (211, 219))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (348, 372))	('cancer', 'Disease', (195, 201))	('IL-18', 'Gene', '3606', (39, 44))	('nasopharyngeal carcinoma', 'Disease', (149, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('associated', 'Reg', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (178, 201))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (149, 173))	('the -137 G>C', 'Var', (207, 219))	('gastrointestinal cancer', 'Disease', (178, 201))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (178, 201))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (348, 372))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
439946	24066061	The variations in IL-18 gene promoter are able to influence IL-18 production and activity.	('IL-18', 'Gene', (18, 23))	('variations', 'Var', (4, 14))	('IL-18', 'Gene', '3606', (60, 65))	('IL-18', 'Gene', '3606', (18, 23))	('IL-18', 'Gene', (60, 65))	('activity', 'MPA', (81, 89))	('influence', 'Reg', (50, 59))
439947	24066061	The IL-18 gene promoter -607 C>A (rs1946518) and -137 G>C (rs187238) polymorphisms are two of the most common single nucleotide polymorphisms (SNPs).	('rs187238', 'Mutation', 'rs187238', (59, 67))	('rs1946518', 'Var', (34, 43))	('-607 C>A', 'Mutation', 'rs1946518', (24, 32))	('rs187238', 'Var', (59, 67))	('IL-18', 'Gene', '3606', (4, 9))	('-137 G>C', 'Mutation', 'rs187238', (49, 57))	('IL-18', 'Gene', (4, 9))	('rs1946518', 'Mutation', 'rs1946518', (34, 43))
439950	24066061	Additionally, cloning and gene expression analysis showed that the polymorphisms in IL-18 promoter region caused the differences in transcription factor binding and had an impact on IL-18 gene activity.	('IL-18', 'Gene', (182, 187))	('IL-18', 'Gene', '3606', (84, 89))	('IL-18', 'Gene', (84, 89))	('activity', 'MPA', (193, 201))	('differences', 'Reg', (117, 128))	('impact', 'Reg', (172, 178))	('transcription factor', 'MPA', (132, 152))	('IL-18', 'Gene', '3606', (182, 187))	('polymorphisms', 'Var', (67, 80))
439955	24066061	: "cancer", "carcinoma", "tumor" or "neoplasms") and polymorphism or variation.	('"carcinoma", "tumor', 'Disease', 'MESH:D009369', (12, 31))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('variation', 'Var', (69, 78))	('cancer', 'Disease', (3, 9))	('neoplasms', 'Disease', 'MESH:D009369', (37, 46))	('polymorphism', 'Var', (53, 65))	('neoplasms', 'Disease', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
439956	24066061	The following criteria were used for the literature selection: (a) only the case-control studies were considered; (b) the association of cancer risk with -607 C>A and -137 G>C polymorphisms was clearly investigated; (c) sufficient genotype distribution information in cases and controls.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('-607 C>A', 'Mutation', 'rs1946518', (154, 162))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('-137 G>C', 'Mutation', 'rs187238', (167, 175))	('cancer', 'Disease', (137, 143))	('-607 C>A', 'Var', (154, 162))
439959	24066061	Odds ratio (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between IL-18 gene promoter polymorphisms (-607 C>A and -137G>C) and cancer risk, based on the genotype frequencies in cases and controls.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('-137G>C', 'Mutation', 'rs187238', (155, 162))	('IL-18', 'Gene', (107, 112))	('-607 C>A', 'Var', (142, 150))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('-607 C>A', 'Mutation', 'rs1946518', (142, 150))	('cancer', 'Disease', (168, 174))	('IL-18', 'Gene', '3606', (107, 112))
439966	24066061	As for gastrointestinal cancer, we also found that the -607 C>A polymorphism was significantly associated with increased cancer risk in heterozygote comparison (CA vs. CC: OR = 1.32, 95%CI: 1.08, 1.63; Pheterogeneity = 0.327) and dominant model (CA/AA vs. CC: OR = 1.25, 95% CI: 1.05, 1.50; Pheterogeneity = 0.458, Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (7, 30))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastrointestinal cancer', 'Disease', (7, 30))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('-607 C>A', 'Mutation', 'rs1946518', (55, 63))	('the -607 C>A', 'Var', (51, 63))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (7, 30))	('cancer', 'Disease', (121, 127))
439971	24066061	As shown in Table 3, we found no significant association of the -137 G>C polymorphism in IL-18 promoter region with overall cancer risk in any of four models.	('cancer', 'Disease', (124, 130))	('-137 G>C', 'Mutation', 'rs187238', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('the -137 G>C', 'Var', (60, 72))	('IL-18', 'Gene', '3606', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('IL-18', 'Gene', (89, 94))
439972	24066061	When stratified by cancer types, it was found that individuals with the C allele had higher risk of nasopharyngeal carcinoma in four models : homozygote comparison (CC vs. GG: OR = 2.10, 95%CI: 1.34, 3.29; Pheterogeneity = 0.538), heterozygote comparison (GC vs. GG: OR = 1.48, 95%CI: 1.18, 1.86; Pheterogeneity = 0.512), dominant model (GC/CC vs. GG: OR = 1.57, 95%CI: 1.26, 1.96; Pheterogeneity = 0.373, Figure 3), and recessive model (CC vs. GG/GC: OR = 1.82, 95%CI: 1.17, 2.84; Pheterogeneity = 0.611).	('C allele', 'Var', (72, 80))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (100, 124))	('nasopharyngeal carcinoma', 'Disease', (100, 124))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (100, 124))
439975	24066061	IL-18 promoter -607 C>A and -137 G>C polymorphisms showed strong linkage disequilibrium, which was also confirmed by HaploView software (version 4.2).	('linkage', 'Interaction', (65, 72))	('promoter -607 C>A', 'Var', (6, 23))	('IL-18', 'Gene', '3606', (0, 5))	('-137 G>C', 'Mutation', 'rs187238', (28, 36))	('IL-18', 'Gene', (0, 5))	('-607 C>A', 'Mutation', 'rs1946518', (15, 23))
439976	24066061	In overall analysis, no haplotype was correlated with a significantly increased risk of overall cancers (Table 4).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('haplotype', 'Var', (24, 33))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))
439983	24066061	To our knowledge, this is the first meta-analysis to explore the association between IL-18 gene promoter polymorphisms (-607 C>A and -137 G>C) and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('-607 C>A', 'Var', (120, 128))	('-137 G>C', 'Mutation', 'rs187238', (133, 141))	('-607 C>A', 'Mutation', 'rs1946518', (120, 128))	('association', 'Interaction', (65, 76))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('IL-18', 'Gene', '3606', (85, 90))	('cancer', 'Disease', (147, 153))	('IL-18', 'Gene', (85, 90))
439984	24066061	We demonstrated that IL-18 gene promoter -607 C>A polymorphism was associated with a statistical increased risk of cancer susceptibility in the variant CA heterozygote and CA/AA genotype compared with the CC wild type homozygote, especially in nasopharyngeal carcinoma and gastrointestinal cancer, however, an opposite trend was found in genitourinary system cancer.	('gastrointestinal cancer', 'Disease', (273, 296))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (244, 268))	('genitourinary system', 'Phenotype', 'HP:0000119', (338, 358))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (273, 296))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('genitourinary system cancer', 'Disease', 'MESH:D014565', (338, 365))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('-607 C>A', 'Mutation', 'rs1946518', (41, 49))	('cancer', 'Disease', 'MESH:D009369', (359, 365))	('variant', 'Var', (144, 151))	('promoter -607 C>A polymorphism', 'Var', (32, 62))	('IL-18', 'Gene', (21, 26))	('nasopharyngeal carcinoma', 'Disease', (244, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('genitourinary system cancer', 'Disease', (338, 365))	('genitourinary system cancer', 'Phenotype', 'HP:0007379', (338, 365))	('cancer', 'Disease', (115, 121))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (244, 268))	('cancer', 'Disease', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('IL-18', 'Gene', '3606', (21, 26))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (273, 296))	('cancer', 'Disease', (359, 365))
439992	24066061	It has shown that the polymorphisms of IL-18 could influence gene activity and expression of IL-18.	('polymorphisms', 'Var', (22, 35))	('expression', 'MPA', (79, 89))	('gene activity', 'MPA', (61, 74))	('IL-18', 'Gene', (93, 98))	('IL-18', 'Gene', '3606', (39, 44))	('IL-18', 'Gene', (39, 44))	('influence', 'Reg', (51, 60))	('IL-18', 'Gene', '3606', (93, 98))
439993	24066061	Together with the critical role of IL-18 in cancer immunity regulation, the polymorphisms of IL-18 would be related to cancer risks.	('IL-18', 'Gene', '3606', (35, 40))	('IL-18', 'Gene', (93, 98))	('IL-18', 'Gene', (35, 40))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('polymorphisms', 'Var', (76, 89))	('IL-18', 'Gene', '3606', (93, 98))	('related', 'Reg', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
439998	24066061	However, Jaiswal's study was the only study which reported that the CA/AA genotype could be associated with reduced cancer risk in Asians.	('CA/AA', 'Var', (68, 73))	('reduced', 'NegReg', (108, 115))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
440000	24066061	So we found that cancer types greatly affected the association between IL-18 gene promoter -607 C>A polymorphism and cancer risk, but ethnicities failed.	('polymorphism', 'Var', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('association', 'Interaction', (51, 62))	('affected', 'Reg', (38, 46))	('IL-18', 'Gene', '3606', (71, 76))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('IL-18', 'Gene', (71, 76))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('promoter -607 C>A polymorphism', 'Var', (82, 112))	('-607 C>A', 'Mutation', 'rs1946518', (91, 99))
440001	24066061	Among 21 eligible studies based on -137 G>C, carriers of the variant C allele were only reported with a significantly increased cancer risk compared with those of G allele in nasopharyngeal carcinoma.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('nasopharyngeal carcinoma', 'Disease', (175, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (175, 199))	('variant', 'Var', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('-137 G>C', 'Mutation', 'rs187238', (35, 43))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (175, 199))	('cancer', 'Disease', (128, 134))
440003	24066061	Furthermore, Monroy and colleagues found significantly reduced cancer risk with GC/CC genotype in hodgkin disease.	('hodgkin disease', 'Disease', 'MESH:D006689', (98, 113))	('reduced', 'NegReg', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('hodgkin disease', 'Phenotype', 'HP:0012189', (98, 113))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('GC/CC', 'Var', (80, 85))	('hodgkin disease', 'Disease', (98, 113))
440007	24066061	But for the four studies of genitourinary system cancer, two of them found significant increased risk with C variant allele carriers, while the other two of them found a trend of reduced cancer risk in contrast.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('genitourinary system cancer', 'Disease', 'MESH:D014565', (28, 55))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('genitourinary system cancer', 'Disease', (28, 55))	('genitourinary system', 'Phenotype', 'HP:0000119', (28, 48))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('genitourinary system cancer', 'Phenotype', 'HP:0007379', (28, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('C variant allele carriers', 'Var', (107, 132))	('cancer', 'Disease', (49, 55))
440010	24066061	We also found the association between the -137 G>C and cancer risk was significant in Asians, but a trend of reduced cancer risk was found in Caucasians.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('the -137 G>C', 'Var', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('-137 G>C', 'Mutation', 'rs187238', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (55, 61))
440014	24066061	In conclusion, we demonstrate that IL-18 gene promoter -607 C>A polymorphism is significantly associated with overall cancer risk, especially in nasopharyngeal carcinoma and gastrointestinal cancer; and the -137 G>C polymorphism is associated with increased overall cancer risk in Asian populations and also significantly increase the risk of nasopharyngeal carcinoma.	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (145, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (343, 367))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (174, 197))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('IL-18', 'Gene', '3606', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (358, 367))	('gastrointestinal cancer', 'Disease', (174, 197))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (174, 197))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (145, 169))	('associated', 'Reg', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (343, 367))	('cancer', 'Disease', (118, 124))	('increase', 'Reg', (322, 330))	('increased', 'PosReg', (248, 257))	('the -137 G>C', 'Var', (203, 215))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('-607 C>A', 'Mutation', 'rs1946518', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('IL-18', 'Gene', (35, 40))	('nasopharyngeal carcinoma', 'Disease', (145, 169))	('cancer', 'Disease', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('nasopharyngeal carcinoma', 'Disease', (343, 367))	('promoter -607 C>A', 'Var', (46, 63))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('-137 G>C', 'Mutation', 'rs187238', (207, 215))
440055	21572509	In order to compare and contrast data generated by SIVQ-LCM versus usual phenotype-based LCM, we performed expression microarray analysis on normal esophageal epithelium and matched the tumor using both dissection methods.	('SIVQ-LCM', 'Var', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (186, 191))
440119	20885923	On experimental investigation, it was found that PPARgamma suppresses gastric carcinogenesis and that PPARgamma ligands such as troglitazone and ciglitazone are potential agents for gastric carcinoma because they inhibit PPARgamma-dependant cell proliferation.	('troglitazone', 'Chemical', 'MESH:D000077288', (128, 140))	('gastric carcinogenesis', 'Disease', (70, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('gastric carcinoma', 'Disease', 'MESH:D013274', (182, 199))	('ciglitazone', 'Chemical', 'MESH:C039671', (145, 156))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (70, 92))	('PPARgamma-dependant cell proliferation', 'CPA', (221, 259))	('gastric carcinoma', 'Disease', (182, 199))	('inhibit', 'NegReg', (213, 220))	('PPARgamma', 'Var', (49, 58))	('suppresses', 'NegReg', (59, 69))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (182, 199))
440121	20885923	The PPARgamma Pro12Ala polymorphism has been reported to show decreased binding to the promoter element and demonstrates weaker transactivation of responsive promoters.	('decreased', 'NegReg', (62, 71))	('transactivation', 'MPA', (128, 143))	('binding', 'Interaction', (72, 79))	('PPARgamma', 'Gene', (4, 13))	('weaker', 'NegReg', (121, 127))	('polymorphism', 'Var', (23, 35))	('Pro12Ala', 'Chemical', '-', (14, 22))
440122	20885923	It has been reported that PPARgamma polymorphism (Pro12Ala) is associated with various disease including diabetes, asthma, endometriosis, polycystic ovary, and colorectal cancer.	('polycystic ovary', 'Disease', 'MESH:D011085', (138, 154))	('Pro12Ala', 'Chemical', '-', (50, 58))	('asthma', 'Disease', 'MESH:D001249', (115, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('polycystic ovary', 'Phenotype', 'HP:0000147', (138, 154))	('asthma', 'Phenotype', 'HP:0002099', (115, 121))	('colorectal cancer', 'Disease', (160, 177))	('associated', 'Reg', (63, 73))	('PPARgamma', 'Gene', (26, 35))	('asthma', 'Disease', (115, 121))	('polycystic ovary', 'Disease', (138, 154))	('diabetes', 'Disease', 'MESH:D003920', (105, 113))	('endometriosis', 'Disease', 'MESH:D004715', (123, 136))	('endometriosis', 'Disease', (123, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('endometriosis', 'Phenotype', 'HP:0030127', (123, 136))	('diabetes', 'Disease', (105, 113))	('Pro12Ala', 'Var', (50, 58))
440123	20885923	Regarding to gastric disease, this PPARgamma polymorphism is associated with not only gastric ulcer but also gastric adenocarcinoma.	('associated with', 'Reg', (61, 76))	('polymorphism', 'Var', (45, 57))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (109, 131))	('gastric adenocarcinoma', 'Disease', (109, 131))	('gastric ulcer', 'Disease', (86, 99))	('gastric disease', 'Disease', 'MESH:D013274', (13, 28))	('gastric ulcer', 'Disease', 'MESH:D013276', (86, 99))	('gastric disease', 'Disease', (13, 28))	('gastric ulcer', 'Phenotype', 'HP:0002592', (86, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('PPARgamma', 'Gene', (35, 44))
440125	20885923	More interestingly, they demonstrated that PPARgamma expression was weaker in the colon tissue of mice deleted for the Toll-like receptor (TLR4) than in that of wild-type mice.	('mice', 'Species', '10090', (171, 175))	('PPARgamma', 'Gene', (43, 52))	('weaker', 'NegReg', (68, 74))	('TLR4', 'Gene', (139, 143))	('deleted', 'Var', (103, 110))	('TLR4', 'Gene', '21898', (139, 143))	('expression', 'MPA', (53, 63))	('mice', 'Species', '10090', (98, 102))
440126	20885923	Furthermore, in colonic epithelial cells such as HT-29 and Caco-2, PPARgamma expression was markedly increased because of the presence of LPSs.	('expression', 'MPA', (77, 87))	('PPARgamma', 'Gene', (67, 76))	('increased', 'PosReg', (101, 110))	('LPS', 'Chemical', 'MESH:D008070', (138, 141))	('LPSs', 'Var', (138, 142))	('HT-29', 'CellLine', 'CVCL:0320', (49, 54))
440131	20885923	They demonstrated the dramatic protective effects of rosiglitazone on both local and remote organ injury after intestinal ischemia-reperfusion injury and showed that the endogenous absence of PPARgamma leads to aggravated injury in this model.	('PPARgamma', 'Protein', (192, 201))	('organ injury', 'Disease', 'MESH:D019965', (92, 104))	('intestinal ischemia', 'Phenotype', 'HP:0002637', (111, 130))	('ischemia-reperfusion injury', 'Disease', (122, 149))	('organ injury', 'Disease', (92, 104))	('aggravated', 'PosReg', (211, 221))	('injury', 'CPA', (222, 228))	('absence', 'Var', (181, 188))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (53, 66))	('ischemia-reperfusion injury', 'Disease', 'MESH:D015427', (122, 149))
440149	20885923	In fact, they also showed that PPARgamma deficiency in Tregs impairs the ability of Tregs to prevent T-cell transfer-induced colitis.	('impairs', 'NegReg', (61, 68))	('colitis', 'Disease', 'MESH:D003092', (125, 132))	('T-cell transfer-induced', 'CPA', (101, 124))	('colitis', 'Disease', (125, 132))	('deficiency', 'Var', (41, 51))	('colitis', 'Phenotype', 'HP:0002583', (125, 132))	('PPARgamma', 'Gene', (31, 40))
440151	20885923	showed that conjugated linoleic acid ameliorated colitis.	('conjugated linoleic acid', 'Var', (12, 36))	('colitis', 'Disease', 'MESH:D003092', (49, 56))	('colitis', 'Disease', (49, 56))	('ameliorated', 'PosReg', (37, 48))	('linoleic acid', 'Chemical', 'MESH:D019787', (23, 36))	('colitis', 'Phenotype', 'HP:0002583', (49, 56))
440156	20885923	Heterozygous PPARgamma-knockout mice were refractory to 5-ASA treatment, and 5-ASA directly induced PPARgamma expression in colonic epithelial cells in vitro.	('induced', 'Reg', (92, 99))	('5-ASA', 'Var', (77, 82))	('5-ASA', 'Chemical', 'MESH:D019804', (77, 82))	('mice', 'Species', '10090', (32, 36))	('expression', 'MPA', (110, 120))	('5-ASA', 'Chemical', 'MESH:D019804', (56, 61))	('PPARgamma', 'Gene', (100, 109))
440171	32691176	Here, we present the first case of a primary SS of the esophagus in the presence of SS18-SSX2 fusion transcripts.	('primary SS', 'Disease', (37, 47))	('SS', 'Phenotype', 'HP:0012570', (84, 86))	('SS', 'Phenotype', 'HP:0012570', (89, 91))	('SS18', 'Gene', (84, 88))	('SSX2', 'Gene', '6757', (89, 93))	('SS', 'Phenotype', 'HP:0012570', (45, 47))	('SSX2', 'Gene', (89, 93))	('fusion transcripts', 'Var', (94, 112))	('SS18', 'Gene', '6760', (84, 88))
440183	32691176	The majority of patients with SS carry the pathognomonic t(X;18) (p11.2;q11.2) translocation, resulting in fusion of the SS18 (formerly SYT) gene on chromosome 18 with an SSX gene on chromosome X.	('SS18', 'Gene', (121, 125))	('SS', 'Phenotype', 'HP:0012570', (30, 32))	('SYT', 'Gene', '6760', (136, 139))	('SS', 'Phenotype', 'HP:0012570', (171, 173))	('patients', 'Species', '9606', (16, 24))	('SSX', 'Gene', '6757', (171, 174))	('fusion', 'Var', (107, 113))	('SSX', 'Gene', (171, 174))	('SS18', 'Gene', '6760', (121, 125))	('SYT', 'Gene', (136, 139))	('SS', 'Phenotype', 'HP:0012570', (121, 123))
440184	32691176	Here, we report the first case of monophasic SS of the esophagus in the presence of SS18-SSX2 fusion transcripts detected by reverse transcription-polymerase chain reaction (RT-PCR) analysis using a paraffin-embedded tumor specimen, which was originally misdiagnosed as leiomyoma.	('SS', 'Phenotype', 'HP:0012570', (84, 86))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('leiomyoma', 'Disease', (270, 279))	('SS', 'Phenotype', 'HP:0012570', (89, 91))	('SS18', 'Gene', (84, 88))	('SSX2', 'Gene', '6757', (89, 93))	('SS18', 'Gene', '6760', (84, 88))	('SS', 'Phenotype', 'HP:0012570', (45, 47))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('SSX2', 'Gene', (89, 93))	('leiomyoma', 'Disease', 'MESH:D007889', (270, 279))	('fusion transcripts', 'Var', (94, 112))	('paraffin', 'Chemical', 'MESH:D010232', (199, 207))
440239	31616504	The upregulated DEGs were significantly associated with extracellular matrix organization, disassembly, and the phosphoinositide-3 kinase/AKT, Rap1 and Ras signaling pathways, while the downregulated genes were associated with the Wnt signalling pathway.	('Wnt signalling pathway', 'Pathway', (231, 253))	('extracellular matrix organization', 'CPA', (56, 89))	('Rap1', 'Gene', (143, 147))	('AKT', 'Gene', (138, 141))	('disassembly', 'CPA', (91, 102))	('Ras signaling pathways', 'Pathway', (152, 174))	('DEGs', 'Var', (16, 20))	('upregulated', 'PosReg', (4, 15))	('DEG', 'Chemical', 'MESH:C042934', (16, 19))	('Rap1', 'Gene', '5906', (143, 147))	('AKT', 'Gene', '207', (138, 141))
440251	31616504	A large number of microRNA (miR) biomarkers have been identified; for instance, the loss of miR-31 is considered as an early molecular marker for the metaplasia-to-dysplasia transition of EAC, while miR-194, miR-196a and miR-375 are considered as oncogenic factors.	('miR-375', 'Gene', '494324', (221, 228))	('miR-31', 'Gene', '407035', (92, 98))	('metaplasia-to-dysplasia', 'Disease', (150, 173))	('EAC', 'Phenotype', 'HP:0011459', (188, 191))	('miR-375', 'Gene', (221, 228))	('EAC', 'Disease', (188, 191))	('loss', 'Var', (84, 88))	('EAC', 'Disease', 'MESH:D004941', (188, 191))	('miR-31', 'Gene', (92, 98))	('metaplasia-to-dysplasia', 'Disease', 'MESH:D008679', (150, 173))
440276	31616504	As an ordinal categorical variable, overexpressed METTL7B was significantly associated with a higher risk of recurrence.	('overexpressed', 'Var', (36, 49))	('METTL7B', 'Gene', '196410', (50, 57))	('METTL7B', 'Gene', (50, 57))
440297	31616504	Accordingly, Fan et al demonstrated that inhibition of ERK activation prevented proliferation of human esophageal cancer cells by inducing cell cycle arrest in G0/G1 phase.	('inducing', 'Reg', (130, 138))	('esophageal cancer', 'Disease', (103, 120))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (139, 156))	('proliferation', 'CPA', (80, 93))	('human', 'Species', '9606', (97, 102))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('inhibition', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prevented', 'NegReg', (70, 79))	('cell cycle arrest in G0/G1 phase', 'CPA', (139, 171))	('ERK', 'Gene', '5594', (55, 58))	('ERK', 'Gene', (55, 58))
440367	30766640	reported that during gastric ESD, compared with injection of air, injection of CO2 might reduce residual gas in the alimentary canal.	('gastric ESD', 'Disease', (21, 32))	('reduce', 'NegReg', (89, 95))	('CO2', 'Chemical', 'MESH:D002245', (79, 82))	('residual gas in the alimentary canal', 'MPA', (96, 132))	('injection', 'Var', (66, 75))
440407	28814885	Endogenous peroxidase activity was blocked with 0.3% H2O2 in methanol for 20 min, and nonspecific binding was blocked with 10% normal serum for 20 min followed by a buffer wash.	('methanol', 'Chemical', 'MESH:D000432', (61, 69))	('H2O2', 'Chemical', 'MESH:D006861', (53, 57))	('Endogenous', 'MPA', (0, 10))	('H2O2', 'Var', (53, 57))	('activity', 'MPA', (22, 30))	('nonspecific binding', 'Interaction', (86, 105))
440418	28814885	The staining intensity of IGF2BP3 was higher in pT1a-MM than that in pT1a-EP and pT1a-LPM (Table 2).	('higher', 'PosReg', (38, 44))	('staining intensity', 'MPA', (4, 22))	('IGF2BP3', 'Gene', '10643', (26, 33))	('IGF2BP3', 'Gene', (26, 33))	('pT1a-MM', 'Var', (48, 55))
440562	25885021	HGF binds c-Met, a tyrosine kinase receptor as exclusive ligand induces the activation of oncogenic pathways, angiogenesis and scattering of cells, leading to metastasis.	('binds', 'Var', (4, 9))	('c-Met', 'Gene', (10, 15))	('c-Met', 'Gene', '4233', (10, 15))	('metastasis', 'CPA', (159, 169))	('HGF', 'Gene', (0, 3))	('leading to', 'Reg', (148, 158))	('HGF', 'Gene', '3082', (0, 3))	('scattering of cells', 'CPA', (127, 146))	('oncogenic pathways', 'Pathway', (90, 108))	('angiogenesis', 'CPA', (110, 122))	('activation', 'PosReg', (76, 86))
440564	25885021	found Met expression to be an independent prognostic risk factor in esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (68, 93))	('Met expression', 'Var', (6, 20))	('esophageal adenocarcinoma', 'Disease', (68, 93))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (68, 93))
440603	24779651	For example, the conjugation of phage-encoded short peptides with liposomes or nanochemotherapy drugs has achieved higher concentrations of drugs in targeted tumor tissues, thereby reducing the side effects experienced by normal tissues.	('tumor', 'Disease', (158, 163))	('reducing', 'NegReg', (181, 189))	('side effects', 'MPA', (194, 206))	('phage-encoded', 'Var', (32, 45))	('concentrations', 'MPA', (122, 136))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('higher', 'PosReg', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('conjugation', 'Interaction', (17, 28))
440633	24779651	For example, positive staining (e.g., a brown color) was associated with esophageal cancer cells incubated with phage clones P4 and P12 (Figure 4, A & C), and was not observed for normal esophageal tissues incubated with the same two clones (Figure 4, B & D).	('P12', 'Gene', (132, 135))	('P12', 'Gene', '56655', (132, 135))	('positive', 'PosReg', (13, 21))	('esophageal cancer', 'Disease', (73, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('phage clones P4', 'Var', (112, 127))
440671	22920974	With this formula, we can then model the probability of complications (normal-tissue complication probability, or NTCP) as a function of Deff as follows:   where   where TD50 is the dose that is expected to result in a 50% complication probability, and m is a measure of the slope of the sigmoid curve represented by the integral of the normal distribution.	('NTCP', 'Gene', (114, 118))	('TD50', 'Var', (170, 174))	('NTCP', 'Gene', '6554', (114, 118))	('complication', 'MPA', (223, 235))
440687	22920974	This finding was confirmed when our 10-fold cross-validation showed that the model based on fractional DVH resulted in a lower mean-squared difference between predicted and observed esophagitis than the model based on the DVH corresponding to complete treatment.	('esophagitis', 'Phenotype', 'HP:0100633', (182, 193))	('esophagitis', 'Disease', (182, 193))	('esophagitis', 'Disease', 'MESH:D004941', (182, 193))	('fractional DVH', 'Var', (92, 106))	('lower', 'NegReg', (121, 126))
440754	23452637	Commercially available RFA devices include the HALO360, HALO90, HALO60, and HALO90Ultra (Covidien, Mansfield MA, USA).	('HALO90', 'Var', (56, 62))	('HALO360', 'Chemical', '-', (47, 54))	('HALO60', 'Var', (64, 70))	('HALO90', 'Chemical', '-', (56, 62))	('HALO90', 'Chemical', '-', (76, 82))	('HALO90Ultra', 'CellLine', 'CVCL:1B47', (76, 87))	('HALO360', 'Var', (47, 54))	('HALO90Ultra', 'Var', (76, 87))
440762	23452637	A randomized, multicenter, sham-controlled trial showed a rate of CR-D in 81% of participants with HGD compared to 19% in the sham arm.	('CR-D', 'Disease', (66, 70))	('CR-D', 'Chemical', '-', (66, 70))	('HGD', 'Var', (99, 102))	('participants', 'Species', '9606', (81, 93))
440763	23452637	The rate of development of EAC was reduced from 16% in the RFA group compared to 4% in the sham arm.	('RFA', 'Var', (59, 62))	('EAC', 'Chemical', '-', (27, 30))	('reduced', 'NegReg', (35, 42))	('EAC', 'Disease', (27, 30))	('development', 'CPA', (12, 23))
440781	23452637	One of the advantages of PDT is its significant depth of penetration and ease of wide field application as compared to APC, MPEC, and RFA.	('PDT', 'Var', (25, 28))	('APC', 'Disease', 'MESH:D011125', (119, 122))	('APC', 'Disease', (119, 122))	('MPEC', 'Chemical', '-', (124, 128))
440783	23452637	Nevertheless, only PDT and radiofrequency ablation have been shown to have durable results in reducing the risks of EAC in BE complicated by dysplasia (CR-D 77% at 5 years for PDT) Experience from the Mayo Clinic demonstrate that patients with HGD treated with PDT had long-term survival outcomes even comparable to esophagectomy.	('dysplasia', 'Disease', (141, 150))	('Mayo', 'Species', '162683', (201, 205))	('PDT', 'Var', (261, 264))	('dysplasia', 'Disease', 'MESH:D004476', (141, 150))	('patients', 'Species', '9606', (230, 238))	('BE', 'Phenotype', 'HP:0100580', (123, 125))	('EAC', 'Disease', (116, 119))	('CR-D', 'Chemical', '-', (152, 156))	('EAC', 'Chemical', '-', (116, 119))
440806	33373373	However, patients with pesticide intoxication had a significantly higher risk of esophageal cancer (adjusted HR = 2.52, 95% CI = 1.52-4.18) than those without pesticide/detergent intoxication.	('patients', 'Species', '9606', (9, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('pesticide intoxication', 'Var', (23, 45))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', (81, 98))
440836	33373373	Furthermore, participants in the pesticide/detergent intoxication and control cohorts were compared for common comorbidities, including hypertension (ICD-9-CM codes 401-405), diabetes mellitus (ICD-9-CM code 250), chronic obstructive pulmonary disease (ICD-9-CM codes 491, 492, and 496), obesity (ICD-9-CM code 278), alcohol-related illness (ICD-9-CM codes 291, 303, 305, 571.0, 571.1, 571.2, 571.3, 790.3, A215, and V11.3), ischemic heart disease (ICD-9-CM codes 410-414), cerebrovascular disease (ICD-9-CM codes 430-438), and gastric disease (ICD-9-CM codes 530-534).	('gastric disease', 'Disease', (528, 543))	('alcohol', 'Chemical', 'MESH:D000438', (317, 324))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (214, 251))	('diabetes mellitus', 'Disease', (175, 192))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (214, 251))	('gastric disease', 'Disease', 'MESH:D013272', (528, 543))	('obesity', 'Disease', (288, 295))	('chronic obstructive pulmonary disease', 'Disease', (214, 251))	('hypertension', 'Disease', 'MESH:D006973', (136, 148))	('cerebrovascular disease', 'Disease', (474, 497))	('diabetes mellitus', 'Disease', 'MESH:D003920', (175, 192))	('obesity', 'Disease', 'MESH:D009765', (288, 295))	('hypertension', 'Disease', (136, 148))	('ischemic heart disease', 'Disease', (425, 447))	('cerebrovascular disease', 'Disease', 'MESH:D002561', (474, 497))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (175, 192))	('ischemic heart disease', 'Disease', 'MESH:D003324', (425, 447))	('alcohol-related illness', 'Disease', (317, 340))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (222, 251))	('ICD-9-CM', 'Var', (449, 457))	('participants', 'Species', '9606', (13, 25))	('hypertension', 'Phenotype', 'HP:0000822', (136, 148))	('obesity', 'Phenotype', 'HP:0001513', (288, 295))
440847	33373373	The Kaplan-Meier curve showed that the cumulative incidence of esophageal cancer was higher in the pesticide/detergent cohort than in the comparison cohort throughout the 12-year follow-up period (Fig 1).	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('higher', 'PosReg', (85, 91))	('pesticide/detergent', 'Var', (99, 118))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
440856	33373373	For patients without comorbidity, those with pesticide/detergent intoxication had a significantly higher esophageal cancer risk than those without pesticide/detergent intoxication (adjusted HR = 2.32, 95% CI = 1.32-4.10).	('pesticide/detergent intoxication', 'Var', (45, 77))	('esophageal cancer', 'Disease', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patients', 'Species', '9606', (4, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))
440863	33373373	Several genetic and epigenetic alterations are implicated in both the development and progression of esophageal cancer.	('implicated', 'Reg', (47, 57))	('men', 'Species', '9606', (77, 80))	('esophageal cancer', 'Disease', (101, 118))	('epigenetic alterations', 'Var', (20, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
440874	33373373	Therefore, patients with ICD-9-CM codes 983.1 and 983.2 (acidic and alkali corrosive injury), 983.9 (caustic intoxication), or 989.6 (detergent intoxication) were identified, which expanded the dataset and weakened the results.	('weakened', 'NegReg', (206, 214))	('alkali corrosive injury', 'Disease', (68, 91))	('alkali corrosive injury', 'Disease', 'MESH:D006934', (68, 91))	('patients', 'Species', '9606', (11, 19))	('983.9', 'Var', (94, 99))
440878	33373373	In previous studies, lye ingestion resulted in squamous cell carcinoma in the esophagus rather than adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (100, 114))	('carcinoma in the esophagus', 'Phenotype', 'HP:0011459', (61, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('adenocarcinoma', 'Disease', (100, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('resulted in', 'Reg', (35, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 70))	('ingestion', 'Var', (25, 34))	('squamous cell carcinoma', 'Disease', (47, 70))
440886	33373373	In this study, the relative risk of esophageal cancer increased significantly by 2.52x in the pesticide group, and it was 2.47x even after excluding the comorbidity of alcohol-related illness.	('pesticide', 'Var', (94, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (36, 53))	('alcohol', 'Chemical', 'MESH:D000438', (168, 175))	('increased', 'PosReg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancer', 'Disease', (36, 53))
440951	33373373	"Patients with pesticide/detergent intoxication were significantly associated with increased risk of esophagus cancer than the patients without pesticide/detergent intoxication for without co-morbidity (adjusted HR=2.32, 95%CI=1.32-4.10).	('Patients', 'Species', '9606', (1, 9))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('pesticide/detergent intoxication', 'Var', (15, 47))
440954	33373373	However, in this study, esophageal cancer predominately occurred in the pesticide group.	('occurred', 'Reg', (56, 64))	('esophageal cancer', 'Disease', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('pesticide', 'Var', (72, 81))
441094	28206968	Both low MCT1 and high MCT4 histoscore predicted survival in univariate analysis (P < 0.01).	('MCT1', 'Gene', '6566', (9, 13))	('low', 'Var', (5, 8))	('MCT4', 'Gene', (23, 27))	('survival', 'Disease', (49, 57))	('MCT4', 'Gene', '9123', (23, 27))	('MCT1', 'Gene', (9, 13))	('predicted', 'Reg', (39, 48))
441130	28206968	Low MCT1 histoscore predicted survival in univariate (P = 0.009, Figure 2), but not in multivariate analysis (data not shown).	('MCT1', 'Gene', '6566', (4, 8))	('MCT1', 'Gene', (4, 8))	('predicted', 'Reg', (20, 29))	('Low', 'Var', (0, 3))
441154	28206968	High MCT4 expression has been shown to correlate to poor prognosis in breast, lung, gastric, colon and prostate cancer.	('MCT4', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('breast', 'Disease', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('expression', 'MPA', (10, 20))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('MCT4', 'Gene', '9123', (5, 9))	('lung', 'Disease', (78, 82))	('colon and prostate cancer', 'Disease', 'MESH:D011471', (93, 118))	('gastric', 'Disease', (84, 91))
441178	28206968	Low cytoplasmic expression of MCT1 and high expression of MCT4 associate with advanced stage and poor prognosis in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (115, 140))	('high', 'Var', (39, 43))	('MCT1', 'Gene', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('MCT4', 'Gene', '9123', (58, 62))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (115, 140))	('MCT1', 'Gene', '6566', (30, 34))	('MCT4', 'Gene', (58, 62))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (115, 140))
441225	27816689	The final histopathology confirmed the diagnosis of stage IIA poorly differentiated squamous cell carcinoma p-G3, p-T2, p-N0, p-R0.	('p-N0', 'Var', (120, 124))	('p-T2', 'Var', (114, 118))	('p-G3', 'Var', (108, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('squamous cell carcinoma', 'Disease', (84, 107))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 107))
441243	26959737	To this end, the expression levels of miR-26a and miR-144 in ESCC clinical tissues and cell lines were investigated by qRT-PCR.	('clinical', 'Species', '191496', (66, 74))	('miR-26a', 'Var', (38, 45))	('miR-144', 'Var', (50, 57))
441247	26959737	COX-2 was confirmed as a target of miR-26a and miR-144.	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '4513', (0, 5))	('miR-26a', 'Var', (35, 42))	('miR-144', 'Var', (47, 54))
441256	26959737	We and others have shown that (i) COX-2 expression is a frequent phenomenon in human ESCC tissue samples and positive expression is related with lymphatic metastasis, (ii) COX-2 inhibitors can inhibit tumor cell proliferation and induce apoptosis by inducing G0 / G1 cell cycle arrest and suppressing Bcl-2 expression as well as prevent tumor formation in vivo through the inhibition of COX-2.	('tumor', 'Disease', (337, 342))	('apoptosis', 'CPA', (237, 246))	('COX-2', 'Gene', (387, 392))	('Bcl-2', 'Gene', '596', (301, 306))	('inducing', 'PosReg', (250, 258))	('inhibition', 'NegReg', (373, 383))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('human', 'Species', '9606', (79, 84))	('COX-2', 'Gene', '4513', (387, 392))	('suppressing', 'NegReg', (289, 300))	('tumor', 'Disease', (201, 206))	('COX-2', 'Gene', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('prevent', 'NegReg', (329, 336))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('induce', 'PosReg', (230, 236))	('COX-2', 'Gene', (34, 39))	('COX-2', 'Gene', '4513', (172, 177))	('inhibit', 'NegReg', (193, 200))	('inhibitors', 'Var', (178, 188))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (267, 284))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('COX-2', 'Gene', '4513', (34, 39))	('Bcl-2', 'Gene', (301, 306))	('expression', 'MPA', (307, 317))	('G0 / G1 cell cycle arrest', 'CPA', (259, 284))
441257	26959737	(iii) COX-2 inhibitors also inhibit migration and invasion of ESCC cells.	('COX-2', 'Gene', (6, 11))	('inhibitors', 'Var', (12, 22))	('COX-2', 'Gene', '4513', (6, 11))	('inhibit', 'NegReg', (28, 35))
441269	26959737	found that miR-26a and miR-144 were associated with the different tumor stage classifications (Table 1 in the reference paper).	('miR-144', 'Var', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('miR-26a', 'Var', (11, 18))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('associated', 'Reg', (36, 46))
441270	26959737	Therefore, we hypothesized that both miR-26a and miR-144 could inhibit ESCC by inhibiting COX-2.	('COX-2', 'Gene', (90, 95))	('ESCC', 'Disease', (71, 75))	('inhibiting', 'NegReg', (79, 89))	('miR-144', 'Var', (49, 56))	('miR-26a', 'Var', (37, 44))	('inhibit', 'NegReg', (63, 70))	('COX-2', 'Gene', '4513', (90, 95))
441272	26959737	Our study showed that miR-26a and miR-144 inhibit proliferation and metastasis of ESCC by inhibiting COX-2 expression.	('COX-2', 'Gene', (101, 106))	('ESCC', 'Disease', (82, 86))	('miR-144', 'Var', (34, 41))	('proliferation', 'CPA', (50, 63))	('expression', 'MPA', (107, 117))	('miR-26a', 'Var', (22, 29))	('metastasis', 'CPA', (68, 78))	('inhibit', 'NegReg', (42, 49))	('inhibiting', 'NegReg', (90, 100))	('COX-2', 'Gene', '4513', (101, 106))
441275	26959737	Compared to adjacent normal tissues, the expressions of miR-26a and miR-144 were significantly downregulated in tumor tissues (Figure 1A, 1B).	('miR-144', 'Gene', (68, 75))	('downregulated', 'NegReg', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('miR-26a', 'Var', (56, 63))	('expressions', 'MPA', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))
441276	26959737	The expression levels of miR-26a and miR-144 in 11 ESCC cell lines were also significantly lower compared with that of Het-1A, a human immortalized esophageal epithelia cell line (Figure 1C, 1D).	('lower', 'NegReg', (91, 96))	('expression levels', 'MPA', (4, 21))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (148, 168))	('miR-26a', 'Var', (25, 32))	('miR-144', 'Var', (37, 44))	('esophageal epithelia', 'Disease', (148, 168))	('esophageal epithelia', 'Disease', 'MESH:D004941', (148, 168))	('human', 'Species', '9606', (129, 134))
441277	26959737	CCK8 assay data showed that proliferation of EC9706 and EC109 cell lines stably transfected with miR-26a or miR-144 was not inhibited, while the percentage of growth inhibition in co-expressed miR-26a and miR-144 was significantly inhibited (Figure 2A).	('miR-26a', 'Var', (193, 200))	('EC9706', 'CellLine', 'CVCL:E307', (45, 51))	('miR-144', 'Var', (205, 212))	('inhibited', 'NegReg', (231, 240))	('growth inhibition', 'CPA', (159, 176))
441278	26959737	Compared with the typical morphology of control cells, EC9706 and EC109 cells stably transfected with miR-26a, miR-144, or both were smaller in volume with a round-to-fusiform cell body (Figure 3A).	('miR-26a', 'Var', (102, 109))	('EC9706', 'CellLine', 'CVCL:E307', (55, 61))	('smaller', 'NegReg', (133, 140))	('miR-144', 'Var', (111, 118))
441279	26959737	This phenotype implied that miR-26a or mir-144 might affect metastasis of ESCC cells.	('miR-26a', 'Var', (28, 35))	('mir-144', 'Gene', '406936', (39, 46))	('mir-144', 'Gene', (39, 46))	('affect', 'Reg', (53, 59))	('ESCC cells', 'Disease', (74, 84))	('metastasis', 'CPA', (60, 70))
441280	26959737	To verify whether COX-2 is a target of miR-26a or miR-144 in human ESCC, we performed the following experiments.	('COX-2', 'Gene', '4513', (18, 23))	('miR-26a', 'Var', (39, 46))	('human', 'Species', '9606', (61, 66))	('COX-2', 'Gene', (18, 23))	('miR-144', 'Var', (50, 57))
441281	26959737	Firstly, the predicted binding sites of hsa-miR-26a and hsa-miR-144 in the 3'-UTR of COX2 mRNA is shown according to computational prediction, from which the luciferase reporters containing mutant binding sites were constructed (Figure 4A), to verify whether COX-2 is a direct target of miR-26a or miR-144 in human ESCC.	('COX-2', 'Gene', '4513', (259, 264))	('human', 'Species', '9606', (309, 314))	('COX-2', 'Gene', (259, 264))	('COX2', 'Gene', (85, 89))	('mutant', 'Var', (190, 196))	('hsa-miR-144', 'Gene', '406936', (56, 67))	('COX2', 'Gene', '4513', (85, 89))	('hsa-miR-144', 'Gene', (56, 67))
441282	26959737	The expression levels of miR-26a and miR-144 in EC9706 or EC109 stably transfected with miR-26a or miR-144 or both increased significantly (Figure 4B).	('expression levels', 'MPA', (4, 21))	('miR-144', 'Var', (99, 106))	('increased', 'PosReg', (115, 124))	('EC9706', 'CellLine', 'CVCL:E307', (48, 54))	('miR-26a', 'Var', (88, 95))
441283	26959737	Secondly, we investigated the correlation of miR-26a or miR-144 with COX-2 expression in ESCC cells.	('miR-144', 'Var', (56, 63))	('COX-2', 'Gene', '4513', (69, 74))	('COX-2', 'Gene', (69, 74))	('miR-26a', 'Var', (45, 52))
441284	26959737	Western blot analysis showed that overexpression of miR-26a, miR-144, or both in EC9706 and EC109 cells significantly reduced COX-2 expression at the protein level (Figure 4C).	('EC9706', 'CellLine', 'CVCL:E307', (81, 87))	('miR-144', 'Var', (61, 68))	('miR-26a', 'Var', (52, 59))	('reduced', 'NegReg', (118, 125))	('COX-2', 'Gene', '4513', (126, 131))	('COX-2', 'Gene', (126, 131))	('expression', 'MPA', (132, 142))
441286	26959737	Thirdly, the inhibited proliferation of cells co-overexpression of miR-26a and miR-144 was promoted when PGE2 was added to the culture medium (Figure 4E; P < 0.001).	('promoted', 'PosReg', (91, 99))	('co-overexpression', 'PosReg', (46, 63))	('inhibited', 'NegReg', (13, 22))	('miR-144', 'Var', (79, 86))	('PGE2', 'Chemical', 'MESH:D015232', (105, 109))	('miR-26a', 'Gene', (67, 74))
441287	26959737	Addition of PGE2 into the culture medium resulted in a significant increase in migration and invasion ability of cells stably transfected with miR-26a, or miR-144, or both (Figure 4F; P < 0.001).	('migration', 'CPA', (79, 88))	('PGE2', 'Gene', (12, 16))	('miR-144', 'Var', (155, 162))	('PGE2', 'Chemical', 'MESH:D015232', (12, 16))	('increase', 'PosReg', (67, 75))	('invasion ability', 'CPA', (93, 109))	('miR-26a', 'Var', (143, 150))
441289	26959737	Results showed that reporter activity of WT pMIR-COX-2 was significantly decreased in cells that over-expressed miR-26a or miR-144, as compared with the control cells (P < 0.01; Figure 4G).	('COX-2', 'Gene', (49, 54))	('miR-144', 'Var', (123, 130))	('decreased', 'NegReg', (73, 82))	('reporter activity', 'MPA', (20, 37))	('over-expressed', 'PosReg', (97, 111))	('miR-26a', 'Var', (112, 119))	('COX-2', 'Gene', '4513', (49, 54))
441290	26959737	Co-expression of miR-26a and miR-144 in ESCC cell lines significantly inhibited the growth of xenograft tumors in nude mice, compared with mice inoculated with parental EC9706 or EC109 cells (Figure 5A).	('miR-144', 'Var', (29, 36))	('mice', 'Species', '10090', (119, 123))	('EC9706', 'CellLine', 'CVCL:E307', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('nude mice', 'Species', '10090', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('xenograft tumors', 'Disease', 'MESH:D009369', (94, 110))	('mice', 'Species', '10090', (139, 143))	('inhibited', 'NegReg', (70, 79))	('xenograft tumors', 'Disease', (94, 110))	('miR-26a', 'Var', (17, 24))
441292	26959737	In the present study, we investigated the effect of miR-26a and miR-144 on human ESCC.	('miR-26a', 'Var', (52, 59))	('human', 'Species', '9606', (75, 80))	('miR-144', 'Var', (64, 71))
441293	26959737	A comparison between 30 pairs of ESCC tumor and adjacent normal tissues showed that the expression levels of miR-26a and miR-144 were significantly decreased in ESCC tumor (P < 0.001).	('ESCC tumor', 'Disease', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('ESCC tumor', 'Disease', 'MESH:D004938', (33, 43))	('ESCC tumor', 'Disease', (161, 171))	('decreased', 'NegReg', (148, 157))	('expression levels', 'MPA', (88, 105))	('miR-26a', 'Var', (109, 116))	('ESCC tumor', 'Disease', 'MESH:D004938', (161, 171))	('miR-144', 'Var', (121, 128))
441295	26959737	Taken together, all of the data from the in vitro and in vivo studies indicated that miR-26a and miR-144 may function as tumor suppressors in ESCC.	('miR-26a', 'Gene', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('miR-144', 'Var', (97, 104))	('ESCC', 'Disease', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
441296	26959737	Thirdly, COX-2 as a direct target of miR-26a and miR-144 in ESCC cells was confirmed by means of luciferase reporter, western blot and ELISA.	('COX-2', 'Gene', '4513', (9, 14))	('miR-26a', 'Var', (37, 44))	('COX-2', 'Gene', (9, 14))	('miR-144', 'Var', (49, 56))
441297	26959737	Our findings provide direct evidence to support that miR-26a and miR-144 are tumor suppressors in ESCC and inhibit ESCC by repressing COX-2 expression.	('inhibit', 'NegReg', (107, 114))	('ESCC', 'Disease', (115, 119))	('expression', 'MPA', (140, 150))	('COX-2', 'Gene', '4513', (134, 139))	('miR-144', 'Var', (65, 72))	('ESCC', 'Disease', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('COX-2', 'Gene', (134, 139))	('miR-26a', 'Var', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('repressing', 'NegReg', (123, 133))	('tumor', 'Disease', (77, 82))
441310	26959737	Although several reports showed that miR-144 is downregulated in hepatocellular carcinoma, non-small cell lung cancer, osteosarcoma, prostate cancer, cervical squamous cell carcinoma and colorectal cancer, other studies showed that miR-144 can promote growth of HeLa cells and cell proliferation, migration, and invasion in nasopharyngeal carcinoma.	('colorectal cancer', 'Disease', (187, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('hepatocellular carcinoma', 'Disease', (65, 89))	('non-small cell lung cancer', 'Disease', (91, 117))	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('miR-144', 'Gene', (37, 44))	('invasion', 'CPA', (312, 320))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('nasopharyngeal carcinoma', 'Disease', (324, 348))	('downregulated', 'NegReg', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('miR-144', 'Var', (232, 239))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (91, 117))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))	('HeLa', 'CellLine', 'CVCL:0030', (262, 266))	('cervical squamous cell carcinoma', 'Disease', (150, 182))	('cell proliferation', 'CPA', (277, 295))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (324, 348))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (95, 117))	('migration', 'CPA', (297, 306))	('promote', 'PosReg', (244, 251))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 182))	('growth', 'CPA', (252, 258))	('osteosarcoma', 'Disease', (119, 131))	('prostate cancer', 'Disease', 'MESH:D011471', (133, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (339, 348))	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('osteosarcoma', 'Disease', 'MESH:D012516', (119, 131))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (91, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (65, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('prostate cancer', 'Disease', (133, 148))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (324, 348))
441313	26959737	For example, miR-26a inhibits growth of lung cancer cells by inhibiting EZH2 expression, but promotes lung cancer progression by suppressing PTEN.	('inhibiting', 'NegReg', (61, 71))	('PTEN', 'Gene', (141, 145))	('promotes', 'PosReg', (93, 101))	('inhibits', 'NegReg', (21, 29))	('PTEN', 'Gene', '5728', (141, 145))	('lung cancer', 'Disease', (102, 113))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('EZH2', 'Gene', '2146', (72, 76))	('EZH2', 'Gene', (72, 76))	('miR-26a', 'Var', (13, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('suppressing', 'NegReg', (129, 140))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('growth', 'CPA', (30, 36))	('expression', 'MPA', (77, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (40, 51))
441317	26959737	In this study, we found that overexpression of miR-26a or miR-144 alone was not strong enough to inhibit proliferation of ESCC cells, but they still can inhibit COX-2 expression in cancer cells.	('inhibit', 'NegReg', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('miR-144', 'Var', (58, 65))	('COX-2', 'Gene', '4513', (161, 166))	('COX-2', 'Gene', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('expression', 'MPA', (167, 177))	('miR-26a', 'Var', (47, 54))
441322	26959737	This suggests that there is an additive inhibitory effect by the co-expressed miR-26a and miR-144 on COX-2 expression and cell proliferation and metastasis in ESCC.	('miR-26a', 'Gene', (78, 85))	('metastasis', 'CPA', (145, 155))	('COX-2', 'Gene', (101, 106))	('expression', 'MPA', (107, 117))	('COX-2', 'Gene', '4513', (101, 106))	('miR-144', 'Var', (90, 97))	('cell proliferation', 'CPA', (122, 140))	('ESCC', 'Disease', (159, 163))
441325	26959737	Since COX-2 is considered a potential therapeutic target of ESCC, our findings suggest that miR-26a and miR-144 may contribute to a novel therapeutic approach for ESCC.	('ESCC', 'Disease', (163, 167))	('contribute', 'Reg', (116, 126))	('COX-2', 'Gene', '4513', (6, 11))	('miR-144', 'Var', (104, 111))	('miR-26a', 'Var', (92, 99))	('COX-2', 'Gene', (6, 11))
441327	26959737	COX-2 is confirmed as a direct target of miR-26a or miR-144, and inhibition of COX-2 expression might be the action mechanism underlying their anti-tumor functions.	('expression', 'MPA', (85, 95))	('inhibition', 'NegReg', (65, 75))	('miR-26a', 'Var', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('COX-2', 'Gene', '4513', (0, 5))	('COX-2', 'Gene', '4513', (79, 84))	('miR-144', 'Var', (52, 59))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
293472	26959737	The human ESCC cell lines KYSE30, KYSE70, KYSE150, KYSE410, KYSE450, KYSE510, EC9706, and EC109 were kindly provided by the Cancer Institute and Hospital, Chinese Academy of Medical Science.	('EC9706', 'CellLine', 'CVCL:E307', (78, 84))	('KYSE150', 'Var', (42, 49))	('human', 'Species', '9606', (4, 9))	('KYSE70', 'Var', (34, 40))	('KYSE510', 'Var', (69, 76))	('KYSE410', 'Var', (51, 58))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('KYSE450', 'Var', (60, 67))
441333	26959737	Introduction of the expression plasmids carrying miR-26a, miR-144, and miR-26a-144 into EC9706 and EC109 cells was performed using Lipofectamine 2000 (Invitrogen, USA) in accordance with the manufacturer's instructions.	('miR-144', 'Var', (58, 65))	('miR-26a', 'Gene', (49, 56))	('miR-26a-144', 'Var', (71, 82))	('EC9706', 'CellLine', 'CVCL:E307', (88, 94))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (131, 149))
441337	26959737	Luciferase reporters of COX-2 with mutant binding sites (underlined and italicized) of miR-26a or miR-144 were made using two DNA fragments with 5' SacI and 3' HindIII sites (underlined) and protective bases.	('miR-144', 'Gene', (98, 105))	('binding', 'Interaction', (42, 49))	('mutant', 'Var', (35, 41))	('miR-26a', 'Gene', (87, 94))	('COX-2', 'Gene', '4513', (24, 29))	('COX-2', 'Gene', (24, 29))
441340	26959737	Stably transfected cells (1.5 x 106 in 0.2 ml) were injected subcutaneously into the right (EC9706-miR26a-144 or EC109-miR26a-144) and left (EC9706-vector or EC109-vector) dorsal flank of 5-week-old severe combined immunodeficiency (SCID) mice (Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences), five mice per group.	('mice', 'Species', '10090', (329, 333))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (99, 102))	('miR', 'Gene', (119, 122))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (199, 231))	('EC9706-vector', 'Var', (141, 154))	('EC9706', 'CellLine', 'CVCL:E307', (141, 147))	('immunodeficiency', 'Phenotype', 'HP:0002721', (215, 231))	('immunodeficiency', 'Disease', 'MESH:D007153', (215, 231))	('SCID', 'Disease', 'MESH:D053632', (233, 237))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (206, 231))	('SCID', 'Disease', (233, 237))	('immunodeficiency', 'Disease', (215, 231))	('EC9706', 'CellLine', 'CVCL:E307', (92, 98))	('EC109-vector', 'Var', (158, 170))	('mice', 'Species', '10090', (239, 243))
441343	26959737	There were two groups (EC9706-vector or EC109 and EC9706-miR26a-144 or EC109-miR26a-144) in animal study and each group had five mice.	('miR', 'Gene', (77, 80))	('EC9706', 'CellLine', 'CVCL:E307', (23, 29))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('EC109', 'Var', (40, 45))	('EC9706-vector', 'Var', (23, 36))	('mice', 'Species', '10090', (129, 133))	('EC9706', 'CellLine', 'CVCL:E307', (50, 56))	('miR', 'Gene', '220972', (77, 80))
441389	28860457	The histology types were restricted according to the International Classification of Disease-Oncology-3rd edition (ICD-O-3), with codes of 8050, 8140-8147, 8160-8162, 8180-8221, 8250-8507, 8514-8551, 8571-8574, 8576, and 8940-8941 and tumor site codes of 160-162.	('8250-8507', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('8576', 'Var', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('8571-8574', 'Var', (200, 209))	('8514-8551', 'Var', (189, 198))	('8180-8221', 'Var', (167, 176))	('tumor', 'Disease', (235, 240))	('8140-8147', 'Var', (145, 154))	('8160-8162', 'Var', (156, 165))	('Oncology', 'Phenotype', 'HP:0002664', (93, 101))	('8940-8941', 'Var', (221, 230))
441405	28860457	According to the X-tile analysis results (Supplementary Figure 2a and b), LNR was classified into LNR1 (value 0), LNR2 (0 < LNR2 <= 0.125) LNR3 (0.125 < LNR3 <= 0.425) and LNR4 (0.425 < LNR4 <= 1.000), and LODDS was classified into LODDS1 (-5.20 <= LODDS1 <= -2.800), LODDS2 (-2.800 < LODDS2 <= -1.600), LODDS3 (-1.600 < LODDS3 <= -0.310) and LODDS4 (-0.310 < LODDS4 <= 4.270).	('LODDS', 'Chemical', '-', (206, 211))	('LODDS', 'Chemical', '-', (285, 290))	('LODDS', 'Chemical', '-', (232, 237))	('LODDS', 'Chemical', '-', (249, 254))	('-1.600 <', 'Var', (312, 320))	('-0.310', 'Var', (351, 357))	('LODDS', 'Chemical', '-', (321, 326))	('-2.800', 'Var', (276, 282))	('LODDS', 'Chemical', '-', (304, 309))	('LODDS', 'Chemical', '-', (343, 348))	('LODDS', 'Chemical', '-', (360, 365))	('LODDS', 'Chemical', '-', (268, 273))
441439	28860457	It has been reported that LNR was a reliable indicator to improve node classification for esophageal cancer and gastric cancer with less influence by insufficient number of lymph nodes retrieved.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('improve', 'PosReg', (58, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('LNR', 'Var', (26, 29))	('gastric cancer', 'Disease', (112, 126))	('esophageal cancer', 'Disease', (90, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))
441461	28060765	Genetic polymorphisms in TERT are associated with increased risk of esophageal cancer Single nucleotide polymorphisms (SNPs) in TERT may be associated with susceptibility to esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('associated', 'Reg', (34, 44))	('associated', 'Reg', (140, 150))	('esophageal cancer', 'Disease', (174, 191))	('Single nucleotide polymorphisms', 'Var', (86, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (174, 191))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TERT', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('TERT', 'Gene', '7015', (128, 132))	('TERT', 'Gene', '7015', (25, 29))	('TERT', 'Gene', (128, 132))	('esophageal cancer', 'Disease', (68, 85))
441463	28060765	Of the four SNPs examined, rs10069690 and rs2242652 were correlated with esophageal cancer risk.	('rs2242652', 'Mutation', 'rs2242652', (42, 51))	('rs2242652', 'Var', (42, 51))	('esophageal cancer', 'Disease', (73, 90))	('correlated', 'Reg', (57, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rs10069690', 'Mutation', 'rs10069690', (27, 37))	('rs10069690', 'Var', (27, 37))
441464	28060765	Additionally, after adjusting for age and gender, the "Trs10069690Ars2242652", "Trs10069690Grs2242652" haplotypes were associated with an increased risk of esophageal cancer, while the and "Crs10069690Grs2242652" haplotype was associated with a decreased risk of esophageal cancer.	('rs10069690', 'Mutation', 'rs10069690', (191, 201))	('rs2242652', 'Mutation', 'rs2242652', (202, 211))	('rs10069690', 'Mutation', 'rs10069690', (56, 66))	('Trs10069690Grs2242652', 'Var', (80, 101))	('rs2242652', 'Mutation', 'rs2242652', (92, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('rs10069690', 'Mutation', 'rs10069690', (81, 91))	('esophageal cancer', 'Disease', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('esophageal cancer', 'Disease', (263, 280))	('rs2242652', 'Mutation', 'rs2242652', (67, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (263, 280))	('Crs10069690Grs2242652', 'Var', (190, 211))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
441474	28060765	Many events can result in telomere dysfunctions, including gradual shortening caused by incomplete chromosome replication, oxidative DNA damage, or mutations in structural proteins, such as TERT.	('oxidative', 'MPA', (123, 132))	('mutations', 'Var', (148, 157))	('gradual', 'MPA', (59, 66))	('incomplete chromosome replication', 'CPA', (88, 121))	('telomere dysfunctions', 'Disease', (26, 47))	('TERT', 'Gene', (190, 194))	('result', 'Reg', (16, 22))	('TERT', 'Gene', '7015', (190, 194))
441476	28060765	In addition, multiple independent variants at the TERT locus are associated with telomere length and risk of malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('malignant tumors', 'Disease', (109, 125))	('variants', 'Var', (34, 42))	('TERT', 'Gene', '7015', (50, 54))	('malignant tumors', 'Disease', 'MESH:D018198', (109, 125))	('associated', 'Reg', (65, 75))	('telomere length', 'CPA', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('TERT', 'Gene', (50, 54))
441488	28060765	The rs10069690, rs2242652, and rs2853676 SNPs were associated with 1.70-fold (95% CI, 1.33 - 12.18, p = 2.50E-05), 1.48-fold (95% CI, 1.17 - 1.89, p = 0.001), and 1.33-fold (95% CI, 1.04 - 1.70, P = 0.023) increases in the risk of developing esophageal cancer, respectively.	('rs2853676 SNPs', 'Var', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('increases', 'PosReg', (206, 215))	('rs10069690', 'Mutation', 'rs10069690', (4, 14))	('esophageal cancer', 'Disease', (242, 259))	('rs10069690', 'Var', (4, 14))	('rs2242652', 'Mutation', 'rs2242652', (16, 25))	('rs2853676', 'Mutation', 'rs2853676', (31, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (242, 259))	('rs2242652', 'Var', (16, 25))
441489	28060765	Two of these SNPs (rs10069690 and rs2242652) were still correlated with esophageal cancer in the allelic model after Bonferroni correction.	('rs2242652', 'Var', (34, 43))	('rs10069690', 'Mutation', 'rs10069690', (19, 29))	('rs10069690', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('correlated with', 'Reg', (56, 71))	('rs2242652', 'Mutation', 'rs2242652', (34, 43))
441491	28060765	The "T/C-T/T" genotype at the rs10069690 SNP increased the risk of esophageal cancer in the dominant model (OR = 1.95; 95% CI, 1.43 - 2.73, p = 5.89E-06), and the "T" allele increased the risk of esophageal in the log-additive model (OR = 1.71; 95% CI, 1.33 - 2.20, p = 3.02E-05).	('rs10069690', 'Mutation', 'rs10069690', (30, 40))	('esophageal', 'Disease', (196, 206))	('rs10069690', 'Var', (30, 40))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))
441493	28060765	For the rs2242652 SNP, the "G/A-A/A" genotype increased the risk of esophageal cancer 1.64-fold (95% CI, 1.24 - 2.197; p = 5.5E-04) in the dominant model, and the "A" allele increased the risk 1.48-fold (95% CI, 1.18 - 1.93; p = 0.001) in the log-additive model.	('rs2242652 SNP', 'Var', (8, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('"G/A-A', 'Gene', (27, 33))	('rs2242652', 'Mutation', 'rs2242652', (8, 17))	('"G/A-A', 'Gene', '2548', (27, 33))	('esophageal cancer', 'Disease', (68, 85))
441495	28060765	Interestingly, a third SNP (rs2853676) was associated with susceptibility to esophageal cancer after adjustment for age and gender.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('men', 'Species', '9606', (107, 110))	('rs2853676', 'Var', (28, 37))	('rs2853676', 'Mutation', 'rs2853676', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))
441496	28060765	Specifically, the "C/T-T/T" genotype increased the risk of esophageal cancer in the dominant model (OR = 1.44; 95% CI, 1.05 - 1.99, p = 0.026), and the "T" allele increased the risk in the log-additive model (OR = 1.36; 95% CI, 1.02 - 1.79, p = 0.034).	('esophageal cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('C/T-T', 'Disease', (19, 24))	('increased', 'PosReg', (37, 46))	('C/T-T', 'Disease', 'MESH:C537418', (19, 24))	('T" allele', 'Var', (153, 162))
441497	28060765	After the Bonferroni correction, mutations at rs10069690 (dominant p = 1.732E-04; additive p < 0.005) and rs2242652 (dominant p = 0.016; additive p = 0.024) were still associated with an increased risk of esophageal cancer.	('rs2242652', 'Var', (106, 115))	('associated', 'Reg', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('esophageal cancer', 'Disease', (205, 222))	('esophageal cancer', 'Disease', 'MESH:D004938', (205, 222))	('rs10069690', 'Mutation', 'rs10069690', (46, 56))	('rs2242652', 'Mutation', 'rs2242652', (106, 115))
441499	28060765	LD was determined pairwise among all four SNPs, the haplotype structure of the TERT gene was analyzed, and single LD blocks consisting of two SNPs (rs10069690 and 2242652) were detected (Figure 1).	('2242652', 'Var', (163, 170))	('TERT', 'Gene', (79, 83))	('TERT', 'Gene', '7015', (79, 83))	('rs10069690', 'Mutation', 'rs10069690', (148, 158))	('rs10069690', 'Var', (148, 158))
441500	28060765	Finally, a haplotype-based association study was performed to examine associations between TERT haplotype and risk of esophageal cancer (Table 4), and p-values were calculated using the Wald test.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('TERT', 'Gene', (91, 95))	('associations', 'Interaction', (70, 82))	('TERT', 'Gene', '7015', (91, 95))	('haplotype', 'Var', (96, 105))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))
441501	28060765	After adjusting for age and gender, the "TA" (95% CI, 1.91 - 2.12; p = 0.002) and "TG" (95% CI, 1.20 - 11.1; p = 0.022) haplotypes increased the risk of esophageal cancer 1.59-fold and 3.66-fold, respectively.	('TG', 'Chemical', '-', (83, 85))	('increased', 'PosReg', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('haplotypes', 'Var', (120, 130))	('esophageal cancer', 'Disease', (153, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
441504	28060765	We found that the rs10069690, rs2242652, and rs2853676 TERT genetic polymorphisms were associated with an increased risk of esophageal cancer in a northwestern Chinese patient population.	('esophageal cancer', 'Disease', (124, 141))	('rs10069690', 'Mutation', 'rs10069690', (18, 28))	('patient', 'Species', '9606', (168, 175))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('associated', 'Reg', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('TERT', 'Gene', (55, 59))	('rs2853676', 'Mutation', 'rs2853676', (45, 54))	('TERT', 'Gene', '7015', (55, 59))	('rs2853676', 'Var', (45, 54))	('rs10069690', 'Var', (18, 28))	('rs2242652', 'Mutation', 'rs2242652', (30, 39))	('rs2242652', 'Var', (30, 39))
441517	28060765	The TERT gene sequence in general is thought to be indicative of an individual's susceptibility to cancer, and epidemiological studies have identified associations between specific TERT polymorphisms and cancer development.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('associations', 'Interaction', (151, 163))	('TERT', 'Gene', (181, 185))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('TERT', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', (99, 105))	('TERT', 'Gene', '7015', (181, 185))	('TERT', 'Gene', '7015', (4, 8))	('polymorphisms', 'Var', (186, 199))	('men', 'Species', '9606', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
441518	28060765	Rs10069690 was originally discovered in a genome-wide association study of AAs, and we suspected that this SNP might also affect the risk of developing esophageal cancer.	('esophageal cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('affect', 'Reg', (122, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('Rs10069690', 'Mutation', 'Rs10069690', (0, 10))	('Rs10069690', 'Var', (0, 10))
441519	28060765	Another previous study found that the variant allele at TERT rs4246742 was inversely associated with breast cancer risk, while positive associations were found for rs10069690 (OR = 1.13), rs2242652 (OR = 1.51), and rs2853676 (OR 1.23).	('rs2242652', 'Mutation', 'rs2242652', (188, 197))	('rs2242652', 'Var', (188, 197))	('inversely', 'NegReg', (75, 84))	('rs2853676', 'Var', (215, 224))	('rs10069690', 'Mutation', 'rs10069690', (164, 174))	('rs2853676', 'Mutation', 'rs2853676', (215, 224))	('rs10069690', 'Var', (164, 174))	('rs4246742', 'Mutation', 'rs4246742', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('TERT', 'Gene', (56, 60))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('TERT', 'Gene', '7015', (56, 60))
441520	28060765	The rs2853676 polymorphism is also associated with an increased risk of glioma.	('glioma', 'Disease', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('rs2853676', 'Var', (4, 13))	('rs2853676', 'Mutation', 'rs2853676', (4, 13))
441521	28060765	The additive ORs of the rs2853676 and rs2242652 SNPs for the risk of melanoma were 1.43 and 1.50, respectively.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('rs2242652', 'Var', (38, 47))	('rs2242652', 'Mutation', 'rs2242652', (38, 47))	('rs2853676', 'Var', (24, 33))	('rs2853676', 'Mutation', 'rs2853676', (24, 33))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
441522	28060765	Certain rs10069690 and rs2242652 SNP alleles are also associated with increased risk of estrogen receptor-negative cancers.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('rs10069690', 'Mutation', 'rs10069690', (8, 18))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rs2242652', 'Mutation', 'rs2242652', (23, 32))	('rs2242652', 'Var', (23, 32))	('rs10069690', 'Var', (8, 18))
441523	28060765	Furthermore, recent studies have shown that rs2853677 is associated with the risk of lung adenocarcinoma in Japanese and European populations.	('rs2853677', 'Var', (44, 53))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('rs2853677', 'Mutation', 'rs2853677', (44, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lung adenocarcinoma', 'Disease', (85, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (85, 104))
441524	28060765	Here, we found that the rs10069690, rs2242652, and rs2853676 TERT genetic polymorphisms were associated with an increased risk of esophageal cancer in a northwestern Chinese patient population; subsequent studies should be conducted to examine these associations in patients from other regions and ethnic groups.	('patient', 'Species', '9606', (266, 273))	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('patients', 'Species', '9606', (266, 274))	('patient', 'Species', '9606', (174, 181))	('TERT', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('TERT', 'Gene', '7015', (61, 65))	('rs10069690', 'Mutation', 'rs10069690', (24, 34))	('rs10069690', 'Var', (24, 34))	('rs2242652', 'Mutation', 'rs2242652', (36, 45))	('esophageal cancer', 'Disease', (130, 147))	('rs2853676', 'Mutation', 'rs2853676', (51, 60))	('rs2242652', 'Var', (36, 45))
441525	28060765	We also identified an LD block consisting of the rs10069690 and 2242652 SNPs, both of which increased susceptibility to esophageal cancer.	('susceptibility', 'Reg', (102, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('increased', 'PosReg', (92, 101))	('rs10069690', 'Mutation', 'rs10069690', (49, 59))	('esophageal cancer', 'Disease', (120, 137))	('rs10069690', 'Var', (49, 59))	('2242652', 'Var', (64, 71))
441526	28060765	A previous study found that the rare Grs4246742Ars2736100Trs2853676 TERT haplotype was directly associated with telomere length.	('TERT', 'Gene', (68, 72))	('TERT', 'Gene', '7015', (68, 72))	('associated', 'Reg', (96, 106))	('Grs4246742Ars2736100Trs2853676', 'Chemical', '-', (37, 67))	('telomere', 'MPA', (112, 120))	('Grs4246742Ars2736100Trs2853676', 'Var', (37, 67))
441527	28060765	Future studies should evaluate the association between the rs4246742 andrs2736100 SNPs and susceptibility to esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs4246742', 'Var', (59, 68))	('andrs2736100', 'Var', (69, 81))	('esophageal cancer', 'Disease', (109, 126))	('rs4246742', 'Mutation', 'rs4246742', (59, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
441530	28060765	Additional studies are needed to clarify the genetic mechanisms underlying esophageal carcinogenesis by fine-mapping the susceptibility regions of the variants.	('esophageal carcinogenesis', 'Disease', (75, 100))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (75, 100))	('variants', 'Var', (151, 159))
441531	28060765	In conclusion, we demonstrated that the rs10069690, rs2242652, and rs2853676 genetic polymorphisms in the TERT loci are associated with an increased risk of esophageal cancer in a northwestern Chinese patient population.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('associated', 'Reg', (120, 130))	('rs2853676', 'Var', (67, 76))	('rs10069690', 'Mutation', 'rs10069690', (40, 50))	('rs10069690', 'Var', (40, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('TERT', 'Gene', (106, 110))	('rs2242652', 'Var', (52, 61))	('rs2242652', 'Mutation', 'rs2242652', (52, 61))	('TERT', 'Gene', '7015', (106, 110))	('rs2853676', 'Mutation', 'rs2853676', (67, 76))	('patient', 'Species', '9606', (201, 208))	('esophageal cancer', 'Disease', (157, 174))
441551	25793653	Heterogeneity in the structure or blood supply is a well-recognized feature of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (79, 89))	('Heterogeneity', 'Var', (0, 13))	('malignancy', 'Disease', (79, 89))
441622	25793653	In survival analysis, patients with low MPP showed better OS, and MPP was demonstrated to be an independent prognostic factor associated with OS.	('MPP', 'Gene', (40, 43))	('low', 'Var', (36, 39))	('patients', 'Species', '9606', (22, 30))	('better', 'PosReg', (51, 57))	('low MPP', 'Phenotype', 'HP:0003402', (36, 43))
441624	25793653	Therefore, we assume that high MPP tumor, which tends to show high MVD, may be associated with poor OS in STS.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('STS', 'Disease', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('STS', 'Phenotype', 'HP:0030448', (106, 109))	('high MPP', 'Var', (26, 34))
441650	26136410	In addition, serum Prostaglandin E2 (PGE2) levels were significantly decreased in the specific medical food group and increased in the control group (P = 0.002).	('specific medical food', 'Var', (86, 107))	('decreased', 'NegReg', (69, 78))	('increased', 'PosReg', (118, 127))	('Prostaglandin E2', 'Chemical', 'MESH:D015232', (19, 35))	('PGE2', 'Chemical', 'MESH:D015232', (37, 41))
441725	26136410	At baseline, no differences were observed between the Active and Control group, whereas patients in group >=5% WL had a significant worse performance status compared with patients in group 0-5% WL (P < 0.01, data not shown).	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (171, 179))	('WL', 'Phenotype', 'HP:0001824', (111, 113))	('WL', 'Phenotype', 'HP:0001824', (194, 196))	('>=5% WL', 'Var', (106, 113))	('worse', 'NegReg', (132, 137))	('performance status', 'MPA', (138, 156))
441748	26136410	However, the presence of high protein and leucine in the Active medical food may have contributed to the preservation of body weight.	('leucine', 'Chemical', 'MESH:D007930', (42, 49))	('high protein', 'Protein', (25, 37))	('leucine', 'Var', (42, 49))	('body weight', 'CPA', (121, 132))
441780	26136410	In the patient group, baseline CRP levels were significantly higher in group >=5% WL, compared with group 0-5% WL, indicating a more severe inflammatory state of the patients in group >=5% WL.	('WL', 'Phenotype', 'HP:0001824', (82, 84))	('>=5% WL', 'Var', (77, 84))	('patient', 'Species', '9606', (7, 14))	('higher', 'PosReg', (61, 67))	('WL', 'Phenotype', 'HP:0001824', (189, 191))	('WL', 'Phenotype', 'HP:0001824', (111, 113))	('CRP', 'Gene', (31, 34))	('patient', 'Species', '9606', (166, 173))	('patients', 'Species', '9606', (166, 174))	('CRP', 'Gene', '1401', (31, 34))
441799	25528766	gp130757FF xIL-1RT1-/- mice were generated to determine the pathological consequence of ablated IL-1 signaling in the IL-11 dependent gp130757FF mouse model of gastric tumorigenesis.	('gastric tumor', 'Disease', (160, 173))	('ablated', 'Var', (88, 95))	('IL-1', 'Gene', '111343', (96, 100))	('gastric tumor', 'Disease', 'MESH:D013274', (160, 173))	('gastric tumor', 'Phenotype', 'HP:0006753', (160, 173))	('gp130', 'Gene', (0, 5))	('IL-1RT1', 'Gene', '16177', (12, 19))	('gp130', 'Gene', (134, 139))	('IL-1', 'Gene', (118, 122))	('IL-1', 'Gene', '111343', (118, 122))	('gp130', 'Gene', '16195', (0, 5))	('IL-1', 'Gene', (12, 16))	('IL-1', 'Gene', (96, 100))	('IL-1RT1', 'Gene', (12, 19))	('gp130', 'Gene', '16195', (134, 139))	('mouse', 'Species', '10090', (145, 150))	('IL-1', 'Gene', '111343', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('mice', 'Species', '10090', (23, 27))
441814	25528766	Clinical studies have demonstrated a strong correlation between IL-1beta polymorphisms and predisposition to gastric cancer development.	('predisposition to gastric cancer', 'Phenotype', 'HP:0006753', (91, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('IL-1beta', 'Gene', (64, 72))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('polymorphisms', 'Var', (73, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))
441818	25528766	IL-1beta belongs to a large family of cytokines of which the best characterized are IL-1alpha, IL-1beta, IL-18 and IL-33.	('IL-33', 'Gene', '77125', (115, 120))	('IL-18', 'Gene', '16173', (105, 110))	('IL-1alpha', 'Gene', (84, 93))	('IL-18', 'Gene', (105, 110))	('IL-33', 'Gene', (115, 120))	('IL-1beta', 'Var', (95, 103))
441851	25528766	In gp130757FF CD45+/CD11b- cells IL-1alpha and IL-1beta were decreased by -2.0 +- 0.4 and -11.5 +- 1.6 respectively (Fig.	('decreased', 'NegReg', (61, 70))	('gp130', 'Gene', '16195', (3, 8))	('CD45+/CD11b-', 'Var', (14, 26))	('gp130', 'Gene', (3, 8))
441852	25528766	This increase was even greater in gp130757FF CD45+/CD11b+/Gr-1- cells (IL-1alpha: 147.3 +- 55.0 fold; IL-1beta: 11.6 +- 3.9 fold; Fig.	('CD45+/CD11b+/Gr-1-', 'Var', (45, 63))	('gp130', 'Gene', '16195', (34, 39))	('gp130', 'Gene', (34, 39))
441853	25528766	Once again this increase was more pronounced in gp130757FF CD45+/CD11b+/Gr-1+ cells (IL-1alpha: 41.1 +- 27.7 fold and IL-1beta: 25.8 +- 19.6 fold; Fig.	('gp130', 'Gene', (48, 53))	('gp130', 'Gene', '16195', (48, 53))	('CD45+/CD11b+/Gr-1+', 'Var', (59, 77))
441903	25528766	These data show that the loss of IL-1 signaling does not influence IL-11-mediated STAT3 activation.	('loss', 'Var', (25, 29))	('STAT3', 'Gene', '20848', (82, 87))	('IL-1', 'Gene', (33, 37))	('IL-1', 'Gene', '111343', (33, 37))	('IL-1', 'Gene', '111343', (67, 71))	('STAT3', 'Gene', (82, 87))	('IL-1', 'Gene', (67, 71))
441920	25528766	CD11b+/Gr-1INT MDSCs were enriched in wildtype mice treated with IL-11 (WT-control: 1.0 +- 0.04 fold; WT-IL11: 1.4 +- 0.13 fold) but this did not occur in the absence of IL-1 signaling (IL-1RT1-control: 1.03 +- 0.06; IL-1RT1-IL-11:1.05 +- 0.08; Fig.	('IL-1', 'Gene', '111343', (217, 221))	('IL-1', 'Gene', '111343', (65, 69))	('IL-1', 'Gene', (217, 221))	('IL-1RT1', 'Gene', '16177', (186, 193))	('IL-1RT1', 'Gene', (186, 193))	('IL-1', 'Gene', (65, 69))	('CD11b+/Gr-1INT', 'Var', (0, 14))	('IL-1', 'Gene', (170, 174))	('IL-1', 'Gene', '111343', (186, 190))	('IL-1', 'Gene', '111343', (170, 174))	('IL-1', 'Gene', (225, 229))	('IL-1', 'Gene', (186, 190))	('IL-1', 'Gene', '111343', (225, 229))	('IL-1RT1', 'Gene', (217, 224))	('IL-1RT1', 'Gene', '16177', (217, 224))	('mice', 'Species', '10090', (47, 51))
441967	25528766	Supporting evidence comes from individuals carrying polymorphisms in the IL-1alpha, IL-1beta and IL-1RN gene cluster that lead to elevated expression of IL-1 cytokines, and who are actually protected from gastro-eosphageal reflux disease and Barrett's esophagitis, suggesting that a delicate balance is at play, with expression of IL-1 cytokines in the proximal stomach and esophagus under some circumstances leading to pathology, and in others being protective.	('IL-1', 'Gene', '111343', (73, 77))	('IL-1', 'Gene', '111343', (97, 101))	('IL-1', 'Gene', '111343', (153, 157))	('IL-1', 'Gene', (331, 335))	('gastro-eosphageal reflux disease', 'Disease', 'MESH:D005764', (205, 237))	('elevated', 'PosReg', (130, 138))	('IL-1', 'Gene', (84, 88))	('gastro-eosphageal reflux disease', 'Disease', (205, 237))	('reflux disease', 'Phenotype', 'HP:0002020', (223, 237))	('IL-1RN', 'Gene', (97, 103))	("Barrett's esophagitis", 'Disease', (242, 263))	('IL-1', 'Gene', '111343', (331, 335))	('leading to', 'Reg', (409, 419))	('IL-1', 'Gene', '111343', (84, 88))	('esophagitis', 'Phenotype', 'HP:0100633', (252, 263))	("Barrett's esophagitis", 'Phenotype', 'HP:0100580', (242, 263))	('IL-1', 'Gene', (73, 77))	('IL-1', 'Gene', (97, 101))	('polymorphisms', 'Var', (52, 65))	('IL-1', 'Gene', (153, 157))	("Barrett's esophagitis", 'Disease', 'MESH:D001471', (242, 263))	('expression', 'MPA', (139, 149))	('IL-1RN', 'Gene', '16181', (97, 103))
441973	25528766	In mice, the loss of IL-1alpha, but not IL-1beta, results in decreased survival rates in response to lethal endotoxemia, and impaired immune function during infection.	('infection', 'Disease', (157, 166))	('IL-1alpha', 'Gene', (21, 30))	('infection', 'Disease', 'MESH:D007239', (157, 166))	('impaired', 'NegReg', (125, 133))	('impaired immune function', 'Phenotype', 'HP:0002721', (125, 149))	('endotoxemia', 'Disease', 'MESH:D019446', (108, 119))	('mice', 'Species', '10090', (3, 7))	('survival rates', 'CPA', (71, 85))	('endotoxemia', 'Disease', (108, 119))	('immune function', 'CPA', (134, 149))	('decreased', 'NegReg', (61, 70))	('loss', 'Var', (13, 17))
441975	25528766	We suggest that in our model the absence of patent IL-1alpha alarmin function in the stomach due to IL-1RT1 deletion results in inappropriate activation of cellular infiltrate, ultimately resulting in chronic damage, and enhanced tumorigenesis.	('tumor', 'Disease', (230, 235))	('resulting in', 'Reg', (188, 200))	('activation', 'PosReg', (142, 152))	('damage', 'MPA', (209, 215))	('cellular infiltrate', 'MPA', (156, 175))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('enhanced', 'PosReg', (221, 229))	('IL-1RT1', 'Gene', '16177', (100, 107))	('IL-1RT1', 'Gene', (100, 107))	('deletion', 'Var', (108, 116))
441979	25528766	In the gastrointestinal tract, MDSC-induced tumor immune tolerance has been demonstrated to promote gastric and esophageal cancers, suggesting that enrichment of MDSCs directly correlates to gastric and esophageal disease outcomes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('esophageal cancers', 'Disease', 'MESH:D004938', (112, 130))	('promote', 'PosReg', (92, 99))	('MDSC-induced', 'Var', (31, 43))	('esophageal disease', 'Disease', 'MESH:D004935', (203, 221))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('gastrointestinal tract', 'Disease', (7, 29))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (7, 29))	('gastric and esophageal cancer', 'Disease', 'MESH:D013274', (100, 129))	('tumor', 'Disease', (44, 49))	('esophageal cancers', 'Disease', (112, 130))	('esophageal disease', 'Disease', (203, 221))
441981	25528766	Furthermore, IL-6 signaling, a potent STAT3 inducer, is required for IL-1beta-induced gastric and esophageal pathology, indicating that STAT3 signaling is necessary for MDSC expansion and explains how both overexpression and ablated IL-1 signaling can induce cardiac pathology through STAT3 dependent MDSC enrichment.	('IL-1', 'Gene', (233, 237))	('IL-1', 'Gene', (69, 73))	('STAT3', 'Gene', '20848', (285, 290))	('IL-1', 'Gene', '111343', (233, 237))	('IL-1', 'Gene', '111343', (69, 73))	('STAT3', 'Gene', (285, 290))	('cardia', 'Disease', 'MESH:D004938', (259, 265))	('cardia', 'Disease', (259, 265))	('ablated', 'Var', (225, 232))	('IL-6', 'Gene', (13, 17))	('IL-6', 'Gene', '16193', (13, 17))	('STAT3', 'Gene', '20848', (136, 141))	('induce', 'Reg', (252, 258))	('STAT3', 'Gene', '20848', (38, 43))	('STAT3', 'Gene', (136, 141))	('STAT3', 'Gene', (38, 43))
441983	25528766	One mechanism by which MDSCs may promote tumor growth is through expression of arginase-1, which in turn diminishes T cell mediated anti-tumor responses.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('promote', 'PosReg', (33, 40))	('tumor', 'Disease', (137, 142))	('diminishes T cell', 'Phenotype', 'HP:0005403', (105, 122))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('arginase-1', 'Gene', (79, 89))	('arginase-1', 'Gene', '11846', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('MDSCs', 'Var', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('diminishes', 'NegReg', (105, 115))	('expression', 'Reg', (65, 75))
441986	25528766	Here we have demonstrated that IL-1RT1-/- signaling is not required for IL-11/STAT3 mediated pathology, with genetic depletion of IL-1RT1-/- resulting in a more severe tumor phenotype by promoting an anti-inflammatory, pro-tumorigenic environment.	('anti-inflammatory', 'MPA', (200, 217))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('IL-1RT1', 'Gene', (130, 137))	('tumor', 'Disease', (168, 173))	('IL-1RT1', 'Gene', '16177', (130, 137))	('STAT3', 'Gene', '20848', (78, 83))	('resulting in', 'Reg', (141, 153))	('promoting', 'PosReg', (187, 196))	('STAT3', 'Gene', (78, 83))	('IL-1RT1', 'Gene', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('IL-1RT1', 'Gene', '16177', (31, 38))	('genetic depletion', 'Var', (109, 126))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
442091	23101992	Diminishing the PAH content of mate could also reduce other adverse effects of PAH exposure, including its effects on cardiovascular diseases .	('PAH', 'Chemical', 'MESH:D011084', (79, 82))	('reduce', 'NegReg', (47, 53))	('Diminishing', 'Var', (0, 11))	('PAH', 'Chemical', 'MESH:D011084', (16, 19))	('cardiovascular diseases', 'Disease', (118, 141))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (118, 141))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (118, 141))
442107	21822428	Severe esophageal lesions were significantly more common in BRI (+) patients (14/25) compared to BRI (-) ones (P = 0.0049).	('BRI (+', 'Var', (60, 66))	('esophageal lesions', 'Disease', (7, 25))	('esophageal lesions', 'Disease', 'MESH:D004935', (7, 25))
442132	21822428	The aim was to investigate possible associations existing between GERD/DGER and the early stages of carcinogenesis.	('carcinogenesis', 'Disease', (100, 114))	('carcinogenesis', 'Disease', 'MESH:D063646', (100, 114))	('GERD/DGER', 'Var', (66, 75))
442149	19523197	PMNs strongly amplifies C. albicans-mediated induction of hBDs.	('hBD', 'Gene', (58, 61))	('PMNs', 'Var', (0, 4))	('C. albicans', 'Species', '5476', (24, 35))	('hBD', 'Gene', '100187828', (58, 61))
442176	19523197	OE21, KYSE70, KYSE7150, KYSE7180, KYSE410 and Colo680N) with established inducers of hBD-expression.	('KYSE7150', 'Var', (14, 22))	('hBD', 'Gene', '100187828', (85, 88))	('Colo680N', 'Var', (46, 54))	('hBD', 'Gene', (85, 88))	('KYSE70', 'Var', (6, 12))	('KYSE410', 'Var', (34, 41))	('KYSE7180', 'Var', (24, 32))
442228	19523197	Inhibiton of the NF-kappaB or of the MAPK/AP-1 pathway significantly reduced the induction of hBD-2 expression confirming the central role of both transcription factors.	('reduced', 'NegReg', (69, 76))	('induction', 'MPA', (81, 90))	('Inhibiton', 'Var', (0, 9))	('NF-kappaB', 'Gene', '4790', (17, 26))	('expression', 'MPA', (100, 110))	('hBD-2', 'Gene', (94, 99))	('NF-kappaB', 'Gene', (17, 26))	('AP-1', 'Gene', '3725', (42, 46))	('AP-1', 'Gene', (42, 46))	('hBD-2', 'Gene', '1673', (94, 99))
442236	19523197	Inhibition of the MAPK/AP-1 pathway reduced the expression of both hBDs under this condition.	('hBD', 'Gene', (67, 70))	('AP-1', 'Gene', (23, 27))	('AP-1', 'Gene', '3725', (23, 27))	('expression', 'MPA', (48, 58))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (36, 43))	('hBD', 'Gene', '100187828', (67, 70))
442243	19523197	Finally we demonstrated that hBD-3 expression was induced by transactivation of the EGFR independent of EGF (Figure 8 and 9).	('EGF', 'Gene', '1950', (104, 107))	('induced', 'Reg', (50, 57))	('hBD-3', 'Gene', '55894', (29, 34))	('EGF', 'Gene', (84, 87))	('EGF', 'Gene', '1950', (84, 87))	('expression', 'MPA', (35, 45))	('EGFR', 'Gene', '1956', (84, 88))	('EGF', 'Gene', (104, 107))	('hBD-3', 'Gene', (29, 34))	('EGFR', 'Gene', (84, 88))	('transactivation', 'Var', (61, 76))
442248	19523197	ADAM10, -12 and -17 are the sheddases of the EGFR ligands in response to various stimuli.	('ADAM10', 'Var', (0, 6))	('EGFR', 'Gene', '1956', (45, 49))	('EGFR', 'Gene', (45, 49))
442261	19523197	Inhibitors utilized were: PD98059 (Calbiochem) at 10 muM, SB203580 (Tocris, Ellusville, USA) at 10 muM, SP600125 (Tocris, Ellusville, USA) at 20 muM.	('muM', 'Gene', (99, 102))	('PD98059', 'Chemical', 'MESH:C093973', (26, 33))	('muM', 'Gene', (53, 56))	('muM', 'Gene', '56925', (145, 148))	('SB203580', 'Var', (58, 66))	('muM', 'Gene', (145, 148))	('SB203580', 'Chemical', 'MESH:C093642', (58, 66))	('muM', 'Gene', '56925', (99, 102))	('SP600125', 'Chemical', 'MESH:C432165', (104, 112))	('PD98059', 'Var', (26, 33))	('muM', 'Gene', '56925', (53, 56))	('SP600125', 'Var', (104, 112))
442318	33566182	In this case, high PEEP to release the lung from atelectasis might aggravate the hypotension by raising intrathoracic pressure.	('aggravate the hypotension', 'Phenotype', 'HP:0001278', (67, 92))	('hypotension', 'Disease', 'MESH:D007022', (81, 92))	('PEEP', 'Phenotype', 'HP:0012497', (19, 23))	('intrathoracic pressure', 'MPA', (104, 126))	('atelectasis', 'Phenotype', 'HP:0100750', (49, 60))	('raising', 'PosReg', (96, 103))	('hypotension', 'Disease', (81, 92))	('raising intrathoracic pressure', 'Phenotype', 'HP:0002516', (96, 126))	('hypotension', 'Phenotype', 'HP:0002615', (81, 92))	('high PEEP', 'Var', (14, 23))	('aggravate', 'PosReg', (67, 76))
442362	32039007	Clinical studies have demonstrated that a high number of M2 TAMs in tumor cause chemoresistance and radioprotective effects, leading to therapy failure and poor prognosis in patients.	('tumor', 'Disease', (68, 73))	('chemoresistance', 'CPA', (80, 95))	('Clinical', 'Species', '191496', (0, 8))	('failure', 'Disease', (144, 151))	('radioprotective effects', 'CPA', (100, 123))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('M2 TAMs', 'Var', (57, 64))	('failure', 'Disease', 'MESH:D017093', (144, 151))
442367	32039007	In order to resolve these disputes, researches have shown that polarization of TAMs in cancer, more specifically the M1/M2 ratio, is a more biologically relevant indicator to prognose cancer as compared to whole TAM densities.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('M1/M2', 'MPA', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('polarization', 'Var', (63, 75))
442370	32039007	demonstrated that in locally advanced cervical cancers (LACC), a more frequent complete pathological response to chemotherapy (CT) or radiotherapy (RT) was observed in patients with high M1/M2 ratio.	('high M1/M2 ratio', 'Var', (182, 198))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Disease', (47, 54))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
442374	32039007	Among these patients, those with high M1/M2 ratio exhibited a longer 5-years-disease-free (67.2 vs. 44.3%; P = 0.019) and 5 years overall survival (OS) compared to cases with low M1/M2 ratio (69.3 vs. 46.9%, P = 0.037).	('patients', 'Species', '9606', (12, 20))	('overall survival', 'CPA', (130, 146))	('longer', 'PosReg', (62, 68))	('high M1/M2 ratio', 'Var', (33, 49))
442394	32039007	For example, in breast cancer studies, infiltration of M2 TAMs in tumor stroma instead of tumor nests was associated with larger tumor size, higher histological grade, higher 5-year recurrence, and 5-year breast cancer mortality, in addition to being an independent predictor of recurrence-free survival (RFS) and OS.	('higher', 'PosReg', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('tumor', 'Disease', (129, 134))	('breast cancer', 'Disease', (205, 218))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('histological grade', 'CPA', (148, 166))	('breast cancer', 'Disease', (16, 29))	('infiltration', 'Var', (39, 51))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (90, 95))	('tumor stroma', 'Disease', (66, 78))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor stroma', 'Disease', 'MESH:D009369', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('higher', 'PosReg', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
442395	32039007	Similarly, in esophageal carcinoma, infiltration of M2 TAMs in tumor stroma was strongly associated with more malignant characteristics such as metastasis and clinical stage progression.	('associated', 'Reg', (89, 99))	('clinical', 'Species', '191496', (159, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('tumor stroma', 'Disease', 'MESH:D009369', (63, 75))	('esophageal carcinoma', 'Disease', (14, 34))	('tumor stroma', 'Disease', (63, 75))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (14, 34))	('clinical stage progression', 'CPA', (159, 185))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (14, 34))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('metastasis', 'Disease', 'MESH:D009362', (144, 154))	('metastasis', 'Disease', (144, 154))	('M2 TAMs', 'Protein', (52, 59))	('infiltration', 'Var', (36, 48))
442405	32039007	The ImmunoRatio software for example, segments immunostained and hematoxylin-stained cellular areas from the user-submitted image and calculates the labeling index for ER, PR, and Ki-67 in breast cancer.	('PR', 'Gene', '5241', (172, 174))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ER', 'Gene', '2099', (168, 170))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('Ki-67', 'Var', (180, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('breast cancer', 'Disease', (189, 202))	('hematoxylin', 'Chemical', 'MESH:D006416', (65, 76))
442532	31624722	This is also comparable with a study done on the influence on survival of delay in the presentation and treatment of symptomatic breast cancer, where 32% of patients had symptoms for 12 or more weeks before their first hospital visit and 32% of patients with delays of 12 or more weeks had locally advanced or metastatic disease, compared with only 10% of those with delays of less than 12 weeks (P < 0.0001).	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('patients', 'Species', '9606', (245, 253))	('locally advanced or metastatic disease', 'CPA', (290, 328))	('patients', 'Species', '9606', (157, 165))	('men', 'Species', '9606', (109, 112))	('delays', 'Var', (259, 265))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
442621	30675281	The transfection of STAT3 decoy ODN can significantly inhibit the activity of esophageal squamous cell carcinoma cells and enhance apoptosis of cells, which has potential clinical value.	('STAT3 decoy', 'Var', (20, 31))	('enhance', 'PosReg', (123, 130))	('esophageal squamous cell carcinoma', 'Disease', (78, 112))	('inhibit', 'NegReg', (54, 61))	('activity', 'MPA', (66, 74))	('transfection', 'Var', (4, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (78, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('apoptosis of cells', 'CPA', (131, 149))
442648	30675281	Then, 2-4 microg of STAT3 decoy ODN/mutant ODN (100 pmol) and 5 microl of Lipofectamine were respectively dissolved in serum-free and antibiotic-free medium, and mixed were thoroughly.	('ODN/mutant', 'Var', (32, 42))	('Lipofectamine', 'Chemical', 'MESH:C086724', (74, 87))	('ODN', 'Gene', (43, 46))
442708	30675281	From the results of the immunofluorescence detection, liposomes, ultrasound microbubbles and ultrasound microbubbles combined with ultrasound irradiation can successfully transfect ODNs into cancer cells, indicating that liposomes and ultrasound microbubbles are all effective transfer tools.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('transfect', 'Var', (171, 180))
442709	30675281	The flow cytometry and MTT assay analysis results revealed that the three groups of cancer cells successfully transfected with STAT3 decoy ODN had an increased rate of apoptosis at the early stages, and cell proliferation activity gradually decreased, suggesting that the antisense transfection was successful and STAT3 decoy ODN was active.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('MTT', 'Chemical', 'MESH:C070243', (23, 26))	('cancer', 'Disease', (84, 90))	('decreased', 'NegReg', (241, 250))	('apoptosis', 'CPA', (168, 177))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cell proliferation activity', 'CPA', (203, 230))	('STAT3 decoy ODN', 'Var', (127, 142))
442713	30675281	The present study found that the expression levels of STAT3 and p-STAT3 protein in cancer cells transfected with STAT3 decoy ODN significantly decreased.	('decreased', 'NegReg', (143, 152))	('p-STAT3', 'Var', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('expression levels', 'MPA', (33, 50))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
442715	30675281	Therefore, STAT3 decoy ODN has an inhibitory effect on esophageal squamous carcinoma cells grown in vitro.	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (55, 84))	('inhibitory', 'NegReg', (34, 44))	('esophageal squamous carcinoma', 'Disease', (55, 84))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (55, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (66, 84))	('STAT3 decoy', 'Var', (11, 22))
442716	30675281	A study conducted by Liu et al demonstrated that antisense ODN STAT3 can inhibit tumor cell activity, but does not have any adverse effects on normal cells.	('antisense', 'Var', (49, 58))	('ODN STAT3', 'Gene', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('inhibit', 'NegReg', (73, 80))
442741	29802647	Histological subtypes of esophageal cancer were classified as follows: squamous cell carcinoma (International Classification of Diseases for Oncology third edition morphological codes 8050-8078, 8083-8084), adenocarcinoma (8140-8141, 8143-8145, 8190-8231, 8260-8263, 8310, 8401, 8480-8490, 8550-8551, 8570-8574, 8576), other specified (unspecified carcinoma: 8010-8035; sarcoma: 8800-8811, 8830, 8840-8921, 8990-8991, 9040-9044, 9120-9133, 9150, 9540-9581), and unspecified (8000-8005).	('carcinoma', 'Disease', 'MESH:D002277', (348, 357))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('8990-8991', 'Var', (407, 416))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (207, 221))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('9040-9044', 'Var', (418, 427))	('sarcoma', 'Disease', 'MESH:D012509', (370, 377))	('8480-8490', 'Var', (279, 288))	('8010-8035', 'Var', (359, 368))	('unspecified', 'Species', '32644', (462, 473))	('carcinoma', 'Disease', (212, 221))	('sarcoma', 'Disease', (370, 377))	('Oncology', 'Phenotype', 'HP:0002664', (141, 149))	('9150', 'Var', (440, 444))	('unspecified', 'Species', '32644', (336, 347))	('8840-8921', 'Var', (396, 405))	('carcinoma', 'Phenotype', 'HP:0030731', (348, 357))	('esophageal cancer', 'Disease', 'MESH:D004938', (25, 42))	('carcinoma', 'Disease', (348, 357))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('squamous cell carcinoma', 'Disease', (71, 94))	('carcinoma', 'Disease', (85, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (370, 377))	('esophageal cancer', 'Disease', (25, 42))	('carcinoma', 'Disease', 'MESH:D002277', (212, 221))	('8140-8141', 'Var', (223, 232))	('9540-9581', 'Var', (446, 455))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('adenocarcinoma', 'Disease', (207, 221))	('9120-9133', 'Var', (429, 438))
442811	28070182	However, many patients with HGD or IMC have nodularity in their BE segment and EMR is commonly performed to remove these nodular areas before treatment with RFA.	('IMC', 'Disease', (35, 38))	('nodularity', 'Var', (44, 54))	('BE', 'Phenotype', 'HP:0100580', (64, 66))	('HGD', 'Disease', (28, 31))	('patients', 'Species', '9606', (14, 22))
442838	28070182	Two RCTs of RFA versus only endoscopic surveillance in BE showed that RFA had a high rate of complete eradication of dysplasia and IM and decreased disease progression compared with the control group.	('BE', 'Phenotype', 'HP:0100580', (55, 57))	('eradication of dysplasia', 'Disease', 'MESH:D004476', (102, 126))	('RFA', 'Var', (70, 73))	('decreased', 'NegReg', (138, 147))	('eradication of dysplasia', 'Disease', (102, 126))	('disease progression', 'CPA', (148, 167))
442839	28070182	In the AIM Dysplasia Trial, 127 patients with dysplastic BE in a 2 : 1 ratio were randomized to receive either RFA (84 patients) or a sham procedure (43 patients).	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (119, 127))	('RFA', 'Var', (111, 114))	('AIM Dysplasia Trial', 'Disease', 'MESH:D004476', (7, 26))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('AIM Dysplasia Trial', 'Disease', (7, 26))	('dysplastic', 'Disease', (46, 56))	('dysplastic', 'Disease', 'MESH:D004416', (46, 56))
442840	28070182	Among all patients, regardless of the grade of dysplasia, complete eradication of all intestinal metaplasia occurred in 77.4% of the patients assigned to the RFA group, as compared with 2.3% of those assigned to the control group (P < 0.001).	('intestinal metaplasia', 'Disease', (86, 107))	('patients', 'Species', '9606', (133, 141))	('dysplasia', 'Disease', (47, 56))	('eradication', 'NegReg', (67, 78))	('dysplasia', 'Disease', 'MESH:D004476', (47, 56))	('patients', 'Species', '9606', (10, 18))	('RFA', 'Var', (158, 161))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (86, 107))
442844	28070182	Among patients in the RFA group, complete eradication occurred in 92.6% cases of dysplasia and 88.2% of intestinal metaplasia, compared to 27.9% for dysplasia and 0% for intestinal metaplasia among patients in the control group (P < 0.001).	('dysplasia', 'Disease', (149, 158))	('patients', 'Species', '9606', (198, 206))	('RFA', 'Var', (22, 25))	('dysplasia', 'Disease', 'MESH:D004476', (149, 158))	('intestinal metaplasia', 'Disease', (104, 125))	('intestinal metaplasia', 'Disease', (170, 191))	('patients', 'Species', '9606', (6, 14))	('dysplasia', 'Disease', (81, 90))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (170, 191))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (104, 125))	('dysplasia', 'Disease', 'MESH:D004476', (81, 90))
442846	28070182	Indeed, this study underwent early termination due to superiority of ablation compared to surveillance, since patients in the ablation group were less likely than the control group to progress to high-grade dysplasia or adenocarcinoma.	('dysplasia or adenocarcinoma', 'Disease', (207, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('ablation', 'Var', (126, 134))	('dysplasia or adenocarcinoma', 'Disease', 'MESH:D000230', (207, 234))	('patients', 'Species', '9606', (110, 118))
442847	28070182	A retrospective study compared 65 BE patients with HGD or IMC treated with EMR and RFA for nodular disease and 104 patients treated with RFA alone for BE with nonnodular disease; EMR and RFA achieved CE-D and CE-IM in 94% and 88% of patients, respectively, compared with 82.7% and 77.6% of patients, respectively, in the RFA alone group (P = 0.06 and P = 0.13, resp.).	('patients', 'Species', '9606', (115, 123))	('CE-IM', 'Chemical', '-', (209, 214))	('nodular disease', 'Disease', (162, 177))	('CE-D', 'Chemical', '-', (200, 204))	('nodular disease', 'Disease', (91, 106))	('RFA', 'Var', (187, 190))	('patients', 'Species', '9606', (290, 298))	('patients', 'Species', '9606', (37, 45))	('BE', 'Phenotype', 'HP:0100580', (34, 36))	('patients', 'Species', '9606', (233, 241))	('EMR', 'Var', (179, 182))	('CE-D', 'MPA', (200, 204))	('nodular disease', 'Disease', 'MESH:D020518', (162, 177))	('BE', 'Phenotype', 'HP:0100580', (151, 153))	('nodular disease', 'Disease', 'MESH:D020518', (91, 106))
442850	28070182	Complete eradication of dysplasia was achieved in 18/33 patients (54.5%) with PDT and in 47/53 patients (88.7%) with RFA (P = 0.001).	('eradication of dysplasia', 'Disease', (9, 33))	('patients', 'Species', '9606', (56, 64))	('PDT', 'Var', (78, 81))	('patients', 'Species', '9606', (95, 103))	('eradication of dysplasia', 'Disease', 'MESH:D004476', (9, 33))
442888	26509124	Woo and Nacke reported that robotic surgery patients had a significant reduction in blood transfusions and length of stay compared to sternotomy patients.	('patients', 'Species', '9606', (145, 153))	('patients', 'Species', '9606', (44, 52))	('reduction', 'NegReg', (71, 80))	('robotic surgery', 'Var', (28, 43))	('length of stay', 'CPA', (107, 121))	('blood transfusions', 'MPA', (84, 102))
442970	26516633	Because SOX15 depletion retarded CP-A cell growth and survival, we harvested cells 72 hours after infection, when they appeared healthy but the SOX15 mRNA levels were appreciably reduced (Figure 3B).	('SOX15 mRNA levels', 'MPA', (144, 161))	('depletion', 'Var', (14, 23))	('retarded CP-A', 'Disease', 'MESH:C566991', (24, 37))	('retarded CP-A', 'Disease', (24, 37))	('reduced', 'NegReg', (179, 186))	('survival', 'CPA', (54, 62))
442981	26516633	Indeed, the effects of SOX15 depletion were statistically significantly greater on these genes than on random sets of genes expressed in CP-A cells (P < .017; Figure 5C, bottom).	('depletion', 'Var', (29, 38))	('CP-A', 'Gene', (137, 141))	('greater', 'PosReg', (72, 79))	('SOX15', 'Gene', (23, 28))	('CP-A', 'Gene', '1357', (137, 141))
442993	26516633	The lack of overt esophageal defects in Sox15 mutant mice is compatible with the considerable known redundancies among SOX-family TFs.	('SOX', 'Gene', '104009', (119, 122))	('esophageal defects', 'Disease', 'MESH:D004941', (18, 36))	('esophageal defects', 'Disease', (18, 36))	('mutant', 'Var', (46, 52))	('SOX', 'Gene', (119, 122))	('Sox15', 'Gene', (40, 45))	('Sox15', 'Gene', '20670', (40, 45))	('mice', 'Species', '10090', (53, 57))
442999	25910248	However, splenectomy remained controversial for hypersplenism in WD as it was reported that splenectomy leaded to serious emotional and neurological deterioration in WD patients with hypersplenism.	('neurological deterioration', 'Disease', (136, 162))	('splenectomy', 'Var', (92, 103))	('leaded to', 'Reg', (104, 113))	('WD', 'Disease', 'MESH:D006527', (166, 168))	('patients', 'Species', '9606', (169, 177))	('hypersplenism', 'Disease', 'MESH:D006971', (48, 61))	('neurological deterioration', 'Phenotype', 'HP:0002344', (136, 162))	('hypersplenism', 'Disease', (48, 61))	('hypersplenism', 'Disease', 'MESH:D006971', (183, 196))	('neurological deterioration', 'Disease', 'MESH:D019636', (136, 162))	('hypersplenism', 'Phenotype', 'HP:0001971', (48, 61))	('WD', 'Disease', 'MESH:D006527', (65, 67))	('hypersplenism', 'Disease', (183, 196))	('hypersplenism', 'Phenotype', 'HP:0001971', (183, 196))
443014	25910248	Furthermore, some anti-copper drugs, such as penicillamine, trientine and tetrathiomolybdate can occasionally cause bone marrow depression, anemia, leucopenia, immunological lesions, and even paradoxical symptom worsening.	('bone marrow depression', 'Disease', (116, 138))	('tetrathiomolybdate', 'Chemical', 'MESH:C020809', (74, 92))	('leucopenia', 'Disease', (148, 158))	('penicillamine', 'Chemical', 'MESH:D010396', (45, 58))	('depression', 'Phenotype', 'HP:0000716', (128, 138))	('anemia', 'Disease', (140, 146))	('immunological lesions', 'Disease', (160, 181))	('leucopenia', 'Disease', 'MESH:C536227', (148, 158))	('trientine', 'Chemical', 'MESH:D014266', (60, 69))	('anti-copper', 'Var', (18, 29))	('tetrathiomolybdate', 'Var', (74, 92))	('anemia', 'Disease', 'MESH:D000740', (140, 146))	('immunological lesions', 'Disease', 'MESH:D007154', (160, 181))	('cause', 'Reg', (110, 115))	('bone marrow depression', 'Disease', 'MESH:D001855', (116, 138))	('copper', 'Chemical', 'MESH:D003300', (23, 29))	('bone marrow depression', 'Phenotype', 'HP:0005528', (116, 138))	('anemia', 'Phenotype', 'HP:0001903', (140, 146))
443019	25910248	However, it was reported that splenectomy for the treatment of hypersplenism leaded to serious emotional and neurological deterioration in WD patients.	('splenectomy', 'Var', (30, 41))	('neurological deterioration', 'Phenotype', 'HP:0002344', (109, 135))	('hypersplenism', 'Disease', 'MESH:D006971', (63, 76))	('leaded to', 'Reg', (77, 86))	('hypersplenism', 'Disease', (63, 76))	('hypersplenism', 'Phenotype', 'HP:0001971', (63, 76))	('neurological deterioration', 'Disease', 'MESH:D019636', (109, 135))	('WD', 'Disease', 'MESH:D006527', (139, 141))	('patients', 'Species', '9606', (142, 150))	('neurological deterioration', 'Disease', (109, 135))
443091	25910248	Studies in patients with hepatitis C virus-related liver cirrhosis and in animals with liver cirrhosis showed that splenectomy can attenuate liver fibrosis and inflammatory responses.	('liver fibrosis', 'Disease', 'MESH:D008103', (141, 155))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (51, 66))	('cirrhosis', 'Phenotype', 'HP:0001394', (57, 66))	('hepatitis', 'Phenotype', 'HP:0012115', (25, 34))	('liver cirrhosis', 'Disease', 'MESH:D008103', (51, 66))	('liver fibrosis', 'Phenotype', 'HP:0001395', (141, 155))	('hepatitis C virus', 'Species', '11103', (25, 42))	('liver cirrhosis', 'Disease', 'MESH:D008103', (87, 102))	('cirrhosis', 'Phenotype', 'HP:0001394', (93, 102))	('attenuate', 'NegReg', (131, 140))	('liver cirrhosis', 'Disease', (51, 66))	('inflammatory responses', 'CPA', (160, 182))	('splenectomy', 'Var', (115, 126))	('liver fibrosis', 'Disease', (141, 155))	('patients', 'Species', '9606', (11, 19))	('liver cirrhosis', 'Disease', (87, 102))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (87, 102))
443114	25910248	In combination with our long previous experiences, the indications for splenectomy were in those patients with the following conditions: moderate to severe degree of splenomegaly; no or a small amount of ascites; both leukocyte and platelet or single decreasing, especially platelet count below 60x109 /L and leukocyte count below 3.0x109 /L; recurrence of digestive bleeding; liver function of Child-Pugh A and B.	('ascites', 'Disease', 'MESH:D001201', (204, 211))	('splenomegaly', 'Disease', (166, 178))	('ascites', 'Phenotype', 'HP:0001541', (204, 211))	('recurrence of digestive bleeding', 'Phenotype', 'HP:0004798', (343, 375))	('Child', 'Species', '9606', (395, 400))	('splenomegaly', 'Disease', 'MESH:D013163', (166, 178))	('liver', 'Disease', (377, 382))	('bleeding', 'Disease', 'MESH:D006470', (367, 375))	('bleeding', 'Disease', (367, 375))	('digestive bleeding', 'Phenotype', 'HP:0002239', (357, 375))	('splenomegaly', 'Phenotype', 'HP:0001744', (166, 178))	('below 60x109', 'Var', (289, 301))	('ascites', 'Disease', (204, 211))	('patients', 'Species', '9606', (97, 105))
443119	25910248	Devascularization but not a shunt was an ideal management for this condition, as a shunt may enable the copper in systemic circulation directly to the central nervous system, which may lead to emotional and neurological deterioration.	('shunt', 'Var', (83, 88))	('copper', 'Chemical', 'MESH:D003300', (104, 110))	('neurological deterioration', 'Disease', 'MESH:D019636', (207, 233))	('lead to', 'Reg', (185, 192))	('neurological deterioration', 'Disease', (207, 233))	('neurological deterioration', 'Phenotype', 'HP:0002344', (207, 233))
443153	31809876	Inclusion criteria were histologically/cytologically confirmed stage IIA-IIIB NSCLC, World Health Organization performance status (PS) 0 or 1, suitability for CRT agreed by multidisciplinary team, no prior anticancer therapy, forced expiratory volume >=1 L or 40% of predicted, carbon monoxide diffusing capacity >=40% predicted, biochemistry and hematology baselines suitable for chemotherapy, and glomerular filtration rate >=60 mL/min.	('>=40', 'Var', (313, 317))	('carbon monoxide', 'Chemical', 'MESH:D002248', (278, 293))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('>=1', 'Var', (251, 254))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('carbon monoxide diffusing capacity', 'MPA', (278, 312))	('forced expiratory', 'MPA', (226, 243))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
443201	31809876	In univariable analyses, OS was significantly associated with treatment schedule and CTV/ITV V95%, the fractional volume of CTV (for 3D-CT imaged patients) or ITV (4D-CT) receiving >=95% of the prescribed dose level (HR, 0.88; 95% CI, 0.77-1.00; P = .05).	('V95%', 'Var', (93, 97))	('OS', 'Chemical', '-', (25, 27))	('patients', 'Species', '9606', (146, 154))	('CTV/ITV', 'Gene', (85, 92))
443232	31809876	CTV/ITV V95% was significantly associated with OS in IDEAL-CRT, with an HR of 0.88 representing a 12% increase in the hazard rate for death per 1% loss in CTV/ITV fractional volume receiving >=95% of the prescribed dose.	('V95%', 'Var', (8, 12))	('CTV/ITV V95%', 'Var', (0, 12))	('loss', 'NegReg', (147, 151))	('CTV/ITV', 'MPA', (155, 162))	('OS', 'Chemical', '-', (47, 49))	('IDEAL-CRT', 'Disease', (53, 62))
443233	31809876	When patients were dichotomized into those with CTV/ITV V95% >99% or <=99% (105 vs 11 patients), an HR of 0.46 (95% CI, 0.23-0.90) was found, favoring the V95% >99% group.	('V95% >99', 'Var', (155, 163))	('V95% >99%', 'Var', (56, 65))	('patients', 'Species', '9606', (5, 13))	('patients', 'Species', '9606', (86, 94))
443242	29228750	Dietary fat intake and risk of esophageal carcinoma: a meta-analysis of observational studies Dietary fat intake is potentially associated with the onset of esophageal carcinoma (EC), but evidence from observational studies has remained unclear.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('Dietary', 'Var', (94, 101))	('fat', 'Gene', '2195', (8, 11))	('esophageal carcinoma', 'Disease', (157, 177))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (157, 177))	('fat', 'Gene', (102, 105))	('esophageal carcinoma', 'Disease', (31, 51))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (31, 51))	('fat', 'Gene', '2195', (102, 105))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (157, 177))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (31, 51))	('EC', 'Phenotype', 'HP:0011459', (179, 181))	('associated', 'Reg', (128, 138))	('fat', 'Gene', (8, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
443259	29228750	High SFA intake was associated with increased EAC risk (RR: 1.88, 95% CI: 1.28-2.77; I2 = 70.0%), and Egger's test detect no obvious publication bias (P = 0.134).	('SFA', 'Chemical', 'MESH:D005227', (5, 8))	('EAC', 'Phenotype', 'HP:0011459', (46, 49))	('EAC', 'Disease', (46, 49))	('High', 'Var', (0, 4))
443262	29228750	High MUFA intake was associated with increased EAC risk (RR: 1.70, 95% CI: 1.01-2.84; I2 = 76.8%).	('MUFA', 'Chemical', 'MESH:D005227', (5, 9))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('EAC', 'Disease', (47, 50))	('High', 'Var', (0, 4))
443280	27893424	Aberrant DNA methylation has been associated with various human diseases, including cancer, autoimmune diseases, mental illness, and cardiovascular diseases.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('associated', 'Reg', (34, 44))	('cardiovascular diseases', 'Disease', (133, 156))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (133, 156))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (84, 90))	('autoimmune diseases', 'Disease', (92, 111))	('human', 'Species', '9606', (58, 63))	('mental illness', 'Disease', 'MESH:D008607', (113, 127))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (133, 156))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (92, 111))	('DNA', 'Protein', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('autoimmune diseases', 'Disease', 'MESH:D001327', (92, 111))	('mental illness', 'Disease', (113, 127))
443282	27893424	In this epidemiological study, we analyzed the impact of aberrant DNA methylation levels on the clinical and pathological features of ESCC in a Chinese population, and we investigated the methylation profile as a potential biomarker for the diagnosis of esophageal cancer.	('esophageal cancer', 'Disease', (254, 271))	('esophageal cancer', 'Disease', 'MESH:D004938', (254, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('aberrant', 'Var', (57, 65))
443296	27893424	Methylation of PRDM16 gene had the highest diagnostic value, with the AUC (95% CI) of 0.967 (0.921-1.000), followed by PIK3R1, with the AUC (95% CI) of 0.930 (0.863-0.998).	('PIK3R1', 'Gene', '5295', (119, 125))	('PIK3R1', 'Gene', (119, 125))	('Methylation', 'Var', (0, 11))	('PRDM16', 'Gene', (15, 21))	('PRDM16', 'Gene', '63976', (15, 21))
443299	27893424	The methylation of PRDM16 gene showed the highest diagnostic value, with the AUC (95% CI) of 0.988 (0.965-1.000), followed by PIK3R1, with the AUC (95% CI) of 0.969 (0.928-1.000).	('PIK3R1', 'Gene', (126, 132))	('methylation', 'Var', (4, 15))	('PRDM16', 'Gene', (19, 25))	('PRDM16', 'Gene', '63976', (19, 25))	('PIK3R1', 'Gene', '5295', (126, 132))
443307	27893424	For example, samples from patients with N1-3 stage had an average cumulative methylation value of 9.56 in RASSF1 gene, which was significantly higher than that in patients at N0 stage (cumulative methylation value: 3.54).	('mul', 'Gene', (68, 71))	('patients', 'Species', '9606', (163, 171))	('N1-3 stage', 'Var', (40, 50))	('mul', 'Gene', '4591', (187, 190))	('patients', 'Species', '9606', (26, 34))	('RASSF1', 'Gene', '11186', (106, 112))	('higher', 'PosReg', (143, 149))	('mul', 'Gene', (187, 190))	('RASSF1', 'Gene', (106, 112))	('methylation', 'MPA', (77, 88))	('mul', 'Gene', '4591', (68, 71))
443316	27893424	In this study, we used a two-stage study design, sequenced 1160 CpG sites in the promoter region of 16 candidate genes, and demonstrated that aberrant DNA methylation can be a potential biomarker for esophageal cancer.	('aberrant', 'Var', (142, 150))	('esophageal cancer', 'Disease', (200, 217))	('esophageal cancer', 'Disease', 'MESH:D004938', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('DNA', 'Protein', (151, 154))
443321	27893424	The malfunction of PRDM16 is related to a poor prognosis of cancer patients.	('patients', 'Species', '9606', (67, 75))	('related', 'Reg', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('PRDM16', 'Gene', (19, 25))	('PRDM16', 'Gene', '63976', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('malfunction', 'Var', (4, 15))
443329	27893424	Similar CDKN2A methylation patterns have been observed in gastric and nasopharyngeal carcinoma.	('gastric', 'Disease', (58, 65))	('methylation', 'Var', (15, 26))	('CDKN2A', 'Gene', (8, 14))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (70, 94))	('observed', 'Reg', (46, 54))	('CDKN2A', 'Gene', '1029', (8, 14))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (70, 94))	('nasopharyngeal carcinoma', 'Disease', (70, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))
443336	27893424	Third, aberrant DNA methylation usually occurs somatically in cancer cells and can also be detected in peripheral blood samples.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('aberrant', 'Var', (7, 15))	('DNA', 'Protein', (16, 19))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
443337	27893424	In conclusion, aberrant DNA methylation is a promising biomarker that has a good predictive value for identifying esophageal cancer in a molecular diagnostic laboratory.	('DNA', 'Protein', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('aberrant', 'Var', (15, 23))
443338	27893424	The hypermethylation status of PRDM16, PIK3R1, and CDKN2A genes might be used as a potential biomarker for the diagnosis of ESCC.	('CDKN2A', 'Gene', '1029', (51, 57))	('PRDM16', 'Gene', (31, 37))	('PRDM16', 'Gene', '63976', (31, 37))	('hypermethylation status', 'Var', (4, 27))	('PIK3R1', 'Gene', '5295', (39, 45))	('CDKN2A', 'Gene', (51, 57))	('PIK3R1', 'Gene', (39, 45))	('ESCC', 'Disease', (124, 128))
443375	26863569	NRG-1beta is a product of one of the sixteen different transcripts of neuregulin-1, and induces therapy resistance to the EGFR-targeting antibody cetuximab in colorectal cancer, RAF inhibitors in BRAF mutant melanoma, and MEK inhibitors in metastatic uveal melanoma.	('induces', 'Reg', (88, 95))	('neuregulin-1', 'Gene', (70, 82))	('MEK', 'Gene', '5609', (222, 225))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('mutant', 'Var', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('uveal melanoma', 'Phenotype', 'HP:0007716', (251, 265))	('EGFR', 'Gene', (122, 126))	('MEK', 'Gene', (222, 225))	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('BRAF', 'Gene', '673', (196, 200))	('RAF', 'Gene', '22882', (197, 200))	('BRAF', 'Gene', (196, 200))	('therapy resistance', 'MPA', (96, 114))	('colorectal cancer', 'Disease', (159, 176))	('cetuximab', 'Chemical', 'MESH:D000068818', (146, 155))	('uveal melanoma', 'Disease', 'MESH:C536494', (251, 265))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('RAF', 'Gene', (197, 200))	('NRG-1beta', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('RAF', 'Gene', '22882', (178, 181))	('melanoma', 'Disease', (257, 265))	('EGFR', 'Gene', '1956', (122, 126))	('neuregulin-1', 'Gene', '3084', (70, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('uveal melanoma', 'Disease', (251, 265))	('RAF', 'Gene', (178, 181))
443376	26863569	Proteases that can cleave the different neuregulin variants include the disintegrin and metalloproteinase proteins ADAM10 and ADAM17.	('ADAM17', 'Gene', '6868', (126, 132))	('variants', 'Var', (51, 59))	('ADAM17', 'Gene', (126, 132))	('ADAM10', 'Gene', '102', (115, 121))	('ADAM10', 'Gene', (115, 121))
443382	26863569	The mechanisms of resistance against trastuzumab are various and include the upregulation of other tyrosine kinase receptors such as IGF1R or MET receptor, or reactivating mutations and protein overexpression in the pathway downstream of HER2, including PTEN, PI3K, and c-SRC.	('mutations', 'Var', (172, 181))	('trastuzumab', 'Chemical', 'MESH:D000068878', (37, 48))	('c-SRC', 'Gene', (270, 275))	('overexpression', 'PosReg', (194, 208))	('IGF1R', 'Gene', (133, 138))	('HER2', 'Gene', (238, 242))	('PI3K', 'Disease', (260, 264))	('HER2', 'Gene', '2064', (238, 242))	('reactivating', 'MPA', (159, 171))	('IGF1R', 'Gene', '3480', (133, 138))	('protein', 'Protein', (186, 193))	('pathway', 'Pathway', (216, 223))	('upregulation', 'PosReg', (77, 89))	('c-SRC', 'Gene', '6714', (270, 275))	('PTEN', 'Gene', (254, 258))	('PTEN', 'Gene', '5728', (254, 258))
443412	26863569	Thus, the upregulation of HER3 is the most conserved and consistent response following HER2 inhibition.	('inhibition', 'Var', (92, 102))	('HER2', 'Gene', '2064', (87, 91))	('HER3', 'Protein', (26, 30))	('upregulation', 'PosReg', (10, 22))	('HER2', 'Gene', (87, 91))
443417	26863569	Taken together, these data show a consistent mechanism of resistance upon long-term trastuzumab treatment through upregulation of HER3, and show that inhibition of this receptor can circumvent resistance to trastuzumab.	('trastuzumab', 'Chemical', 'MESH:D000068878', (84, 95))	('upregulation', 'PosReg', (114, 126))	('inhibition', 'Var', (150, 160))	('HER3', 'Protein', (130, 134))	('trastuzumab', 'Chemical', 'MESH:D000068878', (207, 218))
443424	26863569	To functionally assess if this ADAM10 is involved in the release of NRG-1beta, cells were either treated with an ADAM10 inhibitor, or transduced with silencing RNA against ADAM10.	('RNA', 'Gene', (160, 163))	('ADAM10', 'Gene', '102', (113, 119))	('ADAM10', 'Gene', (113, 119))	('ADAM10', 'Gene', '102', (172, 178))	('ADAM10', 'Gene', '102', (31, 37))	('ADAM10', 'Gene', (172, 178))	('silencing', 'Var', (150, 159))	('ADAM10', 'Gene', (31, 37))
443427	26863569	Similarly, no effect of ADAM10 knockdown was observed in otherwise untreated cells by microscopy (Figures 5A and 5C, upper row) and cell viability assays (Figures 5B and 5D, left panels), while in long-term trastuzumab treated cells, ADAM10 knockdown decreased cell numbers (Figures 5A and 5C, middle row).	('knockdown', 'Var', (241, 250))	('ADAM10', 'Gene', '102', (24, 30))	('ADAM10', 'Gene', '102', (234, 240))	('decreased', 'NegReg', (251, 260))	('ADAM10', 'Gene', (24, 30))	('trastuzumab', 'Chemical', 'MESH:D000068878', (207, 218))	('ADAM10', 'Gene', (234, 240))	('cell numbers', 'CPA', (261, 273))
443428	26863569	To assess the downstream signaling effects of long-term HER2 inhibition and ADAM10 knockdown, AKT and ERK phosphorylation was determined under these conditions.	('HER2', 'Gene', (56, 60))	('HER2', 'Gene', '2064', (56, 60))	('ERK', 'Gene', '5594', (102, 105))	('ADAM10', 'Gene', '102', (76, 82))	('ERK', 'Gene', (102, 105))	('ADAM10', 'Gene', (76, 82))	('knockdown', 'Var', (83, 92))
443444	26863569	Blocking the HER3 receptor is therefore effective not only by blocking HER3 that is upregulated in response to the loss of HER2, but also by targeting the interaction between HER3 and HER2.	('HER2', 'Gene', (184, 188))	('upregulated', 'PosReg', (84, 95))	('interaction', 'Interaction', (155, 166))	('blocking', 'NegReg', (62, 70))	('HER2', 'Gene', '2064', (184, 188))	('HER2', 'Gene', (123, 127))	('HER3', 'Protein', (71, 75))	('HER3', 'Protein', (13, 17))	('loss', 'Var', (115, 119))	('HER3', 'Protein', (175, 179))	('targeting', 'Reg', (141, 150))	('HER2', 'Gene', '2064', (123, 127))
443456	26863569	ADAM10 inhibitor GI 254023X and recombinant hNRG-1beta were purchased from R&D systems (Oxon, United Kingdom).	('GI 254023X', 'Var', (17, 27))	('ADAM10', 'Gene', (0, 6))	('ADAM10', 'Gene', '102', (0, 6))
443569	25898903	In general, the transthoracic approach is more aggressive than the transhiatal approach and is more likely to cause cardiopulmonary complications, anastomotic and chylous leaks, vocal cord paralysis, and wound infection.	('vocal cord paralysis', 'Disease', (178, 198))	('wound', 'CPA', (204, 209))	('transthoracic', 'Var', (16, 29))	('cardiopulmonary', 'Disease', (116, 131))	('paralysis', 'Phenotype', 'HP:0003470', (189, 198))	('vocal cord paralysis', 'Disease', 'MESH:D014826', (178, 198))	('infection', 'Disease', (210, 219))	('infection', 'Disease', 'MESH:D007239', (210, 219))	('vocal cord paralysis', 'Phenotype', 'HP:0001605', (178, 198))	('cause', 'Reg', (110, 115))	('anastomotic', 'Disease', (147, 158))
443729	23767033	Most patients diagnosed preoperatively with T2-T3N0Mo had lymph node metastasis in the surgical result.	('lymph node metastasis', 'CPA', (58, 79))	('patients', 'Species', '9606', (5, 13))	('T2-T3N0Mo', 'Var', (44, 53))
443776	23118554	When cells were exposed to 600 microM H2O2 for 24 hours, cell viability was decreased to 40%.	('H2O2', 'Var', (38, 42))	('cell viability', 'CPA', (57, 71))	('decreased', 'NegReg', (76, 85))	('H2O2', 'Chemical', 'MESH:D006861', (38, 42))
443778	23118554	H2O2-treated cells were shown to express 5-lipoxygenase, whereas the cells pretreated with eupatilin exhibited reduction in the expression of 5-lipoxygenase.	('5-lipoxygenase', 'Enzyme', (41, 55))	('eupatilin', 'Chemical', 'MESH:C045325', (91, 100))	('expression', 'MPA', (128, 138))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2-treated', 'Var', (0, 12))
443779	23118554	The H2O2-induced increase of 5-lipoxygenase expression was prevented by SB202190, SP600125, or NAC.	('prevented', 'NegReg', (59, 68))	('SP600125', 'Chemical', 'MESH:C432165', (82, 90))	('SB202190', 'Chemical', 'MESH:C090942', (72, 80))	('SP600125', 'Var', (82, 90))	('SB202190', 'Var', (72, 80))	('H2O2-induced', 'Var', (4, 16))	('5-lipoxygenase expression', 'MPA', (29, 54))	('increase', 'PosReg', (17, 25))	('NAC', 'Gene', (95, 98))	('NAC', 'Gene', '7504', (95, 98))	('H2O2', 'Chemical', 'MESH:D006861', (4, 8))
443780	23118554	We further demonstrated that the level of leukotriene B4 (LTB4) was also reduced by eupatilin, SB202190, SP600125, NAC, or nordihydroguaiaretic acid (a lipoxygenase inhibitor) pretreatment.	('eupatilin', 'Chemical', 'MESH:C045325', (84, 93))	('SP600125', 'Chemical', 'MESH:C432165', (105, 113))	('nordihydroguaiaretic acid', 'Chemical', 'MESH:D009637', (123, 148))	('reduced', 'NegReg', (73, 80))	('leukotriene B4', 'MPA', (42, 56))	('LT', 'Chemical', 'MESH:D015289', (58, 60))	('SP600125', 'Var', (105, 113))	('oxygen', 'Chemical', 'MESH:D010100', (155, 161))	('leukotriene B4', 'Chemical', 'MESH:D007975', (42, 56))	('level', 'MPA', (33, 38))	('NAC', 'Gene', (115, 118))	('NAC', 'Gene', '7504', (115, 118))	('SB202190', 'Chemical', 'MESH:C090942', (95, 103))	('eupatilin', 'Var', (84, 93))	('SB202190', 'Var', (95, 103))
443781	23118554	H2O2 induced the activation of p38MAPK and JNK, this activation was inhibited by eupatilin.	('p38', 'Gene', (31, 34))	('eupatilin', 'Chemical', 'MESH:C045325', (81, 90))	('JNK', 'Gene', (43, 46))	('activation', 'PosReg', (17, 27))	('p38', 'Gene', '1432', (31, 34))	('JNK', 'Gene', '5599', (43, 46))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))
443834	23118554	Moreover, cell viability after exposure to 600 microM H2O2 was reduced to 40% of the control.	('H2O2', 'Chemical', 'MESH:D006861', (54, 58))	('H2O2', 'Var', (54, 58))	('cell viability', 'CPA', (10, 24))	('reduced', 'NegReg', (63, 70))
443835	23118554	In addition, morphologic observation of EECs treated with H2O2 was performed to identify the H2O2-induced morphologic change (Fig.	('H2O2', 'Chemical', 'MESH:D006861', (58, 62))	('H2O2', 'Chemical', 'MESH:D006861', (93, 97))	('EEC', 'Gene', (40, 43))	('EEC', 'Gene', '1913', (40, 43))	('H2O2-induced', 'Var', (93, 105))
443836	23118554	After H2O2 treatment, the number of cells was reduced and a high fraction of cells exhibited cytoplasmic condensation.	('exhibited', 'Reg', (83, 92))	('cytoplasmic condensation', 'CPA', (93, 117))	('reduced', 'NegReg', (46, 53))	('H2O2', 'Chemical', 'MESH:D006861', (6, 10))	('H2O2', 'Var', (6, 10))
443844	23118554	H2O2 induced cytoplasmic condensation of EECs, whereas the morphology of cells incubated with H2O2 in the presence of 150 microM eupatilin was shown to maintain similar to control.	('eupatilin', 'Chemical', 'MESH:C045325', (129, 138))	('H2O2', 'Chemical', 'MESH:D006861', (94, 98))	('cytoplasmic condensation', 'CPA', (13, 37))	('EEC', 'Gene', (41, 44))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('EEC', 'Gene', '1913', (41, 44))	('H2O2', 'Var', (0, 4))
443850	23118554	5-Lox expression by H2O2 was reduced 10% by eupatillin.	('Lox', 'Gene', (2, 5))	('Lox', 'Gene', '4015', (2, 5))	('eupatillin', 'Chemical', '-', (44, 54))	('H2O2', 'Chemical', 'MESH:D006861', (20, 24))	('H2O2', 'Var', (20, 24))
443851	23118554	Serum-starved EECs were treated with or without 150 microM eupatilin for 12 hours, 5 mM NAC, 30 microM SB202190 or 30 microM SP600125 for 1 hours prior to 300 microM H2O2 stimulation for 24 hours.	('NAC', 'Gene', '7504', (88, 91))	('SP600125', 'Chemical', 'MESH:C432165', (125, 133))	('EEC', 'Gene', '1913', (14, 17))	('SB202190', 'Chemical', 'MESH:C090942', (103, 111))	('SP600125', 'Var', (125, 133))	('H2O2', 'Chemical', 'MESH:D006861', (166, 170))	('eupatilin', 'Chemical', 'MESH:C045325', (59, 68))	('SB202190', 'Var', (103, 111))	('EEC', 'Gene', (14, 17))	('NAC', 'Gene', (88, 91))
443852	23118554	3A, pretreatment of the cells with SB202190, SP600125 or NAC significantly reduced H2O2-induced the 5-LOX expression.	('H2O2', 'Chemical', 'MESH:D006861', (83, 87))	('NAC', 'Gene', (57, 60))	('5-LOX expression', 'MPA', (100, 116))	('NAC', 'Gene', '7504', (57, 60))	('SB202190', 'Chemical', 'MESH:C090942', (35, 43))	('SB202190', 'Var', (35, 43))	('reduced', 'NegReg', (75, 82))	('SP600125', 'Chemical', 'MESH:C432165', (45, 53))	('H2O2-induced', 'MPA', (83, 95))	('SP600125', 'Var', (45, 53))
443855	23118554	3B showed that treatment of cultured EECs with H2O2 caused a significant increase in the production of LTB4.	('production', 'MPA', (89, 99))	('increase', 'PosReg', (73, 81))	('EEC', 'Gene', (37, 40))	('LT', 'Chemical', 'MESH:D015289', (103, 105))	('LTB4', 'MPA', (103, 107))	('EEC', 'Gene', '1913', (37, 40))	('H2O2', 'Chemical', 'MESH:D006861', (47, 51))	('H2O2', 'Var', (47, 51))
443856	23118554	However, when EECs were treated with eupatilin, SB202190, SP600125, NAC or NDGA (a lipoxygenase inhibitor), the levels of LTB4 production was significantly reduced by all of them.	('SB202190', 'Chemical', 'MESH:C090942', (48, 56))	('EEC', 'Gene', '1913', (14, 17))	('NAC', 'Gene', (68, 71))	('NDGA', 'Chemical', 'MESH:D009637', (75, 79))	('LTB4 production', 'MPA', (122, 137))	('LT', 'Chemical', 'MESH:D015289', (122, 124))	('eupatilin', 'Chemical', 'MESH:C045325', (37, 46))	('NAC', 'Gene', '7504', (68, 71))	('SP600125', 'Chemical', 'MESH:C432165', (58, 66))	('SB202190', 'Var', (48, 56))	('reduced', 'NegReg', (156, 163))	('oxygen', 'Chemical', 'MESH:D010100', (86, 92))	('levels', 'MPA', (112, 118))	('SP600125', 'Var', (58, 66))	('EEC', 'Gene', (14, 17))
443861	23118554	p38 MAPK and JNK phosphorylation levels were significantly increased by 300 microM H2O2.	('H2O2', 'Chemical', 'MESH:D006861', (83, 87))	('H2O2', 'Var', (83, 87))	('p38', 'Gene', (0, 3))	('p38', 'Gene', '1432', (0, 3))	('JNK', 'Gene', (13, 16))	('JNK', 'Gene', '5599', (13, 16))	('increased', 'PosReg', (59, 68))
443863	23118554	4A, was increased to 40% of the control and JNK activation after exposure to 300 microM H2O2, in Fig.	('JNK', 'Gene', (44, 47))	('increased', 'PosReg', (8, 17))	('H2O2', 'Var', (88, 92))	('H2O2', 'Chemical', 'MESH:D006861', (88, 92))	('JNK', 'Gene', '5599', (44, 47))	('activation', 'PosReg', (48, 58))
443864	23118554	Serum-starved EECs were treated in the presence or absence of 150 microM eupatilin for 12 hr and with NAC, SB202190 or SP600125 for 1 hr prior to 300 microM H2O2 treatment for 24 hr.	('EEC', 'Gene', '1913', (14, 17))	('NAC', 'Gene', (102, 105))	('NAC', 'Gene', '7504', (102, 105))	('SB202190', 'Chemical', 'MESH:C090942', (107, 115))	('H2O2', 'Chemical', 'MESH:D006861', (157, 161))	('SP600125', 'Var', (119, 127))	('SP600125', 'Chemical', 'MESH:C432165', (119, 127))	('SB202190', 'Var', (107, 115))	('eupatilin', 'Chemical', 'MESH:C045325', (73, 82))	('EEC', 'Gene', (14, 17))
443866	23118554	Pretreatment with eupatilin, NAC, SB202190, or SP600125 inhibited the expression of H2O2-induced p38 MAPK and JNK phosphorylation.	('eupatilin', 'Chemical', 'MESH:C045325', (18, 27))	('JNK', 'Gene', (110, 113))	('SB202190', 'Chemical', 'MESH:C090942', (34, 42))	('p38', 'Gene', (97, 100))	('JNK', 'Gene', '5599', (110, 113))	('SB202190', 'Var', (34, 42))	('H2O2', 'Chemical', 'MESH:D006861', (84, 88))	('SP600125', 'Chemical', 'MESH:C432165', (47, 55))	('expression', 'MPA', (70, 80))	('H2O2-induced', 'Gene', (84, 96))	('p38', 'Gene', '1432', (97, 100))	('SP600125', 'Var', (47, 55))	('inhibited', 'NegReg', (56, 65))	('NAC', 'Gene', (29, 32))	('NAC', 'Gene', '7504', (29, 32))
443873	23118554	However, eupatilin enhanced the reduction of cell viability by H2O2.	('H2O2', 'Var', (63, 67))	('cell viability', 'CPA', (45, 59))	('reduction', 'NegReg', (32, 41))	('eupatilin', 'Chemical', 'MESH:C045325', (9, 18))	('H2O2', 'Chemical', 'MESH:D006861', (63, 67))
443881	23118554	As one study previously demonstrated, methyl jasmonate which is a plant stress hormone, induced apoptosis in human prostate carcinoma cells via 5-LOX dependent pathway.	('human', 'Species', '9606', (109, 114))	('5-LOX dependent pathway', 'Pathway', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (115, 133))	('methyl jasmonate', 'Chemical', 'MESH:C072239', (38, 54))	('prostate carcinoma', 'Disease', (115, 133))	('methyl', 'Var', (38, 44))	('apoptosis', 'CPA', (96, 105))	('prostate carcinoma', 'Disease', 'MESH:D011472', (115, 133))
443882	23118554	In our study, co-treatment of eupatilin with H2O2 inhibited the increase of the H2O2-stimulated 5-LOX expression and LTB4 production.	('5-LOX expression', 'MPA', (96, 112))	('H2O2', 'Chemical', 'MESH:D006861', (80, 84))	('LTB4 production', 'MPA', (117, 132))	('LT', 'Chemical', 'MESH:D015289', (117, 119))	('eupatilin', 'Chemical', 'MESH:C045325', (30, 39))	('H2O2', 'Chemical', 'MESH:D006861', (45, 49))	('H2O2-stimulated', 'Var', (80, 95))	('inhibited', 'NegReg', (50, 59))
443885	23118554	Modulation of the MAPK signaling pathways by H2O2 is distinctive, depending on the cell type, concentration and duration of exposure.	('MAPK signaling pathways', 'Pathway', (18, 41))	('H2O2', 'Chemical', 'MESH:D006861', (45, 49))	('H2O2', 'Var', (45, 49))
443887	23118554	As shown in our results, the H2O2-induced 5-LOX expression and LTB4 production were mediated by activation of p38 MAPK and JNK.	('p38', 'Gene', (110, 113))	('5-LOX expression', 'MPA', (42, 58))	('H2O2-induced', 'Var', (29, 41))	('H2O2', 'Chemical', 'MESH:D006861', (29, 33))	('LTB4 production', 'MPA', (63, 78))	('JNK', 'Gene', (123, 126))	('LT', 'Chemical', 'MESH:D015289', (63, 65))	('JNK', 'Gene', '5599', (123, 126))	('p38', 'Gene', '1432', (110, 113))	('activation', 'PosReg', (96, 106))
443889	23118554	Considering the inhibitory effect of SB202190and SP600125on the 5-LOX expression, eupatilin may involve inhibition of the p38 MAPK and JNK pathways.	('inhibition', 'NegReg', (104, 114))	('SB202190and', 'Var', (37, 48))	('SB202190and', 'Chemical', '-', (37, 48))	('eupatilin', 'Chemical', 'MESH:C045325', (82, 91))	('SP600125on', 'Var', (49, 59))	('JNK', 'Gene', (135, 138))	('p38', 'Gene', '1432', (122, 125))	('SP600125on', 'Chemical', '-', (49, 59))	('JNK', 'Gene', '5599', (135, 138))	('5-LOX expression', 'MPA', (64, 80))	('p38', 'Gene', (122, 125))
443890	23118554	In macrophages LTB4 or LTD4 have pro-proliferative effects through MAPK and phosphatidyl inositol 3-kinase pathways.	('LT', 'Chemical', 'MESH:D015289', (15, 17))	('LT', 'Chemical', 'MESH:D015289', (23, 25))	('LTB4', 'Var', (15, 19))	('pro-proliferative effects', 'CPA', (33, 58))	('phosphatidyl inositol 3-kinase pathways', 'Pathway', (76, 115))	('LTD4', 'Var', (23, 27))
443901	22919278	Alterations of the TP53 Gene in Gastric and Esophageal Carcinogenesis TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability.	('Esophageal Carcinogenesis', 'Disease', 'MESH:D063646', (44, 69))	('Esophageal Carcinogenesis', 'Disease', (44, 69))	('TP53', 'Gene', '7157', (70, 74))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('TP53', 'Gene', (70, 74))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
443902	22919278	The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation.	('esophageal', 'Disease', (19, 29))	('cancers', 'Disease', (42, 49))	('gastric cancers', 'Disease', 'MESH:D013274', (34, 49))	('genetic', 'Var', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('gastric cancers', 'Disease', (34, 49))	('gastric cancers', 'Phenotype', 'HP:0012126', (34, 49))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))
443903	22919278	Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis.	('TP53', 'Gene', (85, 89))	('participation', 'Reg', (32, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('gastric carcinogenesis', 'Disease', (113, 135))	('genetic alterations', 'Var', (58, 77))	('carcinogenesis', 'Disease', (121, 135))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (113, 135))
443904	22919278	Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH), overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('loss', 'NegReg', (55, 59))	('TP53', 'Gene', (39, 43))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('overexpression', 'PosReg', (85, 99))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('loss', 'NegReg', (137, 141))	('mutations', 'Var', (44, 53))	('function', 'MPA', (149, 157))	('esophageal', 'Disease', (190, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (205, 219))	('gastric cancers', 'Disease', (205, 220))	('gastric cancers', 'Phenotype', 'HP:0012126', (205, 220))
443914	22919278	Over 50% of human cancers present inactivated TP53, due loss of function mutations, among 95% of them occurred within the genomic region encoding the sequence-specific DNA-binding domain of TP53.	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('loss of function', 'NegReg', (56, 72))	('TP53', 'Gene', (46, 50))	('human', 'Species', '9606', (12, 17))	('mutations', 'Var', (73, 82))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
443917	22919278	The genetic and epigenetic alteration more common in BE is the inactivation of CDKN2A on chromosome 9p.	('CDKN2A', 'Gene', '1029', (79, 85))	('BE', 'Phenotype', 'HP:0100580', (53, 55))	('inactivation', 'Var', (63, 75))	('common', 'Reg', (43, 49))	('CDKN2A', 'Gene', (79, 85))
443918	22919278	In a study that assessed the prognostic value of TP53 mutations in EA was observed that 47% of the tumors analyzed had TP53 mutations, predominantly G:C to A:T transitions at CpG dinucleotides.	('mutations', 'Var', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('G:C to A:T transitions', 'Var', (149, 171))	('EA', 'Phenotype', 'HP:0011459', (67, 69))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('TP53', 'Gene', (119, 123))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
443919	22919278	The esophagus is most frequently exposed to carcinogens as the stomach or colon, such carcinogens present in food or dietary factors act as inducers of TP53 mutations in ESCC in some areas considered high risk, such as China, Southern Brazil, and Taiwan.	('ESCC', 'Gene', (170, 174))	('colon', 'Disease', 'MESH:D015179', (74, 79))	('mutations', 'Var', (157, 166))	('TP53', 'Gene', (152, 156))	('colon', 'Disease', (74, 79))
443924	22919278	It was verified that LOH without copy number change at the TP53 locus was observed in TP53 mutant ESCC, suggesting that copy-neutral LOH occurring as a result of chromosomal instability might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with TP53 mutation.	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (256, 295))	('TP53', 'Gene', (86, 90))	('chromosomal instability', 'Phenotype', 'HP:0040012', (162, 185))	('esophageal squamous cell carcinogenesis', 'Disease', (256, 295))	('mutant', 'Var', (91, 97))	('TP53', 'Gene', (312, 316))
443925	22919278	Molecular studies have supplied important information on the genetic events in GC involving a number of genetic and epigenetic alterations including oncogenes as amplification of c-MYC, c-ERBB2, c-MET, E-cadherin (CDH1), tumor suppressor genes with mutations of APC, TP53, and cell cycle regulators, cell adhesion molecules and DNA repair genes.	('CDH1', 'Gene', '999', (214, 218))	('c-MET', 'Gene', (195, 200))	('mutations', 'Var', (249, 258))	('c-MET', 'Gene', '4233', (195, 200))	('GC', 'Phenotype', 'HP:0012126', (79, 81))	('c-MYC', 'Gene', '4609', (179, 184))	('E-cadherin', 'Gene', '999', (202, 212))	('CDH1', 'Gene', (214, 218))	('APC', 'Disease', 'MESH:D011125', (262, 265))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('E-cadherin', 'Gene', (202, 212))	('c-ERBB2', 'Gene', (186, 193))	('APC', 'Disease', (262, 265))	('c-MYC', 'Gene', (179, 184))	('c-ERBB2', 'Gene', '2064', (186, 193))	('TP53', 'Gene', (267, 271))
443926	22919278	Some studies showed that mutations tend to affect mainly intestinal-type tumors, while others found that the incidence of mutation is similar in both intestinal and diffuse-type tumors, ranging between 25% and 40% of the cases studied.	('mutations', 'Var', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('intestinal-type tumors', 'Disease', 'MESH:D007414', (57, 79))	('affect', 'Reg', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('intestinal-type tumors', 'Disease', (57, 79))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
443927	22919278	According tumor stage, TP53 abnormalities appear to occur early in intestinal-type cancers, but some studies showed that the frequency of TP53 mutation in both early and advanced intestinal-type is consistent at around 40% each, similar to that observed in advanced diffuse-type, while in early diffuse-type TP53 mutations are uncommon.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('intestinal-type cancers', 'Disease', 'MESH:D007414', (67, 90))	('intestinal-type cancers', 'Disease', (67, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', (138, 142))	('mutation', 'Var', (143, 151))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
443928	22919278	C to T mutations are also induced by nitric oxide, a substance produced during infection by H. pylori bacterium.	('H. pylori', 'Species', '210', (92, 101))	('induced', 'Reg', (26, 33))	('nitric oxide', 'Chemical', 'MESH:D009569', (37, 49))	('C to T', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
443929	22919278	The authors also reported an association between TP53 mutation and patients with high/high-middle differentiated type-GC, indicating that these mutations are responsible for the initiation stages of gastric carcinoma, rather than the slowing of differentiation.	('mutation', 'Var', (54, 62))	('gastric carcinoma', 'Disease', 'MESH:D013274', (199, 216))	('TP53', 'Gene', (49, 53))	('high/high-middle', 'Var', (81, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('gastric carcinoma', 'Disease', (199, 216))	('GC', 'Phenotype', 'HP:0012126', (118, 120))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (199, 216))
443930	22919278	Under cellular stress, p53 accumulates in the cytosol or mitochondria and leads to the direct activation of proapoptotic Bcl-2 family members, such as Bax and/or Bak, so it selectively activates p53-mediated apoptosis.	('Bax', 'Gene', '581', (151, 154))	('Bak', 'Gene', (162, 165))	('p53-mediated apoptosis', 'CPA', (195, 217))	('p53', 'Var', (23, 26))	('Bcl-2', 'Gene', (121, 126))	('Bak', 'Gene', '578', (162, 165))	('Bcl-2', 'Gene', '596', (121, 126))	('Bax', 'Gene', (151, 154))	('activates', 'PosReg', (185, 194))	('accumulates', 'PosReg', (27, 38))	('activation', 'PosReg', (94, 104))
443937	22919278	So far, many efforts have been applied for understanding the mechanisms involving TP53 mutations in carcinogenesis and development of the gastrointestinal tract; it is clear participation of TP53 gene alterations in early stages and progression of these tumor types.	('TP53', 'Gene', (82, 86))	('alterations', 'Var', (201, 212))	('TP53', 'Gene', (191, 195))	('participation', 'Reg', (174, 187))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('gastrointestinal tract', 'Disease', (138, 160))	('mutations', 'Var', (87, 96))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (138, 160))
443938	22919278	The expression analysis on p53 protein level by immunohistochemical staining has been performed on routine paraffin embedded material and the overexpression and an accumulation of protein is used as an indicator of mutant form of TP53 gene, which has been shown to be a powerful marker of malignancy.	('TP53', 'Gene', (230, 234))	('malignancy', 'Disease', 'MESH:D009369', (289, 299))	('paraffin', 'Chemical', 'MESH:D010232', (107, 115))	('malignancy', 'Disease', (289, 299))	('mutant', 'Var', (215, 221))
443940	22919278	Moreover, p53 expression confirmed multifocal dysplasia in BE esophageal mucosectomies and the patients displayed increased aneusomy for chromosome 17 along the sequence of cancer progression.	('expression', 'Var', (14, 24))	('aneusomy', 'Var', (124, 132))	('confirmed', 'Reg', (25, 34))	('multifocal dysplasia', 'Disease', (35, 55))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('BE', 'Phenotype', 'HP:0100580', (59, 61))	('p53', 'Gene', (10, 13))	('multifocal dysplasia', 'Disease', 'None', (35, 55))
443941	22919278	To characterize p53 alterations in multiple esophageal carcinomas and to study their roles in carcinogenesis, p53 immunohistochemical and mutation analyses using laser capture microdissection on surgically resected were performed in esophageal carcinomas.	('esophageal carcinomas', 'Disease', (44, 65))	('alterations', 'Var', (20, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('esophageal carcinomas', 'Disease', (233, 254))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (44, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (244, 254))	('p53', 'Gene', (16, 19))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (233, 254))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (44, 65))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (233, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))
443945	22919278	All GC cases presented higher frequencies of trisomy or tetrasomy of chromosome 17 and TP53 deletion, and immunohistochemistry detected overexpression of p53 protein in 80% of the assessed cases.	('trisomy', 'Disease', 'MESH:D014314', (45, 52))	('trisomy', 'Disease', (45, 52))	('TP53', 'Gene', (87, 91))	('deletion', 'Var', (92, 100))	('GC', 'Phenotype', 'HP:0012126', (4, 6))	('tetrasomy', 'Var', (56, 65))
443949	22919278	Presumably, it is not only one molecular factor that can predict the biological behavior of these cancers, but patterns of TP53 mutations and protein overexpression would appear to be an useful biomarker of tumor progression, prognosis, and prediction of response to treatment of gastroesophageal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastroesophageal cancer', 'Disease', (280, 303))	('mutations', 'Var', (128, 137))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('overexpression', 'PosReg', (150, 164))	('protein', 'Protein', (142, 149))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (280, 303))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('TP53', 'Gene', (123, 127))
443950	22919278	However, the most investigated polymorphism in this gene is a nonsynonymous single base pair change in a proline-rich domain located in exon 4 codon 72 (TP53 Arg72Pro, rs 1042522), which consists in a substitution of cytosine (C) for guanine (G) and results in the substitution of arginine (Arg72:CGC) by proline (Pro72:CCC).	('Arg72Pro', 'SUBSTITUTION', 'None', (158, 166))	('guanine', 'Chemical', 'MESH:D006147', (234, 241))	('arginine', 'Chemical', 'MESH:D001120', (281, 289))	('arginine', 'MPA', (281, 289))	('CG', 'Phenotype', 'HP:0005231', (297, 299))	('cytosine', 'Chemical', 'MESH:D003596', (217, 225))	('Pro72', 'Chemical', '-', (314, 319))	('Arg72Pro', 'Var', (158, 166))	('Arg72', 'Var', (291, 296))	('GC', 'Phenotype', 'HP:0012126', (298, 300))	('proline', 'Chemical', 'MESH:D011392', (305, 312))	('proline', 'Chemical', 'MESH:D011392', (105, 112))
443952	22919278	This change in amino acid sequence may alter the ability of p53 to bind to response elements in target genes and thus induce gene transcription, its interaction with p73 and its targeting of the proteasome.	('alter', 'Reg', (39, 44))	('p73', 'Gene', '7161', (166, 169))	('interaction', 'Interaction', (149, 160))	('p73', 'Gene', (166, 169))	('bind', 'Interaction', (67, 71))	('p53', 'Gene', (60, 63))	('gene transcription', 'MPA', (125, 143))	('ability', 'MPA', (49, 56))	('induce', 'PosReg', (118, 124))	('change', 'Var', (5, 11))
443954	22919278	Some studies have reported the identification of Arg72Pro polymorphism and its role in many kinds of cancers such as cervical, lung, breast, colorectal, esophageal, and gastric.	('role', 'Reg', (79, 83))	('colorectal', 'Disease', (141, 151))	('breast', 'Disease', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('Arg72Pro', 'SUBSTITUTION', 'None', (49, 57))	('cervical', 'Disease', (117, 125))	('gastric', 'Disease', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Arg72Pro', 'Var', (49, 57))	('lung', 'Disease', (127, 131))	('esophageal', 'Disease', (153, 163))
443955	22919278	In the last decades, several studies had been focused in the association between Arg72Pro polymorphism and esophageal cancer (EC) susceptibility, but the results are still conflicting and heterogeneous.	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Arg72Pro', 'Var', (81, 89))	('Arg72Pro', 'SUBSTITUTION', 'None', (81, 89))	('association', 'Interaction', (61, 72))
443956	22919278	However, other studies did not find any association between Arg72Pro polymorphism and susceptibility to ESCC, either to EA, age of onset and stage of disease at the time of the diagnosis detection.	('Arg72Pro', 'SUBSTITUTION', 'None', (60, 68))	('Arg72Pro', 'Var', (60, 68))	('ESCC', 'Disease', (104, 108))	('EA', 'Phenotype', 'HP:0011459', (120, 122))
443957	22919278	Piao et al., in South Korea population, observed the Arg72Pro polymorphism was associated with an increased risk of EC and also found that smoking status changed the association between the Arg72Pro polymorphism and the risk of this cancer, so that the Odds Ratio of the Arg/Pro genotype was higher in ever-smokers than in never-smokers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Arg72Pro', 'Var', (190, 198))	('Arg72Pro', 'Var', (53, 61))	('Arg72Pro', 'SUBSTITUTION', 'None', (190, 198))	('association', 'Interaction', (166, 177))	('Arg72Pro', 'SUBSTITUTION', 'None', (53, 61))
443958	22919278	In addition, a study in a Chinese mainland population found that the Pro/Pro genotype was significantly associated with an increased risk of ESCC and the association was especially noteworthy in women and in younger patients.	('Pro/Pro', 'Var', (69, 76))	('ESCC', 'Disease', (141, 145))	('women', 'Species', '9606', (195, 200))
443961	22919278	However, when the authors performed a stratified analysis by ethnicity, the increased risk of EC associated with Arg72Pro polymorphism (Pro/Arg + Pro/Pro versus Arg/Arg) was more evident in Asian group, thus their results suggest that Arg72Pro polymorphism may contribute to EC development, especially in Asians.	('Arg72Pro', 'Var', (235, 243))	('Arg72Pro', 'Var', (113, 121))	('contribute', 'Reg', (261, 271))	('Arg72Pro', 'SUBSTITUTION', 'None', (235, 243))	('Arg72Pro', 'SUBSTITUTION', 'None', (113, 121))
443962	22919278	Despite of various studies assessing the functional TP53 Arg72Pro polymorphism in relation to EC susceptibility, the results remain conflicting probably due to methodological errors such as selection bias, inappropriate specimens used for genotyping, or limited statistical power and also ethnicity.	('Arg72Pro', 'SUBSTITUTION', 'None', (57, 65))	('Arg72Pro', 'Var', (57, 65))	('TP53', 'Gene', (52, 56))
443968	22919278	Therefore, p53 and other members of its family as p63 and p73 act in an intricate regulatory network controlling the expression of hundreds of target genes that regulate the cell cycle for the maintenance of genetic stability and preventing cancer formation.	('p53', 'Gene', (11, 14))	('p73', 'Var', (58, 61))	('p63', 'Gene', '8626', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer formation', 'CPA', (241, 257))	('regulate', 'Reg', (161, 169))	('p63', 'Gene', (50, 53))
443995	19136271	Overexpression of GLUT-1, the human erythrocyte glucose transporter, has been correlated with poor prognosis in patients with squamous esophageal cancer and has been associated with progression of the Barrett's metaplasia-dysplasia-adenocarcinoma sequence.	('human', 'Species', '9606', (30, 35))	('GLUT-1', 'Gene', (18, 24))	('GLUT-1', 'Gene', '6513', (18, 24))	('squamous esophageal cancer', 'Disease', 'MESH:D004938', (126, 152))	('glucose', 'Chemical', 'MESH:D005947', (48, 55))	('patients', 'Species', '9606', (112, 120))	('squamous esophageal cancer', 'Disease', (126, 152))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', 'MESH:D008679', (211, 246))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('associated with', 'Reg', (166, 181))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', (211, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
443996	19136271	Changes in the tumor suppressor gene expression of p53 are an early and frequent event in the pathogenesis of esophageal adenocarcinoma.	('p53', 'Gene', '7157', (51, 54))	('p53', 'Gene', (51, 54))	('esophageal adenocarcinoma', 'Disease', (110, 135))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (110, 135))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (110, 135))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('Changes', 'Var', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
443998	19136271	Previous work has suggested the p53 mutations and/or overexpression in esophageal adenocarcinoma is a predictor of reduced postoperative survival following esophageal resection.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (71, 96))	('overexpression', 'PosReg', (53, 67))	('esophageal adenocarcinoma', 'Disease', (71, 96))	('reduced', 'NegReg', (115, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('mutations', 'Var', (36, 45))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (71, 96))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('postoperative', 'CPA', (123, 136))
444003	19136271	Hence, cyclin D1 alterations have become a potential biomarker for the progression of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (86, 111))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (86, 111))	('cyclin D1', 'Gene', '595', (7, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('alterations', 'Var', (17, 28))	('cyclin D1', 'Gene', (7, 16))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (86, 111))
444062	19136271	As FDG-SUVmax has been correlated with poorer survival in previously published studies, further examination of tumor markers may provide insight into the mechanisms important for esophageal carcinogenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (179, 204))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('esophageal carcinogenesis', 'Disease', (179, 204))	('FDG-SUVmax', 'Var', (3, 13))	('tumor', 'Disease', (111, 116))	('poorer', 'NegReg', (39, 45))	('FDG', 'Chemical', 'MESH:D019788', (3, 6))
444074	19136271	Robust response to EGFR inhibitors in NSCLC was attributable to activating EGFR mutations including the in-frame deletion delE746-A750 and the missense L858R.	('NSCLC', 'Disease', (38, 43))	('delE746-A750', 'Var', (122, 134))	('activating', 'PosReg', (64, 74))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (19, 23))	('missense L858R', 'Var', (143, 157))	('L858R', 'Mutation', 'rs121434568', (152, 157))	('EGFR', 'Gene', (75, 79))
444076	19136271	One previous study of 17 adenocarcinoma specimens found the same two activating EGFR mutations which predicted robust EGFR inhibitor response in NSCLC.	('men', 'Species', '9606', (45, 48))	('NSCLC', 'Disease', (145, 150))	('EGFR', 'Gene', '1956', (80, 84))	('activating', 'PosReg', (69, 79))	('EGFR', 'Gene', (80, 84))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('mutations', 'Var', (85, 94))	('adenocarcinoma', 'Disease', (25, 39))	('EGFR', 'Gene', (118, 122))	('EGFR', 'Gene', '1956', (118, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (25, 39))
444077	19136271	However, despite the presence of the same mutations in esophageal adenocarcinoma, clinical response to EGFR inhibition in esophageal adenocarcinoma has been modest.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (55, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('EGFR', 'Gene', '1956', (103, 107))	('inhibition', 'NegReg', (108, 118))	('EGFR', 'Gene', (103, 107))	('esophageal adenocarcinoma', 'Disease', (122, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (122, 147))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (122, 147))	('esophageal adenocarcinoma', 'Disease', (55, 80))	('mutations', 'Var', (42, 51))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (55, 80))
444131	19424485	In contrast, a positive correlation between an increased number of copies of the GRB7 gene and elevated mRNA expression levels was found in gastric cancers.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('gastric cancers', 'Disease', 'MESH:D013274', (140, 155))	('elevated', 'PosReg', (95, 103))	('gastric cancers', 'Disease', (140, 155))	('gastric cancers', 'Phenotype', 'HP:0012126', (140, 155))	('copies', 'Var', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('increased', 'PosReg', (47, 56))	('mRNA expression levels', 'MPA', (104, 126))	('GRB7', 'Gene', (81, 85))
444134	19424485	Co-amplification of ERBB2 and GRB7 was also found in human breast cancer cell lines, and has been additionally detected in non-invasive ductal carcinomas in situ .	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('GRB7', 'Protein', (30, 34))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('ERBB2', 'Gene', '2064', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('found', 'Reg', (44, 49))	('ERBB2', 'Gene', (20, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('ductal carcinomas', 'Disease', 'MESH:D044584', (136, 153))	('human', 'Species', '9606', (53, 58))	('ductal carcinomas in situ', 'Phenotype', 'HP:0030075', (136, 161))	('ductal carcinomas', 'Disease', (136, 153))	('Co-amplification', 'Var', (0, 16))
444138	19424485	Nevertheless, no association was found between common single-nucleotide polymorphisms (SNPs) in genes within the ERBB2 amplicon and the risk of developing breast cancer in a study conducted in over two thousand patients when compared to a similar number of control subjects.	('patients', 'Species', '9606', (211, 219))	('ERBB2', 'Gene', (113, 118))	('ERBB2', 'Gene', '2064', (113, 118))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('single-nucleotide polymorphisms', 'Var', (54, 85))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))
444139	19424485	The GRB7 gene also co-amplifies with additional genes located within the ERBB2 amplicon such as CAB1, A39, C51 and MLN64 in gastric and breast cancers.	('MLN64', 'Gene', '10948', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CAB1', 'Gene', (96, 100))	('MLN64', 'Gene', (115, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('CAB1', 'Gene', '10948', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('C51', 'Var', (107, 110))	('breast cancers', 'Phenotype', 'HP:0003002', (136, 150))	('gastric and breast cancers', 'Disease', 'MESH:D013274', (124, 150))	('ERBB2', 'Gene', (73, 78))	('ERBB2', 'Gene', '2064', (73, 78))	('A39', 'Var', (102, 105))	('GRB7', 'Gene', (4, 8))
444149	19424485	High expression of a prominent 4.7 kb transcript for the human GRB10 splice variant denoted GRB10/IR-SV1 (insulin receptor bind spliced variant 1) (hGrb10alpha), a 548 amino acid (61.9 kDa) protein, with a deletion of 80 amino acids in the PH domain and a distinct N-terminus addition as compared to the mouse Grb10, are found in skeletal muscle and pancreas, and in lesser quantities in heart, brain, placenta, lung, liver and kidney.	('hGrb10', 'Gene', (148, 154))	('hGrb10', 'Gene', '2887', (148, 154))	('insulin receptor', 'Gene', '3643', (106, 122))	('GRB10', 'Gene', (63, 68))	('skeletal muscle and pancreas', 'Disease', 'MESH:D010190', (330, 358))	('deletion', 'Var', (206, 214))	('mouse', 'Species', '10090', (304, 309))	('insulin receptor', 'Gene', (106, 122))	('human', 'Species', '9606', (57, 62))
444179	19424485	As a consequence of imprinting, a deviation of a Mendelian 1:1 female/male transmission ratio of the grandparental alleles in the paternal chromosome containing the imprinted gene GRB10 was found in females as compared to males where the fraction of the transmitted grandmaternal alleles was 0.38 and 0.5 respectively due to uneven loss of human embryos in the former.	('imprinting', 'Var', (20, 30))	('human', 'Species', '9606', (340, 345))	('GRB10', 'Gene', (180, 185))	('rat', 'Species', '10116', (88, 91))
444183	19424485	Furthermore, dysregulation of GRB10 has been detected in human metastatic malignant melanomas.	('detected', 'Reg', (45, 53))	('dysregulation', 'Var', (13, 26))	('malignant melanomas', 'Phenotype', 'HP:0002861', (74, 93))	('malignant melanomas', 'Disease', 'MESH:D008545', (74, 93))	('malignant melanomas', 'Disease', (74, 93))	('GRB10', 'Protein', (30, 35))	('human', 'Species', '9606', (57, 62))
444184	19424485	Several transgenic mouse lines with ectopic overexpression of Grb10 have been shown to present growth retardation after weaning and hyperinsulinemia due to insulin resistance.	('insulin', 'Gene', (156, 163))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (132, 148))	('Grb10', 'Gene', (62, 67))	('transgenic', 'Species', '10090', (8, 18))	('ectopic', 'Var', (36, 43))	('insulin', 'Gene', '3630', (156, 163))	('growth retardation', 'Disease', 'MESH:D006130', (95, 113))	('growth retardation', 'Disease', (95, 113))	('insulin resistance', 'Phenotype', 'HP:0000855', (156, 174))	('insulin', 'Gene', (137, 144))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (132, 148))	('growth retardation', 'Phenotype', 'HP:0001510', (95, 113))	('hyperinsulinemia', 'Disease', (132, 148))	('insulin', 'Gene', '3630', (137, 144))	('mouse', 'Species', '10090', (19, 24))
444185	19424485	Conversely, knockout mice with a disrupted Grb10 gene exhibited body overgrowth, particularly due to muscle mass increase accompanied by decreased adiposity, as well as increased glucose tolerance, insulin sensitivity and insulin-mediated cellular signaling.	('body overgrowth', 'CPA', (64, 79))	('insulin', 'Gene', (198, 205))	('mice', 'Species', '10090', (21, 25))	('insulin', 'Gene', (222, 229))	('muscle mass increase', 'Phenotype', 'HP:0003712', (101, 121))	('increased glucose', 'Phenotype', 'HP:0003074', (169, 186))	('adiposity', 'MPA', (147, 156))	('overgrowth', 'Phenotype', 'HP:0001548', (69, 79))	('glucose', 'Chemical', 'MESH:D005947', (179, 186))	('increased glucose tolerance', 'Phenotype', 'HP:0040270', (169, 196))	('disrupted', 'Var', (33, 42))	('increased', 'PosReg', (169, 178))	('insulin', 'Gene', '3630', (198, 205))	('insulin', 'Gene', '3630', (222, 229))	('increase', 'PosReg', (113, 121))	('glucose tolerance', 'CPA', (179, 196))	('decreased adiposity', 'Phenotype', 'HP:0040063', (137, 156))	('Grb10', 'Gene', (43, 48))	('decreased', 'NegReg', (137, 146))	('muscle mass', 'CPA', (101, 112))
444187	19424485	In this context, it has been shown that some SNPs in the GRB10 gene correlates indeed with type 2 diabetes in human.	('type 2 diabetes', 'Disease', (91, 106))	('GRB10', 'Gene', (57, 62))	('type 2 diabetes', 'Disease', 'MESH:D003924', (91, 106))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (91, 106))	('SNPs', 'Var', (45, 49))	('human', 'Species', '9606', (110, 115))	('with', 'Reg', (86, 90))
444188	19424485	Albeit the important role of Grb10 in organismal development, and in contrast to the RET tyrosine kinase, which is one of its upstream signaling receptors, mutations in GRB10 were not linked to Hirschsprung disease, a congenital condition characterized by the absence of intrinsic enteric ganglion cells in some sectors of the gastrointestinal track, including the colon, which results in a distended atonic megacolon.	('megacolon', 'Phenotype', 'HP:0002251', (408, 417))	('Hirschsprung disease', 'Disease', (194, 214))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (194, 214))	('Hirschsprung disease', 'Disease', 'MESH:D006627', (194, 214))	('mutations', 'Var', (156, 165))	('enteric ganglion', 'Phenotype', 'HP:0004362', (281, 297))	('linked', 'Reg', (184, 190))	('atonic megacolon', 'Disease', 'MESH:D008531', (401, 417))	('results in', 'Reg', (378, 388))	('atonic megacolon', 'Disease', (401, 417))	('GRB10', 'Gene', (169, 174))	('tyrosine', 'Chemical', 'MESH:D014443', (89, 97))
444198	19424485	Also, mutations in GRB10 accounting for a proline to serine substitution at residue 95 of Grb10 were detected in two out of 58 screened SRS patients, although an additional study did not reveal GRB10 mutations in a subset of 18 SRS patients with non-matUPD7.	('SRS', 'Gene', '140821', (136, 139))	('Grb10', 'Gene', (90, 95))	('SRS', 'Gene', (228, 231))	('patients', 'Species', '9606', (232, 240))	('GRB10', 'Gene', (19, 24))	('detected', 'Reg', (101, 109))	('SRS', 'Gene', (136, 139))	('proline to serine substitution at residue 95', 'Mutation', 'rs80244589', (42, 86))	('SRS', 'Gene', '140821', (228, 231))	('patients', 'Species', '9606', (140, 148))	('mutations', 'Var', (6, 15))
444200	19424485	Furthermore, no epimutations in the differentially-methylated region of the GRB10 gene were found in a large set of 46 screened SRS patients performed in two independent studies.	('epimutations', 'Var', (16, 28))	('SRS', 'Gene', '140821', (128, 131))	('GRB10', 'Gene', (76, 81))	('patients', 'Species', '9606', (132, 140))	('SRS', 'Gene', (128, 131))
444211	19424485	Given the negative control exerted by the Grb10 and Grb14 proteins on cell proliferation (see for reviews and references therein), it should be of interest to perform a systematic screening of tumors in search of disabling mutations affecting the GRB10 and GRB14 genes, in order to determine whether they might work as tumor suppressor genes.	('tumor', 'Disease', (319, 324))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('GRB10', 'Gene', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('rat', 'Species', '10116', (82, 85))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Disease', (193, 198))	('mutations', 'Var', (223, 232))	('GRB14', 'Gene', (257, 262))
444212	19424485	Alternatively, and given that Grb10 also appears to exert a promitogenic function in some context, it should be of interest to explore whether mutations in the GRB10 gene, in addition to those already known, could be of relevance to explain the high proliferation rate of some tumors.	('GRB10', 'Gene', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('promitogenic function', 'MPA', (60, 81))	('rat', 'Species', '10116', (257, 260))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('rat', 'Species', '10116', (264, 267))	('mutations', 'Var', (143, 152))	('tumors', 'Disease', (277, 283))
444221	19043591	The results of this study suggest the environment of the esophagus in BE patients can both generate and select for clones with p16 mutations.	('mutations', 'Var', (131, 140))	('BE', 'Phenotype', 'HP:0100580', (70, 72))	('p16', 'Gene', (127, 130))	('p16', 'Gene', '1029', (127, 130))	('patients', 'Species', '9606', (73, 81))
444223	19043591	Germline mutations in p16 have been associated with familial melanoma syndromes, and somatic alterations in p16 have been detected in a wide variety of cancers.	('Germline mutations', 'Var', (0, 18))	('cancers', 'Disease', (152, 159))	('p16', 'Gene', '1029', (108, 111))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('familial melanoma syndromes', 'Disease', (52, 79))	('p16', 'Gene', '1029', (22, 25))	('familial melanoma syndromes', 'Disease', 'OMIM:155600', (52, 79))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('p16', 'Gene', (108, 111))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('associated', 'Reg', (36, 46))	('p16', 'Gene', (22, 25))	('detected', 'Reg', (122, 130))
444224	19043591	Given its role in modulating cell proliferation, it is not surprising that p16 alterations are one of the most common genetic/epigenetic alterations in cancer.	('alterations', 'Var', (79, 90))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('p16', 'Gene', '1029', (75, 78))	('cell proliferation', 'CPA', (29, 47))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('p16', 'Gene', (75, 78))
444230	19043591	A number of studies have examined the involvement of p16 mutations in esophageal cancer, the majority of which have focused primarily upon SCC.	('SCC', 'Gene', '6317', (139, 142))	('p16', 'Gene', (53, 56))	('esophageal cancer', 'Disease', (70, 87))	('involvement', 'Reg', (38, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('mutations', 'Var', (57, 66))	('p16', 'Gene', '1029', (53, 56))	('SCC', 'Gene', (139, 142))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
444231	19043591	Less is know concerning the frequency and spectrum of p16 mutations in EA, and very little about p16 mutations in BE.	('p16', 'Gene', (54, 57))	('mutations', 'Var', (58, 67))	('p16', 'Gene', '1029', (97, 100))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('p16', 'Gene', '1029', (54, 57))	('p16', 'Gene', (97, 100))	('EA', 'Phenotype', 'HP:0011459', (71, 73))
444232	19043591	Here, we report p16 mutation detection and characterization in a prospective cohort study of 304 patients with BE and from 19 patients for which esophagectomy samples were available.	('BE', 'Phenotype', 'HP:0100580', (111, 113))	('p16', 'Gene', '1029', (16, 19))	('mutation', 'Var', (20, 28))	('patients', 'Species', '9606', (126, 134))	('p16', 'Gene', (16, 19))	('patients', 'Species', '9606', (97, 105))
444233	19043591	We find p16 mutations can occur very early during neoplastic progression in BE, and the spectrum of mutation is consistent with that of oxidative damage that can be generated as a result of chronic reflux.	('BE', 'Phenotype', 'HP:0100580', (76, 78))	('p16', 'Gene', '1029', (8, 11))	('mutations', 'Var', (12, 21))	('chronic reflux', 'Phenotype', 'HP:0002020', (190, 204))	('p16', 'Gene', (8, 11))
444251	19043591	Evaluation of mutations in exon 2 of the p16 gene was performed on an aliquot of genomic DNA that had undergone whole genome amplification (PEP) as previously described.	('p16', 'Gene', (41, 44))	('PEP', 'Gene', (140, 143))	('PEP', 'Gene', '5047', (140, 143))	('mutations', 'Var', (14, 23))	('p16', 'Gene', '1029', (41, 44))
444252	19043591	We sequenced exon 2 of p16 since the vast majority of p16 mutations reported in the literature lie within this exon.	('p16', 'Gene', (54, 57))	('mutations', 'Var', (58, 67))	('p16', 'Gene', (23, 26))	('p16', 'Gene', '1029', (54, 57))	('p16', 'Gene', '1029', (23, 26))
444254	19043591	The mutation sequence for 2 patients have been previously reported and the frequency of p16 mutations, but not the sequences, for a subset of the patients in this study (N = 107) was reported in a previous publication.	('p16', 'Gene', (88, 91))	('mutations', 'Var', (92, 101))	('p16', 'Gene', '1029', (88, 91))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (146, 154))
444257	19043591	LOH was further defined as copy neutral (loss of one allele, but no change in copy number) or copy loss LOH (loss of one allele due to deletion of p16 sequence).	('deletion', 'Var', (135, 143))	('p16', 'Gene', (147, 150))	('loss', 'NegReg', (109, 113))	('p16', 'Gene', '1029', (147, 150))	('copy', 'Var', (94, 98))	('loss', 'NegReg', (41, 45))
444258	19043591	Deletion data were available for 105 samples from 65 patients for analysis of copy neutral and copy loss LOH.	('copy', 'Var', (95, 99))	('copy neutral', 'Var', (78, 90))	('patients', 'Species', '9606', (53, 61))	('Deletion', 'Var', (0, 8))
444260	19043591	Assessment of a trend for more p16 mutations in samples from patients with more advanced histologic diagnoses was performed using the Cochran-Armitage trend test.	('p16', 'Gene', '1029', (31, 34))	('p16', 'Gene', (31, 34))	('patients', 'Species', '9606', (61, 69))	('mutations', 'Var', (35, 44))
444264	19043591	Three patients had two different p16 mutations that were located in spatially distinct regions of the Barrett's segment.	('mutations', 'Var', (37, 46))	('p16', 'Gene', '1029', (33, 36))	('p16', 'Gene', (33, 36))	('patients', 'Species', '9606', (6, 14))
444266	19043591	Sixty percent of the mutations occurred at three sites-bp 172 (R58X), bp 238 (R80X) and bp 247 (H83Y)-and were all C T transitions.	('R80X', 'Mutation', 'rs121913388', (78, 82))	('H83Y', 'Mutation', 'rs121913385', (96, 100))	('R80X', 'Var', (78, 82))	('R58X', 'Mutation', 'rs121913387', (63, 67))	('occurred', 'Reg', (31, 39))	('mutations', 'Var', (21, 30))
444267	19043591	Of the 36 point mutations, 88% (32/36) resulted in either a conservative amino acid change or no change in the coding sequence of p14 ARF.	('p14 ARF', 'Gene', '1029', (130, 137))	('resulted in', 'Reg', (39, 50))	('point mutations', 'Var', (10, 25))	('p14 ARF', 'Gene', (130, 137))	('conservative amino acid', 'MPA', (60, 83))
444268	19043591	Seven patients of the 27 having samples from esophagectomy specimens had mutations in p16 (Table 3).	('p16', 'Gene', (86, 89))	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (73, 82))	('p16', 'Gene', '1029', (86, 89))
444269	19043591	Some patients (n = 8) had samples available both from baseline endoscopy as well as from an esophagectomy: of these 8 patients, all those that had a p16 mutation present in the esophagectomy specimen (n = 4) had the same mutation(s) present at baseline endoscopy.	('p16', 'Gene', '1029', (149, 152))	('patients', 'Species', '9606', (5, 13))	('p16', 'Gene', (149, 152))	('patients', 'Species', '9606', (118, 126))	('mutation', 'Var', (153, 161))
444271	19043591	Consistent with earlier studies, clonal cell populations with p16 mutations were found to have expanded in the Barrett's segment.	('mutations', 'Var', (66, 75))	('p16', 'Gene', '1029', (62, 65))	('p16', 'Gene', (62, 65))
444272	19043591	Among patients whose Barrett's segment length was >=2 cm, p16 mutations extended over an average of 66.4% of the Barrett's epithelium, including cases in which the same mutation was detected in 6 biopsies across 12 cm of esophageal mucosa.	('p16', 'Gene', (58, 61))	('esophageal mucosa', 'Disease', (221, 238))	('esophageal mucosa', 'Disease', 'MESH:D004941', (221, 238))	('patients', 'Species', '9606', (6, 14))	('p16', 'Gene', '1029', (58, 61))	('mutations', 'Var', (62, 71))
444273	19043591	p16 mutation represents one of the two hits required to inactivate the gene, along with copy neutral LOH, deletion/copy loss LOH, or promoter hypermethylation; therefore, we examined the associations between p16 mutation, LOH and deletion in patients with BE.	('examined', 'Reg', (174, 182))	('p16', 'Gene', (0, 3))	('mutation', 'Var', (212, 220))	('BE', 'Phenotype', 'HP:0100580', (256, 258))	('p16', 'Gene', '1029', (208, 211))	('deletion', 'Var', (230, 238))	('p16', 'Gene', '1029', (0, 3))	('p16', 'Gene', (208, 211))	('patients', 'Species', '9606', (242, 250))
444274	19043591	However, we found copy neutral LOH was much more common in samples with a p16 mutation (7/8, 87.5%) than in samples without a p16 mutation (20/45, 44.4%) (p = 0.05), and that p16 mutation was found in samples with copy neutral LOH significantly more often than with copy loss LOH (7/27 vs 1/26, p = 0.05).	('p16', 'Gene', (74, 77))	('mutation', 'Var', (78, 86))	('p16', 'Gene', (175, 178))	('copy neutral', 'Var', (214, 226))	('p16', 'Gene', (126, 129))	('copy', 'Disease', (18, 22))	('p16', 'Gene', '1029', (74, 77))	('p16', 'Gene', '1029', (175, 178))	('p16', 'Gene', '1029', (126, 129))
444275	19043591	Finally, we examined the order in which p16 mutation and LOH (either type) occurred in this BE cohort.	('p16', 'Gene', (40, 43))	('mutation', 'Var', (44, 52))	('BE', 'Phenotype', 'HP:0100580', (92, 94))	('p16', 'Gene', '1029', (40, 43))
444277	19043591	Previous studies examining the frequency of p16 mutation in esophageal cancer have focused primarily upon SCC in surgical resections, with reported frequencies of mutation ranging from 0% to 52%, with most studies reporting 15-20%.	('p16', 'Gene', (44, 47))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('SCC', 'Gene', '6317', (106, 109))	('esophageal cancer', 'Disease', (60, 77))	('p16', 'Gene', '1029', (44, 47))	('mutation', 'Var', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('SCC', 'Gene', (106, 109))
444278	19043591	We found 15.8% of esophagectomy samples to have p16 mutations, similar to the frequency in BE patients (14.5%) .	('mutations', 'Var', (52, 61))	('p16', 'Gene', '1029', (48, 51))	('patients', 'Species', '9606', (94, 102))	('BE', 'Phenotype', 'HP:0100580', (91, 93))	('p16', 'Gene', (48, 51))	('esophagectomy', 'Disease', (18, 31))
444279	19043591	Our study provides the most extensive examination to date of p16 mutations in a premalignant tissue (BE).	('p16', 'Gene', '1029', (61, 64))	('p16', 'Gene', (61, 64))	('mutations', 'Var', (65, 74))	('BE', 'Phenotype', 'HP:0100580', (101, 103))
444280	19043591	p16 mutations were detected at all histologic grades, indicating they can develop as very early events in neoplastic progression of BE.	('mutations', 'Var', (4, 13))	('p16', 'Gene', '1029', (0, 3))	('p16', 'Gene', (0, 3))	('BE', 'Phenotype', 'HP:0100580', (132, 134))
444281	19043591	Since p16 can be inactivated by multiple mechanisms, including methylation and LOH, analysis of cancer risk associated with p16 mutation alone was not possible in this study.	('p16', 'Gene', '1029', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('p16', 'Gene', (6, 9))	('LOH', 'Var', (79, 82))	('p16', 'Gene', (124, 127))	('methylation', 'Var', (63, 74))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('p16', 'Gene', '1029', (6, 9))	('cancer', 'Disease', (96, 102))
444282	19043591	However, we have evaluated a cohort of 138 patients for whom mutation, LOH and methylation were evaluated and found no difference in cancer risk between patients with p16 mutation alone vs. methylation or LOH alone (TG Paulson, unpublished observations).	('patients', 'Species', '9606', (153, 161))	('mutation', 'Var', (171, 179))	('patients', 'Species', '9606', (43, 51))	('p16', 'Gene', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('p16', 'Gene', '1029', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
444285	19043591	Mutations at the p16 codons altered in BE have been observed in a variety of cancers, including melanoma, bladder, oral SCC and NSCLC.	('observed', 'Reg', (52, 60))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('BE', 'Phenotype', 'HP:0100580', (39, 41))	('cancers', 'Disease', (77, 84))	('p16', 'Gene', (17, 20))	('NSCLC', 'Disease', (128, 133))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('bladder', 'Disease', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('p16', 'Gene', '1029', (17, 20))	('melanoma', 'Disease', (96, 104))	('SCC', 'Gene', (120, 123))
444286	19043591	Two of the three most common mutations observed in BE, at amino acids 58 and 80 (bp 172 and 238, respectively), result in a truncated protein, and the third most common BE alteration, H83Y (bp 247), has been shown to be defective in biochemical analyses.	('BE', 'Phenotype', 'HP:0100580', (169, 171))	('H83Y (bp 247', 'Var', (184, 196))	('result in', 'Reg', (112, 121))	('H83Y', 'Mutation', 'rs121913385', (184, 188))	('protein', 'Protein', (134, 141))	('truncated', 'MPA', (124, 133))	('BE', 'Phenotype', 'HP:0100580', (51, 53))
444289	19043591	Direct exposure to acid and bile reflux and the subsequent chronic inflammation are two potential sources of oxidative damage characteristic of patients with BE.The higher frequency of p16 mutation at later stages of BE and the fact that genetic alterations that have been shown to occur later during neoplastic progression in BE, such as p53 mutations, also display a similar mutation spectrum, suggest that the ROS generated by tissue damage and inflammation continue to act through neoplastic progression.	('inflammation', 'Disease', 'MESH:D007249', (448, 460))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('p16', 'Gene', (185, 188))	('ROS', 'Chemical', '-', (413, 416))	('BE', 'Phenotype', 'HP:0100580', (327, 329))	('mutation', 'Var', (189, 197))	('patients', 'Species', '9606', (144, 152))	('inflammation', 'Disease', (448, 460))	('inflammation', 'Disease', (67, 79))	('BE', 'Phenotype', 'HP:0100580', (158, 160))	('mutations', 'Var', (343, 352))	('p53', 'Gene', (339, 342))	('p53', 'Gene', '7157', (339, 342))	('BE', 'Phenotype', 'HP:0100580', (217, 219))	('p16', 'Gene', '1029', (185, 188))
444294	19043591	Our study was performed in a tertiary referral center and our research cohort therefore has a higher percentage of patients with a diagnosis of dysplasia than the general BE population; however, this is unlikely to have affected the p16 mutation spectrum reported here because we also detected p16 mutations in patients without high-grade dysplasia, indicating p16 mutations can occur very early during neoplastic progression.	('p16', 'Gene', '1029', (233, 236))	('dysplasia', 'Disease', 'MESH:D004476', (144, 153))	('patients', 'Species', '9606', (115, 123))	('dysplasia', 'Disease', 'MESH:D004476', (339, 348))	('p16', 'Gene', (294, 297))	('p16', 'Gene', (233, 236))	('dysplasia', 'Disease', (144, 153))	('p16', 'Gene', '1029', (361, 364))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('patients', 'Species', '9606', (311, 319))	('mutations', 'Var', (298, 307))	('p16', 'Gene', '1029', (294, 297))	('p16', 'Gene', (361, 364))	('dysplasia', 'Disease', (339, 348))
444296	19043591	All of the data obtained in this study are consistent with Knudsen's two-hit model for inactivating tumor suppressor genes.	('tumor', 'Disease', (100, 105))	('inactivating', 'Var', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))
444302	19043591	The frequency of p16 mutation we detected is higher than previously reported in EA or in BE found in surgical resections.	('p16', 'Gene', (17, 20))	('mutation', 'Var', (21, 29))	('EA', 'Phenotype', 'HP:0011459', (80, 82))	('BE', 'Phenotype', 'HP:0100580', (89, 91))	('p16', 'Gene', '1029', (17, 20))
444303	19043591	The results from this study provide strong evidence that alterations in p16 occur early during neoplastic progression in patients with BE and that the physiological consequences of chronic gastroduodenal reflux are the likely causes of these alterations.	('p16', 'Gene', '1029', (72, 75))	('BE', 'Phenotype', 'HP:0100580', (135, 137))	('alterations', 'Var', (57, 68))	('p16', 'Gene', (72, 75))	('gastroduodenal reflux', 'Phenotype', 'HP:0002020', (189, 210))	('patients', 'Species', '9606', (121, 129))
444311	33391428	The apoptotic cell analysis showed that the knockdown of TRIM37 increased apoptosis in comparison with the control.	('apoptosis', 'CPA', (74, 83))	('TRIM37', 'Gene', (57, 63))	('knockdown', 'Var', (44, 53))	('TRIM37', 'Gene', '4591', (57, 63))	('increased', 'PosReg', (64, 73))
444312	33391428	In TRIM37 overexpressing GC cells, knockdown of TRIM37 suppressed the migration and invasion.	('knockdown', 'Var', (35, 44))	('TRIM37', 'Gene', '4591', (3, 9))	('TRIM37', 'Gene', '4591', (48, 54))	('suppressed', 'NegReg', (55, 65))	('TRIM37', 'Gene', (3, 9))	('TRIM37', 'Gene', (48, 54))
444316	33391428	Although accumulating evidence shows that several genetic alterations can cause tumor progression and tumorigenesis in GC, some therapeutic targets have been identified, such as gene amplification of MET and ERBB2; mutations in TP53, APC, and E-cadherin ; K-ras  and hypermethylation of p16 ; oncogenic activation of beta-catenin; and inactivation of the mismatch-repair gene hMLH1, which is associated with microsatellite instability.	('ERBB2', 'Gene', (208, 213))	('microsatellite instability', 'Disease', 'MESH:D053842', (408, 434))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('microsatellite instability', 'Disease', (408, 434))	('TP53', 'Gene', (228, 232))	('K-ras', 'Gene', '3845', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('MET', 'Gene', (200, 203))	('alterations', 'Var', (58, 69))	('ERBB2', 'Gene', '2064', (208, 213))	('beta-catenin', 'Gene', (317, 329))	('beta-catenin', 'Gene', '1499', (317, 329))	('hMLH1', 'Gene', (376, 381))	('mutations', 'Var', (215, 224))	('E-cadherin', 'Gene', (243, 253))	('E-cadherin', 'Gene', '999', (243, 253))	('hMLH1', 'Gene', '4292', (376, 381))	('inactivation', 'Var', (335, 347))	('activation', 'PosReg', (303, 313))	('p16', 'Gene', (287, 290))	('APC', 'Disease', 'MESH:D011125', (234, 237))	('tumor', 'Disease', (80, 85))	('K-ras', 'Gene', (256, 261))	('APC', 'Disease', (234, 237))	('MET', 'Gene', '79811', (200, 203))	('hypermethylation', 'Var', (267, 283))	('TP53', 'Gene', '7157', (228, 232))	('p16', 'Gene', '1029', (287, 290))	('tumor', 'Disease', (102, 107))	('cause', 'Reg', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (102, 107))
444322	33391428	In addition, TRIM37 is located at the critical region of 17q23, in which genomic high-copy amplification has been reported to contribute to the progression of several types of cancer, including prostate cancer, germ cell, glioblastoma, head and neck squamous cell carcinoma, as well as GC.	('glioblastoma', 'Disease', (222, 234))	('TRIM37', 'Gene', '4591', (13, 19))	('high-copy amplification', 'Var', (81, 104))	('germ cell', 'Disease', (211, 220))	('glioblastoma', 'Phenotype', 'HP:0012174', (222, 234))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('contribute to', 'Reg', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('prostate cancer', 'Disease', 'MESH:D011471', (194, 209))	('prostate cancer', 'Phenotype', 'HP:0012125', (194, 209))	('prostate cancer', 'Disease', (194, 209))	('neck squamous cell carcinoma', 'Disease', (245, 273))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('TRIM37', 'Gene', (13, 19))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (245, 273))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (250, 273))	('cancer', 'Disease', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('glioblastoma', 'Disease', 'MESH:D005909', (222, 234))	('cancer', 'Disease', (176, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))
444326	33391428	We also demonstrated that knockdown of TRIM37 expression in TRIM37-overexpressing GC cells suppressed cell proliferation, migration, invasion, and chemoresistance to cisplatin (CDDP).	('suppressed', 'NegReg', (91, 101))	('invasion', 'CPA', (133, 141))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('CDDP', 'Chemical', '-', (177, 181))	('TRIM37', 'Gene', (39, 45))	('knockdown', 'Var', (26, 35))	('TRIM37', 'Gene', (60, 66))	('migration', 'CPA', (122, 131))	('TRIM37', 'Gene', '4591', (39, 45))	('chemoresistance', 'CPA', (147, 162))	('cell proliferation', 'CPA', (102, 120))	('TRIM37', 'Gene', '4591', (60, 66))
444347	33391428	To assess the chemoresistance of GC cell lines to CDDP and paclitaxel (PTX), NUGC4 (wild-type TP53) and MKN7 (mutant TP53) that had been transfected with siRNA-TRIM37 and its control were plated onto 6-well plates (NUGC4, 3 x 104 cells; MKN7, 5 x 104 cells per well) and incubated overnight under normal culture conditions.	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('PTX', 'Chemical', 'MESH:D017239', (71, 74))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('mutant', 'Var', (110, 116))	('TRIM37', 'Gene', (160, 166))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('CDDP', 'Chemical', '-', (50, 54))	('TRIM37', 'Gene', '4591', (160, 166))
444366	33391428	The status of these TP53 mutations in various cell lines was positively associated with those in the database (http://p53.free.fr/index.html; W: wild-type TP53, M: mutant TP53).	('TP53', 'Gene', (171, 175))	('mutant', 'Var', (164, 170))	('mutations', 'Var', (25, 34))	('TP53', 'Gene', (20, 24))	('TP53', 'Gene', '7157', (155, 159))	('p53', 'Gene', (118, 121))	('TP53', 'Gene', (155, 159))	('p53', 'Gene', '7157', (118, 121))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', '7157', (171, 175))
444367	33391428	Note that, among TP53-mutated GC cell lines, KATO-III and HGC27 cells have a p53 gene deletion and a frameshift mutation, respectively.	('frameshift mutation', 'Var', (101, 120))	('HGC27', 'CellLine', 'CVCL:1279', (58, 63))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
444380	33391428	To gain insights into the potential role of TRIM37 as an oncogene whose overexpression may be associated with gastric carcinogenesis, we first performed a cell-proliferation assay using siRNAs specific to TRIM37 to investigate whether knockdown of TRIM37 would suppress the proliferation of GC cells that overexpress TRIM37.	('TRIM37', 'Gene', '4591', (44, 50))	('TRIM37', 'Gene', (248, 254))	('knockdown', 'Var', (235, 244))	('TRIM37', 'Gene', (317, 323))	('gastric carcinogenesis', 'Disease', (110, 132))	('TRIM37', 'Gene', (205, 211))	('TRIM37', 'Gene', '4591', (248, 254))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (110, 132))	('GC cells', 'CPA', (291, 299))	('associated', 'Reg', (94, 104))	('TRIM37', 'Gene', '4591', (317, 323))	('TRIM37', 'Gene', (44, 50))	('TRIM37', 'Gene', '4591', (205, 211))	('proliferation', 'CPA', (274, 287))	('overexpress', 'PosReg', (305, 316))	('suppress', 'NegReg', (261, 269))
444382	33391428	The proliferation of these cell lines was particularly suppressed following the knockdown of endogenous TRIM37 expression (Figure 2B).	('knockdown', 'Var', (80, 89))	('proliferation', 'CPA', (4, 17))	('TRIM37', 'Gene', (104, 110))	('TRIM37', 'Gene', '4591', (104, 110))	('suppressed', 'NegReg', (55, 65))	('endogenous', 'Var', (93, 103))
444383	33391428	To investigate the mechanisms by which the knockdown of TRIM37 suppressed cell proliferation, we performed a cell cycle analysis and an apoptosis assay.	('cell proliferation', 'CPA', (74, 92))	('TRIM37', 'Gene', (56, 62))	('knockdown', 'Var', (43, 52))	('TRIM37', 'Gene', '4591', (56, 62))	('suppressed', 'NegReg', (63, 73))
444384	33391428	FACS analysis demonstrated that transfection of TP53 wild-type NUGC4 cells with siRNA-TRIM37 resulted in an accumulation of cells in G2/M phase compared with their transfection with control siRNA, while transfection of TP53 mutant MKN7 with siRNA-TRIM37 resulted in an accumulation of cells in the sub-G1 phase compared with transfection with control siRNA (Figure 2B).	('TRIM37', 'Gene', (86, 92))	('TP53', 'Gene', '7157', (48, 52))	('mutant', 'Var', (224, 230))	('TRIM37', 'Gene', '4591', (247, 253))	('TP53', 'Gene', (219, 223))	('accumulation', 'PosReg', (108, 120))	('TP53', 'Gene', (48, 52))	('TRIM37', 'Gene', '4591', (86, 92))	('cells', 'CPA', (124, 129))	('accumulation', 'PosReg', (269, 281))	('G2/M phase', 'CPA', (133, 143))	('TRIM37', 'Gene', (247, 253))	('sub-G1 phase', 'CPA', (298, 310))	('TP53', 'Gene', '7157', (219, 223))
444385	33391428	Apoptotic cell analysis showed that transfection of TP53 wild-type NUGC4 and TP53 mutant MKN7 with siRNA-TRIM37 increased early apoptosis (annexin V-positive/PI-negative) and late apoptosis (annexin V/PI-double positive), respectively, at 72 h post-transfection compared with transfection with control siRNA (Figure 2B).	('NUGC4', 'Gene', (67, 72))	('late apoptosis', 'CPA', (175, 189))	('TRIM37', 'Gene', '4591', (105, 111))	('TP53', 'Gene', '7157', (52, 56))	('annexin V', 'Gene', '308', (139, 148))	('MKN7', 'Gene', (89, 93))	('TP53', 'Gene', (52, 56))	('annexin V', 'Gene', (139, 148))	('annexin V', 'Gene', '308', (191, 200))	('annexin V', 'Gene', (191, 200))	('TRIM37', 'Gene', (105, 111))	('increased', 'PosReg', (112, 121))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('mutant', 'Var', (82, 88))
444386	33391428	These findings suggest that the knockdown of TRIM37 overexpression induces cell apoptosis.	('cell apoptosis', 'CPA', (75, 89))	('TRIM37', 'Gene', '4591', (45, 51))	('knockdown', 'Var', (32, 41))	('induces', 'Reg', (67, 74))	('overexpression', 'PosReg', (52, 66))	('TRIM37', 'Gene', (45, 51))
444389	33391428	We examined the ability of TP53 wild-type NUGC4 and TP53 mutant MKN7 cells transfected with siRNA-TRIM37 to move through pores under different conditions.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('TRIM37', 'Gene', '4591', (98, 104))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))	('mutant', 'Var', (57, 63))	('TRIM37', 'Gene', (98, 104))
444391	33391428	These results suggest that the overexpression of TRIM37 may enhance the ability of GC cells to migrate and invade in both the p53 wild-type and the p53 mutant cell lines.	('p53', 'Gene', '7157', (126, 129))	('p53', 'Gene', (148, 151))	('TRIM37', 'Gene', (49, 55))	('p53', 'Gene', '7157', (148, 151))	('invade', 'CPA', (107, 113))	('TRIM37', 'Gene', '4591', (49, 55))	('mutant', 'Var', (152, 158))	('enhance', 'PosReg', (60, 67))	('p53', 'Gene', (126, 129))	('overexpression', 'PosReg', (31, 45))
444393	33391428	The knockdown of TRIM37 expression by transfection with siRNA-TRIM37 suppressed the production of ZEB1 and induced the production of E-cadherin in both TP53 wild-type and TP53 mutant cells (NUGC4 and MKN7, Figure 3A).	('TP53', 'Gene', (171, 175))	('TRIM37', 'Gene', '4591', (17, 23))	('TRIM37', 'Gene', '4591', (62, 68))	('mutant', 'Var', (176, 182))	('production', 'MPA', (119, 129))	('E-cadherin', 'Gene', (133, 143))	('TP53', 'Gene', '7157', (152, 156))	('TP53', 'Gene', '7157', (171, 175))	('ZEB1', 'Gene', (98, 102))	('induced', 'PosReg', (107, 114))	('ZEB1', 'Gene', '6935', (98, 102))	('suppressed', 'NegReg', (69, 79))	('TP53', 'Gene', (152, 156))	('E-cadherin', 'Gene', '999', (133, 143))	('TRIM37', 'Gene', (17, 23))	('TRIM37', 'Gene', (62, 68))
444396	33391428	Recently, it has been reported that high levels of expression of TRIM37 are associated with chemoresistance to CDDP in esophageal cancer and osteosarcoma.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CDDP', 'Chemical', '-', (111, 115))	('TRIM37', 'Gene', (65, 71))	('high levels of', 'Var', (36, 50))	('cancer', 'Disease', (130, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (141, 153))	('chemoresistance', 'CPA', (92, 107))	('associated', 'Reg', (76, 86))	('osteosarcoma', 'Disease', (141, 153))	('expression', 'MPA', (51, 61))	('TRIM37', 'Gene', '4591', (65, 71))	('osteosarcoma', 'Disease', 'MESH:D012516', (141, 153))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
444398	33391428	When treated with CDDP, transfection of TP53 wild-type NUGC4 and TP53 mutant MKN7 with siRNA-TRIM37 increased early apoptosis, at 72 h post-transfection, compared with transfection with control siRNA.	('CDDP', 'Chemical', '-', (18, 22))	('TP53', 'Gene', '7157', (65, 69))	('increased', 'PosReg', (100, 109))	('TP53', 'Gene', (65, 69))	('MKN7', 'Gene', (77, 81))	('mutant', 'Var', (70, 76))	('TRIM37', 'Gene', (93, 99))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('TRIM37', 'Gene', '4591', (93, 99))
444399	33391428	However, when treated with PTX, chemosensitivity was not related to the status of TRIM37 expression in either the TP53 wild-type NUGC4 or TP53 mutant MKN7 (Figure 4A and 4B).	('TRIM37', 'Gene', '4591', (82, 88))	('TP53', 'Gene', '7157', (138, 142))	('mutant', 'Var', (143, 149))	('TP53', 'Gene', (138, 142))	('TP53', 'Gene', '7157', (114, 118))	('PTX', 'Chemical', 'MESH:D017239', (27, 30))	('TP53', 'Gene', (114, 118))	('TRIM37', 'Gene', (82, 88))
444401	33391428	Furthermore, the knockdown of TRIM37 inhibits cell proliferation, migration, invasion, and chemoresistance to CDDP.	('TRIM37', 'Gene', '4591', (30, 36))	('CDDP', 'Chemical', '-', (110, 114))	('migration', 'CPA', (66, 75))	('invasion', 'CPA', (77, 85))	('chemoresistance to CDDP', 'CPA', (91, 114))	('TRIM37', 'Gene', (30, 36))	('knockdown', 'Var', (17, 26))	('inhibits', 'NegReg', (37, 45))	('cell proliferation', 'CPA', (46, 64))
444406	33391428	This result suggests that immunoreactivity to TRIM37 may be a useful independent prognostic factor in patients with GC.	('immunoreactivity', 'Var', (26, 42))	('patients', 'Species', '9606', (102, 110))	('TRIM37', 'Gene', (46, 52))	('TRIM37', 'Gene', '4591', (46, 52))
444409	33391428	In our in vitro analyses, knockdown of TRIM37 overexpression induced G2/M cell-cycle arrest in wild-type TP53 cells and G0/G1 cell-cycle arrest in mutant TP53 cells.	('arrest', 'Disease', (137, 143))	('mutant', 'Var', (147, 153))	('overexpression', 'PosReg', (46, 60))	('TP53', 'Gene', (154, 158))	('TP53', 'Gene', '7157', (154, 158))	('TRIM37', 'Gene', (39, 45))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('TRIM37', 'Gene', '4591', (39, 45))	('arrest', 'Disease', (85, 91))
444414	33391428	We found that the knockdown of TRIM37 suppressed cell migration and invasion in both wild-type and mutant TP53 cells.	('cell migration', 'CPA', (49, 63))	('TRIM37', 'Gene', '4591', (31, 37))	('suppressed', 'NegReg', (38, 48))	('TP53', 'Gene', (106, 110))	('mutant', 'Var', (99, 105))	('TP53', 'Gene', '7157', (106, 110))	('TRIM37', 'Gene', (31, 37))
444423	33391428	We found that knockdown of TRIM37 was associated with chemoresistance to CDDP, but not with chemoresistance to PTX.	('CDDP', 'Chemical', '-', (73, 77))	('TRIM37', 'Gene', (27, 33))	('PTX', 'Chemical', 'MESH:D017239', (111, 114))	('associated', 'Reg', (38, 48))	('chemoresistance', 'CPA', (54, 69))	('TRIM37', 'Gene', '4591', (27, 33))	('knockdown', 'Var', (14, 23))
444471	30421504	Using highly related coding genes based on GO Biological Process enrichment analysis, we observed that lncRNAs may play important roles in the progresses associated with peptide cross-link, keratinization, and nucleosome assembly (Fig 2d).	('peptide', 'Var', (170, 177))	('lncRNAs', 'Gene', (103, 110))	('men', 'Species', '9606', (71, 74))
444486	30421504	Population-based studies have shown that esophageal cancer is predominant in men aged >= 60 years, many of whom also have a history of heavy tobacco and alcohol use.27 China has a high-incidence of ESCC, the most common histological subtype of esophageal cancer.5, 28 The mean ESCC male to female ratio is 3:1.4, 29, 30 Based on these epidemiological characteristics, we chose patients in the GSE53625 dataset, which represents features of ESCC.	('GSE53625', 'Var', (393, 401))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', (244, 261))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('alcohol use', 'Phenotype', 'HP:0030955', (153, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('men', 'Species', '9606', (77, 80))	('patients', 'Species', '9606', (377, 385))	('tobacco', 'Species', '4097', (141, 148))	('alcohol', 'Chemical', 'MESH:D000438', (153, 160))	('esophageal cancer', 'Disease', (41, 58))
444491	30421504	also reported that lncRNA CCAT1, which shows significantly increased expression in ESCC, could serve as a scaffold for two distinct epigenetic modifications that facilitate cell growth and migration.34 These results indicate that lncRNA may affect the regulation of epigenetics.	('regulation', 'MPA', (252, 262))	('CCAT1', 'Gene', '100507056', (26, 31))	('CCAT1', 'Gene', (26, 31))	('lncRNA', 'Var', (230, 236))	('affect', 'Reg', (241, 247))
444517	30518397	Recent studies demonstrated that inflammation could initiate and promote malignant transformation, whereas the genetic and epigenetic changes of malignant cells could generate the inflammatory microenvironment to further support the progression of the tumor.	('support', 'PosReg', (221, 228))	('malignant transformation', 'CPA', (73, 97))	('genetic', 'Var', (111, 118))	('inflammation', 'Disease', 'MESH:D007249', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('epigenetic changes', 'Var', (123, 141))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('inflammation', 'Disease', (33, 45))	('promote', 'PosReg', (65, 72))	('tumor', 'Disease', (252, 257))
444543	30518397	The primary antibodies against phospho-STAT3 (Tyr705), STAT3, phospho-JAK2 (Tyr1007/1008), JAK2, PARP, MCL1, XIAP, Cox2 and iNOS were purchased from Cell Signaling Technology (Danvers, MA).	('JAK2', 'Gene', (70, 74))	('JAK2', 'Gene', '3717', (91, 95))	('Cox2', 'Gene', (115, 119))	('iNOS', 'Gene', '4843', (124, 128))	('iNOS', 'Gene', (124, 128))	('Tyr705', 'Var', (46, 52))	('XIAP', 'Gene', (109, 113))	('Tyr1007', 'Chemical', '-', (76, 83))	('JAK2', 'Gene', (91, 95))	('MCL1', 'Gene', '4170', (103, 107))	('Tyr1007/1008', 'Var', (76, 88))	('PARP', 'Gene', (97, 101))	('PARP', 'Gene', '1302', (97, 101))	('MCL1', 'Gene', (103, 107))	('XIAP', 'Gene', '331', (109, 113))	('Tyr705', 'Chemical', '-', (46, 52))	('JAK2', 'Gene', '3717', (70, 74))	('Cox2', 'Gene', '4513', (115, 119))
444568	30518397	After throughly washing with TBST, the slides were incubated overnight at 4  C with primary antibodies: p-STAT3, Cox-2 and Caspase-3 diluted in 5% BSA-TBST (1:50) respectively.	('Caspase-3', 'Gene', (123, 132))	('TBST', 'Chemical', '-', (29, 33))	('Caspase-3', 'Gene', '836', (123, 132))	('Cox-2', 'Gene', '4513', (113, 118))	('TBST', 'Chemical', '-', (151, 155))	('p-STAT3', 'Var', (104, 111))	('Cox-2', 'Gene', (113, 118))
444585	30518397	The curcumin-induced apoptosis was also significantly blocked by Z-VAD-FMK, a potent caspase inhibitor (Fig.	('blocked', 'NegReg', (54, 61))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (65, 74))	('Z-VAD-FMK', 'Var', (65, 74))	('curcumin', 'Chemical', 'MESH:D003474', (4, 12))	('apoptosis', 'CPA', (21, 30))
444588	30518397	In contrast, the presence of AG490, a STAT3 inhibitor, markedly enhanced the effect of curcumin on inducing ESCC cell death (Fig.	('AG490', 'Var', (29, 34))	('AG490', 'Chemical', 'MESH:C095512', (29, 34))	('ESCC cell death', 'Disease', 'MESH:D004938', (108, 123))	('ESCC cell death', 'Disease', (108, 123))	('curcumin', 'Chemical', 'MESH:D003474', (87, 95))	('enhanced', 'PosReg', (64, 72))
444599	30518397	Glu898, Val911, Tyr931, Leu932, Ser936, Asp939 and Asp994 of JAK2 formed strong interactions with curcumin.	('Leu932', 'Chemical', '-', (24, 30))	('JAK2', 'Gene', '3717', (61, 65))	('Asp939', 'Var', (40, 46))	('Tyr931', 'Var', (16, 22))	('curcumin', 'Chemical', 'MESH:D003474', (98, 106))	('Asp994', 'Var', (51, 57))	('Ser936', 'Chemical', '-', (32, 38))	('Val911', 'Var', (8, 14))	('Leu932', 'Var', (24, 30))	('Asp939', 'Chemical', '-', (40, 46))	('JAK2', 'Gene', (61, 65))	('Glu898', 'Chemical', '-', (0, 6))	('Glu898', 'Var', (0, 6))	('interactions', 'Interaction', (80, 92))	('Val911', 'Chemical', '-', (8, 14))	('Tyr931', 'Chemical', '-', (16, 22))	('Asp994', 'Chemical', '-', (51, 57))	('Ser936', 'Var', (32, 38))
444600	30518397	Among them, Val911, Tyr931 and Ser936 may interact hydrophobically with curcumin, whereas Glu898, Leu932, Asp939 and Asp994 are able to form H-bonds with curcumin.	('Tyr931', 'Chemical', '-', (20, 26))	('hydrophobically', 'MPA', (51, 66))	('Asp994', 'Var', (117, 123))	('Asp939', 'Var', (106, 112))	('Tyr931', 'Var', (20, 26))	('Leu932', 'Var', (98, 104))	('Glu898', 'Var', (90, 96))	('Asp994', 'Chemical', '-', (117, 123))	('Val911', 'Chemical', '-', (12, 18))	('curcumin', 'Chemical', 'MESH:D003474', (154, 162))	('Asp939', 'Chemical', '-', (106, 112))	('Ser936', 'Chemical', '-', (31, 37))	('Glu898', 'Chemical', '-', (90, 96))	('Val911', 'Var', (12, 18))	('Leu932', 'Chemical', '-', (98, 104))	('H-bonds', 'Interaction', (141, 148))	('curcumin', 'Chemical', 'MESH:D003474', (72, 80))	('interact', 'Interaction', (42, 50))	('Ser936', 'Var', (31, 37))	('form', 'Reg', (136, 140))
444616	30518397	The representative photos of the excised tumors from EG60 and EG84 were shown in Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('EG60', 'Var', (53, 57))	('EG84', 'Var', (62, 66))	('tumors', 'Disease', (41, 47))
444623	30518397	The IHC analysis with specific antibodies showed that the levels of phosphorylated STAT3 and its target protein Cox2 were markedly decreased in tumors treated with curcumin or curcumin prevention, whereas caspase 3 staining was significantly increased in these tumors (Fig.	('tumors', 'Disease', (144, 150))	('curcumin', 'Var', (176, 184))	('staining', 'MPA', (215, 223))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('curcumin', 'Chemical', 'MESH:D003474', (164, 172))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('increased', 'PosReg', (242, 251))	('curcumin', 'Chemical', 'MESH:D003474', (176, 184))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('caspase 3', 'Gene', (205, 214))	('caspase 3', 'Gene', '836', (205, 214))	('curcumin', 'Var', (164, 172))	('levels', 'MPA', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('Cox2', 'Gene', '4513', (112, 116))	('decreased', 'NegReg', (131, 140))	('Cox2', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
444640	30518397	Both constitutive and IL6-induced STAT3 activations were strongly inhibited by curcumin treatment in EC9706 and TE13 cells (Fig.	('IL6', 'Gene', '3569', (22, 25))	('STAT3', 'MPA', (34, 39))	('EC9706', 'Var', (101, 107))	('curcumin', 'Chemical', 'MESH:D003474', (79, 87))	('activations', 'PosReg', (40, 51))	('inhibited', 'NegReg', (66, 75))	('TE13', 'CellLine', 'CVCL:4463', (112, 116))	('IL6', 'Gene', (22, 25))	('EC9706', 'CellLine', 'CVCL:E307', (101, 107))
444649	30518397	5a-c, preventive administration of curcumin was markedly more effective in inhibiting PDXs derived from EG2, EG37 and EG60 than giving curcumin only after innoculation of tumors.	('inhibiting', 'NegReg', (75, 85))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('curcumin', 'Chemical', 'MESH:D003474', (135, 143))	('EG60', 'Var', (118, 122))	('PDXs', 'MPA', (86, 90))	('EG37', 'Var', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('curcumin', 'Chemical', 'MESH:D003474', (35, 43))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
444685	29933640	Due to different definitions of exposure categories in separate studies, a fixed-effect dose-response analysis was performed to quantitatively estimate the potential association between the increment per day for dietary vitamin E intake and the esophageal cancer risk.	('increment', 'Var', (190, 199))	('vitamin E', 'Chemical', 'MESH:D014810', (220, 229))	('esophageal cancer', 'Disease', (245, 262))	('rat', 'Species', '10116', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('esophageal cancer', 'Disease', 'MESH:D004938', (245, 262))	('men', 'Species', '9606', (195, 198))
444699	29933640	In general, in the cases with the highest vs. the lowest category of the dietary vitamin E intake, dietary vitamin E has a rather inverse association with both the risk of EAC (OR = 0.66, 95% CI: 0.49-0.88) and the risk of ESCC (OR = 0.29, 95% CI: 0.18-0.44).	('vitamin E', 'Chemical', 'MESH:D014810', (81, 90))	('inverse', 'NegReg', (130, 137))	('vitamin E', 'Chemical', 'MESH:D014810', (107, 116))	('rat', 'Species', '10116', (123, 126))	('ESCC', 'Disease', (223, 227))	('EAC', 'Phenotype', 'HP:0011459', (172, 175))	('dietary', 'Var', (99, 106))	('EAC', 'Disease', (172, 175))
444760	28928830	The present study focuses on lncRNA paternally expressed 10 (PEG10; NONCODE Gene ID NONHSAG048235), which is located on human chromosome 7 between the 94285681 and 94298949 base sites and is 763 bp in length.	('human', 'Species', '9606', (120, 125))	('94298949 base', 'Var', (164, 177))	('si', 'Chemical', 'MESH:C099952', (178, 180))	('94285681', 'Var', (151, 159))	('PEG10', 'Gene', '23089', (61, 66))	('PEG10', 'Gene', (61, 66))
444761	28928830	It was demonstrated that aberrant expression of PEG10 is associated with a number of malignancies, including hepatocellular carcinoma, B-cell lymphocytic leukemia, lymphoma and esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (177, 194))	('leukemia', 'Phenotype', 'HP:0001909', (154, 162))	('PEG10', 'Gene', '23089', (48, 53))	('malignancies', 'Disease', 'MESH:D009369', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('si', 'Chemical', 'MESH:C099952', (40, 42))	('B-cell lymphocytic leukemia, lymphoma', 'Disease', 'MESH:D015448', (135, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('lymphoma', 'Phenotype', 'HP:0002665', (164, 172))	('aberrant expression', 'Var', (25, 44))	('PEG10', 'Gene', (48, 53))	('malignancies', 'Disease', (85, 97))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (109, 133))	('hepatocellular carcinoma', 'Disease', (109, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (109, 133))	('esophageal cancer', 'Disease', (177, 194))	('associated', 'Reg', (57, 67))
444811	28928830	Expression levels quantified as 2-DeltaDeltaCq values were 2.448+-0.440, 1.762+-0.280 and 0.552+-0.209 in PEG10+, NC and si-lnc groups, respectively (Fig.	('PEG10+', 'Gene', '23089', (106, 112))	('2-DeltaDeltaCq', 'Chemical', '-', (32, 46))	('si-lnc', 'Var', (121, 127))	('si', 'Chemical', 'MESH:C099952', (6, 8))	('si', 'Chemical', 'MESH:C099952', (121, 123))	('PEG10+', 'Gene', (106, 112))
444813	28928830	Post-hoc testing demonstrated that lncRNA PEG10 expression was significantly reduced in cells transfected with silencer si-lnc RNA compared with PEG10+ and NC cells (P<0.05), while lncRNA PEG10 expression was enhanced in PEG10+ cells compared with NC cells (P<0.05).	('PEG10', 'Gene', '23089', (42, 47))	('PEG10', 'Gene', (42, 47))	('enhanced', 'PosReg', (209, 217))	('PEG10', 'Gene', '23089', (145, 150))	('PEG10', 'Gene', (145, 150))	('si', 'Chemical', 'MESH:C099952', (200, 202))	('PEG10+', 'Gene', (145, 151))	('si-lnc', 'Var', (120, 126))	('si', 'Chemical', 'MESH:C099952', (120, 122))	('expression', 'MPA', (48, 58))	('PEG10', 'Gene', '23089', (221, 226))	('PEG10+', 'Gene', '23089', (145, 151))	('PEG10', 'Gene', (221, 226))	('reduced', 'NegReg', (77, 84))	('si', 'Chemical', 'MESH:C099952', (63, 65))	('PEG10', 'Gene', '23089', (188, 193))	('si', 'Chemical', 'MESH:C099952', (111, 113))	('si', 'Chemical', 'MESH:C099952', (54, 56))	('PEG10', 'Gene', (188, 193))	('PEG10+', 'Gene', (221, 227))	('expression', 'MPA', (194, 204))	('PEG10+', 'Gene', '23089', (221, 227))
444814	28928830	The alterations in lncRNA PEG10 expression in transfected FaDu cells were associated with alterations in proliferative capacity.	('PEG10', 'Gene', (26, 31))	('alterations', 'Reg', (90, 101))	('alterations', 'Var', (4, 15))	('proliferative capacity', 'CPA', (105, 127))	('si', 'Chemical', 'MESH:C099952', (38, 40))	('expression', 'MPA', (32, 42))	('PEG10', 'Gene', '23089', (26, 31))
444815	28928830	Mean OD450 values from replicate cell proliferation assays of PEG10+, NC and si-lnc cells, respectively, were as follows: 24 h: 0.496+-0.075, 0.384+-0.035 and 0.260+-0.052; 48 h: 0.892+-0.033, 0.672+-0.046 and 0.428+-0.080; 72 h: 1.124+-0.101, 0.900+-0.073 and 0.560+-0.037; 96 h: 1.308+-0.101, 1.054+-0.102 and 0.752+-0.056.	('si', 'Chemical', 'MESH:C099952', (77, 79))	('0.900+-0.073', 'Var', (244, 256))	('PEG10+', 'Gene', (62, 68))	('PEG10+', 'Gene', '23089', (62, 68))
444818	28928830	In Transwell assays, the means of cell numbers penetrating the membranes in the PEG10+, NC and si-lnc groups were 1.408+-0.099x105, 0.988+-0.092x105 and 0.672+-0.081x105, respectively.	('si-lnc', 'Var', (95, 101))	('PEG10+', 'Gene', (80, 86))	('si', 'Chemical', 'MESH:C099952', (95, 97))	('PEG10+', 'Gene', '23089', (80, 86))	('0.988+-0.092x105', 'Var', (132, 148))	('cell numbers penetrating', 'CPA', (34, 58))
444820	28928830	By contrast, the number of invading cells in the si-lnc group was significantly lower compared with the that in the PEG10+ and NC groups (P<0.05; Fig.	('si-lnc', 'Var', (49, 55))	('PEG10+', 'Gene', (116, 122))	('lower', 'NegReg', (80, 85))	('si', 'Chemical', 'MESH:C099952', (66, 68))	('si', 'Chemical', 'MESH:C099952', (49, 51))	('PEG10+', 'Gene', '23089', (116, 122))
444834	28928830	Previously, dysregulation of lncRNAs has been detected in numerous types of cancer, including breast cancer, hepatocellular carcinoma, melanoma, bladder and prostate cancer.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('lncRNAs', 'Protein', (29, 36))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (109, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('dysregulation', 'Var', (12, 25))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('hepatocellular carcinoma', 'Disease', (109, 133))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Disease', (94, 107))	('bladder and prostate cancer', 'Disease', 'MESH:D001749', (145, 172))	('cancer', 'Disease', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', (76, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('detected', 'Reg', (46, 54))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (109, 133))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
445270	26338109	Patients with resection for esophageal carcinoma were selected using the ICD-10 code at admission (C15*, C160, or D130).	('C160', 'Var', (105, 109))	('esophageal carcinoma', 'Disease', (28, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (28, 48))	('Patients', 'Species', '9606', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (28, 48))	('C15*', 'Var', (99, 103))	('D130', 'Var', (114, 118))
445291	26338109	A recent randomized controlled found a 12 % incidence of pneumonia for patients undergoing minimal invasive esophageal resection while open (transhiatal or transthoracic) esophageal resection is associated with a 27 and 57 % incidence of pulmonary complications.	('pulmonary complications', 'Phenotype', 'HP:0006532', (238, 261))	('pulmonary complications', 'Disease', (238, 261))	('patients', 'Species', '9606', (71, 79))	('pneumonia', 'Phenotype', 'HP:0002090', (57, 66))	('pulmonary complications', 'Disease', 'MESH:D008171', (238, 261))	('minimal', 'Var', (91, 98))	('pneumonia', 'Disease', (57, 66))	('pneumonia', 'Disease', 'MESH:D011014', (57, 66))
445312	23656920	For American Joint Committee on Cancer (AJCC) stage III esophageal cancer (T1-2N2M0, T3N1-2M0, T4N1-3M0), there was significant improvement in OS (p = 0.002) in the PORT group, not only for lymph-node metastatic ratio (LNMR) >=0.25 (p = 0.001), but also for LNMR <0.25 (p = 0.043).	('Cancer', 'Disease', (32, 38))	('T1-2N2M0', 'Var', (75, 83))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))	('T4N1-3M0', 'Var', (95, 103))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('III esophageal cancer', 'Disease', 'MESH:D004938', (52, 73))	('improvement', 'PosReg', (128, 139))	('III esophageal cancer', 'Disease', (52, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('T3N1-2M0', 'Var', (85, 93))	('OS', 'Chemical', '-', (143, 145))
445322	23656920	This was done to remove possible bias, because most patients with T3-4N0M0 disease received PORT which just encompassed the tumor bed.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('T3-4N0M0 disease', 'Var', (66, 82))	('tumor', 'Disease', (124, 129))	('patients', 'Species', '9606', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
445356	23656920	For American Joint Committee on Cancer (AJCC) stage III esophageal cancer (T1-2N2M0, T3N1-2M0, T4N1-3M0), 414 patients received surgery alone and 238 patients received PORT.	('T1-2N2M0', 'Var', (75, 83))	('Cancer', 'Disease', (32, 38))	('T4N1-3M0', 'Var', (95, 103))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('III esophageal cancer', 'Disease', 'MESH:D004938', (52, 73))	('patients', 'Species', '9606', (110, 118))	('III esophageal cancer', 'Disease', (52, 73))	('patients', 'Species', '9606', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('T3N1-2M0', 'Var', (85, 93))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
445380	23656920	However, all of the previous mentioned trials did not stratify the patients based on their stage and likely were not large enough to detect an improvement in survival only for those patients with lymph nodes positive or deeply invading tumor.	('patients', 'Species', '9606', (67, 75))	('lymph nodes positive', 'Var', (196, 216))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Disease', (236, 241))
445383	23656920	performed a retrospective review using the Surveillance Epidemiology and End Results (SEER) database to analyze whether there was survival benefit to adjuvant radiation in stage T3-4N0M0 or T1-4N1M0 esophageal cancer who were definitively treated with esophagectomy.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('T1-4N1M0', 'Var', (190, 198))	('esophageal cancer', 'Disease', (199, 216))	('esophageal cancer', 'Disease', 'MESH:D004938', (199, 216))
445385	23656920	For AJCC stage III esophageal carcinoma (T3N1M0 or T4N0-1M0), 346 patients underwent surgery alone and 231 patients received PORT.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (19, 39))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (19, 39))	('T3N1M0', 'Var', (41, 47))	('T4N0-1M0', 'Var', (51, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('esophageal carcinoma', 'Disease', (19, 39))	('patients', 'Species', '9606', (107, 115))	('patients', 'Species', '9606', (66, 74))
445400	23656920	Results from a recent multicenter phase III randomized trial (CROSS study) showed that neoadjuvant chemoradiotherapy improved OS compared to surgery alone in patients with resectable (T2-3N0-1M0) esophageal or EGJ cancers.	('EGJ cancers', 'Disease', 'MESH:D009369', (210, 221))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('esophageal', 'Disease', (196, 206))	('improved', 'PosReg', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('EGJ cancers', 'Disease', (210, 221))	('OS', 'Chemical', '-', (64, 66))	('OS', 'Chemical', '-', (126, 128))	('patients', 'Species', '9606', (158, 166))	('T2-3N0-1M0', 'Var', (184, 194))	('esophageal', 'Disease', 'MESH:D004941', (196, 206))
445464	22655259	Although high leptin levels have been reported to increase the risk of BE in two studies, one study observed a stronger effect in men (Kendall et al.,), and the only other study observed a stronger effect in women (Thompson et al.,).	('men', 'Species', '9606', (210, 213))	('high leptin levels', 'Phenotype', 'HP:0031793', (9, 27))	('women', 'Species', '9606', (208, 213))	('BE', 'Phenotype', 'HP:0100580', (71, 73))	('leptin', 'Gene', '3952', (14, 20))	('leptin', 'Gene', (14, 20))	('men', 'Species', '9606', (130, 133))	('high', 'Var', (9, 13))
445474	22655259	While many aspects of the role of diet on EAC and BE etiology remain unclear, observational studies have reported that high levels of consumption of saturated fat and processed meat, low fruit and vegetable consumption, low dietary antioxidant intake, and low intakes of certain minerals are all associated with increased risks of both EAC and BE (Mayne et al.,; Anderson et al.,; Kubo and Corley,; Wu et al.,; Kubo et al.,; Mulholland et al.,; Thompson et al.,; Murphy et al.,).	('BE', 'Phenotype', 'HP:0100580', (344, 346))	('low', 'Var', (256, 259))	('saturated fat', 'Chemical', '-', (149, 162))	('EAC and BE', 'Gene', '1540', (42, 52))	('BE', 'Phenotype', 'HP:0100580', (50, 52))	('EAC and BE', 'Gene', '1540', (336, 346))	('low', 'NegReg', (220, 223))	('low', 'Var', (183, 186))
445529	32416156	Small interfering RNA library screening and high-content imaging analysis outlined changes in BE high-grade dysplasia (HGD) and EAC cell morphologies after gene silencing.	('BE', 'Phenotype', 'HP:0100580', (94, 96))	('dysplasia', 'Disease', (108, 117))	('gene silencing', 'Var', (156, 170))	('EAC cell morphologies', 'CPA', (128, 149))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('dysplasia', 'Disease', 'MESH:C536170', (108, 117))	('changes', 'Reg', (83, 90))
445557	32416156	Locally weighted polynomial regression normalization first was performed to account for cell shape changes as a consequence of alterations in cell density that occur as a result of gene loss-mediated cell death, growth inhibition, or regional variations (Figure 1B).	('gene', 'Var', (181, 185))	('rat', 'Species', '10116', (131, 134))	('cell density', 'CPA', (142, 154))	('cell shape', 'CPA', (88, 98))	('growth inhibition', 'CPA', (212, 229))
445566	32416156	Silencing GPS1 and SPRY1 expression resulted in significant increases in the rate of scratch-wound closure (Figure 4B and C), which was not associated with changes in either cell viability (Figure 4D) or exact cell counts (Figure 4E).	('rat', 'Species', '10116', (77, 80))	('scratch-wound closure', 'CPA', (85, 106))	('SPRY1', 'Gene', '10252', (19, 24))	('SPRY1', 'Gene', (19, 24))	('GPS1', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('increases', 'PosReg', (60, 69))	('rat', 'Species', '10116', (87, 90))
445568	32416156	Comparatively, silencing of RRM2 and ITGB8 resulted in significant effects on proliferative potential (Figure 4D and E), which consequently negatively affected scratch-wound assays.	('rat', 'Species', '10116', (162, 165))	('RRM2', 'Gene', (28, 32))	('ITGB8', 'Gene', '3696', (37, 42))	('RRM2', 'Gene', '6241', (28, 32))	('proliferative potential', 'CPA', (78, 101))	('affected', 'Reg', (151, 159))	('effects', 'Reg', (67, 74))	('rat', 'Species', '10116', (5, 8))	('silencing', 'Var', (15, 24))	('rat', 'Species', '10116', (85, 88))	('ITGB8', 'Gene', (37, 42))	('negatively', 'NegReg', (140, 150))	('scratch-wound assays', 'CPA', (160, 180))
445578	32416156	However, silencing GPS1 expression in both BE-HGD and EAC cells resulted in stabilization of beta-catenin protein expression in esophageal cells at 72 and 96 hours after siRNA transfection (Figure 6C and E).	('EAC', 'Phenotype', 'HP:0011459', (54, 57))	('beta-catenin', 'Gene', (93, 105))	('silencing', 'Var', (9, 18))	('BE', 'Phenotype', 'HP:0100580', (43, 45))	('GPS1', 'Gene', (19, 23))	('beta-catenin', 'Gene', '1499', (93, 105))
445592	32416156	The striking elongations or polarizations observed in RRM2-silenced BE-HGD cells (Figures 2 and 3) are specific to the RRM2 subunit with no such phenotypes observed in siRNA screening data of RRM1 and RRM2B knockdown (Figure 10).	('RRM2B', 'Gene', (201, 206))	('RRM1', 'Gene', (192, 196))	('RRM2B', 'Gene', '50484', (201, 206))	('RRM2', 'Gene', '6241', (201, 205))	('knockdown', 'Var', (207, 216))	('RRM2', 'Gene', (201, 205))	('BE', 'Phenotype', 'HP:0100580', (68, 70))	('RRM2', 'Gene', (54, 58))	('elongations', 'CPA', (13, 24))	('polarizations', 'CPA', (28, 41))	('RRM2', 'Gene', '6241', (54, 58))	('RRM1', 'Gene', '6240', (192, 196))	('RRM2', 'Gene', '6241', (119, 123))	('RRM2', 'Gene', (119, 123))
445594	32416156	However, clear differences in cell number were observed between nontargeting siRNA control wells and siRRM2-transfected wells, indicative of changes in cell proliferation or apoptosis resulting from RRM2 silencing.	('differences', 'Reg', (15, 26))	('RRM2', 'Gene', (199, 203))	('RRM2', 'Gene', (103, 107))	('cell number', 'CPA', (30, 41))	('RRM2', 'Gene', '6241', (199, 203))	('silencing', 'Var', (204, 213))	('RRM2', 'Gene', '6241', (103, 107))	('apoptosis', 'CPA', (174, 183))	('changes', 'Reg', (141, 148))	('rat', 'Species', '10116', (164, 167))	('cell proliferation', 'CPA', (152, 170))
445595	32416156	Under flow cytometric cell-cycle analysis, RRM2 silencing resulted in decreased G0/G1 cell populations (55% +- 2.6%), increased S phase (10.2% +- 1.8%), and increased sub-G1 phase (31% +- 2.6%) cell populations in comparison with nontargeting siRNA-transfected EAC cells in flow cytometric analyses (G0/G1, 80.3% +- 2.2%; S phase, 2.4% +- 0.4%; sub-G1, 7.9% +- 1.7%) indicative of some cell-cycle arrest and apoptosis (Figure 11C).	('silencing', 'Var', (48, 57))	('arrest', 'Disease', 'MESH:D006323', (397, 403))	('decreased', 'NegReg', (70, 79))	('increased', 'PosReg', (118, 127))	('EAC', 'Phenotype', 'HP:0011459', (261, 264))	('S phase', 'CPA', (128, 135))	('increased', 'PosReg', (157, 166))	('apoptosis', 'CPA', (408, 417))	('arrest', 'Disease', (397, 403))	('sub-G1', 'CPA', (167, 173))	('G0/G1 cell populations', 'CPA', (80, 102))	('RRM2', 'Gene', (43, 47))	('RRM2', 'Gene', '6241', (43, 47))
445600	32416156	Thus, changes in RRM2 levels may underlie epithelial-mesenchymal phenotypes and transitions that have been shown to contribute to metastasis, genomic instabilities, and aneuploidy, common events in esophageal adenocarcinogenesis.	('RRM2', 'Gene', (17, 21))	('epithelial-mesenchymal', 'CPA', (42, 64))	('carcinogenesis', 'Disease', (214, 228))	('contribute', 'Reg', (116, 126))	('aneuploidy', 'Disease', (169, 179))	('underlie', 'Reg', (33, 41))	('changes', 'Var', (6, 13))	('metastasis', 'CPA', (130, 140))	('aneuploidy', 'Disease', 'MESH:D000782', (169, 179))	('genomic instabilities', 'CPA', (142, 163))	('RRM2', 'Gene', '6241', (17, 21))	('carcinogenesis', 'Disease', 'MESH:D063646', (214, 228))
445616	32416156	Silencing of GPS1 in esophageal CP-D BE-HGD cells resulted in an amoeboid-like morphology, a loss of cell polarity, significantly faster cellular locomotion, and cortactin-positive pseudopodia consistent with an amoeboid transition.	('cortactin', 'Gene', (162, 171))	('cortactin', 'Gene', '2017', (162, 171))	('loss', 'NegReg', (93, 97))	('amoeboid-like morphology', 'CPA', (65, 89))	('BE', 'Phenotype', 'HP:0100580', (37, 39))	('faster', 'PosReg', (130, 136))	('cell polarity', 'CPA', (101, 114))	('GPS1', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('cellular locomotion', 'CPA', (137, 156))
445626	32416156	Thus, the S-phase cell-cycle arrest, decreased rates of scratch-wound closure, and increased apoptosis observed in our study after RRM2 silencing may result in part from effects on dNTP synthesis rates.	('dNTP synthesis rates', 'MPA', (181, 201))	('increased', 'PosReg', (83, 92))	('rat', 'Species', '10116', (196, 199))	('arrest', 'Disease', 'MESH:D006323', (29, 35))	('rates', 'CPA', (47, 52))	('effects', 'Reg', (170, 177))	('rat', 'Species', '10116', (47, 50))	('RRM2', 'Gene', '6241', (131, 135))	('RRM2', 'Gene', (131, 135))	('rat', 'Species', '10116', (58, 61))	('arrest', 'Disease', (29, 35))	('dNTP', 'Chemical', '-', (181, 185))	('silencing', 'Var', (136, 145))	('apoptosis', 'CPA', (93, 102))	('decreased', 'NegReg', (37, 46))
445635	32416156	For example, the genes PRC1, KIF11, and CDC25B, with known roles in cytokinesis and mitosis, were uncovered to result in distinctive morphologic changes and multinucleated cells upon silencing in this study.	('CDC25B', 'Gene', (40, 46))	('silencing', 'Var', (183, 192))	('mitosis', 'Disease', (84, 91))	('mitosis', 'Disease', 'None', (84, 91))	('KIF11', 'Gene', (29, 34))	('CDC25B', 'Gene', '994', (40, 46))	('PRC1', 'Gene', (23, 27))	('PRC1', 'Gene', '9055', (23, 27))	('multinucleated cells', 'CPA', (157, 177))	('KIF11', 'Gene', '3832', (29, 34))
445648	32416156	GPS1 (Hs00358804_m1), RRM1 (Hs01040698_m1), RRM2 (Hs00357247_g1), and RRM2B (Hs00968432_m1) primers also were used.	('Hs00358804_m1', 'Var', (6, 19))	('Hs01040698_m1', 'Var', (28, 41))	('RRM2', 'Gene', '6241', (70, 74))	('RRM2', 'Gene', (70, 74))	('RRM1', 'Gene', (22, 26))	('Hs00968432_m1', 'Var', (77, 90))	('RRM2B', 'Gene', (70, 75))	('RRM2', 'Gene', '6241', (44, 48))	('RRM2', 'Gene', (44, 48))	('RRM1', 'Gene', '6240', (22, 26))	('RRM2B', 'Gene', '50484', (70, 75))	('Hs00357247_g1', 'Var', (50, 63))
445777	31983558	Additional covariates available included age, binary status of chronic obstructive pulmonary disease (COPD) presence or absence, disease histology (SCLC vs NSCLC), the volume of the planning target volume, heart dose metrics (mean heart dose, heart V5, V30, V40, V45, and V60), performance status, and disease stage.	('heart V5', 'Var', (243, 251))	('SCLC', 'Disease', 'MESH:D018288', (148, 152))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (63, 100))	('COPD', 'Disease', 'MESH:D029424', (102, 106))	('V45', 'Var', (263, 266))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (71, 100))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (63, 100))	('COPD', 'Disease', (102, 106))	('chronic obstructive pulmonary disease', 'Disease', (63, 100))	('V60', 'Var', (272, 275))	('V40', 'Var', (258, 261))	('SCLC', 'Disease', (157, 161))	('SCLC', 'Disease', 'MESH:D018288', (157, 161))	('NSCLC', 'Disease', (156, 161))	('V30', 'Var', (253, 256))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('SCLC', 'Disease', (148, 152))
445821	31983558	Our data showed that pre- to posttreatment SUV changes were predictive of OS; however, data were not available to analyze whether death was due to cardiac-related events or to assess the effect of pre-existing cardiac comorbidities (heart disease, use of beta-blockers).	('death', 'Disease', 'MESH:D003643', (130, 135))	('death', 'Disease', (130, 135))	('OS', 'Disease', (74, 76))	('heart disease', 'Disease', (233, 246))	('SUV', 'MPA', (43, 46))	('changes', 'Var', (47, 54))	('heart disease', 'Disease', 'MESH:D006331', (233, 246))
445873	31496743	The original whole lung volume, GTV, PTVHigh, PTVLow, and dose-level volumes of the lung V10, V20, V27, V30, and V50% of the maximal prescribed dose, where dose volume Vx was defined as the total organ volume exceeding a radiation dose of "x", were generated as regions of interest (ROIs) at planning CT and were co-registered to the corresponding relative PET/CT.	('V27', 'Gene', '28803', (99, 102))	('V27', 'Gene', (99, 102))	('GTV', 'Chemical', '-', (32, 35))	('V30', 'Var', (104, 107))
445904	31496743	For chronic radiation pulmonary fibrosis, both simple and multivariate regression analyses demonstrated a significant correlation between %DeltaSUVR of V50%, V27, and V30.	('chronic radiation pulmonary fibrosis', 'Disease', (4, 40))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (22, 40))	('V50%', 'Var', (152, 156))	('V27', 'Gene', '28803', (158, 161))	('chronic radiation pulmonary fibrosis', 'Disease', 'MESH:D011832', (4, 40))	('V30', 'Var', (167, 170))	('V27', 'Gene', (158, 161))
445908	31496743	The cutoff value at the 6.2% increment of V20 area DeltaSUVR and the 8.9% increment of V27 area DeltaSUVR were selected as the new bio-physic constraint.	('V27', 'Gene', (87, 90))	('V27', 'Gene', '28803', (87, 90))	('V20', 'Var', (42, 45))
445911	31496743	The cutoff values at the 6.2% increment of V20 area DeltaSUVR and the 8.9% increment of V27 area DeltaSUVR are powerful predictors of acute RP and chronic lung fibrosis, respectively, and could potentially represent a new bio-physic constraint model in treatment planning for NACCRT in patients with advanced thoracic esophageal squamous cell carcinoma.	('V20 area DeltaSUVR', 'Var', (43, 61))	('lung fibrosis', 'Disease', 'MESH:D005355', (155, 168))	('V27', 'Gene', '28803', (88, 91))	('patients', 'Species', '9606', (286, 294))	('lung fibrosis', 'Disease', (155, 168))	('acute RP', 'Disease', (134, 142))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (318, 352))	('NACCRT', 'Chemical', '-', (276, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (329, 352))	('V27', 'Gene', (88, 91))	('lung fibrosis', 'Phenotype', 'HP:0002206', (155, 168))	('esophageal squamous cell carcinoma', 'Disease', (318, 352))
446027	30820189	These data suggest that raltitrexed may increase radiosensitivity by inhibiting the repair of DSBs.	('raltitrexed', 'Chemical', 'MESH:C068874', (24, 35))	('DSBs', 'Chemical', '-', (94, 98))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (40, 65))	('repair', 'MPA', (84, 90))	('radiosensitivity', 'MPA', (49, 65))	('increase', 'PosReg', (40, 48))	('inhibiting', 'NegReg', (69, 79))	('raltitrexed', 'Var', (24, 35))
446101	29083537	The incidences of postoperative respiratory (57.6% vs. 8.3%) and nervous system complications (10.6% vs. 2.7%), postoperative infection (32.9% vs. 5.0%), and chylothorax (8.2% vs. 0.9%) were significantly higher in the G-UPE than in the G-Regular group (P < 0.05) (Table 3).	('chylothorax', 'Disease', (158, 169))	('postoperative infection', 'Disease', 'MESH:D010149', (112, 135))	('nervous system complications', 'Disease', 'MESH:D009422', (65, 93))	('higher', 'PosReg', (205, 211))	('G-UPE', 'Var', (219, 224))	('chylothorax', 'Phenotype', 'HP:0010310', (158, 169))	('respiratory', 'CPA', (32, 43))	('nervous system complications', 'Disease', (65, 93))	('postoperative infection', 'Disease', (112, 135))
446109	29083537	The incidence of postoperative respiratory and nervous system complications was significantly higher in the G-UPE than the G-Regular group.	('G-UPE', 'Var', (108, 113))	('higher', 'PosReg', (94, 100))	('postoperative respiratory and nervous system complications', 'Disease', 'MESH:D011183', (17, 75))
446111	29083537	Postoperative infection and chylothorax also occurred significantly more frequently in the G-UPE than in the G-Regular group.	('chylothorax', 'Disease', (28, 39))	('chylothorax', 'Phenotype', 'HP:0010310', (28, 39))	('Postoperative infection', 'Disease', (0, 23))	('occurred', 'Reg', (45, 53))	('G-UPE', 'Var', (91, 96))	('Postoperative infection', 'Disease', 'MESH:D010149', (0, 23))
446129	28128281	The ADP-ribosyltransferase TccC3 from the insect bacterial pathogen Photorhabdus luminescence modifies actin to force its aggregation.	('modifies', 'Var', (94, 102))	('Photorhabdus', 'Species', '29488', (68, 80))	('aggregation', 'MPA', (122, 133))	('TccC3', 'Gene', (27, 32))	('force', 'Reg', (112, 117))	('ADP', 'Chemical', 'MESH:D000244', (4, 7))	('actin', 'Protein', (103, 108))
446132	28128281	Here, we used PA as a double mutant (N682A, D683A; mPA) which cannot bind to the two natural anthrax receptors.	('N682A', 'Var', (37, 42))	('PA', 'Chemical', '-', (52, 54))	('PA', 'Chemical', '-', (14, 16))	('N682A', 'Mutation', 'p.N682A', (37, 42))	('D683A', 'Mutation', 'p.D683A', (44, 49))	('D683A', 'Var', (44, 49))	('anthrax', 'Species', '1392', (93, 100))
446149	28128281	In our study, we used PA as a double mutant (N682A, D683A) which cannot bind to the two natural anthrax receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein 2 (CMG2).	('D683A', 'Var', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('N682A', 'Mutation', 'p.N682A', (45, 50))	('tumor', 'Disease', (115, 120))	('anthrax', 'Species', '1392', (96, 103))	('D683A', 'Mutation', 'p.D683A', (52, 57))	('PA', 'Chemical', '-', (22, 24))	('N682A', 'Var', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
446159	28128281	This modification blocks the interaction of actin with thymosin-beta4, an actin sequestering protein resulting in uncontrolled actin polymerization and subsequent cell death.	('modification', 'Var', (5, 17))	('interaction', 'Interaction', (29, 40))	('actin', 'Protein', (44, 49))	('thymosin-beta4', 'Gene', '7114', (55, 69))	('blocks', 'NegReg', (18, 24))	('uncontrolled actin polymerization', 'MPA', (114, 147))	('thymosin-beta4', 'Gene', (55, 69))	('cell death', 'CPA', (163, 173))
446213	28128281	Using two well characterized esophageal cancer cell lines, OE21 as a typical esophageal squamous cell carcinoma (ESCC) showing high expression of EGFR and OE33 esophageal adenocarcinoma (EAC), characterized by high expression of HER2, we established a model system to study the specificity of engineered toxins directed to surface molecules, which are highly expressed on several tumor cells.	('esophageal adenocarcinoma', 'Disease', (160, 185))	('EGFR', 'Gene', (146, 150))	('esophageal cancer', 'Disease', (29, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('HER2', 'Gene', '2064', (229, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('EAC', 'Phenotype', 'HP:0011459', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', (380, 385))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (160, 185))	('OE33', 'Var', (155, 159))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('HER2', 'Gene', (229, 233))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (160, 185))	('tumor', 'Disease', 'MESH:D009369', (380, 385))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
446216	28128281	Binding of the monomers to the natural anthrax receptors is prohibited by two mutations.	('prohibited', 'NegReg', (60, 70))	('anthrax receptors', 'Protein', (39, 56))	('mutations', 'Var', (78, 87))	('Binding', 'Interaction', (0, 7))	('anthrax', 'Species', '1392', (39, 46))
446217	28128281	Instead, the mutated monomers are re-directed to EGFR or HER2, receptors overexpressed on the surface of cancer cells, by fusion of EGF or of an affibody directed against HER2 to the N-terminus of mPA, respectively.	('fusion', 'Interaction', (122, 128))	('EGF', 'Gene', '1950', (132, 135))	('cancer', 'Disease', (105, 111))	('HER2', 'Gene', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('HER2', 'Gene', '2064', (57, 61))	('HER2', 'Gene', (171, 175))	('HER2', 'Gene', '2064', (171, 175))	('EGF', 'Gene', (49, 52))	('PA', 'Chemical', '-', (198, 200))	('mutated', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('EGF', 'Gene', (132, 135))	('EGF', 'Gene', '1950', (49, 52))
446220	28128281	This toxin modifies actin at a unique site (threonine-148) resulting in actin aggregation by inhibiting binding of the actin sequestering protein thymosin-beta4 and leading to cell death.	('actin aggregation', 'MPA', (72, 89))	('threonine-148', 'Var', (44, 57))	('modifies', 'Reg', (11, 19))	('thymosin-beta4', 'Gene', (146, 160))	('binding', 'Interaction', (104, 111))	('thymosin-beta4', 'Gene', '7114', (146, 160))	('cell death', 'CPA', (176, 186))	('inhibiting', 'NegReg', (93, 103))	('threonine', 'Chemical', 'MESH:D013912', (44, 53))	('leading to', 'Reg', (165, 175))
446222	28128281	Although both cell lines express EGFR and HER2, the stronger HER2 expression of OE33 mediate an about 100-fold higher specificity towards mPA-ZHER2 mediated intoxication.	('HER2', 'Gene', '2064', (42, 46))	('expression', 'MPA', (66, 76))	('HER2', 'Gene', (143, 147))	('PA', 'Chemical', '-', (139, 141))	('HER2', 'Gene', (61, 65))	('HER2', 'Gene', '2064', (143, 147))	('higher', 'PosReg', (111, 117))	('HER2', 'Gene', '2064', (61, 65))	('OE33', 'Var', (80, 84))	('HER2', 'Gene', (42, 46))	('stronger', 'PosReg', (52, 60))
446322	22528514	ESCC patients having high expression of nuclear survivin were less likely to develop nodal metastasis when compared to those patients with low expression of nuclear survivin.	('patients', 'Species', '9606', (5, 13))	('nodal metastasis', 'CPA', (85, 101))	('high expression', 'Var', (21, 36))	('develop', 'PosReg', (77, 84))	('less', 'NegReg', (62, 66))	('patients', 'Species', '9606', (125, 133))
446325	22528514	ESCC patients having high or low expression of nuclear survivin had a median survival of 17.90 months (95 % CI: 4.67-31.13 months) and 14.75 months (95 % CI: 12.84-16.67 months), respectively.	('survivin', 'Protein', (55, 63))	('low', 'NegReg', (29, 32))	('patients', 'Species', '9606', (5, 13))	('high', 'Var', (21, 25))	('nuclear survivin', 'Protein', (47, 63))	('expression', 'MPA', (33, 43))
446328	22528514	ESCC patients with high expression of nuclear survivin are mostly in early-stage of disease without nodal metastasis.	('patients', 'Species', '9606', (5, 13))	('early-stage of disease', 'Disease', (69, 91))	('high expression', 'Var', (19, 34))	('survivin', 'Protein', (46, 54))	('nuclear survivin', 'Protein', (38, 54))
446333	22528514	Survivin is proposed to inhibit apoptosis after its phosphorylation by p34cdc2/cyclin B complex, while a survivin mutant (with mutation at alanine, T34A), which is not able to undergo phosphorylation, can induce apoptosis probably by substrate competition.	('T34A', 'Mutation', 'c.34T>A', (148, 152))	('p34cdc2', 'Gene', (71, 78))	('apoptosis', 'CPA', (32, 41))	('p34cdc2', 'Gene', '983', (71, 78))	('apoptosis', 'CPA', (212, 221))	('alanine', 'Chemical', 'MESH:D000409', (139, 146))	('survivin', 'Gene', (105, 113))	('induce', 'Reg', (205, 211))	('inhibit', 'NegReg', (24, 31))	('T34A', 'Var', (148, 152))
446334	22528514	As different post-translational modifications could affect epitope accessibility of nuclear and cytoplasmic survivin, it is postulated that only cytoplasmic survivin can associate with and be phosphorylated by p34cdc2/cyclin B complex.	('epitope accessibility', 'MPA', (59, 80))	('p34cdc2', 'Gene', '983', (210, 217))	('modifications', 'Var', (32, 45))	('p34cdc2', 'Gene', (210, 217))	('associate', 'Interaction', (170, 179))	('affect', 'Reg', (52, 58))
446337	22528514	Cells expressing survivin with mutation at nuclear exportation signal (NES) accumulated in the nucleus, and these cells demonstrated reduced cytoprotective capabilities because of the inability of these survivin mutants in protecting cells against X-irradiation and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.	('inability', 'NegReg', (184, 193))	('survivin', 'Gene', (203, 211))	('TRAIL', 'Gene', (305, 310))	('accumulated', 'PosReg', (76, 87))	('TNF-related apoptosis-inducing ligand', 'Gene', (266, 303))	('mutation', 'Var', (31, 39))	('cytoprotective capabilities', 'CPA', (141, 168))	('TRAIL', 'Gene', '8743', (305, 310))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (266, 303))	('reduced', 'NegReg', (133, 140))	('mutants', 'Var', (212, 219))
446338	22528514	The survivin antibody we used in this study can recognize all splice variants of survivin, including survivin-2b for which this variant has proven pro-apoptotic effect by acting as a natural antagonist of anti-apoptotic survivin in tumor cells.	('variant', 'Var', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('survivin-2b', 'Gene', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (232, 237))	('pro-apoptotic', 'MPA', (147, 160))	('survivin', 'Gene', (81, 89))
446372	20857495	By contrast, Cox-2 deletion offers protection in Zn-sufficient (ZS) mice.	('mice', 'Species', '10090', (68, 72))	('ZS', 'Chemical', '-', (64, 66))	('Zn', 'Chemical', 'MESH:D015032', (49, 51))	('deletion', 'Var', (19, 27))	('Cox-2', 'Gene', (13, 18))
446400	20857495	The report that deletion of the Cox-2 gene in Apc knockout mice greatly reduces intestinal polyp formation provides genetic evidence that COX-2 plays a key role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('mice', 'Species', '10090', (59, 63))	('intestinal polyp', 'Phenotype', 'HP:0005266', (80, 96))	('Apc', 'Gene', (46, 49))	('reduces', 'NegReg', (72, 79))	('Apc', 'Gene', '11789', (46, 49))	('deletion', 'Var', (16, 24))	('greatly reduces intestinal polyp', 'Phenotype', 'HP:0200008', (64, 96))	('Cox-2', 'Gene', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('COX-2', 'Gene', (138, 143))	('COX-2', 'Gene', '19225', (138, 143))	('intestinal', 'Disease', (80, 90))
446403	20857495	Our previous work showed that in ZD rats pharmacologic COX-2 inhibition by the drug celecoxib did not prevent tongue carcinogenesis, and in ZD mice genetic Cox-2 deletion actually enhanced NMBA-induced forestomach tumorigenesis.	('deletion', 'Var', (162, 170))	('forestomach tumor', 'Disease', 'MESH:D013274', (202, 219))	('COX-2', 'Gene', (55, 60))	('forestomach tumor', 'Disease', (202, 219))	('COX-2', 'Gene', '19225', (55, 60))	('ZD', 'Chemical', '-', (140, 142))	('ZD', 'Chemical', '-', (33, 35))	('tongue carcinogenesis', 'Disease', 'MESH:D063646', (110, 131))	('NMBA', 'Chemical', 'MESH:C014707', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('enhanced', 'PosReg', (180, 188))	('Cox-2', 'Gene', (156, 161))	('tongue carcinogenesis', 'Disease', (110, 131))	('rats', 'Species', '10116', (36, 40))	('celecoxib', 'Chemical', 'MESH:D000068579', (84, 93))	('mice', 'Species', '10090', (143, 147))
446448	20857495	To investigate whether a Zn-deficient condition eliminates the antitumor effect of genetic Cox-2 disruption in NQO-induced tongue carcinogenesis as it does in NMBA-induced forestomach carcinogenesis,Cox-2-/-, Cox-2+/-, and WT mice on ZD vs. ZS diets were exposed to drinking water containing 20 ppm of NQO for 19 weeks followed by 30 ppm for another 7 weeks.	('disruption', 'Var', (97, 107))	('NQO', 'Chemical', 'MESH:D015112', (302, 305))	('forestomach carcinogenesis', 'Disease', 'MESH:D013274', (172, 198))	('ZD', 'Chemical', '-', (234, 236))	('tongue carcinogenesis', 'Disease', 'MESH:D063646', (123, 144))	('NQO', 'Chemical', 'MESH:D015112', (111, 114))	('mice', 'Species', '10090', (226, 230))	('Zn', 'Chemical', 'MESH:D015032', (25, 27))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tongue carcinogenesis', 'Disease', (123, 144))	('eliminates', 'NegReg', (48, 58))	('ZS', 'Chemical', '-', (241, 243))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('forestomach carcinogenesis', 'Disease', (172, 198))	('tumor', 'Disease', (67, 72))	('water', 'Chemical', 'MESH:D014867', (275, 280))	('NMBA', 'Chemical', 'MESH:C014707', (159, 163))
446458	20857495	1a and b, Supporting Information Table 1), demonstrating that combined ZD and Cox-2 ablation led to a worse tumor outcome.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('rat', 'Species', '10116', (50, 53))	('ablation', 'Var', (84, 92))	('tumor', 'Disease', (108, 113))	('Cox-2', 'Gene', (78, 83))	('ZD', 'Chemical', '-', (71, 73))
446466	20857495	Next, we compared the effect of Cox-2 deletion on gene expression changes in ZD forestomach and in ZS forestomach.	('Cox-2', 'Gene', (32, 37))	('gene expression changes', 'MPA', (50, 73))	('ZD', 'Chemical', '-', (77, 79))	('deletion', 'Var', (38, 46))	('ZS forestomach', 'Disease', 'MESH:D015211', (99, 113))	('ZS forestomach', 'Disease', (99, 113))
446468	20857495	There are no common changes in gene expression between these two class comparisons, and Cox-2 deletion causes fewer changes in ZS than ZD forestomach.	('ZS', 'Chemical', '-', (127, 129))	('Cox-2', 'Gene', (88, 93))	('deletion', 'Var', (94, 102))	('ZD', 'Chemical', '-', (135, 137))
446472	20857495	The most upregulated genes are implicated in the following processes: Sprr2h/2f and Krt6a/16 in cytoskeleton metabolism and S100a8 and S100a9 (upregulated 24- and 2.2-fold) in inflammatory/defense/immune responses.	('S100a9', 'Gene', (135, 141))	('upregulated', 'PosReg', (9, 20))	('Sprr2h/2f', 'Var', (70, 79))	('upregulated', 'PosReg', (143, 154))	('Krt6a', 'Gene', '16687', (84, 89))	('cytoskeleton metabolism', 'MPA', (96, 119))	('inflammatory/defense/immune', 'CPA', (176, 203))	('Krt6a', 'Gene', (84, 89))	('S100a8', 'Gene', (124, 130))
446473	20857495	Interestingly, S100a8/a9 were also upregulated 4.2- and 2.4-fold in ZD:WT vs. ZS:WT forestomach (Supporting Information Table 3).	('ZD', 'Chemical', '-', (68, 70))	('upregulated', 'PosReg', (35, 46))	('ZS', 'Chemical', '-', (78, 80))	('S100a8/a9', 'Var', (15, 24))
446475	20857495	In preneoplastic ZD:Cox-2-/-vs. ZS:Cox-2-/- forestomach (Supporting Information Table 7a), we found significantly overrepresented biological processes only among the upregulated genes; including in particular, response to external stimulus comprising S100a8/a9 and 14 genes (p = 3.98E-004) and response to stimulus comprising S100a8/a9 and 34 genes (p = 5.04E-004).	('upregulated', 'PosReg', (166, 177))	('S100a8/a9', 'Var', (326, 335))	('ZS', 'Chemical', '-', (32, 34))	('biological processes', 'CPA', (130, 150))	('S100a8/a9', 'Var', (251, 260))	('overrepresented', 'PosReg', (114, 129))	('response', 'MPA', (210, 218))	('ZD', 'Chemical', '-', (17, 19))
446476	20857495	Thus, DAVID supports the premise that S100a8/a9 are relevant markers associated with ZD-induced hyperplasia in ZD:Cox-2-/- forestomach.	('hyperplasia', 'Disease', 'MESH:D006965', (96, 107))	('associated', 'Reg', (69, 79))	('S100a8/a9', 'Var', (38, 47))	('ZD', 'Chemical', '-', (111, 113))	('ZD', 'Chemical', '-', (85, 87))	('hyperplasia', 'Disease', (96, 107))
446494	20857495	Additionally, qRT-PCR analysis shows that S100a8 and S100a9 mRNA expression was significantly reduced in ZR:Cox-2-/-vs. ZD:Cox-2-/- forestomach (Fig.	('S100a8', 'Var', (42, 48))	('mRNA expression', 'MPA', (60, 75))	('reduced', 'NegReg', (94, 101))	('S100a9', 'Var', (53, 59))	('ZD', 'Chemical', '-', (120, 122))
446497	20857495	The PCNA-labeling index (%) was significantly lower in ZR:Cox-2-/- than ZD:Cox-2-/- forestomach (Fig.	('ZR:Cox-2-/-', 'Var', (55, 66))	('ZD', 'Chemical', '-', (72, 74))	('lower', 'NegReg', (46, 51))	('PCNA-labeling index', 'MPA', (4, 23))
446500	20857495	1), also overexpresses the proinflammation genes S100a8/a9 discovered in forestomach, we determined S100a8/a9 mRNA and protein expression levels in tongue and forestomach from the four mouse groups (profiling studies) by qRT-PCR and immunoblotting.	('inflammation', 'Disease', (30, 42))	('mouse', 'Species', '10090', (185, 190))	('S100a8/a9', 'Var', (100, 109))	('inflammation', 'Disease', 'MESH:D007249', (30, 42))
446501	20857495	As in forestomach, S100a8/a9 mRNA expression was strongest in ZD:Cox-2-/- tongue, followed by ZD:WT tongue, and negligible in ZS:Cox-2-/- and ZS:WT tongue (Fig.	('mRNA expression', 'MPA', (29, 44))	('S100a8/a9', 'Gene', (19, 28))	('ZD', 'Chemical', '-', (94, 96))	('ZS', 'Chemical', '-', (126, 128))	('ZD:Cox-2-/- tongue', 'Var', (62, 80))	('strongest', 'PosReg', (49, 58))	('ZS', 'Chemical', '-', (142, 144))	('ZD', 'Chemical', '-', (62, 64))
446507	20857495	Using IHC we examined expression of seven markers: PCNA, p53, and five S100A8:NF-kappaB signaling markers (S100A8, S100A9, RAGE, NF-kappaBp65 and cyclin D1).	('cyclin D1', 'Gene', (146, 155))	('S100A9', 'Gene', '20202', (115, 121))	('S100A8', 'Var', (107, 113))	('S100A9', 'Gene', (115, 121))	('cyclin D1', 'Gene', '12443', (146, 155))	('p65', 'Gene', (138, 141))	('p65', 'Gene', '19697', (138, 141))
446511	20857495	In addition, these carcinomas overexpressed phospho-NF-kappaB p65 (Supporting Information Fig.	('phospho-NF-kappaB', 'Var', (44, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('p65', 'Gene', '19697', (62, 65))	('p65', 'Gene', (62, 65))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('carcinomas', 'Disease', (19, 29))	('carcinomas', 'Disease', 'MESH:D002277', (19, 29))	('overexpressed', 'PosReg', (30, 43))
446513	20857495	Collectively, these data demonstrate that under complete or partial genetic Cox-2 ablation, ZD stimulated RAGE-S100A8 inflammatory signaling cancer-and p53-associated response pathways, thereby driving malignant tumor progression and bypassing the antitumor effect of COX-2 blockade.	('inflammatory signaling', 'MPA', (118, 140))	('rat', 'Species', '10116', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('COX-2', 'Gene', (268, 273))	('ablation', 'Var', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('cancer', 'Disease', (141, 147))	('malignant tumor', 'Disease', (202, 217))	('driving', 'PosReg', (194, 201))	('p53-associated response pathways', 'Pathway', (152, 184))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('malignant tumor', 'Disease', 'MESH:D018198', (202, 217))	('ZD', 'Chemical', '-', (92, 94))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', (212, 217))	('COX-2', 'Gene', '19225', (268, 273))	('stimulated', 'PosReg', (95, 105))	('Cox-2', 'Gene', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('RAGE-S100A8', 'Gene', (106, 117))	('tumor', 'Disease', (252, 257))
446517	20857495	In a NMBA-induced forestomach carcinogenesis study, we showed that 14 weeks after ZR, ZR:Cox-2-/- mice had significantly lower forestomach tumor incidence and multiplicity than ZD:Cox-2-/- mice (Fig.	('forestomach tumor', 'Disease', 'MESH:D013274', (127, 144))	('multiplicity', 'CPA', (159, 171))	('forestomach tumor', 'Disease', (127, 144))	('NMBA', 'Chemical', 'MESH:C014707', (5, 9))	('mice', 'Species', '10090', (189, 193))	('ZD', 'Chemical', '-', (177, 179))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('forestomach carcinogenesis', 'Disease', (18, 44))	('lower', 'NegReg', (121, 126))	('ZR:Cox-2-/-', 'Var', (86, 97))	('mice', 'Species', '10090', (98, 102))	('forestomach carcinogenesis', 'Disease', 'MESH:D013274', (18, 44))
446518	20857495	In addition, S100a8/a9 mRNA expression was significantly lower in ZR:Cox-2-/-vs. ZD:Cox-2-/- forestomach (Fig.	('ZD', 'Chemical', '-', (81, 83))	('mRNA expression', 'MPA', (23, 38))	('S100a8/a9', 'Var', (13, 22))	('lower', 'NegReg', (57, 62))
446523	20857495	3b-3d), and effectively restores the antitumor effect of Cox-2 ablation (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('Cox-2', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('ablation', 'Var', (63, 71))	('restores', 'NegReg', (24, 32))
446526	20857495	Our study shows that the antitumor effect of genetic disruption of Cox-2 in tongue cancer prevention is bypassed by Zn depletion (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('tongue cancer', 'Disease', (76, 89))	('Zn', 'Chemical', 'MESH:D015032', (116, 118))	('Cox-2', 'Gene', (67, 72))	('tongue cancer', 'Disease', 'MESH:D014062', (76, 89))	('genetic disruption', 'Var', (45, 63))
446533	20857495	Our conclusion that S100a8/a9 are relevant ZD-induced markers belonging to an inflammatory pathway that drives forestomach cell proliferation rather than an epiphenomenon of this process or of dietary Zn-deficit is supported by DAVID bioinformatics (Table 7a).	('rat', 'Species', '10116', (135, 138))	('Zn', 'Chemical', 'MESH:D015032', (201, 203))	('S100a8/a9', 'Var', (20, 29))	('ZD', 'Chemical', '-', (43, 45))	('forestomach cell proliferation', 'CPA', (111, 141))	('rat', 'Species', '10116', (142, 145))
446534	20857495	S100A8/A9 have emerged as important markers for inflammation-associated cancers.	('inflammation-associated cancers', 'Disease', 'MESH:D007249', (48, 79))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('S100A8/A9', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('inflammation-associated cancers', 'Disease', (48, 79))
446539	20857495	In a colitis-induced mouse cancer model, S100A8/A9 and RAGE augment carcinogenesis and in an inflammation-associated liver cancer model, S100A8/A9 are identified as NF-kappaB target genes and their overexpression promotes malignant progression.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('liver cancer', 'Disease', (117, 129))	('S100A8/A9', 'Var', (41, 50))	('inflammation', 'Disease', (93, 105))	('colitis', 'Phenotype', 'HP:0002583', (5, 12))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('carcinogenesis', 'Disease', (68, 82))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('overexpression promotes', 'PosReg', (198, 221))	('mouse', 'Species', '10090', (21, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('malignant progression', 'CPA', (222, 243))	('colitis', 'Disease', (5, 12))	('augment', 'PosReg', (60, 67))	('S100A8/A9', 'Var', (137, 146))	('liver cancer', 'Disease', 'MESH:D006528', (117, 129))	('colitis', 'Disease', 'MESH:D003092', (5, 12))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (27, 33))	('inflammation', 'Disease', 'MESH:D007249', (93, 105))
446540	20857495	Conversely, blockade of RAGE suppresses tumor growth and metastasis.	('suppresses', 'NegReg', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (40, 45))	('RAGE', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('blockade', 'Var', (12, 20))
446548	20857495	Our recent report in rat esophagus that dietary Zn regulates S100A8 expression and modulates the link between S100A8-RAGE and downstream NF-kappaB/COX-2 provides the first evidence that Zn has an inflammation-modulating role in essophageal cancer initiation/reversal.	('S100A8', 'Gene', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('expression', 'MPA', (68, 78))	('Zn', 'Chemical', 'MESH:D015032', (186, 188))	('inflammation', 'Disease', (196, 208))	('essophageal cancer initiation', 'Disease', 'MESH:D009369', (228, 257))	('rat', 'Species', '10116', (21, 24))	('inflammation', 'Disease', 'MESH:D007249', (196, 208))	('regulates', 'Reg', (51, 60))	('essophageal cancer initiation', 'Disease', (228, 257))	('link', 'Interaction', (97, 101))	('S100A8-RAGE', 'Var', (110, 121))	('COX-2', 'Gene', (147, 152))	('Zn', 'Chemical', 'MESH:D015032', (48, 50))	('COX-2', 'Gene', '19225', (147, 152))
446549	20857495	Here we demonstrate that with COX-2 pathway blockade prolonged dietary ZD causes chronic inflammation in the tongue/forestomach by activating alternative inflammatory RAGE-S100A8/A9 and p53 response pathways, thereby fueling tumor progression and bypassing the antitumor effect of Cox-2 deletion.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('dietary', 'Var', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('alternative', 'MPA', (142, 153))	('tumor', 'Disease', (265, 270))	('fueling', 'PosReg', (217, 224))	('tumor', 'Disease', (225, 230))	('COX-2', 'Gene', (30, 35))	('activating', 'PosReg', (131, 141))	('COX-2', 'Gene', '19225', (30, 35))	('ZD', 'Chemical', '-', (71, 73))	('inflammation', 'Disease', 'MESH:D007249', (89, 101))	('p53 response pathways', 'Pathway', (186, 207))	('inflammation', 'Disease', (89, 101))	('tumor', 'Disease', 'MESH:D009369', (265, 270))
446574	32863360	In this previous study, 712 patients were investigated retrospectively, and the cancer risks in the 379 (55.1%) patients with specialized intestinal metaplasia were similar to those of the remaining 309 (44.9%, p=NS) patients without intestinal metaplasia.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('NS', 'Disease', 'MESH:D009404', (213, 215))	('patients', 'Species', '9606', (112, 120))	('specialized', 'Var', (126, 137))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('patients', 'Species', '9606', (217, 225))	('patients', 'Species', '9606', (28, 36))	('cancer', 'Disease', (80, 86))
446602	32863360	A randomized trial of ESD versus EMR for early Barrett's neoplasia showed that ESD achieved a higher R0 resection rate; however, it was more time-consuming and caused more severe adverse events.	('R0 resection', 'CPA', (101, 113))	('neoplasia', 'Disease', (57, 66))	('neoplasia', 'Phenotype', 'HP:0002664', (57, 66))	('ESD', 'Var', (79, 82))	('neoplasia', 'Disease', 'MESH:D009369', (57, 66))
446642	33067427	In all treatment groups, the expression levels of p-PI3K, p-Akt, p-p70S6K, Caspase-3, and Bcl-2 were significantly reduced, while the expression levels of p-AMPK, cleaved Caspase-3, and Bax increased, and the total levels of Akt, PI3K, and p70S6K levels remained unchanged.	('Bax', 'Gene', (186, 189))	('reduced', 'NegReg', (115, 122))	('p70S6K', 'Gene', (240, 246))	('Bax', 'Gene', '581', (186, 189))	('expression levels', 'MPA', (134, 151))	('Caspase-3', 'Gene', '836', (171, 180))	('p70S6K', 'Gene', '6198', (67, 73))	('AMPK', 'Gene', '5562', (157, 161))	('Akt', 'Gene', (60, 63))	('expression levels', 'MPA', (29, 46))	('cleaved', 'MPA', (163, 170))	('Caspase-3', 'Gene', '836', (75, 84))	('Bcl-2', 'Gene', (90, 95))	('Akt', 'Gene', '207', (60, 63))	('Akt', 'Gene', (225, 228))	('p70S6K', 'Gene', '6198', (240, 246))	('Caspase-3', 'Gene', (171, 180))	('p70S6K', 'Gene', (67, 73))	('Akt', 'Gene', '207', (225, 228))	('Bcl-2', 'Gene', '596', (90, 95))	('p-PI3K', 'Var', (50, 56))	('increased', 'PosReg', (190, 199))	('AMPK', 'Gene', (157, 161))	('Caspase-3', 'Gene', (75, 84))
446656	33067427	Meanwhile, through the combined treatment of cDDP and other drugs, such as Oridoni, inhibition of mTOR expression can enhance the effects of cytotoxicity and cellular apoptosis.	('cellular apoptosis', 'CPA', (158, 176))	('cytotoxicity', 'Disease', 'MESH:D064420', (141, 153))	('enhance', 'PosReg', (118, 125))	('mTOR', 'Gene', '2475', (98, 102))	('combined', 'Interaction', (23, 31))	('mTOR', 'Gene', (98, 102))	('inhibition', 'Var', (84, 94))	('cytotoxicity', 'Disease', (141, 153))	('cDDP', 'Chemical', 'MESH:D002945', (45, 49))
446669	33067427	After treatment with cordycepin (50 muM) and cDDP (2 muM) for 10 days, it was observed that colony formation in HK and K180 esophageal cancer cells was also significantly inhibited (Fig.	('esophageal cancer', 'Disease', (124, 141))	('50 muM', 'Var', (33, 39))	('colony formation', 'CPA', (92, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('inhibited', 'NegReg', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cordycepin', 'Chemical', 'MESH:C058120', (21, 31))	('cDDP', 'Chemical', 'MESH:D002945', (45, 49))
446678	33067427	Using Pharma Mapper, we obtained information about the top 300 potential protein targets for cordycepin (Table S1), Cordycepin inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production by activating AMP-activated protein kinase (AMPK) signaling.	('inhibits', 'NegReg', (127, 135))	('activating', 'PosReg', (217, 227))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (136, 154))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Cordycepin', 'Chemical', 'MESH:C058120', (116, 126))	('tumor necrosis factor (TNF)-alpha', 'Gene', '7124', (169, 202))	('Cordycepin', 'Var', (116, 126))	('AMP-activated protein kinase', 'Gene', '5562', (228, 256))	('AMP-activated protein kinase', 'Gene', (228, 256))	('AMPK', 'Gene', '5562', (258, 262))	('AMPK', 'Gene', (258, 262))	('cordycepin', 'Chemical', 'MESH:C058120', (93, 103))
446681	33067427	We found that the protein expression levels of p-AMPK, cleaved Caspase-3, and Bax were upregulated in cells treated with monotherapy and combination therapy, while the levels of p-PI3K, p-Akt, Caspase-3, and Bcl-2 were down-regulated, and the total Akt, PI3K and GAPDH levels remained unchanged.	('GAPDH', 'Gene', '2597', (263, 268))	('Caspase-3', 'Gene', (193, 202))	('Akt', 'Gene', (188, 191))	('cleaved', 'MPA', (55, 62))	('Caspase-3', 'Gene', (63, 72))	('Akt', 'Gene', '207', (188, 191))	('GAPDH', 'Gene', (263, 268))	('AMPK', 'Gene', (49, 53))	('combination', 'Var', (137, 148))	('Bax', 'Gene', (78, 81))	('down-regulated', 'NegReg', (219, 233))	('Bcl-2', 'Gene', (208, 213))	('Akt', 'Gene', (249, 252))	('Caspase-3', 'Gene', '836', (193, 202))	('Bax', 'Gene', '581', (78, 81))	('Akt', 'Gene', '207', (249, 252))	('Caspase-3', 'Gene', '836', (63, 72))	('AMPK', 'Gene', '5562', (49, 53))	('Bcl-2', 'Gene', '596', (208, 213))	('upregulated', 'PosReg', (87, 98))	('protein expression levels', 'MPA', (18, 43))
446682	33067427	Importantly, compared with the single-drug treatment group, the efficacy of the drug combination treatment group showed significant differences (cordycepin + cDDP and cordycepin **p < 0.1; cordycepin + cDDP and cDDP, **p < 0.1), as shown in Fig.	('cDDP', 'Chemical', 'MESH:D002945', (158, 162))	('cordycepin + cDDP', 'Var', (189, 206))	('cordycepin', 'Chemical', 'MESH:C058120', (167, 177))	('cDDP', 'Chemical', 'MESH:D002945', (211, 215))	('cordycepin', 'Chemical', 'MESH:C058120', (189, 199))	('cordycepin', 'Chemical', 'MESH:C058120', (145, 155))	('cDDP', 'Chemical', 'MESH:D002945', (202, 206))	('cDDP', 'Var', (211, 215))
446739	33067427	The formula for calculating tumor volume is as follows: V = 0.5 ab2 (a, the longest tumor axis; b, the shortest tumor axis).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('V = 0.5 ab2', 'Var', (56, 67))
446766	31917701	Moreover, it was reported that 5-FU could result in severe toxicity (such as stomatitis and severe pancytopenia) for patients who are deficient in dihydropyrimidine dehydrogenase, which is involved in the degradation of 5-FU.	('deficient', 'NegReg', (134, 143))	('stomatitis', 'Phenotype', 'HP:0010280', (77, 87))	('pancytopenia', 'Disease', 'MESH:D010198', (99, 111))	('5-FU', 'Var', (31, 35))	('toxicity', 'Disease', 'MESH:D064420', (59, 67))	('5-FU', 'Chemical', 'MESH:D005472', (220, 224))	('toxicity', 'Disease', (59, 67))	('patients', 'Species', '9606', (117, 125))	('5-FU', 'Chemical', 'MESH:D005472', (31, 35))	('deficient in dihydropyrimidine dehydrogenase', 'Phenotype', 'HP:0003654', (134, 178))	('pancytopenia', 'Phenotype', 'HP:0001876', (99, 111))	('stomatitis', 'Disease', 'MESH:D013280', (77, 87))	('stomatitis', 'Disease', (77, 87))	('result in', 'Reg', (42, 51))	('pancytopenia', 'Disease', (99, 111))
446822	31917701	reported that raltitrexed could decrease cell viability and proliferation, cause apoptosis and enhance the radiosensitivity of ESCC cells.	('cause', 'Reg', (75, 80))	('cell viability', 'CPA', (41, 55))	('raltitrexed', 'Chemical', 'MESH:C068874', (14, 25))	('apoptosis', 'CPA', (81, 90))	('radiosensitivity', 'CPA', (107, 123))	('decrease', 'NegReg', (32, 40))	('enhance', 'PosReg', (95, 102))	('raltitrexed', 'Var', (14, 25))
446830	31917701	However, 5-FU inhibits TS through its metabolite 5-fluoro-deoxyuridine monophosphate (FdUMP), while raltitrexed directly and specifically inhibits TS without requiring any modulating agent.	('inhibits', 'NegReg', (14, 22))	('5-fluoro-deoxyuridine monophosphate', 'Chemical', '-', (49, 84))	('TS', 'Gene', '7298', (23, 25))	('inhibits', 'NegReg', (138, 146))	('raltitrexed', 'Chemical', 'MESH:C068874', (100, 111))	('5-FU', 'Var', (9, 13))	('TS', 'Gene', '7298', (147, 149))	('5-FU', 'Chemical', 'MESH:D005472', (9, 13))
446855	31695414	High SNHG8 expression was revealed to closely correlate with primary tumor invasion depth, lymph node metastases, TNM stage, and worse overall survival among patients with ESCC.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor invasion depth', 'Disease', (69, 89))	('High', 'Var', (0, 4))	('TNM', 'Gene', '10178', (114, 117))	('expression', 'MPA', (11, 21))	('SNHG8', 'Gene', (5, 10))	('ESCC', 'Disease', 'MESH:C562729', (172, 176))	('tumor invasion depth', 'Disease', 'MESH:D007222', (69, 89))	('metastases', 'Disease', (102, 112))	('ESCC', 'Disease', (172, 176))	('patients', 'Species', '9606', (158, 166))	('TNM', 'Gene', (114, 117))	('metastases', 'Disease', 'MESH:D009362', (102, 112))
446856	31695414	Functional investigation showed that ablation of SNHG8 notably restricted ESCC cell proliferation, migration, and invasion while inducing apoptosis in vitro and hindered tumor growth in vivo.	('restricted', 'NegReg', (63, 73))	('ESCC cell proliferation', 'Disease', (74, 97))	('hindered', 'NegReg', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('ESCC cell proliferation', 'Disease', 'MESH:C562729', (74, 97))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('ablation', 'Var', (37, 45))	('tumor', 'Disease', (170, 175))	('apoptosis', 'CPA', (138, 147))	('invasion', 'CPA', (114, 122))	('migration', 'CPA', (99, 108))	('inducing', 'Reg', (129, 137))	('SNHG8', 'Gene', (49, 54))
446860	31695414	Moreover, silencing of miR-411 abrogated the influence of SNHG8 downregulation in ESCC cells.	('abrogated', 'NegReg', (31, 40))	('ESCC', 'Disease', (82, 86))	('downregulation', 'NegReg', (64, 78))	('miR-411', 'Gene', '693121', (23, 30))	('SNHG8', 'Gene', (58, 63))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))	('silencing', 'Var', (10, 19))	('miR-411', 'Gene', (23, 30))
446872	31695414	For instance, LINC01980, SNHG6, and AK001796 are upregulated in ESCC and play oncogenic roles in the malignant phenotypes.	('AK001796', 'Gene', '541471', (36, 44))	('ESCC', 'Disease', (64, 68))	('LINC01980', 'Chemical', 'None', (14, 23))	('AK001796', 'Gene', (36, 44))	('SNHG6', 'Gene', (25, 30))	('LINC01980', 'Var', (14, 23))	('upregulated', 'PosReg', (49, 60))	('ESCC', 'Disease', 'MESH:C562729', (64, 68))	('SNHG6', 'Gene', '641638', (25, 30))
446873	31695414	On the contrary, neighboring enhancer of FOXA2 (NEF), growth arrest-specific 5 (GAS5), and FER1L417 are downregulated in ESCC and can restrain cancer progression.	('restrain', 'NegReg', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('FOXA2', 'Gene', '3170', (41, 46))	('FOXA2', 'Gene', (41, 46))	('GAS5', 'Gene', (80, 84))	('GAS5', 'Gene', '60674', (80, 84))	('ESCC', 'Disease', 'MESH:C562729', (121, 125))	('growth arrest-specific 5', 'Gene', '60674', (54, 78))	('enhancer', 'PosReg', (29, 37))	('growth arrest', 'Phenotype', 'HP:0001510', (54, 67))	('downregulated', 'NegReg', (104, 117))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('growth arrest-', 'Phenotype', 'HP:0031164', (54, 68))	('FER1L417', 'Var', (91, 99))	('growth arrest-specific 5', 'Gene', (54, 78))	('ESCC', 'Disease', (121, 125))
446887	31695414	Four human ESCC cell lines, Eca109, KYSE70, KYSE150, and TE-1, were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China).	('KYSE70', 'Var', (36, 42))	('ESCC', 'Disease', 'MESH:C562729', (11, 15))	('ESCC', 'Disease', (11, 15))	('human', 'Species', '9606', (5, 10))	('TE-1', 'CellLine', 'CVCL:1759', (57, 61))
446910	31695414	The wild-type (wt) SNHG8 that contained the predicted miR-411-binding site and mutant (mut) SNHG8 was chemically synthesized by GenePharma and integrated into pMIR-REPORT luciferase reporter plasmids (Promega Corporation, Madison, WI, USA) to produce the pMIR-SNHG8-wt (SNHG8-wt) and pMIR-SNHG8-mut (SNHG8-mut) reporter plasmids.	('miR-411', 'Gene', (54, 61))	('mutant', 'Var', (79, 85))	('SNHG8', 'Gene', (92, 97))	('miR-411', 'Gene', '693121', (54, 61))
446917	31695414	After that, the membranes were incubated with primary antibodies against KPNA2 (ab170495; Abcam, Cambridge, UK) or GAPDH (ab128915; Abcam) at 4  C overnight.	('ab128915;', 'Var', (122, 131))	('GAPDH', 'Gene', '2597', (115, 120))	('KPNA2', 'Gene', (73, 78))	('GAPDH', 'Gene', (115, 120))
446922	31695414	In addition, the expression of SNHG8 was assessed in a panel of ESCC cell lines: Eca109, KYSE70, KYSE150, and TE-1.	('SNHG8', 'Gene', (31, 36))	('ESCC', 'Disease', (64, 68))	('KYSE150', 'Var', (97, 104))	('TE-1', 'CellLine', 'CVCL:1759', (110, 114))	('KYSE70', 'Var', (89, 95))	('ESCC', 'Disease', 'MESH:C562729', (64, 68))
446928	31695414	Notably, patients with high SNHG8 expression had shorter overall survival relative to the patients with low SNHG8 expression (Figure 1C, P=0.0119).	('patients', 'Species', '9606', (9, 17))	('shorter', 'NegReg', (49, 56))	('overall survival', 'MPA', (57, 73))	('high SNHG8 expression', 'Var', (23, 44))	('patients', 'Species', '9606', (90, 98))
446930	31695414	To assess the influence of SNHG8 on the malignant characteristics of ESCC, Eca109 and TE-1 cells were transfected with si-SNHG8 or si-scramble.	('si-SNHG8', 'Gene', (119, 127))	('ESCC', 'Disease', 'MESH:C562729', (69, 73))	('TE-1', 'CellLine', 'CVCL:1759', (86, 90))	('ESCC', 'Disease', (69, 73))	('si-scramble', 'Var', (131, 142))	('si-SNHG8', 'Gene', '100093630', (119, 127))
446931	31695414	RT-qPCR analysis revealed that SNHG8 expression was efficiently decreased in Eca109 and TE-1 cells after si-SNHG8 transfection as compared with that in cells transfected with si-scramble, implying the successful SNHG8 silencing after transfection (Figure 2A, P<0.05).	('SNHG8', 'Gene', (31, 36))	('si-SNHG8', 'Gene', (105, 113))	('silencing', 'NegReg', (218, 227))	('transfection', 'Var', (114, 126))	('si-SNHG8', 'Gene', '100093630', (105, 113))	('expression', 'MPA', (37, 47))	('TE-1', 'CellLine', 'CVCL:1759', (88, 92))	('decreased', 'NegReg', (64, 73))
446932	31695414	The effect of SNHG8 knockdown on the proliferation of Eca109 and TE-1 cells was determined in CCK-8 assay.	('knockdown', 'Var', (20, 29))	('SNHG8', 'Gene', (14, 19))	('TE-1', 'CellLine', 'CVCL:1759', (65, 69))
446933	31695414	Si-SNHG8 transfection markedly restrained the proliferative capacity of Eca109 and TE-1 cells compared with the si-scramble group (Figure 2B, P<0.05).	('restrained', 'NegReg', (31, 41))	('Si', 'Chemical', 'MESH:D012825', (0, 2))	('TE-1', 'CellLine', 'CVCL:1759', (83, 87))	('Si-SNHG8 transfection', 'Var', (0, 21))	('proliferative capacity of Eca109', 'CPA', (46, 78))	('transfection', 'Var', (9, 21))
446947	31695414	Meanwhile, the data obtained in the RT-qPCR analysis revealed that silencing of SNHG8 increased miR-411 expression in Eca109 and TE-1 cells (Figure 3G, P<0.05).	('miR-411', 'Gene', '693121', (96, 103))	('SNHG8', 'Gene', (80, 85))	('increased', 'PosReg', (86, 95))	('miR-411', 'Gene', (96, 103))	('expression', 'MPA', (104, 114))	('silencing', 'Var', (67, 76))	('TE-1', 'CellLine', 'CVCL:1759', (129, 133))
446951	31695414	We also observed in the Transwell migration and invasion assays that when Eca109 and TE-1 cells were transfected with miR-411 mimics, the migration (Figure 4C, P<0.05) and invasion (Figure 4D, P<0.05) remarkably decreased compared with that in miR-NC-transfected cells.	('decreased', 'NegReg', (212, 221))	('migration', 'CPA', (138, 147))	('mimics', 'Var', (126, 132))	('TE-1', 'CellLine', 'CVCL:1759', (85, 89))	('miR-411', 'Gene', '693121', (118, 125))	('miR', 'Gene', '220972', (244, 247))	('invasion', 'CPA', (172, 180))	('miR', 'Gene', (244, 247))	('miR', 'Gene', '220972', (118, 121))	('miR', 'Gene', (118, 121))	('miR-411', 'Gene', (118, 125))
446956	31695414	The luciferase activity of the KPNA2-wt plasmid was significantly decreased by miR-411 mimics transfection (P<0.05).	('miR-411', 'Gene', '693121', (79, 86))	('decreased', 'NegReg', (66, 75))	('activity', 'MPA', (15, 23))	('miR-411', 'Gene', (79, 86))	('luciferase', 'Enzyme', (4, 14))	('transfection', 'Var', (94, 106))
446968	31695414	To confirm that silencing of SNHG8 has an inhibitory influence on the malignant behaviors of ESCC cells via the miR-411-KPNA2 axis, Eca109 and TE-1 cells were cotransfected with si-SNHG8 and miR-411 inhibitor or NC inhibitor; then cell proliferation, apoptosis, migration, and invasion were analyzed by CCK-8, flow-cytometric, and Transwell migration and invasion assays, respectively.	('influence', 'Reg', (53, 62))	('TE-1', 'CellLine', 'CVCL:1759', (143, 147))	('miR-411', 'Gene', (112, 119))	('SNHG8', 'Gene', (29, 34))	('ESCC', 'Disease', 'MESH:C562729', (93, 97))	('malignant behaviors of', 'CPA', (70, 92))	('si-SNHG8', 'Gene', (178, 186))	('silencing', 'Var', (16, 25))	('miR-411', 'Gene', (191, 198))	('miR-411', 'Gene', '693121', (112, 119))	('miR-411', 'Gene', '693121', (191, 198))	('ESCC', 'Disease', (93, 97))	('si-SNHG8', 'Gene', '100093630', (178, 186))
446979	31695414	Furthermore, the protein level of KPNA2 turned out to be lower in the nude mice injected with the SNHG8 knockdown Eca109 cells (Figure 8F, P<0.05).	('protein level', 'MPA', (17, 30))	('SNHG8', 'Gene', (98, 103))	('lower', 'NegReg', (57, 62))	('nude mice', 'Species', '10090', (70, 79))	('knockdown', 'Var', (104, 113))
446980	31695414	These results revealed that SNHG8 knockdown hinders tumor growth of ESCC cells in vivo via upregulation of miR-411 and a consequent decrease of KPNA2 expression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('expression', 'MPA', (150, 160))	('ESCC', 'Disease', 'MESH:C562729', (68, 72))	('tumor', 'Disease', (52, 57))	('ESCC', 'Disease', (68, 72))	('upregulation', 'PosReg', (91, 103))	('miR-411', 'Gene', '693121', (107, 114))	('hinders', 'NegReg', (44, 51))	('KPNA2', 'Gene', (144, 149))	('knockdown', 'Var', (34, 43))	('SNHG8', 'Gene', (28, 33))	('miR-411', 'Gene', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('decrease', 'NegReg', (132, 140))
446982	31695414	The dysregulation of lncRNAs has been demonstrated to closely correlate with the malignancy of ESCC by affecting tumor processes.	('ESCC', 'Disease', 'MESH:C562729', (95, 99))	('tumor', 'Disease', (113, 118))	('dysregulation', 'Var', (4, 17))	('ESCC', 'Disease', (95, 99))	('affecting', 'Reg', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
446990	31695414	SNHG8 is validated as an independent prognostic factor of tumor recurrence in patients with hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('patients', 'Species', '9606', (78, 86))	('SNHG8', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('hepatocellular carcinoma', 'Disease', (92, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))
446992	31695414	Patients with non-small cell lung cancer overexpressing SNHG8 show shorter overall survival and shorter progression-free survival relative to the patients with low SNHG8 expression.	('SNHG8', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('shorter', 'NegReg', (96, 103))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (14, 40))	('progression-free survival', 'CPA', (104, 129))	('Patients', 'Species', '9606', (0, 8))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (14, 40))	('shorter', 'NegReg', (67, 74))	('overall survival', 'MPA', (75, 91))	('overexpressing', 'Var', (41, 55))	('non-small cell lung cancer', 'Disease', (14, 40))	('patients', 'Species', '9606', (146, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (18, 40))
446996	31695414	Patients with ESCC overexpressing SNHG8 showed worse overall survival than did patients with low SNHG8 expression.	('ESCC', 'Disease', 'MESH:C562729', (14, 18))	('overexpressing', 'PosReg', (19, 33))	('Patients', 'Species', '9606', (0, 8))	('ESCC', 'Disease', (14, 18))	('SNHG8', 'Var', (34, 39))	('overall', 'MPA', (53, 60))	('patients', 'Species', '9606', (79, 87))	('worse', 'NegReg', (47, 52))
447000	31695414	In hepatocellular carcinoma, silencing of SNHG8 suppresses cell growth, invasion, and lung metastasis in vitro and in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('silencing', 'Var', (29, 38))	('invasion', 'CPA', (72, 80))	('suppresses', 'NegReg', (48, 58))	('SNHG8', 'Gene', (42, 47))	('lung metastasis', 'CPA', (86, 101))	('cell growth', 'CPA', (59, 70))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
447001	31695414	In non-small cell lung cancer, SNHG8 knockdown results in inhibition of cell proliferation and metastasis in vitro, increase in cell apoptosis and cell cycle arrest, and suppression in tumor growth in vivo.	('tumor', 'Disease', (185, 190))	('SNHG8', 'Gene', (31, 36))	('cell cycle arrest', 'CPA', (147, 164))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('knockdown', 'Var', (37, 46))	('suppression', 'NegReg', (170, 181))	('cell proliferation', 'CPA', (72, 90))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('increase', 'PosReg', (116, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('inhibition', 'NegReg', (58, 68))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('non-small cell lung cancer', 'Disease', (3, 29))	('cell apoptosis', 'CPA', (128, 142))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
447003	31695414	Herein, we revealed that SNHG8 silencing restricted cell proliferative, migratory, and invasive abilities of ESCC cells; increased the percentage of apoptotic cells; and hindered the growth of transplanted tumors in vivo.	('silencing', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cell proliferative', 'CPA', (52, 70))	('ESCC', 'Disease', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('increased', 'PosReg', (121, 130))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('hindered', 'NegReg', (170, 178))	('ESCC', 'Disease', 'MESH:C562729', (109, 113))	('invasive abilities', 'CPA', (87, 105))	('restricted', 'NegReg', (41, 51))	('SNHG8', 'Gene', (25, 30))
447008	31695414	High KPNA2 expression shows an obvious correlation with poor differentiation, tumor depth, lymphatic invasion, venous invasion, and tumor stage.	('tumor depth', 'Disease', (78, 89))	('poor differentiation', 'CPA', (56, 76))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('High', 'Var', (0, 4))	('KPNA2', 'Gene', (5, 10))	('venous invasion', 'Disease', 'MESH:D009361', (111, 126))	('expression', 'MPA', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (132, 137))	('lymphatic invasion', 'CPA', (91, 109))	('tumor', 'Disease', (78, 83))	('venous invasion', 'Disease', (111, 126))	('tumor depth', 'Disease', 'MESH:D007222', (78, 89))
447009	31695414	The prognosis of patients with ESCC overexpressing KPNA2 is shorter than that of patients with low KPNA2 expression, as revealed by univariate analysis.	('overexpressing', 'PosReg', (36, 50))	('patients', 'Species', '9606', (81, 89))	('ESCC', 'Disease', 'MESH:C562729', (31, 35))	('KPNA2', 'Var', (51, 56))	('patients', 'Species', '9606', (17, 25))	('ESCC', 'Disease', (31, 35))	('shorter', 'NegReg', (60, 67))
447011	31695414	Hence, the KPNA2 knockdown due to SNHG8 silencing and miR-411 upregulation could be a promising therapeutic strategy against ESCC.	('miR-411', 'Gene', (54, 61))	('ESCC', 'Disease', 'MESH:C562729', (125, 129))	('miR-411', 'Gene', '693121', (54, 61))	('silencing', 'NegReg', (40, 49))	('SNHG8', 'Gene', (34, 39))	('knockdown', 'Var', (17, 26))	('KPNA2', 'Gene', (11, 16))	('ESCC', 'Disease', (125, 129))	('upregulation', 'PosReg', (62, 74))
447017	31695414	In summary, this study revealed that SNHG8 may perform oncogenic functions in the progression of ESCC by sponging miR-411 to upregulate KPNA2.	('SNHG8', 'Gene', (37, 42))	('ESCC', 'Disease', 'MESH:C562729', (97, 101))	('miR-411', 'Gene', '693121', (114, 121))	('KPNA2', 'Gene', (136, 141))	('sponging', 'Var', (105, 113))	('miR-411', 'Gene', (114, 121))	('upregulate', 'PosReg', (125, 135))	('ESCC', 'Disease', (97, 101))
447021	31333776	The meta-analysis included 58 eligible studies demonstrated that harboring XPA rs10817938, XPD rs238406 increased overall cancer risk, however, XPA rs2808668 SNP in overall cancer analysis and XPF rs3136038 in the digestive system remarkably reduced the cancer risk.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('XPD', 'Gene', '2068', (91, 94))	('cancer', 'Disease', (254, 260))	('XPA', 'Gene', '7507', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('rs3136038', 'Mutation', 'rs3136038', (197, 206))	('XPA', 'Gene', (144, 147))	('rs238406', 'Mutation', 'rs238406', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('rs2808668 SNP', 'Var', (148, 161))	('rs238406', 'Var', (95, 103))	('XPD', 'Gene', (91, 94))	('XPF', 'Gene', (193, 196))	('rs10817938', 'Var', (79, 89))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('XPA', 'Gene', (75, 78))	('XPA', 'Gene', '7507', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('increased', 'PosReg', (104, 113))	('rs10817938', 'Mutation', 'rs10817938', (79, 89))	('cancer', 'Disease', (122, 128))	('rs2808668', 'Mutation', 'rs2808668', (148, 157))	('XPF', 'Gene', '2072', (193, 196))	('reduced', 'NegReg', (242, 249))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
447022	31333776	Moreover, no correlation was investigated for XPC rs1870134, WRN rs1346044 and rs1801195.	('rs1346044', 'Var', (65, 74))	('rs1801195', 'Var', (79, 88))	('XPC', 'Gene', (46, 49))	('rs1870134', 'Var', (50, 59))	('rs1870134', 'Mutation', 'rs1870134', (50, 59))	('XPC', 'Gene', '7508', (46, 49))	('WRN', 'Gene', (61, 64))	('WRN', 'Gene', '7486', (61, 64))	('rs1801195', 'Mutation', 'rs1801195', (79, 88))	('rs1346044', 'Mutation', 'rs1346044', (65, 74))
447027	31333776	Accumulating evidence showed that common mutations or polymorphisms in DNA repair genes involved in altering protein function and capacity to repair damaged DNA, thus deficits in repair capacity which lead to genetic instability, pathogenesis and carcinogenesis, however, the results were inconsistent in distinct cancers, and need further to be elucidated and pay more attention.	('mutations', 'Var', (41, 50))	('genetic instability', 'MPA', (209, 228))	('cancers', 'Disease', 'MESH:D009369', (314, 321))	('altering', 'Reg', (100, 108))	('carcinogenesis', 'Disease', 'MESH:D063646', (247, 261))	('cancers', 'Disease', (314, 321))	('repair capacity', 'MPA', (179, 194))	('protein function', 'MPA', (109, 125))	('carcinogenesis', 'Disease', (247, 261))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('deficits', 'NegReg', (167, 175))	('DNA repair', 'Gene', (71, 81))	('lead to', 'Reg', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))
447029	31333776	The molecular basis of XP has been attributed to mutations in seven XP proteins (A-through-G: XPA, XPB, XPC, XPD, XPE, XPF, and XPG) that are required for NER-mediated removal of DNA damage and XP-variant (XPV).	('XPC', 'Gene', (104, 107))	('XPE', 'Gene', '1643', (114, 117))	('mutations', 'Var', (49, 58))	('XPA', 'Gene', '7507', (94, 97))	('XPC', 'Gene', '7508', (104, 107))	('XPG', 'Gene', '2073', (128, 131))	('XPA', 'Gene', (94, 97))	('XPF', 'Gene', (119, 122))	('XPD', 'Gene', '2068', (109, 112))	('XPG', 'Gene', (128, 131))	('XPB', 'Gene', (99, 102))	('XPE', 'Gene', (114, 117))	('XPB', 'Gene', '2071', (99, 102))	('XPD', 'Gene', (109, 112))	('XPF', 'Gene', '2072', (119, 122))	('XP-variant', 'Var', (194, 204))
447035	31333776	Inactivating mutations or genetic variations in DNA repair genes can modify an individual's capacity to repair damaged DNA, and thus lead to the clinical disorder xeroderma pigmentosum (XP) and a predisposition to the development of cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('lead to', 'Reg', (133, 140))	('genetic variations', 'Var', (26, 44))	('Inactivating mutations', 'Var', (0, 22))	('xeroderma pigmentosum', 'Disease', (163, 184))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (163, 184))	('DNA repair genes', 'Gene', (48, 64))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('capacity', 'MPA', (92, 100))	('cancers', 'Disease', (233, 240))	('modify', 'Reg', (69, 75))
447037	31333776	Previous accumulating studies provided evidence about the association of SNPs in DNA repair gene with cancer risk, and most widely studied polymorphism including XPA rs2808668, rs10817938, XPC rs1870134, XPD rs238406, XPF rs3136038, WRN rs1801195, rs1346044.	('XPC', 'Gene', '7508', (189, 192))	('rs3136038', 'Mutation', 'rs3136038', (222, 231))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('rs1801195', 'Mutation', 'rs1801195', (237, 246))	('XPC', 'Gene', (189, 192))	('rs238406', 'Mutation', 'rs238406', (208, 216))	('XPD', 'Gene', (204, 207))	('WRN', 'Gene', '7486', (233, 236))	('rs10817938', 'Var', (177, 187))	('WRN', 'Gene', (233, 236))	('association', 'Interaction', (58, 69))	('rs1346044', 'Var', (248, 257))	('XPF', 'Gene', (218, 221))	('rs2808668', 'Mutation', 'rs2808668', (166, 175))	('cancer', 'Disease', (102, 108))	('rs2808668', 'Var', (166, 175))	('SNPs', 'Var', (73, 77))	('rs1346044', 'Mutation', 'rs1346044', (248, 257))	('rs10817938', 'Mutation', 'rs10817938', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('DNA repair gene', 'Gene', (81, 96))	('XPA', 'Gene', '7507', (162, 165))	('XPA', 'Gene', (162, 165))	('rs1870134', 'Mutation', 'rs1870134', (193, 202))	('XPF', 'Gene', '2072', (218, 221))	('XPD', 'Gene', '2068', (204, 207))
447038	31333776	The SNPs XPA rs10817938, XPA rs2808668 and XPF rs3136038 are all the polymorphisms in the site of the gene promoter.	('rs10817938', 'Var', (13, 23))	('rs10817938', 'Mutation', 'rs10817938', (13, 23))	('XPF', 'Gene', (43, 46))	('rs3136038', 'Mutation', 'rs3136038', (47, 56))	('XPA', 'Gene', (9, 12))	('XPA', 'Gene', '7507', (9, 12))	('rs2808668', 'Mutation', 'rs2808668', (29, 38))	('XPA', 'Gene', '7507', (25, 28))	('rs2808668', 'Var', (29, 38))	('rs3136038', 'Var', (47, 56))	('XPA', 'Gene', (25, 28))	('XPF', 'Gene', '2072', (43, 46))
447039	31333776	The SNP rs10817938 is located in the 5'-untranslated region (UTR), which is a T to C substitution distant from the transcriptional start site (TSS) about -2718bp, meanwhile, rs2808668 is a T to C substitution located -514bp from the TSS within XPA gene, which have been reported novel promoter SNPs in the XPA loci associated with cancer risk and development including hepatic cancer (HCC), breast cancer, gastric cancer, oral squamous cell carcinoma (OSCC).	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (422, 450))	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('cancer', 'Disease', (414, 420))	('hepatic cancer', 'Disease', (369, 383))	('gastric cancer', 'Disease', (406, 420))	('oral squamous cell carcinoma', 'Disease', (422, 450))	('cancer', 'Phenotype', 'HP:0002664', (414, 420))	('cancer', 'Disease', (398, 404))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('hepatic cancer', 'Disease', 'MESH:D008113', (369, 383))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (427, 450))	('gastric cancer', 'Disease', 'MESH:D013274', (406, 420))	('hepatic cancer', 'Phenotype', 'HP:0002896', (369, 383))	('cancer', 'Disease', 'MESH:D009369', (377, 383))	('cancer', 'Disease', 'MESH:D009369', (414, 420))	('XPA', 'Gene', (244, 247))	('XPA', 'Gene', '7507', (244, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (391, 404))	('rs10817938', 'Var', (8, 18))	('cancer', 'Disease', 'MESH:D009369', (398, 404))	('gastric cancer', 'Phenotype', 'HP:0012126', (406, 420))	('rs2808668', 'Mutation', 'rs2808668', (174, 183))	('breast cancer', 'Disease', 'MESH:D001943', (391, 404))	('cancer', 'Disease', (331, 337))	('breast cancer', 'Disease', (391, 404))	('rs2808668', 'Var', (174, 183))	('XPA', 'Gene', (306, 309))	('XPA', 'Gene', '7507', (306, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (441, 450))	('cancer', 'Disease', (377, 383))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('rs10817938', 'Mutation', 'rs10817938', (8, 18))
447040	31333776	Furthermore the SNP rs3136038 is near the 5' end of XPF gene (also known as ERCC4, excision repair cross-complementation group 4 gene) exhibits remarkably associated with the susceptibility of variety of cancer such as breast cancer, lung cancer, ESCC, gastric cancer, etc.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('gastric cancer', 'Disease', (253, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('ESCC', 'Disease', (247, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('gastric cancer', 'Disease', 'MESH:D013274', (253, 267))	('cancer', 'Disease', (239, 245))	('rs3136038', 'Mutation', 'rs3136038', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('ERCC4', 'Gene', '2072', (76, 81))	('cancer', 'Disease', (261, 267))	('ERCC4', 'Gene', (76, 81))	('XPF', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Disease', (204, 210))	('susceptibility', 'Reg', (175, 189))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('SNP rs3136038', 'Var', (16, 29))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('lung cancer', 'Disease', (234, 245))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('breast cancer', 'Disease', (219, 232))	('gastric cancer', 'Phenotype', 'HP:0012126', (253, 267))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('associated with', 'Reg', (155, 170))	('XPF', 'Gene', '2072', (52, 55))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('lung cancer', 'Disease', 'MESH:D008175', (234, 245))
447041	31333776	The other selected candidate SNPs XPC rs1870134 (Leu16Met), XPD rs238406 (Arg156Arg), WRN rs1346044 (Cys1367Arg) and WRN rs1801195 (Leu1074Phe) are all located in the Exon and Intron sites of the corresponding genes.	('XPD', 'Gene', '2068', (60, 63))	('WRN', 'Gene', (86, 89))	('Cys1367Arg', 'Var', (101, 111))	('Leu16Met', 'Var', (49, 57))	('WRN', 'Gene', (117, 120))	('WRN', 'Gene', '7486', (117, 120))	('rs1870134', 'Mutation', 'rs1870134', (38, 47))	('rs238406', 'Mutation', 'rs238406', (64, 72))	('XPD', 'Gene', (60, 63))	('Leu16Met', 'SUBSTITUTION', 'None', (49, 57))	('Leu1074Phe', 'Chemical', '-', (132, 142))	('XPC', 'Gene', '7508', (34, 37))	('rs238406 (Arg156Arg', 'Var', (64, 83))	('Cys1367Arg', 'SUBSTITUTION', 'None', (101, 111))	('rs1801195', 'Mutation', 'rs1801195', (121, 130))	('XPC', 'Gene', (34, 37))	('rs1346044', 'Mutation', 'rs1346044', (90, 99))	('WRN', 'Gene', '7486', (86, 89))	('Leu1074Phe', 'Var', (132, 142))
447042	31333776	Recent studies have shown that polymorphisms at Exon 1 (C>G, rs1870134) of XPC gene, Exon 6 (A>C, rs238406) of XPD gene, Exon 34 (C>T, rs1346044) and Exon 26 (T>G, rs1801195) of WRN gene have been correlated with several types of cancer including breast and prostate cancers, however, these results were inconclusive.	('rs1346044', 'Mutation', 'rs1346044', (135, 144))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('prostate cancer', 'Phenotype', 'HP:0012125', (258, 273))	('rs238406', 'Mutation', 'rs238406', (98, 106))	('XPD', 'Gene', (111, 114))	('breast and prostate cancers', 'Disease', 'MESH:D011471', (247, 274))	('prostate cancers', 'Phenotype', 'HP:0012125', (258, 274))	('XPC', 'Gene', '7508', (75, 78))	('C>T', 'Var', (130, 133))	('XPC', 'Gene', (75, 78))	('rs1801195', 'Mutation', 'rs1801195', (164, 173))	('cancer', 'Disease', (230, 236))	('WRN', 'Gene', (178, 181))	('WRN', 'Gene', '7486', (178, 181))	('rs1870134', 'Mutation', 'rs1870134', (61, 70))	('C>G', 'Var', (56, 59))	('cancer', 'Disease', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('polymorphisms', 'Var', (31, 44))	('XPD', 'Gene', '2068', (111, 114))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('correlated', 'Reg', (197, 207))	('T>G', 'Var', (159, 162))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('A>C, rs238406', 'Var', (93, 106))
447043	31333776	Thus, considering the critical role of these genetic variations in the DNA repair genes, and understanding the association between these SNPs and cancer susceptibility is urgently required.	('DNA repair genes', 'Gene', (71, 87))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('genetic variations', 'Var', (45, 63))
447048	31333776	In addition, genes alterations of these DNA repair genes were represented including mutation, fusion, amplification, deep deletion by using cBioPortal tool based on TCGA datasets.	('DNA repair genes', 'Gene', (40, 56))	('deep deletion', 'Var', (117, 130))	('amplification', 'Var', (102, 115))	('TC', 'Chemical', 'MESH:D013667', (165, 167))	('fusion', 'Var', (94, 100))	('CG', 'Chemical', 'MESH:C028505', (166, 168))	('mutation', 'Var', (84, 92))
447049	31333776	All the searched eligible original studies and review articles were reviewed carefully to identify the relevant articles by using the following search terms "rs1346044, Cys1367Arg" or "rs1801195, Leu1074Phe" or "rs2808668" or "rs10817938" or "rs1870134, Leu16Met" or "rs3136038" or "rs238406, Arg156Arg" and "polymorphism or SNP or single nucleotide polymorphism or variation or mutation" and "cancer or carcinoma or tumor or neoplasm", (the search was updated on May 13, 2018).	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('rs1346044', 'Mutation', 'rs1346044', (158, 167))	('rs3136038', 'Mutation', 'rs3136038', (268, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (404, 413))	('Cys1367Arg', 'Var', (169, 179))	('rs10817938', 'Mutation', 'rs10817938', (227, 237))	('Leu16Met', 'Var', (254, 262))	('carcinoma or tumor', 'Disease', (404, 422))	('rs1870134', 'Mutation', 'rs1870134', (243, 252))	('SNP', 'Var', (325, 328))	('Leu1074Phe', 'Chemical', '-', (196, 206))	('single nucleotide polymorphism', 'Var', (332, 362))	('neoplasm', 'Disease', 'MESH:D009369', (426, 434))	('tumor', 'Phenotype', 'HP:0002664', (417, 422))	('rs1801195', 'Mutation', 'rs1801195', (185, 194))	('cancer', 'Disease', (394, 400))	('neoplasm', 'Disease', (426, 434))	('rs2808668', 'Mutation', 'rs2808668', (212, 221))	('variation', 'Var', (366, 375))	('Leu16Met', 'SUBSTITUTION', 'None', (254, 262))	('carcinoma or tumor', 'Disease', 'MESH:D009369', (404, 422))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('Cys1367Arg', 'SUBSTITUTION', 'None', (169, 179))	('rs238406', 'Mutation', 'rs238406', (283, 291))	('rs2808668" or "rs10817938" or "rs1870134', 'Var', (212, 252))
447066	31333776	These gene alterations of XPA, XPC, XPC, XPF, WRN were displayed including mutation, fusion, amplification, deep deletion by using cBioPortal online tool based on TCGA database(Case Set: 63658 patients/65690 samples).	('amplification', 'Var', (93, 106))	('fusion', 'Var', (85, 91))	('patients', 'Species', '9606', (193, 201))	('CG', 'Chemical', 'MESH:C028505', (164, 166))	('XPF', 'Gene', '2072', (41, 44))	('deep deletion', 'Var', (108, 121))	('XPC', 'Gene', (36, 39))	('XPC', 'Gene', '7508', (31, 34))	('WRN', 'Gene', '7486', (46, 49))	('mutation', 'Var', (75, 83))	('WRN', 'Gene', (46, 49))	('XPA', 'Gene', '7507', (26, 29))	('XPF', 'Gene', (41, 44))	('XPC', 'Gene', '7508', (36, 39))	('XPA', 'Gene', (26, 29))	('XPC', 'Gene', (31, 34))	('TC', 'Chemical', 'MESH:D013667', (163, 165))
447067	31333776	The detail cancer type, mutation fusion amphomdel and alteration frequency of those genes are shown in Figure 3.	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mutation', 'Var', (24, 32))
447068	31333776	Although the total genetic alteration levels of the candidate genes were not very high only from 0.8%-3% (Figure 3A), the alteration frequency showed an higher levels in 33 types of cancers, especially in bladder cancer, BCLA, which were more than 25% (Figure 3B).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('alteration', 'Var', (122, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (205, 219))	('bladder cancer', 'Disease', (205, 219))	('bladder cancer', 'Phenotype', 'HP:0009725', (205, 219))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('BCLA', 'Disease', (221, 225))
447071	31333776	Finally, 58 studies were met the inclusion criteria, 4 studies evaluated the association of XPA rs10817938 with cancer risk, 8 reports determined the SNP rs2808668 of XPA gene and cancer susceptibility, 8 publications were XPC rs1870134 polymorphism, 10 reports studied XPF rs3136038 polymorphism, 24 reports determined XPD rs238406 SNP, 4 reports and 11 reports analyzed WRN rs1801195 and rs1346044, respectively.	('XPC', 'Gene', (223, 226))	('cancer', 'Disease', (112, 118))	('WRN', 'Gene', (372, 375))	('WRN', 'Gene', '7486', (372, 375))	('XPD', 'Gene', '2068', (320, 323))	('XPA', 'Gene', '7507', (167, 170))	('XPF', 'Gene', '2072', (270, 273))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('association', 'Interaction', (77, 88))	('XPA', 'Gene', (167, 170))	('rs2808668', 'Mutation', 'rs2808668', (154, 163))	('cancer', 'Disease', (180, 186))	('rs1801195', 'Mutation', 'rs1801195', (376, 385))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('rs1870134', 'Mutation', 'rs1870134', (227, 236))	('rs1346044', 'Var', (390, 399))	('XPD', 'Gene', (320, 323))	('rs10817938', 'Var', (96, 106))	('rs3136038', 'Mutation', 'rs3136038', (274, 283))	('XPA', 'Gene', '7507', (92, 95))	('XPA', 'Gene', (92, 95))	('rs1346044', 'Mutation', 'rs1346044', (390, 399))	('XPF', 'Gene', (270, 273))	('rs238406', 'Mutation', 'rs238406', (324, 332))	('XPC', 'Gene', '7508', (223, 226))	('rs10817938', 'Mutation', 'rs10817938', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (180, 186))
447072	31333776	for XPA rs2808668, Sun, K for et al.	('rs2808668', 'Var', (8, 17))	('XPA', 'Gene', (4, 7))	('XPA', 'Gene', '7507', (4, 7))	('rs2808668', 'Mutation', 'rs2808668', (8, 17))
447073	31333776	for WRN rs1346044, Liu, Y for et al.	('WRN', 'Gene', (4, 7))	('rs1346044', 'Var', (8, 17))	('WRN', 'Gene', '7486', (4, 7))	('rs1346044', 'Mutation', 'rs1346044', (8, 17))
447074	31333776	for XPF rs3136038, Chang, J.S.	('XPF', 'Gene', '2072', (4, 7))	('rs3136038', 'Mutation', 'rs3136038', (8, 17))	('XPF', 'Gene', (4, 7))	('rs3136038', 'Var', (8, 17))
447075	31333776	; Miercla, A for XPD rs238406 (Table S1).	('rs238406', 'Var', (21, 29))	('XPD', 'Gene', '2068', (17, 20))	('XPD', 'Gene', (17, 20))	('rs238406', 'Mutation', 'rs238406', (21, 29))
447076	31333776	In this final meta-analysis, XPA rs10817938 included 1775 cases and 2156 controls, as well as XPA rs2808668 included 2616 cases and 3099 controls.	('rs2808668', 'Var', (98, 107))	('XPA', 'Gene', '7507', (94, 97))	('XPA', 'Gene', (94, 97))	('XPA', 'Gene', '7507', (29, 32))	('XPA', 'Gene', (29, 32))	('rs10817938', 'Var', (33, 43))	('rs2808668', 'Mutation', 'rs2808668', (98, 107))	('rs10817938', 'Mutation', 'rs10817938', (33, 43))
447077	31333776	Meanwhile, XPC rs1870134, XPD rs238406, and XPF rs3136038 contained 4987 cases and 6193 controls; 6999 cases and 8652 controls; 5247 cases and 5607 controls, respectively.	('XPD', 'Gene', '2068', (26, 29))	('XPF', 'Gene', (44, 47))	('XPC', 'Gene', '7508', (11, 14))	('rs3136038', 'Var', (48, 57))	('rs1870134', 'Mutation', 'rs1870134', (15, 24))	('rs1870134', 'Var', (15, 24))	('rs238406', 'Mutation', 'rs238406', (30, 38))	('XPD', 'Gene', (26, 29))	('XPF', 'Gene', '2072', (44, 47))	('rs3136038', 'Mutation', 'rs3136038', (48, 57))	('XPC', 'Gene', (11, 14))	('rs238406', 'Var', (30, 38))
447078	31333776	Moreover, cases and controls for WRN rs1801195 and rs1346044 were 3161 and 3142, 6538 and 7657, respectively.	('rs1801195', 'Mutation', 'rs1801195', (37, 46))	('rs1346044', 'Var', (51, 60))	('WRN', 'Gene', (33, 36))	('WRN', 'Gene', '7486', (33, 36))	('rs1801195', 'Var', (37, 46))	('rs1346044', 'Mutation', 'rs1346044', (51, 60))
447080	31333776	The meta-analysis results of the XPA rs10817938, rs2808668 polymorphism and cancer risk are shown in Table 1, Table S2, and Figure 4, 5, S3, S4.	('rs2808668', 'Mutation', 'rs2808668', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('XPA', 'Gene', (33, 36))	('XPA', 'Gene', '7507', (33, 36))	('rs2808668', 'Var', (49, 58))	('rs10817938', 'Var', (37, 47))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('rs10817938', 'Mutation', 'rs10817938', (37, 47))
447081	31333776	Overall, harboring XPA rs10817938 homozygous CC genotype, C allele, and CC/CT genotype in dominant model showed significant association with increased cancer risk [CC vs.TT in homozygous model: OR (95%CI) = 1.68 (1.02- 2.76), P = 0.04; C vs. T allele in additive model: OR (95%CI) = 1.20 (1.04-1.38), P = 0.01; and CC/CT vs. TT in dominant model: 1.37 (1.09-1.74), P = 0.008] (Figure 4, 5,S3, S4A).	('rs10817938', 'Mutation', 'rs10817938', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('XPA', 'Gene', '7507', (19, 22))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('XPA', 'Gene', (19, 22))	('rs10817938', 'Var', (23, 33))
447083	31333776	The effect of XPC, XPD, and XPF polymorphism on cancer risk in overall and subgroup analysis was presented in Table 1, Table S2 and Figure 4, 5, S3, S4: C, D, and E. In the overall analysis, the SNP rs238406 of XPD gene was associated with an increased overall cancer risk, however, XPF rs3136038 showed significantly decreased cancer risk, and no significant association was determined in XPC rs1870134 polymorphism.	('decreased cancer', 'Disease', (318, 334))	('XPC', 'Gene', '7508', (14, 17))	('cancer', 'Disease', (328, 334))	('cancer', 'Disease', (48, 54))	('decreased cancer', 'Disease', 'MESH:D009369', (318, 334))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('XPC', 'Gene', (14, 17))	('XPD', 'Gene', '2068', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('XPF', 'Gene', (283, 286))	('XPD', 'Gene', (211, 214))	('cancer', 'Disease', (261, 267))	('XPF', 'Gene', (28, 31))	('rs238406', 'Mutation', 'rs238406', (199, 207))	('rs1870134', 'Mutation', 'rs1870134', (394, 403))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('XPC', 'Gene', '7508', (390, 393))	('SNP rs238406', 'Var', (195, 207))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('XPF', 'Gene', '2072', (283, 286))	('XPD', 'Gene', (19, 22))	('rs3136038', 'Var', (287, 296))	('rs3136038', 'Mutation', 'rs3136038', (287, 296))	('XPF', 'Gene', '2072', (28, 31))	('XPC', 'Gene', (390, 393))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('XPD', 'Gene', '2068', (211, 214))
447084	31333776	SNP rs238406 AA genotype or A allele carriers showed significantly increased overall cancer risk [AA vs.CC in homozygote model: OR (95%CI) = 1.20 (1.02-1.41), P = 0.03; A vs. C allele in additive model: OR (95%CI) = 1.08 (1.00-1.18), P=0.04; and AA vs. CC/CA in recessive model: OR (95%CI) = 1.21 (1.05- 1.40), P=0.007].	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('SNP rs238406', 'Var', (0, 12))	('rs238406', 'Mutation', 'rs238406', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
447085	31333776	Because of the relatively higher heterogeneities (I2 = 61.1) of rs238406, the further stratification analysis was assessed by using nervous system, basal cell cancer, digestive system, urinary system, genital system and respiratory system cancer, and subsequently, we found significant impact on cancer risk in the subgroup of basal cell cancer [AA vs.CC in homozygote model: OR (95%CI) = 1.38 (1.05-1.81), P = 0.02; A vs. C allele in additive model: OR (95%CI) = 1.18 (1.03- 1.35), P = 0.02; and AA vs. CC/ CA in recessive model: OR (95%CI) = 1.30 (1.03-1.65), P = 0.03], however no association observed with cancer risk in the other groups.	('respiratory system cancer', 'Disease', (220, 245))	('cancer', 'Disease', 'MESH:D009369', (610, 616))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('respiratory system cancer', 'Disease', 'MESH:D015619', (220, 245))	('cancer', 'Disease', (159, 165))	('basal cell cancer', 'Disease', (327, 344))	('basal cell cancer', 'Disease', 'MESH:D002280', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('rs238406', 'Mutation', 'rs238406', (64, 72))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('rs238406', 'Var', (64, 72))	('impact', 'Reg', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Disease', (610, 616))	('cancer', 'Phenotype', 'HP:0002664', (610, 616))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('basal cell cancer', 'Disease', (148, 165))	('cancer', 'Disease', (338, 344))	('basal cell cancer', 'Disease', 'MESH:D002280', (327, 344))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Disease', (296, 302))
447086	31333776	Furthermore, only patients with prostate cancer carrying XPC rs1870134 C allele or CC/CG genotype in the dominant model are associated with decreased cancer risk [C vs. G allele in additive model: OR (95%CI) = 0.82 (0.72- 0.95), P = 0.007; CC/CG vs.GG in dominant model: 0.77 (0.65-0.92), P = 0.004].	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('prostate cancer', 'Disease', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('CG', 'Chemical', 'MESH:C028505', (243, 245))	('CG', 'Chemical', 'MESH:C028505', (86, 88))	('XPC', 'Gene', (57, 60))	('decreased cancer', 'Disease', 'MESH:D009369', (140, 156))	('decreased cancer', 'Disease', (140, 156))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('patients', 'Species', '9606', (18, 26))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('rs1870134', 'Mutation', 'rs1870134', (61, 70))	('XPC', 'Gene', '7508', (57, 60))	('CC/CG', 'Var', (83, 88))
447087	31333776	Moreover, XPF rs3136038 polymorphism was associated with decreased overall cancer risk in the patients with additive model [OR (95%CI) = 0.91 (0.86-0.96), P = 0.001, Table 1] and dominant model [OR (95%CI) = 0.89 (0.81-0.98), P = 0.02, Table S2].	('XPF', 'Gene', '2072', (10, 13))	('patients', 'Species', '9606', (94, 102))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('rs3136038', 'Var', (14, 23))	('cancer', 'Disease', (75, 81))	('rs3136038', 'Mutation', 'rs3136038', (14, 23))	('XPF', 'Gene', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('decreased', 'NegReg', (57, 66))
447088	31333776	More importantly, similar results were found in the stratification group of digestive system cancer patients who harboring TT genotype [OR (95%CI) = 0.64 (0.48-0.87), P = 0.004], T allele in additive model [OR (95%CI) = 0.82 (0.72- 0.94), P = 0.003], dominant model [OR (95%CI) = 0.81 (0.68-0.96), P=0.02] and recessive model [OR (95%CI) = 0.70 (0.52-0.96), P = 0.025] significantly decreased cancer risk, however, there was no association observed in other subgroups.	('system cancer', 'Disease', (86, 99))	('decreased cancer', 'Disease', (383, 399))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('T allele', 'Var', (179, 187))	('patients', 'Species', '9606', (100, 108))	('decreased cancer', 'Disease', 'MESH:D009369', (383, 399))	('system cancer', 'Disease', 'MESH:D009369', (86, 99))
447089	31333776	Although no significant association between polymorphisms of WRN rs1801195, rs1346044 and cancer risk in overall meta-analysis results was found, the further stratification analysis showed significantly increased cancer risk in the genital system subgroup patients with rs1801195 genotype and breast cancer with rs1346044 genotype, as shown in Table 1, Table S2 and Figure 4, 5, S3, S4: F and G. For SNP rs1801195, genital system cancer patients correlated with increased cancer risk when carrying TT genotype [OR (95%CI) = 1.37 (1.08-1.73), P=0.009], T allele [OR (95%CI) = 1.15 (1.02-1.29), P = 0.02], and recessive model [OR (95%CI) = 1.44 (1.17-1.78), P = 0.001].	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs1801195', 'Mutation', 'rs1801195', (270, 279))	('T allele [', 'Var', (552, 562))	('genital system cancer', 'Disease', 'MESH:D009369', (415, 436))	('cancer', 'Disease', (430, 436))	('breast cancer', 'Phenotype', 'HP:0003002', (293, 306))	('cancer', 'Disease', 'MESH:D009369', (472, 478))	('cancer', 'Phenotype', 'HP:0002664', (430, 436))	('SNP rs1801195', 'Var', (400, 413))	('rs1346044', 'Var', (76, 85))	('cancer', 'Disease', (213, 219))	('WRN', 'Gene', (61, 64))	('WRN', 'Gene', '7486', (61, 64))	('breast cancer', 'Disease', (293, 306))	('rs1346044', 'Var', (312, 321))	('breast cancer', 'Disease', 'MESH:D001943', (293, 306))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (300, 306))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('rs1346044', 'Mutation', 'rs1346044', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('rs1346044', 'Mutation', 'rs1346044', (312, 321))	('genital system cancer', 'Disease', (415, 436))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (430, 436))	('rs1801195', 'Mutation', 'rs1801195', (65, 74))	('patients', 'Species', '9606', (437, 445))	('cancer', 'Disease', (472, 478))	('patients', 'Species', '9606', (256, 264))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (472, 478))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('rs1801195', 'Var', (270, 279))	('rs1801195', 'Mutation', 'rs1801195', (404, 413))
447090	31333776	Moreover, breast cancer patients with rs1346044 CC genotype [OR (95%CI) = 1.47 (1.10-1.97), P = 0.010], C allele [OR (95%CI) = 1.15 (1.04-1.26), P = 0.005], dominant model[OR (95%CI) = 1.14 (1.02-1.28), P = 0.018] and recessive model [OR (95%CI) = 1.37 (1.03-1.83), P = 0.03] significantly correlated with elevated cancer susceptibility.	('elevated cancer', 'Disease', 'MESH:D009369', (306, 321))	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('breast cancer', 'Disease', (10, 23))	('correlated', 'Reg', (290, 300))	('patients', 'Species', '9606', (24, 32))	('rs1346044', 'Mutation', 'rs1346044', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('rs1346044 CC', 'Var', (38, 50))	('elevated cancer', 'Disease', (306, 321))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
447091	31333776	In this meta-analysis, no significant heterogeneities were found in the overall analysis of XPA rs10817938, rs2808668, XPC rs1870134, XPF rs3136038, and WRN rs1801195.	('XPF', 'Gene', '2072', (134, 137))	('rs1870134', 'Mutation', 'rs1870134', (123, 132))	('WRN', 'Gene', '7486', (153, 156))	('XPF', 'Gene', (134, 137))	('rs10817938', 'Var', (96, 106))	('rs1801195', 'Mutation', 'rs1801195', (157, 166))	('rs2808668', 'Mutation', 'rs2808668', (108, 117))	('rs2808668', 'Var', (108, 117))	('WRN', 'Gene', (153, 156))	('XPC', 'Gene', (119, 122))	('rs10817938', 'Mutation', 'rs10817938', (96, 106))	('rs3136038', 'Mutation', 'rs3136038', (138, 147))	('XPA', 'Gene', '7507', (92, 95))	('rs1801195', 'Var', (157, 166))	('XPA', 'Gene', (92, 95))	('XPC', 'Gene', '7508', (119, 122))	('rs1870134', 'Var', (123, 132))
447092	31333776	However, the moderate heterogeneity was observed when all the studies were analyzed for all the cases of XPD rs238406 under the homozygous model (I2 = 61.1%) and WRN rs1346044 under the homozygous model (I2 = 61.7%) (Table 1, Table S2).	('rs1346044', 'Mutation', 'rs1346044', (166, 175))	('WRN', 'Gene', '7486', (162, 165))	('rs238406', 'Mutation', 'rs238406', (109, 117))	('WRN', 'Gene', (162, 165))	('rs1346044', 'Var', (166, 175))	('XPD', 'Gene', (105, 108))	('XPD', 'Gene', '2068', (105, 108))
447093	31333776	After stratification analysis, the heterogeneity of SNP rs238406 was found accused of the nervous system cancer and urinary system cancer, which is available in the higher I2 value, 82.9% and 93.2%, respectively.	('SNP rs238406', 'Var', (52, 64))	('urinary system cancer', 'Disease', (116, 137))	('nervous system cancer', 'Disease', 'MESH:D009369', (90, 111))	('rs238406', 'Mutation', 'rs238406', (56, 64))	('urinary system cancer', 'Disease', 'MESH:D001749', (116, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('nervous system cancer', 'Phenotype', 'HP:0004375', (90, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('nervous system cancer', 'Disease', (90, 111))
447094	31333776	For another SNP rs1346044, the heterogeneity exists the subgroup of digestive system cancer (I2 = 82.3%), and other subgroups showed no heterogeneity (Figure 4, 5, S3, S4 G).	('system cancer', 'Disease', 'MESH:D009369', (78, 91))	('rs1346044', 'Mutation', 'rs1346044', (16, 25))	('system cancer', 'Disease', (78, 91))	('SNP', 'Var', (12, 15))	('S4 G', 'Mutation', 'p.S4G', (168, 172))	('rs1346044', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
447099	31333776	Previous accumulating studies established that aberrant expression of the core DNA repair genes such as XPs and WRN can modulate the capability of DNA damage and/or repair and subsequently contribute to carcinogenesis.	('aberrant expression', 'Var', (47, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (203, 217))	('carcinogenesis', 'Disease', (203, 217))	('WRN', 'Gene', '7486', (112, 115))	('modulate', 'Reg', (120, 128))	('DNA damage', 'MPA', (147, 157))	('contribute to', 'Reg', (189, 202))	('WRN', 'Gene', (112, 115))	('repair', 'MPA', (165, 171))	('XPs', 'Gene', (104, 107))
447103	31333776	More importantly, these genes alteration frequency displayed higher levels in 33 types of cancers.	('cancers', 'Disease', (90, 97))	('alteration', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('higher', 'PosReg', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
447104	31333776	So we hypothesized that the genetic variations of DNA repair core genes, especially in the 5'UTR (XPA rs10817938 and rs2808668, XPF rs3136038) or Exon sites (XPC rs1870134, XPD rs238406, WRN rs1346044 and rs1801195) may play a critical role in altering protein function and capability to repair damaged DNA, thus affecting the cancer risk.	('rs10817938', 'Var', (102, 112))	('rs1346044', 'Mutation', 'rs1346044', (191, 200))	('rs1870134', 'Var', (162, 171))	('altering', 'Reg', (244, 252))	('XPD', 'Gene', (173, 176))	('XPF', 'Gene', '2072', (128, 131))	('rs1801195', 'Var', (205, 214))	('cancer', 'Disease', (327, 333))	('rs10817938', 'Mutation', 'rs10817938', (102, 112))	('WRN', 'Gene', '7486', (187, 190))	('rs1801195', 'Mutation', 'rs1801195', (205, 214))	('WRN', 'Gene', (187, 190))	('rs238406', 'Mutation', 'rs238406', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('affecting', 'Reg', (313, 322))	('protein', 'Protein', (253, 260))	('rs3136038', 'Mutation', 'rs3136038', (132, 141))	('rs1870134', 'Mutation', 'rs1870134', (162, 171))	('XPF', 'Gene', (128, 131))	('XPD', 'Gene', '2068', (173, 176))	('XPC', 'Gene', '7508', (158, 161))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('rs2808668', 'Mutation', 'rs2808668', (117, 126))	('rs2808668', 'Var', (117, 126))	('XPC', 'Gene', (158, 161))	('XPA', 'Gene', '7507', (98, 101))	('XPA', 'Gene', (98, 101))
447106	31333776	Recent studies reported that the potentially functional SNPs in the XPA gene, especially in the transcription factors binding sites (TFBS) such as novel SNPs rs10817938 and rs2808668, which located at the XPA prompter region and may be involved in the cancer risk.	('involved', 'Reg', (236, 244))	('rs10817938', 'Var', (158, 168))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('rs10817938', 'Mutation', 'rs10817938', (158, 168))	('cancer', 'Disease', (252, 258))	('XPA', 'Gene', '7507', (205, 208))	('XPA', 'Gene', (205, 208))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('functional', 'Reg', (45, 55))	('XPA', 'Gene', '7507', (68, 71))	('rs2808668', 'Mutation', 'rs2808668', (173, 182))	('rs2808668', 'Var', (173, 182))	('XPA', 'Gene', (68, 71))
447107	31333776	reported that the risk effect of rs10817938 T to C substitution not only had a strong impact on transcription activity, XPA mRNA and protein expression, but also obviously showed a significant gene-environment interaction with the smoking status of the patients.	('patients', 'Species', '9606', (253, 261))	('transcription activity', 'MPA', (96, 118))	('rs10817938', 'Mutation', 'rs10817938', (33, 43))	('XPA', 'Gene', '7507', (120, 123))	('impact', 'Reg', (86, 92))	('rs10817938 T', 'Var', (33, 45))	('XPA', 'Gene', (120, 123))
447108	31333776	In the present meta-analysis, 1775 cases and 2156 controls included for SNP rs10817938, a significantly increased cancer risk was observed harboring CC, CC/CT genotype, or C allele on the overall analysis as well as the stratification analysis in the digestive system cancers.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', (268, 274))	('system cancers', 'Disease', (261, 275))	('system cancers', 'Disease', 'MESH:D009369', (261, 275))	('CC/CT', 'Disease', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('rs10817938', 'Mutation', 'rs10817938', (76, 86))	('SNP rs10817938', 'Var', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('cancer', 'Disease', (114, 120))
447109	31333776	However, no significant association was observed between rs2808668 and cancer susceptibility in the overall analysis, and 8 studies were included with 2616 cases and 3099 controls.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs2808668', 'Mutation', 'rs2808668', (57, 66))	('rs2808668', 'Var', (57, 66))
447110	31333776	Thereafter stratified analyses showed that carrying XPA rs2808668 homozygous CC genotype or C allele was associated with significantly decreased cancer risk in the subgroup of including lung cancer and breast cancer except for digestive system cancer.	('decreased cancer', 'Disease', (135, 151))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('XPA', 'Gene', (52, 55))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('XPA', 'Gene', '7507', (52, 55))	('rs2808668', 'Mutation', 'rs2808668', (56, 65))	('rs2808668', 'Var', (56, 65))	('breast cancer', 'Disease', (202, 215))	('system cancer', 'Disease', 'MESH:D009369', (237, 250))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('decreased cancer', 'Disease', 'MESH:D009369', (135, 151))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('system cancer', 'Disease', (237, 250))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
447111	31333776	Recent studies reported that XPA rs2808668 can interact with environmental factor such as drinking in gastric cancer, and clinicopathological parameters such as tumor size, metastatic status at onset and mitotic index in gastrointestinal stromal cancer.	('gastrointestinal stromal cancer', 'Disease', 'MESH:D046152', (221, 252))	('interact', 'Reg', (47, 55))	('gastric cancer', 'Disease', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('XPA', 'Gene', '7507', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mitotic index', 'CPA', (204, 217))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('metastatic status', 'CPA', (173, 190))	('XPA', 'Gene', (29, 32))	('rs2808668', 'Mutation', 'rs2808668', (33, 42))	('gastrointestinal stromal cancer', 'Disease', (221, 252))	('rs2808668', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
447112	31333776	These findings highlight an obvious divergence between the SNP rs2808668 or rs10817938and cancer risk, although these SNPs were all in the XPA promoter region, which might be partially explained by environmental factors or clinicopathological parameters interacted with genetic variants synergistically contributing to the carcinogenesis.	('carcinogenesis', 'Disease', (323, 337))	('rs2808668', 'Mutation', 'rs2808668', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs2808668', 'Var', (63, 72))	('rs10817938', 'Mutation', 'rs10817938', (76, 86))	('XPA', 'Gene', (139, 142))	('XPA', 'Gene', '7507', (139, 142))	('rs10817938and', 'Var', (76, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (323, 337))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
447115	31333776	Next, endonuclease is required for NER steps, XPF, a 103 kDa protein, is structure-specific nuclease that recognizes the DNA junction 5' to the adducted base(s).	('XPF', 'Gene', (46, 49))	('DNA', 'Var', (121, 124))	('XPF', 'Gene', '2072', (46, 49))
447117	31333776	In this pooled meta-analysis, 8 studied in 4987 cases and 6193 controls for XPC rs1870134, 24 studies with 6999 cases and 8652 controls for XPD rs238406, and 10 studies of 5247 cases and 5607 controls for XPF rs3136038 polymorphisms were recruited.	('XPD', 'Gene', (140, 143))	('rs238406', 'Var', (144, 152))	('XPF', 'Gene', (205, 208))	('XPC', 'Gene', (76, 79))	('rs3136038', 'Mutation', 'rs3136038', (209, 218))	('rs1870134', 'Mutation', 'rs1870134', (80, 89))	('XPD', 'Gene', '2068', (140, 143))	('XPC', 'Gene', '7508', (76, 79))	('rs1870134', 'Var', (80, 89))	('XPF', 'Gene', '2072', (205, 208))	('rs238406', 'Mutation', 'rs238406', (144, 152))
447119	31333776	For XPF rs3136038 polymorphism, a reduced overall cancer risk was noted in the additive model.	('XPF', 'Gene', '2072', (4, 7))	('rs3136038', 'Mutation', 'rs3136038', (8, 17))	('reduced', 'NegReg', (34, 41))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('XPF', 'Gene', (4, 7))	('rs3136038', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
447120	31333776	In the subgroup analysis, harboring rs3136038 TT genotype, dominant model or recessive model significantly reduced cancer risk in the digestive system cancer, however, no association was observed in the other subgroup.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('rs3136038', 'Mutation', 'rs3136038', (36, 45))	('reduced', 'NegReg', (107, 114))	('system cancer', 'Disease', 'MESH:D009369', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('system cancer', 'Disease', (144, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('rs3136038 TT', 'Var', (36, 48))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
447121	31333776	These results hint that genetic variants involved in the carcinogenesis dependent on the cancer type-specificity such as cancer subgroup based on organ systems.	('carcinogenesis', 'Disease', 'MESH:D063646', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('carcinogenesis', 'Disease', (57, 71))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('variants', 'Var', (32, 40))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
447122	31333776	In addition, no significant association was determined in XPC rs1870134 polymorphism and cancer susceptibility.	('XPC', 'Gene', '7508', (58, 61))	('rs1870134', 'Var', (62, 71))	('rs1870134', 'Mutation', 'rs1870134', (62, 71))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('XPC', 'Gene', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
447123	31333776	Only one report demonstrated that XPC rs1870134 polymorphism is a cancer risk biomarker for prostate cancer, which suggested more and further research about this association is necessary.	('rs1870134', 'Var', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('rs1870134', 'Mutation', 'rs1870134', (38, 47))	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('XPC', 'Gene', '7508', (34, 37))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('XPC', 'Gene', (34, 37))	('cancer', 'Disease', (66, 72))
447126	31333776	It is assumed that WRN genetic variants such as rs1346044 and rs1801195 may correlate with the susceptibility to cancers.	('rs1801195', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('rs1346044', 'Var', (48, 57))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('WRN', 'Gene', (19, 22))	('cancers', 'Disease', (113, 120))	('WRN', 'Gene', '7486', (19, 22))	('rs1801195', 'Mutation', 'rs1801195', (62, 71))	('rs1346044', 'Mutation', 'rs1346044', (48, 57))
447128	31333776	Despite the fact that no association observed between overall cancer risk and these 2 SNPs, further stratification analysis found that increased cancer risk in the genital system patients with rs1801195 TT genotype and breast cancer with rs1346044 CC genotype.	('cancer', 'Disease', (145, 151))	('rs1346044 CC', 'Var', (238, 250))	('rs1801195', 'Mutation', 'rs1801195', (193, 202))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('rs1346044', 'Mutation', 'rs1346044', (238, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', (219, 232))	('rs1801195 TT', 'Var', (193, 205))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
447129	31333776	Both of the rs1346044 and rs1801195are located at Exon region of WRN gene, which contains a T to C substitution for rs1346044 (amino acids change: Cys1367Arg), and a T to G substitution for rs1801195 (amino acids change: Leu1074Phe).	('WRN', 'Gene', (65, 68))	('Leu1074Phe', 'Var', (221, 231))	('WRN', 'Gene', '7486', (65, 68))	('rs1801195are', 'Var', (26, 38))	('rs1346044', 'Mutation', 'rs1346044', (12, 21))	('Leu1074Phe', 'Chemical', '-', (221, 231))	('rs1801195', 'Mutation', 'rs1801195', (26, 35))	('rs1801195', 'Var', (190, 199))	('rs1346044', 'Mutation', 'rs1346044', (116, 125))	('rs1801195', 'Mutation', 'rs1801195', (190, 199))	('rs1346044', 'Var', (12, 21))	('Cys1367Arg', 'SUBSTITUTION', 'None', (147, 157))	('Cys1367Arg', 'Var', (147, 157))	('rs1346044', 'Var', (116, 125))
447130	31333776	It is plausible that the amino acids substitution can change the tertiary structure, which results in the direct binding of BRCA1 and then alter the function of the WRN protein in facilitating the carcinogenesis, which only partially explains the cancer risk associated with these SNPs because of not all types of cancer susceptibility observed, and further studies are needed.	('alter', 'Reg', (139, 144))	('carcinogenesis', 'Disease', (197, 211))	('BRCA1', 'Gene', '672', (124, 129))	('results in', 'Reg', (91, 101))	('cancer', 'Disease', (247, 253))	('BRCA1', 'Gene', (124, 129))	('WRN', 'Gene', '7486', (165, 168))	('carcinogenesis', 'Disease', 'MESH:D063646', (197, 211))	('cancer', 'Disease', 'MESH:D009369', (314, 320))	('WRN', 'Gene', (165, 168))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('change', 'Reg', (54, 60))	('tertiary structure', 'MPA', (65, 83))	('binding', 'Interaction', (113, 120))	('amino acids substitution', 'Var', (25, 49))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('function', 'MPA', (149, 157))	('cancer', 'Disease', (314, 320))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))
447132	31333776	First, although overall recruited eligible studies sample is relatively large, only 4 studies were included for the SNPs XPA rs10817938 and WRN rs1801195, thus the results cannot be rule out the possibility of fortuitous considering the limited small size for these two SNPs.	('WRN', 'Gene', (140, 143))	('XPA', 'Gene', (121, 124))	('XPA', 'Gene', '7507', (121, 124))	('rs1801195', 'Mutation', 'rs1801195', (144, 153))	('rs10817938', 'Var', (125, 135))	('rs10817938', 'Mutation', 'rs10817938', (125, 135))	('WRN', 'Gene', '7486', (140, 143))
447135	31333776	The meta-analysis included the latest publications exhibit that harboring SNPs XPA rs10817938 and XPD rs238406 were significantly associated with increased overall cancer risk, however, polymorphisms of XPA rs2808668 in overall cancer analysis and XPF rs3136038 in the digestive system remarkably reduced the susceptibility of cancer.	('susceptibility', 'MPA', (309, 323))	('XPF', 'Gene', '2072', (248, 251))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('XPA', 'Gene', (79, 82))	('cancer', 'Disease', (327, 333))	('XPA', 'Gene', '7507', (79, 82))	('XPD', 'Gene', '2068', (98, 101))	('rs3136038', 'Mutation', 'rs3136038', (252, 261))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('rs10817938', 'Var', (83, 93))	('cancer', 'Disease', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', (164, 170))	('rs2808668', 'Mutation', 'rs2808668', (207, 216))	('rs238406', 'Mutation', 'rs238406', (102, 110))	('rs10817938', 'Mutation', 'rs10817938', (83, 93))	('XPF', 'Gene', (248, 251))	('rs2808668', 'Var', (207, 216))	('XPD', 'Gene', (98, 101))	('XPA', 'Gene', '7507', (203, 206))	('associated', 'Reg', (130, 140))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('XPA', 'Gene', (203, 206))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('reduced', 'NegReg', (297, 304))	('polymorphisms', 'Var', (186, 199))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
447136	31333776	In addition, no relationship to the overall cancer risk was observed in SNPs of XPC rs1870134, WRN rs1346044 and rs1801195 to data included literature.	('cancer', 'Disease', (44, 50))	('WRN', 'Gene', '7486', (95, 98))	('XPC', 'Gene', (80, 83))	('rs1801195', 'Mutation', 'rs1801195', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('XPC', 'Gene', '7508', (80, 83))	('WRN', 'Gene', (95, 98))	('rs1870134', 'Var', (84, 93))	('rs1346044', 'Mutation', 'rs1346044', (99, 108))	('rs1870134', 'Mutation', 'rs1870134', (84, 93))	('rs1801195', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
447144	30244869	Consistently, Sox2 ablation in mice causes esophageal agenesis.	('ablation', 'Var', (19, 27))	('esophageal agenesis', 'Disease', (43, 62))	('mice', 'Species', '10090', (31, 35))	('Sox2', 'Gene', (14, 18))
447161	30244869	Respiratory specification in response to Wnt and BMP activation results in expression of the transcription factor Nkx2-1 whereas inhibition of BMP in the dorsal foregut promotes development of Sox2-expressing esophageal epithelium.	('promotes', 'PosReg', (169, 177))	('BMP', 'Gene', (49, 52))	('sin', 'Gene', (204, 207))	('inhibition', 'Var', (129, 139))	('Respiratory specification', 'CPA', (0, 25))	('results in', 'Reg', (64, 74))	('development', 'CPA', (178, 189))	('rat', 'Species', '10116', (5, 8))	('sin', 'Gene', '55718', (204, 207))	('Nkx2-1', 'Gene', (114, 120))	('BMP', 'Gene', '649', (143, 146))	('BMP', 'Gene', '649', (49, 52))	('BMP', 'Gene', (143, 146))
447175	30244869	We found that shorter duration of chiron, a canonical Wnt pathway activator (through GSK3beta inhibition), or Wnt3a treatment following DE formation resulted in formation of anterior foregut (AFG) spheroids expressing HNF1beta and SOX2, with low levels of posterior foregut markers PROX1 and HNF6 (Figure 1A-E,S1A-G).	('HNF1beta', 'Var', (218, 226))	('sin', 'Gene', (213, 216))	('HNF6', 'Gene', '3175', (292, 296))	('HNF6', 'Gene', (292, 296))	('sin', 'Gene', '55718', (213, 216))	('rat', 'Species', '10116', (24, 27))
447177	30244869	From this, we concluded that the regional identity of these foregut spheroids (HNF1B+/SOX2+, PROX1-/HNF6-) are distal to the pharynx and proximal to the posterior foregut.	('HNF6', 'Gene', (100, 104))	('HNF1B+/SOX2+', 'Var', (79, 91))	('HNF6', 'Gene', '3175', (100, 104))
447189	30244869	Taken together, inhibition of BMP signaling in cultures of AFG spheroids promoted a dorsal anterior foregut identity.	('dorsal anterior foregut identity', 'CPA', (84, 116))	('BMP', 'Gene', '649', (30, 33))	('BMP', 'Gene', (30, 33))	('promoted', 'PosReg', (73, 81))	('inhibition', 'Var', (16, 26))
447190	30244869	To determine if dorsally-patterned AFG spheroids were competent to grow into esophageal organoids, we cultured them suspended in matrigel with EGF alone or in the context of manipulation of other pathways predicted to promote esophageal development including Wnt activation (chiron), extended BMP inhibition (Noggin), activation of hedgehog (SAG, a smoothened agonist), and FGF10.	('BMP', 'Gene', '649', (293, 296))	('FGF10', 'Gene', (374, 379))	('Noggin', 'Gene', (309, 315))	('promote', 'PosReg', (218, 225))	('esophageal development', 'CPA', (226, 248))	('BMP', 'Gene', (293, 296))	('manipulation', 'Var', (174, 186))	('Wnt activation', 'CPA', (259, 273))	('extended', 'MPA', (284, 292))	('Noggin)', 'Gene', '9241', (309, 316))
447230	30244869	We generated two mouse models to inducibly delete Sox2 in the foregut endoderm prior to initiation of esophageal development (FoxA2CreER ;Sox2fl/fl and Sox2CreER/fl).	('mouse', 'Species', '10090', (17, 22))	(';Sox', 'Gene', (137, 141))	(';Sox', 'Gene', '104009', (137, 141))	('delete', 'Var', (43, 49))	('rat', 'Species', '10116', (7, 10))	('Sox2', 'Gene', (50, 54))
447231	30244869	In both models, early deletion of Sox2 in the foregut resulted in complete esophageal agenesis, with the foregut region between the pharynx and stomach remaining as one tube lacking p63 and broadly expressing the respiratory marker Nkx2-1 (Figure 5C-F,S6A-D).	('esophageal', 'Disease', (75, 85))	('Sox2', 'Gene', (34, 38))	('p63', 'Gene', (182, 185))	('sin', 'Gene', (204, 207))	('deletion', 'Var', (22, 30))	('p63', 'Gene', '8626', (182, 185))	('sin', 'Gene', '55718', (204, 207))	('rat', 'Species', '10116', (218, 221))	('5C-F', 'Chemical', 'MESH:C504520', (247, 251))
447235	30244869	Sox2CreER/fl embryos had increased cleaved Caspase 3 staining in the dorsal foregut at the level where separation would normally be occurring, suggesting that cells of the presumptive esophagus were undergoing cell death (Figure 5G-H,S6U).	('increased', 'PosReg', (25, 34))	('staining', 'MPA', (53, 61))	('Sox2CreER/fl', 'Var', (0, 12))	('cleaved', 'MPA', (35, 42))	('S6U', 'Chemical', 'MESH:C008993', (234, 237))	('rat', 'Species', '10116', (107, 110))
447237	30244869	In both control and Sox2 knockout foreguts, there appears to be a point where the epithelium narrows midway along the dorsal-ventral axis, suggesting that the epithelium is attempting to separate into the two tubes regardless of the presence of Sox2 protein (Figure S6M-T).	('Sox2', 'Gene', (20, 24))	('knockout', 'Var', (25, 33))	('rat', 'Species', '10116', (191, 194))
447243	30244869	Knocking down sox2 using morpholino injections in Xenopus endoderm explants and activating canonical Wnt signaling with Bio did not activate nkx2-1 expression in the absence of BMP4 (Figure 6A-B, 6E-F).	('BMP', 'Gene', '649', (177, 180))	('nkx2-1', 'Gene', (141, 147))	('Knocking down', 'Var', (0, 13))	('6E-F', 'Chemical', 'MESH:C086465', (196, 200))	('Xenopus', 'Species', '8355', (50, 57))	('BMP', 'Gene', (177, 180))	('sin', 'Gene', (20, 23))	('sox2', 'Gene', (14, 18))	('sin', 'Gene', '55718', (20, 23))	('activating canonical Wnt signaling', 'MPA', (80, 114))
447244	30244869	However, treatment with Bio and BMP4 expanded the nkx2-1 domain upon sox2 knock down as it was in the mouse Sox2 knockout (Figure 6CD).	('BMP', 'Gene', '649', (32, 35))	('nkx2-1 domain', 'MPA', (50, 63))	('BMP', 'Gene', (32, 35))	('expanded', 'PosReg', (37, 45))	('knock down', 'Var', (74, 84))	('mouse', 'Species', '10090', (102, 107))	('sox2', 'Gene', (69, 73))
447247	30244869	SOX2 knockdown in human dorsal anterior foregut cultures (dAFG) resulted in ectopic expression of NKX2-1 mRNA and protein (Figure 6G-J, 6L-M).	('knockdown', 'Var', (5, 14))	('human', 'Species', '9606', (18, 23))	('ectopic expression', 'MPA', (76, 94))	('NKX2-1', 'Gene', (98, 104))	('SOX2', 'Gene', (0, 4))	('mRNA and', 'MPA', (105, 113))
447255	30244869	The loss of SOX2, however, resulted in many transcriptional changes in the dorsal foregut and relatively few in the ventral foregut, including increased expression of NKX2-1 and reduced expression of FOXE1, NTN1, and GDNF (Figure 7A-B, 7D,S7B, Table S3).	('GDNF', 'Gene', (217, 221))	('increased', 'PosReg', (143, 152))	('NTN1', 'Gene', (207, 211))	('NTN1', 'Gene', '9423', (207, 211))	('transcriptional', 'MPA', (44, 59))	('SOX2', 'Gene', (12, 16))	('NKX2-1', 'Gene', (167, 173))	('expression', 'MPA', (186, 196))	('expression', 'MPA', (153, 163))	('FOXE1', 'Gene', (200, 205))	('reduced', 'NegReg', (178, 185))	('loss', 'Var', (4, 8))
447257	30244869	In the ventral cultures, 374 genes are upregulated by BMP treatment, and of these, 38 were decreased and 5 were increased in response to loss of SOX2 (Figure 7D).	('BMP', 'Gene', '649', (54, 57))	('upregulated', 'PosReg', (39, 50))	('SOX2', 'Gene', (145, 149))	('increased', 'PosReg', (112, 121))	('loss', 'Var', (137, 141))	('BMP', 'Gene', (54, 57))
447259	30244869	We used intersectional analysis to identify genes that BMP likely regulates through repression of SOX2 and found 46 genes (12.3%) that are both upregulated by both BMP treatment and SOX2 knockdown ("Genes negatively regulated by SOX2").	('repression', 'NegReg', (84, 94))	('upregulated', 'PosReg', (144, 155))	('BMP', 'Gene', (55, 58))	('knockdown', 'Var', (187, 196))	('BMP', 'Gene', '649', (164, 167))	('regulates', 'Reg', (66, 75))	('SOX2', 'Gene', (98, 102))	('BMP', 'Gene', (164, 167))	('BMP', 'Gene', '649', (55, 58))	('SOX2', 'Gene', (182, 186))
447260	30244869	We also found 81 genes (14.9%) that are both downregulated by both BMP treatment and SOX2 knockdown ("Genes positively regulated by SOX2") (Figure 7B).	('BMP', 'Gene', '649', (67, 70))	('knockdown', 'Var', (90, 99))	('BMP', 'Gene', (67, 70))	('downregulated', 'NegReg', (45, 58))	('SOX2', 'Gene', (85, 89))
447261	30244869	In addition, >80% of BMP-regulated transcripts were unchanged in response to SOX2 knockdown, consistent with the conclusion that BMP has a role in ventral foregut specification independent of SOX2 repression.	('ventral foregut specification', 'CPA', (147, 176))	('knockdown', 'Var', (82, 91))	('BMP', 'Gene', '649', (129, 132))	('SOX2', 'Gene', (77, 81))	('BMP', 'Gene', '649', (21, 24))	('BMP', 'Gene', (129, 132))	('BMP', 'Gene', (21, 24))
447263	30244869	To investigate this, we deleted Sox2 from the mouse foregut using two genetic models, Foxa2CreER;Sox2fl/fl and Sox2CreER/fl and measured canonical Wnt/beta-catenin activity by analyzing expression of the Wnt target gene Axin2.	('measured', 'Reg', (128, 136))	('canonical Wnt/beta-catenin', 'MPA', (137, 163))	('deleted', 'Var', (24, 31))	('sin', 'Gene', (61, 64))	('mouse', 'Species', '10090', (46, 51))	(';Sox', 'Gene', (96, 100))	('Sox2', 'Gene', (32, 36))	(';Sox', 'Gene', '104009', (96, 100))	('sin', 'Gene', '55718', (61, 64))
447285	30244869	Since SOX2 mutations can cause esophageal atresia in mice and humans, we used HEOs to identify how SOX2 may control human esophageal development since the mechanism underlying its action was unclear.	('mutations', 'Var', (11, 20))	('sin', 'Gene', '55718', (145, 148))	('mice', 'Species', '10090', (53, 57))	('human', 'Species', '9606', (62, 67))	('esophageal atresia', 'Phenotype', 'HP:0002032', (31, 49))	('human esophageal development', 'CPA', (116, 144))	('esophageal atresia', 'Disease', 'MESH:D004933', (31, 49))	('esophageal atresia', 'Disease', (31, 49))	('cause', 'Reg', (25, 30))	('HEO', 'Chemical', 'MESH:C105575', (78, 81))	('sin', 'Gene', (145, 148))	('humans', 'Species', '9606', (62, 68))	('control', 'Reg', (108, 115))	('SOX2', 'Gene', (6, 10))	('human', 'Species', '9606', (116, 121))
447288	30244869	In human foregut cultures, SOX2 also regulates transcript levels of SFRP2, and loss of SOX2 causes increased Wnt activity in the dorsal foregut.	('regulates', 'Reg', (37, 46))	('SOX2', 'Gene', (87, 91))	('loss', 'Var', (79, 83))	('human', 'Species', '9606', (3, 8))	('SFRP2', 'Gene', (68, 73))	('transcript levels', 'MPA', (47, 64))	('increased', 'PosReg', (99, 108))	('Wnt activity in the dorsal foregut', 'CPA', (109, 143))
447293	30244869	We identified that in both humans and mice, SOX2 represses Wnt activity and that failure to do so results in inappropriate dorsal activation of the respiratory program.	('humans', 'Species', '9606', (27, 33))	('Wnt activity', 'MPA', (59, 71))	('mice', 'Species', '10090', (38, 42))	('rat', 'Species', '10116', (153, 156))	('represses', 'NegReg', (49, 58))	('respiratory program', 'MPA', (148, 167))	('dorsal activation', 'MPA', (123, 140))	('SOX2', 'Var', (44, 48))
447296	30244869	Wild-type and mutant mice and Xenopus laevis were used for studies on foregut and esophageal embryonic development.	('esophageal embryonic', 'Disease', 'MESH:D004941', (82, 102))	('mice', 'Species', '10090', (21, 25))	('mutant', 'Var', (14, 20))	('esophageal embryonic', 'Disease', (82, 102))	('Xenopus laevis', 'Species', '8355', (30, 44))
447315	30244869	Additional factors were tested during this time (described in results), such as CHIR99021 ("chiron" or "chr", 2 muM, Tocris), Wnt3a (500 ng mL-1, R&D systems), SB431542 (10 muM, Tocris), DEAB (10 muM, Sigma), and retinoic acid (2 muM).	('muM', 'Gene', '56925', (196, 199))	('muM', 'Gene', '56925', (230, 233))	('muM', 'Gene', (112, 115))	('SB431542', 'Chemical', 'MESH:C459179', (160, 168))	('SB431542', 'Var', (160, 168))	('muM', 'Gene', (196, 199))	('muM', 'Gene', (230, 233))	('muM', 'Gene', '56925', (173, 176))	('DEAB', 'Chemical', 'MESH:C007368', (187, 191))	('retinoic acid', 'Chemical', 'MESH:D014212', (213, 226))	('muM', 'Gene', (173, 176))	('muM', 'Gene', '56925', (112, 115))
447324	30244869	Rafts were initially cultured for 4 days with the addition of Y-27632 (10 muM) prior to exposure to the liquid-air interface to generate a stratified epithelium.	('muM', 'Gene', (74, 77))	('rat', 'Species', '10116', (132, 135))	('Y-27632', 'Var', (62, 69))	('Y-27632', 'Chemical', 'MESH:C108830', (62, 69))	('muM', 'Gene', '56925', (74, 77))	('rat', 'Species', '10116', (141, 144))
447330	30244869	In Sox2CreER experiments, pregnant dams were gavaged at 8.5dpc to knockout Sox2 prior to tracheoesophageal separation, and 9.5dpc to knockout Sox2 during/after tracheoesophageal separation.	('knockout', 'Var', (66, 74))	('rat', 'Species', '10116', (111, 114))	('tracheoesophageal separation', 'Phenotype', 'HP:0002575', (160, 188))	('rat', 'Species', '10116', (182, 185))	('tracheoesophageal separation', 'Phenotype', 'HP:0002575', (89, 117))	('Sox2', 'Gene', (75, 79))
447367	30244869	The accession numbers for the samples are: GSM1120313 and GSM1120314 (small intestine), GSM1010946 and GSM1120308 (lung), GSM1120307 and GSM11010960 (stomach), GSM1120315 and GSM1010974 (large intestine), GSM1010956 and GSM1120303 (esophagus), GSM2343841 and GSM234564 (lower leg skin), and GSM1592609-GSM1592611 (EPC2 day 0 cultures).	('GSM1120315', 'Var', (160, 170))	('GSM1120314', 'Var', (58, 68))	('GSM1120307', 'Chemical', 'MESH:C581775', (122, 132))	('GSM234564', 'Chemical', 'MESH:C581775', (259, 268))	('GSM1120308', 'Var', (103, 113))	('GSM2343841', 'Chemical', 'MESH:C581775', (244, 254))	('GSM1010956', 'Var', (205, 215))	('GSM1120315', 'Chemical', 'MESH:C581775', (160, 170))	('GSM2343841', 'Var', (244, 254))	('GSM1120303', 'Chemical', 'MESH:C581775', (220, 230))	('GSM1120313', 'Chemical', 'MESH:C581775', (43, 53))	('GSM1120307', 'Var', (122, 132))	('GSM1010946', 'Var', (88, 98))	('GSM1010974', 'Chemical', 'MESH:C581775', (175, 185))	('GSM1120314', 'Chemical', 'MESH:C581775', (58, 68))	('lower leg', 'Phenotype', 'HP:0006385', (270, 279))	('GSM1592609-GSM1592611', 'Var', (291, 312))	('GSM1120308', 'Chemical', 'MESH:C581775', (103, 113))	('GSM234564', 'Var', (259, 268))	('GSM1010956', 'Chemical', 'MESH:C581775', (205, 215))	('GSM1010974', 'Var', (175, 185))	('GSM1120303', 'Var', (220, 230))	('GSM11010960', 'Var', (137, 148))	('GSM1120313', 'Var', (43, 53))	('GSM1010946', 'Chemical', 'MESH:C581775', (88, 98))	('GSM1592609-GSM1592611', 'Chemical', 'MESH:C581775', (291, 312))
447386	30075571	During esophageal carcinogenesis, there is altered expression, mutation, and/or epigenetically silencing of many genes.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (7, 32))	('mutation', 'Var', (63, 71))	('esophageal carcinogenesis', 'Disease', (7, 32))	('expression', 'MPA', (51, 61))	('epigenetically silencing', 'Var', (80, 104))	('altered', 'Reg', (43, 50))
447389	30075571	Aberrant ERCC1 expression was associated with genomic instability and cancer development, as well as resistance to cancer chemotherapy and radiation therapy.	('associated', 'Reg', (30, 40))	('cancer', 'Disease', (115, 121))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('genomic instability', 'CPA', (46, 65))	('ERCC1', 'Gene', (9, 14))	('expression', 'MPA', (15, 25))	('ERCC1', 'Gene', '2067', (9, 14))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
447427	30075571	Moreover, expression of ERCC1 (chi2 = 41.814, P < .05) and survivin (chi2 = 3.414, P < .05) were associated with poor OS (Fig.	('survivin', 'Protein', (59, 67))	('ERCC1', 'Gene', (24, 29))	('ERCC1', 'Gene', '2067', (24, 29))	('associated', 'Reg', (97, 107))	('poor OS', 'Disease', (113, 120))	('expression', 'Var', (10, 20))
447448	30075571	In contrast, during cancer chemotherapy, cisplatin, one of mostly used anticancer agents in solid tumors, induces DNA intrastrand crosslink to trigger a series of intracellular events, leading to cancer cell death.	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cisplatin', 'Var', (41, 50))	('cancer cell death', 'Disease', (196, 213))	('solid tumors', 'Disease', (92, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('DNA intrastrand crosslink', 'MPA', (114, 139))	('solid tumors', 'Disease', 'MESH:D009369', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer cell death', 'Disease', 'MESH:D003643', (196, 213))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('induces', 'Reg', (106, 113))	('trigger', 'Reg', (143, 150))	('cancer', 'Disease', (75, 81))	('leading to', 'Reg', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
447464	26857264	Genomic landscape of somatic alterations in esophageal squamous cell carcinoma and gastric cancer Gastric cancer and esophageal cancer are the 2nd and 6th leading causes of cancer death worldwide.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('esophageal cancer', 'Disease', (117, 134))	('cancer death', 'Disease', (173, 185))	('esophageal squamous cell carcinoma', 'Disease', (44, 78))	('Gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('alterations', 'Var', (29, 40))	('Gastric cancer', 'Disease', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Disease', (83, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (44, 78))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('cancer death', 'Disease', 'MESH:D003643', (173, 185))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
447467	26857264	The A>C mutations in GCA suggested that oxidation of guanine may be a potential mechanism underlying cancer mutagenesis.	('GCA', 'Gene', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('guanine', 'Chemical', 'MESH:D006147', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('oxidation', 'MPA', (40, 49))	('A>C', 'Var', (4, 7))
447468	26857264	Furthermore, we identified genes with mutations in gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2, FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel cancer-associated genes, KISS1R, AMH, MNX1, WNK2, and PRKRIR.	('FGF2', 'Gene', (130, 134))	('ESCC', 'Gene', (70, 74))	('PRKRIR', 'Gene', '5612', (254, 260))	('KISS1R', 'Gene', '84634', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('FBXW7', 'Gene', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('CHEK2', 'Gene', '11200', (171, 176))	('KISS1R', 'Gene', (225, 231))	('PTCH', 'Gene', '5727', (149, 153))	('WNK2', 'Gene', (244, 248))	('NF1', 'Gene', '4763', (155, 158))	('AMH', 'Gene', '268', (233, 236))	('BRCA2', 'Gene', '675', (123, 128))	('cancer', 'Disease', (97, 103))	('TP53', 'Gene', '7157', (111, 115))	('ERBB2', 'Gene', (160, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (51, 65))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('mutations', 'Var', (38, 47))	('NF1', 'Gene', (155, 158))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('JAK3', 'Gene', (117, 121))	('FBXW7', 'Gene', '55294', (136, 141))	('ERBB2', 'Gene', '2064', (160, 165))	('MNX1', 'Gene', '3110', (238, 242))	('FGF2', 'Gene', '2247', (130, 134))	('AMH', 'Gene', (233, 236))	('PTCH', 'Gene', (149, 153))	('gastric cancer', 'Disease', (51, 65))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('MNX1', 'Gene', (238, 242))	('JAK3', 'Gene', '3718', (117, 121))	('MSH3', 'Gene', (143, 147))	('PRKRIR', 'Gene', (254, 260))	('WNK2', 'Gene', '65268', (244, 248))	('TP53', 'Gene', (111, 115))	('MSH3', 'Gene', '4437', (143, 147))	('BRCA2', 'Gene', (123, 128))	('cancer', 'Disease', (59, 65))	('CHEK2', 'Gene', (171, 176))	('cancer', 'Disease', (200, 206))
447469	26857264	Finally, we identified recurrent chromosome alterations in at least 30% of tumors in genes including MACROD2, FHIT, and PARK2 that were often intragenic deletions.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('MACROD2', 'Gene', (101, 108))	('MACROD2', 'Gene', '140733', (101, 108))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('FHIT', 'Gene', (110, 114))	('FHIT', 'Gene', '2272', (110, 114))	('PARK2', 'Gene', '5071', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('chromosome alterations', 'Var', (33, 55))	('PARK2', 'Gene', (120, 125))
447476	26857264	The reason for the high rates of GCA and ESCC in this geographic area and their relation to each other remains unclear, but there are almost certainly common etiologically important environmental exposures, and a recent genome-wide association study of germline DNA found that the same single nucleotide polymorphisms (SNPs) in the PLCE1 gene had the strongest associations with risk for both GCA and ESCC.	('GCA', 'Disease', (393, 396))	('ESCC', 'Disease', (401, 405))	('single nucleotide polymorphisms', 'Var', (286, 317))	('associations', 'Interaction', (361, 373))	('PLCE1', 'Gene', (332, 337))	('PLCE1', 'Gene', '51196', (332, 337))
447479	26857264	The identification of IDH1/2 mutations, initially in glioma and more recently in many other cancers such as AML, has transformed our understanding of cancer by relating mutations to metabolic control and epigenetic regulation.	('AML', 'Disease', (108, 111))	('IDH1/2', 'Gene', (22, 28))	('cancer', 'Disease', (92, 98))	('glioma', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('AML', 'Disease', 'MESH:D015470', (108, 111))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancer', 'Disease', (150, 156))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('IDH1/2', 'Gene', '3417;3418', (22, 28))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
447481	26857264	But mutant IDHs produce 2-hydroxyglutarate, which inhibits the methyl cytosine hydroxylase TET2 as well as H3K36 demethylases, thus changes the global epigenetic landscape.	('changes', 'Reg', (132, 139))	('IDH', 'Gene', (11, 14))	('IDH', 'Gene', '3417', (11, 14))	('mutant', 'Var', (4, 10))	('global epigenetic landscape', 'MPA', (144, 171))	('TET2', 'Gene', '54790', (91, 95))	('H3K36 demethylases', 'Enzyme', (107, 125))	('TET2', 'Gene', (91, 95))	('inhibits', 'NegReg', (50, 58))	('methyl cytosine', 'Enzyme', (63, 78))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (24, 42))
447482	26857264	The importance of these structural changes has been well documented in the case of BCR-ABL in leukemia, TMPRESS2-ERG in prostate cancer, and EML4-ALK in lung cancer.	('EML4-ALK in lung cancer', 'Disease', (141, 164))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('TMPRESS2-ERG', 'Var', (104, 116))	('BCR-ABL', 'Gene', '25', (83, 90))	('prostate cancer', 'Disease', (120, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('leukemia', 'Disease', (94, 102))	('leukemia', 'Disease', 'MESH:D007938', (94, 102))	('EML4-ALK in lung cancer', 'Disease', 'MESH:D008175', (141, 164))	('BCR-ABL', 'Gene', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))
447484	26857264	performed exome sequencing of 22 gastric cancer samples and identified frequent mutations in ARID1A.	('gastric cancer', 'Disease', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (33, 47))	('mutations', 'Var', (80, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('ARID1A', 'Gene', '8289', (93, 99))	('ARID1A', 'Gene', (93, 99))
447485	26857264	Mutations in ARID1A were particularly high in gastric cancers with microsatellite instability (MSI) (83%) or with Epstein-Barr virus (EBV) infection (73%).	('gastric cancers', 'Disease', 'MESH:D013274', (46, 61))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('MSI', 'Disease', (95, 98))	('ARID1A', 'Gene', '8289', (13, 19))	('ARID1A', 'Gene', (13, 19))	('gastric cancers', 'Phenotype', 'HP:0012126', (46, 61))	('Epstein-Barr virus (EBV) infection', 'Disease', 'MESH:D020031', (114, 148))	('Mutations', 'Var', (0, 9))	('microsatellite instability', 'MPA', (67, 93))	('MSI', 'Disease', 'None', (95, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('gastric cancers', 'Disease', (46, 61))	('high', 'Reg', (38, 42))
447486	26857264	Exome sequencing of 15 gastric adenocarcinomas and their matched normal DNAs by Zang et al also identified frequent mutations of ARID1A.	('ARID1A', 'Gene', '8289', (129, 135))	('ARID1A', 'Gene', (129, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('mutations', 'Var', (116, 125))	('15 gastric adenocarcinomas', 'Disease', (20, 46))	('15 gastric adenocarcinomas', 'Disease', 'MESH:D013274', (20, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))
447488	26857264	A study by Agrawal et al reported exomic sequencing of 11 esophageal adenocarcinomas (EAC) and 12 esophageal squamous cell carcinomas (ESCC) and found frequent NOTCH1 mutations in ESCC.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (109, 133))	('NOTCH1', 'Gene', '4851', (160, 166))	('NOTCH1', 'Gene', (160, 166))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (58, 84))	('mutations', 'Var', (167, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (58, 83))	('esophageal squamous cell carcinomas', 'Disease', (98, 133))	('EAC', 'Phenotype', 'HP:0011459', (86, 89))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (98, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('esophageal adenocarcinomas', 'Disease', (58, 84))
447493	26857264	They found that RHOA mutations are specific for diffuse-type tumors.	('diffuse-type tumors', 'Disease', 'MESH:D009369', (48, 67))	('RHOA', 'Gene', '387', (16, 20))	('diffuse-type tumors', 'Disease', (48, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('RHOA', 'Gene', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (21, 30))
447497	26857264	recently reported exome sequencing of 90 ESCC and whole genome sequencing of 14 ESCC and found that an APOBEC-mediated mutational signature in 47% of tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('BE', 'Chemical', 'MESH:D001608', (106, 108))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mutational', 'Var', (119, 129))	('APOBEC-mediated', 'Gene', (103, 118))
447514	26857264	Concordances for CC0996, EC1475, and EC8413 were below 99%.	('EC1475', 'Var', (25, 31))	('EC8413', 'CellLine', 'CVCL:K067', (37, 43))	('CC0996', 'Var', (17, 23))	('EC8413', 'Var', (37, 43))	('EC1475', 'CellLine', 'CVCL:5V07', (25, 31))
447516	26857264	We carried out validation for a subset of somatic missense mutations in subjects CC0996 and EC0379 using Sanger sequencing.	('EC0379', 'Var', (92, 98))	('missense mutations', 'Var', (50, 68))	('EC0379', 'CellLine', 'CVCL:8Z57', (92, 98))	('CC0996', 'Var', (81, 87))
447522	26857264	We used the following cascade of filters to identify potential cancer driver mutations: Selection of variants based on common variants database (1000 genome, CGI database, and NHLBI ESP exomes); Selection of variants based on predicted deleterious effects (literature, SIFT, phyloP, etc).	('SIFT', 'Disease', (269, 273))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (77, 86))	('variants', 'Var', (208, 216))	('SIFT', 'Disease', 'None', (269, 273))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
447524	26857264	We included homozygous, hemizygous, or compound heterozygous; Selection of variants were based on cancer driver variants.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('variants', 'Var', (75, 83))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
447530	26857264	We noted that BC5439, CC1649, CC1730, and EC1475 had much higher mutation rates, exceeding 40 million per Mb in intergenic regions.	('EC1475', 'Var', (42, 48))	('CC1730', 'Var', (30, 36))	('BC5439', 'Var', (14, 20))	('CC1649', 'Var', (22, 28))	('EC1475', 'CellLine', 'CVCL:5V07', (42, 48))
447531	26857264	However, we saw high A>C mutation rates in six of the 11 gastric cancers.	('gastric cancers', 'Phenotype', 'HP:0012126', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('A>C mutation', 'Var', (21, 33))	('gastric cancers', 'Disease', (57, 72))	('gastric cancers', 'Disease', 'MESH:D013274', (57, 72))
447532	26857264	This increased A>C mutation was also observed in several recent studies involving EAC and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('EAC', 'Disease', (82, 85))	('A>C mutation', 'Var', (15, 27))	('gastric cancer', 'Disease', (90, 104))
447533	26857264	We characterized somatic mutations to identify potential cancer driver mutations by analyzing our WGS data using Ingenuity Variant Analysis (IVA).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('IVA', 'Disease', (141, 144))	('mutations', 'Var', (71, 80))	('IVA', 'Disease', 'MESH:C538167', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
447536	26857264	Tumors with mutations in the 24 genes are illustrated in Figure 3.	('Tumors', 'Disease', (0, 6))	('mutations', 'Var', (12, 21))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))
447546	26857264	Four tumors deleted exon 6 of MACROD2 (NM_080676), which removed amino acids 140-180 and also caused frame-shift (Figure 5a).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('MACROD2', 'Gene', (30, 37))	('amino acids 140-180', 'MPA', (65, 84))	('MACROD2', 'Gene', '140733', (30, 37))	('caused', 'Reg', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('deleted', 'Var', (12, 19))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('frame-shift', 'MPA', (101, 112))
447547	26857264	The change likely resulted in a loss-function mutation of MACROD2.	('loss-function', 'NegReg', (32, 45))	('MACROD2', 'Gene', (58, 65))	('mutation', 'Var', (46, 54))	('MACROD2', 'Gene', '140733', (58, 65))
447548	26857264	Seven tumors deleted exon 5 of FHIT (NM_002012), which removed the first 35 amino acids and also shifted the reading frame (Figure 5b).	('deleted', 'Var', (13, 20))	('removed', 'NegReg', (55, 62))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('shifted', 'Reg', (97, 104))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('FHIT', 'Gene', (31, 35))	('FHIT', 'Gene', '2272', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
447549	26857264	The locations and sizes of PARK2 deletions varied (Figure 5c).	('PARK2', 'Gene', '5071', (27, 32))	('deletions', 'Var', (33, 42))	('PARK2', 'Gene', (27, 32))
447551	26857264	All three genes, MACROD2, FHIT, and PARK2, contained deletions involving coding exons with 16, 9, and 6 tumors having deletions in MACROD2, FHIT, and PARK2, respectively.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('deletions', 'Var', (53, 62))	('contained', 'Reg', (43, 52))	('FHIT', 'Gene', '2272', (26, 30))	('tumors', 'Disease', (104, 110))	('PARK2', 'Gene', (36, 41))	('FHIT', 'Gene', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('PARK2', 'Gene', '5071', (150, 155))	('FHIT', 'Gene', '2272', (140, 144))	('PARK2', 'Gene', (150, 155))	('MACROD2', 'Gene', (131, 138))	('MACROD2', 'Gene', '140733', (131, 138))	('FHIT', 'Gene', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('MACROD2', 'Gene', (17, 24))	('PARK2', 'Gene', '5071', (36, 41))	('deletions', 'Var', (118, 127))	('MACROD2', 'Gene', '140733', (17, 24))
447552	26857264	Since these structural variations are caused by deletions, we reviewed the deletion analysis reports from TCGA gastric cancer data performed by the Broad GDAC team, which has 441 STAD tumor samples analyzed.	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('tumor', 'Disease', (184, 189))	('deletions', 'Var', (48, 57))	('gastric cancer', 'Disease', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('caused', 'Reg', (38, 44))
447558	26857264	The presence of A>C mutations in GCA, GNCA, and ESCC suggest the oxidation of guanine as a potential mutagen for gastric cancer and ESCC.	('oxidation', 'MPA', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('A>C mutations', 'Var', (16, 29))	('guanine', 'Chemical', 'MESH:D006147', (78, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))
447561	26857264	In the case of MACROD2, exon 6 of MACROD2 (NM_080676), spanning amino acids 140-180, was deleted.	('MACROD2', 'Gene', (15, 22))	('MACROD2', 'Gene', '140733', (15, 22))	('NM_080676', 'Var', (43, 52))	('MACROD2', 'Gene', (34, 41))	('MACROD2', 'Gene', '140733', (34, 41))
447562	26857264	Similarly, exon 5 of FHIT (NM_002012), containing the first 35 amino acids, was deleted in multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('FHIT', 'Gene', (21, 25))	('FHIT', 'Gene', '2272', (21, 25))	('NM_002012', 'Var', (27, 36))	('multiple tumors', 'Disease', 'MESH:D009369', (91, 106))	('multiple tumors', 'Disease', (91, 106))
447563	26857264	In the case of PARK2, the deletions were more heterogeneous, and varied from deletions involving one to three exons of exons 2, 3, and 4 (NM_004562).	('PARK2', 'Gene', (15, 20))	('deletions', 'Var', (77, 86))	('PARK2', 'Gene', '5071', (15, 20))
447570	26981122	Recent findings suggest that nAChRs not only mediate nicotine addiction in the brain but also contribute to the development and progression of cancers directly induced by nicotine and its derived carcinogenic nitrosamines whereas deregulation of the nAChRs is observed in many cancers, and genome-wide association studies (GWAS) indicate that SNPs nAChRs associate with risks of lung cancers and nicotine addiction.	('nicotine addiction', 'Disease', (396, 414))	('lung cancers', 'Phenotype', 'HP:0100526', (379, 391))	('nAChR', 'Gene', (250, 255))	('carcinogenic', 'Disease', 'MESH:D063646', (196, 208))	('nicotine', 'Chemical', 'MESH:D009538', (53, 61))	('nicotine', 'Chemical', 'MESH:D009538', (171, 179))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))	('cancers', 'Disease', 'MESH:D009369', (384, 391))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('SNPs', 'Var', (343, 347))	('cancers', 'Disease', (277, 284))	('lung cancer', 'Phenotype', 'HP:0100526', (379, 390))	('nAChR', 'Gene', '1137', (348, 353))	('nAChR', 'Gene', '1137', (29, 34))	('lung cancers', 'Disease', 'MESH:D008175', (379, 391))	('nAChR', 'Gene', (29, 34))	('nicotine', 'Chemical', 'MESH:D009538', (396, 404))	('nAChR', 'Gene', (348, 353))	('cancers', 'Phenotype', 'HP:0002664', (384, 391))	('carcinogenic', 'Disease', (196, 208))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Disease', (384, 391))	('nitrosamines', 'Chemical', 'MESH:D009602', (209, 221))	('lung cancers', 'Disease', (379, 391))	('nAChR', 'Gene', '1137', (250, 255))
447579	26981122	Among the carcinogens presented in tobacco, nicotine acts on nAChRs in the central nervous system (CNS) and causes addiction to smoke.	('nAChR', 'Gene', (61, 66))	('addiction to smoke', 'MPA', (115, 133))	('nicotine', 'Chemical', 'MESH:D009538', (44, 52))	('tobacco', 'Species', '4097', (35, 42))	('causes', 'Reg', (108, 114))	('nicotine', 'Var', (44, 52))	('nAChR', 'Gene', '1137', (61, 66))
447581	26981122	Recent studies indicated nicotine is able to induce cancer directly via promoting proliferation, inhibiting apoptosis of cancer cells, and stimulating tumor angiogenesis.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('nicotine', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('promoting', 'PosReg', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('stimulating', 'Reg', (139, 150))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cancer', 'Disease', (121, 127))	('nicotine', 'Chemical', 'MESH:D009538', (25, 33))	('apoptosis', 'CPA', (108, 117))	('proliferation', 'CPA', (82, 95))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('inhibiting', 'NegReg', (97, 107))	('cancer', 'Disease', (52, 58))
447598	26981122	Single nucleotide polymorphisms (SNPs) of the chromosome 15q25 region, which contains alpha5-alpha3-beta4 nAChR gene cluster (CHRNA5-CHRNA3-CHRNB4), is frequently associated with nicotine- (tobacco-) dependence, chronic obstructive pulmonary disease (COPD), and lung cancer in genome-wide association studies (GWAS).	('nAChR', 'Gene', '1137', (106, 111))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('COPD', 'Disease', 'MESH:D029424', (251, 255))	('nAChR', 'Gene', (106, 111))	('COPD', 'Disease', (251, 255))	('lung cancer', 'Disease', (262, 273))	('nicotine', 'Chemical', 'MESH:D009538', (179, 187))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (212, 249))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (212, 249))	('tobacco', 'Species', '4097', (190, 197))	('chronic obstructive pulmonary disease', 'Disease', (212, 249))	('CHRNA5-CHRNA3-CHRNB4', 'Disease', 'None', (126, 146))	('lung cancer', 'Disease', 'MESH:D008175', (262, 273))	('CHRNA5-CHRNA3-CHRNB4', 'Disease', (126, 146))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (220, 249))	('associated with', 'Reg', (163, 178))	('COPD', 'Phenotype', 'HP:0006510', (251, 255))
447599	26981122	The association of the SNPs of 15q25 genomic region with COPD and lung cancer could mediate by the combined effects of the oncogenic nAChR signaling and the neurological effects of nicotine addiction.	('COPD', 'Disease', 'MESH:D029424', (57, 61))	('COPD', 'Disease', (57, 61))	('nAChR', 'Gene', (133, 138))	('association', 'Interaction', (4, 15))	('lung cancer', 'Disease', (66, 77))	('SNPs', 'Var', (23, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('nicotine', 'Chemical', 'MESH:D009538', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('COPD', 'Phenotype', 'HP:0006510', (57, 61))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('nAChR', 'Gene', '1137', (133, 138))
447600	26981122	Among these SNPs rs16969968 in CHRNA5, rs1051730 in CHRNA3, and rs8034191 are the most studied three SNPs of the region.	('CHRNA5', 'Gene', (31, 37))	('rs1051730', 'Mutation', 'rs1051730', (39, 48))	('rs16969968', 'Mutation', 'rs16969968', (17, 27))	('CHRNA3', 'Gene', '1136', (52, 58))	('rs1051730', 'Var', (39, 48))	('CHRNA5', 'Gene', '1138', (31, 37))	('rs8034191', 'Mutation', 'rs8034191', (64, 73))	('CHRNA3', 'Gene', (52, 58))	('rs16969968', 'Var', (17, 27))	('rs8034191', 'Var', (64, 73))
447601	26981122	CHRNA3 and CHRNA5 are arranged in a tail-to-tail configuration on the opposite strand of the DNA, and the two variants rs1051730 and rs16969968 are in a complete linkage disequilibrium [r 2 = 0.98 in samples of Europeans/Caucasians].	('CHRNA5', 'Gene', (11, 17))	('CHRNA3', 'Gene', '1136', (0, 6))	('CHRNA5', 'Gene', '1138', (11, 17))	('rs1051730', 'Mutation', 'rs1051730', (119, 128))	('rs16969968', 'Var', (133, 143))	('rs1051730', 'Var', (119, 128))	('CHRNA3', 'Gene', (0, 6))	('rs16969968', 'Mutation', 'rs16969968', (133, 143))
447602	26981122	Similarly rs1051370 is in strong linkage disequilibrium with rs8034191; thus some studies report the results for rs1051370 only.	('rs1051370', 'Mutation', 'rs1051370', (113, 122))	('rs1051370', 'Mutation', 'rs1051370', (10, 19))	('rs8034191', 'Mutation', 'rs8034191', (61, 70))	('rs1051370', 'Var', (10, 19))	('rs1051370', 'Var', (113, 122))	('rs8034191', 'Var', (61, 70))
447603	26981122	reported rs1051730 is associated with larger tumor size at diagnosis of squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('rs1051730', 'Var', (9, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('squamous cell carcinoma', 'Disease', (72, 95))	('tumor', 'Disease', (45, 50))	('rs1051730', 'Mutation', 'rs1051730', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
447604	26981122	rs16969968 is a G-to-A [aspartic acid- (D-) to-asparagine (N)] missense variant at amino acid position 398 of CHRNA5 [alpha5 (Asn398) D398N].	('CHRNA5', 'Gene', (110, 116))	('rs16969968', 'Mutation', 'rs16969968', (0, 10))	('D398N', 'Mutation', 'rs16969968', (134, 139))	('Asn398', 'Chemical', '-', (126, 132))	('aspartic acid', 'Chemical', 'MESH:D001224', (24, 37))	('asparagine', 'Chemical', 'MESH:D001216', (47, 57))	('CHRNA5', 'Gene', '1138', (110, 116))	('rs16969968', 'Var', (0, 10))
447605	26981122	And 398N is less potent than the variant 398D in protecting cells against the nicotine alpha7-nAChR mediated signaling making cells more susceptible to proliferation and migration.	('alpha7-nAChR', 'Gene', (87, 99))	('migration', 'CPA', (170, 179))	('susceptible', 'Reg', (137, 148))	('nicotine', 'Chemical', 'MESH:D009538', (78, 86))	('alpha7-nAChR', 'Gene', '11441', (87, 99))	('398N', 'Var', (4, 8))	('more', 'PosReg', (132, 136))
447606	26981122	Consistently, risk allele D-Asparagine is observed to reduce the function of alpha4beta2alpha5-nAChR.	('D-Asparagine', 'Var', (26, 38))	('nAChR', 'Gene', '1137', (95, 100))	('reduce', 'NegReg', (54, 60))	('nAChR', 'Gene', (95, 100))	('D-Asparagine', 'Chemical', '-', (26, 38))	('function', 'MPA', (65, 73))
447607	26981122	Alternatively, polymorphisms in linkage disequilibrium with rs16969968 may modulate the expression of CHRNA5.	('CHRNA5', 'Gene', '1138', (102, 108))	('rs16969968', 'Var', (60, 70))	('modulate', 'Reg', (75, 83))	('rs16969968', 'Mutation', 'rs16969968', (60, 70))	('CHRNA5', 'Gene', (102, 108))	('polymorphisms', 'Var', (15, 28))	('expression', 'MPA', (88, 98))
447609	26981122	Depending on the balanced regulation of the nAChRs, bronchial mucosa may undergo repair and recovery or give rise to precancerous lesion or hyperplasia when these receptors are deregulated.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('nAChR', 'Gene', (44, 49))	('hyperplasia', 'Disease', 'MESH:D006965', (140, 151))	('give rise to', 'Reg', (104, 116))	('hyperplasia', 'Disease', (140, 151))	('precancerous lesion', 'Disease', (117, 136))	('recovery', 'CPA', (92, 100))	('precancerous lesion', 'Disease', 'MESH:D011230', (117, 136))	('deregulated', 'Var', (177, 188))	('nAChR', 'Gene', '1137', (44, 49))	('repair', 'CPA', (81, 87))
447610	26981122	Moreover, NKK induced bronchial cell proliferation and the susceptibility to the tumorigenic transformation were reported to associate with different variants of human alpha9-nAChR subunit protein (S442 as the most frequent).	('variants', 'Var', (150, 158))	('nAChR', 'Gene', '1137', (175, 180))	('bronchial cell proliferation', 'CPA', (22, 50))	('nAChR', 'Gene', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('human', 'Species', '9606', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
447611	26981122	Thus polymorphisms in CHRNA5-CHRNA3-CHRNB4 gene cluster may modulate the dynamics of the normal bronchial epithelium under stress conditions to influence cancer risks.	('dynamics of the normal bronchial epithelium', 'MPA', (73, 116))	('modulate', 'Reg', (60, 68))	('influence', 'Reg', (144, 153))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('CHRNA5-CHRNA3-CHRNB4', 'Disease', 'None', (22, 42))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('CHRNA5-CHRNA3-CHRNB4', 'Disease', (22, 42))	('polymorphisms', 'Var', (5, 18))
447613	26981122	Besides, the effects of the 15q25 polymorphism may impact on the neural behavioral effects on addiction to nicotine, resulting in an increased tobacco consumption, and so forth.	('15q25', 'Gene', (28, 33))	('tobacco consumption', 'MPA', (143, 162))	('polymorphism', 'Var', (34, 46))	('behavioral effects', 'Phenotype', 'HP:0000708', (72, 90))	('tobacco', 'Species', '4097', (143, 150))	('addiction to nicotine', 'MPA', (94, 115))	('increased', 'PosReg', (133, 142))	('impact', 'Reg', (51, 57))	('nicotine', 'Chemical', 'MESH:D009538', (107, 115))
447614	26981122	reported rs8034191, rs1051730, and rs16969968 identified in previous GWAS are extremely rare in Asians, whereas they have identified four novel SNPs that were associated with significantly increased lung cancer risk and smoking behavior in Chinese population.	('lung cancer', 'Disease', 'MESH:D008175', (199, 210))	('rs8034191', 'Mutation', 'rs8034191', (9, 18))	('rs16969968', 'Mutation', 'rs16969968', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('rs1051730', 'Mutation', 'rs1051730', (20, 29))	('lung cancer', 'Disease', (199, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (199, 210))	('rs8034191', 'Var', (9, 18))	('rs1051730', 'Var', (20, 29))	('rs16969968', 'Var', (35, 45))	('increased', 'PosReg', (189, 198))
447615	26981122	Particularly they have identified that rs6495309T>C considerably influenced the CHRNA3 promoter activity, leading to higher alpha3-nAChR protein level and an increased risk of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('rs6495309T>C', 'DBSNP_MENTION', 'None', (39, 51))	('CHRNA3', 'Gene', '1136', (80, 86))	('nAChR', 'Gene', (131, 136))	('nAChR', 'Gene', '1137', (131, 136))	('higher', 'PosReg', (117, 123))	('lung cancer', 'Disease', (176, 187))	('rs6495309T>C', 'Var', (39, 51))	('CHRNA3', 'Gene', (80, 86))	('influenced', 'Reg', (65, 75))
447617	26981122	Thus individuals with rs6495309C allele may need to consume more nicotine to reach the addictive neurological effects, leading to higher levels of exposure to smoking.	('rs6495309C', 'Var', (22, 32))	('levels of exposure to smoking', 'MPA', (137, 166))	('higher', 'PosReg', (130, 136))	('rs6495309', 'Mutation', 'rs6495309', (22, 31))	('nicotine', 'Chemical', 'MESH:D009538', (65, 73))	('addictive neurological effects', 'Phenotype', 'HP:0030858', (87, 117))
447630	26981122	Such an effect of nAChR signaling is also observed in many other types of cancers; for instance, the proliferation of mesothelioma cells is stimulated by nicotine through activation of the ERK1-ERK2 signaling cascade and nicotine also inhibits the apoptosis of the cell through activation of NF-kappaB and phosphorylation of BAD.	('NF-kappaB', 'Protein', (292, 301))	('BAD', 'Protein', (325, 328))	('nAChR', 'Gene', '1137', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('ERK2', 'Gene', '5594', (194, 198))	('cancers', 'Disease', (74, 81))	('stimulated', 'PosReg', (140, 150))	('nAChR', 'Gene', (18, 23))	('ERK1', 'Gene', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('ERK2', 'Gene', (194, 198))	('proliferation', 'CPA', (101, 114))	('ERK1', 'Gene', '5595', (189, 193))	('nicotine', 'Chemical', 'MESH:D009538', (154, 162))	('activation', 'PosReg', (278, 288))	('apoptosis of the', 'CPA', (248, 264))	('inhibits', 'NegReg', (235, 243))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('phosphorylation', 'MPA', (306, 321))	('mesothelioma', 'Disease', (118, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('nicotine', 'Chemical', 'MESH:D009538', (221, 229))	('nicotine', 'Var', (154, 162))	('activation', 'PosReg', (171, 181))
447633	26981122	Researches indicated NNK can cause the decreased GABA level in PAC cells and further leads to decreased GABA dependent migration of PAC cells in vitro.	('GABA level', 'MPA', (49, 59))	('NNK', 'Var', (21, 24))	('PAC', 'Phenotype', 'HP:0006699', (63, 66))	('GABA', 'Chemical', 'MESH:D005680', (104, 108))	('NNK', 'Chemical', 'MESH:C016583', (21, 24))	('GABA', 'Chemical', 'MESH:D005680', (49, 53))	('decreased', 'NegReg', (94, 103))	('PAC', 'Phenotype', 'HP:0006699', (132, 135))	('GABA dependent migration of', 'CPA', (104, 131))	('decreased GABA level', 'Phenotype', 'HP:0410054', (39, 59))	('decreased', 'NegReg', (39, 48))
447634	26981122	Desensitization of alpha4beta2-nAChR is the major cause for decreased release of GABA in smokers and NNK treated hamsters.	('NNK', 'Chemical', 'MESH:C016583', (101, 104))	('decreased', 'NegReg', (60, 69))	('GABA', 'Chemical', 'MESH:D005680', (81, 85))	('nAChR', 'Gene', '1137', (31, 36))	('release of GABA', 'MPA', (70, 85))	('Desensitization', 'Var', (0, 15))	('nAChR', 'Gene', (31, 36))
447637	26981122	reported the tumor suppressor function of GABA in lung adenocarcinoma; similarly GABA can inhibit Galphai-mediated inhibition of adenylyl cyclase and further leads to the inhibition of isoproterenol induced DNA synthesis and migration.	('inhibit', 'NegReg', (90, 97))	('tumor', 'Disease', (13, 18))	('Galphai-mediated', 'Protein', (98, 114))	('GABA', 'Chemical', 'MESH:D005680', (81, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('GABA', 'Var', (81, 85))	('migration', 'CPA', (225, 234))	('inhibition', 'NegReg', (171, 181))	('lung adenocarcinoma', 'Disease', (50, 69))	('isoproterenol induced DNA synthesis', 'MPA', (185, 220))	('isoproterenol', 'Chemical', 'MESH:D007545', (185, 198))	('GABA', 'Chemical', 'MESH:D005680', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (50, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
447654	26981122	Moreover, the effect of alpha7-nAChR on angiogenesis is further demonstrated by the alpha7-nAChR antagonist MG624 decrease of the angiogenesis effect of nicotine in vitro and in xenograft mouse model of small cell lung cancer.	('mouse', 'Species', '10090', (188, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('small cell lung cancer', 'Disease', (203, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('nicotine', 'Chemical', 'MESH:D009538', (153, 161))	('MG624', 'Var', (108, 113))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))	('alpha7-nAChR', 'Gene', (84, 96))	('angiogenesis', 'CPA', (130, 142))	('alpha7-nAChR', 'Gene', '11441', (24, 36))	('alpha7-nAChR', 'Gene', '11441', (84, 96))	('decrease', 'NegReg', (114, 122))	('small cell lung cancer', 'Disease', 'MESH:D055752', (203, 225))	('alpha7-nAChR', 'Gene', (24, 36))	('MG624', 'Chemical', 'MESH:C118602', (108, 113))
447655	26981122	The effect of MG624 is probably mediated by inhibition of nicotine induced release of fibroblast growth factor 2 (FGF2) through activation of early growth response gene 1.	('activation', 'PosReg', (128, 138))	('fibroblast growth factor 2', 'Gene', (86, 112))	('FGF2', 'Gene', '2247', (114, 118))	('fibroblast growth factor 2', 'Gene', '2247', (86, 112))	('inhibition', 'NegReg', (44, 54))	('MG624', 'Chemical', 'MESH:C118602', (14, 19))	('nicotine', 'Chemical', 'MESH:D009538', (58, 66))	('FGF2', 'Gene', (114, 118))	('MG624', 'Var', (14, 19))
447658	26981122	Interestingly, knockdown of CHRNA9 in endothelial cells enhanced nicotine induced cell proliferation, migration, and tube formation.	('knockdown', 'Var', (15, 24))	('tube formation', 'CPA', (117, 131))	('CHRNA9', 'Gene', '55584', (28, 34))	('nicotine induced', 'MPA', (65, 81))	('cell proliferation', 'CPA', (82, 100))	('enhanced', 'PosReg', (56, 64))	('nicotine', 'Chemical', 'MESH:D009538', (65, 73))	('migration', 'CPA', (102, 111))	('CHRNA9', 'Gene', (28, 34))
447662	26981122	Interestingly, antagonists of endothelial nAChR can also suppress the angiogenic processes of VEGF and FGF.	('nAChR', 'Gene', '1137', (42, 47))	('VEGF', 'Gene', (94, 98))	('antagonists', 'Var', (15, 26))	('suppress', 'NegReg', (57, 65))	('nAChR', 'Gene', (42, 47))	('VEGF', 'Gene', '7422', (94, 98))
447671	26981122	In addition, NNK can cause ERK1-ERK2 dependent phosphorylation of m-calpains and mu-calpains and further promote the migration of small cell lung cancer (SCLC) cells.	('promote', 'PosReg', (105, 112))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('migration', 'CPA', (117, 126))	('ERK2', 'Gene', '5594', (32, 36))	('SCLC', 'Disease', (154, 158))	('ERK1', 'Gene', (27, 31))	('SCLC', 'Phenotype', 'HP:0030357', (154, 158))	('ERK2', 'Gene', (32, 36))	('phosphorylation', 'MPA', (47, 62))	('NNK', 'Chemical', 'MESH:C016583', (13, 16))	('ERK1', 'Gene', '5595', (27, 31))	('cause', 'Reg', (21, 26))	('NNK', 'Var', (13, 16))	('small cell lung cancer', 'Disease', 'MESH:D055752', (130, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('m-calpains', 'Protein', (66, 76))	('mu-calpains', 'Protein', (81, 92))	('small cell lung cancer', 'Disease', (130, 152))	('SCLC', 'Disease', 'MESH:D018288', (154, 158))
447673	26981122	Furthermore, NNK can activate BCL-2 to inhibit apoptosis of SCLC cells, whereas PKC inhibitor staurosporine, ERK1-ERK2 inhibitor PD98059, or knockdown of MYC can block the effect.	('ERK2', 'Gene', (114, 118))	('knockdown', 'Var', (141, 150))	('ERK1', 'Gene', '5595', (109, 113))	('ERK1', 'Gene', (109, 113))	('BCL-2', 'Gene', (30, 35))	('activate', 'PosReg', (21, 29))	('PD98059', 'Chemical', 'MESH:C093973', (129, 136))	('apoptosis', 'CPA', (47, 56))	('inhibit', 'NegReg', (39, 46))	('SCLC', 'Disease', 'MESH:D018288', (60, 64))	('MYC', 'Gene', '4609', (154, 157))	('SCLC', 'Disease', (60, 64))	('ERK2', 'Gene', '5594', (114, 118))	('NNK', 'Chemical', 'MESH:C016583', (13, 16))	('MYC', 'Gene', (154, 157))	('SCLC', 'Phenotype', 'HP:0030357', (60, 64))	('BCL-2', 'Gene', '596', (30, 35))	('staurosporine', 'Chemical', 'MESH:D019311', (94, 107))
447676	26981122	Consistently, inhibition of PKC or ERK1-ERK2 or upregulation of intracellular cyclic adenosine monophosphate (cAMP) can strongly suppress the nAChR-stimulated responses of SCLC in vitro.	('ERK1', 'Gene', (35, 39))	('SCLC', 'Phenotype', 'HP:0030357', (172, 176))	('ERK2', 'Gene', '5594', (40, 44))	('cyclic adenosine monophosphate', 'Chemical', 'MESH:D000242', (78, 108))	('intracellular cyclic adenosine monophosphate', 'MPA', (64, 108))	('suppress', 'NegReg', (129, 137))	('PKC', 'Enzyme', (28, 31))	('nAChR', 'Gene', '1137', (142, 147))	('cAMP', 'Chemical', 'MESH:D000242', (110, 114))	('nAChR', 'Gene', (142, 147))	('ERK1', 'Gene', '5595', (35, 39))	('inhibition', 'Var', (14, 24))	('SCLC', 'Disease', (172, 176))	('ERK2', 'Gene', (40, 44))	('SCLC', 'Disease', 'MESH:D018288', (172, 176))	('upregulation', 'PosReg', (48, 60))
447686	26981122	The deregulation of nAChR subunits in primary lung cancer tissues is also evidenced by the epigenetic alterations of the nAChR genes.	('nAChR', 'Gene', '1137', (20, 25))	('nAChR', 'Gene', (20, 25))	('epigenetic alterations', 'Var', (91, 113))	('primary lung cancer', 'Disease', (38, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('nAChR', 'Gene', '1137', (121, 126))	('primary lung cancer', 'Disease', 'MESH:D008175', (38, 57))	('nAChR', 'Gene', (121, 126))	('deregulation', 'MPA', (4, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
447687	26981122	reported that cholinergic receptor, nicotinic, alpha 3 (CHRNA3) gene encoding the alpha3-nAChR subunit is frequently hypermethylated and silenced in lung cancer, and DNA methylation inhibitors can cause demethylation of CHRNA3 promoter and reactivation of the gene.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('nAChR', 'Gene', '1137', (89, 94))	('CHRNA3', 'Gene', '1136', (220, 226))	('CHRNA3', 'Gene', '1136', (56, 62))	('nAChR', 'Gene', (89, 94))	('cholinergic receptor, nicotinic, alpha 3', 'Gene', '1136', (14, 54))	('silenced', 'NegReg', (137, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('demethylation', 'MPA', (203, 216))	('methylation', 'Var', (170, 181))	('lung cancer', 'Disease', (149, 160))	('CHRNA3', 'Gene', (220, 226))	('CHRNA3', 'Gene', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('reactivation', 'MPA', (240, 252))
447689	26981122	They also observed a dramatic increase of Ca2+ influx response in the presence of nicotine elicited by knockdown of CHRNA3 in alpha3-nAChR positive lung cancer cells, followed by activation of the AKT prosurvival pathway.	('AKT', 'Gene', '207', (197, 200))	('Ca2+', 'Chemical', 'MESH:D000069285', (42, 46))	('nAChR', 'Gene', (133, 138))	('CHRNA3', 'Gene', (116, 122))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('Ca2+ influx response', 'MPA', (42, 62))	('AKT', 'Gene', (197, 200))	('nicotine', 'Chemical', 'MESH:D009538', (82, 90))	('lung cancer', 'Disease', (148, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('activation', 'PosReg', (179, 189))	('increase', 'PosReg', (30, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('CHRNA3', 'Gene', '1136', (116, 122))	('knockdown', 'Var', (103, 112))	('nAChR', 'Gene', '1137', (133, 138))
447690	26981122	Moreover, alpha3-nAChR depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNA3 gene in human cancer.	('epigenetic', 'Var', (114, 124))	('human', 'Species', '9606', (157, 162))	('nAChR', 'Gene', '1137', (17, 22))	('CHRNA3', 'Gene', '1136', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('nAChR', 'Gene', (17, 22))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('CHRNA3', 'Gene', (142, 148))
447694	26981122	Importantly, they have also identified downregulation of p63 after knockdown of CHRNA5 or CHRNA3, which offered an explanation for the resistance to apoptosis in CHRNA3 downregulated lung cancers.	('lung cancers', 'Disease', 'MESH:D008175', (183, 195))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('CHRNA5', 'Gene', (80, 86))	('p63', 'Gene', (57, 60))	('knockdown', 'Var', (67, 76))	('p63', 'Gene', '8626', (57, 60))	('lung cancers', 'Disease', (183, 195))	('CHRNA3', 'Gene', '1136', (90, 96))	('CHRNA3', 'Gene', '1136', (162, 168))	('CHRNA5', 'Gene', '1138', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('lung cancers', 'Phenotype', 'HP:0100526', (183, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('CHRNA3', 'Gene', (90, 96))	('downregulated', 'NegReg', (169, 182))	('downregulation', 'NegReg', (39, 53))	('CHRNA3', 'Gene', (162, 168))
447695	26981122	Moreover, knockdown of CHRNA3 in A549 cells downregulates the cell-cell adhesion molecules and reduces the components of tight junctions (ZO-1) and adherens junctions (P120), analogous to epithelial cells undergoing epithelial-mesenchyme transition.	('tight junctions', 'MPA', (121, 136))	('CHRNA3', 'Gene', '1136', (23, 29))	('cell-cell adhesion molecules', 'Protein', (62, 90))	('downregulates', 'NegReg', (44, 57))	('CHRNA3', 'Gene', (23, 29))	('adherens junctions', 'MPA', (148, 166))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('components', 'MPA', (107, 117))	('knockdown', 'Var', (10, 19))	('reduces', 'NegReg', (95, 102))
447699	26981122	NNK can induce pancreatic cancer through the genotoxic effect of DNA adducts causing RAS gene mutations but also has a hyperproliferative effect on pancreatic duct epithelia through beta-adrenergic transactivation of EGF receptors.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (15, 32))	('hyperproliferative', 'PosReg', (119, 137))	('mutations', 'Var', (94, 103))	('RAS gene', 'Gene', (85, 93))	('genotoxic', 'MPA', (45, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (15, 32))	('induce', 'Reg', (8, 14))	('pancreatic cancer', 'Disease', (15, 32))	('pancreatic duct epithelia', 'Disease', (148, 173))	('NNK', 'Chemical', 'MESH:C016583', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('EGF', 'Gene', (217, 220))	('pancreatic duct epithelia', 'Disease', 'MESH:D021441', (148, 173))	('EGF', 'Gene', '1950', (217, 220))
447704	26981122	Together these findings suggest nAChR mediated catecholamine synthesis, release, and transactivation of the EGFR signaling pathway promote the progression of pancreatic cancers.	('transactivation', 'Var', (85, 100))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (158, 176))	('nAChR', 'Gene', (32, 37))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('pancreatic cancers', 'Disease', 'MESH:D010190', (158, 176))	('pancreatic cancers', 'Disease', (158, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (158, 175))	('release', 'MPA', (72, 79))	('catecholamine', 'Chemical', 'MESH:D002395', (47, 60))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('nAChR', 'Gene', '1137', (32, 37))	('promote', 'PosReg', (131, 138))
447708	26981122	The oncogenic effects of nAChR signaling in pancreatic cancer are also supported by the animal experiments, and N-nitroso compounds, formed from nicotine by nitrosation during the processing of tobacco plants, can cause pancreatic cancer in Syrian golden hamsters.	('cause', 'Reg', (214, 219))	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('nicotine', 'Chemical', 'MESH:D009538', (145, 153))	('N-nitroso compounds', 'Chemical', '-', (112, 131))	('tobacco', 'Species', '4097', (194, 201))	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('nAChR', 'Gene', '1137', (25, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('nAChR', 'Gene', (25, 30))	('N-nitroso compounds', 'Var', (112, 131))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Syrian golden hamsters', 'Species', '10036', (241, 263))	('pancreatic cancer', 'Disease', (44, 61))	('pancreatic cancer', 'Disease', (220, 237))
447720	26981122	Besides, nicotine promotes head and neck cancer through activation of endogenous FOXM1 activity by loss of heterozygosity involving the whole of chromosome 13 and copy number abnormality (CNA) in oral keratinocytes (KC).	('head and neck cancer', 'Phenotype', 'HP:0012288', (27, 47))	('copy number abnormality', 'Disease', (163, 186))	('nicotine', 'Chemical', 'MESH:D009538', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('activity', 'MPA', (87, 95))	('endogenous', 'MPA', (70, 80))	('neck cancer', 'Disease', 'MESH:D006258', (36, 47))	('neck cancer', 'Disease', (36, 47))	('FOXM1', 'Gene', '2305', (81, 86))	('FOXM1', 'Gene', (81, 86))	('copy number abnormality', 'Disease', 'MESH:D007674', (163, 186))	('heterozygosity', 'Var', (107, 121))	('loss', 'NegReg', (99, 103))	('activation', 'PosReg', (56, 66))
447731	20473931	The methylation status of AIM1, APC, CALCA, DCC, DLEC, DLC1, ESR, FHIT, KIF1A, and PGP9.5 was significantly associated with NPC compared to controls.	('APC', 'Disease', (32, 35))	('NPC', 'Phenotype', 'HP:0100630', (124, 127))	('DCC', 'Gene', '1630', (44, 47))	('KIF1A', 'Gene', '547', (72, 77))	('CALCA', 'Gene', '796', (37, 42))	('NPC', 'Gene', (124, 127))	('AIM1', 'Gene', (26, 30))	('CALCA', 'Gene', (37, 42))	('DCC', 'Gene', (44, 47))	('methylation status', 'Var', (4, 22))	('DLEC', 'Gene', (49, 53))	('AIM1', 'Gene', '202', (26, 30))	('PGP9.5', 'Gene', '7345', (83, 89))	('NPC', 'Gene', '4864', (124, 127))	('associated', 'Reg', (108, 118))	('DLC1', 'Gene', (55, 59))	('KIF1A', 'Gene', (72, 77))	('FHIT', 'Gene', (66, 70))	('DLEC', 'Gene', '170482', (49, 53))	('PGP9.5', 'Gene', (83, 89))	('APC', 'Disease', 'MESH:D011125', (32, 35))	('FHIT', 'Gene', '2272', (66, 70))
447735	20473931	Our results indicate that methylation of novel biomarkers in NPC could be used to enhance early detection approaches.	('NPC', 'Gene', (61, 64))	('methylation', 'Var', (26, 37))	('NPC', 'Phenotype', 'HP:0100630', (61, 64))	('NPC', 'Gene', '4864', (61, 64))
447752	20473931	Molecular events like loss of heterozygosity, EBV viral loads, and EGFR amplifications and over-expression have shown promising results in NPC.	('heterozygosity', 'Var', (30, 44))	('over-expression', 'Var', (91, 106))	('EBV', 'Species', '10376', (46, 49))	('NPC', 'Phenotype', 'HP:0100630', (139, 142))	('amplifications', 'Var', (72, 86))	('NPC', 'Gene', (139, 142))	('NPC', 'Gene', '4864', (139, 142))	('EGFR', 'Gene', (67, 71))	('loss', 'Var', (22, 26))
447753	20473931	Abnormal expression of genes and in particular tumor suppressor gene silencing is a common event in cancer.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('expression', 'MPA', (9, 19))	('Abnormal', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('silencing', 'NegReg', (69, 78))	('tumor', 'Disease', (47, 52))
447755	20473931	Gene-specific methylation of promoter regions of tumor suppressor genes has been described in a variety of human cancers.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('human', 'Species', '9606', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('tumor', 'Disease', (49, 54))	('cancers', 'Disease', (113, 120))	('methylation', 'Var', (14, 25))	('described', 'Reg', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
447761	20473931	Histologically normal epithelial cells exposed to carcinogenic insults undergo molecular alterations including p53 mutations and promoter methylation.	('mutations', 'Var', (115, 124))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('promoter', 'MPA', (129, 137))	('carcinogenic insults', 'Disease', 'MESH:D063646', (50, 70))	('carcinogenic insults', 'Disease', (50, 70))
447765	20473931	Genes showing differential methylation patterns and were subsequently evaluated in sample set of NPC tumors and controls.	('NPC tumors', 'Disease', 'MESH:D052556', (97, 107))	('NPC', 'Phenotype', 'HP:0100630', (97, 100))	('NPC tumors', 'Disease', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('methylation patterns', 'Var', (27, 47))
447781	20473931	They include 3 tumor suppressor genes (DLC1, DLEC, and TIG1) reported as hypermethylated in more than 70% of the NPC and not in normal nasopharyngeal samples and/or immortalized nasopharyngeal cell lines.	('DLC1', 'Gene', (39, 43))	('TIG1', 'Gene', '5918', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('NPC', 'Phenotype', 'HP:0100630', (113, 116))	('tumor', 'Disease', (15, 20))	('DLEC', 'Gene', '170482', (45, 49))	('NPC', 'Gene', (113, 116))	('NPC', 'Gene', '4864', (113, 116))	('TIG1', 'Gene', (55, 59))	('DLEC', 'Gene', (45, 49))	('hypermethylated', 'Var', (73, 88))
447823	20473931	The frequencies of methylation between nasopharyngeal carcinoma samples and controls as well as the cutoff values used are shown in Table 2.	('methylation', 'Var', (19, 30))	('carcinoma', 'Disease', 'MESH:D002277', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('nasopharyngeal', 'Disease', (39, 53))	('carcinoma', 'Disease', (54, 63))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (39, 63))
447828	20473931	The methylation of the individual genes affects the probability of the samples being classified as a tumor or a control tissue.	('affects', 'Reg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
447841	20473931	A significant association with methylation and increased age was found for APC (p value 0.02).	('methylation', 'Var', (31, 42))	('APC', 'Disease', 'MESH:D011125', (75, 78))	('APC', 'Disease', (75, 78))
447851	20473931	These results suggest that methylation contributes to the regulation of gene expression for the candidate genes we tested in NPC.	('NPC', 'Phenotype', 'HP:0100630', (125, 128))	('NPC', 'Gene', (125, 128))	('methylation', 'Var', (27, 38))	('NPC', 'Gene', '4864', (125, 128))	('gene expression', 'MPA', (72, 87))	('regulation', 'MPA', (58, 68))
447853	20473931	We performed colony focus assays after 2 weeks of selection in the presence of G418.	('G418', 'Var', (79, 83))	('G418', 'Chemical', 'MESH:C010680', (79, 83))	('colony focus assays', 'CPA', (13, 32))
447858	20473931	Promoter methylation of tumor suppressor genes is an important mechanism of gene inactivation in human cancer.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('human', 'Species', '9606', (97, 102))	('Promoter methylation', 'Var', (0, 20))	('cancer', 'Disease', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
447861	20473931	The genes included in our study either had been widely reported as silenced by methylation in other tumor types or were identified recently by our unbiased pharmacologic unmasking strategy.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('silenced', 'NegReg', (67, 75))	('methylation', 'Var', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
447870	20473931	Our group has reported hypermethylation of AIM1 in bladder cancer and of KIF1A in a variety of human cancers including head and neck cancer, bladder, and breast cancer.	('bladder cancer', 'Disease', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('AIM1', 'Gene', '202', (43, 47))	('KIF1A', 'Gene', '547', (73, 78))	('hypermethylation', 'Var', (23, 39))	('AIM1', 'Gene', (43, 47))	('human', 'Species', '9606', (95, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('KIF1A', 'Gene', (73, 78))	('head and neck cancer', 'Phenotype', 'HP:0012288', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('neck cancer', 'Disease', 'MESH:D006258', (128, 139))	('breast cancer', 'Disease', (154, 167))	('neck cancer', 'Disease', (128, 139))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder', 'Disease', (141, 148))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))
447874	20473931	PGP9.5 is a neuron specific protein that can function as a hydroxylase and a ligase and has been reported as hypemerthylated in gastric and esophageal squamous cell carcinomas.	('esophageal squamous cell carcinomas', 'Disease', (140, 175))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (140, 175))	('PGP9.5', 'Gene', '7345', (0, 6))	('hypemerthylated', 'Var', (109, 124))	('PGP9.5', 'Gene', (0, 6))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (151, 175))	('gastric', 'Disease', (128, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
447875	20473931	APC, CALCA and FHIT have been reported as hypermethylated in a variety of malignancies such as colon cancer, breast cancer, and head and neck cancer.	('FHIT', 'Gene', (15, 19))	('malignancies', 'Disease', (74, 86))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('APC', 'Disease', (0, 3))	('hypermethylated', 'Var', (42, 57))	('CALCA', 'Gene', '796', (5, 10))	('FHIT', 'Gene', '2272', (15, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (95, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('CALCA', 'Gene', (5, 10))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('breast cancer', 'Disease', (109, 122))	('colon cancer', 'Disease', 'MESH:D015179', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('head and neck cancer', 'Phenotype', 'HP:0012288', (128, 148))	('neck cancer', 'Disease', 'MESH:D006258', (137, 148))	('neck cancer', 'Disease', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('colon cancer', 'Disease', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('malignancies', 'Disease', 'MESH:D009369', (74, 86))
447876	20473931	From a diagnostic point of view, a panel of only two gene markers could achieve sensitivity values close to 80% while still preserving high specificities (PGPG9.5 and KIF1A, PGP9.5 and DCC, PGP9.5 and DLC1, and KIF1A and DLEC).	('PGPG9.5', 'Var', (155, 162))	('DLEC', 'Gene', '170482', (221, 225))	('KIF1A', 'Gene', (211, 216))	('KIF1A', 'Gene', (167, 172))	('DCC', 'Gene', '1630', (185, 188))	('PGP9.5', 'Gene', (174, 180))	('DLEC', 'Gene', (221, 225))	('PGP9.5', 'Gene', '7345', (190, 196))	('KIF1A', 'Gene', '547', (211, 216))	('PGP9.5', 'Gene', (190, 196))	('KIF1A', 'Gene', '547', (167, 172))	('DCC', 'Gene', (185, 188))	('specificities', 'MPA', (140, 153))	('PGP9.5', 'Gene', '7345', (174, 180))
447877	20473931	We were also able to confirm a very high frequency of DLC1 and DLEC methylation for NPC.	('DLEC', 'Gene', (63, 67))	('methylation', 'Var', (68, 79))	('NPC', 'Gene', (84, 87))	('NPC', 'Phenotype', 'HP:0100630', (84, 87))	('DLEC', 'Gene', '170482', (63, 67))	('NPC', 'Gene', '4864', (84, 87))	('DLC1', 'Gene', (54, 58))
447894	20473931	demonstrated that promoter methylation silenced expression of DCC by immunohistochemistry in head and neck squamous cell carcinomas.	('promoter methylation', 'Var', (18, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('expression', 'MPA', (48, 58))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (102, 131))	('silenced', 'NegReg', (39, 47))	('DCC', 'Gene', (62, 65))	('neck squamous cell carcinomas', 'Disease', (102, 131))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (107, 131))	('DCC', 'Gene', '1630', (62, 65))
447895	20473931	They also showed that transfection of DCC lead to dramatic decrease in growth by CFA and this result was recreated in our NPC cell lines.	('growth', 'MPA', (71, 77))	('DCC', 'Gene', '1630', (38, 41))	('NPC', 'Gene', '4864', (122, 125))	('transfection', 'Var', (22, 34))	('decrease', 'NegReg', (59, 67))	('NPC', 'Gene', (122, 125))	('DCC', 'Gene', (38, 41))	('NPC', 'Phenotype', 'HP:0100630', (122, 125))
447896	20473931	Furthermore we showed a decrease in the invasion potential of the NPC cells upon DCC transfection.	('DCC', 'Gene', (81, 84))	('NPC', 'Gene', '4864', (66, 69))	('transfection', 'Var', (85, 97))	('decrease', 'NegReg', (24, 32))	('DCC', 'Gene', '1630', (81, 84))	('NPC', 'Gene', (66, 69))	('NPC', 'Phenotype', 'HP:0100630', (66, 69))
447899	20473931	showed DLC1 was a downregulated by methylation in NPC and suppression of growth in the CNE cell line.	('CNE', 'CellLine', 'CVCL:6888', (87, 90))	('NPC', 'Phenotype', 'HP:0100630', (50, 53))	('downregulated', 'NegReg', (18, 31))	('NPC', 'Gene', (50, 53))	('DLC1', 'Gene', (7, 11))	('methylation', 'Var', (35, 46))	('NPC', 'Gene', '4864', (50, 53))	('growth in the CNE cell line', 'CPA', (73, 100))	('suppression', 'NegReg', (58, 69))
447902	20473931	Given the frequency of inactivation and their biological roles, it is possible that DCC and DLC1 could be important players in cell migration and particularly in NPC neck metastasis.	('cell migration', 'CPA', (127, 141))	('DLC1', 'Gene', (92, 96))	('NPC neck metastasis', 'Disease', 'MESH:D052556', (162, 181))	('NPC neck metastasis', 'Disease', (162, 181))	('DCC', 'Gene', (84, 87))	('NPC', 'Phenotype', 'HP:0100630', (162, 165))	('DCC', 'Gene', '1630', (84, 87))	('inactivation', 'Var', (23, 35))
447941	33540736	Similarly, intestinal metaplasia within the stomach can lead to the development of intestinal-type gastric adenocarcinoma over time.	('intestinal-type gastric adenocarcinoma', 'Disease', (83, 121))	('men', 'Species', '9606', (75, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('intestinal-type gastric adenocarcinoma', 'Disease', 'MESH:D013274', (83, 121))	('intestinal metaplasia', 'Var', (11, 32))	('lead to', 'Reg', (56, 63))
447945	33540736	Non-invasive approaches to screening for premalignant lesions of the esophagus include devices such as the "EsophaCap" and cytosponge -TFF3 that detect genetic and epigenetic alterations on samples gathered non-invasively and can be used by primary care physicians to screen for Barrett's esophagus.	('TFF3', 'Gene', '7033', (135, 139))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (279, 298))	('epigenetic alterations', 'Var', (164, 186))	("Barrett's esophagus", 'Disease', (279, 298))	('genetic', 'Var', (152, 159))	('TFF3', 'Gene', (135, 139))
447981	33540736	In terms of N staging, EUS has acceptable accuracy, with a pooled sensitivity for diagnosing esophageal cancer of 85% and EUS fine needle aspiration (FNA) increasing the sensitivity for diagnosing esophageal cancer to 97% (95% CI: 0.92-0.99).	('cancer', 'Disease', (208, 214))	('aspiration', 'Phenotype', 'HP:0002835', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('fine needle', 'Var', (126, 137))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
447984	33540736	Barrett's esophagus with low- or high-grade dysplasia (HGD) without visible lesions can be treated with radio-frequency ablation (RFA) or cryoablation therapies.	('low-', 'Var', (25, 29))	('dysplasia', 'Disease', 'MESH:C536170', (44, 53))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (0, 19))	("Barrett's esophagus", 'Disease', (0, 19))	('dysplasia', 'Disease', (44, 53))
448010	33540736	This approach is important as cardiac dose is increasingly seen as an independent risk factor for reduced survival and has been correlated with excess G3+ cardiac toxicity.	('cardiac toxicity', 'Disease', 'MESH:D066126', (155, 171))	('cardiac toxicity', 'Disease', (155, 171))	('reduced', 'NegReg', (98, 105))	('survival', 'MPA', (106, 114))	('G3+', 'Chemical', '-', (151, 154))	('cardiac', 'Var', (30, 37))
448019	33540736	Early studies on patients who received 4000 cGy followed by surgery 1-4 weeks after found no difference in resectability or survival compared to surgery alone.	('resectability', 'CPA', (107, 120))	('4000 cGy', 'Var', (39, 47))	('patients', 'Species', '9606', (17, 25))
448050	33540736	With a goal of improving on the near 50% local failure rate seen in previous studies as well as overcoming high rates of persistent disease, dose escalation in the modern era appears to be more tolerable but still carries an elevated risk of toxicity as well as minimal evidence of clinical benefit.	('dose', 'Var', (141, 145))	('toxicity', 'Disease', 'MESH:D064420', (242, 250))	('toxicity', 'Disease', (242, 250))
448071	33540736	It demonstrated that pembrolizumab plus chemotherapy improved overall survival in patients with squamous cell carcinoma of the esophagus with PD-L1 CPS >=10 tumors, all squamous cell carcinomas, all patients with CPS >=10, and the study population as a whole.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 192))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('PD-L1', 'Gene', (142, 147))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 119))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('PD-L1', 'Gene', '29126', (142, 147))	('CPS', 'Chemical', '-', (148, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (169, 193))	('overall survival', 'MPA', (62, 78))	('squamous cell carcinoma', 'Disease', (96, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('patients', 'Species', '9606', (82, 90))	('tumors', 'Disease', (157, 163))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (169, 193))	('CPS >=10', 'Var', (148, 156))	('improved', 'PosReg', (53, 61))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (110, 136))	('pembrolizumab', 'Chemical', 'MESH:C582435', (21, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('squamous cell carcinomas', 'Disease', (169, 193))	('patients', 'Species', '9606', (199, 207))	('CPS', 'Chemical', '-', (213, 216))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
448100	33540736	Rarely, genetic mutations such as CDH-1 contribute to familial predisposition to gastric adenocarcinoma.	('CDH-1', 'Gene', (34, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (81, 103))	('gastric adenocarcinoma', 'Disease', (81, 103))	('genetic mutations', 'Var', (8, 25))	('CDH-1', 'Gene', '999', (34, 39))
448125	33540736	These tumors may express mutations in tyrosine kinase (TK), KIT receptor, or platelet-derived growth factor (PDGF).	('PDGF', 'Gene', '5156', (109, 113))	('mutations', 'Var', (25, 34))	('express', 'Reg', (17, 24))	('KIT', 'Gene', '3815', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tyrosine kinase', 'Gene', (38, 53))	('KIT', 'Gene', (60, 63))	('PDGF', 'Gene', (109, 113))	('tyrosine kinase', 'Gene', '7294', (38, 53))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('TK', 'Gene', '7294', (55, 57))
448130	33540736	Laparoscopic or minimally invasive resections have been associated with less blood loss, lower rates of complications, and shorter hospital stays without compromise of oncologic principles.	('minimally invasive', 'Var', (16, 34))	('Laparoscopic', 'Disease', (0, 12))	('blood loss', 'Disease', (77, 87))	('blood loss', 'Disease', 'MESH:D006473', (77, 87))
448137	33540736	Imatinib is the treatment of choice in this setting; however, tumors that have a platelet-derived growth factor receptor-alpha (PDGFRA) D842V mutation, or a succinate dehydrogenase (SDH)-deficient or neurofibromatosis (NF)-related GIST, are considered resistant to imatinib and will not benefit from neoadjuvant treatment; in these cases, upfront surgery is recommended.	('D842V', 'Var', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('neurofibromatosis', 'Disease', 'MESH:C537392', (200, 217))	('SDH', 'Gene', '6390', (182, 185))	('neurofibromatosis', 'Disease', (200, 217))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('succinate dehydrogenase', 'Gene', '6390', (157, 180))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('tumors', 'Disease', (62, 68))	('NF', 'Phenotype', 'HP:0001067', (219, 221))	('platelet-derived growth factor receptor-alpha', 'Gene', '5156', (81, 126))	('imatinib', 'Chemical', 'MESH:D000068877', (265, 273))	('SDH', 'Gene', (182, 185))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('men', 'Species', '9606', (317, 320))	('platelet-derived growth factor receptor-alpha', 'Gene', (81, 126))	('men', 'Species', '9606', (363, 366))	('men', 'Species', '9606', (21, 24))	('succinate dehydrogenase', 'Gene', (157, 180))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (200, 217))	('PDGFRA', 'Gene', '5156', (128, 134))	('PDGFRA', 'Gene', (128, 134))	('D842V', 'Mutation', 'rs121908585', (136, 141))
448138	33540736	Tumors that harbor an exon 9 KIT mutation should be treated with an initial dose of 800 mg per day.	('mutation', 'Var', (33, 41))	('KIT', 'Gene', '3815', (29, 32))	('KIT', 'Gene', (29, 32))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
448162	33540736	H. pylori is noted as a causative factor for MALT lymphoma and eradication of H. pylori can result in remission in 50-90% of cases.	('H. pylori', 'Species', '210', (78, 87))	('MALT lymphoma', 'Disease', 'MESH:D018442', (45, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('H. pylori', 'Species', '210', (0, 9))	('H. pylori', 'Disease', (0, 9))	('eradication', 'Var', (63, 74))	('MALT lymphoma', 'Disease', (45, 58))	('H. pylori', 'Gene', (78, 87))
448163	33540736	Therefore, eradication of H. pylori is regarded as a first-line treatment for gastric MALT lymphoma, with remission favorably associated with early lesions, lesions limited to the mucosa, and absence of the API2MALT1 mutation.	('H. pylori', 'Species', '210', (26, 35))	('men', 'Species', '9606', (69, 72))	('gastric MALT lymphoma', 'Disease', (78, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('absence', 'NegReg', (192, 199))	('gastric MALT lymphoma', 'Disease', 'MESH:C535648', (78, 99))	('gastric MALT lymphoma', 'Phenotype', 'HP:0045038', (78, 99))	('mutation', 'Var', (217, 225))	('API2MALT1', 'Gene', (207, 216))
448177	33540736	However, if pT2+ or pN+, adjuvant chemotherapy is given with consideration for radiotherapy based on risk factors of positive margins or inadequate nodal dissection (D1, or <15 total LN).	('nodal', 'Gene', '4838', (148, 153))	('nodal', 'Gene', (148, 153))	('pN', 'Gene', '79650', (20, 22))	('pT2+', 'Var', (12, 16))
448184	33540736	Elective node coverage can be omitted in patients with pT2-3N0 disease with D2 nodal dissection with >=15 LN removed.	('patients', 'Species', '9606', (41, 49))	('pT2-3N0', 'Var', (55, 62))	('nodal', 'Gene', '4838', (79, 84))	('nodal', 'Gene', (79, 84))
448247	27458102	COX2 (cyclooxygenase 2) expression was decreased and E-cadherin expression was increased in the KYSE170K xenografts, which was caused by the downregulation of ZIP5.	('increased', 'PosReg', (79, 88))	('KYSE170K', 'Var', (96, 104))	('expression', 'MPA', (64, 74))	('E-cadherin', 'Gene', (53, 63))	('expression', 'MPA', (24, 34))	('E-cadherin', 'Gene', '999', (53, 63))	('cyclooxygenase 2', 'Gene', '5743', (6, 22))	('COX2', 'Gene', '5743', (0, 4))	('COX2', 'Gene', (0, 4))	('cyclooxygenase 2', 'Gene', (6, 22))	('decreased', 'NegReg', (39, 48))
448249	27458102	Collectively, these findings indicate that knocking down ZIP5 by small interfering RNA (siRNA) might be a novel treatment strategy for esophageal cancer with ZIP5 overexpression.	('small interfering', 'Var', (65, 82))	('esophageal cancer', 'Disease', (135, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('ZIP5', 'Gene', (57, 61))	('knocking down', 'Var', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
448258	27458102	Moreover, much evidence indicates that Zn deficiency promotes the effects of N-nitrosomethylbenzylamine (NMBA)/4-NQO, which acts as an esophageal carcinogen in rodents.	('NMBA', 'Chemical', 'MESH:C014707', (105, 109))	('promotes', 'PosReg', (53, 61))	('Zn', 'Chemical', 'MESH:D015032', (39, 41))	('deficiency', 'Var', (42, 52))	('effects', 'MPA', (66, 73))	('4-NQO', 'Chemical', 'MESH:D015112', (111, 116))	('N-nitrosomethylbenzylamine', 'Chemical', 'MESH:C014707', (77, 103))
448261	27458102	A study found that ZIP1 deficiency was related to prostate cancer, and ZIP1 supplementation was used as a treatment for prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('ZIP1', 'Gene', '27173', (19, 23))	('ZIP1', 'Gene', '27173', (71, 75))	('deficiency', 'Var', (24, 34))	('prostate cancer', 'Disease', (50, 65))	('related', 'Reg', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('prostate cancer', 'Disease', (120, 135))	('ZIP1', 'Gene', (19, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('ZIP1', 'Gene', (71, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))
448263	27458102	thought ZIP4 was overexpressed in pancreatic cancer and silencing ZIP4 in pancreatic cancer cell lines could inhibit metastasis, tumor size in nude mice, and increase survival of mice with cancer.	('silencing', 'Var', (56, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('survival', 'CPA', (167, 175))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('mice', 'Species', '10090', (148, 152))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Disease', (129, 134))	('increase', 'PosReg', (158, 166))	('metastasis', 'CPA', (117, 127))	('mice', 'Species', '10090', (179, 183))	('inhibit', 'NegReg', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('nude mice', 'Species', '10090', (143, 152))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('cancer', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('pancreatic cancer', 'Disease', (74, 91))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('pancreatic cancer', 'Disease', (34, 51))	('cancer', 'Disease', (189, 195))	('ZIP4', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))
448265	27458102	found the abnormal expression of ZIP7 could promote the invasive growth of breast cancer by increasing the activation of growth factor receptor.	('ZIP7', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('growth', 'Protein', (121, 127))	('breast cancer', 'Disease', (75, 88))	('promote', 'PosReg', (44, 51))	('increasing', 'PosReg', (92, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('activation', 'MPA', (107, 117))	('abnormal expression', 'Var', (10, 29))	('invasive growth', 'CPA', (56, 71))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('ZIP7', 'Gene', '7922', (33, 37))
448267	27458102	found that ZIP11 deficiency was associated with high-grade glioma and IDH1 mutation.	('glioma', 'Disease', (59, 65))	('ZIP11', 'Gene', '201266', (11, 16))	('mutation', 'Var', (75, 83))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('deficiency', 'Var', (17, 27))	('IDH1', 'Gene', '3417', (70, 74))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('ZIP11', 'Gene', (11, 16))	('associated', 'Reg', (32, 42))	('IDH1', 'Gene', (70, 74))
448274	27458102	Furthermore, the percentage of cells in the G0/G1 phase in the KYSE170K cell line was higher than that in the KYSE170S cell line.	('KYSE170S', 'CellLine', 'CVCL:1358', (110, 118))	('KYSE170K', 'Var', (63, 71))	('higher', 'PosReg', (86, 92))	('cells in the G0/G1 phase', 'CPA', (31, 55))
448275	27458102	ZIP5 knockdown decreased the expression of COX2 and increased the expression of E-cadherin in vitro.	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '999', (80, 90))	('increased', 'PosReg', (52, 61))	('COX2', 'Gene', (43, 47))	('knockdown', 'Var', (5, 14))	('COX2', 'Gene', '5743', (43, 47))	('expression', 'MPA', (66, 76))	('decreased', 'NegReg', (15, 24))	('expression', 'MPA', (29, 39))	('ZIP5', 'Gene', (0, 4))
448277	27458102	The human esophageal cancer cell lines KYSE70, KYSE150, KYSE170, KYSE180, KYSE510, Eca109, Eca9706, and CaES17 were donated by the MD Anderson Cancer Center, USA.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('KYSE510', 'Var', (74, 81))	('esophageal cancer', 'Disease', (10, 27))	('human', 'Species', '9606', (4, 9))	('Cancer', 'Disease', (143, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (10, 27))	('Cancer', 'Disease', 'MESH:D009369', (143, 149))	('Cancer', 'Phenotype', 'HP:0002664', (143, 149))	('KYSE150', 'Var', (47, 54))	('KYSE180', 'Var', (65, 72))	('Eca9706', 'CellLine', 'CVCL:E307', (91, 98))
448300	27458102	To successfully obtain the ZIP5 knockdown esophageal cancer cell lines from KYSE170, KYSE170K, and the control group KYSE170S, the esophageal cancer cell line KYSE170 was infected with virus packaged with lentivirus plasmids PSD31-ZIP5-shRNA and PSD31-scramble-shRNA.	('esophageal cancer', 'Disease', (42, 59))	('KYSE170K', 'Var', (85, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('esophageal cancer', 'Disease', (131, 148))	('infected', 'Disease', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('KYSE170S', 'CellLine', 'CVCL:1358', (117, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('PSD31-scramble-shRNA', 'Var', (246, 266))	('PSD31-ZIP5-shRNA', 'Var', (225, 241))	('infected', 'Disease', 'MESH:D007239', (171, 179))
448326	27458102	Abnormal Zn homeostasis can lead to a variety of health problems including growth retardation, hypogonadism, immunodeficiency, and neuronal and sensory dysfunctions.	('Zn homeostasis', 'MPA', (9, 23))	('growth retardation', 'Disease', 'MESH:D006130', (75, 93))	('hypogonadism, immunodeficiency', 'Disease', 'MESH:D007006', (95, 125))	('growth retardation', 'Disease', (75, 93))	('hypogonadism', 'Phenotype', 'HP:0000135', (95, 107))	('Abnormal Zn homeostasis', 'Phenotype', 'HP:0008277', (0, 23))	('Zn', 'Chemical', 'MESH:D015032', (9, 11))	('immunodeficiency', 'Phenotype', 'HP:0002721', (109, 125))	('growth retardation', 'Phenotype', 'HP:0001510', (75, 93))	('Abnormal', 'Var', (0, 8))	('lead to', 'Reg', (28, 35))
448328	27458102	indicated that dietary Zn deficiency had a strong association with ESCC in the high-incidence region by finding an inverse relationship between Zn levels in biopsy samples and the subsequent risk of advancing to ESCC.	('advancing', 'PosReg', (199, 208))	('deficiency', 'Var', (26, 36))	('ESCC', 'Disease', (67, 71))	('ESCC', 'Disease', (212, 216))	('Zn', 'Chemical', 'MESH:D015032', (144, 146))	('Zn', 'Chemical', 'MESH:D015032', (23, 25))	('inverse', 'NegReg', (115, 122))
448336	27458102	ZIP1, ZIP2, and ZIP3 deficiencies were associated with prostate cancer.	('deficiencies', 'Var', (21, 33))	('ZIP1', 'Gene', (0, 4))	('ZIP3', 'Gene', (16, 20))	('prostate cancer', 'Disease', 'MESH:D011471', (55, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (55, 70))	('ZIP2', 'Gene', '29986', (6, 10))	('ZIP1', 'Gene', '27173', (0, 4))	('associated', 'Reg', (39, 49))	('ZIP2', 'Gene', (6, 10))	('ZIP3', 'Gene', '29985', (16, 20))	('prostate cancer', 'Disease', (55, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
448338	27458102	indicated that the silencing of ZIP4 in ASPC-1 and BxPC-3 would decrease cell proliferation, migration, and invasion and inhibit tumor volume and weight in the nude mouse subcutaneous model.	('inhibit', 'NegReg', (121, 128))	('mouse', 'Species', '10090', (165, 170))	('decrease', 'NegReg', (64, 72))	('BxPC-3', 'CellLine', 'CVCL:0186', (51, 57))	('ZIP4', 'Gene', (32, 36))	('silencing', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cell proliferation', 'CPA', (73, 91))	('tumor', 'Disease', (129, 134))	('invasion', 'CPA', (108, 116))
448342	27458102	Many studies indicated that the dysregulated expression of ZIP6 was associated with cell invasion and metastasis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('associated', 'Reg', (68, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('dysregulated', 'Var', (32, 44))	('expression', 'MPA', (45, 55))	('metastasis', 'CPA', (102, 112))	('cell invasion', 'CPA', (84, 97))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('ZIP6', 'Gene', (59, 63))
448346	27458102	found that the removal of ZIP7 destroyed the activation of epithelial growth factor receptor/IGF receptor/Src signaling by reducing intracellular Zn levels, and increased tumor killing, preventing further development of resistance in breast cancer.	('reducing', 'NegReg', (123, 131))	('preventing', 'NegReg', (186, 196))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('epithelial', 'MPA', (59, 69))	('intracellular Zn levels', 'MPA', (132, 155))	('Src', 'Gene', (106, 109))	('ZIP7', 'Gene', '7922', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Disease', (234, 247))	('ZIP7', 'Gene', (26, 30))	('Zn', 'Chemical', 'MESH:D015032', (146, 148))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('Src', 'Gene', '6714', (106, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('increased', 'PosReg', (161, 170))	('removal', 'Var', (15, 22))	('tumor', 'Disease', (171, 176))
448351	27458102	suggested that ZIP5 mRNA associated with polysomes, while the protein was internalized and degraded in enterocytes, acinar cells, and endoderm cells during Zn deficiency.	('polysomes', 'Protein', (41, 50))	('Zn', 'Chemical', 'MESH:D015032', (156, 158))	('associated', 'Interaction', (25, 35))	('deficiency', 'Var', (159, 169))	('degraded', 'NegReg', (91, 99))
448358	27458102	The role of ZIP5 knockdown in inhibiting tumor growth was that growth of xenografts was slowed to a certain extent.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('inhibiting', 'NegReg', (30, 40))	('tumor', 'Disease', (41, 46))	('ZIP5', 'Gene', (12, 16))	('knockdown', 'Var', (17, 26))	('slowed', 'NegReg', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('growth of xenografts', 'CPA', (63, 83))
448380	27458102	A previous study suggested that E-cadherin deficiency was associated with cancer invasion, metastasis, and prognosis in a variety of tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('prognosis', 'CPA', (107, 116))	('E-cadherin', 'Gene', (32, 42))	('associated', 'Reg', (58, 68))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('E-cadherin', 'Gene', '999', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('metastasis', 'CPA', (91, 101))	('cancer', 'Disease', (74, 80))	('deficiency', 'Var', (43, 53))
448381	27458102	In this study, we suggested that ZIP5 knockdown inhibited the growth of xenografts in vivo through decreased COX2 expression and elevated E-cadherin expression.	('decreased', 'NegReg', (99, 108))	('COX2', 'Gene', '5743', (109, 113))	('COX2', 'Gene', (109, 113))	('ZIP5', 'Gene', (33, 37))	('elevated', 'PosReg', (129, 137))	('growth of xenografts in vivo', 'CPA', (62, 90))	('inhibited', 'NegReg', (48, 57))	('expression', 'MPA', (149, 159))	('expression', 'MPA', (114, 124))	('knockdown', 'Var', (38, 47))	('E-cadherin', 'Gene', (138, 148))	('E-cadherin', 'Gene', '999', (138, 148))
448432	32986344	Among men, highest mortality was due to lung and liver cancers (5- year average M/I 61.3, 59.7 respectively), while those among women were due to stomach and gall bladder cancers (5- year average M/I 59.6, 54.8 respectively).	('M/I 59', 'Var', (196, 202))	('M/I 61', 'SUBSTITUTION', 'None', (80, 86))	('lung', 'Disease', (40, 44))	('men', 'Species', '9606', (130, 133))	('women', 'Species', '9606', (128, 133))	('stomach', 'Disease', (146, 153))	('mortality', 'Disease', (19, 28))	('liver cancers', 'Disease', 'MESH:D006528', (49, 62))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('M/I 61', 'Var', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('liver cancers', 'Phenotype', 'HP:0002896', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mortality', 'Disease', 'MESH:D003643', (19, 28))	('men', 'Species', '9606', (6, 9))	('gall bladder cancers', 'Disease', (158, 178))	('bladder cancers', 'Phenotype', 'HP:0009725', (163, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('gall bladder cancers', 'Disease', 'MESH:D005706', (158, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (163, 177))	('liver cancers', 'Disease', (49, 62))	('M/I 59', 'SUBSTITUTION', 'None', (196, 202))
448449	32986344	(Hankinson et al., 2004; Haverkos, 2005; Crosbie et al., 2013) In recent studies, high risk HPV has also been associated with the pathogenesis of breast carcinoma (Lawson et al., 2015).	('HPV', 'Species', '10566', (92, 95))	('breast carcinoma', 'Phenotype', 'HP:0003002', (146, 162))	('high risk', 'Var', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('associated', 'Reg', (110, 120))	('breast carcinoma', 'Disease', (146, 162))	('breast carcinoma', 'Disease', 'MESH:D001943', (146, 162))
448457	32986344	This rate was much higher than those reported my most PBCRs across the country (M/I % for Males: Range 10.1(Delhi)- 68.9 (Barshi Rural), Females: Range 8.0 (Delhi)- 66.3 (Barshi Rural) and showed a significant increment with time in most types of cancers.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('higher', 'PosReg', (19, 25))	('Delhi', 'Var', (157, 162))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('men', 'Species', '9606', (215, 218))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))
448473	32755068	Cox multivariate regression analysis revealed that the addition of nCRT for truly node-negative patients with tumor length >= 3 cm, pT1-2N0 (early-staged) and localized disease were independent risk factors for survival than surgery alone (P < 0.01).	('CRT', 'Gene', (68, 71))	('pT1-2N0', 'Var', (132, 139))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('patients', 'Species', '9606', (96, 104))	('CRT', 'Gene', '799', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
448478	32755068	Finally, compared with surgery alone, cN0 esophageal cancer with falsely node-negative (pN+) or localized truly node-negative (pT3-4N0) gain a significant survival benefit from neoadjuvant chemoradiation.	('pT3', 'Gene', '7694', (127, 130))	('node-negative', 'Reg', (73, 86))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('pT3', 'Gene', (127, 130))	('cN0', 'Var', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('gain', 'PosReg', (136, 140))	('survival benefit', 'CPA', (155, 171))
448512	32755068	For cN0/pN0 esophageal carcinoma patients, the five-year OS (67.8% vs. 62.5%; P = 0.175) and CSS (75.3% vs. 72.7%; P = 0.37) were identical in the CRT + S and SA groups.	('CRT', 'Gene', (147, 150))	('patients', 'Species', '9606', (33, 41))	('cN0/pN0', 'Var', (4, 11))	('SA', 'Chemical', '-', (159, 161))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (12, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('esophageal carcinoma', 'Disease', (12, 32))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (12, 32))	('CRT', 'Gene', '799', (147, 150))
448517	32755068	On subgroup analysis, this finding was driven by patients with cN0/pN+ and cN0/pT3-4N0 status.	('pT3', 'Gene', '7694', (79, 82))	('cN0/pN+', 'Var', (63, 70))	('pT3', 'Gene', (79, 82))	('patients', 'Species', '9606', (49, 57))
448535	32755068	Nonetheless, in order to reduce the tumor downstaging effect of neoadjuvant therapy, as well as the potential misclassification of clinical nodal status, we matched the clinical node-negative stage to pathologic stage and performed analysis on patients who were in cN0/pN0 and cN0/pN+ status.	('cN0/pN0', 'Var', (265, 272))	('downstaging', 'NegReg', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cN0/pN+', 'Var', (277, 284))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('patients', 'Species', '9606', (244, 252))	('tumor', 'Disease', (36, 41))
448536	32755068	This study showed that patients with EC who were cN0/pN+ or pT3-4N0 derived a significant survival benefit from nCRT, even after propensity score-adjusted for other demographic and pathological data.	('pT3', 'Gene', (60, 63))	('EC', 'Phenotype', 'HP:0011459', (37, 39))	('patients', 'Species', '9606', (23, 31))	('survival', 'MPA', (90, 98))	('CRT', 'Gene', '799', (113, 116))	('benefit', 'PosReg', (99, 106))	('cN0/pN+', 'Var', (49, 56))	('CRT', 'Gene', (113, 116))	('pT3', 'Gene', '7694', (60, 63))
448546	32755068	4 ,  6  In our study, survival of patients with pT1-2N0 disease was better with upfront surgery due to the avoidance of unnecessary and possibly harmful treatment in this population that could cause deconditioning, chemoradiation-related morbidity or mortality, treatment delay, and potentially increase surgical complications and mortality.	('pT1-2N0', 'Var', (48, 55))	('mortality', 'Disease', (251, 260))	('cause', 'Reg', (193, 198))	('mortality', 'Disease', (331, 340))	('better', 'PosReg', (68, 74))	('deconditioning', 'CPA', (199, 213))	('mortality', 'Disease', 'MESH:D003643', (331, 340))	('surgical complications', 'CPA', (304, 326))	('mortality', 'Disease', 'MESH:D003643', (251, 260))	('survival', 'MPA', (22, 30))	('patients', 'Species', '9606', (34, 42))	('increase', 'PosReg', (295, 303))
448554	31886162	Genetic Polymorphisms in the RAD51 Gene with a Risk of Head and Neck Cancer and Esophageal Cancer: A Meta-Analysis The role of RAD51 gene polymorphisms with the development of head and neck cancer (HNC) and esophageal cancer (EC) remains controversial.	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Head and Neck Cancer', 'Disease', 'MESH:D006258', (55, 75))	('Cancer', 'Disease', (69, 75))	('cancer', 'Disease', (190, 196))	('Cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (207, 224))	('Cancer', 'Disease', 'MESH:D009369', (69, 75))	('Polymorphisms', 'Var', (8, 21))	('RAD51', 'Gene', (127, 132))	('RAD51', 'Gene', '5888', (127, 132))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('esophageal cancer', 'Disease', (207, 224))	('head and neck cancer', 'Phenotype', 'HP:0012288', (176, 196))	('RAD51', 'Gene', (29, 34))	('RAD51', 'Gene', '5888', (29, 34))	('neck cancer', 'Disease', 'MESH:D006258', (185, 196))	('neck cancer', 'Disease', (185, 196))	('Head and Neck Cancer', 'Phenotype', 'HP:0012288', (55, 75))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', (218, 224))	('HNC', 'Phenotype', 'HP:0012288', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('polymorphisms', 'Var', (138, 151))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('head and neck cancer', 'Disease', 'MESH:D006258', (176, 196))
448555	31886162	This meta-analysis was conducted to evaluate the correlation between the RAD51 polymorphisms and these two cancers quantitatively.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('RAD51', 'Gene', (73, 78))	('polymorphisms', 'Var', (79, 92))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
448556	31886162	Overall, a significant correlation was observed between the rs1801320 polymorphism and the increased risk of these two cancers (OR = 1.32, 95%CI = 1.03-1.71 for C vs. G; OR = 1.50, 95%CI = 1.03-2.19 for CG vs. GG; and OR = 1.44, 95%CI = 1.05-1.99 for CC+CG vs. GG).	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('CC+CG', 'Disease', (251, 256))	('rs1801320', 'Mutation', 'rs1801320', (60, 69))	('rs1801320', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
448557	31886162	Moreover, our analysis revealed that no statistical evidence of correlation was discovered between the polymorphism of rs1801321 and the increased risk of HNC.	('polymorphism', 'Var', (103, 115))	('HNC', 'Disease', (155, 158))	('rs1801321', 'Gene', (119, 128))	('rs1801321', 'Mutation', 'rs1801321', (119, 128))	('HNC', 'Phenotype', 'HP:0012288', (155, 158))
448558	31886162	However, stratified analysis based on ethnicity suggested that rs1801321 polymorphism was related to the decreased risk of HNC among Caucasians (OR = 0.82, 95%CI = 0.72-0.95 for T vs. G).	('HNC', 'Disease', (123, 126))	('rs1801321', 'Var', (63, 72))	('HNC', 'Phenotype', 'HP:0012288', (123, 126))	('decreased', 'NegReg', (105, 114))	('rs1801321', 'DBSNP_MENTION', 'None', (63, 72))
448559	31886162	rs1801320 polymorphism was strongly associated with the risk of these two associated cancers, especially with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('rs1801320', 'DBSNP_MENTION', 'None', (0, 9))	('esophageal cancer', 'Disease', (110, 127))	('rs1801320', 'Var', (0, 9))	('associated', 'Reg', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
448560	31886162	Moreover, our results revealed that rs1801321 polymorphism was correlated to the decreased risk of HNC among Caucasians.	('decreased', 'NegReg', (81, 90))	('rs1801321', 'Var', (36, 45))	('HNC', 'Phenotype', 'HP:0012288', (99, 102))	('rs1801321', 'DBSNP_MENTION', 'None', (36, 45))	('HNC', 'Disease', (99, 102))
448569	31886162	135 G/C (rs1801320) and 172 G/T (rs1801321) are two common RAD51 single nucleotide polymorphisms (SNPs), which might influence mRNA stability and relate to altered translational efficiency; thus, these two gene polymorphisms might lead to carcinogenesis.	('135 G/C', 'Mutation', 'rs1801320', (0, 7))	('lead to', 'Reg', (231, 238))	('mRNA stability', 'MPA', (127, 141))	('translational efficiency', 'MPA', (164, 188))	('carcinogenesis', 'Disease', 'MESH:D063646', (239, 253))	('172 G/T', 'Mutation', 'rs1801321', (24, 31))	('rs1801321', 'DBSNP_MENTION', 'None', (33, 42))	('rs1801320', 'Var', (9, 18))	('carcinogenesis', 'Disease', (239, 253))	('altered', 'Reg', (156, 163))	('influence', 'Reg', (117, 126))	('rs1801321', 'Var', (33, 42))	('rs1801320', 'DBSNP_MENTION', 'None', (9, 18))	('RAD51', 'Gene', (59, 64))
448570	31886162	demonstrated G135C polymorphism in RAD51 gene was strongly related to EC, while Zhang et al.	('related', 'Reg', (59, 66))	('G135C', 'Mutation', 'rs1801320', (13, 18))	('G135C polymorphism', 'Var', (13, 31))	('RAD51', 'Gene', (35, 40))
448571	31886162	Selection strategy was carried out by combination of the following terms: "RAD51", "135G/C", "rs1801320", "172G/T", "rs1801321", "polymorphism", "polymorphisms", "variant", "mutation", "SNP", "HNC", "head and neck", "oral", "oral cavity", "pharyngeal", "laryngeal", "nasopharyngeal", "oropharyngeal", "laryngopharyngeal", "hypopharyngeal", "esophageal", "oesophageal", "cancer", "carcinoma", "tumor", "tumour", "malignancy", and "neoplasm".	('neoplasm', 'Phenotype', 'HP:0002664', (430, 438))	('172G/T', 'SUBSTITUTION', 'None', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (393, 398))	('malignancy', 'Disease', 'MESH:D009369', (412, 422))	('tumour', 'Phenotype', 'HP:0002664', (402, 408))	('malignancy', 'Disease', (412, 422))	('rs1801320', 'Var', (94, 103))	('172G/T', 'Var', (107, 113))	('HNC', 'Phenotype', 'HP:0012288', (193, 196))	('rs1801321', 'Var', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (393, 398))	('tumor', 'Disease', (393, 398))	('carcinoma', 'Phenotype', 'HP:0030731', (380, 389))	('135G/C', 'Mutation', 'rs1801320', (84, 90))	('rs1801320', 'DBSNP_MENTION', 'None', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('rs1801321', 'DBSNP_MENTION', 'None', (117, 126))
448572	31886162	All the enrolled papers were related to RAD51 G135C (rs1801320) polymorphism.	('rs1801320', 'DBSNP_MENTION', 'None', (53, 62))	('G135C', 'Var', (46, 51))	('rs1801320', 'Var', (53, 62))	('G135C', 'SUBSTITUTION', 'None', (46, 51))	('RAD51', 'Gene', (40, 45))
448574	31886162	With respect to RAD51 G135C (rs1801320) polymorphism, the random-effects model was performed under all genetic models because the statistical heterogeneity between articles was substantial (value of P in Q-test < 0.10 or I2 > 50%).	('G135C', 'SUBSTITUTION', 'None', (22, 27))	('G135C', 'Var', (22, 27))	('rs1801320', 'Var', (29, 38))	('rs1801320', 'DBSNP_MENTION', 'None', (29, 38))
448575	31886162	We discovered a significant relationship between the rs1801320 polymorphism and the increased risk of these two cancers under all genetic models except homozygous and recessive models (OR = 1.32, (95%CI, P) = (1.03-1.71, 0.032) for C vs. G, Figure 2; OR = 1.34, (95%CI, P) = (0.69-2.61, 0.388) for CC vs. GG; OR = 1.50, (95%CI, P) = (1.03-2.19, 0.033) for CG vs. GG; OR = 1.44, (95%CI, P) = (1.05-1.99, 0.026) for CC+CG vs. GG; and OR = 1.15, (95%CI, P) = (0.57-2.34, 0.696) for CC vs. CG+GG).	('polymorphism', 'Var', (63, 75))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('rs1801320', 'DBSNP_MENTION', 'None', (53, 62))	('rs1801320', 'Var', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CC+CG', 'Disease', (414, 419))
448576	31886162	As for RAD51 G172T (rs1801321) polymorphism, four papers enrolled were all related to HNC instead of EC.	('HNC', 'Disease', (86, 89))	('rs1801321', 'Var', (20, 29))	('G172T', 'SUBSTITUTION', 'None', (13, 18))	('G172T', 'Var', (13, 18))	('HNC', 'Phenotype', 'HP:0012288', (86, 89))	('rs1801321', 'DBSNP_MENTION', 'None', (20, 29))
448577	31886162	Significant correlation was not observed between rs1801321 polymorphism and susceptibility to HNC.	('rs1801321', 'Var', (49, 58))	('HNC', 'Disease', (94, 97))	('rs1801321', 'DBSNP_MENTION', 'None', (49, 58))	('HNC', 'Phenotype', 'HP:0012288', (94, 97))
448578	31886162	In our subgroup analyses by genotyping method, ethnicity, and sample size, a significant correlation could be observed between the rs1801321 polymorphism and the decreased risk of HNC for Caucasians only (OR (95%CI) = 0.82 (0.72-0.95) for T vs. G).	('HNC', 'Phenotype', 'HP:0012288', (180, 183))	('rs1801321', 'DBSNP_MENTION', 'None', (131, 140))	('decreased', 'NegReg', (162, 171))	('HNC', 'Disease', (180, 183))	('rs1801321', 'Var', (131, 140))
448580	31886162	In all studies, no remarkable publication bias was shown by the P value in the Egger test (C vs. G: P = 0.980; CC vs. GG: P = 0.299; CG vs. GG: P = 0.710; CC+CG vs. GG: P = 0.848; CC vs. CG+GG: P = 0.374; T vs. G: P = 0.540; TT vs. GG: P = 0.579; TG vs. GG: P = 0.669; TT+TG vs. GG: P = 0.625; TT vs. TG+GG: P = 0.595) and Begg's funnel plot (Figure 4, C vs. G of rs1801320) for rs1801320 and rs1801321 polymorphisms.	('rs1801320', 'Var', (364, 373))	('rs1801321', 'DBSNP_MENTION', 'None', (393, 402))	('rs1801320', 'Var', (379, 388))	('rs1801320', 'DBSNP_MENTION', 'None', (364, 373))	('rs1801321', 'Var', (393, 402))	('rs1801320', 'DBSNP_MENTION', 'None', (379, 388))
448582	31886162	Two common RAD51 SNPs (rs1801320 and rs1801321) might influence mRNA stability and relate to the expression level of RAD51 protein.	('mRNA stability', 'MPA', (64, 78))	('RAD51', 'Gene', (11, 16))	('rs1801320', 'DBSNP_MENTION', 'None', (23, 32))	('expression level', 'MPA', (97, 113))	('rs1801321', 'DBSNP_MENTION', 'None', (37, 46))	('rs1801320', 'Var', (23, 32))	('relate', 'Reg', (83, 89))	('rs1801321', 'Var', (37, 46))	('influence', 'Reg', (54, 63))
448583	31886162	Our results revealed that rs1801320 polymorphism was significantly correlated to the risk of these two cancers under the allelic, heterozygous, and dominant genetic models.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('correlated', 'Reg', (67, 77))	('rs1801320', 'DBSNP_MENTION', 'None', (26, 35))	('rs1801320', 'Var', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
448585	31886162	In the subgroup analyses of rs1801320 polymorphism according to a genotyping method, a statistically significant relationship was found in the PCR-RFLP genotyping method subgroup under allelic, heterozygous, and dominant genetic models, but not in the PCR genotyping method subgroup.	('rs1801320', 'DBSNP_MENTION', 'None', (28, 37))	('PCR-RFLP genotyping', 'Disease', (143, 162))	('rs1801320', 'Var', (28, 37))	('significant relationship', 'Reg', (101, 125))
448586	31886162	In the subgroup analyses based on ethnicity, we discovered rs1801320 polymorphism increased the risk of HNC and EC in Asian populations, but not in Caucasian populations.	('HNC', 'Phenotype', 'HP:0012288', (104, 107))	('HNC', 'Disease', (104, 107))	('rs1801320', 'DBSNP_MENTION', 'None', (59, 68))	('increased', 'PosReg', (82, 91))	('rs1801320', 'Var', (59, 68))
448587	31886162	When stratified by sample size, the rs1801320 polymorphism was related to the increased risk of HNC and EC in a large sample subgroup under the allelic, heterozygous, and dominant genetic models, which was the same as the overall results.	('HNC', 'Disease', (96, 99))	('rs1801320', 'DBSNP_MENTION', 'None', (36, 45))	('HNC', 'Phenotype', 'HP:0012288', (96, 99))	('rs1801320', 'Var', (36, 45))
448588	31886162	Stratified analysis according to tumor type indicated that a marked correlation could be found between rs1801320 polymorphism and EC under the allelic, homozygous, and recessive genetic models, but not found between the SNP and the HNC.	('rs1801320', 'Var', (103, 112))	('HNC', 'Phenotype', 'HP:0012288', (232, 235))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('rs1801320', 'DBSNP_MENTION', 'None', (103, 112))	('polymorphism', 'Var', (113, 125))
448589	31886162	This indicated that rs1801320 polymorphism would contribute to the development of EC.	('rs1801320', 'DBSNP_MENTION', 'None', (20, 29))	('contribute', 'Reg', (49, 59))	('rs1801320', 'Var', (20, 29))
448590	31886162	In the subgroup analyses of rs1801321 polymorphism by a genotyping method and sample size, no statistical evidence of correlation was observed between rs1801321 SNP and HNC.	('rs1801321', 'DBSNP_MENTION', 'None', (151, 160))	('HNC', 'Phenotype', 'HP:0012288', (169, 172))	('rs1801321', 'Var', (28, 37))	('rs1801321', 'Var', (151, 160))	('HNC', 'Disease', (169, 172))	('rs1801321', 'DBSNP_MENTION', 'None', (28, 37))
448591	31886162	Stratified analysis based on ethnicity, our results revealed that rs1801321 SNP was related to the decreased risk of HNC among Caucasian populations under an allelic genetic model.	('HNC', 'Phenotype', 'HP:0012288', (117, 120))	('decreased', 'NegReg', (99, 108))	('rs1801321', 'Var', (66, 75))	('HNC', 'Disease', (117, 120))	('rs1801321', 'DBSNP_MENTION', 'None', (66, 75))
448592	31886162	It is particularly worth mentioning here that rs1801320 polymorphism could increase the risk of EC, which had not been shown before.	('rs1801320', 'DBSNP_MENTION', 'None', (46, 55))	('rs1801320', 'Var', (46, 55))	('increase', 'PosReg', (75, 83))
448593	31886162	Secondly, this is the first study not only to assess the correlation between RAD51 SNPs and two associated cancers (HNC and EC) but also to discover a relationship between the rs1801320 polymorphism and the risk of EC.	('rs1801320', 'Var', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('RAD51', 'Gene', (77, 82))	('rs1801320', 'DBSNP_MENTION', 'None', (176, 185))	('HNC', 'Phenotype', 'HP:0012288', (116, 119))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
448594	31886162	The present meta-analysis explored that rs1801320 SNP was significantly correlated with the risk of these two associated cancers.	('correlated', 'Reg', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('rs1801320', 'DBSNP_MENTION', 'None', (40, 49))	('rs1801320', 'Var', (40, 49))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
448596	30931333	 PLCE1 Polymorphisms and Risk of Esophageal and Gastric Cancer in a Northwestern Chinese Population The reported risk susceptibility between phospholipase C epsilon 1 (PLCE1) polymorphisms and esophageal cancer (EC) and gastric cancer (GC) remained inconsistent and controversial, especially on variants other than rs2274223.	('gastric cancer', 'Phenotype', 'HP:0012126', (220, 234))	('PLCE1', 'Gene', (168, 173))	('polymorphisms', 'Var', (175, 188))	('Esophageal and Gastric Cancer', 'Disease', 'MESH:D013274', (33, 62))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('gastric cancer', 'Disease', (220, 234))	('phospholipase C epsilon 1', 'Gene', '51196', (141, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))	('phospholipase C epsilon 1', 'Gene', (141, 166))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('esophageal cancer', 'Disease', (193, 210))	('gastric cancer', 'Disease', 'MESH:D013274', (220, 234))	('PLCE1', 'Gene', (1, 6))	('PLCE1', 'Gene', '51196', (1, 6))	('rs2274223', 'Mutation', 'rs2274223', (315, 324))	('rs2274223', 'Var', (315, 324))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (48, 62))	('PLCE1', 'Gene', '51196', (168, 173))
448598	30931333	Here we conducted a case-control study from northwest China, genotyped seven tag single nucleotide polymorphisms (SNPs) in PLCE1 with multiplexed SNP MassARRAY assay.	('RA', 'Chemical', 'MESH:D011883', (156, 158))	('PLCE1', 'Gene', '51196', (123, 128))	('single nucleotide polymorphisms', 'Var', (81, 112))	('PLCE1', 'Gene', (123, 128))
448600	30931333	Results showed that the minor alleles of rs3765524, rs2274223, and rs10509670 were associated with increased risk of EC and GC.	('rs3765524', 'Mutation', 'rs3765524', (41, 50))	('rs2274223', 'Var', (52, 61))	('rs3765524', 'Var', (41, 50))	('rs10509670', 'Var', (67, 77))	('rs2274223', 'Mutation', 'rs2274223', (52, 61))	('rs10509670', 'Mutation', 'rs10509670', (67, 77))
448601	30931333	By stratification, a more significant association was found in subgroups of male, age >= 54, tumor stages of I-II and tumor size <= 5 cm, EC and cardia cancer (CC) of stomach, and moderate to well differentiated squamous carcinoma.	('<= 5', 'Var', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('squamous carcinoma', 'Disease', 'MESH:D002294', (212, 230))	('significant association', 'Reg', (26, 49))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('squamous carcinoma', 'Disease', (212, 230))	('tumor', 'Disease', (93, 98))	('cardia cancer', 'Disease', (145, 158))	('moderate', 'Disease', (180, 188))	('tumor', 'Disease', (118, 123))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (212, 230))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cardia cancer', 'Disease', 'MESH:D004938', (145, 158))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
448602	30931333	In addition, a significant association for rs3765524 with noncardia cancer (NCC) and adenocarcinoma which is predominant in China was also observed.	('rs3765524', 'Var', (43, 52))	('noncardia cancer', 'Disease', (58, 74))	('adenocarcinoma', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('noncardia cancer', 'Disease', 'MESH:D009369', (58, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('rs3765524', 'Mutation', 'rs3765524', (43, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))
448603	30931333	Further expression analysis identified that PLCE1 was downregulated in NCC tissues comparing to their adjacent noncancerous tissues, and its protein expression was higher in genotype rs3765524 CT/TT than in rs3765524 CC.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('protein expression', 'MPA', (141, 159))	('rs3765524', 'Mutation', 'rs3765524', (183, 192))	('PLCE1', 'Gene', (44, 49))	('rs3765524', 'Mutation', 'rs3765524', (207, 216))	('higher', 'PosReg', (164, 170))	('PLCE1', 'Gene', '51196', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rs3765524 CT/TT', 'Var', (183, 198))	('downregulated', 'NegReg', (54, 67))	('NCC', 'Disease', (71, 74))	('cancer', 'Disease', (114, 120))
448604	30931333	In summary, our study suggests that PLCE1 polymorphisms may affect its gene expression and are associated with not only EC and CC, but also, to some extent, NCC risk in this study population.	('gene expression', 'MPA', (71, 86))	('NCC', 'Disease', (157, 160))	('PLCE1', 'Gene', (36, 41))	('PLCE1', 'Gene', '51196', (36, 41))	('polymorphisms', 'Var', (42, 55))	('affect', 'Reg', (60, 66))	('associated with', 'Reg', (95, 110))
448608	30931333	Genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs), mostly rs2274223 A>G, and rs3765524 C>T in PLCE1 gene as shared susceptibility loci for EC and GC.	('rs2274223 A>G', 'Var', (102, 115))	('rs3765524', 'Mutation', 'rs3765524', (121, 130))	('rs2274223', 'Mutation', 'rs2274223', (102, 111))	('PLCE1', 'Gene', (138, 143))	('rs3765524 C>T', 'Var', (121, 134))	('PLCE1', 'Gene', '51196', (138, 143))
448609	30931333	Although several independent candidate-gene studies have confirmed the association between EC, GC, and PLCE1 SNPs subsequently, there is more limited data on variants other than rs2274223, especially for GC.	('association', 'Interaction', (71, 82))	('rs2274223', 'Mutation', 'rs2274223', (178, 187))	('rs2274223', 'Var', (178, 187))	('PLCE1', 'Gene', (103, 108))	('PLCE1', 'Gene', '51196', (103, 108))
448611	30931333	To further explore the association between PLCE1 polymorphisms and risk of EC and GC or their subtypes, we collected blood samples from Chinese northwestern population and used multiplexed SNP MassARRAY assay to sequence a panel of tag SNPs (tSNPs) of PLCE1 in a case-control study.	('PLCE1', 'Gene', (43, 48))	('PLCE1', 'Gene', '51196', (43, 48))	('PLCE1', 'Gene', (252, 257))	('polymorphisms', 'Var', (49, 62))	('PLCE1', 'Gene', '51196', (252, 257))	('RA', 'Chemical', 'MESH:D011883', (199, 201))
448620	30931333	A panel of seven tSNPs of rs3765524, rs3818432, rs2274223, rs10509670, rs11187852, rs3781264, and rs11187866 in PLCE1 gene were included in this study.	('rs3818432', 'Var', (37, 46))	('rs2274223', 'Var', (48, 57))	('rs11187866', 'Var', (98, 108))	('rs3765524', 'Var', (26, 35))	('rs3781264', 'Var', (83, 92))	('rs10509670', 'Var', (59, 69))	('rs11187852', 'Mutation', 'rs11187852', (71, 81))	('PLCE1', 'Gene', (112, 117))	('rs3818432', 'Mutation', 'rs3818432', (37, 46))	('rs11187866', 'Mutation', 'rs11187866', (98, 108))	('PLCE1', 'Gene', '51196', (112, 117))	('rs3765524', 'Mutation', 'rs3765524', (26, 35))	('rs10509670', 'Mutation', 'rs10509670', (59, 69))	('rs11187852', 'Var', (71, 81))	('rs3781264', 'Mutation', 'rs3781264', (83, 92))	('rs2274223', 'Mutation', 'rs2274223', (48, 57))
448632	30931333	Results showed that there were three tSNPs (rs3765524, rs2274223, and rs10509670) associated with the risk of EC and GC: rs3765524 (CT vs CC, OR = 1.66, 95% CI 1.16-2.38, P = 0.006; CT/TT vs CC, OR = 1.65, 95% CI 1.17-2.34, P = 0.004); rs2274223 (AG vs AA, OR = 1.57, 95% CI 1.10-2.26, P = 0.014; AG/GG vs AA, OR = 1.55, 95% CI 1.10-2.20, P = 0.013); rs10509670 (AG vs AA, OR = 1.54, 95% CI 1.07-2.21, P = 0.019; AG/GG vs AA, OR = 1.54, 95% CI 1.09-2.18, P = 0.014).	('rs3765524', 'Mutation', 'rs3765524', (121, 130))	('rs2274223', 'Mutation', 'rs2274223', (55, 64))	('rs3765524', 'Var', (44, 53))	('rs2274223', 'Var', (55, 64))	('rs10509670', 'Var', (70, 80))	('associated', 'Reg', (82, 92))	('rs10509670', 'Var', (351, 361))	('rs2274223', 'Mutation', 'rs2274223', (236, 245))	('rs2274223', 'Var', (236, 245))	('rs10509670', 'Mutation', 'rs10509670', (70, 80))	('rs3765524', 'Var', (121, 130))	('rs3765524', 'Mutation', 'rs3765524', (44, 53))	('rs10509670', 'Mutation', 'rs10509670', (351, 361))
448634	30931333	Subblock 1 (r2 > 0.79) was composed of four tSNPs of rs3765524, rs3818432, rs2274223, and rs10509670, where the three risk SNPs identified above were included.	('rs3818432', 'Var', (64, 73))	('rs10509670', 'Var', (90, 100))	('rs2274223', 'Mutation', 'rs2274223', (75, 84))	('rs2274223', 'Var', (75, 84))	('rs3765524', 'Mutation', 'rs3765524', (53, 62))	('rs3818432', 'Mutation', 'rs3818432', (64, 73))	('rs10509670', 'Mutation', 'rs10509670', (90, 100))	('rs3765524', 'Var', (53, 62))
448635	30931333	Subblock 2 (r2 > 0.87) included the later three tSNPs of rs11187852, rs3781264, and rs11187866.	('rs11187866', 'Var', (84, 94))	('rs3781264', 'Var', (69, 78))	('rs11187852', 'Mutation', 'rs11187852', (57, 67))	('rs11187866', 'Mutation', 'rs11187866', (84, 94))	('rs11187852', 'Var', (57, 67))	('rs3781264', 'Mutation', 'rs3781264', (69, 78))
448638	30931333	Then we performed a stratified analysis to determine the association between the three tSNPs (rs3765524, rs2274223, and rs10509670) and clinicopathologic data in dominant model (Table 4).	('rs3765524', 'Mutation', 'rs3765524', (94, 103))	('rs10509670', 'Mutation', 'rs10509670', (120, 130))	('rs2274223', 'Mutation', 'rs2274223', (105, 114))	('rs2274223', 'Var', (105, 114))	('rs3765524', 'Var', (94, 103))	('rs10509670', 'Var', (120, 130))
448639	30931333	Significant association between the three tSNPs and risk of EC and GC was observed for subgroup patients of male, age >=54, tumor stages of I-II and tumor size <= 5 cm, EC and cardia cancer (CC), and moderate to well differentiated squamous carcinoma.	('squamous carcinoma', 'Disease', (232, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('moderate', 'CPA', (200, 208))	('cardia cancer', 'Disease', (176, 189))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (232, 250))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (149, 154))	('patients', 'Species', '9606', (96, 104))	('squamous carcinoma', 'Disease', 'MESH:D002294', (232, 250))	('cardia cancer', 'Disease', 'MESH:D004938', (176, 189))	('<= 5', 'Var', (160, 164))
448640	30931333	In addition, a significant association for rs3765524 with noncardia cancer (NCC) and adenocarcinoma was also observed.	('rs3765524', 'Var', (43, 52))	('noncardia cancer', 'Disease', (58, 74))	('adenocarcinoma', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('noncardia cancer', 'Disease', 'MESH:D009369', (58, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('rs3765524', 'Mutation', 'rs3765524', (43, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))	('association', 'Reg', (27, 38))
448641	30931333	Now that the association between PLCE1 polymorphisms and GC risk exhibited disparity according to the tumor subsites, we then evaluated the expression distribution of PLCE1 protein in human GC and adjacent noncancer tissues (ANC) by tissue microarray.	('polymorphisms', 'Var', (39, 52))	('PLCE1', 'Gene', (33, 38))	('PLCE1', 'Gene', '51196', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('PLCE1', 'Gene', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PLCE1', 'Gene', '51196', (167, 172))	('cancer', 'Disease', (209, 215))	('human', 'Species', '9606', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
448647	30931333	As presented in Figures 3(a)(i) and 3(a)(ii), compared with ANC tissues, the two procession units were both downregulated in NCC tissues (PLCE1A: 22 of 28, 78.57%, P = 0.034; PLCE1B: 21 of 28, 75.00%, P = 0.021), while there was no significant difference between genotype rs3765524 CC and rs3765524 CT/TT both in ANC (Figures 3(b)(i) and 3(b)(ii)) and in NCC (Figures 3(c)(i) and 3(c)(ii)).	('rs3765524 CC', 'Var', (272, 284))	('PLCE1', 'Gene', '51196', (175, 180))	('rs3765524', 'Mutation', 'rs3765524', (289, 298))	('PLCE1', 'Gene', (175, 180))	('rs3765524', 'Var', (289, 298))	('downregulated', 'NegReg', (108, 121))	('PLCE1', 'Gene', (138, 143))	('PLCE1', 'Gene', '51196', (138, 143))	('rs3765524', 'Mutation', 'rs3765524', (272, 281))
448648	30931333	For protein translation, immunohistochemistry (IHC) staining revealed that PLCE1 protein expression was generally downregulated in NCC than in their ANC tissues regardless of rs3765524 genotype (6 of 13, 46.15%, P = 0.018, see in Figures 4(a), 4(b), and 4(c)(i)).	('rs3765524', 'Mutation', 'rs3765524', (175, 184))	('rs3765524', 'Var', (175, 184))	('PLCE1', 'Gene', (75, 80))	('PLCE1', 'Gene', '51196', (75, 80))	('protein translation', 'MPA', (4, 23))	('downregulated', 'NegReg', (114, 127))	('NCC', 'Disease', (131, 134))	('protein', 'Protein', (81, 88))
448649	30931333	By genotyping, the PLCE1 protein expression was found higher in group of rs3765524 CT/TT than in group of rs3765524 CC both in ANC (Figure 4(c)(ii).	('rs3765524', 'Mutation', 'rs3765524', (73, 82))	('higher', 'PosReg', (54, 60))	('PLCE1', 'Gene', (19, 24))	('protein', 'Protein', (25, 32))	('PLCE1', 'Gene', '51196', (19, 24))	('rs3765524', 'Mutation', 'rs3765524', (106, 115))	('rs3765524 CT/TT', 'Var', (73, 88))	('expression', 'MPA', (33, 43))
448650	30931333	GWAS study found that some SNPs in PLCE1 corresponding to Y, C2, and RA domain were associated with the risk of EC and GC.	('PLCE1', 'Gene', '51196', (35, 40))	('RA', 'Chemical', 'MESH:D011883', (69, 71))	('SNPs', 'Var', (27, 31))	('associated', 'Reg', (84, 94))	('PLCE1', 'Gene', (35, 40))
448655	30931333	By referring to the frequencies of SNPs in Chinese Han population in HapMap database, after removing the SNPs with minimum allele frequency (MAF) less than 0.05, seven candidate SNPs in the region were selected in our study, where rs3765524 was in exon 24 and in Y domain, rs3818432 was in intron 24, rs2274223 was in exon 26 and in C2 domain, rs10509670 was in intron 26, rs11187852 and rs3781264 were in intron 27, and rs11187866 was in intron 32.	('rs11187866', 'Var', (421, 431))	('rs11187852', 'Var', (373, 383))	('rs3765524', 'Var', (231, 240))	('rs2274223', 'Mutation', 'rs2274223', (301, 310))	('rs3765524', 'Mutation', 'rs3765524', (231, 240))	('rs2274223', 'Var', (301, 310))	('rs11187852', 'Mutation', 'rs11187852', (373, 383))	('rs10509670', 'Var', (344, 354))	('rs3818432', 'Mutation', 'rs3818432', (273, 282))	('rs11187866', 'Mutation', 'rs11187866', (421, 431))	('rs3781264', 'Var', (388, 397))	('rs3781264', 'Mutation', 'rs3781264', (388, 397))	('rs10509670', 'Mutation', 'rs10509670', (344, 354))	('rs3818432', 'Var', (273, 282))
448656	30931333	By genotyping and logistic regression, we not only confirmed the two previous reported SNPs of rs3765524 and rs2274223 but also revealed that another SNP of rs10509670 in PLCE1 was associated with the risk of EC and GC susceptibility.	('rs10509670', 'Var', (157, 167))	('associated', 'Reg', (181, 191))	('rs3765524', 'Var', (95, 104))	('rs10509670', 'Mutation', 'rs10509670', (157, 167))	('PLCE1', 'Gene', (171, 176))	('rs3765524', 'Mutation', 'rs3765524', (95, 104))	('rs2274223', 'Var', (109, 118))	('PLCE1', 'Gene', '51196', (171, 176))	('rs2274223', 'Mutation', 'rs2274223', (109, 118))
448657	30931333	rs3765524 C>T causes an amino acid change from Thr to Ile (ACC1777ATC), and rs2274223 A>G can also cause a missense mutation of His to Arg (CAC1927CGC).	('cause', 'Reg', (99, 104))	('CAC1927CGC', 'Mutation', 'c.1927CAC>CGC', (140, 150))	('amino acid change', 'MPA', (24, 41))	('Thr', 'Chemical', 'MESH:D013912', (47, 50))	('rs3765524 C>T', 'Var', (0, 13))	('Arg', 'Chemical', 'MESH:D001120', (135, 138))	('rs2274223 A>G', 'Var', (76, 89))	('His', 'Chemical', 'MESH:D006639', (128, 131))	('ACC1777ATC', 'Mutation', 'c.1777ACC>ATC', (59, 69))	('rs3765524', 'Mutation', 'rs3765524', (0, 9))	('Ile', 'Chemical', 'MESH:D007532', (54, 57))	('rs2274223', 'Mutation', 'rs2274223', (76, 85))
448659	30931333	We noticed that Thr, His, and Arg are frequently modified amino acid residues in human proteins.	('Thr', 'Chemical', 'MESH:D013912', (16, 19))	('Thr', 'Var', (16, 19))	('His', 'Chemical', 'MESH:D006639', (21, 24))	('His', 'Var', (21, 24))	('Arg', 'Var', (30, 33))	('Arg', 'Chemical', 'MESH:D001120', (30, 33))	('human', 'Species', '9606', (81, 86))
448661	30931333	In the case of rs3765524, we found that although there was no difference in mRNA transcription between wild type and mutant type (Figure 3), there was a difference in protein expression (Figure 4).	('rs3765524', 'Mutation', 'rs3765524', (15, 24))	('rs3765524', 'Var', (15, 24))	('protein expression', 'MPA', (167, 185))	('mRNA transcription', 'MPA', (76, 94))	('difference', 'Reg', (153, 163))
448662	30931333	Among them, the expression of CT/TT genotype was higher than that of CC genotype in both NCC and ANC groups, implying that the amino acid change by the polymorphism of rs3765524 might lead to different protein modifications or structural changes, ultimately affecting PLCE1 expression or stability.	('expression', 'MPA', (274, 284))	('stability', 'MPA', (288, 297))	('PLCE1', 'Gene', '51196', (268, 273))	('rs3765524', 'Mutation', 'rs3765524', (168, 177))	('structural', 'MPA', (227, 237))	('rs3765524', 'Var', (168, 177))	('protein modifications', 'MPA', (202, 223))	('PLCE1', 'Gene', (268, 273))	('affecting', 'Reg', (258, 267))	('higher', 'PosReg', (49, 55))	('expression', 'MPA', (16, 26))	('lead to', 'Reg', (184, 191))	('amino acid', 'MPA', (127, 137))
448663	30931333	The third loci of rs10509670 located in the intron of PLCE1 gene has also shown to be associated with risk of EC and GC in the experiment.	('rs10509670', 'Var', (18, 28))	('associated', 'Reg', (86, 96))	('PLCE1', 'Gene', (54, 59))	('PLCE1', 'Gene', '51196', (54, 59))	('rs10509670', 'Mutation', 'rs10509670', (18, 28))
448664	30931333	We hypothesize that rs10509670 A>G may affect PLCE1 gene structure or expression by regulating gene splicing or transcription.	('rs10509670 A>G', 'Var', (20, 34))	('PLCE1', 'Gene', (46, 51))	('PLCE1', 'Gene', '51196', (46, 51))	('structure', 'MPA', (57, 66))	('affect', 'Reg', (39, 45))	('rs10509670', 'Mutation', 'rs10509670', (20, 30))	('expression', 'MPA', (70, 80))	('regulating', 'Reg', (84, 94))	('gene splicing', 'MPA', (95, 108))	('transcription', 'MPA', (112, 125))
448666	30931333	Previous studies have exhibited different associations between PLCE1 polymorphisms and the risk of EC and GC, especially for different tumor subsites of GC in several candidate-gene studies.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('polymorphisms', 'Var', (69, 82))	('PLCE1', 'Gene', (63, 68))	('PLCE1', 'Gene', '51196', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
448667	30931333	The latest large meta-analyses confirmed the G allele of PLCE1 rs2274223 to be associated with an increased risk of cardia cancer (CC) rather than noncardia cancer (NCC).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PLCE1', 'Gene', (57, 62))	('cardia cancer', 'Disease', 'MESH:D004938', (116, 129))	('cardia cancer', 'Disease', 'MESH:D004938', (150, 163))	('PLCE1', 'Gene', '51196', (57, 62))	('cardia cancer', 'Disease', (116, 129))	('rs2274223', 'Mutation', 'rs2274223', (63, 72))	('noncardia cancer', 'Disease', (147, 163))	('rs2274223', 'Var', (63, 72))	('noncardia cancer', 'Disease', 'MESH:D009369', (147, 163))
448668	30931333	In our stratification analysis, we not only confirmed the T allele of rs3765524 and G allele of rs2274223 but also identified that the G allele of rs10509670 was associated with increased risk of EC and CC susceptibility.	('rs2274223', 'Mutation', 'rs2274223', (96, 105))	('rs2274223', 'Var', (96, 105))	('rs10509670', 'Var', (147, 157))	('rs3765524', 'Mutation', 'rs3765524', (70, 79))	('rs10509670', 'Mutation', 'rs10509670', (147, 157))	('rs3765524', 'Var', (70, 79))
448669	30931333	Furthermore, we revealed a significant association of rs3765524 C>T with the increased risk of NCC and adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('rs3765524 C>T', 'Var', (54, 67))	('rs3765524', 'Mutation', 'rs3765524', (54, 63))	('adenocarcinoma', 'Disease', (103, 117))	('association', 'Reg', (39, 50))	('adenocarcinoma', 'Disease', 'MESH:D000230', (103, 117))	('NCC', 'Disease', (95, 98))
448674	30931333	In terms of the comparison of minor-major alleles of rs2274223 with PLCE1 expression, the results for EC were also inconsistent, and there is no report about CC and NCC until now.	('PLCE1', 'Gene', (68, 73))	('rs2274223', 'Mutation', 'rs2274223', (53, 62))	('PLCE1', 'Gene', '51196', (68, 73))	('rs2274223', 'Var', (53, 62))
448677	30931333	This result, together with the association of rs3765524 C>T with NCC risk, suggests that PLCE1 protein may be involved in carcinogenesis of NCC.	('rs3765524 C>T', 'Var', (46, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))	('rs3765524', 'Mutation', 'rs3765524', (46, 55))	('NCC', 'Disease', (140, 143))	('carcinogenesis', 'Disease', (122, 136))	('NCC', 'Disease', (65, 68))	('involved', 'Reg', (110, 118))	('PLCE1', 'Gene', (89, 94))	('PLCE1', 'Gene', '51196', (89, 94))	('protein', 'Protein', (95, 102))
448680	30931333	We also found that rs3765524 genotype may affect PLCE1 expression, where PLCE1 expression was higher in group of rs3765524 CT/TT than in group of CC.	('affect', 'Reg', (42, 48))	('rs3765524', 'Var', (113, 122))	('PLCE1', 'Gene', '51196', (49, 54))	('PLCE1', 'Gene', (73, 78))	('expression', 'MPA', (79, 89))	('PLCE1', 'Gene', '51196', (73, 78))	('rs3765524', 'Mutation', 'rs3765524', (19, 28))	('expression', 'MPA', (55, 65))	('rs3765524', 'Mutation', 'rs3765524', (113, 122))	('higher', 'PosReg', (94, 100))	('rs3765524', 'Var', (19, 28))	('PLCE1', 'Gene', (49, 54))
448681	30931333	This strongly suggests, as one of the contributors, the reference allele C of rs3765524 loss of expression in tumor, but the mutated T allele, on the other hand, produces a "dominant negative" phenotype, which is related to the increased risk of NCC.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('expression', 'MPA', (96, 106))	('rs3765524', 'Mutation', 'rs3765524', (78, 87))	('loss of', 'NegReg', (88, 95))	('NCC', 'Disease', (246, 249))	('rs3765524', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
448683	30931333	PLCE1A and PLCE1B arise from alternative splicing at the amino terminus of PLCE1 protein.	('alternative splicing', 'Var', (29, 49))	('PLCE1', 'Gene', (75, 80))	('PLCE1', 'Gene', '51196', (75, 80))	('PLCE1', 'Gene', (0, 5))	('PLCE1', 'Gene', '51196', (0, 5))	('PLCE1', 'Gene', (11, 16))	('PLCE1', 'Gene', '51196', (11, 16))
448689	30931333	Our study reveals that PLCE1 polymorphisms may affect gene expression and function and are associated with the risk of not only EC and CC, but also, to some extent, NCC in northwestern Chinese population.	('gene expression', 'MPA', (54, 69))	('NCC', 'Disease', (165, 168))	('PLCE1', 'Gene', (23, 28))	('PLCE1', 'Gene', '51196', (23, 28))	('affect', 'Reg', (47, 53))	('polymorphisms', 'Var', (29, 42))	('function', 'MPA', (74, 82))	('associated', 'Reg', (91, 101))
448698	30221248	This trial included individuals with T1N1 or T2-3N0-1 esophageal cancer (75% adenocarcinoma, 23% squamous cell carcinoma).	('T1N1', 'Var', (37, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('T2-3N0-1 esophageal cancer', 'Disease', (45, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('T2-3N0-1 esophageal cancer', 'Disease', 'MESH:C535434', (45, 71))	('squamous cell carcinoma', 'Disease', (97, 120))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 120))	('adenocarcinoma', 'Disease', (77, 91))
448703	30221248	It provides an important understanding of the symptomatic differences between treatment modalities: namely that patients can expect a transient worsening in all functional measures following nCRT, but they can also expect to return to the symptom profile otherwise expected after surgery alone by 3 months.	('functional measures', 'MPA', (161, 180))	('worsening', 'NegReg', (144, 153))	('nCRT', 'Var', (191, 195))	('patients', 'Species', '9606', (112, 120))
448735	28640357	Molecular genetic studies of EAC have revealed that mutations in key cancer-causing genes, such as TP53, CDKN2A, and SMAD4, are involved in the genesis and advancement of EAC.	('mutations', 'Var', (52, 61))	('TP53', 'Gene', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('CDKN2A', 'Gene', (105, 111))	('SMAD4', 'Gene', '4089', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CDKN2A', 'Gene', '1029', (105, 111))	('TP53', 'Gene', '7157', (99, 103))	('involved', 'Reg', (128, 136))	('EAC', 'Disease', (171, 174))	('SMAD4', 'Gene', (117, 122))	('cancer', 'Disease', (69, 75))
448738	28640357	Notably, fusion genes can also serve as diagnostic markers and therapeutic targets, as shown for FGFR3-TACC3 fusions in glioblastoma and EML4-ALK fusions in lung cancer.	('fusions', 'Var', (146, 153))	('EML4', 'Gene', (137, 141))	('ALK', 'Gene', '238', (142, 145))	('TACC3', 'Gene', '10460', (103, 108))	('lung cancer', 'Disease', (157, 168))	('glioblastoma', 'Disease', (120, 132))	('FGFR3', 'Gene', '2261', (97, 102))	('glioblastoma', 'Disease', 'MESH:D005909', (120, 132))	('TACC3', 'Gene', (103, 108))	('fusions', 'Var', (109, 116))	('EML4', 'Gene', '27436', (137, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('FGFR3', 'Gene', (97, 102))	('ALK', 'Gene', (142, 145))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))
448750	28640357	The TruSight RNA Pan-Cancer panel is a targeted sequencing strategy that enables measurement of gene expression, variant calling, and fusion detection of cancer-related genes with limited sample quantity.	('Pan-Cancer', 'Disease', 'MESH:C537931', (17, 27))	('variant', 'Var', (113, 120))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('Pan-Cancer', 'Disease', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
448751	28640357	This approach has the ability to detect fusions between any of the 1385 genes in the panel, but also between any of these genes and other novel fusion partners, for instance FGFR1-X fusions, where X is any possible gene.	('fusions', 'Var', (40, 47))	('detect', 'Reg', (33, 39))	('FGFR1', 'Gene', (174, 179))	('FGFR1', 'Gene', '2260', (174, 179))	('fusions', 'Var', (182, 189))
448774	28640357	Fusion events involving FGFR2 are frequent in human solid tumors, including intrahepatic cholangiocarcinoma (iCCA), glioblastoma, breast, lung and prostate cancers - e.g., FGFR2-PPHLN1, FGFR2-BICC1, and FGFR2-CCDC6 .	('FGFR2', 'Gene', (172, 177))	('prostate cancer', 'Phenotype', 'HP:0012125', (147, 162))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('FGFR2', 'Gene', (186, 191))	('lung and prostate cancers', 'Disease', 'MESH:D011471', (138, 163))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 107))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('frequent', 'Reg', (34, 42))	('intrahepatic cholangiocarcinoma', 'Disease', (76, 107))	('PPHLN1', 'Gene', (178, 184))	('CCDC6', 'Gene', '8030', (209, 214))	('CCDC6', 'Gene', (209, 214))	('prostate cancers', 'Phenotype', 'HP:0012125', (147, 163))	('FGFR2', 'Gene', '2263', (172, 177))	('FGFR2', 'Gene', '2263', (203, 208))	('glioblastoma', 'Disease', (116, 128))	('FGFR2', 'Gene', '2263', (186, 191))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('human', 'Species', '9606', (46, 51))	('breast', 'Disease', (130, 136))	('FGFR2', 'Gene', (24, 29))	('BICC1', 'Gene', '80114', (192, 197))	('PPHLN1', 'Gene', '51535', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('BICC1', 'Gene', (192, 197))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Fusion', 'Var', (0, 6))	('FGFR2', 'Gene', '2263', (24, 29))	('tumors', 'Disease', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('FGFR2', 'Gene', (203, 208))
448775	28640357	In the current study, two of 55 EAC patients, EAC3869 and EAC5061, were validated by PCR to be harboring the FGFR2-GAB2 fusion transcript (Figures 1C and D).	('patients', 'Species', '9606', (36, 44))	('GAB2', 'Gene', (115, 119))	('EAC', 'Disease', (32, 35))	('EAC3869', 'Var', (46, 53))	('EAC5061', 'Var', (58, 65))	('FGFR2', 'Gene', (109, 114))	('FGFR2', 'Gene', '2263', (109, 114))	('GAB2', 'Gene', '9846', (115, 119))
448778	28640357	Given the high frequency of fusion events involving FGFR2 in other cancer types, we conclude that the FGFR2-GAB2 fusion transcript reported here likely resulted from a genomic DNA rearrangement.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('FGFR2', 'Gene', (52, 57))	('FGFR2', 'Gene', '2263', (52, 57))	('cancer', 'Disease', (67, 73))	('fusion', 'Var', (113, 119))	('GAB2', 'Gene', (108, 112))	('resulted from', 'Reg', (152, 165))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('FGFR2', 'Gene', (102, 107))	('GAB2', 'Gene', '9846', (108, 112))	('FGFR2', 'Gene', '2263', (102, 107))
448782	28640357	One fragment consisted of partial intron 3 and partial exon 4 of MDM2, located on chromosome 3, while the other fragment comprised a partial antisense isoform of MELK (Figure 3C).	('partial exon 4', 'Var', (47, 61))	('MDM2', 'Gene', '4193', (65, 69))	('MDM2', 'Gene', (65, 69))	('MELK', 'Gene', (162, 166))	('MELK', 'Gene', '9833', (162, 166))
448785	28640357	Additionally, the two samples harboring NPC1-MELK (EAC3253-T and EAC3274-T) also contained other fusion transcripts, as shown in Figure 1C, suggesting that EAC3253-T and EAC3274-T were subject to complex chromosomal rearrangements having at least three fusion points involving more than a single chromosome.	('NPC1', 'Gene', '4864', (40, 44))	('NPC1', 'Gene', (40, 44))	('EAC3253-T', 'Var', (156, 165))	('EAC3274-T', 'Var', (170, 179))	('MELK', 'Gene', (45, 49))	('EAC3274-T', 'CellLine', 'CVCL:9P12', (65, 74))	('MELK', 'Gene', '9833', (45, 49))	('subject', 'Reg', (185, 192))	('EAC3274-T', 'CellLine', 'CVCL:9P12', (170, 179))
448786	28640357	In addition, both patients had advanced tumors (T4N2M0 and T3aN1M0, respectively).	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('T3aN1M0', 'Var', (59, 66))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
448788	28640357	Chromosomal rearrangements are a hallmark of carcinogenesis in many human tumor types.	('human', 'Species', '9606', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('tumor', 'Disease', (74, 79))	('carcinogenesis', 'Disease', (45, 59))	('Chromosomal rearrangements', 'Var', (0, 26))
448789	28640357	Recently, several large cohort studies based on next-generation sequencing have reported high-frequency chromosomal rearrangements in esophageal adenocarcinoma (EAC) .	('chromosomal rearrangements', 'Var', (104, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (134, 159))	('esophageal adenocarcinoma', 'Disease', (134, 159))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (134, 159))
448792	28640357	FGFR2 fusion events have been recently described in multiple cancer types, including glioblastoma, iCCA, bladder, lung, breast and prostate cancers.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('breast and prostate cancers', 'Disease', 'MESH:D011471', (120, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('fusion', 'Var', (6, 12))	('lung', 'Disease', (114, 118))	('prostate cancers', 'Phenotype', 'HP:0012125', (131, 147))	('iCCA', 'Disease', (99, 103))	('glioblastoma', 'Disease', (85, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('FGFR2', 'Gene', (0, 5))	('cancer', 'Disease', (61, 67))	('bladder', 'Disease', (105, 112))	('cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('FGFR2', 'Gene', '2263', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('described', 'Reg', (39, 48))
448794	28640357	FGFR2 fusions are, in fact, the most recurrent chromosomal rearrangements in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('FGFR2', 'Gene', (0, 5))	('fusions', 'Var', (6, 13))	('FGFR2', 'Gene', '2263', (0, 5))	('human', 'Species', '9606', (77, 82))
448796	28640357	However, the FGFR2-GAB2 fusion found in this study was a low-frequency event, being detected in only 2 of 55 (3.6%) patients with EAC, suggesting that different cancer types may be unique in this regard.	('GAB2', 'Gene', '9846', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('fusion', 'Var', (24, 30))	('patients', 'Species', '9606', (116, 124))	('GAB2', 'Gene', (19, 23))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('EAC', 'Disease', (130, 133))	('FGFR2', 'Gene', '2263', (13, 18))	('cancer', 'Disease', (161, 167))	('FGFR2', 'Gene', (13, 18))
448801	28640357	Interestingly, nine of ten FGFR2 fusions reported to date involve the same breakpoint (exon 19) and contain the principal functional domain of WT FGFR2.	('FGFR2', 'Gene', (27, 32))	('FGFR2', 'Gene', '2263', (27, 32))	('FGFR2', 'Gene', (146, 151))	('FGFR2', 'Gene', '2263', (146, 151))	('fusions', 'Var', (33, 40))
448806	28640357	According to the findings of FGFR2 fusion genes in previous studies as well as our own, the breakpoint location of FGFR2 rearrangements are stable in intron 19.	('FGFR2', 'Gene', (115, 120))	('FGFR2', 'Gene', '2263', (115, 120))	('FGFR2', 'Gene', '2263', (29, 34))	('FGFR2', 'Gene', (29, 34))	('rearrangements', 'Var', (121, 135))
448812	28640357	In addition, drug targeting of FGFR2 fusions has proven to be an effective therapeutic approach in certain cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('FGFR2', 'Gene', '2263', (31, 36))	('FGFR2', 'Gene', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('fusions', 'Var', (37, 44))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
448814	28640357	Thus, FGFR2-GAB2 may represent a potential target of FGFR2 inhibitors in EAC patients; this possibility merits further study.	('EAC', 'Disease', (73, 76))	('GAB2', 'Gene', '9846', (12, 16))	('patients', 'Species', '9606', (77, 85))	('GAB2', 'Gene', (12, 16))	('FGFR2', 'Gene', (53, 58))	('inhibitors', 'Var', (59, 69))	('FGFR2', 'Gene', '2263', (53, 58))	('FGFR2', 'Gene', '2263', (6, 11))	('FGFR2', 'Gene', (6, 11))
448831	28640357	In conclusion, we discovered and validated five novel fusion transcripts in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (76, 101))	('fusion transcripts', 'Var', (54, 72))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (76, 101))
448835	28406985	Metformin with low cost and toxicity has proved to have anti-cancer effects in  numerous cancers, while its role and mechanism in ESCC has seldom been studied.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('numerous cancers', 'Disease', (80, 96))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Metformin', 'Var', (0, 9))	('toxicity', 'Disease', 'MESH:D064420', (28, 36))	('toxicity', 'Disease', (28, 36))	('cancer', 'Disease', (89, 95))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('numerous cancers', 'Disease', 'MESH:D009369', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
448837	28406985	Our in vivo experiment also showed that metformin markedly inhibited KYSE450 xenograft tumors growth compared to those treated with normal saline.	('xenograft tumors growth', 'Disease', 'MESH:D006130', (77, 100))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('metformin', 'Chemical', 'MESH:D008687', (40, 49))	('inhibited', 'NegReg', (59, 68))	('xenograft tumors growth', 'Disease', (77, 100))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('KYSE450', 'CellLine', 'CVCL:1353', (69, 76))	('metformin', 'Var', (40, 49))
448849	28406985	Many studies have shown that cancer in diabetics treated with metformin have a lower incidence and mortality rate than those without.	('cancer', 'Disease', (29, 35))	('diabetics', 'Disease', (39, 48))	('incidence', 'CPA', (85, 94))	('lower', 'NegReg', (79, 84))	('metformin', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('metformin', 'Chemical', 'MESH:D008687', (62, 71))	('mortality rate', 'CPA', (99, 113))	('diabetics', 'Disease', 'MESH:D003920', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
448851	28406985	In addition, Bowler et al also found lower mortality rate for patients with metformin verse those with sulfonylurea.	('metformin', 'Var', (76, 85))	('mortality rate', 'MPA', (43, 57))	('lower', 'NegReg', (37, 42))	('patients', 'Species', '9606', (62, 70))	('metformin', 'Chemical', 'MESH:D008687', (76, 85))
448853	28406985	Furthermore, a number of studies have confirmed that metformin inhibited the proliferation ability of EC, lung cancer, gastric cancer and others in vitro and in vivo.	('proliferation ability', 'CPA', (77, 98))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', (106, 117))	('metformin', 'Chemical', 'MESH:D008687', (53, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric cancer', 'Disease', (119, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('inhibited', 'NegReg', (63, 72))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('metformin', 'Var', (53, 62))
448860	28406985	In some kinds of cancers, metformin could dampen tumorigenicity via inhibition of mTOR signaling pathway.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('metformin', 'Chemical', 'MESH:D008687', (26, 35))	('tumor', 'Disease', (49, 54))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('mTOR', 'Gene', (82, 86))	('inhibition', 'NegReg', (68, 78))	('mTOR', 'Gene', '2475', (82, 86))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('dampen', 'NegReg', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('metformin', 'Var', (26, 35))
448933	28406985	After xenograft tumors were taken out, it was obvious that those treated with metformin for consecutively 15 days were smaller than those treated with normal saline (Fig 3A).	('xenograft tumors', 'Disease', 'MESH:D009369', (6, 22))	('smaller', 'NegReg', (119, 126))	('metformin', 'Chemical', 'MESH:D008687', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('xenograft tumors', 'Disease', (6, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('metformin', 'Var', (78, 87))
448937	28406985	The results of TUNNL showed that the rate of apoptosis in metformin group was greater than those in control group.	('apoptosis', 'CPA', (45, 54))	('metformin', 'Chemical', 'MESH:D008687', (58, 67))	('metformin', 'Var', (58, 67))
448939	28406985	Taken together, metformin inhibited xenograft tumor growth in vivo.	('metformin', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('metformin', 'Chemical', 'MESH:D008687', (16, 25))	('inhibited', 'NegReg', (26, 35))	('xenograft tumor', 'Disease', 'MESH:D009369', (36, 51))	('xenograft tumor', 'Disease', (36, 51))
448941	28406985	Consistent with the results in vitro, the expression of 4EBP1 and S6K1 were all markedly reduced in tumors treated with metformin than those treated with normal saline (Fig 4A, 4B, 4C and 4D).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('metformin', 'Var', (120, 129))	('4EBP1', 'Gene', (56, 61))	('metformin', 'Chemical', 'MESH:D008687', (120, 129))	('expression', 'MPA', (42, 52))	('S6K1', 'Gene', '6198', (66, 70))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('S6K1', 'Gene', (66, 70))	('reduced', 'NegReg', (89, 96))	('4EBP1', 'Gene', '1978', (56, 61))
448965	28406985	A number of meta analyses had found that metformin could reduce the incidence and mortality of cancer in patients with type 2 diabetes, and improve the prognosis of patients with cancer.	('type 2 diabetes', 'Disease', (119, 134))	('prognosis', 'CPA', (152, 161))	('reduce', 'NegReg', (57, 63))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('improve', 'PosReg', (140, 147))	('mortality', 'CPA', (82, 91))	('cancer', 'Disease', (95, 101))	('metformin', 'Var', (41, 50))	('type 2 diabetes', 'Disease', 'MESH:D003924', (119, 134))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (119, 134))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('patients', 'Species', '9606', (165, 173))	('metformin', 'Chemical', 'MESH:D008687', (41, 50))	('cancer', 'Disease', (179, 185))
448970	28406985	Sesen et al reported that metformin significantly reduced human glioma cell proliferation, the number of GB cells undergoing division and enhanced cell cycle arrest.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('cell cycle arrest', 'CPA', (147, 164))	('human', 'Species', '9606', (58, 63))	('metformin', 'Chemical', 'MESH:D008687', (26, 35))	('enhanced', 'PosReg', (138, 146))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (147, 164))	('glioma', 'Disease', (64, 70))	('reduced', 'NegReg', (50, 57))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('metformin', 'Var', (26, 35))
448972	28406985	Consistent with these previous reports, we showed that metformin inhibited ESCC cell proliferation and increased cell apoptosis efficiently.	('metformin', 'Chemical', 'MESH:D008687', (55, 64))	('increased', 'PosReg', (103, 112))	('cell apoptosis', 'CPA', (113, 127))	('ESCC', 'Disease', (75, 79))	('inhibited', 'NegReg', (65, 74))	('metformin', 'Var', (55, 64))
448974	28406985	We showed that daily treatment of xenograft tumor of KYSE540 with metformin (5.75 mg/kg/d) markedly reduced tumor growth compared to those treated with normal saline.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('KYSE540', 'Var', (53, 60))	('xenograft tumor', 'Disease', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('reduced', 'NegReg', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('xenograft tumor', 'Disease', 'MESH:D009369', (34, 49))	('metformin', 'Chemical', 'MESH:D008687', (66, 75))	('tumor', 'Disease', (44, 49))
448985	28406985	The average density of stain both S6K1 and 4EBP1 in xenograft tumor treated with metformin was weaker than those in xenograft tumor treated with normal saline.	('metformin', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('weaker', 'NegReg', (95, 101))	('xenograft tumor', 'Disease', 'MESH:D009369', (52, 67))	('xenograft tumor', 'Disease', (116, 131))	('metformin', 'Chemical', 'MESH:D008687', (81, 90))	('xenograft tumor', 'Disease', 'MESH:D009369', (116, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('S6K1 and 4EBP1', 'Gene', '6198', (34, 48))	('xenograft tumor', 'Disease', (52, 67))	('density', 'MPA', (12, 19))
448995	28406985	In summary, this study highlighted a new effect of metformin in its anti-cancer action in ESCC and indicated that metformin inhibited the proliferation and promoted the apoptosis markedly in ESCC cell line: KYSE450.	('cancer', 'Disease', (73, 79))	('apoptosis', 'CPA', (169, 178))	('KYSE450', 'CellLine', 'CVCL:1353', (207, 214))	('metformin', 'Chemical', 'MESH:D008687', (114, 123))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('proliferation', 'CPA', (138, 151))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('metformin', 'Var', (114, 123))	('ESCC', 'Disease', (90, 94))	('inhibited', 'NegReg', (124, 133))	('metformin', 'Chemical', 'MESH:D008687', (51, 60))	('promoted', 'PosReg', (156, 164))
449094	27073394	The 3- and 5-year survival rates were likely lower in the heavy smoking group, especially in patients treated by chemoradiotherapy (HR = 2.43, 95% CI 1.38-4.27, p = 0.002).	('lower', 'NegReg', (45, 50))	('heavy smoking', 'Var', (58, 71))	('patients', 'Species', '9606', (93, 101))
449110	27073394	showed that smoking can also cause tumor hypoxia, affecting its sensitivity to chemotherapy.	('sensitivity to chemotherapy', 'MPA', (64, 91))	('smoking', 'Var', (12, 19))	('affecting', 'Reg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor hypoxia', 'Disease', (35, 48))	('tumor hypoxia', 'Disease', 'MESH:D000860', (35, 48))	('cause', 'Reg', (29, 34))
449111	27073394	So, we speculate that smoking not only is inducing malignant transformation of normal cells but may also change tumor cell gene or related metabolic activity and thus make tumor cells more aggressive and have poorer sensitivity to radiotherapy and chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('malignant transformation', 'CPA', (51, 75))	('aggressive', 'CPA', (189, 199))	('more', 'PosReg', (184, 188))	('tumor', 'Disease', (172, 177))	('inducing', 'Reg', (42, 50))	('smoking', 'Var', (22, 29))	('make', 'Reg', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('metabolic activity', 'MPA', (139, 157))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('change', 'Reg', (105, 111))
449152	26303127	Typical IMRT lung planning goals included a V20<35%, a mean lung dose<20 Gy, and a lung V5<65-70%, although patients were still treated at physician discretion when these constraints could not be achieved.	('patients', 'Species', '9606', (108, 116))	('lung', 'MPA', (60, 64))	('V20<35%', 'Var', (44, 51))
449178	26303127	Use of staging PET-CT was significantly higher among IMRT (n=37, 100%) and 3DCRT-IFRT patients (n=38, 88.4%) compared to 3DCRT-ENI patients (n=40, 61.5%) (p<0.001).	('patients', 'Species', '9606', (131, 139))	('ENI', 'Chemical', '-', (127, 130))	('higher', 'PosReg', (40, 46))	('3DCRT-IFRT', 'Var', (75, 85))	('patients', 'Species', '9606', (86, 94))
449185	26303127	The median PTV (using the boost PTV volume for 3DCRT-ENI plans) for all patients was 461.1 cc (range: 63.5-1404.7), with a smaller median PTV for the ENI group (406.0 cc; range: 63.5-628.1) compared to the IMRT group (515 cc; range: 170-1182) (p=0.02) and a trend toward reduced volume compared to the IFRT group (433 cc; range: 137-1405) (p=0.06).	('ENI', 'Var', (150, 153))	('reduced', 'NegReg', (271, 278))	('smaller', 'NegReg', (123, 130))	('ENI', 'Chemical', '-', (53, 56))	('volume', 'MPA', (279, 285))	('ENI', 'Chemical', '-', (150, 153))	('patients', 'Species', '9606', (72, 80))
449186	26303127	3DCRT-ENI plans were dosimetrically inferior, with a higher mean cardiac dose compared to IMRT (p=0.007) and a trend toward higher cardiac dose compared to 3D-IFRT (p=0.08).	('higher', 'PosReg', (53, 59))	('ENI', 'Chemical', '-', (6, 9))	('cardiac dose', 'MPA', (65, 77))	('cardiac dose', 'MPA', (131, 143))	('higher', 'PosReg', (124, 130))	('3DCRT-ENI', 'Var', (0, 9))
449187	26303127	3DCRT-ENI also resulted in a higher maximum spinal cord dose compared to both 3DCRT-IFRT (p=0.0003) and IMRT (p<0.0001).	('3DCRT-ENI', 'Var', (0, 9))	('ENI', 'Chemical', '-', (6, 9))	('spinal cord dose', 'MPA', (44, 60))
449193	26303127	We demonstrated the expected reductions in heart and spinal cord dose with the omission of ENI, but did not clearly identify dosimetric differences between 3DCRT-IFRT and IMRT.	('ENI', 'Gene', (91, 94))	('reductions', 'NegReg', (29, 39))	('omission', 'Var', (79, 87))	('ENI', 'Chemical', '-', (91, 94))	('heart and', 'MPA', (43, 52))
449194	26303127	The median PTV size was larger among IMRT patients, likely reflecting selection bias for use of IMRT for larger or more advanced tumors and suggesting IMRT may allow safe delivery of thoracic radiotherapy for patients with larger target volumes, although the size difference between IMRT and 3DCRT-IFRT did not reach statistical significance.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('IMRT', 'Var', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (42, 50))	('larger', 'PosReg', (24, 30))
449289	26336413	A tendency toward lower postoperative mortality among patients undergoing MIE/HMIE was found in both groups.	('MIE', 'Chemical', '-', (79, 82))	('postoperative mortality', 'MPA', (24, 47))	('MIE/HMIE', 'Var', (74, 82))	('patients', 'Species', '9606', (54, 62))	('lower', 'NegReg', (18, 23))	('MIE', 'Chemical', '-', (74, 77))	('HMIE', 'Chemical', '-', (78, 82))
449295	26336413	The patients after MIE were hospitalized for shorter periods of time, exhibited lower blood loss, and suffered from fewer pulmonary and postoperative complications in total.	('pulmonary', 'Disease', 'MESH:D008171', (122, 131))	('blood loss', 'Disease', (86, 96))	('pulmonary', 'Disease', (122, 131))	('MIE', 'Chemical', '-', (19, 22))	('lower', 'NegReg', (80, 85))	('MIE', 'Var', (19, 22))	('patients', 'Species', '9606', (4, 12))	('blood loss', 'Disease', 'MESH:D006473', (86, 96))
449386	24475043	However, it has been reported that the success rate of tumor growth by the implantation of VX2 fragments was higher than by inoculation with intact VX2 cells in organs such as the liver and the lung.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('fragments', 'Var', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('higher', 'PosReg', (109, 115))	('tumor', 'Disease', (55, 60))	('VX2', 'Gene', (91, 94))
449455	22713587	Grade 3 treatment-related gastritis were observed in 6 patients (27.3%) and 7 patients (25.0%) in the R-FP and R-TP group, respectively.	('gastritis', 'Phenotype', 'HP:0005263', (26, 35))	('-TP', 'Chemical', 'MESH:C011314', (112, 115))	('R-FP', 'Var', (102, 106))	('R-FP', 'Chemical', 'MESH:D012293', (102, 106))	('patients', 'Species', '9606', (78, 86))	('gastritis', 'Disease', (26, 35))	('patients', 'Species', '9606', (55, 63))	('gastritis', 'Disease', 'MESH:D005756', (26, 35))
449466	22713587	The tumor response rate was nearly 72% in R-TP and R-FP group respectively, with a 3-year survival rate of 14%.	('tumor', 'Disease', (4, 9))	('-TP', 'Chemical', 'MESH:C011314', (43, 46))	('R-FP', 'Var', (51, 55))	('R-FP', 'Chemical', 'MESH:D012293', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('R-TP', 'Var', (42, 46))
449468	22713587	from Princess Alexandra Hospital reported their treatment outcomes using DDP and 5-FU plus radiotherapy (range: 45-60 Gy) for recurrent esophageal cancer.	('esophageal cancer', 'Disease', (136, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('5-FU', 'Chemical', 'MESH:D005472', (81, 85))	('DDP', 'Var', (73, 76))	('DDP', 'Chemical', 'MESH:D002945', (73, 76))
449473	22713587	By sub-group analysis in the present study, the median OS of the 28 patients received R-TP regimen (16.3 months) was significantly superior than that of other patients who received R-FP regimen (9.8 months) (p < 0.05).	('R-TP regimen', 'Var', (86, 98))	('superior', 'PosReg', (131, 139))	('R-FP', 'Chemical', 'MESH:D012293', (181, 185))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (159, 167))	('-TP', 'Chemical', 'MESH:C011314', (87, 90))
449488	22713587	In the present study, grade 3 treatment-related gastritis were recorded in 6 patients (27.3%) and 7 patients (25.0%) in the R-FP and R-TP group, respectively.	('gastritis', 'Disease', 'MESH:D005756', (48, 57))	('-TP', 'Chemical', 'MESH:C011314', (134, 137))	('gastritis', 'Phenotype', 'HP:0005263', (48, 57))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (100, 108))	('R-FP', 'Chemical', 'MESH:D012293', (124, 128))	('R-FP', 'Var', (124, 128))	('gastritis', 'Disease', (48, 57))
449578	18479519	There was a significant positive correlation between SIR's of esophageal and stomach cancer which may be an indication that these two cancer sites in the region share common risk factors such as smoking, low socio-economic status, low fruit and vegetable intake, and gastric atrophy.	('low socio-economic status', 'Var', (204, 229))	('low', 'NegReg', (231, 234))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (134, 140))	('gastric atrophy', 'Disease', (267, 282))	('stomach cancer', 'Disease', 'MESH:D013274', (77, 91))	('esophageal', 'Disease', (62, 72))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('gastric atrophy', 'Disease', 'MESH:D013274', (267, 282))	('stomach cancer', 'Phenotype', 'HP:0012126', (77, 91))	('stomach cancer', 'Disease', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal', 'Disease', 'MESH:D004941', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
449596	33879677	Prognostic value of long noncoding RNA urothelial carcinoma-associated 1 in esophageal carcinoma Currently, an increasing number of long noncoding RNAs (LncRNAs) have been reported to be abnormally expressed in human carcinomas and play a vital role in tumourigenesis.	('carcinomas', 'Disease', (217, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (217, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('urothelial carcinoma', 'Disease', (39, 59))	('long noncoding', 'Var', (132, 146))	('esophageal carcinoma', 'Disease', (76, 96))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (39, 59))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (76, 96))	('carcinomas', 'Disease', 'MESH:D009369', (217, 227))	('human', 'Species', '9606', (211, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (76, 96))
449644	33879677	Tumorigenesis is caused by the activation of proto-oncogenes, the inactivation of tumor suppressor genes and the immortalization of cells.	('Tumorigenesis', 'CPA', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('inactivation', 'Var', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('immortalization', 'CPA', (113, 128))	('tumor', 'Disease', (82, 87))	('activation', 'PosReg', (31, 41))	('proto-oncogenes', 'Protein', (45, 60))
449769	33605068	Finally, all the enrolled patients were treated with fluorouracil-based concurrent chemotherapy, and it has been reported that salvage CRT could significantly improve survival when compared to salvage radiotherapy alone.	('fluorouracil', 'Chemical', 'MESH:D005472', (53, 65))	('patients', 'Species', '9606', (26, 34))	('survival', 'MPA', (167, 175))	('improve', 'PosReg', (159, 166))	('salvage CRT', 'Var', (127, 138))
449799	33402118	Inhibition of H19 expression by antisense oligonucleotide transfection was shown to induce MDR1 promoter methylation and decrease the expression of multidrug resistance-associated protein 1 (MDR1) and its transcript P-glycoprotein (P-gp); this resulted in significant reduction in DOX 50% inhibition concentration (IC50) in R-HepG2 cells and enhanced their sensitivity to DOX (Tsang and Kwok).	('P-glycoprotein', 'Gene', '5243', (216, 230))	('oligonucleotide', 'Chemical', 'MESH:D009841', (42, 57))	('MDR1', 'Gene', '5243', (191, 195))	('antisense oligonucleotide transfection', 'Var', (32, 70))	('sensitivity to DOX', 'MPA', (357, 375))	('HepG2', 'CellLine', 'CVCL:0027', (326, 331))	('DOX 50% inhibition concentration', 'MPA', (281, 313))	('multidrug resistance-associated protein 1', 'Gene', '5243', (148, 189))	('DOX', 'Chemical', 'MESH:D004317', (281, 284))	('enhanced', 'PosReg', (342, 350))	('MDR1', 'Gene', (91, 95))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('MDR1', 'Gene', (191, 195))	('methylation', 'MPA', (105, 116))	('expression', 'MPA', (134, 144))	('P-gp', 'Gene', (232, 236))	('H19', 'Gene', (14, 17))	('DOX', 'Chemical', 'MESH:D004317', (372, 375))	('induce', 'Reg', (84, 90))	('Inhibition', 'Var', (0, 10))	('decrease', 'NegReg', (121, 129))	('P-glycoprotein', 'Gene', (216, 230))	('H19', 'Gene', '283120', (14, 17))	('MDR1', 'Gene', '5243', (91, 95))	('multidrug resistance-associated protein 1', 'Gene', (148, 189))	('P-gp', 'Gene', '5243', (232, 236))	('reduction', 'NegReg', (268, 277))
449802	33402118	According to the authors, antagonizing H19 diminished the expression of zinc finger E-box binding homeobox 1 (ZEB1) and P-gp, and upregulated the expression of E-cadherin (EC); thus, the chemotherapy resistance of HCC cells was reversed by blocking the EMT process (Li et al.).	('EMT process', 'CPA', (253, 264))	('zinc finger E-box binding homeobox 1', 'Gene', (72, 108))	('expression', 'MPA', (58, 68))	('zinc finger E-box binding homeobox 1', 'Gene', '6935', (72, 108))	('expression', 'MPA', (146, 156))	('upregulated', 'PosReg', (130, 141))	('antagonizing', 'Var', (26, 38))	('HCC', 'Gene', '619501', (214, 217))	('ZEB1', 'Gene', '6935', (110, 114))	('H19', 'Gene', (39, 42))	('HCC', 'Gene', (214, 217))	('P-gp', 'Gene', (120, 124))	('H19', 'Gene', '283120', (39, 42))	('E-cadherin', 'Gene', (160, 170))	('E-cadherin', 'Gene', '999', (160, 170))	('EC', 'Gene', '999', (172, 174))	('P-gp', 'Gene', '5243', (120, 124))	('diminished', 'NegReg', (43, 53))	('ZEB1', 'Gene', (110, 114))
449803	33402118	In previous studies, GST-II was shown to promote chemotherapy resistance by influencing the biotransformation and metabolic processes (Liang), and Ding's research confirmed that down-regulation of H19 can block the MAPK/ERK signaling pathway, reducing the levels of MDR1 and GST-II; this was shown to facilitate cell apoptosis and suppress cell viability, eventually reversing the chemotherapy resistance of CD133 + HCC stem cells (Ding et al.).	('influencing', 'Reg', (76, 87))	('block', 'NegReg', (205, 210))	('reversing', 'NegReg', (367, 376))	('down-regulation', 'Var', (178, 193))	('Ding', 'Gene', '6045', (147, 151))	('Ding', 'Gene', '6045', (432, 436))	('cell apoptosis', 'CPA', (312, 326))	('Ding', 'Gene', (147, 151))	('Ding', 'Gene', (432, 436))	('H19', 'Gene', (197, 200))	('MDR1', 'Gene', '5243', (266, 270))	('H19', 'Gene', '283120', (197, 200))	('HCC', 'Gene', '619501', (416, 419))	('facilitate', 'PosReg', (301, 311))	('ERK', 'Gene', '5594', (220, 223))	('reducing', 'NegReg', (243, 251))	('HCC', 'Gene', (416, 419))	('cell viability', 'CPA', (340, 354))	('suppress', 'NegReg', (331, 339))	('ERK', 'Gene', (220, 223))	('CD133', 'Gene', (408, 413))	('CD133', 'Gene', '8842', (408, 413))	('MDR1', 'Gene', (266, 270))
449808	33402118	Restrained expression of lncRNA H19 and over-expression of miR-193a-3p tended to significantly increase the proliferation and survival rate of Bel-7402 cells, when these were tolerant to radiation (single-dose X-ray) and chemotherapeutic agents (DOX, paclitaxel, vinorelbine, 5-FU) (Ma et al.).	('Bel-7402', 'CellLine', 'CVCL:5492', (143, 151))	('survival rate', 'CPA', (126, 139))	('lncRNA', 'Gene', (25, 31))	('increase', 'PosReg', (95, 103))	('H19', 'Gene', '283120', (32, 35))	('H19', 'Gene', (32, 35))	('proliferation', 'CPA', (108, 121))	('miR-193a-3p', 'Var', (59, 70))	('DOX', 'Chemical', 'MESH:D004317', (246, 249))	('over-expression', 'PosReg', (40, 55))	('5-FU', 'Chemical', 'MESH:D005472', (276, 280))	('vinorelbine', 'Chemical', 'MESH:D000077235', (263, 274))	('paclitaxel', 'Chemical', 'MESH:D017239', (251, 261))
449823	33402118	In addition, activation of Wnt/beta-catenin pathway by H19 overexpression was also shown to be involved in inducing resistance to methotrexate in HT-29-R cells (Wu et al.).	('H19', 'Gene', '283120', (55, 58))	('resistance to methotrexate', 'MPA', (116, 142))	('beta-catenin', 'Gene', (31, 43))	('H19', 'Gene', (55, 58))	('Wnt', 'Gene', '7471', (27, 30))	('inducing', 'PosReg', (107, 115))	('overexpression', 'Var', (59, 73))	('HT-29-R', 'CellLine', 'CVCL:4V27', (146, 153))	('beta-catenin', 'Gene', '1499', (31, 43))	('Wnt', 'Gene', (27, 30))	('activation', 'PosReg', (13, 23))	('methotrexate', 'Chemical', 'MESH:D008727', (130, 142))
449827	33402118	Different from the above mechanism, H19 can combine with miR-194-5p and mediate the silent information regulator 1 (SIRT1) dependent autophagy pathway to inhibit apoptosis of CRC cells and enhance their chemoresistance; this increased the IC50 of 5-Fu by 227.43% in H19 transfecting group compared with 5-FU sensitive cells HCT8 (Wang et al.).	('autophagy pathway', 'CPA', (133, 150))	('IC50', 'MPA', (239, 243))	('SIRT1', 'Gene', '23411', (116, 121))	('increased', 'PosReg', (225, 234))	('inhibit', 'NegReg', (154, 161))	('apoptosis of CRC cells', 'CPA', (162, 184))	('enhance', 'PosReg', (189, 196))	('SIRT1', 'Gene', (116, 121))	('H19', 'Gene', '283120', (36, 39))	('5-FU', 'Chemical', 'MESH:D005472', (303, 307))	('H19', 'Gene', '283120', (266, 269))	('H19', 'Gene', (36, 39))	('transfecting', 'Var', (270, 282))	('H19', 'Gene', (266, 269))	('silent information regulator 1', 'Gene', (84, 114))	('chemoresistance', 'CPA', (203, 218))	('5-Fu', 'Chemical', 'MESH:D005472', (247, 251))	('silent information regulator 1', 'Gene', '23411', (84, 114))
449838	33402118	The tumoral volume in vitro after sequential administration of DTA-H19 and GEM was significantly lower than that observed after GEM monotherapy; this suggested that DTA-H19 enhances the antitumor activity of chemotherapy (Sorin et al.).	('tumor', 'Disease', (4, 9))	('GEM', 'Chemical', 'MESH:C056507', (128, 131))	('enhances', 'PosReg', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('DTA-H19', 'Chemical', '-', (165, 172))	('DTA-H19', 'Var', (165, 172))	('GEM', 'Chemical', 'MESH:C056507', (75, 78))	('tumor', 'Disease', (190, 195))	('DTA-H19', 'Chemical', '-', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
449846	33402118	In ESCA radioresistant cells KYSE150R, knockdown of H19 downregulated the WNT1 via upregulating miR-22-3p expression, which caused the inhibition of cell migration, proliferation, and stemness (Luo et al.).	('miR-22-3p', 'Gene', (96, 105))	('miR-22-3p', 'Gene', '407008', (96, 105))	('inhibition', 'NegReg', (135, 145))	('H19', 'Gene', '283120', (52, 55))	('knockdown', 'Var', (39, 48))	('expression', 'MPA', (106, 116))	('H19', 'Gene', (52, 55))	('WNT1', 'Gene', (74, 78))	('upregulating', 'PosReg', (83, 95))	('downregulated', 'NegReg', (56, 69))	('cell migration', 'CPA', (149, 163))	('WNT1', 'Gene', '7471', (74, 78))	('stemness', 'CPA', (184, 192))
449848	33402118	So far, in a study, knockdown of lncRNA H19 repressed cell proliferation, migration, and EMT via the STAT3-EZH2-beta-catenin pathway (Chen et al.).	('STAT3', 'Gene', '6774', (101, 106))	('cell proliferation', 'CPA', (54, 72))	('STAT3', 'Gene', (101, 106))	('EZH2', 'Gene', '2146', (107, 111))	('H19', 'Gene', (40, 43))	('migration', 'CPA', (74, 83))	('H19', 'Gene', '283120', (40, 43))	('EZH2', 'Gene', (107, 111))	('repressed', 'NegReg', (44, 53))	('beta-catenin', 'Gene', (112, 124))	('knockdown', 'Var', (20, 29))	('EMT', 'CPA', (89, 92))	('beta-catenin', 'Gene', '1499', (112, 124))
449852	33402118	Knockdown of H19 was shown to reduce the viability of GC cells MKN7 treated by DOX and alleviate chemoresistance; the effects were mediated via modulation of the H19-IGF2BP3 axis (Ishii et al.).	('modulation', 'Var', (144, 154))	('chemoresistance', 'CPA', (97, 112))	('DOX', 'Chemical', 'MESH:D004317', (79, 82))	('H19', 'Gene', '283120', (162, 165))	('reduce', 'NegReg', (30, 36))	('H19', 'Gene', (162, 165))	('viability', 'CPA', (41, 50))	('H19', 'Gene', '283120', (13, 16))	('IGF2BP3', 'Gene', '10643', (166, 173))	('IGF2BP3', 'Gene', (166, 173))	('alleviate', 'PosReg', (87, 96))	('H19', 'Gene', (13, 16))
449856	33402118	After treatment with GEM, the survival rate of CCA cells QBC939 and the weight of the tumor were significantly lower in H19 high expression group; the findings suggested that high expression of H19 can increase the sensitivity of CCA cells to GEM (Qiu).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('H19', 'Gene', (120, 123))	('CCA', 'Phenotype', 'HP:0030153', (47, 50))	('tumor', 'Disease', (86, 91))	('CCA', 'Phenotype', 'HP:0030153', (230, 233))	('high expression', 'Var', (175, 190))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('H19', 'Gene', (194, 197))	('GEM', 'Chemical', 'MESH:C056507', (243, 246))	('CCA', 'Disease', (230, 233))	('H19', 'Gene', '283120', (194, 197))	('GEM', 'Chemical', 'MESH:C056507', (21, 24))	('increase', 'PosReg', (202, 210))	('sensitivity', 'MPA', (215, 226))	('H19', 'Gene', '283120', (120, 123))
449895	32990834	The postoperative pathological diagnosis was of poorly differentiated adenocarcinoma (T3 70 x 45 mm) with lymph node metastasis (N3) (pT3 pN3 pM0 pStage III; Fig.	('lymph node metastasis', 'Disease', (106, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('T3', 'Var', (86, 88))	('adenocarcinoma', 'Disease', (70, 84))	('adenocarcinoma', 'Disease', 'MESH:D000230', (70, 84))
449903	32990834	Following diagnosis of cT1aN0M0 based on the Union for International Cancer Control TNM Classification 8th edition, subtotal esophagectomy was performed with lymph node and neck dissection.	('cT1aN0M0', 'Var', (23, 31))	('TNM', 'Gene', (84, 87))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancer', 'Disease', (69, 75))	('TNM', 'Gene', '10178', (84, 87))	('Cancer', 'Disease', 'MESH:D009369', (69, 75))
449922	32990834	COX2-selective inhibitors and aspirin may increase apoptosis, suppress growth of esophageal adenocarcinoma, and shorten BE.	('suppress', 'NegReg', (62, 70))	('growth', 'MPA', (71, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('shorten', 'NegReg', (112, 119))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (81, 106))	('esophageal adenocarcinoma', 'Disease', (81, 106))	('BE', 'Phenotype', 'HP:0100580', (120, 122))	('COX2', 'Gene', '5743', (0, 4))	('COX2', 'Gene', (0, 4))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (81, 106))	('apoptosis', 'CPA', (51, 60))	('inhibitors', 'Var', (15, 25))	('increase', 'PosReg', (42, 50))	('aspirin', 'Chemical', 'MESH:D001241', (30, 37))
449954	28754000	Differences in cancer cells behavior stem from the dysregulation of a number of growth signals that are involved in the direct entry into and progression through the cell cycle.	('cancer cells', 'Disease', 'MESH:C538614', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('dysregulation', 'Var', (51, 64))	('cancer cells', 'Disease', (15, 27))
449957	28754000	A number of oncogenes and tumor suppressor genes such as p53, c-Myc and transforming growth factor-beta (TGF-beta) are mutated in cancer cells and have been observed to play key roles in cancer cell proliferation, invasion and metastasis.	('play', 'Reg', (169, 173))	('oncogenes', 'Gene', (12, 21))	('TGF-beta', 'Gene', '7040', (105, 113))	('roles', 'Reg', (178, 183))	('p53', 'Gene', '7157', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('transforming growth factor-beta', 'Gene', (72, 103))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer cells', 'Disease', (130, 142))	('TGF-beta', 'Gene', (105, 113))	('p53', 'Gene', (57, 60))	('tumor', 'Disease', (26, 31))	('metastasis', 'CPA', (227, 237))	('c-Myc', 'Gene', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cancer cells', 'Disease', 'MESH:C538614', (130, 142))	('c-Myc', 'Gene', '4609', (62, 67))	('invasion', 'CPA', (214, 222))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', (130, 136))	('transforming growth factor-beta', 'Gene', '7040', (72, 103))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('mutated', 'Var', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
449967	28754000	Though cancer cell chemoresistance is usually attributed to heterogeneity within the cancer cell population, mutations and epigenetic alterations influencing the metabolism and retention of drugs by cancer cells, additional causes could play important roles in the development of this phenomenon.	('metabolism', 'MPA', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('influencing', 'Reg', (146, 157))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer cells', 'Disease', (199, 211))	('retention of drugs', 'MPA', (177, 195))	('mutations', 'Var', (109, 118))	('epigenetic alterations', 'Var', (123, 145))	('cancer', 'Disease', (199, 205))	('cancer', 'Disease', (7, 13))	('cancer cells', 'Disease', 'MESH:C538614', (199, 211))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
449974	28754000	Several mutations to key genes encoding important proteins responsible for xenobiotic metabolism, as well as import and export of drugs from cells such as the ABC transporters have been identified and shown to influence how tumor cells respond to several drugs.	('import', 'MPA', (109, 115))	('ABC', 'Gene', (159, 162))	('xenobiotic metabolism', 'Disease', (75, 96))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('xenobiotic metabolism', 'Disease', 'MESH:D008659', (75, 96))	('tumor', 'Disease', (224, 229))	('mutations', 'Var', (8, 17))	('respond to several drugs', 'MPA', (236, 260))	('influence', 'Reg', (210, 219))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
449983	28754000	A combination of genetic mutations and epigenetic alterations results in tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('epigenetic alterations', 'Var', (39, 61))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('results in', 'Reg', (62, 72))	('genetic mutations', 'Var', (17, 34))
449987	28754000	Variants of cancer cells that do not respond to a drug can result in relapse.	('cancer cells', 'Disease', (12, 24))	('cancer cells', 'Disease', 'MESH:C538614', (12, 24))	('Variants', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('result in', 'Reg', (59, 68))	('relapse', 'CPA', (69, 76))
449988	28754000	Hypermethylation of the multi-drug resistance protein 1 (MDR1) gene promoter has been reported to cause downregulation of certain genes involved in apoptosis.	('genes', 'MPA', (130, 135))	('MDR1', 'Gene', (57, 61))	('MDR1', 'Gene', '5243', (57, 61))	('Hypermethylation', 'Var', (0, 16))	('multi-drug resistance protein 1', 'Gene', (24, 55))	('downregulation', 'NegReg', (104, 118))	('multi-drug resistance protein 1', 'Gene', '5243', (24, 55))	('drug resistance', 'Phenotype', 'HP:0020174', (30, 45))
449989	28754000	Methylation of the O(6)-methylguanine DNA methyltransferase (MGMT) gene is known to cause silencing of several genes.	('Methylation', 'Var', (0, 11))	('O(6)-methylguanine DNA methyltransferase', 'Gene', '4255', (19, 59))	('silencing', 'MPA', (90, 99))	('MGMT', 'Gene', '4255', (61, 65))	('MGMT', 'Gene', (61, 65))
450059	28754000	Thus at some point tumor cells are exposed to sub-lethal levels of TPZ with the consequent development of chemoresistance.	('TPZ', 'Chemical', 'MESH:D000077704', (67, 70))	('TPZ', 'Var', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('chemoresistance', 'CPA', (106, 121))
450061	28754000	Changes in pH inside and outside of cancer cells can have a lasting effect on chemotherapeutic drugs.	('cancer cells', 'Disease', (36, 48))	('cancer cells', 'Disease', 'MESH:C538614', (36, 48))	('Changes', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('effect', 'Reg', (68, 74))
450086	28754000	Treatment of WJ-MSCs with 1 microM 5-azacytidine resulted in their differentiation into myofibroblastic lineages expressing increased levels of alpha-SMA and type I collagen.	('levels of alpha-SMA', 'MPA', (134, 153))	('increased', 'PosReg', (124, 133))	('differentiation', 'CPA', (67, 82))	('5-azacytidine', 'Chemical', 'MESH:D001374', (35, 48))	('5-azacytidine', 'Var', (35, 48))
450093	28754000	In addition, TGF-beta knockdown in both WHCO1 and MDA MB 231 cells during co-culture decreased alpha-SMA protein levels in MSCs (Figure 4E,F).	('decreased', 'NegReg', (85, 94))	('MDA MB 231', 'CellLine', 'CVCL:0062', (50, 60))	('knockdown', 'Var', (22, 31))	('TGF-beta', 'Gene', '7040', (13, 21))	('TGF-beta', 'Gene', (13, 21))	('alpha-SMA protein levels', 'MPA', (95, 119))
450098	28754000	MSCs can also promote drug resistance both by secreting protective cytokines, and by preventing cancer cell apoptosis.	('secreting protective cytokines', 'MPA', (46, 76))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('promote', 'PosReg', (14, 21))	('drug resistance', 'Phenotype', 'HP:0020174', (22, 37))	('preventing', 'NegReg', (85, 95))	('MSCs', 'Var', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('drug', 'CPA', (22, 26))
450103	28754000	Perturbation of these mechanisms can promote pathological conditions such as fibrosis and cancer.	('fibrosis', 'Disease', 'MESH:D005355', (77, 85))	('promote', 'PosReg', (37, 44))	('fibrosis', 'Disease', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('Perturbation', 'Var', (0, 12))
450119	28754000	Inhibition of lysyl oxidase (LOX) softens the ECM.	('lysyl', 'Enzyme', (14, 19))	('softens', 'NegReg', (34, 41))	('LOX', 'Gene', '4015', (29, 32))	('Inhibition', 'Var', (0, 10))	('LOX', 'Gene', (29, 32))	('ECM', 'CPA', (46, 49))
450146	28754000	Overexpression of COL11A1 is associated with progression of several cancers and poor survival.	('COL11A1', 'Gene', '1301', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('COL11A1', 'Gene', (18, 25))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('Overexpression', 'Var', (0, 14))	('associated', 'Reg', (29, 39))
450156	28754000	LN-332 can bind the integrin alpha3beta1 receptor which is reported to be enhanced in gefitinib resistance in hepatocellular carcinomas (HCCs).	('bind', 'Interaction', (11, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('integrin alpha3beta1 receptor', 'Protein', (20, 49))	('gefitinib resistance', 'MPA', (86, 106))	('HCCs', 'Phenotype', 'HP:0001402', (137, 141))	('LN-332', 'Var', (0, 6))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (110, 135))	('gefitinib', 'Chemical', 'MESH:D000077156', (86, 95))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (110, 135))	('hepatocellular carcinomas', 'Disease', (110, 135))	('enhanced', 'PosReg', (74, 82))
450158	28754000	It was demonstrated that LN-332 does not only protect hepatic cancer cells against therapeutic drugs but it promotes cell proliferation upon sorafenib exposure.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('hepatic cancer', 'Disease', (54, 68))	('sorafenib', 'Chemical', 'MESH:D000077157', (141, 150))	('LN-332', 'Var', (25, 31))	('cell proliferation', 'CPA', (117, 135))	('hepatic cancer', 'Disease', 'MESH:D008113', (54, 68))	('promotes', 'PosReg', (108, 116))	('hepatic cancer', 'Phenotype', 'HP:0002896', (54, 68))	('cancer cells', 'Disease', (62, 74))	('cancer cells', 'Disease', 'MESH:C538614', (62, 74))
450188	28754000	Perturbing or removing all the supporting cells and non-cellular components in the TM should ultimately lead to tumor regression or tumor cell reversion.	('removing', 'NegReg', (14, 22))	('Perturbing', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', (112, 117))	('lead to', 'Reg', (104, 111))
450200	28754000	Modifying or degrading even part of the ECM might create a highway through which cancer cells can migrate to other tissues or organs.	('cancer cells', 'Disease', (81, 93))	('cancer cells', 'Disease', 'MESH:C538614', (81, 93))	('degrading', 'NegReg', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Modifying', 'Var', (0, 9))
450202	28754000	Inhibitors against P glycoprotein may be considered to be the best treatment of cancer and prevention of MDR.	('P glycoprotein', 'Gene', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Inhibitors', 'Var', (0, 10))	('P glycoprotein', 'Gene', '5243', (19, 33))	('MDR', 'Disease', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
450204	28754000	The same study also demonstrated that shRNA knockdown of PDK2 in breast cancer cell lines resulted in significant decrease in resistance to anticancer agent paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (157, 167))	('PDK2', 'Gene', '5164', (57, 61))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('PDK2', 'Gene', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('breast cancer', 'Disease', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('cancer', 'Disease', (144, 150))	('knockdown', 'Var', (44, 53))	('decrease', 'NegReg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (72, 78))
450205	28754000	These results suggest that inhibition of MDR and P-gp through the inactivation of PKD2 might be a potential strategy to overcome chemoresistance.	('PKD2', 'Gene', (82, 86))	('MDR', 'Protein', (41, 44))	('P-gp', 'Gene', '283871', (49, 53))	('inactivation', 'Var', (66, 78))	('chemoresistance', 'CPA', (129, 144))	('P-gp', 'Gene', (49, 53))	('PKD2', 'Gene', '5311', (82, 86))
450277	25516722	Furthermore, transfection of miR-22 expression plasmid could significantly inhibit the cell proliferation, migration and invasion in Eca109 and Kyse410 ESCC cell lines.	('transfection', 'Var', (13, 25))	('inhibit', 'NegReg', (75, 82))	('miR-22', 'Gene', '407004', (29, 35))	('cell proliferation', 'CPA', (87, 105))	('miR-22', 'Gene', (29, 35))
450300	25516722	We performed MTT cell proliferation assays with transfected miR-22 in Eca109 and Kyse410 cells.	('miR-22', 'Gene', (60, 66))	('miR-22', 'Gene', '407004', (60, 66))	('transfected', 'Var', (48, 59))	('MTT', 'Chemical', 'MESH:C070243', (13, 16))
450301	25516722	Our results showed that restoration of miR-22 expression suppressed cell proliferation in both of the ESCC cell lines (Figure 3B and C).	('restoration', 'Var', (24, 35))	('cell proliferation', 'CPA', (68, 86))	('miR-22', 'Gene', '407004', (39, 45))	('miR-22', 'Gene', (39, 45))	('expression', 'MPA', (46, 56))	('suppressed', 'NegReg', (57, 67))
450324	25516722	The ESCC cell lines, including Kyse140, Kyse510, Eca109, TE-1, Kyse410, EC18, HKESC1 and 108CA, were grown in the Dulbecco's modified Eagle's medium (DMEM, Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (FBS) (HyClone, Logan, UT, USA) at 37 C in a humidified atmosphere of 5% CO2.	('DMEM', 'Chemical', '-', (150, 154))	('Kyse510', 'Var', (40, 47))	('CO2', 'Chemical', '-', (301, 304))	('Kyse140', 'Var', (31, 38))	('FBS', 'Disease', (229, 232))	('Kyse410', 'Var', (63, 70))	('HKESC1', 'CellLine', 'CVCL:D568', (78, 84))	('FBS', 'Disease', 'MESH:D005198', (229, 232))	('bovine', 'Species', '9913', (215, 221))
450365	31623145	Pathological causes of chronic hypergastrinemia include any disease causing hypo-/achlorhydria (including potent gastric anti-secretory drugs such as PPIs, pernicious anemia, atrophic gastritis, failure to develop functional parietal cells because of an inherited disorder such as defects in the genes encoding the gastric H+K+ acid pump); overproduction of gastrin due to the presence of NETs ectopically secreting gastrin (gastrinoma), as well as other disease states such as chronic gastric infections such as Helicobacter pylori, renal failure, and massive small bowel resections.	('inherited disorder', 'Disease', (254, 272))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (31, 47))	('overproduction', 'PosReg', (340, 354))	('anemia', 'Disease', (167, 173))	('gastric infections', 'Disease', 'MESH:D013274', (486, 504))	('gastritis', 'Phenotype', 'HP:0005263', (184, 193))	('gastric H', 'Disease', 'MESH:D013274', (315, 324))	('defects', 'Var', (281, 288))	('gastric infections', 'Disease', (486, 504))	('secretin', 'Gene', '6343', (406, 414))	('gastrin', 'Protein', (358, 365))	('Helicobacter pylori', 'Species', '210', (513, 532))	('gastrinoma', 'Disease', 'MESH:D015408', (425, 435))	('secretin', 'Gene', (406, 414))	('hypo-/achlorhydria', 'Disease', (76, 94))	('gastric H', 'Disease', (315, 324))	('inherited disorder', 'Disease', 'MESH:D030342', (254, 272))	('atrophic gastritis', 'Disease', 'MESH:D005757', (175, 193))	('achlorhydria', 'Phenotype', 'HP:0032448', (82, 94))	('anemia', 'Disease', 'MESH:D000740', (167, 173))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (175, 193))	('chronic hypergastrinemia', 'Disease', (23, 47))	('Helicobacter pylori', 'Disease', (513, 532))	('renal failure', 'Phenotype', 'HP:0000083', (534, 547))	('chronic hypergastrinemia', 'Disease', 'MESH:D002908', (23, 47))	('gastric infections', 'Phenotype', 'HP:0004798', (486, 504))	('renal failure', 'Disease', 'MESH:D051437', (534, 547))	('atrophic gastritis', 'Disease', (175, 193))	('gastrinoma', 'Disease', (425, 435))	('renal failure', 'Disease', (534, 547))	('anemia', 'Phenotype', 'HP:0001903', (167, 173))	('hypo-/achlorhydria', 'Disease', 'MESH:D000126', (76, 94))
450383	31623145	The continued question of long-term safety of PPIs on this issue occurs because it remains unclear to many what degrees of advanced proliferative effects and what frequency of Type 1 or 2 gastric carcinoids there will be seen in human gastric ECL cells during very long-term/lifetime PPI treatment.	('gastric carcinoids', 'Disease', (188, 206))	('PPI', 'Var', (284, 287))	('carcinoid', 'Phenotype', 'HP:0100570', (196, 205))	('man', 'Species', '9606', (102, 105))	('rat', 'Species', '10116', (139, 142))	('carcinoids', 'Phenotype', 'HP:0100570', (196, 206))	('gastric carcinoids', 'Disease', 'MESH:D002276', (188, 206))	('human', 'Species', '9606', (229, 234))	('man', 'Species', '9606', (231, 234))
450386	31623145	Furthermore, a number of these chronic hypergastrinemic conditions such as pernicious anemia, atrophic gastritis, and lack of gastric ATPase genes are associated with the development of gastric carcinoid tumors.	('lack', 'Var', (118, 122))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (94, 112))	('hypergastrinemic conditions', 'Phenotype', 'HP:0500167', (39, 66))	('anemia', 'Disease', 'MESH:D000740', (86, 92))	('gastric carcinoid tumors', 'Disease', 'MESH:D002276', (186, 210))	('carcinoid', 'Phenotype', 'HP:0100570', (194, 203))	('associated', 'Reg', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('anemia', 'Phenotype', 'HP:0001903', (86, 92))	('gastric carcinoid tumors', 'Disease', (186, 210))	('hypergastrinemic conditions', 'Disease', 'MESH:C535721', (39, 66))	('atrophic gastritis', 'Disease', 'MESH:D005757', (94, 112))	('gastritis', 'Phenotype', 'HP:0005263', (103, 112))	('gastric ATPase', 'Protein', (126, 140))	('atrophic gastritis', 'Disease', (94, 112))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('anemia', 'Disease', (86, 92))	('hypergastrinemic conditions', 'Disease', (39, 66))
450396	31623145	The above results, with a rapidly increasing and prolonged use of PPIs coupled with their ability to cause chronic hypergastrinemia with proliferative gastric ECL cell changes in man; their ability to cause gastric carcinoid tumors in rodents, but not humans with chronic PPI use over <5 years; and the experimental result of gastrin's effect on a number of other cancer's growth have led to debate over their safety during prolonged, life-time usage.	('cause', 'Reg', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('chronic hypergastrinemia', 'Disease', (107, 131))	('gastric carcinoid tumors', 'Disease', (207, 231))	('humans', 'Species', '9606', (252, 258))	('gastric carcinoid tumors', 'Disease', 'MESH:D002276', (207, 231))	('man', 'Species', '9606', (179, 182))	('chronic hypergastrinemia', 'Disease', 'MESH:D002908', (107, 131))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (115, 131))	('cancer', 'Disease', 'MESH:D009369', (364, 370))	('man', 'Species', '9606', (254, 257))	('cause', 'Reg', (101, 106))	('cancer', 'Disease', (364, 370))	('carcinoid', 'Phenotype', 'HP:0100570', (215, 224))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('rat', 'Species', '10116', (144, 147))	('PPIs', 'Var', (66, 70))
450397	31623145	In addition to the question of the long-term possibility of chronic hypergastrinemia-induced gastric carcinoids, in a number of other recent specific studies, as well as observational and epidemiological studies, other possible PPI-induced side-effects with potential long-term safety considerations are being reported, which are attributed to the PPI-induced chronic hypergastrinemia, hypoachlorhydria, to other mechanisms, or due to unknown mechanisms.	('chronic hypergastrinemia', 'Disease', (360, 384))	('hypergastrinemia-induced gastric carcinoids', 'Disease', 'MESH:D002276', (68, 111))	('chronic hypergastrinemia, hypoachlorhydria', 'Disease', 'MESH:D002908', (360, 402))	('chronic hypergastrinemia', 'Disease', 'MESH:D002908', (360, 384))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (368, 384))	('hypergastrinemia-induced gastric carcinoids', 'Disease', (68, 111))	('carcinoid', 'Phenotype', 'HP:0100570', (101, 110))	('chronic hypergastrinemia', 'Disease', 'MESH:D002908', (60, 84))	('chronic hypergastrinemia', 'Disease', (60, 84))	('PPI-induced', 'Var', (348, 359))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (68, 84))	('achlorhydria', 'Phenotype', 'HP:0032448', (390, 402))	('carcinoids', 'Phenotype', 'HP:0100570', (101, 111))	('rat', 'Species', '10116', (292, 295))
450398	31623145	Also receiving increased attention are the possible effects of chronic hypergastrinemia on non ECL cell tumor growth, as well as a number of primarily observational/epidemiological recent studies reporting an association of chronic PPI use with the development renal diseases; increasing the incidence of various lung and GI infections; affecting the absorption of various nutrients; participating in drug interactions that have therapeutic implication; contributing to bone fractures; and contributing to the development of important CNS diseases such as dementia.	('dementia', 'Phenotype', 'HP:0000726', (556, 564))	('bone fractures', 'Disease', (470, 484))	('contributing', 'Reg', (490, 502))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('absorption of various nutrients', 'MPA', (351, 382))	('hypergastrinemia on non ECL cell tumor', 'Disease', (71, 109))	('increasing', 'PosReg', (277, 287))	('bone fracture', 'Phenotype', 'HP:0020110', (470, 483))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (71, 87))	('participating', 'Reg', (384, 397))	('contributing', 'Reg', (454, 466))	('dementia', 'Disease', (556, 564))	('bone fractures', 'Phenotype', 'HP:0020110', (470, 484))	('dementia', 'Disease', 'MESH:D003704', (556, 564))	('renal diseases', 'Disease', (261, 275))	('interactions', 'Interaction', (406, 418))	('affecting', 'Reg', (337, 346))	('chronic hypergastrinemia', 'Disease', (63, 87))	('chronic hypergastrinemia', 'Disease', 'MESH:D002908', (63, 87))	('bone fractures', 'Disease', 'MESH:D050723', (470, 484))	('chronic', 'Var', (224, 231))	('PPI', 'Gene', (232, 235))	('renal diseases', 'Disease', 'MESH:D007674', (261, 275))	('hypergastrinemia on non ECL cell tumor', 'Disease', 'MESH:D002289', (71, 109))	('lung', 'Disease', (313, 317))	('GI infections', 'Disease', 'MESH:D005767', (322, 335))	('GI infections', 'Disease', (322, 335))	('GI infections', 'Phenotype', 'HP:0004798', (322, 335))
450400	31623145	This study reported that the only possible PPI-induced safety difference detected was an increased incidence of enteric infections in the PPI-treated patients.	('patients', 'Species', '9606', (150, 158))	('enteric infections', 'Disease', 'MESH:D004751', (112, 130))	('enteric infections', 'Disease', (112, 130))	('PPI-treated', 'Var', (138, 149))
450417	31623145	Specifically, both of these latter conditions are associated with gastric inflammation, the development of gastric mucosal atrophy, and the presence of these correlates with the development of gastric carcinoids, and in fact, without their presence, ECL cell proliferative changes occur, but gastric carcinoid tumors are infrequent.	('gastric mucosal atrophy', 'Disease', (107, 130))	('gastric inflammation', 'Disease', 'MESH:D007249', (66, 86))	('gastric carcinoids', 'Disease', 'MESH:D002276', (193, 211))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('rat', 'Species', '10116', (266, 269))	('carcinoid', 'Phenotype', 'HP:0100570', (201, 210))	('gastric mucosal atrophy', 'Disease', 'MESH:D013274', (107, 130))	('tumors', 'Phenotype', 'HP:0002664', (310, 316))	('carcinoid', 'Phenotype', 'HP:0100570', (300, 309))	('gastric inflammation', 'Disease', (66, 86))	('carcinoids', 'Phenotype', 'HP:0100570', (201, 211))	('gastric inflammation', 'Phenotype', 'HP:0005263', (66, 86))	('presence', 'Var', (140, 148))	('gastric carcinoids', 'Disease', (193, 211))	('associated', 'Reg', (50, 60))	('gastric carcinoid tumors', 'Disease', 'MESH:D002276', (292, 316))	('gastric carcinoid tumors', 'Disease', (292, 316))
450419	31623145	Helicobacter pylori (HP) infections can cause atrophic gastritis, and in patients with HP infections, the use of PPIs augments the mucosal inflammation and accelerates gastric mucosal atrophy, which may contribute to the development of gastric cancer.	('augments', 'PosReg', (118, 126))	('Helicobacter pylori', 'Species', '210', (0, 19))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (46, 64))	('HP', 'Species', '210', (21, 23))	('gastric mucosal atrophy', 'Disease', (168, 191))	('atrophic gastritis', 'Disease', (46, 64))	('cause', 'Reg', (40, 45))	('gastric cancer', 'Disease', (236, 250))	('Helicobacter pylori', 'Disease', (0, 19))	('PPIs', 'Var', (113, 117))	('mucosal inflammation', 'Disease', 'MESH:D007249', (131, 151))	('gastric mucosal atrophy', 'Disease', 'MESH:D013274', (168, 191))	('infections', 'Var', (25, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('HP infections', 'Disease', 'MESH:C537262', (87, 100))	('use', 'Var', (106, 109))	('HP infections', 'Disease', (87, 100))	('gastritis', 'Phenotype', 'HP:0005263', (55, 64))	('patients', 'Species', '9606', (73, 81))	('accelerates', 'PosReg', (156, 167))	('rat', 'Species', '10116', (162, 165))	('mucosal inflammation', 'Disease', (131, 151))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('atrophic gastritis', 'Disease', 'MESH:D005757', (46, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('HP', 'Species', '210', (87, 89))
450472	31623145	As pointed out above, 20-25% of ZES patients have it as part of the autosomal dominant disorder MEN1, which is due to a mutation in the 10-exon MEN1 gene on chromosome 11q13, which encodes for a 610 amino acid protein, menin, which is a nuclear protein interacting with numerous transcription factors involved in genomic stability, transcriptional control, cell division, and cell cycle control.	('MEN1', 'Gene', '4221', (144, 148))	('menin', 'Gene', (219, 224))	('MEN1', 'Gene', (96, 100))	('MEN1', 'Gene', '4221', (96, 100))	('patients', 'Species', '9606', (36, 44))	('mutation', 'Var', (120, 128))	('due to', 'Reg', (111, 117))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (68, 95))	('menin', 'Gene', '4221', (219, 224))	('autosomal dominant disorder', 'Disease', (68, 95))	('MEN1', 'Gene', (144, 148))
450478	31623145	Therefore, the combination of early onset of ZES in MEN1 patients, combined with lifelong chronic hypergastrinemia and mutations in the MEN1 gene predisposing them to the development of endocrine tumors, these patients not only very frequently develop advanced ECL cell changes, but also gastric carcinoids, which are more aggressive than type 1 sporadic gastric carcinoids in CAG/PA or other hypergastrinemia states.	('endocrine tumors', 'Disease', 'MESH:D004701', (186, 202))	('endocrine tumors', 'Disease', (186, 202))	('lifelong chronic hypergastrinemia', 'Disease', (81, 114))	('PA', 'Chemical', 'MESH:D011478', (381, 383))	('MEN1', 'Gene', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (393, 409))	('lifelong chronic hypergastrinemia', 'Disease', 'MESH:C565569', (81, 114))	('carcinoid', 'Phenotype', 'HP:0100570', (296, 305))	('develop', 'Reg', (244, 251))	('patients', 'Species', '9606', (210, 218))	('hypergastrinemia', 'Disease', (393, 409))	('mutations', 'Var', (119, 128))	('ECL cell', 'Disease', (261, 269))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('gastric carcinoids in CAG', 'Disease', (355, 380))	('hypergastrinemia', 'Disease', 'None', (393, 409))	('carcinoids', 'Phenotype', 'HP:0100570', (363, 373))	('MEN1', 'Gene', '4221', (52, 56))	('gastric carcinoids', 'Disease', 'MESH:D002276', (288, 306))	('gastric carcinoids in CAG', 'Disease', 'MESH:D002276', (355, 380))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (98, 114))	('carcinoid', 'Phenotype', 'HP:0100570', (363, 372))	('gastric carcinoids', 'Disease', (288, 306))	('patients', 'Species', '9606', (57, 65))	('MEN1', 'Gene', (52, 56))	('hypergastrinemia', 'Disease', (98, 114))	('carcinoids', 'Phenotype', 'HP:0100570', (296, 306))	('hypergastrinemia', 'Disease', 'None', (98, 114))	('MEN1', 'Gene', '4221', (136, 140))	('gastric carcinoids', 'Disease', 'MESH:D002276', (355, 373))
450493	31623145	These results support the proposal that in MEN1/ZES patients the presence of their MEN1 gene mutation and its subsequent cellular effects are responsible for the increased gastric mucosal proliferative effects of the chronic hypergastrinemia.	('MEN1', 'Gene', (83, 87))	('chronic hypergastrinemia', 'Disease', (217, 241))	('gastric mucosal', 'Disease', 'MESH:D013274', (172, 187))	('increased', 'PosReg', (162, 171))	('MEN1', 'Gene', '4221', (83, 87))	('chronic hypergastrinemia', 'Disease', 'MESH:D002908', (217, 241))	('increased gastric', 'Phenotype', 'HP:0005207', (162, 179))	('gastric mucosal', 'Disease', (172, 187))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (225, 241))	('MEN1', 'Gene', (43, 47))	('rat', 'Species', '10116', (195, 198))	('MEN1', 'Gene', '4221', (43, 47))	('mutation', 'Var', (93, 101))	('patients', 'Species', '9606', (52, 60))	('presence', 'Var', (65, 73))
450496	31623145	In dog, rat, and mouse, long-term PPI treatment resulted in an increase in oxyntic mucosal thickness and folding, similar to that seen in both groups of ZES patients.	('increase', 'PosReg', (63, 71))	('rat', 'Species', '10116', (8, 11))	('mouse', 'Species', '10090', (17, 22))	('folding', 'CPA', (105, 112))	('PPI', 'Var', (34, 37))	('mucosal thickness', 'Disease', (83, 100))	('patients', 'Species', '9606', (157, 165))	('mucosal thickness', 'Disease', 'MESH:D052016', (83, 100))	('dog', 'Species', '9615', (3, 6))
450498	31623145	Long-term treatment in rats with either PPIs or the insurmountable H2 antagonist, loxtidine, resulted in advanced ECL changes and gastric carcinoids, whereas in mice, chronic PPI treatment caused advanced ECL changes, but no gastric carcinoids, similar to that seen in sporadic ZES.	('rats', 'Species', '10116', (23, 27))	('mice', 'Species', '10090', (161, 165))	('carcinoid', 'Phenotype', 'HP:0100570', (233, 242))	('ECL changes', 'MPA', (114, 125))	('PPIs', 'Var', (40, 44))	('gastric carcinoids', 'Disease', 'MESH:D002276', (130, 148))	('gastric carcinoids', 'Disease', 'MESH:D002276', (225, 243))	('carcinoid', 'Phenotype', 'HP:0100570', (138, 147))	('carcinoids', 'Phenotype', 'HP:0100570', (233, 243))	('loxtidine', 'Chemical', 'MESH:C039993', (82, 91))	('H2', 'Chemical', '-', (67, 69))	('carcinoids', 'Phenotype', 'HP:0100570', (138, 148))	('gastric carcinoids', 'Disease', (130, 148))	('gastric carcinoids', 'Disease', (225, 243))
450514	31623145	In patients taking long-term PPIs or other potent gastric acid suppressants, the gastric mucosal changes also show many similarities to the findings in ZES patients, particularly in patients with sporadic ZES.	('patients', 'Species', '9606', (156, 164))	('gastric mucosal', 'Disease', (81, 96))	('PPIs', 'Var', (29, 33))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (182, 190))	('man', 'Species', '9606', (115, 118))	('gastric mucosal', 'Disease', 'MESH:D013274', (81, 96))	('ZES', 'Disease', (152, 155))
450520	31623145	These differences include the importance of female gender showing more advanced ECL cell changes with chronic PPI treatment or with H2-receptor antagonists, whereas it was not an important variable for ECL cell changes in the NIH sporadic ZES study or in the ZES/MEN1 study study.	('H2', 'Chemical', '-', (132, 134))	('NIH sporadic', 'Disease', 'MESH:D020821', (226, 238))	('MEN1', 'Gene', (263, 267))	('PPI', 'Var', (110, 113))	('MEN1', 'Gene', '4221', (263, 267))	('NIH sporadic', 'Disease', (226, 238))
450523	31623145	In contrast, in non-ZES patients taking long-term PPIs or other potent gastric acid suppressants, the presence of H. pylori was an independent risk factor for both increased ECL cell density and the degree of ECL cell proliferative change.	('ECL cell density', 'CPA', (174, 190))	('rat', 'Species', '10116', (225, 228))	('H. pylori', 'Var', (114, 123))	('presence', 'Var', (102, 110))	('patients', 'Species', '9606', (24, 32))	('H. pylori', 'Species', '210', (114, 123))	('increased', 'PosReg', (164, 173))
450564	31623145	A particularly important predisposing factor for the development of GC is the presence of gastritis which worldwide is closely related to the presence of H. pylori infection and a recent meta-analysis concluded that eradication of H. pylori was reducing the risk of GC.	('gastritis', 'Disease', (90, 99))	('H. pylori', 'Species', '210', (231, 240))	('H. pylori infection', 'Phenotype', 'HP:0005202', (154, 173))	('eradication', 'Var', (216, 227))	('pylori infection', 'Disease', 'MESH:D016481', (157, 173))	('H. pylori', 'Species', '210', (154, 163))	('gastritis', 'Disease', 'MESH:D005756', (90, 99))	('pylori infection', 'Disease', (157, 173))	('gastritis', 'Phenotype', 'HP:0005263', (90, 99))	('reducing', 'NegReg', (245, 253))
450566	31623145	Gastritis increases the risk of GC when it effects the oxyntic mucosa of the stomach, principally when its presence results in the development of oxyntic atrophy and with time the development of intestinal metaplasia.	('presence', 'Var', (107, 115))	('Gastritis increases', 'Disease', (0, 19))	('atrophy', 'Disease', 'MESH:D001284', (154, 161))	('results in', 'Reg', (116, 126))	('Gastritis', 'Phenotype', 'HP:0005263', (0, 9))	('atrophy', 'Disease', (154, 161))	('Gastritis increases', 'Disease', 'MESH:D005756', (0, 19))
450567	31623145	More recent studies demonstrate that treatment with PPIs resulting in reduced acidity leads to the migration of H. pylori from the antrum to the corpus resulting in an increased colonization of the gastric corpus, which is associated with the development of corpus inflammation, gastritis, and an increase risk of developing atrophic gastritis.	('H. pylori', 'Species', '210', (112, 121))	('inflammation', 'Disease', 'MESH:D007249', (265, 277))	('colonization', 'CPA', (178, 190))	('PPIs', 'Var', (52, 56))	('rat', 'Species', '10116', (102, 105))	('gastritis', 'Phenotype', 'HP:0005263', (334, 343))	('gastritis', 'Phenotype', 'HP:0005263', (279, 288))	('acidity', 'MPA', (78, 85))	('inflammation', 'Disease', (265, 277))	('reduced', 'NegReg', (70, 77))	('gastritis', 'Disease', 'MESH:D005756', (334, 343))	('gastritis', 'Disease', 'MESH:D005756', (279, 288))	('rat', 'Species', '10116', (27, 30))	('migration', 'CPA', (99, 108))	('atrophic gastritis', 'Disease', 'MESH:D005757', (325, 343))	('gastritis', 'Disease', (334, 343))	('gastritis', 'Disease', (279, 288))	('increased', 'PosReg', (168, 177))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (325, 343))	('H. pylori', 'Gene', (112, 121))	('atrophic gastritis', 'Disease', (325, 343))
450577	31623145	In one study, which included 63,397 individuals from Hong Kong, the use of PPIs was associated with a HR of 2.24 for developing gastric cancer, while the use of histamine H2 receptor antagonists was associated with no increased risk.	('gastric cancer', 'Disease', (128, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (128, 142))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('PPIs', 'Var', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
450588	31623145	This could occur because studies show that PPIs can essential render many ZES severely hypo-/achlorhydric.	('man', 'Species', '9606', (69, 72))	('hypo-/achlorhydric', 'Disease', (87, 105))	('PPIs', 'Var', (43, 47))
450593	31623145	In other studies, glycine-extended gastrin (Gly-Gastrin) is reported to have proliferative effects on the colonic mucosa in mice overexpressing Gly-Gastrin; and similar effects are seen in transgenic mice over-expressing progastrin, which in the latter case, in the presence of p53 mutations, CRC is seen.	('Gly-Gastrin', 'Chemical', '-', (144, 155))	('Gly-Gastrin', 'Chemical', '-', (44, 55))	('p53', 'Gene', (278, 281))	('extended gastrin', 'Phenotype', 'HP:0500167', (26, 42))	('transgenic mice', 'Species', '10090', (189, 204))	('rat', 'Species', '10116', (84, 87))	('colonic mucosa', 'Disease', 'MESH:D015179', (106, 120))	('mice', 'Species', '10090', (124, 128))	('glycine', 'Chemical', 'MESH:D005998', (18, 25))	('p53', 'Gene', '22060', (278, 281))	('mice', 'Species', '10090', (200, 204))	('proliferative effects', 'CPA', (77, 98))	('colonic mucosa', 'Disease', (106, 120))	('mutations', 'Var', (282, 291))	('extended', 'Chemical', '-', (26, 34))
450616	31623145	Gastrin has been shown to stimulate the growth of PDAC cells in an autocrine manner; and inhibition of gastrin by various methods including receptor antagonists, gastrin anti-sense, administration of gastrin- neutralizing antibodies, or gastrin receptor downregulation.	('man', 'Species', '9606', (77, 80))	('inhibition', 'Var', (89, 99))	('stimulate', 'PosReg', (26, 35))	('rat', 'Species', '10116', (190, 193))	('downregulation', 'NegReg', (254, 268))	('growth', 'CPA', (40, 46))	('PDAC', 'Chemical', '-', (50, 54))	('gastrin receptor', 'Gene', '887', (237, 253))	('gastrin receptor', 'Gene', (237, 253))
450648	31623145	Several studies report that chronic PPI treatment can increase both urine and fecal Mg losses, however the exact mechanism is not clear at this point.	('PPI', 'Var', (36, 39))	('Mg', 'Chemical', 'MESH:D008274', (84, 86))	('increase', 'PosReg', (54, 62))	('urine', 'MPA', (68, 73))
450650	31623145	This confusion exists because with VB12, iron, and calcium, some studies, but not others, show decreased absorption/body stores with chronic PPI use.	('decreased', 'NegReg', (95, 104))	('B12', 'Gene', (36, 39))	('B12', 'Gene', '4709', (36, 39))	('iron', 'Chemical', 'MESH:D007501', (41, 45))	('absorption/body stores', 'MPA', (105, 127))	('PPI', 'Var', (141, 144))	('calcium', 'Chemical', 'MESH:D002118', (51, 58))	('confusion', 'Phenotype', 'HP:0001289', (5, 14))
450654	31623145	In this study, there was no alterations in serum folate or hematological parameters, however VB12 levels were significantly reduced in PPI treated patients compared to those taking histamine H2 receptor antagonists (p = 0.03) (Figure 4, right panels).	('reduced', 'NegReg', (124, 131))	('rat', 'Species', '10116', (32, 35))	('folate', 'Chemical', 'MESH:D005492', (49, 55))	('patients', 'Species', '9606', (147, 155))	('PPI treated', 'Var', (135, 146))	('B12', 'Gene', (94, 97))	('B12', 'Gene', '4709', (94, 97))
450658	31623145	In a retrospective study of 61 patients with hypersecretory states (45 = ZES, 15 = other) who had chronic treatment (31% with a mean of eight years), 10% were found to have had low VB12 levels and 31% had normal VB12 levels with VB12 deficiency)(decreased serum homocysteine levels with normal folate levels).	('folate', 'Chemical', 'MESH:D005492', (294, 300))	('folate levels', 'MPA', (294, 307))	('deficiency', 'Var', (234, 244))	('B12', 'Gene', (230, 233))	('B12', 'Gene', (182, 185))	('B12', 'Gene', (213, 216))	('B12', 'Gene', '4709', (182, 185))	('B12', 'Gene', '4709', (213, 216))	('patients', 'Species', '9606', (31, 39))	('serum homocysteine levels', 'MPA', (256, 281))	('B12', 'Gene', '4709', (230, 233))	('low', 'NegReg', (177, 180))	('decreased', 'NegReg', (246, 255))	('homocysteine', 'Chemical', 'MESH:D006710', (262, 274))	('VB12 deficiency', 'Phenotype', 'HP:0100502', (229, 244))
450660	31623145	Therefore, while these two studies on ZES patients treated long-term with PPIs show an increased rate of VB12 deficiency, they come to different conclusions on the mechanism.	('rat', 'Species', '10116', (97, 100))	('VB12 deficiency', 'Phenotype', 'HP:0100502', (105, 120))	('B12', 'Gene', (106, 109))	('B12', 'Gene', '4709', (106, 109))	('deficiency', 'Var', (110, 120))	('patients', 'Species', '9606', (42, 50))
450661	31623145	The NIH study provides evidence that it is directly related to the PPI treatment through duration of treatment and degree of acid suppression, whereas the other study does not support this conclusion that support that the VB12 deficiency due to acid-related, but does not establish the mechanism of the deficiency.	('VB12 deficiency', 'Phenotype', 'HP:0100502', (222, 237))	('rat', 'Species', '10116', (91, 94))	('deficiency', 'Var', (227, 237))	('B12', 'Gene', (223, 226))	('B12', 'Gene', '4709', (223, 226))	('acid-related', 'MPA', (245, 257))
450662	31623145	The divergence of results in the two ZES studies of VB12 deficiency with chronic PPI treatment mirror the difference in results of the possible effects of chronic PPI treatment in VB12 level/stores in non-ZES patients.	('deficiency', 'Var', (57, 67))	('B12', 'Gene', (53, 56))	('B12', 'Gene', '4709', (53, 56))	('B12', 'Gene', (181, 184))	('patients', 'Species', '9606', (209, 217))	('VB12 deficiency', 'Phenotype', 'HP:0100502', (52, 67))	('B12', 'Gene', '4709', (181, 184))
450663	31623145	In these studies, many but not all report a 2-4-fold increased risk of VB12 deficiency/low serum VB12 levels with chronic PPI treatment.	('VB12 deficiency', 'Phenotype', 'HP:0100502', (71, 86))	('B12', 'Gene', (98, 101))	('B12', 'Gene', '4709', (98, 101))	('deficiency/low', 'NegReg', (76, 90))	('man', 'Species', '9606', (18, 21))	('deficiency/low', 'Var', (76, 90))	('B12', 'Gene', (72, 75))	('B12', 'Gene', '4709', (72, 75))
450676	31623145	Treatment of eight such patients with PPIs decreased serum ferritin and reduced mean hemoglobin levels led the authors to conclude it was reducing iron overabsorption and my lower the need for chelation therapy.	('reduced', 'NegReg', (72, 79))	('lower', 'NegReg', (174, 179))	('iron overabsorption', 'MPA', (147, 166))	('decreased serum ferritin', 'Phenotype', 'HP:0012343', (43, 67))	('serum ferritin', 'MPA', (53, 67))	('need for chelation therapy', 'MPA', (184, 210))	('reducing', 'NegReg', (138, 146))	('reduced mean hemoglobin', 'Phenotype', 'HP:0001903', (72, 95))	('patients', 'Species', '9606', (24, 32))	('mean hemoglobin levels', 'MPA', (80, 102))	('decreased', 'NegReg', (43, 52))	('PPIs', 'Var', (38, 42))	('iron', 'Chemical', 'MESH:D007501', (147, 151))
450678	31623145	The PPI-treated patients (n = 85) compared to a group not taking PPIs (n = 118) had a 3.3-fold higher incidence of iron deficiency anemia.	('PPI-treated', 'Var', (4, 15))	('anemia', 'Phenotype', 'HP:0001903', (131, 137))	('patients', 'Species', '9606', (16, 24))	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (115, 137))	('high', 'Gene', (95, 99))	('iron deficiency anemia', 'Disease', 'MESH:D018798', (115, 137))	('iron deficiency anemia', 'Disease', (115, 137))	('high', 'Gene', '104137', (95, 99))
450682	31623145	The PPI-treated group (n = 363) had lower serum iron levels (p < 001), lower serum ferritin levels (p < 0.001), and lower hemoglobin levels (p = 0.007).	('lower', 'NegReg', (116, 121))	('hemoglobin levels', 'MPA', (122, 139))	('lower', 'NegReg', (36, 41))	('lower serum iron', 'Phenotype', 'HP:0040303', (36, 52))	('PPI-treated', 'Var', (4, 15))	('lower serum ferritin', 'Phenotype', 'HP:0012343', (71, 91))	('iron', 'Chemical', 'MESH:D007501', (48, 52))	('lower hemoglobin', 'Phenotype', 'HP:0001903', (116, 132))	('serum iron levels', 'MPA', (42, 59))	('lower hemoglobin levels', 'Phenotype', 'HP:0020062', (116, 139))	('serum ferritin levels', 'MPA', (77, 98))	('lower', 'NegReg', (71, 76))
450683	31623145	Multivariate analysis showed that PPI use was independently associated with the development of iron deficiency anemia (OR:1.6).	('anemia', 'Phenotype', 'HP:0001903', (111, 117))	('iron deficiency anemia', 'Disease', 'MESH:D018798', (95, 117))	('iron deficiency anemia', 'Disease', (95, 117))	('PPI', 'Var', (34, 37))	('associated with', 'Reg', (60, 75))	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (95, 117))
450686	31623145	The use of either PPIs or a histamine H2 receptor antagonist for >=2 years was associated with an increased risk of iron deficiency anemia and the risk increased with increasing potency of acid inhibition and decreased after the anti-secretory drugs were stopped.	('PPIs', 'Var', (18, 22))	('iron deficiency anemia', 'Disease', 'MESH:D018798', (116, 138))	('potency', 'MPA', (178, 185))	('iron deficiency anemia', 'Disease', (116, 138))	('anemia', 'Phenotype', 'HP:0001903', (132, 138))	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (116, 138))
450689	31623145	These latter studies support the conclusion that PPIs can have a clinical effect on iron absorption in man.	('iron absorption', 'MPA', (84, 99))	('iron', 'Chemical', 'MESH:D007501', (84, 88))	('PPIs', 'Var', (49, 53))	('man', 'Species', '9606', (103, 106))
450695	31623145	Evidence suggests the development of the hypomagnesemia is a general class effect, because it was reported with all PPIs except esomeprazole and it recurred with substitution of another PPI, but not when a histamine H2-receptor antagonists is used.	('hypomagnesemia', 'Disease', 'MESH:C537153', (41, 55))	('histamine H2-receptor', 'Gene', (206, 227))	('histamine H2-receptor', 'Gene', '3274', (206, 227))	('esomeprazole', 'Chemical', 'MESH:D064098', (128, 140))	('hypomagnesemia', 'Disease', (41, 55))	('substitution', 'Var', (162, 174))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (41, 55))
450697	31623145	It has recently been shown that the regulation of transient receptor potential melastatin-6 transporters (TRPM) in the colon by PPIs may explain their effects on Mg homeostasis.	('effects', 'Reg', (151, 158))	('Mg homeostasis', 'MPA', (162, 176))	('Mg', 'Chemical', 'MESH:D008274', (162, 164))	('TRPM', 'Gene', (106, 110))	('PPIs', 'Var', (128, 132))
450707	31623145	The above rate PPI-induced hypomagnesemia in the NIH ZES patients is considerably lower than the rate of 15-55% reported in some series of non-ZES patients.	('PPI-induced', 'Var', (15, 26))	('rat', 'Species', '10116', (97, 100))	('hypomagnesemia in the NIH ZES', 'Disease', 'MESH:C537153', (27, 56))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (147, 155))	('hypomagnesemia in the NIH ZES', 'Disease', (27, 56))	('rat', 'Species', '10116', (10, 13))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (27, 41))	('lower', 'NegReg', (82, 87))
450713	31623145	The effect of PPIs on calcium absorption and metabolism is particularly controversial and an important subject because numerous studies, but not all, have reported that patients treated with PPIs have an increased occurrence of bone fractures, particularly of the vertebral column and hip.	('PPIs', 'Var', (191, 195))	('patients', 'Species', '9606', (169, 177))	('bone fracture', 'Phenotype', 'HP:0020110', (228, 241))	('calcium', 'Chemical', 'MESH:D002118', (22, 29))	('bone fractures', 'Disease', (228, 242))	('bone fractures', 'Disease', 'MESH:D050723', (228, 242))	('bone fractures', 'Phenotype', 'HP:0020110', (228, 242))
450718	31623145	At present, there is no agreement of the mechanism by which PPIs could be causing the increase occurrence of bone fractures.	('bone fractures', 'Disease', 'MESH:D050723', (109, 123))	('bone fractures', 'Phenotype', 'HP:0020110', (109, 123))	('bone fracture', 'Phenotype', 'HP:0020110', (109, 122))	('bone fractures', 'Disease', (109, 123))	('PPIs', 'Var', (60, 64))
450722	31623145	Although a placebo controlled, double-blind trial in postmenopausal females found decreased calcium absorption with PPI treatment, the results suggesting PPI causes osteoporosis are largely negative, as are studies reporting PPI treatment does not cause changes in bone mineral density or bone structure that would predispose to fracture.	('fracture', 'Disease', 'MESH:D050723', (329, 337))	('osteoporosis', 'Disease', 'MESH:D010024', (165, 177))	('fracture', 'Disease', (329, 337))	('osteoporosis', 'Disease', (165, 177))	('PPI', 'Var', (154, 157))	('calcium absorption', 'MPA', (92, 110))	('PPI', 'Var', (116, 119))	('calcium', 'Chemical', 'MESH:D002118', (92, 99))	('predispose to fracture', 'Phenotype', 'HP:0002659', (315, 337))	('osteoporosis', 'Phenotype', 'HP:0000939', (165, 177))	('decreased', 'NegReg', (82, 91))
450731	31623145	Therefore, the presence of ZES introduces additional causes for effects on calcium homeostasis and/or bone metabolism, which could contribute to bone fractures and thus confounds the ability to determine the possible role of PPIs only in these processes.	('bone fracture', 'Phenotype', 'HP:0020110', (145, 158))	('bone fractures', 'Disease', (145, 159))	('bone metabolism', 'CPA', (102, 117))	('presence', 'Var', (15, 23))	('calcium', 'Chemical', 'MESH:D002118', (75, 82))	('bone fractures', 'Phenotype', 'HP:0020110', (145, 159))	('bone fractures', 'Disease', 'MESH:D050723', (145, 159))	('contribute', 'Reg', (131, 141))	('calcium', 'CPA', (75, 82))	('effects', 'Reg', (64, 71))
450888	28092855	The quantification was performed by selected reaction monitoring (SRM) at negative mode to detect the specific precursor to product ion transitions m/z 179   59 for D-mannose, and m/z 185   92 for IS (IS fragmentation pattern is shown in Supplementary material Fig.	('m/z 185   92', 'Var', (180, 192))	('m/z 179   59', 'Var', (148, 160))	('D-mannose', 'Chemical', 'MESH:D008358', (165, 174))
450943	28857475	Additionally, IFITM3 overexpression, advanced T status, poor degree of differentiation, and large tumor size were not only associated with poor survival but were high lymphatic metastatic recurrence predictors in ESCC patients (P < 0.05).	('patients', 'Species', '9606', (218, 226))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('IFITM3', 'Gene', '10410', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('overexpression', 'PosReg', (21, 35))	('IFITM3', 'Gene', (14, 20))	('ESCC', 'Disease', (213, 217))	('poor', 'Var', (56, 60))	('tumor', 'Disease', (98, 103))
450989	28857475	However, in patients with low IFITM3 expression, the survival rate was 58.4% and the lymphatic metastatic recurrence rate was only 64.9% (Table 1).	('patients', 'Species', '9606', (12, 20))	('low', 'Var', (26, 29))	('lymphatic metastatic recurrence', 'CPA', (85, 116))	('IFITM3', 'Gene', (30, 36))	('IFITM3', 'Gene', '10410', (30, 36))
451035	27370795	TLR5, TLR7, and TLR8 activation increases proliferation, and TLR2, TLR4, and TLR9 activation induces invasion in gastrointestinal cancer cells.	('proliferation', 'CPA', (42, 55))	('gastrointestinal cancer', 'Disease', (113, 136))	('activation', 'Var', (21, 31))	('TLR9', 'Gene', (77, 81))	('TLR7', 'Gene', (6, 10))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (113, 136))	('invasion', 'CPA', (101, 109))	('TLR2', 'Gene', (61, 65))	('TLR5', 'Gene', (0, 4))	('induces', 'Reg', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('TLR4', 'Gene', (67, 71))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (113, 136))	('increases', 'PosReg', (32, 41))	('TLR8', 'Gene', (16, 20))
451068	27370795	In addition, TLR2, TLR3, and TLR5 showed occasional nuclear expression throughout the alimentary tract in humans, and in mouse samples, nuclear expression was seen with TLR3 to TLR6 and TLR9 in the alimentary tract.	('TLR5', 'Gene', (29, 33))	('TLR3', 'Var', (169, 173))	('nuclear expression', 'MPA', (136, 154))	('TLR6', 'Gene', '21899', (177, 181))	('mouse', 'Species', '10090', (121, 126))	('TLR2', 'Gene', (13, 17))	('nuclear expression', 'MPA', (52, 70))	('TLR3', 'Gene', (19, 23))	('TLR6', 'Gene', (177, 181))	('humans', 'Species', '9606', (106, 112))	('TLR9', 'Gene', (186, 190))
451078	27370795	In humans, the small intestine showed significantly (p<0.05) higher TLR expression compared with the large intestine for TLR3, TLR4, TLR5, TLR7, and TLR8, and in normal mice, similar difference was seen for TLR1 to TLR9 (Table 2).	('TLR8', 'Var', (149, 153))	('higher', 'PosReg', (61, 67))	('TLR5', 'Var', (133, 137))	('expression', 'MPA', (72, 82))	('humans', 'Species', '9606', (3, 9))	('mice', 'Species', '10090', (169, 173))	('TLR4', 'Var', (127, 131))	('TLR', 'Gene', (68, 71))	('TLR3', 'Var', (121, 125))
451089	27370795	Similar difference between endocrine and exocrine parts was seen with TLR1, TLR6, TLR7, and TLR8 in the normal mice pancreas and with TLR3, TLR5, and TLR6 in germ-free mice pancreas.	('TLR6', 'Gene', '21899', (76, 80))	('TLR1', 'Var', (70, 74))	('TLR7', 'Var', (82, 86))	('TLR6', 'Gene', (76, 80))	('mice', 'Species', '10090', (168, 172))	('mice', 'Species', '10090', (111, 115))	('TLR8', 'Var', (92, 96))	('TLR6', 'Gene', '21899', (150, 154))	('TLR3', 'Var', (134, 138))	('TLR6', 'Gene', (150, 154))
451094	27370795	The stomach showed significantly higher (p<0.05) TLR2 and TLR5 expressions in normal mice and TLR2, TLR3, and TLR9 in the large intestine.	('mice', 'Species', '10090', (85, 89))	('higher', 'PosReg', (33, 39))	('expressions', 'MPA', (63, 74))	('TLR2', 'Var', (94, 98))	('TLR5', 'Gene', (58, 62))	('TLR2', 'Gene', (49, 53))
451164	27133685	If intravenous gadolinium-based contrast material was administered, post-contrast sequences included T1W, FS T1W, or 3D T1W GRE.	('T1W', 'Var', (101, 104))	('FS T1W', 'Var', (106, 112))	('gadolinium', 'Chemical', 'MESH:D005682', (15, 25))
451322	25349686	Among 107 patients who had features of mucosal injury on endoscopy, most of them (76%) had LA-Grade A, 18% had LA-Grade B, 4% had LA-Grade C, and 2% had LA-Grade D. 154 patients (41%) were found to have hiatus hernia with a mean+-SD length of 3.26+-1.04 cm and only 54% of them had varying grades of endoscopic esophagitis.	('mucosal injury', 'Disease', (39, 53))	('LA-Grade', 'Var', (111, 119))	('hiatus hernia', 'Disease', (203, 216))	('patients', 'Species', '9606', (169, 177))	('hiatus hernia', 'Disease', 'MESH:D006551', (203, 216))	('mucosal injury', 'Disease', 'MESH:D052016', (39, 53))	('esophagitis', 'Phenotype', 'HP:0100633', (311, 322))	('hernia', 'Phenotype', 'HP:0100790', (210, 216))	('LA-Grade A', 'Var', (91, 101))	('patients', 'Species', '9606', (10, 18))	('esophagitis', 'Disease', (311, 322))	('hiatus hernia', 'Phenotype', 'HP:0002036', (203, 216))	('esophagitis', 'Disease', 'MESH:D004941', (311, 322))
451409	25328413	In addition, the frequent genetic and epigenetic alterations of p53-regulated miRNAs in tumors indicate that they play an important role in cancer initiation and/or progression.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('role', 'Reg', (132, 136))	('play', 'Reg', (114, 118))	('cancer', 'Disease', (140, 146))	('p53-regulated', 'Gene', (64, 77))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('epigenetic alterations', 'Var', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('genetic', 'Var', (26, 33))
451416	25328413	Tumors of the GI tract harbor mutations in the p53 tumor suppressor gene (TP53) with a prevalence ranging from 31% to 45% (Figure 1C).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('Tumors of the GI tract', 'Phenotype', 'HP:0007378', (0, 22))	('Tumors of the GI tract', 'Disease', (0, 22))	('TP53', 'Gene', '7157', (74, 78))	('mutations', 'Var', (30, 39))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Tumors of the GI tract', 'Disease', 'MESH:D004067', (0, 22))	('TP53', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
451419	25328413	Moreover, p53 inhibits epithelial to mesenchymal transition (EMT), stemness, and metabolic adaptations, which are typically found in tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('stemness', 'Disease', 'MESH:D020295', (67, 75))	('stemness', 'Disease', (67, 75))	('metabolic adaptations', 'CPA', (81, 102))	('inhibits', 'NegReg', (14, 22))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('epithelial to mesenchymal transition', 'CPA', (23, 59))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('p53', 'Var', (10, 13))
451429	25328413	It was shown that p53 interacts with the DEAD-box RNA helicase p68 (also known as DDX5) and enhances its interaction with the Drosha complex.	('p68', 'Gene', (63, 66))	('p68', 'Gene', '1655', (63, 66))	('enhances', 'PosReg', (92, 100))	('interacts', 'Interaction', (22, 31))	('Drosha', 'Gene', (126, 132))	('Drosha', 'Gene', '29102', (126, 132))	('DDX5', 'Gene', (82, 86))	('interaction', 'Interaction', (105, 116))	('DDX5', 'Gene', '1655', (82, 86))	('p53', 'Var', (18, 21))
451433	25328413	Finally, p53 also affects miRNA target gene selection by regulating mRNA-binding proteins, such as RNA-binding-motif protein 38, which competes with miR-NAs for binding to 3'-UTRs of mRNAs.	('miRNA', 'MPA', (26, 31))	('p53', 'Var', (9, 12))	('RNA-binding-motif protein 38', 'Gene', '55544', (99, 127))	('regulating', 'Reg', (57, 67))	('mRNA-binding', 'MPA', (68, 80))	('binding', 'Interaction', (161, 168))	('RNA-binding-motif protein 38', 'Gene', (99, 127))	('affects', 'Reg', (18, 25))
451434	25328413	miRNAs transcriptionally induced by p53 include the miR-34, miR-200, miR-15a/16-1, and miR-192/194/215 clusters, as well as miR-145 and miR-107.	('miR-145', 'Var', (124, 131))	('miR-34', 'Gene', '407040', (52, 58))	('miR-107', 'Gene', '406901', (136, 143))	('miR-15a/16-1', 'Gene', (69, 81))	('p53', 'Gene', (36, 39))	('miR-192', 'Gene', '406967', (87, 94))	('miR-192', 'Gene', (87, 94))	('miR-107', 'Gene', (136, 143))	('miR-34', 'Gene', (52, 58))	('miR-200', 'Var', (60, 67))
451435	25328413	Yet some of these miRNAs, such as miR-16-1, miR-145, and miR-199a-3p, are also regulated on the post-transcriptional level by p53.	('miR-199a-3p', 'Gene', (57, 68))	('miR-145', 'Var', (44, 51))	('miR-199a-3p', 'Gene', '406977', (57, 68))	('miR-16-1', 'Var', (34, 42))
451449	25328413	Furthermore, SIRT1 was shown to mediate activation of p53 by miR-34a.	('activation', 'PosReg', (40, 50))	('SIRT1', 'Gene', (13, 18))	('miR-34a', 'Var', (61, 68))	('SIRT1', 'Gene', '23411', (13, 18))
451454	25328413	By repressing both SIRT1 and MYC, miR-34a may therefore efficiently suppress this circuitry.	('miR-34a', 'Var', (34, 41))	('MYC', 'Gene', '4609', (29, 32))	('SIRT1', 'Gene', (19, 24))	('suppress', 'NegReg', (68, 76))	('MYC', 'Gene', (29, 32))	('SIRT1', 'Gene', '23411', (19, 24))
451455	25328413	Another double-negative feedback loop involving miR-34a was discovered by Siemens et al, who demonstrated that miR-34a directly targets and suppresses the EMT-inducing transcription factor (EMT-TF) SNAIL, whereas SNAIL represses the miR-34a and miR-34b/c genes by directly binding to their promoters in CRC cell lines (Figure 3C).	('binding', 'Interaction', (273, 280))	('miR-34b', 'Gene', (245, 252))	('suppresses', 'NegReg', (140, 150))	('SNAIL', 'Gene', (198, 203))	('miR-34b', 'Gene', '407041', (245, 252))	('SNAIL', 'Gene', '6615', (198, 203))	('miR-34a', 'Var', (111, 118))	('CRC', 'Phenotype', 'HP:0003003', (303, 306))	('SNAIL', 'Gene', '6615', (213, 218))	('SNAIL', 'Gene', (213, 218))	('miR-34a', 'Gene', (233, 240))
451462	25328413	Accordingly, ectopic SNAIL induced EMT by directly activating ZNF281 and concomitantly repressing miR-34a expression, which leads to a further increase in ZNF281 levels.	('ZNF281', 'Gene', (155, 161))	('EMT', 'CPA', (35, 38))	('ZNF281', 'Gene', '23528', (155, 161))	('ectopic', 'Var', (13, 20))	('expression', 'MPA', (106, 116))	('ZNF281', 'Gene', '23528', (62, 68))	('activating', 'PosReg', (51, 61))	('miR-34a', 'Gene', (98, 105))	('ZNF281', 'Gene', (62, 68))	('increase', 'PosReg', (143, 151))	('SNAIL', 'Gene', '6615', (21, 26))	('SNAIL', 'Gene', (21, 26))
451466	25328413	Furthermore, we identified the IL-6 receptor (IL-6R) as a direct target of miR-34a.	('IL-6R', 'Gene', '3570', (46, 51))	('miR-34a', 'Var', (75, 82))	('IL-6R', 'Gene', (46, 51))	('IL-6 receptor', 'Gene', '3570', (31, 44))	('IL-6 receptor', 'Gene', (31, 44))
451475	25328413	Using xenograft or genetically engineered mouse models of melanoma, lymphoma, multiple myeloma, breast, prostate, pancreatic, and non-small-cell lung cancer, the authors observed an inhibition of tumor growth by 20% to 83% after reintroduc tion of miR-34a.	('tumor', 'Disease', (196, 201))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('inhibition', 'NegReg', (182, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('multiple myeloma', 'Disease', 'MESH:D009101', (78, 94))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('pancreatic', 'Disease', 'MESH:D010195', (114, 124))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (134, 156))	('multiple myeloma', 'Disease', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('melanoma, lymphoma', 'Disease', 'MESH:D008545', (58, 76))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (130, 156))	('pancreatic', 'Disease', (114, 124))	('miR-34a', 'Var', (248, 255))	('lung cancer', 'Disease', (145, 156))	('mouse', 'Species', '10090', (42, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (68, 76))	('multiple myeloma', 'Phenotype', 'HP:0006775', (78, 94))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
451476	25328413	Importantly, no severe toxicity caused by systemic miR-34a delivery has been observed in mice.	('toxicity', 'Disease', (23, 31))	('mice', 'Species', '10090', (89, 93))	('toxicity', 'Disease', 'MESH:D064420', (23, 31))	('miR-34a', 'Var', (51, 58))
451480	25328413	However, since the majority of human tumors lack normal p53 function, replacement of miR-34 may enhance the efficacy of standard cancer therapies.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('p53', 'Protein', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('replacement', 'Var', (70, 81))	('enhance', 'PosReg', (96, 103))	('miR-34', 'Gene', (85, 91))	('cancer', 'Disease', (129, 135))	('efficacy', 'CPA', (108, 116))	('human', 'Species', '9606', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('miR-34', 'Gene', '407040', (85, 91))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
451481	25328413	Indeed, in prostate, colorectal, and bladder cancer cells, reintroduction of miR-34a precursors enhanced the sensitivity toward camptothecin, paclitaxel, 5-fluorouracil, and cisplatin.	('reintroduction', 'Var', (59, 73))	('5-fluorouracil', 'MPA', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('enhanced', 'PosReg', (96, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))	('paclitaxel', 'Chemical', 'MESH:D017239', (142, 152))	('camptothecin', 'Chemical', 'MESH:D002166', (128, 140))	('colorectal', 'Disease', 'MESH:D015179', (21, 31))	('bladder cancer', 'Disease', (37, 51))	('bladder cancer', 'Disease', 'MESH:D001749', (37, 51))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (154, 168))	('miR-34a', 'Gene', (77, 84))	('colorectal', 'Disease', (21, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (174, 183))	('sensitivity toward camptothecin', 'MPA', (109, 140))
451482	25328413	Furthermore, lentiviral transduction of miR-34a sensitized gastric and pancreatic cancer cells to radiation and to the chemotherapeutic drugs docetaxel, gemcitabine, cisplatin, and doxorubicin.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('sensitized', 'Reg', (48, 58))	('gastric', 'Disease', (59, 66))	('docetaxel', 'Chemical', 'MESH:D000077143', (142, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('doxorubicin', 'Chemical', 'MESH:D004317', (181, 192))	('gemcitabine', 'Chemical', 'MESH:C056507', (153, 164))	('miR-34a', 'Gene', (40, 47))	('lentiviral', 'Var', (13, 23))	('pancreatic cancer', 'Disease', (71, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))
451483	25328413	Moreover, we recently showed that c-Kit is an important miR-34a target that mediates, at least in part, chemosensitization by miR-34a in CRC cell lines.	('c-Kit', 'Gene', (34, 39))	('c-Kit', 'Gene', '3815', (34, 39))	('chemosensitization', 'MPA', (104, 122))	('CRC', 'Phenotype', 'HP:0003003', (137, 140))	('miR-34a', 'Var', (126, 133))
451485	25328413	Downregulation of miR-34 expression in tumors has been frequently attributed to methylation of the CpG islands present in promoters of miR-34a and miR-34b/c.	('miR-34', 'Gene', (18, 24))	('tumors', 'Disease', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('miR-34', 'Gene', '407040', (147, 153))	('miR-34', 'Gene', (135, 141))	('Downregulation', 'NegReg', (0, 14))	('expression', 'MPA', (25, 35))	('miR-34', 'Gene', '407040', (135, 141))	('miR-34', 'Gene', '407040', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('miR-34b', 'Gene', (147, 154))	('miR-34b', 'Gene', '407041', (147, 154))	('methylation', 'Var', (80, 91))	('miR-34', 'Gene', (147, 153))
451487	25328413	Moreover, a significant inverse correlation between miR-34a methylation and expression has been observed in colon tumors.	('colon tumors', 'Phenotype', 'HP:0100273', (108, 120))	('colon tumors', 'Disease', 'MESH:D015179', (108, 120))	('miR-34a', 'Gene', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('methylation', 'Var', (60, 71))	('colon tumors', 'Disease', (108, 120))	('expression', 'MPA', (76, 86))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('inverse', 'NegReg', (24, 31))
451491	25328413	Several reports showed that miR-34 methylation may also have prognostic value.	('miR-34', 'Gene', '407040', (28, 34))	('methylation', 'Var', (35, 46))	('miR-34', 'Gene', (28, 34))
451492	25328413	In our study, miR-34a methylation in primary CRC was significantly associated with increased formation of lymph node and liver metastases.	('miR-34a', 'Gene', (14, 21))	('increased', 'PosReg', (83, 92))	('CRC', 'Phenotype', 'HP:0003003', (45, 48))	('liver metastases', 'Disease', (121, 137))	('associated', 'Reg', (67, 77))	('liver metastases', 'Disease', 'MESH:D009362', (121, 137))	('methylation', 'Var', (22, 33))
451493	25328413	Recently, Wu et al analyzed miR-34a/b/c methylation in stool samples of 82 CRC patients and 40 controls.	('miR-34a/b/c', 'Var', (28, 39))	('CRC', 'Disease', (75, 78))	('patients', 'Species', '9606', (79, 87))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))
451494	25328413	They demonstrated that detection of miR-34a and miR-34b/c methylation could identify CRC with a remarkable sensitivity of 76.8% or 95% and a specificity of 93.6% or 100%, respectively.	('miR-34b', 'Gene', '407041', (48, 55))	('CRC', 'Disease', (85, 88))	('methylation', 'Var', (58, 69))	('miR-34a', 'Var', (36, 43))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))	('miR-34b', 'Gene', (48, 55))
451497	25328413	Notably, a knockout of DLEU2 or of the miR-15a/16-1-bearing intron in mice confirmed that loss of miR-15a/16-1 causes chronic lymphocytic leukemia.	('miR-15a/16-1', 'Gene', (98, 110))	('loss', 'Var', (90, 94))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (118, 146))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('mice', 'Species', '10090', (70, 74))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (118, 146))	('causes', 'Reg', (111, 117))	('chronic lymphocytic leukemia', 'Disease', (118, 146))
451504	25328413	Recently, we demonstrated that miR-15a/16-1 also inhibit EMT, invasion, and metastasis of CRC cells by directly targeting the EMT-TF AP4.	('targeting', 'Reg', (112, 121))	('miR-15a/16-1', 'Var', (31, 43))	('metastasis of CRC cells', 'CPA', (76, 99))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('invasion', 'CPA', (62, 70))	('EMT', 'CPA', (57, 60))	('AP4', 'Gene', (133, 136))	('AP4', 'Gene', '7023', (133, 136))	('inhibit', 'NegReg', (49, 56))
451507	25328413	p53 controls the expression of miR-145 by two mechanisms: first, p53 directly induces the transcription of the miR-145 gene, and second, p53 enhances miR-145 maturation via modulation of Drosha-mediated miRNA processing.	('Drosha', 'Gene', (187, 193))	('enhances', 'PosReg', (141, 149))	('modulation', 'Reg', (173, 183))	('miR-145 gene', 'Gene', (111, 123))	('p53', 'Var', (137, 140))	('Drosha', 'Gene', '29102', (187, 193))	('miR-145', 'Protein', (150, 157))	('transcription', 'MPA', (90, 103))	('p53', 'Var', (65, 68))	('induces', 'PosReg', (78, 85))
451508	25328413	In line with a regulation by p53, expression of miR-145 is significantly lower in various tumors that harbor p53 mutations, including esophageal, gastric, pancreatic, colorectal, and bladder cancers.	('esophageal', 'Disease', (134, 144))	('expression', 'MPA', (34, 44))	('colorectal', 'Disease', (167, 177))	('gastric', 'Disease', (146, 153))	('mutations', 'Var', (113, 122))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('miR-145', 'Gene', (48, 55))	('pancreatic', 'Disease', (155, 165))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('bladder cancers', 'Phenotype', 'HP:0009725', (183, 198))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('bladder cancer', 'Phenotype', 'HP:0009725', (183, 197))	('colorectal', 'Disease', 'MESH:D015179', (167, 177))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('p53', 'Gene', (109, 112))	('bladder cancers', 'Disease', 'MESH:D001749', (183, 198))	('lower', 'NegReg', (73, 78))	('bladder cancers', 'Disease', (183, 198))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('pancreatic', 'Disease', 'MESH:D010195', (155, 165))
451509	25328413	Accordingly, ectopic miR-145 suppresses migration, invasion, and metastasis of gastric and colorectal cancer cells.	('suppresses', 'NegReg', (29, 39))	('metastasis', 'CPA', (65, 75))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ectopic', 'Var', (13, 20))	('gastric', 'Disease', (79, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('miR-145', 'Gene', (21, 28))	('migration', 'CPA', (40, 49))	('invasion', 'CPA', (51, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))
451510	25328413	Moreover, therapeutic polyethylenimine-mediated reintroduction of miR-145 reduces proliferation and increases apoptosis of CRC cells in xenograft mouse models.	('reintroduction', 'Var', (48, 62))	('increases', 'PosReg', (100, 109))	('mouse', 'Species', '10090', (146, 151))	('miR-145', 'Gene', (66, 73))	('proliferation', 'CPA', (82, 95))	('polyethylenimine', 'Chemical', 'MESH:D011094', (22, 38))	('reduces', 'NegReg', (74, 81))	('apoptosis', 'CPA', (110, 119))	('CRC', 'Phenotype', 'HP:0003003', (123, 126))
451512	25328413	Similar to miR-34, miR-200, and miR-15a/16-1, miR-145 has also been shown to represent a mediator of p53-induced MET, the reversion of EMT (Figure 3C).	('miR-34', 'Gene', '407040', (11, 17))	('miR-145', 'Var', (46, 53))	('EMT', 'CPA', (135, 138))	('p53-induced', 'Var', (101, 112))	('miR-34', 'Gene', (11, 17))
451518	25328413	Loss of p53 leads to increased generation of induced pluripotent stem cells and expansion of cancer stem cells.	('cancer', 'Disease', (93, 99))	('increased', 'PosReg', (21, 30))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('p53', 'Gene', (8, 11))	('expansion', 'CPA', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('induced pluripotent stem cells', 'MPA', (45, 75))	('Loss', 'Var', (0, 4))
451519	25328413	This effect might at least in part be due to the lack of p53-induced miR-145 expression and consequent upregulation of OCT4.	('expression', 'MPA', (77, 87))	('upregulation', 'PosReg', (103, 115))	('lack', 'NegReg', (49, 53))	('p53-induced', 'Var', (57, 68))	('OCT4', 'Gene', '5460', (119, 123))	('OCT4', 'Gene', (119, 123))	('miR-145', 'Gene', (69, 76))
451525	25328413	Furthermore, low expression of miR-194 and miR-215 significantly correlates with a high probability of relapse and shorter survival in colorectal patients.	('colorectal', 'Disease', (135, 145))	('low', 'NegReg', (13, 16))	('miR-194', 'Var', (31, 38))	('expression', 'MPA', (17, 27))	('miR-215', 'Gene', (43, 50))	('shorter', 'NegReg', (115, 122))	('miR-215', 'Gene', '406997', (43, 50))	('colorectal', 'Disease', 'MESH:D015179', (135, 145))	('patients', 'Species', '9606', (146, 154))	('relapse', 'CPA', (103, 110))
451527	25328413	Moreover, miR-192 suppresses liver metastasis of CRC cells by targeting BCL2, ZEB2, and VEGF-A, while miR-194 inhibits EMT in endometrial cells by targeting BMI-1.	('ZEB2', 'Gene', '9839', (78, 82))	('EMT in endometrial', 'CPA', (119, 137))	('liver metastasis of CRC cells', 'CPA', (29, 58))	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('miR-194', 'Var', (102, 109))	('inhibits', 'NegReg', (110, 118))	('ZEB2', 'Gene', (78, 82))	('BCL2', 'Gene', '596', (72, 76))	('miR-192', 'Gene', '406967', (10, 17))	('miR-192', 'Gene', (10, 17))	('BMI-1', 'Gene', (157, 162))	('VEGF-A', 'Gene', '7422', (88, 94))	('BCL2', 'Gene', (72, 76))	('suppresses', 'NegReg', (18, 28))	('VEGF-A', 'Gene', (88, 94))	('BMI-1', 'Gene', '648', (157, 162))
451528	25328413	Importantly, similar to other p53-induced miRNAs, miR-192, miR-194, and miR-215 also directly target MDM2 and therefore interfere with the autoregulatory MDM2/p53 loop (Figure 3A).	('miR-192', 'Gene', (50, 57))	('miR-215', 'Gene', '406997', (72, 79))	('interfere with', 'NegReg', (120, 134))	('miR-194', 'Var', (59, 66))	('MDM2', 'Gene', '4193', (154, 158))	('MDM2', 'Gene', (154, 158))	('miR-215', 'Gene', (72, 79))	('MDM2', 'Gene', '4193', (101, 105))	('miR-192', 'Gene', '406967', (50, 57))	('MDM2', 'Gene', (101, 105))	('target', 'Reg', (94, 100))
451536	25328413	Several studies showed that ectopic expression of miR-107 enhances EMT, migration, and promotes metastatic dissemination, whereas the loss of miR-107 represses migration and metastasis of colorectal, breast, and gastric cancer cells.	('miR-107', 'Gene', '406901', (142, 149))	('migration', 'CPA', (72, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (212, 226))	('metastatic dissemination', 'CPA', (96, 120))	('miR-107', 'Gene', '406901', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('miR-107', 'Gene', (142, 149))	('colorectal', 'Disease', 'MESH:D015179', (188, 198))	('EMT', 'CPA', (67, 70))	('breast', 'Disease', (200, 206))	('miR-107', 'Gene', (50, 57))	('gastric cancer', 'Disease', 'MESH:D013274', (212, 226))	('colorectal', 'Disease', (188, 198))	('gastric cancer', 'Disease', (212, 226))	('promotes', 'PosReg', (87, 95))	('represses', 'NegReg', (150, 159))	('enhances', 'PosReg', (58, 66))	('loss', 'Var', (134, 138))
451545	25328413	These tumor suppressing effects could be partially attributed to the miR-107-mediated repression of the response to hypoxia and angiogenesis via targeting of HIF 1beta, resulting in a decreased supply of oxygen and nutrients and subsequent inhibition of tumor growth.	('inhibition', 'NegReg', (240, 250))	('miR-107', 'Gene', (69, 76))	('HIF 1beta', 'Gene', (158, 167))	('tumor', 'Disease', (254, 259))	('hypoxia', 'Disease', (116, 123))	('hypoxia', 'Disease', 'MESH:D000860', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('decreased', 'NegReg', (184, 193))	('oxygen', 'Chemical', 'MESH:D010100', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('miR-107', 'Gene', '406901', (69, 76))	('targeting', 'Var', (145, 154))	('tumor', 'Disease', (6, 11))
451546	25328413	The decrease in functional HIF1alpha-HIF1beta dimers after p53-mediated activation of miR-107 may suppress glycolysis under hypoxic conditions.	('activation', 'PosReg', (72, 82))	('HIF1alpha-HIF1beta', 'Gene', (27, 45))	('miR-107', 'Gene', (86, 93))	('HIF1alpha-HIF1beta', 'Gene', '3091;405', (27, 45))	('p53-mediated', 'Var', (59, 71))	('decrease', 'NegReg', (4, 12))	('hypoxic conditions', 'Disease', (124, 142))	('miR-107', 'Gene', '406901', (86, 93))	('suppress', 'NegReg', (98, 106))	('hypoxic conditions', 'Disease', 'MESH:D009135', (124, 142))	('glycolysis', 'MPA', (107, 117))	('functional', 'MPA', (16, 26))
451550	25328413	A possible explanation may be that p53 induces miR-107 and thereby downregulates DICER1 to limit the production of p53-induced miRNAs, which would otherwise lead to an unrestrained induction of p53 because of the positive feedback loops these often form with p53.	('downregulates', 'NegReg', (67, 80))	('production', 'MPA', (101, 111))	('limit', 'NegReg', (91, 96))	('DICER1', 'Gene', '23405', (81, 87))	('miR-107', 'Gene', '406901', (47, 54))	('DICER1', 'Gene', (81, 87))	('p53', 'Var', (35, 38))	('miR-107', 'Gene', (47, 54))	('induces', 'Reg', (39, 46))
451558	25328413	Since these miRNAs diminish the tumor suppressive activity of p53, they often represent oncomirs.	('miRNAs', 'Var', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('diminish', 'NegReg', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('p53', 'Protein', (62, 65))	('tumor', 'Disease', (32, 37))
451566	25328413	Additionally, miR-25, miR-30d, miR-33, miR-98, miR-150, miR-214, miR-375, miR-380, and miR-1285 also downregulate p53 protein levels through seed-matching sequences in the 3'-UTR of TP53.	('miR-214', 'Gene', (56, 63))	('miR-375', 'Gene', (65, 72))	('TP53', 'Gene', (182, 186))	('miR-33', 'Gene', (31, 37))	('miR-150', 'Gene', (47, 54))	('miR-1285', 'Var', (87, 95))	('p53 protein levels', 'MPA', (114, 132))	('miR-25', 'Gene', '407014', (14, 20))	('downregulate', 'NegReg', (101, 113))	('miR-98', 'Gene', '407054', (39, 45))	('miR-380', 'Gene', (74, 81))	('TP53', 'Gene', '7157', (182, 186))	('miR-33', 'Gene', '407039', (31, 37))	('miR-150', 'Gene', '406942', (47, 54))	('miR-30d', 'Gene', (22, 29))	('miR-214', 'Gene', '406996', (56, 63))	('miR-25', 'Gene', (14, 20))	('miR-98', 'Gene', (39, 45))	('miR-375', 'Gene', '494324', (65, 72))	('miR-380', 'Gene', '494329', (74, 81))	('miR-30d', 'Gene', '407033', (22, 29))
451569	25328413	MiR-30d is an important regulator of autophagy, and interestingly, amplification of the MIR30D gene was found in ~30% of 1,283 analyzed solid tumors, including bladder, colorectal, and pancreatic cancer.	('pancreatic cancer', 'Disease', (185, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('MIR30D', 'Gene', '407033', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('found', 'Reg', (104, 109))	('solid tumors', 'Disease', (136, 148))	('bladder', 'Disease', (160, 167))	('pancreatic cancer', 'Disease', 'MESH:D010190', (185, 202))	('colorectal', 'Disease', (169, 179))	('amplification', 'Var', (67, 80))	('MIR30D', 'Gene', (88, 94))	('MiR-30d', 'Gene', (0, 7))	('MiR-30d', 'Gene', '407033', (0, 7))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (185, 202))	('colorectal', 'Disease', 'MESH:D015179', (169, 179))
451570	25328413	As described above, the expression of the p53 inhibitors MDM2 and MDM4 is directly repressed by several p53-induced miRNAs: MDM2 is a target of miR-145, miR-192/194/215, miR-605, and miR-29b, whereas MDM4 is targeted by the miR-34 family members (Figure 3A).	('miR-34', 'Gene', (224, 230))	('miR-34', 'Gene', '407040', (224, 230))	('MDM4', 'Gene', '4194', (66, 70))	('MDM2', 'Gene', '4193', (57, 61))	('miR-29b', 'Gene', '407024', (183, 190))	('MDM2', 'Gene', (57, 61))	('miR-605', 'Gene', (170, 177))	('MDM4', 'Gene', (66, 70))	('MDM4', 'Gene', '4194', (200, 204))	('miR-192', 'Gene', (153, 160))	('MDM4', 'Gene', (200, 204))	('MDM2', 'Gene', '4193', (124, 128))	('miR-192', 'Gene', '406967', (153, 160))	('miR-605', 'Gene', '693190', (170, 177))	('MDM2', 'Gene', (124, 128))	('miR-145', 'Var', (144, 151))	('miR-29b', 'Gene', (183, 190))
451577	25328413	Interestingly, Cyclin G1 is also directly induced by p53 and therefore forms a negative feedback loop with p53.	('Cyclin G1', 'Gene', (15, 24))	('Cyclin G1', 'Gene', '900', (15, 24))	('induced', 'Reg', (42, 49))	('p53', 'Var', (53, 56))
451579	25328413	Indeed, it has been shown that ectopic miR-122 expression increases the sensitivity of HCC cell lines to the chemotherapeutic agent doxorubicin, which is known to induce p53.	('increases', 'PosReg', (58, 67))	('sensitivity', 'MPA', (72, 83))	('ectopic', 'Var', (31, 38))	('miR-122', 'Gene', (39, 46))	('miR-122', 'Gene', '406906', (39, 46))	('doxorubicin', 'Chemical', 'MESH:D004317', (132, 143))
451590	25328413	Promisingly, improved delivery using novel nanoparticles was recently employed to show that a combination of miR-34a mimics and siRNAs directed at mutant oncogenes is more effective than either RNA alone in a pre-clinical mouse model of lung cancer.	('mutant', 'Var', (147, 153))	('effective', 'MPA', (172, 181))	('lung cancer', 'Disease', (237, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (237, 248))	('mouse', 'Species', '10090', (222, 227))	('miR-34a', 'Gene', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('lung cancer', 'Disease', 'MESH:D008175', (237, 248))	('siRNAs', 'Gene', (128, 134))
451607	24885648	Clinicopathologic findings on blood examination were metabolic alkalosis (pH 7.51 [reference value 7.351-7.463], HCO3 38.6 mmol/L [reference value 18-24 mmol/L]), hypokalemia (2.9 mmol/L [reference value 3.6-5.6 mmol/L]), both likely attributable to the vomiting, and a mild, stress- induced hyperglycemia (132 mg/dl [reference value 55-100 mg/dl]).	('hypokalemia', 'Disease', 'MESH:D007008', (163, 174))	('metabolic alkalosis', 'Disease', 'MESH:D000471', (53, 72))	('hypokalemia', 'Disease', (163, 174))	('metabolic alkalosis', 'Phenotype', 'HP:0200114', (53, 72))	('hypokalemia', 'Phenotype', 'HP:0002900', (163, 174))	('pH', 'Var', (74, 76))	('hyperglycemia', 'Phenotype', 'HP:0003074', (292, 305))	('vomiting', 'Phenotype', 'HP:0002013', (254, 262))	('HCO3', 'Chemical', 'MESH:D001639', (113, 117))	('hyperglycemia', 'Disease', 'MESH:D006943', (292, 305))	('vomiting', 'Disease', (254, 262))	('vomiting', 'Disease', 'MESH:D014839', (254, 262))	('stress- induced hyperglycemia', 'Phenotype', 'HP:0011998', (276, 305))	('metabolic alkalosis', 'Disease', (53, 72))	('hyperglycemia', 'Disease', (292, 305))	('alkalosis', 'Phenotype', 'HP:0001948', (63, 72))
451680	24130810	A number of single nucleotide polymorphisms (SNPs) of IL-18 gene have been identified and investigated.	('IL-18', 'Gene', (54, 59))	('single nucleotide polymorphisms', 'Var', (12, 43))	('IL-18', 'Gene', '3606', (54, 59))
451682	24130810	The C to A substitution at position -607 disrupts a consensus cAMP-responsive element protein-binding site, causing altered transcription factor binding and gene expression.	('disrupts', 'NegReg', (41, 49))	('gene expression', 'MPA', (157, 172))	('C to A substitution', 'Var', (4, 23))	('transcription factor', 'MPA', (124, 144))	('substitution', 'Var', (11, 23))	('cAMP', 'Chemical', '-', (62, 66))	('altered', 'Reg', (116, 123))
451687	24130810	Search terms included: "Interleukin-18" or "IL-18" or "rs1946518" in combination with "polymorphism" or "variant" and ''cancer'' or ''neoplasm'' or ''malignancy''.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	("''cancer", 'Disease', (118, 126))	('rs1946518', 'Mutation', 'rs1946518', (55, 64))	("''neoplasm'' or ''malignancy", 'Disease', 'MESH:D009369', (132, 160))	("''cancer", 'Disease', 'MESH:D009369', (118, 126))	('neoplasm', 'Phenotype', 'HP:0002664', (134, 142))	('polymorphism" or "variant', 'Var', (87, 112))	('IL-18', 'Gene', '3606', (44, 49))	('Interleukin-18', 'Gene', '3606', (24, 38))	('rs1946518', 'Var', (55, 64))	('IL-18', 'Gene', (44, 49))	("''neoplasm'' or ''malignancy", 'Disease', (132, 160))	('Interleukin-18', 'Gene', (24, 38))
451688	24130810	Studies were selected according to the following inclusion criteria: (i) case-control studies; (ii) investigating the association between IL-18 rs1946518 (C>A) SNP and cancer risk; (iii)cancers diagnosed by histopathology; (iiii) providing detail genotype frequencies.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('IL-18', 'Gene', (138, 143))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('rs1946518', 'Var', (144, 153))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('rs1946518', 'Mutation', 'rs1946518', (144, 153))	('IL-18', 'Gene', '3606', (138, 143))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
451691	24130810	The association strength between -607 C/A (rs1946518) polymorphism and cancer risk was measured by odds ratio (OR) with 95% confidence intervals (95% CI).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('association', 'Interaction', (4, 15))	('cancer', 'Disease', (71, 77))	('-607 C/A', 'Mutation', 'rs1946518', (33, 41))	('rs1946518', 'Mutation', 'rs1946518', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs1946518', 'Var', (43, 52))
451695	24130810	In the study reported by Haghshenas MR and colleagues, they investigated rs1946518 polymorphisms and colorectal cancer, as well as stomach cancer, and the data was presented separately, thus both of them were considered as a separate study in this meta-analysis.	('rs1946518', 'Mutation', 'rs1946518', (73, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('stomach cancer', 'Disease', 'MESH:D013274', (131, 145))	('stomach cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('stomach cancer', 'Disease', (131, 145))	('polymorphisms', 'Var', (83, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('rs1946518 polymorphisms', 'Var', (73, 96))	('investigated', 'Reg', (60, 72))	('colorectal cancer', 'Disease', (101, 118))
451700	24130810	In a stratified analysis by specific cancer types, -607C/A polymorphisms in IL-18 gene promoter was significantly associated with an increased risk of nasopharyngeal carcinoma (CA vs CC:OR =1.330, 95% CI: 1.029,1.719; Pheterogeneity=0.704; AA/CA vs. CC:OR =1.323, 95% CI: 1.037,1.687; Pheterogeneity=0.823) and esophageal cancer(CA vs CC:OR =1.371, 95% CI: 1.045,1.800; Pheterogeneity=0.528; AA/CA vs. CC:OR =1.289, 95% CI: 1.002,1.658; Pheterogeneity=0.700) in the heterozygous model and dominant model.	('-607C/A', 'Mutation', 'rs1946518', (51, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (311, 328))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('IL-18', 'Gene', '3606', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('nasopharyngeal carcinoma', 'Disease', (151, 175))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (151, 175))	('cancer', 'Disease', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('cancer', 'Disease', (322, 328))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (151, 175))	('polymorphisms', 'Var', (59, 72))	('IL-18', 'Gene', (76, 81))	('associated', 'Reg', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('esophageal cancer', 'Disease', (311, 328))
451702	24130810	According to ethnicity, the polymorphism presented a significantly increased risk of cancer among Asian population in the heterozygous model and dominant model(CA vs CC:OR =1.191, 95% CI: 1.047,1.356; Pheterogeneity=0.487; AA/CA vs. CC:OR =1.197, 95% CI: 1.023,1.401; Pheterogeneity=0.088); however, no significant association was found in Caucasian and African population (shown in Table 2).	('cancer', 'Disease', (85, 91))	('polymorphism', 'Var', (28, 40))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
451703	24130810	In the stratified analysis by source of control groups, we found that the -607C/A polymorphisms in IL-18 gene promoter was associated with a significantly increased risk in hospital-based controls in the allelic model (A vs C:OR =1.247, 95% CI: 1.022, 1.523; Pheterogeneity=0.005), heterozygous model(A vs C:OR =1.353, 95% CI: 1.115, 1.642; Pheterogeneity=0.435), and dominant model(A vs C:OR =1.362, 95% CI: 1.134,1.635; Pheterogeneity=0.116).	('the -607C/A', 'Var', (70, 81))	('-607C/A', 'Mutation', 'rs1946518', (74, 81))	('IL-18', 'Gene', '3606', (99, 104))	('IL-18', 'Gene', (99, 104))
451710	24130810	This finding indicates that the genetic variant in IL-18 gene promoter region may crucially modify the susceptibility of cancers.	('IL-18', 'Gene', '3606', (51, 56))	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('genetic variant', 'Var', (32, 47))	('IL-18', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('modify', 'Reg', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
451720	24130810	However, no evidence of association was found in any genetic model between-607C/A polymorphisms in IL-18 gene promoter and the risk of prostate cancer, colorectal cancer, breast cancer, cervical cancer, or other cancers.	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('polymorphisms', 'Var', (82, 95))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('colorectal cancer', 'Disease', (152, 169))	('IL-18', 'Gene', '3606', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('-607C/A', 'Mutation', 'rs1946518', (74, 81))	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('breast cancer', 'Disease', (171, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('prostate cancer', 'Disease', 'MESH:D011471', (135, 150))	('prostate cancer', 'Phenotype', 'HP:0012125', (135, 150))	('cancers', 'Disease', (212, 219))	('IL-18', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('prostate cancer', 'Disease', (135, 150))	('cervical cancer', 'Disease', (186, 201))	('cervical cancer', 'Disease', 'MESH:D002583', (186, 201))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
451752	22450065	Two-tailed Fisher's exact test was performed in GraphPad software [http://www.graphpad.com/quickcalcs/contingency1.cfm] to determine if there significant difference in the frequencies of copy number changes between the two cancer types.	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('copy number changes', 'Var', (187, 206))
451755	22450065	We also observed other regions of gain such as on 1p, 1q, 6p, 7q22, 8p, 10q, 11q, 12p11, 13q, 15q, 19q, 20q, and loss on 4p, 4q, 5q, 6q, 9p, 11p, 12q, 18q, 20p, 21q, and 22q in both ESCC and EA.	('gain', 'PosReg', (34, 38))	('SCC', 'Gene', (183, 186))	('loss', 'NegReg', (113, 117))	('12p11', 'Var', (82, 87))	('SCC', 'Gene', '6317', (183, 186))
451758	22450065	Similarly, 8/13 (62%) of the copy number loss regions were observed at significantly higher frequencies in ESCC in comparison to EAC.	('SCC', 'Gene', (108, 111))	('SCC', 'Gene', '6317', (108, 111))	('copy number loss', 'Var', (29, 45))	('higher', 'PosReg', (85, 91))
451765	22450065	Interestingly, we observed two loci that displayed an opposite pattern of copy number changes in the two cancers (indicated by '*' in Figure 1 and Table 2).	('copy', 'Var', (74, 78))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
451771	22450065	We found considerable similarity between these two tumor types but also many focal regions of DNA amplification or loss that are more frequent in one histologic type than in the other.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('loss', 'NegReg', (115, 119))	('tumor', 'Disease', (51, 56))	('DNA amplification', 'Var', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
451775	22450065	For example, studies have been conducted with EGFR inhibitors in esophageal cancer and the results showed 8% partial responses in patients with advanced ESCC and no significant benefit for patients with EAC.	('esophageal cancer', 'Disease', (65, 82))	('SCC', 'Gene', '6317', (154, 157))	('EGFR', 'Gene', '1956', (46, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('patients', 'Species', '9606', (130, 138))	('EGFR', 'Gene', (46, 50))	('SCC', 'Gene', (154, 157))	('patients', 'Species', '9606', (189, 197))	('inhibitors', 'Var', (51, 61))
451777	22450065	CDK6 in particular is interesting as we have recently reported that amplification of this region is associated with poor survival in EAC.	('CDK6', 'Gene', (0, 4))	('associated', 'Reg', (100, 110))	('CDK6', 'Gene', '1021', (0, 4))	('EAC', 'Disease', (133, 136))	('amplification', 'Var', (68, 81))
451779	22450065	We also showed that small interfering RNA knockdown, or inhibition with the CDK4/6 inhibitor PD-0332991 (Pfizer, New York, NY), resulted in reduced proliferation and anchorage independent growth in EAC cell lines.	('inhibition', 'NegReg', (56, 66))	('PD-0332991', 'Chemical', 'MESH:C500026', (93, 103))	('proliferation', 'CPA', (148, 161))	('small interfering', 'Var', (20, 37))	('CDK4/6', 'Gene', '1019;1021', (76, 82))	('RNA', 'Gene', (38, 41))	('reduced', 'NegReg', (140, 147))	('CDK4/6', 'Gene', (76, 82))	('anchorage independent growth', 'CPA', (166, 194))	('knockdown', 'Var', (42, 51))
451780	22450065	Thus, CDK6 inhibitors may provide a novel therapeutic target for EAC.	('CDK6', 'Gene', '1021', (6, 10))	('EAC', 'Disease', (65, 68))	('inhibitors', 'Var', (11, 21))	('CDK6', 'Gene', (6, 10))
451786	22450065	These very focal amplification events have been identified previously in EAC, and Lin et al, also demonstrated that GATA4 is over-expressed in association with amplification in EAC.	('EAC', 'Disease', (177, 180))	('amplification', 'Var', (160, 173))	('over-expressed', 'PosReg', (125, 139))	('GATA4', 'Gene', '2626', (116, 121))	('GATA4', 'Gene', (116, 121))
451800	22450065	Finally, other areas of differential amplification include 19p, which was amplified 11% of ESCC but lost in 11% of EAC19p and contains ZNF492, another putative cancer gene.	('EAC19p', 'Var', (115, 121))	('ZNF492', 'Gene', '57615', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('SCC', 'Gene', '6317', (92, 95))	('cancer', 'Disease', (160, 166))	('lost', 'NegReg', (100, 104))	('ZNF492', 'Gene', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('SCC', 'Gene', (92, 95))	('contains', 'Reg', (126, 134))
451801	22450065	In addition amplification of 2q31-q33 is more prevalent in ESCC but contains approximately 160 genes with no clear candidate as the drivers.	('SCC', 'Gene', '6317', (60, 63))	('prevalent', 'Reg', (46, 55))	('amplification', 'Var', (12, 25))	('SCC', 'Gene', (60, 63))	('2q31-q33', 'Gene', (29, 37))
451802	22450065	In summary, we have used high resolution SNP array analysis to determine the frequencies of DNA copy number gains and losses across the entire genome of 70 ESCC and 189 EAC samples.	('SCC', 'Gene', (157, 160))	('DNA', 'Gene', (92, 95))	('losses', 'NegReg', (118, 124))	('gains', 'PosReg', (108, 113))	('SCC', 'Gene', '6317', (157, 160))	('copy number', 'Var', (96, 107))
451822	33578925	Fusion of the androgen receptor (AR) target gene TMPRSS2 to the ETS (E26 transcription-specific) gene family (ERG, ETV1, and ETV4), particularly the TMPRSS2-ERG, commonly occurs in PC and plays important role in PC initiation and progression.	('ERG', 'Gene', (157, 160))	('TMPRSS2', 'Gene', '7113', (149, 156))	('ERG', 'Gene', '2078', (110, 113))	('TMPRSS2', 'Gene', (149, 156))	('ETV1', 'Gene', (115, 119))	('ERG', 'Gene', '2078', (157, 160))	('androgen receptor', 'Gene', (14, 31))	('AR', 'Gene', '367', (33, 35))	('role', 'Reg', (204, 208))	('androgen receptor', 'Gene', '367', (14, 31))	('ETV4', 'Gene', (125, 129))	('ETV1', 'Gene', '2115', (115, 119))	('occurs', 'Reg', (171, 177))	('TMPRSS2', 'Gene', '7113', (49, 56))	('ETV4', 'Gene', '2118', (125, 129))	('Fusion', 'Var', (0, 6))	('PC', 'Gene', '5091', (212, 214))	('PC', 'Phenotype', 'HP:0012125', (212, 214))	('PC', 'Gene', '5091', (181, 183))	('PC', 'Phenotype', 'HP:0012125', (181, 183))	('ERG', 'Gene', (110, 113))	('TMPRSS2', 'Gene', (49, 56))
451836	33578925	Ectopic expression of CNTN1 in LNCaP cells enhances cell proliferation.	('CNTN1', 'Gene', (22, 27))	('cell proliferation', 'CPA', (52, 70))	('enhances', 'PosReg', (43, 51))	('Ectopic expression', 'Var', (0, 18))	('LNCaP', 'CellLine', 'CVCL:0395', (31, 36))
451838	33578925	The 10 leading-edge genes of this enrichment are novel to PC; they display differential expression in PC compared to normal prostate tissue, PCs with TMPRSS2-ERG fusion compared to those without the fusion, and mPCs compared to primary PC.	('PC', 'Gene', '5091', (102, 104))	('PC', 'Phenotype', 'HP:0012125', (102, 104))	('PC', 'Gene', '5091', (212, 214))	('PC', 'Phenotype', 'HP:0012125', (212, 214))	('PC', 'Gene', '5091', (141, 143))	('PC', 'Gene', '5091', (58, 60))	('PC', 'Phenotype', 'HP:0012125', (236, 238))	('PC', 'Phenotype', 'HP:0012125', (58, 60))	('PC', 'Phenotype', 'HP:0012125', (141, 143))	('TMPRSS2', 'Gene', '7113', (150, 157))	('men', 'Species', '9606', (40, 43))	('PC', 'Gene', '5091', (236, 238))	('fusion', 'Var', (162, 168))	('ERG', 'Gene', '2078', (158, 161))	('expression', 'MPA', (88, 98))	('ERG', 'Gene', (158, 161))	('TMPRSS2', 'Gene', (150, 157))
451871	33578925	In comparison to LNCaP EV cells, LNCaP CNTN1 cells display increases in cell proliferation (Figure 1B) and colony formation (Figure 1C,D), supporting CNTN1 enhancing LNCaP cell proliferation.	('colony formation', 'CPA', (107, 123))	('LNCaP', 'CellLine', 'CVCL:0395', (33, 38))	('CNTN1', 'Var', (150, 155))	('LNCaP cell proliferation', 'CPA', (166, 190))	('cell proliferation', 'CPA', (72, 90))	('LNCaP', 'CellLine', 'CVCL:0395', (166, 171))	('LNCaP', 'CellLine', 'CVCL:0395', (17, 22))	('enhancing', 'PosReg', (156, 165))	('LNCaP CNTN1', 'CellLine', 'CVCL:0395', (33, 44))	('increases', 'PosReg', (59, 68))
451888	33578925	PCs within iCluster 1 are featured with ETV1 and ETV4 fusion, SHOP mutations, FOXA1 mutations, and CHD1 deletion, but lack ERG fusion.	('fusion', 'Var', (54, 60))	('ERG', 'Gene', (123, 126))	('ETV1', 'Gene', '2115', (40, 44))	('PC', 'Gene', '5091', (0, 2))	('CHD1', 'Gene', (99, 103))	('FOXA1', 'Gene', '3169', (78, 83))	('PC', 'Phenotype', 'HP:0012125', (0, 2))	('CHD1', 'Gene', '1105', (99, 103))	('ETV4', 'Gene', (49, 53))	('lack ERG', 'Phenotype', 'HP:0000550', (118, 126))	('FOXA1', 'Gene', (78, 83))	('mutations', 'Var', (67, 76))	('mutations', 'Var', (84, 93))	('ETV4', 'Gene', '2118', (49, 53))	('ERG', 'Gene', '2078', (123, 126))	('ETV1', 'Gene', (40, 44))	('deletion', 'Var', (104, 112))
451889	33578925	iCluster 2 PCs are enriched with ERG fusion and PTEN deletion.	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('PC', 'Gene', '5091', (11, 13))	('deletion', 'Var', (53, 61))	('PC', 'Phenotype', 'HP:0012125', (11, 13))	('ERG', 'Gene', '2078', (33, 36))	('ERG', 'Gene', (33, 36))
451891	33578925	TP53 hetero-deficiency and RB1 deletion occur more frequently in iCluster 1 and iCluster 2 PCs.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('RB1', 'Gene', '5925', (27, 30))	('hetero-deficiency', 'Disease', (5, 22))	('iCluster', 'Disease', (65, 73))	('deletion', 'Var', (31, 39))	('PC', 'Gene', '5091', (91, 93))	('hetero-deficiency', 'Disease', 'MESH:D007153', (5, 22))	('PC', 'Phenotype', 'HP:0012125', (91, 93))	('RB1', 'Gene', (27, 30))
451898	33578925	Trends (p < 0.1) of differential expression in PCs with TMPRSS2-ERG fusion compared to those without the fusion also occur in NANS, C1orf106, FBOX6, and SRD5A3 (Figure 4).	('ERG', 'Gene', (64, 67))	('C1orf106', 'Gene', '55765', (132, 140))	('PC', 'Gene', '5091', (47, 49))	('PC', 'Phenotype', 'HP:0012125', (47, 49))	('fusion', 'Var', (68, 74))	('TMPRSS2', 'Gene', '7113', (56, 63))	('TMPRSS2', 'Gene', (56, 63))	('expression', 'MPA', (33, 43))	('C1orf106', 'Gene', (132, 140))	('ERG', 'Gene', '2078', (64, 67))
451915	33578925	While tumors within the group marked with high expression of either TMEM45B or FBXO6 are at higher risks of relapse, the reverse patterns are observed for NANS and ARFGEF3 (Figure 8).	('ARFGEF3', 'Gene', (164, 171))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('TMEM45B', 'Gene', (68, 75))	('ARFGEF3', 'Gene', '57221', (164, 171))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('high', 'Var', (42, 46))	('relapse', 'CPA', (108, 115))	('FBXO6', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
451936	33578925	Furthermore, LE gene panel score remains a risk factor of ccRCC death after adjusting for age at diagnosis, sex, tumor stage, and tumor grade (Table 3).	('ccRCC death', 'Disease', (58, 69))	('tumor', 'Disease', (113, 118))	('ccRCC death', 'Disease', 'MESH:D003643', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('LE gene panel score', 'Var', (13, 32))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('risk factor', 'Reg', (43, 54))	('tumor', 'Disease', (130, 135))
451969	33578925	Collectively, we provide a comprehensive set of evidence supporting the LE gene panel as a novel prognostic biomarker for multiple cancer types.	('LE gene panel', 'Var', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', (131, 137))
451980	33578925	FBXO6 can induce Chk1 degradation.	('Chk1', 'Gene', (17, 21))	('FBXO6', 'Var', (0, 5))	('Chk1', 'Gene', '1111', (17, 21))
452001	33578925	Consistent with ARFGEF2 protein expression being detected in a subclass of bone metastatic CRPCs, we observed its differential expression in PCs with TMPRSS2-ERG fusion vs. those without the fusion (Figure 4), mPCs vs. primary PCs (Figure 3B), as well as CRPC vs. androgen-sensitive PCs (Figure 6).	('ARFGEF2', 'Gene', (16, 23))	('PC', 'Gene', '5091', (257, 259))	('expression', 'MPA', (127, 137))	('PC', 'Gene', '5091', (227, 229))	('PC', 'Gene', '5091', (141, 143))	('PC', 'Phenotype', 'HP:0012125', (227, 229))	('PC', 'Phenotype', 'HP:0012125', (211, 213))	('PC', 'Phenotype', 'HP:0012125', (257, 259))	('PC', 'Phenotype', 'HP:0012125', (141, 143))	('TMPRSS2', 'Gene', '7113', (150, 157))	('PC', 'Gene', '5091', (93, 95))	('PC', 'Gene', '5091', (283, 285))	('PC', 'Gene', '5091', (211, 213))	('PC', 'Phenotype', 'HP:0012125', (93, 95))	('fusion', 'Var', (162, 168))	('ERG', 'Gene', '2078', (158, 161))	('ERG', 'Gene', (158, 161))	('TMPRSS2', 'Gene', (150, 157))
452015	33363385	We identified mutations associated with sex, early ESCC, high TMB, and metastasis lymph nodes.	('early ESCC', 'Disease', (45, 55))	('TMB', 'Chemical', '-', (62, 65))	('associated', 'Reg', (24, 34))	('high TMB', 'Disease', (57, 65))	('metastasis lymph nodes', 'Disease', (71, 93))	('sex', 'Disease', (40, 43))	('mutations', 'Var', (14, 23))
452016	33363385	KMT2D mutations associated with sex (P = 0.035), tumor stage (P = 0.016), high TMB (P = 0.0072), and overall survival of patients (P = 0.0026).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TMB', 'Chemical', '-', (79, 82))	('tumor', 'Disease', (49, 54))	('sex', 'Disease', (32, 35))	('KMT2D', 'Gene', (0, 5))	('KMT2D', 'Gene', '8085', (0, 5))	('associated', 'Reg', (16, 26))	('high', 'Disease', (74, 78))	('patients', 'Species', '9606', (121, 129))	('mutations', 'Var', (6, 15))
452017	33363385	SPEN mutations associated with high TMB (P = 0.0016) and metastasis-positive lymph nodes (P = 0.027).	('metastasis-positive lymph nodes', 'CPA', (57, 88))	('high', 'Disease', (31, 35))	('SPEN', 'Gene', '23013', (0, 4))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (15, 25))	('TMB', 'Chemical', '-', (36, 39))	('SPEN', 'Gene', (0, 4))
452027	33363385	The mutation of TP53 is considered an early event in ESCC carcinogenesis, and some studies have shown that patients with TP53 alterations respond better to angiogenesis inhibitors than those without the alterations.	('patients', 'Species', '9606', (107, 115))	('ESCC', 'Disease', (53, 57))	('respond', 'MPA', (138, 145))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('carcinogenesis', 'Disease', (58, 72))	('TP53', 'Gene', '7157', (16, 20))	('better', 'PosReg', (146, 152))	('alterations', 'Var', (126, 137))	('TP53', 'Gene', (16, 20))
452028	33363385	As both an oncogene and a tumor suppressor, NOTCH1 is closely related to human carcinogenesis, and NOTCH1 mutations have been observed in many cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('NOTCH1', 'Gene', '4851', (99, 105))	('NOTCH1', 'Gene', '4851', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('NOTCH1', 'Gene', (99, 105))	('human', 'Species', '9606', (73, 78))	('NOTCH1', 'Gene', (44, 50))	('observed', 'Reg', (126, 134))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('carcinogenesis', 'Disease', (79, 93))	('mutations', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
452035	33363385	Many studies have focused on the molecular mechanism of ESCC incidence and found that tobacco and alcohol use contribute to genome variations, such as TP53 gene mutations, in ESCC.	('ESCC', 'Disease', (56, 60))	('alcohol use', 'Phenotype', 'HP:0030955', (98, 109))	('TP53', 'Gene', (151, 155))	('alcohol', 'Chemical', 'MESH:D000438', (98, 105))	('tobacco', 'Species', '4097', (86, 93))	('ESCC', 'Disease', (175, 179))	('mutations', 'Var', (161, 170))	('TP53', 'Gene', '7157', (151, 155))
452041	33363385	Genomic alterations were identified according to a previous study: Briefly, single nucleotide variants were identified with MuTect (v1.17) and insertion-deletion polymorphisms were identified using PINDEL (v0.2.4); the functional impact of these mutations was annotated with SnpEff3.0.	('v1.17', 'Gene', '28822', (132, 137))	('MuTect', 'Gene', (124, 130))	('insertion-deletion polymorphisms', 'Var', (143, 175))	('mutations', 'Var', (246, 255))	('v1.17', 'Gene', (132, 137))
452042	33363385	We estimated the Tumor mutational burden (TMB) in each patient by counting the somatic mutations from the coding region, including single nucleotide variants and insertion-deletion polymorphisms, per megabase of sequence examined.	('insertion-deletion polymorphisms', 'Var', (162, 194))	('TMB', 'Chemical', '-', (42, 45))	('single nucleotide variants', 'Var', (131, 157))	('Tumor', 'Phenotype', 'HP:0002664', (17, 22))	('patient', 'Species', '9606', (55, 62))
452049	33363385	We detected 2,859 alterations in the 225 samples of Chinese patients with ESCC, including 1,109 substitution/insertion-deletion polymorphisms, 1,172 gene amplifications, 420 truncations, 90 homozygous gene deletions, and 66 fusions/rearrangements.	('substitution/insertion-deletion polymorphisms', 'Var', (96, 141))	('truncations', 'MPA', (174, 185))	('ESCC', 'Disease', (74, 78))	('patients', 'Species', '9606', (60, 68))	('substitution/insertion-deletion', 'Var', (96, 127))
452052	33363385	The amplification of FGF19, FGF3 and FGF4 were all located on chromosome 11q13 and occurred together in patients.	('FGF4', 'Gene', (37, 41))	('FGF3', 'Gene', '2248', (28, 32))	('FGF19', 'Gene', (21, 26))	('FGF19', 'Gene', '9965', (21, 26))	('FGF4', 'Gene', '2249', (37, 41))	('amplification', 'Var', (4, 17))	('FGF3', 'Gene', (28, 32))	('patients', 'Species', '9606', (104, 112))	('occurred', 'Reg', (83, 91))
452054	33363385	The most common fusion/rearrangement mutations occurred in CDKN2A.	('CDKN2A', 'Gene', (59, 65))	('fusion/rearrangement', 'Var', (16, 36))	('CDKN2A', 'Gene', '1029', (59, 65))
452055	33363385	We observed more mutations in the cell cycle, fibroblast growth factor, PI3K/MTOR, and histone modification pathways in ESCC than in the homologous recombination deficiency, DNA mismatch repair, and WNT pathways.	('histone modification pathways', 'Pathway', (87, 116))	('ESCC', 'Disease', (120, 124))	('MTOR', 'Gene', (77, 81))	('fibroblast growth factor', 'Pathway', (46, 70))	('MTOR', 'Gene', '2475', (77, 81))	('cell cycle', 'Pathway', (34, 44))	('mutations', 'Var', (17, 26))
452065	33363385	Interestingly, we found that mutations of LRP1, AXIN2, CFTR, CREB3L1, and TAF1 occurred exclusively in female patients.	('CFTR', 'Gene', '1080', (55, 59))	('TAF1', 'Gene', '6872', (74, 78))	('AXIN2', 'Gene', (48, 53))	('AXIN2', 'Gene', '8313', (48, 53))	('LRP1', 'Gene', (42, 46))	('mutations', 'Var', (29, 38))	('TAF1', 'Gene', (74, 78))	('CREB3L1', 'Gene', (61, 68))	('CFTR', 'Gene', (55, 59))	('LRP1', 'Gene', '4035', (42, 46))	('CREB3L1', 'Gene', '90993', (61, 68))	('occurred', 'Reg', (79, 87))	('patients', 'Species', '9606', (110, 118))
452066	33363385	The mutational frequencies of LRP1 (P=0.0049), JAK2 (P=0.0091), CDK12 (P=0.018), AXIN2 (P=0.029), CFTR (P=0.029), CREB3L1 (P=0.029), TAF1 (P=0.029), and KMT2D (P=0.035) were significantly higher in female than in male patients (Figure 3A).	('AXIN2', 'Gene', (81, 86))	('LRP1', 'Gene', (30, 34))	('KMT2D', 'Gene', (153, 158))	('LRP1', 'Gene', '4035', (30, 34))	('CDK12', 'Gene', (64, 69))	('mutational', 'Var', (4, 14))	('JAK2', 'Gene', '3717', (47, 51))	('CREB3L1', 'Gene', (114, 121))	('higher', 'PosReg', (188, 194))	('TAF1', 'Gene', '6872', (133, 137))	('CFTR', 'Gene', '1080', (98, 102))	('AXIN2', 'Gene', '8313', (81, 86))	('CDK12', 'Gene', '51755', (64, 69))	('KMT2D', 'Gene', '8085', (153, 158))	('CFTR', 'Gene', (98, 102))	('patients', 'Species', '9606', (218, 226))	('CREB3L1', 'Gene', '90993', (114, 121))	('JAK2', 'Gene', (47, 51))	('TAF1', 'Gene', (133, 137))
452069	33363385	We found that the mutational frequencies of NOTCH2 (11.93% vs 2.56%, P=0.027) and SPEN (9.17% vs 1.28%, P=0.027) were significantly higher in lymph node metastasis-positive patients than in negative patients, whereas the mutational frequencies of FOS (0.92% vs 8.97%, P=0.01), DOT1L (0.00% vs 6.41%, P=0.012), and VEGFA (0.00% vs 5.13%, P=0.029) were significantly lower in lymph node metastasis-positive patients than in negative patients (Figure 3B).	('FOS', 'Gene', (247, 250))	('NOTCH2', 'Gene', '4853', (44, 50))	('FOS', 'Gene', '2353', (247, 250))	('DOT1L', 'Gene', '84444', (277, 282))	('VEGFA', 'Gene', '7422', (314, 319))	('patients', 'Species', '9606', (173, 181))	('lymph node', 'Disease', (374, 384))	('NOTCH2', 'Gene', (44, 50))	('higher', 'PosReg', (132, 138))	('mutational', 'Var', (18, 28))	('SPEN', 'Gene', '23013', (82, 86))	('patients', 'Species', '9606', (431, 439))	('lower', 'NegReg', (365, 370))	('lymph', 'Disease', (142, 147))	('DOT1L', 'Gene', (277, 282))	('VEGFA', 'Gene', (314, 319))	('SPEN', 'Gene', (82, 86))	('patients', 'Species', '9606', (405, 413))	('patients', 'Species', '9606', (199, 207))
452070	33363385	We also analyzed the associations of gene alterations with tumors stage.	('alterations', 'Var', (42, 53))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('associations', 'Interaction', (21, 33))
452072	33363385	The mutational frequencies of DOT1L (P=0.009), BMPR1A (P=0.024) and KMT2D (P=0.016) were significantly higher in early-stage tumors than in advanced-stage tumors (Figure 3C).	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('BMPR1A', 'Gene', (47, 53))	('BMPR1A', 'Gene', '657', (47, 53))	('DOT1L', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (125, 131))	('KMT2D', 'Gene', '8085', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('DOT1L', 'Gene', '84444', (30, 35))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('KMT2D', 'Gene', (68, 73))	('higher', 'Reg', (103, 109))	('mutational', 'Var', (4, 14))
452074	33363385	Statistical analysis revealed that mutations of KMT2D (P=0.0072) and SPEN (P=0.0016) were significantly associated with high TMB (Figure 3D and E).	('associated', 'Reg', (104, 114))	('SPEN', 'Gene', '23013', (69, 73))	('TMB', 'Chemical', '-', (125, 128))	('high TMB', 'Disease', (120, 128))	('KMT2D', 'Gene', '8085', (48, 53))	('KMT2D', 'Gene', (48, 53))	('SPEN', 'Gene', (69, 73))	('mutations', 'Var', (35, 44))
452077	33363385	We found that KMT2D mutation was significantly associated with overall survival (P=0.026), but did not correlate with disease-free survival (P=0.08) (Figure 4).	('overall survival', 'MPA', (63, 79))	('KMT2D', 'Gene', '8085', (14, 19))	('associated with', 'Reg', (47, 62))	('mutation', 'Var', (20, 28))	('KMT2D', 'Gene', (14, 19))
452078	33363385	We also analyzed the relationship between mutations in genes in related pathways and the prognosis of ESCC patients but did not detect a correlation.	('analyzed', 'Reg', (8, 16))	('ESCC', 'Disease', (102, 106))	('patients', 'Species', '9606', (107, 115))	('mutations', 'Var', (42, 51))
452080	33363385	We detected mutations in 24 genes:CCND1, CDKN2A, PIK3CA, CDKN2B, FBXW7, EGFR, FGFR1, PTEN, BRCA1, ERBB2, BRCA2, MET, STK11, CDK4, CDK6, ERBB3, KDR, VEGFRA, ARAF, CD274, FGFR3, PDCD1LG2, PDGFB, and TSC1:that are targeted by available drugs.	('ARAF', 'Gene', '369', (156, 160))	('ERBB2', 'Gene', '2064', (98, 103))	('ARAF', 'Gene', (156, 160))	('CCND1', 'Gene', '595', (34, 39))	('EGFR', 'Gene', '1956', (72, 76))	('CDK6', 'Gene', (130, 134))	('BRCA2', 'Gene', (105, 110))	('TSC1', 'Gene', (197, 201))	('KDR', 'Gene', '3791', (143, 146))	('CDKN2B', 'Gene', '1030', (57, 63))	('CD274', 'Gene', '29126', (162, 167))	('CCND1', 'Gene', (34, 39))	('PTEN', 'Gene', (85, 89))	('PIK3CA', 'Gene', '5290', (49, 55))	('BRCA1', 'Gene', '672', (91, 96))	('STK11', 'Gene', '6794', (117, 122))	('MET', 'Gene', (112, 115))	('BRCA1', 'Gene', (91, 96))	('ERBB3', 'Gene', (136, 141))	('FGFR1', 'Gene', (78, 83))	('FBXW7', 'Gene', '55294', (65, 70))	('CDK4', 'Gene', '1019', (124, 128))	('TSC1', 'Gene', '7248', (197, 201))	('PDCD1LG2', 'Gene', '80380', (176, 184))	('EGFR', 'Gene', '1956', (149, 153))	('CDKN2A', 'Gene', (41, 47))	('BRCA2', 'Gene', '675', (105, 110))	('PTEN', 'Gene', '5728', (85, 89))	('CD274', 'Gene', (162, 167))	('PDGFB', 'Gene', '5155', (186, 191))	('EGFR', 'Gene', (72, 76))	('PIK3CA', 'Gene', (49, 55))	('PDCD1LG2', 'Gene', (176, 184))	('ERBB3', 'Gene', '2065', (136, 141))	('FGFR3', 'Gene', (169, 174))	('CDKN2A', 'Gene', '1029', (41, 47))	('KDR', 'Gene', (143, 146))	('MET', 'Gene', '79811', (112, 115))	('ERBB2', 'Gene', (98, 103))	('CDK6', 'Gene', '1021', (130, 134))	('FGFR1', 'Gene', '2260', (78, 83))	('mutations', 'Var', (12, 21))	('CDKN2B', 'Gene', (57, 63))	('PDGFB', 'Gene', (186, 191))	('FBXW7', 'Gene', (65, 70))	('STK11', 'Gene', (117, 122))	('FGFR3', 'Gene', '2261', (169, 174))	('EGFR', 'Gene', (149, 153))	('CDK4', 'Gene', (124, 128))
452081	33363385	In this cohort, nearly 61% (137/225) of patients harbored at least 1 mutation of CCND1, CDKN2A, CDKN2B, CDK4, or CDK6, and nearly 37% (84/225) of patients harbored at least 1 mutation of PIK3CA, FBXW7, PTEN, STK11, or TSC1.	('FBXW7', 'Gene', '55294', (195, 200))	('CDK6', 'Gene', (113, 117))	('harbored', 'Reg', (49, 57))	('PIK3CA', 'Gene', (187, 193))	('PTEN', 'Gene', (202, 206))	('CCND1', 'Gene', '595', (81, 86))	('CDKN2A', 'Gene', (88, 94))	('CDKN2B', 'Gene', '1030', (96, 102))	('TSC1', 'Gene', (218, 222))	('CCND1', 'Gene', (81, 86))	('CDK4', 'Gene', (104, 108))	('PTEN', 'Gene', '5728', (202, 206))	('patients', 'Species', '9606', (146, 154))	('STK11', 'Gene', (208, 213))	('TSC1', 'Gene', '7248', (218, 222))	('CDKN2A', 'Gene', '1029', (88, 94))	('FBXW7', 'Gene', (195, 200))	('harbored', 'Reg', (155, 163))	('CDK4', 'Gene', '1019', (104, 108))	('PIK3CA', 'Gene', '5290', (187, 193))	('STK11', 'Gene', '6794', (208, 213))	('CDK6', 'Gene', '1021', (113, 117))	('patients', 'Species', '9606', (40, 48))	('mutation', 'Var', (69, 77))	('CDKN2B', 'Gene', (96, 102))
452082	33363385	Cancers with mutations in CCND1, CDKN2A, CDKN2B, CDK4, and CDK6 respond to drugs such as palbociclib, ribociclib, and abemaciclib.	('respond', 'Reg', (64, 71))	('CDK4', 'Gene', (49, 53))	('CDKN2A', 'Gene', (33, 39))	('CDKN2B', 'Gene', (41, 47))	('Cancers', 'Disease', (0, 7))	('CDKN2A', 'Gene', '1029', (33, 39))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('CDK6', 'Gene', (59, 63))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('CCND1', 'Gene', (26, 31))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('CDK6', 'Gene', '1021', (59, 63))	('mutations', 'Var', (13, 22))	('CCND1', 'Gene', '595', (26, 31))	('CDKN2B', 'Gene', '1030', (41, 47))	('CDK4', 'Gene', '1019', (49, 53))
452083	33363385	Cancers with mutations in PIK3CA, FBXW7, PTEN, STK11, and TSC1 respond to drugs such as everolimus and temsirolimus (Figure 5).	('temsirolimus', 'Chemical', 'MESH:C401859', (103, 115))	('Cancers', 'Disease', (0, 7))	('PIK3CA', 'Gene', '5290', (26, 32))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('STK11', 'Gene', '6794', (47, 52))	('respond', 'Reg', (63, 70))	('FBXW7', 'Gene', '55294', (34, 39))	('everolimus', 'Chemical', 'MESH:D000068338', (88, 98))	('PTEN', 'Gene', (41, 45))	('TSC1', 'Gene', (58, 62))	('PIK3CA', 'Gene', (26, 32))	('temsirolimus', 'MPA', (103, 115))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('everolimus', 'MPA', (88, 98))	('TSC1', 'Gene', '7248', (58, 62))	('mutations', 'Var', (13, 22))	('PTEN', 'Gene', '5728', (41, 45))	('STK11', 'Gene', (47, 52))	('FBXW7', 'Gene', (34, 39))
452093	33363385	We detected frequent mutations in TP53, CCND1, FAT1, and CDKN2A, as in other studies, and further identified frequent mutations in FGF19, FGF3, FGF4, and KMT2D.	('FGF3', 'Gene', '2248', (138, 142))	('TP53', 'Gene', (34, 38))	('FGF4', 'Gene', '2249', (144, 148))	('CDKN2A', 'Gene', (57, 63))	('FGF4', 'Gene', (144, 148))	('FAT1', 'Gene', '2195', (47, 51))	('mutations', 'Var', (118, 127))	('KMT2D', 'Gene', (154, 159))	('KMT2D', 'Gene', '8085', (154, 159))	('CCND1', 'Gene', (40, 45))	('CDKN2A', 'Gene', '1029', (57, 63))	('FGF19', 'Gene', '9965', (131, 136))	('FGF19', 'Gene', (131, 136))	('FAT1', 'Gene', (47, 51))	('FGF3', 'Gene', (138, 142))	('CCND1', 'Gene', '595', (40, 45))	('TP53', 'Gene', '7157', (34, 38))	('mutations', 'Var', (21, 30))
452096	33363385	Similar to a previous study, we also observed frequent amplification of CCND1, FGF19, FGF3, and FGF4, which supports the occurrence of chromosome 11q13 instability in ESCC patients.	('CCND1', 'Gene', (72, 77))	('amplification', 'Var', (55, 68))	('FGF19', 'Gene', '9965', (79, 84))	('CCND1', 'Gene', '595', (72, 77))	('ESCC', 'Disease', (167, 171))	('FGF19', 'Gene', (79, 84))	('FGF3', 'Gene', '2248', (86, 90))	('FGF4', 'Gene', (96, 100))	('patients', 'Species', '9606', (172, 180))	('FGF3', 'Gene', (86, 90))	('FGF4', 'Gene', '2249', (96, 100))
452098	33363385	Mutation of KMT2D frequently occurs in follicular lymphoma and diffuse large B-cell lymphoma.	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('lymphoma', 'Disease', 'MESH:D008223', (84, 92))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('KMT2D', 'Gene', (12, 17))	('KMT2D', 'Gene', '8085', (12, 17))	('Mutation', 'Var', (0, 8))	('B-cell lymphoma', 'Disease', (77, 92))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (77, 92))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (77, 92))	('occurs', 'Reg', (29, 35))	('lymphoma', 'Disease', (50, 58))	('lymphoma', 'Disease', (84, 92))
452099	33363385	Mutation of KMT2D has also been reported as a tumor inhibitor, but few studies have reported a high frequency of KMT2D mutations in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('KMT2D', 'Gene', (12, 17))	('KMT2D', 'Gene', '8085', (12, 17))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', (46, 51))	('KMT2D', 'Gene', (113, 118))	('KMT2D', 'Gene', '8085', (113, 118))	('mutations', 'Var', (119, 128))	('ESCC', 'Disease', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
452100	33363385	Mutation of KMT2D is reportedly associated with poor prognosis in many cancers, such as non-small-cell lung carcinoma, breast cancer, and ovarian metastases of colorectal cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('associated', 'Reg', (32, 42))	('lung carcinoma', 'Disease', 'MESH:D008175', (103, 117))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('KMT2D', 'Gene', '8085', (12, 17))	('breast cancer', 'Disease', (119, 132))	('cancers', 'Disease', (71, 78))	('ovarian metastases of colorectal cancer', 'Disease', (138, 177))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('lung carcinoma', 'Disease', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('ovarian metastases of colorectal cancer', 'Disease', 'MESH:D009362', (138, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (92, 117))	('KMT2D', 'Gene', (12, 17))	('Mutation', 'Var', (0, 8))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (88, 117))
452101	33363385	On the contrary, mutation of KMT2D correlates with longer survival of small cell lung cancer patients.	('lung cancer', 'Disease', (81, 92))	('KMT2D', 'Gene', '8085', (29, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('KMT2D', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutation', 'Var', (17, 25))	('longer', 'PosReg', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('patients', 'Species', '9606', (93, 101))
452103	33363385	In this study, we identified frequent mutation of KMT2D and found that these mutations were associated with sex, early tumor stage, and high TMB.	('tumor', 'Disease', (119, 124))	('high', 'Disease', (136, 140))	('sex', 'Disease', (108, 111))	('KMT2D', 'Gene', (50, 55))	('KMT2D', 'Gene', '8085', (50, 55))	('TMB', 'Chemical', '-', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutation', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('associated', 'Reg', (92, 102))
452105	33363385	In addition, we found that patients with a KMT2D mutation had better disease-free and overall survival than those without a KMT2D mutation, suggesting that KMT2D mutation is associated with a good ESCC prognosis.	('KMT2D', 'Gene', (124, 129))	('KMT2D', 'Gene', '8085', (124, 129))	('KMT2D', 'Gene', (43, 48))	('disease-free', 'CPA', (69, 81))	('better', 'PosReg', (62, 68))	('ESCC', 'Disease', (197, 201))	('KMT2D', 'Gene', (156, 161))	('KMT2D', 'Gene', '8085', (156, 161))	('mutation', 'Var', (49, 57))	('KMT2D', 'Gene', '8085', (43, 48))	('patients', 'Species', '9606', (27, 35))	('mutation', 'Var', (162, 170))
452109	33363385	The high expression of SPEN was associated with metastasis in breast cancer.	('SPEN', 'Gene', '23013', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('SPEN', 'Gene', (23, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('high', 'Var', (4, 8))	('associated with', 'Reg', (32, 47))	('metastasis', 'CPA', (48, 58))
452113	33363385	Interestingly, both NOTCH2 and SPEN mutations were associated with lymph node metastases in our cohort.	('SPEN', 'Gene', (31, 35))	('metastases', 'Disease', 'MESH:D009362', (78, 88))	('NOTCH2', 'Gene', '4853', (20, 26))	('mutations', 'Var', (36, 45))	('associated with', 'Reg', (51, 66))	('SPEN', 'Gene', '23013', (31, 35))	('metastases', 'Disease', (78, 88))	('NOTCH2', 'Gene', (20, 26))
452114	33363385	These results suggested that SPEN mutations may predict the poor prognosis of ESCC patients.	('ESCC', 'Disease', (78, 82))	('SPEN', 'Gene', (29, 33))	('patients', 'Species', '9606', (83, 91))	('SPEN', 'Gene', '23013', (29, 33))	('mutations', 'Var', (34, 43))
452115	33363385	Meanwhile, our results also showed the association between SPEN mutation and high TMB.	('mutation', 'Var', (64, 72))	('SPEN', 'Gene', '23013', (59, 63))	('high TMB', 'Disease', (77, 85))	('SPEN', 'Gene', (59, 63))	('TMB', 'Chemical', '-', (82, 85))	('association', 'Interaction', (39, 50))
452117	33363385	These results also suggested the potential association between SPEN mutations and a good prognosis.	('mutations', 'Var', (68, 77))	('SPEN', 'Gene', '23013', (63, 67))	('SPEN', 'Gene', (63, 67))
452120	33363385	Interestingly, we identified associations between mutation of FOS, DOT1L, and VEGFA and metastasis-negative lymph nodes in ESCC.	('FOS', 'Gene', (62, 65))	('DOT1L', 'Gene', (67, 72))	('VEGFA', 'Gene', '7422', (78, 83))	('ESCC', 'Disease', (123, 127))	('FOS', 'Gene', '2353', (62, 65))	('associations', 'Interaction', (29, 41))	('DOT1L', 'Gene', '84444', (67, 72))	('VEGFA', 'Gene', (78, 83))	('metastasis-negative lymph nodes', 'CPA', (88, 119))	('mutation', 'Var', (50, 58))
452121	33363385	The mutation of FOS is reportedly associated with poor prognosis in colorectal cancer, and high expression of DOT1L and VEGFA indicates poor prognosis in many cancers, such as lung cancer, gastric cancer, and clear cell renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('mutation', 'Var', (4, 12))	('FOS', 'Gene', (16, 19))	('gastric cancer', 'Disease', (189, 203))	('VEGFA', 'Gene', (120, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (209, 240))	('FOS', 'Gene', '2353', (16, 19))	('cancers', 'Disease', (159, 166))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('DOT1L', 'Gene', '84444', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('expression', 'MPA', (96, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (189, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('lung cancer', 'Disease', (176, 187))	('VEGFA', 'Gene', '7422', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (209, 240))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('colorectal cancer', 'Disease', (68, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('clear cell renal cell carcinoma', 'Disease', (209, 240))	('DOT1L', 'Gene', (110, 115))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (220, 240))
452129	33363385	This supported the reliability of correlations between high TMB-related gene mutations such as those in KMT2B and SPEN, and between high TMB and clinical characteristics such as drinking status.	('KMT2B', 'Gene', (104, 109))	('high', 'Gene', (55, 59))	('drinking status', 'Disease', (178, 193))	('TMB', 'Chemical', '-', (137, 140))	('SPEN', 'Gene', (114, 118))	('KMT2B', 'Gene', '9757', (104, 109))	('mutations', 'Var', (77, 86))	('TMB', 'Chemical', '-', (60, 63))	('SPEN', 'Gene', '23013', (114, 118))	('correlations', 'Interaction', (34, 46))
452131	33363385	High TMB was reported to associate with prolonged progression-free and overall survival after immunotherapy.	('prolonged', 'PosReg', (40, 49))	('High TMB', 'Var', (0, 8))	('overall survival', 'CPA', (71, 87))	('TMB', 'Chemical', '-', (5, 8))	('progression-free', 'CPA', (50, 66))
452135	33363385	Targeting these genes influences the occurrence and development of tumors by inhibiting cell proliferation, angiogenesis, invasion, and metastasis; promoting cell apoptosis; and regulating key molecules or signal transduction pathways of inflammation.	('inhibiting', 'NegReg', (77, 87))	('promoting', 'PosReg', (148, 157))	('cell proliferation', 'CPA', (88, 106))	('occurrence', 'CPA', (37, 47))	('invasion', 'CPA', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('influences', 'Reg', (22, 32))	('inflammation', 'Disease', 'MESH:D007249', (238, 250))	('development', 'CPA', (52, 63))	('regulating', 'Reg', (178, 188))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cell apoptosis', 'CPA', (158, 172))	('signal transduction pathways', 'Pathway', (206, 234))	('angiogenesis', 'CPA', (108, 120))	('tumors', 'Disease', (67, 73))	('key molecules', 'Pathway', (189, 202))	('inflammation', 'Disease', (238, 250))	('metastasis', 'CPA', (136, 146))	('Targeting', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
452136	33363385	Recently, studies reported that targeted therapies for EGFR mutations showed only limited success in improving the overall survival of ESCC patients in clinical trials.	('EGFR', 'Gene', '1956', (55, 59))	('ESCC', 'Disease', (135, 139))	('EGFR', 'Gene', (55, 59))	('patients', 'Species', '9606', (140, 148))	('mutations', 'Var', (60, 69))
452140	33363385	We also analyzed the relationship between the number of metastatic lymph nodes and prognosis, and the potential prognostic role of SPEN and KMT2D mutations.	('mutations', 'Var', (146, 155))	('SPEN', 'Gene', (131, 135))	('KMT2D', 'Gene', (140, 145))	('KMT2D', 'Gene', '8085', (140, 145))	('SPEN', 'Gene', '23013', (131, 135))
452155	31564977	The GPS was calculated as: a score of 0 for normal CRP (<10.0 mg/L) and albumin (>35.0 g/L) levels, 1 for either an abnormal CRP (>10.0 mg/L) or abnormal albumin level (<35.0 g/L) and 2 for both abnormal CRP (>10.0 mg/L) and abnormal albumin (<35.0 g/L) levels.	('CRP', 'Gene', '1401', (51, 54))	('CRP', 'Gene', (125, 128))	('albumin', 'Gene', (154, 161))	('CRP', 'Gene', (204, 207))	('albumin', 'Gene', (234, 241))	('CRP', 'Gene', '1401', (125, 128))	('albumin', 'Gene', '213', (72, 79))	('CRP', 'Gene', '1401', (204, 207))	('albumin', 'Gene', '213', (234, 241))	('abnormal albumin', 'Phenotype', 'HP:0012116', (145, 161))	('albumin', 'Gene', (72, 79))	('abnormal albumin level', 'Phenotype', 'HP:0012116', (145, 167))	('abnormal albumin', 'Phenotype', 'HP:0012116', (225, 241))	('CRP', 'Gene', (51, 54))	('abnormal', 'Var', (116, 124))	('albumin', 'Gene', '213', (154, 161))
452231	30087579	TPT1 has recently been identified as related to human skin squamous cell carcinoma and is targeted by miRNA-216b-5p in pancreatic cancer.	('TPT1', 'Gene', (0, 4))	('pancreatic cancer', 'Disease', (119, 136))	('human', 'Species', '9606', (48, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('related', 'Reg', (37, 44))	('targeted', 'Reg', (90, 98))	('miRNA-216b-5p', 'Var', (102, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (119, 136))	('skin squamous cell carcinoma', 'Disease', (54, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (119, 136))	('skin squamous cell carcinoma', 'Phenotype', 'HP:0006739', (54, 82))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('skin squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))	('TPT1', 'Gene', '7178', (0, 4))
452240	30087579	KEGG analysis indicated that differentially expressed circRNAs were associated with multiple cancers.	('differentially', 'Var', (29, 43))	('associated', 'Reg', (68, 78))	('multiple cancers', 'Disease', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('circRNAs', 'Gene', (54, 62))	('multiple cancers', 'Disease', 'MESH:D009369', (84, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
452341	29024498	The rate of grade 3 or 4 radiation esophagitis in the CCRT group (26.5%) was higher than in the RT alone group (20.6%), but the difference was not statistically significant (P = 0.168).	('radiation esophagitis', 'Disease', 'MESH:D004194', (25, 46))	('esophagitis', 'Phenotype', 'HP:0100633', (35, 46))	('radiation esophagitis', 'Disease', (25, 46))	('CCRT', 'Var', (54, 58))
452359	29024498	The rate of grade 4 esophagitis in the CCRT group (12.2%) was higher than in the RT alone group (5%).	('CCRT', 'Var', (39, 43))	('esophagitis', 'Phenotype', 'HP:0100633', (20, 31))	('esophagitis', 'Disease', (20, 31))	('esophagitis', 'Disease', 'MESH:D004941', (20, 31))	('grade', 'Disease', (12, 17))
452414	28138712	The mutant genes are transcribed and translated into proteins, and the expression levels of proteins dictate the tumor phenotype and regulate its biological behavior.	('tumor', 'Disease', (113, 118))	('expression', 'MPA', (71, 81))	('dictate', 'Reg', (101, 108))	('mutant', 'Var', (4, 10))	('regulate', 'Reg', (133, 141))	('biological behavior', 'CPA', (146, 165))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
452424	28138712	DES, TPM3, TPM2 and vimentin are important in maintaining the stability of the cytoskeleton, and changes in vimentin expression were associated with liver cancer metastasis and recurrence.	('vimentin', 'Gene', (20, 28))	('changes', 'Var', (97, 104))	('DES', 'Gene', (0, 3))	('vimentin', 'Gene', (108, 116))	('TPM3', 'Gene', (5, 9))	('recurrence', 'CPA', (177, 187))	('expression', 'MPA', (117, 127))	('TPM2', 'Gene', (11, 15))	('vimentin', 'Gene', '7431', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('liver cancer', 'Phenotype', 'HP:0002896', (149, 161))	('vimentin', 'Gene', '7431', (20, 28))	('liver cancer metastasis', 'Disease', 'MESH:D009362', (149, 172))	('TPM3', 'Gene', '7170', (5, 9))	('liver cancer metastasis', 'Disease', (149, 172))	('TPM2', 'Gene', '7169', (11, 15))	('DES', 'Gene', '1674', (0, 3))	('associated', 'Reg', (133, 143))
452427	28138712	MGC29506 promoted the progress of gastric cancer via altering the cell cycle.	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))	('progress', 'CPA', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cell cycle', 'CPA', (66, 76))	('MGC29506', 'Var', (0, 8))	('gastric cancer', 'Disease', (34, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('altering', 'Reg', (53, 61))	('promoted', 'PosReg', (9, 17))
452565	17559659	Nevertheless, patients after a GJJ have fewer recurrences of obstructive symptoms and therefore the need for reinterventions is lower in GJJ patients than in those being treated with a stent.	('patients', 'Species', '9606', (141, 149))	('GJJ', 'Var', (137, 140))	('lower', 'NegReg', (128, 133))	('patients', 'Species', '9606', (14, 22))
452590	32873775	Flow cytometric analysis showed SFE induced cell apoptosis and cycle arrest in G2/M phase.	('arrest', 'Disease', 'MESH:D006323', (69, 75))	('cell apoptosis', 'CPA', (44, 58))	('arrest', 'Disease', (69, 75))	('SFE', 'Var', (32, 35))	('SFE', 'Chemical', 'MESH:C473643', (32, 35))
452591	32873775	Also, scrape motility and transwell assays presented SFE reduced esophageal cancer cell metastasis.	('esophageal cancer', 'Disease', (65, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('SFE', 'Var', (53, 56))	('reduced', 'NegReg', (57, 64))	('SFE', 'Chemical', 'MESH:C473643', (53, 56))
452610	32873775	According to microarray results, we confirmed these four genes were the targets of SFE in esophageal cancer cells, and SFE could inhibit esophageal cancer progression through suppressing SCD and CDH3 expression, and activating the GADD45B-MAP2K3-p38-p53 feedback loop.	('GADD45B', 'Gene', '4616', (231, 238))	('activating', 'PosReg', (216, 226))	('SFE', 'Chemical', 'MESH:C473643', (83, 86))	('CDH3', 'Gene', '1001', (195, 199))	('expression', 'MPA', (200, 210))	('SFE', 'Var', (119, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('esophageal cancer', 'Disease', (137, 154))	('SFE', 'Chemical', 'MESH:C473643', (119, 122))	('MAP2K3', 'Gene', (239, 245))	('p38', 'Gene', (246, 249))	('CDH3', 'Gene', (195, 199))	('esophageal cancer', 'Disease', (90, 107))	('p53', 'Gene', '7157', (250, 253))	('p38', 'Gene', '1432', (246, 249))	('inhibit', 'NegReg', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('suppressing', 'NegReg', (175, 186))	('p53', 'Gene', (250, 253))	('SCD', 'Gene', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('GADD45B', 'Gene', (231, 238))	('SCD', 'Gene', '6319', (187, 190))	('MAP2K3', 'Gene', '5606', (239, 245))
452611	32873775	In conclusion, our findings identify the key genes and signaling pathways involved in SFE inhibiting metastasis and proliferation of esophageal cancer.	('SFE', 'Var', (86, 89))	('SFE', 'Chemical', 'MESH:C473643', (86, 89))	('metastasis', 'CPA', (101, 111))	('esophageal cancer', 'Disease', (133, 150))	('proliferation', 'CPA', (116, 129))	('inhibiting', 'NegReg', (90, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
452614	32873775	There was no significant difference in mice body weight, while the tumor volume and lumps weight in mice treated with SFE were obviously smaller than that of the control group (Fig.	('smaller', 'NegReg', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mice', 'Species', '10090', (100, 104))	('SFE', 'Var', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('SFE', 'Chemical', 'MESH:C473643', (118, 121))	('lumps weight', 'CPA', (84, 96))	('tumor', 'Disease', (67, 72))	('mice', 'Species', '10090', (39, 43))
452619	32873775	Fluorescence-activated cell sorting (FACS) analysis showed a significantly higher level of apoptosis in SFE-treated EC109 and KYSE510 cells than that in DMSO-treated cells (Fig.	('DMSO', 'Chemical', 'MESH:D004121', (153, 157))	('apoptosis', 'CPA', (91, 100))	('higher', 'PosReg', (75, 81))	('SFE', 'Chemical', 'MESH:C473643', (104, 107))	('KYSE510', 'CellLine', 'CVCL:1354', (126, 133))	('SFE-treated', 'Var', (104, 115))
452621	32873775	As the mitochondrial pathway and the death receptor pathway are reported to mediate caspases activation, and caspase-9 and caspase-8 belonged to the two pathways respectively, we predicted SFE induced mitochondrial apoptosis in esophageal cancer cells and then measured the mitochondrial membrane potential, the decrease of which was a characteristic performance in mitochondrial apoptosis.	('caspases', 'Gene', (84, 92))	('SFE', 'Var', (189, 192))	('caspase-9', 'Gene', '842', (109, 118))	('death', 'Disease', (37, 42))	('caspase-8', 'Gene', '841', (123, 132))	('SFE', 'Chemical', 'MESH:C473643', (189, 192))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('caspases', 'Gene', '841;842', (84, 92))	('caspase-9', 'Gene', (109, 118))	('mitochondrial membrane potential', 'MPA', (274, 306))	('esophageal cancer', 'Disease', (228, 245))	('mitochondrial apoptosis', 'CPA', (201, 224))	('death', 'Disease', 'MESH:D003643', (37, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (228, 245))	('caspase-8', 'Gene', (123, 132))
452623	32873775	2e also indirectly indicated SFE induced esophageal cancer cell apoptosis dose-dependently and time-dependently.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('SFE', 'Var', (29, 32))	('SFE', 'Chemical', 'MESH:C473643', (29, 32))	('esophageal cancer', 'Disease', (41, 58))
452626	32873775	So we detected EMT markers expression, and found epithelial cell-related protein levels were promoted by SFE treatment while those of mesenchymal cell-related protein were significantly downregulated (Fig.	('epithelial cell-related protein levels', 'MPA', (49, 87))	('SFE', 'Var', (105, 108))	('downregulated', 'NegReg', (186, 199))	('promoted', 'PosReg', (93, 101))	('SFE', 'Chemical', 'MESH:C473643', (105, 108))
452628	32873775	3a, upper), and found that SCD and CDH3 mRNA levels decreased most significantly in SFE-treated cells (Fig.	('SFE', 'Chemical', 'MESH:C473643', (84, 87))	('CDH3', 'Gene', '1001', (35, 39))	('SCD', 'Gene', '6319', (27, 30))	('decreased', 'NegReg', (52, 61))	('SCD', 'Gene', (27, 30))	('SFE-treated', 'Var', (84, 95))	('CDH3', 'Gene', (35, 39))
452642	32873775	Interestingly, SFE improved p53 protein level rather than transcriptionally regulated p53 gene (Supplementary Fig.	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (86, 89))	('p53', 'Gene', '7157', (28, 31))	('SFE', 'Var', (15, 18))	('improved', 'PosReg', (19, 27))	('SFE', 'Chemical', 'MESH:C473643', (15, 18))	('p53', 'Gene', (86, 89))
452670	32873775	More and more evidence suggest that isothiocyanates from cruciferous vegetables is associated with a decreased risk of various cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('isothiocyanates', 'Chemical', 'MESH:D017879', (36, 51))	('decreased', 'NegReg', (101, 110))	('isothiocyanates', 'Var', (36, 51))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
452746	31011254	Core tip: This study for the first time demonstrated that programmed death ligand 1 (PD-L1) can be expressed by gastric neuroendocrine carcinoma (G-NEC) cancer cells and the high PD-L1 expression was associated with a poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (120, 144))	('cancer', 'Disease', (153, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('gastric neuroendocrine carcinoma', 'Disease', (112, 144))	('PD-L1', 'Gene', (85, 90))	('high', 'Var', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('gastric neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (112, 144))
452747	31011254	And the high expression of PD-L1 may be due to the copy number variation of PD-L1 gene or stimulation of tumor infiltrating lymphocytes.	('tumor', 'Disease', (105, 110))	('expression', 'MPA', (13, 23))	('copy number variation', 'Var', (51, 72))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('PD-L1', 'Gene', (27, 32))	('PD-L1', 'Gene', (76, 81))
452763	31011254	CD8+ tumor infiltrating lymphocytes (TILs) are the key effector in antitumor immune response, and its presence has been reported to be a favorable prognostic factor in some malignancies, such as colorectal cancer, esophageal cancer, and breast cancer.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('CD8', 'Gene', '925', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('colorectal cancer', 'Phenotype', 'HP:0003003', (195, 212))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('breast cancer', 'Disease', (237, 250))	('presence', 'Var', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('CD8', 'Gene', (0, 3))	('tumor', 'Disease', (71, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (195, 212))	('malignancies', 'Disease', 'MESH:D009369', (173, 185))	('esophageal cancer', 'Disease', 'MESH:D004938', (214, 231))	('malignancies', 'Disease', (173, 185))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('colorectal cancer', 'Disease', (195, 212))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('esophageal cancer', 'Disease', (214, 231))	('tumor', 'Disease', (5, 10))
452765	31011254	And previous studies have reported that the infiltration of FOXP3+ Tregs is correlated with the upregulation of PD-L1 in gastric cancer, breast cancer, and colorectal cancer.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (156, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (137, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PD-L1', 'Gene', (112, 117))	('gastric cancer', 'Disease', (121, 135))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('FOXP3+', 'Var', (60, 66))	('colorectal cancer', 'Disease', (156, 173))	('upregulation', 'PosReg', (96, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
452776	31011254	Blocking was done with 10% bull serum albumin for 30 min, then slides were incubated with antibodies against CD8 (1:200, 17335-1-AP, ProteinTech, United States), FOXP3 (1:200, 22228-1-AP, ProteinTech), PD-1 (1:25, ab140950, Abcam, United Kindom), and PD-L1 (1:500, ab205921, Abcam) at 4  C overnight.	('CD8', 'Gene', (109, 112))	('PD-1', 'Gene', (202, 206))	('CD8', 'Gene', '925', (109, 112))	('PD-1', 'Gene', '5133', (202, 206))	('1:500', 'Var', (258, 263))	('1:200', 'Var', (169, 174))	('1:200', 'Var', (114, 119))
452792	31011254	We found that the FOXP3+ Treg cell infiltration was significantly associated with age (P = 0.019), gender (P = 0.015), and tumor location (P = 0.018).	('FOXP3+', 'Var', (18, 24))	('tumor', 'Disease', (123, 128))	('associated', 'Reg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
452797	31011254	For Kaplan-Meier analysis, the OS of patients with high expression of PD-L1 was significantly shorter compared with patients with low PD-L1 expression (P = 0.016).	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (116, 124))	('shorter', 'NegReg', (94, 101))	('high expression', 'Var', (51, 66))	('PD-L1', 'Gene', (70, 75))
452803	31011254	In a cohort of 19 G-NEC patients, we found that 6/19 demonstrated a copy number gain of PD-L1 compared to normal human tissue.	('copy number', 'Var', (68, 79))	('PD-L1', 'Gene', (88, 93))	('gain', 'PosReg', (80, 84))	('patients', 'Species', '9606', (24, 32))	('human', 'Species', '9606', (113, 118))
452823	31011254	We found that a large number of patients demonstrated a copy number alteration and PD-L1 expression was significantly higher in cases with PD-L1 copy number gain, implying that PD-L1 gene alteration is a mechanism of PD-L1 overexpression, similar to a study in thymic cancer.	('higher', 'PosReg', (118, 124))	('thymic cancer', 'Disease', (261, 274))	('patients', 'Species', '9606', (32, 40))	('expression', 'MPA', (89, 99))	('thymic cancer', 'Disease', 'MESH:D013953', (261, 274))	('alteration', 'Var', (188, 198))	('copy number alteration', 'Var', (56, 78))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('overexpression', 'PosReg', (223, 237))	('PD-L1', 'Gene', (83, 88))	('PD-L1 copy number gain', 'Disease', 'MESH:D010300', (139, 161))	('PD-L1 copy number gain', 'Disease', (139, 161))
452824	31011254	Some recent research indicated that PD-L1 expression was associated with favorable OS in several malignancies, such as colorectal cancer, thymic cancer, breast cancer, and non-small cell lung cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('malignancies', 'Disease', (97, 109))	('thymic cancer', 'Disease', (138, 151))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (176, 198))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (172, 198))	('expression', 'Var', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('thymic cancer', 'Disease', 'MESH:D013953', (138, 151))	('colorectal cancer', 'Disease', (119, 136))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (172, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('PD-L1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('non-small cell lung cancer', 'Disease', (172, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('breast cancer', 'Disease', (153, 166))
452834	31011254	In conclusion, this study for the first time demonstrated that the high PD-L1 expression by tumor cells was associated with a poor prognosis in G-NECs, especially in the PD-1+ subgroup.	('expression', 'MPA', (78, 88))	('high', 'Var', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PD-1', 'Gene', (170, 174))	('tumor', 'Disease', (92, 97))	('PD-1', 'Gene', '5133', (170, 174))	('NECs', 'Phenotype', 'HP:0100634', (146, 150))	('PD-L1', 'Gene', (72, 77))	('G-NECs', 'Disease', (144, 150))
452839	31011254	This study for the first time demonstrated that PD-L1 can be expressed by G-NEC cancer cells and the high PD-L1 expression was associated with a poor prognosis.	('associated', 'Reg', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PD-L1', 'Gene', (106, 111))	('PD-L1', 'Gene', (48, 53))	('high', 'Var', (101, 105))	('cancer', 'Disease', (80, 86))	('expression', 'MPA', (112, 122))
452861	29507470	Additionally, recent meta-analyses have shown that NSBB decrease mortality in cirrhotic patients to a greater degree than would be expected from the reduced rate of variceal bleeding, and also protect against spontaneous bacterial peritonitis.	('variceal bleeding', 'Disease', (165, 182))	('patients', 'Species', '9606', (88, 96))	('bacterial peritonitis', 'Disease', (221, 242))	('peritonitis', 'Phenotype', 'HP:0002586', (231, 242))	('NSBB', 'Var', (51, 55))	('variceal bleeding', 'Disease', 'MESH:D014648', (165, 182))	('mortality', 'MPA', (65, 74))	('decrease', 'NegReg', (56, 64))	('bacterial peritonitis', 'Disease', 'MESH:D010534', (221, 242))
452918	29507470	Concurrently, NSBB therapy significantly ameliorated systemic endotoxemia at the one- and three-month follow-up intervals, but endotoxemia prevention was not correlated with the respective reductions of serum MDA and LOOH.	('endotoxemia', 'Disease', 'MESH:D019446', (62, 73))	('endotoxemia', 'Disease', (127, 138))	('serum MDA', 'MPA', (203, 212))	('endotoxemia', 'Disease', (62, 73))	('systemic endotoxemia', 'Disease', 'MESH:D019446', (53, 73))	('systemic endotoxemia', 'Disease', (53, 73))	('ameliorated', 'PosReg', (41, 52))	('NSBB', 'Var', (14, 18))	('MDA', 'Chemical', 'MESH:D008315', (209, 212))	('endotoxemia', 'Disease', 'MESH:D019446', (127, 138))	('LOOH', 'Chemical', 'MESH:D008054', (217, 221))
452937	29507470	Beyond their well-established preventive role in variceal bleeding, we feel that future studies should focus on answering whether the NSBB-induced systemic antioxidant effect and gut barrier function improvement could result in the prevention of other cirrhosis-related complications, leading to a better clinical outcome in terms of morbidity and mortality.	('NSBB-induced', 'Var', (134, 146))	('cirrhosis', 'Phenotype', 'HP:0001394', (252, 261))	('result in', 'Reg', (218, 227))	('cirrhosis', 'Disease', 'MESH:D005355', (252, 261))	('variceal bleeding', 'Disease', (49, 66))	('cirrhosis', 'Disease', (252, 261))	('variceal bleeding', 'Disease', 'MESH:D014648', (49, 66))
452940	28694421	Human esophageal squamous cell carcinoma (ESCC) cell line CaEs-17, TE-1, EC109, KYSE510, KYSE140, KYSE70, and KYSE30 were selected to detect their sensitivity to cisplatin.	('Human', 'Species', '9606', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('esophageal squamous cell carcinoma', 'Disease', (6, 40))	('KYSE140', 'Chemical', '-', (89, 96))	('EC109', 'CellLine', 'CVCL:6898', (73, 78))	('KYSE70', 'Var', (98, 104))	('KYSE30', 'Var', (110, 116))	('KYSE510', 'Var', (80, 87))	('TE', 'Chemical', 'MESH:D013691', (67, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('KYSE140', 'Var', (89, 96))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (6, 40))
452960	28694421	In esophageal squamous cell carcinoma (ESCC), KLF4 is decreased; and KLF4 deletion in mice leads to squamous cell dysplasia.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('KLF4', 'MPA', (46, 50))	('deletion', 'Var', (74, 82))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('mice', 'Species', '10090', (86, 90))	('squamous cell dysplasia', 'Disease', 'MESH:D002294', (100, 123))	('KLF4', 'Gene', (69, 73))	('decreased', 'NegReg', (54, 63))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (100, 123))	('leads to', 'Reg', (91, 99))	('squamous cell dysplasia', 'Disease', (100, 123))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))
452962	28694421	The KLF4 gene has been shown to be epigenetically inactivated in human cervical cancer and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('human', 'Species', '9606', (65, 70))	('KLF4 gene', 'Gene', (4, 13))	('cervical cancer', 'Disease', (71, 86))	('cervical cancer', 'Disease', 'MESH:D002583', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('epigenetically inactivated', 'Var', (35, 61))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('lung cancer', 'Disease', (91, 102))
452963	28694421	Moreover, KLF4 enhances the sensitivity of cisplatin to lung cancer cells.	('KLF4', 'Var', (10, 14))	('enhances', 'PosReg', (15, 23))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('sensitivity of cisplatin', 'MPA', (28, 52))
452966	28694421	Two human ESCC cell lines (TE-1 and KYSE140) were selected from seven cell lines (CaEs-17, TE-1, EC109, KYSE510, KYSE140, KYSE70, and KYSE30) according to the cell line sensitivity of cisplatin.	('KYSE140', 'Chemical', '-', (36, 43))	('KYSE70', 'Var', (122, 128))	('human', 'Species', '9606', (4, 9))	('KYSE30', 'Var', (134, 140))	('KYSE140', 'Chemical', '-', (113, 120))	('TE', 'Chemical', 'MESH:D013691', (27, 29))	('EC109', 'CellLine', 'CVCL:6898', (97, 102))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('KYSE510', 'Var', (104, 111))	('TE', 'Chemical', 'MESH:D013691', (91, 93))	('KYSE140', 'Var', (113, 120))
452968	28694421	Human ESCC cell line CaEs-17, TE-1, EC109, KYSE510, KYSE140, KYSE70, and KYSE30 were cultured in RPMI1640 (Gibco) supplemented with 10% (v/v) fetal calf serum (FBS, Gibco) at 37 C in a humidified 5% CO2 incubator.	('Human', 'Species', '9606', (0, 5))	('CO2', 'Chemical', '-', (199, 202))	('KYSE70', 'Var', (61, 67))	('RPMI1640', 'Chemical', '-', (97, 105))	('KYSE140', 'Var', (52, 59))	('FBS', 'Disease', (160, 163))	('calf', 'Species', '9913', (148, 152))	('TE', 'Chemical', 'MESH:D013691', (30, 32))	('EC109', 'CellLine', 'CVCL:6898', (36, 41))	('KYSE140', 'Chemical', '-', (52, 59))	('FBS', 'Disease', 'MESH:D005198', (160, 163))
452987	28694421	The sensitivity to cisplatin of KYSE140 was relatively high compared to the other five cell lines; whereas TE-1 was the relative less sensitive to cisplatin as compared with the other five.	('KYSE140', 'Chemical', '-', (32, 39))	('sensitivity to cisplatin', 'MPA', (4, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('TE', 'Chemical', 'MESH:D013691', (107, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('KYSE140', 'Var', (32, 39))
452990	28694421	Additionally, cisplatin sensitivity of KYSE140 was significantly higher than TE-1, KYSE510, and KYSE70 under 5 mg/L cisplatin; and significantly higher than TE-1, CaEs-17, KYSE510, KYSE70, and KYSE30 under 10 mg/L cisplatin (Figure 1).	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('TE', 'Chemical', 'MESH:D013691', (157, 159))	('KYSE140', 'Chemical', '-', (39, 46))	('cisplatin sensitivity', 'MPA', (14, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('TE', 'Chemical', 'MESH:D013691', (77, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('higher', 'PosReg', (65, 71))	('KYSE140', 'Var', (39, 46))	('higher', 'PosReg', (145, 151))
452991	28694421	Relative high levels of KLF4 were found in ESCC cell line CaEs-17, EC109, KYSE140, KYSE70, and KYSE30; while relative low levels of KLF4 were found in TE-1 and KYSE510 (Figure 2A).	('KYSE30', 'Var', (95, 101))	('KYSE140', 'Var', (74, 81))	('TE', 'Chemical', 'MESH:D013691', (151, 153))	('KYSE140', 'Chemical', '-', (74, 81))	('EC109', 'CellLine', 'CVCL:6898', (67, 72))	('KYSE70', 'Var', (83, 89))
452992	28694421	Our results showed that the promoter region was mostly unmethylated in CaEs-17, EC109, KYSE140, KYSE70, and KYSE30 cells; whereas, relatively hypermethylated in TE-1 and KYSE510 (Figure 2B).	('TE', 'Chemical', 'MESH:D013691', (161, 163))	('EC109', 'CellLine', 'CVCL:6898', (80, 85))	('KYSE70', 'Var', (96, 102))	('KYSE140', 'Chemical', '-', (87, 94))	('KYSE510', 'Var', (170, 177))
452993	28694421	Moreover, combining our results of cisplatin sensitivity of the seven ESCC cell lines, we found that a high level of KLF4 was associated with high sensitivity to cisplatin.	('associated', 'Reg', (126, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('high sensitivity to cisplatin', 'MPA', (142, 171))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('high', 'Var', (103, 107))
453023	28694421	However, it should be noted that besides the downregulation of KLF4 through the aforementioned mechanisms, splicing variants of KLF4 also play an important role in tumor formation and progression.	('progression', 'CPA', (184, 195))	('tumor', 'Disease', (164, 169))	('splicing variants', 'Var', (107, 124))	('downregulation', 'NegReg', (45, 59))	('KLF4', 'Gene', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('play', 'Reg', (138, 142))
453029	28694421	In cervical cancer, methylation in the promoter region could inhibit expression of KLF4 and restoring KLF4 expression using demethylating agent 5-Azacytidine (5-Aza) could enhance the sensitivity to cisplatin of cervical cancer cells.	('5-Aza', 'Chemical', 'MESH:D001374', (159, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (199, 208))	('enhance', 'PosReg', (172, 179))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('KLF4', 'Protein', (83, 87))	('restoring', 'PosReg', (92, 101))	('expression', 'MPA', (107, 117))	('inhibit', 'NegReg', (61, 68))	('cervical cancer', 'Disease', (3, 18))	('cervical cancer', 'Disease', (212, 227))	('sensitivity to cisplatin', 'MPA', (184, 208))	('methylation', 'Var', (20, 31))	('expression', 'MPA', (69, 79))	('cervical cancer', 'Disease', 'MESH:D002583', (212, 227))	('5-Azacytidine', 'Chemical', 'MESH:D001374', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('5-Aza', 'Chemical', 'MESH:D001374', (144, 149))
453031	28694421	In the present study, under the final concentration of 0.5 mg/L, 0.1 mg/L, 2.5 mg/L, 5 mg/L, and 10 mg/L of cisplatin, cell viability was significantly decreased after treatment of demethylation reagents 5-Aza-CdR in TE-1 cells.	('TE', 'Chemical', 'MESH:D013691', (217, 219))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('5-Aza', 'Chemical', 'MESH:D001374', (204, 209))	('decreased', 'NegReg', (152, 161))	('cell viability', 'CPA', (119, 133))	('0.1', 'Var', (65, 68))
453032	28694421	These results suggested that demethylation in the promoter region and the restored expression of KLF4 could inhibit cell proliferation and increase the sensitivity to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('sensitivity to cisplatin', 'MPA', (152, 176))	('increase', 'PosReg', (139, 147))	('expression', 'MPA', (83, 93))	('restored', 'PosReg', (74, 82))	('KLF4', 'Gene', (97, 101))	('inhibit', 'NegReg', (108, 115))	('cell proliferation', 'CPA', (116, 134))	('demethylation', 'Var', (29, 42))
453033	28694421	In the meanwhile, the cell viability of KYSE140 was significantly decreased compared with TE-1 cells, which suggested that hypomethylation in promoter and high level of KLF4 could inhibit the proliferation of human ESCC cells.	('human', 'Species', '9606', (209, 214))	('proliferation', 'CPA', (192, 205))	('KYSE140', 'Chemical', '-', (40, 47))	('inhibit', 'NegReg', (180, 187))	('decreased', 'NegReg', (66, 75))	('TE', 'Chemical', 'MESH:D013691', (90, 92))	('cell viability', 'CPA', (22, 36))	('hypomethylation', 'Var', (123, 138))
453034	28694421	In oral squamous cell carcinoma, overexpression of KLF4 has been reported to promote cell cycle arrest in vitro and induce apoptosis in vivo.	('induce', 'PosReg', (116, 122))	('cell cycle arrest', 'CPA', (85, 102))	('promote', 'PosReg', (77, 84))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('KLF4', 'Gene', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('apoptosis', 'CPA', (123, 132))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('overexpression', 'Var', (33, 47))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))
453035	28694421	Consistent with these findings, the results of flow cytometry assay showed that the apoptosis rate was significantly increased in KYSE140 cells when cells were treated with 1 mg/L cisplatin, compared with TE-1 cells, suggesting that high levels of KLF4 with promoter hypomethylation could induce cell apoptosis in human ESCC cells.	('apoptosis rate', 'CPA', (84, 98))	('increased', 'PosReg', (117, 126))	('KYSE140', 'Chemical', '-', (130, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (180, 189))	('promoter hypomethylation', 'Var', (258, 282))	('cell apoptosis', 'CPA', (296, 310))	('human', 'Species', '9606', (314, 319))	('induce', 'PosReg', (289, 295))	('TE', 'Chemical', 'MESH:D013691', (205, 207))
453036	28694421	Moreover, when TE-1 cells were treated with cisplatin at a final concentration of 5 mg/L and 10 mg/L, the apoptosis of TE-1 cells was significantly increased after 5-Aza-CdR treatment, suggesting enhanced sensitivity to cisplatin of human ESCC cells by high level of KLF4.	('cisplatin', 'Chemical', 'MESH:D002945', (220, 229))	('enhanced', 'PosReg', (196, 204))	('TE', 'Chemical', 'MESH:D013691', (119, 121))	('human', 'Species', '9606', (233, 238))	('increased', 'PosReg', (148, 157))	('apoptosis', 'CPA', (106, 115))	('5-Aza-CdR', 'Var', (164, 173))	('sensitivity', 'MPA', (205, 216))	('TE', 'Chemical', 'MESH:D013691', (15, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('5-Aza', 'Chemical', 'MESH:D001374', (164, 169))
453039	28694421	We found that in KYSE140 cell line with high levels of KLF4, the percentage of cells arrested at S phase was significantly higher than TE-1 cells.	('KLF4', 'Var', (55, 59))	('higher', 'PosReg', (123, 129))	('cells arrested at S phase', 'CPA', (79, 104))	('TE', 'Chemical', 'MESH:D013691', (135, 137))	('KYSE140', 'Chemical', '-', (17, 24))	('high levels', 'Var', (40, 51))
453042	28694421	Our findings showed that KLF4, acting as a tumor suppressor in human ESCC cells, was downregulated in human ESCC cells by hypermethylation in the promoter region.	('downregulated', 'NegReg', (85, 98))	('human', 'Species', '9606', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('KLF4', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('hypermethylation', 'Var', (122, 138))	('human', 'Species', '9606', (102, 107))
453145	26896963	Treatment with DCF in esophageal cancer is reported to be associated with increased response rates but also with a highly increased incidence of toxicities, the most common of which are hematological and gastrointestinal.	('toxicities', 'Disease', (145, 155))	('response', 'MPA', (84, 92))	('gastrointestinal', 'Disease', (204, 220))	('DCF', 'Var', (15, 18))	('increased', 'PosReg', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('toxicities', 'Disease', 'MESH:D064420', (145, 155))	('DCF', 'Chemical', '-', (15, 18))	('gastrointestinal', 'Disease', 'MESH:D005767', (204, 220))	('hematological', 'Disease', (186, 199))	('esophageal cancer', 'Disease', (22, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))
453151	26896963	They also had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, a life expectancy of >12 weeks, and adequate liver, bone marrow, renal, and cardiovascular function as indicated by a serum bilirubin <=1.5 mg/dl, neutrophil count >=1500/mm3, serum aspartate aminotransferase and alanine aminotransferase <=twice the upper limit of normal range, platelet count >=10 x 104/mm3, hemoglobin >=8.0 g/dl, and creatinine <=1.2 mg/dl (or creatinine clearance >60 ml/min).	('creatinine clearance', 'MPA', (458, 478))	('bilirubin', 'Chemical', 'MESH:D001663', (218, 227))	('>=10', 'Var', (388, 392))	('platelet', 'MPA', (373, 381))	('Oncology', 'Phenotype', 'HP:0002664', (45, 53))	('hemoglobin', 'MPA', (404, 414))	('creatinine', 'MPA', (431, 441))	('creatinine', 'Chemical', 'MESH:D003404', (458, 468))	('creatinine', 'Chemical', 'MESH:D003404', (431, 441))	('alanine aminotransferase', 'Gene', (307, 331))	('>=1500/mm3', 'Var', (258, 268))	('serum bilirubin', 'MPA', (212, 227))	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (270, 302))	('alanine aminotransferase', 'Gene', '2875', (307, 331))	('serum aspartate aminotransferase', 'MPA', (270, 302))
453178	26896963	In this phase II trial, we expected that the clinical incidence of toxicities with Bi-DCF would increase above that with FP in the preoperative design, and that the rate of treatment completion would be lower than that in JCOG 9907 (89.6 %).	('Bi-DCF', 'Chemical', '-', (83, 89))	('lower', 'NegReg', (203, 208))	('toxicities', 'Disease', (67, 77))	('Bi-DCF', 'Var', (83, 89))	('toxicities', 'Disease', 'MESH:D064420', (67, 77))	('increase', 'PosReg', (96, 104))
453218	26896963	TXT 75-100 mg/m2 every 3-4 weeks is associated with a quite pronounced neutropenia, up to 44 % rate of febrile neutropenia in patients with recurrent ovarian cancer.	('TXT 75-100 mg/m2', 'Var', (0, 16))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (140, 164))	('neutropenia', 'Disease', (111, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (150, 164))	('neutropenia', 'Disease', (71, 82))	('ovarian cancer', 'Disease', (150, 164))	('TXT', 'Chemical', 'MESH:D000077143', (0, 3))	('ovarian cancer', 'Phenotype', 'HP:0100615', (150, 164))	('febrile neutropenia', 'Disease', (103, 122))	('febrile neutropenia', 'Disease', 'MESH:D009503', (103, 122))	('patients', 'Species', '9606', (126, 134))	('neutropenia', 'Phenotype', 'HP:0001875', (111, 122))	('neutropenia', 'Disease', 'MESH:D009503', (111, 122))	('neutropenia', 'Phenotype', 'HP:0001875', (71, 82))	('neutropenia', 'Disease', 'MESH:D009503', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
453219	26896963	Several reports revealed that the major toxicity of DCF repeated every 3-4 weeks at doses of TXT 50-75 mg/m2, CDDP60-75 mg/m2, and 5-FU 700-800 mg/m2 was myelosuppression, and the frequencies of grade 3/4 leucopenia and neutropenia in a phase II study were 33.3 % and 90 %, respectively, (Table 5).	('toxicity', 'Disease', 'MESH:D064420', (40, 48))	('neutropenia', 'Disease', (220, 231))	('toxicity', 'Disease', (40, 48))	('leucopenia', 'Disease', (205, 215))	('DCF', 'Chemical', '-', (52, 55))	('neutropenia', 'Disease', 'MESH:D009503', (220, 231))	('myelosuppression', 'Disease', 'MESH:D001855', (154, 170))	('neutropenia', 'Phenotype', 'HP:0001875', (220, 231))	('CDDP60-75 mg/m2', 'Var', (110, 125))	('CDDP60', 'Chemical', '-', (110, 116))	('leucopenia', 'Disease', 'MESH:C536227', (205, 215))	('5-FU 700-800 mg/m2', 'Var', (131, 149))	('TXT', 'Chemical', 'MESH:D000077143', (93, 96))	('myelosuppression', 'Disease', (154, 170))	('5-FU', 'Chemical', 'MESH:D005472', (131, 135))
453243	24166133	Differences in the histological type of esophagogastric junction cancer were not independent prognostic factors for survival, and there appears to be a benefit to dissecting the number 1, 2, 3 and 7 lymph nodes.	('junction cancer', 'Disease', (56, 71))	('dissecting', 'Var', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('junction cancer', 'Disease', 'MESH:D009369', (56, 71))
453281	24166133	In 16 patients with mediastinal lymph node metastasis, the average total number of metastatic lymph nodes was 6.7, which was significantly higher than that (2.5) in the 68 patients who were positive for metastasis to only the abdominal lymph nodes.	('patients', 'Species', '9606', (172, 180))	('patients', 'Species', '9606', (6, 14))	('mediastinal lymph node metastasis', 'Var', (20, 53))	('higher', 'PosReg', (139, 145))
453306	24166133	In 16 patients with mediastinal lymph nodes metastasis, the average total number of metastatic lymph nodes was 6.7, which was significantly higher than that (2.5) in the 68 patients who were positive only for metastasis to abdominal lymph nodes.	('mediastinal lymph nodes metastasis', 'Var', (20, 54))	('higher', 'PosReg', (140, 146))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (173, 181))
453354	19956829	Although EGFR inhibitors have significant efficacy and less toxicity than conventional chemotherapeutics, cancer patients show highly variable responses to these agents.	('toxicity', 'Disease', (60, 68))	('patients', 'Species', '9606', (113, 121))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('cancer', 'Disease', (106, 112))	('toxicity', 'Disease', 'MESH:D064420', (60, 68))	('inhibitors', 'Var', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
453416	19956829	Acquired activating mutations of the intracellular tyrosine kinase domain of the EGFR are known to drive the neoplastic behavior of non-small cell lung cancer.	('tyrosine', 'Chemical', 'MESH:D014443', (51, 59))	('drive', 'PosReg', (99, 104))	('non-small cell lung cancer', 'Disease', (132, 158))	('EGFR', 'Gene', '1956', (81, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('activating', 'PosReg', (9, 19))	('neoplastic behavior', 'CPA', (109, 128))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (132, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (132, 158))	('mutations', 'Var', (20, 29))	('EGFR', 'Gene', (81, 85))
453417	19956829	Furthermore, cancers with these mutations are much more sensitive to the inhibitory effects of the EGFR inhibitors erlotinib and gefitinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (115, 124))	('EGFR', 'Gene', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('more', 'PosReg', (51, 55))	('mutations', 'Var', (32, 41))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('gefitinib', 'Chemical', 'MESH:D000077156', (129, 138))	('cancers', 'Disease', (13, 20))	('EGFR', 'Gene', '1956', (99, 103))	('sensitive', 'MPA', (56, 65))	('inhibitory effects', 'MPA', (73, 91))
453418	19956829	In addition, also in lung cancer, cells that become resistant to these therapies often harbor a second EGFR mutation or a point mutation in the K-RAS oncogene.	('EGFR', 'Gene', '1956', (103, 107))	('K-RAS', 'Gene', '3845', (144, 149))	('K-RAS', 'Gene', (144, 149))	('harbor', 'Reg', (87, 93))	('lung cancer', 'Disease', (21, 32))	('EGFR', 'Gene', (103, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutation', 'Var', (108, 116))	('point mutation', 'Var', (122, 136))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))
453419	19956829	There are reports of similar EGFR mutations in esophageal adenocarcinoma; however, their impact on the biology and response to therapy of these tumors is unknown.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (47, 72))	('esophageal adenocarcinoma', 'Disease', (47, 72))	('EGFR', 'Gene', '1956', (29, 33))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (47, 72))	('EGFR', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mutations', 'Var', (34, 43))
453420	19956829	Mutations in EGFR and/or the downstream signaling proteins K-RAS and PI3KCA have been implicated in differential inhibition of the ERK and AKT pathways in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('ERK', 'Gene', '5594', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('K-RAS', 'Gene', (59, 64))	('AKT', 'Gene', '207', (139, 142))	('ERK', 'Gene', (131, 134))	('tumor', 'Disease', (155, 160))	('PI3KCA', 'Gene', (69, 75))	('inhibition', 'NegReg', (113, 123))	('Mutations', 'Var', (0, 9))	('AKT', 'Gene', (139, 142))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('K-RAS', 'Gene', '3845', (59, 64))
453421	19956829	Furthermore, deletion mutation of the PTEN tumor suppressor protein can lead to constitutive activation of AKT, independent of mitogenic stimuli.	('PTEN', 'Gene', '5728', (38, 42))	('deletion mutation', 'Var', (13, 30))	('AKT', 'Gene', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('constitutive activation', 'MPA', (80, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('AKT', 'Gene', '207', (107, 110))	('PTEN', 'Gene', (38, 42))
453422	19956829	Given the observed differential response of these four esophageal cancer patients to gefitinib we measured PTEN protein expression in tumor cells and also performed genomic sequencing analysis of mutational hotspots in exons 18-21 of EGFR, exons 2 and 3 of K-RAS and exons 9 and 22 of PI3KCA.	('EGFR', 'Gene', '1956', (234, 238))	('PTEN', 'Gene', (107, 111))	('EGFR', 'Gene', (234, 238))	('K-RAS', 'Gene', '3845', (257, 262))	('PTEN', 'Gene', '5728', (107, 111))	('gefitinib', 'Chemical', 'MESH:D000077156', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('PI3KCA', 'Gene', (285, 291))	('esophageal cancer', 'Disease', (55, 72))	('K-RAS', 'Gene', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('patients', 'Species', '9606', (73, 81))	('mutational', 'Var', (196, 206))	('tumor', 'Disease', (134, 139))
453424	19956829	These results suggest that the differential sensitivity of ERK and AKT pathways to gefitinib in patient 1 is not due to gain of function mutations in PI3KCA or deletion mutations in PTEN genes.	('ERK', 'Gene', (59, 62))	('AKT', 'Gene', '207', (67, 70))	('PI3KCA', 'Gene', (150, 156))	('gefitinib', 'Chemical', 'MESH:D000077156', (83, 92))	('AKT', 'Gene', (67, 70))	('gain of function', 'PosReg', (120, 136))	('deletion mutations', 'Var', (160, 178))	('mutations', 'Var', (137, 146))	('patient', 'Species', '9606', (96, 103))	('ERK', 'Gene', '5594', (59, 62))	('PTEN', 'Gene', (182, 186))	('PTEN', 'Gene', '5728', (182, 186))
453437	19956829	Examples of alternative regulation are widely known and include: PTEN deletion/deactivation to activate AKT, independent activation of RAS and MAP kinase pathways and upregulation of other membrane tyrosine kinase receptors such as MET, HER-2, PDGFR.	('PTEN', 'Gene', (65, 69))	('RAS', 'Pathway', (135, 138))	('deletion/deactivation', 'Var', (70, 91))	('PTEN', 'Gene', '5728', (65, 69))	('MAP kinase pathways', 'Pathway', (143, 162))	('AKT', 'Gene', (104, 107))	('tyrosine', 'Chemical', 'MESH:D014443', (198, 206))	('deletion/deactivation', 'NegReg', (70, 91))	('upregulation', 'PosReg', (167, 179))	('AKT', 'Gene', '207', (104, 107))	('PDGFR', 'Gene', (244, 249))	('activate', 'PosReg', (95, 103))	('HER-2', 'Gene', (237, 242))	('PDGFR', 'Gene', '5159', (244, 249))	('MET', 'Gene', (232, 235))	('activation', 'PosReg', (121, 131))	('HER-2', 'Gene', '2064', (237, 242))
453438	19956829	While we identified no mutations in the known mutational hotspots of exons of EGFR, K-RAS and PI3KCA genes and no deletion of PTEN, this does not exclude other bypass mechanisms or the presence of other infrequent mutations within these genes.	('PI3KCA', 'Gene', (94, 100))	('K-RAS', 'Gene', '3845', (84, 89))	('PTEN', 'Gene', '5728', (126, 130))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('K-RAS', 'Gene', (84, 89))	('PTEN', 'Gene', (126, 130))	('deletion', 'Var', (114, 122))
453459	33850955	Although many genomic variations critical to ESCC have been identified through whole-exome/genome sequencing, the transformation and development of normal esophageal epithelial tissue into precancerous lesions through successive mutations and into invasive carcinoma, respectively, remain to be elucidated as all related previous studies are cross-sectional in nature.	('invasive carcinoma', 'Disease', 'MESH:D009361', (248, 266))	('mutations', 'Var', (229, 238))	('invasive carcinoma', 'Disease', (248, 266))	('cancer', 'Disease', (192, 198))	('ESCC', 'Disease', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
453493	31509954	Perhaps these alterations facilitate Barrett's progression, whereas in non-progressive disease, cells follow the rules of increased oxidative stress ultimately triggers cell apoptosis, thereby preventing propagation and survival.	('alterations', 'Var', (14, 25))	('rat', 'Species', '10116', (18, 21))	('oxidative stress', 'MPA', (132, 148))	('triggers', 'Reg', (160, 168))	('facilitate', 'PosReg', (26, 36))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (122, 148))	('propagation', 'CPA', (204, 215))	('survival', 'CPA', (220, 228))	('preventing', 'NegReg', (193, 203))	('oxidative stress', 'Phenotype', 'HP:0025464', (132, 148))	('Barrett', 'Disease', (37, 44))	('cell apoptosis', 'CPA', (169, 183))
453504	31509954	Mitochondrial deoxyribonucleic acid (DNA) is more vulnerable to oxidative injury and the accumulation of random mutations compared to nuclear DNA, due to the DNA's close proximity to ROS production sites (i.e., the mitochondria themselves) and the reduced proficiency of mitochondrial DNA repair mechanisms.	('oxidative injury', 'Disease', (64, 80))	('DNA', 'Chemical', 'MESH:D000596', (285, 288))	('DNA', 'Chemical', 'MESH:D000596', (142, 145))	('deoxyribonucleic acid', 'Chemical', 'MESH:D000596', (14, 35))	('oxidative injury', 'Disease', 'MESH:D028361', (64, 80))	('mutations', 'Var', (112, 121))	('DNA', 'Chemical', 'MESH:D000596', (37, 40))	('DNA', 'Chemical', 'MESH:D000596', (158, 161))
453514	31509954	Our group has previously demonstrated a strong relationship between mitochondrial mutations and oxidative stress in the inflammatory condition, rheumatoid arthritis, using 8-oxo-7, 8-dihydro-2'-deoxyguanine (8-oxo-dG) and 4-hydroxy-2-nonenal (4-HNE).	('rheumatoid arthritis', 'Disease', (144, 164))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (144, 164))	('rat', 'Species', '10116', (32, 35))	('HNE', 'Gene', '1991', (245, 248))	('oxidative', 'MPA', (96, 105))	('oxidative stress', 'Phenotype', 'HP:0025464', (96, 112))	('8-oxo-7', 'Chemical', 'MESH:C036009', (172, 179))	("8-dihydro-2'-deoxyguanine", 'Chemical', 'MESH:D003848', (181, 206))	('arthritis', 'Phenotype', 'HP:0001369', (155, 164))	('mutations', 'Var', (82, 91))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (144, 164))	('HNE', 'Gene', (245, 248))	('4-hydroxy-2-nonenal', 'Chemical', 'MESH:C027576', (222, 241))
453536	31509954	Ki67 was 3.1-fold higher in EAC stroma compared with SIM stroma (p = 0.035), and 1.6-fold higher in EAC epithelium compared with SIM epithelium (p = 0.012) (Figure 3).	('EAC', 'Disease', 'MESH:D004941', (100, 103))	('EAC', 'Disease', 'MESH:D004941', (28, 31))	('Ki67', 'Var', (0, 4))	('EAC', 'Phenotype', 'HP:0011459', (100, 103))	('EAC', 'Phenotype', 'HP:0011459', (28, 31))	('higher', 'PosReg', (90, 96))	('higher', 'PosReg', (18, 24))	('EAC', 'Disease', (100, 103))	('EAC', 'Disease', (28, 31))
453557	31509954	We chose 8-oxo-dG, a pro-mutagenic lesion, and a marker of oxidative stress formed in the presence of excessive ROS production and associated with increased levels of random mitochondrial point mutations and inflammation.	('excessive ROS production', 'Phenotype', 'HP:0025464', (102, 126))	('increased', 'PosReg', (147, 156))	('inflammation', 'Disease', 'MESH:D007249', (208, 220))	('8-oxo-dG', 'Var', (9, 17))	('oxidative stress', 'Phenotype', 'HP:0025464', (59, 75))	('inflammation', 'Disease', (208, 220))	('random mitochondrial point mutations', 'MPA', (167, 203))	('levels', 'MPA', (157, 163))	('ROS production', 'MPA', (112, 126))
453574	31509954	However, in an environment of enhanced mutagenesis, the knock-on effect was disturbed respiratory chain function, defective oxidative phosphorylation and no subsequent increase in the production of ROS.	('oxidative phosphorylation', 'MPA', (124, 149))	('rat', 'Species', '10116', (91, 94))	('respiratory chain function', 'MPA', (86, 112))	('disturbed', 'Reg', (76, 85))	('mutagenesis', 'Var', (39, 50))	('defective', 'NegReg', (114, 123))
453877	30256853	who detected BPV-4 DNA in 61 out of 67 papillomas in which the copy number could be as high as 1 x 105 genomes per cell, indicating the presence of high viral load in infected tissues.	('BPV-4', 'Var', (13, 18))	('papilloma', 'Phenotype', 'HP:0012740', (39, 48))	('papillomas', 'Disease', 'MESH:D010212', (39, 49))	('papillomas', 'Disease', (39, 49))	('BPV-4', 'Species', '10562', (13, 18))	('papillomas', 'Phenotype', 'HP:0012740', (39, 49))	('detected', 'Reg', (4, 12))
453891	29447301	Human ESCC cells, TE8 and TE11, were cultured, and depletion of mtDNA content was induced by knockdown of mitochondrial transcription factor A expression or treatment with ethidium bromide.	('knockdown', 'Var', (93, 102))	('Human', 'Species', '9606', (0, 5))	('mitochondrial transcription factor A', 'Gene', '7019', (106, 142))	('induced', 'Reg', (82, 89))	('mitochondrial transcription factor A', 'Gene', (106, 142))	('ethidium bromide', 'Chemical', 'MESH:D004996', (172, 188))	('depletion of', 'MPA', (51, 63))
453893	29447301	Low mtDNA copy number in resected cancerous tissues was significantly correlated with pathological depth of tumor invasion (p = 0.045) and pathological stage (p = 0.025).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cancerous', 'Disease', 'MESH:D009369', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('mtDNA', 'Gene', (4, 9))	('cancerous', 'Disease', (34, 43))	('Low', 'Var', (0, 3))
453898	29447301	In conclusion, a low copy number of mtDNA is associated with tumor progression in ESCC.	('ESCC', 'Disease', (82, 86))	('low copy number', 'Var', (17, 32))	('associated with', 'Reg', (45, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mtDNA', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
453904	29447301	Alterations in mtDNA copy numbers in various human cancers have been studied in the past few decades, but the mtDNA copy number and its significance in ESCC remain unclear.	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('human', 'Species', '9606', (45, 50))	('mtDNA', 'Gene', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('ESCC', 'Disease', (152, 156))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
453912	29447301	Depletion of mtDNA content was induced by knockdown of mitochondrial transcription factor A (TFAM) expression or treatment with ethidium bromide (EtBr, 100 ng/ml) for 4 passages.	('expression', 'MPA', (99, 109))	('mitochondrial transcription factor A', 'Gene', (55, 91))	('EtBr', 'Chemical', 'MESH:D004996', (146, 150))	('ethidium bromide', 'Chemical', 'MESH:D004996', (128, 144))	('mitochondrial transcription factor A', 'Gene', '7019', (55, 91))	('induced', 'Reg', (31, 38))	('Depletion', 'MPA', (0, 9))	('TFAM', 'Gene', (93, 97))	('knockdown', 'Var', (42, 51))
453925	29447301	Harvested cells were stained with an APC conjugated anti-CD44 antibody (4103011, BioLegend, San Diego, CA, USA).	('CD44', 'Gene', '960', (57, 61))	('4103011', 'Var', (72, 79))	('CD44', 'Gene', (57, 61))
453939	29447301	Lower copy number was significantly correlated with high pathological tumor invasion and stage (pT, p = 0.045; pStage p = 0.025; Table 2).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Lower copy number', 'Var', (0, 17))	('tumor', 'Disease', (70, 75))	('stage', 'CPA', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
453941	29447301	On univariate analysis of OS, pathological AJCC/UICC T (tumor size) and N (node involvement) factors and mtDNA copy number were significant predictors of survival (S1 Table).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('mtDNA', 'Gene', (105, 110))	('AJCC/UICC', 'Gene', (43, 52))	('copy number', 'Var', (111, 122))
453943	29447301	The extracellular lactate concentrations of mtDNA-depleted cells were higher than control cells (TE8: 1.34+-0.03 or 1.44+-0.01 vs 1.13+-0.01 mug/muL, p<0.01; TE11: 1.34+-0.03 (p<0.01) or 1.26+-0.01 (p = 0.011) vs 0.83+-0.16; Fig 2D).	('lactate', 'Chemical', 'MESH:D019344', (18, 25))	('mtDNA-depleted', 'Var', (44, 58))	('muL', 'Gene', '4591', (145, 148))	('extracellular lactate concentrations', 'MPA', (4, 40))	('muL', 'Gene', (145, 148))	('higher', 'PosReg', (70, 76))
453949	29447301	mtDNA depletion of TE8 and TE11 by treatment with EtBr also led to slow proliferation and tolerance to hypoxia, compared with parental cells (S1C and S1D Fig).	('slow proliferation', 'CPA', (67, 85))	('TE8', 'Var', (19, 22))	('tolerance', 'CPA', (90, 99))	('depletion', 'NegReg', (6, 15))	('EtBr', 'Chemical', 'MESH:D004996', (50, 54))	('hypoxia', 'Disease', (103, 110))	('EtBr', 'Gene', (50, 54))	('hypoxia', 'Disease', 'MESH:D000860', (103, 110))	('TE11', 'Var', (27, 31))
453951	29447301	In mtDNA-depleted TE8 and TE11, the mRNA expression of E-cadherin was downregulated, whereas the mRNA expression of N-cadherin, vimentin, and zeb1 was upregulated (Fig 4A).	('E-cadherin', 'Gene', (55, 65))	('E-cadherin', 'Gene', '999', (55, 65))	('vimentin', 'Gene', '7431', (128, 136))	('N-cadherin', 'Gene', (116, 126))	('mRNA expression', 'MPA', (36, 51))	('vimentin', 'Gene', (128, 136))	('N-cadherin', 'Gene', '1000', (116, 126))	('upregulated', 'PosReg', (151, 162))	('downregulated', 'NegReg', (70, 83))	('zeb1', 'Gene', '6935', (142, 146))	('TE11', 'Var', (26, 30))	('zeb1', 'Gene', (142, 146))	('mRNA expression', 'MPA', (97, 112))
453960	29447301	Two recent reports investigated the mutation of mtDNA in esophageal cancer and revealed that D-loop alterations were frequent and that the alteration was associated with poor prognosis.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('mtDNA', 'Gene', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('D-loop', 'MPA', (93, 99))	('investigated', 'Reg', (19, 31))	('esophageal cancer', 'Disease', (57, 74))	('associated', 'Reg', (154, 164))	('mutation', 'Var', (36, 44))
453961	29447301	The mutation in the D-loop region also has been linked to reduced mtDNA copy number in other cancers.	('cancers', 'Disease', (93, 100))	('mtDNA', 'Gene', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('mutation', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('reduced', 'NegReg', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
453963	29447301	We found that mtDNA copy number in ESCC was significantly lower than that of non-cancerous tissues and that low mtDNA copy number was associated with tumor progression and poor prognosis.	('mtDNA', 'Gene', (14, 19))	('low', 'Var', (108, 111))	('associated', 'Reg', (134, 144))	('cancerous', 'Disease', 'MESH:D009369', (81, 90))	('ESCC', 'Disease', (35, 39))	('lower', 'NegReg', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cancerous', 'Disease', (81, 90))	('mtDNA', 'Gene', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (150, 155))
453964	29447301	Alterations in mtDNA copy numbers in other human cancers have been previously studied.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Alterations', 'Var', (0, 11))	('mtDNA', 'Gene', (15, 20))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('human', 'Species', '9606', (43, 48))
453972	29447301	We also found that ESCC cells with low mtDNA copy number have mesenchymal characteristics and cancer stemness, which play an important role in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer stemness', 'Disease', (94, 109))	('mtDNA', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mesenchymal characteristics', 'CPA', (62, 89))	('low', 'Var', (35, 38))	('cancer stemness', 'Disease', 'MESH:D009369', (94, 109))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
453973	29447301	Cells with low mtDNA copy number have higher migration activity in renal cell carcinoma and a stem-like, migratory, and invasive phenotype in breast cancer.	('renal cell carcinoma', 'Disease', (67, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('stem-like', 'CPA', (94, 103))	('mtDNA', 'Gene', (15, 20))	('breast cancer', 'Disease', (142, 155))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (67, 87))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('low', 'Var', (11, 14))	('higher', 'PosReg', (38, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('migration activity', 'CPA', (45, 63))
453975	29447301	Moreover, in this study, transmission electron microscopy revealed that TFAM knockdown cells showed mitochondrial swelling and dissolved cristae.	('mitochondrial swelling', 'Disease', (100, 122))	('mitochondrial swelling', 'Disease', 'MESH:D028361', (100, 122))	('knockdown', 'Var', (77, 86))	('dissolved cristae', 'CPA', (127, 144))	('TFAM', 'Gene', (72, 76))	('mitochondrial swelling', 'Phenotype', 'HP:0030774', (100, 122))
453979	29447301	The present study showed that low mtDNA copy number is correlated with tumor invasion, epithelial-to-mesenchymal transition, cancer stemness, and poor prognosis in ESCC.	('epithelial-to-mesenchymal transition', 'CPA', (87, 123))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('low', 'Var', (30, 33))	('tumor', 'Disease', (71, 76))	('ESCC', 'Disease', (164, 168))	('cancer stemness', 'Disease', 'MESH:D009369', (125, 140))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mtDNA', 'Gene', (34, 39))	('cancer stemness', 'Disease', (125, 140))
454151	28236016	Regardless of these limitations, the inserting of a fcSEMS reduced the risk of recurrent dysphagia due to dislocation, and improved dysphagia scores similar to our findings (Table 3) as well as to earlier descriptive studies on scSEMS.	('dysphagia', 'Disease', 'MESH:D003680', (132, 141))	('dysphagia', 'Phenotype', 'HP:0002015', (89, 98))	('reduced', 'NegReg', (59, 66))	('inserting', 'Var', (37, 46))	('dysphagia', 'Disease', (132, 141))	('dysphagia', 'Disease', 'MESH:D003680', (89, 98))	('dysphagia', 'Phenotype', 'HP:0002015', (132, 141))	('dislocation', 'Disease', (106, 117))	('fcSEMS', 'Gene', (52, 58))	('improved', 'PosReg', (123, 131))	('dysphagia', 'Disease', (89, 98))
454250	28467773	We showed that silencing ERBB4, IRF2 and CXCR4 together by RNAi inhibited CRI, which was similar to that of miR-302b over-expression.	('CXCR4', 'Gene', (41, 46))	('IRF2', 'Gene', '3660', (32, 36))	('CRI', 'CPA', (74, 77))	('RNAi', 'Gene', (59, 63))	('inhibited', 'NegReg', (64, 73))	('ERBB4', 'Gene', '2066', (25, 30))	('silencing', 'Var', (15, 24))	('miR-302b', 'Gene', '442894', (108, 116))	('IRF2', 'Gene', (32, 36))	('miR-302b', 'Gene', (108, 116))	('CXCR4', 'Gene', '7852', (41, 46))	('ERBB4', 'Gene', (25, 30))	('expression', 'Species', '29278', (122, 132))
454265	28467773	The cells were co-transfected with pmirGLO -WT or pmirGLO -MT and miR-302b or mock (pcDNA 6.2-GW/EmGFP-miR).	('pmirGLO -MT', 'Var', (50, 61))	('miR', 'Gene', (66, 69))	('miR', 'Gene', '220972', (66, 69))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('miR-302b', 'Gene', '442894', (66, 74))	('miR-302b', 'Gene', (66, 74))
454334	28440945	They were closely surveyed and re-diagnosed with submucosal carcinoma at intervals of 6, 6, 7, 18, 19, 34, 36, and 48 months later; in one case, T2N0M0 carcinoma developed from MD 46 months later and in the other, T2N0M0 was diagnosed 52 months after the initial diagnosis of Bch.	('carcinoma', 'Disease', 'MESH:D002277', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('carcinoma', 'Disease', (60, 69))	('T2N0M0', 'Var', (145, 151))	('submucosal carcinoma', 'Disease', 'MESH:C563509', (49, 69))	('carcinoma', 'Disease', (152, 161))	('carcinoma', 'Disease', 'MESH:D002277', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('submucosal carcinoma', 'Disease', (49, 69))	('Bch', 'Chemical', '-', (276, 279))
454371	27428362	Lower esophageal subsite (33-40 cm) was also associated with a higher risk of cardiac death.	('33-40 cm', 'Var', (26, 34))	('cardiac death', 'Disease', 'MESH:D003643', (78, 91))	('cardiac death', 'Disease', (78, 91))	('cardiac death', 'Phenotype', 'HP:0001645', (78, 91))
454435	27428362	An analysis of dose-volume histograms comparing proton versus traditional x-ray therapy has shown that protons can reduce the irradiation dose and volume of heart irradiation in esophageal cancer, potentially decreasing complications.	('esophageal cancer', 'Disease', (178, 195))	('protons', 'Var', (103, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('decreasing', 'NegReg', (209, 219))	('irradiation dose', 'MPA', (126, 142))	('reduce', 'NegReg', (115, 121))
454494	24868168	In contrast, in another large multicenter study from France including 203 patients, no difference was found in the overall adenoma detection rate between standard-resolution (<=410,000 pixels) WLE and high-resolution (850,000 pixels) WLE coupled with pan-colonic chromoendoscopy with indigo carmine (49.5% versus 59.4%, respectively).	('adenoma', 'Disease', 'MESH:D000236', (123, 130))	('850,000 pixels', 'Var', (218, 232))	('indigo carmine', 'Chemical', 'MESH:D007203', (284, 298))	('patients', 'Species', '9606', (74, 82))	('WLE', 'Chemical', '-', (193, 196))	('adenoma', 'Disease', (123, 130))	('rat', 'Species', '10116', (141, 144))	('WLE', 'Chemical', '-', (234, 237))
454567	24868168	A single-mode (Gaussian beam profile) fiber, acting as both the illumination point source and the detection pinhole, and a miniature objective lens at the distal end of a conventional video endoscope (EG3870K, EC-3870CILK; Pentax, Hoya Corporation, Japan) enable confocal microscopy in addition to standard video endoscopy.	('EC', 'Chemical', '-', (210, 212))	('rat', 'Species', '10116', (241, 244))	('EC-3870CILK', 'Var', (210, 221))	('EG3870K', 'Var', (201, 208))
454647	24868168	FOVs are 300 mum x300 mum, 120 mum x120 mum, and 400 mum x400 mum for x570 pEC, x1,400 pEC, and x580 iEC, respectively.	('x570 pEC', 'Var', (70, 78))	('mum', 'Gene', '56925', (40, 43))	('EC', 'Chemical', '-', (102, 104))	('mum', 'Gene', '56925', (53, 56))	('EC', 'Chemical', '-', (76, 78))	('mum', 'Gene', (22, 25))	('x580 iEC', 'Var', (96, 104))	('mum', 'Gene', '56925', (13, 16))	('mum', 'Gene', (40, 43))	('mum', 'Gene', '56925', (62, 65))	('mum', 'Gene', (53, 56))	('mum', 'Gene', (13, 16))	('mum', 'Gene', '56925', (31, 34))	('mum', 'Gene', (62, 65))	('EC', 'Chemical', '-', (88, 90))	('mum', 'Gene', (31, 34))	('mum', 'Gene', '56925', (22, 25))
454663	23273065	In vitro binding studies using flow cytometry demonstrated specific binding of M225-PEG-NP to EGFR-expressing cells with minimal non-specific binding in EGFR- cells.	('binding', 'Interaction', (68, 75))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', '1956', (153, 157))	('EGFR', 'Gene', (94, 98))	('EGFR', 'Gene', (153, 157))	('M225-PEG-NP', 'Var', (79, 90))	('M225-PEG-NP', 'Chemical', '-', (79, 90))
454667	23273065	Finally, M225-PEG-NP demonstrated binding to EGFR-expressing regions in human esophageal tissue sections.	('EGFR', 'Gene', (45, 49))	('binding', 'Interaction', (34, 41))	('M225-PEG-NP', 'Var', (9, 20))	('M225-PEG-NP', 'Chemical', '-', (9, 20))	('human', 'Species', '9606', (72, 77))	('EGFR', 'Gene', '1956', (45, 49))
454677	23273065	Imaging of aberrant molecular expression in cells and tissues is a promising method for early detection of dysplasia or cancer since molecular changes occur at earlier time points than visible physical changes.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('dysplasia or cancer', 'Disease', 'MESH:D009369', (107, 126))	('dysplasia or cancer', 'Disease', (107, 126))	('aberrant', 'Var', (11, 19))
454693	23273065	In the present work, a fluorescence-based probe against the EGFR protein was synthesized by conjugation of M225, a murine monoclonal antibody against human EGFR, to fluorescent polystyrene NP via a polyethylene glycol (PEG) linker.	('human', 'Species', '9606', (150, 155))	('polystyrene', 'Chemical', 'MESH:D011137', (177, 188))	('EGFR', 'Gene', (60, 64))	('M225', 'Var', (107, 111))	('M225', 'Chemical', '-', (107, 111))	('EGFR', 'Gene', '1956', (156, 160))	('murine', 'Species', '10090', (115, 121))	('EGFR', 'Gene', (156, 160))	('EGFR', 'Gene', '1956', (60, 64))	('PEG', 'Chemical', 'MESH:D011092', (219, 222))	('polyethylene glycol', 'Chemical', 'MESH:D011092', (198, 217))
454708	23273065	M225 + PEG-NP formulations were then dialyzed against deionized water in 300kDa MWCO Spectra/Por CE dialysis membranes for 2 days at 4 C to remove unreacted M225 and dialyzed for 1 day against 150 mM sodium chloride for buffer exchange.	('PEG-NP', 'Chemical', '-', (7, 13))	('M225', 'Chemical', '-', (157, 161))	('Por', 'Gene', '5447', (93, 96))	('water', 'Chemical', 'MESH:D014867', (64, 69))	('Por', 'Gene', (93, 96))	('M225', 'Var', (157, 161))	('sodium chloride', 'Chemical', 'MESH:D012965', (200, 215))	('M225', 'Chemical', '-', (0, 4))
454718	23273065	Preferential and specific binding of M225-PEG-NP nanoparticles to EGFR-expressing cells was confirmed using flow cytometry.	('EGFR', 'Gene', '1956', (66, 70))	('M225-PEG-NP', 'Var', (37, 48))	('EGFR', 'Gene', (66, 70))	('M225-PEG-NP', 'Chemical', '-', (37, 48))	('binding', 'Interaction', (26, 33))
454724	23273065	To further show specificity of M225-PEG-NP to EGFR, H520 and A431 cells were grown on glass coverslips and treated with PEG-NP or M225-PEG-NP for 30 minutes at room temperature, counterstained with 2 mug/mL DAPI for 10 minutes, mounted onto slides with Fluoromount, and imaged using a Zeiss LSM 510 META confocal microscope.	('M225-PEG-NP', 'Var', (130, 141))	('PEG-NP', 'Chemical', '-', (135, 141))	('M225-PEG-NP', 'Chemical', '-', (130, 141))	('EGFR', 'Gene', '1956', (46, 50))	('PEG-NP', 'Chemical', '-', (36, 42))	('DAPI', 'Chemical', 'MESH:C007293', (207, 211))	('M225-PEG-NP', 'Var', (31, 42))	('PEG-NP', 'Var', (120, 126))	('EGFR', 'Gene', (46, 50))	('M225-PEG-NP', 'Chemical', '-', (31, 42))	('PEG-NP', 'Chemical', '-', (120, 126))	('A431', 'CellLine', 'CVCL:0037', (61, 65))
454735	23273065	Adjacent tissue sections were stained with M225-PEG-NP for 30 minutes at 37 C and counterstained with DAPI for 10 minutes at room temperature to demonstrate localization of M225-PEG-NP in areas of EGFR-expression.	('M225-PEG-NP', 'Var', (173, 184))	('M225-PEG-NP', 'Chemical', '-', (173, 184))	('M225-PEG-NP', 'Chemical', '-', (43, 54))	('EGFR', 'Gene', '1956', (197, 201))	('EGFR', 'Gene', (197, 201))	('DAPI', 'Chemical', 'MESH:C007293', (102, 106))
454739	23273065	Particles were therefore PEGylated to increase the hydrophilicity of NP surfaces and prevent NP aggregation, to neutralize charge from surface amine groups thereby minimizing nonspecific binding to cells, and to provide a point of attachment for the targeting ligand.	('charge', 'MPA', (123, 129))	('increase', 'PosReg', (38, 46))	('nonspecific', 'MPA', (175, 186))	('PEG', 'Chemical', 'MESH:D011092', (25, 28))	('minimizing', 'NegReg', (164, 174))	('hydrophilicity', 'MPA', (51, 65))	('amine', 'Chemical', 'MESH:D000588', (143, 148))	('NP aggregation', 'CPA', (93, 107))	('neutralize', 'Var', (112, 122))
454754	23273065	Thus, PEGylation was shown to reduce aggregation.	('PEG', 'Chemical', 'MESH:D011092', (6, 9))	('aggregation', 'MPA', (37, 48))	('reduce', 'NegReg', (30, 36))	('PEGylation', 'Var', (6, 16))
454765	23273065	A431 (EGFR+) cells treated with M225-PEG-NP 100, 500, 900 nanoparticles had mean fluorescence intensities (MFI) of 6.8 +- 1.0, 48.0 +- 6.5, and 88.9 +- 8.0, respectively, which were significantly greater (p < 0.05) than fluorescence intensities of untreated controls and A431 cells treated with PEGylated NPs (1.7 +- 0.0 and 2.1 +- 0.0, respectively) (Figure 1).	('fluorescence', 'MPA', (81, 93))	('greater', 'PosReg', (196, 203))	('M225-PEG-NP', 'Chemical', '-', (32, 43))	('EGFR', 'Gene', (6, 10))	('A431', 'CellLine', 'CVCL:0037', (271, 275))	('A431', 'CellLine', 'CVCL:0037', (0, 4))	('M225-PEG-NP 100', 'Var', (32, 47))	('PEG', 'Chemical', 'MESH:D011092', (37, 40))	('PEG', 'Chemical', 'MESH:D011092', (295, 298))	('EGFR', 'Gene', '1956', (6, 10))
454766	23273065	M225-PEG-NP exhibited no significant binding in EGFR- H520 cells (p > 0.05).	('binding', 'Interaction', (37, 44))	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'Gene', (48, 52))	('M225-PEG-NP', 'Var', (0, 11))	('M225-PEG-NP', 'Chemical', '-', (0, 11))
454767	23273065	Thus, conjugation of M225 to the surface of PEGylated NP resulted in efficient labeling of EGFR+ cells.	('labeling', 'MPA', (79, 87))	('M225', 'Chemical', '-', (21, 25))	('EGFR', 'Gene', (91, 95))	('conjugation', 'Var', (6, 17))	('PEG', 'Chemical', 'MESH:D011092', (44, 47))	('M225', 'Var', (21, 25))	('EGFR', 'Gene', '1956', (91, 95))
454768	23273065	In addition, M225-PEG-NP nanoparticles exhibited antibody dose-dependent binding to EGFR-expressing cells with binding increasing proportionally with number of conjugated antibodies.	('binding', 'Interaction', (73, 80))	('M225-PEG-NP', 'Var', (13, 24))	('EGFR', 'Gene', '1956', (84, 88))	('M225-PEG-NP', 'Chemical', '-', (13, 24))	('antibody', 'Protein', (49, 57))	('EGFR', 'Gene', (84, 88))
454770	23273065	Resulting fluorescence intensities (2.2 +- 0.1, 2.8 +- 0.7, 3.1 +- 0.4 for M225-PEG-NP 100, 500, and 900, respectively) were comparable to baseline fluorescence intensities of untreated cells (1.8 +- 0.0) and of A431 cells treated with PEGylated NPs (2.2 +- 0.1).	('A431', 'CellLine', 'CVCL:0037', (212, 216))	('M225-PEG-NP', 'Chemical', '-', (75, 86))	('PEG', 'Chemical', 'MESH:D011092', (80, 83))	('PEG', 'Chemical', 'MESH:D011092', (236, 239))	('fluorescence', 'MPA', (10, 22))	('M225-PEG-NP 100', 'Var', (75, 90))
454772	23273065	Confocal images of H520 and A431 cells treated with PEG-NP and M225-PEG-NP support binding specificity of M225-PEG-NP to EGFR (Figure 2).	('M225-PEG-NP', 'Chemical', '-', (63, 74))	('PEG-NP', 'Chemical', '-', (111, 117))	('EGFR', 'Gene', '1956', (121, 125))	('M225-PEG-NP', 'Var', (106, 117))	('A431', 'CellLine', 'CVCL:0037', (28, 32))	('EGFR', 'Gene', (121, 125))	('M225-PEG-NP', 'Chemical', '-', (106, 117))	('PEG-NP', 'Chemical', '-', (68, 74))	('PEG-NP', 'Chemical', '-', (52, 58))
454773	23273065	PEG-NP-treated cells demonstrated no background signal, and M225-PEG-NP-treated A431 cells showed significantly greater fluorescence signal compared to H520 cells.	('PEG-NP', 'Chemical', '-', (65, 71))	('M225-PEG-NP-treated', 'Var', (60, 79))	('M225-PEG-NP', 'Chemical', '-', (60, 71))	('fluorescence signal', 'MPA', (120, 139))	('A431', 'CellLine', 'CVCL:0037', (80, 84))	('PEG-NP', 'Chemical', '-', (0, 6))	('greater', 'PosReg', (112, 119))
454775	23273065	To compare the effect of M225 immobilization by conjugation versus adsorption on nanoparticle binding to EGFR-expressing cells, in vitro binding studies using flow cytometry were completed using M225-PEG-NP and M225 + PEG-NP each prepared using 100, 500, and 900 M225 per NP.	('PEG-NP', 'Chemical', '-', (200, 206))	('PEG-NP', 'Chemical', '-', (218, 224))	('EGFR', 'Gene', '1956', (105, 109))	('M225', 'Chemical', '-', (211, 215))	('M225-PEG-NP', 'Var', (195, 206))	('M225', 'Chemical', '-', (263, 267))	('EGFR', 'Gene', (105, 109))	('M225-PEG-NP', 'Chemical', '-', (195, 206))	('M225', 'Chemical', '-', (25, 29))	('M225', 'Chemical', '-', (195, 199))
454781	23273065	For example, survival of A431 cells treated with 0.2 mg/mL Np was only 24% but was 62% and 61% for PEG-NP and M225-PEG-NP, respectively (Figure 4).	('M225-PEG-NP', 'Chemical', '-', (110, 121))	('A431', 'CellLine', 'CVCL:0037', (25, 29))	('PEG-NP', 'Chemical', '-', (115, 121))	('PEG-NP', 'Var', (99, 105))	('PEG-NP', 'Chemical', '-', (99, 105))	('M225-PEG-NP', 'Var', (110, 121))
454782	23273065	Reduction of surface charge density through PEGylation has previously been shown to reduce cytotoxicity in amine-terminated poly(amidoamine) dendrimers and may possibly contribute to the reduction of cytotoxicity in this instance.	('reduce', 'NegReg', (84, 90))	('poly(amidoamine) dendrimers', 'Chemical', '-', (124, 151))	('surface charge density', 'MPA', (13, 35))	('cytotoxicity', 'Disease', 'MESH:D064420', (91, 103))	('cytotoxicity', 'Disease', 'MESH:D064420', (200, 212))	('amine', 'Chemical', 'MESH:D000588', (134, 139))	('PEGylation', 'Var', (44, 54))	('PEG', 'Chemical', 'MESH:D011092', (44, 47))	('Reduction', 'NegReg', (0, 9))	('amine', 'Chemical', 'MESH:D000588', (107, 112))	('cytotoxicity', 'Disease', (91, 103))	('cytotoxicity', 'Disease', (200, 212))
454785	23273065	The IC50 values of PEG-NP and M225-PEG-NP in H520 cells was > 2 mg/mL and in A431 cells was ~ 0.25 mg/mL for PEG-NP and ~ 0.8 mg/mL for M225-PEG-NP.	('PEG-NP', 'Chemical', '-', (35, 41))	('PEG-NP', 'Chemical', '-', (141, 147))	('M225-PEG-NP', 'Var', (136, 147))	('M225-PEG-NP', 'Chemical', '-', (136, 147))	('M225-PEG-NP', 'Var', (30, 41))	('PEG-NP', 'Var', (109, 115))	('M225-PEG-NP', 'Chemical', '-', (30, 41))	('PEG-NP', 'Chemical', '-', (19, 25))	('PEG-NP', 'Chemical', '-', (109, 115))	('PEG-NP', 'Var', (19, 25))	('A431', 'CellLine', 'CVCL:0037', (77, 81))
454796	23273065	For the purposes of this study, differential EGFR expression patterns in transverse esophageal tissue sections provided an opportunity to evaluate the binding of M225-PEG-NP for targeted imaging of EGFR under ex vivo conditions.	('EGFR', 'Gene', (198, 202))	('M225-PEG-NP', 'Chemical', '-', (162, 173))	('EGFR', 'Gene', (45, 49))	('binding', 'Interaction', (151, 158))	('EGFR', 'Gene', '1956', (198, 202))	('M225-PEG-NP', 'Var', (162, 173))	('EGFR', 'Gene', '1956', (45, 49))
454797	23273065	M225-PEG-NP were applied to tissue sections adjacent to EGFR-stained sections to demonstrate co-localization of EGFR and M225-PEG-NP (Figure 5 and Supporting Information Figure S2 and S3, second and third row).	('EGFR', 'Gene', (112, 116))	('EGFR', 'Gene', '1956', (56, 60))	('co-localization', 'MPA', (93, 108))	('EGFR', 'Gene', (56, 60))	('M225-PEG-NP', 'Var', (121, 132))	('M225-PEG-NP', 'Chemical', '-', (0, 11))	('EGFR', 'Gene', '1956', (112, 116))	('M225-PEG-NP', 'Chemical', '-', (121, 132))
454798	23273065	M225-PEG-NP demonstrated minimal binding in esophagus squamous epithelium and esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('esophageal adenocarcinoma', 'Disease', (78, 103))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (78, 103))	('M225-PEG-NP', 'Var', (0, 11))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (78, 103))	('M225-PEG-NP', 'Chemical', '-', (0, 11))	('esophagus squamous', 'Disease', (44, 62))	('binding', 'Interaction', (33, 40))	('minimal', 'NegReg', (25, 32))
454804	23273065	In summary, fluorescent nanoparticles for targeted optical imaging of EGFR were synthesized through a series of surface modifications to amino-functionalized dye-filled polystyrene NPs including PEGylation and bioconjugation of M225 antibodies.	('EGFR', 'Gene', '1956', (70, 74))	('M225', 'Var', (228, 232))	('M225', 'Chemical', '-', (228, 232))	('EGFR', 'Gene', (70, 74))	('PEGylation', 'Var', (195, 205))	('polystyrene', 'Chemical', 'MESH:D011137', (169, 180))	('PEG', 'Chemical', 'MESH:D011092', (195, 198))
454805	23273065	M225-PEG-NP demonstrated specific binding to EGFR and conjugation of M225 to NP surfaces via a PEG linker was shown to display higher immunoreactivity than direct adsorption of M225 to PEGylated NP surfaces.	('M225', 'Var', (69, 73))	('M225', 'Chemical', '-', (69, 73))	('EGFR', 'Gene', (45, 49))	('binding', 'Interaction', (34, 41))	('PEG', 'Chemical', 'MESH:D011092', (95, 98))	('PEG', 'Chemical', 'MESH:D011092', (5, 8))	('M225', 'Chemical', '-', (177, 181))	('immunoreactivity', 'MPA', (134, 150))	('higher', 'PosReg', (127, 133))	('M225-PEG-NP', 'Chemical', '-', (0, 11))	('PEG', 'Chemical', 'MESH:D011092', (185, 188))	('M225', 'Chemical', '-', (0, 4))	('EGFR', 'Gene', '1956', (45, 49))
454806	23273065	M225-PEG-NP were shown to bind to human esophageal tissue sections in areas of EGFR expression, demonstrating the potential of targeted fluorescent nanoparticles for in vivo molecular imaging using endoscopy.	('human', 'Species', '9606', (34, 39))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('M225-PEG-NP', 'Var', (0, 11))	('M225-PEG-NP', 'Chemical', '-', (0, 11))
454896	31490550	Diabetes and hyperglycemia may also be associated with gastroparesis via diabetic (vagal) neuropathy, which is thought to result from modification of proteins by advanced glycation end-products leading to development of atrophy and degeneration of nerve fibers.	('hyperglycemia', 'Phenotype', 'HP:0003074', (13, 26))	('result', 'Reg', (122, 128))	('modification', 'Var', (134, 146))	('gastroparesis via diabetic (vagal) neuropathy', 'Disease', 'MESH:D003929', (55, 100))	('hyperglycemia', 'Disease', 'MESH:D006943', (13, 26))	('degeneration of nerve', 'Phenotype', 'HP:0002180', (232, 253))	('neuropathy', 'Phenotype', 'HP:0009830', (90, 100))	('Diabetes', 'Disease', 'MESH:D003920', (0, 8))	('associated', 'Reg', (39, 49))	('Diabetes', 'Disease', (0, 8))	('hyperglycemia', 'Disease', (13, 26))	('gastroparesis', 'Phenotype', 'HP:0002578', (55, 68))	('atrophy and degeneration of nerve fibers', 'Disease', 'MESH:D009410', (220, 260))	('proteins', 'Protein', (150, 158))
454927	31807012	Inhibition of BANCR expression could effectively reduce the invasion and migration ability of esophageal squamous cell carcinoma.	('BANCR', 'Gene', (14, 19))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('Inhibition', 'Var', (0, 10))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (94, 128))	('reduce', 'NegReg', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('BANCR', 'Gene', '100885775', (14, 19))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))
454928	31807012	After silencing BANCR, the expression of wnt3a, survivin, beta-catenin and c-myc protein was downregulated compared with the negative control group (p<0.05).	('beta-catenin', 'Gene', (58, 70))	('survivin', 'Protein', (48, 56))	('BANCR', 'Gene', '100885775', (16, 21))	('c-myc', 'Gene', '4609', (75, 80))	('beta-catenin', 'Gene', '1499', (58, 70))	('expression', 'MPA', (27, 37))	('BANCR', 'Gene', (16, 21))	('downregulated', 'NegReg', (93, 106))	('wnt3a', 'Gene', (41, 46))	('silencing', 'Var', (6, 15))	('c-myc', 'Gene', (75, 80))	('wnt3a', 'Gene', '89780', (41, 46))
454960	31807012	For transfection, KYSE30 and TE10 cells were treated with 50 nM si-BANCR and si-NC for 4 hrs, respectively, and then replaced with normal growth medium for normal culture.	('si-NC', 'Var', (77, 82))	('BANCR', 'Gene', '100885775', (67, 72))	('BANCR', 'Gene', (67, 72))
454984	31807012	As shown in Figure 2, the survival time of patients with high expression of BANCR was shorter than that of patients with low expression of BANCR (p<0.05).	('BANCR', 'Gene', '100885775', (76, 81))	('survival time', 'CPA', (26, 39))	('BANCR', 'Gene', '100885775', (139, 144))	('shorter', 'NegReg', (86, 93))	('patients', 'Species', '9606', (43, 51))	('BANCR', 'Gene', (76, 81))	('BANCR', 'Gene', (139, 144))	('patients', 'Species', '9606', (107, 115))	('high expression', 'Var', (57, 72))
454985	31807012	The median survival time of patients with low expression of BANCR and high expression of BANCR was 34 months and 18 months, respectively.	('BANCR', 'Gene', (89, 94))	('BANCR', 'Gene', '100885775', (60, 65))	('BANCR', 'Gene', '100885775', (89, 94))	('high', 'Var', (70, 74))	('BANCR', 'Gene', (60, 65))	('patients', 'Species', '9606', (28, 36))
454990	31807012	The above experimental results indicated that inhibition of BANCR expression could effectively attenuate the migration ability of KYSE30 and T10 cells.	('BANCR', 'Gene', '100885775', (60, 65))	('BANCR', 'Gene', (60, 65))	('attenuate', 'NegReg', (95, 104))	('inhibition', 'Var', (46, 56))
454994	31807012	The assay of protein expressions suggested that compared with NC group, silencing of BANCR in both KYSE30 and TE10 cells significantly suppressed the protein expressions of wnt3a, c-myc protein, survivin and beta-catenin (p<0.05, Figure 6).	('survivin', 'Protein', (195, 203))	('BANCR', 'Gene', (85, 90))	('wnt3a', 'Gene', (173, 178))	('silencing', 'Var', (72, 81))	('wnt3a', 'Gene', '89780', (173, 178))	('c-myc', 'Gene', '4609', (180, 185))	('c-myc', 'Gene', (180, 185))	('BANCR', 'Gene', '100885775', (85, 90))	('beta-catenin', 'Gene', '1499', (208, 220))	('beta-catenin', 'Gene', (208, 220))	('suppressed', 'NegReg', (135, 145))	('protein expressions', 'MPA', (150, 169))
454998	31807012	Inhibition of BANCR expression could effectively reduce the cell invasion and migration of ESCC, and the protein levels of four important proteins (wnt3a, survivin, beta-catenin and c-myc) in the Wnt/beta-catenin signaling pathway were significantly decreased.	('ESCC', 'Disease', 'MESH:C562729', (91, 95))	('survivin', 'MPA', (155, 163))	('BANCR', 'Gene', (14, 19))	('wnt3a', 'Gene', '89780', (148, 153))	('c-myc', 'Gene', '4609', (182, 187))	('beta-catenin', 'Gene', (165, 177))	('ESCC', 'Disease', (91, 95))	('beta-catenin', 'Gene', '1499', (165, 177))	('c-myc', 'Gene', (182, 187))	('beta-catenin', 'Gene', (200, 212))	('beta-catenin', 'Gene', '1499', (200, 212))	('protein levels of four', 'MPA', (105, 127))	('Inhibition', 'Var', (0, 10))	('reduce', 'NegReg', (49, 55))	('BANCR', 'Gene', '100885775', (14, 19))	('cell invasion', 'CPA', (60, 73))	('wnt3a', 'Gene', (148, 153))	('decreased', 'NegReg', (250, 259))
455001	31807012	Li et al have found BANCR is highly expressed in human malignant melanoma cell lines and tissues, and silencing of BANCR inhibited cell proliferation by inhibiting MAPK signaling pathway.	('MAPK signaling pathway', 'Pathway', (164, 186))	('BANCR', 'Gene', '100885775', (115, 120))	('BANCR', 'Gene', (115, 120))	('BANCR', 'Gene', (20, 25))	('human', 'Species', '9606', (49, 54))	('malignant melanoma', 'Phenotype', 'HP:0002861', (55, 73))	('cell proliferation', 'CPA', (131, 149))	('malignant melanoma', 'Disease', (55, 73))	('BANCR', 'Gene', '100885775', (20, 25))	('malignant melanoma', 'Disease', 'MESH:D008545', (55, 73))	('silencing', 'Var', (102, 111))	('inhibited', 'NegReg', (121, 130))	('inhibiting', 'NegReg', (153, 163))
455017	31807012	The results of protein expressions indicate that silencing of BANCR in both KYSE30 and TE10 cells significantly suppressed the protein expressions of wnt3a, c-myc protein, survivin and beta-catenin.	('c-myc', 'Gene', (157, 162))	('protein expressions', 'MPA', (127, 146))	('silencing', 'Var', (49, 58))	('suppressed', 'NegReg', (112, 122))	('survivin', 'Protein', (172, 180))	('BANCR', 'Gene', (62, 67))	('beta-catenin', 'Gene', '1499', (185, 197))	('wnt3a', 'Gene', (150, 155))	('wnt3a', 'Gene', '89780', (150, 155))	('BANCR', 'Gene', '100885775', (62, 67))	('c-myc', 'Gene', '4609', (157, 162))	('beta-catenin', 'Gene', (185, 197))
455019	31807012	In summary, long-chain noncoding BANCR was highly expressed in individuals withESCC, and the higher the expression was, the shorter the survival of ESCC patients was.	('long-chain noncoding', 'Var', (12, 32))	('BANCR', 'Gene', '100885775', (33, 38))	('patients', 'Species', '9606', (153, 161))	('ESCC', 'Disease', 'MESH:C562729', (79, 83))	('ESCC', 'Disease', (148, 152))	('shorter', 'NegReg', (124, 131))	('ESCC', 'Disease', 'MESH:C562729', (148, 152))	('expression', 'MPA', (104, 114))	('ESCC', 'Disease', (79, 83))	('BANCR', 'Gene', (33, 38))	('survival', 'MPA', (136, 144))
455023	31138277	Somatic mutation and clonal expansions in human tissues Recent sequencing studies on healthy skin and esophagus have found that, as we age, these tissues become colonized by mutant clones of cells carrying driver mutations in traditional cancer genes.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('human', 'Species', '9606', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('mutant', 'Var', (174, 180))
455025	31138277	Yet, some somatic mutations that occur early in development can cause developmental disorders, and the accumulation of somatic mutations is responsible for cancer and might contribute to ageing.	('contribute', 'Reg', (173, 183))	('developmental disorders', 'Disease', (70, 93))	('cancer', 'Disease', (156, 162))	('cause', 'Reg', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('developmental disorders', 'Disease', 'MESH:D002658', (70, 93))	('responsible', 'Reg', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mutations', 'Var', (127, 136))	('mutations', 'Var', (18, 27))
455026	31138277	In the 1990s, studies using p53-immunostaining reported the existence of small groups or clones of a few hundred cells carrying mutations in TP53 in sun-exposed skin.	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (28, 31))	('mutations', 'Var', (128, 137))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))
455027	31138277	More unexpectedly, we found evidence of positive selection of somatic mutations in at least six cancer genes, revealing that when mutations occur in key cancer genes, proliferation of these cells accelerates, leading to clonal expansions.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('clonal expansions', 'CPA', (220, 237))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('accelerates', 'PosReg', (196, 207))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (130, 139))	('leading to', 'Reg', (209, 219))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('proliferation', 'CPA', (167, 180))	('cancer', 'Disease', (96, 102))
455028	31138277	We found that by middle age, sun-exposed skin is made up of thousands of such clones with one in every four cells carrying a positively selected mutation in a cancer gene.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('mutation', 'Var', (145, 153))
455029	31138277	To our surprise, we found that although the mutation rate in esophageal epithelium was ten-fold lower than that in sun-exposed skin, consistent with the absence of ultraviolet exposure, positive selection was stronger, leading to clones carrying mutations in cancer genes colonizing the majority of the esophagus by middle age.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('mutations', 'Var', (246, 255))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Disease', (259, 265))
455030	31138277	We detected positive selection driving clonal expansions in at least 14 cancer genes, with a density of several hundred densely packed mutant clones per square centimeter by middle age (Fig.	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutant', 'Var', (135, 141))	('cancer', 'Disease', (72, 78))
455031	31138277	Remarkably, in most of the middle-aged and elderly patients studied, mutations in NOTCH1 and TP53 were found in more than 30% and in 5-20% of the cells, respectively.	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (93, 97))	('NOTCH1', 'Gene', '4851', (82, 88))	('TP53', 'Gene', (93, 97))	('NOTCH1', 'Gene', (82, 88))	('patients', 'Species', '9606', (51, 59))	('found', 'Reg', (103, 108))
455036	31138277	The high frequency of cancer-driving mutations in normal tissues may lead some to believe that somatic mutation and clonal selection are not sufficient to explain cancer development and that other factors must be required to initiate cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (234, 240))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
455038	31138277	Although we see large numbers of mutations in cancer genes in normal skin and esophagus, these mutations occur in different clones scattered throughout the tissue.	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (33, 42))
455039	31138277	Most cells carry no or one driver mutation and the frequency of driver mutations is such that the probability of a single cell carrying the right combinations of multiple driver events does not appear incompatible with the incidence of cancer in the general population.	('mutations', 'Var', (71, 80))	('cancer', 'Disease', (236, 242))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))
455044	31138277	This suggests that structural driver mutations may be an important rate-limiting step in the evolution of many tumors.	('mutations', 'Var', (37, 46))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))
455045	31138277	Notwithstanding the importance of other factors in cancer evolution, the observation of large numbers of cancer-driving mutations in normal tissues is not inconsistent with the traditional model of cancer development by progressive acquisition of driver mutations.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
455046	31138277	was the observation that, by middle age, more than 30% of the cells in normal esophagus carry mutations inactivating the NOTCH1 gene.	('mutations inactivating', 'Var', (94, 116))	('NOTCH1', 'Gene', (121, 127))	('NOTCH1', 'Gene', '4851', (121, 127))
455048	31138277	Other explanations are possible, but it is conceivable and even likely that the mutation of some genes favors clonal expansions within normal tissues without increasing (or even decreasing) the risk of further evolution into cancer.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (225, 231))	('clonal expansions', 'CPA', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('favors', 'PosReg', (103, 109))	('mutation', 'Var', (80, 88))
455049	31138277	Somatic evolution is not a linear road towards cancer and some mutations that drive clonal expansions may blindly push cells down evolutionary paths away from cancer.	('cancer', 'Disease', (159, 165))	('mutations', 'Var', (63, 72))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('push', 'Reg', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('evolutionary paths', 'CPA', (130, 148))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
455051	31138277	However, as with other forms of molecular damage postulated to contribute to ageing, such as epigenetic drift, telomere shortening, or protein aggregation, mutations have largely been assumed to be deleterious to the carrying cell, progressively reducing cellular fitness.	('protein aggregation', 'Disease', 'MESH:D066263', (135, 154))	('mutations', 'Var', (156, 165))	('cellular fitness', 'CPA', (255, 271))	('protein aggregation', 'Disease', (135, 154))	('reducing', 'NegReg', (246, 254))
455054	31138277	However, certain observations, such as the higher frequency of NOTCH1 mutations in normal esophageal cells than in esophageal cancers, challenge commonly held assumptions and may call for some revision of our current lists of cancer-driving genes.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('esophageal cancers', 'Disease', (115, 133))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('esophageal cancers', 'Disease', 'MESH:D004938', (115, 133))	('NOTCH1', 'Gene', '4851', (63, 69))	('NOTCH1', 'Gene', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
455055	31138277	The widespread presence of cancer-driver mutations in healthy tissues also highlights the challenges faced by early cancer detection based on liquid biopsies, but also suggests promising avenues, such as focusing on more discriminatory driver genes, combinations of mutations, and copy-number changes.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
455060	31186712	Aberrant expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1) has been reported to activate multiple growth-regulatory pathways, induce antiapoptotic abilities in numerous types of cancer cells and promote chemoresistance.	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Disease', (194, 200))	('lymphoma', 'Disease', (25, 33))	('activate', 'PosReg', (96, 104))	('lymphoma', 'Disease', 'MESH:D008223', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('antiapoptotic abilities', 'CPA', (149, 172))	('lymphoma', 'Phenotype', 'HP:0002665', (25, 33))	('growth-regulatory pathways', 'Pathway', (114, 140))	('chemoresistance', 'CPA', (219, 234))	('induce', 'PosReg', (142, 148))	('B lymphoma', 'Phenotype', 'HP:0012191', (23, 33))	('BMI1', 'Gene', (69, 73))	('promote', 'PosReg', (211, 218))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
455062	31186712	The present study identified that knockdown of BMI1 promoted cytotoxic effects of cisplatin, and co-inhibition of Mel18 and BMI1 enhanced cisplatin-induced apoptosis and cytotoxicity.	('cytotoxicity', 'Disease', (170, 182))	('cisplatin-induced apoptosis', 'CPA', (138, 165))	('enhanced', 'PosReg', (129, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('Mel18', 'Gene', (114, 119))	('promoted', 'PosReg', (52, 60))	('cytotoxicity', 'Disease', 'MESH:D064420', (170, 182))	('knockdown', 'Var', (34, 43))	('cytotoxic effects of cisplatin', 'MPA', (61, 91))	('BMI1', 'Gene', (47, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('BMI1', 'Gene', (124, 128))	('co-inhibition', 'Var', (97, 110))
455063	31186712	Inhibition of BMI1 and Mel18 also suppressed the expression of c-Myc.	('c-Myc', 'Gene', (63, 68))	('suppressed', 'NegReg', (34, 44))	('Mel18', 'Gene', (23, 28))	('expression', 'MPA', (49, 59))	('Inhibition', 'Var', (0, 10))	('BMI1', 'Gene', (14, 18))	('c-Myc', 'Gene', '4609', (63, 68))
455065	31186712	In summary, the current study demonstrated that inhibition of BMI1 and Mel18 could increase the sensitivity of esophageal cancer cells to cisplatin via inhibition of c-Myc.	('c-Myc', 'Gene', '4609', (166, 171))	('increase', 'PosReg', (83, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('inhibition', 'NegReg', (152, 162))	('sensitivity', 'MPA', (96, 107))	('esophageal cancer', 'Disease', (111, 128))	('Mel18', 'Gene', (71, 76))	('inhibition', 'Var', (48, 58))	('c-Myc', 'Gene', (166, 171))	('BMI1', 'Gene', (62, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
455073	31186712	A number of studies have demonstrated that aberrant overexpression of BMI1 is associated with advanced stages, aggressive clinicopathological behaviors, therapeutic resistance and poor prognosis in melanoma, glioma and other types of tumor.	('associated', 'Reg', (78, 88))	('tumor', 'Disease', (234, 239))	('glioma', 'Disease', (208, 214))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('therapeutic resistance', 'CPA', (153, 175))	('melanoma', 'Disease', (198, 206))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('overexpression', 'PosReg', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('BMI1', 'Gene', (70, 74))	('aberrant', 'Var', (43, 51))
455074	31186712	BMI1 also serves a crucial role in cisplatin chemoresistance and inhibition of BMI1 can reverse cisplatin insensitivity.	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('cisplatin chemoresistance', 'MPA', (35, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('cisplatin insensitivity', 'MPA', (96, 119))	('inhibition', 'Var', (65, 75))	('BMI1', 'Gene', (79, 83))
455087	31186712	However, certain studies have indicated that BMI1 and Mel18 exhibit synergistic roles in the regulation of homeobox (HOX) genes, skeletal patterning, H3K27 trimethylation and colitis-associated cancer development.	('colitis', 'Disease', (175, 182))	('cancer', 'Disease', (194, 200))	('colitis', 'Phenotype', 'HP:0002583', (175, 182))	('Mel18', 'Gene', (54, 59))	('homeobox (HOX) genes', 'Gene', (107, 127))	('skeletal patterning', 'CPA', (129, 148))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('H3K27', 'Protein', (150, 155))	('trimethylation', 'Var', (156, 170))	('BMI1', 'Gene', (45, 49))	('colitis', 'Disease', 'MESH:D003092', (175, 182))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
455090	31186712	Our pilot study suggested that inhibition of BMI1 significantly effects cisplatin-induced proliferation and clonal growth of ESCC cells.	('cisplatin-induced', 'MPA', (72, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('clonal growth', 'CPA', (108, 121))	('inhibition', 'Var', (31, 41))	('BMI1', 'Gene', (45, 49))	('effects', 'Reg', (64, 71))
455131	31186712	1A, BMI1 expression was markedly lower in the transfected EC109 and TE1 cells compared with the negative control cells.	('EC109', 'CellLine', 'CVCL:6898', (58, 63))	('BMI1', 'Gene', (4, 8))	('expression', 'MPA', (9, 19))	('transfected', 'Var', (46, 57))	('lower', 'NegReg', (33, 38))
455132	31186712	To examine the effects of cisplatin on the survival of BMI1 knockdown cells, a CCK-8 assay was performed following treatment of the cells with cisplatin for 24 h. Following treatment with various concentrations of cisplatin, it was identified that the BMI1 shRNA-transfected cells demonstrated lower cell viabilities compared with the NC shRNA-transfected cells (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('cell viabilities', 'CPA', (300, 316))	('lower', 'NegReg', (294, 299))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('BMI1 shRNA-transfected', 'Var', (252, 274))
455135	31186712	These results indicate that BMI1 knockdown increases sensitivity to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('knockdown', 'Var', (33, 42))	('increases', 'PosReg', (43, 52))	('sensitivity to cisplatin', 'MPA', (53, 77))	('BMI1', 'Gene', (28, 32))
455138	31186712	As expected, the cell viability was significantly lower for the BMI1 shRNA-transfected cells compared with the NC cells following treatment with cisplatin in EC109 cells (P<0.05; Fig.	('lower', 'NegReg', (50, 55))	('cell viability', 'CPA', (17, 31))	('BMI1 shRNA-transfected', 'Var', (64, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('EC109', 'CellLine', 'CVCL:6898', (158, 163))
455139	31186712	A combination of Mel18 and BMI inhibition significantly enhanced the sensitivity to cisplatin compared with BMI inhibition alone in EC109 cells (P<0.05, Fig.	('BMI', 'Gene', (27, 30))	('sensitivity to cisplatin', 'MPA', (69, 93))	('EC109', 'CellLine', 'CVCL:6898', (132, 137))	('enhanced', 'PosReg', (56, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('inhibition', 'Var', (31, 41))	('Mel18', 'Gene', (17, 22))
455140	31186712	Overexpression of Mel18 combined with BMI1 inhibition did not enhance the sensitivity to cisplatin compared with BMI inhibition alone in EC109 cells (Fig.	('EC109', 'CellLine', 'CVCL:6898', (137, 142))	('inhibition', 'Var', (43, 53))	('enhance', 'PosReg', (62, 69))	('BMI1', 'Gene', (38, 42))	('sensitivity to cisplatin', 'MPA', (74, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('Mel18', 'Gene', (18, 23))
455143	31186712	It was revealed that depletion of BMI1 increased sensitivity to cisplatin (Fig.	('sensitivity to cisplatin', 'MPA', (49, 73))	('increased', 'PosReg', (39, 48))	('depletion', 'Var', (21, 30))	('BMI1', 'Gene', (34, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))
455144	31186712	Furthermore, depletion of Mel18 and BMI1 in the two ESCC cell lines further increased sensitivity to cisplatin compared with individual depletion of BMI1 (Fig.	('BMI1', 'Gene', (36, 40))	('sensitivity to cisplatin', 'MPA', (86, 110))	('increased', 'PosReg', (76, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('depletion', 'Var', (13, 22))	('Mel18', 'Gene', (26, 31))
455147	31186712	To evaluate the effect of BMI1 and Mel18 knockdown on cisplatin-induced apoptosis, the apoptotic rates of stably transfected ESCC cells were examined following treatment with 5 microM of cisplatin for 24 h. Consistent with the cytotoxic effects observed with the cell viability assay, combined inhibition of BMI1 and Mel18 increased the rate of apoptosis compared with the BMI1 inhibition group (P<0.05) or the NC group (P<0.01), as presented in Fig.	('increased', 'PosReg', (323, 332))	('inhibition', 'Var', (294, 304))	('Mel18', 'Gene', (317, 322))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('apoptosis', 'CPA', (345, 354))
455151	31186712	To further investigate the mechanism underlying the enhancement of cisplatin-induced apoptosis by the silencing of BMI1 and Mel18, the present study examined the expression levels of proteins associated with these pathways, including total NF-kappaB, total-Akt, phosphorylated-Akt, c-Myc, caspase-3, BAX and Bcl-2, in the stably transfected cells.	('c-Myc', 'Gene', '4609', (282, 287))	('Mel18', 'Gene', (124, 129))	('caspase-3', 'Gene', (289, 298))	('NF-kappaB', 'Gene', '4790', (240, 249))	('Bcl-2', 'Gene', '596', (308, 313))	('Akt', 'Gene', (277, 280))	('silencing', 'Var', (102, 111))	('Akt', 'Gene', '207', (277, 280))	('Akt', 'Gene', (257, 260))	('Akt', 'Gene', '207', (257, 260))	('BAX', 'Gene', (300, 303))	('BAX', 'Gene', '581', (300, 303))	('enhancement', 'PosReg', (52, 63))	('BMI1', 'Gene', (115, 119))	('c-Myc', 'Gene', (282, 287))	('Bcl-2', 'Gene', (308, 313))	('NF-kappaB', 'Gene', (240, 249))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('caspase-3', 'Gene', '836', (289, 298))
455152	31186712	5, the expression levels of caspase-3, BAX markedly increased and Bcl-2 markedly decreased in cells transfected with Mel18 shRNA and BMI1 shRNA compared with cells transfected with NC or BMI shRNA (all P<0.05), which indicated that BMII1 and Mel18-induced apoptosis may be closely associated with the mitochondrial apoptotic pathway.	('decreased', 'NegReg', (81, 90))	('BAX', 'Gene', (39, 42))	('increased', 'PosReg', (52, 61))	('Bcl-2', 'Gene', (66, 71))	('BAX', 'Gene', '581', (39, 42))	('expression levels', 'MPA', (7, 24))	('caspase-3', 'Gene', '836', (28, 37))	('Bcl-2', 'Gene', '596', (66, 71))	('caspase-3', 'Gene', (28, 37))	('Mel18 shRNA', 'Var', (117, 128))	('BMI1 shRNA', 'Var', (133, 143))
455157	31186712	With the same does of cisplatin, the size of EC109 xenograft tumors in the BMI1 shRNA group were significantly smaller compared with the NC group (P<0.05; Fig.	('EC109', 'Gene', (45, 50))	('xenograft tumors', 'Disease', 'MESH:D009369', (51, 67))	('EC109', 'CellLine', 'CVCL:6898', (45, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (22, 31))	('xenograft tumors', 'Disease', (51, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('smaller', 'NegReg', (111, 118))	('BMI1 shRNA', 'Var', (75, 85))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
455158	31186712	In addition, the tumor volume was markedly lower in the BMI1 and Mel18 shRNA group compared with the BMI1 inhibition alone group (P<0.05; Fig.	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('BMI1', 'Var', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('Mel18 shRNA', 'Var', (65, 76))	('lower', 'NegReg', (43, 48))
455163	31186712	Previous studies have demonstrated that inhibition of BMI1 can regulate the expression of MDR1, affect platinum transport and hydration, and promote the chemotherapy sensitivity of ovarian, breast and pancreatic cancer.	('hydration', 'MPA', (126, 135))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (201, 218))	('affect', 'Reg', (96, 102))	('inhibition', 'Var', (40, 50))	('BMI1', 'Gene', (54, 58))	('platinum', 'Chemical', 'MESH:D010984', (103, 111))	('ovarian', 'Disease', (181, 188))	('MDR1', 'Gene', '5243', (90, 94))	('breast and pancreatic cancer', 'Disease', 'MESH:D010190', (190, 218))	('chemotherapy sensitivity', 'CPA', (153, 177))	('expression', 'MPA', (76, 86))	('regulate', 'Reg', (63, 71))	('platinum', 'CPA', (103, 111))	('promote', 'PosReg', (141, 148))	('MDR1', 'Gene', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
455172	31186712	Compared with the BMI1-inhibited group and the negative control group, inhibition of Mel18 and BMI1 markedly enhanced the short-term and long-term sensitivity of esophageal cancer cells to cisplatin, and these effects were consistent with the impacts on apoptosis and changes of protein levels associated with the mitochondrial apoptotic pathway.	('protein levels', 'MPA', (279, 293))	('inhibition', 'Var', (71, 81))	('sensitivity', 'MPA', (147, 158))	('esophageal cancer', 'Disease', (162, 179))	('BMI1', 'Gene', (95, 99))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Mel18', 'Gene', (85, 90))	('enhanced', 'PosReg', (109, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))
455173	31186712	During an investigation of the core proteins associated with the mitochondrial apoptosis pathway, the expression level of c-Myc was identified to exhibit the most notable change following Mel18 and BMI1 inhibition.	('change', 'Reg', (171, 177))	('BMI1', 'Gene', (198, 202))	('inhibition', 'Var', (203, 213))	('Mel18', 'Gene', (188, 193))	('c-Myc', 'Gene', '4609', (122, 127))	('expression level', 'MPA', (102, 118))	('c-Myc', 'Gene', (122, 127))
455175	31186712	BMI1 has been identified to cooperate with c-Myc within the cell nucleus and BMI1 overexpression can inhibit c-Myc-induced apoptosis via negative regulation of the Ink4a-Arf pathway.	('c-Myc', 'Gene', (109, 114))	('negative regulation', 'NegReg', (137, 156))	('Ink4a-Arf pathway', 'Pathway', (164, 181))	('inhibit', 'NegReg', (101, 108))	('BMI1', 'Gene', (77, 81))	('c-Myc', 'Gene', '4609', (43, 48))	('c-Myc', 'Gene', '4609', (109, 114))	('c-Myc', 'Gene', (43, 48))	('overexpression', 'Var', (82, 96))
455179	31186712	To the best of our knowledge, the current study was the first to demonstrate that inhibition of BMI1 can increase the chemosensitivity of ESCC to platinum-based chemotherapy.	('platinum', 'Chemical', 'MESH:D010984', (146, 154))	('inhibition', 'Var', (82, 92))	('increase', 'PosReg', (105, 113))	('BMI1', 'Gene', (96, 100))	('ESCC', 'Disease', (138, 142))	('chemosensitivity', 'MPA', (118, 134))
455336	30261713	They discerned that if the tumor depth was greater than the sm2, patients showed higher rates of lymph node involvement and hematological recurrence, such as liver or lung metastases.	('lymph node involvement', 'CPA', (97, 119))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('sm2', 'Var', (60, 63))	('tumor', 'Disease', (27, 32))	('higher', 'PosReg', (81, 87))	('liver or lung metastases', 'Disease', (158, 182))	('patients', 'Species', '9606', (65, 73))	('liver or lung metastases', 'Disease', 'MESH:D009362', (158, 182))	('hematological recurrence', 'CPA', (124, 148))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
455340	30261713	The 5-year overall survival rates of the patients were decreased according to the depth of tumor invasion as follows: approximately 90% for m1/m2, 71% for m3, and 70% for submucosal cancer (p=0.007).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('m1/m2', 'Var', (140, 145))	('overall survival rates', 'CPA', (11, 33))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('submucosal cancer', 'Disease', 'MESH:D009369', (171, 188))	('decreased', 'NegReg', (55, 64))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('submucosal cancer', 'Disease', (171, 188))	('tumor', 'Disease', (91, 96))
455398	28864539	Consistent with this observation, obesity-induced MCP-1 (and IL1-beta) expression in mammary fat depots leads to increased macrophage recruitment.	('obesity', 'Phenotype', 'HP:0001513', (34, 41))	('expression', 'Var', (71, 81))	('macrophage recruitment', 'CPA', (123, 145))	('IL1-beta', 'Gene', '3553', (61, 69))	('obesity', 'Disease', 'MESH:D009765', (34, 41))	('IL1-beta', 'Gene', (61, 69))	('increased', 'PosReg', (113, 122))	('obesity', 'Disease', (34, 41))	('increased macrophage', 'Phenotype', 'HP:0004311', (113, 133))
455428	28864539	For example, crosstalk between leptin and IGF-1 has been reported to induce invasion and migration of breast cancer cells.	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('leptin', 'Protein', (31, 37))	('induce', 'PosReg', (69, 75))	('IGF-1', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('invasion', 'CPA', (76, 84))	('crosstalk', 'Var', (13, 22))
455528	28864539	Furthermore, this result was more significant in samples of obese patients (BMI>=30 kg/m2) compared to overweight (25-30 kg/m2) or lean (<25 kg/m2) patients.	('patients', 'Species', '9606', (148, 156))	('obese', 'Disease', 'MESH:D009765', (60, 65))	('BMI>=30 kg/m2', 'Var', (76, 89))	('obese', 'Disease', (60, 65))	('overweight', 'Phenotype', 'HP:0025502', (103, 113))	('patients', 'Species', '9606', (66, 74))
455572	28892579	Esophageal squamous cell carcinoma is considered to be an aggressive carcinoma based on its malignant transformation, carcinogenesis, invasion, and lymph node metastasis.1, 2  A member of the p53 transcription factor family, p63 (TP63), shares significant homology with p53 and plays a role in maintaining the viability and proliferative capacity of basal epithelial cells.3 Alternative splicing of the TP63 gene produces transcripts encoding two isoforms, one with (TAp63) and one without (DeltaNp63) the transactivation domain.4, 5, 6 The 3q27-q29 chromosomal region containing the TP63 gene is frequently amplified early in the development of squamous carcinoma7, 8 and may play important roles in a variety of squamous cell carcinomas (SCCs) including lung, head and neck, bladder, and cervical cancers.9, 10, 11  Indeed, the elevated expression of the DeltaN isoform of p63 serves as a diagnostic marker used to distinguish SCC from adenocarcinoma in lung cancer, as well as CK5/6 or CK14.8, 12, 13, 14, 15 DeltaNp63 serves as a transactivator through a second transactivation domain and also acts as a dominant-negative transcriptional repressor that inhibits p53- or TAp63-mediated transcription, activities that are consistent with its potential role as an oncogene.5, 16, 17 Although these findings suggest that DeltaNp63 is an SCC oncogene, the biological roles and the pathologic relevance of p63 in tumorigenesis have not been fully elucidated.18, 19 Additionally, the loss of p53 function is considered to play an essential role in carcinogenesis and the progression of esophageal cancer malignancies.20, 21 The TAp63 isoforms are inhibited by interactions with cancer-associated p53 mutants.11, 22  In this report, we investigate the association between the expression of DeltaNp63 and ESCC biology.	('squamous carcinoma7', 'Disease', 'MESH:D002294', (646, 665))	('carcinogenesis', 'Disease', (1545, 1559))	('cancer', 'Phenotype', 'HP:0002664', (961, 967))	('SCC', 'Gene', '6317', (740, 743))	('carcinogenesis', 'Disease', 'MESH:D063646', (1545, 1559))	('TP63', 'Gene', '8626', (230, 234))	('adenocarcinoma in lung cancer', 'Disease', 'MESH:D008175', (938, 967))	('p63', 'Gene', (1404, 1407))	('cancer', 'Disease', 'MESH:D009369', (1675, 1681))	('inhibited', 'NegReg', (1644, 1653))	('p63', 'Gene', '8626', (1404, 1407))	('cancer', 'Disease', (799, 805))	('SCC', 'Gene', (929, 932))	('TP63', 'Gene', '8626', (403, 407))	('TP63', 'Gene', '8626', (584, 588))	('p63', 'Gene', (225, 228))	('cervical cancers', 'Disease', (790, 806))	('cancer', 'Disease', 'MESH:D009369', (1594, 1600))	('p63', 'Gene', '8626', (1018, 1021))	('p63', 'Gene', '8626', (225, 228))	('cervical cancers', 'Disease', 'MESH:D002583', (790, 806))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (714, 738))	('mutants.11', 'Var', (1697, 1707))	('CK5/6', 'Gene', (980, 985))	('esophageal cancer malignancies', 'Disease', 'MESH:D004938', (1583, 1613))	('TP63', 'Gene', (230, 234))	('lung cancer', 'Phenotype', 'HP:0100526', (956, 967))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (714, 737))	('p63', 'Gene', (469, 472))	('p63', 'Gene', '8626', (469, 472))	('squamous cell carcinomas', 'Disease', (714, 738))	('cancer', 'Disease', (1594, 1600))	('SCC', 'Gene', (740, 743))	('p63', 'Gene', (1792, 1795))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('SCC', 'Gene', '6317', (1801, 1804))	('carcinoma', 'Phenotype', 'HP:0030731', (728, 737))	('p63', 'Gene', '8626', (1792, 1795))	('cancer', 'Disease', 'MESH:D009369', (961, 967))	('TP63', 'Gene', (403, 407))	('cancers', 'Phenotype', 'HP:0002664', (799, 806))	('TP63', 'Gene', (584, 588))	('carcinoma', 'Phenotype', 'HP:0030731', (655, 664))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (0, 34))	('cancer', 'Phenotype', 'HP:0002664', (799, 805))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (714, 738))	('men', 'Species', '9606', (638, 641))	('interactions', 'Interaction', (1657, 1669))	('SCC', 'Gene', '6317', (1337, 1340))	('adenocarcinoma in lung cancer', 'Disease', (938, 967))	('carcinogenesis', 'Disease', (118, 132))	('cancer', 'Disease', (1675, 1681))	('tumor', 'Phenotype', 'HP:0002664', (1411, 1416))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('p53', 'Gene', (1693, 1696))	('p63', 'Gene', (1627, 1630))	('Esophageal squamous cell carcinoma', 'Disease', (0, 34))	('p63', 'Gene', '8626', (1627, 1630))	('carcinoma', 'Phenotype', 'HP:0030731', (943, 952))	('aggressive carcinoma', 'Disease', 'MESH:D001523', (58, 78))	('squamous carcinoma7', 'Disease', (646, 665))	('SCC', 'Gene', (1801, 1804))	('CK14', 'Gene', (989, 993))	('CK5/6', 'Gene', '3852', (980, 985))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('p63', 'Gene', (1327, 1330))	('p63', 'Gene', (1176, 1179))	('p63', 'Gene', '8626', (1327, 1330))	('aggressive carcinoma', 'Disease', (58, 78))	('p63', 'Gene', '8626', (1176, 1179))	('p63', 'Gene', (875, 878))	('SCCs', 'Phenotype', 'HP:0002860', (740, 744))	('cancer', 'Disease', 'MESH:D009369', (799, 805))	('cancer', 'Disease', (961, 967))	('p63', 'Gene', '8626', (875, 878))	('SCC', 'Gene', (1337, 1340))	('esophageal cancer malignancies', 'Disease', (1583, 1613))	('cancer', 'Phenotype', 'HP:0002664', (1675, 1681))	('carcinomas', 'Phenotype', 'HP:0030731', (728, 738))	('SCC', 'Gene', '6317', (929, 932))	('cancer', 'Phenotype', 'HP:0002664', (1594, 1600))	('tumor', 'Disease', (1411, 1416))	('p63', 'Gene', (497, 500))	('p63', 'Gene', '8626', (497, 500))	('CK14', 'Gene', '3861', (989, 993))	('tumor', 'Disease', 'MESH:D009369', (1411, 1416))	('p63', 'Gene', (1018, 1021))
455591	28892579	Expression of DeltaNp63 and p53 was determined by immunohistochemical staining with an anti-DeltaNp63 rabbit polyclonal antibody (1:100 dilution) and an anti-p53 mouse mAb (DO7, 1:50 dilution; Dako) as previously described.25, 26 DeltaNp63 expression was considered positive if nuclear staining was present, and was scored semiquantitatively based on the percentage of positive cells as follows: 0, 0%; 1, 1%-25%; and 2, >25%.	('p63', 'Gene', '8626', (236, 239))	('p63', 'Gene', (98, 101))	('p63', 'Gene', (20, 23))	('p63', 'Gene', '8626', (98, 101))	('mouse', 'Species', '10090', (162, 167))	('p63', 'Gene', '8626', (20, 23))	('rabbit', 'Species', '9986', (102, 108))	('described.25', 'Var', (213, 225))	('p63', 'Gene', (236, 239))
455635	28892579	The expression of DeltaNp63 has been reported as a highly specific diagnostic marker of various human SCCs, including lung, head and neck, bladder, and cervical cancers.8, 9, 10, 11 In fact, the amplification and overexpression of p63 has been frequently observed in lung cancers and in head and neck cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('lung cancers', 'Phenotype', 'HP:0100526', (267, 279))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('amplification', 'Var', (195, 208))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('p63', 'Gene', (231, 234))	('cervical cancers', 'Disease', (152, 168))	('cervical cancers', 'Disease', 'MESH:D002583', (152, 168))	('SCCs', 'Phenotype', 'HP:0002860', (102, 106))	('p63', 'Gene', '8626', (231, 234))	('head and neck cancers', 'Phenotype', 'HP:0012288', (287, 308))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Phenotype', 'HP:0002664', (301, 308))	('human', 'Species', '9606', (96, 101))	('p63', 'Gene', (24, 27))	('p63', 'Gene', '8626', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('SCC', 'Gene', (102, 105))	('head and neck cancers', 'Disease', 'MESH:D006258', (287, 308))	('SCC', 'Gene', '6317', (102, 105))	('lung cancers', 'Disease', 'MESH:D008175', (267, 279))	('overexpression', 'PosReg', (213, 227))	('observed', 'Reg', (255, 263))	('lung cancers', 'Disease', (267, 279))
455642	28892579	Whereas we could not establish a significant correlation between DeltaNp63 and mutant p53 (Fig.	('p63', 'Gene', (71, 74))	('mutant', 'Var', (79, 85))	('p63', 'Gene', '8626', (71, 74))	('p53', 'Gene', (86, 89))
455655	27439769	In vitro, CXCL12 exposure or overexpression enhanced ESCC proliferation; and AMD3100, a specific inhibitor of CXCR4, equally decreased proliferation irrespective of CXCL12 exposure or overexpression.	('SCC', 'Gene', '6317', (54, 57))	('decreased', 'NegReg', (125, 134))	('proliferation', 'CPA', (135, 148))	('AMD3100', 'Chemical', 'MESH:C088327', (77, 84))	('SCC', 'Gene', (54, 57))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('enhanced', 'PosReg', (44, 52))	('AMD3100', 'Var', (77, 84))
455656	27439769	In the mouse model, AMD3100 significantly decreased ESCC tumor size (p = 0.03).	('SCC', 'Gene', '6317', (53, 56))	('decreased', 'NegReg', (42, 51))	('AMD3100', 'Chemical', 'MESH:C088327', (20, 27))	('mouse', 'Species', '10090', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('AMD3100', 'Var', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('SCC', 'Gene', (53, 56))	('decreased ESCC', 'Phenotype', 'HP:0025022', (42, 56))	('tumor', 'Disease', (57, 62))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))
455657	27439769	CXCL12 stimulates ESCC proliferation, and its expression levels are related to lower RFS in patients with ESCC.	('SCC', 'Gene', '6317', (19, 22))	('lower', 'NegReg', (79, 84))	('expression levels', 'MPA', (46, 63))	('SCC', 'Gene', (107, 110))	('patients', 'Species', '9606', (92, 100))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('stimulates', 'PosReg', (7, 17))	('CXCL12', 'Var', (0, 6))	('SCC', 'Gene', (19, 22))	('SCC', 'Gene', '6317', (107, 110))	('RFS', 'MPA', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))
455668	27439769	AMD3100 is a highly specific CXCR4 antagonist inhibiting CXCL12-mediated Ca2+ flux in a number of cells expressing CXCR4, but has no inhibitory effect on chemokine induced signalling from other chemokine receptors.	('inhibiting', 'NegReg', (46, 56))	('CXCL12-mediated Ca2+ flux', 'MPA', (57, 82))	('Ca2+', 'Chemical', 'MESH:D000069285', (73, 77))	('CXCR4', 'Var', (115, 120))	('chemokine receptor', 'Gene', '7852', (194, 212))	('chemokine receptor', 'Gene', (194, 212))	('AMD3100', 'Chemical', 'MESH:C088327', (0, 7))
455669	27439769	AMD3100 interacts with CXCR4 extracellularly and mechanistically prevents the binding of CXCL12 to CXCR4 and thus downstream signalling of CXCR4.. AMD3100 is not toxic to host cells at concentrations up to 500 mM and the CXCL12/CXCR4 blockade efficiently decreases cancer cell proliferation.	('decreases', 'NegReg', (255, 264))	('AMD3100', 'Var', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('AMD3100', 'Chemical', 'MESH:C088327', (147, 154))	('AMD3100', 'Chemical', 'MESH:C088327', (0, 7))
455672	27439769	Our in vitro and in vivo results show that CXCL12 promotes ESCC proliferation.	('CXCL12', 'Var', (43, 49))	('SCC', 'Gene', '6317', (60, 63))	('promotes', 'PosReg', (50, 58))	('SCC', 'Gene', (60, 63))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))
455687	27439769	Total RNA from each ESCC cell line was extracted and analysed by quantitative real-time RT-PCR using the 7300 Real Time PCR system (Applied BioSystems, Carlsbad, CA), TaqMan Gene Expression Master Mix (Applied BioSystems) and ready-to-use CXCR4/CXCL12 primers (Assay ID: Hs00607978_m1 for CXCR4 and Hs00171022_m1 for CXCL12; Applied BioSystems).	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('SCC', 'Gene', (21, 24))	('SCC', 'Gene', '6317', (21, 24))	('Hs00171022_m1', 'Var', (299, 312))
455705	27439769	We found that patients with a positive expression of CXCL12 tended to have a higher lymph node recurrence rate than other patients (Table 3, p = 0.08).	('lymph node recurrence rate', 'CPA', (84, 110))	('CXCL12', 'Var', (53, 59))	('higher', 'PosReg', (77, 83))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (14, 22))
455707	27439769	The patients with a positive CXCL12 expression exhibited a significantly lower RFS (p = 0.02).	('RFS', 'MPA', (79, 82))	('CXCL12 expression', 'Var', (29, 46))	('patients', 'Species', '9606', (4, 12))	('lower', 'NegReg', (73, 78))
455708	27439769	Patients with CXCL12-positive ESCC tended to have a poor prognosis regardless of the positive or negative expression of CXCR4.	('SCC', 'Gene', (31, 34))	('SCC', 'Phenotype', 'HP:0002860', (31, 34))	('SCC', 'Gene', '6317', (31, 34))	('Patients', 'Species', '9606', (0, 8))	('CXCL12-positive', 'Var', (14, 29))
455710	27439769	In conclusion, a positive CXCL12 expression is an independent risk factor for subsequent tumor recurrence, showing the highest hazard ratio compared with other pathological features.	('positive', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('CXCL12 expression', 'MPA', (26, 43))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
455713	27439769	As shown in Table 5, ESCC with positive expression of both CXCR4 and CXCL12 exhibited a significantly higher MIB-1 index than the other three groups (24.1 vs 7.5 %, p = 0.02).	('MIB-1', 'Gene', (109, 114))	('CXCR4', 'Var', (59, 64))	('higher', 'PosReg', (102, 108))	('MIB-1', 'Gene', '57534', (109, 114))	('SCC', 'Gene', (22, 25))	('SCC', 'Phenotype', 'HP:0002860', (22, 25))	('SCC', 'Gene', '6317', (22, 25))
455714	27439769	These results suggest that CXCL12 expression increases the proliferation of ESCC through signal transduction after binding to the CXCR4, which in turn leads to an earlier recurrence after surgery.	('proliferation', 'CPA', (59, 72))	('leads to', 'Reg', (151, 159))	('increases', 'PosReg', (45, 54))	('CXCL12 expression', 'Var', (27, 44))	('SCC', 'Gene', (77, 80))	('binding', 'Interaction', (115, 122))	('signal transduction', 'MPA', (89, 108))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))	('SCC', 'Gene', '6317', (77, 80))
455719	27439769	We established six different TE4CXCL12+ cell lines that overexpressed CXCL12 by gene transfer and used one for further investigation.	('gene transfer', 'Var', (80, 93))	('TE4CXCL12+', 'Chemical', '-', (29, 39))	('overexpressed', 'PosReg', (56, 69))
455722	27439769	However, when exposed to AMD3100, the TE4 cells showed a significantly lower proliferation index than untreated TE4 cells (p = 0.001).	('AMD3100', 'Chemical', 'MESH:C088327', (25, 32))	('proliferation index', 'CPA', (77, 96))	('AMD3100', 'Var', (25, 32))	('lower', 'NegReg', (71, 76))
455724	27439769	Figure 7 shows the proliferation index of TE4 and TE4CXCL12+ in the presence or absence of AMD3100.	('TE4CXCL12+', 'Var', (50, 60))	('AMD3100', 'Gene', (91, 98))	('TE4CXCL12+', 'Chemical', '-', (50, 60))	('AMD3100', 'Chemical', 'MESH:C088327', (91, 98))	('proliferation index', 'CPA', (19, 38))
455725	27439769	The TE4CXCL12+ cells showed a significantly higher proliferation index than the original TE4 cells (p = 0.03).	('higher', 'PosReg', (44, 50))	('TE4CXCL12+', 'Chemical', '-', (4, 14))	('proliferation index', 'CPA', (51, 70))	('TE4CXCL12+', 'Var', (4, 14))
455727	27439769	These results indicate that CXCL12 expressed by TE4 or TE4CXCL12+ is secreted, binds to its specific receptor, CXCR4, on the cell membrane and stimulates cellular proliferation via signal transduction.	('TE4CXCL12+', 'Chemical', '-', (55, 65))	('TE4CXCL12+', 'Var', (55, 65))	('signal transduction', 'CPA', (181, 200))	('cellular proliferation', 'CPA', (154, 176))	('stimulates', 'PosReg', (143, 153))	('TE4', 'Var', (48, 51))
455729	27439769	Figure 8 shows the different tumor sizes following a subcutaneous injection of TE4CXCL12+ in the back of nude mice combined or not with a continuous subcutaneous infusion of AMD3100.	('TE4CXCL12+', 'Var', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('nude mice', 'Species', '10090', (105, 114))	('tumor', 'Disease', (29, 34))	('AMD3100', 'Chemical', 'MESH:C088327', (174, 181))	('TE4CXCL12+', 'Chemical', '-', (79, 89))
455730	27439769	Mice injected with TE4CXCL12+ and infused with AMD3100 had smaller tumors than the controls at all time points.	('AMD3100', 'Var', (47, 54))	('smaller', 'NegReg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TE4CXCL12+', 'Chemical', '-', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('AMD3100', 'Chemical', 'MESH:C088327', (47, 54))
455732	27439769	This result indicates that AMD3100 decreases ESCC proliferation by inhibiting the CXCL12/CXCR4 signalling pathway artificially enhanced by TE4CXCL12.	('enhanced', 'PosReg', (127, 135))	('AMD3100', 'Chemical', 'MESH:C088327', (27, 34))	('AMD3100', 'Var', (27, 34))	('decreases', 'NegReg', (35, 44))	('CXCL12/CXCR4 signalling pathway', 'Pathway', (82, 113))	('SCC', 'Gene', (46, 49))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('decreases ESCC', 'Phenotype', 'HP:0025022', (35, 49))	('inhibiting', 'NegReg', (67, 77))	('SCC', 'Gene', '6317', (46, 49))
455735	27439769	These results suggest that CXCL12 expression in ESCC promotes the proliferation of the tumor and has a direct impact on the recurrence rate, independent of invasion or metastasis.	('promotes', 'PosReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SCC', 'Gene', (49, 52))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('tumor', 'Disease', (87, 92))	('CXCL12 expression', 'Var', (27, 44))	('SCC', 'Gene', '6317', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('recurrence rate', 'CPA', (124, 139))	('impact', 'Reg', (110, 116))
455738	27439769	In contrast, CXCR4 expression was related to a higher MIB-1 index, but was not significantly correlated with RFS.	('index', 'MPA', (60, 65))	('MIB-1', 'Gene', '57534', (54, 59))	('higher', 'PosReg', (47, 53))	('CXCR4 expression', 'Var', (13, 29))	('MIB-1', 'Gene', (54, 59))
455742	27439769	Third, AMD3100 inhibits the tumor growth of ESCC expressing CXCL12 in vivo, which has not been previously reported.	('AMD3100', 'Chemical', 'MESH:C088327', (7, 14))	('tumor', 'Disease', (28, 33))	('SCC', 'Gene', (45, 48))	('AMD3100', 'Var', (7, 14))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('SCC', 'Gene', '6317', (45, 48))	('inhibits', 'NegReg', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
455744	27439769	reported that the overexpression of CXCL12 and CXCR4 induces autocrine and paracrine cellular proliferation in human pituitary adenomas.	('CXCL12', 'Var', (36, 42))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (117, 135))	('human', 'Species', '9606', (111, 116))	('pituitary adenomas', 'Disease', (117, 135))	('pituitary adenomas', 'Disease', 'MESH:D010911', (117, 135))	('overexpression', 'PosReg', (18, 32))
455749	27439769	However, our immunohistochemical analyses demonstrated that patients with positive CXCL12 expression, including both CXCR4 positive and negative patients, have a poorer prognosis.	('patients', 'Species', '9606', (145, 153))	('CXCL12', 'MPA', (83, 89))	('patients', 'Species', '9606', (60, 68))	('positive', 'Var', (74, 82))
455750	27439769	This result indicates the possibility of additional mechanisms (other than binding to CXCR4 and an enhancement of proliferation) by which CXCL12 promotes ESCC development.	('SCC', 'Gene', (155, 158))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('enhancement', 'PosReg', (99, 110))	('SCC', 'Gene', '6317', (155, 158))	('proliferation', 'CPA', (114, 127))	('promotes', 'PosReg', (145, 153))	('CXCL12', 'Var', (138, 144))
455752	27439769	reported that CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers.	('ovarian cancers', 'Disease', 'MESH:D010051', (108, 123))	('vascular endothelial growth factor', 'Gene', (25, 59))	('neoangiogenesis', 'CPA', (83, 98))	('induce', 'PosReg', (76, 82))	('vascular endothelial growth factor', 'Gene', '7422', (25, 59))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ovarian cancers', 'Phenotype', 'HP:0100615', (108, 123))	('ovarian cancers', 'Disease', (108, 123))	('CXCL12', 'Var', (14, 20))	('human', 'Species', '9606', (102, 107))
455754	27439769	Several studies by other groups have demonstrated that the expression of CXCR4 or CXCL12 in cancer cells worsens the prognosis in patients with ESCC.	('cancer', 'Disease', (92, 98))	('worsens', 'NegReg', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('SCC', 'Gene', (145, 148))	('SCC', 'Phenotype', 'HP:0002860', (145, 148))	('patients', 'Species', '9606', (130, 138))	('CXCL12', 'Var', (82, 88))	('CXCR4', 'Var', (73, 78))	('SCC', 'Gene', '6317', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('expression', 'Var', (59, 69))	('prognosis', 'CPA', (117, 126))
455757	27439769	further reported that positive CXCL12 expression was associated with poor prognosis in patients with ESCC; however, similar to our results, positive CXCR4 expression was not.	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('CXCL12 expression', 'MPA', (31, 48))	('SCC', 'Gene', '6317', (102, 105))	('positive', 'Var', (22, 30))	('patients', 'Species', '9606', (87, 95))	('SCC', 'Gene', (102, 105))
455760	27439769	AMD3100 did not fully prevent the proliferation of the TE4 and TE4CXCL12+ cell lines in our study, suggesting that CXCL12 may promote the proliferation of ESCC through other pathways in addition to CXCR4.	('TE4CXCL12+', 'Chemical', '-', (63, 73))	('proliferation', 'CPA', (138, 151))	('promote', 'PosReg', (126, 133))	('SCC', 'Gene', (156, 159))	('SCC', 'Phenotype', 'HP:0002860', (156, 159))	('SCC', 'Gene', '6317', (156, 159))	('CXCL12', 'Var', (115, 121))	('AMD3100', 'Chemical', 'MESH:C088327', (0, 7))
455764	27439769	CXCL12 promotes ESCC progression through not only CXCR4 but also CXCR7, and causes poorer RFS).	('CXCR7', 'Gene', '57007', (65, 70))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('SCC', 'Gene', '6317', (17, 20))	('CXCR4', 'MPA', (50, 55))	('poorer', 'NegReg', (83, 89))	('promotes', 'PosReg', (7, 15))	('CXCR7', 'Gene', (65, 70))	('CXCL12', 'Var', (0, 6))	('SCC', 'Gene', (17, 20))
455765	27439769	Although CXCL12 promoted the proliferation index in vitro, and AMD3100 suppressed the proliferation index in vitro, as well as the tumor size in vivo, our study did not disclose whether the CXCL12/CXCR4 axis is responsible for ESCC survival or apoptosis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('promoted', 'PosReg', (16, 24))	('AMD3100', 'Chemical', 'MESH:C088327', (63, 70))	('proliferation index', 'CPA', (86, 105))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('SCC', 'Gene', (228, 231))	('tumor', 'Disease', (131, 136))	('AMD3100', 'Var', (63, 70))	('proliferation index', 'CPA', (29, 48))	('SCC', 'Phenotype', 'HP:0002860', (228, 231))	('SCC', 'Gene', '6317', (228, 231))	('suppressed', 'NegReg', (71, 81))
455774	27439769	In this study, we demonstrated that the expression of CXCL12 in ESCC is an independent risk factor of recurrence after surgery through immunohistochemistry and we showed that CXCL12 promotes ESCC proliferation.	('SCC', 'Phenotype', 'HP:0002860', (192, 195))	('SCC', 'Gene', (65, 68))	('SCC', 'Gene', '6317', (192, 195))	('CXCL12', 'Var', (175, 181))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('promotes', 'PosReg', (182, 190))	('SCC', 'Gene', (192, 195))
455797	27295551	For example, HDAC4 expression not only is significantly associated with tumor size in malignant thyroid lesions but also promotes tumor growth through suppressing p21 expression in colon cancer, glioblastoma, ovarian cancer, and gastric cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('p21', 'Gene', '1026', (163, 166))	('ovarian cancer', 'Disease', 'MESH:D010051', (209, 223))	('associated', 'Reg', (56, 66))	('glioblastoma', 'Disease', 'MESH:D005909', (195, 207))	('tumor', 'Disease', (130, 135))	('expression', 'MPA', (167, 177))	('colon cancer', 'Disease', (181, 193))	('glioblastoma', 'Disease', (195, 207))	('gastric cancer', 'Disease', (229, 243))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('ovarian cancer', 'Disease', (209, 223))	('HDAC4', 'Gene', '9759', (13, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (195, 207))	('ovarian cancer', 'Phenotype', 'HP:0100615', (209, 223))	('thyroid lesions', 'Disease', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', (72, 77))	('expression', 'Var', (19, 29))	('colon cancer', 'Phenotype', 'HP:0003003', (181, 193))	('p21', 'Gene', (163, 166))	('gastric cancer', 'Disease', 'MESH:D013274', (229, 243))	('promotes', 'PosReg', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('HDAC4', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('thyroid lesions', 'Disease', 'MESH:D013959', (96, 111))	('suppressing', 'NegReg', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('colon cancer', 'Disease', 'MESH:D015179', (181, 193))	('gastric cancer', 'Phenotype', 'HP:0012126', (229, 243))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
455803	27295551	HDAC4 mRNA was also determined in cell lines, which shows significantly higher expression in EC/CUHK1, KYSE30, KYSE140, KYSE150, and KYSE180 EC cell lines than the immortalized human esophageal cell line NE1 (P< 0.05) (Fig.	('EC/CUHK1', 'Gene', (93, 101))	('EC', 'Phenotype', 'HP:0011459', (141, 143))	('expression', 'MPA', (79, 89))	('KYSE180 EC', 'CellLine', 'CVCL:1349', (133, 143))	('NE1', 'CellLine', 'CVCL:E306', (204, 207))	('HDAC4', 'Gene', '9759', (0, 5))	('KYSE30', 'Var', (103, 109))	('HDAC4', 'Gene', (0, 5))	('KYSE150', 'Var', (120, 127))	('higher', 'PosReg', (72, 78))	('KYSE140', 'Var', (111, 118))	('human', 'Species', '9606', (177, 182))	('EC/CUHK1', 'CellLine', 'CVCL:E317', (93, 101))	('EC', 'Phenotype', 'HP:0011459', (93, 95))
455808	27295551	The results show that high HDAC4 expression is significantly correlated with high pathological grade (poor differentiation), T stage, N stage and advanced TNM stage in ESCC patients (Table 1), indicating that HDAC4 overexpression is associated with ESCC progression.	('ESCC', 'Disease', (249, 253))	('associated', 'Reg', (233, 243))	('patients', 'Species', '9606', (173, 181))	('TNM', 'Gene', '10178', (155, 158))	('high', 'Var', (22, 26))	('HDAC4', 'Gene', '9759', (209, 214))	('HDAC4', 'Gene', (209, 214))	('TNM', 'Gene', (155, 158))	('expression', 'MPA', (33, 43))	('HDAC4', 'Gene', '9759', (27, 32))	('HDAC4', 'Gene', (27, 32))
455809	27295551	To further explore the prognostic value of HDAC4 in ESCC patients, we analyzed overall survival (OS) and progression-free survival (PFS) of ESCC patients with high or low HDAC4 expression using Kaplan-Meier method and Log-rank test.	('patients', 'Species', '9606', (145, 153))	('low', 'NegReg', (167, 170))	('patients', 'Species', '9606', (57, 65))	('ESCC', 'Disease', (140, 144))	('HDAC4', 'Gene', '9759', (171, 176))	('HDAC4', 'Gene', '9759', (43, 48))	('HDAC4', 'Gene', (171, 176))	('HDAC4', 'Gene', (43, 48))	('high', 'Var', (159, 163))
455810	27295551	The 5-year OS and PFS of patients with high HDAC4 expression were only 20.15% and 30.92%, which were considerably shorter than those with HDAC4 low expression (68.75% and 53.59%) (Fig.	('high', 'Var', (39, 43))	('HDAC4', 'Gene', '9759', (44, 49))	('patients', 'Species', '9606', (25, 33))	('HDAC4', 'Gene', (44, 49))	('HDAC4', 'Gene', '9759', (138, 143))	('HDAC4', 'Gene', (138, 143))
455811	27295551	Thus, high level of HDAC4 is significantly correlated with poor prognosis of ESCC patients.	('high level', 'Var', (6, 16))	('ESCC', 'Disease', (77, 81))	('patients', 'Species', '9606', (82, 90))	('correlated', 'Reg', (43, 53))	('HDAC4', 'Gene', '9759', (20, 25))	('HDAC4', 'Gene', (20, 25))
455818	27295551	The results show that stage I-II patients with high level of HDAC4 mRNA have remarkably poorer OS than those with low level (Supplementary Fig.	('patients', 'Species', '9606', (33, 41))	('HDAC4', 'Gene', (61, 66))	('HDAC4', 'Gene', '9759', (61, 66))	('high level', 'Var', (47, 57))	('poorer', 'NegReg', (88, 94))
455826	27295551	Because HDAC4 knockdown inhibits proliferation of EC cells, we asked whether cell cycle is affected by HDAC4 knockdown.	('EC', 'Phenotype', 'HP:0011459', (50, 52))	('inhibits', 'NegReg', (24, 32))	('HDAC4', 'Gene', '9759', (8, 13))	('HDAC4', 'Gene', (8, 13))	('proliferation', 'CPA', (33, 46))	('knockdown', 'Var', (14, 23))	('HDAC4', 'Gene', (103, 108))	('HDAC4', 'Gene', '9759', (103, 108))
455829	27295551	These results indicate that HDAC4 knockdown causes G1 cell cycle arrest in both EC cell lines.	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('arrest', 'Disease', (65, 71))	('HDAC4', 'Gene', '9759', (28, 33))	('knockdown', 'Var', (34, 43))	('EC', 'Phenotype', 'HP:0011459', (80, 82))	('HDAC4', 'Gene', (28, 33))
455830	27295551	The retinoblastoma (Rb) protein is important for G1/S cell cycle transition, which is regulated by two cyclin-dependent kinase (CDK) complexes, CDK4/6-Cyclin D and CDK2-Cyclin E. The CDK inhibitors p21 and p27 oppose the effect of CDK4/6-Cyclin D and CDK2-Cyclin E. We examined whether HDAC4 knockdown affects the level of Rb phosphorylation (pRb), p21/p27 and CDK2/4.	('Rb', 'Gene', '5925', (323, 325))	('CDK2', 'Gene', '1017', (361, 365))	('p27', 'Gene', '3429', (206, 209))	('CDK2', 'Gene', (164, 168))	('retinoblastoma', 'Gene', (4, 18))	('Rb', 'Phenotype', 'HP:0009919', (20, 22))	('CDK4/6', 'Gene', (231, 237))	('p27', 'Gene', (206, 209))	('CDK2', 'Gene', (361, 365))	('p21', 'Gene', (349, 352))	('Rb', 'Gene', '5925', (344, 346))	('Rb', 'Phenotype', 'HP:0009919', (323, 325))	('HDAC4', 'Gene', (286, 291))	('CDK4/6', 'Gene', '1019;1021', (144, 150))	('pRb', 'Gene', (343, 346))	('p21', 'Gene', (198, 201))	('CDK4/6', 'Gene', '1019;1021', (231, 237))	('Rb', 'Phenotype', 'HP:0009919', (344, 346))	('p27', 'Gene', '3429', (353, 356))	('p27', 'Gene', (353, 356))	('retinoblastoma', 'Gene', '5925', (4, 18))	('pRb', 'Gene', '5925', (343, 346))	('affects', 'Reg', (302, 309))	('CDK2', 'Gene', '1017', (251, 255))	('retinoblastoma', 'Phenotype', 'HP:0009919', (4, 18))	('p21', 'Gene', '1026', (349, 352))	('CDK2', 'Gene', (251, 255))	('Rb', 'Gene', '5925', (20, 22))	('CDK2/4', 'Gene', '1017;1019', (361, 367))	('CDK2', 'Gene', '1017', (164, 168))	('CDK4/6', 'Gene', (144, 150))	('p21', 'Gene', '1026', (198, 201))	('CDK2/4', 'Gene', (361, 367))	('HDAC4', 'Gene', '9759', (286, 291))	('knockdown', 'Var', (292, 301))
455831	27295551	Indeed, HDAC4 knockdown in EC/CUHK1 and KYSE30 cells causes a decrease in CDK2/4 and pRb, but an increase in p21 and p27 (Fig.3E).	('CDK2/4', 'Gene', (74, 80))	('increase', 'PosReg', (97, 105))	('HDAC4', 'Gene', '9759', (8, 13))	('HDAC4', 'Gene', (8, 13))	('EC/CUHK1', 'CellLine', 'CVCL:E317', (27, 35))	('pRb', 'Gene', '5925', (85, 88))	('p27', 'Gene', '3429', (117, 120))	('decrease', 'NegReg', (62, 70))	('pRb', 'Gene', (85, 88))	('p27', 'Gene', (117, 120))	('knockdown', 'Var', (14, 23))	('p21', 'Gene', (109, 112))	('p21', 'Gene', '1026', (109, 112))	('Rb', 'Phenotype', 'HP:0009919', (86, 88))	('EC', 'Phenotype', 'HP:0011459', (27, 29))	('CDK2/4', 'Gene', '1017;1019', (74, 80))
455835	27295551	In wound healing assay, cell migration rate is markedly decreased in HDAC4 knock-down cells compared with control cells (by approximately 65% and 50% at 12 h and 24 h, respectively) (Fig.	('HDAC4', 'Gene', (69, 74))	('knock-down', 'Var', (75, 85))	('cell migration rate', 'CPA', (24, 43))	('decreased', 'NegReg', (56, 65))	('HDAC4', 'Gene', '9759', (69, 74))
455836	27295551	Because HDAC4 knock down inhibits migration of EC cells, we asked if EMT is involved.	('inhibits', 'NegReg', (25, 33))	('knock down', 'Var', (14, 24))	('HDAC4', 'Gene', '9759', (8, 13))	('HDAC4', 'Gene', (8, 13))	('EC', 'Phenotype', 'HP:0011459', (47, 49))	('migration of EC cells', 'CPA', (34, 55))
455838	27295551	The expression of the epithelial markers E-cadherin and alpha-catenin are increased, whereas that of the mesenchymal marker Vimentin is reduced in EC/CUHK1 and KYSE30 cells following HDAC4 knockdown (Fig.	('Vimentin', 'Gene', (124, 132))	('alpha-catenin', 'Protein', (56, 69))	('HDAC4', 'Gene', (183, 188))	('HDAC4', 'Gene', '9759', (183, 188))	('expression', 'MPA', (4, 14))	('Vimentin', 'Gene', '7431', (124, 132))	('EC/CUHK1', 'CellLine', 'CVCL:E317', (147, 155))	('increased', 'PosReg', (74, 83))	('EC', 'Phenotype', 'HP:0011459', (147, 149))	('reduced', 'NegReg', (136, 143))	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))	('knockdown', 'Var', (189, 198))
455840	27295551	Unbalanced histone acetylation/deacetylation is often associated with cancer initiation and progression.	('Unbalanced', 'Var', (0, 10))	('cancer initiation', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('acetylation/deacetylation', 'MPA', (19, 44))	('histone', 'Protein', (11, 18))	('cancer initiation', 'Disease', 'MESH:D009369', (70, 87))	('associated', 'Reg', (54, 64))
455843	27295551	Halkidou et al report that high level of HDAC4 in nucleus is associated with hormone-resistant in prostate cancer patients.	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('hormone-resistant', 'Disease', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('prostate cancer', 'Disease', (98, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('patients', 'Species', '9606', (114, 122))	('associated', 'Reg', (61, 71))	('HDAC4', 'Gene', '9759', (41, 46))	('high level', 'Var', (27, 37))	('HDAC4', 'Gene', (41, 46))
455844	27295551	Recently, Gruhn and his colleagues found that high HDAC4 expression is associated with poor survival, high initial leukocyte count, T cell ALL and prednisone poor-response in childhood acute lymphoblastic leukemia.	('HDAC4', 'Gene', '9759', (51, 56))	('high', 'Var', (46, 50))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (185, 213))	('HDAC4', 'Gene', (51, 56))	('prednisone', 'Chemical', 'MESH:D011241', (147, 157))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (191, 213))	('acute lymphoblastic leukemia', 'Disease', (185, 213))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (185, 213))	('leukemia', 'Phenotype', 'HP:0001909', (205, 213))
455845	27295551	In this study, we find for the first time that HDAC4 mRNA and protein are overexpressed in ESCC tissues compared with matched normal esophageal tissues, and high mRNA level is associated with low differentiation (high pathological grade), lymph node metastasis, large or invasive tumor and advanced TNM stage in ESCC patients.	('low differentiation', 'CPA', (192, 211))	('invasive tumor', 'Disease', 'MESH:D009369', (271, 285))	('invasive tumor', 'Disease', (271, 285))	('TNM', 'Gene', '10178', (299, 302))	('mRNA level', 'MPA', (162, 172))	('lymph node metastasis', 'CPA', (239, 260))	('HDAC4', 'Gene', (47, 52))	('high', 'Var', (157, 161))	('ESCC', 'Disease', (312, 316))	('associated', 'Reg', (176, 186))	('HDAC4', 'Gene', '9759', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('overexpressed', 'PosReg', (74, 87))	('patients', 'Species', '9606', (317, 325))	('TNM', 'Gene', (299, 302))
455848	27295551	For example, inhibition of HDAC4 reduces viability of non-small cell lung cancer.	('viability', 'MPA', (41, 50))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (54, 80))	('inhibition', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('non-small cell lung cancer', 'Disease', (54, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (54, 80))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (58, 80))	('reduces', 'NegReg', (33, 40))	('HDAC4', 'Gene', '9759', (27, 32))	('HDAC4', 'Gene', (27, 32))
455855	27295551	HDAC4 knockdown markedly inhibits EC cell proliferation as a result of G1 cell cycle arrest.	('inhibits', 'NegReg', (25, 33))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('EC', 'Phenotype', 'HP:0011459', (34, 36))	('HDAC4', 'Gene', '9759', (0, 5))	('HDAC4', 'Gene', (0, 5))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('knockdown', 'Var', (6, 15))	('arrest', 'Disease', (85, 91))
455859	27295551	For example, Hrzenjak at al reported that HDAC2 down-regulation results in increased p21 expression; Wilson et al showed that up-regulation of HDAC3 leads to inhibition of p21 expression, and that HDAC3 silencing enhances the expression of p21 in colon cancer cells; Li et al found that HDAC6 down-regulation increases p21 expression and cell cycle arrest in EC9706 cells.	('arrest', 'Disease', (349, 355))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (338, 355))	('p21', 'Gene', (240, 243))	('HDAC3', 'Gene', (143, 148))	('colon cancer', 'Phenotype', 'HP:0003003', (247, 259))	('expression', 'MPA', (226, 236))	('expression', 'MPA', (176, 186))	('inhibition', 'NegReg', (158, 168))	('HDAC3', 'Gene', (197, 202))	('down-regulation', 'NegReg', (48, 63))	('down-regulation', 'NegReg', (293, 308))	('expression', 'MPA', (89, 99))	('colon cancer', 'Disease', 'MESH:D015179', (247, 259))	('p21', 'Gene', '1026', (319, 322))	('up-regulation', 'PosReg', (126, 139))	('increased', 'PosReg', (75, 84))	('arrest', 'Disease', 'MESH:D006323', (349, 355))	('p21', 'Gene', (85, 88))	('EC', 'Phenotype', 'HP:0011459', (359, 361))	('silencing', 'Var', (203, 212))	('HDAC3', 'Gene', '8841', (143, 148))	('p21', 'Gene', '1026', (240, 243))	('p21', 'Gene', (172, 175))	('increases', 'PosReg', (309, 318))	('HDAC2', 'Gene', (42, 47))	('HDAC2', 'Gene', '3066', (42, 47))	('HDAC3', 'Gene', '8841', (197, 202))	('enhances', 'PosReg', (213, 221))	('colon cancer', 'Disease', (247, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('p21', 'Gene', '1026', (85, 88))	('EC9706', 'CellLine', 'CVCL:E307', (359, 365))	('p21', 'Gene', '1026', (172, 175))	('p21', 'Gene', (319, 322))
455935	26754834	Specifically, patients with low CRP (<10 mg/L) and high albumin levels (>=35 g/L) were assigned a score of 0, those with one of the two biochemical abnormalities were assigned a score of 1, and those with both high CRP levels and low albumin levels were assigned a score of 2.	('<10', 'Var', (37, 40))	('high albumin', 'Phenotype', 'HP:0012117', (51, 63))	('CRP', 'Gene', (215, 218))	('CRP', 'Gene', (32, 35))	('albumin', 'Gene', (234, 241))	('albumin', 'Gene', '213', (234, 241))	('CRP', 'Gene', '1401', (215, 218))	('low albumin', 'Phenotype', 'HP:0003073', (230, 241))	('CRP', 'Gene', '1401', (32, 35))	('albumin', 'Gene', (56, 63))	('albumin', 'Gene', '213', (56, 63))	('low', 'NegReg', (28, 31))	('patients', 'Species', '9606', (14, 22))
455973	26754834	reported that D-dimer could also induce the spread of tumors by stimulating tumor cells to adhere to endothelial cells.	('D-dimer', 'Var', (14, 21))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('stimulating', 'Reg', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (54, 59))	('adhere', 'CPA', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('induce', 'PosReg', (33, 39))	('tumors', 'Disease', (54, 60))
456213	33280513	Using Pearson's correlation test, the hub genes in the GSE92396 (Figure 4D) and GSE100942 (Figure 4E) datasets were correlated strongly shown by these heat maps.	('GSE92396', 'Gene', (55, 63))	('GSE100942', 'Var', (80, 89))	('hub', 'Gene', (38, 41))	('hub', 'Gene', '1993', (38, 41))
456217	33280513	Patients with EC who had low expression level of COL3A1 showed worse overall survival times (P < 0.05, Figure 5C).	('COL3A1', 'Gene', '1281', (49, 55))	('worse', 'NegReg', (63, 68))	('low expression level', 'Var', (25, 45))	('Patients', 'Species', '9606', (0, 8))	('COL3A1', 'Gene', (49, 55))
456219	33280513	EC patients who had low expression of COL1A1 showed worse overall survival times (P < 0.05, Figure 5E).	('low expression', 'Var', (20, 34))	('COL1A1', 'Gene', '1277', (38, 44))	('COL1A1', 'Gene', (38, 44))	('patients', 'Species', '9606', (3, 11))
456252	33280513	A mutation in COL3A1 causes vascular Ehlers-Danlos syndrome (vEDS), a rare, life-threatening genetic disease.	('mutation', 'Var', (2, 10))	('vEDS', 'Disease', 'None', (61, 65))	('COL3A1', 'Gene', '1281', (14, 20))	('causes', 'Reg', (21, 27))	('genetic disease', 'Disease', 'MESH:D030342', (93, 108))	('vascular Ehlers-Danlos syndrome', 'Disease', (28, 59))	('COL3A1', 'Gene', (14, 20))	('genetic disease', 'Disease', (93, 108))	('vascular Ehlers-Danlos syndrome', 'Disease', 'MESH:D004535', (28, 59))	('vEDS', 'Disease', (61, 65))
456253	33280513	The abnormal expression of COL3A1 in various cancer is significantly connected with bad overall survival rates, e.g.	('abnormal', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('expression', 'MPA', (13, 23))	('COL3A1', 'Gene', (27, 33))	('connected', 'Reg', (69, 78))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('COL3A1', 'Gene', '1281', (27, 33))
456254	33280513	in bladder cancer, breast cancer, and smoking-related lung cancer; its expression may affect the tumor microenvironment and regulate the ECM through collagen degradation and deposition to promote tumor progression.	('affect', 'Reg', (86, 92))	('tumor', 'Disease', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('men', 'Species', '9606', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('regulate', 'Reg', (124, 132))	('ECM', 'MPA', (137, 140))	('lung cancer', 'Disease', (54, 65))	('collagen', 'MPA', (149, 157))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('promote', 'PosReg', (188, 195))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('deposition', 'MPA', (174, 184))	('breast cancer', 'Disease', (19, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'Var', (71, 81))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))
456274	32024999	Indeed, domain disruptions in human cancers can lead to misregulation of gene expression.	('human', 'Species', '9606', (30, 35))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('domain disruptions', 'Var', (8, 26))	('lead', 'Reg', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('misregulation of gene expression', 'MPA', (56, 88))
456277	32024999	Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes.	('chromatin folding maps', 'MPA', (97, 119))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SVs', 'Chemical', '-', (9, 12))	('lead to', 'Reg', (17, 24))	('change', 'Reg', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('SVs', 'Var', (9, 12))	('cancer', 'Disease', (127, 133))	('TADs', 'Protein', (48, 52))
456278	32024999	A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs).	('chromatin domains', 'MPA', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('effects', 'Reg', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('structural variations', 'Var', (53, 74))
456303	32024999	As a result, 5.0%, 8.5%, 12.8% and 19.9% of all deletions, inversions, duplications and complex events were called BA events, respectively (Fig.	('duplications', 'Var', (71, 83))	('deletions', 'Var', (48, 57))	('BA', 'Chemical', '-', (115, 117))	('inversions', 'Var', (59, 69))
456311	32024999	Interestingly, TAD boundaries are significantly less likely (P < 0.02) to be affected by known deletion and duplication polymorphisms derived from genomes of healthy human populations (Extended Data Fig.	('duplication polymorphisms', 'Var', (108, 133))	('human', 'Species', '9606', (166, 171))	('deletion', 'Var', (95, 103))
456312	32024999	Genomic length of the germline alterations tends to be shorter compared with somatic alterations observed in tumors due to negative selection against large SVs in the germline.	('alterations', 'Var', (31, 42))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('SVs', 'Chemical', '-', (156, 159))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('shorter', 'NegReg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
456330	32024999	Of those recurrently affected boundaries, two adjacent boundaries between KIAA1549 and BRAF were prone to BA-duplications specifically in samples of pilocytic astrocytoma (Fig.	('BA', 'Chemical', '-', (106, 108))	('BRAF', 'Gene', '673', (87, 91))	('prone', 'Reg', (97, 102))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (149, 170))	('astrocytoma', 'Phenotype', 'HP:0009592', (159, 170))	('BA-duplications', 'Var', (106, 121))	('BRAF', 'Gene', (87, 91))	('KIAA1549', 'Gene', (74, 82))	('pilocytic astrocytoma', 'Disease', (149, 170))	('KIAA1549', 'Gene', '57670', (74, 82))
456334	32024999	We also observed a higher mutational load specifically on chromosome 12 in leiomyosarcoma samples (Fig.	('leiomyosarcoma', 'Disease', (75, 89))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (75, 89))	('higher', 'PosReg', (19, 25))	('mutational', 'Var', (26, 36))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (75, 89))
456335	32024999	Another recurrent BA-SV event was the high number of BA-deletions around RBFOX1 in colorectal adenocarcinoma samples (Extended Data Fig.	('colorectal adenocarcinoma', 'Disease', (83, 108))	('RBFOX1', 'Gene', '54715', (73, 79))	('BA', 'Chemical', '-', (18, 20))	('RBFOX1', 'Gene', (73, 79))	('BA-deletions', 'Var', (53, 65))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (83, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('BA-SV', 'Chemical', '-', (18, 23))	('BA', 'Chemical', '-', (53, 55))
456341	32024999	For instance, a CTCF site near FOXC1 overlaps with recurrent deletions in esophageal, gastric and colon adenocarcinomas (Fig.	('deletions', 'Var', (61, 70))	('CTCF', 'Gene', '10664', (16, 20))	('FOXC1', 'Gene', (31, 36))	('gastric and colon adenocarcinomas', 'Disease', 'MESH:D013274', (86, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('FOXC1', 'Gene', '2296', (31, 36))	('CTCF', 'Gene', (16, 20))	('esophageal', 'Disease', (74, 84))
456353	32024999	For example, a BA-deletion in a malignant lymphoma sample was associated with a 37-fold increase in the expression level of WNT4 compared with the rest of samples from patients with lymphoma (Fig.	('WNT4', 'Gene', (124, 128))	('WNT4', 'Gene', '54361', (124, 128))	('lymphoma', 'Disease', (182, 190))	('malignant lymphoma', 'Disease', (32, 50))	('lymphoma', 'Disease', (42, 50))	('increase', 'PosReg', (88, 96))	('lymphoma', 'Disease', 'MESH:D008223', (182, 190))	('BA', 'Chemical', '-', (15, 17))	('patients', 'Species', '9606', (168, 176))	('BA-deletion', 'Var', (15, 26))	('lymphoma', 'Disease', 'MESH:D008223', (42, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (182, 190))	('lymphoma', 'Phenotype', 'HP:0002665', (42, 50))	('malignant lymphoma', 'Disease', 'MESH:D008223', (32, 50))	('expression level', 'MPA', (104, 120))
456354	32024999	Similarly, a BA-deletion in the genome of a patient with breast adenocarcinoma correlated with 26-fold overexpression of SLC22A2 compared with the rest of the patients with breast cancer (Fig.	('BA', 'Chemical', '-', (13, 15))	('patient', 'Species', '9606', (44, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (57, 78))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (57, 78))	('breast adenocarcinoma', 'Disease', (57, 78))	('SLC22A2', 'Gene', '6582', (121, 128))	('overexpression', 'PosReg', (103, 117))	('SLC22A2', 'Gene', (121, 128))	('patient', 'Species', '9606', (159, 166))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('patients', 'Species', '9606', (159, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('BA-deletion', 'Var', (13, 24))	('breast cancer', 'Disease', (173, 186))
456363	32024999	We observed that deletions significantly occurred in LADs and duplications in inter-LADs, whereas SVs were less likely to occur between LADs and inter-LADs (Extended Data Fig.	('deletions', 'Var', (17, 26))	('SVs', 'Chemical', '-', (98, 101))	('duplications', 'Var', (62, 74))	('occurred', 'Reg', (41, 49))	('LADs', 'Disease', (53, 57))
456365	32024999	These observations suggest that gene regulation in cancer genomes is multifactorial, although disruptions in chromatin folding domains may contribute to expression levels in certain cases, the effects of disruption do not always coincide with the expression changes.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('expression levels', 'MPA', (153, 170))	('disruptions', 'Var', (94, 105))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('contribute', 'Reg', (139, 149))
456376	32024999	Our analysis revealed that intra-TAD/SV interactions were stronger than the inter-TAD/SV interactions, when controlling for genomic distance effects, which suggests that the SVs can lead to cross-boundary interactions and potentially the formation of new chromatin folding domains based on the location of existing nearby TAD boundaries (Fig.	('SVs', 'Var', (174, 177))	('chromatin folding domains', 'MPA', (255, 280))	('intra-TAD/SV interactions', 'Disease', 'MESH:C563663', (27, 52))	('lead to', 'Reg', (182, 189))	('cross-boundary interactions', 'MPA', (190, 217))	('inter-TAD/SV', 'Disease', '-', (76, 88))	('inter-TAD/SV', 'Disease', (76, 88))	('SVs', 'Chemical', '-', (174, 177))	('intra-TAD/SV interactions', 'Disease', (27, 52))
456377	32024999	For instance, an inversion in OE33 cells that encompassed ERBB2 formed a neo-TAD on chromosome 17 (Fig.	('inversion', 'Var', (17, 26))	('ERBB2', 'Gene', (58, 63))	('ERBB2', 'Gene', '2064', (58, 63))
456378	32024999	5c) and a duplication near KRAS in SW480 cells (Extended Data Fig.	('KRAS', 'Gene', (27, 31))	('duplication', 'Var', (10, 21))	('KRAS', 'Gene', '3845', (27, 31))
456380	32024999	We noticed that complex rearrangements in which deletion, inversion or duplication break-ends overlapped resulted in marked changes in Hi-C maps.	('duplication', 'Var', (71, 82))	('Hi-C', 'Chemical', '-', (135, 139))	('Hi-C', 'MPA', (135, 139))	('changes', 'Reg', (124, 131))	('deletion', 'Var', (48, 56))
456383	32024999	For example, the MYC locus in SW480 cells contains 135 rearrangements in a 4-Mb genomic window (Fig.	('MYC', 'Gene', '4609', (17, 20))	('rearrangements', 'Var', (55, 69))	('MYC', 'Gene', (17, 20))
456390	32024999	Additionally, we observed a difference between the disruptions between different SV types; deletions tended to occur within TADs and LADs, whereas duplications tended to span TADs and generally occurred within inter-LAD regions.	('deletions', 'Var', (91, 100))	('SV type', 'Disease', 'MESH:D017827', (81, 88))	('SV type', 'Disease', (81, 88))
456402	32024999	We used HiCPlotter to plot Hi-C data with different features, TAD boundaries or gene-expression fold changes after deletion between repressed and active domains.	('Hi-C', 'Chemical', '-', (27, 31))	('deletion', 'Var', (115, 123))	('gene-expression', 'MPA', (80, 95))	('changes', 'Reg', (101, 108))
456403	32024999	ENCODE replication timing data were downloaded from the UCSC Genome Browser ENCODE portal for the following cell types: BJ, GM06990, GM12801, GM12812, GM12813, GM12878, HeLa-S3, HepG2, HUVEC, IMR-90, K-562, MCF-7, NHEK and SK-N-SH.	('BJ', 'CellLine', 'CVCL:6573;-0.019172924845188632', (120, 122))	('GM06990', 'Var', (124, 131))	('GM12801', 'Var', (133, 140))	('GM12878', 'Var', (160, 167))	('GM12812', 'Var', (142, 149))	('K-562', 'CellLine', 'CVCL:0004;-0.036774859271425306', (200, 205))	('HeLa', 'CellLine', 'CVCL:0030;0.025873122387212497', (169, 173))	('HepG2', 'CellLine', 'CVCL:0027;0.0033931770107794024', (178, 183))	('GM12878', 'Chemical', '-', (160, 167))	('MCF-7', 'CellLine', 'CVCL:0031;-0.01003965147582838', (207, 212))	('GM12813', 'Var', (151, 158))	('IMR-90', 'CellLine', 'CVCL:0347;-0.05874739001530446', (192, 198))
456409	32024999	The single junction events were interpreted, as the 'basic' SV types (deletion, tandem duplication, translocation and inversions).	('SV type', 'Disease', 'MESH:D017827', (60, 67))	('tandem duplication', 'Var', (80, 98))	('SV type', 'Disease', (60, 67))	('translocation', 'Var', (100, 113))
456421	32024999	Observed SVs and BA-SVs across cancer studies were plotted as stacked bar charts representing deletions, inversions and duplications.	('SVs', 'Chemical', '-', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('BA-SVs', 'Chemical', '-', (17, 23))	('deletions', 'Var', (94, 103))	('SVs', 'Chemical', '-', (20, 23))	('cancer', 'Disease', (31, 37))
456428	32024999	We plotted the observed values for BA-SV deletions, inversions, duplications or complex rearrangements separately.	('BA-SV', 'Gene', (35, 40))	('BA-SV', 'Chemical', '-', (35, 40))	('deletions', 'Var', (41, 50))
456446	32024999	Aligned sequencing data, as well as somatic and germline variant calls from PCAWG tumors, including SNVs, indels, copy number alterations and SVs, are available for download at https://dcc.icgc.org/releases/PCAWG.	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('PCAWG', 'Gene', (76, 81))	('copy number alterations', 'Var', (114, 137))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SVs', 'Chemical', '-', (142, 145))
456472	27815921	This complication can result from perioperative tracheal injury, ischemic lesions due to devascularization of the trachea and main bronchus by extensive lymph node dissection, or leakage of the esophagointestinal anastomosis, and it may present early after esophagectomy or relatively late in the follow-up.	('leakage', 'Var', (179, 186))	('result from', 'Reg', (22, 33))	('devascularization', 'CPA', (89, 106))	('ischemic lesions', 'Disease', (65, 81))	('esophagointestinal anastomosis', 'Disease', (194, 224))	('tracheal injury', 'Disease', (48, 63))	('ischemic lesions', 'Disease', 'MESH:D007511', (65, 81))	('esophagointestinal anastomosis', 'Disease', 'MESH:C563598', (194, 224))	('tracheal injury', 'Disease', 'MESH:D008476', (48, 63))
456491	26085818	Single nucleotide polymorphisms in CRTC1 and BARX1 are associated with esophageal adenocarcinoma Recently, single nucleotide polymorphisms (SNPs) associated with esophageal adenocarcinoma (EAC) and Barrett's esophagus (BE) were identified; rs10419226 (CRTC1), rs11789015 (BARX1), rs2687201 (FOXP1), rs2178146 (FOXF1), rs3111601 (FOXF1), and rs9936833 (FOXF1).	('rs2178146', 'Var', (299, 308))	('BARX1', 'Gene', (272, 277))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (71, 96))	('CRTC1', 'Gene', '23373', (252, 257))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (198, 217))	('rs2687201', 'Mutation', 'rs2687201', (280, 289))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (71, 96))	('rs2687201', 'Var', (280, 289))	('rs9936833', 'Mutation', 'rs9936833', (341, 350))	('rs3111601', 'Mutation', 'rs3111601', (318, 327))	('rs2178146', 'Mutation', 'rs2178146', (299, 308))	('esophageal adenocarcinoma', 'Disease', (71, 96))	('associated', 'Reg', (55, 65))	('FOXF1', 'Gene', (329, 334))	('BARX1', 'Gene', '56033', (45, 50))	('EAC', 'Phenotype', 'HP:0011459', (189, 192))	('rs10419226', 'Mutation', 'rs10419226', (240, 250))	('CRTC1', 'Gene', '23373', (35, 40))	('rs3111601', 'Var', (318, 327))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (162, 187))	('CRTC1', 'Gene', (252, 257))	('FOXP1', 'Gene', '27086', (291, 296))	('FOXF1', 'Gene', '2294', (329, 334))	('FOXF1', 'Gene', (352, 357))	('rs10419226', 'Var', (240, 250))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (162, 187))	('BARX1', 'Gene', '56033', (272, 277))	('rs9936833', 'Var', (341, 350))	('rs11789015', 'Var', (260, 270))	('FOXF1', 'Gene', '2294', (352, 357))	('rs11789015', 'Mutation', 'rs11789015', (260, 270))	('FOXF1', 'Gene', (310, 315))	('esophageal adenocarcinoma', 'Disease', (162, 187))	('FOXP1', 'Gene', (291, 296))	('BARX1', 'Gene', (45, 50))	('FOXF1', 'Gene', '2294', (310, 315))	('CRTC1', 'Gene', (35, 40))	('BE', 'Phenotype', 'HP:0100580', (219, 221))
456494	26085818	Rs10419226 (CRTC1) showed a significantly increased EAC risk for the minor allele (OR = 1.17, P = 0.001), and rs11789015 (BARX1) showed a significantly decreased risk for the minor allele (OR = 0.85, P = 0.004) in the logistic regression analysis.	('CRTC1', 'Gene', '23373', (12, 17))	('EAC', 'Disease', (52, 55))	('Rs10419226', 'Mutation', 'Rs10419226', (0, 10))	('Rs10419226', 'Var', (0, 10))	('rs11789015', 'Var', (110, 120))	('rs11789015', 'Mutation', 'rs11789015', (110, 120))	('decreased', 'NegReg', (152, 161))	('EAC', 'Phenotype', 'HP:0011459', (52, 55))	('CRTC1', 'Gene', (12, 17))
456495	26085818	The meta-analysis of the original GWAS and the current study revealed an improved level of significance for rs10419226 (CRTC1) (OR = 1.18, P = 6.66 x 10-10) and rs11789015 (BARX1) (OR = 0.83, P = 1.13 x 10-8).	('rs11789015', 'Mutation', 'rs11789015', (161, 171))	('rs11789015', 'Var', (161, 171))	('CRTC1', 'Gene', (120, 125))	('rs10419226', 'Var', (108, 118))	('CRTC1', 'Gene', '23373', (120, 125))	('rs10419226', 'Mutation', 'rs10419226', (108, 118))
456496	26085818	This independent and large Dutch case-control study confirms the association of rs10419226 (CRTC1) and rs11789015 (BARX1) with the risk of EAC.	('rs11789015', 'Var', (103, 113))	('rs11789015', 'Mutation', 'rs11789015', (103, 113))	('CRTC1', 'Gene', '23373', (92, 97))	('rs10419226', 'Var', (80, 90))	('EAC', 'Disease', (139, 142))	('rs10419226', 'Mutation', 'rs10419226', (80, 90))	('CRTC1', 'Gene', (92, 97))	('EAC', 'Phenotype', 'HP:0011459', (139, 142))
456506	26085818	From this perspective the identification of single nucleotide polymorphisms (SNPs), which identifies high-risk patients, could make the surveillance of BE patients more cost-effective and could be helpful by diagnosing patients with EAC in an early and curable stage and thereby increase the prognosis remarkably.	('BE', 'Phenotype', 'HP:0100580', (152, 154))	('EAC', 'Phenotype', 'HP:0011459', (233, 236))	('patients', 'Species', '9606', (111, 119))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (219, 227))	('single nucleotide polymorphisms', 'Var', (44, 75))	('EAC', 'Disease', (233, 236))	('increase', 'PosReg', (279, 287))
456507	26085818	This study revealed three SNPs associated with EAC: rs10419226 (CRTC1), rs11789015 (BARX1), and rs2687201 (FOXP1).	('rs2687201', 'Mutation', 'rs2687201', (96, 105))	('rs11789015', 'Var', (72, 82))	('rs2687201', 'Var', (96, 105))	('CRTC1', 'Gene', (64, 69))	('rs10419226', 'Var', (52, 62))	('CRTC1', 'Gene', '23373', (64, 69))	('rs11789015', 'Mutation', 'rs11789015', (72, 82))	('FOXP1', 'Gene', '27086', (107, 112))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('rs10419226', 'Mutation', 'rs10419226', (52, 62))	('EAC', 'Disease', (47, 50))	('FOXP1', 'Gene', (107, 112))
456508	26085818	In addition, evidence was found that rs9936833 (FOXF1), previously associated with BE, was also associated with EAC and that the SNPs: rs2178146 and rs3111601 near rs9936833 had even a stronger association with EAC.	('BE', 'Phenotype', 'HP:0100580', (83, 85))	('rs9936833', 'Var', (164, 173))	('EAC', 'Disease', (211, 214))	('rs2178146', 'Var', (135, 144))	('rs9936833', 'Mutation', 'rs9936833', (164, 173))	('associated', 'Reg', (96, 106))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('FOXF1', 'Gene', '2294', (48, 53))	('rs2178146', 'Mutation', 'rs2178146', (135, 144))	('EAC', 'Disease', (112, 115))	('rs3111601', 'Mutation', 'rs3111601', (149, 158))	('rs3111601', 'Var', (149, 158))	('FOXF1', 'Gene', (48, 53))	('rs9936833', 'Var', (37, 46))	('EAC', 'Phenotype', 'HP:0011459', (211, 214))	('rs9936833', 'Mutation', 'rs9936833', (37, 46))
456510	26085818	in 2012, simultaneously rs9257809 (MHC) was found to be associated with BE.	('MHC', 'Gene', (35, 38))	('MHC', 'Gene', '3107', (35, 38))	('rs9257809', 'Mutation', 'rs9257809', (24, 33))	('associated', 'Reg', (56, 66))	('rs9257809', 'Var', (24, 33))	('BE', 'Phenotype', 'HP:0100580', (72, 74))
456517	26085818	For cases, a multiplex SNaPshot assay was designed; multiplex polymerase chain reaction was used to amplify the regions of the SNPs: rs2178146 (FOXF1), rs10419226 (CRTC1), rs9936833 (FOXF1), rs2687201 (FOXP1), rs11789015 (BARX1), and rs3111601 (FOXF1) (Hg19).	('rs3111601', 'Var', (234, 243))	('rs11789015', 'Var', (210, 220))	('rs11789015', 'Mutation', 'rs11789015', (210, 220))	('rs9936833', 'Var', (172, 181))	('CRTC1', 'Gene', '23373', (164, 169))	('rs2178146', 'Mutation', 'rs2178146', (133, 142))	('FOXP1', 'Gene', (202, 207))	('rs10419226', 'Mutation', 'rs10419226', (152, 162))	('CRTC1', 'Gene', (164, 169))	('rs9936833', 'Mutation', 'rs9936833', (172, 181))	('rs10419226', 'Var', (152, 162))	('rs2687201', 'Mutation', 'rs2687201', (191, 200))	('FOXF1', 'Gene', (144, 149))	('rs2687201', 'Var', (191, 200))	('rs3111601', 'Mutation', 'rs3111601', (234, 243))	('FOXF1', 'Gene', (183, 188))	('FOXF1', 'Gene', '2294', (144, 149))	('FOXF1', 'Gene', (245, 250))	('FOXP1', 'Gene', '27086', (202, 207))	('rs2178146', 'Var', (133, 142))	('FOXF1', 'Gene', '2294', (183, 188))	('FOXF1', 'Gene', '2294', (245, 250))
456525	26085818	The distribution of genotype frequencies for the investigated SNPs was consistent with Hardy-Weinberg equilibrium (P > 0.05), except for FOXF1 rs3111601 (P = 0.013).	('rs3111601', 'Mutation', 'rs3111601', (143, 152))	('FOXF1', 'Gene', '2294', (137, 142))	('rs3111601', 'Var', (143, 152))	('FOXF1', 'Gene', (137, 142))	('Hardy-Weinberg equilibrium', 'Disease', (87, 113))
456526	26085818	The allelic association of the six SNPs with EAC showed significantly increased risk for the minor allele of rs10419226 (CRTC1) (OR = 1.17, P = 0.001) and significantly decreased risk for the minor allele of rs11789015 (BARX1) (OR = 0.85, P = 0.004).	('rs10419226', 'Mutation', 'rs10419226', (109, 119))	('rs11789015', 'Var', (208, 218))	('rs11789015', 'Mutation', 'rs11789015', (208, 218))	('CRTC1', 'Gene', (121, 126))	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('decreased', 'NegReg', (169, 178))	('rs10419226', 'Var', (109, 119))	('CRTC1', 'Gene', '23373', (121, 126))	('EAC', 'Disease', (45, 48))
456527	26085818	The meta-analysis of the original GWAS and the current study revealed more accurate effect estimate and improved level of significance for rs10419226 (CRTC1) (OR = 1.18, P = 6.66 x 10-10) and rs11789015 (BARX1) (OR = 0.83, P = 1.13 x 10-8), and in addition for rs2178146 (FOXF1) (OR = 0.87, P = 9.37 x 10-7), while there was no significant allelic association with EAC in the currently studied population [Table 1].	('EAC', 'Phenotype', 'HP:0011459', (365, 368))	('rs2178146', 'Mutation', 'rs2178146', (261, 270))	('rs10419226', 'Mutation', 'rs10419226', (139, 149))	('rs2178146', 'Var', (261, 270))	('rs11789015', 'Var', (192, 202))	('rs11789015', 'Mutation', 'rs11789015', (192, 202))	('FOXF1', 'Gene', '2294', (272, 277))	('EAC', 'Disease', (365, 368))	('CRTC1', 'Gene', (151, 156))	('rs10419226', 'Var', (139, 149))	('FOXF1', 'Gene', (272, 277))	('CRTC1', 'Gene', '23373', (151, 156))
456528	26085818	The GT genotype for rs10419226 (CRTC1) increased the risk of EAC in comparison with the GG genotype (OR = 1.07, P = 0.428), which became significant for the TT genotype (OR = 1.39, P = 0.001).	('CRTC1', 'Gene', (32, 37))	('rs10419226', 'Var', (20, 30))	('CRTC1', 'Gene', '23373', (32, 37))	('EAC', 'Phenotype', 'HP:0011459', (61, 64))	('rs10419226', 'Mutation', 'rs10419226', (20, 30))	('EAC', 'Disease', (61, 64))
456529	26085818	The rs11789015 (BARX1) AG genotype decreased the risk of EAC in comparison with the AA genotype (OR = 0.95, P = 0.456), this decrease in risk became significant for the genotype GG (OR = 0.57, P = 3.68 x 10-4) [Supplementary Table 2].	('rs11789015', 'Var', (4, 14))	('rs11789015', 'Mutation', 'rs11789015', (4, 14))	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('decreased', 'NegReg', (35, 44))	('EAC', 'Disease', (57, 60))
456530	26085818	In this study two SNPs, rs10419226 (CRTC1) and rs11789015 (BARX1), were replicated to be associated with EAC.	('associated', 'Reg', (89, 99))	('CRTC1', 'Gene', (36, 41))	('rs10419226', 'Var', (24, 34))	('CRTC1', 'Gene', '23373', (36, 41))	('EAC', 'Disease', (105, 108))	('rs10419226', 'Mutation', 'rs10419226', (24, 34))	('rs11789015', 'Var', (47, 57))	('rs11789015', 'Mutation', 'rs11789015', (47, 57))	('EAC', 'Phenotype', 'HP:0011459', (105, 108))
456532	26085818	This was expected, since the present case-control study revealed a significantly increased risk of EAC for the minor allele T of rs10419226 (CRTC1) and a significantly decreased risk of EAC for the minor allele G of rs11789015 (BARX1).	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('rs11789015', 'Mutation', 'rs11789015', (216, 226))	('rs10419226', 'Mutation', 'rs10419226', (129, 139))	('EAC', 'Disease', (99, 102))	('CRTC1', 'Gene', (141, 146))	('rs10419226', 'Var', (129, 139))	('CRTC1', 'Gene', '23373', (141, 146))	('EAC', 'Phenotype', 'HP:0011459', (186, 189))
456533	26085818	In addition, rs2178146 (FOXF1) showed an improved level of significance in the meta-analysis while it did not reach significance in the allelic analysis of the present study cohort.	('improved', 'PosReg', (41, 49))	('FOXF1', 'Gene', '2294', (24, 29))	('FOXF1', 'Gene', (24, 29))	('rs2178146', 'Mutation', 'rs2178146', (13, 22))	('rs2178146', 'Var', (13, 22))
456534	26085818	Rs10419226 is an intronic variant in the CRTC1 gene, which is encoding for CREB-regulated transcription co-activator that has been found previously to be associated with the oncogenic activity.	('CREB', 'Gene', (75, 79))	('CREB', 'Gene', '1385', (75, 79))	('Rs10419226', 'Var', (0, 10))	('CRTC1', 'Gene', (41, 46))	('CRTC1', 'Gene', '23373', (41, 46))	('oncogenic activity', 'CPA', (174, 192))	('associated', 'Reg', (154, 164))	('Rs10419226', 'Mutation', 'Rs10419226', (0, 10))
456535	26085818	The down-regulation or loss of LKB1, a tumor suppressor kinase, activates CRTC1 signaling and the transcriptional activity of the downstream targets of CRTC1.	('CRTC1', 'Gene', '23373', (74, 79))	('CRTC1', 'Gene', '23373', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('LKB1', 'Gene', (31, 35))	('activates', 'PosReg', (64, 73))	('CRTC1', 'Gene', (152, 157))	('LKB1', 'Gene', '6794', (31, 35))	('tumor', 'Disease', (39, 44))	('loss', 'Var', (23, 27))	('CRTC1', 'Gene', (74, 79))	('down-regulation', 'NegReg', (4, 19))	('transcriptional activity', 'MPA', (98, 122))
456536	26085818	In addition, altered LKB1/CRTC1 signaling has been demonstrated to induce a migratory and invasive phenotype in esophageal cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('CRTC1', 'Gene', (26, 31))	('LKB1', 'Gene', (21, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))	('CRTC1', 'Gene', '23373', (26, 31))	('LKB1', 'Gene', '6794', (21, 25))	('induce', 'Reg', (67, 73))	('esophageal cancer', 'Disease', (112, 129))	('altered', 'Var', (13, 20))	('migratory', 'CPA', (76, 85))
456537	26085818	Rs11789015 is located in an intron of BARX1, a homeobox transcription factor.	('Rs11789015', 'Mutation', 'Rs11789015', (0, 10))	('BARX1', 'Gene', (38, 43))	('Rs11789015', 'Var', (0, 10))
456538	26085818	The homolog of BARX1 has been found to be associated with the differentiation of the esophagus and trachea in developing mouse embryos and in addition to be associated with the down-regulation of the Wnt pathway in stomach morphogenesis and differentiation.	('stomach morphogenesis', 'CPA', (215, 236))	('down-regulation', 'NegReg', (177, 192))	('differentiation', 'CPA', (62, 77))	('associated', 'Reg', (42, 52))	('mouse', 'Species', '10090', (121, 126))	('BARX1', 'Gene', (15, 20))	('Wnt pathway', 'Pathway', (200, 211))	('homolog', 'Var', (4, 11))
456543	26085818	This independent and large Dutch case-control study replicated the association of rs10419226 (CRTC1) and rs11789015 (BARX1) with the risk of EAC.	('EAC', 'Disease', (141, 144))	('rs10419226', 'Mutation', 'rs10419226', (82, 92))	('rs11789015', 'Var', (105, 115))	('CRTC1', 'Gene', (94, 99))	('rs11789015', 'Mutation', 'rs11789015', (105, 115))	('EAC', 'Phenotype', 'HP:0011459', (141, 144))	('rs10419226', 'Var', (82, 92))	('CRTC1', 'Gene', '23373', (94, 99))
456569	26021196	A 2012 meta-analysis found a lower annual incidence of esophageal adenocarcinoma in short segment Barrett's patients (< 3cm), than in the overall Barrett's population (0.19% vs. 0.33% per year).	('patients', 'Species', '9606', (108, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('short segment', 'Var', (84, 97))	('lower', 'NegReg', (29, 34))	('esophageal adenocarcinoma', 'Disease', (55, 80))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (55, 80))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (55, 80))
456583	26021196	A 2013 case-control study of approximately 600 patients demonstrated that while the presence of hiatal hernia increased the risk for Barrett's esophagus, it did not increase the risk of neoplastic progression to adenocarcinoma/high-grade dysplasia.	('hiatal hernia', 'Disease', 'MESH:D006551', (96, 109))	("Barrett's esophagus", 'Disease', (133, 152))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (133, 152))	('hiatal hernia', 'Disease', (96, 109))	('patients', 'Species', '9606', (47, 55))	('dysplasia', 'Disease', (238, 247))	('adenocarcinoma', 'Disease', (212, 226))	('hernia', 'Phenotype', 'HP:0100790', (103, 109))	('hiatal hernia', 'Phenotype', 'HP:0002036', (96, 109))	('presence', 'Var', (84, 92))	('dysplasia', 'Disease', 'MESH:D004476', (238, 247))	('adenocarcinoma', 'Disease', 'MESH:D000230', (212, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
456589	26021196	Ulceration within a Barrett's segment is also associated with an increased risk of neoplastic progression to adenocarcinoma/high-grade dysplasia.	('Ulceration', 'Var', (0, 10))	('adenocarcinoma', 'Disease', (109, 123))	('dysplasia', 'Disease', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('adenocarcinoma', 'Disease', 'MESH:D000230', (109, 123))	('dysplasia', 'Disease', 'MESH:D004476', (135, 144))	('neoplastic progression', 'CPA', (83, 105))
456590	26021196	The above mentioned population based case-control study from Northern Ireland also found that patients with ulceration in the Barrett's segment at diagnosis, but not elsewhere in the esophagus, were more likely to progress to cancer or high-grade dysplasia than those without (HR 1.72; 95% CI 1.08-2.76).	('ulceration', 'Var', (108, 118))	('dysplasia', 'Disease', 'MESH:D004476', (247, 256))	('patients', 'Species', '9606', (94, 102))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('dysplasia', 'Disease', (247, 256))	('progress', 'PosReg', (214, 222))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
456621	26021196	In the patients that were confirmed to have low-grade dysplasia on expert review, the risk of neoplastic progression was 9.1% per patient-year with a median follow up of over 3 years.	('patient', 'Species', '9606', (130, 137))	('dysplasia', 'Disease', (54, 63))	('patient', 'Species', '9606', (7, 14))	('dysplasia', 'Disease', 'MESH:D004476', (54, 63))	('low-grade', 'Var', (44, 53))	('patients', 'Species', '9606', (7, 15))
456626	26021196	Finally, in a population-based, cohort study from Denmark the standardized incidence ratio for esophageal adenocarcinoma in patients with low-grade dysplasia was 5.1 per 1000 patient years (95% CI 3.0-8.6).	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('dysplasia', 'Disease', (148, 157))	('low-grade', 'Var', (138, 147))	('patient', 'Species', '9606', (175, 182))	('dysplasia', 'Disease', 'MESH:D004476', (148, 157))	('esophageal adenocarcinoma', 'Disease', (95, 120))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (95, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (95, 120))	('patient', 'Species', '9606', (124, 131))	('patients', 'Species', '9606', (124, 132))
456633	26021196	A nested case-control study demonstrated similar results; loss of p53 (RR 14.0; 95% CI 5.3-37.2) and overexpression of p53 (RR 5.6, 95% CI 3.1-10.3) were associated with a higher risk of progression to adenocarcinoma/high-grade dysplasia.	('overexpression', 'PosReg', (101, 115))	('p53', 'Gene', '7157', (66, 69))	('loss', 'Var', (58, 62))	('dysplasia', 'Disease', (228, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('p53', 'Gene', '7157', (119, 122))	('adenocarcinoma', 'Disease', (202, 216))	('adenocarcinoma', 'Disease', 'MESH:D000230', (202, 216))	('dysplasia', 'Disease', 'MESH:D004476', (228, 237))	('p53', 'Gene', (119, 122))	('p53', 'Gene', (66, 69))
456634	26021196	In addition, biopsies with both low-grade dysplasia and aberrant p53 expression appear to have higher rates of neoplastic progression.	('neoplastic progression', 'CPA', (111, 133))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('dysplasia', 'Disease', 'MESH:D004476', (42, 51))	('aberrant', 'Var', (56, 64))	('expression', 'MPA', (69, 79))	('dysplasia', 'Disease', (42, 51))
456641	26021196	A combination of 17p LOH, 9p LOH, and aneuploidy/tetraploidy was found to have a relative risk of 38.7 (95% CI 10.8-138.5) for neoplastic progression and a 10-year cumulative incidence of adenocarcinoma of nearly 80%.	('aneuploidy/tetraploidy', 'Disease', (38, 60))	('9p LOH', 'Var', (26, 32))	('adenocarcinoma', 'Disease', (188, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('adenocarcinoma', 'Disease', 'MESH:D000230', (188, 202))	('aneuploidy/tetraploidy', 'Disease', 'MESH:D057891', (38, 60))	('neoplastic progression', 'CPA', (127, 149))
456672	26021196	Lastly, examination of germline mutations in patients with Barrett's esophagus and esophageal adenocarcinoma has yielded interesting results.	('germline', 'Var', (23, 31))	('patients', 'Species', '9606', (45, 53))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (83, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	("Barrett's esophagus", 'Disease', (59, 78))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (59, 78))	('esophageal adenocarcinoma', 'Disease', (83, 108))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (83, 108))
456673	26021196	In a model-free linkage analysis comparing both concordant sibling pairs with Barrett's and esophageal adenocarcinoma and discordant sibling pairs, three genes were identified with significant mutations (MSR1, ASCC1, and CTHRC1).	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('ASCC1', 'Gene', '51008', (210, 215))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (92, 117))	('CTHRC1', 'Gene', '115908', (221, 227))	('esophageal adenocarcinoma', 'Disease', (92, 117))	('CTHRC1', 'Gene', (221, 227))	('mutations', 'Var', (193, 202))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (92, 117))	('ASCC1', 'Gene', (210, 215))	('MSR1', 'Gene', (204, 208))	('Barrett', 'Disease', (78, 85))	('MSR1', 'Gene', '4481', (204, 208))
456757	25127938	Nearly half of the patients enrolled in the Registry (48%) had nondysplastic Barrett's esophagus at baseline, and another 48% had dysplasia (21% low grade [LGD], 19% high grade [HGD], and 8% indefinite) (Table 1).	("nondysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (63, 96))	('patients', 'Species', '9606', (19, 27))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (77, 96))	("nondysplastic Barrett's esophagus", 'Disease', (63, 96))	('low grade', 'Var', (145, 154))	('dysplasia', 'Disease', (130, 139))	('dysplasia', 'Disease', 'MESH:D004476', (130, 139))
456849	23857477	Greater proportions of patients on bisphosphonates were also prescribed PPIs and had GERD symptoms than those not on bisphosphonates, although the differences in GERD symptoms were not statistically signifi-cant (Table 2).	('PPIs', 'Var', (72, 76))	('patients', 'Species', '9606', (23, 31))	('bisphosphonates', 'Chemical', 'MESH:D004164', (117, 132))	('GERD symptoms', 'Disease', (85, 98))	('bisphosphonates', 'Chemical', 'MESH:D004164', (35, 50))
456863	23857477	A similar relationship was also present when examining PPI use; we observed an association between oral bisphosphonates and BE among those using PPIs (OR = 2.71; 95% CI: 1.15 - 6.41) but no significant association in patients without PPI use (OR = 1.56; 95% CI: 0.32 - 7.52).	('oral', 'Protein', (99, 103))	('PPIs', 'Var', (145, 149))	('bisphosphonates', 'Chemical', 'MESH:D004164', (104, 119))	('patients', 'Species', '9606', (217, 225))	('BE', 'Phenotype', 'HP:0100580', (124, 126))
456878	23857477	The inhibition of esophageal epithelial stem cells could potentiate the damage of gastroesophageal reflux and lead to inactivation of squamous differentiation and activation of columnar differentiation.	('potentiate', 'PosReg', (57, 67))	('activation', 'PosReg', (163, 173))	('inactivation', 'NegReg', (118, 130))	('damage of gastroesophageal reflux', 'Disease', 'MESH:D005764', (72, 105))	('squamous differentiation', 'CPA', (134, 158))	('inhibition', 'Var', (4, 14))	('damage of gastroesophageal reflux', 'Disease', (72, 105))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (82, 105))	('columnar differentiation', 'CPA', (177, 201))
456907	23857477	In conclusion, among 285 veterans with denitive BE and 1,618 controls, we found a significant association between oral bisphosphonate use and an increased risk of BE, especially among patients with GERD symptoms, those on PPI treatment, or those not taking NSAIDs.	('bisphosphonate', 'Chemical', 'MESH:D004164', (119, 133))	('BE', 'Phenotype', 'HP:0100580', (163, 165))	('patients', 'Species', '9606', (184, 192))	('GERD symptoms', 'Disease', (198, 211))	('PPI', 'Var', (222, 225))	('men', 'Species', '9606', (231, 234))	('BE', 'Phenotype', 'HP:0100580', (48, 50))
456973	23573079	So far, about 6 types of TE are available for different tone enhancement for specific condition: TE-p (enhanced R component), TE-v (suppressed R component similar to NBI system), TE-b (for BE), TE-e (for esophagus), TE-g (for stomach), and TE-c (for intestines).	('BE', 'Phenotype', 'HP:0100580', (189, 191))	('TE-g', 'Var', (216, 220))	('TE-e', 'Var', (194, 198))	('TE-c', 'Gene', (240, 244))	('enhanced', 'PosReg', (103, 111))	('TE-v', 'Var', (126, 130))	('R component', 'MPA', (143, 154))	('TE-c', 'Gene', '7006', (240, 244))
457011	23573079	According to Arima's classification system, most were normal mucosa (79.5) or inflammatory changes (15.4%) in type 1; 64.1% were inflammation and 14.1% were mild-to-moderate dysplasia in type 2; 86.9% were m1~m1 cancers in type 3; and 89.6% were m3 or deeper cancers in type 4.	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancers', 'Disease', (212, 219))	('mild-to-moderate', 'Disease', (157, 173))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('deeper cancers', 'Disease', (252, 266))	('cancers', 'Disease', (259, 266))	('m1~m1', 'Var', (206, 211))	('inflammation', 'Disease', (129, 141))	('inflammation', 'Disease', 'MESH:D007249', (129, 141))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('deeper cancers', 'Disease', 'MESH:D009369', (252, 266))	('dysplasia', 'Disease', (174, 183))	('dysplasia', 'Disease', 'MESH:D004476', (174, 183))
457025	23573079	have shown that the specific FICE modes A (R 550 nm, gain 2; G 500 nm, gain 2; B 470 nm, gain 3) and C (R 540 nm, gain 2; G 415 nm, gain 2; B 415 nm, gain 3) significantly enhanced the visibility of IPCLs of ESCC mucosa.	('enhanced', 'PosReg', (172, 180))	('G 500 nm', 'Var', (61, 69))	('IPCLs', 'Chemical', '-', (199, 204))
457059	23573079	PPV and NPV for HGIN or cancer were 0.29 and 0.87, respectively, for 450-fold magnification and 0.44 and 0.83, respectively, for 1125-fold magnification.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('HGIN', 'Disease', (16, 20))	('1125-fold', 'Var', (129, 138))
457101	23573079	In this study, irregular vascularity and irregularity or absence of microsurface pattern with well-delineated DL were highly associated with carcinomatous gastric mucosa.	('irregularity', 'Var', (41, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('irregular', 'Var', (15, 24))	('carcinomatous gastric mucosa', 'Disease', 'MESH:D055756', (141, 169))	('absence', 'NegReg', (57, 64))	('associated', 'Reg', (125, 135))	('carcinomatous gastric mucosa', 'Disease', (141, 169))	('carcinomatous gastric mucosa', 'Phenotype', 'HP:0031498', (141, 169))
457153	22737419	The highest number of cancer related deaths belongs to lung cancer (1.3 million deaths per year), gastric cancer (803000/year), colorectal cancer (639,000/year), liver cancer (610,000/year) and breast cancer (519,000).	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (201, 207))	('liver cancer', 'Disease', 'MESH:D006528', (162, 174))	('803000/year', 'Var', (114, 125))	('lung cancer', 'Disease', (55, 66))	('cancer', 'Disease', (106, 112))	('colorectal cancer', 'Disease', (128, 145))	('cancer', 'Disease', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('death', 'Disease', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('liver cancer', 'Phenotype', 'HP:0002896', (162, 174))	('liver cancer', 'Disease', (162, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('death', 'Disease', (37, 42))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('gastric cancer', 'Disease', (98, 112))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('death', 'Disease', 'MESH:D003643', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (194, 207))	('cancer', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('cancer', 'Disease', (60, 66))	('death', 'Disease', 'MESH:D003643', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
457172	22737419	Esophageal, gastric and colorectal cancers were defined by C15, C16 and C18-C20, respectively.	('Esophageal', 'Disease', (0, 10))	('C15', 'Gene', (59, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('colorectal cancers', 'Disease', 'MESH:D015179', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('C18-C20', 'Var', (72, 79))	('colorectal cancers', 'Disease', (24, 42))	('gastric', 'Disease', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('C15', 'Gene', '51316', (59, 62))	('C16', 'Var', (64, 67))
457268	16186185	FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer The FAS receptor-ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis.	('FAS', 'Chemical', 'MESH:C038178', (0, 3))	('cervical cancer', 'Disease', (97, 112))	('FAS', 'Chemical', 'MESH:C038178', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('carcinogenesis', 'Disease', 'MESH:D063646', (295, 309))	('participate', 'Reg', (256, 267))	('polymorphism', 'Var', (11, 23))	('FASL', 'Gene', '356', (0, 4))	('tumor', 'Disease', (271, 276))	('carcinogenesis', 'Disease', (295, 309))	('corruption', 'Var', (201, 211))	('FASL', 'Gene', (0, 4))	('increased', 'PosReg', (43, 52))	('cervical cancer', 'Disease', 'MESH:D002583', (97, 112))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
457269	16186185	42:479-484) that functional polymorphisms in FAS and FAS ligand (FASL) are associated with susceptibility to lung cancer and esophageal cancer; however, the mechanisms underlying this association have not been elucidated.	('FAS', 'Chemical', 'MESH:C038178', (65, 68))	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('FASL', 'Gene', '356', (65, 69))	('esophageal cancer', 'Disease', (125, 142))	('FAS', 'Chemical', 'MESH:C038178', (53, 56))	('polymorphisms', 'Var', (28, 41))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('FASL', 'Gene', (65, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('FAS ligand', 'Gene', '356', (53, 63))	('associated', 'Reg', (75, 85))	('FAS ligand', 'Gene', (53, 63))	('susceptibility', 'Reg', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('FAS', 'Chemical', 'MESH:C038178', (45, 48))
457270	16186185	We show that the FAS -1377G, FAS -670A, and FASL -844T variants are expressed more highly on ex vivo-stimulated T cells than the FAS -1377A, FAS -670G, and FASL -844C variants.	('FASL', 'Gene', (156, 160))	('FAS', 'Chemical', 'MESH:C038178', (141, 144))	('variants', 'Var', (55, 63))	('FAS', 'Chemical', 'MESH:C038178', (156, 159))	('FASL', 'Gene', (44, 48))	('FAS', 'Chemical', 'MESH:C038178', (44, 47))	('FAS', 'Chemical', 'MESH:C038178', (129, 132))	('FAS', 'Chemical', 'MESH:C038178', (29, 32))	('FAS -1377G', 'Var', (17, 27))	('FAS -670A', 'Var', (29, 38))	('FASL', 'Gene', '356', (156, 160))	('FASL', 'Gene', '356', (44, 48))	('FAS', 'Chemical', 'MESH:C038178', (17, 20))
457273	16186185	Together, these observations suggest that genetic polymorphisms in the FAS-FASL pathway confer host susceptibility to cervical cancers, which might be caused by immune escape of tumor cells because of enhanced AICD of tumor-specific T cells.	('FASL', 'Gene', '356', (75, 79))	('tumor', 'Disease', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('AICD', 'CPA', (210, 214))	('FASL', 'Gene', (75, 79))	('FAS', 'Chemical', 'MESH:C038178', (71, 74))	('FAS', 'Chemical', 'MESH:C038178', (75, 78))	('susceptibility', 'Reg', (100, 114))	('cervical cancers', 'Disease', (118, 134))	('enhanced', 'PosReg', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('tumor', 'Disease', (218, 223))	('genetic polymorphisms', 'Var', (42, 63))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cervical cancers', 'Disease', 'MESH:D002583', (118, 134))
457274	16186185	Accumulating evidence also demonstrates that AICD is one of the important mechanisms responsible for the increased apoptosis rate among tumor infiltration lymphocytes (TILs), which may protect transformed cells from elimination by antitumor immune responses and, therefore, contribute to carcinogenesis and cancer progression.	('cancer', 'Disease', (307, 313))	('carcinogenesis', 'Disease', 'MESH:D063646', (288, 302))	('AICD', 'Var', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('contribute', 'Reg', (274, 284))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('carcinogenesis', 'Disease', (288, 302))	('tumor', 'Disease', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('increased', 'PosReg', (105, 114))	('apoptosis', 'CPA', (115, 124))	('tumor', 'Disease', (136, 141))
457287	16186185	Single nucleotide polymorphisms (SNPs) in the promoter regions of FASL and FAS have been linked to the differential expression of these two genes.	('expression', 'MPA', (116, 126))	('FAS', 'Chemical', 'MESH:C038178', (66, 69))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('FASL', 'Gene', '356', (66, 70))	('FAS', 'Gene', (75, 78))	('FAS', 'Chemical', 'MESH:C038178', (75, 78))	('FASL', 'Gene', (66, 70))	('linked', 'Reg', (89, 95))
457289	16186185	In regards to the FAS gene, G A transition at position -1377 and A G transition at position -670 in the promoter region destroy stimulatory protein 1 and signal transducer and activator of transcription 1 protein binding element, respectively, and thus diminish promoter activity and decrease FAS expression.	('FAS', 'Chemical', 'MESH:C038178', (18, 21))	('binding', 'Interaction', (213, 220))	('stimulatory', 'MPA', (128, 139))	('FAS', 'Chemical', 'MESH:C038178', (293, 296))	('transition at', 'Var', (32, 45))	('destroy', 'NegReg', (120, 127))	('signal transducer and activator of transcription 1', 'Gene', '6772', (154, 204))	('FAS', 'Protein', (293, 296))	('diminish', 'NegReg', (253, 261))	('expression', 'MPA', (297, 307))	('promoter activity', 'MPA', (262, 279))	('decrease', 'NegReg', (284, 292))
457290	16186185	We have recently shown that these functional polymorphisms in FASL and FAS have great impact on susceptibility to cancers of the esophagus and lung.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers of the esophagus', 'Disease', (114, 138))	('FAS', 'Gene', (71, 74))	('FAS', 'Chemical', 'MESH:C038178', (62, 65))	('FAS', 'Chemical', 'MESH:C038178', (71, 74))	('susceptibility', 'Reg', (96, 110))	('FASL', 'Gene', '356', (62, 66))	('polymorphisms', 'Var', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('impact', 'Reg', (86, 92))	('FASL', 'Gene', (62, 66))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (114, 138))	('lung', 'Disease', (143, 147))
457291	16186185	The effect of the FAS polymorphism on the risk of cervical cancer has been reported, but the studies were limited to the -670A G polymorphism, and the results were controversial.	('FAS', 'Chemical', 'MESH:C038178', (18, 21))	('cervical cancer', 'Disease', 'MESH:D002583', (50, 65))	('cervical cancer', 'Disease', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('-670A G', 'Var', (121, 128))
457292	16186185	To date, no study has been reported to examine the association between functional polymorphisms in FASL and the risk for the development of cervical cancer.	('FASL', 'Gene', '356', (99, 103))	('polymorphisms', 'Var', (82, 95))	('cervical cancer', 'Disease', (140, 155))	('cervical cancer', 'Disease', 'MESH:D002583', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('FASL', 'Gene', (99, 103))
457293	16186185	We wanted to determine whether the polymorphisms in FAS-FASL have effects on the expression of FAS and FASL and AICD of T cells induced by PHA and HeLa cells in vitro.	('FASL', 'Gene', (56, 60))	('FAS', 'Chemical', 'MESH:C038178', (103, 106))	('FAS', 'Chemical', 'MESH:C038178', (52, 55))	('FAS', 'Chemical', 'MESH:C038178', (56, 59))	('FAS', 'Gene', (95, 98))	('FASL', 'Gene', '356', (103, 107))	('FASL', 'Gene', '356', (56, 60))	('FAS', 'Chemical', 'MESH:C038178', (95, 98))	('polymorphisms', 'Var', (35, 48))	('HeLa', 'CellLine', 'CVCL:0030', (147, 151))	('FASL', 'Gene', (103, 107))	('expression', 'MPA', (81, 91))	('effects', 'Reg', (66, 73))
457294	16186185	We also performed a case-control study to examine the association between FAS-FASL polymorphism and the risk of cervical cancer.	('polymorphism', 'Var', (83, 95))	('FASL', 'Gene', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cervical cancer', 'Disease', (112, 127))	('cervical cancer', 'Disease', 'MESH:D002583', (112, 127))	('FAS', 'Chemical', 'MESH:C038178', (74, 77))	('FAS', 'Chemical', 'MESH:C038178', (78, 81))	('association', 'Interaction', (54, 65))	('FASL', 'Gene', '356', (78, 82))
457301	16186185	The allelic frequencies for the FAS -1377A and FAS -670G alleles were 0.317 and 0.343 in controls, respectively, compared with 0.312 and 0.332 in patients.	('FAS', 'Chemical', 'MESH:C038178', (32, 35))	('FAS -1377A', 'Var', (32, 42))	('FAS -670G', 'Var', (47, 56))	('FAS', 'Chemical', 'MESH:C038178', (47, 50))	('patients', 'Species', '9606', (146, 154))
457310	16186185	Because of tight linkage, the haplotype of FAS -1377G A and FAS -670A G did not further increase the risk of the cancer (unpublished data).	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('FAS -1377G A', 'Var', (43, 55))	('cancer', 'Disease', (113, 119))	('FAS', 'Chemical', 'MESH:C038178', (43, 46))	('FAS', 'Chemical', 'MESH:C038178', (60, 63))	('FAS -670A G', 'Var', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
457311	16186185	In view of the fact that FAS and FASL work together in apoptotic cell death, we examined whether there was a statistical interaction between the SNP in FAS and FASL that was associated with the risk of cervical cancer.	('associated', 'Reg', (174, 184))	('FASL', 'Gene', (160, 164))	('FASL', 'Gene', (33, 37))	('SNP', 'Var', (145, 148))	('FAS', 'Chemical', 'MESH:C038178', (152, 155))	('FAS', 'Chemical', 'MESH:C038178', (160, 163))	('FAS', 'Chemical', 'MESH:C038178', (33, 36))	('cervical cancer', 'Disease', (202, 217))	('cervical cancer', 'Disease', 'MESH:D002583', (202, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('FASL', 'Gene', '356', (160, 164))	('FASL', 'Gene', '356', (33, 37))	('FAS', 'Chemical', 'MESH:C038178', (25, 28))
457315	16186185	It was found that the proportion of CD25+/CD4+ cells (mean +- SD, n = 40) in the PBMC cultures with PHA was 50.83 +- 14.08%, which was significantly higher than that in the cultures without PHA (2.27 +- 0.88%; P < 0.001).	('CD25', 'Gene', (36, 40))	('CD4', 'Gene', (42, 45))	('CD25', 'Gene', '3559', (36, 40))	('CD4', 'Gene', '920', (42, 45))	('PHA', 'Var', (100, 103))	('higher', 'PosReg', (149, 155))
457316	16186185	In parallel, the IL-2 level (mean +- SD, n = 40) in the PBMC culture media with PHA was significantly higher than that in the PBMC culture media without PHA (191.25 +- 66.	('higher', 'PosReg', (102, 108))	('PHA', 'Var', (80, 83))	('IL-2', 'Gene', (17, 21))	('IL-2', 'Gene', '3558', (17, 21))
457320	16186185	Moreover, neither the elevated population of CD25+/CD4+ cells nor IL-2 concentration in the media was correlated to FAS -1377, FAS -670, or FASL -844 genotypes (unpublished data).	('FAS', 'Chemical', 'MESH:C038178', (140, 143))	('FASL', 'Gene', '356', (140, 144))	('CD4', 'Gene', (51, 54))	('IL-2', 'Gene', '3558', (66, 70))	('CD4', 'Gene', '920', (51, 54))	('FAS', 'Chemical', 'MESH:C038178', (127, 130))	('IL-2', 'Gene', (66, 70))	('CD25', 'Gene', (45, 49))	('FAS -1377', 'Var', (116, 125))	('FAS -670', 'Var', (127, 135))	('FASL', 'Gene', (140, 144))	('CD25', 'Gene', '3559', (45, 49))	('FAS', 'Chemical', 'MESH:C038178', (116, 119))
457324	16186185	The FAS -1377GG or GA genotype had a significantly heightened FAS expression levels (mean +- SD) compared with the AA genotype (66.63 +- 3.53% [n = 12] and 57.92 +- 2.61% [n = 22] vs. 46.31 +- 5.02% [n = 6]; P = 0.002 and 0.048, respectively), whereas the levels were not significantly different (P = 0.355) between the GG and GA genotype.	('FAS', 'Chemical', 'MESH:C038178', (4, 7))	('FAS -1377GG', 'Var', (4, 15))	('heightened', 'PosReg', (51, 61))	('FAS expression levels', 'MPA', (62, 83))	('FAS', 'Chemical', 'MESH:C038178', (62, 65))
457329	16186185	These findings clearly demonstrated that the investigated polymorphisms in the promoter region of FAS and FASL have a substantial impact on the activation-induced expression of FAS and FASL on T cells.	('FAS', 'Chemical', 'MESH:C038178', (185, 188))	('FASL', 'Gene', '356', (106, 110))	('impact', 'Reg', (130, 136))	('FAS', 'Gene', (177, 180))	('FAS', 'Chemical', 'MESH:C038178', (177, 180))	('FASL', 'Gene', '356', (185, 189))	('FASL', 'Gene', (106, 110))	('polymorphisms', 'Var', (58, 71))	('FAS', 'Gene', (98, 101))	('FASL', 'Gene', (185, 189))	('FAS', 'Chemical', 'MESH:C038178', (98, 101))	('activation-induced expression', 'MPA', (144, 173))	('FAS', 'Chemical', 'MESH:C038178', (106, 109))
457337	16186185	The FAS-FASL system regulates the AICD process of T cells, and genetic variations in these cell death pathway genes may thus influence susceptibility to cancers.	('genetic variations', 'Var', (63, 81))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('FAS', 'Chemical', 'MESH:C038178', (4, 7))	('cancers', 'Disease', (153, 160))	('FASL', 'Gene', (8, 12))	('FAS', 'Chemical', 'MESH:C038178', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('FASL', 'Gene', '356', (8, 12))	('influence', 'Reg', (125, 134))
457338	16186185	Functional germline and somatic mutations in the FAS gene, and perhaps also in the FASL gene, that impair apoptotic signal transduction are associated with susceptibility to cancer.	('susceptibility', 'Reg', (156, 170))	('impair', 'NegReg', (99, 105))	('associated', 'Reg', (140, 150))	('FAS', 'Chemical', 'MESH:C038178', (83, 86))	('FAS', 'Chemical', 'MESH:C038178', (49, 52))	('FASL', 'Gene', '356', (83, 87))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('germline', 'Var', (11, 19))	('mutations', 'Var', (32, 41))	('FASL', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('apoptotic signal transduction', 'MPA', (106, 135))	('FAS', 'Gene', (49, 52))
457339	16186185	We have recently reported that functional SNPs in FAS and FASL increase the risk of esophageal cancer and lung cancer in a Chinese population.	('increase', 'PosReg', (63, 71))	('lung cancer', 'Disease', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('functional SNPs', 'Var', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('FAS', 'Gene', (50, 53))	('FASL', 'Gene', '356', (58, 62))	('FAS', 'Chemical', 'MESH:C038178', (50, 53))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('FASL', 'Gene', (58, 62))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('FAS', 'Chemical', 'MESH:C038178', (58, 61))
457345	16186185	FASL -844T C polymorphism has been shown to have a substantial impact on promoter activity of the FASL genes in an in vitro assay system because it is located in a binding motif for transcription factor CAAT/enhancer-binding protein beta.	('polymorphism', 'Var', (13, 25))	('FASL', 'Gene', '356', (98, 102))	('FASL', 'Gene', '356', (0, 4))	('FASL', 'Gene', (98, 102))	('FASL', 'Gene', (0, 4))	('impact', 'Reg', (63, 69))	('promoter activity', 'MPA', (73, 90))
457347	16186185	Our data in the present study provide evidence for the first time that the -844T C polymorphism in FASL strongly influences the expression of FASL ex vivo on T cells stimulated by either cervical cancer cells or PHA.	('influences', 'Reg', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('FASL', 'Gene', '356', (99, 103))	('the -844T C', 'Var', (71, 82))	('FASL', 'Gene', '356', (142, 146))	('FASL', 'Gene', (99, 103))	('expression', 'MPA', (128, 138))	('FASL', 'Gene', (142, 146))	('cervical cancer', 'Disease', (187, 202))	('cervical cancer', 'Disease', 'MESH:D002583', (187, 202))
457351	16186185	On the other hand, it has been shown that various types of tumors express FASL, and aberrant FASL expression has been linked to cervical carcinogenesis and tumor progression.	('FASL', 'Gene', '356', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (137, 151))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('FASL', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('linked', 'Reg', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('FASL', 'Gene', '356', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('carcinogenesis', 'Disease', (137, 151))	('tumor', 'Disease', (156, 161))	('aberrant', 'Var', (84, 92))	('FASL', 'Gene', (93, 97))	('expression', 'MPA', (98, 108))
457355	16186185	We did not observe any substantial association between the investigated functional polymorphisms in FAS and the rate of AICD of T cells stimulated by PHA or HeLa cells, although the polymorphisms did somewhat influence the expression of the FAS gene ex vivo on T cells.	('FAS', 'Gene', (100, 103))	('influence', 'Reg', (209, 218))	('polymorphisms', 'Var', (83, 96))	('HeLa', 'CellLine', 'CVCL:0030', (157, 161))	('FAS', 'Gene', (241, 244))	('FAS', 'Chemical', 'MESH:C038178', (241, 244))	('FAS', 'Chemical', 'MESH:C038178', (100, 103))
457356	16186185	This finding was consistent with the population data in the present study but was inconsistent with our previous results from large molecular epidemiological studies on esophageal and lung cancer showing a positive association between the FAS polymorphisms and risk of these cancers.	('polymorphisms', 'Var', (243, 256))	('esophageal', 'Disease', 'MESH:D004941', (169, 179))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('FAS', 'Gene', (239, 242))	('FAS', 'Chemical', 'MESH:C038178', (239, 242))	('esophageal', 'Disease', (169, 179))	('lung cancer', 'Disease', (184, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('cancers', 'Disease', (275, 282))
457365	16186185	Although little is known about polymorphisms in FASL and susceptibility to cervical cancer, at least three studies have been published regarding the FAS -670 polymorphism and the risk of cervical cancer.	('polymorphism', 'Var', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cervical cancer', 'Disease', 'MESH:D002583', (75, 90))	('FAS', 'Chemical', 'MESH:C038178', (48, 51))	('FAS', 'Chemical', 'MESH:C038178', (149, 152))	('cervical cancer', 'Disease', (75, 90))	('FAS -670', 'Gene', (149, 157))	('FASL', 'Gene', '356', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('FASL', 'Gene', (48, 52))	('cervical cancer', 'Disease', (187, 202))	('cervical cancer', 'Disease', 'MESH:D002583', (187, 202))
457366	16186185	conducted a study in a Chinese population in Taiwan and reported that the FAS -670A allele was associated with an increased risk of squamous intraepithelial lesions and squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 192))	('squamous intraepithelial lesions', 'Disease', (132, 164))	('squamous intraepithelial lesions', 'Disease', 'MESH:D000081483', (132, 164))	('squamous cell carcinoma', 'Disease', (169, 192))	('FAS', 'Chemical', 'MESH:C038178', (74, 77))	('FAS -670A', 'Var', (74, 83))
457369	16186185	In this study with 615 healthy controls, we observed a frequency of 12.2% for the variant FAS -670GG genotype, which is not significantly different from that reported by Dybikowska et al.	('variant', 'Var', (82, 89))	('FAS -670GG', 'Gene', (90, 100))	('FAS', 'Chemical', 'MESH:C038178', (90, 93))
457370	16186185	Both FAS -670A G and FAS -1377G A SNPs were shown to have a biological impact on the transcriptional activity of the FAS gene, although the effect of -670A G is still ambiguous.	('impact', 'Reg', (71, 77))	('FAS', 'Chemical', 'MESH:C038178', (117, 120))	('transcriptional activity', 'MPA', (85, 109))	('FAS gene', 'Gene', (117, 125))	('FAS -1377G A', 'Var', (21, 33))	('FAS -670A G', 'Var', (5, 16))	('FAS', 'Chemical', 'MESH:C038178', (5, 8))	('FAS', 'Chemical', 'MESH:C038178', (21, 24))
457371	16186185	We found a heightened expression of FAS on T cells stimulated by PHA that was associated with either the FAS -1377AA or FAS -670GG genotype.	('FAS -1377AA', 'Var', (105, 116))	('heightened', 'PosReg', (11, 21))	('FAS', 'Gene', (36, 39))	('FAS', 'Chemical', 'MESH:C038178', (105, 108))	('FAS', 'Chemical', 'MESH:C038178', (36, 39))	('FAS -670GG', 'Var', (120, 130))	('expression', 'MPA', (22, 32))	('FAS', 'Chemical', 'MESH:C038178', (120, 123))
457374	16186185	In conclusion, our study demonstrates an association between the genotype and phenotype of FASL polymorphism and suggests that heightened AICD of T lymphocytes and/or counterattack of tumor cells against TILs resulting from functional polymorphisms in the FAS-FASL pathway may be involved in the mechanism underlying an individual's susceptibility to the development of cervical cancer.	('FASL', 'Gene', '356', (91, 95))	('polymorphisms', 'Var', (235, 248))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('polymorphism', 'Var', (96, 108))	('FASL', 'Gene', '356', (260, 264))	('cervical cancer', 'Disease', (370, 385))	('association', 'Interaction', (41, 52))	('cervical cancer', 'Disease', 'MESH:D002583', (370, 385))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('FAS', 'Chemical', 'MESH:C038178', (91, 94))	('FASL', 'Gene', (260, 264))	('tumor', 'Disease', (184, 189))	('FASL', 'Gene', (91, 95))	('FAS', 'Chemical', 'MESH:C038178', (256, 259))	('FAS', 'Chemical', 'MESH:C038178', (260, 263))
457402	16186185	The association between FAS and FASL polymorphisms and the risk of cervical carcinoma was estimated using ORs and their 95% CIs, which were calculated by unconditional logistic regression.	('polymorphisms', 'Var', (37, 50))	('cervical carcinoma', 'Disease', 'MESH:D002575', (67, 85))	('FAS', 'Chemical', 'MESH:C038178', (24, 27))	('FASL', 'Gene', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('FAS', 'Chemical', 'MESH:C038178', (32, 35))	('FASL', 'Gene', '356', (32, 36))	('cervical carcinoma', 'Disease', (67, 85))	('FAS', 'Gene', (24, 27))
457417	32695851	3 presents the transparent views of docked complexes showing ligand-receptor interactions in the binding pocket for the best selected active compounds (L1, L4, L6, L11, L15, L16, L17, L18, L19, and L20) against EC-109 (receptor) using Pymol which was based on the lowest IC50 in the range of <= 10 muM.	('L15', 'Gene', '28901', (169, 172))	('interactions', 'Interaction', (77, 89))	('L20', 'Gene', '28876', (198, 201))	('L11', 'Gene', (164, 167))	('L17', 'Gene', (179, 182))	('L16', 'Gene', (174, 177))	('L19', 'Gene', '28940', (189, 192))	('L11', 'Gene', '28943', (164, 167))	('L17', 'Gene', '28889', (179, 182))	('EC-109', 'Chemical', '-', (211, 217))	('L18', 'Gene', (184, 187))	('L15', 'Gene', (169, 172))	('L16', 'Gene', '28875', (174, 177))	('L18', 'Gene', '28939', (184, 187))	('L19', 'Gene', (189, 192))	('L20', 'Gene', (198, 201))	('L1', 'Var', (152, 154))
457421	32695851	The datasets of the compounds L5and L18that formed one hydrogen bond each are also listed in Table 4.	('hydrogen bond', 'MPA', (55, 68))	('L18', 'Gene', '28939', (36, 39))	('L5and', 'Var', (30, 35))	('hydrogen', 'Chemical', 'MESH:D006859', (55, 63))	('L18', 'Gene', (36, 39))
457422	32695851	For L5the hydrogen bond datasets include (SER-26, LIG: N) and (GLU-108, LIG: O) with the bond distance of 2.2 and 3.3 respectively, while L8 formed four hydrogen bonds (PHE-14, LIG: O; ILE-103, LIG: N; ASP-104, LIG: N; SER-106, LIG: H) with bond distance 2.9, 3.6, 3.4, 2.1 respectively (Table 4).	('PHE-14', 'Var', (169, 175))	('GLU', 'Chemical', 'MESH:D018698', (63, 66))	('LIG', 'Gene', '3093', (72, 75))	('LIG', 'Gene', '3093', (228, 231))	('LIG', 'Gene', (72, 75))	('LIG', 'Gene', (228, 231))	('LIG', 'Gene', '3093', (211, 214))	('PHE', 'Chemical', 'MESH:D010649', (169, 172))	('ASP', 'Chemical', 'MESH:D001224', (202, 205))	('LIG', 'Gene', (211, 214))	('SER', 'Chemical', 'MESH:D012694', (219, 222))	('hydrogen', 'Chemical', 'MESH:D006859', (10, 18))	('LIG', 'Gene', '3093', (177, 180))	('LIG', 'Gene', (177, 180))	('LIG', 'Gene', '3093', (50, 53))	('hydrogen', 'Chemical', 'MESH:D006859', (153, 161))	('LIG', 'Gene', (194, 197))	('LIG', 'Gene', '3093', (194, 197))	('LIG', 'Gene', (50, 53))	('ILE', 'Chemical', 'MESH:D007532', (185, 188))	('SER', 'Chemical', 'MESH:D012694', (42, 45))
457423	32695851	The datasets of compounds L1-L4, L6-L7, L9-L19, and L20presented in Table 4 were with neither hydrogen bonding nor any bond distance.	('L6-L7', 'Var', (33, 38))	('L1-L4', 'Var', (26, 31))	('L19', 'Gene', '28940', (43, 46))	('L19', 'Gene', (43, 46))	('hydrogen', 'Chemical', 'MESH:D006859', (94, 102))	('L20', 'Gene', (52, 55))	('L20', 'Gene', '28876', (52, 55))
457436	32226522	In this study, we explored the role of miR-34a-5p in ESCC and the possible regulatory mechanism.	('miR-34a-5p', 'Chemical', '-', (39, 49))	('miR-34a-5p', 'Var', (39, 49))	('ESCC', 'Disease', (53, 57))
457439	32226522	By bioinformatics analysis and luciferase reporter assay, miR-34a-5p was identified for directly targeting LEF1.	('LEF1', 'Gene', (107, 111))	('miR-34a-5p', 'Chemical', '-', (58, 68))	('miR-34a-5p', 'Var', (58, 68))	('LEF1', 'Gene', '51176', (107, 111))
457440	32226522	Then we investigated the expression of miR-34a-5p and LEF1 in ESCC.	('miR-34a-5p', 'Var', (39, 49))	('LEF1', 'Gene', '51176', (54, 58))	('LEF1', 'Gene', (54, 58))	('miR-34a-5p', 'Chemical', '-', (39, 49))	('ESCC', 'Disease', (62, 66))
457442	32226522	Overexpression of miR-34a-5p could inhibit proliferation, migration, invasion and EMT of ESCC cells.	('miR-34a-5p', 'Chemical', '-', (18, 28))	('EMT of ESCC cells', 'CPA', (82, 99))	('invasion', 'CPA', (69, 77))	('proliferation', 'CPA', (43, 56))	('miR-34a-5p', 'Var', (18, 28))	('inhibit', 'NegReg', (35, 42))	('migration', 'CPA', (58, 67))
457443	32226522	The rescue experiment showed that re-expression of LEF1 reversed the suppressive effect caused by miR-34a-5p.	('miR-34a-5p', 'Var', (98, 108))	('miR-34a-5p', 'Chemical', '-', (98, 108))	('LEF1', 'Gene', '51176', (51, 55))	('LEF1', 'Gene', (51, 55))	('suppressive effect', 'MPA', (69, 87))
457444	32226522	At last, we found that miR-34a-5p could suppress Hippo-YAP1/TAZ signaling pathway in ESCC.	('TAZ', 'Gene', (60, 63))	('miR-34a-5p', 'Var', (23, 33))	('YAP1', 'Gene', (55, 59))	('YAP1', 'Gene', '10413', (55, 59))	('suppress', 'NegReg', (40, 48))	('ESCC', 'Disease', (85, 89))	('miR-34a-5p', 'Chemical', '-', (23, 33))	('TAZ', 'Gene', '6901', (60, 63))
457445	32226522	Conclusion: Our results indicate miR-34a-5p inhibits proliferation, migration, invasion and EMT in ESCC by targeting LEF1 and suppressing the Hippo-YAP1/TAZ signaling pathway, which may provide a new antitumor strategy to delay ESCC progress.	('ESCC', 'Disease', (228, 232))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('suppressing', 'NegReg', (126, 137))	('targeting', 'Reg', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('YAP1', 'Gene', '10413', (148, 152))	('ESCC', 'Disease', (99, 103))	('proliferation', 'CPA', (53, 66))	('LEF1', 'Gene', '51176', (117, 121))	('inhibits', 'NegReg', (44, 52))	('EMT', 'CPA', (92, 95))	('miR-34a-5p', 'Var', (33, 43))	('YAP1', 'Gene', (148, 152))	('invasion', 'CPA', (79, 87))	('TAZ', 'Gene', '6901', (153, 156))	('migration', 'CPA', (68, 77))	('TAZ', 'Gene', (153, 156))	('miR-34a-5p', 'Chemical', '-', (33, 43))	('tumor', 'Disease', (204, 209))	('LEF1', 'Gene', (117, 121))
457458	32226522	In this study, we identified LEF1 as a direct target of miR-34a-5p via binding to the 3'-UTR of LEF1.	('LEF1', 'Gene', (29, 33))	('LEF1', 'Gene', '51176', (96, 100))	('LEF1', 'Gene', (96, 100))	('binding', 'Interaction', (71, 78))	('miR-34a-5p', 'Var', (56, 66))	('LEF1', 'Gene', '51176', (29, 33))	('miR-34a-5p', 'Chemical', '-', (56, 66))
457459	32226522	Inhibition of LEF1 by miR-34a-5p could suppress the migration, invasion and epithelial-mesenchymal transition (EMT) of ESCC.	('migration', 'CPA', (52, 61))	('miR-34a-5p', 'Var', (22, 32))	('miR-34a-5p', 'Chemical', '-', (22, 32))	('LEF1', 'Gene', '51176', (14, 18))	('invasion', 'CPA', (63, 71))	('suppress', 'NegReg', (39, 47))	('Inhibition', 'Var', (0, 10))	('epithelial-mesenchymal transition', 'CPA', (76, 109))	('LEF1', 'Gene', (14, 18))
457460	32226522	What's more, miR-34a-5p could inactivate Hippo-YAP/TAZ signaling pathway.	('inactivate', 'NegReg', (30, 40))	('miR-34a-5p', 'Var', (13, 23))	('TAZ', 'Gene', '6901', (51, 54))	('YAP', 'Gene', '10413', (47, 50))	('miR-34a-5p', 'Chemical', '-', (13, 23))	('TAZ', 'Gene', (51, 54))	('YAP', 'Gene', (47, 50))
457461	32226522	Targeting miR-34a-5p and LEF1 may provide a new antitumor strategy to delay ESCC progress.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('miR-34a-5p', 'Chemical', '-', (10, 20))	('tumor', 'Disease', (52, 57))	('ESCC progress', 'Disease', (76, 89))	('LEF1', 'Gene', '51176', (25, 29))	('LEF1', 'Gene', (25, 29))	('miR-34a-5p', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
457477	32226522	For the rescue study, cells were co-transfected with miR-34a-5p mimic and LEF1 expression plasmid without the 3  UTR (to avoid downregulation by miR-34a-5p).	('miR-34a-5p', 'Var', (53, 63))	('miR-34a-5p', 'Chemical', '-', (145, 155))	('LEF1', 'Gene', '51176', (74, 78))	('LEF1', 'Gene', (74, 78))	('miR-34a-5p', 'Chemical', '-', (53, 63))
457478	32226522	The wild-type sequence containing the predicted target sites of miR-34a-5p in the 3  UTR of LEF1 mRNA was synthesized by Heyuan Bio-technology Company (Shanghai, China).	('miR-34a-5p', 'Var', (64, 74))	('LEF1', 'Gene', (92, 96))	('LEF1', 'Gene', '51176', (92, 96))	('miR-34a-5p', 'Chemical', '-', (64, 74))
457485	32226522	However, knockdown of LEF1 in Eca109 and TE1 cells decreased the migratory and invasive abilities compared to those in the corresponding groups (Fig.	('LEF1', 'Gene', (22, 26))	('LEF1', 'Gene', '51176', (22, 26))	('knockdown', 'Var', (9, 18))	('decreased', 'NegReg', (51, 60))
457486	32226522	The CCK-8 assays indicated that LEF1 overexpression promoted the proliferation of ESCC cells (Fig.	('proliferation', 'CPA', (65, 78))	('LEF1', 'Gene', (32, 36))	('ESCC', 'Disease', (82, 86))	('overexpression', 'Var', (37, 51))	('promoted', 'PosReg', (52, 60))	('LEF1', 'Gene', '51176', (32, 36))
457494	32226522	Next, to validate that LEF1 was a direct target of miR-34a-5p, a dual-luciferase reporter assay was performed.	('miR-34a-5p', 'Var', (51, 61))	('LEF1', 'Gene', '51176', (23, 27))	('LEF1', 'Gene', (23, 27))	('miR-34a-5p', 'Chemical', '-', (51, 61))
457495	32226522	Results showed that co-transfection of pmirGLO-LEF1-wt and miR-34a-5p mimic led to a significant decrease in luciferase activity compared with the NC group, whereas co-transfection of pmirGLO-LEF1-mut and miR-34a-5p mimic had no effect on luciferase activity (Fig.	('LEF1', 'Gene', '51176', (192, 196))	('LEF1', 'Gene', '51176', (47, 51))	('LEF1', 'Gene', (47, 51))	('luciferase', 'Enzyme', (109, 119))	('miR-34a-5p', 'Chemical', '-', (205, 215))	('LEF1', 'Gene', (192, 196))	('miR-34a-5p', 'Var', (59, 69))	('decrease', 'NegReg', (97, 105))	('activity', 'MPA', (120, 128))	('miR-34a-5p', 'Chemical', '-', (59, 69))
457496	32226522	To further confirm the functional effect of miR-34a-5p on LEF1, we overexpressed miR-34a-5p in Eca109 and TE1 cell lines.	('miR-34a-5p', 'Var', (81, 91))	('miR-34a-5p', 'Chemical', '-', (44, 54))	('miR-34a-5p', 'Chemical', '-', (81, 91))	('LEF1', 'Gene', '51176', (58, 62))	('LEF1', 'Gene', (58, 62))
457501	32226522	As expected, we found that miR-34a-5p was significantly decreased in most of the ESCC tissue compared with that in the matched controls (Fig.	('ESCC', 'Disease', (81, 85))	('miR-34a-5p', 'Var', (27, 37))	('decreased', 'NegReg', (56, 65))	('miR-34a-5p', 'Chemical', '-', (27, 37))
457503	32226522	Linear regression analysis showed a possible relevance between miR-34a-5p and LEF1 in the clinical tissues (Fig.	('LEF1', 'Gene', '51176', (78, 82))	('LEF1', 'Gene', (78, 82))	('miR-34a-5p', 'Var', (63, 73))	('miR-34a-5p', 'Chemical', '-', (63, 73))
457505	32226522	LEF1 was obviously upregulated in the Eca109 and TE1 compared with the HEEC (Fig.	('upregulated', 'PosReg', (19, 30))	('Eca109', 'Var', (38, 44))	('LEF1', 'Gene', '51176', (0, 4))	('LEF1', 'Gene', (0, 4))
457509	32226522	Using CCK-8 assay, overexpression of miR-34a-5p significantly inhibited cell proliferation, while downregulation of miR-34a-5p promoted cell proliferation of Eca109 and TE1 cell lines (Fig.	('overexpression', 'PosReg', (19, 33))	('miR-34a-5p', 'Var', (37, 47))	('downregulation', 'NegReg', (98, 112))	('miR-34a-5p', 'Chemical', '-', (37, 47))	('promoted', 'PosReg', (127, 135))	('cell proliferation', 'CPA', (72, 90))	('inhibited', 'NegReg', (62, 71))	('miR-34a-5p', 'Chemical', '-', (116, 126))	('miR-34a-5p', 'Gene', (116, 126))	('cell proliferation', 'CPA', (136, 154))
457510	32226522	Using Transwell assay, we found that miR-34a-5p overexpression significantly inhibited the migration and invasion of ESCC cells, whereas downregulation of miR-34a-5p promoted the migration and invasion of ESCC cells (Fig.	('miR-34a-5p', 'Chemical', '-', (155, 165))	('miR-34a-5p', 'Var', (37, 47))	('migration', 'CPA', (179, 188))	('inhibited', 'NegReg', (77, 86))	('downregulation', 'NegReg', (137, 151))	('miR-34a-5p', 'Chemical', '-', (37, 47))	('miR-34a-5p', 'Var', (155, 165))	('promoted', 'PosReg', (166, 174))	('ESCC', 'Disease', (205, 209))	('invasion', 'CPA', (193, 201))
457511	32226522	Results of wound healing assay suggested that miR-34a-5p inhibited motility of Eca109 and TE1 cell lines (Fig.	('inhibited', 'NegReg', (57, 66))	('motility of Eca109', 'CPA', (67, 85))	('miR-34a-5p', 'Chemical', '-', (46, 56))	('miR-34a-5p', 'Var', (46, 56))
457512	32226522	Our study demonstrated that overexpression of miR-34a-5p significantly increased the epithelial marker of E-cadherin, and reduced the mesenchymal cell marker of N-cadherin (Fig.	('miR-34a-5p', 'Var', (46, 56))	('N-cadherin', 'Gene', (161, 171))	('miR-34a-5p', 'Chemical', '-', (46, 56))	('N-cadherin', 'Gene', '1000', (161, 171))	('E-cadherin', 'Gene', (106, 116))	('increased', 'PosReg', (71, 80))	('E-cadherin', 'Gene', '999', (106, 116))	('reduced', 'NegReg', (122, 129))	('mesenchymal cell', 'CPA', (134, 150))
457513	32226522	Taken together, our findings suggested that miR-34a-5p could significantly repress the proliferation, migration, invasion, and EMT of ESCC cells.	('invasion', 'CPA', (113, 121))	('miR-34a-5p', 'Var', (44, 54))	('proliferation', 'CPA', (87, 100))	('ESCC', 'Disease', (134, 138))	('miR-34a-5p', 'Chemical', '-', (44, 54))	('migration', 'CPA', (102, 111))	('repress', 'NegReg', (75, 82))	('EMT', 'CPA', (127, 130))
457514	32226522	To further demonstrate whether LEF1 could mediate the effect of miR-34a-5p on ESCC cells, a rescue strategy was employed.	('miR-34a-5p', 'Var', (64, 74))	('LEF1', 'Gene', '51176', (31, 35))	('LEF1', 'Gene', (31, 35))	('miR-34a-5p', 'Chemical', '-', (64, 74))
457516	32226522	Through cell migration and invasion assays, we found that exogenous LEF1 expression reversed the suppression of migration and invasion caused by miR-34a-4p overexpression (Fig 6a, b, c).	('LEF1', 'Gene', '51176', (68, 72))	('overexpression', 'PosReg', (156, 170))	('suppression', 'NegReg', (97, 108))	('LEF1', 'Gene', (68, 72))	('miR-34a-4p', 'Var', (145, 155))
457518	32226522	Western blotting analysis showed that the expression of LEF1 inhibited expression of E-Cadherin but restored expression of N-Cadherin (Fig.	('expression', 'MPA', (71, 81))	('inhibited', 'NegReg', (61, 70))	('expression', 'MPA', (109, 119))	('N-Cadherin', 'Gene', (123, 133))	('restored', 'PosReg', (100, 108))	('N-Cadherin', 'Gene', '1000', (123, 133))	('E-Cadherin', 'Gene', (85, 95))	('expression', 'Var', (42, 52))	('E-Cadherin', 'Gene', '999', (85, 95))	('LEF1', 'Gene', '51176', (56, 60))	('LEF1', 'Gene', (56, 60))
457520	32226522	Considering the targeting effect of miR-34a-5p on LEF1, we detected the YAP1/TAZ expression of Hippo signaling pathway by overexpression of miR-34a-5p in ESCC cells.	('TAZ', 'Gene', '6901', (77, 80))	('LEF1', 'Gene', (50, 54))	('TAZ', 'Gene', (77, 80))	('miR-34a-5p', 'Var', (140, 150))	('Hippo signaling pathway', 'Pathway', (95, 118))	('overexpression', 'PosReg', (122, 136))	('miR-34a-5p', 'Chemical', '-', (36, 46))	('YAP1', 'Gene', (72, 76))	('YAP1', 'Gene', '10413', (72, 76))	('miR-34a-5p', 'Chemical', '-', (140, 150))	('LEF1', 'Gene', '51176', (50, 54))
457526	32226522	MicroRNAs have an important role in biological processes and aberrant miRNA expression is associated with many cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('aberrant', 'Var', (61, 69))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (90, 100))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))
457531	32226522	In many tumors, miR-34a-5p has been proved downregulated and inhibits tumor progress.	('miR-34a-5p', 'Var', (16, 26))	('downregulated', 'NegReg', (43, 56))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('miR-34a-5p', 'Chemical', '-', (16, 26))	('tumor', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumor', 'Disease', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('inhibits', 'NegReg', (61, 69))
457532	32226522	Thus, miR-34a-5p has been considered an ideal therapeutic tool to combat metastasis, chemoresistance and tumor recurrence.	('metastasis', 'CPA', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('chemoresistance', 'CPA', (85, 100))	('miR-34a-5p', 'Var', (6, 16))	('tumor', 'Disease', (105, 110))	('miR-34a-5p', 'Chemical', '-', (6, 16))
457535	32226522	Moreover, in vitro trials demonstrated miR-34a-5p inhibited proliferation, migration, invasion, and EMT in ESCC cells.	('miR-34a-5p', 'Var', (39, 49))	('miR-34a-5p', 'Chemical', '-', (39, 49))	('proliferation', 'CPA', (60, 73))	('ESCC', 'Disease', (107, 111))	('migration', 'CPA', (75, 84))	('invasion', 'CPA', (86, 94))	('inhibited', 'NegReg', (50, 59))	('EMT', 'CPA', (100, 103))
457536	32226522	Taken together, we believed that miR-34a-5p could be served as a tumor suppressor in ESCC.	('miR-34a-5p', 'Var', (33, 43))	('tumor', 'Disease', (65, 70))	('miR-34a-5p', 'Chemical', '-', (33, 43))	('ESCC', 'Disease', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
457538	32226522	In the present study, we confirmed that miR-34a-5p could target LEF1 directly by binding to the 3'-UTR of LEF1.	('LEF1', 'Gene', '51176', (64, 68))	('LEF1', 'Gene', '51176', (106, 110))	('LEF1', 'Gene', (64, 68))	('miR-34a-5p', 'Var', (40, 50))	('LEF1', 'Gene', (106, 110))	('miR-34a-5p', 'Chemical', '-', (40, 50))	('binding', 'Interaction', (81, 88))
457539	32226522	By a rescue experiment, we found that ectopic LEF1 expression could reverse the suppression of migration, invasion and EMT caused by miR-34a-4p overexpression, validating the molecular biological function of miR-34a-5p was mediated by suppression of LEF1.	('LEF1', 'Gene', (46, 50))	('suppression', 'NegReg', (80, 91))	('LEF1', 'Gene', '51176', (250, 254))	('miR-34a-5p', 'Chemical', '-', (208, 218))	('LEF1', 'Gene', (250, 254))	('invasion', 'CPA', (106, 114))	('miR-34a-4p', 'Gene', (133, 143))	('overexpression', 'PosReg', (144, 158))	('ectopic', 'Var', (38, 45))	('EMT', 'CPA', (119, 122))	('migration', 'CPA', (95, 104))	('LEF1', 'Gene', '51176', (46, 50))
457540	32226522	Previous studies have confirmed that miR-34a-5p may regulate Notch signaling pathway, PI3K/Akt signaling pathway, SIRT1/HIF-1alpha signaling, Wnt/beta-Catenin signaling pathway.	('beta-Catenin', 'Gene', (146, 158))	('Akt', 'Gene', '207', (91, 94))	('SIRT1', 'Gene', (114, 119))	('beta-Catenin', 'Gene', '1499', (146, 158))	('miR-34a-5p', 'Var', (37, 47))	('HIF-1alpha', 'Gene', '3091', (120, 130))	('Akt', 'Gene', (91, 94))	('miR-34a-5p', 'Chemical', '-', (37, 47))	('SIRT1', 'Gene', '23411', (114, 119))	('Notch', 'Gene', '4851;4854', (61, 66))	('HIF-1alpha', 'Gene', (120, 130))	('regulate', 'Reg', (52, 60))	('Notch', 'Gene', (61, 66))
457541	32226522	LEF1, a key molecule in Wnt/beta-Catenin signaling pathway, was targeted by miR-34a-5p in our study, indicating miR-34a-5p could inhibit Wnt/beta-Catenin signaling pathway.	('beta-Catenin', 'Gene', (141, 153))	('beta-Catenin', 'Gene', '1499', (141, 153))	('miR-34a-5p', 'Var', (112, 122))	('miR-34a-5p', 'Chemical', '-', (112, 122))	('inhibit', 'NegReg', (129, 136))	('LEF1', 'Gene', '51176', (0, 4))	('beta-Catenin', 'Gene', (28, 40))	('miR-34a-5p', 'Var', (76, 86))	('beta-Catenin', 'Gene', '1499', (28, 40))	('LEF1', 'Gene', (0, 4))	('miR-34a-5p', 'Chemical', '-', (76, 86))
457547	32226522	The results showed that YAP1/TAZ expression was downregulated compared to the control groups, indicating that miR-34a-5p inhibited Hippo-YAP1/TAZ signaling pathway in ESCC.	('miR-34a-5p', 'Var', (110, 120))	('YAP1', 'Gene', '10413', (137, 141))	('YAP1', 'Gene', (24, 28))	('TAZ', 'Gene', (29, 32))	('miR-34a-5p', 'Chemical', '-', (110, 120))	('YAP1', 'Gene', '10413', (24, 28))	('ESCC', 'Disease', (167, 171))	('TAZ', 'Gene', (142, 145))	('TAZ', 'Gene', '6901', (142, 145))	('YAP1', 'Gene', (137, 141))	('inhibited', 'NegReg', (121, 130))	('TAZ', 'Gene', '6901', (29, 32))
457549	32226522	Moreover, miR-34a-5p could inactivate Hippo-YAP1/TAZ signaling pathway to aggravate EMT.	('miR-34a-5p', 'Chemical', '-', (10, 20))	('YAP1', 'Gene', (44, 48))	('TAZ', 'Gene', '6901', (49, 52))	('TAZ', 'Gene', (49, 52))	('YAP1', 'Gene', '10413', (44, 48))	('EMT', 'CPA', (84, 87))	('aggravate', 'PosReg', (74, 83))	('inactivate', 'NegReg', (27, 37))	('miR-34a-5p', 'Var', (10, 20))
457560	31331361	HERG1 knockdown reduced tumor growth and metastasis in athymic mice.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('mice', 'Species', '10090', (63, 67))	('reduced', 'NegReg', (16, 23))	('HERG1', 'Gene', '3757', (0, 5))	('knockdown', 'Var', (6, 15))	('HERG1', 'Gene', (0, 5))
457562	31331361	Changes in HERG1 expression affected the expression of cell cycle- and EMT-related proteins; these effects were reversed by altering the expression of thioredoxin domain-containing protein 5 (TXNDC5), which is also associated with the clinicopathological characteristics of patients with ESCC and is relevant to HERG1 in pathological biopsies.	('HERG1', 'Gene', (11, 16))	('thioredoxin domain-containing protein 5', 'Gene', (151, 190))	('HERG1', 'Gene', '3757', (11, 16))	('ESCC', 'Disease', (288, 292))	('expression', 'MPA', (41, 51))	('patients', 'Species', '9606', (274, 282))	('altering', 'Reg', (124, 132))	('thioredoxin domain-containing protein 5', 'Gene', '81567', (151, 190))	('HERG1', 'Gene', '3757', (312, 317))	('affected', 'Reg', (28, 36))	('Changes', 'Var', (0, 7))	('HERG1', 'Gene', (312, 317))	('associated', 'Reg', (215, 225))
457563	31331361	Additionally, HERG1 expression altered phosphoinositide 3-kinase (PI3K) and AKT phosphorylation, thereby affecting TXNDC5 expression.	('HERG1', 'Gene', (14, 19))	('altered', 'Reg', (31, 38))	('phosphoinositide 3-kinase', 'Gene', (39, 64))	('AKT', 'Gene', '207', (76, 79))	('affecting', 'Reg', (105, 114))	('expression', 'Var', (20, 30))	('AKT', 'Gene', (76, 79))	('PI3', 'Gene', '5266', (66, 69))	('phosphorylation', 'MPA', (80, 95))	('phosphoinositide 3-kinase', 'Gene', '5295', (39, 64))	('PI3', 'Gene', (66, 69))	('TXNDC5', 'Gene', (115, 121))	('HERG1', 'Gene', '3757', (14, 19))
457565	31331361	Our findings provided novel insights into the pathology of ESCC and role of HERG1 in tumor progression, suggesting that targeting HERG1 has potential diagnostic and therapeutic value for ESCC treatment.	('ESCC', 'Disease', (187, 191))	('tumor', 'Disease', (85, 90))	('HERG1', 'Gene', '3757', (76, 81))	('HERG1', 'Gene', (76, 81))	('targeting', 'Var', (120, 129))	('ESCC', 'Disease', (59, 63))	('HERG1', 'Gene', '3757', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('HERG1', 'Gene', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
457569	31331361	The QT interval on the surface electrocardiogram is attributable to mutations, dysregulated expression levels, or impaired activity of HERG1 channels, which results in potentially fatal ventricular arrhythmia.	('dysregulated', 'Var', (79, 91))	('HERG1', 'Gene', '3757', (135, 140))	('results in', 'Reg', (157, 167))	('ventricular arrhythmia', 'Disease', 'MESH:D001145', (186, 208))	('HERG1', 'Gene', (135, 140))	('ventricular arrhythmia', 'Phenotype', 'HP:0004308', (186, 208))	('mutations', 'Var', (68, 77))	('expression levels', 'MPA', (92, 109))	('QT interval', 'Disease', (4, 15))	('ventricular arrhythmia', 'Disease', (186, 208))	('activity', 'MPA', (123, 131))	('impaired', 'NegReg', (114, 122))	('arrhythmia', 'Phenotype', 'HP:0011675', (198, 208))
457590	31331361	For the rescue experiments, 50 nM cDNA or siRNA targeting TXNDC5 (sequences in Additional file 1: Tables S1 and S3, respectively) were transiently transfected into KYSE-30 cells stably silenced for HERG1 or into TE-1 cells overexpressing HERG1, using Lipofectamine 2000 according to the manufacturer's instructions.	('TE-1', 'CellLine', 'CVCL:1759', (212, 216))	('silenced', 'Var', (185, 193))	('HERG1', 'Gene', '3757', (198, 203))	('D', 'Chemical', 'MESH:D003903', (35, 36))	('HERG1', 'Gene', '3757', (238, 243))	('HERG1', 'Gene', (198, 203))	('HERG1', 'Gene', (238, 243))	('TXNDC5', 'Gene', (58, 64))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (251, 269))	('D', 'Chemical', 'MESH:D003903', (61, 62))
457632	31331361	Notably, HERG1 score and the frequency of elevated protein level were significantly higher in samples at more advanced TNM stages (p = 0.000), T grades (p = 0.002), N grades (p = 0.000), and those from patients who were dead at the completion of the follow-up (p = 0.000) (Fig.	('TNM', 'Gene', '10178', (119, 122))	('HERG1', 'Gene', '3757', (9, 14))	('TNM', 'Gene', (119, 122))	('HERG1', 'Gene', (9, 14))	('protein level', 'MPA', (51, 64))	('patients', 'Species', '9606', (202, 210))	('N grades', 'Var', (165, 173))	('elevated', 'PosReg', (42, 50))	('higher', 'PosReg', (84, 90))
457636	31331361	ESCC cell growth and proliferation were promoted by ectopic HERG1 expression and inhibited by HERG1 silencing, as determined by colony formation and MTT assays (Fig.	('HERG1', 'Gene', '3757', (94, 99))	('silencing', 'Var', (100, 109))	('promoted', 'PosReg', (40, 48))	('MTT', 'Chemical', '-', (149, 152))	('inhibited', 'NegReg', (81, 90))	('HERG1', 'Gene', (94, 99))	('expression', 'MPA', (66, 76))	('HERG1', 'Gene', '3757', (60, 65))	('ectopic', 'Var', (52, 59))	('ESCC cell growth', 'CPA', (0, 16))	('HERG1', 'Gene', (60, 65))
457637	31331361	Equal concentrations of cells were also seeded into 12-well plates, and HERG1 overexpression/knockdown increased/decreased the number of ESCC cells compared to that in the control group (Fig.	('HERG1', 'Gene', '3757', (72, 77))	('HERG1', 'Gene', (72, 77))	('ESCC', 'Disease', (137, 141))	('increased/decreased', 'NegReg', (103, 122))	('increased/decreased', 'PosReg', (103, 122))	('overexpression/knockdown', 'PosReg', (78, 102))	('overexpression/knockdown', 'Var', (78, 102))
457639	31331361	Moreover, HERG1 overexpression and knockdown prevented and caused, respectively, a growth arrest in the G1 phase of the cell cycle (Fig.	('knockdown', 'Var', (35, 44))	('overexpression', 'PosReg', (16, 30))	('caused', 'Reg', (59, 65))	('prevented', 'NegReg', (45, 54))	('growth arrest', 'Disease', (83, 96))	('growth arrest', 'Disease', 'MESH:D006323', (83, 96))	('growth arrest', 'Phenotype', 'HP:0001510', (83, 96))	('HERG1', 'Gene', '3757', (10, 15))	('HERG1', 'Gene', (10, 15))
457640	31331361	HERG1 overexpression induced downregulation of p21 and upregulation of cyclin D1 in ESCC cells, whereas HERG1 knockdown induced upregulation of p21 and downregulation of cyclin D1 (Fig.	('knockdown', 'Var', (110, 119))	('downregulation', 'NegReg', (29, 43))	('downregulation', 'NegReg', (152, 166))	('upregulation', 'PosReg', (128, 140))	('HERG1', 'Gene', '3757', (104, 109))	('p21', 'MPA', (47, 50))	('cyclin D1', 'MPA', (71, 80))	('HERG1', 'Gene', (104, 109))	('p21', 'MPA', (144, 147))	('overexpression', 'PosReg', (6, 20))	('HERG1', 'Gene', '3757', (0, 5))	('HERG1', 'Gene', (0, 5))	('upregulation', 'PosReg', (55, 67))
457643	31331361	Wound healing assays showed that HERG1 overexpression substantially accelerated wound closure, whereas HERG1 knockdown had opposite effects (Fig.	('HERG1', 'Gene', (103, 108))	('HERG1', 'Gene', '3757', (33, 38))	('HERG1', 'Gene', (33, 38))	('accelerated', 'PosReg', (68, 79))	('overexpression', 'Var', (39, 53))	('wound closure', 'CPA', (80, 93))	('HERG1', 'Gene', '3757', (103, 108))
457650	31331361	Interestingly, TXNDC5 mRNA and protein levels in ESCC cells were clearly increased upon HERG1 overexpression and decreased upon HERG1 knockdown (Fig.	('overexpression', 'PosReg', (94, 108))	('increased', 'PosReg', (73, 82))	('HERG1', 'Gene', '3757', (128, 133))	('HERG1', 'Gene', (128, 133))	('HERG1', 'Gene', '3757', (88, 93))	('knockdown', 'Var', (134, 143))	('HERG1', 'Gene', (88, 93))	('decreased', 'NegReg', (113, 122))
457653	31331361	We obtained similar results by analyzing the levels of cell cycle-related and EMT markers upon simultaneous TXNDC5 knockdown and HERG1 overexpression or TXNDC5 overexpression and HERG1 silencing (Fig.	('HERG1', 'Gene', '3757', (129, 134))	('HERG1', 'Gene', (129, 134))	('silencing', 'NegReg', (185, 194))	('TXNDC5', 'Gene', (108, 114))	('HERG1', 'Gene', '3757', (179, 184))	('HERG1', 'Gene', (179, 184))	('overexpression', 'PosReg', (135, 149))	('knockdown', 'Var', (115, 124))
457659	31331361	Notably, the overall survival rates of the patients were significantly decreased in patients with both high HERG1 and TXNDC5 expression than in patients with both low HERG1 and TXNDC5 expression (Fig.	('HERG1', 'Gene', '3757', (108, 113))	('patients', 'Species', '9606', (84, 92))	('overall survival rates', 'CPA', (13, 35))	('patients', 'Species', '9606', (43, 51))	('HERG1', 'Gene', (108, 113))	('HERG1', 'Gene', '3757', (167, 172))	('patients', 'Species', '9606', (144, 152))	('HERG1', 'Gene', (167, 172))	('TXNDC5', 'MPA', (118, 124))	('high', 'Var', (103, 107))	('decreased', 'NegReg', (71, 80))
457661	31331361	Although we observed an increase in the level of the phosphorylated (active) form of PI3K and AKT upon HERG1 overexpression in TE-1 cells, there was a decrease in PI3K and AKT phosphorylation upon HERG1 knockdown in KYSE-30 cells.	('increase', 'PosReg', (24, 32))	('PI3', 'Gene', (163, 166))	('AKT', 'Gene', (94, 97))	('HERG1', 'Gene', '3757', (197, 202))	('HERG1', 'Gene', (197, 202))	('knockdown', 'Var', (203, 212))	('TE-1', 'CellLine', 'CVCL:1759', (127, 131))	('AKT', 'Gene', (172, 175))	('AKT', 'Gene', '207', (94, 97))	('PI3', 'Gene', '5266', (85, 88))	('AKT', 'Gene', '207', (172, 175))	('phosphorylated', 'MPA', (53, 67))	('PI3', 'Gene', '5266', (163, 166))	('HERG1', 'Gene', '3757', (103, 108))	('HERG1', 'Gene', (103, 108))	('level', 'MPA', (40, 45))	('decrease', 'NegReg', (151, 159))	('PI3', 'Gene', (85, 88))	('overexpression', 'Var', (109, 123))
457663	31331361	TE-1 cells treated with LY294002 (a PI3K/AKT inhibitor) for 24 h in combination with or without HERG1 overexpression exhibited significant decreases in TXNDC5, cyclin D1, vimentin, and fibronectin expression and increases in p21 and E-cadherin mRNA levels (Fig.	('cyclin D1', 'MPA', (160, 169))	('PI3', 'Gene', '5266', (36, 39))	('HERG1', 'Gene', (96, 101))	('LY294002', 'Var', (24, 32))	('vimentin', 'MPA', (171, 179))	('TE-1', 'CellLine', 'CVCL:1759', (0, 4))	('PI3', 'Gene', (36, 39))	('HERG1', 'Gene', '3757', (96, 101))	('decreases', 'NegReg', (139, 148))	('AKT', 'Gene', '207', (41, 44))	('TXNDC5', 'MPA', (152, 158))	('fibronectin expression', 'MPA', (185, 207))	('AKT', 'Gene', (41, 44))	('increases', 'PosReg', (212, 221))
457664	31331361	6b), whereas KYSE-30 cells exhibiting AKT overexpression in the presence or absence of HERG1 knockdown displayed significant increases in TXNDC5, cyclin D1, vimentin, and fibronectin expression and decreases in p21 and E-cadherin mRNA levels.	('knockdown', 'Var', (93, 102))	('HERG1', 'Gene', (87, 92))	('AKT', 'Gene', (38, 41))	('vimentin', 'MPA', (157, 165))	('increases', 'PosReg', (125, 134))	('TXNDC5', 'MPA', (138, 144))	('fibronectin expression', 'MPA', (171, 193))	('overexpression', 'PosReg', (42, 56))	('decreases', 'NegReg', (198, 207))	('AKT', 'Gene', '207', (38, 41))	('cyclin D1', 'MPA', (146, 155))	('HERG1', 'Gene', '3757', (87, 92))
457665	31331361	We then performed xenograft studies to investigate whether HERG1 deregulation is associated with tumorigenesis and/or metastasis formation.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('deregulation', 'Var', (65, 77))	('HERG1', 'Gene', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('HERG1', 'Gene', '3757', (59, 64))	('metastasis formation', 'CPA', (118, 138))	('associated', 'Reg', (81, 91))
457669	31331361	Furthermore, consistent with these findings, we observed that the expression of Ki-67, a proliferation marker, significantly decreased upon HERG1 silencing (Fig.	('silencing', 'Var', (146, 155))	('decreased', 'NegReg', (125, 134))	('Ki-67', 'Gene', (80, 85))	('expression', 'MPA', (66, 76))	('HERG1', 'Gene', '3757', (140, 145))	('HERG1', 'Gene', (140, 145))
457672	31331361	Moreover, HERG1 knockdown reduced metastases in the lungs of each mouse, with histological examination confirming the presence of these pulmonary metastases (Fig.	('metastases', 'Disease', (146, 156))	('pulmonary metastases', 'Disease', 'MESH:D009362', (136, 156))	('pulmonary metastases', 'Disease', (136, 156))	('mouse', 'Species', '10090', (66, 71))	('knockdown', 'Var', (16, 25))	('metastases', 'Disease', 'MESH:D009362', (146, 156))	('reduced', 'NegReg', (26, 33))	('metastases', 'Disease', (34, 44))	('HERG1', 'Gene', '3757', (10, 15))	('metastases', 'Disease', 'MESH:D009362', (34, 44))	('HERG1', 'Gene', (10, 15))
457689	31331361	We found that changes in HERG1 levels altered the expression of EMT markers in ESCC cells, and that HERG1 levels are associated with EMT markers in ESCC tumor samples.	('altered', 'Reg', (38, 45))	('HERG1', 'Gene', (100, 105))	('HERG1', 'Gene', (25, 30))	('associated', 'Reg', (117, 127))	('ESCC tumor', 'Disease', 'MESH:D004938', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('changes', 'Var', (14, 21))	('HERG1', 'Gene', '3757', (25, 30))	('ESCC tumor', 'Disease', (148, 158))	('HERG1', 'Gene', '3757', (100, 105))	('expression', 'MPA', (50, 60))
457691	31331361	Aberrant TXNDC5 expression has been reported in multiple malignancies, and is involved in the modulation of tumor cell cycle, proliferation, and migration, likely representing an important event in the progression of cervical cancer, prostate cancer, and lung cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (234, 249))	('prostate cancer', 'Phenotype', 'HP:0012125', (234, 249))	('tumor', 'Disease', (108, 113))	('prostate cancer', 'Disease', (234, 249))	('lung cancer', 'Disease', 'MESH:D008175', (255, 266))	('malignancies', 'Disease', 'MESH:D009369', (57, 69))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('proliferation', 'CPA', (126, 139))	('Aberrant', 'Var', (0, 8))	('malignancies', 'Disease', (57, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (255, 266))	('TXNDC5', 'Gene', (9, 15))	('involved', 'Reg', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cervical cancer', 'Disease', 'MESH:D002583', (217, 232))	('cervical cancer', 'Disease', (217, 232))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('lung cancer', 'Disease', (255, 266))	('migration', 'CPA', (145, 154))	('reported', 'Reg', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
457694	31331361	Moreover, dysregulation of HERG1 or TXNDC5 may contribute to myocardial disease.	('contribute', 'Reg', (47, 57))	('TXNDC5', 'Gene', (36, 42))	('dysregulation', 'Var', (10, 23))	('myocardial disease', 'Disease', (61, 79))	('HERG1', 'Gene', '3757', (27, 32))	('HERG1', 'Gene', (27, 32))	('myocardial disease', 'Disease', 'MESH:D009202', (61, 79))
457697	31331361	In addition, a survival analysis revealed that the prognosis of patients who exhibited high TXNDC5 expression was clearly poorer than that of patients exhibiting medium or low TXNDC5 expression.	('patients', 'Species', '9606', (64, 72))	('TXNDC5', 'Gene', (92, 98))	('high', 'Var', (87, 91))	('patients', 'Species', '9606', (142, 150))	('poorer', 'NegReg', (122, 128))
457698	31331361	Importantly, silencing or overexpression of HERG1 affected proliferation, invasion, and EMT in vitro, and these effects were reversed by overexpression or downregulation of TXNDC5, respectively, strongly indicating that TXNDC5 is critical for the function of HERG1.	('proliferation', 'CPA', (59, 72))	('invasion', 'CPA', (74, 82))	('HERG1', 'Gene', '3757', (259, 264))	('overexpression', 'PosReg', (26, 40))	('silencing', 'Var', (13, 22))	('HERG1', 'Gene', (259, 264))	('HERG1', 'Gene', '3757', (44, 49))	('downregulation', 'NegReg', (155, 169))	('EMT in vitro', 'CPA', (88, 100))	('HERG1', 'Gene', (44, 49))	('affected', 'Reg', (50, 58))
457760	29245236	Milne et al performed p53 and loss of heterozygosity (LOH) analyses on 2 collision and 3 composite tumors of SqC-adenocarcinoma of the gastroesophageal junction and found shared p53 mutations and common LOH patterns.	('SqC', 'Phenotype', 'HP:0002860', (109, 112))	('p53', 'Gene', (22, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('tumors of SqC-adenocarcinoma of the gastroesophageal junction', 'Disease', 'MESH:D008309', (99, 160))	('p53', 'Gene', '7157', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))	('mutations', 'Var', (182, 191))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
457792	29033478	Due to the relationship between increased dosage and effusion rates, IMRT potentially could result in fewer incidences of pleural and pericardial effusion in esophageal cancer patients compared to standard 3D-CRT treatment.	('effusion', 'Disease', (53, 61))	('patients', 'Species', '9606', (176, 184))	('pleural and pericardial effusion', 'Disease', 'MESH:D010996', (122, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('effusion', 'Disease', 'MESH:D010996', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('effusion', 'Disease', 'MESH:D010996', (53, 61))	('effusion', 'Disease', (146, 154))	('fewer', 'NegReg', (102, 107))	('IMRT', 'Var', (69, 73))	('pericardial effusion', 'Phenotype', 'HP:0001698', (134, 154))	('esophageal cancer', 'Disease', (158, 175))
457828	29033478	For posterior inference, we implement a Markov Chain Monte Carlo (MCMC) sampling scheme with stochastic search variable selection (SVSS) applied on the three hazard functions that use add, delete and swap moves.	('add', 'Var', (184, 187))	('delete', 'Var', (189, 195))	('swap', 'Gene', '50618', (200, 204))	('swap', 'Gene', (200, 204))	('MCMC', 'Chemical', '-', (66, 70))
457831	29033478	This is done through add, delete, and swap moves.	('swap', 'Gene', '50618', (38, 42))	('add', 'Var', (21, 24))	('delete', 'Var', (26, 32))	('swap', 'Gene', (38, 42))
457860	29033478	For taug = (.05, .1, ..., .9) and g = 1, 2, 3 run an MCMC as described in section 2.4 for the DIC-taug procedure using the quantities from step 2 while skipping any (tau1, tau2, tau3) vectors that do not change the variables included in each hazard Find the combination tau1, tau2, tau3 that produces the smallest DIC.	('tau3', 'Var', (282, 286))	('MCMC', 'Chemical', '-', (53, 57))	('tau2', 'Var', (276, 280))	('g = 1, 2, 3', 'Gene', '10672', (34, 45))	('tau1', 'Var', (270, 274))
457889	29033478	by imposing the constraint zg1 + zg2 = 2, corresponding to a prior effective sample size of 2 for the beta prior of the covariate inclusion probability, with some desirable mean percentage of inclusion.	('eta', 'Gene', (103, 106))	('zg1 + zg2 =', 'Var', (27, 38))	('eta', 'Gene', '1909', (103, 106))
457897	29033478	Patients with diabetes and adeno histology had significantly increased hazards of death before pleural effusion (P = .99) and patients with a good KPS score had a significantly reduced hazard of death before pleural effusion P <.01.	('KPS score', 'Gene', (147, 156))	('death', 'Disease', 'MESH:D003643', (82, 87))	('pleural effusion P', 'Disease', 'MESH:D010996', (208, 226))	('death', 'Disease', (82, 87))	('adeno', 'Var', (27, 32))	('diabetes', 'Disease', (14, 22))	('death', 'Disease', 'MESH:D003643', (195, 200))	('pleural effusion', 'Disease', 'MESH:D010996', (95, 111))	('diabetes', 'Disease', 'MESH:D003920', (14, 22))	('reduced', 'NegReg', (177, 184))	('death', 'Disease', (195, 200))	('Patients', 'Species', '9606', (0, 8))	('pleural effusion', 'Phenotype', 'HP:0002202', (95, 111))	('pleural effusion', 'Disease', 'MESH:D010996', (208, 224))	('patients', 'Species', '9606', (126, 134))	('pleural effusion P', 'Disease', (208, 226))	('pleural effusion', 'Disease', (95, 111))	('pleural effusion', 'Phenotype', 'HP:0002202', (208, 224))
457901	29033478	Table 4 shows that patients with IMRT had significantly decreased hazards of pericardial effusion and death before pericardial effusion, compared to those who received 3D-CRT (P < .01 for both hazards).	('death', 'Disease', 'MESH:D003643', (102, 107))	('IMRT', 'Var', (33, 37))	('death', 'Disease', (102, 107))	('patients', 'Species', '9606', (19, 27))	('pericardial effusion', 'Disease', 'MESH:D010490', (115, 135))	('pericardial effusion', 'Disease', 'MESH:D010490', (77, 97))	('pericardial effusion', 'Phenotype', 'HP:0001698', (115, 135))	('pericardial effusion', 'Disease', (115, 135))	('decreased', 'NegReg', (56, 65))	('pericardial effusion', 'Phenotype', 'HP:0001698', (77, 97))	('pericardial effusion', 'Disease', (77, 97))
458072	26176242	Patients with tumors T1 e T2 had longer survival rates than the ones with T3, T4 and IVB classifications (p<0.001) After multivariate model adjustment, there are still significant differences concerning factors such as gender (HR: 1.67; CI 95% 1.09 to 2.55; p=0.019), metastatic lymph nodes according to the 6th AJCC edition (HR: 1.63; CI 95% 1.13 to 2.36; p=0.010) and T3 staging in relation to group T1-T2 (HR: 1.52; CI 95% 1.04 to 2.23; p=0.032).	('men', 'Species', '9606', (146, 149))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('T1 e T2', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('longer', 'PosReg', (33, 39))
458094	23638721	Patients with clinical stage II-IVa (T1-4N0-1M0 or M1a) ESCC were enrolled between 2004 and 2011.	('ESCC', 'Disease', (56, 60))	('Patients', 'Species', '9606', (0, 8))	('T1-4N0-1M0', 'Var', (37, 47))
458113	23638721	Based on above thinking, our institution had engaged in clinical trials of ENI LCAHRT concurrently with cisplatin-based chemotherapy (CHT) for ESCC since 2004.	('CHT', 'Disease', (134, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('CHT', 'Disease', 'None', (134, 137))	('ESCC', 'Disease', (143, 147))	('ENI', 'Var', (75, 78))
458117	23638721	The eligibility criteria were as following: (1) a Karnofsky Performance Status (KPS) >= 70; (2) patients <= 75 years old; (3) histologically confirmed ESCC with the previously untreated; (4) TNM stage for II, III, and IVa (cervical or celiac node metastasis, not include organ metastasis according to AJCC 2002); (5) weight loss <= 5%; (6) life expectancy >= 3 months; (7) absolute white blood cell count >= 4000/ml, platelets >= 100,000/ml, total bilirubin level <= 1.5 mg/dl, serum creatinine level <=1.5 times the upper limit of normal, and aspartate/alanine aminotransferase levels <= 2.5 times the upper limit of normal.	('serum creatinine level', 'MPA', (478, 500))	('platelets', 'CPA', (417, 426))	('aspartate/alanine aminotransferase levels', 'MPA', (544, 585))	('ESCC', 'Disease', (151, 155))	('total bilirubin level', 'MPA', (442, 463))	('>= 4000/ml', 'Var', (405, 415))	('patients', 'Species', '9606', (96, 104))	('weight loss', 'Phenotype', 'HP:0001824', (317, 328))
458158	23638721	Recently, three independent meta-analysis from China strengthened the evidence of therapeutically beneficial of LCAHRT compared with CF for esophageal carcinoma.	('esophageal carcinoma', 'Disease', (140, 160))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (140, 160))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (140, 160))	('LCAHRT', 'Var', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
458185	23638721	In conclusion, this phase II study with limited number of patients demonstrated that ENI LCAHRT concurrently with CHT was generally tolerated, and the treatment outcome was satisfactory.	('patients', 'Species', '9606', (58, 66))	('CHT', 'Disease', 'None', (114, 117))	('CHT', 'Disease', (114, 117))	('ENI', 'Var', (85, 88))
458205	31803920	MicroRNA-135 (MiR-135) is a member of the miRNA family that plays an important role in a variety of cancers, and has two isoforms, miR-135a and miR-135b.	('role', 'Reg', (79, 83))	('miR-135b', 'Gene', '442891', (144, 152))	('MiR-135', 'Chemical', '-', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('miR-135', 'Chemical', '-', (144, 151))	('miR-135a', 'Var', (131, 139))	('miR-135b', 'Gene', (144, 152))	('plays', 'Reg', (60, 65))	('miR-135', 'Chemical', '-', (131, 138))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
458210	31803920	In addition, based on a bioinformatics analysis, miR-135 was considered worthy of further investigation as a potential novel biomarker for the diagnosis and prognosis of esophageal squamous cell carcinoma (ESCC) and PC.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (170, 204))	('miR-135', 'Chemical', '-', (49, 56))	('miR-135', 'Var', (49, 56))	('esophageal squamous cell carcinoma', 'Disease', (170, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))
458236	31803920	Seven studies that included a total of 765 patients reported the level of miR-135 expression and DFS of digestive system cancers.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (43, 51))	('miR-135', 'Var', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('miR-135', 'Chemical', '-', (74, 81))
458240	31803920	Moreover, there was a significant association between OS and digestive system cancer observed in the subgroups of cancer type (PC and ESCC), cancer classification (digestive gland and tract), source of control (curve and reported), sample size (large and small), biomarker subtype (miR-135a and miR-135b), publication year (2012-2016 and 2017-2019), and quality score (more than 6 and less than 6).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('miR-135', 'Chemical', '-', (295, 302))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('miR-135b', 'Gene', (295, 303))	('miR-135', 'Chemical', '-', (282, 289))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('miR-135a', 'Var', (282, 290))	('miR-135b', 'Gene', '442891', (295, 303))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', (114, 120))
458245	31803920	In the analysis of single tumor types, we found that high miR-135 expression was associated with a poor OS for colon adenocarcinoma (HR: 1.526; 95% CI: 1.051-2.214; P=0.026), pancreatic adenocarcinoma (HR: 1.403; 95% CI: 1.042-1.888; P=0.026), liver HCC (HR: 1.654; 95% CI: 1.221-2.241; P=0.001), and stomach adenocarcinoma (HR: 1.303; 95% CI: 1.010-1.681; P=0.042) (Table 3).	('stomach adenocarcinoma', 'Disease', (301, 323))	('expression', 'MPA', (66, 76))	('miR-135', 'Gene', (58, 65))	('pancreatic adenocarcinoma', 'Disease', (175, 200))	('colon adenocarcinoma', 'Disease', (111, 131))	('miR-135', 'Chemical', '-', (58, 65))	('liver HCC', 'Disease', 'MESH:D006528', (244, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('tumor', 'Disease', (26, 31))	('high', 'Var', (53, 57))	('liver HCC', 'Disease', (244, 253))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (175, 200))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (111, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (175, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (301, 323))
458259	31803920	An increasing number of studies have shown that the deregulation of miRNA function is associated with an increasing number of human diseases, particularly cancer.	('miRNA function', 'Protein', (68, 82))	('human', 'Species', '9606', (126, 131))	('deregulation', 'Var', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('associated', 'Reg', (86, 96))	('human diseases', 'Disease', (126, 140))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
458272	31803920	Therefore, although meta-analyses have shown that several miRNAs, including miR-17-5p and miR-133a, could predict the prognosis of digestive system tumors, a meta-analysis was required to assess the relationship between miR-135 and digestive system cancers.	('digestive system tumors', 'Phenotype', 'HP:0007378', (131, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('miR-17-5p', 'Gene', '406952', (76, 85))	('cancers', 'Disease', (249, 256))	('miR-135', 'Chemical', '-', (220, 227))	('miR-17-5p', 'Gene', (76, 85))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('predict', 'Reg', (106, 113))	('miR-133a', 'Var', (90, 98))
458274	31803920	For example, miR-135 can modulate critical signaling pathways (e.g., JAK/STAT, P38MAPK/NF-kappaB, PTEN/PI3k/AKT, and RERG) that indirectly regulate metabolism.	('AKT', 'Gene', '207', (108, 111))	('regulate', 'Reg', (139, 147))	('miR-135', 'Chemical', '-', (13, 20))	('metabolism', 'MPA', (148, 158))	('AKT', 'Gene', (108, 111))	('NF-kappaB', 'Gene', '4790', (87, 96))	('miR-135', 'Var', (13, 20))	('JAK/STAT', 'Disease', (69, 77))	('modulate', 'Reg', (25, 33))	('PTEN', 'Gene', (98, 102))	('RERG', 'Gene', (117, 121))	('RERG', 'Gene', '85004', (117, 121))	('PTEN', 'Gene', '5728', (98, 102))	('NF-kappaB', 'Gene', (87, 96))	('critical signaling pathways', 'Pathway', (34, 61))
458277	31803920	found that miR-135 increased the levels of phosphorylated key kinases in the JAK/STAT pathway and functioned as a tumor promoter by targeting TRIM16.	('targeting', 'Reg', (132, 141))	('TRIM16', 'Gene', '10626', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('TRIM16', 'Gene', (142, 148))	('miR-135', 'Chemical', '-', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('JAK/STAT pathway', 'Pathway', (77, 93))	('increased', 'PosReg', (19, 28))	('miR-135', 'Var', (11, 18))	('levels of phosphorylated key kinases', 'MPA', (33, 69))
458278	31803920	Furthermore, the deregulation of miR-135 function has been associated with both breast cancer and Hodgkin lymphoma.	('miR-135', 'Gene', (33, 40))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (98, 114))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (98, 114))	('associated', 'Reg', (59, 69))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lymphoma', 'Phenotype', 'HP:0002665', (106, 114))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('miR-135', 'Chemical', '-', (33, 40))	('Hodgkin lymphoma', 'Disease', (98, 114))	('deregulation', 'Var', (17, 29))
458292	31737678	In addition, 3 DEMIs (miR-490-3p, miR-133a-3p, and miR-552-3p) and 281 target genes were identified, and the 3 DEMIs showed high diagnostic value in READ and moderate diagnostic value in ESCA, GAC, and COAD.	('COAD', 'Disease', (202, 206))	('GAC', 'Disease', (193, 196))	('miR-490', 'Gene', '574443', (22, 29))	('miR-490', 'Gene', (22, 29))	('ESCA', 'Phenotype', 'HP:0011459', (187, 191))	('ESCA', 'Disease', (187, 191))	('miR-133a-3p', 'Var', (34, 45))	('miR-552', 'Gene', (51, 58))	('miR-552', 'Gene', '693137', (51, 58))
458296	31737678	The dysregulated miRNA expression is correlated with human diseases, and some miRNAs also play a causal role in the biological processes of the tumor microenvironment.	('play', 'Reg', (90, 94))	('miRNA expression', 'MPA', (17, 33))	('human', 'Species', '9606', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('dysregulated', 'Var', (4, 16))
458300	31737678	One upregulated miRNA (miR-552) and two downregulated miRNAs (miR-490 and miR-133a-2) were identified as DEMIs according to the intersection taken between upregulated and downregulated miRNAs in the cancers of the digestive tract (Figure 6).	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('downregulated', 'NegReg', (171, 184))	('miR-133a-2', 'Gene', '406923', (74, 84))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('upregulated', 'PosReg', (4, 15))	('upregulated', 'PosReg', (155, 166))	('cancers of the digestive tract', 'Phenotype', 'HP:0007378', (199, 229))	('miR-490', 'Var', (62, 69))	('miR-552', 'Var', (23, 30))	('miR-133a-2', 'Gene', (74, 84))
458305	31737678	The expression differences and expression trends of miR-7-5p, miR-323a, and miR-328 in CRC, ESCA, and GAC were verified by GSE89974, GSE114110, GSE93415, and GSE54397.	('miR-328', 'Gene', (76, 83))	('miR-7-5p', 'Gene', '407045', (52, 60))	('miR-323a', 'Gene', (62, 70))	('CRC', 'Phenotype', 'HP:0003003', (87, 90))	('GSE114110', 'Var', (133, 142))	('ESCA', 'Phenotype', 'HP:0011459', (92, 96))	('miR-7-5p', 'Gene', (52, 60))
458310	31737678	indicated that the circulating miR-17-5p and miR-92a-3p were significantly related to the pathological stage and grade in patients with CRC.	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('related', 'Reg', (75, 82))	('miR-92a-3p', 'Var', (45, 55))	('miR-17-5p', 'Gene', '406952', (31, 40))	('miR-17-5p', 'Gene', (31, 40))	('CRC', 'Disease', (136, 139))	('pathological stage', 'CPA', (90, 108))
458316	31737678	This is similar to the result of Zhang et al., who studied the correlation between five miRNAs (miR-191, miR-28-3p, miR-145, miR-328, and miR-18a) in the serum of NSCLC patients and the three-year overall survival rate of the two groups.	('miR-28', 'Gene', (105, 111))	('miR-191', 'Gene', '406966', (96, 103))	('miR-28', 'Gene', '407020', (105, 111))	('miR-191', 'Gene', (96, 103))	('miR-18a', 'Gene', (138, 145))	('miR-145', 'Gene', (116, 123))	('miR-18a', 'Gene', '406953', (138, 145))	('miR-145', 'Gene', '406937', (116, 123))	('miR-328', 'Var', (125, 132))
458318	31737678	Furthermore, in vitro functional tests of Ma cell lines (U251 and U87) showed that high expression of miR-328 could significantly inhibit the proliferation, invasion, and migration of two types of glial cells, and miR-328 could inhibit the invasion and proliferation of malignant cells, indicating a good prognosis for glioma.	('miR-328', 'Var', (214, 221))	('inhibit', 'NegReg', (228, 235))	('glioma', 'Phenotype', 'HP:0009733', (319, 325))	('proliferation', 'CPA', (142, 155))	('U87', 'CellLine', 'CVCL:0022', (66, 69))	('inhibit', 'NegReg', (130, 137))	('invasion', 'CPA', (157, 165))	('migration of two types of glial cells', 'CPA', (171, 208))	('glioma', 'Disease', (319, 325))	('miR-328', 'Gene', (102, 109))	('high', 'Var', (83, 87))	('U251', 'CellLine', 'CVCL:0021', (57, 61))
458319	31737678	But other cancer studies have shown that miR-323a can be used as a prognostic marker for acute coronary syndrome (ACS), cervical cancer, and glioblastoma.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('acute coronary syndrome', 'Disease', 'MESH:D054058', (89, 112))	('cervical cancer', 'Disease', (120, 135))	('acute coronary syndrome', 'Disease', (89, 112))	('coronary syndrome', 'Phenotype', 'HP:0001677', (95, 112))	('glioblastoma', 'Disease', (141, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))	('miR-323a', 'Var', (41, 49))
458320	31737678	explored the diagnostic and prognostic value of miRNAs in ESCA based on the TCGA data and found the combined AUC of five miRNAs (miRNA-93, miRNA-21, miRNA-4746, miRNA-196a-1, and miRNA-196a-2) was 0.985.	('miRNA-93', 'Gene', (129, 137))	('miRNA-21', 'Gene', '406991', (139, 147))	('miRNA-93', 'Gene', '407051', (129, 137))	('miRNA-196a-1', 'Var', (161, 173))	('ESCA', 'Phenotype', 'HP:0011459', (58, 62))	('ESCA', 'Disease', (58, 62))	('miRNA-196a-2', 'Var', (179, 191))	('miRNA-21', 'Gene', (139, 147))	('miRNA-4746', 'Var', (149, 159))
458321	31737678	The AUC values of miR-106a-5p and miR-19b-3p were 0.786 and 0.786, respectively.	('AUC', 'MPA', (4, 7))	('miR-19b', 'Gene', '406980', (34, 41))	('miR-19b', 'Gene', (34, 41))	('miR-106a-5p', 'Var', (18, 29))
458322	31737678	detected the expression of miR-21, miR-29a, miR-92a, miR-125b, and miR-223 in 85 patients with CRC utilizing qRT-PCR, evaluated their diagnostic value, and found the combined AUC of the miRNA was 0.952.	('miR-125b', 'Var', (53, 61))	('miR-223', 'Gene', '407008', (67, 74))	('miR-21', 'Gene', (27, 33))	('miR-29a', 'Gene', (35, 42))	('miR-29a', 'Gene', '407021', (35, 42))	('CRC', 'Phenotype', 'HP:0003003', (95, 98))	('miR-92a', 'Var', (44, 51))	('miR-223', 'Gene', (67, 74))	('miR-21', 'Gene', '406991', (27, 33))
458323	31737678	The expression level of miR-490-3p in Helicobacter pylori- (HP-) positive GAC was significantly associated with lymph node metastasis and tumor differentiation.	('Helicobacter pylori', 'Species', '210', (38, 57))	('associated', 'Reg', (96, 106))	('expression', 'MPA', (4, 14))	('lymph node metastasis', 'CPA', (112, 133))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('miR-490-3p', 'Var', (24, 34))	('Helicobacter pylori-', 'Disease', (38, 58))	('tumor differentiation', 'CPA', (138, 159))
458324	31737678	revealed that hypermethylation of the miR-490-3p promoter downregulated the expression of miR-490-3p in colorectal cancer, which revealed that miR-490-3p suppresses the proliferation of tumor cells by inducing apoptosis and inhibits the initiation of epithelial-to-mesenchymal transition (EMT) in vitro and in vivo, indicating that its expression was continuously downregulated in CRC malignancy and CRC cell lines.	('inhibits', 'NegReg', (224, 232))	('inducing', 'PosReg', (201, 209))	('CRC malignancy', 'Disease', 'MESH:D015179', (381, 395))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('CRC', 'Phenotype', 'HP:0003003', (381, 384))	('suppresses', 'NegReg', (154, 164))	('initiation', 'CPA', (237, 247))	('CRC malignancy', 'Disease', (381, 395))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('miR-490-3p', 'Var', (143, 153))	('downregulated', 'NegReg', (58, 71))	('proliferation', 'CPA', (169, 182))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('CRC', 'Phenotype', 'HP:0003003', (400, 403))	('apoptosis', 'CPA', (210, 219))
458327	31737678	Wang and Liu suggested that miR-552 was highly expressed in CRC through qRT-PCR experiments on 183 CRC patients and precancerous tissues, and high expression of miR-552 was significantly related to histological grade, lymph node metastasis, and TNM stage.	('miR-552', 'Var', (161, 168))	('TNM', 'Gene', (245, 248))	('related', 'Reg', (187, 194))	('CRC', 'Phenotype', 'HP:0003003', (99, 102))	('CRC', 'Disease', (60, 63))	('miR-552', 'Gene', (28, 35))	('lymph node metastasis', 'CPA', (218, 239))	('TNM', 'Gene', '10178', (245, 248))	('CRC', 'Phenotype', 'HP:0003003', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
458336	29845775	Western blot and ELISA revealed high constitutive secretion of proMMP-7 in an EAC cell line (OE33) that was inhibited by the phosphatidylinositol (PI) 3-kinase inhibitor LY294002 but not by inhibitors of protein kinase C, or MAP kinase activation.	('LY294002', 'Chemical', 'MESH:C085911', (170, 178))	('LY294002', 'Var', (170, 178))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (125, 145))	('proMMP-7', 'Gene', (63, 71))	('OE33', 'Chemical', '-', (93, 97))	('inhibited', 'NegReg', (108, 117))	('proMMP', 'Chemical', '-', (63, 69))
458359	29845775	The EAC and gastroesophageal junction cancer cell lines, OE33 and OE19, respectively, were obtained from American Type Culture Collection (Manassas, VA, USA); OE33-Gr cells, expressing CCK2R, have previously been described (Haigh et al.	('gastroesophageal junction cancer', 'Disease', (12, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('OE33-Gr', 'Var', (159, 166))	('gastroesophageal junction cancer', 'Disease', 'MESH:D008309', (12, 44))	('OE33', 'Chemical', '-', (57, 61))	('CCK2R', 'Gene', (185, 190))	('CCK2R', 'Gene', '887', (185, 190))	('OE19', 'CellLine', 'CVCL:1622', (66, 70))	('OE33', 'Chemical', '-', (159, 163))
458364	29845775	Wang (Columbia University, New York, USA), Gly-extended gastrin-17 (G17-gly) and C-terminal flanking peptide extended gastrin (G17-CFP) were purchased from Pepsyn (Liverpool, Lancs, UK); brefeldin A (BFA), Ro32-04332, U0126 and LY294002 were obtained from Merck Millipore (Watford, Herts, UK).	('Gly', 'Chemical', 'MESH:D005998', (43, 46))	('extended gastrin', 'Phenotype', 'HP:0500167', (109, 125))	('LY294002', 'Chemical', 'MESH:C085911', (228, 236))	('extended gastrin', 'Phenotype', 'HP:0500167', (47, 63))	('BFA', 'Chemical', 'MESH:D020126', (200, 203))	('G17', 'Gene', '5089', (68, 71))	('G17', 'Gene', (127, 130))	('G17', 'Gene', '5089', (127, 130))	('Ro32', 'Chemical', '-', (206, 210))	('gastrin', 'Gene', '2520', (56, 63))	('U0126', 'Chemical', 'MESH:C113580', (218, 223))	('gastrin', 'Gene', '2520', (118, 125))	('gly', 'Chemical', 'MESH:D005998', (72, 75))	('LY294002', 'Var', (228, 236))	('gastrin', 'Gene', (56, 63))	('G17', 'Gene', (68, 71))	('gastrin', 'Gene', (118, 125))
458389	29845775	Undiluted OE33 cell CM with or without MMP-7 knockdown was placed in the well.	('MMP-7', 'Gene', (39, 44))	('OE33', 'Chemical', '-', (10, 14))	('knockdown', 'Var', (45, 54))
458390	29845775	In addition, immunoneutralization using a mouse monoclonal anti-human MMP-7 (1:200; R & D Systems) was employed to study CAM migration in response to OE33 CM.	('human', 'Species', '9606', (64, 69))	('study CAM', 'CPA', (115, 124))	('mouse', 'Species', '10090', (42, 47))	('to OE33', 'Var', (147, 154))	('OE33', 'Chemical', '-', (150, 154))	('CAM', 'Chemical', '-', (121, 124))
458416	29845775	However, inhibitors of both protein kinase C (Ro32-0432) and p42/44 MAP-kinase activation (U0126) had only a small effect on proMMP-7 in the medium indicating that secretion was unlikely to be attributable to drive from these signaling pathways (Fig 4A,B); at the concentrations used, Ro32,0432 and U0126 have been shown to virtually abolish the MMP-1 response to PMA (Kumar et al.	('Ro32', 'Chemical', '-', (46, 50))	('MMP-1', 'Gene', '4312', (346, 351))	('proMMP', 'Chemical', '-', (125, 131))	('U0126', 'Chemical', 'MESH:C113580', (299, 304))	('MMP-1', 'Gene', (346, 351))	('p42', 'Gene', (61, 64))	('abolish', 'NegReg', (334, 341))	('p42', 'Gene', '2038', (61, 64))	('Ro32', 'Chemical', '-', (285, 289))	('U0126', 'Var', (299, 304))	('U0126', 'Chemical', 'MESH:C113580', (91, 96))	('PMA', 'Chemical', 'MESH:D013755', (364, 367))
458417	29845775	Interestingly, an inhibitor of phosphatidylinositol-3-kinase (PI 3-kinase)(LY294002) decreased the abundance of proMMP-7 in medium detected by western blot (Fig.	('decreased', 'NegReg', (85, 94))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (31, 51))	('proMMP-7', 'Protein', (112, 120))	('PI 3', 'Gene', '5266', (62, 66))	('LY294002', 'Chemical', 'MESH:C085911', (75, 83))	('proMMP', 'Chemical', '-', (112, 118))	('gly', 'Chemical', 'MESH:D005998', (10, 13))	('abundance', 'MPA', (99, 108))	('LY294002', 'Var', (75, 83))	('PI 3', 'Gene', (62, 66))
458418	29845775	The effect of LY294002 in suppressing PI 3-kinase in OE33 cells was verified by demonstrating inhibition of phosphorylation of the downstream target, Akt (Fig.	('Akt', 'Gene', '207', (150, 153))	('inhibition', 'NegReg', (94, 104))	('OE33', 'Chemical', '-', (53, 57))	('LY294002', 'Var', (14, 22))	('PI 3', 'Gene', '5266', (38, 42))	('Akt', 'Gene', (150, 153))	('phosphorylation', 'MPA', (108, 123))	('LY294002', 'Chemical', 'MESH:C085911', (14, 22))	('PI 3', 'Gene', (38, 42))	('suppressing', 'NegReg', (26, 37))
458427	29845775	Following incubation of myofibroblasts with MMP-7 for 30 min, we then identified 98-130 (mean 113, in three replicates) semi- or non-tryptic fragments of MMP-7 which on alignment indicated endopeptidase cleavages particularly in the region 175-217 (numbering from the initiator Met in preproMMP-7), followed by carboxy- and aminopeptidase trimming of the cleavage products (Fig 6C).	('MMP-7', 'Gene', (154, 159))	('indicated', 'Reg', (179, 188))	('preproMMP-', 'Chemical', '-', (285, 295))	('cleavages', 'Var', (203, 212))	('endopeptidase', 'Enzyme', (189, 202))
458432	29845775	The OE33 cell CM significantly increased both migration and invasion of EAC CAMs but following MMP-7 knockdown there was a significant reduction in cell migration in response to CM, and a smaller reduction in invasion (Fig.	('reduction', 'NegReg', (135, 144))	('MMP-7', 'Gene', (95, 100))	('invasion', 'CPA', (209, 217))	('cell migration', 'CPA', (148, 162))	('OE33', 'Chemical', '-', (4, 8))	('CAM', 'Chemical', '-', (76, 79))	('reduction', 'NegReg', (196, 205))	('knockdown', 'Var', (101, 110))
458434	29845775	Moreover, OE33 CM stimulated migration of a third EAC CAM and this was inhibited by MMP-7 immunoneutralization (CM: 1.8 +- 0.2 fold increase in migration over control, vs. 1.0 +- 0.12 fold after immunoneutralization).	('CAM', 'Chemical', '-', (54, 57))	('increase', 'PosReg', (132, 140))	('migration', 'CPA', (29, 38))	('OE33 CM', 'Var', (10, 17))	('OE33', 'Chemical', '-', (10, 14))	('migration', 'CPA', (144, 153))	('stimulated', 'PosReg', (18, 28))
458435	29845775	Interestingly, OE33 CM also increased proliferation of myofibroblasts in serum-free medium, but the knockdown of MMP-7 had no effect on proliferation in these experiments (Fig.	('increased', 'PosReg', (28, 37))	('OE33', 'Chemical', '-', (15, 19))	('proliferation', 'CPA', (38, 51))	('OE33 CM', 'Var', (15, 22))	('gly', 'Chemical', 'MESH:D005998', (10, 13))
458448	29845775	Barrett's esophagus patients are typically treated with proton pump inhibitors to suppress acid secretion; however, inhibition of acid secretion also removes an inhibitory effect of acid on the G-cell leading to increased circulating gastrin (Lamberts et al.	('inhibition', 'Var', (116, 126))	('inhibitory effect of acid on the', 'MPA', (161, 193))	('increased circulating gastrin', 'Phenotype', 'HP:0500167', (212, 241))	('gastrin', 'Gene', '2520', (234, 241))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (0, 19))	('patients', 'Species', '9606', (20, 28))	('gastrin', 'Gene', (234, 241))	('acid secretion', 'MPA', (91, 105))	('increased', 'PosReg', (212, 221))	('removes', 'NegReg', (150, 157))
458454	29845775	Unexpectedly, however, we found an inverse relationship between CCK2R abundance and increasing serum gastrin concentrations.	('increasing', 'PosReg', (84, 94))	('gastrin', 'Gene', (101, 108))	('CCK2R', 'Gene', (64, 69))	('abundance', 'Var', (70, 79))	('CCK2R', 'Gene', '887', (64, 69))	('gastrin', 'Gene', '2520', (101, 108))	('increasing serum gastrin', 'Phenotype', 'HP:0500167', (84, 108))
458461	29845775	2007) and it is known that OE33 cells over-express Akt while the PI 3-kinase inhibitor LY294002 suppressed stimulated proliferation (Beales et al.	('Akt', 'Gene', (51, 54))	('LY294002', 'Var', (87, 95))	('PI 3', 'Gene', '5266', (65, 69))	('over-express', 'PosReg', (38, 50))	('stimulated proliferation', 'CPA', (107, 131))	('OE33', 'Chemical', '-', (27, 31))	('suppressed', 'NegReg', (96, 106))	('Akt', 'Gene', '207', (51, 54))	('PI 3', 'Gene', (65, 69))	('LY294002', 'Chemical', 'MESH:C085911', (87, 95))
458462	29845775	The present data indicate that LY294002 also significantly reduced the abundance of proMMP-7 in medium and cell extracts compatible with inhibition of expression.	('LY294002', 'Var', (31, 39))	('proMMP-7', 'Gene', (84, 92))	('reduced', 'NegReg', (59, 66))	('proMMP', 'Chemical', '-', (84, 90))	('LY294002', 'Chemical', 'MESH:C085911', (31, 39))	('abundance', 'MPA', (71, 80))
458470	29845775	In this sense, there may be parallels between the role of MMP-7 in shaping the esophageal microenvironment and that in the stomach and colon where there is already evidence that MMP-7 stimulates stromal cell function via cleavage of insulin-like growth factor binding proteins (IGFBPs) leading to increased bioavailability of IGF-I and -II (Hemers et al.	('stromal cell function', 'CPA', (195, 216))	('IGFBPs', 'Gene', '3488', (278, 284))	('IGFBPs', 'Gene', (278, 284))	('MMP-7', 'Var', (178, 183))	('increased', 'PosReg', (297, 306))	('IGF-I and -II', 'Gene', '3479;3481', (326, 339))	('cleavage', 'Var', (221, 229))	('bioavailability', 'MPA', (307, 322))	('stimulates', 'PosReg', (184, 194))
458480	29344159	In vitro experiments revealed that the expression of p-p38 induced esophageal cancer Eca-109 and TE-1 cell viability, and resistance to thalidomide treatment, as well as in the expression of IDO without the application of lipopolysaccharides.	('resistance', 'CPA', (122, 132))	('IDO', 'Gene', (191, 194))	('expression', 'Var', (39, 49))	('induced', 'PosReg', (59, 66))	('lipopolysaccharides', 'Chemical', 'MESH:D008070', (222, 241))	('TE-1', 'CellLine', 'CVCL:1759', (97, 101))	('esophageal cancer', 'Disease', (67, 84))	('p38', 'Gene', '1432', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('IDO', 'Gene', '3620', (191, 194))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('thalidomide', 'Chemical', 'MESH:D013792', (136, 147))	('p38', 'Gene', (55, 58))
458494	29344159	Furthermore, in certain other tumor types, the inhibition of p38 enhances sensitivity to chemotherapy, suggesting that p38 may serve as an oncogene in cancer progression.	('sensitivity to chemotherapy', 'MPA', (74, 101))	('p38', 'Gene', '1432', (119, 122))	('p38', 'Gene', '1432', (61, 64))	('inhibition', 'Var', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('p38', 'Gene', (119, 122))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('enhances', 'PosReg', (65, 73))	('p38', 'Gene', (61, 64))	('tumor', 'Disease', (30, 35))
458570	29344159	Blocking p38 using SB203580 markedly reduced IDO expression compared with parental cells (Fig.	('SB203580', 'Var', (19, 27))	('p38', 'Gene', (9, 12))	('IDO', 'Gene', '3620', (45, 48))	('IDO', 'Gene', (45, 48))	('reduced', 'NegReg', (37, 44))	('p38', 'Gene', '1432', (9, 12))	('SB203580', 'Chemical', 'MESH:C093642', (19, 27))
458584	29344159	The results of the present study indicated that thalidomide was able to induce apoptosis in esophageal cancer cell types Eca-109 and TE-1, although its mechanism remains to be elucidated.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('thalidomide', 'Var', (48, 59))	('apoptosis', 'CPA', (79, 88))	('esophageal cancer', 'Disease', (92, 109))	('thalidomide', 'Chemical', 'MESH:D013792', (48, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))	('TE-1', 'CellLine', 'CVCL:1759', (133, 137))
458621	29259379	Conventional method: In the abdominal phase, after stomach mobilization and lymph node dissection, a laparoscopic cutting stapler was used to transect the stomach and gastric cardia in a tumor-free cardia region.	('transect', 'Var', (142, 150))	('tumor-free cardia', 'Disease', 'MESH:D000072662', (187, 204))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('gastric cardia', 'Disease', (167, 181))	('gastric cardia', 'Disease', 'MESH:D004938', (167, 181))	('tumor-free cardia', 'Disease', (187, 204))
458622	29259379	The lesser curvature was transected at the first or second branch of the right gastric artery, which was followed by suturing with a stapler.	('transected', 'Var', (25, 35))	('gastric artery', 'Disease', (79, 93))	('gastric artery', 'Disease', 'MESH:D013274', (79, 93))
458640	29099815	Expression of Heat Shock Protein-27 (Hsp27) and P38MAPK in Esophageal Squamous Cell Carcinoma Esophageal squamous cell carcinoma (ESCC) is a worldwide concern.	('Carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('P38MAPK', 'Var', (48, 55))	('Shock', 'Phenotype', 'HP:0031273', (19, 24))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (94, 128))	('Esophageal Squamous Cell Carcinoma', 'Disease', (59, 93))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (59, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('Esophageal squamous cell carcinoma', 'Disease', (94, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('Hsp27', 'Gene', '3315', (37, 42))	('Hsp27', 'Gene', (37, 42))
458704	29099815	Hsp27 function is associated with deleterious outcomes in cancer and is associated with the development of drug resistance.	('function', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Hsp27', 'Gene', '3315', (0, 5))	('Hsp27', 'Gene', (0, 5))	('associated with', 'Reg', (72, 87))	('drug resistance', 'Phenotype', 'HP:0020174', (107, 122))	('associated', 'Reg', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('drug resistance', 'MPA', (107, 122))
458705	29099815	Some studies have found that exogenous Hsp27 uniquely blocks differentiation of monocytes to dendritic cells.	('Hsp27', 'Gene', '3315', (39, 44))	('Hsp27', 'Gene', (39, 44))	('blocks', 'NegReg', (54, 60))	('differentiation of monocytes to dendritic cells', 'CPA', (61, 108))	('exogenous', 'Var', (29, 38))
458723	29099815	Recent studies of epithelial cells with disruption of P38MAPK have shown that its role in cancer cells is to suppress lung, liver, and colon tumor formation in vivo.	('P38', 'Gene', '1432', (54, 57))	('colon tumor', 'Disease', 'MESH:D015179', (135, 146))	('lung', 'CPA', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('liver', 'CPA', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('disruption', 'Var', (40, 50))	('suppress', 'NegReg', (109, 117))	('colon tumor', 'Phenotype', 'HP:0100273', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('colon tumor', 'Disease', (135, 146))	('cancer', 'Disease', (90, 96))	('P38', 'Gene', (54, 57))
458767	28415791	The combination of FAPalpha, CEA, CYFRA211 and SCCA resulted in an improvement in AUC (0.745) compared to the combination of the three traditional biomarkers (AUC = 0.690) (Figure 2B).	('SCCA', 'Gene', (47, 51))	('FAPalpha', 'Gene', (19, 27))	('improvement', 'PosReg', (67, 78))	('CYFRA211', 'Var', (34, 42))	('CEA', 'Gene', (29, 32))	('CEA', 'Gene', '5670', (29, 32))
458809	28415791	Low HDL-C level was found to be a risky and prognostic factor of multiple cancers in several epidemiologic studies.	('multiple cancers', 'Disease', (65, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('multiple cancers', 'Disease', 'MESH:D009369', (65, 81))	('Low HDL', 'Phenotype', 'HP:0003233', (0, 7))	('HDL-C', 'Protein', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Low', 'Var', (0, 3))
458852	26147197	A previous study showed that altered expression of mRNA in cancer tissue may play an oncogenic role and promote tumor development; therefore, in the present findings, we focus only on the overexpression of VGCCs in different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('altered', 'Var', (29, 36))	('promote', 'PosReg', (104, 111))	('expression', 'MPA', (37, 47))	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', (234, 240))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
458866	26147197	For instance, slight variations in Ca2+ could regulate specific cell functions, whereas a substantial alteration of Ca2+ could be responsible for cell proliferation and motility or even cell apoptosis.	('regulate', 'Reg', (46, 54))	('responsible', 'Reg', (130, 141))	('variations', 'Var', (21, 31))	('specific cell functions', 'CPA', (55, 78))	('motility', 'CPA', (169, 177))	('Ca2+', 'Chemical', 'MESH:D000069285', (35, 39))	('cell proliferation', 'CPA', (146, 164))	('Ca2+', 'Chemical', 'MESH:D000069285', (116, 120))
458868	26147197	The L-type, N-Type, P-type, T-type and R-type calcium channels that constitute the VGCC family are involved in the development of various types of cancer (Table 1).	('P-type', 'Var', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('calcium', 'Chemical', 'MESH:D002118', (46, 53))	('involved', 'Reg', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
458873	26147197	A previous study showed that altered gene expression in cancer tissue may play an oncogenic role and promote tumor development; therefore, in the present findings, we focus only on the overexpression of VGCCs in different types of cancer.	('promote', 'PosReg', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('altered', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Disease', (109, 114))
458899	26147197	Several calcium channel blockers, such as verapamil, nifedipine, TH-1177, 2-APB, and SK&F 96365, have been confirmed to inhibit receptor-gated calcium channels, but the particular subtypes of calcium channel have not been investigated.	('nifedipine', 'Chemical', 'MESH:D009543', (53, 63))	('inhibit receptor-gated calcium', 'MPA', (120, 150))	('calcium', 'Chemical', 'MESH:D002118', (8, 15))	('APB', 'Gene', (76, 79))	('verapamil', 'Chemical', 'MESH:D014700', (42, 51))	('calcium', 'Chemical', 'MESH:D002118', (192, 199))	('APB', 'Gene', '6051', (76, 79))	('calcium', 'Chemical', 'MESH:D002118', (143, 150))	('TH-1177', 'Chemical', 'MESH:C405269', (65, 72))	('SK&', 'Var', (85, 88))
458904	26147197	Ca2+ channel activity also triggers oxidative phosphorylation, programmed cell death, and alterations in the apoptosis signaling pathway.	('alterations', 'Reg', (90, 101))	('Ca2+ channel activity', 'Var', (0, 21))	('Ca2+', 'Chemical', 'MESH:D000069285', (0, 4))	('oxidative phosphorylation', 'MPA', (36, 61))	('triggers', 'Reg', (27, 35))	('programmed cell death', 'CPA', (63, 84))	('apoptosis signaling pathway', 'Pathway', (109, 136))
458936	26147197	Different mutations in alpha subunit 1A lead to certain neuronal degradation diseases such as episodic ataxia type-2, familial hemiplegic migraine and spinocerebellar ataxia type-6.	('episodic ataxia type-2', 'Disease', (94, 116))	('neuronal degradation diseases', 'Disease', (56, 85))	('neuronal degradation diseases', 'Disease', 'MESH:D055959', (56, 85))	('lead to', 'Reg', (40, 47))	('spinocerebellar ataxia type-6', 'Disease', (151, 180))	('episodic ataxia', 'Phenotype', 'HP:0002131', (94, 109))	('ataxia', 'Phenotype', 'HP:0001251', (103, 109))	('migraine', 'Phenotype', 'HP:0002076', (138, 146))	('familial hemiplegic migraine', 'Disease', 'MESH:D020325', (118, 146))	('familial hemiplegic migraine', 'Disease', (118, 146))	('episodic ataxia type-2', 'Disease', 'MESH:C535506', (94, 116))	('spinocerebellar ataxia type-6', 'Disease', 'MESH:D020754', (151, 180))	('mutations', 'Var', (10, 19))	('ataxia', 'Phenotype', 'HP:0001251', (167, 173))
458980	26147197	The BMC Cancer database revealed CACNA1C expression in invasive lobular breast carcinoma/normal tissue with a 1.9-fold change (Table 2); thus, we speculated that patients with invasive lobular breast carcinoma with high expression of CACNA1C relative to normal tissue were at risk for metastasis to the gastrointestinal tract, peritoneum, retroperitoneum, and gynecological organs.	('metastasis', 'CPA', (285, 295))	('gastrointestinal tract', 'Disease', (303, 325))	('high expression', 'Var', (215, 230))	('patients', 'Species', '9606', (162, 170))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D018275', (55, 88))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (303, 325))	('CACNA1C', 'Gene', (234, 241))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D018275', (176, 209))	('breast carcinoma', 'Phenotype', 'HP:0003002', (72, 88))	('breast carcinoma', 'Phenotype', 'HP:0003002', (193, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('invasive lobular breast carcinoma', 'Disease', (55, 88))	('invasive lobular breast carcinoma', 'Disease', (176, 209))	('CACNA1C', 'Gene', '775', (33, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('CACNA1C', 'Gene', (33, 40))	('Cancer', 'Phenotype', 'HP:0002664', (8, 14))	('CACNA1C', 'Gene', '775', (234, 241))
458981	26147197	The TCGA and PNAS databases indicated that CACNA1D was significantly overexpressed relative to normal tissue in invasive lobular breast carcinoma with invasive ductal and lobular carcinoma (Table 2), which again implies that patients with high expression of CACNA1D were likely to develop those diseases.	('CACNA1D', 'Gene', (258, 265))	('lobular carcinoma', 'Disease', 'MESH:D018275', (171, 188))	('develop', 'PosReg', (281, 288))	('overexpressed', 'PosReg', (69, 82))	('lobular carcinoma', 'Disease', (171, 188))	('patients', 'Species', '9606', (225, 233))	('high expression', 'Var', (239, 254))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (171, 188))	('breast carcinoma', 'Phenotype', 'HP:0003002', (129, 145))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D018275', (112, 145))	('CACNA1D', 'Gene', '776', (43, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('CACNA1D', 'Gene', (43, 50))	('CACNA1D', 'Gene', '776', (258, 265))	('invasive lobular breast carcinoma', 'Disease', (112, 145))
458985	26147197	The Nat Med database showed a 2.3-fold change in CACNA1I in invasive breast carcinoma stroma, again implying that patients with high CACNA1G expression would likely develop cancer.	('breast carcinoma', 'Phenotype', 'HP:0003002', (69, 85))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('Nat', 'Gene', '6046', (4, 7))	('develop', 'PosReg', (165, 172))	('CACNA1I', 'Gene', (49, 56))	('cancer', 'Disease', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('CACNA1I', 'Gene', '8911', (49, 56))	('Nat', 'Gene', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('expression', 'MPA', (141, 151))	('CACNA1G', 'Gene', (133, 140))	('high', 'Var', (128, 132))	('invasive breast carcinoma stroma', 'Disease', (60, 92))	('patients', 'Species', '9606', (114, 122))	('invasive breast carcinoma stroma', 'Disease', 'MESH:D018270', (60, 92))	('change', 'Reg', (39, 45))	('CACNA1G', 'Gene', '8913', (133, 140))
459007	26147197	A recent study indicated an association between oncogenic K-Ras IP3-dependent suppression and a calcium release mechanism that strongly suggests a role for IP3 in the function of ligand-gated calcium channels involved in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('calcium release mechanism', 'MPA', (96, 121))	('K-Ras', 'Gene', '3845', (58, 63))	('IP3', 'Chemical', 'MESH:D015544', (156, 159))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('oncogenic', 'Var', (48, 57))	('K-Ras', 'Gene', (58, 63))	('calcium', 'Chemical', 'MESH:D002118', (192, 199))	('calcium', 'Chemical', 'MESH:D002118', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('IP3', 'Chemical', 'MESH:D015544', (64, 67))	('suppression', 'NegReg', (78, 89))	('colorectal cancer', 'Disease', (221, 238))
459030	24936140	Hypermethylation of CpG islands is an important mechanism to inactivate tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inactivate', 'NegReg', (61, 71))	('tumor', 'Disease', (72, 77))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
459031	24936140	In addition, DNA methylation is frequently not restricted to a single CpG island but affects multiple independent loci, which is reflective of a widespread deregulation of DNA methylation pattern in different types of tumors.	('affects', 'Reg', (85, 92))	('methylation', 'Var', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
459071	24936140	Finally, we obtained nine DNA methylation probes which were significantly associated with poor prognosis of patients (Figure 1B).	('patients', 'Species', '9606', (108, 116))	('methylation', 'Var', (30, 41))	('associated', 'Reg', (74, 84))
459077	24936140	CpG hypermethylation of all eight genes showed an association with poor survival outcome, suggesting that these eight genes may function as tumor suppressor-like genes in ESCC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (140, 145))	('association', 'Reg', (50, 61))	('tumor', 'Disease', (176, 181))	('ESCC', 'Disease', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('hypermethylation', 'Var', (4, 20))
459088	24936140	The Table 2 shows that the methylation level of eight-gene panel was an independent prognosis factor in ESCC patients even after adjusting for other variables including tumor stage, age and cancer recurrence status by the multivariate analysis (hazard ratio, HR, 1.996; 95% confidence interval, CI, 1.153-3.456; P=0.014).	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('methylation', 'Var', (27, 38))	('ESCC', 'Disease', (104, 108))	('tumor', 'Disease', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
459090	24936140	Given that aberrant methylation can result in transcriptional silencing of the target gene, we further examined the mRNA expression level of SOX17 in 61 ESCC patients.	('transcriptional', 'MPA', (46, 61))	('result in', 'Reg', (36, 45))	('SOX17', 'Gene', (141, 146))	('methylation', 'Var', (20, 31))	('aberrant methylation', 'Var', (11, 31))	('patients', 'Species', '9606', (158, 166))	('SOX17', 'Gene', '64321', (141, 146))	('ESCC', 'Disease', (153, 157))
459091	24936140	The qRT-PCR results indicated that mRNA level of SOX17 was significantly lower in the high methylation group than the low methylation group of tumor tissues from ESCC patients (P=0.018, Figure 4A).	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('patients', 'Species', '9606', (167, 175))	('mRNA level', 'MPA', (35, 45))	('SOX17', 'Gene', (49, 54))	('high methylation', 'Var', (86, 102))	('lower', 'NegReg', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('ESCC', 'Disease', (162, 166))	('SOX17', 'Gene', '64321', (49, 54))
459092	24936140	Importantly, an inverse correlation between SOX17 DNA methylation and mRNA expression was observed (r= -0.418, P<0.01, Figure 4B), suggesting that DNA hypermethylation of SOX17 resulted in low mRNA expression in ESCC patients.	('DNA hypermethylation', 'Var', (147, 167))	('SOX17', 'Gene', '64321', (171, 176))	('ESCC', 'Disease', (212, 216))	('SOX17', 'Gene', '64321', (44, 49))	('low', 'NegReg', (189, 192))	('patients', 'Species', '9606', (217, 225))	('SOX17', 'Gene', (171, 176))	('SOX17', 'Gene', (44, 49))	('mRNA expression', 'MPA', (193, 208))
459102	24936140	They further compared the methylation patterns of ESCC patients with esophageal mucosa from four healthy individuals and the TFF1 promoter methylation was speculated to represent an early event in the development of ESCC.	('ESCC', 'Disease', (50, 54))	('ESCC', 'Disease', (216, 220))	('TFF1', 'Gene', '7031', (125, 129))	('patients', 'Species', '9606', (55, 63))	('TFF1', 'Gene', (125, 129))	('methylation', 'Var', (139, 150))
459109	24936140	These results suggested that DNA hypermethylation is a predominant mechanism for SOX17 gene silencing, which is in agreement with previous reports of esophageal cancer patients determined by methylation-specific PCR method.	('DNA hypermethylation', 'Var', (29, 49))	('esophageal cancer', 'Disease', (150, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('silencing', 'NegReg', (92, 101))	('SOX17', 'Gene', '64321', (81, 86))	('patients', 'Species', '9606', (168, 176))	('SOX17', 'Gene', (81, 86))
459145	22618519	The following endoscopes were used: GIF-Q240, GIF-Q240Z, GIF-Q260Z, GIF-H260, and GIF-Q260J (Olympus Optical Co., Ltd., Tokyo, Japan).	('Q240Z', 'Var', (50, 55))	('Q260J', 'SUBSTITUTION', 'None', (86, 91))	('Q260Z', 'Var', (61, 66))	('Q260Z', 'SUBSTITUTION', 'None', (61, 66))	('Q240Z', 'SUBSTITUTION', 'None', (50, 55))	('Q260J', 'Var', (86, 91))
459313	22542728	GISTs were originally thought to be leiomyomas or leiomyosarcomas; however, with the discovery of KIT-activating mutations and expression of the KIT protein, distinguishing GIST from smooth muscle tumors is now relatively straightforward in most cases by demonstrating the immunohistochemical detection of KIT (CD117).	('leiomyosarcomas', 'Disease', 'MESH:D007890', (50, 65))	('GIST', 'Phenotype', 'HP:0100723', (173, 177))	('GISTs', 'Phenotype', 'HP:0100723', (0, 5))	('CD117', 'Gene', '3815', (311, 316))	('leiomyosarcomas', 'Disease', (50, 65))	('leiomyomas', 'Disease', 'MESH:D007889', (36, 46))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('mutations', 'Var', (113, 122))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('muscle tumors', 'Disease', 'MESH:D009217', (190, 203))	('leiomyomas', 'Disease', (36, 46))	('muscle tumors', 'Disease', (190, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('CD117', 'Gene', (311, 316))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (50, 65))
459347	22542728	On FDG-PET/CT, interval decrease in SUVmax was noted, which is also in line with previous reports, and is considered to be good treatment response.	('FDG-PET/CT', 'Var', (3, 13))	('SUVmax', 'MPA', (36, 42))	('decrease', 'NegReg', (24, 32))	('men', 'Species', '9606', (133, 136))	('FDG', 'Chemical', 'MESH:D019788', (3, 6))
459352	17718912	Fez1/Lzts1 a new mitotic regulator implicated in cancer development Considerable evidence has accumulated suggesting that cancer has genetic origin, based on the development of genomic alterations, such as deletions, mutations, and/or methylations in critical genes for homeostasis of cellular functions, including cell survival, DNA replication and cell cycle control.	('methylations', 'Var', (235, 247))	('cell cycle', 'CPA', (350, 360))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('DNA replication', 'CPA', (330, 345))	('cancer', 'Disease', (122, 128))	('Lzts1', 'Gene', (5, 10))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cell survival', 'CPA', (315, 328))	('Lzts1', 'Gene', '11178', (5, 10))	('Fez1', 'Gene', (0, 4))	('Fez1', 'Gene', '9638', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('deletions', 'Var', (206, 215))	('mutations', 'Var', (217, 226))	('rat', 'Species', '10116', (189, 192))	('cancer', 'Disease', (49, 55))
459353	17718912	Mechanism controlling the precise timing and sequence of cell cycle events as well as checkpoints insuring fidelity of those events are key targets that when disrupted could result in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('result in', 'Reg', (174, 183))	('disrupted', 'Var', (158, 167))
459372	17718912	Western blot and RT-PCR analyses in different cancer derived cell lines showed similar result, arguing that loss or reduction of LZTS1 is a frequent event in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('LZTS1', 'Gene', (129, 134))	('loss', 'Var', (108, 112))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('reduction', 'NegReg', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
459373	17718912	In addition LZTS1 is also mutated and/or deleted in several cancer types.	('LZTS1', 'Gene', (12, 17))	('deleted', 'Var', (41, 48))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
459376	17718912	In a primary esophageal tumor, alteration of TCC to CCC at codon 29 resulted in the substitution of Ser-29 with Pro-29, which is a predicted cAMP-dependent kinase phosphorylation site.	('cAMP', 'Chemical', '-', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('esophageal tumor', 'Disease', 'MESH:D004938', (13, 29))	('substitution', 'Var', (84, 96))	('esophageal tumor', 'Disease', (13, 29))	('resulted in', 'Reg', (68, 79))	('TCC to CCC at codon 29', 'Mutation', 'c.29TCC>CCC', (45, 67))	('Ser-29', 'Var', (100, 106))	('Ser-29 with Pro', 'Mutation', 'rs28937897', (100, 115))	('esophageal tumor', 'Phenotype', 'HP:0100751', (13, 29))	('TCC', 'Gene', (45, 48))	('alteration', 'Var', (31, 41))	('rat', 'Species', '10116', (35, 38))
459378	17718912	Our LOH study indicated that these two patients had allelic losses at the D8S261 marker.	('allelic losses', 'Var', (52, 66))	('D8S261', 'Gene', (74, 80))	('S261', 'CellLine', 'CVCL:2490', (76, 80))	('patients', 'Species', '9606', (39, 47))
459379	17718912	Thus, these tumor cells retained the mutated LZTS1 allele and lost the normal LZTS1 allele by point mutation.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('point mutation', 'Var', (94, 108))	('lost', 'NegReg', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutated', 'Var', (37, 44))	('LZTS1', 'Gene', (45, 50))
459380	17718912	The third point mutation was the change of CAG/Gln to TAG/Stop at codon 501 in a prostate cancer cell line, PC3, which resulted in coding of a putative 166-aa protein lacking the C terminus.	('lacking', 'NegReg', (167, 174))	('prostate cancer', 'Disease', (81, 96))	('CAG/Gln to TAG/Stop', 'Var', (43, 62))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('CAG', 'Chemical', '-', (43, 46))	('PC3', 'CellLine', 'CVCL:0035', (108, 111))	('Gln', 'Chemical', 'MESH:D005973', (47, 50))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('change', 'Var', (33, 39))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('C terminus', 'MPA', (179, 189))
459381	17718912	The fourth mutation was a somatic missense mutation (CAC/His to CGC/Arg at LZTS1 codon 17) of one allele in a diffuse-type gastric carcinoma.	('His', 'Chemical', 'MESH:D006639', (57, 60))	('gastric carcinoma', 'Disease', 'MESH:D013274', (123, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('CAC/His to CGC/Arg', 'Var', (53, 71))	('gastric carcinoma', 'Disease', (123, 140))	('Arg', 'Chemical', 'MESH:D001120', (68, 71))	('CAC', 'Chemical', '-', (53, 56))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (123, 140))
459383	17718912	The transcript from two independent esophageal cancers showed a frameshift within the ORF, which resulted in coding a short 76-aa protein.	('esophageal cancers', 'Disease', 'MESH:D004938', (36, 54))	('resulted in coding a', 'Reg', (97, 117))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('frameshift', 'Var', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancers', 'Disease', (36, 54))
459388	17718912	Experimental studies using different cancer derived cell lines from human bladder, breast and prostate tumor, showed that reintroduction of LZTS1 results in inhibition of tumor cell growth in vitro and/or tumorigenicity in vivo.	('breast and prostate tumor', 'Disease', 'MESH:D011471', (83, 108))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('human', 'Species', '9606', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Disease', (37, 43))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('reintroduction', 'Var', (122, 136))	('LZTS1', 'Gene', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('inhibition', 'NegReg', (157, 167))	('tumor', 'Disease', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('prostate tumor', 'Phenotype', 'HP:0100787', (94, 108))
459389	17718912	In one study, introduction of full-length LZTS1 cDNA resulted in suppression of tumorigenicity in nude mice, in the inhibition of stable colony-forming efficiencies of ~50% of highly metastatic rat prostate cells and human prostate and embryonic kidney cells, and in the reduction of cell growth with accumulation of cells at late S to G2/M stage of cell cycle.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('embryonic kidney cells', 'Disease', 'MESH:D007674', (236, 258))	('embryonic kidney cells', 'Disease', (236, 258))	('rat', 'Species', '10116', (194, 197))	('suppression', 'NegReg', (65, 76))	('human', 'Species', '9606', (217, 222))	('nude mice', 'Species', '10090', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cell growth', 'CPA', (284, 295))	('stable colony-forming efficiencies', 'CPA', (130, 164))	('tumor', 'Disease', (80, 85))	('inhibition', 'NegReg', (116, 126))	('highly metastatic rat prostate cells', 'CPA', (176, 212))	('LZTS1', 'Var', (42, 47))	('reduction', 'NegReg', (271, 280))
459394	17718912	The neoplasms in Lzts1-/- mice were breast tumors, hepatocellular carcinomas, lymphomas, soft tissue sarcomas, and lung adenomas, a spectrum suggesting that Lzts1 absence affects multiple cell types in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('breast tumors', 'Phenotype', 'HP:0100013', (36, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('hepatocellular carcinomas', 'Disease', (51, 76))	('neoplasms', 'Phenotype', 'HP:0002664', (4, 13))	('Lzts1', 'Gene', (157, 162))	('sarcomas', 'Disease', 'MESH:D012509', (101, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (101, 109))	('lymphomas', 'Disease', (78, 87))	('Lzts1-/-', 'Var', (17, 25))	('sarcomas', 'Disease', (101, 109))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('absence', 'NegReg', (163, 170))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (89, 109))	('neoplasms', 'Disease', 'MESH:D009369', (4, 13))	('lung adenomas', 'Disease', 'MESH:D000236', (115, 128))	('lung adenomas', 'Disease', (115, 128))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mice', 'Species', '10090', (26, 30))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (51, 76))	('neoplasms', 'Disease', (4, 13))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (51, 76))	('breast tumors', 'Disease', (36, 49))	('breast tumors', 'Disease', 'MESH:D001943', (36, 49))	('lymphomas', 'Disease', 'MESH:D008223', (78, 87))	('lymphomas', 'Phenotype', 'HP:0002665', (78, 87))
459400	17718912	Biochemical investigation of the mouse Lzts1 gene using fibroblasts derived from Lzts1wt and null embryos (MEF), revealed that Lzts1 wt and null MEFs displayed a normal progression along the different phases of the cell cycle but showed a faster M phase progression associated to a lower Cyclin B1/Cdk1 activity.	('activity', 'MPA', (303, 311))	('Cyclin B1', 'Gene', '268697', (288, 297))	('Cyclin B1', 'Gene', (288, 297))	('lower', 'NegReg', (282, 287))	('MEFs', 'CellLine', 'CVCL:9115', (145, 149))	('M phase progression', 'CPA', (246, 265))	('MEF', 'Gene', '56501', (107, 110))	('mouse', 'Species', '10090', (33, 38))	('MEF', 'Gene', (145, 148))	('MEF', 'Gene', '56501', (145, 148))	('MEF', 'Gene', (107, 110))	('faster', 'PosReg', (239, 245))	('Lzts1', 'Var', (127, 132))
459401	17718912	Using video time-lapse microscopy, we were able to demonstrate that the faster M progression of Lzts1-/- cells was due to the time they spent in prophase.	('faster', 'PosReg', (72, 78))	('Lzts1-/-', 'Var', (96, 104))	('rat', 'Species', '10116', (58, 61))	('M progression', 'CPA', (79, 92))
459404	17718912	The mechanism whereby Lzts1 absence decreases Cdk1 activity was sought investigating the molecule responsible for Cdk1 activation: namely Cdc25C.	('activity', 'MPA', (51, 59))	('Lzts1', 'Gene', (22, 27))	('Cdc25C', 'Gene', '995', (138, 144))	('decreases', 'NegReg', (36, 45))	('Cdk1', 'Protein', (46, 50))	('absence', 'Var', (28, 35))	('Cdc25C', 'Gene', (138, 144))
459408	17718912	Recently we discovered that mitotic Lzts1-/- MEFs showed a higher Cdk1-pY15/Cdk1 ratio accompanied by lower levels of endogenous Cdc25C that results in a lower association between endogenous Cdc25C and endogenous Cdk1.	('lower', 'NegReg', (102, 107))	('lower', 'NegReg', (154, 159))	('Cdc25C', 'Gene', (191, 197))	('Cdc25C', 'Gene', '995', (129, 135))	('rat', 'Species', '10116', (81, 84))	('Cdc25C', 'Gene', '995', (191, 197))	('MEFs', 'CellLine', 'CVCL:9115', (45, 49))	('Cdc25C', 'Gene', (129, 135))	('association', 'Interaction', (160, 171))	('Lzts1-/- MEFs', 'Var', (36, 49))	('higher', 'PosReg', (59, 65))	('Cdk1-pY15/Cdk1 ratio', 'MPA', (66, 86))
459412	17718912	One intriguing observation is that Lzts1 absence seems to affects Cdc25C levels in mitotic MEFs but not in cells returned in G1 after the completion of cell division.	('Lzts1', 'Gene', (35, 40))	('Cdc25C', 'Gene', '995', (66, 72))	('MEFs', 'CellLine', 'CVCL:9115', (91, 95))	('affects', 'Reg', (58, 65))	('absence', 'Var', (41, 48))	('Cdc25C', 'Gene', (66, 72))
459415	17718912	In fact their mutations can lead to failure of cell cycle checkpoint controls resulting in the accumulation of genetic changes contributing to a tumor phenotype.	('accumulation', 'PosReg', (95, 107))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('mutations', 'Var', (14, 23))	('genetic changes', 'MPA', (111, 126))
459417	17718912	We focus here on a newly identified factor: Lzts1 which alterations lead to premature mitotic exit that results in chromosomal instability and aneuploidy.	('lead to', 'Reg', (68, 75))	('alterations', 'Var', (56, 67))	('chromosomal instability', 'MPA', (115, 138))	('aneuploidy', 'Disease', 'MESH:D000782', (143, 153))	('rat', 'Species', '10116', (60, 63))	('Lzts1', 'Gene', (44, 49))	('premature', 'MPA', (76, 85))	('aneuploidy', 'Disease', (143, 153))	('chromosomal instability', 'Phenotype', 'HP:0040012', (115, 138))	('results in', 'Reg', (104, 114))
459437	32652008	However, our current methods to individualize cancer treatments are still largely based on genomic mutational data obtained from tissue sampling that is limited in quantity, obtained at discreet time points during the disease, and often not reflective of overall tumor heterogeneity.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', (263, 268))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutational', 'Var', (99, 109))
459463	32652008	Interestingly, human cancer organoids had fewer and different growth medium requirements compared to normal human colon organoids, including independence from Wnt3A, R-spondin, Noggin, nicotinamide, and gastrin with varied dependence on EGF, A83-01, or SB202190, consistent with tumors evolving factor independence (Figure 1).	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('SB202190', 'Var', (253, 261))	('R-spondin', 'Gene', '192199', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('nicotinamide', 'Chemical', 'MESH:D009536', (185, 197))	('Wnt3A', 'Gene', '89780', (159, 164))	('tumors', 'Disease', (279, 285))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('R-spondin', 'Gene', (166, 175))	('human', 'Species', '9606', (108, 113))	('SB202190', 'Chemical', 'MESH:C090942', (253, 261))	('A83-01', 'Chemical', 'MESH:C507011', (242, 248))	('cancer', 'Disease', (21, 27))	('human', 'Species', '9606', (15, 20))	('Wnt3A', 'Gene', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))
459470	32652008	For example, the somatic mutational differences between each organoid and primary tumor sample range from 0% to 38% with some of these different mutations involving cancer-related genes including APC, SMAD4, and POLE.	('primary tumor', 'Disease', 'MESH:D001932', (74, 87))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('SMAD4', 'Gene', (201, 206))	('mutations', 'Var', (145, 154))	('APC', 'Disease', 'MESH:D011125', (196, 199))	('APC', 'Disease', (196, 199))	('primary tumor', 'Disease', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
459474	32652008	To address this discrepancy, the colorectal cancer organoids were maintained in culture media lacking Wnt3a in an attempt to preferentially select for cancer growth conditions given the high prevalence of APC pathway mutations (i.e.	('APC', 'Disease', (205, 208))	('rectal cancer', 'Phenotype', 'HP:0100743', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('APC', 'Disease', 'MESH:D011125', (205, 208))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('mutations', 'Var', (217, 226))	('colorectal cancer', 'Disease', (33, 50))
459488	32652008	The cancer organoids in this study maintained genomic stability over long-term culture in terms of both somatic mutations and copy number variants.	('copy number variants', 'Var', (126, 146))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('genomic stability', 'CPA', (46, 63))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))
459491	32652008	Thus, the authors employed several enrichment techniques including changing digestion times, preferential biopsy sampling, manual selection and replating, and use of nutlin-3a, a small-molecular inhibitor of the p53 inhibitor MDM2, to select organoids with TP53 mutations.	('p53', 'Gene', '7157', (212, 215))	('TP53', 'Gene', (257, 261))	('MDM2', 'Gene', '4193', (226, 230))	('MDM2', 'Gene', (226, 230))	('p53', 'Gene', (212, 215))	('mutations', 'Var', (262, 271))
459503	32652008	Not only were factors found to be dispensable for some tumors, but factors including A83-01 and normoxia conditions were found to be detrimental to the growth of some cancer organoids.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('detrimental', 'NegReg', (133, 144))	('cancer', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('growth', 'CPA', (152, 158))	('A83-01', 'Var', (85, 91))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('A83-01', 'Chemical', 'MESH:C507011', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
459508	32652008	Specifically, used nutlin-3 to enrich for TP53-mutated tumoroids, ROCK inhibitor-free culture media to enrich for RHO pathway-altered tumoroids, TGF-beta without A83-01 to enrich for TGF-beta-insensitive ones, and EGF and FGF10-free culture media to enrich for growth factor pathway-constitutively activated gastric cancer organoids.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('RHO', 'Gene', (114, 117))	('TGF-beta', 'Gene', (183, 191))	('TGF-beta', 'Gene', (145, 153))	('pathway-altered', 'Reg', (118, 133))	('gastric cancer', 'Disease', (308, 322))	('tumor', 'Disease', (55, 60))	('A83-01', 'Chemical', 'MESH:C507011', (162, 168))	('TP53-mutated', 'Var', (42, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (308, 322))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('TGF-beta', 'Gene', '7039', (183, 191))	('TGF-beta', 'Gene', '7039', (145, 153))	('gastric cancer', 'Phenotype', 'HP:0012126', (308, 322))	('tumor', 'Disease', (134, 139))
459516	32652008	When well-defined genetic alterations drive cancer formation (e.g.	('genetic alterations', 'Var', (18, 37))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('drive', 'Reg', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
459517	32652008	if most tumors in an organ depend on the same key driver mutation), genetically engineered mouse models can often recapitulate the development of cancers in vivo; key examples include pancreatic (mutations in KRAS) and colorectal (mutations in the Wnt pathway) malignancies.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('malignancies', 'Disease', 'MESH:D009369', (261, 273))	('pancreatic', 'Disease', (184, 194))	('colorectal', 'Disease', 'MESH:D015179', (219, 229))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('malignancies', 'Disease', (261, 273))	('tumors', 'Disease', (8, 14))	('colorectal', 'Disease', (219, 229))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('Wnt', 'Gene', '89780;22416', (248, 251))	('Wnt', 'Gene', (248, 251))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('KRAS', 'Gene', (209, 213))	('mouse', 'Species', '10090', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('mutations', 'Var', (196, 205))
459528	32652008	They show that organoids derived from these precancerous lesions have relatively few mutations compared to cancer organoids and harbor transcriptomic differences unique from cancer and normal organoids.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('mutations', 'Var', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (107, 113))
459535	32652008	used CRISPR-Cas9 to introduce KRAS, CDKN2A, TP53, and SMAD4 mutations in normal pancreatic organoids.	('CDKN2A', 'Gene', (36, 42))	('CRISPR', 'Gene', '70873', (5, 11))	('SMAD4', 'Gene', (54, 59))	('CDKN2A', 'Gene', '1029', (36, 42))	('CRISPR', 'Gene', (5, 11))	('mutations', 'Var', (60, 69))	('KRAS', 'Gene', (30, 34))	('TP53', 'Gene', (44, 48))
459537	32652008	used CRISPR-Cas9 technology to delete MLH1 and NTHL1 in normal human colon organoids to mimic mismatch repair deficiency and base excision repair deficiency, respectively.	('delete', 'Var', (31, 37))	('mimic', 'Reg', (88, 93))	('NTHL1', 'Gene', (47, 52))	('CRISPR', 'Gene', '70873', (5, 11))	('human', 'Species', '9606', (63, 68))	('NTHL1', 'Gene', '4913', (47, 52))	('deficiency', 'Disease', (110, 120))	('deficiency', 'Disease', (146, 156))	('deficiency', 'Disease', 'MESH:D007153', (110, 120))	('MLH1', 'Gene', '4292', (38, 42))	('MLH1', 'Gene', (38, 42))	('CRISPR', 'Gene', (5, 11))	('deficiency', 'Disease', 'MESH:D007153', (146, 156))	('base excision repair', 'MPA', (125, 145))	('mismatch repair', 'MPA', (94, 109))
459538	32652008	These altered colon organoids displayed mutational accumulation and profiles that matched those seen in mismatch repair-deficient or germline NTHL1-mutated human cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Disease', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('NTHL1', 'Gene', '4913', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('NTHL1', 'Gene', (142, 147))	('mutational', 'Var', (40, 50))	('human', 'Species', '9606', (156, 161))	('profiles', 'MPA', (68, 76))
459540	32652008	They showed that organoids with CDH1 mutations displayed a degree of ROCK inhibitor independence (reflection of anoikis independence); however, the double knockout organoids (with both CDH1- and RHOA-inactivating mutations) had enhancement of this phenotype, suggesting that RHOA inactivation is a necessary step in CDH1 mutation-driven gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (337, 359))	('CDH1', 'Gene', (185, 189))	('CDH1', 'Gene', (316, 320))	('enhancement', 'PosReg', (228, 239))	('CDH1', 'Gene', '999', (185, 189))	('CDH1', 'Gene', (32, 36))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (337, 359))	('mutations', 'Var', (37, 46))	('CDH1', 'Gene', '999', (316, 320))	('ROCK inhibitor independence', 'MPA', (69, 96))	('RHOA', 'Gene', '387', (195, 199))	('RHOA', 'Gene', '387', (275, 279))	('CDH1', 'Gene', '999', (32, 36))	('RHOA', 'Gene', (195, 199))	('RHOA', 'Gene', (275, 279))
459542	32652008	Using organoids derived from human Barrett's esophagus, the precursor lesion to esophageal adenocarcinoma, introduced APC mutations via CRISPR-Cas9 to mimic Wnt pathway activation, a common molecular pathway seen in esophageal carcinogenesis.	('human', 'Species', '9606', (29, 34))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('CRISPR', 'Gene', '70873', (136, 142))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('Wnt', 'Gene', '89780;22416', (157, 160))	('Wnt', 'Gene', (157, 160))	('CRISPR', 'Gene', (136, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (227, 241))	('mutations', 'Var', (122, 131))	('carcinogenesis', 'Disease', (227, 241))	('APC', 'Disease', 'MESH:D011125', (118, 121))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (35, 54))	('APC', 'Disease', (118, 121))	('adenocarcinoma', 'Disease', (91, 105))
459543	32652008	They showed that the mutated organoids had demonstration of cancer-like histology and growth behavior.	('growth behavior', 'CPA', (86, 101))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('mutated', 'Var', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
459570	32652008	Genetically manipulating tumoroids will allow further detailed insights into the origins and drivers of cancer development.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (25, 30))	('Genetically', 'Var', (0, 11))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
459588	32652008	By virtue of having available detailed molecular profiling or each tumor organoid, the authors were able to make correlations between organoid responses (IC50 values) with genomic alterations including TP53 loss-of-function mutations associated with resistance to the MDM2 inhibitor nutlin-3a and KRAS mutations associated with resistance to anti-EGFR inhibitors.	('TP53', 'Gene', (202, 206))	('mutations', 'Var', (302, 311))	('EGFR', 'Gene', '1956', (347, 351))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('EGFR', 'Gene', (347, 351))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('KRAS', 'Gene', (297, 301))	('MDM2', 'Gene', '4193', (268, 272))	('loss-of-function', 'NegReg', (207, 223))	('MDM2', 'Gene', (268, 272))	('tumor', 'Disease', (67, 72))	('mutations', 'Var', (224, 233))
459643	32652008	Support is provided by the NIDDK R01s (DK094989, DK105129, and DK110406) P30 (DK052574), Alvin J. Siteman Cancer Center/Barnes Jewish Hospital Foundation Cancer Frontier Fund, NIH NCI (P30 CA091842 and U54 CA163060), The Barnard Trust, and DeNardo Education & Research Foundation grants to J.C.M.	('U54 CA163060', 'Var', (202, 214))	('P30', 'Gene', (73, 76))	('Cancer', 'Disease', (154, 160))	('DK110406', 'Var', (63, 71))	('DK094989', 'Var', (39, 47))	('Cancer', 'Disease', (106, 112))	('Cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('Cancer', 'Disease', 'MESH:D009369', (106, 112))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('P30', 'Gene', '201161', (185, 188))	('NIH NCI', 'CellLine', 'CVCL:0601', (176, 183))	('DK105129', 'Var', (49, 57))	('P30', 'Gene', '201161', (73, 76))	('P30', 'Gene', (185, 188))
459644	31804468	Aberrant hypermethylation-mediated downregulation of antisense lncRNA ZNF667-AS1 and its sense gene ZNF667 correlate with progression and prognosis of esophageal squamous cell carcinoma Natural antisense lncRNAs can interfere with their corresponding sense transcript to elicit concordant or discordant regulation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('elicit', 'Reg', (271, 277))	('esophageal squamous cell carcinoma', 'Disease', (151, 185))	('hypermethylation-mediated', 'Var', (9, 34))	('downregulation', 'NegReg', (35, 49))	('ZNF667', 'Gene', '63934', (100, 106))	('ZNF667-AS1', 'Gene', '100128252', (70, 80))	('ZNF667', 'Gene', (100, 106))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (151, 185))	('ZNF667', 'Gene', (70, 76))	('ZNF667', 'Gene', '63934', (70, 76))	('ZNF667-AS1', 'Gene', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
459648	31804468	The expression levels of ZNF667-AS1 and ZNF667 were significantly reversed by treatment with 5-Aza-dC and TSA in esophageal cancer cell lines.	('expression levels', 'MPA', (4, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('5-Aza-dC', 'Chemical', 'MESH:C014347', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ZNF667-AS1', 'Gene', '100128252', (25, 35))	('ZNF667-AS1', 'Gene', (25, 35))	('esophageal cancer', 'Disease', (113, 130))	('ZNF667', 'Var', (40, 46))	('TSA', 'Chemical', 'MESH:C070842', (106, 109))
459649	31804468	The CpG sites hypermethylation within proximal promoter influenced the binding ability of transcription factor E2F1 to the binding sites and then affected the transcription and expression of ZNF667-AS1 and ZNF667.	('binding', 'Interaction', (123, 130))	('hypermethylation', 'Var', (14, 30))	('ZNF667-AS1', 'Gene', '100128252', (191, 201))	('E2F1', 'Gene', (111, 115))	('ZNF667-AS1', 'Gene', (191, 201))	('expression', 'MPA', (177, 187))	('transcription', 'MPA', (159, 172))	('ZNF667', 'Gene', (206, 212))	('methyl', 'Chemical', 'MESH:C031105', (19, 25))	('binding', 'Interaction', (71, 78))	('affected', 'Reg', (146, 154))	('influenced', 'Reg', (56, 66))
459650	31804468	Overexpression of ZNF667-AS1 and ZNF667 suppressed the viability, migration, and invasion of esophageal cancer cells in vitro.	('migration', 'CPA', (66, 75))	('suppressed', 'NegReg', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('invasion', 'CPA', (81, 89))	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('viability', 'CPA', (55, 64))	('ZNF667-AS1', 'Gene', '100128252', (18, 28))	('ZNF667', 'Var', (33, 39))	('rat', 'Species', '10116', (69, 72))	('ZNF667-AS1', 'Gene', (18, 28))
459670	31804468	Sharing with the same CpG islands, whether expression of ZNF667-AS1 and ZNF667 are both regulated by DNA methylation in ESCC is unclear, furthermore, and the roles of both genes and the regulatory effect of each other in ESCC need to be clarified.	('ESCC', 'Disease', 'MESH:C562729', (120, 124))	('ZNF667-AS1', 'Gene', '100128252', (57, 67))	('ZNF667', 'Var', (72, 78))	('ZNF667-AS1', 'Gene', (57, 67))	('ESCC', 'Disease', (120, 124))	('ESCC', 'Disease', 'MESH:C562729', (221, 225))	('methyl', 'Chemical', 'MESH:C031105', (105, 111))	('ESCC', 'Disease', (221, 225))
459673	31804468	We first scanned the relative expression level of ZNF667-AS1 and ZNF667 in various tumor types in Gene Expression Profiling Interactive Analysis (GEPIA) data set, and found significant downregulation of ZNF667-AS1 and ZNF667 in most of the tumor types, including bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), and esophageal carcinoma (ESCA) (Fig.	('ESCA', 'Disease', (360, 364))	('tumor', 'Disease', (83, 88))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (338, 358))	('BLCA', 'Disease', 'MESH:D001749', (293, 297))	('ESCA', 'Disease', 'MESH:D004938', (360, 364))	('bladder urothelial carcinoma', 'Disease', (263, 291))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (240, 245))	('BRCA', 'Phenotype', 'HP:0003002', (327, 331))	('esophageal carcinoma', 'Disease', (338, 358))	('breast invasive carcinoma', 'Disease', (300, 325))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (263, 291))	('ZNF667-AS1', 'Gene', '100128252', (203, 213))	('ZNF667-AS1', 'Gene', (203, 213))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (349, 358))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('ESCA', 'Phenotype', 'HP:0011459', (360, 364))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (300, 325))	('BRCA', 'Gene', '672', (327, 331))	('downregulation', 'NegReg', (185, 199))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (338, 358))	('ZNF667', 'Var', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('ZNF667-AS1', 'Gene', '100128252', (50, 60))	('ZNF667-AS1', 'Gene', (50, 60))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (300, 325))	('BRCA', 'Gene', (327, 331))	('BLCA', 'Disease', (293, 297))
459675	31804468	Similarly, the relative expression levels of ZNF667-AS1 and ZNF667 in ESCC tissues were significantly decreased compared with corresponding normal tissues (P < 0.05) (Fig.	('decreased', 'NegReg', (102, 111))	('expression levels', 'MPA', (24, 41))	('ESCC', 'Disease', 'MESH:C562729', (70, 74))	('ZNF667-AS1', 'Gene', '100128252', (45, 55))	('ESCC', 'Disease', (70, 74))	('ZNF667', 'Var', (60, 66))	('ZNF667-AS1', 'Gene', (45, 55))
459676	31804468	Among them, the expression levels of ZNF667-AS1 in 86 cases (63.7%) and ZNF667 in 78 cases (57.8%) of tumors were lower than that in the corresponding normal tissues by more than 50%.	('ZNF667-AS1', 'Gene', '100128252', (37, 47))	('ZNF667-AS1', 'Gene', (37, 47))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('ZNF667', 'Var', (72, 78))	('expression levels', 'MPA', (16, 33))	('lower', 'NegReg', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
459679	31804468	We also detected positive correlation between the expression level of ZNF667-AS1 and ZNF667 in ESCC tissues (P < 0.05) (Fig.	('ESCC', 'Disease', 'MESH:C562729', (95, 99))	('ESCC', 'Disease', (95, 99))	('ZNF667-AS1', 'Gene', (70, 80))	('ZNF667-AS1', 'Gene', '100128252', (70, 80))	('ZNF667', 'Var', (85, 91))	('expression', 'MPA', (50, 60))
459682	31804468	We analyzed the distribution of CpG islands in the promoter and exon 1 regions of ZNF667-AS1 and ZNF667 by MethPrimer, and found two reversely distributed CpG islands spanning the promoter region to exon 1 of both genes (Fig.	('ZNF667', 'Var', (97, 103))	('ZNF667-AS1', 'Gene', (82, 92))	('ZNF667-AS1', 'Gene', '100128252', (82, 92))
459684	31804468	2b, c, the expression levels of ZNF667-AS1 and ZNF667 were significantly increased in the 5-Aza-dC or TSA treated cells, especially in the 5-Aza-dC+TSA treated cells.	('increased', 'PosReg', (73, 82))	('ZNF667-AS1', 'Gene', '100128252', (32, 42))	('ZNF667', 'Gene', (47, 53))	('ZNF667-AS1', 'Gene', (32, 42))	('TSA', 'Chemical', 'MESH:C070842', (148, 151))	('expression levels', 'MPA', (11, 28))	('5-Aza-dC', 'Chemical', 'MESH:C014347', (90, 98))	('5-Aza-dC', 'Chemical', 'MESH:C014347', (139, 147))	('5-Aza-dC', 'Var', (90, 98))	('TSA', 'Chemical', 'MESH:C070842', (102, 105))
459685	31804468	The methylation status of CpG loci in the distal promoter, proximal promoter, and exon 1 regions of ZNF667-AS1 and ZNF667 was then verified by BGS assay, and frequent hypermethylation of CpG loci was observed in three regions (Fig.	('methyl', 'Chemical', 'MESH:C031105', (4, 10))	('ZNF667-AS1', 'Gene', '100128252', (100, 110))	('ZNF667-AS1', 'Gene', (100, 110))	('hypermethylation', 'Var', (167, 183))	('methyl', 'Chemical', 'MESH:C031105', (172, 178))
459687	31804468	2e, hemimethylation or fully methylation of three regions was observed in esophageal cancer cells before 5-Aza-dC treatment, and fully methylation of region 2 was especially observed in four cancer cells.	('fully methylation', 'MPA', (23, 40))	('hemimethylation', 'Var', (4, 19))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('methyl', 'Chemical', 'MESH:C031105', (29, 35))	('methyl', 'Chemical', 'MESH:C031105', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('methyl', 'Chemical', 'MESH:C031105', (8, 14))	('cancer', 'Disease', (85, 91))	('esophageal cancer', 'Disease', (74, 91))	('5-Aza-dC', 'Chemical', 'MESH:C014347', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('observed', 'Reg', (62, 70))
459690	31804468	Of ESCC tissues and the corresponding normal tissues, methylation frequencies were as follows: 77.0% (104/135) and 34.1% (46/135) at region 1, 60.7% (82/135) and 11.1% (15/135) at region 2, 79.3% (107/135) and 20.7% (28/135) at region 3 (Supplementary Table 3).	('methylation', 'Var', (54, 65))	('ESCC', 'Disease', (3, 7))	('ESCC', 'Disease', 'MESH:C562729', (3, 7))	('methyl', 'Chemical', 'MESH:C031105', (54, 60))
459693	31804468	The expression of ZNF667-AS1 and ZNF667 was detected to be inversely correlated with the methylation status of region 2 (P < 0.05), but not with region 1 and region 3 (P > 0.05) (Fig.	('methyl', 'Chemical', 'MESH:C031105', (89, 95))	('correlated', 'Interaction', (69, 79))	('expression', 'MPA', (4, 14))	('ZNF667-AS1', 'Gene', '100128252', (18, 28))	('ZNF667', 'Var', (33, 39))	('methylation status', 'MPA', (89, 107))	('ZNF667-AS1', 'Gene', (18, 28))
459694	31804468	Furthermore, the 5-year survival rate of ESCC patients with region 2 hypermethylation was significantly lower compared with those with unmethylation of this region (P < 0.05) (Fig.	('patients', 'Species', '9606', (46, 54))	('ESCC', 'Disease', 'MESH:C562729', (41, 45))	('hypermethylation', 'Var', (69, 85))	('rat', 'Species', '10116', (33, 36))	('ESCC', 'Disease', (41, 45))	('lower', 'NegReg', (104, 109))	('methyl', 'Chemical', 'MESH:C031105', (74, 80))	('methyl', 'Chemical', 'MESH:C031105', (137, 143))
459695	31804468	Cox multivariate analysis further demonstrated that region 2 hypermethylation was also an independent prognostic factor for ESCC patients' survival in addition to the factors such as TNM stage, pathological differentiation, lymph node metastasis, and family history of UGIC (Supplementary Table 5).	('UGIC', 'Disease', 'MESH:D005770', (269, 273))	('UGIC', 'Disease', (269, 273))	('methyl', 'Chemical', 'MESH:C031105', (66, 72))	('patients', 'Species', '9606', (129, 137))	('ESCC', 'Disease', 'MESH:C562729', (124, 128))	('TNM', 'Gene', '10178', (183, 186))	('rat', 'Species', '10116', (41, 44))	('hypermethylation', 'Var', (61, 77))	('TNM', 'Gene', (183, 186))	('ESCC', 'Disease', (124, 128))
459698	31804468	The luciferase activity of in vitro methylated pGL3-A1 and pGL3-Z2 was significantly decreased compared with unmethylated pGL3-A1 and pGL3-Z2 constructs, while methylated pGL3-Z1 construct demonstrated no apparent decrease of luciferase activity compared with unmethylated pGL3-Z1 construct (Fig.	('pGL3', 'Gene', '6391', (171, 175))	('methyl', 'Chemical', 'MESH:C031105', (262, 268))	('pGL3', 'Gene', '6391', (59, 63))	('pGL3', 'Gene', (273, 277))	('pGL3', 'Gene', (122, 126))	('pGL3', 'Gene', '6391', (273, 277))	('pGL3', 'Gene', '6391', (122, 126))	('activity', 'MPA', (15, 23))	('methyl', 'Chemical', 'MESH:C031105', (36, 42))	('rat', 'Species', '10116', (196, 199))	('activity', 'MPA', (237, 245))	('pGL3', 'Gene', (47, 51))	('luciferase', 'Enzyme', (226, 236))	('pGL3', 'Gene', (134, 138))	('luciferase', 'Enzyme', (4, 14))	('methyl', 'Chemical', 'MESH:C031105', (111, 117))	('methylated', 'Var', (36, 46))	('pGL3', 'Gene', '6391', (47, 51))	('decreased', 'NegReg', (85, 94))	('pGL3', 'Gene', '6391', (134, 138))	('methyl', 'Chemical', 'MESH:C031105', (160, 166))	('pGL3', 'Gene', (59, 63))	('pGL3', 'Gene', (171, 175))
459704	31804468	The binding properties of E2F1 or Sp1 at site 2 or site 5 of ZNF667-AS1 were further validated by ChIP assay in Eca109 cells with or without 5-Aza-dC treatment.	('ZNF667-AS1', 'Gene', '100128252', (61, 71))	('ZNF667-AS1', 'Gene', (61, 71))	('binding', 'Interaction', (4, 11))	('E2F1', 'Var', (26, 30))	('5-Aza-dC', 'Chemical', 'MESH:C014347', (141, 149))
459705	31804468	3f, significant increased enrichment in site 2 and site 5 with anti-E2F1 antibody was observed in 5-Aza-dC treated Eca109 cells compared with control, while no apparent variation was detected with anti-Sp1 antibody in 5-Aza-dC treated Eca109 cells, suggesting the key transcriptional regulation of E2F1 on ZNF667-AS1 and ZNF667 transcription within the proximal promoter.	('ZNF667', 'Gene', (321, 327))	('anti-E2F1', 'Var', (63, 72))	('increased', 'PosReg', (16, 25))	('E2F1', 'Gene', (298, 302))	('ZNF667-AS1', 'Gene', '100128252', (306, 316))	('ZNF667-AS1', 'Gene', (306, 316))	('5-Aza-dC', 'Chemical', 'MESH:C014347', (98, 106))	('5-Aza-dC', 'Chemical', 'MESH:C014347', (218, 226))
459706	31804468	Co-transfection of pGL3-A1 or pGL3-Z2 and E2F1 significantly raised the luciferase activity, while the stimulating effect was abrogated when pGL3-A1 or pGL3-Z2 construct was in vitro methylated, suggesting that CpG sites hypermethylation within proximal promoter of ZNF667-AS1 or ZNF667 might abolish E2F1 binding and the following transcriptional activation of them (Fig.	('pGL3', 'Gene', '6391', (30, 34))	('abolish', 'NegReg', (293, 300))	('pGL3', 'Gene', (19, 23))	('E2F1', 'Protein', (301, 305))	('pGL3', 'Gene', '6391', (19, 23))	('pGL3', 'Gene', (152, 156))	('raised', 'PosReg', (61, 67))	('binding', 'Interaction', (306, 313))	('pGL3', 'Gene', '6391', (152, 156))	('transcriptional', 'MPA', (332, 347))	('methyl', 'Chemical', 'MESH:C031105', (226, 232))	('ZNF667-AS1', 'Gene', '100128252', (266, 276))	('ZNF667-AS1', 'Gene', (266, 276))	('pGL3', 'Gene', (141, 145))	('activity', 'MPA', (83, 91))	('activation', 'PosReg', (348, 358))	('methyl', 'Chemical', 'MESH:C031105', (183, 189))	('pGL3', 'Gene', '6391', (141, 145))	('pGL3', 'Gene', (30, 34))	('ZNF667', 'Var', (280, 286))	('luciferase', 'Enzyme', (72, 82))
459707	31804468	Furthermore, 5-Aza-dC treatment and E2F1 overexpression significantly increased the expression level of ZNF667-AS1 and ZNF667 compared with single 5-Aza-dC treatment or E2F1 overexpression cells (Fig.	('5-Aza-dC', 'Chemical', 'MESH:C014347', (147, 155))	('ZNF667', 'Var', (119, 125))	('increased', 'PosReg', (70, 79))	('E2F1', 'Gene', (36, 40))	('expression level', 'MPA', (84, 100))	('ZNF667-AS1', 'Gene', '100128252', (104, 114))	('ZNF667-AS1', 'Gene', (104, 114))	('5-Aza-dC', 'Chemical', 'MESH:C014347', (13, 21))
459714	31804468	Moreover, pcDNA3.1-ZNF667 transfection significantly inhibited migration and invasive ability of Eca109 and TE13 cells (Fig.	('invasive ability of Eca109', 'CPA', (77, 103))	('inhibited', 'NegReg', (53, 62))	('transfection', 'Var', (26, 38))	('pcDNA3.1-ZNF667', 'Var', (10, 25))	('rat', 'Species', '10116', (66, 69))
459715	31804468	3E), and knockdown of ZNF667 significantly increased the viability, migration, and invasion ability of Kyse170 cells (Supplementary Fig.	('knockdown', 'Var', (9, 18))	('ZNF667', 'Gene', (22, 28))	('rat', 'Species', '10116', (71, 74))	('invasion ability', 'CPA', (83, 99))	('increased', 'PosReg', (43, 52))	('viability', 'CPA', (57, 66))	('migration', 'CPA', (68, 77))
459720	31804468	Similarly, overexpression or knockdown of ZNF667-AS1 led to an increased or reduced protein expression level of ZNF667 (Fig.	('knockdown', 'Var', (29, 38))	('ZNF667', 'Gene', (112, 118))	('ZNF667-AS1', 'Gene', '100128252', (42, 52))	('reduced', 'NegReg', (76, 83))	('protein expression level', 'MPA', (84, 108))	('ZNF667-AS1', 'Gene', (42, 52))
459727	31804468	Hypermethylation of E-cadherin at promoter CpG sites is a recognized mechanism of its inactivation in many cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Hypermethylation', 'Var', (0, 16))	('inactivation', 'NegReg', (86, 98))	('E-cadherin', 'Gene', (20, 30))	('E-cadherin', 'Gene', '999', (20, 30))	('methyl', 'Chemical', 'MESH:C031105', (5, 11))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
459738	31804468	Loss of TET1 increased EZH2 expression and reduced UTX expression in DLD1 cells, thus increasing histone H3K27 tri-methylation on target gene promoter and leading to repression of the target gene.	('UTX', 'Gene', (51, 54))	('histone H3K27', 'Protein', (97, 110))	('tri-methylation', 'MPA', (111, 126))	('expression', 'MPA', (28, 38))	('methyl', 'Chemical', 'MESH:C031105', (115, 121))	('UTX', 'Gene', '7403', (51, 54))	('TET1', 'Gene', '80312', (8, 12))	('TET1', 'Gene', (8, 12))	('repression', 'MPA', (166, 176))	('EZH2', 'Gene', '2146', (23, 27))	('increasing', 'PosReg', (86, 96))	('reduced', 'NegReg', (43, 50))	('Loss', 'Var', (0, 4))	('increased', 'PosReg', (13, 22))	('EZH2', 'Gene', (23, 27))
459749	31804468	Single transfection of pcDNA3.1-TET1 or pcDNA3.1-UTX decreased the viability of Eca109 cells, while co-transfection of pcDNA3.1-TET1 and pcDNA3.1-UTX significantly decreased the viability of Eca109 cells than the solely transfected cells; furthermore, co-overexpression of ZNF667-AS1, TET1, and UTX strikingly inhibited the viability of Eca109 cells, and co-overexpression of TET1 and UTX accompanied with knockdown of ZNF667-AS1 partially offseted the inhibitory effect (Fig.	('UTX', 'Gene', '7403', (295, 298))	('TET1', 'Gene', (376, 380))	('offseted', 'NegReg', (440, 448))	('TET1', 'Gene', '80312', (285, 289))	('TET1', 'Gene', (128, 132))	('TET1', 'Gene', (32, 36))	('viability', 'CPA', (324, 333))	('ZNF667-AS1', 'Gene', '100128252', (419, 429))	('ZNF667-AS1', 'Gene', (419, 429))	('UTX', 'Gene', (385, 388))	('TET1', 'Gene', (285, 289))	('ZNF667-AS1', 'Gene', '100128252', (273, 283))	('knockdown', 'Var', (406, 415))	('ZNF667-AS1', 'Gene', (273, 283))	('UTX', 'Gene', (146, 149))	('UTX', 'Gene', '7403', (385, 388))	('UTX', 'Gene', '7403', (146, 149))	('TET1', 'Gene', '80312', (376, 380))	('decreased', 'NegReg', (53, 62))	('inhibited', 'NegReg', (310, 319))	('UTX', 'Gene', (49, 52))	('decreased', 'NegReg', (164, 173))	('UTX', 'Gene', '7403', (49, 52))	('TET1', 'Gene', '80312', (128, 132))	('UTX', 'Gene', (295, 298))	('TET1', 'Gene', '80312', (32, 36))
459751	31804468	As a head-to-head lncRNA, ZNF667-AS1 and its antisense transcript ZNF667 are both located in 19q13.43.	('ZNF667-AS1', 'Gene', '100128252', (26, 36))	('ZNF667', 'Var', (66, 72))	('ZNF667-AS1', 'Gene', (26, 36))
459752	31804468	The role of ZNF667-AS1 and ZNF667 has been reported in several types of cancers; however, the functional role of them in ESCC has not been clarified.	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('ZNF667-AS1', 'Gene', '100128252', (12, 22))	('ZNF667-AS1', 'Gene', (12, 22))	('ZNF667', 'Var', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ESCC', 'Disease', 'MESH:C562729', (121, 125))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('reported', 'Reg', (43, 51))	('ESCC', 'Disease', (121, 125))
459755	31804468	This epigenetic silencing was also seen in human breast cancer cell lines and in a majority of human breast tumor tissues.	('human', 'Species', '9606', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast tumor', 'Disease', (101, 113))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast tumor', 'Disease', 'MESH:D061325', (101, 113))	('epigenetic silencing', 'Var', (5, 25))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('breast tumor', 'Phenotype', 'HP:0100013', (101, 113))	('human', 'Species', '9606', (43, 48))
459756	31804468	Furthermore, analysis of TCGA data across 16 human cancers revealed that deregulation of ZNF667-AS1 expression due to DNA hypermethylation was a frequent event in most common human cancers.	('human', 'Species', '9606', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('ZNF667-AS1', 'Gene', '100128252', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('ZNF667-AS1', 'Gene', (89, 99))	('expression', 'MPA', (100, 110))	('human', 'Species', '9606', (45, 50))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('methyl', 'Chemical', 'MESH:C031105', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (181, 188))	('DNA hypermethylation', 'Var', (118, 138))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('deregulation', 'MPA', (73, 85))
459760	31804468	Similarly, Aberrant methylation and downregulation of ZNF667-AS1 promoted the malignant progression of laryngeal squamous cell carcinoma.	('downregulation', 'NegReg', (36, 50))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 136))	('malignant progression', 'CPA', (78, 99))	('ZNF667-AS1', 'Gene', '100128252', (54, 64))	('ZNF667-AS1', 'Gene', (54, 64))	('laryngeal squamous cell carcinoma', 'Disease', (103, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('promoted', 'PosReg', (65, 73))	('methylation', 'Var', (20, 31))	('Aberrant methylation', 'Var', (11, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('methyl', 'Chemical', 'MESH:C031105', (20, 26))
459761	31804468	In this study, we also found downregulation of ZNF667-AS1 in esophageal cancer cell lines and ESCC tissues, and proximal promoter hypermethylation may be one of the mechanisms in leading to its silencing; together with the inhibiting effect of ZNF667-AS1 on esophageal cancer cells viability, migration, and invasion; suggesting the tumor-suppressor role of ZNF667-AS1 in ESCC tumorigenesis.	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('ZNF667-AS1', 'Gene', '100128252', (47, 57))	('ZNF667-AS1', 'Gene', (47, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (258, 275))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('esophageal cancer', 'Disease', (61, 78))	('downregulation', 'NegReg', (29, 43))	('ZNF667-AS1', 'Gene', '100128252', (358, 368))	('esophageal cancer', 'Disease', (258, 275))	('tumor', 'Disease', (377, 382))	('ESCC', 'Disease', 'MESH:C562729', (372, 376))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('silencing', 'MPA', (194, 203))	('ZNF667-AS1', 'Gene', '100128252', (244, 254))	('tumor', 'Disease', 'MESH:D009369', (377, 382))	('ZNF667-AS1', 'Gene', (244, 254))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('ESCC', 'Disease', 'MESH:C562729', (94, 98))	('rat', 'Species', '10116', (296, 299))	('ESCC', 'Disease', (372, 376))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('tumor', 'Disease', (333, 338))	('methyl', 'Chemical', 'MESH:C031105', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('hypermethylation', 'Var', (130, 146))	('ESCC', 'Disease', (94, 98))	('ZNF667-AS1', 'Gene', (358, 368))
459763	31804468	ZNF667 was also detected to inhibit the expression and the promoter activity of the rat proapoptotic gene Bax gene, and at the same time prevented apoptosis of H9c2 cells, induced by H2O2 and Dox.	('expression', 'MPA', (40, 50))	('prevented', 'NegReg', (137, 146))	('H9c2', 'CellLine', 'CVCL:0286', (160, 164))	('rat', 'Species', '10116', (84, 87))	('Dox', 'Chemical', 'MESH:C561093', (192, 195))	('ZNF667', 'Var', (0, 6))	('Bax', 'Gene', (106, 109))	('Bax', 'Gene', '24887', (106, 109))	('promoter activity', 'MPA', (59, 76))	('apoptosis', 'CPA', (147, 156))	('H2O2', 'Chemical', 'MESH:D014867', (183, 187))	('inhibit', 'NegReg', (28, 35))
459770	31804468	The promoter region of gene contains many binding sites of transcription factors and aberrant CpG dinucleotides hypermethylation in this region may directly or indirectly affect the binding ability of transcription factors.	('methyl', 'Chemical', 'MESH:C031105', (117, 123))	('transcription', 'Protein', (201, 214))	('aberrant', 'Var', (85, 93))	('dinucleotides', 'Chemical', 'MESH:C015772', (98, 111))	('binding', 'Interaction', (182, 189))	('affect', 'Reg', (171, 177))
459771	31804468	Further analyses verified the CpG sites hypermethylation within two binding sites of E2F1 in the proximal promoter region of ZNF667-AS1 and ZNF667 may influence the binding ability of E2F1 to the binding sites, and further led to the transcriptional inhibition of ZNF667-AS1 and ZNF667.	('methyl', 'Chemical', 'MESH:C031105', (45, 51))	('binding', 'Interaction', (165, 172))	('led to', 'Reg', (223, 229))	('hypermethylation', 'Var', (40, 56))	('ZNF667-AS1', 'Gene', '100128252', (264, 274))	('ZNF667-AS1', 'Gene', (264, 274))	('E2F1', 'Gene', (85, 89))	('influence', 'Reg', (151, 160))	('ZNF667-AS1', 'Gene', '100128252', (125, 135))	('ZNF667-AS1', 'Gene', (125, 135))	('transcriptional', 'MPA', (234, 249))
459772	31804468	Moreover, pGL3-Z1 construct (-269 to +75 bp) also demonstrated relative higher luciferase activity, however, methylated pGL3-Z1 construct demonstrated no apparent decrease of luciferase activity compared with unmethylated pGL3-Z1 construct, suggesting that other transcription factors may also participate in the transcriptional regulation of ZNF667 and the binding ability cannot be influenced by CpG dinucleotides hypermethylation.	('pGL3', 'Gene', '6391', (222, 226))	('pGL3', 'Gene', '6391', (120, 124))	('activity', 'MPA', (90, 98))	('-269', 'Var', (29, 33))	('dinucleotides', 'Chemical', 'MESH:C015772', (402, 415))	('pGL3', 'Gene', '6391', (10, 14))	('methyl', 'Chemical', 'MESH:C031105', (421, 427))	('rat', 'Species', '10116', (145, 148))	('participate', 'Reg', (294, 305))	('methyl', 'Chemical', 'MESH:C031105', (211, 217))	('luciferase', 'Enzyme', (79, 89))	('methyl', 'Chemical', 'MESH:C031105', (109, 115))	('higher', 'PosReg', (72, 78))	('rat', 'Species', '10116', (57, 60))	('pGL3', 'Gene', (222, 226))	('pGL3', 'Gene', (120, 124))	('pGL3', 'Gene', (10, 14))
459775	31804468	As an epithelial marker, E-cadherin was inactivated in many kinds of cancers, and its inactivation was partly attributed to the aberrant promoter CpG sites hypermethylation.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('hypermethylation', 'Var', (156, 172))	('E-cadherin', 'Gene', (25, 35))	('inactivated', 'NegReg', (40, 51))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('E-cadherin', 'Gene', '999', (25, 35))	('cancers', 'Disease', (69, 76))	('methyl', 'Chemical', 'MESH:C031105', (161, 167))
459777	31804468	E-cadherin has been reported to be the TET target gene, and ZNF667 could be regulated by CpG sites methylation.	('regulated', 'Reg', (76, 85))	('methylation', 'Var', (99, 110))	('ZNF667', 'Gene', (60, 66))	('E-cadherin', 'Gene', (0, 10))	('methyl', 'Chemical', 'MESH:C031105', (99, 105))	('CpG sites methylation', 'Var', (89, 110))	('E-cadherin', 'Gene', '999', (0, 10))
459778	31804468	In this study, promoter CpG sites hypermethylation status of ZNF667 and E-cadherin was found to be demethylated by TET1, and ZNF667-AS1 could interact and recruit TET1 to ZNF667 and E-cadherin to hydrolyze 5'-mc to 5'-hmc and further activates their expression.	('hypermethylation', 'Var', (34, 50))	('TET1', 'Gene', (163, 167))	('interact', 'Interaction', (142, 150))	('TET1', 'Gene', (115, 119))	("5'-mc", 'Chemical', 'MESH:D044503', (206, 211))	('ZNF667-AS1', 'Gene', '100128252', (125, 135))	('ZNF667-AS1', 'Gene', (125, 135))	('recruit', 'PosReg', (155, 162))	('ZNF667', 'Gene', (61, 67))	('methyl', 'Chemical', 'MESH:C031105', (101, 107))	('activates', 'PosReg', (234, 243))	("hydrolyze 5'-mc to 5'-hmc", 'MPA', (196, 221))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))	('TET1', 'Gene', '80312', (115, 119))	('TET1', 'Gene', '80312', (163, 167))	("5'-hmc", 'Chemical', 'MESH:C011865', (215, 221))	('methyl', 'Chemical', 'MESH:C031105', (39, 45))	('E-cadherin', 'Gene', (182, 192))	('E-cadherin', 'Gene', '999', (182, 192))	('expression', 'MPA', (250, 260))
459783	31804468	Furthermore, ZNF667-AS1 and ZNF667 may serve as potential prognostic markers in predicting ESCC patients' survival.	('ZNF667', 'Var', (28, 34))	('ESCC', 'Disease', (91, 95))	('ZNF667-AS1', 'Gene', '100128252', (13, 23))	('ZNF667-AS1', 'Gene', (13, 23))	('patients', 'Species', '9606', (96, 104))	('ESCC', 'Disease', 'MESH:C562729', (91, 95))
459805	31804468	The pGL3-A1, pGL3-Z1, and pGL3-Z2 constructs were, respectively, in vitro methylated as described previously.	('pGL3', 'Gene', '6391', (4, 8))	('pGL3', 'Gene', (13, 17))	('pGL3', 'Gene', (26, 30))	('methyl', 'Chemical', 'MESH:C031105', (74, 80))	('pGL3', 'Gene', (4, 8))	('pGL3', 'Gene', '6391', (26, 30))	('methylated', 'Var', (74, 84))	('pGL3', 'Gene', '6391', (13, 17))
459810	31804468	The Eca109 and TE13 cells were, respectively, transfected with pcDNA3.1-ZNF667-AS1 or pcDNA3.1-ZNF667 expression plasmid or the empty vector (pcDNA3.1-NC) as control at a final concentration of 2 microg/microL using FuGENE HD Transfection Reagent (Promega, Madison, WI, USA).	('pcDNA3.1-ZNF667', 'Var', (86, 101))	('rat', 'Species', '10116', (184, 187))	('ZNF667-AS1', 'Gene', (72, 82))	('ZNF667-AS1', 'Gene', '100128252', (72, 82))	('HD', 'Disease', 'MESH:D006816', (223, 225))
459811	31804468	For inhibition of ZNF667-AS1 or ZNF667, Kyse170 cells were, respectively, transfected with ZNF667-AS1- or ZNF667-specific shRNA plasmid using FuGENE HD Transfection Reagent, and a scrambled shRNA was used as a negative control.	('ZNF667-AS1', 'Gene', '100128252', (91, 101))	('HD', 'Disease', 'MESH:D006816', (149, 151))	('ZNF667-AS1', 'Gene', (91, 101))	('ZNF667-specific', 'Var', (106, 121))	('ZNF667-AS1', 'Gene', '100128252', (18, 28))	('ZNF667-AS1', 'Gene', (18, 28))
459813	31804468	The viability of pcDNA3.1-ZNF667-AS1 or pcDNA3.1-ZNF667 transfected Eca109 and TE13 cells or shRNA transfected Kyse170 cells was determined by cell-counting kit-8 (CCK-8) assay following the manufacturer's guidelines.	('pcDNA3.1-ZNF667', 'Var', (40, 55))	('ZNF667-AS1', 'Gene', '100128252', (26, 36))	('ZNF667-AS1', 'Gene', (26, 36))
459844	31299933	Multiple factors could contribute to sex dimorphism of human cancers, such as sex-specific genetic variations and mutations and sex-specific responses to carcinogens.	('mutations', 'Var', (114, 123))	('human', 'Species', '9606', (55, 60))	('genetic variations', 'Var', (91, 109))	('contribute', 'Reg', (23, 33))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('variations', 'Var', (99, 109))
459992	28577763	They regulate numerous cellular processes and dysregulation of their function has been associated with the pathogenesis of many diseases, including cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('regulate', 'Reg', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('associated', 'Reg', (87, 97))	('cellular', 'CPA', (23, 31))	('dysregulation', 'Var', (46, 59))
459995	28577763	In another pilot study, a different combination of two miRNAs, miR-194-5p and miR-451a, were significantly increased and one, miR136, significantly decreased in BE compared to controls.	('miR-451a', 'Gene', '574411', (78, 86))	('miR-451a', 'Gene', (78, 86))	('miR136', 'Gene', '406927', (126, 132))	('miR-194-5p', 'Var', (63, 73))	('increased', 'PosReg', (107, 116))	('decreased', 'NegReg', (148, 157))	('miR136', 'Gene', (126, 132))	('BE', 'Phenotype', 'HP:0100580', (161, 163))
460016	27810391	Cancer location is not important for adenocarcinoma staging, but in conjunction with grade it is necessary to subgroup pT3N0M0 squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('adenocarcinoma staging', 'Disease', 'MESH:D000230', (37, 59))	('pT3N0M0', 'Var', (119, 126))	('adenocarcinoma staging', 'Disease', (37, 59))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('squamous cell carcinoma', 'Disease', (127, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 150))
460022	27810391	Subcategorization of T1 combined with grade requires three pStage I subgroups: pStage IA (pT1aN0M0G1), pStage IB (pT1aN0M0G2 and pT1bN0M0G1-2), and pStage IC (pT1N0M0G3 and pT2N0M0G1-2).	('pT1', 'Gene', '58492', (114, 117))	('pT2N0M0G1-2', 'Var', (173, 184))	('pT1', 'Gene', (159, 162))	('pT1', 'Gene', (90, 93))	('pStage IB', 'Disease', (103, 112))	('pT1', 'Gene', (114, 117))	('pStage IA', 'Disease', (79, 88))	('pT1', 'Gene', '58492', (129, 132))	('pT1', 'Gene', '58492', (159, 162))	('pT1', 'Gene', '58492', (90, 93))	('pT1', 'Gene', (129, 132))
460023	27810391	pT2N0M0G3 remains the sole cancer in pStage IIA.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('pStage IIA', 'Disease', (37, 47))	('pT2N0M0G3', 'Var', (0, 9))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
460026	27810391	pT2N1M0 and pT1N2M0 form pStage IIIA, whereas pT2N2M0, pT3N1-2M0, and pT4aN0-1M0 form pStage IIIB.	('pStage IIIA', 'Disease', (25, 36))	('pT2N2M0', 'Var', (46, 53))	('pT1', 'Gene', '58492', (12, 15))	('pT2N1M0', 'Var', (0, 7))	('pT3N1-2M0', 'Var', (55, 64))	('pT1', 'Gene', (12, 15))	('pT4aN0-1M0', 'Var', (70, 80))
460028	27810391	pT4aN2M0, pT4bN0-2M0, and pTanyN3M0 are pStage IVA.	('IVA', 'Disease', (47, 50))	('IVA', 'Disease', 'MESH:C538167', (47, 50))	('pTanyN3M0', 'Var', (26, 35))	('pT4aN2M0', 'Var', (0, 8))	('pT4bN0-2M0', 'Var', (10, 20))
460030	27810391	Subcategorization of T1 combined with grade requires two pStage I subgroups: pStage IA (pT1aN0M0G1) and pStage IB (pT1aN0M0G2-3, pT1bN0M0, and pT2N0M0G1).	('pT1', 'Gene', '58492', (115, 118))	('pStage IA', 'Disease', (77, 86))	('pT2N0M0G1', 'Var', (143, 152))	('pT1', 'Gene', '58492', (88, 91))	('pT1', 'Gene', '58492', (129, 132))	('pT1', 'Gene', (115, 118))	('pT1', 'Gene', (88, 91))	('pT1', 'Gene', (129, 132))
460031	27810391	pStage IIA comprises pT2N0M0G2-3 cancers, pT3N0M0 cancers of the lower thoracic esophagus, and pT3N0M0G1 cancers of the upper middle thoracic esophagus.	('cancers of the upper middle thoracic esophagus', 'Disease', 'MESH:D004938', (105, 151))	('cancers of the upper middle thoracic esophagus', 'Disease', (105, 151))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('pT2N0M0G2-3', 'Var', (21, 32))	('pT3N0M0', 'Var', (42, 49))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('pT3N0M0G1', 'Var', (95, 104))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', (50, 57))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
460032	27810391	pStage IIB comprises T3N0M0G2-3 cancers of the upper middle thoracic esophagus and pT1N1M0 cancers.	('cancers of the upper middle thoracic esophagus', 'Disease', (32, 78))	('pT1', 'Gene', '58492', (83, 86))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (32, 39))	('cancers', 'Disease', (91, 98))	('pT1', 'Gene', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers of the upper middle thoracic esophagus', 'Disease', 'MESH:D004938', (32, 78))	('T3N0M0G2-3', 'Var', (21, 31))
460035	27810391	Drivers of this addition include absence of equivalent pathologic (pTNM) categories for the peculiar postneoadjuvant pathologic categories (ypT0N0-3M0 and ypTisN0-3M0), dissimilar stage group compositions, and markedly different survival profiles.	('TNM', 'Gene', '10178', (68, 71))	('ypTisN0-3M0', 'Var', (155, 166))	('TNM', 'Gene', (68, 71))	('ypT0N0-3M0', 'Var', (140, 150))	('postneoadjuvant pathologic', 'Disease', (101, 127))
460038	27810391	ypStage IIIB comprises ypT1-3N2M0, ypT3N1M0, and ypT4aN0M0 cancers.	('cancers', 'Disease', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ypT1', 'Gene', (23, 27))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('ypT1', 'Gene', '5861', (23, 27))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('ypT4aN0M0', 'Var', (49, 58))	('ypT3N1M0', 'Var', (35, 43))
460039	27810391	ypStage IVA includes ypT4aN1-2M0, ypT4bN0-2M0, and yp TanyN3M0.	('yp TanyN3M0', 'Var', (51, 62))	('ypT4aN1-2M0', 'Var', (21, 32))	('IVA', 'Disease', (8, 11))	('ypT4bN0-2M0', 'Var', (34, 45))	('IVA', 'Disease', 'MESH:C538167', (8, 11))
460044	27810391	cStage IVA consists of T4bN0-1M0 and all cN2-N3M0 cancers.	('cN2', 'Gene', '55748', (41, 44))	('IVA', 'Disease', (7, 10))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('T4bN0-1M0', 'Var', (23, 32))	('cancers', 'Disease', (50, 57))	('IVA', 'Disease', 'MESH:C538167', (7, 10))	('cN2', 'Gene', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
460046	27810391	cStage II comprises cT2N0-1M0 and cT3N0M0 cancers.	('cancers', 'Disease', (42, 49))	('cT3N0M0', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
460047	27810391	cStage III comprises cT3N1M0 and cT1-3N2M0 cancers.	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cT1-3N2M0', 'Var', (33, 42))
460048	27810391	cT4N0-2M0 and all cN3M0 cancers are placed in cStage IVA.	('IVA', 'Disease', (53, 56))	('IVA', 'Disease', 'MESH:C538167', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cN3M0', 'Var', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))
460148	23016606	Invasive carcinoma was found in 6 of 44 patients with nodular mucosa and a negative EUS, or 14% of such patients who had an EMR (6/44).	('carcinoma', 'Disease', 'MESH:D002277', (9, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('patients', 'Species', '9606', (40, 48))	('found', 'Reg', (23, 28))	('nodular mucosa', 'Var', (54, 68))	('carcinoma', 'Disease', (9, 18))	('patients', 'Species', '9606', (104, 112))
460234	25743452	p63 and Sox2 define the development of the normal esophageal epithelium; loss of either results in the failure of squamous epithelial formation and the persistence of mucus-producing ciliated columnar epithelial cells in embryonic and newborn mice.	('failure', 'NegReg', (103, 110))	('loss', 'Var', (73, 77))	('squamous epithelial formation', 'CPA', (114, 143))	('columnar epithelia', 'Disease', (192, 210))	('columnar epithelia', 'Disease', 'None', (192, 210))	('mice', 'Species', '10090', (243, 247))
460267	25743452	In contrast the CP-A, B, C, and D cell lines all have documented chromosomal abnormalities, including 17p loss of heterozygosity or p53 mutations documented in CP-B, C, and D lines.	('CP-A, B', 'Gene', '1357;1360', (16, 23))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('chromosomal abnormalities', 'Disease', (65, 90))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (65, 90))	('mutations', 'Var', (136, 145))	('CP-B', 'Gene', '1360', (160, 164))	('CP-B', 'Gene', (160, 164))	('loss of heterozygosity', 'NegReg', (106, 128))
460291	25743452	In addition, using this same OTC system, we determined through a genetic approach that the onset of a true BE from keratinocytes is a multistep process that requires increased proliferation, senescence inhibition, and epigenetic alterations.	('rat', 'Species', '10116', (183, 186))	('rat', 'Species', '10116', (117, 120))	('senescence', 'CPA', (191, 201))	('epigenetic alterations', 'Var', (218, 240))	('increased', 'PosReg', (166, 175))	('rat', 'Species', '10116', (233, 236))
460334	24885614	The polled en bloc resection rate was 99% (95% CI, 98%-100%) for large tumor (D >= 25 mm) and 100% (95% CI, 99%-100%) for small tumor (Figure 2).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('small tumor', 'Disease', 'MESH:D058405', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('D >= 25 mm', 'Var', (78, 88))	('small tumor', 'Disease', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', (71, 76))
460376	24349361	Association between the STK15 F31I Polymorphism and Cancer Susceptibility: A Meta-Analysis Involving 43,626 Subjects The association between the Serine/threonine kinase 15 (STK15) F31I polymorphism (rs2273535) and cancer susceptibility remains controversial.	('cancer', 'Disease', (214, 220))	('Serine/threonine kinase 15', 'Gene', (145, 171))	('F31I', 'Mutation', 'rs2273535', (30, 34))	('F31I', 'Var', (180, 184))	('STK15', 'Gene', (24, 29))	('Cancer', 'Disease', (52, 58))	('rs2273535', 'Var', (199, 208))	('Serine/threonine kinase 15', 'Gene', '6790', (145, 171))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('STK15', 'Gene', '6790', (24, 29))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('rs2273535', 'Mutation', 'rs2273535', (199, 208))	('F31I', 'Mutation', 'rs2273535', (180, 184))	('STK15', 'Gene', '6790', (173, 178))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('STK15', 'Gene', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
460378	24349361	Our results indicate statistical evidence of an association between the STK15 F31I polymorphism and the increased risk of overall cancer in four genetic models: AA vs. TA+TT, AA vs. TT, AA vs. TA, and A vs. T. In a stratified analysis by cancer type, there was an increased risk of breast cancer in four genetic models: AA vs. TA+TT, AA vs. TT, AA vs. TA, and A vs. T, as well as esophageal cancer in two genetic models: AA vs. TA+TT and AA vs. TA.	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('STK15', 'Gene', (72, 77))	('cancer', 'Disease', (391, 397))	('cancer', 'Phenotype', 'HP:0002664', (391, 397))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('F31I', 'Mutation', 'rs2273535', (78, 82))	('polymorphism', 'Var', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('STK15', 'Gene', '6790', (72, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (282, 295))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('breast cancer', 'Disease', 'MESH:D001943', (282, 295))	('breast cancer', 'Disease', (282, 295))	('cancer', 'Disease', 'MESH:D009369', (391, 397))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('esophageal cancer', 'Disease', 'MESH:D004938', (380, 397))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal cancer', 'Disease', (380, 397))	('cancer', 'Disease', (289, 295))
460380	24349361	In summary, this meta-analysis demonstrates that the STK15 F31I polymorphism may be a risk factor for cancer.	('F31I polymorphism', 'Var', (59, 76))	('STK15', 'Gene', (53, 58))	('risk factor', 'Reg', (86, 97))	('STK15', 'Gene', '6790', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('F31I', 'Mutation', 'rs2273535', (59, 63))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('polymorphism', 'Var', (64, 76))
460386	24349361	A non-synonymous single nucleotide polymorphism (SNP) of STK15, the F31I polymorphism (rs2273535), has been identified in the coding region of STK15.	('F31I', 'Mutation', 'rs2273535', (68, 72))	('STK15', 'Gene', (57, 62))	('STK15', 'Gene', '6790', (57, 62))	('rs2273535', 'Var', (87, 96))	('STK15', 'Gene', (143, 148))	('STK15', 'Gene', '6790', (143, 148))	('rs2273535', 'Mutation', 'rs2273535', (87, 96))
460387	24349361	The STK15 F31I polymorphism (91 T A), a SNP in exon 3 of STK15, encodes a phenylalanine isoleucine substitution at amino acid residue 31 (F31I).	('STK15', 'Gene', (57, 62))	('STK15', 'Gene', '6790', (57, 62))	('STK15', 'Gene', '6790', (4, 9))	('STK15', 'Gene', (4, 9))	('F31I', 'Mutation', 'rs2273535', (10, 14))	('F31I', 'Mutation', 'rs2273535', (138, 142))	('phenylalanine isoleucine', 'Chemical', '-', (74, 98))	('F31I', 'Var', (10, 14))
460388	24349361	In recent years, the F31I polymorphism has been intensely investigated for its association with the risk of multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('multiple cancers', 'Disease', (108, 124))	('F31I', 'Mutation', 'rs2273535', (21, 25))	('multiple cancers', 'Disease', 'MESH:D009369', (108, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('F31I', 'Var', (21, 25))
460389	24349361	Many studies have indicated that the STK15 F31I polymorphism is a general low penetrance susceptibility gene in a number of cancers, particularly breast, colorectal, and esophageal cancer.	('F31I', 'Mutation', 'rs2273535', (43, 47))	('STK15', 'Gene', '6790', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('esophageal cancer', 'Disease', (170, 187))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast', 'Disease', (146, 152))	('colorectal', 'Disease', (154, 164))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))	('F31I', 'Var', (43, 47))	('cancers', 'Disease', (124, 131))	('STK15', 'Gene', (37, 42))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
460390	24349361	Therefore, to confirm the role of the STK15 F31I polymorphism in tumorigenesis, we conducted a comprehensive meta-analysis on eligible case-control studies published to date.	('F31I', 'Mutation', 'rs2273535', (44, 48))	('tumor', 'Disease', (65, 70))	('STK15', 'Gene', (38, 43))	('STK15', 'Gene', '6790', (38, 43))	('F31I', 'Var', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
460391	24349361	To the best of our knowledge, this is the most comprehensive meta-analysis regarding the STK15 F31I polymorphism and its association with cancer risk.	('cancer', 'Disease', (138, 144))	('F31I', 'Mutation', 'rs2273535', (95, 99))	('association', 'Interaction', (121, 132))	('STK15', 'Gene', (89, 94))	('STK15', 'Gene', '6790', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('F31I', 'Var', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
460393	24349361	Eligible studies had to meet the following criteria: 1) evaluated the STK15 F31I polymorphism and cancer risk, 2) designed as a case-control study, 3) provided data on genotype or allele frequency in case groups and control groups, 4) provided the genotyping method and ethnicity, and 5) control genotype distributions consistent with Hardy-Weinberg equilibrium (HWE).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('F31I', 'Var', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('STK15', 'Gene', (70, 75))	('STK15', 'Gene', '6790', (70, 75))	('Hardy-Weinberg equilibrium', 'Disease', (335, 361))	('F31I', 'Mutation', 'rs2273535', (76, 80))
460396	24349361	The crude odds ratio (OR) with the corresponding 95% confidence intervals (95% CI) was used to measure the strength of the association between the STK15 F31I polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('STK15', 'Gene', (147, 152))	('F31I', 'Var', (153, 157))	('STK15', 'Gene', '6790', (147, 152))	('F31I', 'Mutation', 'rs2273535', (153, 157))
460399	24349361	Overall, 27 total case-control studies on the association between the STK15 F31I polymorphism and cancer risk were recruited in this meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('F31I polymorphism', 'Var', (76, 93))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('association', 'Interaction', (46, 57))	('STK15', 'Gene', (70, 75))	('STK15', 'Gene', '6790', (70, 75))	('F31I', 'Mutation', 'rs2273535', (76, 80))	('polymorphism', 'Var', (81, 93))
460403	24349361	The distribution of the STK15 F31I polymorphism and allele among patients and controls is listed in Table 2 .	('F31I', 'Var', (30, 34))	('F31I', 'Mutation', 'rs2273535', (30, 34))	('STK15', 'Gene', (24, 29))	('STK15', 'Gene', '6790', (24, 29))	('patients', 'Species', '9606', (65, 73))
460404	24349361	In total, 19,267 multiple cancer cases and 24,359 controls from 27 eligible and original case-control studies were recruited for meta-analysis of the association between the STK15 F31I polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('polymorphism', 'Var', (185, 197))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('F31I polymorphism', 'Var', (180, 197))	('STK15', 'Gene', (174, 179))	('STK15', 'Gene', '6790', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', (202, 208))	('F31I', 'Mutation', 'rs2273535', (180, 184))
460405	24349361	After combining all qualified studies, there was statistical evidence of an association between the STK15 F31I polymorphism and increased overall cancer risk in four genetic models: AA vs. TA+TT (OR, 1.18; 95% CI, 1.06-1.31; P=0.002), AA vs. TT (OR, 1.16; 95% CI, 1.01-1.32; P=0.035), AA vs. TA (OR, 1.18; 95% CI, 1.06-1.30; P=0.001), and A vs. T (OR, 1.08; 95% CI, 1.01-1.14; P=0.015) (Table 3 , Figure 2 ).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('F31I', 'Mutation', 'rs2273535', (106, 110))	('polymorphism', 'Var', (111, 123))	('STK15', 'Gene', (100, 105))	('STK15', 'Gene', '6790', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('F31I polymorphism', 'Var', (106, 123))
460413	24349361	Many studies have linked tumor development and progression to the amplification and overexpression of STK15 in multiple human cancers (such as breast cancer, colorectal cancer, esophageal cancer, as well as other types of cancer).	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('overexpression', 'PosReg', (84, 98))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('cancer', 'Disease', (169, 175))	('breast cancer', 'Disease', (143, 156))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('human', 'Species', '9606', (120, 125))	('STK15', 'Gene', (102, 107))	('cancer', 'Disease', (222, 228))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', (150, 156))	('linked tumor', 'Disease', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('colorectal cancer', 'Disease', 'MESH:D015179', (158, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('esophageal cancer', 'Disease', 'MESH:D004938', (177, 194))	('amplification', 'Var', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('STK15', 'Gene', '6790', (102, 107))	('colorectal cancer', 'Disease', (158, 175))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancer', 'Disease', (188, 194))	('esophageal cancer', 'Disease', (177, 194))	('linked tumor', 'Disease', 'MESH:D009369', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
460414	24349361	The STK15 F31I polymorphism has been extensively investigated, and many studies have examined the hypothesis that this polymorphism is relevant to the risk of a variety of cancers; however, the results remain inconclusive and ambiguous.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('STK15', 'Gene', '6790', (4, 9))	('STK15', 'Gene', (4, 9))	('F31I', 'Mutation', 'rs2273535', (10, 14))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('F31I', 'Var', (10, 14))
460415	24349361	Therefore, we conducted a comprehensive meta-analysis to assess the strength of the association between the STK15 F31I polymorphism and overall cancer risk, and further performed a stratified analysis by ethnicity and cancer type.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('STK15', 'Gene', '6790', (108, 113))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('polymorphism', 'Var', (119, 131))	('STK15', 'Gene', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('F31I', 'Mutation', 'rs2273535', (114, 118))
460416	24349361	This meta-analysis, including 27 case-control studies, identified associations between STK15 F31I polymorphism and cancer risk.	('cancer', 'Disease', (115, 121))	('associations', 'Interaction', (66, 78))	('F31I polymorphism', 'Var', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('STK15', 'Gene', (87, 92))	('F31I', 'Mutation', 'rs2273535', (93, 97))	('polymorphism', 'Var', (98, 110))	('STK15', 'Gene', '6790', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
460417	24349361	STK15 F31I polymorphisms (AA vs. TA+TT, AA vs. TT, AA vs. TA, and A vs. T) significantly increased overall cancer risk.	('F31I polymorphisms', 'Var', (6, 24))	('STK15', 'Gene', (0, 5))	('STK15', 'Gene', '6790', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('F31I', 'Mutation', 'rs2273535', (6, 10))	('polymorphisms', 'Var', (11, 24))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('increased', 'PosReg', (89, 98))	('cancer', 'Disease', (107, 113))
460418	24349361	In a stratified analysis by cancer type, STK15 F31I polymorphisms (AA vs. TA+TT, AA vs. TT, AA vs. TA, and A vs. T) were also associated with a significant increase in breast cancer risk and esophageal cancer (AA vs. TA+TT and AA vs. TA).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('cancer', 'Disease', (175, 181))	('breast cancer', 'Disease', (168, 181))	('STK15', 'Gene', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('F31I', 'Mutation', 'rs2273535', (47, 51))	('increase', 'PosReg', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('STK15', 'Gene', '6790', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', (28, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('polymorphisms', 'Var', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('F31I polymorphisms', 'Var', (47, 65))	('cancer', 'Disease', (202, 208))	('esophageal cancer', 'Disease', (191, 208))
460419	24349361	In a stratified analysis by ethnicity, the association of STK15 F31I polymorphisms was significant in Asians but not Caucasians.	('association', 'Interaction', (43, 54))	('F31I', 'Mutation', 'rs2273535', (64, 68))	('STK15', 'Gene', (58, 63))	('STK15', 'Gene', '6790', (58, 63))	('polymorphisms', 'Var', (69, 82))	('F31I polymorphisms', 'Var', (64, 82))
460422	24349361	Thus, any severe defects in STK15, such as mutations, would lead to drastic genomic instability and trigger apoptosis through cell cycle checkpoint surveillance.	('lead to', 'Reg', (60, 67))	('genomic instability', 'CPA', (76, 95))	('cell cycle checkpoint surveillance', 'CPA', (126, 160))	('STK15', 'Gene', (28, 33))	('STK15', 'Gene', '6790', (28, 33))	('mutations', 'Var', (43, 52))	('trigger', 'Reg', (100, 107))	('apoptosis', 'CPA', (108, 117))
460423	24349361	Consequently, a cell harboring a defective STK15 may lead to cancer.	('lead to', 'Reg', (53, 60))	('STK15', 'Gene', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('STK15', 'Gene', '6790', (43, 48))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('defective', 'Var', (33, 42))
460424	24349361	Our results demonstrate a significant statistical impact of STK15 F31I polymorphism on cancer risk.	('cancer', 'Disease', (87, 93))	('F31I polymorphism', 'Var', (66, 83))	('impact', 'Reg', (50, 56))	('STK15', 'Gene', (60, 65))	('STK15', 'Gene', '6790', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('F31I', 'Mutation', 'rs2273535', (66, 70))	('polymorphism', 'Var', (71, 83))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
460425	24349361	The STK15 F31I polymorphism (T A), which leads to an amino acid residue substitution at codon 31 phenylalanine (Phe) to isoleucine (Ile), is associated with cellular transformation and dramatically increases chromosomal instability.	('leads to', 'Reg', (41, 49))	('phenylalanine', 'Chemical', 'MESH:D010649', (97, 110))	('STK15', 'Gene', (4, 9))	('Phe', 'Chemical', 'MESH:D010649', (112, 115))	('STK15', 'Gene', '6790', (4, 9))	('phenylalanine', 'MPA', (97, 110))	('F31I', 'Mutation', 'rs2273535', (10, 14))	('associated with', 'Reg', (141, 156))	('increases', 'PosReg', (198, 207))	('isoleucine', 'Chemical', 'MESH:D007532', (120, 130))	('Ile', 'Chemical', 'MESH:D007532', (132, 135))	('cellular transformation', 'CPA', (157, 180))	('chromosomal instability', 'Phenotype', 'HP:0040012', (208, 231))	('substitution', 'Var', (72, 84))	('chromosomal', 'MPA', (208, 219))	('F31I', 'Var', (10, 14))
460426	24349361	The STK15 F31I polymorphism (T A) variant changes the activity of the STK15 box 1, leading to an obstruction in p53 binding and the decreased degradation of STK15.	('binding', 'Interaction', (116, 123))	('STK15', 'Gene', (157, 162))	('degradation', 'MPA', (142, 153))	('F31I', 'Var', (10, 14))	('STK15', 'Gene', (4, 9))	('STK15', 'Gene', '6790', (157, 162))	('STK15', 'Gene', '6790', (4, 9))	('F31I', 'Mutation', 'rs2273535', (10, 14))	('p53', 'Gene', (112, 115))	('activity', 'MPA', (54, 62))	('decreased', 'NegReg', (132, 141))	('changes', 'Reg', (42, 49))	('STK15', 'Gene', (70, 75))	('STK15', 'Gene', '6790', (70, 75))	('p53', 'Gene', '7157', (112, 115))	('obstruction', 'NegReg', (97, 108))
460428	24349361	In this meta-analysis, our results demonstrate that the T A change in STK15 may lead to STK15-triggered elevation of cell centrosome proliferation, cell transformation, and dramatically increased chromosomal instability, which may increase the risk of multiple cancers.	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (186, 219))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('STK15', 'Gene', '6790', (88, 93))	('multiple cancers', 'Disease', (252, 268))	('increased', 'PosReg', (186, 195))	('cell transformation', 'CPA', (148, 167))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('chromosomal instability', 'Phenotype', 'HP:0040012', (196, 219))	('T A change', 'Var', (56, 66))	('multiple cancers', 'Disease', 'MESH:D009369', (252, 268))	('STK15', 'Gene', (70, 75))	('chromosomal instability', 'MPA', (196, 219))	('increase', 'Reg', (231, 239))	('elevation', 'PosReg', (104, 113))	('STK15', 'Gene', '6790', (70, 75))	('cell centrosome proliferation', 'CPA', (117, 146))	('STK15', 'Gene', (88, 93))
460430	24349361	The results demonstrate that the STK15 F31I polymorphism is associated with an increased risk of breast cancer and esophageal cancer, but not colorectal cancer and other cancers.	('STK15', 'Gene', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('polymorphism', 'Var', (44, 56))	('F31I polymorphism', 'Var', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('STK15', 'Gene', '6790', (33, 38))	('F31I', 'Mutation', 'rs2273535', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (115, 132))	('colorectal cancer', 'Disease', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Disease', (97, 110))
460432	24349361	Stratified analysis was also performed regarding ethnicity for the STK15 F31I polymorphism.	('F31I', 'Mutation', 'rs2273535', (73, 77))	('STK15', 'Gene', (67, 72))	('F31I', 'Var', (73, 77))	('STK15', 'Gene', '6790', (67, 72))
460433	24349361	The STK15 F31I polymorphism is associated with the risk of cancer in Asians but not Caucasians.	('STK15', 'Gene', (4, 9))	('STK15', 'Gene', '6790', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('associated', 'Reg', (31, 41))	('F31I', 'Mutation', 'rs2273535', (10, 14))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('F31I', 'Var', (10, 14))
460434	24349361	This meta-analysis confirmed the mutual effect of genetic diversity and variants in different populations to the risks of various cancers.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('variants', 'Var', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
460437	24349361	Significant heterogeneity was observed between publications for STK15 F31I polymorphisms.	('STK15', 'Gene', (64, 69))	('F31I', 'Var', (70, 74))	('STK15', 'Gene', '6790', (64, 69))	('F31I', 'Mutation', 'rs2273535', (70, 74))
460443	24349361	Considering the complexity of cancer etiology and the low penetrance cancer susceptibility gene effects from STK15 F31I SNP, these important environmental factors should not be ignored.	('effects', 'Reg', (96, 103))	('STK15', 'Gene', (109, 114))	('STK15', 'Gene', '6790', (109, 114))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('F31I', 'Var', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('F31I', 'Mutation', 'rs2273535', (115, 119))	('cancer', 'Disease', (69, 75))
460444	24349361	In summary, this meta-analysis suggests the STK15 F31I polymorphism represents a low risk factor for cancer, especially in Asians, in breast cancer and esophageal cancer subgroup.	('STK15', 'Gene', '6790', (44, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('breast cancer', 'Disease', (134, 147))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('esophageal cancer', 'Disease', (152, 169))	('F31I polymorphism', 'Var', (50, 67))	('cancer', 'Disease', (163, 169))	('F31I', 'Mutation', 'rs2273535', (50, 54))	('STK15', 'Gene', (44, 49))	('polymorphism', 'Var', (55, 67))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
460445	24349361	In the future, more studies with large sample sizes should be carried out to clarify the association between STK15 F31I polymorphism and cancer risk, especially for gene-gene and gene-environment interactions.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('STK15', 'Gene', (109, 114))	('STK15', 'Gene', '6790', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('F31I', 'Mutation', 'rs2273535', (115, 119))	('polymorphism', 'Var', (120, 132))
460452	33571139	Further investigations proposed two signaling pathways that might involve in the MCTP1-mediated drug-resistance of esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('drug-resistance', 'Phenotype', 'HP:0020174', (96, 111))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('MCTP1-mediated', 'Var', (81, 95))
460462	33571139	For example, the hypermethylation in the promoter regions of APC, RB1, and CDKN2A was found in EC cells.	('found', 'Reg', (86, 91))	('APC', 'Disease', 'MESH:D011125', (61, 64))	('CDKN2A', 'Gene', (75, 81))	('RB1', 'Gene', '5925', (66, 69))	('APC', 'Disease', (61, 64))	('CDKN2A', 'Gene', '1029', (75, 81))	('hypermethylation', 'Var', (17, 33))	('RB1', 'Gene', (66, 69))
460468	33571139	The drug dose for 50% cells killed by the following drugs: Docetaxel (Doc), Nedaplatin (Ned), Mitomycin (Mit) and Cisplatin (Cis) after a treatment of 72hr, was determined in the following ten EC cell lines: Kyse410, Kyse150, Kyse450, Kyse140, Kyse30, Kyse510, COLO680n, Kyse180, Kyse70 and TE-1 (Figure 1).	('Kyse510', 'Var', (252, 259))	('COLO680n', 'Var', (261, 269))	('Kyse150', 'Var', (217, 224))	('Ned', 'Chemical', 'MESH:C053989', (88, 91))	('Doc', 'Chemical', 'MESH:D000077143', (59, 62))	('Docetaxel', 'Chemical', 'MESH:D000077143', (59, 68))	('Mit', 'Chemical', 'MESH:D016685', (94, 97))	('Kyse70', 'Var', (280, 286))	('Mitomycin', 'Chemical', 'MESH:D016685', (94, 103))	('Kyse30', 'Var', (244, 250))	('Kyse450', 'Var', (226, 233))	('Ned', 'Chemical', 'MESH:C053989', (76, 79))	('Mit', 'Chemical', 'MESH:D016685', (105, 108))	('Kyse410', 'Var', (208, 215))	('Cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('Kyse180', 'Var', (271, 278))	('Doc', 'Chemical', 'MESH:D000077143', (70, 73))	('Nedaplatin', 'Chemical', 'MESH:C053989', (76, 86))	('Kyse140', 'Var', (235, 242))
460470	33571139	As found previously, the hypermethylation of genes may affect the physiological properties of cancer cells.	('hypermethylation', 'Var', (25, 41))	('affect', 'Reg', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
460471	33571139	More importantly, totally six pathways TGFbeta, NFkappaB, MAPK/JNK, cAMP/PKA, Hypoxia and IL-6 differed by more than two-folds in Kyse510 and Kyse450 cells, suggesting that they might play a role in EC drug resistance.	('Hypoxia', 'Disease', (78, 85))	('play', 'Reg', (184, 188))	('IL-6', 'Gene', (90, 94))	('Kyse510', 'Var', (130, 137))	('IL-6', 'Gene', '3569', (90, 94))	('TGFbeta', 'Gene', (39, 46))	('cAMP', 'Chemical', '-', (68, 72))	('role', 'Reg', (191, 195))	('JNK', 'Gene', '5599', (63, 66))	('drug resistance', 'Phenotype', 'HP:0020174', (202, 217))	('NFkappaB', 'Gene', (48, 56))	('Hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('TGFbeta', 'Gene', '7039', (39, 46))	('NFkappaB', 'Gene', '4790', (48, 56))	('JNK', 'Gene', (63, 66))	('differed', 'Reg', (95, 103))
460475	33571139	Thus, down-regulation of MCTP1 in Kyse450 cells results in a higher activity of cAMP/PKA pathway, which perfectly meets the negative correlation of cAMP/PKA pathway and the MCTP1 level.	('cAMP', 'Chemical', '-', (80, 84))	('Kyse450', 'Var', (34, 41))	('higher', 'PosReg', (61, 67))	('activity', 'MPA', (68, 76))	('MCTP1', 'Gene', (25, 30))	('down-regulation', 'NegReg', (6, 21))	('cAMP/PKA pathway', 'Pathway', (80, 96))	('cAMP', 'Chemical', '-', (148, 152))
460484	33571139	For the further design of the clinical kit, further studies should be performed to verify the correlation between methylation of MCTP1 and chemotherapy tolerance in esophageal cancer cells, and more clinical samples are needed to verify the reliability of MCTP1 as a marker of chemotherapy tolerance in esophageal cancer.	('kit', 'Gene', '3815', (39, 42))	('cancer', 'Disease', (314, 320))	('MCTP1', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('methylation', 'Var', (114, 125))	('kit', 'Gene', (39, 42))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (314, 320))
460486	33571139	The nine esophageal cancer cell lines: Kyse410, Kyse150, Kyse450, Kyse140, Kyse30, Kyse510, COLO680n, Kyse180, Kyse70 and TE-1 used in this study were bought from the Chinese Academy of Sciences Collection Committee of cultural collections.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Kyse140', 'Var', (66, 73))	('Kyse410', 'Var', (39, 46))	('Kyse30', 'Var', (75, 81))	('Kyse150', 'Var', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('Kyse510', 'Var', (83, 90))	('COLO680n', 'Var', (92, 100))
460500	33571139	Cells infected lentivirus or control or transfected with MCTP1 siRNA or control siRNA were seeded in 96-well plates at a density of 5x103 cells per well, and cell proliferation assays were performed every 24 hr using CCK8.	('MCTP1', 'Var', (57, 62))	('infected', 'Disease', 'MESH:D007239', (6, 14))	('infected', 'Disease', (6, 14))
460543	32431558	Therefore, HCPCS codes C9025 and J9308 were used in combination with National Drug Code (NDC) and Generic Product Identifier (GPI) codes to identify ramucirumab in claims.	('ramucirumab', 'Chemical', 'MESH:C543333', (149, 160))	('J9308', 'Var', (33, 38))	('C9025', 'Var', (23, 28))	('ramucirumab', 'Gene', (149, 160))	('J9308', 'CellLine', 'CVCL:M891', (33, 38))
460567	32431558	Treatment augmentation changed with ramucirumab (p=0.03, Table 2), but not with trastuzumab (p=0.58, Table 1).	('trastuzumab', 'Chemical', 'MESH:D000068878', (80, 91))	('augmentation', 'PosReg', (10, 22))	('ramucirumab', 'Var', (36, 47))	('ramucirumab', 'Chemical', 'MESH:C543333', (36, 47))
460607	31725654	High ERalpha expression was associated with poor OS (HR = 1.58, 95% CI = 1.29-1.94, P < .001) and ERbeta with better OS (HR = 0.56, 95% CI = 0.37-0.83, P = .004) in gastroesophageal cancer.	('ERalpha', 'Gene', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('High', 'Var', (0, 4))	('gastroesophageal cancer', 'Disease', (165, 188))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (165, 188))
460609	31725654	Meanwhile, worse OS was found in esophageal squamous cell carcinoma (ESCC) patients with high ERalpha expression (HR = 1.74, 95% CI = 1.33-2.26, P < .001), and favorable OS in ESCC with ERbeta overexpression (HR = 0.40, 95% CI = 0.31-0.52, P < .001).	('ESCC', 'Disease', (176, 180))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (33, 67))	('ESCC', 'Disease', 'MESH:C562729', (69, 73))	('patients', 'Species', '9606', (75, 83))	('ESCC', 'Disease', 'MESH:C562729', (176, 180))	('high', 'Var', (89, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('ESCC', 'Disease', (69, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('esophageal squamous cell carcinoma', 'Disease', (33, 67))
460610	31725654	Besides, high ERalpha expression was associated with lower tumor differentiation in ESCC (OR = 1.64; 95% CI = 1.02-2.64, P = .04) and ERbeta was linked with better tumor differentiation in gastric adenocarcinoma (GCA) (OR = 0.49; 95% CI = 0.26-0.94, P = .03).	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('ESCC', 'Disease', (84, 88))	('GCA', 'Disease', 'MESH:D013274', (213, 216))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (189, 211))	('better', 'PosReg', (157, 163))	('gastric adenocarcinoma', 'Disease', (189, 211))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('ESCC', 'Disease', 'MESH:C562729', (84, 88))	('GCA', 'Disease', (213, 216))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('ERalpha', 'Protein', (14, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('lower', 'NegReg', (53, 58))	('expression', 'MPA', (22, 32))	('high', 'Var', (9, 13))
460640	31725654	Two studies with 1034 tissues revealed a statistically correlations between high ERbeta expression and better tumor differentiation in GCA (OR = 0.49, 95% CI = 0.26-0.94, P = .03).	('GCA', 'Disease', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('ERbeta', 'Protein', (81, 87))	('better', 'PosReg', (103, 109))	('high', 'Var', (76, 80))	('expression', 'MPA', (88, 98))	('GCA', 'Disease', 'MESH:D013274', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
460649	31725654	One previous study in our laboratory found that ESCC patients with ERalpha negative (-)/ERbeta positive (+) have a better OS than those with ERalpha (+)/ERbeta(+) and ERalpha (+)/ERbeta(-) expression.	('ESCC', 'Disease', (48, 52))	('ERalpha', 'Var', (67, 74))	('patients', 'Species', '9606', (53, 61))	('ESCC', 'Disease', 'MESH:C562729', (48, 52))
460687	30920880	The specific indications of chemotherapy in the cisplatin plus fluorouracil group were fluorouracil 1,800 mg/m2 continuous intravenous 72 h on day 1 and cisplatin 25 mg/m2/d on days 1 to 3 every 4 weeks for two cycles in concurrent chemotherapy and two cycles in consolidation chemotherapy.	('fluorouracil', 'Var', (87, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('fluorouracil', 'Chemical', 'MESH:D005472', (63, 75))	('fluorouracil', 'Chemical', 'MESH:D005472', (87, 99))	('cisplatin', 'Var', (153, 162))
460732	30920880	Moreover, severe anemia was also higher in the cisplatin plus fluorouracil group than in the paclitaxel plus fluorouracil group (7.3% v 2.8%, respectively).	('higher', 'PosReg', (33, 39))	('cisplatin', 'Var', (47, 56))	('fluorouracil', 'Chemical', 'MESH:D005472', (109, 121))	('paclitaxel', 'Chemical', 'MESH:D017239', (93, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('anemia', 'Disease', (17, 23))	('anemia', 'Disease', 'MESH:D000740', (17, 23))	('anemia', 'Phenotype', 'HP:0001903', (17, 23))	('fluorouracil', 'Chemical', 'MESH:D005472', (62, 74))
460773	30788198	International Classification of Diseases (ICD) for Oncology, 3rd edition codes data was extracted for squamous cell carcinoma (8070/3) and adenocarcinoma (8140/3).	('8070/3', 'Var', (127, 133))	('squamous cell carcinoma', 'Disease', (102, 125))	('ICD', 'Disease', (42, 45))	('adenocarcinoma', 'Disease', 'MESH:D000230', (139, 153))	('Oncology', 'Phenotype', 'HP:0002664', (51, 59))	('8140/3', 'Var', (155, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('adenocarcinoma', 'Disease', (139, 153))	('ICD', 'Disease', 'OMIM:252500', (42, 45))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))
460822	30270520	Therefore, dysregulations of NCOA1 have been found in a variety of cancer types.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('NCOA1', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('dysregulations', 'Var', (11, 25))	('found', 'Reg', (45, 50))
460825	30270520	Results from multiple cohorts of ESCC patients strongly suggest that the levels of NCOA1 could serve as an independent predictor of overall survival.	('ESCC', 'Disease', (33, 37))	('patients', 'Species', '9606', (38, 46))	('NCOA1', 'Gene', (83, 88))	('levels', 'Var', (73, 79))
460826	30270520	These findings not only indicate that NCOA1 plays important roles in human ESCC but the levels of NCOA1 also could serve as a potential prognostic biomarker of ESCC and targeting NCOA1 could be an efficacious strategy in ESCC treatment.	('targeting', 'Var', (169, 178))	('ESCC', 'Disease', (160, 164))	('levels', 'MPA', (88, 94))	('human', 'Species', '9606', (69, 74))	('NCOA1', 'Gene', (179, 184))	('ESCC', 'Disease', (221, 225))
460834	30270520	A dataset (titled "Hu Esophagus 2 statistics") from the Oncomine database (https://www.oncomine.org//) was used to analyze the copy numbers of NCOA1 in ESCC tissues.	('copy numbers', 'Var', (127, 139))	('NCOA1', 'Gene', (143, 148))	('oncomine', 'Chemical', '-', (87, 95))
460845	30270520	Given the fact that dysregulation of NCOA1 was found in multiple types of cancers, we were interested in knowing if this coactivator plays any role in ESCC.	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('ESCC', 'Disease', (151, 155))	('found', 'Reg', (47, 52))	('NCOA1', 'Gene', (37, 42))	('cancers', 'Disease', (74, 81))	('dysregulation', 'Var', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
460851	30270520	Based on these criteria, Kaplan-Meier analysis found that ESCC patients with overexpression of NCOA1 have poor overall survival; the median survival time for ESCC patients with high NCOA1 was 16.0 months compared to 41.0 months for those with low NCOA1 expression (P = 0.017, log-rank test, Figure 3B).	('high', 'Var', (177, 181))	('patients', 'Species', '9606', (163, 171))	('NCOA1', 'Gene', (95, 100))	('patients', 'Species', '9606', (63, 71))
460852	30270520	Figure 3C showed that ESCC patients with high NCOA1 expression are closely associated with poorer overall survival (P = 0.014, log-rank test).	('NCOA1', 'Gene', (46, 51))	('ESCC', 'Disease', (22, 26))	('high', 'Var', (41, 45))	('expression', 'MPA', (52, 62))	('patients', 'Species', '9606', (27, 35))	('poorer', 'NegReg', (91, 97))	('overall', 'MPA', (98, 105))
460855	30270520	Since KYSE510 has the highest NCOA1 expression among all the ESCC cells analyzed (Figure 1C), we decided to conduct these experiments in this specific cell line.	('highest', 'Reg', (22, 29))	('KYSE510', 'Var', (6, 13))	('NCOA1', 'Gene', (30, 35))	('KYSE510', 'CellLine', 'CVCL:1354', (6, 13))	('expression', 'MPA', (36, 46))
460857	30270520	Figure 4A showed that compared to the control knocking down NCOA1 significantly inhibited proliferation of KYSE510 cells (P < 0.05).	('KYSE510', 'CellLine', 'CVCL:1354', (107, 114))	('knocking down', 'Var', (46, 59))	('NCOA1', 'Gene', (60, 65))	('proliferation of KYSE510 cells', 'CPA', (90, 120))	('inhibited', 'NegReg', (80, 89))
460858	30270520	In addition, Figure 4B,C showed that knockdown NCOA1 in KYSE510 cell significantly decreased cell migration and invasion (P < 0.05).	('KYSE510', 'CellLine', 'CVCL:1354', (56, 63))	('NCOA1', 'Gene', (47, 52))	('decreased', 'NegReg', (83, 92))	('knockdown', 'Var', (37, 46))
460863	30270520	Despite the fact that dysregulation of NCOA1 has been documented in multiple types of human cancers,2, 27, 47, 48, 49, 50 the clinical importance of NCOA1 in tumor progression and clinical outcome of human ESCC were unappreciated.	('dysregulation', 'Var', (22, 35))	('tumor', 'Disease', (158, 163))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('NCOA1', 'Gene', (39, 44))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('human', 'Species', '9606', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
460904	28795270	Recent progress in molecular biology has implicated several genetic and epigenetic alterations in both the carcinogenesis and progression of esophageal cancer.	('epigenetic alterations', 'Var', (72, 94))	('esophageal cancer', 'Disease', (141, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('carcinogenesis', 'Disease', 'MESH:D063646', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('carcinogenesis', 'Disease', (107, 121))
460912	28795270	Colorectal tumorigenesis has also been regarded as a multi-step process related to the accumulation of genetic alterations with two potential oncogenic pathways: the adenoma-carcinoma sequence pathway and de novo carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('carcinogenesis', 'Disease', 'MESH:D063646', (213, 227))	('tumor', 'Disease', (11, 16))	('alterations', 'Var', (111, 122))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (166, 183))	('carcinogenesis', 'Disease', (213, 227))	('adenoma-carcinoma', 'Disease', (166, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
461017	25434658	All ESD procedures and prior mapping endoscopies were performed according to local protocol with GIF-H260, GIF-H260Z or GIF-Q260J endoscopes (Olympus Medical Systems Co, Ltd, Tokyo, Japan) using a standard video endoscopy processor (EVIS Lucera; Olympus Medical Systems Co, Ltd, Tokyo, Japan).	('GIF', 'Gene', (97, 100))	('GIF', 'Gene', '2694', (107, 110))	('Q260J', 'SUBSTITUTION', 'None', (124, 129))	('GIF', 'Gene', '2694', (120, 123))	('H260Z', 'SUBSTITUTION', 'None', (111, 116))	('GIF', 'Gene', (120, 123))	('H260Z', 'Var', (111, 116))	('Q260J', 'Var', (124, 129))	('GIF', 'Gene', '2694', (97, 100))	('GIF', 'Gene', (107, 110))
461079	28402938	Finally, the modified proteins are recognized by mannose-6-phosphate receptors in the lysosome, where the proenzymes are hydrolyzed at low pH, resulting in the removal of the prodomains to yield active and mature cathepsins (Figure 1).	('cathepsins', 'Enzyme', (213, 223))	('modified', 'Var', (13, 21))	('yield', 'Reg', (189, 194))	('mannose-6-phosphate', 'Chemical', 'MESH:C027693', (49, 68))	('proteins', 'Protein', (22, 30))	('removal', 'MPA', (160, 167))	('active', 'MPA', (195, 201))
461095	28402938	Similar to other cancers, digestive cancers exhibit a complex progression via multistep pathways involving the activation of oncogenes, such as K-sam and c-met, and the inactivation of anti-oncogenes, such as adenomatous polyposis coli (APC) and tumor protein 53 (TP53).	('K-sam', 'Gene', (144, 149))	('c-met', 'Gene', '4233', (154, 159))	('TP53', 'Gene', '7157', (264, 268))	('APC', 'Phenotype', 'HP:0005227', (237, 240))	('tumor protein 53', 'Gene', (246, 262))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('cancers', 'Disease', (17, 24))	('tumor protein 53', 'Gene', '7157', (246, 262))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('APC', 'Gene', (237, 240))	('activation', 'PosReg', (111, 121))	('TP53', 'Gene', (264, 268))	('c-met', 'Gene', (154, 159))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('inactivation', 'Var', (169, 181))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (209, 235))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (209, 235))	('K-sam', 'Gene', '2263', (144, 149))	('adenomatous polyposis coli', 'Disease', (209, 235))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('APC', 'Gene', '324', (237, 240))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
461107	28402938	The deletion of cathepsins B and S in RIP1-Tag2 mice yielded no differences in tumor invasion.	('tumor', 'Disease', (79, 84))	('cathepsins B', 'Protein', (16, 28))	('RIP1', 'Gene', '19766', (38, 42))	('mice', 'Species', '10090', (48, 52))	('deletion', 'Var', (4, 12))	('RIP1', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
461117	28402938	Previous studies have demonstrated that cathepsin D exacerbates the invasion of esophageal squamous cell carcinoma, and high cathepsin D expression is associated with poor prognosis.	('cathepsin D', 'Gene', '1509', (125, 136))	('expression', 'MPA', (137, 147))	('exacerbates', 'PosReg', (52, 63))	('cathepsin D', 'Gene', (125, 136))	('high', 'Var', (120, 124))	('invasion', 'CPA', (68, 76))	('cathepsin D', 'Gene', (40, 51))	('cathepsin D', 'Gene', '1509', (40, 51))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (80, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('esophageal squamous cell carcinoma', 'Disease', (80, 114))
461142	28402938	The knockdown of cathepsin X inhibits the proliferation of gastric cancer cells.	('cathepsin X', 'Gene', '1513', (17, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('proliferation of', 'CPA', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cathepsin X', 'Gene', (17, 28))	('inhibits', 'NegReg', (29, 37))	('gastric cancer', 'Disease', (59, 73))	('knockdown', 'Var', (4, 13))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))
461156	28402938	Compared with cathepsin B-negative tumors, cathepsin B-positive colon cancers are more likely to have K-ras and BRAF mutations and have higher multivariate hazard ratios.	('cathepsin B', 'Gene', (14, 25))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('cathepsin B', 'Gene', '1508', (14, 25))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('colon cancers', 'Phenotype', 'HP:0003003', (64, 77))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('colon cancers', 'Disease', 'MESH:D015179', (64, 77))	('K-ras', 'Gene', '3845', (102, 107))	('cathepsin B', 'Gene', (43, 54))	('mutations', 'Var', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('colon cancers', 'Disease', (64, 77))	('cathepsin B', 'Gene', '1508', (43, 54))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('higher', 'PosReg', (136, 142))	('tumors', 'Disease', (35, 41))	('K-ras', 'Gene', (102, 107))
461157	28402938	A previous study investigated two colon carcinoma cell lines, namely HCT-116 (with a mutated K-ras allele) and HKh-2 (with a disruption in the mutated allele), and showed that cathepsin B expression and activity are higher in HCT116 cells than in HKh-2 cells.	('K-ras', 'Gene', (93, 98))	('HCT-116', 'CellLine', 'CVCL:0291', (69, 76))	('colon carcinoma', 'Disease', 'MESH:D015179', (34, 49))	('cathepsin B', 'Gene', '1508', (176, 187))	('K-ras', 'Gene', '3845', (93, 98))	('colon carcinoma', 'Disease', (34, 49))	('expression', 'MPA', (188, 198))	('HCT116', 'CellLine', 'CVCL:0291', (226, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('higher', 'PosReg', (216, 222))	('cathepsin B', 'Gene', (176, 187))	('HKh-2', 'CellLine', 'CVCL:9797', (247, 252))	('HCT116', 'Var', (226, 232))	('HKh-2', 'CellLine', 'CVCL:9797', (111, 116))	('activity', 'MPA', (203, 211))
461158	28402938	The researchers speculated that active K-ras increases cathepsin B, and cathepsin B then initiates a proteolytic cascade in colon carcinoma cells.	('increases', 'PosReg', (45, 54))	('K-ras', 'Gene', (39, 44))	('cathepsin B', 'Gene', (55, 66))	('cathepsin B', 'Gene', (72, 83))	('proteolytic cascade', 'MPA', (101, 120))	('colon carcinoma', 'Disease', 'MESH:D015179', (124, 139))	('K-ras', 'Gene', '3845', (39, 44))	('colon carcinoma', 'Disease', (124, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('initiates', 'Reg', (89, 98))	('cathepsin B', 'Gene', '1508', (55, 66))	('cathepsin B', 'Gene', '1508', (72, 83))	('active', 'Var', (32, 38))
461162	28402938	Interestingly, its function changes as the tumor progresses, and loss of cathepsin X contributes to tumor progression and local invasion.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('contributes', 'Reg', (85, 96))	('loss', 'Var', (65, 69))	('local invasion', 'CPA', (122, 136))	('tumor', 'Disease', (100, 105))	('cathepsin X', 'Gene', '1513', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cathepsin X', 'Gene', (73, 84))	('function', 'MPA', (19, 27))
461183	28402938	For example, VBY-825 can reversibly inhibit cathepsins B, L and S to decrease tumor growth in a mouse pancreatic islet cancer model.	('VBY-825', 'Chemical', 'MESH:C555884', (13, 20))	('mouse', 'Species', '10090', (96, 101))	('pancreatic islet cancer', 'Disease', (102, 125))	('inhibit', 'NegReg', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('VBY-825', 'Var', (13, 20))	('decrease', 'NegReg', (69, 77))	('pancreatic islet cancer', 'Disease', 'MESH:D010190', (102, 125))	('cathepsins B', 'Enzyme', (44, 56))	('tumor', 'Disease', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
461186	28402938	However, unlike the high level of cathepsins in other digestive cancers, Lingyu Qin et al.	('Qin', 'Gene', '2290', (80, 83))	('Lingyu', 'Var', (73, 79))	('Qin', 'Gene', (80, 83))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
461191	28402938	Both the cathepsin B-specific inhibitor CA-074 Me and the cathepsin D inhibitor pepstatin A can markedly decrease apoptosis.	('cathepsin B', 'Gene', '1508', (9, 20))	('apoptosis', 'CPA', (114, 123))	('CA-074 Me', 'Chemical', 'MESH:C400541', (40, 49))	('CA-074 Me', 'Var', (40, 49))	('cathepsin B', 'Gene', (9, 20))	('cathepsin D', 'Gene', '1509', (58, 69))	('pepstatin A', 'Chemical', 'MESH:C031375', (80, 91))	('decrease', 'NegReg', (105, 113))	('cathepsin D', 'Gene', (58, 69))
461211	28353588	The tumor cells were diffusely positive for CD20, PAX-5, Bcl-2 and follicular dendritic cells were positive for CD21, CD23.	('tumor', 'Disease', (4, 9))	('PAX-5', 'Gene', (50, 55))	('CD21', 'Var', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CD23', 'Var', (118, 122))	('Bcl', 'Phenotype', 'HP:0012191', (57, 60))	('CD20', 'Gene', (44, 48))
461251	28353588	Moreover, t(11;18)(q21;q21)-negative gastric MALT lymphomas have shown complete response to H pylori eradication.	('gastric MALT lymphomas', 'Disease', 'MESH:D018442', (37, 59))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('gastric MALT lymphoma', 'Phenotype', 'HP:0045038', (37, 58))	('gastric MALT lymphomas', 'Disease', (37, 59))	('lymphomas', 'Phenotype', 'HP:0002665', (50, 59))	('gastric MALT lymphomas', 'Phenotype', 'HP:0045038', (37, 59))	('t(11;18)(q21;q21)-negative', 'Var', (10, 36))	('t(11;18)(q21;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (10, 27))	('H pylori', 'Species', '210', (92, 100))
461268	28353588	In follicular colonization, the tumor cells (CD20+, Bcl-2+, CD10-, and Bcl-6-) colonize the reactive follicles composed of dendritic cells (CD21+, CD23+) with distorting the original follicular structure (Fig.	('CD10-', 'Var', (60, 65))	('Bcl', 'Phenotype', 'HP:0012191', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('distorting', 'NegReg', (159, 169))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CD21+', 'Var', (140, 145))	('CD23+', 'Var', (147, 152))	('CD20+', 'Var', (45, 50))	('tumor', 'Disease', (32, 37))	('Bcl', 'Phenotype', 'HP:0012191', (71, 74))
461273	28353588	Fortunately, with the improvement in molecular techniques, gene rearrangement and clonality analysis have been used to differentiate them based on the hypothesis that immunoglobulin gene rearrangements occur in B cell tumorigenesis, and not in chronic inflammation.	('immunoglobulin gene', 'Gene', (167, 186))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('inflammation', 'Disease', 'MESH:D007249', (252, 264))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('rearrangements', 'Var', (187, 201))	('inflammation', 'Disease', (252, 264))	('tumor', 'Disease', (218, 223))
461276	28353588	Among them, t(11; 18)(q21;q21) was the first to be discovered followed by t(1; 14)(p22; q32), t(14; 18)(q32;q21), t(3; 14)(p14.1;q32), aneuploidy (Trisomy 3, 18), and TNFAIP3 abnormality.	('t(11; 18)(q21;q21', 'Var', (12, 29))	('t(3', 'Var', (114, 117))	('aneuploidy', 'Disease', (135, 145))	('aneuploidy', 'Disease', 'MESH:D000782', (135, 145))	('t(1; 14)(p22; q32', 'Var', (74, 91))	('t(14; 18)(q32;q21', 'Var', (94, 111))	('TNFAIP3', 'Gene', (167, 174))
461327	27999323	According to the receiver operating characteristic (ROC) curve, the cutoff value was 2447.26 copies/mL for the diagnosis of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('esophageal cancer', 'Disease', (124, 141))	('2447.26', 'Var', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
461333	27999323	Patients with N0 status, stage I-II or absent lymphovascular invasion had better DFS.	('DFS', 'MPA', (81, 84))	('Patients', 'Species', '9606', (0, 8))	('N0 status', 'Var', (14, 23))
461382	23274581	KRAS and BRAF Mutations in 203 Esophageal Squamous Cell Carcinomas: Pyrosequencing Technology and Literature Review Epidermal growth factor receptor (EGFR) signaling is one of the most promising targets for molecular-targeted therapies in esophageal squamous cell carcinoma (ESCC).	('KRAS', 'Gene', '3845', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', (239, 273))	('Carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('Esophageal Squamous Cell Carcinomas', 'Disease', 'MESH:D000077277', (31, 66))	('BRAF', 'Gene', (9, 13))	('Squamous Cell Carcinomas', 'Phenotype', 'HP:0002860', (42, 66))	('Epidermal growth factor receptor', 'Gene', (116, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (250, 273))	('Epidermal growth factor receptor', 'Gene', '1956', (116, 148))	('Esophageal Squamous Cell Carcinomas', 'Disease', (31, 66))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (239, 273))	('Mutations', 'Var', (14, 23))	('KRAS', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('BRAF', 'Gene', '673', (9, 13))
461383	23274581	The validity of the KRAS pyrosequencing method was initially demonstrated by detection of all 4 types of KRAS mutations [c.35G>T (codon 12 GGT>GTT), c.35G>A (codon 12 GGT>GAT), c.34G>T (codon 12 GGT>TGT), c.38G>A mutation (codon 13 GGC>GAC)], which had been previously diagnosed using Scorpion-ARMS technology, in 9 colon cancer tissues (9 of 9; 100 %).	('codon 12 GGT>TGT', 'Mutation', 'rs121913530', (186, 202))	('colon cancer', 'Disease', (316, 328))	('c.35G>A', 'Mutation', 'rs121913529', (149, 156))	('codon 13 GGC>GAC', 'Mutation', 'rs112445441', (223, 239))	('KRAS', 'Gene', (105, 109))	('c.38G>A', 'Var', (205, 212))	('c.35G>A', 'Var', (149, 156))	('[c.35G>T', 'Var', (120, 128))	('codon 12 GGT>GAT', 'Mutation', 'rs121913529', (158, 174))	('colon cancer', 'Phenotype', 'HP:0003003', (316, 328))	('c.38G>A', 'Mutation', 'rs112445441', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('c.34G>T', 'Var', (177, 184))	('c.34G>T', 'Mutation', 'rs121913530', (177, 184))	('codon 12 GGT>GTT', 'Mutation', 'rs121913529', (130, 146))	('colon cancer', 'Disease', 'MESH:D015179', (316, 328))	('c.35G>T', 'Mutation', 'rs121913529', (121, 128))
461384	23274581	Similar results were demonstrated for BRAF mutational status in 3 colon cancer cell lines (HCT116, Colo201, and HT29), which were validated by Sanger dideoxy sequencing.	('HCT116', 'CellLine', 'CVCL:0291', (91, 97))	('colon cancer', 'Disease', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('HT29', 'CellLine', 'CVCL:0320', (112, 116))	('BRAF', 'Gene', (38, 42))	('colon cancer', 'Phenotype', 'HP:0003003', (66, 78))	('colon cancer', 'Disease', 'MESH:D015179', (66, 78))	('mutational status', 'Var', (43, 60))
461389	23274581	Mutations in the Kirsten Ras 1 (KRAS) and V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) genes may be predictive of response to drugs directly linked to the EGFR pathway.	('BRAF', 'Gene', (90, 94))	('Kirsten Ras 1', 'Gene', '16653', (17, 30))	('Kirsten Ras 1', 'Gene', (17, 30))	('V-Raf Murine Sarcoma Viral Oncogene Homolog B1', 'Gene', '673', (42, 88))	('KRAS', 'Gene', (32, 36))	('Sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('Mutations', 'Var', (0, 9))	('V-Raf Murine Sarcoma Viral Oncogene Homolog B1', 'Gene', (42, 88))
461394	23274581	We initially quantified KRAS and BRAF mutation in 204 cancer specimens and obtained valid results in 203 cases (99.5 %).	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('BRAF', 'Gene', (33, 37))	('cancer', 'Disease', (54, 60))	('mutation', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('KRAS', 'Gene', (24, 28))
461395	23274581	A total of 9 patients with colon cancers harboring 4 different KRAS mutations [c.35G>T (codon 12 GGT>GTT; p.Gly12Val), c.35G>A (codon 12 GGT>GAT; p.Gly12Asp), c.34G>T (codon 12 GGT>TGT; p.Gly12Cys), and c.38G>A mutation (codon 13 GGC>GAC; p.Gly13Asp)], which had been already diagnosed by Scorpion-ARMS technology, were also included in this study to validate the pyrosequencing method for the detection of KRAS mutations.	('colon cancers', 'Phenotype', 'HP:0003003', (27, 40))	('patients', 'Species', '9606', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('c.35G>T', 'Mutation', 'rs121913529', (79, 86))	('codon 12 GGT>GTT', 'Mutation', 'rs121913529', (88, 104))	('c.38G>A mutation', 'Var', (203, 219))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('colon cancers', 'Disease', 'MESH:D015179', (27, 40))	('[c.35G>T', 'Var', (78, 86))	('c.34G>T', 'Mutation', 'rs121913530', (159, 166))	('c.35G>A', 'Mutation', 'rs121913529', (119, 126))	('c.34G>T', 'Var', (159, 166))	('codon 12 GGT>GAT', 'Mutation', 'rs121913529', (128, 144))	('c.35G>A', 'Var', (119, 126))	('p.Gly12Asp', 'Mutation', 'rs121913529', (146, 156))	('colon cancers', 'Disease', (27, 40))	('p.Gly13Asp', 'Mutation', 'rs112445441', (239, 249))	('codon 13 GGC>GAC', 'Mutation', 'rs112445441', (221, 237))	('p.Gly12Cys', 'Mutation', 'rs121913530', (186, 196))	('colon cancer', 'Phenotype', 'HP:0003003', (27, 39))	('p.Gly12Val', 'Mutation', 'rs121913529', (106, 116))	('c.38G>A', 'Mutation', 'rs112445441', (203, 210))	('codon 12 GGT>TGT', 'Mutation', 'rs121913530', (168, 184))
461398	23274581	DNA was also extracted from 3 cell lines: Colo201 and HT29 with the BRAF mutation c.1799T>A (p.V600E), and HCT116 with wild-type BRAF using a QIAmp DNA mini kit (Qiagen, Valencia, CA).	('c.1799T>A', 'Mutation', 'rs113488022', (82, 91))	('p.V600E', 'Mutation', 'rs113488022', (93, 100))	('HT29', 'CellLine', 'CVCL:0320', (54, 58))	('BRAF', 'Gene', (68, 72))	('HCT116', 'CellLine', 'CVCL:0291', (107, 113))	('c.1799T>A', 'Var', (82, 91))
461404	23274581	The primer KRAS-PF1 (5'-TGTGGTAGTTGGAGCTG-3'; pyrosequencing nucleotide dispensation order, ACTGATCG ATCGATCGATCGATCGATCG) could detect the c.35G>T (codon 12 GTT) and c.35G>A (codon 12 GAT) mutations.	('GAT', 'Gene', '10249', (116, 119))	('GAT', 'Gene', (185, 188))	('GAT', 'Gene', '10249', (104, 107))	('c.35G>T', 'Var', (140, 147))	('GAT', 'Gene', '10249', (185, 188))	('GAT', 'Gene', '10249', (108, 111))	('GAT', 'Gene', (104, 107))	('GAT', 'Gene', (108, 111))	('c.35G>T', 'Mutation', 'rs121913529', (140, 147))	('TGT', 'Gene', (24, 27))	('TGT', 'Gene', '81890', (24, 27))	('GAT', 'Gene', (95, 98))	('GAT', 'Gene', '10249', (95, 98))	('GAT', 'Gene', '10249', (112, 115))	('c.35G>A', 'Mutation', 'rs121913529', (167, 174))	('GAT', 'Gene', (112, 115))	('GAT', 'Gene', (116, 119))	('c.35G>A', 'Var', (167, 174))
461406	23274581	The primer KRAS-PF3 (5'-TGGTAGTTGGAGCTGGT-3'; pyrosequencing nucleotide dispensation order, GATGCATGCATGCATGCATGCATGCATGC) could detect the c.34G>A (codon 13 GAC) mutation.	('c.34G>A', 'Var', (140, 147))	('GAT', 'Gene', (92, 95))	('c.34G>A', 'Mutation', 'rs121913530', (140, 147))	('GAT', 'Gene', '10249', (92, 95))
461411	23274581	We first examined the validity of the pyrosequencing method using eleven colon cancer tissues harboring 4 different KRAS mutations [c.35G>T (codon 12 GGT>GTT; p.Gly12Val), c.35G>A (codon 12 GGT>GAT; p.Gly12Asp), c.34G>T (codon 12 GGT>TGT; p.Gly12Cys), and c.38G>A mutation (codon 13 GGC>GAC; p.Gly13Asp)].	('KRAS', 'Gene', (116, 120))	('colon cancer', 'Phenotype', 'HP:0003003', (73, 85))	('p.Gly12Cys', 'Mutation', 'rs121913530', (239, 249))	('c.35G>T', 'Mutation', 'rs121913529', (132, 139))	('colon cancer', 'Disease', 'MESH:D015179', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('p.Gly12Asp', 'Mutation', 'rs121913529', (199, 209))	('codon 12 GGT>GTT', 'Mutation', 'rs121913529', (141, 157))	('p.Gly13Asp', 'Mutation', 'rs112445441', (292, 302))	('c.35G>A', 'Mutation', 'rs121913529', (172, 179))	('colon cancer', 'Disease', (73, 85))	('[c.35G>T', 'Var', (131, 139))	('c.35G>A', 'Var', (172, 179))	('c.34G>T', 'Var', (212, 219))	('c.34G>T', 'Mutation', 'rs121913530', (212, 219))	('p.Gly12Val', 'Mutation', 'rs121913529', (159, 169))	('codon 12 GGT>GAT', 'Mutation', 'rs121913529', (181, 197))	('c.38G>A', 'Var', (256, 263))	('codon 13 GGC>GAC', 'Mutation', 'rs112445441', (274, 290))	('codon 12 GGT>TGT', 'Mutation', 'rs121913530', (221, 237))	('c.38G>A', 'Mutation', 'rs112445441', (256, 263))
461412	23274581	1), which demonstrated that the method was reliable for the detection of KRAS mutations in tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('KRAS', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
461413	23274581	Pyrosequence analysis of KRAS codon 12 and 13 mutations was successful for 203 of 204 (99.5 %) ESCC paraffin-embedded tissues.	('paraffin', 'Chemical', 'MESH:D010232', (100, 108))	('KRAS', 'Gene', (25, 29))	('ESCC', 'Disease', (95, 99))	('mutations', 'Var', (46, 55))
461418	23274581	Furthermore, the BRAF mutation could be detected in paraffin-embedded tissues of colon cancer that had been previously diagnosed by Sanger dideoxy sequencing.	('mutation', 'Var', (22, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colon cancer', 'Disease', 'MESH:D015179', (81, 93))	('paraffin', 'Chemical', 'MESH:D010232', (52, 60))	('colon cancer', 'Disease', (81, 93))
461419	23274581	Collectively, these preliminary experiments supported the validity of the pyrosequencing method for the detection of BRAF mutation in paraffin-embedded specimens.	('mutation', 'Var', (122, 130))	('paraffin', 'Chemical', 'MESH:D010232', (134, 142))	('BRAF', 'Gene', (117, 121))
461421	23274581	The validity of the pyrosequencing method for detecting KRAS and BRAF mutations was initially demonstrated using colon cancer cell lines and colon cancer tissues harboring KRAS and BRAF mutations.	('KRAS', 'Gene', (172, 176))	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('colon cancer', 'Phenotype', 'HP:0003003', (141, 153))	('mutations', 'Var', (186, 195))	('colon cancer', 'Disease', (141, 153))	('KRAS', 'Gene', (56, 60))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('colon cancer', 'Disease', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('colon cancer', 'Disease', 'MESH:D015179', (141, 153))
461422	23274581	In addition, the BRAF mutation was absent in ESCC tumors.	('mutation', 'Var', (22, 30))	('ESCC tumors', 'Disease', (45, 56))	('ESCC tumors', 'Disease', 'MESH:D004938', (45, 56))	('BRAF', 'Gene', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
461424	23274581	Mutations in the KRAS gene occur early in the development of several types of cancers.	('occur', 'Reg', (27, 32))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', (78, 85))	('KRAS', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
461426	23274581	The phenomenon of publication bias occurs because studies with null findings (e.g., absence of KRAS mutation in tumors) have a higher likelihood of being unwritten and unpublished compared with those with significant results (e.g., presence of KRAS mutation in tumors).	('absence', 'NegReg', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutation', 'Var', (100, 108))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('KRAS', 'Gene', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
461428	23274581	The V600E point mutation in exon 15 of the BRAF gene has been shown to be associated with insensitivity to antigrowth signals, cell-cycle dysregulation, tumor invasion and metastasis, escape from apoptosis, unlimited replicative potential and angiogenesis, and can be used as a predictive biomarker for BRAF-targeted therapy.	('V600E', 'Var', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('unlimited replicative potential', 'CPA', (207, 238))	('angiogenesis', 'CPA', (243, 255))	('cell-cycle dysregulation', 'CPA', (127, 151))	('BRAF', 'Gene', (43, 47))	('V600E', 'Mutation', 'rs113488022', (4, 9))	('escape', 'CPA', (184, 190))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('insensitivity to antigrowth signals', 'MPA', (90, 125))	('associated', 'Reg', (74, 84))
461429	23274581	In addition, the prognostic role of the BRAF mutation has been emphasized in several types of cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('BRAF', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutation', 'Var', (45, 53))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
461430	23274581	One study showed the absence of a BRAF mutation in 35 ESCCs, and the other showed that only 1 tumor harbored a BRAF mutation among 80 ESCC tumors.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutation', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('ESCC tumors', 'Disease', 'MESH:D004938', (134, 145))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('BRAF', 'Gene', (34, 38))	('ESCC tumors', 'Disease', (134, 145))
461441	19783551	Various signaling defects upstream of mTOR, some of which are relatively common, have been identified in cancer cells and result in loss of cell growth control, unrestrained proliferation, tumor angiogenesis, and other malignant characteristics.	('cell growth control', 'CPA', (140, 159))	('tumor', 'Disease', (189, 194))	('defects', 'Var', (18, 25))	('loss', 'NegReg', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('malignant characteristics', 'CPA', (219, 244))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('identified', 'Reg', (91, 101))	('mTOR', 'Gene', (38, 42))	('mTOR', 'Gene', '2475', (38, 42))	('unrestrained proliferation', 'CPA', (161, 187))
461442	19783551	Defects in mTOR itself have not been identified in cancer, rendering this kinase both a well-situated and stable target for therapeutic intervention in cancers driven by defects in the mTOR signaling pathway.	('mTOR', 'Gene', (185, 189))	('mTOR', 'Gene', '2475', (185, 189))	('cancers', 'Disease', (152, 159))	('cancer', 'Disease', (152, 158))	('mTOR', 'Gene', (11, 15))	('mTOR', 'Gene', '2475', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('defects', 'Var', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
461443	19783551	RAD001 (everolimus) blocks the mTOR pathway by forming a complex with the immunophilin FK506-binding protein-12, which also binds mTOR with high affinity.	('mTOR', 'Gene', (31, 35))	('blocks', 'NegReg', (20, 26))	('mTOR', 'Gene', '2475', (31, 35))	('everolimus', 'Chemical', 'MESH:D000068338', (8, 18))	('binds', 'Interaction', (124, 129))	('complex', 'Interaction', (57, 64))	('F', 'Chemical', 'MESH:D005461', (87, 88))	('mTOR', 'Gene', (130, 134))	('mTOR', 'Gene', '2475', (130, 134))	('RAD001', 'Var', (0, 6))
461461	19783551	DLTs in >=2/6 patients in Cohort 1 would result in study discontinuation; DLTs in >=2/6 patients in Cohort 2 or 3 would result in additional patient enrollment in Cohorts 1 and 2, respectively.	('patient', 'Species', '9606', (88, 95))	('study', 'MPA', (51, 56))	('DLTs', 'Var', (74, 78))	('discontinuation', 'NegReg', (57, 72))	('patients', 'Species', '9606', (88, 96))	('patient', 'Species', '9606', (141, 148))	('patient', 'Species', '9606', (14, 21))	('DLTs', 'Var', (0, 4))	('patients', 'Species', '9606', (14, 22))
461481	19783551	Since RAD001 markedly diminished the size of the patient's metastatic focus, the cause of death was hemorrhage from either the right supraclavicular metastatic focus or the enriched vessels.	('diminished', 'NegReg', (22, 32))	('hemorrhage', 'Disease', (100, 110))	('patient', 'Species', '9606', (49, 56))	('hemorrhage', 'Disease', 'MESH:D006470', (100, 110))	('size', 'MPA', (37, 41))	('RAD001', 'Var', (6, 12))
461496	19783551	Previous studies have reported that patients receiving RAD001 manifested hyperglycemia and hyperlipidemia, probably as a result of inhibition of mTOR-regulated glucose and lipid metabolism.	('hyperlipidemia', 'Disease', (91, 105))	('patients', 'Species', '9606', (36, 44))	('mTOR', 'Gene', (145, 149))	('lipid', 'Chemical', 'MESH:D008055', (172, 177))	('inhibition', 'NegReg', (131, 141))	('glucose', 'Chemical', 'MESH:D005947', (160, 167))	('lipid', 'Chemical', 'MESH:D008055', (96, 101))	('mTOR', 'Gene', '2475', (145, 149))	('hyperlipidemia', 'Disease', 'MESH:D006949', (91, 105))	('hyperlipidemia', 'Phenotype', 'HP:0003077', (91, 105))	('hyperglycemia', 'Phenotype', 'HP:0003074', (73, 86))	('hyperglycemia', 'Disease', 'MESH:D006943', (73, 86))	('RAD001', 'Var', (55, 61))	('hyperglycemia', 'Disease', (73, 86))
461510	19783551	The likelihood that these findings will extend to other patients is supported by recent studies suggesting that defects in the mTOR signaling pathway are important in the pathogenesis of these cancers.	('patients', 'Species', '9606', (56, 64))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('cancers', 'Disease', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('mTOR', 'Gene', (127, 131))	('defects', 'Var', (112, 119))	('mTOR', 'Gene', '2475', (127, 131))
461559	33758286	In addition, in the positive resection margin group, RLN resection was more frequent during surgery and the mean number of lateral LN metastases increased, which was statistically significant (p = 0.014 and 0.009 respectively).	('LN metastases', 'Disease', (131, 144))	('increased', 'PosReg', (145, 154))	('positive', 'Var', (20, 28))	('RLN resection', 'Disease', (53, 66))	('LN metastases', 'Disease', 'MESH:D009362', (131, 144))
461598	33758286	reported that microscopic positive tumour margins did not affect disease-free survival in the majority of patients with PTC, but was associated with a four-fold increased risk of recurrence in T4a patients.	('patients', 'Species', '9606', (197, 205))	('microscopic positive', 'Var', (14, 34))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('patients', 'Species', '9606', (106, 114))	('T4a', 'Gene', '6317', (193, 196))	('PTC', 'Phenotype', 'HP:0002895', (120, 123))	('T4a', 'Gene', (193, 196))	('tumour', 'Disease', (35, 41))
461624	33007962	Dysregulated miRNAs have been shown to participate in almost all CCA hallmarks, including cell proliferation, migration and invasion, apoptosis, and the epithelial-to-mesenchymal transition.	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('migration', 'CPA', (110, 119))	('epithelial-to-mesenchymal transition', 'CPA', (153, 189))	('apoptosis', 'CPA', (134, 143))	('participate', 'Reg', (39, 50))	('cell proliferation', 'CPA', (90, 108))	('CCA', 'Phenotype', 'HP:0030153', (65, 68))	('Dysregulated', 'Var', (0, 12))	('CCA', 'Disease', (65, 68))
461637	33007962	While preliminary studies have not shown promising effects in PD-L1-positive CCA, a subsequent phase II study demonstrated an overall response rate of 40.9%, with an average survival of 24.3 months in previously treated patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) advanced CCA.	('microsatellite', 'Var', (234, 248))	('PD-L1', 'Gene', '29126', (62, 67))	('CCA', 'Phenotype', 'HP:0030153', (316, 319))	('patients', 'Species', '9606', (220, 228))	('PD-L1', 'Gene', (62, 67))	('CCA', 'Disease', (316, 319))	('CCA', 'Phenotype', 'HP:0030153', (77, 80))
461638	33007962	Tumors with MSI-H/dMMR carry a high mutational burden and the potential for increased neoantigen load, eliciting a response to anti-PD-1 antibody immunotherapy.	('response', 'MPA', (115, 123))	('eliciting', 'Reg', (103, 112))	('increased', 'PosReg', (76, 85))	('mutational burden', 'MPA', (36, 53))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('neoantigen load', 'MPA', (86, 101))	('MSI-H/dMMR', 'Var', (12, 22))
461643	33007962	Pemigatinib, a selective inhibitor of FGFR, achieved an objective response of 36% and a median PFS of 6.9 months in previously treated patients with intrahepatic CCA who have FGFR2 fusions or rearrangements.	('Pemigatinib', 'Chemical', '-', (0, 11))	('patients', 'Species', '9606', (135, 143))	('rearrangements', 'Var', (192, 206))	('FGFR', 'Gene', (38, 42))	('CCA', 'Phenotype', 'HP:0030153', (162, 165))	('FGFR2', 'Gene', (175, 180))	('fusions', 'Var', (181, 188))	('FGFR2', 'Gene', '2263', (175, 180))
461650	33007962	Increasing evidence suggests that aberrant expression of several miRNAs is involved in modulating the response to chemotherapy or other targeted treatments (Table 1).	('involved', 'Reg', (75, 83))	('aberrant expression', 'Var', (34, 53))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('response to chemotherapy', 'CPA', (102, 126))	('modulating', 'Reg', (87, 97))
461667	33007962	In contrast, inhibition of miR-141 reduced the growth of CCA cell lines.	('miR-141', 'Gene', '406933', (27, 34))	('CCA', 'Phenotype', 'HP:0030153', (57, 60))	('reduced', 'NegReg', (35, 42))	('inhibition', 'Var', (13, 23))	('CCA', 'Disease', (57, 60))	('growth', 'CPA', (47, 53))	('miR-141', 'Gene', (27, 34))
461670	33007962	Moreover, the silencing of miR-141 expression increased CLOCK protein expression in CCA cells.	('silencing', 'Var', (14, 23))	('miR-141', 'Gene', '406933', (27, 34))	('CLOCK', 'Gene', '9575', (56, 61))	('increased', 'PosReg', (46, 55))	('CLOCK', 'Gene', (56, 61))	('expression', 'MPA', (35, 45))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('miR-141', 'Gene', (27, 34))
461675	33007962	Inhibition of miR-200b increased the expression of protein tyrosine phosphatase, nonreceptor type 12 (PTPN12), leading to the decreased phosphorylation of Src at tyrosine 182, which is essential to mediate downstream signal transduction for cell proliferation and differentiation.	('tyrosine', 'Chemical', 'MESH:D014443', (59, 67))	('decreased', 'NegReg', (126, 135))	('phosphorylation', 'MPA', (136, 151))	('tyrosine', 'Chemical', 'MESH:D014443', (162, 170))	('PTPN12', 'Gene', '5782', (102, 108))	('miR-200b', 'Gene', '406984', (14, 22))	('Src', 'Gene', (155, 158))	('Src', 'Gene', '6714', (155, 158))	('expression', 'MPA', (37, 47))	('increased', 'PosReg', (23, 32))	('Inhibition', 'Var', (0, 10))	('protein tyrosine phosphatase, nonreceptor type 12', 'Gene', '5782', (51, 100))	('miR-200b', 'Gene', (14, 22))	('PTPN12', 'Gene', (102, 108))
461683	33007962	Aberrant expression of these miRNAs is frequent in various cancers, acting as tumor suppressors or oncogenes in a cellular context-dependent manner.	('Aberrant expression', 'Var', (0, 19))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('tumor', 'Disease', (78, 83))	('cancers', 'Disease', (59, 66))
461686	33007962	Ectopic expression of miR-29b sensitized KMCH CCA cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through directly suppressing Mcl-1.	('Mcl-1', 'MPA', (152, 157))	('TRAIL', 'Gene', (98, 103))	('suppressing', 'NegReg', (140, 151))	('miR-29b', 'Gene', (22, 29))	('Ectopic expression', 'Var', (0, 18))	('miR-29b', 'Gene', '407024', (22, 29))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))	('TRAIL', 'Gene', '8743', (98, 103))	('sensitized', 'Reg', (30, 40))
461687	33007962	On the other hand, the silencing of miR-29b in normal cholangiocytes increased Mcl-1 protein expression, resulting in reduced TRAIL-mediated apoptosis.	('increased', 'PosReg', (69, 78))	('miR-29b', 'Gene', (36, 43))	('TRAIL', 'Gene', (126, 131))	('reduced', 'NegReg', (118, 125))	('silencing', 'Var', (23, 32))	('miR-29b', 'Gene', '407024', (36, 43))	('increased Mcl', 'Phenotype', 'HP:0005518', (69, 82))	('Mcl-1 protein expression', 'MPA', (79, 103))	('TRAIL', 'Gene', '8743', (126, 131))
461693	33007962	Silencing of PI3KR1 or MMP-2 expression further decreased the viability of HuH28 cells upon gemcitabine treatment.	('MMP-2', 'Gene', '4313', (23, 28))	('viability', 'CPA', (62, 71))	('decreased', 'NegReg', (48, 57))	('PI3KR1', 'Gene', (13, 19))	('MMP-2', 'Gene', (23, 28))	('Silencing', 'Var', (0, 9))	('gemcitabine', 'Chemical', 'MESH:C056507', (92, 103))	('HuH28', 'CellLine', 'CVCL:2955', (75, 80))
461705	33007962	On the other hand, inhibition of miR-211 reduced the migration and invasion of malignant cholangiocytes by modulating the PTEN-dependent beta-catenin/cJun signaling pathway.	('cJun', 'Gene', '3725', (150, 154))	('reduced', 'NegReg', (41, 48))	('beta-catenin', 'Gene', (137, 149))	('beta-catenin', 'Gene', '1499', (137, 149))	('inhibition', 'Var', (19, 29))	('modulating', 'Reg', (107, 117))	('cJun', 'Gene', (150, 154))	('miR-211', 'Gene', '406993', (33, 40))	('miR-211', 'Gene', (33, 40))	('invasion of malignant cholangiocytes', 'CPA', (67, 103))	('PTEN', 'Gene', (122, 126))	('PTEN', 'Gene', '5728', (122, 126))
461720	33007962	Moreover, miR-130a-3p was found to be involved in regulating the cisplatin response in esophageal squamous cell carcinoma and gastric cancer, and gemcitabine resistance in hepatocellular carcinoma.	('cisplatin response', 'MPA', (65, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('gastric cancer', 'Disease', (126, 140))	('gemcitabine', 'Chemical', 'MESH:C056507', (146, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (172, 196))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('miR-130a-3p', 'Chemical', '-', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (172, 196))	('gemcitabine', 'MPA', (146, 157))	('involved', 'Reg', (38, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('hepatocellular carcinoma', 'Disease', (172, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('miR-130a-3p', 'Var', (10, 21))
461721	33007962	reported that tumors with higher expression of miR-130a-3p were associated with poorer survival in patients with CCA.	('survival', 'MPA', (87, 95))	('higher', 'PosReg', (26, 32))	('miR-130a-3p', 'Chemical', '-', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('CCA', 'Disease', (113, 116))	('tumors', 'Disease', (14, 20))	('poorer', 'NegReg', (80, 86))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('miR-130a-3p', 'Var', (47, 58))	('expression', 'MPA', (33, 43))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('CCA', 'Phenotype', 'HP:0030153', (113, 116))
461723	33007962	Ectopic expression of miR-130a-3p in parental CCA cells increased gemcitabine resistance.	('increased', 'PosReg', (56, 65))	('gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('gemcitabine resistance', 'MPA', (66, 88))	('miR-130a-3p', 'Var', (22, 33))	('CCA', 'Phenotype', 'HP:0030153', (46, 49))	('miR-130a-3p', 'Chemical', '-', (22, 33))	('Ectopic expression', 'MPA', (0, 18))
461724	33007962	Peroxisome proliferator-activated receptor-gamma (PPARgamma) is the direct target of miR-130a-3p.	('miR-130a-3p', 'Chemical', '-', (85, 96))	('Peroxisome proliferator-activated receptor-gamma', 'Gene', '5468', (0, 48))	('Peroxisome proliferator-activated receptor-gamma', 'Gene', (0, 48))	('PPARgamma', 'Gene', '5468', (50, 59))	('miR-130a-3p', 'Var', (85, 96))	('PPARgamma', 'Gene', (50, 59))
461727	33007962	Aberrant expression of miR-1249 has previously been reported in several cancer types.	('miR-1249', 'Gene', '100302149', (23, 31))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('reported', 'Reg', (52, 60))	('expression', 'MPA', (9, 19))	('miR-1249', 'Gene', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
461730	33007962	Overexpressed miR-1249-3p enhanced tumor growth and invasion of hepatocellular carcinoma.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('enhanced', 'PosReg', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('miR-1249-3p', 'Chemical', '-', (14, 25))	('tumor', 'Disease', (35, 40))	('miR-1249-3p', 'Var', (14, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (64, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('invasion', 'CPA', (52, 60))	('hepatocellular carcinoma', 'Disease', (64, 88))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (64, 88))
461733	33007962	Inhibition of miR-1249 enhanced the sensitivity of doublet chemotherapy, including cisplatin and gemcitabine.	('enhanced', 'PosReg', (23, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('miR-1249', 'Gene', (14, 22))	('Inhibition', 'Var', (0, 10))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('cisplatin', 'MPA', (83, 92))	('miR-1249', 'Gene', '100302149', (14, 22))	('sensitivity', 'MPA', (36, 47))
461744	33007962	Furthermore, miR-210 decreased gemcitabine sensitivity by targeting HIF-3alpha, a negative regulator of HIF-1alpha.	('HIF-3alpha', 'Gene', (68, 78))	('miR-210', 'Var', (13, 20))	('HIF-1alpha', 'Gene', (104, 114))	('decreased', 'NegReg', (21, 30))	('gemcitabine', 'Chemical', 'MESH:C056507', (31, 42))	('targeting', 'Reg', (58, 67))	('HIF-3alpha', 'Gene', '64344', (68, 78))	('HIF-1alpha', 'Gene', '3091', (104, 114))	('gemcitabine sensitivity', 'MPA', (31, 54))
461748	33007962	On the other hand, cisplatin forms monoadducts or interstrand or intrastrand crosslinks between purine bases and inhibits repair of DNA damage.	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('crosslinks', 'Var', (77, 87))	('repair of DNA damage', 'MPA', (122, 142))	('purine', 'Chemical', 'MESH:C030985', (96, 102))	('inhibits', 'NegReg', (113, 121))
461761	33007962	Upregulation of miR-200b/c inhibited migration, invasion, and distant metastasis of CCA cells, while silencing miR-200b/c promoted the metastatic process through modulating Zeb1/2 and the Rho-associated protein kinase 2 (ROCK2) pathway.	('miR-200b', 'Gene', (111, 119))	('Zeb1/2', 'Gene', '6935;9839', (173, 179))	('silencing', 'Var', (101, 110))	('miR-200b', 'Gene', (16, 24))	('migration', 'CPA', (37, 46))	('inhibited', 'NegReg', (27, 36))	('distant metastasis', 'CPA', (62, 80))	('ROCK2', 'Gene', '9475', (221, 226))	('Rho-associated protein kinase 2', 'Gene', (188, 219))	('Rho-associated protein kinase 2', 'Gene', '9475', (188, 219))	('miR-200b', 'Gene', '406984', (111, 119))	('invasion', 'CPA', (48, 56))	('CCA', 'Phenotype', 'HP:0030153', (84, 87))	('miR-200b', 'Gene', '406984', (16, 24))	('Upregulation', 'PosReg', (0, 12))	('metastatic process', 'CPA', (135, 153))	('modulating', 'Reg', (162, 172))	('promoted', 'PosReg', (122, 130))	('ROCK2', 'Gene', (221, 226))	('Zeb1/2', 'Gene', (173, 179))
461779	33007962	Taken together, miR-320 could increase sensitivity to 5-FU by targeting Mcl-1 in CCA.	('miR-320', 'Var', (16, 23))	('CCA', 'Disease', (81, 84))	('sensitivity to 5-FU', 'MPA', (39, 58))	('miR-320', 'Chemical', '-', (16, 23))	('targeting', 'Reg', (62, 71))	('Mcl-1', 'Gene', (72, 77))	('increase', 'PosReg', (30, 38))	('CCA', 'Phenotype', 'HP:0030153', (81, 84))	('5-FU', 'Chemical', 'MESH:D005472', (54, 58))
461780	33007962	A number of emerging targeted drugs have been investigated to treat CCA, such as FGFR2 small molecule kinase inhibitors, mutant IDH inhibitors, Mcl-1 selective inhibitors, and MEK inhibitors.	('CCA', 'Phenotype', 'HP:0030153', (68, 71))	('mutant', 'Var', (121, 127))	('IDH', 'Gene', (128, 131))	('IDH', 'Gene', '3417', (128, 131))	('FGFR2', 'Gene', (81, 86))	('CCA', 'Disease', (68, 71))	('MEK', 'Gene', (176, 179))	('MEK', 'Gene', '5609', (176, 179))	('FGFR2', 'Gene', '2263', (81, 86))
461784	33007962	On the other hand, heat shock protein (Hsp) 90 has been shown to serve as a chaperone of FGFR, providing a biochemical basis for targeting CCA with FGFR aberrations.	('aberrations', 'Var', (153, 164))	('heat shock protein (Hsp) 90', 'Gene', (19, 46))	('CCA', 'Disease', (139, 142))	('CCA', 'Phenotype', 'HP:0030153', (139, 142))	('shock', 'Phenotype', 'HP:0031273', (24, 29))	('heat shock protein (Hsp) 90', 'Gene', '3320', (19, 46))
461789	33007962	SRY-related HMG-box 4 (SOX4) was identified as a target of miR-138.	('SRY-related HMG-box 4', 'Gene', (0, 21))	('miR-138', 'Var', (59, 66))	('SOX4', 'Gene', (23, 27))	('SRY-related HMG-box 4', 'Gene', '6659', (0, 21))	('miR-138', 'Chemical', '-', (59, 66))	('SOX4', 'Gene', '6659', (23, 27))
461798	33007962	Additionally, they found that the hypermethylated promoter region and aberrant splicing of hOCT1 lead to decreased hOCT1 expression and sorafenib response.	('hOCT1', 'Gene', '6580', (91, 96))	('expression', 'MPA', (121, 131))	('hOCT1', 'Gene', '6580', (115, 120))	('hypermethylated', 'Var', (34, 49))	('hOCT1', 'Gene', (115, 120))	('aberrant splicing', 'Var', (70, 87))	('sorafenib', 'Chemical', 'MESH:D000077157', (136, 145))	('decreased', 'NegReg', (105, 114))	('sorafenib response', 'MPA', (136, 154))	('hOCT1', 'Gene', (91, 96))
461799	33007962	Ectopic expression of hOCT1 increased sorafenib uptake in malignant cholangiocytes, enhancing the cytotoxic effect of sorafenib.	('increased', 'PosReg', (28, 37))	('cytotoxic effect', 'CPA', (98, 114))	('Ectopic expression', 'Var', (0, 18))	('sorafenib', 'Chemical', 'MESH:D000077157', (118, 127))	('hOCT1', 'Gene', '6580', (22, 27))	('enhancing', 'PosReg', (84, 93))	('sorafenib', 'Chemical', 'MESH:D000077157', (38, 47))	('hOCT1', 'Gene', (22, 27))
461801	33007962	identified that Hsp 90 inhibitors are effective in CCA cell lines from a high-throughput screening.	('CCA', 'Disease', (51, 54))	('inhibitors', 'Var', (23, 33))	('CCA', 'Phenotype', 'HP:0030153', (51, 54))	('Hsp', 'Gene', (16, 19))	('Hsp', 'Gene', '7190', (16, 19))
461815	33007962	Antagonism of miR-25 increased death receptor 4 (DR4) protein expression, sensitizing malignant cholangiocytes to apoptosis.	('increased', 'PosReg', (21, 30))	('Antagonism', 'Var', (0, 10))	('expression', 'MPA', (62, 72))	('sensitizing', 'Reg', (74, 85))	('death receptor 4', 'Gene', '8797', (31, 47))	('death receptor 4', 'Gene', (31, 47))	('DR4', 'Gene', '8797', (49, 52))	('miR-25', 'Gene', '407014', (14, 20))	('miR-25', 'Gene', (14, 20))	('apoptosis', 'CPA', (114, 123))	('DR4', 'Gene', (49, 52))
461841	33007962	Inhibition of CXCR4 signaling decreases CCA cells migration and invasion.	('decreases', 'NegReg', (30, 39))	('invasion', 'CPA', (64, 72))	('CCA', 'Disease', (40, 43))	('CXCR4', 'Gene', '7852', (14, 19))	('Inhibition', 'Var', (0, 10))	('CCA', 'Phenotype', 'HP:0030153', (40, 43))	('CXCR4', 'Gene', (14, 19))
461910	31481019	The primers of TEX-9 are 5'- GTCTGTGTCTCACGAGAAGCA-3' (F) and 5'-TAGCTTGTTGAACCACGTCAG-3' (R).	('TEX-9', 'Gene', '374618', (15, 20))	('TEX-9', 'Gene', (15, 20))	("5'-TAGCTTGTTGAACCACGTCAG-3", 'Var', (62, 88))
461938	31481019	ESCC cells (EC109 and KYSE510) with single TEX9 knockdown (SKD cell) and double TEX9, eIF3b knockdown (DKD cell) were respectively established (Additional file 3: Figure S1B and C).	('knockdown', 'Var', (92, 101))	('double TEX9', 'Var', (73, 84))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('EC109', 'CellLine', 'CVCL:6898', (12, 17))	('eIF3b', 'Gene', (86, 91))	('eIF3b', 'Gene', '8668', (86, 91))
461940	31481019	Both of SKD and DKD cells had lower proliferative ability than control cells using colony-formation assay (Fig.	('lower', 'NegReg', (30, 35))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('proliferative ability', 'CPA', (36, 57))	('DKD', 'Var', (16, 19))
461941	31481019	The tumor xenograft assay also showed that si-Control groups could form significantly larger tumors than the SKD groups did, which indicated that knockdown of TEX9 significantly inhibited the proliferative ability of ESCC cells in vivo (Fig.	('tumor', 'Disease', (4, 9))	('knockdown', 'Var', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('TEX9', 'Gene', (159, 163))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (93, 98))	('inhibited', 'NegReg', (178, 187))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Disease', (93, 99))	('proliferative ability', 'CPA', (192, 213))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
461945	31481019	Western blot analyses of crucial molecules in those pathways were performed to evaluate their expression as a function of TEX9 and eIF3b depletion.	('depletion', 'Var', (137, 146))	('expression', 'MPA', (94, 104))	('eIF3b', 'Gene', (131, 136))	('eIF3b', 'Gene', '8668', (131, 136))	('si', 'Chemical', 'MESH:D012825', (100, 102))
461946	31481019	The result revealed that phosphorylated AKT (pAKT) was significantly decreased in both ESCC cells with TEX9 SKD and DKD, however, total AKT protein and the other pathways were not changed (Fig.	('AKT', 'Gene', '207', (46, 49))	('phosphorylated', 'MPA', (25, 39))	('AKT', 'Gene', '207', (40, 43))	('decreased', 'NegReg', (69, 78))	('AKT', 'Gene', (46, 49))	('TEX9 SKD', 'Var', (103, 111))	('DKD', 'Var', (116, 119))	('AKT', 'Gene', '207', (136, 139))	('AKT', 'Gene', (40, 43))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('AKT', 'Gene', (136, 139))
461949	31481019	4c and d, SC79 treatment abolished the inhibitory effects of TEX9 SKD or DKD on proliferation and migration of ESCC cells.	('SC79', 'Chemical', '-', (10, 14))	('DKD', 'Var', (73, 76))	('proliferation', 'CPA', (80, 93))	('migration', 'CPA', (98, 107))	('TEX9', 'Gene', (61, 65))	('ESCC', 'Disease', (111, 115))
461951	31481019	Several studies have demonstrated that overexpressed eIF3b could promote the progression of malignant cancers such as glioblastoma cells,colon cancer, osteosarcoma and lung cancer.	('malignant cancers', 'Disease', (92, 109))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('colon cancer', 'Phenotype', 'HP:0003003', (137, 149))	('malignant cancers', 'Disease', 'MESH:D009369', (92, 109))	('promote', 'PosReg', (65, 72))	('eIF3b', 'Gene', '8668', (53, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('colon cancer', 'Disease', 'MESH:D015179', (137, 149))	('overexpressed', 'Var', (39, 52))	('osteosarcoma and lung cancer', 'Disease', 'MESH:D008175', (151, 179))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('progression', 'CPA', (77, 88))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('colon cancer', 'Disease', (137, 149))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('eIF3b', 'Gene', (53, 58))	('glioblastoma', 'Disease', (118, 130))
461955	31481019	Through SKD of TEX9 or DKD of TEX9 and eIF3b, we demonstrated that TEX9 could synergize with eIF3b to promote the proliferation and migration, and inhibit the apoptosis of ESCC cells through the activation of AKT signaling pathway.	('eIF3b', 'Gene', '8668', (39, 44))	('eIF3b', 'Gene', (39, 44))	('DKD', 'Var', (23, 26))	('TEX9', 'Var', (67, 71))	('AKT', 'Gene', '207', (209, 212))	('migration', 'CPA', (132, 141))	('promote', 'PosReg', (102, 109))	('proliferation', 'CPA', (114, 127))	('eIF3b', 'Gene', (93, 98))	('inhibit', 'NegReg', (147, 154))	('si', 'Chemical', 'MESH:D012825', (213, 215))	('eIF3b', 'Gene', '8668', (93, 98))	('AKT', 'Gene', (209, 212))	('si', 'Chemical', 'MESH:D012825', (165, 167))	('apoptosis', 'CPA', (159, 168))
461966	31481019	In addition, a rare variant Q1631H in DNA repair gene TEX15 is associated with prostate cancer risk and truncating variants in TEX15 were proved to be potential breast cancer risk factor.	('prostate cancer', 'Disease', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('Q1631H', 'Mutation', 'rs142485241', (28, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Disease', (161, 174))	('associated', 'Reg', (63, 73))	('TEX15', 'Gene', '56154', (54, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('TEX15', 'Gene', (54, 59))	('TEX15', 'Gene', '56154', (127, 132))	('Q1631H', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TEX15', 'Gene', (127, 132))
461977	28680059	GWAS follow-up study of esophageal squamous cell carcinoma identifies potential genetic loci associated with family history of upper gastrointestinal cancer Based on our initial genome-wide association study (GWAS) on esophageal squamous cell carcinoma (ESCC) in Han Chinese, we conducted a follow-up study to examine the single nucleotide polymorphisms (SNPs) associated with family history (FH) of upper gastrointestinal cancer (UGI) cancer in cases with ESCC.	('cancer', 'Disease', (423, 429))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('upper gastrointestinal cancer', 'Disease', 'MESH:D004067', (400, 429))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (406, 429))	('esophageal squamous cell carcinoma', 'Disease', (24, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (229, 252))	('cancer', 'Disease', (150, 156))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (218, 252))	('single nucleotide polymorphisms', 'Var', (322, 353))	('cancer', 'Disease', (436, 442))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('upper gastrointestinal cancer', 'Disease', (400, 429))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (133, 156))	('upper gastrointestinal cancer', 'Disease', 'MESH:D004067', (127, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('cancer', 'Disease', 'MESH:D009369', (423, 429))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (24, 58))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (436, 442))	('upper gastrointestinal cancer', 'Disease', (127, 156))	('esophageal squamous cell carcinoma', 'Disease', (218, 252))
461981	28680059	We identified potential genetic variants associated with FH of UGI cancer.	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('variants', 'Var', (32, 40))	('FH of UGI cancer', 'Disease', (57, 73))	('FH of UGI cancer', 'Disease', 'MESH:D006938', (57, 73))
461988	28680059	Based on our initial GWAS for ESCC in high-risk populations of Han Chinese ethnicity, we conducted additional analyses of the association of single nucleotide polymorphisms (SNPs) with FH of UGI cancer in ESCC cases.	('FH of UGI cancer', 'Disease', (185, 201))	('FH of UGI cancer', 'Disease', 'MESH:D006938', (185, 201))	('association', 'Interaction', (126, 137))	('single nucleotide polymorphisms', 'Var', (141, 172))	('ESCC', 'Disease', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
461992	28680059	The smallest P value was observed for rs140792366 (P = 7.65 x 10-7), which is in the gene GRIK4 (located at 11q23.3).	('rs140792366', 'Var', (38, 49))	('rs140792366', 'Mutation', 'rs140792366', (38, 49))	('GRIK4', 'Gene', '2900', (90, 95))	('GRIK4', 'Gene', (90, 95))
461994	28680059	Among the 18 SNPs tested in replication, we did not see an alternative (minor) allele for rs141703242 (surrogate of rs186503151) or rs184911713 (surrogate of rs187481103).	('rs141703242', 'Var', (90, 101))	('rs141703242', 'Mutation', 'rs141703242', (90, 101))	('rs184911713', 'Mutation', 'rs184911713', (132, 143))	('rs187481103', 'Mutation', 'rs187481103', (158, 169))	('rs186503151', 'Mutation', 'rs186503151', (116, 127))	('rs184911713', 'Var', (132, 143))
461996	28680059	The candidate SNP with strongest associations with FH in the discovery (rs140792366) had much lower MAF in the stage 2 and was not replicated.	('MAF', 'Gene', '4094', (100, 103))	('MAF', 'Gene', (100, 103))	('rs140792366', 'Var', (72, 83))	('rs140792366', 'Mutation', 'rs140792366', (72, 83))
461997	28680059	Rs79747906 in DLGAP1 (located at 18p11.31, odds ratio [OR] = 1.91 and P = 5.79 x 10-6 in the meta-analysis of discovery set) had the smallest p-value in the replication analysis with FH defined for relatives in three generations and was significant at a nominal significance level (OR = 1.23, P = 0.006) (Tables 1 and 2).	('DLGAP1', 'Gene', '9229', (14, 20))	('Rs79747906', 'Mutation', 'Rs79747906', (0, 10))	('DLGAP1', 'Gene', (14, 20))	('Rs79747906', 'Var', (0, 10))	('p-value', 'MPA', (142, 149))
462000	28680059	We annotated the two SNPs (rs79747906 and rs12461816) that showed suggestive association with FH in the replication.	('rs79747906', 'Var', (27, 37))	('rs79747906', 'Mutation', 'rs79747906', (27, 37))	('association', 'Reg', (77, 88))	('rs12461816', 'Var', (42, 52))	('rs12461816', 'Mutation', 'rs12461816', (42, 52))
462001	28680059	The functional analysis revealed that rs79747906 C allele may have a weak CTCF binding function.	('weak', 'NegReg', (69, 73))	('CTCF', 'Gene', '10664', (74, 78))	('rs79747906', 'Mutation', 'rs79747906', (38, 48))	('rs79747906 C', 'Var', (38, 50))	('CTCF', 'Gene', (74, 78))
462002	28680059	SNP rs12461816 has a potential weak polycomb-repressed state of transcription in stomach smooth muscle and the T allele of rs12461816 abolishes a methylated CpG in normal esophagus and gastric tissues (Table 3 and Supplementary Figures 1 and 2).	('abolishes', 'NegReg', (134, 143))	('rs12461816', 'Var', (123, 133))	('rs12461816', 'Mutation', 'rs12461816', (123, 133))	('rs12461816', 'Mutation', 'rs12461816', (4, 14))	('polycomb-repressed state of transcription', 'MPA', (36, 77))	('methylated CpG', 'MPA', (146, 160))
462003	28680059	In the expression quantitative trait loci (eQTL) analyses, rs12461816 T allele was significantly associated with increased cis expression of AC004791.2 in normal esophageal muscularis (P = 6.00 x 10-7) and mucosa (P = 7.30 x 10-4), normal stomach mucosa (P = 9.50 x 10-7), and whole blood (P = 2.5 x 10-5).	('rs12461816', 'Mutation', 'rs12461816', (59, 69))	('cis expression', 'MPA', (123, 137))	('rs12461816 T', 'Var', (59, 71))	('increased', 'PosReg', (113, 122))	('AC004791.2', 'Gene', (141, 151))
462005	28680059	For rs79747906, the C allele was suggestively associated with altered expression of several genes such as LPIN2, although none of these associations were significant after adjustment for multiple comparisons (Supplementary Tables 3 and 4).	('LPIN2', 'Gene', '9663', (106, 111))	('altered', 'Reg', (62, 69))	('LPIN2', 'Gene', (106, 111))	('rs79747906', 'Mutation', 'rs79747906', (4, 14))	('rs79747906', 'Var', (4, 14))	('expression', 'MPA', (70, 80))
462010	28680059	Rs79747906 is located in the intergenic region close to DLGAP1, SNPs of which have been associated with obsessive-compulsive disorder.	('obsessive-compulsive disorder', 'Disease', (104, 133))	('DLGAP1', 'Gene', (56, 62))	('DLGAP1', 'Gene', '9229', (56, 62))	('Rs79747906', 'Mutation', 'Rs79747906', (0, 10))	('obsessive-compulsive disorder', 'Phenotype', 'HP:0000722', (104, 133))	('obsessive-compulsive disorder', 'Disease', 'MESH:D009771', (104, 133))	('Rs79747906', 'Var', (0, 10))	('associated', 'Reg', (88, 98))
462013	28680059	We also found that the rs79747906 C allele may alter several DNA binding motifs of homeobox transcriptional factors and proteins, including CDP, Nanog, PAX4, and SMAD2 (ENCODE and HaploRegv4) and scores high as a regulatory SNP for embryonic stem and progenitor cells of other tissues (RegulomeDB and HaploRegv4).	('Nanog', 'Gene', '79923', (145, 150))	('Nanog', 'Gene', (145, 150))	('CDP', 'Gene', (140, 143))	('binding', 'Interaction', (65, 72))	('alter', 'Reg', (47, 52))	('homeobox transcriptional factors', 'Protein', (83, 115))	('rs79747906 C', 'Var', (23, 35))	('SMAD2', 'Gene', (162, 167))	('SMAD2', 'Gene', '4087', (162, 167))	('CDP', 'Gene', '1523', (140, 143))	('PAX4', 'Gene', '5078', (152, 156))	('rs79747906', 'Mutation', 'rs79747906', (23, 33))	('PAX4', 'Gene', (152, 156))	('proteins', 'Protein', (120, 128))
462014	28680059	Collectively, these findings suggest that the genetic region containing rs79747906 has the potential to change chromatin architecture in esophageal epithelia and/or in esophageal stem cells via protein binding.	('chromatin architecture', 'MPA', (111, 133))	('rs79747906', 'Var', (72, 82))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (137, 157))	('change', 'Reg', (104, 110))	('rs79747906', 'Mutation', 'rs79747906', (72, 82))	('protein', 'Protein', (194, 201))	('esophageal epithelia', 'Disease', (137, 157))	('esophageal epithelia', 'Disease', 'MESH:D004941', (137, 157))
462017	28680059	LPIN2 protein is known for its role in metabolism, with LPIN2 SNPs associated with metabolic traits, which may be important for UGI cancer.	('LPIN2', 'Gene', (0, 5))	('LPIN2', 'Gene', '9663', (0, 5))	('UGI cancer', 'Disease', (128, 138))	('metabolic traits', 'MPA', (83, 99))	('LPIN2', 'Gene', '9663', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('LPIN2', 'Gene', (56, 61))	('UGI cancer', 'Disease', 'MESH:D009369', (128, 138))	('associated', 'Reg', (67, 77))	('SNPs', 'Var', (62, 66))
462019	28680059	The T allele of rs12461816 (19p13.12) was associated with FH and can abolish a methylated CpG in normal esophagus and stomach tissues.	('associated', 'Reg', (42, 52))	('rs12461816', 'Var', (16, 26))	('rs12461816', 'Mutation', 'rs12461816', (16, 26))	('abolish', 'NegReg', (69, 76))	('methylated CpG', 'MPA', (79, 93))
462020	28680059	In keeping with a methylated and condensed DNA status, rs12461816 is also located to a potential polycomb-repressed DNA region in stomach smooth muscle, suggesting a possible transcriptional repression function for this region regulated by epigenetics.	('rs12461816', 'Var', (55, 65))	('transcriptional', 'MPA', (175, 190))	('rs12461816', 'Mutation', 'rs12461816', (55, 65))
462021	28680059	Notably, rs12461816 T allele was strongly associated with increased expression of AC004791.2.	('rs12461816', 'Mutation', 'rs12461816', (9, 19))	('increased', 'PosReg', (58, 67))	('expression', 'MPA', (68, 78))	('rs12461816 T', 'Var', (9, 21))	('AC004791.2', 'Gene', (82, 92))
462022	28680059	The expression of multiple other genes with important functions may be altered by rs12461816 variant too, such as CYP4F11, which encodes a cytochrome P450 enzyme (and is important for arachidonic acid or fatty acid metabolism).	('CYP4F11', 'Gene', '57834', (114, 121))	('CYP4F11', 'Gene', (114, 121))	('arachidonic acid', 'Chemical', 'MESH:D016718', (184, 200))	('fatty acid', 'Chemical', 'MESH:D005227', (204, 214))	('expression', 'MPA', (4, 14))	('rs12461816', 'Var', (82, 92))	('altered', 'Reg', (71, 78))	('rs12461816', 'Mutation', 'rs12461816', (82, 92))
462024	28680059	We identified potential genetic variants associated with FH of UGI cancer in ESCC cases.	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('variants', 'Var', (32, 40))	('FH of UGI cancer', 'Disease', (57, 73))	('FH of UGI cancer', 'Disease', 'MESH:D006938', (57, 73))
462046	28427211	When compared to the wild-type genotype, the homozygous variant of BRM-741 carried an adjusted OS hazard ratio (aHR) of 1.64 (95% CI:1.1-2.4); for BRM-1321, the aHR was 2.09 (95% CI:1.4-3.0).	('variant', 'Var', (56, 63))	('BRM', 'Gene', '6595', (67, 70))	('BRM', 'Gene', (147, 150))	('OS', 'Chemical', '-', (95, 97))	('BRM', 'Gene', '6595', (147, 150))	('BRM', 'Gene', (67, 70))
462050	28427211	BRM polymorphisms were associated with OS in EAC in this study.	('associated with', 'Reg', (23, 38))	('BRM', 'Gene', (0, 3))	('polymorphisms', 'Var', (4, 17))	('OS', 'Chemical', '-', (39, 41))	('BRM', 'Gene', '6595', (0, 3))	('EAC', 'Disease', (45, 48))
462054	28427211	Exome and whole-genome sequencing studies have identified several significantly mutated genes in both squamous cell esophageal carcinoma and EAC.	('EAC', 'Disease', (141, 144))	('squamous cell esophageal carcinoma', 'Phenotype', 'HP:0030359', (102, 136))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (116, 136))	('mutated', 'Var', (80, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell esophageal carcinoma', 'Disease', (102, 136))	('squamous cell esophageal carcinoma', 'Disease', 'MESH:D000077277', (102, 136))
462075	28427211	In Kaplan Meier curves (Figure 1) and in univariable and multivariable Cox models (Table 3 and Supplementary Table 1), Homozygous variants of BRM-741 were associated strongly with worse OS (adjusted HR [aHR] 1.64; 95% CI: 1.1-2.4; p = 0.0026] and with worse PFS (aHR 1.65; 95% CI: 1.1-2.4; p = 0.009), when each was compared to the wild-type genotype.	('Cox', 'Gene', (71, 74))	('variants', 'Var', (130, 138))	('OS', 'Chemical', '-', (186, 188))	('PFS', 'MPA', (258, 261))	('worse OS', 'MPA', (180, 188))	('BRM', 'Gene', (142, 145))	('Cox', 'Gene', '1351', (71, 74))	('BRM', 'Gene', '6595', (142, 145))
462076	28427211	Similar findings were observed for the BRM-1321 homozygous variants for OS (aHR 2.09; 95% CI: 1.4-3.0; p = 0.0005) and PFS 2.29; 95% CI: 1.6-3.4; p < 0.0001).	('BRM', 'Gene', (39, 42))	('OS', 'Chemical', '-', (72, 74))	('variants', 'Var', (59, 67))	('BRM', 'Gene', '6595', (39, 42))
462077	28427211	Carrying the double homozygous BRM-741 and BRM-1321 variants was associated strongly with substantially worse OS (aHR 2.21; 95% CI:1.4-3.6, p < 0.0001) and PFS (aHR 2.47; 95% CI: 1.5-4.0, p < 0.0001), when compared to the double wild-type genotypes.	('BRM', 'Gene', (43, 46))	('OS', 'Chemical', '-', (110, 112))	('variants', 'Var', (52, 60))	('BRM', 'Gene', (31, 34))	('BRM', 'Gene', '6595', (43, 46))	('worse', 'NegReg', (104, 109))	('BRM', 'Gene', '6595', (31, 34))	('PFS', 'CPA', (156, 159))
462079	28427211	In this study we report that BRM-741 and BRM-1321 polymorphisms are independent prognostic factors for EAC outcome in our dataset.	('EAC', 'Disease', (103, 106))	('BRM', 'Gene', (41, 44))	('BRM', 'Gene', '6595', (29, 32))	('BRM', 'Gene', '6595', (41, 44))	('BRM', 'Gene', (29, 32))	('polymorphisms', 'Var', (50, 63))
462081	28427211	previously demonstrated that the double homozygous BRM variants increased the risk of all stages of lung cancer among ever-smokers, with adjusted odds ratio [aOR] of 2.19; 95% CI, 1.4-3.4; P = 0.0006).	('variants', 'Var', (55, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('BRM', 'Gene', (51, 54))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('increased', 'PosReg', (64, 73))	('BRM', 'Gene', '6595', (51, 54))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
462084	28427211	However, this esophageal cancer analyses did not have adequate power to evaluate EAC separately from esophageal squamous cell carcinoma; We recently increased the sample size of EACs to 270 and compared it to matched controls; BRM variants continued to have an aOR of EAC risk of around 1.7 (p = 0.09; unpublished).	('BRM', 'Gene', '6595', (227, 230))	('EAC', 'Disease', (268, 271))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('esophageal cancer', 'Disease', (14, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (101, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('BRM', 'Gene', (227, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('variants', 'Var', (231, 239))	('esophageal squamous cell carcinoma', 'Disease', (101, 135))
462085	28427211	An association between other BRM genetic variants and hepatocellular carcinoma (HCC) risk was also reported in two separate case-control studies in Chinese patients (though those specific genetic variants appeared to be restricted mainly to patients of East Asian descent).	('patients', 'Species', '9606', (156, 164))	('variants', 'Var', (41, 49))	('HCC', 'Gene', '619501', (80, 83))	('BRM', 'Gene', '6595', (29, 32))	('BRM', 'Gene', (29, 32))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 78))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (54, 78))	('hepatocellular carcinoma', 'Disease', (54, 78))	('HCC', 'Gene', (80, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('patients', 'Species', '9606', (241, 249))
462086	28427211	The totality of data suggest that these BRM promoter polymorphisms have the ability to regulate BRM expression, and these genetic susceptibility markers are associated with increased risk of multiple different cancer types.	('ability', 'MPA', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('associated with', 'Reg', (157, 172))	('BRM', 'Gene', (96, 99))	('BRM', 'Gene', '6595', (40, 43))	('expression', 'MPA', (100, 110))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('regulate', 'Reg', (87, 95))	('BRM', 'Gene', '6595', (96, 99))	('cancer', 'Disease', (210, 216))	('BRM', 'Gene', (40, 43))	('polymorphisms', 'Var', (53, 66))
462090	28427211	A sub-analysis of patients treated by cisplatin-based chemotherapy versus not also found no substantial differences in the outcome relationships with BRM polymorphisms.	('BRM', 'Gene', (150, 153))	('polymorphisms', 'Var', (154, 167))	('BRM', 'Gene', '6595', (150, 153))	('patients', 'Species', '9606', (18, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))
462091	28427211	However, the ability of these promoter polymorphisms to lead to suppression of BRM function through decreased gene expression is of great potential clinical relevance.	('polymorphisms', 'Var', (39, 52))	('BRM', 'Gene', (79, 82))	('decreased', 'NegReg', (100, 109))	('suppression', 'NegReg', (64, 75))	('gene expression', 'MPA', (110, 125))	('BRM', 'Gene', '6595', (79, 82))
462092	28427211	Our study contributes to the growing evidence that the BRM polymorphisms are strong germline biomarkers that may select out a subset of high risk patients that are less likely to develop cancer, and another subset with poor prognoses that fail standard treatments.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('polymorphisms', 'Var', (59, 72))	('BRM', 'Gene', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('patients', 'Species', '9606', (146, 154))	('BRM', 'Gene', '6595', (55, 58))
462093	28427211	In addition, there are potential treatment implications in finding an association between the BRM promoter variants and EAC outcome.	('EAC outcome', 'Disease', (120, 131))	('BRM', 'Gene', (94, 97))	('variants', 'Var', (107, 115))	('BRM', 'Gene', '6595', (94, 97))
462095	28427211	Further, the double homozygous variants resulted in the epigenetic loss of BRM expression in dozens of cancer cell lines and primary lung and HCC tumors.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('expression', 'MPA', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('BRM', 'Gene', '6595', (75, 78))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('HCC tumors', 'Disease', (142, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (103, 109))	('BRM', 'Gene', (75, 78))	('HCC tumors', 'Disease', 'MESH:D006528', (142, 152))	('epigenetic', 'Var', (56, 66))
462096	28427211	Flavonoids may also reverse these epigenetic loss of expression.	('loss of expression', 'NegReg', (45, 63))	('epigenetic', 'Var', (34, 44))	('Flavonoids', 'Chemical', 'MESH:D005419', (0, 10))
462097	28427211	Although epigenetic BRM silencing has yet to be proven as an effective oncogenic driver, the current data suggest that reversing epigenetic dysregulation can lead to a novel preventive and therapeutic approaches in selected solid malignancies.	('malignancies', 'Disease', 'MESH:D009369', (230, 242))	('epigenetic dysregulation', 'Var', (129, 153))	('epigenetic', 'Var', (9, 19))	('BRM', 'Gene', (20, 23))	('lead to', 'Reg', (158, 165))	('malignancies', 'Disease', (230, 242))	('BRM', 'Gene', '6595', (20, 23))
462106	28427211	In summary, two promoter BRM germline variants were associated with worse outcome in our esophageal adenocarcinoma (EAC) patients.	('variants', 'Var', (38, 46))	('BRM', 'Gene', (25, 28))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (89, 114))	('esophageal adenocarcinoma', 'Disease', (89, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (89, 114))	('BRM', 'Gene', '6595', (25, 28))	('patients', 'Species', '9606', (121, 129))
462125	28427211	Association of the polymorphisms with overall (OS) and the exploratory progression free survival (PFS) were assessed using multivariable Cox proportional hazards models.	('Cox', 'Gene', (137, 140))	('polymorphisms', 'Var', (19, 32))	('Cox', 'Gene', '1351', (137, 140))	('OS', 'Chemical', '-', (47, 49))
462181	28028307	After univariate and multivariate Cox regression analysis, eight lncRNAs (GS1-600G8.5, LINC00365, CTD-2357A8.3, RP11-705O24.1, LINC01554, RP1-90J4.1, RP11-327J17.1, and LINC00176) were finally screened out to establish a predictive model by which patients could be classified into high-risk and low-risk groups with significantly different overall survival.	('CTD', 'Gene', (98, 101))	('LINC00176', 'Gene', (169, 178))	('LINC00365', 'Gene', '100874146', (87, 96))	('RP11', 'Gene', '26121', (112, 116))	('LINC00365', 'Gene', (87, 96))	('LINC00176', 'Gene', '284739', (169, 178))	('RP1', 'Gene', (138, 141))	('CTD', 'Gene', '1283', (98, 101))	('LINC01554', 'Gene', '202299', (127, 136))	('RP11', 'Gene', '26121', (150, 154))	('RP1', 'Gene', '6101', (138, 141))	('Cox', 'Gene', '1351', (34, 37))	('patients', 'Species', '9606', (247, 255))	('RP11', 'Gene', (112, 116))	('GS1-600G8.5', 'Var', (74, 85))	('RP1', 'Gene', (150, 153))	('RP1', 'Gene', (112, 115))	('Cox', 'Gene', (34, 37))	('RP1', 'Gene', '6101', (150, 153))	('RP1', 'Gene', '6101', (112, 115))	('RP11', 'Gene', (150, 154))	('LINC01554', 'Gene', (127, 136))
462190	28028307	It has been reported that dysregulated lncRNAs are associated with cancer pathogenesis and function as oncogenic or tumor suppressive regulators in cancer development.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', (116, 121))	('lncRNAs', 'Protein', (39, 46))	('cancer', 'Disease', (67, 73))	('men', 'Species', '9606', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('dysregulated', 'Var', (26, 38))
462220	28028307	Among these, GS1-600G8.5, LINC00365, CTD-2357A8.3, RP11-705O24.1, LINC01554, and RP1-90J4.1 showed positive coefficients in Cox regression analysis, indicating high-risk signatures for these six lncRNAs since their high expression signified a shorter overall survival of patients.	('LINC00365', 'Gene', '100874146', (26, 35))	('CTD', 'Gene', '1283', (37, 40))	('LINC00365', 'Gene', (26, 35))	('Cox', 'Gene', '1351', (124, 127))	('GS1-600G8.5', 'Var', (13, 24))	('RP11', 'Gene', (51, 55))	('shorter', 'NegReg', (243, 250))	('RP1', 'Gene', (51, 54))	('Cox', 'Gene', (124, 127))	('RP1', 'Gene', (81, 84))	('LINC01554', 'Gene', (66, 75))	('RP1', 'Gene', '6101', (51, 54))	('RP1', 'Gene', '6101', (81, 84))	('patients', 'Species', '9606', (271, 279))	('CTD', 'Gene', (37, 40))	('overall', 'MPA', (251, 258))	('RP11', 'Gene', '26121', (51, 55))	('expression', 'MPA', (220, 230))	('LINC01554', 'Gene', '202299', (66, 75))
462234	28028307	The results showed that co-expressed PCGs were enriched in 73 GO BP terms, which mainly clustered in regulation of diverse biological processes (such as GO: 0010906~regulation of glucose metabolic process, GO: 0010628~positive regulation of gene expression, GO: 0043410~positive regulation of MAPK cascade), transport of various substances (including GO: 0071805~potassium ion transmembrane transport, GO: 0035879~plasma membrane lactate transport, GO: 0098719~sodium ion import across plasma membrane) and response to different stimulants (such as GO: 0042594~response to starvation, GO: 0043627~response to estrogen, GO: 0042493~response to drug) (The top 30 GO BP terms were shown in Table 4).	('GO: 0071805~potassium', 'Var', (351, 372))	('GO: 0043627~response', 'Var', (585, 605))	('glucose', 'Chemical', 'MESH:D005947', (179, 186))	('GO: 0042493~response', 'Var', (619, 639))	('GO: 0043410~positive', 'Var', (258, 278))	('0035879~plasma membrane lactate transport', 'MPA', (406, 447))	('0071805~potassium ion transmembrane transport', 'MPA', (355, 400))	('PCGs', 'Chemical', '-', (37, 41))
462255	28028307	Inhibition of MAPK pathways suppresses proliferation and induces apoptosis of esophageal cancer cells.	('induces', 'Reg', (57, 64))	('MAPK pathways', 'Pathway', (14, 27))	('suppresses', 'NegReg', (28, 38))	('apoptosis', 'CPA', (65, 74))	('Inhibition', 'Var', (0, 10))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
462268	26759717	Recurrent somatic amplifications at 8q were found to be enriched in stage I tumors and the deletions of 4p-q and 5q were particularly identified in stage III tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('III tumors', 'Disease', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('deletions', 'Var', (91, 100))	('I tumors', 'Disease', 'MESH:D009369', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('I tumors', 'Disease', 'MESH:D009369', (156, 164))	('III tumors', 'Disease', 'MESH:D009369', (154, 164))	('I tumors', 'Disease', (74, 82))	('identified', 'Reg', (134, 144))	('4p-q', 'Gene', (104, 108))
462271	26759717	Although the cancer-associated genes TP53, PIK3CA, CDKN2A and their pathways showed no significant difference between stage I and stage III tumors, we identified and validated a prevalence of mutations in NOTCH1 and in the NOTCH pathway that indicate that they are involved in the preclinical and early stages of ESCC.	('NOTCH pathway', 'Pathway', (223, 236))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('ESCC', 'Disease', (313, 317))	('III tumors', 'Disease', 'MESH:D009369', (136, 146))	('TP53', 'Gene', (37, 41))	('CDKN2A', 'Gene', (51, 57))	('mutations', 'Var', (192, 201))	('PIK3CA', 'Gene', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('NOTCH1', 'Gene', (205, 211))	('clinical', 'Species', '191496', (284, 292))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CDKN2A', 'Gene', '1029', (51, 57))	('NOTCH1', 'Gene', '4851', (205, 211))	('cancer', 'Disease', (13, 19))	('TP53', 'Gene', '7157', (37, 41))	('PIK3CA', 'Gene', '5290', (43, 49))	('III tumors', 'Disease', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))
462281	26759717	Analyses of somatic copy number alterations (SCNAs) using array-based technologies have identified frequently altered regions such as 3q26, 11q13.3 and 8q24.3, and exome-wide investigations have revealed point mutations in the well-known cancer-associated genes TP53, PIK3CA, CDKN2A and novel genes ZNF750, FAT1, FAT2 and FAM135B.	('FAT1', 'Gene', '2195', (307, 311))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('CDKN2A', 'Gene', (276, 282))	('FAT1', 'Gene', (307, 311))	('FAM135B', 'Gene', (322, 329))	('PIK3CA', 'Gene', '5290', (268, 274))	('TP53', 'Gene', '7157', (262, 266))	('TP53', 'Gene', (262, 266))	('FAM135B', 'Gene', '51059', (322, 329))	('ZNF750', 'Gene', (299, 305))	('FAT2', 'Gene', '2196', (313, 317))	('CDKN2A', 'Gene', '1029', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('FAT2', 'Gene', (313, 317))	('PIK3CA', 'Gene', (268, 274))	('point mutations', 'Var', (204, 219))
462292	26759717	Candidate non-silent mutations identified from 48 stage I and 48 stage III tumors were selected for TCS (at least 365x; Additional file 3: Table S2C).	('III tumors', 'Disease', (71, 81))	('TCS', 'Chemical', '-', (100, 103))	('non-silent mutations', 'Var', (10, 30))	('III tumors', 'Disease', 'MESH:D009369', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
462293	26759717	We found 73 (range 24-189) non-silent mutations per tumor in this cohort, and this rate is in line with published rates (Additional file 5: Figure S2C), underscoring the representative nature of our analysis.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('non-silent mutations', 'Var', (27, 47))
462297	26759717	Genomic identification of significant targets in cancer (GISTIC) analysis in the WGS set yielded universal deletions affecting 4p, 11p, 16p, 19p and 19q, and frequent gains of 3q, 5p, 7p, 7q, 8p, 8q, 12p, 14q, 18p, 20q, 21q, Xp and Xq (Additional file 6: Figure S3C).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('gains', 'PosReg', (167, 172))	('deletions', 'Var', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
462298	26759717	In particular, recurrent somatic amplifications at 8q (containing MYC and FAM84B) were found to be enriched in stage I tumors; the deletions of 4p-q (containing VEGFC, FBXW7 and FAT1) and 5q (containing PTTG and MAML1) were particularly identified in stage III tumors (p < 0.05, Fisher's exact test, Fig.	('III tumors', 'Disease', 'MESH:D009369', (257, 267))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('MYC', 'Gene', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('FBXW7', 'Gene', (168, 173))	('I tumors', 'Disease', (117, 125))	('PTTG', 'Gene', (203, 207))	('VEGFC', 'Gene', '7424', (161, 166))	('deletions', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('MYC', 'Gene', '4609', (66, 69))	('4p-q', 'Gene', (144, 148))	('FAT1', 'Gene', (178, 182))	('identified', 'Reg', (237, 247))	('FBXW7', 'Gene', '55294', (168, 173))	('III tumors', 'Disease', (257, 267))	('MAML1', 'Gene', (212, 217))	('FAM84B', 'Gene', (74, 80))	('FAM84B', 'Gene', '157638', (74, 80))	('PTTG', 'Gene', '9232', (203, 207))	('I tumors', 'Disease', 'MESH:D009369', (117, 125))	('FAT1', 'Gene', '2195', (178, 182))	('MAML1', 'Gene', '9794', (212, 217))	('I tumors', 'Disease', 'MESH:D009369', (259, 267))	('VEGFC', 'Gene', (161, 166))
462299	26759717	Furthermore, copy-number analyses verified the amplifications of candidate genes located within these significantly altered regions in 36 atypical hyperplasia tissues (Fig.	('hyperplasia', 'Disease', 'MESH:D006965', (147, 158))	('hyperplasia', 'Disease', (147, 158))	('amplifications', 'Var', (47, 61))
462300	26759717	Thus, although stage I and stage III tumors of ESCC are genomically similar, our results reveal that the copy-number variations exhibit a pattern that is associated with the clinical stage of the tumor.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (196, 201))	('copy-number variations', 'Var', (105, 127))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('III tumors', 'Disease', 'MESH:D009369', (33, 43))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('clinical', 'Species', '191496', (174, 182))	('associated', 'Reg', (154, 164))	('III tumors', 'Disease', (33, 43))
462301	26759717	We also applied a modified GISTIC method to profile genome segments with copy number variations in the 14 tumors analyzed by WGS, which revealed 126 significantly altered regions (Additional file 7: Figure S4).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('copy number variations', 'Var', (73, 95))	('14 tumors', 'Disease', 'MESH:C567448', (103, 112))	('altered', 'Reg', (163, 170))	('14 tumors', 'Disease', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
462309	26759717	In addition, we knocked down FAM84B in KYSE150 and TE-1 cells that have high levels of endogenous FAM84B and observed that FAM84B depletion attenuated cell growth, migration and invasion (Fig.	('FAM84B', 'Gene', (123, 129))	('FAM84B', 'Gene', '157638', (123, 129))	('FAM84B', 'Gene', '157638', (98, 104))	('depletion', 'Var', (130, 139))	('FAM84B', 'Gene', (29, 35))	('invasion', 'CPA', (178, 186))	('FAM84B', 'Gene', '157638', (29, 35))	('attenuated', 'NegReg', (140, 150))	('cell growth', 'CPA', (151, 162))	('knocked down', 'Var', (16, 28))	('FAM84B', 'Gene', (98, 104))
462314	26759717	This analysis led to the identification of eight SMGs with q < 0.2 (Additional file 12: Table S6A).	('SMG', 'Gene', '23034', (49, 52))	('q < 0.2', 'Var', (59, 66))	('SMG', 'Gene', (49, 52))
462316	26759717	Of the 104 tumors that we comprehensively characterized, 50 % (52 out of 104 cases) displayed mutations in two or more SMGs, 44 % (46 out of 104 cases) of cases harbored alterations in one SMG, and six cases did not have mutations in any of the SMGs.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('SMG', 'Gene', (245, 248))	('mutations', 'Var', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('SMG', 'Gene', '23034', (245, 248))	('SMG', 'Gene', (119, 122))	('alterations', 'Reg', (170, 181))	('tumors', 'Disease', (11, 17))	('SMG', 'Gene', '23034', (119, 122))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('SMG', 'Gene', (189, 192))	('SMG', 'Gene', '23034', (189, 192))
462319	26759717	The other four SMGs, each contributing relatively infrequently, were responsible for the remaining 14 % (26 of 184) of the non-silent mutations (Fig.	('non-silent mutations', 'Var', (123, 143))	('SMG', 'Gene', (15, 18))	('SMG', 'Gene', '23034', (15, 18))
462321	26759717	Interestingly, a pronounced diversity of NOTCH1 mutations was observed in 35 % of stage I tumors but in only 8 % of stage III tumors (p < 0.0006, Fisher's test).	('III tumors', 'Disease', (122, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('I tumors', 'Disease', 'MESH:D009369', (124, 132))	('NOTCH1', 'Gene', '4851', (41, 47))	('NOTCH1', 'Gene', (41, 47))	('III tumors', 'Disease', 'MESH:D009369', (122, 132))	('I tumors', 'Disease', (88, 96))	('mutations', 'Var', (48, 57))	('I tumors', 'Disease', 'MESH:D009369', (88, 96))
462323	26759717	NOTCH1 mutations are relatively common in head and neck squamous cell carcinoma (HNSCC), lung SCC and breast cancer, with 5 % to 15 % of tumors harboring protein-coding changes.	('breast cancer', 'Disease', (102, 115))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('neck squamous cell carcinoma', 'Disease', (51, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (51, 79))	('common', 'Reg', (32, 38))	('lung SCC', 'Disease', (89, 97))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('mutations', 'Var', (7, 16))
462324	26759717	In our cohort, 22 somatic mutations were identified in NOTCH1 with a mutation frequency of 21 % (Additional file 12: Table S6B).	('mutations', 'Var', (26, 35))	('NOTCH1', 'Gene', '4851', (55, 61))	('NOTCH1', 'Gene', (55, 61))
462325	26759717	Notably, we found another six non-silent mutations including four missense and two frameshift indels, with a mutation frequency of 16.7 % in the 36 atypical hyperplasia tissues (Additional file 13: Table S7).	('hyperplasia', 'Disease', 'MESH:D006965', (157, 168))	('missense', 'Var', (66, 74))	('hyperplasia', 'Disease', (157, 168))	('frameshift indels', 'Var', (83, 100))
462326	26759717	Moreover, the nonsense mutations observed in NOTCH1 generate a premature stop codon, resulting in a C-terminally truncated NOTCH1 protein lacking a PEST sequence (a sequence rich in proline, glutamic acid, serine and threonine) that is important for transcription activation.	('threonine', 'Chemical', 'MESH:D013912', (217, 226))	('proline', 'Chemical', 'MESH:D011392', (182, 189))	('NOTCH1', 'Gene', '4851', (123, 129))	('lacking', 'NegReg', (138, 145))	('serine', 'Chemical', 'MESH:D012694', (206, 212))	('glutamic acid', 'Chemical', 'MESH:D018698', (191, 204))	('mutations', 'Var', (23, 32))	('NOTCH1', 'Gene', (123, 129))	('C-terminally truncated', 'MPA', (100, 122))	('NOTCH1', 'Gene', '4851', (45, 51))	('NOTCH1', 'Gene', (45, 51))	('protein', 'Protein', (130, 137))
462327	26759717	In addition, five out of nine mutations identified in NOTCH2/3 were truncating, and two stopgains were identified in RBPJ, one of the target genes of NOTCH.	('RBPJ', 'Gene', (117, 121))	('NOTCH2', 'Gene', '4853', (54, 60))	('RBPJ', 'Gene', '3516', (117, 121))	('truncating', 'MPA', (68, 78))	('mutations', 'Var', (30, 39))	('NOTCH2', 'Gene', (54, 60))
462328	26759717	Thus, in contrast to T-cell acute lymphoblastic leukemia, chronic lymphoblastic leukemia and breast cancer, in which NOTCH1 serves as an oncogene, this pattern of mutations suggest that the NOTCH pathway has a tumor suppressing role in ESCC.	('ESCC', 'Disease', (236, 240))	('NOTCH pathway', 'Pathway', (190, 203))	('leukemia', 'Phenotype', 'HP:0001909', (48, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('NOTCH1', 'Gene', (117, 123))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('tumor', 'Disease', (210, 215))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('NOTCH1', 'Gene', '4851', (117, 123))	('chronic lymphoblastic leukemia', 'Disease', 'MESH:D015451', (58, 88))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (21, 56))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('chronic lymphoblastic leukemia', 'Phenotype', 'HP:0005550', (58, 88))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (28, 56))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (34, 56))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (21, 56))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (66, 88))	('T-cell acute lymphoblastic leukemia', 'Disease', (21, 56))	('chronic lymphoblastic leukemia', 'Disease', (58, 88))	('mutations', 'Var', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
462329	26759717	Of related interest, 8 % of ESCC tumors (12 % of stage I tumors and 4 % of stage III tumors) harbored mutations in the F-box protein FBXW7 (Fig.	('III tumors', 'Disease', (81, 91))	('FBXW7', 'Gene', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('I tumors', 'Disease', (55, 63))	('ESCC tumors', 'Disease', (28, 39))	('mutations', 'Var', (102, 111))	('harbored', 'Reg', (93, 101))	('I tumors', 'Disease', 'MESH:D009369', (83, 91))	('III tumors', 'Disease', 'MESH:D009369', (81, 91))	('ESCC tumors', 'Disease', 'MESH:D004938', (28, 39))	('I tumors', 'Disease', 'MESH:D009369', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('FBXW7', 'Gene', '55294', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
462332	26759717	Moreover, most of the mutations occur within the WD40 domain involved in substrate recognition; mutation of this site prevents the recognition of targets such as NOTCH1 for degradation.	('NOTCH1', 'Gene', '4851', (162, 168))	('NOTCH1', 'Gene', (162, 168))	('mutation', 'Var', (96, 104))	('recognition', 'MPA', (131, 142))	('mutations', 'Var', (22, 31))	('prevents', 'NegReg', (118, 126))
462333	26759717	In particular, mutations occurred in genes associated with pyrimidine metabolism (31 % of stage I tumors versus 13 % of stage III), glycine/serine/threonine metabolism (16 % versus 2 %) and fructose and mannose metabolism (16 % versus 2 %).	('threonine', 'Chemical', 'MESH:D013912', (147, 156))	('serine', 'Chemical', 'MESH:D012694', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('I tumors', 'Disease', (96, 104))	('mutations', 'Var', (15, 24))	('I tumors', 'Disease', 'MESH:D009369', (96, 104))	('glycine', 'Chemical', 'MESH:D005998', (132, 139))	('glycine/serine/threonine metabolism', 'MPA', (132, 167))	('fructose', 'Chemical', 'MESH:D005632', (190, 198))	('mannose', 'Chemical', 'MESH:D008358', (203, 210))	('pyrimidine', 'Chemical', 'MESH:C030986', (59, 69))	('pyrimidine metabolism', 'MPA', (59, 80))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
462345	26759717	Moreover, genomic characterization of different stages of ESCC tumors led us to identify dysregulated NOTCH1 and NOTCH signaling predominantly in stage I tumors, indicating the involvement of this gene and its pathway in the early development of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('involvement', 'Reg', (177, 188))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('NOTCH signaling', 'MPA', (113, 128))	('ESCC tumors', 'Disease', (58, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('NOTCH1', 'Gene', '4851', (102, 108))	('ESCC tumors', 'Disease', 'MESH:D004938', (58, 69))	('I tumors', 'Disease', (152, 160))	('NOTCH1', 'Gene', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('I tumors', 'Disease', 'MESH:D009369', (152, 160))	('dysregulated', 'Var', (89, 101))
462346	26759717	Thus, the prevalence of NOTCH1 provides a potential biomarker to detect ESCC in its early stages.	('NOTCH1', 'Gene', (24, 30))	('prevalence', 'Var', (10, 20))	('NOTCH1', 'Gene', '4851', (24, 30))	('ESCC', 'Disease', (72, 76))
462348	26759717	The spectrum of mutations involving the NOTCH pathway in our cohort is consistent with it having a tumor suppressor role in ESCC rather than an oncogenic function.	('tumor', 'Disease', (99, 104))	('mutations', 'Var', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('NOTCH pathway', 'Pathway', (40, 53))	('ESCC', 'Disease', (124, 128))
462359	26759717	At least 65x target depth and 30-fold haploid coverage for tumors and normal samples were achieved in all samples.	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('haploid', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
462370	26759717	distance between adjacent somatic SNV distance should be over 10 bp; v. mapping qualities of reads supporting mutant alleles in the tumor should be significantly higher than 30 (Wilcoxon rank sum test, p < 0.2); vi.base qualities of reads supporting mutant alleles in the tumor should be significantly higher than 20 (Wilcoxon rank sum test, p < 0.05); vii.mutations should not be enriched within 5 bp 5' or 3' of read end (Wilcoxon rank sum test, p < 0.1); viii.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('mutant', 'Var', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (272, 277))
462389	26759717	Prevalidated primers for the relevant genes were obtained from Applied Biosystems (accession numbers Hs02758348_Cn for MYC, Hs00655850_Cn for FAM84B, Hs01654625_Cn for VEGFC, Hs05965356_Cn for FBXW7 and Hs00703603_Cn for FAT1).	('FAT1', 'Gene', '2195', (221, 225))	('Hs00703603_Cn', 'Var', (203, 216))	('FBXW7', 'Gene', (193, 198))	('FAT1', 'Gene', (221, 225))	('Hs02758348_Cn', 'Var', (101, 114))	('VEGFC', 'Gene', (168, 173))	('FAM84B', 'Gene', (142, 148))	('Hs05965356_Cn', 'Var', (175, 188))	('Hs00655850_Cn', 'Var', (124, 137))	('MYC', 'Gene', '4609', (119, 122))	('Hs01654625_Cn', 'Var', (150, 163))	('FBXW7', 'Gene', '55294', (193, 198))	('FAM84B', 'Gene', '157638', (142, 148))	('MYC', 'Gene', (119, 122))	('VEGFC', 'Gene', '7424', (168, 173))
462406	26759717	BWA Burrows-Wheeler Aligner ESCC Esophageal squamous cell carcinoma FAM84B Family with sequence similarity 84, member B GISTIC Genomic identification of significant targets in cancer HNSCC Head and neck squamous cell carcinoma IGV Integrative genomics viewer SCNA Somatic copy number alterations SMG Significantly mutated gene SNV Single nucleotide variation TCS Target capture sequencing WES Whole-exome sequencing WGS Whole-genome sequencing	('SMG', 'Gene', '23034', (296, 299))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (198, 226))	('FAM84B', 'Gene', '157638', (68, 74))	('Single nucleotide variation', 'Var', (331, 358))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('SMG', 'Gene', (296, 299))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (33, 67))	('neck squamous cell carcinoma', 'Disease', (198, 226))	('TCS', 'Chemical', '-', (359, 362))	('FAM84B', 'Gene', (68, 74))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('Esophageal squamous cell carcinoma', 'Disease', (33, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
462417	23554759	GlcNAcylation plays a role in normal biological processes, and its dysregulation is involved in certain human diseases such as diabetes mellitus and neurologic disorders.	('dysregulation', 'Var', (67, 80))	('GlcNAcylation', 'MPA', (0, 13))	('diabetes mellitus', 'Disease', 'MESH:D003920', (127, 144))	('GlcNAcylation', 'Chemical', '-', (0, 13))	('human', 'Species', '9606', (104, 109))	('neurologic disorders', 'Disease', (149, 169))	('neurologic disorders', 'Disease', 'MESH:D009422', (149, 169))	('neurologic disorders', 'Phenotype', 'HP:0000707', (149, 169))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (127, 144))	('involved', 'Reg', (84, 92))	('diabetes mellitus', 'Disease', (127, 144))
462464	23554759	This process produces many aneuploid cells, which result in tumor occurrence.	('result in', 'Reg', (50, 59))	('aneuploid cells', 'Var', (27, 42))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
462467	23554759	Gu found that GlcNAcylated p120 and beta-catenin affect the metastasis of breast cancer, especially in lymph node metastasis[33].	('lymph node metastasis', 'CPA', (103, 124))	('breast cancer', 'Disease', (74, 87))	('affect', 'Reg', (49, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('beta-catenin', 'Gene', (36, 48))	('p120', 'Gene', '1500', (27, 31))	('metastasis', 'CPA', (60, 70))	('p120', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('beta-catenin', 'Gene', '1499', (36, 48))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('GlcNAcylated', 'Var', (14, 26))
462468	23554759	In brief, based on our study, we concluded that high expression of OGT promoted the increase of O-GlcNAcation in esophageal squamous cell carcinoma and the high level of O-GlcNAcation may stabilize proteins, leading to changes in cellular signal transduction and resulting tumorigenesis and metastasis.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('O-GlcNAcation', 'MPA', (96, 109))	('changes', 'Reg', (219, 226))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('increase', 'PosReg', (84, 92))	('proteins', 'Protein', (198, 206))	('O-GlcNAcation', 'Chemical', '-', (170, 183))	('high expression', 'Var', (48, 63))	('tumor', 'Disease', (273, 278))	('O-GlcNAcation', 'Chemical', '-', (96, 109))	('cellular signal transduction', 'MPA', (230, 258))	('OGT', 'Gene', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('stabilize', 'MPA', (188, 197))
462531	22920951	When stratifying based on stage, however, there was a significant survival benefit with adjuvant RT for stage III patients, with an improvement in 5-year OS from 13.1 to 35.1%, (P = 0.003) but not for stage II patients.	('improvement', 'PosReg', (132, 143))	('survival', 'MPA', (66, 74))	('benefit', 'PosReg', (75, 82))	('patients', 'Species', '9606', (210, 218))	('OS', 'Chemical', '-', (154, 156))	('adjuvant', 'Var', (88, 96))	('patients', 'Species', '9606', (114, 122))
462533	22920951	They reported that adjuvant RT was associated with a statistically significant improvement in survival, but only in those patients with three or more involved lymph nodes; no such association was found in patients with one or two involved lymph nodes.	('patients', 'Species', '9606', (205, 213))	('improvement', 'PosReg', (79, 90))	('survival', 'MPA', (94, 102))	('patients', 'Species', '9606', (122, 130))	('adjuvant', 'Var', (19, 27))
462553	22920951	The retrospective study indicated that adjuvant RT was associated with a statistically significant improvement in survival, but only in those patients with three or more involved lymph nodes.	('survival', 'MPA', (114, 122))	('patients', 'Species', '9606', (142, 150))	('improvement', 'PosReg', (99, 110))	('adjuvant', 'Var', (39, 47))
462659	19750231	In addition to age-related bone loss, osteoporosis in men is frequently secondary to other comorbidities such as glucocorticoid use, hypogonadism, vitamin D deficiency, cigarette smoking, heavy alcohol intake, immobility, or inadequate dietary calcium intake.	('bone loss', 'Phenotype', 'HP:0002797', (27, 36))	('immobility', 'Disease', (210, 220))	('osteoporosis', 'Disease', (38, 50))	('osteoporosis', 'Phenotype', 'HP:0000939', (38, 50))	('vitamin D', 'Chemical', 'MESH:D014807', (147, 156))	('osteoporosis', 'Disease', 'MESH:D010024', (38, 50))	('deficiency', 'Var', (157, 167))	('inadequate dietary calcium intake', 'Phenotype', 'HP:0002901', (225, 258))	('hypogonadism', 'Disease', (133, 145))	('heavy alcohol intake', 'Phenotype', 'HP:0030955', (188, 208))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (147, 167))	('hypogonadism', 'Phenotype', 'HP:0000135', (133, 145))	('bone loss', 'Disease', 'MESH:D016301', (27, 36))	('men', 'Species', '9606', (54, 57))	('alcohol', 'Chemical', 'MESH:D000438', (194, 201))	('hypogonadism', 'Disease', 'MESH:D007006', (133, 145))	('bone loss', 'Disease', (27, 36))	('secondary', 'Reg', (72, 81))	('calcium', 'Chemical', 'MESH:D002118', (244, 251))
462683	19750231	Teriparatide has been shown to raise BMD in men at the hip and spine more than alendronate alone, and it reduces vertebral fractures by 90%.	('raise', 'PosReg', (31, 36))	('Teriparatide', 'Chemical', 'MESH:D019379', (0, 12))	('vertebral fractures', 'Disease', (113, 132))	('alendronate', 'Chemical', 'MESH:D019386', (79, 90))	('BMD', 'MPA', (37, 40))	('Teriparatide', 'Var', (0, 12))	('vertebral fracture', 'Phenotype', 'HP:0002953', (113, 131))	('men', 'Species', '9606', (44, 47))	('reduces', 'NegReg', (105, 112))	('vertebral fractures', 'Disease', 'MESH:D050723', (113, 132))	('vertebral fractures', 'Phenotype', 'HP:0002953', (113, 132))
462714	19750231	The subjects who received pamidronate for five years continued to have a small yet significant greater increase in lumbar spine BMD compared to those subjects who had initially received placebo.	('pamidronate', 'Var', (26, 37))	('pamidronate', 'Chemical', 'MESH:D000077268', (26, 37))	('increase', 'PosReg', (103, 111))	('lumbar spine BMD', 'CPA', (115, 131))
462855	19750231	Among the men that survived five years after diagnosis, they found that 19.4% men on ADT experienced a fracture, as compared to 12.6% those not receiving ADT (p < 0.001).	('men', 'Species', '9606', (10, 13))	('fracture', 'Disease', 'MESH:D050723', (103, 111))	('ADT', 'Var', (85, 88))	('men', 'Species', '9606', (78, 81))	('fracture', 'Disease', (103, 111))	('experienced', 'Reg', (89, 100))	('ADT', 'Chemical', '-', (154, 157))	('ADT', 'Chemical', '-', (85, 88))
462856	19750231	Furthermore, fractures at every site, fractures requiring hospitalization, and diagnosis of osteoporosis were all significantly increased in patients receiving ADT.	('ADT', 'Var', (160, 163))	('osteoporosis', 'Phenotype', 'HP:0000939', (92, 104))	('patients', 'Species', '9606', (141, 149))	('increased', 'PosReg', (128, 137))	('fractures', 'Disease', (13, 22))	('fractures', 'Disease', (38, 47))	('fractures', 'Disease', 'MESH:D050723', (13, 22))	('ADT', 'Chemical', '-', (160, 163))	('osteoporosis', 'Disease', 'MESH:D010024', (92, 104))	('fractures', 'Disease', 'MESH:D050723', (38, 47))	('osteoporosis', 'Disease', (92, 104))
462902	19750231	The frequency of a composite of reports of bone or back pain, myalgias, and arthralgias was 9% among zoledronic acid-treated subjects vs 5% among those receiving placebo.	('pain', 'Phenotype', 'HP:0012531', (56, 60))	('back pain', 'Phenotype', 'HP:0003418', (51, 60))	('myalgias', 'Disease', (62, 70))	('back pain', 'Disease', 'MESH:D001416', (51, 60))	('arthralgias', 'Phenotype', 'HP:0002829', (76, 87))	('zoledronic', 'Var', (101, 111))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (101, 116))	('myalgias', 'Phenotype', 'HP:0003326', (62, 70))	('arthralgias', 'Disease', (76, 87))	('myalgias', 'Disease', 'MESH:D063806', (62, 70))	('arthralgias', 'Disease', 'MESH:D018771', (76, 87))	('back pain', 'Disease', (51, 60))
462990	34011067	Kaplan-Meier survival analysis suggested that ESCC patients with high PDGFA expression were associated with poorer overall survival compared to those with low PDGFA expression (P < .05), especially in advanced T stage (P < .05).	('ESCC', 'Disease', (46, 50))	('PDGFA', 'Gene', '5154', (159, 164))	('overall survival', 'MPA', (115, 131))	('poorer', 'NegReg', (108, 114))	('expression', 'MPA', (76, 86))	('PDGFA', 'Gene', (70, 75))	('high', 'Var', (65, 69))	('patients', 'Species', '9606', (51, 59))	('PDGFA', 'Gene', (159, 164))	('PDGFA', 'Gene', '5154', (70, 75))
462991	34011067	Cox analyses showed that high expression of PDGFA was an independent predictor for poor prognosis in ESCC patients.	('PDGFA', 'Gene', (44, 49))	('PDGFA', 'Gene', '5154', (44, 49))	('high', 'Var', (25, 29))	('patients', 'Species', '9606', (106, 114))	('ESCC', 'Disease', (101, 105))
462992	34011067	Gene set enrichment analysis identified 3 signaling pathways (extracellular matrix receptor interaction, focal adhesion, and glycosaminoglycan biosynthesis chondroitin sulfate) that were enriched in PDGFA high expression phenotype (all P < .01).	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (125, 142))	('signaling pathways', 'Pathway', (42, 60))	('PDGFA', 'Gene', (199, 204))	('PDGFA', 'Gene', '5154', (199, 204))	('focal adhesion', 'MPA', (105, 119))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (156, 175))	('high expression', 'Var', (205, 220))
463005	34011067	In addition, numerous clinical studies indicated that high expression of PDGFs was positively associated with clinicopathological parameters including TNM stage, lymph node metastasis, and depth of invasion.	('lymph node metastasis', 'CPA', (162, 183))	('depth of invasion', 'CPA', (189, 206))	('high', 'Var', (54, 58))	('PDGF', 'Gene', '5154;5155;56034;80310', (73, 77))	('PDGF', 'Gene', (73, 77))	('expression', 'MPA', (59, 69))	('associated', 'Reg', (94, 104))	('TNM stage', 'CPA', (151, 160))
463013	34011067	The difference in PDGFA expression between tumoral and nontumoral tissues was analyzed using GSE53625, GSE23400, and GSE67269.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumoral', 'Disease', (43, 50))	('tumoral', 'Disease', 'MESH:D009369', (43, 50))	('tumoral', 'Disease', (58, 65))	('tumoral', 'Disease', 'MESH:D009369', (58, 65))	('PDGFA', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('GSE23400', 'Var', (103, 111))	('PDGFA', 'Gene', '5154', (18, 23))	('GSE53625', 'Var', (93, 101))
463025	34011067	GSEA was carried out to explore the signaling pathway associated with PDGFA expression in tumoral tissues of GSE53625, GSE23400, and GSE67269 using GSEA 4.1.0.	('GSE53625', 'Var', (109, 117))	('GSEA', 'Chemical', '-', (148, 152))	('GSE23400', 'Var', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('PDGFA', 'Gene', (70, 75))	('tumoral', 'Disease', (90, 97))	('tumoral', 'Disease', 'MESH:D009369', (90, 97))	('GSEA', 'Chemical', '-', (0, 4))	('PDGFA', 'Gene', '5154', (70, 75))
463029	34011067	ESCC patients in GSE53625 were divided into high-PDGFA (n = 89) and low-PDGFA expression (n = 90) groups according to the median expression value of PDGFA, and Kaplan-Meier analysis and log-rank test were used to compare the OS between the 2 groups.	('PDGFA', 'Gene', '5154', (49, 54))	('patients', 'Species', '9606', (5, 13))	('PDGFA', 'Gene', '5154', (149, 154))	('GSE53625', 'Var', (17, 25))	('ESCC', 'Disease', (0, 4))	('PDGFA', 'Gene', (49, 54))	('PDGFA', 'Gene', (72, 77))	('PDGFA', 'Gene', '5154', (72, 77))	('PDGFA', 'Gene', (149, 154))
463033	34011067	In datasets of GSE53625, GSE23400, and GSE67269, it was indicated that PDGFA expression was significantly higher in ESCC samples than in adjacent normal tissues (Fig.	('expression', 'MPA', (77, 87))	('PDGFA', 'Gene', (71, 76))	('GSE53625', 'Var', (15, 23))	('ESCC', 'Disease', (116, 120))	('GSE67269', 'Var', (39, 47))	('PDGFA', 'Gene', '5154', (71, 76))	('higher', 'PosReg', (106, 112))	('GSE23400', 'Var', (25, 33))
463036	34011067	ESCC patients in GSE53625 were divided into high and low groups based on the median expression value of PDGFA in tumoral tissues and the relationship between PDGFA expression and clinicopathological parameters were investigated using chi-square test.	('patients', 'Species', '9606', (5, 13))	('tumoral', 'Disease', (113, 120))	('tumoral', 'Disease', 'MESH:D009369', (113, 120))	('GSE53625', 'Var', (17, 25))	('PDGFA', 'Gene', (158, 163))	('PDGFA', 'Gene', '5154', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('PDGFA', 'Gene', (104, 109))	('PDGFA', 'Gene', '5154', (104, 109))
463040	34011067	The results revealed that ESCC patients with high PDGFA mRNA expression had a poorer OS compared with those with low PDGFA mRNA expression (Fig.	('PDGFA', 'Gene', (50, 55))	('ESCC', 'Disease', (26, 30))	('PDGFA', 'Gene', '5154', (50, 55))	('high', 'Var', (45, 49))	('PDGFA', 'Gene', (117, 122))	('patients', 'Species', '9606', (31, 39))	('PDGFA', 'Gene', '5154', (117, 122))
463042	34011067	Subgroup analysis results suggested that high PDGFA expression was associated with unfavorable OS in patients with advanced T stage (T3 + T4) (Fig.	('patients', 'Species', '9606', (101, 109))	('high', 'Var', (41, 45))	('unfavorable', 'Disease', (83, 94))	('expression', 'MPA', (52, 62))	('associated', 'Reg', (67, 77))	('PDGFA', 'Gene', (46, 51))	('PDGFA', 'Gene', '5154', (46, 51))
463049	34011067	To investigate the signaling pathways associated with PDGFA, GSEA was performed between high and low PDGFA expression datasets based on GSE53625, GSE23400, and GSE67269.	('PDGFA', 'Gene', '5154', (101, 106))	('GSE67269', 'Var', (160, 168))	('PDGFA', 'Gene', (54, 59))	('PDGFA', 'Gene', '5154', (54, 59))	('GSE53625', 'Var', (136, 144))	('GSEA', 'Chemical', '-', (61, 65))	('GSE23400', 'Var', (146, 154))	('PDGFA', 'Gene', (101, 106))
463050	34011067	The results demonstrated that 3 signaling pathways were significantly enriched in PDGFA high expression phenotype, including extracellular matrix (ECM) receptor interaction, focal adhesion, and glycosaminoglycan biosynthesis chondroitin sulfate, which were shared by GSE53625, GSE23400, and GSE67269 (Fig.	('PDGFA', 'Gene', (82, 87))	('GSE53625', 'Var', (267, 275))	('PDGFA', 'Gene', '5154', (82, 87))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (194, 211))	('GSE67269', 'Var', (291, 299))	('GSE23400', 'Var', (277, 285))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (225, 244))	('signaling pathways', 'Pathway', (32, 50))	('focal adhesion', 'MPA', (174, 188))	('glycosaminoglycan', 'MPA', (194, 211))
463074	34011067	Additionally, Kaplan-Meier analysis showed that high PDGFA expression was associated with unfavorable prognosis ESCC patients, especially in advanced T stage.	('PDGFA', 'Gene', (53, 58))	('PDGFA', 'Gene', '5154', (53, 58))	('ESCC', 'Disease', (112, 116))	('expression', 'MPA', (59, 69))	('patients', 'Species', '9606', (117, 125))	('high', 'Var', (48, 52))
463075	34011067	Subsequent Cox regression analysis indicated that high PDGFA expression was an independent factor to predict unfavorable prognosis, which coincided with the results from a few clinical studies about other kinds of tumors, such as osteosarcoma, nephroblastoma, cholangiocarcinoma, gastric cancer, oral squamous cell carcinoma, and neuroblastoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (260, 278))	('gastric cancer', 'Disease', 'MESH:D013274', (280, 294))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (301, 324))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('nephroblastoma', 'Phenotype', 'HP:0002667', (244, 258))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('osteosarcoma', 'Phenotype', 'HP:0002669', (230, 242))	('gastric cancer', 'Phenotype', 'HP:0012126', (280, 294))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('PDGFA', 'Gene', '5154', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('high', 'Var', (50, 54))	('neuroblastoma', 'Disease', (330, 343))	('nephroblastoma', 'Disease', 'MESH:D009396', (244, 258))	('osteosarcoma', 'Disease', (230, 242))	('osteosarcoma', 'Disease', 'MESH:D012516', (230, 242))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (296, 324))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (260, 278))	('neuroblastoma', 'Phenotype', 'HP:0003006', (330, 343))	('gastric cancer', 'Disease', (280, 294))	('nephroblastoma', 'Disease', (244, 258))	('oral squamous cell carcinoma', 'Disease', (296, 324))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('PDGFA', 'Gene', (55, 60))	('neuroblastoma', 'Disease', 'MESH:D009447', (330, 343))	('cholangiocarcinoma', 'Disease', (260, 278))
463081	34011067	The results of GSEA showed that "ECM receptor interaction," "focal adhesion," and "glycosaminoglycan biosynthesis chondroitin sulfate" were significantly enriched in PDGFA high expression phenotype.	('PDGFA', 'Gene', '5154', (166, 171))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (83, 100))	('glycosaminoglycan biosynthesis chondroitin sulfate', 'MPA', (83, 133))	('GSEA', 'Chemical', '-', (15, 19))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (114, 133))	('high expression', 'Var', (172, 187))	('PDGFA', 'Gene', (166, 171))	('focal adhesion', 'CPA', (61, 75))
463112	30241323	Prominent mechanisms involve various biological regulatory processes, such as decreased drug transport, increased cellular detoxification by cellular thiols glutathione (GSH) and metallothionein (MT), changes in DNA repair involving increased nucleotide excision repair and/or loss of mismatch repair, increased tolerance of DNA adducts, and defeated apoptotic cell death pathway.	('changes', 'Var', (201, 208))	('DNA', 'Gene', (212, 215))	('increased', 'PosReg', (302, 311))	('nucleotide excision repair', 'MPA', (243, 269))	('increased', 'PosReg', (104, 113))	('tolerance', 'MPA', (312, 321))	('glutathione', 'Chemical', 'MESH:D005978', (157, 168))	('cellular detoxification', 'MPA', (114, 137))	('defeated', 'PosReg', (342, 350))	('thiols', 'Chemical', 'MESH:D013438', (150, 156))	('GSH', 'Chemical', 'MESH:D005978', (170, 173))	('drug transport', 'MPA', (88, 102))	('loss', 'NegReg', (277, 281))	('decreased', 'NegReg', (78, 87))	('apoptotic cell death pathway', 'CPA', (351, 379))	('mismatch repair', 'MPA', (285, 300))	('increased', 'PosReg', (233, 242))
463127	30241323	Figure 1C shows that proliferation of parental SLMT-1 cells was suppressed under 9.1 mug/mL CDDP by 9 times at 96 h of incubation, while the proliferation of SLMT-1/CDDP1R cells was suppressed only by 2.3 times under 9.1 mug/mL CDDP at 96 h of incubation.	('CDDP', 'Var', (92, 96))	('SLMT', 'Gene', (47, 51))	('proliferation', 'CPA', (21, 34))	('CDDP', 'Chemical', 'MESH:D002945', (165, 169))	('SLMT', 'Gene', '3488', (158, 162))	('SLMT', 'Gene', (158, 162))	('suppressed', 'NegReg', (64, 74))	('CDDP', 'Chemical', 'MESH:D002945', (228, 232))	('CDDP', 'Chemical', 'MESH:D002945', (92, 96))	('SLMT', 'Gene', '3488', (47, 51))
463131	30241323	LINC00520, SLITRK6, LOC100506377 and COL15A1 were the most upregulated genes(from 8.79 to 16.89 folds) in SLMT-1/CDDP1R.	('gen', 'Gene', '348654', (71, 74))	('SLMT', 'Gene', (106, 110))	('gen', 'Gene', (71, 74))	('COL15A1', 'Gene', (37, 44))	('upregulated', 'PosReg', (59, 70))	('LOC100506377', 'Var', (20, 32))	('CDDP', 'Chemical', 'MESH:D002945', (113, 117))	('SLITRK6', 'Gene', '84189', (11, 18))	('SLITRK6', 'Gene', (11, 18))	('SLMT', 'Gene', '3488', (106, 110))
463142	30241323	The results of IHC staining (Figure 4C-F) showed the effective transfection of Myc-tagged IGFBP5/pcMV3-C-Myc vector and Myc-tagged pcMv/hygro-negative control vector in all the four transfected cell lines (SLMT-1-pcMV3 (Figure 4C), SLMT-1R-pcMV3 (Figure 4D), SLMT-1-IGFBP5 (Figure 4E) and SLMT-1R-IGFBP5 (Figure 4F)).	('SLMT', 'Gene', '3488', (289, 293))	('IGFBP5', 'Gene', '3488', (297, 303))	('IGFBP5', 'Gene', '3488', (266, 272))	('SLMT', 'Gene', (289, 293))	('IGFBP5', 'Gene', '3488', (90, 96))	('-IGFBP5', 'Gene', '3488', (296, 303))	('IGFBP5', 'Gene', (297, 303))	('transfection', 'CPA', (63, 75))	('-IGFBP5', 'Gene', '3488', (265, 272))	('IGFBP5', 'Gene', (266, 272))	('IGFBP5', 'Gene', (90, 96))	('SLMT', 'Gene', '3488', (232, 236))	('Myc-tagged', 'Var', (79, 89))	('SLMT', 'Gene', '3488', (206, 210))	('SLMT', 'Gene', (232, 236))	('SLMT', 'Gene', (206, 210))	('vector and Myc', 'Gene', '4609', (109, 123))	('-IGFBP5', 'Gene', (296, 303))	('-IGFBP5', 'Gene', (265, 272))	('SLMT', 'Gene', '3488', (259, 263))	('SLMT', 'Gene', (259, 263))
463144	30241323	Moreover, as shown in Figure 5, the transfection of IGFBP5 expression vector into SLMT-1/CDDP1R cells remarkably increased the expression of IGFBP-5 in SLMT-1R-IGFBP5 cells (p = 0.0006).	('CDDP', 'Chemical', 'MESH:D002945', (89, 93))	('IGFBP', 'Gene', '3486;3488', (160, 165))	('-IGFBP5', 'Gene', (159, 166))	('IGFBP', 'Gene', (141, 146))	('IGFBP5', 'Gene', (52, 58))	('IGFBP', 'Gene', '3486;3488', (141, 146))	('SLMT', 'Gene', '3488', (82, 86))	('SLMT', 'Gene', (82, 86))	('SLMT', 'Gene', '3488', (152, 156))	('IGFBP', 'Gene', '3486;3488', (52, 57))	('IGFBP', 'Gene', (52, 57))	('SLMT', 'Gene', (152, 156))	('transfection', 'Var', (36, 48))	('expression', 'MPA', (127, 137))	('-IGFBP5', 'Gene', '3488', (159, 166))	('IGFBP5', 'Gene', '3488', (160, 166))	('increased', 'PosReg', (113, 122))	('IGFBP5', 'Gene', (160, 166))	('IGFBP5', 'Gene', '3488', (52, 58))	('IGFBP', 'Gene', (160, 165))
463165	30241323	It was revealed that the increase in autophagy activity in cisplatin-resistant EC109 (Esophgeal Cancer; Chinese origin) cells compared with the parental EC109 and inhibition on autophagy was able to enhance the cytotoxic effect of cisplatin on the resistant cell line.	('EC109', 'CellLine', 'CVCL:6898', (79, 84))	('Esophgeal Cancer', 'Disease', (86, 102))	('autophagy activity', 'CPA', (37, 55))	('enhance', 'PosReg', (199, 206))	('cisplatin', 'Chemical', 'MESH:D002945', (231, 240))	('autophagy', 'CPA', (177, 186))	('EC109', 'CellLine', 'CVCL:6898', (153, 158))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cisplatin-resistant', 'Var', (59, 78))	('increase', 'PosReg', (25, 33))	('cytotoxic effect', 'CPA', (211, 227))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('inhibition', 'Var', (163, 173))	('Esophgeal Cancer', 'Disease', 'MESH:D009369', (86, 102))
463169	30241323	Another member of IGFBPs family, IGFBP3, was also shown to have similar effect in the study conducted andover-expressing IGFBP3 enhanced sensitivity of KYSE30 (Kyoto, YShimada, Esophageal; Japanese origin) cells to cisplatin, and knocking-down of IGFBP3 by specific siRNA reduced sensitivity of KYSE30 to cisplatin.	('sensitivity of KYSE30 to cisplatin', 'MPA', (280, 314))	('enhanced', 'PosReg', (128, 136))	('IGFBP3', 'Gene', '3486', (121, 127))	('IGFBP3', 'Gene', '3486', (33, 39))	('sensitivity', 'MPA', (137, 148))	('reduced', 'NegReg', (272, 279))	('IGFBP3', 'Gene', '3486', (247, 253))	('cisplatin', 'Chemical', 'MESH:D002945', (215, 224))	('IGFBP', 'Gene', (18, 23))	('IGFBP', 'Gene', '3486;3488', (18, 23))	('IGFBP', 'Gene', (121, 126))	('IGFBP', 'Gene', '3486;3488', (121, 126))	('knocking-down', 'Var', (230, 243))	('IGFBP', 'Gene', (33, 38))	('IGFBP', 'Gene', '3486;3488', (33, 38))	('IGFBP3', 'Gene', (121, 127))	('IGFBP', 'Gene', '3486;3488', (247, 252))	('IGFBP', 'Gene', (247, 252))	('IGFBP3', 'Gene', (33, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (305, 314))	('IGFBP3', 'Gene', (247, 253))
463179	30241323	The use of monoclonal antibodies against IGF-1R accompanying cisplatin improved inhibitory efficacy in small cell lung cancer in vivo and in vitro in nude mice bearing the tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('inhibitory efficacy', 'MPA', (80, 99))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (103, 125))	('small cell lung cancer', 'Disease', (103, 125))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('nude mice', 'Species', '10090', (150, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('IGF-1R', 'Gene', (41, 47))	('small cell lung cancer', 'Disease', 'MESH:D055752', (103, 125))	('improved', 'PosReg', (71, 79))	('monoclonal', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
463182	30241323	p53 is a key regulator in DNA damaging signaling and degradation of p53 protein might aid the damaged cells to escape from apoptosis, and thus acquired cisplatin-resistance.	('acquired', 'PosReg', (143, 151))	('escape from apoptosis', 'CPA', (111, 132))	('cisplatin-resistance', 'MPA', (152, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('degradation', 'Var', (53, 64))	('aid', 'PosReg', (86, 89))	('p53', 'Gene', (68, 71))
463239	30141152	The patient was diagnosed with cT3N1M0 stage IIIa rectal cancer according to the Japanese Classification of Colorectal Carcinoma 8th edition.	('rectal cancer', 'Disease', (50, 63))	('Carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('patient', 'Species', '9606', (4, 11))	('rectal cancer', 'Disease', 'MESH:D012004', (50, 63))	('Colorectal Carcinoma 8th edition', 'Disease', 'MESH:D015179', (108, 140))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Colorectal Carcinoma 8th edition', 'Disease', (108, 140))	('rectal cancer', 'Phenotype', 'HP:0100743', (50, 63))	('cT3N1M0', 'Var', (31, 38))
463247	30141152	The pathological diagnosis was moderately differentiated adenocarcinoma, T3 (SS), INFb, ly1, v2, PN1a, pPM(-), pDM(-), pRM(-), pN0, and stage IIA (Fig.	('ly1', 'Var', (88, 91))	('adenocarcinoma', 'Disease', (57, 71))	('adenocarcinoma', 'Disease', 'MESH:D000230', (57, 71))	('stage IIA', 'Disease', (136, 145))	('pDM(-', 'Var', (111, 116))	('moderately', 'Disease', (31, 41))	('pPM(-', 'Var', (103, 108))	('PN1a', 'Var', (97, 101))	('pRM(-', 'Var', (119, 124))	('pN0', 'Var', (127, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
463261	30141152	The pathological diagnosis was moderately differentiated adenocarcinoma, T3 (SS), INFb, ly1, v1, PN0, pPM(-), pDM(-), pRM(-), pN0, and stage IIA.	('pN0', 'Var', (126, 129))	('ly1', 'Var', (88, 91))	('adenocarcinoma', 'Disease', 'MESH:D000230', (57, 71))	('pPM(-', 'Var', (102, 107))	('pRM(-', 'Var', (118, 123))	('pDM(-', 'Var', (110, 115))	('moderately differentiated', 'CPA', (31, 56))	('PN0', 'Var', (97, 100))	('stage IIA', 'Disease', (135, 144))	('adenocarcinoma', 'Disease', (57, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
463275	30141152	The pathological diagnosis was well-differentiated adenocarcinoma, T3 (SS), INFc, ly0, v1, PN1a, pPM(-), pDM(-), pRM(-), pN1 (1/18), and stage IIIa.	('pN1', 'Gene', (121, 124))	('adenocarcinoma', 'Disease', 'MESH:D000230', (51, 65))	('PN1a', 'Var', (91, 95))	('adenocarcinoma', 'Disease', (51, 65))	('pDM(-', 'Var', (105, 110))	('pN1', 'Gene', '5270', (121, 124))	('pPM(-', 'Var', (97, 102))	('stage IIIa', 'Disease', (137, 147))	('pRM(-', 'Var', (113, 118))	('ly0', 'Var', (82, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
463351	27903148	Overweight and obesity are associated with an increased risk of developing several GI cancers, including esophageal, gastric, hepatocellular, pancreatic and colorectal.	('GI cancers', 'Disease', (83, 93))	('pancreatic', 'Disease', 'MESH:D010195', (142, 152))	('obesity', 'Disease', 'MESH:D009765', (15, 22))	('GI cancer', 'Phenotype', 'HP:0007378', (83, 92))	('obesity', 'Disease', (15, 22))	('pancreatic', 'Disease', (142, 152))	('GI cancers', 'Disease', 'MESH:D009369', (83, 93))	('colorectal', 'Disease', 'MESH:D015179', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Overweight', 'Var', (0, 10))	('gastric', 'Disease', (117, 124))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('colorectal', 'Disease', (157, 167))	('obesity', 'Phenotype', 'HP:0001513', (15, 22))	('hepatocellular', 'Disease', (126, 140))	('esophageal', 'Disease', (105, 115))
463361	27903148	Among 243 patients with stage I-III squamous cell carcinoma, overweight or obesity at the time of esophagectomy were independently associated with a three-fold higher risk of experiencing disease recurrence or death when compared to normal weight (HR: 2.94, 95% CI: 1.13-7.6; P=.027).	('death', 'Disease', (210, 215))	('obesity', 'Disease', (75, 82))	('overweight', 'Phenotype', 'HP:0025502', (61, 71))	('obesity', 'Phenotype', 'HP:0001513', (75, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('disease recurrence', 'Disease', (188, 206))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (36, 59))	('death', 'Disease', 'MESH:D003643', (210, 215))	('patients', 'Species', '9606', (10, 18))	('squamous cell carcinoma', 'Disease', (36, 59))	('overweight', 'Var', (61, 71))	('obesity', 'Disease', 'MESH:D009765', (75, 82))
463367	27903148	Among 216 patients with pT2/T3 tumors, overweight and obesity at the time of gastrectomy were independently associated with a shorter five-year survival rate when compared to normal weight (37.8% v 58.5%; P=.03).	('obesity', 'Disease', 'MESH:D009765', (54, 61))	('overweight', 'Phenotype', 'HP:0025502', (39, 49))	('shorter', 'NegReg', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('obesity', 'Disease', (54, 61))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('T3 tumors', 'Disease', 'MESH:C537047', (28, 37))	('T3 tumors', 'Disease', (28, 37))	('overweight', 'Var', (39, 49))	('patients', 'Species', '9606', (10, 18))	('five-year survival', 'MPA', (134, 152))	('obesity', 'Phenotype', 'HP:0001513', (54, 61))
463379	27903148	Among 159 patients with hepatocellular carcinoma who underwent liver transplantation, overweight and obesity were associated with doubling in the incidence of recurrent disease (16% v 8%; P<.05) and shortened time to recurrence (~10 months v ~24 months; P<.05), compared to normal weight, respectively.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (24, 48))	('obesity', 'Disease', 'MESH:D009765', (101, 108))	('hepatocellular carcinoma', 'Disease', (24, 48))	('recurrent', 'MPA', (159, 168))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (24, 48))	('obesity', 'Disease', (101, 108))	('shortened', 'NegReg', (199, 208))	('overweight', 'Var', (86, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('obesity', 'Phenotype', 'HP:0001513', (101, 108))	('overweight', 'Phenotype', 'HP:0025502', (86, 96))	('patients', 'Species', '9606', (10, 18))
463380	27903148	Overweight and obesity are also associated with significantly lower five-year survival rates in patients who undergo repeat hepatectomy for recurrent hepatocellular carcinoma (51.9% v 92.0%; P<.05).	('obesity', 'Disease', 'MESH:D009765', (15, 22))	('obesity', 'Disease', (15, 22))	('obesity', 'Phenotype', 'HP:0001513', (15, 22))	('Overweight', 'Var', (0, 10))	('lower', 'NegReg', (62, 67))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (150, 174))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (150, 174))	('patients', 'Species', '9606', (96, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('hepatocellular carcinoma', 'Disease', (150, 174))
463395	27903148	Several polymorphisms associated with obesity-related genes may influence recurrence among colon cancer, and metabolomic and transcriptomic signaling of intra-abdominal adipose tissue may differ by disease stage.	('polymorphisms', 'Var', (8, 21))	('colon cancer', 'Disease', 'MESH:D015179', (91, 103))	('obesity', 'Phenotype', 'HP:0001513', (38, 45))	('colon cancer', 'Disease', (91, 103))	('influence', 'Reg', (64, 73))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('obesity', 'Disease', 'MESH:D009765', (38, 45))	('recurrence', 'Disease', (74, 84))	('obesity', 'Disease', (38, 45))	('differ', 'Reg', (188, 194))
463414	27903148	However, purposeful alterations in energy balance related behaviors improve cardiovascular and metabolic risk factors (hypertension, impaired fasting glucose, visceral obesity), and improve a variety of patient-reported outcomes including physical function and overall quality of life.	('visceral obesity', 'Disease', (159, 175))	('alterations', 'Var', (20, 31))	('visceral obesity', 'Disease', 'MESH:D056128', (159, 175))	('improve', 'PosReg', (68, 75))	('impaired fasting glucose', 'Phenotype', 'HP:0040270', (133, 157))	('obesity', 'Phenotype', 'HP:0001513', (168, 175))	('hypertension', 'Phenotype', 'HP:0000822', (119, 131))	('visceral obesity', 'Phenotype', 'HP:0012743', (159, 175))	('improve', 'PosReg', (182, 189))	('hypertension', 'Disease', (119, 131))	('cardiovascular', 'MPA', (76, 90))	('glucose', 'Chemical', 'MESH:D005947', (150, 157))	('patient', 'Species', '9606', (203, 210))	('physical function', 'CPA', (239, 256))	('impaired fasting glucose', 'MPA', (133, 157))	('hypertension', 'Disease', 'MESH:D006973', (119, 131))
463445	27903148	Among patients with colon cancer, overweight and obesity are associated with increased risk of presenting with T3/T4 tumors and N1/N2 lymph node staging.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('N1/N2 lymph node staging', 'CPA', (128, 152))	('obesity', 'Phenotype', 'HP:0001513', (49, 56))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('overweight', 'Phenotype', 'HP:0025502', (34, 44))	('colon cancer', 'Phenotype', 'HP:0003003', (20, 32))	('colon cancer', 'Disease', 'MESH:D015179', (20, 32))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('overweight', 'Var', (34, 44))	('patients', 'Species', '9606', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('obesity', 'Disease', 'MESH:D009765', (49, 56))	('colon cancer', 'Disease', (20, 32))	('obesity', 'Disease', (49, 56))	('T3/T4', 'Disease', (111, 116))
463509	28383075	The prevalence of esophageal cancer exhibited a marked sex difference, and it was a significant predictor for prognosis for T2-T3but not for T4 esophageal SCC.	('esophageal cancer', 'Disease', (18, 35))	('SCC', 'Gene', (155, 158))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('T2-T3but', 'Var', (124, 132))	('SCC', 'Gene', '6317', (155, 158))
463519	28383075	For esophageal adenocarcinoma, it has been reported that (neo-) adjuvant radiotherapy are of significant survival benefit to T3N0M0 stage, but not significantly good to T2N0M0.	('T3N0M0', 'Var', (125, 131))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (4, 29))	('esophageal adenocarcinoma', 'Disease', (4, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('survival', 'CPA', (105, 113))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (4, 29))
463552	27483432	SIRT3 expression was significantly associated with overall survival in gastric cancer (HR = 0.62, 95% CI = 0.43-0.89, P = 0.009) and hepatocellular carcinoma patients (HR = 0.56, 95% CI = 0.42-0.74, P<0.0001), cancer/non-cancer tissues in hepatocellular carcinoma patients (OR = 0.04, 95% CI = 0.01-0.16, P<0.0001), lymph node metastasis in breast cancer patients (OR = 2.20, 95% CI = 1.49-3.26, P<0.0001), and also pathological differentiation in hepatocellular carcinoma patients (OR = 0.69, 95% CI = 0.48-0.98, P = 0.04) and gastric cancer patients (OR = 0.33, 95% CI = 0.21-0.50, P<0.00001), by subgroup analyses.	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Disease', 'MESH:D001943', (341, 354))	('breast cancer', 'Disease', (341, 354))	('cancer', 'Disease', 'MESH:D009369', (536, 542))	('patients', 'Species', '9606', (158, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('hepatocellular carcinoma', 'Disease', (239, 263))	('expression', 'Var', (6, 16))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (133, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (528, 542))	('patients', 'Species', '9606', (355, 363))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('patients', 'Species', '9606', (473, 481))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (448, 472))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('hepatocellular carcinoma', 'Disease', (133, 157))	('non-cancer', 'Disease', 'MESH:D009369', (217, 227))	('cancer', 'Disease', (79, 85))	('patients', 'Species', '9606', (543, 551))	('SIRT3', 'Gene', (0, 5))	('cancer', 'Disease', (348, 354))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('lymph node metastasis', 'CPA', (316, 337))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (221, 227))	('gastric cancer', 'Disease', (528, 542))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('non-cancer', 'Disease', (217, 227))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (239, 263))	('patients', 'Species', '9606', (264, 272))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (448, 472))	('cancer', 'Disease', (536, 542))	('cancer', 'Phenotype', 'HP:0002664', (536, 542))	('associated', 'Reg', (35, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (528, 542))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (239, 263))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (341, 354))	('carcinoma', 'Phenotype', 'HP:0030731', (463, 472))	('hepatocellular carcinoma', 'Disease', (448, 472))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
463557	27483432	SIRT3 was thought to participate a wide range of cancerous functions, including genomic instability and mutation, resisting cell death, sustaining proliferative signaling, deregulating cellular energetics, evading growth suppressors, as well as tumor-promoting inflammation.	('inflammation', 'Disease', 'MESH:D007249', (261, 273))	('proliferative signaling', 'MPA', (147, 170))	('tumor', 'Disease', (245, 250))	('cellular energetics', 'MPA', (185, 204))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('deregulating', 'Reg', (172, 184))	('cancerous functions', 'Disease', (49, 68))	('growth suppressors', 'CPA', (214, 232))	('cancerous functions', 'Disease', 'MESH:D009369', (49, 68))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('mutation', 'Var', (104, 112))	('cell death', 'CPA', (124, 134))	('evading', 'NegReg', (206, 213))	('sustaining', 'PosReg', (136, 146))	('SIRT3', 'Gene', (0, 5))	('inflammation', 'Disease', (261, 273))
463560	27483432	Expression of SIRT3 was reported to be significantly associated with poor prognosis in cancers such as breast cancer, colon cancer, and esophageal cancer; but opposite results were reported in hepatocellular carcinoma and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Disease', (222, 236))	('colon cancer', 'Disease', (118, 130))	('Expression', 'Var', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('breast cancer', 'Disease', (103, 116))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (193, 217))	('gastric cancer', 'Disease', 'MESH:D013274', (222, 236))	('associated', 'Reg', (53, 63))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('colon cancer', 'Phenotype', 'HP:0003003', (118, 130))	('cancers', 'Disease', (87, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (193, 217))	('gastric cancer', 'Phenotype', 'HP:0012126', (222, 236))	('colon cancer', 'Disease', 'MESH:D015179', (118, 130))	('esophageal cancer', 'Disease', (136, 153))	('SIRT3', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('hepatocellular carcinoma', 'Disease', (193, 217))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
463578	27483432	However, in subgroup analyses, for lymph node metastasis of breast cancer in the SIRT3 positivity/high group, as compared with the SIRT3 negative/low group, was statistically significant (OR = 2.20, 95% CI = 1.49-3.26, P<0.0001).	('positivity/high', 'Var', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('significant', 'Reg', (175, 186))	('lymph node metastasis of breast cancer', 'Disease', (35, 73))	('SIRT3', 'Gene', (81, 86))	('lymph node metastasis of breast cancer', 'Disease', 'MESH:D009362', (35, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
463612	27483432	Furthermore, the prognostic finding that patients with higher expression of SIRT3 had shorter overall survival in our meta-analysis also reveal that SIRT3 function as tumor promoter after cells have been completely transformed.	('overall survival', 'MPA', (94, 110))	('shorter', 'NegReg', (86, 93))	('SIRT3', 'Gene', (76, 81))	('SIRT3', 'Gene', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('patients', 'Species', '9606', (41, 49))	('higher', 'PosReg', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('expression', 'Var', (62, 72))	('tumor', 'Disease', (167, 172))
463631	27143917	Patients with a high level of BC200 had a shorter disease-free survival and overall survival than those with low BC200 expression (P=0.034 and P=0.031, respectively).	('shorter', 'NegReg', (42, 49))	('high', 'Var', (16, 20))	('overall survival', 'CPA', (76, 92))	('BC200', 'Gene', '618', (30, 35))	('Patients', 'Species', '9606', (0, 8))	('BC200', 'Gene', (113, 118))	('disease-free survival', 'CPA', (50, 71))	('BC200', 'Gene', (30, 35))	('BC200', 'Gene', '618', (113, 118))
463635	27143917	Although many genetic and epigenetic changes are found to be correlated with ESCC, the underlying mechanisms of carcinogenesis remain poorly understood.	('carcinogenesis', 'Disease', 'MESH:D063646', (112, 126))	('epigenetic changes', 'Var', (26, 44))	('carcinogenesis', 'Disease', (112, 126))	('ESCC', 'Disease', (77, 81))	('genetic', 'Var', (14, 21))	('correlated', 'Reg', (61, 71))
463702	27143917	MALAT-1 knockdown induced a decrease in proliferation-enhanced apoptosis, inhibited migration/invasion, and reduced colony formation and led to cell cycle arrest at the G2/M phase.	('inhibited', 'NegReg', (74, 83))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('migration/invasion', 'CPA', (84, 102))	('reduced', 'NegReg', (108, 115))	('knockdown', 'Var', (8, 17))	('MALAT-1', 'Gene', '378938', (0, 7))	('colony formation', 'CPA', (116, 132))	('cell cycle arrest at the G2/M phase', 'CPA', (144, 179))	('decrease', 'NegReg', (28, 36))	('apoptosis', 'CPA', (63, 72))	('proliferation-enhanced', 'CPA', (40, 62))	('MALAT-1', 'Gene', (0, 7))
463786	25237038	Progression from HGD to cancer within the same time frame was observed in 2.4% (one subject) in the RFA arm compared with 19% in the sham arm.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('HGD', 'Gene', '3081', (17, 20))	('HGD', 'Gene', (17, 20))	('RFA', 'Var', (100, 103))
463818	23917221	Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment Periostin (POSTN), a matricellular protein, has been reported to be important in supporting tumor cell dissemination.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('p53', 'Gene', '7157', (33, 36))	('mutant', 'Var', (26, 32))	('esophageal tumor', 'Disease', 'MESH:D004938', (105, 121))	('tumor', 'Disease', (231, 236))	('p53', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Periostin', 'Gene', '10631', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('induction', 'Reg', (69, 78))	('Periostin', 'Gene', (139, 148))	('STAT1 signaling', 'MPA', (82, 97))	('invasion', 'CPA', (48, 56))	('Periostin', 'Gene', '10631', (0, 9))	('esophageal tumor', 'Disease', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('esophageal tumor', 'Phenotype', 'HP:0100751', (105, 121))	('Periostin', 'Gene', (0, 9))	('tumor', 'Disease', (116, 121))
463820	23917221	In this study, we observe that the inducible knockdown of POSTN decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that POSTN cooperates with a conformational missense p53 mutation to enhance invasion.	('enhance', 'PosReg', (222, 229))	('decreases esophageal squamous cell carcinoma (ESCC) tumor', 'Disease', 'MESH:D000077277', (64, 121))	('mutation', 'Var', (210, 218))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('invasion', 'CPA', (230, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('POSTN', 'Gene', (58, 63))
463821	23917221	Pathway analyses reveal that invasive esophageal cells expressing POSTN and p53R175H mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells into the extracellular matrix.	('p53R175H', 'Mutation', 'p.R53,175H', (76, 84))	('signal transducer and activator of transcription 1', 'Gene', '6772', (116, 166))	('facilitates', 'PosReg', (300, 311))	('invasion', 'CPA', (312, 320))	('activation', 'PosReg', (102, 112))	('foster', 'PosReg', (258, 264))	('STAT1', 'Gene', (222, 227))	('permissive', 'MPA', (267, 277))	('p53R175H', 'Var', (76, 84))
463822	23917221	Furthermore, we find that STAT1 is activated in ESCC xenograft tumors, but this activation is attenuated with inducible knockdown of POSTN in ESCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('ESCC xenograft tumors', 'Disease', 'MESH:D004938', (48, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('POSTN', 'Gene', (133, 138))	('ESCC tumors', 'Disease', (142, 153))	('knockdown', 'Var', (120, 129))	('ESCC xenograft tumors', 'Disease', (48, 69))	('STAT1', 'MPA', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('activated', 'PosReg', (35, 44))	('ESCC tumors', 'Disease', 'MESH:D004938', (142, 153))
463827	23917221	Common risk factors associated with ESCC are smoking tobacco, excessive alcohol use, aromatic hydrocarbons in smoked foods and particular nutritional deficiencies.	('tobacco', 'Species', '4097', (53, 60))	('aromatic hydrocarbons', 'Chemical', 'MESH:D006841', (85, 106))	('alcohol use', 'Phenotype', 'HP:0030955', (72, 83))	('alcohol', 'Chemical', 'MESH:D000438', (72, 79))	('particular nutritional deficiencies', 'Disease', (127, 162))	('aromatic', 'Var', (85, 93))	('particular nutritional deficiencies', 'Disease', 'MESH:D044342', (127, 162))	('ESCC', 'Disease', (36, 40))
463828	23917221	For example, aberrant expression of epidermal growth factor receptor (EGFR) and cyclin D1, activation of human telomerase, inactivation of p16Ink4a and p120 catenin and somatic mutations in the DNA-binding domain (DBD) of the p53 tumor-suppressor gene all have been found to be involved in the initiation and progression of ESCC.	('ESCC', 'Disease', (324, 328))	('activation', 'PosReg', (91, 101))	('human', 'Species', '9606', (105, 110))	('inactivation', 'Var', (123, 135))	('cyclin D1', 'Gene', (80, 89))	('EGFR', 'Gene', '1956', (70, 74))	('involved', 'Reg', (278, 286))	('epidermal growth factor receptor', 'Gene', (36, 68))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('p16Ink4a', 'Gene', '1029', (139, 147))	('cyclin D1', 'Gene', '595', (80, 89))	('aberrant', 'Var', (13, 21))	('tumor', 'Disease', (230, 235))	('p120 catenin', 'Gene', '1500', (152, 164))	('epidermal growth factor receptor', 'Gene', '1956', (36, 68))	('p120 catenin', 'Gene', (152, 164))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('expression', 'MPA', (22, 32))	('mutations in', 'Var', (177, 189))	('p16Ink4a', 'Gene', (139, 147))	('EGFR', 'Gene', (70, 74))	('human', 'Protein', (105, 110))
463829	23917221	EGFR and cyclin D1 overexpression correlate with squamous dysplasia or neoplastic lesions, which are early events in tumor initiation, whereas inactivation of p16Ink4a and p120 catenin and mutations in p53 have been associated with later stages of ESCC progression.	('squamous dysplasia', 'Disease', 'MESH:D002294', (49, 67))	('tumor initiation', 'Disease', 'MESH:D009369', (117, 133))	('associated', 'Reg', (216, 226))	('cyclin D1', 'Gene', (9, 18))	('tumor initiation', 'Disease', (117, 133))	('squamous dysplasia', 'Disease', (49, 67))	('overexpression', 'PosReg', (19, 33))	('p120 catenin', 'Gene', '1500', (172, 184))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('p120 catenin', 'Gene', (172, 184))	('cyclin D1', 'Gene', '595', (9, 18))	('neoplastic lesions', 'Disease', (71, 89))	('ESCC', 'Disease', (248, 252))	('mutations', 'Var', (189, 198))	('EGFR', 'Gene', (0, 4))	('neoplastic lesions', 'Disease', 'MESH:D051437', (71, 89))	('p16Ink4a', 'Gene', '1029', (159, 167))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (71, 89))	('inactivation', 'Var', (143, 155))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (49, 67))	('EGFR', 'Gene', '1956', (0, 4))	('p53', 'Gene', (202, 205))	('p16Ink4a', 'Gene', (159, 167))
463830	23917221	The majority of human cancers harbor missense mutations in TP53, which not only lead to loss of wild-type p53 transcriptional activity but also an accumulation of mutant p53 protein with gain-of-function activities.	('missense mutations', 'Var', (37, 55))	('accumulation', 'PosReg', (147, 159))	('TP53', 'Gene', (59, 63))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('transcriptional activity', 'MPA', (110, 134))	('p53', 'Gene', (170, 173))	('cancers', 'Disease', (22, 29))	('activities', 'MPA', (204, 214))	('mutant', 'Var', (163, 169))	('loss', 'NegReg', (88, 92))	('p53', 'Protein', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('human', 'Species', '9606', (16, 21))	('gain-of-function', 'PosReg', (187, 203))	('TP53', 'Gene', '7157', (59, 63))	('protein', 'Protein', (174, 181))
463831	23917221	These missense mutations tend to occur in the DBD of TP53 and result in the loss of wild-type p53 function.	('loss', 'NegReg', (76, 80))	('missense mutations', 'Var', (6, 24))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))	('function', 'MPA', (98, 106))
463832	23917221	DNA-contact mutants such as R273H and R248Q have mutations in residues that are involved in DNA binding, whereas DNA-conformational mutants such as R175H, R248W and V143A cause global conformation distortions in the DBD.	('R248Q', 'Var', (38, 43))	('cause', 'Reg', (171, 176))	('R175H', 'Mutation', 'rs28934578', (148, 153))	('V143A', 'Var', (165, 170))	('R248W', 'Mutation', 'rs121912651', (155, 160))	('V143A', 'Mutation', 'rs1454329666', (165, 170))	('R175H', 'Var', (148, 153))	('R248Q', 'Mutation', 'rs11540652', (38, 43))	('R248W', 'Var', (155, 160))	('global conformation distortions', 'MPA', (177, 208))	('R273H', 'Var', (28, 33))	('R273H', 'Mutation', 'rs28934576', (28, 33))
463833	23917221	Common hotspot mutations such as p53R175H and p53R273H found in human cancers have been genetically engineered into mouse models, respectively, corresponding to p53R172H and p53R270H mice.	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('p53R175H', 'Var', (33, 41))	('p53R172H', 'Var', (161, 169))	('p53R175H', 'Mutation', 'p.R53,175H', (33, 41))	('mice', 'Species', '10090', (183, 187))	('p53R270H', 'Var', (174, 182))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('mouse', 'Species', '10090', (116, 121))	('p53R273H', 'Var', (46, 54))
463834	23917221	p53R172H and p53R270H heterozygous mice not only develop osteosarcomas and carcinomas but also display a metastatic phenotype similar to p53 heterozygous mice.	('mice', 'Species', '10090', (154, 158))	('develop', 'PosReg', (49, 56))	('p53R172H', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('metastatic', 'CPA', (105, 115))	('p53R270H', 'Var', (13, 21))	('mice', 'Species', '10090', (35, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('osteosarcomas', 'Phenotype', 'HP:0002669', (57, 70))	('osteosarcomas and carcinomas', 'Disease', 'MESH:D012516', (57, 85))
463835	23917221	In fact, R175H, R248W and R273H confer a selective growth advantage to increasingly malignant ESCC.	('growth advantage', 'CPA', (51, 67))	('R175H', 'Mutation', 'rs28934578', (9, 14))	('R248W', 'Mutation', 'rs121912651', (16, 21))	('R175H', 'Var', (9, 14))	('R273H', 'Mutation', 'rs28934576', (26, 31))	('R248W', 'Var', (16, 21))	('R273H', 'Var', (26, 31))
463836	23917221	During tumor progression, acquisition of oncogenic and tumor-suppressor mutations cause cancer cells to activate adjacent stromal components and induce the release of cytokines, growth factors and extracellular matrix (ECM) proteins into the tumor stroma to create a microenvironment permissive for growth and dissemination.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Disease', (88, 94))	('induce', 'Reg', (145, 151))	('tumor stroma', 'Disease', 'MESH:D009369', (242, 254))	('tumor', 'Disease', (242, 247))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('mutations', 'Var', (72, 81))	('release', 'MPA', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor stroma', 'Disease', (242, 254))	('cytokines', 'MPA', (167, 176))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('activate', 'PosReg', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
463840	23917221	In addition, dysregulation of their expression is observed in many solid tumors as well as in sera and is often correlated with poorer prognosis and outcomes in cancer patients, thus implicating the importance of their contributions towards cancer progression.	('solid tumors', 'Disease', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('correlated', 'Reg', (112, 122))	('dysregulation', 'Var', (13, 26))	('solid tumors', 'Disease', 'MESH:D009369', (67, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (161, 167))	('expression', 'MPA', (36, 46))
463844	23917221	Bioinformatic network analyses identified the signal transducer and activator of transcription 1 (STAT1) signaling network as a putative pathway induced by POSTN expression in a mutant p53 background, which was validated by expression studies.	('mutant', 'Var', (178, 184))	('p53', 'Gene', (185, 188))	('POSTN', 'Gene', (156, 161))	('induced', 'Reg', (145, 152))	('signal transducer and activator of transcription 1', 'Gene', '6772', (46, 96))
463845	23917221	Moreover, genetic knockdown of STAT1 in invasive and transformed, genetically engineered esophageal cells (EPC-hTERT-EGFR-p53R175H) attenuated invasion into the microenvironment.	('knockdown', 'Var', (18, 27))	('hTERT', 'Gene', '7015', (111, 116))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('STAT1', 'Gene', (31, 36))	('hTERT', 'Gene', (111, 116))	('attenuated', 'NegReg', (132, 142))	('p53R175H', 'Mutation', 'p.R53,175H', (122, 130))	('invasion into the microenvironment', 'CPA', (143, 177))
463847	23917221	Given that high POSTN expression has been associated with poor patient survival outcomes in ESCC, we postulated that POSTN has a key role in promoting ESCC development.	('ESCC', 'Disease', (92, 96))	('promoting', 'PosReg', (141, 150))	('POSTN', 'Protein', (16, 21))	('ESCC', 'Disease', (151, 155))	('patient', 'Species', '9606', (63, 70))	('high', 'Var', (11, 15))	('expression', 'MPA', (22, 32))
463848	23917221	Indeed, in immunocompromised mice bearing tumor xenografts of two independent ESCC cell lines (TE11 and HCE4) that were stably transfected with a tetracycline-inducible shRNA targeted to POSTN, we observed that inducible ablation of POSTN expression and deposition in the stroma after initial establishment of these xenograft tumors (Figures 1a and b) led to decreased tumor growth and invasion as well as a decrease in proliferation (Figures 1c and d; Supplementary Figures S1a and S1b), indicating that POSTN contributes functionally in facilitating tumor growth and invasion in ESCC.	('invasion', 'CPA', (386, 394))	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('tetracycline', 'Chemical', 'MESH:D013752', (146, 158))	('invasion', 'CPA', (569, 577))	('proliferation', 'CPA', (420, 433))	('tumor', 'Disease', 'MESH:D009369', (552, 557))	('tumor', 'Disease', (369, 374))	('mice', 'Species', '10090', (29, 33))	('POSTN', 'Gene', (233, 238))	('decreased tumor', 'Disease', 'MESH:D009369', (359, 374))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (369, 374))	('decrease', 'NegReg', (408, 416))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (326, 331))	('tumor', 'Phenotype', 'HP:0002664', (552, 557))	('decreased tumor', 'Disease', (359, 374))	('tumor', 'Disease', (552, 557))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('xenograft tumors', 'Disease', (316, 332))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('xenograft tumors', 'Disease', 'MESH:D009369', (316, 332))	('ablation', 'Var', (221, 229))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('POSTN', 'Gene', (505, 510))
463849	23917221	As we have identified POSTN expression to be upregulated in transformed, genetically engineered esophageal cells with p53R175H mutation and overexpressing EGFR (EPC-hTERT-EGFR-p53R175H), both common genetic alterations in ESCC, we hypothesized that the invasive capabilities of POSTN are mediated by either of these genetic alterations.	('EGFR', 'Gene', (171, 175))	('p53R175H', 'Mutation', 'p.R53,175H', (176, 184))	('p53R175H', 'Mutation', 'p.R53,175H', (118, 126))	('EGFR', 'Gene', '1956', (155, 159))	('hTERT', 'Gene', (165, 170))	('expression', 'MPA', (28, 38))	('p53R175H mutation', 'Var', (118, 135))	('EGFR', 'Gene', (155, 159))	('POSTN', 'Gene', (22, 27))	('upregulated', 'PosReg', (45, 56))	('EGFR', 'Gene', '1956', (171, 175))	('hTERT', 'Gene', '7015', (165, 170))
463856	23917221	Interestingly, mutant p53 alone is seen to be more invasive compared with overexpression of EGFR alone, suggesting that POSTN may act to augment this invasion.	('augment', 'NegReg', (137, 144))	('p53', 'Gene', (22, 25))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('mutant', 'Var', (15, 21))
463857	23917221	Collectively, these data suggest that POSTN cooperates with mutant p53R175H to enhance invasion of esophageal cells into the underlying stromal ECM.	('mutant p53R175H', 'Var', (60, 75))	('p53R175H', 'Var', (67, 75))	('p53R175H', 'Mutation', 'p.R53,175H', (67, 75))	('enhance', 'PosReg', (79, 86))	('invasion', 'CPA', (87, 95))
463858	23917221	As p53 missense mutations fell into two broad categories of either conformational or DNA-binding mutants that each might lead to the acquisition of differing gain-of-function phenotypes, we next wanted to explore whether the ability of POSTN to promote invasion is dependent upon the conformation of mutant p53 as observed with p53R175H or on its DNA-contact-binding abilities.	('promote', 'PosReg', (245, 252))	('mutant', 'Var', (300, 306))	('p53', 'Gene', (307, 310))	('invasion', 'CPA', (253, 261))	('missense mutations', 'Var', (7, 25))	('mutants', 'Var', (97, 104))	('p53R175H', 'Mutation', 'p.R53,175H', (328, 336))	('p53', 'Gene', (3, 6))
463859	23917221	First, we retrovirally overexpressed POSTN in EPC-hTERT cells stably expressing different p53 point mutations, DNA-contact mutant p53R273H (EPC-hTERT-p53R273H-POSTN) and in a temperature-sensitive conformational mutant, p53V143A (EPC-hTERT-p53V143A-POSTN).	('p53', 'Gene', (90, 93))	('hTERT', 'Gene', (144, 149))	('hTERT', 'Gene', (234, 239))	('p53R273H', 'Var', (130, 138))	('hTERT', 'Gene', '7015', (50, 55))	('p53V143A', 'Var', (220, 228))	('hTERT', 'Gene', '7015', (234, 239))	('hTERT', 'Gene', '7015', (144, 149))	('hTERT', 'Gene', (50, 55))
463864	23917221	To assess whether invasion can be affected pharmacologically by restoring wild-type p53 signaling, we utilized 5-iminodaunorubicin (5-ID), a small molecule compound which has been established previously to restore wild-type 53 signaling such as apoptosis and cell-cycle arrest via induction of p21.	('induction', 'Var', (281, 290))	('cell-cycle arrest', 'CPA', (259, 276))	('5-iminodaunorubicin', 'Chemical', 'MESH:C018979', (111, 130))	('p21', 'Gene', (294, 297))	('apoptosis', 'CPA', (245, 254))	('p21', 'Gene', '644914', (294, 297))
463870	23917221	Furthermore, western blot analysis shows that STAT1 phosphorylation (Tyr701) is seen only in EPC-hTERT-p53R175H-POSTN cells compared with its empty vector control cells and EPC-hTERT-EGFR-POSTN cells, indicating that STAT1 activation is induced in the context of p53 mutation and POSTN (Supplementary Figure S5).	('EPC-hTERT-p53R175H-POSTN', 'Gene', '10631', (93, 117))	('hTERT', 'Gene', '7015', (97, 102))	('mutation', 'Var', (267, 275))	('EPC-hTERT-p53R175H-POSTN', 'Gene', (93, 117))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('Tyr701', 'Chemical', '-', (69, 75))	('hTERT', 'Gene', '7015', (177, 182))	('p53', 'Gene', (263, 266))	('hTERT', 'Gene', (97, 102))	('STAT1 phosphorylation', 'MPA', (46, 67))	('hTERT', 'Gene', (177, 182))
463875	23917221	Interestingly, we observed decreased nuclear STAT1 phosphorylation both in ESCC xenograft tumor cells and stroma with induction of POSTN knockdown by doxycycline (Figures 6a and b).	('decreased', 'NegReg', (27, 36))	('ESCC xenograft tumor', 'Disease', 'MESH:D004938', (75, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ESCC xenograft tumor', 'Disease', (75, 95))	('knockdown', 'Var', (137, 146))	('doxycycline', 'Chemical', 'MESH:D004318', (150, 161))	('nuclear STAT1 phosphorylation', 'MPA', (37, 66))
463876	23917221	Additionally, lysates from these xenograft tumors were analyzed, and we noted that POSTN knockdown in these tumors resulted in decreased STAT1 expression, a concomitant decrease in p53 expression as well as a decrease in downstream STAT1-related genes (Figures 6c and d; Supplementary Figure S8).	('STAT1', 'Gene', (137, 142))	('p53', 'Gene', (181, 184))	('xenograft tumors', 'Disease', (33, 49))	('decreased', 'NegReg', (127, 136))	('decrease', 'NegReg', (169, 177))	('STAT1-related genes', 'Gene', (232, 251))	('expression', 'MPA', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('decrease', 'NegReg', (209, 217))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('xenograft tumors', 'Disease', 'MESH:D009369', (33, 49))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('knockdown', 'Var', (89, 98))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
463879	23917221	Our finding that the propensity for POSTN to invade is mediated by mutant p53R175H, a p53 DBD conformational mutant found in approximately 6% of human cancers, prompted us to test whether this phenotype is recapitulated with other p53 missense mutations.	('p53R175H', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('p53R175H', 'Mutation', 'p.R53,175H', (74, 82))	('invade', 'CPA', (45, 51))	('human', 'Species', '9606', (145, 150))	('mediated', 'Reg', (55, 63))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))	('mutant p53R175H', 'Var', (67, 82))
463880	23917221	Due to the high prevalence of p53 mutations in human cancers, there has been an accelerated interest towards development of therapeutics focused on restoration of wild-type p53 function in tumors.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('p53', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('human', 'Species', '9606', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('mutations', 'Var', (34, 43))
463881	23917221	Small molecule screens have identified promising small molecule compounds that selectively target and stabilize the core DBD of mutant p53 in tumor cells and restores wild-type p53 activities such as apoptosis and proliferation in vitro.	('activities', 'MPA', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('mutant', 'Var', (128, 134))	('p53', 'Gene', (135, 138))	('proliferation', 'CPA', (214, 227))	('restores', 'PosReg', (158, 166))	('apoptosis', 'CPA', (200, 209))
463882	23917221	Interestingly, a recent study demonstrated the therapeutic efficacy of restoring wild-type p53 in p53R172H mice, which corresponds to human p53R175H, suggesting that the removal of mutant p53 dominant-negative effect on functional wild-type p53 can halt tumor growth and subsequent tumor invasion.	('mutant', 'Var', (181, 187))	('human', 'Species', '9606', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('mice', 'Species', '10090', (107, 111))	('halt', 'NegReg', (249, 253))	('removal', 'Var', (170, 177))	('p53', 'Gene', (188, 191))	('p53R175H', 'Mutation', 'p.R53,175H', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('dominant-negative', 'NegReg', (192, 209))
463883	23917221	Using a combination of genetic and pharmacological approaches to restore wild-type p53 activities in invasive cells overexpressing mutant p53, our results of decreased cell motility and invasion are novel.	('invasion', 'CPA', (186, 194))	('p53', 'Gene', (138, 141))	('mutant', 'Var', (131, 137))	('decreased cell motility', 'Disease', 'MESH:D015835', (158, 181))	('activities', 'MPA', (87, 97))	('decreased cell motility', 'Disease', (158, 181))
463885	23917221	Initiation of local invasion and dissemination of aggressive carcinomas is often characterized by alterations in cell adhesion molecules that affect cell-cell/cell-matrix interactions and can occur as a result of crosstalk between malignant tumor cells and various components of surrounding neoplastic stroma such as the ECM, inflammatory and endothelial cells and fibroblasts.	('neoplastic stroma', 'Disease', (291, 308))	('dissemination of aggressive carcinomas', 'Disease', 'MESH:D001523', (33, 71))	('affect', 'Reg', (142, 148))	('tumor', 'Disease', (241, 246))	('dissemination of aggressive carcinomas', 'Disease', (33, 71))	('crosstalk', 'Reg', (213, 222))	('cell-cell/cell-matrix interactions', 'CPA', (149, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('alterations', 'Var', (98, 109))	('cell adhesion molecules', 'Protein', (113, 136))	('neoplastic stroma', 'Disease', 'MESH:D009369', (291, 308))
463895	23917221	Notably, we found that STAT1 is strongly expressed in a cohort of primary human ESCC tumors compared with matched normal tissue, supporting our premise that STAT1 fosters invasiveness of ESCC tumors.	('invasiveness of ESCC tumors', 'Disease', (171, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('STAT1', 'Var', (157, 162))	('ESCC tumors', 'Disease', (80, 91))	('fosters', 'PosReg', (163, 170))	('ESCC tumors', 'Disease', 'MESH:D004938', (80, 91))	('human', 'Species', '9606', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('invasiveness of ESCC tumors', 'Disease', 'MESH:D004938', (171, 198))	('ESCC tumors', 'Disease', 'MESH:D004938', (187, 198))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
463897	23917221	We demonstrated the novel finding that POSTN mediates its invasive capabilities through cooperation with mutant p53R175H.	('p53R175H', 'Mutation', 'p.R53,175H', (112, 120))	('mutant p53R175H', 'Var', (105, 120))	('p53R175H', 'Var', (112, 120))	('invasive capabilities', 'CPA', (58, 79))
463898	23917221	Furthermore, we identified that a STAT1 network acts as an effector of POSTN-mediated tumor invasion as underscored by knockdown of STAT1.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('STAT1', 'Gene', (132, 137))	('knockdown', 'Var', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
463901	23917221	Indeed, we have observed that knockdown of POSTN in ESCC tumor xenografts leads to a significant decrease in the tumor-initiating cell (CD44hiCD24lo) population (Supplementary Figure S10).	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('POSTN', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('knockdown', 'Var', (30, 39))	('decrease', 'NegReg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (57, 62))
463904	23917221	Stable transduction of transformed EPC-hTERT cells with EGFR and p53R175H retroviral vectors is described previously in Okawa et al.	('hTERT', 'Gene', '7015', (39, 44))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (56, 60))	('hTERT', 'Gene', (39, 44))	('p53R175H', 'Var', (65, 73))	('p53R175H', 'Mutation', 'p.R53,175H', (65, 73))
463908	23917221	p53R273H and p53V143A was subcloned into the pBABE-puro retroviral vector.	('p53V143A', 'Var', (13, 21))	('R273H', 'Mutation', 'rs28934576', (3, 8))	('p53R273H', 'Var', (0, 8))
463909	23917221	The R273H p53 mutant was prepared using QuikChange site mutagenesis kit (Agilent Technologies, Redwood, CA, USA) according to the manufacturer's instructions.	('R273H', 'Var', (4, 9))	('R273H', 'Mutation', 'rs28934576', (4, 9))	('p53', 'Gene', (10, 13))	('Redwood', 'Species', '28980', (95, 102))
463910	23917221	The primers used for R273H p53 mutation is as follows: Sense 5'-GCTTTGAGGTGCATGTTTGTGCCACG-3' and antisense 5'-CGTGGGCACAAACATGCACCTCAAAGC-3'.	('R273H', 'Var', (21, 26))	('R273H', 'Mutation', 'rs28934576', (21, 26))	('p53', 'Gene', (27, 30))
463931	21481261	Detection of erbB2 copy number variations in plasma of patients with esophageal carcinoma Mortality is high in patients with esophageal carcinoma as tumors are rarely detected before the disease has progressed to an advanced stage.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('erbB2', 'Gene', '2064', (13, 18))	('copy number variations', 'Var', (19, 41))	('erbB2', 'Gene', (13, 18))	('esophageal carcinoma', 'Disease', (69, 89))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (69, 89))	('tumors', 'Disease', (149, 155))	('esophageal carcinoma', 'Disease', (125, 145))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (69, 89))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (125, 145))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('patients', 'Species', '9606', (55, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (125, 145))	('patients', 'Species', '9606', (111, 119))
463936	21481261	The real-time PCR assays for erbB2 gene showed significant (P = 0.001) copy number variations in the plasma of patients with esophageal carcinoma, as compared to healthy controls with high sensitivity (80%) and specificity (95%).	('copy number variations', 'Var', (71, 93))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (125, 145))	('esophageal carcinoma', 'Disease', (125, 145))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (125, 145))	('erbB2', 'Gene', '2064', (29, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('erbB2', 'Gene', (29, 34))	('patients', 'Species', '9606', (111, 119))
463937	21481261	These variations in erbB2 were negatively correlated to the progression free survival of these patients (P = 0.03), and revealed a further risk category stratification of patients with low VEGF expression levels.	('erbB2', 'Gene', '2064', (20, 25))	('negatively', 'NegReg', (31, 41))	('erbB2', 'Gene', (20, 25))	('patients', 'Species', '9606', (95, 103))	('variations', 'Var', (6, 16))	('VEGF', 'Gene', '7422', (189, 193))	('patients', 'Species', '9606', (171, 179))	('correlated', 'Reg', (42, 52))	('VEGF', 'Gene', (189, 193))	('progression free survival', 'CPA', (60, 85))
463938	21481261	The copy number variation of erbB2 gene from plasma can be used as prognostic marker for early detection of patients at risk of worse clinical outcome in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('copy number variation', 'Var', (4, 25))	('erbB2', 'Gene', '2064', (29, 34))	('patients', 'Species', '9606', (108, 116))	('erbB2', 'Gene', (29, 34))	('esophageal cancer', 'Disease', (154, 171))
463950	21481261	Another study underlined the lack of a prognostic impact of erbB2 amplification in primary ECs.	('amplification', 'Var', (66, 79))	('erbB2', 'Gene', (60, 65))	('EC', 'Phenotype', 'HP:0011459', (91, 93))	('primary ECs', 'Disease', (83, 94))	('erbB2', 'Gene', '2064', (60, 65))
463951	21481261	An additionally study showed gene-specific quantitative PCR amplification of the erbB2 gene in tumor cells from lymph nodes and bone marrow from 98 patients with EC.	('patients', 'Species', '9606', (148, 156))	('EC', 'Phenotype', 'HP:0011459', (162, 164))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('erbB2', 'Gene', '2064', (81, 86))	('PCR amplification', 'Var', (56, 73))	('tumor', 'Disease', (95, 100))	('erbB2', 'Gene', (81, 86))
463954	21481261	While a gain in erbB2 in a single disseminated cancer cell has been shown to be an important risk factor in multivariate analysis, erbB2 amplification in primary tumors was not associated with poor survival both in a group of patients that were analyzed for disseminated cancer cells, and in a study cohort comprising twice as many patients.	('primary tumors', 'Disease', (154, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('primary tumors', 'Disease', 'MESH:D009369', (154, 168))	('amplification', 'Var', (137, 150))	('cancer', 'Disease', (47, 53))	('erbB2', 'Gene', '2064', (16, 21))	('erbB2', 'Gene', '2064', (131, 136))	('patients', 'Species', '9606', (332, 340))	('patients', 'Species', '9606', (226, 234))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('gain', 'PosReg', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('erbB2', 'Gene', (131, 136))	('cancer', 'Disease', (271, 277))	('erbB2', 'Gene', (16, 21))
463955	21481261	Furthermore, erbB2 gene amplification has been demonstrated in the esophageal adenocarcinoma histotype, in 39 patients versus 39 control samples.	('erbB2', 'Gene', '2064', (13, 18))	('esophageal adenocarcinoma', 'Disease', (67, 92))	('erbB2', 'Gene', (13, 18))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (67, 92))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (67, 92))	('amplification', 'Var', (24, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('patients', 'Species', '9606', (110, 118))
463968	21481261	We show that sensitive and fast real-time PCR technology can indeed detect erbB2 CN variations in the free DNA from plasma of EC patients collected before tumors resection and chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('patients', 'Species', '9606', (129, 137))	('EC', 'Phenotype', 'HP:0011459', (126, 128))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('variations', 'Var', (84, 94))	('erbB2', 'Gene', '2064', (75, 80))	('erbB2', 'Gene', (75, 80))	('detect', 'Reg', (68, 74))
463969	21481261	We also show that erbB2 CN variations correlates to VEGF levels and that together can be used as predictive markers for worse clinical outcome.	('VEGF', 'Gene', (52, 56))	('erbB2', 'Gene', '2064', (18, 23))	('variations', 'Var', (27, 37))	('VEGF', 'Gene', '7422', (52, 56))	('erbB2', 'Gene', (18, 23))
464010	21481261	Receiver operating characteristic (ROC) curves and the area under the ROC curves were generated to calculate the specificity and sensitivity of erbB2 CN variation in the healthy controls and the EC patients.	('erbB2', 'Gene', '2064', (144, 149))	('patients', 'Species', '9606', (198, 206))	('EC', 'Phenotype', 'HP:0011459', (195, 197))	('erbB2', 'Gene', (144, 149))	('variation', 'Var', (153, 162))
464021	21481261	The association of the erbB2 CN variations with the clinicopathological characteristics of the EC patients are summarized in the Additional file 1: Supplemental table S1.	('EC', 'Phenotype', 'HP:0011459', (95, 97))	('patients', 'Species', '9606', (98, 106))	('men', 'Species', '9606', (154, 157))	('erbB2', 'Gene', '2064', (23, 28))	('variations', 'Var', (32, 42))	('erbB2', 'Gene', (23, 28))
464026	21481261	We used Kaplan-Meier analyses to look for correlations between the erbB2 CN variations and EC patient progression-free survival.	('EC', 'Phenotype', 'HP:0011459', (91, 93))	('variations', 'Var', (76, 86))	('patient', 'Species', '9606', (94, 101))	('erbB2', 'Gene', '2064', (67, 72))	('erbB2', 'Gene', (67, 72))
464031	21481261	In further analyses according to the tumor grading, the EC patients with a tumor grading G2 can be further stratified according to erbB2 CN <=2 and erbB2 CN >2, which were again significantly negatively correlated to the survival rates of these EC patients (P = 0.03; Figure 2B).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('EC', 'Phenotype', 'HP:0011459', (245, 247))	('survival', 'CPA', (221, 229))	('tumor', 'Disease', (75, 80))	('CN >2', 'Var', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('patients', 'Species', '9606', (59, 67))	('negatively', 'NegReg', (192, 202))	('CN <=2', 'Var', (137, 143))	('erbB2', 'Gene', '2064', (148, 153))	('erbB2', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('EC', 'Phenotype', 'HP:0011459', (56, 58))	('patients', 'Species', '9606', (248, 256))	('erbB2', 'Gene', '2064', (131, 136))	('tumor', 'Disease', (37, 42))	('erbB2', 'Gene', (131, 136))	('correlated', 'Reg', (203, 213))
464033	21481261	Here, erbB2 CN variations were significantly correlated to the survival rates of the adenocarcinoma cases (P = 0.03; Figure 2C).	('erbB2', 'Gene', '2064', (6, 11))	('adenocarcinoma', 'Disease', (85, 99))	('erbB2', 'Gene', (6, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))	('variations', 'Var', (15, 25))	('correlated', 'Reg', (45, 55))
464038	21481261	The erbB2 CN variations did not show any significant direct associations with VEGF levels in the plasma (Figure 4A).	('erbB2', 'Gene', '2064', (4, 9))	('variations', 'Var', (13, 23))	('erbB2', 'Gene', (4, 9))	('VEGF', 'Gene', (78, 82))	('associations', 'Interaction', (60, 72))	('VEGF', 'Gene', '7422', (78, 82))
464060	21481261	Thus, the data in this TOGA trial showed that trastuzumab with chemotherapy is superior to chemotherapy alone, with median overall survival significantly improved with trastuzumab compared to chemotherapy alone: 13.5 versus 11.1 months, respectively.	('trastuzumab', 'Var', (168, 179))	('improved', 'PosReg', (154, 162))	('trastuzumab', 'Chemical', 'MESH:D000068878', (168, 179))	('overall survival', 'MPA', (123, 139))	('trastuzumab', 'Chemical', 'MESH:D000068878', (46, 57))
464068	21481261	We have here identified erbB2 CN variations in the cell-free DNA of 41 patients with EC in comparison with 34 healthy controls.	('erbB2', 'Gene', '2064', (24, 29))	('erbB2', 'Gene', (24, 29))	('patients', 'Species', '9606', (71, 79))	('EC', 'Phenotype', 'HP:0011459', (85, 87))	('variations', 'Var', (33, 43))
464086	21481261	The EC patients with erbB2 CN <=2 showed a better survival with respect to those with CN >2 erbB2.	('CN <=2', 'Var', (27, 33))	('erbB2', 'Gene', '2064', (21, 26))	('erbB2', 'Gene', (21, 26))	('EC', 'Phenotype', 'HP:0011459', (4, 6))	('better', 'PosReg', (43, 49))	('erbB2', 'Gene', '2064', (92, 97))	('survival', 'CPA', (50, 58))	('patients', 'Species', '9606', (7, 15))	('erbB2', 'Gene', (92, 97))
464088	21481261	These data emphasize the results obtained by Mimura et al., that found an association only between the survival rate and the erbB2 gene amplification (7 positive patients versus 59 negative patients) detected by fluorescence in situ hybridization (FISH) method and not between the survival rate and positive or negative erbB2 staining detected by immunohistochemistry assay.	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (190, 198))	('erbB2', 'Gene', '2064', (125, 130))	('erbB2', 'Gene', (125, 130))	('erbB2', 'Gene', '2064', (320, 325))	('amplification', 'Var', (136, 149))	('erbB2', 'Gene', (320, 325))
464089	21481261	Furthermore, Kuwabara et al., also demonstrated the correspondence between gene amplification (analyzed by FISH) and protein expression (analyzed by immunohistochemistry) of erbB2, underlining that gene amplification is an indicator of poor prognosis in esophageal carcinoma.	('erbB2', 'Gene', '2064', (174, 179))	('erbB2', 'Gene', (174, 179))	('esophageal carcinoma', 'Disease', (254, 274))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (254, 274))	('gene amplification', 'Var', (198, 216))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (254, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
464090	21481261	In particular, we found that an erbB2 CN >2 was correlated to a worst survival rate in the adenocarcinoma histotype.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('CN >2', 'Var', (38, 43))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('erbB2', 'Gene', '2064', (32, 37))	('erbB2', 'Gene', (32, 37))	('adenocarcinoma', 'Disease', (91, 105))
464094	21481261	We also confirmed the importance of the VEGF expression in our dataset, demonstrating that high VEGF expression impairs the survival rate of these EC patients.	('impairs', 'NegReg', (112, 119))	('high', 'Var', (91, 95))	('VEGF', 'Gene', (40, 44))	('survival rate', 'CPA', (124, 137))	('VEGF', 'Gene', '7422', (96, 100))	('patients', 'Species', '9606', (150, 158))	('EC', 'Phenotype', 'HP:0011459', (147, 149))	('VEGF', 'Gene', '7422', (40, 44))	('expression', 'MPA', (101, 111))	('VEGF', 'Gene', (96, 100))
464099	21481261	Thus, inhibition of erbB2 activity might represent a new avenue for successful inhibition of potential metastasis formation, and represents a new therapeutic target for future personalized cancer therapies.	('erbB2', 'Gene', '2064', (20, 25))	('potential metastasis formation', 'CPA', (93, 123))	('erbB2', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('inhibition', 'NegReg', (79, 89))	('inhibition', 'Var', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('activity', 'MPA', (26, 34))	('cancer', 'Disease', (189, 195))
464100	21481261	These data indicate the association between erbB2 CN variations and progression-free survival in these patients with EC.	('erbB2', 'Gene', '2064', (44, 49))	('erbB2', 'Gene', (44, 49))	('association', 'Interaction', (24, 35))	('variations', 'Var', (53, 63))	('EC', 'Phenotype', 'HP:0011459', (117, 119))	('patients', 'Species', '9606', (103, 111))	('progression-free survival', 'CPA', (68, 93))
464103	21481261	EC: esophageal carcinoma; CN: copy number variations; CTCs: circulating tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('esophageal carcinoma', 'Disease', (4, 24))	('tumor', 'Disease', (72, 77))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (4, 24))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (4, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('copy number variations', 'Var', (30, 52))	('EC', 'Phenotype', 'HP:0011459', (0, 2))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
464172	30057371	Several meta-analyses have confirmed that the gene variants of caspases-2, 5, 7, 8, 9 and 10 disturbed the apoptotic mechanism and thus affected the risk of some cancers[-].	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Disease', (162, 169))	('affected', 'Reg', (136, 144))	('variants', 'Var', (51, 59))	('disturbed', 'Reg', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('apoptotic mechanism', 'CPA', (107, 126))	('caspases-2', 'Gene', (63, 73))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
464174	30057371	It has been reported that polymorphic variation in CASP8 influences cancer risk, such as the variant D302H (rs1045485), the 652 6N insertion/deletion (ins/del) promoter variant (rs3834129), and the IVS12-19G/A (rs3769818).	('rs1045485', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs3769818', 'Var', (211, 220))	('IVS12-19G/A (rs3769818', 'Var', (198, 220))	('D302H', 'Mutation', 'rs1045485', (101, 106))	('D302H (rs1045485', 'Var', (101, 117))	('rs3834129', 'Var', (178, 187))	('CASP8', 'Gene', (51, 56))	('rs3769818', 'Mutation', 'rs3769818', (211, 220))	('rs3834129', 'Mutation', 'rs3834129', (178, 187))	('cancer risk', 'CPA', (68, 79))	('influences', 'Reg', (57, 67))	('IVS12-19G/A', 'Mutation', 'rs3769818', (198, 209))	('polymorphic', 'Var', (26, 37))	('rs1045485', 'Mutation', 'rs1045485', (108, 117))
464177	30057371	We carried out a search in PubMed and Embase databases with the following keywords: ('CASP8' or 'caspase-8', or 'rs3834129', 'cancer' or 'neoplasm' or 'carcinoma' or 'tumor' and 'polymorphism' or 'single nucleotide polymorphisms' or 'SNPs' (last search was updated on Dec 31, 2015).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('rs3834129', 'Var', (113, 122))	("'neoplasm'", 'Phenotype', 'HP:0002664', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('rs3834129', 'DBSNP_MENTION', 'None', (113, 122))	('tumor', 'Disease', (167, 172))
464183	30057371	Previous studies found that genetic mutations of caspases 8 in tumor cells reduce the cell sensitivity to apoptosis, which may be related to the occurrence and development of tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('reduce', 'NegReg', (75, 81))	('caspases', 'Protein', (49, 57))	('cell sensitivity to apoptosis', 'CPA', (86, 115))	('genetic mutations', 'Var', (28, 45))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
464184	30057371	reached a similar conclusion that CASP8 -652 6N ins/del polymorphism may play a protective role in colorectal cancer development.	('colorectal cancer', 'Disease', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CASP8 -652', 'Gene', (34, 44))	('6N ins/del polymorphism', 'Var', (45, 68))	('-652 6N ins/del', 'Mutation', 'rs3834129', (40, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
464211	30314454	It has further been demonstrated that that high expression of vimentin and FN is associated with advanced stage and poor prognosis in ESCC.	('FN', 'Gene', '2335', (75, 77))	('high', 'Var', (43, 47))	('vimentin', 'Gene', (62, 70))	('ESCC', 'Disease', (134, 138))	('associated', 'Reg', (81, 91))	('vimentin', 'Gene', '7431', (62, 70))
464294	29179470	Inhibition of STAT3 also suppressed the growth and colony formation, and induced apoptosis in the esophageal squamous cell carcinoma cells containing constitutively activated STAT3.	('STAT3', 'Gene', (14, 19))	('esophageal squamous cell carcinoma', 'Disease', (98, 132))	('apoptosis', 'CPA', (81, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('suppressed', 'NegReg', (25, 35))	('Inhibition', 'Var', (0, 10))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (98, 132))	('induced', 'Reg', (73, 80))
464295	29179470	Furthermore, the STAT3 inhibitor effectively blocked the growth of patient-derived tumor xenografts that harbored phosphorylated STAT3, but acted less effective on the xenografts derived from primary tumors that contained low levels of activated STAT3.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('phosphorylated STAT3', 'Var', (114, 134))	('primary tumors', 'Disease', (192, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (83, 88))	('primary tumors', 'Disease', 'MESH:D009369', (192, 206))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', (200, 205))	('growth', 'CPA', (57, 63))	('blocked', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('patient', 'Species', '9606', (67, 74))
464305	29179470	These data indicate that constitutively activated STAT3 plays a critical role in ESCC and targeting STAT3 is a potential effective therapeutic strategy for the cancer.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('ESCC', 'Disease', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('targeting', 'Var', (90, 99))
464307	29179470	Among the 7 tumors samples from patients with ESCC, 6 of them clearly expressed STAT3 and p-STAT3 (Tyr-705) when examined by immunoblotting (Figure 1A).	('ESCC', 'Disease', (46, 50))	('patients', 'Species', '9606', (32, 40))	('expressed', 'Reg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('Tyr', 'Chemical', 'MESH:D014443', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('p-STAT3 (Tyr-705', 'Var', (90, 106))	('STAT3', 'Var', (80, 85))
464310	29179470	To further explore the role of activated STAT3 in esophageal cancers, 8 different ESCC cell lines were examined by immunoblotting using the anti-STAT3 and anti-phosphorylated STAT3 (Tyr-705) antibodies.	('esophageal cancers', 'Disease', 'MESH:D004938', (50, 68))	('Tyr-705', 'Var', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancers', 'Disease', (50, 68))	('Tyr', 'Chemical', 'MESH:D014443', (182, 185))
464311	29179470	While most of the cells expressed STAT3, TE1 and TE13 contained high level of phosphorylated STAT3, and Eca109, EC9706, and KYSE450 had relative low but detectable levels of pSTAT3 (Figure 1B).	('phosphorylated STAT3', 'MPA', (78, 98))	('EC9706', 'CellLine', 'CVCL:E307', (112, 118))	('pSTAT3', 'MPA', (174, 180))	('EC9706', 'Var', (112, 118))
464319	29179470	While the level of Cox2, upregulated by activated STAT3 in the cells, is decreased in TE13 and EC9706 upon Stattic treatment, the level of iNOS and pentraxin-3, whose expression were negatively regulated by p-STAT3, were increased in Stattic-treated cells.	('level', 'MPA', (130, 135))	('TE13', 'Var', (86, 90))	('EC9706', 'CellLine', 'CVCL:E307', (95, 101))	('pentraxin-3', 'Gene', '5806', (148, 159))	('decreased', 'NegReg', (73, 82))	('level', 'MPA', (10, 15))	('pentraxin-3', 'Gene', (148, 159))	('increased', 'PosReg', (221, 230))	('upregulated', 'PosReg', (25, 36))	('EC9706', 'Var', (95, 101))
464333	29179470	After these mice were sacrificed by the end of the 2nd week, the volume of the tumors from mice received Stattic were less than one fourth of that from mice given the vehicle (Figure 4B).	('mice', 'Species', '10090', (91, 95))	('less', 'NegReg', (118, 122))	('Stattic', 'Var', (105, 112))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mice', 'Species', '10090', (152, 156))	('mice', 'Species', '10090', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
464334	29179470	5-FU also had notable effect in inhibiting the growth of the xenografts, although it appeared significantly less effective compared with Stattic under these experimental conditions.	('inhibiting', 'NegReg', (32, 42))	('5-FU', 'Var', (0, 4))	('5-FU', 'Chemical', 'MESH:D005472', (0, 4))	('growth of the xenografts', 'CPA', (47, 71))
464335	29179470	Noteworthily, Stattic and 5-FU together had strong synergistic anti-tumor action, leading to significant greater tumor growth inhibition.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (113, 118))	('5-FU', 'Chemical', 'MESH:D005472', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Stattic', 'Var', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('greater', 'PosReg', (105, 112))
464342	29179470	Interestingly, while PDX from primary tumors EG30 and EG37 were more sensitive to Stattic than 5-FU, xenografts derived from primary tumors EG2 and EG14 were significantly more sensitive to 5-FU, and were only moderately susceptible to the inhibitory action of Stattic (Figure 5A & 5B and Supplementary Figure 2A & 2B).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('sensitive', 'MPA', (177, 186))	('5-FU', 'Chemical', 'MESH:D005472', (95, 99))	('primary tumors', 'Disease', 'MESH:D009369', (30, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('primary tumors', 'Disease', (125, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EG30', 'Var', (45, 49))	('primary tumors', 'Disease', 'MESH:D009369', (125, 139))	('5-FU', 'Chemical', 'MESH:D005472', (190, 194))	('more', 'PosReg', (172, 176))	('5-FU', 'MPA', (190, 194))	('sensitive', 'MPA', (69, 78))	('primary tumors', 'Disease', (30, 44))
464344	29179470	Immunohistochemical analysis showed that 5-FU induced a significant increase of activated caspase-3 and TUNEL-positive cells, whereas the increases induced by Stattic were more moderate (Figure 5D and Supplementary Figure 2D).	('activated', 'CPA', (80, 89))	('5-FU', 'Var', (41, 45))	('caspase-3', 'Gene', (90, 99))	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('caspase-3', 'Gene', '836', (90, 99))	('increase', 'PosReg', (68, 76))	('TUNEL-positive cells', 'CPA', (104, 124))
464345	29179470	Taken together, these data demonstrated that activated STAT3 is required for the growth and survival of the tumors that contained high level of the protein, and targeting pSTAT3 could be an effective strategy for the treatment of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('pSTAT3', 'Gene', (171, 177))	('targeting', 'Var', (161, 170))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('tumors', 'Disease', 'MESH:D009369', (236, 242))
464348	29179470	Compared with that of EG2 and EG14, the expression of NAV2, KIRRET3, and EPHA7 was significantly elevated in xenografts of EG37 (Figure 6D), whereas that of BNC1, TNFSF18, and PROS1 was significantly decreased (Figure 6E).	('elevated', 'PosReg', (97, 105))	('expression', 'MPA', (40, 50))	('BNC1', 'Gene', (157, 161))	('NAV2', 'Gene', (54, 58))	('KIRRET3', 'Gene', (60, 67))	('EPHA7', 'Gene', '2045', (73, 78))	('BNC1', 'Gene', '646', (157, 161))	('PROS1', 'Gene', (176, 181))	('NAV2', 'Gene', '89797', (54, 58))	('TNFSF18', 'Gene', (163, 170))	('PROS1', 'Gene', '5627', (176, 181))	('decreased', 'NegReg', (200, 209))	('TNFSF18', 'Gene', '8995', (163, 170))	('EPHA7', 'Gene', (73, 78))	('EG37', 'Var', (123, 127))
464357	29179470	COX-2 inhibition led to decreased cell proliferation, PGE2 production and overall tumor progression in vitro and in vivo.	('decreased', 'NegReg', (24, 33))	('cell proliferation', 'CPA', (34, 52))	('PGE2 production', 'MPA', (54, 69))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('COX-2', 'Gene', '4513', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibition', 'Var', (6, 16))	('COX-2', 'Gene', (0, 5))	('tumor', 'Disease', (82, 87))	('PGE2', 'Chemical', 'MESH:D015232', (54, 58))
464372	29179470	ESCC cell lines, EC1, Eca109, EC9706, KYSE 70 and KYSE 140 were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS) (Hyclone, UT), 100U/ml penicillin, and 100mug/ml streptomycin.	('EC9706', 'CellLine', 'CVCL:E307', (30, 36))	('EC1', 'Gene', (17, 20))	('FBS', 'Disease', (128, 131))	('EC1', 'Gene', '4819', (17, 20))	('EC9706', 'Var', (30, 36))	('FBS', 'Disease', 'MESH:D005198', (128, 131))	('bovine', 'Species', '9913', (114, 120))	('streptomycin', 'Chemical', 'MESH:D013307', (182, 194))	('RPMI', 'Chemical', '-', (76, 80))	('penicillin', 'Chemical', 'MESH:D010406', (156, 166))
464401	27154178	Patients with a high RDW had a significantly poorer prognosis in terms of CSS than those with a low RDW (p = 0.004).	('high RDW', 'Var', (16, 24))	('CSS', 'Chemical', '-', (74, 77))	('CSS', 'CPA', (74, 77))	('Patients', 'Species', '9606', (0, 8))
464402	27154178	Among non-elderly patients, multivariate analysis demonstrated that pStage (p = 0.0120), and a high RDW (p = 0.0092) were independent risk factors for a worse prognosis.	('patients', 'Species', '9606', (18, 26))	('high RDW', 'Var', (95, 103))	('pStage', 'MPA', (68, 74))
464403	27154178	In addition, non-elderly patients with a high RDW had a significantly poorer prognosis in terms of CSS than those with a low RDW (p = 0.0003).	('poorer', 'NegReg', (70, 76))	('CSS', 'Disease', (99, 102))	('high RDW', 'Var', (41, 49))	('CSS', 'Chemical', '-', (99, 102))	('patients', 'Species', '9606', (25, 33))
464405	27154178	We confirmed that a high RDW was significantly associated with the CSS of esophageal cancer patients after curative esophagectomy.	('CSS', 'Disease', (67, 70))	('associated with', 'Reg', (47, 62))	('CSS', 'Chemical', '-', (67, 70))	('patients', 'Species', '9606', (92, 100))	('esophageal cancer', 'Disease', (74, 91))	('high RDW', 'Var', (20, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
464430	27154178	Patients with a RDW, PDW, or MPV greater than these cut-off values were considered to have a high RDW, PDW, and MPV, while the remaining patients were considered to have a low RDW, PDW, and MPV, respectively.	('RDW', 'MPA', (98, 101))	('patients', 'Species', '9606', (137, 145))	('PDW', 'MPA', (103, 106))	('Patients', 'Species', '9606', (0, 8))	('MPV', 'Var', (112, 115))
464434	27154178	The potential prognostic factors for esophageal cancer were age (<70 vs >=70 years), sex (female vs male), pathological stage (pStage; I/II vs III), tumor size (<3 cm vs >=3 cm), operation time (<600 min vs >=600 min), intraoperative blood loss (<500 mL vs >=500 mL), serum squamous cell carcinoma antigen (SCC) value (<1.5 vs >=1.5), RDW (<50 vs >=50), PDW (<15.3 vs >=15.3), and MPV (<11.5 vs >=11.5).	('RDW', 'MPA', (335, 338))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('intraoperative blood loss', 'Disease', (219, 244))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('tumor', 'Disease', (149, 154))	('esophageal cancer', 'Disease', (37, 54))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (274, 297))	('<50', 'Var', (340, 343))	('squamous cell carcinoma', 'Disease', (274, 297))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (219, 244))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
464440	27154178	Patients with a high RDW had a significantly poorer prognosis in terms of CSS than those with a low RDW (p = 0.004) (Fig.	('high RDW', 'Var', (16, 24))	('CSS', 'Chemical', '-', (74, 77))	('CSS', 'Disease', (74, 77))	('Patients', 'Species', '9606', (0, 8))
464445	27154178	Non-elderly patients with a high RDW had a significantly poorer prognosis in terms of CSS than those with a low RDW (p = 0.0003) (Fig.	('CSS', 'Chemical', '-', (86, 89))	('patients', 'Species', '9606', (12, 20))	('CSS', 'Disease', (86, 89))	('high RDW', 'Var', (28, 36))	('poorer', 'NegReg', (57, 63))
464463	27154178	Univariate and multivariate analyses demonstrated that a high RDW was independently associated with poor prognosis in esophageal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('high RDW', 'Var', (57, 65))	('patients', 'Species', '9606', (136, 144))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))
464488	27154178	A high RDW may by correlated with tumor depth and pathological stage in advanced-staged esophageal cancer patients.	('correlated', 'Reg', (18, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('tumor', 'Disease', (34, 39))	('high', 'Var', (2, 6))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('esophageal cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
464492	27154178	In conclusion, we confirmed that a high RDW was associated with the CSS of esophageal cancer patients after curative esophagectomy.	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('CSS', 'Disease', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('associated with', 'Reg', (48, 63))	('high RDW', 'Var', (35, 43))	('CSS', 'Chemical', '-', (68, 71))	('esophageal cancer', 'Disease', (75, 92))	('patients', 'Species', '9606', (93, 101))
464541	27716069	Of those gastric cancer patients under age 46, which was 99 (9.8 %) patients, the distribution of UGI cancer within age groups was as follows: under age 26, 9 patients (0.9 %); age 26-35, 30 patients (3 %); and age 36-45, 60 patients (6 %).	('under age 26', 'Var', (143, 155))	('UGI cancer', 'Disease', 'MESH:D009369', (98, 108))	('patients', 'Species', '9606', (191, 199))	('gastric cancer', 'Disease', (9, 23))	('patients', 'Species', '9606', (225, 233))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (9, 23))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (68, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (9, 23))	('UGI cancer', 'Disease', (98, 108))	('patients', 'Species', '9606', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
464638	26819644	MOLs appear to have an adverse prognostic effect in patients with ESCC, although currently there are no independent reports of this effect.	('SCC', 'Gene', (67, 70))	('MOLs', 'Var', (0, 4))	('SCC', 'Gene', '6317', (67, 70))	('patients', 'Species', '9606', (52, 60))
464678	26819644	studied postoperative pathological results in 95 patients with clinical T1-T3N0M0 thoracic esophageal cancers.	('thoracic esophageal cancers', 'Disease', 'MESH:D004938', (82, 109))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('T1-T3N0M0', 'Var', (72, 81))	('thoracic esophageal cancers', 'Disease', (82, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('patients', 'Species', '9606', (49, 57))
464770	25375090	Moreover, we demonstrated that miR-9 interacted with the 3'-untranslated region of E-cadherin and down-regulated its expression, which induced beta-catenin nuclear translocation and subsequently up-regulated c-myc and CD44 expression.	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('CD44', 'Gene', '960', (218, 222))	('beta-catenin', 'Gene', '1499', (143, 155))	('induced', 'Reg', (135, 142))	('CD44', 'Gene', (218, 222))	('expression', 'MPA', (223, 233))	('expression', 'MPA', (117, 127))	('c-myc', 'Gene', '4609', (208, 213))	('miR-9', 'Var', (31, 36))	('beta-catenin', 'Gene', (143, 155))	('up-regulated', 'PosReg', (195, 207))	('c-myc', 'Gene', (208, 213))	('down-regulated', 'NegReg', (98, 112))
464772	25375090	Taken together, our study demonstrates that miR-9 plays an important role in ESCC metastasis by activating beta-catenin pathway and inducing EMT via targeting E-cadherin.	('E-cadherin', 'Gene', '999', (159, 169))	('EMT', 'CPA', (141, 144))	('beta-catenin', 'Gene', (107, 119))	('ESCC metastasis', 'Disease', (77, 92))	('miR-9', 'Var', (44, 49))	('inducing', 'PosReg', (132, 140))	('activating', 'PosReg', (96, 106))	('beta-catenin', 'Gene', '1499', (107, 119))	('targeting', 'Reg', (149, 158))	('E-cadherin', 'Gene', (159, 169))
464780	25375090	Although E-cadherin has been documented as a target of miR-9 in breast cancer, we further demonstrated that miR-9 directly targeted the 3'-UTR of E-Cadherin and activated the beta-catenin signaling pathway in ESCC.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('E-cadherin', 'Gene', '999', (9, 19))	('breast cancer', 'Disease', (64, 77))	('E-Cadherin', 'Gene', '999', (146, 156))	('beta-catenin', 'Gene', '1499', (175, 187))	('activated', 'PosReg', (161, 170))	('ESCC', 'Disease', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('beta-catenin', 'Gene', (175, 187))	('E-cadherin', 'Gene', (9, 19))	('E-Cadherin', 'Gene', (146, 156))	('miR-9', 'Var', (108, 113))
464791	25375090	Foci formation and tumor formation in nude mice showed that miR-9 could increase number of foci formed and promote tumor growth in tested mice in KYSE410 cells, but not in HKESC1 cells (Figure 2B and 2C).	('mice', 'Species', '10090', (43, 47))	('increase', 'PosReg', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('miR-9', 'Var', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', (115, 120))	('mice', 'Species', '10090', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('nude mice', 'Species', '10090', (38, 47))	('tumor', 'Disease', (19, 24))	('number of foci formed', 'CPA', (81, 102))	('promote', 'PosReg', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('HKESC1', 'CellLine', 'CVCL:D568', (172, 178))
464792	25375090	Cell migration assay showed that miR-9 could significantly increase cell motility in HKESC1 and KYSE410 cells compared with the empty vector-transfected cells (P < 0.01, Figure 3A).	('cell motility', 'CPA', (68, 81))	('miR-9', 'Var', (33, 38))	('HKESC1', 'CellLine', 'CVCL:D568', (85, 91))	('increase', 'PosReg', (59, 67))
464793	25375090	When endogenous miR-9 was silenced by a siRNA against miR-9 in KYSE30 and KYSE510 cells (Figure 3B), the number of migrated cells decreased significantly compared with scramble siRNA-transfected control cells (P < 0.01, Figure 3C).	('KYSE510', 'Var', (74, 81))	('KYSE510', 'CellLine', 'CVCL:1354', (74, 81))	('miR-9', 'Gene', (16, 21))	('miR-9', 'Gene', (54, 59))	('silenced', 'NegReg', (26, 34))	('number of migrated cells', 'CPA', (105, 129))	('decreased', 'NegReg', (130, 139))
464802	25375090	The pulmonary metastatic nodules induced by 410-miR-9 cells could be only observed in one mouse whereas no visible tumor nodule was observed in 410-Vec mice (Figure 3F).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('mouse', 'Species', '10090', (90, 95))	('pulmonary metastatic nodules', 'CPA', (4, 32))	('mice', 'Species', '10090', (152, 156))	('410-miR-9', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
464805	25375090	3'-UTR of E-cadherin mRNA contains one complementary site for miR-9.	('miR-9', 'Var', (62, 67))	('E-cadherin', 'Gene', '999', (10, 20))	('E-cadherin', 'Gene', (10, 20))
464807	25375090	qRT-PCR and western blotting results showed that expression of E-cadherin was significantly reduced in HKESC1 and KYSE410 when miR-9 was stably transfected into these cells compared with empty vector-transfected control cells (P < 0.01, Figure 4A).	('HKESC1', 'CellLine', 'CVCL:D568', (103, 109))	('E-cadherin', 'Gene', '999', (63, 73))	('expression', 'MPA', (49, 59))	('HKESC1', 'Gene', (103, 109))	('reduced', 'NegReg', (92, 99))	('E-cadherin', 'Gene', (63, 73))	('KYSE410', 'Var', (114, 121))
464809	25375090	A luciferase reporter assay was then performed to verify whether E-cadherin is the direct target of miR-9.	('miR-9', 'Var', (100, 105))	('E-cadherin', 'Gene', (65, 75))	('E-cadherin', 'Gene', '999', (65, 75))
464811	25375090	Decreased luciferase activity in miR-9 overexpressed cells was observed compared with the control cell (Figure 4C), indicating that E-cadherin was a downstream target of miR-9.	('E-cadherin', 'Gene', (132, 142))	('E-cadherin', 'Gene', '999', (132, 142))	('miR-9', 'Gene', (33, 38))	('luciferase', 'Enzyme', (10, 20))	('Decreased', 'NegReg', (0, 9))	('overexpressed', 'Var', (39, 52))	('activity', 'MPA', (21, 29))
464823	25375090	IF result showed that beta-catenin translocation from the cell membrane to nucleus was observed in both miR-9-transfected HKESC1 and KYSE410 cells, whereas beta-catenin was mainly located on the membrane in the empty vector-transfected cells (Figure 5A).	('beta-catenin', 'Gene', '1499', (22, 34))	('miR-9-transfected', 'Var', (104, 121))	('beta-catenin', 'Gene', (156, 168))	('HKESC1', 'CellLine', 'CVCL:D568', (122, 128))	('beta-catenin', 'Gene', (22, 34))	('beta-catenin', 'Gene', '1499', (156, 168))	('translocation', 'MPA', (35, 48))	('observed', 'Reg', (87, 95))
464827	25375090	When miR-9 was knocked down in KYSE30 and KYSE510 cells, the protein levels of c-myc, CD44 and VEGF were decreased (Figure 5C).	('CD44', 'Gene', (86, 90))	('knocked down', 'Var', (15, 27))	('VEGF', 'Gene', '7422', (95, 99))	('c-myc', 'Gene', '4609', (79, 84))	('c-myc', 'Gene', (79, 84))	('miR-9', 'Gene', (5, 10))	('VEGF', 'Gene', (95, 99))	('CD44', 'Gene', '960', (86, 90))	('KYSE510', 'CellLine', 'CVCL:1354', (42, 49))	('decreased', 'NegReg', (105, 114))
464841	25375090	In the present study, E-cadherin was down-regulated in miR-9 overexpressed cells and up-regulated when endogenous miR-9 was silenced.	('miR-9', 'Gene', (55, 60))	('up-regulated', 'PosReg', (85, 97))	('E-cadherin', 'Gene', (22, 32))	('E-cadherin', 'Gene', '999', (22, 32))	('overexpressed', 'Var', (61, 74))	('down-regulated', 'NegReg', (37, 51))
464849	25375090	It was also reported that loss of E-cadherin activates EGFR-MEK/ERK signaling and promotes invasion in non-small cell lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('EGFR', 'Gene', '1956', (55, 59))	('activates', 'PosReg', (45, 54))	('MEK', 'Gene', '5609', (60, 63))	('promotes', 'PosReg', (82, 90))	('invasion', 'CPA', (91, 99))	('EGFR', 'Gene', (55, 59))	('ERK', 'Gene', '5594', (64, 67))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (103, 129))	('E-cadherin', 'Gene', (34, 44))	('E-cadherin', 'Gene', '999', (34, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('ERK', 'Gene', (64, 67))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (103, 129))	('loss', 'Var', (26, 30))	('non-small cell lung cancer', 'Disease', (103, 129))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))	('MEK', 'Gene', (60, 63))
464857	25375090	Changes of 2 mesenchymal markers (Vimentin and Fibronectin) were also detected in miR-9 overexpressed and silenced cells, suggesting that the metastatic effect of miR-9 was via inducing EMT in ESCC.	('miR-9', 'Var', (163, 168))	('ESCC', 'Disease', (193, 197))	('Vimentin', 'Gene', (34, 42))	('Fibronectin', 'Gene', '2335', (47, 58))	('Vimentin', 'Gene', '7431', (34, 42))	('Fibronectin', 'Gene', (47, 58))	('inducing', 'PosReg', (177, 185))	('metastatic effect', 'CPA', (142, 159))	('EMT', 'CPA', (186, 189))
464859	25375090	Six ESCC cell lines (KYSE30, KYSE140, KYSE180, KYSE410, KYSE510, and KYSE520) were obtained from DSMZ (Braunschweig, Germany), the German Resource Centre for Biological Material.	('KYSE510', 'CellLine', 'CVCL:1354', (56, 63))	('KYSE410', 'Var', (47, 54))	('KYSE30', 'Var', (21, 27))	('KYSE520', 'Var', (69, 76))	('KYSE510', 'Var', (56, 63))	('KYSE140', 'Var', (29, 36))	('KYSE180', 'Var', (38, 45))
464897	32461336	Here, we provide evidence that loss of SPINK7 mediates its pro-EoE effects via kallikrein 5 (KLK5) and its substrate, protease-activated receptor 2 (PAR2).	('SPINK7', 'Gene', (39, 45))	('loss', 'Var', (31, 35))	('protease-activated receptor 2', 'Gene', '14063', (118, 147))	('kallikrein 5', 'Gene', '68668', (79, 91))	('EoE', 'Phenotype', 'HP:0410151', (63, 66))	('kallikrein 5', 'Gene', (79, 91))	('protease-activated receptor 2', 'Gene', (118, 147))	('pro-EoE effects', 'MPA', (59, 74))
464898	32461336	Overexpression of KLK5 in differentiated esophageal epithelial cells recapitulated the effect of SPINK7 gene silencing, including barrier impairment and loss of desmoglein-1 expression.	('desmoglein-1', 'Gene', '13510', (161, 173))	('SPINK7', 'Gene', (97, 103))	('expression', 'MPA', (174, 184))	('loss', 'NegReg', (153, 157))	('gene', 'Var', (104, 108))	('desmoglein-1', 'Gene', (161, 173))
464900	32461336	Inhibition of PAR2 blunted the cytokine production associated with loss of SPINK7 in epithelial cells and attenuated the allergen-induced esophageal eosinophilia in vivo.	('attenuated', 'NegReg', (106, 116))	('blunted', 'NegReg', (19, 26))	('PAR2', 'Gene', (14, 18))	('cytokine production', 'MPA', (31, 50))	('SPINK7', 'Gene', (75, 81))	('esophageal eosinophilia', 'Disease', (138, 161))	('loss', 'Var', (67, 71))	('eosinophilia', 'Phenotype', 'HP:0001880', (149, 161))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (138, 161))
464901	32461336	Clinical samples substantiated dysregulated PAR2 expression in the esophagus of patients with EoE, and delivery of the clinically approved drug alpha1 antitrypsin (A1AT, a protease inhibitor) inhibited experimental EoE.	('dysregulated', 'Var', (31, 43))	('experimental EoE', 'Disease', (202, 218))	('alpha1 antitrypsin', 'Gene', '5265', (144, 162))	('patients', 'Species', '9606', (80, 88))	('A1AT', 'Gene', '5265', (164, 168))	('expression', 'MPA', (49, 59))	('inhibited', 'NegReg', (192, 201))	('alpha1 antitrypsin', 'Gene', (144, 162))	('EoE', 'Phenotype', 'HP:0410151', (94, 97))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('A1AT', 'Gene', (164, 168))	('PAR2', 'Gene', (44, 48))	('EoE', 'Phenotype', 'HP:0410151', (215, 218))
464911	32461336	As a control, loss of SPINK7 did not modify expression of serine proteases like KLKs (fig.	('serine protease', 'Gene', '50908', (58, 73))	('loss', 'Var', (14, 18))	('serine protease', 'Gene', (58, 73))	('SPINK7', 'Gene', (22, 28))
464923	32461336	Overexpression of KLK5 impaired the barrier function as assessed by transcellular permeability, measured by the flux of macromolecules [fluorescein isothiocyanate (FITC)-dextran] and the transepithelial electrical resistance (Fig.	('transcellular permeability', 'MPA', (68, 94))	('dextran', 'Chemical', 'MESH:D003911', (170, 177))	('transepithelial electrical resistance', 'MPA', (187, 224))	('barrier function', 'MPA', (36, 52))	('impaired', 'NegReg', (23, 31))	('fluorescein isothiocyanate', 'Chemical', '-', (136, 162))	('Overexpression', 'Var', (0, 14))	('FITC', 'Chemical', '-', (164, 168))	('KLK5', 'Gene', (18, 22))
464929	32461336	Intranasal allergen increased the expression of serum immunoglobulin E (IgE) in the OVA-treated mice compared to control saline-treated mice in both Klk5+/+ and Klk5-/- genotypes (Fig.	('serum immunoglobulin E', 'Protein', (48, 70))	('increased', 'PosReg', (20, 29))	('mice', 'Species', '10090', (136, 140))	('expression', 'MPA', (34, 44))	('mice', 'Species', '10090', (96, 100))	('Klk5+/+', 'Var', (149, 156))
464930	32461336	Trypsin-like activity in the esophagus of the OVA-treated Klk5+/+ mice was increased by 50% compared to that of saline-treated wild-type mice but not OVA-treated Klk5-/- mice (P = 0.025; Fig.	('Klk5+/+', 'Var', (58, 65))	('Trypsin-like activity', 'MPA', (0, 21))	('mice', 'Species', '10090', (66, 70))	('mice', 'Species', '10090', (170, 174))	('increased', 'PosReg', (75, 84))	('mice', 'Species', '10090', (137, 141))
464933	32461336	The number of eosinophils in the esophagus was decreased by threefold in OVA-treated Klk5-/- mice compared to OVA-treated Klk5+/+ mice (P = 0.0003; Fig.	('mice', 'Species', '10090', (130, 134))	('mice', 'Species', '10090', (93, 97))	('Klk5-/-', 'Var', (85, 92))	('decreased', 'NegReg', (47, 56))
464936	32461336	In addition, the epithelial thickness was increased in OVA-treated Klk5+/+ mice compared to control mice (Fig.	('increased', 'PosReg', (42, 51))	('mice', 'Species', '10090', (75, 79))	('epithelial thickness', 'CPA', (17, 37))	('mice', 'Species', '10090', (100, 104))	('Klk5+/+', 'Var', (67, 74))
464939	32461336	In contrast to the decreased eosinophil number in the blood of the Klk5-/- mice, blood mast cell protease 1 (MCPT1, a marker of mast cell load and degranulation) was comparable between Klk5-/- and Klk5+/+ mice (Fig.	('Klk5-/-', 'Var', (185, 192))	('mice', 'Species', '10090', (75, 79))	('decreased eosinophil number', 'Phenotype', 'HP:0031891', (19, 46))	('MCPT1', 'Gene', '17224', (109, 114))	('mice', 'Species', '10090', (205, 209))	('mast cell protease 1', 'Gene', (87, 107))	('MCPT1', 'Gene', (109, 114))	('mast cell protease 1', 'Gene', '17224', (87, 107))
464940	32461336	Collectively, these findings demonstrate that esophageal proteolytic activity is induced after allergenic stimuli and that Klk5 depletion decreases the esophageal proteolytic activity and eosinophil accumulation in the esophagus and circulation.	('decreases', 'NegReg', (138, 147))	('esophageal proteolytic', 'MPA', (46, 68))	('eosinophil accumulation', 'MPA', (188, 211))	('eosinophil accumulation', 'Phenotype', 'HP:0001880', (188, 211))	('Klk5', 'Protein', (123, 127))	('depletion', 'Var', (128, 137))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('esophageal proteolytic activity', 'MPA', (152, 183))
464941	32461336	We have previously shown that alpha1 antitrypsin (A1AT), which is a broad serine protease inhibitor, was able to rescue the effects of SPINK7 deficiency in esophageal epithelial cells in vitro.	('alpha1 antitrypsin', 'Gene', '5265', (30, 48))	('A1AT', 'Gene', (50, 54))	('serine protease', 'Gene', '50908', (74, 89))	('serine protease', 'Gene', (74, 89))	('alpha1 antitrypsin', 'Gene', (30, 48))	('A1AT', 'Gene', '5265', (50, 54))	('deficiency', 'Var', (142, 152))	('SPINK7', 'Gene', (135, 141))
464983	32461336	Analysis of 16S sequencing revealed that the commensal microbiome in the esophagus in the Klk5-/- mice was modified compared to Klk5+/+ mice, with an increase in the portion of Proteobacteria and a decrease in Firmicutes, Bacteroidetes, and Cyanobacteria (Fig.	('decrease', 'NegReg', (198, 206))	('mice', 'Species', '10090', (136, 140))	('Proteobacteria', 'CPA', (177, 191))	('C', 'Chemical', 'MESH:D002244', (241, 242))	('Klk5-/-', 'Var', (90, 97))	('modified', 'Reg', (107, 115))	('Cyanobacteria', 'CPA', (241, 254))	('increase', 'PosReg', (150, 158))	('Bacteroidetes', 'CPA', (222, 235))	('Firmicutes', 'CPA', (210, 220))	('mice', 'Species', '10090', (98, 102))
464984	32461336	The abundance of Ruminococcaceae and Lachnospiraceae bacteria, which are increased in the intestine of patients with milk allergy, was decreased in the Klk5-/- mice compared to Klk5+/+ mice (table S2).	('Lachnospiraceae', 'Gene', (37, 52))	('milk allergy', 'Disease', (117, 129))	('Klk5-/-', 'Var', (152, 159))	('mice', 'Species', '10090', (185, 189))	('milk allergy', 'Disease', 'MESH:D016269', (117, 129))	('mice', 'Species', '10090', (160, 164))	('decreased', 'NegReg', (135, 144))	('allergy', 'Phenotype', 'HP:0012393', (122, 129))	('milk allergy', 'Phenotype', 'HP:0100327', (117, 129))	('patients', 'Species', '9606', (103, 111))	('abundance', 'MPA', (4, 13))
465001	32461336	ENMD-1068 inhibited polyI:C-induced TSLP production by SPINK7 knockout EPC2 cells (Fig.	('ENMD-1068', 'Chemical', 'MESH:C518710', (0, 9))	('polyI', 'Chemical', 'MESH:D011069', (20, 25))	('EPC2', 'Gene', '227867', (71, 75))	('C', 'Chemical', 'MESH:D002244', (73, 74))	('EPC2', 'Gene', (71, 75))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('knockout', 'Var', (62, 70))	('SPINK7', 'Gene', (55, 61))
465011	32461336	ENMD-1068 inhibited IgE production by threefold in OVA-treated compared to control mice (P = 0.0005; Fig.	('ENMD-1068', 'Chemical', 'MESH:C518710', (0, 9))	('IgE production', 'MPA', (20, 34))	('inhibited', 'NegReg', (10, 19))	('mice', 'Species', '10090', (83, 87))	('ENMD-1068', 'Var', (0, 9))
465013	32461336	ENMD-1068 also inhibited esophageal CCL24 production by >2-fold in OVA-treated compared to control mice (P = 0.002; Fig.	('mice', 'Species', '10090', (99, 103))	('inhibited', 'NegReg', (15, 24))	('ENMD-1068', 'Chemical', 'MESH:C518710', (0, 9))	('CCL24', 'Gene', (36, 41))	('CCL24', 'Gene', '56221', (36, 41))	('ENMD-1068', 'Var', (0, 9))
465032	32461336	Our findings show that pharmacological delivery of A1AT is sufficient to correct SPINK7 deficiency in vitro and attenuate experimental EoE in vivo.	('EoE', 'Phenotype', 'HP:0410151', (135, 138))	('A1AT', 'Gene', '5265', (51, 55))	('SPINK7', 'Gene', (81, 87))	('attenuate', 'NegReg', (112, 121))	('A1AT', 'Gene', (51, 55))	('deficiency', 'Var', (88, 98))
465037	32461336	The importance of KLK5 in barrier integrity and eliciting TH2 responses is illustrated by predisposition to atopy in individuals harboring loss-of-function mutations in the protease inhibitor SPINK5 (termed Netherthon's syndrome).	('predisposition to atopy', 'Phenotype', 'HP:0001047', (90, 113))	('mutations', 'Var', (156, 165))	('TH2', 'Gene', '15111', (58, 61))	('atopy', 'Disease', (108, 113))	('TH2', 'Gene', (58, 61))	('SPINK5', 'Gene', (192, 198))	('loss-of-function', 'NegReg', (139, 155))
465040	32461336	Consistent with its role in barrier function and type 2 immune responses, Klk5 deletion reverses the Netherthon's syndrome phenotype in Spink5-/- mice, at least in part.	('Spink5', 'Gene', '72432', (136, 142))	('Spink5', 'Gene', (136, 142))	('reverses', 'NegReg', (88, 96))	('Klk5', 'Gene', (74, 78))	('mice', 'Species', '10090', (146, 150))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('deletion', 'Var', (79, 87))	("Netherthon's syndrome phenotype", 'Disease', (101, 132))
465042	32461336	Therefore, we suggest that both SPINK5 and SPINK7 countermeasure KLK5 activity in the human esophagus.	('SPINK7', 'Var', (43, 49))	('KLK5', 'Protein', (65, 69))	('human', 'Species', '9606', (86, 91))	('activity', 'MPA', (70, 78))
465043	32461336	PAR2 antagonism also inhibited cytokine release from SPINK7 gene-deleted epithelial cells in vitro and decreased allergen-induced esophageal eosinophilia in vivo.	('antagonism', 'Var', (5, 15))	('SPINK7', 'Gene', (53, 59))	('cytokine release', 'MPA', (31, 47))	('PAR2', 'Gene', (0, 4))	('decreased', 'NegReg', (103, 112))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (130, 153))	('inhibited', 'NegReg', (21, 30))	('esophageal eosinophilia', 'Disease', (130, 153))	('eosinophilia', 'Phenotype', 'HP:0001880', (141, 153))
465048	32461336	Our data demonstrate that PAR2 antagonism inhibits polyI: C-induced Toll-like receptor (TLR) signaling.	('PAR2', 'Protein', (26, 30))	('polyI: C', 'Chemical', 'MESH:D011070', (51, 59))	('antagonism', 'Var', (31, 41))	('inhibits', 'NegReg', (42, 50))
465069	32461336	Having established the capacity of proteolytic activity restriction to independently regulate esophageal eosinophilia, we asked whether inhibition of the downstream signaling of KLK5 would attenuate the pathogenesis of EoE.	('inhibition', 'Var', (136, 146))	('attenuate', 'NegReg', (189, 198))	('esophageal eosinophilia', 'Disease', (94, 117))	('EoE', 'Disease', (219, 222))	('EoE', 'Phenotype', 'HP:0410151', (219, 222))	('KLK5', 'Gene', (178, 182))	('eosinophilia', 'Phenotype', 'HP:0001880', (105, 117))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (94, 117))
465076	32461336	Loss of Klk5 may affect the activity of other proteases that might activate PAR2 and/or regulate the epithelial barrier function; therefore, Klk5 deficiency was sufficient to abrogate esophageal eosinophilia.	('Klk5', 'Gene', (141, 145))	('activity', 'MPA', (28, 36))	('eosinophilia', 'Phenotype', 'HP:0001880', (195, 207))	('PAR2', 'Enzyme', (76, 80))	('Klk5', 'Gene', (8, 12))	('esophageal eosinophilia', 'Disease', (184, 207))	('abrogate', 'NegReg', (175, 183))	('affect', 'Reg', (17, 23))	('Loss', 'Var', (0, 4))	('deficiency', 'Var', (146, 156))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (184, 207))	('activate', 'PosReg', (67, 75))
465080	32461336	We suggest that protein replacement therapy with protease inhibitors is a particularly attractive strategy for treatment of EoE for three reasons: (i) proteolytic inhibition can restore the epithelial barrier, which, in turn, might restrain inflammation by preventing luminal stimuli from penetrating into the tissue; (ii) the potential for some protease inhibitors (such as A1AT) to act against a broad range of proteases, including PAR2-activating proteases; and (iii) inhibition of proteolytic activity can block several inflammatory processes, including processing and activation of cytokines.	('inflammation', 'Disease', 'MESH:D007249', (241, 253))	('inflammation', 'Disease', (241, 253))	('activation', 'MPA', (573, 583))	('A1AT', 'Gene', (375, 379))	('PAR2-activating proteases', 'Enzyme', (434, 459))	('luminal', 'Chemical', 'MESH:D010634', (268, 275))	('inhibition', 'Var', (471, 481))	('restrain', 'NegReg', (232, 240))	('A1AT', 'Gene', '5265', (375, 379))	('proteases', 'Enzyme', (413, 422))	('act', 'Reg', (384, 387))	('processing', 'MPA', (558, 568))	('EoE', 'Phenotype', 'HP:0410151', (124, 127))	('block', 'NegReg', (510, 515))	('inflammatory processes', 'CPA', (524, 546))
465084	32461336	We induced an experimental EoE murine model and assessed the proteolytic activity, serum IgE, and MCPT1, CCL11, and CCL24 concentrations and the number of eosinophils in the esophagus, lungs, and blood in Klk5-/- mice compared to Klk5+/+ mice.	('CCL11', 'Gene', (105, 110))	('CCL11', 'Gene', '20292', (105, 110))	('mice', 'Species', '10090', (213, 217))	('proteolytic activity', 'MPA', (61, 81))	('CCL24', 'Gene', (116, 121))	('Klk5-/-', 'Var', (205, 212))	('MCPT1', 'Gene', '17224', (98, 103))	('EoE', 'Phenotype', 'HP:0410151', (27, 30))	('MCPT1', 'Gene', (98, 103))	('CCL24', 'Gene', '56221', (116, 121))	('mice', 'Species', '10090', (238, 242))	('murine', 'Species', '10090', (31, 37))
465103	29632636	Knocking down of c-Myc expression resulted in upregulation of integrin subunits alpha5 and beta3.	('c-Myc', 'Protein', (17, 22))	('Knocking down', 'Var', (0, 13))	('upregulation', 'PosReg', (46, 58))	('beta3', 'Gene', '1934', (91, 96))	('beta3', 'Gene', (91, 96))	('integrin subunits alpha5', 'Protein', (62, 86))
162336	29632636	As deregulation of these processes are features of cancer, it is likely that miRNAs play a role in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('deregulation', 'Var', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('carcinogenesis', 'Disease', (99, 113))	('mi', 'Chemical', 'MESH:C011506', (77, 79))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
465111	29632636	Surprisingly, in EAC, we showed that miR-145 was oncogenic and was able to protect the cells against cell death induced by detachment (anoikis) and enhance cell invasion.	('death', 'Disease', 'MESH:D003643', (106, 111))	('death', 'Disease', (106, 111))	('miR-145', 'Var', (37, 44))	('cell invasion', 'CPA', (156, 169))	('men', 'Species', '9606', (129, 132))	('enhance', 'PosReg', (148, 155))
465119	29632636	Therefore, to investigate the pathway by which miR-145 leads to upregulation of integrin alpha5 and beta3, the role of the oncogene c-Myc was evaluated.	('miR-145', 'Var', (47, 54))	('integrin alpha5 and beta3', 'Gene', '3678', (80, 105))	('upregulation', 'PosReg', (64, 76))
465120	29632636	c-Myc is a well known target of miR-145 and has been shown, in the literature, to repress the expression of several integrins in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('miR-145', 'Var', (32, 39))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('expression', 'MPA', (94, 104))	('integrins', 'Protein', (116, 125))	('repress', 'NegReg', (82, 89))
465127	29632636	There was no difference in cell proliferation between the control siRNA and the c-Myc siRNA cells 72h after transfection (Figure 2B); however the c-Myc siRNA cells exhibited better adhesion to fibronectin coated plates compared to control siRNA (Figure 3B).	('fibronectin', 'Gene', '2335', (193, 204))	('adhesion', 'CPA', (181, 189))	('c-Myc', 'Var', (146, 151))	('better', 'PosReg', (174, 180))	('fibronectin', 'Gene', (193, 204))
465131	29632636	However, inhibition of alpha5beta1 activity did not sensitize SK-GT-4 miR-145 cells to anoikis (Figure 3B) or decrease their invasive ability (Figure 3C).	('alpha5beta1 activity', 'Protein', (23, 43))	('SK-GT-4', 'Chemical', '-', (62, 69))	('invasive ability', 'CPA', (125, 141))	('anoikis', 'CPA', (87, 94))	('decrease', 'NegReg', (110, 118))	('inhibition', 'Var', (9, 19))
465143	29632636	First, the miR-145 tumors displayed a greater geographic necrosis than the control tumors (all miR-145 tumors had necrosis compared to 50% of pcmv tumors).	('tumors', 'Disease', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('miR-145', 'Gene', (95, 102))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('necrosis', 'Disease', (57, 65))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('pcmv', 'Chemical', '-', (142, 146))	('necrosis', 'Disease', 'MESH:D009336', (114, 122))	('miR-145', 'Var', (11, 18))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('necrosis', 'Disease', (114, 122))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (83, 89))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
465149	29632636	Around 4 weeks after flank injection of tumor cells, SK-GT-4 miR-145 cells formed larger tumors compared to pcmv (Figure 4A and Supplementary Figure 2A) and the miR-145 tumors were more than twice as big as the SK-GT-4 pcmv at the time of sacrifice.	('tumors', 'Disease', (89, 95))	('pcmv', 'Chemical', '-', (219, 223))	('SK-GT-4', 'Var', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('miR-145', 'Gene', (61, 68))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('SK-GT-4', 'Chemical', '-', (53, 60))	('tumor', 'Disease', (40, 45))	('men', 'Species', '9606', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('pcmv', 'Chemical', '-', (108, 112))	('SK-GT-4', 'Chemical', '-', (211, 218))	('tumors', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
465154	29632636	Previous reports of the role of miR-145 on fibroblasts and endothelial cells demonstrated that expression of miR-145 results in the transformation of fibroblasts to myofibroblasts and the stromal expression of miR-145 resulted in increased angiogenesis, both of which are known to increase and maintain the tumor growth.	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('miR-145', 'Gene', (109, 116))	('expression', 'Var', (95, 105))	('tumor', 'Disease', (307, 312))	('increased', 'PosReg', (230, 239))	('angiogenesis', 'CPA', (240, 252))	('miR-145', 'Gene', (210, 217))
465159	29632636	This was a surprising result since the SK-GT-4 displayed a high invasive potential in vitro.	('SK-GT-4', 'Chemical', '-', (39, 46))	('SK-GT-4', 'Var', (39, 46))	('invasive potential', 'CPA', (64, 82))
465162	29632636	When this technique was used, cancer cells were detected in 10 out of 13 mice lungs in the SK-GT-4 miR-145 xenografts but in only 4 out 12 mice lungs for the SK-GT-4 pcmv xenografts (Figure 5D).	('mice', 'Species', '10090', (73, 77))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('miR-145', 'Var', (99, 106))	('SK-GT-4', 'Chemical', '-', (91, 98))	('pcmv', 'Chemical', '-', (166, 170))	('mice', 'Species', '10090', (139, 143))	('SK-GT-4', 'Chemical', '-', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('SK-GT-4 miR-145', 'Var', (91, 106))
465167	29632636	We discovered that SK-GT-4 miR-145 cells expressed higher level of integrins alpha5 and beta3 compared to the SK-GT-4 pcmv cells.	('integrins alpha5', 'Protein', (67, 83))	('SK-GT-4', 'Chemical', '-', (110, 117))	('beta3', 'Gene', '1934', (88, 93))	('beta3', 'Gene', (88, 93))	('SK-GT-4', 'Var', (19, 26))	('pcmv', 'Chemical', '-', (118, 122))	('higher', 'PosReg', (51, 57))	('SK-GT-4', 'Chemical', '-', (19, 26))
465169	29632636	We demonstrated that the expression of c-Myc and integrins alpha5 and beta3 were inversely correlated and that we could reproduce the miR-145 effects on cell adhesion to fibronectin and anoikis resistance in SK-GT-4 pcmv cells by knock down of c-Myc expression.	('pcmv', 'Chemical', '-', (216, 220))	('beta3', 'Gene', (70, 75))	('miR-145', 'Gene', (134, 141))	('beta3', 'Gene', '1934', (70, 75))	('effects', 'Reg', (142, 149))	('fibronectin', 'Gene', (170, 181))	('cell adhesion', 'CPA', (153, 166))	('SK-GT-4', 'Chemical', '-', (208, 215))	('anoikis resistance', 'CPA', (186, 204))	('knock down', 'Var', (230, 240))	('c-Myc', 'Protein', (244, 249))	('fibronectin', 'Gene', '2335', (170, 181))
465172	29632636	An interesting finding with our tumor model was the fact that SK-GT-4 miR-145 cells created bigger tumors than the SK-GT-4 pcmv cells.	('tumor', 'Disease', (99, 104))	('SK-GT-4', 'Chemical', '-', (62, 69))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('SK-GT-4', 'Var', (62, 69))	('SK-GT-4', 'Chemical', '-', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (32, 37))	('pcmv', 'Chemical', '-', (123, 127))	('tumors', 'Disease', (99, 105))
465176	29632636	After 8 weeks, we could only detect one metastasis using H&E in one of 25 mice (with SK-GT-4 miR-145 cells), but by using the FISH technique, we could detect twice as many tumor cells in the mice lungs of mi-145 group compared to the pcmv group.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('pcmv', 'Chemical', '-', (234, 238))	('mi', 'Chemical', 'MESH:C011506', (205, 207))	('mi', 'Chemical', 'MESH:C011506', (93, 95))	('mi', 'Chemical', 'MESH:C011506', (191, 193))	('mice', 'Species', '10090', (191, 195))	('of mi-145', 'Var', (202, 211))	('mi', 'Chemical', 'MESH:C011506', (74, 76))	('SK-GT-4', 'Chemical', '-', (85, 92))	('mice', 'Species', '10090', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
465280	29509684	Full energy modulation eliminates the need for range shifters and patient-specific compensators and collimators, thus reducing the lag time to treatment and cost of patient set-up.	('reducing', 'NegReg', (118, 126))	('modulation', 'Var', (12, 22))	('patient', 'Species', '9606', (165, 172))	('patient', 'Species', '9606', (66, 73))
465317	29509684	From a clinical point of view, the high LET of CIRT improves the peak-to-plateau ratio, thus allowing a higher chance of tumor cell kill/control while maintaining a low risk of normal tissue complications.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('peak-to-plateau ratio', 'MPA', (65, 86))	('CIRT', 'Var', (47, 51))	('improves', 'PosReg', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
465323	29509684	In brief, carbon beams have improved dose distribution over photons due to their characteristic Bragg peak.	('improved', 'PosReg', (28, 36))	('carbon', 'Chemical', 'MESH:D002244', (10, 16))	('carbon beams', 'Var', (10, 22))	('Bragg peak', 'MPA', (96, 106))	('dose distribution', 'MPA', (37, 54))
465324	29509684	Given the reduced charge-to-mass ratio, carbon ion beams also have reduced lateral scattering compared to proton irradiation.	('charge-to-mass ratio', 'MPA', (18, 38))	('lateral scattering', 'MPA', (75, 93))	('reduced', 'NegReg', (67, 74))	('carbon ion beams', 'Var', (40, 56))	('carbon', 'Chemical', 'MESH:D002244', (40, 46))
465330	29509684	Sub-lethal damage repair is expected in the normal tissue low-LET regions with CIRT compared to the high-LET tumor region which is strategically located within the Bragg peak.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CIRT', 'Var', (79, 83))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
465331	29509684	Additionally, unlike photons where cells are more sensitive in the M/G2 phases, carbon ions are able to induce tumor kill independent of the cell cycle phase.	('M/G2', 'Var', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('carbon', 'Chemical', 'MESH:D002244', (80, 86))	('M/G2', 'SUBSTITUTION', 'None', (67, 71))	('tumor', 'Disease', (111, 116))
465385	29599927	However, high-expression of CXCR2 in digestive tract cancer (HR = 1.26, 95% CI = 0.68-2.35, p = 0.46; I2 = 73%, p = 0.005) has no effect on OS statistically.	('high-expression', 'Var', (9, 24))	('CXCR2', 'Gene', '3579', (28, 33))	('CXCR2', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (37, 59))	('tract cancer', 'Disease', 'MESH:D014571', (47, 59))	('tract cancer', 'Disease', (47, 59))
465386	29599927	As shown in Figure 4, significant difference was detected between high- and low-expression of CXCR2 without heterogeneity in group with multivariate models (HR = 1.78, 95% CI = 1.52-2.08, p < 0.01; I2 = 0%, p = 0.76).	('CXCR2', 'Gene', '3579', (94, 99))	('high-', 'Var', (66, 71))	('low-expression', 'NegReg', (76, 90))	('CXCR2', 'Gene', (94, 99))
465388	29599927	As shown in Figure 5, there was significant difference between high- and low-expression of CXCR2 without heterogeneity in Asian group (HR = 1.93, 95% CI = 1.58-2.34, p < 0.01; I2 = 0%, p = 0.76).	('CXCR2', 'Gene', (91, 96))	('high-', 'Var', (63, 68))	('CXCR2', 'Gene', '3579', (91, 96))	('low-expression', 'NegReg', (73, 87))
465390	29599927	As what was shown in Figure 6, there was significant difference between high- and low-expression of CXCR2 without heterogeneity in small sample size group (HR = 1.81, 95% CI = 1.46-2.24, p < 0.01; I2 = 0%, p = 0.68).	('CXCR2', 'Gene', (100, 105))	('CXCR2', 'Gene', '3579', (100, 105))	('high-', 'Var', (72, 77))	('low-expression', 'NegReg', (82, 96))
465397	29599927	In our meta-analysis, it was presented that high expression of CXCR2 was significantly related to shorten OS and was a risk factor of OS.	('CXCR2', 'Gene', '3579', (63, 68))	('high expression', 'Var', (44, 59))	('CXCR2', 'Gene', (63, 68))	('shorten OS', 'Disease', (98, 108))	('related', 'Reg', (87, 94))	('risk factor', 'Reg', (119, 130))
465398	29599927	Among the studies included in quantitative synthesis, the synthetic analysis of 4 eligible studies reported that high CXCR2 expression was correlated with shorten recurrence-free survival (RFS).	('high', 'Var', (113, 117))	('shorten', 'NegReg', (155, 162))	('CXCR2', 'Gene', '3579', (118, 123))	('recurrence-free survival', 'CPA', (163, 187))	('CXCR2', 'Gene', (118, 123))
465437	28134235	In recent decades, studies have illustrated that n-3 PUFAs as well as its metabolites (resolvins and protectin D1) are able to inhibit the generation of inflammatory factors and lessen cytokine response by inhibiting NF-kappaB, subsequently activating its immune regulation function.	('n', 'Chemical', 'MESH:D009584', (249, 250))	('n', 'Chemical', 'MESH:D009584', (148, 149))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (281, 282))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('rat', 'Species', '10116', (143, 146))	('inhibit', 'NegReg', (127, 134))	('n', 'Chemical', 'MESH:D009584', (272, 273))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('NF-kappaB', 'Gene', '18033', (217, 226))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('n', 'Chemical', 'MESH:D009584', (199, 200))	('protectin', 'Gene', (101, 110))	('rat', 'Species', '10116', (38, 41))	('immune regulation', 'MPA', (256, 273))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('n', 'Chemical', 'MESH:D009584', (128, 129))	('generation of inflammatory factors', 'MPA', (139, 173))	('n', 'Chemical', 'MESH:D009584', (207, 208))	('n', 'Chemical', 'MESH:D009584', (191, 192))	('n', 'Chemical', 'MESH:D009584', (183, 184))	('n', 'Chemical', 'MESH:D009584', (214, 215))	('cytokine response', 'MPA', (185, 202))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('lessen', 'NegReg', (178, 184))	('protectin', 'Gene', '25407', (101, 110))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('n-3', 'Var', (49, 52))	('n', 'Chemical', 'MESH:D009584', (236, 237))	('n', 'Chemical', 'MESH:D009584', (276, 277))	('activating', 'PosReg', (241, 251))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (260, 261))	('3 PUFAs', 'Chemical', '-', (51, 58))	('inhibiting', 'NegReg', (206, 216))	('NF-kappaB', 'Gene', (217, 226))	('lessen cytokine response', 'Phenotype', 'HP:0031407', (178, 202))
465469	28134235	Western blot was utilized to detect the expression of PI3K, Akt, p-Akt, NF-kappaBp50, and NF-kappaBp65 protein in inflammation of esophageal mucosa of rats fed different ratio of n-6/n-3 PUFAs in the forage diet.	('Akt', 'Gene', '24185', (67, 70))	('n', 'Chemical', 'MESH:D009584', (194, 195))	('Akt', 'Gene', '24185', (60, 63))	('3 PUFAs', 'Chemical', '-', (185, 192))	('NF-kappaB', 'Gene', (72, 81))	('rat', 'Species', '10116', (151, 154))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('Akt', 'Gene', (67, 70))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('NF-kappaB', 'Gene', '18033', (90, 99))	('n-6', 'Chemical', '-', (179, 182))	('Akt', 'Gene', (60, 63))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('n', 'Chemical', 'MESH:D009584', (183, 184))	('NF-kappaB', 'Gene', '18033', (72, 81))	('rats', 'Species', '10116', (151, 155))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('PI3K', 'Var', (54, 58))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('inflammation of esophageal mucosa', 'Disease', 'MESH:D007249', (114, 147))	('rat', 'Species', '10116', (170, 173))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (179, 180))	('inflammation of esophageal mucosa', 'Disease', (114, 147))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('NF-kappaB', 'Gene', (90, 99))
465477	28134235	Some studies have suggested that the inhibition of PI3K/AKT reduced the release of multiple inflammatory factors.	('inhibition', 'Var', (37, 47))	('release of multiple inflammatory factors', 'MPA', (72, 112))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('AKT', 'Gene', (56, 59))	('AKT', 'Gene', '24185', (56, 59))	('reduced', 'NegReg', (60, 67))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (93, 94))
465485	25655557	Its eradication would eliminate a major worldwide cause of cancer death, so there is much interest in identifying how, if, and when this can be accomplished.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('eradication', 'Var', (4, 15))	('eliminate', 'NegReg', (22, 31))	('cancer death', 'Disease', (59, 71))	('cancer death', 'Disease', 'MESH:D003643', (59, 71))
465487	25655557	Gastric adenocarcinoma is one of many cancers associated with inflammation, which is induced by H pylori infection, yet the bacteria also cause genetic and epigenetic changes that lead to genetic instability in gastric epithelial cells.	('epigenetic changes', 'Var', (156, 174))	('inflammation', 'Disease', 'MESH:D007249', (62, 74))	('inflammation', 'Disease', (62, 74))	('H pylori infection', 'Disease', (96, 114))	('H pylori infection', 'Phenotype', 'HP:0005202', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('genetic instability', 'MPA', (188, 207))	('Gastric adenocarcinoma', 'Disease', (0, 22))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('cause', 'Reg', (138, 143))	('Gastric adenocarcinoma', 'Disease', 'MESH:D013274', (0, 22))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('lead', 'Reg', (180, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('cancers', 'Disease', (38, 45))	('H pylori infection', 'Disease', 'MESH:D016481', (96, 114))
465492	25655557	Elimination of H pylori will dramatically reduce the incidence of gastric cancer.	('reduce the incidence of gastric cancer', 'Phenotype', 'HP:0006753', (42, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('Elimination', 'Var', (0, 11))	('H pylori', 'Disease', (15, 23))	('reduce', 'NegReg', (42, 48))	('H pylori', 'Species', '210', (15, 23))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
465495	25655557	More importantly, curing the infection in animal models frequently results in resolution of the malignancy or dysplastic changes, calling into question their relevance to human gastric adenocarcinoma .	('resolution', 'CPA', (78, 88))	('infection', 'Disease', (29, 38))	('infection', 'Disease', 'MESH:D007239', (29, 38))	('malignancy', 'Disease', 'MESH:D009369', (96, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('results in', 'Reg', (67, 77))	('malignancy', 'Disease', (96, 106))	('dysplastic', 'Disease', 'MESH:D004416', (110, 120))	('dysplastic', 'Disease', (110, 120))	('curing', 'Var', (18, 24))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (177, 199))	('human', 'Species', '9606', (171, 176))	('gastric adenocarcinoma', 'Disease', (177, 199))
465497	25655557	For reviews of basic issues related to the ability of H pylori to survive on the surface of the stomach, the role of virulence factors in the pathogenesis of gastric cancer, H pylori induced inflammation and genetic instability in the gastric mucosa, and on the history of H pylori-related disease see .	('inflammation', 'Disease', 'MESH:D007249', (191, 203))	('genetic instability', 'Var', (208, 227))	('inflammation', 'Disease', (191, 203))	('gastric cancer', 'Disease', 'MESH:D013274', (158, 172))	('gastric cancer', 'Phenotype', 'HP:0012126', (158, 172))	('gastric cancer', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('H pylori', 'Species', '210', (54, 62))	('H pylori', 'Species', '210', (273, 281))	('H pylori', 'Species', '210', (174, 182))
465518	25655557	Eradicating H pylori before the development of atrophic changes can essentially eliminate cancer risk.	('atrophic', 'Disease', 'MESH:D020966', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('eliminate', 'NegReg', (80, 89))	('H pylori', 'Disease', (12, 20))	('Eradicating', 'Var', (0, 11))	('atrophic', 'Disease', (47, 55))	('men', 'Species', '9606', (39, 42))	('H pylori', 'Species', '210', (12, 20))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
465530	25655557	H pylori eradication reduces that risk approximately 3-fold .	('eradication', 'Var', (9, 20))	('H pylori', 'Species', '210', (0, 8))	('H pylori', 'Disease', (0, 8))
465541	25655557	Any increase following H pylori eradication would also reduce overgrowth of non-H pylori bacteria and potentially reduce or eliminate their deleterious effects .	('deleterious effects', 'MPA', (140, 159))	('overgrowth', 'Phenotype', 'HP:0001548', (62, 72))	('H pylori', 'Species', '210', (80, 88))	('reduce', 'NegReg', (55, 61))	('eradication', 'Var', (32, 43))	('overgrowth', 'MPA', (62, 72))	('H pylori', 'Species', '210', (23, 31))
465545	25655557	Importantly, all H pylori strains cause gastric inflammation and disease; no avirulent strains have been identified.	('gastric inflammation', 'Phenotype', 'HP:0005263', (40, 60))	('gastric inflammation and disease', 'Disease', 'MESH:D007249', (40, 72))	('H pylori', 'Species', '210', (17, 25))	('H pylori', 'Disease', (17, 25))	('strains', 'Var', (26, 33))	('cause', 'Reg', (34, 39))
465547	25655557	H pylori eradication eliminates the noxious stimulus and promotes resolution of inflammation.	('inflammation', 'Disease', 'MESH:D007249', (80, 92))	('H pylori', 'Species', '210', (0, 8))	('inflammation', 'Disease', (80, 92))	('resolution', 'CPA', (66, 76))	('eliminates', 'NegReg', (21, 31))	('noxious stimulus', 'MPA', (36, 52))	('eradication', 'Var', (9, 20))	('promotes', 'PosReg', (57, 65))
465562	25655557	Evidence for a direct role of intestinal metaplasia or spasmolytic polypeptide-expressing metaplasia in gastric carcinogenesis is circumstantial; it is possible that reversal of atrophy may result in detectable changes (eg, related to transdifferention) that do not, however, significantly modify cancer risk .	('cancer', 'Disease', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('reversal', 'Var', (166, 174))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (30, 51))	('gastric carcinogenesis', 'Disease', (104, 126))	('atrophy', 'Disease', 'MESH:D001284', (178, 185))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (104, 126))	('atrophy', 'Disease', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('transdifferention', 'CPA', (235, 252))	('intestinal metaplasia', 'Disease', (30, 51))
465624	25655557	The bacteria have been proposed to cause a variety of extra-gastric diseases and metabolic derangements, either directly, through molecular mimicry, or indirectly, by producing chronic inflammation .	('metabolic derangements', 'Phenotype', 'HP:0001939', (81, 103))	('bacteria', 'Var', (4, 12))	('producing', 'Reg', (167, 176))	('metabolic', 'MPA', (81, 90))	('extra-gastric diseases', 'Disease', (54, 76))	('extra-gastric diseases', 'Disease', 'MESH:D013274', (54, 76))	('inflammation', 'Disease', 'MESH:D007249', (185, 197))	('cause', 'Reg', (35, 40))	('men', 'Species', '9606', (98, 101))	('inflammation', 'Disease', (185, 197))
465629	25655557	Although these 2 events might be unrelated, H pylori infection has been linked with systemic inflammation, atherosclerosis, lipid disorders, heart disease, alternations in vitamin B12 metabolism, and changes in the microbiome.	('changes', 'Reg', (200, 207))	('vitamin B12', 'Chemical', 'MESH:D014805', (172, 183))	('heart disease', 'Disease', 'MESH:D006331', (141, 154))	('systemic inflammation', 'Disease', (84, 105))	('atherosclerosis', 'Disease', (107, 122))	('alternations', 'Var', (156, 168))	('linked', 'Reg', (72, 78))	('vitamin B12 metabolism', 'MPA', (172, 194))	('H pylori infection', 'Disease', 'MESH:D016481', (44, 62))	('H pylori infection', 'Phenotype', 'HP:0005202', (44, 62))	('lipid disorders', 'Disease', (124, 139))	('systemic inflammation', 'Disease', 'MESH:D007249', (84, 105))	('heart disease', 'Disease', (141, 154))	('H pylori infection', 'Disease', (44, 62))	('lipid', 'Chemical', 'MESH:D008055', (124, 129))	('atherosclerosis', 'Phenotype', 'HP:0002621', (107, 122))	('atherosclerosis', 'Disease', 'MESH:D050197', (107, 122))
465677	25655557	Obesity is a manifestation of an imbalance between energy intake and expenditure, so the absence of H pylori might increase appetite and intake.	('H pylori', 'Species', '210', (100, 108))	('H pylori', 'Gene', (100, 108))	('imbalance', 'Phenotype', 'HP:0002172', (33, 42))	('increase', 'PosReg', (115, 123))	('Obesity', 'Disease', (0, 7))	('absence', 'Var', (89, 96))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('increase appetite', 'Phenotype', 'HP:0002591', (115, 132))
465678	25655557	However, it not clear whether absence of H pylori might also encourage behaviors that reduce energy consumption.	('energy consumption', 'MPA', (93, 111))	('H pylori', 'Species', '210', (41, 49))	('absence', 'Var', (30, 37))	('encourage', 'PosReg', (61, 70))	('reduce', 'NegReg', (86, 92))
465700	20354452	The mechanisms of tumor resistance to irinotecan include mutations of the Topo I gene and stable decrements in Topo I activity.	('Topo I', 'Enzyme', (111, 117))	('tumor', 'Disease', (18, 23))	('activity', 'MPA', (118, 126))	('irinotecan', 'Chemical', 'MESH:D000077146', (38, 48))	('Topo I', 'Gene', (74, 80))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('decrements', 'NegReg', (97, 107))
465805	22701179	On the other hand, while CCN1 is known to adopt different receptors to diversify its signaling in the same tissue, as best exemplified in fibroblasts, where it induces cell adhesion through alpha 6 beta 1 and heparan sulfate proteoglycans, cell migration through alpha v beta 5, and cell proliferation through alpha v beta 3, it was also shown to activate both NF-kappaB and MAPK signaling in breast cancer cells through the same receptor, namely alpha v beta 3.	('cell adhesion', 'CPA', (168, 181))	('cell migration', 'CPA', (240, 254))	('NF-kappaB', 'Pathway', (361, 370))	('activate', 'PosReg', (347, 355))	('breast cancer', 'Disease', 'MESH:D001943', (393, 406))	('MAPK', 'Gene', (375, 379))	('CCN1', 'Var', (25, 29))	('MAPK', 'Gene', '5595;5594;5595', (375, 379))	('induces', 'PosReg', (160, 167))	('breast cancer', 'Disease', (393, 406))	('cancer', 'Phenotype', 'HP:0002664', (400, 406))	('heparan sulfate', 'Protein', (209, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (393, 406))	('cell proliferation', 'CPA', (283, 301))
465806	22701179	Overexpression of CCN1 has been found to activate beta-catenin translocation in several cell systems including glioma, non-small-cell lung cancer cells, and gastric epithelial cells, whereas beta-catenin translocation can in turn promote CCN1 expression through Wnt signaling.	('CCN1', 'Gene', (238, 242))	('lung cancer', 'Disease', (134, 145))	('glioma', 'Disease', (111, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('expression', 'MPA', (243, 253))	('activate', 'PosReg', (41, 49))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('promote', 'PosReg', (230, 237))	('beta-catenin translocation', 'MPA', (50, 76))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('Overexpression', 'Var', (0, 14))	('CCN1', 'Gene', (18, 22))
465836	22701179	In addition, beta-catenin translocation can also destabilize intercellular connection, facilitating cancer metastasis.	('facilitating', 'Reg', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer metastasis', 'Disease', (100, 117))	('beta-catenin', 'Protein', (13, 25))	('cancer metastasis', 'Disease', 'MESH:D009362', (100, 117))	('destabilize', 'NegReg', (49, 60))	('translocation', 'Var', (26, 39))	('intercellular connection', 'CPA', (61, 85))
465888	20647328	We found that, the incidence of esophageal adenocarcinoma was significantly lower in animals treated with Urso-Aspirin compared to controls (p<0.05, FIGURE 1A).	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (32, 57))	('esophageal adenocarcinoma', 'Disease', (32, 57))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (32, 57))	('Urso-Aspirin', 'Var', (106, 118))	('lower', 'NegReg', (76, 81))	('Urso-Aspirin', 'Chemical', '-', (106, 118))
465903	20647328	The protein normalized luciferase activity showed that Urso-Aspirin caused a four-fold reduction in CDK2 promoter activity compared to control (100+-20 vs. 22.2+-6, p<0.01 FIGURE 2C).	('Urso-Aspirin', 'Chemical', '-', (55, 67))	('CDK2', 'Gene', (100, 104))	('CDK2', 'Gene', '1017', (100, 104))	('Urso-Aspirin', 'Var', (55, 67))	('reduction', 'NegReg', (87, 96))
465914	20647328	Congruent with the above data, the shGLI1 transfected cells had up to a five-fold reduction in CDK2 promoter activity when compared to control.	('CDK2', 'Gene', (95, 99))	('transfected', 'Var', (42, 53))	('reduction', 'NegReg', (82, 91))	('GLI1', 'Gene', '2735', (37, 41))	('CDK2', 'Gene', '1017', (95, 99))	('GLI1', 'Gene', (37, 41))
465938	20647328	Luciferase activity showed that Urso-Aspirin caused a 59+-8% reduction in the GLI-luciferase reporter activity compared to control, (p<0.01) (FIGURE 5D).	('Urso-Aspirin', 'Chemical', '-', (32, 44))	('GLI', 'Gene', (78, 81))	('reduction', 'NegReg', (61, 70))	('activity', 'MPA', (102, 110))	('GLI', 'Gene', '2735', (78, 81))	('Urso-Aspirin', 'Var', (32, 44))
465943	20647328	However, in FLO-1 cells that were transfected with GLI1 prior to treatment with Urso-Aspirin, there was no significant reduction in proliferation compared to control (11%, p=0.54) (FIGURE 6A).	('GLI1', 'Gene', (51, 55))	('rat', 'Species', '10116', (139, 142))	('GLI1', 'Gene', '2735', (51, 55))	('Urso-Aspirin', 'Chemical', '-', (80, 92))	('proliferation', 'CPA', (132, 145))	('reduction', 'NegReg', (119, 128))	('transfected', 'Var', (34, 45))
465963	20647328	Our in-vitro results show that Urso-Aspirin decreases Barrett's epithelial cell proliferation, a key cellular process that is known to be associated with neoplastic progression in Barrett's epithelial cells.	('Urso-Aspirin', 'Chemical', '-', (31, 43))	('Barrett', 'Disease', (54, 61))	('Urso-Aspirin', 'Var', (31, 43))	('decreases', 'NegReg', (44, 53))	('rat', 'Species', '10116', (87, 90))
466100	33672007	Auto-antibodies are classically associated with autoimmune diseases, where they are an integral part of diagnostic panels.	('autoimmune diseases', 'Disease', 'MESH:D001327', (48, 67))	('Auto-antibodies', 'Var', (0, 15))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (48, 67))	('autoimmune diseases', 'Disease', (48, 67))	('associated', 'Reg', (32, 42))
466102	33672007	Auto-antibodies might initially represent an epiphenomenon derived from the inflammatory environment induced by the tumor.	('men', 'Species', '9606', (96, 99))	('Auto-antibodies', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('men', 'Species', '9606', (53, 56))	('tumor', 'Disease', (116, 121))
466114	33672007	In these pathological conditions, auto-antibodies cause inflammation in joints, such as in rheumatoid arthritis (RA), or can affect the lungs, blood cells, nerves, and kidneys in systemic lupus erythematosus (SLE), or intestines, such as in inflammatory bowel disease (IBD).	('cause', 'Reg', (50, 55))	('affect', 'Reg', (125, 131))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (179, 207))	('inflammation', 'Disease', (56, 68))	('joints', 'Disease', (72, 78))	('RA', 'Disease', 'MESH:D001172', (113, 115))	('rheumatoid arthritis', 'Disease', (91, 111))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (179, 207))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (91, 111))	('RA', 'Phenotype', 'HP:0001370', (113, 115))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (241, 267))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (241, 267))	('IBD', 'Disease', 'MESH:D015212', (269, 272))	('inflammatory bowel disease', 'Disease', (241, 267))	('auto-antibodies', 'Var', (34, 49))	('systemic lupus erythematosus', 'Disease', (179, 207))	('IBD', 'Phenotype', 'HP:0002037', (269, 272))	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('joints', 'Disease', 'MESH:D007592', (72, 78))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (91, 111))	('IBD', 'Disease', (269, 272))	('SLE', 'Disease', 'MESH:D008180', (209, 212))	('SLE', 'Disease', (209, 212))	('arthritis', 'Phenotype', 'HP:0001369', (102, 111))	('SLE', 'Phenotype', 'HP:0002725', (209, 212))
466123	33672007	The second class of antigens are derived from normal genes by somatic mutation, deletion, or epigenetic modifications and are called tumor-specific antigens (TSAs).	('deletion', 'Var', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('epigenetic modifications', 'Var', (93, 117))	('tumor', 'Disease', (133, 138))
466128	33672007	Polymorphisms in various genes can result in defective regulation or reduced threshold for lymphocyte activation, and environmental factors (e.g., infections, traumas) initiate or augment activation of self-reactive lymphocytes that have escaped control and that can react against auto-antigens.	('traumas', 'Disease', 'MESH:D014947', (159, 166))	('activation', 'MPA', (188, 198))	('initiate', 'Reg', (168, 176))	('reduced threshold for lymphocyte activation', 'Phenotype', 'HP:0005419', (69, 112))	('reduced', 'NegReg', (69, 76))	('men', 'Species', '9606', (183, 186))	('men', 'Species', '9606', (125, 128))	('Polymorphisms', 'Var', (0, 13))	('traumas', 'Disease', (159, 166))	('infections', 'Disease', 'MESH:D007239', (147, 157))	('self-reactive lymphocytes', 'CPA', (202, 227))	('augment', 'PosReg', (180, 187))	('defective', 'NegReg', (45, 54))	('threshold for lymphocyte activation', 'MPA', (77, 112))	('infections', 'Disease', (147, 157))	('regulation', 'MPA', (55, 65))
466134	33672007	However, there is growing evidence suggesting that B cells and antibodies can also be involved in tumor promotion and resistance to cancer therapy, with the observation that B cell depletion can suppress tumor growth in mice.	('cancer', 'Disease', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mice', 'Species', '10090', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('depletion', 'Var', (181, 190))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', (98, 103))	('suppress', 'NegReg', (195, 203))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
466135	33672007	In ovarian cancer, the presence of CD20+ B cells has been associated with an increased survival, while in contrast, the presence of regulatory B cells (Bregs) induces immunosuppressive effects, supporting tumor growth.	('immunosuppressive effects', 'MPA', (167, 192))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CD20+ B cells', 'Var', (35, 48))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('survival', 'CPA', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('ovarian cancer', 'Disease', (3, 17))	('increased', 'PosReg', (77, 86))	('supporting', 'PosReg', (194, 204))
466155	33672007	A peptide microarray study was conducted to evaluate the production of auto-antibodies against MGMT, and the authors found a good correlation between the presence of the MGMT-2 peptide auto-antibodies and the risk of chemotherapy resistance and disease recurrence.	('chemotherapy resistance', 'CPA', (217, 240))	('MGMT', 'Gene', '4255', (170, 174))	('MGMT', 'Gene', (170, 174))	('MGMT', 'Gene', '4255', (95, 99))	('disease recurrence', 'CPA', (245, 263))	('presence', 'Var', (154, 162))	('MGMT', 'Gene', (95, 99))
466163	33672007	Diffuse gastrointestinal cancers are mainly related to abnormal expression or mutations of E-cadherin, a cell-cell adhesion protein.	('gastrointestinal cancers', 'Disease', (8, 32))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (8, 31))	('abnormal', 'Var', (55, 63))	('related', 'Reg', (44, 51))	('E-cadherin', 'Gene', (91, 101))	('E-cadherin', 'Gene', '999', (91, 101))	('mutations', 'Var', (78, 87))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (8, 32))
466173	33672007	Lymphatic node metastases and distant metastases, but not overall survival, were all significantly associated with the presence of p53 auto-antibodies.	('metastases', 'Disease', (15, 25))	('metastases', 'Disease', 'MESH:D009362', (38, 48))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('auto-antibodies', 'Var', (135, 150))	('metastases', 'Disease', 'MESH:D009362', (15, 25))	('presence', 'Var', (119, 127))	('metastases', 'Disease', (38, 48))	('associated', 'Reg', (99, 109))
466176	33672007	A different six-antigen panel, including CTAG1B/CTAG2, DDX53, IGF2BP2, P53P53, and MAGEA3, detected 13% of gastric cancer patients.	('P53P53', 'Var', (71, 77))	('DDX53', 'Gene', '168400', (55, 60))	('CTAG1B', 'Gene', '1485', (41, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('CTAG2', 'Gene', (48, 53))	('IGF2BP2', 'Gene', '10644', (62, 69))	('CTAG2', 'Gene', '30848', (48, 53))	('MAGEA3', 'Gene', '4102', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('detected', 'Reg', (91, 99))	('patients', 'Species', '9606', (122, 130))	('IGF2BP2', 'Gene', (62, 69))	('MAGEA3', 'Gene', (83, 89))	('gastric cancer', 'Disease', (107, 121))	('CTAG1B', 'Gene', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))	('DDX53', 'Gene', (55, 60))
466187	33672007	MUC4 is an antigen that is normally not expressed in the pancreas but often appears in tumor cells and can induce the production of auto-antibodies and reactive T cells, especially against MUC4 forms carrying aberrant glycosylation patterns or mutations, or differing for alternative splicing.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (209, 231))	('MUC4', 'Gene', (189, 193))	('MUC4', 'Gene', (0, 4))	('induce', 'Reg', (107, 113))	('aberrant', 'Var', (209, 217))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutations', 'Var', (244, 253))	('MUC4', 'Gene', '4585', (189, 193))	('MUC4', 'Gene', '4585', (0, 4))
466193	33672007	In 2013, the general concept of "driver genes" was introduced to indicate mutations of about 140 genes that can lead or "drive" carcinogenesis following intragenic mutations, acting on 12 pathways and 3 functions: cell fate, cell survival, and genome maintenance.	('carcinogenesis', 'Disease', (128, 142))	('lead', 'Reg', (112, 116))	('mutations', 'Var', (74, 83))	('acting', 'Reg', (175, 181))	('drive', 'PosReg', (121, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (128, 142))	('mutations', 'Var', (164, 173))
466194	33672007	A typical tumor contains two to eight driver mutations, while all the others do not confer growth advantage.	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
466202	33672007	Importantly, there was a higher cumulative survival rate in patients with serum anti-NY-ESO-1 positivity than in those with serum negativity among the patients with stage III or IV.	('NY-ESO-1', 'Gene', (85, 93))	('cumulative survival rate', 'CPA', (32, 56))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (151, 159))	('NY-ESO-1', 'Gene', '1485', (85, 93))	('positivity', 'Var', (94, 104))	('higher', 'PosReg', (25, 31))
466210	33672007	The current most specific and reliable biomarkers of esophageal cells' malignant transformation are aberrant expression of p53, reported in 50-60% of patients; moreover, early stage dysplasia is often associated with high or low expression of p53.	('dysplasia', 'Disease', (182, 191))	('low', 'NegReg', (225, 228))	('high', 'Var', (217, 221))	('patients', 'Species', '9606', (150, 158))	('p53', 'Gene', (123, 126))	('p53', 'Gene', (243, 246))	('p53', 'Gene', '7157', (243, 246))	('dysplasia', 'Disease', 'MESH:C536170', (182, 191))	('p53', 'Gene', '7157', (123, 126))	('expression', 'MPA', (229, 239))
466213	33672007	Monitoring of auto-antibodies against p53 in post-surgical patients is predictive of residual tumor cells and recurrence.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('auto-antibodies', 'Var', (14, 29))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('patients', 'Species', '9606', (59, 67))
466257	33672007	Early detection (within 30 days) of more than one auto-antibody type among anti-nuclear antigens (ANAs), anti-extractable nuclear antigens (ENAs), and anti-smooth cell antigens (ASMAs), in patients treated with nivolumab-based salvage therapy, associated with prolonged progression-free survival.	('anti-extractable', 'Var', (105, 121))	('prolonged', 'PosReg', (260, 269))	('nivolumab', 'Chemical', 'MESH:D000077594', (211, 220))	('anti-nuclear antigens', 'Protein', (75, 96))	('progression-free survival', 'CPA', (270, 295))	('patients', 'Species', '9606', (189, 197))
466259	33672007	Some of these proteins (CT47A, PAGE3, VCX, MAGEB1, LIN28B, or C12orf54) were proven to induce the production of auto-antibodies, although in a limited number of cases.	('production', 'MPA', (98, 108))	('VCX', 'Gene', '26609', (38, 41))	('PAGE3', 'Gene', (31, 36))	('LIN28B', 'Gene', '389421', (51, 57))	('C12orf54', 'Gene', (62, 70))	('CT47A', 'Var', (24, 29))	('VCX', 'Gene', (38, 41))	('CT47A', 'CellLine', 'CVCL:L675', (24, 29))	('auto-antibodies', 'MPA', (112, 127))	('MAGEB1', 'Gene', '4112', (43, 49))	('MAGEB1', 'Gene', (43, 49))	('PA', 'Phenotype', 'HP:0003765', (31, 33))	('induce', 'PosReg', (87, 93))	('PAGE3', 'Gene', '139793', (31, 36))	('C12orf54', 'Gene', '121273', (62, 70))	('LIN28B', 'Gene', (51, 57))
466267	33672007	Out of the detected proteins, the highest score was for PI3K and p53.	('PI3K', 'Var', (56, 60))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))
466270	33672007	Serum p53 auto-antibodies have also been shown to be associated with aggressiveness of breast cancer.	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('auto-antibodies', 'Var', (10, 25))	('aggressiveness of breast cancer', 'Disease', 'MESH:D001943', (69, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('associated', 'Reg', (53, 63))	('aggressiveness of breast cancer', 'Disease', (69, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('aggressiveness', 'Phenotype', 'HP:0000718', (69, 83))
466279	33672007	Additionally, FATE1 could be relevant also in other tumors as it has been reported that its silencing increased sensitivity of the NCI-H1155 NSLC cell line to paclitaxel and reduced the viability of a variety of other cancer cell lines.	('FATE1', 'Gene', '89885', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('sensitivity', 'MPA', (112, 123))	('FATE1', 'Gene', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('paclitaxel', 'Chemical', 'MESH:D017239', (159, 169))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (218, 224))	('tumors', 'Disease', (52, 58))	('silencing', 'Var', (92, 101))	('NCI-H1155 NSLC', 'CellLine', 'CVCL:1456', (131, 145))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('viability', 'CPA', (186, 195))	('increased', 'PosReg', (102, 111))	('reduced', 'NegReg', (174, 181))	('LC', 'Phenotype', 'HP:0100526', (143, 145))
466323	33672007	A combination of ELISAs for anti-CA15-3, anti-CEA, and anti-CA19-9 reliably discriminated CINs from normal cases, and cancer from normal cases, suggesting that this combination assay could be useful for primary screening of cervical cancer.	('cancer', 'Disease', (118, 124))	('CA15-3', 'Gene', (33, 39))	('discriminated', 'Reg', (76, 89))	('CA15-3', 'Gene', '4582', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('CEA', 'Gene', (46, 49))	('CINs', 'Disease', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (233, 239))	('CEA', 'Gene', '1084', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('CA19-9', 'Chemical', 'MESH:C086528', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('anti-CA19-9', 'Var', (55, 66))
466327	33672007	Several cancer progression subclassifications (using three stages and two grades) have been introduced to define the chance of recurrence, which, in more progressive cases, is very high (50-70%) and will eventually lead to a muscle-invasive disease (MIBC) variant that is associated with a very poor prognosis.	('muscle-invasive disease', 'Disease', 'MESH:D009362', (225, 248))	('cancer', 'Disease', (8, 14))	('lead to', 'Reg', (215, 222))	('MIBC', 'Chemical', '-', (250, 254))	('variant', 'Var', (256, 263))	('muscle-invasive disease', 'Disease', (225, 248))	('BC', 'Phenotype', 'HP:0009725', (252, 254))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
466342	33672007	have described the association of detection of Kelch-like protein 11 auto-antibodies to testicular seminoma in patients with paraneoplastic encephalitis.	('auto-antibodies', 'Var', (69, 84))	('paraneoplastic encephalitis', 'Disease', (125, 152))	('Kelch-like protein 11', 'Gene', '55175', (47, 68))	('encephalitis', 'Phenotype', 'HP:0002383', (140, 152))	('testicular seminoma', 'Phenotype', 'HP:0100617', (88, 107))	('testicular seminoma', 'Disease', 'MESH:D018239', (88, 107))	('testicular seminoma', 'Disease', (88, 107))	('paraneoplastic encephalitis', 'Disease', 'MESH:D010257', (125, 152))	('Kelch-like protein 11', 'Gene', (47, 68))	('patients', 'Species', '9606', (111, 119))
466349	33672007	Interestingly, the detected levels of anti-double strand DNA (dsDNA) and anti-ssDNA were relatively low compared to another study by Swissa et al., who showed high levels in 23.8% NHL patients as well as anti-RNP and anti-SM antibodies that were not detected in most of the control group.	('NHL', 'Disease', (180, 183))	('anti-double', 'Var', (38, 49))	('patients', 'Species', '9606', (184, 192))
466356	33672007	Different from lymphomas and many other cancers, melanomas are often characterized by a very high mutational load, which increases the likelihood of this type of tumor generating neoantigens.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('tumor', 'Disease', (162, 167))	('neoantigens', 'MPA', (179, 190))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('increases', 'PosReg', (121, 130))	('lymphomas', 'Disease', (15, 24))	('cancers', 'Disease', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mutational load', 'Var', (98, 113))	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('melanomas', 'Disease', 'MESH:D008545', (49, 58))	('melanomas', 'Disease', (49, 58))	('generating', 'Reg', (168, 178))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('lymphomas', 'Disease', 'MESH:D008223', (15, 24))	('lymphomas', 'Phenotype', 'HP:0002665', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
466357	33672007	In melanomas, the prognostic value of the mutational load has been investigated and was found to be associated with the clinical benefits of immunotherapy such as the adoptive T cell therapy (ACT), which has shown remarkable results in clinical trials in certain patient groups while failing in others.	('patient', 'Species', '9606', (263, 270))	('mutational load', 'Var', (42, 57))	('melanomas', 'Disease', (3, 12))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanomas', 'Phenotype', 'HP:0002861', (3, 12))	('melanomas', 'Disease', 'MESH:D008545', (3, 12))
466359	33672007	This also aligns well with the observation that tumors with a high mutational load respond better to treatment with immune checkpoint inhibitors in melanoma and lung cancer, and is indicative of an increased production of neoantigens.	('better', 'PosReg', (91, 97))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('respond', 'MPA', (83, 90))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('lung cancer', 'Disease', (161, 172))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('high mutational load', 'Var', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))	('men', 'Species', '9606', (106, 109))
466372	33672007	There are several paraneoplastic syndromes associated to auto-antibodies.	('paraneoplastic syndromes', 'Disease', 'MESH:D010257', (18, 42))	('paraneoplastic syndromes', 'Disease', (18, 42))	('associated', 'Reg', (43, 53))	('auto-antibodies', 'Var', (57, 72))
466375	33672007	To summarize, Table 1 presents the antigens mentioned in the above paragraphs in alphabetical order and Table 2 lists the main auto-antibody combinations that seem promising in early cancer detection or in the prediction of cancer prognosis.	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('combinations', 'Var', (141, 153))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('men', 'Species', '9606', (44, 47))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
466379	33672007	Thus, while mutations of some common antigens, such as p53, have been well documented, much less is known about the mutational status of the newly identified auto-antigens, leaving open the question of their true nature.	('men', 'Species', '9606', (79, 82))	('mutations', 'Var', (12, 21))	('p53', 'Gene', '7157', (55, 58))	('p53', 'Gene', (55, 58))
466392	33672007	Auto-antibodies might initially represent a simple epiphenomenon or a by-product of the inflammatory microenvironment but could become a main player in the tumor progression, conditioning its evolution and outcome.	('Auto-antibodies', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('men', 'Species', '9606', (113, 116))	('tumor', 'Disease', (156, 161))	('men', 'Species', '9606', (59, 62))
466468	30398947	Deficits of selenium and zinc in foods also seem to have an important role in malignant transformation of esophageal epithelium in this region.	('Deficits', 'Var', (0, 8))	('selenium', 'MPA', (12, 20))	('selenium', 'Chemical', 'MESH:D012643', (12, 20))	('malignant transformation', 'CPA', (78, 102))
466483	31622423	Processed meat intake and chronic disease morbidity and mortality: An overview of systematic reviews and meta-analyses Despite the nutritional value of meat, a large volume of reviews and meta-analyses suggests that processed meat intake is associated with an increased risk of chronic diseases.	('chronic diseases', 'Disease', (278, 294))	('chronic disease', 'Disease', 'MESH:D002908', (278, 293))	('processed meat', 'Var', (216, 230))	('chronic disease', 'Disease', (26, 41))	('chronic disease', 'Disease', 'MESH:D002908', (26, 41))	('chronic diseases', 'Disease', 'MESH:D002908', (278, 294))
466506	31622423	In Choi et all, they reported meta-analyses subdivided by study design showing that the direct associations between a high processed meat intake and risk of esophageal cancer remained for the case-control studies (RR: 1.36, 95% CI: 1.07, 1.74) but not for the cohort studies (RR: 1.25, 95% CI: 0.83, 1.86).	('high', 'Var', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('esophageal cancer', 'Disease', (157, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))
466530	31622423	Also, the increased risk of Non-Hodgkin lymphoma with high processed meat intake seemed to be driven by the results from the case-control studies.	('Non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (28, 48))	('Non-Hodgkin lymphoma', 'Disease', (28, 48))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (32, 48))	('Non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (28, 48))	('lymphoma', 'Phenotype', 'HP:0002665', (40, 48))	('high processed', 'Var', (54, 68))
466537	31622423	Many previous reviews report adverse associations between a high processed meat intake and risk of various cancers, T2D and CVD, but most were of moderate methodological quality, where evidence for associations were more often found when reviews were based on results from case-control than when based on cohort studies, suggesting that the better the study design, the lower the probability of an association.	('CVD', 'Disease', 'MESH:D002318', (124, 127))	('lower', 'NegReg', (370, 375))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('high', 'Var', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CVD', 'Disease', (124, 127))	('T2D', 'Disease', (116, 119))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
466627	30626762	Therefore, we hypothesized that treatment for canine ME could prolong the survival time, even in those with both ME and AP.	('canine ME', 'Var', (46, 55))	('AP', 'Phenotype', 'HP:0011951', (120, 122))	('canine', 'Species', '9615', (46, 52))	('prolong', 'PosReg', (62, 69))	('survival time', 'CPA', (74, 87))
466642	30510209	Based on these promising data, modulation of miRNA levels might possibly open a new era of targeted molecular based therapy in cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('modulation', 'Var', (31, 41))	('miR', 'Gene', '220972', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('miR', 'Gene', (45, 48))	('cancer', 'Disease', (127, 133))
466643	30510209	In support of this, multiple studies in recent years have shown that modulation of miRNAs impacts on cellular behaviour and response to chemotherapy in different tumor types.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('modulation', 'Var', (69, 79))	('tumor', 'Disease', (162, 167))	('cellular behaviour', 'CPA', (101, 119))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('impacts', 'Reg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('response to chemotherapy', 'CPA', (124, 148))
466695	30510209	Recently, we introduced the concept that modified miRNA expression in both directions can interfere with the available degree of regulatory freedom of cellular functional complexes and thus change their functional readout.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('functional readout', 'MPA', (203, 221))	('modified', 'Var', (41, 49))	('change', 'Reg', (190, 196))	('available degree of regulatory freedom', 'MPA', (109, 147))	('interfere', 'NegReg', (90, 99))
466700	30510209	Taken together, our data showed that manipulating the expression levels of miR-130a-3p and miR-148a-3p in both directions led to similar effects on chemotherapy response, and modulation of miR-148a-3p levels in both directions affected the metastatic potential of cell lines in the same way.	('metastatic potential of cell lines', 'CPA', (240, 274))	('manipulating', 'Var', (37, 49))	('miR-148a', 'Gene', '406940', (189, 197))	('miR-130a', 'Gene', '406919', (75, 83))	('miR-148a', 'Gene', (189, 197))	('miR-148a', 'Gene', '406940', (91, 99))	('modulation', 'Var', (175, 185))	('affected', 'Reg', (227, 235))	('chemotherapy response', 'CPA', (148, 169))	('miR-148a', 'Gene', (91, 99))	('effects', 'Reg', (137, 144))	('miR-130a', 'Gene', (75, 83))
466718	30510209	Consequently, modulation of miR-130a levels by upregulation can either sensitise cells to chemotherapeutic agents or contribute to drug resistance.	('modulation', 'Var', (14, 24))	('drug resistance', 'CPA', (131, 146))	('miR-130a', 'Gene', (28, 36))	('drug resistance', 'Phenotype', 'HP:0020174', (131, 146))	('upregulation', 'PosReg', (47, 59))	('miR-130a', 'Gene', '406919', (28, 36))	('sensitise', 'Reg', (71, 80))	('contribute to', 'Reg', (117, 130))
466723	30510209	increase in apoptosis or chemosensitivity following modulation of the miRNA of interest in one direction, and decrease in apoptosis or chemosensitivity when expression of the miRNA was modified in the other direction.	('chemosensitivity', 'CPA', (25, 41))	('modulation', 'Var', (52, 62))	('apoptosis', 'MPA', (122, 131))	('miR', 'Gene', '220972', (175, 178))	('miR', 'Gene', (175, 178))	('chemosensitivity', 'CPA', (135, 151))	('miR', 'Gene', '220972', (70, 73))	('decrease', 'NegReg', (110, 118))	('miR', 'Gene', (70, 73))	('increase', 'PosReg', (0, 8))	('apoptosis', 'CPA', (12, 21))
466744	30510209	For example, knockdown as well as enhanced miR-31 expression in AsPC-1 cells decreased the ability to migrate (miR-31 inhibition: -33%, miR-31 upregulation: -61%) or invade (miR-31 inhibition: -27%, miR-31 upregulation: -74%).	('miR-31', 'Gene', (199, 205))	('miR-31', 'Gene', '407035', (43, 49))	('enhanced', 'PosReg', (34, 42))	('AsPC-1', 'CellLine', 'CVCL:0152', (64, 70))	('miR-31', 'Gene', (111, 117))	('decreased', 'NegReg', (77, 86))	('miR-31', 'Gene', '407035', (136, 142))	('miR-31', 'Gene', '407035', (199, 205))	('miR-31', 'Gene', '407035', (174, 180))	('upregulation', 'PosReg', (143, 155))	('knockdown', 'Var', (13, 22))	('miR-31', 'Gene', (43, 49))	('invade', 'CPA', (166, 172))	('miR-31', 'Gene', '407035', (111, 117))	('miR-31', 'Gene', (174, 180))	('expression', 'MPA', (50, 60))	('miR-31', 'Gene', (136, 142))
466759	30510209	For example, ectopic expression of miR-148a induced apoptosis by suppression of Bcl-2 and activation of a caspase cascade in colorectal cancer cells.	('activation', 'PosReg', (90, 100))	('colorectal cancer', 'Disease', (125, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('suppression', 'NegReg', (65, 76))	('Bcl-2', 'Gene', (80, 85))	('miR-148a', 'Gene', '406940', (35, 43))	('caspase cascade', 'Pathway', (106, 121))	('Bcl-2', 'Gene', '596', (80, 85))	('miR-148a', 'Gene', (35, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('ectopic expression', 'Var', (13, 31))	('apoptosis', 'Disease', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
466779	30510209	The four ESCC cell lines KYSE-70, KYSE-140, KYSE-270 and KYSE-410 were grown to 60-80% confluence, followed by a transfection with either mimics or inhibitors of miR-130a-3p or miR-148a-3p (Qiagen, #MSY0000243, #MSY0000425, #MIN0000243, #MIN0000425), or the negative scramble-control (Qiagen, #SI03650318) using Lipofectamine 2000 transfection agent (Life Technologies, #11668027).	('#MIN0000425', 'Var', (237, 248))	('miR-148a', 'Gene', (177, 185))	('#MSY0000425', 'Var', (211, 222))	('#MIN0000243', 'Var', (224, 235))	('miR-130a', 'Gene', (162, 170))	('miR-148a', 'Gene', '406940', (177, 185))	('miR-130a', 'Gene', '406919', (162, 170))
466781	30510209	Transfected cells were treated 24 h post-transfection with Cisplatin (Teva GmbH) or 5-FU (Medac GmbH), which represent the standard chemotherapy treatment for esophageal cancer.	('esophageal cancer', 'Disease', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Medac', 'Chemical', '-', (90, 95))	('Teva', 'Chemical', '-', (70, 74))	('Cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('5-FU', 'Var', (84, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('5-FU', 'Chemical', 'MESH:D005472', (84, 88))
466796	30510209	The effect that modulating miRNA expression had on the response to chemotherapy was analysed as described previously.	('modulating', 'Var', (16, 26))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))
466832	24036867	The volume of lung irradiated by a dose of 5, 10, 13, 20, and 30 Gy (V5, V10, V13, V20, and V30, respectively) was also calculated and compared.	('V20', 'Var', (83, 86))	('V10', 'Var', (73, 76))	('V13', 'Gene', '28816', (78, 81))	('V30', 'Var', (92, 95))	('V13', 'Gene', (78, 81))
466857	24036867	V10 and V13 were also suggested to be strong indicators for pulmonary pneumonitis in a retrospective study.	('pulmonary pneumonitis', 'Disease', 'MESH:D011014', (60, 81))	('V13', 'Gene', (8, 11))	('pulmonary pneumonitis', 'Disease', (60, 81))	('V13', 'Gene', '28816', (8, 11))	('V10', 'Var', (0, 3))
466969	28948163	revealed that high BMI could significantly enhance overall survival of esophageal cancer (HR = 0.78, 95% CI = 0.71-0.85), which was consistent with this study.	('overall survival', 'CPA', (51, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('high', 'Var', (14, 18))	('esophageal cancer', 'Disease', (71, 88))	('BMI', 'Gene', (19, 22))	('enhance', 'PosReg', (43, 50))
466976	28948163	Overweight and obesity in esophageal survivors may induce anastomotic leakage (RR = 1.04, 95% CI = 1.02-1.06), wound infection (RR = 1.03, 95% CI = 1.00-1.05), slow growth of anastomosis, and cardiovascular diseases.	('obesity', 'Disease', 'MESH:D009765', (15, 22))	('cardiovascular diseases', 'Disease', (192, 215))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (192, 214))	('obesity', 'Disease', (15, 22))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (192, 215))	('wound infection', 'CPA', (111, 126))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (192, 215))	('Overweight', 'Var', (0, 10))	('induce', 'Reg', (51, 57))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('slow growth', 'Phenotype', 'HP:0001510', (160, 171))	('slow growth of anastomosis', 'CPA', (160, 186))	('obesity', 'Phenotype', 'HP:0001513', (15, 22))	('anastomotic leakage', 'CPA', (58, 77))
466997	27442643	In conclusion, patients with BMIs >=23 kg/m2 experienced better OS, and multivariate analysis further indicated that BMI >=23 kg/m2 was an independent predictor of survival.	('better', 'PosReg', (57, 63))	('patients', 'Species', '9606', (15, 23))	('BMIs >=23 kg/m2', 'Var', (29, 44))
467011	27442643	Thus, we used Asian-specific BMI cut-offs and merged the obese and overweight groups, as in a previous Asian study: underweight (<18.5 kg/m2), normal weight (18.5-22.9 kg/m2), overweight and obese (>=23.0 kg/m2).	('obese', 'Disease', 'MESH:D009765', (191, 196))	('overweight', 'Phenotype', 'HP:0025502', (67, 77))	('obese', 'Disease', 'MESH:D009765', (57, 62))	('obese', 'Disease', (57, 62))	('obese', 'Disease', (191, 196))	('overweight', 'Phenotype', 'HP:0025502', (176, 186))	('<18.5 kg/m2', 'Var', (129, 140))	('18.5-22.9', 'Var', (158, 167))
467038	27442643	It remains unclear why high-BMI patients enjoy better OS, although some hypotheses have been suggested, including that the resection margins of high-BMI patients may more often be tumor-free after esophagectomy.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('high-BMI', 'Var', (144, 152))	('tumor', 'Disease', (180, 185))
467042	27442643	In conclusion, patients with a BMI >=23 kg/m2 experienced better OS, and multivariate analysis further indicated that a BMI >=23 kg/m2 was an independent predictor of survival.	('better', 'PosReg', (58, 64))	('BMI >=23 kg/m2', 'Var', (31, 45))	('patients', 'Species', '9606', (15, 23))
467079	27421772	We hypothesized that alterations in Ep-ICD and EpEx sub-cellular localization in membrane, cytoplasm and nucleus could influence oral cancer pathogenesis and may correlate with clinical outcome in these patients.	('oral cancer', 'Disease', (129, 140))	('Ep-ICD', 'Gene', (36, 42))	('influence', 'Reg', (119, 128))	('patients', 'Species', '9606', (203, 211))	('pathogenesis', 'CPA', (141, 153))	('EpEx', 'Gene', (47, 51))	('correlate', 'Reg', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alterations', 'Var', (21, 32))	('oral cancer', 'Disease', 'MESH:D009062', (129, 140))
467132	27421772	OSCC patients with increased combination of Ep-ICDNuc and EpExMem had significantly reduced mean DFS of 33.7 months as compared to patients with low Ep-ICDNuc and EpExMem score (mean DFS = 46.3 months; p = 0.018, Fig.	('patients', 'Species', '9606', (131, 139))	('Ep-ICDNuc', 'Var', (44, 53))	('patients', 'Species', '9606', (5, 13))	('OSCC', 'Chemical', '-', (0, 4))	('reduced', 'NegReg', (84, 91))	('OSCC', 'Disease', (0, 4))
467147	27421772	In an earlier study, we reported that Ep-ICDNuc accumulation predicted poor prognosis in thyroid carcinomas and was elevated in patients with anaplastic tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('Ep-ICDNuc', 'Var', (38, 47))	('poor', 'NegReg', (71, 75))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (89, 107))	('elevated', 'PosReg', (116, 124))	('anaplastic tumors', 'Disease', 'MESH:D002277', (142, 159))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (89, 107))	('thyroid carcinomas', 'Disease', (89, 107))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('anaplastic tumors', 'Disease', (142, 159))	('patients', 'Species', '9606', (128, 136))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (89, 106))
467148	27421772	Notably, we observed that OSCC patients showing increased EpExMem and Ep-ICDNuc had reduced disease free survival and poor prognosis as compared to patients who did not show this increase, suggesting that dynamic changes in EpExMem and Ep-ICDNuc must be taken into account collectively to assess their prognostic utility in OSCC.	('increased', 'PosReg', (48, 57))	('patients', 'Species', '9606', (148, 156))	('OSCC', 'Disease', (324, 328))	('OSCC', 'Disease', (26, 30))	('Ep-ICDNuc', 'Var', (70, 79))	('EpExMem', 'Var', (58, 65))	('reduced', 'NegReg', (84, 91))	('disease free survival', 'CPA', (92, 113))	('patients', 'Species', '9606', (31, 39))	('OSCC', 'Chemical', '-', (324, 328))	('OSCC', 'Chemical', '-', (26, 30))
467247	32781500	ICIs, specifically PD-1, PDL-1 and CTLA-4 inhibitors have been approved for the treatment of a variety of solid tumors, initially beginning with melanoma in 2011.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('solid tumors', 'Disease', (106, 118))	('CTLA-4', 'Gene', (35, 41))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PDL-1', 'Gene', '29126', (25, 30))	('inhibitors', 'Var', (42, 52))	('men', 'Species', '9606', (85, 88))	('CTLA-4', 'Gene', '1493', (35, 41))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('PDL-1', 'Gene', (25, 30))	('PD-1', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
467272	32781500	The study demonstrated that overall survival for patients in the pembrolizumab arm was non-inferior to those receiving standard chemotherapy for patients whose tumors had a CPS >= 1.	('patients', 'Species', '9606', (145, 153))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('CPS', 'Chemical', '-', (173, 176))	('CPS >= 1', 'Var', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('patients', 'Species', '9606', (49, 57))	('tumors', 'Disease', (160, 166))	('pembrolizumab', 'Chemical', 'MESH:C582435', (65, 78))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
467274	32781500	Patient who had received pembrolizumab had median overall survival of 10.6 months compared with 11.1 months for those who received chemotherapy only.	('pembrolizumab', 'Chemical', 'MESH:C582435', (25, 38))	('overall survival', 'MPA', (50, 66))	('pembrolizumab', 'Var', (25, 38))	('Patient', 'Species', '9606', (0, 7))
467291	32781500	However, a subgroup analysis demonstrated a significant benefit for use of pembrolizumab over a taxane in patients with a deficient mismatch repair (dMMR) GEJ or gastric cancer.	('dMMR', 'Chemical', '-', (149, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (162, 176))	('deficient mismatch', 'Var', (122, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('pembrolizumab', 'Chemical', 'MESH:C582435', (75, 88))	('mismatch', 'Var', (132, 140))	('patients', 'Species', '9606', (106, 114))	('gastric cancer', 'Disease', (162, 176))	('taxane', 'Chemical', 'MESH:C080625', (96, 102))
467384	32781500	There are currently ongoing ICI combination studies including ICIs with TGF-beta inhibitors, with indoleamine dioxygenase inhibitors, with intra-arterial therapies, with radiation and with angiogenesis inhibitors.	('TGF-beta', 'Gene', '7039', (72, 80))	('indoleamine dioxygenase', 'MPA', (98, 121))	('TGF-beta', 'Gene', (72, 80))	('inhibitors', 'Var', (81, 91))
467385	32781500	Some ongoing Phase III ICIs combination studies include: Nivolumab plus ipilimumab in advanced HCC as first line therapy (NCT03510871, NCT03222076, NCT03203304, NCT01658878, NCT04039607) and durvalumab plus tremelimumab in advanced HCC as second line therapy (NCT03298451).	('Nivolumab', 'Chemical', 'MESH:D000077594', (57, 66))	('durvalumab plus tremelimumab', 'Disease', 'MESH:D007625', (191, 219))	('advanced', 'Disease', (86, 94))	('ipilimumab', 'Chemical', 'MESH:D000074324', (72, 82))	('NCT03510871', 'Var', (122, 133))	('durvalumab plus tremelimumab', 'Disease', (191, 219))	('NCT03203304', 'Var', (148, 159))	('NCT03222076', 'Var', (135, 146))
467386	32781500	Phase III studies involving ICI and angiogenesis inhibitors include: nivolumab plus sorafenib in advanced HCC as first line therapy (NCT02576509, NCT01658878, NCT03439891), pembrolizumab plus lenvatinib in patients with advanced HCC as first line therapy (NCT03713593), atezolizumab plus cabozantinib in advanced HCC as first line therapy (NCT03755791), atezolizumab plus bevacizumab in advanced HCC as first line therapy (NCT03434379), durvalumab plus bevacizumab in localized and locally advanced HCC (NCT03847428, NCT03778957), camrelizumab plus apatinib in advanced HCC as first line therapy (NCT02942329, NCT03764293), tislelizumab plus sorafenib for advanced HCC as first line therapy (NCT03412773) and sintilimab plus IBI305 in advanced HCC as first line therapy (NCT03794440).	('bevacizumab', 'Chemical', 'MESH:D000068258', (372, 383))	('sorafenib', 'Chemical', 'MESH:D000077157', (642, 651))	('tislelizumab plus sorafenib', 'Disease', (624, 651))	('sorafenib', 'Chemical', 'MESH:D000077157', (84, 93))	('atezolizumab', 'Chemical', 'MESH:C000594389', (270, 282))	('NCT03412773', 'Var', (692, 703))	('tislelizumab plus sorafenib', 'Disease', 'MESH:D007625', (624, 651))	('lenvatinib', 'Chemical', 'MESH:C531958', (192, 202))	('atezolizumab plus bevacizumab', 'Disease', (354, 383))	('nivolumab', 'Chemical', 'MESH:D000077594', (69, 78))	('atezolizumab plus bevacizumab', 'Disease', 'MESH:D007625', (354, 383))	('cabozantinib', 'Chemical', 'MESH:C558660', (288, 300))	('pembrolizumab', 'Chemical', 'MESH:C582435', (173, 186))	('atezolizumab', 'Chemical', 'MESH:C000594389', (354, 366))	('bevacizumab', 'Chemical', 'MESH:D000068258', (453, 464))	('durvalumab', 'Chemical', 'MESH:C000613593', (437, 447))	('NCT02942329', 'Var', (597, 608))	('patients', 'Species', '9606', (206, 214))	('NCT03764293', 'CellLine', 'None', (610, 621))
467404	32781500	KEYNOTE-158, was a nonrandomized, open label, multisite phase II study that enrolled patients with histologically or cytologically confirmed MSI-H/dMMR advanced non-colorectal cancer, including biliary adenocarcinoma, who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years until disease progression, unacceptable toxicity or patient withdrawal.	('patient', 'Species', '9606', (85, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (165, 182))	('non-colorectal cancer', 'Disease', 'MESH:D015179', (161, 182))	('patient', 'Species', '9606', (374, 381))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('dMMR', 'Chemical', '-', (147, 151))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('MSI-H/dMMR', 'Var', (141, 151))	('toxicity', 'Disease', 'MESH:D064420', (362, 370))	('toxicity', 'Disease', (362, 370))	('biliary adenocarcinoma', 'Disease', 'MESH:D000230', (194, 216))	('pembrolizumab', 'Chemical', 'MESH:C582435', (270, 283))	('non-colorectal cancer', 'Disease', (161, 182))	('biliary adenocarcinoma', 'Disease', (194, 216))
467405	32781500	There are ongoing phase II trials with first line combination nivolumab plus ipilimumab in advanced cholangiocarcinoma (NCT03101566, NCT02834013), second line pembrolizumab monotherapy in advanced cholangiocarcinoma (NCT03110328, NCT02628067), second line nivolumab in advanced cholangiocarcinoma (NCT02829918), first line durvalumab and tremelimumab with chemotherapy in advanced cholangiocarcinoma (NCT03473574, NCT03046862, NCT03704480), first line toripalimab with chemotherapy in advanced cholangiocarcinoma (NCT03796429, NCT03982680, NCT04027764).	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('nivolumab', 'Chemical', 'MESH:D000077594', (256, 265))	('cholangiocarcinoma', 'Disease', (100, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('durvalumab', 'Chemical', 'MESH:C000613593', (323, 333))	('pembrolizumab', 'Chemical', 'MESH:C582435', (159, 172))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (494, 512))	('NCT02829918', 'Var', (298, 309))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (278, 296))	('NCT04027764', 'Var', (540, 551))	('nivolumab', 'Chemical', 'MESH:D000077594', (62, 71))	('tremelimumab', 'Chemical', 'MESH:C520704', (338, 350))	('NCT03110328', 'Var', (217, 228))	('cholangiocarcinoma', 'Disease', (494, 512))	('NCT03704480', 'Var', (427, 438))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (494, 512))	('cholangiocarcinoma', 'Disease', (278, 296))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (278, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (381, 399))	('ipilimumab', 'Chemical', 'MESH:D000074324', (77, 87))	('NCT03982680', 'Var', (527, 538))	('NCT03473574', 'Var', (401, 412))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (197, 215))	('cholangiocarcinoma', 'Disease', (381, 399))	('carcinoma', 'Phenotype', 'HP:0030731', (503, 512))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (381, 399))	('cholangiocarcinoma', 'Disease', (197, 215))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (197, 215))	('NCT03796429', 'Var', (514, 525))
467406	32781500	There are ongoing phase III trials of first line durvalumab with chemotherapy for advanced cholangiocarcinoma (NCT03875235) and first line pembrolizumab with chemotherapy in advanced cholangiocarcinoma (NCT03260712, NCT03111732, NCT04003636).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('NCT03875235', 'Var', (111, 122))	('durvalumab', 'Chemical', 'MESH:C000613593', (49, 59))	('NCT03260712', 'Var', (203, 214))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('pembrolizumab', 'Chemical', 'MESH:C582435', (139, 152))	('NCT03111732', 'Var', (216, 227))	('cholangiocarcinoma', 'Disease', (183, 201))	('NCT04003636', 'Var', (229, 240))	('cholangiocarcinoma', 'Disease', (91, 109))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (183, 201))
467440	32781500	Another option is encorafenib along with cetuximab for BRAF mutation positive tumors.	('cetuximab', 'Chemical', 'MESH:D000068818', (41, 50))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutation positive', 'Var', (60, 77))	('BRAF', 'Gene', '673', (55, 59))	('encorafenib', 'Chemical', 'MESH:C000601108', (18, 29))	('BRAF', 'Gene', (55, 59))
467552	32629742	The immunohistochemistry results indicated cytokeratin CK34betaE12 (+++), CK Pan (+++), CK5/6 (+++), and smooth muscle actin SMA(-), which supported a diagnosis of SCC (Fig.	('+++', 'Var', (82, 85))	('SCC', 'Phenotype', 'HP:0002860', (164, 167))	('CK5/6', 'Gene', '3852', (88, 93))	('SCC', 'Disease', (164, 167))	('CK5/6', 'Gene', (88, 93))	('cytokeratin', 'Var', (43, 54))	('CK Pan (+++', 'Var', (74, 85))
467671	32052040	The heart and pericardium V5-V100-BED were significantly higher in patients with symptomatic PE than in those without symptomatic PE (heart: V5-V95-BED, P < 0.001; V100-BED, P = 0.0053, and pericardium: V5-V40-BED, V55-V95-BED, P < 0.001; V45-50-BED, V100-BED, P < 0.05, respectively).	('a', 'Gene', '351', (195, 196))	('a', 'Gene', '351', (6, 7))	('a', 'Gene', '351', (68, 69))	('a', 'Gene', '351', (10, 11))	('PE', 'Phenotype', 'HP:0001698', (93, 95))	('patients', 'Species', '9606', (67, 75))	('higher', 'PosReg', (57, 63))	('a', 'Gene', '351', (186, 187))	('a', 'Gene', '351', (125, 126))	('PE', 'Phenotype', 'HP:0001698', (130, 132))	('a', 'Gene', '351', (51, 52))	('V5-V40-BED', 'Var', (203, 213))	('a', 'Gene', '351', (19, 20))	('V55-V95-BED', 'Var', (215, 226))	('a', 'Gene', '351', (88, 89))	('V100-BED', 'Var', (251, 259))	('a', 'Gene', '351', (98, 99))	('a', 'Gene', '351', (136, 137))
467804	32052040	showed that IMRT results in a lower risk of non-disease-related death, especially heart-related death, compared with 3D-CRT in the treatment of esophageal cancer.	('a', 'Gene', '351', (152, 153))	('death', 'Disease', (96, 101))	('a', 'Gene', '351', (134, 135))	('death', 'Disease', (64, 69))	('a', 'Gene', '351', (149, 150))	('a', 'Gene', '351', (84, 85))	('a', 'Gene', '351', (77, 78))	('a', 'Gene', '351', (59, 60))	('a', 'Gene', '351', (28, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('a', 'Gene', '351', (107, 108))	('a', 'Gene', '351', (52, 53))	('death', 'Disease', 'MESH:D003643', (96, 101))	('a', 'Gene', '351', (156, 157))	('a', 'Gene', '351', (91, 92))	('a', 'Gene', '351', (98, 99))	('esophageal cancer', 'Disease', (144, 161))	('IMRT', 'Var', (12, 16))	('death', 'Disease', 'MESH:D003643', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('a', 'Gene', '351', (66, 67))	('a', 'Gene', '351', (9, 10))
467850	31632889	Fistulae between the respiratory and gastrointestinal tracts can simulate bronchiectasis and result in recurrent episodes of inflammatory or infectious conditions.	('bronchiectasis', 'Phenotype', 'HP:0002110', (74, 88))	('bronchiectasis', 'Disease', (74, 88))	('bronchiectasis', 'Disease', 'MESH:D001987', (74, 88))	('result in', 'Reg', (93, 102))	('recurrent episodes', 'Phenotype', 'HP:0002719', (103, 121))	('Fistulae', 'Var', (0, 8))
467959	31462302	To optimize expression of introduced TCR in T cells, TCR was constructed in a beta/alpha chain order and constant regions was replaced by mouse counterparts modified with interchain disulfide bond and hydrophobic substitution as previously described (Fig.	('disulfide', 'Chemical', 'MESH:D004220', (182, 191))	('a beta', 'Gene', (76, 82))	('mouse', 'Species', '10090', (138, 143))	('a beta', 'Gene', '14961', (76, 82))	('hydrophobic substitution', 'Var', (201, 225))
467977	31462302	Recently, most studies demonstrated that TILs were cultured with autologous dendritic cells pulsed with neoantigens to enrich tumor-reactive TILs and isolate their TCRs, but only less than 1% of all somatic mutations could induce T-cell immune response in epithelial cancers.	('TIL', 'Gene', '7096', (41, 44))	('induce', 'Reg', (223, 229))	('TIL', 'Gene', '7096', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('epithelial cancers', 'Disease', (256, 274))	('epithelial cancer', 'Phenotype', 'HP:0031492', (256, 273))	('TIL', 'Gene', (41, 44))	('mutations', 'Var', (207, 216))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('T-cell immune response', 'CPA', (230, 252))	('TIL', 'Gene', (141, 144))	('epithelial cancers', 'Disease', 'MESH:D000077216', (256, 274))	('tumor', 'Disease', (126, 131))
467984	31462302	And then we found that PBLs modified by the most dominant TCR could identify and kill autologous tumor cells in vivo and in vitro.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('identify', 'CPA', (68, 76))	('tumor', 'Disease', (97, 102))	('modified', 'Var', (28, 36))	('TCR', 'Gene', (58, 61))
468020	30123073	Compared with the control groups, the mRNA and protein expression levels of mature IL-1beta and IL-18 were increased in the alcohol-treated group, further consolidating our results that alcohol could induce pyroptosis and activate the inflammatory response to promote the occurrence and development of esophagitis.	('promote', 'PosReg', (260, 267))	('pyroptosis', 'MPA', (207, 217))	('increased', 'PosReg', (107, 116))	('esophagitis', 'Disease', (302, 313))	('induce', 'Reg', (200, 206))	('inflammatory response', 'CPA', (235, 256))	('esophagitis', 'Phenotype', 'HP:0100633', (302, 313))	('esophagitis', 'Disease', 'MESH:D004941', (302, 313))	('alcohol', 'Chemical', 'MESH:D000438', (124, 131))	('alcohol', 'Var', (186, 193))	('activate', 'PosReg', (222, 230))	('development', 'CPA', (287, 298))	('alcohol', 'Chemical', 'MESH:D000438', (186, 193))
468046	30123073	Several studies showed that alcohol consumption was associated with an increased risk of reflux esophagitis.	('increased risk of reflux', 'Phenotype', 'HP:0002020', (71, 95))	('esophagitis', 'Phenotype', 'HP:0100633', (96, 107))	('reflux esophagitis', 'Disease', 'MESH:D005764', (89, 107))	('alcohol', 'Chemical', 'MESH:D000438', (28, 35))	('reflux esophagitis', 'Disease', (89, 107))	('alcohol consumption', 'Var', (28, 47))
468048	30123073	Furthermore, alcohol accumulation could activate caspase-1, IL-1beta and IL-18, amplifying the inflammatory response to aggravate the progress of diseases through pyroptosis pathway.	('alcohol accumulation', 'Phenotype', 'HP:0030955', (13, 33))	('pyroptosis pathway', 'Pathway', (163, 181))	('IL-1beta', 'Gene', (60, 68))	('alcohol', 'Var', (13, 20))	('alcohol', 'Chemical', 'MESH:D000438', (13, 20))	('IL-18', 'Gene', (73, 78))	('progress of', 'CPA', (134, 145))	('amplifying', 'PosReg', (80, 90))	('aggravate', 'PosReg', (120, 129))	('inflammatory response', 'CPA', (95, 116))	('activate', 'PosReg', (40, 48))	('caspase-1', 'Protein', (49, 58))
468054	30123073	Our study, for the first time, identified that alcohol accumulation could cause inflammatory response and induce pyroptosis.	('induce', 'Reg', (106, 112))	('pyroptosis', 'CPA', (113, 123))	('alcohol accumulation', 'Phenotype', 'HP:0030955', (47, 67))	('inflammatory response', 'CPA', (80, 101))	('alcohol', 'Chemical', 'MESH:D000438', (47, 54))	('alcohol accumulation', 'Var', (47, 67))	('cause', 'Reg', (74, 79))
468081	30123073	The PVDF membranes were blocked with 5% BSA in 0.05% Tween 20-TBS for 1 hour and were incubated with the corresponding primary antibody diluted in blocking buffer overnight at 4 C. The dilutions for primary antibodies were as follows: anti-caspase-1 (1:1000, Cell Signaling; 2225), anti-IL-1beta and anti-IL-18 (1:400; Santa Cruz Biotech).	('PVDF', 'Chemical', 'MESH:C024865', (4, 8))	('anti-IL-1beta', 'Var', (282, 295))	('Tween 20-TBS', 'Chemical', '-', (53, 65))	('anti-caspase-1', 'Var', (235, 249))	('anti-IL-18', 'Var', (300, 310))
468101	29595629	Many previous studies have suggested risk factors for esophageal cancer, including cigarette smoking, alcohol drinking, and body mass index, whereas the consumption of vegetables and fruits play an essential role in reducing the incidence rate of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('esophageal cancer', 'Disease', (247, 264))	('body mass index', 'Var', (124, 139))	('alcohol drinking', 'Phenotype', 'HP:0030955', (102, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (247, 264))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('alcohol', 'Chemical', 'MESH:D000438', (102, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))
468192	29581763	The 5-year survival rate of all cancer combined in patients from Qidong (32.72%) was higher than that in patients from Haimen (29.57%) (P=0.0001) (Figure 3A).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('patients', 'Species', '9606', (105, 113))	('higher', 'PosReg', (85, 91))	('cancer', 'Disease', (32, 38))	('Qidong', 'Var', (65, 71))	('survival', 'CPA', (11, 19))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('men', 'Species', '9606', (122, 125))
468287	28441719	ROS can activate downstream key transcription factors such as nuclear factor-erythroid 2-related factor-2 (Nrf2), nuclear factor kappaB (NFkappaB) and mitogen-activated protein kinase (MAPK).	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('NFkappaB', 'Gene', (137, 145))	('NFkappaB', 'Gene', '4790', (137, 145))	('nuclear factor kappaB', 'Gene', '4790', (114, 135))	('activate', 'PosReg', (8, 16))	('nuclear factor kappaB', 'Gene', (114, 135))	('Nrf2', 'Gene', (107, 111))	('nuclear factor-erythroid 2-related factor-2', 'Gene', (62, 105))	('nuclear factor-erythroid 2-related factor-2', 'Gene', '83619', (62, 105))
468288	28441719	Alterations of NFkappaB and MAPK signaling are key oncogenic events during ESCC tumor promotion and progression.	('NFkappaB', 'Gene', '4790', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('NFkappaB', 'Gene', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Alterations', 'Var', (0, 11))	('ESCC', 'Disease', (75, 79))	('tumor', 'Disease', (80, 85))	('rat', 'Species', '10116', (4, 7))	('MAPK signaling', 'Pathway', (28, 42))
468379	28441719	Increased ROS can result in a decrease in GSH and NADPH, and converts these into oxidized GSSG and NADP+, respectively.	('GSH', 'Chemical', '-', (42, 45))	('NADPH', 'MPA', (50, 55))	('ROS', 'Var', (10, 13))	('NADP+', 'Chemical', 'MESH:D009249', (99, 104))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('decrease', 'NegReg', (30, 38))	('GSH', 'MPA', (42, 45))	('GSSG', 'Chemical', 'MESH:D019803', (90, 94))	('NADPH', 'Chemical', 'MESH:D009249', (50, 55))
468392	28441719	C3G can inhibit oxidative stress in preclinical skin cancer model and stimulate biosynthesis of GSH in mice with hepatic oxidative damage.	('GSH', 'Chemical', '-', (96, 99))	('hepatic oxidative damage', 'Disease', 'MESH:D004194', (113, 137))	('biosynthesis', 'MPA', (80, 92))	('inhibit', 'NegReg', (8, 15))	('hepatic oxidative damage', 'Disease', (113, 137))	('mice', 'Species', '10090', (103, 107))	('C3G', 'Var', (0, 3))	('oxidative stress', 'MPA', (16, 32))	('skin cancer', 'Phenotype', 'HP:0008069', (48, 59))	('C3G', 'Chemical', 'MESH:C114438', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('skin cancer', 'Disease', (48, 59))	('GSH', 'Protein', (96, 99))	('oxidative stress', 'Phenotype', 'HP:0025464', (16, 32))	('stimulate', 'PosReg', (70, 79))	('skin cancer', 'Disease', 'MESH:D012878', (48, 59))
468393	28441719	Our studies indicated that C3R, C3G, and C3S inhibit cell proliferation and oncogenic signaling pathways in ESCC cell lines.	('C3R, C3G', 'Gene', '63881', (27, 35))	('C3S', 'Var', (41, 44))	('C3S', 'Chemical', '-', (41, 44))	('oncogenic signaling pathways', 'Pathway', (76, 104))	('inhibit', 'NegReg', (45, 52))	('cell proliferation', 'CPA', (53, 71))	('rat', 'Species', '10116', (65, 68))
468399	28441719	ROS can activate MAPK family members including p38 MAPK and JNK, which subsequently activate genes involved in cellular proliferation.	('MAPK family', 'Pathway', (17, 28))	('cellular proliferation', 'CPA', (111, 133))	('JNK', 'Pathway', (60, 63))	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('activate', 'PosReg', (8, 16))	('genes', 'Gene', (93, 98))	('rat', 'Species', '10116', (127, 130))	('activate', 'PosReg', (84, 92))	('p38', 'Gene', '81649', (47, 50))	('p38', 'Gene', (47, 50))
468404	28441719	H2O2 can also induce the activation of NFkappaB, IkappaBalpha, and p38 MAPK in epithelial cells.	('IkappaBalpha', 'Gene', '25493', (49, 61))	('IkappaBalpha', 'Gene', (49, 61))	('NFkappaB', 'Gene', '4790', (39, 47))	('NFkappaB', 'Gene', (39, 47))	('p38', 'Gene', (67, 70))	('p38', 'Gene', '81649', (67, 70))	('activation', 'PosReg', (25, 35))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))
468416	28441719	Numerous studies show that there are functional cross-talks between Nrf2 and NFkappaB in oxidative stress and inflammation related carcinogenesis, e.g., the inhibition of Nrf2 can exacerbate NFkappaB activity; on the other hand, NFkappaB can modulate transcription and activity of Nrf2.	('NFkappaB', 'Gene', (229, 237))	('inflammation', 'Disease', (110, 122))	('modulate', 'Reg', (242, 250))	('oxidative stress', 'Phenotype', 'HP:0025464', (89, 105))	('Nrf2', 'Gene', (171, 175))	('NFkappaB', 'Gene', '4790', (77, 85))	('activity', 'MPA', (200, 208))	('Nrf2', 'Enzyme', (281, 285))	('carcinogenesis', 'Disease', (131, 145))	('NFkappaB', 'Gene', (77, 85))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('NFkappaB', 'Gene', '4790', (191, 199))	('activity', 'MPA', (269, 277))	('transcription', 'MPA', (251, 264))	('inflammation', 'Disease', 'MESH:D007249', (110, 122))	('NFkappaB', 'Gene', (191, 199))	('NFkappaB', 'Gene', '4790', (229, 237))	('exacerbate', 'PosReg', (180, 190))	('inhibition', 'Var', (157, 167))
468420	28441719	In a mouse model of azoxymethane/dextran sodium sulfate-induced colorectal cancer, deficiencies in antioxidant genes such as GPx3 increase the number of tumors in mice.	('colorectal cancer', 'Disease', (64, 81))	('GPx3', 'Gene', '14778', (125, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('GPx3', 'Gene', (125, 129))	('azoxymethane', 'Chemical', 'MESH:D001397', (20, 32))	('deficiencies', 'Var', (83, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('mice', 'Species', '10090', (163, 167))	('increase', 'PosReg', (130, 138))	('tumors', 'Disease', (153, 159))	('mouse', 'Species', '10090', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('dextran sodium sulfate', 'Chemical', '-', (33, 55))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
468421	28441719	The findings from the current study combined with our previous observations demonstrate that BRB inhibits tumor development in rat esophagus, at least in part, through the reversal of oxidative stress and suppression of NFkappaB/MAPK activation, in parallel to the inhibition of inflammation.	('inflammation', 'Disease', (279, 291))	('rat', 'Species', '10116', (83, 86))	('oxidative stress', 'MPA', (184, 200))	('suppression', 'NegReg', (205, 216))	('inhibits', 'NegReg', (97, 105))	('NFkappaB', 'Gene', (220, 228))	('inflammation', 'Disease', 'MESH:D007249', (279, 291))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('NFkappaB', 'Gene', '4790', (220, 228))	('rat', 'Species', '10116', (127, 130))	('BRB', 'Chemical', '-', (93, 96))	('BRB', 'Var', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('activation', 'PosReg', (234, 244))	('oxidative stress', 'Phenotype', 'HP:0025464', (184, 200))	('tumor', 'Disease', (106, 111))
468424	28441719	Moreover, this study showed that the level of H2O2 is correlated with NFkappaB p65 and p38 MAPK in the esophagus of rats treated with NMBA and dietary BRB.	('rats', 'Species', '10116', (116, 120))	('p65', 'Gene', '25716', (79, 82))	('BRB', 'Chemical', '-', (151, 154))	('p38', 'Gene', '81649', (87, 90))	('p38', 'Gene', (87, 90))	('H2O2', 'Chemical', 'MESH:D006861', (46, 50))	('H2O2', 'Var', (46, 50))	('NMBA', 'Chemical', 'MESH:C014707', (134, 138))	('p65', 'Gene', (79, 82))	('NFkappaB', 'Gene', (70, 78))	('NFkappaB', 'Gene', '4790', (70, 78))
468433	25243545	FTEP was also associated with a lower rate of pulmonary complications (odds ratio = 0.655; 95% confidence interval = 0.456, 0.942; P = 0.022).	('pulmonary complications', 'Disease', (46, 69))	('pulmonary complications', 'Phenotype', 'HP:0006532', (46, 69))	('FTEP', 'Chemical', '-', (0, 4))	('pulmonary complications', 'Disease', 'MESH:D008171', (46, 69))	('FTEP', 'Var', (0, 4))	('lower', 'NegReg', (32, 37))
468434	25243545	These findings suggest that an FTEP reduces patients' LOS, perioperative morbidity and hospital charges.	('perioperative morbidity', 'CPA', (59, 82))	('FTEP', 'Var', (31, 35))	('patients', 'Species', '9606', (44, 52))	('hospital charges', 'CPA', (87, 103))	('FTEP', 'Chemical', '-', (31, 35))	('reduces', 'NegReg', (36, 43))
468499	25243545	Given that MIE is a recent development, the proportion of patients who underwent MIE in group B was unsurprisingly higher than that in group A. Multivariable analysis revealed MIE to be associated with pulmonary complications but not LOS.	('pulmonary complications', 'Disease', 'MESH:D008171', (202, 225))	('MIE', 'Chemical', '-', (11, 14))	('patients', 'Species', '9606', (58, 66))	('MIE', 'Chemical', '-', (176, 179))	('MIE', 'Var', (176, 179))	('MIE', 'Chemical', '-', (81, 84))	('pulmonary complications', 'Phenotype', 'HP:0006532', (202, 225))	('associated with', 'Reg', (186, 201))	('pulmonary complications', 'Disease', (202, 225))
468508	25243545	This suggested that a FTEP reduced hospital charges without compromising the safety of the patients.	('reduced', 'NegReg', (27, 34))	('hospital charges', 'MPA', (35, 51))	('patients', 'Species', '9606', (91, 99))	('FTEP', 'Chemical', '-', (22, 26))	('FTEP', 'Var', (22, 26))
468543	26876429	Inducing the gag reflex causes the abdominal walls to contract and expel gastric content.	('Inducing', 'Var', (0, 8))	('gag reflex', 'Disease', (13, 23))	('abdominal walls', 'CPA', (35, 50))	('gag', 'Chemical', 'MESH:D006025', (13, 16))	('expel gastric content', 'MPA', (67, 88))
468589	26876429	Hoarseness can be a general sign of self-induced vomiting given that stomach acid in vomit may irritate the vocal chords and surrounding tissue.	('vomit may irritate the vocal chords', 'Disease', (85, 120))	('vomit', 'Phenotype', 'HP:0002013', (85, 90))	('Hoarseness', 'Phenotype', 'HP:0001609', (0, 10))	('-induced vomiting', 'Phenotype', 'HP:0002572', (40, 57))	('Hoarseness', 'Disease', (0, 10))	('vomiting', 'Phenotype', 'HP:0002013', (49, 57))	('vomit', 'Phenotype', 'HP:0002013', (49, 54))	('stomach acid', 'Chemical', '-', (69, 81))	('vomit may irritate the vocal chords', 'Disease', 'MESH:D014839', (85, 120))	('vomiting', 'Disease', (49, 57))	('vomiting', 'Disease', 'MESH:D014839', (49, 57))	('stomach acid', 'Var', (69, 81))
468600	26876429	Notably, the discontinuation of these medications may induce a dyspepsia syndrome (e.g., nausea, heartburn) due to acid rebound hypersecretion.	('dyspepsia syndrome', 'Disease', 'MESH:D004415', (63, 81))	('nausea', 'Phenotype', 'HP:0002018', (89, 95))	('nausea', 'Disease', (89, 95))	('nausea', 'Disease', 'MESH:D009325', (89, 95))	('dyspepsia syndrome', 'Disease', (63, 81))	('discontinuation', 'Var', (13, 28))	('dyspepsia', 'Phenotype', 'HP:0410281', (63, 72))	('acid rebound hypersecretion', 'MPA', (115, 142))	('induce', 'Reg', (54, 60))	('heartburn', 'Phenotype', 'HP:0002020', (97, 106))
468618	26876429	Gastroesophageal intussusception can cause obstruction and is a precursor to Mallory-Weiss tears, or tears at the membrane where the esophagus and upper part of the stomach meet.	('Mallory-Weiss tears', 'Disease', 'MESH:D008309', (77, 96))	('intussusception', 'Phenotype', 'HP:0002576', (17, 32))	('tears', 'Phenotype', 'HP:0009926', (101, 106))	('Mallory-Weiss tears', 'Phenotype', 'HP:0032062', (77, 96))	('obstruction', 'Disease', 'MESH:D000402', (43, 54))	('obstruction', 'Disease', (43, 54))	('tears', 'Phenotype', 'HP:0009926', (91, 96))	('Mallory-Weiss tears', 'Disease', (77, 96))	('tears', 'Var', (101, 106))	('Gastroesophageal intussusception', 'Disease', (0, 32))
468676	26876429	Finally, abuse of the laxative phenolphthalein has been associated with osteomalacia (softening of the bones).	('osteomalacia', 'Disease', 'MESH:D010018', (72, 84))	('phenolphthalein', 'Var', (31, 46))	('osteomalacia', 'Disease', (72, 84))	('associated', 'Reg', (56, 66))	('phenolphthalein', 'Chemical', 'MESH:D020113', (31, 46))	('osteomalacia', 'Phenotype', 'HP:0002749', (72, 84))	('softening of the bones', 'Phenotype', 'HP:0002749', (86, 108))
468688	26876429	Common side effects of thyroid medication misuse include nervousness, insomnia, and anxiety, whereas severe side effects include hypertension, cardiac arrhythmias, and heart failure.	('cardiac arrhythmias', 'Disease', 'MESH:D001145', (143, 162))	('cardiac arrhythmias', 'Disease', (143, 162))	('anxiety', 'Disease', 'MESH:D001008', (84, 91))	('hypertension', 'Disease', (129, 141))	('insomnia', 'Disease', (70, 78))	('heart failure', 'Disease', (168, 181))	('insomnia', 'Phenotype', 'HP:0100785', (70, 78))	('hypertension', 'Phenotype', 'HP:0000822', (129, 141))	('insomnia', 'Disease', 'MESH:D007319', (70, 78))	('misuse', 'Var', (42, 48))	('arrhythmias', 'Phenotype', 'HP:0011675', (151, 162))	('anxiety', 'Disease', (84, 91))	('cardiac arrhythmias', 'Phenotype', 'HP:0011675', (143, 162))	('anxiety', 'Phenotype', 'HP:0000739', (84, 91))	('nervousness', 'Disease', (57, 68))	('hypertension', 'Disease', 'MESH:D006973', (129, 141))	('heart failure', 'Disease', 'MESH:D006333', (168, 181))	('heart failure', 'Phenotype', 'HP:0001635', (168, 181))
468723	26275387	hTERT mRNA and FDG-PET/CT were demonstrated to be correlated with the clinical parameters of metastasis and recurrence (P < 0.001), and of recurrence and tumor number in cancer compared with noncancer patients, respectively.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('patients', 'Species', '9606', (201, 209))	('cancer', 'Disease', (194, 200))	('hTERT', 'Gene', (0, 5))	('cancer', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('metastasis', 'CPA', (93, 103))	('correlated', 'Reg', (50, 60))	('FDG', 'Chemical', 'MESH:D019788', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('hTERT', 'Gene', '7015', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('FDG-PET/CT', 'Var', (15, 25))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('recurrence', 'CPA', (139, 149))	('tumor', 'Disease', (154, 159))
468808	30130469	Cancer cells exhibit an iron-seeking phenotype achieved through dysregulation of iron metabolic proteins.	('dysregulation', 'Var', (64, 77))	('iron', 'Chemical', 'MESH:D007501', (81, 85))	('iron', 'Protein', (81, 85))	('iron', 'Chemical', 'MESH:D007501', (24, 28))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('iron-seeking', 'Disease', (24, 36))
468830	30130469	Hereditary hemochromatosis, the prototypical disease of excessive iron overload, can arise from mutations in a variety of genes involved in regulating systemic iron uptake, including the hemochromatosis gene itself (HFE), hepcidin (HAMP), hemojuvelin (HFE2), ferroportin (SLC40A1), and transferrin receptor 2 (TFR2).	('SLC40A1', 'Gene', '30061', (272, 279))	('hemochromatosis', 'Gene', '3077', (11, 26))	('HFE', 'Gene', (252, 255))	('HFE2', 'Gene', (252, 256))	('Hereditary hemochromatosis', 'Disease', 'MESH:D006432', (0, 26))	('SLC40A1', 'Gene', (272, 279))	('mutations', 'Var', (96, 105))	('hepcidin', 'Gene', (222, 230))	('hemochromatosis', 'Gene', (187, 202))	('arise from', 'Reg', (85, 95))	('TFR2', 'Gene', (310, 314))	('HFE', 'Gene', '3077', (216, 219))	('Hereditary hemochromatosis', 'Disease', (0, 26))	('hemochromatosis', 'Gene', (11, 26))	('HAMP', 'Gene', '57817', (232, 236))	('hepcidin', 'Gene', '57817', (222, 230))	('TFR2', 'Gene', '7036', (310, 314))	('HFE2', 'Gene', '148738', (252, 256))	('HFE', 'Gene', (216, 219))	('HFE', 'Gene', '3077', (252, 255))	('HAMP', 'Gene', (232, 236))	('iron', 'Chemical', 'MESH:D007501', (66, 70))	('hemojuvelin', 'Gene', '148738', (239, 250))	('hemochromatosis', 'Gene', '3077', (187, 202))	('iron', 'Chemical', 'MESH:D007501', (160, 164))	('transferrin receptor 2', 'Gene', (286, 308))	('transferrin receptor 2', 'Gene', '7036', (286, 308))	('hemojuvelin', 'Gene', (239, 250))
468831	30130469	The result of these mutations is markedly elevated body iron.	('body iron', 'MPA', (51, 60))	('elevated', 'PosReg', (42, 50))	('mutations', 'Var', (20, 29))	('iron', 'Chemical', 'MESH:D007501', (56, 60))
468861	30130469	Nitroso compounds are potential carcinogens and exacerbate the risk of colon cancer.	('exacerbate', 'PosReg', (48, 58))	('Nitroso', 'Var', (0, 7))	('Nitroso compounds', 'Chemical', 'MESH:D009603', (0, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('colon cancer', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
468862	30130469	For example, in a combined study of two large cohorts of US health professionals [the Nurses' Health Study (n=87,108 women; 1980-2010) and the Health Professionals Follow-up Study (n=47,389 men; 1986-2010)], processed meat intake was positively associated with an increased risk of colorectal cancer (HR, 1.15; 95% CI, 1.01-1.32).	('colorectal cancer', 'Disease', 'MESH:D015179', (282, 299))	('colorectal cancer', 'Phenotype', 'HP:0003003', (282, 299))	('men', 'Species', '9606', (190, 193))	('colorectal cancer', 'Disease', (282, 299))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('men', 'Species', '9606', (119, 122))	('women', 'Species', '9606', (117, 122))	('processed meat', 'Var', (208, 222))
468864	30130469	Similarly, a meta-analysis of 13 case-control studies in the Japanese population showed an association between meat consumption and an increased risk of colorectal cancer (RR, 1.34; 95% CI, 1.12-1.59).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('meat consumption', 'Var', (111, 127))	('colorectal cancer', 'Disease', (153, 170))
468901	30130469	Combined with the prevalence of a polymorphic variant of a gene that predisposes to hemochromatosis [the Q248H allele of ferroportin (FPN)], this dietary exposure is thought to underlie the increased risk for hepatocellular carcinoma in this population.	('hepatocellular carcinoma', 'Disease', (209, 233))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (209, 233))	('increased risk for hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (190, 233))	('Q248H', 'Var', (105, 110))	('hemochromatosis', 'Gene', (84, 99))	('Q248H', 'Mutation', 'rs11568350', (105, 110))	('hemochromatosis', 'Gene', '3077', (84, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (209, 233))
468923	30130469	Dysregulation of systemic iron homeostasis is commonly seen in cancer patients and is manifested as a decreased red blood cell count, or anemia.	('patients', 'Species', '9606', (70, 78))	('red blood cell count', 'MPA', (112, 132))	('systemic iron homeostasis', 'MPA', (17, 42))	('decreased', 'NegReg', (102, 111))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('anemia', 'Disease', (137, 143))	('anemia', 'Disease', 'MESH:D000740', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('iron', 'Chemical', 'MESH:D007501', (26, 30))	('cancer', 'Disease', (63, 69))	('anemia', 'Phenotype', 'HP:0001903', (137, 143))	('decreased red blood cell count', 'Phenotype', 'HP:0020060', (102, 132))
468957	30130469	Although it has not been studied, ferritinophagy may also contribute to an increased LIP in cancer, since autophagy is upregulated in cancer and contributes to tumor growth and aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (177, 191))	('increased LIP', 'Phenotype', 'HP:0012471', (75, 88))	('cancer', 'Disease', (92, 98))	('upregulated', 'PosReg', (119, 130))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('contributes', 'Reg', (145, 156))	('autophagy', 'CPA', (106, 115))	('aggressiveness', 'Disease', 'MESH:D001523', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (160, 165))	('aggressiveness', 'Disease', (177, 191))	('ferritinophagy', 'Var', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
468960	30130469	In colorectal cancer, activating BRAF mutations, important oncogenic drivers, are associated with increased IRP2 levels.	('IRP2', 'Gene', '3658', (108, 112))	('BRAF', 'Gene', '673', (33, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('BRAF', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('increased IRP2 levels', 'Phenotype', 'HP:0032299', (98, 119))	('colorectal cancer', 'Disease', (3, 20))	('increased', 'PosReg', (98, 107))	('IRP2', 'Gene', (108, 112))	('mutations', 'Var', (38, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('activating', 'PosReg', (22, 32))
468961	30130469	BRAF has an important role in promoting MEK (mitogen-activated protein kinase kinase) activation, and the inhibition of MEK signaling by trametinib suppressed IRP2 and TFR1, and reduced intracellular iron.	('MEK', 'Gene', (120, 123))	('activation', 'MPA', (86, 96))	('intracellular iron', 'MPA', (186, 204))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('IRP2', 'Gene', (159, 163))	('promoting', 'PosReg', (30, 39))	('IRP2', 'Gene', '3658', (159, 163))	('inhibition', 'Var', (106, 116))	('mitogen-activated protein kinase kinase', 'Gene', '5609', (45, 84))	('suppressed', 'NegReg', (148, 158))	('MEK', 'Gene', '5609', (40, 43))	('TFR1', 'Gene', '7037', (168, 172))	('trametinib', 'Chemical', 'MESH:C560077', (137, 147))	('MEK', 'Gene', '5609', (120, 123))	('TFR1', 'Gene', (168, 172))	('mitogen-activated protein kinase kinase', 'Gene', (45, 84))	('iron', 'Chemical', 'MESH:D007501', (200, 204))	('reduced', 'NegReg', (178, 185))	('MEK', 'Gene', (40, 43))
468965	30130469	Wnt is also activated in an iron-dependent manner in colon cancer, with mutations in adenomatous polyposis coli (APC), a tumor suppressor.	('mutations', 'Var', (72, 81))	('APC', 'Disease', 'MESH:D011125', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('colon cancer', 'Disease', 'MESH:D015179', (53, 65))	('iron', 'Chemical', 'MESH:D007501', (28, 32))	('APC', 'Disease', (113, 116))	('tumor', 'Disease', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Wnt', 'Gene', (0, 3))	('colon cancer', 'Disease', (53, 65))	('adenomatous polyposis coli', 'Gene', '324', (85, 111))	('Wnt', 'Gene', '7472', (0, 3))	('colon cancer', 'Phenotype', 'HP:0003003', (53, 65))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (85, 111))	('adenomatous polyposis coli', 'Gene', (85, 111))	('APC', 'Phenotype', 'HP:0005227', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
468974	30130469	A particularly compelling series of studies demonstrated that ferric nitrilotriacetate is sufficient to induce kidney tumors in rats.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('kidney tumors', 'Disease', (111, 124))	('induce', 'PosReg', (104, 110))	('rats', 'Species', '10116', (128, 132))	('ferric nitrilotriacetate', 'Chemical', 'MESH:C020326', (62, 86))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('kidney tumors', 'Disease', 'MESH:D007680', (111, 124))	('kidney tumors', 'Phenotype', 'HP:0009726', (111, 124))	('ferric', 'Var', (62, 68))
468977	30130469	In the 1980s, Graf & Eaton proposed that phytic acid compounds in dietary fiber reduced the risk of colorectal cancer by chelation of dietary iron.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('Graf', 'Gene', '23092', (14, 18))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('iron', 'Chemical', 'MESH:D007501', (142, 146))	('Graf', 'Gene', (14, 18))	('fiber', 'NegReg', (74, 79))	('colorectal cancer', 'Disease', (100, 117))	('that phytic acid', 'Var', (36, 52))	('phytic acid', 'Chemical', 'MESH:D010833', (41, 52))
468980	30130469	In a mouse model, dietary heme induced gut dysbiosis, lipid peroxidation, and aggravated colitis, thereby potentiating the development of adenoma.	('men', 'Species', '9606', (130, 133))	('dysbiosis', 'Disease', 'MESH:D064806', (43, 52))	('lipid', 'Chemical', 'MESH:D008055', (54, 59))	('colitis', 'Phenotype', 'HP:0002583', (89, 96))	('dietary', 'Var', (18, 25))	('mouse', 'Species', '10090', (5, 10))	('adenoma', 'Disease', 'MESH:D000236', (138, 145))	('colitis', 'Disease', 'MESH:D003092', (89, 96))	('heme', 'Chemical', 'MESH:D006418', (26, 30))	('gut', 'MPA', (39, 42))	('lipid peroxidation', 'MPA', (54, 72))	('potentiating', 'PosReg', (106, 118))	('aggravated', 'PosReg', (78, 88))	('adenoma', 'Disease', (138, 145))	('induced', 'Reg', (31, 38))	('dysbiosis', 'Disease', (43, 52))	('colitis', 'Disease', (89, 96))
468988	30130469	Tumor growth can also be modulated by manipulating the proteins of iron metabolism.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('proteins', 'Protein', (55, 63))	('modulated', 'Reg', (25, 34))	('manipulating', 'Var', (38, 50))	('iron', 'Chemical', 'MESH:D007501', (67, 71))	('Tumor growth', 'CPA', (0, 12))
468990	30130469	Disrupting IRPs can also reduce tumor growth.	('IRP', 'Gene', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Disrupting', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('reduce', 'NegReg', (25, 31))	('IRP', 'Gene', '7472', (11, 14))	('tumor', 'Disease', (32, 37))
468996	30130469	Indeed, iron depletion by iron chelators, FPN overexpression, and IRP2 knockdown exerts its inhibitory effect on tumor growth by reducing cancer cell proliferation.	('tumor', 'Disease', (113, 118))	('iron depletion', 'MPA', (8, 22))	('cancer', 'Disease', (138, 144))	('IRP2', 'Gene', '3658', (66, 70))	('knockdown', 'Var', (71, 80))	('inhibitory effect', 'MPA', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('iron', 'Chemical', 'MESH:D007501', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('IRP2', 'Gene', (66, 70))	('iron', 'Chemical', 'MESH:D007501', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('reducing', 'NegReg', (129, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
468997	30130469	DMT1 knockdown also inhibits proliferation in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (46, 63))	('inhibits', 'NegReg', (20, 28))	('knockdown', 'Var', (5, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('proliferation', 'CPA', (29, 42))	('colorectal cancer', 'Disease', (46, 63))	('DMT1', 'Gene', (0, 4))	('DMT1', 'Gene', '4891', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
469000	30130469	However, iron depletion also induces p53-independent mechanisms of cell cycle inhibition, including the regulation of cyclins and cyclin-dependent kinases.	('induces', 'Reg', (29, 36))	('cell cycle', 'CPA', (67, 77))	('inhibition', 'NegReg', (78, 88))	('cyclin-dependent', 'Enzyme', (130, 146))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('iron', 'Chemical', 'MESH:D007501', (9, 13))	('cyclins', 'Protein', (118, 125))	('iron depletion', 'Var', (9, 23))
469004	30130469	Mechanistically, iron depletion appears to inhibit cancer cell motility, invasion, and the transforming growth factor-beta-induced epithelial-to-mesenchymal transition.	('inhibit', 'NegReg', (43, 50))	('transforming growth factor-beta', 'Gene', (91, 122))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('iron depletion', 'Var', (17, 31))	('transforming growth factor-beta', 'Gene', '7124', (91, 122))	('invasion', 'CPA', (73, 81))	('iron', 'Chemical', 'MESH:D007501', (17, 21))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
469013	30130469	The induction of apoptosis by iron depletion was demonstrated following treatment with iron chelators or the widespread disruption of iron homeostasis by IRP2 knockdown.	('iron', 'Chemical', 'MESH:D007501', (134, 138))	('disruption of iron homeostasis', 'Phenotype', 'HP:0011031', (120, 150))	('knockdown', 'Var', (159, 168))	('iron', 'Chemical', 'MESH:D007501', (87, 91))	('IRP2', 'Gene', (154, 158))	('men', 'Species', '9606', (77, 80))	('IRP2', 'Gene', '3658', (154, 158))	('iron', 'Chemical', 'MESH:D007501', (30, 34))
469016	30130469	Apoptosis induced by iron depletion occurs by both p53-dependent and p53-independent mechanisms.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('iron', 'Chemical', 'MESH:D007501', (21, 25))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('iron depletion', 'Var', (21, 35))	('Apoptosis', 'CPA', (0, 9))
469017	30130469	Iron depletion has further been shown to augment apoptosis induced by the deprivation of other factors, such as IL-3.	('Iron depletion', 'Var', (0, 14))	('IL-3', 'Gene', '3562', (112, 116))	('men', 'Species', '9606', (44, 47))	('augment', 'PosReg', (41, 48))	('IL-3', 'Gene', (112, 116))	('Iron', 'Chemical', 'MESH:D007501', (0, 4))	('apoptosis', 'CPA', (49, 58))
469020	30130469	ROS-mediated oxidation of cardiolipin, a mitochondrial inner membrane lipid that sequesters cytochrome c, is thought to contribute to the release of cytochrome c in response to apoptotic stimuli.	('ROS-mediated', 'Var', (0, 12))	('cardiolipin', 'Chemical', 'MESH:D002308', (26, 37))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('cytochrome c', 'Gene', (149, 161))	('contribute', 'Reg', (120, 130))	('lipid', 'Chemical', 'MESH:D008055', (70, 75))	('cytochrome c', 'Gene', (92, 104))	('cytochrome c', 'Gene', '54205', (149, 161))	('cytochrome c', 'Gene', '54205', (92, 104))
469024	30130469	SiRNA knockdown of ACO1, as well as the use of iron chelators (deferoxamine and ciclopirox), resulted in iron depletion and favored the production of the soluble, antiapoptotic form of FAS.	('ACO1', 'Gene', (19, 23))	('ciclopirox', 'Chemical', 'MESH:D000077768', (80, 90))	('favored', 'PosReg', (124, 131))	('iron depletion', 'MPA', (105, 119))	('iron', 'Chemical', 'MESH:D007501', (105, 109))	('deferoxamine', 'Chemical', 'MESH:D003676', (63, 75))	('resulted in', 'Reg', (93, 104))	('knockdown', 'Var', (6, 15))	('iron', 'Chemical', 'MESH:D007501', (47, 51))	('production of the soluble', 'MPA', (136, 161))	('ACO1', 'Gene', '48', (19, 23))
469025	30130469	Conversely, siRNA knockdown of FTL, as well as hemin treatment, resulted in iron accumulation and favored the production of the membrane-bound, proapoptotic form of FAS.	('knockdown', 'Var', (18, 27))	('resulted in', 'Reg', (64, 75))	('FTL', 'Gene', '2512', (31, 34))	('iron', 'Chemical', 'MESH:D007501', (76, 80))	('men', 'Species', '9606', (58, 61))	('favored', 'PosReg', (98, 105))	('production of the membrane-bound', 'MPA', (110, 142))	('hemin', 'Chemical', 'MESH:D006427', (47, 52))	('iron accumulation', 'MPA', (76, 93))	('FTL', 'Gene', (31, 34))
469032	30130469	Iron overload can induce necroptosis in vitro.	('induce', 'Reg', (18, 24))	('necroptosis', 'CPA', (25, 36))	('Iron', 'Chemical', 'MESH:D007501', (0, 4))	('Iron', 'Var', (0, 4))
469040	30130469	Interestingly, through disruption of Fe-S cluster proteins, ascorbate-generated H2O2 induces additional increases in the LIP, further contributing to the increased toxicity of ascorbate in cancer cells versus normal cells.	('Fe-S cluster', 'Gene', (37, 49))	('H2O2', 'Gene', (80, 84))	('ascorbate', 'Chemical', 'MESH:D001205', (176, 185))	('LIP', 'MPA', (121, 124))	('disruption', 'Var', (23, 33))	('toxicity', 'Disease', 'MESH:D064420', (164, 172))	('H2O2', 'Chemical', 'MESH:D006861', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('increases', 'PosReg', (104, 113))	('toxicity', 'Disease', (164, 172))	('ascorbate', 'Chemical', 'MESH:D001205', (60, 69))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('increased', 'PosReg', (154, 163))	('Fe-S', 'Chemical', 'MESH:D007501', (37, 41))	('cancer', 'Disease', (189, 195))
469059	30130469	GKT137831, an inhibitor specific to NOX1 and NOX4, partially inhibited the induction of ferroptosis.	('GKT137831', 'Chemical', 'MESH:C576694', (0, 9))	('ferroptosis', 'Disease', (88, 99))	('inhibited', 'NegReg', (61, 70))	('NOX1', 'Gene', '27035', (36, 40))	('NOX4', 'Gene', (45, 49))	('NOX1', 'Gene', (36, 40))	('GKT137831', 'Var', (0, 9))	('NOX4', 'Gene', '50507', (45, 49))
469185	32898941	The pCR rate was also lower in patients with high post-CRT PLR > 83.0 (38.4% vs. 76.5%, p=0.004).	('pCR', 'Disease', (4, 7))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('lower', 'NegReg', (22, 27))	('post-CRT PLR', 'Gene', (50, 62))
469222	31555743	Further support for the importance of dysregulation of cyclin D1-CDK4/6 stems from the demonstration that inactivation of p16INK4a or deletion of Fbxo4, the specificity component of the E3 ligase that directs cyclin D1 degradation, cooperates with BrafV600E to induce metastatic melanoma, while reduced cyclin D1 gene dosage abrogates melanoma development in mouse models, implicating inhibition of cyclin D1-CDK4/6 as a potential strategy for melanoma therapy.	('inactivation', 'Var', (106, 118))	('Fbxo4', 'Gene', (146, 151))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('mouse', 'Species', '10090', (359, 364))	('melanoma', 'Phenotype', 'HP:0002861', (444, 452))	('induce', 'PosReg', (261, 267))	('melanoma', 'Disease', (444, 452))	('p16INK4a', 'Gene', (122, 130))	('abrogates', 'NegReg', (325, 334))	('deletion', 'Var', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (444, 452))	('melanoma', 'Disease', 'MESH:D008545', (335, 343))	('melanoma', 'Phenotype', 'HP:0002861', (335, 343))	('melanoma', 'Disease', (279, 287))	('melanoma', 'Disease', (335, 343))	('BrafV600E', 'Mutation', 'rs113488022', (248, 257))	('melanoma', 'Disease', 'MESH:D008545', (279, 287))
469229	31555743	In addition, recent studies demonstrated that inhibition of mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K) pathways enhances the efficacy of CDK4/6i in esophageal squamous cell carcinoma and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('HER2', 'Gene', (266, 270))	('esophageal squamous cell carcinoma', 'Disease', (185, 219))	('mitogen-activated protein kinase', 'Pathway', (60, 92))	('CDK4/6i', 'Protein', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('efficacy', 'MPA', (162, 170))	('epidermal growth factor receptor 2', 'Gene', '2064', (230, 264))	('human', 'Species', '9606', (224, 229))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (196, 219))	('epidermal growth factor receptor 2', 'Gene', (230, 264))	('breast cancer', 'Phenotype', 'HP:0003002', (281, 294))	('HER2', 'Gene', '2064', (266, 270))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (103, 123))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (185, 219))	('breast cancer', 'Disease', 'MESH:D001943', (281, 294))	('enhances', 'PosReg', (149, 157))	('breast cancer', 'Disease', (281, 294))	('inhibition', 'Var', (46, 56))
469239	31555743	We therefore established CDK4/6i-resistant (CR) cells via long-term culture with palbociclib using either melanoma 1205Lu (1205CR1, 1205CR2, 1205CR6, and 1205CR7)- or esophageal TE7 (TE7CR)-derived cells.	('1205CR6', 'Var', (141, 148))	('melanoma', 'Disease', (106, 114))	('1205CR2', 'Var', (132, 139))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('CR2', 'Species', '2498238', (136, 139))
469241	31555743	Clones (1205CR1, 1205CR2, 1205CR6, and 1205CR7) are cross-resistant to ribociclib (LEE011) (fig.	('1205CR2', 'Var', (17, 24))	('CR2', 'Species', '2498238', (21, 24))	('1205CR1', 'Var', (8, 15))	('1205CR6', 'Var', (26, 33))
469243	31555743	We first assessed potential alterations of DNA and mRNA expression in control versus palbociclib-treated cells [1-day treatment for cell cycle arrest and 8-day treatment for senescence ] and CR clones (1205CR1, 1205CR2, 1205CR6, 1205CR7, and TE7CR) by whole-exome sequencing and RNA-seq (Fig.	('1205CR6', 'Var', (220, 227))	('alterations', 'Reg', (28, 39))	('1205CR7', 'Var', (229, 236))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (132, 149))	('DNA', 'MPA', (43, 46))	('CR2', 'Species', '2498238', (215, 218))	('mRNA expression', 'MPA', (51, 66))	('TE7CR', 'Var', (242, 247))	('1205CR1', 'Var', (202, 209))
469245	31555743	The top ranked biological pathways from systems-level analysis of the RNA-seq data revealed that senescence-associated pathways such as cytokine-cytokine receptor pathway, cell adhesion molecules pathway, tumor necrosis factor signaling pathway, and DNA replication pathway that is primarily controlled by E2f transcription factors are significantly different between senescent and CR cells, supporting our previous work that CDK4/6i resulted in cell cycle arrest and senescence (fig.	('senescence', 'CPA', (468, 478))	('cell cycle arrest', 'CPA', (446, 463))	('resulted', 'Reg', (434, 442))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('necrosis', 'Disease', (211, 219))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (446, 463))	('CDK4/6i', 'Var', (426, 433))	('necrosis', 'Disease', 'MESH:D009336', (211, 219))
469246	31555743	The PI3K-Akt pathway is also significantly suppressed in CDK4/6i-induced senescent cells and reactivated in 1205CR1, 1205CR2, 1205CR6, and 1205CR7 cells, suggesting a link between E2f and PI3K-Akt pathways (fig.	('PI3K-Akt pathway', 'Pathway', (4, 20))	('1205CR1', 'Var', (108, 115))	('CR2', 'Species', '2498238', (121, 124))	('reactivated', 'PosReg', (93, 104))	('senescent', 'CPA', (73, 82))	('CDK4/6i-induced', 'Var', (57, 72))	('PI3K-Akt pathways', 'Pathway', (188, 205))	('suppressed', 'NegReg', (43, 53))
469247	31555743	A heat map comparing 1205Lu parental cells, CDK4/6i-treated cells, CR cells, and Gene Set Enrichment Analysis (GSEA; www.broadinstitute.org/GSEA) using CDK4/6i-treated cells and CR cells revealed that CDK4/6i significantly inhibits the expression of E2f targets and mTOR-dependent signaling (Fig.	('CDK4/6i', 'Var', (201, 208))	('E2f targets', 'MPA', (250, 261))	('mTOR', 'Gene', '2475', (266, 270))	('inhibits', 'NegReg', (223, 231))	('mTOR', 'Gene', (266, 270))	('expression', 'MPA', (236, 246))
469248	31555743	To verify the differential expression of E2f targets, we assessed mRNA and protein accumulation of CDK1, Flap endonuclease 1 (FEN1), and proliferating cell nuclear antigen (PCNA), well-known E2f1 targets, and demonstrated that their expression is significantly reduced in CDK4/6i-treated cells (Fig.	('proliferating cell nuclear antigen', 'Gene', (137, 171))	('reduced', 'NegReg', (261, 268))	('FEN1', 'Gene', '2237', (126, 130))	('PCNA', 'Gene', (173, 177))	('expression', 'MPA', (233, 243))	('FEN1', 'Gene', (126, 130))	('proliferating cell nuclear antigen', 'Gene', '5111', (137, 171))	('Flap endonuclease 1', 'Gene', '2237', (105, 124))	('CDK1', 'Gene', (99, 103))	('PCNA', 'Gene', '5111', (173, 177))	('CDK1', 'Gene', '983', (99, 103))	('Flap endonuclease 1', 'Gene', (105, 124))	('CDK4/6i-treated', 'Var', (272, 287))
469249	31555743	We also established CDK4/6i-resistant cells in WM3918 melanoma cells [3918CR1, 3918CR2, and 3918CR4; resistance was confirmed by 5-bromo-2'-deoxyuridine (BrdU) incorporation and expression of E2f targets; fig.	("5-bromo-2'-deoxyuridine", 'Chemical', 'MESH:D001973', (129, 152))	('3918CR4', 'Var', (92, 99))	('CR2', 'Species', '2498238', (83, 86))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('3918CR2', 'Var', (79, 86))
469250	31555743	S2, A and B] and observed Rb retention in 3918CR1, 3918CR2, and 3918CR4 cells (fig.	('CR2', 'Species', '2498238', (55, 58))	('Rb retention', 'CPA', (26, 38))	('3918CR1', 'Var', (42, 49))
469251	31555743	The retention of Rb in 1205CR6-7, 3918CR1, 3918CR2, and 3918CR4 versus its loss in 1205CR1-2, TE7CR, and TE10CR (CR cells derived from esophageal TE7 and TE10) reveals differing mechanisms of resistance to CDK4/6i (Fig.	('TE10CR', 'Var', (105, 111))	('3918CR2', 'Var', (43, 50))	('CR2', 'Species', '2498238', (47, 50))	('3918CR4', 'Var', (56, 63))	('loss', 'NegReg', (75, 79))
469252	31555743	Although CDK2, CDK4, and CDK6 levels are relatively stable when comparing 1205CR1 and 1205CR2 with 1205CR6 and 1205CR7 (Fig.	('CDK2', 'Gene', '1017', (9, 13))	('CDK4', 'Gene', (15, 19))	('1205CR2', 'Var', (86, 93))	('CR2', 'Species', '2498238', (90, 93))	('CDK4', 'Gene', '1019', (15, 19))	('CDK6', 'Gene', (25, 29))	('1205CR1', 'Var', (74, 81))	('CDK6', 'Gene', '1021', (25, 29))	('CDK2', 'Gene', (9, 13))
469257	31555743	Consistently, AZD5438 also suppressed E2f targets such as CDK1, FEN1, and PCNA, indicating that E2f1 activity is suppressed by AZD5438 (Fig.	('PCNA', 'Gene', (74, 78))	('FEN1', 'Gene', (64, 68))	('AZD5438', 'Var', (14, 21))	('AZD5438', 'Chemical', 'MESH:C521840', (14, 21))	('PCNA', 'Gene', '5111', (74, 78))	('suppressed', 'NegReg', (27, 37))	('activity', 'MPA', (101, 109))	('E2f', 'MPA', (38, 41))	('CDK1', 'Gene', (58, 62))	('CDK1', 'Gene', '983', (58, 62))	('FEN1', 'Gene', '2237', (64, 68))	('AZD5438', 'Chemical', 'MESH:C521840', (127, 134))	('AZD5438', 'Var', (127, 134))
469259	31555743	BrdU incorporation and senescence-associated beta-galactosidase (SA-beta-gal) assay revealed that CDK2 knockdown induced G1 cell cycle arrest after 2 days and senescence by 8 days in 1205CR6-7 cells (fig.	('senescence', 'CPA', (159, 169))	('SA-beta', 'Gene', (65, 72))	('induced', 'Reg', (113, 120))	('SA-beta', 'Gene', '9467', (65, 72))	('CDK2', 'Gene', '1017', (98, 102))	('G1 cell cycle arrest', 'CPA', (121, 141))	('knockdown', 'Var', (103, 112))	('CDK2', 'Gene', (98, 102))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (124, 141))
469260	31555743	We confirmed reduced CDK2 expression following siCDK2 transfection, while CDK1 expression is not affected (fig.	('expression', 'MPA', (26, 36))	('CDK1', 'Gene', '983', (74, 78))	('CDK2', 'Gene', (21, 25))	('CDK1', 'Gene', (74, 78))	('CDK2', 'Gene', (49, 53))	('CDK2', 'Gene', '1017', (21, 25))	('CDK2', 'Gene', '1017', (49, 53))	('reduced', 'NegReg', (13, 20))	('transfection', 'Var', (54, 66))
469261	31555743	Consistently, CDK2 knockdown also suppressed E2f1 transcriptional activity in 1205CR6-7 cells (fig.	('knockdown', 'Var', (19, 28))	('suppressed', 'NegReg', (34, 44))	('CDK2', 'Gene', (14, 18))	('CDK2', 'Gene', '1017', (14, 18))	('E2f1', 'Gene', (45, 49))	('transcriptional activity', 'MPA', (50, 74))
469265	31555743	We also assessed CDK4 and CDK6, since CDK6 overexpression is thought to be a potential mechanism of resistance to LY2835219, a unique CDK4/6i.	('LY2835219', 'Chemical', 'MESH:C000597454', (114, 123))	('CDK6', 'Gene', (26, 30))	('overexpression', 'PosReg', (43, 57))	('CDK6', 'Gene', '1021', (26, 30))	('CDK4', 'Gene', (17, 21))	('CDK6', 'Gene', (38, 42))	('CDK6', 'Gene', '1021', (38, 42))	('CDK4', 'Gene', '1019', (17, 21))	('CDK4', 'Gene', (134, 138))	('CDK4', 'Gene', '1019', (134, 138))	('LY2835219', 'Var', (114, 123))
469288	31555743	Knockdown of SLC36A1 mitigated mTORC1 signaling as assessed by p-S6 (Fig.	('mitigated', 'NegReg', (21, 30))	('Knockdown', 'Var', (0, 9))	('SLC36A1', 'Gene', (13, 20))	('mTORC1', 'Gene', '382056', (31, 37))	('mTORC1', 'Gene', (31, 37))
469289	31555743	SA-beta-gal staining revealed that acute knockdown of SLC36A1 resensitized CR cells to CDK4/6i-induced senescence, while parental cells did not undergo senescence by knockdown of SLC36A1 (Fig.	('SA-beta', 'Gene', (0, 7))	('SLC36A1', 'Gene', (54, 61))	('SA-beta', 'Gene', '9467', (0, 7))	('senescence', 'MPA', (103, 113))	('CDK4/6i-induced', 'Var', (87, 102))
469295	31555743	Further support stems from data demonstrating that E2f1 confers anticancer drug resistance by targeting the ATP-binding cassette (ABC) transporter family members and B cell lymphoma 2 (Bcl-2) via the p73/DNp73-miR205 circuitry.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('E2f1', 'Var', (51, 55))	('B cell lymphoma 2', 'Gene', (166, 183))	('ATP', 'Chemical', 'MESH:D000255', (108, 111))	('drug resistance', 'Phenotype', 'HP:0020174', (75, 90))	('confers', 'Reg', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Bcl-2', 'Gene', (185, 190))	('p73', 'Gene', '7161', (200, 203))	('p73', 'Gene', (200, 203))	('Bcl-2', 'Gene', '596', (185, 190))	('p73', 'Gene', '7161', (206, 209))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (166, 181))	('p73', 'Gene', (206, 209))	('B cell lymphoma 2', 'Gene', '596', (166, 183))	('ABC', 'Gene', '10058', (130, 133))	('lymphoma', 'Phenotype', 'HP:0002665', (173, 181))	('cancer', 'Disease', (68, 74))	('ABC', 'Gene', (130, 133))	('targeting', 'Reg', (94, 103))
469296	31555743	We hypothesized that E2f1 (or related E2f2/3) directly regulates SLC36A1 expression and thereby regulates mTORC1 activity.	('E2f1', 'Var', (21, 25))	('mTORC1', 'Gene', '382056', (106, 112))	('SLC36A1', 'Gene', (65, 72))	('E2f2/3', 'Gene', '1870;1871', (38, 44))	('expression', 'MPA', (73, 83))	('mTORC1', 'Gene', (106, 112))	('activity', 'MPA', (113, 121))	('regulates', 'Reg', (96, 105))	('regulates', 'Reg', (55, 64))	('E2f2/3', 'Gene', (38, 44))
469298	31555743	Critically, E2f1 is the most abundant E2f family member in melanoma cells and is overexpressed when compared with normal melanocytes.	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('E2f1', 'Var', (12, 16))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
469303	31555743	However, this model does not address the initial event that triggers increased SLC36A1 expression, which is necessary to provide the initial reactivation of mTORC1 in 1205CR6-7, 3918CR1, 3918CR2, and 3918CR4 cells, where Rb is retained.	('3918CR1', 'Var', (178, 185))	('increased', 'PosReg', (69, 78))	('mTORC1', 'Gene', '382056', (157, 163))	('CR2', 'Species', '2498238', (191, 194))	('expression', 'MPA', (87, 97))	('SLC36A1', 'Gene', (79, 86))	('mTORC1', 'Gene', (157, 163))	('3918CR2', 'Var', (187, 194))	('3918CR4 cells', 'Var', (200, 213))
469307	31555743	5A) and 3918CR1, 3918CR2, and 3918CR4 (fig.	('CR2', 'Species', '2498238', (21, 24))	('3918CR4', 'Var', (30, 37))	('3918CR2', 'Var', (17, 24))	('3918CR1', 'Var', (8, 15))
469311	31555743	To determine the potential contribution of FXR1 to CDK4/6i resistance, we knocked down FXR1.	('knocked down', 'Var', (74, 86))	('FXR1', 'Gene', '8087', (43, 47))	('FXR1', 'Gene', (43, 47))	('FXR1', 'Gene', (87, 91))	('FXR1', 'Gene', '8087', (87, 91))
469312	31555743	FXR1 knockdown resulted in markedly reduced SLC36A1 protein levels in 1205CR6-7 cells (Fig.	('SLC36A1 protein levels', 'MPA', (44, 66))	('FXR1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('FXR1', 'Gene', '8087', (0, 4))	('reduced', 'NegReg', (36, 43))
469315	31555743	FXR1 knockdown had little effect on mRNA levels of SLC36A1 (fig.	('FXR1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('mRNA levels', 'MPA', (36, 47))	('SLC36A1', 'Gene', (51, 58))	('FXR1', 'Gene', '8087', (0, 4))
469316	31555743	In contrast, p53, phosphatase and tensin homolog (Pten), and p21 mRNAs were induced by FXR1 knockdown, consistent with FXR1 targeting p53, Pten, and p21 mRNAs for degradation (fig.	('FXR1', 'Gene', (119, 123))	('Pten', 'Gene', '5728', (139, 143))	('Pten', 'Gene', (139, 143))	('Pten', 'Gene', (50, 54))	('p53', 'Gene', '7157', (134, 137))	('p21', 'Gene', '1026', (149, 152))	('Pten', 'Gene', '5728', (50, 54))	('p21', 'Gene', (149, 152))	('knockdown', 'Var', (92, 101))	('p53', 'Gene', '7157', (13, 16))	('FXR1', 'Gene', '8087', (119, 123))	('induced', 'PosReg', (76, 83))	('FXR1', 'Gene', (87, 91))	('p21', 'Gene', '1026', (61, 64))	('p53', 'Gene', (13, 16))	('p53', 'Gene', (134, 137))	('p21', 'Gene', (61, 64))	('FXR1', 'Gene', '8087', (87, 91))
469322	31555743	shFXR1 reduced SLC36A1 mRNA in the polysomes and increased in monosome fractions compared to control, indicating that knockdown of FXR1 attenuates translation of SLC36A1 (Fig.	('FXR1', 'Gene', (2, 6))	('reduced', 'NegReg', (7, 14))	('SLC36A1 mRNA in', 'MPA', (15, 30))	('FXR1', 'Gene', '8087', (131, 135))	('knockdown', 'Var', (118, 127))	('FXR1', 'Gene', '8087', (2, 6))	('translation', 'MPA', (147, 158))	('FXR1', 'Gene', (131, 135))	('SLC36A1', 'Gene', (162, 169))	('attenuates', 'NegReg', (136, 146))
469323	31555743	Ribosomal protein RPS18S mRNA was unchanged with knockdown of FXR1 (Fig.	('RPS18', 'Gene', (18, 23))	('knockdown', 'Var', (49, 58))	('Ribosomal protein', 'MPA', (0, 17))	('RPS18', 'Gene', '6222', (18, 23))	('FXR1', 'Gene', (62, 66))	('FXR1', 'Gene', '8087', (62, 66))
469332	31555743	To test this, we knocked down FXR1 in 1205CR6-7 cells.	('FXR1', 'Gene', '8087', (30, 34))	('knocked down', 'Var', (17, 29))	('FXR1', 'Gene', (30, 34))
469340	31555743	Consistent with a role for FXR1 in acquisition of a senescent phenotype, knockdown of FXR1 with two independent hairpins enhanced CDK4/6i-induced senescence (Fig.	('FXR1', 'Gene', '8087', (86, 90))	('FXR1', 'Gene', (27, 31))	('enhanced', 'PosReg', (121, 129))	('FXR1', 'Gene', (86, 90))	('FXR1', 'Gene', '8087', (27, 31))	('CDK4/6i-induced', 'Protein', (130, 145))	('knockdown', 'Var', (73, 82))
469363	31555743	Inhibition of CDK4/6 has emerged as a powerful anticancer therapeutic.	('CDK4/6', 'Protein', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
469364	31555743	Selective CDK4/6i or CDK4/6i's such as palbociclib and ribociclib are approved by the FDA and are currently being evaluated in phase 3 clinical trials for estrogen receptor (ER+)/HER2- breast cancer and phase 1 for metastatic melanoma harboring Neuroblastoma RAS Viral Oncogene Homolog (NRAS) mutation or CDKN2A loss.	('Neuroblastoma', 'Phenotype', 'HP:0003006', (245, 258))	('CDKN2A', 'Gene', (305, 311))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', (185, 198))	('NRAS', 'Gene', (287, 291))	('estrogen receptor', 'Gene', (155, 172))	('CDKN2A', 'Gene', '1029', (305, 311))	('loss', 'NegReg', (312, 316))	('metastatic melanoma harboring Neuroblastoma', 'Disease', (215, 258))	('estrogen receptor', 'Gene', '2099', (155, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('HER2', 'Gene', (179, 183))	('NRAS', 'Gene', '4893', (287, 291))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('mutation', 'Var', (293, 301))	('HER2', 'Gene', '2064', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('metastatic melanoma harboring Neuroblastoma', 'Disease', 'MESH:D009447', (215, 258))
469366	31555743	While CDK4/6i is expected to benefit patients, including those whom harbor vemurafenib resistance, patients are likely to develop resistance to palbociclib/ribociclib, emphasizing the importance for additional treatment options.	('develop', 'PosReg', (122, 129))	('patients', 'Species', '9606', (37, 45))	('resistance', 'Var', (87, 97))	('vemurafenib', 'Gene', (75, 86))	('resistance', 'MPA', (130, 140))	('vemurafenib', 'Chemical', 'MESH:C551177', (75, 86))	('patients', 'Species', '9606', (99, 107))	('benefit', 'PosReg', (29, 36))	('CDK4/6i', 'Var', (6, 13))
469367	31555743	Reactivation of MAPK or mTOR signaling can contribute to resistance to CDK4/6i or CKD4/6i's.	('contribute', 'Reg', (43, 53))	('CKD4/6i', 'Var', (82, 89))	('CDK4/6i', 'Var', (71, 78))	('MAPK', 'Protein', (16, 20))	('Reactivation', 'MPA', (0, 12))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))
469371	31555743	As a consequence of mTORC1 reactivation, the expression of cell cycle regulators, such as CDK2, is restored/increased, thereby triggering cell division through E2f-dependent activation (Fig.	('CDK2', 'Gene', '1017', (90, 94))	('restored/increased', 'PosReg', (99, 117))	('mTORC1', 'Gene', '382056', (20, 26))	('triggering', 'Reg', (127, 137))	('CDK2', 'Gene', (90, 94))	('expression', 'MPA', (45, 55))	('mTORC1', 'Gene', (20, 26))	('reactivation', 'Var', (27, 39))	('activation', 'PosReg', (174, 184))	('cell division', 'CPA', (138, 151))
469373	31555743	To test the generality of SLC36A1 as a driver of CDK4/6i resistance in melanoma, we overexpressed SLC36A1 in a variety of melanoma cell lines and confirmed that SLC36A1 overrides CDK4/6i-induced senescence in all of melanoma cell lines tested.	('melanoma cell lines', 'Disease', (216, 235))	('senescence', 'MPA', (195, 205))	('melanoma cell lines', 'Disease', (122, 141))	('SLC36A1', 'Gene', (98, 105))	('SLC36A1', 'Var', (161, 168))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('overrides', 'PosReg', (169, 178))	('melanoma cell lines', 'Disease', 'MESH:D008545', (216, 235))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('melanoma cell lines', 'Disease', 'MESH:D008545', (122, 141))	('melanoma', 'Disease', (216, 224))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))
469374	31555743	To further assess whether our findings are universal in cells spontaneously developed CDK4/6i resistance, we established another CDK4/6i-resistant cells derived from the WM3918 melanoma cell line (3918CR1, 3918CR2, and 3918CR4).	('3918CR2', 'Var', (206, 213))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('3918CR4', 'Var', (219, 226))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('3918CR1', 'Var', (197, 204))	('CR2', 'Species', '2498238', (210, 213))
469375	31555743	Last, we observed Rb retention, increased FXR1, SLC36A1, p-S6, and CDK2 in 3918CR1, 3918CR2, and 3918CR4 cells compared to CDK4/6i exposure for 8 days in WM3918 cells, which is consistent with our model that FXR1 overexpression contributes to resistance to CDK4/6i through SLC36A1 (Fig.	('CDK2', 'Gene', '1017', (67, 71))	('FXR1', 'Gene', '8087', (208, 212))	('Rb retention', 'CPA', (18, 30))	('FXR1', 'Gene', (42, 46))	('resistance', 'MPA', (243, 253))	('CR2', 'Species', '2498238', (88, 91))	('SLC36A1', 'Gene', (48, 55))	('p-S6', 'Var', (57, 61))	('increased', 'PosReg', (32, 41))	('FXR1', 'Gene', (208, 212))	('CDK2', 'Gene', (67, 71))	('FXR1', 'Gene', '8087', (42, 46))
469381	31555743	However, 1205Lu melanoma cells harbor an Fbxo4 mutation (I377M) that is refractory to substrate binding including FXR1.	('I377M', 'Var', (57, 62))	('Fbxo4', 'Gene', (41, 46))	('FXR1', 'Gene', '8087', (114, 118))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('I377M', 'Mutation', 'p.I377M', (57, 62))	('melanoma', 'Disease', (16, 24))	('FXR1', 'Gene', (114, 118))
469384	31555743	Critically, FXR1 drives reexpression of SLC36A1 in CR cells where it contributes to reactivation of mTOR; SLC36A1 is both necessary and sufficient for resistance to CDK4/6i.	('reactivation', 'MPA', (84, 96))	('FXR1', 'Gene', '8087', (12, 16))	('SLC36A1', 'Var', (106, 113))	('mTOR', 'Gene', (100, 104))	('FXR1', 'Gene', (12, 16))	('mTOR', 'Gene', '2475', (100, 104))
469393	31555743	Authenticated human melanoma cell lines (1205Lu, WM983B, WM239A, 451Lu, WM3918, and WM983BR) were obtained from the Wistar Institute collection (Philadelphia, PA) and cultured in Tu 2% media [80% MCDB153 medium supplemented with 20% Leibovitz L-15, 2% fetal bovine serum (FBS), and 1.68 mM CaCl2].	('bovine', 'Species', '9913', (258, 264))	('melanoma cell lines', 'Disease', (20, 39))	('human', 'Species', '9606', (14, 19))	('CaCl2', 'Chemical', 'MESH:D002122', (290, 295))	('WM3918', 'Var', (72, 78))	('WM983B', 'Var', (49, 55))	('melanoma cell lines', 'Disease', 'MESH:D008545', (20, 39))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('1205Lu', 'Var', (41, 47))
469415	31555743	HEK293T cells were transfected with the SLC36A1 promoter plasmid with E2f1, E2f2, E2f3a, or E2f1 E132 expression plasmids.	('E2f3', 'Gene', (82, 86))	('E2f2', 'Gene', '1870', (76, 80))	('E2f1', 'Var', (70, 74))	('E2f2', 'Gene', (76, 80))	('E2f3', 'Gene', '1871', (82, 86))	('E2f1 E132 expression', 'Var', (92, 112))
469417	31555743	Immunoprecipitation was performed with the antibodies indicated as follows: E2f1 and normal IgG were obtained from Cell Signaling Technology.	('IgG', 'Gene', '16059', (92, 95))	('IgG', 'Gene', (92, 95))	('E2f1', 'Var', (76, 80))
469425	31555743	A total of 2500 cells were fed on 96-well plates and treated with CDK4/6i or CKD4/6i's (either palbociclib or ribociclib) and everolimus for 4 days.	('CKD4/6i', 'Var', (77, 84))	('CDK4/6i', 'Var', (66, 73))	('everolimus', 'Chemical', 'MESH:C107135', (126, 136))
469434	31555743	Last, we exploited the GEnome MINIng (GEMINI) framework to further annotate each variant by comparing it to several genome annotations from multiple sources including Encyclopedia of DNA Elements (ENCODE) tracks, University of California, Santa Cruz (UCSC) tracks, Online Mendelian Inheritance in Man (OMIM), The Single Nucleotide Polymorphism Database (dbSNP), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Human Protein Reference Database (HPRD).	('Man', 'Species', '9606', (297, 300))	('HPRD', 'Disease', (448, 452))	('variant', 'Var', (81, 88))	('Human', 'Species', '9606', (414, 419))	('HPRD', 'Disease', 'None', (448, 452))
469444	31145271	The pooled results showed that low PNI score was significantly correlated with poorer overall survival (OS) of esophageal cancer (pooled HR = 1.418 95%CI: 1.200-1.676, P = .000), poorer recurrence free survival (HR = 1.880 95%CI: 1.207-2.929, P = .005) but not cancer specific survival (CSS) (HR = 1.948 95%CI: 0.544-6.977, P = .306).	('overall', 'MPA', (86, 93))	('recurrence free survival', 'CPA', (186, 210))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', (122, 128))	('poorer', 'NegReg', (179, 185))	('esophageal cancer', 'Disease', (111, 128))	('poorer', 'NegReg', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('PNI score', 'Gene', (35, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('low', 'Var', (31, 34))
469470	31145271	Subgroup analysis was used to explore the potential source of heterogeneity for OS among several related clinical features, demonstrating that low-PNI score predicted worse OS in patient with ESCC regardless of the sample size (>=200 or <200), cut-off value (>45 and <=45), publication country (China or Japan).	('ESCC', 'Disease', (192, 196))	('patient', 'Species', '9606', (179, 186))	('low-PNI score', 'Var', (143, 156))	('worse OS', 'Disease', (167, 175))	('ESCC', 'Disease', 'MESH:C562729', (192, 196))
469471	31145271	Subgroups stratified by TNM stage suggested that a low PNI predicted negative OS in ESCC without stage IV (HR = 1.314, 95% CI 1.072-1.610, P = .008, I2 = 61.1%), or at all stages (HR = 1.662, 95% CI 1.240-2.228, P = .001, I2 = 0%).	('ESCC', 'Disease', (84, 88))	('TNM', 'Gene', '10178', (24, 27))	('negative', 'NegReg', (69, 77))	('low', 'Var', (51, 54))	('ESCC', 'Disease', 'MESH:C562729', (84, 88))	('TNM', 'Gene', (24, 27))	('PNI', 'Gene', (55, 58))
469474	31145271	The result indicated that low-PNI score was statistically significant correlated with early relapse of ESCC (P = .005) with no heterogeneity (I2 = 0.0%, P = .938) (Fig.	('ESCC', 'Disease', (103, 107))	('low-PNI score', 'Var', (26, 39))	('correlated', 'Reg', (70, 80))	('ESCC', 'Disease', 'MESH:C562729', (103, 107))
469480	31145271	We come to the results that low-PNI score was significantly associated with poorer OS and RFS, but not CSS, and higher stage ESCC patients tended to have higher rate of low PNI.	('RFS', 'CPA', (90, 93))	('ESCC', 'Disease', 'MESH:C562729', (125, 129))	('patients', 'Species', '9606', (130, 138))	('low-PNI score', 'Var', (28, 41))	('poorer', 'Disease', (76, 82))	('ESCC', 'Disease', (125, 129))
469488	31145271	Yang and his colleagues conducted a meta-analysis of eleven studies demonstrated that low PNI was significantly associated with poorer OS and CSS in colorectal cancer.	('PNI', 'Gene', (90, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('poorer OS', 'Disease', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('low', 'Var', (86, 89))	('CSS', 'Disease', (142, 145))	('colorectal cancer', 'Disease', (149, 166))
469489	31145271	Sun et al revealed in another meta-analysis that low PNI was related to poorer OS despite cancer types, but it had no relationship with CSS.	('PNI', 'MPA', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('poorer OS', 'Disease', (72, 81))	('low', 'Var', (49, 52))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
469503	31145271	In conclusion, low PNI was significantly related with OS and recurrence free survival but not CSS in ESCC.	('low', 'Var', (15, 18))	('PNI', 'MPA', (19, 22))	('ESCC', 'Disease', 'MESH:C562729', (101, 105))	('related', 'Reg', (41, 48))	('recurrence free survival', 'CPA', (61, 85))	('ESCC', 'Disease', (101, 105))
469515	31146546	In the Exploratory Group, when the REEC value was >1.095, patients had a longer median overall survival (OS) and median disease-free survival (DFS) than those whose REEC value was < 1.095 (70.01+-2.01 months versus 50.92+-2.85 months and 75.66+-1.35 months versus 53.68+-2.81 months, respectively, p < 0.001).	('disease-free survival', 'CPA', (120, 141))	('overall survival', 'CPA', (87, 103))	('>1.095', 'Var', (50, 56))	('patients', 'Species', '9606', (58, 66))	('longer', 'PosReg', (73, 79))
469609	31146546	Koike et al showed that DeltaNp63 is potentially useful for the monitoring of patients with recurrent ESCC, with a sensitivity of 60%.	('SCC', 'Gene', (103, 106))	('DeltaNp63', 'Var', (24, 33))	('SCC', 'Gene', '6317', (103, 106))	('patients', 'Species', '9606', (78, 86))
469632	31146546	On the other hand, because patients with low REEC values had a higher risk of recurrence, meticulous follow-up is essential, and adjuvant therapy for these patients should be considered.	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (27, 35))	('low', 'Var', (41, 44))	('REEC', 'MPA', (45, 49))
469643	29746493	CDO1 methylation accumulates during the ACS process, and consistently contributes to CRC progression.	('methylation', 'Var', (5, 16))	('CDO1', 'Gene', '1036', (0, 4))	('CDO1', 'Gene', (0, 4))	('contributes to', 'Reg', (70, 84))	('CRC', 'Disease', (85, 88))	('accumulates', 'PosReg', (17, 28))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))
469646	29746493	CRC is caused by genetic abnormalities such as genetic mutations or deletions, and accumulation of epigenetic abnormalities such as methylation of DNA.	('genetic abnormalities', 'Disease', 'MESH:D030342', (102, 123))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('DNA', 'Gene', (147, 150))	('deletions', 'Var', (68, 77))	('genetic mutations', 'Var', (47, 64))	('genetic abnormalities', 'Disease', 'MESH:D030342', (17, 38))	('genetic abnormalities', 'Disease', (102, 123))	('accumulation', 'PosReg', (83, 95))	('genetic abnormalities', 'Disease', (17, 38))	('CRC', 'Disease', (0, 3))	('caused by', 'Reg', (7, 16))	('methylation', 'Var', (132, 143))
469652	29746493	As one type of epigenetic abnormality associated with CRC, we have reported the aberrant methylation of cysteine dioxygenase type 1 (CDO1).	('CDO1', 'Gene', (133, 137))	('cysteine dioxygenase type 1', 'Gene', '1036', (104, 131))	('CRC', 'Disease', (54, 57))	('abnormality', 'Disease', 'MESH:D000014', (26, 37))	('abnormality', 'Disease', (26, 37))	('cysteine dioxygenase type 1', 'Gene', (104, 131))	('CRC', 'Phenotype', 'HP:0003003', (54, 57))	('aberrant', 'Var', (80, 88))	('methylation', 'MPA', (89, 100))	('CDO1', 'Gene', '1036', (133, 137))
469655	29746493	Methylation of the CDO1 promoter region has been found in esophageal cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, lung cancer, breast cancer, bladder cancer, prostate cancer, endometrial cancer, and hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('hepatitis', 'Phenotype', 'HP:0012115', (217, 226))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (243, 267))	('CDO1', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('gastric cancer', 'Disease', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Methylation', 'Var', (0, 11))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (176, 191))	('bladder cancer', 'Disease', (160, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('lung cancer', 'Disease', (132, 143))	('cholangiocarcinoma', 'Disease', (112, 130))	('CDO1', 'Gene', '1036', (19, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (176, 191))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (243, 267))	('prostate cancer', 'Disease', (176, 191))	('found', 'Reg', (49, 54))	('esophageal cancer', 'Disease', (58, 75))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('colorectal cancer', 'Disease', (93, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hepatocellular carcinoma', 'Disease', (243, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('endometrial cancer', 'Phenotype', 'HP:0012114', (193, 211))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('endometrial cancer', 'Disease', (193, 211))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('breast cancer', 'Disease', (145, 158))	('endometrial cancer', 'Disease', 'MESH:D016889', (193, 211))	('hepatitis B virus', 'Species', '10407', (217, 234))
469656	29746493	The degree of malignancy or cancer progression with methylation has been reported for some cancers: gallbladder cancer, Barrett esophagus cancer, esophageal squamous cell carcinoma, and HBV-related HCC.	('cancer', 'Disease', (138, 144))	('gallbladder cancer', 'Disease', (100, 118))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (120, 137))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (146, 180))	('malignancy', 'Disease', 'MESH:D009369', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('HBV-related HCC', 'Disease', (186, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('gallbladder cancer', 'Disease', 'MESH:D005706', (100, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Barrett esophagus cancer', 'Disease', (120, 144))	('malignancy', 'Disease', (14, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('methylation', 'Var', (52, 63))	('cancer', 'Disease', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Disease', (91, 98))	('cancer', 'Disease', (91, 97))	('esophageal squamous cell carcinoma', 'Disease', (146, 180))	('Barrett esophagus cancer', 'Disease', 'MESH:D001471', (120, 144))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
469657	29746493	In breast cancer, gallbladder cancer, renal clear-cell cancer, esophageal squamous cell carcinoma, and lung cancer, methylation abnormalities in CDO1 have been reported as a prognostic factor.	('gallbladder cancer', 'Disease', 'MESH:D005706', (18, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('lung cancer', 'Disease', (103, 114))	('renal clear-cell cancer', 'Disease', (38, 61))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('CDO1', 'Gene', (145, 149))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('gallbladder cancer', 'Disease', (18, 36))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('methylation abnormalities', 'Var', (116, 141))	('CDO1', 'Gene', '1036', (145, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (22, 36))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('renal clear-cell cancer', 'Disease', 'MESH:C538614', (38, 61))
469663	29746493	Although CDO1 methylation is clearly associated with carcinogenesis, at what stage of carcinogenesis aberrant methylation of CDO1 occurs is unclear.	('carcinogenesis', 'Disease', (86, 100))	('carcinogenesis', 'Disease', 'MESH:D063646', (53, 67))	('carcinogenesis', 'Disease', (53, 67))	('methylation', 'Var', (14, 25))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('CDO1', 'Gene', (125, 129))	('CDO1', 'Gene', '1036', (125, 129))	('CDO1', 'Gene', (9, 13))	('associated', 'Reg', (37, 47))	('CDO1', 'Gene', '1036', (9, 13))
469664	29746493	Thus, the aim of our study was to elucidate how CDO1 methylation contributes to carcinogenesis during the carcinogenic process of CRC, and to clarify the clinical significance of CDO1 methylation in primary CRC.	('carcinogenic process', 'Disease', (106, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('CDO1', 'Gene', (179, 183))	('carcinogenic process', 'Disease', 'MESH:D009385', (106, 126))	('CDO1', 'Gene', '1036', (179, 183))	('CDO1', 'Gene', '1036', (48, 52))	('contributes', 'Reg', (65, 76))	('CDO1', 'Gene', (48, 52))	('methylation', 'Var', (53, 64))	('CRC', 'Phenotype', 'HP:0003003', (207, 210))	('clinical', 'Species', '191496', (154, 162))	('carcinogenesis', 'Disease', (80, 94))
469666	29746493	Epi proColon , which was approved by the Food and Drug Administration in 2016, is based on methylation of SEPT9 in serum.	('SEPT9', 'Gene', (106, 111))	('methylation', 'Var', (91, 102))	('SEPT9', 'Gene', '10801', (106, 111))
469719	29746493	The results of bisulfite sequencing of SEPT9 showed hypermethylation in DLD1 cells (99.2%) and hypomethylation in HepG2 (0%) cells (S2 Fig).	('HepG2', 'CellLine', 'CVCL:0027', (114, 119))	('SEPT9', 'Gene', (39, 44))	('hypermethylation', 'Var', (52, 68))	('SEPT9', 'Gene', '10801', (39, 44))	('hypomethylation', 'Var', (95, 110))	('bisulfite', 'Chemical', 'MESH:C042345', (15, 24))
469724	29746493	Accumulation of methylation abnormalities in CDO1 may be involved in liver metastasis, and thus, we evaluated regulation of cell proliferation by CDO1 with the anchorage-independent colony formation assay.	('CDO1', 'Gene', '1036', (45, 49))	('CDO1', 'Gene', (45, 49))	('methylation abnormalities', 'Var', (16, 41))	('liver metastasis', 'Disease', 'MESH:D009362', (69, 85))	('liver metastasis', 'Disease', (69, 85))	('CDO1', 'Gene', '1036', (146, 150))	('CDO1', 'Gene', (146, 150))	('involved', 'Reg', (57, 65))
469729	29746493	Significantly high expression of CDO1 was observed in the hypomethylated group (p < 0.0001) (Fig 4).	('expression', 'MPA', (19, 29))	('high', 'PosReg', (14, 18))	('CDO1', 'Gene', '1036', (33, 37))	('hypomethylated', 'Var', (58, 72))	('CDO1', 'Gene', (33, 37))
469760	29746493	Our study for the first time revealed the clinicopathological characteristics associated with methylation of CDO1 in CRC tissue and clarified the relationship between CDO1 methylation and ACS.	('associated', 'Reg', (78, 88))	('CDO1', 'Gene', (167, 171))	('ACS', 'Disease', (188, 191))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('methylation', 'Var', (94, 105))	('CDO1', 'Gene', '1036', (109, 113))	('CDO1', 'Gene', (109, 113))	('CDO1', 'Gene', '1036', (167, 171))
469761	29746493	Methylation of DNA in cancer cells causes gene inactivation and contributes to carcinogenesis.	('contributes', 'Reg', (64, 75))	('gene', 'MPA', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('Methylation', 'Var', (0, 11))	('cancer', 'Disease', (22, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('carcinogenesis', 'Disease', (79, 93))	('DNA', 'Gene', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('inactivation', 'NegReg', (47, 59))
469762	29746493	Our previous studies showed that CDO1 methylation occurs more frequently in CRC tissue than in NAM.	('CRC', 'Disease', (76, 79))	('methylation', 'Var', (38, 49))	('CRC', 'Phenotype', 'HP:0003003', (76, 79))	('CDO1', 'Gene', '1036', (33, 37))	('CDO1', 'Gene', (33, 37))
469768	29746493	Regarding the relationship between methylation abnormalities in CDO1 and expression of CDO1 protein, our previous studies showed a significant relationship in gallbladder cancer.	('CDO1', 'Gene', '1036', (64, 68))	('methylation abnormalities', 'Var', (35, 60))	('CDO1', 'Gene', (64, 68))	('gallbladder cancer', 'Disease', (159, 177))	('gallbladder cancer', 'Disease', 'MESH:D005706', (159, 177))	('relationship', 'Reg', (143, 155))	('CDO1', 'Gene', '1036', (87, 91))	('CDO1', 'Gene', (87, 91))	('expression', 'MPA', (73, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('protein', 'Protein', (92, 99))
469771	29746493	These findings suggest that methylation may also be functionally involved in CRC phenotypes in clinical samples.	('CRC', 'Disease', (77, 80))	('involved', 'Reg', (65, 73))	('clinical samples', 'Species', '191496', (95, 111))	('methylation', 'Var', (28, 39))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))
469779	29746493	CDO1 methylation was also significantly related to histological type, tumor diameter, liver metastasis, pT, Dukes classification, and v. This result clinically confirmed a previous study reporting that CDO1 participates in tumor cell growth, cell migration, invasion, and colony formation.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('CDO1', 'Gene', (202, 206))	('invasion', 'CPA', (258, 266))	('cell migration', 'CPA', (242, 256))	('CDO1', 'Gene', '1036', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('liver metastasis', 'Disease', 'MESH:D009362', (86, 102))	('methylation', 'Var', (5, 16))	('tumor', 'Disease', (223, 228))	('CDO1', 'Gene', (0, 4))	('clinical', 'Species', '191496', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('colony formation', 'CPA', (272, 288))	('related', 'Reg', (40, 47))	('participates', 'Reg', (207, 219))	('CDO1', 'Gene', '1036', (0, 4))	('tumor', 'Disease', (70, 75))	('liver metastasis', 'Disease', (86, 102))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
469780	29746493	Consistent with this observation, using an anchorage-independent colony formation assay, this study showed that cell proliferation was suppressed following transfection of CDO1 into a CRC cell line.	('cell proliferation', 'CPA', (112, 130))	('CDO1', 'Gene', '1036', (172, 176))	('CDO1', 'Gene', (172, 176))	('CRC', 'Phenotype', 'HP:0003003', (184, 187))	('suppressed', 'NegReg', (135, 145))	('transfection', 'Var', (156, 168))
469781	29746493	Thus, our basic experiments confirmed the linkage between CDO1 methylation abnormalities and the clinicopathological background.	('CDO1', 'Gene', '1036', (58, 62))	('linkage', 'Reg', (42, 49))	('methylation abnormalities', 'Var', (63, 88))	('CDO1', 'Gene', (58, 62))
469783	29746493	This finding suggests that CDO1 methylation may accumulate with tumor progression of CRC.	('methylation', 'Var', (32, 43))	('tumor', 'Disease', (64, 69))	('CDO1', 'Gene', '1036', (27, 31))	('CDO1', 'Gene', (27, 31))	('CRC', 'Disease', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('accumulate', 'PosReg', (48, 58))
469785	29746493	Such prognostic associations with CDO1 methylation have been previously reported in various histological types of cancers such as renal clear-cell carcinoma, breast adenocarcinoma, and esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('esophageal squamous cell carcinoma', 'Disease', (185, 219))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (158, 179))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('renal clear-cell carcinoma', 'Phenotype', 'HP:0006770', (130, 156))	('methylation', 'Var', (39, 50))	('CDO1', 'Gene', (34, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (196, 219))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (185, 219))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('CDO1', 'Gene', '1036', (34, 38))	('renal clear-cell carcinoma', 'Disease', (130, 156))	('reported', 'Reg', (72, 80))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (158, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('renal clear-cell carcinoma', 'Disease', 'MESH:C538614', (130, 156))	('breast adenocarcinoma', 'Disease', (158, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
469786	29746493	The results of our study again for the first time suggested that CDO1 methylation may be involved in the malignant progression of CRC.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('involved', 'Reg', (89, 97))	('CDO1', 'Gene', (65, 69))	('CDO1', 'Gene', '1036', (65, 69))	('methylation', 'Var', (70, 81))	('CRC', 'Disease', (130, 133))
469792	29746493	Although CDO1 methylation abnormalities involved in carcinogenesis have been reported, the CDO1 oncogenic relevance during tumor progression remains unclear.	('CDO1', 'Gene', '1036', (91, 95))	('tumor', 'Disease', (123, 128))	('methylation abnormalities', 'Var', (14, 39))	('abnormalities', 'Var', (26, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (52, 66))	('CDO1', 'Gene', '1036', (9, 13))	('CDO1', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('carcinogenesis', 'Disease', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('CDO1', 'Gene', (91, 95))
469797	29746493	These results suggested that aberrant methylation of CDO1 is involved in the development of adenoma.	('CDO1', 'Gene', '1036', (53, 57))	('adenoma', 'Disease', 'MESH:D000236', (92, 99))	('aberrant methylation', 'Var', (29, 49))	('adenoma', 'Disease', (92, 99))	('involved', 'Reg', (61, 69))	('methylation', 'Var', (38, 49))	('CDO1', 'Gene', (53, 57))
469798	29746493	Furthermore, the fact that TaqMeth V also differed significantly between low-grade adenoma and high-grade adenoma suggested that CDO1 methylation contributes to the growth of adenoma and an increased grade of atypia.	('methylation', 'Var', (134, 145))	('adenoma', 'Disease', 'MESH:D000236', (175, 182))	('adenoma', 'Disease', 'MESH:D000236', (106, 113))	('adenoma', 'Disease', 'MESH:D000236', (83, 90))	('adenoma', 'Disease', (106, 113))	('adenoma', 'Disease', (175, 182))	('growth', 'MPA', (165, 171))	('TaqMeth V', 'Chemical', '-', (27, 36))	('adenoma', 'Disease', (83, 90))	('CDO1', 'Gene', '1036', (129, 133))	('CDO1', 'Gene', (129, 133))
469808	29746493	In other words, these observations suggest that methylation of SEPT9 is superior as a marker of cancer, and methylation of CDO1 can be detected with high frequency in some types of adenoma.	('CDO1', 'Gene', '1036', (123, 127))	('CDO1', 'Gene', (123, 127))	('adenoma', 'Disease', 'MESH:D000236', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SEPT9', 'Gene', '10801', (63, 68))	('detected', 'Reg', (135, 143))	('adenoma', 'Disease', (181, 188))	('SEPT9', 'Gene', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('methylation', 'Var', (108, 119))	('methylation', 'Var', (48, 59))	('cancer', 'Disease', (96, 102))
469811	29746493	Because CDO1 expression is inhibited by methylation in cancer cells, the production of glutathione is increased and resistance to reactive oxygen species is enhanced.	('production of glutathione', 'MPA', (73, 98))	('methylation', 'Var', (40, 51))	('increased', 'PosReg', (102, 111))	('expression', 'MPA', (13, 23))	('enhanced', 'PosReg', (157, 165))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (130, 153))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('glutathione', 'Chemical', 'MESH:D005978', (87, 98))	('inhibited', 'NegReg', (27, 36))	('resistance to reactive oxygen species', 'MPA', (116, 153))	('CDO1', 'Gene', '1036', (8, 12))	('CDO1', 'Gene', (8, 12))	('cancer', 'Disease', (55, 61))
469815	29746493	Interestingly, venous invasion was also marginally associated with CDO1 methylation in primary CRC tissues.	('CDO1', 'Gene', '1036', (67, 71))	('venous invasion', 'CPA', (15, 30))	('associated', 'Reg', (51, 61))	('methylation', 'Var', (72, 83))	('CRC', 'Phenotype', 'HP:0003003', (95, 98))	('CDO1', 'Gene', (67, 71))
469816	29746493	As mentioned above, our study suggested that aberrant methylation of CDO1 is involved in the development and growth of adenoma, progression of atypia, oncogenic transformation, invasion, and metastasis.	('invasion', 'CPA', (177, 185))	('involved', 'Reg', (77, 85))	('oncogenic transformation', 'CPA', (151, 175))	('adenoma', 'Disease', (119, 126))	('CDO1', 'Gene', '1036', (69, 73))	('CDO1', 'Gene', (69, 73))	('metastasis', 'CPA', (191, 201))	('aberrant methylation', 'Var', (45, 65))	('adenoma', 'Disease', 'MESH:D000236', (119, 126))
469817	29746493	Namely, CDO1 methylation induces cellular atypia, and the increased accumulation of CDO1 methylation generates CRC.	('increased accumulation', 'PosReg', (58, 80))	('CRC', 'Disease', (111, 114))	('CDO1', 'Gene', '1036', (8, 12))	('methylation', 'Var', (13, 24))	('induces', 'Reg', (25, 32))	('methylation', 'Var', (89, 100))	('CDO1', 'Gene', '1036', (84, 88))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('cellular atypia', 'CPA', (33, 48))	('CDO1', 'Gene', (8, 12))	('CDO1', 'Gene', (84, 88))
469823	29746493	When excised samples were used, methylation abnormalities of CDO1 could be distinguished from normal mucosa at the stage of adenoma as well as cancer tissue.	('methylation abnormalities', 'Var', (32, 57))	('CDO1', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('adenoma', 'Disease', 'MESH:D000236', (124, 131))	('cancer', 'Disease', (143, 149))	('adenoma', 'Disease', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('CDO1', 'Gene', '1036', (61, 65))
469830	29507700	In a xenotransplantation assay, silencing GRP94 reduced cell proliferation in the zebrafish embryo.	('cell proliferation in the zebrafish embryo', 'CPA', (56, 98))	('reduced', 'NegReg', (48, 55))	('silencing', 'Var', (32, 41))	('GRP94', 'Gene', (42, 47))	('zebrafish', 'Species', '7955', (82, 91))
469831	29507700	Transmission electron microscopy revealed impaired mitochondria in GRP94-KD cells, which exhibited reduced basal respiration, spare respiratory capacity and ATP production and increased oxidative damage compared with scrambled control cells.	('ATP production', 'MPA', (157, 171))	('increased', 'PosReg', (176, 185))	('basal respiration', 'MPA', (107, 124))	('ATP', 'Chemical', 'MESH:D000255', (157, 160))	('oxidative damage', 'MPA', (186, 202))	('mitochondria', 'MPA', (51, 63))	('reduced', 'NegReg', (99, 106))	('GRP94-KD', 'Var', (67, 75))	('spare respiratory capacity', 'MPA', (126, 152))	('impaired', 'NegReg', (42, 50))
469832	29507700	Regarding the molecular mechanism underlying the effects of GRP94 knockdown, we found that silencing GRP94 may reduce the level of NF-kB, c-Jun, p38, IL-6, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) as well as activation of AKT and ERK.	('COX-2', 'Gene', (221, 226))	('p38', 'Gene', '10598', (145, 148))	('IL-6', 'Gene', (150, 154))	('vascular endothelial growth factor', 'Gene', '7422', (156, 190))	('AKT', 'Gene', (253, 256))	('p38', 'Gene', (145, 148))	('VEGF', 'Gene', '7422', (192, 196))	('level', 'MPA', (122, 127))	('COX-2', 'Gene', '5743', (221, 226))	('GRP94', 'Gene', (101, 106))	('VEGF', 'Gene', (192, 196))	('ERK', 'Gene', '5594', (261, 264))	('vascular endothelial growth factor', 'Gene', (156, 190))	('cyclooxygenase-2', 'Gene', '5743', (203, 219))	('AKT', 'Gene', '207', (253, 256))	('c-Jun', 'Gene', '3725', (138, 143))	('activation', 'PosReg', (239, 249))	('silencing', 'Var', (91, 100))	('ERK', 'Gene', (261, 264))	('cyclooxygenase-2', 'Gene', (203, 219))	('c-Jun', 'Gene', (138, 143))	('NF-kB', 'MPA', (131, 136))	('reduce', 'NegReg', (111, 117))	('IL-6', 'Gene', '3569', (150, 154))
469833	29507700	In conclusion, our results indicate that silencing GRP94 in ESCC cells suppressed cancer growth and the metastatic potential via mitochondrial functions and NF-kB/COX-2/VEGF in ESCC cells.	('metastatic potential', 'CPA', (104, 124))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('silencing', 'Var', (41, 50))	('COX-2', 'Gene', (163, 168))	('GRP94', 'Protein', (51, 56))	('VEGF', 'Gene', (169, 173))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('COX-2', 'Gene', '5743', (163, 168))	('mitochondrial functions', 'CPA', (129, 152))	('VEGF', 'Gene', '7422', (169, 173))	('suppressed', 'NegReg', (71, 81))
469839	29507700	p53 gene mutations are frequently detected in esophageal cancer, and dysregulation of cell regulators, such as epidermal growth factor receptor, HER-2/Neu, and vascular endothelial growth factor, has been investigated in ESCC.	('p53', 'Gene', (0, 3))	('detected', 'Reg', (34, 42))	('p53', 'Gene', '7157', (0, 3))	('HER-2/Neu', 'Gene', '2064', (145, 154))	('vascular endothelial growth factor', 'Gene', '7422', (160, 194))	('mutations', 'Var', (9, 18))	('HER-2/Neu', 'Gene', (145, 154))	('epidermal growth factor receptor', 'Gene', (111, 143))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('ESCC', 'Disease', (221, 225))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('vascular endothelial growth factor', 'Gene', (160, 194))	('epidermal growth factor receptor', 'Gene', '1956', (111, 143))
469844	29507700	Silencing GRP94 expression promotes apoptosis with or without ER stress, and blocking GRP94 function may suppress tumorigenesis and metastasis in liver cancer.	('GRP94', 'Gene', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('metastasis in liver cancer', 'Disease', (132, 158))	('apoptosis', 'CPA', (36, 45))	('suppress', 'NegReg', (105, 113))	('liver cancer', 'Phenotype', 'HP:0002896', (146, 158))	('promotes', 'PosReg', (27, 35))	('tumor', 'Disease', (114, 119))	('metastasis in liver cancer', 'Disease', 'MESH:D009362', (132, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Silencing', 'Var', (0, 9))	('blocking', 'NegReg', (77, 85))	('function', 'MPA', (92, 100))	('GRP94', 'Gene', (10, 15))
469849	29507700	Our study demonstrated that GRP94 depletion inhibited cancer cell proliferation and metastatic potential by suppressing the AKT and MAPK pathways.	('GRP94', 'Protein', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('AKT', 'Gene', (124, 127))	('inhibited', 'NegReg', (44, 53))	('metastatic potential', 'CPA', (84, 104))	('cancer', 'Disease', (54, 60))	('depletion', 'Var', (34, 43))	('MAPK pathways', 'Pathway', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('suppressing', 'NegReg', (108, 119))	('AKT', 'Gene', '207', (124, 127))
469850	29507700	In addition, we found that the reduction of IL-6, VEGF and COX-2 levels was due to suppression of NF-kB and AP-1 production after silencing GRP94 in ESCC cells.	('COX-2', 'Gene', '5743', (59, 64))	('reduction', 'NegReg', (31, 40))	('suppression', 'NegReg', (83, 94))	('VEGF', 'Gene', (50, 54))	('NF-kB', 'MPA', (98, 103))	('IL-6', 'Gene', (44, 48))	('IL-6', 'Gene', '3569', (44, 48))	('VEGF', 'Gene', '7422', (50, 54))	('silencing', 'Var', (130, 139))	('COX-2', 'Gene', (59, 64))	('AP-1', 'Gene', '3725', (108, 112))	('AP-1', 'Gene', (108, 112))	('GRP94', 'Protein', (140, 145))
469852	29507700	Patients in the high GRP94 expression group tended to exhibit a higher frequency of lymph node metastasis than patients in the low GRP94 expression group (P = 0.032), and patients with high GRP94 expression levels tended to present at a later disease stage than patients with low GRP94 expression levels, although the difference between these two groups was not significant (P = 0.057).	('patients', 'Species', '9606', (262, 270))	('high', 'Var', (16, 20))	('higher', 'PosReg', (64, 70))	('patients', 'Species', '9606', (171, 179))	('Patients', 'Species', '9606', (0, 8))	('lymph node metastasis', 'Disease', 'MESH:D009362', (84, 105))	('lymph node metastasis', 'Disease', (84, 105))	('GRP94', 'Gene', (21, 26))	('patients', 'Species', '9606', (111, 119))
469855	29507700	Univariate analysis demonstrated that male gender, deeper invasion (T3+T4), lymph node metastasis, advanced pathologic stages (stages III and IV) and high GRP94 expression levels were associated with poorer prognosis.	('GRP94', 'Protein', (155, 160))	('high', 'Var', (150, 154))	('deeper invasion', 'CPA', (51, 66))	('lymph node metastasis', 'Disease', (76, 97))	('lymph node metastasis', 'Disease', 'MESH:D009362', (76, 97))	('expression levels', 'MPA', (161, 178))
469862	29507700	GRP94-KD cells exhibited significantly lower OCR, basal respiration, maximum respiration, and spare respiratory capacity than scrambled control cells.	('mum', 'Gene', (73, 76))	('GRP94-KD', 'Var', (0, 8))	('spare', 'MPA', (94, 99))	('OCR', 'Chemical', '-', (45, 48))	('OCR', 'MPA', (45, 48))	('basal respiration', 'MPA', (50, 67))	('mum', 'Gene', '56925', (73, 76))	('lower', 'NegReg', (39, 44))
469866	29507700	Both AKT and p-AKT levels were reduced after GRP94 knockdown, as shown in Figure 7A.	('GRP94', 'Gene', (45, 50))	('AKT', 'Gene', '207', (15, 18))	('reduced', 'NegReg', (31, 38))	('AKT', 'Gene', '207', (5, 8))	('AKT', 'Gene', (15, 18))	('AKT', 'Gene', (5, 8))	('knockdown', 'Var', (51, 60))
469867	29507700	There was no difference in ERK levels between scrambled control and GRP94-KD cells; however, p-ERK levels were dramatically decreased in GRP94-KD cells compared with scrambled control cells.	('p-ERK', 'Gene', '9451', (93, 98))	('ERK', 'Gene', '5594', (95, 98))	('p-ERK', 'Gene', (93, 98))	('ERK', 'Gene', (95, 98))	('decreased', 'NegReg', (124, 133))	('ERK', 'Gene', '5594', (27, 30))	('GRP94-KD', 'Var', (137, 145))	('ERK', 'Gene', (27, 30))
469868	29507700	In contrast, JNK pathway activity was not affected by GRP94 knockdown.	('JNK', 'Gene', (13, 16))	('GRP94', 'Protein', (54, 59))	('JNK', 'Gene', '5599', (13, 16))	('knockdown', 'Var', (60, 69))
469870	29507700	We next assessed AP-1 (c-Jun and c-Fos) and p38 expression and observed that c-Jun and p38 expression was dramatically suppressed in GRP94-KD cells compared with scrambled control cells (Figure 7B).	('c-Jun', 'Gene', '3725', (23, 28))	('c-Jun', 'Gene', '3725', (77, 82))	('c-Fos', 'Gene', (33, 38))	('suppressed', 'NegReg', (119, 129))	('AP-1', 'Gene', '3725', (17, 21))	('AP-1', 'Gene', (17, 21))	('p38', 'Gene', (87, 90))	('c-Fos', 'Gene', '2353', (33, 38))	('p38', 'Gene', '10598', (87, 90))	('c-Jun', 'Gene', (23, 28))	('p38', 'Gene', (44, 47))	('p38', 'Gene', '10598', (44, 47))	('c-Jun', 'Gene', (77, 82))	('GRP94-KD', 'Var', (133, 141))
469871	29507700	c-Fos levels were unchanged by GRP94 knockdown.	('c-Fos', 'Gene', '2353', (0, 5))	('GRP94', 'Protein', (31, 36))	('knockdown', 'Var', (37, 46))	('c-Fos', 'Gene', (0, 5))
469876	29507700	We found that silencing GRP94 caused reductions in VEGF and IL-6 expression in ESCC cells.	('silencing', 'Var', (14, 23))	('reductions', 'NegReg', (37, 47))	('IL-6', 'Gene', (60, 64))	('VEGF', 'Gene', '7422', (51, 55))	('IL-6', 'Gene', '3569', (60, 64))	('expression', 'MPA', (65, 75))	('VEGF', 'Gene', (51, 55))	('GRP94', 'Gene', (24, 29))
469878	29507700	Took together, these findings showed that silencing GRP94 might influence VEGF and IL-6 expression levels via the NF-kB/COX-2 axis.	('VEGF', 'Gene', '7422', (74, 78))	('silencing', 'Var', (42, 51))	('IL-6', 'Gene', '3569', (83, 87))	('GRP94', 'Protein', (52, 57))	('VEGF', 'Gene', (74, 78))	('influence', 'Reg', (64, 73))	('COX-2', 'Gene', (120, 125))	('IL-6', 'Gene', (83, 87))	('COX-2', 'Gene', '5743', (120, 125))
469903	29507700	Accordingly, GRP94 overexpression is associated with lymph node metastasis and carcinoma recurrence in gastric carcinomas, whereas silencing of GRP94 dramatically inhibits cancer cell migration and proliferation abilities in vitro.	('lymph node metastasis', 'Disease', (53, 74))	('GRP94', 'Protein', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('gastric carcinomas', 'Disease', (103, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('gastric carcinomas', 'Disease', 'MESH:D013274', (103, 121))	('overexpression', 'PosReg', (19, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('carcinoma', 'Disease', (79, 88))	('carcinoma', 'Disease', (111, 120))	('associated', 'Reg', (37, 47))	('silencing', 'Var', (131, 140))	('inhibits', 'NegReg', (163, 171))	('carcinoma', 'Disease', 'MESH:D002277', (79, 88))	('lymph node metastasis', 'Disease', 'MESH:D009362', (53, 74))	('cancer', 'Disease', (172, 178))	('carcinoma', 'Disease', 'MESH:D002277', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('GRP94', 'Gene', (144, 149))
469904	29507700	The present findings support previous reports showing that higher GRP94 expression levels are associated with lower overall survival and higher lympho-node metastasis, while silencing GRP94 impairs mitochondria by reducing basal respiration and ATP production in ESCC cells.	('impairs', 'NegReg', (190, 197))	('mitochondria', 'MPA', (198, 210))	('basal respiration', 'MPA', (223, 240))	('GRP94', 'Gene', (184, 189))	('expression levels', 'MPA', (72, 89))	('GRP94', 'Protein', (66, 71))	('higher', 'PosReg', (137, 143))	('lympho-node metastasis', 'CPA', (144, 166))	('ATP production', 'MPA', (245, 259))	('lower', 'NegReg', (110, 115))	('higher', 'PosReg', (59, 65))	('reducing', 'NegReg', (214, 222))	('overall survival', 'CPA', (116, 132))	('silencing', 'Var', (174, 183))	('ATP', 'Chemical', 'MESH:D000255', (245, 248))
469905	29507700	GRP94 knockdown-induced ER stress dysregulation may be directly linked to mitochondria dysfunction in ESCC cells, resulting in suppression of cancer growth and metastatic potential.	('knockdown-induced', 'Var', (6, 23))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('stress dysregulation', 'Disease', 'MESH:D004194', (27, 47))	('metastatic potential', 'CPA', (160, 180))	('stress dysregulation', 'Disease', (27, 47))	('mitochondria dysfunction', 'Disease', 'MESH:C564925', (74, 98))	('mitochondria dysfunction', 'Disease', (74, 98))	('GRP94', 'Gene', (0, 5))	('suppression', 'NegReg', (127, 138))	('cancer', 'Disease', (142, 148))
469906	29507700	Our findings indicate that GRP94 depletion caused a reduction in the expression of VEGF and its downstream target molecule COX-2, which might be the major factor causing suppression of tumor growth and metastasis.	('tumor', 'Disease', (185, 190))	('VEGF', 'Gene', (83, 87))	('COX-2', 'Gene', '5743', (123, 128))	('depletion', 'Var', (33, 42))	('GRP94', 'Protein', (27, 32))	('suppression', 'NegReg', (170, 181))	('VEGF', 'Gene', '7422', (83, 87))	('expression', 'MPA', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('COX-2', 'Gene', (123, 128))	('reduction', 'NegReg', (52, 61))
469908	29507700	To understand how GRP94 regulates VEGF expression, we conducted a miRNA analysis to determine whether GRP94 depletion suppresses VEGF expression by altering miRNA levels.	('suppresses', 'NegReg', (118, 128))	('miRNA levels', 'MPA', (157, 169))	('VEGF', 'Gene', '7422', (34, 38))	('altering', 'Reg', (148, 156))	('VEGF', 'Gene', (129, 133))	('GRP94', 'Gene', (102, 107))	('depletion', 'Var', (108, 117))	('VEGF', 'Gene', (34, 38))	('VEGF', 'Gene', '7422', (129, 133))
469911	29507700	In conclusion, we observed that GRP94 depletion induces miR107 up-regulation and VEGF suppression in ESCC cells.	('up-regulation', 'PosReg', (63, 76))	('VEGF', 'Gene', '7422', (81, 85))	('suppression', 'NegReg', (86, 97))	('miR107', 'Gene', '406901', (56, 62))	('depletion', 'Var', (38, 47))	('miR107', 'Gene', (56, 62))	('VEGF', 'Gene', (81, 85))	('GRP94', 'Protein', (32, 37))
469912	29507700	Clinical biomarkers shown to be predictive of certain epithelial tumors, such as EGFR or KRAS mutations in colon cancer, are infrequent and/or not predictive of esophageal cancers.	('colon cancer', 'Disease', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('epithelial tumors', 'Disease', (54, 71))	('mutations', 'Var', (94, 103))	('esophageal cancers', 'Disease', (161, 179))	('epithelial tumors', 'Disease', 'MESH:D002277', (54, 71))	('KRAS', 'Gene', '3845', (89, 93))	('EGFR', 'Gene', '1956', (81, 85))	('esophageal cancers', 'Disease', 'MESH:D004938', (161, 179))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('KRAS', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colon cancer', 'Disease', 'MESH:D015179', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('EGFR', 'Gene', (81, 85))
469915	29507700	The current study further demonstrates that GRP94 depletion suppresses AKT and ERK pathway activation.	('ERK', 'Gene', (79, 82))	('AKT', 'Gene', '207', (71, 74))	('activation', 'PosReg', (91, 101))	('suppresses', 'NegReg', (60, 70))	('AKT', 'Gene', (71, 74))	('ERK', 'Gene', '5594', (79, 82))	('GRP94', 'Protein', (44, 49))	('depletion', 'Var', (50, 59))
469922	29507700	Human ESCC cells (CE81T and CE146T) were purchased from the Food Industry Research and Development Institute (Hsinchu City, Taiwan).	('CE146T', 'Var', (28, 34))	('CE81T', 'Var', (18, 23))	('Human', 'Species', '9606', (0, 5))	('CE146T', 'CellLine', 'CVCL:Y008', (28, 34))
469961	26465158	We found 10 significantly recurrent copy number alterations accompanying gene expression changes, including loci 11q13.2, 7p11.2, 3q26.33, and 17q12, which harbored CCND1, EGFR, SOX2, and ERBB2, respectively.	('CCND1', 'Gene', '595', (165, 170))	('EGFR', 'Gene', '1956', (172, 176))	('SOX2', 'Gene', (178, 182))	('EGFR', 'Gene', (172, 176))	('changes', 'Reg', (89, 96))	('CCND1', 'Gene', (165, 170))	('copy number alterations', 'Var', (36, 59))	('gene expression', 'MPA', (73, 88))	('SOX2', 'Gene', '6657', (178, 182))
469965	26465158	Copy number aberrations (CNAs) and accompanying dysregulation of gene expression are known to play a critical role in the pathogenesis of human cancers.	('Copy number aberrations', 'Var', (0, 23))	('human', 'Species', '9606', (138, 143))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('dysregulation of gene expression', 'MPA', (48, 80))
469968	26465158	This series of analyses suggest that GRB7, located on 17q12, was overexpressed due to copy number gains and play a critical role in tumor growth and invasion.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('overexpressed', 'PosReg', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('copy number gains', 'Var', (86, 103))	('tumor', 'Disease', (132, 137))	('GRB7', 'Gene', (37, 41))	('invasion', 'CPA', (149, 157))
469991	26465158	ERBB2 and GRB7 proteins were detected using an anti-ERBB2 rabbit monoclonal antibody (Epitomics, Inc) at a 1:5000 dilution and an anti-GRB7 rabbit monoclonal antibody (Gene Tex International Corporation) at a 1:1000 dilution.	('ERBB2', 'Gene', (0, 5))	('detected', 'Reg', (29, 37))	('rabbit', 'Species', '9986', (140, 146))	('GRB7 proteins', 'Protein', (10, 23))	('rabbit', 'Species', '9986', (58, 64))	('anti-ERBB2', 'Var', (47, 57))
470003	26465158	The most significant deletion peak was observed at chromosome segment 9p21.3, containing CDKN2A (Fig 1b).	('CDKN2A', 'Gene', '1029', (89, 95))	('CDKN2A', 'Gene', (89, 95))	('deletion', 'Var', (21, 29))
470006	26465158	Moreover, deletion peaks of CDKN2A on 9p21.3 and FHIT on 3p14.2 were also observed in the GEO data set.	('CDKN2A', 'Gene', (28, 34))	('deletion', 'Var', (10, 18))	('FHIT', 'Gene', (49, 53))	('FHIT', 'Gene', '2272', (49, 53))	('CDKN2A', 'Gene', '1029', (28, 34))
470016	26465158	The combination of trastuzumab (0.1 mug/mL) plus transfection of siRNA targeting GRB7 had a stronger inhibitory effect on cell growth than administration of trastuzumab or siRNA targeting GRB7 alone (Fig 2d).	('trastuzumab', 'Chemical', 'MESH:D000068878', (157, 168))	('transfection', 'Var', (49, 61))	('siRNA', 'Var', (65, 70))	('inhibitory effect', 'NegReg', (101, 118))	('cell growth', 'CPA', (122, 133))	('GRB7', 'Gene', (81, 85))	('trastuzumab', 'Chemical', 'MESH:D000068878', (19, 30))
470017	26465158	This was observed under a high concentration of trastuzumab (1.0 mug/mL), which indicated that knockdown of GRB7 expression had a synergistic inhibitory effect on ESCC cell lines with amplification of 17q12.	('ESCC', 'Disease', (163, 167))	('synergistic inhibitory effect', 'MPA', (130, 159))	('GRB7', 'Gene', (108, 112))	('trastuzumab', 'Chemical', 'MESH:D000068878', (48, 59))	('knockdown', 'Var', (95, 104))
470020	26465158	With regard to overall survival, patients with high GRB7 expression had a significantly poorer prognosis than those with low GRB7 expression (P = 0.006; Fig 3b).	('GRB7', 'Protein', (52, 56))	('high', 'Var', (47, 51))	('poorer', 'NegReg', (88, 94))	('patients', 'Species', '9606', (33, 41))
470023	26465158	Similar to other cancers, recurrent amplification of 7p11.2, 8q24.21, and 11q13.2, harboring EGFR, MYC, and CCND1, has previously been reported in ESCC.	('EGFR', 'Gene', '1956', (93, 97))	('CCND1', 'Gene', (108, 113))	('MYC', 'Gene', '4609', (99, 102))	('EGFR', 'Gene', (93, 97))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('amplification', 'Var', (36, 49))	('ESCC', 'Disease', (147, 151))	('CCND1', 'Gene', '595', (108, 113))	('cancers', 'Disease', (17, 24))	('reported', 'Reg', (135, 143))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('MYC', 'Gene', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
470025	26465158	Compared with esophageal adenocarcinoma, the estimated frequency of SOX2 amplification was reported to be significantly higher in ESCC.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (14, 39))	('ESCC', 'Disease', (130, 134))	('higher', 'PosReg', (120, 126))	('SOX2', 'Gene', (68, 72))	('SOX2', 'Gene', '6657', (68, 72))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (14, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('esophageal adenocarcinoma', 'Disease', (14, 39))	('amplification', 'Var', (73, 86))
470027	26465158	Additionally, we found additional genes previously not reported in any genome-wide studies in ESCC, such as FOXP1 and NFATC1, which were downregulated due to deletion.	('FOXP1', 'Gene', (108, 113))	('downregulated', 'NegReg', (137, 150))	('NFATC1', 'Gene', (118, 124))	('deletion', 'Var', (158, 166))	('FOXP1', 'Gene', '27086', (108, 113))	('NFATC1', 'Gene', '4772', (118, 124))	('ESCC', 'Gene', (94, 98))
470029	26465158	The significance of HER2 amplification at 17q12 in ESCC has been highlighted in previous studies.	('HER2', 'Gene', '2064', (20, 24))	('ESCC', 'Disease', (51, 55))	('HER2', 'Gene', (20, 24))	('amplification', 'Var', (25, 38))
470030	26465158	The frequency of amplification of HER2 in ESCC ranges from 3.9% to 41.4%.	('HER2', 'Gene', '2064', (34, 38))	('HER2', 'Gene', (34, 38))	('amplification', 'Var', (17, 30))
470038	26465158	Therefore, in addition to its applications in breast and gastric cancers, trastuzumab may be an effective drug for the treatment of patients with ESCC harboring amplification of 17q12.	('gastric cancers', 'Phenotype', 'HP:0012126', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('amplification', 'Var', (161, 174))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('gastric cancers', 'Disease', (57, 72))	('ESCC', 'Disease', (146, 150))	('trastuzumab', 'Chemical', 'MESH:D000068878', (74, 85))	('patients', 'Species', '9606', (132, 140))	('gastric cancers', 'Disease', 'MESH:D013274', (57, 72))
470039	26465158	Moreover, when combined with trastuzumab, knockdown of GRB7 had a synergistic inhibitory effect on cell proliferation.	('GRB7', 'Gene', (55, 59))	('trastuzumab', 'Chemical', 'MESH:D000068878', (29, 40))	('cell proliferation', 'CPA', (99, 117))	('knockdown', 'Var', (42, 51))
470041	26465158	Collectively, we propose GRB7 as a novel therapeutic target in ESCC patients having 17q12 amplification.	('patients', 'Species', '9606', (68, 76))	('17q12 amplification', 'Var', (84, 103))	('ESCC', 'Disease', (63, 67))
470042	26465158	Moreover, since GRB7 reportedly acts with other tyrosine kinase receptors as well as ERBB2, we expect that inhibition of GRB7 would be a novel therapeutic strategy effective for ESCC patients with resistance to trastuzumab.	('GRB7', 'Gene', (121, 125))	('patients', 'Species', '9606', (183, 191))	('inhibition', 'Var', (107, 117))	('ESCC', 'Disease', (178, 182))	('trastuzumab', 'Chemical', 'MESH:D000068878', (211, 222))
470059	23735448	Early low-throughput studies of variants in candidate genes yielded, in the mid-2000s, to the genomics era, in which agnostic genome-wide association studies (GWAS) focused on a million or more individual SNPs, each analyzed in isolation from the others in its association with a cancer type.	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Disease', (280, 286))	('association', 'Interaction', (261, 272))	('variants', 'Var', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))
470116	22666581	As seen in these findings, the incorporation of FDG-PET improves the accuracy of staging and patient selection, providing better treatment strategy including radiotherapy planning.	('FDG', 'Chemical', 'MESH:D019788', (48, 51))	('FDG-PET', 'Gene', (48, 55))	('incorporation', 'Var', (31, 44))	('patient', 'Species', '9606', (93, 100))	('improves', 'PosReg', (56, 64))	('staging', 'CPA', (81, 88))
470176	22666581	In their study, PET/CT changed the stage in 5 of the 29 patients (17%), with the authors concluding that PET/CT improves the accuracy of staging in SCLC.	('SCLC', 'Disease', 'MESH:D018288', (148, 152))	('patients', 'Species', '9606', (56, 64))	('PET/CT', 'Var', (105, 111))	('improves', 'PosReg', (112, 120))	('SCLC', 'Phenotype', 'HP:0030357', (148, 152))	('SCLC', 'Disease', (148, 152))
470233	22666581	Furthermore, they showed that FDG-PET significantly changed the radiation dose for organs at risk, such as heart and lung.	('changed', 'Reg', (52, 59))	('FDG', 'Chemical', 'MESH:D019788', (30, 33))	('radiation dose', 'MPA', (64, 78))	('FDG-PET', 'Var', (30, 37))
470258	34001062	Mechanistically, KDM6B regulates TNFA_SIGNALING_VIA_NFkappaB signalling pathways, and H3K27me3 binds to the promoter region of C/EBPbeta, leading to the promotion of C/EBPbeta transcription.	('H3K27me3', 'Var', (86, 94))	('KDM6B', 'Var', (17, 22))	('C/EBPbeta', 'Gene', '1050', (127, 136))	('regulates', 'Reg', (23, 32))	('C/EBPbeta', 'Gene', (127, 136))	('C/EBPbeta', 'Gene', '1050', (166, 175))	('promotion', 'PosReg', (153, 162))	('transcription', 'MPA', (176, 189))	('C/EBPbeta', 'Gene', (166, 175))	('TNFA_SIGNALING_VIA_NFkappaB', 'Pathway', (33, 60))	('binds', 'Interaction', (95, 100))
470259	34001062	The present study demonstrated that KDM6B promotes ESCC progression by increasing the transcriptional activity of C/EBPbeta depending on its H3K27 demethylase activity.	('increasing', 'PosReg', (71, 81))	('activity', 'MPA', (159, 167))	('transcriptional activity', 'MPA', (86, 110))	('demethylase', 'Gene', (147, 158))	('promotes', 'PosReg', (42, 50))	('C/EBPbeta', 'Gene', '1050', (114, 123))	('ESCC', 'Disease', (51, 55))	('demethylase', 'Gene', '8932', (147, 158))	('C/EBPbeta', 'Gene', (114, 123))	('KDM6B', 'Var', (36, 41))
470265	34001062	Epigenetic modification plays an important role in tumorigenesis and development.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('Epigenetic modification', 'Var', (0, 23))	('development', 'CPA', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
470266	34001062	Many reports have confirmed that epigenetic modification plays a crucial role in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('epigenetic modification', 'Var', (33, 56))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
470267	34001062	Methylation of lysine residue 27 of histone H3 (H3K27), is closely linked to transcriptional repression.	('H3K27', 'Gene', (48, 53))	('histone H3', 'Gene', '260423', (36, 46))	('Methylation', 'Var', (0, 11))	('histone H3', 'Gene', (36, 46))	('lysine', 'Chemical', 'MESH:D008239', (15, 21))	('transcriptional', 'MPA', (77, 92))	('linked', 'Reg', (67, 73))
470268	34001062	Among human cancers, H3K27me3 has been evaluated as a prognostic factor for prostate cancer, breast cancer, ovarian cancer, pancreatic cancer and esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('ovarian cancer', 'Disease', (108, 122))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (135, 141))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('pancreatic cancer', 'Disease', (124, 141))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('H3K27me3', 'Var', (21, 29))	('breast cancer', 'Disease', (93, 106))	('human', 'Species', '9606', (6, 11))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('cancers', 'Disease', (12, 19))	('cancer', 'Disease', (12, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))	('prostate cancer', 'Disease', (76, 91))
470269	34001062	H3K27 methylation and demethylation is a dynamic process that can be catalyzed by Methyltransferase (e.g., EZH2), demethyltransferase (e.g., KDM6A and KDM6B), KDM6B also known as JMJD3.	('demethylation', 'MPA', (22, 35))	('EZH2', 'Gene', '2146', (107, 111))	('KDM6B', 'Var', (159, 164))	('KDM6A', 'Gene', (141, 146))	('methylation', 'Var', (6, 17))	('EZH2', 'Gene', (107, 111))	('JMJD3', 'Gene', (179, 184))	('H3K27', 'Protein', (0, 5))	('Methyltransferase', 'Enzyme', (82, 99))	('KDM6A', 'Gene', '7403', (141, 146))	('JMJD3', 'Gene', '23135', (179, 184))
470270	34001062	As an important histone demethylase, KDM6B can catalyze the demethylation of H3K27me2/3 to activate target genes by using Fe2+ and alpha-ketoglutarate as cofactors.	('Fe2+', 'Chemical', '-', (122, 126))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (131, 150))	('demethylase', 'Gene', (24, 35))	('KDM6B', 'Var', (37, 42))	('demethylase', 'Gene', '8932', (24, 35))	('activate', 'PosReg', (91, 99))	('H3K27me2/3', 'Protein', (77, 87))
470273	34001062	We show that KDM6B is overexpressed in ESCC patients with lymph node metastasis and confirm that KDM6B can promote ESCC cell proliferation, clone formation, G1/S transformation, migration and invasion.	('ESCC', 'Disease', (115, 119))	('patients', 'Species', '9606', (44, 52))	('KDM6B', 'Var', (97, 102))	('invasion', 'CPA', (192, 200))	('G1/S transformation', 'CPA', (157, 176))	('clone formation', 'CPA', (140, 155))	('migration', 'CPA', (178, 187))	('promote', 'PosReg', (107, 114))
470280	34001062	After blocking for 1 h at room temperature with 5% non-fat milk in Phosphate buffered saline with Tween 20 (PBST), the membranes were incubated for overnight with the primary antibodies anti-KDM6B (abs103127, Absin, 1:1000), anti-Tri-Methyl-Histone H3(Lys27) (C36B11) Rabbit mAb (#9733, Cell Signaling, 1:1000), anti- GAPDH (AG019, Beyotime Biotechnology, 1:5000), anti- Histone H3 Mouse Monoclonal Antibody (AF0009, Beyotime Biotechnology, 1:1000).	('Mouse', 'Species', '10090', (382, 387))	('Histone H3', 'Gene', '260423', (371, 381))	('Histone H3', 'Gene', '260423', (241, 251))	('Histone H3', 'Gene', (371, 381))	('PBS', 'Chemical', 'MESH:D007854', (108, 111))	('Histone H3', 'Gene', (241, 251))	('anti-KDM6B', 'Var', (186, 196))
470312	34001062	When the KYSE150 sh-NC and sh-KDM6B-1 cells were at a logarithmic growth phase, they were subcutaneously injected into the armpit of the forelimb of nude mice (0.2 mL, 2 x 106 cells).	('KYSE150 sh-NC', 'Var', (9, 22))	('KYSE150', 'CellLine', 'CVCL:1348', (9, 16))	('sh-KDM6B-1', 'Var', (27, 37))	('nude mice', 'Species', '10090', (149, 158))
470333	34001062	Compared with HEEC, the expression of KEM6B was significantly higher for KYSE150, TE10, and significantly lower for Eca9706, TE11.	('TE10', 'Chemical', '-', (82, 86))	('Eca9706', 'CellLine', 'CVCL:E307', (116, 123))	('lower', 'NegReg', (106, 111))	('KYSE150', 'Var', (73, 80))	('expression', 'MPA', (24, 34))	('TE11', 'Var', (125, 129))	('KYSE150', 'CellLine', 'CVCL:1348', (73, 80))	('Eca9706', 'Var', (116, 123))	('TE10', 'Var', (82, 86))	('higher', 'PosReg', (62, 68))	('HEEC', 'CellLine', 'None', (14, 18))	('TE11', 'Chemical', '-', (125, 129))	('KEM6B', 'Gene', (38, 43))
470338	34001062	1B, the Interference of KDM6B in KYSE150 and TE10 exhibited significantly reduced proliferation compared with controls at 96 h, and overexpressed KDM6B promoted the proliferation of Eca9706 and TE11 cells.	('Eca9706', 'CPA', (182, 189))	('TE11', 'Chemical', '-', (194, 198))	('TE10', 'Chemical', '-', (45, 49))	('Eca9706', 'CellLine', 'CVCL:E307', (182, 189))	('promoted', 'PosReg', (152, 160))	('KDM6B', 'Gene', (24, 29))	('KYSE150', 'Var', (33, 40))	('proliferation', 'CPA', (82, 95))	('KYSE150', 'CellLine', 'CVCL:1348', (33, 40))	('reduced', 'NegReg', (74, 81))	('proliferation', 'CPA', (165, 178))
470339	34001062	Coincidence with CCK8 assay, the Interference of KDM6B also significantly decreased the clone formation ability of KYSE150 and TE10 cells, and the overexpression of KDM6B in Eca9706 and TE11 promoted the clone formation ability of ESCC cells (Fig.	('promoted', 'PosReg', (191, 199))	('KDM6B', 'Var', (49, 54))	('clone formation ability', 'CPA', (204, 227))	('Eca9706', 'Var', (174, 181))	('clone formation ability', 'CPA', (88, 111))	('KYSE150', 'CellLine', 'CVCL:1348', (115, 122))	('decreased', 'NegReg', (74, 83))	('TE10', 'Chemical', '-', (127, 131))	('TE11', 'Chemical', '-', (186, 190))	('Eca9706', 'CellLine', 'CVCL:E307', (174, 181))
470340	34001062	The results demonstrated that knockdown of KDM6B markedly increased the proportion of cells in the G1 phase, but decreased the proportion of cells in the S phase in KYSE150 and TE10 cells; the overexpress of KDM6B induced Eca9706 and TE11 transition from G0/G1 to S phase (Fig.	('Eca9706', 'CellLine', 'CVCL:E307', (222, 229))	('increased', 'PosReg', (58, 67))	('KYSE150', 'CellLine', 'CVCL:1348', (165, 172))	('induced', 'Reg', (214, 221))	('Eca9706', 'Var', (222, 229))	('TE11', 'Chemical', '-', (234, 238))	('TE11 transition', 'CPA', (234, 249))	('KDM6B', 'Var', (43, 48))	('TE10', 'Chemical', '-', (177, 181))	('overexpress', 'PosReg', (193, 204))	('decreased', 'NegReg', (113, 122))	('KDM6B', 'Gene', (208, 213))
470342	34001062	1E showed when KYSE150 and TE10 stably infected by Lv-sh-KDM6B, the migration rate significantly decreased which compared with negative control (p < 0.05), and Eca9706 and TE11 transiently transfected with HA-KDM6B overexpression plasmid, the migration rate increased which compared with negative control(p < 0.05).	('Eca9706', 'Var', (160, 167))	('TE10', 'Chemical', '-', (27, 31))	('Lv-sh-KDM6B', 'Var', (51, 62))	('increased', 'PosReg', (258, 267))	('infected', 'Disease', (39, 47))	('HA-KDM6B', 'Var', (206, 214))	('migration rate', 'CPA', (68, 82))	('decreased', 'NegReg', (97, 106))	('TE11', 'Chemical', '-', (172, 176))	('migration rate', 'CPA', (243, 257))	('Eca9706', 'CellLine', 'CVCL:E307', (160, 167))	('KYSE150', 'CellLine', 'CVCL:1348', (15, 22))	('infected', 'Disease', 'MESH:D007239', (39, 47))
470343	34001062	The Transwell assay also revealed similar results when stable infection by the Lv-sh-KDM6B and transient transfected by the HA-KDM6B overexpression plasmid.	('Lv-sh-KDM6B', 'Var', (79, 90))	('infection', 'Disease', (62, 71))	('infection', 'Disease', 'MESH:D007239', (62, 71))
470344	34001062	Lv-sh-KDM6B interference reduced the KYSE150 and TE10 migration and invading cell number, and HA-KDM6B overexpression increased the Eca9706 and TE11 migration and invading cell number, which compared with the control group (Fig.	('invading cell number', 'CPA', (68, 88))	('reduced', 'NegReg', (25, 32))	('TE10', 'Chemical', '-', (49, 53))	('invading cell number', 'CPA', (163, 183))	('increased', 'PosReg', (118, 127))	('TE11', 'Chemical', '-', (144, 148))	('Eca9706', 'CellLine', 'CVCL:E307', (132, 139))	('KYSE150', 'CPA', (37, 44))	('KYSE150', 'CellLine', 'CVCL:1348', (37, 44))	('HA-KDM6B', 'Var', (94, 102))
470347	34001062	To further investigate the effect of KDM6B on tumor metastasis, we performed pulmonary metastasis assay in nude mice by injecting sh-KDM6B-1 and sh-NC transfected KYSE150 cells through the tail vein.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('sh-KDM6B-1', 'Var', (130, 140))	('KYSE150', 'CellLine', 'CVCL:1348', (163, 170))	('tumor metastasis', 'Disease', (46, 62))	('tumor metastasis', 'Disease', 'MESH:D009362', (46, 62))	('pulmonary metastasis assay', 'CPA', (77, 103))	('nude mice', 'Species', '10090', (107, 116))
470348	34001062	These results suggested that knockdown KDM6B could inhibit KYSE150 cell migration and invasion both in vitro and in vivo.	('KDM6B', 'Gene', (39, 44))	('KYSE150 cell migration', 'CPA', (59, 81))	('knockdown', 'Var', (29, 38))	('KYSE150', 'CellLine', 'CVCL:1348', (59, 66))	('inhibit', 'NegReg', (51, 58))	('invasion', 'CPA', (86, 94))
470350	34001062	Through gene set enrichment analysis (GSEA), we found that the TNFA_SIGNALING_VIA_NFkappaB, INTERFERON_ GAMMA_RESPONSE, P53, and IL6_JAK_STAT3_SIGNALING pathway, which were known to be closely associated with oncogenesis, were significantly suppressed in KYSE150 cells that KDM6B was knockdown as compared with Ctrl cells (Fig.	('GSEA', 'Chemical', '-', (38, 42))	('STAT3', 'Gene', (137, 142))	('SE', 'Disease', 'None', (39, 41))	('KYSE150', 'CellLine', 'CVCL:1348', (255, 262))	('knockdown', 'Var', (284, 293))	('suppressed', 'NegReg', (241, 251))	('P53', 'Gene', (120, 123))	('TNFA_SIGNALING_VIA_NFkappaB', 'Gene', (63, 90))	('P53', 'Gene', '7157', (120, 123))	('SE', 'Disease', 'None', (116, 118))	('STAT3', 'Gene', '6774', (137, 142))	('SE', 'Disease', 'None', (257, 259))
470359	34001062	To further analyze the downstream molecular mechanism of KDM6B in ESCC, we first clarified whether KDM6B exerts demethylase activity in ESCC cells and catalyzes H3K27me3 demethylation.	('demethylase', 'Gene', '8932', (112, 123))	('demethylase', 'Gene', (112, 123))	('H3K27me3', 'Var', (161, 169))	('KDM6B', 'Gene', (99, 104))
470360	34001062	Then we performed ChIP-seq and ChIP-qPCR assays to compare the possible alterations H3K27me3 of the KDM6B regulated genes after KDM6B knockout in KYSE150 cells.	('H3K27me3', 'Var', (84, 92))	('alterations', 'Reg', (72, 83))	('KYSE150', 'CellLine', 'CVCL:1348', (146, 153))	('KDM6B regulated genes', 'Gene', (100, 121))
470362	34001062	As expected, the expression of C/EBPbeta in the KDM6B knockout KYSE150 cells were associated with an increased H3K27me3 around the promoter within 2 kb upstream or 100 bp downstream of the transcription start site (TSS),which is shown in the Integrative Genomics Viewer (IGV) software and validated by ChIP-qPCR (Fig.	('knockout', 'Var', (54, 62))	('C/EBPbeta', 'Gene', '1050', (31, 40))	('increased', 'PosReg', (101, 110))	('KYSE150', 'CellLine', 'CVCL:1348', (63, 70))	('KDM6B', 'Gene', (48, 53))	('C/EBPbeta', 'Gene', (31, 40))	('H3K27me3', 'Protein', (111, 119))
470363	34001062	In parallel, We used GSK-J4 to inhibit KDM6B in ESCC cells, and ChIP-qPCR also found that inhibiting KDM6B can significantly reduce the expression level of H3K27me3 in the C/EBPbeta promoter region (Fig.	('C/EBPbeta', 'Gene', '1050', (172, 181))	('C/EBPbeta', 'Gene', (172, 181))	('inhibiting', 'Var', (90, 100))	('reduce', 'NegReg', (125, 131))	('expression level', 'MPA', (136, 152))	('KDM6B', 'Gene', (101, 106))	('H3K27me3', 'Protein', (156, 164))
470372	34001062	Then KDM6B promotes proliferation and metastasis in ESCC cells partly through activating the transcription of C/EBPbeta by demethylating the repressive H3K27me3 markers on the promoters (Fig.	('proliferation', 'CPA', (20, 33))	('activating', 'PosReg', (78, 88))	('demethylating', 'Var', (123, 136))	('transcription', 'MPA', (93, 106))	('C/EBPbeta', 'Gene', '1050', (110, 119))	('KDM6B', 'Var', (5, 10))	('C/EBPbeta', 'Gene', (110, 119))	('promotes', 'PosReg', (11, 19))	('H3K27me3', 'Protein', (152, 160))	('metastasis', 'CPA', (38, 48))
470374	34001062	CCK8 assay showed that treatment of KYSE150 with GSK-J4 inhibits relative cell viability compared with DMSO control at 96 h (Fig.	('inhibits', 'NegReg', (56, 64))	('KYSE150', 'Var', (36, 43))	('GSK-J4', 'Gene', (49, 55))	('DMSO', 'Chemical', 'MESH:D004121', (103, 107))	('KYSE150', 'CellLine', 'CVCL:1348', (36, 43))	('cell viability', 'CPA', (74, 88))
470375	34001062	7b), as expected, treat with GSK-J4 significantly decreased the clone formation ability of KYSE150 cells, and treat with GSK-J4 markedly induced G1/S cell cycle arrest in KYSE150 cells (Fig.	('KYSE150', 'CellLine', 'CVCL:1348', (171, 178))	('arrest', 'Disease', (161, 167))	('clone formation ability of KYSE150 cells', 'CPA', (64, 104))	('GSK-J4', 'Gene', (121, 127))	('induced', 'Reg', (137, 144))	('decreased', 'NegReg', (50, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (150, 167))	('KYSE150', 'CellLine', 'CVCL:1348', (91, 98))	('treat', 'Var', (110, 115))	('arrest', 'Disease', 'MESH:D006323', (161, 167))
470377	34001062	H3K27me3/2 are repressive histone modifications important for gene silencing, and removal of such marks by KDM6B allows for activation of genes both during normal development and tissue differentiation as well as during carcinogenesis.	('activation', 'PosReg', (124, 134))	('KDM6B', 'Gene', (107, 112))	('H3K27me3/2', 'Var', (0, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (220, 234))	('genes', 'Gene', (138, 143))	('carcinogenesis', 'Disease', (220, 234))	('removal', 'Var', (82, 89))
470380	34001062	For example, KDM6B induces the expression of cervical cancer marker p16INK4A and promotes the proliferation of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('promotes', 'PosReg', (81, 89))	('p16INK4A', 'Gene', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('p16INK4A', 'Gene', '1029', (68, 76))	('proliferation', 'CPA', (94, 107))	('expression', 'MPA', (31, 41))	('cancer', 'Disease', (111, 117))	('induces', 'PosReg', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('KDM6B', 'Var', (13, 18))
470384	34001062	Consistent with this, another demethylase KDM6A mainly functions as a tumor suppressor gene, and its mutation has led to the occurrence of many tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('KDM6A', 'Gene', (42, 47))	('demethylase', 'Gene', (30, 41))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('led to', 'Reg', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', (70, 75))	('demethylase', 'Gene', '8932', (30, 41))	('KDM6A', 'Gene', '7403', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('occurrence', 'Reg', (125, 135))	('mutation', 'Var', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
470387	34001062	Besides, EZH2 (Enhancer of Zeste Homology 2, Zeste homology enhancer 2), as the catalytic subunit of the PRC2 complex, can promote the methylation of H3K27, thereby epigenetically silencing the gene.	('silencing', 'NegReg', (180, 189))	('Enhancer of Zeste Homology 2', 'Gene', (15, 43))	('Enhancer of Zeste Homology 2', 'Gene', '2146', (15, 43))	('promote', 'PosReg', (123, 130))	('epigenetically', 'Var', (165, 179))	('methylation', 'MPA', (135, 146))	('H3K27', 'Protein', (150, 155))	('EZH2', 'Gene', (9, 13))	('EZH2', 'Gene', '2146', (9, 13))
470391	34001062	The combination of histone modifications and other regulatory processes can affect overall biological outcomes, and the dysregulation of methylases and demethylases in tumors can also lead to different consequences.	('affect', 'Reg', (76, 82))	('modifications', 'Var', (27, 40))	('histone', 'Protein', (19, 26))	('demethylase', 'Gene', '8932', (152, 163))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('methylases', 'Enzyme', (137, 147))	('lead', 'Reg', (184, 188))	('biological outcomes', 'MPA', (91, 110))	('demethylase', 'Gene', (152, 163))
470393	34001062	we found that TNFA_SIGNALING_VIA_NFkappaB, INTERFERON_ GAMMA_RESPONSE, P53, and IL6_JAK_STAT3_SIGNALING pathway were significantly suppressed in KDM6B knockdown KYSE150 as compared with Ctrl cells, and those signaling pathways were known to be closely associated with oncogenesis.	('P53', 'Gene', (71, 74))	('SE', 'Disease', 'None', (163, 165))	('KYSE150', 'CellLine', 'CVCL:1348', (161, 168))	('P53', 'Gene', '7157', (71, 74))	('STAT3', 'Gene', '6774', (88, 93))	('TNFA_SIGNALING_VIA_NFkappaB', 'Pathway', (14, 41))	('SE', 'Disease', 'None', (67, 69))	('STAT3', 'Gene', (88, 93))	('KDM6B', 'Gene', (145, 150))	('suppressed', 'NegReg', (131, 141))	('knockdown', 'Var', (151, 160))
470397	34001062	Our results preliminarily verified that KDM6B regulates the expression of C/EBPbeta by demethylating H3K27me3 and promotes the progress of ESCC.	('expression', 'MPA', (60, 70))	('progress', 'CPA', (127, 135))	('regulates', 'Reg', (46, 55))	('demethylating', 'Var', (87, 100))	('C/EBPbeta', 'Gene', '1050', (74, 83))	('KDM6B', 'Var', (40, 45))	('promotes', 'PosReg', (114, 122))	('C/EBPbeta', 'Gene', (74, 83))	('H3K27me3', 'Protein', (101, 109))	('ESCC', 'Disease', (139, 143))
470401	34001062	However, whether KDM6B plays a carcinogenic or anticancer role in certain tumors may depend on the specific tissue and cell type.	('KDM6B', 'Var', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('carcinogenic', 'Disease', 'MESH:D063646', (31, 43))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('carcinogenic', 'Disease', (31, 43))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (74, 80))
470402	34001062	In conclusion, our results suggest that KDM6B was highly overexpressed in metastatic ESCC tissues, and KDM6B promotes ESCC progression by increasing the transcriptional activity of C/EBPbeta depending on its H3K27 demethylase activity.	('ESCC', 'Disease', (118, 122))	('C/EBPbeta', 'Gene', (181, 190))	('demethylase', 'Gene', (214, 225))	('progression', 'CPA', (123, 134))	('KDM6B', 'Var', (103, 108))	('demethylase', 'Gene', '8932', (214, 225))	('transcriptional activity', 'MPA', (153, 177))	('C/EBPbeta', 'Gene', '1050', (181, 190))	('increasing', 'PosReg', (138, 148))	('promotes', 'PosReg', (109, 117))
470408	34001062	Information on RNA-seq and ChIP-seq are available in https://www.ncbi.nlm.nih.gov/sra/PRJNA691394, the submission ID are SUB8898024 and SUB8899697, respectively.	('sra', 'Gene', '10011', (82, 85))	('sra', 'Gene', (82, 85))	('SUB8899697', 'Var', (136, 146))	('SUB8898024', 'Var', (121, 131))
470427	33476486	We identified many somatic copy number alterations of ESCC, among which the copy number amplification of Homo sapiens BAALC antisense RNA 1 (BAALC-AS1, NR_109954.1) attracted our attention.	('BAALC antisense RNA 1', 'Gene', (118, 139))	('BAALC antisense RNA 1', 'Gene', '100499183', (118, 139))	('BAALC-AS1', 'Gene', '100499183', (141, 150))	('copy number alterations', 'Var', (27, 50))	('ESCC', 'Gene', (54, 58))	('alterations', 'Var', (39, 50))	('BAALC-AS1', 'Gene', (141, 150))	('copy', 'Var', (76, 80))
470462	33476486	Antibodies against c-Myc (cat# 13987S), cyclin D (cat# 2978S), and CDK4 (cat# 12790S) were all from Cell Signaling Technology (Danvers, MA, USA); antibodies against CDK2 (cat# ab32147), IgG (cat# ab171870), and actin (cat# ab179467) were from Abcam (Cambridge, MA, USA); antibody against G3BP2 (cat# 16276-1-AP) was from Proteintech (Wuhan, Hubei, China); and antibody against cyclin E (cat# sc-377100) was from Santa Cruz Biotechnology (Santa Cruz, CA, USA).	('CDK2', 'Gene', (165, 169))	('CDK4', 'Gene', (67, 71))	('c-Myc', 'Gene', '4609', (19, 24))	('cat#', 'Var', (191, 195))	('CDK2', 'Gene', '1017', (165, 169))	('CDK4', 'Gene', '1019', (67, 71))	('G3BP2', 'Gene', '9908', (288, 293))	('cat# ab32147', 'Var', (171, 183))	('G3BP2', 'Gene', (288, 293))	('c-Myc', 'Gene', (19, 24))
470508	33476486	Figure 2D shows that the percentage of cells in S and G2/M phases was decreased in both KYSE-450 and KYSE-510 cells in which BAALC-AS1 was knocked down.	('KYSE-510', 'CellLine', 'CVCL:1354', (101, 109))	('BAALC-AS1', 'Gene', '100499183', (125, 134))	('KYSE-510', 'Var', (101, 109))	('decreased', 'NegReg', (70, 79))	('BAALC-AS1', 'Gene', (125, 134))
470509	33476486	After siRNA transfection for BAALC-AS1 in ESCC cells, the expression levels of Cyclin D, Cyclin E, Cyclin-dependent kinase 2 (CDK2), and CDK4 were also decreased (Figure 2E).	('Cyclin-dependent kinase 2', 'Gene', (99, 124))	('expression levels', 'MPA', (58, 75))	('Cyclin', 'Gene', '5111', (99, 105))	('CDK2', 'Gene', (126, 130))	('Cyclin', 'Gene', '5111', (89, 95))	('Cyclin', 'Gene', (79, 85))	('BAALC-AS1', 'Gene', '100499183', (29, 38))	('Cyclin', 'Gene', '5111', (79, 85))	('CDK4', 'Gene', '1019', (137, 141))	('CDK4', 'Gene', (137, 141))	('Cyclin', 'Gene', (99, 105))	('decreased', 'NegReg', (152, 161))	('Cyclin', 'Gene', (89, 95))	('Cyclin-dependent kinase 2', 'Gene', '1017', (99, 124))	('CDK2', 'Gene', '1017', (126, 130))	('transfection', 'Var', (12, 24))	('BAALC-AS1', 'Gene', (29, 38))
470511	33476486	The percentage of cells in S and G2/M phases was increased in both KYSE-180 and KYSE-410 cells in which BAALC-AS1 was overexpressed (Figure 3D).	('KYSE-410', 'CellLine', 'CVCL:1352', (80, 88))	('BAALC-AS1', 'Gene', '100499183', (104, 113))	('increased', 'PosReg', (49, 58))	('KYSE-410', 'Var', (80, 88))	('BAALC-AS1', 'Gene', (104, 113))
470513	33476486	We conducted wound healing assays and observed that BAALC-AS1 knockdown decreased cell migration in both KYSE-450 and KYSE-510 cells (Figure 4A).	('cell migration', 'CPA', (82, 96))	('BAALC-AS1', 'Gene', '100499183', (52, 61))	('decreased', 'NegReg', (72, 81))	('BAALC-AS1', 'Gene', (52, 61))	('KYSE-510', 'CellLine', 'CVCL:1354', (118, 126))	('knockdown', 'Var', (62, 71))
470515	33476486	Similarly, BAALC-AS1 knockdown decreased cell invasion in both KYSE-450 and KYSE-510 cells (Figure 4B), while BAALC-AS1 overexpression increased invasion in both KYSE-180 and KYSE-410 cells (Supplementary Figure S3B).	('KYSE-510', 'CellLine', 'CVCL:1354', (76, 84))	('cell invasion', 'CPA', (41, 54))	('BAALC-AS1', 'Gene', '100499183', (11, 20))	('BAALC-AS1', 'Gene', '100499183', (110, 119))	('decreased', 'NegReg', (31, 40))	('increased', 'PosReg', (135, 144))	('BAALC-AS1', 'Gene', (11, 20))	('KYSE-410', 'CellLine', 'CVCL:1352', (175, 183))	('BAALC-AS1', 'Gene', (110, 119))	('knockdown', 'Var', (21, 30))	('invasion', 'CPA', (145, 153))
470521	33476486	Moreover, we concerned about the health and body weight of the mice, but found that there was no obvious toxicity after BAALC-AS1 knockdown or overexpression (Figure 5D).	('BAALC-AS1', 'Gene', (120, 129))	('mice', 'Species', '10090', (63, 67))	('knockdown', 'Var', (130, 139))	('BAALC-AS1', 'Gene', '100499183', (120, 129))	('toxicity', 'Disease', 'MESH:D064420', (105, 113))	('toxicity', 'Disease', (105, 113))
470523	33476486	After BAALC-AS1 was knocked down, the expression of Ki67 was significantly decreased and the degree of differentiation was relatively high, and the opposite results were observed after the overexpression of BAALC-AS1 (Figure 5E).	('BAALC-AS1', 'Gene', (207, 216))	('BAALC-AS1', 'Gene', '100499183', (6, 15))	('expression', 'MPA', (38, 48))	('Ki67', 'Gene', '17345', (52, 56))	('knocked down', 'Var', (20, 32))	('BAALC-AS1', 'Gene', (6, 15))	('differentiation', 'CPA', (103, 118))	('high', 'PosReg', (134, 138))	('BAALC-AS1', 'Gene', '100499183', (207, 216))	('Ki67', 'Gene', (52, 56))	('decreased', 'NegReg', (75, 84))
470528	33476486	Moreover, the mRNA and protein expression of G3BP2 changed little upon BAALC-AS1 knockdown in KYSE-450 cells (Figure 6D-E).	('BAALC-AS1', 'Gene', (71, 80))	('knockdown', 'Var', (81, 90))	('BAALC-AS1', 'Gene', '100499183', (71, 80))	('G3BP2', 'Gene', '9908', (45, 50))	('G3BP2', 'Gene', (45, 50))
470531	33476486	We also detected down-regulated c-Myc mRNA and protein levels after BAALC-AS1 knockdown in KYSE-450 cells (Figure 6G-H).	('BAALC-AS1', 'Gene', (68, 77))	('knockdown', 'Var', (78, 87))	('down-regulated', 'NegReg', (17, 31))	('c-Myc', 'Gene', '4609', (32, 37))	('c-Myc', 'Gene', (32, 37))	('BAALC-AS1', 'Gene', '100499183', (68, 77))
470532	33476486	In addition, BALC-AS1 knockdown shortened the half-life of c-Myc mRNA (Figure 6I).	('c-Myc', 'Gene', (59, 64))	('shortened', 'NegReg', (32, 41))	('knockdown', 'Var', (22, 31))	('half-life', 'MPA', (46, 55))	('c-Myc', 'Gene', '4609', (59, 64))	('AS1', 'Gene', '5729', (18, 21))	('AS1', 'Gene', (18, 21))
470534	33476486	We then determined whether BAALC-AS1 enhanced c-Myc expression by binding to G3BP2 and found that G3BP2 knockdown significantly abrogated the si/BAALC-AS1-induced c-Myc down-regulation (Figure 6J and Supplementary Figure S5B).	('BAALC-AS1', 'Gene', '100499183', (27, 36))	('down-regulation', 'NegReg', (169, 184))	('G3BP2', 'Gene', '9908', (98, 103))	('G3BP2', 'Gene', '9908', (77, 82))	('abrogated', 'NegReg', (128, 137))	('c-Myc', 'Gene', '4609', (163, 168))	('c-Myc', 'Gene', '4609', (46, 51))	('binding', 'Interaction', (66, 73))	('G3BP2', 'Gene', (98, 103))	('BAALC-AS1', 'Gene', '100499183', (145, 154))	('G3BP2', 'Gene', (77, 82))	('BAALC-AS1', 'Gene', (27, 36))	('c-Myc', 'Gene', (163, 168))	('c-Myc', 'Gene', (46, 51))	('BAALC-AS1', 'Gene', (145, 154))	('enhanced', 'PosReg', (37, 45))	('knockdown', 'Var', (104, 113))
470537	33476486	Furthermore, silencing G3BP2 rescued the si/BAALC-AS1-reduced luciferase activity via the c-Myc 3'-UTR-containing reporter (Figure 6L).	('BAALC-AS1', 'Gene', (44, 53))	('G3BP2', 'Gene', (23, 28))	('activity', 'MPA', (73, 81))	('c-Myc', 'Gene', '4609', (90, 95))	('c-Myc', 'Gene', (90, 95))	('G3BP2', 'Gene', '9908', (23, 28))	('luciferase', 'Enzyme', (62, 72))	('BAALC-AS1', 'Gene', '100499183', (44, 53))	('silencing', 'Var', (13, 22))
470540	33476486	Silencing c-Myc abrogated the stimulatory effect of BAALC-AS1 overexpression on cell growth (Figure 7C) and proliferation (Figure 7D).	('BAALC-AS1', 'Gene', '100499183', (52, 61))	('c-Myc', 'Gene', (10, 15))	('BAALC-AS1', 'Gene', (52, 61))	('abrogated', 'NegReg', (16, 25))	('overexpression', 'PosReg', (62, 76))	('stimulatory effect', 'MPA', (30, 48))	('Silencing', 'Var', (0, 9))	('c-Myc', 'Gene', '4609', (10, 15))	('cell growth', 'CPA', (80, 91))
470545	33476486	We found that BAALC-AS1 expression was decreased following c-Myc knockdown (Figure 8A).	('c-Myc', 'Gene', (59, 64))	('c-Myc', 'Gene', '4609', (59, 64))	('expression', 'MPA', (24, 34))	('decreased', 'NegReg', (39, 48))	('BAALC-AS1', 'Gene', (14, 23))	('knockdown', 'Var', (65, 74))	('BAALC-AS1', 'Gene', '100499183', (14, 23))
470557	33476486	We were surprised that the RNA and protein levels of c-Myc were down-regulated when BAALC-AS1 was knocked down.	('BAALC-AS1', 'Gene', (84, 93))	('down-regulated', 'NegReg', (64, 78))	('knocked down', 'Var', (98, 110))	('c-Myc', 'Gene', '4609', (53, 58))	('BAALC-AS1', 'Gene', '100499183', (84, 93))	('c-Myc', 'Gene', (53, 58))
470559	33476486	We found that BAALC-AS1 was down-regulated while c-Myc was up-regulated after G3BP2 was knocked down.	('knocked down', 'Var', (88, 100))	('up-regulated', 'PosReg', (59, 71))	('G3BP2', 'Gene', '9908', (78, 83))	('c-Myc', 'Gene', '4609', (49, 54))	('c-Myc', 'Gene', (49, 54))	('down-regulated', 'NegReg', (28, 42))	('G3BP2', 'Gene', (78, 83))	('BAALC-AS1', 'Gene', (14, 23))	('BAALC-AS1', 'Gene', '100499183', (14, 23))
470601	31917882	The PVDF membrane was then blocked with 0.5% bovine serum albumin (Amresco) followed by incubation overnight at 4 C with primary antibodies against LGR6 (1:2000, Abcam) and beta-actin (1:2000, Abcam).	('beta-actin', 'Gene', '728378', (173, 183))	('serum albumin', 'Gene', (52, 65))	('beta-actin', 'Gene', (173, 183))	('PVDF', 'Chemical', 'MESH:C024865', (4, 8))	('LGR6', 'Gene', (148, 152))	('1:2000', 'Var', (185, 191))	('LGR6', 'Gene', '59352', (148, 152))	('serum albumin', 'Gene', '213', (52, 65))
470621	31917882	Kaplan-Meier survival analysis showed that the 5-year survival of ESCC patients with high LGR6 expression was significantly lower than that of ESCC patients with low LGR6 expression (log-rank test, P < .001; Figure 5).	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (71, 79))	('LGR6', 'Gene', (90, 94))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('LGR6', 'Gene', (166, 170))	('expression', 'Var', (95, 105))	('high', 'Var', (85, 89))	('lower', 'NegReg', (124, 129))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('ESCC', 'Disease', (66, 70))	('LGR6', 'Gene', '59352', (90, 94))	('LGR6', 'Gene', '59352', (166, 170))
470698	27959959	Immunotherapy with anti-programmed death-1 or anti-programmed death ligand-1 antibodies has shown promising results in a number of malignant tumors.	('malignant tumors', 'Disease', 'MESH:D018198', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('anti-programmed', 'Var', (19, 34))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('malignant tumors', 'Disease', (131, 147))
470722	27959959	Immunohistochemical staining was performed in 53 patients: some positive staining was observed in 26/36 patients analyzed for cytokeratin subtype expression (CK5/6, CK8, CK18, CKpan); 26/27 patients stained positive for AE1/AE3; 21/25 patients stained positive for bcl-2; 27/27 patients stained positive for CK34betaE; 6/6 patients stained positive for p63; 5/8 patients stained positive for NSE; and 0/29 patients stained positive for chra.	('AE1', 'Gene', (220, 223))	('patients', 'Species', '9606', (190, 198))	('bcl-2', 'Gene', '596', (265, 270))	('patients', 'Species', '9606', (362, 370))	('patients', 'Species', '9606', (323, 331))	('CK34betaE', 'Var', (308, 317))	('patients', 'Species', '9606', (235, 243))	('CK18', 'Gene', (170, 174))	('CK5/6', 'Gene', '3852', (158, 163))	('CK18', 'Gene', '3875', (170, 174))	('AE3', 'Gene', (224, 227))	('CK8', 'Gene', '3856', (165, 168))	('NSE', 'Gene', '2026', (392, 395))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (104, 112))	('NSE', 'Gene', (392, 395))	('CK5/6', 'Gene', (158, 163))	('p63', 'Gene', (353, 356))	('AE1', 'Gene', '6521', (220, 223))	('patients', 'Species', '9606', (406, 414))	('p63', 'Gene', '8626', (353, 356))	('CK8', 'Gene', (165, 168))	('bcl-2', 'Gene', (265, 270))	('patients', 'Species', '9606', (278, 286))	('AE3', 'Gene', '6508', (224, 227))
470752	27959959	reported that BSCCE and typical SCC show distinct genetic and epigenetic alterations, such as PIK3CA mutation and LINE-1 methylation.	('LINE-1', 'Gene', (114, 120))	('SCC', 'Gene', (15, 18))	('PIK3CA', 'Gene', (94, 100))	('methylation', 'Var', (121, 132))	('SCC', 'Gene', (32, 35))	('mutation', 'Var', (101, 109))	('SCC', 'Gene', '6317', (15, 18))	('SCC', 'Gene', '6317', (32, 35))	('PIK3CA', 'Gene', '5290', (94, 100))
470770	27959959	In the present study, although no significant correlation between the NLR and pathological N, pathological T, or TNM stage was identified, patients in the high NLR group had significantly more > 5.00 cm tumors.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('patients', 'Species', '9606', (139, 147))	('TNM', 'Gene', (113, 116))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('TNM', 'Gene', '10178', (113, 116))	('high', 'Var', (155, 159))	('NLR', 'Gene', (160, 163))
470771	27959959	Furthermore, relative lymphocytopenia (lymphocyte count <=2.13x109/L) was observed in the high NLR group, which could reflect an immunosuppressive status that would favor tumor development and metastasis.	('lymphocytopenia', 'Phenotype', 'HP:0001888', (22, 37))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('metastasis', 'CPA', (193, 203))	('tumor', 'Disease', (171, 176))	('men', 'Species', '9606', (184, 187))	('lymphocytopenia', 'Disease', 'MESH:D008231', (22, 37))	('lymphocytopenia', 'Disease', (22, 37))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('high', 'Var', (90, 94))	('NLR', 'Gene', (95, 98))	('favor', 'PosReg', (165, 170))
470797	25987188	In mice, AURKA genetic ablation or null mutation leads to mitotic arrest and embryonic death at the blastocyst stage.	('mitotic arrest', 'Disease', (58, 72))	('embryonic death at the blastocyst', 'Disease', (77, 110))	('null mutation', 'Var', (35, 48))	('mice', 'Species', '10090', (3, 7))	('AURKA', 'Gene', (9, 14))	('mitotic arrest', 'Disease', 'MESH:D006323', (58, 72))	('embryonic death at the blastocyst', 'Disease', 'MESH:D003643', (77, 110))	('genetic ablation', 'Var', (15, 31))
470809	25987188	Additionally, AURKA inhibition or knockdown was shown to induce senescence in multiple myeloma and colon cancer cells.	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('senescence', 'MPA', (64, 74))	('AURKA', 'Gene', (14, 19))	('inhibition', 'Var', (20, 30))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('colon cancer', 'Disease', (99, 111))	('multiple myeloma', 'Phenotype', 'HP:0006775', (78, 94))	('induce', 'Reg', (57, 63))	('multiple myeloma', 'Disease', 'MESH:D009101', (78, 94))	('knockdown', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('multiple myeloma', 'Disease', (78, 94))
470826	25987188	Amplifications of chromosomal region 20q13, where AURKA is located, have been described in gastric and esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('described', 'Reg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Amplifications', 'Var', (0, 14))	('gastric and esophageal cancers', 'Disease', 'MESH:D013274', (91, 121))
470827	25987188	Polymorphisms in the AURKA gene have also been reported in UGI cancers.	('UGI cancers', 'Disease', (59, 70))	('AURKA', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Polymorphisms', 'Var', (0, 13))	('UGI cancers', 'Disease', 'MESH:D009369', (59, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('reported', 'Reg', (47, 55))
470846	25987188	Inhibition of AURKA using investigational MLN8054 or MLN8237 led to reversal of anti-apoptotic signaling cascades with activation of pro-apoptotic p73 in p53 deficient cells with re-expression of several pro-apoptotic proteins such as PUMA, NOXA, and p21.	('p73', 'Gene', (147, 150))	('anti-apoptotic signaling', 'MPA', (80, 104))	('MLN8237', 'Var', (53, 60))	('p73', 'Gene', '7161', (147, 150))	('activation', 'PosReg', (119, 129))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('MLN8054', 'Var', (42, 49))
470847	25987188	AURKA inhibition by small molecule MLN8237 as a single agent or in combination with Cisplatin or Docetaxel significantly enhanced cell death in esophageal adenocarcinoma xenograft mouse model.	('cell death', 'CPA', (130, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('Cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('MLN8237', 'Chemical', 'MESH:C550258', (35, 42))	('enhanced', 'PosReg', (121, 129))	('mouse', 'Species', '10090', (180, 185))	('esophageal adenocarcinoma', 'Disease', (144, 169))	('AURKA', 'Enzyme', (0, 5))	('MLN8237', 'Var', (35, 42))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (144, 169))	('inhibition', 'NegReg', (6, 16))	('Docetaxel', 'Chemical', 'MESH:D000077143', (97, 106))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (144, 169))
470851	25987188	Genetic variations in the AURKA gene were also detected and associated with aneuploidy in human colon tumors and low penetrance CRC susceptibility factor.	('aneuploidy', 'Disease', (76, 86))	('colon tumors', 'Disease', 'MESH:D015179', (96, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('colon tumors', 'Disease', (96, 108))	('human', 'Species', '9606', (90, 95))	('aneuploidy', 'Disease', 'MESH:D000782', (76, 86))	('CRC', 'Phenotype', 'HP:0003003', (128, 131))	('Genetic variations', 'Var', (0, 18))	('colon tumors', 'Phenotype', 'HP:0100273', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('AURKA', 'Gene', (26, 31))	('associated with', 'Reg', (60, 75))
470856	25987188	For instance, Tseng and colleagues found that AURKA enhances formation and aggregation of mutant Ras (RasV12) through regulation of RAS/MEK/ERK pathways and AKT phosphorylation in colon cancer.	('MEK', 'Gene', (136, 139))	('enhances', 'PosReg', (52, 60))	('colon cancer', 'Disease', (180, 192))	('MEK', 'Gene', '5609', (136, 139))	('mutant', 'Var', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colon cancer', 'Disease', 'MESH:D015179', (180, 192))	('Ras (RasV12', 'Gene', (97, 108))	('AKT', 'Gene', '207', (157, 160))	('ERK', 'Gene', '5594', (140, 143))	('regulation', 'Reg', (118, 128))	('colon cancer', 'Phenotype', 'HP:0003003', (180, 192))	('aggregation', 'CPA', (75, 86))	('ERK', 'Gene', (140, 143))	('AKT', 'Gene', (157, 160))	('RasV12', 'Gene', (102, 108))	('formation', 'MPA', (61, 70))
470857	25987188	Aurora kinase pharmacological inhibition sensitized colon cancer cells to Tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TRAIL', 'Gene', '8743', (145, 150))	('TNF-related apoptosis-inducing ligand', 'Gene', (106, 143))	('Aurora kinase', 'Gene', '41446', (0, 13))	('colon cancer', 'Disease', 'MESH:D015179', (52, 64))	('Tumor necrosis factor', 'Gene', (74, 95))	('Tumor necrosis factor', 'Gene', '7124', (74, 95))	('TNF', 'Gene', (106, 109))	('sensitized', 'Reg', (41, 51))	('TNF', 'Gene', (97, 100))	('TRAIL', 'Gene', (145, 150))	('colon cancer', 'Disease', (52, 64))	('TNF', 'Gene', '7124', (106, 109))	('Tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TNF', 'Gene', '7124', (97, 100))	('Aurora kinase', 'Gene', (0, 13))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (106, 143))	('inhibition', 'Var', (30, 40))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))
470858	25987188	In addition, AURKA inhibition, using specific or pan Aurora kinase inhibitors, sensitized colon cancer cells to chemotherapy, TNF or TRAIL induced apoptosis as well as mitotic failure and cell death when inhibited along with SRC.	('AURKA', 'Gene', (13, 18))	('SRC', 'Gene', (225, 228))	('TNF', 'Gene', '7124', (126, 129))	('Aurora kinase', 'Gene', (53, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (90, 102))	('sensitized', 'Reg', (79, 89))	('inhibition', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TRAIL', 'Gene', '8743', (133, 138))	('colon cancer', 'Disease', 'MESH:D015179', (90, 102))	('mitotic failure', 'Disease', 'MESH:C536987', (168, 183))	('Aurora kinase', 'Gene', '41446', (53, 66))	('apoptosis', 'CPA', (147, 156))	('TNF', 'Gene', (126, 129))	('TRAIL', 'Gene', (133, 138))	('SRC', 'Gene', '6714', (225, 228))	('mitotic failure', 'Disease', (168, 183))	('cell death', 'CPA', (188, 198))	('colon cancer', 'Disease', (90, 102))	('chemotherapy', 'CPA', (112, 124))
470859	25987188	Other reports showed that pharmacological inhibition of AURKA with MLN8054 in colon cancer HCT-116 xenografts induces senescence in vivo.	('colon cancer', 'Phenotype', 'HP:0003003', (78, 90))	('colon cancer', 'Disease', 'MESH:D015179', (78, 90))	('MLN8054', 'Var', (67, 74))	('HCT-116', 'CellLine', 'CVCL:0291', (91, 98))	('AURKA', 'Gene', (56, 61))	('colon cancer', 'Disease', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('induces', 'Reg', (110, 117))	('senescence', 'MPA', (118, 128))
470861	25987188	Overexpression of AURKA was reported in pancreatic cancer, in the early stages of abnormalities in pancreatic ducts and ductal dysplasia in transgenic mouse model for pancreatic cancer, and linked to chromosome instability and centrosome abnormality.	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mouse', 'Species', '10090', (151, 156))	('AURKA', 'Gene', (18, 23))	('abnormalities in pancreatic ducts and ductal dysplasia', 'Disease', 'MESH:D021441', (82, 136))	('linked', 'Reg', (190, 196))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('Overexpression', 'Var', (0, 14))	('transgenic', 'Species', '10090', (140, 150))	('pancreatic cancer', 'Disease', (40, 57))	('chromosome instability', 'Phenotype', 'HP:0040012', (200, 222))	('pancreatic cancer', 'Disease', (167, 184))
470867	25987188	Additionally, AURKA can phosphorylate RalA at Ser194 and regulate its subcellular localization, which is essential for Ras-mediated cellular transformation.	('Ser194', 'Var', (46, 52))	('regulate', 'Reg', (57, 65))	('RalA', 'Gene', (38, 42))	('subcellular localization', 'MPA', (70, 94))	('Ser194', 'Chemical', '-', (46, 52))	('RalA', 'Gene', '5898', (38, 42))
470868	25987188	However, further studies by the same group failed to show correlation of RalA (S194) phosphorylation with responsiveness to MLN8237, indicating that the principal target of AURKA may not be RalA.	('RalA', 'Gene', (190, 194))	('RalA', 'Gene', '5898', (73, 77))	('RalA', 'Gene', '5898', (190, 194))	('RalA', 'Gene', (73, 77))	('MLN8237', 'Chemical', 'MESH:C550258', (124, 131))	('MLN8237', 'Var', (124, 131))
470875	25987188	For example, a report showed that the pan Aurora inhibitor PHA-739358 inhibits HCC tumor growth in a tumor xenograft mouse model.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('mouse', 'Species', '10090', (117, 122))	('tumor', 'Disease', (101, 106))	('inhibits', 'NegReg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('HCC', 'Gene', (79, 82))	('PHA-739358', 'Var', (59, 69))	('HCC', 'Phenotype', 'HP:0001402', (79, 82))	('HCC', 'Gene', '619501', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
470876	25987188	Further, AURKA inhibition with small molecule R1498 was found to target mitosis pathway and suppress angiogenesis.	('inhibition', 'NegReg', (15, 25))	('mitosis', 'Disease', 'None', (72, 79))	('angiogenesis', 'CPA', (101, 113))	('suppress', 'NegReg', (92, 100))	('mitosis', 'Disease', (72, 79))	('R1498', 'Var', (46, 51))	('target', 'Reg', (65, 71))
470880	25987188	Both generations work as highly specific ATP-competitive AURKA inhibitors with an IC50 of 2 nM in chronic myeloid leukemia (CML) for MLN8237.	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (98, 122))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (98, 122))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (106, 122))	('chronic myeloid leukemia', 'Disease', (98, 122))	('MLN8237', 'Chemical', 'MESH:C550258', (133, 140))	('ATP', 'Chemical', 'MESH:D000255', (41, 44))	('CML', 'Disease', 'MESH:D015464', (124, 127))	('leukemia', 'Phenotype', 'HP:0001909', (114, 122))	('MLN8237', 'Var', (133, 140))	('CML', 'Disease', (124, 127))	('CML', 'Phenotype', 'HP:0005506', (124, 127))	('AURKA', 'Protein', (57, 62))
470881	25987188	The MLN8237 IC50 values vary in other cancers, ranging from 6.7 nM in HeLa cells to 469 nM in DLD-1 colon cancer cell line.	('HeLa', 'CellLine', 'CVCL:0030', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('DLD-1 colon cancer', 'Disease', 'MESH:C573012', (94, 112))	('MLN8237', 'Chemical', 'MESH:C550258', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('IC50', 'MPA', (12, 16))	('MLN8237', 'Var', (4, 11))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('DLD-1 colon cancer', 'Disease', (94, 112))	('cancers', 'Disease', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
470882	25987188	MLN8237 can target AURKB at higher doses (396.5 nM).	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('MLN8237', 'Var', (0, 7))	('AURKB', 'Gene', (19, 24))	('AURKB', 'Gene', '9212', (19, 24))
470883	25987188	The first generation MLN8054 was terminated in phase 1 clinical trials due to off-target toxicities.	('MLN8054', 'Var', (21, 28))	('toxicities', 'Disease', 'MESH:D064420', (89, 99))	('toxicities', 'Disease', (89, 99))
470887	25987188	Investigations of MLN8237 in preclinical studies have shown that it induces abnormal G2/M cell cycle arrest, abnormalities in mitotic spindles, and apoptosis in upper GI cancers.	('induces', 'Reg', (68, 75))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (90, 107))	('arrest', 'Disease', (101, 107))	('arrest', 'Disease', 'MESH:D006323', (101, 107))	('upper GI cancers', 'Disease', (161, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('MLN8237', 'Chemical', 'MESH:C550258', (18, 25))	('upper GI cancers', 'Disease', 'MESH:D009369', (161, 177))	('abnormalities', 'Var', (109, 122))	('apoptosis', 'CPA', (148, 157))	('MLN8237', 'Var', (18, 25))
470888	25987188	In addition, MLN8237 down-regulates several oncogenic pathways such as NF-kappaB, AKT, and STAT3 in cancer cells.	('oncogenic pathways', 'Pathway', (44, 62))	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('NF-kappaB', 'Gene', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('down-regulates', 'NegReg', (21, 35))	('STAT3', 'Gene', '6774', (91, 96))	('MLN8237', 'Var', (13, 20))	('AKT', 'Gene', '207', (82, 85))	('STAT3', 'Gene', (91, 96))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('NF-kappaB', 'Gene', '4790', (71, 80))	('AKT', 'Gene', (82, 85))
470889	25987188	On the other hand, several reports demonstrated that treatment with MLN8237 could activate p53 and p73 apoptotic pathways.	('activate', 'PosReg', (82, 90))	('MLN8237', 'Chemical', 'MESH:C550258', (68, 75))	('MLN8237', 'Var', (68, 75))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('p73', 'Gene', '7161', (99, 102))	('p73', 'Gene', (99, 102))	('men', 'Species', '9606', (58, 61))
470890	25987188	The effects of MLN8237 were tested in several non-GI cancers.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('MLN8237', 'Var', (15, 22))	('non-GI cancers', 'Disease', 'MESH:D009369', (46, 60))	('non-GI cancers', 'Disease', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tested', 'Reg', (28, 34))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))
470891	25987188	It has been shown that MLN8237 sensitized PC3 and DU145 prostate cancer cells to radiation, increased the DNA double-strand breaks, induced G2/M cell cycle arrest and polyploidy.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (145, 162))	('MLN8237', 'Var', (23, 30))	('arrest', 'Disease', 'MESH:D006323', (156, 162))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('prostate cancer', 'Disease', (56, 71))	('DU145', 'CellLine', 'CVCL:0105', (50, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('increased', 'PosReg', (92, 101))	('polyploidy', 'Disease', (167, 177))	('DNA double-strand breaks', 'MPA', (106, 130))	('PC3', 'CellLine', 'CVCL:0035', (42, 45))	('arrest', 'Disease', (156, 162))	('polyploidy', 'Disease', 'MESH:D011123', (167, 177))	('MLN8237', 'Chemical', 'MESH:C550258', (23, 30))	('induced', 'Reg', (132, 139))
470892	25987188	Treatment of OVCAR-5 and SKOV3ip2 ovarian cancer cells with MLN8237 resulted in inhibition of cytoskeletal regulatory SRC (assessed by decreased phosphorylation at Tyr-416) and decreased migration and adhesion.	('MLN8237', 'Chemical', 'MESH:C550258', (60, 67))	('SRC', 'Gene', '6714', (118, 121))	('men', 'Species', '9606', (5, 8))	('SRC', 'Gene', (118, 121))	('inhibition', 'NegReg', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ovarian cancer', 'Phenotype', 'HP:0100615', (34, 48))	('adhesion', 'CPA', (201, 209))	('MLN8237', 'Var', (60, 67))	('ovarian cancer', 'Disease', 'MESH:D010051', (34, 48))	('ovarian cancer', 'Disease', (34, 48))	('decreased', 'NegReg', (135, 144))	('decreased', 'NegReg', (177, 186))	('Tyr', 'Chemical', 'MESH:D014443', (164, 167))	('SKOV3ip2', 'CellLine', 'CVCL:0C84', (25, 33))
470893	25987188	Moreover, MLN8237 has been tested on many pediatric cancer cell lines like Ewing sarcoma, neuroblastoma, glioblastoma, rhabdomyosarcoma, ALL, and AML where it inhibited cell growth and delayed tumor growth.	('cell growth', 'CPA', (169, 180))	('neuroblastoma', 'Disease', (90, 103))	('AML', 'Disease', (146, 149))	('neuroblastoma', 'Phenotype', 'HP:0003006', (90, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('MLN8237', 'Chemical', 'MESH:C550258', (10, 17))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('neuroblastoma', 'Disease', 'MESH:D009447', (90, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('Ewing sarcoma', 'Disease', (75, 88))	('delayed', 'NegReg', (185, 192))	('rhabdomyosarcoma', 'Disease', (119, 135))	('tumor', 'Disease', (193, 198))	('glioblastoma', 'Disease', (105, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (119, 135))	('cancer', 'Disease', (52, 58))	('inhibited', 'NegReg', (159, 168))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (119, 135))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('MLN8237', 'Var', (10, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('AML', 'Disease', 'MESH:D015470', (146, 149))
470894	25987188	In vitro and in vivo tumor xenografts mouse models showed that MLN8237 enhances anti-tumor activity of chemotherapeutics.	('tumor', 'Disease', (85, 90))	('mouse', 'Species', '10090', (38, 43))	('tumor', 'Disease', (21, 26))	('enhances', 'PosReg', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('MLN8237', 'Chemical', 'MESH:C550258', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('MLN8237', 'Var', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
470895	25987188	For instance, dual treatment of MLN8237 with Docetaxel enhanced apoptosis and anti-tumor activity in lymphoma and UGI adenocarcinomas cell models.	('lymphoma', 'Phenotype', 'HP:0002665', (101, 109))	('MLN8237', 'Var', (32, 39))	('men', 'Species', '9606', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('enhanced', 'PosReg', (55, 63))	('apoptosis', 'CPA', (64, 73))	('adenocarcinomas', 'Disease', 'MESH:D000230', (118, 133))	('lymphoma', 'Disease', (101, 109))	('adenocarcinomas', 'Disease', (118, 133))	('Docetaxel', 'Chemical', 'MESH:D000077143', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('MLN8237', 'Chemical', 'MESH:C550258', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('lymphoma', 'Disease', 'MESH:D008223', (101, 109))
470896	25987188	Similarly, a combination of Cisplatin with MLN8237 had robust anti-tumor activity in tumor xenograft models of esophageal adenocarcinomas.	('tumor', 'Disease', (85, 90))	('esophageal adenocarcinomas', 'Disease', (111, 137))	('MLN8237', 'Chemical', 'MESH:C550258', (43, 50))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (111, 136))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('MLN8237', 'Var', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (111, 137))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
470897	25987188	In B-cell Non-Hodgkin Lymphoma, MLN8237 in combination with Vincristine and Rituximab showed robust cell death in vitro and had curative effects in vivo using mantle cell lymphoma (MCL) mouse xenograft model.	('Non-Hodgkin Lymphoma', 'Phenotype', 'HP:0012539', (10, 30))	('MLN8237', 'Var', (32, 39))	('Non-Hodgkin Lymphoma', 'Disease', (10, 30))	('Non-Hodgkin Lymphoma', 'Disease', 'MESH:D008228', (10, 30))	('MCL', 'Disease', 'MESH:C535516', (181, 184))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (159, 179))	('lymphoma', 'Phenotype', 'HP:0002665', (171, 179))	('mouse', 'Species', '10090', (186, 191))	('mantle cell lymphoma', 'Disease', (159, 179))	('cell death', 'CPA', (100, 110))	('Vincristine', 'Chemical', 'MESH:D014750', (60, 71))	('Hodgkin Lymphoma', 'Phenotype', 'HP:0012189', (14, 30))	('Lymphoma', 'Phenotype', 'HP:0002665', (22, 30))	('cell lymphoma', 'Phenotype', 'HP:0012191', (166, 179))	('B-cell Non-Hodgkin Lymphoma', 'Phenotype', 'HP:0012191', (3, 30))	('MCL', 'Disease', (181, 184))	('MLN8237', 'Chemical', 'MESH:C550258', (32, 39))	('Rituximab', 'Chemical', 'MESH:D000069283', (76, 85))
470899	25987188	Notably, there are 49 clinical trials with MLN8237 in leukemia, breast, lung, colorectal, ovarian, and pancreatic cancers (clinicaltrials.gov; March 2015).	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('MLN8237', 'Chemical', 'MESH:C550258', (43, 50))	('ovarian', 'Disease', (90, 97))	('colorectal', 'Disease', 'MESH:D015179', (78, 88))	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (103, 121))	('MLN8237', 'Var', (43, 50))	('lung', 'Disease', (72, 76))	('breast', 'Disease', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('colorectal', 'Disease', (78, 88))	('pancreatic cancers', 'Disease', 'MESH:D010190', (103, 121))	('pancreatic cancers', 'Disease', (103, 121))	('leukemia', 'Disease', (54, 62))	('leukemia', 'Disease', 'MESH:D007938', (54, 62))
470901	25987188	The recommended phase 2 dose of MLN8237 is 50 mg orally given twice daily on days 1-7 of a 21-day cycle for various solid tumors and hematologic malignancies.	('MLN8237', 'Var', (32, 39))	('solid tumors', 'Disease', (116, 128))	('hematologic malignancies', 'Disease', 'MESH:D019337', (133, 157))	('men', 'Species', '9606', (9, 12))	('hematologic malignancies', 'Disease', (133, 157))	('solid tumors', 'Disease', 'MESH:D009369', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('MLN8237', 'Chemical', 'MESH:C550258', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
470902	25987188	Phase 2 studies of MLN8237 as a single agent are ongoing in multiple tumor types including lung, breast, ovarian, UGI, and pancreatic cancers (Table 2).	('lung', 'Disease', (91, 95))	('MLN8237', 'Chemical', 'MESH:C550258', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('MLN8237', 'Var', (19, 26))	('breast', 'Disease', (97, 103))	('multiple tumor', 'Disease', (60, 74))	('UGI', 'Disease', (114, 117))	('pancreatic cancers', 'Disease', 'MESH:D010190', (123, 141))	('pancreatic cancers', 'Disease', (123, 141))	('multiple tumor', 'Disease', 'MESH:D009369', (60, 74))	('ovarian', 'Disease', (105, 112))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (123, 141))
470904	25987188	A recent phase 2 clinical trial of MLN8237 as a single agent in advanced solid tumors revealed that 9% of patients (4 out of 47 patients) with gastro-esophageal adenocarcinoma partially responded to the treatment.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('MLN8237', 'Chemical', 'MESH:C550258', (35, 42))	('solid tumors', 'Disease', (73, 85))	('men', 'Species', '9606', (208, 211))	('gastro-esophageal adenocarcinoma', 'Disease', 'MESH:D005764', (143, 175))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (106, 114))	('MLN8237', 'Var', (35, 42))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (150, 175))	('gastro-esophageal adenocarcinoma', 'Disease', (143, 175))	('patients', 'Species', '9606', (128, 136))	('solid tumors', 'Disease', 'MESH:D009369', (73, 85))
470906	25987188	This clinical trial will be the first to evaluate MLN8237 exclusively in gastrointestinal tumors (clinicaltrials.gov, Table 2).	('MLN8237', 'Var', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (73, 96))	('gastrointestinal tumors', 'Disease', (73, 96))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (73, 96))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))
470907	25987188	However, ENMD-2076 was found to inhibit several other oncogenic kinases at different IC50 including FLT3 (1.86 nM), SRC (20.2 nM), VEGFR3 (15.9 nM), VEGFR2 (58.2 nM), PDGFRalpha (56.4 nM), and FGFR1 (92.7 nM).	('PDGFRalpha', 'Gene', (167, 177))	('FGFR1', 'Gene', (193, 198))	('FLT3', 'Gene', (100, 104))	('VEGFR3', 'Gene', '2324', (131, 137))	('inhibit', 'NegReg', (32, 39))	('VEGFR2', 'Gene', '3791', (149, 155))	('FGFR1', 'Gene', '2260', (193, 198))	('SRC', 'Gene', '6714', (116, 119))	('SRC', 'Gene', (116, 119))	('VEGFR3', 'Gene', (131, 137))	('VEGFR2', 'Gene', (149, 155))	('oncogenic', 'Enzyme', (54, 63))	('FLT3', 'Gene', '2322', (100, 104))	('PDGFRalpha', 'Gene', '5156', (167, 177))	('ENMD-2076', 'Var', (9, 18))
470909	25987188	ENMD-2076 was found to be selectively toxic to multiple myeloma (MM) cells but minimally toxic to hematopoietic progenitor cells.	('multiple myeloma', 'Disease', (47, 63))	('multiple myeloma', 'Phenotype', 'HP:0006775', (47, 63))	('ENMD-2076', 'Var', (0, 9))	('multiple myeloma', 'Disease', 'MESH:D009101', (47, 63))
470912	25987188	Additionally, ENMD-2076 was shown to down-regulate phosphorylation of STAT3 at Ser-727.	('STAT3', 'Gene', (70, 75))	('Ser', 'Chemical', 'MESH:D012694', (79, 82))	('ENMD-2076', 'Var', (14, 23))	('down-regulate', 'NegReg', (37, 50))	('STAT3', 'Gene', '6774', (70, 75))
470914	25987188	In a patient-derived xenograft model of CRC, ENMD-2076 inhibited tumor growth, which led to regression; this was associated with significant reduction in 18-FDG uptake at day 3 and 21 of treatment.	('patient', 'Species', '9606', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('FDG', 'Gene', '23583', (157, 160))	('FDG', 'Gene', (157, 160))	('ENMD-2076', 'Var', (45, 54))	('men', 'Species', '9606', (192, 195))	('regression', 'MPA', (92, 102))	('CRC', 'Phenotype', 'HP:0003003', (40, 43))	('inhibited', 'NegReg', (55, 64))	('reduction', 'NegReg', (141, 150))
470915	25987188	In breast cancer, ENMD-2076 was most effective against triple-negative tumors with increased mutant p53 expression.	('increased', 'PosReg', (83, 92))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('p53', 'Gene', '7157', (100, 103))	('mutant', 'Var', (93, 99))	('expression', 'MPA', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('p53', 'Gene', (100, 103))
470920	25987188	MK-5018 also inhibits AURKB and AURKC, although at higher doses (200 folds higher than AURKA) with various IC50 values among different cancer cell lines.	('cancer', 'Disease', (135, 141))	('AURKB', 'Gene', (22, 27))	('AURKC', 'Gene', '6795', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('MK-5018', 'Var', (0, 7))	('AURKB', 'Gene', '9212', (22, 27))	('AURKC', 'Gene', (32, 37))	('MK-5018', 'Chemical', '-', (0, 7))	('inhibits', 'NegReg', (13, 21))
470921	25987188	Tumor xenografts treated with MK-5018 showed significant tumor inhibition at doses of 15 or 30 mg/kg twice daily for 12 days, indicating the high tolerability of the drug.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MK-5018', 'Var', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('MK-5018', 'Chemical', '-', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
470922	25987188	In addition to a typical AURKA inhibition response (polyploidy and cell cycle arrest), inhibition of NF-kappaB activity and reduction of cytokine production were observed after treatment of ovarian cancer stem cells with MK-5108.	('MK-5108', 'Var', (221, 228))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (67, 84))	('cytokine production', 'MPA', (137, 156))	('inhibition', 'NegReg', (87, 97))	('arrest', 'Disease', (78, 84))	('reduction', 'NegReg', (124, 133))	('activity', 'MPA', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('men', 'Species', '9606', (182, 185))	('NF-kappaB', 'Gene', (101, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (190, 204))	('polyploidy', 'Disease', (52, 62))	('polyploidy', 'Disease', 'MESH:D011123', (52, 62))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('NF-kappaB', 'Gene', '4790', (101, 110))	('ovarian cancer', 'Disease', (190, 204))	('MK-5108', 'Chemical', 'MESH:C547876', (221, 228))	('reduction of cytokine production', 'Phenotype', 'HP:0031407', (124, 156))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))
470924	25987188	For instance, MK-5108, in combination with histone deacetylase inhibitor, vorinostat, induced lymphoma cell death along with reduction of c-Myc, hTERT, and micro RNA levels in vitro.	('reduction', 'NegReg', (125, 134))	('hTERT', 'Gene', '7015', (145, 150))	('lymphoma', 'Phenotype', 'HP:0002665', (94, 102))	('c-Myc', 'Gene', (138, 143))	('lymphoma cell death', 'Disease', 'MESH:D003643', (94, 113))	('vorinostat', 'Chemical', 'MESH:D000077337', (74, 84))	('lymphoma cell death', 'Disease', (94, 113))	('hTERT', 'Gene', (145, 150))	('micro RNA levels', 'MPA', (156, 172))	('MK-5108', 'Var', (14, 21))	('c-Myc', 'Gene', '4609', (138, 143))	('MK-5108', 'Chemical', 'MESH:C547876', (14, 21))
470925	25987188	In a colon cancer xenograft mouse model, MK-5108 was tested in combination with Docetaxel and showed additive anti-tumor activity as compared to animals that received Docetaxel alone.	('Docetaxel', 'Chemical', 'MESH:D000077143', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mouse', 'Species', '10090', (28, 33))	('colon cancer', 'Disease', 'MESH:D015179', (5, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (5, 17))	('Docetaxel', 'Chemical', 'MESH:D000077143', (167, 176))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (115, 120))	('MK-5108', 'Var', (41, 48))	('colon cancer', 'Disease', (5, 17))	('MK-5108', 'Chemical', 'MESH:C547876', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
470936	25987188	One of the most widely studied inhibitors is MLN8237 (alisertib), which has been investigated in preclinical studies using in vitro and tumor xenograft mouse models with promising anti-tumor effects, alone and in combination with Cisplatin or Docetaxel.	('tumor', 'Disease', (185, 190))	('alisertib', 'Chemical', 'MESH:C550258', (54, 63))	('Docetaxel', 'Chemical', 'MESH:D000077143', (243, 252))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('mouse', 'Species', '10090', (152, 157))	('MLN8237', 'Chemical', 'MESH:C550258', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('MLN8237', 'Var', (45, 52))	('Cisplatin', 'Chemical', 'MESH:D002945', (230, 239))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (136, 141))
470939	25987188	The most advanced clinical trial (phase 3) is testing MLN8237 in hematologic malignancies (clinical trial# NCT01482962).	('MLN8237', 'Var', (54, 61))	('hematologic malignancies', 'Disease', 'MESH:D019337', (65, 89))	('hematologic malignancies', 'Disease', (65, 89))	('MLN8237', 'Chemical', 'MESH:C550258', (54, 61))
470940	25987188	In solid tumors, phase 2 clinical trials are currently testing MLN8237 alone or in combination with other chemotherapeutics or biologics (Paclitaxel, Erlotinib, Rituximab, Vincristine among others, Table 2).	('Rituximab', 'Chemical', 'MESH:D000069283', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('solid tumors', 'Disease', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('MLN8237', 'Var', (63, 70))	('MLN8237', 'Chemical', 'MESH:C550258', (63, 70))	('Paclitaxel', 'Chemical', 'MESH:D017239', (138, 148))	('Vincristine', 'Chemical', 'MESH:D014750', (172, 183))	('Erlotinib', 'Chemical', 'MESH:D000069347', (150, 159))	('solid tumors', 'Disease', 'MESH:D009369', (3, 15))
470941	25987188	ENMD-2076 is another specific AURKA inhibitor, currently in phase 2 for ovarian and breast cancers (NCT01914510, NCT01639248, NCT01104675) that has not been tested in GI cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('NCT01104675', 'Var', (126, 137))	('NCT01914510', 'Var', (100, 111))	('GI cancers', 'Disease', (167, 177))	('breast cancers', 'Phenotype', 'HP:0003002', (84, 98))	('GI cancers', 'Disease', 'MESH:D009369', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('NCT01639248', 'Var', (113, 124))	('ovarian and breast cancers', 'Disease', 'MESH:D010051', (72, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
471267	20507889	Metformin is associated with a lower cancer incidence among diabetics and with lower cancer mortality among patients with type 2 diabetes.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('type 2 diabetes', 'Disease', (122, 137))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('lower', 'NegReg', (79, 84))	('Metformin', 'Var', (0, 9))	('lower', 'NegReg', (31, 36))	('cancer', 'Disease', (85, 91))	('type 2 diabetes', 'Disease', 'MESH:D003924', (122, 137))	('diabetics', 'Disease', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('patients', 'Species', '9606', (108, 116))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('diabetics', 'Disease', 'MESH:D003920', (60, 69))
471274	20507889	There is increasing evidence that attaining >9,000 daily steps as an indicator of physical activity is associated with a lower likelihood of being obese, including among lower income and racial/ethnic minority populations.	('attaining', 'Var', (34, 43))	('lower', 'NegReg', (121, 126))	('obese', 'Disease', (147, 152))	('obese', 'Disease', 'MESH:D009765', (147, 152))
471308	19784073	Thus, GASC1 is a driving oncogene in the 9p23-24 amplicon in human breast cancer and targeted inhibition of GASC1 histone demethylase in cancer could provide potential new avenues for therapeutic development.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('GASC1', 'Gene', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('GASC1', 'Gene', '23081', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (74, 80))	('GASC1', 'Gene', (6, 11))	('cancer', 'Disease', (137, 143))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('inhibition', 'Var', (94, 104))	('human', 'Species', '9606', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('GASC1', 'Gene', '23081', (6, 11))	('breast cancer', 'Disease', (67, 80))
471309	19784073	It is increasingly apparent that cancer development not only depends on genetic alterations but also on epigenetic changes involving histone modifications and DNA methylation.	('genetic alterations', 'Var', (72, 91))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('histone modifications', 'MPA', (133, 154))	('DNA', 'MPA', (159, 162))
471310	19784073	Genetic and epigenetic alterations in cancer cells interact directly and indirectly.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('epigenetic alterations', 'Var', (12, 34))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('interact', 'Reg', (51, 59))	('cancer', 'Disease', (38, 44))
471311	19784073	Specifically, a genetic alteration in the gene encoding an 'epigenetic enzyme' can lead to changes within the histone code, which is involved in both tumorigenesis and cancer stem cell-generated hierarchies in multiple tumor types.	('genetic alteration', 'Var', (16, 34))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (219, 224))	('histone', 'MPA', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('lead to changes', 'Reg', (83, 98))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Disease', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', (150, 155))
471312	19784073	Genetic alterations on chromsome 9p have been observed in a wide range of human cancers including lung, breast, bladder, esophageal and others.	('Genetic alterations', 'Var', (0, 19))	('esophageal', 'Disease', 'MESH:D004941', (121, 131))	('observed', 'Reg', (46, 54))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast', 'Disease', (104, 110))	('cancers', 'Disease', (80, 87))	('esophageal', 'Disease', (121, 131))	('bladder', 'Disease', (112, 119))	('human', 'Species', '9606', (74, 79))	('lung', 'Disease', (98, 102))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
471313	19784073	Recent studies using comparative genomic hybridization (CGH) and FISH have revealed that amplification of DNA at 9p23-24 frequently occurs in several human tumors, including esophageal and breast cancers.	('human', 'Species', '9606', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('breast cancers', 'Phenotype', 'HP:0003002', (189, 203))	('esophageal and breast cancers', 'Disease', 'MESH:D004938', (174, 203))	('DNA at', 'Gene', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('occurs', 'Reg', (132, 138))	('amplification', 'Var', (89, 102))	('tumors', 'Disease', (156, 162))
471315	19784073	In addition, coexistence of the amplification of 9p23-24 has been reported in BRCA2 mutation carriers in breast cancer patients.	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('BRCA2', 'Gene', (78, 83))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('BRCA2', 'Gene', '675', (78, 83))	('breast cancer', 'Disease', (105, 118))	('mutation', 'Var', (84, 92))
471318	19784073	Lysine residues in histone tails can be mono, di or trimethylated.	('histone', 'Protein', (19, 26))	('mono', 'Var', (40, 44))	('trimethylated', 'Var', (52, 65))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('Lysine residues', 'Var', (0, 15))
471319	19784073	showed that GASC1 demethylates the H3K9me3/me2 marks both in vitro and in vivo.	('GASC1', 'Gene', (12, 17))	('GASC1', 'Gene', '23081', (12, 17))	('H3K9me3/me2', 'Var', (35, 46))
471324	19784073	Depletion of Gasc1 by small interfering RNA (siRNA) in ES cells induced differentiation with a global increase in H3K9me3, confirming that the histone demethylase activity of Gasc1 is linked to the maintenance of pluripotency.	('Gasc1', 'Gene', (13, 18))	('pluripotency', 'Disease', 'None', (213, 225))	('differentiation', 'CPA', (72, 87))	('H3K9me3', 'MPA', (114, 121))	('induced', 'Reg', (64, 71))	('Depletion', 'Var', (0, 9))	('increase', 'PosReg', (102, 110))	('pluripotency', 'Disease', (213, 225))
471351	19784073	Furthermore, GASC1 protein levels were analyzed by western blot in SUM149, HCC1954, HCC70 and Colo 824 cells, which have the 9p23-24 amplicon, and in MCF10A and SUM-52, which do not have the 9p23-24 amplicon.	('GASC1', 'Gene', '23081', (13, 18))	('9p23-24 amplicon', 'Var', (125, 141))	('HCC1954', 'CellLine', 'CVCL:1259', (75, 82))	('MCF10A', 'CellLine', 'CVCL:0598', (150, 156))	('Colo', 'Species', '307630', (94, 98))	('GASC1', 'Gene', (13, 18))	('SUM149', 'CellLine', 'CVCL:3422', (67, 73))
471357	19784073	demonstrated that amplification of the 9p21-24 region that includes GASC1 is most prevalent in basal-like, triple-negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast cancer', 'Disease', (123, 136))	('basal-like', 'Disease', (95, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('prevalent', 'Reg', (82, 91))	('GASC1', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('amplification', 'Var', (18, 31))	('GASC1', 'Gene', '23081', (68, 73))
471366	19784073	Our findings demonstrated that amplification and over expression of GASC1 are more prevalent in basal-like breast cancer.	('GASC1', 'Gene', '23081', (68, 73))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('over expression', 'PosReg', (49, 64))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('GASC1', 'Gene', (68, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('amplification', 'Var', (31, 44))	('prevalent', 'Reg', (83, 92))
471375	19784073	After 3 weeks, MCF10A-GASC1 cells grew into robust colonies in soft agar, a property not observed in the parental MCF10A cells or in MCF10A cells containing the control vector (Figure 4A).	('agar', 'Chemical', 'MESH:D000362', (68, 72))	('MCF10A-GASC1', 'CellLine', 'CVCL:0598', (15, 27))	('MCF10A', 'CellLine', 'CVCL:0598', (114, 120))	('MCF10A', 'CellLine', 'CVCL:0598', (15, 21))	('grew', 'CPA', (34, 38))	('MCF10A', 'CellLine', 'CVCL:0598', (133, 139))	('MCF10A-GASC1', 'Var', (15, 27))
471380	19784073	Recently, GASC1 was found to be an epigenetic modifier of the key self-renewal regulators, Oct4 and Nanog, through H3K9 marks in embryonic stem (ES) cells.	('GASC1', 'Gene', '23081', (10, 15))	('H3K9 marks', 'Var', (115, 125))	('GASC1', 'Gene', (10, 15))
471383	19784073	When the cells from mammospheres were re-plated under normal culture conditions, viable cells in the mammospheres adhered to the culture dish and proliferated resulting in a large number of proliferative colonies derived from MCF-10-GASC1 cells compared to parental MCF-10A cells (Figure 5A).	('proliferated', 'CPA', (146, 158))	('proliferative colonies derived', 'CPA', (190, 220))	('MCF-10-GASC1', 'CellLine', 'CVCL:5555', (226, 238))	('MCF-10A', 'CellLine', 'CVCL:0598', (266, 273))	('MCF-10-GASC1', 'Var', (226, 238))
471387	19784073	To more directly assess the contribution of endogenous GASC1 over expression on the transformation of breast cancer cells and to establish proof-of-concept of targeted treatment, we examined the biological effect of GASC1 inhibition on the proliferation of breast cancer cells with GASC1 amplification, and control MCF10A cells.	('GASC1', 'Gene', '23081', (216, 221))	('GASC1', 'Gene', (282, 287))	('breast cancer', 'Disease', (102, 115))	('GASC1', 'Gene', (55, 60))	('amplification', 'Var', (288, 301))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('GASC1', 'Gene', '23081', (282, 287))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('GASC1', 'Gene', '23081', (55, 60))	('breast cancer', 'Disease', (257, 270))	('MCF10A', 'CellLine', 'CVCL:0598', (315, 321))	('GASC1', 'Gene', (216, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
471388	19784073	We used an Expression Arrest GIPZ lentiviral shRNAmir system from OpenBiosystems (http://www.openbiosystems.com/) to stably knock down GASC1 expression.	('GASC1', 'Gene', (135, 140))	('GASC1', 'Gene', '23081', (135, 140))	('expression', 'MPA', (141, 151))	('knock', 'Var', (124, 129))
471389	19784073	HCC1954 and Colo824 cells with high-level GASC1 gene amplification were infected with the lentivirus supernatants for knock-down of GASC1.	('GASC1', 'Gene', '23081', (42, 47))	('GASC1', 'Gene', (132, 137))	('GASC1', 'Gene', '23081', (132, 137))	('Colo', 'Species', '307630', (12, 16))	('HCC1954', 'CellLine', 'CVCL:1259', (0, 7))	('GASC1', 'Gene', (42, 47))	('knock-down', 'Var', (118, 128))
471395	19784073	Figure 5B shows that GASC1 knock down dramatically slowed cell growth and inhibited colony formation of HCC1954 and Colo 824 cells.	('inhibited', 'NegReg', (74, 83))	('colony formation of HCC1954', 'CPA', (84, 111))	('HCC1954', 'CellLine', 'CVCL:1259', (104, 111))	('Colo', 'Species', '307630', (116, 120))	('GASC1', 'Gene', '23081', (21, 26))	('slowed cell growth', 'Phenotype', 'HP:0001510', (51, 69))	('slowed', 'NegReg', (51, 57))	('cell growth', 'CPA', (58, 69))	('GASC1', 'Gene', (21, 26))	('knock down', 'Var', (27, 37))
471396	19784073	The dramatic inhibition of HCC1954 and Colo824 cell growth by knock-down of GASC1 were reproduced with a pLKO GASC1 shRNA (Figure 5C).	('GASC1', 'Gene', (76, 81))	('GASC1', 'Gene', (110, 115))	('HCC1954', 'CPA', (27, 34))	('HCC1954', 'CellLine', 'CVCL:1259', (27, 34))	('GASC1', 'Gene', '23081', (76, 81))	('GASC1', 'Gene', '23081', (110, 115))	('knock-down', 'Var', (62, 72))	('inhibition', 'NegReg', (13, 23))	('Colo', 'Species', '307630', (39, 43))
471397	19784073	The knock-down of GASC1 inhibited cell growth of SUM-149 by ~ 50% and had only a slight effect on the cell growth of MCF10A cells (Data not shown).	('MCF10A', 'CellLine', 'CVCL:0598', (117, 123))	('GASC1', 'Gene', '23081', (18, 23))	('inhibited', 'NegReg', (24, 33))	('knock-down', 'Var', (4, 14))	('cell growth', 'CPA', (34, 45))	('GASC1', 'Gene', (18, 23))
471403	19784073	One interesting gene that was up-regulated in MCF10A-GASC1 cells is NOTCH1, which showed 5- fold increased mRNA level in MCF10A-GASC1 cells compared with the MCF10A control.	('MCF10A-GASC1', 'Gene', (46, 58))	('increased', 'PosReg', (97, 106))	('mRNA level', 'MPA', (107, 117))	('MCF10A', 'CellLine', 'CVCL:0598', (121, 127))	('MCF10A-GASC1', 'CellLine', 'CVCL:0598', (121, 133))	('MCF10A', 'CellLine', 'CVCL:0598', (46, 52))	('NOTCH1', 'Gene', (68, 74))	('MCF10A-GASC1', 'Var', (121, 133))	('up-regulated', 'PosReg', (30, 42))	('MCF10A', 'CellLine', 'CVCL:0598', (158, 164))	('MCF10A-GASC1', 'CellLine', 'CVCL:0598', (46, 58))
471405	19784073	Additionally, NOTCH1 mRNA expression level is ~10-fold higher in MCF10A-GASC1 mammosphere cells than in MCF10A control cells (Figure 6A).	('MCF10A', 'CellLine', 'CVCL:0598', (104, 110))	('MCF10A', 'CellLine', 'CVCL:0598', (65, 71))	('MCF10A-GASC1', 'CellLine', 'CVCL:0598', (65, 77))	('mRNA expression level', 'MPA', (21, 42))	('MCF10A-GASC1', 'Var', (65, 77))	('higher', 'PosReg', (55, 61))	('NOTCH1', 'Gene', (14, 20))
471409	19784073	The effect was more remarkable in Colo824 cells, which have high-level NOTCH1 expression, where knock down of GASC1 down regulated NOTCH1 by ~80%.	('knock down', 'Var', (96, 106))	('GASC1', 'Gene', (110, 115))	('Colo', 'Species', '307630', (34, 38))	('GASC1', 'Gene', '23081', (110, 115))	('NOTCH1', 'MPA', (131, 137))	('down regulated', 'NegReg', (116, 130))
471410	19784073	We used ChiP-sequencing to characterize genome-wide relationships between H3K9me1 and H3K9m3 in GASC1 amplified breast cancer cells and control MCF10A cells.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('GASC1', 'Gene', '23081', (96, 101))	('breast cancer', 'Disease', (112, 125))	('MCF10A', 'CellLine', 'CVCL:0598', (144, 150))	('amplified', 'Var', (102, 111))	('GASC1', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
471411	19784073	The preliminary analysis revealed an enrichment of DNA sequences associated H3K9m1 activated marks in the NOTCH1 genomic region of the GASC1 amplified cells compared to MCF10A.	('GASC1', 'Gene', (135, 140))	('activated', 'Reg', (83, 92))	('GASC1', 'Gene', '23081', (135, 140))	('MCF10A', 'CellLine', 'CVCL:0598', (169, 175))	('marks', 'MPA', (93, 98))	('H3K9m1', 'Var', (76, 82))
471412	19784073	Moreover, in the GASC1 amplified cells the number of H3K9m1 marks were dramatically greater than the number of H3K9m3 repressive marks (Supplementary Figure S6).	('GASC1', 'Gene', (17, 22))	('GASC1', 'Gene', '23081', (17, 22))	('H3K9m1', 'Var', (53, 59))	('greater', 'PosReg', (84, 91))
471413	19784073	Further, we established a GASC1 mutation lentiviral expression construct with the demethylase catalytic domain deleted.	('GASC1', 'Gene', '23081', (26, 31))	('mutation', 'Var', (32, 40))	('GASC1', 'Gene', (26, 31))
471414	19784073	Both wild-type and mutant-type GASC1 were transduced into MCF10A cells.	('GASC1', 'Gene', (31, 36))	('MCF10A', 'CellLine', 'CVCL:0598', (58, 64))	('GASC1', 'Gene', '23081', (31, 36))	('mutant-type', 'Var', (19, 30))
471418	19784073	(9) found that gain of 9p22-24 was more prevalent in ER-negative breast cancer, and Han et al.	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('9p22-24', 'Var', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('gain', 'PosReg', (15, 19))
471419	19784073	(28) demonstrated that 9p21-24 gain was more frequent in the basal-like, triple-negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('gain', 'PosReg', (31, 35))	('basal-like', 'Disease', (61, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('9p21-24', 'Var', (23, 30))
471425	19784073	Demethylation of H3K9 activates transcription and loss of H3K9 methyltransferase activity is likely associated with many types of tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('H3K9', 'Protein', (17, 21))	('loss', 'NegReg', (50, 54))	('associated', 'Reg', (100, 110))	('Demethylation', 'Var', (0, 13))	('H3K9', 'Protein', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('activates', 'PosReg', (22, 31))	('methyltransferase', 'Enzyme', (63, 80))	('activity', 'MPA', (81, 89))	('transcription', 'MPA', (32, 45))
471427	19784073	RIZ1 expression and activity are reduced in many human cancers by genomic deletion, frameshift and missense mutations as well as promoter methylation.	('activity', 'MPA', (20, 28))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('expression', 'MPA', (5, 15))	('missense mutations', 'Var', (99, 117))	('frameshift', 'Var', (84, 94))	('human', 'Species', '9606', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('promoter methylation', 'Var', (129, 149))	('reduced', 'NegReg', (33, 40))	('genomic deletion', 'Var', (66, 82))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('RIZ1', 'Gene', (0, 4))	('cancers', 'Disease', (55, 62))
471431	19784073	H3K36 methylation marks are also associated with cancer.	('methylation marks', 'Var', (6, 23))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('H3K36', 'Protein', (0, 5))	('associated', 'Reg', (33, 43))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
471433	19784073	demonstrated that H3K36 methylation was deregulated due to a translocation resulting in a NUP98-NSD1 fusion protein in human acute myeloid leukemia (AML).	('translocation', 'Var', (61, 74))	('AML', 'Disease', (149, 152))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (125, 147))	('NSD1', 'Gene', (96, 100))	('methylation', 'MPA', (24, 35))	('AML', 'Phenotype', 'HP:0004808', (149, 152))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('AML', 'Disease', 'MESH:D015470', (149, 152))	('human', 'Species', '9606', (119, 124))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (125, 147))	('NUP98', 'Gene', '4928', (90, 95))	('H3K36', 'Protein', (18, 23))	('NSD1', 'Gene', '64324', (96, 100))	('acute myeloid leukemia', 'Disease', (125, 147))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (131, 147))	('NUP98', 'Gene', (90, 95))
471444	19784073	Sphere-forming cells derived from MCF10A-GASC1 cells dramatically over expressed NANOG compared with sphere forming cells from MCF10A control cells (Supplementary Figure S8).	('MCF10A', 'CellLine', 'CVCL:0598', (127, 133))	('NANOG', 'Gene', (81, 86))	('MCF10A-GASC1', 'CellLine', 'CVCL:0598', (34, 46))	('MCF10A-GASC1', 'Var', (34, 46))	('over expressed', 'PosReg', (66, 80))	('MCF10A', 'CellLine', 'CVCL:0598', (34, 40))	('NANOG', 'Gene', '79923', (81, 86))
471448	19784073	As GASC1 is the target of OCT4, as well as a key regulator of NANOG, alteration of GASC1 could enhance and/or disrupt the autoregulatory circuit of the stem cell transcription factors in human cancer cells.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('GASC1', 'Gene', '23081', (3, 8))	('cancer', 'Disease', (193, 199))	('GASC1', 'Gene', '23081', (83, 88))	('disrupt', 'NegReg', (110, 117))	('NANOG', 'Gene', '79923', (62, 67))	('OCT4', 'Gene', '5460', (26, 30))	('autoregulatory circuit', 'MPA', (122, 144))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('NANOG', 'Gene', (62, 67))	('alteration', 'Var', (69, 79))	('human', 'Species', '9606', (187, 192))	('OCT4', 'Gene', (26, 30))	('GASC1', 'Gene', (3, 8))	('enhance', 'PosReg', (95, 102))	('GASC1', 'Gene', (83, 88))
471449	19784073	NOTCH1 and NOTCH4 are involved in normal development of mammary gland, and mutated forms of these genes are associated with the development of mouse mammary tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('mouse', 'Species', '10090', (143, 148))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('NOTCH4', 'Gene', '18132', (11, 17))	('mutated', 'Var', (75, 82))	('associated with', 'Reg', (108, 123))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('NOTCH4', 'Gene', (11, 17))
471451	19784073	demonstrated that induction of NOTCH signaling promotes self-renewal of normal human mammary stem cells.	('human', 'Species', '9606', (79, 84))	('promotes', 'PosReg', (47, 55))	('induction', 'Var', (18, 27))	('NOTCH signaling', 'Gene', (31, 46))	('self-renewal of normal human mammary stem cells', 'CPA', (56, 103))
471454	19784073	Our preliminary ChiP-sequencing assays found that H3K9me1 active marks were more highly enriched on NOTCH1 genomic loci in GASC1 amplified cells compared with control cells.	('GASC1', 'Gene', '23081', (123, 128))	('amplified', 'Var', (129, 138))	('GASC1', 'Gene', (123, 128))	('NOTCH1', 'Gene', (100, 106))	('H3K9me1', 'Var', (50, 57))
471455	19784073	Thus, the histone-modifying activity of GASC1 may regulate the expression of NOTCH1 and NANOG through H3K9 and H3K36 marks in human breast cancer cells.	('regulate', 'Reg', (50, 58))	('NANOG', 'Gene', (88, 93))	('human', 'Species', '9606', (126, 131))	('NOTCH1', 'Gene', (77, 83))	('H3K9', 'Protein', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'MPA', (63, 73))	('GASC1', 'Gene', (40, 45))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('H3K36', 'Var', (111, 116))	('breast cancer', 'Disease', (132, 145))	('GASC1', 'Gene', '23081', (40, 45))	('NANOG', 'Gene', '79923', (88, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
471458	19784073	Deregulation of GASC1 histone demethylase activity may result in cellular transformation and stem cell phenotypes through alteration of the epigenetic histone code in human cancer.	('result in', 'Reg', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('activity', 'MPA', (42, 50))	('cancer', 'Disease', (173, 179))	('histone demethylase', 'Enzyme', (22, 41))	('Deregulation', 'Var', (0, 12))	('epigenetic histone code', 'MPA', (140, 163))	('GASC1', 'Gene', (16, 21))	('stem cell phenotypes', 'CPA', (93, 113))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('GASC1', 'Gene', '23081', (16, 21))	('alteration', 'Reg', (122, 132))	('human', 'Species', '9606', (167, 172))	('cellular transformation', 'CPA', (65, 88))
471477	29423052	MAGE-A11 is activated through TFCP2/ZEB1 binding sites de-methylation as well as histone modification and facilitates ESCC tumor growth Recently, we have reported that the product of Melanoma Antigens Genes (MAGE) family member MAGE-A11 is an independent poor prognostic marker for esophageal squamous cell carcinoma (ESCC).	('Melanoma', 'Disease', (183, 191))	('MAGE', 'Gene', (208, 212))	('tumor', 'Disease', (123, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (282, 316))	('MAGE-A11', 'Gene', (0, 8))	('ZEB1', 'Gene', (36, 40))	('TFCP2', 'Gene', (30, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (293, 316))	('de-methylation', 'Var', (55, 69))	('Melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('MAGE-A11', 'Gene', '4110', (228, 236))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('facilitates', 'PosReg', (106, 117))	('TFCP2', 'Gene', '7024', (30, 35))	('MAGE-A11', 'Gene', (228, 236))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('ZEB1', 'Gene', '6935', (36, 40))	('Melanoma', 'Disease', 'MESH:D008545', (183, 191))	('esophageal squamous cell carcinoma', 'Disease', (282, 316))	('MAGE-A11', 'Gene', '4110', (0, 8))
471482	29423052	Following MAGE-A11 promoter methylation, the methyl-CpG-binding protein MeCP2 was found to bind the methylated MAGE-A11 promoter to mediate histone deactylation by recruiting HDAC1 and HDAC2.	('MAGE-A11', 'Gene', (10, 18))	('MAGE-A11', 'Gene', '4110', (111, 119))	('histone deactylation', 'MPA', (140, 160))	('HDAC1', 'Gene', (175, 180))	('HDAC2', 'Gene', '3066', (185, 190))	('recruiting', 'PosReg', (164, 174))	('HDAC2', 'Gene', (185, 190))	('MAGE-A11', 'Gene', (111, 119))	('MeCP2', 'Gene', '4204', (72, 77))	('HDAC1', 'Gene', '3065', (175, 180))	('methylation', 'Var', (28, 39))	('MeCP2', 'Gene', (72, 77))	('MAGE-A11', 'Gene', '4110', (10, 18))
471508	29423052	In addition, ESCC patients with positive expression of MAGE-A11 have significantly reduced 5-year overall survival (P < 0.001; Figure 1B).	('positive expression', 'Var', (32, 51))	('reduced', 'NegReg', (83, 90))	('ESCC', 'Disease', (13, 17))	('MAGE-A11', 'Gene', (55, 63))	('patients', 'Species', '9606', (18, 26))	('overall survival', 'MPA', (98, 114))	('MAGE-A11', 'Gene', '4110', (55, 63))
471511	29423052	The esophageal cancer Eca109 cells bearing enforced MAGE-A11 expression and their corresponding control cells were subcutaneously injected into nude mice.	('enforced', 'Var', (43, 51))	('MAGE-A11', 'Gene', '4110', (52, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('MAGE-A11', 'Gene', (52, 60))	('nude mice', 'Species', '10090', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal cancer', 'Disease', (4, 21))
471512	29423052	As shown in Figure 1C and Supplementary Figure 1, the xenografts formed by MAGE-A11 overexpression cells revealed increased cell growth than the control tumors.	('MAGE-A11', 'Gene', (75, 83))	('cell growth', 'CPA', (124, 135))	('increased', 'PosReg', (114, 123))	('overexpression', 'Var', (84, 98))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('MAGE-A11', 'Gene', '4110', (75, 83))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
471523	29423052	In MAGE-A11 low-expressed cells, MAGE-A11 was induced by DAC treatment, whereas it was only slightly induced in MAGE-A11 high-expressed cells (Figure 1G).	('MAGE-A11', 'Gene', '4110', (3, 11))	('low-expressed', 'Var', (12, 25))	('MAGE-A11', 'Gene', (3, 11))	('DAC', 'Chemical', '-', (57, 60))	('MAGE-A11', 'Gene', '4110', (33, 41))	('MAGE-A11', 'Gene', '4110', (112, 120))	('MAGE-A11', 'Gene', (33, 41))	('MAGE-A11', 'Gene', (112, 120))
471530	29423052	As shown in Figure 2A, this CpG island was moderately to highly methylated in TE1, KYSE170, KYSE30, Eca109 cells which had relatively low level of MAGE-A11 expression, while this region was hypomethylated in Ec9706 and TE13 cells expressing high level of MAGE-A11.	('KYSE30', 'Var', (92, 98))	('Ec9706', 'CellLine', 'CVCL:E307', (208, 214))	('MAGE-A11', 'Gene', (255, 263))	('MAGE-A11', 'Gene', (147, 155))	('MAGE-A11', 'Gene', '4110', (147, 155))	('MAGE-A11', 'Gene', '4110', (255, 263))
471546	29423052	ChIP results showed that the specific binding of SP1 to MAGE-A11 promoter was increased as compared with IgG control in TE13 cells which showed high expression of MAGE-A11 and hypomethylation of MAGE-A11 promoter (33.46 of fold enrichment) (Figure 3B and 3C).	('MAGE-A11', 'Gene', '4110', (195, 203))	('MAGE-A11', 'Gene', (195, 203))	('MAGE-A11', 'Gene', '4110', (56, 64))	('MAGE-A11', 'Gene', '4110', (163, 171))	('binding', 'Interaction', (38, 45))	('MAGE-A11', 'Gene', (56, 64))	('hypomethylation', 'Var', (176, 191))	('increased', 'PosReg', (78, 87))	('MAGE-A11', 'Gene', (163, 171))
471552	29423052	To further confirm whether the binding of TFCP2 and ZEB1 to MAGE-A11 promoter could regulate the transcription activity of MAGE-A11, we constructed the luciferase reporters carrying deletion mutants of MAGE-A11 promoter (Figure 3D), and performed the in vitro luciferase reporter assay.	('ZEB1', 'Gene', (52, 56))	('MAGE-A11', 'Gene', (202, 210))	('regulate', 'Reg', (84, 92))	('mutants', 'Var', (191, 198))	('deletion mutants', 'Var', (182, 198))	('TFCP2', 'Gene', (42, 47))	('MAGE-A11', 'Gene', '4110', (60, 68))	('MAGE-A11', 'Gene', '4110', (123, 131))	('MAGE-A11', 'Gene', (60, 68))	('transcription activity', 'MPA', (97, 119))	('MAGE-A11', 'Gene', (123, 131))	('ZEB1', 'Gene', '6935', (52, 56))	('MAGE-A11', 'Gene', '4110', (202, 210))	('TFCP2', 'Gene', '7024', (42, 47))
471554	29423052	This result was further confirmed by the luciferase reporter assay carrying deletion mutants of MAGE-A11 promoter (Figure 3F).	('deletion mutants', 'Var', (76, 92))	('MAGE-A11', 'Gene', (96, 104))	('MAGE-A11', 'Gene', '4110', (96, 104))
471555	29423052	To address whether these transcription factors regulate MAGE-A11 transcription activity in a methylation-dependent manner in ESCC cells, we transfected TFCP2, ZEB1 and SP1 expression plasmid in TE13 cells which carried hypomethylation of MAGE-A11 promoter.	('hypomethylation', 'Var', (219, 234))	('ZEB1', 'Gene', (159, 163))	('ZEB1', 'Gene', '6935', (159, 163))	('MAGE-A11', 'Gene', '4110', (56, 64))	('TFCP2', 'Gene', '7024', (152, 157))	('MAGE-A11', 'Gene', '4110', (238, 246))	('MAGE-A11', 'Gene', (56, 64))	('MAGE-A11', 'Gene', (238, 246))	('TFCP2', 'Gene', (152, 157))
471557	29423052	However, in Eca109 cells which carried hypermethylation of MAGE-A11 promoter, MAGE-A11 was not or only slightly induced by TFCP2, ZEB1 and SP1 at the mRNA level and protein level, respectively (Figure 4C, 4D and 4E).	('MAGE-A11', 'Gene', (78, 86))	('MAGE-A11', 'Gene', '4110', (59, 67))	('MAGE-A11', 'Gene', (59, 67))	('ZEB1', 'Gene', '6935', (130, 134))	('TFCP2', 'Gene', (123, 128))	('ZEB1', 'Gene', (130, 134))	('MAGE-A11', 'Gene', '4110', (78, 86))	('hypermethylation', 'Var', (39, 55))	('TFCP2', 'Gene', '7024', (123, 128))
471565	29423052	Following methylation, methyl-CpG-binding proteins (MBPs), such as MBD1, MBD2, MeCP2 are commonly recruited to CpG sites, and repress transcription by recruiting Sin3A, which interacts with histone deacetylases (HDACs), and form a corepressor complex.	('Sin3A', 'Gene', '25942', (162, 167))	('repress', 'NegReg', (126, 133))	('transcription', 'MPA', (134, 147))	('recruited', 'PosReg', (98, 107))	('MeCP2', 'Gene', '4204', (79, 84))	('MBD2', 'Gene', '8932', (73, 77))	('recruiting', 'PosReg', (151, 161))	('interacts', 'Interaction', (175, 184))	('MeCP2', 'Gene', (79, 84))	('Sin3A', 'Gene', (162, 167))	('MBD1', 'Gene', (67, 71))	('methylation', 'Var', (10, 21))	('MBD1', 'Gene', '4152', (67, 71))	('methyl-CpG-binding', 'Protein', (23, 41))	('HDAC', 'Gene', (212, 216))	('MBD2', 'Gene', (73, 77))	('HDAC', 'Gene', '9734', (212, 216))
471569	29423052	In addition, siRNA-mediated knockdown of MeCP2 increased the DAC-induced MAGE-A11 expression at mRNA level and protein level (Figure 5C and 5D).	('expression', 'MPA', (82, 92))	('MAGE-A11', 'Gene', '4110', (73, 81))	('MAGE-A11', 'Gene', (73, 81))	('DAC', 'Chemical', '-', (61, 64))	('increased', 'PosReg', (47, 56))	('MeCP2', 'Gene', '4204', (41, 46))	('knockdown', 'Var', (28, 37))	('MeCP2', 'Gene', (41, 46))
471570	29423052	Subsequently, to investigate whether HDACs, known to be repressors of transcription, were related the MAGE-A11 promoter methylation, ChIP analysis was performed using antibodies targeting HDAC1, HDAC2, H3K9Ac, and H3Ac in Eca109 and TE13 cells.	('HDAC', 'Gene', '9734', (37, 41))	('H3Ac', 'Gene', (214, 218))	('HDAC1', 'Gene', (188, 193))	('HDAC2', 'Gene', (195, 200))	('HDAC2', 'Gene', '3066', (195, 200))	('HDAC1', 'Gene', '3065', (188, 193))	('HDAC', 'Gene', (37, 41))	('HDAC', 'Gene', (188, 192))	('MAGE-A11', 'Gene', '4110', (102, 110))	('MAGE-A11', 'Gene', (102, 110))	('HDAC', 'Gene', (195, 199))	('HDAC', 'Gene', '9734', (188, 192))	('HDAC', 'Gene', '9734', (195, 199))	('H3K9Ac', 'Var', (202, 208))
471572	29423052	DAC-induced demethylation of MAGE-A11 promoter blocks binding of HDAC1 and HDAC2 in Eca109 cells.	('demethylation', 'Var', (12, 25))	('blocks', 'NegReg', (47, 53))	('HDAC2', 'Gene', (75, 80))	('HDAC2', 'Gene', '3066', (75, 80))	('MAGE-A11', 'Gene', '4110', (29, 37))	('HDAC1', 'Gene', (65, 70))	('DAC', 'Chemical', '-', (66, 69))	('MAGE-A11', 'Gene', (29, 37))	('DAC', 'Chemical', '-', (0, 3))	('HDAC1', 'Gene', '3065', (65, 70))	('binding', 'Interaction', (54, 61))	('DAC', 'Chemical', '-', (76, 79))
471573	29423052	Simultaneously, H3K9Ac and H3Ac bind to the hypomethylated MAGE-A11 promoter in TE 13 cells, but not bind to the hypermethylated MAGE-A11 promoter in Eca109 cells.	('MAGE-A11', 'Gene', '4110', (59, 67))	('MAGE-A11', 'Gene', (59, 67))	('H3Ac', 'Var', (27, 31))	('bind', 'Interaction', (32, 36))	('H3K9Ac', 'Var', (16, 22))	('MAGE-A11', 'Gene', '4110', (129, 137))	('MAGE-A11', 'Gene', (129, 137))
471574	29423052	DAC-induced demethylation of MAGE-A11 promoter increased the binding of H3K9Ac and H3Ac in Eca109 cells.	('demethylation', 'Var', (12, 25))	('H3K9Ac', 'Protein', (72, 78))	('MAGE-A11', 'Gene', '4110', (29, 37))	('increased', 'PosReg', (47, 56))	('H3Ac', 'Protein', (83, 87))	('MAGE-A11', 'Gene', (29, 37))	('DAC', 'Chemical', '-', (0, 3))	('binding', 'Interaction', (61, 68))
471579	29423052	According to the results of Figure 6A, MAGE-A11 promoter in Eca109 cells exhibited increased occupancy of inactivation marks such as H3K27me3 as well as H3K9me3, and decreased occupancy of activation mark H3K4me3.	('increased', 'PosReg', (83, 92))	('H3K27me3', 'Protein', (133, 141))	('activation', 'MPA', (189, 199))	('H3K4me3', 'Protein', (205, 212))	('decreased', 'NegReg', (166, 175))	('occupancy', 'MPA', (176, 185))	('MAGE-A11', 'Gene', '4110', (39, 47))	('occupancy', 'MPA', (93, 102))	('inactivation', 'MPA', (106, 118))	('MAGE-A11', 'Gene', (39, 47))	('H3K9me3', 'Var', (153, 160))
471580	29423052	In contrast, MAGE-A11 promoter in TE13 cells exhibited decreased occupancy of H3K27me3 as well as H3K9me3, and increased occupancy of activation mark H3K4me3.	('increased', 'PosReg', (111, 120))	('H3K4me3', 'Var', (150, 157))	('H3K27me3', 'Protein', (78, 86))	('MAGE-A11', 'Gene', (13, 21))	('occupancy', 'MPA', (65, 74))	('activation', 'PosReg', (134, 144))	('decreased', 'NegReg', (55, 64))	('occupancy', 'MPA', (121, 130))	('MAGE-A11', 'Gene', '4110', (13, 21))	('H3K9me3', 'Protein', (98, 105))
471581	29423052	After treatment with DAC, the occupancy of H3K27me3 as well as H3K9me3 on MAGE-A11 promoter in Eca109 cells was decreased, whereas the occupancy of H3K4me3 was increased.	('occupancy', 'MPA', (30, 39))	('H3K27me3', 'Var', (43, 51))	('MAGE-A11', 'Gene', '4110', (74, 82))	('DAC', 'Chemical', '-', (21, 24))	('H3K9me3', 'Var', (63, 70))	('MAGE-A11', 'Gene', (74, 82))	('decreased', 'NegReg', (112, 121))
471582	29423052	When we knockdown EZH2 which is a component of polycomb repressor complex (PRC)-2 and mediate trimethylation of H3K27, the occupancy of H3K27me3 on MAGE-A11 promoter was decreased (Figure 6B), and the expression of MAGE-A11 was increased (Figure 6C).	('MAGE-A11', 'Gene', '4110', (148, 156))	('knockdown', 'Var', (8, 17))	('occupancy', 'MPA', (123, 132))	('PR', 'Gene', '5241', (75, 77))	('MAGE-A11', 'Gene', '4110', (215, 223))	('EZH2', 'Gene', '2146', (18, 22))	('increased', 'PosReg', (228, 237))	('decreased', 'NegReg', (170, 179))	('EZH2', 'Gene', (18, 22))	('MAGE-A11', 'Gene', (148, 156))	('MAGE-A11', 'Gene', (215, 223))	('H3K27me3', 'Var', (136, 144))	('expression', 'MPA', (201, 211))
471583	29423052	DZNep, a pharmacologic inhibitor of EZH2, recapitulated the effects of EZH2 knockdown (Figure 6D).	('EZH2', 'Gene', (71, 75))	('knockdown', 'Var', (76, 85))	('EZH2', 'Gene', '2146', (36, 40))	('DZNep', 'Chemical', '-', (0, 5))	('EZH2', 'Gene', '2146', (71, 75))	('EZH2', 'Gene', (36, 40))
471587	29423052	These epigenetic changes promote the re-expression of MAGE-A11 and facilitate the cell proliferation and tumor growth of ESCC.	('re-expression', 'MPA', (37, 50))	('tumor', 'Disease', (105, 110))	('cell proliferation', 'CPA', (82, 100))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('epigenetic changes', 'Var', (6, 24))	('MAGE-A11', 'Gene', '4110', (54, 62))	('facilitate', 'PosReg', (67, 77))	('promote', 'PosReg', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('MAGE-A11', 'Gene', (54, 62))	('ESCC', 'Disease', (121, 125))
471591	29423052	DNA methylation is the major epigenetic mechanism silencing CTA genes in normal somatic cells, and CTA genes expression can be induced in cancer cells by DNA demethylating agents or knockdown of (DNA methyltransferases) DNMTs.	('cancer', 'Disease', (138, 144))	('expression', 'MPA', (109, 119))	('silencing', 'NegReg', (50, 59))	('CTA genes', 'Gene', (60, 69))	('CTA genes', 'Gene', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('knockdown', 'Var', (182, 191))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('induced', 'PosReg', (127, 134))
471592	29423052	As suggested by James et al., CpG island of MAGE-A11 promoter is hypermethylated in benign prostate intraepithelial neoplasia, but hypomethylated in prostate cancer, especially at the transcription start site (TSS)-resident CpG sites.	('hypomethylated', 'Var', (131, 145))	('benign prostate intraepithelial neoplasia', 'Disease', 'MESH:D019048', (84, 125))	('benign prostate intraepithelial neoplasia', 'Phenotype', 'HP:0008711', (84, 125))	('prostate cancer', 'Disease', 'MESH:D011471', (149, 164))	('prostate cancer', 'Phenotype', 'HP:0012125', (149, 164))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (100, 125))	('MAGE-A11', 'Gene', '4110', (44, 52))	('benign prostate intraepithelial neoplasia', 'Disease', (84, 125))	('MAGE-A11', 'Gene', (44, 52))	('prostate cancer', 'Disease', (149, 164))	('neoplasia', 'Phenotype', 'HP:0002664', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
471594	29423052	In addition, in prostate cancer, DNA methylation regulates nucleosome occupancy specifically at the -1 positioned necleosome of MAGE-A11, therefore strongly repressing MAGE-A11 promoter activity.	('MAGE-A11', 'Gene', '4110', (168, 176))	('prostate cancer', 'Disease', (16, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('MAGE-A11', 'Gene', '4110', (128, 136))	('methylation', 'Var', (37, 48))	('MAGE-A11', 'Gene', (168, 176))	('promoter activity', 'MPA', (177, 194))	('MAGE-A11', 'Gene', (128, 136))	('nucleosome occupancy', 'MPA', (59, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (16, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (16, 31))	('regulates', 'Reg', (49, 58))	('repressing', 'NegReg', (157, 167))
471604	29423052	Although hypermethylation of CpG-rich MAGE gene promoters plays a crucial role in the silencing of MAGE genes, up-regulation of MAGE gene could not be always observed although tumor cells were treated by the DNA methylase inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('silencing', 'MPA', (86, 95))	('hypermethylation', 'Var', (9, 25))	('MAGE genes', 'Gene', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
471606	29423052	Following methylation, some MBPs are commonly recruited to CpG sites, and repress transcription by recruiting HDACs.	('transcription', 'MPA', (82, 95))	('HDAC', 'Gene', (110, 114))	('methylation', 'Var', (10, 21))	('HDAC', 'Gene', '9734', (110, 114))
471613	29423052	Following MeCP2 binding to the methylated CpG sites, the recruitment of HDAC1 and HDAC2 was also increased, and the binding of H3Ac and H3K9Ac was decreased, leading to the deacetylation of histone and gene repression.	('histone', 'Protein', (190, 197))	('HDAC2', 'Gene', (82, 87))	('binding', 'Interaction', (116, 123))	('increased', 'PosReg', (97, 106))	('HDAC2', 'Gene', '3066', (82, 87))	('HDAC1', 'Gene', '3065', (72, 77))	('decreased', 'NegReg', (147, 156))	('recruitment', 'MPA', (57, 68))	('deacetylation', 'MPA', (173, 186))	('gene repression', 'CPA', (202, 217))	('methylated', 'Var', (31, 41))	('H3Ac', 'Protein', (127, 131))	('MeCP2', 'Gene', '4204', (10, 15))	('MeCP2', 'Gene', (10, 15))	('HDAC1', 'Gene', (72, 77))	('binding', 'Interaction', (16, 23))	('H3K9Ac', 'Protein', (136, 142))
471615	29423052	According to our present study, following MeCP2 binding to the methylated CpG sites, the occupancy of inactivation histone marks such as H3K27me3 and H3K9me3 was increased, whereas the occupancy of activation mark H3K4me3 was decreased.	('H3K9me3', 'Var', (150, 157))	('occupancy', 'MPA', (89, 98))	('increased', 'PosReg', (162, 171))	('binding', 'Interaction', (48, 55))	('H3K27me3', 'Var', (137, 145))	('MeCP2', 'Gene', '4204', (42, 47))	('methylated', 'Var', (63, 73))	('inactivation', 'MPA', (102, 114))	('MeCP2', 'Gene', (42, 47))
471616	29423052	The occupancy of these marks can be regulated by demethylating agent DAC, suggesting that histone methylation is a subsequent event following MAGE-A11 promoter methylation.	('methylation', 'Var', (160, 171))	('MAGE-A11', 'Gene', '4110', (142, 150))	('MAGE-A11', 'Gene', (142, 150))	('histone methylation', 'MPA', (90, 109))	('DAC', 'Chemical', '-', (69, 72))
471618	29423052	Therefore, we sought to find the feasibility of modulating histone acetylation and methylation together with DNA methylation as a strategy to enhance MAGE-A11 activation under conditions potentially achievable in clinical settings.	('MAGE-A11', 'Gene', (150, 158))	('activation', 'MPA', (159, 169))	('enhance', 'PosReg', (142, 149))	('MAGE-A11', 'Gene', '4110', (150, 158))	('modulating', 'Var', (48, 58))
471620	29423052	We recently reported epigenetic modulation by zebularine (another DNA methyltransferase inhibitor) - induced MAGE-A11 expression in breast cancer cells and facilitated cytotoxicity via MAGE-A11-specific cytotoxic T lymphocytes.	('cytotoxicity', 'Disease', 'MESH:D064420', (168, 180))	('facilitated', 'PosReg', (156, 167))	('zebularine', 'Chemical', 'MESH:C009131', (46, 56))	('MAGE-A11', 'Gene', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Disease', (132, 145))	('MAGE-A11', 'Gene', '4110', (109, 117))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('cytotoxicity', 'Disease', (168, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('expression', 'MPA', (118, 128))	('MAGE-A11', 'Gene', (109, 117))	('MAGE-A11', 'Gene', '4110', (185, 193))	('epigenetic modulation', 'Var', (21, 42))
471666	27958230	Similarly, pooled analysis suggested that patients who received NCRTS exhibited a significantly increased 3-year SR [RR: 1.26, 95% CI: 1.14-1.39, P < 0.001; nonsignificant heterogeneity; Figure 3].	('patients', 'Species', '9606', (42, 50))	('increased', 'PosReg', (96, 105))	('NCRTS', 'Var', (64, 69))	('SR [', 'CPA', (113, 117))
471679	27958230	Third, a significant increase in the survival outcomes for SCC or AC by NCRTS was indicated in the meta-analysis by Sjoquist et al., whereas only improvements in the 3- and 5-year survival outcomes for SCC, but not AC, were evaluated in our previous meta-analysis.	('SCC', 'Gene', (202, 205))	('SCC', 'Gene', (59, 62))	('SCC', 'Phenotype', 'HP:0002860', (202, 205))	('SCC', 'Gene', '6317', (202, 205))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('SCC', 'Gene', '6317', (59, 62))	('increase', 'PosReg', (21, 29))	('NCRTS', 'Var', (72, 77))
471681	27958230	reported that patients treated with NCRTS were disposed toward higher 1-, 3-, and 5-year SRs than patients who did not receive the NCRTS treatment.	('higher', 'PosReg', (63, 69))	('patients', 'Species', '9606', (14, 22))	('NCRTS', 'Var', (36, 41))	('patients', 'Species', '9606', (98, 106))
471690	27958230	Similarly, as the common reason for EC-related death, recurrence was lower in patients receiving NCRTS than those treated with SA.	('NCRTS', 'Var', (97, 102))	('death', 'Disease', 'MESH:D003643', (47, 52))	('death', 'Disease', (47, 52))	('EC', 'Phenotype', 'HP:0011459', (36, 38))	('patients', 'Species', '9606', (78, 86))	('lower', 'NegReg', (69, 74))	('SA', 'Chemical', '-', (127, 129))	('recurrence', 'MPA', (54, 64))
471731	24481406	Low intake of folate was associated with increased risk of esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('Low intake of folate', 'Phenotype', 'HP:0100507', (0, 20))	('Low intake', 'Var', (0, 10))	('esophageal squamous cell carcinoma', 'Disease', (59, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('folate', 'Chemical', 'MESH:D005492', (14, 20))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (59, 93))
471746	24481406	Cases were defined using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) (Esophageal cancer: C15.0-15.9; Gastric cancer: C16.0 (GCA) and C16.1-16.7 (NCGA)).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Gastric cancer', 'Disease', (140, 154))	('Oncology', 'Phenotype', 'HP:0002664', (74, 82))	('C16.1-16.7', 'Var', (172, 182))	('Esophageal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('C16.0', 'Var', (156, 161))	('C16.1-16.7', 'CellLine', 'CVCL:0H98', (172, 182))	('Gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('Esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
471747	24481406	The esophageal cancer cases were further classified into ESCC (code: 8050-8076) and EAC (code: 8140, 8142, 8144, 8261, 8310, 8480, 8481, 8570, 8260, 8263, and 8490).	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('8261', 'Var', (113, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('ESCC', 'Disease', (57, 61))	('8260', 'Var', (143, 147))	('8310', 'Var', (119, 123))	('8570', 'Var', (137, 141))	('8144', 'Var', (107, 111))	('8142', 'Var', (101, 105))	('8481', 'Var', (131, 135))	('EAC', 'Disease', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('8480', 'Var', (125, 129))	('esophageal cancer', 'Disease', (4, 21))
471793	24481406	Large studies that assess the interrelation between folate intake, genetic polymorphism in folate pathway, and other factors such as alcohol and smoking would be particularly valuable.	('folate', 'Chemical', 'MESH:D005492', (52, 58))	('genetic polymorphism', 'Var', (67, 87))	('alcohol', 'Chemical', 'MESH:D000438', (133, 140))	('folate pathway', 'Pathway', (91, 105))	('folate', 'Chemical', 'MESH:D005492', (91, 97))
471796	22675025	Aberrant expression of casein kinase 2 (CK2) is associated with tumor progression; however, the molecular mechanism by which CK2 modulates tumorigenesis is incompletely understood.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CK2', 'Gene', (125, 128))	('tumor', 'Disease', (64, 69))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (48, 58))	('CK2', 'Gene', (40, 43))	('CK2', 'Gene', '13000', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CK2', 'Gene', '13000', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
471807	22675025	The sumoylation of NCoR by SUMO and ubiquitin-conjugating enzyme 9 (Ubc9), an E2 conjugation enzyme, results in enhanced NCoR-dependent transcriptional repression.	('enhanced', 'PosReg', (112, 120))	('ubiquitin-conjugating enzyme 9', 'Gene', '7329', (36, 66))	('Ubc9', 'Gene', '7329', (68, 72))	('NCoR', 'Gene', (19, 23))	('Ubc9', 'Gene', (68, 72))	('ubiquitin-conjugating enzyme 9', 'Gene', (36, 66))	('sumoylation', 'Var', (4, 15))	('NCoR-dependent transcriptional repression', 'MPA', (121, 162))
471809	22675025	SMRT phosphorylation leads to nuclear export and proteasomal degradation, reducing repression.	('leads to', 'Reg', (21, 29))	('proteasomal degradation', 'MPA', (49, 72))	('phosphorylation', 'Var', (5, 20))	('SMRT', 'Gene', '9612', (0, 4))	('repression', 'MPA', (83, 93))	('SMRT', 'Gene', (0, 4))	('nuclear export', 'MPA', (30, 44))	('reducing', 'NegReg', (74, 82))
471813	22675025	Additionally, CK2 dysregulation in tumor cells may influence apoptotic activity and enhance cell survival.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CK2', 'Gene', '13000', (14, 17))	('apoptotic activity', 'CPA', (61, 79))	('tumor', 'Disease', (35, 40))	('dysregulation', 'Var', (18, 31))	('influence', 'Reg', (51, 60))	('cell survival', 'CPA', (92, 105))	('enhance', 'PosReg', (84, 91))	('CK2', 'Gene', (14, 17))
471815	22675025	In transgenic mice, CK2 overexpression cooperates with c-myc or loss (or mutation) of p53 at the lpr locus to promote tumorigenesis.	('CK2', 'Gene', '13000', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('lpr', 'Gene', '14102', (97, 100))	('myc', 'Gene', '4609', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('p53', 'Gene', '22060', (86, 89))	('lpr', 'Gene', (97, 100))	('loss', 'NegReg', (64, 68))	('tumor', 'Disease', (118, 123))	('promote', 'PosReg', (110, 117))	('transgenic mice', 'Species', '10090', (3, 18))	('CK2', 'Gene', (20, 23))	('mutation', 'Var', (73, 81))	('myc', 'Gene', (57, 60))	('p53', 'Gene', (86, 89))
471820	22675025	Although aberrant expression of CK2 is known to be involved in many cancers, the mechanism by which CK2 promotes tumorigenesis remains obscure.	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('CK2', 'Gene', (32, 35))	('CK2', 'Gene', '13000', (100, 103))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('involved', 'Reg', (51, 59))	('promotes', 'PosReg', (104, 112))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('CK2', 'Gene', '13000', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('aberrant', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CK2', 'Gene', (100, 103))
471838	22675025	For accurate determination of the phosphorylation site in NCoR, we generated glutathione S-transferase (GST)-tagged mutant plasmids in which serine was substituted for alanine, and mutant plasmids were screened using in vitro kinase assays.	('alanine', 'Chemical', 'MESH:D000409', (168, 175))	('GST', 'Gene', (104, 107))	('glutathione S-transferase', 'Gene', (77, 102))	('glutathione S-transferase', 'Gene', '373156', (77, 102))	('GST', 'Gene', '373156', (104, 107))	('serine', 'Chemical', 'MESH:D012694', (141, 147))	('mutant', 'Var', (116, 122))
471839	22675025	Replacement with alanine of both Ser-2143 and Ser-2144 in the NRID domain had a negligible effect on phosphorylation; however, mutation of Ser-2436 resulted in complete loss of phosphorylation in the NRID domain, providing evidence that the Ser-2436 residue of NCoR is critical for CK2alpha-dependent phosphorylation (Figure 1D).	('alanine', 'Chemical', 'MESH:D000409', (17, 24))	('CK2alpha', 'Gene', '1459', (282, 290))	('CK2alpha', 'Gene', (282, 290))	('Ser', 'Chemical', 'MESH:D012694', (241, 244))	('loss', 'NegReg', (169, 173))	('mutation', 'Var', (127, 135))	('Ser', 'Chemical', 'MESH:D012694', (46, 49))	('Ser', 'Chemical', 'MESH:D012694', (33, 36))	('Ser', 'Chemical', 'MESH:D012694', (139, 142))	('phosphorylation', 'MPA', (177, 192))	('Ser-2436', 'Gene', (139, 147))
471840	22675025	To further examine whether NCoR Ser-2436 is phosphorylated by CK2alpha and to study the biological importance of phosphorylation at this site, we generated a phosphospecific NCoR antibody that specifically recognizes phosphorylated Ser-2436 (Ser(P)-2436) in NCoR.	('Ser-2436 (Ser', 'Mutation', 'rs897031421', (232, 245))	('Ser', 'Chemical', 'MESH:D012694', (232, 235))	('Ser', 'Chemical', 'MESH:D012694', (32, 35))	('Ser(P)', 'Chemical', '-', (242, 248))	('Ser', 'Chemical', 'MESH:D012694', (242, 245))	('Ser-2436', 'Var', (232, 240))	('CK2alpha', 'Gene', '1459', (62, 70))	('CK2alpha', 'Gene', (62, 70))
471843	22675025	To further test the specificity of the antibody, we cotransfected HeLa cells with green fluorescent protein (GFP)-tagged variants of wild-type NCoR, NCoRS2143/2144A, NCoRS2436A, and/or Myc-tagged CK2alpha.	('Myc', 'Gene', '4609', (185, 188))	('Myc', 'Gene', (185, 188))	('NCoRS2436A', 'Var', (166, 176))	('variants', 'Var', (121, 129))	('CK2alpha', 'Gene', '1459', (196, 204))	('CK2alpha', 'Gene', (196, 204))	('NCoRS2143/2144A', 'Var', (149, 164))	('HeLa', 'CellLine', 'CVCL:0030', (66, 70))	('NCoR', 'Gene', (143, 147))
471845	22675025	The phosphospecific antibody detected Ser-2463 in NCoRWT and the NCoRS2143/2144A double mutant, but not in the NCoRS2436A mutant.	('NCoRS2143/2144A', 'Var', (65, 80))	('Ser-2463', 'Var', (38, 46))	('Ser', 'Chemical', 'MESH:D012694', (38, 41))
471849	22675025	NCoR-15/16WT protein was efficiently phosphorylated in HeLa cells (Figure 1G), whereas TBB treatment in the same cells resulted in loss of phosphorylation events similar to that seen with the control plasmid (Figure S2D).	('NCoR-15/16WT', 'Var', (0, 12))	('loss', 'NegReg', (131, 135))	('TBB', 'Chemical', '-', (87, 90))	('phosphorylation events', 'MPA', (139, 161))	('HeLa', 'CellLine', 'CVCL:0030', (55, 59))
471852	22675025	Finally, to confirm that the modification by CK2 occurs at Ser-2436, the nonphosphopeptide corresponding region between residues 2431 and 2440 of NCoR was incubated with immunoprecipitated CK2 and/or TBB and subjected to matrix-assisted laser desorption ionization time-of-flight analysis.	('CK2', 'Gene', '13000', (45, 48))	('Ser-2436', 'Var', (59, 67))	('CK2', 'Gene', '13000', (189, 192))	('Ser', 'Chemical', 'MESH:D012694', (59, 62))	('NCoR', 'Gene', (146, 150))	('TBB', 'Chemical', '-', (200, 203))	('CK2', 'Gene', (189, 192))	('CK2', 'Gene', (45, 48))
471853	22675025	A peptide with molecular mass corresponding to the Ser-2436-phosphorylated peptide was observed after addition of CK2, whereas TBB treatment failed to show the peak corresponding to the phosphorylated peptide (Figure S3).	('TBB', 'Chemical', '-', (127, 130))	('CK2', 'Gene', (114, 117))	('CK2', 'Gene', '13000', (114, 117))	('Ser', 'Chemical', 'MESH:D012694', (51, 54))	('Ser-2436-phosphorylated', 'Var', (51, 74))
471854	22675025	Together these data establish that Ser-2436 is a major NCoR phosphorylation site in vivo and can be activated by CK2.	('Ser', 'Chemical', 'MESH:D012694', (35, 38))	('Ser-2436', 'Var', (35, 43))	('CK2', 'Gene', (113, 116))	('NCoR phosphorylation', 'MPA', (55, 75))	('CK2', 'Gene', '13000', (113, 116))
471856	22675025	TBB treatment dose-dependently decreased both expression and phosphorylation of full-length NCoRWT; however, TBB had a negligible effect on NCoRS2436A (Figure 2A).	('TBB', 'Chemical', '-', (109, 112))	('phosphorylation', 'MPA', (61, 76))	('TBB', 'Chemical', '-', (0, 3))	('decreased', 'NegReg', (31, 40))	('NCoRS2436A', 'Var', (140, 150))	('expression', 'MPA', (46, 56))
471864	22675025	Both knockdown of CK2 and inhibition of CK2 activity dramatically reduced the endogenous NCoR level, likely silencing NCoR (Figures 2G and S4B).	('CK2', 'Gene', (18, 21))	('silencing', 'NegReg', (108, 117))	('reduced', 'NegReg', (66, 73))	('knockdown', 'Var', (5, 14))	('NCoR', 'MPA', (118, 122))	('CK2', 'Gene', '13000', (18, 21))	('CK2', 'Gene', (40, 43))	('endogenous NCoR level', 'MPA', (78, 99))	('CK2', 'Gene', '13000', (40, 43))
471865	22675025	Consistently, MG132 treatment dramatically restored the level of endogenous NCoR (Figure 2D) without affecting the level of NCoR phosphorylation.	('MG132', 'Var', (14, 19))	('level', 'MPA', (56, 61))	('MG132', 'Chemical', 'MESH:C072553', (14, 19))	('restored', 'PosReg', (43, 51))
471866	22675025	Notably, CK2 knockdown led to reduced NCoR protein levels, but not reduced NCoR mRNA levels, further supporting our notion that CK2 plays an important role in NCoR stability (Figure 2E).	('NCoR protein levels', 'MPA', (38, 57))	('CK2', 'Gene', (128, 131))	('CK2', 'Gene', (9, 12))	('CK2', 'Gene', '13000', (128, 131))	('CK2', 'Gene', '13000', (9, 12))	('reduced', 'NegReg', (30, 37))	('knockdown', 'Var', (13, 22))
471869	22675025	Notably, NCoR stability was specifically abolished by only TBB and not by other kinase-specific inhibitors (Figure 2H).	('abolished', 'NegReg', (41, 50))	('TBB', 'Var', (59, 62))	('NCoR stability', 'MPA', (9, 23))	('TBB', 'Chemical', '-', (59, 62))
471874	22675025	TBB treatment increased the ubiquitination of the NCoR-15/16WT domain and MG132 treatment further enhanced the effect by TBB (Figure 2I).	('enhanced', 'PosReg', (98, 106))	('increased', 'PosReg', (14, 23))	('NCoR-15/16WT', 'Protein', (50, 62))	('ubiquitination', 'MPA', (28, 42))	('TBB', 'Chemical', '-', (0, 3))	('MG132', 'Chemical', 'MESH:C072553', (74, 79))	('TBB', 'Chemical', '-', (121, 124))	('MG132', 'Var', (74, 79))
471875	22675025	Furthermore, ubiquitination of NCoR-15/16S2436A was greatly increased by MG132 compared with both NCoR-15/16WT and NCoR-15/16S2143/2144A.	('ubiquitination', 'MPA', (13, 27))	('increased', 'PosReg', (60, 69))	('MG132', 'Chemical', 'MESH:C072553', (73, 78))	('MG132', 'Var', (73, 78))	('NCoR-15/16S2436A', 'Gene', (31, 47))
471887	22675025	The patterns of invasion activity in both cancer cell lines are closely correlated with CK2 activity, as either TBB treatment or knockdown of CK2 efficiently reversed the invasiveness of both cell types (Figure 4B).	('TBB', 'Chemical', '-', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('CK2', 'Gene', '13000', (142, 145))	('knockdown', 'Var', (129, 138))	('CK2', 'Gene', (88, 91))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('invasiveness', 'CPA', (171, 183))	('CK2', 'Gene', '13000', (88, 91))	('CK2', 'Gene', (142, 145))
471888	22675025	Interestingly, combinatorial treatment with siRNAs against NCoR and TBB synergistically suppressed the invasiveness of HCE4 cancer cells as compared with individual treatment (Figures 4C, S7, and S8A).	('TBB', 'Gene', (68, 71))	('TBB', 'Chemical', '-', (68, 71))	('cancer', 'Disease', (124, 130))	('NCoR', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('suppressed', 'NegReg', (88, 98))	('HCE4', 'CellLine', 'CVCL:1271', (119, 123))	('siRNAs', 'Var', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
471889	22675025	More interestingly, overexpression of mutant NCoRS2436A protein failed to enhance the invasiveness of HCE4 cells compared with wild-type NCoR, suggesting that CK2-mediated phosphorylation of NCoR is crucial for NCoR-mediated invasion of cancer cells.	('mutant', 'Var', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('CK2', 'Gene', '13000', (159, 162))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('invasiveness of HCE4 cells', 'CPA', (86, 112))	('HCE4', 'CellLine', 'CVCL:1271', (102, 106))	('cancer', 'Disease', (237, 243))	('NCoRS2436A', 'Gene', (45, 55))	('CK2', 'Gene', (159, 162))
471894	22675025	This reversed pattern of E-cadherin expression likely depends on the level of CK2, but not of NCoR, because silencing of NCoR had a negligible effect on the levels of E-cadherin.	('silencing', 'Var', (108, 117))	('NCoR', 'Gene', (121, 125))	('E-cadherin', 'Gene', (167, 177))	('E-cadherin', 'Gene', '999', (167, 177))	('CK2', 'Gene', (78, 81))	('E-cadherin', 'Gene', '999', (25, 35))	('E-cadherin', 'Gene', (25, 35))	('CK2', 'Gene', '13000', (78, 81))
471900	22675025	Among genes derepressed by depletion of either CK2 or NCoR, those coderepressed by more than twofold were selected.	('NCoR', 'Gene', (54, 58))	('CK2', 'Gene', '13000', (47, 50))	('depletion', 'Var', (27, 36))	('CK2', 'Gene', (47, 50))
471902	22675025	Both reverse transcriptase (RT)-PCR and real-time PCR analysis validated the cDNA microarray analysis results, confirming the derepression of the four genes by knockdown of either CK2 or NCoR and the differential expression of the four genes in both TE2 and HCE4 cells (Figures 5B and S8C).	('TE2', 'Gene', '8260', (250, 253))	('TE2', 'Gene', (250, 253))	('HCE4', 'CellLine', 'CVCL:1271', (258, 262))	('knockdown', 'Var', (160, 169))	('CK2', 'Gene', (180, 183))	('CK2', 'Gene', '13000', (180, 183))	('NCoR', 'Gene', (187, 191))	('derepression', 'NegReg', (126, 138))
471908	22675025	Both knockdown of CK2 and NCoR commonly derepressed IP-10 transcription; however, the transcriptional level of CXCL12 was not altered, suggesting the selective regulation of IP-10 transcription by the CK2 and NCoR signaling network (Figure 5C).	('CK2', 'Gene', (18, 21))	('CXCL12', 'Gene', (111, 117))	('IP-10', 'Gene', (174, 179))	('CK2', 'Gene', (201, 204))	('derepressed', 'Reg', (40, 51))	('knockdown', 'Var', (5, 14))	('IP-10', 'Gene', (52, 57))	('CK2', 'Gene', '13000', (18, 21))	('CXCL12', 'Gene', '6387', (111, 117))	('CK2', 'Gene', '13000', (201, 204))
471910	22675025	Importantly, the knockdown of SMRT had no effect on the derepression of IP-10, emphasizing the unique role of NCoR in the transcriptional repression of IP-10 (Figure 5C).	('SMRT', 'Gene', '9612', (30, 34))	('IP-10', 'Gene', (72, 77))	('derepression', 'MPA', (56, 68))	('SMRT', 'Gene', (30, 34))	('knockdown', 'Var', (17, 26))
471911	22675025	More importantly, knockdown of HDAC3, but not other class I HDACs, specifically relieved the transcriptional repression of IP-10 in a manner similar to siNCoR treatment, demonstrating the crucial role of the NCoR-HDAC3 axis in the transcriptional repression of IP-10 (Figure 5E).	('HDAC3', 'Gene', (213, 218))	('knockdown', 'Var', (18, 27))	('HDAC3', 'Gene', '8841', (31, 36))	('IP-10', 'Gene', (123, 128))	('relieved', 'NegReg', (80, 88))	('HDAC3', 'Gene', (31, 36))	('HDAC3', 'Gene', '8841', (213, 218))	('transcriptional repression', 'MPA', (93, 119))	('siNCoR', 'Chemical', '-', (152, 158))
471913	22675025	Intriguingly, E-cadherin transcription was selectively derepressed by depletion of Snail1, but not by depletion of NCoR.	('E-cadherin', 'Gene', '999', (14, 24))	('derepressed', 'NegReg', (55, 66))	('Snail1', 'Gene', (83, 89))	('depletion', 'Var', (70, 79))	('E-cadherin', 'Gene', (14, 24))	('Snail1', 'Gene', '6615', (83, 89))
471921	22675025	As controls, neither NCoR nor HDAC3 associated with the coding region of the IP-10 gene (Figure S11A, P2).	('S11A', 'Var', (96, 100))	('S11A', 'SUBSTITUTION', 'None', (96, 100))	('HDAC3', 'Gene', '8841', (30, 35))	('HDAC3', 'Gene', (30, 35))	('IP-10', 'Gene', (77, 82))
471922	22675025	Consistent with previous studies, knockdown of c-Jun greatly abolished recruitment of the NCoR-HDAC3 complex to the AP1 site of IP-10 (Figure S11B, P1).	('c-Jun', 'Gene', '3725', (47, 52))	('AP1', 'Gene', (116, 119))	('recruitment', 'MPA', (71, 82))	('S11B', 'SUBSTITUTION', 'None', (142, 146))	('S11B', 'Var', (142, 146))	('c-Jun', 'Gene', (47, 52))	('abolished', 'NegReg', (61, 70))	('knockdown', 'Var', (34, 43))	('HDAC3', 'Gene', '8841', (95, 100))	('HDAC3', 'Gene', (95, 100))	('AP1', 'Gene', '3725', (116, 119))
471930	22675025	The increased invasiveness of TE4 cells by CK2 seems to be NCoR-dependent, because the depletion of NCoR diminished the CK2-enhanced invasion of TE2 cells (Figure 6D).	('invasiveness', 'CPA', (14, 26))	('CK2', 'Gene', '13000', (120, 123))	('diminished', 'NegReg', (105, 115))	('invasion', 'CPA', (133, 141))	('CK2', 'Gene', (43, 46))	('TE2', 'Gene', '8260', (145, 148))	('NCoR', 'Protein', (100, 104))	('depletion', 'Var', (87, 96))	('CK2', 'Gene', (120, 123))	('CK2', 'Gene', '13000', (43, 46))	('TE2', 'Gene', (145, 148))
471941	22675025	Moreover, NCoR knockdown had no effect on E-cadherin transcription.	('E-cadherin', 'Gene', '999', (42, 52))	('E-cadherin', 'Gene', (42, 52))	('knockdown', 'Var', (15, 24))	('NCoR', 'Gene', (10, 14))
471956	22675025	Interestingly, we found that silencing or inhibiting CK2alpha resulted in a reduced NCoR level, and MG132 treatment efficiently blocked the ubiquitin-dependent proteasomal degradation of NCoR.	('ubiquitin-dependent proteasomal degradation', 'MPA', (140, 183))	('silencing', 'Var', (29, 38))	('inhibiting', 'NegReg', (42, 52))	('MG132', 'Chemical', 'MESH:C072553', (100, 105))	('NCoR level', 'MPA', (84, 94))	('CK2alpha', 'Gene', '1459', (53, 61))	('CK2alpha', 'Gene', (53, 61))	('reduced', 'NegReg', (76, 83))	('MG132', 'Gene', (100, 105))	('blocked', 'NegReg', (128, 135))
471957	22675025	The effect of CK2alpha-dependent phosphorylation on protein stability was found to be unique to NCoR, because both CK2alpha knockdown and TBB treatment had no effect on SMRT levels.	('knockdown', 'Var', (124, 133))	('CK2alpha', 'Gene', '1459', (115, 123))	('CK2alpha', 'Gene', (115, 123))	('SMRT', 'Gene', (169, 173))	('protein stability', 'MPA', (52, 69))	('TBB', 'Chemical', '-', (138, 141))	('CK2alpha', 'Gene', '1459', (14, 22))	('CK2alpha', 'Gene', (14, 22))	('SMRT', 'Gene', '9612', (169, 173))
471965	22675025	Furthermore, silencing of HDAC3 also selectively derepresses IP-10 transcription in a manner similar to siNCoR or siCK2, suggesting the functional engagement of NCoR-HDAC3 corepressor complex in transcriptional repression of IP-10.	('derepresses', 'Reg', (49, 60))	('HDAC3', 'Gene', (26, 31))	('CK2', 'Gene', '13000', (116, 119))	('HDAC3', 'Gene', '8841', (166, 171))	('silencing', 'Var', (13, 22))	('HDAC3', 'Gene', (166, 171))	('siNCoR', 'Chemical', '-', (104, 110))	('HDAC3', 'Gene', '8841', (26, 31))	('CK2', 'Gene', (116, 119))	('IP-10', 'Gene', (61, 66))	('transcription', 'MPA', (67, 80))
471967	22675025	IP-10 has recently been shown to inhibit growth, angiogenesis, and metastasis in experimental tumors.	('growth', 'CPA', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('inhibit', 'NegReg', (33, 40))	('IP-10', 'Var', (0, 5))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('metastasis in', 'CPA', (67, 80))	('angiogenesis', 'CPA', (49, 61))
471976	22675025	Importantly, failure of the derepression of IP-10 by depletion of Snail1 again confirmed our notion that the CK2 signaling cascade likely promotes the invasion of tumor cells by suppressing a subset of genes with selective recruitment of corepressor complexes.	('depletion', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('suppressing', 'NegReg', (178, 189))	('CK2', 'Gene', (109, 112))	('promotes', 'PosReg', (138, 146))	('tumor', 'Disease', (163, 168))	('CK2', 'Gene', '13000', (109, 112))	('Snail1', 'Gene', (66, 72))	('Snail1', 'Gene', '6615', (66, 72))
472028	33652661	Dysregulated lncRNAs are involved in all hallmarks of cancer including metabolic alterations.	('involved', 'Reg', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('lncRNAs', 'Protein', (13, 20))	('metabolic', 'MPA', (71, 80))	('Dysregulated', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
472090	33652661	In contrast, tumor-suppressive lncRNA RAD51 Antisense RNA1 (RAD51-AS1) regulates CRC progression by acting as a competing endogenous RNA (ceRNA) for miR-29b-3p and miR-29c-3p.	('tumor', 'Disease', (13, 18))	('RAD51', 'Gene', (38, 43))	('regulates', 'Reg', (71, 80))	('CRC progression', 'CPA', (81, 96))	('RAD51', 'Gene', '5888', (38, 43))	('miR-29b-3p', 'Var', (149, 159))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('AS1', 'Gene', '5729', (66, 69))	('AS1', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('RAD51', 'Gene', (60, 65))	('miR-29c-3p', 'Var', (164, 174))	('RAD51', 'Gene', '5888', (60, 65))
472096	33652661	In the molecular context, lncARSR sponges miR-34a-5p and, consequently, enhances hexokinase 1 (HK1)-mediated aerobic glycolysis in vitro and in vivo.	('HK1', 'Gene', '3098', (95, 98))	('HK1', 'Gene', (95, 98))	('hexokinase 1', 'Gene', (81, 93))	('miR-34a-5p', 'Var', (42, 52))	('enhances', 'PosReg', (72, 80))	('hexokinase 1', 'Gene', '3098', (81, 93))
472118	33652661	Mechanistically, LINC01554 expression is inhibited by miR-365a-3p at the transcriptional level.	('expression', 'MPA', (27, 37))	('inhibited', 'NegReg', (41, 50))	('miR-365a-3p', 'Var', (54, 65))	('LINC01554', 'Gene', (17, 26))	('LINC01554', 'Gene', '202299', (17, 26))
472125	33652661	Additionally, HOTAIR might act as a decoy of miR-130a-3p, which normally targets HIF1alpha.	('HIF1alpha', 'Gene', (81, 90))	('HOTAIR', 'Gene', '100124700', (14, 20))	('HIF1alpha', 'Gene', '3091', (81, 90))	('miR-130a-3p', 'Var', (45, 56))	('HOTAIR', 'Gene', (14, 20))
472129	33652661	RAET1K silencing significantly suppressed HCC cell proliferation and invasion.	('HCC cell proliferation', 'CPA', (42, 64))	('invasion', 'CPA', (69, 77))	('suppressed', 'NegReg', (31, 41))	('RAET1K', 'Gene', '646024', (0, 6))	('RAET1K', 'Gene', (0, 6))	('silencing', 'Var', (7, 16))	('HCC', 'Phenotype', 'HP:0001402', (42, 45))
472130	33652661	It also suppressed the hypoxia-induced increase in lactate concentration and glucose uptake while miR-100-5p inhibition reversed the effects of RAET1K silencing on hypoxia-induced glycolysis in HCC cells.	('silencing', 'Var', (151, 160))	('hypoxia', 'Disease', 'MESH:D000860', (23, 30))	('miR-100-5p', 'Chemical', '-', (98, 108))	('hypoxia', 'Disease', (23, 30))	('glucose uptake', 'MPA', (77, 91))	('HCC', 'Phenotype', 'HP:0001402', (194, 197))	('hypoxia', 'Disease', (164, 171))	('hypoxia', 'Disease', 'MESH:D000860', (164, 171))	('glucose', 'Chemical', 'MESH:D005947', (77, 84))	('RAET1K', 'Gene', '646024', (144, 150))	('RAET1K', 'Gene', (144, 150))	('lactate', 'Chemical', 'MESH:D019344', (51, 58))	('lactate concentration', 'MPA', (51, 72))	('suppressed', 'NegReg', (8, 18))
472142	33652661	HCC cells treated with a high glucose concentration were shown to have an increased expression of miR-483-3p and a decreased expression of lncRNA maternally expressed gene 3 (MEG3).	('high glucose', 'Phenotype', 'HP:0003074', (25, 37))	('miR-483-3p', 'Chemical', '-', (98, 108))	('decreased', 'NegReg', (115, 124))	('glucose', 'Chemical', 'MESH:D005947', (30, 37))	('increased', 'PosReg', (74, 83))	('expression', 'MPA', (125, 135))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('MEG3', 'Gene', (175, 179))	('expression', 'MPA', (84, 94))	('MEG3', 'Gene', '55384', (175, 179))	('miR-483-3p', 'Var', (98, 108))
472145	33652661	When MEG3 is downregulated, overexpressed miR-483-3p suppresses ERp29 expression.	('ERp29', 'Gene', (64, 69))	('suppresses', 'NegReg', (53, 63))	('MEG3', 'Gene', (5, 9))	('ERp29', 'Gene', '10961', (64, 69))	('downregulated', 'NegReg', (13, 26))	('miR-483-3p', 'Var', (42, 52))	('MEG3', 'Gene', '55384', (5, 9))	('miR-483-3p', 'Chemical', '-', (42, 52))
472152	33652661	Aerobic glycolysis was efficiently elevated by PDK1 overexpression while the mitochondrial respiration was inhibited.	('PDK1', 'Gene', '5170', (47, 51))	('Aerobic glycolysis', 'MPA', (0, 18))	('PDK1', 'Gene', (47, 51))	('overexpression', 'Var', (52, 66))	('elevated', 'PosReg', (35, 43))
472216	33652661	found that lncRNA antisense non-coding RNA at the INK4 locus (ANRIL) is overexpressed in acute myeloid leukemia (AML) patients and promotes disease development and progression via the modulation of glucose metabolism.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (95, 111))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('ANRIL', 'Gene', '100048912', (62, 67))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('AML', 'Phenotype', 'HP:0004808', (113, 116))	('AML', 'Disease', (113, 116))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (89, 111))	('glucose metabolism', 'Disease', (198, 216))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (89, 111))	('ANRIL', 'Gene', (62, 67))	('promotes', 'PosReg', (131, 139))	('disease development', 'CPA', (140, 159))	('progression', 'CPA', (164, 175))	('overexpressed', 'PosReg', (72, 85))	('glucose metabolism', 'Disease', 'MESH:D044882', (198, 216))	('INK4', 'Gene', '1029', (50, 54))	('modulation', 'Reg', (184, 194))	('acute myeloid leukemia', 'Disease', (89, 111))	('lncRNA antisense non-coding RNA', 'Var', (11, 42))	('INK4', 'Gene', (50, 54))	('patients', 'Species', '9606', (118, 126))
472226	33652661	The knockdown of LINP1 expression remarkably suppresses the glucose uptake and AML cell maintenance.	('AML', 'Disease', (79, 82))	('AML', 'Phenotype', 'HP:0004808', (79, 82))	('glucose', 'Chemical', 'MESH:D005947', (60, 67))	('LINP1', 'Gene', '108570035', (17, 22))	('LINP1', 'Gene', (17, 22))	('AML', 'Disease', 'MESH:D015470', (79, 82))	('suppresses', 'NegReg', (45, 55))	('knockdown', 'Var', (4, 13))	('glucose uptake', 'CPA', (60, 74))
472247	33652661	Furthermore, overexpressed LINC00174 leads to an increased cell proliferation, tumor growth, migration, invasion and glycolysis of glioma cells.	('glioma', 'Disease', (131, 137))	('tumor', 'Disease', (79, 84))	('migration', 'CPA', (93, 102))	('increased', 'PosReg', (49, 58))	('glycolysis', 'CPA', (117, 127))	('cell proliferation', 'CPA', (59, 77))	('LINC00174', 'Gene', (27, 36))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('LINC00174', 'Gene', '285908', (27, 36))	('invasion', 'CPA', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('overexpressed', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
472258	33652661	SNHG1 regulates pleckstrin homology like domain family A member 1 (PHLDA1) expression by sponging miR-194, leading to an increased glioma cell glucose uptake, proliferation, migration, invasion, angiogenesis and in vivo tumor growth.	('glioma', 'Disease', (131, 137))	('PHLDA1', 'Gene', '22822', (67, 73))	('tumor', 'Disease', (220, 225))	('proliferation', 'CPA', (159, 172))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('migration', 'CPA', (174, 183))	('SNHG1', 'Gene', (0, 5))	('invasion', 'CPA', (185, 193))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('pleckstrin homology like domain family A member 1', 'Gene', '22822', (16, 65))	('increased', 'PosReg', (121, 130))	('PHLDA1', 'Gene', (67, 73))	('SNHG1', 'Gene', '23642', (0, 5))	('sponging', 'Var', (89, 97))	('angiogenesis', 'CPA', (195, 207))	('glucose', 'Chemical', 'MESH:D005947', (143, 150))	('pleckstrin homology like domain family A member 1', 'Gene', (16, 65))
472268	33652661	They reported inhibited glucose consumption, lactate production and cell viability of osteosarcoma cells upon TUG1 knockdown.	('lactate production', 'MPA', (45, 63))	('cell viability', 'CPA', (68, 82))	('glucose', 'Chemical', 'MESH:D005947', (24, 31))	('TUG1', 'Gene', '55000', (110, 114))	('TUG1', 'Gene', (110, 114))	('osteosarcoma', 'Disease', (86, 98))	('glucose consumption', 'MPA', (24, 43))	('osteosarcoma', 'Phenotype', 'HP:0002669', (86, 98))	('inhibited', 'NegReg', (14, 23))	('osteosarcoma', 'Disease', 'MESH:D012516', (86, 98))	('lactate', 'Chemical', 'MESH:D019344', (45, 52))	('knockdown', 'Var', (115, 124))
472276	33652661	The disruption of lncRNA HAND2-AS1 results in osteosarcoma cell proliferation through the alteration of glucose metabolism.	('results in', 'Reg', (35, 45))	('alteration', 'Reg', (90, 100))	('glucose metabolism', 'Disease', 'MESH:D044882', (104, 122))	('HAND2', 'Gene', (25, 30))	('osteosarcoma', 'Disease', (46, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (46, 58))	('disruption', 'Var', (4, 14))	('osteosarcoma', 'Disease', 'MESH:D012516', (46, 58))	('AS1', 'Gene', '5729', (31, 34))	('AS1', 'Gene', (31, 34))	('glucose metabolism', 'Disease', (104, 122))	('HAND2', 'Gene', '9464', (25, 30))
472288	33652661	Mechanistically, AC020978 directly interacts with PKM2 and enhances the stability of this protein, which is crucial for the Warburg effect.	('stability', 'MPA', (72, 81))	('AC020978', 'Var', (17, 25))	('PKM2', 'Gene', (50, 54))	('enhances', 'PosReg', (59, 67))	('PKM2', 'Gene', '5315', (50, 54))	('interacts', 'Interaction', (35, 44))
472289	33652661	In addition, AC020978 promotes the nuclear translocation of PKM2.	('promotes', 'PosReg', (22, 30))	('PKM2', 'Gene', '5315', (60, 64))	('nuclear translocation', 'MPA', (35, 56))	('AC020978', 'Var', (13, 21))	('PKM2', 'Gene', (60, 64))
472299	33652661	MALAT1 knockdown decreases glucose consumption and lactate production.	('decreases glucose consumption', 'Disease', (17, 46))	('lactate production', 'MPA', (51, 69))	('MALAT1', 'Gene', '378938', (0, 6))	('MALAT1', 'Gene', (0, 6))	('decreases glucose consumption', 'Disease', 'MESH:D014397', (17, 46))	('lactate', 'Chemical', 'MESH:D019344', (51, 58))	('knockdown', 'Var', (7, 16))
472310	33652661	Overexpression is associated with advanced stage cancer, a shorter OS (p = 0.027), DFS (p = 0.033), frequent recurrences, increased cell proliferation and transformation via a stem-like cancer cell induction.	('transformation', 'CPA', (155, 169))	('DFS', 'CPA', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('shorter', 'NegReg', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('Overexpression', 'Var', (0, 14))	('cell proliferation', 'CPA', (132, 150))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('increased', 'PosReg', (122, 131))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
472313	33652661	Cheng and colleagues identified a novel lncRNA lnc-p23154 associated with oral squamous cell carcinoma (OSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('associated', 'Reg', (58, 68))	('oral squamous cell carcinoma', 'Disease', (74, 102))	('lnc-p23154', 'Var', (47, 57))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 102))
472314	33652661	Additionally, they found that lnc-p23154 is involved in OSCC glycolysis where it upregulates GLUT-1 expression.	('OSCC', 'Disease', (56, 60))	('involved', 'Reg', (44, 52))	('GLUT-1', 'Gene', (93, 99))	('GLUT-1', 'Gene', '6513', (93, 99))	('upregulates', 'PosReg', (81, 92))	('expression', 'MPA', (100, 110))	('lnc-p23154', 'Var', (30, 40))
472315	33652661	Lnc-p23154 is primarily located in the nucleus and binds to the promoter region of miR-378a-3p, which represses GLUT-1 expression.	('expression', 'MPA', (119, 129))	('Lnc-p23154', 'Var', (0, 10))	('GLUT-1', 'Gene', (112, 118))	('GLUT-1', 'Gene', '6513', (112, 118))	('represses', 'NegReg', (102, 111))
472316	33652661	Therefore, lnc-p23154 plays an important role in GLUT-1-mediated glycolysis by inhibiting miR-378a-3p transcription and accelerating OSCC metastasis.	('GLUT-1', 'Gene', (49, 55))	('lnc-p23154', 'Var', (11, 21))	('GLUT-1', 'Gene', '6513', (49, 55))	('accelerating', 'PosReg', (120, 132))	('inhibiting', 'NegReg', (79, 89))	('OSCC', 'Disease', (133, 137))	('miR-378a-3p transcription', 'MPA', (90, 115))
472323	33652661	Metabolic disarrangement is associated with poor outcomes in certain cancers.	('Metabolic disarrangement', 'Var', (0, 24))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
472332	33652661	A blockade of these mechanisms may alleviate cancer progression, therefore rendering lncRNAs a promising therapeutic target.	('blockade', 'Var', (2, 10))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('alleviate', 'NegReg', (35, 44))
472351	32256808	Fan et al revealed that miR-125b inhibits cell proliferation and induces cell apoptosis in ESCC by targeting Bcl2 modifying factor.	('cell apoptosis', 'CPA', (73, 87))	('Bcl2 modifying factor', 'Gene', (109, 130))	('targeting', 'Reg', (99, 108))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('ESCC', 'Disease', (91, 95))	('induces', 'Reg', (65, 72))	('cell proliferation', 'CPA', (42, 60))	('miR-125b', 'Var', (24, 32))	('Bcl2 modifying factor', 'Gene', '90427', (109, 130))	('ESCC', 'Phenotype', 'HP:0011459', (91, 95))	('inhibits', 'NegReg', (33, 41))	('miR-125b', 'Chemical', '-', (24, 32))
472352	32256808	In another clinical study by Dong et al, miR-216 a/b was demonstrated to be inversely correlated with lymph node metastasis and the Tumor-Node-Metastasis (TNM) stage of ESCC, which indicated that plasma miRNA-216a/b may serve as potential biomarkers for the diagnosis of ESCC, and that dysregulation of miR-216a/b may be involved in the progression of ESCC.	('si', 'Chemical', 'MESH:D012825', (344, 346))	('miR', 'Gene', '220972', (203, 206))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('ESCC', 'Phenotype', 'HP:0011459', (271, 275))	('miR-216 a/b', 'Gene', (41, 52))	('si', 'Chemical', 'MESH:D012825', (264, 266))	('ESCC', 'Phenotype', 'HP:0011459', (169, 173))	('si', 'Chemical', 'MESH:D012825', (150, 152))	('miR', 'Gene', '220972', (41, 44))	('ESCC', 'Disease', (271, 275))	('ESCC', 'Phenotype', 'HP:0011459', (352, 356))	('miR', 'Gene', (203, 206))	('miR', 'Gene', '220972', (303, 306))	('miR-216a/b', 'Gene', (303, 313))	('ESCC', 'Disease', (169, 173))	('ESCC', 'Disease', (352, 356))	('miR', 'Gene', (41, 44))	('Tumor', 'Phenotype', 'HP:0002664', (132, 137))	('miR', 'Gene', (303, 306))	('dysregulation', 'Var', (286, 299))	('involved', 'Reg', (321, 329))	('miR-216 a/b', 'Gene', '406998', (41, 52))	('miR-216a/b', 'Gene', '406998', (303, 313))
472417	32256808	EC9706 with blank treated or stably transfected with miR-NC or miR-144 lentivirus (1.5x106 in 0.2 ml) were injected subcutaneously into the right dorsal flank of each mouse.	('EC9706', 'Var', (0, 6))	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('mouse', 'Species', '10090', (167, 172))
472434	32256808	There was no statistically significant association observed regarding the miR-144, TIGAR expression and sex, age and tumor grading.	('miR-144', 'Var', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('TIGAR', 'Gene', (83, 88))	('tumor', 'Disease', (117, 122))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('TIGAR', 'Gene', '57103', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('si', 'Chemical', 'MESH:D012825', (27, 29))
472444	32256808	Compared with the control groups, miR-144 overexpression markedly inhibited tumor volume, which indicated that miR-144 could inhibit ESCC tumor growth in vivo (Fig.	('inhibit', 'NegReg', (125, 132))	('ESCC tumor', 'Disease', (133, 143))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('ESCC', 'Phenotype', 'HP:0011459', (133, 137))	('ESCC tumor', 'Disease', 'MESH:D004938', (133, 143))	('inhibited', 'NegReg', (66, 75))	('miR-144', 'Var', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
472446	32256808	Furthermore, the results of IHC staining revealed that miR-144 inhibited Ki-67 expression in vivo (Fig.	('Ki-67', 'Gene', '17345', (73, 78))	('expression', 'MPA', (79, 89))	('Ki-67', 'Gene', (73, 78))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('inhibited', 'NegReg', (63, 72))	('miR-144', 'Var', (55, 62))
472449	32256808	Dual luciferase reporter gene assays revealed that miR-144 effectively weakened the luciferase activity of TIGAR wild-type by ~50% (P<0.05).	('luciferase', 'Enzyme', (84, 94))	('TIGAR', 'Gene', (107, 112))	('weakened', 'NegReg', (71, 79))	('miR-144', 'Var', (51, 58))	('activity', 'MPA', (95, 103))	('TIGAR', 'Gene', '57103', (107, 112))
472450	32256808	However, miR-144 did not affect the luciferase activity of TIGAR with mutant type 3'UTR (Fig.	('TIGAR', 'Gene', (59, 64))	('type', 'Gene', (77, 81))	('mutant', 'Var', (70, 76))	('luciferase', 'Enzyme', (36, 46))	('TIGAR', 'Gene', '57103', (59, 64))
472451	32256808	PCR analysis confirmed the successful knockdown of TIGAR using the si-TIGAR (Fig.	('si', 'Chemical', 'MESH:D012825', (67, 69))	('TIGAR', 'Gene', (70, 75))	('TIGAR', 'Gene', (51, 56))	('TIGAR', 'Gene', '57103', (51, 56))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('TIGAR', 'Gene', '57103', (70, 75))	('knockdown', 'Var', (38, 47))
472460	32256808	Furthermore, it was revealed that miR-144 directly targeted TIGAR in ESCC cells.	('targeted', 'Reg', (51, 59))	('miR-144', 'Var', (34, 41))	('TIGAR', 'Gene', '57103', (60, 65))	('ESCC', 'Phenotype', 'HP:0011459', (69, 73))	('TIGAR', 'Gene', (60, 65))
472467	32256808	A recent study by Gao et al demonstrated that the miR-144/451 cluster may serve an important role in the progression of ESCC and may be considered as a biomarker for the detection of ESCC at an early stage of disease.	('ESCC', 'Phenotype', 'HP:0011459', (183, 187))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('ESCC', 'Disease', (120, 124))	('miR-144/451', 'Var', (50, 61))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('ESCC', 'Phenotype', 'HP:0011459', (120, 124))	('ESCC', 'Disease', (183, 187))
472473	32256808	Furthermore, it was demonstrated that siRNA-mediated TIGAR knockdown was able to obtain similar inhibitory outcomes as with the overexpression of miR-144.	('si', 'Chemical', 'MESH:D012825', (138, 140))	('TIGAR', 'Gene', '57103', (53, 58))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('TIGAR', 'Gene', (53, 58))	('si', 'Chemical', 'MESH:D012825', (38, 40))	('knockdown', 'Var', (59, 68))
472476	32256808	Silencing of TIGAR in glioblastoma cell lines was revealed to cause higher levels of Fru-2,6-P2 in these cells, increase glycolysis and lead to the accumulation of reactive oxygen species, which finally promoted cell death.	('reactive oxygen species', 'MPA', (164, 187))	('Fru', 'Gene', '9278', (85, 88))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('glioblastoma', 'Disease', (22, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('higher', 'PosReg', (68, 74))	('promoted', 'PosReg', (203, 211))	('Fru', 'Gene', (85, 88))	('increase', 'PosReg', (112, 120))	('cell death', 'CPA', (212, 222))	('accumulation', 'PosReg', (148, 160))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (164, 187))	('TIGAR', 'Gene', '57103', (13, 18))	('glycolysis', 'MPA', (121, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('Silencing', 'Var', (0, 9))	('TIGAR', 'Gene', (13, 18))
472482	32256808	Additional groups, such as miR-144+ overexpression of TIGAR were also not investigated, which would be useful in confirming the results of the present study and should be the focus of future studies.	('TIGAR', 'Gene', '57103', (54, 59))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('miR-144+', 'Var', (27, 35))	('TIGAR', 'Gene', (54, 59))
472506	31002675	Mutations of the tumor suppressor gene TP53, rare in IM but prevalent in HGD and ECA/GEJ Aca, are associated with a worse prognosis in cancer patients.	('HGD', 'Disease', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer', 'Disease', (135, 141))	('tumor', 'Disease', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ECA/GEJ', 'Disease', (81, 88))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('patients', 'Species', '9606', (142, 150))	('associated', 'Reg', (98, 108))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('TP53', 'Gene', (39, 43))
472513	31002675	We have shown that deletion of the maspin gene in mice results in embryonic lethality, and conditional maspin knockout leads to context-dependent epithelial pathologies, including hyperplasia of the mammary and glands as well as adenocarcinoma of the lung.	('leads to', 'Reg', (119, 127))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (229, 255))	('hyperplasia', 'Disease', (180, 191))	('deletion', 'Var', (19, 27))	('embryonic lethality', 'Disease', 'MESH:D020964', (66, 85))	('embryonic lethality', 'Disease', (66, 85))	('maspin', 'Gene', (35, 41))	('hyperplasia', 'Disease', 'MESH:D006965', (180, 191))	('hyperplasia of the mammary', 'Phenotype', 'HP:0010313', (180, 206))	('mice', 'Species', '10090', (50, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('knockout', 'Var', (110, 118))	('adenocarcinoma of the lung', 'Disease', (229, 255))
472542	31002675	In particular, TP53 deletion or mutation (signified by increased TP53 stability and IHC signal) occurs frequently in advanced ECA/GEJ Aca.	('TP53', 'Gene', '7157', (65, 69))	('ECA/GEJ Aca', 'Disease', (126, 137))	('TP53', 'Gene', (65, 69))	('increased', 'PosReg', (55, 64))	('TP53', 'Gene', '7157', (15, 19))	('deletion', 'Var', (20, 28))	('TP53', 'Gene', (15, 19))	('mutation', 'Var', (32, 40))
472573	30012096	In addition, we report ZNF750 and CDC27, of which the somatic statuses and the genetic burdens consistently influence the activities of specific mutational signatures in ESCC: the somatic ZNF750 status is associated with the AID/APOBEC-related mutational process (FDR = 0.0637); the somatic CDC27 copy-number is associated with the "NpCpG" (FDR = 0.00615) and the AID/APOBEC-related mutational processes (FDR = 8.69 x 10- 4).	('CDC27', 'Gene', (34, 39))	('associated', 'Reg', (312, 322))	('ZNF750', 'Gene', (23, 29))	('AID', 'Gene', (364, 367))	('AID', 'Gene', '57379', (364, 367))	('ZNF750', 'Gene', (188, 194))	('AID', 'Gene', '57379', (225, 228))	('AID', 'Gene', (225, 228))	('CDC27', 'Gene', '996', (291, 296))	('copy-number', 'Var', (297, 308))	('ZNF750', 'Gene', '79755', (23, 29))	('ZNF750', 'Gene', '79755', (188, 194))	('CDC27', 'Gene', (291, 296))	('associated', 'Reg', (205, 215))	('CDC27', 'Gene', '996', (34, 39))
472584	30012096	The mutational processes are represented by distinct patterns of frequencies of trinucleotide sequences surrounding the base of substitution, which is also known as the somatic mutational signatures.	('substitution', 'Var', (128, 140))	('trinucleotide', 'Chemical', '-', (80, 93))	('trinucleotide sequences', 'Var', (80, 103))
472587	30012096	For instance, the overall somatic mutational burden in melanoma is associated with germline MC1R status; and in breast cancer it is associated with the germline RAD51B status (rs2588809).	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('rs2588809', 'Mutation', 'rs2588809', (176, 185))	('RAD51B', 'Gene', '5890', (161, 167))	('MC1R', 'Gene', '4157', (92, 96))	('melanoma', 'Disease', (55, 63))	('germline', 'Var', (83, 91))	('associated', 'Reg', (67, 77))	('associated', 'Reg', (132, 142))	('RAD51B', 'Gene', (161, 167))	('rs2588809', 'Var', (176, 185))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('MC1R', 'Gene', (92, 96))
472589	30012096	These studies suggest that both germline and somatic alterations can drive the mutational processes in cancers and the driver genes may play a decisive role in the development of the disease.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutational processes', 'MPA', (79, 99))	('alterations', 'Var', (53, 64))	('drive', 'Reg', (69, 74))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
472592	30012096	The "NpCpG" signature (characterized by C > T at NpCpG trinucleotide), which has been previously reported in ESCC, is highly similar to the COSMIC signature 1 (deamination of 5-methycytosine; CS = 0.93) and signature 6 (defective DNA mismatch repair; CS = 0.86).	('NpCpG', 'Gene', (49, 54))	('5-methycytosine', 'Chemical', '-', (175, 190))	('deamination of 5-methycytosine', 'MPA', (160, 190))	('C > T', 'Var', (40, 45))	('trinucleotide', 'Chemical', '-', (55, 68))	('CS', 'Chemical', '-', (192, 194))	('CS', 'Chemical', '-', (251, 253))
472593	30012096	The "AID/APOBEC-1" signature (C > G at TpCpN trinucleotide) and "AID/APOBEC-2" signature (C > T at TpCpN trinucleotide) match the COSMIC signature 13 (CS = 0.95) and signature 2 (CS = 0.84), respectively.	('C > G', 'Var', (30, 35))	('AID', 'Gene', '57379', (65, 68))	('APOBEC-1', 'Gene', '339', (9, 17))	('trinucleotide', 'Chemical', '-', (45, 58))	('APOBEC-1', 'Gene', (9, 17))	('CS', 'Chemical', '-', (179, 181))	('AID', 'Gene', '57379', (5, 8))	('AID', 'Gene', (5, 8))	('trinucleotide', 'Chemical', '-', (105, 118))	('CS', 'Chemical', '-', (151, 153))	('APOBEC-2', 'Gene', '10930', (69, 77))	('AID', 'Gene', (65, 68))	('APOBEC-2', 'Gene', (69, 77))
472597	30012096	CDC27 somatic amplification is significantly enriched in this subtype (n = 22, FDR = 0.0682).	('CDC27', 'Gene', '996', (0, 5))	('somatic amplification', 'Var', (6, 27))	('CDC27', 'Gene', (0, 5))
472599	30012096	The non-synonymous mutations of ZNF750 (n = 8, FDR = 0.0471; Fig.	('ZNF750', 'Gene', '79755', (32, 38))	('ZNF750', 'Gene', (32, 38))	('non-synonymous mutations', 'Var', (4, 28))
472601	30012096	Besides, subtype 3 also significantly enriches TP53 mutations (n = 89, FDR = 7.38 x 10- 7; Fig.	('mutations', 'Var', (52, 61))	('enriches', 'Reg', (38, 46))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))
472603	30012096	Our results suggest two new candidate genes: FAM90A1 (family with sequence similarity 90, member A1, MIM: 613041, FDR < 1 x 10- 10) and TNRC6A (trinucleotide repeat containing 6A, MIM: 610739, FDR = 9 x 10- 10).	('TNRC6A', 'Gene', (136, 142))	('trinucleotide', 'Chemical', '-', (144, 157))	('MIM: 613041', 'Var', (101, 112))	('FAM90A1', 'Gene', '55138', (45, 52))	('TNRC6A', 'Gene', '27327', (136, 142))	('FAM90A1', 'Gene', (45, 52))
472604	30012096	For FAM90A1, we report an in-frame insertion (c.1031_1032insCGT [p.T344_S345insV]), which presents in 8 patients.	('p.T344_S345insV', 'Mutation', 'rs71265055', (65, 80))	('c.1031_1032insCGT [p.T344_S345insV]', 'Var', (46, 81))	('FAM90A1', 'Gene', '55138', (4, 11))	('c.1031_1032insCGT', 'Mutation', 'rs71265055', (46, 63))	('patients', 'Species', '9606', (104, 112))	('FAM90A1', 'Gene', (4, 11))
472605	30012096	And for TNRC6A, we report an in-frame deletion (c.333_344del12 [p.P115_Q118delPQPQ]) which presents in seven patients (Additional file 3: Table S2).	('patients', 'Species', '9606', (109, 117))	('p.P115_Q118del', 'DELETION', 'None', (64, 78))	('c.333_344del12', 'Mutation', 'c.333_344del12', (48, 62))	('TNRC6A', 'Gene', (8, 14))	('p.P115_Q118del', 'Var', (64, 78))	('TNRC6A', 'Gene', '27327', (8, 14))
472607	30012096	For example, TNRC6A mutation is suggestively associated with poor overall survival in subtype 1 (HR = 2.77, 95% CI = 0.982-7.79, P = 0.0541); whereas the somatic statuses of FAM90A1 (HR = 2.62, 95% CI = 1.04-5.58, P = 0.0407), FBXW7 (HR = 3.13, 95% CI = 1.13-8.7, P = 0.0281) and PIK3CA (HR = 6.96, 95% CI = 2.7-17.9, P = 5.76 x 10- 5) are significantly predictive in subtype 3 (Fig.	('subtype 3', 'Disease', (368, 377))	('PIK3CA', 'Gene', '5290', (280, 286))	('TNRC6A', 'Gene', (13, 19))	('TNRC6A', 'Gene', '27327', (13, 19))	('mutation', 'Var', (20, 28))	('FBXW7', 'Gene', '55294', (227, 232))	('FBXW7', 'Gene', (227, 232))	('FAM90A1', 'Gene', '55138', (174, 181))	('FAM90A1', 'Gene', (174, 181))	('PIK3CA', 'Gene', (280, 286))
472609	30012096	We noticed that CDC27 (17q21.32) is both amplified in 15.90% (n = 48; FDR = 2.68 x 10- 10) and deleted in 51.6% (n = 156; FDR = 9.05 x 10- 22) of the patients (Fig.	('CDC27', 'Gene', '996', (16, 21))	('patients', 'Species', '9606', (150, 158))	('deleted', 'Var', (95, 102))	('CDC27', 'Gene', (16, 21))
472614	30012096	As for specific subtypes of substitutions, the frequency of C > A is higher in CHS (FDR = 0.00119) whereas the T > C frequency is higher in CHB (FDR = 0.00154; Fig.	('CHS', 'Disease', (79, 82))	('CHS', 'Disease', 'MESH:D002609', (79, 82))	('T > C', 'Var', (111, 116))	('C > A', 'Var', (60, 65))
472618	30012096	We find that the activity of the "NpCpG" signature increases in tumors carrying non-synonymous somatic PTCH1 mutations (FDR = 0.0895; Fig.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('PTCH1', 'Gene', '5727', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('PTCH1', 'Gene', (103, 108))	('increases', 'PosReg', (51, 60))	('mutations', 'Var', (109, 118))	('activity', 'MPA', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
472619	30012096	3a); but decreases in tumors with non-synonymous somatic mutations in TP53 (FDR = 1.67 x 10- 4; Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('non-synonymous somatic mutations', 'Var', (34, 66))	('TP53', 'Gene', '7157', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('decreases', 'NegReg', (9, 18))	('TP53', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
472621	30012096	Moreover, the activity of the "AID/APOBEC-2" signature activity significantly increases with the somatic mutations of FBXW7 (FDR = 0.0283; Fig.	('FBXW7', 'Gene', (118, 123))	('AID', 'Gene', (31, 34))	('activity', 'MPA', (55, 63))	('activity', 'MPA', (14, 22))	('AID', 'Gene', '57379', (31, 34))	('FBXW7', 'Gene', '55294', (118, 123))	('mutations', 'Var', (105, 114))	('increases', 'PosReg', (78, 87))	('APOBEC-2', 'Gene', '10930', (35, 43))	('APOBEC-2', 'Gene', (35, 43))
472626	30012096	In particular, the somatic TP53 status is significantly correlated with high frequency of C > A, C > T, T > A and low frequency of T > C substitutions (FDR < 0.1; Additional file 9: Figure S4b).	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('T > A', 'Var', (104, 109))	('C > T', 'Var', (97, 102))	('C > A', 'Var', (90, 95))
472627	30012096	For instance, MYC amplifications, CDC27 deletions and FHIT deletions are all significantly associated with the higher burden of SNVs (FDR < 0.1; Additional file 9: Figure S4c).	('CDC27', 'Gene', (34, 39))	('FHIT', 'Gene', (54, 58))	('deletions', 'Var', (40, 49))	('MYC', 'Gene', (14, 17))	('FHIT', 'Gene', '2272', (54, 58))	('deletions', 'Var', (59, 68))	('MYC', 'Gene', '4609', (14, 17))	('CDC27', 'Gene', '996', (34, 39))	('associated', 'Reg', (91, 101))
472628	30012096	And the CDC27 amplifications, alone, is associated with lower frequency of C > A substitution (FDR = 0.00216; Additional file 9: Figure S4d).	('C >', 'Var', (75, 78))	('substitution', 'Var', (81, 93))	('CDC27', 'Gene', '996', (8, 13))	('amplifications', 'Var', (14, 28))	('CDC27', 'Gene', (8, 13))	('lower', 'NegReg', (56, 61))
472629	30012096	As for the mutational signatures, the activity of the "NpCpG" signature increases significantly with somatic CDC27 amplifications (FDR = 0.00615; Fig.	('activity', 'MPA', (38, 46))	('increases', 'PosReg', (72, 81))	('amplifications', 'Var', (115, 129))	('CDC27', 'Gene', '996', (109, 114))	('CDC27', 'Gene', (109, 114))
472633	30012096	And the genetic burden of CDC27 is associated with both the activity of the "NpCpG" signature (FDR = 7.93 x 10- 9; Fig.	('associated', 'Reg', (35, 45))	('CDC27', 'Gene', '996', (26, 31))	('genetic burden', 'Var', (8, 22))	('activity', 'MPA', (60, 68))	('CDC27', 'Gene', (26, 31))
472637	30012096	As results, four genes (DNAH11, CHEK2, HECTD4 and HEATR3) are associated with the activities of either mutation signatures or specific types of substitutions (FDR < 0.1, Additional file 12: Figure S7a and b).	('HECTD4', 'Gene', (39, 45))	('activities', 'MPA', (82, 92))	('associated', 'Reg', (62, 72))	('HECTD4', 'Gene', '283450', (39, 45))	('DNAH11', 'Gene', (24, 30))	('CHEK2', 'Gene', (32, 37))	('CHEK2', 'Gene', '11200', (32, 37))	('HEATR3', 'Gene', (50, 56))	('HEATR3', 'Gene', '55027', (50, 56))	('substitutions', 'Var', (144, 157))	('DNAH11', 'Gene', '8701', (24, 30))
472638	30012096	The activity of the "AID/APOBEC-1" signature is associated with the genetic burden CHEK2 (22q12.1; FDR = 0.0406), HEATR3 (16q12.1; FDR = 0.0406) and SMG6 (17p13.3; FDR = 0.0108; Additional file 12: Figure S7c).	('AID', 'Gene', '57379', (21, 24))	('SMG6', 'Gene', (149, 153))	('16q12.1', 'Var', (122, 129))	('CHEK2', 'Gene', '11200', (83, 88))	('CHEK2', 'Gene', (83, 88))	('HEATR3', 'Gene', (114, 120))	('HEATR3', 'Gene', '55027', (114, 120))	('SMG6', 'Gene', '23293', (149, 153))	('AID', 'Gene', (21, 24))	('activity', 'MPA', (4, 12))	('APOBEC-1', 'Gene', (25, 33))	('APOBEC-1', 'Gene', '339', (25, 33))
472640	30012096	As results, we verified the associations between the somatic TP53 mutations and the activities of the "NpCpG" signature (P = 2.21 x 10- 7; Fig.	('mutations', 'Var', (66, 75))	('associations', 'Interaction', (28, 40))	('activities', 'MPA', (84, 94))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
472646	30012096	The somatic landscape of the cancers are results of diverse mutational processes driven by both germline and somatic alterations in certain genes.	('alterations', 'Var', (117, 128))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))
472653	30012096	Recent studies claim that both germline and somatic variants can influence the mutational processes in cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutational processes', 'CPA', (79, 99))	('variants', 'Var', (52, 60))	('influence', 'Reg', (65, 74))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
472659	30012096	The driver mutations in cancer is often confounded by outnumbered passenger mutations, which can only be distinguished by systematic functional validation.	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))
472663	30012096	Similar associations between the population-genetical background and the somatic mutations is previously reported in prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('mutations', 'Var', (81, 90))	('prostate cancer', 'Disease', (117, 132))
472678	30012096	We intersected the resulting germline variants with the variants from the 1000 Genomes Project (TGP) phase 3 databases then performed principal component analysis in a combined cohort of 103 CHB and 105 CHS from TGP and 302 ESCC samples.	('CHS', 'Disease', (203, 206))	('CHS', 'Disease', 'MESH:D002609', (203, 206))	('variants', 'Var', (38, 46))
472681	30012096	We obtained the autosomal segments of copy-number changes using circular binary segmentation (CBS) and determined the somatic copy-number status of each segment by the log2-adjusted ratio-of-depth.	('changes', 'Var', (50, 57))	('CBS', 'Disease', (94, 97))	('CBS', 'Disease', 'MESH:D006712', (94, 97))	('copy-number', 'Var', (38, 49))
472685	30012096	ACR Alternate-allele Coverage Rate ANOVA Analysis of variance CBS Circular Binary Segmentation CHB Han Chinese in Beijing CHS Southern Han Chinese COSMIC Catalogue of Somatic Mutations in Cancer CS Cosine Similarity EAC Esophageal Adenocarcinoma EC Esophageal Cancer ESCC Esophageal Squamous Cell Carcinoma InDels Insertions and Deletions PPI Protein-protein Interaction SCNAs Somatic Copy-number Alterations SKAT SNP-set Kernel Association Test SMGs Significantly Mutated Genes SNVs Single Nucleotide Variants TGP The 1000 Genomes Project WES Whole-exome Sequencing QL conceived the study.	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (220, 245))	('CS', 'Chemical', '-', (195, 197))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (249, 266))	('Esophageal Adenocarcinoma', 'Disease', (220, 245))	('CHS', 'Disease', 'MESH:D002609', (122, 125))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (272, 306))	('Carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('CHS', 'Disease', (122, 125))	('Esophageal Squamous Cell Carcinoma', 'Disease', (272, 306))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (283, 306))	('Deletions', 'Var', (329, 338))	('Esophageal Cancer', 'Disease', (249, 266))	('Cancer', 'Phenotype', 'HP:0002664', (260, 266))	('CBS', 'Disease', 'MESH:D006712', (62, 65))	('Cancer', 'Phenotype', 'HP:0002664', (188, 194))	('EAC', 'Phenotype', 'HP:0011459', (216, 219))	('CBS', 'Disease', (62, 65))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (220, 245))
472690	29565465	We previously identified FAT1 as one of the significant mutant genes in esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (72, 106))	('mutant', 'Var', (56, 62))	('FAT1', 'Gene', '2195', (25, 29))	('esophageal squamous cell carcinoma', 'Disease', (72, 106))	('FAT1', 'Gene', (25, 29))
472691	29565465	In the present study, the knockdown of FAT1 expression in YSE2 and Colo680N cell lines was carried out by lentivirus, and we found that knockdown of FAT1 led to acceleration of cell migration and invasion.	('FAT1', 'Gene', '2195', (149, 153))	('invasion', 'CPA', (196, 204))	('FAT1', 'Gene', '2195', (39, 43))	('FAT1', 'Gene', (149, 153))	('knockdown', 'Var', (136, 145))	('FAT1', 'Gene', (39, 43))	('cell migration', 'CPA', (177, 191))	('acceleration', 'PosReg', (161, 173))
472692	29565465	Furthermore, we detected the cell adhesive force and cell elasticity force by atomic force microscopy (AFM) and found that the suppression of endogenous expression of FAT1 led to a decrease in the cell adhesive force and increase in the cell elasticity force compared with the control groups.	('cell adhesive force', 'CPA', (197, 216))	('FAT1', 'Gene', '2195', (167, 171))	('decrease', 'NegReg', (181, 189))	('increase', 'PosReg', (221, 229))	('suppression', 'Var', (127, 138))	('FAT1', 'Gene', (167, 171))	('cell elasticity force', 'CPA', (237, 258))
472700	29565465	Among these SMGs, FAT1 was mutated in 15% of ESCC tumors.	('FAT1', 'Gene', (18, 22))	('mutated', 'Var', (27, 34))	('ESCC tumors', 'Disease', (45, 56))	('ESCC tumors', 'Disease', 'MESH:D004938', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('FAT1', 'Gene', '2195', (18, 22))
472714	29565465	Moreover, the cell adhesive force and cell elasticity force after FAT1 knockdown were detected by AFM.	('FAT1', 'Gene', (66, 70))	('detected', 'Reg', (86, 94))	('knockdown', 'Var', (71, 80))	('cell elasticity force', 'CPA', (38, 59))	('FAT1', 'Gene', '2195', (66, 70))	('cell adhesive force', 'CPA', (14, 33))
472742	29565465	We found that FAT1 was mutated frequently in ESCC.	('FAT1', 'Gene', '2195', (14, 18))	('mutated', 'Var', (23, 30))	('ESCC', 'Disease', (45, 49))	('FAT1', 'Gene', (14, 18))
472743	29565465	In addition, we analyzed several types of squamous cell carcinomas in a TCGA database using cBioPortal, and found that FAT1 was mutated frequently in squamous cell carcinomas (Fig.	('squamous cell carcinomas', 'Disease', (150, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('mutated', 'Var', (128, 135))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (150, 174))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (42, 66))	('squamous cell carcinomas', 'Disease', (42, 66))	('FAT1', 'Gene', '2195', (119, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (42, 66))	('FAT1', 'Gene', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (150, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
472744	29565465	In ESCC, the frequency of FAT1 mutations was 11.7%, in head and neck squamous cell carcinoma (HNSCC), the frequency of FAT1 mutations was 21.7%, in lung squamous cell carcinoma (LSCC), the frequency of FAT1 mutations was 14.6%, and in oral squamous cell carcinoma (OSCC), the frequency of FAT1 mutations was 30%.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (240, 263))	('FAT1', 'Gene', '2195', (26, 30))	('FAT1', 'Gene', '2195', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('FAT1', 'Gene', (202, 206))	('neck squamous cell carcinoma', 'Disease', (64, 92))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (64, 92))	('FAT1', 'Gene', (289, 293))	('ESCC', 'Disease', (3, 7))	('mutations', 'Var', (31, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('FAT1', 'Gene', '2195', (202, 206))	('FAT1', 'Gene', (26, 30))	('FAT1', 'Gene', (119, 123))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (235, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('FAT1', 'Gene', '2195', (289, 293))	('mutations', 'Var', (124, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('oral squamous cell carcinoma', 'Disease', (235, 263))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 176))	('lung squamous cell carcinoma', 'Disease', (148, 176))
472753	29565465	The results showed that FAT1 depletion led to a significant increase in cell migration and invasion abilities in the YSE2 and Colo680N cell lines (Fig.	('depletion', 'Var', (29, 38))	('cell migration', 'CPA', (72, 86))	('increase', 'PosReg', (60, 68))	('FAT1', 'Gene', '2195', (24, 28))	('invasion abilities', 'CPA', (91, 109))	('FAT1', 'Gene', (24, 28))
472754	29565465	In the present study, AFM was used to visualize the morphology of YSE2 and Colo680N FAT1-knockdown cells in comparison to the corresponding control groups, respectively.	('Colo680N', 'Var', (75, 83))	('FAT1', 'Gene', '2195', (84, 88))	('FAT1', 'Gene', (84, 88))
472755	29565465	The results demonstrated that the cells became relatively thinner following FAT1 knockdown.	('FAT1', 'Gene', '2195', (76, 80))	('knockdown', 'Var', (81, 90))	('FAT1', 'Gene', (76, 80))	('thinner', 'NegReg', (58, 65))
472757	29565465	The results indicate that the cell surface may be smoother after knockdown of FAT1 (Fig.	('FAT1', 'Gene', (78, 82))	('knockdown', 'Var', (65, 74))	('FAT1', 'Gene', '2195', (78, 82))
472764	29565465	In glioblastoma multiforme, colorectal cancer and head and neck cancer, FAT1 was identified as a tumor suppressor, for which somatic mutations lead to aberrant Wnt signaling pathway activation.	('tumor suppressor', 'Gene', (97, 113))	('FAT1', 'Gene', '2195', (72, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('tumor suppressor', 'Gene', '7248', (97, 113))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (133, 142))	('head and neck cancer', 'Phenotype', 'HP:0012288', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('glioblastoma multiforme', 'Disease', (3, 26))	('activation', 'PosReg', (182, 192))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (3, 26))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('Wnt signaling pathway', 'Pathway', (160, 181))	('head and neck cancer', 'Disease', 'MESH:D006258', (50, 70))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FAT1', 'Gene', (72, 76))	('lead to', 'Reg', (143, 150))	('colorectal cancer', 'Disease', (28, 45))
472773	29565465	Lian et al reported that artesunate attenuates cellular migration and invasion by affecting cellular mechanical properties in glioma.	('affecting', 'Reg', (82, 91))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('artesunate', 'Var', (25, 35))	('artesunate', 'Chemical', 'MESH:D000077332', (25, 35))	('cellular mechanical properties', 'CPA', (92, 122))	('Lian', 'Species', '155640', (0, 4))	('glioma', 'Disease', (126, 132))	('attenuates', 'NegReg', (36, 46))	('cellular migration', 'CPA', (47, 65))	('invasion', 'CPA', (70, 78))
472778	29565465	In the present study, we verified that FAT1 knockdown effectively accelerated cell migration and invasion.	('FAT1', 'Gene', '2195', (39, 43))	('FAT1', 'Gene', (39, 43))	('knockdown', 'Var', (44, 53))	('accelerated', 'PosReg', (66, 77))	('invasion', 'CPA', (97, 105))	('cell migration', 'CPA', (78, 92))
472786	29565465	The datasets of FAT1 mutation in squamous cell carcinomas were obtained from the TCGA database.	('squamous cell carcinomas', 'Disease', (33, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('FAT1', 'Gene', '2195', (16, 20))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (33, 57))	('mutation', 'Var', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('FAT1', 'Gene', (16, 20))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (33, 57))
472789	29573636	POH1 Knockdown Induces Cancer Cell Apoptosis via p53 and Bim12345 The ubiquitin-proteasome system is implicated in cell apoptosis that is frequently dysregulated in human cancers.	('Bim', 'Gene', (57, 60))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('Induces', 'Reg', (15, 22))	('human', 'Species', '9606', (165, 170))	('POH1', 'Gene', '10213', (0, 4))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Bim', 'Gene', '10018', (57, 60))	('Cancer Cell Apoptosis', 'CPA', (23, 44))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('Knockdown', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('POH1', 'Gene', (0, 4))
472792	29573636	The knockdown of POH1 significantly inhibited tumor cell proliferation and induced apoptosis mediated by the mitochondrial pathway in vitro.	('induced', 'Reg', (75, 82))	('inhibited', 'NegReg', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('mitochondrial pathway', 'Pathway', (109, 130))	('apoptosis', 'CPA', (83, 92))	('POH1', 'Gene', (17, 21))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
472795	29573636	POH1 depletion resulted in cell apoptosis by increasing the stability of p53 and Bim and inhibiting their ubiquitination.	('ubiquitination', 'MPA', (106, 120))	('stability', 'MPA', (60, 69))	('depletion', 'Var', (5, 14))	('Bim', 'Gene', (81, 84))	('Bim', 'Gene', '10018', (81, 84))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('inhibiting', 'NegReg', (89, 99))	('increasing', 'PosReg', (45, 55))	('cell apoptosis', 'CPA', (27, 41))	('POH1', 'Gene', (0, 4))
472796	29573636	Overall, POH1 knockdown induced cell apoptosis through increased expression of p53 and Bim via enhanced protein stability and attenuated degradation.	('attenuated', 'NegReg', (126, 136))	('cell apoptosis', 'CPA', (32, 46))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('Bim', 'Gene', '10018', (87, 90))	('increased', 'PosReg', (55, 64))	('POH1', 'Gene', (9, 13))	('expression', 'MPA', (65, 75))	('degradation', 'MPA', (137, 148))	('Bim', 'Gene', (87, 90))	('knockdown', 'Var', (14, 23))	('enhanced', 'PosReg', (95, 103))	('protein', 'MPA', (104, 111))
472799	29573636	Dysregulation in apoptosis may lead to a variety of diseases such as cancer.	('apoptosis', 'Protein', (17, 26))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lead to', 'Reg', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
472807	29573636	For instance, siRNA-mediated knockdown of POH1 had a considerable impact on cell viability and induced cell arrest in the G0-G1 phase, ultimately leading to senescence.	('leading to', 'Reg', (146, 156))	('POH1', 'Gene', (42, 46))	('knockdown', 'Var', (29, 38))	('senescence', 'MPA', (157, 167))	('induced', 'Reg', (95, 102))	('arrest', 'Disease', 'MESH:D006323', (108, 114))	('cell viability', 'CPA', (76, 90))	('arrest', 'Disease', (108, 114))	('impact', 'Reg', (66, 72))
472810	29573636	Whether POH1 deregulation contributes to the intrinsic pathway of apoptosis in cancer is questionable.	('intrinsic pathway of', 'Pathway', (45, 65))	('contributes', 'Reg', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('POH1', 'Gene', (8, 12))	('cancer', 'Disease', (79, 85))	('deregulation', 'Var', (13, 25))
472812	29573636	Furthermore, we observed that POH1 silencing induced cell apoptosis through an increase in the expression of p53 and Bim mediated by enhanced protein stability.	('increase', 'PosReg', (79, 87))	('silencing', 'Var', (35, 44))	('cell apoptosis', 'CPA', (53, 67))	('protein stability', 'MPA', (142, 159))	('Bim', 'Gene', (117, 120))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('Bim', 'Gene', '10018', (117, 120))	('POH1', 'Gene', (30, 34))	('enhanced', 'PosReg', (133, 141))	('expression', 'MPA', (95, 105))
472868	29573636	According to the mRNA levels of POH1 in 182 EC patients of TGCA dataset, high expression of POH1 suggests a trend of poor prognosis in terms of overall survival (log-rank test; P = .030; Supplementary Figure 1).	('poor', 'NegReg', (117, 121))	('EC', 'Phenotype', 'HP:0011459', (44, 46))	('patients', 'Species', '9606', (47, 55))	('POH1', 'Gene', (92, 96))	('high expression', 'Var', (73, 88))
472870	29573636	MTT assay revealed that the knockdown of POH1 resulted in a significant inhibition of cell viability (Figure 2B).	('cell viability', 'CPA', (86, 100))	('knockdown', 'Var', (28, 37))	('POH1', 'Gene', (41, 45))	('MTT', 'Chemical', '-', (0, 3))	('inhibition', 'NegReg', (72, 82))
472872	29573636	To assess the effect of POH1 knockdown on tumor growth in vivo, each nude mouse was implanted subcutaneously under the right armpit with 5 x 106 relative cells (QGY-7701, EC109, or HCT116).	('POH1', 'Gene', (24, 28))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('HCT116', 'CellLine', 'CVCL:0291', (181, 187))	('EC', 'Phenotype', 'HP:0011459', (171, 173))	('mouse', 'Species', '10090', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('EC109', 'CellLine', 'CVCL:6898', (171, 176))	('QGY-7701', 'Var', (161, 169))
472874	29573636	Intratumoral injection of POH1 siRNA significantly inhibited tumor growth as compared with the scrambled siRNA injection (Figure 3A1, B1, & C1).	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('POH1 siRNA', 'Var', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (5, 10))	('inhibited', 'NegReg', (51, 60))	('tumor', 'Disease', (61, 66))
472875	29573636	Furthermore, the tumor weight was lighter in POH1 siRNA groups as compared with the control groups (Figure 3A2, B2, & C2).	('POH1 siRNA', 'Var', (45, 55))	('tumor', 'Disease', (17, 22))	('lighter', 'NegReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
472876	29573636	The tumor volumes were significantly smaller in POH1 siRNA groups (Figure 3A3, B3, & C3).	('tumor', 'Disease', (4, 9))	('smaller', 'NegReg', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('POH1 siRNA', 'Var', (48, 58))
472877	29573636	The analyses of terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay revealed more apoptotic cells in POH1 siRNA groups as compared to the control groups (Figure 3D), and the differences observed were statistically significant (Figure 3E).	('terminal deoxynucleotidyl transferase', 'Gene', (16, 53))	('TdT', 'Gene', '1791', (55, 58))	('TdT', 'Gene', (55, 58))	('dUTP', 'Chemical', 'MESH:C027078', (60, 64))	('terminal deoxynucleotidyl transferase', 'Gene', '1791', (16, 53))	('POH1 siRNA', 'Var', (130, 140))	('apoptotic cells', 'CPA', (111, 126))
472878	29573636	Analyses of IHC staining results of the xenograft confirmed that the expression of POH1 was lower in POH1 siRNA groups than the control groups, while the expression of p53, Bim, caspase-3, and caspase-9 was higher in POH1 siRNA groups as compared with the control groups (Supplementary Figure 2).	('caspase-3', 'Gene', '836', (178, 187))	('POH1', 'Gene', (83, 87))	('higher', 'PosReg', (207, 213))	('p53', 'Gene', '7157', (168, 171))	('caspase-9', 'Gene', (193, 202))	('POH1 siRNA', 'Var', (101, 111))	('expression', 'MPA', (69, 79))	('caspase-9', 'Gene', '842', (193, 202))	('Bim', 'Gene', (173, 176))	('caspase-3', 'Gene', (178, 187))	('p53', 'Gene', (168, 171))	('lower', 'NegReg', (92, 97))	('Bim', 'Gene', '10018', (173, 176))	('expression', 'MPA', (154, 164))
472881	29573636	Furthermore, knockdown of POH1 upregulated the protein levels of p53 and its targets such as p21, Bax, and Puma but not Noxa.	('Bax', 'Gene', '581', (98, 101))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('protein levels', 'MPA', (47, 61))	('Bax', 'Gene', (98, 101))	('p21', 'Gene', (93, 96))	('upregulated', 'PosReg', (31, 42))	('p21', 'Gene', '644914', (93, 96))	('POH1', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))
472883	29573636	The proapoptotic protein Bim was notably upregulated in cells upon POH1 knockdown, but the expression of other apoptosis-related proteins, including Bak, Bcl-xl, and Bid, remained unchanged (Figure 4B).	('Bak', 'Gene', '578', (149, 152))	('Bid', 'Gene', (166, 169))	('Bcl-xl', 'Gene', '598', (154, 160))	('upregulated', 'PosReg', (41, 52))	('Bim', 'Gene', (25, 28))	('Bim', 'Gene', '10018', (25, 28))	('POH1', 'Gene', (67, 71))	('Bcl-xl', 'Gene', (154, 160))	('knockdown', 'Var', (72, 81))	('Bid', 'Gene', '637', (166, 169))	('Bak', 'Gene', (149, 152))
472884	29573636	In addition, knockdown of POH1 upregulated the protein levels of Mcl-1, but the overexpression of POH1 failed to affect the expression of MCl-1 (Supplementary Figure 6).	('Mcl-1', 'Gene', '4170', (65, 70))	('MCl-1', 'Gene', '4170', (138, 143))	('MCl-1', 'Gene', (138, 143))	('upregulated', 'PosReg', (31, 42))	('Mcl-1', 'Gene', (65, 70))	('POH1', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))
472887	29573636	JC-1 staining showed that POH1 knockdown increased the red-to-green fluorescence intensity ratio, indicative of the damage of the mitochondrial transmembrane potential:one of the signatures of apoptosis mediated by the mitochondrial pathway (Figure 4E).	('damage', 'MPA', (116, 122))	('increased', 'PosReg', (41, 50))	('mitochondrial transmembrane potential', 'MPA', (130, 167))	('red-to-green fluorescence intensity ratio', 'MPA', (55, 96))	('JC-1', 'Chemical', 'MESH:C068624', (0, 4))	('POH1', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))
472888	29573636	In this study, both p53 and Bim were upregulated after POH1 knockdown.	('p53', 'Gene', (20, 23))	('POH1', 'Gene', (55, 59))	('p53', 'Gene', '7157', (20, 23))	('upregulated', 'PosReg', (37, 48))	('knockdown', 'Var', (60, 69))	('Bim', 'Gene', (28, 31))	('Bim', 'Gene', '10018', (28, 31))
472890	29573636	Both knockdown and overexpression of POH1 had no effect on the mRNA level of p53 and Bim, indicative of the posttranslational regulation of p53 and Bim by POH1 (Supplementary Figure 3).	('Bim', 'Gene', (85, 88))	('mRNA level', 'MPA', (63, 73))	('Bim', 'Gene', '10018', (85, 88))	('knockdown', 'Var', (5, 14))	('p53', 'Gene', (140, 143))	('p53', 'Gene', (77, 80))	('POH1', 'Gene', (37, 41))	('p53', 'Gene', '7157', (77, 80))	('Bim', 'Gene', (148, 151))	('Bim', 'Gene', '10018', (148, 151))	('p53', 'Gene', '7157', (140, 143))
472894	29573636	POH1 knockdown decreased p53 and Bim ubiquitination in QGY-7701, EC109, and HCT116 cells (Figure 5D & E).	('p53', 'Gene', (25, 28))	('EC109', 'CellLine', 'CVCL:6898', (65, 70))	('p53', 'Gene', '7157', (25, 28))	('Bim', 'Gene', '10018', (33, 36))	('knockdown', 'Var', (5, 14))	('HCT116', 'CellLine', 'CVCL:0291', (76, 82))	('decreased', 'NegReg', (15, 24))	('EC', 'Phenotype', 'HP:0011459', (65, 67))	('POH1', 'Gene', (0, 4))	('Bim', 'Gene', (33, 36))
472895	29573636	These data confirmed that POH1 depletion attenuates the proteasome-mediated degradation of p53 and Bim.	('proteasome-mediated degradation', 'MPA', (56, 87))	('attenuates', 'NegReg', (41, 51))	('Bim', 'Gene', (99, 102))	('Bim', 'Gene', '10018', (99, 102))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('depletion', 'Var', (31, 40))	('POH1', 'Gene', (26, 30))
472896	29573636	We assessed if p53 and Bim were involved in apoptosis mediated by POH1 depletion.	('Bim', 'Gene', (23, 26))	('Bim', 'Gene', '10018', (23, 26))	('depletion', 'Var', (71, 80))	('POH1', 'Gene', (66, 70))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('involved', 'Reg', (32, 40))
472897	29573636	Cells treated with POH1 siRNA and p53 or Bim siRNA for 48 hours showed attenuation in the cleaved form of caspase-9 and caspase-3 as compared with those treated with only POH1 siRNA (Figure 6A).	('cleaved form', 'MPA', (90, 102))	('p53', 'Gene', (34, 37))	('attenuation', 'NegReg', (71, 82))	('p53', 'Gene', '7157', (34, 37))	('caspase-9', 'Gene', '842', (106, 115))	('Bim', 'Gene', (41, 44))	('Bim', 'Gene', '10018', (41, 44))	('POH1 siRNA', 'Var', (19, 29))	('caspase-9', 'Gene', (106, 115))	('caspase-3', 'Gene', (120, 129))	('caspase-3', 'Gene', '836', (120, 129))
472898	29573636	p53 or Bim siRNA markedly decreased the apoptosis driven by POH1 depletion.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('apoptosis', 'CPA', (40, 49))	('Bim', 'Gene', (7, 10))	('Bim', 'Gene', '10018', (7, 10))	('depletion', 'Var', (65, 74))	('POH1', 'Gene', (60, 64))	('decreased', 'NegReg', (26, 35))
472899	29573636	The average percentage of apoptotic cells was 35.2% and 30.5% in QGY-7701 cells co-transfected with POH1 siRNA and p53 or Bim siRNA, respectively, versus 48.2% in POH1-knockdown cells (Figure 6B); 18.5% and 14.9% in EC109 cells co-transfected with POH1 siRNA and p53 or Bim siRNA, respectively, versus 26.2% in POH1-knockdown cells (Figure 6C); and 31.2% and 29.5% in HCT116 cells co-transfected with POH1 siRNA and p53 or Bim siRNA, respectively, versus 45.1% in POH1-knockdown cells (Figure 6D).	('Bim', 'Gene', (270, 273))	('Bim', 'Gene', '10018', (270, 273))	('p53', 'Gene', '7157', (416, 419))	('Bim', 'Gene', (122, 125))	('EC109', 'CellLine', 'CVCL:6898', (216, 221))	('Bim', 'Gene', '10018', (122, 125))	('p53', 'Gene', (115, 118))	('p53', 'Gene', (263, 266))	('p53', 'Gene', '7157', (115, 118))	('POH1 siRNA', 'Var', (401, 411))	('Bim', 'Gene', (423, 426))	('EC', 'Phenotype', 'HP:0011459', (216, 218))	('Bim', 'Gene', '10018', (423, 426))	('HCT116', 'CellLine', 'CVCL:0291', (368, 374))	('p53', 'Gene', '7157', (263, 266))	('p53', 'Gene', (416, 419))
472904	29573636	Two recent studies revealed the correlation between high POH1 expression and poor overall survival in multiple myeloma and breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('poor', 'NegReg', (77, 81))	('expression', 'MPA', (62, 72))	('breast cancer', 'Disease', (123, 136))	('POH1', 'Protein', (57, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('overall survival', 'MPA', (82, 98))	('high', 'Var', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('multiple myeloma', 'Phenotype', 'HP:0006775', (102, 118))	('multiple myeloma', 'Disease', 'MESH:D009101', (102, 118))	('multiple myeloma', 'Disease', (102, 118))
472906	29573636	We studied the oncogenic function of POH1 in solid tumors; knockdown of POH1 expression in QGY-7701, EC109, and HCT116 cells decreased cell viability and induced apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('EC', 'Phenotype', 'HP:0011459', (101, 103))	('EC109', 'CellLine', 'CVCL:6898', (101, 106))	('POH1', 'Gene', (72, 76))	('induced', 'Reg', (154, 161))	('decreased', 'NegReg', (125, 134))	('solid tumors', 'Disease', (45, 57))	('cell viability', 'CPA', (135, 149))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('knockdown', 'Var', (59, 68))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('apoptosis', 'CPA', (162, 171))	('HCT116', 'CellLine', 'CVCL:0291', (112, 118))
472908	29573636	Furthermore, POH1 silencing resulted in the activation of PARP1, caspase-9, caspase-3, and cytochrome c and upregulation of p53, p21, Bax, Puma, Noxa, and Bim.	('cytochrome c', 'Gene', (91, 103))	('activation', 'PosReg', (44, 54))	('Bim', 'Gene', '10018', (155, 158))	('PARP1', 'Gene', (58, 63))	('Puma', 'CPA', (139, 143))	('caspase-9', 'Gene', '842', (65, 74))	('Bim', 'Gene', (155, 158))	('upregulation', 'PosReg', (108, 120))	('p53', 'Gene', '7157', (124, 127))	('caspase-3', 'Gene', '836', (76, 85))	('Bax', 'Gene', (134, 137))	('cytochrome c', 'Gene', '54205', (91, 103))	('caspase-9', 'Gene', (65, 74))	('POH1', 'Gene', (13, 17))	('PARP1', 'Gene', '142', (58, 63))	('Bax', 'Gene', '581', (134, 137))	('p53', 'Gene', (124, 127))	('silencing', 'Var', (18, 27))	('caspase-3', 'Gene', (76, 85))	('p21', 'Gene', (129, 132))	('p21', 'Gene', '644914', (129, 132))
472909	29573636	In addition, our results suggest that MCl-1 is upregulated after POH1 silenced, and several studies have shown that inhibitor of the 26S proteasome induced the expression of Mcl-1.	('expression', 'MPA', (160, 170))	('POH1', 'Gene', (65, 69))	('upregulated', 'PosReg', (47, 58))	('MCl-1', 'Gene', '4170', (38, 43))	('Mcl-1', 'Gene', (174, 179))	('MCl-1', 'Gene', (38, 43))	('silenced', 'Var', (70, 78))	('26S proteasome', 'Protein', (133, 147))	('Mcl-1', 'Gene', '4170', (174, 179))	('inhibitor', 'Var', (116, 125))
472910	29573636	Taken together, we hypothesize that silence of POH1 causes dysfunction of proteasome and increases the expression of MCl-1.	('dysfunction', 'MPA', (59, 70))	('expression', 'MPA', (103, 113))	('MCl-1', 'Gene', '4170', (117, 122))	('MCl-1', 'Gene', (117, 122))	('proteasome', 'Protein', (74, 84))	('silence', 'Var', (36, 43))	('POH1', 'Gene', (47, 51))	('increases', 'PosReg', (89, 98))
472911	29573636	JC-1 staining showed that POH1 knockdown decreased mitochondrial transmembrane potential.	('decreased', 'NegReg', (41, 50))	('JC-1', 'Chemical', 'MESH:C068624', (0, 4))	('mitochondrial transmembrane potential', 'MPA', (51, 88))	('POH1', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))
472912	29573636	Recent studies have suggested that knockdown of POH1 may induce cancer cell apoptosis.	('knockdown', 'Var', (35, 44))	('POH1', 'Gene', (48, 52))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('induce', 'PosReg', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
472917	29573636	As p53 siRNA and Bim siRNA failed to completely inhibit the apoptosis driven by POH1 depletion, the effect of POH1 knockdown may, at least in part, be dependent on p53 and Bim.	('POH1', 'Gene', (110, 114))	('p53', 'Gene', '7157', (3, 6))	('p53', 'Gene', '7157', (164, 167))	('Bim', 'Gene', (17, 20))	('knockdown', 'Var', (115, 124))	('Bim', 'Gene', (172, 175))	('Bim', 'Gene', '10018', (172, 175))	('apoptosis', 'MPA', (60, 69))	('Bim', 'Gene', '10018', (17, 20))	('p53', 'Gene', (164, 167))	('p53', 'Gene', (3, 6))	('inhibit', 'NegReg', (48, 55))
472918	29573636	In addition, our data showed POH1 knockdown induced higher apoptosis in HCT116 p53+/+ cells as compared with HCT116 p53-/- cells (Supplementary Figure 5).	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('HCT116', 'CellLine', 'CVCL:0291', (109, 115))	('POH1', 'Gene', (29, 33))	('p53', 'Gene', '7157', (116, 119))	('apoptosis', 'CPA', (59, 68))	('higher', 'PosReg', (52, 58))	('HCT116', 'CellLine', 'CVCL:0291', (72, 78))	('knockdown', 'Var', (34, 43))	('p53', 'Gene', (116, 119))
472922	29573636	We found that POH1 knockdown increased the protein level of p53 and Bim but failed to affect their mRNA levels.	('Bim', 'Gene', (68, 71))	('knockdown', 'Var', (19, 28))	('Bim', 'Gene', '10018', (68, 71))	('increased', 'PosReg', (29, 38))	('p53', 'Gene', (60, 63))	('protein level', 'MPA', (43, 56))	('p53', 'Gene', '7157', (60, 63))	('POH1', 'Gene', (14, 18))
472923	29573636	Furthermore, the half-life of both p53 and Bim was longer in POH1-knockdown cells, and the levels of ubiquitinated p53 and Bim decreased in POH1-knockdown cells.	('Bim', 'Gene', (123, 126))	('half-life', 'MPA', (17, 26))	('Bim', 'Gene', (43, 46))	('decreased', 'NegReg', (127, 136))	('levels of ubiquitinated', 'MPA', (91, 114))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('Bim', 'Gene', '10018', (43, 46))	('Bim', 'Gene', '10018', (123, 126))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('POH1-knockdown', 'Var', (61, 75))	('longer', 'PosReg', (51, 57))	('POH1-knockdown', 'Gene', (61, 75))
472924	29573636	Although it may seem a bit contradictory, we demonstrate that knockdown of POH1 (a deubiquitining enzyme) could diminish the ubiquitin modification of p53 and Bim, and we speculated there were some reasons.	('ubiquitin modification', 'MPA', (125, 147))	('p53', 'Gene', '7157', (151, 154))	('diminish', 'NegReg', (112, 120))	('Bim', 'Gene', (159, 162))	('POH1', 'Gene', (75, 79))	('Bim', 'Gene', '10018', (159, 162))	('p53', 'Gene', (151, 154))	('knockdown', 'Var', (62, 71))
472926	29573636	Similarly, as a deubiquitinating enzyme, USP22 silenced leads to increased FBP1 ubiquitination and decreased FBP1 protein occupancy at the p21 gene.	('increased', 'PosReg', (65, 74))	('decreased', 'NegReg', (99, 108))	('FBP1', 'Gene', (109, 113))	('FBP1', 'Gene', (75, 79))	('USP22', 'Gene', (41, 46))	('ubiquitination', 'MPA', (80, 94))	('USP22', 'Gene', '23326', (41, 46))	('p21', 'Gene', (139, 142))	('FBP1', 'Gene', '2203', (109, 113))	('p21', 'Gene', '644914', (139, 142))	('silenced', 'Var', (47, 55))	('FBP1', 'Gene', '2203', (75, 79))
472927	29573636	Unfortunately, knockdown of POH1 had no effect on the mRNA and protein level of JNK and PKM2 in our study (Data not shown).	('POH1', 'Gene', (28, 32))	('knockdown', 'Var', (15, 24))	('JNK', 'Gene', (80, 83))	('JNK', 'Gene', '5599', (80, 83))	('PKM2', 'Gene', (88, 92))	('PKM2', 'Gene', '5315', (88, 92))
472929	29573636	Collectively, we proposed that knockdown of POH1 would increase stability and inhibit ubiquitination of p53 and Bim.	('Bim', 'Gene', (112, 115))	('p53', 'Gene', (104, 107))	('increase', 'PosReg', (55, 63))	('stability', 'MPA', (64, 73))	('p53', 'Gene', '7157', (104, 107))	('Bim', 'Gene', '10018', (112, 115))	('inhibit', 'NegReg', (78, 85))	('ubiquitination', 'MPA', (86, 100))	('POH1', 'Gene', (44, 48))	('knockdown', 'Var', (31, 40))
472936	29573636	Another study showed that knockdown of RNF2 induces apoptosis by enhancing p53 stability.	('RNF2', 'Gene', (39, 43))	('enhancing', 'PosReg', (65, 74))	('RNF2', 'Gene', '6045', (39, 43))	('knockdown', 'Var', (26, 35))	('p53', 'Gene', (75, 78))	('apoptosis', 'CPA', (52, 61))	('p53', 'Gene', '7157', (75, 78))
472939	29573636	POH1 depletion, on the other hand, induces cell apoptosis by increasing stability and inhibiting ubiquitination of p53 and Bim.	('Bim', 'Gene', (123, 126))	('depletion', 'Var', (5, 14))	('increasing', 'PosReg', (61, 71))	('cell apoptosis', 'CPA', (43, 57))	('stability', 'MPA', (72, 81))	('Bim', 'Gene', '10018', (123, 126))	('p53', 'Gene', (115, 118))	('inhibiting', 'NegReg', (86, 96))	('p53', 'Gene', '7157', (115, 118))	('ubiquitination', 'MPA', (97, 111))	('POH1', 'Gene', (0, 4))
473001	29238109	Although FDG-PET/CT appears to be more specific for detection of loco-regional LNs and peritoneal lesions as compared to CT alone, it is actually less sensitive.)	('FDG-PET/CT', 'Var', (9, 19))	('loco-regional LNs', 'Disease', (65, 82))	('FDG', 'Chemical', 'MESH:D019788', (9, 12))
473009	29238109	More recently, a multicenter retrospective study investigated 1754 patients with T1-4N0-3M0 gastric cancer who had received D2 gastrectomy and lymphadenectomy procedures with a median follow-up period of 31 months.	('patients', 'Species', '9606', (67, 75))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('T1-4N0-3M0', 'Var', (81, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))
473019	29238109	of 266 patients with colon cancer who were assessed with both FDG-PET/CT and conventional studies for colon cancer staging, FDG-PET/CT results led to a change in management for 1 of 40 (2.5%) with clinical stage I, 0 of 25 (0%) with stage II, 9 of 138 (6.5%) with stage III, and 8 of 63 (12.7%) with stage IV disease.)	('management', 'MPA', (162, 172))	('FDG', 'Chemical', 'MESH:D019788', (124, 127))	('FDG', 'Chemical', 'MESH:D019788', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('colon cancer', 'Phenotype', 'HP:0003003', (21, 33))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('colon cancer', 'Disease', 'MESH:D015179', (21, 33))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', (102, 114))	('FDG-PET/CT', 'Var', (124, 134))	('change', 'Reg', (152, 158))	('colon cancer', 'Disease', (21, 33))	('patients', 'Species', '9606', (7, 15))
473077	28927095	ESCC is hypothesized to develop due to risk factors including the accumulation of genetic mutations, tobacco, alcohol consumption, consuming hot food or water frequently, a low intake of fresh fruit and vegetables, obesity and poor diet, local environmental conditions and lifestyle.	('obesity', 'Phenotype', 'HP:0001513', (215, 222))	('water', 'Chemical', 'MESH:D014867', (153, 158))	('obesity', 'Disease', 'MESH:D009765', (215, 222))	('genetic mutations', 'Var', (82, 99))	('obesity', 'Disease', (215, 222))	('ESCC', 'Disease', (0, 4))	('poor diet', 'Phenotype', 'HP:0011968', (227, 236))	('alcohol', 'Chemical', 'MESH:D000438', (110, 117))	('tobacco', 'Species', '4097', (101, 108))	('low', 'NegReg', (173, 176))
473122	28927095	There is evidence that MAGE proteins are involved in the regulation of apoptosis; for example, MAGE-A3 has been identified to inhibit the activation of caspase 12 in vitro and caspase 12 in turn is capable of inducing apoptosis.	('inducing', 'Reg', (209, 217))	('MAGE-A3', 'Gene', '4102', (95, 102))	('apoptosis', 'CPA', (218, 227))	('activation', 'MPA', (138, 148))	('MAGE-A3', 'Gene', (95, 102))	('inhibit', 'NegReg', (126, 133))	('caspase', 'Var', (176, 183))	('caspase', 'Protein', (152, 159))
473146	28199974	We employed transient transfection experiments, clonogenic assays and cell cycle profiling to evaluate the biological consequences of miR-204 perturbation.	('miR-204', 'Gene', '406987', (134, 141))	('perturbation', 'Var', (142, 154))	('miR-204', 'Gene', (134, 141))
473169	28199974	We showed that manipulating the levels of miR-204 (by means of agonist molecules) in representative GC and CC cell lines, led to a reversal of the identified gene target signature.	('miR-204', 'Gene', '406987', (42, 49))	('miR-204', 'Gene', (42, 49))	('manipulating', 'Var', (15, 27))
473216	28199974	Next, we assessed whether manipulating the levels of the miR-204 gene targets in the GTL-16 and HUCCT1 cells, by means of transfecting mimic-204, could affect some of their protumorigenic properties.	('transfecting', 'Var', (122, 134))	('GTL-16', 'Chemical', '-', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('miR-204', 'Gene', (57, 64))	('tumor', 'Disease', (176, 181))	('manipulating', 'Var', (26, 38))	('affect', 'Reg', (152, 158))	('miR-204', 'Gene', '406987', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
473222	28199974	In detail, silencing of SHCBP1 in HUCCT1 cells strongly increased the Sub-G1 cells (Figure 6A).	('silencing', 'Var', (11, 20))	('Sub-G1 cells', 'CPA', (70, 82))	('increased', 'PosReg', (56, 65))	('SHCBP1', 'Gene', '79801', (24, 30))	('SHCBP1', 'Gene', (24, 30))
473224	28199974	Silencing of the mentioned genes affected very similarly both the GTL-16 and HUCCT1 cells, with the exception of FOXM1 in the GTL-16 cells (Figure 6B).	('affected', 'Reg', (33, 41))	('GTL-16', 'Chemical', '-', (66, 72))	('GTL-16', 'Chemical', '-', (126, 132))	('FOXM1', 'Gene', (113, 118))	('FOXM1', 'Gene', '2305', (113, 118))	('Silencing', 'Var', (0, 9))
473225	28199974	Clonogenic assays revealed that silencing of each of the target caused a reduction in colony formation, thus fully matching what observed when ectopically expressing the miR-204 (Figure 6C-6D).	('miR-204', 'Gene', (170, 177))	('silencing', 'Var', (32, 41))	('miR-204', 'Gene', '406987', (170, 177))	('colon', 'Disease', (86, 91))	('reduction', 'NegReg', (73, 82))	('colon', 'Disease', 'MESH:D015179', (86, 91))
473226	28199974	Interestingly, silencing of KIF15 did not affect and rather increased the colony forming ability of both the transfected cell lines, despite silencing of the latter elicited increased sub-G1 cells in both cell lines (Figure 6C-6D).	('silencing', 'NegReg', (141, 150))	('sub-G1 cells', 'CPA', (184, 196))	('colon', 'Disease', 'MESH:D015179', (74, 79))	('silencing', 'Var', (15, 24))	('KIF15', 'Gene', '56992', (28, 33))	('colon', 'Disease', (74, 79))	('KIF15', 'Gene', (28, 33))	('increased', 'PosReg', (174, 183))	('increased', 'PosReg', (60, 69))
473247	28199974	More in detail, while silencing of SHCBP1, RAD51, NOTCH1 and FOXM1 significantly increased the cells in the sub-G1 phase, all of the tested miR-204 targets (except for KIF15) affected the clonogenicity of the transfected cell lines.	('miR-204', 'Gene', '406987', (140, 147))	('NOTCH1', 'Gene', '4851', (50, 56))	('clonogenicity of the transfected cell lines', 'CPA', (188, 231))	('SHCBP1', 'Gene', (35, 41))	('increased', 'PosReg', (81, 90))	('NOTCH1', 'Gene', (50, 56))	('affected', 'Reg', (175, 183))	('miR-204', 'Gene', (140, 147))	('KIF15', 'Gene', '56992', (168, 173))	('FOXM1', 'Gene', (61, 66))	('silencing', 'Var', (22, 31))	('FOXM1', 'Gene', '2305', (61, 66))	('RAD51', 'Gene', (43, 48))	('cells in the sub-G1 phase', 'CPA', (95, 120))	('KIF15', 'Gene', (168, 173))	('RAD51', 'Gene', '5888', (43, 48))	('SHCBP1', 'Gene', '79801', (35, 41))
473251	28199974	With regard to this, we also observed different kinetics between the two cell lines analyzed (GTL-16 and HUCCT1, respectively, with the GTL-16 exhibiting a earlier modulation of the targets when transfected with the mimic-204 (as compared with the HUCCT1 cells, transfected in very similar conditions).	('GTL-16', 'Chemical', '-', (136, 142))	('GTL-16', 'Gene', (136, 142))	('GTL-16', 'Chemical', '-', (94, 100))	('mimic-204', 'Var', (216, 225))
473266	28199974	Human gastric cancer cell lineGTL-16 was grown in DMEM medium (Invitrogen) supplemented with 10% fetal bovine serum (FBS), penicillin (100 U/ml) and streptomycin (100ug/ml) at 37 C in a balanced air humidified incubator with 5% CO2.	('Human', 'Species', '9606', (0, 5))	('GTL-16', 'Chemical', '-', (30, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (6, 20))	('CO2', 'Chemical', '-', (228, 231))	('bovine', 'Species', '9913', (103, 109))	('FBS', 'Disease', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('penicillin', 'Chemical', 'MESH:D010406', (123, 133))	('streptomycin', 'Chemical', 'MESH:D013307', (149, 161))	('FBS', 'Disease', 'MESH:D005198', (117, 120))	('DMEM medium', 'Chemical', '-', (50, 61))	('gastric cancer', 'Disease', (6, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (6, 20))	('100ug/ml', 'Var', (163, 171))
473267	28199974	The cholangiocarcinoma cell line HUCCT1 was grown in RPMI medium (Invitrogen) supplemented with 10% fetal bovine serum (FBS), penicillin (100 U/ml) and streptomycin (100ug/ml) at 37 C in a balanced air humidified incubator with 5% CO2.	('bovine', 'Species', '9913', (106, 112))	('CO2', 'Chemical', '-', (231, 234))	('streptomycin', 'Chemical', 'MESH:D013307', (152, 164))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (4, 22))	('penicillin', 'Chemical', 'MESH:D010406', (126, 136))	('FBS', 'Disease', 'MESH:D005198', (120, 123))	('100ug/ml', 'Var', (166, 174))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (4, 22))	('RPMI medium', 'Chemical', '-', (53, 64))	('100 U/ml', 'Var', (138, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('FBS', 'Disease', (120, 123))	('cholangiocarcinoma', 'Disease', (4, 22))
473299	25298750	MSCs have also been shown to have anti-angiogenic effect both in vitro and in mouse models of melanoma.	('anti-angiogenic effect', 'CPA', (34, 56))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('MSCs', 'Var', (0, 4))	('mouse', 'Species', '10090', (78, 83))
473306	25298750	The gated cells were analyzed for the expression of cell membrane proteins markers and found to be negative for the expression of hematopoietic markers such as CD45, CD14, CD19 and also HLA-DR (MHC II) and CD34 (endothelial/hematopoietic stem cell markers), but were positive for CD29, CD44, CD73, CD90 and CD105, which are generally considered for markers of mesenchymal stem cells (Figure 1A).	('CD44', 'Gene', (286, 290))	('CD29', 'Gene', (280, 284))	('CD44', 'Gene', '960', (286, 290))	('CD45', 'Gene', (160, 164))	('CD73', 'Gene', '4907', (292, 296))	('CD105', 'Var', (307, 312))	('CD19', 'Gene', '930', (172, 176))	('CD14', 'Gene', '929', (166, 170))	('CD14', 'Gene', (166, 170))	('CD73', 'Gene', (292, 296))	('CD19', 'Gene', (172, 176))	('CD34', 'Gene', (206, 210))	('CD90', 'Gene', '7070', (298, 302))	('HLA-DR', 'Var', (186, 192))	('CD29', 'Gene', '3688', (280, 284))	('CD45', 'Gene', '5788', (160, 164))	('CD34', 'Gene', '947', (206, 210))	('CD90', 'Gene', (298, 302))
473326	25298750	This result indicated, in a manner, that hUCMSCs enhanced lymph node metastasis of esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('enhanced', 'PosReg', (49, 57))	('metastasis of esophageal carcinoma', 'Disease', (69, 103))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('metastasis of esophageal carcinoma', 'Disease', 'MESH:D009362', (69, 103))	('hUCMSCs', 'Var', (41, 48))
473378	25298750	The cells were stained with the following antibodies: CD14-FITC, CD19-ECD, CD29-FITC, CD34-PE, CD44-FITC, CD45-FITC, CD73-PE, CD90-FITC, CD105-PE, HLA-DR-FITC (BD Pharmingen, USA).	('CD19', 'Gene', '930', (65, 69))	('CD34', 'Gene', (86, 90))	('CD105-PE', 'Var', (137, 145))	('CD73', 'Gene', '4907', (117, 121))	('CD14-FITC', 'Var', (54, 63))	('CD45-FITC', 'Var', (106, 115))	('DR-FITC', 'Chemical', '-', (151, 158))	('CD44-FITC', 'Var', (95, 104))	('CD29-FITC', 'Var', (75, 84))	('CD73', 'Gene', (117, 121))	('EC', 'Phenotype', 'HP:0011459', (70, 72))	('CD90-FITC', 'Var', (126, 135))	('CD19', 'Gene', (65, 69))	('CD34', 'Gene', '947', (86, 90))
473410	33506107	CircRNA circ_0004370 promotes cell proliferation, migration, and invasion and inhibits cell apoptosis of esophageal cancer via miR-1301-3p/COL1A1 axis The aim of this study was to investigate the circ_0004370 expression in EC, its effects on cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) process, and the underlying regulatory mechanisms in EC.	('invasion', 'CPA', (284, 292))	('COL1A1', 'Gene', (139, 145))	('miR-1301', 'Gene', (127, 135))	('circ_0004370', 'Chemical', '-', (196, 208))	('circ_0004370', 'Var', (196, 208))	('miR-1301', 'Gene', '100302246', (127, 135))	('COL1A1', 'Gene', '1277', (139, 145))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cell proliferation', 'CPA', (242, 260))	('migration', 'CPA', (273, 282))	('circ_0004370', 'Chemical', '-', (8, 20))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('apoptosis', 'CPA', (262, 271))	('inhibits', 'NegReg', (78, 86))
473413	33506107	We discovered that circ_0004370 was remarkably upregulated in EC tissues and cells.	('upregulated', 'PosReg', (47, 58))	('circ_0004370', 'Chemical', '-', (19, 31))	('circ_0004370', 'Var', (19, 31))
473414	33506107	Knockdown of circ_0004370 inhibited cell proliferation, migration as well as invasion, and promoted apoptosis in vitro, while its effect was rescued by miR-1301-3p inhibition.	('migration', 'CPA', (56, 65))	('circ_0004370', 'Var', (13, 25))	('promoted', 'PosReg', (91, 99))	('circ_0004370', 'Chemical', '-', (13, 25))	('inhibited', 'NegReg', (26, 35))	('invasion', 'CPA', (77, 85))	('apoptosis', 'CPA', (100, 109))	('miR-1301-3p', 'Chemical', '-', (152, 163))	('cell proliferation', 'CPA', (36, 54))
473415	33506107	And circ_0004370 mediated the EMT process in EC cells.	('circ_0004370', 'Chemical', '-', (4, 16))	('circ_0004370', 'Var', (4, 16))	('EMT process', 'CPA', (30, 41))
473416	33506107	Moreover, we explored its regulatory mechanism and found that circ_0004370 directly bound to miR-1301-3p and COL1A1 was verified as a target of miR-1301-3p.	('miR-1301-3p', 'Chemical', '-', (144, 155))	('circ_0004370', 'Chemical', '-', (62, 74))	('circ_0004370', 'Var', (62, 74))	('bound', 'Interaction', (84, 89))	('miR-1301-3p', 'Chemical', '-', (93, 104))
473417	33506107	COL1A1 was highly expressed in EC cells and upregulation of COL1A1 reversed the effects of miR-1301-3p on cell proliferation, migration, invasion, and apoptosis.	('cell proliferation', 'CPA', (106, 124))	('miR-1301-3p', 'Chemical', '-', (91, 102))	('invasion', 'CPA', (137, 145))	('upregulation', 'PosReg', (44, 56))	('COL1A1', 'Gene', (60, 66))	('apoptosis', 'CPA', (151, 160))	('migration', 'CPA', (126, 135))	('miR-1301-3p', 'Var', (91, 102))
473418	33506107	In addition, silencing of circ_0004370 reduced tumor volumes and weights in vivo.	('circ_0004370', 'Chemical', '-', (26, 38))	('circ_0004370', 'Gene', (26, 38))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('reduced', 'NegReg', (39, 46))	('tumor', 'Disease', (47, 52))	('silencing', 'Var', (13, 22))
473420	33506107	Circ_0004370 promotes EC proliferation, migration and invasion, and EMT process and suppresses apoptosis by regulating the miR-1301-3p/COL1A1 axis, indicating that circ_0004370 may be used as a potential therapeutic target for EC.	('EC proliferation', 'CPA', (22, 38))	('EMT process', 'CPA', (68, 79))	('suppresses', 'NegReg', (84, 94))	('invasion', 'CPA', (54, 62))	('promotes', 'PosReg', (13, 21))	('circ_0004370', 'Chemical', '-', (164, 176))	('apoptosis', 'CPA', (95, 104))	('Circ_0004370', 'Chemical', '-', (0, 12))	('miR-1301-3p', 'Chemical', '-', (123, 134))	('migration', 'CPA', (40, 49))	('regulating', 'Reg', (108, 118))	('Circ_0004370', 'Var', (0, 12))	('miR-1301-3p/COL1A1', 'MPA', (123, 141))
473428	33506107	It has been shown that miRNAs are related to the human cancer development and act as tumor promoters or suppressors.	('tumor', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (49, 54))	('miRNAs', 'Var', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', (55, 61))
473429	33506107	The first research found that miR-1301-3p directly bound to oncogene neuroblastoma Ras viral homolog (N-Ras) and acted as a tumor inhibitor in glioma.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('miR-1301-3p', 'Chemical', '-', (30, 41))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('N-Ras', 'Gene', '4893', (102, 107))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('neuroblastoma', 'Phenotype', 'HP:0003006', (69, 82))	('tumor', 'Disease', (124, 129))	('bound', 'Interaction', (51, 56))	('neuroblastoma', 'Disease', 'MESH:D009447', (69, 82))	('glioma', 'Disease', (143, 149))	('miR-1301-3p', 'Var', (30, 41))	('N-Ras', 'Gene', (102, 107))	('neuroblastoma', 'Disease', (69, 82))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
473430	33506107	Besides, miR-1301-3p was suggested to be an effective biomarker for colorectal cancer.	('colorectal cancer', 'Disease', (68, 85))	('miR-1301-3p', 'Chemical', '-', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('miR-1301-3p', 'Var', (9, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))
473431	33506107	Furthermore, a recent article showed that miR-1301-3p repressed cell viability of human breast cancer by directly targeting the immature colon carcinoma transcript 1 (ICT1).	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('repressed', 'PosReg', (54, 63))	('miR-1301-3p', 'Chemical', '-', (42, 53))	('human', 'Species', '9606', (82, 87))	('ICT1', 'Gene', (167, 171))	('miR-1301-3p', 'Var', (42, 53))	('immature colon carcinoma transcript 1', 'Gene', '3396', (128, 165))	('immature colon carcinoma transcript 1', 'Gene', (128, 165))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ICT1', 'Gene', '3396', (167, 171))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('targeting', 'Reg', (114, 123))	('cell viability', 'CPA', (64, 78))
473432	33506107	proved that miR-1301-3p/INCENP axis played the crucial role in the development of ESCC, which provided us new insights into the mechanism of miR-1301-3p in EC.	('INCENP', 'Gene', '3619', (24, 30))	('ESCC', 'Disease', (82, 86))	('INCENP', 'Gene', (24, 30))	('miR-1301-3p', 'Var', (141, 152))	('miR-1301-3p', 'Chemical', '-', (141, 152))	('miR-1301-3p', 'Chemical', '-', (12, 23))
473438	33506107	In this study, we uncovered that knockdown of circ_0004370 in EC was linked to restrain EC cell viability, proliferation, apoptosis, migration, invasion, and in vivo tumor formation.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('restrain', 'NegReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('knockdown', 'Var', (33, 42))	('apoptosis', 'CPA', (122, 131))	('proliferation', 'CPA', (107, 120))	('invasion', 'CPA', (144, 152))	('tumor', 'Disease', (166, 171))	('migration', 'CPA', (133, 142))	('circ_0004370', 'Var', (46, 58))	('circ_0004370', 'Chemical', '-', (46, 58))
473439	33506107	In the study of its regulatory mechanism, we found that circ_0004370 bound to miR-1301-3p and inhibited its expression in EC cells.	('miR-1301-3p', 'Chemical', '-', (78, 89))	('bound', 'Interaction', (69, 74))	('circ_0004370', 'Chemical', '-', (56, 68))	('circ_0004370', 'Var', (56, 68))	('expression', 'MPA', (108, 118))	('inhibited', 'NegReg', (94, 103))
473440	33506107	In addition, miR-1301-3p directly targeted COL1A1 and miR-1301-3p overexpression reduced the expression of COL1A1.	('COL1A1', 'Gene', (107, 113))	('miR-1301-3p', 'Chemical', '-', (54, 65))	('miR-1301-3p', 'Chemical', '-', (13, 24))	('COL1A1', 'Gene', (43, 49))	('expression', 'MPA', (93, 103))	('reduced', 'NegReg', (81, 88))	('miR-1301-3p', 'Var', (54, 65))	('miR-1301-3p', 'Var', (13, 24))
473461	33506107	Primary antibodies anti-GAPDH (1:1,000; Cell Signaling Technology, Danvers, MA, USA), anti-COL1A1 (1:1,000; Abcam, Cambridge, United Kingdom), anti-E-cadherin (1:1,000; Abcam), anti-N-cadherin (1:1,000; Abcam), and anti-Vimentin (1:1,000; Abcam) seeded into membrane at 4 C overnight.	('GAPDH', 'Gene', '2597', (24, 29))	('E-cadherin', 'Gene', (148, 158))	('GAPDH', 'Gene', (24, 29))	('Vimentin', 'Gene', '7431', (220, 228))	('N-cadherin', 'Gene', (182, 192))	('E-cadherin', 'Gene', '999', (148, 158))	('N-cadherin', 'Gene', '1000', (182, 192))	('anti-COL1A1', 'Var', (86, 97))	('Vimentin', 'Gene', (220, 228))
473470	33506107	The binding sites between circ_0004370 and miR-1301-3p and miR-1301-3p and COL1A1 were predicted by online software.	('circ_0004370', 'Chemical', '-', (26, 38))	('binding', 'Interaction', (4, 11))	('miR-1301-3p', 'Var', (59, 70))	('miR-1301-3p', 'Gene', (43, 54))	('miR-1301-3p', 'Chemical', '-', (43, 54))	('COL1A1', 'Gene', (75, 81))	('miR-1301-3p', 'Chemical', '-', (59, 70))	('circ_0004370', 'Gene', (26, 38))
473471	33506107	The sequences of wild type circ_0004370 (WT-circ_0004370), mutant circ_0004370 (MUT-circ_0004370), wild type COL1A1 3'UTR, and mutant COL1A1 3'UTR involving the putative-binding sites of miR-1301-3p were cloned into the pMIR-REPORT luciferase vector (OBio Biology, Shanghai, China).	('mutant', 'Var', (127, 133))	('miR-1301-3p', 'Chemical', '-', (187, 198))	('circ_0004370', 'Chemical', '-', (27, 39))	('mutant', 'Var', (59, 65))	('circ_0004370', 'Gene', (66, 78))	('COL1A1', 'Gene', (134, 140))	('circ_0004370', 'Chemical', '-', (66, 78))	('circ_0004370', 'Chemical', '-', (44, 56))	('circ_0004370', 'Chemical', '-', (84, 96))
473473	33506107	RNA pull-down assay was utilized to detect potential target relationship between circ_0004370 and miR-1301-3p.	('circ_0004370', 'Chemical', '-', (81, 93))	('miR-1301-3p', 'Var', (98, 109))	('circ_0004370', 'Var', (81, 93))	('miR-1301-3p', 'Chemical', '-', (98, 109))
473476	33506107	The female nude mice (4-week-old) with no specific pathogen-free (SPF) were subcutaneously injected with EC cells transfected with sh-NC or sh-circ_0004370 at a concentration of 5 x 106 cells/200 microL in sterile saline.	('sh-circ_0004370', 'Var', (140, 155))	('circ_0004370', 'Chemical', '-', (143, 155))	('nude mice', 'Species', '10090', (11, 20))	('sh-NC', 'Gene', (131, 136))
473479	33506107	The expression level of circ_0004370 in EC tissues was significantly higher than that in the adjacent normal controls (Figure 1a).	('expression level', 'MPA', (4, 20))	('circ_0004370', 'Chemical', '-', (24, 36))	('higher', 'PosReg', (69, 75))	('circ_0004370', 'Var', (24, 36))
473480	33506107	There was the correlation between circ_0004370 expression and clinicopathological features of ESCC patients (Table 1).	('circ_0004370', 'Chemical', '-', (34, 46))	('ESCC patients', 'Disease', (94, 107))	('patients', 'Species', '9606', (99, 107))	('circ_0004370 expression', 'Var', (34, 57))
473481	33506107	The expression of circ_0004370 was increased in OE19, TE11, KYSE410, and EC109 cells compared with the HEEC cells, and the increase of expression was most obvious in OE19 and EC109 cells, so these two cell lines were selected for future experiments (Figure 1b).	('increased', 'PosReg', (35, 44))	('circ_0004370', 'Chemical', '-', (18, 30))	('EC109', 'CellLine', 'CVCL:6898', (73, 78))	('expression', 'MPA', (4, 14))	('circ_0004370', 'Var', (18, 30))	('EC109', 'CellLine', 'CVCL:6898', (175, 180))
473482	33506107	Furthermore, the circ_0004370 circular structure was more stable than the linear structure of the PRRX1 mRNA in OE19 and EC109 cells (Figure 1c and d).	('circ_0004370', 'Chemical', '-', (17, 29))	('circ_0004370', 'Var', (17, 29))	('EC109', 'CellLine', 'CVCL:6898', (121, 126))	('PRRX1', 'Gene', (98, 103))	('PRRX1', 'Gene', '5396', (98, 103))
473485	33506107	Loss-of-function experiments were performed to observe whether circ_0004370 affected the behavior of EC cells.	('behavior of EC cells', 'CPA', (89, 109))	('Loss-of-function', 'NegReg', (0, 16))	('circ_0004370', 'Var', (63, 75))	('circ_0004370', 'Chemical', '-', (63, 75))	('affected', 'Reg', (76, 84))
473486	33506107	After transfection with si-NC, si-circ #1, si-circ #2, or si-circ #3 in EC cells, it was found that the expression level of circ_0004370 was significantly decreased in OE19 and EC109 cells, and because of the better efficiency of si-circ #1, it was used in the subsequent experiments (Figure 2a).	('si-circ', 'Var', (43, 50))	('better', 'PosReg', (209, 215))	('si-circ', 'Var', (58, 65))	('efficiency', 'MPA', (216, 226))	('circ_0004370', 'Chemical', '-', (124, 136))	('si-circ', 'Var', (31, 38))	('circ_0004370', 'Var', (124, 136))	('si-NC', 'Var', (24, 29))	('decreased', 'NegReg', (155, 164))	('EC109', 'CellLine', 'CVCL:6898', (177, 182))	('expression level', 'MPA', (104, 120))
473487	33506107	CCK-8 assay determined that knocking down circ_0004370 significantly decreased OE19 and EC109 cell viability (Figure 2b).	('knocking down', 'Var', (28, 41))	('circ_0004370', 'Gene', (42, 54))	('decreased', 'NegReg', (69, 78))	('circ_0004370', 'Chemical', '-', (42, 54))	('EC109', 'CellLine', 'CVCL:6898', (88, 93))	('CCK-8', 'Chemical', '-', (0, 5))
473489	33506107	Furthermore, flow cytometry indicated that the cell apoptosis in circ_0004370 knockdown group was markedly increased in OE19 and EC109 cells (Figure 2d).	('cell apoptosis', 'CPA', (47, 61))	('increased', 'PosReg', (107, 116))	('circ_0004370', 'Chemical', '-', (65, 77))	('circ_0004370', 'Var', (65, 77))	('EC109', 'CellLine', 'CVCL:6898', (129, 134))
473490	33506107	Then, the results of transwell assay indicated that cell migration and invasion were reduced in the transfecting with si-circ #1 group in OE19 and EC109 cells (Figure 2e and f).	('transfecting', 'Var', (100, 112))	('EC109', 'CellLine', 'CVCL:6898', (147, 152))	('cell migration', 'CPA', (52, 66))	('invasion', 'CPA', (71, 79))	('si-circ', 'Var', (118, 125))	('reduced', 'NegReg', (85, 92))
473491	33506107	Western blot analysis indicated that the protein level of E-cadherin was markedly upregulated after knocking down circ_0004370 in OE19 and EC109 cells, whereas the protein levels of N-cadherin and Vimentin were downregulated after knocking down circ_0004370 in OE19 and EC109 cells (Figure 2g).	('N-cadherin', 'Gene', (182, 192))	('upregulated', 'PosReg', (82, 93))	('circ_0004370', 'Chemical', '-', (114, 126))	('N-cadherin', 'Gene', '1000', (182, 192))	('circ_0004370', 'Var', (114, 126))	('Vimentin', 'Gene', (197, 205))	('EC109', 'CellLine', 'CVCL:6898', (139, 144))	('E-cadherin', 'Gene', (58, 68))	('E-cadherin', 'Gene', '999', (58, 68))	('Vimentin', 'Gene', '7431', (197, 205))	('downregulated', 'NegReg', (211, 224))	('EC109', 'CellLine', 'CVCL:6898', (270, 275))	('knocking down circ_0004370', 'Var', (100, 126))	('circ_0004370', 'Chemical', '-', (245, 257))	('protein level', 'MPA', (41, 54))
473493	33506107	Circ_0004370 was predicted to contain the binding sites with miR-1301-3p using starBase v2.0 software (Figure 3a).	('miR-1301-3p', 'Chemical', '-', (61, 72))	('miR-1301-3p', 'Var', (61, 72))	('binding', 'Interaction', (42, 49))	('Circ_0004370', 'Chemical', '-', (0, 12))
473495	33506107	After overexpression of miR-1301-3p with different concentrations of miR-1301-3p mimics (25, 50, and 100 nM, respectively), the luciferase activity in OE19 and EC109 cells containing the WT-circ_0004370 was decreased in a dose-dependent manner, while the luciferase activity in MUT-circ0004370 group was not changed in OE19 and EC109 cell lines (Figure 3b and c).	('miR-1301-3p', 'Var', (24, 35))	('miR-1301-3p', 'Var', (69, 80))	('activity', 'MPA', (139, 147))	('EC109', 'CellLine', 'CVCL:6898', (160, 165))	('circ_0004370', 'Chemical', '-', (190, 202))	('EC109', 'CellLine', 'CVCL:6898', (328, 333))	('miR-1301-3p', 'Chemical', '-', (24, 35))	('miR-1301-3p', 'Chemical', '-', (69, 80))	('decreased', 'NegReg', (207, 216))	('luciferase', 'Enzyme', (128, 138))
473496	33506107	Then the RNA pull-down assay was utilized to further verify the correlation between circ_0004370 and miR-1301-3p.	('miR-1301-3p', 'Var', (101, 112))	('circ_0004370', 'Chemical', '-', (84, 96))	('miR-1301-3p', 'Chemical', '-', (101, 112))	('circ_0004370', 'Var', (84, 96))
473497	33506107	The results presented that circ_0004370 was more enriched in bio-miR-1301-3p-transfected EC cells when compared with bio-NC-transfected EC cells (Figure 3d).	('circ_0004370', 'Var', (27, 39))	('bio-miR-1301-3p-transfected', 'Var', (61, 88))	('circ_0004370', 'Chemical', '-', (27, 39))	('miR-1301-3p', 'Chemical', '-', (65, 76))
473499	33506107	The expression of miR-1301-3p had a negative correlation with the expression of circ_0004370 in EC tissues (Figure 3f).	('miR-1301-3p', 'Var', (18, 29))	('expression', 'MPA', (66, 76))	('circ_0004370', 'Gene', (80, 92))	('miR-1301-3p', 'Chemical', '-', (18, 29))	('circ_0004370', 'Chemical', '-', (80, 92))	('negative', 'NegReg', (36, 44))
473500	33506107	Also, miR-1301-3p was upregulated by circ_0004370 knockdown in OE19 and EC109 cells (Figure 3h).	('circ_0004370 knockdown', 'Var', (37, 59))	('upregulated', 'PosReg', (22, 33))	('EC109', 'CellLine', 'CVCL:6898', (72, 77))	('knockdown', 'Var', (50, 59))	('miR-1301-3p', 'Chemical', '-', (6, 17))	('miR-1301-3p', 'Gene', (6, 17))	('circ_0004370', 'Chemical', '-', (37, 49))
473502	33506107	To confirm whether the interaction between miR-1301-3p and circ_0004370 affects the cells function, we first used RT-qPCR to detect the miR-1301-3p expression.	('miR-1301-3p', 'Chemical', '-', (136, 147))	('circ_0004370', 'Chemical', '-', (59, 71))	('miR-1301-3p', 'Chemical', '-', (43, 54))	('circ_0004370', 'Var', (59, 71))	('cells function', 'CPA', (84, 98))	('affects', 'Reg', (72, 79))	('miR-1301-3p', 'Var', (136, 147))	('interaction', 'Interaction', (23, 34))
473503	33506107	As expected, the miR-1301-3p expression was greatly reduced after the transfection of anti-miR-1301-3p (Figure 4a).	('miR-1301-3p', 'Chemical', '-', (91, 102))	('reduced', 'NegReg', (52, 59))	('miR-1301-3p expression', 'MPA', (17, 39))	('miR-1301-3p', 'Chemical', '-', (17, 28))	('anti-miR-1301-3p', 'Var', (86, 102))
473504	33506107	Interestingly, the expression level of miR-1301-3p was upregulated by circ_0004370 knockdown and restored after the addition of anti-miR-1301-3p (Figure 4b).	('miR-1301-3p', 'Chemical', '-', (39, 50))	('miR-1301-3p', 'Chemical', '-', (133, 144))	('circ_0004370', 'Chemical', '-', (70, 82))	('expression level', 'MPA', (19, 35))	('upregulated', 'PosReg', (55, 66))	('circ_0004370 knockdown', 'Var', (70, 92))	('restored', 'PosReg', (97, 105))	('miR-1301-3p', 'Var', (39, 50))	('knockdown', 'Var', (83, 92))
473505	33506107	The cell viability assay showed that the effect of circ_0004370 knockdown was reversed by the miR-1301-3p inhibitor (Figure 4c).	('miR-1301-3p', 'Chemical', '-', (94, 105))	('circ_0004370 knockdown', 'Var', (51, 73))	('circ_0004370', 'Chemical', '-', (51, 63))	('knockdown', 'Var', (64, 73))
473506	33506107	The experiment of cell cloning proved that when the expression level of circ_0004370 was downregulated, cell cloning in EC cells was significantly decreased, while the number of cell cloning was recovered after the addition of miR-1301-3p inhibitor (Figure 4d).	('expression level', 'MPA', (52, 68))	('cell cloning', 'CPA', (104, 116))	('decreased', 'NegReg', (147, 156))	('downregulated', 'NegReg', (89, 102))	('circ_0004370', 'Var', (72, 84))	('miR-1301-3p', 'Chemical', '-', (227, 238))	('circ_0004370', 'Chemical', '-', (72, 84))
473507	33506107	In cell apoptosis experiments, the number of apoptosis was upregulated by the circ_0004370 knockdown, but it was decreased by addition of anti-miR-1301-3p (Figure 4e).	('circ_0004370', 'Chemical', '-', (78, 90))	('circ_0004370 knockdown', 'Var', (78, 100))	('knockdown', 'Var', (91, 100))	('upregulated', 'PosReg', (59, 70))	('miR-1301-3p', 'Chemical', '-', (143, 154))	('apoptosis', 'CPA', (45, 54))	('decreased', 'NegReg', (113, 122))
473508	33506107	The transwell assay showed that knockdown of circ_0004370 significantly decreased the cell migration and invasion, while inhibition of miR-1301-3p rescued the function of circ_0004370 knockdown (Figure 4f and g).	('circ_0004370', 'Chemical', '-', (171, 183))	('miR-1301-3p', 'Chemical', '-', (135, 146))	('circ_0004370', 'Chemical', '-', (45, 57))	('decreased', 'NegReg', (72, 81))	('circ_0004370', 'Var', (45, 57))	('circ_0004370', 'Var', (171, 183))
473509	33506107	Besides, the western blot analysis showed that the addition of anti-miR-1301-3p rescued the EMT process changes caused by knockdown of circ_0004370 in OE19 cells and EC109 cells (Figure 4h).	('EC109', 'CellLine', 'CVCL:6898', (166, 171))	('miR-1301-3p', 'Chemical', '-', (68, 79))	('knockdown', 'Var', (122, 131))	('circ_0004370', 'Gene', (135, 147))	('circ_0004370', 'Chemical', '-', (135, 147))	('EMT process changes', 'CPA', (92, 111))
473513	33506107	The expression levels of COL1A1 and miR-1301-3p were negatively correlated in EC tissues (Figure 5e).	('expression levels', 'MPA', (4, 21))	('miR-1301-3p', 'Chemical', '-', (36, 47))	('negatively', 'NegReg', (53, 63))	('miR-1301-3p', 'Var', (36, 47))	('COL1A1', 'Gene', (25, 31))
473515	33506107	Besides, results from starBase v2.0 software predicted that there was a binding site between COL1A1 and miR-1301-3p (Figure 5i).	('miR-1301-3p', 'Chemical', '-', (104, 115))	('miR-1301-3p', 'Var', (104, 115))	('binding', 'Interaction', (72, 79))	('COL1A1', 'Gene', (93, 99))
473516	33506107	In the dual-luciferase reporter experiment, it was further verified that miR-1301-3p could directly bind to 3'UTR of COL1A1 in OE19 and EC109 cells (Figure 5j and k).	('miR-1301-3p', 'Var', (73, 84))	('EC109', 'CellLine', 'CVCL:6898', (136, 141))	('bind', 'Interaction', (100, 104))	('miR-1301-3p', 'Chemical', '-', (73, 84))	('COL1A1', 'Gene', (117, 123))
473517	33506107	MiR-1301-3p downregulated the expression of COL1A1 mRNA and protein, and miR-1301-3p inhibitor upregulated the expression of COL1A1 mRNA and protein (Figure 5l and m).	('downregulated', 'NegReg', (12, 25))	('mRNA', 'MPA', (132, 136))	('upregulated', 'PosReg', (95, 106))	('expression', 'MPA', (30, 40))	('MiR-1301', 'Gene', (0, 8))	('3p', 'Chemical', '-', (82, 84))	('MiR-1301', 'Gene', '100302246', (0, 8))	('miR-1301-3p', 'Chemical', '-', (73, 84))	('COL1A1', 'Gene', (44, 50))	('miR-1301-3p', 'Var', (73, 84))	('expression', 'MPA', (111, 121))	('3p', 'Chemical', '-', (9, 11))	('mRNA', 'MPA', (51, 55))	('COL1A1', 'Gene', (125, 131))
473518	33506107	Together, it was demonstrated that miR-1301-3p could regulate the expression of COL1A1.	('COL1A1', 'Gene', (80, 86))	('regulate', 'Reg', (53, 61))	('miR-1301-3p', 'Var', (35, 46))	('expression', 'MPA', (66, 76))	('miR-1301-3p', 'Chemical', '-', (35, 46))
473520	33506107	Then, we examined the protein expression of COL1A1 after transfecting with miR-NC, miR-1301-3p, miR-1301-3p + pcDNA, or miR-1301-3p + COL1A1.	('miR-1301-3p +', 'Var', (120, 133))	('miR-1301-3p', 'Var', (83, 94))	('miR-1301-3p', 'Chemical', '-', (120, 131))	('COL1A1', 'Gene', (44, 50))	('miR-1301-3p', 'Chemical', '-', (96, 107))	('miR-1301-3p', 'Chemical', '-', (83, 94))	('examined', 'Reg', (9, 17))	('miR-1301-3p +', 'Var', (96, 109))
473521	33506107	The results showed that the expression level of COL1A1 was decreased after transfecting miR-1301-3p, whereas the protein expression was increased after transfecting with miR-1301-3p + COL1A1 compared with transfection of miR-1301-3p + pcDNA (Figure 6b, P < 0.001).	('miR-1301-3p', 'Chemical', '-', (170, 181))	('protein expression', 'MPA', (113, 131))	('miR-1301-3p', 'Chemical', '-', (88, 99))	('decreased', 'NegReg', (59, 68))	('miR-1301-3p +', 'Var', (170, 183))	('increased', 'PosReg', (136, 145))	('miR-1301-3p', 'Var', (88, 99))	('miR-1301-3p', 'Chemical', '-', (221, 232))	('expression level', 'MPA', (28, 44))	('COL1A1', 'Gene', (48, 54))
473523	33506107	The results revealed that upregulation of miR-1301-3p markedly reduced cell viability in OE19 and EC109 cells, whereas transfection with COL1A1 rescued the cell viability in EC cells (Figure 6c).	('reduced', 'NegReg', (63, 70))	('miR-1301-3p', 'Chemical', '-', (42, 53))	('miR-1301-3p', 'Var', (42, 53))	('upregulation', 'PosReg', (26, 38))	('EC109', 'CellLine', 'CVCL:6898', (98, 103))	('cell viability', 'CPA', (71, 85))
473524	33506107	Then the cell cloning assay proved that cell cloning was significantly reduced in EC cells transfected with miR-1301-3p; however, the number of cell cloning was recovered after transfection of COL1A1 (Figure 6d).	('miR-1301-3p', 'Chemical', '-', (108, 119))	('cell cloning', 'CPA', (40, 52))	('reduced', 'NegReg', (71, 78))	('miR-1301-3p', 'Var', (108, 119))
473525	33506107	The results indicated that transfection of COL1A1 could partially reverse the effects of miR-1301-3p on cell apoptosis (Figure 6e).	('miR-1301-3p', 'Chemical', '-', (89, 100))	('cell apoptosis', 'CPA', (104, 118))	('COL1A1', 'Gene', (43, 49))	('transfection', 'Var', (27, 39))
473526	33506107	The results of transwell assay showed that miR-1301-3p significantly decreased the cell migration and invasion, while addition of COL1A1 rescued the function of miR-1301-3p in EC cells (Figure 6f and g).	('miR-1301-3p', 'Var', (161, 172))	('cell migration', 'CPA', (83, 97))	('miR-1301-3p', 'Chemical', '-', (43, 54))	('decreased', 'NegReg', (69, 78))	('miR-1301-3p', 'Chemical', '-', (161, 172))	('miR-1301-3p', 'Var', (43, 54))
473527	33506107	The western blot assay showed that addition of COL1A1 rescued the effect of miR-1301-3p on EMT process in OE19 cells and EC109 cells (Figure 6h and i).	('EC109', 'CellLine', 'CVCL:6898', (121, 126))	('miR-1301-3p', 'Var', (76, 87))	('EMT process', 'CPA', (91, 102))	('miR-1301-3p', 'Chemical', '-', (76, 87))
473530	33506107	We used a xenograft nude mouse model and found that knockdown of circ_0004370 broadly suppressed the tumor volumes and weights (Figure 7a and b).	('circ_0004370', 'Chemical', '-', (65, 77))	('mouse', 'Species', '10090', (25, 30))	('circ_0004370', 'Var', (65, 77))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('suppressed', 'NegReg', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
473531	33506107	Moreover, the RT-qPCR showed that circ_0004370 was significantly decreased and miR-1301-3p expression was remarkably increased with downregulation of circ_0004370 (Figure 7c and d).	('downregulation', 'NegReg', (132, 146))	('circ_0004370', 'Var', (150, 162))	('increased', 'PosReg', (117, 126))	('circ_0004370', 'Chemical', '-', (150, 162))	('decreased', 'NegReg', (65, 74))	('circ_0004370', 'Chemical', '-', (34, 46))	('miR-1301-3p expression', 'MPA', (79, 101))	('miR-1301-3p', 'Chemical', '-', (79, 90))	('circ_0004370', 'MPA', (34, 46))
473532	33506107	Knockdown of circ_0004370 also decreased COL1A1 protein level in tissues (Figure 7e).	('circ_0004370', 'Chemical', '-', (13, 25))	('circ_0004370', 'Var', (13, 25))	('COL1A1 protein level', 'MPA', (41, 61))	('decreased', 'NegReg', (31, 40))
473533	33506107	In conclusion, circ_0004370 promoted EC growth by regulating miR-1301-3p/COL1A1 axis.	('regulating', 'Reg', (50, 60))	('miR-1301-3p', 'Chemical', '-', (61, 72))	('miR-1301-3p/COL1A1 axis', 'MPA', (61, 84))	('promoted', 'PosReg', (28, 36))	('circ_0004370', 'Var', (15, 27))	('circ_0004370', 'Chemical', '-', (15, 27))
473535	33506107	This is a malignant lesion caused by an abnormality of esophageal squamous epithelial cells or adenocytes.	('malignant lesion', 'Disease', 'MESH:D009369', (10, 26))	('caused by', 'Reg', (27, 36))	('malignant lesion', 'Disease', (10, 26))	('abnormality', 'Var', (40, 51))
473538	33506107	In the current research, we concluded that circ_0004370 served as a tumor promoter to activate cell viability, cloning, migration and invasion, and EMT process and restrain cell apoptosis via miR-1301-3p/COL1A1 axis.	('circ_0004370', 'Var', (43, 55))	('tumor', 'Disease', (68, 73))	('cell apoptosis', 'CPA', (173, 187))	('restrain', 'NegReg', (164, 172))	('miR-1301-3p', 'Chemical', '-', (192, 203))	('circ_0004370', 'Chemical', '-', (43, 55))	('activate', 'PosReg', (86, 94))	('invasion', 'CPA', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('EMT process', 'CPA', (148, 159))	('cloning', 'CPA', (111, 118))	('cell viability', 'CPA', (95, 109))
473539	33506107	Consistent with a previous report which reported the abnormal circ_0004370 expression in EC, our study first detected that circ_0004370 was upregulated in EC tissues and cells (OE19, TE11, KYSE410, and EC109).	('EC109', 'CellLine', 'CVCL:6898', (202, 207))	('circ_0004370', 'Chemical', '-', (123, 135))	('circ_0004370', 'Var', (123, 135))	('upregulated', 'PosReg', (140, 151))	('circ_0004370', 'Chemical', '-', (62, 74))
473541	33506107	Furthermore, knockdown of circ_0004370 in vivo showed that tumor volumes and weights were significantly decreased in xenograft mouse model.	('mouse', 'Species', '10090', (127, 132))	('circ_0004370', 'Chemical', '-', (26, 38))	('tumor', 'Disease', (59, 64))	('decreased', 'NegReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('knockdown', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('circ_0004370', 'Var', (26, 38))
473544	33506107	Besides, we predicted that circ_0004370 bound to the miR-1301-3p using online software.	('circ_0004370', 'Var', (27, 39))	('miR-1301-3p', 'Chemical', '-', (53, 64))	('circ_0004370', 'Chemical', '-', (27, 39))	('bound', 'Reg', (40, 45))
473545	33506107	Further dual-luciferase reporter analyzed the direct targeting relationship between circ_0004370 and miR-1301-3p.	('miR-1301-3p', 'Var', (101, 112))	('circ_0004370', 'Chemical', '-', (84, 96))	('miR-1301-3p', 'Chemical', '-', (101, 112))	('circ_0004370', 'Var', (84, 96))
473547	33506107	Consistent with this, in this study we found the markedly inverse correlation between circ_0004370 and miR-1301-3p in EC.	('inverse', 'NegReg', (58, 65))	('miR-1301-3p', 'Var', (103, 114))	('circ_0004370', 'Var', (86, 98))	('circ_0004370', 'Chemical', '-', (86, 98))	('miR-1301-3p', 'Chemical', '-', (103, 114))
473548	33506107	Knockdown of circ_0004370 could affect the functions of EC cells, such as cell proliferation, cell cloning, migration, and invasion, whereas miR-1301-3p inhibitor rescued the functions of circ_0004370 knockdown.	('circ_0004370', 'Var', (13, 25))	('cell proliferation', 'CPA', (74, 92))	('migration', 'CPA', (108, 117))	('circ_0004370', 'Chemical', '-', (13, 25))	('invasion', 'CPA', (123, 131))	('cell cloning', 'CPA', (94, 106))	('affect', 'Reg', (32, 38))	('functions', 'MPA', (43, 52))	('miR-1301-3p', 'Chemical', '-', (141, 152))	('circ_0004370', 'Chemical', '-', (188, 200))
473549	33506107	Our results provided a fresh evidence for the role of circ_0004370 in EC to downregulate miR-1301-3p.	('miR-1301-3p', 'Chemical', '-', (89, 100))	('miR-1301-3p', 'MPA', (89, 100))	('circ_0004370', 'Chemical', '-', (54, 66))	('circ_0004370', 'Var', (54, 66))	('downregulate', 'NegReg', (76, 88))
473552	33506107	Additionally, COL1A1 knockdown suppressed the metastasis of breast cancer cells.	('breast cancer', 'Disease', (60, 73))	('COL1A1', 'Gene', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('suppressed', 'NegReg', (31, 41))	('knockdown', 'Var', (21, 30))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
473554	33506107	In our findings, starbase software predicted that miR-1301-3p directly targeted COL1A1, and further experiments proved that there was a negative correlation between them.	('miR-1301-3p', 'Chemical', '-', (50, 61))	('COL1A1', 'Gene', (80, 86))	('miR-1301-3p', 'Var', (50, 61))	('targeted', 'Reg', (71, 79))
473555	33506107	Moreover, cell proliferation, apoptosis, migration, and other experiments demonstrated that COL1A1 could restore the effect of miR-1301-3p.	('migration', 'CPA', (41, 50))	('apoptosis', 'CPA', (30, 39))	('cell proliferation', 'CPA', (10, 28))	('miR-1301-3p', 'Chemical', '-', (127, 138))	('COL1A1', 'Gene', (92, 98))	('miR-1301-3p', 'Var', (127, 138))
473556	33506107	Finally, we found that knockdown of circ_0004370 upregulated miR-1301-3p and further downregulated COL1A1 expression.	('downregulated', 'NegReg', (85, 98))	('miR-1301-3p', 'Chemical', '-', (61, 72))	('expression', 'MPA', (106, 116))	('miR-1301-3p', 'MPA', (61, 72))	('upregulated', 'PosReg', (49, 60))	('COL1A1', 'Gene', (99, 105))	('circ_0004370', 'Chemical', '-', (36, 48))	('circ_0004370', 'Var', (36, 48))
473557	33506107	Previous studies exhibited that circNEK6 promoted thyroid cancer progression through Wnt signaling pathway.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Wnt signaling pathway', 'Pathway', (85, 106))	('promoted', 'PosReg', (41, 49))	('thyroid cancer', 'Disease', (50, 64))	('circNEK6', 'Var', (32, 40))	('thyroid cancer', 'Phenotype', 'HP:0002890', (50, 64))	('thyroid cancer', 'Disease', 'MESH:D013964', (50, 64))
473558	33506107	In addition, circ_100290 played the critical role in colorectal cancer initiation via Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', (90, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('circ_100290', 'Var', (13, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('beta-catenin', 'Gene', '1499', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('colorectal cancer', 'Disease', (53, 70))
473559	33506107	However, it is not clear whether circ_0004370 affects the development of EC by the Wnt signaling pathway, which will be the focus of our future study.	('circ_0004370', 'Chemical', '-', (33, 45))	('circ_0004370', 'Var', (33, 45))	('affects', 'Reg', (46, 53))
473560	33506107	We have detected the effect of circ_0004370 depletion on tumor growth in vivo.	('circ_0004370', 'Chemical', '-', (31, 43))	('circ_0004370', 'Var', (31, 43))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
473563	33506107	In conclusion, we discovered circ_0004370 was upregulated in EC cells and tissues.	('circ_0004370', 'Var', (29, 41))	('circ_0004370', 'Chemical', '-', (29, 41))	('upregulated', 'PosReg', (46, 57))
473564	33506107	Moreover, as a tumor promoter in EC, circ_0004370 could greatly promote the cell viability, cloning, migration, and invasion, remarkably suppressed apoptosis, and affected EMT process of EC through regulation of miR-1301-3p/COL1A1 axis.	('cloning', 'CPA', (92, 99))	('promote', 'PosReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('migration', 'CPA', (101, 110))	('suppressed', 'NegReg', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('EMT process', 'CPA', (172, 183))	('invasion', 'CPA', (116, 124))	('cell viability', 'CPA', (76, 90))	('miR-1301-3p', 'Chemical', '-', (212, 223))	('tumor', 'Disease', (15, 20))	('apoptosis', 'CPA', (148, 157))	('affected', 'Reg', (163, 171))	('circ_0004370', 'Chemical', '-', (37, 49))	('circ_0004370', 'Var', (37, 49))
473662	32885158	Refusing surgery was associated with a significantly higher, and potentially preventable, cancer-specific mortality.	('higher', 'PosReg', (53, 59))	('mortality', 'Disease', 'MESH:D003643', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mortality', 'Disease', (106, 115))	('Refusing surgery', 'Var', (0, 16))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
473677	32328390	Polyflex stents were associated with frequent complications such as severe chest pain, bleeding, perforation, bleeding, reflux, food impaction, and fistula formation.	('food impaction', 'Disease', (128, 142))	('bleeding', 'Disease', (87, 95))	('chest pain', 'Phenotype', 'HP:0100749', (75, 85))	('Polyflex', 'Var', (0, 8))	('chest pain', 'Disease', 'MESH:D002637', (75, 85))	('food impaction', 'Phenotype', 'HP:0031984', (128, 142))	('fistula', 'Disease', 'MESH:D005402', (148, 155))	('fistula', 'Disease', (148, 155))	('chest pain', 'Disease', (75, 85))	('pain', 'Phenotype', 'HP:0012531', (81, 85))	('reflux', 'Disease', (120, 126))	('bleeding', 'Disease', 'MESH:D006470', (87, 95))	('bleeding', 'Disease', 'MESH:D006470', (110, 118))	('perforation', 'Disease', (97, 108))	('bleeding', 'Disease', (110, 118))
473699	32328390	There was an increased risk of significant complications (chest pain, bleeding, and stent migration) with the large-diameter stents as compared with smaller-diameter prostheses.	('chest pain', 'Phenotype', 'HP:0100749', (58, 68))	('bleeding', 'Disease', (70, 78))	('stent migration', 'CPA', (84, 99))	('large-diameter', 'Var', (110, 124))	('chest pain', 'Disease', 'MESH:D002637', (58, 68))	('pain', 'Phenotype', 'HP:0012531', (64, 68))	('chest pain', 'Disease', (58, 68))	('bleeding', 'Disease', 'MESH:D006470', (70, 78))
473772	31369967	We showed that STAT1 was activated by phosphorylation of residue pY701upon long-term repeated exposure to acidified, bile salt-containing medium compared to pH 4 media alone or bile salt addition alone using Western blotting, demonstrating a synergistic effect of the combination treatment.	('phosphorylation', 'MPA', (38, 53))	('bile salt', 'Chemical', 'MESH:D001647', (177, 186))	('pY701upon', 'Var', (65, 74))	('pY701upon', 'Chemical', '-', (65, 74))	('STAT1', 'Gene', (15, 20))	('STAT1', 'Gene', '6772', (15, 20))	('activated', 'PosReg', (25, 34))	('bile salt', 'Chemical', 'MESH:D001647', (117, 126))
473774	31369967	STAT3 signaling was induced as seen by phosphorylation on pY705 in pH4 media alone and the combination with bile salt.	('phosphorylation', 'MPA', (39, 54))	('pY705', 'Chemical', '-', (58, 63))	('pH4 media', 'Chemical', '-', (67, 76))	('pY705', 'Var', (58, 63))	('STAT3', 'Gene', '6774', (0, 5))	('STAT3', 'Gene', (0, 5))	('bile salt', 'Chemical', 'MESH:D001647', (108, 117))
473783	31369967	We surmise that the increase in expression and secretion leads to autocrine signaling activation, as we observed activation of SMAD2/3 by phosphorylation of Ser423/425 residues upon pH 4 and combined treatments compared to untreated-control and bile salt only (Fig.	('secretion', 'MPA', (47, 56))	('bile salt', 'Chemical', 'MESH:D001647', (245, 254))	('autocrine signaling activation', 'MPA', (66, 96))	('SMAD2/3', 'Gene', (127, 134))	('SMAD2/3', 'Gene', '4087;4088', (127, 134))	('activation', 'PosReg', (113, 123))	('phosphorylation', 'MPA', (138, 153))	('Ser423', 'Chemical', '-', (157, 163))	('expression', 'MPA', (32, 42))	('Ser423/425 residues', 'Var', (157, 176))	('increase', 'PosReg', (20, 28))
473784	31369967	Furthermore, non-canonical ActA signaling involving ERK1/2 was induced specifically in the combination of acidified media/bile salt resulting in increased phosphorylation of Thr202/Tyr204, possibly as a stress response.	('non-canonical ActA signaling', 'MPA', (13, 41))	('Thr202', 'Chemical', '-', (174, 180))	('ERK1/2', 'Gene', (52, 58))	('ERK1/2', 'Gene', '5595;5594', (52, 58))	('increased', 'PosReg', (145, 154))	('Tyr204', 'Chemical', '-', (181, 187))	('bile salt', 'Chemical', 'MESH:D001647', (122, 131))	('phosphorylation', 'MPA', (155, 170))	('Thr202/Tyr204', 'Var', (174, 187))	('induced', 'Reg', (63, 70))
473786	31369967	We show that pH4 and bile salt exposure induced an increase in cell motility on a basement membrane (Fig.	('increase', 'PosReg', (51, 59))	('salt exposure', 'Phenotype', 'HP:0000127', (26, 39))	('pH4', 'Chemical', '-', (13, 16))	('pH4', 'Var', (13, 16))	('cell motility on a basement membrane', 'CPA', (63, 99))	('bile salt', 'Chemical', 'MESH:D001647', (21, 30))
473802	31369967	Furthermore, expression of YAP1, FOXO3 and KRT17 was inhibited following treatment with A83-01, implying an association with ActA/TGFbeta signaling (Fig.	('TGFbeta', 'Gene', (130, 137))	('YAP1', 'Gene', (27, 31))	('inhibited', 'NegReg', (53, 62))	('expression', 'MPA', (13, 23))	('KRT17', 'Gene', '3872', (43, 48))	('A83-01', 'Var', (88, 94))	('association', 'Interaction', (108, 119))	('TGFbeta', 'Gene', '7039', (130, 137))	('KRT17', 'Gene', (43, 48))	('FOXO3', 'Gene', (33, 38))
473809	31369967	Furthermore, pH4, bile salt-tolerant cells in three-dimensional cultures were characterized by a focal loss of KRT14-positive cells correlating with a concomitant increase in KRT8 (Fig.	('pH4', 'Var', (13, 16))	('pH4', 'Chemical', '-', (13, 16))	('salt-tolerant', 'Phenotype', 'HP:0000127', (23, 36))	('KRT14-positive', 'Protein', (111, 125))	('increase', 'PosReg', (163, 171))	('KRT8', 'MPA', (175, 179))	('bile salt', 'Chemical', 'MESH:D001647', (18, 27))	('loss', 'NegReg', (103, 107))
473815	31369967	ActA mediates several aspects of normal wound healing in squamous epithelia, e.g., overexpression of the soluble ActA antagonist Follistatin in the epidermis of transgenic mice reveals the importance for ActA signaling in wound closure; after injury, a severe delay in wound healing and reduced granulation tissue formation was observed with inhibition of ActA.	('Follistatin', 'Gene', '14313', (129, 140))	('delay', 'NegReg', (260, 265))	('granulation tissue formation', 'CPA', (295, 323))	('inhibition', 'Var', (342, 352))	('squamous epithelia', 'Phenotype', 'HP:0002860', (57, 75))	('wound healing', 'CPA', (269, 282))	('reduced', 'NegReg', (287, 294))	('transgenic mice', 'Species', '10090', (161, 176))	('Follistatin', 'Gene', (129, 140))
473816	31369967	Surprisingly, transgenic mice overexpressing ActA in epidermal keratinocytes display enhanced granulation tissue formation after wounding as well as epidermal hyperplasia and dermal fibrosis in normal skin.	('hyperplasia', 'Disease', (159, 170))	('granulation tissue formation after wounding', 'CPA', (94, 137))	('enhanced', 'PosReg', (85, 93))	('fibrosis', 'Disease', (182, 190))	('transgenic mice', 'Species', '10090', (14, 29))	('hyperplasia', 'Disease', 'MESH:D006965', (159, 170))	('fibrosis', 'Disease', 'MESH:D005355', (182, 190))	('ActA', 'Var', (45, 49))
473828	31369967	Based on murine models such as the IL-1beta transgenic model of chronic esophagitis and a model by Wang, in which damage at the squamous columnar junction lead to an expansion of KRT7+ progenitors cells in the cardia, it is thought that the migration of precursor cells from the neighboring gastric cardia or the squamous columnar junction is responsible for the replacement of the injured squamous epithelium with a metaplastic columnar epithelium.	('esophagitis', 'Disease', (72, 83))	('cardia', 'Disease', 'MESH:D004938', (299, 305))	('IL-1beta', 'Gene', '16175', (35, 43))	('transgenic', 'Species', '10090', (44, 54))	('gastric cardia or the squamous columnar junction', 'Disease', 'MESH:D004938', (291, 339))	('esophagitis', 'Disease', 'MESH:D004938', (72, 83))	('cardia', 'Disease', 'MESH:D004938', (210, 216))	('squamous columnar junction', 'Disease', 'MESH:D002294', (128, 154))	('KRT7', 'Gene', (179, 183))	('esophagitis', 'Phenotype', 'HP:0100633', (72, 83))	('squamous columnar junction', 'Disease', (128, 154))	('damage', 'Var', (114, 120))	('IL-1beta', 'Gene', (35, 43))	('KRT7', 'Gene', '110310', (179, 183))	('cardia', 'Disease', (299, 305))	('squamous columnar junction', 'Disease', 'MESH:D002294', (313, 339))	('murine', 'Species', '10090', (9, 15))	('cardia', 'Disease', (210, 216))	('expansion', 'PosReg', (166, 175))	('gastric cardia or the squamous columnar junction', 'Disease', (291, 339))
473830	31369967	This process has been coined paligenosis, which supports injury repair and regeneration but can also introduce an increased risk for tumorigenesis, as mutations can accumulate and propagate during phases of de-and re-differentiation.	('mutations', 'Var', (151, 160))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
473834	31369967	De-differentiation of keratinocytes is often suspected to accompany tissue repair and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tissue repair', 'CPA', (68, 81))	('tumor', 'Disease', (86, 91))	('De-differentiation', 'Var', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
473863	31354211	In high-risk areas of esophageal cancer in China, squatting down to eat hot food can increase the risk of esophageal cancer (OR=4.13, 95% CI: 2.13-8.05).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('squatting', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('hot', 'Gene', '137872', (72, 75))	('esophageal cancer', 'Disease', (106, 123))	('hot', 'Gene', (72, 75))
473893	30719108	Wang et al identified that the rs3200401 CC genotype of MALAT1 was associated with poor survival for patients with advanced lung adenocarcinoma.	('patients', 'Species', '9606', (101, 109))	('MALAT1', 'Gene', '378938', (56, 62))	('rs3200401', 'Mutation', 'rs3200401', (31, 40))	('rs3200401 CC', 'Var', (31, 43))	('MALAT1', 'Gene', (56, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('advanced lung adenocarcinoma', 'Disease', (115, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('poor', 'NegReg', (83, 87))	('advanced lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 143))
473920	30719108	Overall, the pooled results confirmed a significant association between high MALAT1 expression and poor OS in digestive system malignancies, with a HR value of 1.62 (95% CI, 1.35-1.88; P<0.001; Fig.	('OS', 'Chemical', '-', (104, 106))	('system malignancies', 'Disease', (120, 139))	('system malignancies', 'Disease', 'MESH:D009369', (120, 139))	('MALAT1', 'Gene', (77, 83))	('MALAT1', 'Gene', '378938', (77, 83))	('expression', 'MPA', (84, 94))	('poor OS', 'Disease', (99, 106))	('high', 'Var', (72, 76))
473922	30719108	A significant association was identified between the expression of MALAT1 and the OS of patients with digestive system malignant tumors in China (HR, 1.63; 95% CI, 1.34-1.91).	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('malignant tumors', 'Disease', (119, 135))	('expression', 'Var', (53, 63))	('patients', 'Species', '9606', (88, 96))	('malignant tumors', 'Disease', 'MESH:D018198', (119, 135))	('MALAT1', 'Gene', '378938', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MALAT1', 'Gene', (67, 73))	('digestive system malignant tumors', 'Phenotype', 'HP:0006749', (102, 135))	('OS', 'Chemical', '-', (82, 84))
473923	30719108	The association between MALAT1 and OS was significant in studies with a sample size >=100 (HR, 1.57; 95% CI, 1.27-1.88; P<0.001) and <100 (HR, 1.76; 95% CI, 1.21-2.31; P<0.001).	('OS', 'Chemical', '-', (35, 37))	('MALAT1', 'Gene', '378938', (24, 30))	('MALAT1', 'Gene', (24, 30))	('<100', 'Var', (133, 137))
473951	30719108	The present study demonstrated that high expression levels of MALAT1 were associated with poor OS in patients (HR, 1.62; 95% CI, 1.35-1.88).	('expression levels', 'MPA', (41, 58))	('patients', 'Species', '9606', (101, 109))	('MALAT1', 'Gene', (62, 68))	('poor OS', 'Disease', (90, 97))	('OS', 'Chemical', '-', (95, 97))	('high', 'Var', (36, 40))	('MALAT1', 'Gene', '378938', (62, 68))
473952	30719108	Furthermore, subgroup analysis revealed a significant association between high expression of MALAT1 and disease prognosis, while country, type of cancer, sample size and analysis method did not significantly affect these pooled results.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('high expression', 'Var', (74, 89))	('disease prognosis', 'CPA', (104, 121))	('MALAT1', 'Gene', '378938', (93, 99))	('MALAT1', 'Gene', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
473959	30719108	Notably, a Chinese study identified a positive association between single nucleotide polymorphisms in MALAT1 and cancer risk, therefore, genetic variants in MALAT1 may serve crucial roles in the development of cancer in Chinese populations.	('MALAT1', 'Gene', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('MALAT1', 'Gene', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('single nucleotide polymorphisms', 'Var', (67, 98))	('positive', 'PosReg', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('MALAT1', 'Gene', '378938', (102, 108))	('cancer', 'Disease', (210, 216))	('MALAT1', 'Gene', '378938', (157, 163))
474214	28615060	After backwards selection, MVA (Table 3) revealed that cumulative radiation dose >56Gy and ICHT were independent positive predictive factors for DFS [(p < 0.03) and (p < 0.02), respectively], and OS [(p < 0.006) and (p < 0.004), respectively].	('ICHT', 'Disease', (91, 95))	('>56Gy', 'Var', (81, 86))	('ICHT', 'Disease', 'None', (91, 95))	('DFS', 'Disease', (145, 148))
474243	28615060	reported that OS, cause specific survival (CSS), and local relapse-free survival (LRFS) rates were significantly higher in patients receiving a radiation dose >50Gy than in those < 50Gy.	('patients', 'Species', '9606', (123, 131))	('local relapse-free survival', 'CPA', (53, 80))	('higher', 'PosReg', (113, 119))	('CSS', 'Chemical', '-', (43, 46))	('>50Gy', 'Var', (159, 164))	('cause specific survival', 'CPA', (18, 41))
474265	28538413	The pathological and molecular tests revealed his diagnosis of BRAF-mutant, advanced PMME with localized pulmonary metastasis.	('BRAF-mutant', 'Var', (63, 74))	('PMME', 'Disease', (85, 89))	('localized pulmonary metastasis', 'Disease', (95, 125))	('localized pulmonary metastasis', 'Disease', 'MESH:D009362', (95, 125))	('PMME', 'Chemical', '-', (85, 89))
474293	28538413	In addition, molecular study of the patient indicated mutation of V-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E.	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (66, 112))	('BRAF', 'Gene', (114, 118))	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', (66, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('V600E', 'Mutation', 'rs113488022', (120, 125))	('V600E', 'Var', (120, 125))	('patient', 'Species', '9606', (36, 43))
474320	28538413	A meta-analysis of present trials shows that PD-1 and PD-L1 inhibitors are associated with improved response rates and durability, and also tolerable toxicity in advanced melanoma patients.	('durability', 'CPA', (119, 129))	('PD-1', 'Gene', (45, 49))	('toxicity', 'Disease', 'MESH:D064420', (150, 158))	('inhibitors', 'Var', (60, 70))	('toxicity', 'Disease', (150, 158))	('PD-L1', 'Gene', (54, 59))	('response rates', 'CPA', (100, 114))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('PD-L1', 'Gene', '29126', (54, 59))	('improved', 'PosReg', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('patients', 'Species', '9606', (180, 188))
474322	28538413	BRAF inhibitors, as compared with conventional chemotherapy, improve progression-free survival of patients with BRAF mutation, which is found in 50% of the advanced melanoma patients.	('improve', 'PosReg', (61, 68))	('progression-free survival', 'CPA', (69, 94))	('BRAF', 'Gene', (112, 116))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (174, 182))	('mutation', 'Var', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
474323	28538413	BRAF mutation, an independent prognostic factor of resected stage IIIB and IIIC melanoma, is associated with rapid progression and loco-regional recurrence of the disease.	('IIIC melanoma', 'Disease', (75, 88))	('IIIC melanoma', 'Disease', 'MESH:D008545', (75, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('associated', 'Reg', (93, 103))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
474324	28538413	A combination of BRAF and mitogen-activated protein kinase/extracellular signal-regulated kinase activator kinase (MEK) inhibitors could be considered as first-line or second-line therapy for BRAF mutant, previously untreated melanoma patients, as compared with BRAF inhibitor alone, which might reverse or delay the emergence of acquired resistance.	('acquired resistance', 'MPA', (330, 349))	('patients', 'Species', '9606', (235, 243))	('BRAF', 'Gene', (192, 196))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('mutant', 'Var', (197, 203))	('MEK', 'Gene', (115, 118))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('MEK', 'Gene', '5609', (115, 118))	('melanoma', 'Disease', (226, 234))
474325	28538413	Moreover, triple combination of immunotherapy, BRAF and MEK inhibitors may be another choice for refractory BRAF(V600E) mutant patients with metastatic melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('BRAF', 'Gene', (108, 112))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('V600E', 'Mutation', 'rs113488022', (113, 118))	('patients', 'Species', '9606', (127, 135))	('MEK', 'Gene', (56, 59))	('MEK', 'Gene', '5609', (56, 59))	('V600E) mutant', 'Var', (113, 126))	('mutant', 'Var', (120, 126))
474330	27323412	Here we found that miR-495 are lower in clinical ESCC tissues than in adjacent non-tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('lower', 'NegReg', (31, 36))	('miR-495', 'Var', (19, 26))	('ESCC', 'Disease', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
474333	27323412	miR-495 targeted a site in the 3'-UTR of Akt1, and miR-495 levels correlated inversely with Akt1 protein levels in ESCC tissue samples.	('Akt1', 'Gene', '207', (92, 96))	('Akt1', 'Gene', (41, 45))	('targeted', 'Reg', (8, 16))	('Akt1', 'Gene', '207', (41, 45))	('Akt1', 'Gene', (92, 96))	('miR-495', 'Var', (0, 7))
474335	27323412	In addition, miR-495 suppressed cell cycle transition and the EMT signaling pathway through targeting Akt1, thereby inhibiting ESCC cell proliferation, migration, and invasion.	('inhibiting', 'NegReg', (116, 126))	('migration', 'CPA', (152, 161))	('targeting', 'Reg', (92, 101))	('ESCC', 'Disease', (127, 131))	('suppressed', 'NegReg', (21, 31))	('Akt1', 'Gene', '207', (102, 106))	('invasion', 'CPA', (167, 175))	('EMT signaling pathway', 'Pathway', (62, 83))	('cell cycle transition', 'CPA', (32, 53))	('miR-495', 'Var', (13, 20))	('Akt1', 'Gene', (102, 106))
474336	27323412	Our results suggest that miR-495 may act as a tumor suppressor by targeting Akt1 in ESCC.	('miR-495', 'Var', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('ESCC', 'Disease', (84, 88))	('tumor', 'Disease', (46, 51))	('Akt1', 'Gene', (76, 80))	('targeting', 'Reg', (66, 75))	('Akt1', 'Gene', '207', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
474341	27323412	Deregulation of miRNAs has been reported to both activate and inhibit tumor progression.	('miRNAs', 'Protein', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Deregulation', 'Var', (0, 12))	('activate', 'PosReg', (49, 57))	('tumor', 'Disease', (70, 75))	('inhibit', 'NegReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
474342	27323412	For example, previous studies have demonstrated the dysregulation of miR-495 in multiple types of cancers, including pancreatic cancer, ovarian cancer, renal cancer, gastric cancer, hepatocellular cancer, and gallbladder cancer.	('gastric cancer', 'Disease', (166, 180))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('dysregulation', 'Var', (52, 65))	('cancers', 'Disease', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('gallbladder cancer', 'Disease', (209, 227))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('ovarian cancer', 'Disease', 'MESH:D010051', (136, 150))	('pancreatic cancer', 'Disease', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('hepatocellular cancer', 'Disease', (182, 203))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (182, 203))	('renal cancer', 'Disease', (152, 164))	('ovarian cancer', 'Disease', (136, 150))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (182, 203))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('renal cancer', 'Phenotype', 'HP:0009726', (152, 164))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('gallbladder cancer', 'Disease', 'MESH:D005706', (209, 227))	('miR-495', 'Gene', (69, 76))	('renal cancer', 'Disease', 'MESH:D007680', (152, 164))
474344	27323412	Additionally, bioinformatic analysis predicts that miR-495 might regulate the expression of Akt1 protein by directly targeting the 3'-UTR of its mRNA, which plays a central role in the PI3K/AKT pathway.	('Akt1', 'Gene', '207', (92, 96))	('expression', 'MPA', (78, 88))	('miR-495', 'Var', (51, 58))	('AKT', 'Gene', '207', (190, 193))	("3'-UTR of its mRNA", 'MPA', (131, 149))	('regulate', 'Reg', (65, 73))	('protein', 'Protein', (97, 104))	('AKT', 'Gene', (190, 193))	('targeting', 'Reg', (117, 126))	('Akt1', 'Gene', (92, 96))
474346	27323412	Furthermore, we experimentally confirmed that miR-495 decreased tumor progression in vitro and in vivo by directly targeting Akt1.	('tumor', 'Disease', (64, 69))	('Akt1', 'Gene', (125, 129))	('miR-495', 'Var', (46, 53))	('decreased', 'NegReg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('targeting', 'Reg', (115, 124))	('Akt1', 'Gene', '207', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
474352	27323412	The expression level of miR-495 was higher in human esophageal epithelial cell lines (HEEC) than in the ECA109, TE-1, and KYSE410 cell lines (Figure 1C).	('miR-495', 'Var', (24, 31))	('expression level', 'MPA', (4, 20))	('higher', 'PosReg', (36, 42))	('human', 'Species', '9606', (46, 51))	('HEEC', 'CellLine', 'None', (86, 90))
474356	27323412	Thus, miR-495 could directly target the seed region of the Akt1 3'-UTR.	('Akt1', 'Gene', '207', (59, 63))	('Akt1', 'Gene', (59, 63))	('miR-495', 'Var', (6, 13))
474361	27323412	Bivariate correlation analysis suggested a negative correlation between miR-495 expression and Akt1 protein levels (Figure 3F).	('Akt1', 'Gene', (95, 99))	('miR-495', 'Var', (72, 79))	('Akt1', 'Gene', '207', (95, 99))	('negative', 'NegReg', (43, 51))
474362	27323412	The studies about the expression levels of Akt1 mRNA in ESCC cell lines showed that, Akt1 mRNA expression was not obviously affected by the up- or down- regulation of miR-495 (Figure 3G and 3I).	('down- regulation', 'NegReg', (147, 163))	('Akt1', 'Gene', '207', (43, 47))	('up-', 'PosReg', (140, 143))	('Akt1', 'Gene', '207', (85, 89))	('Akt1', 'Gene', (43, 47))	('Akt1', 'Gene', (85, 89))	('miR-495', 'Var', (167, 174))	('expression', 'MPA', (95, 105))
474363	27323412	These studies indicated that miR-495 may suppress Akt1 protein levels by inhibiting translation rather than by affecting Akt1 mRNA stability.	('Akt1', 'Gene', '207', (121, 125))	('Akt1', 'Gene', '207', (50, 54))	('Akt1', 'Gene', (121, 125))	('translation', 'MPA', (84, 95))	('miR-495', 'Var', (29, 36))	('Akt1', 'Gene', (50, 54))	('suppress', 'NegReg', (41, 49))	('inhibiting', 'NegReg', (73, 83))
474364	27323412	To explore whether miR-495 inhibited ESCC cell viability by directly targeting STAT3, we adopted a "rescue" methodology.	('ESCC', 'Disease', (37, 41))	('targeting', 'Reg', (69, 78))	('STAT3', 'Gene', '6774', (79, 84))	('miR-495', 'Var', (19, 26))	('inhibited', 'NegReg', (27, 36))	('STAT3', 'Gene', (79, 84))
474366	27323412	As expected, Akt1 expression promoted ESCC cells growth and metastasis.	('promoted', 'PosReg', (29, 37))	('Akt1', 'Gene', '207', (13, 17))	('ESCC', 'Disease', (38, 42))	('metastasis', 'CPA', (60, 70))	('expression', 'Var', (18, 28))	('Akt1', 'Gene', (13, 17))
474367	27323412	In contrast, inhibition of AKT1 had the opposite effects (Figure 4B, 4C, 4D).	('AKT1', 'Gene', '207', (27, 31))	('AKT1', 'Gene', (27, 31))	('inhibition', 'Var', (13, 23))
474369	27323412	Western blots demonstrated that the Akt1 protein expression were significantly upregulated in cells treated with plasmid compared with those treated with the negative control, even though miR-495 was suppressed in these cells (Figure 5A).	('Akt1', 'Gene', '207', (36, 40))	('protein', 'Protein', (41, 48))	('plasmid', 'Var', (113, 120))	('Akt1', 'Gene', (36, 40))	('upregulated', 'PosReg', (79, 90))
474370	27323412	Moreover, restoration of Akt1 levels partially abolished the suppressive influence of miR-495s on cell growth and metastasis (Figure 5B, 5C, 5D).	('Akt1', 'Gene', (25, 29))	('miR-495s', 'Var', (86, 94))	('abolished', 'NegReg', (47, 56))	('Akt1', 'Gene', '207', (25, 29))
474371	27323412	Hence, our results suggest that the tumor-suppressing effects of miR-495 in ESCC might be a consequence of its ability to decrease Akt1 expression.	('expression', 'MPA', (136, 146))	('miR-495', 'Var', (65, 72))	('decrease', 'NegReg', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('Akt1', 'Gene', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('ESCC', 'Disease', (76, 80))	('Akt1', 'Gene', '207', (131, 135))	('tumor', 'Disease', (36, 41))
474373	27323412	The proteins Foxo1, p27kip1, p21Cip1, and Cyclin D1 were also regulated by miR-495 and Akt1 (Figure 6A).	('Cyclin D1', 'Gene', (42, 51))	('Foxo1', 'Gene', '2308', (13, 18))	('Foxo1', 'Gene', (13, 18))	('p21Cip1', 'Gene', '1026', (29, 36))	('Akt1', 'Gene', '207', (87, 91))	('Akt1', 'Gene', (87, 91))	('p27kip1', 'Gene', '1027', (20, 27))	('miR-495', 'Var', (75, 82))	('p21Cip1', 'Gene', (29, 36))	('p27kip1', 'Gene', (20, 27))	('Cyclin D1', 'Gene', '595', (42, 51))	('regulated', 'Reg', (62, 71))
474375	27323412	We examined the levels of epithelial and mesenchymal markers in ESCC cell lines transfected with miR-495 or Akt1.	('Akt1', 'Gene', '207', (108, 112))	('Akt1', 'Gene', (108, 112))	('miR-495', 'Var', (97, 104))
474376	27323412	Western blots revealed that the mesenchymal markers (Fibronectin and Vimentin) and epithelial markers (E-cadherin) were also regulated by miR-495 and Akt1.	('Akt1', 'Gene', (150, 154))	('Fibronectin', 'Gene', (53, 64))	('Fibronectin', 'Gene', '2335', (53, 64))	('Vimentin', 'Gene', (69, 77))	('miR-495', 'Var', (138, 145))	('Vimentin', 'Gene', '7431', (69, 77))	('Akt1', 'Gene', '207', (150, 154))	('mesenchymal markers', 'CPA', (32, 51))	('E-cadherin', 'Gene', (103, 113))	('E-cadherin', 'Gene', '999', (103, 113))	('regulated', 'Reg', (125, 134))
474378	27323412	Our findings suggested that miR-495 and Akt1 may regulate ESCC cell invasion and migration through regulating the EMT signaling pathway.	('miR-495', 'Var', (28, 35))	('regulating', 'Reg', (99, 109))	('Akt1', 'Gene', (40, 44))	('regulate', 'Reg', (49, 57))	('ESCC', 'Disease', (58, 62))	('migration', 'CPA', (81, 90))	('EMT signaling pathway', 'Pathway', (114, 135))	('Akt1', 'Gene', '207', (40, 44))
474379	27323412	Altered miRNA expression has been reported to be closely related with the initiation and progression of cancer by activating or inhibiting various processes.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('miRNA', 'Protein', (8, 13))	('Altered', 'Var', (0, 7))	('inhibiting', 'NegReg', (128, 138))	('activating', 'PosReg', (114, 124))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
474385	27323412	Our findings demonstrate that miR-495 can inhibit the progression of esophageal cancer.	('progression', 'CPA', (54, 65))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('miR-495', 'Var', (30, 37))	('inhibit', 'NegReg', (42, 49))
474386	27323412	A recent study demonstrated that miR-495 decreases cell proliferation and tumor angiogenesis by inhibiting the expression and activity of Runt-related transcription factor 3 (RUNX3) in gastric cancer cells.	('gastric cancer', 'Phenotype', 'HP:0012126', (185, 199))	('RUNX3', 'Gene', (175, 180))	('Runt-related transcription factor 3', 'Gene', '864', (138, 173))	('decreases', 'NegReg', (41, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (185, 199))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Runt-related transcription factor 3', 'Gene', (138, 173))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('expression', 'MPA', (111, 121))	('gastric cancer', 'Disease', (185, 199))	('tumor', 'Disease', (74, 79))	('cell proliferation', 'CPA', (51, 69))	('miR-495', 'Var', (33, 40))	('inhibiting', 'NegReg', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('activity', 'MPA', (126, 134))	('RUNX3', 'Gene', '864', (175, 180))
474387	27323412	To further explore the mechanisms underlying miR-495-mediated inhibition of ESCC cells ability, we examined whether miR-495 targeted Akt1.	('Akt1', 'Gene', (133, 137))	('miR-495', 'Var', (116, 123))	('Akt1', 'Gene', '207', (133, 137))
474392	27323412	Here, we demonstrated that miR-495 could inhibit ESCC cell growth and metastasis in vitro and in vivo by downregulating Akt1.	('miR-495', 'Var', (27, 34))	('Akt1', 'Gene', '207', (120, 124))	('inhibit', 'NegReg', (41, 48))	('ESCC', 'Disease', (49, 53))	('downregulating', 'NegReg', (105, 119))	('Akt1', 'Gene', (120, 124))
474393	27323412	Akt1 overexpression partially reversed the miR-495-mediated inhibition of ESCC cells ability.	('Akt1', 'Gene', (0, 4))	('Akt1', 'Gene', '207', (0, 4))	('ESCC cells ability', 'CPA', (74, 92))	('miR-495-mediated', 'Var', (43, 59))
474394	27323412	Our results demonstrated the anti-tumor effect of miR-495 and that miR-495 might be a useful prognostic marker for ESCC.	('ESCC', 'Disease', (115, 119))	('tumor', 'Disease', (34, 39))	('miR-495', 'Var', (50, 57))	('miR-495', 'Var', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
474396	27323412	Our results suggest that miR-495 could regulate the protein levels of Foxo1, p27kip1, p21Cip1, and Cyclin D1, all of these genes are downstream of Akt1, and subsequently inhibit cancer cell growth by promoting cell cycle arrest.	('regulate', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Akt1', 'Gene', '207', (147, 151))	('p21Cip1', 'Gene', '1026', (86, 93))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (210, 227))	('p21Cip1', 'Gene', (86, 93))	('Foxo1', 'Gene', '2308', (70, 75))	('Foxo1', 'Gene', (70, 75))	('p27kip1', 'Gene', '1027', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('protein levels', 'MPA', (52, 66))	('miR-495', 'Var', (25, 32))	('p27kip1', 'Gene', (77, 84))	('promoting', 'PosReg', (200, 209))	('Akt1', 'Gene', (147, 151))	('inhibit', 'NegReg', (170, 177))	('cell cycle arrest', 'CPA', (210, 227))	('Cyclin D1', 'Gene', '595', (99, 108))	('cancer', 'Disease', (178, 184))	('Cyclin D1', 'Gene', (99, 108))
474398	27323412	Overexpression of Foxo1 proteins can activate the cell cycle inhibitors, such as p27kip1 and p21Cip1, and suppress cell cycle promoters, such as cyclin D1, ultimately resulting in G1/S cell arrest.	('activate', 'PosReg', (37, 45))	('resulting in', 'Reg', (167, 179))	('proteins', 'Protein', (24, 32))	('cyclin D1', 'Gene', (145, 154))	('G1/S cell arrest', 'CPA', (180, 196))	('Foxo1', 'Gene', '2308', (18, 23))	('Foxo1', 'Gene', (18, 23))	('p21Cip1', 'Gene', (93, 100))	('p27kip1', 'Gene', (81, 88))	('Overexpression', 'Var', (0, 14))	('cell cycle promoters', 'MPA', (115, 135))	('p21Cip1', 'Gene', '1026', (93, 100))	('cell cycle', 'CPA', (50, 60))	('suppress', 'NegReg', (106, 114))	('p27kip1', 'Gene', '1027', (81, 88))	('cyclin D1', 'Gene', '595', (145, 154))
474399	27323412	Similarly, we found that miR-495 decreased Cyclin D1 and increased Foxo1, p27kip1, and p21Cip1 levels by reducing Akt1 protein levels.	('Akt1', 'Gene', '207', (114, 118))	('miR-495', 'Var', (25, 32))	('p21Cip1', 'Gene', (87, 94))	('Cyclin D1', 'Gene', '595', (43, 52))	('p27kip1', 'Gene', '1027', (74, 81))	('p27kip1', 'Gene', (74, 81))	('Cyclin D1', 'Gene', (43, 52))	('Akt1', 'Gene', (114, 118))	('p21Cip1', 'Gene', '1026', (87, 94))	('increased', 'PosReg', (57, 66))	('Foxo1', 'Gene', '2308', (67, 72))	('reducing', 'NegReg', (105, 113))	('Foxo1', 'Gene', (67, 72))	('decreased', 'NegReg', (33, 42))
474402	27323412	Restoring Akt1 levels in cells overexpressing miR-495 attenuated the latter's effects on mesenchymal cell-specific markers (Vimentin and Fibronectin) and epithelial cell-specific markers (E-cadherin).	('Vimentin', 'Gene', (124, 132))	('Fibronectin', 'Gene', '2335', (137, 148))	('Akt1', 'Gene', (10, 14))	('Fibronectin', 'Gene', (137, 148))	('mesenchymal cell-specific markers', 'CPA', (89, 122))	('Vimentin', 'Gene', '7431', (124, 132))	('E-cadherin', 'Gene', (188, 198))	('E-cadherin', 'Gene', '999', (188, 198))	('miR-495', 'Var', (46, 53))	('Akt1', 'Gene', '207', (10, 14))	('attenuated', 'NegReg', (54, 64))
474403	27323412	In the present study, miR-495 has been demonstrated to be downregulated in ESCC tumor specimens and was negatively correlated with Akt1 protein levels.	('ESCC tumor', 'Disease', (75, 85))	('negatively', 'NegReg', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('correlated', 'Interaction', (115, 125))	('ESCC tumor', 'Disease', 'MESH:D004938', (75, 85))	('miR-495', 'Var', (22, 29))	('downregulated', 'NegReg', (58, 71))	('Akt1', 'Gene', (131, 135))	('Akt1', 'Gene', '207', (131, 135))
474404	27323412	In addition, ectopic miR-495 expression inhibited ESCC cell proliferation, migration, and invasion through direct targeting of Akt1 and subsequently altering downstream protein levels.	('protein levels', 'MPA', (169, 183))	('miR-495', 'Gene', (21, 28))	('inhibited', 'NegReg', (40, 49))	('Akt1', 'Gene', '207', (127, 131))	('ectopic', 'Var', (13, 20))	('altering', 'Reg', (149, 157))	('invasion', 'CPA', (90, 98))	('migration', 'CPA', (75, 84))	('ESCC', 'Disease', (50, 54))	('Akt1', 'Gene', (127, 131))
474416	27323412	Lentiviral construct containing pre-miR-495 was packaged using the ViraPower Mix (Invitrogen, Carlsbad, CA).	('Mix', 'Gene', (77, 80))	('pre-miR-495', 'Var', (32, 43))	('Mix', 'Gene', '83881', (77, 80))
474420	27323412	For pGL3-Akt1-3'-UTR-Mut vector (Mt vector), the predicted binding region of miR-495 were mutated (Figure 2D).	('mutated', 'Var', (90, 97))	('binding', 'Interaction', (59, 66))	('pGL3', 'Gene', '6391', (4, 8))	('Akt1', 'Gene', (9, 13))	('pGL3', 'Gene', (4, 8))	('Akt1', 'Gene', '207', (9, 13))
474450	26444413	A large-scale genome-wide association study (GWAS) of a Chinese Han populations recently identified a new ESCC susceptibility locus at chromosome 18q12.2, tagged by a non-synonymous SNP of rs7242481, which is located in the 5'UTR in SLC39A6.	('rs7242481', 'Mutation', 'rs7242481', (189, 198))	('rs7242481', 'Var', (189, 198))	('ESCC', 'Disease', (106, 110))	('SLC39A6', 'Gene', '25800', (233, 240))	('SLC39A6', 'Gene', (233, 240))
474492	26444413	Four esophageal cancer cell lines (Eca109, EC9706, TE-1, and KYSE-150) and a normal esophageal epithelium (NEE) cell line (HEEC) were purchased from the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (Shanghai, China).	('HEEC', 'CellLine', 'None', (123, 127))	('EC9706', 'Var', (43, 49))	('esophageal cancer', 'Disease', (5, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (5, 22))	('EC9706', 'CellLine', 'CVCL:E307', (43, 49))
474532	26444413	2F, all esophageal cancer cell lines expressed high levels of modified SLC39A6 protein (68 kDa) compared with NEE cell.	('protein', 'Protein', (79, 86))	('SLC39A6', 'Gene', '25800', (71, 78))	('esophageal cancer', 'Disease', (8, 25))	('SLC39A6', 'Gene', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('modified', 'Var', (62, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (8, 25))
474533	26444413	Aberrant SLC39A6 expression in both ESCC tissues and ESCC cells suggests that increased SLC39A6 expression might be associated with tumor progression.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (17, 27))	('SLC39A6', 'Gene', '25800', (9, 16))	('expression', 'MPA', (96, 106))	('SLC39A6', 'Gene', '25800', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('increased', 'PosReg', (78, 87))	('SLC39A6', 'Gene', (9, 16))	('tumor', 'Disease', (132, 137))	('SLC39A6', 'Gene', (88, 95))	('associated', 'Reg', (116, 126))
474546	26444413	Patients with SLC39A6 overexpression had worse OS and greater risk of death after surgery than those with a weak or negative SLC39A6 expression (P = 0.009, Fig.	('SLC39A6', 'Gene', (14, 21))	('SLC39A6', 'Gene', '25800', (125, 132))	('SLC39A6', 'Gene', (125, 132))	('Patients', 'Species', '9606', (0, 8))	('death', 'Disease', 'MESH:D003643', (70, 75))	('death', 'Disease', (70, 75))	('overexpression', 'Var', (22, 36))	('SLC39A6', 'Gene', '25800', (14, 21))
474558	26444413	5e), and the number of colonies decreased by an average of four- to eightfold in ECA109 and EC9706 cells compared with that in the control cells (P < 0.05, n = 3, Fig.	('EC9706', 'CellLine', 'CVCL:E307', (92, 98))	('decreased', 'NegReg', (32, 41))	('EC9706', 'Var', (92, 98))
474560	26444413	5g-i, the results show a higher frequency of cells programmed for both early and late phases of apoptosis in SLC39A6 knockdown cells compared with that in vector controls.	('SLC39A6', 'Gene', (109, 116))	('SLC39A6', 'Gene', '25800', (109, 116))	('knockdown', 'Var', (117, 126))
474562	26444413	The late apoptosis rate for these cells increased by 13.38- and 6.39-fold respectively, indicating that downregulation of SLC39A6 promoted the apoptosis of ESCC cells.	('downregulation', 'Var', (104, 118))	('promoted', 'PosReg', (130, 138))	('apoptosis', 'CPA', (143, 152))	('SLC39A6', 'Gene', '25800', (122, 129))	('SLC39A6', 'Gene', (122, 129))
474565	26444413	The epithelial marker E-cadherin was significantly upregulated, whereas the mesenchymal markers vimentin was significantly reduced in Eca109 cells with knockdown of SLC39A6 compared with the controls siRNA groups (Fig.	('SLC39A6', 'Gene', (165, 172))	('knockdown', 'Var', (152, 161))	('mesenchymal', 'CPA', (76, 87))	('vimentin', 'Gene', (96, 104))	('epithelial', 'CPA', (4, 14))	('E-cadherin', 'Gene', (22, 32))	('E-cadherin', 'Gene', '999', (22, 32))	('upregulated', 'PosReg', (51, 62))	('SLC39A6', 'Gene', '25800', (165, 172))	('vimentin', 'Gene', '7431', (96, 104))	('reduced', 'NegReg', (123, 130))
474566	26444413	In addition, cell morphology examination indicated that knockdown of SLC39A6 resulted in morphological changes in Eca109 cells (Fig.	('morphological changes', 'CPA', (89, 110))	('SLC39A6', 'Gene', '25800', (69, 76))	('SLC39A6', 'Gene', (69, 76))	('knockdown', 'Var', (56, 65))
474567	26444413	In the reciprocal experiments, we examined whether knocking down SLC39A6 would inhibit ESCC cell invasiveness using SLC39A6 siRNA.	('inhibit', 'NegReg', (79, 86))	('SLC39A6', 'Gene', '25800', (65, 72))	('men', 'Species', '9606', (24, 27))	('SLC39A6', 'Gene', (65, 72))	('knocking down', 'Var', (51, 64))	('SLC39A6', 'Gene', '25800', (116, 123))	('SLC39A6', 'Gene', (116, 123))	('ESCC cell invasiveness', 'CPA', (87, 109))
474574	26444413	SLC39A6, a member of a new subfamily of zinc transporters, is involved in maintaining the intracellular homeostasis of zinc, an ion that is essential in the control of gene transcription, differentiation, development and growth, suggesting that its altered distribution might promote tumorigenesis.	('intracellular', 'MPA', (90, 103))	('men', 'Species', '9606', (212, 215))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('altered', 'Var', (249, 256))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('SLC39A6', 'Gene', '25800', (0, 7))	('tumor', 'Disease', (284, 289))	('SLC39A6', 'Gene', (0, 7))	('promote', 'PosReg', (276, 283))
474592	26444413	We have, for the first time, independently observed that high SLC39A6 expression in Han and Kazakh patients with ESCC was associated with poor differentiation.	('SLC39A6', 'Gene', (62, 69))	('associated', 'Reg', (122, 132))	('ESCC', 'Disease', (113, 117))	('high', 'Var', (57, 61))	('patients', 'Species', '9606', (99, 107))	('expression', 'MPA', (70, 80))	('SLC39A6', 'Gene', '25800', (62, 69))	('poor differentiation', 'CPA', (138, 158))
474595	26444413	We also observed that high SLC39A6 expression in Kazakh patients was associated with TNM stage, but differ from those in Han.	('patients', 'Species', '9606', (56, 64))	('SLC39A6', 'Gene', (27, 34))	('TNM stage', 'Disease', (85, 94))	('high', 'Var', (22, 26))	('associated', 'Reg', (69, 79))	('expression', 'MPA', (35, 45))	('SLC39A6', 'Gene', '25800', (27, 34))
474597	26444413	Here, indirectly consistent with these previous reports, we found that knockdown of SLC39A6 expression significantly reduced proliferation and promoted ESCC cell apoptosis.	('reduced', 'NegReg', (117, 124))	('SLC39A6', 'Gene', '25800', (84, 91))	('proliferation', 'CPA', (125, 138))	('knockdown', 'Var', (71, 80))	('promoted', 'PosReg', (143, 151))	('SLC39A6', 'Gene', (84, 91))	('ESCC', 'Disease', (152, 156))
474601	26444413	Our studies indicate that the targeting of SLC39A6 might be potential therapeutic strategy for blocking ESCC proliferation by restriction specific minerals, such as zinc, via knockdown of SLC39A6.	('blocking', 'NegReg', (95, 103))	('ESCC', 'Disease', (104, 108))	('SLC39A6', 'Gene', '25800', (43, 50))	('knockdown', 'Var', (175, 184))	('SLC39A6', 'Gene', (43, 50))	('SLC39A6', 'Gene', '25800', (188, 195))	('SLC39A6', 'Gene', (188, 195))
474612	26444413	Given that the induction of EMT by ectopic expression of either the Twist or Snail transcription factors generated stem cell-like cells, we proposed that SLC39A6 might regulate the stemness of esophageal cancer and promote the invasion of ESCC cells by affecting the expression of STAT3 and Snail, which needs further exploration.	('Snail', 'Gene', '6615', (291, 296))	('Snail', 'Gene', (291, 296))	('Snail', 'Gene', (77, 82))	('affecting', 'Reg', (253, 262))	('Snail', 'Gene', '6615', (77, 82))	('promote', 'PosReg', (215, 222))	('STAT3', 'Gene', '6774', (281, 286))	('ESCC', 'Disease', (239, 243))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('stemness of esophageal cancer', 'Disease', (181, 210))	('STAT3', 'Gene', (281, 286))	('regulate', 'Reg', (168, 176))	('SLC39A6', 'Gene', '25800', (154, 161))	('stemness of esophageal cancer', 'Disease', 'MESH:D004938', (181, 210))	('ectopic', 'Var', (35, 42))	('invasion', 'CPA', (227, 235))	('SLC39A6', 'Gene', (154, 161))	('expression', 'MPA', (267, 277))
474619	26444413	Moreover, knockdown of SLC39A6 expression modulated the malignant phenotype of ESCC cells, resulting in significantly reduced proliferation and invasion with MET phenotype in vitro.	('proliferation', 'CPA', (126, 139))	('reduced', 'NegReg', (118, 125))	('invasion', 'CPA', (144, 152))	('modulated', 'Reg', (42, 51))	('SLC39A6', 'Gene', '25800', (23, 30))	('ESCC', 'Disease', (79, 83))	('malignant phenotype', 'CPA', (56, 75))	('SLC39A6', 'Gene', (23, 30))	('knockdown', 'Var', (10, 19))
474711	31345182	Thirdly, an S100AX-AKT3-related pathway was activated, which increased migration and metastasis of KYSE-180-12 Gy and KYE-180-30 Gy cells.	('migration', 'CPA', (71, 80))	('AKT3', 'Gene', (19, 23))	('increased', 'PosReg', (61, 70))	('KYSE-180-12 Gy', 'Var', (99, 113))	('KYE-180-30', 'Var', (118, 128))	('metastasis', 'CPA', (85, 95))	('AKT3', 'Gene', '10000', (19, 23))
474724	31345182	We obtained bulk cell RNA-seq data from KYSE-180, KYSE-180-12 Gy, KYSE-180-30 Gy cells, and primary and recurrent tumor tissues from an ESCC radiotherapy patient.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('patient', 'Species', '9606', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('KYSE-180-12', 'Var', (50, 61))
474733	31345182	These procedures were repeated either two or five times to achieve a total dose of either 12 Gy (KYSE-180-12 Gy and KYSE-150-12 Gy) or 30 Gy (KYSE-180-30 Gy and KYSE-150-30 Gy).	('KYSE-150-30 Gy', 'Var', (161, 175))	('KYSE-150-12', 'Var', (116, 127))	('KYSE-150', 'CellLine', 'CVCL:1348', (116, 124))	('KYSE-180-30 Gy', 'Var', (142, 156))	('KYSE-150', 'CellLine', 'CVCL:1348', (161, 169))
474822	31133018	It is worth mentioning that five of the six patients with a cT4 in the first time cohort had a SCC despite exclusion of patients with invasion in the aorta or trachea.	('SCC', 'Gene', '6317', (95, 98))	('patients', 'Species', '9606', (44, 52))	('cT4', 'Var', (60, 63))	('patients', 'Species', '9606', (120, 128))	('SCC', 'Gene', (95, 98))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))
474941	29070049	Analysis of the causes of failure after radical surgery in patients with PT3N0M0 thoracic esophageal squamous cell carcinoma and consideration of postoperative radiotherapy Five-year overall survival rate of TESCC after surgery is low (approximately 30% to 60%), so it is meaningful to discuss the significance of PORT.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (90, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('SCC', 'Gene', (210, 213))	('PT3N0M0', 'Var', (73, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('SCC', 'Phenotype', 'HP:0002860', (210, 213))	('SCC', 'Gene', '6317', (210, 213))	('patients', 'Species', '9606', (59, 67))	('esophageal squamous cell carcinoma', 'Disease', (90, 124))
474942	29070049	We retrospectively collected the data of 227 patients with PT3N0M0 esophageal cancer (EC).	('PT3N0M0', 'Var', (59, 66))	('patients', 'Species', '9606', (45, 53))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('EC', 'Phenotype', 'HP:0011459', (86, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))
474948	29070049	PORT is recommended to patients with PT3N0M0 upper TESCC.	('SCC', 'Gene', '6317', (53, 56))	('patients', 'Species', '9606', (23, 31))	('PT3N0M0', 'Var', (37, 44))	('SCC', 'Gene', (53, 56))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))
474950	29070049	Radical esophagectomy (RO) is the mainstay of treatment for PT3N0M0 thoracic esophageal squamous cell carcinoma (TESCC).	('Radical esophagectomy', 'Chemical', '-', (0, 21))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('PT3N0M0', 'Var', (60, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('SCC', 'Gene', (115, 118))	('Radical esophagectomy', 'Disease', (0, 21))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('SCC', 'Gene', '6317', (115, 118))
474954	29070049	reported that compared with surgery alone, postoperative assisted three-dimensional conformal radiotherapy (3D-CRT) decreased postoperative recurrence rate of PT3N0M0 TESCC and increased the 5-year disease-free survival (DFS) and OS.	('OS', 'Chemical', '-', (230, 232))	('PT3N0M0', 'Var', (159, 166))	('SCC', 'Gene', (169, 172))	('increased', 'PosReg', (177, 186))	('SCC', 'Phenotype', 'HP:0002860', (169, 172))	('SCC', 'Gene', '6317', (169, 172))	('decreased', 'NegReg', (116, 125))	('disease-free survival', 'CPA', (198, 219))
474993	29070049	These findings suggested that major postoperative failure for pT3N0M0 TESCC patients was attributed to mediastinal lymphatic recurrence.	('pT3N0M0', 'Var', (62, 69))	('mediastinal lymphatic', 'Disease', (103, 124))	('patients', 'Species', '9606', (76, 84))	('mediastinal lymphatic recurrence', 'Phenotype', 'HP:0100721', (103, 135))	('postoperative failure', 'Disease', 'MESH:D010149', (36, 57))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('postoperative failure', 'Disease', (36, 57))	('SCC', 'Gene', '6317', (72, 75))
475000	29070049	indicated that compared with those undergoing surgery alone, 3-year OS of patients with pT3N0M0 EC receiving PORT was increased by 8%; there was no difference in 5-year OS.	('patients', 'Species', '9606', (74, 82))	('OS', 'Chemical', '-', (169, 171))	('increased', 'PosReg', (118, 127))	('pT3N0M0 EC', 'Var', (88, 98))	('EC', 'Phenotype', 'HP:0011459', (96, 98))	('OS', 'Chemical', '-', (68, 70))
475002	29070049	demonstrated that the 5-year OS and progression-free survival rates were 74 and 71%, assuming that 3D-CRT was safe and effective for postoperative patients with pT2-3N0M0 EC, and the recurrence rate and survival rates were higher than previously reported in the literature.	('OS', 'Chemical', '-', (29, 31))	('survival rates', 'CPA', (203, 217))	('EC', 'Phenotype', 'HP:0011459', (171, 173))	('patients', 'Species', '9606', (147, 155))	('higher', 'PosReg', (223, 229))	('recurrence rate', 'CPA', (183, 198))	('pT2-3N0M0 EC', 'Var', (161, 173))
475011	29070049	Postoperative radiochemotherapy (PORCT) can improve the long-term survival of EC patients, but further studies are required to confirm whether PORCT can effectively reduce distant metastasis rate of the pT3N0M0 TESCC, thereby improving the survival rate.	('SCC', 'Phenotype', 'HP:0002860', (213, 216))	('distant metastasis rate', 'CPA', (172, 195))	('pT3N0M0', 'Var', (203, 210))	('SCC', 'Gene', '6317', (213, 216))	('EC', 'Phenotype', 'HP:0011459', (78, 80))	('survival', 'CPA', (240, 248))	('patients', 'Species', '9606', (81, 89))	('reduce', 'NegReg', (165, 171))	('improving', 'PosReg', (226, 235))	('SCC', 'Gene', (213, 216))
475025	29280467	The reoptimized VMAT62.5 VT plans showed improved sparing of the TV volume, but only the proton plans showed significant sparing for bone V10Gy and bone mean dose, especially for patients with a larger PTV.	('PTV', 'Chemical', '-', (202, 205))	('TV volume', 'CPA', (65, 74))	('bone V10Gy', 'CPA', (133, 143))	('bone mean dose', 'CPA', (148, 162))	('VMAT62.5', 'Var', (16, 24))	('sparing', 'MPA', (50, 57))	('patients', 'Species', '9606', (179, 187))	('VT', 'Disease', 'MESH:D017180', (25, 27))
475040	29280467	Studies of patients who underwent fractionated radiation therapy have indicated that at less than ~50 Gy, bone marrow has a large capacity for repair and regeneration (although this could require many months or even years).	('patients', 'Species', '9606', (11, 19))	('less than ~50 Gy', 'Var', (88, 104))	('repair', 'CPA', (143, 149))
475042	29280467	Most of the data concerning the risk of HT and bone marrow irradiation have been collected from studies of anal cancer or cervical cancer, in which the large planning treatment volumes (PTVs) often abut or overlap the pelvic bones (pelvis, sacrum, lumbar spine).	('cancer', 'Disease', (131, 137))	('anal cancer', 'Phenotype', 'HP:0032186', (107, 118))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('abut', 'Var', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cervical cancer', 'Disease', 'MESH:D002583', (122, 137))	('PTV', 'Chemical', '-', (186, 189))	('cervical cancer', 'Disease', (122, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('HT', 'Disease', 'MESH:D006973', (40, 42))
475043	29280467	Dose-volume metrics such as the mean pelvic bone dose and pelvic bone V10Gy and V20Gy (percentage of volume receiving >= xGy) have been linked to the risk of grade >=2 leukopenia and neutropenia, when the external contour of the pelvic bony structures was used as a surrogate for bone marrow irradiation.	('leukopenia', 'Disease', 'MESH:D007970', (168, 178))	('grade', 'Disease', (158, 163))	('neutropenia', 'Disease', (183, 194))	('V10Gy', 'Var', (70, 75))	('leukopenia', 'Phenotype', 'HP:0001882', (168, 178))	('neutropenia', 'Phenotype', 'HP:0001875', (183, 194))	('neutropenia', 'Disease', 'MESH:D009503', (183, 194))	('V20Gy', 'Var', (80, 85))	('leukopenia', 'Disease', (168, 178))	('linked', 'Reg', (136, 142))
475050	29280467	A recent study of 52 lung cancer patients treated with 3-dimensional (3D) conformal radiation therapy and IMRT found the TV dose parameters (mean dose, V20Gy, and V30Gy) were associated with the risk of grade >=3 leukopenia.	('associated', 'Reg', (175, 185))	('leukopenia', 'Disease', 'MESH:D007970', (213, 223))	('patients', 'Species', '9606', (33, 41))	('V30Gy', 'Var', (163, 168))	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('V20Gy', 'Var', (152, 157))	('leukopenia', 'Phenotype', 'HP:0001882', (213, 223))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('leukopenia', 'Disease', (213, 223))
475051	29280467	A study of 41 esophageal cancer patients investigated similar dose-volume parameters (TV mean dose, V20Gy, and V10Gy) to propose cutoff values to avoid the development of grade >=3 leukopenia.	('leukopenia', 'Disease', 'MESH:D007970', (181, 191))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('esophageal cancer', 'Disease', (14, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('leukopenia', 'Phenotype', 'HP:0001882', (181, 191))	('V10Gy', 'Var', (111, 116))	('V20Gy', 'Var', (100, 105))	('leukopenia', 'Disease', (181, 191))
475069	29280467	The median TV V10Gy for this group of patients was similar to that of the 3D50 plans (median 54.3%, IQR 47.9%-58.5%), VMAT50 plans (median 50.7%, IQR 46.6%-57.5%), and VMAT62.5 plans (median 51.0%, IQR 47.7%-58.4%), although the VMAT62.5bm plans showed a small reduction in TV V10Gy (median 45.5%, IQR 41.2%-51.1%).	('TV V10Gy', 'MPA', (274, 282))	('patients', 'Species', '9606', (38, 46))	('VMAT62.5bm', 'Var', (229, 239))	('reduction', 'NegReg', (261, 270))
475076	29280467	For the bone mean dose, a general increase in dose with PTV was seen for the 3D50, VMAT50, and VMAT62.5 plans.	('VMAT62.5', 'Var', (95, 103))	('PTV', 'Chemical', '-', (56, 59))	('VMAT50', 'Var', (83, 89))	('increase', 'PosReg', (34, 42))	('3D50', 'Var', (77, 81))	('bone mean dose', 'MPA', (8, 22))
475077	29280467	For 16 of 21 patients, the V10Gy dose was greater with the VMAT50 plans than with the 3D50 plans owing to the increased low-dose bath generated by the arc therapy technique.	('V10Gy dose', 'MPA', (27, 37))	('low-dose bath', 'MPA', (120, 133))	('increased', 'PosReg', (110, 119))	('greater', 'PosReg', (42, 49))	('patients', 'Species', '9606', (13, 21))	('VMAT50', 'Var', (59, 65))
475081	29280467	The SFO62.5 and VMAT62.5bm plans showed the lowest risk of HT, which was greatly reduced compared with the 3D50, VMAT50, and standard VMAT62.5 plans.	('VMAT62.5bm', 'Var', (16, 26))	('HT', 'Disease', 'MESH:D006973', (59, 61))	('SFO62.5', 'Var', (4, 11))
475084	29280467	The dose to the bones and TV was compared for each patient for SFO62.5 versus VMAT62.5 and SFO62.5 versus VMAT62.5bm (Fig.	('patient', 'Species', '9606', (51, 58))	('SFO62.5', 'Var', (91, 98))	('SFO62.5', 'Var', (63, 70))
475085	29280467	The SFO62.5 plans compared with the original VMAT plans reduced the mean dose to the bones by a median of 4.5 Gy (IQR 3.6-5.4; Z = -4.015; P<.001) or a median of 3.1 Gy (IQR 2.6-3.6; P=.002) compared with the reoptimized VMAT62.5bm plans.	('dose', 'MPA', (73, 77))	('original VMAT plans', 'Disease', (36, 55))	('SFO62.5 plans', 'Var', (4, 17))	('reduced', 'NegReg', (56, 63))	('plans', 'Var', (12, 17))	('original VMAT plans', 'Disease', 'MESH:D007280', (36, 55))
475087	29280467	On reoptimization of the VMAT plans, the median reduction with SFO62.5 became 0.2% (IQR -1.9% to 1.3%) and did not appear to correlate with either the percentage of TV overlap (r=-0.125; n=20; P=.601) or PTV (not shown).	('PTV', 'Chemical', '-', (204, 207))	('reduction', 'NegReg', (48, 57))	('SFO62.5', 'Var', (63, 70))
475155	26497059	We found that the incidence of POCD in elderly patients undergoing major surgery was higher in those receiving sevoflurane general anesthesia than those receiving total intravenous anesthesia with propofol.	('sevoflurane', 'Var', (111, 122))	('POCD', 'Disease', (31, 35))	('higher', 'PosReg', (85, 91))	('patients', 'Species', '9606', (47, 55))	('POCD', 'Chemical', '-', (31, 35))	('propofol', 'Chemical', 'MESH:D015742', (197, 205))	('sevoflurane', 'Chemical', 'MESH:D000077149', (111, 122))
475156	26497059	We also found that methylprednisolone afforded a degree of neuroprotection in those receiving sevoflurane anesthesia, and that POCD was associated with elevated postoperative plasma concentrations of TNF-alpha, IL-6 and S100beta protein.	('TNF-alpha', 'Protein', (200, 209))	('neuroprotection', 'CPA', (59, 74))	('elevated', 'PosReg', (152, 160))	('POCD', 'Chemical', '-', (127, 131))	('plasma concentrations', 'MPA', (175, 196))	('methylprednisolone', 'Chemical', 'MESH:D008775', (19, 37))	('POCD', 'Var', (127, 131))	('sevoflurane', 'Chemical', 'MESH:D000077149', (94, 105))	('S100beta', 'Gene', '6285', (220, 228))	('S100beta', 'Gene', (220, 228))
475159	26497059	Exposure to a low concentration of halothane or N2O reportedly causes visual impairment, and reduces instantaneous memory, and athletic and cognitive abilities.	('halothane', 'Chemical', 'MESH:D006221', (35, 44))	('visual impairment', 'Disease', 'MESH:D014786', (70, 87))	('reduces', 'NegReg', (93, 100))	('visual impairment', 'Phenotype', 'HP:0000505', (70, 87))	('N2O', 'Var', (48, 51))	('causes', 'Reg', (63, 69))	('N2O', 'Chemical', 'MESH:D009609', (48, 51))	('instantaneous memory', 'CPA', (101, 121))	('visual impairment', 'Disease', (70, 87))
475174	26497059	Administration of a neutralizing antibody for IL-6 also significantly improves long-term potentiation (LTP) and spatial memory in rats.	('IL-6', 'Gene', (46, 50))	('rats', 'Species', '10116', (130, 134))	('neutralizing antibody', 'Var', (20, 41))	('spatial memory', 'CPA', (112, 126))	('long-term potentiation', 'CPA', (79, 101))	('improves', 'PosReg', (70, 78))
475190	25896907	Genetic polymorphisms of NAMPT related with susceptibility to esophageal Squamous cell carcinoma Nicotinamide phosphoribosyl transferase (Nampt) plays a crucial role in tumorigenesis.	('esophageal Squamous cell carcinoma', 'Disease', 'MESH:D000077277', (62, 96))	('NAMPT', 'Gene', (25, 30))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('esophageal Squamous cell carcinoma', 'Disease', (62, 96))	('related', 'Reg', (31, 38))	('polymorphisms', 'Var', (8, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
475193	25896907	Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), genotypes at rs61330082, rs2505568 and rs9034 of NAMPT were identified.	('rs61330082', 'Var', (98, 108))	('rs2505568', 'Mutation', 'rs2505568', (110, 119))	('rs2505568', 'Var', (110, 119))	('NAMPT', 'Gene', (134, 139))	('rs61330082', 'Mutation', 'rs61330082', (98, 108))	('rs9034', 'Mutation', 'rs9034', (124, 130))	('rs9034', 'Var', (124, 130))
475194	25896907	The presence of genotypes CT and TT and allele T at rs61330082 was less frequent in ESCC cases than in controls (48.89% vs. 53.33%, P < 0.01, 95% CI: 0.33-0.68; 18.52% vs. 30.37%, P < 0.01, 95% CI: 0.22-0.50; 42.96% vs. 57.04%, P < 0.01, 95% CI: 0.38-0.61; respectively).	('rs61330082', 'Mutation', 'rs61330082', (52, 62))	('rs61330082', 'Var', (52, 62))	('ESCC', 'Disease', (84, 88))
475195	25896907	No statistically significant differences existed in the distributions of genotypes or alleles at rs2505568 or rs9034 between ESCC cases and controls.	('rs2505568', 'Mutation', 'rs2505568', (97, 106))	('rs2505568', 'Var', (97, 106))	('rs9034', 'Mutation', 'rs9034', (110, 116))	('ESCC', 'Disease', (125, 129))	('rs9034', 'Var', (110, 116))
475205	25896907	Three SNPs of NAMPT, including rs61330082 in the promoter region and rs2505568 and rs9034 in the 3'untranslated region (3' UTR), were selected for this study because of their potential effects on the influence of Nampt expression.	('rs61330082', 'Mutation', 'rs61330082', (31, 41))	('rs2505568', 'Mutation', 'rs2505568', (69, 78))	('rs2505568', 'Var', (69, 78))	('rs61330082', 'Var', (31, 41))	('rs9034', 'Mutation', 'rs9034', (83, 89))	('rs9034', 'Var', (83, 89))
475209	25896907	Genotypes at rs61330082, rs2505568 and rs9034 of NAMPT were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).	('rs9034', 'Mutation', 'rs9034', (39, 45))	('NAMPT', 'Gene', (49, 54))	('rs61330082', 'Var', (13, 23))	('rs2505568', 'Mutation', 'rs2505568', (25, 34))	('rs9034', 'Var', (39, 45))	('rs2505568', 'Var', (25, 34))	('rs61330082', 'Mutation', 'rs61330082', (13, 23))
475210	25896907	Sequencing primers for rs61330082 and rs2505568 were used as previously described, and primers for rs9034 were designed using PRIMER 5.0 software (Canada).	('rs61330082', 'Var', (23, 33))	('rs2505568', 'Var', (38, 47))	('rs9034', 'Mutation', 'rs9034', (99, 105))	('rs61330082', 'Mutation', 'rs61330082', (23, 33))	('rs2505568', 'Mutation', 'rs2505568', (38, 47))
475218	25896907	Thus, subjects with genotypes CT or TT or allele Tat rs61330082 were less susceptible to ESCC (OR = 0.47, 95% CI: 0.33-0.68; OR = 0.33, 95% CI: 0.22-0.50; OR = 0.48, 95% CI: 0.38-0.61; respectively).	('rs61330082', 'Mutation', 'rs61330082', (53, 63))	('ESCC', 'Disease', (89, 93))	('rs61330082', 'Var', (53, 63))	('less', 'NegReg', (69, 73))	('susceptible', 'MPA', (74, 85))
475227	25896907	Considering the rs61330082 loci in the promoter region, its genetic mutation might influence the structure or function of Nampt protein.	('rs61330082', 'Var', (16, 26))	('function', 'MPA', (110, 118))	('rs61330082', 'Mutation', 'rs61330082', (16, 26))	('structure', 'MPA', (97, 106))	('influence', 'Reg', (83, 92))	('Nampt protein', 'Protein', (122, 135))
475231	25896907	In spite of the importance of the 3' UTR on the regulation of gene expression, polymorphisms at rs2505568 and rs9034 were found to be independent risk factors for the development of ESCC, also partially coinciding with Zhang's study, although pathogenesis between ESCC and bladder cancer is comparatively limited.	('rs2505568', 'Mutation', 'rs2505568', (96, 105))	('bladder cancer', 'Disease', 'MESH:D001749', (273, 287))	('bladder cancer', 'Disease', (273, 287))	('polymorphisms', 'Var', (79, 92))	('ESCC', 'Disease', (182, 186))	('bladder cancer', 'Phenotype', 'HP:0009725', (273, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('risk factors', 'Reg', (146, 158))	('rs9034', 'Mutation', 'rs9034', (110, 116))	('rs9034', 'Var', (110, 116))
475277	25421419	This study suggests a reduced risk of esophageal SCC with higher GL level particularly in men, but provides no evidence for the role of GI in the development of esophageal cancer.	('esophageal SCC', 'Disease', 'MESH:D004941', (38, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('GL level', 'MPA', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('men', 'Species', '9606', (90, 93))	('higher', 'Var', (58, 64))	('men', 'Species', '9606', (153, 156))	('reduced', 'NegReg', (22, 29))	('esophageal cancer', 'Disease', (161, 178))	('esophageal SCC', 'Disease', (38, 52))
475278	25421419	In addition, increased fiber intake appears to be associated with lower risk of all histological types of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('fiber', 'Chemical', 'MESH:D004043', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('fiber intake', 'Var', (23, 35))	('lower', 'NegReg', (66, 71))	('esophageal cancer', 'Disease', (106, 123))	('increased', 'PosReg', (13, 22))
475287	25421419	Further, a high-GI diet may increase cancer risk by modulating the insulin-like-growth factor (IGF) axis.	('insulin', 'Gene', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('high-GI', 'Var', (11, 18))	('insulin', 'Gene', '3630', (67, 74))	('cancer', 'Disease', (37, 43))	('modulating', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('increase', 'PosReg', (28, 36))
475306	25421419	The cases consisted of 299 (M/F 271/28) EAC cases, 337 (M/F 289/48) EGJAC cases, and 245 (M/F147/98) ESCC cases for analysis.	('M/F 289', 'Var', (56, 63))	('EAC', 'Disease', (40, 43))	('M/F147', 'Var', (90, 96))	('M/F 289', 'SUBSTITUTION', 'None', (56, 63))	('M/F 271', 'SUBSTITUTION', 'None', (28, 35))	('M/F 271', 'Var', (28, 35))	('M/F147', 'SUBSTITUTION', 'None', (90, 96))
475365	25421419	It has been suggested that the direction and magnitude of glycemic indicators-cancer associations may be explained by the way in which high GI or high GL track with other dietary and lifestyle factors related to cancer development.	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('high GI', 'Var', (135, 142))	('high GL', 'Var', (146, 153))	('men', 'Species', '9606', (226, 229))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('associations', 'Interaction', (85, 97))
475412	25358439	It is reported that EREG is epigenetically silenced in gastric cancer cells by aberrant DNA methylation and histone modification.	('gastric cancer', 'Disease', (55, 69))	('EREG', 'Gene', '2069', (20, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('EREG', 'Gene', (20, 24))	('histone modification', 'MPA', (108, 128))	('aberrant DNA methylation', 'Var', (79, 103))
475426	24666414	High Lgr5 expression was significantly correlated with lymph node metastasis (p = 0.003), late stage (p = 0.003) and unfavorable response to chemotherapy (p = 0.013) according to RECIST 1.0 criteria.	('High', 'Var', (0, 4))	('correlated', 'Reg', (39, 49))	('late stage', 'CPA', (90, 100))	('Lgr5', 'Gene', (5, 9))	('expression', 'MPA', (10, 20))	('Lgr5', 'Gene', '8549', (5, 9))	('lymph node metastasis', 'CPA', (55, 76))
475429	24666414	Furthermore, high levels of Lgr5 expression appeared to be associated with poorer survival in patients with SCCE.	('high levels', 'Var', (13, 24))	('Lgr5', 'Gene', (28, 32))	('patients', 'Species', '9606', (94, 102))	('associated', 'Reg', (59, 69))	('Lgr5', 'Gene', '8549', (28, 32))	('survival', 'MPA', (82, 90))	('SCCE', 'Disease', (108, 112))	('expression', 'MPA', (33, 43))	('poorer', 'NegReg', (75, 81))
475432	24666414	Perturbations in Wnt signaling cause human cancers .	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('Wnt signaling', 'Pathway', (17, 30))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cause', 'Reg', (31, 36))	('human', 'Species', '9606', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Perturbations', 'Var', (0, 13))
475461	24666414	High expression of Lgr5 was associated with a shorter overall survival time (Figure  3, p = 0.001).	('High', 'Var', (0, 4))	('overall survival', 'MPA', (54, 70))	('Lgr5', 'Gene', (19, 23))	('shorter', 'NegReg', (46, 53))	('Lgr5', 'Gene', '8549', (19, 23))
475462	24666414	The overall 1-, 2-, and 5-year cumulative survival rates in patients with high expression levels of Lgr5 were 20%, 0%, and 0%, respectively, compared with 70%, 40%, and 10% in patients with low Lgr5 expression.	('Lgr5', 'Gene', (100, 104))	('patients', 'Species', '9606', (176, 184))	('high expression', 'Var', (74, 89))	('patients', 'Species', '9606', (60, 68))	('Lgr5', 'Gene', (194, 198))	('Lgr5', 'Gene', '8549', (100, 104))	('Lgr5', 'Gene', '8549', (194, 198))
475476	24666414	The median survival in patients with high expression levels of Lgr5 was 7 months, which was 11 months shorter than in patients with lower expression of Lgr5.	('patients', 'Species', '9606', (23, 31))	('Lgr5', 'Gene', (152, 156))	('high expression levels', 'Var', (37, 59))	('Lgr5', 'Gene', '8549', (63, 67))	('patients', 'Species', '9606', (118, 126))	('Lgr5', 'Gene', '8549', (152, 156))	('Lgr5', 'Gene', (63, 67))
475487	24666414	Lgr5 knockdown was shown to induce cell death , and furthermore, a recently-developed monoclonal antibody (KM4056) was reported to have potent complement-dependent cytotoxicity activity in vitro, and to show strong anti-tumor activity in vivo .	('death', 'Disease', 'MESH:D003643', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('death', 'Disease', (40, 45))	('knockdown', 'Var', (5, 14))	('tumor', 'Disease', (220, 225))	('Lgr5', 'Gene', '8549', (0, 4))	('cytotoxicity', 'Disease', (164, 176))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('Lgr5', 'Gene', (0, 4))	('complement-dependent', 'MPA', (143, 163))	('cytotoxicity', 'Disease', 'MESH:D064420', (164, 176))
475491	24666414	In summary, overexpression of Lgr5 was significantly correlated with lymph node metastasis, tumor stage and response to chemotherapy, while high levels of Lgr5 expression were also associated with poor survival in patients with SCCE.	('associated', 'Reg', (181, 191))	('overexpression', 'PosReg', (12, 26))	('Lgr5', 'Gene', (155, 159))	('patients', 'Species', '9606', (214, 222))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('correlated', 'Reg', (53, 63))	('poor', 'NegReg', (197, 201))	('Lgr5', 'Gene', '8549', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Lgr5', 'Gene', '8549', (155, 159))	('tumor', 'Disease', (92, 97))	('Lgr5', 'Gene', (30, 34))	('lymph node metastasis', 'CPA', (69, 90))	('high levels', 'Var', (140, 151))
475571	18848939	Hepatocellular carcinoma developed in a similar proportion of peginterferon-treated patients, 4.5% (23/495), and controls, 4.9% (25/510).	('patients', 'Species', '9606', (84, 92))	('peginterferon-treated', 'Var', (62, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))
475590	18848939	The cumulative incidence of HCC 3 and 5 years after randomization was 5.3% and 13.1%, 2.4% and 5.7%, and 0.6% and 2.6% for patients with baseline platelet count <100, 100-149, and >150 x 1000/mm3, respectively.	('patients', 'Species', '9606', (123, 131))	('>150 x 1000/mm3', 'Var', (180, 195))	('HCC 3 and 5', 'Gene', '6358;4172', (28, 39))	('100-149', 'Var', (167, 174))	('<100', 'Var', (161, 165))
475639	12153764	SNO cells treated with DEN + FB1 showed greater cytotoxicity than did cells treated with FB1 alone, whereas FB1 appeared to inhibit the cytotoxic effect exerted by CAT alone.	('cytotoxic effect', 'CPA', (136, 152))	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('DEN + FB1', 'Var', (23, 32))	('cytotoxicity', 'Disease', (48, 60))	('inhibit', 'NegReg', (124, 131))	('DEN', 'Chemical', 'MESH:D004052', (23, 26))	('CAT', 'Chemical', 'MESH:C034221', (164, 167))
475648	33340431	The abnormal expression of MTA2 in ESCC contributed to the proliferation, metastasis, and EMT phenotype of ESCC cells through a novel EIF4E-Twist positive feedback loop.	('proliferation', 'CPA', (59, 72))	('Twist', 'Gene', (140, 145))	('abnormal', 'Var', (4, 12))	('EIF4E', 'Gene', (134, 139))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('EMT phenotype', 'CPA', (90, 103))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('contributed', 'Reg', (40, 51))	('metastasis', 'CPA', (74, 84))	('MTA2', 'Gene', (27, 31))	('Twist', 'Gene', '7291', (140, 145))	('EIF4E', 'Gene', '1977', (134, 139))
475660	33340431	17  Moreover, MTA2 has been shown to be associated with motile and anchorage-independent growth phenotypes of estrogen receptor alpha (ERalpha)-negative breast cancer cells, and higher levels of MTA2 have been associated with increased risk of early recurrence.	('estrogen receptor alpha', 'Gene', '2099', (110, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('breast cancer', 'Disease', (153, 166))	('early recurrence', 'CPA', (244, 260))	('higher levels', 'Var', (178, 191))	('MTA2', 'Gene', (14, 18))	('motile', 'CPA', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('estrogen receptor alpha', 'Gene', (110, 133))	('ERalpha', 'Gene', '2099', (135, 142))	('associated', 'Reg', (40, 50))	('ERalpha', 'Gene', (135, 142))
475661	33340431	18  Chen and colleagues also revealed that high MTA2 expression in pancreatic ductal adenocarcinoma serves as an independent biomarker for poor survival.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (67, 99))	('pancreatic ductal adenocarcinoma', 'Disease', (67, 99))	('high', 'Var', (43, 47))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (67, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('MTA2', 'Gene', (48, 52))	('expression', 'MPA', (53, 63))	('si', 'Chemical', 'MESH:D012825', (59, 61))
475700	33340431	Total RNA from human KYSE30 ESCC cells, in which MTA2 was stably knocked down, and control KYSE30 cells were isolated and quantified.	('MTA2', 'Gene', (49, 53))	('knocked down', 'Var', (65, 77))	('human', 'Species', '9606', (15, 20))
475721	33340431	For the tumor formation assay, 1 x 106 KYSE30/shNC or KYSE30/shMTA2 and KYSE30/CD511B or KYSE30/MTA2 cells in 100 muL PBS were injected subcutaneously into the right flank of each mouse.	('KYSE30/CD511B', 'Var', (72, 85))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mouse', 'Species', '10090', (180, 185))	('tumor', 'Disease', (8, 13))	('PBS', 'Chemical', 'MESH:D007854', (118, 121))
475739	33340431	Additionally, predictive analysis using 79 ESCC tissues with complete follow-up information revealed that high MTA2 expression in ESCC tissues was associated with reduced overall survival (Figure 1F), supplementing GEPIA data (http://gepia.cancer-pku.cn/index.html), in which high MTA2 expression was correlated with poor survival in mesothelioma (Figure S1d), adrenocortical carcinoma (Figure S1e), and hepatocellular liver carcinoma (Figure S1f), But it lacked survival data for ESCC.	('gepia.cancer-pku', 'Disease', 'MESH:D009369', (234, 250))	('hepatocellular liver', 'Phenotype', 'HP:0001404', (404, 424))	('MTA2', 'Gene', (281, 285))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (361, 385))	('high', 'Var', (276, 280))	('hepatocellular liver carcinoma', 'Disease', (404, 434))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('mesothelioma', 'Disease', (334, 346))	('hepatocellular liver carcinoma', 'Disease', 'MESH:D006528', (404, 434))	('expression', 'MPA', (286, 296))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (361, 385))	('mesothelioma', 'Disease', 'MESH:D008654', (334, 346))	('si', 'Chemical', 'MESH:D012825', (292, 294))	('adrenocortical carcinoma', 'Disease', (361, 385))	('hepatocellular liver carcinoma', 'Phenotype', 'HP:0001402', (404, 434))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (425, 434))	('poor', 'NegReg', (317, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('reduced', 'NegReg', (163, 170))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('gepia.cancer-pku', 'Disease', (234, 250))
475744	33340431	As shown in Figure 2A, after transfection with siRNA to knockdown the expression of MTA2, the wound healing process was delayed.	('MTA2', 'Gene', (84, 88))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('delayed', 'NegReg', (120, 127))	('wound healing process', 'CPA', (94, 115))	('expression', 'MPA', (70, 80))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('knockdown', 'Var', (56, 65))
475745	33340431	Moreover, the number of cells penetrating the membrane of the chambers in both the migration and invasion assays was significantly lower in the MTA2 knockdown group compared with that in the control group (Figure 2B,C).	('invasion assays', 'CPA', (97, 112))	('knockdown', 'Var', (149, 158))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('MTA2', 'Gene', (144, 148))	('lower', 'NegReg', (131, 136))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('migration', 'CPA', (83, 92))
475748	33340431	Moreover, we also found that compared with the controls, MTA2 depletion impeded KYSE30 and KYSE510 cell proliferation, based on an MTS assay (Figure S2c), while MTA2 overexpression promoted the viability of both cell lines (Figure S2d).	('KYSE510 cell proliferation', 'CPA', (91, 117))	('MTS', 'Gene', (131, 134))	('MTA2', 'Gene', (57, 61))	('KYSE510', 'CellLine', 'CVCL:1354', (91, 98))	('MTS', 'Gene', '8201', (131, 134))	('promoted', 'PosReg', (181, 189))	('depletion', 'Var', (62, 71))	('impeded', 'NegReg', (72, 79))	('si', 'Chemical', 'MESH:D012825', (176, 178))
475751	33340431	To further examine the oncogenic activity of MTA2 in tumor progression in vivo, we generated animal models by subcutaneously injecting KYSE30/shMTA2 or KYSE30/MTA2 cells into nude mice.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('KYSE30/shMTA2', 'Var', (135, 148))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('nude mice', 'Species', '10090', (175, 184))	('si', 'Chemical', 'MESH:D012825', (66, 68))
475752	33340431	Both the control and KYSE30/MTA2 groups formed tumors after injection, and the tumor formation rate in the KYSE30/shMTA2 group was 80% (4/5).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', (79, 84))	('KYSE30/shMTA2', 'Var', (107, 120))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
475753	33340431	Xenograft growth rate and average tumor weight were both lower in the MTA2 knockdown group compared with in the control group (Figure 3A).	('Xenograft growth rate', 'CPA', (0, 21))	('tumor', 'Disease', (34, 39))	('knockdown', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('MTA2', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('lower', 'NegReg', (57, 62))
475754	33340431	Moreover, expression levels of both the cell proliferation marker Ki-67 and the tumor angiogenesis marker CD31 were significantly reduced in MTA2 knockdown tumors (Figure 3B).	('knockdown', 'Var', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('expression levels', 'MPA', (10, 27))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('reduced', 'NegReg', (130, 137))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('CD31', 'MPA', (106, 110))	('MTA2', 'Gene', (141, 145))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('cell', 'CPA', (40, 44))	('tumors', 'Disease', (156, 162))
475755	33340431	In contrast, tumors formed by MTA2-overexpressed cells were markedly larger than those in the control group (Figure 3C).	('larger', 'PosReg', (69, 75))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('cells', 'Var', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('MTA2-overexpressed', 'Gene', (30, 48))
475760	33340431	These results strongly suggested that knockdown of MTA2 impeded the growth and metastasis of esophageal carcinoma cells in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('metastasis of esophageal carcinoma', 'Disease', (79, 113))	('MTA2', 'Gene', (51, 55))	('metastasis of esophageal carcinoma', 'Disease', 'MESH:D009362', (79, 113))	('impeded', 'NegReg', (56, 63))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (93, 113))	('knockdown', 'Var', (38, 47))
475765	33340431	As shown in Figure 4C, compared with the control cells, MTA2 deficiency repressed the expression of N-cadherin and vimentin, while the MTA2 knockdown group exhibited increased E-cadherin staining at the cell membrane.	('E-cadherin', 'Gene', '999', (176, 186))	('vimentin', 'Gene', '7431', (115, 123))	('increased', 'PosReg', (166, 175))	('vimentin', 'Gene', (115, 123))	('N-cadherin', 'Gene', (100, 110))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('N-cadherin', 'Gene', '1000', (100, 110))	('MTA2', 'Gene', (56, 60))	('E-cadherin', 'Gene', (176, 186))	('MTA2', 'Gene', (135, 139))	('deficiency', 'Var', (61, 71))
475776	33340431	Additionally, high EIF4E expression was correlated with low survival probability in patients with glioma (Figure S3a), patients with liver hepatocellular carcinoma (Figure S3b), and patients with lung adenocarcinoma (Figure S3c) in GEPIA analysis, indicating a similar function with MTA2.	('lung adenocarcinoma', 'Disease', (196, 215))	('patients', 'Species', '9606', (182, 190))	('EIF4E', 'Gene', '1977', (19, 24))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (133, 163))	('EIF4E', 'Gene', (19, 24))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (196, 215))	('patients', 'Species', '9606', (84, 92))	('expression', 'MPA', (25, 35))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (139, 163))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (196, 215))	('high', 'Var', (14, 18))	('glioma', 'Disease', (98, 104))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('si', 'Chemical', 'MESH:D012825', (261, 263))	('low', 'NegReg', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('liver hepatocellular carcinoma', 'Disease', (133, 163))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('patients', 'Species', '9606', (119, 127))	('survival', 'MPA', (60, 68))	('si', 'Chemical', 'MESH:D012825', (243, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))
475779	33340431	Firstly, knockdown of MTA2 decreased the expression of EIF4E, while overexpression of MTA2 exerts contrast function in level of EIF4E (Figure 6A).	('EIF4E', 'Gene', (128, 133))	('knockdown', 'Var', (9, 18))	('MTA2', 'Gene', (22, 26))	('expression', 'MPA', (41, 51))	('EIF4E', 'Gene', '1977', (55, 60))	('decreased', 'NegReg', (27, 36))	('EIF4E', 'Gene', '1977', (128, 133))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('EIF4E', 'Gene', (55, 60))
475780	33340431	Consistently, the immunohistochemistry results showed that the expression of EIF4E in transplanted tumors in the MTA2 knockdown group was decreased, while the expression of EIF4E in the MTA2 overexpression group was reversed (Figure 6B).	('EIF4E', 'Gene', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('MTA2', 'Gene', (113, 117))	('EIF4E', 'Gene', (77, 82))	('knockdown', 'Var', (118, 127))	('si', 'Chemical', 'MESH:D012825', (201, 203))	('decreased', 'NegReg', (138, 147))	('si', 'Chemical', 'MESH:D012825', (165, 167))	('expression', 'MPA', (63, 73))	('EIF4E', 'Gene', '1977', (173, 178))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('EIF4E', 'Gene', '1977', (77, 82))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('tumors', 'Disease', (99, 105))
475784	33340431	First, we knocked down or overexpressed EIF4E in ESCC cells (Figure S4a,b), and then transwell assays were performed.	('overexpressed', 'PosReg', (26, 39))	('EIF4E', 'Gene', (40, 45))	('knocked', 'Var', (10, 17))	('EIF4E', 'Gene', '1977', (40, 45))
475787	33340431	Accordingly, the inhibition of the migration and invasion that was induced by MTA2 knockdown was abrogated as a result of the forced expression of EIF4E.	('EIF4E', 'Gene', '1977', (147, 152))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('MTA2', 'Gene', (78, 82))	('abrogated', 'NegReg', (97, 106))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('EIF4E', 'Gene', (147, 152))	('inhibition', 'NegReg', (17, 27))	('knockdown', 'Var', (83, 92))
475788	33340431	However, knockdown of EIF4E in MTA2 overexpression cells could partially inhibit the increase in migration or invasion caused by MTA2 overexpression (Figure 6F).	('migration', 'CPA', (97, 106))	('knockdown', 'Var', (9, 18))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('si', 'Chemical', 'MESH:D012825', (144, 146))	('EIF4E', 'Gene', '1977', (22, 27))	('inhibit', 'NegReg', (73, 80))	('increase', 'PosReg', (85, 93))	('EIF4E', 'Gene', (22, 27))
475792	33340431	However, knocking down EIF4E with siRNAs demonstrated the opposite result (Figure 7B), and was in agreement with the pro-metastatic role of EIF4E.	('EIF4E', 'Gene', (23, 28))	('EIF4E', 'Gene', (140, 145))	('knocking down', 'Var', (9, 22))	('EIF4E', 'Gene', '1977', (23, 28))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('EIF4E', 'Gene', '1977', (140, 145))
475793	33340431	Then, rescue experiments showed that ectopic overexpression of EIF4E reversed the decrease in N-cadherin and vimentin levels caused by MTA2 depletion, while the MTA2-induced increase in N-cadherin and vimentin expression was inhibited by EIF4E absence.	('EIF4E', 'Gene', '1977', (63, 68))	('vimentin', 'Gene', '7431', (201, 209))	('MTA2', 'MPA', (135, 139))	('N-cadherin', 'Gene', '1000', (186, 196))	('decrease', 'NegReg', (82, 90))	('depletion', 'Var', (140, 149))	('vimentin', 'Gene', (201, 209))	('vimentin', 'Gene', '7431', (109, 117))	('N-cadherin', 'Gene', (94, 104))	('EIF4E', 'Gene', (63, 68))	('EIF4E', 'Gene', '1977', (238, 243))	('vimentin', 'Gene', (109, 117))	('si', 'Chemical', 'MESH:D012825', (216, 218))	('N-cadherin', 'Gene', (186, 196))	('N-cadherin', 'Gene', '1000', (94, 104))	('EIF4E', 'Gene', (238, 243))	('si', 'Chemical', 'MESH:D012825', (55, 57))
475794	33340431	Downregulation of MTA2 led to a promotion of E-cadherin and ZO-1 expression, but this promotion was greatly attenuated by EIF4E overexpression (Figure 7C,D).	('overexpression', 'PosReg', (128, 142))	('si', 'Chemical', 'MESH:D012825', (138, 140))	('ZO-1', 'Gene', (60, 64))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('EIF4E', 'Gene', (122, 127))	('Downregulation', 'Var', (0, 14))	('promotion', 'PosReg', (32, 41))	('expression', 'MPA', (65, 75))	('ZO-1', 'Gene', '7082', (60, 64))	('MTA2', 'Gene', (18, 22))	('EIF4E', 'Gene', '1977', (122, 127))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))
475809	33340431	The result suggested that, after MTA2 knockdown, the promoter acetylation level of E-cadherin was increased, while overexpression of MTA2 could decrease the level of acetylation (Figure 8G).	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('acetylation', 'MPA', (166, 177))	('promoter acetylation level', 'MPA', (53, 79))	('increased', 'PosReg', (98, 107))	('knockdown', 'Var', (38, 47))	('si', 'Chemical', 'MESH:D012825', (125, 127))	('MTA2', 'Gene', (33, 37))
475811	33340431	We found that the acetylation of E-cadherin was markedly increased upon MTA2 knockdown.	('E-cadherin', 'Gene', (33, 43))	('E-cadherin', 'Gene', '999', (33, 43))	('knockdown', 'Var', (77, 86))	('increased', 'PosReg', (57, 66))	('MTA2', 'Gene', (72, 76))	('acetylation', 'MPA', (18, 29))
475820	33340431	The rescue experiment showed that ectopic overexpression of Twist reversed the increase in E-cadherin and ZO-1 levels caused by MTA2 depletion, while expression of N-cadherin and vimentin was elevated after Twist reintroduction compared with that in the MTA2 knockdown group (Figure 8K).	('increase', 'PosReg', (79, 87))	('vimentin', 'Gene', (179, 187))	('N-cadherin', 'Gene', (164, 174))	('ZO-1', 'Gene', (106, 110))	('N-cadherin', 'Gene', '1000', (164, 174))	('Twist', 'Gene', '7291', (207, 212))	('MTA2', 'Gene', (128, 132))	('Twist', 'Gene', (60, 65))	('E-cadherin', 'Gene', (91, 101))	('elevated', 'PosReg', (192, 200))	('E-cadherin', 'Gene', '999', (91, 101))	('expression', 'MPA', (150, 160))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('Twist', 'Gene', (207, 212))	('Twist', 'Gene', '7291', (60, 65))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('depletion', 'Var', (133, 142))	('ZO-1', 'Gene', '7082', (106, 110))	('vimentin', 'Gene', '7431', (179, 187))
475823	33340431	Moreover, high MTA2 expression in ESCC tissues was associated with a poor survival prognosis.	('MTA2', 'Gene', (15, 19))	('expression', 'MPA', (20, 30))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('high', 'Var', (10, 14))
475831	33340431	Results showed that, compared with controls, MTA2 depletion suppressed the expression of mesenchymal markers, and upregulated the expression of epithelial markers.	('expression', 'MPA', (130, 140))	('upregulated', 'PosReg', (114, 125))	('suppressed', 'NegReg', (60, 70))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('MTA2', 'Gene', (45, 49))	('depletion', 'Var', (50, 59))	('epithelial', 'CPA', (144, 154))	('mesenchymal markers', 'CPA', (89, 108))	('expression', 'MPA', (75, 85))
475836	33340431	Among these genes, we found that eukaryotic initiation factor 4E (EIF4E) expression was consistently and significantly decreased in ESCC cells with depletion of MTA2 compared with that in controls.	('si', 'Chemical', 'MESH:D012825', (79, 81))	('decreased', 'NegReg', (119, 128))	('EIF4E', 'Gene', '1977', (66, 71))	('eukaryotic initiation factor 4E', 'Gene', '1977', (33, 64))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('MTA2', 'Gene', (161, 165))	('EIF4E', 'Gene', (66, 71))	('expression', 'MPA', (73, 83))	('eukaryotic initiation factor 4E', 'Gene', (33, 64))	('depletion', 'Var', (148, 157))	('ESCC', 'Disease', (132, 136))
475839	33340431	30  According to Pettersson and colleagues, inhibition of EIF4E reduced breast cancer cell metastasis by suppressing TGFbeta-induced EMT.	('suppressing', 'NegReg', (105, 116))	('EIF4E', 'Gene', '1977', (58, 63))	('inhibition', 'Var', (44, 54))	('TGFbeta', 'Gene', '7039', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('EIF4E', 'Gene', (58, 63))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('reduced', 'NegReg', (64, 71))	('breast cancer', 'Disease', (72, 85))	('TGFbeta', 'Gene', (117, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
475840	33340431	31  The phosphorylation of EIF4E promoted EMT and prostate tumor cell metastasis via translational control of SNAIL and MMP-3.	('SNAIL', 'Gene', '6615', (110, 115))	('SNAIL', 'Gene', (110, 115))	('promoted', 'PosReg', (33, 41))	('phosphorylation', 'Var', (8, 23))	('prostate tumor', 'Disease', (50, 64))	('EIF4E', 'Gene', '1977', (27, 32))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('prostate tumor', 'Phenotype', 'HP:0100787', (50, 64))	('MMP-3', 'Gene', '4314', (120, 125))	('EIF4E', 'Gene', (27, 32))	('MMP-3', 'Gene', (120, 125))	('prostate tumor', 'Disease', 'MESH:D011471', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
475841	33340431	28  In our present study, the introduction of exogenous EIF4E promoted ESCC cell migration and invasion, as well as the EMT phenotype compared with those of the controls.	('invasion', 'CPA', (95, 103))	('ESCC cell migration', 'CPA', (71, 90))	('EIF4E', 'Gene', '1977', (56, 61))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('EIF4E', 'Gene', (56, 61))	('introduction', 'Var', (30, 42))	('promoted', 'PosReg', (62, 70))	('EMT phenotype', 'CPA', (120, 133))
475854	33340431	Further studies indicated that MTA2 could reduce the acetylation level of E-cadherin, thus inhibiting expression of E-cadherin.	('inhibiting', 'NegReg', (91, 101))	('expression', 'MPA', (102, 112))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', (116, 126))	('E-cadherin', 'Gene', '999', (74, 84))	('MTA2', 'Var', (31, 35))	('acetylation level', 'MPA', (53, 70))	('E-cadherin', 'Gene', '999', (116, 126))	('reduce', 'NegReg', (42, 48))	('si', 'Chemical', 'MESH:D012825', (108, 110))
475856	33340431	Collectively, our findings illustrated that the aberrant expression of MTA2 promotes proliferation, invasion, and metastasis of human ESCC cells through regulation of EMT, which is mainly dependent on the EIF4E-Twist positive feedback loop (Figure 8L).	('Twist', 'Gene', (211, 216))	('MTA2', 'Gene', (71, 75))	('EIF4E', 'Gene', (205, 210))	('metastasis', 'CPA', (114, 124))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('aberrant expression', 'Var', (48, 67))	('EIF4E', 'Gene', '1977', (205, 210))	('invasion', 'CPA', (100, 108))	('human', 'Species', '9606', (128, 133))	('si', 'Chemical', 'MESH:D012825', (219, 221))	('promotes', 'PosReg', (76, 84))	('Twist', 'Gene', '7291', (211, 216))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('proliferation', 'CPA', (85, 98))	('EMT', 'Gene', (167, 170))
475858	31945090	Pan-cancer analysis of somatic mutations and epigenetic alterations in insulated neighbourhood boundaries Recent evidence shows that the disruption of constitutive insulated neighbourhoods might lead to oncogene dysregulation.	('mutations', 'Var', (31, 40))	('epigenetic alterations', 'Var', (45, 67))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('lead to', 'Reg', (195, 202))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('oncogene dysregulation', 'MPA', (203, 225))
475859	31945090	We present here a systematic pan-cancer characterisation of the associations between constitutive boundaries and genome alterations in cancer.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('genome alterations', 'Var', (113, 131))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('associations', 'Interaction', (64, 76))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
475860	31945090	Specifically, we investigate the enrichment of somatic mutation, abnormal methylation, and copy number alteration events in the proximity of CTCF bindings overlapping with topological boundaries (junctions) in 26 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('abnormal', 'Var', (65, 73))	('bindings', 'Interaction', (146, 154))	('CTCF', 'Gene', (141, 145))	('copy number', 'CPA', (91, 102))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('methylation', 'MPA', (74, 85))
475861	31945090	Focusing on CTCF motifs that are both in-boundary (overlapping with junctions) and active (overlapping with peaks of CTCF expression), we find a significant enrichment of somatic mutations in several cancer types.	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (200, 206))	('mutations', 'Var', (179, 188))
475862	31945090	Furthermore, mutated junctions are significantly conserved across cancer types, and we also observe a positive selection of transversions rather than transitions in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('transversions', 'Var', (124, 137))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutated', 'Var', (13, 20))	('cancer', 'Disease', (66, 72))
475864	31945090	Finally, in several cancer types we observe that copy number alterations tend to overlap with active junctions more often than in matched normal samples.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('copy number alterations', 'Var', (49, 72))	('cancer', 'Disease', (20, 26))	('active junctions', 'MPA', (94, 110))
475865	31945090	While several articles have recently reported a mutational enrichment at CTCF binding sites for specific cancer types, our analysis is pan-cancer and investigates abnormal methylation and copy number alterations in addition to somatic mutations.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutational', 'Var', (48, 58))	('cancer', 'Disease', (139, 145))
475870	31945090	Hypermethylation of CTCF binding sites has been observed to lead to loss of insulation between topological domains and consequent aberrant gene activation in gliomas.	('insulation between topological domains', 'MPA', (76, 114))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('Hypermethylation', 'Var', (0, 16))	('gene', 'MPA', (139, 143))	('activation', 'PosReg', (144, 154))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('loss', 'NegReg', (68, 72))	('gliomas', 'Disease', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))
475871	31945090	Microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent acute lymphoblastic leukemia proto-oncogenes have also been reported.	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (103, 125))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('lymphoblastic leukemia', 'Disease', (103, 125))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (97, 125))	('Microdeletions', 'Var', (0, 14))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (103, 125))
475872	31945090	The same study also identified an enrichment in boundary CTCF site mutations in the genomes of esophageal and liver carcinoma.	('esophageal', 'Disease', (95, 105))	('liver carcinoma', 'Disease', (110, 125))	('liver carcinoma', 'Disease', 'MESH:D006528', (110, 125))	('mutations', 'Var', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('CTCF', 'Gene', (57, 61))	('liver carcinoma', 'Phenotype', 'HP:0001402', (110, 125))
475873	31945090	Furthermore, genomic rearrangements with breakpoints within TADs can lead to breakage or fusion of TADs that might result in oncogene activation, as observed in prostate cancer, where chromosomal deletions lead to the establishment of new domain boundaries and the rearrangement of gene interactions.	('chromosomal deletions', 'Var', (184, 205))	('gene', 'Protein', (282, 286))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('rearrangements', 'Var', (21, 35))	('breakage', 'Var', (77, 85))	('activation', 'PosReg', (134, 144))	('oncogene', 'MPA', (125, 133))	('prostate cancer', 'Disease', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('rearrangement', 'Reg', (265, 278))	('lead', 'Reg', (69, 73))	('breakpoints', 'Var', (41, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (161, 176))	('interactions', 'Interaction', (287, 299))
475874	31945090	Hotspots of mutations within CTCF motifs have been independently observed in melanoma related to UV exposure, and in gastrointestinal cancers.	('CTCF motifs', 'Gene', (29, 40))	('gastrointestinal cancers', 'Disease', 'MESH:D005770', (117, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('mutations', 'Var', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('observed', 'Reg', (65, 73))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (117, 140))	('gastrointestinal cancers', 'Disease', (117, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
475883	31945090	While mutations in CTCF binding sites have been reported to occur frequently in several cancers, the significance of these findings across the broad spectrum of cancer types has not yet been evaluated.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('binding', 'Interaction', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CTCF', 'Gene', (19, 23))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (6, 15))	('occur', 'Reg', (60, 65))
475884	31945090	Specifically, we selected 14 cancer types for which at least 200,000 mutations across all patients were reported:this threshold was imposed in order to ensure adequate statistics.	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
475886	31945090	Fig 2, left subplot, shows the accumulation of mutations in esophageal adenocarcinoma (ESAD), one of the tumour types for which this phenomenon was more evident.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('ESAD', 'Phenotype', 'HP:0011459', (87, 91))	('ESAD', 'Disease', 'MESH:D004941', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (60, 85))	('esophageal adenocarcinoma', 'Disease', (60, 85))	('tumour', 'Disease', (105, 111))	('mutations', 'Var', (47, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (60, 85))	('ESAD', 'Disease', (87, 91))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
475894	31945090	Hence, it could be argued that the enrichment of mutations in active in-boundary motifs is due to the proximity of these motifs to promoters, rather than to a cancer specific mechanism.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('mutations', 'Var', (49, 58))
475897	31945090	In no cancer type did we observe an enrichment of mutations in promoters, supporting the hypothesis that the accumulation of mutations in active CTCF motifs is not due to the overlap of promoters, and hence, not due to the open state of the chromatin.	('mutations', 'Var', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (50, 59))	('CTCF motifs', 'Gene', (145, 156))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))
475899	31945090	We also tried to test if mutations tend to cluster on active enhancers, defined as the intersection of H3K4me1 and H3K27Ac histone modifications, but for such regions we found a very small intersection with active in-boundary CTCF motifs and it was not possible to perform a significative statistical test.	('H3K27Ac', 'Var', (115, 122))	('H3K4me1', 'Chemical', 'MESH:C024755', (103, 110))	('mutations', 'Var', (25, 34))
475901	31945090	Notably, in the list of oncogenes we find TGFB1, whose up-regulation has been recently associated with disruption of CTCF binding motif due to somatic mutations in the melanoma A375 cell line.	('up-regulation', 'PosReg', (55, 68))	('TGFB1', 'Gene', (42, 47))	('A375', 'CellLine', 'CVCL:0132', (177, 181))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('mutations', 'Var', (151, 160))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
475905	31945090	Next, we investigated whether the somatic mutations in active in-boundary motifs preferentially belong to a certain class of mutations, which could point to a specific tumourigenic mechanism.	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('tumour', 'Disease', (168, 174))	('point', 'Reg', (148, 153))	('mutations', 'Var', (42, 51))	('belong', 'Reg', (96, 102))
475907	31945090	Table 3 reports the counts of transition and transversion mutations for active in-boundary and active off-boundary motifs for all considered cancers.	('transversion mutations', 'Var', (45, 67))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
475911	31945090	Assuming that similar results can be generalised to somatic alterations, this finding suggests that transversions on CTCF motifs might have a stronger effect than transitions, which could hint towards a positive selection of transversions rather than transitions in insulated neighborhood boundaries in tumour cells, as these alterations are more likely to disrupt boundaries than transitions.	('neighborhood boundaries in tumour', 'Disease', (276, 309))	('neighborhood boundaries in tumour', 'Disease', 'MESH:D009369', (276, 309))	('tumour', 'Phenotype', 'HP:0002664', (303, 309))	('CTCF motifs', 'Gene', (117, 128))	('transversions', 'Var', (100, 113))
475913	31945090	We considered the five tumour types for which we have the highest number of mutations (see Table B in S1 File):and studied their mutation patterns.	('tumour', 'Disease', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('mutations', 'Var', (76, 85))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))
475914	31945090	Esophageal Adenocarcinoma (ESAD), Liver Cancer (LIRI) and Breast Cancer (BRCA) were associated with the largest enrichment of in-boundary mutations in all 3 considered ChIA-PET experiments (see Table 2).	('Liver Cancer', 'Disease', 'MESH:D006528', (34, 46))	('Breast Cancer', 'Disease', 'MESH:D001943', (58, 71))	('Liver Cancer', 'Phenotype', 'HP:0002896', (34, 46))	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('Breast Cancer', 'Disease', (58, 71))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004941', (0, 25))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Breast Cancer', 'Phenotype', 'HP:0003002', (58, 71))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ESAD', 'Disease', (27, 31))	('BRCA', 'Disease', (73, 77))	('Liver Cancer', 'Disease', (34, 46))	('mutations', 'Var', (138, 147))	('ESAD', 'Disease', 'MESH:D004941', (27, 31))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('BRCA', 'Disease', 'MESH:D001943', (73, 77))	('Esophageal Adenocarcinoma', 'Disease', (0, 25))	('ESAD', 'Phenotype', 'HP:0011459', (27, 31))
475918	31945090	Point mutations in skin cancer (MELA) and skin adenocarcinoma (SKCA) are shown in Fig 5D and 5E.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('skin cancer', 'Phenotype', 'HP:0008069', (19, 30))	('skin cancer', 'Disease', (19, 30))	('SKCA', 'Disease', 'MESH:D000230', (63, 67))	('skin cancer', 'Disease', 'MESH:D012878', (19, 30))	('MELA', 'Phenotype', 'HP:0002861', (32, 36))	('MELA', 'Disease', 'MESH:D008545', (32, 36))	('skin adenocarcinoma', 'Disease', 'MESH:D000230', (42, 61))	('skin adenocarcinoma', 'Disease', (42, 61))	('Point mutations', 'Var', (0, 15))	('MELA', 'Disease', (32, 36))	('SKCA', 'Disease', (63, 67))
475919	31945090	These mutations are consistent with the observed enrichment of C T and CC TT mutations in ultraviolet exposure-driven melanoma tumours.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('CC TT', 'Gene', (71, 76))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('melanoma tumours', 'Disease', 'MESH:D008545', (118, 134))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('melanoma tumours', 'Disease', (118, 134))	('mutations', 'Var', (77, 86))
475922	31945090	In our analysis we found that signature SBS26, which is associated with defective DNA mismatch repair, is particularly prominent in the active in-boundary motifs in Esophageal Adenocarcinoma (ESAD Fig 6), Liver Cancer (LIRI, Fig I in S1 File) and Breast Cancer (BRCA, Fig H in S1 File), although the exposure of the same signature is not relevant in the whole genome of the same tumors.	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('BRCA', 'Disease', 'MESH:D001943', (262, 266))	('Liver Cancer', 'Disease', (205, 217))	('tumors', 'Phenotype', 'HP:0002664', (379, 385))	('Esophageal Adenocarcinoma', 'Disease', (165, 190))	('ESAD', 'Phenotype', 'HP:0011459', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('Cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumors', 'Disease', (379, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('Liver Cancer', 'Disease', 'MESH:D006528', (205, 217))	('Breast Cancer', 'Disease', 'MESH:D001943', (247, 260))	('BRCA', 'Phenotype', 'HP:0003002', (262, 266))	('Liver Cancer', 'Phenotype', 'HP:0002896', (205, 217))	('Breast Cancer', 'Disease', (247, 260))	('tumors', 'Disease', 'MESH:D009369', (379, 385))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004941', (165, 190))	('Breast Cancer', 'Phenotype', 'HP:0003002', (247, 260))	('ESAD', 'Disease', (192, 196))	('defective', 'Var', (72, 81))	('SBS26', 'Var', (40, 45))	('BRCA', 'Disease', (262, 266))	('ESAD', 'Disease', 'MESH:D004941', (192, 196))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))
475923	31945090	For what it concerns Skin Sancer (MELA) and Skin Adenocarcinoma (SKCA) we found that within in-boundary motifs the signature SBS7b has the highest exposure and not signature SBS7a as in the whole genome (Figs J and K in S1 File).	('SKCA', 'Disease', 'MESH:D000230', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('SBS7b', 'Var', (125, 130))	('Skin Adenocarcinoma', 'Disease', (44, 63))	('MELA', 'Disease', (34, 38))	('exposure', 'MPA', (147, 155))	('MELA', 'Phenotype', 'HP:0002861', (34, 38))	('Skin Adenocarcinoma', 'Disease', 'MESH:D000230', (44, 63))	('SKCA', 'Disease', (65, 69))	('MELA', 'Disease', 'MESH:D008545', (34, 38))
475924	31945090	We also found a significant overlap of frequently mutated boundaries across tumour types in the same five tumour types (Melanoma, Esophageal Adenocarcinoma, Skin Adenocarcinoma, Liver Cancer and Breast Cancer) associated with the highest number of mutations, see Fig F in S1 File.	('mutations', 'Var', (248, 257))	('Melanoma', 'Disease', 'MESH:D008545', (120, 128))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Breast Cancer', 'Disease', (195, 208))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004941', (130, 155))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))	('Breast Cancer', 'Phenotype', 'HP:0003002', (195, 208))	('Melanoma', 'Disease', (120, 128))	('Skin Adenocarcinoma, Liver Cancer', 'Disease', 'MESH:D006528', (157, 190))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (130, 155))	('Melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('Esophageal Adenocarcinoma', 'Disease', (130, 155))	('tumour', 'Disease', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('Liver Cancer', 'Phenotype', 'HP:0002896', (178, 190))	('Breast Cancer', 'Disease', 'MESH:D001943', (195, 208))
475926	31945090	All pair-wise comparisons resulted in very significant p-values, confirming that mutations in boundaries do not happen by random chance, hinting to a concerted oncogenic mechanism to dysregulate key cancer driver genes.	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (199, 205))
475928	31945090	Increased methylation leading to disruption of CTCF binding patterns has also been observed in immortalized cell lines, suggesting that abnormal methylation of CTFC motifs might be a mechanism of cancer gene dysregulation.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('abnormal', 'Var', (136, 144))	('methylation', 'MPA', (145, 156))	('mechanism', 'Reg', (183, 192))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))
475933	31945090	In several cancer types we observed hypermethylation on in-boundary motifs.	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('hypermethylation', 'Var', (36, 52))
475943	31945090	Copy number alterations (CNA) are a main tumorigenic driver in many cancer types.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (41, 46))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
475944	31945090	In the context of neighbourhood dysregulation, recent work has reported tandem duplications intersecting with a TAD that led to de novo 3D contact domain formation.	('neighbourhood dysregulation', 'Disease', (18, 45))	('neighbourhood dysregulation', 'Disease', 'MESH:D021081', (18, 45))	('3D contact domain formation', 'MPA', (136, 163))	('tandem duplications', 'Var', (72, 91))	('led to', 'Reg', (121, 127))
475946	31945090	Motivated by these findings, we investigate here whether copy number alterations may contribute to cancer phenotypes by disrupting topologically associated domain boundaries.	('disrupting', 'NegReg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('contribute', 'Reg', (85, 95))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('copy number alterations', 'Var', (57, 80))	('topologically associated domain', 'MPA', (131, 162))
475956	31945090	In recent work, principal component analysis (PCA) on CNA data was performed on various cancer types, and Ovarian, Lung and Breast (basal subtype) cancers were found to have a similar signature characterised by a higher degree of copy number alterations compared to other types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('copy number alterations', 'Var', (230, 253))	('Ovarian', 'Disease', (106, 113))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('Breast (basal subtype) cancers', 'Disease', 'MESH:D001943', (124, 154))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (147, 153))	('Lung', 'Disease', (115, 119))
475961	31945090	In for instance, the loss of one boundary enables a constitutive enhancer to interact aberrantly with PDGFRA, a prominent oncogene in glioma.	('loss', 'Var', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('PDGFRA', 'Gene', (102, 108))	('enhancer', 'PosReg', (65, 73))	('glioma', 'Disease', (134, 140))	('interact', 'Interaction', (77, 85))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
475963	31945090	In, mutations of one insulator region identified as a melanoma driver are associated with the upregulation of TGFB1, although another study on melanoma could not find evidence of gene expression enrichment.	('upregulation', 'PosReg', (94, 106))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('TGFB1', 'Gene', (110, 115))	('mutations', 'Var', (4, 13))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))
475964	31945090	Other studies have described gene expression changes in the proximity of mutation hotspots at CTCF binding sites in gastrointestinal cancer.	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (116, 139))	('gastrointestinal cancer', 'Disease', (116, 139))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (116, 139))	('CTCF', 'Gene', (94, 98))	('changes', 'Reg', (45, 52))	('mutation', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('gene expression', 'MPA', (29, 44))
475965	31945090	While each of these results individually suggests an important role for the dysregulation of some constitutive neighbourhoods in specific tumors, a conclusive pan-cancer analysis is not yet available.	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('dysregulation', 'Var', (76, 89))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
475967	31945090	Table 5 summarises our analysis: we find that somatic mutations, methylation, and copy number variations are significantly enriched in the neighbourhood boundaries in some specific cancer types.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('methylation', 'Var', (65, 76))	('copy number variations', 'Var', (82, 104))	('cancer', 'Disease', (181, 187))
475970	31945090	We also observe a very significant overlap of frequently mutated active boundaries on these five cancers (Table G in S1 File), confirming that mutations in boundary do not happen at random.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutated', 'Var', (57, 64))
475971	31945090	A positive selection of transversions versus transitions seems to be prevalent in most cancer types.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('transversions', 'Var', (24, 37))
475974	31945090	Finally, we observe that copy number alterations significantly overlap with active junctions in four cancer types, namely in Breast Cancer (BRCA), Lung Adenocarcinoma (LUAD), Lung Squamous Carcinoma (LUSC) and Ovarian Cancer (OV), all of them cancers where important oncogenic CNA signatures have been identified.	('Squamous Carcinoma', 'Disease', 'MESH:D002294', (180, 198))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('LUSC', 'Phenotype', 'HP:0030359', (200, 204))	('Breast Cancer', 'Phenotype', 'HP:0003002', (125, 138))	('Squamous Carcinoma', 'Disease', (180, 198))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('Ovarian Cancer', 'Disease', (210, 224))	('Carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('LUAD', 'Phenotype', 'HP:0030078', (168, 172))	('Ovarian Cancer', 'Disease', 'MESH:D010051', (210, 224))	('copy number alterations', 'Var', (25, 48))	('overlap', 'Reg', (63, 70))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA', 'Disease', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('OV', 'Disease', 'MESH:D010051', (226, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('BRCA', 'Disease', 'MESH:D001943', (140, 144))	('Lung Adenocarcinoma', 'Disease', (147, 166))	('Lung Adenocarcinoma', 'Disease', 'MESH:C538231', (147, 166))	('LUAD', 'Disease', (168, 172))	('Squamous Carcinoma', 'Phenotype', 'HP:0002860', (180, 198))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (210, 224))	('Breast Cancer', 'Disease', 'MESH:D001943', (125, 138))	('LUAD', 'Disease', 'MESH:C538231', (168, 172))	('cancer', 'Disease', (101, 107))	('OV', 'Phenotype', 'HP:0100615', (226, 228))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('cancer', 'Disease', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Disease', (243, 250))	('Lung Squamous Carcinoma', 'Phenotype', 'HP:0030359', (175, 198))	('BRCA', 'Phenotype', 'HP:0003002', (140, 144))	('Breast Cancer', 'Disease', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
475983	31798787	HMIE was significantly associated with less blood loss (SMD = -0.43, 95%CI: -0.66, -0.20; P = 0.0002) and lower incidence of pulmonary complications (OR = 0.72, 95%CI: 0.57, 0.90; P = 0.004).	('lower', 'NegReg', (106, 111))	('pulmonary complications', 'CPA', (125, 148))	('less', 'NegReg', (39, 43))	('blood loss', 'Disease', 'MESH:D006473', (44, 54))	('HMIE', 'Var', (0, 4))	('pulmonary complications', 'Phenotype', 'HP:0006532', (125, 148))	('blood loss', 'Disease', (44, 54))
476010	31798787	In addition, patients with MIE had better quality of life scores compared to those with OE in the global health, pain, and physical activity domains.	('quality of', 'MPA', (42, 52))	('patients', 'Species', '9606', (13, 21))	('pain', 'Phenotype', 'HP:0012531', (113, 117))	('pain', 'Disease', 'MESH:D010146', (113, 117))	('better', 'PosReg', (35, 41))	('pain', 'Disease', (113, 117))	('MIE', 'Var', (27, 30))
476028	22751465	Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor (AhR), Sp1, and Nrf2 within its promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction.	('Upregulation', 'PosReg', (0, 12))	('attenuated', 'NegReg', (199, 209))	('deletion', 'Var', (132, 140))	('AhR', 'Gene', (87, 90))	('occupancy', 'MPA', (47, 56))	('aryl hydrocarbon receptor', 'Gene', (60, 85))	('AhR', 'Gene', '196', (87, 90))	('ABCG2', 'Gene', (210, 215))	('Nrf2', 'Gene', (102, 106))	('induction', 'MPA', (216, 225))	('ABCG2', 'Gene', (16, 21))	('Sp1', 'Gene', (93, 96))	('increased', 'PosReg', (37, 46))	('aryl hydrocarbon receptor', 'Gene', '196', (60, 85))	('Nrf2', 'Gene', '4780', (102, 106))
476029	22751465	Under conditions potentially achievable in clinical settings, treatment with mithramycin diminished basal as well as cigarette smoke condensate-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly down-regulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells.	('ABCG2', 'Gene', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('tumor', 'Disease', (282, 287))	('AhR', 'Gene', '196', (166, 169))	('Sp1', 'MPA', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('ABCG2', 'Gene', (243, 248))	('mithramycin', 'Chemical', 'MESH:D008926', (77, 88))	('diminished', 'NegReg', (89, 99))	('increases', 'PosReg', (153, 162))	('down-regulated', 'NegReg', (228, 242))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('esophageal cancer', 'Disease', 'MESH:D004938', (309, 326))	('AhR', 'Gene', (166, 169))	('Nrf2', 'Gene', '4780', (180, 184))	('inhibited', 'NegReg', (254, 263))	('esophageal cancer', 'Disease', (309, 326))	('proliferation', 'CPA', (264, 277))	('Nrf2', 'Gene', (180, 184))	('mithramycin', 'Var', (77, 88))
476036	22751465	In addition to being a significant risk factor for major morbidity and mortality in individuals undergoing potentially curative resections, cigarette smoking diminishes responses to chemo- and radiation therapy, enhances systemic metastases, and decreases survival of patients with locally advanced or disseminated lung and esophageal cancers; the mechanisms underlying these phenomena have not been fully established.	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('diminishes', 'NegReg', (158, 168))	('metastases', 'Disease', 'MESH:D009362', (230, 240))	('locally advanced', 'Disease', (282, 298))	('survival', 'CPA', (256, 264))	('cigarette smoking', 'Var', (140, 157))	('metastases', 'Disease', (230, 240))	('cancers', 'Phenotype', 'HP:0002664', (335, 342))	('enhances', 'PosReg', (212, 220))	('lung and esophageal cancers', 'Disease', 'MESH:D004938', (315, 342))	('decreases', 'NegReg', (246, 255))	('patients', 'Species', '9606', (268, 276))
476037	22751465	Previously, we reported that under clinically relevant exposure conditions, cigarette smoke enhances tumorigenicity of lung cancer cells via polycomb-mediated repression of Dickkopf-1 (Dkk1), which encodes an antagonist of Wnt signaling.	('Dickkopf-1', 'Gene', (173, 183))	('lung cancer', 'Disease', (119, 130))	('Dkk1', 'Gene', '22943', (185, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('enhances', 'PosReg', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Dkk1', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Wnt', 'Gene', '7474', (223, 226))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('Wnt', 'Gene', (223, 226))	('Dickkopf-1', 'Gene', '22943', (173, 183))	('polycomb-mediated', 'Var', (141, 158))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
476040	22751465	In more recent studies, we observed that cigarette smoke mediates epigenetic repression of miR-487b in lung cancer cells, resulting in over-expression of polycomb group proteins BMI1 and SUZ12, as well as Wnt5A, k-ras and C-myc, all of which have been implicated in modulating stem cell pluripotency; consistent with these observations, knock-down of miR-487b increases proliferation and tumorigenicity of lung cancer cells (Xi et al, submitted).	('C-myc', 'Gene', '4609', (222, 227))	('k-ras', 'Gene', '3845', (212, 217))	('lung cancer', 'Disease', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (388, 393))	('increases', 'PosReg', (360, 369))	('k-ras', 'Gene', (212, 217))	('miR-487b', 'Gene', (351, 359))	('Wnt5A', 'Gene', '7474', (205, 210))	('lung cancer', 'Disease', 'MESH:D008175', (406, 417))	('BMI1', 'Gene', '648', (178, 182))	('knock-down', 'Var', (337, 347))	('SUZ12', 'Gene', (187, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (406, 417))	('proliferation', 'CPA', (370, 383))	('miR-487b', 'Gene', '664616', (91, 99))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('C-myc', 'Gene', (222, 227))	('SUZ12', 'Gene', '23512', (187, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('tumor', 'Disease', (388, 393))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('Wnt5A', 'Gene', (205, 210))	('miR-487b', 'Gene', (91, 99))	('over-expression', 'PosReg', (135, 150))	('tumor', 'Disease', 'MESH:D009369', (388, 393))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('BMI1', 'Gene', (178, 182))	('miR-487b', 'Gene', '664616', (351, 359))	('lung cancer', 'Disease', (406, 417))
476071	22751465	Briefly, lentiviral shRNA techniques were used to knock-down ABCG2 in A549 and EsC2 cells exhibiting relatively high-level ABCG2 expression.	('knock-down', 'Var', (50, 60))	('EsC2', 'Gene', '84901', (79, 83))	('A549', 'CellLine', 'CVCL:0023', (70, 74))	('ABCG2', 'Gene', (61, 66))	('EsC2', 'Gene', (79, 83))
476072	22751465	Subsequent experiments demonstrated that knock-down of ABCG2 significantly decreased proliferation and migration of A549 lung cancer cells, and to lesser extent EsC2 cells (Figure 1D).	('A549 lung cancer', 'Disease', 'MESH:D008175', (116, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('EsC2', 'Gene', '84901', (161, 165))	('ABCG2', 'Gene', (55, 60))	('knock-down', 'Var', (41, 51))	('A549 lung cancer', 'Disease', (116, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('decreased', 'NegReg', (75, 84))	('EsC2', 'Gene', (161, 165))	('proliferation', 'CPA', (85, 98))	('migration', 'CPA', (103, 112))
476073	22751465	Additionally, knock-down of ABCG2 significantly inhibited soft agar clonogenicity of A549 cells (Figure 1D).	('soft agar clonogenicity of A549 cells', 'CPA', (58, 95))	('A549', 'CellLine', 'CVCL:0023', (85, 89))	('agar', 'Chemical', 'MESH:D000362', (63, 67))	('inhibited', 'NegReg', (48, 57))	('knock-down', 'Var', (14, 24))	('ABCG2', 'Gene', (28, 33))
476096	22751465	In additional experiments, shRNA techniques were used to knock-down HDAC6, which is required for activation and nuclear transport of AhR in response to tobacco carcinogens.	('HDAC6', 'Gene', '10013', (68, 73))	('HDAC6', 'Gene', (68, 73))	('AhR', 'Gene', (133, 136))	('AhR', 'Gene', '196', (133, 136))	('tobacco', 'Species', '4097', (152, 159))	('knock-down', 'Var', (57, 67))
476104	22751465	CSC-mediated luciferase activities of ABCG2-245 following deletion of one of the remaining XRE (ABCG2-XRE del 245 luc) or combined deletion of this XRE with mutation of the 5 Sp1 sites (ABCG2-Sp1 mut-XRE del 198 luc) were further decreased, approximating those seen for PGL3 basic luc.	('decreased', 'NegReg', (230, 239))	('PGL3', 'Gene', (270, 274))	('CSC-mediated', 'MPA', (0, 12))	('ABCG2-245', 'Gene', (38, 47))	('deletion', 'Var', (58, 66))	('PGL3', 'Gene', '6391', (270, 274))	('deletion', 'Var', (131, 139))
476111	22751465	Furthermore, mithramycin decreased basal as well as CSC-mediated expression of Nuclear Factor Erythroid Related Factor 2 (Nrf2), which has been shown recently to modulate ABCG2 expression.	('mithramycin', 'Var', (13, 24))	('Nrf2', 'Gene', (122, 126))	('mithramycin', 'Chemical', 'MESH:D008926', (13, 24))	('decreased', 'NegReg', (25, 34))	('Nuclear Factor Erythroid Related Factor 2', 'Gene', (79, 120))	('CSC-mediated expression', 'MPA', (52, 75))	('ABCG2', 'Gene', (171, 176))	('expression', 'MPA', (177, 187))	('Nuclear Factor Erythroid Related Factor 2', 'Gene', '4780', (79, 120))	('Nrf2', 'Gene', '4780', (122, 126))
476125	22751465	Furthermore, tumors from mice treated with 2mg/kg mithramycin had 50% fewer mitoses relative to control tumors (data not shown).	('mitoses', 'CPA', (76, 83))	('mice', 'Species', '10090', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Disease', (13, 19))	('fewer', 'NegReg', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('mithramycin', 'Var', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mithramycin', 'Chemical', 'MESH:D008926', (50, 61))
476157	22751465	Our experiments demonstrated that knock-down of ABCG2 inhibits proliferation, migration, and clonogenicity of lung and esophageal cancer cells; these findings suggest that ABCG2 modulates intracellular processes other than extrusion of xenobiotics.	('ABCG2', 'Gene', (172, 177))	('modulates', 'Reg', (178, 187))	('knock-down', 'Var', (34, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('extrusion of xenobiotics', 'MPA', (223, 247))	('ABCG2', 'Gene', (48, 53))	('migration', 'CPA', (78, 87))	('extrusion of xenobiotics', 'Phenotype', 'HP:0031838', (223, 247))	('inhibits', 'NegReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal cancer', 'Disease', (119, 136))
476160	22751465	Despite the fact that knock-down of ABCG2 decreased proliferation, migration and clonogenicity of lung and esophageal cancer cells, our current data do not establish, nor imply that down-regulation of ABCG2 is the primary mechanism by which mithramycin inhibits proliferation and tumorigenicity of these cancer cells.	('decreased', 'NegReg', (42, 51))	('proliferation', 'CPA', (262, 275))	('cancer', 'Disease', (304, 310))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('down-regulation', 'NegReg', (182, 197))	('ABCG2', 'Gene', (36, 41))	('inhibits', 'NegReg', (253, 261))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('clonogenicity', 'CPA', (81, 94))	('knock-down', 'Var', (22, 32))	('esophageal cancer', 'Disease', (107, 124))	('ABCG2', 'Gene', (201, 206))	('tumor', 'Disease', (280, 285))	('cancer', 'Disease', (118, 124))	('proliferation', 'CPA', (52, 65))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mithramycin', 'Chemical', 'MESH:D008926', (241, 252))	('migration', 'CPA', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
476161	22751465	Indeed, our micro-array analysis revealed that mithramycin significantly down-regulated hundreds of genes mediating stem cell signaling, cell cycle progression, chromatin remodeling, and DNA damage response.	('cell cycle progression', 'CPA', (137, 159))	('mithramycin', 'Var', (47, 58))	('mithramycin', 'Chemical', 'MESH:D008926', (47, 58))	('stem cell', 'CPA', (116, 125))	('down-regulated', 'NegReg', (73, 87))
476265	27528866	Underestimating the depth of the submucosal layer and inaccurate identification of the cutting line may cause perforation and/or residual tumor.	('Underestimating', 'Var', (0, 15))	('tumor', 'Disease', (138, 143))	('perforation', 'CPA', (110, 121))	('inaccurate', 'Var', (54, 64))	('cause', 'Reg', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
476318	26916665	EMT is a key step in tumor invasion and metastasis, and the induction of EMT leads to the downregulation of E-cadherin, expression of distinct mesenchymal markers such as vimentin, fibronectin, and N-cadherin, and morphological changes.	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('N-cadherin', 'Gene', '1000', (198, 208))	('morphological changes', 'CPA', (214, 235))	('expression', 'MPA', (120, 130))	('induction', 'Var', (60, 69))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('EMT', 'Gene', (73, 76))	('fibronectin', 'Gene', '2335', (181, 192))	('vimentin', 'Gene', '7431', (171, 179))	('N-cadherin', 'Gene', (198, 208))	('downregulation', 'NegReg', (90, 104))	('vimentin', 'Gene', (171, 179))	('fibronectin', 'Gene', (181, 192))
476329	26916665	Slides were incubated with the following primary antibodies overnight at 4  C: mouse anti-E-cadherin (1:100; DAKO System), anti-vimentin (1:800; DAKO System), anti-N-cadherin (1:400; Abcam), anti-snail (1:800; Abcam), and anti-slug (1:400; Abcam).	('vimentin', 'Gene', '7431', (128, 136))	('mouse', 'Species', '10090', (79, 84))	('1:800', 'Var', (138, 143))	('N-cadherin', 'Gene', (164, 174))	('1:800', 'Var', (203, 208))	('vimentin', 'Gene', (128, 136))	('slug', 'Gene', '6591', (227, 231))	('snail', 'Gene', '6615', (196, 201))	('1:100', 'Var', (102, 107))	('E-cadherin', 'Gene', '999', (90, 100))	('N-cadherin', 'Gene', '1000', (164, 174))	('slug', 'Gene', (227, 231))	('E-cadherin', 'Gene', (90, 100))	('1:400', 'Var', (176, 181))	('snail', 'Gene', (196, 201))
476393	26916665	Furthermore, the presence of Snail was associated with tumor differentiation, depth of tumor invasion and TNM stage (P < 0.05, Additional file 2: Table S2).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('TNM', 'Gene', '10178', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (55, 60))	('TNM', 'Gene', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('associated', 'Reg', (39, 49))	('presence', 'Var', (17, 25))	('Snail', 'Gene', '6615', (29, 34))	('Snail', 'Gene', (29, 34))
476487	26205792	With adjustment for age, gender, tumor location, T stage, N stage, and TNM stage, analysis of the association between SES and health-care delay revealed that shorter delay (<=2 months) was significantly associated with a higher SES (OR 2.271; 95% CI 1.069-4.853; P = 0.034).	('TNM', 'Gene', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('TNM', 'Gene', '10178', (71, 74))	('SES', 'Disease', (228, 231))	('tumor', 'Disease', (33, 38))	('shorter delay', 'Var', (158, 171))
476543	25184121	Upper esophageal duplication cysts can cause stridor and/or a nonproductive cough, while cysts in the middle and lower esophagus can cause dysphagia, epigastric discomfort, chest pain, and/or vomiting.	('epigastric discomfort', 'Disease', (150, 171))	('stridor', 'Phenotype', 'HP:0010307', (45, 52))	('dysphagia', 'Disease', (139, 148))	('cough', 'Disease', 'MESH:D003371', (76, 81))	('cause', 'Reg', (133, 138))	('epigastric discomfort', 'Phenotype', 'HP:0410019', (150, 171))	('cause', 'Reg', (39, 44))	('cough', 'Disease', (76, 81))	('cysts', 'Var', (89, 94))	('stridor', 'Disease', (45, 52))	('esophageal duplication', 'Phenotype', 'HP:0100681', (6, 28))	('dysphagia', 'Phenotype', 'HP:0002015', (139, 148))	('chest pain', 'Disease', 'MESH:D002637', (173, 183))	('chest pain', 'Disease', (173, 183))	('Upper esophageal duplication cysts', 'Disease', (0, 34))	('vomiting', 'Disease', 'MESH:D014839', (192, 200))	('cough', 'Phenotype', 'HP:0012735', (76, 81))	('vomiting', 'Phenotype', 'HP:0002013', (192, 200))	('vomiting', 'Disease', (192, 200))	('nonproductive cough', 'Phenotype', 'HP:0031246', (62, 81))	('chest pain', 'Phenotype', 'HP:0100749', (173, 183))	('pain', 'Phenotype', 'HP:0012531', (179, 183))	('dysphagia', 'Disease', 'MESH:D003680', (139, 148))
476549	25184121	Even expert endosonographers can mistake a duplication cyst for a more ominous lesion, and aspirating a lesion of concern should not be considered a breach of the standard of care.	('duplication cyst', 'Disease', (43, 59))	('mistake', 'Var', (33, 40))	('ominous lesion', 'Disease', 'MESH:D051437', (71, 85))	('ominous lesion', 'Disease', (71, 85))
476563	25184121	Patients with gastric duplication cysts can be asymptomatic but can also develop symptoms such as diffuse abdominal pain, epigastric pain, vomiting, weight loss, gastric outlet obstruction, ulcerated antral mass, or failure to thrive.	('gastric', 'Gene', (14, 21))	('gastric outlet obstruction', 'Disease', 'MESH:D017219', (162, 188))	('develop', 'PosReg', (73, 80))	('ulcerated antral mass', 'Disease', (190, 211))	('abdominal pain', 'Phenotype', 'HP:0002027', (106, 120))	('gastric duplication', 'Phenotype', 'HP:0011139', (14, 33))	('epigastric pain', 'Phenotype', 'HP:0410019', (122, 137))	('epigastric pain', 'Disease', 'MESH:D010146', (122, 137))	('Patients', 'Species', '9606', (0, 8))	('failure to thrive', 'Phenotype', 'HP:0001508', (216, 233))	('epigastric pain', 'Disease', (122, 137))	('abdominal pain', 'Disease', (106, 120))	('duplication', 'Var', (22, 33))	('gastric outlet obstruction', 'Disease', (162, 188))	('vomiting', 'Disease', 'MESH:D014839', (139, 147))	('weight loss', 'Disease', 'MESH:D015431', (149, 160))	('abdominal pain', 'Disease', 'MESH:D015746', (106, 120))	('diffuse abdominal pain', 'Phenotype', 'HP:0002574', (98, 120))	('pain', 'Phenotype', 'HP:0012531', (133, 137))	('failure to', 'Disease', (216, 226))	('weight loss', 'Phenotype', 'HP:0001824', (149, 160))	('vomiting', 'Phenotype', 'HP:0002013', (139, 147))	('vomiting', 'Disease', (139, 147))	('weight loss', 'Disease', (149, 160))	('pain', 'Phenotype', 'HP:0012531', (116, 120))
476584	25184121	reported a patient with a duplication cyst in the second and third portion of the duodenum with duodenoduodenal intussuception, melena, and abdominal pain.	('duplication', 'Var', (26, 37))	('abdominal pain', 'Disease', (140, 154))	('melena', 'Phenotype', 'HP:0002249', (128, 134))	('duodenoduodenal intussuception', 'Disease', (96, 126))	('abdominal pain', 'Disease', 'MESH:D015746', (140, 154))	('melena', 'Disease', (128, 134))	('patient', 'Species', '9606', (11, 18))	('pain', 'Phenotype', 'HP:0012531', (150, 154))	('abdominal pain', 'Phenotype', 'HP:0002027', (140, 154))
476634	20070190	For example, with strong evidence for Cox2 inhibitors reducing genetic changes in the progression of normal colonic epithelium to adenomatous polyp and to colon cancer, trials would need to accommodate the duration of time needed to interrupt this process and then observe a reduction in the incidence of cancer.	('adenomatous polyp', 'Disease', (130, 147))	('inhibitors', 'Var', (43, 53))	('colon cancer', 'Disease', 'MESH:D015179', (155, 167))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (130, 147))	('cancer', 'Disease', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('adenomatous polyp', 'Disease', 'MESH:D018256', (130, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (155, 167))	('Cox2', 'Gene', '4513', (38, 42))	('genetic', 'Var', (63, 70))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('Cox2', 'Gene', (38, 42))	('cancer', 'Disease', (161, 167))	('colon cancer', 'Disease', (155, 167))	('reducing', 'NegReg', (54, 62))	('reduction', 'NegReg', (275, 284))
476805	19292923	The non-invasive assessment of liver cirrhosis was blindly performed de novo to all patients by radiologists on the basis of US/US-doppler examinations (coarse echo-texture, nodularity presence, increased caudate/right lobe ratio, hypertrophy of the left lobe, characterized by a rounded inferior marginal edge, and portal vein enlargement with decreased flow velocity, absence of a normal doppler waveform, hepatofugal flow).	('caudate/right', 'MPA', (205, 218))	('cirrhosis', 'Phenotype', 'HP:0001394', (37, 46))	('liver cirrhosis', 'Disease', 'MESH:D008103', (31, 46))	('patients', 'Species', '9606', (84, 92))	('hypertrophy of the left lobe', 'Disease', 'MESH:D006984', (231, 259))	('vein enlargement', 'Disease', (323, 339))	('hypertrophy of the left lobe', 'Disease', (231, 259))	('nodularity', 'Var', (174, 184))	('decreased', 'NegReg', (345, 354))	('rat', 'Species', '10116', (224, 227))	('vein enlargement', 'Disease', 'MESH:D006529', (323, 339))	('hepatofugal', 'MPA', (408, 419))	('increased', 'PosReg', (195, 204))	('liver cirrhosis', 'Disease', (31, 46))	('flow velocity', 'MPA', (355, 368))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (31, 46))
476850	19292923	When comparing ROC curves to classify the collaterals presence, NH4 levels gave the best AUROC among PLTS count and SLD at US, significantly superior to the other ones.	('NH4', 'Chemical', '-', (64, 67))	('SLD', 'Disease', (116, 119))	('NH4 levels', 'Var', (64, 74))	('SLD', 'Disease', 'None', (116, 119))	('AUROC', 'MPA', (89, 94))
476869	19292923	According to our results, patients with high levels of NH4 should undergo endoscopy faster.	('NH4', 'Chemical', '-', (55, 58))	('high levels', 'Var', (40, 51))	('NH4', 'Gene', (55, 58))	('patients', 'Species', '9606', (26, 34))
476906	32546278	However, the mechanism by which modulation of AHR can inhibit tumor metastasis remains unknown.	('AHR', 'Gene', '196', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('AHR', 'Gene', (46, 49))	('inhibit', 'NegReg', (54, 61))	('tumor metastasis', 'Disease', 'MESH:D009362', (62, 78))	('modulation', 'Var', (32, 42))	('tumor metastasis', 'Disease', (62, 78))
476907	32546278	Thus, we aim to investigate the underlying mechanism regarding reversing EMT process of ESCC through modulation of AHR.	('ESCC', 'Disease', (88, 92))	('modulation', 'Var', (101, 111))	('AHR', 'Gene', (115, 118))	('AHR', 'Gene', '196', (115, 118))
476910	32546278	AHR was overexpressed in ESCC and modulation of AHR by DIM could inhibit migration and invasion as well as downregulate mesenchymal cell markers beta-Catenin, Vimentin and Slug and upregulate epithelial cell marker Claudin-1.	('mesenchymal cell markers', 'CPA', (120, 144))	('DIM', 'Chemical', 'MESH:C016392', (55, 58))	('Slug', 'Gene', '6591', (172, 176))	('upregulate', 'PosReg', (181, 191))	('AHR', 'Gene', '196', (0, 3))	('epithelial cell', 'CPA', (192, 207))	('AHR', 'Gene', '196', (48, 51))	('modulation', 'Var', (34, 44))	('beta-Catenin', 'Gene', (145, 157))	('downregulate', 'NegReg', (107, 119))	('Claudin-1', 'Gene', '9076', (215, 224))	('Slug', 'Gene', (172, 176))	('AHR', 'Gene', (0, 3))	('AHR', 'Gene', (48, 51))	('Vimentin', 'Gene', (159, 167))	('Vimentin', 'Gene', '7431', (159, 167))	('Claudin-1', 'Gene', (215, 224))	('inhibit', 'NegReg', (65, 72))	('beta-Catenin', 'Gene', '1499', (145, 157))
476914	32546278	Meanwhile, blockade of RhoA/ROCK1 pathway also exerted prohibitive effects on EMT and metastasis.	('RhoA', 'Gene', (23, 27))	('ROCK1', 'Gene', '6093', (28, 33))	('ROCK1', 'Gene', (28, 33))	('blockade', 'Var', (11, 19))	('RhoA', 'Gene', '387', (23, 27))
476916	32546278	Co-IP results showed DIM could modulate AHR to reverse EMT directly through inhibition of interaction between AHR and EGFR (epidermal growth factor receptor) so as to block RhoA/ROCK1-mediated COX2/PGE2 pathway which was connected by NF-kappaB.	('COX2', 'Gene', '5743', (193, 197))	('AHR', 'Gene', '196', (40, 43))	('DIM', 'Chemical', 'MESH:C016392', (21, 24))	('AHR', 'Gene', '196', (110, 113))	('epidermal growth factor receptor', 'Gene', (124, 156))	('RhoA', 'Gene', (173, 177))	('EGFR', 'Gene', '1956', (118, 122))	('ROCK1', 'Gene', (178, 183))	('modulate', 'Var', (31, 39))	('epidermal growth factor receptor', 'Gene', '1956', (124, 156))	('COX2', 'Gene', (193, 197))	('inhibition', 'NegReg', (76, 86))	('interaction', 'Interaction', (90, 101))	('AHR', 'Gene', (40, 43))	('NF-kappaB', 'Gene', (234, 243))	('RhoA', 'Gene', '387', (173, 177))	('PGE2', 'Chemical', 'MESH:D015232', (198, 202))	('block', 'NegReg', (167, 172))	('AHR', 'Gene', (110, 113))	('NF-kappaB', 'Gene', '4790', (234, 243))	('ROCK1', 'Gene', '6093', (178, 183))	('EGFR', 'Gene', (118, 122))
476917	32546278	In brief, modulation of AHR by DIM can reverse EMT process and inhibit metastasis of ESCC through repressing RhoA/ROCK1-mediated COX2/PGE2 pathway.	('ROCK1', 'Gene', (114, 119))	('AHR', 'Gene', (24, 27))	('DIM', 'Chemical', 'MESH:C016392', (31, 34))	('ROCK1', 'Gene', '6093', (114, 119))	('EMT process', 'CPA', (47, 58))	('COX2', 'Gene', (129, 133))	('modulation', 'Var', (10, 20))	('RhoA', 'Gene', (109, 113))	('PGE2', 'Chemical', 'MESH:D015232', (134, 138))	('COX2', 'Gene', '5743', (129, 133))	('ESCC', 'Disease', (85, 89))	('RhoA', 'Gene', '387', (109, 113))	('repressing', 'NegReg', (98, 108))	('metastasis of', 'CPA', (71, 84))	('AHR', 'Gene', '196', (24, 27))	('inhibit', 'NegReg', (63, 70))
476922	32546278	Evidences show that I3C can exert its anti-tumor properties through regulating cell growth, cell cycle and division, apoptosis and metastasis mainly through aryl hydrocarbon receptor (AHR).	('aryl hydrocarbon receptor', 'Gene', '196', (157, 182))	('aryl hydrocarbon receptor', 'Gene', (157, 182))	('metastasis', 'CPA', (131, 141))	('AHR', 'Gene', '196', (184, 187))	('regulating', 'Reg', (68, 78))	('AHR', 'Gene', (184, 187))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('division', 'CPA', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('I3C', 'Chemical', 'MESH:C016517', (20, 23))	('apoptosis', 'CPA', (117, 126))	('cell cycle', 'CPA', (92, 102))	('tumor', 'Disease', (43, 48))	('cell growth', 'CPA', (79, 90))	('I3C', 'Var', (20, 23))
476925	32546278	Our previous study have reported that both knockdown of AHR and modulation of AHR by DIM could inhibit ESCC growth, induce cell cycle arrest and promote apoptosis.	('induce', 'PosReg', (116, 122))	('arrest', 'Disease', (134, 140))	('AHR', 'Gene', '196', (56, 59))	('AHR', 'Gene', (56, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (123, 140))	('inhibit', 'NegReg', (95, 102))	('modulation', 'Var', (64, 74))	('knockdown', 'Var', (43, 52))	('AHR', 'Gene', '196', (78, 81))	('AHR', 'Gene', (78, 81))	('arrest', 'Disease', 'MESH:D006323', (134, 140))	('DIM', 'Chemical', 'MESH:C016392', (85, 88))	('ESCC', 'Disease', (103, 107))	('promote', 'PosReg', (145, 152))	('apoptosis', 'CPA', (153, 162))
476933	32546278	Occasionally, I3C has been reported to inhibit AHR binding to the COX2 promoter.	('I3C', 'Var', (14, 17))	('inhibit', 'NegReg', (39, 46))	('AHR', 'Gene', '196', (47, 50))	('AHR', 'Gene', (47, 50))	('COX2', 'Gene', (66, 70))	('I3C', 'Chemical', 'MESH:C016517', (14, 17))	('COX2', 'Gene', '5743', (66, 70))
476984	32546278	Meanwhile, since I3C could inhibit AHR binding to COX2 promoter, we also detected COX2 levels and result showed that DIM could also decrease COX2 expression (Fig.	('AHR', 'Gene', (35, 38))	('COX2', 'Gene', '5743', (50, 54))	('decrease', 'NegReg', (132, 140))	('DIM', 'Var', (117, 120))	('DIM', 'Chemical', 'MESH:C016392', (117, 120))	('COX2', 'Gene', (82, 86))	('I3C', 'Chemical', 'MESH:C016517', (17, 20))	('COX2', 'Gene', '5743', (82, 86))	('I3C', 'Var', (17, 20))	('AHR', 'Gene', '196', (35, 38))	('expression', 'MPA', (146, 156))	('COX2', 'Gene', '5743', (141, 145))	('COX2', 'Gene', (141, 145))	('COX2', 'Gene', (50, 54))	('inhibit', 'NegReg', (27, 34))
477000	32546278	4b, after knockdown of ROCK1, F-actin and mesenchymal cell markers as well as MMP1 and MMP2 expression levels were decreased while epithelial cell marker Claudin-1 was upregulated.	('ROCK1', 'Gene', '6093', (23, 28))	('ROCK1', 'Gene', (23, 28))	('MMP2', 'Gene', (87, 91))	('upregulated', 'PosReg', (168, 179))	('MMP1', 'Gene', (78, 82))	('decreased', 'NegReg', (115, 124))	('Claudin-1', 'Gene', (154, 163))	('MMP2', 'Gene', '4313', (87, 91))	('Claudin-1', 'Gene', '9076', (154, 163))	('expression levels', 'MPA', (92, 109))	('F-actin', 'MPA', (30, 37))	('knockdown', 'Var', (10, 19))	('MMP1', 'Gene', '4312', (78, 82))
477023	32546278	WB results indicated PGE2 could exacerbate EMT process while DIM could actually reverse EMT in part (Fig.	('EMT process', 'CPA', (43, 54))	('PGE2', 'Chemical', 'MESH:D015232', (21, 25))	('PGE2', 'Var', (21, 25))	('exacerbate', 'PosReg', (32, 42))	('DIM', 'Chemical', 'MESH:C016392', (61, 64))
477027	32546278	WB results demonstrated that after knockdown of AHR, all RhoA, ROCK1 and COX2 expression levels were synergically decreased (Fig.	('knockdown', 'Var', (35, 44))	('AHR', 'Gene', '196', (48, 51))	('ROCK1', 'Gene', '6093', (63, 68))	('ROCK1', 'Gene', (63, 68))	('decreased', 'NegReg', (114, 123))	('COX2', 'Gene', (73, 77))	('RhoA', 'Gene', (57, 61))	('COX2', 'Gene', '5743', (73, 77))	('RhoA', 'Gene', '387', (57, 61))	('AHR', 'Gene', (48, 51))
477029	32546278	Next, we used ROCK1 siRNAs and RhoA/ROCK1 pathway inhibitor Fasudil to treat ESCC cells and results exhibited after knockdown of ROCK1 or inhibition of the pathway, COX2 protein expression levels were decreased in the same way (Fig.	('ROCK1', 'Gene', '6093', (129, 134))	('ROCK1', 'Gene', (129, 134))	('RhoA', 'Gene', (31, 35))	('ROCK1', 'Gene', '6093', (36, 41))	('ROCK1', 'Gene', (36, 41))	('Fasudil', 'Chemical', 'MESH:C049347', (60, 67))	('RhoA', 'Gene', '387', (31, 35))	('COX2', 'Gene', (165, 169))	('knockdown', 'Var', (116, 125))	('decreased', 'NegReg', (201, 210))	('ROCK1', 'Gene', '6093', (14, 19))	('ROCK1', 'Gene', (14, 19))	('COX2', 'Gene', '5743', (165, 169))	('inhibition', 'Var', (138, 148))
477031	32546278	Finally, after knockdown of COX2 with siRNAs, there were no clear alterations of ROCK1 protein expression levels, which represented COX2 was the downstream gene of ROCK1 (Fig.	('knockdown', 'Var', (15, 24))	('ROCK1', 'Gene', (81, 86))	('ROCK1', 'Gene', '6093', (81, 86))	('ROCK1', 'Gene', '6093', (164, 169))	('ROCK1', 'Gene', (164, 169))	('COX2', 'Gene', '5743', (28, 32))	('COX2', 'Gene', (28, 32))	('COX2', 'Gene', '5743', (132, 136))	('COX2', 'Gene', (132, 136))
477032	32546278	To summarize, DIM modulated AHR to reverse EMT through repressing RhoA/ROCK1-mediated COX2/PGE2 pathway.	('RhoA', 'Gene', (66, 70))	('ROCK1', 'Gene', '6093', (71, 76))	('PGE2', 'Chemical', 'MESH:D015232', (91, 95))	('repressing', 'Reg', (55, 65))	('DIM', 'Chemical', 'MESH:C016392', (14, 17))	('RhoA', 'Gene', '387', (66, 70))	('modulated', 'Var', (18, 27))	('ROCK1', 'Gene', (71, 76))	('COX2', 'Gene', '5743', (86, 90))	('AHR', 'Gene', '196', (28, 31))	('AHR', 'Gene', (28, 31))	('COX2', 'Gene', (86, 90))
477043	32546278	Similarly, DIM could inhibit expression levels of EGFR and p-EGFR as well as NF-kappaB p65 and p-p65 (Fig.	('DIM', 'Chemical', 'MESH:C016392', (11, 14))	('p-p65', 'Var', (95, 100))	('NF-kappaB', 'Gene', (77, 86))	('EGFR', 'Gene', '1956', (50, 54))	('expression levels', 'MPA', (29, 46))	('inhibit', 'NegReg', (21, 28))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', '1956', (61, 65))	('NF-kappaB', 'Gene', '4790', (77, 86))	('EGFR', 'Gene', (61, 65))
477044	32546278	To sum up, DIM could modulate AHR to transfer into the nuclei for participation in transcription activity and to weaken interaction with EGFR leading to inhibition of RhoA/ROCK1-mediated COX2/PGE2 pathway connected by NF-kappaB to finally reverse EMT process of ESCC (Fig.	('interaction', 'Interaction', (120, 131))	('RhoA', 'Gene', '387', (167, 171))	('COX2', 'Gene', (187, 191))	('ROCK1', 'Gene', (172, 177))	('EGFR', 'Gene', (137, 141))	('PGE2', 'Chemical', 'MESH:D015232', (192, 196))	('AHR', 'Gene', '196', (30, 33))	('DIM', 'Chemical', 'MESH:C016392', (11, 14))	('ROCK1', 'Gene', '6093', (172, 177))	('modulate', 'Var', (21, 29))	('EGFR', 'Gene', '1956', (137, 141))	('ESCC', 'Disease', (262, 266))	('COX2', 'Gene', '5743', (187, 191))	('inhibition', 'NegReg', (153, 163))	('NF-kappaB', 'Gene', (218, 227))	('weaken', 'NegReg', (113, 119))	('RhoA', 'Gene', (167, 171))	('AHR', 'Gene', (30, 33))	('NF-kappaB', 'Gene', '4790', (218, 227))
477052	32546278	Therefore, we want to explore whether DIM can reverse EMT process of ESCC through modulation of AHR.	('modulation', 'Var', (82, 92))	('ESCC', 'Disease', (69, 73))	('DIM', 'Chemical', 'MESH:C016392', (38, 41))	('AHR', 'Gene', '196', (96, 99))	('AHR', 'Gene', (96, 99))
477058	32546278	DLC1 SAM domain-binding peptides have been reported to inhibit breast cancer growth and migration through inactivation of RhoA and ROCK1 can promote migration and invasion of non small cell lung cancer by activating PTEN/PI3K/FAK pathway.	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('FAK', 'Gene', (226, 229))	('ROCK1', 'Gene', (131, 136))	('lung cancer', 'Disease', (190, 201))	('inhibit', 'NegReg', (55, 62))	('invasion', 'CPA', (163, 171))	('migration', 'CPA', (149, 158))	('FAK', 'Gene', '5747', (226, 229))	('promote', 'PosReg', (141, 148))	('PTEN', 'Gene', (216, 220))	('activating', 'PosReg', (205, 215))	('inactivation', 'Var', (106, 118))	('DLC1', 'Gene', '10395', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('DLC1', 'Gene', (0, 4))	('RhoA', 'Gene', (122, 126))	('ROCK1', 'Gene', '6093', (131, 136))	('PTEN', 'Gene', '5728', (216, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('migration', 'CPA', (88, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (179, 201))	('RhoA', 'Gene', '387', (122, 126))
477068	32546278	Inhibition of COX2/PGE2 pathway can effectively suppress tumor growth, EMT and metastasis of non small cell lung cancer or extrahepatic cholangiocarcinoma through PLA2G4A/PGE2/STAT3 pathway.	('PGE2', 'Chemical', 'MESH:D015232', (171, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('PLA2G4A', 'Gene', '5321', (163, 170))	('COX2', 'Gene', (14, 18))	('extrahepatic cholangiocarcinoma', 'Disease', (123, 154))	('PGE2', 'Chemical', 'MESH:D015232', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (97, 119))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (136, 154))	('lung cancer', 'Disease', (108, 119))	('tumor', 'Disease', (57, 62))	('suppress', 'NegReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 154))	('Inhibition', 'Var', (0, 10))	('COX2', 'Gene', '5743', (14, 18))	('PLA2G4A', 'Gene', (163, 170))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('STAT3', 'Gene', (176, 181))	('EMT', 'CPA', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('metastasis', 'CPA', (79, 89))	('STAT3', 'Gene', '6774', (176, 181))
477071	32546278	Since both RhoA/ROCK1 pathway and COX2/PGE2 pathway are able to reverse EMT and inhibit metastasis regulated by modulation of AHR by DIM, we wonder whether some interactions exist.	('RhoA', 'Gene', (11, 15))	('ROCK1', 'Gene', '6093', (16, 21))	('ROCK1', 'Gene', (16, 21))	('metastasis', 'CPA', (88, 98))	('inhibit', 'NegReg', (80, 87))	('RhoA', 'Gene', '387', (11, 15))	('EMT', 'CPA', (72, 75))	('COX2', 'Gene', '5743', (34, 38))	('COX2', 'Gene', (34, 38))	('DIM', 'Chemical', 'MESH:C016392', (133, 136))	('AHR', 'Gene', '196', (126, 129))	('modulation', 'Var', (112, 122))	('AHR', 'Gene', (126, 129))	('PGE2', 'Chemical', 'MESH:D015232', (39, 43))
477077	32546278	That is to say, DIM exerts its reversal of EMT process mainly through modulation of AHR to inhibit EGFR/RhoA/ROCK1/NF-kappaB/COX2/PGE2 pathway.	('EGFR', 'Gene', (99, 103))	('PGE2', 'Chemical', 'MESH:D015232', (130, 134))	('modulation', 'Var', (70, 80))	('RhoA', 'Gene', '387', (104, 108))	('ROCK1', 'Gene', '6093', (109, 114))	('inhibit', 'NegReg', (91, 98))	('AHR', 'Gene', '196', (84, 87))	('AHR', 'Gene', (84, 87))	('DIM', 'Chemical', 'MESH:C016392', (16, 19))	('ROCK1', 'Gene', (109, 114))	('NF-kappaB', 'Gene', '4790', (115, 124))	('COX2', 'Gene', (125, 129))	('EGFR', 'Gene', '1956', (99, 103))	('NF-kappaB', 'Gene', (115, 124))	('COX2', 'Gene', '5743', (125, 129))	('RhoA', 'Gene', (104, 108))
477079	32546278	Therefore, blockade of AHR as the original source of EMT process in ESCC with DIM as the modulator is of significance.	('AHR', 'Gene', '196', (23, 26))	('AHR', 'Gene', (23, 26))	('DIM', 'Chemical', 'MESH:C016392', (78, 81))	('blockade', 'Var', (11, 19))
477089	32477927	Methods: Expression of MyD88 and nuclear factor kappaB (NF-kappaB) p105/p50 and infection of H. pylori were detected by immunohistochemistry in gastric cardia tissue.	('p105/p50', 'Var', (67, 75))	('NF-kappaB', 'Gene', '4790', (56, 65))	('infection', 'Disease', (80, 89))	('gastric cardia', 'Disease', (144, 158))	('MyD88', 'Gene', (23, 28))	('H. pylori', 'Species', '210', (93, 102))	('NF-kappaB', 'Gene', (56, 65))	('infection', 'Disease', 'MESH:D007239', (80, 89))	('gastric cardia', 'Disease', 'MESH:D004938', (144, 158))
477090	32477927	The correlation of MyD88 expression to NF-kappaB p105/p50 expression, H. pylori infection, and clinicopathologic characteristics in gastric cardia tissue was analyzed.	('NF-kappaB', 'Gene', '4790', (39, 48))	('gastric cardia', 'Disease', (132, 146))	('NF-kappaB', 'Gene', (39, 48))	('p105/p50 expression', 'Var', (49, 68))	('gastric cardia', 'Disease', 'MESH:D004938', (132, 146))	('infection', 'Disease', (80, 89))	('H. pylori infection', 'Phenotype', 'HP:0005202', (70, 89))	('MyD88', 'Gene', (19, 24))	('H. pylori', 'Species', '210', (70, 79))	('infection', 'Disease', 'MESH:D007239', (80, 89))
477095	32477927	Patients with high MyD88 staining revealed a better differentiation (p = 0.02).	('better', 'PosReg', (45, 51))	('differentiation', 'MPA', (52, 67))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('MyD88', 'Gene', (19, 24))
477096	32477927	MyD88 also positively correlated with NF-kappaB p105/p50 expression (p = 0.012) in cancer tissue.	('NF-kappaB', 'Gene', '4790', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('correlated', 'Reg', (22, 32))	('NF-kappaB', 'Gene', (38, 47))	('p105/p50', 'Var', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('MyD88', 'Gene', (0, 5))
477120	32477927	Previous study suggested that abnormal expression of MyD88 was closely associated with the development of tumor and resistance of drugs.	('abnormal', 'Var', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('MyD88', 'Gene', (53, 58))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('expression', 'MPA', (39, 49))	('resistance of drugs', 'CPA', (116, 135))	('associated', 'Reg', (71, 81))
477123	32477927	MyD88-deficient mice models have shown MyD88 may either promote or suppress tumor development.	('MyD88', 'Var', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('suppress', 'NegReg', (67, 75))	('tumor', 'Disease', (76, 81))	('promote', 'PosReg', (56, 63))	('mice', 'Species', '10090', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
477134	32477927	Next, the tissues were incubated overnight at 4 C with the following antibodies: anti-MyD88 rabbit monoclonal antibody (ab133739; Abcam; Cambridge, MA, United States), anti-NF-kappaB p105/p50 rabbit monoclonal antibody (ab32360; Abcam; Cambridge, MA, United States), or anti-H. pylori rabbit polyclonal antibody (RAB-0064; Fuzhou Maixin Biotechnology; Fuzhou, Fujian Province, China).	('NF-kappaB', 'Gene', '4790', (173, 182))	('p105/p50', 'Var', (183, 191))	('NF-kappaB', 'Gene', (173, 182))	('H. pylori', 'Species', '210', (275, 284))
477137	32477927	The expression of MyD88 and NF-kappaB p105/p50 was rated (0-3) semiquantitatively according to the signal intensity (0 = no immunostaining, 1 = weak positive staining, 2 = moderate positive staining, 3 = strong positive staining).	('NF-kappaB', 'Gene', (28, 37))	('MyD88', 'Gene', (18, 23))	('p105/p50', 'Var', (38, 46))	('NF-kappaB', 'Gene', '4790', (28, 37))
477142	32477927	Spearman correlation was used to determine the correlation between MyD88 and NF-kappaB p105/p50.	('NF-kappaB', 'Gene', (77, 86))	('MyD88', 'Gene', (67, 72))	('NF-kappaB', 'Gene', '4790', (77, 86))	('p105/p50', 'Var', (87, 95))
477157	32477927	We used an antibody that can recognize both p105 and p50 proteins to quantify NF-kappaB p105/p50 protein in the same cohort of samples.	('p105/p50 protein', 'Var', (88, 104))	('NF-kappaB', 'Gene', '4790', (78, 87))	('NF-kappaB', 'Gene', (78, 87))
477158	32477927	Immunohistochemical staining detected NF-kappaB p105/p50 in all non-malignant and malignant samples.	('NF-kappaB', 'Gene', '4790', (38, 47))	('detected', 'Reg', (29, 37))	('NF-kappaB', 'Gene', (38, 47))	('p105/p50', 'Var', (48, 56))
477159	32477927	Expression of NF-kappaB p105/p50 was higher in GCC (n = 104) than in non-malignant tissues (n = 94) (p = 0.000).	('higher', 'PosReg', (37, 43))	('Expression', 'MPA', (0, 10))	('NF-kappaB', 'Gene', '4790', (14, 23))	('GCC', 'Disease', (47, 50))	('p105/p50', 'Var', (24, 32))	('NF-kappaB', 'Gene', (14, 23))
477161	32477927	The strongest immunostaining of NF-kappaB p105/p50 and MyD88 coexisted in tumors (Figure 3).	('immunostaining', 'MPA', (14, 28))	('NF-kappaB', 'Gene', (32, 41))	('MyD88', 'Gene', (55, 60))	('strongest', 'Reg', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('p105/p50', 'Var', (42, 50))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('NF-kappaB', 'Gene', '4790', (32, 41))	('tumors', 'Disease', (74, 80))
477173	32477927	Lipopolysaccharide (LPS) is found in the outer membrane of Helicobacter, and it was reported that LPS could upregulate MyD88 expression.	('upregulate', 'PosReg', (108, 118))	('MyD88', 'Gene', (119, 124))	('expression', 'MPA', (125, 135))	('Helicobacter', 'Species', '210', (59, 71))	('Lipopolysaccharide', 'Chemical', 'MESH:D008070', (0, 18))	('LPS', 'Var', (98, 101))
477183	32477927	Evidence showed that MyD88 can induce proinflammatory response and inflammation, which is regarded as the most important factor contributing to tumorigenesis.	('tumor', 'Disease', (144, 149))	('proinflammatory response', 'MPA', (38, 62))	('induce', 'PosReg', (31, 37))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('inflammation', 'Disease', (67, 79))	('MyD88', 'Var', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
477198	32477927	With the constant accumulation of different gene mutation and expression during tumor differentiation, MyD88 expression might be changing.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('MyD88', 'Gene', (103, 108))	('expression', 'MPA', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('changing', 'Reg', (129, 137))	('tumor', 'Disease', (80, 85))	('mutation', 'Var', (49, 57))
477201	32477927	Nuclear factor kappaB is the important signaling molecule downstream of MyD88 and data on how MyD88 deficiency affects carcinogenesis involved the role of NF-kappaB in cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carcinogenesis', 'Disease', 'MESH:D063646', (119, 133))	('MyD88', 'Gene', (94, 99))	('NF-kappaB', 'Gene', (155, 164))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('NF-kappaB', 'Gene', '4790', (155, 164))	('deficiency', 'Var', (100, 110))	('carcinogenesis', 'Disease', (119, 133))	('cancer', 'Disease', (168, 174))	('affects', 'Reg', (111, 118))
477204	32477927	Adverse stimuli can activate NF-kappaB pathway, and p50 translocates into the nucleus then changes cell signaling.	('cell signaling', 'MPA', (99, 113))	('changes', 'Reg', (91, 98))	('NF-kappaB', 'Gene', (29, 38))	('NF-kappaB', 'Gene', '4790', (29, 38))	('p50', 'Var', (52, 55))
477205	32477927	We found that MyD88 had significantly positive relationship with NF-kappaB p105/p50, suggesting that p105/p50 and MyD88 are both involved in GCC tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('involved', 'Reg', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('MyD88', 'Gene', (114, 119))	('NF-kappaB', 'Gene', '4790', (65, 74))	('tumor', 'Disease', (145, 150))	('NF-kappaB', 'Gene', (65, 74))	('GCC', 'Disease', (141, 144))	('p105/p50', 'Var', (101, 109))
477212	32477927	Furthermore, NF-kappaB p105/p50 showed positive relationship with MyD88 expression in GCC tissue.	('MyD88', 'Gene', (66, 71))	('positive', 'PosReg', (39, 47))	('p105/p50', 'Var', (23, 31))	('NF-kappaB', 'Gene', '4790', (13, 22))	('expression', 'MPA', (72, 82))	('NF-kappaB', 'Gene', (13, 22))
477221	31646078	CD80 expression was increased in epithelial cells during metaplasia in the inflammatory esophageal carcinogenesis cascade.	('increased', 'PosReg', (20, 29))	('expression', 'MPA', (5, 15))	('metaplasia', 'Var', (57, 67))	('CD80', 'Gene', (0, 4))	('inflammatory esophageal carcinogenesis', 'Disease', 'MESH:D063646', (75, 113))	('inflammatory esophageal carcinogenesis', 'Disease', (75, 113))
477260	31646078	The infiltration of cytotoxic T lymphocytes remained substantially unchanged along the carcinogenesis cascade (Figure 1d), as well as the percentage of activated cytotoxic lymphocytes bearing CD28, the CD80 receptor (Figure 1e).	('rat', 'Species', '10116', (10, 13))	('infiltration', 'MPA', (4, 16))	('CD28', 'Var', (192, 196))
477263	31646078	To demonstrate the functional role of CD80 in immune surveillance during esophageal carcinogenesis progression, we used the same reflux model of esophageal carcinogenesis on CD80-/- or C57BL/6 mice, and subjected or not C57BL/6 operated mice to treatment with a neutralizing antibody against CD80 (Figure 3a).	('rat', 'Species', '10116', (231, 234))	('CD80-/-', 'Var', (174, 181))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (73, 98))	('esophageal carcinogenesis', 'Disease', (73, 98))	('CD80', 'Gene', (292, 296))	('mice', 'Species', '10090', (237, 241))	('mice', 'Species', '10090', (193, 197))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (145, 170))	('esophageal carcinogenesis', 'Disease', (145, 170))	('rat', 'Species', '10116', (10, 13))
477264	31646078	Consistent with a pivotal role for CD80 in esophageal cancer immune surveillance, 4 out of 8 CD80-/- mice and 5 out of 7 WT+anti-CD80 mice developed dysplasia in the fore stomach, at much higher compared to that observed in control WT mice (1/6) (Figure 3b).	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('dysplasia', 'Disease', 'MESH:D015792', (149, 158))	('mice', 'Species', '10090', (134, 138))	('dysplasia', 'Disease', (149, 158))	('mice', 'Species', '10090', (101, 105))	('CD80-/-', 'Var', (93, 100))	('esophageal cancer', 'Disease', (43, 60))	('mice', 'Species', '10090', (235, 239))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
477266	31646078	Moreover, expression of KI67, a marker of proliferative activity in malignant tumors, was significantly increased in the medium and upper third of the crypts in the esophagus, anastomosis and stomach mucosa of mice treated with anti-CD80 antibody compared to controls (Figure 3d), thus showing the protective role of CD80 in esophageal carcinogenesis progression.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (325, 350))	('KI67', 'Gene', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('anti-CD80', 'Var', (228, 237))	('esophageal carcinogenesis', 'Disease', (325, 350))	('malignant tumors', 'Disease', (68, 84))	('mice', 'Species', '10090', (210, 214))	('increased', 'PosReg', (104, 113))	('malignant tumors', 'Disease', 'MESH:D009369', (68, 84))	('expression', 'MPA', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('KI67', 'Gene', '17345', (24, 28))	('rat', 'Species', '10116', (49, 52))	('anastomosis', 'Disease', (176, 187))	('anastomosis', 'Disease', 'MESH:C563598', (176, 187))
477273	31646078	Moreover, our in vivo experiments with CD80-/- mice and WT mice treated with anti-CD80 indicate that the lack of CD80 favors the development of dysplasia, as shown by KI67 staining above the basal third of the mucosal crypts.	('lack', 'Var', (105, 109))	('favors', 'PosReg', (118, 124))	('mice', 'Species', '10090', (59, 63))	('mice', 'Species', '10090', (47, 51))	('KI67', 'Gene', '17345', (167, 171))	('dysplasia', 'Disease', 'MESH:D015792', (144, 153))	('KI67', 'Gene', (167, 171))	('CD80', 'Gene', (113, 117))	('dysplasia', 'Disease', (144, 153))
477277	31646078	Moreover, our human data suggest that the CD80 - CD28 crosstalk probably occurs even in EAC but its effect is inhibited by the PD-L1 - PD1 crosstalk.	('EAC', 'Phenotype', 'HP:0011459', (88, 91))	('human', 'Species', '9606', (14, 19))	('PD1', 'Gene', '5133', (135, 138))	('EAC', 'Disease', (88, 91))	('PD1', 'Gene', (135, 138))	('EAC', 'Disease', 'MESH:D004941', (88, 91))	('CD80 - CD28', 'Var', (42, 53))
477279	30559182	Spatially resolved metabolomics to discover tumor-associated metabolic alterations Tumor cells reprogram their metabolism to support cell growth, proliferation, and differentiation, thus driving cancer progression.	('differentiation', 'CPA', (165, 180))	('metabolism', 'MPA', (111, 121))	('Tumor', 'Phenotype', 'HP:0002664', (83, 88))	('proliferation', 'CPA', (146, 159))	('driving', 'Reg', (187, 194))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('alterations', 'Var', (71, 82))	('cell growth', 'CPA', (133, 144))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('reprogram', 'Reg', (95, 104))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
477310	30559182	We report a method for the high-throughput discovery of tumor-associated metabolite and enzyme alterations based on a spatially resolved MSI metabolomics approach.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('MSI', 'Gene', (137, 140))	('alterations', 'Var', (95, 106))	('MSI', 'Gene', '5928', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
477344	30559182	Notably, we identified dysregulated PYCR2 in ESCC.	('ESCC', 'Disease', (45, 49))	('PYCR2', 'Gene', (36, 41))	('dysregulated', 'Var', (23, 35))	('PYCR2', 'Gene', '29920', (36, 41))
477443	29906417	Expression of MIR194 is increased in BE samples via epigenetic mechanisms that might be involved in BE pathogenesis.	('BE', 'Phenotype', 'HP:0100580', (100, 102))	('Expression', 'MPA', (0, 10))	('BE', 'Phenotype', 'HP:0100580', (37, 39))	('MIR', 'Gene', '220972', (14, 17))	('MIR', 'Gene', (14, 17))	('epigenetic', 'Var', (52, 62))	('increased', 'PosReg', (24, 33))
477452	29906417	As most patients with BE will not progress to cancer, we have investigated additional nucleic acid biomarkers for the Cytosponge, including methylation and p53 mutations to stratify patients according to their risk of progression to cancer.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('mutations', 'Var', (160, 169))	('cancer', 'Disease', (46, 52))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('BE', 'Phenotype', 'HP:0100580', (22, 24))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('patients', 'Species', '9606', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('patients', 'Species', '9606', (8, 16))
477474	29906417	The hybridized chip was scanned using the G2565BA Microarray Scanner (Agilent Technologies) and analyzed using GenePix Pro software v4.1 (Molecular Devices Corporation, San Jose, CA).	('G2565BA', 'Var', (42, 49))	('v4.1', 'Gene', '28783', (132, 136))	('v4.1', 'Gene', (132, 136))
477525	29906417	Stepwise selection of the 11 validated miRNAs and TFF3 retained just 3 miRNAs (MIR192, 196a, and 199a) as well as TFF3 and 5-fold cross-validation of this model provided an AUC of 0.93 (95% CI 0.90-0.97) with sensitivity 93.1% and specificity 93.7% (Table 2).	('miR', 'Gene', (71, 74))	('miR', 'Gene', '220972', (39, 42))	('TFF3', 'Gene', '7033', (50, 54))	('miR', 'Gene', (39, 42))	('MIR192', 'Gene', '406967', (79, 85))	('196a', 'Var', (87, 91))	('TFF3', 'Gene', '7033', (114, 118))	('miR', 'Gene', '220972', (71, 74))	('TFF3', 'Gene', (50, 54))	('TFF3', 'Gene', (114, 118))	('MIR192', 'Gene', (79, 85))
477535	29906417	We also incorporated mRNAs down-regulated >20% following MIR192 transfection using data from a published microarray dataset to populate our list of predicted targets.	('transfection', 'Var', (64, 76))	('MIR192', 'Gene', (57, 63))	('mRNAs', 'MPA', (21, 26))	('MIR192', 'Gene', '406967', (57, 63))	('down-regulated', 'NegReg', (27, 41))
477540	29906417	GRHL3, one putative target mRNA of MIR194 (Figure 5A) was significantly down-regulated on MIR194 overexpression (fold change >3, Figure 5B i-ii), whereas the other 5 miRNA targets examined were not significantly repressed on transfection (Supplementary Figure 4).	('GRHL3', 'Gene', '57822', (0, 5))	('down-regulated', 'NegReg', (72, 86))	('MIR', 'Gene', '220972', (90, 93))	('MIR', 'Gene', (90, 93))	('MIR', 'Gene', '220972', (35, 38))	('overexpression', 'Var', (97, 111))	('MIR', 'Gene', (35, 38))	('miR', 'Gene', '220972', (166, 169))	('miR', 'Gene', (166, 169))	('GRHL3', 'Gene', (0, 5))
477541	29906417	To further characterize this relationship, NES cells were transfected with antisense oligonucleotides against MIR194 (anti-MIR194).	('MIR', 'Gene', '220972', (123, 126))	('MIR', 'Gene', (123, 126))	('oligonucleotides', 'Chemical', 'MESH:D009841', (85, 101))	('MIR', 'Gene', '220972', (110, 113))	('MIR', 'Gene', (110, 113))	('antisense oligonucleotides', 'Var', (75, 101))
477572	29906417	Some initial efforts were made to understand the cause of these up-regulated miRNAs by examining genomic and epigenetic alterations, and we identified hypomethylation distribution in the promotor region of the cluster MIR192-194 that could explain the up-regulation of clustered miRNAs.	('miR', 'Gene', (77, 80))	('MIR192', 'Gene', (218, 224))	('hypomethylation', 'Var', (151, 166))	('MIR192', 'Gene', '406967', (218, 224))	('miR', 'Gene', '220972', (279, 282))	('miR', 'Gene', (279, 282))	('up-regulation', 'PosReg', (252, 265))	('up-regulated', 'PosReg', (64, 76))	('miR', 'Gene', '220972', (77, 80))
477575	29906417	GRHL3 positively regulates the tumor suppressor PTEN, whereas GRHL3 knockout results in squamous cell carcinoma development in vivo associated with activation of phosphatidylinositol-3-kinase signaling.	('GRHL3', 'Gene', '57822', (0, 5))	('PTEN', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('GRHL3', 'Gene', (0, 5))	('PTEN', 'Gene', '5728', (48, 52))	('activation', 'PosReg', (148, 158))	('GRHL3', 'Gene', '57822', (62, 67))	('GRHL3', 'Gene', (62, 67))	('tumor', 'Disease', (31, 36))	('knockout', 'Var', (68, 76))	('phosphatidylinositol-3-kinase signaling', 'MPA', (162, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 111))	('squamous cell carcinoma', 'Disease', (88, 111))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
477578	29906417	Previous studies revealed that the loss of PTEN expression is an independent negative prognostic factor in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (107, 132))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (107, 132))	('negative', 'NegReg', (77, 85))	('expression', 'MPA', (48, 58))	('loss', 'Var', (35, 39))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('esophageal adenocarcinoma', 'Disease', (107, 132))
477580	29906417	Hypomethylation found in the promoter regions of these biomarker miRNAs could contribute to the dysregulation of miRNAs with phenotypic consequences through their target mRNA network.	('dysregulation', 'MPA', (96, 109))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (113, 116))	('Hypomethylation', 'Var', (0, 15))	('contribute', 'Reg', (78, 88))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))
477636	29455652	EAC arises from metaplastic Barrett's esophagus (BE) and related to gastro-esophageal reflux (GER) and obesity.	('GER', 'Gene', '59330', (94, 97))	('esophageal reflux', 'Phenotype', 'HP:0002020', (75, 92))	('obesity', 'Phenotype', 'HP:0001513', (103, 110))	('gastro-esophageal reflux', 'Disease', (68, 92))	('GER', 'Gene', (94, 97))	('related', 'Reg', (57, 64))	('BE', 'Phenotype', 'HP:0100580', (49, 51))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (28, 47))	('metaplastic', 'Var', (16, 27))	("Barrett's esophagus", 'Disease', (28, 47))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (28, 47))	('obesity', 'Disease', 'MESH:D009765', (103, 110))	('EAC', 'Disease', (0, 3))	('obesity', 'Disease', (103, 110))
477655	29455652	EGFR overexpression and amplification was frequently observed in ESCC and correlated with advanced tumor stage and poor prognosis.	('tumor', 'Disease', (99, 104))	('EGFR', 'Gene', (0, 4))	('overexpression', 'PosReg', (5, 19))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('amplification', 'Var', (24, 37))	('correlated', 'Reg', (74, 84))	('ESCC', 'Disease', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('EGFR', 'Gene', '1956', (0, 4))
477658	29455652	Overexpression of EGFR was correlated with poor prognosis.	('Overexpression', 'Var', (0, 14))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))
477664	29455652	The EGFR amplification has been associated with diseases outcome in ESCC.	('amplification', 'Var', (9, 22))	('ESCC', 'Disease', (68, 72))	('EGFR', 'Gene', (4, 8))	('associated with', 'Reg', (32, 47))	('EGFR', 'Gene', '1956', (4, 8))
477665	29455652	ESCC patients with low copy number observed to have longer survival as compared with patients with high copy number of EGFR gene.	('low copy number', 'Var', (19, 34))	('patients', 'Species', '9606', (5, 13))	('longer', 'PosReg', (52, 58))	('patients', 'Species', '9606', (85, 93))	('ESCC', 'Disease', (0, 4))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (119, 123))
477666	29455652	EGFR amplification has been associated with advanced pathological stage and tumor lymph node metastasis.	('EGFR', 'Gene', (0, 4))	('tumor lymph node metastasis', 'Disease', 'MESH:D009362', (76, 103))	('associated', 'Reg', (28, 38))	('amplification', 'Var', (5, 18))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('advanced pathological stage', 'CPA', (44, 71))	('EGFR', 'Gene', '1956', (0, 4))	('tumor lymph node metastasis', 'Disease', (76, 103))
477678	29455652	EGFR has been studied extensively in relation to lung adenocarcinoma to target the mutant EGFR using erlotinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (101, 110))	('lung adenocarcinoma', 'Disease', (49, 68))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (49, 68))	('EGFR', 'Gene', (0, 4))	('mutant', 'Var', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (90, 94))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (49, 68))	('EGFR', 'Gene', '1956', (0, 4))
477689	29455652	In an in vitro study on ESCC cell lines (TE8, T.T and T.Tn), Gefitinib inhibited cellular proliferation in a dose-dependent manner, induced cell cycle arrest, inhibited ligand induced autophosphorylation of EGFR, downstream signaling pathways including Ras/Raf/MAPK and PI3K/Akt, and cell death.	('T.Tn', 'Var', (54, 58))	('arrest', 'Disease', (151, 157))	('ligand', 'Interaction', (169, 175))	('PI3', 'Gene', '5266', (270, 273))	('Akt', 'Gene', (275, 278))	('Raf', 'Gene', '22882', (257, 260))	('EGFR', 'Gene', (207, 211))	('Akt', 'Gene', '207', (275, 278))	('arrest', 'Disease', 'MESH:D006323', (151, 157))	('autophosphorylation', 'MPA', (184, 203))	('Gefitinib', 'Var', (61, 70))	('PI3', 'Gene', (270, 273))	('induced', 'Reg', (132, 139))	('inhibited', 'NegReg', (159, 168))	('cell death', 'CPA', (284, 294))	('Gefitinib', 'Chemical', 'MESH:D000077156', (61, 70))	('inhibited', 'NegReg', (71, 80))	('EGFR', 'Gene', '1956', (207, 211))	('cellular proliferation', 'CPA', (81, 103))	('Raf', 'Gene', (257, 260))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (140, 157))
477702	29455652	Icotinib was clinically evaluated for the treatment of previously treated advanced ESCC patients who either had overexpression or amplification of EGFR in a single arm, multi-centric phase-II clinical trial.	('EGFR', 'Gene', (147, 151))	('overexpression', 'PosReg', (112, 126))	('patients', 'Species', '9606', (88, 96))	('amplification', 'Var', (130, 143))	('Icotinib', 'Chemical', 'MESH:C531470', (0, 8))	('ESCC', 'Disease', (83, 87))	('EGFR', 'Gene', '1956', (147, 151))
477724	29455652	Furthermore, treatment of these cell lines with anti-VEGFR1/2 antibodies inhibits proliferation of ESCC cells denotes validity of VEGFRs as the genuine targets in ESCC.	('VEGFR1/2', 'Gene', (53, 61))	('VEGFR', 'Gene', (53, 58))	('VEGFR1/2', 'Gene', '2321;3791', (53, 61))	('inhibits', 'NegReg', (73, 81))	('VEGFR', 'Gene', (130, 135))	('ESCC', 'Disease', (99, 103))	('antibodies', 'Var', (62, 72))	('proliferation', 'CPA', (82, 95))	('VEGFR', 'Gene', '3791', (53, 58))	('VEGFR', 'Gene', '3791', (130, 135))
477745	29455652	Amplification of MET oncogene was found in 4-10% of gastric cancer cases.	('Amplification', 'Var', (0, 13))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('found', 'Reg', (34, 39))	('MET oncogene', 'Gene', (17, 29))	('gastric cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))
477755	29455652	In ESCC cell lines (KYSE70 and KYSE180), AXL was playing an important as it exerted resistance towards PI3Kalpha via EGFR/PKC/mTOR pathway.	('resistance', 'MPA', (84, 94))	('PI3Kalpha', 'Gene', '5290', (103, 112))	('EGFR', 'Gene', '1956', (117, 121))	('PKC', 'Disease', 'MESH:C537180', (122, 125))	('EGFR', 'Gene', (117, 121))	('PI3Kalpha', 'Gene', (103, 112))	('PKC', 'Disease', (122, 125))	('AXL', 'Gene', '558', (41, 44))	('KYSE180', 'Var', (31, 38))	('mTOR', 'Gene', (126, 130))	('mTOR', 'Gene', '2475', (126, 130))	('AXL', 'Gene', (41, 44))
477765	29455652	Overexpression of PTK7 has been reported in a number of different malignancies including oral tongue squamous cell carcinoma (OTSCC), colorectal, and intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', (150, 181))	('colorectal', 'Disease', 'MESH:D015179', (134, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('PTK7', 'Gene', '5754', (18, 22))	('oral tongue squamous cell carcinoma', 'Disease', (89, 124))	('colorectal', 'Disease', (134, 144))	('PTK7', 'Gene', (18, 22))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('reported', 'Reg', (32, 40))	('Overexpression', 'Var', (0, 14))	('malignancies', 'Disease', (66, 78))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 124))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))
477774	29455652	An improved sensitivity to radiation was found upon silencing IGF1R at in vitro and in vivo levels in ESCC cell lines.	('IGF1R', 'Gene', '3480', (62, 67))	('silencing', 'Var', (52, 61))	('improved', 'PosReg', (3, 11))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (12, 36))	('sensitivity', 'MPA', (12, 23))	('IGF1R', 'Gene', (62, 67))
477779	29455652	There are  established clinical development programs for IGF1R inhibitors among patients with gastric or gastro-intestinal adenocarcinoma, but little has been done (from the clinical perspective) in the indication of ESCC.	('gastro-intestinal adenocarcinoma', 'Disease', 'MESH:D007414', (105, 137))	('IGF1R', 'Gene', (57, 62))	('gastro-intestinal adenocarcinoma', 'Disease', (105, 137))	('patients', 'Species', '9606', (80, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('gastric', 'Disease', (94, 101))	('IGF1R', 'Gene', '3480', (57, 62))	('inhibitors', 'Var', (63, 73))
477783	29455652	Expression of PDGFRalpha was studied in cancer-associated fibroblast derived from ESCC patients and observed as an essential factor in ESCC progression; and expression of PDGFRbeta was found to be associated with poorly differentiated tumors but not with prognosis.	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('PDGFRalpha', 'Gene', '5156', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('PDGFRbeta', 'Gene', '5159', (171, 180))	('PDGFRalpha', 'Gene', (14, 24))	('cancer', 'Disease', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('PDGFRbeta', 'Gene', (171, 180))	('expression', 'Var', (157, 167))	('associated', 'Reg', (197, 207))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('patients', 'Species', '9606', (87, 95))	('tumors', 'Disease', (235, 241))
477891	23715646	Existing evidence promoted surgery as an integral component of successful trimodality therapy, and established that surgery significantly improves locoregional control as compared to definitive CXRT.	('improves', 'PosReg', (138, 146))	('locoregional control', 'CPA', (147, 167))	('surgery', 'Var', (116, 123))	('CXRT', 'Chemical', '-', (194, 198))
477907	23715646	Although the number of patients in this subgroup may be too small to reach valid conclusions, the findings are consistent with our previous work indicating that surgery improves the outcomes of patients with high SUV after CXRT.	('high', 'Var', (208, 212))	('patients', 'Species', '9606', (194, 202))	('improves', 'PosReg', (169, 177))	('patients', 'Species', '9606', (23, 31))	('CXRT', 'Chemical', '-', (223, 227))
477946	27394396	On the one hand, alkalis ingestion results in liquefactive necrosis and saponification leading to deep tissue penetration and full thickness injury.	('saponification', 'CPA', (72, 86))	('necrosis', 'Disease', (59, 67))	('deep tissue penetration', 'CPA', (98, 121))	('thickness injury', 'Disease', 'MESH:C535655', (131, 147))	('necrosis', 'Disease', 'MESH:D009336', (59, 67))	('alkalis ingestion', 'Phenotype', 'HP:0001948', (17, 34))	('thickness injury', 'Disease', (131, 147))	('alkalis ingestion', 'Var', (17, 34))
477948	27394396	It has to be noted, though, that strong acids may cause severe tissue damage and systematic complications similar to those of alkalis.	('cause', 'Reg', (50, 55))	('complications', 'CPA', (92, 105))	('damage', 'Disease', (70, 76))	('strong', 'Chemical', '-', (33, 39))	('strong acids', 'Var', (33, 45))	('damage', 'Disease', 'MESH:D004194', (70, 76))
477966	26196392	Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1.	('p27KIP1', 'Gene', (112, 119))	('up-regulation', 'PosReg', (83, 96))	('p21CIP1', 'Var', (100, 107))	('p27KIP1', 'Gene', '1027', (112, 119))	('G0/G1 phase arrest', 'CPA', (45, 63))
477967	26196392	Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo.	('p21CIP1', 'Var', (50, 57))	('cyclin', 'Gene', (94, 100))	('AMPK', 'Gene', (39, 43))	('down-regulation', 'NegReg', (75, 90))	('p27KIP1', 'Var', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('p53', 'Var', (45, 48))	('up-regulation', 'PosReg', (22, 35))	('anti-tumor action', 'CPA', (123, 140))	('cyclin', 'Gene', '5111', (94, 100))
477971	26196392	Metformin improves insulin resistance and the metabolic syndrome, which are considered to be carcinogenic factors.	('insulin resistance', 'Phenotype', 'HP:0000855', (19, 37))	('insulin', 'Gene', (19, 26))	('insulin', 'Gene', '3630', (19, 26))	('Metformin', 'Var', (0, 9))	('improves', 'PosReg', (10, 18))	('metabolic syndrome', 'Disease', 'MESH:D008659', (46, 64))	('metabolic syndrome', 'Disease', (46, 64))	('carcinogenic', 'Disease', 'MESH:D063646', (93, 105))	('carcinogenic', 'Disease', (93, 105))
477972	26196392	Recent epidemiological studies have shown that metformin reduces the risk of developing gastroenterological cancer, including ESCC in some diabetic patients.	('gastroenterological cancer', 'Disease', 'MESH:D009369', (88, 114))	('gastroenterological cancer', 'Disease', (88, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ESCC', 'Disease', (126, 130))	('gastroenterological cancer', 'Phenotype', 'HP:0007378', (88, 114))	('metformin', 'Var', (47, 56))	('reduces', 'NegReg', (57, 64))
477999	26196392	Similarly, substantial numbers of p53 and p21CIP1 positive cells were observed around the necrosis area on the immunohistochmically stained tumor tissue sections from the metformin treatment.	('necrosis', 'Disease', (90, 98))	('necrosis', 'Disease', 'MESH:D009336', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('p21CIP1 positive', 'Var', (42, 58))	('p53', 'Protein', (34, 37))
478000	26196392	AMPK activity is suppressed in tumors with oncogenic mutations, including Akt over activation and an LKB1 deficiency.	('Akt', 'Gene', '207', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('mutations', 'Var', (53, 62))	('suppressed', 'NegReg', (17, 27))	('Akt', 'Gene', (74, 77))	('AMPK activity', 'MPA', (0, 13))	('over activation', 'PosReg', (78, 93))	('LKB1 deficiency', 'Disease', (101, 116))	('LKB1 deficiency', 'Disease', 'MESH:D007153', (101, 116))
478004	26196392	P53 and p21CIP1 were reported to inhibit angiogenesis by suppressing the production of the vascular endothelial growth factor.	('p21CIP1', 'Var', (8, 15))	('vascular endothelial growth factor', 'Gene', (91, 125))	('inhibit', 'NegReg', (33, 40))	('vascular endothelial growth factor', 'Gene', '7422', (91, 125))	('P53', 'Gene', (0, 3))	('angiogenesis', 'CPA', (41, 53))	('P53', 'Gene', '7157', (0, 3))	('suppressing', 'NegReg', (57, 68))
478063	25788859	However, a significant increase in tumor growth inhibition occurred for the cells treated with 5-FU combinated with myricetin.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('5-FU', 'Chemical', 'MESH:D005472', (95, 99))	('myricetin', 'Chemical', 'MESH:C040015', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('increase', 'PosReg', (23, 31))	('5-FU', 'Var', (95, 99))
478066	25788859	The phases distribution of cell cycle indicated that both 5-FU and myricetin could increase the percentage of EC9706 cells in G0/G1 phase and prevent cells entering into the S phase.	('myricetin', 'Chemical', 'MESH:C040015', (67, 76))	('increase', 'PosReg', (83, 91))	('EC9706', 'Var', (110, 116))	('5-FU', 'Chemical', 'MESH:D005472', (58, 62))	('EC9706', 'CellLine', 'CVCL:E307', (110, 116))	('prevent', 'NegReg', (142, 149))	('cells entering into the S phase', 'CPA', (150, 181))	('G0/G1 phase', 'CPA', (126, 137))
478067	25788859	As shown in Figure 3, EC9706 cells treated with myricetin or 5-FU resulted in a statistically significant increase in the G0/G1 phase that was accompanied by a decrease in the S phase.	('decrease', 'NegReg', (160, 168))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('S phase', 'CPA', (176, 183))	('5-FU', 'Var', (61, 65))	('myricetin', 'Chemical', 'MESH:C040015', (48, 57))	('increase', 'PosReg', (106, 114))	('EC9706', 'CellLine', 'CVCL:E307', (22, 28))	('G0/G1 phase', 'CPA', (122, 133))
478068	25788859	Furthermore when 5-FU combination with myricetin, the G0/G1 phase percentage increased significantly to 85.9%, compared with 5-FU alone (68.8%) or myricetin alone (62.1%).	('myricetin', 'Chemical', 'MESH:C040015', (39, 48))	('5-FU', 'Chemical', 'MESH:D005472', (17, 21))	('combination', 'Interaction', (22, 33))	('5-FU', 'Chemical', 'MESH:D005472', (125, 129))	('myricetin', 'Chemical', 'MESH:C040015', (147, 156))	('increased', 'PosReg', (77, 86))	('5-FU', 'Var', (17, 21))	('G0/G1 phase percentage', 'CPA', (54, 76))
478071	25788859	The cell stained with Annexin V-positive, PI-positive or both positive were defined to apoptosis cells.	('Annexin V', 'Gene', '308', (22, 31))	('Annexin V', 'Gene', (22, 31))	('PI-positive', 'Var', (42, 53))
478083	25788859	However, a significant slower down in tumor growth occurred for mice treated with 5-FU combination with myricetin.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('5-FU', 'Chemical', 'MESH:D005472', (82, 86))	('mice', 'Species', '10090', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('myricetin', 'Chemical', 'MESH:C040015', (104, 113))	('5-FU', 'Var', (82, 86))	('slower down', 'NegReg', (23, 34))
478109	25788859	The result showed the tumor growth speed was significantly slower down in occurred for mice treated by 5-FU combine with myricetin.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('slower down', 'NegReg', (59, 70))	('mice', 'Species', '10090', (87, 91))	('5-FU combine', 'Var', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('5-FU', 'Chemical', 'MESH:D005472', (103, 107))	('tumor', 'Disease', (22, 27))	('myricetin', 'Chemical', 'MESH:C040015', (121, 130))
478124	25240386	However, another comprehensive review evaluating 1,125 ileocolic participants showed stapled anastomosis was associated with fewer leaks than hand-sewn anastomosis although there was no difference for stricture formation, anastomotic hemorrhage, anastomotic time, re-operation rate, mortality rate, or intra-abdominal abscess formation.	('fewer', 'NegReg', (125, 130))	('stapled', 'Var', (85, 92))	('intra-abdominal abscess', 'Disease', 'MESH:D018784', (302, 325))	('anastomotic hemorrhage', 'Disease', (222, 244))	('participants', 'Species', '9606', (65, 77))	('abscess', 'Phenotype', 'HP:0025615', (318, 325))	('anastomotic hemorrhage', 'Disease', 'MESH:D006470', (222, 244))	('leaks', 'MPA', (131, 136))	('abdominal abscess', 'Phenotype', 'HP:0025181', (308, 325))	('intra-abdominal abscess', 'Disease', (302, 325))
478206	24047604	Reflux may occur due to abnormalities in the relaxation of the lower esophageal sphincter (LES), inhibition of the diaphragmatic crural sling, or change in the positive pressure gradient present between the stomach and the gastroesophageal junction.	('esophageal sphincter', 'Disease', (69, 89))	('gastroesophageal junction', 'Disease', (223, 248))	('inhibition', 'NegReg', (97, 107))	('relaxation', 'MPA', (45, 55))	('Reflux', 'Disease', (0, 6))	('esophageal sphincter', 'Disease', 'MESH:D009122', (69, 89))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (223, 248))	('change', 'Reg', (146, 152))	('positive pressure gradient', 'MPA', (160, 186))	('abnormalities', 'Var', (24, 37))
478259	23124992	The esophageal cancers were characterized as follows: (1) location in the upper, middle or lower thoracic regions; (2) tumor size <=5 cm or >5 cm; (3) tumor stage T2, T3 or T4; and (4) lymph node stage N1, N2 or N3.	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('esophageal cancers', 'Disease', (4, 22))	('<=5', 'Var', (130, 133))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('esophageal cancers', 'Disease', 'MESH:D004938', (4, 22))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
478284	23124992	Patients with stage N2 or N3 disease were more likely to have recurrences, metastases or death than patients with stage N1 disease.	('death', 'Disease', 'MESH:D003643', (89, 94))	('metastases', 'Disease', (75, 85))	('recurrences', 'CPA', (62, 73))	('death', 'Disease', (89, 94))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (100, 108))	('N3 disease', 'Var', (26, 36))	('stage N2', 'Var', (14, 22))	('metastases', 'Disease', 'MESH:D009362', (75, 85))
478288	23124992	Patients with stage N2 or N3 disease were more likely than those with stage N1 disease to have recurrences and metastases.	('metastases', 'Disease', (111, 121))	('N3 disease', 'Var', (26, 36))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('Patients', 'Species', '9606', (0, 8))
478424	32349989	The current study found causal detrimental effects of T2DM on several cancers.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('T2DM', 'Var', (54, 58))	('men', 'Species', '9606', (36, 39))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Disease', (70, 77))
478427	32349989	Evidence from epidemiological studies indicates that T2DM is a risk factor for overall cancer and several site-specific cancers, such as colorectal, liver, kidney, uterine, and breast cancer.	('cancer', 'Disease', (184, 190))	('breast cancer', 'Disease', (177, 190))	('T2DM', 'Var', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (120, 126))	('uterine', 'Disease', (164, 171))	('colorectal', 'Disease', (137, 147))	('liver', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (87, 93))	('colorectal', 'Disease', 'MESH:D015179', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('risk', 'Reg', (63, 67))	('kidney', 'Disease', (156, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))
478443	32349989	Single nucleotide polymorphisms (SNPs) that met the locus-wide significance level (P < 10-5) and the genome-wide statistical significance threshold (P < 5 x 10-8) were proposed as instrumental variables for T2DM (n = 403), FG (n = 35), FI (n = 18), and pancreatic cancer (n = 22).	('Single nucleotide polymorphisms', 'Var', (0, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (253, 270))	('T2DM', 'Disease', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('men', 'Species', '9606', (186, 189))	('pancreatic cancer', 'Disease', (253, 270))	('pancreatic cancer', 'Disease', 'MESH:D010190', (253, 270))
478463	32349989	However, there was some evidence of associations of genetic liability to T2DM with higher odds of liver, pancreatic, kidney, uterine, and cervical cancer and lower odds of melanoma and esophageal cancer (Fig.	('uterine', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lower', 'NegReg', (158, 163))	('liver', 'Disease', (98, 103))	('pancreatic', 'Disease', 'MESH:D010195', (105, 115))	('T2DM', 'Gene', (73, 77))	('pancreatic', 'Disease', (105, 115))	('kidney', 'Disease', (117, 123))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('genetic liability', 'Var', (52, 69))	('melanoma and esophageal cancer', 'Disease', 'MESH:D004938', (172, 202))	('associations', 'Interaction', (36, 48))	('cervical cancer', 'Disease', (138, 153))	('cervical cancer', 'Disease', 'MESH:D002583', (138, 153))	('higher', 'PosReg', (83, 89))
478477	32349989	For example, the OR was >1.5 for genetically predicted high FG levels in relation to biliary tract cancer (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('men', 'Species', '9606', (113, 116))	('high', 'Var', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
478486	32349989	An umbrella meta-analysis of 27 studies found that having T2DM was associated with a 10% higher risk of developing cancer (38,010 cancer cases) and a 16% higher cancer mortality rate (11,386 cancer-caused deaths).	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', (130, 136))	('higher', 'PosReg', (154, 160))	('mortality', 'Disease', 'MESH:D003643', (168, 177))	('deaths', 'Disease', 'MESH:D003643', (205, 211))	('deaths', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Disease', (161, 167))	('T2DM', 'Var', (58, 62))	('mortality', 'Disease', (168, 177))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
478487	32349989	In a national register-based cohort study in Australia, the standardized incidence and mortality ratios for all cancers combined were significantly higher (ORs ranging from 1.03 to 1.22) among both men and women with T2DM than in individuals without diabetes.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('men', 'Species', '9606', (208, 211))	('T2DM', 'Var', (217, 221))	('cancers', 'Disease', (112, 119))	('diabetes', 'Disease', (250, 258))	('men', 'Species', '9606', (198, 201))	('mortality', 'Disease', (87, 96))	('women', 'Species', '9606', (206, 211))	('diabetes', 'Disease', 'MESH:D003920', (250, 258))	('higher', 'PosReg', (148, 154))
478516	32349989	A nationwide Australian study showed that long-term T2DM was associated with the age-standardized incidence ratio of cervical cancer but not with mortality from cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mortality', 'Disease', (146, 155))	('cervical cancer', 'Disease', 'MESH:D002583', (161, 176))	('cervical cancer', 'Disease', 'MESH:D002583', (117, 132))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mortality', 'Disease', 'MESH:D003643', (146, 155))	('cervical cancer', 'Disease', (161, 176))	('cervical cancer', 'Disease', (117, 132))	('T2DM', 'Var', (52, 56))	('associated', 'Reg', (61, 71))
478527	32349989	Even though most observational studies observed a strong inverse association between T2DM and risk of prostate cancer, the current study provides limited evidence supporting such a causal association, which is supported by a previous MR study.	('inverse', 'NegReg', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('prostate cancer', 'Disease', (102, 117))	('T2DM', 'Var', (85, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (102, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))
478529	32349989	There was suggestive evidence of a positive association of T2DM with liver cancer in the present MR study, confirming previous observational findings, which is likely to occur through driving nonalcoholic fatty liver disease, which can progress to hepatocellular carcinoma.	('fatty liver disease', 'Disease', (205, 224))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (248, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('liver disease', 'Phenotype', 'HP:0001392', (211, 224))	('hepatocellular carcinoma', 'Disease', (248, 272))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (248, 272))	('liver cancer', 'Phenotype', 'HP:0002896', (69, 81))	('liver cancer', 'Disease', 'MESH:D006528', (69, 81))	('fatty liver disease', 'Disease', 'MESH:D005234', (205, 224))	('liver cancer', 'Disease', (69, 81))	('T2DM', 'Var', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('association', 'Interaction', (44, 55))	('fatty liver', 'Phenotype', 'HP:0001397', (205, 216))
478530	32349989	The detrimental effects of T2DM in relation to certain site-specific cancers may be driven by high insulin levels in response to insulin resistance that occurs in the development of prediabetes.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('high', 'PosReg', (94, 98))	('insulin', 'Gene', (129, 136))	('insulin', 'Gene', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('men', 'Species', '9606', (9, 12))	('insulin', 'Gene', '3630', (129, 136))	('insulin', 'Gene', '3630', (99, 106))	('T2DM', 'Var', (27, 31))	('prediabetes', 'Disease', (182, 193))	('insulin resistance', 'Phenotype', 'HP:0000855', (129, 147))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('men', 'Species', '9606', (174, 177))	('cancers', 'Disease', (69, 76))	('prediabetes', 'Disease', 'MESH:D011236', (182, 193))
478542	32349989	We still cannot exclude that there is any direct causal pathway from the T2DM-predisposing genetic variants to cancer.	('variants', 'Var', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('T2DM-predisposing', 'Gene', (73, 90))
478610	29785080	No consensus is available in the previous literature concerning whether elevated RDW is a negative or favorable prognostic factor for EC patients.	('RDW', 'MPA', (81, 84))	('elevated', 'Var', (72, 80))	('patients', 'Species', '9606', (137, 145))
478623	29785080	In 2007, Felker et al found that RDW could serve as an independent predictor of morbidity and mortality in heart failure.	('heart failure', 'Disease', (107, 120))	('heart failure', 'Disease', 'MESH:D006333', (107, 120))	('RDW', 'Var', (33, 36))	('heart failure', 'Phenotype', 'HP:0001635', (107, 120))
478624	29785080	Recent studies have revealed that RDW is associated with prognosis in several types of cancer, such as lung cancer, prostate cancer and EC.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('associated', 'Reg', (41, 51))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (116, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('prostate cancer', 'Disease', (116, 131))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('RDW', 'Var', (34, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('prostate cancer', 'Disease', 'MESH:D011471', (116, 131))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
478636	29785080	All six studies reported a correlation between RDW and OS/CSS, and two of the studies also investigated the association between RDW and DFS.	('OS', 'Chemical', '-', (55, 57))	('correlation', 'Interaction', (27, 38))	('DFS', 'Disease', (136, 139))	('RDW', 'Var', (47, 50))	('CSS', 'Chemical', '-', (58, 61))	('OS/CSS', 'Disease', (55, 61))
478639	29785080	The pooled results showed that the RDW was not associated with OS or CSS (HR = 1.27, 95%CI: 0.97-1.57, P = 0.000; Figure 2), with significant heterogeneity among the six studies (I2 = 53.6%, P = 0.056; Figure 2); thus, the random-effects model was adopted for further analyses.	('RDW', 'Var', (35, 38))	('CSS', 'Chemical', '-', (69, 72))	('CSS', 'Disease', (69, 72))	('OS', 'Chemical', '-', (63, 65))
478645	29785080	Therefore, we performed a subgroup analysis based on the study type (Supplementary Figure 3) and found that a high RDW was significantly associated with poor OS/CSS in patients with EC in the subgroup of retrospective studies.	('high RDW', 'Var', (110, 118))	('men', 'Species', '9606', (75, 78))	('poor OS/CSS', 'Disease', (153, 164))	('patients', 'Species', '9606', (168, 176))	('CSS', 'Chemical', '-', (161, 164))	('OS', 'Chemical', '-', (158, 160))
478649	29785080	For studies with patient number <= 400, a high RDW was significantly associated with poor OS/CSS in patients with EC.	('poor OS/CSS', 'Disease', (85, 96))	('OS', 'Chemical', '-', (90, 92))	('CSS', 'Chemical', '-', (93, 96))	('patient', 'Species', '9606', (17, 24))	('patient', 'Species', '9606', (100, 107))	('patients', 'Species', '9606', (100, 108))	('high RDW', 'Var', (42, 50))
478651	29785080	The P values regarding OS/CSS were 0.133 (Begg's test; Supplementary Figure 6) and 0.005 (Egger's test; Supplementary Figure 7).	('OS', 'Chemical', '-', (23, 25))	('men', 'Species', '9606', (110, 113))	('OS/CSS', 'Disease', (23, 29))	('CSS', 'Chemical', '-', (26, 29))	('men', 'Species', '9606', (61, 64))	('0.005', 'Var', (83, 88))
478666	29785080	Four small-scale retrospective studies demonstrated that an elevated RDW was a predictor of unfavorable prognosis in EC patients, and the underlying mechanism might be one of the following.	('RDW', 'MPA', (69, 72))	('patients', 'Species', '9606', (120, 128))	('elevated', 'Var', (60, 68))
478670	29785080	Third, RDW has been found to be correlated with malnutrition, which is an independent risk factor for nosocomial infections associated with poor therapeutic response, an increased rate of treatment-related toxicity, reduced survival rates, and poor quality of life.	('survival rates', 'CPA', (224, 238))	('reduced', 'NegReg', (216, 223))	('malnutrition', 'Phenotype', 'HP:0004395', (48, 60))	('nosocomial infections', 'Disease', (102, 123))	('toxicity', 'Disease', 'MESH:D064420', (206, 214))	('toxicity', 'Disease', (206, 214))	('men', 'Species', '9606', (193, 196))	('malnutrition', 'Disease', (48, 60))	('malnutrition', 'Disease', 'MESH:D044342', (48, 60))	('nosocomial infections', 'Disease', 'MESH:D003428', (102, 123))	('RDW', 'Var', (7, 10))
478672	29785080	This finding is consistent with the results of another cohort study with data from 26709 nondiabetic adults with more than 14 years of follow-up, which indicated that a low RDW was significantly associated with an increased incidence of diabetes mellitus independent of traditional risk factors.	('diabetes mellitus', 'Disease', (237, 254))	('diabetes mellitus', 'Disease', 'MESH:D003920', (237, 254))	('associated with', 'Reg', (195, 210))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (237, 254))	('RDW', 'MPA', (173, 176))	('low', 'Var', (169, 172))
478699	29785080	This systematic review and meta-analysis indicated that elevated RDW was not an independent risk factor for the worse outcome of EC patients overall, whether it's for overall survival/cancer-specific survival [hazard ratio (HR) = 1.27, 95% confidence interval (CI): 0.97-1.57, P = 0.000] or disease-free survival (HR = 1.42, 95% CI: 0.96-1.88, P = 0.000).	('cancer', 'Disease', (184, 190))	('elevated', 'Var', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('RDW', 'MPA', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('patients', 'Species', '9606', (132, 140))
478718	29233191	MicroRNAs (miRNAs) are a class of endogenous and small noncoding RNAs, which function in RNA silencing and post-transcriptional regulation of gene expression via base-pairing with complementary sequences within mRNA molecules.	('men', 'Species', '9606', (186, 189))	('base-pairing', 'Var', (162, 174))	('post-transcriptional', 'MPA', (107, 127))	('RNA', 'MPA', (89, 92))
478724	29233191	Moreover, compared with the healthy gingiva, in periodontitis cases, six miRNAs (let-7a, let-7c, miR-130a, miR-301a, miR-520d and miR-548a) were up-regulated more than eightfold.	('up-regulated', 'PosReg', (145, 157))	('miR-301a', 'Gene', (107, 115))	('miR-301a', 'Gene', '407027', (107, 115))	('let-7a', 'Var', (81, 87))	('miR-130a', 'Gene', (97, 105))	('periodontitis', 'Disease', 'MESH:D010518', (48, 61))	('periodontitis', 'Phenotype', 'HP:0000704', (48, 61))	('miR-520d', 'Gene', '574482', (117, 125))	('periodontitis', 'Disease', (48, 61))	('miR-548a', 'Var', (130, 138))	('miR-520d', 'Gene', (117, 125))	('let-7c', 'Gene', (89, 95))	('miR-130a', 'Gene', '406919', (97, 105))	('let-7c', 'Gene', '406885', (89, 95))
478765	29233191	As shown in the figure, MKRMDA, HGIMDA, RLSMDA, HDMP, WBSMDA, MCMDA, RKNNMDA obtained AUCs of 0.9040, 0.8781, 0.8426, 0.8366, 0.8030, 0.8749 and 0.7159 in the global LOOCV, respectively.	('0.8426', 'Var', (110, 116))	('0.8749', 'Var', (134, 140))	('0.8366', 'Var', (118, 124))	('MKRMDA', 'Chemical', '-', (24, 30))	('0.7159', 'Var', (145, 151))	('WBSMDA', 'Chemical', '-', (54, 60))	('0.8030', 'Var', (126, 132))	('0.8781', 'Var', (102, 108))	('0.9040', 'Var', (94, 100))
478766	29233191	For the local LOOCV, MKRMDA, HGIMDA, RLSMDA, HDMP, WBSMDA, RWRMDA, MCMDA and RKNNMDA obtained AUCs of 0.8446, 0.8077, 0.6953, 0.7702, 0.8031, 0.7891, 0.7718 and 0.8221, respectively.	('0.6953', 'Var', (118, 124))	('0.8031', 'Var', (134, 140))	('0.8077', 'Var', (110, 116))	('WBSMDA', 'Chemical', '-', (51, 57))	('0.7702', 'Var', (126, 132))	('0.7718', 'Var', (150, 156))	('0.7891', 'Var', (142, 148))	('MKRMDA', 'Chemical', '-', (21, 27))	('0.8221', 'Var', (161, 167))	('0.8446', 'Var', (102, 108))
478795	29233191	Recent experimental research found that miR-17-5p showed an increased expression level compared with normal canine peripheral blood mononuclear cells and normal lymph nodes (LN).	('miR-17-5p', 'Var', (40, 49))	('canine', 'Species', '9615', (108, 114))	('expression level', 'MPA', (70, 86))	('miR-17-5p', 'Chemical', '-', (40, 49))	('men', 'Species', '9606', (13, 16))	('increased', 'PosReg', (60, 69))
478829	29233191	The AUC scores, 0.9040 in global LOOCV and 0.8446 in local LOOCV, demonstrated the reliable and effective performance of MKRMDA.	('0.8446', 'Var', (43, 49))	('0.9040', 'Var', (16, 22))	('MKRMDA', 'Chemical', '-', (121, 127))
478854	24152793	More attention has turned to the wide functional diversity of DUBs because they have a profound impact on the regulation of multiple biological processes including cell-cycle control, DNA repair, chromatin remodeling and several signaling pathways that are frequently altered in tumor development.	('signaling pathways', 'Pathway', (229, 247))	('chromatin remodeling', 'MPA', (196, 216))	('regulation', 'MPA', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Disease', (279, 284))	('cell-cycle control', 'MPA', (164, 182))	('DUBs', 'Var', (62, 66))	('impact', 'Reg', (96, 102))	('DNA repair', 'MPA', (184, 194))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
478859	24152793	Moreover, WP1130 has also been found to promote Mcl-1 degradation and increases tumor cell sensitivity to chemotherapies in colon adenocarcinomas and lung cancers.	('promote', 'PosReg', (40, 47))	('Mcl-1', 'Gene', '4170', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('WP1130', 'Var', (10, 16))	('Mcl-1', 'Gene', (48, 53))	('colon adenocarcinomas and lung cancers', 'Disease', 'MESH:D008175', (124, 162))	('increases tumor', 'Disease', 'MESH:D009369', (70, 85))	('lung cancers', 'Phenotype', 'HP:0100526', (150, 162))	('increases tumor', 'Disease', (70, 85))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('WP1130', 'Chemical', 'MESH:C519751', (10, 16))
478924	24152793	They found USP9X knockdown alone caused a modest decrease in tumour growth but specifically stabilized MCL1 by removing its degradative Lys 48-linked polyubiquitin chains to promoting cell survival.	('tumour growth', 'Disease', (61, 74))	('tumour growth', 'Disease', 'MESH:D006130', (61, 74))	('Lys', 'Chemical', 'MESH:D008239', (136, 139))	('stabilized', 'Reg', (92, 102))	('degradative Lys 48-linked polyubiquitin chains', 'MPA', (124, 170))	('USP9X', 'Gene', (11, 16))	('decrease', 'NegReg', (49, 57))	('MCL1', 'Gene', '4170', (103, 107))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('MCL1', 'Gene', (103, 107))	('knockdown', 'Var', (17, 26))	('USP9X', 'Gene', '8239', (11, 16))	('promoting', 'PosReg', (174, 183))	('removing', 'NegReg', (111, 119))
479007	24467939	This study was supported in part by: R21CA127057 (FMK), R01 CA 142840-03 (FMK), NSFC81372413 and NSFC81172133 (SY).	('NSFC81172133', 'Var', (97, 109))	('SY', 'CellLine', 'CVCL:7028', (111, 113))	('R01 CA 142840-03', 'Var', (56, 72))	('NSFC81372413', 'Var', (80, 92))	('R21CA127057', 'Var', (37, 48))
479036	33170337	Although no transfusion was performed in either group, the amount of intraoperative blood loss was significantly lower in the RAMIE group (P = 0.036).	('intraoperative blood loss', 'Disease', 'MESH:D016063', (69, 94))	('intraoperative blood loss', 'Disease', (69, 94))	('lower', 'NegReg', (113, 118))	('RAMIE', 'Var', (126, 131))
479076	33194789	Existing studies prove that changes in the composition and function of the oral microbiota are involved in esophageal diseases like reflux esophagitis, Barrett's esophagus (BE), and EC (Cao,; Ajayi et al.,; Corning et al.,; May and Abrams,).	("Barrett's esophagus", 'Disease', (152, 171))	('reflux esophagitis', 'Disease', 'MESH:D005764', (132, 150))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (152, 171))	('reflux esophagitis', 'Disease', (132, 150))	('esophageal diseases', 'Disease', (107, 126))	('BE', 'Phenotype', 'HP:0100580', (173, 175))	('function', 'MPA', (59, 67))	('esophageal diseases', 'Disease', 'MESH:D004935', (107, 126))	('esophagitis', 'Phenotype', 'HP:0100633', (139, 150))	('changes', 'Var', (28, 35))	('involved', 'Reg', (95, 103))
479149	32508914	Significant Raman peaks corresponding to the nonlesional tissues were observed at 826 cm-1 (tyrosine), 852 cm-1 (proline, tyrosine), 891 cm-1 (saccharide), 992 cm-1 (unknown), 1103 cm-1 (phenylalanine), 1171 cm-1 (phenylalanine, tyrosine), 1206 cm-1 (tyrosine), 1234 cm-1 (amide III), 1292 cm-1 (cytosine), 1417 cm-1 (C=C stretching in quinoid ring), 1479 cm-1 (amide II), 1517 cm-1 (beta-carotene accumulation), 1560 cm-1 (tryptophan), 1634 cm-1 (amide I), 1678 cm-1 (NADH), and 1729 cm-1 (ester group).	('1292', 'Var', (285, 289))	('1634 cm-1', 'Var', (437, 446))	('1517 cm-1', 'Var', (373, 382))	('tyrosine', 'Chemical', 'MESH:D014443', (229, 237))	('tryptophan', 'Chemical', 'MESH:D014364', (424, 434))	('phenylalanine', 'Chemical', 'MESH:D010649', (214, 227))	('1417', 'Var', (307, 311))	('tyrosine', 'Chemical', 'MESH:D014443', (92, 100))	('phenylalanine', 'Chemical', 'MESH:D010649', (187, 200))	('1479 cm-1', 'Var', (351, 360))	('tyrosine', 'Chemical', 'MESH:D014443', (251, 259))	('tyrosine', 'Chemical', 'MESH:D014443', (122, 130))
479150	32508914	In contrast, significant Raman peaks corresponding to the lesional tissues, including HGIN and adenocarcinoma, were observed in the Raman spectra at 826 cm-1, 888 cm-1, 977 cm-1, 987 cm-1, 1101 cm-1, 1171 cm-1, 1209 cm-1, 1236 cm-1, 1294 cm-1, 1324 cm-1 (collagen and purine bases of DNA), 1413 cm-1, 1517 cm-1, 1562 cm-1, and 1682 cm-1.	('1413 cm-1', 'Var', (290, 299))	('purine', 'Chemical', 'MESH:C030985', (268, 274))	('adenocarcinoma', 'Disease', (95, 109))	('HGIN', 'Disease', (86, 90))
479151	32508914	As shown in Figure 6, the Raman spectrum of the HGIN tissues exhibits significant peaks at 826 cm-1, 838 cm-1 (amine deformation vibrations), 849 cm-1, 861 cm-1, 875 cm-1 (tryptophan), 889 cm-1, 987 cm-1, 1101 cm-1, 1171 cm-1, 1209 cm- 1, 1235 cm-1, 1253 cm-1 (C-O4 aromatic stretching), 1324 cm-1, 1413 cm-1, and 1562 cm-1, while the Raman spectrum of the adenocarcinoma tissues displays significant peaks at 820 cm-1 (structural protein modes of tumors), 849 cm-1, 861 cm-1, 875 cm-1, 887 cm-1, 948 cm-1 (single-bond stretching vibrations of the amino acids proline and valine and polysaccharides), 977 cm-1, 1102 cm-1, 1171 cm-1, 1209 cm-1, 1236 cm-1, 1293 cm-1, 1323 cm-1, 1413 cm-1, 1517 cm-1, 1531 cm-1 (carotenoid, absent from the normal tissue spectrum), and 1562 cm-1.	('977 cm-1', 'Var', (601, 609))	('tumor', 'Phenotype', 'HP:0002664', (448, 453))	('849 cm-1', 'Var', (457, 465))	('1293 cm-1', 'Var', (655, 664))	('tumors', 'Phenotype', 'HP:0002664', (448, 454))	('saccharides', 'Chemical', 'MESH:D002241', (587, 598))	('amine', 'Chemical', 'MESH:D000588', (111, 116))
479153	32508914	Studies on patients with gastric cancer or esophageal cancer have shown that the levels of phenylalanine in the serum, urine, and stomach contents of patients with tumors are higher than those in healthy people.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('higher', 'PosReg', (175, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (25, 39))	('people', 'Species', '9606', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Var', (164, 170))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('levels of phenylalanine', 'MPA', (81, 104))	('gastric cancer', 'Disease', (25, 39))
479173	30196238	Radiobiology principles infer that delay of RT may affect the outcome by permitting proliferation of clonogenic cells within the field and the spread of cancer beyond the treatment volume, leading to a decrease in the probability of local and distant control.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('delay', 'Var', (35, 40))	('affect', 'Reg', (51, 57))	('men', 'Species', '9606', (176, 179))	('decrease', 'NegReg', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))
479219	30196238	Our study is the first to evaluate the impact of delay in initiation of postoperative RT on survival of patients with esophageal cancer, finding that delay is associated with reduced OS but not PFS.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('reduced', 'NegReg', (175, 182))	('OS', 'Chemical', '-', (183, 185))	('patients', 'Species', '9606', (104, 112))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('delay', 'Var', (150, 155))
479235	30196238	In addition, the combination of platinum and nonplatinum in chemotherapy regimen, and the toxicity of chemoradiotherapy, may affect the survival of patients, leading to the deviation of the results of this study.	('platinum', 'Chemical', 'MESH:D010984', (48, 56))	('patients', 'Species', '9606', (148, 156))	('affect', 'Reg', (125, 131))	('survival', 'CPA', (136, 144))	('platinum', 'Chemical', 'MESH:D010984', (32, 40))	('men', 'Species', '9606', (77, 80))	('toxicity', 'Disease', 'MESH:D064420', (90, 98))	('toxicity', 'Disease', (90, 98))	('nonplatinum', 'Var', (45, 56))
479236	30196238	In conclusion, given the result of this prospective multicentric study, delaying postoperative RT of esophageal cancer does not impact PFS, while leading to a significant reduction on OS if delaying longer than 42 days.	('OS', 'Chemical', '-', (184, 186))	('delaying', 'Var', (72, 80))	('reduction', 'NegReg', (171, 180))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
479242	29409459	A novel three-lncRNA signature, comprised of RP11-366H4.1.1 (ENSG00000248370), LINC00460 (ENSG00000233532) and AC093850.2 (ENSG00000230838), was identified.	('RP11', 'Gene', '26121', (45, 49))	('ENSG00000233532', 'Var', (90, 105))	('LINC00460', 'Gene', (79, 88))	('ENSG00000230838', 'Var', (123, 138))	('LINC00460', 'Gene', '728192', (79, 88))	('ENSG00000248370', 'Var', (61, 76))	('RP11', 'Gene', (45, 49))
479259	29409459	Finally, we built another three-lncRNA signature (RP11-366H4.1.1, LINC00460 and AC093850.2) that was highly associated with the overall survival and disease-free survival of patients with ESCC, and further validated its prognostic value in an independent cohort of 119 patients (GSE53624) from the Gene Expression Omnibus (GEO) database.	('RP11', 'Gene', (50, 54))	('ESCC', 'Disease', (188, 192))	('LINC00460', 'Gene', (66, 75))	('patients', 'Species', '9606', (174, 182))	('associated with', 'Reg', (108, 123))	('AC093850.2', 'Var', (80, 90))	('RP11', 'Gene', '26121', (50, 54))	('LINC00460', 'Gene', '728192', (66, 75))	('disease-free survival', 'CPA', (149, 170))	('patients', 'Species', '9606', (269, 277))
479270	29409459	Cells were transfected with siRNAs against RP11-366H4.1.1, LINC00460 and AC093850.2, with scrambled siRNA used as a negative control.	('LINC00460', 'Gene', '728192', (59, 68))	('LINC00460', 'Gene', (59, 68))	('RP11', 'Gene', (43, 47))	('AC093850.2', 'Var', (73, 83))	('RP11', 'Gene', '26121', (43, 47))
479282	29409459	The optimal cut-off point of lncRNA expression (2-DeltaDeltaCt, DeltaDeltaCt = DeltaCt tumor - DeltaCt normal, DeltaCt = Ct (selected lncRNA) - Ct (beta-actin)) and risk score were assessed by the X-tile program.	('beta-actin', 'Gene', '728378', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('beta-actin', 'Gene', (148, 158))	('DeltaDeltaCt', 'Var', (64, 76))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
479288	29409459	The results showed that RP11-366H4.1.1, LINC00460 and AC093850.2 were closely associated both with OS and DFS among ESCC patients (Fig.	('associated', 'Reg', (78, 88))	('LINC00460', 'Gene', '728192', (40, 49))	('RP11', 'Gene', '26121', (24, 28))	('AC093850.2', 'Var', (54, 64))	('DFS', 'Disease', (106, 109))	('RP11', 'Gene', (24, 28))	('OS', 'Chemical', '-', (99, 101))	('patients', 'Species', '9606', (121, 129))	('LINC00460', 'Gene', (40, 49))
479289	29409459	2), with patients expressing higher levels of AC093850.2, LINC00460 and RP11-366H4.1.1 tending to have shorter survival time and earlier recurrence.	('patients', 'Species', '9606', (9, 17))	('RP11', 'Gene', (72, 76))	('LINC00460', 'Gene', '728192', (58, 67))	('LINC00460', 'Gene', (58, 67))	('RP11', 'Gene', '26121', (72, 76))	('shorter', 'NegReg', (103, 110))	('survival time', 'CPA', (111, 124))	('AC093850.2', 'Var', (46, 56))
479292	29409459	We selected AC093850.2, LINC00460 and RP11-366H4.1.1 to build a multivariable Cox regression model in the training set.	('Cox', 'Gene', '1351', (78, 81))	('Cox', 'Gene', (78, 81))	('RP11', 'Gene', '26121', (38, 42))	('LINC00460', 'Gene', '728192', (24, 33))	('LINC00460', 'Gene', (24, 33))	('AC093850.2', 'Var', (12, 22))	('RP11', 'Gene', (38, 42))
479293	29409459	Risk score of the predictive model for OS was obtained as follows: (0.882 x AC093850.2) + (1.219 x LINC00460) + (0.921 x RP11-366H4.1.1).	('LINC00460', 'Gene', '728192', (99, 108))	('RP11', 'Gene', (121, 125))	('LINC00460', 'Gene', (99, 108))	('RP11', 'Gene', '26121', (121, 125))	('OS', 'Chemical', '-', (39, 41))	('0.882', 'Var', (68, 73))
479310	29409459	In the present study, we found another three-lncRNA signature (AC093850.2, LINC00460 and RP11-366H4.1.1) in 138 paired ESCC tissues and adjacent normal tissues and robustly predicted the survival of patients.	('LINC00460', 'Gene', '728192', (75, 84))	('LINC00460', 'Gene', (75, 84))	('RP11', 'Gene', '26121', (89, 93))	('AC093850.2', 'Var', (63, 73))	('predicted', 'Reg', (173, 182))	('patients', 'Species', '9606', (199, 207))	('RP11', 'Gene', (89, 93))
479311	29409459	Furthermore, we analyzed the expression of the three lncRNAs in another 18 types of cancers from data derived from the TCGA database and found that only AC093850.2 and LINC00460 are associated with breast invasive carcinoma (BRCA) patient survival, whereas LINC00460 and RP11-366H4.1.1 are associated with head and neck squamous cell carcinoma (HNSC) patient survival (Additional file 1: Table S3 and Figure S1).	('RP11', 'Gene', '26121', (271, 275))	('LINC00460', 'Gene', (168, 177))	('LINC00460', 'Gene', '728192', (257, 266))	('patient', 'Species', '9606', (351, 358))	('breast invasive carcinoma', 'Disease', (198, 223))	('patient', 'Species', '9606', (231, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('LINC00460', 'Gene', '728192', (168, 177))	('BRCA', 'Gene', '672', (225, 229))	('RP11', 'Gene', (271, 275))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (306, 343))	('associated with', 'Reg', (182, 197))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('BRCA', 'Gene', (225, 229))	('associated', 'Reg', (290, 300))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (320, 343))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('LINC00460', 'Gene', (257, 266))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (198, 223))	('AC093850.2', 'Var', (153, 163))
479317	29409459	Ten lncRNAs with higher URWScores were selected, and the association of these lncRNAs with the prognosis of OS and DFS of patients with esophageal cancer in the training set were analyzed, resulting in identification of the three lncRNA signature, composed of AC093850.2, LINC00460 and RP11-366H4.1.1, which was verified in test set (n = 61) and in an independent cohort (n = 119) (Fig.	('esophageal cancer', 'Disease', (136, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('RP11', 'Gene', (286, 290))	('OS', 'Chemical', '-', (108, 110))	('LINC00460', 'Gene', '728192', (272, 281))	('LINC00460', 'Gene', (272, 281))	('RP11', 'Gene', '26121', (286, 290))	('patients', 'Species', '9606', (122, 130))	('AC093850.2', 'Var', (260, 270))
479320	29409459	As for AC093850.2, LINC00460 and RP11-366H4.1.1, the expression of the three lncRNAs was associated with the prognosis of OS and DFS for patients in the training set (n = 77) (Fig.	('associated with', 'Reg', (89, 104))	('DFS', 'Disease', (129, 132))	('AC093850.2', 'Var', (7, 17))	('RP11', 'Gene', (33, 37))	('patients', 'Species', '9606', (137, 145))	('RP11', 'Gene', '26121', (33, 37))	('OS', 'Chemical', '-', (122, 124))	('expression', 'MPA', (53, 63))	('LINC00460', 'Gene', '728192', (19, 28))	('LINC00460', 'Gene', (19, 28))
479326	29409459	A novel three-lncRNA signature, composed of RP11-366H4.1.1, LINC00460 and AC093850.2, is identified as a potential predictor of overall survival and disease-free survival in patients with esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (188, 222))	('LINC00460', 'Gene', '728192', (60, 69))	('LINC00460', 'Gene', (60, 69))	('esophageal squamous cell carcinoma', 'Disease', (188, 222))	('RP11', 'Gene', (44, 48))	('patients', 'Species', '9606', (174, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('RP11', 'Gene', '26121', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('AC093850.2', 'Var', (74, 84))
479382	28245263	Dysplasia was defined as loss of polarity in the epithelial cells, nuclear pleomorphism and hyperchromasia, abnormal single cell keratinization (dyskeratosis), and increased or abnormal mitoses.	('polarity', 'MPA', (33, 41))	('dyskeratosis', 'Disease', (145, 157))	('hyperchromasia', 'Disease', (92, 106))	('hyperchromasia', 'Disease', 'None', (92, 106))	('dyskeratosis', 'Disease', 'MESH:D019871', (145, 157))	('nuclear pleomorphism', 'Var', (67, 87))	('loss', 'NegReg', (25, 29))	('Dysplasia', 'Disease', (0, 9))	('Dysplasia', 'Disease', 'MESH:D004476', (0, 9))
479413	28245263	The logistic model showed that absence of areca nut chewing history (P = 0.018, odds ratio = 2.483, 95% confidence interval: 1.171-5.266) and absence of smoking history (P = 0.013, odds ratio = 5.073, 95% confidence interval: 1.417-18.158) were independently correlated with pCR after preoperative chemoradiotherapy.	('absence', 'Var', (31, 38))	('areca nut', 'Species', '184783', (42, 51))	('pCR', 'Disease', (275, 278))	('correlated with', 'Reg', (259, 274))
479417	28245263	The 4-NQO is one of the carcinogens which can induce esophageal carcinogenesis and may serve as a surrogate for tobacco exposure.	('esophageal carcinogenesis', 'Disease', (53, 78))	('tobacco', 'Species', '4097', (112, 119))	('induce', 'PosReg', (46, 52))	('4-NQO', 'Var', (4, 9))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (53, 78))	('4-NQO', 'Chemical', 'MESH:D015112', (4, 9))
479447	28245263	Mutations of the TP53 gene resulting from areca nut chewing might be one possibility.	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (17, 21))	('areca nut', 'Species', '184783', (42, 51))	('TP53', 'Gene', (17, 21))
479448	28245263	found that the presence of TP53 gene mutations was associated with non-pCR after chemoradiotherapy in ESCC patients.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('non-pCR', 'Disease', (67, 74))	('associated with', 'Reg', (51, 66))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (107, 115))
479449	28245263	also revealed that ESCC patients with wild-type TP53 gene status had a higher pCR rate to neoadjuvant chemoradiotherapy.	('higher', 'PosReg', (71, 77))	('TP53', 'Gene', '7157', (48, 52))	('ESCC', 'Disease', (19, 23))	('neoadjuvant chemoradiotherapy', 'CPA', (90, 119))	('TP53', 'Gene', (48, 52))	('wild-type', 'Var', (38, 47))	('patients', 'Species', '9606', (24, 32))	('pCR', 'Disease', (78, 81))
479451	28245263	also reported that ESCC in areca nut chewers exhibited a significantly higher incidence of TP53 gene mutations than in non-chewers (67.6% versus 32.4%, P = 0.007).	('TP53', 'Gene', '7157', (91, 95))	('TP53', 'Gene', (91, 95))	('mutations', 'Var', (101, 110))	('areca nut', 'Species', '184783', (27, 36))
479471	21480386	Overexpression of VILIP-1 in aggressive SCC cells led to enhanced cAMP production, in turn causing a reduction in invasive properties.	('reduction', 'NegReg', (101, 110))	('SCC', 'Gene', '6317', (40, 43))	('VILIP-1', 'Gene', '7447', (18, 25))	('cAMP production', 'MPA', (66, 81))	('VILIP-1', 'Gene', (18, 25))	('SCC', 'Phenotype', 'HP:0002860', (40, 43))	('invasive properties', 'CPA', (114, 133))	('Overexpression', 'Var', (0, 14))	('SCC', 'Gene', (40, 43))	('enhanced', 'PosReg', (57, 65))
479485	21480386	In non-small cell lung carcinoma statistical analysis of expression and promoter methylation showed significant relationship between promoter methylation and protein expression downregulation as well as between survival and downregulation of VILIP-1 expression.	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (3, 32))	('downregulation', 'NegReg', (177, 191))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (3, 32))	('protein expression', 'MPA', (158, 176))	('VILIP-1', 'Gene', '7447', (242, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('non-small cell lung carcinoma', 'Disease', (3, 32))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (7, 32))	('downregulation', 'NegReg', (224, 238))	('promoter methylation', 'Var', (133, 153))	('VILIP-1', 'Gene', (242, 249))	('expression', 'MPA', (250, 260))
479508	21480386	Migration capacity of glial cells and non-small cell lung cancer cells is increased by PKG activity, whereas in colon cancer cells induction of PKG inhibits cell migration.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (38, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cell migration', 'CPA', (157, 171))	('Migration capacity', 'CPA', (0, 18))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('PKG', 'Enzyme', (87, 90))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('inhibits', 'NegReg', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (42, 64))	('increased', 'PosReg', (74, 83))	('colon cancer', 'Disease', (112, 124))	('rat', 'Species', '10116', (3, 6))	('rat', 'Species', '10116', (165, 168))	('activity', 'Var', (91, 99))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
479514	21480386	Isoform-specific polyclonal antibodies against ACIII (sc-32113), V/VI (sc-590), VII (sc-32120), IX (sc-20765), monoclonal antibodies against beta-actin (sc-81178) and HRP-labeled secondary antibodies were purchased from Santa Cruz Biotechnologies (Santa Cruz, CA).	('beta-actin', 'Gene', '11461', (141, 151))	('VII', 'Disease', 'MESH:D016538', (80, 83))	('ACIII', 'Gene', '104111', (47, 52))	('VII', 'Disease', (80, 83))	('ACIII', 'Gene', (47, 52))	('beta-actin', 'Gene', (141, 151))	('sc-32120', 'Var', (85, 93))
479518	21480386	When injected s.c. into nude mice, CC4A gave rise to a high-grade SCC or spindle cell carcinoma (or SCC IV), whereas CC4B gave rise to a well-differentiated, less aggressive, and low-grade SCC (SCCII).	('SCC', 'Gene', (66, 69))	('SCC', 'Gene', (189, 192))	('SCC', 'Gene', (100, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('CC4A', 'Var', (35, 39))	('spindle cell carcinoma', 'Disease', (73, 95))	('SCC', 'Gene', '6317', (66, 69))	('SCC', 'Gene', '6317', (189, 192))	('SCC', 'Gene', '6317', (100, 103))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('SCC', 'Phenotype', 'HP:0002860', (189, 192))	('nude mice', 'Species', '10090', (24, 33))	('spindle cell carcinoma', 'Disease', 'MESH:D002277', (73, 95))	('SCC', 'Gene', (194, 197))	('CC4A', 'Mutation', 'c.4CC>A', (35, 39))	('SCC', 'Phenotype', 'HP:0002860', (194, 197))	('SCC', 'Gene', '6317', (194, 197))
479519	21480386	CH72 also gave rise to a low-grade SCC after s.c. inoculation, and CH72T3 is a subcloned cell line obtained by in vivo passaging of CH72 into nude mice that resulted in a high-grade SCC.	('SCC', 'Gene', (182, 185))	('SCC', 'Phenotype', 'HP:0002860', (182, 185))	('CH72T3', 'Var', (67, 73))	('SCC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('SCC', 'Gene', '6317', (182, 185))	('SCC', 'Gene', '6317', (35, 38))	('nude mice', 'Species', '10090', (142, 151))	('CH72', 'Var', (0, 4))
479521	21480386	CC4A and CH72T3 were transfected with VILIP-1-GFP-vector or empty-GFP-vector whereas CC4B and CH72 were transfected with VILIP-1-siRNA or scrambled siRNA using Optimem and lipofectamin (Invitrogen) following the manufacturers instructions.	('VILIP-1', 'Gene', '7447', (38, 45))	('VILIP-1', 'Gene', '7447', (121, 128))	('VILIP-1', 'Gene', (38, 45))	('lipofectamin', 'Chemical', '-', (172, 184))	('CC4A', 'Mutation', 'c.4CC>A', (0, 4))	('Optimem', 'Chemical', '-', (160, 167))	('VILIP-1', 'Gene', (121, 128))	('CH72T3', 'Var', (9, 15))
479533	21480386	Cells (3 x 104 cells/well) were plated on glass coverslips coated with fibronectin, poly-D-lysine in PBS.	('fibronectin', 'Gene', '14268', (71, 82))	('PBS', 'Chemical', '-', (101, 104))	('poly-D-lysine', 'Chemical', '-', (84, 97))	('fibronectin', 'Gene', (71, 82))	('poly-D-lysine', 'Var', (84, 97))
479547	21480386	In aggressive and invasive SCC cells, CC4A and CH72T3 cells, little VILIP-1 expression and low cAMP levels are detectable, whereas less aggressive SCCs, CC4B and CH72, show high expression of VILIP-1 protein, high cAMP levels and cAMP-mediated decrease of in vivo and in vitro growth and invasiveness of SCC cells.	('VILIP-1', 'Gene', (68, 75))	('expression', 'MPA', (178, 188))	('SCC', 'Gene', '6317', (27, 30))	('SCC', 'Gene', '6317', (147, 150))	('decrease', 'NegReg', (244, 252))	('VILIP-1', 'Gene', '7447', (68, 75))	('cAMP levels', 'MPA', (214, 225))	('SCC', 'Gene', (27, 30))	('SCC', 'Gene', (147, 150))	('SCC', 'Gene', '6317', (304, 307))	('VILIP-1', 'Gene', (192, 199))	('CH72T3', 'Var', (47, 53))	('VILIP-1', 'Gene', '7447', (192, 199))	('SCC', 'Gene', (304, 307))	('cAMP-', 'Gene', (230, 235))	('CC4A', 'Mutation', 'c.4CC>A', (38, 42))	('cAMP-', 'Gene', '12796', (230, 235))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('SCC', 'Phenotype', 'HP:0002860', (27, 30))	('cAMP levels', 'MPA', (95, 106))	('SCC', 'Phenotype', 'HP:0002860', (304, 307))
479560	21480386	First we evaluated the migratory capacity of aggressive (CC4A, CH72T3) versus non aggressive SCC (CC4B, CH72) cells without and with VILIP-1-expression, respectively (Fig.	('CC4A', 'Mutation', 'c.4CC>A', (57, 61))	('VILIP-1', 'Gene', (133, 140))	('migratory capacity', 'CPA', (23, 41))	('rat', 'Species', '10116', (26, 29))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('VILIP-1', 'Gene', '7447', (133, 140))	('SCC', 'Gene', '6317', (93, 96))	('CH72T3', 'Var', (63, 69))
479572	21480386	Another possibility would be that VILIP-1 expression suppresses NPR-A and B expression levels, and a loss of VILIP-1 would enhance NPR-A and B expression levels and explain the observed enhanced cGMP levels.	('VILIP-1', 'Gene', (109, 116))	('cGMP levels', 'MPA', (195, 206))	('enhance', 'PosReg', (123, 130))	('suppresses', 'NegReg', (53, 63))	('cGMP', 'Chemical', 'MESH:D006152', (195, 199))	('loss', 'Var', (101, 105))	('VILIP-1', 'Gene', (34, 41))	('VILIP-1', 'Gene', '7447', (109, 116))	('enhanced', 'PosReg', (186, 194))	('VILIP-1', 'Gene', '7447', (34, 41))
479584	21480386	Over-expression of VILIP-1-GFP versus GFP control in CC4A and CH72T3 cells led to significant reduction in cell migration of about -31% for CC4A and -23% for CH72T3 cells (Fig.	('Over-expression', 'PosReg', (0, 15))	('rat', 'Species', '10116', (115, 118))	('reduction', 'NegReg', (94, 103))	('CH72T3', 'Var', (158, 164))	('cell migration', 'CPA', (107, 121))	('VILIP-1', 'Gene', '7447', (19, 26))	('CC4A', 'Mutation', 'c.4CC>A', (140, 144))	('VILIP-1', 'Gene', (19, 26))	('CC4A', 'Mutation', 'c.4CC>A', (53, 57))
479586	21480386	Although SCC cells are somewhat more difficult to transfect than other cell lines with transfection efficiencies of about 50% for VILIP-1-GFP and 60-70% for VILIP-1 siRNA, as measured with BLOCK-iT (Invitrogen), significant and highly significant effects were observed for VILIP-1-overexpression and knock down, respectively (Fig.	('knock down', 'Var', (300, 310))	('effects', 'Reg', (247, 254))	('VILIP-1', 'Gene', (157, 164))	('VILIP-1', 'Gene', '7447', (130, 137))	('SCC', 'Gene', (9, 12))	('VILIP-1', 'Gene', '7447', (273, 280))	('VILIP-1', 'Gene', '7447', (157, 164))	('SCC', 'Phenotype', 'HP:0002860', (9, 12))	('SCC', 'Gene', '6317', (9, 12))	('VILIP-1', 'Gene', (130, 137))	('VILIP-1', 'Gene', (273, 280))
479596	21480386	Complementary, KT5823, an inhibitor of cGMP-pathway, reduced cell migration by -13% and -12% as predicted by the opposite effect of cGMP activator experiments in less aggressive SCC lines (table 2).	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('KT5823', 'Var', (15, 21))	('SCC', 'Gene', '6317', (178, 181))	('cGMP', 'Chemical', 'MESH:D006152', (132, 136))	('KT5823', 'Chemical', 'MESH:C073601', (15, 21))	('reduced', 'NegReg', (53, 60))	('cell migration', 'CPA', (61, 75))	('rat', 'Species', '10116', (69, 72))	('SCC', 'Gene', (178, 181))	('cGMP', 'Chemical', 'MESH:D006152', (39, 43))
479626	21480386	Although an unexpected result at first, this phenomenon is supported by data from the literature showing that 8-Br-cGMP has a migration-promoting effect in fibroblasts, mammary tumor and non-small cell human lung cancer cells, whereas 8-Br-cAMP had a migration inhibiting role in fibroblasts.	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('migration-promoting', 'CPA', (126, 145))	('rat', 'Species', '10116', (129, 132))	('human', 'Species', '9606', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('8-Br-cGMP', 'Var', (110, 119))	('rat', 'Species', '10116', (254, 257))	('8-Br-cGMP', 'Chemical', 'MESH:C083763', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('lung cancer', 'Disease', (208, 219))	('rat', 'Species', '10116', (90, 93))
479633	21480386	When we used the PKG inhibitor KT5823 in migration assays we obtained data implying PKG in the enhancing effect of cGMP signaling on cell migration.	('cGMP signaling', 'MPA', (115, 129))	('cell migration', 'CPA', (133, 147))	('enhancing', 'PosReg', (95, 104))	('rat', 'Species', '10116', (44, 47))	('cGMP', 'Chemical', 'MESH:D006152', (115, 119))	('KT5823', 'Chemical', 'MESH:C073601', (31, 37))	('rat', 'Species', '10116', (141, 144))	('PKG', 'Var', (84, 87))
479650	21480386	We have previously shown in C6 glioma cells that VILIP-1 expression leads to enhanced cAMP- and cGMP-accumulation which is paralleled by changes in cell morphology, such as cell rounding and differentiation.	('VILIP-1', 'Gene', '7447', (49, 56))	('enhanced', 'PosReg', (77, 85))	('C6 glioma', 'Disease', 'MESH:C567307', (28, 37))	('VILIP-1', 'Gene', (49, 56))	('expression', 'Var', (57, 67))	('changes', 'Reg', (137, 144))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('cell rounding', 'CPA', (173, 186))	('C6 glioma', 'Disease', (28, 37))	('differentiation', 'CPA', (191, 206))	('cAMP- and cGMP', 'Gene', '12796', (86, 100))
479826	30871476	The use of single nucleotide polymorphisms (SNPs) to map BE/EAC genes has previously provided insufficient genetic information to fully characterize the heterogeneous nature of the disease.	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('single nucleotide polymorphisms', 'Var', (11, 42))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('BE/EAC', 'Gene', '1540', (57, 63))	('BE/EAC', 'Gene', (57, 63))
479827	30871476	tracts of homozygosity (TOH), repetitive elements, and insertion/deletions, may provide a comprehensive understanding of the development of BE/EAC.	('men', 'Species', '9606', (44, 47))	('EAC', 'Phenotype', 'HP:0011459', (143, 146))	('TOH', 'Chemical', '-', (24, 27))	('men', 'Species', '9606', (132, 135))	('BE/EAC', 'Gene', '1540', (140, 146))	('insertion/deletions', 'Var', (55, 74))	('BE', 'Phenotype', 'HP:0100580', (140, 142))	('BE/EAC', 'Gene', (140, 146))
479832	30871476	Interestingly, four BE/EAC-associated genes within the TOH regions consistently showed insertions and deletions that overlapped across eight exomes.	('EAC', 'Phenotype', 'HP:0011459', (23, 26))	('TOH', 'Chemical', '-', (55, 58))	('deletions', 'Var', (102, 111))	('insertions', 'Var', (87, 97))	('BE/EAC', 'Gene', '1540', (20, 26))	('BE', 'Phenotype', 'HP:0100580', (20, 22))	('BE/EAC', 'Gene', (20, 26))
479834	30871476	The integration of common TOHs (cTOHs) with repetitive elements, insertions, and deletions within exomes can help functionally prioritize factors contributing to low to moderate penetrance predisposition to BE/EAC.	('cTOHs', 'Chemical', '-', (32, 37))	('deletions', 'Var', (81, 90))	('BE/EAC', 'Gene', '1540', (207, 213))	('BE', 'Phenotype', 'HP:0100580', (207, 209))	('EAC', 'Phenotype', 'HP:0011459', (210, 213))	('BE/EAC', 'Gene', (207, 213))	('TOH', 'Chemical', '-', (26, 29))	('TOH', 'Chemical', '-', (33, 36))	('men', 'Species', '9606', (58, 61))
479852	30871476	Whole-exome sequencing studies have investigated the genomic alterations in a larger sample size and reported mutations in ELMO1 and DOCK2.	('ELMO1', 'Gene', (123, 128))	('mutations', 'Var', (110, 119))	('DOCK2', 'Gene', (133, 138))	('ELMO1', 'Gene', '9844', (123, 128))	('DOCK2', 'Gene', '1794', (133, 138))
479854	30871476	In the study reported here, we attempt to merge multiple types of genomic changes, including repeats, TOHs, and insertions/deletions, across platforms to better understand the progression of BE to EAC.	('TOHs', 'Disease', (102, 106))	('EAC', 'Gene', '1540', (197, 200))	('BE', 'Phenotype', 'HP:0100580', (191, 193))	('insertions/deletions', 'Var', (112, 132))	('EAC', 'Gene', (197, 200))	('TOH', 'Chemical', '-', (102, 105))	('EAC', 'Phenotype', 'HP:0011459', (197, 200))
479865	30871476	We identified insertions and deletions within the cTOH regions, and their distributions varied in the eight BE/EAC patients (Fig.	('EAC', 'Phenotype', 'HP:0011459', (111, 114))	('BE', 'Phenotype', 'HP:0100580', (108, 110))	('patients', 'Species', '9606', (115, 123))	('BE/EAC', 'Gene', '1540', (108, 114))	('BE/EAC', 'Gene', (108, 114))	('insertions', 'Var', (14, 24))	('deletions', 'Var', (29, 38))	('cTOH', 'Chemical', '-', (50, 54))	('varied', 'Reg', (88, 94))
479866	30871476	We located 180 positions of insertions and deletions on genes across all cTOH regions.	('deletions', 'Var', (43, 52))	('cTOH', 'Chemical', '-', (73, 77))	('insertions', 'Var', (28, 38))
479867	30871476	The genes that consistently showed insertions and deletions that overlapped across all samples were WDR63 (a WD repeat in domain 63), VPS13B (a vacuolar protein sorting homolog 13 B), MON2 (a regulator to endosome-to-Golgi trafficking), and CTAGE5 (a cutaneous T-cell lymphoma-associated antigen 1), Additional file 1.	('VPS13B', 'Gene', (134, 140))	('WDR63', 'Gene', (100, 105))	('VPS13B', 'Gene', '157680', (134, 140))	('WD', 'Disease', 'MESH:D006527', (109, 111))	('cutaneous T-cell lymphoma-associated antigen 1', 'Gene', (251, 297))	('WDR63', 'Gene', '126820', (100, 105))	('cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (251, 276))	('cutaneous T-cell lymphoma-associated antigen 1', 'Gene', '64693', (251, 297))	('insertions', 'Var', (35, 45))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (261, 276))	('cell lymphoma', 'Phenotype', 'HP:0012191', (263, 276))	('MON2', 'Gene', (184, 188))	('WD', 'Disease', 'MESH:D006527', (100, 102))	('MON2', 'Gene', '23041', (184, 188))	('lymphoma', 'Phenotype', 'HP:0002665', (268, 276))	('CTAGE5', 'Gene', (241, 247))	('CTAGE5', 'Gene', '4253', (241, 247))	('deletions', 'Var', (50, 59))
479886	30871476	GNA12 can be upregulated by GPCR and then trigger RhoGEF, Rho, ROCK, and subsequently affect tissue invasion and metastasis.	('affect', 'Reg', (86, 92))	('GNA12', 'Gene', (0, 5))	('GPCR', 'Var', (28, 32))	('upregulated', 'PosReg', (13, 24))	('RhoGEF', 'Gene', (50, 56))	('GNA12', 'Gene', '2768', (0, 5))	('Rho', 'Gene', (58, 61))	('ROCK', 'CPA', (63, 67))	('trigger', 'Reg', (42, 49))	('tissue invasion', 'CPA', (93, 108))
479891	30871476	Then, we integrated the exome sequence data within the TOH regions to identify IRs or direct repeats and insertion/deletions to prioritize genes and pathways that are important in BE/EAC.	('TOH', 'Chemical', '-', (55, 58))	('BE/EAC', 'Gene', '1540', (180, 186))	('BE/EAC', 'Gene', (180, 186))	('EAC', 'Phenotype', 'HP:0011459', (183, 186))	('insertion/deletions', 'Var', (105, 124))	('BE', 'Phenotype', 'HP:0100580', (180, 182))
479899	30871476	Interestingly with the integrated data from IRs, insertion/deletions, and significant cTOHs, we were able to identify key genes that may have a role in BE/EAC.	('BE', 'Phenotype', 'HP:0100580', (152, 154))	('BE/EAC', 'Gene', '1540', (152, 158))	('insertion/deletions', 'Var', (49, 68))	('EAC', 'Phenotype', 'HP:0011459', (155, 158))	('BE/EAC', 'Gene', (152, 158))	('cTOHs', 'Chemical', '-', (86, 91))
479900	30871476	The frequencies of IRs, insertions, and deletions in the case-only exome data implies that the variants maybe important in BE and EAC.	('deletions', 'Var', (40, 49))	('insertions', 'Var', (24, 34))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('EAC', 'Gene', '1540', (130, 133))	('BE', 'Phenotype', 'HP:0100580', (123, 125))	('variants', 'Var', (95, 103))	('EAC', 'Gene', (130, 133))
479902	30871476	Previous studies have shown that hypomethylation is more prevalent in the repeat regions and has diverse ways of contributing to cancer behavior.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer behavior', 'Disease', (129, 144))	('contributing', 'Reg', (113, 125))	('hypomethylation', 'Var', (33, 48))	('cancer behavior', 'Disease', 'MESH:D009369', (129, 144))
479903	30871476	For example, hypomethylation of repeated DNA sequences is largely responsible for the global DNA hypomethylation that is frequently observed in cancers.	('hypomethylation', 'Var', (13, 28))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('global', 'MPA', (86, 92))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
479906	30871476	BE/EAC-associated aberrations in the miRNA and/or epigenetic patterns can explain the development and clinical stages of the diseases.	('BE/EAC', 'Gene', '1540', (0, 6))	('BE/EAC', 'Gene', (0, 6))	('aberrations', 'Var', (18, 29))	('explain', 'Reg', (74, 81))	('epigenetic patterns', 'MPA', (50, 69))	('men', 'Species', '9606', (93, 96))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('miRNA', 'MPA', (37, 42))	('BE', 'Phenotype', 'HP:0100580', (0, 2))
479918	30871476	WDR63 is downregulated in lung cancers, probably through DNA methylation.	('WDR63', 'Gene', '126820', (0, 5))	('methylation', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('lung cancers', 'Disease', 'MESH:D008175', (26, 38))	('lung cancers', 'Phenotype', 'HP:0100526', (26, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('WDR63', 'Gene', (0, 5))	('downregulated', 'NegReg', (9, 22))	('lung cancers', 'Disease', (26, 38))
479920	30871476	Both miR-4423 and WDR63 can be affected by DNA damage or rearrangement (e.g., due to IRs) and stress-induced transcription factors.	('men', 'Species', '9606', (66, 69))	('WDR63', 'Gene', '126820', (18, 23))	('miR-4423', 'Gene', '100616481', (5, 13))	('affected', 'Reg', (31, 39))	('miR-4423', 'Gene', (5, 13))	('rearrangement', 'Var', (57, 70))	('WDR63', 'Gene', (18, 23))
479940	30871476	Insertion or deletion (indel) realignment, base- and quality-score recalibrations from the resultant binary alignment map (BAM) files were performed with GATK, Sequence Alignment/Map (SAMtools), and Picard.	('deletion', 'Var', (13, 21))	('men', 'Species', '9606', (37, 40))	('men', 'Species', '9606', (113, 116))	('Insertion', 'Var', (0, 9))	('men', 'Species', '9606', (174, 177))
479941	30871476	Nucleotide repeat elements are abundant in the human genome and may have significant roles in disease development.	('Nucleotide repeat elements', 'Var', (0, 26))	('roles', 'Reg', (85, 90))	('men', 'Species', '9606', (109, 112))	('human', 'Species', '9606', (47, 52))	('men', 'Species', '9606', (21, 24))
479946	30871476	The genes associated with BE/EAC and containing insertion/deletion within contigs across all samples were collected in a tab-separated value (TSV) file and visualized using R packages: ggplot2 and ggbio.	('EAC', 'Phenotype', 'HP:0011459', (29, 32))	('insertion/deletion', 'Var', (48, 66))	('BE/EAC', 'Gene', '1540', (26, 32))	('BE', 'Phenotype', 'HP:0100580', (26, 28))	('BE/EAC', 'Gene', (26, 32))
479947	30871476	Since the key genes identified within cTOH regions that overlapped with the insertions/deletions and IRs may have possible roles in either the development or progression of BE to EAC, we used MetaCore bioinformatics software and curated Comparative Toxicogenomics Database to analyze biological pathways as well as disease and gene networks that are associated with BE/EAC.	('EAC', 'Gene', (179, 182))	('EAC', 'Phenotype', 'HP:0011459', (369, 372))	('EAC', 'Gene', '1540', (369, 372))	('BE', 'Phenotype', 'HP:0100580', (173, 175))	('EAC', 'Gene', (369, 372))	('cTOH', 'Chemical', '-', (38, 42))	('insertions/deletions', 'Var', (76, 96))	('EAC', 'Phenotype', 'HP:0011459', (179, 182))	('BE', 'Phenotype', 'HP:0100580', (366, 368))	('roles', 'Reg', (123, 128))	('men', 'Species', '9606', (150, 153))	('BE/EAC', 'Gene', '1540', (366, 372))	('BE/EAC', 'Gene', (366, 372))	('EAC', 'Gene', '1540', (179, 182))
480034	29670413	Little is known regarding the functional status of patients with end-stage benign disease post-esophagectomy; what our study and other studies have suggested is that patients with end-stage benign disease may have higher psychological concerns than their malignant counterparts.	('higher', 'PosReg', (214, 220))	('end-stage benign disease', 'Var', (180, 204))	('patients', 'Species', '9606', (51, 59))	('patients', 'Species', '9606', (166, 174))	('psychological concerns', 'CPA', (221, 243))
480092	29438423	Thrombocytopenia was defined as platelet count lower than 150.000/mul; subgroups were stratified into severe (lower than 50.000/mul), moderate (50.000-100.000/mul) and mild (100.000-150.000/mul).	('platelet count lower', 'Phenotype', 'HP:0001873', (32, 52))	('Thrombocytopenia', 'Disease', (0, 16))	('100.000-150.000/mul', 'Var', (174, 193))	('50.000-100.000/mul', 'Var', (144, 162))	('Thrombocytopenia', 'Phenotype', 'HP:0001873', (0, 16))	('lower than 50.000/mul', 'Var', (110, 131))	('Thrombocytopenia', 'Disease', 'MESH:D013921', (0, 16))
480111	29438423	In our study, the IPF% was associated with stage of cirrhosis and esophageal varices.	('esophageal varices', 'Disease', (66, 84))	('cirrhosis', 'Disease', (52, 61))	('IPF', 'Var', (18, 21))	('associated', 'Reg', (27, 37))	('cirrhosis', 'Phenotype', 'HP:0001394', (52, 61))	('IPF', 'Chemical', '-', (18, 21))	('esophageal varices', 'Phenotype', 'HP:0002040', (66, 84))	('cirrhosis', 'Disease', 'MESH:D005355', (52, 61))
480257	29162972	In our study, we determined that stenting can impede the progress of dysphagia symptoms and improve quality of life which is consistent with the literature.	('quality', 'MPA', (100, 107))	('improve', 'PosReg', (92, 99))	('progress', 'MPA', (57, 65))	('dysphagia', 'Phenotype', 'HP:0002015', (69, 78))	('stenting', 'Var', (33, 41))	('dysphagia symptoms', 'Disease', (69, 87))	('impede', 'NegReg', (46, 52))	('dysphagia symptoms', 'Disease', 'MESH:D003680', (69, 87))
480296	28423740	The results showed that CRT+S contributed to the better long-term survival compared with surgery, CT+S and RT+S while RT+S seemed to have no positive effect on survival time, and even resulted in a worsened prognosis.	('worsened', 'NegReg', (198, 206))	('RT+S', 'Var', (107, 111))	('CT+S', 'Gene', (98, 102))	('long-term survival', 'CPA', (56, 74))	('CT+S', 'Gene', '7276', (98, 102))	('better', 'PosReg', (49, 55))	('CRT+S', 'Var', (24, 29))	('prognosis', 'MPA', (207, 216))
480326	27414086	Strikingly, NDRG1 overexpression induces the epithelial mesenchymal transition (EMT) through activating the Wnt signaling pathway in ESCC cells, decreased the expression of E-cadherin and enhanced the expression of Snail.	('epithelial mesenchymal transition', 'CPA', (45, 78))	('Snail', 'Gene', (215, 220))	('enhanced', 'PosReg', (188, 196))	('E-cadherin', 'Gene', (173, 183))	('Snail', 'Gene', '6615', (215, 220))	('E-cadherin', 'Gene', '999', (173, 183))	('NDRG1', 'Gene', (12, 17))	('expression', 'MPA', (159, 169))	('overexpression', 'Var', (18, 32))	('decreased', 'NegReg', (145, 154))	('activating', 'PosReg', (93, 103))	('Wnt signaling pathway', 'Pathway', (108, 129))	('expression', 'MPA', (201, 211))	('induces', 'PosReg', (33, 40))
480349	27414086	For NDRG1 overexpression, the KYSE 30 cells were transfected with the pCMV6-entry-NDRG1 or pCMV6 empty vector (Origen, Rockville MD) by Lipofectamine 2000 (Invitrogen, USA).	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (136, 154))	('pCMV6-entry-NDRG1', 'Var', (70, 87))	('NDRG1', 'Gene', (4, 9))
480351	27414086	HEK293 cells were transiently transfected with pCMV6-entry-NDRG1, pCMV6-entry-TLE2, and pCMV6 empty vectors using the Lipofectamine 2000 reagent according to the manufacturer's protocol.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (118, 136))	('TLE2', 'Gene', '7089', (78, 82))	('TLE2', 'Gene', (78, 82))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('pCMV6-entry-NDRG1', 'Var', (47, 64))
480371	27414086	The xenograft tumor volume was compared between the KYSE 30-NDRG1 and KYSE-vec control groups by Student's t tests in the mouse xenograft assay.	('tumor', 'Disease', (14, 19))	('KYSE 30-NDRG1', 'Var', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mouse', 'Species', '10090', (122, 127))
480381	27414086	However, NDRG1 positivity did not have a significant association with other clinic pathological factors, including gender, age, pathological grade, tumor diameter, tumor position, lymphatic metastasis and AJCC stage (Table 1).	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('lymphatic', 'Disease', (180, 189))	('NDRG1', 'Gene', (9, 14))	('tumor', 'Disease', (148, 153))	('positivity', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
480384	27414086	NDRG1 overexpression significantly enhanced motility in wound-healing assays in KYSE 30 cells and also elevated MMP2 activity, a surrogate marker of metastasis.	('overexpression', 'Var', (6, 20))	('MMP2', 'Gene', '4313', (112, 116))	('enhanced', 'PosReg', (35, 43))	('motility in wound-healing assays', 'CPA', (44, 76))	('elevated', 'PosReg', (103, 111))	('NDRG1', 'Gene', (0, 5))	('MMP2', 'Gene', (112, 116))
480386	27414086	Consistent with the phenotypic changes associated with NDRG1 overexpression, we also observed an increase in the expression of mesenchymal markers, including N-cadherin, Snail and MMP1, but we did not observe decreased expression of the epithelial marker E-cadherin at the protein level (Fig.	('expression', 'MPA', (113, 123))	('MMP1', 'Gene', (180, 184))	('N-cadherin', 'Gene', (158, 168))	('increase', 'PosReg', (97, 105))	('NDRG1', 'Gene', (55, 60))	('N-cadherin', 'Gene', '1000', (158, 168))	('MMP1', 'Gene', '4312', (180, 184))	('E-cadherin', 'Gene', (255, 265))	('E-cadherin', 'Gene', '999', (255, 265))	('Snail', 'Gene', (170, 175))	('overexpression', 'Var', (61, 75))	('Snail', 'Gene', '6615', (170, 175))
480388	27414086	2D and 2E the expression levels of the angiogenesis-related genes ANGPT1 and TGFB1, invasion and metastasis-related genes MMP1, MMP2, PLAUR and SERPINB5, adhesion-related genes MTSS1 and SYK, cell cycle-related gene CDC25A, and oncogenic transcription factor MYC were significantly enhanced after NDRG1 overexpression.	('MMP1', 'Gene', '4312', (122, 126))	('ANGPT1', 'Gene', '284', (66, 72))	('SERPINB5', 'Gene', (144, 152))	('MMP1', 'Gene', (122, 126))	('TGFB1', 'Gene', '7040', (77, 82))	('CDC25A', 'Gene', '993', (216, 222))	('SYK', 'Gene', '6850', (187, 190))	('TGFB1', 'Gene', (77, 82))	('oncogenic', 'MPA', (228, 237))	('MTSS1', 'Gene', (177, 182))	('expression levels', 'MPA', (14, 31))	('MYC', 'Gene', '4609', (259, 262))	('PLAUR', 'Gene', '5329', (134, 139))	('MMP2', 'Gene', (128, 132))	('NDRG1', 'Gene', (297, 302))	('ANGPT1', 'Gene', (66, 72))	('CDC25A', 'Gene', (216, 222))	('MTSS1', 'Gene', '9788', (177, 182))	('SERPINB5', 'Gene', '5268', (144, 152))	('overexpression', 'Var', (303, 317))	('MMP2', 'Gene', '4313', (128, 132))	('PLAUR', 'Gene', (134, 139))	('enhanced', 'PosReg', (282, 290))	('MYC', 'Gene', (259, 262))	('angiogenesis-related', 'CPA', (39, 59))	('SYK', 'Gene', (187, 190))
480395	27414086	Inversely, NDRG1 knock-down induced TLE2 upregulation at the transcript level in KYSE 30 cells.	('NDRG1', 'Gene', (11, 16))	('TLE2', 'Gene', '7089', (36, 40))	('TLE2', 'Gene', (36, 40))	('knock-down', 'Var', (17, 27))	('upregulation', 'PosReg', (41, 53))
480400	27414086	To determine whether NDRG1 overexpression or knock-down impacts TLE2 protein expression, we used western blot analysis to assess TLE2 expression.	('TLE2', 'Gene', '7089', (129, 133))	('TLE2', 'Gene', (129, 133))	('TLE2', 'Gene', '7089', (64, 68))	('protein', 'Protein', (69, 76))	('knock-down', 'Var', (45, 55))	('TLE2', 'Gene', (64, 68))	('NDRG1', 'Gene', (21, 26))	('impacts', 'Reg', (56, 63))
480401	27414086	4A, NDRG1 overexpression and knock-down altered TLE2 expression at the protein level in KYSE 30 cells.	('TLE2', 'Gene', '7089', (48, 52))	('altered', 'Reg', (40, 47))	('NDRG1', 'Gene', (4, 9))	('knock-down', 'Var', (29, 39))	('TLE2', 'Gene', (48, 52))	('expression', 'MPA', (53, 63))
480406	27414086	3F, we found that beta-catenin was enriched in both the cytosolic and nuclear fractions; in contrast, the inverse was found for TLE2, which was greatly decreased in the nuclear fraction after NDRG1 overexpression compared with the control group.	('TLE2', 'Gene', (128, 132))	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (18, 30))	('decreased', 'NegReg', (152, 161))	('overexpression', 'Var', (198, 212))	('NDRG1', 'Gene', (192, 197))	('TLE2', 'Gene', '7089', (128, 132))
480412	27414086	Together, these data indicate that NDRG1 overexpression promotes the activation of the Wnt signaling pathway, through increased beta-catenin and decreased TLE2.	('NDRG1', 'Gene', (35, 40))	('TLE2', 'Gene', (155, 159))	('overexpression', 'Var', (41, 55))	('beta-catenin', 'Gene', (128, 140))	('Wnt signaling pathway', 'Pathway', (87, 108))	('beta-catenin', 'Gene', '1499', (128, 140))	('increased', 'PosReg', (118, 127))	('decreased', 'NegReg', (145, 154))	('TLE2', 'Gene', '7089', (155, 159))
480413	27414086	To examine whether NDRG1 ectopic overexpression could affect tumor growth in vivo, we performed in vivo experiments via subcutaneous transplantation of transduced cells into nude mice, whereby we compared tumor growth rates induced by KYSE 30-Vec and KYSE 30-NDRG1 cells in a xenograft model.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('NDRG1', 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('nude mice', 'Species', '10090', (174, 183))	('ectopic', 'Var', (25, 32))	('tumor', 'Disease', (205, 210))	('affect', 'Reg', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (61, 66))
480414	27414086	5A, the tumor growth rate of KYSE 30-NDRG1 cells was significantly faster than that of KYSE 30-Vec cells 20 d after inoculation by subcutaneous injection.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('faster', 'PosReg', (67, 73))	('KYSE 30-NDRG1', 'Var', (29, 42))
480418	27414086	Our previous data showed that NDRG1 overexpression reduced TLE2 and affected the Wnt signaling pathway.	('reduced', 'NegReg', (51, 58))	('Wnt signaling pathway', 'Pathway', (81, 102))	('affected', 'Reg', (68, 76))	('NDRG1', 'Gene', (30, 35))	('TLE2', 'Gene', '7089', (59, 63))	('TLE2', 'Gene', (59, 63))	('overexpression', 'Var', (36, 50))
480419	27414086	To further investigate whether NDRG1 overexpression could impact the Wnt signaling pathway, we analyzed the expression of TLE2, beta-catenin and E-cadherin.	('NDRG1', 'Gene', (31, 36))	('E-cadherin', 'Gene', '999', (145, 155))	('beta-catenin', 'Gene', (128, 140))	('beta-catenin', 'Gene', '1499', (128, 140))	('Wnt signaling pathway', 'Pathway', (69, 90))	('impact', 'Reg', (58, 64))	('TLE2', 'Gene', '7089', (122, 126))	('TLE2', 'Gene', (122, 126))	('overexpression', 'Var', (37, 51))	('E-cadherin', 'Gene', (145, 155))
480441	27414086	TLE2 expression results in transcriptional repression of specific gene regulatory sequences, via the recruitment of Groucho.	('results in', 'Reg', (16, 26))	('expression', 'Var', (5, 15))	('TLE2', 'Gene', '7089', (0, 4))	('transcriptional repression', 'MPA', (27, 53))	('TLE2', 'Gene', (0, 4))
480443	27414086	Other reports have shown that the modification of TLE by XIAP-mediated ubiquitylation decreases its affinity with beta-catenin, thereby allowing the formation of the beta-catenin/TCF complex and thus the switch to an activated Wnt signaling pathway.	('beta-catenin', 'Gene', (114, 126))	('TCF', 'Gene', (179, 182))	('TCF', 'Gene', '3172', (179, 182))	('beta-catenin', 'Gene', (166, 178))	('XIAP', 'Gene', '331', (57, 61))	('formation', 'Interaction', (149, 158))	('TLE', 'Disease', 'MESH:D004833', (50, 53))	('beta-catenin', 'Gene', '1499', (114, 126))	('TLE', 'Disease', (50, 53))	('modification', 'Var', (34, 46))	('decreases', 'NegReg', (86, 95))	('beta-catenin', 'Gene', '1499', (166, 178))	('activated Wnt signaling pathway', 'Pathway', (217, 248))	('allowing', 'Reg', (136, 144))	('XIAP', 'Gene', (57, 61))	('switch', 'Reg', (204, 210))	('affinity', 'Interaction', (100, 108))
480480	26682276	Inhibition of COX activity decreases the formation of prostanoids (e.g., PGE2 and TXA2) that promote inflammation, pain, fever, and platelet aggregation.	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('fever', 'Phenotype', 'HP:0001945', (121, 126))	('pain', 'Phenotype', 'HP:0012531', (115, 119))	('platelet aggregation', 'Disease', 'MESH:D001791', (132, 152))	('COX', 'Gene', (14, 17))	('inflammation', 'Disease', (101, 113))	('pain', 'Disease', 'MESH:D010146', (115, 119))	('PGE2', 'Chemical', 'MESH:D015232', (73, 77))	('decreases', 'NegReg', (27, 36))	('prostanoids', 'Chemical', 'MESH:D011453', (54, 65))	('platelet aggregation', 'Disease', (132, 152))	('Inhibition', 'Var', (0, 10))	('fever', 'Disease', 'MESH:D005334', (121, 126))	('platelet aggregation', 'Phenotype', 'HP:0003540', (132, 152))	('fever', 'Disease', (121, 126))	('promote', 'PosReg', (93, 100))	('formation of prostanoids', 'MPA', (41, 65))	('pain', 'Disease', (115, 119))	('COX', 'Gene', '1351', (14, 17))
480515	26682276	A possible reason is that the prevailing model of carcinogenesis states that cancer is caused by genetic mutations, and thermal tissue injury is not regarded as a significant source of mutations.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('carcinogenesis', 'Disease', (50, 64))	('caused', 'Reg', (87, 93))	('mutations', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('carcinogenesis', 'Disease', 'MESH:D063646', (50, 64))
480547	26682276	A recent article showed that inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration by increasing tissue levels of PGE2.	('potentiates', 'PosReg', (86, 97))	('prostaglandin', 'Chemical', 'MESH:D011453', (47, 60))	('tissue levels of PGE2', 'MPA', (132, 153))	('tissue regeneration', 'CPA', (98, 117))	('15-PGDH', 'Gene', (78, 85))	('15-PGDH', 'Gene', '3248', (78, 85))	('increasing', 'PosReg', (121, 131))	('PGE2', 'Chemical', 'MESH:D015232', (149, 153))	('inhibition', 'Var', (29, 39))
480553	26682276	But in each of these cell divisions, our DNA has been copied and has accumulated alterations that may lead to cancer.	('cancer', 'Disease', (110, 116))	('lead to', 'Reg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('alterations', 'Var', (81, 92))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
480571	26682276	Restricting the levels of the growth hormone (GH) and the insulin-like growth factor 1 (IGF1), the major mediator of the effects of GH, may also restrict the division rates of stem cells and may reduce cancer risk.	('IGF1', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('insulin-like growth factor 1', 'Gene', (58, 86))	('reduce', 'NegReg', (195, 201))	('GH', 'Gene', '2688', (46, 48))	('growth hormone', 'Gene', (30, 44))	('Restricting', 'Var', (0, 11))	('division rates of stem cells', 'CPA', (158, 186))	('restrict', 'NegReg', (145, 153))	('insulin-like growth factor 1', 'Gene', '3479', (58, 86))	('growth hormone', 'Gene', '2688', (30, 44))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('IGF1', 'Gene', '3479', (88, 92))	('GH', 'Gene', '2688', (132, 134))
480576	26682276	Interestingly, fasting and low protein intake can reduce serum IGF1 levels, and can also reduce tumor growth in animals and cancer risk in some human populations.	('cancer', 'Disease', (124, 130))	('IGF1', 'Gene', '3479', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('reduce', 'NegReg', (50, 56))	('human', 'Species', '9606', (144, 149))	('tumor', 'Disease', (96, 101))	('reduce', 'NegReg', (89, 95))	('IGF1', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('low protein intake', 'Phenotype', 'HP:0003075', (27, 45))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('serum', 'MPA', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('low protein intake', 'Var', (27, 45))
480583	26682276	Then, they interpreted that the parameters "stem cell divisions" and "DNA replication mutations" could be interchanged, and proposed that approximately two-thirds (65%) of the mutations required to originate a cancer were random mutations arising during DNA replication.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutations', 'Var', (176, 185))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (210, 216))
480592	26682276	Finding a chemopreventive drug to selectively kill mutated stem cells before they give rise to cancer is possible.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('mutated', 'Var', (51, 58))
480602	25726761	Furthermore, we found that both NELL1 and NELL2 inhibit RCC cell migration, and NELL1 further inhibits RCC cell adhesion.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('inhibits', 'NegReg', (94, 102))	('NELL1', 'Var', (80, 85))	('rat', 'Species', '10116', (68, 71))	('inhibit', 'NegReg', (48, 55))
480603	25726761	These results suggest that silencing of NELL gene expression by promoter hypermethylation plays roles in RCC progression by affecting cancer cell behavior.	('NELL gene', 'Gene', (40, 49))	('silencing', 'NegReg', (27, 36))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('promoter hypermethylation', 'Var', (64, 89))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('cancer', 'Disease', (134, 140))	('RCC', 'Disease', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('affecting', 'Reg', (124, 133))
480610	25726761	Loss of heterozygosity or mutations of the von Hippel-Lindau (VHL) tumor suppressor gene and the mesenchymal-epithelial transition (c-MET) proto-oncogene, which are responsible for inherited tumor syndromes involving the kidney, have been found in sporadic RCC.	('c-MET', 'Gene', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Loss', 'NegReg', (0, 4))	('mutations', 'Var', (26, 35))	('inherited tumor', 'Disease', 'None', (181, 196))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (43, 72))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('inherited tumor', 'Disease', (181, 196))	('RCC', 'Disease', (257, 260))	('RCC', 'Phenotype', 'HP:0005584', (257, 260))	('c-MET', 'Gene', '4233', (132, 137))	('RCC', 'Disease', 'MESH:C538614', (257, 260))
480611	25726761	Epigenetic inactivation by DNA methylation was shown to cause downregulation of the mRNA expression of RAS-associated domain family-1A (RASSF1A), a tumor suppressor gene, in RCC.	('RASSF1A', 'Gene', '11186', (136, 143))	('mRNA expression', 'MPA', (84, 99))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('methylation', 'Var', (31, 42))	('RCC', 'Disease', (174, 177))	('downregulation', 'NegReg', (62, 76))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('RAS-associated domain family-1A', 'Gene', '11186', (103, 134))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('RASSF1A', 'Gene', (136, 143))	('RAS-associated domain family-1A', 'Gene', (103, 134))	('Epigenetic inactivation', 'Var', (0, 23))	('DNA methylation', 'Var', (27, 42))
480629	25726761	Four-micron sections of CCRCC samples were analyzed by immunohistochemistry (IHC) using anti-NELL1 and anti-NELL2 antibodies (HPA051535, 1/100 and HPA035715, 1/300 dilutions; Sigma-Aldrich, St. Louis, MO, USA) according to the manufacturer's protocol, except that antigen retrieval was carried out at 121 C for 15 min.	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('HPA035715', 'Var', (147, 156))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('HPA051535', 'Var', (126, 135))
480643	25726761	The lower side of the Transwell membrane inserts (product #3422; Corning, Corning, NY, USA) was coated with 40 nM or 400 nM AP, NELL1-AP, or NELL2-AP protein at 4 C overnight, blocked with 20 mg/mL BSA in PBS for 3 h at 4 C, and then washed with RPMI-1640.	('RPMI-1640', 'Chemical', '-', (246, 255))	('NELL2-AP', 'Var', (141, 149))	('NELL1-AP', 'Var', (128, 136))
480658	25726761	Aberrant DNA hypermethylation of promoter CpG islands with associated gene silencing plays crucial roles in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('gene', 'MPA', (70, 74))	('silencing', 'NegReg', (75, 84))	('tumor', 'Disease', (108, 113))
480659	25726761	Because hypermethylation of the NELL1 5'-UTR has been reported in esophageal adenocarcinoma and colorectal cancer, we speculated that the downregulation of the NELL1 and NELL2 genes observed in RCC may be caused by promoter hypermethylation in those genes.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (66, 91))	('hypermethylation', 'Var', (8, 24))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (66, 91))	('NELL1', 'Gene', (160, 165))	('NELL2', 'Gene', (170, 175))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('colorectal cancer', 'Disease', (96, 113))	('reported', 'Reg', (54, 62))	('downregulation', 'NegReg', (138, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))	('esophageal adenocarcinoma', 'Disease', (66, 91))
480664	25726761	To further investigate promoter methylation status, we carried out BSP of the CpG islands that included the putative promoter regions of NELL1 (-690 to -100) and NELL2 (-320 to +678) in RCC cell lines (Fig.4).	('-320 to +678', 'Var', (169, 181))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('-690 to -100', 'Var', (144, 156))
480671	25726761	If the NELL1/2 downregulation observed in RCC cells is caused by promoter hypermethylation, the expression would be recovered by CpG demethylation.	('downregulation', 'NegReg', (15, 29))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('promoter hypermethylation', 'Var', (65, 90))	('NELL1/2', 'Gene', (7, 14))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
480672	25726761	In order to test this hypothesis, we treated RCC cell lines with 5 muM 5-azacytidine and examined the effects on the NELL1/2 mRNA expression.	('5-azacytidine', 'Var', (71, 84))	('5-azacytidine', 'Chemical', 'MESH:D001374', (71, 84))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
480674	25726761	The NELL1 expression in TUHR14TKB cells was also significantly increased after 5-azacytidine treatment.	('increased', 'PosReg', (63, 72))	('5-azacytidine', 'Chemical', 'MESH:D001374', (79, 92))	('expression', 'MPA', (10, 20))	('5-azacytidine', 'Var', (79, 92))	('NELL1', 'Gene', (4, 9))
480675	25726761	The NELL2 expression in OS-RC-2 cells was elevated by 5-azacytidine treatment (Fig.4f).	('5-azacytidine', 'Var', (54, 67))	('expression', 'MPA', (10, 20))	('5-azacytidine', 'Chemical', 'MESH:D001374', (54, 67))	('NELL2', 'Gene', (4, 9))	('elevated', 'PosReg', (42, 50))	('OS-RC-2', 'CellLine', 'CVCL:1626', (24, 31))
480677	25726761	Whereas the increases of NELL1 and NELL2 expression by 5-azacytidine were statistically significant in most of the above RCC cell lines, their expression levels after treatment were still lower than those in HKE293T (Figs2,4e,f), suggesting that promoter methylation partially contributes to the silencing of NELL expression.	('expression levels', 'MPA', (143, 160))	('NELL2', 'Gene', (35, 40))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('lower', 'NegReg', (188, 193))	('RCC', 'Disease', (121, 124))	('expression', 'MPA', (41, 51))	('HKE293T', 'CellLine', 'CVCL:0063', (208, 215))	('increases', 'PosReg', (12, 21))	('5-azacytidine', 'Chemical', 'MESH:D001374', (55, 68))	('5-azacytidine', 'Var', (55, 68))	('NELL1', 'Gene', (25, 30))
480678	25726761	In contrast, the luciferase activity was significantly reduced by treatment with M.SssI, which methylates all cytosine residues within the dinucleotide recognition sequence 5'-CpG-3'.	('activity', 'MPA', (28, 36))	('reduced', 'NegReg', (55, 62))	('luciferase', 'Enzyme', (17, 27))	('dinucleotide', 'Chemical', 'MESH:D015226', (139, 151))	('cytosine', 'Chemical', 'MESH:D003596', (110, 118))	('M.SssI', 'Var', (81, 87))
480689	25726761	NELL1-AP significantly inhibited the migration of OS-RC-2 and VMRC-RCW cells in a dose-dependent manner.	('VMRC-RCW', 'CellLine', 'CVCL:1790', (62, 70))	('inhibited', 'NegReg', (23, 32))	('NELL1-AP', 'Var', (0, 8))	('OS-RC-2', 'CellLine', 'CVCL:1626', (50, 57))	('rat', 'Species', '10116', (40, 43))	('migration of OS-RC-2', 'CPA', (37, 57))
480690	25726761	NELL2-AP also significantly inhibited the migration of OS-RC-2, but not that of VMRC-RCW cells (Fig.5a-d).	('migration', 'CPA', (42, 51))	('OS-RC-2', 'CellLine', 'CVCL:1626', (55, 62))	('NELL2-AP', 'Var', (0, 8))	('VMRC-RCW', 'CellLine', 'CVCL:1790', (80, 88))	('inhibited', 'NegReg', (28, 37))	('rat', 'Species', '10116', (45, 48))
480699	25726761	For example, NELL1 gene loss was observed in more than 40% of Hodgkin's lymphoma patients.	('patients', 'Species', '9606', (81, 89))	("Hodgkin's lymphoma", 'Disease', (62, 80))	('NELL1', 'Gene', (13, 18))	('gene', 'Var', (19, 23))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (62, 80))	('loss', 'NegReg', (24, 28))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (62, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))
480712	25726761	In cancer cells, many tumor suppressor genes have been shown to be silenced by promoter hypermethylation, including p16/CDKN2/MTS1, retinoblastoma gene, and EphA7.	('p16', 'Gene', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('EphA7', 'Gene', (157, 162))	('p16', 'Gene', '1029', (116, 119))	('promoter hypermethylation', 'Var', (79, 104))	('MTS1', 'Gene', '1029', (126, 130))	('CDKN2', 'Gene', '1029', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('retinoblastoma', 'Gene', '5925', (132, 146))	('retinoblastoma', 'Phenotype', 'HP:0009919', (132, 146))	('silenced', 'NegReg', (67, 75))	('MTS1', 'Gene', (126, 130))	('EphA7', 'Gene', '2045', (157, 162))	('CDKN2', 'Gene', (120, 125))	('cancer', 'Disease', (3, 9))	('retinoblastoma', 'Gene', (132, 146))	('tumor', 'Disease', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
480714	25726761	DNA methylation profiling of 10 tumor suppressor genes in 100 kidney cancers showed hypermethylation of promoter DNA in 93% of kidney tumor cases, approximately two-thirds of which have two or more hypermethylated genes.	('100 kidney cancers', 'Disease', (58, 76))	('kidney cancers', 'Phenotype', 'HP:0009726', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('kidney tumor', 'Phenotype', 'HP:0009726', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (134, 139))	('kidney tumor', 'Disease', 'MESH:D007674', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('promoter DNA', 'Gene', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('hypermethylation', 'Var', (84, 100))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('tumor', 'Disease', (32, 37))	('kidney tumor', 'Disease', (127, 139))	('100 kidney cancers', 'Disease', 'MESH:D007680', (58, 76))
480715	25726761	Promoter hypermethylation and silencing of the NELL1 gene were detected in approximately 44% of colorectal carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('silencing', 'MPA', (30, 39))	('detected', 'Reg', (63, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('NELL1', 'Gene', (47, 52))	('colorectal carcinomas', 'Disease', (96, 117))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (96, 117))	('Promoter hypermethylation', 'Var', (0, 25))
480718	25726761	In vitro assays of cell behavior in the present study indicated that both NELL1 and NELL2 inhibit RCC cell migration and that NELL1 further inhibits RCC cell adhesion.	('inhibit', 'NegReg', (90, 97))	('inhibits', 'NegReg', (140, 148))	('RCC', 'Disease', (149, 152))	('NELL1', 'Var', (126, 131))	('rat', 'Species', '10116', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('NELL2', 'Gene', (84, 89))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
480719	25726761	As regulation of cell migration and adhesion plays crucial roles in cancer invasion and metastasis, these results raise the possibility that loss of NELL expression in RCC is involved in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (187, 193))	('involved', 'Reg', (175, 183))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('loss', 'Var', (141, 145))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (68, 74))	('NELL', 'Protein', (149, 153))	('rat', 'Species', '10116', (25, 28))	('RCC', 'Disease', (168, 171))
480720	25726761	Although no significant correlation was found between NELL expression levels and the size or extent of the primary tumor (pT stages), our data show that hypermethylation and downregulation of the NELL genes already occurs at early stages of RCC progression.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('downregulation', 'NegReg', (174, 188))	('hypermethylation', 'Var', (153, 169))	('NELL genes', 'Gene', (196, 206))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('RCC', 'Disease', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
480742	24728101	This aberrant activation of the Wnt/beta-catenin pathway has been implicated in radioresistance of solid tumors such as glioblastoma, breast cancer, and head and neck cancer.	('activation', 'PosReg', (14, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('radioresistance', 'CPA', (80, 95))	('solid tumors', 'Disease', (99, 111))	('implicated', 'Reg', (66, 76))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('Wnt/beta-catenin pathway', 'Pathway', (32, 56))	('breast cancer', 'Disease', (134, 147))	('neck cancer', 'Disease', 'MESH:D006258', (162, 173))	('neck cancer', 'Disease', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (120, 132))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('head and neck cancer', 'Phenotype', 'HP:0012288', (153, 173))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('aberrant', 'Var', (5, 13))	('glioblastoma', 'Disease', (120, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
480773	24728101	To develop xenograft tumors, cultured KYSE-410 and KYSE-410R cells were harvested by exposure to trypsin-EDTA, washed with PBS, and implanted into the right flanks of 4-week-old male NOD/SCID mice, weight 6.1-7.2 g (1.0x105 cells for both KYSE-410 and KYSE-410R).	('SCID', 'Disease', (187, 191))	('NOD', 'Gene', '1822', (183, 186))	('mice', 'Species', '10090', (192, 196))	('xenograft tumors', 'Disease', 'MESH:D009369', (11, 27))	('PBS', 'Chemical', 'MESH:D007854', (123, 126))	('KYSE-410R', 'Var', (252, 261))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('NOD', 'Gene', (183, 186))	('EDTA', 'Chemical', 'MESH:D004492', (105, 109))	('xenograft tumors', 'Disease', (11, 27))	('SCID', 'Disease', 'MESH:D053632', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
480785	24728101	Phosphorylation of beta-catenin at Ser33 and Ser37 was decreased in radioresistant cells (Figure S2A); this can promote beta-catenin stabilization and accumulation.	('Ser37', 'Chemical', '-', (45, 50))	('promote', 'PosReg', (112, 119))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('stabilization', 'MPA', (133, 146))	('accumulation', 'MPA', (151, 163))	('beta-catenin', 'Protein', (19, 31))	('Phosphorylation', 'MPA', (0, 15))	('decreased', 'NegReg', (55, 64))	('Ser33', 'Chemical', '-', (35, 40))	('beta-catenin', 'Protein', (120, 132))	('Ser37', 'Var', (45, 50))
480789	24728101	Additionally, Western blot analysis identified phosphorylated GSK3beta (p-Ser9 GSK3beta), total GSK3beta, phosphorylated beta-catenin (p-Ser33/Ser37/Thr41beta-catenin and p-Ser45 beta-catenin) and total beta-catenin in KYSE-410 cells when treated with irradiation.	('GSK3beta', 'Gene', '2932', (96, 104))	('GSK3beta', 'Gene', '2932', (62, 70))	('GSK3beta', 'Gene', '2932', (79, 87))	('Ser33', 'Chemical', '-', (137, 142))	('Ser45', 'Chemical', '-', (173, 178))	('beta-catenin', 'Protein', (203, 215))	('p-Ser33/Ser37/Thr41beta-catenin', 'Var', (135, 166))	('p-Ser45', 'Var', (171, 178))	('Thr41beta-catenin', 'Chemical', '-', (149, 166))	('GSK3beta', 'Gene', (62, 70))	('GSK3beta', 'Gene', (79, 87))	('GSK3beta', 'Gene', (96, 104))	('Ser37', 'Chemical', '-', (143, 148))
480790	24728101	The data showed the p-Ser33/Ser37/Thr41 beta-catenin levels relative to total beta-catenin levels in 5 fraction irradiated cells were decreased 2.8 fold compared to the non-irradiation control.	('decreased', 'NegReg', (134, 143))	('Ser37', 'Chemical', '-', (28, 33))	('Ser33', 'Chemical', '-', (22, 27))	('p-Ser33/Ser37/Thr41', 'Var', (20, 39))	('beta-catenin levels', 'MPA', (40, 59))	('Thr41', 'Chemical', '-', (34, 39))
480791	24728101	The p-Ser9 GSK3beta levels relative to total GSK3beta levels in 5 fraction irradiated cells were increased 1.2 fold compared to the non-irradiation control (Figure S2C.).	('GSK3beta', 'Gene', (11, 19))	('increased', 'PosReg', (97, 106))	('GSK3beta', 'Gene', '2932', (45, 53))	('GSK3beta', 'Gene', '2932', (11, 19))	('p-Ser9', 'Var', (4, 10))	('GSK3beta', 'Gene', (45, 53))
480792	24728101	The results showed that compared to KYSE-410 cells, the expression of Wnt ligands Wnt1, beta-catenin, the common Wnt receptors frizzled 1-4 (Fzd1- 4) and the intracellular signal transducers Gsk3b was upregulated in KYSE-410R cells.	('Gsk3b', 'Gene', '2932', (191, 196))	('Fzd1- 4', 'Gene', (141, 148))	('KYSE-410R', 'Var', (216, 225))	('Wnt1', 'Gene', (82, 86))	('beta-catenin', 'Protein', (88, 100))	('frizzled 1-4', 'Gene', (127, 139))	('Fzd1- 4', 'Gene', '8321;2535;7976;8322', (141, 148))	('expression', 'MPA', (56, 66))	('frizzled 1-4', 'Gene', '8321;2535;7976;8322', (127, 139))	('Gsk3b', 'Gene', (191, 196))	('Wnt1', 'Gene', '7471', (82, 86))	('upregulated', 'PosReg', (201, 212))
480808	24728101	The percentage of beta-tubulin and gamma-H2AX co-stain in nucleus was significantly increased in the presence of anti-WISP-1.	('beta-tubulin', 'Protein', (18, 30))	('anti-WISP-1', 'Var', (113, 124))	('increased', 'PosReg', (84, 93))	('H2AX', 'Gene', '3014', (41, 45))	('H2AX', 'Gene', (41, 45))
480830	24728101	It is possible that the presence of WISP-1 inhibited the normal response of Chk2 to irradiation.	('presence', 'Var', (24, 32))	('Chk2', 'Gene', (76, 80))	('inhibited', 'NegReg', (43, 52))	('WISP-1', 'Gene', (36, 42))	('response', 'MPA', (64, 72))	('Chk2', 'Gene', '11200', (76, 80))
480838	24496158	Prognostic Significance of Glasgow Prognostic Score in Patients Undergoing Esophagectomy for Esophageal Squamous Cell Carcinoma Recent studies have revealed that Glasgow prognostic score (GPS), an inflammation-based prognostic score, is inversely related to prognosis in a variety of cancers; high levels of GPS is associated with poor prognosis.	('GPS', 'Chemical', '-', (308, 311))	('cancers', 'Disease', 'MESH:D009369', (284, 291))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('cancers', 'Disease', (284, 291))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('high levels', 'Var', (293, 304))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('Esophageal Squamous Cell Carcinoma', 'Disease', (93, 127))	('Carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('Patients', 'Species', '9606', (55, 63))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('GPS', 'Chemical', '-', (188, 191))
480844	24496158	The 5-year CSS in patients with GPS0, GPS1, and GPS2 were 60.8%, 34.7% and 10.7%, respectively (P < 0.001).	('GPS', 'Chemical', '-', (32, 35))	('GPS2', 'Gene', '2874', (48, 52))	('GPS', 'Chemical', '-', (38, 41))	('GPS2', 'Gene', (48, 52))	('GPS', 'Chemical', '-', (48, 51))	('CSS', 'MPA', (11, 14))	('patients', 'Species', '9606', (18, 26))	('GPS1', 'Gene', (38, 42))	('GPS1', 'Gene', '2873', (38, 42))	('CSS', 'Chemical', '-', (11, 14))	('GPS0', 'Var', (32, 36))
480847	24496158	High levels of GPS is associated with tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('High levels', 'Var', (0, 11))	('GPS', 'Protein', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('GPS', 'Chemical', '-', (15, 18))	('associated', 'Reg', (22, 32))
480875	24496158	Patients with both an elevated CRP (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a score of 2 (GPS2).	('GPS2', 'Gene', (105, 109))	('hypoalbuminemia', 'Disease', (50, 65))	('>10 mg/L', 'Var', (36, 44))	('elevated CRP', 'Phenotype', 'HP:0011227', (22, 34))	('Patients', 'Species', '9606', (0, 8))	('GPS2', 'Gene', '2874', (105, 109))	('CRP', 'Gene', (31, 34))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (50, 65))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (50, 65))	('CRP', 'Gene', '1401', (31, 34))
480885	24496158	The 1-year CSS in patients with GPS0, GPS1, and GPS2 were 92.7%, 71.1%, and 53.6%, respectively (P < 0.001).	('GPS', 'Chemical', '-', (32, 35))	('GPS2', 'Gene', '2874', (48, 52))	('GPS', 'Chemical', '-', (38, 41))	('GPS2', 'Gene', (48, 52))	('GPS', 'Chemical', '-', (48, 51))	('CSS', 'MPA', (11, 14))	('patients', 'Species', '9606', (18, 26))	('GPS1', 'Gene', (38, 42))	('GPS1', 'Gene', '2873', (38, 42))	('CSS', 'Chemical', '-', (11, 14))	('GPS0', 'Var', (32, 36))
480888	24496158	The 5-year CSS in patients with GPS0, GPS1, and GPS2 were 60.8%, 34.7%, and 10.7%, respectively (P < 0.001) [Figure 2].	('GPS', 'Chemical', '-', (32, 35))	('GPS2', 'Gene', '2874', (48, 52))	('GPS', 'Chemical', '-', (38, 41))	('GPS2', 'Gene', (48, 52))	('GPS', 'Chemical', '-', (48, 51))	('CSS', 'MPA', (11, 14))	('patients', 'Species', '9606', (18, 26))	('GPS1', 'Gene', (38, 42))	('GPS1', 'Gene', '2873', (38, 42))	('CSS', 'Chemical', '-', (11, 14))	('GPS0', 'Var', (32, 36))
480903	24496158	From the database of 493 consecutive patients with ESCC who underwent surgery, our results clearly demonstrated that GPS can serve as an independent predictor of long-term survival for patients with ESCC.	('patients', 'Species', '9606', (37, 45))	('GPS', 'Chemical', '-', (117, 120))	('ESCC', 'Disease', (199, 203))	('patients', 'Species', '9606', (185, 193))	('GPS', 'Var', (117, 120))
480905	24496158	In conclusion, our study demonstrated that high levels of GPS is associated with tumor progression.	('high levels', 'Var', (43, 54))	('GPS', 'Chemical', '-', (58, 61))	('associated', 'Reg', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('GPS', 'Protein', (58, 61))
480975	31396997	The distribution of lesions according to macroscopic findings were as follows (s-BEA in SSBE vs LSBE): flat type (0-IIb), 3.2% (3/95) vs 32.6% (15/46) (P < 0.001); accompanied type 0-IIb, 2.1% (2/95) vs 21.7% (10/46) (P < 0.001); and complex type (0-I + IIb, 0-IIa + IIc, etc.	('BEA', 'Disease', (81, 84))	('BE', 'Disease', 'MESH:D001471', (98, 100))	('BEA', 'Disease', 'MESH:D001471', (81, 84))	('BE', 'Phenotype', 'HP:0100580', (90, 92))	('0-I + IIb', 'Var', (248, 257))	('BEA', 'Phenotype', 'HP:0100580', (81, 84))	('BE', 'Disease', 'MESH:D001471', (90, 92))	('BE', 'Phenotype', 'HP:0100580', (81, 83))	('BE', 'Phenotype', 'HP:0100580', (98, 100))	('LSBE', 'Chemical', '-', (96, 100))	('BE', 'Disease', 'MESH:D001471', (81, 83))
481064	31423110	Knocking down the RASSF-1A gene in SCC9 cells promotes cell migration and proliferation, while reducing apoptosis and increasing CyclinD1 protein expression.	('increasing', 'PosReg', (118, 128))	('Knocking down', 'Var', (0, 13))	('proliferation', 'CPA', (74, 87))	('SCC9', 'CellLine', 'CVCL:1685', (35, 39))	('promotes', 'PosReg', (46, 54))	('cell migration', 'CPA', (55, 69))	('RASSF-1A', 'Gene', (18, 26))	('apoptosis', 'CPA', (104, 113))	('reducing', 'NegReg', (95, 103))	('CyclinD1 protein expression', 'MPA', (129, 156))
481073	31423110	Usually, cancer begins with a single cell mutation in a somatic cell that leads to further proliferation, which activates the protooncogene and becomes an oncogene.	('cancer', 'Disease', (9, 15))	('further proliferation', 'CPA', (83, 104))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('activates', 'PosReg', (112, 121))	('mutation', 'Var', (42, 50))	('leads to', 'Reg', (74, 82))	('protooncogene', 'MPA', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
481076	31423110	If epigenetic modification abnormalities in somatic cells lead to abnormal expression of certain genes, such as oncogene activation and tumor suppressor gene inactivation, abnormal proliferation of somatic cells.	('abnormal proliferation', 'CPA', (172, 194))	('oncogene activation', 'Gene', (112, 131))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('epigenetic modification abnormalities', 'Var', (3, 40))	('lead to abnormal', 'Reg', (58, 74))	('tumor', 'Disease', (136, 141))	('expression', 'MPA', (75, 85))
481077	31423110	Recent studies have also shown that the occurrence of many malignant tumors is closely related to the epigenetic disorder of the cellular genome.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('malignant tumors', 'Disease', (59, 75))	('malignant tumors', 'Disease', 'MESH:D018198', (59, 75))	('related', 'Reg', (87, 94))	('epigenetic disorder', 'Var', (102, 121))
481081	31423110	If the epigenetic test is performed on the tissues, prediction or diagnosis can be made at an early stage or even before the cancer, and early prevention or treatment can improve the survival rate and improve the prognosis.	('improve', 'PosReg', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('epigenetic test', 'Var', (7, 22))	('survival rate', 'CPA', (183, 196))	('prognosis', 'CPA', (213, 222))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('improve', 'PosReg', (201, 208))
481086	31423110	Ectopic expression of c-Fos in HNSCC cells also displays increased sphere formation.	('sphere formation', 'CPA', (67, 83))	('c-Fos', 'Gene', (22, 27))	('HNSCC', 'Phenotype', 'HP:0012288', (31, 36))	('Ectopic expression', 'Var', (0, 18))	('c-Fos', 'Gene', '2353', (22, 27))	('increased', 'PosReg', (57, 66))	('HNSCC', 'CellLine', 'CVCL:5985', (31, 36))
481089	31423110	OSCC is a multi-factor participation, a common malignant tumor with multiple genes, and the inactivation and loss of tumor suppressor genes are closely related to its occurrence and development.	('inactivation', 'Var', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('malignant tumor', 'Disease', 'MESH:D018198', (47, 62))	('loss of tumor', 'Disease', 'MESH:D009369', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('loss of tumor', 'Disease', (109, 122))	('OSCC', 'Disease', (0, 4))	('malignant tumor', 'Disease', (47, 62))
481127	31423110	The results of CCK8 showed that the growth curve of SCC9 cells knocking down RASSF-1A gene was significantly higher than that of the control group at 72 and 96 h, with a significant difference (Fig.	('knocking down', 'Var', (63, 76))	('growth curve', 'CPA', (36, 48))	('higher', 'PosReg', (109, 115))	('RASSF-1A', 'Gene', (77, 85))	('SCC9', 'CellLine', 'CVCL:1685', (52, 56))
481128	31423110	Flow cytometry showed that the percentage of cells knocking down the RASSF-1A gene in the S phase was significantly higher than that in the control group, indicating that the proliferation of SCC9 cells was significantly increased after knocking down the gene (Fig.	('knocking down', 'Var', (237, 250))	('higher', 'PosReg', (116, 122))	('increased', 'PosReg', (221, 230))	('SCC9', 'CellLine', 'CVCL:1685', (192, 196))	('knocking down', 'Var', (51, 64))	('RASSF-1A', 'Gene', (69, 77))	('proliferation', 'CPA', (175, 188))
481130	31423110	It was found that knocking down RASSF1A protein increased the expression of CyclinD2 protein in cells (Fig.	('increased', 'PosReg', (48, 57))	('CyclinD2', 'Gene', '894', (76, 84))	('knocking down', 'Var', (18, 31))	('expression', 'MPA', (62, 72))	('RASSF1A', 'Gene', (32, 39))	('protein', 'Protein', (40, 47))	('protein', 'Protein', (85, 92))	('CyclinD2', 'Gene', (76, 84))
481133	31423110	The results showed that the expression of MMP2 protein in cells was significantly increased compared with the control group after knockdown of RASSF1A gene (Fig.	('protein', 'Protein', (47, 54))	('RASSF1A', 'Gene', (143, 150))	('MMP2', 'Gene', (42, 46))	('expression', 'MPA', (28, 38))	('knockdown', 'Var', (130, 139))	('increased', 'PosReg', (82, 91))	('MMP2', 'Gene', '4313', (42, 46))
481134	31423110	Usually cell proliferation and apoptosis are present at the same time, so we also detected SCC9 cells after knocking down the RASSF-1A gene.	('knocking down', 'Var', (108, 121))	('SCC9', 'CellLine', 'CVCL:1685', (91, 95))	('RASSF-1A', 'Gene', (126, 134))
481138	31423110	After knocking down RASSF-1A gene on SCC9 cells, CyclinD1 gene and protein levels were significantly increased, and the difference was statistically significant compared with the control group (Fig.	('RASSF-1A gene', 'Gene', (20, 33))	('SCC9', 'CellLine', 'CVCL:1685', (37, 41))	('increased', 'PosReg', (101, 110))	('knocking down', 'Var', (6, 19))
481143	31423110	The RASSF-1A gene was overexpressed in the mouse by adenovirus, and the expression of RASSF-1A protein in the tumor tissue of the virus group was found to be increased by western blot and the difference was statistically significant (Fig.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('expression', 'MPA', (72, 82))	('virus', 'Var', (130, 135))	('RASSF-1A', 'Gene', (86, 94))	('mouse', 'Species', '10090', (43, 48))	('protein', 'Protein', (95, 102))	('increased', 'PosReg', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
481146	31423110	The weight and volume of the tumor tissue overexpressing the RASSF-1A gene were significantly lower than those of the control group, with a significant difference (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('RASSF-1A', 'Gene', (61, 69))	('gene', 'Var', (70, 74))	('tumor', 'Disease', (29, 34))	('lower', 'NegReg', (94, 99))	('overexpressing', 'PosReg', (42, 56))
481157	31423110	Molecular epidemiological studies have shown that OSCC is a multi-gene multi-step malignant tumor involving the activation of proto-oncogenes and the inactivation of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('malignant tumor', 'Disease', 'MESH:D018198', (82, 97))	('OSCC', 'Disease', (50, 54))	('inactivation', 'Var', (150, 162))	('activation', 'PosReg', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('malignant tumor', 'Disease', (82, 97))
481161	31423110	Current studies have demonstrated that cell cycle-dependent protein kinase 2A gene and RAS association domain family 1A (RASSF1A gene) promoter methylation play an important role in the early diagnosis and prognosis of non-small cell lung cancer.	('methylation', 'Var', (144, 155))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (219, 245))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('RASSF1A gene', 'Gene', (121, 133))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (219, 245))	('non-small cell lung cancer', 'Disease', (219, 245))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (223, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
481162	31423110	The RASSF1A gene is a tumor suppressor gene, and its methylation impairs the cell regulation mechanism and causes cancer through multiple downstream transcription pathways.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('RASSF1A', 'Gene', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('causes', 'Reg', (107, 113))	('methylation', 'Var', (53, 64))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('impairs', 'NegReg', (65, 72))	('tumor', 'Disease', (22, 27))	('cell regulation mechanism', 'CPA', (77, 102))	('cancer', 'Disease', (114, 120))
481170	31423110	Kaplan-Meier single factor analysis showed that RASSF1A positive patients had higher survival time than negative patient.	('patient', 'Species', '9606', (113, 120))	('survival time', 'CPA', (85, 98))	('higher', 'PosReg', (78, 84))	('RASSF1A', 'Gene', (48, 55))	('positive', 'Var', (56, 64))	('patient', 'Species', '9606', (65, 72))	('patients', 'Species', '9606', (65, 73))
481173	31423110	At the same time, we detected tumor-associated proliferating proteins and found that high expression of CyclinD1 protein was observed in tumor cells that knocked down RASSF-1A.	('protein', 'Protein', (113, 120))	('tumor', 'Disease', (137, 142))	('RASSF-1A', 'Gene', (167, 175))	('knocked down', 'Var', (154, 166))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('expression', 'MPA', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('CyclinD1', 'Gene', (104, 112))	('tumor', 'Disease', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
481174	31423110	In vivo experiments also found that after overexpression of RASSF-1A gene in oral cancer model mice, tumor growth was slowed, tumor volume was decreased, and CyclinD1 protein expression in tumor tissues was decreased.	('oral cancer', 'Disease', (77, 88))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('overexpression', 'PosReg', (42, 56))	('decreased', 'NegReg', (207, 216))	('RASSF-1A', 'Gene', (60, 68))	('decreased', 'NegReg', (143, 152))	('slowed', 'NegReg', (118, 124))	('tumor', 'Disease', (126, 131))	('tumor', 'Disease', (189, 194))	('gene', 'Var', (69, 73))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('oral cancer', 'Disease', 'MESH:D009062', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('CyclinD1 protein expression', 'MPA', (158, 185))
481196	29534501	Human adenoviruses represent an interesting oncolytic virotherapy platform given their (1) high transduction efficiency in transformed cells (~10,000 viral particles per infected cell), (2) lack of integration into the host genome resulting in a lowered risk of insertional mutagenesis, (3) low seroprevalence with regards to specific serotypes, (4) high fidelity DNA polymerase, which confers relative stability, and (5) ability to attain tumor specificity through substitution of the viral promoter with cancer tissue selective promoters or mutations that enable virus replication to occur preferentially in transformed cells.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Disease', (506, 512))	('tumor', 'Phenotype', 'HP:0002664', (440, 445))	('tumor', 'Disease', (440, 445))	('substitution', 'Var', (466, 478))	('nab', 'Chemical', '-', (559, 562))	('cancer', 'Phenotype', 'HP:0002664', (506, 512))	('insertional mutagenesis', 'MPA', (262, 285))	('mutations', 'Var', (543, 552))	('tumor', 'Disease', 'MESH:D009369', (440, 445))	('adenovirus', 'Species', '28285', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (506, 512))	('lack', 'Var', (190, 194))
481201	29534501	Thus far, a series of clinical trials using H101 combined with standard chemotherapy demonstrated a better overall response in head and neck cancers.	('H101', 'Var', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('neck cancers', 'Disease', 'MESH:D006258', (136, 148))	('head and neck cancers', 'Phenotype', 'HP:0012288', (127, 148))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('neck cancers', 'Disease', (136, 148))
481206	29534501	Ad40 and Ad41 are responsible for acute diarrhea and gastroenteritis, mostly in children.	('acute diarrhea', 'Disease', (34, 48))	('Ad41', 'Var', (9, 13))	('gastroenteritis', 'Disease', (53, 68))	('children', 'Species', '9606', (80, 88))	('gastroenteritis', 'Disease', 'MESH:D005759', (53, 68))	('diarrhea', 'Phenotype', 'HP:0002014', (40, 48))	('acute diarrhea', 'Disease', 'MESH:D003967', (34, 48))	('responsible', 'Reg', (18, 29))	('Ad40', 'Var', (0, 4))
481208	29534501	Additionally, tumor specificity and tropism can be enhanced through promoter driven replication.	('tumor', 'Disease', (14, 19))	('tropism', 'CPA', (36, 43))	('enhanced', 'PosReg', (51, 59))	('promoter driven replication', 'Var', (68, 95))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
481211	29534501	Ads provide the possibility for hexon swapping and fiber pseudotyping among the subgroups, which is attractive toward maximizing targeting and delaying immune neutralization.	('hexon', 'Protein', (32, 37))	('subgroup', 'Species', '167158', (80, 88))	('swapping', 'Var', (38, 46))
481214	29534501	One of the first such Ad vectors was designed to induce cell cycle arrest, which enhanced the oncolytic effect, with reduced nuclear factor kappa-B (NF-kappaB) and maximized apoptosis, primarily in p53 mutant cells.	('NF-kappaB', 'Gene', (149, 158))	('p53', 'Gene', '22060', (198, 201))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('enhanced', 'PosReg', (81, 89))	('maximized', 'PosReg', (164, 173))	('reduced', 'NegReg', (117, 124))	('cell cycle arrest', 'CPA', (56, 73))	('apoptosis', 'CPA', (174, 183))	('p53', 'Gene', (198, 201))	('NF-kappaB', 'Gene', '4790', (149, 158))	('oncolytic effect', 'CPA', (94, 110))	('mutant', 'Var', (202, 208))
481218	29534501	Four drugs were analyzed in combination with a modified Ad5, which encompassed the deletion of the 55 kDa-encoding E1B region as and a part of the E3 region.	('Ad5', 'Gene', (56, 59))	('Ad5', 'Gene', '8081', (56, 59))	('E1B', 'Gene', '100306944', (115, 118))	('E1B', 'Gene', (115, 118))	('deletion', 'Var', (83, 91))
481223	29534501	As such, cisplatin could lead to cross-resistance with Ad vectors.	('cisplatin', 'Var', (9, 18))	('cross-resistance', 'MPA', (33, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('lead to', 'Reg', (25, 32))	('Ad vectors', 'Protein', (55, 65))
481285	29534501	Following vector delivery, the administered prodrug ZD2767 was converted by CPG2 into a cytotoxic drug and resulted in tumor growth regression or complete tumor eradication in xenografts.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (119, 124))	('CPG2', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ZD2767', 'Var', (52, 58))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
481288	29534501	Furthermore, ST13, a colorectal cancer-specific tumor suppressor gene, was inserted into a CRAds under the control of CEA promoter resulting in significant levels of apoptosis in colon cancer cells.	('colon cancer', 'Disease', 'MESH:D015179', (179, 191))	('CRAd', 'Gene', (91, 95))	('CEA', 'Gene', '111518', (118, 121))	('rectal cancer', 'Phenotype', 'HP:0100743', (25, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (21, 38))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('CRAd', 'Gene', '19683', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('inserted', 'Var', (75, 83))	('colon cancer', 'Disease', (179, 191))	('apoptosis', 'MPA', (166, 175))	('tumor', 'Disease', (48, 53))	('ST13', 'Gene', '70356', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (21, 38))	('CEA', 'Gene', (118, 121))	('ST13', 'Gene', (13, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (179, 191))	('colorectal cancer', 'Disease', (21, 38))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
481293	29534501	A clinical trial testing Telomelysin in esophageal cancer is eagerly awaited, as the first Ad trial for this type of cancer.	('Telomelysin', 'Var', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('esophageal cancer', 'Disease', (40, 57))
481308	29221179	In conclusion, marital status was associated with superior survival among U.S. patients with esophageal cancer in a large population-based study.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('superior', 'PosReg', (50, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('patients', 'Species', '9606', (79, 87))	('marital status', 'Var', (15, 29))
481368	29221179	Only histological codes according to ICD-O-3 for adenocarcinoma (code: 8140-8145, 8147, 8150, 8210-8211, 8255-8323, 8480-8490, 8560-8576) and squamous cell carcinoma (code: 8052-8078, 8083-8084, 8094) of the esophagus were included in the analysis.	('8480-8490', 'Var', (116, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('8083-8084', 'Var', (184, 193))	('squamous cell carcinoma', 'Disease', (142, 165))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 165))	('adenocarcinoma', 'Disease', (49, 63))	('adenocarcinoma', 'Disease', 'MESH:D000230', (49, 63))	('8147', 'Var', (82, 86))
481502	25945277	Histopathological examination of the surgical specimen revealed a gastric adenocarcinoma pT3N0MxL0V0R0 (37 lymph nodes were examined).	('gastric adenocarcinoma', 'Disease', (66, 88))	('pT3N0MxL0V0R0', 'Var', (89, 102))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (66, 88))
481522	25945277	These strictures lower the patient's quality of life due to their possible complications like malnutrition, pain, or perforation.	('pain', 'Phenotype', 'HP:0012531', (108, 112))	('malnutrition', 'Phenotype', 'HP:0004395', (94, 106))	('lower', 'NegReg', (17, 22))	('pain', 'Disease', 'MESH:D010146', (108, 112))	('pain', 'Disease', (108, 112))	('quality of life', 'CPA', (37, 52))	('patient', 'Species', '9606', (27, 34))	('perforation', 'Disease', (117, 128))	('strictures', 'Var', (6, 16))	('malnutrition', 'Disease', 'MESH:D044342', (94, 106))	('malnutrition', 'Disease', (94, 106))
481536	20818175	Genetic knockdown of Axl in EAC cell lines inhibited invasion, migration and in vivo engraftment, which was accompanied by downregulation in the activity of the Ral GTPase proteins (RalA and RalB).	('Ral', 'Gene', (182, 185))	('EAC', 'Gene', (28, 31))	('invasion', 'CPA', (53, 61))	('activity', 'MPA', (145, 153))	('Ral', 'Gene', '5898', (182, 185))	('inhibited', 'NegReg', (43, 52))	('RalA', 'Gene', (182, 186))	('RalB', 'Gene', (191, 195))	('downregulation', 'NegReg', (123, 137))	('EAC', 'Phenotype', 'HP:0011459', (28, 31))	('Ral', 'Gene', '5898', (161, 164))	('Ral', 'Gene', (161, 164))	('knockdown', 'Var', (8, 17))	('Ral', 'Gene', '5898', (191, 194))	('GTP', 'Chemical', 'MESH:D006160', (165, 168))	('Ral', 'Gene', (191, 194))	('EAC', 'Gene', '1540', (28, 31))	('RalB', 'Gene', '5899', (191, 195))	('RalA', 'Gene', '5898', (182, 186))
481538	20818175	Pharmacological inhibition of Axl with R428 in EAC cell lines significantly reduced anchorage-independent growth, invasion and migration.	('anchorage-independent growth', 'CPA', (84, 112))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('Axl', 'Protein', (30, 33))	('reduced', 'NegReg', (76, 83))	('EAC', 'Gene', '1540', (47, 50))	('EAC', 'Gene', (47, 50))	('R428', 'Var', (39, 43))
481539	20818175	Blockade of Axl function abrogated phosphorylation of ERBB2 (Her-2/neu) at the Tyr877 residue, indicative of receptor crosstalk.	('abrogated', 'NegReg', (25, 34))	('Tyr877', 'Chemical', '-', (79, 85))	('ERBB2', 'Gene', '2064', (54, 59))	('Tyr877', 'Var', (79, 85))	('ERBB2', 'Gene', (54, 59))	('Axl', 'Protein', (12, 15))	('Her-2/neu', 'Gene', '2064', (61, 70))	('Her-2/neu', 'Gene', (61, 70))	('phosphorylation', 'MPA', (35, 50))
481574	20818175	We next investigated whether knockdown of Axl function in EAC lines would impact upon their transformed phenotype.	('transformed phenotype', 'CPA', (92, 113))	('knockdown', 'Var', (29, 38))	('impact', 'Reg', (74, 80))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('EAC', 'Gene', '1540', (58, 61))	('Axl', 'Protein', (42, 45))	('EAC', 'Gene', (58, 61))
481577	20818175	The deleterious impact of Axl knockdown on the transformed phenotype of EAC was further underscored by the significant inhibition of anchorage independent growth in OE33 cells (Fig.	('anchorage independent growth', 'CPA', (133, 161))	('EAC', 'Gene', '1540', (72, 75))	('EAC', 'Gene', (72, 75))	('inhibition', 'NegReg', (119, 129))	('knockdown', 'Var', (30, 39))	('EAC', 'Phenotype', 'HP:0011459', (72, 75))
481583	20818175	Thus, in the JH-EsoAd1 cells, Axl knockdown completely eliminated Gas6-induced phosphorylation of Akt at the Ser473 residue and modestly decreased Erk1/2 phosphorylation (Fig.	('Erk1/2', 'Gene', '5595;5594', (147, 153))	('Gas6', 'Gene', (66, 70))	('phosphorylation', 'MPA', (154, 169))	('Gas6', 'Gene', '2621', (66, 70))	('Erk1/2', 'Gene', (147, 153))	('Akt', 'Gene', '207', (98, 101))	('Ser473', 'Chemical', '-', (109, 115))	('Akt', 'Gene', (98, 101))	('knockdown', 'Var', (34, 43))	('eliminated', 'NegReg', (55, 65))	('decreased', 'NegReg', (137, 146))
481585	20818175	Nonetheless, in light of the significant phenotypic effects of Axl knockdown on OE33, comparable to that observed in JH-EsoAd1 cells (see above), we postulated the existence of an effector mechanism regulated by Axl that is independent of either PI-3-kinase/Akt or MAPK pathways.	('knockdown', 'Var', (67, 76))	('Akt', 'Gene', '207', (258, 261))	('Axl', 'Protein', (212, 215))	('Akt', 'Gene', (258, 261))
481591	20818175	Axl knockdown strikingly inhibited this EGF-dependent activation of RalA and RalB (Fig.	('EGF', 'Gene', (40, 43))	('RalB', 'Gene', '5899', (77, 81))	('RalA', 'Gene', (68, 72))	('RalB', 'Gene', (77, 81))	('EGF', 'Gene', '1950', (40, 43))	('activation', 'PosReg', (54, 64))	('RalA', 'Gene', '5898', (68, 72))	('inhibited', 'NegReg', (25, 34))	('knockdown', 'Var', (4, 13))	('Axl', 'Protein', (0, 3))
481593	20818175	In both JH-EsoAd1 and OE33 cells with Axl knockdown, reduction in Ral activity in the presence of EGF was also accompanied by a profound decrease in GTP-bound Cdc42 protein (Fig.	('EGF', 'Gene', (98, 101))	('decrease', 'NegReg', (137, 145))	('Cdc42', 'Gene', (159, 164))	('Ral', 'Gene', (66, 69))	('GTP', 'Chemical', 'MESH:D006160', (149, 152))	('reduction', 'NegReg', (53, 62))	('GTP-bound', 'MPA', (149, 158))	('Ral', 'Gene', '5898', (66, 69))	('EGF', 'Gene', '1950', (98, 101))	('Cdc42', 'Gene', '998', (159, 164))	('knockdown', 'Var', (42, 51))
481595	20818175	Rlf-CAAX expression restored RalA-GTP levels in OE33 AXL shRNA clones to that observed in scrambled shRNA infected OE33 clones (Fig.	('Rlf', 'Gene', (0, 3))	('RalA', 'Gene', (29, 33))	('expression', 'Var', (9, 19))	('AXL', 'Gene', '558', (53, 56))	('restored', 'PosReg', (20, 28))	('GTP', 'Chemical', 'MESH:D006160', (34, 37))	('RalA', 'Gene', '5898', (29, 33))	('Rlf', 'Gene', '6018', (0, 3))	('AXL', 'Gene', (53, 56))	('OE33', 'Var', (48, 52))
481599	20818175	In OE33 cells, R428 demonstrated dose-dependent and significant reduction in both anchorage independent growth in soft agar and in vitro invasion (Fig.	('anchorage independent growth in soft agar', 'CPA', (82, 123))	('R428', 'Var', (15, 19))	('reduction', 'NegReg', (64, 73))	('agar', 'Chemical', 'MESH:D000362', (119, 123))
481602	20818175	The Tyr877 residue of ERBB2 correlates with, and provides a convenient readout of, the biological activity of the receptor.	('ERBB2', 'Gene', '2064', (22, 27))	('ERBB2', 'Gene', (22, 27))	('Tyr877', 'Var', (4, 10))	('biological activity', 'MPA', (87, 106))	('Tyr877', 'Chemical', '-', (4, 10))
481603	20818175	We found dose-dependent reduction in ERBB2 Tyr877 phosphorylation upon exposure to R428 (Fig.	('ERBB2', 'Gene', (37, 42))	('phosphorylation', 'MPA', (50, 65))	('ERBB2', 'Gene', '2064', (37, 42))	('Tyr877', 'Chemical', '-', (43, 49))	('R428', 'Var', (83, 87))	('Tyr877', 'Var', (43, 49))	('reduction', 'NegReg', (24, 33))
481605	20818175	As an extrapolation of these results, we found that co-treatment of OE33 cells with R428 sensitized them to lapatinib in vitro (the IC50 of single agent lapatinib was 5.5 vs 0.4 muM upon combination) (Fig.	('lapatinib', 'Chemical', 'MESH:D000077341', (108, 117))	('sensitized', 'Reg', (89, 99))	('lapatinib', 'Chemical', 'MESH:D000077341', (153, 162))	('R428', 'Var', (84, 88))
481611	20818175	Bioinformatics analyses of the SAGE libraries identified the L-SAGE tag corresponding to the AXL gene transcript as being progressively upregulated during the transition from NSE through dysplasia to EAC.	('upregulated', 'PosReg', (136, 147))	('EAC', 'Gene', '1540', (200, 203))	('AXL', 'Gene', (93, 96))	('dysplasia', 'Disease', (187, 196))	('L-SAGE', 'Var', (61, 67))	('EAC', 'Gene', (200, 203))	('dysplasia', 'Disease', 'MESH:D004476', (187, 196))	('NSE', 'Disease', (175, 178))	('AXL', 'Gene', '558', (93, 96))	('EAC', 'Phenotype', 'HP:0011459', (200, 203))
481614	20818175	Since then, aberrant expression of Axl has been reported in a number of solid tumors, including pancreatic and breast cancers and gliomas, amongst others.	('Axl', 'Protein', (35, 38))	('solid tumors', 'Disease', 'MESH:D009369', (72, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancers', 'Phenotype', 'HP:0003002', (111, 125))	('reported', 'Reg', (48, 56))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('gliomas', 'Disease', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('solid tumors', 'Disease', (72, 84))	('pancreatic and breast cancers', 'Disease', 'MESH:D010190', (96, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('aberrant expression', 'Var', (12, 31))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
481619	20818175	In EAC cell lines, genetic knockdown of endogenous Axl mitigated multiple aspects of the transformed phenotype, such as cell motility (migration and invasion), anchorage independent growth and engraftment in immunocompromised mice, reiterating the importance of sustained Axl function for tumor maintenance.	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('knockdown', 'Var', (27, 36))	('mice', 'Species', '10090', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('mitigated', 'NegReg', (55, 64))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('tumor', 'Disease', (289, 294))	('EAC', 'Gene', '1540', (3, 6))	('engraftment', 'CPA', (193, 204))	('EAC', 'Gene', (3, 6))	('anchorage independent growth', 'CPA', (160, 188))
481621	20818175	In our current experiments, while Gas6-dependent enhanced phosphorylation of Akt Ser473 and p42/p44 was observed in both Axl-expressing EAC cell lines, knockdown of Axl failed to abrogate the activation of these effector pathways in OE33 cells, despite the obvious effects on phenotype.	('Akt', 'Gene', '207', (77, 80))	('EAC', 'Gene', '1540', (136, 139))	('p42', 'Gene', '23552', (92, 95))	('phosphorylation', 'MPA', (58, 73))	('p42', 'Gene', (92, 95))	('enhanced', 'PosReg', (49, 57))	('EAC', 'Phenotype', 'HP:0011459', (136, 139))	('Akt', 'Gene', (77, 80))	('Ser473', 'Var', (81, 87))	('Ser473', 'Chemical', '-', (81, 87))	('Gas6', 'Gene', '2621', (34, 38))	('abrogate', 'NegReg', (179, 187))	('p44', 'Gene', (96, 99))	('p44', 'Gene', '2966', (96, 99))	('EAC', 'Gene', (136, 139))	('Gas6', 'Gene', (34, 38))
481628	20818175	Genetic knockdown of Axl leads to profound diminishing of GTP-bound (active) Ral proteins in both OE33 and JH-EsoAd1 cells.	('knockdown', 'Var', (8, 17))	('GTP', 'Chemical', 'MESH:D006160', (58, 61))	('Ral', 'Gene', '5898', (77, 80))	('diminishing', 'NegReg', (43, 54))	('Ral', 'Gene', (77, 80))
481632	20818175	In this study, we also confirm that R428, a newly described orally bioavailable and selective small molecule antagonist of Axl function, blocks invasion and anchorage independent growth of EAC cells in vitro.	('blocks', 'NegReg', (137, 143))	('anchorage independent growth', 'CPA', (157, 185))	('EAC', 'Phenotype', 'HP:0011459', (189, 192))	('R428', 'Var', (36, 40))	('EAC', 'Gene', '1540', (189, 192))	('EAC', 'Gene', (189, 192))
481633	20818175	R428 inhibits in vivo metastases in multiple breast cancer preclinical models, which engenders the possibility that this agent might be beneficial in advanced EACs, especially in those adenocarcinomas that demonstrate evidence of Axl overexpression.	('EAC', 'Gene', '1540', (159, 162))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('EAC', 'Gene', (159, 162))	('R428', 'Var', (0, 4))	('adenocarcinomas', 'Disease', 'MESH:D000230', (185, 200))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('metastases', 'Disease', (22, 32))	('adenocarcinomas', 'Disease', (185, 200))	('breast cancer', 'Disease', (45, 58))	('metastases', 'Disease', 'MESH:D009362', (22, 32))	('EAC', 'Phenotype', 'HP:0011459', (159, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('inhibits', 'NegReg', (5, 13))	('Axl', 'Protein', (230, 233))	('overexpression', 'PosReg', (234, 248))
481638	20818175	We speculate that combinatorial therapy using R428 or similar Axl inhibitors might provide additional efficacy in preclinical models of EAC in vivo and are currently pursuing this subject of investigation.	('EAC', 'Phenotype', 'HP:0011459', (136, 139))	('EAC', 'Gene', '1540', (136, 139))	('R428', 'Var', (46, 50))	('EAC', 'Gene', (136, 139))	('efficacy', 'PosReg', (102, 110))
481675	33392090	Follow-up examinations included tumor markers (CEA, CA19-9 and CA72-4), chest X-ray, abdominopelvic computed tomography (CT), and annual endoscopy.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('CA72-4', 'Var', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CA19-9', 'Var', (52, 58))	('CEA', 'Gene', (47, 50))	('CEA', 'Gene', '1084', (47, 50))	('tumor', 'Disease', (32, 37))
481685	33392090	In addition, the NPS remarkably increased among cases having the serum Alb (mg/dl) < 40 (P< 0.001), TC (mg/dl) <= 180 (P< 0.001), LMR <= 4.44 (P< 0.001), while NLR > 2.96 (P< 0.001).	('LMR', 'Chemical', '-', (130, 133))	('NPS', 'MPA', (17, 20))	('Alb', 'Gene', '213', (71, 74))	('TC', 'Chemical', '-', (100, 102))	('LMR <= 4.44', 'Var', (130, 141))	('increased', 'PosReg', (32, 41))	('Alb', 'Gene', (71, 74))
481689	33392090	In addition, OS was markedly impaired among cases having serum Alb level (mg/dl) < 40 (HR = 0.68, P= 0.002), LMR <= 4.44 (HR = 1.77, P< 0.001), together with NLR> 2.96 (HR = 1.58, P = 0.022) ( Table 2 ,  Supplemental Figure 4 ).	('LMR <=', 'Var', (109, 115))	('impaired', 'NegReg', (29, 37))	('Alb', 'Gene', (63, 66))	('LMR', 'Chemical', '-', (109, 112))	('Alb', 'Gene', '213', (63, 66))
481710	33392090	Low cholesterol level has been reported to link with poor prognosis for many human tumors, such as GC, EC and renal cell carcinoma (RCC).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('Low cholesterol level', 'Phenotype', 'HP:0003146', (0, 21))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('Low', 'Var', (0, 3))	('EC and renal cell carcinoma', 'Disease', 'MESH:C538614', (103, 130))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('cholesterol', 'Chemical', 'MESH:D002784', (4, 15))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('human', 'Species', '9606', (77, 82))
481737	33392090	This work was supported by grants from the National Natural Science Foundation of China (81772642), the Beijing Municipal Science & Technology Commission (Z161100000116045), and Capital's Funds for Health Improvement and Research (CFH 2018-2-4022).	('CFH', 'Gene', '3075', (231, 234))	('Commission', 'Var', (143, 153))	('CFH', 'Gene', (231, 234))
481775	31435164	Other studies hypothesized that nonulcer dyspepsia, including globus sensation, is due to chronic inflammation produced by H. pylori in the gastric mucosa of the IP.	('H. pylori', 'Species', '210', (123, 132))	('nonulcer dyspepsia', 'Disease', (32, 50))	('globus sensation', 'Disease', (62, 78))	('inflammation', 'Disease', 'MESH:D007249', (98, 110))	('dyspepsia', 'Phenotype', 'HP:0410281', (41, 50))	('due to', 'Reg', (83, 89))	('inflammation', 'Disease', (98, 110))	('H. pylori', 'Var', (123, 132))	('nonulcer dyspepsia', 'Disease', 'MESH:D004415', (32, 50))
481854	31435164	Long-term use of PPI also raises the question if it could influence the development of the heterotopic mucosa of the intestinal metaplasia or atrophy.	('men', 'Species', '9606', (79, 82))	('atrophy', 'Disease', (142, 149))	('intestinal metaplasia', 'Disease', (117, 138))	('PPI', 'Var', (17, 20))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (117, 138))	('influence', 'Reg', (58, 67))	('atrophy', 'Disease', 'MESH:D001284', (142, 149))
481863	31435164	A high-dose PPI paired with endoscopic thermal coagulation led to long-term amelioration of dysphagia in one case of IP with stricture and even to the recovery of the mucosa with normal squamous epithelium.	('dysphagia', 'Disease', 'MESH:D003680', (92, 101))	('amelioration', 'PosReg', (76, 88))	('dysphagia', 'Disease', (92, 101))	('dysphagia', 'Phenotype', 'HP:0002015', (92, 101))	('PPI', 'Var', (12, 15))
481946	30957414	More LNEs were significantly associated with better survival in patients with or without LN metastasis (N negative patients: HR 0.982, 95% CI 0.977-0.987, P < 0.001; N positive patients: HR 0.989, 95% CI 0.984-0.993, P < 0.001) (Table 3).	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (64, 72))	('better', 'PosReg', (45, 51))	('patients', 'Species', '9606', (177, 185))	('survival', 'CPA', (52, 60))	('LNEs', 'Var', (5, 9))
482015	30258932	For example, in breast cancer, overexpression of NEAT1 promotes EMT and invasion in vitro as well as dissemination and metastasis in vivo.	('breast cancer', 'Disease', (16, 29))	('overexpression', 'Var', (31, 45))	('promotes', 'PosReg', (55, 63))	('NEAT1', 'Gene', '283131', (49, 54))	('NEAT1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('dissemination', 'CPA', (101, 114))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
482016	30258932	Exogenous modulation of NEAT1 modulates gemcitabine sensitivity in cholangiocarcinoma.	('modulates', 'Reg', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('modulation', 'Var', (10, 20))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('gemcitabine sensitivity', 'MPA', (40, 63))	('NEAT1', 'Gene', '283131', (24, 29))	('NEAT1', 'Gene', (24, 29))	('cholangiocarcinoma', 'Disease', (67, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))
482018	30258932	Moreover, in breast cancer, hepatocellular carcinoma, and papillary kidney cancer, whole-genome analysis indicates NEAT1 carries specific mutations that affect their expression levels.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (28, 52))	('kidney cancer', 'Phenotype', 'HP:0009726', (68, 81))	('hepatocellular carcinoma', 'Disease', (28, 52))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (28, 52))	('papillary kidney cancer', 'Disease', (58, 81))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('affect', 'Reg', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('expression levels', 'MPA', (166, 183))	('breast cancer', 'Disease', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('papillary kidney cancer', 'Phenotype', 'HP:0006766', (58, 81))	('NEAT1', 'Gene', (115, 120))	('NEAT1', 'Gene', '283131', (115, 120))	('papillary kidney cancer', 'Disease', 'MESH:D007681', (58, 81))	('mutations', 'Var', (138, 147))
482019	30258932	rs512715 of NEAT1 is also associated with an increased risk of cervical cancer.	('rs512715', 'Mutation', 'rs512715', (0, 8))	('NEAT1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cervical cancer', 'Disease', 'MESH:D002583', (63, 78))	('rs512715', 'Var', (0, 8))	('cervical cancer', 'Disease', (63, 78))	('NEAT1', 'Gene', '283131', (12, 17))	('associated', 'Reg', (26, 36))
482042	30258932	However, a recent study indicated that in breast invasive cancer, from TCGA datasets, NEAT1 was focally deleted in ~8% of breast cancers and its promoters carried various mutations, and three out of the four mutations they validated reproducibly decreased NEAT1 expression compared with the wild type sequence.	('NEAT1', 'Gene', '283131', (256, 261))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('breast cancers', 'Disease', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('NEAT1', 'Gene', (256, 261))	('deleted', 'NegReg', (104, 111))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('expression', 'MPA', (262, 272))	('breast invasive cancer', 'Disease', (42, 64))	('mutations', 'Var', (208, 217))	('NEAT1', 'Gene', '283131', (86, 91))	('breast invasive cancer', 'Disease', 'MESH:D001943', (42, 64))	('NEAT1', 'Gene', (86, 91))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('mutations', 'Var', (171, 180))	('decreased', 'NegReg', (246, 255))
482055	30258932	In lung cancer, NEAT1 is up-regulated by the direct binding of Oct4, since knockdown of NEAT1 abolishes Oct4-mediated lung cancer cell growth and motility.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('Oct4', 'Gene', '5460', (63, 67))	('lung cancer', 'Disease', (118, 129))	('abolishes', 'NegReg', (94, 103))	('NEAT1', 'Gene', (88, 93))	('Oct4', 'Gene', (104, 108))	('knockdown', 'Var', (75, 84))	('binding', 'Interaction', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('NEAT1', 'Gene', (16, 21))	('lung cancer', 'Disease', (3, 14))	('Oct4', 'Gene', (63, 67))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('NEAT1', 'Gene', '283131', (88, 93))	('up-regulated', 'PosReg', (25, 37))	('motility', 'CPA', (146, 154))	('NEAT1', 'Gene', '283131', (16, 21))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('Oct4', 'Gene', '5460', (104, 108))
482067	30258932	The aberrant expression of NEAT1 in certain types of cancer may be resulted from the cooperation and antagonism between different transcription factors.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('expression', 'MPA', (13, 23))	('aberrant', 'Var', (4, 12))	('NEAT1', 'Gene', '283131', (27, 32))	('NEAT1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('resulted from', 'Reg', (67, 80))
482074	30258932	In laryngeal squamous cell cancer, high expression of NEAT1 decreases miR-107 expression, thus regulating CDK6 level and exerting an oncogenic effect.	('decreases', 'NegReg', (60, 69))	('regulating', 'Reg', (95, 105))	('laryngeal squamous cell cancer', 'Disease', (3, 33))	('NEAT1', 'Gene', (54, 59))	('expression', 'MPA', (78, 88))	('NEAT1', 'Gene', '283131', (54, 59))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D002294', (3, 33))	('CDK6', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CDK6', 'Gene', '1021', (106, 110))	('oncogenic effect', 'CPA', (133, 149))	('high expression', 'Var', (35, 50))	('miR-107', 'Gene', '406901', (70, 77))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (13, 33))	('miR-107', 'Gene', (70, 77))
482093	30258932	Recently, several studies have revealed the mutations and polymorphisms of NEAT1 are also closely correlated with the prognosis of cancers, which has added complexity to NEAT1-associated signaling and function.	('NEAT1', 'Gene', '283131', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('NEAT1', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('polymorphisms', 'Var', (58, 71))	('correlated', 'Reg', (98, 108))	('mutations', 'Var', (44, 53))	('NEAT1', 'Gene', '283131', (170, 175))	('NEAT1', 'Gene', (170, 175))
482094	30258932	Moreover, since the two major isoforms of NEAT1 produced from alternative transcription have been reported to have different cellular location and tumor regulation properties, it is necessary to distinguish the exact expression and function of these two isoforms.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('NEAT1', 'Gene', '283131', (42, 47))	('alternative transcription', 'Var', (62, 87))	('NEAT1', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
482097	28415770	Human 8-oxoguanine DNA glycosylase gene polymorphism (Ser326Cys) and cancer risk: updated meta-analysis Genetic polymorphism of human 8-oxoguanine glycosylase 1 (hOGG1) has been reported to have a relationship with the risk of the development of various cancers.	('Human', 'Species', '9606', (0, 5))	('relationship', 'Reg', (197, 209))	('cancer', 'Disease', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (134, 146))	('hOGG1', 'Gene', '4968', (162, 167))	('Ser326Cys', 'SUBSTITUTION', 'None', (54, 63))	('Ser326Cys', 'Var', (54, 63))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (6, 18))	('human', 'Species', '9606', (128, 133))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('8-oxoguanine DNA glycosylase', 'Gene', (6, 34))	('hOGG1', 'Gene', (162, 167))	('cancers', 'Disease', (254, 261))	('8-oxoguanine DNA glycosylase', 'Gene', '4968', (6, 34))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('polymorphism', 'Var', (112, 124))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Disease', 'MESH:D009369', (254, 261))
482098	28415770	Many studies have described the influence of Ser326Cys polymorphism of the hOGG1 gene on cancer susceptibility.	('Ser326Cys', 'SUBSTITUTION', 'None', (45, 54))	('hOGG1', 'Gene', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('hOGG1', 'Gene', '4968', (75, 80))	('Ser326Cys', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
482099	28415770	Therefore, we performed a meta-analysis to more precisely determine the relationship between the hOGG1 polymorphism and the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('polymorphism', 'Var', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('hOGG1', 'Gene', '4968', (97, 102))	('hOGG1', 'Gene', (97, 102))	('cancer', 'Disease', (139, 145))
482102	28415770	Our meta-analysis revealed that G allele of Ser326Cys polymorphism of the hOGG1 gene statistically increased the susceptibility of cancer (all population, OR = 1.092, 95% CI = 1.051-1.134, p < 0.001; in Asian, OR = 1.095, 95% CI = 1.048-1.145, p < 0.001; in Caucasian, OR = 1.097, 95% CI = 1.033-1.179, p = 0.002).	('cancer', 'Disease', (131, 137))	('hOGG1', 'Gene', (74, 79))	('susceptibility', 'Reg', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('hOGG1', 'Gene', '4968', (74, 79))	('Ser326Cys', 'Var', (44, 53))	('increased', 'PosReg', (99, 108))	('Ser326Cys', 'SUBSTITUTION', 'None', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
482104	28415770	The present meta-analysis concluded that the G allele was associated with an increased risk of cancer.	('G allele', 'Var', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))
482105	28415770	It suggested that the hOGG1 polymorphism may be a candidate marker of cancer.	('polymorphism', 'Var', (28, 40))	('hOGG1', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('hOGG1', 'Gene', '4968', (22, 27))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
482108	28415770	Several recent studies focused on the genetic background and how the single nucleotide polymorphism (SNP) of specific genes, including DNA damage, can enhance cancer susceptibility.	('cancer', 'Disease', (159, 165))	('enhance', 'PosReg', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('single nucleotide polymorphism', 'Var', (69, 99))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
482112	28415770	Abnormal balance results in DNA mutations that can activate oncogenes or inactivate tumor suppressor genes, which leads to cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('activate', 'PosReg', (51, 59))	('leads to', 'Reg', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', (84, 89))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (123, 129))	('Abnormal balance', 'Phenotype', 'HP:0002141', (0, 16))	('oncogenes', 'Protein', (60, 69))	('inactivate', 'NegReg', (73, 83))
482114	28415770	A relationship of BER to cancer progression has been drawn from the observation that mutations or altered expression in BER genes.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('expression', 'MPA', (106, 116))	('mutations', 'Var', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('altered', 'Reg', (98, 105))	('BER genes', 'Gene', (120, 129))
482117	28415770	ROS can lead to mutagenic base 8oxoG formation in DNA and carcinogenesis.	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('8oxoG', 'Chemical', 'MESH:C453560', (31, 36))	('mutagenic base 8oxoG formation', 'MPA', (16, 46))	('carcinogenesis', 'Disease', (58, 72))	('lead to', 'Reg', (8, 15))
482119	28415770	Many previous studies showed the relationship between the Ser326Cys polymorphism of hOGG1 gene and cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('hOGG1', 'Gene', '4968', (84, 89))	('Ser326Cys', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Ser326Cys', 'SUBSTITUTION', 'None', (58, 67))	('hOGG1', 'Gene', (84, 89))
482120	28415770	Meta-analysis on the hOGG1 polymorphism and the risk of bladder cancer shows no statistically significant association.	('polymorphism', 'Var', (27, 39))	('hOGG1', 'Gene', '4968', (21, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('hOGG1', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))
482122	28415770	The hOGG1 polymorphism may be also contributed to the susceptibility of digestive cancers, colorectal cancer, esophageal squamous cell carcinoma but shows a lack of association in gastric cancer.	('colorectal cancer', 'Disease', (91, 108))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (110, 144))	('cancers', 'Disease', (82, 89))	('hOGG1', 'Gene', '4968', (4, 9))	('gastric cancer', 'Disease', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('hOGG1', 'Gene', (4, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('contributed', 'Reg', (35, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (180, 194))	('polymorphism', 'Var', (10, 22))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('esophageal squamous cell carcinoma', 'Disease', (110, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (180, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))
482123	28415770	In addition, the hOGG1 polymorphism is associated with hepatocellular carcinoma, head and neck cancer, and prostate cancer, not with lung cancer.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (55, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('head and neck cancer', 'Disease', 'MESH:D006258', (81, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('associated', 'Reg', (39, 49))	('prostate cancer', 'Disease', (107, 122))	('lung cancer', 'Disease', (133, 144))	('hepatocellular carcinoma', 'Disease', (55, 79))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('head and neck cancer', 'Phenotype', 'HP:0012288', (81, 101))	('hOGG1', 'Gene', '4968', (17, 22))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (55, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('hOGG1', 'Gene', (17, 22))	('polymorphism', 'Var', (23, 35))
482124	28415770	Meta-analysis study in 2011 year reported that the evidence of the association between the hOGG1 polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('hOGG1', 'Gene', (91, 96))	('polymorphism', 'Var', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('hOGG1', 'Gene', '4968', (91, 96))	('association', 'Interaction', (67, 78))	('cancer', 'Disease', (114, 120))
482125	28415770	Since 2011, many studies reported the relation between the hOGG1 polymorphism and various cancer risks.	('hOGG1', 'Gene', '4968', (59, 64))	('polymorphism', 'Var', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('relation', 'Reg', (38, 46))	('hOGG1', 'Gene', (59, 64))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
482126	28415770	Therefore, the purpose of this meta-analysis is to update previous meta-analysis with the aim of elucidating the association of the hOGG1 polymorphism and risk of cancer.	('hOGG1', 'Gene', (132, 137))	('association', 'Interaction', (113, 124))	('polymorphism', 'Var', (138, 150))	('hOGG1', 'Gene', '4968', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
482127	28415770	In present study, we performed the meta-analysis to assess relationship between the hOGG1 polymorphism and risk of cancer.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('polymorphism', 'Var', (90, 102))	('hOGG1', 'Gene', '4968', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('hOGG1', 'Gene', (84, 89))
482129	28415770	Finally, a total of 127 genetic studies about the hOGG1 polymorphism and cancer were analyzed for meta-analysis (Supplementary Table 1).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('polymorphism', 'Var', (56, 68))	('hOGG1', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('hOGG1', 'Gene', '4968', (50, 55))
482134	28415770	The minor G allele frequency in the total cancer was higher more than that of control (36.67% vs. 34.66%).	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('minor G', 'Var', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
482138	28415770	The CG+GG genotypes frequency in the total cancer was higher more than that of control (56.83% vs. 54.98%).	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('higher', 'PosReg', (54, 60))	('cancer', 'Disease', (43, 49))	('CG+GG', 'Var', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
482142	28415770	The CG+GG genotypes frequency in the total cancer was higher more than that of control (16.44% vs. 14.31%).	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('higher', 'PosReg', (54, 60))	('cancer', 'Disease', (43, 49))	('CG+GG', 'Var', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
482145	28415770	Table 2 and Table 3 present the results of meta-analysis of association between the hOGG1 polymorphism and risk of cancer according to ethnic difference.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('polymorphism', 'Var', (90, 102))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('hOGG1', 'Gene', '4968', (84, 89))	('association', 'Interaction', (60, 71))	('hOGG1', 'Gene', (84, 89))
482146	28415770	In Asian population, analysis of allele, dominant, and recessive models showed the association with risk of cancer (C vs. G, OR=1.095, 95% CI=1.048-1.145, p<0.001: CC vs. CG+GG, OR=1.096, 95% CI=1.015-1.183, p=0.019; CC+CG vs. GG, OR=1.171, 95% CI=1.070-1.282, p=0.001 in Table 2).	('CC+CG vs.', 'Var', (217, 226))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CC+CG', 'Chemical', '-', (217, 222))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
482147	28415770	According to the type of cancer, risk of lung, breast, and head and neck cancers was associated with the hOGG1 polymorphism (p<0.05, Table 2).	('cancer', 'Disease', (73, 79))	('lung', 'Disease', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('head and neck cancer', 'Phenotype', 'HP:0012288', (59, 79))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('hOGG1', 'Gene', (105, 110))	('head and neck cancers', 'Disease', 'MESH:D006258', (59, 80))	('polymorphism', 'Var', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('head and neck cancers', 'Phenotype', 'HP:0012288', (59, 80))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('hOGG1', 'Gene', '4968', (105, 110))	('cancer', 'Disease', (25, 31))	('breast', 'Disease', (47, 53))	('associated', 'Reg', (85, 95))
482148	28415770	In Caucasian population, analysis of allele and recessive models showed the association with risk of cancer (C vs. G, OR=1.097, 95% CI=1.021-1.179, p=0.012: CC+CG vs. GG, OR=1.158, 95% CI=1.005-1.334, p=0.043 in Table 3).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CC+CG', 'Var', (157, 162))	('CC+CG', 'Chemical', '-', (157, 162))
482149	28415770	According to type of cancer, risk of colorectal, esophageal, and head and neck cancer was associated with the hOGG1 polymorphism (p<0.05, Table 3).	('polymorphism', 'Var', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('colorectal', 'Disease', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('head and neck cancer', 'Phenotype', 'HP:0012288', (65, 85))	('associated', 'Reg', (90, 100))	('hOGG1', 'Gene', '4968', (110, 115))	('esophageal', 'Disease', (49, 59))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('head and neck cancer', 'Disease', 'MESH:D006258', (65, 85))	('cancer', 'Disease', (79, 85))	('hOGG1', 'Gene', (110, 115))	('colorectal', 'Disease', 'MESH:D015179', (37, 47))
482156	28415770	These results indicate that individual with minor G allele of the hOGG1 polymorphism may be increased risk of cancer.	('cancer', 'Disease', (110, 116))	('hOGG1', 'Gene', '4968', (66, 71))	('polymorphism', 'Var', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('hOGG1', 'Gene', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
482160	28415770	Low OGG activity in peripheral blood mononuclear cells increases risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('Low', 'Var', (0, 3))	('activity', 'MPA', (8, 16))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('OGG', 'Protein', (4, 7))
482163	28415770	A previous study on lung cancer patients showed a close relationship between Ser326Cys polymorphism and OGG1 mRNA levels.	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Ser326Cys', 'Var', (77, 86))	('lung cancer', 'Disease', (20, 31))	('Ser326Cys', 'SUBSTITUTION', 'None', (77, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('mRNA levels', 'MPA', (109, 120))	('OGG1', 'Gene', (104, 108))	('OGG1', 'Gene', '4968', (104, 108))
482164	28415770	The Ser326Cys polymorphisms have been shown to be associated with delayed repair of oxidative DNA damage.	('delayed repair of oxidative DNA damage', 'MPA', (66, 104))	('polymorphisms', 'Var', (14, 27))	('Ser326Cys', 'SUBSTITUTION', 'None', (4, 13))	('Ser326Cys', 'Var', (4, 13))
482165	28415770	In a recent study, changes in the functional and structural characteristics of the hOGG1 protein by the Ser326Cys polymorphism using in silico computational biology tools have been reported.	('structural characteristics', 'MPA', (49, 75))	('Ser326Cys', 'SUBSTITUTION', 'None', (104, 113))	('Ser326Cys', 'Var', (104, 113))	('hOGG1', 'Gene', '4968', (83, 88))	('functional', 'MPA', (34, 44))	('changes', 'Reg', (19, 26))	('hOGG1', 'Gene', (83, 88))
482166	28415770	According to this study, hOGG1 326Cys variant is smaller and more hydrophobic than wild type, which can have deleterious effects on the function of the hOGG1 protein.	('function', 'MPA', (136, 144))	('hOGG1', 'Gene', '4968', (25, 30))	('effects', 'Reg', (121, 128))	('more', 'PosReg', (61, 65))	('hOGG1', 'Gene', '4968', (152, 157))	('hydrophobic', 'MPA', (66, 77))	('326Cys', 'Chemical', '-', (31, 37))	('hOGG1', 'Gene', (25, 30))	('326Cys', 'Var', (31, 37))	('hOGG1', 'Gene', (152, 157))
482167	28415770	And this variant has been found to be closely related to breast cancer.	('breast cancer', 'Disease', (57, 70))	('variant', 'Var', (9, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('related', 'Reg', (46, 53))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
482168	28415770	Although the relationship between hOGG1 expression and cancer risk and the Ser326Cys hOGG1 polymorphism and the expression of OGG1 has been reported, the results of previous genetic studies on the relationship between hOGG1 polymorphism and various cancers risks were conflicting and contradictory.	('OGG1', 'Gene', '4968', (86, 90))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('cancers', 'Disease', (249, 256))	('cancer', 'Disease', (249, 255))	('OGG1', 'Gene', (219, 223))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('OGG1', 'Gene', '4968', (219, 223))	('hOGG1', 'Gene', '4968', (85, 90))	('hOGG1', 'Gene', (85, 90))	('hOGG1', 'Gene', '4968', (218, 223))	('cancer', 'Disease', (55, 61))	('hOGG1', 'Gene', '4968', (34, 39))	('OGG1', 'Gene', (35, 39))	('OGG1', 'Gene', '4968', (35, 39))	('hOGG1', 'Gene', (218, 223))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('hOGG1', 'Gene', (34, 39))	('Ser326Cys', 'SUBSTITUTION', 'None', (75, 84))	('Ser326Cys', 'Var', (75, 84))	('OGG1', 'Gene', (126, 130))	('OGG1', 'Gene', '4968', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('OGG1', 'Gene', (86, 90))
482169	28415770	Meta-analysis on the hOGG1 polymorphism and the risk of bladder cancer, gastric cancer, and lung cancer shows no statistically significant association.	('polymorphism', 'Var', (27, 39))	('lung cancer', 'Disease', (92, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('hOGG1', 'Gene', '4968', (21, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('hOGG1', 'Gene', (21, 26))	('gastric cancer', 'Disease', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))
482170	28415770	But the other meta-analysis reported that the hOGG1 polymorphism may contribute to the susceptibility of digestive cancers, breast cancer, colorectal cancer, esophageal squamous cell carcinoma, hepatocellular carcinoma, head and neck cancer, and prostate cancer.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (158, 192))	('head and neck cancer', 'Phenotype', 'HP:0012288', (220, 240))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancers', 'Disease', (115, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('contribute', 'Reg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('polymorphism', 'Var', (52, 64))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (194, 218))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('prostate cancer', 'Disease', 'MESH:D011471', (246, 261))	('breast cancer', 'Disease', (124, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (139, 156))	('head and neck cancer', 'Disease', 'MESH:D006258', (220, 240))	('prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('prostate cancer', 'Disease', (246, 261))	('esophageal squamous cell carcinoma', 'Disease', (158, 192))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (194, 218))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('hOGG1', 'Gene', '4968', (46, 51))	('hepatocellular carcinoma', 'Disease', (194, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('hOGG1', 'Gene', (46, 51))	('colorectal cancer', 'Disease', (139, 156))
482171	28415770	2012 investigated whether the hOGG1 polymorphism was associated with prostate cancer using meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('hOGG1', 'Gene', (30, 35))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('associated', 'Reg', (53, 63))	('polymorphism', 'Var', (36, 48))	('hOGG1', 'Gene', '4968', (30, 35))	('prostate cancer', 'Disease', (69, 84))
482172	28415770	The meta-analysis included genotype data of rs3218997 SNP of OGG1 that reported by Agalliu et al.	('OGG1', 'Gene', (61, 65))	('rs3218997 SNP', 'Var', (44, 57))	('rs3218997', 'Mutation', 'rs3218997', (44, 53))	('OGG1', 'Gene', '4968', (61, 65))
482173	28415770	Because rs3218997 SNP is different from Ser326Cys of hOGG1, the genetic data had to be excluded for the exact meta-analysis.	('hOGG1', 'Gene', (53, 58))	('Ser326Cys', 'SUBSTITUTION', 'None', (40, 49))	('Ser326Cys', 'Var', (40, 49))	('rs3218997', 'Mutation', 'rs3218997', (8, 17))	('hOGG1', 'Gene', '4968', (53, 58))	('rs3218997 SNP', 'Var', (8, 21))
482174	28415770	In present study, total of 126 genetic studies about the hOGG1 polymorphism and cancer were analyzed for meta-analysis.	('polymorphism', 'Var', (63, 75))	('hOGG1', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('hOGG1', 'Gene', '4968', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
482175	28415770	Significant relationship between the hOGG1 polymorphism and overall cancer risk was found.	('hOGG1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('hOGG1', 'Gene', '4968', (37, 42))	('cancer', 'Disease', (68, 74))	('polymorphism', 'Var', (43, 55))
482176	28415770	In subgroup analyses by cancer types, the significant association between the hOGG1 polymorphism and colorectal, lung, prostate, and head and neck cancer risk was detected.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('hOGG1', 'Gene', (78, 83))	('prostate', 'Disease', (119, 127))	('colorectal', 'Disease', (101, 111))	('head and neck cancer', 'Disease', 'MESH:D006258', (133, 153))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('hOGG1', 'Gene', '4968', (78, 83))	('polymorphism', 'Var', (84, 96))	('cancer', 'Disease', (147, 153))	('lung', 'Disease', (113, 117))	('head and neck cancer', 'Phenotype', 'HP:0012288', (133, 153))	('colorectal', 'Disease', 'MESH:D015179', (101, 111))
482177	28415770	In addition, in subgroup analyses by ethnicities, we found that the hOGG1 polymorphism was significantly associated with overall cancer risk in both Caucasian and Asian population.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('hOGG1', 'Gene', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (129, 135))	('associated', 'Reg', (105, 115))	('polymorphism', 'Var', (74, 86))	('hOGG1', 'Gene', '4968', (68, 73))
482178	28415770	In Asian population, lung, breast, and head and neck cancer showed a relation with the hOGG1 polymorphism but in Caucasian population only head and neck cancer showed.	('lung', 'Disease', (21, 25))	('head and neck cancer', 'Disease', 'MESH:D006258', (139, 159))	('breast', 'Disease', (27, 33))	('hOGG1', 'Gene', '4968', (87, 92))	('head and neck cancer', 'Disease', 'MESH:D006258', (39, 59))	('polymorphism', 'Var', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('hOGG1', 'Gene', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('head and neck cancer', 'Phenotype', 'HP:0012288', (139, 159))	('relation', 'Interaction', (69, 77))	('head and neck cancer', 'Phenotype', 'HP:0012288', (39, 59))
482180	28415770	Overall cancer risk and the hOGG1 polymorphism was significantly associated in our results (allele, p<0.001; dominant, p=0.004; recessive, p<0.001) and previous study showed similar result.	('hOGG1', 'Gene', '4968', (28, 33))	('polymorphism', 'Var', (34, 46))	('cancer', 'Disease', (8, 14))	('associated', 'Reg', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('hOGG1', 'Gene', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
482184	28415770	The hOGG1 polymorphism had a connection with the colorectal cancer risk among the total population, and especially among Caucasians.	('connection', 'Reg', (29, 39))	('polymorphism', 'Var', (10, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('hOGG1', 'Gene', (4, 9))	('colorectal cancer', 'Disease', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('hOGG1', 'Gene', '4968', (4, 9))
482185	28415770	One meta-analysis on breast cancer reported the association between the hOGG1 polymorphism and breast cancer risk but another study suggested a lack of association.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('hOGG1', 'Gene', '4968', (72, 77))	('association', 'Interaction', (48, 59))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('hOGG1', 'Gene', (72, 77))	('polymorphism', 'Var', (78, 90))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
482186	28415770	An association between the hOGG1 polymorphism and breast cancer risk was found only in Asian population (allele, p=0.019; recessive model, p=0.026).	('hOGG1', 'Gene', '4968', (27, 32))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('polymorphism', 'Var', (33, 45))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('hOGG1', 'Gene', (27, 32))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
482188	28415770	reported the relation between the hOGG1 polymorphism and esophageal cancer risk but meta-analysis by Wang showed no association.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('hOGG1', 'Gene', '4968', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('polymorphism', 'Var', (40, 52))	('hOGG1', 'Gene', (34, 39))	('esophageal cancer', 'Disease', (57, 74))
482189	28415770	In our study, an association between the hOGG1 polymorphism and esophageal cancer risk was found in dominant model in Caucasian population (p=0.013).	('polymorphism', 'Var', (47, 59))	('hOGG1', 'Gene', '4968', (41, 46))	('hOGG1', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
482190	28415770	Previous meta-analysis reported that the hOGG1 polymorphism had a relation to hepatocellular cancer.	('hepatocellular cancer', 'Disease', 'MESH:D006528', (78, 99))	('hepatocellular cancer', 'Disease', (78, 99))	('hOGG1', 'Gene', '4968', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (78, 99))	('relation', 'Reg', (66, 74))	('hOGG1', 'Gene', (41, 46))	('polymorphism', 'Var', (47, 59))
482192	28415770	Similar to previous study, our study showed the relation between the hOGG1 polymorphism and head and neck cancer.	('hOGG1', 'Gene', '4968', (69, 74))	('head and neck cancer', 'Disease', 'MESH:D006258', (92, 112))	('relation', 'Reg', (48, 56))	('hOGG1', 'Gene', (69, 74))	('polymorphism', 'Var', (75, 87))	('head and neck cancer', 'Phenotype', 'HP:0012288', (92, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
482196	28415770	In spite of some limitations, this meta-analysis could provide the evidence of the strong association between the hOGG1 polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('hOGG1', 'Gene', '4968', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('polymorphism', 'Var', (120, 132))	('hOGG1', 'Gene', (114, 119))
482197	28415770	In summary, G allele of Ser326Cys polymorphism might play a role in the carcinogenesis and the genotype and allele frequencies difference makes the ethnicity difference in carcinogenesis.	('makes', 'Reg', (138, 143))	('play', 'Reg', (53, 57))	('role', 'Reg', (60, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (172, 186))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))	('carcinogenesis', 'Disease', (72, 86))	('Ser326Cys', 'Var', (24, 33))	('carcinogenesis', 'Disease', (172, 186))	('Ser326Cys', 'SUBSTITUTION', 'None', (24, 33))
482198	28415770	If further study with large sample size in diverse ethnic populations were performed, it would provide more precise understanding of the association between the hOGG1 polymorphism and various cancer risks.	('association', 'Interaction', (137, 148))	('hOGG1', 'Gene', (161, 166))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('hOGG1', 'Gene', '4968', (161, 166))	('polymorphism', 'Var', (167, 179))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
482201	28415770	We searched meta-analysis study about the hOGG1 polymorphism and also searched the association study between the hOGG1 polymorphism and risk of cancer.	('hOGG1', 'Gene', '4968', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('polymorphism', 'Var', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('hOGG1', 'Gene', (113, 118))	('cancer', 'Disease', (144, 150))	('hOGG1', 'Gene', (42, 47))	('hOGG1', 'Gene', '4968', (113, 118))
482202	28415770	The keywords to find these studies were following: "8-oxoguanine DNA glycosylase", "hOGG1", or "DNA repair gene", AND "polymorphism", "polymorphisms", or "variant" AND "Ser326Cys" AND "cancer or carcinoma", or "meta analysis".	('carcinoma', 'Disease', (195, 204))	('Ser326Cys', 'Var', (169, 178))	('"8-oxoguanine DNA glycosylase"', 'Gene', (51, 81))	('"8-oxoguanine DNA glycosylase"', 'Gene', '4968', (51, 81))	('Ser326Cys', 'SUBSTITUTION', 'None', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('hOGG1', 'Gene', '4968', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('carcinoma', 'Disease', 'MESH:D002277', (195, 204))	('variant', 'Var', (155, 162))	('cancer', 'Disease', (185, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('hOGG1', 'Gene', (84, 89))
482204	28415770	Selected studies were included in the meta-analysis if they met the following criteria: (1) Investigated the association study between the hOGG1 polymorphism and cancer; (2) A comparison between cancer and control; (3) Included genotype and allele distributions of Ser326Cys polymorphism for genetic analysis.	('Ser326Cys', 'SUBSTITUTION', 'None', (265, 274))	('Ser326Cys', 'Var', (265, 274))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('polymorphism', 'Var', (145, 157))	('hOGG1', 'Gene', '4968', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('association', 'Interaction', (109, 120))	('hOGG1', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
482205	28415770	The data of first author's name, year of publication, country of origin, ethnicity of study population, sample size of cancer and control, and genotype frequencies of the hOGG1 polymorphism in cancer and control were extracted from the final selected studies.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('hOGG1', 'Gene', (171, 176))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('polymorphism', 'Var', (177, 189))	('hOGG1', 'Gene', '4968', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
482207	28415770	The pooled p value, OR, and 95% CI were used to assess the strength of association between risk of cancer and the hOGG1 polymorphism.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('hOGG1', 'Gene', '4968', (114, 119))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('polymorphism', 'Var', (120, 132))	('hOGG1', 'Gene', (114, 119))
482248	28404928	The curves implied that patients with high TC and LDL-C obviously got a trend towards superior DFS (for TC, p = 0.045; for LDL-C, p < 0.001) and OS (for TC, p = 0.043; for LDL-C, p < 0.001).	('LDL-C', 'Gene', (172, 177))	('TC', 'Chemical', '-', (43, 45))	('LDL-C', 'Gene', '22796', (123, 128))	('superior', 'PosReg', (86, 94))	('LDL-C', 'Gene', '22796', (172, 177))	('OS', 'Chemical', '-', (145, 147))	('high', 'Var', (38, 42))	('TC', 'Chemical', '-', (153, 155))	('LDL-C', 'Gene', '22796', (50, 55))	('TC', 'Chemical', '-', (104, 106))	('LDL-C', 'Gene', (50, 55))	('DFS', 'CPA', (95, 98))	('patients', 'Species', '9606', (24, 32))	('LDL-C', 'Gene', (123, 128))
482265	28404928	In the analysis of DFS (Figure 4), patients with high LDL-C had longer DFS in stage III (p = 0.023) group.	('DFS', 'MPA', (71, 74))	('longer', 'PosReg', (64, 70))	('high LDL-C', 'Phenotype', 'HP:0003141', (49, 59))	('LDL-C', 'Gene', (54, 59))	('high', 'Var', (49, 53))	('LDL-C', 'Gene', '22796', (54, 59))	('patients', 'Species', '9606', (35, 43))
482287	28404928	The mortality of patients with low LDL-C was 70.1%, which was 1.44 times higher than that in high LDL-C group (p = 0.002).	('LDL-C', 'Gene', '22796', (35, 40))	('LDL-C', 'Gene', (35, 40))	('high LDL-C', 'Phenotype', 'HP:0003141', (93, 103))	('LDL-C', 'Gene', (98, 103))	('low LDL', 'Phenotype', 'HP:0003563', (31, 38))	('patients', 'Species', '9606', (17, 25))	('LDL-C', 'Gene', '22796', (98, 103))	('low', 'Var', (31, 34))
482296	28404928	Thirdly, other reports confirmed that oxidized low-density lipoprotein (oxLDL-C) had cytotoxicity on different cell lines and could activate apoptosis of esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('LDL-C', 'Gene', (74, 79))	('cytotoxicity', 'Disease', (85, 97))	('LDL-C', 'Gene', '22796', (74, 79))	('activate', 'PosReg', (132, 140))	('oxidized low-density', 'Var', (38, 58))	('apoptosis', 'CPA', (141, 150))	('esophageal cancer', 'Disease', (154, 171))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))
482318	28404928	The area under the ROC curve (AUC) was 0.636 (95% CI, 0.561-0.710; p = 0.001) for LDL-C and 0.622 (95% CI, 0.547-0.697; p = 0.002) for LHR in 3-year OS.	('OS', 'Chemical', '-', (149, 151))	('LDL-C', 'Gene', (82, 87))	('LDL-C', 'Gene', '22796', (82, 87))	('LHR', 'Gene', '3973', (135, 138))	('LHR', 'Gene', (135, 138))	('0.622', 'Var', (92, 97))
482319	28404928	As to 5-year OS, the AUC was 0.606 (95% CI, 0.528-0.685; p = 0.009) for LDL-C and 0.618 (95% CI, 0.541-0.695; p = 0.004) for LHR.	('LDL-C', 'Gene', (72, 77))	('LDL-C', 'Gene', '22796', (72, 77))	('0.618', 'Var', (82, 87))	('LHR', 'Gene', '3973', (125, 128))	('OS', 'Chemical', '-', (13, 15))	('LHR', 'Gene', (125, 128))
482321	28404928	Second, we did not figure out the causal relationship of low serum lipids and cancer development.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('low', 'Var', (57, 60))	('lipids', 'Chemical', 'MESH:D008055', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
482322	28404928	It is hard to say whether low TC and LDL-C can promote cancer development or is the result of advanced cancer.	('TC', 'Chemical', '-', (30, 32))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('low', 'Var', (26, 29))	('promote', 'PosReg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('LDL-C', 'Gene', '22796', (37, 42))	('low TC and LDL-C', 'Phenotype', 'HP:0003563', (26, 42))	('LDL-C', 'Gene', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (55, 61))
482381	24081534	In particular, graft necrosis due to thrombosis, kinks, etc., following vascular anastomosis requires secondary reconstructive surgery.	('kinks', 'Var', (49, 54))	('necrosis', 'Disease', 'MESH:D009336', (21, 29))	('thrombosis', 'Disease', (37, 47))	('graft necrosis', 'Phenotype', 'HP:0010885', (15, 29))	('graft', 'Disease', (15, 20))	('thrombosis', 'Disease', 'MESH:D013927', (37, 47))	('necrosis', 'Disease', (21, 29))
482400	24081534	In point of swallowing function, the isoperistalsis of the jejunum flap may help swallowing transit compared with the myocutaneous flap reconstruction.	('help', 'PosReg', (76, 80))	('flap', 'Gene', (131, 135))	('flap', 'Gene', '241', (67, 71))	('flap', 'Gene', (67, 71))	('isoperistalsis', 'Var', (37, 51))	('flap', 'Gene', '241', (131, 135))	('swallowing transit', 'MPA', (81, 99))
482415	18664505	Epigenetic inactivation of members of the glutathione pathway can be an important mechanism in Barrett's tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('glutathione', 'Chemical', 'MESH:D005978', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('glutathione pathway', 'Pathway', (42, 61))	('tumor', 'Disease', (105, 110))	('Epigenetic inactivation', 'Var', (0, 23))
482419	18664505	There are increasing evidences demonstrating that oxidative injury due to H2O2 and other endogenous ROS are a major cause of DNA damage that correlate with multiple human diseases including cancer.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('human', 'Species', '9606', (165, 170))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('H2O2', 'Chemical', 'MESH:D006861', (74, 78))	('H2O2', 'Var', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('oxidative injury', 'Disease', 'MESH:D004194', (50, 66))	('rat', 'Species', '10116', (38, 41))	('oxidative injury', 'Disease', (50, 66))
482427	18664505	Aberrant DNA methylation, namely overall DNA hypomethylation and regional DNA hypermethylation has been linked to carcinogenesis of various organs.	('Aberrant', 'Var', (0, 8))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('carcinogenesis', 'Disease', (114, 128))	('linked', 'Reg', (104, 110))
482428	18664505	Aberrant DNA methylation of CpG islands in the promoter region has been associated with gene silencing of several genes in cancer such as p16, hMLH1 and CDH1 genes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('p16', 'Gene', '1029', (138, 141))	('Aberrant', 'Var', (0, 8))	('hMLH1', 'Gene', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('hMLH1', 'Gene', '4292', (143, 148))	('gene', 'MPA', (88, 92))	('CDH1', 'Gene', (153, 157))	('p16', 'Gene', (138, 141))	('cancer', 'Disease', (123, 129))	('CDH1', 'Gene', '999', (153, 157))	('DNA', 'MPA', (9, 12))
482429	18664505	Dysfunction of the GSTP1 gene through aberrant DNA methylation has been demonstrated in several human tumors, especially in prostate carcinoma.	('tumors', 'Disease', (102, 108))	('GSTP1', 'Gene', '2950', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('DNA methylation', 'MPA', (47, 62))	('prostate carcinoma', 'Disease', (124, 142))	('human', 'Species', '9606', (96, 101))	('aberrant', 'Var', (38, 46))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (124, 142))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('prostate carcinoma', 'Disease', 'MESH:D011472', (124, 142))	('rat', 'Species', '10116', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('GSTP1', 'Gene', (19, 24))
482451	18664505	Cell lysates from SKGT4 cancer cell line was obtained following the treatment of cells with DMSO (control), 5-Aza or 5-Aza/TSA as described above.	('DMSO', 'Chemical', 'MESH:D004121', (92, 96))	('TSA', 'Chemical', 'MESH:C012589', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('5-Aza', 'Chemical', 'MESH:D001374', (117, 122))	('5-Aza', 'Chemical', 'MESH:D001374', (108, 113))	('5-Aza', 'Var', (108, 113))	('5-Aza/TSA', 'Var', (117, 126))	('SKGT4', 'CellLine', 'CVCL:2195', (18, 23))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))
482487	18664505	We further analyzed the promoter DNA methylation against mRNA expression levels in BACs and found that tumors with hypermethylation (>=10%) had significant down-regulation for GPX3 (P=.021), GPX7 (P=.02), and GSTM2 (P=.0228) as compared to tumors with absent to low promoter DNA methylation level (0 - 9%) (Figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GSTM2', 'Gene', (209, 214))	('down-regulation', 'NegReg', (156, 171))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('hypermethylation', 'Var', (115, 131))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', (240, 246))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('GPX3', 'Gene', (176, 180))	('GPX3', 'Gene', '2878', (176, 180))	('GPX7', 'Gene', '2882', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('GSTM2', 'Gene', '2946', (209, 214))	('GPX7', 'Gene', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
482497	18664505	The Western blot analysis using the SKGT4 cancer cell line, as a model, confirmed the up-regulation of GPX3, GPX7, and GSTM2 proteins following the 5-Aza and 5-Aza/TSA treatments (Figure 6).	('GPX7', 'Gene', (109, 113))	('up-regulation', 'PosReg', (86, 99))	('GSTM2', 'Gene', (119, 124))	('SKGT4', 'CellLine', 'CVCL:2195', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('5-Aza', 'Chemical', 'MESH:D001374', (148, 153))	('TSA', 'Chemical', 'MESH:C012589', (164, 167))	('proteins', 'Protein', (125, 133))	('GPX3', 'Gene', (103, 107))	('5-Aza', 'Var', (148, 153))	('GPX3', 'Gene', '2878', (103, 107))	('GSTM2', 'Gene', '2946', (119, 124))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('GPX7', 'Gene', '2882', (109, 113))	('5-Aza', 'Chemical', 'MESH:D001374', (158, 163))
482505	18664505	In this case, the accumulation of ROS will produce oxidative DNA damage that plays an important role in DNA mutagenesis and cell death.	('oxidative DNA damage', 'MPA', (51, 71))	('ROS', 'Chemical', 'MESH:D017382', (34, 37))	('ROS', 'Protein', (34, 37))	('accumulation', 'Var', (18, 30))	('produce', 'Reg', (43, 50))
482507	18664505	The aberrant DNA hypermethylation of gene promoter regions is an important epigenetic mechanism that regulates gene expression leading to down-regulation and silencing of several tumor suppressor genes such as p16, APC, and MGMT.	('MGMT', 'Gene', '4255', (224, 228))	('APC', 'Disease', (215, 218))	('down-regulation', 'NegReg', (138, 153))	('aberrant', 'Var', (4, 12))	('p16', 'Gene', (210, 213))	('APC', 'Disease', 'MESH:D011125', (215, 218))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('silencing', 'NegReg', (158, 167))	('regulates', 'Reg', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('p16', 'Gene', '1029', (210, 213))	('MGMT', 'Gene', (224, 228))	('tumor', 'Disease', (179, 184))
482508	18664505	Several recent reports have demonstrated a link between inflammation and the epigenetic inactivation of genes.	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('inflammation', 'Disease', (56, 68))	('genes', 'Gene', (104, 109))	('rat', 'Species', '10116', (35, 38))	('epigenetic inactivation', 'Var', (77, 100))
482509	18664505	Aberrant DNA methylation of several tumor-related genes has been reported in cancer-related inflammatory diseases such as gastritis, chronic colitis and chronic pancreatitis.	('pancreatitis', 'Disease', (161, 173))	('gastritis', 'Phenotype', 'HP:0005263', (122, 131))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('chronic colitis', 'Phenotype', 'HP:0100281', (133, 148))	('tumor', 'Disease', (36, 41))	('gastritis', 'Disease', 'MESH:D005756', (122, 131))	('colitis', 'Disease', (141, 148))	('reported', 'Reg', (65, 73))	('Aberrant DNA methylation', 'Var', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('gastritis', 'Disease', (122, 131))	('colitis', 'Disease', 'MESH:D003092', (141, 148))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (153, 173))	('cancer', 'Disease', (77, 83))	('pancreatitis', 'Phenotype', 'HP:0001733', (161, 173))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colitis', 'Phenotype', 'HP:0002583', (141, 148))	('pancreatitis', 'Disease', 'MESH:D010195', (161, 173))
482511	18664505	This process can trigger the carcinogenesis cascade by allowing a cumulative increase in the mutation load in the cell and leading to progression towards cancer.	('carcinogenesis', 'Disease', (29, 43))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('trigger', 'Reg', (17, 24))	('increase', 'PosReg', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('mutation', 'Var', (93, 101))	('carcinogenesis', 'Disease', 'MESH:D063646', (29, 43))
482515	18664505	A significant increase in DNA methylation of GPX3, GPX7, GSTM2, and GSTM3 was also detected in BE and BD as compared with normal samples, suggesting that DNA hypermethylation of these genes may be an early event in the Barrett's esophagus-dysplasia-adenocarcinoma sequence.	('hypermethylation', 'Var', (158, 174))	('esophagus-dysplasia-adenocarcinoma', 'Disease', 'MESH:C562730', (229, 263))	('DNA', 'MPA', (26, 29))	('GSTM2', 'Gene', '2946', (57, 62))	('GPX3', 'Gene', (45, 49))	('GPX7', 'Gene', '2882', (51, 55))	('GPX3', 'Gene', '2878', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('GPX7', 'Gene', (51, 55))	('esophagus-dysplasia-adenocarcinoma', 'Disease', (229, 263))	('GSTM3', 'Gene', (68, 73))	('BE', 'Phenotype', 'HP:0100580', (95, 97))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (219, 238))	('GSTM3', 'Gene', '2947', (68, 73))	('GSTM2', 'Gene', (57, 62))	('increase', 'PosReg', (14, 22))
482530	18664505	The mutated GSTM3 gene has been linked to an increased susceptibility for the development of bladder cancer.	('mutated', 'Var', (4, 11))	('GSTM3', 'Gene', (12, 17))	('bladder cancer', 'Disease', (93, 107))	('GSTM3', 'Gene', '2947', (12, 17))	('linked', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))
482531	18664505	The mutations and allelic loss of GSTM3 can lead to lack of detoxification by glutathione conjugation and predispose to bladder cancer.	('glutathione', 'Chemical', 'MESH:D005978', (78, 89))	('bladder cancer', 'Disease', 'MESH:D001749', (120, 134))	('detoxification by glutathione conjugation', 'MPA', (60, 101))	('lack', 'NegReg', (52, 56))	('bladder cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('GSTM3', 'Gene', (34, 39))	('GSTM3', 'Gene', '2947', (34, 39))	('mutations', 'Var', (4, 13))	('predispose', 'Reg', (106, 116))	('bladder cancer', 'Phenotype', 'HP:0009725', (120, 134))
482534	18664505	Nevertheless, our findings indicate that DNA hypermethylation of tumor samples plays a role in regulating GSTM5 mRNA expression and is possibly involved in Barrett's carcinogenesis.	('regulating', 'Reg', (95, 105))	("Barrett's carcinogenesis", 'Disease', (156, 180))	('hypermethylation', 'Var', (45, 61))	('GSTM5', 'Gene', '2949', (106, 111))	('tumor', 'Disease', (65, 70))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (156, 180))	('GSTM5', 'Gene', (106, 111))	('involved', 'Reg', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
482536	18664505	We have confirmed our results and have shown that the 5-Aza treatment demethylated the DNA as compared to the DMSO-treated control cells and restored the expression of GPX3, GPX7, GSTM2, GSTM3, and GSTM5.	('GSTM3', 'Gene', (187, 192))	('GSTM5', 'Gene', (198, 203))	('GPX7', 'Gene', '2882', (174, 178))	('GPX7', 'Gene', (174, 178))	('GSTM3', 'Gene', '2947', (187, 192))	('GPX3', 'Gene', (168, 172))	('GPX3', 'Gene', '2878', (168, 172))	('GSTM2', 'Gene', (180, 185))	('demethylated', 'Var', (70, 82))	('restored', 'PosReg', (141, 149))	('DMSO', 'Chemical', 'MESH:D004121', (110, 114))	('5-Aza', 'Chemical', 'MESH:D001374', (54, 59))	('GSTM2', 'Gene', '2946', (180, 185))	('GSTM5', 'Gene', '2949', (198, 203))	('expression', 'MPA', (154, 164))
482539	18664505	This finding confirms the epigenetic regulation of these genes and supports earlier reports that a combination of 5-Aza and TSA can have synergistic effects in the reactivation of epigenetically silenced tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('epigenetic regulation', 'MPA', (26, 47))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('5-Aza', 'Chemical', 'MESH:D001374', (114, 119))	('tumor', 'Disease', (204, 209))	('TSA', 'Chemical', 'MESH:C012589', (124, 127))	('epigenetically', 'Var', (180, 194))	('reactivation', 'MPA', (164, 176))
482544	18664505	The epigenetic inactivation of members of the glutathione pathway can be an important mechanism in the development of Barrett's adenocarcinoma.	("Barrett's adenocarcinoma", 'Disease', (118, 142))	('glutathione pathway', 'Pathway', (46, 65))	('epigenetic inactivation', 'Var', (4, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('glutathione', 'Chemical', 'MESH:D005978', (46, 57))	("Barrett's adenocarcinoma", 'Disease', 'MESH:D001471', (118, 142))
482552	18076279	Both red and processed meat intakes were positively associated with cancers of the colorectum and lung; furthermore, red meat intake was associated with an elevated risk for cancers of the esophagus and liver.	('associated', 'Reg', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('associated', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers of the colorectum', 'Disease', 'MESH:D009369', (68, 93))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (174, 198))	('liver', 'Disease', (203, 208))	('cancers of the esophagus', 'Disease', (174, 198))	('red meat', 'Var', (117, 125))	('cancers of the colorectum', 'Disease', (68, 93))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (174, 198))	('lung', 'Disease', (98, 102))
482599	18076279	Advanced prostate cancer may have a distinct etiology; therefore, we used the Tumor-Node-Metastasis classification system, and defined those with clinical or pathologic stage T3, T4, or N1 or M1, as well as individuals who died of prostate cancer, to have advanced disease.	('prostate cancer', 'Disease', (231, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Advanced prostate cancer', 'Disease', (0, 24))	('Advanced prostate cancer', 'Disease', 'MESH:D011471', (0, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (231, 246))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('N1 or M1', 'Var', (186, 194))	('prostate cancer', 'Disease', 'MESH:D011471', (9, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (9, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (231, 246))	('Tumor', 'Phenotype', 'HP:0002664', (78, 83))
482626	18076279	In further sex-specific analyses, red meat intake was positively associated with pancreatic cancer among men only (HR = 1.43; 95% CI = 1.11-1.83; p for trend = 0.001; p interaction by sex = 0.03); this risk was not attenuated by fine control for smoking.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('men', 'Species', '9606', (105, 108))	('associated', 'Interaction', (65, 75))	('red meat', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))
482647	18076279	We observed borderline statistically significant elevated risks for advanced prostate cancer with both red and processed meat intake, for laryngeal cancer with red meat, and for bladder cancer and myeloma and with processed meat intake.	('myeloma', 'Disease', (197, 204))	('red meat', 'Var', (160, 168))	('laryngeal cancer', 'Disease', (138, 154))	('bladder cancer', 'Phenotype', 'HP:0009725', (178, 192))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (138, 154))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('advanced prostate cancer', 'Disease', (68, 92))	('advanced prostate cancer', 'Disease', 'MESH:D011471', (68, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('myeloma', 'Disease', 'MESH:D009101', (197, 204))	('bladder cancer', 'Disease', 'MESH:D001749', (178, 192))	('bladder cancer', 'Disease', (178, 192))	('laryngeal cancer', 'Disease', 'MESH:D007822', (138, 154))
482671	18076279	The evidence for a positive association between meat intake and gastric cancer has been more consistent for processed meat than red meat, with elevated risks for processed meat in several case-control and cohort studies, whereas red meat has been positively associated in some, but not all studies.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gastric cancer', 'Disease', (64, 78))	('processed meat', 'Var', (162, 176))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))
482685	18076279	Human exposure to NOCs and subsequent cancer risk has not been studied extensively; although a Finnish cohort reported an increased risk of colorectal cancer with exogenous exposure to N-nitrosodimethylamine (from smoked and salted meats).	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('NOC', 'Gene', '25819', (18, 21))	('colorectal cancer', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('N-nitrosodimethylamine', 'Var', (185, 207))	('N-nitrosodimethylamine', 'Chemical', 'MESH:D004128', (185, 207))	('rectal cancer', 'Phenotype', 'HP:0100743', (144, 157))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('cancer', 'Disease', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('NOC', 'Gene', (18, 21))
482808	32021959	We observed that a higher NLR was significantly associated with male gender (OR 1.6, 95% CI = 1.13-2.27, P = .008) and T3 or T4 of tumor depth (OR 2.28, 95% CI = 1.67-3.11, P < .00001; Table 2).	('NLR', 'MPA', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor depth', 'Disease', 'MESH:D007222', (131, 142))	('tumor depth', 'Disease', (131, 142))	('T3 or T4', 'Var', (119, 127))
482820	32021959	Results of the meta-analysis showed a strong association between poor prognosis and high pretreatment NLR and CAR.	('CAR', 'Gene', '653108', (110, 113))	('CAR', 'Gene', (110, 113))	('NLR', 'Gene', (102, 105))	('high pretreatment', 'Var', (84, 101))
482831	30514328	Alterations of microRNAs are common in cancers, and many of these micro RNAs are potential therapeutic and diagnostic targets to treat these cancers.	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Alterations', 'Var', (0, 11))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
482846	30514328	Collectively, our findings suggested upregulated expression of miR-10b-3p caused by promoter hypomethylation contributed to the progression of ESCC; Thus, miR-10b-3p is a potentially effective biomarker for ESCC that could have further therapeutic implications.	('miR-10b-3', 'Gene', (155, 164))	('upregulated', 'PosReg', (37, 48))	('miR-10b-3', 'Gene', (63, 72))	('expression', 'Species', '29278', (49, 59))	('ESCC', 'Disease', (143, 147))	('expression', 'MPA', (49, 59))	('3p', 'Chemical', '-', (163, 165))	('3p', 'Chemical', '-', (71, 73))	('miR-10b-3', 'Gene', '10288', (63, 72))	('miR-10b-3', 'Gene', '10288', (155, 164))	('promoter hypomethylation', 'Var', (84, 108))
482855	30514328	In colorectal cancer, high levels of miR-135b expression and low levels of miR-590-5p expression are associated with clinical stages and survival progression.	('survival progression', 'CPA', (137, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('expression', 'Species', '29278', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('expression', 'Species', '29278', (46, 56))	('associated', 'Reg', (101, 111))	('expression', 'MPA', (46, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('miR-135b', 'Var', (37, 45))
482856	30514328	The mammalian miR-10b family includes miR-10b-3p and miR-10b-5p.	('miR-10b-3', 'Gene', '10288', (38, 47))	('miR-10b-5p', 'Var', (53, 63))	('3p', 'Chemical', '-', (46, 48))	('mammalian', 'Species', '9606', (4, 13))	('miR-10b-3', 'Gene', (38, 47))
482857	30514328	Although miR-10b-3p and miR-10b-5p have identical seed sequences, they probably regulate different pathways.	('regulate', 'Reg', (80, 88))	('miR-10b-5p', 'Var', (24, 34))	('miR-10b-3', 'Gene', (9, 18))	('3p', 'Chemical', '-', (17, 19))	('miR-10b-3', 'Gene', '10288', (9, 18))
482869	30514328	The human ESCC cell lines TE-1, EC-109, KYSE30, KYSE150, KYSE180, KYSE450 and KYSE510 were obtained from the Cell Culture Center of Peking Union Medical College (Beijing, China) and Typical Culture Cell Bank of Chinese Academy of Sciences (Shanghai, China).	('KYSE510', 'Var', (78, 85))	('KYSE30', 'Var', (40, 46))	('human', 'Species', '9606', (4, 9))	('KYSE450', 'Var', (66, 73))	('KYSE180', 'Var', (57, 64))
482951	30514328	We also found that the densities of methylated CpG dinucleotides were higher in normal tissues than in ESCC tissues (Fig.	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (47, 64))	('methylated', 'Var', (36, 46))	('densities', 'MPA', (23, 32))	('CpG', 'Protein', (47, 50))	('higher', 'PosReg', (70, 76))
482955	30514328	Correspondingly, there were lower expression levels of miR-10b-3p in KYSE150 and KYSE450 cell lines treated with 5-aza-CdR compared to two untreated cell lines, which were negatively correlated with methylation status in ESCC cell lines (Fig.	('5-aza-CdR', 'Var', (113, 122))	('3p', 'Chemical', '-', (63, 65))	('lower', 'NegReg', (28, 33))	('miR-10b-3', 'Gene', (55, 64))	('miR-10b-3', 'Gene', '10288', (55, 64))	('expression levels', 'MPA', (34, 51))	('expression', 'Species', '29278', (34, 44))
482956	30514328	There was direct evidence that the overexpression of miR-10b-3p in ESCC tissues was correlated with promoter hypomethylation, and demethylation of the promoter genes could upregulate the expression of miR-10b-3p.	('miR-10b-3', 'Gene', '10288', (53, 62))	('demethylation', 'Var', (130, 143))	('miR-10b-3', 'Gene', (201, 210))	('expression', 'MPA', (187, 197))	('miR-10b-3', 'Gene', '10288', (201, 210))	('expression', 'Species', '29278', (39, 49))	('expression', 'Species', '29278', (187, 197))	('miR-10b-3', 'Gene', (53, 62))	('upregulate', 'PosReg', (172, 182))	('3p', 'Chemical', '-', (61, 63))	('overexpression', 'PosReg', (35, 49))	('promoter hypomethylation', 'MPA', (100, 124))	('3p', 'Chemical', '-', (209, 211))
482962	30514328	However, upon miR-10b-3p overexpression, the percentages of KYSE150 and KYSE450 cells in the early and late phases of apoptosis clearly decreased compared with the percentages measured in the controls (Additional file 1: Figure S1).	('miR-10b-3', 'Gene', (14, 23))	('overexpression', 'Var', (25, 39))	('KYSE450', 'Var', (72, 79))	('miR-10b-3', 'Gene', '10288', (14, 23))	('expression', 'Species', '29278', (29, 39))	('3p', 'Chemical', '-', (22, 24))	('decreased', 'NegReg', (136, 145))
482973	30514328	The fragments containing the miR-10b-3p binding sequence or mutated sequence in the 3'UTR region of FOXO3 were cloned into the pmiR-RB-REPORT vector luciferase reporter.	('miR-10b-3', 'Gene', (29, 38))	('FOXO3', 'Gene', (100, 105))	('3p', 'Chemical', '-', (37, 39))	('mutated', 'Var', (60, 67))	('miR-10b-3', 'Gene', '10288', (29, 38))
482974	30514328	These reporter constructs were cotransfected with miR-10b-3p mimic or miR-NC into KYSE150 and KYSE450 cells, and the luciferase activities were subsequently measured.	('3p', 'Chemical', '-', (58, 60))	('miR-NC', 'Var', (70, 76))	('miR-10b-3', 'Gene', (50, 59))	('activities', 'MPA', (128, 138))	('luciferase', 'Enzyme', (117, 127))	('miR-10b-3', 'Gene', '10288', (50, 59))
482979	30514328	The evidence was obtained from the observation that FOXO3 mRNA and protein (endogenous) expression in ESCC cells was abolished by mimic transfection and recovered by transfection of both pEGFP-N1-FOXO3 expression constructs (Fig.	('pEGFP-N1-FOXO3', 'Var', (187, 201))	('expression', 'Species', '29278', (202, 212))	('abolished', 'NegReg', (117, 126))	('expression', 'Species', '29278', (88, 98))	('FOXO3', 'Gene', (52, 57))	('expression', 'MPA', (88, 98))
482983	30514328	The apoptosis was measured by FACS analysis also indicated increases of early and late phase of apoptosis in cells with FOXO3 plasmid overexpression in KYSE 30 and KYSE 510 cell lines (Additional file 4: Figure S3c, d).	('FOXO3', 'Gene', (120, 125))	('expression', 'Species', '29278', (138, 148))	('early', 'MPA', (72, 77))	('apoptosis', 'CPA', (96, 105))	('overexpression', 'Var', (134, 148))	('increases', 'PosReg', (59, 68))
483010	30514328	Collectively, our findings suggested upregulated expression of miR-10b-3p caused by promoter hypomethylation contributed to the progression of ESCC and miR-10b-3p suppresses tumor initiation and progression of esophageal cancer by regulating FOXO3 (Fig.	('regulating', 'Reg', (231, 241))	('suppresses', 'NegReg', (163, 173))	('miR-10b-3', 'Gene', (152, 161))	('3p', 'Chemical', '-', (71, 73))	('3p', 'Chemical', '-', (160, 162))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('miR-10b-3', 'Gene', '10288', (152, 161))	('upregulated', 'PosReg', (37, 48))	('miR-10b-3', 'Gene', (63, 72))	('expression', 'MPA', (49, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (210, 227))	('miR-10b-3', 'Gene', '10288', (63, 72))	('esophageal cancer', 'Disease', (210, 227))	('ESCC', 'Disease', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('promoter hypomethylation', 'Var', (84, 108))	('FOXO3', 'Gene', (242, 247))	('tumor', 'Disease', (174, 179))	('expression', 'Species', '29278', (49, 59))	('progression', 'CPA', (195, 206))	('tumor', 'Disease', 'MESH:D009369', (174, 179))
483011	30514328	The importance of miRNA functions and dysfunctions in various human cancers suggests that modulation of miRNA expression may serve as a novel diagnostic and therapeutic modality for cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('miRNA', 'Protein', (104, 109))	('dysfunctions', 'Disease', 'MESH:D006331', (38, 50))	('dysfunctions', 'Disease', (38, 50))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('modulation', 'Var', (90, 100))	('expression', 'Species', '29278', (110, 120))	('cancers', 'Disease', (68, 75))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))
483013	30514328	The reduced expression of microRNAs such as miR-138 and miR-145 has been noted in ESCC tissues.	('miR-138', 'Var', (44, 51))	('reduced', 'NegReg', (4, 11))	('ESCC', 'Disease', (82, 86))	('expression', 'Species', '29278', (12, 22))	('expression', 'MPA', (12, 22))	('miR-145', 'Var', (56, 63))
483014	30514328	And miR-21, miR-200c and miR-133a have been reported to be upregulated in esophageal cancer.	('miR-200c', 'Gene', (12, 20))	('miR-200c', 'Gene', '406985', (12, 20))	('miR-21', 'Gene', (4, 10))	('miR-133a', 'Var', (25, 33))	('esophageal cancer', 'Disease', (74, 91))	('upregulated', 'PosReg', (59, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('miR-21', 'Gene', '406991', (4, 10))
483025	30514328	also demonstrated that a high expression level of miR-103/107 in serum was an independent poor prognostic factor in patients with ESCC, as determined by multivariate Cox regression.	('miR-103/107', 'Var', (50, 61))	('ESCC', 'Disease', (130, 134))	('patients', 'Species', '9606', (116, 124))	('expression level', 'MPA', (30, 46))	('expression', 'Species', '29278', (30, 40))
483056	30514328	In conclusion, we observed upregulation of miR-10b-3p in esophageal tissues and demonstrated that miR-10b-3p may act as an independent predictor of OS for ESCC patients; we also discovered the hypomethylation of the promoter of miR-10b-3p is the primary cause for its overexpression.	('expression', 'Species', '29278', (272, 282))	('patients', 'Species', '9606', (160, 168))	('miR-10b-3', 'Gene', '10288', (98, 107))	('miR-10b-3', 'Gene', '10288', (228, 237))	('miR-10b-3', 'Gene', '10288', (43, 52))	('3p', 'Chemical', '-', (51, 53))	('hypomethylation', 'Var', (193, 208))	('miR-10b-3', 'Gene', (228, 237))	('miR-10b-3', 'Gene', (98, 107))	('overexpression', 'PosReg', (268, 282))	('miR-10b-3', 'Gene', (43, 52))	('3p', 'Chemical', '-', (236, 238))	('ESCC', 'Disease', (155, 159))	('3p', 'Chemical', '-', (106, 108))
483149	25989802	The Prognostic Significance of FGFR4 Gly388 Polymorphism in Esophageal Squamous Cell Carcinoma after Concurrent Chemoradiotherapy The purpose of this study is to investigate the role of fibroblast growth factor receptor 4 (FGFR4) polymorphism in esophageal cancer after chemoradiotherapy (CRT).	('FGFR4', 'Gene', (223, 228))	('FGFR4', 'Gene', '2264', (31, 36))	('FGFR4', 'Gene', (31, 36))	('Gly388', 'Chemical', '-', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('Carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Esophageal Squamous Cell Carcinoma', 'Disease', (60, 94))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (60, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (246, 263))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('Gly388', 'Var', (37, 43))	('esophageal cancer', 'Disease', (246, 263))	('fibroblast growth factor receptor 4', 'Gene', (186, 221))	('fibroblast growth factor receptor 4', 'Gene', '2264', (186, 221))	('FGFR4', 'Gene', '2264', (223, 228))	('polymorphism', 'Var', (230, 242))
483153	25989802	However, patients carrying the Gly388 allele showed a better overall response rate than Arg388 carriers (p=0.038).	('patients', 'Species', '9606', (9, 17))	('Gly388', 'Var', (31, 37))	('Arg388', 'Chemical', '-', (88, 94))	('response', 'MPA', (69, 77))	('Gly388', 'Chemical', '-', (31, 37))	('better', 'PosReg', (54, 60))
483154	25989802	In addition, Gly388 allele patients at an earlier stage showed better overall survival (OS) and progression-free survival than Arg388 carriers.	('Arg388', 'Chemical', '-', (127, 133))	('progression-free survival', 'CPA', (96, 121))	('overall survival', 'CPA', (70, 86))	('patients', 'Species', '9606', (27, 35))	('OS', 'Gene', '17451', (88, 90))	('better', 'PosReg', (63, 69))	('Gly388', 'Chemical', '-', (13, 19))	('Gly388 allele', 'Var', (13, 26))
483155	25989802	Among these, the Gly388 allele showed significantly improved OS compared to Arg388 carriers in the lymph node (LN) metastasis group (p=0.042) compared to the no LN metastasis group (p=0.125).	('Gly388', 'Var', (17, 23))	('Arg388', 'Var', (76, 82))	('lymph node', 'CPA', (99, 109))	('improved', 'PosReg', (52, 60))	('Arg388', 'Chemical', '-', (76, 82))	('OS', 'Gene', '17451', (61, 63))	('Gly388', 'Chemical', '-', (17, 23))
483156	25989802	This result suggests that the role of FGFR4 Gly388 in treatment outcomes differs according to esophageal cancer stage.	('FGFR4', 'Gene', '2264', (38, 43))	('Gly388', 'Var', (44, 50))	('esophageal cancer', 'Disease', (94, 111))	('Gly388', 'Chemical', '-', (44, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('FGFR4', 'Gene', (38, 43))
483157	25989802	It showed a predictive role in the response of esophageal cancer patients to CRT with a better trend for OS in Gly388 than Arg388 carriers in the early stages.	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Gly388', 'Var', (111, 117))	('OS', 'Gene', '17451', (105, 107))	('patients', 'Species', '9606', (65, 73))	('esophageal cancer', 'Disease', (47, 64))	('Arg388 carriers', 'Var', (123, 138))	('Gly388', 'Chemical', '-', (111, 117))	('Arg388', 'Chemical', '-', (123, 129))
483158	25989802	In particular, LN-positive early-stage patients carrying the Gly388 allele showed improved OS compared to those carrying Arg388.	('patients', 'Species', '9606', (39, 47))	('Arg388', 'Chemical', '-', (121, 127))	('Gly388', 'Chemical', '-', (61, 67))	('Gly388', 'Var', (61, 67))	('OS', 'Gene', '17451', (91, 93))	('improved', 'PosReg', (82, 90))
483168	25989802	Fibroblast growth factors (FGFs) are divided into four groups (FGF1-4), and dysregulation of their receptors (FGFRs) plays an important role in tumorigenesis.	('tumor', 'Disease', (144, 149))	('FGF1-4', 'Gene', '2259;2246;2247;2248;2249', (63, 69))	('FGF1-4', 'Gene', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('dysregulation', 'Var', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
483171	25989802	An FGFR4 Gly388Arg polymorphism (rs351855), which causes the substitution of arginine for glycine (FGFR4 Arg388) in the transmembrane domain of the receptor, was reported to increase cancer risk, aggressiveness, metastasis, and drug resistance.	('aggressiveness', 'Disease', 'MESH:D001523', (196, 210))	('arginine', 'Chemical', 'MESH:D001120', (77, 85))	('glycine', 'Chemical', 'MESH:D005998', (90, 97))	('FGFR4', 'Gene', (99, 104))	('FGFR4', 'Gene', (3, 8))	('Gly388Arg', 'Var', (9, 18))	('cancer', 'Disease', (183, 189))	('Gly388Arg', 'SUBSTITUTION', 'None', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('drug resistance', 'CPA', (228, 243))	('metastasis', 'CPA', (212, 222))	('rs351855', 'Mutation', 'rs351855', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('aggressiveness', 'Disease', (196, 210))	('increase', 'PosReg', (174, 182))	('aggressiveness', 'Phenotype', 'HP:0000718', (196, 210))	('drug resistance', 'Phenotype', 'HP:0020174', (228, 243))	('FGFR4', 'Gene', '2264', (99, 104))	('Arg388', 'Chemical', '-', (105, 111))	('FGFR4', 'Gene', '2264', (3, 8))
483172	25989802	recently reported a significantly increased risk of head and neck squamous cell carcinoma (HNSCC) with the FGFR4 Gly388 allele, whereas Arg388 resulted in cisplatin sensitivity (p=0.141) in an in vitro assay.	('Gly388', 'Var', (113, 119))	('FGFR4', 'Gene', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (61, 89))	('FGFR4', 'Gene', '2264', (107, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('Gly388', 'Chemical', '-', (113, 119))	('cisplatin sensitivity', 'MPA', (155, 176))	('Arg388', 'Var', (136, 142))	('neck squamous cell carcinoma', 'Disease', (61, 89))	('Arg388', 'Chemical', '-', (136, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
483173	25989802	In addition, Arg388 carriers showed significantly poor survival outcome in head and neck or lung cancer patients.	('lung cancer', 'Disease', (92, 103))	('Arg388', 'Chemical', '-', (13, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('poor', 'NegReg', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('patients', 'Species', '9606', (104, 112))	('Arg388 carriers', 'Var', (13, 28))
483174	25989802	Considering the similar causal factors such as alcohol or smoking and treatment modality of head and neck, lung or esophageal cancer, FGFR4 polymorphism could be a targetable prognostic marker in esophageal cancer, for which there has been no reliable biomarker until now.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung', 'Disease', 'MESH:D008171', (107, 111))	('esophageal cancer', 'Disease', (196, 213))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('lung', 'Disease', (107, 111))	('alcohol', 'Chemical', 'MESH:D000438', (47, 54))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('FGFR4', 'Gene', '2264', (134, 139))	('FGFR4', 'Gene', (134, 139))	('polymorphism', 'Var', (140, 152))
483175	25989802	Thus, we investigated the role of FGFR4 polymorphisms in esophageal squamous cell carcinoma patients who were treated with CRT.	('esophageal squamous cell carcinoma', 'Disease', (57, 91))	('FGFR4', 'Gene', (34, 39))	('polymorphisms', 'Var', (40, 53))	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('investigated', 'Reg', (9, 21))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (57, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('FGFR4', 'Gene', '2264', (34, 39))
483181	25989802	FGFR4 Gly388Arg genotyping was performed using high-resolution melting (HRM) analysis with a Rotor Gene 6000 (Corbett Research, Sydney, Australia).	('FGFR4', 'Gene', (0, 5))	('Gly388Arg', 'SUBSTITUTION', 'None', (6, 15))	('Gly388Arg', 'Var', (6, 15))	('FGFR4', 'Gene', '2264', (0, 5))
483197	25989802	The frequencies of the FGFR4 Gly388Arg polymorphic genotypes were as follows: 94 patients (38.5%) had the Gly388 allele (G/G), 110 (45.4%) were heterozygous for G/A, and 40 (16.4%) had the Arg388 allele (A/A).	('Gly388', 'Chemical', '-', (29, 35))	('Gly388Arg', 'Var', (29, 38))	('Arg388', 'Var', (189, 195))	('Gly388', 'Var', (106, 112))	('Gly388Arg', 'SUBSTITUTION', 'None', (29, 38))	('Arg388', 'Chemical', '-', (189, 195))	('patients', 'Species', '9606', (81, 89))	('Gly388', 'Chemical', '-', (106, 112))	('FGFR4', 'Gene', '2264', (23, 28))	('FGFR4', 'Gene', (23, 28))
483198	25989802	Patients with the G/G allele (91.5%; 95% CI, 82.9 to 95.6) showed significantly better responses to CRT than Arg carriers (82.7%; 95% CI, 75.4 to 88.0; p=0.038) (Table 2).	('G/G', 'Var', (18, 21))	('Patients', 'Species', '9606', (0, 8))	('responses to CRT', 'MPA', (87, 103))	('Arg', 'Chemical', 'MESH:D001120', (109, 112))	('better', 'PosReg', (80, 86))
483199	25989802	However, no significant association was found between the FGFR4 genotype and any clinicopathological parameter examined, including tumor stage, differentiation, and tumor location (Table 1).	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('genotype', 'Var', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('FGFR4', 'Gene', '2264', (58, 63))	('FGFR4', 'Gene', (58, 63))	('tumor', 'Disease', (165, 170))
483203	25989802	In the early stages, patients with the Gly388 allele tended to have somewhat better PFS (unreached median OS [mOS] in G/G, 38 months in Arg388 carriers; 95% CI, 11.9 to 63.9; p=0.506) and OS rates (unreached mOS in G/G, 45 months; 95% CI, 26.1 to 63.5; p=0.773) (Fig.	('better', 'PosReg', (77, 83))	('mOS', 'Gene', (110, 113))	('PFS', 'CPA', (84, 87))	('Arg388', 'Chemical', '-', (136, 142))	('Gly388', 'Chemical', '-', (39, 45))	('OS', 'Gene', '17451', (111, 113))	('patients', 'Species', '9606', (21, 29))	('mOS', 'Gene', '17451', (110, 113))	('mOS', 'Gene', (208, 211))	('OS', 'Gene', '17451', (106, 108))	('Arg388', 'Var', (136, 142))	('OS', 'Gene', '17451', (209, 211))	('OS', 'Gene', '17451', (188, 190))	('mOS', 'Gene', '17451', (208, 211))	('Gly388', 'Var', (39, 45))
483205	25989802	However, patients with advanced stage disease showed similar patterns of PFS (9.6 months in G/G; 95% CI, 6.1 to 13 and 12.6 months in Arg388 carriers; 95% CI, 10.2 to 14.9; p=0.678) and OS (24.7 months in G/G; 95% CI, 19.5 to 29.90 and 22.4 months in Arg388 carriers, 95% CI, 15.3 to 29.5; p=0.668) (Fig.	('patients', 'Species', '9606', (9, 17))	('Arg388 carriers', 'Var', (251, 266))	('Arg388', 'Chemical', '-', (251, 257))	('OS', 'Gene', '17451', (186, 188))	('Arg388', 'Var', (134, 140))	('Arg388', 'Chemical', '-', (134, 140))
483206	25989802	In particular, patients with the Gly388 allele showed a significantly better OS rate than Arg388 carriers in the lymph node (LN) metastasis group (p=0.042) compared to the no LN metastasis group (p=0.125) (Fig.	('patients', 'Species', '9606', (15, 23))	('Arg388', 'Var', (90, 96))	('Gly388', 'Chemical', '-', (33, 39))	('Arg388', 'Chemical', '-', (90, 96))	('better', 'PosReg', (70, 76))	('OS', 'Gene', '17451', (77, 79))	('Gly388', 'Var', (33, 39))
483215	25989802	Studies of FGFR polymorphisms have reported association of Arg388 with increased cancer incidence, tumor size, and recurrence after adjuvant treatment.	('tumor', 'Disease', (99, 104))	('Arg388', 'Var', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('Arg388', 'Chemical', '-', (59, 65))	('cancer', 'Disease', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('FGFR', 'Gene', (11, 15))	('increased', 'PosReg', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('recurrence', 'CPA', (115, 125))	('association', 'Interaction', (44, 55))
483216	25989802	The current study was conducted in order to assess the role of FGFR4 Arg388 in patients treated with CRT for esophageal cancer, which is treated primarily by CRT in inoperable cases.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Arg388', 'Var', (69, 75))	('Arg388', 'Chemical', '-', (69, 75))	('esophageal cancer', 'Disease', (109, 126))	('patients', 'Species', '9606', (79, 87))	('FGFR4', 'Gene', '2264', (63, 68))	('FGFR4', 'Gene', (63, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
483217	25989802	We found that patients with the Gly388 allele showed a significantly better response to CRT than Arg388 carriers, regardless of the cancer stage.	('response to CRT', 'MPA', (76, 91))	('patients', 'Species', '9606', (14, 22))	('Gly388', 'Chemical', '-', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Arg388', 'Chemical', '-', (97, 103))	('better', 'PosReg', (69, 75))	('Gly388', 'Var', (32, 38))	('regardless of the cancer', 'Disease', 'MESH:D009369', (114, 138))	('regardless of the cancer', 'Disease', (114, 138))
483218	25989802	Interestingly, the PFS and OS rates in early esophageal cancer (stages I and II) showed improved survival trends with the Gly388 versus the Arg388 allele.	('Arg388', 'Chemical', '-', (140, 146))	('OS', 'Gene', '17451', (27, 29))	('esophageal cancer', 'Disease', (45, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Gly388', 'Chemical', '-', (122, 128))	('improved', 'PosReg', (88, 96))	('Gly388', 'Var', (122, 128))
483220	25989802	in breast cancer patients, disease-free survival with the Gly388 allele was prolonged significantly compared with the Arg388 allele when patients received adjuvant chemotherapy; however, no difference was observed among patients who underwent adjuvant endocrine therapy.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('Gly388', 'Var', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('patients', 'Species', '9606', (137, 145))	('disease-free survival', 'CPA', (27, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('patients', 'Species', '9606', (220, 228))	('prolonged', 'PosReg', (76, 85))	('Arg388', 'Chemical', '-', (118, 124))	('patients', 'Species', '9606', (17, 25))	('Gly388', 'Chemical', '-', (58, 64))
483225	25989802	Although the difference was not statistically significant, the pattern of survival differed according to stage, showing a tendency to be prolonged in Gly388 versus Arg388 carriers.	('prolonged', 'PosReg', (137, 146))	('Gly388', 'Var', (150, 156))	('Arg388', 'Chemical', '-', (164, 170))	('Gly388', 'Chemical', '-', (150, 156))	('Arg388', 'Var', (164, 170))
483226	25989802	In addition, in early esophageal cancer patients with LN invasion, significantly improved OS was observed in patients with the Gly388 allele compared to Arg388 carriers.	('improved', 'PosReg', (81, 89))	('OS', 'Gene', '17451', (90, 92))	('patients', 'Species', '9606', (109, 117))	('Gly388', 'Var', (127, 133))	('patients', 'Species', '9606', (40, 48))	('Arg388', 'Chemical', '-', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Gly388', 'Chemical', '-', (127, 133))	('esophageal cancer', 'Disease', (22, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))
483230	25989802	Taken together, the current data suggest that targeted therapy for FGFR4 could be more effective at earlier rather than more advanced stages of esophageal cancer, and that another treatment approach is needed for patients carrying Arg388 in order to improve the treatment outcome.	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('FGFR4', 'Gene', '2264', (67, 72))	('FGFR4', 'Gene', (67, 72))	('Arg388', 'Var', (231, 237))	('patients', 'Species', '9606', (213, 221))	('Arg388', 'Chemical', '-', (231, 237))	('esophageal cancer', 'Disease', (144, 161))
483231	25989802	Unexpectedly, a better trend of OS was observed in Gly388 with LN invasion patients compared to Gly388 without LN invasion patients.	('Gly388', 'Chemical', '-', (51, 57))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (123, 131))	('OS', 'Gene', '17451', (32, 34))	('Gly388', 'Var', (51, 57))	('LN invasion', 'Disease', (63, 74))	('Gly388', 'Chemical', '-', (96, 102))
483234	25989802	The molecular mechanism by which the FGFR4 Arg388 polymorphism leads to a more aggressive clinical phenotype is not yet fully understood.	('leads to', 'Reg', (63, 71))	('FGFR4', 'Gene', (37, 42))	('FGFR4', 'Gene', '2264', (37, 42))	('Arg388', 'Var', (43, 49))	('Arg388', 'Chemical', '-', (43, 49))
483236	25989802	showed that the FGFR4 Arg388 polymorphism induced overexpression of FGFR and that this could attenuate the response to chemotherapy.	('FGFR', 'Protein', (68, 72))	('overexpression', 'PosReg', (50, 64))	('FGFR4', 'Gene', '2264', (16, 21))	('Arg388', 'Var', (22, 28))	('FGFR4', 'Gene', (16, 21))	('attenuate', 'NegReg', (93, 102))	('Arg388', 'Chemical', '-', (22, 28))	('response to chemotherapy', 'CPA', (107, 131))
483237	25989802	A similar result was reported in a gastric cancer model showing that an FGFR4 inhibitor and 5-FU reduced proliferation and promoted apoptosis.	('apoptosis', 'CPA', (132, 141))	('FGFR4', 'Gene', '2264', (72, 77))	('FGFR4', 'Gene', (72, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))	('promoted', 'PosReg', (123, 131))	('reduced', 'NegReg', (97, 104))	('proliferation', 'CPA', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('gastric cancer', 'Disease', (35, 49))	('inhibitor', 'Var', (78, 87))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))
483238	25989802	For HNSCC, the association between CRT and FGFR4 was evaluated in vitro, showing increased sensitivity of cells containing the Arg388 allele to cisplatin, which differs from our observations.	('Arg388', 'Var', (127, 133))	('Arg388', 'Chemical', '-', (127, 133))	('FGFR4', 'Gene', '2264', (43, 48))	('FGFR4', 'Gene', (43, 48))	('increased', 'PosReg', (81, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))	('sensitivity', 'MPA', (91, 102))
483239	25989802	In contrast to various results primarily from in vitro studies, there is a lack of clear evidence for any relationship between the FGFR4 Arg388 genotype and protein expression or clinicopathological parameters in cancer patients However, the FGFR4 Gly388 allele has been reported as a prognostic marker for survival in breast and gastric cancer patients.	('gastric cancer', 'Disease', (330, 344))	('cancer', 'Disease', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Gly388', 'Chemical', '-', (248, 254))	('FGFR4', 'Gene', '2264', (131, 136))	('Arg388', 'Chemical', '-', (137, 143))	('FGFR4', 'Gene', (131, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (330, 344))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('FGFR4', 'Gene', '2264', (242, 247))	('Gly388', 'Var', (248, 254))	('FGFR4', 'Gene', (242, 247))	('patients', 'Species', '9606', (220, 228))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('gastric cancer', 'Disease', 'MESH:D013274', (330, 344))	('patients', 'Species', '9606', (345, 353))
483240	25989802	The lack of correlation between genotype and phenotype for FGFR4 may be explained in part by the lack of elevated tyrosine phosphorylation of FGFR4 Arg388 compared with FGFR4 Gly388, the use of different intracellular signal transduction pathway(s) or interactions with different cell surface protein(s), or linkage disequilibrium with other genetic changes that also contribute to a poor prognosis.	('FGFR4', 'Gene', (59, 64))	('interactions', 'Interaction', (252, 264))	('FGFR4', 'Gene', '2264', (142, 147))	('elevated', 'PosReg', (105, 113))	('FGFR4', 'Gene', (142, 147))	('tyrosine', 'Chemical', 'MESH:D014443', (114, 122))	('tyrosine phosphorylation', 'MPA', (114, 138))	('Arg388', 'Var', (148, 154))	('elevated tyrosine', 'Phenotype', 'HP:0003231', (105, 122))	('lack', 'NegReg', (97, 101))	('FGFR4', 'Gene', '2264', (169, 174))	('FGFR4', 'Gene', (169, 174))	('Gly388', 'Chemical', '-', (175, 181))	('Arg388', 'Chemical', '-', (148, 154))	('FGFR4', 'Gene', '2264', (59, 64))
483241	25989802	To the best of our knowledge, this is the first report describing a predictive role for FGFR4 Arg388 after CRT.	('FGFR4', 'Gene', (88, 93))	('Arg388', 'Var', (94, 100))	('FGFR4', 'Gene', '2264', (88, 93))	('Arg388', 'Chemical', '-', (94, 100))
483242	25989802	The biochemical effects of FGFR4 Arg388 with regard to chemotherapy should be evaluated in future studies including other biomarkers.	('Arg388', 'Var', (33, 39))	('FGFR4', 'Gene', '2264', (27, 32))	('FGFR4', 'Gene', (27, 32))	('Arg388', 'Chemical', '-', (33, 39))
483246	25989802	Although the FGFR4 polymorphism examined in this study is not a significant prognostic factor in esophageal cancer treated with CRT, esophageal cancer patients carrying FGFR4 Gly388 showed a good response after CRT.	('Gly388', 'Var', (175, 181))	('FGFR4', 'Gene', '2264', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('esophageal cancer', 'Disease', (97, 114))	('patients', 'Species', '9606', (151, 159))	('FGFR4', 'Gene', '2264', (169, 174))	('FGFR4', 'Gene', (169, 174))	('Gly388', 'Chemical', '-', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('FGFR4', 'Gene', (13, 18))
483247	25989802	Especially in early esophageal cancer, the Gly388 allele resulted in increased OS and PFS, and select patients showing LN invasion showed significant prolonged OS compared to Arg388 carriers.	('esophageal cancer', 'Disease', (20, 37))	('prolonged', 'PosReg', (150, 159))	('increased', 'PosReg', (69, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('OS', 'Gene', '17451', (79, 81))	('Gly388', 'Chemical', '-', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('patients', 'Species', '9606', (102, 110))	('PFS', 'CPA', (86, 89))	('OS', 'Gene', '17451', (160, 162))	('Gly388', 'Var', (43, 49))	('Arg388', 'Chemical', '-', (175, 181))
483250	23874846	Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers.	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (124, 154))	('EGFR', 'Gene', (99, 103))	('gastric cancers', 'Phenotype', 'HP:0012126', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('germline genetic variants', 'Var', (66, 91))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('EGFR', 'Gene', '1956', (99, 103))
483251	23874846	Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs), 1758 gastric cancers (GCs), and 2111 controls.	('EGFR', 'Gene', (112, 116))	('gastric cancers', 'Disease', (184, 199))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (134, 169))	('GCs', 'Phenotype', 'HP:0012126', (201, 204))	('gastric cancers', 'Phenotype', 'HP:0012126', (184, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('GC', 'Phenotype', 'HP:0012126', (201, 203))	('EGFR', 'Gene', '1956', (112, 116))	('SNPs', 'Var', (87, 91))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (145, 169))	('gastric cancers', 'Disease', 'MESH:D013274', (184, 199))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('esophageal squamous cell carcinomas', 'Disease', (134, 169))
483254	23874846	Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC.	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('ESCC', 'Disease', (104, 108))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('genes', 'Var', (49, 54))
483260	23874846	Several studies have also revealed somatic mutations of genes in the EGFR family in esophageal and gastric cancers.	('EGFR', 'Gene', '1956', (69, 73))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (84, 114))	('gastric cancers', 'Phenotype', 'HP:0012126', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('EGFR', 'Gene', (69, 73))	('mutations', 'Var', (43, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
483262	23874846	Given the significance of this pathway, genetic variations in EGFR signaling proteins could correlate with predisposition to esophageal and gastric cancers.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('EGFR', 'Gene', '1956', (62, 66))	('correlate', 'Reg', (92, 101))	('gastric cancers', 'Phenotype', 'HP:0012126', (140, 155))	('genetic variations', 'Var', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('EGFR', 'Gene', (62, 66))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (125, 155))
483264	23874846	Based on our GWAS data in ethnic Chinese subjects, we comprehensively evaluated associations between genetic variants in the EGFR pathway and the risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC) in 1942 ESCC cases, 1758 GC cases (1126 cases of gastric cardia cancer (GCA) and 632 of gastric noncardia cancer (GNCA)), and 2111 controls living in the Taihang Mountain region of China, an area with a high risk of ESCC and GC.	('gastric cardia cancer', 'Disease', (269, 290))	('ESCC', 'Disease', (228, 232))	('esophageal squamous cell carcinoma', 'Disease', (154, 188))	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('GC', 'Phenotype', 'HP:0012126', (216, 218))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('GC', 'Phenotype', 'HP:0012126', (445, 447))	('EGFR', 'Gene', '1956', (125, 129))	('GC', 'Phenotype', 'HP:0012126', (292, 294))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (154, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('GC', 'Phenotype', 'HP:0012126', (245, 247))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('gastric noncardia cancer', 'Disease', 'MESH:D013274', (308, 332))	('associations', 'Interaction', (80, 92))	('variants', 'Var', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('gastric noncardia cancer', 'Disease', (308, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('gastric cancer', 'Disease', (200, 214))	('EGFR', 'Gene', (125, 129))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (269, 290))
483284	23874846	The most significant SNP in GNAI3 was the same for ESCC and GCA (rs1434285), but the most significant SNPs in CHRNE were different for ESCC (rs8081611) and GCA (rs3760490), and these two SNPs were not in high LD (r2 = 0.007).	('GC', 'Phenotype', 'HP:0012126', (60, 62))	('rs3760490', 'Mutation', 'rs3760490', (161, 170))	('rs3760490', 'Var', (161, 170))	('rs8081611', 'Mutation', 'rs8081611', (141, 150))	('rs8081611', 'Var', (141, 150))	('GC', 'Phenotype', 'HP:0012126', (156, 158))	('rs1434285', 'Mutation', 'rs1434285', (65, 74))	('rs1434285', 'Var', (65, 74))
483286	23874846	Although none of the SNPs exceeded the significance level after correcting for multiple comparisons, at a reduced threshold of 0.001, rs1884361 (NRG3) was associated with ESCC risk, and rs9387033 (FYN), rs9788973 (MAP2K4), rs7187863 (PLCG2), and rs7720677 (PRLR) were associated with GC risk.	('FYN', 'Gene', (197, 200))	('rs7720677', 'Var', (246, 255))	('associated', 'Reg', (268, 278))	('rs7187863', 'Mutation', 'rs7187863', (223, 232))	('associated', 'Reg', (155, 165))	('rs9788973', 'Var', (203, 212))	('ESCC', 'Disease', (171, 175))	('FYN', 'Gene', '2534', (197, 200))	('rs9387033', 'Var', (186, 195))	('rs9387033', 'Mutation', 'rs9387033', (186, 195))	('rs1884361', 'Var', (134, 143))	('GC', 'Phenotype', 'HP:0012126', (284, 286))	('rs7720677', 'Mutation', 'rs7720677', (246, 255))	('rs7187863', 'Var', (223, 232))	('rs1884361', 'Mutation', 'rs1884361', (134, 143))	('rs9788973', 'Mutation', 'rs9788973', (203, 212))
483287	23874846	We also identified a correlation for rs549386 (TGFA) with GCA, as well as correlation for rs16947307 and rs9923225 (both in WWOX) with GNCA.	('rs16947307', 'Mutation', 'rs16947307', (90, 100))	('rs549386', 'Mutation', 'rs549386', (37, 45))	('rs9923225', 'Var', (105, 114))	('rs16947307', 'Var', (90, 100))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('rs9923225', 'Mutation', 'rs9923225', (105, 114))	('GCA', 'Disease', (58, 61))	('rs549386', 'Var', (37, 45))	('TGFA', 'Protein', (47, 51))	('correlation', 'Reg', (21, 32))
483288	23874846	Somatic mutations and altered regulation of EGFR pathway genes have been widely implicated in the development and prognosis of esophageal and gastric cancers.	('implicated', 'Reg', (80, 90))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('regulation', 'MPA', (30, 40))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (127, 157))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('altered', 'Var', (22, 29))	('gastric cancers', 'Phenotype', 'HP:0012126', (142, 157))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
483289	23874846	In contrast, it is less clear whether germline genetic variants in the EGFR pathway are associated with these cancers.	('cancers', 'Disease', (110, 117))	('germline genetic variants', 'Var', (38, 63))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('EGFR', 'Gene', '1956', (71, 75))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('associated', 'Reg', (88, 98))	('EGFR', 'Gene', (71, 75))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
483294	23874846	One previous study suggested an association between rs11184738 (PRMT6, located in 1p13.3) and ESCC risk in a GWAS scan but not in the validation stage.	('rs11184738', 'Var', (52, 62))	('rs11184738', 'Mutation', 'rs11184738', (52, 62))	('PRMT6', 'Gene', (64, 69))	('ESCC', 'Disease', (94, 98))
483295	23874846	GNAI3 is located 2.3 Mbps downstream of PRMT6, and the top SNP in GNAI3 (rs1434285) was not in high LD with rs11184738 in our GWAS dataset (r2<0.01).	('rs11184738', 'Mutation', 'rs11184738', (108, 118))	('rs1434285', 'Mutation', 'rs1434285', (73, 82))	('rs1434285', 'Var', (73, 82))	('rs11184738', 'Var', (108, 118))
483296	23874846	One GWAS reported that rs17761864 (SMG6, located in 17p13.3) was associated with risk of ESCC, but SMG6 is located more than 2.5 Mbps downstream from CHRNE.	('associated', 'Reg', (65, 75))	('rs17761864', 'Var', (23, 33))	('ESCC', 'Disease', (89, 93))	('rs17761864', 'Mutation', 'rs17761864', (23, 33))
483300	23874846	The EGFR family has been found to be upregulated and is the target of somatic mutations in UGI cancers, and a clinical trial indicated improved cancer prognosis for therapies targeting the EGFR family.	('EGFR', 'Gene', '1956', (189, 193))	('upregulated', 'PosReg', (37, 48))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('EGFR', 'Gene', (4, 8))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('EGFR', 'Gene', (189, 193))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (95, 101))	('UGI cancers', 'Disease', 'MESH:D009369', (91, 102))	('mutations', 'Var', (78, 87))	('UGI cancers', 'Disease', (91, 102))	('cancer', 'Disease', (144, 150))	('improved', 'PosReg', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('EGFR', 'Gene', '1956', (4, 8))
483303	23874846	In our study, we used prior biological knowledge to systematically investigate associations between genes in the EGFR pathway and risk of ESCC and GC in a high-risk population in north central China.	('associations', 'Interaction', (79, 91))	('GC', 'Phenotype', 'HP:0012126', (147, 149))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('genes', 'Var', (100, 105))	('ESCC', 'Disease', (138, 142))
483304	23874846	To our knowledge, this is the first study to comprehensively investigate the role of genetic variation in EGFR pathway genes and risk of UGI cancers.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('UGI cancers', 'Disease', 'MESH:D009369', (137, 148))	('EGFR', 'Gene', '1956', (106, 110))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('genetic variation', 'Var', (85, 102))	('UGI cancers', 'Disease', (137, 148))	('EGFR', 'Gene', (106, 110))
483388	19931663	In multivariable regression analysis examining the likelihood of tumor recurrence, patients with a partial response or non-response to neoadjuvant therapy were 1.97 and 2.23 times more likely to develop tumor recurrence compared to CR patients.	('develop', 'PosReg', (195, 202))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (65, 70))	('patients', 'Species', '9606', (235, 243))	('patients', 'Species', '9606', (83, 91))	('CR', 'Chemical', '-', (232, 234))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('non-response', 'Var', (119, 131))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
483467	20546628	Three precursor peptides of m/z 857.4628, 1399.7379 and 2511.1833 were confirmed as the tryptic peptides of galectin-7.	('m/z 857.4628', 'Var', (28, 40))	('peptides', 'Chemical', 'MESH:D010455', (96, 104))	('galectin-7', 'Gene', '3963', (108, 118))	('galectin-7', 'Gene', (108, 118))	('2511.1833', 'Var', (56, 65))	('peptides', 'Chemical', 'MESH:D010455', (16, 24))	('1399.7379', 'Var', (42, 51))
483468	20546628	The amino acid sequences of these peptides identified by MS/MS were "76GPGVPFQR83", "100AVVGDAQYHHFR111", and "33FHVNLLCGEEQGSDAALHFNPR54".	('33FHVNLLCGEEQGSDAALHFNPR54', 'Var', (111, 137))	('peptides', 'Chemical', 'MESH:D010455', (34, 42))	('100AVVGDAQYHHFR111', 'Var', (85, 103))
483498	20546628	Galectin-7 expression can be induced by p53 transfection in a human colon carcinoma cell line.	('Galectin-7', 'Gene', '3963', (0, 10))	('transfection', 'Var', (44, 56))	('colon carcinoma', 'Disease', 'MESH:D015179', (68, 83))	('induced', 'Reg', (29, 36))	('colon carcinoma', 'Disease', (68, 83))	('human', 'Species', '9606', (62, 67))	('expression', 'MPA', (11, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('p53', 'Gene', (40, 43))	('Galectin-7', 'Gene', (0, 10))	('p53', 'Gene', '7157', (40, 43))
483557	33786159	In so doing, the overall reflux risk, defined as abnormal esophageal acid exposure on ambulatory pH-impedance testing, was observed in 15% and 23% of the patients following PD and LHM respectively (p = 0.28).	('patients', 'Species', '9606', (154, 162))	('esophageal acid exposure', 'MPA', (58, 82))	('LHM', 'Var', (180, 183))	('PD', 'Disease', 'MESH:D010300', (173, 175))	('reflux', 'Disease', (25, 31))
483569	33786159	Esophagitis of various degrees is commonly encountered in patients with treated achalasia; however, pH-impedance monitoring can reveal that pathological esophageal acid exposure can be due to mechanisms other than prototypical reflux episodes.	('esophageal acid exposure', 'MPA', (153, 177))	('achalasia', 'Disease', (80, 89))	('achalasia', 'Disease', 'MESH:D004931', (80, 89))	('Esophagitis', 'Phenotype', 'HP:0100633', (0, 11))	('pathological', 'Var', (140, 152))	('reflux episodes', 'Phenotype', 'HP:0002020', (227, 242))	('achalasia', 'Phenotype', 'HP:0002571', (80, 89))	('patients', 'Species', '9606', (58, 66))
483652	33634028	RING1 overexpression leads to cellular transformation via enhancing the expression of the proto-oncogenes, c-jun, and c-fos.	('c-fos', 'Gene', (118, 123))	('overexpression', 'Var', (6, 20))	('RING1', 'Gene', (0, 5))	('cellular transformation', 'CPA', (30, 53))	('expression', 'MPA', (72, 82))	('enhancing', 'PosReg', (58, 67))	('c-jun', 'Gene', '3725', (107, 112))	('c-jun', 'Gene', (107, 112))	('c-fos', 'Gene', '2353', (118, 123))	('RING1', 'Gene', '6015', (0, 5))
483657	33634028	In this study, the dysregulation of RING1 was observed in multiple types of cancers and was associated with poor outcomes.	('dysregulation', 'Var', (19, 32))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('observed', 'Reg', (46, 54))	('cancers', 'Disease', (76, 83))	('RING1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('RING1', 'Gene', '6015', (36, 41))	('associated', 'Reg', (92, 102))
483665	33634028	In this study, Kaplan-Meier plotter in breast cancer or Pan-cancer was used to detect the OS, RFS, and DMFS of RING1 to explore its prognostic value in human cancers.	('RFS', 'Gene', '65211', (94, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('RING1', 'Gene', '6015', (111, 116))	('DMFS', 'Var', (103, 107))	('Pan-cancer', 'Disease', (56, 66))	('RFS', 'Gene', (94, 97))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('human', 'Species', '9606', (152, 157))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('Pan-cancer', 'Disease', 'MESH:D009369', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('breast cancer', 'Disease', (39, 52))	('RING1', 'Gene', (111, 116))
483683	33634028	The Kaplan-Meier curve and log-rank test results revealed that patients with high RING1 mRNA expression level have higher OS (overall survival) compared to the low expression group ( Figure 1C ).	('RING1', 'Gene', (82, 87))	('high', 'Var', (77, 81))	('patients', 'Species', '9606', (63, 71))	('RING1', 'Gene', '6015', (82, 87))	('higher', 'PosReg', (115, 121))
483702	33634028	The univariate analysis showed that ER (P = 0.008), P53 (P = 0.013), and RING1 (P = 0.015) were protective factors in breast cancer prognosis, while Her-2 was a risk factor.	('RING1', 'Gene', (73, 78))	('Her-2', 'Gene', '2064', (149, 154))	('ER', 'Gene', '2069', (36, 38))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Her-2', 'Gene', (149, 154))	('P53', 'Var', (52, 55))	('RING1', 'Gene', '6015', (73, 78))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
483724	33634028	Cancer is considered a genetic disease, in which abnormal gene expression causes tumor cells to lose normal characteristics.	('genetic disease', 'Disease', 'MESH:D030342', (23, 38))	('genetic disease', 'Disease', (23, 38))	('abnormal gene expression', 'Var', (49, 73))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('lose', 'NegReg', (96, 100))	('tumor', 'Disease', (81, 86))
483735	33634028	For cancer, recent studies have shown that the abnormal gene expression of RING1 leads to the development of a variety of cancers.	('leads to', 'Reg', (81, 89))	('RING1', 'Gene', (75, 80))	('abnormal gene expression', 'Var', (47, 71))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('RING1', 'Gene', '6015', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('cancer', 'Disease', (4, 10))
483752	33634028	found that RING1 overexpression promotes colony formation, cell multiplication and invasion of hepatic progenitor cells (HPCs), and that it also drives their malignant transformation by activating the Wnt/beta-catenin signal pathway.	('RING1', 'Gene', '6015', (11, 16))	('overexpression', 'Var', (17, 31))	('cell multiplication', 'CPA', (59, 78))	('beta-catenin', 'Gene', (205, 217))	('malignant transformation', 'CPA', (158, 182))	('beta-catenin', 'Gene', '1499', (205, 217))	('invasion', 'CPA', (83, 91))	('drives', 'PosReg', (145, 151))	('colony formation', 'CPA', (41, 57))	('activating', 'PosReg', (186, 196))	('RING1', 'Gene', (11, 16))	('promotes', 'PosReg', (32, 40))
483781	32284773	In 2016, further supporting the theory of a genetic component, Fecteau et al were able to identify a germline mutation associated with a subset of patients with EAC.	('associated with', 'Reg', (119, 134))	('EAC', 'Phenotype', 'HP:0011459', (161, 164))	('patients', 'Species', '9606', (147, 155))	('EAC', 'Disease', (161, 164))	('mutation', 'Var', (110, 118))
483785	32284773	Namely, consumption of hot beverages, nitrosamine (seen in processed meats), red meat, and micronutrient deficiencies (beta-carotene, folate, vitamin C, vitamin E and riboflavin) have all been linked with a higher risk of ESCC.	('nitrosamine', 'Chemical', 'MESH:D009602', (38, 49))	('vitamin C', 'Chemical', 'MESH:D001205', (142, 151))	('ESCC', 'Disease', (222, 226))	('linked', 'Reg', (193, 199))	('deficiencies', 'Var', (105, 117))	('beta-carotene', 'Chemical', 'MESH:D019207', (119, 132))	('vitamin E', 'Chemical', 'MESH:D014810', (153, 162))	('riboflavin', 'Chemical', 'MESH:D012256', (167, 177))	('folate', 'Chemical', 'MESH:D005492', (134, 140))
483874	31822974	DW-MRI during the second week of neoadjuvant chemoradiotherapy is most predictive for pathologic complete response in esophageal cancer.	('DW-MRI', 'Var', (0, 6))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('esophageal cancer', 'Disease', (118, 135))
483901	31822974	based on signal reduction on the b800 DW-MRI scans and tumor regression on the tT2W scans using in-house-developed delineation software.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('reduction', 'NegReg', (16, 25))	('tumor', 'Disease', (55, 60))	('b800 DW-MRI', 'Var', (33, 44))	('signal', 'MPA', (9, 15))
483929	31822974	A predictive probability plot for pCR based on DeltaADC(%) from baseline to week 2 for squamous cell carcinomas and adenocarcinomas is presented in Fig.	('pCR', 'Disease', (34, 37))	('adenocarcinomas', 'Disease', 'MESH:D000230', (116, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('adenocarcinomas', 'Disease', (116, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('DeltaADC', 'Var', (47, 55))	('squamous cell carcinomas', 'Disease', (87, 111))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (87, 111))	('DeltaADC', 'Chemical', '-', (47, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (87, 111))
483942	31822974	Previous studies focusing on DW-MRI scanning in response prediction for esophageal cancer have mostly demonstrated promising findings regarding the predictive value of DeltaADC(%) for response prediction to nCRT.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('DeltaADC', 'Var', (168, 176))	('DeltaADC', 'Chemical', '-', (168, 176))
483955	31822974	A recent meta-analysis demonstrated a pooled AUC of 0.91 (95% CI 0.89-0.94) of DeltaADC(%) values for treatment response prediction in esophageal cancer based on four studies.	('DeltaADC', 'Var', (79, 87))	('esophageal cancer', 'Disease', (135, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('DeltaADC', 'Chemical', '-', (79, 87))
483958	31822974	Exclusion of the aforementioned patients dramatically improved the performance of DeltaADC(%) for pCR prediction, resulting in a c-statistic of 0.97 for week 2.	('patients', 'Species', '9606', (32, 40))	('DeltaADC', 'Var', (82, 90))	('DeltaADC', 'Chemical', '-', (82, 90))	('improved', 'PosReg', (54, 62))	('pCR', 'Disease', (98, 101))
483990	32131772	Lymphatic vessels are believed to play a crucial role in LNM and their presence increases the micro-metastatic risk in locoregional malignancy.	('locoregional malignancy', 'Disease', 'MESH:D009364', (119, 142))	('presence', 'Var', (71, 79))	('micro-metastatic', 'CPA', (94, 110))	('locoregional malignancy', 'Disease', (119, 142))
484018	32131772	.Reports state that patients with T0 (0% chance) or T1a (1-2% chance) esophageal cancer have a minimal risk of local LNM.	('local LNM', 'Disease', (111, 120))	('T1a', 'Var', (52, 55))	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
484027	32131772	Current research has demonstrated that patients with T1b esophageal cancers without LVI have a significantly higher survival rate up to 5 years higher those with LVI.	('T1b', 'Var', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (39, 47))	('survival', 'CPA', (116, 124))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('higher', 'PosReg', (109, 115))	('esophageal cancers', 'Disease', (57, 75))	('esophageal cancers', 'Disease', 'MESH:D004938', (57, 75))
484028	32131772	Our study shows that SEC patients with LVI have a poor OS (HR = 1.62, 95% CI: 1.17-2.26, P = 0.004, I2 = 0.0%), and LVI significantly increases the risk of LNM in SEC (univariate: OR = 5.26, 95% CI: 4-6.91, P < 0.0001, I2 = 30.2%; multivariate: OR = 5.7, 95% CI:4.43-7.33, P < 0.0001; I2 = 16%).	('SE', 'Disease', 'None', (163, 165))	('OS', 'Chemical', '-', (55, 57))	('EC', 'Phenotype', 'HP:0011459', (22, 24))	('LNM', 'Disease', (156, 159))	('EC', 'Phenotype', 'HP:0011459', (164, 166))	('EC', 'Disease', 'MESH:D004938', (22, 24))	('patients', 'Species', '9606', (25, 33))	('LVI', 'Var', (116, 119))	('EC', 'Disease', 'MESH:D004938', (164, 166))	('increases', 'PosReg', (134, 143))	('SE', 'Disease', 'None', (21, 23))
484073	30697605	Regarding tumor depth, clinically T1 esophageal cancers were reported to be suitable for SN mapping.10, 11, 26 In contrast, clinically T3/T4 tumors may cause higher false-negative rates in SN mapping because original lymphatic drainage routes might be changed according to the tumor progression of esophageal cancer.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('SN mapping', 'MPA', (189, 199))	('esophageal cancer', 'Disease', (298, 315))	('false-negative', 'MPA', (165, 179))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('esophageal cancers', 'Disease', (37, 55))	('tumor', 'Disease', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('T3/T4', 'Var', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Disease', (141, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (298, 315))	('esophageal cancers', 'Disease', 'MESH:D004938', (37, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
484076	30697605	Mean number of identified SN was 4.7 per case in our study, but SN mapping was feasible even during thoracoscopic esophagectomy.12 In our study, the distribution of SN showed a wide spread from cervical to abdominal areas.12 In upper thoracic esophageal cancer, SN were frequently identified in the lymph nodes along the bilateral recurrent laryngeal nerve chain (stations #106recR and #106recL in the Japanese guidelines) and lymph nodes in the cervical area.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('#106recL', 'Var', (386, 394))	('laryngeal nerve chain', 'Phenotype', 'HP:0005950', (341, 362))	('upper thoracic esophageal cancer', 'Disease', 'MESH:D004938', (228, 260))	('upper thoracic esophageal cancer', 'Disease', (228, 260))
484078	30697605	In particular, SN were frequently identified in the stations #106recR and #106recL, bifurcational and main bronchus lymph nodes (stations #107 and #109), and middle thoracic paraesophageal nodes (station #108) in middle thoracic esophageal cancer.	('middle thoracic paraesophageal nodes', 'Disease', (158, 194))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('#106recL', 'Var', (74, 82))	('middle thoracic esophageal cancer', 'Disease', 'MESH:D004938', (213, 246))	('middle thoracic paraesophageal nodes', 'Disease', 'MESH:D020244', (158, 194))	('middle thoracic esophageal cancer', 'Disease', (213, 246))
484083	30697605	Moreover, disease-specific survival of the patients with metastatic non-SN was significantly worse than that of the patients with no lymph node metastasis or lymph node metastasis in SN only.	('metastatic', 'Var', (57, 67))	('patients', 'Species', '9606', (43, 51))	('disease-specific survival', 'CPA', (10, 35))	('worse', 'NegReg', (93, 98))	('patients', 'Species', '9606', (116, 124))
484084	30697605	This study demonstrated that SN mapping is useful not only as an accurate diagnostic tool for detecting lymph node metastasis but also for prognostic stratification in patients with cN0 early esophageal cancer.	('cN0', 'Var', (182, 185))	('lymph node metastasis', 'CPA', (104, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (192, 209))	('tin', 'Chemical', 'MESH:D014001', (99, 102))	('patients', 'Species', '9606', (168, 176))	('esophageal cancer', 'Disease', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
484106	30697605	In addition, further investigations should clarify the feasibility and efficacy of novel esophagus-preserving treatments, such as endoscopic submucosal dissection in patients with cT1b esophageal SCC or in EG junction cancer patients having pathologically negative SN confirmed by thoracoscopic or laparoscopic SN mapping and biopsy (Figure 3).	('SCC', 'Gene', (196, 199))	('patients', 'Species', '9606', (225, 233))	('SCC', 'Phenotype', 'HP:0002860', (196, 199))	('SCC', 'Gene', '6317', (196, 199))	('EG junction cancer', 'Disease', 'MESH:D009369', (206, 224))	('cT1b', 'Var', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('EG junction cancer', 'Disease', (206, 224))	('patients', 'Species', '9606', (166, 174))
484112	30697605	The incidence of lymph node metastasis is relatively high even in cN0 early-stage esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('cN0', 'Var', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('esophageal cancer', 'Disease', (82, 99))
484142	27731378	Furthermore, several studies found that AMPK activation can sensitize cancer cells to TRAIL-induced apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('TRAIL', 'Gene', '8743', (86, 91))	('AMPK activation', 'Var', (40, 55))	('sensitize', 'Reg', (60, 69))	('TRAIL', 'Gene', (86, 91))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
484196	27731378	To confirm the direct involvement of CHOP in the thapsigargin-mediated transcriptional activation of DR5, we used two luciferase reporter plasmids: pDR5-WT, which contained the DR5 promoter sequence -605/+3, and pDR5-mCHOP, which contained the same promoter sequence with mutation of the potential CHOP-binding site (-281 to -261).	('-281', 'Var', (317, 321))	('DR5', 'Gene', (149, 152))	('DR5', 'Gene', (177, 180))	('DR5', 'Gene', '8795', (149, 152))	('mCHOP', 'Gene', '13198', (217, 222))	('DR5', 'Gene', (101, 104))	('DR5', 'Gene', '8795', (101, 104))	('mCHOP', 'Gene', (217, 222))	('DR5', 'Gene', '8795', (177, 180))	('thapsigargin', 'Chemical', 'MESH:D019284', (49, 61))	('men', 'Species', '9606', (29, 32))	('DR5', 'Gene', (213, 216))	('DR5', 'Gene', '8795', (213, 216))
484201	27731378	DR5 silencing antagonized thapsigargin-dependent sensitization to TRAIL in EC109 and TE12 cells, as evidenced by significantly increased cell viability (Fig.	('antagonized', 'NegReg', (14, 25))	('DR5', 'Gene', (0, 3))	('sensitization', 'MPA', (49, 62))	('TRAIL', 'Gene', '8743', (66, 71))	('thapsigargin', 'Chemical', 'MESH:D019284', (26, 38))	('DR5', 'Gene', '8795', (0, 3))	('EC109', 'CellLine', 'CVCL:6898', (75, 80))	('TE12', 'CellLine', 'CVCL:1762', (85, 89))	('TRAIL', 'Gene', (66, 71))	('silencing', 'Var', (4, 13))	('increased', 'PosReg', (127, 136))	('cell viability', 'CPA', (137, 151))
484208	27731378	To investigate the activation of AMPK in thapsigargin-induced TRAIL sensitization, EC109 and TE12 cells were treated with Compound C (an AMPK-specific inhibitor) and AMPK siRNA to inhibit the AMPK phosphorylation and reduce AMPK production, respectively.	('EC109', 'CellLine', 'CVCL:6898', (83, 88))	('TRAIL', 'Gene', '8743', (62, 67))	('inhibit', 'NegReg', (180, 187))	('reduce', 'NegReg', (217, 223))	('thapsigargin', 'Chemical', 'MESH:D019284', (41, 53))	('TRAIL', 'Gene', (62, 67))	('AMPK production', 'MPA', (224, 239))	('AMPK', 'Var', (166, 170))	('AMPK phosphorylation', 'MPA', (192, 212))	('TE12', 'CellLine', 'CVCL:1762', (93, 97))
484235	27731378	indicate that modulation of the unfolded protein response mediated by thapsigargin might be useful in sensitizing melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL receptor.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('up-regulation', 'PosReg', (159, 172))	('modulation', 'Var', (14, 24))	('TRAIL', 'Gene', '8743', (176, 181))	('TRAIL', 'Gene', '8743', (132, 137))	('TRAIL', 'Gene', (176, 181))	('thapsigargin', 'Chemical', 'MESH:D019284', (70, 82))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('TRAIL', 'Gene', (132, 137))	('melanoma', 'Disease', (114, 122))
484243	27731378	In vitro siRNA-mediated silencing of the ERS response protein CHOP, as well as DR5 siRNA, significantly reduced thapsigargin or TRAIL-induced cell death.	('thapsigargin', 'Chemical', 'MESH:D019284', (112, 124))	('reduced', 'NegReg', (104, 111))	('DR5', 'Gene', '8795', (79, 82))	('TRAIL', 'Gene', '8743', (128, 133))	('silencing', 'Var', (24, 33))	('TRAIL', 'Gene', (128, 133))	('CHOP', 'Gene', (62, 66))	('thapsigargin', 'MPA', (112, 124))	('DR5', 'Gene', (79, 82))
484244	27731378	Importantly, thapsigargin-induced activation of DR5 promoter activity was abrogated by mutation of the putative CHOP-binding site in the DR5 promoter.	('DR5', 'Gene', '8795', (137, 140))	('DR5', 'Gene', (48, 51))	('thapsigargin', 'Chemical', 'MESH:D019284', (13, 25))	('DR5', 'Gene', '8795', (48, 51))	('abrogated', 'NegReg', (74, 83))	('activation', 'PosReg', (34, 44))	('DR5', 'Gene', (137, 140))	('mutation', 'Var', (87, 95))
484265	27731378	Some reports indicate the ability of AMPK to induce apoptosis of neuroblastoma cells, pancreatic cells, and gastric cancer cells.	('pancreatic', 'Disease', (86, 96))	('neuroblastoma', 'Phenotype', 'HP:0003006', (65, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (108, 122))	('induce', 'PosReg', (45, 51))	('neuroblastoma', 'Disease', 'MESH:D009447', (65, 78))	('pancreatic', 'Disease', 'MESH:D010195', (86, 96))	('apoptosis', 'CPA', (52, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('neuroblastoma', 'Disease', (65, 78))	('gastric cancer', 'Disease', (108, 122))	('AMPK', 'Var', (37, 41))
484266	27731378	These studies suggest that AMPK signaling might facilitate growth inhibition and cell killing, serving as a new therapeutic target in cancer diseases.	('cell killing', 'CPA', (81, 93))	('facilitate', 'PosReg', (48, 58))	('cancer diseases', 'Disease', (134, 149))	('AMPK signaling', 'Var', (27, 41))	('cancer diseases', 'Disease', 'MESH:D009369', (134, 149))	('growth inhibition', 'CPA', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
484269	27731378	ER is the main storage site of Ca2+, and any disruption in its accumulation can also promote ER stress.	('ER stress', 'MPA', (93, 102))	('promote', 'PosReg', (85, 92))	('accumulation', 'MPA', (63, 75))	('Ca2+', 'Chemical', 'MESH:D000069285', (31, 35))	('disruption', 'Var', (45, 55))
484270	27731378	Thapsigargin causes ER calcium depletion through irreversible inhibition of the ER Ca2+-ATPase pump which was responsible for the influx of Ca2+ from cytosol.	('Thapsigargin', 'Chemical', 'MESH:D019284', (0, 12))	('Ca2+', 'Chemical', 'MESH:D000069285', (140, 144))	('Thapsigargin', 'Var', (0, 12))	('ATP', 'Chemical', 'MESH:D000255', (88, 91))	('Ca2+', 'Chemical', 'MESH:D000069285', (83, 87))	('calcium', 'Chemical', 'MESH:D002118', (23, 30))	('inhibition', 'NegReg', (62, 72))	('ER calcium depletion', 'MPA', (20, 40))	('ER Ca2+-ATPase pump', 'Enzyme', (80, 99))
484277	27731378	Because, once activated by energy stress, phosphorylation of AMPK acts to restore energy homeostasis by promoting catabolic pathways generating ATP.	('promoting', 'PosReg', (104, 113))	('energy homeostasis', 'MPA', (82, 100))	('AMPK', 'Gene', (61, 65))	('ATP', 'Chemical', 'MESH:D000255', (144, 147))	('phosphorylation', 'Var', (42, 57))	('rat', 'Species', '10116', (137, 140))	('restore', 'PosReg', (74, 81))	('catabolic pathways generating ATP', 'MPA', (114, 147))
484282	27731378	The results showed that the synergetic cell cytotoxicity induced by thapsigargin and TRAIL in EC109 and TE12 cells was abrogated by Compound C and AMPK siRNA, as reflected by promoting cell survival, suppressing cell apoptosis, reducing ROS production, and decreasing Caspase 3 activity.	('TRAIL', 'Gene', (85, 90))	('ROS production', 'MPA', (237, 251))	('Caspase 3', 'Gene', (268, 277))	('abrogated', 'NegReg', (119, 128))	('activity', 'MPA', (278, 286))	('cell survival', 'CPA', (185, 198))	('ROS', 'Chemical', 'MESH:D017382', (237, 240))	('AMPK', 'Var', (147, 151))	('suppressing', 'NegReg', (200, 211))	('decreasing', 'NegReg', (257, 267))	('thapsigargin', 'Chemical', 'MESH:D019284', (68, 80))	('EC109', 'CellLine', 'CVCL:6898', (94, 99))	('TRAIL', 'Gene', '8743', (85, 90))	('Caspase 3', 'Gene', '836', (268, 277))	('promoting', 'PosReg', (175, 184))	('reducing', 'NegReg', (228, 236))	('cytotoxicity', 'Disease', (44, 56))	('cell apoptosis', 'CPA', (212, 226))	('cytotoxicity', 'Disease', 'MESH:D064420', (44, 56))	('TE12', 'CellLine', 'CVCL:1762', (104, 108))
484322	27731378	In our preliminary experiments, we found that Thapsigargin (lower than 0.6 muM) and TRAIL (lower than 70 ng/ml) for 24 h did not affect the proliferation of the two ESCC cells lines (Data were not shown).	('lower', 'Var', (60, 65))	('Thapsigargin', 'Chemical', 'MESH:D019284', (46, 58))	('muM', 'Gene', '56925', (75, 78))	('TRAIL', 'Gene', '8743', (84, 89))	('rat', 'Species', '10116', (147, 150))	('TRAIL', 'Gene', (84, 89))	('muM', 'Gene', (75, 78))	('men', 'Species', '9606', (25, 28))
484419	25755147	Future studies should prospectively examine if variation in the community composition of microbial diversity in the upper digestive tract may be predictive of obesity risk.	('obesity', 'Disease', (159, 166))	('obesity', 'Phenotype', 'HP:0001513', (159, 166))	('predictive', 'Reg', (145, 155))	('obesity', 'Disease', 'MESH:D009765', (159, 166))	('variation', 'Var', (47, 56))
484422	25755147	BMI was significantly associated with the variation in the community composition of bacteria residing in the upper gastrointestinal tract, as assessed by multiple beta-diversity parameters, even after adjusting for multiple confounders.	('upper gastrointestinal tract', 'Disease', 'MESH:D004067', (109, 137))	('BMI', 'Var', (0, 3))	('upper gastrointestinal tract', 'Disease', (109, 137))	('community composition', 'MPA', (59, 80))	('associated', 'Reg', (22, 32))
484500	25287715	For instance, alcohol consumption coupled with genetic variants in ADH1B and ALDH2, two alcohol metabolizing genes, has effects on early ESCC diagnosis and tumor dissemination.	('tumor dissemination', 'Disease', (156, 175))	('genetic variants', 'Var', (47, 63))	('variants', 'Var', (55, 63))	('ADH1B', 'Gene', (67, 72))	('ALDH2', 'Gene', (77, 82))	('alcohol', 'Chemical', 'MESH:D000438', (88, 95))	('early', 'CPA', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('ADH1B', 'Gene', '125', (67, 72))	('alcohol', 'Chemical', 'MESH:D000438', (14, 21))	('tumor dissemination', 'Disease', 'MESH:D009103', (156, 175))	('effects', 'Reg', (120, 127))	('ALDH2', 'Gene', '217', (77, 82))
484514	24367561	Alterations in Slug expression occur in early stages of development of ESCC and are sustained during disease progression.	('expression', 'MPA', (20, 30))	('ESCC', 'Disease', (71, 75))	('Alterations', 'Var', (0, 11))	('Slug', 'Gene', '6591', (15, 19))	('Slug', 'Gene', (15, 19))
484585	24367561	Overexpression of Slug is associated with malignant progression of esophageal adenocarcinoma, breast cancer, lung cancer, bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('malignant progression', 'CPA', (42, 63))	('lung cancer', 'Disease', (109, 120))	('Slug', 'Gene', '6591', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Disease', (94, 107))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (67, 92))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (67, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('esophageal adenocarcinoma', 'Disease', (67, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (122, 136))	('bladder cancer', 'Disease', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Slug', 'Gene', (18, 22))	('associated', 'Reg', (26, 36))
484733	31906216	Alteration in visceral fat metabolism influences GI motility and stimulates production of adipokines and immunologic factors, thus emphasizing the role of obesity in the increased risk of IBS.	('IBS', 'Disease', 'MESH:D043183', (188, 191))	('IBS', 'Disease', (188, 191))	('GI motility', 'Disease', (49, 60))	('production of adipokines', 'MPA', (76, 100))	('influences', 'Reg', (38, 48))	('Alteration', 'Var', (0, 10))	('obesity', 'Phenotype', 'HP:0001513', (155, 162))	('GI motility', 'Disease', 'MESH:D005767', (49, 60))	('stimulates', 'PosReg', (65, 75))	('obesity', 'Disease', 'MESH:D009765', (155, 162))	('obesity', 'Disease', (155, 162))
484744	31906216	Diverticulosis of the colon is an anatomic alteration of the colonic wall characterized by the presence of extroflexions that occur when colonic mucosa and sub-mucosa herniate through defects in the muscle layer of the colon wall.	('colonic mucosa', 'Disease', (137, 151))	('defects', 'Var', (184, 191))	('Diverticulosis of the colon', 'Disease', 'MESH:D043963', (0, 27))	('colonic mucosa', 'Disease', 'MESH:D015179', (137, 151))	('Diverticulosis of the colon', 'Disease', (0, 27))	('hernia', 'Phenotype', 'HP:0100790', (167, 173))
484794	31906216	A causal association between body fatness and different types of cancer is supported by strong evidence; moreover, excess weight is also well-known as a risk factor for cancer mortality overall.	('fatness', 'Disease', 'MESH:D004620', (34, 41))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('fatness', 'Disease', (34, 41))	('excess', 'Var', (115, 121))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
484809	31906216	Overweight and obesity is also associated with higher risk of liver cancer as well as to negative clinical outcomes, such as time to recurrence, disease-free survival, and overall survival among patients with hepatocellular carcinoma and pancreas cancer.	('hepatocellular carcinoma', 'Disease', (209, 233))	('pancreas cancer', 'Disease', (238, 253))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (209, 233))	('obesity', 'Disease', 'MESH:D009765', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('pancreas cancer', 'Disease', 'MESH:D010190', (238, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('obesity', 'Disease', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('liver cancer', 'Phenotype', 'HP:0002896', (62, 74))	('pancreas cancer', 'Phenotype', 'HP:0002894', (238, 253))	('Overweight', 'Var', (0, 10))	('liver cancer', 'Disease', 'MESH:D006528', (62, 74))	('patients', 'Species', '9606', (195, 203))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('liver cancer', 'Disease', (62, 74))	('obesity', 'Phenotype', 'HP:0001513', (15, 22))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (209, 233))
484812	31906216	Such as, it has been demonstrated in patients with functional dyspepsia compared to healthy volunteers, that infusion of lipid within the duodenum incites strongly greater symptoms, such as nausea, epigastric fullness and bloating.	('greater', 'PosReg', (164, 171))	('epigastric fullness', 'Disease', 'MESH:C537170', (198, 217))	('bloating', 'Disease', (222, 230))	('bloating', 'Phenotype', 'HP:0003270', (222, 230))	('patients', 'Species', '9606', (37, 45))	('epigastric fullness', 'Disease', (198, 217))	('lipid', 'Chemical', 'MESH:D008055', (121, 126))	('functional dyspepsia', 'Disease', (51, 71))	('dyspepsia', 'Phenotype', 'HP:0410281', (62, 71))	('nausea', 'Phenotype', 'HP:0002018', (190, 196))	('nausea', 'Disease', (190, 196))	('functional dyspepsia', 'Disease', 'MESH:D004415', (51, 71))	('nausea', 'Disease', 'MESH:D009325', (190, 196))	('epigastric fullness', 'Phenotype', 'HP:0410019', (198, 217))	('infusion', 'Var', (109, 117))
484815	31906216	Lipids are also able to enhance perception of intestinal stimuli as well as modulate intestinal motor reflexes in patients with IBS.	('modulate', 'Reg', (76, 84))	('Lipids', 'Var', (0, 6))	('intestinal motor reflexes', 'CPA', (85, 110))	('perception of intestinal stimuli', 'MPA', (32, 64))	('enhance', 'PosReg', (24, 31))	('Lipids', 'Chemical', 'MESH:D008055', (0, 6))	('IBS', 'Disease', 'MESH:D043183', (128, 131))	('IBS', 'Disease', (128, 131))	('patients', 'Species', '9606', (114, 122))
484817	31906216	Lipid may also be able to affect GI motility, in particular, lipids can impede small bowel motility, in fact intestinal gas transit is slower by fat leading to bloating.	('impede', 'NegReg', (72, 78))	('bloating', 'Disease', (160, 168))	('bloating', 'Phenotype', 'HP:0003270', (160, 168))	('GI motility', 'Disease', 'MESH:D005767', (33, 44))	('lipids', 'Var', (61, 67))	('GI motility', 'Disease', (33, 44))	('slower', 'NegReg', (135, 141))	('small bowel motility', 'Disease', 'MESH:D007409', (79, 99))	('Lipid', 'Chemical', 'MESH:D008055', (0, 5))	('lipids', 'Chemical', 'MESH:D008055', (61, 67))	('small bowel motility', 'Disease', (79, 99))	('intestinal gas transit', 'MPA', (109, 131))
484835	30223066	Both genetic and environmental factors contribute to the initiation and progression of cancer in the form of germline genetic variations and defects, somatic mutations, and the inflammatory responses resulting from exposure to toxic chemicals, excessive alcohol consumption, and/or viral infection.	('alcohol', 'Chemical', 'MESH:D000431', (254, 261))	('cancer', 'Disease', (87, 93))	('men', 'Species', '9606', (24, 27))	('defects', 'Disease', 'MESH:D030342', (141, 148))	('contribute', 'Reg', (39, 49))	('viral infection', 'Disease', 'MESH:D014777', (282, 297))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('excessive alcohol', 'Phenotype', 'HP:0030955', (244, 261))	('viral infection', 'Disease', (282, 297))	('defects', 'Disease', (141, 148))	('mutations', 'Var', (158, 167))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
484848	30223066	Next, we summarize the incidence data and potential mechanisms of sexual dimorphism in ten human cancer types with higher incidence ratios of at least 2-fold.	('cancer', 'Disease', (97, 103))	('sexual', 'Var', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('human', 'Species', '9606', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
484897	30223066	Although neither ERbeta nor GPER1 is expressed in normal liver and liver tumors from rodents and humans, one recent study showed that global but not liver-specific ablation of Gper1 accelerated hepatocarcinogenesis.	('GPER1', 'Gene', (28, 33))	('liver tumors', 'Phenotype', 'HP:0002896', (67, 79))	('liver tumors', 'Disease', (67, 79))	('humans', 'Species', '9606', (97, 103))	('GPER1', 'Gene', '2852', (28, 33))	('Gper1', 'Gene', '2852', (176, 181))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (194, 214))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ERbeta', 'Gene', '2100', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('accelerated', 'PosReg', (182, 193))	('ablation', 'Var', (164, 172))	('Gper1', 'Gene', (176, 181))	('ERbeta', 'Gene', (17, 23))	('hepatocarcinogenesis', 'Disease', (194, 214))	('liver tumors', 'Disease', 'MESH:D008113', (67, 79))
484901	30223066	Li et al found that both of the ERalpha-mediated protection and AR-mediated facilitation of hepatic tumorigenesis in mice depended on Foxa1/2, while deficiency of Foxa1 and Foxa2 in the mouse liver would reverse the protective role of ERalpha and the detrimental role of AR for HCC; and genetic variants that affected the binding of FOXA2 and ERalpha were associated with the increased incidence of HCC in patients.	('Foxa1', 'Gene', (163, 168))	('FOXA2', 'Gene', (333, 338))	('tumor', 'Disease', (100, 105))	('mice', 'Species', '10090', (117, 121))	('men', 'Species', '9606', (256, 259))	('deficiency', 'Var', (149, 159))	('HCC', 'Disease', (278, 281))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('binding', 'Interaction', (322, 329))	('HCC', 'Disease', 'MESH:D006528', (399, 402))	('HCC', 'Phenotype', 'HP:0001402', (278, 281))	('associated', 'Reg', (356, 366))	('Foxa1/2', 'Gene', '15375;15376', (134, 141))	('Foxa1', 'Gene', '15375', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('genetic variants', 'Var', (287, 303))	('Foxa1', 'Gene', (134, 139))	('mouse', 'Species', '10090', (186, 191))	('HCC', 'Disease', 'MESH:D006528', (278, 281))	('HCC', 'Disease', (399, 402))	('Foxa2', 'Gene', '15376', (173, 178))	('patients', 'Species', '9606', (406, 414))	('HCC', 'Phenotype', 'HP:0001402', (399, 402))	('Foxa1/2', 'Gene', (134, 141))	('Foxa2', 'Gene', (173, 178))	('Foxa1', 'Gene', '15375', (163, 168))	('FOXA2', 'Gene', '15376', (333, 338))	('ERalpha', 'Gene', (343, 350))
484917	30223066	For example, estrogen signaling, through ERalpha or a splicing variant of ERalpha, promoted the growth of gastric cancer cells whereas ERbeta-mediated estrogen signaling inhibited the growth of gastric cancer cells and genetic variants in the ESR2 gene were highly associated with survival in patients with locally advanced gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ERbeta', 'Gene', (135, 141))	('associated with', 'Reg', (265, 280))	('genetic variants', 'Var', (219, 235))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (194, 208))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('gastric cancer', 'Disease', (324, 338))	('inhibited', 'NegReg', (170, 179))	('estrogen', 'Chemical', 'MESH:D004967', (151, 159))	('growth', 'MPA', (184, 190))	('ESR2', 'Gene', '2100', (243, 247))	('gastric cancer', 'Disease', 'MESH:D013274', (324, 338))	('gastric cancer', 'Disease', (194, 208))	('estrogen', 'Chemical', 'MESH:D004967', (13, 21))	('ESR2', 'Gene', (243, 247))	('gastric cancer', 'Disease', (106, 120))	('growth', 'MPA', (96, 102))	('promoted', 'PosReg', (83, 91))	('splicing variant', 'Var', (54, 70))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('gastric cancer', 'Disease', 'MESH:D013274', (194, 208))	('gastric cancer', 'Phenotype', 'HP:0012126', (324, 338))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('ERbeta', 'Gene', '2100', (135, 141))	('patients', 'Species', '9606', (293, 301))	('ERalpha', 'Gene', (74, 81))
484923	30223066	The evidence of estrogen signaling in the growth of kidney cancer cells is limited, e.g., ESR1 polymorphism was associated with the risk of kidney cancer; GPER1 promoted the growth and metastasis of kidney cancer cells; and AR-mediated androgen signaling promoted the growth of kidney cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('kidney cancer', 'Disease', (140, 153))	('kidney cancer', 'Phenotype', 'HP:0009726', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('kidney cancer', 'Disease', (52, 65))	('GPER1', 'Gene', '2852', (155, 160))	('kidney cancer', 'Disease', 'MESH:D007680', (199, 212))	('kidney cancer', 'Disease', 'MESH:D007680', (278, 291))	('metastasis of kidney cancer', 'Disease', 'MESH:D009362', (185, 212))	('GPER1', 'Gene', (155, 160))	('growth', 'CPA', (174, 180))	('ESR1', 'Gene', '2099', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('kidney cancer', 'Phenotype', 'HP:0009726', (199, 212))	('kidney cancer', 'Phenotype', 'HP:0009726', (278, 291))	('metastasis of kidney cancer', 'Disease', (185, 212))	('estrogen', 'Chemical', 'MESH:D004967', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('kidney cancer', 'Disease', (278, 291))	('ESR1', 'Gene', (90, 94))	('polymorphism', 'Var', (95, 107))	('kidney cancer', 'Disease', 'MESH:D007680', (140, 153))	('kidney cancer', 'Disease', 'MESH:D007680', (52, 65))	('androgen', 'Chemical', 'MESH:D000728', (236, 244))	('promoted', 'PosReg', (255, 263))	('growth', 'CPA', (268, 274))	('promoted', 'PosReg', (161, 169))	('associated', 'Reg', (112, 122))	('kidney cancer', 'Phenotype', 'HP:0009726', (140, 153))
484971	30050305	Therefore, pathological angiogenesis is considered a hallmark of tumorigenesis, and tumor development can be curbed by blocking this process.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('pathological', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
484980	30050305	During tumor formation, environmental changes such as hypoxia and genetic mutations to molecules such as K-ras, p53, or HER2/ErbB2 induce the expression of VEGF in cancer cells.	('HER2', 'Gene', '2064', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('K-ras', 'Gene', '3845', (105, 110))	('p53', 'Gene', '7157', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('p53', 'Gene', (112, 115))	('genetic mutations', 'Var', (66, 83))	('hypoxia', 'Disease', (54, 61))	('ErbB2', 'Gene', '2064', (125, 130))	('HER2', 'Gene', (120, 124))	('K-ras', 'Gene', (105, 110))	('cancer', 'Disease', (164, 170))	('VEGF', 'Protein', (156, 160))	('expression', 'MPA', (142, 152))	('hypoxia', 'Disease', 'MESH:D000860', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', (7, 12))	('induce', 'PosReg', (131, 137))	('ErbB2', 'Gene', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
484995	30050305	Apatinib is mainly metabolized by cytochrome P450 (CYP)3A4/5 and CYP2D6, and the major routes of apatinib bioconversion contain E- and Z-cyclopentyl-3-hydroxylation, N-dealkylation, pyridyl-25-N-oxidation, 16-hydroxylation, dioxygenation, and O-glucuronidation after 3-hydroxylation.	('pyridyl-25-N-oxidation', 'Enzyme', (182, 204))	('cytochrome P450', 'Enzyme', (34, 49))	('dioxygenation', 'Enzyme', (224, 237))	('apatinib', 'Chemical', 'MESH:C553458', (97, 105))	('O-glucuronidation', 'MPA', (243, 260))	('oxygen', 'Chemical', 'MESH:D010100', (226, 232))	('apatinib', 'Gene', (97, 105))	('Apatinib', 'Chemical', 'MESH:C553458', (0, 8))	('16-hydroxylation', 'MPA', (206, 222))	('N-dealkylation', 'Var', (166, 180))	('CYP2D6', 'Gene', '1565', (65, 71))	('CYP2D6', 'Gene', (65, 71))
485061	30050305	In NSCLC, there were ~45% patients without epidermal growth factor receptor (EGFR) mutations, and these patients were often found to have progressive disease 4-6 months after first-line treatment.	('mutations', 'Var', (83, 92))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('epidermal growth factor receptor', 'Gene', '1956', (43, 75))	('patients', 'Species', '9606', (104, 112))	('patients', 'Species', '9606', (26, 34))	('EGFR', 'Gene', '1956', (77, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('epidermal growth factor receptor', 'Gene', (43, 75))	('EGFR', 'Gene', (77, 81))
485125	30050305	For the moment, it has been shown that the curative effect of apatinib is slightly better than that of other antiangiogenic drugs such as ramucirumab, bevacizumab, and sunitinib.	('apatinib', 'Chemical', 'MESH:C553458', (62, 70))	('curative effect', 'CPA', (43, 58))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('bevacizumab', 'Chemical', 'MESH:D000068258', (151, 162))	('sunitinib', 'Chemical', 'MESH:D000077210', (168, 177))	('ramucirumab', 'Chemical', 'MESH:C543333', (138, 149))	('apatinib', 'Var', (62, 70))
485158	28322245	In multivariate analysis, high sTIL (HR: 0.664, P = 0.019 for Disease free survival; HR: 0.608, P = 0.005 for Overall survival) was identified as independent better prognostic factor.	('TIL', 'Gene', (32, 35))	('TIL', 'Gene', '7096', (32, 35))	('high', 'Var', (26, 30))
485176	28322245	suggested the presence of TILs was associated with improved survival in a cohort of ESCC patients (n = 33).	('TIL', 'Gene', (26, 29))	('presence', 'Var', (14, 22))	('ESCC', 'Disease', (84, 88))	('improved', 'PosReg', (51, 59))	('survival', 'MPA', (60, 68))	('patients', 'Species', '9606', (89, 97))	('TIL', 'Gene', '7096', (26, 29))
485199	28322245	Among 101 patients with high sTIL (>10%), a significantly better prognosis was observed, with a median DFS and OS of 29.0 and 42.0 months compared to 24.0 and 30.0 months for 134 patients with low sTIL (<=10%) (P = 0.076 and 0.033).	('TIL', 'Gene', (30, 33))	('TIL', 'Gene', '7096', (30, 33))	('TIL', 'Gene', (198, 201))	('better', 'PosReg', (58, 64))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (10, 18))	('TIL', 'Gene', '7096', (198, 201))	('>10%', 'Var', (35, 39))
485201	28322245	Among 44 patients with high sTIL (>10%), a significantly better prognosis was observed, with a median DFS and OS of 20.0 and 26.0 months compared to 13.0 and 21.0 months for 55 patients with low sTIL (<=10%).	('patients', 'Species', '9606', (9, 17))	('TIL', 'Gene', (29, 32))	('TIL', 'Gene', '7096', (196, 199))	('patients', 'Species', '9606', (177, 185))	('TIL', 'Gene', (196, 199))	('>10%', 'Var', (34, 38))	('better', 'PosReg', (57, 63))	('TIL', 'Gene', '7096', (29, 32))
485248	28322245	Our study showed that high sTIL is an independent, favorable prognostic factor in patients with surgically resected ESCC, especially III-IVa patients.	('ESCC', 'Disease', (116, 120))	('high', 'Var', (22, 26))	('patients', 'Species', '9606', (82, 90))	('TIL', 'Gene', '7096', (28, 31))	('TIL', 'Gene', (28, 31))	('patients', 'Species', '9606', (141, 149))
485260	28322245	Monoclonal and polyclonal anti-human antibodies were used for identification of CD4+ T cells (anti-CD4, 4B12, Dako), CD8+ T cells (anti-CD8, Ab4055, Abcam), and Foxp3+ T cells (anti-Foxp3, 236 A/E7, Abcam).	('Foxp3', 'Gene', '50943', (182, 187))	('Foxp3', 'Gene', (182, 187))	('CD8', 'Gene', (136, 139))	('Foxp3', 'Gene', '50943', (161, 166))	('human', 'Species', '9606', (31, 36))	('CD4', 'Gene', (80, 83))	('CD8', 'Gene', '925', (136, 139))	('CD8', 'Gene', (117, 120))	('A/E7', 'Var', (193, 197))	('CD4', 'Gene', (99, 102))	('CD8', 'Gene', '925', (117, 120))	('A/E7', 'SUBSTITUTION', 'None', (193, 197))	('CD4', 'Gene', '920', (80, 83))	('Foxp3', 'Gene', (161, 166))	('CD4', 'Gene', '920', (99, 102))
485339	24714299	The accuracy of miniprobe EUS was significantly higher than that of radial EUS (79.5 % versus 59.6 %, P<0.001), but did not differ significantly from that of conventional endoscopy (79.0 %), thus supporting that EUS does not substantially impact on pretreatment T-staging of patients with early gastric cancer compared with conventional endoscopy.	('miniprobe', 'Var', (16, 25))	('gastric cancer', 'Disease', (295, 309))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('higher', 'PosReg', (48, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (295, 309))	('patients', 'Species', '9606', (275, 283))	('gastric cancer', 'Phenotype', 'HP:0012126', (295, 309))
485342	24714299	Furthermore, recent data deriving from a meta-analysis seem to support that the overall pooled accuracy of EUS in nodal staging of gastric cancers is not high; moreover, the estimates of EUS are higher when dealing with N2- than for N1-tumors (i.e.	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('nodal', 'Gene', (114, 119))	('N1-tumors', 'Disease', (233, 242))	('higher', 'PosReg', (195, 201))	('nodal', 'Gene', '4838', (114, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('gastric cancers', 'Disease', (131, 146))	('gastric cancers', 'Disease', 'MESH:D013274', (131, 146))	('gastric cancers', 'Phenotype', 'HP:0012126', (131, 146))	('N1-tumors', 'Disease', 'MESH:D009369', (233, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('N2-', 'Var', (220, 223))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))
485376	24296751	Autoantibodies to Prx VI, a member of the thiol-specific antioxidant protein family, have been considered to be a specific serologic marker for ESCC.	('ESCC', 'Disease', (144, 148))	('thiol', 'Chemical', 'MESH:D013438', (42, 47))	('Prx', 'Gene', (18, 21))	('Prx', 'Gene', '57716', (18, 21))	('Autoantibodies', 'Var', (0, 14))
485420	24296751	More than half of the ESCC patients examined had autoantibodies to at least 1 of the 6 TAAs, with a specificity of at least 95%.	('autoantibodies', 'Var', (49, 63))	('ESCC', 'Disease', (22, 26))	('patients', 'Species', '9606', (27, 35))
485461	31977864	However, 5-Fu is known to increase acute mucosal reactions, and inducing high rates of esophagitis and cardiotoxicity, and need a longer time spent receiving continuous infusion chemotherapy and longer hospital stays.	('5-Fu', 'Chemical', 'MESH:C411955', (9, 13))	('acute mucosal reactions', 'Disease', 'MESH:D000210', (35, 58))	('cardiotoxicity', 'Disease', 'MESH:D066126', (103, 117))	('acute mucosal reactions', 'Disease', (35, 58))	('cardiotoxicity', 'Disease', (103, 117))	('esophagitis', 'Disease', (87, 98))	('esophagitis', 'Phenotype', 'HP:0100633', (87, 98))	('esophagitis', 'Disease', 'MESH:D004941', (87, 98))	('5-Fu', 'Var', (9, 13))	('increase', 'PosReg', (26, 34))	('inducing', 'Reg', (64, 72))
485508	31977864	In this present study, raltitrexed/nedaplatin was associated with a high ORR rate (90%), prolonged PFS (median: 20 months), prolonged OS (MST: 30 months, 1- and 2-year survival rate: 70.4%, 55.7%), and relatively good feasibility in patients with unresectable, advanced locally esophageal cancer.	('PFS', 'MPA', (99, 102))	('esophageal cancer', 'Disease', (278, 295))	('raltitrexed/nedaplatin', 'Var', (23, 45))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('esophageal cancer', 'Disease', 'MESH:D004938', (278, 295))	('patients', 'Species', '9606', (233, 241))	('nedaplatin', 'Chemical', 'MESH:C053989', (35, 45))
485540	31977864	It was reported that the approach of switching from 5-Fu/capecitabine to raltitrexed for patients with 5-FU cardiotoxicity is safe and offers the lowest risk of recurrent cardiotoxicity.	('cardiotoxicity', 'Disease', (171, 185))	('capecitabine', 'Chemical', 'MESH:C110904', (57, 69))	('5-FU', 'Var', (103, 107))	('cardiotoxicity', 'Disease', 'MESH:D066126', (108, 122))	('5-Fu', 'Chemical', 'MESH:C411955', (52, 56))	('5-FU', 'Chemical', 'MESH:D005472', (103, 107))	('patients', 'Species', '9606', (89, 97))	('cardiotoxicity', 'Disease', (108, 122))	('cardiotoxicity', 'Disease', 'MESH:D066126', (171, 185))
485647	28716721	Next-generation sequencing technologies have allowed us to identify somatic mutations that initiate BE and track genetic changes during development of tumors and invasive cancer.	('BE', 'Phenotype', 'HP:0100580', (100, 102))	('mutations', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('invasive cancer', 'Disease', 'MESH:D009362', (162, 177))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('invasive cancer', 'Disease', (162, 177))	('men', 'Species', '9606', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
485668	28716721	Evidence that germline mutations contribute to development of EA originated from reports of familial aggregation of this cancer and BE.	('BE', 'Phenotype', 'HP:0100580', (132, 134))	('contribute', 'Reg', (33, 43))	('EA', 'Phenotype', 'HP:0011459', (62, 64))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (121, 127))	('men', 'Species', '9606', (54, 57))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('familial aggregation', 'Disease', 'MESH:D020914', (92, 112))	('familial aggregation', 'Disease', (92, 112))	('germline mutations', 'Var', (14, 32))
485670	28716721	Variants in MSR1, on chromosome 8p22, were significantly associated with BE or EA in the validation sample and in the pooled sample.	('MSR1', 'Gene', '4481', (12, 16))	('Variants', 'Var', (0, 8))	('BE', 'Phenotype', 'HP:0100580', (73, 75))	('EA', 'Phenotype', 'HP:0011459', (79, 81))	('BE or EA', 'Disease', (73, 81))	('MSR1', 'Gene', (12, 16))	('associated', 'Reg', (57, 67))
485677	28716721	Using autosomal markers and genome-wide complex trait analysis, Ek et al estimated that 25% (standard error, 5%; one-sided P = 2 x 10-7) of EA cases and 35% of BE cases (standard error, 6%; one-sided P = 1 x 10-9) were determined by the composite effect of many common mutations of small individual relative risk .	('EA', 'Phenotype', 'HP:0011459', (140, 142))	('mutations', 'Var', (269, 278))	('determined by', 'Reg', (219, 232))	('BE', 'Phenotype', 'HP:0100580', (160, 162))	('man', 'Species', '9606', (257, 260))
485678	28716721	Furthermore, they demonstrated substantial polygenic overlap between EA and BE, indicating that shared genes influence the development of the 2 disorders.	('BE', 'Phenotype', 'HP:0100580', (76, 78))	('influence', 'Reg', (109, 118))	('EA', 'Phenotype', 'HP:0011459', (69, 71))	('polygenic', 'Var', (43, 52))	('men', 'Species', '9606', (130, 133))
485679	28716721	A portion of the heritability of EA and BE may be explained by germline variants that affect development and severity of risk factors for these conditions, including symptomatic GER and obesity.	('GER', 'Gene', (178, 181))	('obesity', 'Disease', (186, 193))	('affect', 'Reg', (86, 92))	('men', 'Species', '9606', (100, 103))	('GER', 'Phenotype', 'HP:0002020', (178, 181))	('variants', 'Var', (72, 80))	('BE', 'Phenotype', 'HP:0100580', (40, 42))	('GER', 'Gene', '59330', (178, 181))	('obesity', 'Phenotype', 'HP:0001513', (186, 193))	('EA', 'Phenotype', 'HP:0011459', (33, 35))	('obesity', 'Disease', 'MESH:D009765', (186, 193))
485685	28716721	Using Mendelian randomization methods, researchers associated a risk score based on 29 BMI-associated variants was with a 12%-16% increase in risk of BE and EA, respectively, per 1 kg/m2 increase in BMI  The first GWAS of BE was based on a discovery dataset of 1852 case and 5172 control participants from the Wellcome Trust Case Control Consortium.	('BMI-associated', 'Gene', (87, 101))	('variants', 'Var', (102, 110))	('participants', 'Species', '9606', (288, 300))	('EA', 'Phenotype', 'HP:0011459', (157, 159))	('BE', 'Phenotype', 'HP:0100580', (150, 152))	('BE', 'Phenotype', 'HP:0100580', (222, 224))	('increase', 'PosReg', (130, 138))	('increase in BMI', 'Phenotype', 'HP:0031418', (187, 202))
485690	28716721	Given the importance of GER in development of BE and EA, and the fact that hiatal hernia substantially predisposes to GER, the findings identify mechanisms by which these variants might affect development of BE and EA.	('GER', 'Gene', (24, 27))	('GER', 'Gene', (118, 121))	('hiatal hernia', 'Disease', 'MESH:D006551', (75, 88))	('EA', 'Phenotype', 'HP:0011459', (215, 217))	('hiatal hernia', 'Disease', (75, 88))	('affect', 'Reg', (186, 192))	('BE', 'Phenotype', 'HP:0100580', (208, 210))	('hernia', 'Phenotype', 'HP:0100790', (82, 88))	('men', 'Species', '9606', (200, 203))	('EA', 'Phenotype', 'HP:0011459', (53, 55))	('development', 'CPA', (193, 204))	('hiatal hernia', 'Phenotype', 'HP:0002036', (75, 88))	('GER', 'Gene', '59330', (24, 27))	('men', 'Species', '9606', (38, 41))	('GER', 'Gene', '59330', (118, 121))	('BE', 'Phenotype', 'HP:0100580', (46, 48))	('GER', 'Phenotype', 'HP:0002020', (24, 27))	('GER', 'Phenotype', 'HP:0002020', (118, 121))	('variants', 'Var', (171, 179))
485692	28716721	The large meta-analysis identified an intriguing association between a SNP on chromosome 7q31, located within the CFTR gene, and risk of BE and EA.	('EA', 'Phenotype', 'HP:0011459', (144, 146))	('CFTR', 'Gene', '1080', (114, 118))	('BE', 'Phenotype', 'HP:0100580', (137, 139))	('SNP', 'Var', (71, 74))	('CFTR', 'Gene', (114, 118))
485696	28716721	Somatic mutations occur at high frequencies in the CDKN2A and TP53 tumor suppressor genes in EAs (and other malignancies) ; loss of heterozygosity at these loci has been associated with progression from BE to cancer (see section on somatic mutation analyses).	('CDKN2A', 'Gene', '1029', (51, 57))	('TP53', 'Gene', '7157', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('EAs', 'Disease', (93, 96))	('TP53', 'Gene', (62, 66))	('EAs', 'Chemical', '-', (93, 96))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('malignancies', 'Disease', 'MESH:D009369', (108, 120))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', (209, 215))	('EA', 'Phenotype', 'HP:0011459', (93, 95))	('tumor', 'Disease', (67, 72))	('malignancies', 'Disease', (108, 120))	('CDKN2A', 'Gene', (51, 57))	('associated with', 'Reg', (170, 185))	('BE', 'Phenotype', 'HP:0100580', (203, 205))	('loss of heterozygosity', 'Var', (124, 146))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
485697	28716721	Reasoning that these loci may be implicated in susceptibility to cancer, investigators from the BEACON consortium tested 13 SNPs at the TP53 locus and 24 SNPs in CDKN2A, which were within 2-kb flanking regions and satisfied quality control constraints.	('CDKN2A', 'Gene', (162, 168))	('TP53', 'Gene', '7157', (136, 140))	('CDKN2A', 'Gene', '1029', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('EA', 'Phenotype', 'HP:0011459', (97, 99))	('SNPs', 'Var', (124, 128))	('cancer', 'Disease', (65, 71))	('TP53', 'Gene', (136, 140))	('BE', 'Phenotype', 'HP:0100580', (96, 98))
485698	28716721	While none of the SNPs in TP53 were associated with EA risk, 3 polymorphisms in CDKN2A were associated with a 10%-16% reduction in risk for EA (p<0.05) (Figure 2, Supplementary Table 2).	('TP53', 'Gene', (26, 30))	('EA', 'Phenotype', 'HP:0011459', (140, 142))	('CDKN2A', 'Gene', '1029', (80, 86))	('men', 'Species', '9606', (169, 172))	('reduction', 'NegReg', (118, 127))	('EA', 'Phenotype', 'HP:0011459', (52, 54))	('polymorphisms', 'Var', (63, 76))	('TP53', 'Gene', '7157', (26, 30))	('SNPs', 'Var', (18, 22))	('CDKN2A', 'Gene', (80, 86))
485699	28716721	The investigators then tested whether any of the variants predicted neoplastic progression in a separate prospective cohort of 408 patients with BE, and found that 2 of the variants (rs2518720; hazard ratio, 0.57 and rs3088440; hazard ratio, 0.34) were independently significantly associated with reduced risks of progression.	('patients', 'Species', '9606', (131, 139))	('BE', 'Phenotype', 'HP:0100580', (145, 147))	('rs2518720;', 'Var', (183, 193))	('rs3088440', 'Var', (217, 226))	('reduced', 'NegReg', (297, 304))	('neoplastic progression', 'CPA', (68, 90))	('rs2518720', 'Mutation', 'rs2518720', (183, 192))	('rs3088440', 'Mutation', 'rs3088440', (217, 226))
485700	28716721	Expression of one of the variants (rs3088440) in cell lines indicated that it reduces microRNA-mediated repression of the CDKN2A mRNA.	('microRNA-mediated repression', 'MPA', (86, 114))	('rs3088440', 'Mutation', 'rs3088440', (35, 44))	('CDKN2A', 'Gene', (122, 128))	('CDKN2A', 'Gene', '1029', (122, 128))	('rs3088440', 'Var', (35, 44))	('reduces', 'NegReg', (78, 85))
485704	28716721	They found that the previously identified variant near FOXP1 (rs2687201) significantly modified the association between GER symptoms occurring at least weekly and risk of BE, such that the association was stronger (odds ratio, 6.2) among persons with 0 minor alleles, compared to those with 1 or 2 (odds ratios, 3.6 and 4.0, respectively,) (Pinteraction=0.0005; FDR=0.042.)	('GER', 'Gene', (120, 123))	('rs2687201', 'Mutation', 'rs2687201', (62, 71))	('modified', 'Reg', (87, 95))	('rs2687201', 'Var', (62, 71))	('GER', 'Phenotype', 'HP:0002020', (120, 123))	('association', 'Interaction', (100, 111))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('FOXP1', 'Gene', '27086', (55, 60))	('stronger', 'PosReg', (205, 213))	('persons', 'Species', '9606', (238, 245))	('GER', 'Gene', '59330', (120, 123))	('FOXP1', 'Gene', (55, 60))	('variant', 'Var', (42, 49))
485713	28716721	In our current model, dysplasia progresses to invasive EA via early loss of CDKN2A, emergence of dysplastic clones with mutations in TP53 and/or additional somatic alterations, and increases in copy number .	('dysplasia', 'Disease', 'MESH:D004476', (22, 31))	('CDKN2A', 'Gene', '1029', (76, 82))	('invasive EA', 'Disease', (46, 57))	('copy number', 'MPA', (194, 205))	('dysplasia', 'Disease', (22, 31))	('EA', 'Phenotype', 'HP:0011459', (55, 57))	('mutations in', 'Var', (120, 132))	('loss', 'NegReg', (68, 72))	('dysplastic', 'Disease', 'MESH:D004416', (97, 107))	('TP53', 'Gene', '7157', (133, 137))	('CDKN2A', 'Gene', (76, 82))	('dysplastic', 'Disease', (97, 107))	('TP53', 'Gene', (133, 137))	('increases', 'PosReg', (181, 190))
485714	28716721	Although the basics of this model, largely characterized before the advent of NGS techniques, appear to hold true, sequencing studies have shown the BE genome to be highly complex:even when non-dysplastic for many years :and that progression can be non-linear It is now apparent that point mutations accumulate during early stages of disease and BE lesions often have a higher rate of mutation rate than many common, invasive cancers .	('point mutations', 'Var', (284, 299))	('man', 'Species', '9606', (209, 212))	('cancer', 'Phenotype', 'HP:0002664', (426, 432))	('BE', 'Phenotype', 'HP:0100580', (149, 151))	('accumulate', 'PosReg', (300, 310))	('BE', 'Phenotype', 'HP:0100580', (346, 348))	('dysplastic', 'Disease', (194, 204))	('invasive cancers', 'Disease', 'MESH:D009362', (417, 433))	('cancers', 'Phenotype', 'HP:0002664', (426, 433))	('mutation', 'MPA', (385, 393))	('dysplastic', 'Disease', 'MESH:D004416', (194, 204))	('invasive cancers', 'Disease', (417, 433))	('man', 'Species', '9606', (404, 407))
485715	28716721	At the time BE becomes dysplastic, the tissue has a mutation rate comparable to that of EA.	('dysplastic', 'Disease', 'MESH:D004416', (23, 33))	('EA', 'Phenotype', 'HP:0011459', (88, 90))	('BE', 'Phenotype', 'HP:0100580', (12, 14))	('mutation', 'Var', (52, 60))	('dysplastic', 'Disease', (23, 33))
485716	28716721	Mutations are found in a number of tumor suppressor genes important in chromatin remodeling, such as ARID1A and SMARCA4 (Supplementary table 3).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('ARID1A', 'Gene', (101, 107))	('SMARCA4', 'Gene', '6597', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('Mutations', 'Var', (0, 9))	('ARID1A', 'Gene', '8289', (101, 107))	('men', 'Species', '9606', (127, 130))	('SMARCA4', 'Gene', (112, 119))
485717	28716721	Mutations in TP53 and SMAD4 are usually found only in tissues with high-grade dysplasia and EA, respectively.	('TP53', 'Gene', (13, 17))	('SMAD4', 'Gene', (22, 27))	('found', 'Reg', (40, 45))	('dysplasia', 'Disease', (78, 87))	('Mutations', 'Var', (0, 9))	('SMAD4', 'Gene', '4089', (22, 27))	('dysplasia', 'Disease', 'MESH:D004476', (78, 87))	('TP53', 'Gene', '7157', (13, 17))	('EA', 'Phenotype', 'HP:0011459', (92, 94))
485718	28716721	In contrast to patients with NDBE with no history of disease progression, mutations in TP53 are found in NDBE tissues adjacent to EA .	('patients', 'Species', '9606', (15, 23))	('TP53', 'Gene', '7157', (87, 91))	('BE', 'Phenotype', 'HP:0100580', (107, 109))	('mutations', 'Var', (74, 83))	('TP53', 'Gene', (87, 91))	('BE', 'Phenotype', 'HP:0100580', (31, 33))	('NDBE', 'Chemical', '-', (29, 33))	('NDBE', 'Chemical', '-', (105, 109))	('EA', 'Phenotype', 'HP:0011459', (130, 132))	('found', 'Reg', (96, 101))	('NDBE', 'Disease', (105, 109))
485719	28716721	This observation is consistent with the high allele fraction of TP53 mutations in many different cancer types, indicating that either this mutation appears early during tumorigenesis or it is able to promote expansion of a dominating clone .	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('man', 'Species', '9606', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('expansion', 'MPA', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (169, 174))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('promote', 'PosReg', (200, 207))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
485720	28716721	Mutations in PIK3A and CTNNB1 have also been found in BE, although accumulation of activating mutations and amplifications in oncogenes is a marker of invasive EA .	('CTNNB1', 'Gene', (23, 29))	('mutations', 'Var', (94, 103))	('BE', 'Phenotype', 'HP:0100580', (54, 56))	('Mutations', 'Var', (0, 9))	('amplifications', 'Var', (108, 122))	('activating', 'PosReg', (83, 93))	('CTNNB1', 'Gene', '1499', (23, 29))	('PIK3A', 'Gene', (13, 18))	('EA', 'Phenotype', 'HP:0011459', (160, 162))	('accumulation', 'PosReg', (67, 79))
485721	28716721	However, fewer than 20% of specific variants overlap between adjacent BE and EA, so either the cancer clone diverged at an early stage or originated separately .	('BE', 'Phenotype', 'HP:0100580', (70, 72))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('EA', 'Phenotype', 'HP:0011459', (77, 79))
485726	28716721	Invasive tumors have an increased number copy numbers of several oncogenes (GATA4, KLF5, MYB, PRKCI, CCND1, FGF3, FGF4, FGF19, and VEGFA) and loss of common fragile sites (FHIT, WWOX, PDE4D, PTPRD, and PARK2)  The stochastic and gradual accrual of copy number alterations fits into the linear multistep process of BE progression, but does not entirely account for the frequent whole-genome doubling observed by Stachler at al: particularly in EA tissues with TP53 mutations.	('PRKCI', 'Gene', (94, 99))	('BE', 'Phenotype', 'HP:0100580', (314, 316))	('PARK2', 'Gene', '5071', (202, 207))	('GATA4', 'Gene', (76, 81))	('KLF5', 'Gene', '688', (83, 87))	('FGF4', 'Gene', '2249', (114, 118))	('MYB', 'Gene', '4602', (89, 92))	('PDE4D', 'Gene', (184, 189))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('MYB', 'Gene', (89, 92))	('VEGFA', 'Gene', '7422', (131, 136))	('PTPRD', 'Gene', (191, 196))	('EA', 'Phenotype', 'HP:0011459', (443, 445))	('PARK2', 'Gene', (202, 207))	('KLF5', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (459, 463))	('WWOX', 'Gene', '51741', (178, 182))	('FHIT', 'Gene', (172, 176))	('PTPRD', 'Gene', '5789', (191, 196))	('PRKCI', 'Gene', '5584', (94, 99))	('GATA4', 'Gene', '2626', (76, 81))	('CCND1', 'Gene', '595', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (464, 473))	('FHIT', 'Gene', '2272', (172, 176))	('FGF3', 'Gene', (108, 112))	('FGF4', 'Gene', (114, 118))	('CCND1', 'Gene', (101, 106))	('FGF19', 'Gene', (120, 125))	('FGF19', 'Gene', '9965', (120, 125))	('FGF3', 'Gene', '2248', (108, 112))	('VEGFA', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('accrual of copy number alterations fits', 'Disease', 'MESH:D012640', (237, 276))	('accrual of copy number alterations fits', 'Disease', (237, 276))	('PDE4D', 'Gene', '5144', (184, 189))	('TP53', 'Gene', (459, 463))	('tumors', 'Disease', (9, 15))	('WWOX', 'Gene', (178, 182))
485750	28716721	Other signatures include one associated with aging (S1):a complex pattern caused by defects in the BRCA1/2-regulated homologous recombination pathway (S3); C>T mutations in a TCA/TCT context, due to apolipoprotein B mRNA editing enzyme catalytic polypeptide-like(APOBEC)-mutations (S2); and C>A/T dominant in a GCA/TCT context (S18), also found in gastric carcinoma and neuroblastoma.	('gastric carcinoma', 'Disease', (348, 365))	('BRCA1', 'Gene', (99, 104))	('defects', 'NegReg', (84, 91))	('apolipoprotein B', 'Gene', (199, 215))	('BE', 'Phenotype', 'HP:0100580', (266, 268))	('C>A/T', 'Var', (291, 296))	('neuroblastoma', 'Disease', 'MESH:D009447', (370, 383))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (348, 365))	('apolipoprotein B', 'Gene', '338', (199, 215))	('neuroblastoma', 'Disease', (370, 383))	('gastric carcinoma', 'Disease', 'MESH:D013274', (348, 365))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('C>T mutations', 'Var', (156, 169))	('BRCA1', 'Gene', '672', (99, 104))	('neuroblastoma', 'Phenotype', 'HP:0003006', (370, 383))
485754	28716721	TP53 is by far the most frequently mutated gene:more than 70% of samples contain loss of function mutations in TP53.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('loss of function', 'NegReg', (81, 97))	('TP53', 'Gene', '7157', (111, 115))	('mutations', 'Var', (98, 107))	('TP53', 'Gene', (111, 115))
485757	28716721	structural variants) and gain or losses of genomic regions (copy number alterations)  (Figure 1).	('structural variants', 'Var', (0, 19))	('genomic', 'MPA', (43, 50))	('losses', 'NegReg', (33, 39))	('gain', 'Disease', (25, 29))	('gain', 'Disease', 'MESH:D015430', (25, 29))
485758	28716721	Chromosome instability stands out as a hallmark of EA when compared to squamous esophageal cancer and gastric adenocarcinoma .	('squamous esophageal cancer', 'Disease', 'MESH:D004938', (71, 97))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (102, 124))	('gastric adenocarcinoma', 'Disease', (102, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('Chromosome instability', 'Var', (0, 22))	('squamous esophageal cancer', 'Disease', (71, 97))	('EA', 'Phenotype', 'HP:0011459', (51, 53))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Chromosome instability', 'Phenotype', 'HP:0040012', (0, 22))
485759	28716721	Copy number alterations of genes encoding EGFR, ERBB2, MET, and FGFR2 and other receptor tyrosine kinases are also common in EA and show a high degree of redundancy with downstream targets  (Figure 2, Figure 4, Supplementary Table 2).	('FGFR2', 'Gene', '2263', (64, 69))	('EGFR', 'Gene', '1956', (42, 46))	('men', 'Species', '9606', (217, 220))	('common', 'Reg', (115, 121))	('EA', 'Phenotype', 'HP:0011459', (125, 127))	('EGFR', 'Gene', (42, 46))	('Copy number alterations', 'Var', (0, 23))	('ERBB2', 'Gene', '2064', (48, 53))	('MET', 'Gene', (55, 58))	('ERBB2', 'Gene', (48, 53))	('FGFR2', 'Gene', (64, 69))
485762	28716721	For instance, the fragile histidine triad gene (FHIT or FRA3B) and WW domain containing oxidoreductase gene (WWOX or FRA16D) contain rearrangements in up to 95% of cases.	('rearrangements', 'Var', (133, 147))	('men', 'Species', '9606', (142, 145))	('WWOX', 'Gene', '51741', (109, 113))	('WWOX', 'Gene', (109, 113))	('FRA16D', 'Gene', (117, 123))	('histidine', 'Chemical', 'MESH:D006639', (26, 35))	('FRA3B', 'Gene', (56, 61))	('FHIT', 'Gene', (48, 52))	('to 9', 'Species', '1214577', (154, 158))	('FRA3B', 'Gene', '2272', (56, 61))	('FRA16D', 'Gene', '2463', (117, 123))	('FHIT', 'Gene', '2272', (48, 52))
485764	28716721	RUNX1, a gene translocated in acute myeloid leukemia, and SMYD3, are rearranged in 39% and 27% of cases of EA.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (36, 52))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (30, 52))	('SMYD3', 'Gene', (58, 63))	('SMYD3', 'Gene', '64754', (58, 63))	('acute myeloid leukemia', 'Disease', (30, 52))	('EA', 'Phenotype', 'HP:0011459', (107, 109))	('RUNX1', 'Gene', (0, 5))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (30, 52))	('leukemia', 'Phenotype', 'HP:0001909', (44, 52))	('rearranged', 'Var', (69, 79))	('RUNX1', 'Gene', '861', (0, 5))
485765	28716721	Although functional studies are needed to confirm a driver role in EA, these alterations are possibly the most common after TP53 mutations.	('common', 'Reg', (111, 117))	('TP53', 'Gene', '7157', (124, 128))	('mutations', 'Var', (129, 138))	('TP53', 'Gene', (124, 128))	('EA', 'Phenotype', 'HP:0011459', (67, 69))
485766	28716721	In addition, a peculiar class of structural variations is represented by mobile element insertions that occur as a consequence of the excision and re-insertion of repeated L1 and Alu sequences that are transposed as DNA or through the reverse transcription of an mRNA intermediate.	('Alu', 'Gene', (179, 182))	('men', 'Species', '9606', (83, 86))	('insertions', 'Var', (88, 98))
485767	28716721	In EA, L1 insertions have been reported in the coding sequence of several genes (ERBB4, CTNNA3, CTNNA2, CDH18, and SOX5).	('CTNNA3', 'Gene', '29119', (88, 94))	('CTNNA3', 'Gene', (88, 94))	('CDH18', 'Gene', (104, 109))	('EA', 'Phenotype', 'HP:0011459', (3, 5))	('ERBB4', 'Gene', (81, 86))	('CTNNA2', 'Gene', '1496', (96, 102))	('insertions', 'Var', (10, 20))	('SOX5', 'Gene', '6660', (115, 119))	('CTNNA2', 'Gene', (96, 102))	('L1 insertions', 'Var', (7, 20))	('CDH18', 'Gene', '1016', (104, 109))	('ERBB4', 'Gene', '2066', (81, 86))	('SOX5', 'Gene', (115, 119))
485777	28716721	This process can be repeated for several cell cycles resulting in inverted duplications increase copy numbers of genes including KRAS, MDM2, and VEGFA .	('copy numbers', 'MPA', (97, 109))	('VEGFA', 'Gene', (145, 150))	('increase', 'PosReg', (88, 96))	('inverted duplications', 'Var', (66, 87))	('KRAS', 'Gene', (129, 133))	('KRAS', 'Gene', '3845', (129, 133))	('VEGFA', 'Gene', '7422', (145, 150))	('MDM2', 'Gene', '4193', (135, 139))	('MDM2', 'Gene', (135, 139))
485780	28716721	Since loss of TP53 is the most common mutation, it would make sense to try to restore its function as a therapeutic strategy.	('loss', 'Var', (6, 10))	('TP53', 'Gene', (14, 18))	('TP53', 'Gene', '7157', (14, 18))
485784	28716721	Recent sequencing data indicate that tumors from each patient have dysregulations in multiple receptor tyrosine kinases and their signaling pathways, so multiple agents could be required .	('patient', 'Species', '9606', (54, 61))	('signaling pathways', 'Pathway', (130, 148))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('dysregulations', 'Var', (67, 81))	('receptor tyrosine kinases', 'Enzyme', (94, 119))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
485786	28716721	EA genomes can be grouped into 3 categories according to their dominant mutation signatures: C>A/T dominant (associated with age, S18-like), DNA damage repair impaired (BRCA), and mutagenic (predominantly S17A or S17B) .	('S17A', 'Var', (205, 209))	('C>A/T', 'Var', (93, 98))	('S17B', 'SUBSTITUTION', 'None', (213, 217))	('S17B', 'Var', (213, 217))	('EA', 'Phenotype', 'HP:0011459', (0, 2))	('BRCA', 'Gene', '672', (169, 173))	('S17A', 'Mutation', 'rs1402064476', (205, 209))	('BRCA', 'Gene', (169, 173))	('impaired', 'NegReg', (159, 167))
485787	28716721	EAs with a DNA-damage repair defect signature have significantly more defects in homologous recombination and chromosome segregation pathways and may therefore respond better to DNA-damaging agents or photon irradiation in combination with inhibitors of PARP.	('homologous', 'MPA', (81, 91))	('EAs', 'Chemical', '-', (0, 3))	('EA', 'Phenotype', 'HP:0011459', (0, 2))	('PARP', 'Gene', '1302', (254, 258))	('DNA-damage', 'Gene', (11, 21))	('PARP', 'Gene', (254, 258))	('chromosome', 'CPA', (110, 120))	('defect', 'Var', (29, 35))	('better', 'PosReg', (168, 174))	('defects', 'NegReg', (70, 77))	('respond', 'Reg', (160, 167))
485788	28716721	On the other hand, EAs with a mutagenic signature have a higher neoantigen load and are characterized by infiltration of CD8+ T cells; these are more likely to respond to blockade of PDL1 and CTLA4, as observed in studies of patients with non small-cell lung cancer and melanoma .	('neoantigen load', 'MPA', (64, 79))	('CTLA4', 'Gene', (192, 197))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('melanoma', 'Disease', (270, 278))	('blockade', 'Var', (171, 179))	('more', 'PosReg', (145, 149))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (243, 265))	('small-cell lung cancer', 'Disease', (243, 265))	('patients', 'Species', '9606', (225, 233))	('melanoma', 'Disease', 'MESH:D008545', (270, 278))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('PDL1', 'Gene', (183, 187))	('mutagenic', 'Var', (30, 39))	('CTLA4', 'Gene', '1493', (192, 197))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (243, 265))	('higher', 'PosReg', (57, 63))	('PDL1', 'Gene', '29126', (183, 187))	('EAs', 'Chemical', '-', (19, 22))	('EA', 'Phenotype', 'HP:0011459', (19, 21))
485790	28716721	In peripheral blood samples, circulating tumor DNA has been used successfully to monitor response to therapy, as well as to identify the emergence of novel alterations conferring secondary resistance to targeted therapies  (Figure 5).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('secondary resistance', 'MPA', (179, 199))	('alterations', 'Var', (156, 167))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
485798	28716721	Almost all of the genetic variants discovered have been associated with BE and EA, indicating that EA arises via a metaplasia-dysplasia-carcinoma pathway.	('metaplasia-dysplasia-carcinoma', 'Disease', (115, 145))	('EA', 'Phenotype', 'HP:0011459', (99, 101))	('EA', 'Phenotype', 'HP:0011459', (79, 81))	('associated', 'Reg', (56, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (115, 145))	('BE', 'Phenotype', 'HP:0100580', (72, 74))	('variants', 'Var', (26, 34))
485799	28716721	Annotations of the genes indicate that aberrations in the musculature of the foregut, perhaps during embryogenesis, that likely contribute to GER.	('GER', 'Gene', '59330', (142, 145))	('aberrations in the musculature', 'Phenotype', 'HP:0003011', (39, 69))	('GER', 'Gene', (142, 145))	('aberrations', 'Var', (39, 50))	('GER', 'Phenotype', 'HP:0002020', (142, 145))	('contribute', 'Reg', (128, 138))
485805	28716721	Several pathways are involved in the progression from BE to EA but the final common feature is that of an abnormal copy number profile with large-scale structural variants, and with amplifications and complex rearrangements occurring to a variable extent.	('copy number', 'Var', (115, 126))	('EA', 'Phenotype', 'HP:0011459', (60, 62))	('structural variants', 'Var', (152, 171))	('BE', 'Phenotype', 'HP:0100580', (54, 56))	('men', 'Species', '9606', (218, 221))
485806	28716721	In some instances, disease progression can be very slow with a cumulative number of points mutations in tumor suppressor genes; other tumors have punctuated evolution resulting in rapid progression.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('slow', 'NegReg', (51, 55))	('disease progression', 'CPA', (19, 38))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('points mutations', 'Var', (84, 100))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
485810	28716721	Functional studies of susceptibility loci, to identify causal variants and the carcinogenic mechanisms, may eventually lead to the discovery of biomarkers of risk and targeted approaches to prevention and treatment.	('lead to', 'Reg', (119, 126))	('men', 'Species', '9606', (210, 213))	('variants', 'Var', (62, 70))
485813	28716721	Ideally the term dysplasia would be superceded by a molecular readout detailing TP53 mutations and copy number alterations, so that a risk:benefit profile for endoscopic therapy can be determined.	('dysplasia', 'Disease', 'MESH:D004476', (17, 26))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('copy number alterations', 'Var', (99, 122))	('dysplasia', 'Disease', (17, 26))
485821	28900112	Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('dysplasia', 'Disease', (50, 59))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (143, 168))	('prevalent', 'Reg', (37, 46))	('esophageal adenocarcinoma', 'Disease', (143, 168))	('dysplasia', 'Disease', 'MESH:D004476', (50, 59))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (143, 168))	('ESCC', 'Disease', (83, 87))	('copy number alterations', 'Var', (9, 32))
485827	28900112	The genomic landscape of ESCC has been characterized, revealing that the most common alteration is the mutation of TP53 through single-nucleotide variations and/or copy number losses.	('TP53', 'Gene', '7157', (115, 119))	('TP53', 'Gene', (115, 119))	('single-nucleotide variations', 'Var', (128, 156))	('copy number losses', 'Var', (164, 182))	('mutation', 'Var', (103, 111))
485831	28900112	Previous studies indicated that TP53 is altered in some of the patients with dysplasia, and some copy number alteration (CNA) events, such as amplifications in 3q and 5p and losses in 3p, are also identified in a small dysplasia cohort.	('dysplasia', 'Disease', 'MESH:D004476', (219, 228))	('copy number', 'MPA', (97, 108))	('TP53', 'Gene', '7157', (32, 36))	('dysplasia', 'Disease', (77, 86))	('dysplasia', 'Disease', 'MESH:D004476', (77, 86))	('losses', 'NegReg', (174, 180))	('patients', 'Species', '9606', (63, 71))	('TP53', 'Gene', (32, 36))	('altered', 'Reg', (40, 47))	('amplifications', 'Var', (142, 156))	('small dysplasia cohort', 'Disease', 'MESH:D018288', (213, 235))	('small dysplasia cohort', 'Disease', (213, 235))	('dysplasia', 'Disease', (219, 228))
485835	28900112	noted that there might be two paths for BE to transform to EAC: one way is through a gradual loss of tumor suppressor genes followed by genomic instability and amplification of oncogenes; the other way starts with the inactivation of TP53, followed by whole-genome doubling, which facilitates genomic instability and oncogene activation.	('TP53', 'Gene', '7157', (234, 238))	('facilitates', 'PosReg', (281, 292))	('TP53', 'Gene', (234, 238))	('oncogene', 'CPA', (317, 325))	('activation', 'PosReg', (326, 336))	('loss', 'NegReg', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('genomic instability', 'CPA', (293, 312))	('BE', 'Phenotype', 'HP:0100580', (40, 42))	('EAC', 'Phenotype', 'HP:0011459', (59, 62))	('inactivation', 'Var', (218, 230))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
485840	28900112	Moreover, the 'two-hit' events on TP53 are dominant in the dysplasia and carcinoma samples from the 45 ESCC patients, but rare in the dysplasia samples from the 13 tumor-free patients, suggesting that the full inactivation of TP53 is essential in promoting the development of ESCC.	('carcinoma', 'Disease', (73, 82))	('patients', 'Species', '9606', (108, 116))	('TP53', 'Gene', (226, 230))	('inactivation', 'Var', (210, 222))	('tumor-free', 'Disease', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('carcinoma', 'Disease', 'MESH:D002277', (73, 82))	('TP53', 'Gene', (34, 38))	('tumor-free', 'Disease', 'MESH:D000072662', (164, 174))	('dysplasia', 'Disease', (134, 143))	('TP53', 'Gene', '7157', (226, 230))	('dysplasia', 'Disease', 'MESH:D004476', (134, 143))	('ESCC', 'Disease', (276, 280))	('promoting', 'PosReg', (247, 256))	('patients', 'Species', '9606', (175, 183))	('dysplasia', 'Disease', (59, 68))	('TP53', 'Gene', '7157', (34, 38))	('dysplasia', 'Disease', 'MESH:D004476', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
485851	28900112	Since these lesions were also categorized as low-grade dysplasia (Supplementary Data 3) on histopathology, the smaller number of mutations accumulated compared to LDs in the TD cohort is possibly due to a shorter period after the initiation of neoplasia.	('neoplasia', 'Disease', 'MESH:D009369', (244, 253))	('neoplasia', 'Phenotype', 'HP:0002664', (244, 253))	('dysplasia', 'Disease', (55, 64))	('mutations', 'Var', (129, 138))	('dysplasia', 'Disease', 'MESH:D004476', (55, 64))	('Dat', 'Gene', (80, 83))	('neoplasia', 'Disease', (244, 253))	('Dat', 'Gene', '6531', (80, 83))
485852	28900112	Regarding the mutational context, we observed a strong enrichment of C > T transitions in both squamous dysplasia and ESCC samples, especially at the CpG dinucleotides, which is denoted as signature 1 documented in the COSMIC Mutational Signature Framework (Fig.	('C > T transitions', 'Var', (69, 86))	('ESCC', 'Disease', (118, 122))	('esp', 'Gene', (132, 135))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (150, 167))	('squamous dysplasia', 'Disease', (95, 113))	('squamous dysplasia', 'Disease', 'MESH:D002294', (95, 113))	('esp', 'Gene', '148713', (132, 135))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (95, 113))
485853	28900112	1c, d), suggesting that the spontaneous deamination of cytosine contributes most to the accumulation of mutations during tumorigenesis.	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('cytosine', 'Chemical', 'MESH:D003596', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
485857	28900112	Mutations in TP53 was the most recurrent event, present in dysplasia samples among 95.6% of patients and in ESCCs among 97.8% of patients.	('TP53', 'Gene', (13, 17))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (92, 100))	('Mutations', 'Var', (0, 9))	('dysplasia', 'Disease', (59, 68))	('TP53', 'Gene', '7157', (13, 17))	('dysplasia', 'Disease', 'MESH:D004476', (59, 68))
485859	28900112	However, in ESCC we identified mutations in TP53 with a high frequency in dysplasia samples (95.6%), and some were found even in NTDs (30.8%; Fig.	('mutations', 'Var', (31, 40))	('found', 'Reg', (115, 120))	('NTD', 'Gene', '80199', (129, 132))	('dysplasia', 'Disease', (74, 83))	('dysplasia', 'Disease', 'MESH:D004476', (74, 83))	('TP53', 'Gene', '7157', (44, 48))	('NTD', 'Gene', (129, 132))	('TP53', 'Gene', (44, 48))
485860	28900112	2), suggesting that TP53 mutations may occur very early in ESCC progression.	('mutations', 'Var', (25, 34))	('ESCC', 'Disease', (59, 63))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (20, 24))
485863	28900112	For patients with multiple samples (>=3) from the TD cohort, we portrayed the regional distribution of mutations of dysplasia samples and ESCCs (Fig.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (4, 12))	('dysplasia', 'Disease', (116, 125))	('dysplasia', 'Disease', 'MESH:D004476', (116, 125))
485864	28900112	Mutations were classified as 'trunk' if they were detected in all samples from one patient, 'shared' if they were detected in more than one but not all samples, and 'private' if they were specific to only one sample.	('detected', 'Reg', (50, 58))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (83, 90))
485867	28900112	The mutational burdens of the 4 dysplasia samples and 4 ESCCs were comparable, with an average of 100 mutations (Fig.	('dysplasia', 'Disease', 'MESH:D004476', (32, 41))	('mutations', 'Var', (102, 111))	('dysplasia', 'Disease', (32, 41))
485869	28900112	By contrast, of the 4 dysplasia samples, LD1 shared 42 mutations with the 4 ESCCs, including the well-known ESCC related genes TP53, NFE2L2, and RB1, while the LD2, HD3, and HD4 had nearly no overlapping mutation with all 4 ESCCs.	('RB1', 'Gene', (145, 148))	('HD3', 'Gene', (165, 168))	('NFE2L2', 'Gene', '4780', (133, 139))	('mutations', 'Var', (55, 64))	('LD1', 'Gene', (41, 44))	('HD4', 'Gene', (174, 177))	('HD3', 'Gene', '8841', (165, 168))	('NFE2L2', 'Gene', (133, 139))	('RB1', 'Gene', '5925', (145, 148))	('dysplasia', 'Disease', (22, 31))	('ESCC', 'Disease', (108, 112))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('dysplasia', 'Disease', 'MESH:D004476', (22, 31))	('HD4', 'Gene', '9759', (174, 177))
485870	28900112	To further resolve the clonal relationship of LD1 and matched ESCCs, we calculated the cancer cell fraction (CCF) of mutations in LD1 and the 4 ESCCs.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (117, 126))	('LD1', 'Gene', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
485871	28900112	Of the ESCC private mutations, we found EGFR (p.F712L) in all 4 ESCCs and PIK3CA (p.E545K) in C3 and C4, implying they occurred late during the tumorigenesis progression.	('p.F712L', 'Var', (46, 53))	('tumor', 'Disease', (144, 149))	('p.E545K', 'Mutation', 'rs104886003', (82, 89))	('p.F712L', 'Mutation', 'p.F712L', (46, 53))	('PIK3CA', 'Gene', '5290', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('ESCC private', 'Gene', (7, 19))	('p.E545K', 'Var', (82, 89))	('PIK3CA', 'Gene', (74, 80))
485876	28900112	3d, f), each with one lymph node metastasis, we found that each patient's samples had a common ancestor, with 29 trunk mutations in P12 and 47 trunk mutations in P25.	('P12', 'Gene', (132, 135))	('patient', 'Species', '9606', (64, 71))	('P25', 'Gene', '8851', (162, 165))	('P12', 'Gene', '56655', (132, 135))	('P25', 'Gene', (162, 165))	('mutations', 'Var', (119, 128))
485879	28900112	In P25, metastasis had 91.4% of the mutations shared with one ESCC (C2), indicating that it was disseminated from C2 at a late stage.	('P25', 'Gene', '8851', (3, 6))	('mutations', 'Var', (36, 45))	('P25', 'Gene', (3, 6))
485880	28900112	Through analysis of the CCF values of the mutations in P25_C2 vs. P25_M, we identified a cluster of mutations that are clonal in P25_M but subclonal in P25_C2, which also proved the relationship between the metastasis and C2 (Supplementary Fig.	('mutations', 'Var', (100, 109))	('P25', 'Gene', '8851', (152, 155))	('P25', 'Gene', '8851', (66, 69))	('P25', 'Gene', (55, 58))	('P25', 'Gene', (66, 69))	('P25', 'Gene', '8851', (129, 132))	('P25', 'Gene', (152, 155))	('P25', 'Gene', (129, 132))	('mutations', 'Var', (42, 51))	('P25', 'Gene', '8851', (55, 58))
485888	28900112	Consistently, we found that the dysplasia samples had significantly more subclonal mutations (Fisher's exact test, P = 2.66e-5), strongly implying that the dysplasia samples were highly heterogeneous.	('dysplasia', 'Disease', (156, 165))	('more', 'PosReg', (68, 72))	('dysplasia', 'Disease', (32, 41))	('dysplasia', 'Disease', 'MESH:D004476', (156, 165))	('dysplasia', 'Disease', 'MESH:D004476', (32, 41))	('subclonal mutations', 'Var', (73, 92))
485895	28900112	We then examined the hot regions of CNAs previously reported in ESCC, identifying gains in 3q (especially 3q25.31-3q26.1 and 3q26.3), 5p15.33, 7p12.1-7p11.2, 8q, and 11q13.3-11q13.4, as well as losses in 3p21.31, 9p21.3, and 13q21.1 with high frequencies in both dysplasia samples and ESCCs, and these recurrent CNAs tended to be shared by all samples in each patient (Fig.	('esp', 'Gene', '148713', (95, 98))	('losses', 'NegReg', (194, 200))	('5p15.33', 'Var', (134, 141))	('esp', 'Gene', (95, 98))	('patient', 'Species', '9606', (360, 367))	('gains', 'PosReg', (82, 87))	('dysplasia', 'Disease', (263, 272))	('dysplasia', 'Disease', 'MESH:D004476', (263, 272))	('3p21.31', 'Gene', (204, 211))
485899	28900112	For those frequently altered regions in ESCC, we evaluated the proportion of the CNAs that were ubiquitous, and found that gains in 3q26.3 and 3q25.31-26.1 had significant bias towards being 'trunk' (Fisher's exact test, P = 0.009 and P = 0.05, respectively; Fig.	('esp', 'Gene', (246, 249))	('3q26.3', 'Var', (132, 138))	('gains', 'PosReg', (123, 128))	('3q25.31-26.1', 'Var', (143, 155))	('esp', 'Gene', '148713', (246, 249))
485902	28900112	Through the inspection of focal amplifications and deletions of driver genes, we observed a high occurrence of amplifications in SOX2, PIK3CA, MYC, CCND1, and FGFR1 in both dysplasia samples and ESCCs, but the copy number status did not show obvious progression (Fig.	('CCND1', 'Gene', (148, 153))	('dysplasia', 'Disease', (173, 182))	('CCND1', 'Gene', '595', (148, 153))	('SOX2', 'Gene', '6657', (129, 133))	('amplifications', 'Var', (111, 125))	('SOX2', 'Gene', (129, 133))	('deletions', 'Var', (51, 60))	('PIK3CA', 'Gene', (135, 141))	('PIK3CA', 'Gene', '5290', (135, 141))	('MYC', 'Gene', '4609', (143, 146))	('dysplasia', 'Disease', 'MESH:D004476', (173, 182))	('FGFR1', 'Gene', (159, 164))	('FGFR1', 'Gene', '2260', (159, 164))	('MYC', 'Gene', (143, 146))
485907	28900112	Nevertheless, in several cases from the TD cohort (P6, P8, and P25), while the mutational distributions of the samples in each patient were dissimilar, we observed a high consistency in the copy number patterns, implying that in these patients, the CNAs not only emerged early but also remained steady during the ESCC progression.	('patient', 'Species', '9606', (235, 242))	('patient', 'Species', '9606', (127, 134))	('patients', 'Species', '9606', (235, 243))	('P25', 'Gene', (63, 66))	('ESCC', 'Disease', (313, 317))	('CNAs', 'MPA', (249, 253))	('P25', 'Gene', '8851', (63, 66))	('P6', 'Var', (51, 53))
485911	28900112	In the other 6 cases, although each sample harbored one or more TP53 mutations, none was ubiquitous among all samples.	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (64, 68))	('harbored', 'Reg', (43, 51))	('TP53', 'Gene', (64, 68))
485912	28900112	Moreover, the phylogenies of these 6 cases suggested that samples carrying independent TP53 mutations came from distantly related clones.	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))
485913	28900112	Nevertheless, according to the CCF, most of the mutations in TP53 were clonal.	('mutations', 'Var', (48, 57))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
485914	28900112	In addition, 4 of the 13 NTDs possessed mutations in TP53 (Fig.	('mutations', 'Var', (40, 49))	('NTD', 'Gene', '80199', (25, 28))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))	('NTD', 'Gene', (25, 28))
485915	28900112	Thus, we inferred that mutations in TP53 arose early during ESCC development.	('mutations', 'Var', (23, 32))	('ESCC', 'Disease', (60, 64))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
485916	28900112	Since most of the mutations occurred in the DNA binding domain of the p53 protein (Fig.	('occurred', 'Reg', (28, 36))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('protein', 'Protein', (74, 81))	('mutations', 'Var', (18, 27))
485918	28900112	In contrast to the truncating mutations, which would lead to the depletion of the protein, the missense mutations usually resulted in an enhanced expression of p53 protein (Supplementary Fig.	('enhanced', 'PosReg', (137, 145))	('missense mutations', 'Var', (95, 113))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('expression', 'MPA', (146, 156))
485921	28900112	In the TD cohort, 69 of the 71 dysplasia samples had a mutated TP53 in conjunction with LOH (two-hit), which is similar to the results of ESCCs, in which 51 of the 54 samples harbored the two-hit alterations in TP53.	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('mutated', 'Var', (55, 62))	('dysplasia', 'Disease', 'MESH:D004476', (31, 40))	('TP53', 'Gene', '7157', (211, 215))	('TP53', 'Gene', (211, 215))	('dysplasia', 'Disease', (31, 40))
485923	28900112	In contrast, in the NTD cohort, even 3 NTDs showed LOH in TP53, none of the 10 NTDs harbored both the mutation and LOH in TP53 (samples with more than 1 mutation in TP53 but without LOH were excluded in the statistical analysis; Fig.	('NTD', 'Gene', (20, 23))	('TP53', 'Gene', (122, 126))	('TP53', 'Gene', (165, 169))	('TP53', 'Gene', '7157', (58, 62))	('NTD', 'Gene', (79, 82))	('TP53', 'Gene', (58, 62))	('NTD', 'Gene', '80199', (39, 42))	('LOH', 'Var', (51, 54))	('NTD', 'Gene', '80199', (20, 23))	('NTD', 'Gene', '80199', (79, 82))	('NTD', 'Gene', (39, 42))	('TP53', 'Gene', '7157', (122, 126))	('TP53', 'Gene', '7157', (165, 169))
485927	28900112	In conclusion, we inferred that LOH or mutations in TP53 could either occur early but the further development of ESCC requires the full inactivation of TP53.	('ESCC', 'Disease', (113, 117))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', '7157', (152, 156))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (39, 48))	('TP53', 'Gene', (152, 156))
485939	28900112	In summary, we postulate that the accumulation of CNAs and mutations may represent two distinct genetic timers during tumorigenesis of ESCC.	('ESCC', 'Disease', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('mutations', 'Var', (59, 68))	('CNAs', 'Gene', (50, 54))
485945	28900112	By analyzing the truncal events across cases in the TD cohort, we speculated that mutations in TP53 and gains in 3q are early alterations during the ESCC development.	('ESCC', 'Disease', (149, 153))	('gains', 'PosReg', (104, 109))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
485946	28900112	Moreover, we identified TP53 mutations in 4 NTDs, while gains in 3q were present in 8 NTDs and 2 normal tissues adjacent to tumors, reinforcing the idea that they play essential roles in initiating the tumorigenesis.	('NTD', 'Gene', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (202, 207))	('TP53', 'Gene', (24, 28))	('NTD', 'Gene', '80199', (44, 47))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (24, 28))	('tumor', 'Disease', (124, 129))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('NTD', 'Gene', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('NTD', 'Gene', '80199', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
485952	28900112	As previously discussed by Stachler et al., one major path for BE to transform to EAC is through the inactivation of TP53, followed by whole-genome doubling.	('TP53', 'Gene', '7157', (117, 121))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('TP53', 'Gene', (117, 121))	('inactivation', 'Var', (101, 113))	('BE', 'Phenotype', 'HP:0100580', (63, 65))
485968	28900112	To further confirm the fidelity of mutations that were called as described above, we validated a total of 96 non-silent mutations from 19 samples of 5 patients (SP6, SP14, P5, P11, and P14).	('P14', 'Gene', '1029', (167, 170))	('P14', 'Gene', '1029', (185, 188))	('P14', 'Gene', (167, 170))	('P14', 'Gene', (185, 188))	('patients', 'Species', '9606', (151, 159))	('SP6', 'Var', (161, 164))	('P11', 'Gene', (176, 179))	('P11', 'Gene', '6281', (176, 179))
485972	28900112	To identify potential driver mutations in dysplasia samples and ESCCs, we evaluated the non-synonymous mutations from the following three aspects: (1) Mutations in significantly mutated genes highlighted by recent large cohort sequencing studies of ESCC; (2) Mutations in genes that are documented by the COSMIC database (ESCC-associated or related to other types of cancer); (3) Mutations in genes that are present in the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways in cancer.	('dysplasia', 'Disease', 'MESH:D004476', (42, 51))	('cancer', 'Disease', (482, 488))	('cancer', 'Disease', 'MESH:D009369', (482, 488))	('cancer', 'Disease', 'MESH:D009369', (367, 373))	('Mutations', 'Var', (380, 389))	('cancer', 'Disease', (367, 373))	('cancer', 'Phenotype', 'HP:0002664', (482, 488))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('dysplasia', 'Disease', (42, 51))
486002	28900112	The Fisher's exact test was used to determine whether a potential driver alteration has bias towards being 'trunk', to compare the enrichment in the number of cases harboring mutations in ESCC-associated genes of different pathways, to compare the significant differences in the number of cases harboring the genome doubling event and the 'two-hit' event on TP53.	('ESCC-associated', 'Gene', (188, 203))	('mutations', 'Var', (175, 184))	('TP53', 'Gene', '7157', (358, 362))	('TP53', 'Gene', (358, 362))
486010	24527027	The upregulation of FOXO3, GAPDH, and MYD88 variants in esophageal cancer suggests a role for autophagy and provides new insight into the biology of esophageal cancer.	('GAPDH', 'Gene', '2597', (27, 32))	('MYD88', 'Gene', '4615', (38, 43))	('MYD88', 'Gene', (38, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('esophageal cancer', 'Disease', (56, 73))	('GAPDH', 'Gene', (27, 32))	('autophagy', 'CPA', (94, 103))	('FOXO3', 'Gene', (20, 25))	('esophageal cancer', 'Disease', (149, 166))	('FOXO3', 'Gene', '2309', (20, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('upregulation', 'PosReg', (4, 16))	('variants', 'Var', (44, 52))
486014	24527027	Although some altered oncogenes and tumor suppressor genes have been identified in esophageal cancer (e.g., p53 deletion, p21 alteration, and amplification of CCND1 and c-myc), the fundamental molecular mechanisms leading to esophageal cancer remain unknown.	('p21', 'Gene', (122, 125))	('deletion', 'Var', (112, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (225, 242))	('tumor', 'Disease', (36, 41))	('esophageal cancer', 'Disease', (83, 100))	('CCND1', 'Gene', '595', (159, 164))	('esophageal cancer', 'Disease', (225, 242))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('c-myc', 'Gene', '4609', (169, 174))	('p21', 'Gene', '1026', (122, 125))	('CCND1', 'Gene', (159, 164))	('p53', 'Gene', '7157', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('amplification', 'Var', (142, 155))	('p53', 'Gene', (108, 111))	('c-myc', 'Gene', (169, 174))
486041	24527027	Alternative splicing of MYD88 variants was analyzed using the real-time PCR method.	('MYD88', 'Gene', '4615', (24, 29))	('MYD88', 'Gene', (24, 29))	('variants', 'Var', (30, 38))
486043	24527027	The designed primers locations for the specific MyD88 variants are depicted in Figure 1.	('MyD88', 'Gene', (48, 53))	('variants', 'Var', (54, 62))	('MyD88', 'Gene', '4615', (48, 53))
486045	24527027	The efficiencies of the reactions amplifying the FOXO3, MYD88 variants, GAPDH, and beta actin genes were calculated using a standard curve that consisted of 5 points from 10-fold serial dilutions that were prepared using 100 ng of the synthesized cDNA as the first point.	('FOXO3', 'Gene', '2309', (49, 54))	('MYD88', 'Gene', '4615', (56, 61))	('FOXO3', 'Gene', (49, 54))	('GAPDH', 'Gene', '2597', (72, 77))	('variants', 'Var', (62, 70))	('GAPDH', 'Gene', (72, 77))	('MYD88', 'Gene', (56, 61))	('beta actin', 'Gene', '728378', (83, 93))	('beta actin', 'Gene', (83, 93))
486046	24527027	Expression levels of the FOXO3, MYD88 variants, and GAPDH genes were normalized using the beta actin gene.	('variants', 'Var', (38, 46))	('GAPDH', 'Gene', '2597', (52, 57))	('GAPDH', 'Gene', (52, 57))	('FOXO3', 'Gene', (25, 30))	('MYD88', 'Gene', (32, 37))	('beta actin', 'Gene', (90, 100))	('beta actin', 'Gene', '728378', (90, 100))	('MYD88', 'Gene', '4615', (32, 37))	('FOXO3', 'Gene', '2309', (25, 30))
486057	24527027	The MYD88 variants were amplified using the Step-One-Plus apparatus.	('MYD88', 'Gene', (4, 9))	('MYD88', 'Gene', '4615', (4, 9))	('variants', 'Var', (10, 18))
486059	24527027	The mean fold induction for each MYD88 variant is depicted in Figure 3.	('MYD88', 'Gene', (33, 38))	('MYD88', 'Gene', '4615', (33, 38))	('fold', 'MPA', (9, 13))	('variant', 'Var', (39, 46))
486060	24527027	The results demonstrated a significant shift in the pattern of expression of MYD88 variants 1 and 3 in the esophageal cancer tissues compared with the normal tissues.	('shift', 'Reg', (39, 44))	('variants', 'Var', (83, 91))	('esophageal cancer', 'Disease', (107, 124))	('expression', 'MPA', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('MYD88', 'Gene', '4615', (77, 82))	('MYD88', 'Gene', (77, 82))
486061	24527027	In normal tissues, the expression patterns of the MYD88 variants were as follows: MYD88v1, 10%; MYD88v2, 12%; MYD88v3, 76%; and MYD88v5, 2%.	('MYD88', 'Gene', '4615', (96, 101))	('MYD88', 'Gene', (96, 101))	('MYD88', 'Gene', '4615', (110, 115))	('MYD88', 'Gene', (110, 115))	('MYD88', 'Gene', '4615', (128, 133))	('MYD88', 'Gene', (128, 133))	('variants', 'Var', (56, 64))	('MYD88', 'Gene', '4615', (82, 87))	('MYD88', 'Gene', (82, 87))	('MYD88', 'Gene', '4615', (50, 55))	('MYD88', 'Gene', (50, 55))
486078	24527027	Previous studies demonstrated that MYD88 has an important function in tumorigenesis, and high levels of MYD88 correlate with poor prognosis in patients with colorectal cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('colorectal cancers', 'Disease', 'MESH:D015179', (157, 175))	('MYD88', 'Gene', '4615', (35, 40))	('MYD88', 'Gene', (35, 40))	('tumor', 'Disease', (70, 75))	('MYD88', 'Gene', '4615', (104, 109))	('MYD88', 'Gene', (104, 109))	('patients', 'Species', '9606', (143, 151))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('colorectal cancers', 'Disease', (157, 175))	('high levels', 'Var', (89, 100))
486083	24527027	Our results revealed for the first time that MYD88 variants are upregulated in esophageal cancer tissues compared with normal tissues.	('esophageal cancer', 'Disease', (79, 96))	('MYD88', 'Gene', '4615', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('upregulated', 'PosReg', (64, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('variants', 'Var', (51, 59))	('MYD88', 'Gene', (45, 50))
486084	24527027	Our findings indicated that MYD88 overexpression could lead to autophagy in esophageal cancer.	('overexpression', 'Var', (34, 48))	('autophagy', 'CPA', (63, 72))	('MYD88', 'Gene', (28, 33))	('MYD88', 'Gene', '4615', (28, 33))	('esophageal cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('lead to', 'Reg', (55, 62))
486087	24527027	Interaction of MYD88 with Beclin1 has been previously demonstrated, but no information is available concerning the participation of individual exons in this interaction; thus, the role of each of the MYD88 variants in the interaction with Beclin1 and the subsequent induction of autophagy remains to be elucidated.	('interaction', 'Interaction', (222, 233))	('Beclin1', 'Gene', (239, 246))	('variants', 'Var', (206, 214))	('Interaction', 'Interaction', (0, 11))	('autophagy', 'CPA', (279, 288))	('Beclin1', 'Gene', '8678', (26, 33))	('MYD88', 'Gene', (200, 205))	('MYD88', 'Gene', '4615', (200, 205))	('Beclin1', 'Gene', '8678', (239, 246))	('MYD88', 'Gene', '4615', (15, 20))	('MYD88', 'Gene', (15, 20))	('Beclin1', 'Gene', (26, 33))
486090	24527027	However, cooperation of GAPDH with ATG12 could induce autophagy instead of caspase-independent cell death (CICD).	('GAPDH', 'Gene', '2597', (24, 29))	('GAPDH', 'Gene', (24, 29))	('induce', 'PosReg', (47, 53))	('CICD', 'Disease', (107, 111))	('cooperation', 'Var', (9, 20))	('caspase-independent', 'Disease', (75, 94))	('autophagy', 'CPA', (54, 63))	('ATG12', 'Gene', '9140', (35, 40))	('ATG12', 'Gene', (35, 40))	('CICD', 'Disease', 'None', (107, 111))
486106	24527027	Autophagy has previously been studied as a target for the development of new therapies for esophageal cancer because inhibition of autophagy has the potential to sensitize tumor cells, including chemoresistant cells, to therapeutic agents.	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (172, 177))	('autophagy', 'CPA', (131, 140))	('inhibition', 'Var', (117, 127))	('esophageal cancer', 'Disease', (91, 108))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
486150	23207041	GERD has also been linked to intestinal metaplasia in the GE junction, which may arise from a multilayered epithelium transition state and is believed to represent the biological precursor of dysplasia and cancer.	('intestinal metaplasia', 'Disease', 'MESH:D008679', (29, 50))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('linked to', 'Reg', (19, 28))	('GERD', 'Var', (0, 4))	('intestinal metaplasia', 'Disease', (29, 50))	('dysplasia and cancer', 'Disease', 'MESH:D009369', (192, 212))
486165	23207041	A nested case-control study using subjects from the ATBC trial in Finland reported that H. pylori seropositivity was associated with an odds ratio for GEJAC of 0.31 (95% CI 0.11-0.89).	('ATBC', 'Chemical', '-', (52, 56))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (91, 112))	('seropositivity', 'Var', (98, 112))	('GEJAC', 'Disease', (151, 156))	('H. pylori', 'Species', '210', (88, 97))
486178	23207041	Bisphosphonates are often prescribed for the prevention and treatment of osteoporosis, and are known to cause esophageal irritation and erosion.	('men', 'Species', '9606', (65, 68))	('osteoporosis', 'Disease', 'MESH:D010024', (73, 85))	('Bisphosphonates', 'Chemical', 'MESH:D004164', (0, 15))	('esophageal irritation', 'Disease', 'MESH:D004941', (110, 131))	('osteoporosis', 'Disease', (73, 85))	('cause', 'Reg', (104, 109))	('osteoporosis', 'Phenotype', 'HP:0000939', (73, 85))	('esophageal irritation', 'Disease', (110, 131))	('Bisphosphonates', 'Var', (0, 15))	('erosion', 'Disease', (136, 143))
486240	33604816	McKeown esophagectomy has additional risks for laryngeal elevation disorder and recurrent nerve palsy compared to Ivor Lewis.	('McKeown', 'Var', (0, 7))	('palsy', 'Disease', 'MESH:D010243', (96, 101))	('palsy', 'Disease', (96, 101))	('laryngeal elevation disorder', 'Disease', (47, 75))
486258	33604816	Notably, body weight loss and subnutrition after esophagectomy are known prognostic factors for esophageal cancer.	('weight loss', 'Disease', 'MESH:D015431', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('weight loss', 'Disease', (14, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('weight loss', 'Phenotype', 'HP:0001824', (14, 25))	('subnutrition', 'Var', (30, 42))
486259	33604816	Furthermore, one previous study demonstrated that severe transthyretin, which decreased after esophagectomy, was shown to be a risk factor for anastomotic leak after MIE.	('severe', 'Var', (50, 56))	('anastomotic leak', 'Disease', (143, 159))	('transthyretin', 'Gene', (57, 70))	('transthyretin', 'Gene', '7276', (57, 70))
486300	32792797	The detection rate has improved with positron emission tomography using F-18 FDG (fludeoxyglucoseF18 injection).	('fludeoxyglucoseF18', 'Chemical', 'MESH:D019788', (82, 100))	('F-18 FDG', 'Var', (72, 80))	('detection', 'MPA', (4, 13))
486324	31349612	PD-L1 Blockade by Atezolizumab Downregulates Signaling Pathways Associated with Tumor Growth, Metastasis, and Hypoxia in Human Triple Negative Breast Cancer Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, which shows resistance to common breast cancer therapies, as it lacks the expression of the most common breast cancer targets.	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('Tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PD-L1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('PD-L1', 'Gene', '29126', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('Breast Cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', (173, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('Hypoxia', 'Disease', 'MESH:D000860', (110, 117))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('Breast Cancer', 'Disease', (143, 156))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Signaling Pathways', 'Pathway', (45, 63))	('Downregulates', 'NegReg', (31, 44))	('Hypoxia', 'Disease', (110, 117))	('Metastasis', 'Disease', 'MESH:D009362', (94, 104))	('Metastasis', 'Disease', (94, 104))	('Atezolizumab', 'Chemical', 'MESH:C000594389', (18, 30))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('Breast Cancer', 'Phenotype', 'HP:0003002', (143, 156))	('breast cancer', 'Disease', (225, 238))	('breast cancer', 'Disease', (273, 286))	('breast cancer', 'Phenotype', 'HP:0003002', (344, 357))	('Blockade', 'Var', (6, 14))	('Human', 'Species', '9606', (121, 126))	('breast cancer', 'Disease', 'MESH:D001943', (344, 357))	('breast cancer', 'Disease', (344, 357))
486344	31349612	Despite the fact that the therapeutic efficacy of targeting the PD-1/PD-L1 axis has been shown in patients with melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma, there is accumulating evidence suggesting that PD-L1 can facilitate tumor resistance, and promote tumor growth and survival against traditional cancer therapies and immunotherapy.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('PD-L1', 'Var', (231, 236))	('tumor', 'Disease', (282, 287))	('PD-1/PD-L1 axis', 'Disease', 'MESH:D010300', (64, 79))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('cancer', 'Disease', (328, 334))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('non-small cell lung cancer', 'Disease', (122, 148))	('melanoma', 'Disease', (112, 120))	('PD-1/PD-L1 axis', 'Disease', (64, 79))	('NSCLC', 'Disease', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('renal cell carcinoma', 'Disease', (162, 182))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (162, 182))	('facilitate', 'PosReg', (241, 251))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('survival', 'CPA', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (122, 148))	('cancer', 'Disease', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('patients', 'Species', '9606', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (126, 148))	('promote', 'PosReg', (274, 281))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (162, 182))	('tumor', 'Disease', (252, 257))
486350	31349612	However, the mechanisms by which anti-PD-L1 mAb exerts therapeutic effects on breast cancer cells have not been fully elucidated.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('anti-PD-L1', 'Var', (33, 43))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
486351	31349612	Therefore, it is important to identify the mechanisms and signaling pathways affected by anti-PD-L1 mAb, and to understand how it alters the function and molecular profile of breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('alters', 'Reg', (130, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('anti-PD-L1', 'Var', (89, 99))
486352	31349612	In this study, we sought to identify the mechanisms by which human TNBC cells expressing PD-L1 are affected by anti-PD-L1 mAb treatment using atezolizumab.	('anti-PD-L1', 'Var', (111, 121))	('affected', 'Reg', (99, 107))	('PD-L1', 'Gene', (89, 94))	('atezolizumab', 'Chemical', 'MESH:C000594389', (142, 154))	('human', 'Species', '9606', (61, 66))
486398	31349612	On day six following treatment, using Annexin V and the 7-AAD detection kit, we found that atezolizumab increases the proportion of apoptotic (Annexin V+) and necrotic cells (Annexin V+ 7-AAD+), compared to non-treated cells or those treated with IgG1 (Figure 6A,B).	('atezolizumab', 'Var', (91, 103))	('Annexin V', 'Gene', '308', (175, 184))	('Annexin V', 'Gene', (175, 184))	('Annexin V', 'Gene', '308', (143, 152))	('Annexin V', 'Gene', (143, 152))	('necrotic', 'Disease', (159, 167))	('Annexin V', 'Gene', (38, 47))	('Annexin V', 'Gene', '308', (38, 47))	('increases', 'PosReg', (104, 113))	('necrotic', 'Disease', 'MESH:D009336', (159, 167))	('7-AAD', 'Chemical', 'MESH:C025942', (56, 61))	('apoptotic', 'CPA', (132, 141))	('atezolizumab', 'Chemical', 'MESH:C000594389', (91, 103))	('7-AAD', 'Chemical', 'MESH:C025942', (186, 191))
486404	31349612	Therefore, it is vital to understand the underlying mechanisms by which anti-PD-L1 mAb exerts its effects, and the signaling pathways it regulates to induce anti-tumor responses in TNBC.	('induce', 'PosReg', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('anti-PD-L1', 'Var', (72, 82))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
486408	31349612	Independently of the PD-1/PD-L1 signaling pathway, the intracytoplasmic domain of PD-L1 was shown to be functional, therefore, alterations in PD-L1 protein structure by atezolizumab might have a negative impact on its function.	('function', 'MPA', (218, 226))	('PD-L1 protein', 'Protein', (142, 155))	('negative', 'NegReg', (195, 203))	('PD-1', 'Gene', (21, 25))	('PD-1', 'Gene', '5133', (21, 25))	('protein', 'Protein', (148, 155))	('alterations', 'Var', (127, 138))	('atezolizumab', 'Chemical', 'MESH:C000594389', (169, 181))
486409	31349612	We showed that the blockade of PD-L1 in MDA-MB-231 downregulates genes and signaling pathways associated with tumor aggressiveness, which is consistent with other findings demonstrating the direct role of PD-L1 in promoting tumor cell proliferation and survival.	('survival', 'CPA', (253, 261))	('MDA-MB-231', 'Gene', (40, 50))	('blockade', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('aggressiveness', 'Phenotype', 'HP:0000718', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', (224, 229))	('tumor aggressiveness', 'Disease', (110, 130))	('promoting', 'PosReg', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (110, 130))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (40, 50))	('downregulates', 'NegReg', (51, 64))	('PD-L1', 'Gene', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
486412	31349612	The knockdown of PD-L1, using short interfering RNA, in esophageal cancer cell lines was shown to be effective in reducing EMT.	('esophageal cancer', 'Disease', (56, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('reducing', 'NegReg', (114, 122))	('PD-L1', 'Gene', (17, 22))	('short interfering RNA', 'MPA', (30, 51))	('knockdown', 'Var', (4, 13))	('EMT', 'CPA', (123, 126))
486415	31349612	showed that EMT-converted tumor cells (esophageal cancer cell lines) expressing high levels of PD-L1 are able to induce T cell apoptosis using co-culture systems.	('induce', 'PosReg', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('PD-L1', 'Var', (95, 100))	('esophageal cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', (26, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))	('T cell apoptosis', 'CPA', (120, 136))
486418	31349612	It was reported that PD-L1 expression is regulated by Rad3-related (ATR) kinase, and that the inhibition of ATR downregulates PD-L1 and increases the sensitivity of MDA-MB-231 cells to cytotoxic T cells, killing using co-culture systems.	('sensitivity', 'MPA', (150, 161))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (165, 175))	('downregulates', 'NegReg', (112, 125))	('ATR', 'Gene', '545', (68, 71))	('ATR', 'Gene', (68, 71))	('PD-L1', 'Gene', (126, 131))	('PD-L1', 'Gene', (21, 26))	('inhibition', 'Var', (94, 104))	('ATR', 'Gene', '545', (108, 111))	('ATR', 'Gene', (108, 111))	('increases', 'PosReg', (136, 145))
486419	31349612	Combining the latter finding with our RNA-Seq data, which indicate that the blockade of PD-L1 upregulates genes associated with DNA repair, such as MEN1 and RNASEH1, suggests the involvement of atezolizumab in regulating DNA damage response/genomic instability and telomere integrity in cancer cells.	('DNA damage response/genomic', 'MPA', (221, 248))	('cancer', 'Disease', (287, 293))	('PD-L1', 'Gene', (88, 93))	('RNASEH1', 'Gene', '246243', (157, 164))	('MEN1', 'Gene', '4221', (148, 152))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('MEN1', 'Gene', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('RNASEH1', 'Gene', (157, 164))	('blockade', 'Var', (76, 84))	('atezolizumab', 'Chemical', 'MESH:C000594389', (194, 206))	('upregulates', 'PosReg', (94, 105))
486441	31349612	Following three washes with 1x TBST, membranes were incubated with primary antibodies (1:1000 dilution), including anti-beta-actin and anti-PD-L1 (Cell Signaling Technology, Danvers, MA, USA), in 5% skim dry milk with 1x TBST buffer for overnight at 4  C. Following three washes with 1x TBST, membranes were incubated with an HRP-conjugated anti-rabbit secondary antibody (Abcam, 1:15,000 dilution) for 1 h at room temperature.	('TBST', 'Chemical', '-', (287, 291))	('anti-PD-L1', 'Var', (135, 145))	('beta-actin', 'Gene', '728378', (120, 130))	('rabbit', 'Species', '9986', (346, 352))	('beta-actin', 'Gene', (120, 130))	('TBST', 'Chemical', '-', (31, 35))	('TBST', 'Chemical', '-', (221, 225))
486526	25817897	A large proportion of our patients undergoing RFA had high-grade disease (either HGD or IMC), pre-ablation nodularity, and long segment length, which may increase the rates of recurrence compared to a more general BE population.	('long', 'Var', (123, 127))	('BE', 'Phenotype', 'HP:0100580', (214, 216))	('high-grade', 'Disease', (54, 64))	('HGD', 'Disease', (81, 84))	('patients', 'Species', '9606', (26, 34))	('nodularity', 'Var', (107, 117))
486552	22747995	When focusing on type I cardiac or distal esophagus adenocarcinoma, survival rates obtained by transthoracic esophagectomy appear superior to that by transhiatal esophagectomy.	('esophagus adenocarcinoma', 'Disease', 'MESH:C562730', (42, 66))	('transthoracic', 'Var', (95, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('superior', 'PosReg', (130, 138))	('esophagus adenocarcinoma', 'Disease', (42, 66))	('esophagus adenocarcinoma', 'Phenotype', 'HP:0011459', (42, 66))	('cardia', 'Disease', 'MESH:D004938', (24, 30))	('cardia', 'Disease', (24, 30))
486633	22747995	The Dutch trial show a superiority of transthoracic en bloc resection for type I adenocarcinoma, whereas transthoracic and transhiatal esophagectomy obtain similar survival rates for type II carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('type II carcinomas', 'Disease', 'MESH:D016532', (183, 201))	('type II carcinomas', 'Disease', (183, 201))	('type I adenocarcinoma', 'Disease', (74, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('transthoracic', 'Var', (38, 51))	('type I adenocarcinoma', 'Disease', 'MESH:D000230', (74, 95))
486643	22747995	show that patients undergoing transthoracic en bloc resection for T3 N1 adenocarcinoma of the distal esophagus had a survival benefit over those treated with transhiatal resection when less than 9 involved lymph nodes are present.	('survival benefit', 'CPA', (117, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('adenocarcinoma', 'Disease', (72, 86))	('T3 N1', 'Var', (66, 71))	('adenocarcinoma', 'Disease', 'MESH:D000230', (72, 86))	('patients', 'Species', '9606', (10, 18))
486651	22747995	Preoperative loco regional staging of esophageal cancer with EUS provides excellent T staging accuracy and the accuracy for N staging compares well with positron emission tomography and CT, EUS is also associated with improved survival stratification in patients with esophageal adenocarcinoma.	('EUS', 'Var', (190, 193))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (268, 293))	('improved', 'PosReg', (218, 226))	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('T staging', 'CPA', (84, 93))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (268, 293))	('patients', 'Species', '9606', (254, 262))	('esophageal adenocarcinoma', 'Disease', (268, 293))
486881	32188860	Cre is fused to a mutant hormone receptor so it is only active following treatment with a drug, giving control over when recombination is induced.	('hormone receptor', 'Gene', '15370', (25, 41))	('hormone receptor', 'Gene', (25, 41))	('mutant', 'Var', (18, 24))
486907	32188860	To track the fate of basal cells, Lrig1-cre mice were crossed with the Rosa26flConfetti/wt (Confetti) reporter strain which labels cells with one of four possible fluorescent proteins (green, GFP, cyan, CFP, yellow, YFP, or red RFP) after recombination (Supplementary Fig.	('Lrig1', 'Gene', '16206', (34, 39))	('RFP', 'Gene', '19720', (228, 231))	('Rosa26', 'Gene', '14910', (71, 77))	('cyan', 'Var', (197, 201))	('CFP', 'Gene', '18636', (203, 206))	('GFP', 'Var', (192, 195))	('green', 'Var', (185, 190))	('Rosa26', 'Gene', (71, 77))	('RFP', 'Gene', (228, 231))	('mice', 'Species', '10090', (44, 48))	('Lrig1', 'Gene', (34, 39))	('CFP', 'Gene', (203, 206))	('yellow', 'Var', (208, 214))	('YFP', 'Var', (216, 219))
486920	32188860	As a further validation, we tested the predictions of the SP model against a third, more limited data set from Krt15-crePR1 R26mT/mG mice in which a red-to-green fluorescent reporter was used with inducible Cre expressed from a Krt15 promoter (Supplementary Methods).	('Krt15', 'Gene', '16665', (228, 233))	('SP', 'Chemical', '-', (58, 60))	('mice', 'Species', '10090', (133, 137))	('Krt15', 'Gene', (111, 116))	('Krt15', 'Gene', (228, 233))	('R26mT/mG', 'Var', (124, 132))	('Krt15', 'Gene', '16665', (111, 116))	('tested', 'Reg', (28, 34))
486964	32188860	103124), Keratin 14 antibody (clone Poly19053, Biolegend, Cat.	('Keratin 14', 'Gene', (9, 19))	('Keratin 14', 'Gene', '16664', (9, 19))	('clone Poly19053', 'Var', (30, 45))
486981	32188860	Data on Krt15-crePR1 R26mT/mG mouse esophagus were retrieved by digitalizing Fig.	('Krt15', 'Gene', '16665', (8, 13))	('R26mT/mG', 'Var', (21, 29))	('Krt15', 'Gene', (8, 13))	('mouse', 'Species', '10090', (30, 35))
486998	31082367	In the fundus of mouse stomach injured by infection with Helicobacter pylori or by drugs toxic to parietal cells, the death of parietal cells appears to be accompanied by transdifferentiation of chief cells into proliferative cells that expresses trefoil factor 2 (TFF2, also known as spasmolytic polypeptide).	('mouse', 'Species', '10090', (17, 22))	('TFF2', 'Gene', (265, 269))	('spasmolytic polypeptide', 'Gene', (285, 308))	('infection', 'Disease', (42, 51))	('Helicobacter pylori', 'Var', (57, 76))	('trefoil factor 2', 'Gene', '7032', (247, 263))	('trefoil factor 2', 'Gene', (247, 263))	('infection', 'Disease', 'MESH:D007239', (42, 51))	('Helicobacter pylori', 'Species', '210', (57, 76))	('spasmolytic polypeptide', 'Gene', '7032', (285, 308))	('rat', 'Species', '10116', (219, 222))	('death', 'Disease', 'MESH:D003643', (118, 123))	('death', 'Disease', (118, 123))
487000	31082367	This is a 3-stage process during which the cells: shut down mTORC1 signaling, which enables autophagy to recycle cellular material for use in the synthesis of new cell structures; begin to express genes associated with metaplasia, such as SOX9 and TFF2; and then reactivate mTORC1 signaling, which enables them to re-enter the cell cycle.	('mTORC1', 'Gene', '382056', (60, 66))	('reactivate', 'PosReg', (263, 273))	('shut', 'Var', (50, 54))	('mTORC1', 'Gene', (274, 280))	('mTORC1', 'Gene', (60, 66))	('metaplasia', 'Disease', (219, 229))	('mTORC1', 'Gene', '382056', (274, 280))
487003	31082367	When the mutated cells re-enter the cell cycle with a subsequent injury, however, they might acquire further mutations that eventually block redifferentiation, leading to clonal expansion and carcinogenesis.	('leading to', 'Reg', (160, 170))	('mutated', 'Var', (9, 16))	('carcinogenesis', 'Disease', 'MESH:D063646', (192, 206))	('clonal expansion', 'CPA', (171, 187))	('carcinogenesis', 'Disease', (192, 206))	('redifferentiation', 'MPA', (141, 158))	('mutations', 'Var', (109, 118))
487008	31082367	Although it could be possible that paligenotic dedifferentiation confers stem cell-like self-renewal abilities in addition to the plasticity leading to transdifferentiation, there is no evidence from experiments for this concept.	('paligenotic dedifferentiation', 'Var', (35, 64))	('stem cell-like self-renewal abilities', 'CPA', (73, 110))	('men', 'Species', '9606', (206, 209))
487021	31082367	Disruption of this patterns results in esophageal atresia, a relatively common birth defect (1/3000) in which the proximal portion of the esophagus ends as a blind sac, often accompanied by tracheo-esophageal fistula.	('tracheo-esophageal fistula', 'Phenotype', 'HP:0002575', (190, 216))	('esophageal atresia', 'Disease', 'MESH:D004933', (39, 57))	('birth defect', 'Disease', (79, 91))	('birth defect', 'Disease', 'MESH:D000014', (79, 91))	('esophageal atresia', 'Phenotype', 'HP:0002032', (39, 57))	('tracheo-esophageal fistula', 'Disease', 'MESH:D004937', (190, 216))	('results in', 'Reg', (28, 38))	('tracheo-esophageal fistula', 'Disease', (190, 216))	('esophageal atresia', 'Disease', (39, 57))	('Disruption', 'Var', (0, 10))
487030	31082367	In studies that used immunofluorescence to identify columnar cells that express keratin 8 (KRT8) and squamous cells with KRT14, KRT8+ columnar cells were found to express KRT14 as the esophagus developed.	('KRT8', 'Gene', '3856', (128, 132))	('KRT8', 'Gene', (91, 95))	('keratin 8', 'Gene', (80, 89))	('KRT8', 'Gene', (128, 132))	('KRT8', 'Gene', '3856', (91, 95))	('keratin 8', 'Gene', '3856', (80, 89))	('KRT14', 'Var', (171, 176))
487031	31082367	This switch in protein expression occurred in the absence of cell division or cell death, and was caused by silencing of Krt8 via de novo methylation in the promoter region.	('silencing', 'Var', (108, 117))	('Krt8', 'Gene', '3856', (121, 125))	('caused by', 'Reg', (98, 107))	('death', 'Disease', 'MESH:D003643', (83, 88))	('death', 'Disease', (83, 88))	('protein expression', 'MPA', (15, 33))	('methylation', 'Var', (138, 149))	('Krt8', 'Gene', (121, 125))
487052	31082367	In most cases, squamous islands and the ESMGs beneath them did not share mutations in p16/CDKN2A or p53 with the surrounding Barrett's metaplasia.	('CDKN2A', 'Gene', '1029', (90, 96))	('p16', 'Gene', (86, 89))	('p53', 'Gene', '7157', (100, 103))	('CDKN2A', 'Gene', (90, 96))	('mutations', 'Var', (73, 82))	('p53', 'Gene', (100, 103))	('p16', 'Gene', '1029', (86, 89))
487053	31082367	In 1 patient, however, a squamous island shared a p16/CDKN2A mutation with the surrounding Barrett's metaplasia, indicating a common progenitor for both epithelial types.	('patient', 'Species', '9606', (5, 12))	('mutation', 'Var', (61, 69))	('p16', 'Gene', '1029', (50, 53))	('CDKN2A', 'Gene', (54, 60))	('CDKN2A', 'Gene', '1029', (54, 60))	('p16', 'Gene', (50, 53))
487054	31082367	A study that used non-pathogenic mitochondrial DNA mutations as clonal markers found mitochondrial mutations that were shared between squamous and Barrett's epithelium in 1 patient, supporting the concept that squamous and Barrett's epithelium can derive from the same progenitor cell.	('patient', 'Species', '9606', (173, 180))	('mutations', 'Var', (99, 108))	('mutations', 'Var', (51, 60))
487055	31082367	Consistent with finding from other studies, squamous islands often were found above ESMGs and ducts, and in 1 case the surrounding BE tissue contained a mutation in p53 not found in the squamous island or ESMG, indicating different cells of origin for the Barrett's metaplasia and squamous island.	('p53', 'Gene', '7157', (165, 168))	('p53', 'Gene', (165, 168))	('BE', 'Phenotype', 'HP:0100580', (131, 133))	('mutation in', 'Var', (153, 164))
487074	31082367	Together, these studies demonstrate that GERD induces a proliferative response in cells of the ESMGs and their ducts, and that these cells can repopulate injured esophageal epithelium.	('proliferative response', 'CPA', (56, 78))	('GERD', 'Var', (41, 45))	('rat', 'Species', '10116', (63, 66))	('rat', 'Species', '10116', (31, 34))
487077	31082367	One spheroid type had a solid, squamous appearance and expressed squamous markers such as p63, whereas the other was hollow and expressed columnar cell markers found in Barrett's metaplasia, including AGR2, MUC13, KRT18, MUC1, KRT8, and SOX9.	('MUC1', 'Gene', (221, 225))	('MUC1', 'Gene', (207, 211))	('MUC13', 'Gene', '56667', (207, 212))	('p63', 'Var', (90, 93))	('KRT8', 'Gene', '3856', (227, 231))	('MUC1', 'Gene', '4582', (221, 225))	('KRT18', 'Gene', (214, 219))	('AGR2', 'Gene', '10551', (201, 205))	('MUC1', 'Gene', '4582', (207, 211))	('MUC13', 'Gene', (207, 212))	('KRT8', 'Gene', (227, 231))	("Barrett's metaplasia", 'Disease', (169, 189))	('AGR2', 'Gene', (201, 205))	('KRT18', 'Gene', '3875', (214, 219))
487083	31082367	The L2-IL1B mice developed chronic epithelial inflammation and thickening in the esophagus and forestomach.	('inflammation', 'Disease', 'MESH:D007249', (46, 58))	('L2-IL1B', 'Var', (4, 11))	('thickening', 'CPA', (63, 73))	('inflammation', 'Disease', (46, 58))	('thickening in the esophagus', 'Phenotype', 'HP:0010450', (63, 90))	('mice', 'Species', '10090', (12, 16))
487087	31082367	Interestingly, L2-IL1B mice with disruption of IL6 do not develop metaplasia or dysplasia, indicating that IL6 mediates these processes in this model.	('disruption', 'Var', (33, 43))	('metaplasia or dysplasia', 'Disease', 'MESH:D008679', (66, 89))	('IL6', 'Gene', (47, 50))	('metaplasia or dysplasia', 'Disease', (66, 89))	('mice', 'Species', '10090', (23, 27))
487089	31082367	Among patients with GERD, polymorphisms in the IL1 receptor antagonist (IL1RA) have been linked to increased esophageal levels of IL1B and increased risk of BE.	('esophageal levels of IL1B', 'MPA', (109, 134))	('polymorphisms', 'Var', (26, 39))	('IL1RA', 'Gene', (72, 77))	('GERD', 'Disease', (20, 24))	('IL1 receptor antagonist', 'Gene', (47, 70))	('BE', 'Phenotype', 'HP:0100580', (157, 159))	('IL1RA', 'Gene', '3557', (72, 77))	('patients', 'Species', '9606', (6, 14))	('increased', 'PosReg', (99, 108))	('IL1 receptor antagonist', 'Gene', '3557', (47, 70))
487095	31082367	This study also showed that gastrin can promote the expansion of CCK2R+ cardia progenitor cells in 3-dimensional organoids; the CCK2R inhibitor YF476 blocked the growth of organoids and the progression of Barrett's-like metaplasia in L2-IL1B mice.	('growth of organoids', 'CPA', (162, 181))	('cardia', 'Disease', 'MESH:D004938', (72, 78))	('gastrin', 'Gene', '14459', (28, 35))	('cardia', 'Disease', (72, 78))	('blocked', 'NegReg', (150, 157))	('men', 'Species', '9606', (103, 106))	("Barrett's-like", 'Disease', (205, 219))	('gastrin', 'Gene', (28, 35))	('YF476', 'Var', (144, 149))	('mice', 'Species', '10090', (242, 246))
487106	31082367	Wang et al also showed that deletion of p63 promotes the development of Barrett's-like epithelium in the mouse forestomach.	('promotes', 'PosReg', (44, 52))	('men', 'Species', '9606', (64, 67))	('deletion', 'Var', (28, 36))	('mouse', 'Species', '10090', (105, 110))	('p63', 'Gene', (40, 43))
487108	31082367	The authors studied expression of p63 at different embryonic stages of foregut development and found that p63-positive cells in wild-type mice spread from the esophagus to the forestomach, eventually replacing the CAR4+, KRT7+ simple columnar epithelium that lines the early embryonic forestomach.	('CAR4', 'Gene', '12351', (214, 218))	('men', 'Species', '9606', (86, 89))	('embryonic forestomach', 'Disease', 'MESH:D013274', (275, 296))	('mice', 'Species', '10090', (138, 142))	('p63-positive', 'Var', (106, 118))	('embryonic forestomach', 'Disease', (275, 296))	('CAR4', 'Gene', (214, 218))
487121	31082367	The squamous cells comprising the basal layer of multilayered epithelium express p63, but p63 is rarely detected in Barrett's metaplasia or in esophageal adenocarcinomas (EACs).	("Barrett's metaplasia", 'Disease', (116, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('esophageal adenocarcinomas', 'Disease', 'MESH:D000230', (143, 169))	('p63', 'Var', (81, 84))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (143, 168))	('esophageal adenocarcinomas', 'Disease', (143, 169))
487238	31303787	A Northern Ireland population study reported that although FGA is rare, the risk for EAC or reflux esophagitis reduced after Helicobacter pylori infection and atrophy.	('Helicobacter pylori', 'Var', (125, 144))	('reflux esophagitis', 'Disease', 'MESH:D005764', (92, 110))	('infection and atrophy', 'Disease', 'MESH:D001284', (145, 166))	('EAC', 'Phenotype', 'HP:0011459', (85, 88))	('reflux esophagitis', 'Disease', (92, 110))	('Helicobacter pylori', 'Species', '210', (125, 144))	('reduced', 'NegReg', (111, 118))	('EAC', 'Disease', (85, 88))	('EA', 'Chemical', '-', (85, 87))	('esophagitis', 'Phenotype', 'HP:0100633', (99, 110))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (125, 154))
487307	31170090	It was shown that proliferative rate of CAL27 and FADU cells treated with RHCG-shRNA was remarkably increased compared with negative control, while overexpression of RHCG in JHU011 cells showed the opposite effect (Figure 5D).	('RHCG-shRNA', 'Var', (74, 84))	('CAL27', 'CellLine', 'CVCL:1107', (40, 45))	('increased', 'PosReg', (100, 109))	('proliferative rate', 'CPA', (18, 36))
487308	31170090	Consistent with the results of CCK-8 assays and EdU assays, colony formation assay showed that knockdown of RHCG could promote HNSCC cell proliferation, whereas overexpression of RHCG promoted cell proliferation (Figure 5E).	('EdU', 'Chemical', '-', (48, 51))	('promote', 'PosReg', (119, 126))	('CCK-8', 'Chemical', '-', (31, 36))	('knockdown', 'Var', (95, 104))	('HNSCC cell proliferation', 'CPA', (127, 151))	('RHCG', 'Gene', (108, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))
487310	31170090	At 14 days post-injection, the volumes of tumors established in the RHCG-knockdown group (CAL27 and FADU) were dramatically bigger than those in the control group.	('RHCG-knockdown', 'Gene', (68, 82))	('CAL27', 'CellLine', 'CVCL:1107', (90, 95))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('RHCG-knockdown', 'Var', (68, 82))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('bigger', 'PosReg', (124, 130))
487312	31170090	Since DNA promoter hypermethylation is commonly implicated in inactivation of tumor suppressor genes in cancers, we then investigated whether the RHCG promoter hypermethylation may impair RHCG expression in HNSCC.	('RHCG', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('impair', 'NegReg', (181, 187))	('HNSCC', 'Phenotype', 'HP:0012288', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('hypermethylation', 'Var', (160, 176))	('HNSCC', 'Disease', (207, 212))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('tumor', 'Disease', (78, 83))	('RHCG', 'Gene', (146, 150))	('expression', 'MPA', (193, 203))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
487314	31170090	To determine the prognostic potential of RHCG methylation, the survival curve of 299 HNSCC patients stratified by RHCG methylation level was plotted, it was evident that patients with RHCG hypermethylation had a significantly shorter overall survival time compared with patients with RHCG hypomethylation (p=0.046) (Figure 7I).	('patients', 'Species', '9606', (170, 178))	('hypermethylation', 'Var', (189, 205))	('shorter', 'NegReg', (226, 233))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (270, 278))	('RHCG hypermethylation', 'Var', (184, 205))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('overall survival', 'MPA', (234, 250))
487315	31170090	Furthermore, patients with RHCG hypermethylation and RHCG low expression demonstrated a significantly shorter overall survival compared to those with RHCG hypomethylation and RHCG high expression (p = 0.012) (Figure 7J).	('overall survival', 'MPA', (110, 126))	('shorter', 'NegReg', (102, 109))	('RHCG', 'Gene', (53, 57))	('patients', 'Species', '9606', (13, 21))	('low', 'NegReg', (58, 61))	('hypermethylation', 'Var', (32, 48))
487316	31170090	By combining RHCG methylation level and RHCG expression level, it exhibited a much better prognostic capacity to distinguish patients with poor prognosis from those with good prognosis.	('expression', 'MPA', (45, 55))	('methylation', 'Var', (18, 29))	('patients', 'Species', '9606', (125, 133))
487327	31170090	RHCG silencing in HNSCC cell lines CAL27 and FADU could effectively promote cell viability, colony formation and cell migration and tumor formation in nude mice, while ectopic expression of RHCG in JHU011 cells could suppress these functions, which was in consistence with previous studies.	('CAL27', 'CellLine', 'CVCL:1107', (35, 40))	('HNSCC', 'Phenotype', 'HP:0012288', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('promote', 'PosReg', (68, 75))	('colony formation', 'CPA', (92, 108))	('silencing', 'Var', (5, 14))	('cell viability', 'CPA', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('RHCG', 'Gene', (0, 4))	('tumor', 'Disease', (132, 137))	('cell migration', 'CPA', (113, 127))	('nude mice', 'Species', '10090', (151, 160))
487329	31170090	Ming et al reported that RHCG could suppress the tumorigenicity and metastasis of esophageal squamous cell carcinoma via inhibiting NF-kappaB signaling and MMP1 expression; Wang et al discovered that RHCG might suppress cervical cancer progression through inducing apoptosis regulated by TGF-beta1.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TGF-beta1', 'Gene', (288, 297))	('NF-kappaB signaling', 'MPA', (132, 151))	('cervical cancer', 'Disease', 'MESH:D002583', (220, 235))	('inhibiting', 'NegReg', (121, 131))	('cervical cancer', 'Disease', (220, 235))	('TGF-beta1', 'Gene', '7040', (288, 297))	('metastasis of esophageal squamous cell carcinoma', 'Disease', (68, 116))	('inducing', 'PosReg', (256, 264))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('tumor', 'Disease', (49, 54))	('RHCG', 'Var', (200, 204))	('MMP1', 'Gene', '4312', (156, 160))	('apoptosis', 'CPA', (265, 274))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('metastasis of esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 116))	('MMP1', 'Gene', (156, 160))	('suppress', 'NegReg', (211, 219))	('suppress', 'NegReg', (36, 44))
487331	31170090	Downregulation of tumor suppressor genes is commonly observed in cancers, which is often caused by promoter hypermethylation, histone deacetylation, dysregulation by transcription factors and posttranscriptional silencing by microRNAs.	('promoter', 'MPA', (99, 107))	('dysregulation', 'MPA', (149, 162))	('tumor', 'Disease', (18, 23))	('Downregulation', 'NegReg', (0, 14))	('deacetylation', 'NegReg', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancers', 'Disease', (65, 72))	('posttranscriptional silencing', 'Var', (192, 221))	('histone', 'MPA', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
487362	31170090	The following primary antibodies were used to detect proteins: rabbit anti-RHCG (1:1000; Proteintech, Wuhan, China) and anti-beta-actin (1:4000; Proteintech, Wuhan, China).	('beta-actin', 'Gene', '728378', (125, 135))	('1:4000;', 'Var', (137, 144))	('beta-actin', 'Gene', (125, 135))	('rabbit', 'Species', '9986', (63, 69))
487538	30279962	With increasing heterogeneity, the PSMA expression increased, which might pave the way for an increased uptake of PSMA bound ligands.	('PSMA', 'Gene', (114, 118))	('heterogeneity', 'Var', (16, 29))	('increased', 'PosReg', (51, 60))	('PSMA', 'Gene', '2346', (35, 39))	('PSMA', 'Gene', '2346', (114, 118))	('increased', 'PosReg', (94, 103))	('PSMA', 'Gene', (35, 39))
487619	29977412	High-dose aspirin (325-600 mg/day) has analgesic effects, while low-dose aspirin (75-81 mg/day) is used to prevent cardiovascular disease, colorectal cancer, and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('cardiovascular disease', 'Disease', (115, 137))	('colorectal cancer', 'Disease', 'MESH:D015179', (139, 156))	('analgesic effects', 'MPA', (39, 56))	('325-600 mg/day', 'Var', (19, 33))	('aspirin', 'Chemical', 'MESH:D001241', (10, 17))	('lung cancer', 'Disease', (162, 173))	('aspirin', 'Chemical', 'MESH:D001241', (73, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('prevent', 'NegReg', (107, 114))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (115, 137))	('cardiovascular disease', 'Disease', 'MESH:D002318', (115, 137))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colorectal cancer', 'Disease', (139, 156))
487627	29977412	However, supplementation increased ESCC mortality by 14% in patients 55 years or older, which raises concerns regarding the optimized timing of administration of micronutrient supplement for preventing ESCC.	('supplementation', 'Var', (9, 24))	('increased', 'PosReg', (25, 34))	('rat', 'Species', '10116', (152, 155))	('patients', 'Species', '9606', (60, 68))	('ESCC mortality', 'Disease', (35, 49))	('increased ESCC', 'Phenotype', 'HP:0003565', (25, 39))	('men', 'Species', '9606', (15, 18))	('men', 'Species', '9606', (182, 185))
487654	29977412	Antibodies for COX-1 (#9896; dilution, 1:1000), COX-2 (#12282; dilution, 1:500), PCNA (#13110; dilution, 1:500), cyclin D1 (#2978; dilution, 1:500), cyclin A2 (#4656; dilution, 1:500), and CDK4 (#12790; dilution, 1:500) were purchased from Cell Signaling Technology (Danvers, MA) and used to quantify their respective levels in the esophageal lysates.	('#12282; dilution', 'Var', (55, 71))	('#13110; dilution', 'Var', (87, 103))	('cyclin A2', 'Gene', (149, 158))	('cyclin A2', 'Gene', '114494', (149, 158))	('#2978;', 'Var', (124, 130))	('#9896;', 'Var', (22, 28))	('#4656;', 'Var', (160, 166))	('COX-2', 'Gene', (48, 53))	('#12790; dilution', 'Var', (195, 211))
487656	29977412	Anti-rabbit (#7074S; dilution, 1:3000) and anti-mouse (#7076S; dilution, 1:3000) secondary antibodies were purchased from Cell Signaling Technology (Danvers, MA).	('#7074S;', 'Var', (13, 20))	('rabbit', 'Species', '9986', (5, 11))	('#7076S;', 'Var', (55, 62))	('mouse', 'Species', '10090', (48, 53))
487708	24867265	PLCE1 mRNA and protein expression and survival of patients with esophageal squamous cell carcinoma and gastric adenocarcinoma Germline genetic variants in PLCE1 (10q23) have demonstrated consistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer among Chinese.	('gastric cancer', 'Disease', (270, 284))	('esophageal squamous cell carcinoma', 'Disease', (224, 258))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (103, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('gastric cancer', 'Disease', 'MESH:D013274', (270, 284))	('variants', 'Var', (143, 151))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (224, 258))	('PLCE1', 'Gene', (155, 160))	('PLCE1', 'Gene', '51196', (155, 160))	('patients', 'Species', '9606', (50, 58))	('esophageal squamous cell carcinoma', 'Disease', (64, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (235, 258))	('gastric adenocarcinoma', 'Disease', (103, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('associations', 'Interaction', (198, 210))	('gastric cancer', 'Phenotype', 'HP:0012126', (270, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('PLCE1', 'Gene', (0, 5))	('PLCE1', 'Gene', '51196', (0, 5))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (64, 98))
487712	24867265	Compared with normal tissues, PLCE1 mRNA expression was significantly reduced in ESCC tumors (P=0.03, probe_205112_at), as well as in GCA and GNCA tumors (P<0.0001, each probe).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('mRNA expression', 'MPA', (36, 51))	('reduced', 'NegReg', (70, 77))	('ESCC tumors', 'Disease', 'MESH:D004938', (81, 92))	('GNCA', 'Disease', (142, 146))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('PLCE1', 'Gene', (30, 35))	('tumors', 'Disease', (86, 92))	('probe_205112_at', 'Var', (102, 117))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('PLCE1', 'Gene', '51196', (30, 35))	('GCA', 'Disease', (134, 137))	('GC', 'Phenotype', 'HP:0012126', (134, 136))	('ESCC tumors', 'Disease', (81, 92))
487714	24867265	Increased tumor-normal mRNA fold change (probe_205112_at) was associated with longer survival in ESCC (9.6 months for highest vs lowest quartile; P-trend=0.02).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('longer', 'PosReg', (78, 84))	('tumor', 'Disease', (10, 15))	('probe_205112_at', 'Var', (41, 56))	('mRNA fold', 'MPA', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('ESCC', 'Disease', (97, 101))
487715	24867265	Increased mRNA tumor-normal fold change (probe_205111_at) was associated with longer survival for GCA (10.7 months for highest quartile; P-trend=0.04), but not for GNCA cases (P=0.72).	('longer', 'PosReg', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('probe_205111_at', 'Var', (41, 56))	('tumor', 'Disease', (15, 20))	('GCA', 'Disease', (98, 101))	('GC', 'Phenotype', 'HP:0012126', (98, 100))
487717	24867265	Dysregulated PLCE1 mRNA expression was observed for both ESCC (one probe only) and GCA tumors, and the altered PLCE1 expression appears to be associated with cancer prognosis.	('PLCE1', 'Gene', (111, 116))	('GCA tumors', 'Disease', 'MESH:D009369', (83, 93))	('PLCE1', 'Gene', '51196', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ESCC', 'Disease', (57, 61))	('mRNA expression', 'MPA', (19, 34))	('expression', 'MPA', (117, 127))	('altered', 'Var', (103, 110))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('GC', 'Phenotype', 'HP:0012126', (83, 85))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (158, 164))	('PLCE1', 'Gene', (13, 18))	('associated with', 'Reg', (142, 157))	('PLCE1', 'Gene', '51196', (13, 18))	('GCA tumors', 'Disease', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
487723	24867265	Among them, genetic variants at 10q23 in the phospholipase C epsilon (PLCE1) gene have demonstrated the most consistent and strongest associations with risk of ESCC for Chinese, and also conveyed significant associations with risk of GCA, surpassing genome-wide significance6, offering promise in the further exploration of molecular events of PLCE1 in the development and progression of these cancers.	('PLCE1', 'Gene', (70, 75))	('ESCC', 'Disease', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('phospholipase C epsilon', 'Gene', '5334', (45, 68))	('PLCE1', 'Gene', (344, 349))	('PLCE1', 'Gene', '51196', (70, 75))	('PLCE1', 'Gene', '51196', (344, 349))	('GC', 'Phenotype', 'HP:0012126', (234, 236))	('variants at 10q23', 'Var', (20, 37))	('phospholipase C epsilon', 'Gene', (45, 68))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('associations', 'Interaction', (208, 220))	('cancers', 'Disease', (394, 401))	('associations', 'Interaction', (134, 146))	('GCA', 'Disease', (234, 237))
487726	24867265	Rs932764 and rs3765524 in PLCE1 have been associated with blood pressure and dengue shock syndrome, suggesting possible pleiotropic effects of PLCE1 variants.	('shock syndrome', 'Disease', 'MESH:D012769', (84, 98))	('rs3765524', 'Var', (13, 22))	('Rs932764', 'Var', (0, 8))	('associated', 'Reg', (42, 52))	('shock', 'Phenotype', 'HP:0031273', (84, 89))	('blood pressure', 'Disease', (58, 72))	('PLCE1', 'Gene', (26, 31))	('Rs932764', 'Mutation', 'Rs932764', (0, 8))	('PLCE1', 'Gene', '51196', (26, 31))	('PLCE1', 'Gene', (143, 148))	('shock syndrome', 'Disease', (84, 98))	('rs3765524', 'Mutation', 'rs3765524', (13, 22))	('PLCE1', 'Gene', '51196', (143, 148))
487738	24867265	The U133A, U133A_2 and U133Plus_2 chips all contained the same three probes for PLCE1 (ie, 205111_s_at, 205112_at, and 214159_at).	('PLCE1', 'Gene', (80, 85))	('PLCE1', 'Gene', '51196', (80, 85))	('205111_s_at', 'Var', (91, 102))	('205112_at', 'Var', (104, 113))	('214159_at', 'Var', (119, 128))
487757	24867265	We extracted genotype data for five SNPs which showed significant associations with ESCC and GCA (rs2274223, rs3765524, rs3781264, rs11187842, and rs753724), exceeding genome-wide significance level (P<=2.74x10-8).	('rs753724', 'Mutation', 'rs753724', (147, 155))	('rs3765524', 'Var', (109, 118))	('associations', 'Interaction', (66, 78))	('ESCC', 'Gene', (84, 88))	('rs11187842', 'Var', (131, 141))	('rs2274223', 'Mutation', 'rs2274223', (98, 107))	('GCA', 'Gene', (93, 96))	('rs2274223', 'Var', (98, 107))	('rs11187842', 'Mutation', 'rs11187842', (131, 141))	('rs3765524', 'Mutation', 'rs3765524', (109, 118))	('rs3781264', 'Mutation', 'rs3781264', (120, 129))	('GC', 'Phenotype', 'HP:0012126', (93, 95))	('rs3781264', 'Var', (120, 129))	('rs753724', 'Var', (147, 155))
487758	24867265	Information on PLCE1 mRNA expression was available using each of three probes for paired tumor-normal tissues of ESCC, GCA, and GNCA cases, and analyses were performed using individual probes as well as overall mRNA expression (calculated as the average mRNA expression across all three probes) (GEO accession number of RNA expression array data is GSE2340021 for ESCC and GSE2927222 for GCA and GNCA).	('GC', 'Phenotype', 'HP:0012126', (119, 121))	('PLCE1', 'Gene', (15, 20))	('PLCE1', 'Gene', '51196', (15, 20))	('GSE2340021', 'Var', (349, 359))	('ESCC', 'Disease', (364, 368))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('GCA', 'Disease', (388, 391))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('GC', 'Phenotype', 'HP:0012126', (388, 390))	('GSE2927222', 'Var', (373, 383))
487776	24867265	In GCA, the median tumor-normal expression fold change is 0.75 for probe 205111_s_at, 0.66 for 205112_at, 0.91 for 214159_at, and 0.76 for average of three probes.	('GC', 'Phenotype', 'HP:0012126', (3, 5))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('GCA', 'Disease', (3, 6))	('205112_at', 'Var', (95, 104))	('214159_at', 'Var', (115, 124))
487786	24867265	Median survival times of GCA cases by quartile of tumor expression (probe 205111_at) were 13.2, 16.2, 16.0, and 28.9 months, respectively.	('GC', 'Phenotype', 'HP:0012126', (25, 27))	('probe 205111_at', 'Var', (68, 83))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('GCA', 'Disease', (25, 28))	('tumor', 'Disease', (50, 55))
487792	24867265	A joint analysis of all UGI cancers found significant associations between two SNPs (rs2274223 and rs3765524) and PLCE1 mRNA expression (probe 205111_s_at and 205112_at) (P<0.05).	('PLCE1', 'Gene', (114, 119))	('UGI cancers', 'Disease', (24, 35))	('PLCE1', 'Gene', '51196', (114, 119))	('probe 205111_s_at', 'Var', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('rs3765524', 'Var', (99, 108))	('205112_at', 'Var', (159, 168))	('rs2274223', 'Mutation', 'rs2274223', (85, 94))	('rs3765524', 'Mutation', 'rs3765524', (99, 108))	('rs2274223', 'Var', (85, 94))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('UGI cancers', 'Disease', 'MESH:D009369', (24, 35))
487794	24867265	We did, however, observe a correlation between PLCE1 mRNA using probe 205111_s_at and protein expression in the normal tissues of the four ESCC cases (Spearman correlation r=0.95, P=0.05).	('probe 205111_s_at', 'Var', (64, 81))	('protein expression', 'MPA', (86, 104))	('PLCE1', 'Gene', (47, 52))	('PLCE1', 'Gene', '51196', (47, 52))	('correlation', 'Reg', (27, 38))	('ESCC', 'Disease', (139, 143))
487807	24867265	Silencing PLCE1 has been shown to inhibit bladder tumor growth in vitro and in vivo.	('bladder tumor', 'Disease', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('inhibit', 'NegReg', (34, 41))	('PLCE1', 'Gene', (10, 15))	('Silencing', 'Var', (0, 9))	('PLCE1', 'Gene', '51196', (10, 15))	('bladder tumor', 'Disease', 'MESH:D001749', (42, 55))	('bladder tumor', 'Phenotype', 'HP:0009725', (42, 55))
487808	24867265	PLCE1 stimulation has been shown to induce pro-inflammatory cytokine expression and augment inflammation in response to chemical carcinogens or UV irradiation, which could promote skin cancer development.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('promote', 'PosReg', (172, 179))	('inflammation', 'Disease', (92, 104))	('PLCE1', 'Gene', (0, 5))	('augment', 'PosReg', (84, 91))	('skin cancer', 'Phenotype', 'HP:0008069', (180, 191))	('PLCE1', 'Gene', '51196', (0, 5))	('pro-inflammatory cytokine expression', 'MPA', (43, 79))	('induce', 'PosReg', (36, 42))	('skin cancer', 'Disease', (180, 191))	('stimulation', 'Var', (6, 17))	('skin cancer', 'Disease', 'MESH:D012878', (180, 191))
487814	24867265	Reduced PLCE1 expression appeared to be more consistent in GC tumors than ESCC tumors, which is partly consistent with the stronger genetic effect of PLCE1 SNPs in GC, particularly in GCA, as compared with ESCC.	('GC', 'Phenotype', 'HP:0012126', (164, 166))	('SNPs', 'Var', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PLCE1', 'Gene', (8, 13))	('PLCE1', 'Gene', '51196', (8, 13))	('GC', 'Phenotype', 'HP:0012126', (59, 61))	('tumors than ESCC tumors', 'Disease', (62, 85))	('GCA', 'Disease', (184, 187))	('Reduced', 'NegReg', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('GC', 'Phenotype', 'HP:0012126', (184, 186))	('expression', 'MPA', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('PLCE1', 'Gene', (150, 155))	('PLCE1', 'Gene', '51196', (150, 155))	('tumors than ESCC tumors', 'Disease', 'MESH:D009369', (62, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
487822	24867265	In one study, the rs2274223 G allele (the risk allele from GWAS) was associated with increased PLCE1 mRNA and protein expression in ESCC tumor tissues and cancer cell lines.	('tumor', 'Disease', (137, 142))	('rs2274223 G', 'Var', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('PLCE1', 'Gene', (95, 100))	('increased', 'PosReg', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('PLCE1', 'Gene', '51196', (95, 100))	('rs2274223', 'Mutation', 'rs2274223', (18, 27))	('ESCC', 'Disease', (132, 136))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
487823	24867265	However, in a second study, the same rs2274223 G allele (the risk allele) showed reduced gene expression (n=39) in ESCC.	('ESCC', 'Disease', (115, 119))	('gene expression', 'MPA', (89, 104))	('rs2274223', 'Mutation', 'rs2274223', (37, 46))	('rs2274223 G', 'Var', (37, 48))	('reduced', 'NegReg', (81, 88))
487824	24867265	Our study did not find significant associations between rs2274223 or any of the four other PLCE1 germline SNPs and mRNA expression.	('rs2274223', 'Var', (56, 65))	('PLCE1', 'Gene', (91, 96))	('PLCE1', 'Gene', '51196', (91, 96))	('rs2274223', 'Mutation', 'rs2274223', (56, 65))	('mRNA expression', 'MPA', (115, 130))
487826	24867265	For example, it would be useful to determine if epigenetic changes are involved in PLCE1 expression.	('PLCE1', 'Gene', (83, 88))	('PLCE1', 'Gene', '51196', (83, 88))	('involved', 'Reg', (71, 79))	('epigenetic changes', 'Var', (48, 66))
487871	32585822	Similar to the observed overall estimates, high scores in the MDS had a significant protective effect on the risk of UGI cancer, with a pooled OR (adjusted for trim and fill value) of 0.72 (0.61-0.88).	('high scores', 'Var', (43, 54))	('GI cancer', 'Disease', 'MESH:D009369', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('GI cancer', 'Phenotype', 'HP:0007378', (118, 127))	('GI cancer', 'Disease', (118, 127))	('MDS', 'Disease', 'MESH:D009190', (62, 65))	('MDS', 'Disease', (62, 65))
487886	32585822	The low quality of the overall findings, mainly due to the observed inconsistency and indirectness (limited studies from Asia and no evidence for North America), reduced our confidence in the observed benefit of a low DII score being associated with reduced UGI cancer risk.	('DII', 'Chemical', '-', (218, 221))	('GI cancer', 'Phenotype', 'HP:0007378', (259, 268))	('GI cancer', 'Disease', 'MESH:D009369', (259, 268))	('reduced', 'NegReg', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('low', 'Var', (214, 217))	('DII', 'Gene', (218, 221))	('reduced', 'NegReg', (250, 257))	('GI cancer', 'Disease', (259, 268))
487920	32258099	The expression of Stat3 in both mRNA and protein levels was higher in EC109 cells than HEECs.	('EC109', 'CellLine', 'CVCL:6898', (70, 75))	('higher', 'PosReg', (60, 66))	('expression', 'MPA', (4, 14))	('EC109', 'Var', (70, 75))	('Stat3', 'Gene', (18, 23))
487937	32258099	Inhibition of Stat3 could block the abnormal signal transduction and biological effects of target genes, so Stat3 may be a therapeutic target in treatment of tumors.	('tumors', 'Disease', (158, 164))	('abnormal signal transduction', 'MPA', (36, 64))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('biological effects', 'MPA', (69, 87))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Stat3', 'Gene', (14, 19))	('block', 'NegReg', (26, 31))
487938	32258099	It has been reported that metformin could inhibit proliferation and induce apoptosis of breast cancer cells with Stat3 as a target.	('induce', 'PosReg', (68, 74))	('apoptosis', 'CPA', (75, 84))	('metformin', 'Chemical', 'MESH:D008687', (26, 35))	('proliferation', 'CPA', (50, 63))	('inhibit', 'NegReg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('metformin', 'Var', (26, 35))
487941	32258099	Studies have found that metformin could induce apoptosis of tumor cells by increasing the level of ROS.	('increasing', 'PosReg', (75, 85))	('metformin', 'Var', (24, 33))	('apoptosis', 'CPA', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ROS', 'MPA', (99, 102))	('metformin', 'Chemical', 'MESH:D008687', (24, 33))	('level', 'MPA', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('ROS', 'Chemical', 'MESH:D017382', (99, 102))	('induce', 'PosReg', (40, 46))
487963	32258099	Together, these data indicate that metformin selectively induces apoptosis in ESCC cells without affecting the normal esophageal epithelial cells.	('metformin', 'Chemical', 'MESH:D008687', (35, 44))	('induces', 'Reg', (57, 64))	('apoptosis', 'CPA', (65, 74))	('metformin', 'Var', (35, 44))
487965	32258099	As expected, the basal level of Stat3 expression and the Stat3 phosphorylation in EC109 cells were significantly higher than those in HEECs , suggesting that Stat3 variation is involved in the difference of metformin-induced apoptotic cell death in EC109 cells and HEECs.	('metformin', 'Chemical', 'MESH:D008687', (207, 216))	('variation', 'Var', (164, 173))	('higher', 'PosReg', (113, 119))	('EC109', 'CellLine', 'CVCL:6898', (249, 254))	('death', 'Disease', (240, 245))	('death', 'Disease', 'MESH:D003643', (240, 245))	('EC109', 'CellLine', 'CVCL:6898', (82, 87))	('Stat3', 'Gene', (158, 163))	('Stat3 phosphorylation', 'MPA', (57, 78))	('involved', 'Reg', (177, 185))
487966	32258099	Aberrant Stat3 activation stimulates tumor cell proliferation through inhibition of apoptosis, a function mediated by upregulation of the antiapoptotic gene Bcl-2.	('inhibition', 'NegReg', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('apoptosis', 'CPA', (84, 93))	('Aberrant', 'Var', (0, 8))	('upregulation', 'PosReg', (118, 130))	('Stat3', 'Gene', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('activation stimulates', 'PosReg', (15, 36))	('Bcl-2', 'Gene', (157, 162))	('Bcl-2', 'Gene', '596', (157, 162))
487994	32258099	To our surprise, we found that the Stat3 expression level and activation in EC109 cells were significantly higher than those in HEECs, provoking our further investigation on the role of Stat3 in these two types of cell lines.	('EC109', 'CellLine', 'CVCL:6898', (76, 81))	('activation', 'MPA', (62, 72))	('Stat3 expression level', 'MPA', (35, 57))	('higher', 'PosReg', (107, 113))	('EC109', 'Var', (76, 81))
488000	32258099	Meanwhile, metformin inhibited the Stat3 phosphorylation and downregulated the Bcl-2 expression accompanied by induced apoptosis of ESCC cells.	('downregulated', 'NegReg', (61, 74))	('Bcl-2', 'Gene', '596', (79, 84))	('metformin', 'Var', (11, 20))	('Stat3 phosphorylation', 'MPA', (35, 56))	('inhibited', 'NegReg', (21, 30))	('Bcl-2', 'Gene', (79, 84))	('metformin', 'Chemical', 'MESH:D008687', (11, 20))
488003	32258099	It was found that Stat3 knockdown intensified Bcl-2 repression by metformin.	('intensified', 'PosReg', (34, 45))	('Bcl-2', 'Gene', (46, 51))	('Bcl-2', 'Gene', '596', (46, 51))	('metformin', 'Chemical', 'MESH:D008687', (66, 75))	('knockdown', 'Var', (24, 33))	('Stat3', 'Gene', (18, 23))
488006	32258099	This suggested that metformin induced apoptosis of esophageal carcinoma cells partly regulated by the Stat3/Bcl-2 pathway, which may have little function on normal esophageal epithelial cells.	('esophageal carcinoma', 'Disease', (51, 71))	('Bcl-2', 'Gene', (108, 113))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (51, 71))	('metformin', 'Var', (20, 29))	('apoptosis', 'CPA', (38, 47))	('metformin', 'Chemical', 'MESH:D008687', (20, 29))	('Bcl-2', 'Gene', '596', (108, 113))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
488016	32258099	In addition, metformin also increases the ROS level in HEECs as in EC109 cells.	('increases', 'PosReg', (28, 37))	('metformin', 'Var', (13, 22))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('ROS level', 'MPA', (42, 51))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('EC109', 'CellLine', 'CVCL:6898', (67, 72))
488028	31998417	For example, inhibitors of c-MET, EGFR, HER2, and VEGR have been demonstrated to extend survival in these patients.	('extend', 'PosReg', (81, 87))	('survival', 'CPA', (88, 96))	('HER2', 'Gene', (40, 44))	('EGFR', 'Gene', (34, 38))	('HER2', 'Gene', '2064', (40, 44))	('VEGR', 'Gene', (50, 54))	('inhibitors', 'Var', (13, 23))	('EGFR', 'Gene', '1956', (34, 38))	('c-MET', 'Gene', '4233', (27, 32))	('c-MET', 'Gene', (27, 32))
488032	31998417	Recent research by Xie and colleagues suggests that overexpression of P21 is associated with a poor prognosis in patients with non-small-cell lung cancer, while the loss of P21 protein expression could be a significant predictor of disease progression in patients with pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('non-small-cell lung cancer', 'Disease', (127, 153))	('P21', 'Gene', (70, 73))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (127, 153))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (127, 153))	('P21', 'Gene', (173, 176))	('pancreatic cancer', 'Disease', (269, 286))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('protein', 'Protein', (177, 184))	('pancreatic cancer', 'Disease', 'MESH:D010190', (269, 286))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('overexpression', 'PosReg', (52, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (269, 286))	('loss', 'Var', (165, 169))
488033	31998417	A further study demonstrated that aberrant expression of the P21 protein is associated with vascular invasion, pathological disease stage, and overall survival in patients with gastric cancer.	('gastric cancer', 'Disease', (177, 191))	('aberrant expression', 'Var', (34, 53))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('protein', 'Protein', (65, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (177, 191))	('pathological disease', 'Disease', (111, 131))	('associated', 'Reg', (76, 86))	('vascular invasion', 'CPA', (92, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (177, 191))	('P21', 'Gene', (61, 64))
488039	31998417	In contrast, high P21 expression has been reported to be an unfavorable prognostic factor in patients with prostate cancer and breast cancer.	('prostate cancer', 'Disease', (107, 122))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('breast cancer', 'Disease', (127, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('P21', 'Protein', (18, 21))	('expression', 'MPA', (22, 32))
488040	31998417	However, the results of yet other studies in patients with cervical adenocarcinoma and bladder cancer are consistent with our finding that P21 might act as a tumor suppressor.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('P21', 'Var', (139, 142))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor suppressor', 'CPA', (158, 174))	('cervical adenocarcinoma and bladder cancer', 'Disease', 'MESH:D001749', (59, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
488041	31998417	A previous study in prostate cancer showed that P21 inhibits cell growth by targeting E2F1.	('E2F1', 'Gene', '1869', (86, 90))	('E2F1', 'Gene', (86, 90))	('P21', 'Var', (48, 51))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('cell growth', 'CPA', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('inhibits', 'NegReg', (52, 60))	('targeting', 'Reg', (76, 85))
488107	31481064	found that 5-year survival rates were significantly poorer for patients with a ratio of metastatic LNs (LNR) > 0.2 than survival rates for patients with a ratio of metastatic LNs (LNR) <=0.2 (22% vs. 54%, P < 0.001).	('> 0.2', 'Var', (109, 114))	('patients', 'Species', '9606', (139, 147))	('survival rates', 'CPA', (18, 32))	('poorer', 'NegReg', (52, 58))	('patients', 'Species', '9606', (63, 71))
488144	31481064	retrospectively analyzed 446 patients with distal esophageal cancer after resection and found that, compared to celiac node-negative patients, celiac node-positive patients were at a 52% increased risk of disease-specific mortality.	('patients', 'Species', '9606', (29, 37))	('patients', 'Species', '9606', (133, 141))	('celiac', 'Var', (143, 149))	('esophageal cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (164, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
488170	31293658	The activation of oncogenes and the inactivation of tumor suppressor genes resulting from epigenetic and genetic changes are the core biological processes underlying the occurrence of GC.	('epigenetic', 'Var', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('oncogenes', 'Protein', (18, 27))	('tumor', 'Disease', (52, 57))	('inactivation', 'NegReg', (36, 48))	('genetic changes', 'Var', (105, 120))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('activation', 'PosReg', (4, 14))
488171	31293658	The expression of oncogenes might influence cell signal transduction in several ways and disrupt normal cellular functions, leading to disorders of cell proliferation, differentiation, cycle regulation, and apoptosis, and inducing the transition from normal to cancerous cells.	('cancerous', 'Disease', (261, 270))	('leading to', 'Reg', (124, 134))	('apoptosis', 'CPA', (207, 216))	('normal cellular functions', 'CPA', (97, 122))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cycle regulation', 'CPA', (185, 201))	('cancerous', 'Disease', 'MESH:D009369', (261, 270))	('disorders', 'MPA', (135, 144))	('influence', 'Reg', (34, 43))	('cell proliferation', 'CPA', (148, 166))	('expression', 'Var', (4, 14))	('disrupt', 'NegReg', (89, 96))	('inducing', 'Reg', (222, 230))	('oncogenes', 'Gene', (18, 27))	('differentiation', 'CPA', (168, 183))	('cell', 'CPA', (44, 48))	('transition', 'CPA', (235, 245))
488224	31293658	The postoperative 3-year survival rate was 54.07% in patients with high HCCR-1 expression and 82.43% in patients with low HCCR-1 expression.	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (53, 61))	('HCCR-1', 'Gene', (72, 78))	('expression', 'Var', (79, 89))	('patients', 'Species', '9606', (104, 112))
488225	31293658	Similarly, the postoperative 5-year survival rate was 45.19% in patients with high HCCR-1 expression and 78.38% in patients with low HCCR-1 expression.	('patients', 'Species', '9606', (115, 123))	('high', 'Var', (78, 82))	('patients', 'Species', '9606', (64, 72))	('HCCR-1', 'Gene', (83, 89))	('expression', 'Var', (90, 100))
488243	31293658	Researchers have also found that the survival times of patients with low HCCR-1 expression in esophageal cancer tissues were longer than those of patients with high HCCR-1 expression.	('esophageal cancer', 'Disease', (94, 111))	('longer', 'PosReg', (125, 131))	('HCCR-1', 'Gene', (73, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('survival times', 'CPA', (37, 51))	('patients', 'Species', '9606', (55, 63))	('low', 'Var', (69, 72))	('patients', 'Species', '9606', (146, 154))	('expression', 'Var', (80, 90))
488245	31293658	Furthermore, we also confirmed that increased HCCR-1 expression was an independent factor that led to the poor postoperative prognosis of GC patients, and that the postoperative survival time of GC patients with high HCCR-1 expression was shorter than that of patients with low HCCR-1 expression.	('HCCR-1', 'Gene', (217, 223))	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (141, 149))	('high', 'Var', (212, 216))	('HCCR-1', 'Protein', (46, 52))	('patients', 'Species', '9606', (260, 268))	('increased', 'PosReg', (36, 45))	('shorter', 'NegReg', (239, 246))	('postoperative', 'CPA', (164, 177))
488255	31293658	Studies have shown that NIH/3T3 cells that underwent malignant transformation after transfection with HCCR formed more clones on soft agar and differentiated into epithelial cell carcinomas.	('differentiated', 'CPA', (143, 157))	('clones on', 'CPA', (119, 128))	('epithelial cell carcinomas', 'Disease', (163, 189))	('HCCR', 'Gene', '25875', (102, 106))	('epithelial cell carcinomas', 'Disease', 'MESH:C567703', (163, 189))	('NIH/3T3', 'CellLine', 'CVCL:0594', (24, 31))	('HCCR', 'Gene', (102, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('transfection', 'Var', (84, 96))	('epithelial cell carcinomas', 'Phenotype', 'HP:0031492', (163, 189))
488256	31293658	Xu et al., using MTT experiments, found that transfection of HCCR-1 siRNA into a pancreatic cancer cell line in which HCCR expression was upregulated decreased cell proliferation.	('HCCR', 'Gene', '25875', (118, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('MTT', 'Chemical', 'MESH:C070243', (17, 20))	('HCCR', 'Gene', (118, 122))	('transfection', 'Var', (45, 57))	('HCCR', 'Gene', '25875', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', (81, 98))	('upregulated', 'PosReg', (138, 149))	('HCCR', 'Gene', (61, 65))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('cell proliferation', 'CPA', (160, 178))	('decreased', 'NegReg', (150, 159))
488264	31293658	Our results also confirmed that there was a positive correlation between high EGF expression and increased HCCR-1 expression in GC tissues and cell lines.	('HCCR-1', 'Gene', (107, 113))	('EGF', 'Gene', (78, 81))	('increased', 'PosReg', (97, 106))	('expression', 'MPA', (82, 92))	('EGF', 'Gene', '1950', (78, 81))	('expression', 'MPA', (114, 124))	('high', 'Var', (73, 77))
488453	33522492	5), in agreement with the presence of BRAF mutations in about 70-80% of these cases.	('mutations', 'Var', (43, 52))	('BRAF', 'Gene', (38, 42))	('BRAF', 'Gene', '673', (38, 42))
488465	33522492	Previous studies identified BRAF p.V600E mutation as the most common alteration in HVPTC, as confirmed also in our case.	('p.V600E', 'Mutation', 'rs113488022', (33, 40))	('BRAF', 'Gene', '673', (28, 32))	('p.V600E', 'Var', (33, 40))	('PTC', 'Phenotype', 'HP:0002895', (85, 88))	('BRAF', 'Gene', (28, 32))
488516	32384611	Additionally, gene regulation may play an important role in the susceptibility as well, and the mutagenesis by AFB1 may depend on the context of DNA.	('AFB1', 'Chemical', 'MESH:D016604', (111, 115))	('mutagenesis', 'Var', (96, 107))	('AFB1', 'Gene', (111, 115))
488517	32384611	The mutations single-nucleotide polymorphism and aberrant hypermethylation of tumor-suppressor gene p53 have been found in esophageal carcinogenesis, resulting in the loss of its function to inhibit malignant transformation.	('found', 'Reg', (114, 119))	('esophageal carcinogenesis', 'Disease', (123, 148))	('inhibit', 'NegReg', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (123, 148))	('function', 'MPA', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('loss', 'NegReg', (167, 171))	('tumor', 'Disease', (78, 83))	('aberrant hypermethylation', 'Var', (49, 74))	('malignant transformation', 'CPA', (199, 223))	('p53', 'Gene', (100, 103))
488518	32384611	The presence of the R246S transgene in transgenic mice, which is the equivalent of the human R249S p53 mutant, was found to increase and accelerate the incidence of higher-grade liver cancer upon AFB1 exposure.	('increase', 'PosReg', (124, 132))	('liver cancer', 'Disease', 'MESH:D006528', (178, 190))	('AFB1', 'Chemical', 'MESH:D016604', (196, 200))	('liver cancer', 'Disease', (178, 190))	('accelerate', 'PosReg', (137, 147))	('human', 'Species', '9606', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('transgenic mice', 'Species', '10090', (39, 54))	('liver cancer', 'Phenotype', 'HP:0002896', (178, 190))	('R249S', 'Mutation', 'rs28934571', (93, 98))	('R246S', 'Var', (20, 25))	('R246S', 'Mutation', 'p.R246S', (20, 25))
488551	29019267	GE11-Ori-Se NPs were found to induce cancer cell apoptosis by inducting reactive oxygen species (ROS) production, activating mitochondria-dependent pathway, inhibiting EGFR-mediated PI3K/AKT and inhibiting Ras/Raf/MEK/ERK pathways.	('induce', 'PosReg', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('-Ori-Se NPs', 'Chemical', '-', (4, 15))	('GE11-Ori-Se NPs', 'Var', (0, 15))	('Ras/Raf/MEK/ERK pathways', 'Pathway', (206, 230))	('cancer', 'Disease', (37, 43))	('inhibiting', 'NegReg', (195, 205))	('inhibiting', 'NegReg', (157, 167))	('inducting', 'Reg', (62, 71))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('mitochondria-dependent pathway', 'Pathway', (125, 155))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('activating', 'PosReg', (114, 124))	('EGFR-mediated PI3K/AKT', 'Pathway', (168, 190))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (72, 95))	('NPs', 'Var', (12, 15))
488552	29019267	GE11-Se NPs were also found to show active targeting effects against the tumor tissue in esophageal cancer bearing mice.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Se', 'Chemical', 'MESH:D012643', (5, 7))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('GE11-Se', 'Var', (0, 7))	('tumor', 'Disease', (73, 78))	('cancer', 'Disease', (100, 106))	('mice', 'Species', '10090', (115, 119))	('targeting', 'MPA', (43, 52))
488553	29019267	And in nude mice xenograft model, GE11-Ori-Se NPs significantly inhibited the tumor growth via inhibition of tumor angiogenesis by reducing the angiogenesis-marker CD31 and activation of the immune system by enhancing IL-2 and TNF-alpha production.	('TNF-alpha production', 'MPA', (227, 247))	('-Ori-Se NPs', 'Chemical', '-', (38, 49))	('IL-2', 'MPA', (218, 222))	('activation', 'PosReg', (173, 183))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('inhibited', 'NegReg', (64, 73))	('inhibition', 'NegReg', (95, 105))	('angiogenesis-marker CD31', 'MPA', (144, 168))	('GE11-Ori-Se', 'Var', (34, 45))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('reducing', 'NegReg', (131, 139))	('enhancing', 'PosReg', (208, 217))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('nude mice', 'Species', '10090', (7, 16))	('tumor', 'Disease', (109, 114))
488555	29019267	This cancer-targeted design of Se NPs provides a new strategy for synergistic treating of cancer with higher efficacy and reduced side effects, introducing GE11-Ori-Se NPs as a candidate for further evaluation as a chemotherapeutic agent for EGFR over-expressed esophageal cancers.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (273, 279))	('over-expressed', 'PosReg', (247, 261))	('GE11-Ori-Se', 'Var', (156, 167))	('esophageal cancers', 'Disease', (262, 280))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('cancer', 'Disease', (5, 11))	('Se', 'Chemical', 'MESH:D012643', (31, 33))	('Se', 'Chemical', 'MESH:D012643', (165, 167))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('esophageal cancers', 'Disease', 'MESH:D004938', (262, 280))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('-Ori-Se NPs', 'Chemical', '-', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
488572	29019267	The in vitro cellular uptake mechanism and anticancer activity of GE11-Ori-Se NPs, and the underlying molecular mechanisms were also investigated in this study.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('-Ori-Se NPs', 'Chemical', '-', (70, 81))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('GE11-Ori-Se', 'Var', (66, 77))
488573	29019267	In vivo investigation of nanoparticles on nude mice bearing esophageal cancer xenografts further indicated that GE11-Ori-Se NPs possessed high antitumor efficiency with no systemic toxicity, throwing light on the use of GE11-Ori-Se NPs to be a viable drug candidate for esophageal cancer treatment.	('-Ori-Se NPs', 'Chemical', '-', (116, 127))	('tumor', 'Disease', (147, 152))	('GE11-Ori-Se NPs', 'Var', (112, 127))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('-Ori-Se NPs', 'Chemical', '-', (224, 235))	('throwing light', 'Phenotype', 'HP:0002013', (191, 205))	('cancer', 'Disease', (71, 77))	('toxicity', 'Disease', 'MESH:D064420', (181, 189))	('toxicity', 'Disease', (181, 189))	('cancer', 'Disease', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('nude mice', 'Species', '10090', (42, 51))
488623	29019267	Rhodamine 123-based flow cytometry was used to determine the alterations of mitochondria membrane potential of KYSE-150 cells before and after GE11-Ori-Se NPs treatment.	('KYSE-150', 'CellLine', 'CVCL:1348', (111, 119))	('mitochondria membrane potential', 'MPA', (76, 107))	('-Ori-Se NPs', 'Chemical', '-', (147, 158))	('Rhodamine 123', 'Chemical', 'MESH:D020112', (0, 13))	('alterations', 'Reg', (61, 72))	('GE11-Ori-Se', 'Var', (143, 154))
488647	29019267	For in vivo biodistribution studies of selenium after GE11-Ori-Se NPs administration for 15 d, the mice were sacrificed and tumor, heart, liver, spleen, lung, and kidney were collected and used to determine the selenium content in different tissues using a similar method as reported (Gao et al.,).	('mice', 'Species', '10090', (99, 103))	('-Ori-Se NPs', 'Chemical', '-', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('selenium', 'Chemical', 'MESH:D012643', (211, 219))	('GE11-Ori-Se', 'Var', (54, 65))	('tumor', 'Disease', (124, 129))	('selenium', 'Chemical', 'MESH:D012643', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
488658	29019267	As shown in Figure 1(A), GE11-Ori-Se NPs showed characteristic peaks at 1689.41 and 1456.36 cm-1 from oridonin.	('oridonin', 'Chemical', 'MESH:C011959', (102, 110))	('-Ori-Se NPs', 'Chemical', '-', (29, 40))	('GE11-Ori-Se', 'Var', (25, 36))	('1456.36 cm-1', 'Var', (84, 96))
488661	29019267	GE11-Ori-Se NPs also showed specific absorption at 1523.78 cm-1, which was similar with the specific absorption of GE11 peptide at 1517.03 cm-1, confirming the successful conjugation of GE11 peptide onto Se NPs.	('Se', 'Chemical', 'MESH:D012643', (9, 11))	('conjugation', 'Interaction', (171, 182))	('-Ori-Se NPs', 'Chemical', '-', (4, 15))	('specific absorption', 'MPA', (28, 47))	('Se', 'Chemical', 'MESH:D012643', (204, 206))	('GE11-Ori-Se', 'Var', (0, 11))
488662	29019267	And the UV-vis spectra analysis also demonstrated the characteristic peaks of GE11 peptide on GE11-Ori-Se NPs (Figure S1).	('GE11-Ori-Se', 'Var', (94, 105))	('GE11', 'Gene', (78, 82))	('-Ori-Se NPs', 'Chemical', '-', (98, 109))
488665	29019267	Besides, GE11-Ori-Se NPs showed an average zeta potential of 48 mV, which promoted the nanoparticle system more easily to be internalized by cancer cells due to the positive charge of Se NPs surface (Yu et al.,).	('promoted', 'PosReg', (74, 82))	('-Ori-Se NPs', 'Chemical', '-', (13, 24))	('GE11-Ori-Se', 'Var', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('zeta', 'MPA', (43, 47))	('Se', 'Chemical', 'MESH:D012643', (184, 186))	('positive', 'PosReg', (165, 173))	('Se', 'Chemical', 'MESH:D012643', (18, 20))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
488666	29019267	The size distribution and zeta potential of blank Se NPs (Chi-Se NPs) and Ori-Se NPs were also analyzed, which demonstrated that oridonin loading and GE11 peptide surface decoration increased the average particle size of Se NPs from 55 to 60 nm, and finally to 70 nm for GE11-Ori-Se NPs (Figure S2).	('increased', 'PosReg', (182, 191))	('C', 'Chemical', 'MESH:D002244', (58, 59))	('Se', 'Chemical', 'MESH:D012643', (78, 80))	('-Ori-Se NPs', 'Chemical', '-', (275, 286))	('Se', 'Chemical', 'MESH:D012643', (62, 64))	('oridonin', 'Chemical', 'MESH:C011959', (129, 137))	('GE11 peptide', 'Var', (150, 162))	('Se', 'Chemical', 'MESH:D012643', (221, 223))	('Se', 'Chemical', 'MESH:D012643', (280, 282))	('Se', 'Chemical', 'MESH:D012643', (50, 52))
488675	29019267	At pH 7.4, the nanoparticles were endowed with a similar hydrodynamic diameter (80 nm) compared to the initial solution (70 nm), and the zeta potential of GE11-Ori-Se NPs slightly decreased to 37 mV.	('decreased', 'NegReg', (180, 189))	('GE11-Ori-Se', 'Var', (155, 166))	('zeta potential', 'MPA', (137, 151))	('-Ori-Se NPs', 'Chemical', '-', (159, 170))
488676	29019267	However, in case of pH 5.5, the particle underwent a significant average particle size increase to 190 nm, and the zeta potential of GE11-Ori-Se NPs dramatically decreased to 17 mV.	('increase', 'PosReg', (87, 95))	('decreased', 'NegReg', (162, 171))	('GE11-Ori-Se', 'Var', (133, 144))	('zeta potential', 'MPA', (115, 129))	('-Ori-Se NPs', 'Chemical', '-', (137, 148))
488678	29019267	Under neutral and slightly basic condition (pH 7.4), chitosan was orderly aggregated on the surface of Se NPs due to the deprotonation of its amino groups, which hindered the release of oridonin from nanoparticles.	('chitosan', 'Chemical', 'MESH:D048271', (53, 61))	('oridonin', 'Chemical', 'MESH:C011959', (186, 194))	('deprotonation', 'Var', (121, 134))	('Se', 'Chemical', 'MESH:D012643', (103, 105))	('hindered', 'NegReg', (162, 170))	('release', 'MPA', (175, 182))
488684	29019267	By introducing GE11 peptide onto the surface of Se NPs, the obtained nanoparticles might be an efficient candidate for EGFR targeted cancer treatment.	('introducing', 'Reg', (3, 14))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('Se', 'Chemical', 'MESH:D012643', (48, 50))	('cancer', 'Disease', (133, 139))	('GE11 peptide', 'Var', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
488686	29019267	Obtained results demonstrated that the uptake of GE11-Se NPs in KYSE-150 cells (Figure 3(A)) was higher than that of Chi-Se NPs (Figure 3(B)).	('GE11-Se NPs', 'Var', (49, 60))	('Se', 'Chemical', 'MESH:D012643', (54, 56))	('higher', 'PosReg', (97, 103))	('C', 'Chemical', 'MESH:D002244', (117, 118))	('KYSE-150', 'CellLine', 'CVCL:1348', (64, 72))	('uptake', 'MPA', (39, 45))	('Se', 'Chemical', 'MESH:D012643', (121, 123))
488693	29019267	These results strongly suggested that the selective cellular uptake of GE11-Se NPs by cancer cells could be partially traced to EGFR dependent endocytosis in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (158, 164))	('Se', 'Chemical', 'MESH:D012643', (76, 78))	('EGFR dependent endocytosis', 'MPA', (128, 154))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('GE11-Se', 'Var', (71, 78))	('cancer', 'Disease', (86, 92))
488695	29019267	As shown in Figure 3(H), NaN3 in combination with DOG treatment, or low temperature (4  C), strongly inhibited the uptake of coumarin-6-loaded GE11-Se NPs to 67.04 +- 5.34 and 41.03 +- 2.74% of control, which suggested that coumarin-6-loaded GE11-Se NPs was transported into the cells by means of energy-dependent endocytosis.	('uptake', 'MPA', (115, 121))	('NaN3', 'Var', (25, 29))	('NaN3', 'Chemical', 'MESH:D019810', (25, 29))	('Se', 'Chemical', 'MESH:D012643', (247, 249))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('DOG', 'Species', '9615', (50, 53))	('coumarin-6', 'Chemical', 'MESH:C517282', (224, 234))	('coumarin-6', 'Chemical', 'MESH:C517282', (125, 135))	('Se', 'Chemical', 'MESH:D012643', (148, 150))	('inhibited', 'NegReg', (101, 110))
488706	29019267	The disappeared red fluorescence detected by confocal microscopy and increased low AO signal cells detected by flow cytometry showed significant changes in lysosomal membrane permeation after internalization of GE11-Se NPs into lysosomes of KYSE-150 cells (Figure 4(B,C)), which provide a chance for GE11-Se NPs to be further released into cytoplasm.	('GE11-Se', 'Var', (211, 218))	('C', 'Chemical', 'MESH:D002244', (268, 269))	('Se', 'Chemical', 'MESH:D012643', (305, 307))	('internalization', 'MPA', (192, 207))	('AO', 'Chemical', 'MESH:D000165', (83, 85))	('lysosomal membrane permeation', 'MPA', (156, 185))	('Se', 'Chemical', 'MESH:D012643', (216, 218))	('changes', 'Reg', (145, 152))	('KYSE-150', 'CellLine', 'CVCL:1348', (241, 249))
488709	29019267	As shown in Figure 5(B), GE11-Ori-Se NPs demonstrated dose dependent inhibition effects both on KYSE-150 cells and EC-9706 cells, demonstrating the strong proliferation-inhibition effects of GE11-Ori-Se NPs on cancer cells.	('-Ori-Se NPs', 'Chemical', '-', (195, 206))	('EC-9706', 'CellLine', 'CVCL:E307', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('proliferation-inhibition', 'CPA', (155, 179))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('KYSE-150', 'CellLine', 'CVCL:1348', (96, 104))	('-Ori-Se NPs', 'Chemical', '-', (29, 40))	('GE11-Ori-Se', 'Var', (25, 36))	('cancer', 'Disease', (210, 216))	('inhibition', 'NegReg', (69, 79))
488710	29019267	However, no significant inhibition effects of GE11-Ori-Se NPs were found in FLS cells and THP-1 cells, suggesting the selective inhibition effects of GE11-Ori-Se NPs on cancer cells.	('cancer', 'Disease', (169, 175))	('inhibition', 'NegReg', (128, 138))	('GE11-Ori-Se', 'Var', (150, 161))	('THP-1', 'Gene', '2736', (90, 95))	('THP-1', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('-Ori-Se NPs', 'Chemical', '-', (50, 61))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('-Ori-Se NPs', 'Chemical', '-', (154, 165))
488715	29019267	However, GE11-Ori-Se NPs showed stronger inhibition effects on the viability of KYSE-150 cells.	('-Ori-Se NPs', 'Chemical', '-', (13, 24))	('KYSE-150', 'CellLine', 'CVCL:1348', (80, 88))	('GE11-Ori-Se', 'Var', (9, 20))	('viability of KYSE-150 cells', 'CPA', (67, 94))	('inhibition', 'NegReg', (41, 51))
488716	29019267	Isobologram analysis showed that the viability inhibition of combined Chi-Se NPs and oridonin treatment was significantly synergistic, as evidenced by the location of data point in the isobologram far below the line defining as additive effect (Figure 5(D)).	('Chi-Se', 'Var', (70, 76))	('Se', 'Chemical', 'MESH:D012643', (74, 76))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('inhibition', 'NegReg', (47, 57))	('oridonin', 'Chemical', 'MESH:C011959', (85, 93))
488717	29019267	Taking all results obtained here into account, the strategy to use a GE11-Se NP as a carrier could be a highly efficient way to enhance the efficacy and selectivity of oridonin.	('oridonin', 'Chemical', 'MESH:C011959', (168, 176))	('Se', 'Chemical', 'MESH:D012643', (74, 76))	('selectivity', 'MPA', (153, 164))	('enhance', 'PosReg', (128, 135))	('efficacy', 'MPA', (140, 148))	('GE11-Se', 'Var', (69, 76))
488719	29019267	Thus, we further examined whether cell cycle arrest and apoptosis were also involved in GE11-Ori-Se NPs inhibited cancer cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('arrest', 'Disease', (45, 51))	('GE11-Ori-Se', 'Var', (88, 99))	('arrest', 'Disease', 'MESH:D006323', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (34, 51))	('apoptosis', 'CPA', (56, 65))	('-Ori-Se NPs', 'Chemical', '-', (92, 103))	('cancer', 'Disease', (114, 120))
488720	29019267	The representative cell cycle distribution images demonstrated that the percentage of KYSE-150 cells in G1/G0 phase decreased and the percentage of KYSE-150 cells in S phase significantly increased after GE11-Ori-Se NPs treatment (Figure 6(A)), which implied that cell cycle arrest at S phase might be one of the mechanisms for the anticancer effects of GE11-Ori-Se NPs.	('KYSE-150', 'CellLine', 'CVCL:1348', (86, 94))	('KYSE-150', 'CellLine', 'CVCL:1348', (148, 156))	('GE11-Ori-Se', 'Var', (204, 215))	('arrest', 'Disease', 'MESH:D006323', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('arrest', 'Disease', (275, 281))	('-Ori-Se NPs', 'Chemical', '-', (358, 369))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('-Ori-Se NPs', 'Chemical', '-', (208, 219))	('cancer', 'Disease', (336, 342))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (264, 281))	('increased', 'PosReg', (188, 197))	('decreased', 'NegReg', (116, 125))
488721	29019267	As shown in Figure 6(B), after treated with different concentration of GE11-Ori-Se NPs, the apoptotic KYSE-150 cells increased dose dependently, which demonstrated that cell death induced by GE11-Ori-Se NPs was mainly caused by apoptosis.	('-Ori-Se NPs', 'Chemical', '-', (195, 206))	('death', 'Disease', 'MESH:D003643', (174, 179))	('KYSE-150', 'CellLine', 'CVCL:1348', (102, 110))	('death', 'Disease', (174, 179))	('-Ori-Se NPs', 'Chemical', '-', (75, 86))	('GE11-Ori-Se NPs', 'Var', (191, 206))
488725	29019267	And the average particle size and roughness for the membrane of KYSE-150 cells both increased after GE11-Ori-Se NPs treatment with dose-dependent manner (Figure S7).	('-Ori-Se NPs', 'Chemical', '-', (104, 115))	('roughness for the membrane', 'CPA', (34, 60))	('KYSE-150', 'CellLine', 'CVCL:1348', (64, 72))	('GE11-Ori-Se NPs', 'Var', (100, 115))	('increased', 'PosReg', (84, 93))
488726	29019267	To examine the roles of mitochondria in GE11-Ori-Se NPs induced cancer cell apoptosis, we further tested the mitochondrial membrane potential in response to GE11-Ori-Se NPs exposure by flow cytometry.	('-Ori-Se NPs', 'Chemical', '-', (161, 172))	('GE11-Ori-Se', 'Var', (40, 51))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tested', 'Reg', (98, 104))	('-Ori-Se NPs', 'Chemical', '-', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
488727	29019267	As shown in Figure 6(C), the mitochondrial membrane potential of KYSE-150 cells decreased dose dependently after GE11-Ori-Se NPs treatment, indicating that GE11-Ori-Se NPs could also disrupt the function of mitochondria, which therefore prompting the apoptosis of cancer cells.	('mitochondria', 'MPA', (207, 219))	('-Ori-Se NPs', 'Chemical', '-', (117, 128))	('C', 'Chemical', 'MESH:D002244', (21, 22))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('disrupt', 'NegReg', (183, 190))	('function', 'MPA', (195, 203))	('prompting', 'PosReg', (237, 246))	('decreased', 'NegReg', (80, 89))	('GE11-Ori-Se', 'Var', (113, 124))	('mitochondrial membrane potential', 'MPA', (29, 61))	('-Ori-Se NPs', 'Chemical', '-', (160, 171))	('GE11-Ori-Se NPs', 'Var', (156, 171))	('KYSE-150', 'CellLine', 'CVCL:1348', (65, 73))	('apoptosis', 'CPA', (251, 260))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
488729	29019267	As shown in Figure 7(A), GE11-Ori-Se NPs, Chi-Se NPs and oridonin could all elevate ROS generation in KYSE-150 cells after 5 min treatment, followed by a gradually fall down after 60 min treatment.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('elevate ROS generation', 'Phenotype', 'HP:0025464', (76, 98))	('elevate', 'PosReg', (76, 83))	('Se', 'Chemical', 'MESH:D012643', (34, 36))	('GE11-Ori-Se NPs', 'Var', (25, 40))	('KYSE-150', 'CellLine', 'CVCL:1348', (102, 110))	('fall', 'Phenotype', 'HP:0002527', (164, 168))	('oridonin', 'Chemical', 'MESH:C011959', (57, 65))	('Chi-Se NPs', 'Var', (42, 52))	('-Ori-Se NPs', 'Chemical', '-', (29, 40))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('Se', 'Chemical', 'MESH:D012643', (46, 48))	('ROS generation', 'MPA', (84, 98))
488730	29019267	It was worth to note that GE11-Ori-Se NPs induced higher ROS level than that of oridonin or Chi-Se NPs, suggesting that the combination of Chi-Se NPs and oridonin synergistically further elevated intracellular ROS level in KYSE-150 cells, which therefore resulted in enhanced anticancer activity.	('elevated', 'PosReg', (187, 195))	('Se', 'Chemical', 'MESH:D012643', (143, 145))	('cancer', 'Disease', (280, 286))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('elevated intracellular ROS level', 'Phenotype', 'HP:0025464', (187, 219))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('Chi-Se', 'Var', (139, 145))	('oridonin', 'Chemical', 'MESH:C011959', (80, 88))	('-Ori-Se NPs', 'Chemical', '-', (30, 41))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('Se', 'Chemical', 'MESH:D012643', (35, 37))	('enhanced', 'PosReg', (267, 275))	('ROS', 'Chemical', 'MESH:D017382', (210, 213))	('GE11-Ori-Se', 'Var', (26, 37))	('Se', 'Chemical', 'MESH:D012643', (96, 98))	('C', 'Chemical', 'MESH:D002244', (92, 93))	('intracellular ROS level', 'MPA', (196, 219))	('oridonin', 'Chemical', 'MESH:C011959', (154, 162))	('KYSE-150', 'CellLine', 'CVCL:1348', (223, 231))	('ROS level', 'MPA', (57, 66))
488732	29019267	As indicated in Figure 7(B), we found that GE11-Ori-Se NPs treatment could decrease Bcl-2 expression and also increase Bax expression in KYSE-150 cells, which indicated that mitochondria dysfunction was also involved in GE11-Ori-Se NPs inhibited KYSE-150 cells.	('mitochondria dysfunction', 'Disease', (174, 198))	('increase', 'PosReg', (110, 118))	('decrease', 'NegReg', (75, 83))	('-Ori-Se NPs', 'Chemical', '-', (224, 235))	('Bax expression', 'MPA', (119, 133))	('KYSE-150', 'CellLine', 'CVCL:1348', (246, 254))	('KYSE-150', 'CellLine', 'CVCL:1348', (137, 145))	('GE11-Ori-Se', 'Var', (43, 54))	('Bcl-2 expression', 'MPA', (84, 100))	('-Ori-Se NPs', 'Chemical', '-', (47, 58))	('mitochondria dysfunction', 'Disease', 'MESH:C564925', (174, 198))
488736	29019267	As shown in Figure 7(C), both the expression of mitochondria-dependent caspase-9 and apoptosis effector caspase-3 were increased by GE11-Ori-Se NPs treatment in a dose dependent manner.	('C', 'Chemical', 'MESH:D002244', (21, 22))	('GE11-Ori-Se', 'Var', (132, 143))	('expression', 'MPA', (34, 44))	('mitochondria-dependent', 'MPA', (48, 70))	('caspase-9', 'Gene', (71, 80))	('apoptosis', 'MPA', (85, 94))	('caspase-3', 'Gene', '836', (104, 113))	('-Ori-Se NPs', 'Chemical', '-', (136, 147))	('caspase-9', 'Gene', '842', (71, 80))	('increased', 'PosReg', (119, 128))	('caspase-3', 'Gene', (104, 113))
488737	29019267	The activity of caspase-9 significantly increased to 164.87 +- 3.30% after treated with 32 muM GE11-Ori-Se NPs for 48 h, and the activity of caspase-3 increased to 171.90 +- 9.97% with 32 muM GE11-Ori-Se NPs treatment.	('caspase-3', 'Gene', (141, 150))	('increased', 'PosReg', (151, 160))	('muM', 'Gene', (188, 191))	('caspase-3', 'Gene', '836', (141, 150))	('activity', 'MPA', (4, 12))	('GE11-Ori-Se', 'Var', (95, 106))	('caspase-9', 'Gene', (16, 25))	('activity', 'MPA', (129, 137))	('increased', 'PosReg', (40, 49))	('-Ori-Se NPs', 'Chemical', '-', (196, 207))	('muM', 'Gene', '56925', (91, 94))	('-Ori-Se NPs', 'Chemical', '-', (99, 110))	('muM', 'Gene', (91, 94))	('muM', 'Gene', '56925', (188, 191))	('caspase-9', 'Gene', '842', (16, 25))
488738	29019267	These results collectively suggested that GE11-Ori-Se NPs could induce KYSE-150 cell apoptosis in mitochondria-dependent way.	('induce', 'PosReg', (64, 70))	('GE11-Ori-Se NPs', 'Var', (42, 57))	('KYSE-150', 'CellLine', 'CVCL:1348', (71, 79))	('-Ori-Se NPs', 'Chemical', '-', (46, 57))	('KYSE-150 cell apoptosis', 'CPA', (71, 94))
488740	29019267	Here, we further tested the expression and phosphorylation of EGFR, which showed that GE11-Ori-Se NPs inhibited the phosphorylation of EGFR (Figure 7(D)).	('phosphorylation', 'MPA', (116, 131))	('inhibited', 'NegReg', (102, 111))	('-Ori-Se NPs', 'Chemical', '-', (90, 101))	('EGFR', 'Protein', (135, 139))	('GE11-Ori-Se', 'Var', (86, 97))
488741	29019267	By Western blot analysis, we also found that GE11-Ori-Se NPs inhibited the phosphorylation of PI3K and AKT, which demonstrated that GE11-Ori-Se NPs could inhibit EGFR-mediated PI3K/AKT pathway.	('GE11-Ori-Se', 'Var', (45, 56))	('PI3K', 'Pathway', (94, 98))	('inhibited', 'NegReg', (61, 70))	('-Ori-Se NPs', 'Chemical', '-', (49, 60))	('inhibit', 'NegReg', (154, 161))	('-Ori-Se NPs', 'Chemical', '-', (136, 147))	('GE11-Ori-Se NPs', 'Var', (132, 147))	('phosphorylation', 'MPA', (75, 90))	('AKT', 'Pathway', (103, 106))	('EGFR-mediated PI3K/AKT pathway', 'Pathway', (162, 192))
488742	29019267	As shown in Figure 7(E), the Ras protein level and Raf protein was significantly reduced after GE11-Ori-Se NPs exposure.	('Ras protein level', 'MPA', (29, 46))	('Raf protein', 'Protein', (51, 62))	('reduced', 'NegReg', (81, 88))	('-Ori-Se NPs', 'Chemical', '-', (99, 110))	('GE11-Ori-Se NPs', 'Var', (95, 110))
488743	29019267	Moreover, the results also showed that the treatment of KYSE-150 cells with GE11-Ori-Se NPs resulted in down-regulation in the phosphorylation of MEK and ERK in a dose-dependent manner (Figure 7(E)).	('down-regulation', 'NegReg', (104, 119))	('KYSE-150', 'CellLine', 'CVCL:1348', (56, 64))	('phosphorylation', 'MPA', (127, 142))	('-Ori-Se NPs', 'Chemical', '-', (80, 91))	('MEK', 'Protein', (146, 149))	('GE11-Ori-Se NPs', 'Var', (76, 91))	('ERK', 'Protein', (154, 157))
488744	29019267	These results indicated that GE11-Ori-Se NPs also played the promoting-death role in KYSE-150 cells through inhibiting EGFR-mediated Ras-Raf-MEK-ERK pathway.	('death', 'Disease', 'MESH:D003643', (71, 76))	('EGFR-mediated Ras-Raf-MEK-ERK pathway', 'Pathway', (119, 156))	('death', 'Disease', (71, 76))	('KYSE-150', 'CellLine', 'CVCL:1348', (85, 93))	('inhibiting', 'NegReg', (108, 118))	('-Ori-Se NPs', 'Chemical', '-', (33, 44))	('GE11-Ori-Se NPs', 'Var', (29, 44))
488745	29019267	The targeting ability of GE11-Se NPs in esophageal cancer (KYSE-150 cells) bearing nude mice was estimated using near-infrared fluorescence imaging.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('GE11-Se', 'Var', (25, 32))	('KYSE-150', 'CellLine', 'CVCL:1348', (59, 67))	('nude mice', 'Species', '10090', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('Se', 'Chemical', 'MESH:D012643', (30, 32))
488748	29019267	However, the fluorescence signal from the tumor was much higher in coumarin-6-loaded GE11-Se NPs treated mice than that of coumarin-6-loaded Chi-Se NPs (Figure 8(A,B)), demonstrating the enhanced targeting effects of Se NPs with GE11 surface decoration.	('tumor', 'Disease', (42, 47))	('GE11-Se', 'Var', (85, 92))	('higher', 'PosReg', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('targeting', 'MPA', (196, 205))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('Se', 'Chemical', 'MESH:D012643', (217, 219))	('fluorescence signal', 'MPA', (13, 32))	('coumarin-6', 'Chemical', 'MESH:C517282', (123, 133))	('Se', 'Chemical', 'MESH:D012643', (145, 147))	('enhanced', 'PosReg', (187, 195))	('Se', 'Chemical', 'MESH:D012643', (90, 92))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('mice', 'Species', '10090', (105, 109))	('coumarin-6', 'Chemical', 'MESH:C517282', (67, 77))
488750	29019267	These findings suggested that GE11-Se NPs could be served as a potential esophageal cancer targeting agent in tumor-bearing mice due to the EPR effects of Se NPs and the targeting effects of GE11 peptide against tumor.	('EPR', 'MPA', (140, 143))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('GE11 peptide', 'Var', (191, 203))	('tumor', 'Disease', (110, 115))	('mice', 'Species', '10090', (124, 128))	('Se', 'Chemical', 'MESH:D012643', (35, 37))	('Se', 'Chemical', 'MESH:D012643', (155, 157))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
488751	29019267	To observe the anti-tumor activity and systemic toxicity of GE11-Ori-Se NPs, the crucial index for its future medical potential, we applied different concentrations of GE11-Ori-Se NPs in a esophageal cancer (KYSE-150 cells) xenograft nude mice model.	('-Ori-Se NPs', 'Chemical', '-', (172, 183))	('GE11-Ori-Se NPs', 'Var', (168, 183))	('KYSE-150', 'CellLine', 'CVCL:1348', (208, 216))	('toxicity', 'Disease', 'MESH:D064420', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('toxicity', 'Disease', (48, 56))	('nude mice', 'Species', '10090', (234, 243))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Disease', (20, 25))	('-Ori-Se NPs', 'Chemical', '-', (64, 75))	('cancer', 'Disease', (200, 206))
488753	29019267	We found that administration of GE11-Ori-Se NPs for 15 d substantially suppressed tumor growth with few effects on the body weight of mice (Figure 9(A)).	('mice', 'Species', '10090', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('-Ori-Se NPs', 'Chemical', '-', (36, 47))	('GE11-Ori-Se NPs', 'Var', (32, 47))	('tumor', 'Disease', (82, 87))	('suppressed', 'NegReg', (71, 81))
488754	29019267	Both 5 and 7.5 mg/kg/d GE11-Ori-Se NPs could significantly inhibit tumor growth, and it was also worth to note that nearly 60% of the tumor weight was suppressed by 7.5 mg/kg/d GE11-Ori-Se NPs (Figure 9(B)).	('-Ori-Se NPs', 'Chemical', '-', (181, 192))	('-Ori-Se NPs', 'Chemical', '-', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('GE11-Ori-Se', 'Var', (23, 34))	('suppressed', 'NegReg', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (67, 72))	('inhibit', 'NegReg', (59, 66))	('GE11-Ori-Se NPs', 'Var', (177, 192))	('tumor', 'Disease', (134, 139))
488756	29019267	These results demonstrated the effective in vivo tumor-suppressed capacity of GE11-Ori-Se NPs, showing the potential use of GE11-Ori-Se NPs for cancer treatment.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('-Ori-Se NPs', 'Chemical', '-', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('GE11-Ori-Se', 'Var', (78, 89))	('tumor', 'Disease', (49, 54))	('-Ori-Se NPs', 'Chemical', '-', (128, 139))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
488758	29019267	TNF-alpha, a cell signaling cytokine involved in systemic inflammation and tumor development, was found to be up-regulated by GE11-Ori-Se NPs treatment in tumor-bearing mice (Figure 9(D)), which was a common feature of anticancer drug that could enhance the immune system against cancer cells.	('up-regulated', 'PosReg', (110, 122))	('cancer', 'Disease', (280, 286))	('GE11-Ori-Se NPs', 'Var', (126, 141))	('tumor', 'Disease', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancer', 'Disease', (223, 229))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('inflammation', 'Disease', 'MESH:D007249', (58, 70))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('mice', 'Species', '10090', (169, 173))	('-Ori-Se NPs', 'Chemical', '-', (130, 141))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('inflammation', 'Disease', (58, 70))	('TNF-alpha', 'Gene', (0, 9))	('enhance', 'PosReg', (246, 253))
488759	29019267	IL-2, a type of cytokine signaling molecule in the immune system that regulated the activities of white blood cells responsible for immunity, was found to be increased with GE11-Ori-Se NPs treatment (Figure 9(E)).	('IL-2', 'Gene', (0, 4))	('activities', 'MPA', (84, 94))	('-Ori-Se NPs', 'Chemical', '-', (177, 188))	('GE11-Ori-Se NPs treatment', 'Var', (173, 198))	('increased', 'PosReg', (158, 167))
488760	29019267	The results suggested that GE11-Ori-Se NPs could also regulate the activity of immune system by changing the cytokine secretion of immunity cells to inhibit tumor growth.	('tumor', 'Disease', (157, 162))	('inhibit', 'NegReg', (149, 156))	('-Ori-Se NPs', 'Chemical', '-', (31, 42))	('regulate', 'Reg', (54, 62))	('cytokine secretion of immunity cells', 'MPA', (109, 145))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('activity', 'MPA', (67, 75))	('changing', 'Reg', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('GE11-Ori-Se', 'Var', (27, 38))
488762	29019267	The results (Figure 9(F)) showed the selenium content of all detected tissues or organs in GE11-Ori-Se NPs obviously increased compared with that of control group.	('increased', 'PosReg', (117, 126))	('selenium', 'Chemical', 'MESH:D012643', (37, 45))	('selenium content', 'MPA', (37, 53))	('-Ori-Se NPs', 'Chemical', '-', (95, 106))	('GE11-Ori-Se NPs', 'Var', (91, 106))
488763	29019267	Tumor tissues were found to have much more selenium content, which might be due to the targeting effects of GE11-Ori-Se NPs against cancer cells.	('GE11-Ori-Se', 'Var', (108, 119))	('cancer', 'Disease', (132, 138))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('selenium content', 'MPA', (43, 59))	('selenium', 'Chemical', 'MESH:D012643', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('more', 'PosReg', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('-Ori-Se NPs', 'Chemical', '-', (112, 123))
488769	29019267	The contents of selenium in lung, spleen, and heart also increased with GE11-Ori-Se NPs treatment, but were less than liver, tumor, and kidney.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('selenium', 'Chemical', 'MESH:D012643', (16, 24))	('-Ori-Se NPs', 'Chemical', '-', (76, 87))	('tumor', 'Disease', (125, 130))	('GE11-Ori-Se NPs treatment', 'Var', (72, 97))	('increased', 'PosReg', (57, 66))	('contents of selenium', 'MPA', (4, 24))
488770	29019267	Then, we further tested the expression of some important bio-markers in tumor tissue to investigate the mechanism of tumor inhibition effects of GE11-Ori-Se NPs in vivo.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('GE11-Ori-Se', 'Var', (145, 156))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (117, 122))	('-Ori-Se NPs', 'Chemical', '-', (149, 160))	('tested', 'Reg', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
488776	29019267	The obtained results implied that the expression of CD31 in the tumor tissue decreased after GE11-Ori-Se NPs treatment (Figure 10(B)), suggesting that GE11-Ori-Se NPs inhibited tumor growth partially through its anti-angiogenesis effects.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('inhibited', 'NegReg', (167, 176))	('-Ori-Se NPs', 'Chemical', '-', (155, 166))	('expression', 'MPA', (38, 48))	('GE11-Ori-Se NPs', 'Var', (151, 166))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('-Ori-Se NPs', 'Chemical', '-', (97, 108))	('anti-angiogenesis effects', 'CPA', (212, 237))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (177, 182))	('CD31', 'Gene', (52, 56))	('decreased', 'NegReg', (77, 86))
488777	29019267	To further confirm the toxicity effects of GE11-Ori-Se NPs in vivo, we also applied HE staining to study the structure of tumor, liver and kidney, which were the main organs that gathering selenium contents in mice.	('toxicity', 'Disease', (23, 31))	('mice', 'Species', '10090', (210, 214))	('HE', 'Chemical', 'MESH:D006371', (84, 86))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('GE11-Ori-Se', 'Var', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('-Ori-Se NPs', 'Chemical', '-', (47, 58))	('selenium', 'Chemical', 'MESH:D012643', (189, 197))	('tumor', 'Disease', (122, 127))	('toxicity', 'Disease', 'MESH:D064420', (23, 31))
488778	29019267	The results of HE staining of tumor tissue showed that the tumor after GE11-Ori-Se NPs treatment presented some vacuole-like structures inside, which indicated that GE11-Ori-Se NPs could partially destroy the native structure of tumor (Figure 10(C)).	('native', 'MPA', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('C', 'Chemical', 'MESH:D002244', (246, 247))	('-Ori-Se NPs', 'Chemical', '-', (169, 180))	('destroy', 'NegReg', (197, 204))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (229, 234))	('HE', 'Chemical', 'MESH:D006371', (15, 17))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('GE11-Ori-Se', 'Var', (165, 176))	('-Ori-Se NPs', 'Chemical', '-', (75, 86))	('tumor', 'Disease', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('vacuole-like structures', 'MPA', (112, 135))
488780	29019267	In summary, we introduced the synthesis of GE11-Ori-Se NPs as a cancer targeting delivery system to achieve enhanced anticancer efficacy.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('enhanced', 'PosReg', (108, 116))	('GE11-Ori-Se', 'Var', (43, 54))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('-Ori-Se NPs', 'Chemical', '-', (47, 58))	('cancer', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
488782	29019267	The internalized GE11-Ori-Se NPs could accumulate into lysosomes to release oridonin into cells and then escape from lysosomes after the damage of lysosomal membrane integrity.	('-Ori-Se NPs', 'Chemical', '-', (21, 32))	('GE11-Ori-Se', 'Var', (17, 28))	('release oridonin into cells', 'MPA', (68, 95))	('oridonin', 'Chemical', 'MESH:C011959', (76, 84))
488783	29019267	GE11-Ori-Se NPs were found to induce cancer cell apoptosis by inducting ROS production, activating mitochondria-dependent pathway, inhibiting EGFR-mediated PI3K/AKT and inhibiting Ras/Raf/MEK/ERK pathways.	('induce', 'PosReg', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('-Ori-Se NPs', 'Chemical', '-', (4, 15))	('GE11-Ori-Se NPs', 'Var', (0, 15))	('cancer', 'Disease', (37, 43))	('mitochondria-dependent pathway', 'Pathway', (99, 129))	('ROS production', 'MPA', (72, 86))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('Ras/Raf/MEK/ERK pathways', 'Pathway', (180, 204))	('activating', 'PosReg', (88, 98))	('inducting', 'NegReg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('inhibiting', 'NegReg', (131, 141))	('inhibiting', 'NegReg', (169, 179))	('EGFR-mediated PI3K/AKT', 'Pathway', (142, 164))
488784	29019267	In nude mice xenograft model, GE11-Se NPs showed active targeting effects against tumor.	('GE11-Se', 'Var', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('targeting', 'MPA', (56, 65))	('Se', 'Chemical', 'MESH:D012643', (35, 37))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('nude mice', 'Species', '10090', (3, 12))	('tumor', 'Disease', (82, 87))
488785	29019267	And GE11-Ori-Se NPs was found to significantly inhibit the tumor growth via inhibition of tumor angiogenesis by reducing the angiogenesis-marker CD31 and activation of the immune system by enhancing IL-2 and TNF-alpha production.	('inhibition', 'NegReg', (76, 86))	('immune', 'CPA', (172, 178))	('reducing', 'NegReg', (112, 120))	('tumor', 'Disease', (59, 64))	('TNF-alpha production', 'MPA', (208, 228))	('GE11-Ori-Se NPs', 'Var', (4, 19))	('tumor', 'Disease', (90, 95))	('enhancing', 'PosReg', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('activation', 'PosReg', (154, 164))	('inhibit', 'NegReg', (47, 54))	('-Ori-Se NPs', 'Chemical', '-', (8, 19))	('IL-2', 'MPA', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('angiogenesis-marker CD31', 'MPA', (125, 149))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
488786	29019267	This cancer-targeted design of Se NPs provides a new strategy for synergistic treating of cancer with higher efficacy and decreased side effects, suggesting GE11-Ori-Se NPs as a candidate for further evaluation as a chemotherapeutic agent for human cancers, especially for EGFR over-expressed esophageal cancers.	('-Ori-Se NPs', 'Chemical', '-', (161, 172))	('human', 'Species', '9606', (243, 248))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (304, 311))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('Se', 'Chemical', 'MESH:D012643', (31, 33))	('cancer', 'Disease', (304, 310))	('cancers', 'Disease', (304, 311))	('cancer', 'Disease', (249, 255))	('cancers', 'Disease', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('Se', 'Chemical', 'MESH:D012643', (166, 168))	('EGFR', 'Gene', (273, 277))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('GE11-Ori-Se', 'Var', (157, 168))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('over-expressed', 'PosReg', (278, 292))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancers', 'Disease', 'MESH:D009369', (304, 311))	('esophageal cancers', 'Disease', (293, 311))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer', 'Disease', (90, 96))	('esophageal cancers', 'Disease', 'MESH:D004938', (293, 311))
488802	30565069	Several studies regarding colon cancer have shown that laparoscopic assisted colectomy is associated with less postoperative morbidity when compared to open colectomy in elderly patients.	('laparoscopic', 'Var', (55, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (26, 38))	('patients', 'Species', '9606', (178, 186))	('colon cancer', 'Disease', 'MESH:D015179', (26, 38))	('colon cancer', 'Disease', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
488883	29227857	Therefore, a diagnosis of lower intrathoracic esophageal cancer ypT0N1 (1/7) M0 (Fig.	('thoracic esophageal cancer', 'Disease', (37, 63))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (37, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('ypT0N1', 'Var', (64, 70))
488968	29052514	However, high-dose SBRT was associated with improved median overall survival compared to patients who received less than 40 Gy (20.0 months vs. 8.0 months, p = .026, Fig.	('patients', 'Species', '9606', (89, 97))	('improved', 'PosReg', (44, 52))	('high-dose', 'Var', (9, 18))	('overall survival', 'MPA', (60, 76))
489001	29052514	In our retrospective series, we confirm the generally poor overall prognosis for patients with in-field NSCLC recurrences following CF-EBRT.	('CF-EBRT', 'Var', (132, 139))	('NSCLC', 'Disease', (104, 109))	('patients', 'Species', '9606', (81, 89))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
489037	28303427	Patients were staged according to the 7th TNM classification of the American Joint Committee on Cancer (AJCC) with diagnostic gastroscopy and biopsy, a diagnostic CT thorax/abdomen, 18F-FDG-PET or 18F-FDG-PET/CT, and EUS if possible.	('TNM', 'Gene', '10178', (42, 45))	('18F-FDG-PET/CT', 'Var', (197, 211))	('18F-FDG', 'Chemical', 'MESH:D019788', (182, 189))	('Patients', 'Species', '9606', (0, 8))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Cancer', 'Disease', (96, 102))	('TNM', 'Gene', (42, 45))	('Cancer', 'Disease', 'MESH:D009369', (96, 102))	('CT thorax/abdomen', 'Disease', (163, 180))	('18F-FDG-PET', 'Var', (182, 193))	('18F-FDG', 'Chemical', 'MESH:D019788', (197, 204))
489054	28303427	EUS had changed the curability (incurable to potentially curable) in 5 (1.8%) patients, influenced the extent of LN resection (at node level AJCC Lymph node stations 2-5) in 48 (17.2%), and affected treatment decision-making with FNA in 21 patients (7.5%).	('affected', 'Reg', (190, 198))	('influenced', 'Reg', (88, 98))	('changed', 'Reg', (8, 15))	('patients', 'Species', '9606', (78, 86))	('EUS', 'Var', (0, 3))	('patients', 'Species', '9606', (240, 248))	('curability', 'MPA', (20, 30))
489074	28303427	The only study that compared EUS with 18F-FDG-PET/CT was the study by Schreurs et al., which found that 18F-FDG-PET/CT was the best predictor of curability of the resection.	('18F-FDG', 'Chemical', 'MESH:D019788', (38, 45))	('18F-FDG-PET/CT', 'Var', (104, 118))	('18F-FDG', 'Chemical', 'MESH:D019788', (104, 111))	('curability of the resection', 'CPA', (145, 172))
489076	28303427	Currently, the role of EUS in treatment decision making might be limited: In the current treatment paradigm, treatment decision making in T2-4aN0-3M0 esophageal cancer patients is most commonly based on the presence of comorbidities that might not permit nCRT or dCRT.	('esophageal cancer', 'Disease', (150, 167))	('dCRT', 'Gene', '45841', (263, 267))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('patients', 'Species', '9606', (168, 176))	('T2-4aN0-3M0', 'Var', (138, 149))	('dCRT', 'Gene', (263, 267))
489296	24954627	Dysregulated of LCN2 has been observed in several benign and malignant diseases, including breast, colorectal, pancreatic, ovarian, gastric, thyroid, ovarian, and bladder, as well as kidney cancers.	('bladder', 'Disease', (163, 170))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('LCN2', 'Gene', '3934', (16, 20))	('malignant diseases', 'Disease', 'MESH:D009369', (61, 79))	('colorectal, pancreatic, ovarian, gastric, thyroid, ovarian', 'Disease', 'MESH:D010049', (99, 157))	('kidney cancers', 'Disease', (183, 197))	('malignant diseases', 'Disease', (61, 79))	('LCN2', 'Gene', (16, 20))	('kidney cancers', 'Phenotype', 'HP:0009726', (183, 197))	('Dysregulated', 'Var', (0, 12))	('observed', 'Reg', (30, 38))	('kidney cancers', 'Disease', 'MESH:D007680', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast', 'Disease', (91, 97))
489311	24954627	The other principal characteristic of LCN2 is to capture iron-containing siderophores and transport them to the cell interior after interacting with specific membrane receptors (24p3R, megalin or NGALR), increasing cytoplasmic mineral levels and triggering the iron-dependent reactions.	('interacting', 'Interaction', (132, 143))	('triggering', 'Reg', (246, 256))	('megalin', 'Gene', (185, 192))	('megalin', 'Gene', '4036', (185, 192))	('cytoplasmic mineral levels', 'MPA', (215, 241))	('iron', 'Chemical', 'MESH:D007501', (261, 265))	('NGALR', 'Gene', (196, 201))	('NGALR', 'Gene', '51310', (196, 201))	('LCN2', 'Gene', '3934', (38, 42))	('transport', 'MPA', (90, 99))	('iron', 'Chemical', 'MESH:D007501', (57, 61))	('LCN2', 'Gene', (38, 42))	('increasing', 'PosReg', (204, 214))	('24p3R', 'Var', (178, 183))	('capture', 'MPA', (49, 56))	('iron-dependent reactions', 'MPA', (261, 285))
489315	24954627	Our previous study has identified a novel splicing variant of the LCN2 receptor in ESCC, and both LCN2 and its receptor are overexpressed in ESCC.	('LCN2', 'Gene', '3934', (98, 102))	('splicing variant', 'Var', (42, 58))	('LCN2', 'Gene', (98, 102))	('LCN2', 'Gene', '3934', (66, 70))	('LCN2', 'Gene', (66, 70))
489326	24954627	Another large GO term group was comprised of cell cycle-related GO terms, such as "G1 phase of mitotic cell cycle", "G1/S transition of mitotic cell cycle", "G2/M transition of mitotic cell cycle", "M phase of mitotic cell cycle", "M/G1 transition of mitotic cell cycle", suggesting LCN2 regulates the cell cycle.	('LCN2', 'Gene', '3934', (283, 287))	('regulates', 'Reg', (288, 297))	('M/G1', 'Var', (232, 236))	('M/G1', 'SUBSTITUTION', 'None', (232, 236))	('LCN2', 'Gene', (283, 287))	('cell', 'CPA', (302, 306))
489350	24954627	We assumed the elevated LCN2 protein would cause a wide range of mRNA expression profile alternation through the cascade of PPI activities, and the transcription factors or transcriptional regulators in the PPI sub-network play critical roles in this expression alternation.	('cause', 'Reg', (43, 48))	('mRNA expression profile', 'MPA', (65, 88))	('alternation', 'Reg', (89, 100))	('LCN2', 'Gene', (24, 28))	('elevated', 'Var', (15, 23))	('LCN2', 'Gene', '3934', (24, 28))	('protein', 'Protein', (29, 36))
489357	24954627	The alternation of FOXP1 expression might also change the expression level of its target genes.	('change', 'Reg', (47, 53))	('FOXP1', 'Gene', (19, 24))	('alternation', 'Var', (4, 15))	('FOXP1', 'Gene', '27086', (19, 24))	('expression level of', 'MPA', (58, 77))
489376	24954627	Genetic ablation of DCN leads to enhanced liver tumor incidence by providing an environment devoid of this potent pan-RTK inhibitor.	('liver tumor', 'Disease', 'MESH:D008113', (42, 53))	('DCN', 'Gene', (20, 23))	('liver tumor', 'Phenotype', 'HP:0002896', (42, 53))	('iron', 'Chemical', 'MESH:D007501', (83, 87))	('liver tumor', 'Disease', (42, 53))	('DCN', 'Gene', '1634', (20, 23))	('ablation', 'Var', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('enhanced', 'PosReg', (33, 41))
489384	24954627	Total RNA was amplified and labeled using the Agilent Quick Amp labeling kit by Cy3 or Cy5 and dye swapping.	('Cy3', 'Chemical', '-', (80, 83))	('Amp', 'Chemical', 'MESH:D000249', (60, 63))	('Cy3', 'Var', (80, 83))	('Cy5', 'Var', (87, 90))	('Cy5', 'Chemical', 'MESH:C085321', (87, 90))
489413	24847326	Furthermore, both types of esophageal cancers develop through dysplasia to cancer via genetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('esophageal cancers', 'Disease', (27, 45))	('dysplasia to cancer', 'Disease', 'MESH:D009369', (62, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancers', 'Disease', 'MESH:D004938', (27, 45))	('dysplasia to cancer', 'Disease', (62, 81))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('genetic alterations', 'Var', (86, 105))	('develop', 'Reg', (46, 53))
489428	24847326	High TLR3, 4, and 9 expression in esophageal squamous cell carcinoma cells have been associated with lymph node metastasis and TLR7 and 9 expression to worse histological grade.	('lymph node metastasis', 'CPA', (101, 122))	('expression', 'MPA', (20, 30))	('High', 'Var', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (34, 68))	('esophageal squamous cell carcinoma', 'Disease', (34, 68))	('TLR7', 'Gene', (127, 131))	('TLR3', 'Gene', (5, 9))	('TLR7', 'Gene', '51284', (127, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('TLR3', 'Gene', '7098', (5, 9))	('associated', 'Reg', (85, 95))
489441	24847326	Genetic studies have been performed on Toll-like receptor polymorphisms in esophageal cancer.	('polymorphisms', 'Var', (58, 71))	('esophageal cancer', 'Disease', (75, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))
489442	24847326	Unlike in gastric cancer, polymorphisms in TLR4 + 896A > G and TLR9-1237T/C genes were not associated to esophageal cancer risk.	('896A > G', 'SUBSTITUTION', 'None', (50, 58))	('896A > G', 'Var', (50, 58))	('polymorphisms', 'Var', (26, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (10, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('esophageal cancer', 'Disease', (105, 122))	('TLR9-1237T/C', 'Var', (63, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('TLR4', 'Gene', '7099', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('gastric cancer', 'Disease', (10, 24))	('TLR4', 'Gene', (43, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (10, 24))	('associated', 'Reg', (91, 101))
489521	24260445	AST and ALT were higher (208.0+-112.3 versus 107.0+-87.00, 183.0+-99.9 versus 89.9+-71.1, P<0.001) and direct bilirubin was also higher in the group with LRE (8.64+-2.78 versus 6.00+-2.21).	('AST', 'Gene', (0, 3))	('LRE', 'Var', (154, 157))	('higher', 'PosReg', (129, 135))	('bilirubin', 'Chemical', 'MESH:D001663', (110, 119))	('AST', 'Gene', '26503', (0, 3))	('higher', 'PosReg', (17, 23))	('LRE', 'Chemical', '-', (154, 157))	('ALT', 'Gene', (8, 11))	('ALT', 'Gene', '2875', (8, 11))	('direct bilirubin', 'MPA', (103, 119))
489644	19923027	It is notable that as the respective esophageal doses with Grade 3 or higher toxicity in the current study were 2288 and 2431 cGy, neither of these patients would have fit our current dose constraints.	('2431', 'Var', (121, 125))	('patients', 'Species', '9606', (148, 156))	('toxicity', 'Disease', (77, 85))	('toxicity', 'Disease', 'MESH:D064420', (77, 85))
489645	19923027	Furthermore, the patient with the highest esophageal D1cc (2572 cGy), while not experiencing a documented toxicity, died of disease after 1.2 months.	('patient', 'Species', '9606', (17, 24))	('toxicity', 'Disease', 'MESH:D064420', (106, 114))	('2572 cGy', 'Var', (59, 67))	('toxicity', 'Disease', (106, 114))
489700	19636422	This review article focuses on current experience in using therapeutic EGFR inhibitors as a therapy for patients with esophageal and gastric cancers.	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('gastric cancers', 'Disease', (133, 148))	('gastric cancers', 'Disease', 'MESH:D013274', (133, 148))	('gastric cancers', 'Phenotype', 'HP:0012126', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('esophageal', 'Disease', 'MESH:D004941', (118, 128))	('EGFR', 'Gene', '1956', (71, 75))	('inhibitors', 'Var', (76, 86))	('esophageal', 'Disease', (118, 128))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('EGFR', 'Gene', (71, 75))	('patients', 'Species', '9606', (104, 112))
489739	19636422	The primary intracellular pathways implicated following phosphorylation of EGFR are the phosphoinositol-3-kinase (PI3K)/Akt and RAS/mitogen-activated protein kinase (MAPK) pathways.	('phosphorylation', 'Var', (56, 71))	('Akt', 'Gene', '207', (120, 123))	('EGFR', 'Gene', '1956', (75, 79))	('Akt', 'Gene', (120, 123))	('EGFR', 'Gene', (75, 79))
489743	19636422	Additionally, amplification of the EGFR gene has been detected in some esophageal adenocarcinomas.	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (71, 97))	('EGFR', 'Gene', '1956', (35, 39))	('detected', 'Reg', (54, 62))	('esophageal adenocarcinomas', 'Disease', (71, 97))	('EGFR', 'Gene', (35, 39))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (71, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('amplification', 'Var', (14, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
489749	19636422	Some of the first clinical trials of EGFR inhibitors in esophageal and gastric cancers were those involving small molecule tyrosine kinase inhibitors.	('gastric cancers', 'Disease', (71, 86))	('gastric cancers', 'Phenotype', 'HP:0012126', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tyrosine kinase', 'Gene', (123, 138))	('esophageal', 'Disease', (56, 66))	('EGFR', 'Gene', '1956', (37, 41))	('inhibitors', 'Var', (42, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('EGFR', 'Gene', (37, 41))	('tyrosine kinase', 'Gene', '7294', (123, 138))	('esophageal', 'Disease', 'MESH:D004941', (56, 66))	('gastric cancers', 'Disease', 'MESH:D013274', (71, 86))
489756	19636422	Two of the seven patients tested had EGFR mutations but were not predictive of response.	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('patients', 'Species', '9606', (17, 25))	('mutations', 'Var', (42, 51))
489772	19636422	Investigators also analyzed tumor biopsies for EGFR gene amplification and for mutations involving exons 18, 19, and 21.	('tumor', 'Disease', (28, 33))	('EGFR', 'Gene', (47, 51))	('EGFR', 'Gene', '1956', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutations', 'Var', (79, 88))
489791	19636422	This magnitude of anti tumor activity was seen with EGFR inhibitors in non small cell cancer and colorectal cancer and also with anti-HER2 therapy in patients with breast cancer.	('non small cell cancer', 'Phenotype', 'HP:0030358', (71, 92))	('inhibitors', 'Var', (57, 67))	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('EGFR', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (150, 158))	('colorectal cancer', 'Disease', (97, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('non small cell cancer', 'Disease', 'MESH:D002289', (71, 92))	('HER2', 'Gene', '2064', (134, 138))	('EGFR', 'Gene', '1956', (52, 56))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('breast cancer', 'Disease', (164, 177))	('tumor', 'Disease', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('small cell cancer', 'Phenotype', 'HP:0030357', (75, 92))	('non small cell cancer', 'Disease', (71, 92))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('HER2', 'Gene', (134, 138))
489792	19636422	However, unlike with lung cancer (EGFR gene amplification, EGFR gene mutation, lack of KRAS mutation) and colorectal cancers (lack of KRAS mutations), molecular markers of sensitivity to EGFR blockade are currently unknown for gastroesophageal carcinomas.	('EGFR', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('EGFR', 'Gene', (34, 38))	('lung cancer', 'Disease', (21, 32))	('EGFR', 'Gene', '1956', (187, 191))	('gastroesophageal carcinomas', 'Disease', 'MESH:D005764', (227, 254))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('EGFR', 'Gene', '1956', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('KRAS', 'Gene', '3845', (87, 91))	('colorectal cancers', 'Disease', (106, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('EGFR', 'Gene', '1956', (34, 38))	('KRAS', 'Gene', '3845', (134, 138))	('KRAS', 'Gene', (87, 91))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (233, 253))	('carcinomas', 'Phenotype', 'HP:0030731', (244, 254))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('mutation', 'Var', (69, 77))	('EGFR', 'Gene', (187, 191))	('gastroesophageal carcinomas', 'Disease', (227, 254))	('KRAS', 'Gene', (134, 138))	('colorectal cancers', 'Disease', 'MESH:D015179', (106, 124))
489793	19636422	Despite a valiant effort to identify these markers, more robust and comprehensive tissue-based analyses are needed in order to better select patients with gastroesophageal adenocarcinomas that may derive clinical benefit from EGFR inhibitors.	('inhibitors', 'Var', (231, 241))	('gastroesophageal adenocarcinomas', 'Disease', (155, 187))	('gastroesophageal adenocarcinomas', 'Disease', 'MESH:D005764', (155, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('EGFR', 'Gene', '1956', (226, 230))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (161, 186))	('patients', 'Species', '9606', (141, 149))	('EGFR', 'Gene', (226, 230))
489794	19636422	EGFR inhibitors have shown modest clinical activity, primarily in patients with esophageal and gastroesophageal junction adenocarcinomas.	('EGFR', 'Gene', (0, 4))	('esophageal', 'Disease', 'MESH:D004941', (80, 90))	('esophageal', 'Disease', 'MESH:D004941', (101, 111))	('inhibitors', 'Var', (5, 15))	('esophageal', 'Disease', (80, 90))	('gastroesophageal junction adenocarcinomas', 'Disease', (95, 136))	('EGFR', 'Gene', '1956', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('gastroesophageal junction adenocarcinomas', 'Disease', 'MESH:D008309', (95, 136))	('esophageal', 'Disease', (101, 111))	('patients', 'Species', '9606', (66, 74))
489796	19636422	As we have seen, molecular drivers that determine sensitivity to EGFR inhibitors in esophageal and GEJ adenocarcinomas are different from those important in lung and colorectal cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('EGFR', 'Gene', '1956', (65, 69))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('EGFR', 'Gene', (65, 69))	('esophageal', 'Disease', 'MESH:D004941', (84, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (166, 183))	('colorectal cancers', 'Disease', 'MESH:D015179', (166, 184))	('adenocarcinomas', 'Disease', 'MESH:D000230', (103, 118))	('adenocarcinomas', 'Disease', (103, 118))	('inhibitors', 'Var', (70, 80))	('esophageal', 'Disease', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('colorectal cancers', 'Disease', (166, 184))
489899	33786179	in 2009 concluded that there is no association between the single nucleotide polymorphism (SNP) rs806380 and cannabis dependence, an analysis done by Agrawal et al.	('rs806380', 'Mutation', 'rs806380', (96, 104))	('cannabis dependence', 'Disease', (109, 128))	('rs806380', 'Var', (96, 104))	('single nucleotide polymorphism', 'Var', (59, 89))
489900	33786179	in the same year on rs806380 reported that in fact individuals with this polymorphism are more likely to develop cannabis dependence compared to those with other genotypes.	('develop', 'PosReg', (105, 112))	('rs806380', 'Var', (20, 28))	('cannabis dependence', 'Disease', (113, 132))	('rs806380', 'Mutation', 'rs806380', (20, 28))
489901	33786179	Other studies have also investigated the role of an rs20232239 polymorphism in withdrawal and craving symptoms, and found that certain individuals with this polymorphism are more likely to suffer cannabis withdrawal and craving symptoms compared to those with other genotypes.	('suffer', 'Reg', (189, 195))	('rs20232239', 'Var', (52, 62))	('craving', 'Disease', (220, 227))	('rs20232239', 'Mutation', 'rs20232239', (52, 62))
489902	33786179	Other genetic causes linked to cannabis dependence are polymorphism of the Fatty Acid Amide Hydrolase (FAAH) gene.	('FAAH', 'Gene', (103, 107))	('polymorphism', 'Var', (55, 67))	('Fatty Acid', 'Chemical', 'MESH:D005227', (75, 85))	('causes linked', 'Reg', (14, 27))	('cannabis dependence', 'Disease', (31, 50))
489904	33786179	Although the studies investigating the association of FAAH gene polymorphism and cannabis addiction have also shown inconsistent results, polymorphism rs32440 has been implicated in cannabis addiction.	('cannabis addiction', 'Disease', (182, 200))	('FAAH', 'Gene', (54, 58))	('polymorphism rs32440', 'Var', (138, 158))	('implicated', 'Reg', (168, 178))	('cannabis addiction', 'Disease', (81, 99))	('rs32440', 'Mutation', 'rs32440', (151, 158))
489915	33786179	Stimulation of these receptors is theorized to slow gastric peristalsis and emptying in a dose-dependent manner.	('gastric peristalsis', 'Disease', (52, 71))	('slow', 'NegReg', (47, 51))	('emptying', 'MPA', (76, 84))	('gastric peristalsis', 'Phenotype', 'HP:0100770', (52, 71))	('slow gastric', 'Phenotype', 'HP:0002578', (47, 59))	('Stimulation', 'Var', (0, 11))	('gastric peristalsis', 'Disease', 'MESH:D013274', (52, 71))
490025	33786179	Multiple studies have shown that oral administration of Delta9 - THC was shown to significantly reduce the nausea and vomiting of cancer patients compared to the subjects in the placebo group.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('rat', 'Species', '10116', (46, 49))	('cancer', 'Disease', (130, 136))	('vomiting', 'Disease', (118, 126))	('patients', 'Species', '9606', (137, 145))	('nausea', 'Phenotype', 'HP:0002018', (107, 113))	('nausea', 'Disease', (107, 113))	('nausea', 'Disease', 'MESH:D009325', (107, 113))	('Delta9 - THC', 'Chemical', '-', (56, 68))	('vomiting', 'Phenotype', 'HP:0002013', (118, 126))	('reduce', 'NegReg', (96, 102))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (107, 126))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Delta9 - THC', 'Var', (56, 68))	('vomiting', 'Disease', 'MESH:D014839', (118, 126))
490026	33786179	In comparison to D2 receptor antagonist, research has shown that Delta9 - THC is at least as effective, if not better at suppressing nausea and vomiting.	('nausea', 'Phenotype', 'HP:0002018', (133, 139))	('nausea', 'Disease', (133, 139))	('nausea', 'Disease', 'MESH:D009325', (133, 139))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (133, 152))	('vomiting', 'Phenotype', 'HP:0002013', (144, 152))	('Delta9 - THC', 'Chemical', '-', (65, 77))	('vomiting', 'Disease', (144, 152))	('suppressing', 'NegReg', (121, 132))	('vomiting', 'Disease', 'MESH:D014839', (144, 152))	('Delta9 - THC', 'Var', (65, 77))
490034	33786179	The result showed a significant increase in the pain threshold and reduced pain intensity and odynophagia among patients who received Dronabinol compared to placebo.	('reduced pain', 'Phenotype', 'HP:0007328', (67, 79))	('Dronabinol', 'Var', (134, 144))	('odynophagia', 'Phenotype', 'HP:0032043', (94, 105))	('pain', 'Disease', 'MESH:D010146', (48, 52))	('pain', 'Phenotype', 'HP:0012531', (48, 52))	('pain', 'Disease', (48, 52))	('increase', 'PosReg', (32, 40))	('Dronabinol', 'Chemical', 'MESH:D013759', (134, 144))	('patients', 'Species', '9606', (112, 120))	('reduced', 'NegReg', (67, 74))	('pain', 'Phenotype', 'HP:0012531', (75, 79))	('odynophagia', 'CPA', (94, 105))	('pain', 'Disease', 'MESH:D010146', (75, 79))	('pain', 'Disease', (75, 79))
490135	31314174	Moreover, the silencing of RAC1 inhibited AKT/FOXO3a signaling and cell glycolysis while the upregulation of RAC1 produced an opposite effect.	('silencing', 'Var', (14, 23))	('FOXO3a', 'Gene', (46, 52))	('AKT', 'Gene', (42, 45))	('inhibited', 'NegReg', (32, 41))	('cell glycolysis', 'CPA', (67, 82))	('FOXO3a', 'Gene', '2309', (46, 52))	('AKT', 'Gene', '207', (42, 45))	('RAC1', 'Gene', (27, 31))
490136	31314174	In murine xenograft models, the tumor volume and the expression of glycolytic enzymes were significantly reduced in combination therapy when compared to each monotherapy group.	('expression of', 'MPA', (53, 66))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('glycolytic enzymes', 'Enzyme', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('reduced', 'NegReg', (105, 112))	('murine', 'Species', '10090', (3, 9))	('tumor', 'Disease', (32, 37))	('combination', 'Var', (116, 127))
490137	31314174	Overall, our study demonstrates that targeting RAC1 with an inhibitor overcomes cisplatin resistance in ESCC by suppressing glycolytic enzymes, which provides a promising strategy for treatment of ESCC in clinical practice.	('inhibitor', 'Var', (60, 69))	('glycolytic enzymes', 'MPA', (124, 142))	('suppressing', 'NegReg', (112, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('RAC1', 'Gene', (47, 51))	('ESCC', 'Disease', (104, 108))	('cisplatin resistance', 'MPA', (80, 100))	('overcomes', 'NegReg', (70, 79))
490151	31314174	For example, in lung cancer, silencing of RAC1 is related to an increase in chemosensitivity (Chen et al., 2011).	('RAC1', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('silencing', 'Var', (29, 38))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('increase', 'PosReg', (64, 72))	('chemosensitivity', 'CPA', (76, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('lung cancer', 'Disease', (16, 27))
490168	31314174	Full-length human RAC1 cDNAs (lacking the TAA stop condon and containing EcoRI and XhoI restriction sites) were amplified using a forward primer (5'-TCACCTATCCGCAGGGTCTA-3') and a reverse primer (5'-TCGCTTCGTCAAACACTGTC-3').	('human', 'Species', '9606', (12, 17))	('RAC1 cDNAs', 'Gene', (18, 28))	("5'-TCACCTATCCGCAGGGTCTA-3", 'Var', (146, 171))
490212	31314174	Analysis by multiple Cox regression analysis illustrated that expression of RAC1 was an independent factor for both OS [HR = 2.092, 95% confidence interval (CI) = 1.204-3.635, P < 0.01] and DFS (HR = 1.958, 95% CI = 1.170-3.275, P = 0.011; Fig.	('DFS', 'Disease', (190, 193))	('Cox', 'Gene', '1351', (21, 24))	('RAC1', 'Gene', (76, 80))	('Cox', 'Gene', (21, 24))	('OS', 'Chemical', '-', (116, 118))	('expression', 'Var', (62, 72))
490218	31314174	We analyzed the response of ESCC cells to cisplatin after RAC1 knockdown or overexpression using cell viability assay.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('knockdown', 'Var', (63, 72))	('RAC1', 'Gene', (58, 62))
490219	31314174	The cisplatin resistance of KYSE150 or KYSE510 cells transfected with siRAC1 was markedly decreased than that of the cells transfected with siNC (Fig.	('KYSE510', 'Var', (39, 46))	('siRAC1', 'Var', (70, 76))	('cisplatin resistance', 'MPA', (4, 24))	('KYSE510', 'CellLine', 'CVCL:1354', (39, 46))	('decreased', 'NegReg', (90, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))
490220	31314174	In contrast, the cisplatin resistance of RAC1-plasmid-transfected cells was markedly increased than that of the empty-vector-transfected cells (Fig.	('cisplatin resistance', 'MPA', (17, 37))	('RAC1-plasmid-transfected', 'Var', (41, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (17, 26))	('increased', 'PosReg', (85, 94))
490225	31314174	S1E, the cisplatin resistance of KYSE150 and KYSE510 cells was decreased proportionally to the concentration of EHop-016 when compared to the control group (0 mum EHop-016).	('EHop-016', 'Var', (112, 120))	('decreased', 'NegReg', (63, 72))	('KYSE510', 'CellLine', 'CVCL:1354', (45, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('EHop-016', 'Chemical', '-', (163, 171))	('cisplatin resistance', 'MPA', (9, 29))	('EHop-016', 'Chemical', '-', (112, 120))
490227	31314174	Cells were treated with either cisplatin monotherapy (KYSE150: 20 mum; KYSE510: 5 mum), EHop-016 monotherapy (KYSE150, KYSE510: 10 mum), or combination therapy (cisplatin and EHop-016) for 24 h, followed by PI staining or Annexin V-PI double staining for flow cytometry.	('KYSE150:', 'Var', (54, 62))	('Annexin V', 'Gene', (222, 231))	('EHop-016', 'Chemical', '-', (175, 183))	('KYSE150', 'Var', (110, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('KYSE510', 'CellLine', 'CVCL:1354', (71, 78))	('KYSE510', 'CellLine', 'CVCL:1354', (119, 126))	('KYSE510: 5 mum', 'Var', (71, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('Annexin V', 'Gene', '308', (222, 231))	('EHop-016', 'Chemical', '-', (88, 96))
490228	31314174	Compared to monotherapy of cisplatin, the G2/M cell cycle arrest rate was significantly elevated (KYSE150: 30.3% vs. 23.14%; KYSE510: 33.13% vs. 27.32%).	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('elevated', 'PosReg', (88, 96))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('G2/M cell cycle arrest rate', 'CPA', (42, 69))	('KYSE150', 'Var', (98, 105))	('KYSE510', 'Var', (125, 132))	('KYSE510', 'CellLine', 'CVCL:1354', (125, 132))
490231	31314174	The heatmap demonstrated that after being treated with RAC1 inhibitor or combination therapy, the glycolysis, cell cycle, and p53 pathways in both KYSE150 and KYSE510 cells were significantly inhibited, when compared to the control group or cisplatin monotherapy (Fig.	('KYSE510', 'CellLine', 'CVCL:1354', (159, 166))	('p53', 'Gene', '7157', (126, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (241, 250))	('cell cycle', 'Pathway', (110, 120))	('glycolysis', 'Enzyme', (98, 108))	('combination', 'Var', (73, 84))	('inhibited', 'NegReg', (192, 201))	('KYSE150', 'Var', (147, 154))	('p53', 'Gene', (126, 129))	('RAC1', 'Gene', (55, 59))
490234	31314174	5F-I, with the combination of cisplatin and EHop-016, significant decreases in glucose consumption (Fig.	('decreases in glucose consumption', 'Disease', (66, 98))	('cisplatin', 'Var', (30, 39))	('EHop-016', 'Gene', (44, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('EHop-016', 'Chemical', '-', (44, 52))	('decreases in glucose consumption', 'Disease', 'MESH:D014397', (66, 98))
490238	31314174	5H) were observed in both the KYSE150 and KYSE510 cells, when compared to the cisplatin or EHop-016 single-treatment groups (P < 0.001).	('KYSE150', 'Var', (30, 37))	('KYSE510', 'Var', (42, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('KYSE510', 'CellLine', 'CVCL:1354', (42, 49))	('EHop-016', 'Chemical', '-', (91, 99))
490239	31314174	Based on these results, inhibition of RAC1 overcomes the cisplatin resistance and suppresses ESCC cell glycolysis.	('ESCC cell glycolysis', 'MPA', (93, 113))	('overcomes', 'NegReg', (43, 52))	('suppresses', 'NegReg', (82, 92))	('inhibition', 'Var', (24, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('cisplatin resistance', 'MPA', (57, 77))	('RAC1', 'Gene', (38, 42))
490240	31314174	The critical enzymes for aerobic glycolysis, including PKM, LDHA, ALDOA, and HK1, were suppressed under RAC1 silencing but upregulated in RAC1 overexpression as shown Fig.	('suppressed', 'NegReg', (87, 97))	('RAC1', 'Gene', (104, 108))	('ALDOA', 'Gene', '226', (66, 71))	('upregulated', 'PosReg', (123, 134))	('LDHA', 'Enzyme', (60, 64))	('overexpression', 'PosReg', (143, 157))	('silencing', 'Var', (109, 118))	('PKM', 'Enzyme', (55, 58))	('HK1', 'Enzyme', (77, 80))	('aerobic glycolysis', 'Enzyme', (25, 43))	('ALDOA', 'Gene', (66, 71))
490245	31314174	6E), significant reduction of glycolysis under RAC1 silencing and increases under RAC1 overexpression were observed in both KYSE150 and KYSE510 cells.	('silencing', 'Var', (52, 61))	('increases', 'PosReg', (66, 75))	('KYSE510', 'CellLine', 'CVCL:1354', (136, 143))	('glycolysis', 'MPA', (30, 40))	('RAC1', 'Gene', (47, 51))	('overexpression', 'PosReg', (87, 101))	('RAC1', 'Gene', (82, 86))	('reduction', 'NegReg', (17, 26))
490248	31314174	Knowing that RAC1 deletion suppresses the activation of downstream targets of AKT (Saci et al., 2011), therefore, we hypothesized that the suppressive effect of RAC1 inhibitor on the glycolytic enzymes was due to the inhibition of AKT pathway.	('activation', 'MPA', (42, 52))	('AKT', 'Gene', '207', (231, 234))	('suppressive', 'NegReg', (139, 150))	('glycolytic enzymes', 'Enzyme', (183, 201))	('AKT', 'Gene', '207', (78, 81))	('AKT', 'Gene', (231, 234))	('suppresses', 'NegReg', (27, 37))	('RAC1', 'Gene', (13, 17))	('AKT', 'Gene', (78, 81))	('deletion', 'Var', (18, 26))
490253	31314174	Our findings demonstrated that the phosphorylation of FOXO3a and S6, which served as the markers of mTOR activity (Godel et al., 2011; Saci et al., 2011; Sarbassov et al., 2005), was drastically increased under cisplatin treatment and decreased under RAC1 inhibitor or combination therapy, when compared to the control group or the cisplatin monotherapy group (Fig.	('FOXO3a', 'Gene', (54, 60))	('mTOR', 'Gene', '2475', (100, 104))	('cisplatin', 'Var', (211, 220))	('cisplatin', 'Chemical', 'MESH:D002945', (211, 220))	('phosphorylation', 'MPA', (35, 50))	('decreased', 'NegReg', (235, 244))	('increased', 'PosReg', (195, 204))	('cisplatin', 'Chemical', 'MESH:D002945', (332, 341))	('mTOR', 'Gene', (100, 104))	('FOXO3a', 'Gene', '2309', (54, 60))
490256	31314174	In order to validate the role of FOXO3a in regulating glycolytic enzymes, the effects of FOXO3a knockdown on the glycolytic enzymes were detected by western blot.	('knockdown', 'Var', (96, 105))	('FOXO3a', 'Gene', '2309', (89, 95))	('FOXO3a', 'Gene', (89, 95))	('glycolytic enzymes', 'MPA', (54, 72))	('FOXO3a', 'Gene', '2309', (33, 39))	('FOXO3a', 'Gene', (33, 39))
490257	31314174	S3, FOXO3a silencing decreased the expression of P-FOXO3a, PKM, LDHA, ALDOA, and HK1, which indicated that FOXO3a silencing had an inhibitory effect on the glycolytic enzymes.	('silencing', 'Var', (11, 20))	('PKM', 'Gene', (59, 62))	('HK1', 'Gene', (81, 84))	('decreased', 'NegReg', (21, 30))	('ALDOA', 'Gene', '226', (70, 75))	('FOXO3a', 'Gene', '2309', (4, 10))	('silencing', 'Var', (114, 123))	('expression', 'MPA', (35, 45))	('glycolytic enzymes', 'Enzyme', (156, 174))	('FOXO3a', 'Gene', (4, 10))	('FOXO3a', 'Gene', '2309', (107, 113))	('FOXO3a', 'Gene', '2309', (51, 57))	('FOXO3a', 'Gene', (51, 57))	('FOXO3a', 'Gene', (107, 113))	('LDHA', 'Gene', (64, 68))	('ALDOA', 'Gene', (70, 75))
490258	31314174	In summary, inhibition of RAC1 suppresses glycolysis through the AKT/FOXO3a pathway.	('inhibition', 'Var', (12, 22))	('AKT', 'Gene', (65, 68))	('FOXO3a', 'Gene', '2309', (69, 75))	('glycolysis', 'MPA', (42, 52))	('RAC1', 'Gene', (26, 30))	('AKT', 'Gene', '207', (65, 68))	('FOXO3a', 'Gene', (69, 75))	('suppresses', 'NegReg', (31, 41))
490262	31314174	The tumor necrotic area was significantly increased, while the expression of Ki67 was significantly reduced in tumors of combination therapy group, compared to that of control group or each monotherapy (Fig.	('increased', 'PosReg', (42, 51))	('combination therapy', 'Var', (121, 140))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('reduced', 'NegReg', (100, 107))	('Ki67', 'Gene', (77, 81))	('expression', 'MPA', (63, 73))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor necrotic', 'Disease', 'MESH:D009369', (4, 18))	('tumor necrotic', 'Disease', (4, 18))	('Ki67', 'Gene', '17345', (77, 81))
490272	31314174	For example, in lung cancer and head and neck cell carcinoma, silencing of RAC1 is related to higher cisplatin sensitivity (Chen et al., 2011; Skvortsov et al., 2014).	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('silencing', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('neck cell carcinoma', 'Disease', (41, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('cisplatin sensitivity', 'MPA', (101, 122))	('neck cell carcinoma', 'Disease', 'MESH:D000077195', (41, 60))	('RAC1', 'Gene', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('higher', 'PosReg', (94, 100))	('lung cancer', 'Disease', (16, 27))
490275	31314174	NSC23766 is the first developed and most widely used RAC1 inhibitor targeting the RAC1-GEF interaction (Dutting et al., 2015; Gao et al., 2004; Levay et al., 2013).	('NSC23766', 'Var', (0, 8))	('GEF', 'Gene', '9181', (87, 90))	('GEF', 'Gene', (87, 90))
490276	31314174	Similarly, other RAC inhibitors, including AZA1, EHT 1864, IA-116, and ZINC69391, also have high effective concentrations (IC50 = 10-50 mum) (Cardama et al., 2014; Ferri et al., 2009; Montalvo-Ortiz et al., 2012; Zins et al., 2013).	('Cardama', 'Disease', (142, 149))	('RAC', 'Gene', '207', (17, 20))	('ZINC69391', 'Var', (71, 80))	('AZA1', 'Chemical', '-', (43, 47))	('Cardama', 'Disease', 'None', (142, 149))	('effective concentrations', 'MPA', (97, 121))	('RAC', 'Gene', (17, 20))	('ZINC69391', 'Chemical', 'MESH:C000595961', (71, 80))
490287	31314174	Interestingly, the AKT signaling, which is considered to be the 'glycolytic kinase' that contributes to aerobic glycolysis (Robey and Hay, 2009), is shown to be significantly activated by cisplatin and can be suppressed by the RAC1 inhibitor in our study.	('AKT', 'Gene', '207', (19, 22))	('cisplatin', 'Var', (188, 197))	('activated', 'PosReg', (175, 184))	('AKT', 'Gene', (19, 22))	('aerobic glycolysis', 'MPA', (104, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (188, 197))
490301	31314174	RAC1 deletion inhibits the activation of the translational regulators 4eBP1 and p70 S6 kinase, which are the downstream targets of mTORC1 (Ma and Blenis, 2009), and suppresses the activation of AKT, which is controlled by mTORC2 (Saci et al., 2011).	('mTORC1', 'Gene', (131, 137))	('translational regulators', 'MPA', (45, 69))	('deletion', 'Var', (5, 13))	('mTORC2', 'Gene', (222, 228))	('inhibits', 'NegReg', (14, 22))	('AKT', 'Gene', '207', (194, 197))	('4eBP1', 'Gene', '1978', (70, 75))	('activation', 'MPA', (27, 37))	('mTORC2', 'Gene', '74343', (222, 228))	('mTORC1', 'Gene', '382056', (131, 137))	('AKT', 'Gene', (194, 197))	('activation', 'MPA', (180, 190))	('4eBP1', 'Gene', (70, 75))	('suppresses', 'NegReg', (165, 175))	('RAC1', 'Gene', (0, 4))	('p70', 'Enzyme', (80, 83))
490309	31314174	Inhibition of RAC1 reverses cisplatin resistance in ESCC both in vivo and in vitro via suppressing glycolysis.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('RAC1', 'Gene', (14, 18))	('cisplatin resistance', 'MPA', (28, 48))	('glycolysis', 'MPA', (99, 109))	('reverses', 'NegReg', (19, 27))	('Inhibition', 'Var', (0, 10))	('suppressing', 'NegReg', (87, 98))
490320	30768984	Phamacologic inhibition or knockdown of TGFB or JNK signaling components in EAC cells (FLO-1 or FLO-1 or EsoAd1) significantly reduced cell proliferation, colony formation, cell migration, and/or growth of xenograft tumors in mice, in a SMAD4-independent manner.	('knockdown', 'Var', (27, 36))	('mice', 'Species', '10090', (226, 230))	('tumors', 'Disease', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('cell migration', 'CPA', (173, 187))	('cell proliferation', 'CPA', (135, 153))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('reduced', 'NegReg', (127, 134))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))	('colony formation', 'CPA', (155, 171))	('TGFB', 'Gene', (40, 44))
490321	30768984	Inhibition of the TGFB pathway in BE cell lines reduced proliferation of dysplastic but not non-dysplastic cells.	('TGFB pathway', 'Pathway', (18, 30))	('dysplastic', 'Disease', (96, 106))	('reduced', 'NegReg', (48, 55))	('dysplastic', 'Disease', 'MESH:D004416', (96, 106))	('dysplastic', 'Disease', (73, 83))	('dysplastic', 'Disease', 'MESH:D004416', (73, 83))	('Inhibition', 'Var', (0, 10))	('BE', 'Phenotype', 'HP:0100580', (34, 36))
490323	30768984	Inhibiting these pathways in EAC cells reduces their proliferation, migration, and formation of xenograft tumors.	('EAC', 'Phenotype', 'HP:0011459', (29, 32))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Inhibiting', 'Var', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('migration', 'CPA', (68, 77))	('reduces', 'NegReg', (39, 46))
490327	30768984	Here, we employed systems biology approaches to analyze global transcriptomic profiles derived from treatment-naive BE-associated malignant and non-malignant tissues, enabling us to identify deregulations in signaling pathway activities on a genome-scale, along the BE-to-EAC continuum.	('activities', 'MPA', (226, 236))	('BE', 'Phenotype', 'HP:0100580', (266, 268))	('BE', 'Phenotype', 'HP:0100580', (116, 118))	('men', 'Species', '9606', (105, 108))	('EAC', 'Phenotype', 'HP:0011459', (272, 275))	('signaling pathway', 'Pathway', (208, 225))	('deregulations', 'Var', (191, 204))
490347	30768984	After the xenograft tumors reached a minimum size of 50mm3, mice were randomized and treated with either vehicle, or with 50 mg/kg SP600125 or SB431542 (via i.p), or with 100 mg/kg LY2157299 (via oral gavage), and followed longitudinally.	('LY2157299', 'Chemical', 'MESH:C557799', (181, 190))	('SP600125', 'Chemical', 'MESH:C432165', (131, 139))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('SP600125', 'Var', (131, 139))	('SB431542', 'Chemical', 'MESH:C459179', (143, 151))	('SB431542', 'Var', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mice', 'Species', '10090', (60, 64))
490365	30768984	Treatment of FLO-1 EAC cells with the TGFbetaRI kinase inhibitors (SB431542 or LY2157299) caused significant dose-dependent growth reduction of cells in bulk culture (Figure 3, B and C), with concomitant reduction in SMAD phosphorylation and expression of the canonical TGFbeta downstream target-gene, SERPINE1 (Figure 3, B and C; Supplementary Figure S7A).	('reduction', 'NegReg', (131, 140))	('reduction', 'NegReg', (204, 213))	('EAC', 'Phenotype', 'HP:0011459', (19, 22))	('TGFbetaRI', 'Gene', '7046', (38, 47))	('SB431542', 'Chemical', 'MESH:C459179', (67, 75))	('LY2157299', 'Var', (79, 88))	('growth', 'CPA', (124, 130))	('men', 'Species', '9606', (337, 340))	('SB431542', 'Var', (67, 75))	('SERPINE1', 'Gene', (302, 310))	('SMAD', 'Protein', (217, 221))	('SERPINE1', 'Gene', '5054', (302, 310))	('LY2157299', 'Chemical', 'MESH:C557799', (79, 88))	('men', 'Species', '9606', (5, 8))	('expression', 'MPA', (242, 252))	('TGFbetaRI', 'Gene', (38, 47))
490366	30768984	Similarly, treating FLO-1 cells with a JNK inhibitor, SP600125, blocked JUN phosphorylation and caused marked dose-dependent suppression of cell growth (Figure 3D).	('SP600125', 'Chemical', 'MESH:C432165', (54, 62))	('suppression', 'NegReg', (125, 136))	('SP600125', 'Var', (54, 62))	('cell growth', 'CPA', (140, 151))	('blocked', 'NegReg', (64, 71))	('JUN phosphorylation', 'MPA', (72, 91))
490367	30768984	For TGFbeta pathway, we performed siRNA-based transient knockdown of TGFbetaR1, TGFbetaR2, SMAD2, SMAD3, SMAD4 (Supplementary Figure S7B).	('SMAD3', 'Gene', (98, 103))	('SMAD2', 'Gene', '4087', (91, 96))	('SMAD2', 'Gene', (91, 96))	('TGFbetaR2', 'Gene', (80, 89))	('men', 'Species', '9606', (118, 121))	('TGFbetaR1', 'Gene', (69, 78))	('SMAD3', 'Gene', '4088', (98, 103))	('knockdown', 'Var', (56, 65))
490373	30768984	To further test if pro-growth effects of TGFP-SMAD signaling in EACs are both general and SMAD4-independent (Figure 3), we reprised the above studies in a second EAC cell line model, EsoAd1, that harbors bi-allelic inactivating mutations in SMAD4 (Supplementary Figure S10).	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('men', 'Species', '9606', (254, 257))	('SMAD4', 'Gene', (241, 246))	('bi-allelic inactivating mutations', 'Var', (204, 237))	('EAC', 'Phenotype', 'HP:0011459', (162, 165))
490376	30768984	However, in this second and SMAD4-null EAC model, a significant and dose-dependent suppression of cell culture growth was again achieved by blocking TGFbeta signaling (Figure 4, A and B, Supplementary Figure S12) with small molecule inhibitors (SB431542, LY2157299).	('blocking', 'NegReg', (140, 148))	('SB431542', 'Chemical', 'MESH:C459179', (245, 253))	('suppression', 'NegReg', (83, 94))	('EAC', 'Phenotype', 'HP:0011459', (39, 42))	('LY2157299', 'Var', (255, 264))	('LY2157299', 'Chemical', 'MESH:C557799', (255, 264))	('men', 'Species', '9606', (193, 196))	('TGFbeta', 'Protein', (149, 156))	('cell culture growth', 'CPA', (98, 117))
490377	30768984	We note that, the increased growth suppression observed with SB431542 versus LY2157299 in EsoAdl, but not in FLO-1 (Figure 4, A and B), may reflect EsoAd1's significant expression of ALK7 (Supplementary Figure S13) that is inhibited by SB431542 but not by LY2157299.	('ALK7', 'Gene', '130399', (183, 187))	('SB431542', 'Var', (236, 244))	('men', 'Species', '9606', (195, 198))	('growth suppression', 'CPA', (28, 46))	('SB431542', 'Chemical', 'MESH:C459179', (236, 244))	('SB431542', 'Chemical', 'MESH:C459179', (61, 69))	('SB431542', 'Var', (61, 69))	('ALK7', 'Gene', (183, 187))	('LY2157299', 'Chemical', 'MESH:C557799', (77, 86))	('LY2157299', 'Chemical', 'MESH:C557799', (256, 265))	('LY2157299', 'Var', (77, 86))
490378	30768984	EsoAd1 cell and colony growth were also significantly reduced by siRNA knockdown of TGFbeta ligands, TGFbetaRl, TGFbetaR2, SMAD2, or SMAD3, thus supporting the involvement of these components in a SMAD4-independent growth promoting limb of TGFbeta signaling (Figure 4C).	('TGFbeta', 'Gene', (84, 91))	('SMAD2', 'Gene', (123, 128))	('SMAD2', 'Gene', '4087', (123, 128))	('knockdown', 'Var', (71, 80))	('TGFbetaR2', 'Gene', (112, 121))	('TGFbetaRl', 'Gene', (101, 110))	('reduced', 'NegReg', (54, 61))	('SMAD3', 'Gene', '4088', (133, 138))	('men', 'Species', '9606', (167, 170))	('SMAD3', 'Gene', (133, 138))
490381	30768984	In addition, inhibition of TGFbeta or JNK signaling also markedly reduced EsoAd1 cell's migratory potential (Supplementary Figure S16).	('reduced', 'NegReg', (66, 73))	('inhibition', 'Var', (13, 23))	('TGFbeta', 'Protein', (27, 34))	('men', 'Species', '9606', (115, 118))	('EsoAd1 cell', 'CPA', (74, 85))	('JNK', 'Protein', (38, 41))
490384	30768984	Tumor xenografts were allowed to grow till they were established and had reached a minimum size of 50mm3, when mice were then randomized to start treatment with TGFbetaRI inhibitors (SB431542, i.p; LY2157299, oral gavage), or with vehicles only (see Methods).	('men', 'Species', '9606', (151, 154))	('TGFbetaRI', 'Gene', '7046', (161, 170))	('SB431542', 'Chemical', 'MESH:C459179', (183, 191))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (111, 115))	('LY2157299', 'Chemical', 'MESH:C557799', (198, 207))	('TGFbetaRI', 'Gene', (161, 170))	('SB431542', 'Var', (183, 191))
490385	30768984	EsoAd1 tumors proved strikingly sensitive to inhibition of TGFbeta signaling, with either SB431542 or LY2157299 treatment abrogating the growth of and eradicating these SMAD4-null EsoAd1 tumors (Figure 5A), with none of the TGFbetaRI inhibitor treated mice showing any tumor recurrence during 21 days of post-treatment follow-up.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('EsoAd1', 'Disease', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('men', 'Species', '9606', (314, 317))	('tumor', 'Disease', (187, 192))	('SB431542', 'Chemical', 'MESH:C459179', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('mice', 'Species', '10090', (252, 256))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('abrogating', 'NegReg', (122, 132))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('SB431542', 'Var', (90, 98))	('TGFbetaRI', 'Gene', '7046', (224, 233))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('growth', 'MPA', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Disease', (187, 193))	('eradicating', 'NegReg', (151, 162))	('TGFbetaRI', 'Gene', (224, 233))	('LY2157299', 'Chemical', 'MESH:C557799', (102, 111))	('tumor', 'Disease', (7, 12))	('men', 'Species', '9606', (117, 120))	('tumor', 'Disease', (269, 274))	('LY2157299 treatment', 'Var', (102, 121))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
490386	30768984	Similarly, inhibiting TGFbeta signaling proved highly potent in suppressing the growth of FLO-1 EAC tumors (Figure 5B).	('TGFbeta', 'Protein', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('inhibiting', 'Var', (11, 21))	('FLO-1 EAC tumors', 'Disease', (90, 106))	('suppressing', 'NegReg', (64, 75))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('EAC', 'Phenotype', 'HP:0011459', (96, 99))	('growth', 'MPA', (80, 86))	('FLO-1 EAC tumors', 'Disease', 'MESH:C536611', (90, 106))
490387	30768984	In particular, mice treated with the LY2157299 TGFbetaRI inhibitor showed a near total regression of FLO-1 tumor growth in vivo (Figure 5B).	('tumor growth', 'Disease', (107, 119))	('regression', 'NegReg', (87, 97))	('tumor growth', 'Disease', 'MESH:D006130', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('TGFbetaRI', 'Gene', (47, 56))	('LY2157299', 'Chemical', 'MESH:C557799', (37, 46))	('mice', 'Species', '10090', (15, 19))	('FLO-1', 'Gene', (101, 106))	('TGFbetaRI', 'Gene', '7046', (47, 56))	('LY2157299', 'Var', (37, 46))
490388	30768984	In particular, in both tumor models, IHC analysis showed the presence and nuclear localization of phospho-c-JUN protein and treating xenograft-bearing mice with the JNK inhibitor SP600125 abrogated tumor growth (Figure 5, C and D; Supplementary Figures S17 and S18).	('mice', 'Species', '10090', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor growth', 'Disease', (198, 210))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('abrogated', 'NegReg', (188, 197))	('SP600125', 'Var', (179, 187))	('tumor', 'Disease', (198, 203))	('SP600125', 'Chemical', 'MESH:C432165', (179, 187))	('tumor growth', 'Disease', 'MESH:D006130', (198, 210))	('men', 'Species', '9606', (237, 240))
490392	30768984	Conversely, inhibiting TGFbeta-SMAD signaling (Figure 6B, Supplementary Figure S21) with SB431542 or LY2157299 compounds suppressed the growth of two of the three dysplastic BE cell lines (CP-B, CP-D), but had no effects on growth of the non-dysplastic BE cells (Figure 6B).	('CP-B', 'Gene', (189, 193))	('inhibiting', 'NegReg', (12, 22))	('CP-B', 'Gene', '1360', (189, 193))	('CP-D', 'Gene', (195, 199))	('SB431542', 'Chemical', 'MESH:C459179', (89, 97))	('men', 'Species', '9606', (64, 67))	('CP-D', 'Gene', '1362', (195, 199))	('SB431542', 'Gene', (89, 97))	('growth', 'MPA', (136, 142))	('LY2157299', 'Var', (101, 110))	('dysplastic', 'Disease', 'MESH:D004416', (163, 173))	('dysplastic', 'Disease', 'MESH:D004416', (242, 252))	('BE', 'Phenotype', 'HP:0100580', (174, 176))	('LY2157299', 'Chemical', 'MESH:C557799', (101, 110))	('dysplastic', 'Disease', (163, 173))	('suppressed', 'NegReg', (121, 131))	('dysplastic', 'Disease', (242, 252))	('BE', 'Phenotype', 'HP:0100580', (253, 255))	('TGFbeta-SMAD', 'Protein', (23, 35))
490394	30768984	Of note, knockdown of TGFbeta3 ligand resulted in marked suppression of both non-dysplastic and dysplastic BE cell growth (Supplementary Figure S22), likely suggesting a generalized cytotoxic effect of inhibiting TGFbeta3.	('knockdown', 'Var', (9, 18))	('TGFbeta3', 'Gene', '7043', (213, 221))	('non-dysplastic and dysplastic BE cell growth', 'Disease', 'MESH:D004416', (77, 121))	('TGFbeta3', 'Gene', (22, 30))	('suppression', 'NegReg', (57, 68))	('men', 'Species', '9606', (129, 132))	('TGFbeta3', 'Gene', (213, 221))	('TGFbeta3', 'Gene', '7043', (22, 30))	('BE', 'Phenotype', 'HP:0100580', (107, 109))
490395	30768984	Interrogation of the JNK pathway revealed growth suppression of both non-dysplastic and dysplastic BE cells when treated with either chemical or siRNA inhibitors of JNK (Supplementary Figure S23).	('men', 'Species', '9606', (176, 179))	('BE', 'Phenotype', 'HP:0100580', (99, 101))	('inhibitors', 'Var', (151, 161))	('growth suppression of both non-dysplastic and dysplastic', 'Disease', 'MESH:D004416', (42, 98))	('JNK', 'Gene', (165, 168))
490402	30768984	Nonetheless, given the differences in TP53 mutation status between the non-dysplastic BE (TP53 wild-type) versus dysplastic BE/EAC (TP53 mutant) cells , it is possible that the growth-promoting function of TGFbeta signaling may be dependent on dysfunctional TP53 in this disease.	('BE', 'Phenotype', 'HP:0100580', (86, 88))	('dysplastic', 'Disease', 'MESH:D004416', (113, 123))	('growth-promoting function', 'MPA', (177, 202))	('dysplastic', 'Disease', 'MESH:D004416', (75, 85))	('TP53', 'Gene', '7157', (258, 262))	('mutation', 'Var', (43, 51))	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', (258, 262))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('EAC', 'Phenotype', 'HP:0011459', (127, 130))	('dysfunctional', 'Var', (244, 257))	('BE', 'Phenotype', 'HP:0100580', (124, 126))	('TP53', 'Gene', (90, 94))	('dysplastic', 'Disease', (75, 85))	('dysplastic', 'Disease', (113, 123))	('TP53', 'Gene', '7157', (38, 42))
490403	30768984	Future studies are however warranted to test this association and broader significance of genomic alterations such as TP53 mutations as potential modulators of TGFbeta signaling.	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('mutations', 'Var', (123, 132))
490405	30768984	This functional distinction in the role of TGFbeta as a potential promoter of EAC, but as a suppressor of colon cancer, is further supported by the genetic observations that somatic mutations in TGFbeta signaling elements are rare in EACs (~11%) ; whereas, colon cancers commonly demonstrate mutations in the TGFbetaRII gene (~30%) , or mutations (~24%) or genomic deletions (~60%) in SMAD's  Collectively, these findings point to fundamental differences in the biologic role of TGFbeta-SMAD signaling in EAC versus other gastrointestinal malignancies such as colon cancer.	('colon cancers', 'Phenotype', 'HP:0003003', (257, 270))	('gastrointestinal malignancies', 'Disease', 'MESH:D004067', (522, 551))	('colon cancer', 'Phenotype', 'HP:0003003', (106, 118))	('colon cancer', 'Disease', 'MESH:D015179', (257, 269))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('SMAD', 'Gene', (385, 389))	('gastrointestinal malignancies', 'Disease', (522, 551))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('TGFbetaRII', 'Gene', (309, 319))	('colon cancer', 'Disease', (560, 572))	('men', 'Species', '9606', (216, 219))	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (566, 572))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('colon cancers', 'Disease', 'MESH:D015179', (257, 270))	('colon cancer', 'Disease', 'MESH:D015179', (106, 118))	('EAC', 'Phenotype', 'HP:0011459', (505, 508))	('colon cancers', 'Disease', (257, 270))	('mutations', 'Var', (292, 301))	('men', 'Species', '9606', (436, 439))	('EAC', 'Phenotype', 'HP:0011459', (234, 237))	('colon cancer', 'Phenotype', 'HP:0003003', (560, 572))	('colon cancer', 'Disease', (106, 118))	('EAC', 'Disease', (505, 508))	('mutations', 'Var', (337, 346))	('colon cancer', 'Phenotype', 'HP:0003003', (257, 269))	('TGFbetaRII', 'Gene', '7048', (309, 319))	('genomic deletions', 'Var', (357, 374))	('colon cancer', 'Disease', 'MESH:D015179', (560, 572))
490407	30768984	In line with this, previous studies have shown that transactivation of the JNK pathway facilitates leptin-induced stimulation of proliferation and reduced apoptosis in EAC cells .	('reduced', 'NegReg', (147, 154))	('leptin', 'Gene', '3952', (99, 105))	('EAC', 'Phenotype', 'HP:0011459', (168, 171))	('leptin', 'Gene', (99, 105))	('facilitates', 'PosReg', (87, 98))	('transactivation', 'Var', (52, 67))	('proliferation', 'CPA', (129, 142))	('stimulation', 'PosReg', (114, 125))	('apoptosis', 'CPA', (155, 164))	('JNK pathway', 'Pathway', (75, 86))
490411	30768984	Combination treatment of TGFbetaRI inhibitors (SB431542, LY2157299) with JNK inhibitor (SP600125) at low doses resulted in marked growth suppression of SMAD4-null EsoAd1 cells, as compared to either inhibitor treatment alone (Supplementary Figure S26).	('TGFbetaRI', 'Gene', (25, 34))	('growth suppression', 'CPA', (130, 148))	('SP600125', 'Chemical', 'MESH:C432165', (88, 96))	('TGFbetaRI', 'Gene', '7046', (25, 34))	('men', 'Species', '9606', (232, 235))	('SB431542', 'Chemical', 'MESH:C459179', (47, 55))	('SB431542', 'Var', (47, 55))	('LY2157299', 'Chemical', 'MESH:C557799', (57, 66))	('men', 'Species', '9606', (214, 217))	('LY2157299', 'Var', (57, 66))	('men', 'Species', '9606', (17, 20))
490412	30768984	Moreover, TGFbetaR1 inhibitor treatment showed no effect on reducing c-JUN phosphorylation in EAC cells, with LY2157299 in fact inducing phosphorylation of c-JUN (Supplementary Figure S26), a finding consistent with a prior report on this compound .	('men', 'Species', '9606', (35, 38))	('inducing', 'Reg', (128, 136))	('men', 'Species', '9606', (169, 172))	('phosphorylation', 'MPA', (137, 152))	('LY2157299', 'Var', (110, 119))	('LY2157299', 'Chemical', 'MESH:C557799', (110, 119))	('c-JUN phosphorylation', 'MPA', (69, 90))	('EAC', 'Phenotype', 'HP:0011459', (94, 97))	('reducing', 'NegReg', (60, 68))
490413	30768984	Conversely, treatment with the JNK inhibitor, SP600125, predominantly reduced the phosphorylation of the linker region within SMAD2 (Supplementary Figure S26), again consistent with prior reports of the JNK pathway playing a role in SMAD linker phosphorylation  While these findings hint at a potential benefit of TGFbeta/JNK combination treatment in specific genomic contexts in EACs, future studies will be required to test the generality and mechanisms underlying such potential context dependent synergy between TGFbeta and JNK signaling pathways.	('SMAD2', 'Gene', (126, 131))	('SMAD2', 'Gene', '4087', (126, 131))	('reduced', 'NegReg', (70, 77))	('EAC', 'Phenotype', 'HP:0011459', (380, 383))	('SP600125', 'Var', (46, 54))	('SP600125', 'Chemical', 'MESH:C432165', (46, 54))	('men', 'Species', '9606', (139, 142))	('phosphorylation of the linker region', 'MPA', (82, 118))	('men', 'Species', '9606', (343, 346))	('men', 'Species', '9606', (17, 20))
490415	30768984	Nonetheless, these findings may have translational significance, as the TGFbetaR1 inhibitors are currently being evaluated in human trials as an oral anti-cancer agent.	('human', 'Species', '9606', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('inhibitors', 'Var', (82, 92))	('TGFbetaR1', 'Gene', (72, 81))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
490423	29948477	The 5-year survival rate of patients with pStage IV in UICC classification (including patients with supraclavicular node metastasis) was better than that of patients with pStage IVb in JES classification (not including patients with supraclavicular node metastasis).	('better', 'PosReg', (137, 143))	('supraclavicular node metastasis', 'Disease', 'MESH:D009362', (100, 131))	('supraclavicular node metastasis', 'Disease', (233, 264))	('pStage IV', 'Var', (42, 51))	('survival', 'CPA', (11, 19))	('patients', 'Species', '9606', (157, 165))	('supraclavicular node metastasis', 'Disease', (100, 131))	('patients', 'Species', '9606', (219, 227))	('patients', 'Species', '9606', (28, 36))	('supraclavicular node metastasis', 'Disease', 'MESH:D009362', (233, 264))	('patients', 'Species', '9606', (86, 94))
490429	29855346	In addition to suppressing STAT1 expression, ERK limited STAT1 signaling by decreasing the production of IFNgamma.	('IFNgamma', 'Gene', (105, 113))	('suppressing', 'NegReg', (15, 26))	('IFNgamma', 'Gene', '3458', (105, 113))	('limited', 'NegReg', (49, 56))	('STAT1 signaling', 'MPA', (57, 72))	('STAT1 expression', 'MPA', (27, 43))	('ERK', 'Var', (45, 48))	('decreasing', 'NegReg', (76, 86))
490439	29855346	Aberrations of this pathway occur in the pathogenesis of various human diseases, especially chronic inflammatory diseases and neurodegenerative disorders, even cancer.	('human', 'Species', '9606', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('occur', 'Reg', (28, 33))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (126, 153))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('inflammatory diseases', 'Disease', 'MESH:D007249', (100, 121))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (126, 153))	('Aberrations', 'Var', (0, 11))	('neurodegenerative disorders', 'Disease', (126, 153))	('inflammatory diseases', 'Disease', (100, 121))
490467	29855346	Furthermore, MG132 induced an increase in STAT1 in time-dependent manner (Fig.	('MG132', 'Chemical', 'MESH:C072553', (13, 18))	('MG132', 'Var', (13, 18))	('increase', 'PosReg', (30, 38))	('STAT1 in', 'MPA', (42, 50))
490468	29855346	With the exception of EC1, a cell line that did not express p-STAT1S727, the STAT1 phosphorylation level at Y701 and S727 generally increased in parallel with the total protein level of STAT1.	('p-STAT1S727', 'Var', (60, 71))	('Y701', 'Var', (108, 112))	('S727', 'Var', (117, 121))	('increased', 'PosReg', (132, 141))	('EC1', 'Gene', (22, 25))	('STAT1 phosphorylation level', 'MPA', (77, 104))	('EC1', 'Gene', '4819', (22, 25))
490470	29855346	2a, STAT1 ubiquitination was decreased in the presence of U0126 compared to the negative controls.	('U0126', 'Var', (58, 63))	('decreased', 'NegReg', (29, 38))	('STAT1 ubiquitination', 'MPA', (4, 24))	('U0126', 'Chemical', 'MESH:C113580', (58, 63))
490472	29855346	As mentioned, one previous study using mouse embryonic fibroblasts has shown that ERK phosphorylates STAT1 at S727 and targets it for proteasomal degradation.	('S727', 'Var', (110, 114))	('STAT1', 'Gene', (101, 106))	('targets', 'Reg', (119, 126))	('mouse', 'Species', '10090', (39, 44))	('proteasomal degradation', 'MPA', (134, 157))
490473	29855346	To determine whether the two phosphorylation sites of STAT1 (Y701 and S727) contribute to STAT1 polyubiquitination, we transfected plasmids encoding GFP-tagged STAT1 or the two STAT1 mutants (S727A and Y701F) into the EC1 cells, and the results are illustrated in Fig.	('EC1', 'Gene', '4819', (218, 221))	('S727', 'Var', (70, 74))	('S727A', 'Mutation', 'p.S727A', (192, 197))	('Y701F', 'Mutation', 'p.Y701F', (202, 207))	('S727A', 'Var', (192, 197))	('STAT1', 'Gene', (160, 165))	('polyubiquitination', 'MPA', (96, 114))	('Y701F', 'Var', (202, 207))	('EC1', 'Gene', (218, 221))	('Y701', 'Var', (61, 65))
490474	29855346	As expected, treatment of U0126 effectively decreased the amount of p-ERK, and this change correlated with a reciprocal increase in GFP and STAT1 proteins.	('STAT1 proteins', 'MPA', (140, 154))	('U0126', 'Var', (26, 31))	('U0126', 'Chemical', 'MESH:C113580', (26, 31))	('increase', 'PosReg', (120, 128))	('p-ERK', 'Gene', '9451', (68, 73))	('p-ERK', 'Gene', (68, 73))	('decreased', 'NegReg', (44, 53))
490475	29855346	The levels of both STAT1S727A and STAT1Y701F increased in response to the U0126 treatment.	('U0126', 'Var', (74, 79))	('increased', 'PosReg', (45, 54))	('STAT1S727A', 'Var', (19, 29))	('U0126', 'Chemical', 'MESH:C113580', (74, 79))	('S727A', 'Mutation', 'p.S727A', (24, 29))	('STAT1Y701F', 'Var', (34, 44))
490476	29855346	In addition, silencing of ERK by inhibitor U0126 decreased the polyubiquitination of STAT1, either in the form of wild-type and mutants (Fig.	('mutants', 'Var', (128, 135))	('U0126', 'Var', (43, 48))	('ERK', 'Gene', (26, 29))	('decreased', 'NegReg', (49, 58))	('U0126', 'Chemical', 'MESH:C113580', (43, 48))	('polyubiquitination', 'MPA', (63, 81))	('silencing', 'NegReg', (13, 22))
490478	29855346	2e, we found that U0126 can increase both exogenous STAT1alpha and STAT1beta in both cell lines; in addition, ERK can promote the polyubiquitination of both STAT1alpha and STAT1beta (Fig.	('ERK', 'Gene', (110, 113))	('U0126', 'Chemical', 'MESH:C113580', (18, 23))	('polyubiquitination', 'MPA', (130, 148))	('U0126', 'Var', (18, 23))	('promote', 'PosReg', (118, 125))
490480	29855346	3a, immunoprecipitation of ERK pulled down STAT1 in both cell lines, and MG132 treatment appreciably increased the amount of STAT1 bound to ERK, probably due to the fact that the total amount of STAT1 increased in response to proteasomal inhibition by MG132.	('MG132', 'Chemical', 'MESH:C072553', (252, 257))	('ERK', 'Protein', (140, 143))	('increased', 'PosReg', (101, 110))	('MG132', 'Chemical', 'MESH:C072553', (73, 78))	('bound', 'Interaction', (131, 136))	('MG132', 'Var', (73, 78))
490481	29855346	Reciprocal pull-down experiments showed essentially the same results, except that we did not see a MG132-induced increase in the amount of ERK bound to STAT1, probably due to the fact that the protein level of 'bioavailable' STAT1 was substantially lower than that of ERK.	('lower', 'NegReg', (249, 254))	('MG132-induced', 'Var', (99, 112))	('MG132', 'Chemical', 'MESH:C072553', (99, 104))	('protein level', 'MPA', (193, 206))
490482	29855346	To determine whether the phosphorylation status of STAT1 is required for the ERK-STAT1 interaction in ESCC cells, we transfected EC1 cells with wild-type STAT1, STAT1Y701F or STAT1S727A.	('EC1', 'Gene', '4819', (129, 132))	('STAT1Y701F', 'Var', (161, 171))	('STAT1S727A', 'Var', (175, 185))	('Y701F', 'Mutation', 'p.Y701F', (166, 171))	('EC1', 'Gene', (129, 132))
490485	29855346	Using quantitative RT-PCR, we found that inhibition of ERK by U0126 increased the expression of IFNgamma and IFNgamma receptor in both ESCC cell lines (Fig.	('IFNgamma', 'Gene', (109, 117))	('expression', 'MPA', (82, 92))	('U0126', 'Chemical', 'MESH:C113580', (62, 67))	('IFNgamma', 'Gene', '3458', (109, 117))	('IFNgamma', 'Gene', (96, 104))	('U0126', 'Var', (62, 67))	('IFNgamma', 'Gene', '3458', (96, 104))	('increased', 'PosReg', (68, 77))	('inhibition', 'NegReg', (41, 51))	('ERK', 'Gene', (55, 58))
490490	29855346	4d, U0126 significantly diminished the clonogenic ability of ESCC cell with STAT1 knockdown by siRNA; at the same time, constitutive-active MEK significantly increased the clonogenic ability of ESCC cells transfected with STAT1C (p < 0.05).	('MEK', 'Gene', (140, 143))	('diminished', 'NegReg', (24, 34))	('STAT1C', 'Gene', (222, 228))	('knockdown', 'Var', (82, 91))	('STAT1', 'Gene', (76, 81))	('MEK', 'Gene', '5609', (140, 143))	('U0126', 'Var', (4, 9))	('clonogenic ability', 'CPA', (172, 190))	('STAT1C', 'Gene', '6772', (222, 228))	('U0126', 'Chemical', 'MESH:C113580', (4, 9))	('increased', 'PosReg', (158, 167))	('clonogenic ability', 'CPA', (39, 57))
490491	29855346	The observation that MG132 can induce effective apoptosis in various types of cancer, including ESCC, has been widely published.	('MG132', 'Chemical', 'MESH:C072553', (21, 26))	('MG132', 'Var', (21, 26))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('ESCC', 'Disease', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('apoptosis', 'CPA', (48, 57))
490492	29855346	In view of our findings that STAT1 can induce effective apoptosis in ESCC, and our current observation that proteasome degradation is a key pathway to down-regulate STAT1, we hypothesized that MG132 also induces apoptosis in ESCC via a STAT1-dependent pathway.	('STAT1-dependent pathway', 'Pathway', (236, 259))	('apoptosis', 'CPA', (212, 221))	('down-regulate', 'NegReg', (151, 164))	('MG132', 'Chemical', 'MESH:C072553', (193, 198))	('induces', 'Reg', (204, 211))	('MG132', 'Var', (193, 198))
490493	29855346	First, we confirmed that MG132 effectively induced apoptosis in ESCC cells, as evidenced by the reduction of viable cells as well as enhanced the cleavage of caspase 3 and PARP expression in dose and time dependent manner of MG132 treatment (Fig.	('PARP', 'Gene', '142', (172, 176))	('caspase 3', 'Gene', '836', (158, 167))	('enhanced', 'PosReg', (133, 141))	('MG132', 'Chemical', 'MESH:C072553', (25, 30))	('PARP', 'Gene', (172, 176))	('MG132', 'Var', (25, 30))	('MG132', 'Chemical', 'MESH:C072553', (225, 230))	('viable cells', 'CPA', (109, 121))	('cleavage', 'MPA', (146, 154))	('caspase 3', 'Gene', (158, 167))	('expression', 'MPA', (177, 187))	('reduction', 'NegReg', (96, 105))
490494	29855346	Second, we found that siRNA knockdown of STAT1 significantly attenuated MG132-induced cell inhibition (at 5 muM) in EC1 and KYSE150 cells (Fig.	('EC1', 'Gene', '4819', (116, 119))	('attenuated', 'NegReg', (61, 71))	('EC1', 'Gene', (116, 119))	('STAT1', 'Gene', (41, 46))	('muM', 'Gene', '56925', (108, 111))	('KYSE150', 'CellLine', 'CVCL:1348', (124, 131))	('MG132', 'Chemical', 'MESH:C072553', (72, 77))	('muM', 'Gene', (108, 111))	('knockdown', 'Var', (28, 37))	('MG132-induced', 'Gene', (72, 85))
490496	29855346	Taken together, these observations suggest that MG132-induced apoptosis in ESCC is highly STAT1-dependent.	('MG132', 'Chemical', 'MESH:C072553', (48, 53))	('apoptosis', 'CPA', (62, 71))	('MG132-induced', 'Var', (48, 61))
490502	29855346	We also found that MG132 induced apoptosis is partly dependent on STAT1activation, since STAT1 siRNA attenuate the apoptosis of ESCC cells.	('attenuate', 'NegReg', (101, 110))	('STAT1', 'Var', (89, 94))	('MG132', 'Chemical', 'MESH:C072553', (19, 24))	('apoptosis', 'CPA', (115, 124))	('MG132', 'Var', (19, 24))
490505	29855346	One previous study has shown that reduced STAT1 expression in squamous cell carcinoma of the head and neck is due to gene methylation and silencing of the STAT1 gene.	('silencing', 'NegReg', (138, 147))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 85))	('reduced', 'NegReg', (34, 41))	('STAT1', 'Gene', (42, 47))	('squamous cell carcinoma', 'Disease', (62, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('STAT1', 'Gene', (155, 160))	('expression', 'MPA', (48, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('gene methylation', 'Var', (117, 133))
490506	29855346	Data from our experiments using 5-Aza does not support that STAT1 downregulation in ESCC was because of gene methylation.	('ESCC', 'Gene', (84, 88))	('5-Aza', 'Chemical', 'MESH:D001374', (32, 37))	('downregulation', 'NegReg', (66, 80))	('methylation', 'Var', (109, 120))
490508	29855346	In view of the fact that STAT1 phosphorylation at tyrosine 701 is required for its dimerization, nuclear translocation and DNA-binding, a restoration of STAT1 expression in ESCC may be sufficient to induce apoptosis.	('induce', 'PosReg', (199, 205))	('restoration', 'Var', (138, 149))	('expression', 'MPA', (159, 169))	('STAT1', 'Gene', (153, 158))	('tyrosine', 'Chemical', 'MESH:D014443', (50, 58))	('apoptosis', 'CPA', (206, 215))
490510	29855346	Regarding p-STAT1S727, it is believed to boost the transcriptional activity of STAT1 and it has been implicated to enhance the anti-viral and anti-proliferation function of IFN-gamma.	('STAT1', 'Gene', (79, 84))	('anti-proliferation function', 'CPA', (142, 169))	('transcriptional activity', 'MPA', (51, 75))	('anti-viral', 'CPA', (127, 137))	('p-STAT1S727', 'Var', (10, 21))	('IFN-gamma', 'Gene', (173, 182))	('IFN-gamma', 'Gene', '3458', (173, 182))	('enhance', 'PosReg', (115, 122))	('boost', 'PosReg', (41, 46))
490516	29855346	In addition to promoting the proteasomal degradation of STAT1, our data suggested that ERK dampens STAT1 activation by suppressing the production of IFNgamma, which is known to be a potent activator of STAT1.	('IFNgamma', 'Gene', (149, 157))	('suppressing', 'NegReg', (119, 130))	('IFNgamma', 'Gene', '3458', (149, 157))	('promoting', 'PosReg', (15, 24))	('proteasomal degradation', 'MPA', (29, 52))	('STAT1 activation', 'MPA', (99, 115))	('dampens', 'NegReg', (91, 98))	('ERK', 'Var', (87, 90))
490596	26338196	In the gastrointestinal system, the use of penicillin was associated with an elevated risk of esophageal, gastric and pancreatic cancers in addition to the higher risk for CRC we previously reported.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('gastric', 'Disease', (106, 113))	('pancreatic cancers', 'Disease', (118, 136))	('pancreatic cancers', 'Disease', 'MESH:D010190', (118, 136))	('penicillin', 'Chemical', 'MESH:D010406', (43, 53))	('CRC', 'Phenotype', 'HP:0003003', (172, 175))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('esophageal', 'Disease', (94, 104))	('gastrointestinal system', 'Disease', (7, 30))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (118, 136))	('penicillin', 'Var', (43, 53))	('gastrointestinal system', 'Disease', 'MESH:D005767', (7, 30))
490816	33665161	To conclude, additional study of CSCs in esophageal carcinoma could open promising therapeutic options in esophageal carcinomas by targeting hyper-activated signaling pathways, manipulating miRNA expression and hypoxia mechanisms in esophageal CSCs.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (106, 127))	('miRNA expression', 'MPA', (190, 206))	('esophageal carcinoma', 'Disease', (41, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('manipulating', 'Var', (177, 189))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (41, 61))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (106, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('hypoxia', 'Disease', 'MESH:D000860', (211, 218))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (106, 126))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (41, 61))	('hyper-activated signaling pathways', 'Pathway', (141, 175))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (106, 127))	('targeting', 'Reg', (131, 140))	('esophageal carcinomas', 'Disease', (106, 127))	('hypoxia', 'Disease', (211, 218))
490839	33665161	enhanced DNA repair efficiency, increased expression of detoxification enzymes (ALDH), increased expression of drug resistance proteins, up-regulation of anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-l, Bcl-w), mutations in key signaling molecules, and overexpression of drug efflux pumps (P glycoprotein 1, ABCG2) etc.	('DNA repair efficiency', 'CPA', (9, 30))	('ABCG2', 'Gene', (306, 311))	('expression', 'MPA', (42, 52))	('ABCG2', 'Gene', '9429', (306, 311))	('drug resistance', 'Gene', (111, 126))	('Bcl-xL', 'Gene', '598', (186, 192))	('overexpression', 'PosReg', (251, 265))	('Bcl-w', 'Gene', '599', (201, 206))	('Bcl-2', 'Gene', (179, 184))	('enhanced', 'PosReg', (0, 8))	('drug efflux pumps', 'MPA', (269, 286))	('P glycoprotein 1', 'Gene', '5243', (288, 304))	('expression', 'MPA', (97, 107))	('Bcl-2', 'Gene', '596', (179, 184))	('Bcl-w', 'Gene', (201, 206))	('P glycoprotein 1', 'Gene', (288, 304))	('increased', 'PosReg', (87, 96))	('up-regulation', 'PosReg', (137, 150))	('mutations', 'Var', (209, 218))	('increased', 'PosReg', (32, 41))	('drug resistance', 'Phenotype', 'HP:0020174', (111, 126))	('Bcl-xL', 'Gene', (186, 192))
490854	33665161	Consistently cells with the expression of WNT10A showed enrichment for CD44+/CD24-, and these cells showed increased self-renewal, invasive and metastatic potential.	('increased', 'PosReg', (107, 116))	('WNT10A', 'Gene', '80326', (42, 48))	('expression', 'Var', (28, 38))	('self-renewal', 'CPA', (117, 129))	('CD44+/CD24-', 'Var', (71, 82))	('WNT10A', 'Gene', (42, 48))
490862	33665161	However, aberrant activation of this pathway is associated with many cancers including esophageal cancer.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Disease', (69, 76))	('associated', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('aberrant', 'Var', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('activation', 'PosReg', (18, 28))	('cancer', 'Disease', (69, 75))
490871	33665161	ABT263 reduces the expression of many oncogenes, including genes associated with stemness pathways such as Wnt and YAP/SOX9 axes.	('expression', 'MPA', (19, 29))	('ABT263', 'Var', (0, 6))	('YAP', 'Gene', '10413', (115, 118))	('reduces', 'NegReg', (7, 14))	('SOX9', 'Gene', '6662', (119, 123))	('YAP', 'Gene', (115, 118))	('oncogenes', 'Gene', (38, 47))	('ABT263', 'Chemical', 'MESH:C528561', (0, 6))	('SOX9', 'Gene', (119, 123))
490877	33665161	RARalpha knockdown suppresses the proliferation and metastasis of OSCC cells by minimizing the expression of proliferative markers (PCNA, Ki-67) and matrix metallo-proteinases (MMP7 and MMP9).	('proliferation', 'CPA', (34, 47))	('MMP7', 'Gene', (177, 181))	('RARalpha', 'Gene', (0, 8))	('knockdown', 'Var', (9, 18))	('PCNA', 'Gene', '5111', (132, 136))	('suppresses', 'NegReg', (19, 29))	('MMP7', 'Gene', '4316', (177, 181))	('MMP9', 'Gene', (186, 190))	('MMP9', 'Gene', '4318', (186, 190))	('Ki', 'Chemical', 'MESH:C066186', (138, 140))	('RARalpha', 'Gene', '5914', (0, 8))	('PCNA', 'Gene', (132, 136))	('minimizing', 'NegReg', (80, 90))	('expression', 'MPA', (95, 105))
490878	33665161	Not only that, RARalpha knockdown also enhances drug susceptibility of OSCC cells to 5-fluorouracil and cisplatin.	('RARalpha', 'Gene', '5914', (15, 23))	('drug susceptibility', 'MPA', (48, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('enhances', 'PosReg', (39, 47))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (85, 99))	('RARalpha', 'Gene', (15, 23))	('knockdown', 'Var', (24, 33))
490879	33665161	On top of that, RARalpha knockdown results in inhibition of Wnt/beta-catenin pathway by decreasing GSK3betaphosphorylation at Ser-9 and inducing phosphorylation at Tyr-216, which subsequently results in reduced expression of its downstream targets such as MMP7, MMP9, and P-glycoprotein.	('Ser', 'Chemical', 'MESH:D012694', (126, 129))	('MMP9', 'Gene', '4318', (262, 266))	('MMP9', 'Gene', (262, 266))	('reduced', 'NegReg', (203, 210))	('beta-catenin', 'Gene', (64, 76))	('GSK3beta', 'Gene', (99, 107))	('beta-catenin', 'Gene', '1499', (64, 76))	('inducing', 'Reg', (136, 144))	('MMP7', 'Gene', (256, 260))	('inhibition', 'NegReg', (46, 56))	('decreasing', 'NegReg', (88, 98))	('P-glycoprotein', 'Gene', (272, 286))	('RARalpha', 'Gene', '5914', (16, 24))	('GSK3beta', 'Gene', '2931', (99, 107))	('knockdown', 'Var', (25, 34))	('expression', 'MPA', (211, 221))	('P-glycoprotein', 'Gene', '5243', (272, 286))	('MMP7', 'Gene', '4316', (256, 260))	('phosphorylation', 'MPA', (145, 160))	('Tyr', 'Chemical', 'MESH:D014443', (164, 167))	('RARalpha', 'Gene', (16, 24))
490889	33665161	Furthermore, patient-derived xenograft models clearly demonstrated that inhibition of Notch signaling by gamma-secretase inhibitors is efficacious in downsizing tumor growth.	('patient', 'Species', '9606', (13, 20))	('inhibition', 'Var', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Notch signaling', 'Pathway', (86, 101))	('downsizing tumor', 'Disease', 'MESH:D009369', (150, 166))	('downsizing tumor', 'Disease', (150, 166))
490890	33665161	Thus, inhibition of Notch signaling by DAPT could impair the stemness of OAC cells i.e.	('DAPT', 'Chemical', '-', (39, 43))	('stemness of OAC cells', 'CPA', (61, 82))	('DAPT', 'Gene', (39, 43))	('inhibition', 'Var', (6, 16))	('Notch signaling', 'Pathway', (20, 35))	('impair', 'NegReg', (50, 56))
490893	33665161	GASC1 epigenetically controls the stemness of OSCC by regulation of Notch1.	('stemness of OSCC', 'CPA', (34, 50))	('controls', 'Reg', (21, 29))	('regulation', 'Var', (54, 64))	('Notch1', 'Gene', '4851', (68, 74))	('epigenetically', 'Var', (6, 20))	('GASC1', 'Gene', (0, 5))	('GASC1', 'Gene', '23081', (0, 5))	('Notch1', 'Gene', (68, 74))
490897	33665161	Several stemness phenotypes of CSCs from OSCC were dramatically decreased after GASC1 blockade, which subsequently resulted in reduced Notch1 expression via demethylation of Notch1 promoters (H3K9me2 and H3K9me3).	('GASC1', 'Gene', (80, 85))	('Notch1', 'Gene', '4851', (174, 180))	('H3K9me2', 'Var', (192, 199))	('stemness phenotypes', 'CPA', (8, 27))	('decreased', 'NegReg', (64, 73))	('Notch1', 'Gene', (135, 141))	('demethylation', 'Var', (157, 170))	('GASC1', 'Gene', '23081', (80, 85))	('Notch1', 'Gene', '4851', (135, 141))	('blockade', 'Var', (86, 94))	('expression', 'MPA', (142, 152))	('reduced', 'NegReg', (127, 134))	('Notch1', 'Gene', (174, 180))	('H3K9me3', 'Var', (204, 211))
490899	33665161	This finding suggested that GASC1 promoted stemness in OSCC CSCs cells via Notch1 promoter demethylation.	('stemness', 'CPA', (43, 51))	('GASC1', 'Gene', '23081', (28, 33))	('demethylation', 'Var', (91, 104))	('promoted', 'PosReg', (34, 42))	('GASC1', 'Gene', (28, 33))	('Notch1', 'Gene', (75, 81))	('Notch1', 'Gene', '4851', (75, 81))
490913	33665161	In addition, activation of Hedgehog signaling could be inhibited by targeting transcription factor ATPase family AAA domain-containing protein 2 (ATAD2).	('ATPase family AAA domain-containing protein 2', 'Gene', (99, 144))	('Hedgehog signaling', 'Pathway', (27, 45))	('ATPase family AAA domain-containing protein 2', 'Gene', '29028', (99, 144))	('ATAD2', 'Gene', (146, 151))	('targeting', 'Var', (68, 77))	('inhibited', 'NegReg', (55, 64))
490917	33665161	Moreover, in vivo experiments in nude mice further validated the suppressive effect of siRNA mediated ATAD2 silencing on tumor growth.	('suppressive', 'NegReg', (65, 76))	('silencing', 'Var', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('nude mice', 'Species', '10090', (33, 42))	('tumor', 'Disease', (121, 126))	('ATAD2', 'Gene', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
490919	33665161	YAP1 plays a significant role in the maintenance of stemness of embryonic stem cells as well as contributing to the functions of CSCs.Therefore, deregulation of Hippo and activation of YAP1 in CSCs contributes many important properties of tumors, and thus, targeting YAP1 will be an effective strategy to target CSCs, thereby inhibiting tumor growth.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('Hippo', 'Gene', (161, 166))	('YAP1', 'Gene', '10413', (0, 4))	('YAP1', 'Gene', (185, 189))	('tumor', 'Disease', (337, 342))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('tumors', 'Disease', (239, 245))	('YAP1', 'Gene', (0, 4))	('tumor', 'Disease', (239, 244))	('YAP1', 'Gene', '10413', (267, 271))	('inhibiting', 'NegReg', (326, 336))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('YAP1', 'Gene', (267, 271))	('YAP1', 'Gene', '10413', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('activation', 'PosReg', (171, 181))	('deregulation', 'Var', (145, 157))
490931	33665161	On the other hand, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells inhibited CSC phenotypes in vitro and tumorigenicity in vivo.	('tumor', 'Disease', (119, 124))	('inhibited', 'NegReg', (81, 90))	('SOX9', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('SOX9', 'Gene', '6662', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('knockdown', 'Var', (34, 43))	('CSC phenotypes', 'CPA', (91, 105))	('YAP1', 'Gene', '10413', (47, 51))	('YAP1', 'Gene', (47, 51))
490937	33665161	By blocking YAP1 and CDK6 with the YAP1 inhibitor CA3, and the CDK6 inhibitor LEE001 significantly suppressed esophageal cancer cell growth and CSC properties, particularly in radiation-resistant cells in both OAC and OSCC.	('suppressed', 'NegReg', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CDK6', 'Gene', (21, 25))	('CDK6', 'Gene', '1021', (21, 25))	('YAP1', 'Gene', (35, 39))	('CDK6', 'Gene', (63, 67))	('YAP1', 'Gene', '10413', (35, 39))	('YAP1', 'Gene', (12, 16))	('LEE001', 'Var', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CDK6', 'Gene', '1021', (63, 67))	('CSC properties', 'CPA', (144, 158))	('CA3', 'Gene', '761', (50, 53))	('YAP1', 'Gene', '10413', (12, 16))	('CA3', 'Gene', (50, 53))	('cancer', 'Disease', (121, 127))	('blocking', 'NegReg', (3, 11))
490938	33665161	The combination of LEE001 and CA3 exhibited the highest anti-tumor effects in radiation-resistant cells overexpressing YAP1 and CDK6 in both in vitro and in vivo by sensitizing resistant tumors to irradiation.	('YAP1', 'Gene', '10413', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('CDK6', 'Gene', '1021', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('sensitizing', 'PosReg', (165, 176))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (187, 192))	('LEE001', 'Var', (19, 25))	('CDK6', 'Gene', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('CA3', 'Gene', (30, 33))	('tumor', 'Disease', (61, 66))	('YAP1', 'Gene', (119, 123))	('CA3', 'Gene', '761', (30, 33))
490939	33665161	Thus, it was implied that crosstalk between YAP1 and CDK6 seems to play a pivotal role in conferring radiation resistance and targeting both YAP1 and CDK6 could be a useful therapeutic strategy to treat both esophageal adenocarcinoma and squamous cell carcinoma.	('esophageal adenocarcinoma', 'Disease', (208, 233))	('CDK6', 'Gene', (53, 57))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (219, 261))	('CDK6', 'Gene', '1021', (53, 57))	('targeting', 'Var', (126, 135))	('CDK6', 'Gene', (150, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (208, 233))	('CDK6', 'Gene', '1021', (150, 154))	('YAP1', 'Gene', (141, 145))	('YAP1', 'Gene', '10413', (141, 145))	('YAP1', 'Gene', '10413', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (208, 233))	('crosstalk', 'Var', (26, 35))	('YAP1', 'Gene', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
490943	33665161	Thus, interrupting mTOR with novel therapeutic could induce a reduction of stemness of cancer cells and sensitize them to the therapies.	('stemness of cancer', 'Disease', 'MESH:D009369', (75, 93))	('sensitize', 'Reg', (104, 113))	('interrupting', 'Var', (6, 18))	('mTOR', 'Gene', '2475', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mTOR', 'Gene', (19, 23))	('stemness of cancer', 'Disease', (75, 93))	('reduction', 'NegReg', (62, 71))
490946	33665161	Significant downregulation of mTOR pathway components including phospho-AKT, phospho-S6, phospho-70S6 was seen followed by metformin treatment, which are crucial to maintaining tumor cells' growth.	('downregulation', 'NegReg', (12, 26))	('AKT', 'Gene', '207', (72, 75))	('AKT', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('metformin', 'Chemical', 'MESH:D008687', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('phospho-70S6', 'Var', (89, 101))	('mTOR', 'Gene', '2475', (30, 34))	('tumor', 'Disease', (177, 182))	('mTOR', 'Gene', (30, 34))
490950	33665161	The JAK/STAT signaling pathway has been implicated in various physiological processes, and inhibition of this pathway could impede cancer cell growth and induce apoptosis in various cancers.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('induce', 'PosReg', (154, 160))	('inhibition', 'Var', (91, 101))	('impede', 'NegReg', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('apoptosis', 'CPA', (161, 170))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancers', 'Disease', (182, 189))	('cancer', 'Disease', (182, 188))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
490962	33665161	CSCs (CD44+/CD24-) were significantly enriched in EPC2T and OKF6T cells (transformed keratinocyte cell lines) overexpressing EGFR, which could induce EMT by TGF-beta1 in CSCs derived fromEPC2T and OKF6T cells.	('EPC2T', 'CellLine', 'CVCL:4361', (187, 192))	('OKF6T', 'CellLine', 'CVCL:L222', (197, 202))	('EPC2T', 'CellLine', 'CVCL:4361', (50, 55))	('CD44+/CD24-', 'Var', (6, 17))	('EGFR', 'Gene', '1956', (125, 129))	('OKF6T', 'CellLine', 'CVCL:L222', (60, 65))	('induce', 'PosReg', (143, 149))	('EGFR', 'Gene', (125, 129))	('EMT', 'CPA', (150, 153))	('TGF-beta1', 'Gene', '7040', (157, 166))	('TGF-beta1', 'Gene', (157, 166))	('overexpressing', 'Var', (110, 124))
490965	33665161	These results suggest that inhibition of EGFR may halt EMT by instigating differentiation in non-CSC populations, thereby suppressing enrichment of CSCs via inhibition of EMT.	('EGFR', 'Gene', (41, 45))	('EMT', 'CPA', (55, 58))	('enrichment of CSCs', 'CPA', (134, 152))	('suppressing', 'NegReg', (122, 133))	('inhibition', 'Var', (27, 37))	('inhibition', 'NegReg', (157, 167))	('halt', 'NegReg', (50, 54))	('EGFR', 'Gene', '1956', (41, 45))	('instigating', 'Reg', (62, 73))	('EMT', 'CPA', (171, 174))
490967	33665161	By contrast, some EGFR inhibitors suppress Zinc finger E-box binding proteins (ZEBs) and induce differentiation of CSCs in OSCC.	('induce', 'Reg', (89, 95))	('Zinc', 'Protein', (43, 47))	('differentiation', 'CPA', (96, 111))	('EGFR', 'Gene', '1956', (18, 22))	('inhibitors', 'Var', (23, 33))	('EGFR', 'Gene', (18, 22))	('suppress', 'NegReg', (34, 42))
490968	33665161	These findings suggested that EGFR inhibition might suppress the expression of ZEBs and induce differentiation in a wider variety of cancers, thereby blocking EMT-mediated enrichment of CSCs.	('EGFR', 'Gene', (30, 34))	('suppress', 'NegReg', (52, 60))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('ZEBs', 'Gene', (79, 83))	('EMT-mediated enrichment of CSCs', 'CPA', (159, 190))	('cancers', 'Disease', (133, 140))	('expression', 'MPA', (65, 75))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('differentiation', 'CPA', (95, 110))	('induce', 'Reg', (88, 94))	('inhibition', 'Var', (35, 45))	('EGFR', 'Gene', '1956', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('blocking', 'NegReg', (150, 158))
490970	33665161	The key proteins in the NF-kappaB pathway (e.g., p50, p52, and Rel) were overexpressed in patients with OSCC.	('NF-kappaB pathway', 'Pathway', (24, 41))	('p52', 'Var', (54, 57))	('overexpressed', 'PosReg', (73, 86))	('p50', 'Var', (49, 52))	('Rel', 'MPA', (63, 66))	('patients', 'Species', '9606', (90, 98))	('OSCC', 'Disease', (104, 108))
490971	33665161	In addition, the aberrant activation of the NF-kappaB signaling pathway is a significant predictor for prognosis and recurrence of OSCC, which makes it a potential target in the treatment of patients with OSCC.	('aberrant', 'Var', (17, 25))	('patients', 'Species', '9606', (191, 199))	('OSCC', 'Disease', (131, 135))	('NF-kappaB signaling pathway', 'Pathway', (44, 71))	('activation', 'PosReg', (26, 36))
490973	33665161	Pristimerin demonstrated its anti-OSCC effects through the inhibition of NF-kappaB pathway by suppressing tumor necrosis factor alpha (TNFalpha)-induced Ikappa Balpha phosphorylation, p65 translocation, and the expression of NF-kappaB- dependent genes (e.g., p50, p52, and Rel).Furthermore, pristimerin inhibited cell proliferation, migration, invasion, induced apoptosis, and eliminated cancer stem-like cells (CSCs) derived from OSCC cells.	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('invasion', 'CPA', (344, 352))	('pristimerin', 'Var', (291, 302))	('eliminated', 'NegReg', (377, 387))	('TNFalpha', 'Gene', (135, 143))	('tumor necrosis factor alpha', 'Gene', '7124', (106, 133))	('cancer', 'Disease', (388, 394))	('inhibited', 'NegReg', (303, 312))	('apoptosis', 'CPA', (362, 371))	('pristimerin', 'Chemical', 'MESH:C009043', (291, 302))	('p65', 'Gene', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('induced', 'Reg', (354, 361))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cell proliferation', 'CPA', (313, 331))	('p65', 'Gene', '5970', (184, 187))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('tumor necrosis factor alpha', 'Gene', (106, 133))	('TNFalpha', 'Gene', '7124', (135, 143))
490975	33665161	These results imply that pristimerin could increase chemo-sensitivity by suppressing the therapy-resistant CSC cell population in OSCCs.	('pristimerin', 'Var', (25, 36))	('pristimerin', 'Chemical', 'MESH:C009043', (25, 36))	('chemo-sensitivity', 'MPA', (52, 69))	('increase', 'PosReg', (43, 51))	('suppressing', 'NegReg', (73, 84))	('therapy-resistant CSC cell population', 'CPA', (89, 126))
490976	33665161	Depending on the roles of their target genes, miRNAs can act either as tumor suppressors or oncogenes.	('miRNAs', 'Var', (46, 52))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
490986	33665161	Since miR-203 and Bmi-1 were inversely expressed in SP cells, Bmi-1 might be a direct target of miR-203, thus therapeutics targeting miR-203 or Bmi-1could have the potential to eradicate CSCs in OSCC.	('SP', 'Chemical', '-', (52, 54))	('eradicate', 'NegReg', (177, 186))	('CSCs', 'Disease', (187, 191))	('OSCC', 'Disease', (195, 199))	('miR-203', 'Var', (96, 103))
490987	33665161	Another miRNA, miR-181b in association with STAT3, plays a significant role in stem cell properties of esophageal squamous cell carcinoma stem-like cells.	('stem cell properties of', 'CPA', (79, 102))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (103, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal squamous cell carcinoma', 'Disease', (103, 137))	('STAT3', 'Gene', '6774', (44, 49))	('STAT3', 'Gene', (44, 49))	('miR-181b', 'Var', (15, 23))
490989	33665161	The sphere-forming cells demonstrated cancer stem-like cell properties such as an enhanced population of CD44+/CD24- cells, increased stemness factors, mesenchymal marker expression, ATP-binding cassette (ABC) transporters and tumorigenicity in vivo when compared to that of parental cells.	('ATP-binding cassette', 'MPA', (183, 203))	('enhanced', 'PosReg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Disease', (227, 232))	('increased', 'PosReg', (124, 133))	('stemness factors', 'CPA', (134, 150))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('mesenchymal marker expression', 'CPA', (152, 181))	('cancer', 'Disease', (38, 44))	('CD44+/CD24-', 'Var', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
490995	33665161	However, exogenous overexpression of miR-135a or silencing of SMO decreased the expression of Gli1, Gli2, and Shh, resulting in reduced proliferation migration, invasion and increased apoptosis of CSCs derived from esophageal cancer cells.	('miR-135a', 'Chemical', '-', (37, 45))	('SMO', 'Gene', (62, 65))	('silencing', 'Var', (49, 58))	('Gli1', 'Gene', (94, 98))	('decreased', 'NegReg', (66, 75))	('proliferation migration', 'CPA', (136, 159))	('overexpression', 'PosReg', (19, 33))	('Shh', 'Gene', (110, 113))	('reduced', 'NegReg', (128, 135))	('invasion', 'CPA', (161, 169))	('Gli2', 'Gene', (100, 104))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('expression', 'MPA', (80, 90))	('Shh', 'Gene', '6469', (110, 113))	('Gli1', 'Gene', '2735', (94, 98))	('apoptosis', 'CPA', (184, 193))	('SMO', 'Gene', '6608', (62, 65))	('Gli2', 'Gene', '2736', (100, 104))	('cancer', 'Disease', (226, 232))	('miR-135a', 'Var', (37, 45))	('increased', 'PosReg', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
490996	33665161	Interestingly, silencing of miR-135a was associated with increased carcinogenic capability of miR-135a in CSCs derived from OSCC.	('carcinogenic', 'Disease', 'MESH:D063646', (67, 79))	('carcinogenic', 'Disease', (67, 79))	('miR-135a', 'Gene', (28, 36))	('miR-135a', 'Chemical', '-', (28, 36))	('silencing', 'Var', (15, 24))	('miR-135a', 'Gene', (94, 102))	('increased', 'PosReg', (57, 66))	('miR-135a', 'Chemical', '-', (94, 102))
491005	33665161	Also, dysregulation of miR-455-3ppromoted chemoresistance and tumorigenesis of OSCC cells.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('miR-455-3p', 'Chemical', '-', (23, 33))	('tumor', 'Disease', (62, 67))	('dysregulation', 'Var', (6, 19))	('chemoresistance', 'CPA', (42, 57))	('miR-455-3ppromoted', 'Gene', (23, 41))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
491006	33665161	Interestingly, treatment with a miR-455-3p antagomir significantly chemo-sensitized OSCC cells and decreased CD90+ and CD271 + cell populations (a CSC phenotype) through inhibition of various stemness-associated pathways including Wnt/beta-catenin and TGF- beta signaling.	('miR-455-3p', 'Chemical', '-', (32, 42))	('decreased', 'NegReg', (99, 108))	('CD271', 'Gene', '4804', (119, 124))	('miR-455-3p', 'Var', (32, 42))	('TGF- beta', 'Gene', (252, 261))	('inhibition', 'NegReg', (170, 180))	('CD271', 'Gene', (119, 124))	('OSCC', 'Disease', (84, 88))	('TGF- beta', 'Gene', '7039', (252, 261))	('beta-catenin', 'Gene', (235, 247))	('stemness-associated', 'CPA', (192, 211))	('beta-catenin', 'Gene', '1499', (235, 247))
491018	33665161	Importantly, miR-221 knockdown in 5-FU resistant cells resulted in decreased cell proliferation, increased apoptosis, restored chemo-sensitivity, and led to inactivation of the stem cell pathway Wnt/beta-catenin by activation of DKK2 activity.	('activity', 'MPA', (234, 242))	('beta-catenin', 'Gene', '1499', (199, 211))	('increased', 'PosReg', (97, 106))	('chemo-sensitivity', 'MPA', (127, 144))	('activation', 'PosReg', (215, 225))	('5-FU', 'Chemical', 'MESH:D005472', (34, 38))	('miR-221', 'Gene', '407006', (13, 20))	('restored', 'PosReg', (118, 126))	('miR-221', 'Gene', (13, 20))	('DKK2', 'Gene', '27123', (229, 233))	('knockdown', 'Var', (21, 30))	('decreased', 'NegReg', (67, 76))	('apoptosis', 'CPA', (107, 116))	('DKK2', 'Gene', (229, 233))	('beta-catenin', 'Gene', (199, 211))	('cell proliferation', 'CPA', (77, 95))	('inactivation', 'NegReg', (157, 169))
491021	33665161	Furthermore, a substantial dysregulation of Wnt/beta-catenin signaling and chemoresistance target genes such as CDH1, CD44, MYC, and ABCG2 was reported as a result of miR-221 modulation in OAC.	('beta-catenin', 'Gene', (48, 60))	('CD44', 'Gene', (118, 122))	('MYC', 'Gene', '4609', (124, 127))	('MYC', 'Gene', (124, 127))	('miR-221', 'Gene', '407006', (167, 174))	('OAC', 'Disease', (189, 192))	('beta-catenin', 'Gene', '1499', (48, 60))	('modulation', 'Var', (175, 185))	('ABCG2', 'Gene', (133, 138))	('miR-221', 'Gene', (167, 174))	('CDH1', 'Gene', (112, 116))	('ABCG2', 'Gene', '9429', (133, 138))	('dysregulation', 'MPA', (27, 40))	('CDH1', 'Gene', '999', (112, 116))
491026	33665161	On the other hand, inhibition of HIF1alpha resulted in suppression of tumorigenicity of OSCC cells in both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('suppression', 'NegReg', (55, 66))	('inhibition', 'Var', (19, 29))	('HIF1alpha', 'Gene', '3091', (33, 42))	('tumor', 'Disease', (70, 75))	('HIF1alpha', 'Gene', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
491031	33665161	A significant reduction of cell proliferation, migration and tumor growth was occurred followed by HIF-1alpha knockdown in OSCC cells in vivo.	('knockdown', 'Var', (110, 119))	('cell proliferation', 'CPA', (27, 45))	('HIF-1alpha', 'Gene', '3091', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('migration', 'CPA', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('HIF-1alpha', 'Gene', (99, 109))	('reduction', 'NegReg', (14, 23))	('tumor', 'Disease', (61, 66))
491032	33665161	In addition, knockdown of HIF-1alpha also inhibited spheroid formation, inhibited expression of CSC-related genes and Wnt/beta-catenin target genes, thereby decreased Wnt/beta-catenin activity CSCs derived from OSCC.	('spheroid formation', 'CPA', (52, 70))	('beta-catenin', 'Gene', (122, 134))	('beta-catenin', 'Gene', '1499', (171, 183))	('HIF-1alpha', 'Gene', '3091', (26, 36))	('expression', 'MPA', (82, 92))	('beta-catenin', 'Gene', '1499', (122, 134))	('inhibited', 'NegReg', (42, 51))	('CSC-related genes', 'Gene', (96, 113))	('decreased', 'NegReg', (157, 166))	('HIF-1alpha', 'Gene', (26, 36))	('inhibited', 'NegReg', (72, 81))	('beta-catenin', 'Gene', (171, 183))	('knockdown', 'Var', (13, 22))
491033	33665161	Therefore, targeting hypoxia or its related factor and at the same time, inhibiting Wnt/beta-catenin might be an attractive option against patients with both OSCC and OAC.	('patients', 'Species', '9606', (139, 147))	('OAC', 'Disease', (167, 170))	('hypoxia', 'Disease', 'MESH:D000860', (21, 28))	('inhibiting', 'Var', (73, 83))	('hypoxia', 'Disease', (21, 28))	('beta-catenin', 'Gene', (88, 100))	('OSCC', 'Disease', (158, 162))	('beta-catenin', 'Gene', '1499', (88, 100))
491057	32662535	The c-index for the gene-environment interaction model (0.71) was slightly higher than that for the environmental model (0.67).	('gene-environment', 'Var', (20, 36))	('c-index', 'MPA', (4, 11))	('men', 'Species', '9606', (107, 110))	('higher', 'PosReg', (75, 81))	('men', 'Species', '9606', (32, 35))
491058	32662535	The values of integrated discrimination improvement and net reclassification improvement for the gene-environment interaction model were also slightly higher than those for the environmental model.	('integrated discrimination', 'MPA', (14, 39))	('gene-environment', 'Var', (97, 113))	('higher', 'PosReg', (151, 157))	('improvement', 'PosReg', (40, 51))	('men', 'Species', '9606', (84, 87))	('men', 'Species', '9606', (184, 187))	('men', 'Species', '9606', (47, 50))	('men', 'Species', '9606', (109, 112))
491068	32662535	7 ,  8   A good example is the gene-environment interaction between alcohol consumption and aldehyde dehydrogenase 2 (ALDH2) genotype on the risk of upper aerodigestive tract cancer.	('genotype', 'Var', (125, 133))	('ALDH2', 'Gene', (118, 123))	('aldehyde dehydrogenase 2', 'Gene', '217', (92, 116))	('aldehyde dehydrogenase 2', 'Gene', (92, 116))	('alcohol', 'Chemical', 'MESH:D000438', (68, 75))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('men', 'Species', '9606', (43, 46))	('ALDH2', 'Gene', '217', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
491082	32662535	Upper aerodigestive tract cancer was defined according to the following codes of the International Classification of Diseases for Oncology, Third Edition: oral cavity (C00-C08), pharynx (C10-C13), esophagus (C15), and larynx (C32).	('oral cavity', 'Disease', (155, 166))	('C15', 'Gene', '51316', (208, 211))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('C32', 'Gene', (226, 229))	('Oncology', 'Phenotype', 'HP:0002664', (130, 138))	('C15', 'Gene', (208, 211))	('C32', 'Gene', '51192', (226, 229))	('pharynx', 'Disease', (178, 185))	('C00-C08', 'Var', (168, 175))	('larynx', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('esophagus', 'Disease', (197, 206))	('C10-C13', 'Var', (187, 194))
491089	32662535	In the present study, we extracted genotyping information on rs671 (ALDH2 Glu504Lys) from the above data.	('Glu504Lys', 'Var', (74, 83))	('rs671', 'Mutation', 'rs671', (61, 66))	('ALDH2', 'Gene', '217', (68, 73))	('Glu504Lys', 'SUBSTITUTION', 'None', (74, 83))	('ALDH2', 'Gene', (68, 73))	('rs671', 'Gene', (61, 66))
491096	32662535	The risk category of NRI was arbitrarily defined as <0.25%, 0.25%<= & <1%, and >=1% 10-year absolute risk of developing upper aerodigestive tract cancer.	('0.25%', 'Var', (60, 65))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('developing upper aerodigestive tract', 'Disease', (109, 145))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
491100	32662535	Increasing age, smoking, and alcohol consumption were significantly associated with increased risk of upper aerodigestive tract cancer in the environmental model.	('alcohol consumption', 'Var', (29, 48))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('alcohol', 'Chemical', 'MESH:D000438', (29, 36))	('men', 'Species', '9606', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
491102	32662535	Compared with subjects who were nondrinkers or drank less than 5 days per week or 23 g of ethanol per day, regardless of the ALDH2 genotype, the HR (95% CI) was 6.00 (3.53-10.19) among subjects who drank 5 days or more per week and more than 23 g of ethanol per day and had the Glu/Lys or Lys/Lys genotype.	('ethanol', 'Chemical', 'MESH:D000431', (90, 97))	('Lys', 'Chemical', 'MESH:D008239', (289, 292))	('Lys', 'Chemical', 'MESH:D008239', (293, 296))	('Lys', 'Chemical', 'MESH:D008239', (282, 285))	('Glu', 'Chemical', 'MESH:D018698', (278, 281))	('Glu/Lys', 'Var', (278, 285))	('ethanol', 'Chemical', 'MESH:D000431', (250, 257))	('ALDH2', 'Gene', '217', (125, 130))	('ALDH2', 'Gene', (125, 130))
491108	32662535	Similarly, the gene-environment interaction model for esophageal cancer also improved the model discriminations assessed by the NRI and IDI compared to the environmental model, and the two models were well calibrated (data not shown).	('men', 'Species', '9606', (163, 166))	('cancer', 'Disease', (65, 71))	('gene-environment', 'Var', (15, 31))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('model', 'MPA', (90, 95))	('men', 'Species', '9606', (27, 30))	('improved', 'PosReg', (77, 85))
491113	32662535	Of note, the 10-year absolute risks substantially differed between subjects who had the Glu/Glu genotype and Glu/Lys or Lys/Lys genotype among subjects who drank 5 days or more per week and more than 23 g of ethanol per day (eg, 1.59% vs 6.05% for current smokers at age 60 years or older).	('Lys', 'Chemical', 'MESH:D008239', (124, 127))	('Glu/Lys or Lys/Lys', 'Var', (109, 127))	('ethanol', 'Chemical', 'MESH:D000431', (208, 215))	('Glu', 'Chemical', 'MESH:D018698', (88, 91))	('Glu', 'Chemical', 'MESH:D018698', (92, 95))	('Lys', 'Chemical', 'MESH:D008239', (113, 116))	('Glu', 'Chemical', 'MESH:D018698', (109, 112))	('Lys', 'Chemical', 'MESH:D008239', (120, 123))	('differed', 'Reg', (50, 58))	('Glu/Glu', 'Var', (88, 95))
491168	32239662	However, surgical blood loss of the MISE group was less than that of the OSE group (P < 0.001), and the MISE group had a significantly shorter chest tube duration and postoperative admission duration than the OSE group (P = 0.003 and P = 0.002, respectively) (Table 2).	('blood loss of the MISE', 'Disease', (18, 40))	('OSE', 'Chemical', '-', (209, 212))	('blood loss of the MISE', 'Disease', 'MESH:D006473', (18, 40))	('MISE', 'Var', (104, 108))	('less', 'NegReg', (51, 55))	('chest tube duration', 'CPA', (143, 162))	('OSE', 'Chemical', '-', (73, 76))	('shorter', 'NegReg', (135, 142))
491193	32239662	Some studies have demonstrated that the incidence of respiratory complications was significantly lower with MIE than that with open esophagectomy (OE).12, 16, 17, 18 Straatman et al.12 conducted a randomized controlled trial to compare MIE with OE to treat patients with esophageal cancer and found significantly fewer pulmonary infections after MIE compared with those after OE.	('fewer', 'NegReg', (313, 318))	('esophageal cancer', 'Disease', (271, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('esophageal cancer', 'Disease', 'MESH:D004938', (271, 288))	('patients', 'Species', '9606', (257, 265))	('pulmonary infections', 'Disease', 'MESH:D012141', (319, 339))	('MIE', 'Var', (346, 349))	('pulmonary infections', 'Disease', (319, 339))	('respiratory complications', 'Phenotype', 'HP:0011947', (53, 78))	('pulmonary infections', 'Phenotype', 'HP:0006532', (319, 339))
491249	31839807	Outcome measures were the rates of T0N0 specimens, overall survival, disease-free and cancer-specific survival, postoperative morbidity and mortality.	('men', 'Species', '9606', (45, 48))	('mortality', 'Disease', 'MESH:D003643', (140, 149))	('T0N0', 'Var', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mortality', 'Disease', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
491273	31839807	Endoscopic mucosal resection was performed for SCC smaller than 10 mm and for Paris 0-IIa and 0-IIb EAC, that is, without endoscopic suspicion of deep submucosal invasion.	('0-IIb', 'Var', (94, 99))	('SCC', 'Gene', (47, 50))	('EAC', 'Chemical', '-', (100, 103))	('SCC', 'Gene', '6317', (47, 50))
491371	29863169	The effect of body mass index (BMI) on oncological outcomes after major resection for cancer has also been investigated.20, 21, 22, 23 Although the majority of the studies show a significant association between high BMI and postoperative morbidity, the association of BMI with long-term oncological outcomes is still controversial.	('high', 'Var', (211, 215))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('postoperative', 'Disease', (224, 237))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
491388	29863169	have concluded that surgical complications might be independent predictors of poor long-term survival in patients undergoing esophageal cancer resection, including patients who survived the postoperative period.31, 32 This large, population-based, nationwide cohort study has shown that re-operation within 30 days of primary esophageal resection is associated with increased mortality, even when the initial 3 months after surgery is excluded.	('patients', 'Species', '9606', (105, 113))	('esophageal cancer', 'Disease', (125, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('patients', 'Species', '9606', (164, 172))	('re-operation', 'Var', (287, 299))	('mortality', 'MPA', (376, 385))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
491424	29863169	Interestingly, Chen et al.63 have concluded that high-BMI patients exhibit paradoxically 'superior' survival outcomes compared with normal-BMI patients despite the higher risk of mild postoperative complications.	('survival outcomes', 'CPA', (100, 117))	('patients', 'Species', '9606', (143, 151))	('high-BMI', 'Var', (49, 57))	("'superior'", 'PosReg', (89, 99))	('patients', 'Species', '9606', (58, 66))
491426	29863169	Pan et al.64 reported that high BMI has distinctly different effects on postoperative survival of esophageal adenocarcinoma and esophageal squamous cell carcinoma patients.	('patients', 'Species', '9606', (163, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (128, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (98, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('esophageal adenocarcinoma', 'Disease', (98, 123))	('high BMI', 'Var', (27, 35))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (98, 123))	('esophageal squamous cell carcinoma', 'Disease', (128, 162))
491427	29863169	Overall, high BMI is a potential predictor of improved prognosis in esophageal cancer patients, particularly in esophageal adenocarcinoma patients treated with curative esophagectomy.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('BMI', 'MPA', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (86, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (112, 137))	('esophageal adenocarcinoma', 'Disease', (112, 137))	('improved', 'PosReg', (46, 54))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (112, 137))	('esophageal cancer', 'Disease', (68, 85))	('patients', 'Species', '9606', (138, 146))	('high', 'Var', (9, 13))
491435	29863169	However, better OS observed in patients having high BMI compared with those having low BMI might be attributed to a relatively low pathological stage.	('patients', 'Species', '9606', (31, 39))	('OS', 'Chemical', '-', (16, 18))	('high BMI', 'Var', (47, 55))	('better', 'PosReg', (9, 15))	('low BMI', 'Phenotype', 'HP:0045082', (83, 90))
491436	29863169	have revealed that a BMI <20 is associated with reduced OS and DFS after laparoscopic resection.69 Adachi et al.70 demonstrated in elderly (>=80 years) colorectal cancer patients (stage 0 to III) that a BMI <18.5 is associated with decreased OS and cancer-specific survival.	('patients', 'Species', '9606', (170, 178))	('OS', 'Chemical', '-', (56, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('decreased OS', 'Disease', 'MESH:C567932', (232, 244))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancer', 'Disease', (249, 255))	('OS', 'Chemical', '-', (242, 244))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('BMI <18.5', 'Var', (203, 212))	('colorectal cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('decreased OS', 'Disease', (232, 244))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (163, 169))
491437	29863169	Uratani et al.71 studied stage I-III patients undergoing laparoscopic resection and found that a BMI <20 is correlated with reduced DFS and OS.	('reduced', 'NegReg', (124, 131))	('patients', 'Species', '9606', (37, 45))	('OS', 'Chemical', '-', (140, 142))	('BMI <20', 'Var', (97, 104))	('DFS', 'Disease', (132, 135))
491445	29863169	Perioperative steroid therapy reduces postoperative morbidity but does not improve long-term survival in patients with thoracic esophageal cancer.15, 16, 74 Early administration of sivelestat in patients receiving radical surgery for esophageal cancer can inhibit postoperative systemic inflammatory reactions, and it might also have a beneficial effect on prognosis.75, 76 Some of the examined factors did not differ between the treated and control groups, including IL-8 on postoperative day 1, IL-6 before the surgery and on postoperative day 5, PaO2/FiO2 following the surgery, mortality, anastomotic leakage, severe infection, and renal and hepatic failure.	('infection', 'Disease', (621, 630))	('renal and hepatic failure', 'Disease', 'MESH:D051437', (636, 661))	('infection', 'Disease', 'MESH:D007239', (621, 630))	('esophageal cancer', 'Disease', 'MESH:D004938', (234, 251))	('severe', 'Disease', (614, 620))	('IL-6', 'Gene', '3569', (497, 501))	('esophageal cancer', 'Disease', (234, 251))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (119, 145))	('IL-6', 'Gene', (497, 501))	('severe infection', 'Phenotype', 'HP:0032169', (614, 630))	('anastomotic leak', 'Disease', (593, 609))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('patients', 'Species', '9606', (195, 203))	('IL-8', 'Gene', (468, 472))	('patients', 'Species', '9606', (105, 113))	('anastomotic leak', 'Disease', 'MESH:D057868', (593, 609))	('steroid', 'Chemical', 'MESH:D013256', (14, 21))	('thoracic esophageal cancer', 'Disease', (119, 145))	('hepatic failure', 'Phenotype', 'HP:0001399', (646, 661))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('IL-8', 'Gene', '3576', (468, 472))	('PaO2/FiO2', 'Var', (549, 558))
491503	29284962	There are three main competing hypotheses to explain the relation between low cholesterol and oral cancer.	('low cholesterol', 'Var', (74, 89))	('cholesterol', 'Chemical', 'MESH:D002784', (78, 89))	('oral cancer', 'Disease', 'MESH:D009062', (94, 105))	('oral cancer', 'Disease', (94, 105))	('low cholesterol', 'Phenotype', 'HP:0003146', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
491504	29284962	(a) Low cholesterol may be an indicator of cancer process even before cancer manifests clinically.	('Low', 'Var', (4, 7))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Low cholesterol', 'Phenotype', 'HP:0003146', (4, 19))	('cholesterol', 'Chemical', 'MESH:D002784', (8, 19))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))
491505	29284962	(b) Low cholesterol serves as a marker for some other causal sets of variables, and its association with oral cancer may be secondary even though if it precedes cancer.	('Low', 'Var', (4, 7))	('cancer', 'Disease', (110, 116))	('oral cancer', 'Disease', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('oral cancer', 'Disease', 'MESH:D009062', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('Low cholesterol', 'Phenotype', 'HP:0003146', (4, 19))	('cancer', 'Disease', (161, 167))	('cholesterol', 'Chemical', 'MESH:D002784', (8, 19))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
491506	29284962	(c) Low cholesterol levels may precede the development of cancer and may be causally associated with some forms of cancer.	('Low', 'Var', (4, 7))	('cancer', 'Disease', (115, 121))	('Low cholesterol levels', 'Phenotype', 'HP:0003146', (4, 26))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cholesterol levels', 'MPA', (8, 26))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('Low cholesterol', 'Phenotype', 'HP:0003146', (4, 19))	('cancer', 'Disease', (58, 64))	('cholesterol', 'Chemical', 'MESH:D002784', (8, 19))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('associated', 'Reg', (85, 95))
491567	28656204	After the tumors were removed, the mRNA expression levels of mTOR, p70S6K, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), cellular inhibitor of apoptosis protein 1 (cIAP1) and caspase-3 were detected by RT-PCR.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('4E-binding protein 1', 'Gene', (116, 136))	('4E-binding protein 1', 'Gene', '13685', (116, 136))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('cellular inhibitor of apoptosis protein 1', 'Gene', (146, 187))	('p70S6K', 'Var', (67, 73))	('cellular inhibitor of apoptosis protein 1', 'Gene', '11796', (146, 187))	('mRNA expression levels', 'MPA', (35, 57))
491568	28656204	In addition, we performed western blot analysis and immunohistochemical analysis to determine the protein expression of mTOR, p70S6K, 4EBP1, cIAP1, active caspase-3, Bcl-2 and Bad in the tumor tissue.	('Bcl-2', 'Gene', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('Bcl-2', 'Gene', '12043', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cIAP1', 'Gene', (141, 146))	('tumor', 'Disease', (187, 192))	('mTOR', 'Gene', (120, 124))	('4EBP1', 'Gene', (134, 139))	('p70S6K', 'Var', (126, 132))
491582	28656204	p70S6K is the main downstream target of mTOR which make an important role in the translation initiation, protein synthesis, cell cycle, cell migration in the mTOR/p70S6K pathway.	('protein', 'MPA', (105, 112))	('p70S6K', 'Var', (0, 6))	('translation', 'MPA', (81, 92))	('cell cycle', 'CPA', (124, 134))	('rat', 'Species', '10116', (144, 147))	('cell migration', 'CPA', (136, 150))
491583	28656204	The dysregulation of the pathway is associated with a variety of human diseases, including cancer, diabetes and leukemia.	('leukemia', 'Disease', (112, 120))	('leukemia', 'Phenotype', 'HP:0001909', (112, 120))	('leukemia', 'Disease', 'MESH:D007938', (112, 120))	('human', 'Species', '9606', (65, 70))	('cancer', 'Disease', (91, 97))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (36, 46))	('diabetes', 'Disease', (99, 107))
491596	28656204	Rabbit anti-mTOR (1612-1), p70S6K (T2921), p-p70S6K (ab2571), 4EBP1 (1557-1), p-4EBP1 (2250-1), cIAP1 (3302-1), Bad (1541-1), Bcl-2 (1017-1) and beta-actin monoclonal antibodies, and rat anti-active caspase-3 monoclonal antibody (1476-1) were obtained from Epitomics (Burlingame, CA, USA).	('rat', 'Species', '10116', (183, 186))	('Rabbit', 'Species', '9986', (0, 6))	('p70S6K', 'Var', (27, 33))	('beta-actin', 'Gene', '11461', (145, 155))	('Bcl-2', 'Gene', (126, 131))	('Bcl-2', 'Gene', '12043', (126, 131))	('p-p70S6K', 'Var', (43, 51))	('beta-actin', 'Gene', (145, 155))
491616	28656204	The primers for mTOR, p70S6K, 4EBP1, cAIP1, caspase-3 primers were verified by NCBI and beta-actin was used as an internal reference gene.	('beta-actin', 'Gene', (88, 98))	('beta-actin', 'Gene', '11461', (88, 98))	('p70S6K', 'Var', (22, 28))	('mTOR', 'Gene', (16, 20))	('caspase-3', 'Gene', (44, 53))
491621	28656204	The membranes were then incubated with the primary antibodies, mTOR, p70S6K, p-p70S6K, 4EBP1, p-4EBP1, cIAP1, active caspase-3, Bad and Bcl-2 (dilution, 1:2,000), diluted in TBST overnight at 4 C in a shaker.	('p-p70S6K', 'Var', (77, 85))	('p-4EBP1', 'Var', (94, 101))	('p70S6K', 'Var', (69, 75))	('TBST', 'Chemical', '-', (174, 178))	('Bcl-2', 'Gene', (136, 141))	('Bcl-2', 'Gene', '12043', (136, 141))
491623	28656204	This was followed by the addition of antibodies (mTOR, p70S6K, p-p70S6K, 4EBP1, p-4EBP1, cIAP1, active caspase-3, Bcl-2 and Bad) to the slices and incubation at room temperature for 150 min, paying attention to ensure that the antibodies were in full contact with the tissues.	('Bcl-2', 'Gene', '12043', (114, 119))	('p-p70S6K', 'Var', (63, 71))	('Bcl-2', 'Gene', (114, 119))	('p70S6K', 'Var', (55, 61))	('rat', 'Species', '10116', (171, 174))	('p-4EBP1', 'Var', (80, 87))
491624	28656204	We determined the location of mTOR, p70S6K, p-p70S6K, 4EBP1, p-4EBP1, cIAP1, active caspase-3, Bcl-2 and Bad on the cell membrane, nucleus or cytoplasm.	('p-4EBP1', 'Var', (61, 68))	('cIAP1', 'Gene', (70, 75))	('4EBP1', 'Gene', (54, 59))	('p70S6K', 'Var', (36, 42))	('Bcl-2', 'Gene', '12043', (95, 100))	('Bcl-2', 'Gene', (95, 100))	('mTOR', 'Gene', (30, 34))	('p-p70S6K', 'Var', (44, 52))
491629	28656204	The tumor size of the mice in each group (model, BL, BM, BH, RAPA and BR) was 1.778+-0.176, 1.714+-0.188, 1.115+-0.124, 0.713+-0.122, 0.699+-0.079 and 0.506+-0.076 cm3, respectively and the tumor inhibition rate was 4.1, 37.6, 60.1, 60.9 and 71.7%, respectively (Fig.	('tumor', 'Disease', (4, 9))	('0.713+-0.122', 'Var', (120, 132))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('rat', 'Species', '10116', (207, 210))	('BR', 'Chemical', 'MESH:D001966', (70, 72))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('RAPA', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mice', 'Species', '10090', (22, 26))	('RAPA', 'Gene', '224829', (61, 65))
491639	28656204	The protein expression levels of mTOR, p-p70S6K, p-4EBP1, cIAP1 and Bcl-2 gradually decreased in the treatment groups (BL, BM, BH, RAPA and BR) compared to the model group.	('Bcl-2', 'Gene', '12043', (68, 73))	('cIAP1', 'Gene', (58, 63))	('RAPA', 'Gene', (131, 135))	('p-4EBP1', 'Var', (49, 56))	('RAPA', 'Gene', '224829', (131, 135))	('protein expression levels', 'MPA', (4, 29))	('BR', 'Chemical', 'MESH:D001966', (140, 142))	('mTOR', 'MPA', (33, 37))	('decreased', 'NegReg', (84, 93))	('Bcl-2', 'Gene', (68, 73))	('p-p70S6K', 'Var', (39, 47))
491642	28656204	The immunoreactive scores for mTOR, p-p70S6K, p-4EBP1, cIAP1 and Bcl-2 gradually decreased in each treatment group (BL, BM, BH, RAPA and BR) (Fig.	('decreased', 'NegReg', (81, 90))	('RAPA', 'Gene', (128, 132))	('immunoreactive', 'MPA', (4, 18))	('p-4EBP1', 'Gene', (46, 53))	('RAPA', 'Gene', '224829', (128, 132))	('cIAP1', 'Gene', (55, 60))	('BR', 'Chemical', 'MESH:D001966', (137, 139))	('p-p70S6K', 'Var', (36, 44))	('Bcl-2', 'Gene', (65, 70))	('mTOR', 'Gene', (30, 34))	('Bcl-2', 'Gene', '12043', (65, 70))
491644	28656204	The immunoreactive scores for p70S6K, 4EBP1 did not differ significantly between the groups (model, BL, BM, BH, RAPA and BR (P>0.05) (Fig.	('RAPA', 'Gene', (112, 116))	('BR', 'Chemical', 'MESH:D001966', (121, 123))	('p70S6K', 'Var', (30, 36))	('4EBP1', 'Gene', (38, 43))	('RAPA', 'Gene', '224829', (112, 116))
491667	28656204	The second is responsible for the regulation of kinase activity at the C-terminus (Ser411, Ser424, Ser418 and Thr421).	('Thr421', 'Chemical', '-', (110, 116))	('Ser411', 'Chemical', '-', (83, 89))	('Ser424', 'Var', (91, 97))	('Ser418', 'Chemical', '-', (99, 105))	('Thr421', 'Var', (110, 116))	('Ser424', 'Chemical', '-', (91, 97))	('Ser418', 'Var', (99, 105))	('Ser411', 'Var', (83, 89))
491674	28656204	The results from western blot analysis and immunohistochemistry indicated that the expression of p-p70S6K and p-4EBP1 decreased following treatment with bufalin and/or rapamycin.	('bufalin', 'Chemical', 'MESH:C022777', (153, 160))	('p-p70S6K', 'Var', (97, 105))	('p-4EBP1', 'Var', (110, 117))	('decreased', 'NegReg', (118, 127))	('expression', 'MPA', (83, 93))	('rapamycin', 'Chemical', 'MESH:D020123', (168, 177))
491680	28656204	The results of RT-PCR demonstrated that the mRNA expression levels of p70S6K, 4EBP1 were not significantly altered in each group.	('p70S6K', 'Var', (70, 76))	('4EBP1', 'Gene', (78, 83))	('rat', 'Species', '10116', (29, 32))
491724	27853740	When endotherapy is used to seal the perforation, stenting across the gastroesophageal junction does increase the risk of a life threatening aspiration.	('gastroesophageal junction', 'Disease', (70, 95))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (70, 95))	('stenting', 'Var', (50, 58))	('aspiration', 'Phenotype', 'HP:0002835', (141, 151))
491730	26897248	This study aimed to assess the use of p75NTR in detecting circulating tumor cells (CTCs) in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ESCC', 'Disease', (92, 96))	('tumor', 'Disease', (70, 75))	('p75NTR', 'Var', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
491731	26897248	Peripheral blood mononuclear cell expression of epithelial cell adhesion molecule (EpCAM) and p75NTR was detected in 23 ESCC patients (13 received chemo- or chemoradiotherapy and 10 received curative surgery) and 10 healthy controls by flow cytometry.	('p75NTR', 'Var', (94, 100))	('epithelial cell adhesion molecule', 'Gene', (48, 81))	('ESCC', 'Disease', (120, 124))	('epithelial cell adhesion molecule', 'Gene', '4072', (48, 81))	('patients', 'Species', '9606', (125, 133))
491734	26897248	EpCAM + p75NTR+, but not EpCAM + p75NTR- cell counts, correlated with clinically diagnosed distant metastasis (n = 13, p = 0.006) and pathological venous invasion in resected primary tumors (n = 10, p = 0.016).	('pathological venous invasion', 'CPA', (134, 162))	('primary tumors', 'Disease', 'MESH:D009369', (175, 189))	('EpCAM + p75NTR+', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('distant metastasis', 'CPA', (91, 109))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('primary tumors', 'Disease', (175, 189))
491745	26897248	A recent report demonstrated that p75NTR-positive cells in ESCC cell lines showed significantly higher colony formation, enhanced tumor formation in mice, and greater chemoresistance, along with stronger expression of epithelial mesenchymal transition (EMT)-related genes.	('epithelial', 'Gene', (218, 228))	('p75NTR-positive', 'Var', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('enhanced', 'PosReg', (121, 129))	('stronger', 'PosReg', (195, 203))	('greater', 'PosReg', (159, 166))	('mice', 'Species', '10090', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('chemoresistance', 'CPA', (167, 182))	('expression', 'MPA', (204, 214))	('higher', 'PosReg', (96, 102))	('tumor', 'Disease', (130, 135))	('colony formation', 'CPA', (103, 119))
491746	26897248	The aim of this study was to detect CTCs in the peripheral blood of ESCC patients using combined expression of EpCAM, CD44, and p75NTR to assess its clinical significance.	('CD44', 'Gene', '960', (118, 122))	('CD44', 'Gene', (118, 122))	('ESCC', 'Disease', (68, 72))	('EpCAM', 'Protein', (111, 116))	('p75NTR', 'Var', (128, 134))	('patients', 'Species', '9606', (73, 81))
491770	26897248	EpCAM expression was detected in 100 and 100 % of KYSE30 and KYSE140, respectively.	('EpCAM expression', 'Protein', (0, 16))	('KYSE140', 'Var', (61, 68))	('KYSE140', 'CellLine', 'CVCL:1347', (61, 68))	('detected', 'Reg', (21, 29))	('KYSE30', 'Var', (50, 56))
491783	26897248	A representative figure of cells staining positive for EpCAM-APC (red) and p75NTR-FITC (green), in the cell membranes, is provided in Fig.	('p75NTR-FITC', 'Gene', (75, 86))	('EpCAM-APC', 'Var', (55, 64))	('p75NTR-FITC', 'Gene', '4804', (75, 86))
491785	26897248	The expression of p75NTR was detected in five (50.0 %) tumors, in which the first few layers nearest to the tumor's infiltrative margin exhibited positive staining (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('detected', 'Reg', (29, 37))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (55, 60))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('p75NTR', 'Var', (18, 24))
491786	26897248	There was no relationship between p75NTR expressions in primary tumors versus EpCAM+ cells of the peripheral blood.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('primary tumors', 'Disease', (56, 70))	('primary tumors', 'Disease', 'MESH:D009369', (56, 70))	('p75NTR', 'Var', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
491787	26897248	In this study, we detected CTCs by flow cytometry based on the combined expression of EpCAM and p75NTR in patients with ESCC.	('EpCAM', 'Protein', (86, 91))	('patients', 'Species', '9606', (106, 114))	('ESCC', 'Disease', (120, 124))	('p75NTR', 'Var', (96, 102))
491790	26897248	In addition, our results highlighted that EpCAM + p75NTR+, but not EpCAM + p75NTR- CTC counts, correlated with clinically diagnosed distant metastasis and pathological venous factors in the resected primary tumor, demonstrating the highly invasive and metastatic potential of CTCs with p75NTR expression.	('EpCAM + p75NTR+', 'Var', (42, 57))	('distant metastasis', 'CPA', (132, 150))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('correlated', 'Reg', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))
491798	26897248	A recent report from our laboratory demonstrated that 100 and 3000 cells were minimally required to establish colonies in vitro and mouse xenograft tumors, respectively, using p75NTR+ cells isolated from cultured KYSEs by flow cytometric cell sorting, suggesting decreased cell survival and recovery due to cell damage during isolation procedure.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('xenograft tumors', 'Disease', 'MESH:D009369', (138, 154))	('recovery', 'MPA', (291, 299))	('mouse', 'Species', '10090', (132, 137))	('decreased', 'NegReg', (263, 272))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('p75NTR+', 'Var', (176, 183))	('xenograft tumors', 'Disease', (138, 154))	('cell survival', 'CPA', (273, 286))
491799	26897248	Another possibility is that a small part (1/3000-1/100) of p75NTR+ cells are true CSCs which can establish colonies or xenograft tumors.	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('xenograft tumors', 'Disease', (119, 135))	('p75NTR+ cells', 'Var', (59, 72))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('xenograft tumors', 'Disease', 'MESH:D009369', (119, 135))
491806	26897248	This may suggest possible induction of p75NTR expression after mobilization of the metastatic cancer cells into systemic circulation.	('p75NTR', 'Var', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
491914	26269033	They concluded that nodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI and that IFRT significantly decreased esophageal toxicity in non-small cell carcinoma.	('esophageal toxicity', 'Disease', (168, 187))	('decreased', 'NegReg', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('ENI', 'Chemical', '-', (126, 129))	('IFRT', 'Var', (139, 143))	('esophageal toxicity', 'Disease', 'MESH:D004935', (168, 187))	('nodal failure', 'Disease', (20, 33))	('cell carcinoma', 'Disease', 'MESH:C538614', (201, 215))	('nodal failure', 'Disease', 'MESH:D013611', (20, 33))	('cell carcinoma', 'Disease', (201, 215))
358561	26269033	In a clinical study, combination chemotherapy using NDP and 5-FU has been reported to be a safe and effective method for treating advanced esophageal cancer.	('NDP', 'Var', (52, 55))	('esophageal cancer', 'Disease', (139, 156))	('NDP', 'Chemical', 'MESH:C053989', (52, 55))	('5-FU', 'Chemical', 'MESH:D005472', (60, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
491930	26269033	In the current study, grade 3-4 acute and sub-acute radiation-induced esophagitis was seen in 25 % of the ENI arm and in 10 % of the IFRT arm.	('ENI', 'Chemical', '-', (106, 109))	('esophagitis', 'Phenotype', 'HP:0100633', (70, 81))	('esophagitis', 'Disease', (70, 81))	('ENI', 'Var', (106, 109))	('esophagitis', 'Disease', 'MESH:D004941', (70, 81))
491932	26269033	In Table 1, there are more T1-2 patients in the ENI arm, whereas there are more T4 patients in the IFRT arm.	('patients', 'Species', '9606', (32, 40))	('ENI', 'Chemical', '-', (48, 51))	('ENI', 'Var', (48, 51))	('T1-2', 'Var', (27, 31))	('patients', 'Species', '9606', (83, 91))
491948	24196787	The combined expression of FSCN1 and MMP14 is associated with a poor prognosis, and miR-133a, which regulates their mRNAs, can serve as a strong tumour suppressor of ESCC.	('tumour', 'Disease', (145, 151))	('miR-133a', 'Var', (84, 92))	('miR-133a', 'Chemical', '-', (84, 92))	('MMP14', 'Gene', (37, 42))	('FSCN1', 'Gene', '6624', (27, 32))	('FSCN1', 'Gene', (27, 32))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('associated', 'Reg', (46, 56))	('ESCC', 'Disease', (166, 170))	('MMP14', 'Gene', '4323', (37, 42))
491953	24196787	In cancer cells, aberrantly expressed FSCN1 stabilises actin filaments in invasive foot structures termed invadopodia (Figure 1A).	('FSCN1', 'Gene', (38, 43))	('actin filaments', 'MPA', (55, 70))	('FSCN1', 'Gene', '6624', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('aberrantly expressed', 'Var', (17, 37))	('stabilises', 'PosReg', (44, 54))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
491999	24196787	After transfection of siFSCN1, siMMP14 or the miR-133a mimic, cells were plated in 96-well plates at 5 x 103 cells per well in 100 mul of medium containing 10% FBS.	('miR-133a', 'Chemical', '-', (46, 54))	('FSCN1', 'Gene', (24, 29))	('FSCN1', 'Gene', '6624', (24, 29))	('transfection', 'Var', (6, 18))	('siMMP14', 'Chemical', '-', (31, 38))	('FBS', 'Disease', (160, 163))	('FBS', 'Disease', 'MESH:D005198', (160, 163))
492016	24196787	Positive FSCN1 staining, positive MMP14 staining, the T stage and the N stage were identified as significant independent prognostic factors (Table 2).	('T stage', 'CPA', (54, 61))	('MMP14', 'Gene', '4323', (34, 39))	('positive', 'Var', (25, 33))	('FSCN1', 'Gene', (9, 14))	('FSCN1', 'Gene', '6624', (9, 14))	('MMP14', 'Gene', (34, 39))
492017	24196787	The introduction of each of the four siRNA sequences (siFSCN1-1, siFSCN1-2, siMMP14-1 and siMMP14-2) into T.Tn and TE2 cells led to a significant decrease of the target mRNA and a remarkable decrease in the amount of the target protein.	('TE2', 'Gene', (115, 118))	('siMMP14-1', 'Var', (76, 85))	('FSCN1', 'Gene', '6624', (56, 61))	('siMMP14', 'Chemical', '-', (90, 97))	('FSCN1', 'Gene', (56, 61))	('siMMP14', 'Chemical', '-', (76, 83))	('decrease', 'NegReg', (191, 199))	('TE2', 'Gene', '8260', (115, 118))	('FSCN1', 'Gene', '6624', (67, 72))	('siMMP14-2', 'Var', (90, 99))	('decrease', 'NegReg', (146, 154))	('FSCN1', 'Gene', (67, 72))	('amount of the target protein', 'MPA', (207, 235))
492018	24196787	However, the knockdown of FSCN1 did not lead to a decrease in MMP14 mRNA or protein in the two cell lines.	('FSCN1', 'Gene', '6624', (26, 31))	('decrease', 'NegReg', (50, 58))	('MMP14', 'Gene', '4323', (62, 67))	('MMP14', 'Gene', (62, 67))	('knockdown', 'Var', (13, 22))	('FSCN1', 'Gene', (26, 31))
492019	24196787	Similarly, the knockdown of MMP14 did not affect the expression of FSCN1 mRNA or protein (Figure 2A-C).	('knockdown', 'Var', (15, 24))	('MMP14', 'Gene', '4323', (28, 33))	('MMP14', 'Gene', (28, 33))	('expression', 'MPA', (53, 63))	('FSCN1', 'Gene', (67, 72))	('FSCN1', 'Gene', '6624', (67, 72))
492023	24196787	However, the rate of siMMP14-transfected cells that penetrated the collagen I membrane was significantly lower than that of the cells that penetrated the Matrigel-coated membrane (33.3% vs 54.6% of the negative control (siMMP14-1, P=0.0395) and 12.3% vs 25.2% (siMMP14-2, P=0.0362) in T.Tn cells and 33.6% vs 54.4% (siMMP14-1, P=0.0027) and 14.3% vs 23.9% (siMMP14-2, P=0.0026) in TE2 cells (Figure 2F)).	('lower', 'NegReg', (105, 110))	('siMMP14', 'Chemical', '-', (357, 364))	('siMMP14', 'Chemical', '-', (261, 268))	('siMMP14', 'Chemical', '-', (220, 227))	('siMMP14', 'Chemical', '-', (316, 323))	('siMMP14-transfected', 'Var', (21, 40))	('TE2', 'Gene', '8260', (381, 384))	('TE2', 'Gene', (381, 384))	('siMMP14', 'Chemical', '-', (21, 28))
492024	24196787	We previously reported that miR-133a regulates FSCN1.	('regulates', 'Reg', (37, 46))	('miR-133a', 'Var', (28, 36))	('miR-133a', 'Chemical', '-', (28, 36))	('FSCN1', 'Gene', (47, 52))	('FSCN1', 'Gene', '6624', (47, 52))
492026	24196787	The introduction of a miR-133a mimic into T.Tn and TE2 cells led to significant decreases in both the FSCN1 and MMP14 mRNA levels (56.8% and 42.6% of the negative control in T.Tn cells and 57.0% and 42.5% in the TE2 cells; Figure 3A).	('FSCN1', 'Gene', (102, 107))	('FSCN1', 'Gene', '6624', (102, 107))	('MMP14', 'Gene', '4323', (112, 117))	('MMP14', 'Gene', (112, 117))	('miR-133a', 'Var', (22, 30))	('TE2', 'Gene', '8260', (212, 215))	('miR-133a', 'Chemical', '-', (22, 30))	('decreases', 'NegReg', (80, 89))	('TE2', 'Gene', '8260', (51, 54))	('TE2', 'Gene', (212, 215))	('TE2', 'Gene', (51, 54))
492027	24196787	On the other hand, the introduction of a miR-133a inhibitor into the two cell lines led to significant increases in both the FSCN1 mRNA and MMP14 mRNA levels (140.4% and 157.6% of the negative control in T.Tn cells and 131.0% and 135.0% in TE2 cells; Figure 3B).	('increases', 'PosReg', (103, 112))	('MMP14', 'Gene', '4323', (140, 145))	('MMP14', 'Gene', (140, 145))	('FSCN1', 'Gene', (125, 130))	('miR-133a', 'Chemical', '-', (41, 49))	('TE2', 'Gene', '8260', (240, 243))	('FSCN1', 'Gene', '6624', (125, 130))	('inhibitor', 'Var', (50, 59))	('miR-133a', 'Gene', (41, 49))	('TE2', 'Gene', (240, 243))
492035	24196787	As was observed in the siMMP14-transfected cells, the rate of miR-133a-transfected cells that penetrated the collagen I-coated membrane was significantly lower than that of the cells that penetrated the Matrigel-coated membrane (27.9% vs 44.2% of the negative control (P=0.00390) in T.Tn cells and 24.0% vs 39.2% (P=0.0342) in TE2 cells (Figure 3H)).	('TE2', 'Gene', (327, 330))	('lower', 'NegReg', (154, 159))	('siMMP14', 'Chemical', '-', (23, 30))	('TE2', 'Gene', '8260', (327, 330))	('miR-133a', 'Chemical', '-', (62, 70))	('miR-133a-transfected', 'Var', (62, 82))
492040	24196787	A survival analysis using the Kaplan-Meier method and the log-rank test showed a significant decrease in the OS in the low miR-133a group (P=0.0407, Figure 4E), and the 5-year survival rate was 21.2% (vs 49.4% in the high miR-133a group).	('low miR-133a', 'Var', (119, 131))	('miR-133a', 'Chemical', '-', (222, 230))	('miR-133a', 'Chemical', '-', (123, 131))	('decrease', 'NegReg', (93, 101))	('OS', 'Chemical', '-', (109, 111))
492056	24196787	Although inhibitors of MMPs, especially of MMP14, seem to be a strong candidate tumour suppressor, there are currently no synthetic or biological MMP inhibitors in clinical trials for cancer.	('cancer', 'Disease', (184, 190))	('tumour', 'Disease', (80, 86))	('clinical', 'Species', '191496', (164, 172))	('MMPs', 'Gene', (23, 27))	('MMP14', 'Gene', '4323', (43, 48))	('MMP14', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('inhibitors', 'Var', (9, 19))
492060	24196787	We demonstrated that the prognosis of patients with both FSCN1- and MMP14-positive IHC staining was significantly worse than that of patients whose tumours were positive for only one of the proteins.	('FSCN1', 'Gene', (57, 62))	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('staining', 'Var', (87, 95))	('patients', 'Species', '9606', (133, 141))	('IHC', 'Gene', (83, 86))	('MMP14', 'Gene', '4323', (68, 73))	('MMP14', 'Gene', (68, 73))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('worse', 'NegReg', (114, 119))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('patients', 'Species', '9606', (38, 46))	('FSCN1', 'Gene', '6624', (57, 62))
492061	24196787	Because a FSCN1 inhibitor might not exert sufficient tumour-suppressive activity, and a MMP14 inhibitor might cause adverse effects, an upstream regulator of both FSCN1 and MMP14, not an inhibitor of either of them, could serve as an ideal tumour-suppressive agent.	('MMP14', 'Gene', '4323', (88, 93))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('FSCN1', 'Gene', (10, 15))	('tumour', 'Disease', (53, 59))	('MMP14', 'Gene', (173, 178))	('MMP14', 'Gene', (88, 93))	('FSCN1', 'Gene', '6624', (10, 15))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('FSCN1', 'Gene', (163, 168))	('inhibitor', 'Var', (94, 103))	('FSCN1', 'Gene', '6624', (163, 168))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('tumour', 'Disease', (240, 246))	('MMP14', 'Gene', '4323', (173, 178))
492062	24196787	We have previously reported that miR-133a regulates FSCN1 mRNA.	('miR-133a', 'Var', (33, 41))	('miR-133a', 'Chemical', '-', (33, 41))	('FSCN1', 'Gene', (52, 57))	('FSCN1', 'Gene', '6624', (52, 57))	('regulates', 'Reg', (42, 51))
492063	24196787	We found that miR-133a also regulates MMP14 mRNA, and demonstrated an inverse correlation between miR-133a and FSCN1 and between miR-133a and MMP14, and also demonstrated miR-133a to have tumour-suppressive effects.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('miR-133a', 'Chemical', '-', (129, 137))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('miR-133a', 'Chemical', '-', (98, 106))	('regulates', 'Reg', (28, 37))	('MMP14', 'Gene', '4323', (38, 43))	('tumour', 'Disease', (188, 194))	('miR-133a', 'Var', (171, 179))	('MMP14', 'Gene', (38, 43))	('miR-133a', 'Gene', (98, 106))	('miR-133a', 'Gene', (129, 137))	('FSCN1', 'Gene', '6624', (111, 116))	('miR-133a', 'Chemical', '-', (14, 22))	('miR-133a', 'Chemical', '-', (171, 179))	('FSCN1', 'Gene', (111, 116))	('inverse', 'NegReg', (70, 77))	('miR-133a', 'Gene', (14, 22))	('MMP14', 'Gene', '4323', (142, 147))	('MMP14', 'Gene', (142, 147))
492064	24196787	Many recent experimental and clinical studies have shown that the aberrant expression of miRNAs is associated with tumour aggressiveness.	('tumour aggressiveness', 'Disease', 'MESH:D001523', (115, 136))	('clinical', 'Species', '191496', (29, 37))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('aggressiveness', 'Phenotype', 'HP:0000718', (122, 136))	('miRNAs', 'Gene', (89, 95))	('aberrant expression', 'Var', (66, 85))	('tumour aggressiveness', 'Disease', (115, 136))	('associated', 'Reg', (99, 109))
492132	30410598	Accumulating studies have shown that aberrant expression of PRDX6 is associated with cancer progression.	('aberrant expression', 'Var', (37, 56))	('PRDX6', 'Gene', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('associated', 'Reg', (69, 79))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
492133	30410598	Jo M et al reported that PRDX6-overexpressing transgenic (Tg) mice displayed a greater increase in the growth of lung tumor compared with normal mice.	('increase', 'PosReg', (87, 95))	('PRDX6-overexpressing', 'Gene', (25, 45))	('mice', 'Species', '10090', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('transgenic', 'Var', (46, 56))	('PRDX6-overexpressing', 'PosReg', (25, 45))	('lung tumor', 'Disease', (113, 123))	('lung tumor', 'Disease', 'MESH:D008175', (113, 123))	('mice', 'Species', '10090', (145, 149))	('growth', 'MPA', (103, 109))	('lung tumor', 'Phenotype', 'HP:0100526', (113, 123))
492190	30410598	In contrast, the downregulation of PRDX6 by sh-PRDX6-2 or sh-PRDX6-3 significantly suppressed cell proliferation as measured by an MTT assay (Fig.	('sh-PRDX6-3', 'Var', (58, 68))	('cell proliferation', 'CPA', (94, 112))	('MTT assay', 'CPA', (131, 140))	('downregulation', 'NegReg', (17, 31))	('PRDX6', 'Gene', (35, 40))	('MTT', 'Chemical', 'MESH:C070243', (131, 134))	('suppressed', 'NegReg', (83, 93))
492194	30410598	Forced expression of PRDX6 by Ad-PRDX6 induced a ~1.80-fold increase of cells that invade through the Matrigel and membrane compared with the control Ad-RFP-infected cells (Fig.	('RFP', 'Gene', '2358', (153, 156))	('increase', 'PosReg', (60, 68))	('PRDX6', 'Gene', (21, 26))	('Ad-PRDX6', 'Var', (30, 38))	('RFP', 'Gene', (153, 156))
492206	30410598	To determine the effect of PRDX6 on ESCC growth in vivo, nude mice were first inoculated with Eca-109 cells infected with Ad-PRDX6 or Ad-RFP.	('RFP', 'Gene', (137, 140))	('Ad-PRDX6', 'Var', (122, 130))	('nude mice', 'Species', '10090', (57, 66))	('RFP', 'Gene', '2358', (137, 140))
492211	30410598	In Ad-PRDX6-infected xenografts, the Ki67-positive percentage was significantly increased, compared with Ad-RFP-infected group (Fig.	('Ki67-positive percentage', 'CPA', (37, 61))	('increased', 'PosReg', (80, 89))	('RFP', 'Gene', (108, 111))	('RFP', 'Gene', '2358', (108, 111))	('Ad-PRDX6-infected', 'Var', (3, 20))
492215	30410598	Aberrant expression of PRDX family enzymes has been reported in various kinds of cancers, and thought to be biomarkers and targets of cancer cells.	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', (81, 88))	('reported', 'Reg', (52, 60))	('cancer', 'Disease', (134, 140))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('expression', 'MPA', (9, 19))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PRDX family enzymes', 'Enzyme', (23, 42))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
492229	30410598	In human ovarian cancer cells, PRDX6 overexpression attenuates cisplatin-induced apoptosis .	('ovarian cancer', 'Disease', (9, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('human', 'Species', '9606', (3, 8))	('attenuates', 'NegReg', (52, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (9, 23))	('PRDX6', 'Gene', (31, 36))	('overexpression', 'Var', (37, 51))	('cisplatin-induced', 'MPA', (63, 80))	('ovarian cancer', 'Disease', 'MESH:D010051', (9, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
492233	30410598	Yun HM et al has reported that mutant PRDX6 (C47S) attenuated Erk1/2 activity in lung cancer cells and nude mice.	('lung cancer', 'Disease', (81, 92))	('mutant', 'Var', (31, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('PRDX6', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('attenuated', 'NegReg', (51, 61))	('C47S', 'Mutation', 'p.C47S', (45, 49))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('Erk1/2', 'Enzyme', (62, 68))	('nude mice', 'Species', '10090', (103, 112))
492250	28777781	Cellular metabolisms can produce ROS, and many factors can cause ROS to accumulate or be metabolized more slowly, such as disturbances in their production, distribution, or environmental stressors.	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('production', 'MPA', (144, 154))	('accumulate', 'PosReg', (72, 82))	('men', 'Species', '9606', (180, 183))	('disturbances', 'Var', (122, 134))	('ROS', 'MPA', (33, 36))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))	('produce', 'Reg', (25, 32))
492254	28777781	Cancer initiation is characterized by changes in DNA, such as point mutations or chromosomal aberrations.	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (81, 104))	('chromosomal', 'Disease', (81, 92))	('point mutations', 'Var', (62, 77))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('changes', 'Reg', (38, 45))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
492257	28777781	ROS can lead to the production of C5-OH and C6-OH adducts of pyrimidines, alkyl radical formations in thymine, double- or single-strand breaks by reacting with the sugar moiety of DNA, and protein-DNA cross-links and intra-strand cross-links.	('ROS', 'Var', (0, 3))	('intra-strand cross-links', 'Interaction', (217, 241))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('sugar', 'Chemical', 'MESH:D000073893', (164, 169))	('alkyl radical', 'Chemical', '-', (74, 87))	('thymine', 'Chemical', 'MESH:D013941', (102, 109))	('C5-OH and C6-OH', 'Disease', 'MESH:C537005', (34, 49))	('double- or single-strand breaks', 'MPA', (111, 142))	('alkyl radical formations', 'MPA', (74, 98))	('adducts', 'MPA', (50, 57))	('protein-DNA', 'Protein', (189, 200))	('pyrimidines', 'Chemical', 'MESH:D011743', (61, 72))	('reacting', 'Interaction', (146, 154))	('lead to', 'Reg', (8, 15))
492319	27882097	Furthermore, PEMS may inhibit the tumor growth of the esophageal wall through inflammatory infiltration and targeted drug delivery.	('tumor', 'Disease', (34, 39))	('targeted drug delivery', 'CPA', (108, 130))	('inflammatory infiltration', 'CPA', (78, 103))	('inhibit', 'NegReg', (22, 29))	('PEMS', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
492374	27882097	Furthermore, PEMS has the potential to inhibit tumor growth and some positive results have been published.	('inhibit', 'NegReg', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('PEMS', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
492375	27882097	The results demonstrated that treatment with PEMS resulted in epithelial denudation, mucin hypersecretion and epithelial metaplasia, which led to the hypothesis that PEMS may have anti-tumor effects on malignant biliary stricture in humans.	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('mucin', 'Gene', (85, 90))	('malignant biliary stricture', 'Disease', (202, 229))	('mucin', 'Gene', '100508689', (85, 90))	('epithelial metaplasia', 'Disease', (110, 131))	('epithelial denudation', 'CPA', (62, 83))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('humans', 'Species', '9606', (233, 239))	('PEMS', 'Var', (45, 49))	('epithelial metaplasia', 'Disease', 'MESH:D008679', (110, 131))
492387	27882097	However, in the 6th week, hyperemia was more marked in the PEMS group, as compared with the SEMS group.	('PEMS', 'Var', (59, 63))	('hyperemia', 'Disease', (26, 35))	('hyperemia', 'Disease', 'MESH:D006940', (26, 35))
492473	25320463	Interestingly, supplementation with zinc has been shown to improve the prognosis of cirrhotic patients, as well as the cirrhosis-related symptoms.	('cirrhosis', 'Disease', (119, 128))	('supplementation', 'Var', (15, 30))	('patients', 'Species', '9606', (94, 102))	('cirrhotic', 'Disease', (84, 93))	('cirrhosis', 'Phenotype', 'HP:0001394', (119, 128))	('improve', 'PosReg', (59, 66))	('cirrhosis', 'Disease', 'MESH:D005355', (119, 128))
492511	24602085	These include: gastric motor and sensory functions; production of the appetite -promoting acyl ghrelin by the P/D1 cells of the stomach fundus; a blunted response of the afferent vagus nerve to ingestion of a meal; and impaired release of other gastrointestinal hormones such as CCK, obestatin, GLP-1 or PYY, which usually inhibit gastric emptying and contribute to reduced appetite.	('release', 'MPA', (228, 235))	('P/D1', 'SUBSTITUTION', 'None', (110, 114))	('P/D1', 'Var', (110, 114))	('response', 'MPA', (154, 162))	('CCK', 'Gene', '885', (279, 282))	('reduced', 'NegReg', (366, 373))	('ghrelin', 'Gene', '58991', (95, 102))	('impaired', 'NegReg', (219, 227))	('reduced appetite', 'Phenotype', 'HP:0004396', (366, 382))	('GLP-1', 'Gene', '2641', (295, 300))	('ghrelin', 'Gene', (95, 102))	('inhibit', 'NegReg', (323, 330))	('appetite', 'MPA', (374, 382))	('CCK', 'Gene', (279, 282))	('blunted', 'NegReg', (146, 153))	('gastric', 'MPA', (331, 338))	('gastric emptying', 'Phenotype', 'HP:0002578', (331, 347))	('GLP-1', 'Gene', (295, 300))	('PYY', 'Gene', '5697', (304, 307))	('PYY', 'Gene', (304, 307))
492518	24602085	The potential role of these signaling mechanisms in the development of obesity is also illustrated by the effects of genetic variations in the control of the ligand or its receptor, the effect of obesity on the signaling mechanism, and the potential therapeutic effects of pharmacological doses of the gut hormone or peptide (Table 1).	('men', 'Species', '9606', (63, 66))	('obesity', 'Disease', 'MESH:D009765', (71, 78))	('obesity', 'Phenotype', 'HP:0001513', (196, 203))	('obesity', 'Disease', (71, 78))	('control', 'MPA', (143, 150))	('variations', 'Var', (125, 135))	('obesity', 'Disease', 'MESH:D009765', (196, 203))	('obesity', 'Phenotype', 'HP:0001513', (71, 78))	('obesity', 'Disease', (196, 203))	('effects', 'Reg', (106, 113))	('genetic variations', 'Var', (117, 135))
492522	24602085	genetic polymorphisms of PYY gene, tend to become obese; second, obese individuals have lower concentrations of small intestinal hormones, such as CCK, GLP-1, OXM, and FGF-19 (Table 1); third, obese individuals with insulin resistance may have an increase in small intestinal enterocyte mass when compared to obese individuals without insulin resistance.	('PYY', 'Gene', (25, 28))	('obese', 'Disease', (193, 198))	('obese', 'Disease', 'MESH:D009765', (65, 70))	('insulin', 'Gene', '3630', (335, 342))	('obese', 'Disease', (50, 55))	('obese', 'Disease', (309, 314))	('insulin', 'Gene', '3630', (216, 223))	('obese', 'Disease', 'MESH:D009765', (193, 198))	('obese', 'Disease', 'MESH:D009765', (50, 55))	('concentrations of small intestinal hormones', 'MPA', (94, 137))	('GLP-1', 'Gene', '2641', (152, 157))	('obese', 'Disease', 'MESH:D009765', (309, 314))	('CCK', 'Gene', (147, 150))	('lower', 'NegReg', (88, 93))	('polymorphisms', 'Var', (8, 21))	('OXM', 'MPA', (159, 162))	('insulin', 'Gene', (335, 342))	('small intestinal enterocyte mass', 'MPA', (259, 291))	('FGF-19', 'Gene', '9965', (168, 174))	('insulin', 'Gene', (216, 223))	('FGF-19', 'Gene', (168, 174))	('insulin resistance', 'Phenotype', 'HP:0000855', (335, 353))	('GLP-1', 'Gene', (152, 157))	('increase', 'PosReg', (247, 255))	('insulin resistance', 'Phenotype', 'HP:0000855', (216, 234))	('CCK', 'Gene', '885', (147, 150))	('obese', 'Disease', (65, 70))	('PYY', 'Gene', '5697', (25, 28))
492584	24602085	The association of gastric cancer and obesity was summarized in a meta-analysis which showed that excess BMI was associated with increased risk of gastric cancer.	('gastric cancer', 'Disease', (19, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('gastric cancer', 'Disease', 'MESH:D013274', (19, 33))	('obesity', 'Phenotype', 'HP:0001513', (38, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('excess BMI', 'Phenotype', 'HP:0031418', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('excess', 'Var', (98, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('gastric cancer', 'Disease', (147, 161))	('obesity', 'Disease', 'MESH:D009765', (38, 45))	('BMI', 'Gene', (105, 108))	('obesity', 'Disease', (38, 45))
492608	24602085	Obesity is associated with a higher risk of developing diverticulosis and with more diverticular bleeding and recurrent diverticulitis than normal weight individuals.	('Obesity', 'Var', (0, 7))	('diverticulosis', 'Disease', (55, 69))	('diverticular bleeding', 'Disease', (84, 105))	('diverticulosis', 'Disease', 'MESH:D004240', (55, 69))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('diverticular bleeding', 'Disease', 'MESH:D000076385', (84, 105))	('diverticulitis', 'Disease', 'MESH:D004238', (120, 134))	('diverticulitis', 'Disease', (120, 134))	('recurrent', 'Disease', (110, 119))
492637	24602085	NAFLD is currently the third most common cause of hepatocellular carcinoma (HCC) in the USA, after viral hepatitis and alcoholic cirrhosis.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('viral hepatitis', 'Disease', 'MESH:D006525', (99, 114))	('cirrhosis', 'Phenotype', 'HP:0001394', (129, 138))	('alcoholic cirrhosis', 'Disease', (119, 138))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (50, 74))	('NAFLD', 'Var', (0, 5))	('viral hepatitis', 'Phenotype', 'HP:0006562', (99, 114))	('hepatocellular carcinoma', 'Disease', (50, 74))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (50, 74))	('viral hepatitis', 'Disease', (99, 114))	('alcoholic cirrhosis', 'Disease', 'MESH:D008104', (119, 138))	('alcoholic cirrhosis', 'Phenotype', 'HP:0002613', (119, 138))	('hepatitis', 'Phenotype', 'HP:0012115', (105, 114))
492696	24330742	The levels of miR-34b, miR-142-5p, miR-146b-5p, miR-155, miR-223, and miR-486-5p, enriched in the pulmonary system, as well as of ubiquitous miR-409-3p and of miR-192, which is enriched in the GI system, but is also broadly expressed in other organs including pulmonary system (see Additional file 1: Table S2), were determined by the single target TaqMan  miRNA RT-qPCR assay.	('miR-1', 'Gene', (159, 164))	('miR-1', 'Gene', (23, 28))	('miR-1', 'Gene', (48, 53))	('miR-155', 'Gene', (48, 55))	('miR-1', 'Gene', '79187', (35, 40))	('miR-34b', 'Gene', '407041', (14, 21))	('miR-223', 'Gene', (57, 64))	('miR-155', 'Gene', '406947', (48, 55))	('miR-192', 'Gene', (159, 166))	('miR-1', 'Gene', '79187', (48, 53))	('miR-1', 'Gene', '79187', (159, 164))	('miR-34b', 'Gene', (14, 21))	('miR-1', 'Gene', '79187', (23, 28))	('miR-409', 'Gene', (141, 148))	('miR-409', 'Gene', '574413', (141, 148))	('miR-223', 'Gene', '407008', (57, 64))	('miR-1', 'Gene', (35, 40))	('miR-192', 'Gene', '406967', (159, 166))	('miR-486-5p', 'Var', (70, 80))
492733	22991505	Consistently, PPARs deregulation has been implicated in several pathophysiological conditions, including chronic inflammation and cancer development.	('men', 'Species', '9606', (144, 147))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('cancer', 'Disease', (130, 136))	('inflammation', 'Disease', (113, 125))	('PPAR', 'Gene', '5465', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('implicated', 'Reg', (42, 52))	('PPAR', 'Gene', (14, 18))	('deregulation', 'Var', (20, 32))
492768	22991505	In particular, H. pylori infection is the major causative agent of chronic gastritis and gastrointestinal metaplasia characterized by infiltration of inflammatory cells, enhanced expression of chemokines, NFkappaB activation, COX-2 overexpression, and upregulation of Wnt signaling pathway leading to aberrant cell proliferation, excessive angiogenesis, and inhibition of apoptosis.	('gastritis', 'Phenotype', 'HP:0005263', (75, 84))	('excessive', 'PosReg', (330, 339))	('Wnt signaling pathway', 'Pathway', (268, 289))	('H. pylori', 'Species', '210', (15, 24))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (301, 328))	('COX-2', 'Gene', (226, 231))	('cell proliferation', 'CPA', (310, 328))	('overexpression', 'PosReg', (232, 246))	('activation', 'PosReg', (214, 224))	('angiogenesis', 'CPA', (340, 352))	('COX-2', 'Gene', '4513', (226, 231))	('upregulation', 'PosReg', (252, 264))	('infection', 'Var', (25, 34))	('NFkappaB', 'Gene', '4790', (205, 213))	('expression', 'MPA', (179, 189))	('gastritis and gastrointestinal metaplasia', 'Disease', 'MESH:D005756', (75, 116))	('chronic gastritis', 'Phenotype', 'HP:0005231', (67, 84))	('enhanced', 'PosReg', (170, 178))	('apoptosis', 'CPA', (372, 381))	('H. pylori infection', 'Phenotype', 'HP:0005202', (15, 34))	('NFkappaB', 'Gene', (205, 213))
492771	22991505	Chronic inflammation processes induce development of colitis-associated cancers (CAC) generally initiated by mutations in TP53 or by COX2 overexpression and followed by APC inactivation at later stages.	('colitis', 'Phenotype', 'HP:0002583', (53, 60))	('TP53', 'Gene', (122, 126))	('Chronic inflammation', 'Disease', (0, 20))	('men', 'Species', '9606', (45, 48))	('colitis-associated cancers', 'Disease', (53, 79))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))	('initiated by', 'Reg', (96, 108))	('COX2', 'Gene', (133, 137))	('colitis-associated cancers', 'Disease', 'MESH:D003092', (53, 79))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('COX2', 'Gene', '4513', (133, 137))	('CAC', 'Phenotype', 'HP:0002664', (81, 84))	('APC', 'Gene', (169, 172))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('mutations', 'Var', (109, 118))	('TP53', 'Gene', '7157', (122, 126))	('APC', 'Gene', '324', (169, 172))	('overexpression', 'PosReg', (138, 152))
492783	22991505	PPARalpha also reduces the neovascularization, modulating the expression of VEGF, FGFs, members of the arachidonic acid P450 mono-oxygenases, thrombospondin, and endostatin.	('VEGF', 'Gene', (76, 80))	('neovascularization', 'CPA', (27, 45))	('PPARalpha', 'Var', (0, 9))	('expression', 'MPA', (62, 72))	('VEGF', 'Gene', '7422', (76, 80))	('FGFs', 'Gene', (82, 86))	('endostatin', 'Gene', '80781', (162, 172))	('reduces', 'NegReg', (15, 22))	('endostatin', 'Gene', (162, 172))	('modulating', 'Reg', (47, 57))
492789	22991505	Growing evidence obtained in animal models suggests that PPARalpha has anti-inflammatory effects in vivo but the precise and direct role it plays in intestinal inflammation is not fully elucidated.	('PPARalpha', 'Var', (57, 66))	('intestinal inflammation', 'Disease', (149, 172))	('anti-inflammatory effects', 'MPA', (71, 96))	('intestinal inflammation', 'Disease', 'MESH:D007249', (149, 172))
492812	22991505	In contrast, PPARgamma silencing in GC cell lines reduces cell viability, suggesting that PPARgamma overexpression may induce tumorigenesis.	('cell viability', 'CPA', (58, 72))	('induce', 'PosReg', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('silencing', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('reduces', 'NegReg', (50, 57))	('PPARgamma', 'Gene', (13, 22))	('PPARgamma', 'Gene', (90, 99))	('GC', 'Phenotype', 'HP:0012126', (36, 38))	('overexpression', 'PosReg', (100, 114))	('tumor', 'Disease', (126, 131))
492821	22991505	Finally, PPARgamma reduces the epithelial mesenchymal transition (EMT), a well-known process that allows cancer cells to acquire invasive ability, a prerequisite for metastasis formation.	('epithelial mesenchymal transition', 'CPA', (31, 64))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('PPARgamma', 'Var', (9, 18))	('reduces', 'NegReg', (19, 26))
492823	22991505	Loss-of-function mutations in PPARG have been reported in 8% of human CRCs, implying a protective effect.	('Loss-of-function', 'NegReg', (0, 16))	('human', 'Species', '9606', (64, 69))	('CRC', 'Phenotype', 'HP:0003003', (70, 73))	('PPARG', 'Gene', '5468', (30, 35))	('PPARG', 'Gene', (30, 35))	('mutations', 'Var', (17, 26))	('human CRCs', 'Disease', (64, 74))
492824	22991505	Although these mutations have been classified as "very rare events", increasing evidence suggests that PPARgamma activity is attenuated during the transition from adenoma to adenocarcinoma, likely explaining why PPARgamma agonists are effective in blocking the early stages of tumorigenesis (i.e., ACF formation is inhibited while little or no effect is detected in advanced tumor stages).	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('blocking', 'NegReg', (248, 256))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('adenoma to adenocarcinoma', 'Disease', 'MESH:D000236', (163, 188))	('attenuated', 'NegReg', (125, 135))	('mutations', 'Var', (15, 24))	('inhibited', 'NegReg', (315, 324))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Disease', (375, 380))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('activity', 'MPA', (113, 121))	('PPARgamma', 'Gene', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('tumor', 'Disease', (277, 282))	('adenoma to adenocarcinoma', 'Disease', (163, 188))
492826	22991505	In addition to loss-of-function mutations and inactivating posttranslational modifications, low PPARG expression has been found in 35% of sporadic CRCs due to epigenetic events such as DNA methylation and repressive histone modifications.	('CRC', 'Phenotype', 'HP:0003003', (147, 150))	('CRCs', 'Disease', (147, 151))	('expression', 'MPA', (102, 112))	('low', 'NegReg', (92, 95))	('histone', 'Protein', (216, 223))	('PPARG', 'Gene', '5468', (96, 101))	('loss-of-function', 'NegReg', (15, 31))	('DNA methylation', 'Var', (185, 200))	('PPARG', 'Gene', (96, 101))
492827	22991505	Interestingly, the epigenetic repression appears to be associated with a more aggressive course, EMT activation, and patients' worse prognosis, further supporting the notion that PPARgamma is an independent prognostic factor in CRC.	('aggressive course', 'CPA', (78, 95))	('CRC', 'Disease', (228, 231))	('activation', 'PosReg', (101, 111))	('EMT', 'CPA', (97, 100))	('associated', 'Reg', (55, 65))	('CRC', 'Phenotype', 'HP:0003003', (228, 231))	('patients', 'Species', '9606', (117, 125))	('epigenetic repression', 'Var', (19, 40))
492829	22991505	Concordantly, PPARG genetic variations have recently been correlated with a different risk of IBD incidence.	('correlated with', 'Reg', (58, 73))	('IBD incidence', 'Disease', (94, 107))	('PPARG', 'Gene', '5468', (14, 19))	('PPARG', 'Gene', (14, 19))	('genetic variations', 'Var', (20, 38))
492830	22991505	Low PPARgamma levels have also been found in peripheral mononuclear cells of IBD patients in the absence of specific PPARG mutations.	('PPARG', 'Gene', (117, 122))	('patients', 'Species', '9606', (81, 89))	('IBD', 'Disease', (77, 80))	('PPARG', 'Gene', '5468', (117, 122))	('mutations', 'Var', (123, 132))	('PPARgamma', 'MPA', (4, 13))
492832	22991505	PPARs deregulation during tumorigenesis of the GI tract has been attributed to gene mutations, altered levels of expression and, more recently, epigenetic modifications.	('PPAR', 'Gene', '5465', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('deregulation', 'Reg', (6, 18))	('levels of expression', 'MPA', (103, 123))	('epigenetic modifications', 'Var', (144, 168))	('PPAR', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumorigenesis of the GI tract', 'Phenotype', 'HP:0007378', (26, 55))
492857	22991505	Their expression and activity in tumor cells are modulated by genetic and epigenetic alterations; miRNAs are emerging as a new pathogenetic player.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('epigenetic', 'Var', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('activity', 'MPA', (21, 29))
492863	22991505	Another promising translational outcome of these studies is the possibility to identify PPAR alterations in premalignant lesions so that they can be used as prognostic biomarkers.	('alterations', 'Var', (93, 104))	('PPAR', 'Gene', (88, 92))	('PPAR', 'Gene', '5465', (88, 92))
492906	21299870	Mutant DeltaNp63 3'-UTR, which carried a substitution of four nucleotides (CTTT to GAAA) within the core binding sites of DeltaNp63 3'-UTR (14), was obtained using overlapping extension PCR.	('p63', 'Gene', '8626', (13, 16))	('p63', 'Gene', (128, 131))	('substitution', 'Var', (41, 53))	('p63', 'Gene', '8626', (128, 131))	('p63', 'Gene', (13, 16))
492907	21299870	Normal (or mutant) DeltaNp63 3'-UTR was cloned into the SacI-HindIII site of the pMIR-REPORT luciferase vector (Biosystems) and named as Luc-DeltaNp63 (or Luc-DeltaNp63-mut).	('mutant', 'Var', (11, 17))	('p63', 'Gene', (147, 150))	('p63', 'Gene', (25, 28))	('p63', 'Gene', (165, 168))	('p63', 'Gene', '8626', (147, 150))	('p63', 'Gene', '8626', (25, 28))	('p63', 'Gene', '8626', (165, 168))
492936	21299870	It was known that microRNAs could regulate a variety of cellular pathways by affecting the expression of multiple types of target genes and the alteration of microRNAs expression might contribute to human carcinogenesis.	('affecting', 'Reg', (77, 86))	('expression', 'MPA', (91, 101))	('carcinogenesis', 'Disease', (205, 219))	('human', 'Species', '9606', (199, 204))	('alteration', 'Var', (144, 154))	('contribute', 'Reg', (185, 195))	('regulate', 'Reg', (34, 42))	('cellular pathways', 'Pathway', (56, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (205, 219))
492939	21299870	Our data suggest that re-expressing miR-203 might benefit the treatment of ESCC.	('miR-203', 'Gene', '406986', (36, 43))	('ESCC', 'Disease', (75, 79))	('re-expressing', 'Var', (22, 35))	('miR-203', 'Gene', (36, 43))	('benefit', 'PosReg', (50, 57))
492941	21299870	Moreover, it was reported that inhibition of miR-203 expression could significantly increase the proliferation of Hela cells, whilst re-expression of miR-203 could inhibit the proliferative capacity of cells in human head and neck squamous cell carcinoma, hepatocellular carcinoma, chronic myelogenous leukemia and B cell leukemia.	('proliferative capacity of cells', 'CPA', (176, 207))	('Hela cells', 'CellLine', 'CVCL:0030', (114, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('leukemia', 'Phenotype', 'HP:0001909', (302, 310))	('miR-203', 'Gene', '406986', (45, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('chronic myelogenous leukemia', 'Disease', (282, 310))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (282, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (256, 280))	('inhibit', 'NegReg', (164, 171))	('increase', 'PosReg', (84, 92))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (290, 310))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (217, 254))	('leukemia', 'Phenotype', 'HP:0001909', (322, 330))	('miR-203', 'Gene', (150, 157))	('inhibition', 'Var', (31, 41))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (256, 280))	('neck squamous cell carcinoma', 'Disease', (226, 254))	('B cell leukemia', 'Disease', 'MESH:D015448', (315, 330))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (226, 254))	('proliferation', 'CPA', (97, 110))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (282, 310))	('B cell leukemia', 'Disease', (315, 330))	('miR-203', 'Gene', '406986', (150, 157))	('hepatocellular carcinoma', 'Disease', (256, 280))	('human', 'Species', '9606', (211, 216))	('miR-203', 'Gene', (45, 52))
493038	19542403	MRE magnetic resonance elastography kPa kiloPascal BMI body mass index MELD Model for End Stage Liver Disease EGD esophagogastroduodenoscopy	('esophagogastroduodenoscopy', 'Disease', (114, 140))	('kPa kiloPascal BMI', 'Var', (36, 54))	('MELD', 'Disease', 'None', (71, 75))	('Liver Disease', 'Phenotype', 'HP:0001392', (96, 109))	('MELD', 'Disease', (71, 75))	('Liver Disease EGD', 'Phenotype', 'HP:0410246', (96, 113))
493111	28404915	PD-L1+ as defined as >=1% of tumor cell membranes showing >=1+ intensity.	('PD-L1+', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))
493113	28404915	In the definitive treatment group (patients who received curative esophagectomy or definitive [chemo-]radiation therapy), PD-L1 positivity was associated with a significantly shorter DFS and OS.	('shorter', 'NegReg', (175, 182))	('DFS', 'CPA', (183, 186))	('PD-L1', 'Gene', (122, 127))	('positivity', 'Var', (128, 138))	('patients', 'Species', '9606', (35, 43))
493126	28404915	It is well established that multiple solid tumor types, including melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), thymoma, ovarian, and colorectal cancer, generate an immunosuppressive tumor microenvironment and avoid T cell-mediated cytolysis by expressing PD-L1.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (108, 130))	('thymoma', 'Disease', (140, 147))	('thymoma', 'Phenotype', 'HP:0100522', (140, 147))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', (43, 48))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (104, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('renal cell carcinoma', 'Disease', (76, 96))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (193, 216))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('non-small cell lung cancer', 'Disease', (104, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('PD-L1', 'Var', (284, 289))	('NSCLC', 'Disease', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('immunosuppressive tumor', 'Disease', (193, 216))	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('ovarian', 'Disease', (149, 156))	('thymoma', 'Disease', 'MESH:D013945', (140, 147))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (76, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (104, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('colorectal cancer', 'Disease', (162, 179))
493143	28404915	Table 1 summarizes the percentage of specimens PD-L1+ using different scoring criteria: >=1% (Figure 1B) and >=5% (Figure 1C) of tumor cells showing >=1+ membrane staining intensity, as well as >=25% tumor cells showing >=2+ membrane staining intensity (Figure 1D).	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('PD-L1+', 'Var', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
493153	28404915	Statistical analyses using Spearman Rank Correlation indicated that PD-L1+ specimens were associated with aggressive clinicopathological features, which included deeper tumor invasion (p=0.037) and nodal metastasis (p=0.013).	('deeper tumor', 'Disease', (162, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PD-L1+ specimens', 'Var', (68, 84))	('nodal metastasis', 'CPA', (198, 214))	('deeper tumor', 'Disease', 'MESH:D009369', (162, 174))
493158	28404915	DFS and OS was significantly related to PD-L1 expression (HR=1.942, 95% CI: 1.285, 2.941, p=0.001; HR=1.550, 95% CI: 1.018, 2.358, p=0.0039), PD-L1+ patients exhibited worse DFS and OS than PD-L1- patients (Figure 4A & 4B).	('patients', 'Species', '9606', (149, 157))	('worse', 'NegReg', (168, 173))	('patients', 'Species', '9606', (197, 205))	('DFS', 'MPA', (174, 177))	('PD-L1+', 'Var', (142, 148))
493163	28404915	However, patients who received esophagectomy who had a high TIL score (3) showed a significantly better OS than those with a moderate (2), low (1) or none (0) TIL score (HR=2.264, 95% CI: 1.039, 4.936, p=0.035).	('patients', 'Species', '9606', (9, 17))	('TIL', 'Gene', (60, 63))	('TIL', 'Gene', '7096', (159, 162))	('better', 'PosReg', (97, 103))	('high', 'Var', (55, 59))	('TIL', 'Gene', '7096', (60, 63))	('TIL', 'Gene', (159, 162))	('esophagectomy', 'Disease', (31, 44))
493179	28404915	In this classification, PD-L1+ was defined as specimens with >=1% expression on tumor cell membranes with >=1+ intensity and a TIL score of 3 (high) was considered as TILs+.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('TIL', 'Gene', '7096', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('TIL', 'Gene', (167, 170))	('PD-L1+', 'Var', (24, 30))	('tumor', 'Disease', (80, 85))	('TIL', 'Gene', (127, 130))	('TIL', 'Gene', '7096', (167, 170))
493181	28404915	Similarly, OS was longer for type 1 than type III (p=0.005), indicating that the presence of TILs were associated with a better prognosis.	('TIL', 'Gene', (93, 96))	('TIL', 'Gene', '7096', (93, 96))	('presence', 'Var', (81, 89))
493184	28404915	Analysis of the correlation between PD-L1 expression and clinicopathologic features suggests that tumor PD-L1 positivity might be associated with more aggressive tumor progression, including deeper tumor invasion and more nodal metastasis, which significantly negatively affects the survival of ESCC.	('tumor', 'Disease', (162, 167))	('deeper tumor', 'Disease', (191, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('positivity', 'Var', (110, 120))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('PD-L1', 'Gene', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('deeper tumor', 'Disease', 'MESH:D009369', (191, 203))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('aggressive tumor', 'Disease', 'MESH:D001523', (151, 167))	('ESCC', 'Disease', (295, 299))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('nodal metastasis', 'CPA', (222, 238))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('aggressive tumor', 'Disease', (151, 167))	('more', 'PosReg', (146, 150))	('negatively', 'NegReg', (260, 270))	('associated with', 'Reg', (130, 145))
493187	28404915	Multiple solid tumor types, including melanoma, RCC, NSCLC, bladder, breast, and hepatocellular carcinoma, generate an immunosuppressive tumor microenvironment by expressing PD-L1, thereby avoiding T cell-mediated cytolysis.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('immunosuppressive tumor', 'Disease', (119, 142))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('bladder', 'Disease', (60, 67))	('breast', 'Disease', (69, 75))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('PD-L1', 'Var', (174, 179))	('NSCLC', 'Disease', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('tumor', 'Disease', (137, 142))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (119, 142))	('tumor', 'Disease', (15, 20))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('hepatocellular carcinoma', 'Disease', (81, 105))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
493189	28404915	Similar to previous studies, we choose a 1% PD-L1 cut-off in this study, and found that PD-L1+ patients who received curative esophagectomy or definitive chemo-(radiation) therapy had significantly shorter DFS and OS than PD-L1- patients, and these results provide a rationale for therapeutic intervention targeted to this immunomodulatory axis in these two groups, such as adjuvant therapy with an anti-PD-1/anti-PD-L1 antibody or concurrent anti-PD-1/anti-PD-L1 antibody and radiation treatment.	('PD-1', 'Gene', (448, 452))	('PD-L1+', 'Var', (88, 94))	('DFS', 'CPA', (206, 209))	('patients', 'Species', '9606', (229, 237))	('PD-1', 'Gene', '5133', (448, 452))	('patients', 'Species', '9606', (95, 103))	('PD-1', 'Gene', (404, 408))	('shorter', 'NegReg', (198, 205))	('PD-1', 'Gene', '5133', (404, 408))
493195	28404915	In colorectal cancer, patients with microsatellite unstable (MSI-H) primary tumors have a superior prognosis, associated with increased TILs within tumors and due to MSI-H tumors having an increased mutational burden resulting in increased neoantigen formation.	('neoantigen formation', 'MPA', (240, 260))	('primary tumor', 'Disease', 'MESH:D009369', (68, 81))	('colorectal cancer', 'Disease', (3, 20))	('microsatellite', 'Var', (36, 50))	('primary tumor', 'Disease', (68, 81))	('MSI-H', 'Disease', 'MESH:D000848', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('MSI-H', 'Disease', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('patients', 'Species', '9606', (22, 30))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('MSI-H tumors', 'Disease', 'MESH:D009369', (166, 178))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('MSI-H', 'Disease', 'MESH:D000848', (61, 66))	('TILs within tumors', 'Disease', (136, 154))	('tumors', 'Disease', (148, 154))	('increased', 'PosReg', (230, 239))	('TILs within tumors', 'Disease', 'MESH:D001929', (136, 154))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('MSI-H tumors', 'Disease', (166, 178))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('MSI-H', 'Disease', (166, 171))	('increased', 'PosReg', (126, 135))
493197	28404915	also demonstrated that the presence of TILs was strongly associated with local tumor PD-L1 expression in melanoma patients.	('expression', 'MPA', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('TIL', 'Gene', (39, 42))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('PD-L1', 'Gene', (85, 90))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('TIL', 'Gene', '7096', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('patients', 'Species', '9606', (114, 122))	('presence', 'Var', (27, 35))	('associated', 'Reg', (57, 67))
493203	28404915	For example, radiotherapy could induce immunogenic cell death to liberate neoantigens and promote T-cell infiltration of the tumor.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('radiotherapy', 'Var', (13, 25))	('promote', 'PosReg', (90, 97))	('liberate', 'MPA', (65, 73))	('neoantigens', 'Protein', (74, 85))
493207	28404915	Combination therapy designed to promote T cell infiltration but avoid negative regulation mitigate their attenuation, such as the combination of anti-CTLA-4 and anti-PD-1, might lead to a more robust response.	('PD-1', 'Gene', '5133', (166, 170))	('anti-CTLA-4', 'Var', (145, 156))	('PD-1', 'Gene', (166, 170))	('promote', 'PosReg', (32, 39))	('T cell infiltration', 'CPA', (40, 59))
493251	28404915	In tumor cells, PD-L1+ by a 1% cut off was defined as specimen with >=1% membranous expression on tumor cells with >=1+ intensity, PD-L1+ by a 5% cut off was defined as specimens with >=5% membranous expression on tumor cells with >=1+ intensity, and PD-L1+ by a 25% cut off was defined as specimens with >=25% membranous expression on tumor cells with >=2+ intensity.	('PD-L1+', 'Var', (16, 22))	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (214, 219))	('PD-L1+', 'Var', (131, 137))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (336, 341))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
493264	26704725	In men, increased body fatness at any life period was associated with a higher risk of esophageal adenocarcinoma and colorectal cancer (RR ranged from 1.23 to 3.01), and the heavy-stable/increase trajectory was associated with a higher risk of pancreatic cancer, but lower risk of advanced prostate cancer.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (87, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (244, 261))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('esophageal adenocarcinoma', 'Disease', (87, 112))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('pancreatic cancer', 'Disease', (244, 261))	('advanced prostate cancer', 'Disease', 'MESH:D011471', (281, 305))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('body', 'Var', (18, 22))	('increased body fatness', 'Phenotype', 'HP:0025521', (8, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('advanced prostate cancer', 'Disease', (281, 305))	('colorectal cancer', 'Disease', (117, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (244, 261))	('heavy-stable/increase', 'Var', (174, 195))	('men', 'Species', '9606', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('increased', 'PosReg', (8, 17))	('prostate cancer', 'Phenotype', 'HP:0012125', (290, 305))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (87, 112))
493331	26704725	In women, those in the lean-moderate increase, lean-marked increase, and heavy-stable/increase groups had a higher risk of total and obesity-related cancer, with RRs ranging from 1.06 to 1.39.	('cancer', 'Disease', (149, 155))	('obesity', 'Phenotype', 'HP:0001513', (133, 140))	('obesity', 'Disease', 'MESH:D009765', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lean-marked', 'Var', (47, 58))	('obesity', 'Disease', (133, 140))	('women', 'Species', '9606', (3, 8))	('total', 'Disease', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
493364	26704725	In this study, we found that in women only the lean-marked increase and heavy-stable/increase trajectories were at higher risk of colorectal cancer, while in men, those who had a heavy body shape in any life period had a higher risk (although some of the relative risk estimates were not statistically significant), indicating that early-life obesity may have a predominant effect on colorectal cancer in women whereas late-life obesity may be more important in men.	('colorectal cancer', 'Disease', (130, 147))	('colorectal cancer', 'Disease', (384, 401))	('men', 'Species', '9606', (407, 410))	('lean-marked', 'Var', (47, 58))	('women', 'Species', '9606', (405, 410))	('men', 'Species', '9606', (462, 465))	('men', 'Species', '9606', (34, 37))	('women', 'Species', '9606', (32, 37))	('obesity', 'Phenotype', 'HP:0001513', (429, 436))	('obesity', 'Disease', (343, 350))	('men', 'Species', '9606', (158, 161))	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (384, 401))	('obesity', 'Disease', 'MESH:D009765', (343, 350))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('obesity', 'Disease', (429, 436))	('cancer', 'Phenotype', 'HP:0002664', (395, 401))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('obesity', 'Disease', 'MESH:D009765', (429, 436))	('obesity', 'Phenotype', 'HP:0001513', (343, 350))	('colorectal cancer', 'Disease', 'MESH:D015179', (384, 401))
493380	26704725	This is consistent with previous evidence that MHT use attenuates the obesity-endometrial cancer association, likely due to the central role of unopposed estrogen therapy in endometrial carcinogenesis that overwhelms the effect of adipose tissue-derived estrogen.	('obesity', 'Phenotype', 'HP:0001513', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('attenuates', 'NegReg', (55, 65))	('obesity-endometrial cancer', 'Disease', 'MESH:D016889', (70, 96))	('endometrial cancer', 'Phenotype', 'HP:0012114', (78, 96))	('use', 'Var', (51, 54))	('endometrial carcinogenesis', 'Disease', 'MESH:D063646', (174, 200))	('endometrial carcinogenesis', 'Disease', (174, 200))	('MHT', 'Gene', (47, 50))	('obesity-endometrial cancer', 'Disease', (70, 96))
493420	26069303	We additionally used a genetically engineered mouse model (GEMM) of ESCC by conditionally deleting the cell adhesion molecule p120ctn (L2-Cre;p120ctnLoxP/LoxP) as previously described.	('ESCC', 'Disease', (68, 72))	('p120ctnLoxP/LoxP', 'Var', (142, 158))	('mouse', 'Species', '10090', (46, 51))
493433	26069303	We evaluated the developed PET probe ability to bind periostin in subcutaneous ESCC xenografts and orthotopic spontaneous tumors in the esophagus of GEMM mice with p120ctn conditional knock-out.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Disease', (122, 128))	('p120ctn', 'Var', (164, 171))	('bind', 'Interaction', (48, 52))	('mice', 'Species', '10090', (154, 158))	('PET', 'Gene', '22095', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PET', 'Gene', (27, 30))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
493448	26069303	Two esophageal cancer tissue arrays (ES2081 and ES2001; US Biomax) were stained for periostin expression with slight modification of the technique described above.	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal cancer', 'Disease', (4, 21))	('ES2001', 'Var', (48, 54))	('ES2081', 'Var', (37, 43))
493457	26069303	Direct (saturation) radioligand binding assays showed that 64Cu-DOTA-antiperiostin-F(ab')2 bound specifically to human recombinant periostin fixed to HisLink Protein Purification Resin.	('64Cu-DOTA-antiperiostin-F', 'Var', (59, 84))	('bound', 'Interaction', (91, 96))	('human', 'Species', '9606', (113, 118))	("64Cu-DOTA-antiperiostin-F(ab')2", 'Chemical', '-', (59, 90))
493462	26069303	The TBR monotonously increased in both TE-11 and TT over time; however, the TBR increased at a steeper slope in TE-11 xenografts than TT tumors (Table 1; Fig.	('TBR', 'Chemical', '-', (76, 79))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('TE-11', 'Chemical', '-', (39, 44))	('TE-11', 'Chemical', '-', (112, 117))	('TBR', 'Chemical', '-', (4, 7))	('TE-11', 'Var', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
493463	26069303	The TBR in TE-11 was significantly higher than that in TT xenografts at every time point (P < 0.0001).	('TE-11', 'Var', (11, 16))	('TBR', 'MPA', (4, 7))	('TBR', 'Chemical', '-', (4, 7))	('higher', 'PosReg', (35, 41))	('TE-11', 'Chemical', '-', (11, 16))
493465	26069303	PET/CT imaging with 64Cu-DOTA-antiperiostin-F(ab')2 in the GEMM of orthotopic ESCC showed high periostin tracer uptake (SUVmean, 0.54 +- 0.03) anatomically correlating with the site of enhanced 18F-FDG uptake (SUVmean, 0.91 +- 0.03) (Fig.	('18F-FDG uptake', 'MPA', (194, 208))	('64Cu-DOTA-antiperiostin-F', 'Var', (20, 45))	('18F-FDG', 'Chemical', 'MESH:D019788', (194, 201))	('periostin tracer uptake', 'MPA', (95, 118))	('PET', 'Gene', '22095', (0, 3))	('enhanced', 'PosReg', (185, 193))	('PET', 'Gene', (0, 3))	("64Cu-DOTA-antiperiostin-F(ab')2", 'Chemical', '-', (20, 51))
493466	26069303	We further confirmed that the presence of ESCC at the gastroesophageal junction in the mice demonstrated enhanced 64Cu-DOTA-antiperiostin-F(ab')2 and 18F-FDG uptake using histopathology (Supplemental Fig.	('18F-FDG', 'Chemical', 'MESH:D019788', (150, 157))	('18F-FDG uptake', 'MPA', (150, 164))	('mice', 'Species', '10090', (87, 91))	("64Cu-DOTA-antiperiostin-F(ab')2", 'Chemical', '-', (114, 145))	('64Cu-DOTA-antiperiostin-F', 'MPA', (114, 139))	('presence', 'Var', (30, 38))	('ESCC', 'Gene', (42, 46))	('enhanced', 'PosReg', (105, 113))
493475	26069303	1C and 1D) and spontaneous orthotopic ESCC tumors from GEMM with conditional p120ctn knock-out (L2-Cre; p120ctnLoxP/LoxP) (Supplemental Fig.	('p120ctnLoxP/LoxP', 'Var', (104, 120))	('ESCC tumors', 'Disease', (38, 49))	('ESCC tumors', 'Disease', 'MESH:D004938', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('p120ctn', 'Var', (77, 84))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))
493478	26069303	We observed high radiotracer uptake in the TE-11 xenografts expressing periostin, compared with low tracer uptake in TT xenografts, which minimally express periostin (Fig.	('radiotracer uptake', 'MPA', (17, 35))	('periostin', 'Var', (71, 80))	('TE-11', 'Chemical', '-', (43, 48))
493482	26069303	The model recapitulates the temporal progression of human ESCC by conditional deletion of p120 catenin (p120ctn) in the foregut.	('p120 catenin', 'Gene', '1500', (90, 102))	('p120 catenin', 'Gene', (90, 102))	('p120ctn', 'Var', (104, 111))	('conditional deletion', 'Var', (66, 86))	('human', 'Species', '9606', (52, 57))	('ESCC', 'Disease', (58, 62))
493509	26673820	EC109 was found to be relatively sensitive to both cisplatin and paclitaxel, while KYSE410 was relatively resistant to cisplatin, KYSE510 was relatively resistant to paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (65, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('KYSE410', 'Chemical', '-', (83, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('EC109', 'Var', (0, 5))	('paclitaxel', 'Chemical', 'MESH:D017239', (166, 176))	('EC109', 'CellLine', 'CVCL:6898', (0, 5))	('KYSE410', 'Var', (83, 90))	('KYSE510', 'Var', (130, 137))	('sensitive', 'MPA', (33, 42))
493512	26673820	Blockage of MUC20 and MUC13 decreased the drug-resistance capacity and chemosensitivity, respectively.	('drug-resistance', 'Phenotype', 'HP:0020174', (42, 57))	('Blockage', 'Var', (0, 8))	('drug-resistance capacity', 'MPA', (42, 66))	('MUC13', 'Gene', '56667', (22, 27))	('decreased', 'NegReg', (28, 37))	('MUC20', 'Gene', (12, 17))	('MUC13', 'Gene', (22, 27))	('chemosensitivity', 'CPA', (71, 87))	('MUC20', 'Gene', '200958', (12, 17))
493531	26673820	It was showed that significantly differential expression of 1446 genes was observed in EC109 compared with KYSE410; significantly differential expression of 1386 genes was observed in EC109 compared with KYSE510 (Figure 2).	('expression', 'MPA', (143, 153))	('differential', 'Reg', (130, 142))	('EC109', 'CellLine', 'CVCL:6898', (87, 92))	('EC109', 'CellLine', 'CVCL:6898', (184, 189))	('KYSE410', 'Chemical', '-', (107, 114))	('EC109', 'Var', (184, 189))	('expression', 'MPA', (46, 56))
493533	26673820	To confirm the microarray data, 6 differentially expressed genes which were involved with the signaling pathways important to carcinogenesis were selected, and their difference in expression across the panel of 3 cell lines (EC109, KYSE410, KYSE510) was confirmed by quantitative real-time PCR.	('KYSE410', 'Var', (232, 239))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('EC109', 'CellLine', 'CVCL:6898', (225, 230))	('expression', 'MPA', (180, 190))	('carcinogenesis', 'Disease', (126, 140))	('KYSE410', 'Chemical', '-', (232, 239))
493542	26673820	Knockdown of MUC13 in sensitive cell line EC109 resulted in increased cell survival and inhibited chemosensitivity, whereas, knockdown of MUC20 in resistant cell line KYSE510 promoted cell apoptosis and induced cells more chemosensitive to agent (Figure 6).	('inhibited', 'NegReg', (88, 97))	('knockdown', 'Var', (125, 134))	('MUC20', 'Gene', '200958', (138, 143))	('cell survival', 'CPA', (70, 83))	('promoted', 'PosReg', (175, 183))	('increased', 'PosReg', (60, 69))	('more', 'PosReg', (217, 221))	('MUC13', 'Gene', '56667', (13, 18))	('induced', 'Reg', (203, 210))	('EC109', 'CellLine', 'CVCL:6898', (42, 47))	('MUC13', 'Gene', (13, 18))	('MUC20', 'Gene', (138, 143))	('chemosensitivity', 'CPA', (98, 114))	('cell apoptosis', 'CPA', (184, 198))
493543	26673820	However, knockdown of MUC4 did not affect cell chemosensitivity.	('MUC4', 'Gene', (22, 26))	('knockdown', 'Var', (9, 18))	('MUC4', 'Gene', '4585', (22, 26))
493563	26673820	The possible underlying mechanism is that the expression of MUC4 could inhibit apoptosis by the activation of caspase-9, which further resulted in the development of drug resistance in tumor cells.	('tumor', 'Disease', (185, 190))	('caspase-9', 'Gene', (110, 119))	('expression', 'Var', (46, 56))	('resulted in', 'Reg', (135, 146))	('inhibit', 'NegReg', (71, 78))	('MUC4', 'Gene', '4585', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('apoptosis', 'CPA', (79, 88))	('development', 'Reg', (151, 162))	('drug', 'MPA', (166, 170))	('caspase-9', 'Gene', '842', (110, 119))	('MUC4', 'Gene', (60, 64))	('drug resistance', 'Phenotype', 'HP:0020174', (166, 181))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('activation', 'PosReg', (96, 106))
493566	26673820	By the in vitro experiment, we found that blocking of MUC4 and MUC20 could contribute to the increase in the sensitivity of ESCC cell lines to paclitaxel, whereas blocking of MUC13 resulted in a decrease in the sensitivity of ESCC cell lines to paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (143, 153))	('sensitivity', 'MPA', (109, 120))	('MUC20', 'Gene', '200958', (63, 68))	('increase', 'PosReg', (93, 101))	('MUC13', 'Gene', '56667', (175, 180))	('paclitaxel', 'Chemical', 'MESH:D017239', (245, 255))	('blocking', 'Var', (42, 50))	('MUC4', 'Gene', '4585', (54, 58))	('MUC4', 'Gene', (54, 58))	('sensitivity', 'MPA', (211, 222))	('MUC20', 'Gene', (63, 68))	('MUC13', 'Gene', (175, 180))
493621	24438695	Furthermore, 3-DCRT has been associated with a higher response rate in patients with ESCC, in particular for the tremendous control of mediastinal lymph node metastases .	('3-DCRT', 'Var', (13, 19))	('response', 'MPA', (54, 62))	('patients', 'Species', '9606', (71, 79))	('ESCC', 'Disease', (85, 89))	('lymph node metastases', 'Disease', 'MESH:D009362', (147, 168))	('lymph node metastases', 'Disease', (147, 168))
493687	23561329	Furthermore, the human esophageal SCC cell line CE81T was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after manipulation of IL-6 expression.	('tumor behavior', 'Disease', (129, 143))	('SCC', 'Gene', (34, 37))	('manipulation', 'Var', (173, 185))	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('human', 'Species', '9606', (17, 22))	('SCC', 'Gene', '6317', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor behavior', 'Disease', 'MESH:D001523', (129, 143))	('IL-6', 'Gene', (189, 193))
493698	23561329	Proinflammatory cytokine may contribute to tumor progression by stimulating angiogenesis, invasion and metastasis IL-6 is a pleiotropic cytokine that is capable of modulating diverse cell functions such as inflammatory reactions, and is a major activator of the JAK/STAT3 and PI3K/AKT signaling pathways.	('contribute', 'Reg', (29, 39))	('modulating', 'Reg', (164, 174))	('angiogenesis', 'CPA', (76, 88))	('IL-6', 'Var', (114, 118))	('stimulating', 'PosReg', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('STAT3', 'Gene', '6774', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('STAT3', 'Gene', (266, 271))	('tumor', 'Disease', (43, 48))	('invasion', 'CPA', (90, 98))	('metastasis', 'CPA', (103, 113))
493718	23561329	Stable cancer cells were generated by transfecting CE81T cells with either the IL-6 silencing vectors or control vectors, followed by selection with puromycin for 4 weeks.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('puromycin', 'Chemical', 'MESH:D011691', (149, 158))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('IL-6', 'Gene', (79, 83))	('silencing vectors', 'Var', (84, 101))
493725	23561329	CE81T cancer cell transfectants (1 x 106 per implantation, five animals per group) were subcutaneously implanted in the dorsal gluteal region.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('CE81T', 'Var', (0, 5))
493734	23561329	By viable cell counting over 6 days and observation of xenograft tumors, the IL-6 silencing vector significantly inhibited tumor growth in vitro (Figure 2b) and in vivo (Figure 2c).	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', (65, 70))	('xenograft tumors', 'Disease', 'MESH:D009369', (55, 71))	('inhibited', 'NegReg', (113, 122))	('IL-6', 'Gene', (77, 81))	('silencing vector', 'Var', (82, 98))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('xenograft tumors', 'Disease', (55, 71))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
493737	23561329	Furthermore, as demonstrated using migration scratch assays, IL-6 silencing vector attenuated the invasive capacity of esophageal cancer cells (Figure 3a).	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('attenuated', 'NegReg', (83, 93))	('IL-6', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('silencing vector', 'Var', (66, 82))	('esophageal cancer', 'Disease', (119, 136))
493752	23561329	When esophageal cancer cells with control vectors and those with IL-6 silencing vectors were subcutaneously implanted into mice, we found that the growth inhibiting effect induced by IL-6 silencing vector associated with lower expression levels of EMT- and angiogenesis-related factor (Figure 4c).	('growth', 'CPA', (147, 153))	('expression levels', 'MPA', (227, 244))	('EMT', 'Gene', (248, 251))	('silencing vector', 'Var', (188, 204))	('EMT', 'Gene', '3702', (248, 251))	('lower', 'NegReg', (221, 226))	('esophageal cancer', 'Disease', (5, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (5, 22))	('IL-6', 'Gene', (183, 187))	('mice', 'Species', '10090', (123, 127))
493754	23561329	Regarding clinical data, the expression of IL-6 was significantly associated with a lower rate of response to curative treatment in the 173 esophageal SCC patients (Table 1), and a lower pathological complete response rate in the 55 patients who underwent surgical intervention (Table 3).	('clinical', 'Species', '191496', (10, 18))	('expression', 'Var', (29, 39))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('IL-6', 'Gene', (43, 47))	('lower', 'NegReg', (181, 186))	('SCC', 'Gene', '6317', (151, 154))	('response', 'CPA', (98, 106))	('lower', 'NegReg', (84, 89))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (233, 241))	('SCC', 'Gene', (151, 154))
493755	23561329	Colony-forming assay data (Figure 5a) and the in vivo delay in tumor growth (Figure 5b) demonstrated that the IL-6 silencing vector significantly sensitized esophageal cancer cells to irradiation.	('tumor', 'Disease', (63, 68))	('silencing vector', 'Var', (115, 131))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('sensitized', 'NegReg', (146, 156))	('IL-6', 'Gene', (110, 114))	('esophageal cancer', 'Disease', (157, 174))
493756	23561329	As shown in Figure 5c-d, inhibition of IL-6 increased cell death and DNA damage and attenuated STAT3 activation after irradiation.	('cell death', 'CPA', (54, 64))	('IL-6', 'Gene', (39, 43))	('DNA damage', 'CPA', (69, 79))	('attenuated', 'NegReg', (84, 94))	('inhibition', 'Var', (25, 35))	('STAT3', 'Gene', '6774', (95, 100))	('IL-6 increased', 'Phenotype', 'HP:0030783', (39, 53))	('increased', 'PosReg', (44, 53))	('STAT3', 'Gene', (95, 100))
493759	23561329	As shown in Figure 5d, the IL-6 silencing vector significantly decreased angiogenesis by evidence of decreased MVD and VEGF staining in irradiated tumors.	('VEGF', 'Gene', '7422', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('silencing vector', 'Var', (32, 48))	('decreased', 'NegReg', (63, 72))	('decreased', 'NegReg', (101, 110))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('VEGF', 'Gene', (119, 123))	('IL-6', 'Gene', (27, 31))	('angiogenesis', 'CPA', (73, 85))
493762	23561329	Furthermore, in the subgroup of 118 patients treated with CCRT, but not in the 55 who underwent surgical intervention, positive IL-6 staining retained predictive power concerning survival in a multivariate analysis (Tables 7, 8).	('positive', 'Var', (119, 127))	('patients', 'Species', '9606', (36, 44))	('CCRT', 'Var', (58, 62))	('IL-6', 'Protein', (128, 132))	('survival', 'MPA', (179, 187))
493769	23561329	Furthermore, positive staining for IL-6 was associated with higher tumor stage, higher rates of tumor recurrence and distant metastasis.	('IL-6', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('positive staining', 'Var', (13, 30))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('distant metastasis', 'CPA', (117, 135))	('higher', 'PosReg', (80, 86))
493771	23561329	Data obtained from cell and xenograft tumor growth experiments revealed that inhibiting IL-6 resulted in slower tumor growth and reduced invasiveness.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', (112, 117))	('IL-6', 'Gene', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('slower tumor', 'Disease', 'MESH:D009369', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('inhibiting', 'Var', (77, 87))	('invasiveness', 'CPA', (137, 149))	('reduced', 'NegReg', (129, 136))	('slower tumor', 'Disease', (105, 117))
493774	23561329	In cell experiments, the IL-6 silencing vector induced both an increase in E-cadherin levels in esophageal cancer cells, and decreases in MMP-9 levels.	('increase', 'PosReg', (63, 71))	('MMP-9', 'Gene', '4318', (138, 143))	('E-cadherin', 'Gene', (75, 85))	('decreases', 'NegReg', (125, 134))	('MMP-9', 'Gene', (138, 143))	('esophageal cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('E-cadherin', 'Gene', '999', (75, 85))	('silencing vector', 'Var', (30, 46))	('IL-6', 'Gene', (25, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))
493780	23561329	In the present study, IL-6 silencing vectors significantly decreased IL-6 levels seen in the supernatant of cell culture medium and the serum of mice bearing tumors.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('IL-6 levels', 'MPA', (69, 80))	('decreased', 'NegReg', (59, 68))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('decreased IL-6', 'Phenotype', 'HP:0030783', (59, 73))	('IL-6', 'Gene', (22, 26))	('silencing vectors', 'Var', (27, 44))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
493790	23561329	We demonstrated that positive IL-6 staining was significantly associated with a lower response rate after treatment in patients with esophageal SCC.	('positive', 'Var', (21, 29))	('SCC', 'Gene', (144, 147))	('patients', 'Species', '9606', (119, 127))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('response rate', 'MPA', (86, 99))	('IL-6', 'Gene', (30, 34))	('SCC', 'Gene', '6317', (144, 147))	('lower', 'NegReg', (80, 85))
493794	23561329	Moreover, the data from xenograft tumors demonstrated that inhibition of IL-6 attenuated angiogenesis and decreased p-STAT3 activation after irradiation.	('decreased', 'NegReg', (106, 115))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('xenograft tumors', 'Disease', 'MESH:D009369', (24, 40))	('STAT3', 'Gene', '6774', (118, 123))	('STAT3', 'Gene', (118, 123))	('xenograft tumors', 'Disease', (24, 40))	('inhibition', 'Var', (59, 69))	('angiogenesis', 'CPA', (89, 101))	('IL-6', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('attenuated', 'NegReg', (78, 88))
493852	22024422	Although the trial performed by the German Study Group recognized a benefit for patients receiving neoadjuvant therapy, the benefit was not related to patients that did not respond to neoadjuvant therapy.	('neoadjuvant', 'Var', (99, 110))	('patients', 'Species', '9606', (80, 88))	('benefit', 'PosReg', (68, 75))	('patients', 'Species', '9606', (151, 159))
493893	22024422	The patients with pN0 lymph node status proved to have similar survival rates using both surgical procedures, whereas patients with pN1 lymph node status did not demonstrate a benefit from transthoracal resections.	('pN1', 'Gene', (132, 135))	('pN0 lymph node status', 'Var', (18, 39))	('patients', 'Species', '9606', (4, 12))	('pN1', 'Gene', '5270', (132, 135))	('patients', 'Species', '9606', (118, 126))
493899	22024422	Mutations of the K-RAS-genes, which revealed to predict a therapy-failure in colorectal cancer, are only rarely observed in squamous cell carcinoma of the esophagus.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('colorectal cancer', 'Disease', (77, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('squamous cell carcinoma of the esophagus', 'Disease', (124, 164))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (138, 164))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (124, 164))	('Mutations', 'Var', (0, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('K-RAS-genes', 'Gene', (17, 28))
493900	22024422	EGFR antibodies have been reported to work synergistically in patients with ESCC and are commonly used to enhance the effect of radiochemotherapy.	('enhance', 'PosReg', (106, 113))	('EGFR', 'Gene', (0, 4))	('antibodies', 'Var', (5, 15))	('ESCC', 'Disease', (76, 80))	('patients', 'Species', '9606', (62, 70))	('EGFR', 'Gene', '1956', (0, 4))
493916	23238211	Overweight and obesity are linked to increased incidence and mortality from multiple cancer types, with esophageal adenocarcinoma (EAC) displaying one of the strongest epidemiological associations.	('obesity', 'Disease', 'MESH:D009765', (15, 22))	('obesity', 'Disease', (15, 22))	('esophageal adenocarcinoma (EAC', 'Gene', (104, 134))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('esophageal adenocarcinoma (EAC)', 'Gene', '1540', (104, 135))	('Overweight', 'Var', (0, 10))	('cancer', 'Disease', (85, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('EAC', 'Phenotype', 'HP:0011459', (131, 134))	('obesity', 'Phenotype', 'HP:0001513', (15, 22))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (104, 129))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
493921	23238211	Treatment of tumor cells with exogenous PAI-1 has been found to induce a dose-dependent decrease in vitronectin binding and a corresponding increase in migratory and invasive capacity, with these effects abrogated by an antibody against PAI-1.	('PAI-1', 'Gene', (40, 45))	('tumor', 'Disease', (13, 18))	('binding', 'Interaction', (112, 119))	('decrease', 'NegReg', (88, 96))	('vitronectin', 'Gene', '7448', (100, 111))	('vitronectin', 'Gene', (100, 111))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('exogenous', 'Var', (30, 39))	('increase', 'PosReg', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
493924	23238211	Inhibition of PAI-1 could therefore be particularly relevant in viscerally obese patients with raised circulating levels of this adipokine.	('obese', 'Disease', 'MESH:D009765', (75, 80))	('circulating levels', 'MPA', (102, 120))	('PAI-1', 'Gene', (14, 19))	('patients', 'Species', '9606', (81, 89))	('obese', 'Disease', (75, 80))	('Inhibition', 'Var', (0, 10))
493946	23238211	RNA from original array samples and RNA from an independent cohort of cocultured samples was used for array validations, carried out using the following primer sets with dual labeled probes (Metabion, Munich, Germany): PAI-1 (fw: 5'-GCCATGGAACAAGGATGAGATC-3', rv: 5'-GCCCTGGACCAGCTTCAGA-3', probe: 5'-Fam-CCACAGACGCGATCTTCGTCCAGC-Tamra-3'), and primer/probe sets (Applied Biosystems, Carlsbad, CA, USA): SPP1 (Hs00959010_m1), SNAI2 (Hs00161904_m1), and E-cadherin (Hs01023894_m1).	('Hs00161904_m1', 'Var', (433, 446))	('SPP1', 'Gene', (404, 408))	('SPP1', 'Gene', '6696', (404, 408))	('Hs01023894_m1', 'Var', (465, 478))	('E-cadherin', 'Gene', (453, 463))	('E-cadherin', 'Gene', '999', (453, 463))	('Hs00959010_m1', 'Var', (410, 423))
493986	23238211	Notably, SNAI2 expression was more strongly associated with EAC survival than established prognostic indicators pathological tumor and node stage (P=0.38, P=0.128, respectively), indicating that our sample size is insufficient to detect a significant association with survival using the Cox regression multivariate analysis method.	('Cox', 'Gene', '1351', (287, 290))	('expression', 'Var', (15, 25))	('Cox', 'Gene', (287, 290))	('insufficient', 'Disease', (214, 226))	('insufficient', 'Disease', 'MESH:D000309', (214, 226))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('EAC', 'Gene', '1540', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('EAC', 'Gene', (60, 63))	('tumor', 'Disease', (125, 130))	('SNAI2', 'Gene', (9, 14))	('associated with', 'Reg', (44, 59))
494004	23238211	Furthermore, PAI-1 is a circulating adipokine, which is elevated in obesity, and high-fat diet-induced obese mice deficient in PAI-1 have reduced adipose tissue mass and increased insulin sensitivity, supporting a potential role for modulation of levels of PAI-1 activity in the treatment of obesity and its comorbidities.	('reduced', 'NegReg', (138, 145))	('obesity', 'Disease', (68, 75))	('obese', 'Disease', (103, 108))	('obesity', 'Phenotype', 'HP:0001513', (292, 299))	('insulin', 'Gene', (180, 187))	('PAI-1', 'Gene', (127, 132))	('obesity', 'Disease', 'MESH:D009765', (68, 75))	('adipose', 'Gene', '230796', (146, 153))	('increased', 'PosReg', (170, 179))	('reduced adipose tissue', 'Phenotype', 'HP:0040063', (138, 160))	('obese', 'Disease', 'MESH:D009765', (103, 108))	('PAI-1', 'Gene', (13, 18))	('adipose', 'Gene', (146, 153))	('obesity', 'Disease', (292, 299))	('deficient', 'Var', (114, 123))	('obesity', 'Phenotype', 'HP:0001513', (68, 75))	('insulin', 'Gene', '3630', (180, 187))	('obesity', 'Disease', 'MESH:D009765', (292, 299))	('mice', 'Species', '10090', (109, 113))	('increased insulin sensitivity', 'Phenotype', 'HP:0000855', (170, 199))
494031	31048652	However, the variation of mesenteric vessels around the colon may cause unpredictable ischemia.	('ischemia', 'Disease', (86, 94))	('ischemia', 'Disease', 'MESH:D007511', (86, 94))	('variation', 'Var', (13, 22))
494032	31048652	Although preoperative angiography provides information on the status of the mesenteric blood supply, twisting of the colon because of its position after cervical anastomosis and invisible monitoring may lead to inevitable necrosis.	('twisting', 'Var', (101, 109))	('necrosis', 'Disease', 'MESH:D009336', (222, 230))	('cervical anastomosis', 'Phenotype', 'HP:0002949', (153, 173))	('lead to', 'Reg', (203, 210))	('necrosis', 'Disease', (222, 230))
494075	29769385	Colon cancer studies showed that adding anti-epidermal growth factor receptor (anti-EGFR) inhibitors to irinotecan improved progression-free survival (PFS; 4.1 months in combined group vs. 1.5 months in irinotecan group; p < .001) of irinotecan-resistant metastatic colorectal cancer.	('colorectal cancer', 'Disease', (266, 283))	('Colon cancer', 'Phenotype', 'HP:0003003', (0, 12))	('progression-free', 'MPA', (124, 140))	('epidermal growth factor receptor', 'Gene', (45, 77))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Colon cancer', 'Disease', (0, 12))	('irinotecan', 'Chemical', 'MESH:D000077146', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('improved', 'PosReg', (115, 123))	('EGFR', 'Gene', '1956', (84, 88))	('irinotecan', 'Chemical', 'MESH:D000077146', (234, 244))	('irinotecan', 'Chemical', 'MESH:D000077146', (203, 213))	('colorectal cancer', 'Disease', 'MESH:D015179', (266, 283))	('epidermal growth factor receptor', 'Gene', '1956', (45, 77))	('Colon cancer', 'Disease', 'MESH:D015179', (0, 12))	('colorectal cancer', 'Phenotype', 'HP:0003003', (266, 283))	('EGFR', 'Gene', (84, 88))	('inhibitors', 'Var', (90, 100))
494077	29769385	KRAS mutations have been associated with resistance to anti-EGFR therapy in patients with metastatic colon cancer.	('patients', 'Species', '9606', (76, 84))	('colon cancer', 'Disease', 'MESH:D015179', (101, 113))	('colon cancer', 'Disease', (101, 113))	('associated', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (60, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))	('KRAS', 'Gene', (0, 4))	('EGFR', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (0, 4))
494079	29769385	Notably, KRAS mutations are extremely rare in esophageal cancer (2%).	('KRAS', 'Gene', (9, 13))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('KRAS', 'Gene', '3845', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (14, 23))
494124	30038642	The eligibility criteria included age 18-70 years, Eastern Cooperative Oncology Group (ECOG) status <= 2, histologically proven squamous/adenocarcinoma of esophagus, locally advanced stage (clinically defined as a T3N0 or T3N1 tumor, and stage T2N0 or T2N1 inoperable due to age or medical contraindications), hematological and biochemical parameters suitable for radiotherapy or chemotherapy, no tracheo-esophageal fistula, no prior chest radiotherapy or chemotherapy or definitive surgery, no other primary cancer, and any severe co-morbid disease.	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('adenocarcinoma', 'Disease', (137, 151))	('tumor', 'Disease', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (509, 515))	('Oncology', 'Phenotype', 'HP:0002664', (71, 79))	('adenocarcinoma', 'Disease', 'MESH:D000230', (137, 151))	('tracheo-esophageal fistula', 'Disease', 'MESH:D004937', (397, 423))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cancer', 'Disease', 'MESH:D009369', (509, 515))	('<= 2', 'Var', (100, 104))	('tracheo-esophageal fistula', 'Phenotype', 'HP:0002575', (397, 423))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('cancer', 'Disease', (509, 515))	('tracheo-esophageal fistula', 'Disease', (397, 423))
494127	30038642	Acceptable baseline hematological and biochemical parameters included hemoglobin level > 10 g/dl, leukocyte count > 4.0 x 109/ml, platelet count > 150 x 109/ml, urea < 40 mg/dl, creatinine < 1.5 mg/dl, total bilirubin < 1 mg/dl, and alanine aminotransferase and aspartate aminotransferase levels < 40 IU/ml.	('creatinine', 'Chemical', 'MESH:D003404', (178, 188))	('leukocyte count', 'CPA', (98, 113))	('urea', 'MPA', (161, 165))	('urea', 'Chemical', 'MESH:D014508', (161, 165))	('platelet', 'MPA', (130, 138))	('> 150 x', 'Var', (145, 152))	('aspartate aminotransferase levels', 'MPA', (262, 295))	('bilirubin < 1 mg/dl, and alanine aminotransferase', 'Gene', '2875', (208, 257))	('creatinine', 'MPA', (178, 188))	('< 40', 'Var', (166, 170))	('hemoglobin level', 'MPA', (70, 86))
494218	29393461	In addition, epithelial-mesenchymal transition, and the expression of VEGF-C and MMP9 were effectively decreased by let-7a-mimic or siRNA-Lin28 pretreatment.	('VEGF-C', 'Gene', (70, 76))	('MMP9', 'Gene', '4318', (81, 85))	('epithelial-mesenchymal transition', 'CPA', (13, 46))	('Lin28', 'Gene', (138, 143))	('Lin28', 'Gene', '79727', (138, 143))	('let-7a-mimic', 'Var', (116, 128))	('decreased', 'NegReg', (103, 112))	('expression', 'MPA', (56, 66))	('VEGF-C', 'Gene', '7424', (70, 76))	('let-7a', 'Chemical', '-', (116, 122))	('MMP9', 'Gene', (81, 85))
494230	29393461	Therefore, it is worth considering whether the changes of let-7a have a potential indicative effect of EMT, even metastasis for ESCC.	('let-7a', 'Chemical', '-', (58, 64))	('EMT', 'CPA', (103, 106))	('let-7a', 'Gene', (58, 64))	('changes', 'Var', (47, 54))	('metastasis', 'CPA', (113, 123))	('ESCC', 'Disease', (128, 132))
494240	29393461	Moreover, we showed that Lin28 knock-down or let-7a mimic repressed the invasion, EMT and metastasis.	('let-7a', 'Chemical', '-', (45, 51))	('Lin28', 'Gene', (25, 30))	('Lin28', 'Gene', '79727', (25, 30))	('knock-down', 'Var', (31, 41))	('invasion', 'CPA', (72, 80))
494277	29393461	However, inhibitors of let-7a had no evident effects (data not shown), potentially due to the extremely low inherent expression of the molecules.	('expression', 'MPA', (117, 127))	('inhibitors', 'Var', (9, 19))	('let-7a', 'Gene', (23, 29))	('let-7a', 'Chemical', '-', (23, 29))
494287	29393461	Similarly, the expression of VEGF-C and MMP9, but not VEGF-A and MMP2, varied inversely with let-7a (Fig.	('VEGF-A', 'Gene', (54, 60))	('let-7a', 'Var', (93, 99))	('VEGF-C', 'Gene', (29, 35))	('MMP2', 'Gene', (65, 69))	('MMP9', 'Gene', (40, 44))	('expression', 'MPA', (15, 25))	('let-7a', 'Chemical', '-', (93, 99))	('MMP2', 'Gene', '4313', (65, 69))	('MMP9', 'Gene', '4318', (40, 44))	('VEGF-A', 'Gene', '7422', (54, 60))	('VEGF-C', 'Gene', '7424', (29, 35))
494299	29393461	Similarly, the downregulation of Snail, VEGF-C, and MMP9 after Lin28 knockdown was reverted by LiCl treatment (Fig.	('downregulation', 'NegReg', (15, 29))	('Snail', 'Gene', '6615', (33, 38))	('LiCl', 'Chemical', 'MESH:D018021', (95, 99))	('MMP9', 'Gene', (52, 56))	('VEGF-C', 'Gene', '7424', (40, 46))	('Lin28', 'Gene', '79727', (63, 68))	('MMP9', 'Gene', '4318', (52, 56))	('VEGF-C', 'Gene', (40, 46))	('knockdown', 'Var', (69, 78))	('Lin28', 'Gene', (63, 68))	('Snail', 'Gene', (33, 38))
494303	29393461	In our study, we found low expression of let-7a, let-7b and let-7c in ESCC tumors and that let-7a was significantly inversely correlated with advanced stage, recurrence and poor prognosis.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('inversely', 'NegReg', (116, 125))	('expression', 'MPA', (27, 37))	('let-7b', 'Gene', '406884', (49, 55))	('let-7c', 'Gene', (60, 66))	('let-7a', 'Var', (91, 97))	('let-7a', 'Chemical', '-', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('low', 'NegReg', (23, 26))	('let-7a', 'Gene', (41, 47))	('advanced stage', 'CPA', (142, 156))	('correlated', 'Reg', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('let-7b', 'Gene', (49, 55))	('let-7c', 'Gene', '406885', (60, 66))	('let-7a', 'Chemical', '-', (41, 47))	('recurrence', 'CPA', (158, 168))	('ESCC', 'Disease', (70, 74))
494308	29393461	This evidence indicated that the loss of let-7a has potential to detect early signals of carcinogenic exposures for ESCC.	('let-7a', 'Protein', (41, 47))	('carcinogenic', 'Disease', 'MESH:D063646', (89, 101))	('let-7a', 'Chemical', '-', (41, 47))	('carcinogenic', 'Disease', (89, 101))	('loss', 'Var', (33, 37))
494309	29393461	The Wnt/beta-catenin pathway is involved in the development and homeostasis of many normal organs or tissues, thus its dysfunction often leads to terrible consequences, such as tumors.	('dysfunction', 'Var', (119, 130))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('beta-catenin', 'Gene', (8, 20))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('beta-catenin', 'Gene', '1499', (8, 20))	('tumors', 'Disease', (177, 183))	('leads to', 'Reg', (137, 145))
494314	29393461	As expected, after stimulation of the Wnt pathway by LiCl, malignancy was disrupted by siRNA-Lin28 or let-7a-mimic pretreatment.	('let-7a', 'Chemical', '-', (102, 108))	('Lin28', 'Gene', (93, 98))	('Lin28', 'Gene', '79727', (93, 98))	('malignancy', 'Disease', 'MESH:D009369', (59, 69))	('Wnt pathway', 'Pathway', (38, 49))	('disrupted', 'NegReg', (74, 83))	('let-7a-mimic', 'Var', (102, 114))	('malignancy', 'Disease', (59, 69))	('LiCl', 'Chemical', 'MESH:D018021', (53, 57))
494323	29262545	Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model.	('inhibited', 'NegReg', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Ad-ATF/SOX2', 'Var', (10, 21))	('SCC', 'Gene', (67, 70))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mouse', 'Species', '10090', (81, 86))	('SCC', 'Gene', '6317', (67, 70))	('tumor', 'Disease', (44, 49))
494331	29262545	The identification of these mutations and amplifications can be used to predict sensitivity to clinical inhibitors of pulmonary adenocarcinoma.	('pulmonary adenocarcinoma', 'Disease', (118, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (118, 142))	('mutations', 'Var', (28, 37))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 142))
494339	29262545	Amplification of chromosome 3q26 is the most common of the genetic alterations found in lung SCC.	('common', 'Reg', (45, 51))	('Amplification', 'Var', (0, 13))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('SCC', 'Gene', '6317', (93, 96))
494340	29262545	SOX2 is a candidate oncogene present in this locus and amplification of SOX2 has been reported in lung and esophageal SCC.	('amplification', 'Var', (55, 68))	('SOX2', 'Gene', (72, 76))	('SCC', 'Gene', (118, 121))	('reported', 'Reg', (86, 94))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('SCC', 'Gene', '6317', (118, 121))
494341	29262545	In a previous study, we demonstrated that silencing SOX2 by siRNA induced G1 cell cycle arrest mediated by upregulation of CDKN1A expression resulting in an anti tumor effect in SOX2-expressing lung SCC cells both in vitro and in vivo.	('upregulation', 'PosReg', (107, 119))	('silencing', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('SCC', 'Gene', (199, 202))	('SCC', 'Phenotype', 'HP:0002860', (199, 202))	('tumor', 'Disease', (162, 167))	('CDKN1A', 'Gene', (123, 129))	('SCC', 'Gene', '6317', (199, 202))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('G1 cell cycle arrest', 'CPA', (74, 94))
494343	29262545	In human lung SCC and esophageal SCC sections, SOX2 expression was detected in more than 87.5% of sections (Figure 1B and 1C) suggesting that molecular targeting of SOX2 might be useful for treating SCC.	('SCC', 'Gene', '6317', (33, 36))	('SCC', 'Gene', (199, 202))	('human', 'Species', '9606', (3, 8))	('SCC', 'Phenotype', 'HP:0002860', (199, 202))	('SCC', 'Gene', (14, 17))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('SCC', 'Gene', '6317', (199, 202))	('SCC', 'Gene', '6317', (14, 17))	('SCC', 'Gene', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))	('molecular targeting', 'Var', (142, 161))
494349	29262545	Furthermore, Ad-ATF/SOX2 induced an antitumor effect in SOX2-expressing SCC more effectively than did Ad-shSOX2 both in vitro and in vivo.	('Ad-ATF/SOX2', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('SOX2-expressing', 'Gene', (56, 71))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('SCC', 'Gene', '6317', (72, 75))
494350	29262545	These results indicate that the transcriptional SOX2 inhibition achieved by ATF/SOX2 activated CDKN1A and showed a greater antitumor effect more strongly than post-transcriptional SOX2 inhibition by shRNA.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('inhibition', 'NegReg', (53, 63))	('tumor', 'Disease', (127, 132))	('activated', 'PosReg', (85, 94))	('transcriptional SOX2', 'MPA', (32, 52))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('CDKN1A', 'Enzyme', (95, 101))	('ATF/SOX2', 'Var', (76, 84))
494355	29262545	On the other hand, in the presence of pcDNA3.1 ATF/SOX2, transcriptional activity of the SOX2 was significantly decreased in EBC2 cells (1.9-fold).	('ATF/SOX2', 'Gene', (47, 55))	('EBC', 'Chemical', '-', (125, 128))	('pcDNA3.1', 'Var', (38, 46))	('decreased', 'NegReg', (112, 121))	('transcriptional activity', 'MPA', (57, 81))
494356	29262545	In esophageal SCC cells, the region -1990/+436 exhibited significant transcriptional activity in TE1 cells (32 -fold) and in TE4 cells (65 -fold).	('SCC', 'Gene', (14, 17))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('transcriptional activity', 'MPA', (69, 93))	('SCC', 'Gene', '6317', (14, 17))	('region -1990/+436', 'Var', (29, 46))
494360	29262545	We previously reported that CDKN1A is a SOX2 downstream gene and that silencing of SOX2 increases the expression of CDKN1A which induces cell cycle arrest in lung SCC cells.	('induces', 'Reg', (129, 136))	('SOX2', 'Gene', (83, 87))	('CDKN1A', 'Gene', (116, 122))	('silencing', 'Var', (70, 79))	('expression', 'MPA', (102, 112))	('SCC', 'Gene', (163, 166))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (137, 154))	('increases', 'PosReg', (88, 97))	('SCC', 'Gene', '6317', (163, 166))	('cell cycle arrest', 'CPA', (137, 154))
494362	29262545	We then determined SOX2 and CDKN1A expression in lung and esophageal SCC cells after Ad-shSOX2 or Ad-ATF/SOX2 infection.	('Ad-shSOX2', 'Var', (85, 94))	('SCC', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('CDKN1A', 'Gene', (28, 34))	('SCC', 'Gene', '6317', (69, 72))
494363	29262545	As shown in Figure 4, both Ad-shSOX2 and Ad-ATF/SOX2 effectively suppressed SOX2 expression in EBC2 lung SCC cells, TE1 and TE4 esophageal SCC cells 48 hours after adenoviral infections.	('adenoviral infections', 'Disease', (164, 185))	('SCC', 'Gene', '6317', (139, 142))	('adenoviral infections', 'Disease', 'MESH:D007239', (164, 185))	('Ad-shSOX2', 'Var', (27, 36))	('SOX2', 'Gene', (76, 80))	('suppressed', 'NegReg', (65, 75))	('SCC', 'Gene', (105, 108))	('EBC', 'Chemical', '-', (95, 98))	('SCC', 'Gene', (139, 142))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('SCC', 'Gene', '6317', (105, 108))
494364	29262545	Importantly, in EBC2 cells and TE4 cells, SOX2 protein expression was more robustly suppressed by Ad-shSOX2 than by Ad-ATF/SOX2, however, CDKN1A expression was greater in all kinds of cells in the Ad-ATF/SOX2 treated cells than in Ad-shSOX2 treated cells.	('SOX2', 'Gene', (42, 46))	('expression', 'MPA', (145, 155))	('EBC', 'Chemical', '-', (16, 19))	('greater', 'PosReg', (160, 167))	('CDKN1A', 'Gene', (138, 144))	('Ad-shSOX2', 'Var', (98, 107))	('suppressed', 'NegReg', (84, 94))
494365	29262545	Moreover, as shown in Supplementary Figure 2, G1 cell cycle arrest was induced in EBC2 cells and TE4 cells 36 hours after Ad-ATF/SOX2 infection, whereas the G0/G1 cell population was very weakly increased after Ad-shSOX2 infection.	('Ad-ATF/SOX2 infection', 'Var', (122, 143))	('induced', 'Reg', (71, 78))	('infection', 'Var', (134, 143))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))	('G1 cell cycle arrest', 'CPA', (46, 66))	('EBC', 'Chemical', '-', (82, 85))
494366	29262545	In this study, EBC2 lung SCC cells, TE1 and TE4 esophageal SCC cells harbor mutant TP53.	('SCC', 'Gene', (25, 28))	('SCC', 'Gene', (59, 62))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('TP53', 'Gene', (83, 87))	('mutant', 'Var', (76, 82))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('SCC', 'Gene', '6317', (25, 28))	('SCC', 'Gene', '6317', (59, 62))	('EBC', 'Chemical', '-', (15, 18))
494370	29262545	Furthermore, as shown in Figure 5B and 5C, Ad-ATF/SOX2 significantly decreased colony formation more than Ad-null and Ad-shSOX2 in EBC2, TE1 and TE4 cells.	('Ad-ATF/SOX2', 'Var', (43, 54))	('colony formation', 'CPA', (79, 95))	('decreased', 'NegReg', (69, 78))	('EBC', 'Chemical', '-', (131, 134))
494372	29262545	In this experiment, Ad-shSOX2 inhibited colony formation of EBC2 cells but not of TE1 cells and TE4 cells.	('colony formation', 'CPA', (40, 56))	('Ad-shSOX2', 'Var', (20, 29))	('inhibited', 'NegReg', (30, 39))	('EBC2', 'Gene', (60, 64))	('EBC', 'Chemical', '-', (60, 63))
494373	29262545	On the other hand, CDKN1A expression was clearly different after Ad-null and Ad-shSOX2 infection in EBC2 cells.	('expression', 'MPA', (26, 36))	('CDKN1A', 'Gene', (19, 25))	('EBC', 'Chemical', '-', (100, 103))	('different', 'Reg', (49, 58))	('Ad-shSOX2', 'Var', (77, 86))
494374	29262545	It is possible that Ad-shSOX2 could not significantly inhibit cell viability in EBC2 lung SCC cells just 48 hours after infection but that it could show anti tumor effect in colony formation of EBC cells during a longer time incubation after treatment but not in TE1 and TE4 cells.	('tumor', 'Disease', (158, 163))	('Ad-shSOX2', 'Var', (20, 29))	('SCC', 'Gene', (90, 93))	('colony formation', 'CPA', (174, 190))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('EBC', 'Chemical', '-', (194, 197))	('EBC', 'Chemical', '-', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('SCC', 'Gene', '6317', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
494376	29262545	The tumor volume in the mice group treated with Ad-shSOX2 was approximately 37% of those in the mice group treated with Ad-null (p = 0.0026).	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (96, 100))	('mice', 'Species', '10090', (24, 28))	('Ad-shSOX2', 'Var', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
494382	29262545	These results indicate that Ad-ATF/SOX2 could induce antitumor effect in SCC cells expressing SOX2 but not in normal cells.	('SOX2', 'Var', (94, 98))	('SCC', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('expressing SOX2', 'Var', (83, 98))	('SCC', 'Gene', '6317', (73, 76))	('induce', 'PosReg', (46, 52))	('tumor', 'Disease', (57, 62))
494389	29262545	In this study, SOX2 expression was more robustly suppressed by Ad-shSOX2 than by Ad-ATF/SOX2 in EBC2 cells and TE4 cells.	('EBC', 'Chemical', '-', (96, 99))	('expression', 'MPA', (20, 30))	('Ad-shSOX2', 'Var', (63, 72))	('suppressed', 'NegReg', (49, 59))	('SOX2', 'Gene', (15, 19))
494418	29262545	We designed and constructed an artificial zinc finger protein (AZP) targeting -161 to -143 in the human SOX2 gene, where +1 is the transcription start site, by using our recognition code table as described.	('human', 'Species', '9606', (98, 103))	('targeting -161 to -143', 'Var', (68, 90))	('SOX2', 'Gene', (104, 108))
494443	29262545	The specific probe for CDKN1A (Hs00355782_m1), BMP2 (Hs00154192_m1), SNAI1 (Hs00195591_m1), VIM (Hs00958111_m1), ABL1 (Hs01104728_m1), RTN4 (Hs00199671_m1), KMT2B (Hs00207065_m1), MSH6 (Hs00943000_m1) and Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Hs03929097_g1) were derived from the commercially available TaqMan Gene Expression Assays (Applied Biosystems, Life Technologies, CA).	('Hs00943000_m1', 'Var', (186, 199))	('VIM', 'Gene', '7431', (92, 95))	('Hs00195591_m1', 'Var', (76, 89))	('ABL1', 'Gene', '25', (113, 117))	('Glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (205, 245))	('VIM', 'Gene', (92, 95))	('Hs01104728_m1', 'Var', (119, 132))	('RTN4', 'Gene', '57142', (135, 139))	('KMT2B', 'Gene', '9757', (157, 162))	('Hs03929097_g1', 'Var', (255, 268))	('GAPDH', 'Gene', '2597', (247, 252))	('Hs00207065_m1', 'Var', (164, 177))	('MSH6', 'Gene', (180, 184))	('RTN4', 'Gene', (135, 139))	('MSH6', 'Gene', '2956', (180, 184))	('BMP2', 'Gene', '650', (47, 51))	('GAPDH', 'Gene', (247, 252))	('KMT2B', 'Gene', (157, 162))	('Hs00199671_m1', 'Var', (141, 154))	('SNAI1', 'Gene', '6615', (69, 74))	('SNAI1', 'Gene', (69, 74))	('Hs00154192_m1', 'Var', (53, 66))	('Glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (205, 245))	('BMP2', 'Gene', (47, 51))	('Hs00958111_m1', 'Var', (97, 110))	('ABL1', 'Gene', (113, 117))	('Hs00355782_m1', 'Var', (31, 44))
494447	29262545	EBC2 lung SCC cells were plated in 15 cm dishes at a density of 4 x 106 per dish and cultured overnight at 37 C. The following day cells were infected with Ad-null, Ad-shSOX2 or Ad-ATF/SOX2 at a MOI of 250 for 24 hours.	('EBC', 'Chemical', '-', (0, 3))	('Ad-shSOX2', 'Var', (165, 174))	('SCC', 'Gene', (10, 13))	('Ad-null', 'Var', (156, 163))	('SCC', 'Phenotype', 'HP:0002860', (10, 13))	('Ad-ATF/SOX2', 'Var', (178, 189))	('SCC', 'Gene', '6317', (10, 13))
494486	24694107	High PIGR expression was an independent predictor of a prolonged OS (HR = 0.60, 95% CI 0.36-0.99) and RFS (HR = 0.49, 95% CI 0.27-0.90) in patients with radically resected (R0) primary tumours and of an improved RFS (HR = 0.32, 95% CI 0.15-0.69) in curatively treated patients with R0 resection/distant metastasis-free disease.	('patients', 'Species', '9606', (268, 276))	('metastasis-free disease', 'Disease', 'MESH:D009362', (303, 326))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (139, 147))	('primary tumours', 'Disease', 'MESH:D009369', (177, 192))	('tumours', 'Phenotype', 'HP:0002664', (185, 192))	('metastasis-free disease', 'Disease', (303, 326))	('PIGR', 'Gene', (5, 9))	('PIGR', 'Gene', '5284', (5, 9))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('prolonged', 'PosReg', (55, 64))	('RFS', 'MPA', (102, 105))	('primary tumours', 'Disease', (177, 192))	('RFS', 'MPA', (212, 215))
494498	24694107	PIGR has been described as a putative cancer biomarker in a few studies on different cancer forms, the majority of which indicate an association between low PIGR expression and more aggressive disease.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('PIGR', 'Gene', '5284', (157, 161))	('low', 'Var', (153, 156))	('aggressive disease', 'Disease', (182, 200))	('more', 'Disease', (177, 181))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('PIGR', 'Gene', '5284', (0, 4))	('aggressive disease', 'Disease', 'MESH:D001523', (182, 200))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('expression', 'MPA', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (38, 44))	('PIGR', 'Gene', (157, 161))	('PIGR', 'Gene', (0, 4))
494500	24694107	Low PIGR expression has also been shown to correlate with progression from colon adenoma to carcinoma and with poor prognosis in colon cancer.	('colon adenoma to carcinoma', 'Disease', 'MESH:D000236', (75, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (129, 141))	('Low', 'Var', (0, 3))	('colon cancer', 'Disease', 'MESH:D015179', (129, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('PIGR', 'Gene', '5284', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('expression', 'MPA', (9, 19))	('colon cancer', 'Disease', (129, 141))	('colon adenoma to carcinoma', 'Disease', (75, 101))	('PIGR', 'Gene', (4, 8))
494517	24694107	Kaplan Meier analysis and the log rank test were applied to estimate differences in OS and RFS in strata according to high and low PIGR expression.	('high', 'Var', (118, 122))	('PIGR', 'Gene', (131, 135))	('PIGR', 'Gene', '5284', (131, 135))	('low', 'NegReg', (127, 130))
494533	24694107	In cases with radically resected (R0) primary tumours there was a significant association between high PIGR expression and a prolonged OS (p = 0.030, Figure 3B).	('PIGR', 'Gene', (103, 107))	('primary tumours', 'Disease', 'MESH:D009369', (38, 53))	('high', 'Var', (98, 102))	('prolonged OS', 'Disease', (125, 137))	('primary tumours', 'Disease', (38, 53))	('PIGR', 'Gene', '5284', (103, 107))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
494534	24694107	There was a significant association between high PIGR expression and an improved RFS in cases with R0 resection (p = 0.015, Figure 3C) and in curatively treated patients with R0 resection and no distant metastases (M0, p = 000.2, Figure 3D).	('PIGR', 'Gene', (49, 53))	('expression', 'MPA', (54, 64))	('metastases', 'Disease', 'MESH:D009362', (203, 213))	('high', 'Var', (44, 48))	('improved', 'PosReg', (72, 80))	('PIGR', 'Gene', '5284', (49, 53))	('patients', 'Species', '9606', (161, 169))	('RFS', 'MPA', (81, 84))	('metastases', 'Disease', (203, 213))
494535	24694107	As demonstrated in Table 3, the significant association of PIGR expression and a prolonged OS was confirmed in unadjusted Cox regression analysis (HR 0.58, 95% CI 0.36-0.96, p = 0.032), and remained significant in adjusted analysis (HR 0.60, 95% CI 0.36-0.99, p = 0.044).	('prolonged OS', 'Disease', (81, 93))	('expression', 'Var', (64, 74))	('PIGR', 'Gene', (59, 63))	('PIGR', 'Gene', '5284', (59, 63))
494536	24694107	As further shown in Table 4, PIGR expression was significantly associated with prolonged RFS in unadjusted analysis for cases with R0 resection (HR 0.49, 95% CI 0.27-0.88, p = 0.017) and curatively treated patients with R0 resection/M0 disease (HR 0.37, 95% CI 0.19-0.72, p = 0.004).	('PIGR', 'Gene', (29, 33))	('expression', 'Var', (34, 44))	('prolonged', 'PosReg', (79, 88))	('patients', 'Species', '9606', (206, 214))	('RFS', 'MPA', (89, 92))	('PIGR', 'Gene', '5284', (29, 33))
494540	24694107	The results from this study demonstrate that high PIGR expression is an independent favourable prognostic factor in adenocarcinoma of the upper gastrointestinal tract.	('adenocarcinoma of the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (116, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('PIGR', 'Gene', (50, 54))	('expression', 'MPA', (55, 65))	('high', 'Var', (45, 49))	('PIGR', 'Gene', '5284', (50, 54))	('adenocarcinoma of the upper gastrointestinal tract', 'Disease', (116, 166))
494542	24694107	In the present study, however, there was no significant association between PIGR expression and lymph node metastasis, but high PIGR expression was significantly associated with a less advanced T-stage and uninvolved resection margins.	('PIGR', 'Gene', (128, 132))	('PIGR', 'Gene', (76, 80))	('high', 'Var', (123, 127))	('PIGR', 'Gene', '5284', (128, 132))	('PIGR', 'Gene', '5284', (76, 80))	('less advanced T-stage', 'CPA', (180, 201))
494543	24694107	These findings are also in line with the majority of previous studies on other cancer forms, indicating an association between high PIGR expression and a better prognosis; e.g.	('PIGR', 'Gene', (132, 136))	('expression', 'MPA', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('high', 'Var', (127, 131))	('PIGR', 'Gene', '5284', (132, 136))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
494545	24694107	To date, only one study on HCC has demonstrated an association between high PIGR expression and a higher metastatic potential and worse clinical outcome.	('high', 'Var', (71, 75))	('metastatic potential', 'CPA', (105, 125))	('PIGR', 'Gene', (76, 80))	('PIGR', 'Gene', '5284', (76, 80))	('clinical', 'Species', '191496', (136, 144))	('expression', 'MPA', (81, 91))
494561	24694107	Polymorphonuclear neutrophils (PMNs) that are generally believed to be antitumorigenic have also been reported to actually facilitate tumour progression and invasion.	('Polymorphonuclear', 'Var', (0, 17))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('invasion', 'CPA', (157, 165))	('tumour', 'Disease', (134, 140))	('facilitate', 'PosReg', (123, 133))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
494572	24694107	High PIGR expression is associated with a less advanced T-stage and independently predicts a decreased risk of recurrence and an improved survival in patients with adenocarcinoma of the upper gastrointestinal tract.	('High', 'Var', (0, 4))	('T-stage', 'CPA', (56, 63))	('adenocarcinoma of the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (164, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('PIGR', 'Gene', (5, 9))	('decreased', 'NegReg', (93, 102))	('patients', 'Species', '9606', (150, 158))	('PIGR', 'Gene', '5284', (5, 9))	('improved', 'PosReg', (129, 137))	('adenocarcinoma of the upper gastrointestinal tract', 'Disease', (164, 214))
494785	21997082	It should also be noted that motion also causes Doppler-induced depth error, reduction in spatial resolution, and signal-to-noise ratio degradation.	('degradation', 'NegReg', (136, 147))	('depth error', 'Disease', 'MESH:D007222', (64, 75))	('reduction', 'NegReg', (77, 86))	('spatial resolution', 'MPA', (90, 108))	('motion', 'Var', (29, 35))	('depth error', 'Disease', (64, 75))	('signal-to-noise ratio', 'MPA', (114, 135))
494794	32156725	Splice variant of growth hormone-releasing hormone receptor drives esophageal squamous cell carcinoma conferring a therapeutic target An explanation has been lacking for the suppressive action of antagonists of growth hormone-releasing hormone receptors (GHRH-Rs) on cancers that do not express GHRH-Rs, an established target of the antagonists.	('growth hormone-releasing hormone receptor', 'Gene', '2692', (211, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('growth hormone-releasing hormone receptor', 'Gene', (18, 59))	('Splice variant', 'Var', (0, 14))	('cancers', 'Disease', 'MESH:D009369', (267, 274))	('growth hormone-releasing hormone', 'Gene', '2691', (18, 50))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancers', 'Disease', (267, 274))	('growth hormone-releasing hormone', 'Gene', '2691', (211, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('squamous cell carcinoma', 'Disease', (78, 101))	('growth hormone-releasing hormone receptor', 'Gene', (211, 252))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('growth hormone-releasing hormone receptor', 'Gene', '2692', (18, 59))
494801	32156725	It has been shown that the pituitary type of GHRH-R (pGHRH-R) mediates the inhibition of tumor growth induced by GHRH-R antagonists.	('inhibition', 'NegReg', (75, 85))	('pGHRH-R', 'Chemical', '-', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('antagonists', 'Var', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
494808	32156725	Aberrant RNA splicing is a common characteristic of cancers.	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('Aberrant', 'Var', (0, 8))	('R', 'Chemical', 'MESH:D019344', (9, 10))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
494809	32156725	Products of alternative splicing may display functions distinct from their canonical full-length transcripts, tending to mediate constitutively active proto-oncogenes, regulating cancer stem cells, promoting metastasis, and developing resistance to therapy.	('alternative splicing', 'Var', (12, 32))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('metastasis', 'CPA', (208, 218))	('Products', 'Var', (0, 8))	('regulating', 'Reg', (168, 178))	('promoting', 'PosReg', (198, 207))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('developing', 'Reg', (224, 234))	('cancer', 'Disease', (179, 185))	('resistance to therapy', 'CPA', (235, 256))
494810	32156725	Emerging evidence strongly suggests that hypoxia is a key driver of alternative splicing in cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('alternative splicing', 'Var', (68, 88))	('hypoxia', 'Disease', (41, 48))	('cancers', 'Disease', (92, 99))	('hypoxia', 'Disease', 'MESH:D000860', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
494823	32156725	To investigate whether GHRH-R antagonists have inhibitory effects on human ESCC, ESCC cells KYSE150 and HKESC-2 were treated with different concentrations of MIA-602 for 48 h. MIA-602 began to exert significant inhibitory effects on cell viability at 5 muM in both cells (P < 0.01 for 5 muM, and P < 0.001 for 10 muM) (Fig.	('cell viability', 'CPA', (233, 247))	('muM', 'Gene', (253, 256))	('muM', 'Gene', (287, 290))	('HKESC-2', 'CellLine', 'CVCL:D571', (104, 111))	('MIA', 'Chemical', '-', (158, 161))	('muM', 'Gene', '56925', (313, 316))	('human', 'Species', '9606', (69, 74))	('MIA', 'Chemical', '-', (176, 179))	('muM', 'Gene', (313, 316))	('MIA-602', 'Var', (176, 183))	('muM', 'Gene', '56925', (253, 256))	('muM', 'Gene', '56925', (287, 290))	('KYSE150', 'CellLine', 'CVCL:1348', (92, 99))
494824	32156725	Subsequently, a real-time cell analyzer (RTCA) was used to investigate the dynamic behavior of migration and invasion of KYSE150 cells exposed to MIA-602 (SI Appendix, Fig.	('R', 'Chemical', 'MESH:D019344', (41, 42))	('invasion', 'CPA', (109, 117))	('KYSE150', 'CellLine', 'CVCL:1348', (121, 128))	('MIA', 'Chemical', '-', (146, 149))	('MIA-602', 'Var', (146, 153))
494849	32156725	Cell proliferation monitored by RTCA showed that knockdown of SV1 decreased cell proliferation in KYSE150 cells (P < 0.01) (Fig.	('KYSE150', 'CellLine', 'CVCL:1348', (98, 105))	('knockdown', 'Var', (49, 58))	('decreased', 'NegReg', (66, 75))	('cell proliferation in KYSE150 cells', 'CPA', (76, 111))	('SV1', 'Gene', (62, 65))	('R', 'Chemical', 'MESH:D019344', (32, 33))
494851	32156725	Collectively, these results confirm that SV1 was the target of the GHRH-R antagonist MIA-602 and was able to mediate MIA-602's inhibitory effects in human ESCC.	('human', 'Species', '9606', (149, 154))	('MIA', 'Chemical', '-', (117, 120))	('inhibitory', 'MPA', (127, 137))	('GHRH-R', 'Gene', (67, 73))	('MIA-602', 'Var', (117, 124))	('MIA', 'Chemical', '-', (85, 88))	('ESCC', 'Disease', (155, 159))
494852	32156725	Recently, hypoxia within tumor tissues was indicated as a driver of alternative splicing that contributes to tumorigenic development.	('hypoxia within tumor', 'Disease', 'MESH:D000860', (10, 30))	('R', 'Chemical', 'MESH:D019344', (0, 1))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('hypoxia within tumor', 'Disease', (10, 30))	('tumor', 'Disease', (25, 30))	('alternative splicing', 'Var', (68, 88))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('contributes', 'Reg', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (109, 114))
494868	32156725	TE1 and KYSE140 cells stably overexpressing PFKM were subjected to RTCA assays, and increased proliferation was observed in both cells (SI Appendix, Fig.	('proliferation', 'CPA', (94, 107))	('increased', 'PosReg', (84, 93))	('PFKM', 'Var', (44, 48))	('R', 'Chemical', 'MESH:D019344', (67, 68))
494882	32156725	The nuclear translocation of p65 was blocked by MIA-602, but reappeared after SV1 overexpression (Fig.	('nuclear translocation', 'MPA', (4, 25))	('expression', 'Species', '29278', (86, 96))	('MIA', 'Chemical', '-', (48, 51))	('MIA-602', 'Var', (48, 55))	('p65', 'Protein', (29, 32))
494884	32156725	To demonstrate that GHRH-R antagonists are capable of inhibiting tumor growth by targeting the SV1-PFKM axis in vivo, we established xenograft tumor models by subcutaneous (s.c.) inoculation of KYSE150-SV1, KYSE150-PFKM, and KYSE150-Vector cells into nude mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('KYSE150', 'CellLine', 'CVCL:1348', (207, 214))	('KYSE150-SV1', 'Var', (194, 205))	('KYSE150', 'CellLine', 'CVCL:1348', (225, 232))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('KYSE150', 'CellLine', 'CVCL:1348', (194, 201))	('nude mice', 'Species', '10090', (251, 260))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('inhibiting', 'NegReg', (54, 64))
494887	32156725	Of note, both SV1 and PFKM overexpression partially counteracted the inhibitory effects on tumor growth induced by MIA-602 (Fig.	('expression', 'Species', '29278', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('MIA', 'Chemical', '-', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('MIA-602', 'Var', (115, 122))	('tumor', 'Disease', (91, 96))
494903	32156725	Combining these results with the finding that MIA-602, a highly potent GHRH-R antagonist, exerts antineoplastic effects in ESCC cells, we can consider ESCC a representative model to demonstrate that SV1 mediates the therapeutic effects of GHRH-R antagonists in human tumors with low expression of pGHRH-R.	('antineoplastic effects', 'MPA', (97, 119))	('pGHRH-R', 'Chemical', '-', (297, 304))	('human', 'Species', '9606', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('MIA', 'Chemical', '-', (46, 49))	('expression', 'Species', '29278', (283, 293))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('tumors', 'Disease', (267, 273))	('pGHRH-R', 'Gene', (297, 304))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('MIA-602', 'Var', (46, 53))
494909	32156725	Alternative splicing in tumor cells is one of the cellular adaptations that are largely promoted by the hypoxic microenvironment in solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (24, 29))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('Alternative splicing', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
494917	32156725	In this study, we defined a previously undocumented molecular pathway by which hypoxia acts through a splice variant of a membrane hormone receptor to elevate the glycolytic enzyme PFKM, indicating that hypoxia-induced metabolic changes in cancer cells may involve a more complex regulation.	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('elevate', 'PosReg', (151, 158))	('glycolytic', 'MPA', (163, 173))	('hypoxia', 'Disease', (203, 210))	('hypoxia', 'Disease', 'MESH:D000860', (203, 210))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('hypoxia', 'Disease', (79, 86))	('splice variant', 'Var', (102, 116))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('cancer', 'Disease', (240, 246))
494928	32156725	One major challenge of these inhibitors is their potential toxicity to certain normal tissues that also use glucose as their main energy source, such as brain, retinae, and testis.	('toxicity', 'Disease', 'MESH:D064420', (59, 67))	('glucose', 'Chemical', 'MESH:D005947', (108, 115))	('inhibitors', 'Var', (29, 39))	('toxicity', 'Disease', (59, 67))
495001	30350313	In particular, APC, ARID1A and NOTCH1 were recurrently inactivated by the presence of homozygous mutation as a consequence of aUPD in COAD and READ, STAD and ESCC, respectively.	('NOTCH1', 'Gene', '4851', (31, 37))	('APC', 'Gene', '324', (15, 18))	('ARID1A', 'Gene', '8289', (20, 26))	('COAD', 'Disease', (134, 138))	('ARID1A', 'Gene', (20, 26))	('presence', 'Var', (74, 82))	('READ', 'Disease', (143, 147))	('COAD', 'Disease', 'MESH:D029424', (134, 138))	('APC', 'Gene', (15, 18))	('UPD', 'Gene', '7389', (127, 130))	('NOTCH1', 'Gene', (31, 37))	('UPD', 'Gene', (127, 130))	('READ', 'Disease', 'None', (143, 147))
495002	30350313	Furthermore, while TP53 showed inactivation caused by aUPD at chromosome arm 17p across all tumor types, copy number losses at this genomic position were also frequent.	('UPD', 'Gene', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('copy number losses', 'Var', (105, 123))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('tumor', 'Disease', (92, 97))	('UPD', 'Gene', '7389', (55, 58))	('inactivation', 'MPA', (31, 43))
495003	30350313	By experimental and computationally inferring genome ploidy, we demonstrate that an increased number of aUPD events, both affecting the whole chromosome or segments of it, were present in highly aneuploid genomes compared to near-diploid tumors.	('UPD', 'Gene', '7389', (105, 108))	('affecting', 'Reg', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('UPD', 'Gene', (105, 108))	('diploid tumors', 'Disease', 'MESH:C548012', (230, 244))	('diploid tumors', 'Disease', (230, 244))	('aneuploid', 'Var', (195, 204))
495009	30350313	The data also reveal a nonrandom distribution of aUPDs, with evidence of biallelic inactivation of tumor suppressor genes and activation of oncogenes in a tumor type-specific manner.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('UPD', 'Gene', '7389', (50, 53))	('tumor', 'Disease', (155, 160))	('activation', 'PosReg', (126, 136))	('biallelic inactivation', 'Var', (73, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('oncogenes', 'Gene', (140, 149))	('UPD', 'Gene', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
495011	30350313	ASCAT Allele-Specific Copy Number Analysis of Tumors aUPD somatically acquired uniparental disomy BAF B allele frequency CEP Centromeric FISH probes CIN chromosome instability CNAs copy number alterations cnLOH copy-number neutral loss of heterozygosity COAD colon adenocarcinoma CRC colorectal cancer EAC esophageal adenocarcinoma ESCA esophageal carcinoma ESCC esophageal squamous cell carcinoma FISH Fluorescence in situ hybridization GI gastrointestinal IBD identical-by-descent INDELs short insertions and deletions LOH loss of heterozygosity LRR Log R Ratio MAD Mosaic Alteration Detection MAF Mutation Annotation Format MLPA Multiplex Ligation-dependent Probe Amplification PSCBS Parent-Specific Circular Binary Segmentation READ rectum adenocarcinoma RNAi RNA interference.	('carcinoma', 'Phenotype', 'HP:0030731', (749, 758))	('gastrointestinal', 'Disease', (441, 457))	('UPD', 'Gene', '7389', (54, 57))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (259, 279))	('gastrointestinal', 'Disease', 'MESH:D005767', (441, 457))	('BAF', 'Gene', '8815', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('Tumors', 'Phenotype', 'HP:0002664', (46, 52))	('EAC', 'Phenotype', 'HP:0011459', (302, 305))	('B allele frequency', 'Gene', (102, 120))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (737, 758))	('READ', 'Disease', (732, 736))	('COAD', 'Disease', (254, 258))	('CIN', 'Phenotype', 'HP:0040012', (149, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (284, 301))	('deletions', 'Var', (511, 520))	('B allele frequency', 'Gene', '8815', (102, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (337, 357))	('CIN', 'Disease', 'MESH:D007674', (149, 152))	('CRC', 'Phenotype', 'HP:0003003', (280, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (388, 397))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (306, 331))	('chromosome instability', 'Phenotype', 'HP:0040012', (153, 175))	('esophageal squamous cell carcinoma', 'Disease', (363, 397))	('colorectal cancer', 'Disease', (284, 301))	('Tumors', 'Disease', (46, 52))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (306, 331))	('uniparental disomy', 'Disease', (79, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (348, 357))	('esophageal carcinoma', 'Disease', (337, 357))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('colon adenocarcinoma', 'Disease', (259, 279))	('READ', 'Disease', 'None', (732, 736))	('UPD', 'Gene', (54, 57))	('uniparental disomy', 'Disease', 'MESH:D024182', (79, 97))	('rectum adenocarcinoma', 'Disease', (737, 758))	('esophageal adenocarcinoma', 'Disease', (306, 331))	('Tumors', 'Disease', 'MESH:D009369', (46, 52))	('BAF', 'Gene', (98, 101))	('CIN', 'Disease', (149, 152))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (363, 397))	('COAD', 'Disease', 'MESH:D029424', (254, 258))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (374, 397))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (337, 357))	('colorectal cancer', 'Phenotype', 'HP:0003003', (284, 301))
495013	30350313	In the "two-hit" Knudson's hypothesis, one copy of a TSG is inactivated by a non-synonymous mutation, while the other copy is inactivated by a similar mutation or by a loss of heterozygosity (LOH), acting as the "second hit.	('loss', 'NegReg', (168, 172))	('non-synonymous mutation', 'Var', (77, 100))	('mutation', 'Var', (151, 159))	('TSG', 'Gene', (53, 56))	('inactivated by', 'Reg', (60, 74))	('TSG', 'Gene', '57045', (53, 56))
495017	30350313	Additionally, whole genome duplication, giving rise to highly unstable tetraploid genomes, has been accepted as a common event in several tumor types, and has been postulated as a driver event in the progression of cancer.22 The consequence of a genome tetraploidization includes the acquisition of numerical chromosome instability, which is defined by the increasing rate of mitotic segregation errors.23 Recently, the use of bioinformatic tools has allowed the assessment of allele-specific copy number and, consequently, the identification of the tumor ploidy.24, 25 Therefore, it has been systematically established that highly aneuploid genomes resulting from whole genome duplications (i.e., tetraploidization) are common in cancer, in particular in epithelial tumors.8 In such a polyploid scenario, it is feasible to hypothesize that genomic gains and losses of the same parental chromosome could result in recurrent aUPDs.	('result in', 'Reg', (904, 913))	('tumor', 'Disease', (138, 143))	('cancer', 'Disease', (731, 737))	('tumor', 'Disease', (767, 772))	('cancer', 'Phenotype', 'HP:0002664', (731, 737))	('tumor ploidy', 'Disease', 'MESH:D009369', (550, 562))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (767, 772))	('cancer', 'Disease', (215, 221))	('UPD', 'Gene', '7389', (925, 928))	('tumor', 'Disease', (550, 555))	('tumors', 'Phenotype', 'HP:0002664', (767, 773))	('genomic', 'Var', (841, 848))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('losses', 'NegReg', (859, 865))	('tumor', 'Disease', 'MESH:D009369', (550, 555))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('cancer', 'Disease', 'MESH:D009369', (731, 737))	('chromosome instability', 'Phenotype', 'HP:0040012', (309, 331))	('tumor', 'Phenotype', 'HP:0002664', (767, 772))	('tumor ploidy', 'Disease', (550, 562))	('epithelial tumors', 'Disease', (756, 773))	('epithelial tumors', 'Disease', 'MESH:D002277', (756, 773))	('tumor', 'Phenotype', 'HP:0002664', (550, 555))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('UPD', 'Gene', (925, 928))
495019	30350313	Moreover, by inferring tumor ploidy, we also determined the extent to which highly aneuploid genomes displayed increased frequency of aUPD and, finally, interrogated the presence of constitutive UPD in colorectal cancer (CRC) patients.	('tumor ploidy', 'Disease', (23, 35))	('aneuploid', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('UPD', 'Gene', (195, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('UPD', 'Gene', '7389', (135, 138))	('UPD', 'Gene', (135, 138))	('colorectal cancer', 'Disease', (202, 219))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('CRC', 'Phenotype', 'HP:0003003', (221, 224))	('patients', 'Species', '9606', (226, 234))	('UPD', 'Gene', '7389', (195, 198))	('tumor ploidy', 'Disease', 'MESH:D009369', (23, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))
495032	30350313	Additionally, missense variants were assessed with six different prediction tools: PhyloP (deleteriousness threshold of phyloP46way_placental score >= 1.6), SIFT (prediction of damaging), PolyPhen2 (HumVar prediction of probably damaging or possibly damaging), MutationTaster (prediction of disease-causing or disease-causing-automatic), LRT (prediction of deleterious) and CADD (Phred score >= 15).	('SIFT', 'Disease', 'None', (157, 161))	('MutationTaster', 'Var', (261, 275))	('LRT', 'Disease', (338, 341))	('CADD', 'Disease', (374, 378))	('PolyPhen2', 'Var', (188, 197))	('SIFT', 'Disease', (157, 161))
495040	30350313	The Mann-Whitney sum-rank test was used in order to compare the number of aUPD events between tumor-types and also between highly aneuploid and near-diploid genomes.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('UPD', 'Gene', '7389', (75, 78))	('tumor', 'Disease', (94, 99))	('UPD', 'Gene', (75, 78))	('aneuploid', 'Var', (130, 139))
495046	30350313	Overall, segmental aUPDs were the most frequent alterations with a mean of 3.39 events per sample across all cohorts compared to 0.87 whole chromosome aUPD events (p < 0.0001).	('UPD', 'Gene', '7389', (152, 155))	('UPD', 'Gene', (152, 155))	('segmental', 'Var', (9, 18))	('UPD', 'Gene', '7389', (20, 23))	('UPD', 'Gene', (20, 23))
495058	30350313	Additional regions of interest were those that showed high frequency of aUPD but rarely involved any chromosome loss, such as 6p25.3-p21.1 (15.09%) and 17q21.32-q25.3 (19.05%) in COAD and READ, respectively (Supporting Information Table 1).	('p21', 'Gene', '644914', (133, 136))	('READ', 'Disease', 'None', (188, 192))	('COAD', 'Disease', (179, 183))	('UPD', 'Gene', (73, 76))	('READ', 'Disease', (188, 192))	('p21', 'Gene', (133, 136))	('COAD', 'Disease', 'MESH:D029424', (179, 183))	('17q21.32-q25.3', 'Var', (152, 166))	('UPD', 'Gene', '7389', (73, 76))
495060	30350313	The average number of mutations per sample corresponding to the COAD (N = 235), READ (N = 78), EAC (N = 18) and ESCC (N = 39) cohorts was 123.64, 72.1, 45.83 and 37.03, respectively.	('EAC', 'Phenotype', 'HP:0011459', (95, 98))	('READ', 'Disease', (80, 84))	('ESCC', 'Disease', (112, 116))	('COAD', 'Disease', 'MESH:D029424', (64, 68))	('EAC', 'Disease', (95, 98))	('mutations', 'Var', (22, 31))	('READ', 'Disease', 'None', (80, 84))	('COAD', 'Disease', (64, 68))
495062	30350313	Our analysis indicated that ESCA showed the highest average percentage of mutations per patient in regions affected by aUPDs (11.79% in EAC and 10.75% in ESCC), while STAD, READ and COAD cohorts presented 10.60%, 8.15% and 6.74% of mutated genes simultaneously affected by aUPD, respectively.	('patient', 'Species', '9606', (88, 95))	('ESCA', 'Disease', (28, 32))	('READ', 'Disease', (173, 177))	('EAC', 'Phenotype', 'HP:0011459', (136, 139))	('COAD', 'Disease', (182, 186))	('mutations', 'Var', (74, 83))	('UPD', 'Gene', '7389', (274, 277))	('UPD', 'Gene', '7389', (120, 123))	('UPD', 'Gene', (274, 277))	('COAD', 'Disease', 'MESH:D029424', (182, 186))	('UPD', 'Gene', (120, 123))	('READ', 'Disease', 'None', (173, 177))
495067	30350313	For example, 69.23% of the EAC samples which showed a mutation at TP53 also presented aUPD affecting 17p13.1 (q value < 10-9).	('mutation', 'Var', (54, 62))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('UPD', 'Gene', (87, 90))	('p13', 'Gene', (103, 106))	('EAC', 'Phenotype', 'HP:0011459', (27, 30))	('p13', 'Gene', '440926', (103, 106))	('UPD', 'Gene', '7389', (87, 90))
495068	30350313	Moreover, a mutation in this TSG accompanied by a copy number loss was also detected in all GI cancers.	('loss', 'NegReg', (62, 66))	('copy number', 'MPA', (50, 61))	('detected', 'Reg', (76, 84))	('GI cancers', 'Disease', (92, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('TSG', 'Gene', (29, 32))	('GI cancers', 'Disease', 'MESH:D009369', (92, 102))	('TSG', 'Gene', '57045', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mutation', 'Var', (12, 20))
495069	30350313	In contrast to the aforementioned example in EAC, 73.6% of COAD samples with a mutation at TP53 also displayed simultaneous copy number loss at 17p13.1 (q value <10-9).	('TP53', 'Gene', (91, 95))	('COAD', 'Disease', (59, 63))	('copy', 'MPA', (124, 128))	('TP53', 'Gene', '7157', (91, 95))	('p13', 'Gene', (146, 149))	('mutation', 'Var', (79, 87))	('COAD', 'Disease', 'MESH:D029424', (59, 63))	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('loss', 'NegReg', (136, 140))	('p13', 'Gene', '440926', (146, 149))
495070	30350313	Therefore, our analysis suggested that tumor samples with mutated TP53 showed either aUPD or genomic losses as "second hit" events ranging from 75% to 93.6% across all GI cancers.	('UPD', 'Gene', (86, 89))	('genomic losses', 'CPA', (93, 107))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('GI cancers', 'Disease', (168, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('UPD', 'Gene', '7389', (86, 89))	('tumor', 'Disease', (39, 44))	('GI cancers', 'Disease', 'MESH:D009369', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mutated', 'Var', (58, 65))
495072	30350313	Of note, 34.92% of rectum and 22.29% of colon adenocarcinomas showing an inactivating mutation at APC also displayed aUPD events at 5q22.2 (q value <10-9).	('colon adenocarcinomas', 'Disease', (40, 61))	('UPD', 'Gene', '7389', (118, 121))	('APC', 'Gene', (98, 101))	('colon adenocarcinomas', 'Disease', 'MESH:D003110', (40, 61))	('rectum', 'Disease', (19, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('UPD', 'Gene', (118, 121))	('inactivating mutation', 'Var', (73, 94))	('APC', 'Gene', '324', (98, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
495073	30350313	In contrast, 15.86% and 20.57% of samples with mutated APC displayed copy number losses in READ and COAD, respectively (q value <10-9).	('READ', 'Disease', 'None', (91, 95))	('copy', 'MPA', (69, 73))	('COAD', 'Disease', (100, 104))	('APC', 'Gene', (55, 58))	('losses', 'NegReg', (81, 87))	('READ', 'Disease', (91, 95))	('mutated', 'Var', (47, 54))	('APC', 'Gene', '324', (55, 58))	('COAD', 'Disease', 'MESH:D029424', (100, 104))
495075	30350313	While 75% of the samples showing an inactivating mutation in NOTCH1 also presented aUPD at 9q34.3 (q value = 5.5 x 10-9), aUPD events at 9q22.32 were affecting all samples with mutated PTCH1 (q value <10-9).	('NOTCH1', 'Gene', '4851', (61, 67))	('PTCH1', 'Gene', (185, 190))	('NOTCH1', 'Gene', (61, 67))	('UPD', 'Gene', '7389', (84, 87))	('mutated', 'Var', (177, 184))	('PTCH1', 'Gene', '5727', (185, 190))	('UPD', 'Gene', (84, 87))	('UPD', 'Gene', '7389', (123, 126))	('UPD', 'Gene', (123, 126))	('inactivating mutation', 'Var', (36, 57))
495084	30350313	Aneuploid genomes are common in cancer; we therefore assessed to which extent the total DNA content contributes to the generation of aUPD events.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('Aneuploid', 'Var', (0, 9))	('UPD', 'Gene', '7389', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('UPD', 'Gene', (134, 137))
495095	30350313	In the EPICOLON cohort we detected five UPDs (four patients and one control), six genomic losses (four patients and two controls), one duplication (one control) and one trisomy (one patient).	('duplication', 'Var', (135, 146))	('genomic', 'CPA', (82, 89))	('UPD', 'Gene', '7389', (40, 43))	('patient', 'Species', '9606', (182, 189))	('UPD', 'Gene', (40, 43))	('patient', 'Species', '9606', (51, 58))	('patients', 'Species', '9606', (51, 59))	('patient', 'Species', '9606', (103, 110))	('patients', 'Species', '9606', (103, 111))	('losses', 'NegReg', (90, 96))
495099	30350313	Similarly, a deletion at 10q22.3-q23.2 was validated by MLPA in the peripheral blood DNA, and identified in both the normal colon mucosa and in the corresponding primary tumor of the same patient.	('patient', 'Species', '9606', (188, 195))	('primary tumor', 'Disease', (162, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('deletion', 'Var', (13, 21))	('primary tumor', 'Disease', 'MESH:D009369', (162, 175))
495109	30350313	Specifically, our results confirmed that aUPD events represent an important mechanism to functionally inactivate APC in colon and rectum adenocarcinomas.11, 18, 34, 41, 42, 43 Therefore, these results further strengthen the hypothesis that colorectal tumor cells strive to maintain a disomy for chromosome 5 despite the benefit of inactivating APC.	('disomy', 'Var', (284, 290))	('colorectal tumor', 'Disease', 'MESH:D015179', (240, 256))	('UPD', 'Gene', '7389', (42, 45))	('UPD', 'Gene', (42, 45))	('inactivating', 'Var', (331, 343))	('APC', 'Gene', '324', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('colon and rectum adenocarcinomas', 'Disease', 'MESH:D012004', (120, 152))	('APC', 'Gene', (344, 347))	('APC', 'Gene', '324', (344, 347))	('colorectal tumor', 'Disease', (240, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('APC', 'Gene', (113, 116))
495110	30350313	In contrast to CRC, the loss of 5q in STAD is twice as high as the frequency of aUPD, suggesting different mechanisms to achieve the biallelic inactivation of APC.	('loss', 'Var', (24, 28))	('CRC', 'Phenotype', 'HP:0003003', (15, 18))	('biallelic', 'MPA', (133, 142))	('UPD', 'Gene', '7389', (81, 84))	('APC', 'Gene', (159, 162))	('UPD', 'Gene', (81, 84))	('APC', 'Gene', '324', (159, 162))
495111	30350313	Moreover, we also identified inactivation of NOTCH1 driven by aUPD at chromosome arm 9q as the "second hit" in ESCC.	('UPD', 'Gene', (63, 66))	('NOTCH1', 'Gene', '4851', (45, 51))	('NOTCH1', 'Gene', (45, 51))	('UPD', 'Gene', '7389', (63, 66))	('inactivation', 'Var', (29, 41))
495117	30350313	Copy number gains for KRAS and PIK3CA are common in COAD, READ and STAD; however, NRAS is barely gained in READ, suggesting that aUPD is the main genetic mechanism to achieve homozygous activation of this gene.55 Altogether, even though we cannot discard that a second mutation, epigenetic modifications or DNA conformational changes lead to loss-of-function of TSGs or activation of proto-oncogenes, our results point to an unquestionable relevance of aUPD in cancer as "second hit".	('TSG', 'Gene', (362, 365))	('NRAS', 'Gene', (82, 86))	('KRAS', 'Gene', (22, 26))	('cancer', 'Disease', (461, 467))	('UPD', 'Gene', (130, 133))	('READ', 'Disease', (58, 62))	('UPD', 'Gene', (454, 457))	('cancer', 'Phenotype', 'HP:0002664', (461, 467))	('READ', 'Disease', 'None', (107, 111))	('PIK3CA', 'Gene', '5290', (31, 37))	('COAD', 'Disease', 'MESH:D029424', (52, 56))	('loss-of-function', 'NegReg', (342, 358))	('READ', 'Disease', 'None', (58, 62))	('UPD', 'Gene', '7389', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (461, 467))	('NRAS', 'Gene', '4893', (82, 86))	('UPD', 'Gene', '7389', (454, 457))	('epigenetic modifications', 'Var', (279, 303))	('COAD', 'Disease', (52, 56))	('PIK3CA', 'Gene', (31, 37))	('TSG', 'Gene', '57045', (362, 365))	('activation', 'PosReg', (370, 380))	('KRAS', 'Gene', '3845', (22, 26))	('READ', 'Disease', (107, 111))
495122	30405881	High expression level of CD44v8-10 in cancer stem-like cells is associated with poor prognosis in esophageal squamous cell carcinoma patients treated with chemoradiotherapy Strong reactive oxygen species (ROS) suppression in cancer stem-like cell components in various solid tumors is associated with therapeutic resistance.	('esophageal squamous cell carcinoma', 'Disease', (98, 132))	('cancer', 'Disease', (225, 231))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('solid tumors', 'Disease', 'MESH:D009369', (269, 281))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('ROS', 'Chemical', 'MESH:D017382', (205, 208))	('cancer', 'Disease', (38, 44))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (98, 132))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (180, 203))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('expression level', 'MPA', (5, 21))	('CD44v8-10', 'Var', (25, 34))	('solid tumors', 'Disease', (269, 281))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
495128	30405881	High CD44v8-10 expression was independently associated with poor prognosis in E-SCC patients treated with dCRT (hazard ratio = 2.906, 95% CI = 1.277-6.611, p = 0.011).	('SCC', 'Gene', '6317', (80, 83))	('dCRT', 'Gene', '45841', (106, 110))	('High', 'Var', (0, 4))	('CD44', 'Gene', (5, 9))	('patients', 'Species', '9606', (84, 92))	('dCRT', 'Gene', (106, 110))	('expression', 'MPA', (15, 25))	('SCC', 'Gene', (80, 83))	('CD44', 'Gene', '960', (5, 9))
495156	30405881	In these patients, univariate analysis showed that performance status (PS), tumor size, cStage and high CD44v8-10 expression (histo-score [H-score] >= 151) were associated with poor prognosis (hazard ratio [HR] = 2.975, 95% confidential interval [CI] 1.431-6.186, p = 0.004; HR = 3.755, 95% CI 1.784-7.903, p < 0.001; HR = 5.177, 95% CI 2.448-10.946, p < 0.001; HR = 3.438, 95% CI 1.549-7.631, p = 0.002, respectively) (Table 2).	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CD44', 'Gene', '960', (104, 108))	('high', 'Var', (99, 103))	('CD44', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
495157	30405881	Moreover, multivariate analysis showed that cStage and high CD44v8-10 expression were independent poor prognostic factors (HR = 3.536, 95% CI 1.176-10.626, p = 0.024; HR = 2.844, 95% CI 1.248-6.479, p = 0.013, respectively).	('expression', 'MPA', (70, 80))	('CD44', 'Gene', '960', (60, 64))	('CD44', 'Gene', (60, 64))	('high', 'Var', (55, 59))
495162	30405881	In contrast, overall survival of cStage II + III and cStage IVA + IVB (cM1-lym) subjects with high CD44v8-10 expression was significantly shorter than that of subjects of corresponding stages with low CD44v8-10 expression (p = 0.024, Figure 2C; p = 0.023, Figure 2D, respectively).	('CD44', 'Gene', (201, 205))	('CD44', 'Gene', '960', (201, 205))	('IVA', 'Disease', 'MESH:C538167', (60, 63))	('CD44', 'Gene', '960', (99, 103))	('shorter', 'NegReg', (138, 145))	('CD44', 'Gene', (99, 103))	('IVA', 'Disease', (60, 63))	('high', 'Var', (94, 98))
495169	30405881	As shown in Table 4, the 3-year cumulative lymphatic recurrence rate of subjects with high CD44v8-10 expression was higher than that of subjects with low CD44v8-10 expression (34.9%, 95% CI 13.4-57.5 vs 9.2%, 95% CI 1.5-25.9, p = 0.045).	('higher', 'PosReg', (116, 122))	('CD44', 'Gene', '960', (91, 95))	('CD44', 'Gene', '960', (154, 158))	('lymphatic recurrence', 'CPA', (43, 63))	('CD44', 'Gene', (91, 95))	('CD44', 'Gene', (154, 158))	('expression', 'MPA', (101, 111))	('high', 'Var', (86, 90))
495170	30405881	Our data suggest that patients with high CD44v8-10 expression are at high risk of lymphatic recurrence after dCRT.	('CD44', 'Gene', '960', (41, 45))	('patients', 'Species', '9606', (22, 30))	('CD44', 'Gene', (41, 45))	('lymphatic recurrence', 'CPA', (82, 102))	('dCRT', 'Gene', (109, 113))	('high', 'Var', (36, 40))	('dCRT', 'Gene', '45841', (109, 113))
495200	30405881	Second, H-score >= 151 was provisionally used as the definition for high CD44v8-10 expression, which has not been sufficiently verified.	('CD44', 'Gene', '960', (73, 77))	('H-score >= 151', 'Var', (8, 22))	('CD44', 'Gene', (73, 77))	('expression', 'MPA', (83, 93))
495253	29422970	Increased copy number of mitochondrial DNA predicts poor prognosis of esophageal squamous cell carcinoma Change in mitochondrial DNA (mtDNA) copy number has been reported in esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (174, 208))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('esophageal squamous cell carcinoma', 'Disease', (174, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('copy number', 'Var', (10, 21))	('copy number', 'Var', (141, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('esophageal squamous cell carcinoma', 'Disease', (70, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
495268	29422970	Furthermore, accumulated evidence has demonstrated that in peripheral blood lymphocytes, altered mtDNA content is closely associated with the risk of certain types of cancer.	('associated', 'Reg', (122, 132))	('mtDNA', 'Gene', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('altered', 'Var', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
495303	29422970	Although no statistically significant difference was observed, there was a notable trend toward a positive association between mtDNA copy number and survival status of patients with ESCC (P=0.054).	('positive', 'PosReg', (98, 106))	('copy number', 'Var', (133, 144))	('ESCC', 'Disease', (182, 186))	('patients', 'Species', '9606', (168, 176))	('mtDNA', 'Gene', (127, 132))
495304	29422970	As presented in Table III, mtDNA copy number variations was significantly associated with survival status in patients with ESCC.	('copy number variations', 'Var', (33, 55))	('patients', 'Species', '9606', (109, 117))	('ESCC', 'Disease', (123, 127))	('survival', 'Disease', (90, 98))	('mtDNA', 'Gene', (27, 32))	('associated', 'Reg', (74, 84))
495306	29422970	Multivariable logistic regression was performed to evaluate the independent association of variable mtDNA copy number with age, tumor size, differentiation and lymph node metastasis.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mtDNA', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('copy number', 'Var', (106, 117))	('tumor', 'Disease', (128, 133))
495309	29422970	3, the patients with increased mtDNA copy number experienced shorter survival times than those with decreased mtDNA copy number (median survival time: 42.00 vs. 38.00 months; P=0.03).	('shorter', 'NegReg', (61, 68))	('mtDNA', 'Gene', (31, 36))	('copy number', 'Var', (37, 48))	('survival times', 'CPA', (69, 83))	('patients', 'Species', '9606', (7, 15))
495310	29422970	Similarly, Cox's unvariate regression analysis demonstrated a marked association of increased mtDNA copy number with poor patient survival [hazard ratio (HR), 1.76; 95% CI, 1.06-2.97, P=0.03; Table V] as well as age [HR, 1.75; 95% CI, 1.05-2.91, P=0.03] and TNM stage [HR, 2.40; 95% CI, 1.44-3.99, P<0.01; Table V].	('poor patient survival', 'CPA', (117, 138))	('mtDNA', 'Gene', (94, 99))	('TNM', 'Gene', '10178', (258, 261))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('patient', 'Species', '9606', (122, 129))	('increased', 'PosReg', (84, 93))	('TNM', 'Gene', (258, 261))	('copy number', 'Var', (100, 111))
495328	29422970	In the present study, it was revealed that increased mtDNA content was associated with the survival status of patients with ESCC, and that the patients with high mtDNA content experienced significantly shorter survival times than those with low mtDNA content.	('shorter', 'NegReg', (202, 209))	('survival times', 'CPA', (210, 224))	('high', 'Var', (157, 161))	('patients', 'Species', '9606', (143, 151))	('ESCC', 'Disease', (124, 128))	('patients', 'Species', '9606', (110, 118))	('associated', 'Reg', (71, 81))
495376	28431580	We first examined the expression of CR-1 in two human ESCC cell lines EC109 and TE-1, and found that both of the two cell lines expressed CR-1 at mRNA and protein levels, and the expression level of EC109 cells was approximately 2 ~ 3 fold higher than that of TE-1 cells (Additional file 1: Figure S1A and S1B).	('TE-1', 'CellLine', 'CVCL:1759', (260, 264))	('EC109', 'CellLine', 'CVCL:6898', (70, 75))	('expression', 'MPA', (179, 189))	('human', 'Species', '9606', (48, 53))	('EC109', 'Var', (199, 204))	('TE-1', 'CellLine', 'CVCL:1759', (80, 84))	('CR-1', 'Gene', (138, 142))	('higher', 'PosReg', (240, 246))	('EC109', 'CellLine', 'CVCL:6898', (199, 204))
495384	28431580	The tumors derived from CR-1high cells were markedly larger in size than that of CR-1low (Fig.	('larger', 'PosReg', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CR-1high', 'Var', (24, 32))
495386	28431580	After CR-1 knockdown, the expressions of Sox2, Oct4 and Nanog were significantly down-regulated in shCR1-EC109 cells (Fig.	('expressions', 'MPA', (26, 37))	('down-regulated', 'NegReg', (81, 95))	('Nanog', 'Gene', (56, 61))	('CR', 'Chemical', 'MESH:D002857', (6, 8))	('Oct4', 'Gene', '5460', (47, 51))	('CR-1', 'Gene', (6, 10))	('CR', 'Chemical', 'MESH:D002857', (101, 103))	('Nanog', 'Gene', '79923', (56, 61))	('EC109', 'CellLine', 'CVCL:6898', (105, 110))	('Sox2', 'Gene', '6657', (41, 45))	('knockdown', 'Var', (11, 20))	('Oct4', 'Gene', (47, 51))	('Sox2', 'Gene', (41, 45))
495390	28431580	Silencing CR-1 expression in TE-1 cell line resulted in similar results as that obtained from EC109 cell line (Additional file 1: Figure S2, Table S3).	('Silencing', 'Var', (0, 9))	('EC109', 'CellLine', 'CVCL:6898', (94, 99))	('TE-1', 'CellLine', 'CVCL:1759', (29, 33))	('CR-1', 'Gene', (10, 14))
495392	28431580	The CR-1high cells expressed lower level of E-cadherin but higher level of vimentin compared to CR-1low cells (p < 0.05, Fig.	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('CR-1high', 'Var', (4, 12))	('vimentin', 'Gene', '7431', (75, 83))	('lower', 'NegReg', (29, 34))	('higher', 'PosReg', (59, 65))	('vimentin', 'Gene', (75, 83))
495397	28431580	We further evaluated the effect of silencing CR-1 expression on the migration and invasion capacities of EC109 cells in vitro.	('silencing', 'Var', (35, 44))	('CR-1', 'Gene', (45, 49))	('EC109', 'CellLine', 'CVCL:6898', (105, 110))	('invasion capacities', 'CPA', (82, 101))	('migration', 'CPA', (68, 77))
495398	28431580	Results from transwell matrigel invasion assay showed that knockdown of CR-1 significantly inhibited the invasion capacity of EC109 cells (Fig.	('inhibited', 'NegReg', (91, 100))	('invasion capacity of EC109 cells', 'CPA', (105, 137))	('CR-1', 'Gene', (72, 76))	('knockdown', 'Var', (59, 68))	('EC109', 'CellLine', 'CVCL:6898', (126, 131))
495399	28431580	The number of invasive cells from shCR1 and Mock cells were 99 +- 4.8 and 211 +- 12.3, respectively (p < 0.001).	('CR', 'Chemical', 'MESH:D002857', (36, 38))	('invasive cells', 'CPA', (14, 28))	('shCR1', 'Var', (34, 39))
495403	28431580	The frequency of metastasis to lungs was much lower in nude mice implanted with shCR1 cells as compared to Mock cells (p = 0.030, Fig.	('nude mice', 'Species', '10090', (55, 64))	('metastasis to lungs', 'CPA', (17, 36))	('shCR1 cells', 'Var', (80, 91))	('lower', 'NegReg', (46, 51))	('CR', 'Chemical', 'MESH:D002857', (82, 84))
495406	28431580	In addition, we investigated the expression of matrix metalloproteinases (MMPs), which promote invasion and metastasis of tumor cells by degrading the extracellular matrix, and found that silencing of CR-1 expression significantly down-regulated MMP9 expression at both mRNA and protein levels (Fig.	('MMP9', 'Gene', '4318', (246, 250))	('invasion', 'CPA', (95, 103))	('down-regulated', 'NegReg', (231, 245))	('expression', 'MPA', (251, 261))	('degrading', 'NegReg', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('extracellular matrix', 'MPA', (151, 171))	('MMP9', 'Gene', (246, 250))	('CR-1', 'Gene', (201, 205))	('promote', 'PosReg', (87, 94))	('tumor', 'Disease', (122, 127))	('silencing', 'Var', (188, 197))
495417	28431580	A significant correlation was found between high expression of CR-1 and decreased overall survival rate in ESCC patients (p < 0.001, Fig.	('high expression', 'Var', (44, 59))	('decreased', 'NegReg', (72, 81))	('patients', 'Species', '9606', (112, 120))	('CR-1', 'Gene', (63, 67))	('overall survival', 'MPA', (82, 98))	('ESCC', 'Disease', (107, 111))
495418	28431580	The data obtained from TCGA dataset also indicated that patients with high expression of CR-1 suffered poorer overall survival than those with low expression of CR-1 (p = 0.006, Fig.	('overall survival', 'MPA', (110, 126))	('patients', 'Species', '9606', (56, 64))	('poorer', 'NegReg', (103, 109))	('CR-1', 'Gene', (89, 93))	('high expression', 'Var', (70, 85))
495425	28431580	A significant correlation was found between the staining of ALDH1A1high/CR-1high and decreased overall survival in ESCC patients (p < 0.001, Fig.	('staining', 'Var', (48, 56))	('ESCC', 'Disease', (115, 119))	('ALDH1A1', 'Gene', '216', (60, 67))	('decreased', 'NegReg', (85, 94))	('overall survival', 'MPA', (95, 111))	('ALDH1A1', 'Gene', (60, 67))	('patients', 'Species', '9606', (120, 128))
495440	28431580	Silencing CR-1 expression significantly reduced the expression of stemness-related genes and abilities of self-renewal and tumorigenesis.	('tumor', 'Disease', (123, 128))	('expression', 'MPA', (52, 62))	('CR-1', 'Gene', (10, 14))	('reduced', 'NegReg', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('Silencing', 'Var', (0, 9))	('stemness-related genes', 'Gene', (66, 88))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
495443	28431580	In addition, antisense nucleic acid technique on CR-1, and antagonist of the CR-1 CFC domain have been reported to inhibit human breast cancer, colon cancer and testicular cancer cells growth, suggesting that CR-1 is a valuable therapeutic target for targeting CSLCs in ESCC.	('breast cancer', 'Disease', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('antisense nucleic acid technique', 'Var', (13, 45))	('inhibit', 'NegReg', (115, 122))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('human', 'Species', '9606', (123, 128))	('testicular cancer', 'Phenotype', 'HP:0010788', (161, 178))	('testicular cancer', 'Disease', 'MESH:D013736', (161, 178))	('colon cancer', 'Disease', 'MESH:D015179', (144, 156))	('colon cancer', 'Phenotype', 'HP:0003003', (144, 156))	('testicular cancer', 'Disease', (161, 178))	('colon cancer', 'Disease', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
495445	28431580	Results from the current study suggest that CR-1 regulates EMT in ESCC as knockdown of CR-1 in EC109 and TE-1 cells reversed EMT as well as the invasive and metastatic properties of the cells.	('EMT', 'MPA', (125, 128))	('knockdown', 'Var', (74, 83))	('CR-1', 'Gene', (87, 91))	('ESCC', 'Disease', (66, 70))	('TE-1', 'CellLine', 'CVCL:1759', (105, 109))	('EC109', 'CellLine', 'CVCL:6898', (95, 100))
495448	28431580	We demonstrated that the most ESCCs had positive CR-1 expression, which is closely related to the depth of tumor invasion, lymph node metastasis and poor prognosis in the ESCC patients.	('expression', 'MPA', (54, 64))	('patients', 'Species', '9606', (176, 184))	('positive', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('ESCCs', 'Disease', (30, 35))	('ESCC', 'Disease', (171, 175))	('CR-1', 'Gene', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('related', 'Reg', (83, 90))
495459	27503568	Confocal microscopy revealed that vorinostat caused changes in the distribution of H3K9ac-marked euchromatin and H3K9me3-marked constitutive heterochromatin.	('H3K9ac-marked', 'Protein', (83, 96))	('H3K9me3-marked', 'Var', (113, 127))	('distribution', 'MPA', (67, 79))	('changes', 'Reg', (52, 59))	('vorinostat', 'Chemical', 'MESH:D000077337', (34, 44))
495474	27503568	Alterations of gene expression by vorinostat correlate with site-specific accumulation of acetylated histones, and the altered histone modification patterns are typically assumed to result in the higher-order structural reorganization of the corresponding genomic loci.	('Alterations', 'Var', (0, 11))	('result', 'Reg', (182, 188))	('acetylated histones', 'MPA', (90, 109))	('accumulation', 'PosReg', (74, 86))	('vorinostat', 'Chemical', 'MESH:D000077337', (34, 44))	('gene expression', 'MPA', (15, 30))
495496	27503568	Specifically, we labeled lamin A/C to mark the nuclear lamina; the histone marks H3K9ac, H3K9me3, and H3K27me3 to visualize euchromatin, constitutive heterochromatin, and facultative heterochromatin respectively; and fibrillarin to identify nucleolar regions.	('H3K9ac', 'Var', (81, 87))	('lamin A/C', 'Gene', '4000', (25, 34))	('H3K9me3', 'Var', (89, 96))	('H3K27me3', 'Var', (102, 110))	('lamin A/C', 'Gene', (25, 34))
495500	27503568	As expected, we observed an increase in the expression of active histone marks H3K9ac (p < 0.0001) and H3K4me2 (p < 0.0001) only in drug-treated FLO-1 cells and not in the other cell types (Supplementary Figure S2).	('H3K4me2', 'Var', (103, 110))	('expression', 'MPA', (44, 54))	('active', 'MPA', (58, 64))	('FLO-1', 'Chemical', '-', (145, 150))	('H3K9ac', 'Protein', (79, 85))	('increase', 'PosReg', (28, 36))
495515	27503568	MGMT has been shown to be aberrantly silenced by methylation in Barrett's Esophagus and esophageal adenocarcinoma.	('MGMT', 'Gene', (0, 4))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (88, 113))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('silenced', 'NegReg', (37, 45))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('methylation', 'Var', (49, 60))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (64, 83))	("Barrett's Esophagus", 'Disease', (64, 83))	('MGMT', 'Gene', '4255', (0, 4))
495517	27503568	We observed a differential trend in nuclear repositioning as well as H3K9ac-colocalization of MGMT between normal and abnormal cells.	('MGMT', 'Gene', '4255', (94, 98))	('H3K9ac-colocalization', 'Var', (69, 90))	('nuclear', 'MPA', (36, 43))	('MGMT', 'Gene', (94, 98))
495530	27503568	Upon exposure to the IC50 concentration of the drug, malignant cells preferentially exhibited prominent reductions in the magnitude and heterogeneity of diagnostically relevant morphological parameters such as nuclear volume, nuclear-cytoplasmic ratio, and intra-nuclear chromatin clumpiness relative to pre-cancerous and normal cells.	('reductions', 'NegReg', (104, 114))	('heterogeneity', 'MPA', (136, 149))	('nuclear-cytoplasmic ratio', 'MPA', (226, 251))	('nuclear volume', 'CPA', (210, 224))	('cancerous', 'Disease', (308, 317))	('intra-nuclear chromatin clumpiness', 'CPA', (257, 291))	('magnitude', 'MPA', (122, 131))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('cancerous', 'Disease', 'MESH:D009369', (308, 317))	('IC50 concentration', 'Var', (21, 39))
495555	27503568	The epigenetic disruption of 3D nuclear architecture caused by vorinostat in abnormal cells may represent a biophysical basis for the drug's tumor-selective mechanism of action.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('vorinostat', 'Chemical', 'MESH:D000077337', (63, 73))	('tumor', 'Disease', (141, 146))	('vorinostat', 'Gene', (63, 73))	('epigenetic', 'Var', (4, 14))
495571	27503568	Aberrant expression of HDAC 1 and 2 has been previously reported in BE and EA.	('Aberrant expression', 'Var', (0, 19))	('reported', 'Reg', (56, 64))	('BE', 'Phenotype', 'HP:0100580', (68, 70))	('EA', 'Phenotype', 'HP:0011459', (75, 77))	('HDAC 1 and 2', 'Gene', '3065;3066', (23, 35))
495585	27503568	Experiments were performed in triplicate for each condition for the following proteins: H3K9ac (Millipore, #06-942), H3K9me3 (Abcam, Cambridge, MA, ab8898), H3K27me3 (Millipore, #07-449), lamin A/C (Cell Signaling Technology, Danvers, MA, #2032), lamin B1 (Abcam, ab16048), and lamin B2 (Abcam, ab8983).	('H3K9me3', 'Var', (117, 124))	('lamin B1', 'Gene', '4001', (247, 255))	('lamin B2', 'Gene', (278, 286))	('H3K27me3', 'Var', (157, 165))	('lamin B1', 'Gene', (247, 255))	('lamin A/C', 'Gene', (188, 197))	('lamin B2', 'Gene', '84823', (278, 286))	('H3K9ac', 'Var', (88, 94))	('lamin A/C', 'Gene', '4000', (188, 197))
495592	27503568	Spatial localization was assessed for the following proteins: lamin A/C (Santa Cruz, sc-7292), fibrillarin (Abcam, ab4566), H3K9ac (Millipore, #06-942), H3K9me3 (Abcam, ab8898, and Novus Biologicals, NBP1-30141), and H3K27me3 (Abcam, ab6002 and Millipore, #07-449).	('NBP1', 'Gene', '4682', (200, 204))	('NBP1', 'Gene', (200, 204))	('lamin A/C', 'Gene', '4000', (62, 71))	('H3K9ac', 'Var', (124, 130))	('H3K27me3', 'Var', (217, 225))	('lamin A/C', 'Gene', (62, 71))	('H3K9me3', 'Var', (153, 160))
495618	26445849	It is of note that RA has been used to dramatically improve clinical outcome in patients with acute promyelocytic leukemia (APL); where ninety-eight percent of patients with this disease carry a fusion of the PML and RARalpha genes that impairs the ability of RARalpha to induce hematopoietic stem/progenitor cell differentiation at physiological levels of RA.	('APL', 'Phenotype', 'HP:0004836', (124, 127))	('fusion', 'Var', (195, 201))	('patients', 'Species', '9606', (80, 88))	('induce', 'PosReg', (272, 278))	('APL', 'Disease', 'MESH:D015473', (124, 127))	('patient', 'Species', '9606', (160, 167))	('RARalpha', 'Gene', '5914', (217, 225))	('RARalpha', 'Gene', (260, 268))	('PML', 'Gene', '5371', (209, 212))	('ability', 'MPA', (249, 256))	('patient', 'Species', '9606', (80, 87))	('APL', 'Disease', (124, 127))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (94, 122))	('RARalpha', 'Gene', (217, 225))	('leukemia', 'Phenotype', 'HP:0001909', (114, 122))	('acute promyelocytic leukemia', 'Disease', (94, 122))	('hematopoietic stem/progenitor cell differentiation', 'CPA', (279, 329))	('patients', 'Species', '9606', (160, 168))	('impairs', 'NegReg', (237, 244))	('PML', 'Gene', (209, 212))	('RARalpha', 'Gene', '5914', (260, 268))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (94, 122))
495629	26445849	Tumor cells displaying high ALDEFLUOR  activity have been demonstrated to have enhanced motility and ability to invade through a 3D basement membrane in breast cancer, ovarian cancer, osteosarcoma, esophageal cancer, and prostate cancer; as well as increased therapy resistance in breast cancer, ovarian cancer, osteosarcoma, and prostate cancer.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('ovarian cancer', 'Disease', 'MESH:D010051', (296, 310))	('osteosarcoma', 'Phenotype', 'HP:0002669', (184, 196))	('motility', 'CPA', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('high', 'Var', (23, 27))	('therapy resistance', 'CPA', (259, 277))	('enhanced', 'PosReg', (79, 87))	('increased', 'PosReg', (249, 258))	('ovarian cancer', 'Disease', 'MESH:D010051', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ability', 'CPA', (101, 108))	('osteosarcoma', 'Disease', (312, 324))	('ovarian cancer', 'Disease', (296, 310))	('osteosarcoma', 'Disease', 'MESH:D012516', (312, 324))	('breast cancer', 'Phenotype', 'HP:0003002', (281, 294))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ovarian cancer', 'Phenotype', 'HP:0100615', (296, 310))	('prostate cancer', 'Disease', 'MESH:D011471', (221, 236))	('osteosarcoma', 'Disease', (184, 196))	('osteosarcoma', 'Disease', 'MESH:D012516', (184, 196))	('ovarian cancer', 'Disease', (168, 182))	('prostate cancer', 'Phenotype', 'HP:0012125', (221, 236))	('esophageal cancer', 'Disease', 'MESH:D004938', (198, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('breast cancer', 'Disease', (281, 294))	('prostate cancer', 'Disease', (221, 236))	('prostate cancer', 'Disease', 'MESH:D011471', (330, 345))	('ovarian cancer', 'Phenotype', 'HP:0100615', (168, 182))	('prostate cancer', 'Phenotype', 'HP:0012125', (330, 345))	('prostate cancer', 'Disease', (330, 345))	('esophageal cancer', 'Disease', (198, 215))	('osteosarcoma', 'Phenotype', 'HP:0002669', (312, 324))	('breast cancer', 'Disease', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
495632	26445849	For example, ALDH1A1 expression has been reported to correlate with increased in vitro clonogenic activity in NSCLC, esophageal cancer, ovarian cancer, pancreatic cancer, and renal cancer.	('esophageal cancer', 'Disease', (117, 134))	('renal cancer', 'Disease', 'MESH:D007680', (175, 187))	('expression', 'Var', (21, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('NSCLC', 'Disease', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ALDH1A1', 'Gene', (13, 20))	('increased', 'PosReg', (68, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))	('pancreatic', 'Disease', 'MESH:D010195', (152, 162))	('ovarian cancer', 'Disease', (136, 150))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('renal cancer', 'Disease', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('renal cancer', 'Phenotype', 'HP:0009726', (175, 187))	('pancreatic', 'Disease', (152, 162))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
495655	26445849	Currently two clinical trials are evaluating the effect of disulfiram in treating glioblastoma multiforme (NCT01907165 and NCT01777919; www.clinicaltrials.gov).	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (82, 105))	('NCT01777919', 'Var', (123, 134))	('glioblastoma multiforme', 'Disease', (82, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))
495812	22870241	High-Throughput Genotyping in Metastatic Esophageal Squamous Cell Carcinoma Identifies Phosphoinositide-3-Kinase and BRAF Mutations Given the high incidence of metastatic esophageal squamous cell carcinoma, especially in Asia, we screened for the presence of somatic mutations using OncoMap platform with the aim of defining subsets of patients who may be potential candidate for targeted therapy.	('Metastatic Esophageal Squamous Cell Carcinoma', 'Disease', (30, 75))	('esophageal squamous cell carcinoma', 'Disease', (171, 205))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('Metastatic Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (30, 75))	('Carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('Mutations', 'Var', (122, 131))	('patients', 'Species', '9606', (336, 344))	('BRAF', 'Gene', '673', (117, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (171, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('BRAF', 'Gene', (117, 121))
495818	22870241	The most frequent mutation was PIK3CA mutation (four E545K, five H1047R and one H1047L) (N = 10, 11.5%) followed by MLH1 V384D (N = 7, 8.0%), TP53 (R306, R175H and R273C) (N = 3, 3.5%), BRAF V600E (N = 1, 1.2%), CTNNB1 D32N (N = 1, 1.2%), and EGFR P733L (N = 1, 1.2%).	('V384D', 'Mutation', 'rs63750447', (121, 126))	('CTNNB1', 'Gene', (212, 218))	('E545K', 'Mutation', 'rs104886003', (53, 58))	('R273C', 'Var', (164, 169))	('MLH1', 'Gene', (116, 120))	('TP53', 'Gene', '7157', (142, 146))	('PIK3CA', 'Gene', '5290', (31, 37))	('R175H', 'Mutation', 'rs28934578', (154, 159))	('EGFR', 'Gene', '1956', (243, 247))	('R175H', 'Var', (154, 159))	('P733L', 'Mutation', 'rs121913446', (248, 253))	('MLH1', 'Gene', '4292', (116, 120))	('H1047L', 'Mutation', 'rs121913279', (80, 86))	('CTNNB1', 'Gene', '1499', (212, 218))	('H1047R', 'Var', (65, 71))	('BRAF', 'Gene', '673', (186, 190))	('BRAF', 'Gene', (186, 190))	('P733L', 'Var', (248, 253))	('R273C', 'Mutation', 'rs121913343', (164, 169))	('H1047R', 'Mutation', 'rs121913279', (65, 71))	('TP53', 'Gene', (142, 146))	('V600E', 'Mutation', 'rs113488022', (191, 196))	('D32N', 'Mutation', 'rs28931588', (219, 223))	('PIK3CA', 'Gene', (31, 37))	('EGFR', 'Gene', (243, 247))
495820	22870241	Our study led to the detection of potentially druggable mutations in esophageal SCC which may guide novel therapies in small subsets of esophageal cancer patients.	('esophageal cancer', 'Disease', (136, 153))	('SCC', 'Gene', '6317', (80, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('patients', 'Species', '9606', (154, 162))	('SCC', 'Gene', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))
495832	22870241	Of 11 mutations, 4 mutations were located in PIK3CA, thus the most frequently observed somatic mutations in esophageal SCC.	('SCC', 'Gene', '6317', (119, 122))	('PIK3CA', 'Gene', (45, 51))	('PIK3CA', 'Gene', '5290', (45, 51))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))	('SCC', 'Gene', (119, 122))	('mutations', 'Var', (6, 15))
495833	22870241	All 4 hotspots in PIK3CA, E545K, E542K, H1047R, H1047L, are known to be oncogenic in various tumor types.	('E545K', 'Mutation', 'rs104886003', (26, 31))	('H1047L', 'Mutation', 'rs121913279', (48, 54))	('E545K', 'Var', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('E542K', 'Var', (33, 38))	('H1047R', 'Var', (40, 46))	('H1047L', 'Var', (48, 54))	('tumor', 'Disease', (93, 98))	('PIK3CA', 'Gene', '5290', (18, 24))	('PIK3CA', 'Gene', (18, 24))	('E542K', 'Mutation', 'rs121913273', (33, 38))	('H1047R', 'Mutation', 'rs121913279', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
495834	22870241	There was no significant association between anatomic location and PIK3CA mutations.	('mutations', 'Var', (74, 83))	('PIK3CA', 'Gene', (67, 73))	('PIK3CA', 'Gene', '5290', (67, 73))
495835	22870241	Of the 9 cases with PIK3CA mutations, 4 (44.4%) patients had mid-esophagus, one (11.1%) had upper-esophagus and 4 (44.4%) had distal esophageal cancer.	('mutations', 'Var', (27, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('mid-esophagus', 'Disease', (61, 74))	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))	('esophageal cancer', 'Disease', (133, 150))	('patients', 'Species', '9606', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
495837	22870241	Overall, there was no significant difference in overall survival between the two groups (PIK3CA mutation (+) vs (-), 8.0 and 4.4 months, respectively, P = 0.842) (Figure 1).	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('mutation', 'Var', (96, 104))
495838	22870241	TP53 mutations were observed in 3 cases (3.5%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('observed', 'Reg', (20, 28))
495839	22870241	In addition, we found one BRAF V600E (1 of 80 patients, 1.2%) and one CTNNB1 D32N (1 of 80 patients, 1.2%) and one EGFR P733L (1 of 80 patients, 1.2%).	('P733L', 'Var', (120, 125))	('CTNNB1', 'Gene', '1499', (70, 76))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (135, 143))	('BRAF', 'Gene', '673', (26, 30))	('D32N', 'Mutation', 'rs28931588', (77, 81))	('EGFR', 'Gene', '1956', (115, 119))	('V600E', 'Var', (31, 36))	('BRAF', 'Gene', (26, 30))	('EGFR', 'Gene', (115, 119))	('CTNNB1', 'Gene', (70, 76))	('P733L', 'Mutation', 'rs121913446', (120, 125))	('V600E', 'Mutation', 'rs113488022', (31, 36))
495841	22870241	There was one case (MLH1 V384D) that harbored mutation in both of primary and metastatic tumor tissues.	('V384D', 'Mutation', 'rs63750447', (25, 30))	('MLH1', 'Gene', '4292', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('MLH1', 'Gene', (20, 24))	('V384D', 'Var', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
495845	22870241	We identified that 11% of metastatic esophageal SCC had PIK3CA mutations in exon 9 (E542K, E545K) and exon 20 (H1047R, L) and that 1% of the patients harbored BRAF V600E mutations.	('BRAF', 'Gene', (159, 163))	('E545K', 'Var', (91, 96))	('E542K', 'Var', (84, 89))	('SCC', 'Gene', (48, 51))	('H1047R', 'Mutation', 'rs121913279', (111, 117))	('SCC', 'Phenotype', 'HP:0002860', (48, 51))	('PIK3CA', 'Gene', (56, 62))	('V600E', 'Mutation', 'rs113488022', (164, 169))	('SCC', 'Gene', '6317', (48, 51))	('E542K', 'Mutation', 'rs121913273', (84, 89))	('H1047R', 'Var', (111, 117))	('PIK3CA', 'Gene', '5290', (56, 62))	('E545K', 'Mutation', 'rs104886003', (91, 96))	('patients', 'Species', '9606', (141, 149))	('BRAF', 'Gene', '673', (159, 163))
495846	22870241	There are scarce reports on PIK3CA mutations in esophageal SCC.	('SCC', 'Gene', (59, 62))	('PIK3CA', 'Gene', (28, 34))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('SCC', 'Gene', '6317', (59, 62))	('PIK3CA', 'Gene', '5290', (28, 34))	('mutations', 'Var', (35, 44))
495848	22870241	Based on these results, identification of PIK3CA mutation may define a subset of patients who may be potential candidates for PIK3CA inhibitor treatment.	('PIK3CA', 'Gene', (126, 132))	('PIK3CA', 'Gene', (42, 48))	('patients', 'Species', '9606', (81, 89))	('mutation', 'Var', (49, 57))	('PIK3CA', 'Gene', '5290', (126, 132))	('PIK3CA', 'Gene', '5290', (42, 48))
495849	22870241	In addition, mTOR inhibitors and AKT inhibitors are currently under the investigations to target subsets of tumors with aberrant PIK3 pathway.	('PIK3', 'Gene', '5294', (129, 133))	('aberrant', 'Var', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('AKT', 'Gene', '207', (33, 36))	('tumors', 'Disease', (108, 114))	('mTOR', 'Gene', (13, 17))	('PIK3', 'Gene', (129, 133))	('mTOR', 'Gene', '2475', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('AKT', 'Gene', (33, 36))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
495850	22870241	A recent preclinical study had demonstrated that LY294002, a PI3K inhibitor, reduced the proliferation of the esophageal cancer cell line in vitro .	('proliferation', 'CPA', (89, 102))	('LY294002', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal cancer', 'Disease', (110, 127))	('LY294002', 'Chemical', 'MESH:C085911', (49, 57))	('reduced', 'NegReg', (77, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))
495852	22870241	To the best of our knowledge, this is the first report on the BRAF mutation in esophageal SCC.	('mutation', 'Var', (67, 75))	('SCC', 'Gene', '6317', (90, 93))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('BRAF', 'Gene', (62, 66))	('BRAF', 'Gene', '673', (62, 66))
495854	22870241	The most common mutation is V600E, which dramatically enhances BRAF enzyme activity, and thus induces tumorous transformation.	('V600E', 'Var', (28, 33))	('enhances', 'PosReg', (54, 62))	('induces', 'Reg', (94, 101))	('tumorous', 'Disease', 'MESH:D009369', (102, 110))	('BRAF', 'Gene', '673', (63, 67))	('activity', 'MPA', (75, 83))	('tumorous', 'Disease', (102, 110))	('V600E', 'Mutation', 'rs113488022', (28, 33))	('BRAF', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
495856	22870241	Although preclinical study on efficacy of BRAF inhibitors is yet to be tested in esophageal SCC, prospective screening for the presence of BRAF mutation should be actively considered in esophageal SCC given the lack of treatment options for these patients.	('SCC', 'Gene', '6317', (197, 200))	('BRAF', 'Gene', '673', (42, 46))	('BRAF', 'Gene', (139, 143))	('SCC', 'Gene', '6317', (92, 95))	('mutation', 'Var', (144, 152))	('patients', 'Species', '9606', (247, 255))	('SCC', 'Gene', (197, 200))	('SCC', 'Phenotype', 'HP:0002860', (197, 200))	('BRAF', 'Gene', (42, 46))	('BRAF', 'Gene', '673', (139, 143))	('SCC', 'Gene', (92, 95))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))
495858	22870241	Loss-of-function mutation of TP53 is one of the most common features of human cancers.	('Loss-of-function', 'NegReg', (0, 16))	('mutation', 'Var', (17, 25))	('human', 'Species', '9606', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
495860	22870241	Other investigators have reported the frequency of TP53 mutation in the range from 35% to 80%.	('mutation', 'Var', (56, 64))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (51, 55))
495861	22870241	However, the frequency of TP53 mutation was lower (3.4%) in our series when compared to those reported in previous studies.	('TP53', 'Gene', (26, 30))	('lower', 'NegReg', (44, 49))	('mutation', 'Var', (31, 39))	('TP53', 'Gene', '7157', (26, 30))
495862	22870241	The lower rate of TP53 mutations in this study is likely due to the fact that TP53 was genotyped at only a 7 loci, rather than sequenced, and thus OncoMap is likely to miss many such events.	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))
495865	22870241	As mentioned above, the rate of TP53 mutations were reported exceptionally lower that previous data such as COSMIC database.	('mutations', 'Var', (37, 46))	('lower', 'NegReg', (75, 80))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))
495866	22870241	While the only detected muation in lower third portion of esophagus is TP53 in the results from COSMIC Database, we reported three detected TP 53 mutations located in upper and middle thirds, suggesting omission of TP53 mutation detection possilby located in distal esophagus.	('TP 53', 'Gene', (140, 145))	('mutations', 'Var', (146, 155))	('TP53', 'Gene', '7157', (215, 219))	('TP 53', 'Gene', '7157', (140, 145))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (215, 219))	('TP53', 'Gene', (71, 75))
495870	22870241	The paradigm of cancer treatment is rapidly changing from disease-specific type to target-specific approach such as testing the efficacy of BRAF inhibitors in BRAF mutant solid tumors regardless of primary sites.	('mutant', 'Var', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('BRAF', 'Gene', (159, 163))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('BRAF', 'Gene', '673', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('BRAF', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumors', 'Disease', (177, 183))	('BRAF', 'Gene', '673', (159, 163))
495871	22870241	Using FFPEs, we successfully screened 80 metastatic esophageal SCC and have identified PIK3CA mutation (11.5%) and BRAF mutation (1.2%) as potential targets for further therapeutic development.	('BRAF', 'Gene', '673', (115, 119))	('PIK3CA', 'Gene', '5290', (87, 93))	('BRAF', 'Gene', (115, 119))	('SCC', 'Gene', (63, 66))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('mutation', 'Var', (120, 128))	('SCC', 'Gene', '6317', (63, 66))	('PIK3CA', 'Gene', (87, 93))	('mutation', 'Var', (94, 102))
495873	22870241	Based on this study, we plan to propose clinical trials with PI3K inhibitors and/or BRAF inhibitors.	('BRAF', 'Gene', (84, 88))	('BRAF', 'Gene', '673', (84, 88))	('PI3K inhibitors', 'Var', (61, 76))
495879	22870241	Our current OncoMap v4 interrogates 471 mutations in 41 genes that are relevant for cancer (Table S1).	('mutations', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
495965	32970189	Vagal injury above this very point and damage of the RLN can lead to the development of vocal cord paresis (VCP).	('injury', 'Disease', 'MESH:D014947', (6, 12))	('lead to', 'Reg', (61, 68))	('vocal cord paresis', 'Phenotype', 'HP:0001604', (88, 106))	('injury', 'Disease', (6, 12))	('RLN', 'Gene', (53, 56))	('vocal cord paresis', 'Disease', (88, 106))	('damage', 'Var', (39, 45))	('Vagal injury', 'Phenotype', 'HP:0002886', (0, 12))	('VCP', 'Phenotype', 'HP:0001604', (108, 111))
495969	32970189	Furthermore, bilateral VCP can lead to a mechanically based respiratory insufficiency, which potentially requires tracheotomy.	('bilateral VCP', 'Var', (13, 26))	('respiratory insufficiency', 'Disease', 'MESH:D012131', (60, 85))	('mechanically', 'Disease', (41, 53))	('respiratory insufficiency', 'Disease', (60, 85))	('VCP', 'Phenotype', 'HP:0001604', (23, 26))	('lead to', 'Reg', (31, 38))	('respiratory insufficiency', 'Phenotype', 'HP:0002093', (60, 85))
496054	31535065	The last of which is intimately linked to the laryngeal framework through the cricopharyngeal and thyropharyngeal muscles, the dysfunction of which may perpetuate abnormal pharyngeal and laryngeal MTP.	('dysfunction', 'Var', (127, 138))	('MTP', 'Gene', '4490', (197, 200))	('MTP', 'Gene', (197, 200))	('perpetuate', 'Reg', (152, 162))
496087	29715275	Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent.	('tumours', 'Disease', (141, 148))	('efficacy', 'CPA', (116, 124))	('EAC', 'Phenotype', 'HP:0011459', (53, 56))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('augment', 'NegReg', (104, 111))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('inhibition', 'Var', (73, 83))
496146	29715275	We hypothesized that co-treatment with 5E1 and precision irradiation would augment the growth delay of PDX tumours relative to either treatment alone in model 8 but not in model 7.	('5E1', 'Var', (39, 42))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('growth delay', 'Phenotype', 'HP:0001510', (87, 99))	('growth delay of PDX tumours', 'Disease', 'MESH:D006130', (87, 114))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('growth delay of PDX tumours', 'Disease', (87, 114))	('augment', 'NegReg', (75, 82))
496149	29715275	In all three experiments (Fig 7), administration of 5E1 or LDE225, whether alone or in combination with radiation, resulted in a significant 0.01- to 0.38-fold change in mouse GLI1 transcript levels relative to IgG and "vehicle," respectively.	('mouse GLI1 transcript levels', 'MPA', (170, 198))	('mouse', 'Species', '10090', (170, 175))	('5E1', 'Var', (52, 55))	('LDE225', 'Gene', (59, 65))	('change', 'Reg', (160, 166))
496155	29715275	Hh inhibition following irradiation delayed tumour repopulation in a model that was Hh-responsive but not in a Hh non-responsive model, suggesting a potential clinical role for inhibiting Hh signaling to augment radiosensitivity in a subset of EAC tumours.	('radiosensitivity', 'MPA', (212, 228))	('tumour', 'Disease', (248, 254))	('augment radiosensitivity', 'Phenotype', 'HP:0010997', (204, 228))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('EAC tumours', 'Disease', 'MESH:C536611', (244, 255))	('EAC', 'Phenotype', 'HP:0011459', (244, 247))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('EAC tumours', 'Disease', (244, 255))	('augment', 'PosReg', (204, 211))	('inhibiting', 'Var', (177, 187))	('tumour', 'Disease', 'MESH:D009369', (248, 254))	('tumours', 'Phenotype', 'HP:0002664', (248, 255))	('inhibition', 'NegReg', (3, 13))	('delayed', 'NegReg', (36, 43))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
496208	26993605	In the univariate analysis, patients with positive TSP1 expression exhibited a 2.21-fold increase in the relative risk (RR) for death (P = 0.043).	('death', 'Disease', (128, 133))	('TSP1', 'Gene', '7057', (51, 55))	('TSP1', 'Gene', (51, 55))	('positive', 'Var', (42, 50))	('death', 'Disease', 'MESH:D003643', (128, 133))	('patients', 'Species', '9606', (28, 36))	('increase', 'PosReg', (89, 97))
496211	26993605	Thus, positive expression of TSP1 was an independent prognostic factor in ESCC patients.	('ESCC', 'Disease', (74, 78))	('positive', 'Var', (6, 14))	('TSP1', 'Gene', '7057', (29, 33))	('TSP1', 'Gene', (29, 33))	('patients', 'Species', '9606', (79, 87))
496223	26993605	Chymotrypsin can attack this fragment at position 320/321, and exopeptidase can release the terminal residue of Arg340, thus leading to the formation of our identified fragment.	('leading to', 'Reg', (125, 135))	('Arg340', 'Chemical', '-', (112, 118))	('Arg340', 'Var', (112, 118))	('formation', 'MPA', (140, 149))
496225	26993605	Furthermore, our immunohistochemical staining confirmed that AHSG was negatively expressed in ESCC tumor and non-tumor tissues (data not shown), indicating that the alteration of this fragment might reflect a hypothetical reduction in protease activity in ESCC patients.	('ESCC tumor', 'Disease', 'MESH:D004938', (94, 104))	('non-tumor', 'Disease', 'MESH:D009369', (109, 118))	('activity', 'MPA', (244, 252))	('negatively', 'NegReg', (70, 80))	('ESCC', 'Disease', (256, 260))	('reduction', 'NegReg', (222, 231))	('ESCC tumor', 'Disease', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('non-tumor', 'Disease', (109, 118))	('alteration', 'Var', (165, 175))	('patients', 'Species', '9606', (261, 269))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('AHSG', 'Gene', '197', (61, 65))	('AHSG', 'Gene', (61, 65))
496240	26993605	As a major serum high-abundance protein secreted by hepatocytes, the fragments of FGA have been identified as decreased or increased in several serum/plasma peptide profiling studies.	('increased', 'PosReg', (123, 132))	('FGA', 'Gene', '2243', (82, 85))	('FGA', 'Gene', (82, 85))	('decreased', 'NegReg', (110, 119))	('fragments', 'Var', (69, 78))
496243	26993605	Therefore, the overexpression of this FGA peptide (5,900 Da) mainly reflects the increased protease activities in ESCC tissues.	('5,900 Da', 'Var', (51, 59))	('overexpression', 'PosReg', (15, 29))	('activities', 'MPA', (100, 110))	('FGA', 'Gene', '2243', (38, 41))	('FGA', 'Gene', (38, 41))	('increased', 'PosReg', (81, 90))	('protease', 'MPA', (91, 99))
496245	26993605	Degraded fibrinogen fragments also possess biological functions, including vasoactive effects, mitogenic effects and migratory effects.	('fibrinogen', 'Gene', '2244', (9, 19))	('fibrinogen', 'Gene', (9, 19))	('mitogenic effects', 'CPA', (95, 112))	('vasoactive effects', 'MPA', (75, 93))	('migratory effects', 'CPA', (117, 134))	('Degraded', 'Var', (0, 8))
496252	26993605	Moreover, the aberrant expression of serum AMBP was previously identified in gastric cancer.	('gastric cancer', 'Disease', (77, 91))	('identified', 'Reg', (63, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('AMBP', 'Gene', '259', (43, 47))	('aberrant', 'Var', (14, 22))	('AMBP', 'Gene', (43, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
496253	26993605	Using a strictly matched case-control study design, our diagnostic model and identified peptides were found to be significantly tumor-related.	('peptides', 'Var', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (128, 133))
496300	26585599	cDNA was diluted 50x and assayed in 10 microL PCR reactions according to the protocol for miRCURY LNA  Universal RT microRNA PCR; 4 miRNAs (miRNA-103a-3p, miRNA-191-5p, miRNA-423-3p, and miRNA-451a) and Sp6 were assayed by quantitative polymerase chain reaction (qPCR).	('Sp6', 'Gene', (203, 206))	('miRNA-103a-3p', 'Var', (140, 153))	('Sp6', 'Gene', '80320', (203, 206))
496306	26585599	Comparing the various groups, we found that miRNA-194-5p was highly present in plasma samples from EAC and BE patients compared to controls.	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('miRNA-194-5p', 'Var', (44, 56))	('EAC', 'Disease', (99, 102))	('patients', 'Species', '9606', (110, 118))	('BE', 'Phenotype', 'HP:0100580', (107, 109))
496307	26585599	miRNA-532-3p was highly expressed in both BE and controls compared to EAC, while miRNA-136-5p, -127-3p, -154-5p, and -382-5p were highly present in EAC and controls compared to BE (Fig.	('EAC', 'Disease', (148, 151))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))	('miRNA-532-3p', 'Var', (0, 12))	('BE', 'Phenotype', 'HP:0100580', (177, 179))	('miRNA-136', 'Gene', '406927', (81, 90))	('EAC', 'Phenotype', 'HP:0011459', (148, 151))	('BE', 'Phenotype', 'HP:0100580', (42, 44))	('miRNA-136', 'Gene', (81, 90))
496310	26585599	Particularly, miRNA-382-5p and let-7e-5p were significantly and more than 1.5-fold up-regulated in EAC compared to BE.	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('miRNA-382-5p', 'Var', (14, 26))	('up-regulated', 'PosReg', (83, 95))	('BE', 'Phenotype', 'HP:0100580', (115, 117))	('let-7e', 'Gene', (31, 37))	('let-7e', 'Gene', '406887', (31, 37))
496313	26585599	miRNA-382-5p was significantly higher expressed in plasma samples from EAC compared to BE patients (2.4-fold) (Fig.	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('BE', 'Phenotype', 'HP:0100580', (87, 89))	('EAC', 'Disease', (71, 74))	('higher', 'PosReg', (31, 37))	('patients', 'Species', '9606', (90, 98))	('miRNA-382-5p', 'Var', (0, 12))
496327	26585599	Of the other miRNAs in our dataset, miRNA-382-5p was also found to be increased in plasma of breast cancer patients and included in a panel of miRNAs to detect breast cancer.	('increased', 'PosReg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('miRNA-382-5p', 'Var', (36, 48))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('patients', 'Species', '9606', (107, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
496333	26585599	To determine whether the differential miRNA-451a expression was due to hemolysis, we measured the presence of miRNA-16-5p.	('hemolysis', 'Disease', 'MESH:D006461', (71, 80))	('hemolysis', 'Disease', (71, 80))	('miRNA-451a', 'Var', (38, 48))
496335	26585599	From a Chinese study it is known that 90 of 101 miRNAs are present in both male and female serum, but miRNA-100, -184, and -923 are male-specific, while miRNA-222 is female-specific.	('miRNA-222', 'Gene', '407007', (153, 162))	('miRNA-222', 'Gene', (153, 162))	('miRNA-100', 'Var', (102, 111))
496345	26585599	These markers could make future screening and surveillance protocols that are based on upper endoscopy more (cost-)effective assigning patients to endoscopy when circulating miRNAs suggest that they are at risk of having BE and/or developing EAC, whereas in those not at risk, endoscopy is not indicated.	('patients', 'Species', '9606', (135, 143))	('EAC', 'Disease', (242, 245))	('BE', 'Phenotype', 'HP:0100580', (221, 223))	('circulating miRNAs', 'Var', (162, 180))	('EAC', 'Phenotype', 'HP:0011459', (242, 245))
496346	25821560	Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide.	('Esophageal squamous cell carcinoma', 'Disease', (91, 125))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (42, 62))	('malignancies', 'Disease', 'MESH:D009369', (159, 171))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (31, 62))	('Methylation', 'Var', (0, 11))	('docetaxel', 'Chemical', 'MESH:D000077143', (66, 75))	('paclitaxel', 'Chemical', 'MESH:D017239', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('CHFR', 'Gene', (15, 19))	('CHFR', 'Gene', '55743', (15, 19))	('malignancies', 'Disease', (159, 171))	('esophageal squamous cell cancer', 'Disease', (31, 62))	('sensitizes', 'Reg', (20, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (91, 125))
496347	25821560	Both genetic and epigenetic changes are involved in esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (52, 77))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (52, 77))	('epigenetic changes', 'Var', (17, 35))	('involved', 'Reg', (40, 48))
496348	25821560	CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity.	('cancers', 'Disease', (56, 63))	('CHFR', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('methylation', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('taxane', 'Chemical', 'MESH:C080625', (95, 101))	('found', 'Reg', (26, 31))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
496349	25821560	CHFR methylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 45% (49/109) of invasive cancer.	('I dysplasia', 'Disease', 'MESH:C538215', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('methylation', 'Var', (5, 16))	('II dysplasia', 'Disease', 'MESH:D003784', (146, 158))	('II dysplasia', 'Disease', (110, 122))	('invasive cancer', 'Disease', (179, 194))	('II dysplasia', 'Disease', (146, 158))	('I dysplasia', 'Disease', 'MESH:C538215', (147, 158))	('I dysplasia', 'Disease', 'MESH:C538215', (79, 90))	('I dysplasia', 'Disease', (79, 90))	('invasive cancer', 'Disease', 'MESH:D009362', (179, 194))	('II dysplasia', 'Disease', 'MESH:D003784', (110, 122))
496350	25821560	When treated with docetaxel or paclitaxel, cell viability was lower in CHFR methylated esophageal cancer cells than in unmethylated cells (p<0.05).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('paclitaxel', 'Chemical', 'MESH:D017239', (31, 41))	('docetaxel', 'Chemical', 'MESH:D000077143', (18, 27))	('esophageal cancer', 'Disease', (87, 104))	('CHFR methylated', 'Var', (71, 86))	('lower', 'NegReg', (62, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('cell viability', 'CPA', (43, 57))
496354	25821560	Methylation of CHFR sensitized ESCC cells to taxanes.	('sensitized', 'Reg', (20, 30))	('Methylation', 'Var', (0, 11))	('CHFR', 'Gene', (15, 19))	('CHFR', 'Gene', '55743', (15, 19))	('taxanes', 'Chemical', 'MESH:D043823', (45, 52))
496362	25821560	Accumulation of epigenetic changes in tumor suppressor genes is a well known event in human esophageal carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('esophageal carcinogenesis', 'Disease', (92, 117))	('epigenetic changes', 'Var', (16, 34))	('human', 'Species', '9606', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (92, 117))
496363	25821560	DNA methylation may serve as marker for early cancer diagnosis, chemo-sensitivity as well as prognosis.	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('methylation', 'Var', (4, 15))
496365	25821560	Loss of CHFR expression and promoter region hypermethylation were found frequently in different cancers.	('promoter', 'MPA', (28, 36))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('expression', 'MPA', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Loss', 'NegReg', (0, 4))	('CHFR', 'Gene', (8, 12))	('hypermethylation', 'Var', (44, 60))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
496366	25821560	Methylation of CHFR was also regarded as a marker of taxane sensitivity in various cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CHFR', 'Gene', (15, 19))	('taxane', 'Chemical', 'MESH:C080625', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
496367	25821560	In 35 cases, no significant difference was found in the response of CHFR methylated and unmethylated esophageal cancer patients to the combined cisplatin and 5-fluorouracil therapy plus radiotherapy.	('patients', 'Species', '9606', (119, 127))	('esophageal cancer', 'Disease', (101, 118))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (158, 172))	('methylated', 'Var', (73, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))
496370	25821560	Constant expression was found in KYSE30, KYSE140, KYSE180, KYSE450, KYSE520, TE7 and SEG1 cells while loss of expression was observed in KYSE70, KYSE150 and KYSE510 cells (Figure 1A).	('KYSE520', 'Var', (68, 75))	('SEG1', 'CellLine', 'CVCL:8113', (85, 89))	('KYSE140', 'Var', (41, 48))	('KYSE450', 'Var', (59, 66))	('KYSE180', 'Var', (50, 57))	('KYSE510', 'CellLine', 'CVCL:1354', (157, 164))	('KYSE30', 'Var', (33, 39))
496371	25821560	Complete methylation was found in KYSE70, KYSE150 and KYSE510 cells while KYSE30, KYSE140, KYSE180, KYSE450, KYSE520, TE7 and SEG1 cells were found to be without methylation (Figure 1B).	('KYSE140', 'Var', (82, 89))	('KYSE150', 'Var', (42, 49))	('KYSE30', 'Var', (74, 80))	('KYSE180', 'Var', (91, 98))	('KYSE510', 'CellLine', 'CVCL:1354', (54, 61))	('SEG1', 'CellLine', 'CVCL:8113', (126, 130))	('KYSE70', 'Var', (34, 40))	('methylation', 'MPA', (9, 20))	('KYSE510', 'Var', (54, 61))
496372	25821560	Restoration of CHFR expression was induced by 5-aza-2'-deoxycytidine (5-AZ) treatment in KYSE70, KYSE150 and KYSE510 cells (Figure 1A).	('KYSE510', 'Var', (109, 116))	('expression', 'MPA', (20, 30))	('KYSE150', 'Var', (97, 104))	('KYSE70', 'Var', (89, 95))	('KYSE510', 'CellLine', 'CVCL:1354', (109, 116))	('CHFR', 'Gene', (15, 19))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (46, 68))	('5-AZ', 'Chemical', 'MESH:D000077209', (70, 74))
496373	25821560	These results suggest that the expression of CHFR was regulated by promoter region methylation in esophageal cancer cells.	('regulated', 'Reg', (54, 63))	('CHFR', 'Gene', (45, 49))	('expression', 'MPA', (31, 41))	('esophageal cancer', 'Disease', (98, 115))	('methylation', 'Var', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
496374	25821560	Epigenetic alterations have been shown to progress in frequency during esophageal carcinogenesis.	('Epigenetic alterations', 'Var', (0, 22))	('progress', 'PosReg', (42, 50))	('esophageal carcinogenesis', 'Disease', (71, 96))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (71, 96))
496376	25821560	Promoter region hypermethylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 44.95% (49/109) of invasive esophageal cancer (Figure 1C,1D,1E, Table1).	('II dysplasia', 'Disease', (126, 138))	('II dysplasia', 'Disease', 'MESH:D003784', (162, 174))	('invasive esophageal cancer', 'Disease', (198, 224))	('I dysplasia', 'Disease', (95, 106))	('I dysplasia', 'Disease', 'MESH:C538215', (95, 106))	('found', 'Reg', (37, 42))	('I dysplasia', 'Disease', 'MESH:C538215', (127, 138))	('II dysplasia', 'Disease', (162, 174))	('hypermethylation', 'Var', (16, 32))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('II dysplasia', 'Disease', 'MESH:D003784', (126, 138))	('I dysplasia', 'Disease', 'MESH:C538215', (163, 174))	('invasive esophageal cancer', 'Disease', 'MESH:D004938', (198, 224))
496377	25821560	CHFR was more infrequently methylated in esophageal dysplasia than in invasive esophageal cancer (p<0.01).	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal dysplasia', 'Disease', (41, 61))	('methylated', 'Var', (27, 37))	('invasive esophageal cancer', 'Disease', 'MESH:D004938', (70, 96))	('invasive esophageal cancer', 'Disease', (70, 96))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (41, 61))
496378	25821560	This suggests that CHFR methylation was a late stage event of esophagus carcinogenesis.	('esophagus carcinogenesis', 'Disease', 'MESH:D063646', (62, 86))	('methylation', 'Var', (24, 35))	('esophagus carcinogenesis', 'Disease', (62, 86))
496379	25821560	No association was found between methylation and age, gender, TNM stage, tumor size, differentiation and lymph node metastasis (all p>0.05).	('methylation', 'Var', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('lymph node metastasis', 'Disease', 'MESH:D009362', (105, 126))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('TNM', 'Gene', (62, 65))	('lymph node metastasis', 'Disease', (105, 126))	('TNM', 'Gene', '10178', (62, 65))
496380	25821560	Methylation of CHFR has been shown to sensitize different cancers to taxane treatment.	('taxane', 'Chemical', 'MESH:C080625', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Methylation', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('CHFR', 'Gene', (15, 19))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('sensitize', 'Reg', (38, 47))
496381	25821560	In a small study, no association was found between CHFR methylation and the sensitivity of esophageal cancer to cisplatin and 5-fluorouracil.	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('CHFR', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (126, 140))	('sensitivity', 'MPA', (76, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('esophageal cancer', 'Disease', (91, 108))	('methylation', 'Var', (56, 67))
496384	25821560	Methylated cells (KYSE70, KYSE150) were significantly more likely to undergo apoptosis than unmethylated cells (KYSE140, KYSE450) after paclitaxel or docetaxel treatment (Figure2, table 2, all p< 0.05).	('apoptosis', 'CPA', (77, 86))	('undergo', 'Reg', (69, 76))	('paclitaxel', 'Chemical', 'MESH:D017239', (136, 146))	('docetaxel', 'Chemical', 'MESH:D000077143', (150, 159))	('KYSE70', 'Var', (18, 24))
496387	25821560	While in the paclitaxel and docetaxel treated groups, no significant difference was found between the methylated (KYSE70, KYSE150) and unmethylated cells (KYSE140, KYSE450) when treated with 5-AZ (Figure2, table2, all p>0.05).	('KYSE70', 'Var', (114, 120))	('docetaxel', 'Chemical', 'MESH:D000077143', (28, 37))	('KYSE140', 'Var', (155, 162))	('KYSE150', 'Var', (122, 129))	('paclitaxel', 'Chemical', 'MESH:D017239', (13, 23))	('5-AZ', 'Chemical', 'MESH:D000077209', (191, 195))
496388	25821560	These results further suggest that the methylation of CHFR sensitizes esophageal cancer cells to paclitaxel and docetaxel, while the restoration of CHFR expression with 5-AZ induces resistance to these chemotherapeutic agents.	('sensitizes', 'Reg', (59, 69))	('5-AZ', 'Chemical', 'MESH:D000077209', (169, 173))	('methylation', 'Var', (39, 50))	('esophageal cancer', 'Disease', (70, 87))	('CHFR', 'Gene', (148, 152))	('CHFR', 'Gene', (54, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (97, 107))	('expression', 'MPA', (153, 163))	('resistance', 'MPA', (182, 192))	('docetaxel', 'Chemical', 'MESH:D000077143', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('induces', 'PosReg', (174, 181))
496389	25821560	CHFR methylation has been reported to sensitize cancer cells to taxanes.	('CHFR', 'Gene', (0, 4))	('methylation', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('taxanes', 'Chemical', 'MESH:D043823', (64, 71))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('sensitize', 'Reg', (38, 47))
496390	25821560	In our study, promoter region methylation sensitized KYSE70 and KYSE150 cells to docetaxel and paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (95, 105))	('sensitized', 'Reg', (42, 52))	('methylation', 'Var', (30, 41))	('docetaxel', 'Chemical', 'MESH:D000077143', (81, 90))
496402	25821560	Accumulation of genetic and epigenetic changes has been found in the development of various cancers, including esophageal cancer.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('esophageal cancer', 'Disease', (111, 128))	('epigenetic changes', 'Var', (28, 46))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('genetic', 'Var', (16, 23))	('found', 'Reg', (56, 61))
496405	25821560	It suggests that CHFR methylation is a late stage marker of esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (60, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (60, 94))	('CHFR', 'Gene', (17, 21))	('methylation', 'Var', (22, 33))
496406	25821560	Methylation of CHFR has been regarded as a chemo-sensitive marker in various cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('Methylation', 'Var', (0, 11))	('cancers', 'Disease', (77, 84))	('CHFR', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
496407	25821560	We found CHFR methylation sensitizes esophageal cancer cells to docetaxel and paclitaxel, and 5-AZ induces chemoresistance of CHFR methylated cells to docetaxel and paclitaxel.	('induces', 'Reg', (99, 106))	('docetaxel', 'Chemical', 'MESH:D000077143', (151, 160))	('chemoresistance', 'CPA', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('sensitizes', 'Reg', (26, 36))	('5-AZ', 'Var', (94, 98))	('methylation', 'Var', (14, 25))	('paclitaxel', 'Chemical', 'MESH:D017239', (165, 175))	('esophageal cancer', 'Disease', (37, 54))	('paclitaxel', 'Chemical', 'MESH:D017239', (78, 88))	('5-AZ', 'Chemical', 'MESH:D000077209', (94, 98))	('docetaxel', 'Chemical', 'MESH:D000077143', (64, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
496408	25821560	These results suggest that CHFR methylation is a taxane sensitive marker in human esophageal squamous cancer.	('methylation', 'Var', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('squamous cancer', 'Phenotype', 'HP:0002860', (93, 108))	('taxane', 'Chemical', 'MESH:C080625', (49, 55))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (82, 108))	('esophageal squamous cancer', 'Disease', (82, 108))	('human', 'Species', '9606', (76, 81))
496409	25821560	There are a few reports about the ability of epigenetic therapy to undo chemoresistance and re-sensitize refractory tumors to specific chemotherapy agents.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('undo', 'Reg', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('chemoresistance', 'CPA', (72, 87))	('epigenetic therapy', 'Var', (45, 63))
496413	25821560	This result may be interpreted as a partial explanation for the mechanism by which epigenetic therapy re-sensitizes chemotherapy resistant, refractory tumors.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('epigenetic therapy', 'Var', (83, 101))
496416	25821560	In our study, silencing CHFR by promoter region hypermethylation sensitized esophageal cancer cells to docetaxel and paclitaxel.	('silencing', 'Var', (14, 23))	('docetaxel', 'Chemical', 'MESH:D000077143', (103, 112))	('paclitaxel', 'Chemical', 'MESH:D017239', (117, 127))	('esophageal cancer', 'Disease', (76, 93))	('sensitized', 'Reg', (65, 75))	('hypermethylation', 'Var', (48, 64))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('CHFR', 'Gene', (24, 28))
496421	25821560	Methylation of CHFR is a late stage event in esophageal cancer.	('esophageal cancer', 'Disease', (45, 62))	('Methylation', 'Var', (0, 11))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('CHFR', 'Gene', (15, 19))
496422	25821560	Methylation of CHFR sensitized esophageal cancer cells to docetaxel and paclitaxel.	('docetaxel', 'Chemical', 'MESH:D000077143', (58, 67))	('paclitaxel', 'Chemical', 'MESH:D017239', (72, 82))	('sensitized', 'Reg', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('esophageal cancer', 'Disease', (31, 48))	('Methylation', 'Var', (0, 11))	('CHFR', 'Gene', (15, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))
496423	25821560	Finally, 5-AZ may re-sensitize chemotherapy resistant refractory tumors by inducing cell cycle phase re-distribution.	('tumors', 'Disease', (65, 71))	('chemotherapy', 'Disease', (31, 43))	('5-AZ', 'Var', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cell cycle phase re-distribution', 'CPA', (84, 116))	('inducing', 'PosReg', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('5-AZ', 'Chemical', 'MESH:D000077209', (9, 13))
496424	25821560	Ten human esophageal cancer cell lines (KYSE30, KYSE140, KYSE180, KYSE450, KYSE520, TE7, SEG1, KYSE70, KYSE150 and KYSE510) were used in this study.	('KYSE510', 'CellLine', 'CVCL:1354', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (4, 9))	('esophageal cancer', 'Disease', (10, 27))	('KYSE70', 'Var', (95, 101))	('SEG1', 'CellLine', 'CVCL:8113', (89, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (10, 27))
496436	25821560	Group 2 was treated with 2mumol/L 5-AZ+10mug/ml paclitaxel, 5-AZ+18.4 mug/ml docetaxel (Doc), 5-AZ+ 25 mug/ml VP16, or 5-AZ+10 mug/ml cisplatin for 24 h, 48 h and 72 h respectively.	('5-AZ', 'Chemical', 'MESH:D000077209', (60, 64))	('5-AZ', 'Chemical', 'MESH:D000077209', (119, 123))	('VP16', 'Chemical', 'MESH:D005047', (110, 114))	('5-AZ', 'Chemical', 'MESH:D000077209', (94, 98))	('5-AZ', 'Chemical', 'MESH:D000077209', (34, 38))	('docetaxel', 'Chemical', 'MESH:D000077143', (77, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('5-AZ+ 25 mug/ml', 'Var', (94, 109))	('5-AZ+18.4', 'Var', (60, 69))	('Doc', 'Chemical', 'MESH:D000077143', (88, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))
496538	24684802	Lysine166 within Rac3 was identified as an ubiquitination acceptor site.	('Rac3', 'Gene', (17, 21))	('Lysine166', 'Chemical', '-', (0, 9))	('Lysine166', 'Var', (0, 9))
496546	24684802	Aberrant activation of Rac3 has been recognized to be important in tumor proliferation in both breast cancer and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('Aberrant', 'Var', (0, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('prostate cancer', 'Disease', (113, 128))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('Rac3', 'Protein', (23, 27))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
496550	24684802	Inhibition of Rac3 caused an increase in TNFalpha-induced apoptosis.	('TNFalpha', 'Gene', (41, 49))	('Rac3', 'Gene', (14, 18))	('increase', 'PosReg', (29, 37))	('TNFalpha', 'Gene', '7124', (41, 49))	('Inhibition', 'Var', (0, 10))
496575	24684802	Both forms of tagged-FBXL19 down-regulated endogenous Rac3 expression (up to ~73%) (Figure 1A-B), while over-expression of other E3 ligase subunits (NEDD4L, FBXL18, and FBXL22) had no effect on Rac3 expression (Figure 1C).	('FBXL18', 'Gene', (157, 163))	('tagged-FBXL19', 'Var', (14, 27))	('NEDD4L', 'Gene', (149, 155))	('FBXL22', 'Gene', '283807', (169, 175))	('down-regulated', 'NegReg', (28, 42))	('NEDD4L', 'Gene', '23327', (149, 155))	('FBXL18', 'Gene', '80028', (157, 163))	('expression', 'MPA', (59, 69))	('endogenous', 'MPA', (43, 53))	('FBXL22', 'Gene', (169, 175))	('Rac3', 'Gene', (54, 58))
496581	24684802	Figure 1E and F show that the ectopic expression of FBXL19-V5 or FBXL19-HA diminished Rac3-V5 protein in a dose dependent manner.	('diminished', 'NegReg', (75, 85))	('ectopic expression', 'MPA', (30, 48))	('FBXL19-HA', 'Gene', (65, 74))	('Rac3-V5 protein', 'MPA', (86, 101))	('FBXL19-V5', 'Var', (52, 61))	('FBXL19-HA', 'Gene', '54620', (65, 74))
496586	24684802	In addition, we found that the FBXL19-V5-induced Rac3 degradation was attenuated by MG-132 (up to 45-53%), but not by leupeptin (Figure 2B).	('leupeptin', 'Chemical', 'MESH:C032854', (118, 127))	('attenuated', 'NegReg', (70, 80))	('MG-132', 'Chemical', 'MESH:C072553', (84, 90))	('Rac3 degradation', 'MPA', (49, 65))	('MG-132', 'Var', (84, 90))
496592	24684802	Further, we compared the degree of ubiquitination of Rac3 wild type and Rac3K166R-V5 after incubation with MG-132.	('ubiquitination', 'MPA', (35, 49))	('MG-132', 'Chemical', 'MESH:C072553', (107, 113))	('K166R', 'Mutation', 'p.K166R', (76, 81))	('Rac3K166R-V5', 'Var', (72, 84))
496593	24684802	As shown in Figure 4B, polyubiquitinated Rac3 was immunoprecipitated by an antibody to ubiquitin, and Rac3 K166R exhibits less ubiquitination, compared to Rac3 wild type, suggesting that K166 is an ubiquitin acceptor site within Rac3.	('K166', 'Chemical', '-', (107, 111))	('K166R', 'Var', (107, 112))	('ubiquitination', 'MPA', (127, 141))	('K166', 'Chemical', '-', (187, 191))	('less', 'NegReg', (122, 126))	('Rac3', 'Var', (102, 106))	('K166R', 'Mutation', 'p.K166R', (107, 112))
496594	24684802	Further, an FBXL19 variant with truncation at the COOH (C450) lost the ability to degrade Rac3 (Figure 5B).	('Rac3', 'MPA', (90, 94))	('degrade', 'NegReg', (82, 89))	('variant', 'Var', (19, 26))	('lost', 'NegReg', (62, 66))	('FBXL19', 'Gene', (12, 18))	('COOH', 'Chemical', 'MESH:D002255', (50, 54))
496608	24684802	As expected, we found that FBXL19-V5 reduced Rac3 activity in both OE19 and HEK293 cells (up to 64-89%) (Figure 7B).	('reduced', 'NegReg', (37, 44))	('Rac3', 'Enzyme', (45, 49))	('HEK293', 'CellLine', 'CVCL:0045', (76, 82))	('FBXL19-V5', 'Var', (27, 36))
496628	24684802	In addition, we identified that FBXL19 induced Rac3 ubiquitination at lysine166.	('lysine166', 'Var', (70, 79))	('Rac3 ubiquitination', 'MPA', (47, 66))	('FBXL19', 'Gene', (32, 38))	('lysine166', 'Chemical', '-', (70, 79))
496634	24684802	In tumors of the esophagus and gastroesophageal junction, disturbances in E-cadherin expression have been correlated with increasing invasive capacity, dedifferentiation, and lymph node metastases.	('expression', 'MPA', (85, 95))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('metastases', 'Disease', (186, 196))	('tumors of the esophagus', 'Phenotype', 'HP:0100751', (3, 26))	('increasing', 'PosReg', (122, 132))	('E-cadherin', 'Gene', (74, 84))	('metastases', 'Disease', 'MESH:D009362', (186, 196))	('tumors of the esophagus', 'Disease', (3, 26))	('E-cadherin', 'Gene', '999', (74, 84))	('gastroesophageal junction', 'Disease', (31, 56))	('invasive capacity', 'CPA', (133, 150))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (31, 56))	('tumors of the esophagus', 'Disease', 'MESH:D004938', (3, 26))	('disturbances', 'Var', (58, 70))	('dedifferentiation', 'CPA', (152, 169))
496640	24684802	Interestingly, inhibition of Rac3 by overexpressed inactive form of Rac3 (Rac3N17), Rac3 shRNA, or FBXL19 significantly attenuates TGFbeta1-induced E-cadherin down-regulation (Figure 8).	('down-regulation', 'NegReg', (159, 174))	('inhibition', 'NegReg', (15, 25))	('E-cadherin', 'Gene', (148, 158))	('TGFbeta1', 'Gene', (131, 139))	('attenuates', 'NegReg', (120, 130))	('E-cadherin', 'Gene', '999', (148, 158))	('Rac3N17', 'Gene', (74, 81))	('Rac3N17', 'Gene', '5881', (74, 81))	('Rac3', 'Var', (84, 88))	('FBXL19', 'Gene', (99, 105))	('TGFbeta1', 'Gene', '7040', (131, 139))
496641	24684802	This study discovered that Rac3 plays an important role in the progress of esophageal cancer cells and the FBXL19 may function as a tumor suppressor through its ability to reduce Rac3 levels and inhibits TGFbeta1 pathway.	('TGFbeta1', 'Gene', (204, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('inhibits', 'NegReg', (195, 203))	('FBXL19', 'Var', (107, 113))	('Rac3 levels', 'MPA', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('reduce', 'NegReg', (172, 178))	('tumor', 'Disease', (132, 137))	('esophageal cancer', 'Disease', (75, 92))	('TGFbeta1', 'Gene', '7040', (204, 212))
496645	24684802	This is the first evidence to support that Rac3 plays a critical role in the tumorgenesis of esophageal cancer and that FBXL19 exhibits an anti-tumor property by down-regulation of small GTPase.	('tumor', 'Disease', (144, 149))	('down-regulation', 'NegReg', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('GTP', 'Chemical', 'MESH:D006160', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('small GTPase', 'Protein', (181, 193))	('Rac3', 'Protein', (43, 47))	('tumorgenesis of esophageal cancer', 'Disease', (77, 110))	('tumor', 'Disease', (77, 82))	('tumorgenesis of esophageal cancer', 'Disease', 'MESH:D004938', (77, 110))	('FBXL19', 'Var', (120, 126))
496653	24684802	Site directed mutagenesis was performed to generate Rac3 lysine or serine mutant according to the manufacturer's instructions (Agilent Technologies, Santa Clara, CA, USA).	('Rac3 lysine', 'Var', (52, 63))	('lysine', 'Chemical', 'MESH:D008239', (57, 63))	('serine', 'MPA', (67, 73))	('serine', 'Chemical', 'MESH:D012694', (67, 73))
496668	24684802	This study was supported by the US National Institutes of Health (R01 HL091916 and R01HL112791 to YZ), American Heart Association awards 12SDG9050005 (JZ).	('R01HL112791', 'Var', (83, 94))	('HL091916', 'CellLine', 'CVCL:2492', (70, 78))	('HL112791', 'CellLine', 'CVCL:2492', (86, 94))	('R01 HL091916', 'Var', (66, 78))
496669	24345911	Association between the c.910A>G genetic variant of the XRCC1 gene and susceptibility to esophageal cancer in the Chinese Han population Esophageal cancer (EC) is a common malignancy worldwide.	('esophageal cancer', 'Disease', (89, 106))	('c.910A>G', 'Var', (24, 32))	('malignancy', 'Disease', 'MESH:D009369', (172, 182))	('XRCC1', 'Gene', '7515', (56, 61))	('malignancy', 'Disease', (172, 182))	('c.910A>G', 'Mutation', 'rs25490', (24, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Esophageal cancer', 'Disease', (137, 154))	('XRCC1', 'Gene', (56, 61))	('Association', 'Interaction', (0, 11))	('Esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))
496671	24345911	This study aimed to investigate the effect of XRCC1 genetic variants on susceptibility to EC.	('XRCC1', 'Gene', (46, 51))	('variants', 'Var', (60, 68))	('XRCC1', 'Gene', '7515', (46, 51))
496673	24345911	The c.910A>G genetic variant of the XRCC1 gene was determined by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods.	('c.910A>G', 'Mutation', 'rs25490', (4, 12))	('XRCC1', 'Gene', (36, 41))	('c.910A>G', 'Var', (4, 12))	('XRCC1', 'Gene', '7515', (36, 41))
496675	24345911	The c.910A>G genetic variant was statistically associated with increased susceptibility to EC [GG vs AA: odds ratio (OR)=1.79, 95% confidence interval (CI)=1.12-2.86, P=0.014; GG vs AG/AA: OR=1.76, 95%CI=1.13-2.75, P=0.013; G vs A: OR=1.25, 95%CI=1.01-1.55, P=0.041].	('c.910A>G', 'Mutation', 'rs25490', (4, 12))	('c.910A>G', 'Var', (4, 12))	('susceptibility', 'Reg', (73, 87))
496676	24345911	Our findings suggest that the c.910A>G genetic variant is associated with susceptibility to EC in the Chinese Han population, and might be used as a molecular marker for detecting susceptibility to EC.	('susceptibility', 'Reg', (74, 88))	('c.910A>G', 'Mutation', 'rs25490', (30, 38))	('c.910A>G', 'Var', (30, 38))
496679	24345911	Previous studies demonstrated that the risk of EC has been associated with various factors such as nitrosamine carcinogens, alcohol intake, cigarette smoking, malnutrition, and genetic polymorphisms.	('genetic polymorphisms', 'Var', (177, 198))	('associated', 'Reg', (59, 69))	('malnutrition', 'Disease', (159, 171))	('alcohol', 'Chemical', 'MESH:D000438', (124, 131))	('malnutrition', 'Phenotype', 'HP:0004395', (159, 171))	('nitrosamine', 'Chemical', 'MESH:D009602', (99, 110))
496682	24345911	The XRCC1 protein plays a critical role in the repair of single-strand DNA breaks and in the DNA base excision repair pathway.	('DNA base excision repair pathway', 'Pathway', (93, 125))	('single-strand', 'Var', (57, 70))	('XRCC1', 'Gene', (4, 9))	('XRCC1', 'Gene', '7515', (4, 9))
496683	24345911	Single genetic polymorphisms of the XRCC1 gene could impact the expression and function of the XRCC1 protein, which would influence susceptibility to EC.	('Single genetic polymorphisms', 'Var', (0, 28))	('impact', 'Reg', (53, 59))	('XRCC1', 'Gene', '7515', (36, 41))	('expression', 'MPA', (64, 74))	('XRCC1', 'Gene', (36, 41))	('XRCC1', 'Gene', (95, 100))	('function', 'MPA', (79, 87))	('protein', 'Protein', (101, 108))	('influence susceptibility', 'Reg', (122, 146))	('XRCC1', 'Gene', '7515', (95, 100))
496684	24345911	Evidence from published studies indicated that several single genetic polymorphisms in the XRCC1 gene, such as arginine (Arg)194 tryptophan (Trp), Arg280 histidine (His), and Arg399 glutanine (Gln), have been potentially associated with susceptibility to EC.	('Arg280 histidine', 'Mutation', 'rs25489', (147, 163))	('XRCC1', 'Gene', (91, 96))	('His', 'Chemical', 'MESH:D006639', (165, 168))	('arginine', 'Var', (111, 119))	('susceptibility', 'Reg', (237, 251))	('Trp', 'Chemical', 'MESH:D014364', (141, 144))	('Arg280 histidine', 'Var', (147, 163))	('XRCC1', 'Gene', '7515', (91, 96))	('Arg399 glutanine', 'Var', (175, 191))	('Arg)194 tryptophan', 'SUBSTITUTION', 'None', (121, 139))	('associated', 'Reg', (221, 231))	('Arg399', 'Chemical', '-', (175, 181))	('arginine', 'Chemical', 'MESH:D001120', (111, 119))	('glutanine', 'Chemical', '-', (182, 191))	('Gln', 'Chemical', '-', (193, 196))
496693	24345911	The genotyping of the c.910A>G genetic variant of the XRCC1 gene was analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP).	('c.910A>G', 'Var', (22, 30))	('XRCC1', 'Gene', '7515', (54, 59))	('XRCC1', 'Gene', (54, 59))	('c.910A>G', 'Mutation', 'rs25490', (22, 30))
496697	24345911	Genotyping of the c.910A>G genetic variant of the XRCC1 gene was identified in this study using PCR-RFLP and DNA sequencing methods.	('c.910A>G', 'Mutation', 'rs25490', (18, 26))	('XRCC1', 'Gene', '7515', (50, 55))	('c.910A>G', 'Var', (18, 26))	('XRCC1', 'Gene', (50, 55))
496698	24345911	Our sequence analyses suggested that the c.910A>G genetic variant is caused by an A to G mutation, and this is a nonsynonymous mutation corresponding to a threonine (Thr) to alanine (Ala) amino acid replacement in exon 9 of the XRCC1 gene (p.Thr304Ala, reference sequences: GenBank IDs: NC_000019.9, NM_006297.2, and NP_006288.2).	('Thr', 'Chemical', 'MESH:D013912', (242, 245))	('XRCC1', 'Gene', (228, 233))	('Ala', 'Chemical', 'MESH:D000409', (248, 251))	('c.910A>G', 'Mutation', 'rs25490', (41, 49))	('threonine', 'Chemical', 'MESH:D013912', (155, 164))	('alanine', 'Chemical', 'MESH:D000409', (174, 181))	('Ala', 'Chemical', 'MESH:D000409', (183, 186))	('XRCC1', 'Gene', '7515', (228, 233))	('p.Thr304Ala', 'Mutation', 'rs25490', (240, 251))	('p.Thr304Ala', 'Var', (240, 251))	('caused by', 'Reg', (69, 78))	('c.910A>G', 'Var', (41, 49))	('Thr', 'Chemical', 'MESH:D013912', (166, 169))
496704	24345911	The potential association of the XRCC1 c.910A>G genetic variant with EC risk is shown in Table 3.	('c.910A>G', 'Mutation', 'rs25490', (39, 47))	('XRCC1', 'Gene', (33, 38))	('association', 'Interaction', (14, 25))	('c.910A>G', 'Var', (39, 47))	('XRCC1', 'Gene', '7515', (33, 38))
496706	24345911	In the present study, the influence of the c.910A>G genetic variant of the XRCC1 gene on EC risk was evaluated by association analysis in 383 EC patients and 387 cancer-free Chinese subjects with Han ethnicity.	('patients', 'Species', '9606', (145, 153))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('XRCC1', 'Gene', (75, 80))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('c.910A>G', 'Var', (43, 51))	('XRCC1', 'Gene', '7515', (75, 80))	('c.910A>G', 'Mutation', 'rs25490', (43, 51))
496708	24345911	Results from this study provided more evidence of the role of the XRCC1 gene in the development of EC and suggested that the c.910A>G genetic variant of the XRCC1 gene was statistically associated with EC risk in the Chinese Han population; therefore, this variant could be used as a molecular marker for evaluating susceptibility to EC.	('XRCC1', 'Gene', '7515', (66, 71))	('XRCC1', 'Gene', (157, 162))	('c.910A>G', 'Var', (125, 133))	('c.910A>G', 'Mutation', 'rs25490', (125, 133))	('XRCC1', 'Gene', (66, 71))	('associated with', 'Reg', (186, 201))	('XRCC1', 'Gene', '7515', (157, 162))
496709	24345911	Our findings are consistent with several similar studies that demonstrated the potential association between other XRCC1 genetic variants and the risk of EC (for example, Arg194Trp, Arg280His, and Arg399Gln).	('Arg280His', 'SUBSTITUTION', 'None', (182, 191))	('XRCC1', 'Gene', '7515', (115, 120))	('Arg280His', 'Var', (182, 191))	('association', 'Reg', (89, 100))	('Arg194Trp', 'SUBSTITUTION', 'None', (171, 180))	('XRCC1', 'Gene', (115, 120))	('Arg399Gln', 'Var', (197, 206))	('Arg399Gln', 'SUBSTITUTION', 'None', (197, 206))	('Arg194Trp', 'Var', (171, 180))
496710	24345911	indicated that the Arg194Trp genetic polymorphism may be associated with an increased risk of developing esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', (105, 139))	('Arg194Trp', 'SUBSTITUTION', 'None', (19, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('Arg194Trp', 'Var', (19, 28))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (105, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('associated', 'Reg', (57, 67))
496711	24345911	found that individuals with the Trp/Trp genotype at the XRCC1 Arg194Trp site had a 2-fold increased risk of ESCC compared with the Arg/Arg genotype (adjusted OR=1.98, 95%CI=1.26-3.12).	('Trp', 'Chemical', 'MESH:D014364', (36, 39))	('Trp', 'Chemical', 'MESH:D014364', (32, 35))	('XRCC1', 'Gene', '7515', (56, 61))	('Arg194Trp', 'Var', (62, 71))	('Trp', 'Chemical', 'MESH:D014364', (68, 71))	('Arg', 'Chemical', 'MESH:D001120', (131, 134))	('Arg', 'Chemical', 'MESH:D001120', (135, 138))	('XRCC1', 'Gene', (56, 61))	('Arg194Trp', 'SUBSTITUTION', 'None', (62, 71))	('ESCC', 'Disease', (108, 112))	('Arg', 'Chemical', 'MESH:D001120', (62, 65))	('Trp/Trp', 'Var', (32, 39))
496713	24345911	suggested that the XRCC1 codon 399 Gln/Gln genotype was significantly associated with reduced risk of ESCC (OR=0.31, 95%CI=0.12-0.78, P<0.01).	('Gln', 'Chemical', '-', (39, 42))	('XRCC1', 'Gene', (19, 24))	('reduced', 'NegReg', (86, 93))	('ESCC', 'Disease', (102, 106))	('XRCC1', 'Gene', '7515', (19, 24))	('Gln', 'Chemical', '-', (35, 38))	('codon 399 Gln/Gln', 'Var', (25, 42))
496714	24345911	reported that the XRCC1 399 Gln/Gln genotype was associated with an increased risk of ESCC (OR=5.15, 95%CI=2.42-0.93), and the risk for smokers increased 4.2-fold compared with non-smokers in the 399 Gln/Gln genotype (OR=4.20, 95%CI=2.37-7.44).	('Gln', 'Chemical', '-', (200, 203))	('XRCC1', 'Gene', '7515', (18, 23))	('ESCC', 'Disease', (86, 90))	('XRCC1', 'Gene', (18, 23))	('Gln', 'Chemical', '-', (28, 31))	('399 Gln/Gln', 'Var', (24, 35))	('Gln', 'Chemical', '-', (204, 207))	('Gln', 'Chemical', '-', (32, 35))
496715	24345911	suggested that the XRCC1 Arg399Gln polymorphism may be a potential biomarker for EC susceptibility in Chinese populations, particularly for squamous cell carcinoma.	('XRCC1', 'Gene', (19, 24))	('Arg399Gln', 'Var', (25, 34))	('Arg399Gln', 'SUBSTITUTION', 'None', (25, 34))	('XRCC1', 'Gene', '7515', (19, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))
496716	24345911	demonstrated that XRCC1 Gln variant alleles were associated with an increased risk of ESCC with adjusted ORs of 1.67 (95%CI=1.08-2.59).	('XRCC1', 'Gene', '7515', (18, 23))	('Gln', 'Chemical', '-', (24, 27))	('XRCC1', 'Gene', (18, 23))	('Gln', 'Var', (24, 27))	('ESCC', 'Disease', (86, 90))
496717	24345911	found that both lifestyle-related factors - such as drinking river water, consuming long-term stored rice, and alcohol intake - and the XRCC1 Arg399Gln polymorphism were possible risk factors for ESCC among Chinese people.	('water', 'Chemical', 'MESH:D014867', (67, 72))	('XRCC1', 'Gene', (136, 141))	('Arg399Gln', 'Var', (142, 151))	('Arg399Gln', 'SUBSTITUTION', 'None', (142, 151))	('ESCC', 'Disease', (196, 200))	('risk factors', 'Reg', (179, 191))	('people', 'Species', '9606', (215, 221))	('XRCC1', 'Gene', '7515', (136, 141))	('rice', 'Species', '4530', (101, 105))	('alcohol', 'Chemical', 'MESH:D000438', (111, 118))
496718	24345911	These observations demonstrated that genetic variants of the XRCC1 gene may contribute to genetic effects on the development of EC.	('XRCC1', 'Gene', (61, 66))	('genetic variants', 'Var', (37, 53))	('XRCC1', 'Gene', '7515', (61, 66))	('contribute', 'Reg', (76, 86))	('effects', 'Reg', (98, 105))
496719	24345911	In conclusion, the current study indicates that the c.910A>G genetic variant of the XRCC1 gene may influence the risk of EC.	('c.910A>G', 'Var', (52, 60))	('influence', 'Reg', (99, 108))	('XRCC1', 'Gene', '7515', (84, 89))	('c.910A>G', 'Mutation', 'rs25490', (52, 60))	('XRCC1', 'Gene', (84, 89))
496900	32618129	Following this, we performed HPV DNA typing and the sensitive RNAscope in situ method to screen all the cases for HPV E6/E7 expression, which is a more reliable indicator of transcriptively active HPV in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('HPV', 'Gene', (114, 117))	('tumor', 'Disease', (204, 209))	('E6/E7 expression', 'Var', (118, 134))
496909	32618129	Novel strategies based on molecular genetic fingerprinting such as microsatellite alterations and gene mutations have been introduced to clarify the distinction between a second primary tumor and lung metastasis.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('mutations', 'Var', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('microsatellite alterations', 'Var', (67, 93))
496984	32618129	Conversely, the RNAscope, a new method is not limited by mRNA quality which can directly visualize E6/E7mRNA transcripts in tumor cells on FFPE histologic sections by ISH.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('E6/E7mRNA', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
497100	32047555	Silencing of LRG1 promoted, while overexpression of LRG1 inhibited ESCC cell migration and invasion.	('ESCC', 'Disease', (67, 71))	('LRG1', 'Gene', '116844', (52, 56))	('inhibited', 'NegReg', (57, 66))	('LRG1', 'Gene', (52, 56))	('LRG1', 'Gene', '116844', (13, 17))	('promoted', 'PosReg', (18, 26))	('ESCC', 'Disease', 'MESH:C562729', (67, 71))	('Silencing', 'Var', (0, 9))	('LRG1', 'Gene', (13, 17))
497101	32047555	In line with this, Silencing of LRG1 enhanced, while overexpression of LRG1 reduced TGFbeta signaling and EMT of ESCC cells.	('TGFbeta', 'Gene', (84, 91))	('ESCC', 'Disease', (113, 117))	('LRG1', 'Gene', '116844', (32, 36))	('TGFbeta', 'Gene', '7039', (84, 91))	('LRG1', 'Gene', (32, 36))	('LRG1', 'Gene', '116844', (71, 75))	('reduced', 'NegReg', (76, 83))	('Silencing', 'Var', (19, 28))	('LRG1', 'Gene', (71, 75))	('ESCC', 'Disease', 'MESH:C562729', (113, 117))	('enhanced', 'PosReg', (37, 45))
497150	32047555	2B, LRG1 knockdown significantly promoted the wound closure of KYSE30 cells (P < 0.01 as compared to the scramble control).	('LRG1', 'Gene', (4, 8))	('promoted', 'PosReg', (33, 41))	('knockdown', 'Var', (9, 18))	('wound closure of KYSE30 cells', 'CPA', (46, 75))	('LRG1', 'Gene', '116844', (4, 8))
497152	32047555	In addition, the same stimulatory effects on cell mobility were also observed in TE1 cells upon LRG1 knockdown, providing further validation (Fig.	('cell mobility', 'CPA', (45, 58))	('LRG1', 'Gene', (96, 100))	('LRG1', 'Gene', '116844', (96, 100))	('knockdown', 'Var', (101, 110))
497163	32047555	We therefore examined whether enhanced migration and invasion of ESCC cells with LRG1 knockdown was achieved by promoting EMT.	('LRG1', 'Gene', (81, 85))	('knockdown', 'Var', (86, 95))	('enhanced', 'PosReg', (30, 38))	('ESCC', 'Disease', 'MESH:C562729', (65, 69))	('invasion', 'CPA', (53, 61))	('migration', 'CPA', (39, 48))	('ESCC', 'Disease', (65, 69))	('LRG1', 'Gene', '116844', (81, 85))	('promoting', 'PosReg', (112, 121))	('EMT', 'CPA', (122, 125))
497164	32047555	Western blotting provided confirmation that knockdown of LRG1 increased the protein levels of N-cadherin, VIM and slug, while reduced that of E-cadherin in KYSE30 cells (Fig.	('E-cadherin', 'Gene', (142, 152))	('slug', 'Gene', (114, 118))	('increased', 'PosReg', (62, 71))	('protein levels', 'MPA', (76, 90))	('E-cadherin', 'Gene', '999', (142, 152))	('VIM', 'Gene', '7431', (106, 109))	('slug', 'Gene', '6591', (114, 118))	('N-cadherin', 'Gene', (94, 104))	('LRG1', 'Gene', '116844', (57, 61))	('LRG1', 'Gene', (57, 61))	('knockdown', 'Var', (44, 53))	('N-cadherin', 'Gene', '1000', (94, 104))	('VIM', 'Gene', (106, 109))	('reduced', 'NegReg', (126, 133))
497166	32047555	To provide further evidence, we conducted LRG1 knockdown in TE1 cells observed the same changes (Fig.	('knockdown', 'Var', (47, 56))	('LRG1', 'Gene', '116844', (42, 46))	('LRG1', 'Gene', (42, 46))
497173	32047555	We found that knockdown of LRG1 expression in KYSE30 cells could activate the TGF-beta/SMAD pathway, as revealed by enhanced levels of TGF-beta1 as well as phosphorylated SMAD2/3 (Fig.	('enhanced', 'PosReg', (116, 124))	('LRG1', 'Gene', (27, 31))	('levels', 'MPA', (125, 131))	('TGF-beta', 'Gene', '7039', (78, 86))	('TGF-beta1', 'Gene', '7040', (135, 144))	('activate', 'PosReg', (65, 73))	('SMAD2/3', 'Gene', '4087;4088', (171, 178))	('TGF-beta', 'Gene', (135, 143))	('TGF-beta1', 'Gene', (135, 144))	('knockdown', 'Var', (14, 23))	('SMAD2/3', 'Gene', (171, 178))	('TGF-beta', 'Gene', (78, 86))	('TGF-beta', 'Gene', '7039', (135, 143))	('LRG1', 'Gene', '116844', (27, 31))
497177	32047555	We analyzed the ESCC cell apoptosis by flow cytometry after manipulating LRG1 expression.	('LRG1', 'Gene', '116844', (73, 77))	('manipulating', 'Var', (60, 72))	('LRG1', 'Gene', (73, 77))	('ESCC', 'Disease', (16, 20))	('ESCC', 'Disease', 'MESH:C562729', (16, 20))
497179	32047555	When the protein levels of apoptosis suppressor B-cell lymphoma-2 (Bcl-2) and its downstream protein cleaved caspase-3 and Bax were analyzed, we found that knockdown of LRG1 in KYSE30 up-regulated the amount of Bcl-2, but down-regulated the expression of Bax and cleaved caspase-3 (Fig.	('Bax', 'Gene', '581', (123, 126))	('knockdown', 'Var', (156, 165))	('B-cell lymphoma-2', 'Gene', (48, 65))	('cleaved', 'MPA', (263, 270))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (48, 63))	('expression', 'MPA', (241, 251))	('amount', 'MPA', (201, 207))	('Bax', 'Gene', (255, 258))	('down-regulated', 'NegReg', (222, 236))	('Bax', 'Gene', '581', (255, 258))	('LRG1', 'Gene', (169, 173))	('Bcl-2', 'Gene', (211, 216))	('Bcl-2', 'Gene', (67, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (55, 63))	('B-cell lymphoma-2', 'Gene', '596', (48, 65))	('Bcl-2', 'Gene', '596', (211, 216))	('Bcl-2', 'Gene', '596', (67, 72))	('LRG1', 'Gene', '116844', (169, 173))	('Bax', 'Gene', (123, 126))	('up-regulated', 'PosReg', (184, 196))
497186	32047555	The high expression of LRG1 was found to promote the invasion and migration of those cancer cells.	('invasion', 'CPA', (53, 61))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('LRG1', 'Gene', '116844', (23, 27))	('promote', 'PosReg', (41, 48))	('high expression', 'Var', (4, 19))	('cancer', 'Disease', (85, 91))	('LRG1', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
497189	32047555	Further, we found that silencing of LRG1 accelerated, while overexpression of LRG1 inhibited, the migration and invasion of ESCC cells.	('ESCC', 'Disease', 'MESH:C562729', (124, 128))	('invasion', 'CPA', (112, 120))	('LRG1', 'Gene', '116844', (78, 82))	('LRG1', 'Gene', '116844', (36, 40))	('silencing', 'Var', (23, 32))	('LRG1', 'Gene', (36, 40))	('migration', 'CPA', (98, 107))	('accelerated', 'PosReg', (41, 52))	('LRG1', 'Gene', (78, 82))	('ESCC', 'Disease', (124, 128))
497198	32047555	Our study showed that in ESCC cells E-cadherin was down-regulated, while N-cadherin, VIM and slug were up-regulated upon the silencing of LRG1.	('ESCC', 'Disease', 'MESH:C562729', (25, 29))	('LRG1', 'Gene', '116844', (138, 142))	('slug', 'Gene', '6591', (93, 97))	('silencing', 'Var', (125, 134))	('VIM', 'Gene', '7431', (85, 88))	('up-regulated', 'PosReg', (103, 115))	('LRG1', 'Gene', (138, 142))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('VIM', 'Gene', (85, 88))	('ESCC', 'Disease', (25, 29))	('down-regulated', 'NegReg', (51, 65))	('N-cadherin', 'Gene', (73, 83))	('N-cadherin', 'Gene', '1000', (73, 83))	('slug', 'Gene', (93, 97))
497200	32047555	This appeared to be achieved via regulation of TGF-beta pathway, as manipulating LRG1 expression resulted in corresponding changes in TGF-beta1 levels and the downstream phosphorylation of SMAD2/3.	('LRG1', 'Gene', (81, 85))	('TGF-beta', 'Gene', (134, 142))	('SMAD2/3', 'Gene', (189, 196))	('manipulating', 'Var', (68, 80))	('TGF-beta', 'Gene', '7039', (47, 55))	('TGF-beta', 'Gene', '7039', (134, 142))	('changes', 'Reg', (123, 130))	('LRG1', 'Gene', '116844', (81, 85))	('TGF-beta1', 'Gene', '7040', (134, 143))	('SMAD2/3', 'Gene', '4087;4088', (189, 196))	('TGF-beta', 'Gene', (47, 55))	('TGF-beta1', 'Gene', (134, 143))	('phosphorylation', 'MPA', (170, 185))
497202	32047555	The silencing of LRG1 has been reported to inhibit cell apoptosis of different cancers, yet our study showed that LRG1 may promote apoptosis of ESCC cells as a tumor suppressor.	('cancers', 'Disease', (79, 86))	('ESCC', 'Disease', 'MESH:C562729', (144, 148))	('tumor', 'Disease', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('promote', 'PosReg', (123, 130))	('inhibit', 'NegReg', (43, 50))	('LRG1', 'Gene', '116844', (114, 118))	('ESCC', 'Disease', (144, 148))	('LRG1', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('LRG1', 'Gene', '116844', (17, 21))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('apoptosis', 'CPA', (131, 140))	('LRG1', 'Gene', (17, 21))	('cell apoptosis', 'CPA', (51, 65))	('silencing', 'Var', (4, 13))
497204	32047555	In their functional analysis with shRNA knockdown, silencing of LRG1 appeared to suppress invasion while promoting apoptosis of ESCC cells.	('silencing', 'Var', (51, 60))	('LRG1', 'Gene', (64, 68))	('ESCC', 'Disease', 'MESH:C562729', (128, 132))	('LRG1', 'Gene', '116844', (64, 68))	('suppress', 'NegReg', (81, 89))	('promoting', 'PosReg', (105, 114))	('ESCC', 'Disease', (128, 132))	('apoptosis', 'CPA', (115, 124))	('invasion', 'CPA', (90, 98))
497319	28914471	WASH knockdown decreased the sphere-forming capacity of esophageal cancer cells whereas WASH over-expression exhibited the opposite effect.	('esophageal cancer', 'Disease', (56, 73))	('knockdown', 'Var', (5, 14))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('decreased', 'NegReg', (15, 24))
497320	28914471	Mechanistically, we identified interleukin-8 (IL-8) as a key downstream target of WASH. IL-8 knockdown completely attenuated tumor sphere formation induced by WASH overexpression.	('knockdown', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('IL-8', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('interleukin-8', 'Gene', '3576', (31, 44))	('tumor', 'Disease', (125, 130))	('attenuated', 'NegReg', (114, 124))	('interleukin-8', 'Gene', (31, 44))
497321	28914471	WASH knockdown also delayed the growth of human ESCC xenografts in BALB/c nude mice.	('human', 'Species', '9606', (42, 47))	('knockdown', 'Var', (5, 14))	('nude mice', 'Species', '10090', (74, 83))	('delayed', 'NegReg', (20, 27))	('growth', 'CPA', (32, 38))
497322	28914471	Importantly, high WASH levels were associated with poor clinical prognosis in a total of 145 human ESCC tissues.	('high', 'Var', (13, 17))	('WASH levels', 'MPA', (18, 29))	('clinical', 'Species', '191496', (56, 64))	('human', 'Species', '9606', (93, 98))
497356	28914471	Proportion of stained tumor cells was graded as follows: 0 (no positive tumor cells), 1 (<10% positive tumor cells), 2 (10-50% positive tumor cells), and 3 (>50% positive tumor cells).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('10-50', 'Var', (120, 125))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (136, 141))
497361	28914471	Using sphere formation assays, we screened six human ESCC cell lines (EC1, EC109, KYSE450, KYSE70, TE1, and TE7) and found three of them (KYSE70, KYSE450 and TE1) with the ability to form typical tumor spheres in vitro (Fig.	('tumor', 'Disease', (196, 201))	('EC1', 'CellLine', 'CVCL:5V05', (70, 73))	('KYSE450', 'Var', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('human', 'Species', '9606', (47, 52))	('EC1', 'CellLine', 'CVCL:5V05', (75, 78))	('KYSE70', 'Var', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
497366	28914471	Silencing of WASH expression had little impact on proliferation and survival of esophageal cancer cells in vitro (2Fig.	('WASH expression', 'Gene', (13, 28))	('esophageal cancer', 'Disease', (80, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Silencing', 'Var', (0, 9))
497367	28914471	As expected, WASH knockdown repressed the transcription of stemness genes, such as Nanog, OCT-4, c-Myc and Sox-2, as well as surface markers of CSC, such as CD133 (Fig.	('knockdown', 'Var', (18, 27))	('OCT-4', 'Gene', (90, 95))	('c-Myc', 'Gene', '4609', (97, 102))	('Nanog', 'Gene', (83, 88))	('stemness genes', 'Gene', (59, 73))	('transcription', 'MPA', (42, 55))	('Sox-2', 'Gene', (107, 112))	('c-Myc', 'Gene', (97, 102))	('Sox-2', 'Gene', '6657', (107, 112))	('CD133', 'Gene', (157, 162))	('CD133', 'Gene', '8842', (157, 162))	('Nanog', 'Gene', '79923', (83, 88))	('OCT-4', 'Gene', '5460', (90, 95))
497369	28914471	Similarly, knockdown of WASH expression in KYSE450 cells or TE1 cells impairs cancer stemness properties (Fig.	('impairs cancer stemness properties', 'Disease', (70, 104))	('WASH expression', 'Gene', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('impairs cancer stemness properties', 'Disease', 'MESH:D009422', (70, 104))	('knockdown', 'Var', (11, 20))
497370	28914471	To explore the underlying mechanism, we assessed the profiling of chemokines and cytokines in esophageal cancer cells after silencing of WASH expression.	('silencing', 'Var', (124, 133))	('esophageal cancer', 'Disease', (94, 111))	('WASH', 'Protein', (137, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
497371	28914471	Using multiplex ELISA assays, we found that CXCL8 (also called IL-8) was the highest level of cytokine produced in KYSE70 cells and stable WASH knockdown remarkably blocked the secretion of IL-8 (Fig.	('secretion', 'MPA', (177, 186))	('knockdown', 'Var', (144, 153))	('blocked', 'NegReg', (165, 172))	('CXCL8', 'Gene', '3576', (44, 49))	('CXCL8', 'Gene', (44, 49))
497374	28914471	As shown in Figure 6(a), knockdown of WASH expression significantly delayed tumor growth in vivo.	('delayed', 'NegReg', (68, 75))	('WASH expression', 'Gene', (38, 53))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('knockdown', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
497375	28914471	By 28 days of tumor challenge, KYSE70 cells with stable WASH knockdown developed much smaller tumors compared with control cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('smaller', 'NegReg', (86, 93))	('tumor', 'Disease', (94, 99))	('knockdown', 'Var', (61, 70))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
497377	28914471	Consistent with the in vitro results, knockdown of WASH expression inhibited tumor expression of IL-8 (Fig.	('IL-8', 'Gene', (97, 101))	('inhibited', 'NegReg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('WASH expression', 'Gene', (51, 66))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('knockdown', 'Var', (38, 47))	('tumor', 'Disease', (77, 82))
497396	28914471	In fact, recent data show that WASP-interacting protein (WIP), an actin polymerization regulator, is responsible for mutant p53 oncogenic properties in CSC.23 Further studies are needed to elucidate the link between WASH-mediated cytoskeleton remodeling and maintenance of CSC.	('WASP-interacting protein', 'Gene', (31, 55))	('p53', 'Gene', (124, 127))	('CSC.23', 'Disease', (152, 158))	('mutant', 'Var', (117, 123))	('p53', 'Gene', '7157', (124, 127))	('WASP-interacting protein', 'Gene', '7456', (31, 55))	('WIP', 'Gene', (57, 60))	('WIP', 'Gene', '7456', (57, 60))
497397	28914471	Besides an important regulator of actin assembly, WASP also serves as an adaptor to affect the activation of various downstream signaling.24 In the current study, we found that knockdown of WASH significantly repressed the expression of IL-8 in ESCC cell lines, suggesting an essential role of WASH in regulating the IL-8 pathway.	('WASP', 'Gene', (50, 54))	('WASP', 'Gene', '7454', (50, 54))	('expression', 'MPA', (223, 233))	('knockdown', 'Var', (177, 186))	('repressed', 'NegReg', (209, 218))	('IL-8', 'Gene', (237, 241))
497401	28914471	Given little effect of WASH knockdown on tumor cell growth in vitro, it is more likely that loss of WASH expression affects tumor growth in vivo as a result of dysfunction of IL-8 signaling and stemness maintenance in the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (41, 46))	('IL-8 signaling', 'MPA', (175, 189))	('WASH expression', 'Gene', (100, 115))	('tumor', 'Disease', (124, 129))	('affects', 'Reg', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('loss', 'Var', (92, 96))	('stemness maintenance', 'CPA', (194, 214))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
497464	27978831	Herein, we aimed to comprehensively assess the association between the low IGFBP-3 level and the risk, overall survival and clinical pathological characteristics of esophageal cancer.	('low IGFBP-3 level', 'Phenotype', 'HP:0031037', (71, 88))	('esophageal cancer', 'Disease', (165, 182))	('low', 'Var', (71, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (71, 82))	('IGFBP-3', 'Gene', '3486', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('IGFBP-3', 'Gene', (75, 82))
497466	27978831	With respect to the 3-year survival rate, the RR was 2.163 (p = 0.027), which demonstrated that esophageal cancer patients with low IGFBP-3 level had significantly lower 3-year survival rate; in terms of clinical pathological characteristics, significantly lower IGFBP-3 level was found for patients in all categories; for survival status, patients in low IGFBP-3 level are more likely to be in the dead survival status (OR = 4.480, p = 0.000).	('IGFBP-3', 'Gene', '3486', (132, 139))	('lower', 'NegReg', (164, 169))	('patients', 'Species', '9606', (340, 348))	('lower IGFBP-3 level', 'Phenotype', 'HP:0031037', (257, 276))	('low', 'Var', (352, 355))	('patients', 'Species', '9606', (291, 299))	('low IGFBP-3 level', 'Phenotype', 'HP:0031037', (352, 369))	('IGFBP-3', 'Gene', (263, 270))	('patients', 'Species', '9606', (114, 122))	('low', 'Var', (128, 131))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (352, 363))	('IGFBP-3', 'Gene', '3486', (263, 270))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('IGFBP-3', 'Gene', (356, 363))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('low IGFBP-3 level', 'Phenotype', 'HP:0031037', (128, 145))	('IGFBP-3', 'Gene', (132, 139))	('IGFBP-3', 'Gene', '3486', (356, 363))
497475	27978831	It has been documented that the epigenetic alteration of IGFBP-3 can impact on multiple types of tumors including non-small-cell lung cancer, hepatocellular carcinoma, ovarian cancer, skin cancer, urological cancers, breast cancer, and gastric cancer.	('skin cancer', 'Disease', 'MESH:D012878', (184, 195))	('urological cancers', 'Disease', (197, 215))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (142, 166))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('gastric cancer', 'Disease', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('hepatocellular carcinoma', 'Disease', (142, 166))	('ovarian cancer', 'Disease', 'MESH:D010051', (168, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (118, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('IGFBP-3', 'Gene', (57, 64))	('skin cancer', 'Disease', (184, 195))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('IGFBP-3', 'Gene', '3486', (57, 64))	('ovarian cancer', 'Disease', (168, 182))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (114, 140))	('skin cancer', 'Phenotype', 'HP:0008069', (184, 195))	('lung cancer', 'Disease', (129, 140))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('urological cancers', 'Disease', 'MESH:D014571', (197, 215))	('epigenetic alteration', 'Var', (32, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (168, 182))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (142, 166))	('breast cancer', 'Disease', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('impact', 'Reg', (69, 75))
497476	27978831	As for esophageal cancer, a previous study, aimed to explore the clinical and prognostic significance of IGFBP-3 in patients with esophageal cancer, suggested that both the clinical pathological classifications and poor overall survival were associated with the low IGFBP-3 level.	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('esophageal cancer', 'Disease', (7, 24))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (262, 273))	('poor', 'NegReg', (215, 219))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('patients', 'Species', '9606', (116, 124))	('IGFBP-3', 'Gene', '3486', (266, 273))	('IGFBP-3', 'Gene', '3486', (105, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (7, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('IGFBP-3', 'Gene', (266, 273))	('low IGFBP-3 level', 'Phenotype', 'HP:0031037', (262, 279))	('IGFBP-3', 'Gene', (105, 112))	('low', 'Var', (262, 265))	('overall survival', 'CPA', (220, 236))	('esophageal cancer', 'Disease', (130, 147))
497486	27978831	There were four eligible studies for the analysis of the correlation between the low IGFBP-3 level and the risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('low', 'Var', (81, 84))	('esophageal cancer', 'Disease', (115, 132))	('IGFBP-3', 'Gene', '3486', (85, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (81, 92))	('IGFBP-3', 'Gene', (85, 92))	('low IGFBP-3 level', 'Phenotype', 'HP:0031037', (81, 98))
497488	27978831	3) was higher than one and the p was lower than 0.05 (p = 0.027), indicating that the low IGFBP-3 level was associated with low 3-year survival rate, and for esophageal cancer patients, the 3-year survival rate of patients with low IGFBP-3 level was lower than that in patients with relatively high IGFBP-3 level.	('IGFBP-3', 'Gene', '3486', (299, 306))	('patients', 'Species', '9606', (214, 222))	('IGFBP-3', 'Gene', (90, 97))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (228, 239))	('IGFBP-3', 'Gene', (232, 239))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('IGFBP-3', 'Gene', '3486', (90, 97))	('patients', 'Species', '9606', (269, 277))	('lower', 'NegReg', (250, 255))	('IGFBP-3', 'Gene', '3486', (232, 239))	('low IGFBP-3 level', 'Phenotype', 'HP:0031037', (86, 103))	('low IGFBP-3 level', 'Phenotype', 'HP:0031037', (228, 245))	('low', 'Var', (86, 89))	('low', 'NegReg', (124, 127))	('high IGFBP', 'Phenotype', 'HP:0030269', (294, 304))	('patients', 'Species', '9606', (176, 184))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('IGFBP-3', 'Gene', (299, 306))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (86, 97))	('esophageal cancer', 'Disease', (158, 175))
497502	27978831	In order to comprehensively assess the correlation between low IGFBP-3 level and the risk, overall survival and clinical pathological characteristics of esophageal cancer, we conducted the current meta-analysis incorporating seven eligible studies.	('IGFBP-3', 'Gene', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('low IGFBP-3 level', 'Phenotype', 'HP:0031037', (59, 76))	('esophageal cancer', 'Disease', (153, 170))	('low', 'Var', (59, 62))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (59, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))	('IGFBP-3', 'Gene', '3486', (63, 70))
497504	27978831	As for the overall survival, the esophageal cancer patients in low IGFBP-3 level have lower 3-year survival rate than those in relatively high IGFBP-3 level.	('low IGFBP-3', 'Phenotype', 'HP:0031037', (63, 74))	('IGFBP-3', 'Gene', '3486', (67, 74))	('low IGFBP-3 level', 'Phenotype', 'HP:0031037', (63, 80))	('3-year survival rate', 'CPA', (92, 112))	('lower', 'NegReg', (86, 91))	('high IGFBP', 'Phenotype', 'HP:0030269', (138, 148))	('esophageal cancer', 'Disease', (33, 50))	('IGFBP-3', 'Gene', (67, 74))	('patients', 'Species', '9606', (51, 59))	('IGFBP-3', 'Gene', '3486', (143, 150))	('low', 'Var', (63, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('IGFBP-3', 'Gene', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
497512	27978831	The abnormal expression or dysfunction have been associated with a verity of tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('abnormal', 'Var', (4, 12))	('dysfunction', 'MPA', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
497515	27978831	A study of 500 ESCC patients indicated that IGFBP-3 SNP rs2270628 may be associated with ESCC in the Chinese Han population.	('IGFBP-3', 'Gene', '3486', (44, 51))	('associated', 'Reg', (73, 83))	('ESCC', 'Disease', (89, 93))	('IGFBP-3', 'Gene', (44, 51))	('patients', 'Species', '9606', (20, 28))	('rs2270628', 'Mutation', 'rs2270628', (56, 65))	('rs2270628', 'Var', (56, 65))
497533	27467440	Association Between Germline Mutation in VSIG10L and Familial Barrett Neoplasia Esophageal adenocarcinoma and its precursor lesion Barrett esophagus have seen a dramatic increase in incidence over the past 4 decades yet marked genetic heterogeneity of this disease has precluded advances in understanding its pathogenesis and improving treatment.	('Barrett esophagus', 'Disease', (131, 148))	('Germline Mutation', 'Var', (20, 37))	('Esophageal adenocarcinoma', 'Disease', (80, 105))	('VSIG10L', 'Gene', (41, 48))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (80, 105))	('Familial Barrett Neoplasia', 'Disease', (53, 79))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (131, 148))	('Neoplasia', 'Phenotype', 'HP:0002664', (70, 79))	('Association', 'Interaction', (0, 11))	('Familial Barrett Neoplasia', 'Disease', 'MESH:D001471', (53, 79))
497534	27467440	To identify novel disease susceptibility variants in a familial syndrome of esophageal adenocarcinoma and Barrett esophagus, termed familial Barrett esophagus, by using high-throughput sequencing in affected individuals from a large, multigenerational family.	('variants', 'Var', (41, 49))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (106, 123))	('familial Barrett esophagus', 'Disease', (132, 158))	('familial syndrome of esophageal adenocarcinoma', 'Disease', (55, 101))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('Barrett esophagus', 'Disease', (106, 123))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (141, 158))	('familial syndrome of esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (55, 101))
497535	27467440	We performed whole exome sequencing (WES) from peripheral lymphocyte DNA on 4 distant relatives from our multiplex, multigenerational familial Barrett esophagus family to identify candidate disease susceptibility variants.	('Barrett esophagus', 'Phenotype', 'HP:0100580', (143, 160))	('ela', 'Gene', '100506013', (87, 90))	('variants', 'Var', (213, 221))	('Barrett esophagus', 'Disease', (143, 160))	('ela', 'Gene', (87, 90))
497536	27467440	A multiplex, multigenerational family with 14 members affected (3 members with esophageal adenocarcinoma and 11 with Barrett esophagus) was identified, and whole-exome sequencing identified a germline mutation (S631G) at a highly conserved serine residue in the uncharacterized gene VSIG10L that segregated in affected members.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('S631G', 'Var', (211, 216))	('serine', 'Chemical', 'MESH:D012694', (240, 246))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (117, 134))	('esophageal adenocarcinoma', 'Disease', (79, 104))	('S631G', 'Mutation', 'p.S631G', (211, 216))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))	('VSIG10L', 'Gene', (283, 290))
497537	27467440	Transfection of S631G variant into a 3-dimensional organotypic culture model of normal esophageal squamous cells dramatically inhibited epithelial maturation compared with the wild-type.	('epithelial maturation', 'CPA', (136, 157))	('S631G', 'Var', (16, 21))	('esophageal squamous', 'Disease', 'MESH:D000077277', (87, 106))	('esophageal squamous', 'Disease', (87, 106))	('inhibited', 'NegReg', (126, 135))	('S631G', 'Mutation', 'p.S631G', (16, 21))
497538	27467440	Electron microscopy of squamous esophageal mucosa harboring the S631G variant revealed dilated intercellular spaces and reduced desmosomes.	('S631G', 'Mutation', 'p.S631G', (64, 69))	('desmosomes', 'CPA', (128, 138))	('squamous esophageal mucosa', 'Disease', 'MESH:D000077277', (23, 49))	('S631G', 'Var', (64, 69))	('squamous esophageal mucosa', 'Disease', (23, 49))	('reduced', 'NegReg', (120, 127))
497543	27467440	Of these, a missense variant (S631G) in VSIG10L was completely private.	('VSIG10L', 'Gene', (40, 47))	('S631G', 'Var', (30, 35))	('S631G', 'Mutation', 'p.S631G', (30, 35))
497544	27467440	Sequencing of 19 EAC biopsy specimens showed 1 somatic missense mutation (G769S) that was predicted to significantly alter protein function (see eMethods in the Supplement).	('G769S', 'Mutation', 'p.G769S', (74, 79))	('protein function', 'MPA', (123, 139))	('G769S', 'Var', (74, 79))	('EAC', 'Phenotype', 'HP:0011459', (17, 20))	('alter', 'Reg', (117, 122))
497548	27467440	In contrast, expression of the S631G variant markedly disrupted cellular organization, characterized by epithelial dysmaturation (Figure 2).	('disrupted', 'NegReg', (54, 63))	('cellular organization', 'CPA', (64, 85))	('S631G', 'Mutation', 'p.S631G', (31, 36))	('epithelial dysmaturation', 'Disease', (104, 128))	('S631G', 'Var', (31, 36))
497549	27467440	Similarly, expression of the VSIG10L G769S somatic mutation identified in EAC tissue also inhibited squamous maturation (eFigure 5 in the Supplement).	('VSIG10L', 'Gene', (29, 36))	('EAC', 'Phenotype', 'HP:0011459', (74, 77))	('squamous maturation', 'CPA', (100, 119))	('G769S', 'Var', (37, 42))	('inhibited', 'NegReg', (90, 99))	('G769S', 'Mutation', 'p.G769S', (37, 42))
497550	27467440	Transmission electron microscopy showed that compared with a normal subject and a subject with BE and/or EAC, the proximal esophageal epithelium from individual III-4 who carries the S631G variant demonstrated pronounced dilation of the intercellular space and markedly reduced desmosome formation (Figure 5).	('dilation', 'MPA', (221, 229))	('S631G', 'Var', (183, 188))	('BE', 'Phenotype', 'HP:0100580', (95, 97))	('S631G', 'Mutation', 'p.S631G', (183, 188))	('desmosome formation', 'MPA', (278, 297))	('reduced', 'NegReg', (270, 277))	('EAC', 'Phenotype', 'HP:0011459', (105, 108))
497551	27467440	Mutant VSIG10L impaired squamous cell maturation in an organotypic model and was associated with proton-pump inhibitor refractory dilated intercellular spaces (DIS) and reduced desmosome formation in affected family member III-4, strongly supporting that the inherited defect in VSIG10L predisposes to BE and/or EAC in this family.	('DIS', 'Chemical', '-', (160, 163))	('EAC', 'Phenotype', 'HP:0011459', (312, 315))	('predisposes', 'Reg', (287, 298))	('impaired', 'NegReg', (15, 23))	('VSIG10L', 'Gene', (7, 14))	('BE and/or', 'Disease', (302, 311))	('reduced', 'NegReg', (169, 176))	('inherited defect', 'Disease', (259, 275))	('inherited defect', 'Disease', 'MESH:D030342', (259, 275))	('VSIG10L', 'Gene', (279, 286))	('squamous cell maturation', 'CPA', (24, 48))	('EAC', 'Disease', (312, 315))	('Mutant', 'Var', (0, 6))	('desmosome formation', 'MPA', (177, 196))	('BE', 'Phenotype', 'HP:0100580', (302, 304))
497554	27467440	The 3 instances of unaffected S631G carriers are consistent with an incomplete gender- and age-specific penetrance:2 are young women and 1 is a male with erosive esophagitis (eTable in the Supplement).	('esophagitis', 'Phenotype', 'HP:0100633', (162, 173))	('S631G', 'Var', (30, 35))	('esophagitis', 'Disease', (162, 173))	('esophagitis', 'Disease', 'MESH:D004941', (162, 173))	('women', 'Species', '9606', (127, 132))	('S631G', 'Mutation', 'p.S631G', (30, 35))
497555	27467440	Interestingly, the MSR1 R293X null variant reported in a prior study of FBE did not segregate in this or the 35 other smaller multiplex families with FBE we analyzed but was identified in population controls (unpublished data), illustrating that susceptibility alleles for complex diseases often have limited penetrance, and carriers may not develop disease.	('BE', 'Phenotype', 'HP:0100580', (73, 75))	('R293X', 'Var', (24, 29))	('MSR1', 'Gene', (19, 23))	('BE', 'Phenotype', 'HP:0100580', (151, 153))	('R293X', 'Mutation', 'p.R293X', (24, 29))
497556	27467440	The dramatic findings in the OTC experiments (Figure 2) along with transmission electron microscopy imaging (Figure 5) suggest that mucosal disruption associated with the VSIG10L S631G variant renders the esophagus vulnerable to reflux injury.	('S631G', 'Mutation', 'p.S631G', (179, 184))	('VSIG10L', 'Gene', (171, 178))	('reflux injury', 'Disease', 'MESH:D005764', (229, 242))	('S631G', 'Var', (179, 184))	('reflux injury', 'Disease', (229, 242))
497559	27467440	Thus, as noted in individual III-4, we propose that the dominant negative S631G variant predisposes to reflux injury and the subsequent development of BE and EAC in this family.	('reflux injury', 'Disease', 'MESH:D005764', (103, 116))	('S631G', 'Var', (74, 79))	('predisposes', 'Reg', (88, 99))	('EAC', 'Phenotype', 'HP:0011459', (158, 161))	('reflux injury', 'Disease', (103, 116))	('S631G', 'Mutation', 'p.S631G', (74, 79))	('BE', 'Phenotype', 'HP:0100580', (151, 153))
497561	27467440	Do germline DNA mutations underlie susceptibility to familial Barrett esophagus, familial aggregation of Barrett esophagus, and esophageal adenocarcinoma?	('familial aggregation of Barrett esophagus', 'Disease', 'MESH:D001471', (81, 122))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (128, 153))	('familial Barrett esophagus', 'Disease', (53, 79))	('mutations', 'Var', (16, 25))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (62, 79))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (105, 122))	('familial aggregation of Barrett esophagus', 'Disease', (81, 122))	('esophageal adenocarcinoma', 'Disease', (128, 153))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (128, 153))
497562	27467440	In this genetic study of a multigenerational family with 14 affected individuals, a rare variant in the uncharacterized gene VSIG10L was associated with susceptibility to Barrett esophagus and esophageal adenocarcinoma.	('associated', 'Reg', (137, 147))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (193, 218))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (171, 188))	('esophageal adenocarcinoma', 'Disease', (193, 218))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (193, 218))	('variant', 'Var', (89, 96))	('Barrett esophagus', 'Disease', (171, 188))	('VSIG10L', 'Gene', (125, 132))	('susceptibility', 'Reg', (153, 167))
497566	21164038	JP4-039/F15 or MnSOD-PL increased survival compared to irradiated controls (p<0.0001 for either).	('d', 'Chemical', 'MESH:D003903', (50, 51))	('d', 'Chemical', 'MESH:D003903', (32, 33))	('d', 'Chemical', 'MESH:D003903', (64, 65))	('survival', 'CPA', (34, 42))	('d', 'Chemical', 'MESH:D003903', (59, 60))	('MnSOD-PL', 'Gene', (15, 23))	('JP4-039/F15', 'Var', (0, 11))	('increased', 'PosReg', (24, 33))
497582	21164038	The present study tested the effectiveness of JP4-039 administered intraesophageally in a formulation designed to provide enhanced concentration of the drug in the esophagus.	('d', 'Chemical', 'MESH:D003903', (152, 153))	('enhanced', 'PosReg', (122, 130))	('d', 'Chemical', 'MESH:D003903', (23, 24))	('d', 'Chemical', 'MESH:D003903', (102, 103))	('d', 'Chemical', 'MESH:D003903', (109, 110))	('d', 'Chemical', 'MESH:D003903', (129, 130))	('concentration', 'MPA', (131, 144))	('d', 'Chemical', 'MESH:D003903', (119, 120))	('JP4-039', 'Var', (46, 53))	('d', 'Chemical', 'MESH:D003903', (65, 66))	('d', 'Chemical', 'MESH:D003903', (55, 56))	('tested', 'Reg', (18, 24))	('d', 'Chemical', 'MESH:D003903', (15, 16))
497602	21164038	C57BL/6HNsd female and C57BL/6JHNsd-GFP male mice (22-22 gm) were housed, five per cage, and fed standard laboratory chow according to previous publications, according to IACUC protocols at the Hillman Cancer Center, University of Pittsburgh Cancer Institute.	('Pittsburgh Cancer', 'Disease', (231, 248))	('C57BL/6JHNsd-GFP', 'Var', (23, 39))	('Cancer', 'Phenotype', 'HP:0002664', (242, 248))	('mice', 'Species', '10090', (45, 49))	('Pittsburgh Cancer', 'Disease', 'MESH:D009369', (231, 248))	('d', 'Chemical', 'MESH:D003903', (71, 72))	('d', 'Chemical', 'MESH:D003903', (91, 92))	('d', 'Chemical', 'MESH:D003903', (95, 96))	('d', 'Chemical', 'MESH:D003903', (34, 35))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('d', 'Chemical', 'MESH:D003903', (10, 11))	('d', 'Chemical', 'MESH:D003903', (21, 22))	('d', 'Chemical', 'MESH:D003903', (127, 128))	('d', 'Chemical', 'MESH:D003903', (104, 105))	('d', 'Chemical', 'MESH:D003903', (163, 164))	('d', 'Chemical', 'MESH:D003903', (101, 102))
497629	21164038	First, the clearance of JP4-039 from plasma was tested after the intravenous injection of 10 mg/kg JP4-039 in 100 mul volumes of diluents (Figure 1) using EPR measurements.	('JP4-039', 'Var', (99, 106))	('d', 'Chemical', 'MESH:D003903', (129, 130))	('tested', 'Reg', (48, 54))	('d', 'Chemical', 'MESH:D003903', (53, 54))
497632	21164038	Next, the nitroxide signal of JP4-039 in the esophagus was measured in vivo after giving JP4-039/F15 by swallow.	('nitroxide', 'Chemical', 'MESH:D019811', (10, 19))	('d', 'Chemical', 'MESH:D003903', (17, 18))	('JP4-039', 'Var', (30, 37))	('d', 'Chemical', 'MESH:D003903', (66, 67))	('JP4-039/F15', 'Var', (89, 100))	('nitroxide signal', 'MPA', (10, 26))
497635	21164038	Subgroups receiving MnSOD-PL or JP4-039 in F15 formulation showed a significant increase in survival compared to mice receiving F15 formulation alone (Figure 4).	('survival', 'CPA', (92, 100))	('increase', 'PosReg', (80, 88))	('d', 'Chemical', 'MESH:D003903', (64, 65))	('JP4-039', 'Var', (32, 39))	('MnSOD-PL', 'Var', (20, 28))	('mice', 'Species', '10090', (113, 117))	('d', 'Chemical', 'MESH:D003903', (108, 109))
497637	21164038	To determine whether esophageal radioprotection by JP4-039 may be increased by facilitating migration to the esophagus of bone marrow-derived cells, experimental methods were used, which previously demonstrated the bone marrow origin of progenitors of esophageal squamous epithelium.	('d', 'Chemical', 'MESH:D003903', (74, 75))	('JP4-039', 'Var', (51, 58))	('d', 'Chemical', 'MESH:D003903', (167, 168))	('d', 'Chemical', 'MESH:D003903', (134, 135))	('d', 'Chemical', 'MESH:D003903', (140, 141))	('d', 'Chemical', 'MESH:D003903', (34, 35))	('esophageal squamous epithelium', 'Disease', 'MESH:D000077277', (252, 282))	('d', 'Chemical', 'MESH:D003903', (178, 179))	('d', 'Chemical', 'MESH:D003903', (3, 4))	('d', 'Chemical', 'MESH:D003903', (209, 210))	('migration', 'CPA', (92, 101))	('esophageal squamous epithelium', 'Disease', (252, 282))	('d', 'Chemical', 'MESH:D003903', (198, 199))
497642	21164038	Mice receiving either MnSOD-PL or JP4-039 before irradiation showed improved survival (Figure 5).	('JP4-039', 'Var', (34, 41))	('d', 'Chemical', 'MESH:D003903', (53, 54))	('survival', 'CPA', (77, 85))	('d', 'Chemical', 'MESH:D003903', (75, 76))	('d', 'Chemical', 'MESH:D003903', (66, 67))	('Mice', 'Species', '10090', (0, 4))	('improved', 'PosReg', (68, 76))
497655	21164038	The post-hoc Mann-Whitney test revealed that the 29 Gy group had a significantly higher number of GFP+ cells than the 0 Gy group (p=0.018).	('higher', 'PosReg', (81, 87))	('d', 'Chemical', 'MESH:D003903', (63, 64))	('d', 'Chemical', 'MESH:D003903', (38, 39))	('29 Gy', 'Var', (49, 54))	('GFP+ cells', 'CPA', (98, 108))
497657	21164038	The post-hoc Mann-Whitney test revealed that each of the 29 Gy, JP4-039 + 29 Gy, and 29 Gy + JP4-039 groups had significantly higher numbers than the 0 Gy group (p<0.0001, p=0.0028 and p=0.017, respectively).	('d', 'Chemical', 'MESH:D003903', (183, 184))	('higher', 'PosReg', (126, 132))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('d', 'Chemical', 'MESH:D003903', (38, 39))	('d', 'Chemical', 'MESH:D003903', (110, 111))	('JP4-039 + 29 Gy', 'Var', (64, 79))
497659	21164038	The results at day 60 showed a persistent increase in donor marrow-derived cells in the 29 Gy + JP4-039 group.	('d', 'Chemical', 'MESH:D003903', (67, 68))	('d', 'Chemical', 'MESH:D003903', (73, 74))	('d', 'Chemical', 'MESH:D003903', (54, 55))	('donor', 'Species', '9606', (54, 59))	('d', 'Chemical', 'MESH:D003903', (27, 28))	('donor marrow-derived cells', 'CPA', (54, 80))	('29 Gy + JP4-039', 'Var', (88, 103))	('increase', 'PosReg', (42, 50))	('d', 'Chemical', 'MESH:D003903', (15, 16))
497661	21164038	The post-hoc Mann-Whitney test revealed that the 29 Gy + JP4-039 group had a significantly higher number than the 0 Gy group (p=0.048).	('higher', 'PosReg', (91, 97))	('29 Gy + JP4-039', 'Var', (49, 64))	('d', 'Chemical', 'MESH:D003903', (38, 39))	('d', 'Chemical', 'MESH:D003903', (73, 74))
497676	21164038	Delivery of JP4-039/F15 intraesophageally before or after thoracic irradiation provided significant protection of the esophagus and improved survival.	('d', 'Chemical', 'MESH:D003903', (71, 72))	('d', 'Chemical', 'MESH:D003903', (130, 131))	('JP4-039/F15', 'Var', (12, 23))	('improved', 'PosReg', (132, 140))	('d', 'Chemical', 'MESH:D003903', (86, 87))	('survival', 'CPA', (141, 149))	('d', 'Chemical', 'MESH:D003903', (139, 140))	('d', 'Chemical', 'MESH:D003903', (84, 85))
497690	21164038	While JP4-039 may have prevented quiescent stem cell apoptosis, reduced stromal microenvironmental protection due to more rapid drug clearance may have allowed irradiation killing of more primitive esophageal stem cells and facilitated homing of bone marrow-derived primitive progenitors that protected and persisted to day 60.	('JP4-039', 'Var', (6, 13))	('prevented', 'NegReg', (23, 32))	('d', 'Chemical', 'MESH:D003903', (128, 129))	('homing', 'CPA', (236, 242))	('d', 'Chemical', 'MESH:D003903', (301, 302))	('d', 'Chemical', 'MESH:D003903', (222, 223))	('d', 'Chemical', 'MESH:D003903', (126, 127))	('d', 'Chemical', 'MESH:D003903', (158, 159))	('facilitated', 'PosReg', (224, 235))	('d', 'Chemical', 'MESH:D003903', (70, 71))	('d', 'Chemical', 'MESH:D003903', (31, 32))	('d', 'Chemical', 'MESH:D003903', (110, 111))	('d', 'Chemical', 'MESH:D003903', (315, 316))	('d', 'Chemical', 'MESH:D003903', (164, 165))	('d', 'Chemical', 'MESH:D003903', (234, 235))	('d', 'Chemical', 'MESH:D003903', (258, 259))	('d', 'Chemical', 'MESH:D003903', (305, 306))	('quiescent', 'MPA', (33, 42))	('d', 'Chemical', 'MESH:D003903', (66, 67))	('d', 'Chemical', 'MESH:D003903', (264, 265))	('d', 'Chemical', 'MESH:D003903', (320, 321))
497727	31261551	The main reason for this is that PLDR causes less vascular damage, and retaining vascular network can improve tumor oxygenation.	('vascular damage', 'Disease', 'MESH:D000783', (50, 65))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('improve', 'PosReg', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('vascular damage', 'Disease', (50, 65))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('tumor', 'Disease', (110, 115))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('PLDR', 'Var', (33, 37))
497796	30771195	The histopathological examination revealed invasive ductal carcinoma, pT1N0M0, which was negative for ER, PgR, and human epidermal growth factor receptor 2 (HER2).	('ER', 'Gene', '2099', (158, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('epidermal growth factor receptor 2', 'Gene', '2064', (121, 155))	('epidermal growth factor receptor 2', 'Gene', (121, 155))	('HER2', 'Gene', (157, 161))	('human', 'Species', '9606', (115, 120))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (43, 68))	('PgR', 'Gene', '5241', (106, 109))	('pT1N0M0', 'Var', (70, 77))	('invasive ductal carcinoma', 'Disease', (43, 68))	('HER2', 'Gene', '2064', (157, 161))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (52, 68))	('PgR', 'Gene', (106, 109))	('ER', 'Gene', '2099', (102, 104))
497809	30771195	Histopathological examination revealed invasive ductal carcinoma, pT3N1M0 that was estrogen receptor (ER)- and progesterone receptor (PgR)-positive.	('pT3N1M0', 'Var', (66, 73))	('progesterone receptor', 'Gene', (111, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('estrogen receptor', 'Gene', (83, 100))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (39, 64))	('progesterone receptor', 'Gene', '5241', (111, 132))	('estrogen receptor', 'Gene', '2099', (83, 100))	('invasive ductal carcinoma', 'Disease', (39, 64))	('PgR', 'Gene', '5241', (134, 137))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (48, 64))	('PgR', 'Gene', (134, 137))	('ER', 'Gene', '2099', (102, 104))
497934	29359120	Biopsy of the esophageal mass showed invasive SCC and the patient was ultimately diagnosed with cT3N2cM0 (stage IVA) and uT1bN1M0 (stage IIB) supraglottic and esophageal cancers, respectively.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('patient', 'Species', '9606', (58, 65))	('supraglottic', 'Disease', (142, 154))	('IVA', 'Disease', 'MESH:C538167', (112, 115))	('uT1bN1M0', 'Var', (121, 129))	('esophageal cancers', 'Disease', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('SCC', 'Gene', (46, 49))	('SCC', 'Gene', '6317', (46, 49))	('esophageal cancers', 'Disease', 'MESH:D004938', (159, 177))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('IVA', 'Disease', (112, 115))
497961	29359120	In such cases, the increased acute toxicity rates experienced with altered fractionation may outweigh potential LC benefits.	('acute', 'MPA', (29, 34))	('altered', 'Var', (67, 74))	('toxicity', 'Disease', 'MESH:D064420', (35, 43))	('toxicity', 'Disease', (35, 43))
497970	29359120	In this scenario, the use of AP/PA conformal beams has been shown to reduce the low-dose lung bath by forcing dose centrally within the thorax, as was the case in our patient.	('dose', 'MPA', (110, 114))	('AP/PA conformal', 'Var', (29, 44))	('low-dose', 'MPA', (80, 88))	('patient', 'Species', '9606', (167, 174))	('forcing', 'Reg', (102, 109))	('PA', 'Chemical', 'MESH:D011478', (32, 34))	('reduce', 'NegReg', (69, 75))
498056	28465803	Some authors have suggested that the expression of MAGE1 antigens is associated with dedifferentiation in various tumor entities, although neither we nor other authors found this correlation to exist.	('expression', 'Var', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('associated with', 'Reg', (69, 84))	('MAGE1 antigen', 'Gene', '4100', (51, 64))	('dedifferentiation', 'Disease', (85, 102))	('MAGE1 antigen', 'Gene', (51, 64))
498113	27516997	The mean levels for AFB1, AFB2, AFG1, AFG2 and total aflatoxins in all samples were: 1.4228+-0.4703 ngg-1, 0.0871+-0.03030 ngg-1, 0.27928+-0.0920 ngg-1, 0.04426+-0.0151 ngg-1 and 1.8321+-0.677 ngg-1, respectively.	('aflatoxins', 'Chemical', 'MESH:D000348', (53, 63))	('AFB1', 'Chemical', 'MESH:D016604', (20, 24))	('0.0871+-0.03030 ngg-1', 'Var', (107, 128))	('0.27928+-0.0920 ngg-1', 'Var', (130, 151))	('0.04426+-0.0151 ngg-1', 'Var', (153, 174))	('1.4228+-0.4703 ngg-1', 'Var', (85, 105))
498114	27516997	In samples contained at least one type of aflatoxin, the mean of levels for AFB1, AFB2, AFG1, AFG2 and total aflatoxins are 2.33774+-1.599 ngg-1, 0.12473+-0.1030 ngg-1, 0.4573+-0.3130 ngg-1, 0.716+-0.0511 ngg-1 and 2.6600+-2.41710 ngg-1, respectively.	('2.33774+-1.599 ngg-1', 'Var', (124, 144))	('aflatoxin', 'Chemical', 'MESH:D000348', (42, 51))	('0.4573+-0.3130 ngg-1', 'Var', (169, 189))	('0.716+-0.0511 ngg-1', 'Var', (191, 210))	('aflatoxins', 'Chemical', 'MESH:D000348', (109, 119))	('AFB1', 'Chemical', 'MESH:D016604', (76, 80))	('0.12473+-0.1030 ngg-1', 'Var', (146, 167))	('aflatoxin', 'Chemical', 'MESH:D000348', (109, 118))
498188	23302905	Blocking the programmed death-1 (PD-1) receptor on activated T cells with mAbs has been shown to overcome immune resistance and induce clinical responses in patients with solid tumors.	('solid tumors', 'Disease', (171, 183))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('Blocking', 'Var', (0, 8))	('overcome', 'PosReg', (97, 105))	('programmed death-1', 'Gene', (13, 31))	('immune resistance', 'CPA', (106, 123))	('solid tumors', 'Disease', 'MESH:D009369', (171, 183))	('induce', 'Reg', (128, 134))	('patients', 'Species', '9606', (157, 165))	('programmed death-1', 'Gene', '5133', (13, 31))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('clinical responses', 'CPA', (135, 153))	('PD-1', 'Gene', (33, 37))	('PD-1', 'Gene', '5133', (33, 37))
498200	23302905	One exception is the use of sipuleucel-T. Sipuleucel-T is a DC-containing cellular vaccine loaded with a fusion protein of prostatic acid phosphatase and granulocyte macrophage-colony stimulating factor (PAP-GM-CSF) and has been shown to increase overall survival (OS) in patients with metastatic prostate cancer.	('prostatic acid phosphatase', 'Gene', '55', (123, 149))	('prostate cancer', 'Disease', (297, 312))	('prostatic acid phosphatase', 'Gene', (123, 149))	('OS', 'Chemical', '-', (265, 267))	('increase', 'PosReg', (238, 246))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('prostate cancer', 'Disease', 'MESH:D011471', (297, 312))	('prostate cancer', 'Phenotype', 'HP:0012125', (297, 312))	('granulocyte macrophage-colony stimulating factor', 'Gene', (154, 202))	('Sipuleucel-T', 'Var', (42, 54))	('overall survival', 'MPA', (247, 263))	('GM-CSF', 'Gene', '1437', (208, 214))	('patients', 'Species', '9606', (272, 280))	('GM-CSF', 'Gene', (208, 214))	('granulocyte macrophage-colony stimulating factor', 'Gene', '1437', (154, 202))
498201	23302905	Sipuleucel-T is the first therapeutic cancer vaccine to receive FDA approval and has raised the potential for the use of DC-based vaccines in other cancers, including GI tumors.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('GI tumor', 'Phenotype', 'HP:0007378', (167, 175))	('cancers', 'Disease', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('GI tumors', 'Phenotype', 'HP:0007378', (167, 176))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('Sipuleucel-T', 'Var', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (38, 44))	('GI tumors', 'Disease', (167, 176))	('GI tumors', 'Disease', 'MESH:D009369', (167, 176))
498281	23302905	In a randomized trial, patients with gastric cancer treated with cisplatin/5-FU in combination therapy with tumor-associated lymphocytes purified from ascites, pleural fluid, and/or lymph nodes demonstrated an increased survival compared with those treated with chemotherapy alone.	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('pleural fluid', 'Phenotype', 'HP:0002202', (160, 173))	('patients', 'Species', '9606', (23, 31))	('ascites', 'Phenotype', 'HP:0001541', (151, 158))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('5-FU', 'Chemical', 'MESH:D005472', (75, 79))	('gastric cancer', 'Disease', (37, 51))	('survival', 'CPA', (220, 228))	('cisplatin/5-FU', 'Var', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('increased', 'PosReg', (210, 219))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('ascites', 'Disease', (151, 158))	('pleural', 'Disease', 'MESH:D010995', (160, 167))	('pleural', 'Disease', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))	('ascites', 'Disease', 'MESH:D001201', (151, 158))
498344	24324738	Association of Common Polymorphisms in TNFA, NFkB1 and NFKBIA with Risk and Prognosis of Esophageal Squamous Cell Carcinoma Tumour necrosis factor-alpha (TNF-alpha) and nuclear factor of kappa light chain gene enhancer in activated B cells (NF-kappaB) play critical role in carcinogenesis processes like tumour initiation, proliferation, migration and invasion.	('Tumour necrosis factor', 'Gene', '7124', (124, 146))	('NF-kappaB', 'Gene', '4790', (241, 250))	('Association', 'Interaction', (0, 11))	('TNFA', 'Gene', (39, 43))	('Prognosis of Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (76, 123))	('Prognosis of Esophageal Squamous Cell Carcinoma', 'Disease', (76, 123))	('proliferation', 'CPA', (323, 336))	('carcinogenesis', 'Disease', (274, 288))	('Tumour', 'Phenotype', 'HP:0002664', (124, 130))	('TNF-alpha', 'Gene', '7124', (154, 163))	('NFkB1', 'Gene', (45, 50))	('tumour', 'Phenotype', 'HP:0002664', (304, 310))	('TNF-alpha', 'Gene', (154, 163))	('invasion', 'CPA', (352, 360))	('TNFA', 'Gene', '7124', (39, 43))	('migration', 'CPA', (338, 347))	('carcinogenesis', 'Disease', 'MESH:D063646', (274, 288))	('tumour initiation', 'Disease', 'MESH:D009369', (304, 321))	('Carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('NFkB1', 'Gene', '4790', (45, 50))	('Polymorphisms', 'Var', (22, 35))	('NFKBIA', 'Gene', (55, 61))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('NFKBIA', 'Gene', '4792', (55, 61))	('tumour initiation', 'Disease', (304, 321))	('Tumour necrosis factor', 'Gene', (124, 146))	('NF-kappaB', 'Gene', (241, 250))
498345	24324738	Single nucleotide polymorphisms in TNF-alpha, NF-kappaB and its inhibitor IkappaB genes were shown to be associated with susceptibility and prognosis of several cancers; however, their role in esophageal squamous cell carcinoma (ESCC) is not well recognised.	('SCC', 'Gene', (230, 233))	('NF-kappaB', 'Gene', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('TNF-alpha', 'Gene', '7124', (35, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('SCC', 'Phenotype', 'HP:0002860', (230, 233))	('SCC', 'Gene', '6317', (230, 233))	('TNF-alpha', 'Gene', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('esophageal squamous cell carcinoma', 'Disease', (193, 227))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (193, 227))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('NF-kappaB', 'Gene', '4790', (46, 55))	('cancers', 'Disease', (161, 168))	('associated', 'Reg', (105, 115))
498347	24324738	We genotyped 290 ESCC patients (including 162 followed up cases) and 311 mean age, gender and ethnicity matched controls for TNFA -308G>A, NFkB1 -94ATTG ins/del and NFKBIA (-826C>T and 3'UTRA>G) polymorphisms using PCR alone or followed by RFLP and TaqMan assay.	('NFKBIA', 'Gene', '4792', (165, 171))	('-826C', 'Var', (173, 178))	('SCC', 'Gene', (18, 21))	('NFkB1', 'Gene', (139, 144))	('TNFA', 'Gene', (125, 129))	('patients', 'Species', '9606', (22, 30))	('-826C>T', 'Mutation', 'rs2233406', (173, 180))	('NFkB1', 'Gene', '4790', (139, 144))	('SCC', 'Phenotype', 'HP:0002860', (18, 21))	('SCC', 'Gene', '6317', (18, 21))	('TNFA', 'Gene', '7124', (125, 129))	('NFKBIA', 'Gene', (165, 171))	('-308G>A', 'Mutation', 'rs1800629', (130, 137))
498349	24324738	Haplotypes of NFKBIA -826C>T and 3'UTRA>G polymorphisms, C-826G3'UTR and T-826A3'UTR, were associated with reduced risk of ESCC.	("C-826G3'UTR", 'Var', (57, 68))	("T-826A3'UTR", 'Var', (73, 84))	('NFKBIA', 'Gene', (14, 20))	('reduced', 'NegReg', (107, 114))	('SCC', 'Gene', (124, 127))	('NFKBIA', 'Gene', '4792', (14, 20))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('SCC', 'Gene', '6317', (124, 127))	('-826C>T', 'Mutation', 'rs2233406', (21, 28))
498354	24324738	TNFA-308 and NFKBIA (-826C>T and 3'UTRA>G) polymorphisms may play role in susceptibility but not in prognosis of ESCC patients in northern Indian population.	('-826C>T', 'Var', (21, 28))	('TNFA', 'Gene', (0, 4))	('SCC', 'Gene', (114, 117))	('TNFA', 'Gene', '7124', (0, 4))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('NFKBIA', 'Gene', (13, 19))	('-826C>T', 'Mutation', 'rs2233406', (21, 28))	('patients', 'Species', '9606', (118, 126))	('NFKBIA', 'Gene', '4792', (13, 19))
498358	24324738	Deregulation of TNF-alpha is implicated in wide spectrum of diseases like diabetes, osteoporosis, autoimmune diseases and cancers.	('autoimmune diseases and cancers', 'Disease', 'MESH:D001327', (98, 129))	('osteoporosis', 'Phenotype', 'HP:0000939', (84, 96))	('diabetes', 'Disease', (74, 82))	('Deregulation', 'Var', (0, 12))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (98, 117))	('implicated', 'Reg', (29, 39))	('TNF-alpha', 'Gene', '7124', (16, 25))	('osteoporosis', 'Disease', 'MESH:D010024', (84, 96))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('osteoporosis', 'Disease', (84, 96))	('TNF-alpha', 'Gene', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('diabetes', 'Disease', 'MESH:D003920', (74, 82))
498360	24324738	Several functional polymorphisms are present in the promoter region of TNFA; however the most documented single nucleotide polymorphism (SNP) is located at 308 nucleotide position resulting in substitution of G to A (rs1800629).	('TNFA', 'Gene', '7124', (71, 75))	('rs1800629', 'Mutation', 'rs1800629', (217, 226))	('TNFA', 'Gene', (71, 75))	('rs1800629', 'Var', (217, 226))
498364	24324738	TNFA-308 polymorphism may also have prognostic implication as it was found to confer adverse outcome to head & neck cancer and gastro-esophageal patients.	('patients', 'Species', '9606', (145, 153))	('TNFA', 'Gene', (0, 4))	('cancer', 'Disease', (116, 122))	('gastro-esophageal', 'Disease', (127, 144))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('and', 'Disease', (123, 126))	('polymorphism', 'Var', (9, 21))	('TNFA', 'Gene', '7124', (0, 4))	('head & neck cancer', 'Phenotype', 'HP:0012288', (104, 122))	('head & neck', 'Disease', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('gastro-esophageal', 'Disease', 'MESH:D005764', (127, 144))
498373	24324738	Several polymorphisms are present in NFKB1 (1900 SNPs) and NFKBIA (158 SNPs) according to dbSNP database (www.ncbi.nlm.nih.gov/snp), however, previous studies have extensively explored role of common polymorphic variants in promoter region of NFKB1 (-94 ATTG ins/del; rs28720239) and NFKBIA (-826 C>T; rs2233406) and 3'UTR region of NFKBIA (3'UTR A>G; rs696) in susceptibility and prognosis of various cancers.	('rs2233406', 'Mutation', 'rs2233406', (302, 311))	('cancers', 'Disease', 'MESH:D009369', (402, 409))	('NFKB1', 'Gene', (37, 42))	('NFKB1', 'Gene', '4790', (243, 248))	('rs28720239', 'Mutation', 'rs28720239', (268, 278))	('NFKBIA', 'Gene', (59, 65))	('NFKBIA', 'Gene', '4792', (59, 65))	('-826 C>T', 'Mutation', 'rs2233406', (292, 300))	('NFKB1', 'Gene', (243, 248))	('cancers', 'Phenotype', 'HP:0002664', (402, 409))	('cancers', 'Disease', (402, 409))	('NFKBIA', 'Gene', (333, 339))	('-94 ATTG', 'Var', (250, 258))	('NFKBIA', 'Gene', '4792', (333, 339))	('cancer', 'Phenotype', 'HP:0002664', (402, 408))	('NFKB1', 'Gene', '4790', (37, 42))	('-826 C>T; rs2233406', 'Var', (292, 311))	('rs696', 'Mutation', 'rs696', (352, 357))	('NFKBIA', 'Gene', (284, 290))	('NFKBIA', 'Gene', '4792', (284, 290))
498374	24324738	Literature exploring association of these NFKB1 and NFKBIA variants in EC are missing till now.	('NFKBIA', 'Gene', (52, 58))	('NFKBIA', 'Gene', '4792', (52, 58))	('association', 'Interaction', (21, 32))	('NFKB1', 'Gene', (42, 47))	('variants', 'Var', (59, 67))	('NFKB1', 'Gene', '4790', (42, 47))
498375	24324738	So, in the present study, we investigated the association of TNFA-308 G>A, NFKB1 -94ATTG ins/del and NFKBIA (-826 C>T and 3'UTR A>G) polymorphisms with susceptibility to esophageal squamous cell carcinoma (ESCC) or its clinical phenotypes, their interaction with environmental risk factors and their role in survival outcome of ESCC patients.	('SCC', 'Gene', '6317', (329, 332))	('patients', 'Species', '9606', (333, 341))	('NFKBIA', 'Gene', (101, 107))	('NFKB1', 'Gene', '4790', (75, 80))	('SCC', 'Phenotype', 'HP:0002860', (207, 210))	('association', 'Interaction', (46, 57))	('NFKBIA', 'Gene', '4792', (101, 107))	('SCC', 'Gene', (329, 332))	('-826 C>T', 'Mutation', 'rs2233406', (109, 117))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (170, 204))	('ins/del', 'Var', (89, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('SCC', 'Gene', '6317', (207, 210))	('NFKB1', 'Gene', (75, 80))	('polymorphisms', 'Var', (133, 146))	('TNFA-308', 'Gene', (61, 69))	('SCC', 'Gene', (207, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('-826 C>T', 'Var', (109, 117))	('SCC', 'Phenotype', 'HP:0002860', (329, 332))	('esophageal squamous cell carcinoma', 'Disease', (170, 204))
498396	24324738	Haplotype analysis of NFKBIA polymorphisms was conducted using SNPAnalyzer version 1.0.	('polymorphisms', 'Var', (29, 42))	('NFKBIA', 'Gene', '4792', (22, 28))	('NFKBIA', 'Gene', (22, 28))
498408	24324738	Chi square test showed genotypic frequencies of polymorphisms in TNFA, NFKB1 and NFKBIA were in accordance with HWE in controls (P>0.05 in each case).	('NFKB1', 'Gene', (71, 76))	('TNFA', 'Gene', (65, 69))	('NFKB1', 'Gene', '4790', (71, 76))	('polymorphisms', 'Var', (48, 61))	('TNFA', 'Gene', '7124', (65, 69))	('NFKBIA', 'Gene', (81, 87))	('NFKBIA', 'Gene', '4792', (81, 87))
498411	24324738	No associations of NFKB1 -94 ins/del, and NFKBIA (-826 C>T and 3'UTR A>G) polymorphisms were observed with the overall risk of ESCC.	('NFKBIA', 'Gene', '4792', (42, 48))	('SCC', 'Gene', (128, 131))	('NFKB1', 'Gene', '4790', (19, 24))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Gene', '6317', (128, 131))	('-826 C>T', 'Mutation', 'rs2233406', (50, 58))	('-826 C>T', 'Var', (50, 58))	('NFKBIA', 'Gene', (42, 48))	('NFKB1', 'Gene', (19, 24))
498412	24324738	Univariate and multivariate Cox regression analysis showed no significant effect of TNFA-308 G>A, NFKB1 -94ATTG ins/del, NFKBIA (-826 C>T and 3'UTR A>G) polymorphisms on the survival outcome of ESCC patients (Table 3 and 4).	('TNFA-308', 'Gene', (84, 92))	('SCC', 'Gene', (195, 198))	('NFKBIA', 'Gene', (121, 127))	('SCC', 'Phenotype', 'HP:0002860', (195, 198))	('NFKBIA', 'Gene', '4792', (121, 127))	('SCC', 'Gene', '6317', (195, 198))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('NFKB1', 'Gene', '4790', (98, 103))	('patients', 'Species', '9606', (199, 207))	('-826 C>T', 'Mutation', 'rs2233406', (129, 137))	('-826 C>T', 'Var', (129, 137))	('NFKB1', 'Gene', (98, 103))
498413	24324738	However, when all of the variables in the study (genetic polymorphisms and clinico-pathological variables) were entered in single step in multivariate analysis, presence of metastasis conferred poor survival outcome to ESCC patients (HR = 3.39, 95% CI = 1.44-7.98, P = 0.005).	('SCC', 'Gene', (220, 223))	('SCC', 'Phenotype', 'HP:0002860', (220, 223))	('poor', 'NegReg', (194, 198))	('metastasis', 'CPA', (173, 183))	('SCC', 'Gene', '6317', (220, 223))	('patients', 'Species', '9606', (224, 232))	('presence', 'Var', (161, 169))	('survival', 'MPA', (199, 207))
498415	24324738	We further stratified our overall group of subjects based on gender and found female specific increased risk of ESCC with TNFA -308 GA+AA genotype (OR = 3.25, 95% CI = 1.22-8.66, P =0.019) even after FDR test (q value = 0.069) (Table 5).	('SCC', 'Gene', '6317', (113, 116))	('GA+AA', 'Var', (132, 137))	('TNFA', 'Gene', '7124', (122, 126))	('SCC', 'Gene', (113, 116))	('SCC', 'Phenotype', 'HP:0002860', (113, 116))	('TNFA', 'Gene', (122, 126))
498416	24324738	However, NFKBIA -826 CT and CT+TT genotypes conferred 50% reduced risk of ESCC in female subjects (OR = 0.48, 95% CI = 0.25-0.91, P = 0.025, q = 0.045 and OR = 0.52, 95% CI = 0.28-0.97, P = 0.038, q = 0.057) (Table 5).	('SCC', 'Gene', '6317', (75, 78))	('NFKBIA', 'Gene', (9, 15))	('NFKBIA', 'Gene', '4792', (9, 15))	('CT+TT', 'Var', (28, 33))	('SCC', 'Gene', (75, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('reduced', 'NegReg', (58, 65))
498417	24324738	Association of the TNFA-308 G>A, NFKB1 -94ATTG ins/del and NFKBIA polymorphisms with clinical characteristics (tumour location and regional lymph node involvement) of ESCC Association of the polymorphisms with tumour location showed significant reduced risk of upper and lower third esophageal tumours with NFKBIA -826 CT+TT and 3'UTR AG+GG genotype respectively (OR = 0.41, 95% CI = 0.21-0.80, P = 0.009, q = 0.019 and OR = 0.52, 95% CI = 0.29-0.93, P = 0.028, q = 0.072 respectively) (Table 6).	('SCC', 'Phenotype', 'HP:0002860', (168, 171))	('NFKBIA', 'Gene', (307, 313))	('NFKBIA', 'Gene', '4792', (307, 313))	('G>A', 'Var', (28, 31))	('NFKBIA', 'Gene', (59, 65))	('NFKBIA', 'Gene', '4792', (59, 65))	('SCC', 'Gene', '6317', (168, 171))	('NFKB1', 'Gene', '4790', (33, 38))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('esophageal tumours', 'Disease', 'MESH:D004938', (283, 301))	('tumour', 'Disease', (210, 216))	('SCC', 'Gene', (168, 171))	('esophageal tumours', 'Disease', (283, 301))	('tumours', 'Phenotype', 'HP:0002664', (294, 301))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('NFKB1', 'Gene', (33, 38))	('reduced', 'NegReg', (245, 252))	('tumour', 'Disease', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (294, 300))	('TNFA-308', 'Gene', (19, 27))	('tumour', 'Disease', 'MESH:D009369', (294, 300))	('tumour', 'Disease', (294, 300))	('esophageal tumour', 'Phenotype', 'HP:0100751', (283, 300))
498418	24324738	TNFA -308 or NFKB1 -94 ins/del polymorphisms did not modulate any site-specific risk of ESCC tumours.	('TNFA', 'Gene', (0, 4))	('NFKB1', 'Gene', (13, 18))	('ESCC tumours', 'Disease', (88, 100))	('polymorphisms', 'Var', (31, 44))	('TNFA', 'Gene', '7124', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('NFKB1', 'Gene', '4790', (13, 18))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('ESCC tumours', 'Disease', 'MESH:D004938', (88, 100))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
498419	24324738	We also analysed the role of the genetic variants with regional lymph node involvement and found ESSC patients with TNFA -308 GA or GA+AA genotypes were at two fold increased risk of regional lymph node involvement (GA vs. AA: OR =2.16, 95% CI = 1.27-3.67, P = 0.004, q =0.011; GA +AA vs. AA: OR = 2.18, 95% CI = 1.29-3.68, P = 0.003, q = 0.008) (Table 6).	('variants', 'Var', (41, 49))	('TNFA', 'Gene', '7124', (116, 120))	('patients', 'Species', '9606', (102, 110))	('regional lymph node involvement', 'CPA', (183, 214))	('TNFA', 'Gene', (116, 120))
498422	24324738	Therefore, C-826G3'UTR and T-826A3'UTR haplotypes were associated with reduced risk of ESCC compared to C-826A3'UTR haplotype (OR = 0.73, 95% CI = 0.56-0.96, P = 0.025 and OR = 0.60, 95% CI = 0.37-0.96, P = 0.034) (Table 7).	("C-826G3'UTR", 'Var', (11, 22))	('reduced', 'NegReg', (71, 78))	('SCC', 'Gene', (88, 91))	("T-826A3'UTR", 'Var', (27, 38))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
498428	24324738	Cox regression analysis also did not show any significant hazard of death with any of the risk genotypes i.e., '1' '2' or '3'risk genotypes (Data not shown).	("'3'risk", 'Var', (122, 129))	("'1' '2", 'Var', (111, 117))	('Cox', 'Gene', '1351', (0, 3))	('death', 'Disease', 'MESH:D003643', (68, 73))	('Cox', 'Gene', (0, 3))	('death', 'Disease', (68, 73))
498430	24324738	MDR analysis showed that TNFA -308 polymorphism was the best one factor model and TNFA -308 and NFKBIA 3'UTR were the best model for two factors and TNFA-308, NFKBIA -826, NFKBIA 3'UTR polymorphisms as best model for three factors.	('NFKBIA', 'Gene', (172, 178))	('NFKBIA', 'Gene', (96, 102))	('polymorphism', 'Var', (35, 47))	('NFKBIA', 'Gene', '4792', (172, 178))	('TNFA', 'Gene', '7124', (82, 86))	('NFKBIA', 'Gene', (159, 165))	('NFKBIA', 'Gene', '4792', (96, 102))	('TNFA', 'Gene', '7124', (25, 29))	('TNFA', 'Gene', (149, 153))	('NFKBIA', 'Gene', '4792', (159, 165))	('TNFA', 'Gene', '7124', (149, 153))	('TNFA', 'Gene', (82, 86))	('TNFA', 'Gene', (25, 29))
498434	24324738	We observed that TNFA-308 G>A polymorphism was associated with enhanced risk of ESCC especially in females and in patients with regional lymph node involvements.	('SCC', 'Gene', '6317', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('G>A polymorphism', 'Var', (26, 42))	('TNFA-308', 'Gene', (17, 25))	('SCC', 'Gene', (81, 84))	('patients', 'Species', '9606', (114, 122))
498435	24324738	No independent role of either NFKB1 -94ATTG ins/del or NFKBIA (-826 C>T and 3'UTR A>G) polymorphisms in ESCC susceptibility was found, however, two haplotypes of NFKBIA polymorphisms (C-826 G3'UTR and T-826 A3'UTR) seem to have protective role in ESCC.	('NFKB1', 'Gene', (30, 35))	('NFKB1', 'Gene', '4790', (30, 35))	('NFKBIA', 'Gene', (55, 61))	('SCC', 'Gene', (248, 251))	('-826 C>T', 'Mutation', 'rs2233406', (63, 71))	('NFKBIA', 'Gene', '4792', (55, 61))	('SCC', 'Phenotype', 'HP:0002860', (248, 251))	('NFKBIA', 'Gene', (162, 168))	('SCC', 'Gene', (105, 108))	('SCC', 'Gene', '6317', (248, 251))	("C-826 G3'UTR", 'Var', (184, 196))	("T-826 A3'UTR", 'Var', (201, 213))	('NFKBIA', 'Gene', '4792', (162, 168))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('SCC', 'Gene', '6317', (105, 108))
498436	24324738	MDR analysis showed TNFA -308, NFKBIA -826 and NFKBIA 3'UTR polymorphisms as better predictor for risk of ESCC.	('polymorphisms', 'Var', (60, 73))	('NFKBIA', 'Gene', (31, 37))	('TNFA', 'Gene', (20, 24))	('NFKBIA', 'Gene', '4792', (31, 37))	('SCC', 'Gene', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('TNFA', 'Gene', '7124', (20, 24))	('NFKBIA', 'Gene', (47, 53))	('SCC', 'Gene', '6317', (107, 110))	('NFKBIA', 'Gene', '4792', (47, 53))
498438	24324738	The MAF of TNFA -308 G>A polymorphism in present study was 7.1% which is similar to Hapmap Guajarati Indian (GIH) and Han Chinese (CHB) population (http//hapmap.ncbi.nlm.nih.gov/).	('TNFA', 'Gene', (11, 15))	('CHB', 'Disease', (131, 134))	('G>A', 'Var', (21, 24))	('-308 G>A', 'Mutation', 'rs1800629', (16, 24))	('TNFA', 'Gene', '7124', (11, 15))	('CHB', 'Disease', 'None', (131, 134))
498443	24324738	In contrast to our finding, two previous studies did not find independent association of TNFA -308 G>A polymorphism with susceptibility to gastro-esophageal cancer or ESCC.	('SCC', 'Gene', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('SCC', 'Phenotype', 'HP:0002860', (168, 171))	('TNFA', 'Gene', (89, 93))	('SCC', 'Gene', '6317', (168, 171))	('G>A', 'Var', (99, 102))	('-308 G>A', 'Mutation', 'rs1800629', (94, 102))	('TNFA', 'Gene', '7124', (89, 93))	('gastro-esophageal cancer', 'Disease', 'MESH:D005764', (139, 163))	('gastro-esophageal cancer', 'Disease', (139, 163))
498444	24324738	However, their results should be interpreted cautiously as TNFA-308 polymorphism was not in HWE in controls in these studies (PHWE were less than 0.05).	('TNFA', 'Gene', (59, 63))	('polymorphism', 'Var', (68, 80))	('TNFA', 'Gene', '7124', (59, 63))
498448	24324738	Although, prior studies have shown significant association of the NFKB1 polymorphism with carcinoma of urinary bladder, prostate, cervix and nasopharynx, no role of the polymorphism in ESCC susceptibility was found in the present study.	('SCC', 'Gene', '6317', (186, 189))	('carcinoma of urinary bladder', 'Disease', 'MESH:D001749', (90, 118))	('NFKB1', 'Gene', '4790', (66, 71))	('carcinoma of urinary bladder', 'Disease', (90, 118))	('nasopharynx', 'Disease', (141, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('polymorphism', 'Var', (72, 84))	('NFKB1', 'Gene', (66, 71))	('prostate', 'Disease', (120, 128))	('cervix', 'Disease', (130, 136))	('SCC', 'Gene', (186, 189))	('SCC', 'Phenotype', 'HP:0002860', (186, 189))	('association', 'Interaction', (47, 58))
498451	24324738	We also examined association of two functional polymorphisms in NFKBIA (-826C>T and 3'UTRA>G) with ESCC susceptibility, however no significant role in ESCC was observed.	('SCC', 'Gene', (100, 103))	('-826C>T', 'Mutation', 'rs2233406', (72, 79))	('association', 'Interaction', (17, 28))	('-826C>T', 'Var', (72, 79))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('SCC', 'Gene', '6317', (100, 103))	('SCC', 'Gene', (152, 155))	('NFKBIA', 'Gene', (64, 70))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('SCC', 'Gene', '6317', (152, 155))	('NFKBIA', 'Gene', '4792', (64, 70))
498465	24324738	had shown association of the TNFA -308 polymorphism with lymph node metastasis in gastric cancer patients.	('TNFA', 'Gene', '7124', (29, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('association', 'Interaction', (10, 21))	('lymph node metastasis', 'CPA', (57, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('gastric cancer', 'Disease', (82, 96))	('polymorphism', 'Var', (39, 51))	('TNFA', 'Gene', (29, 33))	('patients', 'Species', '9606', (97, 105))
498470	24324738	We next carried out the haplotype analysis of two NFKBIA polymorphisms which showed significant decreased risk of ESCC with C-826G3'UTR and T-826A3'UTR haplotypes.	('decreased', 'NegReg', (96, 105))	('NFKBIA', 'Gene', (50, 56))	("T-826A3'UTR", 'Var', (140, 151))	('SCC', 'Gene', (115, 118))	('NFKBIA', 'Gene', '4792', (50, 56))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	("C-826G3'UTR", 'Var', (124, 135))	('SCC', 'Gene', '6317', (115, 118))
498471	24324738	Bioinformatics analysis showed that NFKBIA -826 C>T polymorphism may affect binding of transcription factor like BRAC1/2, TBP and MYB, while 3'UTRA>G polymorphism may affect binding of mir-196a (www.SNPinfo.com).	('binding', 'Interaction', (174, 181))	('affect', 'Reg', (69, 75))	('TBP', 'Gene', (122, 125))	('BRAC1/2', 'Protein', (113, 120))	('TBP', 'Gene', '6908', (122, 125))	('polymorphism', 'Var', (52, 64))	('NFKBIA', 'Gene', (36, 42))	('mir-196a', 'Protein', (185, 193))	('affect', 'Reg', (167, 173))	('binding', 'Interaction', (76, 83))	('MYB', 'Gene', '4602', (130, 133))	('NFKBIA', 'Gene', '4792', (36, 42))	('-826 C>T', 'Mutation', 'rs2233406', (43, 51))	('MYB', 'Gene', (130, 133))
498472	24324738	Few studies have also examined the effect of NFKBIA 3'UTRA>G polymorphism on expression of the protein, however, finding are inconsistent.	('NFKBIA', 'Gene', '4792', (45, 51))	('expression', 'MPA', (77, 87))	('NFKBIA', 'Gene', (45, 51))	('polymorphism', 'Var', (61, 73))
498474	24324738	Data demonstrating exact functional role of NFKBIA -826 and 3'UTR polymorphisms in ESCC are lacking, however, it is reasonable to assume that differential expression of IkappaB due to NFKBIA specific haplotypes may result in different NF-kappaB activation, further leading to differential risk for ESCC.	('haplotypes', 'Var', (200, 210))	('NF-kappaB', 'Gene', (235, 244))	('activation', 'PosReg', (245, 255))	('SCC', 'Gene', '6317', (84, 87))	('IkappaB', 'Protein', (169, 176))	('SCC', 'Gene', (299, 302))	('NFKBIA', 'Gene', (184, 190))	('SCC', 'Phenotype', 'HP:0002860', (299, 302))	('NFKBIA', 'Gene', '4792', (184, 190))	('SCC', 'Gene', '6317', (299, 302))	('NFKBIA', 'Gene', (44, 50))	('SCC', 'Gene', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('NFKBIA', 'Gene', '4792', (44, 50))	('NF-kappaB', 'Gene', '4790', (235, 244))
498483	24324738	In summary, our results suggest independent role of TNFA -308 G>A polymorphism and combined effect of TNFA and NFKBIA gene polymorphisms in susceptibility of ESCC in northern Indian population.	('NFKBIA', 'Gene', (111, 117))	('NFKBIA', 'Gene', '4792', (111, 117))	('susceptibility', 'Reg', (140, 154))	('TNFA', 'Gene', '7124', (102, 106))	('TNFA', 'Gene', (52, 56))	('SCC', 'Gene', (159, 162))	('polymorphisms', 'Var', (123, 136))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('SCC', 'Gene', '6317', (159, 162))	('TNFA', 'Gene', '7124', (52, 56))	('-308 G>A', 'Mutation', 'rs1800629', (57, 65))	('TNFA', 'Gene', (102, 106))
498484	24324738	However, none of the genetic variants seem to have implications in prognosis of ESCC.	('SCC', 'Gene', '6317', (81, 84))	('implications', 'Reg', (51, 63))	('variants', 'Var', (29, 37))	('SCC', 'Gene', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))
498515	19468668	Three sets of these raw data were accessible through the GEO Datasets available on PubMed (GSE2769, GSE1420, and GSE2444).	('GSE2769', 'Var', (91, 98))	('GSE1420', 'Chemical', '-', (100, 107))	('GSE2444', 'Chemical', '-', (113, 120))	('GSE2444', 'Var', (113, 120))	('GSE1420', 'Var', (100, 107))	('GSE2769', 'Chemical', '-', (91, 98))
498593	19468668	Transfection of CDX2 into human esophageal squamous epithelial cells induced metaplastic changes in morphology and gene expression.	('metaplastic changes in morphology', 'CPA', (77, 110))	('CDX2', 'Gene', (16, 20))	('Transfection', 'Var', (0, 12))	('CDX2', 'Gene', '1045', (16, 20))	('induced', 'Reg', (69, 76))	('human', 'Species', '9606', (26, 31))	('gene expression', 'MPA', (115, 130))
498651	21288367	Recombinant His-ECRG4 protein was precoated into the wells of 96-well plate and incubated with the total protein from EC9706/pcDNA3.1-FLAG-ECRG1 or EC9706/pcDNA3.1-FLAG cells.	('ECRG4', 'Gene', '84417', (16, 21))	('EC9706/pcDNA3.1-FLAG', 'Var', (148, 168))	('ECRG1', 'Gene', (139, 144))	('ECRG1', 'Gene', '339967', (139, 144))	('EC9706', 'CellLine', 'CVCL:E307', (148, 154))	('His', 'Chemical', 'MESH:D006639', (12, 15))	('EC9706', 'CellLine', 'CVCL:E307', (118, 124))	('ECRG4', 'Gene', (16, 21))
498678	21288367	The proliferation of EC9706 cells with either ECRG4 or ECRG1 transfection were inhibited compared with the control cells.	('ECRG4', 'Gene', '84417', (46, 51))	('proliferation', 'CPA', (4, 17))	('transfection', 'Var', (61, 73))	('ECRG1', 'Gene', (55, 60))	('EC9706', 'CellLine', 'CVCL:E307', (21, 27))	('ECRG1', 'Gene', '339967', (55, 60))	('inhibited', 'NegReg', (79, 88))	('ECRG4', 'Gene', (46, 51))
498679	21288367	Furthermore, the ECRG4 and ECRG1 co-transfection significantly reinforced the cell proliferation inhibition effect, as assessed by the BrdU assay (P < 0.01) (Figure 4).	('co-transfection', 'Var', (33, 48))	('ECRG1', 'Gene', (27, 32))	('reinforced', 'PosReg', (63, 73))	('ECRG1', 'Gene', '339967', (27, 32))	('ECRG4', 'Gene', (17, 22))	('cell proliferation inhibition effect', 'CPA', (78, 114))	('ECRG4', 'Gene', '84417', (17, 22))	('BrdU', 'Chemical', 'MESH:D001973', (135, 139))
498680	21288367	Moreover, cell growth curves also demonstrated that ECRG4 and ECRG1 co-transfection significantly slowed down cancer cells growth by MTT assay (P < 0.01) (Figure 5).	('cancer', 'Disease', (110, 116))	('MTT', 'Chemical', 'MESH:C070243', (133, 136))	('ECRG1', 'Gene', (62, 67))	('co-transfection', 'Var', (68, 83))	('slowed down', 'NegReg', (98, 109))	('ECRG1', 'Gene', '339967', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ECRG4', 'Gene', (52, 57))	('ECRG4', 'Gene', '84417', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
498685	21288367	ECRG4 gene promoter hypermethylation accounted for decreased expression in ESCC, and the low expression of ECRG4 protein in patients with ESCC was associated with poor prognosis.	('hypermethylation', 'Var', (20, 36))	('ECRG4', 'Gene', (0, 5))	('patients', 'Species', '9606', (124, 132))	('low', 'NegReg', (89, 92))	('ESCC', 'Disease', (75, 79))	('decreased', 'NegReg', (51, 60))	('ECRG4', 'Gene', (107, 112))	('ECRG4', 'Gene', '84417', (0, 5))	('expression', 'MPA', (93, 103))	('ECRG4', 'Gene', '84417', (107, 112))	('expression', 'MPA', (61, 71))
498686	21288367	Furthermore, restoration of ECRG4 expression in tumor cells inhibited cell growth and invasion.	('expression', 'MPA', (34, 44))	('tumor', 'Disease', (48, 53))	('ECRG4', 'Gene', (28, 33))	('inhibited', 'NegReg', (60, 69))	('ECRG4', 'Gene', '84417', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('restoration', 'Var', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
498690	21288367	The ECRG1 290 Arg/Gln and Gln/Gln genotypes were associated with increased risk for squamous cell carcinoma, compared with that of 290 Arg/Arg.	('Arg', 'Chemical', 'MESH:D001120', (14, 17))	('ECRG1', 'Gene', '339967', (4, 9))	('290 Arg/Gln', 'SUBSTITUTION', 'None', (10, 21))	('Gln', 'Chemical', 'MESH:D005973', (18, 21))	('Gln/Gln', 'Var', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('Gln', 'Chemical', 'MESH:D005973', (30, 33))	('Arg', 'Chemical', 'MESH:D001120', (135, 138))	('Gln', 'Chemical', 'MESH:D005973', (26, 29))	('Arg', 'Chemical', 'MESH:D001120', (139, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('squamous cell carcinoma', 'Disease', (84, 107))	('ECRG1', 'Gene', (4, 9))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 107))	('290 Arg/Gln', 'Var', (10, 21))
498767	14613581	Aberrant glycosylation involves incomplete synthesis resulting in deletion of normally expressed antigens, with or without, exposure of core sugar and peptide structures.	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('sugar', 'Chemical', 'MESH:D000073893', (141, 146))	('synthesis', 'MPA', (43, 52))	('glycosylation', 'MPA', (9, 22))	('deletion', 'Var', (66, 74))
498771	14613581	Such aberrations in cell surface glycoproteins, especially the carbohydrates are associated frequently with altered adhesion, cell-cell interactions and in signal transduction pathways.	('signal transduction pathways', 'Pathway', (156, 184))	('cell-cell interactions', 'CPA', (126, 148))	('altered', 'Reg', (108, 115))	('aberrations', 'Var', (5, 16))	('cell surface glycoproteins', 'Protein', (20, 46))	('carbohydrates', 'Chemical', 'MESH:D002241', (63, 76))	('adhesion', 'CPA', (116, 124))	('associated', 'Reg', (81, 91))
498776	14613581	Aberrant glycosylation of proteins is a common feature found in ESCC patients and aberrations in adhesive interactions can lead to pathological disorders.	('ESCC patients', 'Disease', (64, 77))	('Aberrant', 'Var', (0, 8))	('adhesive', 'CPA', (97, 105))	('lead to', 'Reg', (123, 130))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('aberrations', 'Var', (82, 93))	('patients', 'Species', '9606', (69, 77))	('proteins', 'Protein', (26, 34))	('glycosylation', 'MPA', (9, 22))
498848	33489910	The meaning of HR < 1 was defined as CCT decreasing the risk of death, and HR > 1 indicated CCT increased the risk of death.	('HR > 1', 'Var', (75, 81))	('death', 'Disease', 'MESH:D003643', (64, 69))	('death', 'Disease', (64, 69))	('decreasing', 'NegReg', (41, 51))	('death', 'Disease', 'MESH:D003643', (118, 123))	('death', 'Disease', (118, 123))
498861	33489910	Koh, H. K. report that CCT prolonged LFFS, and Chen, M. thought there was no difference in LFFS between both groups.	('prolonged', 'PosReg', (27, 36))	('CCT', 'Var', (23, 26))	('LFFS', 'MPA', (37, 41))	('Koh', 'Chemical', 'MESH:C029943', (0, 3))
498889	33489910	The results reveal that there was no significant difference in DCR (OR 1.66; 95% CI 0.53-5.15) and ORR (OR 1.44; 95% CI 0.62-3.35) between the CCRT-CCT and CRT-alone groups.	('DCR', 'Chemical', '-', (63, 66))	('ORR', 'MPA', (99, 102))	('DCR', 'MPA', (63, 66))	('CCRT-CCT', 'Var', (143, 151))
498900	33489910	Each of these 3 studies shows that CCT can prolong patient survival time without increasing treatment-related toxicity, and the results of the data aggregation in our meta-analysis are consistent with their results.	('prolong', 'PosReg', (43, 50))	('toxicity', 'Disease', 'MESH:D064420', (110, 118))	('CCT', 'Var', (35, 38))	('patient', 'Species', '9606', (51, 58))	('toxicity', 'Disease', (110, 118))	('patient survival time', 'CPA', (51, 72))
498901	33489910	At the same time, the toxicities of therapy are similar between the CCRT-CCT and the CCRT-alone groups.	('toxicities', 'Disease', (22, 32))	('CCRT-CCT', 'Var', (68, 76))	('toxicities', 'Disease', 'MESH:D064420', (22, 32))
498930	31511012	Eligibility criteria were patients with resectable esophageal squamous cell or adenocarcinoma (including Siewert II) with the Union for International Cancer Control (UICC) TNM stages cT2+, cT3 cNx or cT4a cNx, 18-75 years old and with an Eastern Co-operative Oncology Group (ECOG) performance status of 0-1.	('cT3 cNx', 'Var', (189, 196))	('Oncology', 'Phenotype', 'HP:0002664', (259, 267))	('esophageal squamous cell or adenocarcinoma', 'Disease', (51, 93))	('Cancer', 'Disease', 'MESH:D009369', (150, 156))	('Cancer', 'Disease', (150, 156))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('patients', 'Species', '9606', (26, 34))	('cT4a cNx', 'Var', (200, 208))	('cT2+', 'Var', (183, 187))	('esophageal squamous cell or adenocarcinoma', 'Disease', 'MESH:D000077277', (51, 93))
498940	31511012	Sarcopenia was defined by previously published sex-specific cut-offs for L3 skeletal muscle index (men: 43 m2/m2 for body mass index (BMI) < 25 kg/m2, 53 cm2/m2 for BMI >= 25 kg/m2; women: 41 cm2/m2).	('Sarcopenia', 'Disease', (0, 10))	('Sarcopenia', 'Disease', 'MESH:D055948', (0, 10))	('< 25 kg/m2', 'Var', (139, 149))	('men', 'Species', '9606', (184, 187))	('men', 'Species', '9606', (99, 102))	('women', 'Species', '9606', (182, 187))
499198	25866627	As a result of these changes, slowed or absent transit occurs through some or all segments of the colon, leading to hard, infrequently passed stools and refractory constipation wherein the colon is converted to an inert tube.	('passed stools', 'Phenotype', 'HP:0040183', (135, 148))	('constipation', 'Disease', (164, 176))	('leading to', 'Reg', (105, 115))	('transit', 'MPA', (47, 54))	('changes', 'Var', (21, 28))	('constipation', 'Phenotype', 'HP:0002019', (164, 176))	('absent', 'NegReg', (40, 46))	('constipation', 'Disease', 'MESH:D003248', (164, 176))
499235	25491224	This will depend on patient performance status: Patients with performance status (PS) 0-2: palliative chemotherapy with any of the following options: ECF modifications (EL-1), docetaxel, cisplatin, and 5-FU (DCF) (EL1) / DCF modifications (EL-2), 5-FU, leucovorin, and oxaliplatin 6 (FOLFOX 6), (EL-2) or capecitabine and oxaliplatin (XELOX)X (EL-2).	('docetaxel', 'Chemical', 'MESH:D000077143', (176, 185))	('EL-2', 'Gene', '6708', (296, 300))	('EL-2', 'Gene', '6708', (240, 244))	('5-FU', 'Chemical', 'MESH:D005472', (202, 206))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (269, 280))	('EL-1', 'Gene', (169, 173))	('EL-2', 'Gene', '6708', (344, 348))	('XELOX', 'Chemical', 'MESH:C519688', (335, 340))	('leucovorin', 'Chemical', 'MESH:D002955', (253, 263))	('5-FU', 'Chemical', 'MESH:D005472', (247, 251))	('EL1', 'Gene', (214, 217))	('DCF', 'Chemical', '-', (208, 211))	('EL1', 'Gene', '2035', (214, 217))	('Patients', 'Species', '9606', (48, 56))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (322, 333))	('EL-2', 'Gene', (240, 244))	('EL-2', 'Gene', (296, 300))	('EL-2', 'Gene', (344, 348))	('DCF', 'Chemical', '-', (221, 224))	('modifications', 'Var', (225, 238))	('patient', 'Species', '9606', (20, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('EL-1', 'Gene', '2035', (169, 173))	('capecitabine', 'Chemical', 'MESH:D000069287', (305, 317))
499242	23675381	Our study revealed that deletions of GSTT1 and GSTM1 genes or the distinct point mutations of XRCC1 gene are associated with cervical and esophageal cancers.	('GSTT1', 'Gene', '2952', (37, 42))	('associated', 'Reg', (109, 119))	('GSTT1', 'Gene', (37, 42))	('GSTM1', 'Gene', '2944', (47, 52))	('deletions', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('esophageal cancers', 'Disease', (138, 156))	('GSTM1', 'Gene', (47, 52))	('cervical', 'Disease', (125, 133))	('esophageal cancers', 'Disease', 'MESH:D004938', (138, 156))	('XRCC1', 'Gene', (94, 99))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
499253	23675381	During the multistage carcinogenesis process, the cells predisposed to cancer accumulate mutations of proto-oncogenes, tumor suppressor genes, and other genes that are directly or indirectly involved in regulation of cell proliferation, survival, and migration.	('tumor', 'Disease', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('carcinogenesis', 'Disease', (22, 36))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('carcinogenesis', 'Disease', 'MESH:D063646', (22, 36))
499254	23675381	Mutations of the same gene may cause the several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Mutations', 'Var', (0, 9))	('cause', 'Reg', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
499255	23675381	Thus, mutations of tumor suppressor gene TP53 were detected in the tumors of all tissues and organs.	('TP53', 'Gene', '7157', (41, 45))	('detected', 'Reg', (51, 59))	('TP53', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', (67, 72))	('tumors', 'Disease', (67, 73))	('mutations', 'Var', (6, 15))
499256	23675381	The spectrum of mutations in key genes involved in the control of genome instability, DNA repair, cell cycle, apoptosis, and such processes as xenobiotics detoxification may vary for different cancer types.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('vary', 'Reg', (174, 178))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
499267	23675381	We studied the following genetic markers: (1) deletion polymorphism of genes participating in second phase of xenobiotic detoxification - glutathione-S-transferases - GSTM1 and GSTT1; (2) two types of single nucleotide polymorphism (SNP) of XRCC1 (Arg194Trp and Arg399Gln), responsible for the repair of double strand DNA breaks; (3) SNP of XRCC3 (Thr241Met), responsible for the repair of single strand DNA breaks; (4) SNP of gene regulating cell cycle and apoptosis - TP53 (Arg72Pro); (5) SNP of cell cycle regulating gene cyclin D1 - CCND1 (A870G).	('TP53', 'Gene', '7157', (470, 474))	('CCND1', 'Gene', (537, 542))	('GSTM1', 'Gene', '2944', (167, 172))	('Arg399Gln', 'SUBSTITUTION', 'None', (262, 271))	('glutathione', 'Chemical', 'MESH:D005978', (138, 149))	('cyclin D1', 'Gene', (525, 534))	('Arg72Pro', 'SUBSTITUTION', 'None', (476, 484))	('A870G', 'Var', (544, 549))	('Arg399Gln', 'Var', (262, 271))	('GSTT1', 'Gene', '2952', (177, 182))	('cyclin D1', 'Gene', '595', (525, 534))	('Thr241Met', 'Var', (348, 357))	('GSTT1', 'Gene', (177, 182))	('TP53', 'Gene', (470, 474))	('Arg194Trp', 'Var', (248, 257))	('Thr241Met', 'SUBSTITUTION', 'None', (348, 357))	('A870G', 'Mutation', 'rs9344', (544, 549))	('GSTM1', 'Gene', (167, 172))	('Arg72Pro', 'Var', (476, 484))	('CCND1', 'Gene', '595', (537, 542))	('Arg194Trp', 'SUBSTITUTION', 'None', (248, 257))
499274	23675381	The genotyping of GSTM1 and GSTT1 deletion polymorphisms was carried out by multiplex PCR amplification.	('GSTT1', 'Gene', '2952', (28, 33))	('GSTM1', 'Gene', '2944', (18, 23))	('GSTT1', 'Gene', (28, 33))	('GSTM1', 'Gene', (18, 23))	('deletion polymorphisms', 'Var', (34, 56))
499275	23675381	The method of site-specific PCR amplification followed by restriction of amplified fragments was used for the genotyping of XRCC1 Arg194Trp; XRCC1 Arg399Gln, XRCC3 Thr241Met, and TP53 Arg72Pro SNPs.	('Arg194Trp', 'Var', (130, 139))	('Arg399Gln', 'Var', (147, 156))	('Arg72Pro', 'Var', (184, 192))	('Arg399Gln', 'SUBSTITUTION', 'None', (147, 156))	('Arg194Trp', 'SUBSTITUTION', 'None', (130, 139))	('Thr241Met', 'Var', (164, 173))	('Arg72Pro', 'SUBSTITUTION', 'None', (184, 192))	('XRCC1', 'Gene', (124, 129))	('Thr241Met', 'SUBSTITUTION', 'None', (164, 173))	('TP53', 'Gene', '7157', (179, 183))	('TP53', 'Gene', (179, 183))
499279	23675381	The method of direct sequencing was applied for genotyping of CCND1 A870G polymorphism for all DNA samples.	('CCND1', 'Gene', (62, 67))	('A870G', 'Var', (68, 73))	('A870G', 'Mutation', 'rs9344', (68, 73))	('CCND1', 'Gene', '595', (62, 67))
499280	23675381	This method also was used for some DNA samples representing esophageal cancer in the case of determination of TP53 Arg72Pro polymorphism.	('Arg72Pro', 'Var', (115, 123))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('esophageal cancer', 'Disease', (60, 77))	('Arg72Pro', 'SUBSTITUTION', 'None', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
499288	23675381	Genotyping of TP53 Arg72Pro polymorphism of some esophageal cancer samples was also carried out by the TaqMan allelic discrimination method.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('esophageal cancer', 'Disease', (49, 66))	('Arg72Pro', 'Var', (19, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('Arg72Pro', 'SUBSTITUTION', 'None', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
499290	23675381	Amplification of TP53 gene fragment (141 bp) containing the polymorphic site Arg72Pro was performed by real-time PCR using a thermocycler iCycler iQ5 (Bio-Rad).	('Rad', 'Gene', (155, 158))	('Arg72Pro', 'Var', (77, 85))	('Arg72Pro', 'SUBSTITUTION', 'None', (77, 85))	('TP53', 'Gene', '7157', (17, 21))	('Rad', 'Gene', '6236', (155, 158))	('TP53', 'Gene', (17, 21))
499298	23675381	Genotyping of the candidate genes (deletions GSTM1 and GSTT1, XRCC1 Arg194Trp and Arg399Gln, XRCC3 Thr241Met, TP53 Arg72Pro, and CCND1 A870G) was performed for the case and control cohorts.	('CCND1', 'Gene', (129, 134))	('XRCC1', 'Gene', (62, 67))	('A870G', 'Mutation', 'rs9344', (135, 140))	('GSTM1', 'Gene', (45, 50))	('Arg72Pro', 'Var', (115, 123))	('TP53', 'Gene', '7157', (110, 114))	('deletions', 'Var', (35, 44))	('Arg194Trp', 'Var', (68, 77))	('Arg72Pro', 'SUBSTITUTION', 'None', (115, 123))	('A870G', 'Var', (135, 140))	('Arg399Gln', 'SUBSTITUTION', 'None', (82, 91))	('GSTT1', 'Gene', '2952', (55, 60))	('GSTM1', 'Gene', '2944', (45, 50))	('Thr241Met', 'Var', (99, 108))	('TP53', 'Gene', (110, 114))	('CCND1', 'Gene', '595', (129, 134))	('Arg194Trp', 'SUBSTITUTION', 'None', (68, 77))	('Arg399Gln', 'Var', (82, 91))	('GSTT1', 'Gene', (55, 60))	('Thr241Met', 'SUBSTITUTION', 'None', (99, 108))
499303	23675381	Thus, according to the dominant model the risk of esophageal cancer development was significantly higher for the following combinations of genotypes: GSTM1 (+- and -/-) (OR = 9.75, p < 0.0001); and GSTT1 (+- and -/-) (OR = 3.29, p = 0.02).	('GSTT1', 'Gene', (198, 203))	('GSTT1', 'Gene', '2952', (198, 203))	('+- and -/-', 'Var', (157, 167))	('GSTM1', 'Gene', '2944', (150, 155))	('higher', 'PosReg', (98, 104))	('GSTM1', 'Gene', (150, 155))	('esophageal cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
499306	23675381	The difference of XRCC1 Arg194Trp polymorphism genotypes distribution between control and esophageal case cohorts was not significant.	('esophageal', 'Disease', 'MESH:D004941', (90, 100))	('Arg194Trp', 'Var', (24, 33))	('XRCC1', 'Gene', (18, 23))	('Arg194Trp', 'SUBSTITUTION', 'None', (24, 33))	('esophageal', 'Disease', (90, 100))
499308	23675381	We have noticed a similar relationship following analysis of the XRCC1 polymorphism - Arg399Gln that indicated OR values [OR = 2.54, p = 0.2 (general model of inheritance); OR = 1.39, p = 0.23; dominant model] were not statistically significant.	('Arg399Gln', 'SUBSTITUTION', 'None', (86, 95))	('XRCC1', 'Gene', (65, 70))	('Arg399Gln', 'Var', (86, 95))
499309	23675381	On the contrary, analysis of the homozygote genotype XRCC3 Met241Met (OR = 7.40, p = 0.02) detected a strong linkage to the esophageal cancer progression.	('XRCC3', 'Gene', (53, 58))	('esophageal cancer', 'Disease', (124, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Met241Met', 'Var', (59, 68))
499311	23675381	Comparison of the TP53 Arg72Pro genotypes distribution between control and case cohorts shows the prevalence of Pro/Pro homozygous (13 versus 5%) and Arg/Pro heterozygous (43 versus 38%) among esophageal cancer patients.	('TP53', 'Gene', '7157', (18, 22))	('patients', 'Species', '9606', (211, 219))	('Arg72Pro', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('TP53', 'Gene', (18, 22))	('Pro/Pro', 'Var', (112, 119))	('Arg/Pro heterozygous', 'Var', (150, 170))	('Arg', 'Chemical', 'MESH:D001120', (150, 153))	('esophageal cancer', 'Disease', (193, 210))	('Arg', 'Chemical', 'MESH:D001120', (23, 26))	('Arg72Pro', 'SUBSTITUTION', 'None', (23, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))
499312	23675381	The association of TP53 Pro72Pro genotype with susceptibility to esophageal cancer has been analyzed by the total model of inheritance - OR = 2.85, p = 0.06.	('esophageal cancer', 'Disease', (65, 82))	('Pro72Pro', 'Var', (24, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))
499313	23675381	The presence of Arg in 72 codon of TP53 gene reduced the risk: OR = 1.66, p = 0.06 (dominant model - Pro72Pro in combination with Arg72Pro); for Arg72Pro genotype - OR = 1.21, p = 0.06.	('Arg72Pro', 'Var', (145, 153))	('Arg72Pro', 'SUBSTITUTION', 'None', (130, 138))	('reduced', 'NegReg', (45, 52))	('Arg', 'Chemical', 'MESH:D001120', (145, 148))	('TP53', 'Gene', '7157', (35, 39))	('Arg', 'Chemical', 'MESH:D001120', (16, 19))	('TP53', 'Gene', (35, 39))	('Arg in', 'Var', (16, 22))	('Arg72Pro', 'SUBSTITUTION', 'None', (145, 153))	('Arg72Pro', 'Var', (130, 138))	('Pro72Pro', 'Var', (101, 109))	('Arg', 'Chemical', 'MESH:D001120', (130, 133))
499315	23675381	Substantial prevalence of CCND1 A870A homozygous has been detected in the esophageal cancer case cohort (38 versus 18% in control).	('A870A', 'Var', (32, 37))	('CCND1', 'Gene', (26, 31))	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('CCND1', 'Gene', '595', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
499316	23675381	The CCND1 A870A genotype is statistically reliable to determine its susceptibility to esophageal cancer (OR = 2.82, p = 0.004).	('CCND1', 'Gene', '595', (4, 9))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CCND1', 'Gene', (4, 9))	('A870A', 'Var', (10, 15))
499317	23675381	Combination with CCND1 G870A genotype (dominant model) reduces the risk: OR = 1.64, p = 0.12.	('CCND1', 'Gene', '595', (17, 22))	('reduces', 'NegReg', (55, 62))	('CCND1', 'Gene', (17, 22))	('G870A', 'Mutation', 'rs9344', (23, 28))	('G870A', 'Var', (23, 28))
499323	23675381	DNA samples representing the cervical cancer case and control cohorts were genotyped for detection of different types of gene polymorphisms: deletions GSTM1 and GSTT1, XRCC1 Arg194Trp and Arg399Gln, XRCC3 Thr241Met, TP53 Arg72Pro, and CCND1 A870G.	('GSTM1', 'Gene', (151, 156))	('Arg194Trp', 'Var', (174, 183))	('GSTT1', 'Gene', '2952', (161, 166))	('XRCC3', 'Gene', (199, 204))	('Arg72Pro', 'SUBSTITUTION', 'None', (221, 229))	('GSTT1', 'Gene', (161, 166))	('A870G', 'Var', (241, 246))	('Arg194Trp', 'SUBSTITUTION', 'None', (174, 183))	('GSTM1', 'Gene', '2944', (151, 156))	('TP53', 'Gene', (216, 220))	('Thr241Met', 'Var', (205, 214))	('Arg399Gln', 'SUBSTITUTION', 'None', (188, 197))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cervical cancer', 'Disease', (29, 44))	('cervical cancer', 'Disease', 'MESH:D002583', (29, 44))	('CCND1', 'Gene', '595', (235, 240))	('Thr241Met', 'SUBSTITUTION', 'None', (205, 214))	('Arg399Gln', 'Var', (188, 197))	('Arg72Pro', 'Var', (221, 229))	('A870G', 'Mutation', 'rs9344', (241, 246))	('CCND1', 'Gene', (235, 240))	('XRCC1', 'Gene', (168, 173))	('deletions', 'Var', (141, 150))	('TP53', 'Gene', '7157', (216, 220))
499326	23675381	Deletion of GSTT1 in homozygous state (-/-) shows the significant association with susceptibility to cervical cancer (OR = 3.99, p = 0.0).	('cervical cancer', 'Disease', 'MESH:D002583', (101, 116))	('GSTT1', 'Gene', (12, 17))	('cervical cancer', 'Disease', (101, 116))	('GSTT1', 'Gene', '2952', (12, 17))	('susceptibility', 'Reg', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Deletion', 'Var', (0, 8))
499330	23675381	In accordance with dominant model for the combination of GSTM1 genotypes (+- and -/-) - OR = 2.66, p < 0.0001.	('GSTM1', 'Gene', (57, 62))	('+-', 'Var', (74, 76))	('GSTM1', 'Gene', '2944', (57, 62))
499332	23675381	The XRCC1 194Arg allele variant shows association with susceptibility to cervical cancer in homozygous (Arg194Arg) and heterozygous (Arg194Trp) states.	('cervical cancer', 'Disease', 'MESH:D002583', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Arg', 'Chemical', 'MESH:D001120', (104, 107))	('Arg', 'Chemical', 'MESH:D001120', (110, 113))	('Arg194Arg', 'Var', (104, 113))	('Arg194Trp', 'SUBSTITUTION', 'None', (133, 142))	('Arg', 'Chemical', 'MESH:D001120', (13, 16))	('XRCC1', 'Gene', (4, 9))	('susceptibility', 'Reg', (55, 69))	('Arg', 'Chemical', 'MESH:D001120', (133, 136))	('Arg194Trp', 'Var', (133, 142))	('cervical cancer', 'Disease', (73, 88))
499334	23675381	According to the dominant model for combinations of genotypes (Arg194Arg and Arg194Trp) - OR = 3.64, p = 0.006.	('Arg', 'Chemical', 'MESH:D001120', (63, 66))	('Arg', 'Chemical', 'MESH:D001120', (69, 72))	('Arg194Trp', 'SUBSTITUTION', 'None', (77, 86))	('Arg', 'Chemical', 'MESH:D001120', (77, 80))	('Arg194Trp', 'Var', (77, 86))	('Arg194Arg', 'Var', (63, 72))
499335	23675381	Polymorphism of 399 codon of XRCC1 gene also shows association with susceptibility to cervical cancer.	('association', 'Reg', (51, 62))	('cervical cancer', 'Disease', (86, 101))	('cervical cancer', 'Disease', 'MESH:D002583', (86, 101))	('Polymorphism of 399 codon', 'Var', (0, 25))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('XRCC1', 'Gene', (29, 34))
499337	23675381	The presence of 399Arg allele variant in genotype reduces the risk, but not statistically reliably: OR = 1.25, p = 0.90 (dominant model - Gln399Gln in combination with Arg399Gln).	('Arg399Gln', 'Var', (168, 177))	('Arg399Gln', 'SUBSTITUTION', 'None', (168, 177))	('Arg', 'Chemical', 'MESH:D001120', (19, 22))	('reduces', 'NegReg', (50, 57))	('Arg', 'Chemical', 'MESH:D001120', (168, 171))	('Gln399Gln', 'Chemical', '-', (138, 147))
499338	23675381	The protective effect of XRCC1 Arg399Arg genotype is weakly expressed (OR = 0.80, p = 0.03).	('Arg', 'Chemical', 'MESH:D001120', (31, 34))	('XRCC1', 'Gene', (25, 30))	('Arg', 'Chemical', 'MESH:D001120', (37, 40))	('Arg399Arg', 'Var', (31, 40))
499339	23675381	Another DNA repair gene XRCC3 demonstrates the strong association between Trp241Met polymorphism and susceptibility to cervical cancer.	('Trp241Met', 'Var', (74, 83))	('cervical cancer', 'Disease', 'MESH:D002583', (119, 134))	('cervical cancer', 'Disease', (119, 134))	('XRCC3', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Trp241Met', 'SUBSTITUTION', 'None', (74, 83))
499340	23675381	In combination with heterozygous genotypes (dominant model - Met241Met and Trp241Met versus Trp241Trp) the risk is significantly reduced: OR = 1.89, p = 0.007.	('Trp241Trp', 'Var', (92, 101))	('Trp241Met', 'Var', (75, 84))	('reduced', 'NegReg', (129, 136))	('Trp241Trp', 'Chemical', '-', (92, 101))	('Trp241Met', 'SUBSTITUTION', 'None', (75, 84))
499342	23675381	Analysis of TP53 Arg72Pro polymorphism genotypes distribution in control and cervical cancer case cohorts shows that Arg72Arg genotype can increase risk of cervical cancer development (OR = 1.46, p = 0.08), but not significantly.	('cervical cancer', 'Disease', (156, 171))	('Arg72Arg', 'Chemical', '-', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cervical cancer', 'Disease', (77, 92))	('cervical cancer', 'Disease', 'MESH:D002583', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Arg72Arg', 'Var', (117, 125))	('TP53', 'Gene', '7157', (12, 16))	('increase', 'PosReg', (139, 147))	('Arg72Pro', 'Var', (17, 25))	('TP53', 'Gene', (12, 16))	('Arg72Pro', 'SUBSTITUTION', 'None', (17, 25))	('cervical cancer', 'Disease', 'MESH:D002583', (156, 171))
499344	23675381	TP53 Pro72Pro genotype demonstrates the protective effect (OR = 0.55, p = 0.08).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('Pro72Pro', 'Var', (5, 13))
499345	23675381	The CCND1 G870A polymorphism does not show significant differences in genotype distribution among healthy women and the cervical cancer patients.	('CCND1', 'Gene', '595', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('G870A', 'Mutation', 'rs9344', (10, 15))	('G870A', 'Var', (10, 15))	('women', 'Species', '9606', (106, 111))	('cervical cancer', 'Disease', (120, 135))	('patients', 'Species', '9606', (136, 144))	('cervical cancer', 'Disease', 'MESH:D002583', (120, 135))	('CCND1', 'Gene', (4, 9))
499347	23675381	Series of mutations in key regulatory genes are the main reason of cancer induction.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
499354	23675381	The frequencies of GSTT1 deletions in healthy residents of Almaty city (0.525) are more similar to Asians (0.80-0.540).	('GSTT1', 'Gene', (19, 24))	('deletions', 'Var', (25, 34))	('GSTT1', 'Gene', '2952', (19, 24))
499355	23675381	The GSTM1 deletions are widely distributed among Asian (0.490-0.540) and European (0.420-0.540) peoples with similar rates.	('GSTM1', 'Gene', '2944', (4, 9))	('peoples', 'Species', '9606', (96, 103))	('GSTM1', 'Gene', (4, 9))	('deletions', 'Var', (10, 19))
499356	23675381	But in our study the frequency of GSTT1 deletions was low: 0.281.	('GSTT1', 'Gene', '2952', (34, 39))	('deletions', 'Var', (40, 49))	('GSTT1', 'Gene', (34, 39))
499357	23675381	The low frequencies of GSTT1 deletions have been suggested for African populations (0.160-0.360) (d'Errico et al.,; Ketterer et al.,; Gao et al.,).	('deletions', 'Var', (29, 38))	('GSTT1', 'Gene', (23, 28))	('GSTT1', 'Gene', '2952', (23, 28))
499363	23675381	Deletions of GST-genes are associated with susceptibility to many cancer types.	('GST-genes', 'Gene', (13, 22))	('susceptibility', 'Reg', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('associated', 'Reg', (27, 37))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('Deletions', 'Var', (0, 9))	('cancer', 'Disease', (66, 72))
499364	23675381	The previous study (Tan et al.,; Gao et al.,; Lu et al.,; Liu and Xu,) reported that deletions of GSTT1 and GSTM1 genes play a significant role in development of esophageal or cervical cancers.	('esophageal or cervical cancers', 'Disease', (162, 192))	('GSTM1', 'Gene', '2944', (108, 113))	('GSTM1', 'Gene', (108, 113))	('GSTT1', 'Gene', '2952', (98, 103))	('deletions', 'Var', (85, 94))	('GSTT1', 'Gene', (98, 103))	('role', 'Reg', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('esophageal or cervical cancers', 'Disease', 'MESH:D004938', (162, 192))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))
499366	23675381	Association of GSTT1 and GSTM1 deletions with esophageal and cervical cancer susceptibility is supported by data obtained by studying populations from India, Korea, Turkey, Great Britain, Italy, USA, and other countries (Ketterer et al.,; Gao et al.,; Zhang et al.,).	('GSTM1', 'Gene', (25, 30))	('GSTT1', 'Gene', '2952', (15, 20))	('GSTT1', 'Gene', (15, 20))	('Turkey', 'Species', '9103', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal and cervical cancer', 'Disease', 'MESH:D004938', (46, 76))	('deletions', 'Var', (31, 40))	('GSTM1', 'Gene', '2944', (25, 30))
499370	23675381	The previous studies also point out to the relation of XRCC1 (Arg399Gln, Arg194Trp) and XRCC3 Trp241Met polymorphisms with colorectal cancer, skin cancer, lung cancer (Cui et al.,; Zhang et al.,), and others.	('XRCC3', 'Gene', (88, 93))	('Trp241Met', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colorectal cancer', 'Disease', (123, 140))	('skin cancer', 'Disease', 'MESH:D012878', (142, 153))	('XRCC1', 'Gene', (55, 60))	('Arg399Gln', 'SUBSTITUTION', 'None', (62, 71))	('lung cancer', 'Disease', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('Arg399Gln', 'Var', (62, 71))	('Arg194Trp', 'Var', (73, 82))	('Trp241Met', 'SUBSTITUTION', 'None', (94, 103))	('skin cancer', 'Disease', (142, 153))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('skin cancer', 'Phenotype', 'HP:0008069', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('Arg194Trp', 'SUBSTITUTION', 'None', (73, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))
499371	23675381	There are data confirming the participation of XRCC1-genes polymorphism to cervical cancer (Li et al.,).	('polymorphism', 'Var', (59, 71))	('cervical cancer', 'Disease', 'MESH:D002583', (75, 90))	('cervical cancer', 'Disease', (75, 90))	('participation', 'Reg', (30, 43))	('XRCC1-genes', 'Gene', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
499372	23675381	have made a conclusion, that Arg194Trp polymorphism may be associated with cervical cancer risk, Arg399Gln polymorphism might be a low-penetrant risk factor for cervical cancer only at Asians.	('cervical cancer', 'Disease', 'MESH:D002583', (75, 90))	('Arg194Trp', 'SUBSTITUTION', 'None', (29, 38))	('cervical cancer', 'Disease', (75, 90))	('Arg399Gln', 'Var', (97, 106))	('associated', 'Reg', (59, 69))	('cervical cancer', 'Disease', 'MESH:D002583', (161, 176))	('Arg399Gln', 'SUBSTITUTION', 'None', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cervical cancer', 'Disease', (161, 176))	('Arg194Trp', 'Var', (29, 38))
499373	23675381	The meta-analysis of 16 studies (Li et al.,) found out that there were no obvious associations of XRCC1 Arg399Gln polymorphism with cervical cancer risk.	('cervical cancer', 'Disease', (132, 147))	('cervical cancer', 'Disease', 'MESH:D002583', (132, 147))	('XRCC1', 'Gene', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Arg399Gln', 'Var', (104, 113))	('Arg399Gln', 'SUBSTITUTION', 'None', (104, 113))	('associations', 'Interaction', (82, 94))
499375	23675381	The study of one Chinese population (Yu et al.,) shows the strong association between XRCC1 Gln399Gln genotype and squamous-cell carcinoma of esophagus, and the smoking people have 4.2-fold increased risk in comparison with not smoking persons.	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('squamous-cell carcinoma of esophagus', 'Disease', 'MESH:D002294', (115, 151))	('people', 'Species', '9606', (169, 175))	('Chinese', 'Species', '10029', (17, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('Gln399Gln', 'Chemical', '-', (92, 101))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (129, 151))	('XRCC1', 'Gene', (86, 91))	('Gln399Gln', 'Var', (92, 101))	('squamous-cell carcinoma of esophagus', 'Disease', (115, 151))	('persons', 'Species', '9606', (236, 243))
499376	23675381	We found out that XRCC1 Arg194Trp polymorphism had been associated with esophageal and cervical cancer in Kazakhstan population, but in different manner.	('esophageal and cervical cancer', 'Disease', 'MESH:D004938', (72, 102))	('Arg194Trp', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('associated', 'Reg', (56, 66))	('XRCC1', 'Gene', (18, 23))	('Arg194Trp', 'SUBSTITUTION', 'None', (24, 33))
499377	23675381	XRCC1 Trp194Trp genotype was associated with susceptibility to esophageal cancer, and XRCC1 Arg194Arg genotype - with cervical cancer.	('cervical cancer', 'Disease', (118, 133))	('Trp194Trp', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('XRCC1', 'Gene', (0, 5))	('Arg', 'Chemical', 'MESH:D001120', (92, 95))	('XRCC1', 'Gene', (86, 91))	('Arg', 'Chemical', 'MESH:D001120', (98, 101))	('Trp194Trp', 'Mutation', 'p.W194W', (6, 15))	('cervical cancer', 'Disease', 'MESH:D002583', (118, 133))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
499378	23675381	Interestingly, the data of meta-analysis revealed the protective effect of the XRCC1 194Trp allele for tobacco-related types of cancer, which was compatible with the evidence of lower mutagen sensitivity for this allele (Rayjean et al.,).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('194Trp', 'Var', (85, 91))	('XRCC1', 'Gene', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tobacco', 'Species', '4097', (103, 110))	('cancer', 'Disease', (128, 134))
499380	23675381	Our research revealed the strong protective effect of XRCC1 194Trp allele in cervical cancer patients.	('XRCC1', 'Gene', (54, 59))	('194Trp allele', 'Var', (60, 73))	('cervical cancer', 'Disease', (77, 92))	('cervical cancer', 'Disease', 'MESH:D002583', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('patients', 'Species', '9606', (93, 101))
499381	23675381	Regarding the XRCC1 Arg399Gln polymorphism our results show the evidence of associations between XRCC1 Gln399Gln genotype carriers and increased risk of cervical and esophageal cancer development, which is confirmed by other studies (Yu et al.,).	('Arg399Gln', 'Var', (20, 29))	('Arg399Gln', 'SUBSTITUTION', 'None', (20, 29))	('esophageal cancer', 'Disease', (166, 183))	('Gln399Gln', 'Var', (103, 112))	('associations', 'Interaction', (76, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('Gln399Gln', 'Chemical', '-', (103, 112))	('XRCC1', 'Gene', (97, 102))	('cervical', 'Disease', (153, 161))
499382	23675381	Published data on the relationship of XRCC3 Trp241Met polymorphism with cancer risk are inconsistent (Au et al.,; Konstantinos and Theodoros,; Settheetham-Ishida et al.,).	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Trp241Met', 'Var', (44, 53))	('polymorphism', 'Var', (54, 66))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Trp241Met', 'SUBSTITUTION', 'None', (44, 53))	('cancer', 'Disease', (72, 78))
499383	23675381	But XRCC3 241Met allele did not increase the risk of cervical cancer development in the Chinese population (He et al.,) and among Thai women (Settheetham-Ishida et al.,).	('cervical cancer', 'Disease', (53, 68))	('increase the risk of cervical cancer', 'Phenotype', 'HP:0030159', (32, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Chinese', 'Species', '10029', (88, 95))	('XRCC3', 'Gene', (4, 9))	('241Met', 'Var', (10, 16))	('cervical cancer', 'Disease', 'MESH:D002583', (53, 68))	('women', 'Species', '9606', (135, 140))
499384	23675381	Our data demonstrate the strong association between XRCC3 Met241Met genotype and expressed risk of susceptibility to both cervical and esophageal cancer in Kazakhstan populations.	('Met241Met', 'Var', (58, 67))	('susceptibility', 'Reg', (99, 113))	('cervical', 'Disease', (122, 130))	('esophageal cancer', 'Disease', (135, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('XRCC3', 'Gene', (52, 57))
499385	23675381	Mutations and polymorphisms of cell cycle regulating genes (CCND1 and TP53) can play the main role in many types of cancer.	('role', 'Reg', (94, 98))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('TP53', 'Gene', '7157', (70, 74))	('CCND1', 'Gene', (60, 65))	('Mutations', 'Var', (0, 9))	('polymorphisms', 'Var', (14, 27))	('TP53', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CCND1', 'Gene', '595', (60, 65))	('play', 'Reg', (80, 84))
499388	23675381	One meta-analysis (Chen et al.,) exhibited the statistically significant association between CCND1 G870A polymorphism and a risk for cancers of the digestive tract, including esophageal cancer (Zhang et al.,; Cescon et al.,).	('esophageal cancer', 'Disease', (175, 192))	('G870A', 'Mutation', 'rs9344', (99, 104))	('significant association', 'Reg', (61, 84))	('CCND1', 'Gene', '595', (93, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('cancers of the digestive tract', 'Phenotype', 'HP:0007378', (133, 163))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('G870A polymorphism', 'Var', (99, 117))	('polymorphism', 'Var', (105, 117))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('CCND1', 'Gene', (93, 98))
499391	23675381	In our study we have shown that CCND1 A870A genotype associates with susceptibility to esophageal cancer, but not to cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('esophageal cancer', 'Disease', (87, 104))	('CCND1', 'Gene', (32, 37))	('cervical cancer', 'Disease', 'MESH:D002583', (117, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('CCND1', 'Gene', '595', (32, 37))	('cervical cancer', 'Disease', (117, 132))	('A870A', 'Var', (38, 43))
499392	23675381	Polymorphism of TP53 Arg72Pro can play dual role in cancer development (Francisco et al.,).	('Arg72Pro', 'SUBSTITUTION', 'None', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Arg72Pro', 'Var', (21, 29))	('TP53', 'Gene', '7157', (16, 20))	('play', 'Reg', (34, 38))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('TP53', 'Gene', (16, 20))
499393	23675381	On the one side, protein product of 72Arg allele more effectively induces apoptosis (Dumont et al.,).	('apoptosis', 'CPA', (74, 83))	('induces', 'Reg', (66, 73))	('72Arg allele', 'Var', (36, 48))	('Arg', 'Chemical', 'MESH:D001120', (38, 41))
499395	23675381	And 72Arg allele faster degradates E6 than 72 Pro (Storey et al.,; Tada et al.,).	('degradates', 'MPA', (24, 34))	('72Arg', 'Var', (4, 9))	('Arg', 'Chemical', 'MESH:D001120', (6, 9))
499396	23675381	Thus, women from Taiwan, Thailand, Korea, Japan, China, and Hong-Kong show no association between TP53 72Arg/Pro polymorphism and HPV-associated and HPV-non-associated cervical cancer (Nishikawa et al.,; Settheetham-Ishida et al.,; Wu et al., and others).	('72Arg/Pro', 'Var', (103, 112))	('72Arg/Pro', 'SUBSTITUTION', 'None', (103, 112))	('cervical cancer', 'Disease', 'MESH:D002583', (168, 183))	('women', 'Species', '9606', (6, 11))	('HPV-associated', 'Disease', (130, 144))	('cervical cancer', 'Disease', (168, 183))	('TP53', 'Gene', '7157', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('polymorphism', 'Var', (113, 125))	('TP53', 'Gene', (98, 102))
499399	23675381	And also there are evidences of influence of TP53 Arg72Pro on development of esophageal cancer (Cescon et al.,; Ma et al.,).	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('TP53', 'Gene', (45, 49))	('influence', 'Reg', (32, 41))	('Arg72Pro', 'Var', (50, 58))	('Arg72Pro', 'SUBSTITUTION', 'None', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('TP53', 'Gene', '7157', (45, 49))
499400	23675381	We find out that TP53 72Pro allele associates with susceptibility to cervical cancer and 72Arg allele shows strong association with esophageal cancer development.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal cancer', 'Disease', (132, 149))	('72Arg allele', 'Var', (89, 101))	('Arg', 'Chemical', 'MESH:D001120', (91, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('cervical cancer', 'Disease', 'MESH:D002583', (69, 84))	('TP53', 'Gene', '7157', (17, 21))	('cervical cancer', 'Disease', (69, 84))	('TP53', 'Gene', (17, 21))
499401	23675381	A large number of molecular epidemiologic studies have been performed to evaluate the role of polymorphisms of GST-, XRCC-, TP53, and CCND1 genes in various neoplasms.	('TP53', 'Gene', '7157', (124, 128))	('XRCC-', 'Gene', (117, 122))	('GST-', 'Gene', (111, 115))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('TP53', 'Gene', (124, 128))	('CCND1', 'Gene', (134, 139))	('neoplasms', 'Disease', (157, 166))	('neoplasms', 'Disease', 'MESH:D009369', (157, 166))	('polymorphisms', 'Var', (94, 107))	('CCND1', 'Gene', '595', (134, 139))
499402	23675381	Studies investigating the combined effect of GST-deletions, XRCC1 (Arg194Trp and Arg399Gln), XRCC3 (Thr241Met), TP53 (Arg72Pro), and CCND1 (A870G) will be very important for further evaluate the role of these polymorphism in different cancers.	('A870G', 'Var', (140, 145))	('Arg72Pro', 'SUBSTITUTION', 'None', (118, 126))	('TP53', 'Gene', '7157', (112, 116))	('Arg399Gln', 'Var', (81, 90))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('CCND1', 'Gene', '595', (133, 138))	('Arg194Trp', 'Var', (67, 76))	('A870G', 'Mutation', 'rs9344', (140, 145))	('XRCC1', 'Gene', (60, 65))	('CCND1', 'Gene', (133, 138))	('Thr241Met', 'Var', (100, 109))	('Arg72Pro', 'Var', (118, 126))	('TP53', 'Gene', (112, 116))	('Thr241Met', 'SUBSTITUTION', 'None', (100, 109))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('Arg194Trp', 'SUBSTITUTION', 'None', (67, 76))	('cancers', 'Disease', (235, 242))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('Arg399Gln', 'SUBSTITUTION', 'None', (81, 90))
499404	23675381	Esophageal cancer - deletions of GSTT1 (OR = 3.29) and GSTM1 (OR = 5.30) genes; XRCC3 Met241Met (OR = 7.40); TP53 Pro72Pro (OR = 2.85), CCND1 A870A (OR = 2.82).	('GSTT1', 'Gene', (33, 38))	('A870A', 'Var', (142, 147))	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('GSTT1', 'Gene', '2952', (33, 38))	('GSTM1', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Met241Met', 'Var', (86, 95))	('TP53', 'Gene', '7157', (109, 113))	('Pro72Pro', 'Var', (114, 122))	('CCND1', 'Gene', (136, 141))	('Esophageal cancer', 'Disease', (0, 17))	('TP53', 'Gene', (109, 113))	('GSTM1', 'Gene', '2944', (55, 60))	('CCND1', 'Gene', '595', (136, 141))	('XRCC3', 'Gene', (80, 85))
499405	23675381	Cervical cancer - deletions of GSTT1 (OR = 3.99) and GSTM1 (OR = 6.50) genes; XRCC1 Arg194Arg (OR = 1.58); XRCC1 Gln399Gln (OR = 3.83), XRCC3 Met241Met (OR = 2.84), and TP53 Arg72Arg (OR = 3.96).	('cancer', 'Disease', (9, 15))	('Met241Met', 'Var', (142, 151))	('XRCC1', 'Gene', (78, 83))	('Arg', 'Chemical', 'MESH:D001120', (90, 93))	('XRCC3', 'Gene', (136, 141))	('GSTM1', 'Gene', (53, 58))	('TP53', 'Gene', '7157', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Arg194Arg', 'Var', (84, 93))	('XRCC1', 'Gene', (107, 112))	('Arg72Arg', 'Chemical', '-', (174, 182))	('Arg', 'Chemical', 'MESH:D001120', (174, 177))	('GSTT1', 'Gene', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('GSTM1', 'Gene', '2944', (53, 58))	('Gln399Gln', 'Chemical', '-', (113, 122))	('TP53', 'Gene', (169, 173))	('GSTT1', 'Gene', '2952', (31, 36))	('Gln399Gln', 'Var', (113, 122))	('Arg', 'Chemical', 'MESH:D001120', (84, 87))	('Arg', 'Chemical', 'MESH:D001120', (179, 182))
499421	33927753	In addition, the pathology of several thoracic malignancies, including lung cancer, esophageal cancer, and breast cancer, is found to exhibit dysregulated lncRNA expression in a variety of malignancies.	('thoracic malignancies', 'Disease', (38, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('cancer', 'Disease', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('thoracic malignancies', 'Disease', 'MESH:D013896', (38, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('malignancies', 'Disease', 'MESH:D009369', (47, 59))	('malignancies', 'Disease', (47, 59))	('malignancies', 'Disease', 'MESH:D009369', (189, 201))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('breast cancer', 'Disease', (107, 120))	('malignancies', 'Disease', (189, 201))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('dysregulated', 'Var', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('lncRNA expression', 'MPA', (155, 172))	('lung cancer', 'Disease', (71, 82))	('cancer', 'Disease', (114, 120))
499445	33927753	When considering the interaction between lncRNAs and clinical features, only five lncRNAs (RP11_71E19.5, RP11_722E23.2, RP11_796E2.4, RP11_95O2.1, and AC004528.4) were significantly associated with patient survival (Figure 1C).	('RP11', 'Gene', '26121', (134, 138))	('patient', 'Species', '9606', (198, 205))	('AC004528.4', 'Var', (151, 161))	('associated with', 'Reg', (182, 197))	('RP11', 'Gene', (105, 109))	('RP11', 'Gene', (91, 95))	('RP11', 'Gene', (134, 138))	('RP11', 'Gene', (120, 124))	('RP11', 'Gene', '26121', (105, 109))	('RP11', 'Gene', '26121', (120, 124))	('patient survival', 'CPA', (198, 214))	('RP11', 'Gene', '26121', (91, 95))
499460	33927753	We found many biological pathways (BPs) influenced by mRNAs that correlate with biomarker lncRNA.	('mRNAs', 'Var', (54, 59))	('biological pathways', 'Pathway', (14, 33))	('influenced', 'Reg', (40, 50))	('BPs', 'Chemical', '-', (35, 38))
499462	33927753	Variation in lncRNA RP11-796E2.4 and RP11-95O2.1 expression mainly affects immune regulation, which is essential for the recognition and elimination of gastric tumor cells (Figures 5C,D).	('RP11', 'Gene', '26121', (20, 24))	('lncRNA', 'Gene', (13, 19))	('affects', 'Reg', (67, 74))	('gastric tumor', 'Disease', 'MESH:D013274', (152, 165))	('gastric tumor', 'Phenotype', 'HP:0006753', (152, 165))	('RP11', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('RP11', 'Gene', '26121', (37, 41))	('Variation', 'Var', (0, 9))	('immune regulation', 'MPA', (75, 92))	('gastric tumor', 'Disease', (152, 165))	('RP11', 'Gene', (20, 24))
499463	33927753	AC004528.4 was mainly involved in the epithelial-mesenchymal transition, which regulates the invasion and metastasis of cancer cells (; Figure 5E).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('involved', 'Reg', (22, 30))	('AC004528.4', 'Var', (0, 10))	('epithelial-mesenchymal transition', 'CPA', (38, 71))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('invasion', 'CPA', (93, 101))
499548	33374641	To further analyze the possible promotion of p65 on gene expression, we selected ChIP-seq analyses of p65 in multiple cancer cells and samples (A549, HeLa, Huh7, LNCaP, MCF-7, and LoVo cells, and GM12892, GM15510, GM18505, GM18526, GM19099, and GM19193 datasets) that met all the quality criteria from the Cistrome database and visualized sample batches with the University of California Santa Cruz (UCSC) Genome Browser assembled for the human genome, GRCh38/hg38.	('human', 'Species', '9606', (439, 444))	('LoVo', 'CellLine', 'CVCL:0399', (180, 184))	('p65', 'Gene', '5970', (102, 105))	('p65', 'Gene', '5970', (45, 48))	('A549', 'CellLine', 'CVCL:0023', (144, 148))	('LNCaP', 'CellLine', 'CVCL:0395', (162, 167))	('hg38', 'Gene', (460, 464))	('hg38', 'Gene', '8549', (460, 464))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('HeLa', 'CellLine', 'CVCL:0030', (150, 154))	('Huh7', 'CellLine', 'CVCL:0336', (156, 160))	('California Santa Cruz', 'Disease', 'MESH:D004670', (377, 398))	('GM12892', 'Var', (196, 203))	('California Santa Cruz', 'Disease', (377, 398))	('p65', 'Gene', (102, 105))	('GM15510', 'Var', (205, 212))	('p65', 'Gene', (45, 48))	('MCF-7', 'CellLine', 'CVCL:0031', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
499550	33374641	As H3K4me1 and H3K4me3 mark enhancers and promoters, respectively, and H3K27ac is associated with the active state of both elements, histone ChIP-seq data of 6 common cell lines (H1-hESC, HSMM, HUVEC, K562, NHEK, and NHLF cells) and esophagus muscularis mucosa samples from the Encyclopedia of DNA Elements (ENCODE) database were also aligned to the GRCh38/hg38 reference assembly to confirm the characteristics of p65-binding sites.	('p65', 'Gene', '5970', (415, 418))	('H3K4me3', 'Var', (15, 22))	('K562', 'CellLine', 'CVCL:0004', (201, 205))	('p65', 'Gene', (415, 418))	('H3K27ac', 'Var', (71, 78))	('hg38', 'Gene', (357, 361))	('hg38', 'Gene', '8549', (357, 361))	('H3K4me1', 'Var', (3, 10))	('H1', 'CellLine', 'CVCL:Z499', (179, 181))
499556	33374641	After verifying that SFE could increase the content of p65 bound to IkappaBalpha and inhibit p65 from entering the nuclear to inactivate the NFkappaB pathway (Figure 4D, Supplementary Figure S7B), we further identified the inhibitory effect of SFE on p65 binding to TNFAIP3 and PLAU, which can be reversed by LPS treatment, analyzed by ChIP-PCR and luciferase reporter assays (Figure 4E, Supplementary Figure S8A).	('NFkappaB', 'Gene', '4790', (141, 149))	('LPS', 'Disease', 'MESH:C536528', (309, 312))	('p65', 'Gene', '5970', (251, 254))	('NFkappaB', 'Gene', (141, 149))	('content', 'MPA', (44, 51))	('p65', 'Gene', '5970', (93, 96))	('inhibit', 'NegReg', (85, 92))	('IkappaBalpha', 'Gene', (68, 80))	('SFE', 'Var', (21, 24))	('binding', 'Interaction', (255, 262))	('IkappaBalpha', 'Gene', '4792', (68, 80))	('PLAU', 'Gene', '5328', (278, 282))	('p65', 'Gene', (55, 58))	('LPS', 'Disease', (309, 312))	('TNFAIP3', 'Gene', '7128', (266, 273))	('SFE', 'Chemical', 'MESH:C473643', (21, 24))	('p65', 'Gene', (251, 254))	('PLAU', 'Gene', (278, 282))	('TNFAIP3', 'Gene', (266, 273))	('inactivate', 'NegReg', (126, 136))	('SFE', 'Chemical', 'MESH:C473643', (244, 247))	('p65', 'Gene', '5970', (55, 58))	('p65', 'Gene', (93, 96))	('increase', 'PosReg', (31, 39))
499577	33374641	After confirming that SFE inactivated the NFkappaB pathway and decreased the content of p65 in the nuclear, we can conclude that SFE prevents p65 from functioning as a regulator of gene expression and resulting in the down-regulation of TNFAIP3 and PLAU.	('SFE', 'Chemical', 'MESH:C473643', (129, 132))	('p65', 'Gene', (88, 91))	('p65', 'Gene', '5970', (142, 145))	('p65', 'Gene', (142, 145))	('prevents', 'NegReg', (133, 141))	('decreased', 'NegReg', (63, 72))	('down-regulation', 'NegReg', (218, 233))	('TNFAIP3', 'Gene', '7128', (237, 244))	('p65', 'Gene', '5970', (88, 91))	('NFkappaB', 'Gene', (42, 50))	('inactivated', 'NegReg', (26, 37))	('SFE', 'Var', (129, 132))	('PLAU', 'Gene', (249, 253))	('TNFAIP3', 'Gene', (237, 244))	('PLAU', 'Gene', '5328', (249, 253))	('NFkappaB', 'Gene', '4790', (42, 50))	('SFE', 'Chemical', 'MESH:C473643', (22, 25))
499578	33374641	The dose-dependent inhibition of SFE on ESCC cell proliferation, invasion and migration had been confirmed previously, and data shown in Figure 5 could also indicate that SFE induced G2/M cell cycle arrest, cell apoptosis, and decreased the metastasis of ESCC cells.	('cell apoptosis', 'CPA', (207, 221))	('arrest', 'Disease', (199, 205))	('SFE', 'Chemical', 'MESH:C473643', (171, 174))	('decreased', 'NegReg', (227, 236))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (188, 205))	('migration', 'CPA', (78, 87))	('metastasis of ESCC cells', 'CPA', (241, 265))	('invasion', 'CPA', (65, 73))	('arrest', 'Disease', 'MESH:D006323', (199, 205))	('SFE', 'Chemical', 'MESH:C473643', (33, 36))	('SFE', 'Var', (171, 174))
499588	33374641	LPS (HY-D1056) and PDTC (HY-18738) was obtained from MedChem Express (Monmouth Junction, New Jersey, USA).	('PDTC', 'Chemical', 'MESH:C020972', (19, 23))	('HY-18738', 'Var', (25, 33))	('LPS', 'Disease', 'MESH:C536528', (0, 3))	('HY-D1056', 'CellLine', 'CVCL:D344', (5, 13))	('LPS', 'Disease', (0, 3))
499613	33374641	ChIP-seq data of p65 with multiple biological sources is displayed in Cistrome Data Browser , and samples passed all the quality controls (A549, Hela, Huh7, LNCaP, MCF-7, LoVo, GM12892, GM15510, GM18505, GM18526, GM19099, GM19193) were aligned to the GRCh38/hg38 reference assembly using UCSC Browser.	('GM19193', 'Var', (222, 229))	('MCF-7', 'CellLine', 'CVCL:0031', (164, 169))	('GM18505', 'Var', (195, 202))	('hg38', 'Gene', (258, 262))	('Huh7', 'CellLine', 'CVCL:0336', (151, 155))	('GM18526', 'Var', (204, 211))	('hg38', 'Gene', '8549', (258, 262))	('Hela', 'CellLine', 'CVCL:0030', (145, 149))	('GM12892', 'Var', (177, 184))	('p65', 'Gene', (17, 20))	('LNCaP', 'CellLine', 'CVCL:0395', (157, 162))	('GM15510', 'Var', (186, 193))	('A549', 'CellLine', 'CVCL:0023', (139, 143))	('LoVo', 'CellLine', 'CVCL:0399', (171, 175))	('p65', 'Gene', '5970', (17, 20))	('GM19099', 'Var', (213, 220))
499618	33374641	Figure S4: Correlation between the expression of CXCL10, TNFAIP3, INHBA, PLAU, and the pathologic stage, pathology T stage of ESCC patients, Figure S5: GO analyses of CXCL10, TNFAIP3, INHBA, and PLAU, Figure S6: NFkappaB p65 regulates the transcription of CXCL10, TNFAIP3, INHBA, and PLAU, Figure S7: SFE inactivates the NFkappaB pathway to reduce TNFAIP3 and PLAU expression, Figure S8: SFE can inhibit NFkappaB from promoting the transcription of TNFAIP3 and PLAU.	('NFkappaB', 'Gene', (404, 412))	('INHBA', 'Gene', (184, 189))	('NFkappaB', 'Gene', (212, 220))	('NFkappaB', 'Gene', '4790', (321, 329))	('PLAU', 'Gene', '5328', (195, 199))	('p65', 'Gene', '5970', (221, 224))	('Figure S8', 'Var', (377, 386))	('SFE', 'Var', (388, 391))	('promoting', 'PosReg', (418, 427))	('NFkappaB', 'Gene', (321, 329))	('CXCL10', 'Gene', '3627', (256, 262))	('CXCL10', 'Gene', '3627', (167, 173))	('PLAU', 'Gene', (195, 199))	('inhibit', 'NegReg', (396, 403))	('TNFAIP3', 'Gene', (264, 271))	('TNFAIP3', 'Gene', '7128', (264, 271))	('PLAU', 'Gene', '5328', (360, 364))	('TNFAIP3', 'Gene', '7128', (57, 64))	('PLAU', 'Gene', '5328', (73, 77))	('expression', 'MPA', (365, 375))	('TNFAIP3', 'Gene', '7128', (175, 182))	('TNFAIP3', 'Gene', (57, 64))	('SFE', 'Chemical', 'MESH:C473643', (301, 304))	('CXCL10', 'Gene', '3627', (49, 55))	('INHBA', 'Gene', '3624', (273, 278))	('TNFAIP3', 'Gene', (175, 182))	('SFE', 'Chemical', 'MESH:C473643', (388, 391))	('TNFAIP3', 'Gene', '7128', (348, 355))	('patients', 'Species', '9606', (131, 139))	('PLAU', 'Gene', (360, 364))	('CXCL10', 'Gene', (256, 262))	('CXCL10', 'Gene', (167, 173))	('PLAU', 'Gene', (73, 77))	('TNFAIP3', 'Gene', (348, 355))	('INHBA', 'Gene', '3624', (66, 71))	('PLAU', 'Gene', '5328', (461, 465))	('INHBA', 'Gene', '3624', (184, 189))	('CXCL10', 'Gene', (49, 55))	('p65', 'Gene', (221, 224))	('PLAU', 'Gene', '5328', (284, 288))	('NFkappaB', 'Gene', '4790', (404, 412))	('TNFAIP3', 'Gene', '7128', (449, 456))	('transcription', 'MPA', (432, 445))	('NFkappaB', 'Gene', '4790', (212, 220))	('INHBA', 'Gene', (273, 278))	('PLAU', 'Gene', (461, 465))	('reduce', 'NegReg', (341, 347))	('TNFAIP3', 'Gene', (449, 456))	('INHBA', 'Gene', (66, 71))	('PLAU', 'Gene', (284, 288))
499631	33262198	Liquid biopsy has been used to detect EGFR DNA mutations that predict sensitivity or resistance to different tyrosine kinase inhibitors.	('EGFR', 'Gene', '1956', (38, 42))	('resistance to different tyrosine kinase inhibitors', 'MPA', (85, 135))	('EGFR', 'Gene', (38, 42))	('mutations', 'Var', (47, 56))	('sensitivity', 'MPA', (70, 81))	('predict', 'Reg', (62, 69))
499632	33262198	Detection of stage I-II lung cancer has been reported by detecting mutations in peripheral blood ctDNA.	('ctDNA', 'Gene', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mutations', 'Var', (67, 76))	('lung cancer', 'Disease', (24, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))
499641	33262198	In 2014 the FDA approved the Cologuard  (FIT-DNA) stool test that measures aberrantly methylated BMP3 and NDRG4 DNA, mutant K-RAS DNA, beta actin and hemoglobin by FIT.	('NDRG4', 'Gene', (106, 111))	('mutant', 'Var', (117, 123))	('K-RAS DNA, beta actin', 'Gene', '728378', (124, 145))	('aberrantly', 'Var', (75, 85))	('NDRG4', 'Gene', '65009', (106, 111))	('FIT', 'Chemical', '-', (164, 167))	('BMP3', 'Gene', '651', (97, 101))	('FIT', 'Chemical', '-', (41, 44))	('BMP3', 'Gene', (97, 101))
499645	33262198	A single blood test has been approved by the FDA for early detection of colorectal carcinoma (Epi proColon ) that detects methylated SEPT9 DNA in plasma.	('methylated', 'Var', (122, 132))	('colorectal carcinoma', 'Disease', (72, 92))	('SEPT9', 'Gene', '10801', (133, 138))	('detects', 'Reg', (114, 121))	('SEPT9', 'Gene', (133, 138))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
499654	33262198	The Prostate Health Index (PHI) includes total PSA, free PSA and [-2]pro PSA.	('[-2]', 'Var', (65, 69))	('Prostate Health Index', 'Disease', (4, 25))	('PSA', 'Gene', '354', (73, 76))	('PSA', 'Gene', (73, 76))	('PSA', 'Gene', '354', (57, 60))	('PSA', 'Gene', (57, 60))	('PSA', 'Gene', '354', (47, 50))	('PSA', 'Gene', (47, 50))
499670	33262198	EDRN investigators identified a two-marker panel of methylated VIM and methylated CCNA1 DNA that detected 95% of Barret's esophagus, dysplasia and esophageal adenocarcinoma with 91% specificity in brushings obtained at endoscopy.	('CCNA1', 'Gene', '8900', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('dysplasia', 'Disease', 'MESH:C536170', (133, 142))	('adenocarcinoma', 'Disease', (158, 172))	('methylated', 'Var', (52, 62))	('methylated', 'Var', (71, 81))	("Barret's esophagus", 'Disease', (113, 131))	('dysplasia', 'Disease', (133, 142))	('adenocarcinoma', 'Disease', 'MESH:D000230', (158, 172))	('VIM', 'Gene', '7431', (63, 66))	('CCNA1', 'Gene', (82, 87))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (147, 172))	("Barret's esophagus", 'Phenotype', 'HP:0100580', (113, 131))	('VIM', 'Gene', (63, 66))
499671	33262198	Detection of methylated VIM and methylated CCNA1 DNA in cells sampled with the balloon device detected non-dysplastic Barret's esophagus with a sensitivity of 90% and specificity of 92%.	('CCNA1', 'Gene', '8900', (43, 48))	('methylated', 'Var', (13, 23))	('CCNA1', 'Gene', (43, 48))	('dysplastic', 'Disease', (107, 117))	("Barret's esophagus", 'Phenotype', 'HP:0100580', (118, 136))	('dysplastic', 'Disease', 'MESH:D004416', (107, 117))	('VIM', 'Gene', '7431', (24, 27))	('methylated', 'Var', (32, 42))	('VIM', 'Gene', (24, 27))
499701	33262198	Five EDRN investigators have helped to develop CancerSEEK that has attempted to detect eight types of cancer in stage I-III by assaying 61 mutations/amplicons in 16 genes and 8 protein biomarkers.	('Cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations/amplicons', 'Var', (139, 158))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
499705	33262198	In the DETECT-A study of 10,006 women not previously known to have cancer, DNA mutations and protein biomarkers detected 26 cancers and 15 were confirmed and localized by PET-CT.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (124, 130))	('women', 'Species', '9606', (32, 37))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('mutations', 'Var', (79, 88))
499720	32906798	FANCD2 Confers a Malignant Phenotype in Esophageal Squamous Cell Carcinoma by Regulating Cell Cycle Progression Fanconi anemia patients with germline FANCD2 defects are susceptible to cancers.	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Esophageal Squamous Cell Carcinoma', 'Disease', (40, 74))	('susceptible', 'Reg', (169, 180))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancers', 'Disease', (184, 191))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (112, 126))	('FA', 'Phenotype', 'HP:0001994', (150, 152))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('Carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('defects', 'Var', (157, 164))	('FANCD2', 'Gene', (150, 156))	('FANCD2', 'Gene', (0, 6))	('Cell Cycle Progression', 'MPA', (89, 111))	('Regulating', 'Reg', (78, 88))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('Fanconi anemia', 'Disease', (112, 126))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (40, 74))	('FANCD2', 'Gene', '211651', (150, 156))	('patients', 'Species', '9606', (127, 135))	('Fanconi anemia', 'Disease', 'MESH:D005199', (112, 126))	('FANCD2', 'Gene', '211651', (0, 6))	('anemia', 'Phenotype', 'HP:0001903', (120, 126))
499737	32906798	FANCD2 deficiency in mice confers cancer susceptibility for acute myeloid leukemia and squamous cell carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('FANCD2', 'Gene', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (60, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('mice', 'Species', '10090', (21, 25))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('acute myeloid leukemia', 'Disease', (60, 82))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('squamous cell carcinomas', 'Disease', (87, 111))	('deficiency', 'Var', (7, 17))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (87, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('cancer', 'Disease', (34, 40))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (60, 82))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (66, 82))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (87, 111))	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))
499738	32906798	Published targeted next-generation sequencing (NGS) analyses show that germline FANCD2 variants are associated with breast cancer and head and neck squamous cell carcinoma (HNSCC) susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('FANCD2', 'Gene', (80, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (134, 171))	('HNSCC', 'Disease', (173, 178))	('variants', 'Var', (87, 95))	('associated', 'Reg', (100, 110))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('FA', 'Phenotype', 'HP:0001994', (80, 82))	('HNSCC', 'Disease', 'MESH:D000077195', (173, 178))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (134, 171))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
499739	32906798	These results suggest that germline FANCD2 mutations increase cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('increase', 'PosReg', (53, 61))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('FANCD2', 'Gene', (36, 42))	('FA', 'Phenotype', 'HP:0001994', (36, 38))
499741	32906798	Overexpression of FANCD2 is positively associated with tumor size and poor prognosis in breast cancer, ovarian cancer, nasopharyngeal carcinoma, glioblastoma, and endometrial carcinoma.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('associated', 'Reg', (39, 49))	('endometrial carcinoma', 'Disease', (163, 184))	('Overexpression', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinoma', 'Disease', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('FA', 'Phenotype', 'HP:0001994', (18, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (163, 184))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))	('carcinoma', 'Disease', (134, 143))	('carcinoma', 'Disease', 'MESH:D009369', (175, 184))	('FANCD2', 'Gene', (18, 24))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (163, 184))	('glioblastoma', 'Disease', (145, 157))	('ovarian cancer', 'Disease', (103, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (119, 143))	('carcinoma', 'Disease', 'MESH:D009369', (134, 143))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('tumor', 'Disease', (55, 60))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))
499746	32906798	Three sets of public RNA sequencing (RNA-seq) data (SRP007169, SRP008496, SRP064894) were downloaded from the SRA database.	('SRA', 'Gene', '24068', (110, 113))	('SRP007169', 'Var', (52, 61))	('SRP008496', 'Var', (63, 72))	('SRP064894', 'Var', (74, 83))	('SRA', 'Gene', (110, 113))
499748	32906798	KYSE30TSI was derived from a subcutaneous tumor established with KYSE30.	('tumor', 'Disease', (42, 47))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (29, 47))	('KYSE30', 'Var', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
499773	32906798	Consistently, FANCD2 protein expression was upregulated (>3-fold) in three ESCC cell lines (KYSE30TSI, KYSE150 and KYSE450) compared with the non-tumorigenic immortalized esophageal epithelial cell line NE1, as shown by Western blotting (Figure 1b and Figure S1).	('NE1', 'CellLine', 'CVCL:E306', (203, 206))	('KYSE150', 'Var', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('upregulated', 'PosReg', (44, 55))	('FANCD2', 'Gene', (14, 20))	('tumor', 'Disease', (146, 151))	('FA', 'Phenotype', 'HP:0001994', (14, 16))	('KYSE30TSI', 'Var', (92, 101))	('KYSE450', 'Var', (115, 122))	('expression', 'MPA', (29, 39))	('protein', 'Protein', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
499775	32906798	Significant suppression of tumor growth was observed in FANCD2-KO cells, as compared to control cells in all three cell lines tested (Figure 2a).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('FANCD2-KO', 'Var', (56, 65))	('tumor', 'Disease', (27, 32))	('FA', 'Phenotype', 'HP:0001994', (56, 58))	('suppression', 'NegReg', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
499777	32906798	Mice bearing FANCD2-KO cells showed significantly better survival than the mice bearing control cells (Figure 2d; Log Rank p = 0.007).	('mice', 'Species', '10090', (75, 79))	('FA', 'Phenotype', 'HP:0001994', (13, 15))	('FANCD2-KO cells', 'Var', (13, 28))	('Mice', 'Species', '10090', (0, 4))	('better', 'PosReg', (50, 56))	('survival', 'CPA', (57, 65))
499791	32906798	Biallelic germline mutations in FANCD2 increase cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('increase', 'PosReg', (39, 47))	('FANCD2', 'Gene', (32, 38))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('FA', 'Phenotype', 'HP:0001994', (32, 34))	('Biallelic germline mutations', 'Var', (0, 28))
499796	32906798	We showed by cell cycle analysis that the tumor-suppressive effect of FANCD2-KO in ESCC was mediated by suppression of cell proliferation through suppression of cell cycle progression.	('suppression', 'NegReg', (104, 115))	('cell proliferation', 'CPA', (119, 137))	('tumor', 'Disease', (42, 47))	('FANCD2-KO', 'Var', (70, 79))	('suppression', 'NegReg', (146, 157))	('FA', 'Phenotype', 'HP:0001994', (70, 72))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('ESCC', 'Disease', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('cell cycle progression', 'CPA', (161, 183))
499798	32906798	The intra-S phase ATR-Chk1 checkpoint promotes FANCD2 mono-ubiquitination and subnuclear foci assemble in response to DNA damage, whereas FANCD2 deficiency leads to a Chk1-dependent G2 accumulation.	('ATR', 'Gene', '245000', (18, 21))	('Chk1', 'Gene', (22, 26))	('Chk1', 'Gene', (167, 171))	('Chk1', 'Gene', '12649', (167, 171))	('response to DNA damage', 'MPA', (106, 128))	('FANCD2', 'Gene', (138, 144))	('promotes', 'PosReg', (38, 46))	('FA', 'Phenotype', 'HP:0001994', (138, 140))	('deficiency', 'Var', (145, 155))	('G2 accumulation', 'MPA', (182, 197))	('leads to', 'Reg', (156, 164))	('FANCD2', 'Gene', (47, 53))	('mono-ubiquitination', 'MPA', (54, 73))	('ATR', 'Gene', (18, 21))	('Chk1', 'Gene', '12649', (22, 26))	('FA', 'Phenotype', 'HP:0001994', (47, 49))
499804	32906798	The FA/BRCA2 pathway is critical for the orchestration of the cellular response to cisplatin and MMC, two DNA cross-linking agents, while FANCD2 deficiency increased chemosensitivity to cisplatin and MMC treatments in HeLa cells.	('BRCA2', 'Gene', '675', (7, 12))	('MMC', 'Chemical', 'MESH:D016685', (200, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('FA', 'Phenotype', 'HP:0001994', (4, 6))	('cisplatin', 'Chemical', 'MESH:D002945', (186, 195))	('FANCD2', 'Gene', (138, 144))	('increased', 'PosReg', (156, 165))	('HeLa', 'CellLine', 'CVCL:0030', (218, 222))	('FA', 'Phenotype', 'HP:0001994', (138, 140))	('deficiency', 'Var', (145, 155))	('BRCA2', 'Gene', (7, 12))	('chemosensitivity', 'MPA', (166, 182))	('MMC', 'Chemical', 'MESH:D016685', (97, 100))
499807	32906798	Our subcellular location study clearly shows the nuclear localization of mono-ubiquitinated FANCD2 in S/G2/early M phases and cytoplasm translocation during mitosis, supporting the multiple roles FANCD2 plays in cell cycle regulation in ESCC cells.	('FA', 'Phenotype', 'HP:0001994', (92, 94))	('FA', 'Phenotype', 'HP:0001994', (196, 198))	('mono-ubiquitinated', 'Var', (73, 91))	('S/G2', 'Var', (102, 106))	('S/G2', 'SUBSTITUTION', 'None', (102, 106))	('FANCD2', 'Gene', (92, 98))
499891	31666442	Does Preoperative Low HbA1c Predict Esophageal Cancer Outcomes?	('Predict', 'Reg', (28, 35))	('Cancer', 'Disease', (47, 53))	('Low', 'Var', (18, 21))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Low HbA1c', 'Phenotype', 'HP:0040217', (18, 27))
499923	31666442	We examined the patients' clinicopathological factors, including demographics, tumor characteristics, and survival, and subsequently compared these factors between the high and low HbA1c groups.	('low HbA1c', 'Phenotype', 'HP:0040217', (177, 186))	('HbA1c', 'Gene', (181, 186))	('tumor', 'Disease', (79, 84))	('patients', 'Species', '9606', (16, 24))	('high', 'Var', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
499931	31666442	The other factors, including low HbA1c (p = 0.17), were not independent prognostic factors for patients with esophageal cancer (Table 2).	('HbA1c', 'Protein', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('patients', 'Species', '9606', (95, 103))	('low', 'Var', (29, 32))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))	('low HbA1c', 'Phenotype', 'HP:0040217', (29, 38))
499934	31666442	By contrast, among the high HbA1c group, 35 of the 107 patients (33%) developed cancer recurrence, including 18 lymph node, 1 local, and 16 distant recurrences.	('high', 'Var', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('high HbA1c', 'Phenotype', 'HP:0040217', (23, 33))	('patients', 'Species', '9606', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
499936	31666442	From the evaluation of clinicopathological and prognostic significance of pretreatment level of HbA1c in patients with esophageal cancer, low HbA1c was found to be significantly associated with advanced tumor depth and poor survival.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('patients', 'Species', '9606', (105, 113))	('associated', 'Reg', (178, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('tumor depth', 'Disease', 'MESH:D007222', (203, 214))	('tumor depth', 'Disease', (203, 214))	('poor survival', 'CPA', (219, 232))	('HbA1c', 'Gene', (142, 147))	('low HbA1c', 'Phenotype', 'HP:0040217', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('low', 'Var', (138, 141))	('esophageal cancer', 'Disease', (119, 136))
499944	31666442	The other limitations of this study were pseudo-low level due to iron administration and pseudo-high level due to aging and/or iron deficiency anemia.	('deficiency anemia', 'Disease', 'MESH:D000740', (132, 149))	('anemia', 'Phenotype', 'HP:0001903', (143, 149))	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (127, 149))	('iron', 'Chemical', 'MESH:D007501', (65, 69))	('pseudo-low', 'Var', (41, 51))	('pseudo-high', 'Var', (89, 100))	('deficiency anemia', 'Disease', (132, 149))	('iron', 'Chemical', 'MESH:D007501', (127, 131))	('due', 'Reg', (107, 110))
499986	30585183	In patients with immune-mediated myopathies, impairments in the skeletal muscles of the posterior pharyngeal wall and proximal third of the esophagus can lead to oropharyngeal dysphagia and, in some cases, dysphonia (i.e., an alteration in the quality of the voice).	('myopathies', 'Disease', (33, 43))	('dysphonia', 'Disease', 'MESH:D055154', (206, 215))	('myopathies', 'Phenotype', 'HP:0003198', (33, 43))	('men', 'Species', '9606', (51, 54))	('dysphonia', 'Phenotype', 'HP:0001618', (206, 215))	('dysphagia', 'Phenotype', 'HP:0002015', (176, 185))	('impairments', 'Var', (45, 56))	('lead to', 'Reg', (154, 161))	('patients', 'Species', '9606', (3, 11))	('dysphonia', 'Disease', (206, 215))	('oropharyngeal dysphagia', 'Phenotype', 'HP:0200136', (162, 185))	('oropharyngeal dysphagia', 'Disease', (162, 185))	('oropharyngeal dysphagia', 'Disease', 'MESH:D003680', (162, 185))	('myopathies', 'Disease', 'MESH:D009135', (33, 43))
499990	30585183	Myositis-associated autoantibodies include anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), anti-cytosolic 50-nucleotidase 1A, anti-Mi-2 nuclear antigen, anti-transcriptional intermediary factor 1-g (TIF-1g), anti-melanoma differentiation-associated gene 5, anti-small ubiquitin-like modifier activating enzyme, anti-nuclear matrix protein 2, anti-Jo1-histidyletransfer RNA synthetase, and anti-signal recognition particle.	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('TIF-1g', 'Gene', '51592', (213, 219))	('melanoma', 'Disease', (227, 235))	('Myositis', 'Phenotype', 'HP:0100614', (0, 8))	('HMGCR', 'Gene', (97, 102))	('TIF-1g', 'Gene', (213, 219))	('anti-Jo1-histidyletransfer', 'Var', (356, 382))	('Myositis', 'Disease', (0, 8))	('anti-3-hydroxy-3-methylglutaryl coenzyme A reductase', 'Gene', '3156', (43, 95))	('HMGCR', 'Gene', '3156', (97, 102))	('Myositis', 'Disease', 'MESH:D009220', (0, 8))	('anti-small', 'Var', (271, 281))
500014	30585183	There are three clinical variants of the recurrent oral aphthous ulcers associated with Behcet's disease: Minor aphthae (<10 mm in diameter), major aphthae (>10 mm in diameter, deeper than minor ulcers and painful) and herpetiform ulcers (numerous clustering pinpoint ulcers) (Figure 1A-C).	('ulcers', 'Disease', (65, 71))	('associated', 'Reg', (72, 82))	('ulcers', 'Disease', (231, 237))	('Minor aphthae', 'Disease', (106, 119))	("Behcet's disease", 'Disease', 'MESH:D001528', (88, 104))	('pain', 'Disease', (206, 210))	('ulcers', 'Disease', 'MESH:D014456', (65, 71))	('oral aphthous', 'Phenotype', 'HP:0011107', (51, 64))	('ulcers', 'Disease', 'MESH:D014456', (231, 237))	('ulcers', 'Disease', (195, 201))	('pain', 'Phenotype', 'HP:0012531', (206, 210))	('recurrent oral aphthous ulcers associated', 'Phenotype', 'HP:0011107', (41, 82))	('aphthous ulcers', 'Phenotype', 'HP:0032154', (56, 71))	('ulcers', 'Disease', (268, 274))	('ulcers', 'Disease', 'MESH:D014456', (195, 201))	('pain', 'Disease', 'MESH:D010146', (206, 210))	('ulcers', 'Disease', 'MESH:D014456', (268, 274))	('>10', 'Var', (157, 160))	("Behcet's disease", 'Disease', (88, 104))
500025	30585183	One study has found that the prevalence of stomatitis was higher in RA patients taking MTX than in those not taking it (37% vs. 19%), but there were no patients receiving folic or folinic acid in either group.	('MTX', 'Chemical', 'MESH:D008727', (87, 90))	('folinic acid', 'Chemical', 'MESH:D002955', (180, 192))	('stomatitis', 'Phenotype', 'HP:0010280', (43, 53))	('stomatitis', 'Disease', (43, 53))	('patients', 'Species', '9606', (71, 79))	('folic', 'Chemical', '-', (171, 176))	('stomatitis', 'Disease', 'MESH:D013280', (43, 53))	('RA', 'Disease', 'MESH:D001172', (68, 70))	('higher', 'PosReg', (58, 64))	('MTX', 'Var', (87, 90))	('patients', 'Species', '9606', (152, 160))
500070	30585183	Drug-induced overgrowth should be considered in IRD patients taking antiepileptic drugs, calcium-channel blockers, and cyclosporine A (Figure 5), and patients should be informed of this possible side effect, which usually resolves after a dose reduction or drug discontinuation.	('overgrowth', 'Phenotype', 'HP:0001548', (13, 23))	('cyclosporine A', 'Chemical', 'MESH:D016572', (119, 133))	('Drug-induced overgrowth', 'Disease', (0, 23))	('patients', 'Species', '9606', (150, 158))	('cyclosporine', 'Var', (119, 131))	('patients', 'Species', '9606', (52, 60))
500071	30585183	Switching to alternative drugs can also be considered: For example, tacrolimus is associated with a lower incidence and later onset of less severe gingival overgrowth than cyclosporine A.	('gingival overgrowth', 'Disease', (147, 166))	('tacrolimus', 'Var', (68, 78))	('gingival overgrowth', 'Phenotype', 'HP:0000212', (147, 166))	('tacrolimus', 'Chemical', 'MESH:D016559', (68, 78))	('cyclosporine A', 'Chemical', 'MESH:D016572', (172, 186))	('gingival overgrowth', 'Disease', 'MESH:D019214', (147, 166))	('overgrowth', 'Phenotype', 'HP:0001548', (156, 166))
500133	30477458	However, CET could not improve the 1-year overall survival and might make patients with metastatic esophageal cancer more susceptible to rash (OR = 5.50; CI = 2.14-14.14).	('rash', 'Disease', 'MESH:D005076', (137, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('CET', 'Var', (9, 12))	('patients', 'Species', '9606', (74, 82))	('rash', 'Disease', (137, 141))	('rash', 'Phenotype', 'HP:0000988', (137, 141))	('susceptible', 'Reg', (122, 133))	('CET', 'Chemical', 'MESH:D000068818', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('esophageal cancer', 'Disease', (99, 116))
500146	30477458	argued that CET could improve clinical therapeutic effects,prolong survival time, and reduce therapeutic side effects in the treatment of intermediate and advanced esophageal cancer.	('esophageal cancer', 'Disease', (164, 181))	('survival time', 'CPA', (67, 80))	('prolong', 'PosReg', (59, 66))	('improve', 'PosReg', (22, 29))	('CET', 'Var', (12, 15))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('CET', 'Chemical', 'MESH:D000068818', (12, 15))	('reduce', 'NegReg', (86, 92))	('therapeutic side effects', 'MPA', (93, 117))	('clinical therapeutic effects', 'CPA', (30, 58))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
500175	30477458	However, CET could improve 2-year overall survival (OR, 2.78; 95% CI, 1.20 to 6.46; p = 0.02; Fig.	('CET', 'Chemical', 'MESH:D000068818', (9, 12))	('improve', 'PosReg', (19, 26))	('overall survival', 'MPA', (34, 50))	('CET', 'Var', (9, 12))
500183	30477458	The pooled results showed that the response rate was significantly higher in CET-administrated patients compared with the CET-free group (OR, 3.34; 95% CI, 1.90 to 5.88; p < 0.0001).	('higher', 'PosReg', (67, 73))	('patients', 'Species', '9606', (95, 103))	('CET-administrated', 'Var', (77, 94))	('CET', 'Chemical', 'MESH:D000068818', (77, 80))	('response', 'MPA', (35, 43))	('CET', 'Chemical', 'MESH:D000068818', (122, 125))
500190	30477458	The meta-analysis of rash also showed that CET-treated patients were more susceptible to rash compared with CET-free-treated participants (OR, 5.50; 95% CI, 2.14 to 14.14; p = 0.0004).	('CET', 'Chemical', 'MESH:D000068818', (108, 111))	('susceptible', 'Reg', (74, 85))	('rash', 'Disease', 'MESH:D005076', (21, 25))	('CET-treated', 'Var', (43, 54))	('rash', 'Disease', 'MESH:D005076', (89, 93))	('patients', 'Species', '9606', (55, 63))	('rash', 'Disease', (89, 93))	('rash', 'Phenotype', 'HP:0000988', (21, 25))	('rash', 'Phenotype', 'HP:0000988', (89, 93))	('rash', 'Disease', (21, 25))	('CET', 'Chemical', 'MESH:D000068818', (43, 46))	('participants', 'Species', '9606', (125, 137))
500199	30477458	Moreover, in line with most studies, our meta-analysis demonstrated that CET could increase the response rate and disease control rate in patients with metastatic esophageal cancer.	('CET', 'Var', (73, 76))	('response rate', 'CPA', (96, 109))	('increase', 'PosReg', (83, 91))	('CET', 'Chemical', 'MESH:D000068818', (73, 76))	('esophageal cancer', 'Disease', (163, 180))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('patients', 'Species', '9606', (138, 146))	('disease control rate', 'CPA', (114, 134))
500209	30477458	Although CET has been shown to be safe when combined with chemotherapy and may increase the efficacy of standard chemotherapy, we did not find significant improvements in overall survival and PFS in esophageal carcinoma.	('increase', 'PosReg', (79, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('CET', 'Var', (9, 12))	('esophageal carcinoma', 'Disease', (199, 219))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (199, 219))	('efficacy', 'MPA', (92, 100))	('CET', 'Chemical', 'MESH:D000068818', (9, 12))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (199, 219))
500221	30477458	argued that CET could significantly increase the overall survival and reduce the recurrence rate and metastatic rate in patients with high EGFR expression, but did not significantly affect these outcomes in patients without high EGFR expression.	('overall survival', 'CPA', (49, 65))	('patients', 'Species', '9606', (207, 215))	('recurrence rate', 'CPA', (81, 96))	('increase', 'PosReg', (36, 44))	('high', 'Var', (134, 138))	('CET', 'Chemical', 'MESH:D000068818', (12, 15))	('EGFR', 'Gene', '1956', (139, 143))	('EGFR', 'Gene', '1956', (229, 233))	('expression', 'Var', (144, 154))	('EGFR', 'Gene', (229, 233))	('reduce', 'NegReg', (70, 76))	('patients', 'Species', '9606', (120, 128))	('metastatic rate', 'CPA', (101, 116))	('EGFR', 'Gene', (139, 143))
500223	30477458	No evidence showed that CET aggravated the known toxic effects of these standard approaches for patients with esophageal cancer.	('CET', 'Chemical', 'MESH:D000068818', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal cancer', 'Disease', (110, 127))	('patients', 'Species', '9606', (96, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('aggravated', 'PosReg', (28, 38))	('CET', 'Var', (24, 27))
500234	30477458	Further studies may concentrate on the efficacy of CET in esophageal cancer patients with high-expressed EGFR.	('patients', 'Species', '9606', (76, 84))	('CET', 'Chemical', 'MESH:D000068818', (51, 54))	('esophageal cancer', 'Disease', (58, 75))	('high-expressed', 'Var', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('EGFR', 'Gene', '1956', (105, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('EGFR', 'Gene', (105, 109))
500241	27875549	In xenograft tumor-bearing mice, CYT-Rx20 significantly reduced tumor growth of the implanted esophageal cancer cells accompanied by decreased Ki-67, phospho-AKT, and phospho-STAT3 expression.	('tumor', 'Disease', (13, 18))	('Ki-67', 'Gene', (143, 148))	('tumor', 'Disease', (64, 69))	('mice', 'Species', '10090', (27, 31))	('reduced', 'NegReg', (56, 63))	('esophageal cancer', 'Disease', (94, 111))	('phospho-AKT', 'Pathway', (150, 161))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('CYT-Rx20', 'Var', (33, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Ki-67', 'Gene', '17345', (143, 148))	('phospho-STAT3 expression', 'MPA', (167, 191))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('decreased', 'NegReg', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
500253	27875549	Our previous studies demonstrated that CYT-Rx20 (3'-hydroxy-4'-methoxy-beta- methyl-beta-nitrostyrene), a synthetic derivative of beta-nitrostyrene, tended to increase the anti-platelet activity and induces breast cancer cell death and autophagy through ROS-mediated MEK/ERK pathway.	('induces', 'PosReg', (199, 206))	('beta-nitrostyrene', 'Chemical', 'MESH:C011955', (84, 101))	('ROS', 'Chemical', '-', (254, 257))	('beta-nitrostyrene', 'Chemical', 'MESH:C011955', (130, 147))	('MEK', 'Gene', '17242', (267, 270))	('breast cancer cell death', 'Disease', (207, 231))	('anti-platelet activity', 'CPA', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('CYT-Rx20', 'Var', (39, 47))	('ERK', 'Gene', '13844', (271, 274))	("3'-hydroxy-4'-methoxy-beta- methyl-beta-nitrostyrene", 'Chemical', 'MESH:C512238', (49, 101))	('autophagy', 'CPA', (236, 245))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('MEK', 'Gene', (267, 270))	('ERK', 'Gene', (271, 274))	('increase', 'PosReg', (159, 167))	('breast cancer cell death', 'Disease', 'MESH:D001943', (207, 231))
500255	27875549	In this study, the anti-esophageal cancer activity of CYT-Rx20 is explored by studying its biological effects and the underlying mechanisms in vitro and in vivo.	('CYT-Rx20', 'Var', (54, 62))	('esophageal cancer', 'Disease', (24, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))
500257	27875549	Antibodies recognizing AKT, phospho-STAT3 (Tyr705), caspase 9, Cdc25C, and cleaved poly(ADP-ribose) polymerase (PARP) (Asp214) were obtained from Cell Signaling Technology (Danvers, MA).	('caspase 9', 'Gene', '12371', (52, 61))	('PARP', 'Gene', (112, 116))	('Cdc25C', 'Gene', '12532', (63, 69))	('PARP', 'Gene', '11545', (112, 116))	('Tyr705', 'Var', (43, 49))	('p21', 'Gene', (121, 124))	('caspase 9', 'Gene', (52, 61))	('poly(ADP-ribose) polymerase', 'Gene', (83, 110))	('Tyr705', 'Chemical', '-', (43, 49))	('p21', 'Gene', '12575', (121, 124))	('poly(ADP-ribose) polymerase', 'Gene', '11545', (83, 110))	('Cdc25C', 'Gene', (63, 69))
500305	27875549	CYT-Rx20 exhibited the potent cytotoxic effect against esophageal cancer cells (KYSE70 and TE8, Fig 1B) in comparison with the HET-1A normal esophageal squamous cell line (S1 Fig).	('cytotoxic effect', 'CPA', (30, 46))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (55, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('CYT-Rx20', 'Var', (0, 8))
500306	27875549	The inhibitory concentrations of IC50 after 48 h treatment with CYT-Rx20 on two esophageal cancer cell lines, KYSE70 and TE8, were 5.16 +- 0.21 and 3.07 +- 0.04 mug/ml, respectively (Table 1), compared to the HET-1A normal esophageal cells (6.05 +- 2.35 mug/ml).	('esophageal cancer', 'Disease', (80, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('CYT-Rx20', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('IC50', 'Gene', (33, 37))
500307	27875549	CYT-Rx20 showed a higher potent of cytotoxicity on esophageal cancer cells than the clinically used drug, 5-Fu (Table 1).	('5-Fu', 'Chemical', 'MESH:D005472', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancer', 'Disease', (51, 68))	('cytotoxicity', 'Disease', (35, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('CYT-Rx20', 'Var', (0, 8))	('cytotoxicity', 'Disease', 'MESH:D064420', (35, 47))
500308	27875549	Next we analyzed cell apoptosis by Annexin V/PI staining after CYT-Rx20 treatment for 48 h. We observed that apoptosis was statistically significantly higher in CYT-Rx20-treated KYSE70 and TE8 cells compared with untreated control cells (KYSE70: 38.4 +- 6.7% vs. 2.9 +- 1.6%, P <0.01; TE8: 41.8 +- 0.2% vs. 5.0 +- 1.3%, P <0.001) (Fig 1C).	('CYT-Rx20-treated', 'Var', (161, 177))	('apoptosis', 'CPA', (109, 118))	('Annexin V', 'Gene', (35, 44))	('higher', 'PosReg', (151, 157))	('Annexin V', 'Gene', '11747', (35, 44))
500311	27875549	We examined the protein levels of epithelial maker (ZO-1) and mesenchymal markers (N-cadherin, ZEB1, Slug, Snail) in esophageal cancer cells by immunoblotting analysis and found that the level of ZO-1 were markedly increased in KYSE70 and TE8 cells with the indicated concentrations of CYT-Rx20 compared with the control (P <0.05 in KYSE70; P <0.001 in TE8) (Fig 2C).	('esophageal cancer', 'Disease', (117, 134))	('CYT-Rx20', 'Var', (286, 294))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('increased', 'PosReg', (215, 224))
500313	27875549	As shown in Fig 3A, decreased protein expression of phospho-p85, phospho-AKT, and phospho-STAT3 was observed in esophageal cancer cells after CYT-Rx20 treatment, while the total form of p85, AKT, and STAT3 was not significantly altered by CYT-Rx20.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('p85', 'Gene', '13601', (60, 63))	('p85', 'Gene', '13601', (186, 189))	('decreased', 'NegReg', (20, 29))	('CYT-Rx20', 'Var', (142, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))	('esophageal cancer', 'Disease', (112, 129))	('p85', 'Gene', (186, 189))	('p85', 'Gene', (60, 63))	('protein expression', 'MPA', (30, 48))
500316	27875549	The results of soft agar assay showed that CYT-Rx20 (1.25, 2.5 or 5 mug/ml) dose-dependently suppressed the anchorage-independent tumor growth of esophageal cancer cells (Fig 4A).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('agar', 'Chemical', 'MESH:D000362', (20, 24))	('esophageal cancer', 'Disease', (146, 163))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('suppressed', 'NegReg', (93, 103))	('CYT-Rx20', 'Var', (43, 51))	('tumor', 'Disease', (130, 135))
500318	27875549	As shown in Fig 4B, KYSE70 tumor growth was significantly suppressed by CYT-Rx20 treatment in comparison with the untreated control group.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CYT-Rx20 treatment', 'Var', (72, 90))	('tumor', 'Disease', (27, 32))	('suppressed', 'NegReg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
500320	27875549	Furthermore, the expression levels of Ki-67, phospho-AKT, and phospho-STAT3 in xenografted tumors were decreased after CYT-Rx20 treatment (Fig 4D).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('expression levels', 'MPA', (17, 34))	('Ki-67', 'Gene', (38, 43))	('decreased', 'NegReg', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Ki-67', 'Gene', '17345', (38, 43))	('CYT-Rx20', 'Var', (119, 127))	('phospho-AKT', 'MPA', (45, 56))
500325	27875549	As shown in Fig 5A, using IVIS Spectrum in vivo imaging system, the mice injected with CYT-Rx20 revealed a significantly lower bioluminescent signal in the abdominal esophagus tissues than the untreated control mice (P < 0.01).	('mice', 'Species', '10090', (68, 72))	('CYT-Rx20', 'Var', (87, 95))	('lower', 'NegReg', (121, 126))	('mice', 'Species', '10090', (211, 215))	('bioluminescent signal in the abdominal esophagus', 'MPA', (127, 175))
500327	27875549	Furthermore, the expression of Ki-67 and phospho-STAT3 in orthotopic esophageal tumor tissues were decreased after CYT-Rx20 treatment (Fig 5B), in agreement with our in vitro observation.	('decreased', 'NegReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Ki-67', 'Gene', (31, 36))	('CYT-Rx20', 'Var', (115, 123))	('expression', 'MPA', (17, 27))	('esophageal tumor', 'Disease', 'MESH:D004938', (69, 85))	('esophageal tumor', 'Disease', (69, 85))	('esophageal tumor', 'Phenotype', 'HP:0100751', (69, 85))	('Ki-67', 'Gene', '17345', (31, 36))
500330	27875549	Previous report demonstrated that CYT-Rx20 inhibited breast cancer cell proliferation and tumorigenesis via increase of ROS-mediated MEK/ERK signaling pathway.	('MEK', 'Gene', (133, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('increase', 'PosReg', (108, 116))	('ROS', 'Chemical', '-', (120, 123))	('inhibited', 'NegReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('ERK', 'Gene', '13844', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('ERK', 'Gene', (137, 140))	('MEK', 'Gene', '17242', (133, 136))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('CYT-Rx20', 'Var', (34, 42))	('breast cancer', 'Disease', (53, 66))
500331	27875549	In this study, we demonstrated for the first time that CYT-Rx20 suppressed the PI3K/AKT and STAT3 signaling pathways and inhibited esophageal cancer cell viability and migration.	('CYT-Rx20', 'Var', (55, 63))	('suppressed', 'NegReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('esophageal cancer', 'Disease', (131, 148))	('STAT3 signaling pathways', 'Pathway', (92, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('inhibited', 'NegReg', (121, 130))
500332	27875549	These results suggested possible tissue-specific anti-cancer activities of CYT-Rx20.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('CYT-Rx20', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (54, 60))
500338	27875549	While a previous study reported the STAT3 mediates PI3K/AKT activation upon interleukin-6 treatment, our study showed a decreased protein expression of phospho-p85, phospho-AKT, and phospho-STAT3 in esophageal cancer cells after CYT-Rx20 treatment (Fig 3A).	('decreased', 'NegReg', (120, 129))	('p85', 'Gene', '13601', (160, 163))	('esophageal cancer', 'Disease', (199, 216))	('esophageal cancer', 'Disease', 'MESH:D004938', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('interleukin-6', 'Gene', '16193', (76, 89))	('interleukin-6', 'Gene', (76, 89))	('p85', 'Gene', (160, 163))	('phospho-STAT3', 'Var', (182, 195))	('protein expression', 'MPA', (130, 148))	('phospho-AKT', 'MPA', (165, 176))
500341	27875549	In addition, esophageal cancer cells co-treated with CYT-Rx20 and SC79 (or colivelin) resulted in enhanced decrease in cell migration (Fig 3D and 3E).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (13, 30))	('SC79', 'Var', (66, 70))	('decrease', 'NegReg', (107, 115))	('CYT-Rx20', 'Var', (53, 61))	('cell migration', 'CPA', (119, 133))	('esophageal cancer', 'Disease', (13, 30))
500344	27875549	Also, Bcr-Abl mutant-transfected leukemic cells are resistance to the killing by imatinib compared with Bcr-Abl-positive parental cells, suggesting that the cancer cells rely on Bcr-Abl for survival.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Bcr-Abl', 'Gene', (6, 13))	('mutant-transfected', 'Var', (14, 32))	('leukemic', 'Disease', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('leukemic', 'Disease', 'MESH:D007938', (33, 41))	('cancer', 'Disease', (157, 163))	('imatinib', 'Chemical', 'MESH:D000068877', (81, 89))
500345	27875549	In another study, treatment of c-MYC-expressing myeloma cells with the 10058-F4 compound, an inhibitor of MYC-MAX heterodimerization, resulted in rapid apoptosis, suggesting that there is an addiction to c-MYC for survival in these cancer cells.	('MYC', 'Gene', (206, 209))	('MYC', 'Gene', (106, 109))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('MYC', 'Gene', '17869', (206, 209))	('cancer', 'Disease', (232, 238))	('myeloma', 'Disease', 'MESH:D009101', (48, 55))	('10058-F4', 'Var', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('MYC', 'Gene', '17869', (33, 36))	('myeloma', 'Disease', (48, 55))	('MYC', 'Gene', (33, 36))	('apoptosis', 'CPA', (152, 161))	('MYC', 'Gene', '17869', (106, 109))
500347	27875549	demonstrated that malignant melanoma cells were addicted to V600EBRAF-driven glycolysis for efficient ATP production.	('melanoma', 'Disease', (28, 36))	('ATP', 'Chemical', 'MESH:D000255', (102, 105))	('malignant melanoma', 'Phenotype', 'HP:0002861', (18, 36))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('V600EBRAF-driven', 'Var', (60, 76))
500351	27875549	CYT-Rx20 suppressed xenografted (Fig 4B) and orthotopic (Fig 5A) esophageal tumor growth along with decreased expression of Ki-67, phospho-AKT, and phospho-STAT3 in tumor tissues (Figs 4D and 5B).	('phospho-AKT', 'Protein', (131, 142))	('Ki-67', 'Gene', '17345', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('esophageal tumor', 'Disease', 'MESH:D004938', (65, 81))	('Ki-67', 'Gene', (124, 129))	('decreased', 'NegReg', (100, 109))	('esophageal tumor', 'Disease', (65, 81))	('expression', 'MPA', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('suppressed', 'NegReg', (9, 19))	('esophageal tumor', 'Phenotype', 'HP:0100751', (65, 81))	('CYT-Rx20', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (165, 170))
500353	27875549	Alterations in cell migration, invasion, EMT, and production of matrix metalloproteinase are associated with diverse pathologic changes, such as angiogenesis, restenosis in grafted or injured vessels, and cancer.	('angiogenesis', 'CPA', (145, 157))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('restenosis', 'Disease', (159, 169))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', (205, 211))	('invasion', 'CPA', (31, 39))	('associated', 'Reg', (93, 103))	('cell migration', 'CPA', (15, 29))	('restenosis', 'Disease', 'MESH:D023903', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('EMT', 'CPA', (41, 44))
500355	27875549	In agreement with this finding, CYT-Rx20 treatment in an orthotopic esophageal tumor model significantly decreased lung metastasis in mice (Fig 5A and 5C).	('esophageal tumor', 'Disease', 'MESH:D004938', (68, 84))	('mice', 'Species', '10090', (134, 138))	('decreased lung', 'Phenotype', 'HP:0002089', (105, 119))	('esophageal tumor', 'Disease', (68, 84))	('lung metastasis', 'Disease', (115, 130))	('lung metastasis', 'Disease', 'MESH:D009362', (115, 130))	('CYT-Rx20', 'Var', (32, 40))	('esophageal tumor', 'Phenotype', 'HP:0100751', (68, 84))	('decreased', 'NegReg', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
500356	27875549	Furthermore, CYT-Rx20 treatment had an inhibitory effect on cancer cell migration and invasion through activation of epithelial maker (ZO-1) and inactivation of mesenchymal markers (N-cadherin, ZEB1, Slug, Snail) (Fig 2C).	('epithelial', 'CPA', (117, 127))	('ZO-1', 'Gene', (135, 139))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('N-cadherin', 'Protein', (182, 192))	('inactivation', 'NegReg', (145, 157))	('cancer', 'Disease', (60, 66))	('mesenchymal', 'CPA', (161, 172))	('CYT-Rx20', 'Var', (13, 21))	('activation', 'PosReg', (103, 113))	('invasion', 'CPA', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Snail', 'Protein', (206, 211))
500361	27875549	Inactivation of STAT3-EMT or AKT-EMT axis has been shown to inhibit cancer cell migration.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('AKT-EMT axis', 'Pathway', (29, 41))	('inhibit', 'NegReg', (60, 67))	('STAT3-EMT', 'Gene', (16, 25))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('Inactivation', 'Var', (0, 12))
500362	27875549	To the best of our knowledge, this is the first report showing the anti-metastasis activity of CYT-Rx20 on esophageal cancer cells.	('esophageal cancer', 'Disease', (107, 124))	('anti-metastasis activity', 'MPA', (67, 91))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CYT-Rx20', 'Var', (95, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))
500363	27875549	In conclusion, CYT-Rx20 inhibited esophageal cancer cell viability and metastasis in vitro and in vivo through down-regulation of AKT and STAT3 activities.	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('down-regulation', 'NegReg', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('metastasis', 'CPA', (71, 81))	('inhibited', 'NegReg', (24, 33))	('CYT-Rx20', 'Var', (15, 23))	('AKT', 'Pathway', (130, 133))	('STAT3 activities', 'MPA', (138, 154))
500383	25652049	To evaluate the sensitivity of the CellSearch system in vitro, five esophageal squamous cell carcinoma cell lines, TE8, TE9 (Riken BioResource Center), KYSE50, KYSE220, and KYSE270, were used.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('esophageal squamous cell carcinoma', 'Disease', (68, 102))	('KYSE270', 'Var', (173, 180))
500412	25652049	A cell-spiking study was done to investigate the sensitivity and linearity of the CellSearch system by spiking a series of serial dilutions of TE8, TE9, KYSE50, KYSE220 and KYSE270 (1000, 100, 50, 10, 5, and 0 cells) into whole blood obtained from a normal healthy volunteer without cancer.	('KYSE50', 'Var', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancer', 'Disease', (283, 289))	('KYSE220', 'Var', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))
500426	25652049	The overall survival rate was significantly lower in patients with CTCs than in those without CTCs (p = 0.002; Fig.	('patients', 'Species', '9606', (53, 61))	('lower', 'NegReg', (44, 49))	('CTCs', 'Var', (67, 71))
500447	25652049	The presence of CTCs was significantly correlated with distant metastases, such as pleural dissemination and hematogenous metastases (p = 0.002), although positive expression of CTCs in distant metastases was lower than expected.	('metastases', 'Disease', (194, 204))	('correlated', 'Reg', (39, 49))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('pleural dissemination and hematogenous metastases', 'Disease', 'MESH:D009362', (83, 132))	('metastases', 'Disease', 'MESH:D009362', (194, 204))	('metastases', 'Disease', (122, 132))	('presence', 'Var', (4, 12))	('metastases', 'Disease', 'MESH:D009362', (122, 132))	('metastases', 'Disease', (63, 73))
500482	20813067	Recently, a proteomics-based approach identified several autoantibodies in sera of patients with ESCC, such as anti-heat shock protein 70 and anti-peroxiredoxin VI.	('shock', 'Phenotype', 'HP:0031273', (121, 126))	('anti-heat', 'Var', (111, 120))	('anti-peroxiredoxin', 'Var', (142, 160))	('SCC', 'Gene', '6317', (98, 101))	('patients', 'Species', '9606', (83, 91))	('SCC', 'Gene', (98, 101))
500487	20813067	First, CDC25B can transform fibroblast cells lacking functional retinoblastoma protein or harboring mutated Ras protein.	('lacking functional', 'NegReg', (45, 63))	('mutated', 'Var', (100, 107))	('retinoblastoma', 'Phenotype', 'HP:0009919', (64, 78))	('CDC25B', 'Gene', '994', (7, 13))	('CDC25B', 'Gene', (7, 13))	('Ras protein', 'Protein', (108, 119))	('retinoblastoma', 'Disease', 'MESH:D012175', (64, 78))	('retinoblastoma', 'Disease', (64, 78))
500490	20813067	We previously reported that aberrant expression of CDC25B in ESCC tumor cells can induce CDC25B autoantibodies in sera of ESCC patients, and antibodies against CDC25B were detected in sera of 36.3% of patients with ESCC, but not in sera of healthy controls, by reverse capture ELISA.	('SCC', 'Gene', '6317', (123, 126))	('CDC25B', 'Gene', '994', (51, 57))	('CDC25B', 'Gene', (51, 57))	('CDC25B', 'Gene', '994', (89, 95))	('SCC', 'Gene', (123, 126))	('induce', 'PosReg', (82, 88))	('CDC25B', 'Gene', (89, 95))	('tumor', 'Disease', (66, 71))	('SCC', 'Gene', '6317', (216, 219))	('CDC25B', 'Gene', '994', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CDC25B', 'Gene', (160, 166))	('SCC', 'Gene', (216, 219))	('patients', 'Species', '9606', (201, 209))	('SCC', 'Gene', '6317', (62, 65))	('SCC', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('aberrant', 'Var', (28, 36))	('patients', 'Species', '9606', (127, 135))
500519	20813067	Under these conditions, the average absorbance was 0.378 (SD = 0.262) in sera from 134 healthy control subjects and 0.917 (SD = 0.473) in sera from 134 patients with primary ESCC (Figure 2A).	('SCC', 'Gene', (175, 178))	('SCC', 'Gene', '6317', (175, 178))	('0.917', 'Var', (116, 121))	('absorbance', 'MPA', (36, 46))	('patients', 'Species', '9606', (152, 160))
500526	20813067	In addition, sera from 41.0% of patients with ESCC were positive for CEA, SCC-Ag or CYFRA21-1, while sera from 64.2% of patients with ESCC were positive for CEA, SCC-Ag, CYFRA21-1 or CDC25B-Abs (Table 2).	('CEA', 'Gene', (69, 72))	('SCC', 'Gene', '6317', (162, 165))	('CEA', 'Gene', '1084', (157, 160))	('SCC', 'Gene', '6317', (74, 77))	('Abs', 'Gene', '51428', (190, 193))	('CEA', 'Gene', '1084', (69, 72))	('SCC', 'Gene', (162, 165))	('SCC', 'Gene', (74, 77))	('CDC25B', 'Gene', '994', (183, 189))	('CYFRA21-1', 'Var', (84, 93))	('CDC25B', 'Gene', (183, 189))	('Abs', 'Gene', (190, 193))	('positive', 'Reg', (56, 64))	('SCC', 'Gene', '6317', (135, 138))	('patients', 'Species', '9606', (32, 40))	('SCC', 'Gene', '6317', (47, 50))	('SCC', 'Gene', (135, 138))	('patients', 'Species', '9606', (120, 128))	('CEA', 'Gene', (157, 160))	('SCC', 'Gene', (47, 50))
500529	20813067	CDC25B-Abs were not obviously correlated with T classification, N classification or metastasis; however, there was a significant association between the presence of CDC25B-Abs and ESCC clinical stage (P = 0.002).	('Abs', 'Gene', (172, 175))	('SCC', 'Gene', (181, 184))	('CDC25B', 'Gene', '994', (165, 171))	('CDC25B', 'Gene', '994', (0, 6))	('CDC25B', 'Gene', (0, 6))	('SCC', 'Gene', '6317', (181, 184))	('CDC25B', 'Gene', (165, 171))	('presence', 'Var', (153, 161))	('Abs', 'Gene', '51428', (7, 10))	('Abs', 'Gene', '51428', (172, 175))	('Abs', 'Gene', (7, 10))
500530	20813067	The percentage of CDC25B-Abs seropositivity was higher in patients with advanced disease than in patients with early disease.	('seropositivity', 'Var', (29, 43))	('Abs', 'Gene', '51428', (25, 28))	('CDC25B', 'Gene', '994', (18, 24))	('higher', 'PosReg', (48, 54))	('CDC25B', 'Gene', (18, 24))	('patients', 'Species', '9606', (58, 66))	('Abs', 'Gene', (25, 28))	('patients', 'Species', '9606', (97, 105))
500537	20813067	Our results showed that the level of circulating CDC25B-Abs had a significant relationship with the prognosis of patients with advanced ESCC (P = 0.001) (Table 3); however, the difference between CDC25B-seropositive patients and CDC25B-seronegative patients was not statistically significant in patients classified into the stage I-II (P = 0.606, log-rank; Figure 3B), T1-T2 (P = 0.320, log-rank; Figure 3D), T3-T4 (P = 0.486, log-rank; Figure 3E) and N0 (P = 0.127, log-rank; Figure 3F) subgroups.	('CDC25B', 'Gene', '994', (196, 202))	('Abs', 'Gene', (56, 59))	('CDC25B', 'Gene', (196, 202))	('patients', 'Species', '9606', (249, 257))	('patients', 'Species', '9606', (113, 121))	('CDC25B', 'Gene', '994', (49, 55))	('patients', 'Species', '9606', (295, 303))	('CDC25B', 'Gene', '994', (229, 235))	('patients', 'Species', '9606', (216, 224))	('CDC25B', 'Gene', (49, 55))	('SCC', 'Gene', '6317', (137, 140))	('Abs', 'Gene', '51428', (56, 59))	('T3-T4', 'Var', (409, 414))	('CDC25B', 'Gene', (229, 235))	('SCC', 'Gene', (137, 140))
500552	20813067	The rate of CDC25B-Abs seropositivity in patients with ESCC was significantly higher than the seropositivity rates of tumor markers SCC-Ag, CEA and CYFRA21-1.	('seropositivity', 'Var', (23, 37))	('Abs', 'Gene', '51428', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('higher', 'PosReg', (78, 84))	('SCC', 'Gene', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('SCC', 'Gene', (132, 135))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Disease', (118, 123))	('Abs', 'Gene', (19, 22))	('SCC', 'Gene', '6317', (56, 59))	('CEA', 'Gene', (140, 143))	('CDC25B', 'Gene', '994', (12, 18))	('CEA', 'Gene', '1084', (140, 143))	('CDC25B', 'Gene', (12, 18))	('SCC', 'Gene', '6317', (132, 135))
500567	20813067	Moreover, high levels of CDC25B-Abs were associated with poor survival in advanced ESCC.	('SCC', 'Gene', '6317', (84, 87))	('poor', 'NegReg', (57, 61))	('CDC25B', 'Gene', '994', (25, 31))	('Abs', 'Gene', (32, 35))	('CDC25B', 'Gene', (25, 31))	('high', 'Var', (10, 14))	('SCC', 'Gene', (84, 87))	('Abs', 'Gene', '51428', (32, 35))
500582	18193101	GERD may lead to the development of serious complications, including ulcers, strictures, bleeding, Barrett's esophagus, and eventually, adenocarcinoma of the esophagus.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	("Barrett's esophagus", 'Disease', (99, 118))	('ulcers', 'Disease', (69, 75))	('ulcers', 'Disease', 'MESH:D014456', (69, 75))	('adenocarcinoma of the esophagus', 'Disease', (136, 167))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (99, 118))	('strictures', 'Disease', (77, 87))	('bleeding', 'Disease', 'MESH:D006470', (89, 97))	('GERD', 'Var', (0, 4))	('bleeding', 'Disease', (89, 97))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (136, 167))	('lead to', 'Reg', (9, 16))
500595	18193101	Our studies have also found that Japanese RE patients had increased relative IL-8 mRNA expression levels, as assessed using real-time PCR technology.	('increased', 'PosReg', (58, 67))	('IL-8', 'Gene', '3576', (77, 81))	('IL-8', 'Gene', (77, 81))	('Japanese', 'Var', (33, 41))	('patients', 'Species', '9606', (45, 53))
500636	18193101	In line with this, the RANTES levels in esophageal mucosa containing intraepithelial eosinophils were significantly higher than in mucosa lacking the cells.	('RANTES', 'Gene', (23, 29))	('RANTES', 'Gene', '6352', (23, 29))	('higher', 'PosReg', (116, 122))	('intraepithelial eosinophils', 'Var', (69, 96))
500673	18193101	In this model, treatment with the PPI rabeprazole almost completely inhibited the development of RE and significantly decreased the expression of cytokines; this suggests that gastric acid reflux may play a role in the induction of chronic esophageal inflammation.	('esophageal inflammation', 'Disease', (240, 263))	('development of RE', 'CPA', (82, 99))	('rabeprazole', 'Chemical', 'MESH:D064750', (38, 49))	('gastric acid reflux', 'MPA', (176, 195))	('inhibited', 'NegReg', (68, 77))	('PPI', 'Var', (34, 37))	('decreased', 'NegReg', (118, 127))	('gastric acid reflux', 'Phenotype', 'HP:0002020', (176, 195))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (240, 263))	('esophageal inflammation', 'Disease', 'MESH:D007249', (240, 263))	('expression of cytokines', 'MPA', (132, 155))
500682	18193101	More recently, it has been shown that exposure to either PPI results in a strong induction of heme oxygenase-1, which has a central role in cellular antioxidant defenses and exerts anti-inflammatory actions at both the mRNA and protein levels; this leads to an increased activity of this enzyme in gastric and endothelial cells.	('heme oxygenase-1', 'Gene', (94, 110))	('increased', 'PosReg', (261, 270))	('induction', 'PosReg', (81, 90))	('PPI', 'Var', (57, 60))	('anti-inflammatory', 'MPA', (181, 198))	('heme oxygenase-1', 'Gene', '3162', (94, 110))	('activity', 'MPA', (271, 279))
500683	18193101	It is unknown whether PPIs can induce heme oxygenase-1 in esophageal cells in vitro and in vivo; however, it is tempting to speculate that the improvement in esophageal immune and inflammatory responses seen with PPI treatment may be in part mediated by beneficial anti-inflammatory effects that go beyond acid suppression.	('inflammatory responses', 'CPA', (180, 202))	('PPI', 'Var', (213, 216))	('heme oxygenase-1', 'Gene', '3162', (38, 54))	('esophageal', 'MPA', (158, 168))	('heme oxygenase-1', 'Gene', (38, 54))	('improvement', 'PosReg', (143, 154))
500706	33324542	The expression of miR-381 is downregulated in lung adenocarcinoma, epithelial ovarian cancer, colon cancer, and breast cancer, suggesting that miR-381 may play a role as a tumor suppressor.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Disease', (112, 125))	('tumor', 'Disease', (172, 177))	('expression', 'MPA', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('miR-381', 'Gene', (18, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('lung adenocarcinoma, epithelial ovarian cancer', 'Disease', 'MESH:D000077192', (46, 92))	('colon cancer', 'Disease', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('miR-381', 'Var', (143, 150))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (67, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('downregulated', 'NegReg', (29, 42))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
500714	33324542	In breast cancer cell lines, overexpression of miR-381 is associated with decreased levels of Wnt axis genes, including CTNNB1, RhoA, ROCK1, and c-MYC.	('RhoA', 'Gene', (128, 132))	('overexpression', 'PosReg', (29, 43))	('miR-381', 'Var', (47, 54))	('c-MYC', 'Gene', (145, 150))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('ROCK1', 'Gene', '6093', (134, 139))	('CTNNB1', 'Gene', (120, 126))	('RhoA', 'Gene', '387', (128, 132))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('ROCK1', 'Gene', (134, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('CTNNB1', 'Gene', '1499', (120, 126))	('decreased', 'NegReg', (74, 83))	('c-MYC', 'Gene', '4609', (145, 150))	('levels of', 'MPA', (84, 93))	('Wnt axis genes', 'Gene', (94, 108))
500729	33324542	In a xenograft mouse model, miR-381 inhibited tumor growth.	('inhibited', 'NegReg', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('miR-381', 'Var', (28, 35))	('tumor', 'Disease', (46, 51))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
500731	33324542	MiR-381 also modulates cell proliferation via the PI3K/AKT/mTOR pathway, which plays a crucial role in cell proliferation, invasion, and survival.	('AKT', 'Gene', (55, 58))	('modulates', 'Reg', (13, 22))	('mTOR', 'Gene', (59, 63))	('AKT', 'Gene', '207', (55, 58))	('mTOR', 'Gene', '2475', (59, 63))	('cell proliferation', 'CPA', (23, 41))	('MiR-381', 'Var', (0, 7))
500732	33324542	MiR-381 acts as a tumor suppressor via inhibiting the ETS1/PI3K/AKT/mTOR pathway activity.	('tumor', 'Disease', (18, 23))	('ETS1', 'Gene', '2113', (54, 58))	('AKT', 'Gene', '207', (64, 67))	('mTOR', 'Gene', '2475', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mTOR', 'Gene', (68, 72))	('activity', 'MPA', (81, 89))	('ETS1', 'Gene', (54, 58))	('inhibiting', 'NegReg', (39, 49))	('AKT', 'Gene', (64, 67))	('MiR-381', 'Var', (0, 7))
500736	33324542	Mechanistically, miR-381 regulates the PI3K/AKT pathway via inhibiting LMO3, and overexpression of miR-381 decreases the protein levels of p-PI3K and p-AKT in cell lines.	('inhibiting', 'NegReg', (60, 70))	('LMO3', 'Gene', (71, 75))	('protein levels', 'MPA', (121, 135))	('LMO3', 'Gene', '55885', (71, 75))	('AKT', 'Gene', '207', (152, 155))	('miR-381', 'Var', (17, 24))	('miR-381', 'Gene', (99, 106))	('decreases', 'NegReg', (107, 116))	('AKT', 'Gene', '207', (44, 47))	('AKT', 'Gene', (152, 155))	('regulates', 'Reg', (25, 34))	('AKT', 'Gene', (44, 47))	('p-PI3K', 'Pathway', (139, 145))
500737	33324542	By inhibiting PI3K/AKT pathway activity, miR-381 could be a tumor suppressor.	('inhibiting', 'NegReg', (3, 13))	('miR-381', 'Var', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('AKT', 'Gene', '207', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('AKT', 'Gene', (19, 22))	('tumor', 'Disease', (60, 65))
500740	33324542	PTTG1 is upregulated in pituitary tumors; in contrast, the levels of microRNA-655, miR-300, miR-381, and miR-329 are decreased in pituitary tumor tissues.	('levels', 'MPA', (59, 65))	('pituitary tumors', 'Disease', 'MESH:D010911', (24, 40))	('upregulated', 'PosReg', (9, 20))	('miR-381', 'MPA', (92, 99))	('pituitary tumor', 'Disease', (130, 145))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('microRNA-655', 'Gene', (69, 81))	('miR-329', 'Gene', '723842', (105, 112))	('PTTG1', 'Gene', (0, 5))	('miR-300', 'Var', (83, 90))	('decreased', 'NegReg', (117, 126))	('pituitary tumor', 'Disease', 'MESH:D010911', (130, 145))	('microRNA-655', 'Gene', '724025', (69, 81))	('pituitary tumors', 'Disease', (24, 40))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('pituitary tumor', 'Disease', 'MESH:D010911', (24, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('miR-329', 'Gene', (105, 112))
500741	33324542	Overexpression of microRNA-655, miR-300, miR-381, and miR-329 decreases the viability and proliferation of human pituitary cells.	('decreases', 'NegReg', (62, 71))	('microRNA-655', 'Gene', (18, 30))	('miR-329', 'Gene', '723842', (54, 61))	('miR-381', 'Var', (41, 48))	('human', 'Species', '9606', (107, 112))	('microRNA-655', 'Gene', '724025', (18, 30))	('miR-300', 'Var', (32, 39))	('miR-329', 'Gene', (54, 61))
500742	33324542	In a xenograft mouse model, microRNA-655, miR-300, miR-381, and miR-329 inhibited tumor growth and PTTG1 expression.	('miR-329', 'Gene', (64, 71))	('microRNA-655', 'Gene', (28, 40))	('miR-300', 'Var', (42, 49))	('PTTG1', 'Gene', (99, 104))	('microRNA-655', 'Gene', '724025', (28, 40))	('miR-329', 'Gene', '723842', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('miR-381', 'Var', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mouse', 'Species', '10090', (15, 20))	('inhibited', 'NegReg', (72, 81))	('tumor', 'Disease', (82, 87))	('expression', 'MPA', (105, 115))
500743	33324542	MicroRNA-655, miR-300, miR-381, and miR-329 target PTTG1 mRNA and inhibit PTTG1 expression.	('miR-381', 'Var', (23, 30))	('PTTG1', 'Gene', (74, 79))	('miR-329', 'Gene', '723842', (36, 43))	('miR-300', 'Var', (14, 21))	('MicroRNA-655', 'Gene', '724025', (0, 12))	('miR-329', 'Gene', (36, 43))	('MicroRNA-655', 'Gene', (0, 12))	('mRNA', 'MPA', (57, 61))	('inhibit', 'NegReg', (66, 73))	('expression', 'MPA', (80, 90))	('PTTG1', 'Gene', (51, 56))
500744	33324542	p53, which is one of the most important tumor suppressor genes and is mutated in a variety of human cancers, can bind to the promoters of microRNA-655, miR-300, miR-381, and miR-329, activating their transcription.	('bind', 'Interaction', (113, 117))	('microRNA-655', 'Gene', '724025', (138, 150))	('miR-300', 'Var', (152, 159))	('activating', 'PosReg', (183, 193))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('p53', 'Gene', '7157', (0, 3))	('microRNA-655', 'Gene', (138, 150))	('miR-381', 'Var', (161, 168))	('miR-329', 'Gene', '723842', (174, 181))	('p53', 'Gene', (0, 3))	('human', 'Species', '9606', (94, 99))	('tumor', 'Disease', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancers', 'Disease', (100, 107))	('miR-329', 'Gene', (174, 181))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('transcription', 'MPA', (200, 213))
500752	33324542	In epithelial ovarian cancer tissues and cell lines, miR-381 expression is decreased, and overexpression of miR-381 significantly inhibits epithelial ovarian cancer cell proliferation, migration, and invasion.	('invasion', 'CPA', (200, 208))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (139, 164))	('miR-381', 'Gene', (53, 60))	('epithelial ovarian cancer', 'Disease', (139, 164))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (139, 164))	('expression', 'MPA', (61, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (150, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('miR-381', 'Var', (108, 115))	('inhibits', 'NegReg', (130, 138))	('epithelial ovarian cancer', 'Disease', (3, 28))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (3, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('migration', 'CPA', (185, 194))	('overexpression', 'PosReg', (90, 104))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (3, 28))	('decreased', 'NegReg', (75, 84))
500757	33324542	In gastric cancer cell lines, inhibition of miR-381 enhances cell proliferation, invasion, and migration.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('inhibition', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('invasion', 'CPA', (81, 89))	('miR-381', 'Gene', (44, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('gastric cancer', 'Disease', (3, 17))	('migration', 'CPA', (95, 104))	('enhances', 'PosReg', (52, 60))	('cell proliferation', 'CPA', (61, 79))
500758	33324542	Mechanistically, miR-381 can target the 3'UTR of ROCK2, which plays an important role in actin cytoskeleton formation, cell proliferation, and cell migration, and inhibit its expression.	('ROCK2', 'Gene', '9475', (49, 54))	('inhibit', 'NegReg', (163, 170))	('expression', 'MPA', (175, 185))	('cell proliferation', 'CPA', (119, 137))	('miR-381', 'Var', (17, 24))	('actin', 'MPA', (89, 94))	('ROCK2', 'Gene', (49, 54))
500759	33324542	Thus, via ROCK2, miR-381 can act as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('miR-381', 'Var', (17, 24))	('ROCK2', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('ROCK2', 'Gene', '9475', (10, 15))
500760	33324542	However, in some types of cancers, miR-381 acts as an oncogene.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('miR-381', 'Var', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
500761	33324542	Gergo et al., identified another pathway, in which miR-381 targets SMARCB1, which encodes a subunit of the SWI/SNF ATP-dependent chromatin-remodeling complex.	('SMARCB1', 'Gene', (67, 74))	('SMARCB1', 'Gene', '6598', (67, 74))	('miR-381', 'Var', (51, 58))
500762	33324542	SMARCB1 expression is absent in 83% of epithelioid sarcomas, and inactivation of SMARCB1 results in aggressive tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (39, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('epithelioid sarcomas', 'Disease', (39, 59))	('inactivation', 'Var', (65, 77))	('SMARCB1', 'Gene', '6598', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('results in', 'Reg', (89, 99))	('tumor', 'Disease', (111, 116))	('SMARCB1', 'Gene', (81, 88))	('SMARCB1', 'Gene', '6598', (0, 7))	('SMARCB1', 'Gene', (0, 7))
500769	33324542	The expression of LRRC4, which is targeted by both miR-381 and miR-182, is decreased in glioma cells.	('glioma', 'Disease', (88, 94))	('expression', 'MPA', (4, 14))	('miR-381', 'Var', (51, 58))	('miR-182', 'Gene', (63, 70))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('LRRC4', 'Gene', (18, 23))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('miR-182', 'Gene', '406958', (63, 70))	('decreased', 'NegReg', (75, 84))
500776	33324542	In breast cancer, endometrial carcinoma, epithelial ovarian cancer, and pancreatic cancer, miR-381 acts as an antioncogene.	('endometrial carcinoma, epithelial ovarian cancer', 'Disease', 'MESH:D010051', (18, 66))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('pancreatic cancer', 'Disease', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (41, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (18, 39))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('miR-381', 'Var', (91, 98))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
500777	33324542	In primary glioma, miR-381 acts as an oncogene and modulates the PI3K/AKT and ERK pathways.	('AKT', 'Gene', '207', (70, 73))	('ERK', 'Gene', '5594', (78, 81))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('modulates', 'Reg', (51, 60))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('AKT', 'Gene', (70, 73))	('ERK', 'Gene', (78, 81))	('glioma', 'Disease', (11, 17))	('miR-381', 'Var', (19, 26))
500788	33324542	Overexpression of miR-381 in OSCC cell lines inhibits cell proliferation by increasing the proportion of G1/G0-phase cells, indicating that miR-381 acts as a tumor suppressor, possibly because miR-381 targets FGFR2 and downregulates it.	('FGFR2', 'Gene', '2263', (209, 214))	('cell proliferation', 'CPA', (54, 72))	('tumor', 'Disease', (158, 163))	('OS', 'Phenotype', 'HP:0002669', (29, 31))	('inhibits', 'NegReg', (45, 53))	('miR-381', 'Var', (140, 147))	('OSCC', 'CellLine', 'CVCL:L894', (29, 33))	('downregulates', 'NegReg', (219, 232))	('increasing', 'PosReg', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('FGFR2', 'Gene', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('miR-381', 'Var', (193, 200))
500791	33324542	Thus, by targeting FGFR2 and inhibiting EMT, miR-381-3p acts as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('miR-381-3p', 'Chemical', '-', (45, 55))	('FGFR2', 'Gene', (19, 24))	('FGFR2', 'Gene', '2263', (19, 24))	('EMT', 'CPA', (40, 43))	('miR-381-3p', 'Var', (45, 55))	('inhibiting', 'NegReg', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('targeting', 'Reg', (9, 18))
500792	33324542	MiR-381 can directly bind to the 3'UTR of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and inhibit its expression.	('C/EBPalpha', 'Gene', '1050', (80, 90))	('CCAAT/enhancer-binding protein alpha', 'Gene', '1050', (42, 78))	('CCAAT/enhancer-binding protein alpha', 'Gene', (42, 78))	('expression', 'MPA', (108, 118))	('bind', 'Interaction', (21, 25))	('inhibit', 'NegReg', (96, 103))	('C/EBPalpha', 'Gene', (80, 90))	('MiR-381', 'Var', (0, 7))
500794	33324542	Thus, miR-381 inhibits Cx43 expression via the C/EBPalpha-binding element AATTGTC in the Cx43 promoter region.	('inhibits', 'NegReg', (14, 22))	('C/EBPalpha', 'Gene', (47, 57))	('Cx43', 'Gene', (23, 27))	('Cx43', 'Gene', '2697', (23, 27))	('miR-381', 'Var', (6, 13))	('C/EBPalpha', 'Gene', '1050', (47, 57))	('Cx43', 'Gene', '2697', (89, 93))	('Cx43', 'Gene', (89, 93))
500796	33324542	Thus, miR-381 can suppress the C/EBPalpha- and Cx43-dependent invasion of breast cancer cells.	('breast cancer', 'Disease', (74, 87))	('suppress', 'NegReg', (18, 26))	('C/EBPalpha', 'Gene', '1050', (31, 41))	('Cx43', 'Gene', '2697', (47, 51))	('miR-381', 'Var', (6, 13))	('Cx43', 'Gene', (47, 51))	('C/EBPalpha', 'Gene', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
500800	33324542	The absence of Cx43 can enhance the aggressiveness of pancreatic cancer, indicating its protective effects.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('Cx43', 'Gene', '2697', (15, 19))	('Cx43', 'Gene', (15, 19))	('enhance', 'PosReg', (24, 31))	('aggressiveness', 'Phenotype', 'HP:0000718', (36, 50))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('aggressiveness of pancreatic cancer', 'Disease', (36, 71))	('absence', 'Var', (4, 11))	('aggressiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (36, 71))
500815	33324542	Inhibition of miR-381 increases the expression of MMP-2 and MMP-9, indicating that downregulation of miR-381 leads to cancer cell migration and invasion.	('miR-381', 'Gene', (101, 108))	('cancer', 'Disease', (118, 124))	('MMP-2', 'Gene', (50, 55))	('leads', 'Reg', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('invasion', 'CPA', (144, 152))	('MMP-2', 'Gene', '4313', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('downregulation', 'NegReg', (83, 97))	('Inhibition', 'Var', (0, 10))	('MMP-9', 'Gene', '4318', (60, 65))	('increases', 'PosReg', (22, 31))	('miR-381', 'Gene', (14, 21))	('MMP-9', 'Gene', (60, 65))	('expression', 'MPA', (36, 46))
500828	33324542	By targeting FGF7, miR-381 also suppresses the migration and invasion of cervical cell lines.	('suppresses', 'NegReg', (32, 42))	('FGF7', 'Gene', '2252', (13, 17))	('targeting', 'Reg', (3, 12))	('FGF7', 'Gene', (13, 17))	('miR-381', 'Var', (19, 26))
500841	33324542	CUL4B epigenetically inhibits many tumor suppressors, including insulin-like growth factor-binding protein 3 (IGFBP3), PTEN, and p16.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('CUL4B', 'Gene', '8450', (0, 5))	('inhibits', 'NegReg', (21, 29))	('p16', 'Gene', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IGFBP3', 'Gene', (110, 116))	('epigenetically', 'Var', (6, 20))	('tumor', 'Disease', (35, 40))	('PTEN', 'Gene', (119, 123))	('CUL4B', 'Gene', (0, 5))	('insulin-like growth factor-binding protein 3', 'Gene', '3486', (64, 108))	('PTEN', 'Gene', '5728', (119, 123))	('p16', 'Gene', '1029', (129, 132))	('IGFBP3', 'Gene', '3486', (110, 116))	('insulin-like growth factor-binding protein 3', 'Gene', (64, 108))
500843	33324542	In gastric carcinoma, CUL4B is upregulated and targeted by miR-381 and miR-489, and silencing of CUL4B inhibits the proliferation and migration of gastric cancer cells via the Wnt/beta-catenin signaling pathway.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('inhibits', 'NegReg', (103, 111))	('miR-381', 'Var', (59, 66))	('CUL4B', 'Gene', '8450', (97, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('silencing', 'Var', (84, 93))	('miR-489', 'Gene', '574442', (71, 78))	('proliferation', 'CPA', (116, 129))	('CUL4B', 'Gene', (22, 27))	('beta-catenin', 'Gene', (180, 192))	('beta-catenin', 'Gene', '1499', (180, 192))	('CUL4B', 'Gene', '8450', (22, 27))	('gastric cancer', 'Disease', (147, 161))	('miR-489', 'Gene', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('upregulated', 'PosReg', (31, 42))	('gastric carcinoma', 'Disease', (3, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('CUL4B', 'Gene', (97, 102))
500845	33324542	Thus, via the miR-381/489-CUL4B axis, miR-381 and miR-489 suppress cell proliferation, gastric carcinoma invasion, and EMT.	('miR-489', 'Gene', (50, 57))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (87, 104))	('gastric carcinoma invasion', 'Disease', 'MESH:D013274', (87, 113))	('CUL4B', 'Gene', (26, 31))	('miR-381', 'Var', (38, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('gastric carcinoma invasion', 'Disease', (87, 113))	('miR-489', 'Gene', '574442', (50, 57))	('EMT', 'CPA', (119, 122))	('cell proliferation', 'CPA', (67, 85))	('CUL4B', 'Gene', '8450', (26, 31))	('suppress', 'NegReg', (58, 66))
500851	33324542	Based on the results of a previous study showing that TMEM16A contributes to cell invasion via the TGF-beta signaling pathway, miR-381 suppresses the TGF-beta signaling pathway and, as a result, inhibits EMT.	('suppresses', 'NegReg', (135, 145))	('inhibits', 'NegReg', (195, 203))	('miR-381', 'Var', (127, 134))	('TGF-beta', 'Gene', '7039', (99, 107))	('TGF-beta', 'Gene', '7039', (150, 158))	('EMT', 'CPA', (204, 207))	('TMEM16A', 'Gene', (54, 61))	('cell invasion', 'CPA', (77, 90))	('TMEM16A', 'Gene', '55107', (54, 61))	('TGF-beta', 'Gene', (99, 107))	('TGF-beta', 'Gene', (150, 158))
500853	33324542	Thus, by targeting TMEM16A, miR-381 can suppress the TGF-beta signaling pathway and inhibit EMT progression, ultimately suppressing cell proliferation, migration, and invasion.	('TGF-beta', 'Gene', '7039', (53, 61))	('migration', 'CPA', (152, 161))	('suppressing', 'NegReg', (120, 131))	('inhibit', 'NegReg', (84, 91))	('TMEM16A', 'Gene', (19, 26))	('miR-381', 'Var', (28, 35))	('EMT progression', 'CPA', (92, 107))	('invasion', 'CPA', (167, 175))	('suppress', 'NegReg', (40, 48))	('cell proliferation', 'CPA', (132, 150))	('TGF-beta', 'Gene', (53, 61))	('TMEM16A', 'Gene', '55107', (19, 26))	('targeting', 'Reg', (9, 18))
500855	33324542	In gastric carcinoma cell lines, knockdown of CAT104 has effects similar to those of an miR-381 inhibitor, indicating that CAT104 inhibits the expression of miR-381, resulting in enhanced cell migration and invasion.	('cell migration', 'CPA', (188, 202))	('CAT104', 'Chemical', '-', (46, 52))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('expression', 'MPA', (143, 153))	('enhanced', 'PosReg', (179, 187))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('CAT104', 'Chemical', '-', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('miR-381', 'Gene', (157, 164))	('CAT104', 'Var', (123, 129))	('gastric carcinoma', 'Disease', (3, 20))	('inhibits', 'NegReg', (130, 138))	('invasion', 'CPA', (207, 215))
500856	33324542	Furthermore, miR-381 targets ZEB1, which is involved in the Wnt/beta-catenin pathway, and induces apoptosis.	('apoptosis', 'CPA', (98, 107))	('ZEB1', 'Gene', '6935', (29, 33))	('induces', 'PosReg', (90, 97))	('miR-381', 'Var', (13, 20))	('ZEB1', 'Gene', (29, 33))	('beta-catenin', 'Gene', (64, 76))	('beta-catenin', 'Gene', '1499', (64, 76))
500873	33324542	In addition, inhibition of ID1 decreases tumor growth in animal models.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('decreases tumor', 'Disease', 'MESH:D002303', (31, 46))	('inhibition', 'Var', (13, 23))	('ID1', 'Gene', '3397', (27, 30))	('decreases tumor', 'Disease', (31, 46))	('ID1', 'Gene', (27, 30))
500877	33324542	Src inhibition can lead to increased miR-381 expression and ID1 downregulation.	('increased', 'PosReg', (27, 36))	('ID1', 'Gene', '3397', (60, 63))	('downregulation', 'NegReg', (64, 78))	('Src', 'Gene', (0, 3))	('Src', 'Gene', '6714', (0, 3))	('inhibition', 'Var', (4, 14))	('expression', 'MPA', (45, 55))	('miR-381', 'Protein', (37, 44))	('ID1', 'Gene', (60, 63))
500879	33324542	Thus, miR-381 is involved in the Src-ID1 pathway and may be a potential target via EMT inhibition.	('Src', 'Gene', (33, 36))	('Src', 'Gene', '6714', (33, 36))	('ID1', 'Gene', '3397', (37, 40))	('involved', 'Reg', (17, 25))	('miR-381', 'Var', (6, 13))	('ID1', 'Gene', (37, 40))
500880	33324542	Overexpression of miR-381-3p significantly inhibits cell proliferation and migration.	('miR-381-3p', 'Var', (18, 28))	('inhibits', 'NegReg', (43, 51))	('miR-381-3p', 'Chemical', '-', (18, 28))
500881	33324542	MiR-381 inhibits bladder cancer cell proliferation by regulating CDK6, resulting in G1-phase arrest.	('regulating', 'Reg', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (17, 31))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('inhibits', 'NegReg', (8, 16))	('arrest', 'Disease', (93, 99))	('CDK6', 'Gene', (65, 69))	('bladder cancer', 'Disease', (17, 31))	('CDK6', 'Gene', '1021', (65, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (17, 31))	('MiR-381', 'Var', (0, 7))
500882	33324542	MiR-381 can also inhibit migration by downregulating MET and CCNA2, thus resulting in EMT progression.	('CCNA2', 'Gene', '890', (61, 66))	('migration', 'CPA', (25, 34))	('resulting in', 'Reg', (73, 85))	('inhibit', 'NegReg', (17, 24))	('EMT progression', 'CPA', (86, 101))	('CCNA2', 'Gene', (61, 66))	('MET', 'Gene', '79811', (53, 56))	('MiR-381', 'Var', (0, 7))	('MET', 'Gene', (53, 56))	('downregulating', 'NegReg', (38, 52))
500884	33324542	Inhibition of miR-381 results in cell proliferation, and liver receptor homolog-1 (LRH-1) is the target of miR-381.	('liver receptor homolog-1', 'Gene', '2494', (57, 81))	('liver receptor homolog-1', 'Gene', (57, 81))	('LRH-1', 'Gene', '2494', (83, 88))	('LRH-1', 'Gene', (83, 88))	('Inhibition', 'Var', (0, 10))	('cell proliferation', 'CPA', (33, 51))	('miR-381', 'Gene', (14, 21))
500887	33324542	In conclusion, through LRH-1, miR-381 inhibits tumor progression in colon cancer.	('LRH-1', 'Gene', (23, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('inhibits', 'NegReg', (38, 46))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('colon cancer', 'Disease', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('LRH-1', 'Gene', '2494', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (47, 52))	('miR-381', 'Var', (30, 37))
500888	33324542	In hepatocellular carcinoma tissues, miR-381 is downregulated, and overexpression of miR-381 in hepatocellular carcinoma cell lines results in decreased cell proliferation and invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('miR-381', 'Var', (85, 92))	('hepatocellular carcinoma', 'Disease', (96, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('decreased', 'NegReg', (143, 152))	('overexpression', 'PosReg', (67, 81))	('downregulated', 'NegReg', (48, 61))	('miR-381', 'Gene', (37, 44))	('cell proliferation', 'CPA', (153, 171))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('invasion', 'CPA', (176, 184))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))
500892	33324542	Overexpression of LRH-1 in breast cancer results in cell migration and invasion.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cell migration', 'CPA', (52, 66))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('invasion', 'CPA', (71, 79))	('LRH-1', 'Gene', '2494', (18, 23))	('breast cancer', 'Disease', (27, 40))	('LRH-1', 'Gene', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('Overexpression', 'Var', (0, 14))
500898	33324542	performed a computational analysis of cancer tissues from 103 breast cancer patients and similarly concluded that the levels of miR-381 and miR-486 are reduced in cancer tissues.	('patients', 'Species', '9606', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('miR-486', 'Gene', '619554', (140, 147))	('levels', 'MPA', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('miR-486', 'Gene', (140, 147))	('reduced', 'NegReg', (152, 159))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('miR-381', 'Var', (128, 135))	('breast cancer', 'Disease', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (69, 75))
500902	33324542	Both miR-381 and miR-486 can target JARID1B and inhibit its expression, which can induce DNA damage accumulation.	('expression', 'MPA', (60, 70))	('induce', 'Reg', (82, 88))	('miR-486', 'Gene', (17, 24))	('miR-486', 'Gene', '619554', (17, 24))	('miR-381', 'Var', (5, 12))	('JARID1B', 'Gene', '10765', (36, 43))	('DNA damage accumulation', 'MPA', (89, 112))	('target', 'Reg', (29, 35))	('JARID1B', 'Gene', (36, 43))	('inhibit', 'NegReg', (48, 55))
500905	33324542	Thus, miR-381-induced JARID1B downregulation causes hypersensitivity to DNA damage and BRCA1 upregulation, which plays an important role in breast cancer migration.	('upregulation', 'PosReg', (93, 105))	('JARID1B', 'Gene', '10765', (22, 29))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('hypersensitivity', 'Disease', (52, 68))	('hypersensitivity', 'Disease', 'MESH:D004342', (52, 68))	('downregulation', 'NegReg', (30, 44))	('BRCA1', 'Gene', '672', (87, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('miR-381-induced', 'Var', (6, 21))	('BRCA1', 'Gene', (87, 92))	('JARID1B', 'Gene', (22, 29))
500907	33324542	WEE1 depletion blocks S phase completion.	('blocks', 'NegReg', (15, 21))	('depletion', 'Var', (5, 14))	('S phase completion', 'CPA', (22, 40))	('WEE1', 'Gene', '7465', (0, 4))	('WEE1', 'Gene', (0, 4))
500916	33324542	In vivo, a study in a xenograft mouse model showed that UBE2C promotes tumor growth, suggesting that UBE2C promotes cell proliferation, in rectal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (139, 155))	('UBE2C', 'Var', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('promotes', 'PosReg', (62, 70))	('promotes', 'PosReg', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mouse', 'Species', '10090', (32, 37))	('rectal carcinoma', 'Disease', 'MESH:D012004', (139, 155))	('tumor', 'Disease', (71, 76))	('rectal carcinoma', 'Disease', (139, 155))	('cell proliferation', 'CPA', (116, 134))
500923	33324542	Thus, miR-381 can suppress the FYN-MAPK pathway.	('FYN', 'Gene', (31, 34))	('suppress', 'NegReg', (18, 26))	('miR-381', 'Var', (6, 13))	('FYN', 'Gene', '2534', (31, 34))
500925	33324542	Thus, miR-381 increases drug sensitivity in breast cancer via the FYN-MAPK pathway.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('increases', 'PosReg', (14, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('breast cancer', 'Disease', (44, 57))	('drug sensitivity', 'Phenotype', 'HP:0020174', (24, 40))	('miR-381', 'Var', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('FYN', 'Gene', (66, 69))	('FYN', 'Gene', '2534', (66, 69))	('drug sensitivity', 'MPA', (24, 40))
500928	33324542	Similar to its effect on DOX sensitivity, miR-381 targets MDR1 and promotes cisplatin sensitivity in breast cancer cells.	('promotes', 'PosReg', (67, 75))	('DOX', 'Chemical', 'MESH:D004317', (25, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('miR-381', 'Var', (42, 49))	('targets', 'Reg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('MDR1', 'Gene', (58, 62))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('cisplatin sensitivity', 'MPA', (76, 97))	('MDR1', 'Gene', '5243', (58, 62))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
500931	33324542	Genetic knockdown of MDR1 enhances the chemosensitivity of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('knockdown', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('MDR1', 'Gene', (21, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('enhances', 'PosReg', (26, 34))	('MDR1', 'Gene', '5243', (21, 25))
500932	33324542	Thus, targeting of MDR1 by miR-381 could be a therapeutic strategy.	('MDR1', 'Gene', (19, 23))	('miR-381', 'Var', (27, 34))	('MDR1', 'Gene', '5243', (19, 23))
500937	33324542	Both miR-381 and miR-495 target the 3'UTR of the MDR1 gene and inhibit its expression.	('miR-495', 'Gene', (17, 24))	('miR-495', 'Gene', '574453', (17, 24))	('MDR1', 'Gene', (49, 53))	('target', 'Reg', (25, 31))	('MDR1', 'Gene', '5243', (49, 53))	('inhibit', 'NegReg', (63, 70))	('expression', 'MPA', (75, 85))	('miR-381', 'Var', (5, 12))
500939	33324542	Thus, miR-381 and miR-495 provide a novel approach to leukemia therapy.	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('miR-381', 'Var', (6, 13))	('miR-495', 'Gene', (18, 25))	('leukemia', 'Disease', (54, 62))	('leukemia', 'Disease', 'MESH:D007938', (54, 62))	('miR-495', 'Gene', '574453', (18, 25))
500942	33324542	In a mouse model, cells with miR-381 inhibition were injected into nude mice, and inhibition of miR-381 was found to promote chemoresistance to Ci and Pa. Drug resistance is also a major problem in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('Drug resistance', 'Phenotype', 'HP:0020174', (155, 170))	('Ci', 'Chemical', 'MESH:D002945', (144, 146))	('mouse', 'Species', '10090', (5, 10))	('inhibition', 'Var', (82, 92))	('nude mice', 'Species', '10090', (67, 76))	('miR-381', 'Gene', (96, 103))	('NSCLC', 'Disease', (198, 203))	('promote', 'PosReg', (117, 124))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('Pa', 'Chemical', 'MESH:D017239', (151, 153))
500944	33324542	In NSCLC cell lines, activation of NF-kappaB leads to cisplatin chemoresistance, and inhibition of NF-kappaB can enhance cisplatin efficiency.	('NSCLC', 'Disease', (3, 8))	('NF-kappaB', 'Gene', '4790', (99, 108))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('cisplatin chemoresistance', 'MPA', (54, 79))	('inhibition', 'Var', (85, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('NF-kappaB', 'Gene', (99, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('NF-kappaB', 'Gene', '4790', (35, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('activation', 'PosReg', (21, 31))	('cisplatin', 'MPA', (121, 130))	('NF-kappaB', 'Gene', (35, 44))	('enhance', 'PosReg', (113, 120))
500945	33324542	MiR-381 suppresses the activation of NF-kappaB via ID1.	('suppresses', 'NegReg', (8, 18))	('ID1', 'Gene', (51, 54))	('NF-kappaB', 'Gene', (37, 46))	('ID1', 'Gene', '3397', (51, 54))	('NF-kappaB', 'Gene', '4790', (37, 46))	('MiR-381', 'Var', (0, 7))
500947	33324542	Moreover, delivery of miR-381 decreases the IC50 values of cisplatin by six fold in NSCLC cell lines, indicating that miR-381 induces cisplatin sensitivity in NSCLC cells.	('induces', 'PosReg', (126, 133))	('decreases', 'NegReg', (30, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('IC50 values of cisplatin', 'MPA', (44, 68))	('cisplatin sensitivity', 'MPA', (134, 155))	('NSCLC', 'Disease', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('NSCLC', 'Disease', (84, 89))	('miR-381', 'Var', (118, 125))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('miR-381', 'Var', (22, 29))
500948	33324542	Thus, in NSCLC cells, miR-381 regulates the cell cycle and chemosensitivity, and restoration of miR-381 expression may be a therapeutic approach in NSCLC.	('chemosensitivity', 'CPA', (59, 75))	('NSCLC', 'Disease', (9, 14))	('NSCLC', 'Disease', (148, 153))	('regulates', 'Reg', (30, 39))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('NSCLC', 'Disease', 'MESH:D002289', (9, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (9, 14))	('miR-381', 'Gene', (96, 103))	('restoration', 'Var', (81, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('cell cycle', 'CPA', (44, 54))
500949	33324542	Though in most occasions miR-381 exerts tumor suppressor functions, in some tumors, miR-381 exerts oncogenic functions.	('miR-381', 'Var', (84, 91))	('exerts', 'Reg', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('oncogenic functions', 'CPA', (99, 118))	('tumors', 'Disease', (76, 82))	('tumor', 'Disease', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('miR-381', 'Gene', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
500953	33324542	The filament light polypeptide (NEFL) gene, a tumor suppressor gene, is also a target of miR-381.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('NEFL', 'Gene', '4747', (32, 36))	('miR-381', 'Var', (89, 96))	('NEFL', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
500980	33324542	MiR-381 can bind to the 3'UTR of the VEGF-C gene and repress its expression, thus repressing VEGF-C-mediated lymphangiogenesis.	('VEGF-C', 'Gene', '7424', (37, 43))	('VEGF-C', 'Gene', (93, 99))	('VEGF-C', 'Gene', (37, 43))	('repress', 'NegReg', (53, 60))	('expression', 'MPA', (65, 75))	('repressing', 'NegReg', (82, 92))	('VEGF-C', 'Gene', '7424', (93, 99))	('MiR-381', 'Var', (0, 7))
500991	33324542	Inhibition of miRNA-381 leads to radioresistance and aggressive behaviors in esophageal squamous cell carcinoma cell lines.	('miRNA-381', 'Chemical', '-', (14, 23))	('aggressive behaviors', 'Disease', 'MESH:D001523', (53, 73))	('aggressive behavior', 'Phenotype', 'HP:0000718', (53, 72))	('radioresistance', 'CPA', (33, 48))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('aggressive behaviors', 'Phenotype', 'HP:0000718', (53, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('aggressive behaviors', 'Disease', (53, 73))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('Inhibition', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('miRNA-381', 'Gene', (14, 23))
500992	33324542	In vivo, cell lines with higher miRNA-381 expression levels generate tumors less aggressively, supporting the hypothesis that miRNA-381 inhibits tumor growth and aggressive behaviors.	('expression', 'MPA', (42, 52))	('tumors less aggressively', 'Disease', 'MESH:D001523', (69, 93))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (145, 150))	('aggressive behaviors', 'Phenotype', 'HP:0000718', (162, 182))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('aggressive behavior', 'Phenotype', 'HP:0000718', (162, 181))	('inhibits', 'NegReg', (136, 144))	('miRNA-381', 'Var', (32, 41))	('aggressive behaviors', 'Disease', (162, 182))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('miRNA-381', 'Var', (126, 135))	('miRNA-381', 'Chemical', '-', (32, 41))	('aggressive behaviors', 'Disease', 'MESH:D001523', (162, 182))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumors less aggressively', 'Disease', (69, 93))	('miRNA-381', 'Chemical', '-', (126, 135))
500993	33324542	One study showed that miRNA-381 is associated with radiosensitivity in esophageal squamous cell carcinoma; miRNA-381 was increased in radiosensitive but decreased in radioresistant esophageal squamous cell carcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('miRNA-381', 'Chemical', '-', (107, 116))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('esophageal squamous cell carcinoma', 'Disease', (181, 215))	('decreased', 'NegReg', (153, 162))	('miRNA-381', 'Var', (107, 116))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('miRNA-381', 'Chemical', '-', (22, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (181, 215))
500995	33324542	MiRNA-381 sensitizes esophageal squamous cell carcinoma cells to irradiation and inhibits their proliferation, migration, and invasion, indicating that miRNA-381 is a potential biomarker and potential therapeutic target for esophageal squamous cell carcinoma.	('inhibits', 'NegReg', (81, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (21, 55))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (224, 258))	('migration', 'CPA', (111, 120))	('miRNA-381', 'Chemical', '-', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('proliferation', 'CPA', (96, 109))	('MiRNA-381', 'Chemical', '-', (0, 9))	('MiRNA-381', 'Var', (0, 9))	('esophageal squamous cell carcinoma', 'Disease', (224, 258))	('esophageal squamous cell carcinoma', 'Disease', (21, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (235, 258))	('invasion', 'CPA', (126, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('sensitizes', 'Reg', (10, 20))
500996	33324542	Moreover, another group found that miR-381 expression is downregulated in esophageal squamous cell carcinoma tissues and cells, and that restoration of miR-381 expression enhances the apoptosis of esophageal squamous cell carcinoma cells.	('expression', 'MPA', (160, 170))	('esophageal squamous cell carcinoma', 'Disease', (74, 108))	('esophageal squamous cell carcinoma', 'Disease', (197, 231))	('downregulated', 'NegReg', (57, 70))	('miR-381', 'Gene', (152, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('enhances', 'PosReg', (171, 179))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (74, 108))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (197, 231))	('miR-381', 'Gene', (35, 42))	('restoration', 'Var', (137, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('expression', 'MPA', (43, 53))	('apoptosis', 'CPA', (184, 193))
500998	33324542	By targeting XIAP, which is upregulated in esophageal squamous cell carcinoma tissues, miR-381 induces caspase-3-dependent apoptosis in these cells.	('esophageal squamous cell carcinoma', 'Disease', (43, 77))	('caspase-3', 'Gene', '836', (103, 112))	('XIAP', 'Gene', '331', (13, 17))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (43, 77))	('miR-381', 'Var', (87, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('upregulated', 'PosReg', (28, 39))	('XIAP', 'Gene', (13, 17))	('induces', 'PosReg', (95, 102))	('caspase-3', 'Gene', (103, 112))
501002	33324542	LRH-1 is a direct target of miR-381.	('miR-381', 'Var', (28, 35))	('LRH-1', 'Gene', (0, 5))	('LRH-1', 'Gene', '2494', (0, 5))
501008	33324542	By binding to the 3'UTR of CD1c, miR-381 significantly reduces CD1c expression at both the mRNA and protein levels.	('CD1c', 'Gene', '911', (63, 67))	('expression', 'MPA', (68, 78))	('binding', 'Interaction', (3, 10))	('CD1c', 'Gene', (27, 31))	('reduces', 'NegReg', (55, 62))	('CD1c', 'Gene', (63, 67))	('CD1c', 'Gene', '911', (27, 31))	('miR-381', 'Var', (33, 40))
501011	33324542	MiR-381 can inhibit CD1c expression via IL-10.	('inhibit', 'NegReg', (12, 19))	('IL-10', 'Gene', (40, 45))	('CD1c', 'Gene', (20, 24))	('IL-10', 'Gene', '3586', (40, 45))	('CD1c', 'Gene', '911', (20, 24))	('MiR-381', 'Var', (0, 7))
501021	33324542	In OSCC, miR-381 suppresses EMT by inhibiting FGFR2.	('OSCC', 'CellLine', 'CVCL:L894', (3, 7))	('EMT', 'CPA', (28, 31))	('FGFR2', 'Gene', (46, 51))	('FGFR2', 'Gene', '2263', (46, 51))	('suppresses', 'NegReg', (17, 27))	('inhibiting', 'NegReg', (35, 45))	('OS', 'Phenotype', 'HP:0002669', (3, 5))	('miR-381', 'Var', (9, 16))
501025	33324542	In gastric carcinoma, miR-381 inhibits Sox4, TMEM16A, and ZEB1 and suppresses metastasis.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('suppresses', 'NegReg', (67, 77))	('TMEM16A', 'Gene', '55107', (45, 52))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('ZEB1', 'Gene', (58, 62))	('gastric carcinoma', 'Disease', (3, 20))	('Sox4', 'Gene', (39, 43))	('Sox4', 'Gene', '6659', (39, 43))	('metastasis', 'CPA', (78, 88))	('TMEM16A', 'Gene', (45, 52))	('ZEB1', 'Gene', '6935', (58, 62))	('inhibits', 'NegReg', (30, 38))	('miR-381', 'Var', (22, 29))
501026	33324542	In lung adenocarcinoma, miR-381 inhibits ID1 and suppresses EMT.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('miR-381', 'Var', (24, 31))	('inhibits', 'NegReg', (32, 40))	('EMT', 'CPA', (60, 63))	('ID1', 'Gene', '3397', (41, 44))	('suppresses', 'NegReg', (49, 59))	('lung adenocarcinoma', 'Disease', (3, 22))	('ID1', 'Gene', (41, 44))
501027	33324542	In colon cancer and hepatocellular carcinoma, miR-381 inhibits LRH-1 and suppresses cell growth.	('suppresses', 'NegReg', (73, 83))	('hepatocellular carcinoma', 'Disease', (20, 44))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (20, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('LRH-1', 'Gene', '2494', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cell growth', 'CPA', (84, 95))	('LRH-1', 'Gene', (63, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('inhibits', 'NegReg', (54, 62))	('miR-381', 'Var', (46, 53))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (20, 44))	('colon cancer', 'Disease', (3, 15))
501029	33324542	In breast cancer, miR-381 inhibits WEE1 and blocks the G2/M transition.	('inhibits', 'NegReg', (26, 34))	('blocks', 'NegReg', (44, 50))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('WEE1', 'Gene', (35, 39))	('WEE1', 'Gene', '7465', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('G2/M transition', 'CPA', (55, 70))	('miR-381', 'Var', (18, 25))
501030	33324542	In colon cancer, miR-381 inhibits UBE2C and, as a result, suppresses cell growth.	('UBE2C', 'Protein', (34, 39))	('miR-381', 'Var', (17, 24))	('inhibits', 'NegReg', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('suppresses', 'NegReg', (58, 68))	('colon cancer', 'Disease', (3, 15))	('cell growth', 'CPA', (69, 80))
501032	33324542	MiR-381 can also increase cisplatin sensitivity in NSCLC.	('cisplatin sensitivity', 'MPA', (26, 47))	('NSCLC', 'Disease', (51, 56))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('increase', 'PosReg', (17, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))	('MiR-381', 'Var', (0, 7))
501035	33324542	In chondrosarcoma, miR-381 inhibits VEGF-dependent lymphangiogenesis, and in esophageal squamous cell carcinoma, miR-381 increases radiosensitivity.	('miR-381', 'Var', (113, 120))	('inhibits', 'NegReg', (27, 35))	('chondrosarcoma', 'Disease', (3, 17))	('increases', 'PosReg', (121, 130))	('VEGF', 'Gene', (36, 40))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('radiosensitivity', 'MPA', (131, 147))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (3, 17))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('VEGF', 'Gene', '7422', (36, 40))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (121, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('miR-381', 'Var', (19, 26))	('chondrosarcoma', 'Disease', 'MESH:D002813', (3, 17))
501036	33324542	In NSCLC, miR-381 suppresses the immune response.	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('immune response', 'CPA', (33, 48))	('miR-381', 'Var', (10, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('suppresses', 'NegReg', (18, 28))
501040	33324542	Considering that miR-381 can enhance chemo- and radiosensitivity, combination treatment with miR-381 and chemotherapy or radiation may be a novel and comprehensive therapeutic strategy for cancer.	('miR-381', 'Var', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('miR-381', 'Var', (93, 100))	('enhance', 'PosReg', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
501041	33324542	The current methods for diagnosing cancer, including detection of serum tumor markers, such as CA125, CA199, and CEA, and traditional imaging techniques, such as CT, have low sensitivity and specificity.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('CA125', 'Gene', '94025', (95, 100))	('tumor', 'Disease', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CA199', 'Var', (102, 107))	('CA125', 'Gene', (95, 100))	('CEA', 'Gene', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('CEA', 'Gene', '5670', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', (35, 41))
501042	33324542	The levels of miR-381 were assessed in multiple cancers, and studies have shown that in some cancers, miR-381 is associated with prognosis and is thus a novel biomarker (Table 4).	('cancers', 'Disease', (48, 55))	('cancers', 'Disease', (93, 100))	('associated with', 'Reg', (113, 128))	('prognosis', 'CPA', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('miR-381', 'Var', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('multiple cancers', 'Disease', (39, 55))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('multiple cancers', 'Disease', 'MESH:D009369', (39, 55))
501045	33324542	In another study that enrolled 103 breast cancer patients, miR-381 was expressed at lower levels in breast cancer samples than in normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('miR-381', 'Var', (59, 66))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (35, 48))	('lower', 'NegReg', (84, 89))	('breast cancer', 'Disease', (100, 113))	('patients', 'Species', '9606', (49, 57))
501048	33324542	Patients with lower levels of miR-381 had poorer survival (P = 0.023) than those with high levels of miR-381.	('Patients', 'Species', '9606', (0, 8))	('poorer', 'NegReg', (42, 48))	('miR-381', 'Var', (30, 37))	('survival', 'MPA', (49, 57))
501065	33324542	Moreover, the Kaplan-Meier curve showed that patients with higher miR-381 expression exhibited better overall survival (P = 0.0001), and miR-381 is an independent prognostic factor for 5-year survival (P = 0.002).	('expression', 'MPA', (74, 84))	('miR-381', 'Var', (137, 144))	('patients', 'Species', '9606', (45, 53))	('miR-381', 'Gene', (66, 73))	('higher', 'PosReg', (59, 65))	('overall survival', 'CPA', (102, 118))	('better', 'PosReg', (95, 101))
501066	33324542	In a study of osteosarcoma, 60 patients were divided into two groups according to miR-381 expression, and miR-381 expression was found to be associated with survival time.	('survival time', 'CPA', (157, 170))	('osteosarcoma', 'Disease', (14, 26))	('osteosarcoma', 'Phenotype', 'HP:0002669', (14, 26))	('miR-381', 'Gene', (82, 89))	('osteosarcoma', 'Disease', 'MESH:D012516', (14, 26))	('associated', 'Reg', (141, 151))	('patients', 'Species', '9606', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('miR-381 expression', 'Var', (106, 124))
501075	33324542	Although various studies have revealed that miR-381 is associated with cancer prognosis, miRNAs still have some disadvantages.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('associated', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-381', 'Var', (44, 51))
501076	33324542	MiR-381 can act as a tumor suppressor in various cancers and, in contrast, can act as an oncogene in other types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('tumor', 'Disease', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cancers', 'Disease', (49, 56))	('MiR-381', 'Var', (0, 7))
501081	33324542	Various studies have been performed to explain the signaling pathways affected by miR-381 in cancer, and the findings have indicated that miR-381 could be a novel therapeutic target in cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('miR-381', 'Gene', (82, 89))	('miR-381', 'Var', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
501085	32793288	Growing evidence demonstrates that dysregulation of AS is associated with tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('associated', 'Reg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('dysregulation', 'Var', (35, 48))
501100	32793288	Dysregulation of AS is associated with manifold pathological processes, including cancers where it promotes cancer development by causing the loss-of-function in tumor suppressors or the activation of oncogenes and cancer pathways.	('Dysregulation', 'Var', (0, 13))	('activation', 'PosReg', (187, 197))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('tumor', 'Disease', (162, 167))	('cancer', 'Disease', (82, 88))	('cancers', 'Disease', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('promotes', 'PosReg', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('loss-of-function', 'NegReg', (142, 158))	('oncogenes', 'Pathway', (201, 210))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))
501108	32793288	Other studies have found that the CXCR3A variant promotes tumor cell growth while the CXCR3B variant induces tumor cell apoptosis.	('CXCR3', 'Gene', '2833', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('CXCR3', 'Gene', (34, 39))	('promotes', 'PosReg', (49, 57))	('induces', 'PosReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CXCR3', 'Gene', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('variant', 'Var', (41, 48))	('CXCR3', 'Gene', '2833', (34, 39))	('tumor', 'Disease', (109, 114))
501109	32793288	In addition, splicing factors have been shown to play a role in regulating tissue- or cell-type-specific AS, Alterations in the expression and activity of critical splicing factors can cause a string of changes to the AS, which then jointly promote tumor cell growth and survival.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('cause', 'Reg', (185, 190))	('survival', 'CPA', (271, 279))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('promote', 'PosReg', (241, 248))	('tumor', 'Disease', (249, 254))	('changes', 'Reg', (203, 210))	('expression', 'MPA', (128, 138))	('activity', 'MPA', (143, 151))	('Alterations', 'Var', (109, 120))
501118	32793288	For example, in "ERBB2  99888  ES", ERBB2 denotes the corresponding parent gene name, 99888 represents the ID of splicing variant and ES indicates the splicing type.	('ERBB2', 'Gene', (36, 41))	('ES', 'Chemical', '-', (134, 136))	('ERBB2', 'Gene', '2064', (36, 41))	('ERBB2', 'Gene', '2064', (17, 22))	('ES', 'Chemical', '-', (31, 33))	('ERBB2', 'Gene', (17, 22))	('99888', 'Var', (86, 91))
501121	32793288	Univariate Cox regression analysis was conducted to detect the association between the alternative splicing (AS) events and the overall survival (OS) of ESCA patients, with P < 0.05 being considered significant.	('alternative splicing', 'Var', (87, 107))	('overall survival', 'MPA', (128, 144))	('association', 'Interaction', (63, 74))	('ESCA', 'Phenotype', 'HP:0011459', (153, 157))	('ESCA', 'Disease', (153, 157))	('ES', 'Chemical', '-', (153, 155))	('patients', 'Species', '9606', (158, 166))
501131	32793288	Within the integrated AS events profiles of 185 ESCA patients from TCGA SpliceSeq, we detected a total of 50342 AS events in 10766 genes, which included 20843 ESs in 7174 genes, 10033 APs in 4046 genes, 8448 ATs in 3690 genes, 4145 AAs in 2871 genes, 3590 ADs in 2463 genes, 3038 RIs in 2001 genes, and 245 MEs in 237 genes (Figure 2A).	('10033', 'Var', (178, 183))	('8448', 'Var', (203, 207))	('AAs', 'Var', (232, 235))	('patients', 'Species', '9606', (53, 61))	('ESCA', 'Phenotype', 'HP:0011459', (48, 52))	('AD', 'Chemical', '-', (256, 258))	('ESCA', 'Disease', (48, 52))	('ES', 'Chemical', '-', (48, 50))	('ME', 'Chemical', '-', (307, 309))	('ES', 'Chemical', '-', (159, 161))
501148	32793288	Moreover, among these seven parent genes, ERBB2 and C19orf82 possessed the most frequent genetic mutation and the missense mutation was the most common alteration (Figure 8A).	('ERBB2', 'Gene', '2064', (42, 47))	('C19orf82', 'Gene', (52, 60))	('C19orf82', 'Gene', '284385', (52, 60))	('missense mutation', 'Var', (114, 131))	('ERBB2', 'Gene', (42, 47))
501149	32793288	The mutant of ERBB2 and C19orf82 also indicated a significantly shorter OS time than the wild type (Figures 8B,C).	('mutant', 'Var', (4, 10))	('C19orf82', 'Gene', (24, 32))	('C19orf82', 'Gene', '284385', (24, 32))	('ERBB2', 'Gene', '2064', (14, 19))	('ERBB2', 'Gene', (14, 19))	('OS time', 'CPA', (72, 79))	('shorter', 'NegReg', (64, 71))
501162	32793288	Dysregulation of AS in cancer-related genes has been found to participate in many biological processes in tumors, and these abnormally regulated genes can be used as molecular markers for cancer prognosis and treatment.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Dysregulation', 'Var', (0, 13))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('biological', 'CPA', (82, 92))	('participate', 'Reg', (62, 73))	('cancer', 'Disease', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
501168	32793288	One study has demonstrated that ECM1b expression sensitizes ESCA cells to cisplatin, a drug commonly used in ESCA patient treatment.	('ES', 'Chemical', '-', (109, 111))	('ECM1', 'Gene', '1893', (32, 36))	('ES', 'Chemical', '-', (60, 62))	('patient', 'Species', '9606', (114, 121))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('expression', 'Var', (38, 48))	('ESCA', 'Phenotype', 'HP:0011459', (109, 113))	('ESCA', 'Phenotype', 'HP:0011459', (60, 64))	('ECM1', 'Gene', (32, 36))	('ESCA', 'Disease', (60, 64))	('sensitizes', 'Reg', (49, 59))
501182	32793288	In agreement with this, some studies have shown that some splicing variants of genes generated through ES was upregulated in some solid cancers, and can increase the motility of cancer cells.	('splicing variants', 'Var', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('increase', 'PosReg', (153, 161))	('cancer', 'Disease', (136, 142))	('upregulated', 'PosReg', (110, 121))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('ES', 'Chemical', '-', (103, 105))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
501183	32793288	D16ERBB2, a splice variant of ERBB2 generated through the skipping of exon 16, has been shown to exert high tumorigenecity, and a close association with increased tumor invasive properties and metastasis.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('ERBB2', 'Gene', '2064', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('skipping', 'Var', (58, 66))	('ERBB2', 'Gene', (30, 35))	('increased', 'PosReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('metastasis', 'CPA', (193, 203))	('tumor', 'Disease', (108, 113))	('ERBB2', 'Gene', '2064', (3, 8))	('ERBB2', 'Gene', (3, 8))	('tumor', 'Disease', (163, 168))
501191	32793288	Therefore, we hypothesize that the cancer-associated outcomes due to AS alteration may be associated with these common pathways.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('alteration', 'Var', (72, 82))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))
501206	32793288	The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgene.2020.00796/full#supplementary-material AA alternate acceptor site AD alternate donor site AP alternate promoter AS alternative splicing AT alternate terminator AUC area under curve DCA decision curve analysis ES exon skip ESCA esophageal carcinoma HR hazard ratio ME mutually exclusive exons OS overall survival PSI Percent Spliced In RI retained intron RNA-seq RNA sequencing ROC receiver operating characteristic SFs splicing factors TCGA The Cancer Genome Atlas.	('Cancer', 'Phenotype', 'HP:0002664', (564, 570))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (346, 366))	('ES', 'Chemical', '-', (328, 330))	('ME', 'Chemical', '-', (383, 385))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (346, 366))	('Cancer', 'Disease', 'MESH:D009369', (564, 570))	('ESCA', 'Phenotype', 'HP:0011459', (341, 345))	('exon', 'Var', (331, 335))	('carcinoma', 'Phenotype', 'HP:0030731', (357, 366))	('AD', 'Chemical', '-', (185, 187))	('DCA', 'Chemical', '-', (300, 303))	('Cancer', 'Disease', (564, 570))	('esophageal carcinoma', 'Disease', (346, 366))	('ES', 'Chemical', '-', (341, 343))
501208	31703610	Previously, analyzing the cancer genomic data have identified associated mutations among a few genes.	('cancer', 'Disease', (26, 32))	('associated', 'Reg', (62, 72))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (73, 82))
501225	31703610	2a, in all comparisons from BRCA, Lamda3 performs superiorly than the other three rule-interestingness measures.	('Lamda3', 'Var', (34, 40))	('BRCA', 'Phenotype', 'HP:0003002', (28, 32))	('BRCA', 'Gene', (28, 32))	('BRCA', 'Gene', '672', (28, 32))
501233	31703610	Although little is known about HOXA4 in breast cancer currently, the co-occurrence of HOXA3, A4, A5 and A7 in these rules identified an intimate expression relationship between HOXA4 and the other three HOXA genes, suggesting its potential role in carcinogenesis.	('HOXA3', 'Gene', (86, 91))	('HOXA4', 'Gene', '3201', (31, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('expression', 'MPA', (145, 155))	('HOXA', 'Gene', '3197', (31, 35))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('HOXA', 'Gene', '3197', (86, 90))	('HOXA4', 'Gene', (31, 36))	('HOXA', 'Gene', (177, 181))	('breast cancer', 'Disease', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('HOXA', 'Gene', '3197', (203, 207))	('HOXA4', 'Gene', '3201', (177, 182))	('HOXA', 'Gene', (31, 35))	('HOXA', 'Gene', (86, 90))	('carcinogenesis', 'Disease', (248, 262))	('HOXA3', 'Gene', '3200', (86, 91))	('HOXA', 'Gene', '3197', (177, 181))	('HOXA4', 'Gene', (177, 182))	('HOXA', 'Gene', (203, 207))	('carcinogenesis', 'Disease', 'MESH:D063646', (248, 262))	('co-occurrence', 'Var', (69, 82))
501242	31703610	3a, Lamda3 is higher than other two measures in all these three cancer datasets based on Supp = 0.2.	('Lamda3', 'Var', (4, 10))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
501261	31703610	Loss of TAP1 has been reported to render some tumor cells to escape the immune surveillance and contribute to the clinical course of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('contribute', 'Reg', (96, 106))	('esophageal cancer', 'Disease', (133, 150))	('Loss', 'Var', (0, 4))	('TAP1', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('TAP1', 'Gene', '6890', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
501275	31501419	On one hand, pyroptosis can inhibit the occurrence and development of tumors; on the other hand, as a type of proinflammatory death, pyroptosis can form a suitable microenvironment for tumor cell growth and thus promote tumor growth.	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('iron', 'Chemical', 'MESH:D007501', (172, 176))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', (70, 75))	('promote', 'PosReg', (212, 219))	('pyroptosis', 'Var', (133, 143))	('occurrence', 'CPA', (40, 50))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('inhibit', 'NegReg', (28, 35))
501297	31501419	On the other hand, as a type of death, pyroptosis can inhibit the occurrence and development of tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inhibit', 'NegReg', (54, 61))	('pyroptosis', 'Var', (39, 49))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))
501302	31501419	In 1999, the Arturo Zychlinsky laboratory found that knocking out caspase-1 could block the cell death caused by Salmonella.	('knocking out', 'Var', (53, 65))	('block', 'NegReg', (82, 87))	('caspase-1', 'Gene', (66, 75))	('Salmonella', 'Species', '90371', (113, 123))	('cell death', 'CPA', (92, 102))
501313	31501419	Many stimulants, such as bacteria, viruses, fungi, uric acid, and ATP, can activate NLRP3 inflammasomes, while flagellin and type III secretory system proteins can be recognized by the NLRC4, and AIM2 inflammasomes primarily recognize double-stranded DNA contained in bacteria or viruses.	('NLRC4', 'Gene', '58484', (185, 190))	('NLRC4', 'Gene', (185, 190))	('activate', 'PosReg', (75, 83))	('NLRP3', 'Gene', '114548', (84, 89))	('double-stranded', 'Var', (235, 250))	('AIM2', 'Gene', '9447', (196, 200))	('ATP', 'Chemical', 'MESH:D000255', (66, 69))	('uric acid', 'Chemical', 'MESH:D014527', (51, 60))	('AIM2', 'Gene', (196, 200))	('NLRP3', 'Gene', (84, 89))
501329	31501419	The overexpression of GSDMD-cNT alone can cause very strong pyroptosis, while the overexpression of the C-terminal domain and full-length GSDMD do not cause pyroptosis.	('pyroptosis', 'MPA', (60, 70))	('cNT', 'Chemical', '-', (28, 31))	('GSDMD-cNT', 'Var', (22, 31))	('cause', 'Reg', (42, 47))
501330	31501419	When activated caspase-1/4/5/11 cleaves the hinge region between the N- and C-terminal domains to produce GSDMD-cNT, the autoinhibition activity of C-terminal domain is relieved, and the lethal activity of the N-terminal domain is released, causing pyroptosis.	('pyroptosis', 'Disease', (249, 259))	('causing', 'Reg', (241, 248))	('caspase-1/4/5/11', 'Gene', '834;837;838', (15, 31))	('cNT', 'Chemical', '-', (112, 115))	('caspase-1/4/5/11', 'Gene', (15, 31))	('cleaves', 'Var', (32, 39))	('autoinhibition activity', 'MPA', (121, 144))	('lethal activity', 'MPA', (187, 202))
501337	31501419	identified a specific caspase-3 cleavage region between the C- and N-terminal domains of DFNA5/GSDME and established that cells undergo apoptosis after mutation in this cutting region.	('GSDME', 'Chemical', '-', (95, 100))	('DFNA5', 'Gene', (89, 94))	('DFNA5', 'Gene', '1687', (89, 94))	('caspase-3', 'Gene', (22, 31))	('undergo', 'Reg', (128, 135))	('caspase-3', 'Gene', '836', (22, 31))	('mutation', 'Var', (152, 160))	('cleavage', 'MPA', (32, 40))
501339	31501419	Recent studies have indicated that apoptotic caspase-8 can also induce the cleavage of GSDMD and DFNA5/GSDME, thus inducing pyroptosis during Yersinia infection, which indicates that apoptosis and pyroptosis may share many signal pathways.	('induce', 'Reg', (64, 70))	('pyroptosis', 'MPA', (124, 134))	('cleavage', 'MPA', (75, 83))	('GSDME', 'Chemical', '-', (103, 108))	('caspase-8', 'Gene', (45, 54))	('apoptotic', 'Var', (35, 44))	('Yersinia infection', 'Disease', 'MESH:D015009', (142, 160))	('DFNA5', 'Gene', '1687', (97, 102))	('caspase-8', 'Gene', '841', (45, 54))	('Yersinia infection', 'Disease', (142, 160))	('inducing', 'Reg', (115, 123))	('DFNA5', 'Gene', (97, 102))
501345	31501419	These studies indicated that pyroptosis may play a dual role in promoting and inhibiting tumor cell growth in different tumor cells.	('pyroptosis', 'Var', (29, 39))	('inhibiting', 'NegReg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', (120, 125))	('promoting', 'PosReg', (64, 73))
501349	31501419	The AIM2 inflammasome can weaken the activation of S6K1 by targeting mTOR, thus inhibiting the growth of cancer cells, and the accumulation of the AIM2 inflammasome can cause HCC cells pyroptosis, exerting antitumor effects.	('S6K1', 'Gene', (51, 55))	('cancer', 'Disease', (105, 111))	('targeting', 'Reg', (59, 68))	('HCC cells pyroptosis', 'CPA', (175, 195))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('activation', 'MPA', (37, 47))	('accumulation', 'Var', (127, 139))	('S6K1', 'Gene', '6198', (51, 55))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('AIM2', 'Gene', '9447', (147, 151))	('AIM2', 'Gene', '9447', (4, 8))	('inhibiting', 'NegReg', (80, 90))	('mTOR', 'Gene', (69, 73))	('weaken', 'NegReg', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('AIM2', 'Gene', (147, 151))	('AIM2', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (69, 73))	('cause', 'Reg', (169, 174))
501358	31501419	Moreover, DFNA5 methylation was found to be associated with lymph node metastasis.	('associated', 'Reg', (44, 54))	('DFNA5', 'Gene', '1687', (10, 15))	('lymph node metastasis', 'CPA', (60, 81))	('DFNA5', 'Gene', (10, 15))	('methylation', 'Var', (16, 27))
501359	31501419	A study comparing paclitaxel (PTX) drug sensitivity before and after low DFNA5/GSDME expression in MCF-7 cells showed that low DFNA5/GSDME expression reduces the sensitivity of MCF-7 cells to PTX drugs, i.e., the decreased-GSDME increases the resistance of MCF-7 cells to PTX.	('decreased-GSDME', 'Var', (213, 228))	('DFNA5', 'Gene', (127, 132))	('low', 'Var', (123, 126))	('PTX', 'Chemical', 'MESH:D017239', (192, 195))	('sensitivity', 'MPA', (162, 173))	('PTX', 'Chemical', 'MESH:D017239', (272, 275))	('resistance', 'MPA', (243, 253))	('DFNA5', 'Gene', '1687', (73, 78))	('reduces', 'NegReg', (150, 157))	('DFNA5', 'Gene', (73, 78))	('DFNA5', 'Gene', '1687', (127, 132))	('paclitaxel', 'Chemical', 'MESH:D017239', (18, 28))	('PTX', 'Chemical', 'MESH:D017239', (30, 33))	('increases', 'PosReg', (229, 238))	('drug sensitivity', 'Phenotype', 'HP:0020174', (35, 51))	('MCF-7', 'CellLine', 'CVCL:0031', (99, 104))	('GSDME', 'Chemical', '-', (79, 84))	('MCF-7', 'CellLine', 'CVCL:0031', (257, 262))	('GSDME', 'Chemical', '-', (223, 228))	('GSDME', 'Chemical', '-', (133, 138))	('MCF-7', 'CellLine', 'CVCL:0031', (177, 182))
501361	31501419	As a member of the p53 family, P63gamma also increases DFNA5 levels, suggesting that DFNA5 is a transcriptional target of the p53 family (Table 1).	('DFNA5', 'Gene', '1687', (85, 90))	('p53', 'Gene', '7157', (126, 129))	('increases', 'PosReg', (45, 54))	('P63gamma', 'Var', (31, 39))	('DFNA5', 'Gene', (85, 90))	('DFNA5', 'Gene', '1687', (55, 60))	('p53', 'Gene', (19, 22))	('DFNA5', 'Gene', (55, 60))	('p53', 'Gene', '7157', (19, 22))	('p53', 'Gene', (126, 129))
501373	31501419	found that inactivation mutations of Tgfbr2 often occur, which upregulates Gsdmc expression, induces tumor cell proliferation and promotes tumorigenesis.	('inactivation mutations', 'Var', (11, 33))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('promotes', 'PosReg', (130, 138))	('Gsdmc', 'Gene', (75, 80))	('induces', 'PosReg', (93, 100))	('Tgfbr2', 'Gene', '7048', (37, 43))	('Tgfbr2', 'Gene', (37, 43))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('Gsdmc', 'Gene', '56169', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('upregulates', 'PosReg', (63, 74))	('expression', 'MPA', (81, 91))
501374	31501419	Therefore, Gsdmc is an oncogene that may act as a new therapeutic target for CRC treatment with the Tgfbr2 mutation.	('Gsdmc', 'Gene', '56169', (11, 16))	('Tgfbr2', 'Gene', (100, 106))	('CRC', 'Disease', (77, 80))	('Tgfbr2', 'Gene', '7048', (100, 106))	('Gsdmc', 'Gene', (11, 16))	('mutation', 'Var', (107, 115))
501378	31501419	In etoposide-resistant melanoma cells, knockout of DFNA5/GSDME increased cell resistance to etoposide, while upregulation of DFNA5/GSDME expression increased the cell sensitivity to etoposide, suggesting that decreased-DNFA5 is related to the increase in etoposide resistance in melanoma cells.	('etoposide', 'Chemical', 'MESH:D005047', (255, 264))	('increased', 'PosReg', (148, 157))	('DFNA5', 'Gene', '1687', (51, 56))	('DNFA5', 'Chemical', '-', (219, 224))	('DFNA5', 'Gene', (125, 130))	('etoposide', 'Chemical', 'MESH:D005047', (182, 191))	('upregulation', 'PosReg', (109, 121))	('cell resistance to etoposide', 'MPA', (73, 101))	('etoposide', 'Chemical', 'MESH:D005047', (92, 101))	('melanoma', 'Disease', (23, 31))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('GSDME', 'Chemical', '-', (131, 136))	('melanoma', 'Disease', 'MESH:D008545', (279, 287))	('DFNA5', 'Gene', '1687', (125, 130))	('DFNA5', 'Gene', (51, 56))	('etoposide', 'Chemical', 'MESH:D005047', (3, 12))	('GSDME', 'Chemical', '-', (57, 62))	('increased', 'PosReg', (63, 72))	('cell sensitivity to etoposide', 'MPA', (162, 191))	('knockout', 'Var', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('melanoma', 'Disease', (279, 287))
501380	31501419	In melanoma cells, silencing eEF-2K promoted doxorubicin-induced pyroptosis, thus sensitizing melanoma cells to doxorubicin.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('melanoma', 'Disease', (94, 102))	('silencing', 'Var', (19, 28))	('eEF-2K', 'Gene', '29904', (29, 35))	('doxorubicin', 'Chemical', 'MESH:D004317', (45, 56))	('eEF-2K', 'Gene', (29, 35))	('doxorubicin-induced pyroptosis', 'MPA', (45, 75))	('sensitizing', 'Reg', (82, 93))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('promoted', 'PosReg', (36, 44))
501388	31501419	Further studies showed that decreased-GSDMD regulated cell cycle-related proteins expression by activating the STAT3 and PI3K/PKB signal pathways, accelerating S/G2 phase transformation and promoting tumor cell growth.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('PKB', 'Gene', '207', (126, 129))	('STAT3', 'Gene', (111, 116))	('accelerating', 'PosReg', (147, 159))	('S/G2', 'Var', (160, 164))	('PKB', 'Gene', (126, 129))	('S/G2', 'SUBSTITUTION', 'None', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('promoting', 'PosReg', (190, 199))	('activating', 'PosReg', (96, 106))	('tumor', 'Disease', (200, 205))	('decreased-GSDMD', 'Var', (28, 43))	('cell', 'Protein', (54, 58))	('STAT3', 'Gene', '6774', (111, 116))
501390	31501419	The silencing of DFNA5/GSDME was first reported in primary GC and GC cell lines.	('GSDME', 'Chemical', '-', (23, 28))	('DFNA5', 'Gene', '1687', (17, 22))	('silencing', 'Var', (4, 13))	('DFNA5', 'Gene', (17, 22))
501395	31501419	DFNA5/GSDME can be downregulated due to promoter methylation.	('DFNA5', 'Gene', (0, 5))	('promoter methylation', 'Var', (40, 60))	('DFNA5', 'Gene', '1687', (0, 5))	('GSDME', 'Chemical', '-', (6, 11))
501402	31501419	showed that knockout of DFNA5/GSDME can induce the apoptosis-to-pyroptosis switch, supporting the notion that the DFNA5/GSDME level determines the death mode of caspase-3-activated cells.	('caspase-3', 'Gene', '836', (161, 170))	('DFNA5', 'Gene', '1687', (24, 29))	('GSDME', 'Chemical', '-', (30, 35))	('knockout', 'Var', (12, 20))	('GSDME', 'Chemical', '-', (120, 125))	('DFNA5', 'Gene', (24, 29))	('DFNA5', 'Gene', '1687', (114, 119))	('caspase-3', 'Gene', (161, 170))	('DFNA5', 'Gene', (114, 119))	('induce', 'Reg', (40, 46))	('apoptosis-to-pyroptosis switch', 'MPA', (51, 81))
501403	31501419	In LC, loss of the DFNA5/GSDME gene promotes drug resistance, while overexpression of DFNA5/GSDME leads to increased drug sensitivity (Table 1).	('DFNA5', 'Gene', (19, 24))	('loss', 'Var', (7, 11))	('drug sensitivity', 'MPA', (117, 133))	('DFNA5', 'Gene', '1687', (86, 91))	('increased', 'PosReg', (107, 116))	('GSDME', 'Chemical', '-', (25, 30))	('drug resistance', 'Phenotype', 'HP:0020174', (45, 60))	('DFNA5', 'Gene', (86, 91))	('DFNA5', 'Gene', '1687', (19, 24))	('drug resistance', 'MPA', (45, 60))	('promotes', 'PosReg', (36, 44))	('drug sensitivity', 'Phenotype', 'HP:0020174', (117, 133))	('GSDME', 'Chemical', '-', (92, 97))
501405	31501419	NLRP3 inflammasome activation can be achieved via a half-ion channel, lysosomal rupture and reactive oxygen species (ROS).	('half-ion', 'Var', (52, 60))	('inflammasome', 'MPA', (6, 18))	('NLRP3', 'Gene', (0, 5))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (92, 115))	('activation', 'PosReg', (19, 29))	('ROS', 'Chemical', 'MESH:D017382', (117, 120))	('NLRP3', 'Gene', '114548', (0, 5))	('lysosomal rupture', 'Disease', 'MESH:D012421', (70, 87))	('lysosomal rupture', 'Disease', (70, 87))
501409	31501419	However, some studies have found that the removal of proinflammatory factors produced by pyroptosis can inhibit the growth of CC cells and simultaneously weaken the bodily immune effect on tumor cells.	('tumor', 'Disease', (189, 194))	('growth of CC cells', 'CPA', (116, 134))	('weaken', 'NegReg', (154, 160))	('pyroptosis', 'Var', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('inhibit', 'NegReg', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
501410	31501419	reported that the expression of pro-IL-18, pro-IL-1beta, and NLRP3 in Barrett's esophageal cancer cells treated with LPS was increased, and the levels of mitochondrial ROS, caspase-1, IL-18, IL-1beta, lactate dehydrogenase (LDH), and pyroptosis were also increased.	('ROS', 'Chemical', 'MESH:D017382', (168, 171))	('increased', 'PosReg', (125, 134))	('IL-1beta', 'Gene', (47, 55))	('IL-18', 'Gene', '3606', (36, 41))	('lactate dehydrogenase', 'MPA', (201, 222))	('NLRP3', 'Gene', (61, 66))	('IL-18', 'Gene', '3606', (184, 189))	('NLRP3', 'Gene', '114548', (61, 66))	('pro-IL-1beta', 'Gene', (43, 55))	('LPS', 'Var', (117, 120))	('expression', 'MPA', (18, 28))	('pyroptosis', 'MPA', (234, 244))	("Barrett's esophageal cancer", 'Disease', 'MESH:D004938', (70, 97))	('IL-1beta', 'Gene', '3553', (191, 199))	("Barrett's esophageal cancer", 'Disease', (70, 97))	('mitochondrial ROS', 'MPA', (154, 171))	('IL-18', 'Gene', (36, 41))	('IL-1beta', 'Gene', (191, 199))	('increased', 'PosReg', (255, 264))	('pro-IL-1beta', 'Gene', '3553', (43, 55))	('IL-18', 'Gene', (184, 189))	('IL-1beta', 'Gene', '3553', (47, 55))	('caspase-1', 'MPA', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('levels', 'MPA', (144, 150))
501420	31501419	treated the tri-negative BC cells with ivermectin and found that ivermectin could activate the pannexin-1 channel and induce the overexpression of P2X4/P2X7 receptor.	('activate', 'PosReg', (82, 90))	('P2X7 receptor', 'Gene', (152, 165))	('pannexin-1', 'Gene', (95, 105))	('ivermectin', 'Var', (65, 75))	('P2X4', 'Gene', '5025', (147, 151))	('P2X4', 'Gene', (147, 151))	('overexpression', 'MPA', (129, 143))	('pannexin-1', 'Gene', '24145', (95, 105))	('P2X7 receptor', 'Gene', '5027', (152, 165))	('induce', 'PosReg', (118, 124))
501422	31501419	In LC treatment, the thiopyran derivative L61H10 has good antitumor activity through an apoptosis-to-pyroptosis switch.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('L61H10', 'Var', (42, 48))	('tumor', 'Disease', (62, 67))	('apoptosis-to-pyroptosis', 'CPA', (88, 111))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
501423	31501419	found that omega-3 docosahexaenoic acid can induce the pyroptosis of tri-negative BC cells and the caspase-1 inhibitor can protect BC cells from omega-3 docosahexaenoic acid-induced-pyroptosis.	('induce', 'PosReg', (44, 50))	('omega-3 docosahexaenoic', 'Var', (11, 34))	('omega-3 docosahexaenoic acid', 'Chemical', '-', (11, 39))	('pyroptosis', 'CPA', (55, 65))	('omega-3 docosahexaenoic acid', 'Chemical', '-', (145, 173))
501430	31501419	In tumor cell lines with low-level GSDME, the expression of GSDME was upregulated in the corresponding cell lines after treatment with the distamine, and the sensitivity of tumor cells to chemotherapy drugs was also increased, which made these cells more prone to pyroptosis.	('distamine', 'Chemical', 'MESH:D010396', (139, 148))	('GSDME', 'Chemical', '-', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', (3, 8))	('GSDME', 'Chemical', '-', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('GSDME', 'Gene', (60, 65))	('tumor', 'Disease', (173, 178))	('GSDME', 'Var', (35, 40))	('low-level GSDME', 'Var', (25, 40))	('prone', 'MPA', (255, 260))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('upregulated', 'PosReg', (70, 81))	('pyroptosis', 'MPA', (264, 274))	('expression', 'MPA', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('increased', 'PosReg', (216, 225))	('sensitivity', 'MPA', (158, 169))
501439	31501419	Intraperitoneal injection of cisplatin or 5-FU resulted in severe small intestinal injury and immune cell infiltration in Gsdme+/+ mice, whereas in Gsdme-/- mice, the signs of tissue damage were reduced.	('cisplatin', 'Var', (29, 38))	('Gsdme', 'Chemical', '-', (122, 127))	('mice', 'Species', '10090', (157, 161))	('5-FU', 'Var', (42, 46))	('5-FU', 'Chemical', 'MESH:D005472', (42, 46))	('intestinal injury', 'Disease', 'MESH:D007415', (72, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('Gsdme', 'Chemical', '-', (148, 153))	('mice', 'Species', '10090', (131, 135))	('intestinal injury', 'Disease', (72, 89))	('immune cell infiltration', 'CPA', (94, 118))
501449	31501419	found that plentiful caspase-1 was activated after LXRbeta agonist T0901317 treatment, while apoptosis-related caspase-3/8/9 were not detected.	('caspase-3', 'Gene', (111, 120))	('T0901317', 'Var', (67, 75))	('T0901317', 'Chemical', 'MESH:C423915', (67, 75))	('caspase-3', 'Gene', '836', (111, 120))	('caspase-1', 'Enzyme', (21, 30))	('LXRbeta', 'Gene', '7376', (51, 58))	('LXRbeta', 'Gene', (51, 58))	('activated', 'PosReg', (35, 44))
501452	31501419	Furthermore, the genetic and pharmacological inactivation of LXR in murine bone marrow-derived macrophages enhanced the inhibitory effects of radiation therapy on tumor growth through the induction of pyroptosis and activation of the inflammatory cascade (Fig.	('pyroptosis', 'MPA', (201, 211))	('inflammatory cascade', 'Pathway', (234, 254))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('inactivation', 'Var', (45, 57))	('LXR', 'Gene', '22259', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('enhanced', 'PosReg', (107, 115))	('inhibitory effects', 'MPA', (120, 138))	('murine', 'Species', '10090', (68, 74))	('tumor', 'Disease', (163, 168))	('LXR', 'Gene', (61, 64))	('activation', 'PosReg', (216, 226))
501455	31501419	found that calpain, caspase-7 and caspase-3 were activated in numerous malignant melanoma cells infected with the herpes simplex virus type 2 (HSV-2) mutant  PK (HSV-2 mutant  PK) to promote the oncolytic effect of DeltaPK.	('numerous malignant melanoma cells infected', 'Disease', 'MESH:D008545', (62, 104))	('promote', 'PosReg', (183, 190))	('caspase-3', 'Gene', '836', (34, 43))	('caspase-7', 'Enzyme', (20, 29))	('HSV-2', 'Gene', (143, 148))	('oncolytic effect', 'CPA', (195, 211))	('malignant melanoma', 'Phenotype', 'HP:0002861', (71, 89))	('herpes simplex', 'Phenotype', 'HP:0012302', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('HSV-2', 'Species', '10310', (143, 148))	('herpes simplex virus type 2', 'Species', '10310', (114, 141))	('caspase-3', 'Gene', (34, 43))	('HSV-2', 'Species', '10310', (162, 167))	('calpain', 'Enzyme', (11, 18))	('mutant', 'Var', (150, 156))	('activated', 'PosReg', (49, 58))	('numerous malignant melanoma cells infected', 'Disease', (62, 104))
501472	31501419	The methylation of DFNA5/GSDME mRNA results in lower DFNA5/GSDME expression in many types of tumor cells than in normal cells, which makes activating pyroptosis difficult in most tumor cells.	('DFNA5', 'Gene', (19, 24))	('DFNA5', 'Gene', (53, 58))	('lower', 'NegReg', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('GSDME', 'Chemical', '-', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('GSDME', 'Chemical', '-', (25, 30))	('tumor', 'Disease', (93, 98))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('expression', 'MPA', (65, 75))	('DFNA5', 'Gene', '1687', (19, 24))	('DFNA5', 'Gene', '1687', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
501486	31181628	More than 15 fumonisin homologues have been known and characterized as fumonisin A, B, C, and P. Further among fumonisin B, FB1, FB2, and FB3 are most abundant with FB1 being the most toxic form that can co-exists with other forms of fumonisin, i.e., FB2 and FB3.	('C', 'Chemical', 'MESH:D002244', (87, 88))	('FB1', 'Gene', '29844', (165, 168))	('fumonisin', 'Chemical', 'MESH:D037341', (234, 243))	('FB1', 'Gene', '29844', (124, 127))	('fumonisin', 'Chemical', 'MESH:D037341', (13, 22))	('FB2', 'Gene', '100282272', (129, 132))	('FB1', 'Gene', (165, 168))	('P. Further', 'Var', (94, 104))	('FB2', 'Gene', '100282272', (251, 254))	('fumonisin', 'Chemical', 'MESH:D037341', (111, 120))	('FB1', 'Gene', (124, 127))	('FB2', 'Gene', (129, 132))	('FB2', 'Gene', (251, 254))	('fumonisin', 'Chemical', 'MESH:D037341', (71, 80))
501492	31181628	In addition, FB1 is implicated with the incidences of hepatocarcinoma, stimulation and suppression of the immune system, defects in the neural-tube, nephrotoxicity, as well as other ailments.	('nephrotoxicity', 'Disease', 'MESH:D007674', (149, 163))	('suppression of the immune system', 'Phenotype', 'HP:0002721', (87, 119))	('nephrotoxicity', 'Disease', (149, 163))	('defects', 'Var', (121, 128))	('FB1', 'Gene', (13, 16))	('hepatocarcinoma', 'Disease', 'None', (54, 69))	('hepatocarcinoma', 'Disease', (54, 69))	('implicated', 'Reg', (20, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('FB1', 'Gene', '29844', (13, 16))
501598	31181628	Furthermore, breastfeeding and weaning practices were considered to be associated with growth impairment in children due to exposure to FB1.	('children', 'Species', '9606', (108, 116))	('FB1', 'Gene', (136, 139))	('growth impairment', 'Disease', 'MESH:D006130', (87, 104))	('growth impairment', 'Phenotype', 'HP:0001510', (87, 104))	('growth impairment', 'Disease', (87, 104))	('exposure', 'Var', (124, 132))	('associated', 'Reg', (71, 81))	('FB1', 'Gene', '29844', (136, 139))
501603	31181628	However, this reduction could be due to the structural modifications of fumonisins while interacting with other components of food that leads to the conjugate's formation.	('formation', 'MPA', (161, 170))	('leads to', 'Reg', (136, 144))	('conjugate', 'MPA', (149, 158))	('modifications', 'Var', (55, 68))	('fumonisin', 'Chemical', 'MESH:D037341', (72, 81))	('interacting', 'Interaction', (89, 100))	('reduction', 'NegReg', (14, 23))
501625	31181628	It was found that the toxin production was significantly inhibited in culture maintained at pH 5 compared to the culture at pH 10.	('inhibited', 'NegReg', (57, 66))	('pH 5', 'Var', (92, 96))	('pH 5', 'Species', '229533', (92, 96))	('toxin production', 'MPA', (22, 38))
501664	31181628	MTA144 was shown to have fumonisin degrading activity.	('fumonisin degrading activity', 'MPA', (25, 53))	('MTA144', 'Var', (0, 6))	('fumonisin', 'Chemical', 'MESH:D037341', (25, 34))
501719	29728688	The last signature, S3, characterized by C>T transitions at NpCpG trinucleotides (analogous to COSMIC signature 1; cosine similarity: 0.89), has been observed in multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('trinucleotides', 'Chemical', '-', (66, 80))	('cancer', 'Disease', (171, 177))	('NpCpG', 'Gene', (60, 65))	('C>T transitions', 'Var', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
501723	29728688	Notably, we observed a relatively high frequency (7.3%, 4/55) of the p.C141R/Y mutation in TP53 (Supplementary information, Figure S5a).	('S5a', 'Gene', '5710', (131, 134))	('S5a', 'Gene', (131, 134))	('TP53', 'Gene', (91, 95))	('p.C141R', 'SUBSTITUTION', 'None', (69, 76))	('p.C141R', 'Var', (69, 76))	('men', 'Species', '9606', (103, 106))	('TP53', 'Gene', '7157', (91, 95))
501724	29728688	Of 15 RB1 mutations, 14 were detected, comprising nine nonsense mutations, four frame-shift indels, and one splice site mutation, which caused truncation (Supplementary information, Table S4).	('RB1', 'Gene', (6, 9))	('RB1', 'Gene', '5925', (6, 9))	('truncation', 'MPA', (143, 153))	('mutations', 'Var', (10, 19))	('men', 'Species', '9606', (161, 164))
501725	29728688	Bi-allelic inactivation of TP53 and RB1 was also observed in 62.5% (15) and 29.2% (7), respectively, of the 24 patients profiled by the OncoScan CNV Assay (Supplementary information, Figure S5b), consistent with the two-hit hypothesis of tumor suppressors.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('S5b', 'Gene', '5711', (190, 193))	('RB1', 'Gene', (36, 39))	('men', 'Species', '9606', (162, 165))	('tumor', 'Disease', (238, 243))	('S5b', 'Gene', (190, 193))	('RB1', 'Gene', '5925', (36, 39))	('Bi-allelic', 'Var', (0, 10))	('patients', 'Species', '9606', (111, 119))
501738	29728688	Furthermore, patients with a NOTCH family mutation experienced a poorer median overall survival (14.5 vs 23 months, P = 0.0045; Supplementary information, Figure S10b), indicating that NOTCH mutations may serve as markers of poor prognosis in SCCE.	('SCCE', 'Disease', (243, 247))	('patients', 'Species', '9606', (13, 21))	('poorer', 'NegReg', (65, 71))	('men', 'Species', '9606', (134, 137))	('mutation', 'Var', (42, 50))	('NOTCH family', 'Gene', (29, 41))	('overall survival', 'MPA', (79, 95))
501739	29728688	Somatic alterations in Wnt pathway components were detected in 96.4% of all patients.	('patients', 'Species', '9606', (76, 84))	('Wnt pathway components', 'Pathway', (23, 45))	('alterations', 'Var', (8, 19))
501740	29728688	These alterations include mutations in APC (3.6%), APC2 (3.6%), AXIN1 (1.8%), FZD5 (1.8%), FZD6 (1.8%) and DVL3 (1.8%), and frequent gain/amplification of FZD6 (78.2%) and DVL3 (72.7%) (Supplementary information, Figure S7c).	('mutations', 'Var', (26, 35))	('men', 'Species', '9606', (192, 195))	('AXIN1', 'Gene', (64, 69))	('DVL3', 'Gene', '1857', (172, 176))	('APC', 'Disease', 'MESH:D011125', (39, 42))	('APC', 'Disease', (39, 42))	('DVL3', 'Gene', '1857', (107, 111))	('APC2', 'Gene', (51, 55))	('DVL3', 'Gene', (172, 176))	('FZD5', 'Gene', (78, 82))	('DVL3', 'Gene', (107, 111))	('gain/amplification', 'PosReg', (133, 151))	('FZD6', 'Gene', '8323', (155, 159))	('FZD6', 'Gene', (155, 159))	('APC', 'Disease', 'MESH:D011125', (51, 54))	('APC', 'Disease', (51, 54))	('FZD6', 'Gene', (91, 95))	('AXIN1', 'Gene', '8312', (64, 69))	('FZD6', 'Gene', '8323', (91, 95))	('FZD5', 'Gene', '7855', (78, 82))	('APC2', 'Gene', '10297', (51, 55))
501747	29728688	In addition, the chromosome-wide distribution of G-scores revealed the similarities between SCCE and ESCC or HNSCC (Supplementary information, Figure S13), particularly in the amplifications of 3q and 8q and the deletion of 3p.	('amplifications', 'Var', (176, 190))	('ESCC', 'Disease', (101, 105))	('deletion', 'Var', (212, 220))	('men', 'Species', '9606', (122, 125))
501754	29728688	Another gene, PTPRM, negatively regulates cell growth and colony formation, and loss of PTPRM promotes oncogenic cell growth in colon cancer.	('cell growth', 'CPA', (42, 53))	('PTPRM', 'Gene', (88, 93))	('oncogenic cell growth', 'CPA', (103, 124))	('colon cancer', 'Disease', (128, 140))	('PTPRM', 'Gene', '5797', (14, 19))	('PTPRM', 'Gene', '5797', (88, 93))	('loss', 'Var', (80, 84))	('PTPRM', 'Gene', (14, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('promotes', 'PosReg', (94, 102))	('colony formation', 'CPA', (58, 74))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
501758	29728688	We also identified mutations in other well-known genes, such as TP53, RB1, NOTCH1, FAT1 and those related to the chromatin remodeling process.	('FAT1', 'Gene', (83, 87))	('RB1', 'Gene', (70, 73))	('NOTCH1', 'Gene', '4851', (75, 81))	('NOTCH1', 'Gene', (75, 81))	('mutations', 'Var', (19, 28))	('RB1', 'Gene', '5925', (70, 73))	('TP53', 'Gene', '7157', (64, 68))	('FAT1', 'Gene', '2195', (83, 87))	('TP53', 'Gene', (64, 68))
501759	29728688	We observed somatic genomic alterations in SCCE similar to those in SCLC such as loss of P53 and RB1 and mutations in the NOTCH family.	('P53', 'Gene', (89, 92))	('RB1', 'Gene', (97, 100))	('SCLC', 'Disease', (68, 72))	('SCLC', 'Disease', 'MESH:D018288', (68, 72))	('P53', 'Gene', '7157', (89, 92))	('RB1', 'Gene', '5925', (97, 100))	('mutations', 'Var', (105, 114))	('SCLC', 'Phenotype', 'HP:0030357', (68, 72))	('loss', 'NegReg', (81, 85))
501764	29050260	Epigenetic silencing of TMEM176A promotes esophageal squamous cell cancer development The function of human transmembrane protein 176A (TMEM176A) in cancer remains unclear.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (42, 73))	('promotes', 'PosReg', (33, 41))	('cancer', 'Disease', (149, 155))	('transmembrane protein 176A', 'Gene', '55365', (108, 134))	('transmembrane protein 176A', 'Gene', (108, 134))	('cancer', 'Disease', (67, 73))	('TMEM176A', 'Gene', '55365', (24, 32))	('TMEM176A', 'Gene', (136, 144))	('esophageal squamous cell cancer', 'Disease', (42, 73))	('TMEM176A', 'Gene', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (53, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Epigenetic silencing', 'Var', (0, 20))	('TMEM176A', 'Gene', '55365', (136, 144))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('human', 'Species', '9606', (102, 107))
501766	29050260	TMEM176A was highly expressed in BIC1 cells and loss of TMEM176A expression was found in TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Segl, KYSE150, YES2 and COLO680N cells.	('loss', 'NegReg', (48, 52))	('YES2', 'Gene', '7526', (165, 169))	('KYSE180', 'Var', (114, 121))	('TMEM176A', 'Gene', (0, 8))	('expression', 'Species', '29278', (65, 75))	('YES2', 'Gene', (165, 169))	('TMEM176A', 'Gene', (56, 64))	('KYSE410', 'Var', (123, 130))	('expression', 'MPA', (65, 75))	('KYSE520', 'Var', (141, 148))	('KYSE150', 'CellLine', 'CVCL:1348', (156, 163))	('KYSE140', 'Var', (105, 112))	('BIC1', 'CellLine', 'CVCL:8092', (33, 37))
501767	29050260	Complete methylation was detected in TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Segl, KYSE150, YES2 and COLO680N cells, while unmethylation was detected in BIC1 cells.	('KYSE520', 'Var', (89, 96))	('YES2', 'Gene', (113, 117))	('KYSE150', 'Var', (104, 111))	('KYSE410', 'Var', (71, 78))	('BIC1', 'CellLine', 'CVCL:8092', (174, 178))	('KYSE150', 'CellLine', 'CVCL:1348', (104, 111))	('methylation', 'MPA', (9, 20))	('KYSE180', 'Var', (62, 69))	('KYSE450', 'Var', (80, 87))	('KYSE140', 'Var', (53, 60))	('YES2', 'Gene', '7526', (113, 117))
501769	29050260	TMEM176A was methylated in 66.7% (178/267) of primary esophageal cancer samples, and promoter region methylation was significantly associated with tumor differentiation (p<0.001) and loss off/reduced expression of TMEM176A (p<0.05).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('TMEM176A', 'Gene', (0, 8))	('primary esophageal cancer', 'Disease', 'MESH:D004938', (46, 71))	('associated', 'Reg', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('expression', 'Species', '29278', (200, 210))	('loss off/reduced', 'NegReg', (183, 199))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('expression', 'MPA', (200, 210))	('primary esophageal cancer', 'Disease', (46, 71))	('methylation', 'Var', (101, 112))	('TMEM176A', 'Gene', (214, 222))
501779	29050260	Epigenetics may play more important roles than genetics in esophageal cancer.	('esophageal cancer', 'Disease', (59, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('Epigenetics', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))
501783	29050260	In our recent study, loss of TMEM176A expression was shown to be a frequent event in human colorectal cancer by transcriptome analysis [Epigenetics 2017, in press].	('loss', 'Var', (21, 25))	('expression', 'Species', '29278', (38, 48))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('TMEM176A', 'Gene', (29, 37))	('human', 'Species', '9606', (85, 90))
501788	29050260	Complete methylation was found in TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Segl, KYSE150, YES2, and COLO680N cells, while unmethylation was detected in BIC1 cells (Figure 1B).	('YES2', 'Gene', (110, 114))	('KYSE150', 'Var', (101, 108))	('YES2', 'Gene', '7526', (110, 114))	('KYSE410', 'Var', (68, 75))	('KYSE520', 'Var', (86, 93))	('BIC1', 'CellLine', 'CVCL:8092', (172, 176))	('KYSE150', 'CellLine', 'CVCL:1348', (101, 108))	('KYSE140', 'Var', (50, 57))	('methylation', 'MPA', (9, 20))	('KYSE180', 'Var', (59, 66))	('KYSE450', 'Var', (77, 84))
501792	29050260	The expression of TMEM176A was induced by DAC in TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Seg1, KYSE150, COLO680N and YES2 cells (Figure 1A).	('DAC', 'Gene', (42, 45))	('KYSE450', 'Var', (92, 99))	('KYSE150', 'CellLine', 'CVCL:1348', (116, 123))	('expression', 'Species', '29278', (4, 14))	('induced', 'PosReg', (31, 38))	('DAC', 'Gene', '6468', (42, 45))	('KYSE140', 'Var', (65, 72))	('expression', 'MPA', (4, 14))	('TMEM176A', 'Gene', (18, 26))	('KYSE180', 'Var', (74, 81))	('YES2', 'Gene', (138, 142))	('YES2', 'Gene', '7526', (138, 142))	('KYSE520', 'Var', (101, 108))	('KYSE410', 'Var', (83, 90))
501795	29050260	TMEM176A was methylated in 66.7% (178/267) of esophageal cancer samples and no methylation (0/27) was found in non-cancerous esophageal mucosa (Figure 1D).	('non-cancerous esophageal mucosa', 'Disease', 'MESH:D004938', (111, 142))	('methylated', 'Var', (13, 23))	('non-cancerous esophageal mucosa', 'Disease', (111, 142))	('TMEM176A', 'Gene', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
501796	29050260	Methylation of TMEM176A was significantly associated with tumor cell differentiation (p<0.01, Table 1), no association was found between TMEM176A methylation and age, gender, lymphatic node metastasis, TNM stage, drinking history, family history, smoking history and tumor size (all p > 0.05, Table 1).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('TNM', 'Gene', '10178', (202, 205))	('associated', 'Reg', (42, 52))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('TNM', 'Gene', (202, 205))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (267, 272))	('TMEM176A', 'Gene', (15, 23))
501797	29050260	Under univariate analysis, TMEM176A methylation (hazard ratio= 2.25, p< 0.01) and tumor differentiation (hazard ratio= 1.841, p< 0.01) were risk factors for poor 5-years OS.	('rat', 'Species', '10116', (56, 59))	('TMEM176A', 'Gene', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('rat', 'Species', '10116', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('poor 5-years OS', 'CPA', (157, 172))	('methylation', 'Var', (36, 47))
501798	29050260	Under multivariate analysis, the risk factors of poor OS were TMEM176A methylation (hazard ratio= 2.237, p<0.01, Table 2) and tumor differentiation (hazard ratio= 1.894, p<0.01, Table 2).	('methylation', 'Var', (71, 82))	('rat', 'Species', '10116', (156, 159))	('rat', 'Species', '10116', (91, 94))	('TMEM176A', 'Gene', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
501799	29050260	In 178 cases of TMEM176A methylated patients, the mean time was 33.875 months and cumulative 5-years OS rate was 34.8%.	('TMEM176A', 'Gene', (16, 24))	('patients', 'Species', '9606', (36, 44))	('methylated', 'Var', (25, 35))	('rat', 'Species', '10116', (104, 107))
501802	29050260	Methylation of 18 CpG sites in the promoter region was associated to loss off/reduced expression of TMEM176A in 184 cases of esophageal cancers (Pearson: R= -0.3683098, p= 0.000, Spearman: rho= -0.3782967, p= 0.000).	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('Methylation', 'Var', (0, 11))	('TMEM176A', 'Gene', (100, 108))	('expression', 'Species', '29278', (86, 96))	('esophageal cancers', 'Disease', (125, 143))	('expression', 'MPA', (86, 96))	('loss off/reduced', 'NegReg', (69, 85))	('esophageal cancers', 'Disease', 'MESH:D004938', (125, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
501806	29050260	Among the 43 cases in which TMEM176A expression was reduced, 30 cases were methylated.	('methylated', 'Var', (75, 85))	('reduced', 'NegReg', (52, 59))	('TMEM176A', 'Gene', (28, 36))	('expression', 'Species', '29278', (37, 47))	('expression', 'MPA', (37, 47))
501808	29050260	These results indicate that the expression of TMEM176A is regulated by promoter region methylation in primary esophageal cancer.	('methylation', 'Var', (87, 98))	('expression', 'MPA', (32, 42))	('primary esophageal cancer', 'Disease', (102, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('primary esophageal cancer', 'Disease', 'MESH:D004938', (102, 127))	('expression', 'Species', '29278', (32, 42))	('regulated', 'Reg', (58, 67))	('TMEM176A', 'Gene', (46, 54))
501811	29050260	The effect of TMEM176A on cell growth was further validated by knocking down TMEM176A in BIC1 cells.	('TMEM176A', 'Gene', (77, 85))	('knocking down', 'Var', (63, 76))	('BIC1', 'CellLine', 'CVCL:8092', (89, 93))
501812	29050260	The OD values were 1.585 +- 0.162 vs. 1.983 +- 0.055 (p<0.01) before and after knockdown TMEM176A in BIC1 cells (Figure 3A).	('knockdown', 'Var', (79, 88))	('TMEM176A', 'Gene', (89, 97))	('BIC1', 'CellLine', 'CVCL:8092', (101, 105))
501816	29050260	The clone number was 108.3 +- 11.4 vs. 139.0 +- 6.0 (p<0.05) before and after knockdown of TMEM176A in BIC1 cells (Figure 3B).	('BIC1', 'CellLine', 'CVCL:8092', (103, 107))	('knockdown', 'Var', (78, 87))	('TMEM176A', 'Gene', (91, 99))
501820	29050260	The number of migratory cells was 78.7 +- 5.2 vs. 193.0 +- 5.3 before and after knockdown of TMEM176A in BIC1 cells (p<0.01, Figure 3E).	('knockdown', 'Var', (80, 89))	('TMEM176A', 'Gene', (93, 101))	('BIC1', 'CellLine', 'CVCL:8092', (105, 109))	('rat', 'Species', '10116', (17, 20))
501821	29050260	The number of migratory cells was significantly reduced after restoration of TMEM176A expression in KYSE410 and KYSE150 cells (Figure 3C).	('KYSE150', 'CellLine', 'CVCL:1348', (112, 119))	('TMEM176A', 'Gene', (77, 85))	('rat', 'Species', '10116', (67, 70))	('restoration', 'NegReg', (62, 73))	('expression', 'Species', '29278', (86, 96))	('reduced', 'NegReg', (48, 55))	('expression', 'MPA', (86, 96))	('KYSE150', 'Var', (112, 119))	('rat', 'Species', '10116', (17, 20))
501824	29050260	The number of invasive cells was significantly reduced after restoration of TMEM176A expression in KYSE410 and KYSE150 cells (Figure 3D).	('expression', 'MPA', (85, 95))	('KYSE150', 'Var', (111, 118))	('KYSE150', 'CellLine', 'CVCL:1348', (111, 118))	('TMEM176A', 'Gene', (76, 84))	('restoration', 'Var', (61, 72))	('expression', 'Species', '29278', (85, 95))	('rat', 'Species', '10116', (66, 69))	('reduced', 'NegReg', (47, 54))
501825	29050260	The number of invasive cells was 55.3 +- 6.0 vs. 105.3 +- 4.5 before and after knockdown of TMEM176A in BIC1 cells (p<0.01, Figure 3E).	('knockdown', 'Var', (79, 88))	('TMEM176A', 'Gene', (92, 100))	('invasive cells', 'CPA', (14, 28))	('BIC1', 'CellLine', 'CVCL:8092', (104, 108))
501829	29050260	The percentage of apoptotic cells increased significantly after re-expression of TMEM176A in KYSE150 cells (p<0.01, Figure 4A).	('TMEM176A', 'Gene', (81, 89))	('re-expression', 'Var', (64, 77))	('apoptotic cells', 'CPA', (18, 33))	('KYSE150', 'CellLine', 'CVCL:1348', (93, 100))	('expression', 'Species', '29278', (67, 77))	('increased', 'PosReg', (34, 43))
501835	29050260	MMP2 and MMP9 expression levels were increased after knockdown of TMEM176A in BIC1 cells (Figure 4B).	('MMP2', 'Gene', (0, 4))	('BIC1', 'CellLine', 'CVCL:8092', (78, 82))	('knockdown', 'Var', (53, 62))	('expression', 'Species', '29278', (14, 24))	('MMP9', 'Gene', (9, 13))	('MMP2', 'Gene', '4313', (0, 4))	('TMEM176A', 'Gene', (66, 74))	('increased', 'PosReg', (37, 46))	('MMP9', 'Gene', '4318', (9, 13))
501838	29050260	The tumor volume was significantly smaller in TMEM176A re-expression KYSE410 cell xenografts compared to TMEM176A unexpressed KYSE410 cell xenografts (P<0.05, Figure 5B & 5C).	('tumor', 'Disease', (4, 9))	('expression', 'Species', '29278', (58, 68))	('TMEM176A re-expression', 'Var', (46, 68))	('smaller', 'NegReg', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('re-expression', 'Var', (55, 68))
501855	29050260	Thus, TMEM176A methylation may serve as an esophageal cancer detection marker.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('methylation', 'Var', (15, 26))	('TMEM176A', 'Gene', (6, 14))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
501856	29050260	Methylation of TMEM176A was significantly associated with tumor differentiation and poor 5-years OS.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('associated', 'Reg', (42, 52))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('poor 5-years OS', 'CPA', (84, 99))	('TMEM176A', 'Gene', (15, 23))
501859	29050260	These results suggest that the expression of TMEM176A is silenced by promoter region hypermethylation in primary human esophageal cancer.	('hypermethylation', 'Var', (85, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('TMEM176A', 'Gene', (45, 53))	('expression', 'Species', '29278', (31, 41))	('silenced', 'NegReg', (57, 65))	('expression', 'MPA', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('human', 'Species', '9606', (113, 118))	('esophageal cancer', 'Disease', (119, 136))
501863	29050260	Thirteen esophageal cancer cell lines (TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Segl, KYSE150, YES2, COLO680N and BIC1) were included in this study.	('KYSE520', 'Var', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('YES2', 'Gene', (115, 119))	('KYSE150', 'CellLine', 'CVCL:1348', (106, 113))	('BIC1', 'CellLine', 'CVCL:8092', (134, 138))	('KYSE450', 'Var', (82, 89))	('esophageal cancer', 'Disease', (9, 26))	('YES2', 'Gene', '7526', (115, 119))	('esophageal cancer', 'Disease', 'MESH:D004938', (9, 26))	('KYSE410', 'Var', (73, 80))
501899	28852310	Nine microRNAs (miR-424-5p, miR-127-3p, miR-98-5p, miR-187-3p, miR-495-3p, miR-34c-5p, miR-223-5p, miR-539-5p, miR-376a-3p, miR-409-3p) were expressed at higher levels in post-ablation neosquamous mucosa than in matched proximal squamous and healthy squamous mucosa.	('miR-127-3p', 'Gene', '100302165', (28, 38))	('miR-34c-5p', 'Var', (75, 85))	('miR-409-3p', 'Var', (124, 134))	('miR-539-5p', 'Var', (99, 109))	('miR-495-3p', 'Var', (63, 73))	('miR-376a-3p', 'Var', (111, 122))	('miR-424-5p', 'Var', (16, 26))	('miR-223-5p', 'Var', (87, 97))	('higher', 'PosReg', (154, 160))	('miR-98-5p', 'Var', (40, 49))	('miR-127-3p', 'Gene', (28, 38))	('miR-187-3p', 'Var', (51, 61))	('neosquamous', 'Disease', (185, 196))
501900	28852310	Three microRNAs (miR-187-3p, miR-135b-5p and miR-31-5p) were expressed at higher levels in post-ablation neosquamous mucosa than in matched proximal squamous and healthy squamous mucosa.	('miR-31', 'Gene', (45, 51))	('miR-135b-5p', 'Var', (29, 40))	('higher', 'PosReg', (74, 80))	('neosquamous', 'Disease', (105, 116))	('miR-187-3p', 'Var', (17, 27))	('miR-31', 'Gene', '407035', (45, 51))
501901	28852310	Core tip: We report that the microRNA profile of esophageal neosquamous mucosa developing after ablation of Barrett's esophagus is different to normal squamous epithelium, and that the differentially expressed microRNAs in neosquamous mucosa may regulate survival signalling pathways and contribute to decreased barrier function in the esophagus.	('microRNAs', 'Var', (210, 219))	('survival signalling pathways', 'Pathway', (255, 283))	('regulate', 'Reg', (246, 254))	('esophageal neosquamous mucosa', 'Disease', 'MESH:D004941', (49, 78))	('differentially', 'Var', (185, 199))	('esophageal neosquamous mucosa', 'Disease', (49, 78))	('decreased', 'NegReg', (302, 311))	('barrier function', 'CPA', (312, 328))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (108, 127))
501917	28852310	Because a single microRNA can target several mRNAs, dysregulated microRNA expression can impact on key biological pathways and contribute to cancer development.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('key biological pathways', 'Pathway', (99, 122))	('dysregulated', 'Var', (52, 64))	('impact', 'Reg', (89, 95))	('contribute to', 'Reg', (127, 140))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
501918	28852310	Dysregulated microRNA expression along the squamous - Barrett's - dysplasia - adenocarcinoma pathway has been reported by several groups.	('Dysregulated', 'Var', (0, 12))	('microRNA', 'Protein', (13, 21))	('dysplasia - adenocarcinoma', 'Disease', 'MESH:D000230', (66, 92))	('dysplasia - adenocarcinoma', 'Disease', (66, 92))
501970	28852310	Three (miR-424-5p, miR-223-5p, miR-409-3p) of the microRNAs that are increased in neosquamous mucosa relative to post-squamous and control-squamous mucosa have been reported to be up-regulated in esophageal adenocarcinoma relative to Barrett's esophagus and normal squamous tissues.	('up-regulated', 'PosReg', (180, 192))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (196, 221))	('miR-223-5p', 'Var', (19, 29))	('esophageal adenocarcinoma', 'Disease', (196, 221))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (196, 221))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (234, 253))	('miR-409-3p', 'Var', (31, 41))
501971	28852310	Wu et al (2013) observed progressively increased expression of miR-424-5p, miR-223-5p and miR-409-3p from normal squamous epithelium to Barrett's to adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (149, 163))	('miR-409-3p', 'Var', (90, 100))	('expression', 'MPA', (49, 59))	('increased', 'PosReg', (39, 48))	('adenocarcinoma', 'Disease', (149, 163))	('miR-223-5p', 'Var', (75, 85))	('miR-424-5p', 'Var', (63, 73))
501972	28852310	MiR-223-5p and miR-409-3p have also been reported to be overexpressed in serum exosomes from patients with esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (107, 132))	('MiR-223-5p', 'Var', (0, 10))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (107, 132))	('miR-409-3p', 'Var', (15, 25))	('overexpressed', 'PosReg', (56, 69))	('patients', 'Species', '9606', (93, 101))	('esophageal adenocarcinoma', 'Disease', (107, 132))
501975	28852310	Our results suggest that altered miRNA expression may contribute to the previously reported defective barrier function in neosquamous epithelium, and this may place the mucosa at increased risk of disease progression relative to normal esophageal squamous mucosa.	('defective', 'NegReg', (92, 101))	('altered', 'Var', (25, 32))	('place', 'Reg', (159, 164))	('miRNA', 'Protein', (33, 38))	('barrier', 'MPA', (102, 109))	('esophageal squamous mucosa', 'Disease', 'MESH:D000077277', (236, 262))	('esophageal squamous mucosa', 'Disease', (236, 262))
501979	28852310	Previous studies have investigated whether post ablation mucosa has genetic alterations in, or increased expression of cancer associated genes.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('genetic alterations', 'Var', (68, 87))	('increased', 'PosReg', (95, 104))	('expression', 'MPA', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
502072	28785139	Surgical resection with removal of associated lymphatic tissue remains the treatment for rectal NETs greater than 20 mm, due to the high risk of lymphatic invasion and metastasis.	('NET', 'Gene', '2047', (96, 99))	('greater than 20', 'Var', (101, 116))	('NET', 'Gene', (96, 99))
502078	28785139	When compared to conventional EMR in a randomized prospective trial of rectal NETs < 15 mm, procedure time was longer in CIEMR but R0 resection was superior (96.7% in CIEMR group compared to 82.14% in EMR group (P = 0.043).	('CIEMR', 'Chemical', '-', (121, 126))	('CIEMR', 'Chemical', '-', (167, 172))	('NET', 'Gene', (78, 81))	('CIEMR', 'Var', (167, 172))	('NET', 'Gene', '2047', (78, 81))
502144	27583914	Subsequently, low serum cholesterol levels were found to be an independent risk factor for GC, especially intestinal-type GC.	('serum cholesterol levels', 'MPA', (18, 42))	('GC', 'Phenotype', 'HP:0012126', (122, 124))	('GC', 'Phenotype', 'HP:0012126', (91, 93))	('cholesterol', 'Chemical', 'MESH:D002784', (24, 35))	('low serum cholesterol', 'Phenotype', 'HP:0003146', (14, 35))	('intestinal-type GC', 'Disease', (106, 124))	('low', 'Var', (14, 17))	('low serum cholesterol levels', 'Phenotype', 'HP:0003146', (14, 42))
502202	27583914	Concurrently, the 2 highest BMI categories (27.5-29.9 and 30.0 or more) were positively associated with an increased risk of gastric cardia high-grade dysplasia in both men and women; only a BMI ranging from 27.5 to 29.9 increased the risk of gastric noncardia high-grade dysplasia in both men and women.	('men', 'Species', '9606', (179, 182))	('gastric cardia high-grade dysplasia', 'Disease', 'MESH:D004938', (125, 160))	('women', 'Species', '9606', (177, 182))	('gastric noncardia high-grade dysplasia', 'Disease', (243, 281))	('men', 'Species', '9606', (169, 172))	('men', 'Species', '9606', (300, 303))	('women', 'Species', '9606', (298, 303))	('gastric noncardia high-grade dysplasia', 'Disease', 'MESH:D008228', (243, 281))	('men', 'Species', '9606', (290, 293))	('gastric cardia high-grade dysplasia', 'Disease', (125, 160))	('27.5-29.9', 'Var', (44, 53))
502216	27583914	Previous studies performed in Western countries categorized BMI using the following guidelines proposed by the WHO: <18.5 kg/m2 (underweight), 18.5 to 24.9 kg/m2 (normal weight), 25 to 29.9 kg/m2 (overweight), 30 to 34.9 kg/m2 (obese class I), 35 to 39.9 kg/m2 (obese class II), and 40 kg/m2 and above (obese class III).	('overweight', 'Phenotype', 'HP:0025502', (197, 207))	('obese', 'Disease', (303, 308))	('obese', 'Disease', 'MESH:D009765', (228, 233))	('obese class I', 'Phenotype', 'HP:0025499', (262, 275))	('obese', 'Disease', (228, 233))	('obese class I', 'Phenotype', 'HP:0025499', (303, 316))	('obese', 'Disease', 'MESH:D009765', (262, 267))	('obese class I', 'Phenotype', 'HP:0025499', (228, 241))	('obese class III', 'Phenotype', 'HP:0025501', (303, 318))	('obese', 'Disease', 'MESH:D009765', (303, 308))	('<18.5 kg/m2', 'Var', (116, 127))	('obese', 'Disease', (262, 267))
502222	27583914	These results suggest a positive association between high serum total cholesterol and an increased risk for rectal cancer.	('high serum total cholesterol', 'Phenotype', 'HP:0003124', (53, 81))	('rectal cancer', 'Phenotype', 'HP:0100743', (108, 121))	('high', 'Var', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rectal cancer', 'Disease', 'MESH:D012004', (108, 121))	('cholesterol', 'Chemical', 'MESH:D002784', (70, 81))	('rectal cancer', 'Disease', (108, 121))
502223	27583914	Among smokers, high serum total cholesterol was related to an increased risk of advanced prostate cancer, but high serum high-density lipoprotein (HDL) cholesterol reduced the risk of prostate cancer overall.	('high serum', 'Var', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('advanced prostate cancer', 'Disease', (80, 104))	('advanced prostate cancer', 'Disease', 'MESH:D011471', (80, 104))	('cholesterol', 'Chemical', 'MESH:D002784', (32, 43))	('prostate cancer', 'Disease', (184, 199))	('cholesterol reduced', 'Phenotype', 'HP:0003146', (152, 171))	('prostate cancer', 'Disease', 'MESH:D011471', (184, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('prostate cancer', 'Phenotype', 'HP:0012125', (184, 199))	('high serum high-density lipoprotein', 'Phenotype', 'HP:0012184', (110, 145))	('prostate cancer', 'Disease', 'MESH:D011471', (89, 104))	('high serum total cholesterol', 'Phenotype', 'HP:0003124', (15, 43))	('cholesterol', 'Chemical', 'MESH:D002784', (152, 163))
502264	27583914	Concurrently, high serum total cholesterol was related to an increased risk of gastric noncardia high-grade dysplasia in women.	('gastric noncardia high-grade dysplasia', 'Disease', 'MESH:D008228', (79, 117))	('gastric noncardia high-grade dysplasia', 'Disease', (79, 117))	('high serum total cholesterol', 'Phenotype', 'HP:0003124', (14, 42))	('high', 'Var', (14, 18))	('cholesterol', 'Chemical', 'MESH:D002784', (31, 42))	('women', 'Species', '9606', (121, 126))
502268	25009749	Recent advances in the molecular biology of esophageal cancer have documented the role of genetic alterations in tumorigenesis.	('tumor', 'Disease', (113, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('genetic alterations', 'Var', (90, 109))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('esophageal cancer', 'Disease', (44, 61))
502273	25009749	This article will briefly review studies on silencing tumor enhancer genes related to the induction of esophageal cancer.	('esophageal cancer', 'Disease', (103, 120))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('silencing', 'Var', (44, 53))
502276	25009749	Evidence-based studies have suggested that genetic polymorphisms in carcinogen-metabolizing enzymes are important in determining an individual's susceptibility to cancer.	('genetic polymorphisms', 'Var', (43, 64))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('carcinogen-metabolizing', 'Enzyme', (68, 91))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
502298	25009749	Regardless of patient origin and suspected etiological factors, genetic changes that are consistently observed in ESCC are as follows: (1) alterations in tumor suppressor genes, specifically p53, resulting in altered DNA replication and repair, cell proliferation, and apoptosis; (2) disruption of the G1/S cell cycle checkpoint and loss of cell cycle control; and (3) alterations in oncogene function resulting in deregulation of cell signaling cascades.	('cell cycle control', 'CPA', (341, 359))	('DNA', 'MPA', (217, 220))	('apoptosis', 'CPA', (269, 278))	('SCC', 'Gene', '6317', (115, 118))	('tumor', 'Disease', (154, 159))	('cell signaling cascades', 'Pathway', (431, 454))	('alterations', 'Var', (139, 150))	('disruption', 'Reg', (284, 294))	('p53', 'Gene', (191, 194))	('oncogene', 'Protein', (384, 392))	('SCC', 'Gene', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cell proliferation', 'CPA', (245, 263))	('alterations', 'Reg', (369, 380))	('patient', 'Species', '9606', (14, 21))	('changes', 'Var', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('altered', 'Reg', (209, 216))	('repair', 'CPA', (237, 243))	('deregulation', 'Reg', (415, 427))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('loss', 'NegReg', (333, 337))
502302	25009749	In addition, a correlation between CD133 expression and the immunolocalization of several markers, such as p53, p16, p27, murine double minute 2 (MDM2), Ki-67, and epidermal growth factor receptor (EGFR), was observed.	('CD133', 'Gene', (35, 40))	('Ki-67', 'Gene', '17345', (153, 158))	('murine double minute 2', 'Gene', '17246', (122, 144))	('epidermal growth factor receptor', 'Gene', (164, 196))	('epidermal growth factor receptor', 'Gene', '13649', (164, 196))	('immunolocalization', 'MPA', (60, 78))	('expression', 'MPA', (41, 51))	('murine double minute 2', 'Gene', (122, 144))	('CD133', 'Gene', '19126', (35, 40))	('Ki-67', 'Gene', (153, 158))	('p27', 'Gene', (117, 120))	('p16', 'Var', (112, 115))	('p27', 'Gene', '12576', (117, 120))	('p53', 'Var', (107, 110))
502305	25009749	Other genetic alterations that are commonly associated with clinical tumors include p53 mutations; loss of p16MST1 and/or p15, and/or RARbeta expression; amplification of cyclin D1, HST-1, EGFR and INT-2; and elevations in iNOS, hTERT, BMP-6, COX-2 and c-Myc expression; as well as cytoplasmic beta-catenin levels.	('RARbeta', 'Gene', (134, 141))	('p15', 'Gene', (122, 125))	('iNOS', 'Gene', (223, 227))	('mutations', 'Var', (88, 97))	('hTERT', 'Gene', '7015', (229, 234))	('beta-catenin', 'Gene', (294, 306))	('BMP-6', 'Gene', '654', (236, 241))	('INT-2', 'Gene', '2248', (198, 203))	('beta-catenin', 'Gene', '1499', (294, 306))	('iNOS', 'Gene', '4843', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('p15', 'Gene', '1030', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('elevations', 'PosReg', (209, 219))	('loss', 'NegReg', (99, 103))	('c-Myc', 'Gene', (253, 258))	('hTERT', 'Gene', (229, 234))	('p16MST1', 'Gene', (107, 114))	('amplification', 'PosReg', (154, 167))	('HST-1', 'Gene', '2249', (182, 187))	('c-Myc', 'Gene', '4609', (253, 258))	('cyclin D1', 'Gene', (171, 180))	('tumors', 'Disease', (69, 75))	('COX-2', 'Gene', (243, 248))	('BMP-6', 'Gene', (236, 241))	('EGFR', 'Gene', (189, 193))	('HST-1', 'Gene', (182, 187))	('cyclin D1', 'Gene', '595', (171, 180))	('INT-2', 'Gene', (198, 203))	('COX-2', 'Gene', '4513', (243, 248))	('p53', 'Gene', (84, 87))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('RARbeta', 'Gene', '5915', (134, 141))
502306	25009749	One or several of these alterations contribute to the growth and metastatic potential of these tumors.	('metastatic potential', 'CPA', (65, 85))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('alterations', 'Var', (24, 35))	('contribute', 'Reg', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('growth', 'CPA', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
502313	25009749	The tumor suppressor p53 is a powerful anti-tumor molecule that is frequently inactivated by mutations or deletions in cancer.	('tumor', 'Disease', (4, 9))	('deletions', 'Var', (106, 115))	('mutations', 'Var', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Disease', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
502314	25009749	However, half of the human tumors express wild type (wt) p53, and its activation by antagonizing its negative regulator MDM2 might offer a new therapeutic strategy.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('antagonizing', 'Var', (84, 96))	('human', 'Species', '9606', (21, 26))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('p53', 'Var', (57, 60))	('activation', 'PosReg', (70, 80))
502320	25009749	Global DNA demethylation results in de-repression and activation of an operator gene through the deactivation of a repressor gene of imprinted alleles, such as H19 and IGF2, as well as the up-regulation of germ cell-restricted genes, many of which are linked to the X chromosome and encode proteins that are recognized by tumor reactive lymphocytes.	('IGF2', 'Gene', (168, 172))	('repressor gene', 'Gene', (115, 129))	('deactivation', 'NegReg', (97, 109))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('activation', 'PosReg', (54, 64))	('germ cell-restricted genes', 'Gene', (206, 232))	('H19', 'Gene', '283120', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('demethylation', 'Var', (11, 24))	('IGF2', 'Gene', '3481', (168, 172))	('H19', 'Gene', (160, 163))	('tumor', 'Disease', (322, 327))	('up-regulation', 'PosReg', (189, 202))	('de-repression', 'NegReg', (36, 49))
502321	25009749	Paradoxically, site-specific DNA methylation silences a variety of tumor suppressor genes, including p16, RASSF1A, FHIT, E-cadherin, and RARb in esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('FHIT', 'Gene', (115, 119))	('RASSF1A', 'Gene', (106, 113))	('methylation', 'Var', (33, 44))	('FHIT', 'Gene', '2272', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('RASSF1A', 'Gene', '11186', (106, 113))	('silences', 'NegReg', (45, 53))	('esophageal cancers', 'Disease', (145, 163))	('RARb', 'Gene', '5915', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('RARb', 'Gene', (137, 141))	('esophageal cancers', 'Disease', 'MESH:D004938', (145, 163))	('tumor', 'Disease', (67, 72))	('E-cadherin', 'Gene', '999', (121, 131))	('p16', 'Gene', (101, 104))	('E-cadherin', 'Gene', (121, 131))
502322	25009749	also showed that TC21 knockdown sensitizes ESCC to cisplatin.	('SCC', 'Gene', '6317', (44, 47))	('TC21', 'Gene', '22800', (17, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('sensitizes', 'Reg', (32, 42))	('TC21', 'Gene', (17, 21))	('knockdown', 'Var', (22, 31))	('SCC', 'Gene', (44, 47))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))
502325	25009749	The implications of the methylation-mediated inactivation of tumor suppressor genes are evident.	('methylation-mediated inactivation', 'Var', (24, 57))	('inactivation', 'Var', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
502327	25009749	Furthermore, several studies suggest that the aberrant methylation of tumor suppressor genes coincides with adverse response to therapy in esophageal cancer patients.	('aberrant methylation', 'Var', (46, 66))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('patients', 'Species', '9606', (157, 165))	('esophageal cancer', 'Disease', (139, 156))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
502328	25009749	Recent studies suggest that the aberrant activity of DNA methyltransferases and histone deacetylases (HDACs) may contribute to the inactivation of tumor suppressor gene expression and perturbed cell cycle regulation in aerodigestive tract malignancies.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('cell cycle regulation', 'CPA', (194, 215))	('malignancies', 'Disease', (239, 251))	('histone', 'Protein', (80, 87))	('aberrant activity', 'Var', (32, 49))	('perturbed', 'NegReg', (184, 193))	('inactivation', 'NegReg', (131, 143))	('perturbed cell cycle', 'Phenotype', 'HP:0011018', (184, 204))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('expression', 'MPA', (169, 179))	('malignancies', 'Disease', 'MESH:D009369', (239, 251))
502332	25009749	Furthermore, FK228 and other HDAC inhibitors markedly enhance p21expression.	('FK228', 'Var', (13, 18))	('p21', 'Gene', '644914', (62, 65))	('FK228', 'Chemical', 'MESH:C087123', (13, 18))	('enhance', 'PosReg', (54, 61))	('p21', 'Gene', (62, 65))
502338	25009749	The aforementioned studies indicate that the manipulation of gene expression as a means to restore cell cycle regulation and induce apoptosis is feasible in esophageal cancer cells in vitro, as well as in clinical settings.	('apoptosis', 'CPA', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cell cycle', 'CPA', (99, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('induce', 'PosReg', (125, 131))	('manipulation', 'Var', (45, 57))	('esophageal cancer', 'Disease', (157, 174))	('restore', 'PosReg', (91, 98))
502348	25009749	Inhibition of MDM2 can restore p53 activity in cancers with wt p53, resulting in anti-tumor effects with apoptosis and growth inhibition.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('activity', 'MPA', (35, 43))	('apoptosis', 'CPA', (105, 114))	('tumor', 'Disease', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('growth inhibition', 'CPA', (119, 136))	('cancers', 'Disease', (47, 54))	('Inhibition', 'Var', (0, 10))	('MDM2', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('p53', 'Protein', (31, 34))
502349	25009749	The silencing of HDM2 mRNA directly enhances MCF-7 cell apoptosis and decreases cell proliferation.	('enhances', 'PosReg', (36, 44))	('HDM2', 'Gene', '4193', (17, 21))	('HDM2', 'Gene', (17, 21))	('decreases', 'NegReg', (70, 79))	('MCF-7', 'CellLine', 'CVCL:0031', (45, 50))	('cell proliferation', 'CPA', (80, 98))	('MCF-7 cell apoptosis', 'CPA', (45, 65))	('silencing', 'Var', (4, 13))
502354	25009749	Cancer is a multistep genetic and epigenetic disease with a complex etiology, and cancer cells have been characterized by several defects, such as mutations, down-regulation, over-expression, and deletions of oncogenes and tumor suppressor genes.	('over-expression', 'PosReg', (175, 190))	('mutations', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('deletions', 'Var', (196, 205))	('cancer', 'Disease', (82, 88))	('Cancer', 'Disease', (0, 6))	('down-regulation', 'NegReg', (158, 173))	('oncogenes', 'Gene', (209, 218))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (223, 228))
502360	25009749	Recent advances in the molecular biology of esophageal cancer have documented the function of genetic alterations in tumorigenesis and have facilitated the development of potential new therapeutic approaches designed to target such genetic alterations.	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('genetic alterations', 'Var', (94, 113))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('esophageal cancer', 'Disease', (44, 61))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
502378	24308314	A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (118, 127))	('telomere', 'Var', (64, 72))	('dysplasia', 'Disease', (118, 127))
502380	24308314	The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia.	('dysplasia', 'Disease', (96, 105))	('dysplasia', 'Disease', 'MESH:D004476', (96, 105))	('telomere length', 'Var', (42, 57))
502397	24308314	Previous work has found that telomere length is associated with cancer incidence and mortality .	('telomere length', 'Var', (29, 44))	('associated', 'Reg', (48, 58))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mortality', 'CPA', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
502405	24308314	Another study suggested that chromosome-specific telomere length in blood cells may be related to esophageal cancer .	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', (98, 115))	('related', 'Reg', (87, 94))	('telomere length', 'Var', (49, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
502434	24308314	Figure  1 shows the ROC curve for the use of telomere length as a diagnostic marker for high-grade dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (99, 108))	('telomere', 'Var', (45, 53))	('dysplasia', 'Disease', (99, 108))
502435	24308314	The area under the curve was 0.55, suggesting that telomere length of esophageal cells collected by balloon cytology is a poor marker of the presence of high-grade dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (164, 173))	('telomere', 'Var', (51, 59))	('dysplasia', 'Disease', (164, 173))
502437	24308314	Table  4 shows the unconditional logistic regression models, both crude and adjusted, for risk of high-grade dysplasia by telomere length.	('dysplasia', 'Disease', (109, 118))	('telomere length', 'Var', (122, 137))	('dysplasia', 'Disease', 'MESH:D004476', (109, 118))
502562	32415564	miRNA arrays showed significant upregulation of seven miRs with tumor suppressor activity (-125b-5P, -132-3P, -548z, -551a, -504, -518 and -34a-5P).	('tumor', 'Disease', (64, 69))	('upregulation', 'PosReg', (32, 44))	('-125b-5P', 'Var', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
502573	32415564	PPI usage in patients with BE has been associated with a lower risk of EAC but this may only be due to an indirect action.	('BE', 'Phenotype', 'HP:0100580', (27, 29))	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('patients', 'Species', '9606', (13, 21))	('EAC', 'Disease', (71, 74))	('PPI', 'Var', (0, 3))
502655	32415564	There were cases of individual miRNAs that exhibited a trend toward downregulation in the zinc-treatment group, such as miR-21-5P (a 38% decrease) and miR-31-5P (a 33% decrease), but these failed to achieve statistical significance (P < 0.15) (data not shown).	('miR-31-5P', 'Var', (151, 160))	('miR-21-5P', 'Chemical', '-', (120, 129))	('decrease', 'NegReg', (137, 145))	('miR-21-5P', 'Var', (120, 129))	('downregulation', 'NegReg', (68, 82))
502656	32415564	Both miR-21-5P and miR-31-5P have exhibited zinc-induced decreases in the esophageal mucosae of rats.	('miR-21-5P', 'Var', (5, 14))	('rats', 'Species', '10116', (96, 100))	('miR-31-5P', 'Var', (19, 28))	('esophageal mucosae', 'MPA', (74, 92))	('decreases', 'NegReg', (57, 66))	('miR-21-5P', 'Chemical', '-', (5, 14))
502666	32415564	The documented role of inflammation-mediated genetic and epigenetic alterations in Barrett's carcinogenesis, and the role of inflammation in cancer generally, have been the subject of many reviews.	('inflammation', 'Disease', 'MESH:D007249', (125, 137))	('inflammation', 'Disease', (125, 137))	('inflammation', 'Disease', 'MESH:D007249', (23, 35))	("Barrett's carcinogenesis", 'Disease', 'MESH:D063646', (83, 107))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('epigenetic alterations', 'Var', (57, 79))	('genetic', 'Var', (45, 52))	('inflammation', 'Disease', (23, 35))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	("Barrett's carcinogenesis", 'Disease', (83, 107))	('cancer', 'Disease', (141, 147))
502690	32415564	miR-125b-5P, increased approximately 2-fold in the zinc group, and is known to be downregulated in triple negative breast cancer cells.	('downregulated', 'NegReg', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('miR-125b-5P', 'Chemical', '-', (0, 11))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('increased', 'PosReg', (13, 22))	('miR-125b-5P', 'Var', (0, 11))
502692	32415564	Most significantly here, miR-125b-5P has been reported to inhibit various signaling elements of EMT in Barrett's metaplasia.	('signaling elements', 'MPA', (74, 92))	("Barrett's metaplasia", 'Disease', (103, 123))	('inhibit', 'NegReg', (58, 65))	('miR-125b-5P', 'Chemical', '-', (25, 36))	('miR-125b-5P', 'Var', (25, 36))
502783	32162106	In all but two patients, mucosal biopsies were taken from different locations in the upper, middle, and lower esophagus using 2.3 mm calipers (MTW Wolfgang Haag KG, Germany) through flexible gastroscopes (Fujinon EG-600WR or EG-600ZW, Fuji Corp, Japan).	('patients', 'Species', '9606', (15, 23))	('Fujinon EG-600WR', 'Var', (205, 221))	('EG-600ZW', 'Var', (225, 233))
502889	32884573	Subsequently, we found that ablation of Bmi1+ cells from mice with ESCC led to inhibition of tumor growth.	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ESCC', 'Gene', (67, 71))	('tumor', 'Disease', (93, 98))	('inhibition', 'NegReg', (79, 89))	('ablation', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
502890	32884573	In addition, our results demonstrated that PTC-209, an inhibitor of Bmi1, was able to inhibit ESCC progression when combined with cisplatin.	('PTC-209', 'Chemical', 'MESH:C586999', (43, 50))	('PTC-209', 'Var', (43, 50))	('inhibit', 'NegReg', (86, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('ESCC', 'Disease', (94, 98))
502915	32884573	We found that (1) the gene ablation of Bmi1 led to increased apoptosis, decreased proliferation, and weakened stemness of ESCC; (2) the Bmi1+ tumor cells led to the progressive growth of epithelial clones and the Bmi1+ tumor cells were tumor-initiating cells in ESCC; and (3) the cisplatin combined with Bmi1 targeting drug could effectively inhibit tumor growth in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('inhibit', 'NegReg', (342, 349))	('growth', 'CPA', (177, 183))	('epithelial clones', 'CPA', (187, 204))	('stemness', 'CPA', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('apoptosis', 'CPA', (61, 70))	('decreased', 'NegReg', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (350, 355))	('weakened', 'NegReg', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('ESCC', 'Disease', (366, 370))	('proliferation', 'CPA', (82, 95))	('Bmi1', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (280, 289))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('gene ablation', 'Var', (22, 35))	('tumor', 'Disease', (236, 241))
502919	32884573	For lineage tracing, after 16 weeks of 4NQO treatment, in Bmi1CreER;RosatdTomato or Bmi1CreER;RosatdTomato;RosaDTA transgenic mice, tamoxifen (0.08 mg/g body weight per day for 3 days; Sigma, T5648-1G) was injected intraperitoneally.	('tamoxifen', 'Chemical', 'MESH:D013629', (132, 141))	('T5648-1G', 'SUBSTITUTION', 'None', (192, 200))	('Bmi1CreER', 'Gene', '12151', (58, 67))	('transgenic mice', 'Species', '10090', (115, 130))	('Bmi1CreER', 'Gene', (58, 67))	('4NQO', 'Chemical', '-', (39, 43))	('T5648-1G', 'Var', (192, 200))	('Tomato', 'Species', '4081', (74, 80))	('Bmi1CreER', 'Gene', '12151', (84, 93))	('Bmi1CreER', 'Gene', (84, 93))	('Tomato', 'Species', '4081', (100, 106))
502928	32884573	Specific primary antibodies including CD44 (1 : 200; Abcam, ab157107), Tp63 (1 : 200; Abcam, ab53039), and KRT5 (1 : 200; Abcam, ab52635) were used.	('1 : 200;', 'Var', (77, 85))	('KRT5', 'Gene', '110308', (107, 111))	('CD44', 'Gene', '12505', (38, 42))	('CD44', 'Gene', (38, 42))	('KRT5', 'Gene', (107, 111))	('Tp63', 'Gene', (71, 75))	('Tp63', 'Gene', '22061', (71, 75))
502972	32884573	The experimental results show that although cisplatin and PTC-209 alone have a certain therapeutic effect, the combination of cisplatin and PTC-209 has the least lesion number and the best therapeutic effect (Figures 5(a) and 5(b)).	('therapeutic', 'CPA', (87, 98))	('PTC-209', 'Chemical', 'MESH:C586999', (140, 147))	('cisplatin', 'Var', (126, 135))	('PTC-209', 'Chemical', 'MESH:C586999', (58, 65))	('combination', 'Var', (111, 122))	('lesion number', 'CPA', (162, 175))	('least', 'NegReg', (156, 161))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('PTC-209', 'Gene', (140, 147))
503006	32228854	While knockout of GPC1 exhibits no abnormalities in morphology, behavior, or life span in adult mice, reduction in brain volume has been reported in early fetal phase.	('mice', 'Species', '10090', (96, 100))	('reduction', 'NegReg', (102, 111))	('knockout', 'Var', (6, 14))	('GPC1', 'Gene', (18, 22))	('brain volume', 'CPA', (115, 127))
503017	32228854	These data indicated that GPC1 would be a promising therapeutic target for CAR-T cell therapies and anti-GPC1 mAb (clone: 1-12) could be used for the generation of CAR-T cells.	('CAR-T', 'Chemical', '-', (75, 80))	('cat', 'Gene', (15, 18))	('CAR-T', 'Chemical', '-', (164, 169))	('anti-GPC1', 'Var', (100, 109))	('cat', 'Gene', '847', (15, 18))
503025	32228854	We further explored antitumor activities of the GPC1-specific hCAR-T cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('hCAR', 'Gene', (62, 66))	('tumor', 'Disease', (24, 29))	('CAR-T', 'Chemical', '-', (63, 68))	('hCAR', 'Gene', '1525', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('GPC1-specific', 'Var', (48, 61))
503069	32228854	As MC38-mGPC1 stably expressed PD-L1, we assessed whether anti-PD-1 Ab could enhance antitumor activities of the mCAR-T cell therapy (Figure 6B).	('mGPC1', 'Gene', '14733', (8, 13))	('anti-PD-1', 'Var', (58, 67))	('mCAR', 'Gene', '13052', (113, 117))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mGPC1', 'Gene', (8, 13))	('CAR-T', 'Chemical', '-', (114, 119))	('enhance', 'PosReg', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mCAR', 'Gene', (113, 117))
503072	32228854	While the mice treated with either anti-PD1 Ab or mCAR-T cells alone showed partial inhibition of tumor growth, two out of the five mice receiving the combination therapy showed complete tumor eradication (Figure 6D).	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('inhibition', 'NegReg', (84, 94))	('mice', 'Species', '10090', (10, 14))	('mCAR', 'Gene', '13052', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cat', 'Gene', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (187, 192))	('mice', 'Species', '10090', (132, 136))	('CAR-T', 'Chemical', '-', (51, 56))	('anti-PD1', 'Var', (35, 43))	('tumor', 'Disease', (98, 103))	('mCAR', 'Gene', (50, 54))	('cat', 'Gene', '847', (198, 201))
503093	32228854	In our study, tumor-specific killing by our CAR-T cells may be explained by a tumor-specific recognition by the anti-GPC1 mAb (clone: 1-12).	('anti-GPC1', 'Var', (112, 121))	('CAR-T', 'Chemical', '-', (44, 49))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
503117	32228854	This synergistic effect may be explained by enhanced effector function of administered CAR-T cells and endogenous antitumor CTL by anti-PD-1 Ab.	('effector function', 'CPA', (53, 70))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('anti-PD-1', 'Var', (131, 140))	('CAR-T', 'Chemical', '-', (87, 92))	('tumor', 'Disease', (118, 123))	('enhanced', 'PosReg', (44, 52))
503122	32228854	By establishing the syngeneic mouse models, we were able to evaluate not only the efficacy but also the safety of GPC1-specific CAR-T cells and their enhanced antitumor activity in combination with anti-PD-1 Ab.	('enhanced', 'PosReg', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('GPC1-specific', 'Var', (114, 127))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('mouse', 'Species', '10090', (30, 35))	('CAR-T', 'Chemical', '-', (128, 133))
503130	32228854	TaqMan RT-PCR (Applied Biosystems) probes were human GPC-1 (Hs00892476_m1) and mouse GPC-1 (Mm00497305_m1).	('Mm00497305_m1', 'Var', (92, 105))	('mouse', 'Species', '10090', (79, 84))	('Hs00892476_m1', 'Var', (60, 73))	('human', 'Species', '9606', (47, 52))
503143	32228854	As shown in Figure 2A and Figure 2:figure supplement 1, the human CAR (hCAR) comprising the scFv GPC1 linked to the human CD8a leader sequence (nucleotides 1-63, GenBank NM 001768.6), human CD28 extracellulaar/transmembrane/intracellular domains (nucleotides 562-882, GenBank NM 001768.6), and human CD3zeta intracellular domain (nucleotides 299-637, GenBank NM_000734.3).	('human', 'Species', '9606', (294, 299))	('CD8a', 'Gene', (122, 126))	('CD8a', 'Gene', '925', (122, 126))	('nucleotides', 'Var', (247, 258))	('nucleotides 299-637', 'Var', (330, 349))	('human', 'Species', '9606', (184, 189))	('hCAR', 'Gene', (71, 75))	('human', 'Species', '9606', (116, 121))	('scFv', 'Gene', (92, 96))	('scFv', 'Gene', '652070', (92, 96))	('human', 'Species', '9606', (60, 65))	('hCAR', 'Gene', '1525', (71, 75))
503158	32228854	Human (M700A and M701B; Endogen) and murine (BD Biosciences) IFNgamma were measured by ELISA.	('Human', 'Species', '9606', (0, 5))	('murine', 'Species', '10090', (37, 43))	('M701B', 'Var', (17, 22))	('M700A', 'Var', (7, 12))	('M701B', 'SUBSTITUTION', 'None', (17, 22))	('M700A', 'Mutation', 'p.M700A', (7, 12))
503166	32228854	Two-fold dilution series of recombinant hGPC1 (6.25-400 nM) or mGPC1 (25-400 nM) was injected for 2 min.	('mGPC1', 'Gene', (63, 68))	('hGPC1', 'Gene', '2817', (40, 45))	('6.25-400 nM', 'Var', (47, 58))	('mGPC1', 'Gene', '14733', (63, 68))	('hGPC1', 'Gene', (40, 45))	('25-400 nM', 'Var', (70, 79))
503200	32228854	It was also shown that the anti-tumor efficacy of the anti-GPC1 CAR-T cells was augmented by the combination with anti-PD-1 antibody.	('combination', 'Interaction', (97, 108))	('CAR-T', 'Chemical', '-', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('augmented', 'PosReg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('anti-GPC1', 'Var', (54, 63))	('tumor', 'Disease', (32, 37))
503210	32228854	2) As for anti-tumor effects of anti-GPC1 CAR-T cells, experimental models are not appropriate to evaluate its potency.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('CAR-T', 'Chemical', '-', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('anti-GPC1', 'Var', (32, 41))
503215	32228854	Anti-tumor efficacy of anti-GPC1 CAR-T cells without IL-2 injections are needed.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('anti-GPC1', 'Var', (23, 32))	('CAR-T', 'Chemical', '-', (33, 38))
503217	32228854	However, it remains unclear whether the epitope spreading plays a crucial role in the anti-tumor effects of anti-GPC1 CAR-T therapy or is merely a by-stander phenomenon.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('anti-GPC1', 'Var', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CAR-T', 'Chemical', '-', (118, 123))	('tumor', 'Disease', (91, 96))
503218	32228854	In order to address this important question, efficacy of anti-GPC1 CAR-T cells should be examined in the mice with a depletion (or deficient) of endogenous T cell (or CD8 T cells).	('depletion', 'MPA', (117, 126))	('CD8', 'Gene', (167, 170))	('CD8', 'Gene', '925', (167, 170))	('anti-GPC1', 'Var', (57, 66))	('mice', 'Species', '10090', (105, 109))	('CAR-T', 'Chemical', '-', (67, 72))
503223	32228854	5) MC38 is known as PD-1 Ab treatment-sensitive tumor.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('MC38', 'Var', (3, 7))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
503257	32228854	And strong antitumor effects of the chicken based GPC1 specific CAR-T cells showed in this study.	('GPC1', 'Var', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('CAR-T', 'Chemical', '-', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('chicken', 'Species', '9031', (36, 43))
503286	32201516	Siglec-15 mutations are widely observed in tumors and interact with different genes in different cancer types.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('interact', 'Reg', (54, 62))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('mutations', 'Var', (10, 19))	('Siglec-15', 'Gene', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
503308	32201516	It has a collection of data on millions of coding mutations, noncoding mutations, genomic rearrangements, fusion genes, copy number abnormalities and gene expression variants in the human genome all in one database so that researchers can explore these data more easily.	('copy number abnormalities', 'Disease', 'MESH:D007674', (120, 145))	('human', 'Species', '9606', (182, 187))	('copy number abnormalities', 'Disease', (120, 145))	('variants', 'Var', (166, 174))
503322	32201516	COSMIC provided information on Siglec-15 mutations in different cancers, which included substitution missense, nonsense and synonymous mutations, and the results are depicted in pie charts.	('mutations', 'Var', (41, 50))	('Siglec-15', 'Gene', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('substitution missense', 'Var', (88, 109))	('nonsense', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
503323	32201516	Nonsense substitutions were found in biliary tract cancer (33.33%), breast cancer (25%) and lung cancer (16.67%), while substitution missense mutations were observed in biliary tract cancer (33.33%), breast cancer (75%), central nervous system cancer (33.33%), hematopoietic and lymphoid cancer (100%), endometrial cancer (100%), large intestine cancer (68.42%), liver cancer (25%), lung cancer (83.33%), esophageal cancer (75%), prostate cancer (100%), skin cancer (100%), stomach cancer (75%), thyroid cancer (100%) and upper aerodigestive tract cancer (60%).	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('endometrial cancer', 'Disease', (303, 321))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('stomach cancer', 'Disease', (474, 488))	('lung cancer', 'Phenotype', 'HP:0100526', (383, 394))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('biliary tract cancer', 'Disease', (37, 57))	('cancer', 'Disease', 'MESH:D009369', (504, 510))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (388, 394))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (279, 294))	('missense mutations', 'Var', (133, 151))	('cancer', 'Disease', (315, 321))	('central nervous system cancer', 'Phenotype', 'HP:0100006', (221, 250))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (37, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('biliary tract cancer', 'Disease', 'MESH:D001661', (37, 57))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', (504, 510))	('breast cancer', 'Disease', (200, 213))	('cancer', 'Disease', (416, 422))	('liver cancer', 'Phenotype', 'HP:0002896', (363, 375))	('liver cancer', 'Disease', (363, 375))	('cancer', 'Disease', 'MESH:D009369', (482, 488))	('lymphoid cancer', 'Disease', 'MESH:D009369', (279, 294))	('upper aerodigestive tract cancer', 'Disease', (522, 554))	('cancer', 'Disease', (288, 294))	('thyroid cancer', 'Disease', (496, 510))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('prostate cancer', 'Disease', 'MESH:D011471', (430, 445))	('prostate cancer', 'Phenotype', 'HP:0012125', (430, 445))	('cancer', 'Disease', (97, 103))	('central nervous system cancer', 'Disease', (221, 250))	('thyroid cancer', 'Disease', 'MESH:D013964', (496, 510))	('biliary tract cancer', 'Disease', (169, 189))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (482, 488))	('cancer', 'Disease', (459, 465))	('nervous system cancer', 'Phenotype', 'HP:0004375', (229, 250))	('esophageal cancer', 'Disease', (405, 422))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (369, 375))	('substitutions', 'Var', (9, 22))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (169, 189))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('endometrial cancer', 'Phenotype', 'HP:0012114', (303, 321))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (548, 554))	('skin cancer', 'Disease', 'MESH:D012878', (454, 465))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (51, 57))	('biliary tract cancer', 'Disease', 'MESH:D001661', (169, 189))	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (522, 554))	('cancer', 'Disease', (548, 554))	('cancer', 'Disease', 'MESH:D009369', (439, 445))	('skin cancer', 'Disease', (454, 465))	('prostate cancer', 'Disease', (430, 445))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('stomach cancer', 'Disease', 'MESH:D013274', (474, 488))	('lymphoid cancer', 'Disease', (279, 294))	('lung cancer', 'Disease', (92, 103))	('large intestine cancer', 'Phenotype', 'HP:0100834', (330, 352))	('stomach cancer', 'Phenotype', 'HP:0012126', (474, 488))	('cancer', 'Disease', (346, 352))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('thyroid cancer', 'Phenotype', 'HP:0002890', (496, 510))	('central nervous system cancer', 'Disease', 'MESH:D002494', (221, 250))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('cancer', 'Disease', (439, 445))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('lung cancer', 'Disease', 'MESH:D008175', (383, 394))	('endometrial cancer', 'Disease', 'MESH:D016889', (303, 321))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (416, 422))	('esophageal cancer', 'Disease', 'MESH:D004938', (405, 422))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('skin cancer', 'Phenotype', 'HP:0008069', (454, 465))	('hematopoietic and', 'Disease', (261, 278))	('lung cancer', 'Disease', (383, 394))	('liver cancer', 'Disease', 'MESH:D006528', (363, 375))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('breast cancer', 'Disease', (68, 81))
503324	32201516	Additionally, synonymous substitution mutations appeared in biliary tract cancer (33.33%), central nervous system cancer (66.67%), large intestine cancer (36.84%), liver cancer (75%), esophageal cancer (25%), parathyroid cancer (100%), stomach cancer (25%) and upper aerodigestive tract cancer (40%).	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (287, 293))	('liver cancer', 'Disease', 'MESH:D006528', (164, 176))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('upper aerodigestive tract cancer', 'Disease', (261, 293))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('thyroid cancer', 'Phenotype', 'HP:0002890', (213, 227))	('synonymous substitution mutations', 'Var', (14, 47))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('nervous system cancer', 'Phenotype', 'HP:0004375', (99, 120))	('liver cancer', 'Phenotype', 'HP:0002896', (164, 176))	('biliary tract cancer', 'Disease', (60, 80))	('liver cancer', 'Disease', (164, 176))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (261, 293))	('stomach cancer', 'Disease', 'MESH:D013274', (236, 250))	('stomach cancer', 'Phenotype', 'HP:0012126', (236, 250))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('parathyroid cancer', 'Disease', 'MESH:D010282', (209, 227))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('large intestine cancer', 'Phenotype', 'HP:0100834', (131, 153))	('parathyroid cancer', 'Disease', (209, 227))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (195, 201))	('esophageal cancer', 'Disease', (184, 201))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (60, 80))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('central nervous system cancer', 'Disease', (91, 120))	('biliary tract cancer', 'Disease', 'MESH:D001661', (60, 80))	('parathyroid cancer', 'Phenotype', 'HP:0006780', (209, 227))	('appeared', 'Reg', (48, 56))	('central nervous system cancer', 'Phenotype', 'HP:0100006', (91, 120))	('cancer', 'Disease', (147, 153))	('stomach cancer', 'Disease', (236, 250))	('central nervous system cancer', 'Disease', 'MESH:D002494', (91, 120))	('cancer', 'Disease', (114, 120))
503325	32201516	C>T and G>A mutations were most common in the Siglec-15 coding strand, both of which were observed in eleven cancer types.	('G>A mutations', 'Var', (8, 21))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('C>T', 'Var', (0, 3))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (109, 115))	('common', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
503326	32201516	A>T and T>A mutations in Siglec-15 were not found in the TCGA cancer samples.	('T>A', 'Var', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Siglec-15', 'Gene', (25, 34))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
503327	32201516	Other types of base mutations occurred sporadically in different cancers (Figure 3a).	('base mutations', 'Var', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('occurred', 'Reg', (30, 38))	('cancers', 'Disease', (65, 72))
503341	32201516	Several lines of evidence have shown that interactions with sialic acid-binding receptors can influence cancer progression; for example, hypersialylation can induce changes in the physical properties of tumor cells and potentiate the evasion of apoptosis in cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('hypersialylation', 'Var', (137, 153))	('influence', 'Reg', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('potentiate', 'PosReg', (219, 229))	('sialic acid', 'Chemical', 'MESH:D019158', (60, 71))	('interactions', 'Interaction', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Disease', (258, 264))	('induce changes', 'Reg', (158, 172))	('cancer', 'Disease', (104, 110))	('evasion', 'MPA', (234, 241))
503349	32201516	Additionally, knockdown of Siglec-15 expression did not cause obvious physical abnormalities but did inhibit tumor growth.	('Siglec-15', 'Gene', (27, 36))	('inhibit', 'NegReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', (109, 114))
503350	32201516	Since no previous studies have focused on Siglec-15 mutations in human cancers, we explored this topic with the help of COSMIC and cBioPortal.	('mutations', 'Var', (52, 61))	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('Siglec-15', 'Gene', (42, 51))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
503351	32201516	As shown in Figure 3, the results from TCGA demonstrated that Siglec-15 mutations occurred widely in human cancers.	('mutations', 'Var', (72, 81))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Siglec-15', 'Gene', (62, 71))	('occurred', 'Reg', (82, 90))	('human', 'Species', '9606', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
503352	32201516	The most common type of Siglec-15 mutation was missense substitution, which could be observed in all tumors with mutations.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Siglec-15', 'Gene', (24, 33))	('missense substitution', 'Var', (47, 68))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
503353	32201516	At the base-pair level, C>T and G>A mutations were the most widely observed in tumors.	('observed', 'Reg', (67, 75))	('C>T', 'Var', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('G>A mutations', 'Var', (32, 45))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
503357	32201516	Alterations in the expression of Siglec-15 may cause a variety of gene changes across different cancers, which could lead to remarkably different results.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cause', 'Reg', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Alterations', 'Var', (0, 11))	('gene changes', 'MPA', (66, 78))	('Siglec-15', 'Gene', (33, 42))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
503361	32201516	For cutaneous melanoma patients, high Siglec-15 expression indicates a high risk of tumor aggressiveness and adverse clinical outcomes.	('high', 'Var', (33, 37))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (84, 104))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('expression', 'MPA', (48, 58))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('Siglec-15', 'Protein', (38, 47))	('tumor aggressiveness', 'Disease', (84, 104))	('cutaneous melanoma', 'Disease', (4, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (90, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (4, 22))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (4, 22))
503371	32201516	Siglec-15 mutations are widely observed in tumors and interact with different genes in different cancer types, which might explain why high Siglec-15 expression does not necessarily indicate a poor prognosis in all cancers.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('expression', 'MPA', (150, 160))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('cancers', 'Disease', (215, 222))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (43, 49))	('mutations', 'Var', (10, 19))	('Siglec-15', 'Gene', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('Siglec-15', 'Gene', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
503459	31730285	We are planning to conduct a further study of SPMs using data from JCOG0502 (UMIN000000551) with an aim of comparing esophagectomy with definitive chemoradiotherapy for T1bN0 esophageal cancer.	('esophageal cancer', 'Disease', (175, 192))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('JCOG0502', 'Chemical', 'MESH:C525065', (67, 75))	('T1bN0', 'Var', (169, 174))
503466	31462294	A significantly higher prevalence of P. hominis was found in cancer patients than that in the control population (41.54 vs 9.15%, chi2 = 42.84, df = 1, P < 0.001), resulting in a 6.75-fold risk of gastrointestinal cancers (OR: 6.75, 95% CI: 3.55-12.83, P < 0.001).	('gastrointestinal cancers', 'Disease', (197, 221))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (197, 221))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('P. hominis', 'Species', '5728', (37, 47))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (197, 220))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancer', 'Disease', (61, 67))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('P. hominis', 'Var', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
503469	31462294	To our knowledge, this study is the first report presenting the high association between P. hominis and gastrointestinal cancers.	('P. hominis', 'Var', (89, 99))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (104, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('P. hominis', 'Species', '5728', (89, 99))	('gastrointestinal cancers', 'Disease', (104, 128))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (104, 128))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
503493	31462294	Pentatrichomonas hominis has also been associated with irritable bowel syndrome, systemic lupus erythematosus and rheumatoid arthritis in humans.	('humans', 'Species', '9606', (138, 144))	('irritable bowel syndrome', 'Disease', (55, 79))	('irritable bowel syndrome', 'Disease', 'MESH:D043183', (55, 79))	('Pentatrichomonas hominis', 'Species', '5728', (0, 24))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (81, 109))	('rheumatoid arthritis', 'Disease', (114, 134))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (114, 134))	('arthritis', 'Phenotype', 'HP:0001369', (125, 134))	('irritable', 'Phenotype', 'HP:0000737', (55, 64))	('systemic lupus erythematosus', 'Disease', (81, 109))	('Pentatrichomonas', 'Var', (0, 16))	('associated', 'Reg', (39, 49))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (81, 109))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (114, 134))
503506	31462294	All novel nucleotide sequences obtained in this study were deposited in the GenBank database under the accession numbers MK177542-MK177552, MN173974-MN173996 and MN189982.	('MN189982', 'CellLine', 'CVCL:U508', (162, 170))	('MN173974-MN173996', 'CellLine', 'CVCL:U508', (140, 157))	('MK177542-MK177552', 'Var', (121, 138))	('MN173974-MN173996', 'Var', (140, 157))	('MN189982', 'Var', (162, 170))
503513	31462294	These results indicate a frequent occurrence of P. hominis in gastrointestinal cancers.	('occurrence', 'Reg', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('P. hominis', 'Var', (48, 58))	('P. hominis', 'Species', '5728', (48, 58))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (62, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('gastrointestinal cancers', 'Disease', (62, 86))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (62, 85))
503519	31462294	Nevertheless, P. hominis infection in stomach cancer was significantly enriched in males compared to females (55.26 vs 15.38%, chi2 = 6.22, df = 1, P = 0.01; Additional file 4: Table S4).	('infection in stomach cancer', 'Disease', 'MESH:D013274', (25, 52))	('P. hominis', 'Var', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('infection in stomach cancer', 'Disease', (25, 52))	('stomach cancer', 'Phenotype', 'HP:0012126', (38, 52))	('P. hominis', 'Species', '5728', (14, 24))
503522	31462294	In detail, P. hominis infections were associated with a 5.93-fold (95% CI: 3.00-11.77), 7.11-fold (95% CI: 3.13-16.11), 34.85-fold (95% CI: 5.94-204.40), 20.38-fold (95% CI: 3.29-126.28) and 14.77-fold (95% CI: 1.03-211.18) risk of colorectal, stomach, esophageal, liver and small intestine cancer, respectively.	('esophageal', 'Disease', (253, 263))	('stomach', 'Disease', (244, 251))	('small intestine cancer', 'Disease', (275, 297))	('infections', 'Disease', 'MESH:D007239', (22, 32))	('P. hominis', 'Var', (11, 21))	('colorectal', 'Disease', (232, 242))	('small intestine cancer', 'Disease', 'MESH:D007414', (275, 297))	('infections', 'Disease', (22, 32))	('liver', 'Disease', (265, 270))	('P. hominis', 'Species', '5728', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('colorectal', 'Disease', 'MESH:D015179', (232, 242))	('small intestine cancer', 'Phenotype', 'HP:0100833', (275, 297))
503523	31462294	These results suggest a high association of P. hominis with gastrointestinal cancers.	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('gastrointestinal cancers', 'Disease', (60, 84))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (60, 84))	('P. hominis', 'Species', '5728', (44, 54))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (60, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('P. hominis', 'Var', (44, 54))	('association', 'Interaction', (29, 40))
503526	31462294	Thirteen sequences were assigned to novel types with a number of single nucleotide polymorphisms (SNPs) compared to KJ404269 (99% identity) including substitutions, insertion and deletion of a single nucleotide (Fig.	('KJ404269', 'Chemical', '-', (116, 124))	('deletion', 'Var', (179, 187))	('insertion', 'Var', (165, 174))	('substitutions', 'Var', (150, 163))
503532	31462294	Currently, P. hominis is considered to be a potential zoonotic parasite and can cause several symptoms, such as diarrhea.	('diarrhea', 'Disease', (112, 120))	('diarrhea', 'Disease', 'MESH:D003967', (112, 120))	('P. hominis', 'Var', (11, 21))	('P. hominis', 'Species', '5728', (11, 21))	('cause', 'Reg', (80, 85))	('diarrhea', 'Phenotype', 'HP:0002014', (112, 120))
503542	31462294	In addition, T. vaginalis was shown to be associated with cervical and prostate cancers.	('T. vaginalis', 'Species', '5722', (13, 25))	('T. vaginalis', 'Var', (13, 25))	('associated', 'Reg', (42, 52))	('prostate cancers', 'Phenotype', 'HP:0012125', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancers', 'Disease', (71, 87))	('cervical', 'Disease', (58, 66))	('prostate cancers', 'Disease', 'MESH:D011471', (71, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
503546	31462294	The high prevalence of P. hominis was not only observed in colorectal cancer, but also in other gastrointestinal cancers, including stomach cancer, liver cancer, esophageal cancer and small intestine cancer.	('small intestine cancer', 'Phenotype', 'HP:0100833', (184, 206))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('liver cancer', 'Phenotype', 'HP:0002896', (148, 160))	('stomach cancer', 'Disease', (132, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('liver cancer', 'Disease', (148, 160))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (96, 120))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (96, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('esophageal cancer', 'Disease', (162, 179))	('observed', 'Reg', (47, 55))	('gastrointestinal cancers', 'Disease', (96, 120))	('small intestine cancer', 'Disease', 'MESH:D007414', (184, 206))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('stomach cancer', 'Disease', 'MESH:D013274', (132, 146))	('stomach cancer', 'Phenotype', 'HP:0012126', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('small intestine cancer', 'Disease', (184, 206))	('colorectal cancer', 'Disease', (59, 76))	('P. hominis', 'Species', '5728', (23, 33))	('liver cancer', 'Disease', 'MESH:D006528', (148, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('P. hominis', 'Var', (23, 33))
503552	31462294	It has been shown that microbiota are highly associated with gastrointestinal and non-gastrointestinal cancers, such as colorectal cancer, liver cancer and breast cancer.	('non-gastrointestinal cancers', 'Disease', (82, 110))	('gastrointestinal', 'Disease', (61, 77))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('microbiota', 'Var', (23, 33))	('liver cancer', 'Disease', 'MESH:D006528', (139, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('gastrointestinal', 'Disease', 'MESH:D005767', (61, 77))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('colorectal cancer', 'Disease', (120, 137))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('liver cancer', 'Phenotype', 'HP:0002896', (139, 151))	('breast cancer', 'Disease', (156, 169))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (86, 109))	('liver cancer', 'Disease', (139, 151))	('associated', 'Reg', (45, 55))	('non-gastrointestinal cancers', 'Disease', 'MESH:D004067', (82, 110))	('gastrointestinal', 'Disease', (86, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('gastrointestinal', 'Disease', 'MESH:D005767', (86, 102))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
503569	31462294	The newly generated sequences were submitted to the GenBank database under the Accession Numbers MK177542-MK177552, MN173974-MN173996 and MN189982.	('MN189982', 'CellLine', 'CVCL:U508', (138, 146))	('MN173974-MN173996', 'CellLine', 'CVCL:U508', (116, 133))	('MN173974-MN173996', 'Var', (116, 133))	('MN189982', 'Var', (138, 146))	('MK177542-MK177552', 'Var', (97, 114))
503645	31551657	SHR-1316, a humanized immunoglobulin IgG4 PD-L1 monoclonal antibody designed and produced in China, and has entered into various clinical studies in solid tumors.	('SHR-1316', 'Var', (0, 8))	('PD-L1', 'Gene', '29126', (42, 47))	('solid tumors', 'Disease', 'MESH:D009369', (149, 161))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('entered', 'Reg', (108, 115))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('human', 'Species', '9606', (12, 17))	('PD-L1', 'Gene', (42, 47))	('solid tumors', 'Disease', (149, 161))
503650	31551657	Therefore, the immunosuppressive response mainly occurred in peripheral tissues for PD-1/PD-L1 antibody; CTLA-4 pathway inhibitors cause more severe autoimmune diseases than PD-1/PD-L1 pathway inhibitors, which limits the clinical application of CTLA-4 inhibitors.	('CTLA-4', 'Gene', '1493', (246, 252))	('PD-L1', 'Gene', '29126', (89, 94))	('inhibitors', 'Var', (120, 130))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (149, 168))	('PD-1', 'Gene', (174, 178))	('CTLA-4', 'Gene', '1493', (105, 111))	('autoimmune diseases', 'Disease', 'MESH:D001327', (149, 168))	('PD-1', 'Gene', '5133', (174, 178))	('PD-L1', 'Gene', (89, 94))	('PD-L1', 'Gene', (179, 184))	('cause', 'Reg', (131, 136))	('CTLA-4', 'Gene', (246, 252))	('CTLA-4', 'Gene', (105, 111))	('autoimmune diseases', 'Disease', (149, 168))	('PD-1', 'Gene', (84, 88))	('PD-L1', 'Gene', '29126', (179, 184))	('PD-1', 'Gene', '5133', (84, 88))
503659	31551657	In the KEYNOTE-180 trial, patients with PD-L1 CPS >=10 had a higher 6-month-PFS rate (22% vs 10%) and 9-month-PFS rate (14% vs 5%) than those with PD-L1 CPS <10.	('PD-L1', 'Gene', '29126', (147, 152))	('higher', 'PosReg', (61, 67))	('PD-L1', 'Gene', (40, 45))	('patients', 'Species', '9606', (26, 34))	('CPS >=10', 'Var', (46, 54))	('PD-L1', 'Gene', (147, 152))	('PD-L1', 'Gene', '29126', (40, 45))
503665	31551657	TMB refers to the total amount of non-synonymous mutations in the tumor gene coding region;the higher TMB means the more neoantigens generated by tumor mutations, the more tumor-infiltrating T lymphocytes, and the stronger anti-tumor immune response.	('mutations', 'Var', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Disease', (172, 177))	('higher', 'PosReg', (95, 101))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('more', 'PosReg', (167, 171))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('stronger', 'PosReg', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TMB', 'MPA', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('more', 'PosReg', (116, 120))	('neoantigens generated', 'MPA', (121, 142))	('tumor', 'Disease', (228, 233))
503672	31551657	Microsatellite instability-high status (MSI-H), also known as deficiencies mismatch repair (dMMR), is caused by mutations in the mismatch repair proteins MLH1, MSH2, PMS2, and MSH6, and induces more neoantigen emergence to increase immune cell infiltration.	('more', 'PosReg', (194, 198))	('increase', 'PosReg', (223, 231))	('MSI', 'Gene', (40, 43))	('mutations', 'Var', (112, 121))	('Microsatellite instability', 'Disease', (0, 26))	('MSI', 'Gene', '5928', (40, 43))	('MSH2', 'Gene', '4436', (160, 164))	('neoantigen emergence', 'MPA', (199, 219))	('immune cell infiltration', 'CPA', (232, 256))	('PMS2', 'Gene', '5395', (166, 170))	('deficiencies mismatch', 'Disease', (62, 83))	('caused by', 'Reg', (102, 111))	('MLH1', 'Gene', (154, 158))	('induces', 'Reg', (186, 193))	('deficiencies mismatch', 'Disease', 'MESH:C536928', (62, 83))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('MSH6', 'Gene', (176, 180))	('MLH1', 'Gene', '4292', (154, 158))	('MSH6', 'Gene', '2956', (176, 180))	('PMS2', 'Gene', (166, 170))	('MSH2', 'Gene', (160, 164))
503674	31551657	Le et al showed that the status of mismatch repair could predict clinical benefit of pembrolizumab and discovered that dMMR tumors were associated with prolonged PFS compared with mismatch repair-proficient tumors, regardless of the origin tissue of cancer.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Disease', (207, 213))	('cancer', 'Disease', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('prolonged', 'PosReg', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('PFS', 'MPA', (162, 165))	('dMMR', 'Var', (119, 123))
503682	31551657	In addition, multiple clinical studies of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors for the treatment of esophageal cancer are also underway (Table 1).	('inhibitors', 'Var', (53, 63))	('esophageal cancer', 'Disease', (117, 134))	('PD-L1', 'Gene', (47, 52))	('CTLA-4', 'Gene', '1493', (78, 84))	('PD-1', 'Gene', (42, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('PD-1', 'Gene', '5133', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PD-L1', 'Gene', '29126', (47, 52))	('CTLA-4', 'Gene', (78, 84))
503710	31148997	Mutations of mitochondrial DNA (mtDNA) have been identified in many diseases including cancers.	('cancers', 'Disease', (87, 94))	('mitochondrial DNA', 'Gene', (13, 30))	('identified', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
503711	31148997	Mutations of mtDNA were investigated as a part of carcinogenesis.	('Mutations', 'Var', (0, 9))	('carcinogenesis', 'Disease', (50, 64))	('mtDNA', 'Gene', (13, 18))	('carcinogenesis', 'Disease', 'MESH:D063646', (50, 64))
503713	31148997	We can say that, these deletions are not associated with progression of normal esophagus to BE and EA and they do not have an important role in detecting esophagitis, BE, EA, and ESSC.	('ESSC', 'Disease', (179, 183))	('esophagitis', 'Disease', 'MESH:D004941', (154, 165))	('EA', 'Phenotype', 'HP:0011459', (99, 101))	('deletions', 'Var', (23, 32))	('EA', 'Phenotype', 'HP:0011459', (171, 173))	('BE', 'Phenotype', 'HP:0100580', (167, 169))	('BE', 'Phenotype', 'HP:0100580', (92, 94))	('esophagitis', 'Phenotype', 'HP:0100633', (154, 165))	('esophagitis', 'Disease', (154, 165))
503723	31148997	Mutations of mtDNA have been associated with seizures, ataxia, cortical blindness, dystonia, exercise intolerance, ophthalmoplegia, optic atrophy, cataracts, diabetes mellitus, short stature, cardiomyopathy and other myopathies, sensorineural hearing loss, and kidney failure (http://www.mitomap.org/).	('ophthalmoplegia', 'Disease', 'MESH:D009886', (115, 130))	('sensorineural hearing loss', 'Disease', 'MESH:D006313', (229, 255))	('kidney failure', 'Phenotype', 'HP:0000083', (261, 275))	('cortical blindness', 'Disease', 'MESH:D019575', (63, 81))	('cortical blindness', 'Phenotype', 'HP:0100704', (63, 81))	('optic atrophy', 'Phenotype', 'HP:0000648', (132, 145))	('myopathies', 'Phenotype', 'HP:0003198', (217, 227))	('cataracts', 'Phenotype', 'HP:0000518', (147, 156))	('ophthalmoplegia', 'Disease', (115, 130))	('kidney failure', 'Disease', 'MESH:D051437', (261, 275))	('short stature', 'Disease', (177, 190))	('myopathies', 'Disease', (217, 227))	('ataxia', 'Disease', (55, 61))	('sensorineural hearing loss', 'Disease', (229, 255))	('dystonia', 'Disease', (83, 91))	('ataxia', 'Disease', 'MESH:D001259', (55, 61))	('cataracts', 'Disease', 'MESH:D002386', (147, 156))	('cardiomyopathy', 'Disease', (192, 206))	('kidney failure', 'Disease', (261, 275))	('dystonia', 'Phenotype', 'HP:0001332', (83, 91))	('Mutations', 'Var', (0, 9))	('blindness', 'Phenotype', 'HP:0000618', (72, 81))	('mtDNA', 'Gene', (13, 18))	('associated', 'Reg', (29, 39))	('diabetes mellitus', 'Disease', (158, 175))	('ophthalmoplegia', 'Phenotype', 'HP:0000602', (115, 130))	('optic atrophy', 'Disease', 'MESH:D009896', (132, 145))	('hearing loss', 'Phenotype', 'HP:0000365', (243, 255))	('myopathies', 'Disease', 'MESH:D009135', (217, 227))	('short stature', 'Phenotype', 'HP:0004322', (177, 190))	('dystonia', 'Disease', 'MESH:D004421', (83, 91))	('seizures', 'Disease', (45, 53))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (192, 206))	('cardiomyopathy', 'Disease', 'MESH:D009202', (192, 206))	('cataracts', 'Disease', (147, 156))	('diabetes mellitus', 'Disease', 'MESH:D003920', (158, 175))	('cortical blindness', 'Disease', (63, 81))	('seizures', 'Disease', 'MESH:D012640', (45, 53))	('ataxia', 'Phenotype', 'HP:0001251', (55, 61))	('seizures', 'Phenotype', 'HP:0001250', (45, 53))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (158, 175))	('sensorineural hearing', 'Phenotype', 'HP:0000407', (229, 250))	('exercise intolerance', 'Disease', (93, 113))	('exercise intolerance', 'Phenotype', 'HP:0003546', (93, 113))	('optic atrophy', 'Disease', (132, 145))
503725	31148997	Many of the mtDNA mutations associated with cancers occur within the non-coding control region (also known as the D-loop) of the mitochondrial genome, which is about 1.1 kb (between bases 16024 and 576) in size.	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('associated', 'Reg', (28, 38))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('mtDNA', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('mutations', 'Var', (18, 27))
503727	31148997	This mutation removes all or part of the genes encoding four complex I subunits, one complex IV subunit, two complex V subunits and five tRNA genes, therefore causing energy production catastrophe and abnormal reactive oxygen species generation.	('energy production catastrophe', 'MPA', (167, 196))	('reactive oxygen species generation', 'MPA', (210, 244))	('causing', 'Reg', (159, 166))	('removes', 'NegReg', (14, 21))	('abnormal reactive oxygen species', 'Phenotype', 'HP:0025464', (201, 233))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (210, 233))	('mutation', 'Var', (5, 13))
503736	31148997	Four couple primers were used: the first (L.9590-H.10368) was to amplify the negative control sequence within the deleted sequence, the second (L.6251-H.7261) was to amplify the positive control sequence out of the deleted sequence, the third (L.7901-H.13631) was to amplify the 4977 bp deletion region and the fourth (L.8531-H.381) was to amplify the 7400 bp deletion region (Table 1).	('L.8531-H.381', 'Var', (319, 331))	('L.6251-H.7261', 'CellLine', 'CVCL:N700', (144, 157))	('L.7901-H.13631', 'Var', (244, 258))
503742	31148997	The mtDNA4977 deletion is associated with ageing and in many cancers.	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('mtDNA4977', 'Gene', (4, 13))	('cancers', 'Disease', (61, 68))	('ageing', 'Disease', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('deletion', 'Var', (14, 22))	('associated', 'Reg', (26, 36))
503745	31148997	reported high frequency of mtDNA4977 deletion in esophageal cancer patients from China, but mutation analysis of the whole mitochondrial genome from Northern India did not find this deletion.	('esophageal cancer', 'Disease', (49, 66))	('patients', 'Species', '9606', (67, 75))	('deletion', 'Var', (37, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('mtDNA4977', 'Gene', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
503746	31148997	This maybe because of Chinese population has a high risk for this cancer and it is possible that the pathogenesis of esophageal cancers in this population includes mtDNA mutations.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mutations', 'Var', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancers', 'Disease', (117, 135))	('esophageal cancers', 'Disease', 'MESH:D004938', (117, 135))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mtDNA', 'Gene', (164, 169))	('cancer', 'Disease', (66, 72))	('cancer', 'Disease', (128, 134))
503747	31148997	Our data provides insights for genotype-phenotype correlations of mtDNA mutations with esophageal diseases.	('mutations', 'Var', (72, 81))	('esophageal diseases', 'Disease', 'MESH:D004935', (87, 106))	('mtDNA', 'Gene', (66, 71))	('esophageal diseases', 'Disease', (87, 106))
503748	31148997	Unlike Abnet et al., we could say that, the 5 kb and 7.4 kb mtDNA deletions are not associated with progression of normal esophagus to BE and EA and they do not have an important role in detecting and prognosis of esophagitis, BE, EA, and ESSC.	('BE', 'Phenotype', 'HP:0100580', (135, 137))	('ESSC', 'Disease', (239, 243))	('EA', 'Phenotype', 'HP:0011459', (142, 144))	('associated', 'Reg', (84, 94))	('deletions', 'Var', (66, 75))	('mtDNA', 'Gene', (60, 65))	('esophagitis', 'Phenotype', 'HP:0100633', (214, 225))	('esophagitis', 'Disease', (214, 225))	('EA', 'Phenotype', 'HP:0011459', (231, 233))	('esophagitis', 'Disease', 'MESH:D004941', (214, 225))	('BE', 'Phenotype', 'HP:0100580', (227, 229))
503770	31086675	It was also reported that the incidence of delirium following surgical treatment of esophageal cancer was significantly lower in the PPI (lansoprazole or omeprazole) group than in the H2RA (famotidine or ranitidine) group, at 43.3 and 16.7%, respectively.	('lower', 'NegReg', (120, 125))	('ranitidine', 'Chemical', 'MESH:D011899', (204, 214))	('delirium', 'Disease', (43, 51))	('delirium', 'Disease', 'MESH:D003693', (43, 51))	('delirium', 'Phenotype', 'HP:0031258', (43, 51))	('PPI', 'Var', (133, 136))	('lansoprazole', 'Chemical', 'MESH:D064747', (138, 150))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('famotidine', 'Chemical', 'MESH:D015738', (190, 200))	('omeprazole', 'Chemical', 'MESH:D009853', (154, 164))
503884	28857247	Furthermore, PQ inhibited cell proliferation and induced cell cycle arrest and apoptosis in KYSE30, KYSE410 and KYSE450 esophageal squamous cell carcinoma (ESCC) cells.	('KYSE30', 'Var', (92, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('inhibited', 'NegReg', (16, 25))	('KYSE450', 'Var', (112, 119))	('arrest', 'Disease', (68, 74))	('PQ', 'Chemical', '-', (13, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (57, 74))	('induced', 'Reg', (49, 56))	('apoptosis', 'CPA', (79, 88))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('cell proliferation', 'CPA', (26, 44))	('KYSE410', 'Var', (100, 107))
503891	28857247	Recently, it has been reported that many diseases are related to the mutation and the expression of different subtypes of FGFR2.	('related', 'Reg', (54, 61))	('mutation', 'Var', (69, 77))	('diseases', 'Disease', (41, 49))	('FGFR2', 'Gene', '2263', (122, 127))	('FGFR2', 'Gene', (122, 127))
503892	28857247	FGFR2 mutation or amplification was found in varied cancers like colon, gastric, endometrial, esophageal and cholangiocarcinoma, it also has a close relationship with tumorigenesis.	('cancers', 'Disease', (52, 59))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (109, 127))	('found', 'Reg', (36, 41))	('amplification', 'MPA', (18, 31))	('endometrial', 'Disease', (81, 92))	('esophageal', 'Disease', (94, 104))	('colon', 'Disease', 'MESH:D015179', (65, 70))	('relationship', 'Reg', (149, 161))	('gastric', 'Disease', (72, 79))	('colon', 'Disease', (65, 70))	('FGFR2', 'Gene', (0, 5))	('tumor', 'Disease', (167, 172))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('FGFR2', 'Gene', '2263', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (109, 127))	('mutation', 'Var', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cholangiocarcinoma', 'Disease', (109, 127))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
503908	28857247	Cells were cultured in RPMI-1640 containing penicillin (100 units/mL), streptomycin (100 mug/mL), and 10% FBS (BI, Israel).	('RPMI-1640', 'Chemical', '-', (23, 32))	('penicillin', 'Chemical', 'MESH:D010406', (44, 54))	('FBS', 'Disease', 'MESH:D005198', (106, 109))	('streptomycin', 'Chemical', 'MESH:D013307', (71, 83))	('100 mug/mL', 'Var', (85, 95))	('FBS', 'Disease', (106, 109))
503914	28857247	KYSE30, KYSE410 or KYSE450 cells (each 8 x 103) were suspended in 0.3% RPMI-1640 agar solution with vehicle, 20, 40 or 60 muM PQ were poured over 0.5% hard-bottomed agar previously in each 6-well plate.	('KYSE410', 'Var', (8, 15))	('PQ', 'Chemical', '-', (126, 128))	('agar', 'Chemical', 'MESH:D000362', (81, 85))	('agar', 'Chemical', 'MESH:D000362', (165, 169))	('muM', 'Gene', (122, 125))	('RPMI-1640', 'Chemical', '-', (71, 80))	('KYSE450', 'Var', (19, 26))	('muM', 'Gene', '56925', (122, 125))
503920	28857247	KYSE30 (1.5 x 105), KYSE410 (2.7 x 105) and KYSE410 (2 x 105) cells were seeded into 60 mm diameter dishes and cultured at 37 C in a 5% CO2 incubator.	('KYSE410', 'Var', (44, 51))	('CO2', 'Chemical', '-', (136, 139))	('KYSE410', 'Var', (20, 27))
503953	28857247	The FGFR2 protein was highly expressed in KYSE30, KYSE410 and KYSE450 ESCC cells, whereas it was barely expressed in normal esophageal cells and other ESCC cells.	('KYSE410', 'Var', (50, 57))	('KYSE450', 'Var', (62, 69))	('FGFR2', 'Gene', '2263', (4, 9))	('KYSE30', 'Var', (42, 48))	('highly', 'PosReg', (22, 28))	('ESCC', 'Disease', (70, 74))	('FGFR2', 'Gene', (4, 9))
503954	28857247	Compared to normal cells, PQ was sharply inhibited cell proliferation of KYSE30, KYSE 410 and KYSE450 ESCC cells in a time- and dose-dependent manner (Fig.	('KYSE 410', 'Var', (81, 89))	('KYSE450', 'Var', (94, 101))	('cell proliferation', 'CPA', (51, 69))	('inhibited', 'NegReg', (41, 50))	('KYSE30', 'Var', (73, 79))	('PQ', 'Chemical', '-', (26, 28))
503958	28857247	Inhibition of FGFR2 can result in many effects on cells such as cell cycle and apoptosis.	('FGFR2', 'Gene', (14, 19))	('FGFR2', 'Gene', '2263', (14, 19))	('result', 'Reg', (24, 30))	('apoptosis', 'CPA', (79, 88))	('effects', 'Reg', (39, 46))	('Inhibition', 'Var', (0, 10))	('cell cycle', 'CPA', (64, 74))
503960	28857247	Results revealed that PQ treatment led to G1 phase arrest of cell cycle in KYSE30, KYSE410 and KYSE450 cells (Fig.	('PQ', 'Chemical', '-', (22, 24))	('arrest', 'Disease', 'MESH:D006323', (51, 57))	('arrest', 'Disease', (51, 57))	('KYSE410', 'Var', (83, 90))	('KYSE450', 'Var', (95, 102))	('KYSE30', 'Var', (75, 81))
503970	28857247	It was verified that PQ suppressed the expression of phosphorylated AKT and mTOR in KYSE30, KYSE410 and KTSE450 cells in a concentration dependent manner (Fig.	('mTOR', 'Gene', (76, 80))	('mTOR', 'Gene', '2475', (76, 80))	('KYSE410', 'Var', (92, 99))	('PQ', 'Chemical', '-', (21, 23))	('suppressed', 'NegReg', (24, 34))	('AKT', 'Gene', '207', (68, 71))	('phosphorylated', 'MPA', (53, 67))	('expression', 'MPA', (39, 49))	('AKT', 'Gene', (68, 71))
503982	28857247	When treated with FGF in KYSE410 cells which cultured with medium not contained serum, phosphorylation of AKT was increased.	('AKT', 'Gene', (106, 109))	('increased', 'PosReg', (114, 123))	('AKT', 'Gene', '207', (106, 109))	('phosphorylation', 'MPA', (87, 102))	('FGF', 'Var', (18, 21))
503986	28857247	In conclusion, we first demonstrate that PQ inhibits the cell growth and induces apoptosis in KYSE30 and KYSE410 ESCC cells by suppressing AKT/mTOR signaling through direct targeting of FGFR2.	('KYSE410', 'Var', (105, 112))	('AKT', 'Gene', '207', (139, 142))	('cell growth', 'CPA', (57, 68))	('FGFR2', 'Gene', (186, 191))	('apoptosis', 'CPA', (81, 90))	('suppressing', 'NegReg', (127, 138))	('PQ', 'Chemical', '-', (41, 43))	('FGFR2', 'Gene', '2263', (186, 191))	('AKT', 'Gene', (139, 142))	('induces', 'Reg', (73, 80))	('mTOR', 'Gene', '2475', (143, 147))	('inhibits', 'NegReg', (44, 52))	('mTOR', 'Gene', (143, 147))
503991	28545451	We knocked down PTK7 in two esophageal squamous cell carcinoma cell lines, TE-5, and TE-9, by siRNA, and evaluated cell proliferation, apoptosis, and migration ofPTK7-defective cells.	('apoptosis', 'CPA', (135, 144))	('PTK7', 'Gene', '5754', (16, 20))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (28, 62))	('PTK7', 'Gene', (162, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('knocked', 'Var', (3, 10))	('esophageal squamous cell carcinoma', 'Disease', (28, 62))	('PTK7', 'Gene', '5754', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('cell proliferation', 'CPA', (115, 133))	('migration', 'CPA', (150, 159))	('PTK7', 'Gene', (16, 20))
504005	28545451	Disruption of PTK7 expression can repress cell proliferation and can promote apoptosis in colon and liver cancers.	('repress', 'NegReg', (34, 41))	('apoptosis', 'CPA', (77, 86))	('PTK7', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('PTK7', 'Gene', '5754', (14, 18))	('cell proliferation', 'CPA', (42, 60))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('liver cancers', 'Phenotype', 'HP:0002896', (100, 113))	('promote', 'PosReg', (69, 76))	('colon and liver cancers', 'Disease', 'MESH:D006528', (90, 113))	('Disruption', 'Var', (0, 10))
504008	28545451	Notably, given that Wnt signaling plays significant roles in human cancer and that a recent study has shown that knockdown of PTK7 can inhibit Wnt/beta-catenin activity, it is conceivable that PTK7 may also be involved in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('beta-catenin', 'Gene', '1499', (147, 159))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (67, 73))	('inhibit', 'NegReg', (135, 142))	('PTK7', 'Gene', (126, 130))	('cancer', 'Disease', (222, 228))	('involved', 'Reg', (210, 218))	('PTK7', 'Gene', '5754', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('knockdown', 'Var', (113, 122))	('PTK7', 'Gene', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('PTK7', 'Gene', '5754', (193, 197))	('beta-catenin', 'Gene', (147, 159))	('human', 'Species', '9606', (61, 66))
504009	28545451	Although dysregulation of PTK7 has been reported in some cancers, its role in tumorigenesis and oncogenic progression awaits further demonstration.	('PTK7', 'Gene', (26, 30))	('PTK7', 'Gene', '5754', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (78, 83))	('reported', 'Reg', (40, 48))	('dysregulation', 'Var', (9, 22))
504023	28545451	We knocked down PTK7 in two esophageal squamous carcinoma cell lines and measured proliferation and apoptosis of these PTK7-deficient cells.	('measured', 'Reg', (73, 81))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (28, 57))	('PTK7', 'Gene', '5754', (119, 123))	('PTK7', 'Gene', '5754', (16, 20))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (39, 57))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (28, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('esophageal squamous carcinoma', 'Disease', (28, 57))	('PTK7', 'Gene', (119, 123))	('knocked', 'Var', (3, 10))	('proliferation', 'CPA', (82, 95))	('apoptosis', 'CPA', (100, 109))	('PTK7', 'Gene', (16, 20))
504033	28545451	Absorbance at 450 nm at each time point was recorded for both targeted-knockdown (siPTK7) and knockdown control (siControl) cells.	('PTK7', 'Gene', (84, 88))	('targeted-knockdown', 'Var', (62, 80))	('PTK7', 'Gene', '5754', (84, 88))
504064	28545451	Notably, in both cases of TE-5 and TE-9, siPTK7 cells had increased populations of both early stage (Annexin V+/PI-) and late stage apoptotic (Annexin V+/PI+) cells (Fig.	('PTK7', 'Gene', '5754', (43, 47))	('Annexin V', 'Gene', '308', (143, 152))	('TE-5', 'Var', (26, 30))	('TE-9', 'Var', (35, 39))	('Annexin V', 'Gene', (143, 152))	('increased', 'PosReg', (58, 67))	('Annexin V', 'Gene', '308', (101, 110))	('Annexin V', 'Gene', (101, 110))	('PTK7', 'Gene', (43, 47))
504069	28545451	Transwell migration assay showed that, in both cases of TE-5 and TE-9, migration of siPTK7 cells was significantly reduced by 60% or more compared with siControl (p < 0.01) (Fig.	('reduced', 'NegReg', (115, 122))	('PTK7', 'Gene', '5754', (86, 90))	('migration', 'CPA', (71, 80))	('PTK7', 'Gene', (86, 90))	('TE-5', 'Var', (56, 60))	('TE-9', 'Var', (65, 69))
504077	28545451	Indeed, disruption of PTK7 expression by siRNA rendered the tumor cells lose the proliferative advantages to the undisturbed counterparts.	('PTK7', 'Gene', (22, 26))	('disruption', 'Var', (8, 18))	('lose', 'NegReg', (72, 76))	('PTK7', 'Gene', '5754', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('proliferative advantages', 'CPA', (81, 105))	('tumor', 'Disease', (60, 65))
504079	28545451	More interestingly, disruption of PTK7 further slowed down cellular migration in vitro, during which the epithelial-mesenchymal transition marker gene E-cadherin was upregulated, suggesting PTK7 may promote metastasis of esophageal squamous cell carcinoma.	('upregulated', 'PosReg', (166, 177))	('slowed down', 'NegReg', (47, 58))	('PTK7', 'Gene', (34, 38))	('PTK7', 'Gene', '5754', (34, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (221, 255))	('promote', 'PosReg', (199, 206))	('metastasis', 'CPA', (207, 217))	('disruption', 'Var', (20, 30))	('cellular migration in vitro', 'CPA', (59, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (232, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('PTK7', 'Gene', (190, 194))	('E-cadherin', 'Gene', (151, 161))	('esophageal squamous cell carcinoma', 'Disease', (221, 255))	('PTK7', 'Gene', '5754', (190, 194))	('E-cadherin', 'Gene', '999', (151, 161))
504082	28545451	When PTK7 expression was disrupted by RNAi, the tumor cells proliferated slowly and became prone to apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('PTK7', 'Gene', '5754', (5, 9))	('prone', 'Reg', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('PTK7', 'Gene', (5, 9))	('disrupted', 'Var', (25, 34))	('apoptosis', 'CPA', (100, 109))	('expression', 'Protein', (10, 20))	('slowly', 'NegReg', (73, 79))
504101	22272361	A Functional NQO1 609C>T Polymorphism and Risk of Gastrointestinal Cancers: A Meta-Analysis The functional polymorphism (rs1800566) in the NQO1 gene, a 609C>T substitution, leading to proline-to-serine amino-acid and enzyme activity changes, has been implicated in cancer risk, but individually published studies showed inconclusive results.	('rs1800566', 'Mutation', 'rs1800566', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('NQO1', 'Gene', (13, 17))	('NQO1', 'Gene', '1728', (139, 143))	('Gastrointestinal Cancers', 'Disease', (50, 74))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('Cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Disease', (265, 271))	('NQO1', 'Gene', (139, 143))	('changes', 'Reg', (233, 240))	('Gastrointestinal Cancers', 'Disease', 'MESH:D004067', (50, 74))	('enzyme activity', 'MPA', (217, 232))	('proline', 'Chemical', 'MESH:D011392', (184, 191))	('serine amino-acid', 'Chemical', '-', (195, 212))	('proline-to-serine amino-acid', 'MPA', (184, 212))	('rs1800566', 'Var', (121, 130))	('NQO1', 'Gene', '1728', (13, 17))	('609C>T', 'Mutation', 'rs1800566', (18, 24))	('implicated', 'Reg', (251, 261))	('609C>T', 'Mutation', 'rs1800566', (152, 158))
504104	22272361	We found that the variant CT heterozygous and CT/TT genotypes of the NQO1 609 C>T polymorphism were associated with a modestly increased risk of GI cancers (CT vs. CC: OR = 1.10, 95% CI = 1.01 - 1.19, P heterogeneity = 0.27, I 2 = 0.15; CT/TT vs. CC: OR = 1.11, 95%CI = 1.02 - 1.20, P heterogeneity = 0.14; I 2 = 0.27).	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('GI cancers', 'Disease', 'MESH:D009369', (145, 155))	('GI cancer', 'Phenotype', 'HP:0007378', (145, 154))	('NQO1 609', 'Gene', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('609 C>T', 'Mutation', 'rs1800566', (74, 81))	('GI cancers', 'Disease', (145, 155))	('C>T', 'Var', (78, 81))
504111	22272361	Recent genome-wide association studies have also identified some susceptible loci harboring common single nucleotide polymorphisms (SNPs) for risk of GI cancers, suggesting that the low-penetrance genes are also involved in the etiology of these diseases.	('GI cancers', 'Disease', (150, 160))	('GI cancer', 'Phenotype', 'HP:0007378', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('GI cancers', 'Disease', 'MESH:D009369', (150, 160))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('single nucleotide polymorphisms', 'Var', (99, 130))
504118	22272361	The most extensively studied SNP of NQO1 is a C-to-T transition at nucleotide position 609 in exon 6 (dbSNP ID: rs1800566, 609C>T;  Figure 1 ), which results in a proline-to-serine amino-acid substitution at codon 187 (Pro187Ser) in the protein.	('proline', 'Chemical', 'MESH:D011392', (163, 170))	('Pro187Ser', 'SUBSTITUTION', 'None', (219, 228))	('C-to-T transition at nucleotide position 609', 'Mutation', 'rs1800566', (46, 90))	('NQO1', 'Gene', (36, 40))	('609C>T', 'Mutation', 'rs1800566', (123, 129))	('proline-to-serine amino-acid substitution', 'MPA', (163, 204))	('Pro187Ser', 'Var', (219, 228))	('results in a', 'Reg', (150, 162))	('rs1800566', 'Mutation', 'rs1800566', (112, 121))	('serine amino-acid', 'Chemical', '-', (174, 191))
504119	22272361	Genotype-phenotype studies of the NQO1 609C>T polymorphism showed that the variant T allele was associated with reduced NQO1 enzymatic activity in both human cell lines and primary human tissues.	('human', 'Species', '9606', (181, 186))	('enzymatic activity', 'MPA', (125, 143))	('variant', 'Var', (75, 82))	('human', 'Species', '9606', (152, 157))	('NQO1', 'Gene', (34, 38))	('reduced', 'NegReg', (112, 119))	('NQO1', 'Enzyme', (120, 124))	('609C>T', 'Mutation', 'rs1800566', (39, 45))
504121	22272361	Furthermore, the TT genotype of the NQO1 609C>T polymorphism was associated with reduced NQO1 protein expression in tumor tissues from a subset of GI cancer patients (cardiac carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, and esophageal squamous cell carcinoma).	('GI cancer', 'Disease', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('patients', 'Species', '9606', (157, 165))	('esophageal squamous cell carcinoma', 'Disease', (241, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('reduced', 'NegReg', (81, 88))	('gastric adenocarcinoma', 'Disease', (186, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('NQO1', 'Gene', (36, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (252, 275))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (210, 235))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('GI cancer', 'Disease', 'MESH:D009369', (147, 156))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (210, 235))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('GI cancer', 'Phenotype', 'HP:0007378', (147, 156))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (241, 275))	('cardiac carcinoma', 'Disease', (167, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('cardiac carcinoma', 'Disease', 'MESH:D006338', (167, 184))	('esophageal adenocarcinoma', 'Disease', (210, 235))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (186, 208))	('609C>T', 'Mutation', 'rs1800566', (41, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('NQO1', 'Gene', (89, 93))	('609C>T', 'Var', (41, 47))	('tumor', 'Disease', (116, 121))
504122	22272361	Because of this SNP's functional consequence, many epidemiological studies have examined the effect of the NQO1 609C>T polymorphism on risk of GI cancers, including cancers of the esophagus, stomach, colorectum, pancreas, and liver.	('609C>T', 'Mutation', 'rs1800566', (112, 118))	('pancreas', 'Disease', (212, 220))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('liver', 'Disease', (226, 231))	('GI cancer', 'Phenotype', 'HP:0007378', (143, 152))	('609C>T', 'Var', (112, 118))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (165, 189))	('stomach', 'Disease', (191, 198))	('GI cancers', 'Disease', (143, 153))	('colorectum', 'Disease', (200, 210))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('GI cancers', 'Disease', 'MESH:D009369', (143, 153))	('cancers of the esophagus', 'Disease', (165, 189))	('NQO1', 'Gene', (107, 111))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (165, 189))
504124	22272361	Therefore, we performed a meta-analysis of published data to evaluate the influence of the NQO1 609C>T polymorphism on the risk of GI cancers.	('GI cancers', 'Disease', 'MESH:D009369', (131, 141))	('GI cancer', 'Phenotype', 'HP:0007378', (131, 140))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('609C>T', 'Mutation', 'rs1800566', (96, 102))	('NQO1', 'Gene', (91, 95))	('609C>T', 'Var', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('GI cancers', 'Disease', (131, 141))
504126	22272361	The following keywords were used: 'NAD(P)H Dehydrogenase (Quinone)' or 'NQO1', 'polymorphism', 'variant', and in combination with 'gastrointestinal/aerodigestive tract cancers', or 'esophageal cancer', 'gastric/stomach' cancer, 'colorectal/colon/rectum cancer', ' pancreatic cancer', 'liver cancer', 'hepatocellular carcinoma', 'gallbladder cancer', and 'small/larger bowel cancer'.	("'colorectal/colon/rectum cancer", 'Disease', 'MESH:D015179', (228, 259))	('NAD(P)H', 'Gene', (35, 42))	("'hepatocellular carcinoma', 'gallbladder cancer", 'Disease', 'MESH:D005706', (300, 347))	("'gastric/stomach' cancer", 'Disease', (202, 226))	("'gastric/stomach' cancer", 'Disease', 'MESH:D013274', (202, 226))	("'gastric/stomach' cancer", 'Phenotype', 'HP:0006753', (202, 226))	("'liver cancer", 'Disease', (284, 297))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancers', 'Disease', (168, 175))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (264, 281))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	("'esophageal cancer", 'Disease', (181, 199))	("'colorectal/colon/rectum cancer", 'Disease', (228, 259))	("'polymorphism", 'Var', (79, 92))	('NAD(P)H', 'Gene', '1666', (35, 42))	("'esophageal cancer", 'Disease', 'MESH:D004938', (181, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('pancreatic cancer', 'Disease', 'MESH:D010190', (264, 281))	('bowel cancer', 'Disease', (368, 380))	('rectum cancer', 'Phenotype', 'HP:0100743', (246, 259))	("'variant", 'Var', (95, 103))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	("'gastrointestinal", 'Disease', 'MESH:D005767', (130, 147))	("'hepatocellular carcinoma'", 'Phenotype', 'HP:0001402', (300, 326))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('pancreatic cancer', 'Disease', (264, 281))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('liver cancer', 'Phenotype', 'HP:0002896', (285, 297))	("'gastrointestinal", 'Disease', (130, 147))	("'liver cancer", 'Disease', 'MESH:D006528', (284, 297))	('bowel cancer', 'Disease', 'MESH:D009369', (368, 380))	("'gallbladder cancer", 'Phenotype', 'HP:0100575', (328, 347))
504128	22272361	Human population-based or hospital-based association studies were included in this meta-analysis, if they met all the following criteria: (1) an independent, unrelated case-control, nested case-control, or cohort study, (2) the NQO1 609C>T polymorphism was determined, (3) the outcome was GI cancers, (4) there were sufficient data for calculating an odds ratio (OR) with 95% confidence interval (CI), and (5) the study was reported in English.	('GI cancers', 'Disease', (289, 299))	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('GI cancer', 'Phenotype', 'HP:0007378', (289, 298))	('GI cancers', 'Disease', 'MESH:D009369', (289, 299))	('609C>T', 'Mutation', 'rs1800566', (233, 239))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('NQO1', 'Var', (228, 232))
504132	22272361	Deviation of genotype frequencies of the NQO1 609C>T polymorphism in control subjects from Hardy-Weinberg equilibrium (HWE) was tested by using the Chi-square goodness of fit, and a P value<0.05 was considered significant.	('609C>T', 'Var', (46, 52))	('goodness of fit', 'Disease', (159, 174))	('NQO1', 'Gene', (41, 45))	('609C>T', 'Mutation', 'rs1800566', (46, 52))	('goodness of fit', 'Disease', 'MESH:D012640', (159, 174))
504133	22272361	Odds ratio (OR) and corresponding 95% confidence interval (95% CI) were used to estimate the association between the NQO1 609C>T polymorphism and cancer risk.	('NQO1', 'Gene', (117, 121))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('association', 'Interaction', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('609C>T', 'Mutation', 'rs1800566', (122, 128))	('609C>T polymorphism', 'Var', (122, 141))
504136	22272361	As of October 6, 2011, we had identified 29 potentially eligible studies that have investigated the association between the NQO1 609C>T polymorphism and risk of GI cancers.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('609C>T', 'Mutation', 'rs1800566', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('609C>T', 'Var', (129, 135))	('GI cancers', 'Disease', (161, 171))	('GI cancer', 'Phenotype', 'HP:0007378', (161, 170))	('GI cancers', 'Disease', 'MESH:D009369', (161, 171))	('NQO1', 'Gene', (124, 128))
504142	22272361	The frequency distributions of the genotypes of the NQO1 609 C>T polymorphism were different between these two ethnic groups.	('609 C>T', 'Mutation', 'rs1800566', (57, 64))	('NQO1', 'Gene', (52, 56))	('609 C>T', 'Var', (57, 64))
504145	22272361	In Asians, no significant association between the NQO1 609C>T polymorphism and the risk of GI cancers was found for all variant genotypes (CT vs.CC: OR = 1.07, 95% CI: 0.94 - 1.23, P heterogeneity = 0.43 and I2 = 0.0; TT vs.CC: OR = 1.25, 95% CI: 0.90 - 1.73, P heterogeneity = 0.05 and I2 = 0.50), the dominant model (CT/TT vs. CC: OR = 1.07, 95% CI: 0.94 - 1.26, P heterogeneity = 0.17 and I2 = 0.32) and the recessive model (TT vs. CT/CC: OR = 1.22, 95% CI: 0.90 - 1.21, P heterogeneity = 0.27 and I2 = 0.52).	('GI cancers', 'Disease', (91, 101))	('GI cancers', 'Disease', 'MESH:D009369', (91, 101))	('609C>T', 'Mutation', 'rs1800566', (55, 61))	('GI cancer', 'Phenotype', 'HP:0007378', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('variant', 'Var', (120, 127))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))
504151	22272361	However, greater FPRP values were observed for other significant associations between the NQO1 609C>T polymorphism and risk of GI cancers.	('NQO1', 'Gene', (90, 94))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('609C>T', 'Var', (95, 101))	('GI cancers', 'Disease', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('GI cancer', 'Phenotype', 'HP:0007378', (127, 136))	('GI cancers', 'Disease', 'MESH:D009369', (127, 137))	('609C>T', 'Mutation', 'rs1800566', (95, 101))
504154	22272361	These findings suggest that the NQO1 609C>T polymorphism may modify the risk of GI cancers.	('GI cancers', 'Disease', (80, 90))	('NQO1', 'Gene', (32, 36))	('609C>T', 'Var', (37, 43))	('GI cancer', 'Phenotype', 'HP:0007378', (80, 89))	('GI cancers', 'Disease', 'MESH:D009369', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('modify', 'Reg', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('609C>T', 'Mutation', 'rs1800566', (37, 43))
504160	22272361	Human NQO1 is polymorphic, of which the NQO1 609C>T polymorphism, in terms of its frequency and phenotypic consequences, is most prominent and thus intensively studied.	('Human', 'Species', '9606', (0, 5))	('NQO1', 'Gene', (40, 44))	('609C>T', 'Mutation', 'rs1800566', (45, 51))	('609C>T', 'Var', (45, 51))
504167	22272361	Such etiologic heterogeneity in GI cancers raises the possibility that the NQO1 polymorphism may be associated with specific types of GI cancers, because NQO1 plays an important role in detoxifying dietary carcinogenic compounds such as HCAs, PAHs and nitrosamines.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('HCAs', 'Chemical', '-', (237, 241))	('GI cancers', 'Disease', (32, 42))	('detoxifying', 'MPA', (186, 197))	('GI cancers', 'Disease', (134, 144))	('NQO1', 'Gene', (75, 79))	('associated', 'Reg', (100, 110))	('GI cancers', 'Disease', 'MESH:D009369', (32, 42))	('GI cancers', 'Disease', 'MESH:D009369', (134, 144))	('nitrosamines', 'Chemical', 'MESH:D009602', (252, 264))	('carcinogenic', 'Disease', (206, 218))	('PAHs', 'Chemical', 'MESH:D011084', (243, 247))	('polymorphism', 'Var', (80, 92))	('carcinogenic', 'Disease', 'MESH:D063646', (206, 218))	('GI cancer', 'Phenotype', 'HP:0007378', (32, 41))	('GI cancer', 'Phenotype', 'HP:0007378', (134, 143))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))
504168	22272361	Therefore, the functional NQO1 609 C>T polymorphism resulting in decreased activity of NQO1 enzyme may increase risk of colorectum cancer.	('609 C>T', 'Mutation', 'rs1800566', (31, 38))	('decreased', 'NegReg', (65, 74))	('609 C>T', 'Var', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('NQO1', 'Gene', (26, 30))	('colorectum cancer', 'Disease', 'MESH:D009369', (120, 137))	('colorectum cancer', 'Disease', (120, 137))	('activity', 'MPA', (75, 83))	('NQO1', 'Gene', (87, 91))	('rectum cancer', 'Phenotype', 'HP:0100743', (124, 137))
504176	22272361	Thirdly, the numbers of published studies were still not sufficiently large for the analysis of the effect of the variant TT genotype on risk of GI cancers and for some subgroups.	('variant', 'Var', (114, 121))	('GI cancers', 'Disease', 'MESH:D009369', (145, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('GI cancer', 'Phenotype', 'HP:0007378', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('GI cancers', 'Disease', (145, 155))
504179	22272361	However, greater FPRP values were observed for the other significant associations between the NQO1 609C>T polymorphism and risk of GI cancers, suggesting some possible bias in the findings.	('609C>T', 'Mutation', 'rs1800566', (99, 105))	('GI cancers', 'Disease', 'MESH:D009369', (131, 141))	('GI cancer', 'Phenotype', 'HP:0007378', (131, 140))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('609C>T', 'Var', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('GI cancers', 'Disease', (131, 141))	('NQO1', 'Gene', (94, 98))
504181	22272361	In summary, despite the above-mentioned limitations, our meta-analysis suggests that the minor allele T of the NQO1 609C>T polymorphism may be associated with a moderately increased risk of GI cancers.	('associated', 'Reg', (143, 153))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('GI cancer', 'Phenotype', 'HP:0007378', (190, 199))	('GI cancers', 'Disease', 'MESH:D009369', (190, 200))	('609C>T', 'Var', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('609C>T', 'Mutation', 'rs1800566', (116, 122))	('GI cancers', 'Disease', (190, 200))	('NQO1', 'Gene', (111, 115))
504184	21317297	Since cyclin D nuclear localization is implicated in tumor development, we examined whether the absence of IKKalpha leads to tumor development as well.	('IKKalpha', 'Gene', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('implicated', 'Reg', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cyclin', 'Gene', '18538', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (53, 58))	('absence', 'Var', (96, 103))	('cyclin', 'Gene', (6, 12))	('leads to', 'Reg', (116, 124))
504190	21317297	Absence of IKKalpha may induce tumorigenicity by nuclear localization of cyclin D1 and modulating the expression of genes involved in neoplastic transformation.	('nuclear localization', 'MPA', (49, 69))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('expression of genes', 'MPA', (102, 121))	('induce', 'PosReg', (24, 30))	('cyclin D1', 'Protein', (73, 82))	('tumor', 'Disease', (31, 36))	('modulating', 'Reg', (87, 97))	('Absence', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('IKKalpha', 'Gene', (11, 19))
504195	21317297	Several studies demonstrated that altered cyclin D1 expression or sub-cellular distribution is associated with a variety of neoplasms including breast, colon, esophagus, lung, and mantle cell lymphoma.	('breast', 'Disease', (144, 150))	('altered', 'Var', (34, 41))	('cyclin D1', 'Protein', (42, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	('esophagus', 'Disease', (159, 168))	('expression', 'MPA', (52, 62))	('lung', 'Disease', (170, 174))	('neoplasms', 'Disease', (124, 133))	('neoplasms', 'Disease', 'MESH:D009369', (124, 133))	('colon', 'Disease', (152, 157))	('mantle cell lymphoma', 'Disease', (180, 200))	('cell lymphoma', 'Phenotype', 'HP:0012191', (187, 200))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (180, 200))	('associated', 'Reg', (95, 105))
504197	21317297	Earlier it was shown that GSK-3beta phosphorylates cyclin D1 at T286, which is required for nuclear export during the S phase of the cell cycle and subsequent proteolysis.	('GSK-3beta', 'Gene', '56637', (26, 35))	('T286', 'Chemical', '-', (64, 68))	('GSK-3beta', 'Gene', (26, 35))	('T286', 'Var', (64, 68))
504198	21317297	Recently, we demonstrated that IKKalpha-/- cells exhibit nuclear localization of cyclin D1 and IKKalpha is required for phosphorylation of cyclin D1 at T286.	('T286', 'Chemical', '-', (152, 156))	('nuclear localization', 'MPA', (57, 77))	('T286', 'Var', (152, 156))	('cyclin', 'Protein', (81, 87))
504199	21317297	Mutation of cyclin D1 at T286 results in constitutive nuclear distribution.	('cyclin D1', 'Gene', (12, 21))	('results in', 'Reg', (30, 40))	('T286', 'Chemical', '-', (25, 29))	('constitutive nuclear distribution', 'MPA', (41, 74))	('T286', 'Var', (25, 29))
504200	21317297	Cyclin D1 T286A mutant in murine cells induces cellular transformation in vitro and leads to tumor development in nude mice.	('T286A', 'Mutation', 'c.286T>A', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Cyclin D1', 'Gene', '12443', (0, 9))	('murine', 'Species', '10090', (26, 32))	('nude mice', 'Species', '10090', (114, 123))	('T286A', 'Var', (10, 15))	('tumor', 'Disease', (93, 98))	('cellular transformation', 'CPA', (47, 70))	('Cyclin D1', 'Gene', (0, 9))	('leads to', 'Reg', (84, 92))	('induces', 'Reg', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
504202	21317297	Further studies with a splice variant of cyclin D1 (cyclin D1b), which lacks C-terminus (including T286) required for its nuclear export, remains distributed in the nucleus similar to cyclin D1 T286A mutant.	('T286', 'Chemical', '-', (194, 198))	('T286A', 'Mutation', 'c.286T>A', (194, 199))	('T286', 'Chemical', '-', (99, 103))	('T286A', 'Var', (194, 199))	('C-terminus', 'MPA', (77, 87))
504203	21317297	Cells expressing cyclin D1b variant acquire a neoplastic phenotype and clinically this variant has been described in esophageal cancer.	('neoplastic phenotype', 'CPA', (46, 66))	('esophageal cancer', 'Disease', (117, 134))	('described', 'Reg', (104, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cyclin D1b', 'Gene', (17, 27))	('variant', 'Var', (28, 35))
504208	21317297	Comparison of microarray data on IKKalpha-/- with IKKalpha reconstituted cells suggest that IKKalpha regulates tumorigenicity by modulating expression of genes known to play a critical role in neoplastic transformation.	('modulating', 'Reg', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('IKKalpha', 'Var', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('regulates', 'Reg', (101, 110))	('expression of genes', 'MPA', (140, 159))
504210	21317297	A Moloney-based retrovirus expressing Myc-tagged IKKalpha or beta-galactosidase was utilized with hygromycin selection to generate stable cell lines from parental IKK knockout cells, expressing IKKalpha (IKKalpha+/+), beta-galactosidase (IKKalpha-/-), or IKKgamma-/-, and has been described previously.	('IKKalpha', 'Var', (194, 202))	('IKKalpha+/+', 'Gene', (204, 215))	('hygromycin', 'Chemical', 'MESH:C026273', (98, 108))	('IKKgamma', 'Gene', (255, 263))	('beta-galactosidase', 'Gene', (218, 236))	('beta-galactosidase', 'Gene', '12091', (218, 236))	('IKKgamma', 'Gene', '16151', (255, 263))	('beta-galactosidase', 'Gene', (61, 79))	('beta-galactosidase', 'Gene', '12091', (61, 79))	('IKKalpha+/+', 'Gene', '12675', (204, 215))
504239	21317297	We previously demonstrated that IKKalpha regulates subcellular distribution and turnover of cyclin D1 by phosphorylation at T286.	('T286', 'Chemical', '-', (124, 128))	('turnover', 'MPA', (80, 88))	('regulates', 'Reg', (41, 50))	('phosphorylation at T286', 'Var', (105, 128))	('subcellular distribution', 'MPA', (51, 75))
504243	21317297	Constitutive nuclear expression of cyclin D1 T286A and a splice variant cyclin D1b is associated with a neoplastic phenotype as suggested by growth in soft agar and tumor formation in nude mice.	('cyclin', 'Gene', (35, 41))	('nude mice', 'Species', '10090', (184, 193))	('T286A', 'Mutation', 'c.286T>A', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('associated', 'Reg', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('T286A', 'Var', (45, 50))	('agar', 'Chemical', 'MESH:D000362', (156, 160))	('cyclin D1b', 'Gene', (72, 82))	('tumor', 'Disease', (165, 170))
504287	21317297	Further studies will therefore be needed to fully characterize the molecular pathways involved in IKK-alpha inactivation in these and other cancers.	('IKK-alpha', 'Gene', (98, 107))	('IKK-alpha', 'Gene', '12675', (98, 107))	('inactivation', 'Var', (108, 120))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
504300	21317297	Decreased expression of IKKalpha in lung cancer cell lines, when taken together with data from murine cells suggest that lack of IKKalpha in lung cancer cell lines may be involved in development of lung cancer in these patients.	('IKKalpha', 'Gene', (129, 137))	('murine', 'Species', '10090', (95, 101))	('lung cancer', 'Disease', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('lung cancer', 'Disease', (198, 209))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Decreased', 'NegReg', (0, 9))	('expression', 'MPA', (10, 20))	('patients', 'Species', '9606', (219, 227))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('lung cancer', 'Disease', (36, 47))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('involved', 'Reg', (171, 179))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('lack', 'Var', (121, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
504309	21317297	Although T286A mutation of cyclin D1 is not described in tumors, transgenic cyclin D1-T286A mice developed B-cell lymphoma.	('T286A', 'Mutation', 'c.286T>A', (86, 91))	('cyclin', 'Var', (76, 82))	('developed', 'PosReg', (97, 106))	('B-cell lymphoma', 'Disease', (107, 122))	('T286A', 'Mutation', 'c.286T>A', (9, 14))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (107, 122))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (107, 122))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('cell lymphoma', 'Phenotype', 'HP:0012191', (109, 122))	('mice', 'Species', '10090', (92, 96))	('T286A', 'Var', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
504313	21317297	We report here that IKKalpha knockout cells with nuclear localization of cyclin D1 are tumorigenic.	('cyclin', 'Gene', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('nuclear localization', 'Var', (49, 69))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
504314	21317297	We found the lack of IKKalpha is associated with nuclear localization of cyclin D1 and ability of these cells to transform to tumors.	('nuclear localization', 'MPA', (49, 69))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('lack', 'Var', (13, 17))	('cyclin D1', 'Protein', (73, 82))	('transform', 'CPA', (113, 122))	('IKKalpha', 'Gene', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
504316	21317297	These findings provide a novel mechanism for development of neoplasia and may explain the observed alteration in cyclin D1 in a variety of cancers, in which there is increased expression of cyclin D1 without a known gain of function mutation in cyclin D1 gene, or other intrinsic abnormalities of cyclin D1 expression such as those induced by gene amplification or translocation.	('neoplasia', 'Disease', 'MESH:D009369', (60, 69))	('cyclin D1', 'Gene', (190, 199))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('increased', 'PosReg', (166, 175))	('cyclin D1', 'Gene', (245, 254))	('cancers', 'Disease', (139, 146))	('alteration', 'Var', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('neoplasia', 'Disease', (60, 69))	('gain of function', 'PosReg', (216, 232))	('expression', 'MPA', (176, 186))	('translocation', 'Var', (365, 378))	('neoplasia', 'Phenotype', 'HP:0002664', (60, 69))	('gene amplification', 'Var', (343, 361))
504317	21317297	Recently, a study by Liu et al identified mutations involving IKKalpha gene in exon 15 in eight of nine poorly differentiated squamous cell carcinoma of skin.	('IKKalpha', 'Gene', (62, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 149))	('squamous cell carcinoma', 'Disease', (126, 149))	('carcinoma of skin', 'Phenotype', 'HP:0008069', (140, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('mutations', 'Var', (42, 51))
504323	21317297	Oncogenic potential of IKKalpha-/- cells is likely mediated by lack of IKKalpha to phosphorylate cyclin D1 and with similar downstream mechanisms to that observed with cyclin D1 T286A or cyclin D1b variant.	('T286A', 'Mutation', 'c.286T>A', (178, 183))	('Oncogenic potential', 'CPA', (0, 19))	('lack', 'NegReg', (63, 67))	('T286A', 'Var', (178, 183))
504327	21317297	Repression of raf, ERK and VEGF-A was noted in epidermal cells by IKKalpha in the study demonstrating mutations involving IKKalpha in squamous cell cancers.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (134, 155))	('raf', 'Gene', (14, 17))	('VEGF-A', 'Gene', '22339', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('VEGF-A', 'Gene', (27, 33))	('ERK', 'Gene', (19, 22))	('mutations', 'Var', (102, 111))	('IKKalpha', 'Gene', (122, 130))	('squamous cell cancers', 'Disease', (134, 155))	('ERK', 'Gene', '26413', (19, 22))	('raf', 'Gene', '387609', (14, 17))	('squamous cell cancers', 'Disease', 'MESH:D002294', (134, 155))
504332	21317297	Genetic changes involving this area are common in different malignancies.	('Genetic changes', 'Var', (0, 15))	('malignancies', 'Disease', (60, 72))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))
504374	33889656	In studies of patients with fungal infections, azoles such as fluconazole (200 mg daily) and voriconazole (300 mg twice a day) achieved pleural and pericardial fluid concentrations that were 20%-100% of those in paired plasma samples; levels increased over time.	('pericardial fluid', 'Phenotype', 'HP:0001698', (148, 165))	('azoles', 'Chemical', 'MESH:D001393', (47, 53))	('fungal infections', 'Disease', (28, 45))	('fungal infections', 'Phenotype', 'HP:0002841', (28, 45))	('fungal infections', 'Disease', 'MESH:D009181', (28, 45))	('300', 'Var', (107, 110))
504392	33223519	High HEIH and KLK5 indicated worse prognosis and high miR-185 suggested better prognosis of EC patients.	('High HEIH', 'Disease', (0, 9))	('patients', 'Species', '9606', (95, 103))	('high miR-185', 'Var', (49, 61))	('KLK5', 'Protein', (14, 18))	('High HEIH', 'Disease', 'MESH:D052456', (0, 9))
504393	33223519	Depleting HEIH or restoring miR-185 suppressed the malignant phenotypes of EC cells, and delayed tumor growth in EC mice.	('malignant phenotypes of', 'CPA', (51, 74))	('delayed', 'NegReg', (89, 96))	('suppressed', 'NegReg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mice', 'Species', '10090', (116, 120))	('Depleting', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('miR-185', 'Gene', (28, 35))	('HEIH', 'Gene', (10, 14))	('tumor', 'Disease', (97, 102))	('HEIH', 'Gene', '100859930', (10, 14))
504395	33223519	Collectively, we reveal that HEIH depletion dampens EC progression by upregulating miR-185 and downregulating KLK5, which provides novel treatments for EC.	('HEIH', 'Gene', '100859930', (29, 33))	('miR-185', 'Gene', (83, 90))	('depletion', 'Var', (34, 43))	('upregulating', 'PosReg', (70, 82))	('dampens', 'NegReg', (44, 51))	('KLK5', 'Gene', (110, 114))	('downregulating', 'NegReg', (95, 109))	('HEIH', 'Gene', (29, 33))
504399	33223519	A recent study has reported that as one of the lncRNAs, lncRNA SNHG7 is elevated in EC, and is capable of facilitating proliferation and limits apoptosis of EC cells.	('lncRNA', 'Var', (56, 62))	('elevate', 'Disease', 'MESH:D006973', (72, 79))	('elevate', 'Disease', (72, 79))	('apoptosis', 'CPA', (144, 153))	('limits', 'NegReg', (137, 143))	('facilitating', 'PosReg', (106, 118))	('SNHG7', 'Gene', '84973', (63, 68))	('SNHG7', 'Gene', (63, 68))	('proliferation', 'CPA', (119, 132))
504404	33223519	It is evidenced that miR-185 is lowly expressed in esophageal squamous cell carcinoma (ESCC) patients and is likely to dampen ESCC migration and invasion.	('patients', 'Species', '9606', (93, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (51, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('ESCC', 'Disease', (126, 130))	('invasion', 'CPA', (145, 153))	('dampen', 'NegReg', (119, 125))	('esophageal squamous cell carcinoma', 'Disease', (51, 85))	('miR-185', 'Var', (21, 28))
504408	33223519	Hence, we made this research to understanding the mechanism of HEIH on EC development through modulation of miR-185 and KLK5.	('modulation', 'Var', (94, 104))	('HEIH', 'Gene', (63, 67))	('miR-185', 'Gene', (108, 115))	('KLK5', 'Gene', (120, 124))	('EC development', 'CPA', (71, 85))	('HEIH', 'Gene', '100859930', (63, 67))
504460	33223519	HEIH containing wild-type (WT) or mutant (MUT) miR-185 response elements were cloned into the pmirGLO vector (Promega) to produce HEIH-WT and HEIH-MUT.	('miR-185', 'Gene', (47, 54))	('HEIH', 'Gene', (130, 134))	('HEIH', 'Gene', (0, 4))	('HEIH', 'Gene', '100859930', (130, 134))	('HEIH-WT and HEIH-MUT', 'Disease', 'MESH:C565390', (130, 150))	('HEIH', 'Gene', (142, 146))	('HEIH', 'Gene', '100859930', (0, 4))	('mutant', 'Var', (34, 40))	('HEIH', 'Gene', '100859930', (142, 146))
504463	33223519	The correctly sequenced KLK5-WT and KLK5-MUT were co-transfected with miR-185 mimic or mimic-NC into TE-1 and KYSE-30 cells, respectively, for 36-48 h, after which luciferase activities were determined by dual luciferase assay system (Promega).	('mimic', 'Var', (78, 83))	('mimic-NC', 'Var', (87, 95))	('miR-185', 'Gene', (70, 77))	('luciferase', 'Enzyme', (164, 174))	('TE', 'Chemical', 'MESH:D013691', (101, 103))	('activities', 'MPA', (175, 185))
504484	33223519	miR-185-5p overexpression was able to inhibit the invasion and migration of ESCC cells, and KLF5 was the core regulatory factor for ESCC cells.	('miR-185-5p', 'Chemical', '-', (0, 10))	('inhibit', 'NegReg', (38, 45))	('KLF5', 'Gene', (92, 96))	('miR-185-5p', 'Var', (0, 10))	('KLF5', 'Gene', '688', (92, 96))	('overexpression', 'PosReg', (11, 25))
504488	33223519	The results revealed that worse prognosis was found in EC patients with high HEIH or KLK5 expression, while better prognosis was observed in EC patients with high miR-185 expression (Fig.	('HEIH', 'Gene', (77, 81))	('HEIH', 'Gene', '100859930', (77, 81))	('KLK5', 'Protein', (85, 89))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (58, 66))	('high', 'Var', (72, 76))
504495	33223519	The results mirrored that EC patients with large tumor, great infiltration depth, and advanced TNM stage had increased proportion of high HEIH expression, indicating that tumor size, infiltration depth, and TNM staging were correlated with HEIH expression, but not with age, gender, and invasion of lymph (Table 1).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('patients', 'Species', '9606', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('high', 'Var', (133, 137))	('HEIH', 'Gene', (240, 244))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('HEIH', 'Gene', '100859930', (240, 244))	('tumor', 'Disease', (49, 54))	('HEIH', 'Gene', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('HEIH', 'Gene', '100859930', (138, 142))
504504	33223519	However, silencing miR-185 weakened the impacts of HEIH downregulation on cell proliferation and cell cycle distribution (Fig.	('cell proliferation', 'CPA', (74, 92))	('cell cycle distribution', 'CPA', (97, 120))	('silencing', 'Var', (9, 18))	('HEIH', 'Gene', (51, 55))	('weakened', 'NegReg', (27, 35))	('downregulation', 'NegReg', (56, 70))	('HEIH', 'Gene', '100859930', (51, 55))	('miR-185', 'Gene', (19, 26))
504518	33223519	1D, F) suggested great abatement in KYSE-30 and TE-1 cells co-transfected with HEIH-WT and miR-185 mimic, while that in cells co-transfected with HEIH-MUT and miR-185 mimic showed no alterations, indicating that miR-185 mimic specifically bound to HEIH.	('HEIH', 'Gene', '100859930', (146, 150))	('TE', 'Chemical', 'MESH:D013691', (48, 50))	('mimic', 'Var', (99, 104))	('HEIH', 'Gene', '100859930', (79, 83))	('HEIH-MUT', 'Disease', 'MESH:C565390', (146, 154))	('HEIH', 'Gene', (248, 252))	('HEIH', 'Gene', (79, 83))	('HEIH-MUT', 'Disease', (146, 154))	('HEIH', 'Gene', (146, 150))	('bound', 'Interaction', (239, 244))	('HEIH-WT', 'Disease', 'MESH:C536751', (79, 86))	('HEIH-WT', 'Disease', (79, 86))	('HEIH', 'Gene', '100859930', (248, 252))
504524	33223519	miR-185 was upregulated, while KLK5 was downregulated in TE-1 cells transfected with miR-185 mimic.	('miR-185', 'Gene', (0, 7))	('downregulated', 'NegReg', (40, 53))	('TE', 'Chemical', 'MESH:D013691', (57, 59))	('mimic', 'Var', (93, 98))	('upregulated', 'PosReg', (12, 23))	('KLK5', 'Gene', (31, 35))
504527	33223519	As to TE-1 cells, downregulating KLK5 repressed cell progression.	('cell progression', 'CPA', (48, 64))	('KLK5', 'Protein', (33, 37))	('TE', 'Chemical', 'MESH:D013691', (6, 8))	('downregulating', 'Var', (18, 32))
504538	33223519	To begin with, we found that HEIH was downregulated in EC tissues and cells, and functional knockout of HEIH impaired EC cell proliferation, invasion, and migration, and elevated cell apoptosis rate in vitro, as well as delayed tumor growth in mice in vivo.	('invasion', 'CPA', (141, 149))	('migration', 'CPA', (155, 164))	('mice', 'Species', '10090', (244, 248))	('knockout', 'Var', (92, 100))	('HEIH', 'Gene', '100859930', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('HEIH', 'Gene', (104, 108))	('delayed', 'NegReg', (220, 227))	('HEIH impaired EC', 'Disease', 'MESH:D060825', (104, 120))	('cell apoptosis rate', 'CPA', (179, 198))	('elevate', 'Disease', 'MESH:D006973', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('HEIH', 'Gene', '100859930', (104, 108))	('tumor', 'Disease', (228, 233))	('HEIH impaired EC', 'Disease', (104, 120))	('elevate', 'Disease', (170, 177))	('HEIH', 'Gene', (29, 33))
504539	33223519	In compliance with our findings, the overexpressed HEIH was presented in ESCC, and depleting HEIH depressed the viability and invasion of ESCC cells.	('HEIH', 'Gene', '100859930', (93, 97))	('depleting', 'Var', (83, 92))	('HEIH depressed', 'Disease', (93, 107))	('HEIH', 'Gene', (51, 55))	('HEIH depressed', 'Disease', 'MESH:D000275', (93, 107))	('HEIH', 'Gene', (93, 97))	('HEIH', 'Gene', '100859930', (51, 55))
504542	33223519	A similar result has proposed the high expression of HEIH in melanoma, and knocking down HEIH greatly prevented melanoma cells from proliferation, migration, and invasion through binding to miR-200b/a/429 (ref.	('HEIH', 'Gene', (53, 57))	('prevented', 'NegReg', (102, 111))	('migration', 'CPA', (147, 156))	('miR-200b', 'Gene', (190, 198))	('binding', 'Interaction', (179, 186))	('HEIH', 'Gene', (89, 93))	('HEIH', 'Gene', '100859930', (53, 57))	('proliferation', 'CPA', (132, 145))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('knocking down', 'Var', (75, 88))	('HEIH', 'Gene', '100859930', (89, 93))	('miR-200b', 'Gene', '406984', (190, 198))	('invasion', 'CPA', (162, 170))
504543	33223519	has proffered that knockdown of HEIH exerted negative impacts on liver cancer cell development and metastasis by modulating miR-199a-3p (ref.	('modulating', 'Reg', (113, 123))	('liver cancer', 'Phenotype', 'HP:0002896', (65, 77))	('miR-199a-3p', 'Gene', '406977', (124, 135))	('HEIH', 'Gene', '100859930', (32, 36))	('knockdown', 'Var', (19, 28))	('negative', 'NegReg', (45, 53))	('miR-199a-3p', 'Gene', (124, 135))	('liver cancer', 'Disease', 'MESH:D006528', (65, 77))	('liver cancer', 'Disease', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('metastasis', 'CPA', (99, 109))	('HEIH', 'Gene', (32, 36))
504547	33223519	Moreover, we uncovered that miR-185 upregulation owned the similar effects of HEIH knockdown on EC cell progression and tumor growth.	('HEIH', 'Gene', (78, 82))	('upregulation', 'PosReg', (36, 48))	('HEIH', 'Gene', '100859930', (78, 82))	('miR-185', 'Gene', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('knockdown', 'Var', (83, 92))	('tumor', 'Disease', (120, 125))
504548	33223519	In a late research by Jing et al., miR-185 expression was low in ESCC and restoring miR-185-disabled ESCC cells to migrate, invade, and develop distal pulmonary metastases.	('pulmonary metastases', 'Disease', 'MESH:D009362', (151, 171))	('pulmonary metastases', 'Disease', (151, 171))	('low', 'NegReg', (58, 61))	('miR-185', 'Gene', (35, 42))	('invade', 'CPA', (124, 130))	('ESCC', 'Disease', (65, 69))	('miR-185-disabled', 'Var', (84, 100))
504549	33223519	Not only in ESCC, the low expression of miR-185 also showed in gastric cancer and elevating miR-185 could restrain cancer progression.	('expression', 'MPA', (26, 36))	('gastric cancer', 'Disease', (63, 77))	('cancer', 'Disease', (115, 121))	('low', 'NegReg', (22, 25))	('restrain', 'NegReg', (106, 114))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('elevating miR-185', 'Var', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-185', 'Var', (92, 99))	('miR-185', 'Gene', (40, 47))	('showed', 'Reg', (53, 59))
504555	33223519	In oral squamous cell carcinoma, KLK5 level was investigated to elevate and silencing KLK5 restricted the metastatic dissemination of cancer cells.	('KLK5', 'Gene', (86, 90))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('elevate', 'Disease', (64, 71))	('silencing', 'Var', (76, 85))	('cancer', 'Disease', (134, 140))	('restricted', 'NegReg', (91, 101))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('elevate', 'Disease', 'MESH:D006973', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
504556	33223519	To conclude, we reveal that HEIH depletion depresses growth of EC cells by upregulating miR-185 and downregulating KLK5 (Supplementary Fig.	('depresses', 'NegReg', (43, 52))	('miR-185', 'Gene', (88, 95))	('upregulating', 'PosReg', (75, 87))	('depletion', 'Var', (33, 42))	('downregulating', 'NegReg', (100, 114))	('KLK5', 'Gene', (115, 119))	('HEIH', 'Gene', (28, 32))	('growth', 'CPA', (53, 59))	('HEIH', 'Gene', '100859930', (28, 32))
504609	31222974	However, the incidence in T1bLVI+ tumors remains high, and the prognosis after LNR was poor, although salvage surgery or radiotherapy/CRT was performed in most patients who experienced solely LNR.	('T1bLVI+', 'Var', (26, 33))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('patients', 'Species', '9606', (160, 168))	('tumors', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
504621	30675222	High PD-L1 expression is associated with a favorable prognosis in patients with esophageal squamous cell carcinoma undergoing postoperative adjuvant radiotherapy Previous results on the prognostic value of programmed death-ligand (PD-L)1 expression in patients with esophageal squamous cell carcinoma (ESCC) remain limited and conflicting.	('esophageal squamous cell carcinoma', 'Disease', (266, 300))	('High', 'Var', (0, 4))	('PD-L1', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('patients', 'Species', '9606', (252, 260))	('PD-L1', 'Gene', '29126', (5, 10))	('PD-L)1', 'Gene', '29126;5133', (231, 237))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (80, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (266, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (277, 300))	('esophageal squamous cell carcinoma', 'Disease', (80, 114))	('patients', 'Species', '9606', (66, 74))
504626	30675222	Median overall survival (OS) time was compared between patients with positive PD-L1 expression and those with negative PD-L1 expression in the overall patient population.	('expression', 'Var', (84, 94))	('PD-L1', 'Gene', (78, 83))	('patient', 'Species', '9606', (151, 158))	('positive', 'Var', (69, 77))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (55, 63))
504628	30675222	In patients treated with adjuvant chemotherapy, median OS was poorer in patients with positive PD-L1 expression compared with those with negative PD-L1 expression.	('expression', 'Var', (101, 111))	('poorer', 'NegReg', (62, 68))	('PD-L1', 'Gene', (95, 100))	('patients', 'Species', '9606', (3, 11))	('positive', 'Var', (86, 94))	('patients', 'Species', '9606', (72, 80))
504630	30675222	High PD-L1 expression was associated with a favorable prognosis in patients with ESCC undergoing postoperative adjuvant radiotherapy, and it was concluded that patients with positive PD-L1 expression might benefit from postoperative adjuvant radiotherapy.	('patients', 'Species', '9606', (160, 168))	('High', 'Var', (0, 4))	('benefit', 'PosReg', (206, 213))	('patients', 'Species', '9606', (67, 75))	('PD-L1', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('ESCC', 'Disease', (81, 85))
504635	30675222	Abnormal PD-L1 expression has been associated with the prognosis and therapeutic response in a number of malignancies, including esophageal cancer.	('malignancies', 'Disease', (105, 117))	('associated', 'Reg', (35, 45))	('Abnormal', 'Var', (0, 8))	('Abnormal PD', 'Phenotype', 'HP:0032199', (0, 11))	('esophageal cancer', 'Disease', (129, 146))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PD-L1', 'Gene', (9, 14))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
504662	30675222	The chi2 test revealed a significant association between positive PD-L1 expression and tumor node metastasis (TNM) stage (P=0.022).	('positive', 'Var', (57, 65))	('tumor node metastasis', 'Disease', 'MESH:D009362', (87, 108))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('expression', 'MPA', (72, 82))	('tumor node metastasis', 'Disease', (87, 108))	('PD-L1', 'Gene', (66, 71))
504668	30675222	For patients with positive PD-L1 expression, the OS time was 52.4 months (95% CI, 30.3-74.5 months), whereas for patients with negative PD-L1 expression, the OS time was 56.4 months (95% CI, 43.0-69.8 months).	('expression', 'Var', (33, 43))	('patients', 'Species', '9606', (113, 121))	('positive', 'Var', (18, 26))	('patients', 'Species', '9606', (4, 12))	('PD-L1', 'Gene', (27, 32))
504675	30675222	Furthermore, in the surgery with adjuvant chemoradiotherapy subgroup, there was a tendency for patients with ESCC that had positive PD-L1 expression to have a shorter OS compared with patients with negative PD-L1 expression [38.5 months (95% CI, 17.8-59.2 months) vs. 69.1 months (95% CI, 25.2-113.0)]; however, this difference was not significant (P=0.061; Fig.	('positive', 'Var', (123, 131))	('PD-L1', 'Gene', (132, 137))	('patients', 'Species', '9606', (95, 103))	('ESCC', 'Disease', (109, 113))	('patients', 'Species', '9606', (184, 192))
504681	30675222	In addition, it was revealed that PD-L1 expression was a potential predictor of a favorable response to radiotherapy in patients with ESCC, although median OS time did not differ significantly between patients with positive and negative PD-L1 expression in the overall population.	('patients', 'Species', '9606', (201, 209))	('expression', 'Var', (40, 50))	('ESCC', 'Disease', (134, 138))	('PD-L1', 'Gene', (34, 39))	('patients', 'Species', '9606', (120, 128))
504684	30675222	In the present study, it was revealed that patients with ESCC with an advanced TNM stage had a significant association with positive PD-L1 expression, and these results suggest that positive PD-L1 expression may be associated with malignant biological behavior in ESCC.	('PD-L1', 'Gene', (191, 196))	('PD-L1', 'Gene', (133, 138))	('ESCC', 'Disease', (57, 61))	('malignant biological behavior', 'CPA', (231, 260))	('ESCC', 'Disease', (264, 268))	('patients', 'Species', '9606', (43, 51))	('positive', 'Var', (182, 190))	('expression', 'MPA', (139, 149))	('associated with', 'Reg', (215, 230))
504685	30675222	The present study also revealed that patients with positive and negative PD-L1 expression had similar median OS time (52.4 months vs. 56.4 months, P=0.466), which is inconsistent with a majority of previous studies.	('patients', 'Species', '9606', (37, 45))	('positive', 'Var', (51, 59))	('negative', 'NegReg', (64, 72))	('PD-L1', 'Gene', (73, 78))
504688	30675222	Notably, the results of the present study indicated that in patients treated with adjuvant radiotherapy, the prognosis was significantly improved in patients with positive PD-L1 expression compared with those with negative PD-L1 expression (median OS time, 84.4 months vs. 36.0 months; P=0.046).	('patients', 'Species', '9606', (149, 157))	('PD-L1', 'Gene', (172, 177))	('patients', 'Species', '9606', (60, 68))	('prognosis', 'CPA', (109, 118))	('improved', 'PosReg', (137, 145))	('positive', 'Var', (163, 171))
504690	30675222	In a study of 177 Japanese patients with ESCC who underwent an esophagectomy without preoperative therapy, PD-L1 expression was significantly associated with an improved prognosis in patients who underwent surgery alone, but not in patients treated with surgery plus postoperative adjuvant chemotherapy.	('patients', 'Species', '9606', (232, 240))	('ESCC', 'Disease', (41, 45))	('expression', 'Var', (113, 123))	('patients', 'Species', '9606', (27, 35))	('PD-L1', 'Gene', (107, 112))	('patients', 'Species', '9606', (183, 191))	('improved', 'PosReg', (161, 169))
504696	30675222	In addition, anti-PD-L1 therapy combined with radiotherapy improves survival compared with radiotherapy alone in mice.	('survival', 'CPA', (68, 76))	('mice', 'Species', '10090', (113, 117))	('anti-PD-L1', 'Var', (13, 23))	('improves', 'PosReg', (59, 67))
504698	30675222	However, in the present study, positive PD-L1 expression was associated with a favorable survival in patients who underwent radiotherapy.	('expression', 'MPA', (46, 56))	('patients', 'Species', '9606', (101, 109))	('PD-L1', 'Gene', (40, 45))	('positive', 'Var', (31, 39))
504699	30675222	It was hypothesized that patients with PD-L1 expression had highly immunogenic tumors prior to radiation therapy, which indicates a strong adaptive immune response.	('PD-L1', 'Gene', (39, 44))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('patients', 'Species', '9606', (25, 33))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('highly immunogenic', 'MPA', (60, 78))	('expression', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
504701	30675222	A number of studies reported that high PD-L1 expression on tumor cells was associated with increased intraepithelial CD3+ T-lymphocytes, and both factors were associated with a favorable prognosis in ESCC.	('PD-L1', 'Gene', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('expression', 'MPA', (45, 55))	('high', 'Var', (34, 38))	('increased', 'PosReg', (91, 100))	('intraepithelial CD3+ T-lymphocytes', 'MPA', (101, 135))	('ESCC', 'Disease', (200, 204))
504711	30675222	In conclusion, the present study demonstrates, to the best of our knowledge, for the first time that high PD-L1 expression in associated with a favorable prognosis in patients with ESCC undergoing postoperative adjuvant radiotherapy.	('patients', 'Species', '9606', (167, 175))	('PD-L1', 'Gene', (106, 111))	('ESCC', 'Disease', (181, 185))	('high', 'Var', (101, 105))	('expression', 'MPA', (112, 122))
504714	30081489	Radiotherapy for T1N0M0 Esophageal Cancer: Analyses of the Predictive Factors and the Role of Endoscopic Submucosal Dissection in the Local Control Several therapeutic options are available for clinical T1N0M0 thoracic esophageal squamous cell carcinoma (stage I ESCC); however, the studies on the treatment results are limited.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (219, 253))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (24, 41))	('men', 'Species', '9606', (303, 306))	('esophageal squamous cell carcinoma', 'Disease', (219, 253))	('Esophageal Cancer', 'Disease', (24, 41))	('T1N0M0', 'Var', (203, 209))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))
504841	29904058	A depressed type tumor (vs. nondepressed type tumor, P = 0.002), length of tumor greater than 20 mm (vs. length of tumor <= 20 mm, P = 0.036), and delayed ESD after initial biopsy (vs. immediate ESD after initial biopsy, P = 0.005) were independent factors predictive of submucosal fibrosis.	('depressed type tumor', 'Disease', 'MESH:D000275', (2, 22))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('depressed type tumor', 'Disease', 'MESH:D000275', (31, 51))	('tumor', 'Disease', (115, 120))	('depressed type tumor', 'Disease', (2, 22))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('depressed type tumor', 'Disease', (31, 51))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (46, 51))	('submucosal fibrosis', 'Disease', 'MESH:D005355', (271, 290))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('delayed ESD', 'Var', (147, 158))	('submucosal fibrosis', 'Disease', (271, 290))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
504895	29904058	It is plausible that a biopsy can induce mucosal ulceration and cause scarring to change over time, which in turn might lead to submucosal fibrosis.	('mucosal ulceration', 'Disease', (41, 59))	('induce', 'Reg', (34, 40))	('submucosal fibrosis', 'Disease', (128, 147))	('mucosal ulceration', 'Disease', 'MESH:D019226', (41, 59))	('lead to', 'Reg', (120, 127))	('scarring', 'MPA', (70, 78))	('biopsy', 'Var', (23, 29))	('scarring', 'Phenotype', 'HP:0100699', (70, 78))	('submucosal fibrosis', 'Disease', 'MESH:D005355', (128, 147))
504940	29844815	According to GO enrichment analysis, DEGs in the co-expression subnetwork of the module blue4 were predominantly enriched in GO terms regarding cell division, including 'spindle organization' [e.g., ubiquitin conjugating enzyme E2 C (UBE2C) and SAC3 domain containing 1 (SAC3D1)], 'cell cycle process' [e.g., UBE2C, minichromosome maintenance complex component 6 (MCM6) and cell division cycle 20 (CDC20)], 'protein binding' (e.g., UBE2C, MCM6 and CDC20) and 'anaphase-promoting complex' (APC; e.g., UBE2C and CDC20; Table I).	('MCM6', 'Gene', '4175', (439, 443))	('APC', 'Disease', 'MESH:D011125', (489, 492))	('APC', 'Disease', (489, 492))	('maintenance complex component 6', 'Gene', (331, 362))	('MCM6', 'Gene', (364, 368))	('CDC20', 'Var', (448, 453))	('SAC3D1', 'Gene', (271, 277))	('SAC3D1', 'Gene', '100519293', (271, 277))	('MCM6', 'Gene', (439, 443))	('maintenance complex component 6', 'Gene', '4175', (331, 362))	('MCM6', 'Gene', '4175', (364, 368))	("'protein", 'Protein', (407, 415))
504944	29844815	The GO and KEGG pathway enrichment analyses for the top 30 DEGs with the highest connectivity degrees in the module blue4 revealed that a number of DEGs were associated with the 'cell cycle' and 'ubiquitin mediated proteolysis' KEGG pathways, including UBE2C, CDC20 and MCM6.	('DEGs', 'Var', (148, 152))	('MCM6', 'Gene', (270, 274))	('associated', 'Reg', (158, 168))	('MCM6', 'Gene', '4175', (270, 274))	("'cell cycle'", 'Pathway', (178, 190))	('CDC20', 'Gene', (260, 265))	("'ubiquitin mediated proteolysis' KEGG pathways", 'Pathway', (195, 241))
504945	29844815	A previous study reported that UBE2C expression was elevated in 73% (11 of 15) of esophageal adenocarcinoma samples relative to Barrett's metaplasia, and the transfection of UBE2C small interfering (si)RNA induced the inhibition of cell proliferation and a distortion in cell cycle distribution.	('distortion', 'Reg', (257, 267))	('inhibition', 'NegReg', (218, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (128, 148))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (82, 107))	('transfection', 'Var', (158, 170))	('UBE2C', 'Gene', (31, 36))	('esophageal adenocarcinoma', 'Disease', (82, 107))	("Barrett's metaplasia", 'Disease', (128, 148))	('small interfering', 'Var', (180, 197))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (82, 107))	('expression', 'MPA', (37, 47))	('cell cycle distribution', 'CPA', (271, 294))	('cell proliferation', 'CPA', (232, 250))	('elevated', 'PosReg', (52, 60))
504970	29844815	Additionally, genetic polymorphisms of CYP3A5 in combination with the sulfotransferase family 1A member 1 *2/*2 genotype are associated with an increased risk of esophageal cancer, suggesting a crucial role for CYP3A5 in esophageal cancer.	('polymorphisms', 'Var', (22, 35))	('esophageal cancer', 'Disease', (162, 179))	('CYP3A5', 'Gene', (39, 45))	('associated', 'Reg', (125, 135))	('CYP3A5', 'Gene', (211, 217))	('sulfotransferase family 1A member 1', 'Gene', '6817', (70, 105))	('esophageal cancer', 'Disease', (221, 238))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('sulfotransferase family 1A member 1', 'Gene', (70, 105))	('esophageal cancer', 'Disease', 'MESH:D004938', (221, 238))	('CYP3A5', 'Gene', '1577', (211, 217))	('CYP3A5', 'Gene', '1577', (39, 45))
504992	28730503	In contrast, the rate of non-specific motility disorders was lower in the HRM group compared to the conventional manometry group (3 vs 12%, P < 0.05).	('lower', 'NegReg', (61, 66))	('HRM', 'Var', (74, 77))	('non-specific', 'Disease', (25, 37))	('motility disorders', 'Disease', 'MESH:D015835', (38, 56))	('motility disorders', 'Disease', (38, 56))
505031	28730503	Ineffective esophageal motility is diagnosed when >50% of swallows is ineffective, that is either failed (DCI <100mmHg cm s) or weak (DCI 100-450 mmHg cm s).	('DCI <100mmHg cm s', 'Var', (106, 123))	('esophageal motility', 'Disease', 'MESH:D015154', (12, 31))	('esophageal motility', 'Disease', (12, 31))	('DCI', 'Chemical', '-', (106, 109))	('DCI', 'Chemical', '-', (134, 137))	('DCI 100-450 mmHg cm s', 'Var', (134, 155))
505054	28693132	A certain mechanism involved oxidative stress-damaged DNA and led to cell transformation, which promoted cancer development.	('oxidative stress', 'Phenotype', 'HP:0025464', (29, 45))	('cancer', 'Disease', (105, 111))	('cell transformation', 'CPA', (69, 88))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('oxidative', 'Var', (29, 38))	('promoted', 'PosReg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('led to', 'Reg', (62, 68))
505082	28693132	As summarized in Table I, the results revealed that the expression level of 4-HNE was associated with the clinical stage (P=0.043).	('4-HNE', 'Chemical', 'MESH:C027576', (76, 81))	('expression level', 'MPA', (56, 72))	('associated', 'Reg', (86, 96))	('4-HNE', 'Var', (76, 81))	('clinical stage', 'CPA', (106, 120))
505103	28693132	However, the accumulation of ROS may induce oxidative stress to damaged cells and contribute to inflammation-induced tissue damage, carcinogenesis, diabetes, cardiovascular disease, Alzheimer's disease, Parkinson's disease and autoimmune diseases.	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (182, 201))	("Alzheimer's disease", 'Disease', (182, 201))	('oxidative stress', 'MPA', (44, 60))	('diabetes', 'Disease', 'MESH:D003920', (148, 156))	('carcinogenesis', 'Disease', (132, 146))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (158, 180))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (182, 201))	('cardiovascular disease', 'Disease', 'MESH:D002318', (158, 180))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	("Parkinson's disease", 'Disease', (203, 222))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('cardiovascular disease', 'Disease', (158, 180))	('accumulation', 'Var', (13, 25))	('autoimmune diseases', 'Disease', 'MESH:D001327', (227, 246))	('ROS', 'Protein', (29, 32))	('oxidative stress', 'Phenotype', 'HP:0025464', (44, 60))	('autoimmune diseases', 'Disease', (227, 246))	('diabetes', 'Disease', (148, 156))	('contribute', 'Reg', (82, 92))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (227, 246))	('induce', 'Reg', (37, 43))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))	('inflammation', 'Disease', (96, 108))	("Parkinson's disease", 'Disease', 'MESH:D010300', (203, 222))
505116	27799939	The results shows that lymph node metastasis of m1, m2, m3, sm1, sm2, and sm3 of superficial esophageal carcinoma was 0%, 0%, 5.3%, 8.7%, 17.6%, and 37.5%, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('lymph node metastasis', 'CPA', (23, 44))	('sm1', 'Gene', '7911', (60, 63))	('sm3', 'Var', (74, 77))	('esophageal carcinoma', 'Disease', (93, 113))	('sm2', 'Gene', (65, 68))	('sm2', 'Gene', '53366', (65, 68))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (93, 113))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (93, 113))	('sm1', 'Gene', (60, 63))	('sm3', 'Chemical', '-', (74, 77))
505118	27799939	A prediction model for lymph node metastasis was established as follows: p = e x/(1 + e x), and x = -5.469 + 0.839 x depth of invasion + 1.992 x lymphavascular metastasis.	('x lymphavascular metastasis', 'Disease', 'MESH:D009362', (143, 170))	('x lymphavascular metastasis', 'Disease', (143, 170))	('x = -5.469', 'Var', (96, 106))
505121	27799939	A variety of complications could develop after surgery, and the quality of patient's life could be greatly influenced because of the modification of esophagus.	('esophagus', 'Disease', (149, 158))	('influenced', 'Reg', (107, 117))	('patient', 'Species', '9606', (75, 82))	('modification', 'Var', (133, 145))
505136	27799939	All patients were categorized into three groups according to the macroscopic type: type 0-I (protruded type), type 0-II (flat type), and type 0-III (excavated type).	('type 0-II', 'Var', (110, 119))	('patients', 'Species', '9606', (4, 12))	('type 0-III', 'Var', (137, 147))
505160	27799939	LNMs were reported in 0%, 0%, 11.8%, 24.0%, 20.5%, and 43.8% of the m1, m2, m3, sm1, sm2, and sm3 carcinoma, respectively.	('sm3', 'Var', (94, 97))	('sm2', 'Gene', (85, 88))	('sm1', 'Gene', '7911', (80, 83))	('sm2', 'Gene', '53366', (85, 88))	('carcinoma', 'Disease', 'MESH:D002277', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('sm3', 'Chemical', '-', (94, 97))	('sm1', 'Gene', (80, 83))	('carcinoma', 'Disease', (98, 107))
505173	27799939	The risk of the lymph node metastasis of 0-I and 0-III type was higher than 0-II type, so we recommend that the depth of infiltration can be further evaluated by magnifying endoscopy and endoscopic ultrasonography.	('men', 'Species', '9606', (98, 101))	('0-III', 'Var', (49, 54))	('lymph node metastasis', 'CPA', (16, 37))
505174	27799939	Our study also showed that the risk of lymph node metastasis in SEC patients with lymphovascular invasion was significantly higher than that in patients with no lymphovascular invasion (32.1% versus 4.6%).	('lymph node metastasis', 'CPA', (39, 60))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (144, 152))	('lymphovascular invasion', 'Var', (82, 105))	('higher', 'PosReg', (124, 130))
505247	26383967	High XRCC3 expression was positively correlated with resistance to chemoradiotherapy in ESCC and an independent predictor for short disease-specific survival of ESCC patients.	('ESCC', 'Disease', (88, 92))	('XRCC3', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('correlated', 'Reg', (37, 47))	('patients', 'Species', '9606', (166, 174))
505252	26383967	In mammals, the core of the HR pathway includes MRN (MRE11, RAD50 and NSB1), which form a complex, RAD51 and RAD51 paralogs (Rad51B, Rad51C, Rad51D, XRCC2, and XRCC3, BRCA1, BRCA2, RAD52, RAD54, and RAD54B).14 The X-ray repair complementing defective repair in Chinese hamster cell (XRCC3) protein, which shares some homology and interacts with RAD51, has roles in both the initiation and late stages of HR and controls the fidelity of HR.15, 16 It has been reported that polymorphisms of the XRCC3 gene are positively associated with an increased risk for numerous cancers and may be effective biomarkers for genetic susceptibility to these diseases.	('XRCC3', 'Gene', (493, 498))	('polymorphisms', 'Var', (472, 485))	('numerous cancers', 'Disease', (557, 573))	('Rad51B', 'Gene', '100756125', (125, 131))	('cancers', 'Phenotype', 'HP:0002664', (566, 573))	('MRE11', 'Gene', (53, 58))	('associated with', 'Reg', (519, 534))	('Rad51B', 'Gene', (125, 131))	('RAD50', 'Gene', '100755349', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (566, 572))	('BRCA1', 'Gene', '100770724', (167, 172))	('Chinese hamster', 'Species', '10029', (261, 276))	('BRCA2', 'Gene', (174, 179))	('RAD52', 'Gene', (181, 186))	('MRE11', 'Gene', '100750877', (53, 58))	('RAD54B', 'Gene', '100758942', (199, 205))	('BRCA1', 'Gene', (167, 172))	('RAD54B', 'Gene', (199, 205))	('RAD52', 'Gene', '100689331', (181, 186))	('BRCA2', 'Gene', '100689197', (174, 179))	('RAD51', 'Gene', '100689324', (109, 114))	('RAD51', 'Gene', '100689324', (345, 350))	('RAD51', 'Gene', (109, 114))	('numerous cancers', 'Disease', 'MESH:D009369', (557, 573))	('Rad51D', 'Gene', (141, 147))	('Rad51D', 'Gene', '100766176', (141, 147))	('RAD51', 'Gene', (345, 350))	('RAD51', 'Gene', '100689324', (99, 104))	('RAD51', 'Gene', (99, 104))	('RAD50', 'Gene', (60, 65))
505300	26383967	However, further analysis showed that high expression of XRCC3 was significantly associated with CRT resistance in ESCC patients.	('ESCC', 'Disease', (115, 119))	('CRT resistance', 'Disease', (97, 111))	('XRCC3', 'Gene', (57, 62))	('high', 'Var', (38, 42))	('CR', 'Chemical', '-', (97, 99))	('patients', 'Species', '9606', (120, 128))	('associated', 'Reg', (81, 91))
505309	26383967	Compared with control cells, inhibition of XRCC3 did not appear to induce KYSE30 or TE-1 cell apoptosis.	('SE', 'Disease', 'None', (76, 78))	('XRCC3', 'Gene', (43, 48))	('inhibition', 'Var', (29, 39))	('TE-1 cell apoptosis', 'CPA', (84, 103))
505315	26383967	However, as measured by RT-PCR, the mRNA levels of Rad51C and XRCC2 were not altered by XRCC3 knockdown in ESCC cells (Fig.	('knockdown', 'Var', (94, 103))	('mRNA levels', 'MPA', (36, 47))	('XRCC3', 'Gene', (88, 93))	('CR', 'Chemical', '-', (28, 30))
505317	26383967	Furthermore, the incidence of telomere dysfunction as judged by telomere dysfunction induced foci (TIF) assays was increased remarkably in XRCC3-knockdown KYSE30 and TE-1 cells compared with control cells after IR exposure (Fig.	('telomere dysfunction', 'Disease', (30, 50))	('telomere dysfunction', 'Disease', (64, 84))	('telomere dysfunction', 'Disease', 'MESH:C536801', (64, 84))	('increased', 'PosReg', (115, 124))	('telomere dysfunction', 'Disease', 'MESH:C536801', (30, 50))	('XRCC3-knockdown', 'Var', (139, 154))	('XRCC3-knockdown', 'Gene', (139, 154))	('SE', 'Disease', 'None', (157, 159))
505323	26383967	A previous study has shown that XRCC3 induces cisplatin resistance in MCF-7 human breast cancer cells by stimulation of Rad51-related recombinational repair.19 Similarly, in the present study, we observed that inhibition of XRCC3 increased the sensitivity of ESCC cells to IR in vitro and in vivo.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('MCF-7', 'CellLine', 'CVCL:0031', (70, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('human', 'Species', '9606', (76, 81))	('sensitivity', 'MPA', (244, 255))	('Rad51', 'Gene', '5888', (120, 125))	('increased', 'PosReg', (230, 239))	('inhibition', 'Var', (210, 220))	('Rad51', 'Gene', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('XRCC3', 'Gene', (224, 229))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
505324	26383967	To the best of our knowledge, apoptosis and MC are the two main mechanisms by which IR induces cell death.27, 28, 29 MC is a delayed type of cell death executed through necrosis, delayed apoptosis or induced senescence days after radiotherapy initiation, which can explain why clinical regression of solid tumors is slow.27 Thus, we examined the effect of XRCC3 inhibition on IR-induced apoptosis and MC using annexin V-FITC/propidium iodide (PI) staining together with flow cytometry and detection of micronuclei, respectively, which are a hallmark of MC.30 Our data revealed that XRCC3 knockdown enhanced apoptotic cell death and MC induced by IR.	('XRCC3', 'Gene', (582, 587))	('MC', 'Chemical', '-', (553, 555))	('solid tumors', 'Disease', 'MESH:D009369', (300, 312))	('necrosis', 'Disease', 'MESH:D009336', (169, 177))	('knockdown', 'Var', (588, 597))	('MC', 'Chemical', '-', (44, 46))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('annexin V', 'Gene', '308', (410, 419))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('MC', 'Chemical', '-', (401, 403))	('solid tumors', 'Disease', (300, 312))	('annexin V', 'Gene', (410, 419))	('apoptotic cell death', 'CPA', (607, 627))	('necrosis', 'Disease', (169, 177))	('propidium iodide', 'Chemical', 'MESH:D011419', (425, 441))	('enhanced', 'PosReg', (598, 606))	('MC', 'Chemical', '-', (117, 119))	('MC', 'Chemical', '-', (632, 634))
505325	26383967	Furthermore, silencing XRCC3 resulted in a significant increase of proteolytic cleavage of caspase-3 and PARP in cells treated with IR.	('PARP', 'Gene', (105, 109))	('XRCC3', 'Gene', (23, 28))	('increase', 'PosReg', (55, 63))	('caspase-3', 'Gene', (91, 100))	('proteolytic cleavage', 'MPA', (67, 87))	('PARP', 'Gene', '1302', (105, 109))	('silencing', 'Var', (13, 22))	('caspase-3', 'Gene', '836', (91, 100))
505327	26383967	A two-hybrid analysis shows that XRCC3 interacts with the human Rad51C protein, which shows apparent 1:1 stoichiometry.31 The DNA-binding activity of XRCC3-Rad51c and Rad51C protein expression is drastically decreased in the absence of XRCC3,32, 33 which was supported by our results.	('Rad51c', 'Gene', (156, 162))	('Rad51c', 'Gene', '5889', (156, 162))	('Rad51C', 'Var', (167, 173))	('expression', 'MPA', (182, 192))	('human', 'Species', '9606', (58, 63))	('decreased', 'NegReg', (208, 217))	('DNA-binding', 'Interaction', (126, 137))	('protein', 'Protein', (174, 181))
505329	26383967	However, as measured by RT-PCR, the mRNA levels of Rad51C and XRCC2 were not altered by XRCC3 knockdown in TE-1 cells (Fig.	('knockdown', 'Var', (94, 103))	('mRNA levels', 'MPA', (36, 47))	('XRCC3', 'Gene', (88, 93))	('CR', 'Chemical', '-', (28, 30))
505332	26383967	Some studies have demonstrated that disruption of telomere maintenance enhances the sensitivity of cancer cells to chemotherapeutic agents and IR.40, 41 In the present study, downregulation of XRCC3 in ESCC cells resulted in disruption of telomere stability and an increase in radiosensitivity.	('XRCC3', 'Gene', (193, 198))	('disruption', 'Var', (36, 46))	('disruption', 'NegReg', (225, 235))	('downregulation', 'NegReg', (175, 189))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('enhances', 'PosReg', (71, 79))	('cancer', 'Disease', (99, 105))	('telomere stability', 'CPA', (239, 257))	('increase in radiosensitivity', 'Phenotype', 'HP:0010997', (265, 293))	('sensitivity', 'MPA', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('radiosensitivity', 'MPA', (277, 293))	('increase', 'PosReg', (265, 273))
505357	22570308	We have shown that pepsin, 0.1mg/ml at pH7 (and thus in non-acidic reflux) causes mitochondrial damage in vitro, induces the expression of multiple genes implicated in stress and toxicity, and induces a proinflammatory cytokine and receptor gene expression profile similar to that observed in patients with GERD.	('acidic reflux', 'Phenotype', 'HP:0002020', (60, 73))	('mitochondrial damage', 'MPA', (82, 102))	('causes', 'Reg', (75, 81))	('pH7', 'Var', (39, 42))	('toxicity', 'Disease', 'MESH:D064420', (179, 187))	('toxicity', 'Disease', (179, 187))	('expression', 'MPA', (125, 135))	('GERD', 'Disease', 'MESH:D005764', (307, 311))	('GERD', 'Disease', (307, 311))	('induces', 'PosReg', (113, 120))	('induces', 'Reg', (193, 200))	('patients', 'Species', '9606', (293, 301))	('pepsin', 'Var', (19, 25))
505387	22570308	Cell cycle analysis of propidium iodide stained FaDu cells treated with pepsin revealed a statistically significant increase in the percentage of cells in S phase following pepsin exposure with a clear dose response (Figure 1C and D).	('pepsin', 'Var', (173, 179))	('increase', 'PosReg', (116, 124))	('propidium iodide', 'Chemical', 'MESH:D011419', (23, 39))
505407	22570308	Although it has been well established that the proteolytic gastric enzyme pepsin contributes significantly to mucosal damage caused by acid reflux, our recent work indicates that pepsin can also induce laryngeal mucosal damage during nonacidic reflux.	('induce', 'Reg', (195, 201))	('mucosal damage', 'Disease', 'MESH:D009059', (110, 124))	('laryngeal mucosal damage', 'Disease', (202, 226))	('pepsin', 'Var', (179, 185))	('acidic reflux', 'Phenotype', 'HP:0002020', (237, 250))	('acid reflux', 'Phenotype', 'HP:0002020', (135, 146))	('mucosal damage', 'Disease', (110, 124))	('laryngeal mucosal damage', 'Disease', 'MESH:D007818', (202, 226))	('mucosal damage', 'Disease', 'MESH:D009059', (212, 226))
505425	23861839	Mitochondrial DNA (mtDNA) mutations, especially the mtDNA 4,977 bp deletion has been found in patients of various types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mtDNA', 'Gene', (52, 57))	('patients', 'Species', '9606', (94, 102))	('mtDNA', 'Gene', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutations', 'Var', (26, 35))	('found', 'Reg', (85, 90))	('cancer', 'Disease', (123, 129))
505428	23861839	In the stratified analysis by cancer type the deletion frequency was even lower in tumor tissue than in adjacent normal tissue of breast cancer (OR = 0.19, 95% CI = 0.06-0.61, P = 0.005 for heterogeneity test, I2 = 82.7%).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('deletion', 'Var', (46, 54))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('tumor', 'Disease', (83, 88))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('lower', 'NegReg', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
505429	23861839	Furthermore, when compared with the normal tissue from the matched healthy controls, increased deletion frequencies were observed in both adjacent non-cancerous tissue (OR = 3.02, 95% CI = 2.13-4.28, P<0.00001 for heterogeneity test, I2 = 53.7%), and cancerous tissue (OR = 1.36, 95% CI = 1.04-1.77, P = 0.02 for heterogeneity test, I2 = 83.5%).	('deletion', 'Var', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancerous', 'Disease', 'MESH:D009369', (251, 260))	('cancerous', 'Disease', 'MESH:D009369', (151, 160))	('cancerous', 'Disease', (251, 260))	('cancerous', 'Disease', (151, 160))
505435	23861839	Defects in mitochondrial function have long been hypothesized to play a role in tumorigenesis, and a large number of mtDNA mutations have been detected in a variety of cancers.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('Defects in mitochondrial function', 'Phenotype', 'HP:0003287', (0, 33))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Defects', 'Var', (0, 7))	('tumor', 'Disease', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('mitochondrial function', 'MPA', (11, 33))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('detected', 'Reg', (143, 151))	('mutations', 'Var', (123, 132))	('mtDNA', 'Gene', (117, 122))
505436	23861839	Reported sequence changes in cancer patients including point mutations, multiple deletions and microsatellite instability (MSI) in coding and noncoding regions.	('cancer', 'Disease', (29, 35))	('MSI', 'Disease', (123, 126))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('point mutations', 'Var', (55, 70))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('MSI', 'Disease', 'None', (123, 126))	('multiple deletions', 'Var', (72, 90))	('microsatellite', 'MPA', (95, 109))
505437	23861839	One of the best-described mtDNA mutation is the mtDNA 4,977 bp or common deletion, which deletes between nucleotides 8,470 and 13,447 of the human mtDNA.	('mtDNA', 'Gene', (48, 53))	('deletes', 'NegReg', (89, 96))	('human', 'Species', '9606', (141, 146))	('mtDNA', 'Gene', (26, 31))	('mutation', 'Var', (32, 40))
505438	23861839	The mitochondrial common deletion has attracted tremendous interests as it is associate with several sporadic diseases including myopathies, Alzheimer disease, Pearson' s syndrome, photoaging of the skin, Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO).	('Kearns-Sayre syndrome', 'Disease', (205, 226))	("Pearson' s syndrome", 'Disease', (160, 179))	('CPEO', 'Phenotype', 'HP:0000544', (283, 287))	('ophthalmoplegia', 'Phenotype', 'HP:0000602', (266, 281))	('chronic progressive external ophthalmoplegia', 'Phenotype', 'HP:0000544', (237, 281))	('myopathies', 'Phenotype', 'HP:0003198', (129, 139))	('progressive external ophthalmoplegia', 'Phenotype', 'HP:0000590', (245, 281))	('myopathies', 'Disease', (129, 139))	('KSS', 'Disease', (228, 231))	("Pearson' s syndrome", 'Disease', 'MESH:C536353', (160, 179))	('progressive external ophthalmoplegia', 'Disease', (245, 281))	('KSS', 'Disease', 'MESH:D007625', (228, 231))	('Kearns-Sayre syndrome', 'Disease', 'MESH:D007625', (205, 226))	('Alzheimer disease', 'Phenotype', 'HP:0002511', (141, 158))	('myopathies', 'Disease', 'MESH:D009135', (129, 139))	('common deletion', 'Var', (18, 33))	('Alzheimer disease', 'Disease', (141, 158))	('progressive external ophthalmoplegia', 'Disease', 'MESH:D017246', (245, 281))	('Alzheimer disease', 'Disease', 'MESH:D000544', (141, 158))
505439	23861839	Although many studies associate this common deletion with tumorigenesis, results from population studies remain conflicting rather than conclusive.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('deletion', 'Var', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
505442	23861839	Mitochondrial DNA deletions serve as biomarkers of aging in the skin, but are typically absent in non melanoma skin cancers.	('Mitochondrial DNA', 'Gene', (0, 17))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma skin cancers', 'Disease', (102, 123))	('skin cancer', 'Phenotype', 'HP:0008069', (111, 122))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('deletions', 'Var', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('skin cancers', 'Phenotype', 'HP:0008069', (111, 123))	('melanoma skin cancers', 'Disease', 'MESH:D012878', (102, 123))
505443	23861839	Thus, the role of this common deletion in tumorigenesis is intriguing, but largely perplexing, and each of these single studies may have been underpowered to detect the association between mtDNA common deletion and cancers because of their small sample size.	('tumor', 'Disease', (42, 47))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('cancers', 'Disease', (215, 222))	('association', 'Interaction', (169, 180))	('deletion', 'Var', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('mtDNA', 'Gene', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
505447	23861839	The following information was extracted from all included publications: the first author, year of publication, cancer types, total number of cases and controls, country and ethnicity of the study population, DNA source, number of included patients, deletion detection method and deletion results of each study.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (239, 247))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('deletion', 'Var', (279, 287))	('deletion detection', 'Var', (249, 267))
505459	23861839	In the stratified analysis by cancer type ( Table 2 ), we found that the difference of detection of 4,977 bp deletion in cancerous samples and corresponding non-cancerous breast samples was more pronounced (OR = 0.19, 95% CI = 0.06-0.61, P = 0.005 for heterogeneity test, I2 = 82.7%;  Fig.	('cancerous', 'Disease', (121, 130))	('cancerous', 'Disease', 'MESH:D009369', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('deletion', 'Var', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (30, 36))	('cancerous', 'Disease', 'MESH:D009369', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancerous', 'Disease', (161, 170))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
505462	23861839	Interestingly, we found the difference in deletion frequency in cancer tissue and in adjacent non-cancerous tissue was becoming more significant when the sample size is larger than 50 (OR = 0.70, 95% CI = 0.58-0.86, P = 0.0005 for heterogeneity test, I2 = 95.1%;  Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancerous', 'Disease', (98, 107))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('deletion', 'Var', (42, 50))	('cancerous', 'Disease', 'MESH:D009369', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
505467	23861839	In this meta-analysis of 1613 cancer cases, 1516 adjacent normals and 638 healthy controls from 33 independent publications, while the mtDNA 4,977 bp deletion was found in both cancerous and adjacent normal tissue, when compared to matched healthy controls, the deletion frequency was significantly lower in tumor tissue than in adjacent non-cancerous tissue among various types of cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', (342, 348))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('cancerous', 'Disease', 'MESH:D009369', (177, 186))	('deletion', 'Var', (262, 270))	('cancerous', 'Disease', 'MESH:D009369', (342, 351))	('cancer', 'Disease', (382, 388))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('cancer', 'Disease', (30, 36))	('cancerous', 'Disease', (177, 186))	('cancerous', 'Disease', (342, 351))	('tumor', 'Disease', (308, 313))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('lower', 'NegReg', (299, 304))	('tumor', 'Disease', 'MESH:D009369', (308, 313))
505473	23861839	For example, the study of Ye found that though all of their samples carry mtDNA 4,977 bp large deletion, they thought there was no correlation between mtDNA 4,977 bp common deletion and cancer risk; Tseng et al demonstrated that the detection frequency of common deletion was more higher in adjacent normal tissue than carcinoma tissue in their 60 breast cancer patients from Taiwan; meanwhile, the analysis of Dani concurred with the results from Tseng in several cancer types.	('patients', 'Species', '9606', (362, 370))	('carcinoma', 'Disease', (319, 328))	('breast cancer', 'Disease', (348, 361))	('cancer', 'Disease', 'MESH:D009369', (465, 471))	('cancer', 'Phenotype', 'HP:0002664', (465, 471))	('higher', 'PosReg', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (465, 471))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('carcinoma', 'Disease', 'MESH:D002277', (319, 328))	('common deletion', 'Var', (256, 271))	('breast cancer', 'Disease', 'MESH:D001943', (348, 361))	('breast cancer', 'Phenotype', 'HP:0003002', (348, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('cancer', 'Disease', (355, 361))	('cancer', 'Disease', 'MESH:D009369', (355, 361))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
505474	23861839	The mtDNA 4,977 bp common deletion mutations is a highly non-specific mutation and as mentioned before has been seen in degenerative disorders as well as in healthy tissues.	('degenerative disorders', 'Disease', (120, 142))	('mtDNA', 'Gene', (4, 9))	('common deletion mutations', 'Var', (19, 44))	('degenerative disorders', 'Disease', 'MESH:D019636', (120, 142))
505475	23861839	Clearly, other cellular as well as tissue specific environmental factors may also affect the outcome of this mutation on the cell survival and tumorigenesis.	('tumor', 'Disease', (143, 148))	('cell survival', 'CPA', (125, 138))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('affect', 'Reg', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('mutation', 'Var', (109, 117))
505478	23861839	Our previous studies have shown that heteroplasmic DNA mutation, where the burden of mutation is less, was more tumorigenic than homoplasmic mutation where all mtDNA is mutated.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('heteroplasmic DNA', 'Var', (37, 54))	('more', 'PosReg', (107, 111))
505479	23861839	Our studies have also shown a difference in the retrograde signaling pathways between homoplasmic mitochondria and heteoplasmic mitochondria with lesser load of a particular mutation activating survival pathways involving ROS and Akt thus making cells tumorigenic while inhibition of tumorigenesis was seen in cells with homoplasmic mutations.	('ROS', 'Protein', (222, 225))	('mutation', 'Var', (174, 182))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('Akt', 'Gene', '207', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('survival pathways', 'Pathway', (194, 211))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('activating', 'PosReg', (183, 193))	('heteoplasmic mitochondria', 'Disease', (115, 140))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumor', 'Disease', (252, 257))	('heteoplasmic mitochondria', 'Disease', 'MESH:C564925', (115, 140))	('tumor', 'Disease', (284, 289))	('ROS', 'Chemical', 'MESH:D017382', (222, 225))	('Akt', 'Gene', (230, 233))
505480	23861839	This supports our hypothesis that a larger mutation load may be required during early stages to tumor development, the mutation being then selected against if the cells have to continue the proliferative growth leading to a greater frequency of mutations in adjacent normal tissue as compared to cancerous tissue.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('mutations', 'Var', (245, 254))	('cancerous', 'Disease', 'MESH:D009369', (296, 305))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancerous', 'Disease', (296, 305))
505490	23861839	Furthermore, the significantly lower mtDNA 4,977 bp deletion frequency in cancer tissue compared with adjacent non-cancerous tissue of larger sample size studies (OR = 0.70, 95% CI = 0.58-0.86, P = 0.0005 for heterogeneity test, I2 = 95.1%) suggests to us that genetic risk of cancer conferred by the common variants was very modest and the penetrance of the variants was very small, which means that even if the variation was crucial for carcinogenesis, extremely large-scale evidence would be necessary to establish with high confidence the presence of specific associations.	('cancer', 'Disease', (115, 121))	('cancerous', 'Disease', (115, 124))	('cancer', 'Disease', (277, 283))	('carcinogenesis', 'Disease', 'MESH:D063646', (439, 453))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lower', 'NegReg', (31, 36))	('cancer', 'Disease', (74, 80))	('carcinogenesis', 'Disease', (439, 453))	('cancerous', 'Disease', 'MESH:D009369', (115, 124))	('variants', 'Var', (308, 316))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('deletion', 'Var', (52, 60))
505491	23861839	However, the results from stratification analysis by measurement method indicated that the tumor tissue deletion frequency was also lower than the adjacent non-cancerous tissue in studies with the detection method of regular PCR (OR = 0.39, 95% CI = 0.18-0.86, P = 0.02 for heterogeneity test, I2 = 91.7%).	('cancerous', 'Disease', (160, 169))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancerous', 'Disease', 'MESH:D009369', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lower', 'NegReg', (132, 137))	('deletion', 'Var', (104, 112))
505557	31908387	In addition, focal areas of brown fat, asymmetric uptake in the vocal cords, and vessel atherosclerosis may lead to false-positive results, although these areas are generally better differentiated from areas of esophageal uptake on PET/CT, rather than on PET images.	('atherosclerosis', 'Phenotype', 'HP:0002621', (88, 103))	('atherosclerosis', 'Disease', 'MESH:D050197', (88, 103))	('asymmetric', 'Var', (39, 49))	('atherosclerosis', 'Disease', (88, 103))
505567	31915702	Genetic variants and other prominent etiological factors encompassing BE (neoplastic precursor lesion of EAC), gastroesophageal reflux disease (GERD), and Helicobacter pylori infection (inverse relation to BE and EAC) played a dominant role in EAC development.	('EAC', 'Disease', (244, 247))	('gastroesophageal reflux disease', 'Disease', (111, 142))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (111, 134))	('Helicobacter pylori infection', 'Disease', (155, 184))	('GERD', 'Disease', 'MESH:D005764', (144, 148))	('Helicobacter pylori infection', 'Disease', 'MESH:D016481', (155, 184))	('GERD', 'Disease', (144, 148))	('EAC', 'Disease', (105, 108))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (155, 184))	('Genetic variants', 'Var', (0, 16))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (111, 142))
505580	31527621	In addition, Rab1A knockdown significantly inhibited the in vitro proliferation and migration abilities of GC cells, as well as the growth of GC xenografts in vivo.	('GC', 'Disease', 'MESH:D013274', (107, 109))	('GC', 'Disease', 'MESH:D013274', (142, 144))	('inhibited', 'NegReg', (43, 52))	('knockdown', 'Var', (19, 28))	('GC', 'Phenotype', 'HP:0012126', (107, 109))	('GC', 'Phenotype', 'HP:0012126', (142, 144))	('growth', 'CPA', (132, 138))	('Rab1A', 'Gene', (13, 18))	('in vitro proliferation', 'CPA', (57, 79))
505616	31527621	3B), and the OS of the Rab1Ahi group was considerably lower compared to that of the Rab1Alo patients (P < 0.001) (Fig.	('Rab1Ahi', 'Var', (23, 30))	('patients', 'Species', '9606', (92, 100))	('lower', 'NegReg', (54, 59))
505618	31527621	To further explore the relationship between mTOR targets and Rab1A in GC, we knocked down Rab1A in the MKN45 and MGC803 cells using the specific shRNA (Fig.	('GC', 'Disease', 'MESH:D013274', (70, 72))	('GC', 'Disease', 'MESH:D013274', (114, 116))	('knocked', 'Var', (77, 84))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('GC', 'Phenotype', 'HP:0012126', (114, 116))	('mTOR', 'Gene', (44, 48))	('mTOR', 'Gene', '2475', (44, 48))	('Rab1A', 'Gene', (90, 95))
505620	31527621	Interestingly, the p-S6K and GLI1 levels decreased significantly after Rab1A knockdown (P < 0.05, Fig.	('p-S6K', 'Gene', (19, 24))	('decreased', 'NegReg', (41, 50))	('Rab1A', 'Gene', (71, 76))	('knockdown', 'Var', (77, 86))	('GLI1', 'Gene', '2735', (29, 33))	('GLI1', 'Gene', (29, 33))	('p-S6K', 'Gene', '6198', (19, 24))
505622	31527621	Furthermore, knocking down AKT significantly downregulated p-mTOR and GLI1 (P < 0.05, Fig.	('knocking down', 'Var', (13, 26))	('AKT', 'Gene', (27, 30))	('GLI1', 'Gene', '2735', (70, 74))	('GLI1', 'Gene', (70, 74))	('AKT', 'Gene', '207', (27, 30))	('downregulated', 'NegReg', (45, 58))	('mTOR', 'Gene', (61, 65))	('mTOR', 'Gene', '2475', (61, 65))
505627	31527621	Furthermore, the chemo-sensitivity of both cell lines treated with cisplatin for 48 hours increased significantly upon Rab1A knockdown (P < 0.05, Fig.	('knockdown', 'Var', (125, 134))	('increased', 'PosReg', (90, 99))	('chemo-sensitivity', 'MPA', (17, 34))	('Rab1A', 'Gene', (119, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))
505634	31527621	Furthermore, it indicated the body weight without tumor weight treated with Rab1A depletion was significant heavier than the control group mice, which reached an obviously difference (P < 0.05, Fig.	('body weight', 'CPA', (30, 41))	('depletion', 'Var', (82, 91))	('heavier', 'PosReg', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mice', 'Species', '10090', (139, 143))	('tumor', 'Disease', (50, 55))	('Rab1A', 'Gene', (76, 81))
505657	31527621	Furthermore, p-S6K and GLI1 levels decreased significantly in human GC cell lines after knocking down Rab1A, while that of HER2 and p-AKT were unaffected.	('AKT', 'Gene', (134, 137))	('human', 'Species', '9606', (62, 67))	('Rab1A', 'Gene', (102, 107))	('HER2', 'Gene', (123, 127))	('decreased', 'NegReg', (35, 44))	('p-S6K', 'Gene', (13, 18))	('GLI1', 'Gene', '2735', (23, 27))	('HER2', 'Gene', '2064', (123, 127))	('knocking down', 'Var', (88, 101))	('GC', 'Disease', 'MESH:D013274', (68, 70))	('GLI1', 'Gene', (23, 27))	('AKT', 'Gene', '207', (134, 137))	('p-S6K', 'Gene', '6198', (13, 18))	('GC', 'Phenotype', 'HP:0012126', (68, 70))
505658	31527621	Furthermore, p-mTOR and GLI1 expression was also significantly reduced after AKT knockdown, while no significant change was observed in SMO expression levels.	('AKT', 'Gene', '207', (77, 80))	('GLI1', 'Gene', (24, 28))	('reduced', 'NegReg', (63, 70))	('mTOR', 'Gene', (15, 19))	('mTOR', 'Gene', '2475', (15, 19))	('knockdown', 'Var', (81, 90))	('AKT', 'Gene', (77, 80))	('expression', 'MPA', (29, 39))	('GLI1', 'Gene', '2735', (24, 28))	('SMO', 'Gene', '6608', (136, 139))	('SMO', 'Gene', (136, 139))
505659	31527621	Finally, p-AKT and SMO levels were also unaffected by GLI1 knockdown.	('AKT', 'Gene', (11, 14))	('GLI1', 'Gene', '2735', (54, 58))	('SMO', 'Gene', (19, 22))	('AKT', 'Gene', '207', (11, 14))	('knockdown', 'Var', (59, 68))	('SMO', 'Gene', '6608', (19, 22))	('GLI1', 'Gene', (54, 58))
505664	31527621	In vitro proliferation and migration abilities of the GC cells were significantly inhibited in the absence of Rab1A, and the xenografts of the Rab1A-knockdown GC cells also grew slower in vivo.	('Rab1A-knockdown', 'Gene', (143, 158))	('GC', 'Disease', 'MESH:D013274', (159, 161))	('inhibited', 'NegReg', (82, 91))	('slower', 'NegReg', (178, 184))	('absence', 'Var', (99, 106))	('grew', 'CPA', (173, 177))	('GC', 'Disease', 'MESH:D013274', (54, 56))	('GC', 'Phenotype', 'HP:0012126', (159, 161))	('GC', 'Phenotype', 'HP:0012126', (54, 56))	('migration abilities', 'CPA', (27, 46))
505665	31527621	These findings clearly showed that Rab1A is essential for GC tumor growth and metastasis, and that silencing Rab1A expression can result in a survival benefit.	('survival benefit', 'CPA', (142, 158))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Rab1A', 'Gene', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('silencing', 'Var', (99, 108))	('tumor', 'Disease', (61, 66))	('GC', 'Disease', 'MESH:D013274', (58, 60))
505666	31527621	In conclusion, pharmacological inhibition of Rab1A is a promising targeted therapeutic strategy against GC.	('GC', 'Phenotype', 'HP:0012126', (104, 106))	('GC', 'Disease', 'MESH:D013274', (104, 106))	('pharmacological', 'Var', (15, 30))	('Rab1A', 'Gene', (45, 50))
505670	31527621	Rab1A knockdown significantly abrogated GC cell growth in vitro and inhibited tumor progression in vivo, indicating a novel therapeutic target against gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (151, 174))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('inhibited', 'NegReg', (68, 77))	('GC', 'Disease', 'MESH:D013274', (40, 42))	('Rab1A', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('GC', 'Phenotype', 'HP:0012126', (40, 42))	('tumor', 'Disease', (78, 83))	('knockdown', 'Var', (6, 15))	('gastrointestinal cancers', 'Disease', (151, 175))	('abrogated', 'NegReg', (30, 39))	('gastrointestinal cancers', 'Disease', 'MESH:D005770', (151, 175))
505705	30450849	Meanwhile, others found that the growth of bladder cancer cells is inhibited upon transfection with si-PLCE1.	('bladder cancer', 'Phenotype', 'HP:0009725', (43, 57))	('inhibited', 'NegReg', (67, 76))	('transfection', 'Var', (82, 94))	('bladder cancer', 'Disease', 'MESH:D001749', (43, 57))	('bladder cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('growth', 'CPA', (33, 39))	('PLCE1', 'Gene', (103, 108))	('PLCE1', 'Gene', '51196', (103, 108))	('si', 'Chemical', 'MESH:D012825', (100, 102))
505741	30450849	The expression of PLCE1 in Eca109 and EC9706 cells was higher than that in HEEC (p=0.002, p=0.003) (Fig.	('EC9706', 'CellLine', 'CVCL:E307', (38, 44))	('expression', 'MPA', (4, 14))	('PLCE1', 'Gene', (18, 23))	('EC9706', 'Var', (38, 44))	('PLCE1', 'Gene', '51196', (18, 23))	('higher', 'PosReg', (55, 61))	('si', 'Chemical', 'MESH:D012825', (10, 12))
505742	30450849	Similarly, the expression of PKCalpha was significantly increased in Eca109 and EC9706 (p=0.005, p=0.007), compared to HEEC (Fig.	('EC9706', 'Var', (80, 86))	('increased', 'PosReg', (56, 65))	('PKCalpha', 'Gene', (29, 37))	('PKCalpha', 'Gene', '5578', (29, 37))	('expression', 'MPA', (15, 25))	('EC9706', 'CellLine', 'CVCL:E307', (80, 86))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('Eca109', 'Var', (69, 75))
505766	30450849	Studies have shown that gene mutation, allele high frequency heterozygosity deletion, and tumor suppressor gene inactivation could promote the development of esophageal cancer.	('inactivation', 'Var', (112, 124))	('esophageal cancer', 'Disease', (158, 175))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('allele high frequency heterozygosity deletion', 'Var', (39, 84))	('gene mutation', 'Var', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('men', 'Species', '9606', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('promote', 'PosReg', (131, 138))
505767	30450849	Moreover, current research has shown that mutation of PLCE1 might promote the development of cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('promote', 'PosReg', (66, 73))	('PLCE1', 'Gene', (54, 59))	('mutation', 'Var', (42, 50))	('PLCE1', 'Gene', '51196', (54, 59))	('men', 'Species', '9606', (85, 88))
505768	30450849	Furthermore, two genome-wide association studies on large samples have identified a new esophageal cancer susceptibility locus, rs2274223, on PLCE1 on chromosome 10q23.	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('PLCE1', 'Gene', (142, 147))	('PLCE1', 'Gene', '51196', (142, 147))	('rs2274223', 'Mutation', 'rs2274223', (128, 137))	('rs2274223', 'Var', (128, 137))	('esophageal cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
505769	30450849	found that PLCE1 rs2274223 could be used to predict the risk of esophageal cancer.	('esophageal cancer', 'Disease', (64, 81))	('rs2274223', 'Mutation', 'rs2274223', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs2274223', 'Var', (17, 26))	('PLCE1', 'Gene', (11, 16))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('PLCE1', 'Gene', '51196', (11, 16))
505770	30450849	revealed that PLCE1 rs2274223 polymorphism is associated with esophageal cancer.	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('associated', 'Reg', (46, 56))	('rs2274223', 'Mutation', 'rs2274223', (20, 29))	('rs2274223', 'Var', (20, 29))	('PLCE1', 'Gene', (14, 19))	('PLCE1', 'Gene', '51196', (14, 19))
505789	30450849	Also, high density lipoprotein promoted the inflammatory effect of macrophages through PKCalpha/NF-kappaB signaling.	('si', 'Chemical', 'MESH:D012825', (14, 16))	('PKCalpha', 'Gene', (87, 95))	('PKCalpha', 'Gene', '5578', (87, 95))	('NF-kappaB', 'Gene', '4790', (96, 105))	('promoted', 'PosReg', (31, 39))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('high density', 'Var', (6, 18))	('NF-kappaB', 'Gene', (96, 105))	('inflammatory effect of macrophages', 'CPA', (44, 78))
505791	30450849	Due to limitations of experimental conditions, only silencing PLCE1 was applied in this study to test our hypothesis of PLCE1 activating NF-kB through PKCa, and additional experiments will be needed to show how PLCE1 modulates the NF-kB pathway.	('PLCE1', 'Gene', '51196', (62, 67))	('silencing', 'Var', (52, 61))	('men', 'Species', '9606', (178, 181))	('men', 'Species', '9606', (28, 31))	('modulates', 'Reg', (217, 226))	('PKCa', 'Gene', '5578', (151, 155))	('PLCE1', 'Gene', (211, 216))	('PLCE1', 'Gene', (120, 125))	('PKCa', 'Gene', (151, 155))	('PLCE1', 'Gene', '51196', (211, 216))	('PLCE1', 'Gene', '51196', (120, 125))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('NF-kB pathway', 'Pathway', (231, 244))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('PLCE1', 'Gene', (62, 67))	('NF-kB', 'Gene', (137, 142))	('activating', 'PosReg', (126, 136))
505820	29463907	In addition to this chemical injury, disruption of the mucosal barrier in the setting of sustained acid likely triggers a local inflammatory response, though this has been more definitively demonstrated in the esophagus in a gastroesophageal reflux disease model.	('disruption', 'Var', (37, 47))	('gastroesophageal reflux disease', 'Disease', (225, 256))	('sustained acid', 'Chemical', '-', (89, 103))	('rat', 'Species', '10116', (197, 200))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (225, 248))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (225, 256))	('triggers', 'Reg', (111, 119))
505982	29463907	Studies in pancreas and other models of tumorigenesis indicate that certain oncogenic mutations, like constitutively active K-Ras, do not have an effect in differentiated cells but can be unmasked when they are expressed in proliferating (i.e., metaplastic) cells.	('mutations', 'Var', (86, 95))	('rat', 'Species', '10116', (231, 234))	('pancreas', 'Disease', (11, 19))	('K-Ras', 'Gene', '3845', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('pancreas', 'Disease', 'MESH:D010190', (11, 19))	('K-Ras', 'Gene', (124, 129))
506005	29463907	As we begin to uncover the molecular players involved in this reprogramming sequence, we can begin to identify how specific mutations contribute to the development and progression of gastric cancer for millions of patients at risk.	('gastric cancer', 'Disease', (183, 197))	('mutations', 'Var', (124, 133))	('patients', 'Species', '9606', (214, 222))	('gastric cancer', 'Disease', 'MESH:D013274', (183, 197))	('contribute', 'Reg', (134, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
506133	27408893	18F-FDG PET/CT has an accuracy of 83.7% in detecting nodal metastases, while CT scan alone exhibits an accuracy of 76.6%.	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('18F-FDG', 'Var', (0, 7))	('metastases', 'Disease', (59, 69))	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))
506218	26023036	There was a significant decrease in the percentage of conversions between the first group of 54 patients and the second group of 54 patients (13 [24 %] vs. 7 [13 %], respectively; p < 0.001).	('decrease', 'NegReg', (24, 32))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (132, 140))	('conversions', 'Var', (54, 65))
506264	26023036	Results from this trial showed a reduced pulmonary complication rate in the MIE group compared with the open group.	('MIE', 'Chemical', '-', (76, 79))	('pulmonary complication rate', 'CPA', (41, 68))	('MIE', 'Var', (76, 79))	('reduced', 'NegReg', (33, 40))
506281	25493573	Genetic variation in this important enzyme such as SNPs can vary by ethnicity and have functional consequences on its activity.	('activity', 'MPA', (118, 126))	('consequences', 'Reg', (98, 110))	('Genetic variation', 'Var', (0, 17))	('N', 'Chemical', 'MESH:D009584', (52, 53))
506283	25493573	Highlighted here are not only this SNP, but other genetic variants associated with SULT1A1 that could modify drug efficacy and xenobiotic metabolism.	('N', 'Chemical', 'MESH:D009584', (36, 37))	('variants', 'Var', (58, 66))	('xenobiotic metabolism', 'Disease', (127, 148))	('SULT1A1', 'Gene', (83, 90))	('modify drug efficacy', 'Phenotype', 'HP:0020173', (102, 122))	('modify', 'Reg', (102, 108))	('xenobiotic metabolism', 'Disease', 'MESH:D008659', (127, 148))	('SULT1A1', 'Gene', '6817', (83, 90))	('drug efficacy', 'MPA', (109, 122))
506285	25493573	This review will focus primarily on the impact of SULT1A1 genetic variation on the response to anticancer therapeutic agents and subsequently how it relates to environmental and dietary exposure to both cancer-causing and cancer-preventative compounds.	('genetic variation', 'Var', (58, 75))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('SULT1A1', 'Gene', '6817', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (222, 228))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('SULT1A1', 'Gene', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
506296	25493573	Additionally, in 2007, copy number variation (CNV) was described in SULT1A1.	('copy number variation', 'Var', (23, 44))	('SULT1A1', 'Gene', '6817', (68, 75))	('SULT1A1', 'Gene', (68, 75))	('N', 'Chemical', 'MESH:D009584', (47, 48))
506297	25493573	Copy number was associated with enzymatic activity, and African-American subjects were significantly more likely to have higher CNV than Caucasians, providing a potential biological basis for the observation that African-Americans tend to have higher basal platelet SULT1A1 activity than Caucasians.	('SULT1A1', 'Gene', '6817', (266, 273))	('CNV', 'MPA', (128, 131))	('basal', 'MPA', (251, 256))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('activity', 'MPA', (274, 282))	('Copy number', 'Var', (0, 11))	('higher', 'PosReg', (244, 250))	('SULT1A1', 'Gene', (266, 273))
506302	25493573	A recent genotype/phenotype association study in a Japanese population demonstrated that CNV was the strongest predictor of SULT1A1 platelet activity, and that all variants combined predicted only 14% of the observed variability in this population.	('CNV', 'MPA', (89, 92))	('variants', 'Var', (164, 172))	('SULT1A1', 'Gene', (124, 131))	('SULT1A1', 'Gene', '6817', (124, 131))	('N', 'Chemical', 'MESH:D009584', (90, 91))
506322	25493573	The role SULT1A1 genetic variation plays in the pharmacokinetics of TAM has also been evaluated.	('SULT1A1', 'Gene', '6817', (9, 16))	('genetic variation', 'Var', (17, 34))	('TAM', 'Chemical', 'MESH:D013629', (68, 71))	('SULT1A1', 'Gene', (9, 16))
506323	25493573	To determine whether genetic variation in TAM-metabolizing enzymes would influence TAM active metabolite bioavailability, Jin et al.	('TAM', 'Chemical', 'MESH:D013629', (83, 86))	('influence', 'Reg', (73, 82))	('TAM active metabolite bioavailability', 'MPA', (83, 120))	('TAM', 'Chemical', 'MESH:D013629', (42, 45))	('genetic variation', 'Var', (21, 38))
506325	25493573	They found that plasma concentrations of TAM and its metabolites were not significantly affected by SULT1A1*1/2 genotype.	('genotype', 'Var', (112, 120))	('SULT1A1', 'Gene', '6817', (100, 107))	('TAM', 'Chemical', 'MESH:D013629', (41, 44))	('SULT1A1', 'Gene', (100, 107))
506326	25493573	However, a trend toward higher concentrations of the active metabolites of TAM, 4-hydroxy-TAM (4-OHT) and endoxifen, could be seen among carriers of the *2/*2 genotype.	('TAM', 'Chemical', 'MESH:D013629', (90, 93))	('concentrations', 'MPA', (31, 45))	('active metabolites', 'MPA', (53, 71))	('TAM', 'Chemical', 'MESH:D013629', (75, 78))	('4-OHT', 'Chemical', 'MESH:C032278', (95, 100))	('higher', 'PosReg', (24, 30))	('4-hydroxy-TAM', 'Chemical', '-', (80, 93))	('endoxifen', 'Chemical', 'MESH:C055492', (106, 115))	('*2/*2', 'Var', (153, 158))
506337	25493573	They also observed a gene-dose effect of increasing metabolic ratios with increasing copies of SULT1A1.	('SULT1A1', 'Gene', (95, 102))	('SULT1A1', 'Gene', '6817', (95, 102))	('copies', 'Var', (85, 91))	('increasing', 'PosReg', (41, 51))	('metabolic ratios', 'MPA', (52, 68))
506339	25493573	SULT1A1 variation has been studied in vitro for its effects on other therapeutic agents it metabolizes.	('SULT1A1', 'Gene', (0, 7))	('variation', 'Var', (8, 17))	('SULT1A1', 'Gene', '6817', (0, 7))
506344	25493573	Fulvestrant is a pure antiestrogen that is approved to treat hormone receptor-positive metastatic breast cancer in postmenopausal women and its sulfation was correlated with both SULT1A1*1/2 genotype (p = 0.023) and copy number (p < 0.0001).	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('SULT1A1', 'Gene', (179, 186))	('women', 'Species', '9606', (130, 135))	('copy number', 'Var', (216, 227))	('cancer in postmenopausal women', 'Phenotype', 'HP:0008209', (105, 135))	('SULT1A1', 'Gene', '6817', (179, 186))	('correlated', 'Reg', (158, 168))	('sulfation', 'MPA', (144, 153))	('Fulvestrant', 'Chemical', 'MESH:D000077267', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
506347	25493573	SULT1A1 copy number (pANOVA = <0.0001) was significantly associated with 4-hydroxy-TOR sulfation demonstrating increasing activity with increasing copies.	('N', 'Chemical', 'MESH:D009584', (23, 24))	('SULT1A1', 'Gene', (0, 7))	('4-hydroxy-TOR', 'Chemical', 'MESH:C062262', (73, 86))	('4-hydroxy-TOR sulfation', 'MPA', (73, 96))	('SULT1A1', 'Gene', '6817', (0, 7))	('increasing', 'PosReg', (111, 121))	('copy number', 'Var', (8, 19))	('activity', 'MPA', (122, 130))
506350	25493573	postulated that variations in enzymatic activity of sulfotransferases due to SNPs could influence breast cancer risk when they observed an increase in gene expression of the SULT1A subfamily of phenol SULTs in ZR75-1 human breast carcinoma cells by 4-OHT treatment.	('4-OHT', 'Chemical', 'MESH:C032278', (249, 254))	('influence', 'Reg', (88, 97))	('human', 'Species', '9606', (217, 222))	('gene expression', 'MPA', (151, 166))	('phenol', 'Chemical', 'MESH:D019800', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('SNPs', 'Gene', (77, 81))	('ZR75-1', 'CellLine', 'CVCL:0588', (210, 216))	('breast carcinoma', 'Disease', 'MESH:D001943', (223, 239))	('variations', 'Var', (16, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('increase', 'PosReg', (139, 147))	('breast carcinoma', 'Phenotype', 'HP:0003002', (223, 239))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Disease', (98, 111))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('breast carcinoma', 'Disease', (223, 239))	('enzymatic', 'MPA', (30, 39))
506356	25493573	Since the original hypothesis, genetic variation in SULT1A1 alone has been found to have varying effects on the risk of developing cancer in multiple sites.	('cancer', 'Disease', (131, 137))	('genetic variation', 'Var', (31, 48))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('effects', 'Reg', (97, 104))	('SULT1A1', 'Gene', (52, 59))	('SULT1A1', 'Gene', '6817', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
506364	25493573	In platelet cytosols the SULT1A1*2 low-activity variant was shown to decrease its DNA-binding capability when compared with SULT1A1*1.	('low-activity', 'NegReg', (35, 47))	('SULT1A1', 'Gene', '6817', (124, 131))	('SULT1A1', 'Gene', (25, 32))	('decrease', 'NegReg', (69, 77))	('SULT1A1', 'Gene', (124, 131))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('SULT1A1', 'Gene', '6817', (25, 32))	('DNA-binding', 'Interaction', (82, 93))	('variant', 'Var', (48, 55))
506368	25493573	Studies examining the relationship between the consumption of well-done meat, SULT1A1 genetic variation and cancer risk have been performed (Table 3).	('SULT1A1', 'Gene', (78, 85))	('genetic variation', 'Var', (86, 103))	('SULT1A1', 'Gene', '6817', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
506369	25493573	A recent meta-analysis of available data revealed a slight increase in breast cancer risk among overall (odds ratio [OR]pooled overall = 1.12; 95% CI: 1.02-1.24) and postmenopausal (ORpooled post = 1.17; 95% CI: 1.03-1.32) carriers of the SULT1A1*2 low-activity variant allele.	('SULT1A1', 'Gene', (239, 246))	('breast cancer', 'Disease', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('SULT1A1', 'Gene', '6817', (239, 246))	('low-activity', 'NegReg', (249, 261))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('variant', 'Var', (262, 269))
506372	25493573	However, upon further investigation, a positive interaction between high smoked meat intake and the SULT1A1*2 low-activity variant allele resulted.	('variant', 'Var', (123, 130))	('SULT1A1', 'Gene', '6817', (100, 107))	('low-activity', 'NegReg', (110, 122))	('SULT1A1', 'Gene', (100, 107))
506375	25493573	Another colorectal cancer study corroborated this finding, with colorectal cancer risk increasing when variants of SULT1A1 and a phase I metabolic enzyme, CYP1B1, were incorporated into the analysis along with red meat doneness intake.	('colorectal cancer', 'Disease', (64, 81))	('incorporated', 'Reg', (168, 180))	('colorectal cancer', 'Disease', 'MESH:D015179', (8, 25))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('CYP1B1', 'Gene', '1545', (155, 161))	('variants', 'Var', (103, 111))	('CYP1B1', 'Gene', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (8, 25))	('SULT1A1', 'Gene', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('increasing', 'PosReg', (87, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('SULT1A1', 'Gene', '6817', (115, 122))	('colorectal cancer', 'Disease', (8, 25))
506388	25493573	The link between this environmental exposure and SULT1A1 genetic variation and cancer risk has been explored (Table 4).	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SULT1A1', 'Gene', (49, 56))	('genetic variation', 'Var', (57, 74))	('SULT1A1', 'Gene', '6817', (49, 56))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
506396	25493573	Within the smoking population there were only marginally significant increases in risk between carriers of the SULT1A1*2 allele and susceptibility to both lung and esophageal cancers in the random-effects model (OR: 1.49, 95% CI: 0.99-2.24, p = 0.058; OR: 1.46, 95% CI: 1.00-2.14, p = 0.052, respectively).	('SULT1A1', 'Gene', '6817', (111, 118))	('lung and esophageal cancers', 'Disease', 'MESH:D004938', (155, 182))	('carriers', 'Var', (95, 103))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('SULT1A1', 'Gene', (111, 118))	('susceptibility', 'Reg', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
506397	25493573	When subgroup analysis by ethnicity was performed, a stronger association between *2 carriers and cancer risk was clear among Asian smokers compared with Caucasian smokers (OR Asians: 2.00, 95% CI: 1.55-2.57, p < 0.001; OR Caucasians: 1.22, 95% CI: 1.02-1.46, p = 0.031).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carriers', 'Var', (85, 93))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
506398	25493573	observed a significant increase in lung cancer risk among smokers with the variant SULT1A1*2 allele (OR: 1.85; 95% CI: 1.44-2.37).	('increase in lung cancer', 'Disease', 'MESH:D008175', (23, 46))	('variant', 'Var', (75, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('SULT1A1', 'Gene', (83, 90))	('SULT1A1', 'Gene', '6817', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('increase in lung cancer', 'Disease', (23, 46))
506407	25493573	A Brazilian study with 202 oral cancer cases and 196 sex- and age-frequency matched controls also reported increases in the risk of oral cancer and cigarette smoking regardless of SULT1A1 genotype, but individuals with the high-activity *1/*1 genotype exhibited greater risk (OR: 10.19; 95% CI: 3.90-26.61) than those with at least one *2 allele (OR: 4.50; 95% CI: 2.09-9.69).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('oral cancer', 'Disease', 'MESH:D009062', (27, 38))	('high-activity *1/*1', 'Var', (223, 242))	('cigarette smoking', 'Disease', (148, 165))	('oral cancer', 'Disease', (27, 38))	('oral cancer', 'Disease', 'MESH:D009062', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('SULT1A1', 'Gene', (180, 187))	('oral cancer', 'Disease', (132, 143))	('SULT1A1', 'Gene', '6817', (180, 187))
506410	25493573	investigated gene CNV in male breast cancer patients and found that 10 out of 72 (13.9%) had gene deletions.	('patients', 'Species', '9606', (44, 52))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('male breast cancer', 'Disease', 'MESH:D018567', (25, 43))	('gene deletions', 'Var', (93, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('male breast cancer', 'Disease', (25, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
506411	25493573	Of the ten patients with gene deletions, all had one copy of SULT1A1 in the tumor samples and two copies in the corresponding blood samples, whereas copy number in blood and normal breast tissue were concordant.	('gene deletions', 'Var', (25, 39))	('SULT1A1', 'Gene', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('SULT1A1', 'Gene', '6817', (61, 68))	('patients', 'Species', '9606', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
506412	25493573	A link was also realized between SULT1A1 gene deletion and BRCA2 mutation (p = 0.0005) in a multivariate analysis.	('SULT1A1', 'Gene', (33, 40))	('BRCA2', 'Gene', '675', (59, 64))	('SULT1A1', 'Gene', '6817', (33, 40))	('mutation', 'Var', (65, 73))	('BRCA2', 'Gene', (59, 64))
506416	25493573	found that epicatechin gallate and epigallocatechin gallate (components of green tea) showed noncompetitive inhibition of SULT1A1 whereas with SULT1A2 and 1A3 they demonstrated mixed type inhibition, suggesting that the mechanism of inhibition varies depending on the individual isoform.	('epigallocatechin gallate', 'Chemical', 'MESH:C045651', (35, 59))	('SULT1A1', 'Gene', (122, 129))	('SULT1A1', 'Gene', '6817', (122, 129))	('SULT1A2', 'Gene', '6799', (143, 150))	('epicatechin gallate', 'Chemical', 'MESH:C062669', (11, 30))	('epigallocatechin gallate', 'Var', (35, 59))	('SULT1A2', 'Gene', (143, 150))	('noncompetitive inhibition', 'MPA', (93, 118))
506427	25493573	The authors conclude that red wine consumption does play a role in PhIP-DNA adduct variation but to a lesser extent than genetic variation.	('N', 'Chemical', 'MESH:D009584', (73, 74))	('PhIP-DNA', 'Gene', (67, 75))	('adduct', 'Var', (76, 82))	('variation', 'Var', (83, 92))	('PhIP', 'Chemical', 'MESH:C049584', (67, 71))
506430	25493573	These findings suggest that the bioavailability of active TAM metabolites due to variations in the most commonly studied coding region SNP, SULT1A1*1/2, and SULT1A1 copy number are not the major determining factors in TAM pharmacokinetics.	('bioavailability', 'MPA', (32, 47))	('SULT1A1', 'Gene', (140, 147))	('SULT1A1', 'Gene', (157, 164))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('SULT1A1', 'Gene', '6817', (140, 147))	('SULT1A1', 'Gene', '6817', (157, 164))	('TAM', 'Chemical', 'MESH:D013629', (218, 221))	('TAM', 'Chemical', 'MESH:D013629', (58, 61))	('variations', 'Var', (81, 91))
506436	25493573	When NF1-A, -B, -C and -X were knocked down with siRNA, SULT1A1 expression was also decreased.	('expression', 'MPA', (64, 74))	('N', 'Chemical', 'MESH:D009584', (5, 6))	('NF1', 'Gene', (5, 8))	('NF1', 'Gene', '4763', (5, 8))	('SULT1A1', 'Gene', (56, 63))	('knocked', 'Var', (31, 38))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('decreased', 'NegReg', (84, 93))	('SULT1A1', 'Gene', '6817', (56, 63))
506438	25493573	Taken all together, we are left with the knowledge that there is more to SULT1A1 variation than can be explained by functional SNPs, CNV and ethnic differences in allele frequency.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('variation', 'Var', (81, 90))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('SULT1A1', 'Gene', (73, 80))	('SULT1A1', 'Gene', '6817', (73, 80))
506440	25493573	Individuals demonstrating high SULT1A1 activity would be expected to exhibit a greater risk of developing cancer owing to a supposed increase in exposure to carcinogenic and mutagenic compounds.	('high', 'Var', (26, 30))	('carcinogenic', 'Disease', 'MESH:D063646', (157, 169))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('carcinogenic', 'Disease', (157, 169))	('SULT1A1', 'Gene', (31, 38))	('activity', 'MPA', (39, 47))	('cancer', 'Disease', (106, 112))	('SULT1A1', 'Gene', '6817', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
506447	25493573	However, this exposure also yielded conflicting results with SULT1A1 genetic variation.	('SULT1A1', 'Gene', (61, 68))	('genetic variation', 'Var', (69, 86))	('SULT1A1', 'Gene', '6817', (61, 68))
506448	25493573	Because SULT1A1 activity is thought to be protective against PAH damage, genetic variations that confer lower enzymatic activity are expected to have an increased risk of cancer susceptibility.	('SULT1A1', 'Gene', '6817', (8, 15))	('genetic variations', 'Var', (73, 91))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('SULT1A1', 'Gene', (8, 15))	('PAH', 'Chemical', 'MESH:D011084', (61, 64))
506452	25493573	Bladder cancer risk was only increased when *1/*1 and another factor was involved.	('cancer', 'Disease', (8, 14))	('*1/*1', 'Var', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
506458	25493573	Environmental exposure to promutagens, procarcinogens and chemopreventives along with variation in the SULT1A1 enzyme could exhibit a cumulative effect in modulating individual response to disease-related chemicals.	('variation', 'Var', (86, 95))	('modulating', 'Reg', (155, 165))	('SULT1A1', 'Gene', (103, 110))	('individual response to', 'MPA', (166, 188))	('SULT1A1', 'Gene', '6817', (103, 110))
506461	25493573	Further investigation into the role chemopreventive agents and SULT1A1 variation plays in modulating SULT1A1 activity and disease outcome is warranted, addressing cancer site differences, as well as ethnic differences in allele frequencies where an allele-dose effect may be observed.	('variation', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('SULT1A1', 'Gene', (63, 70))	('activity', 'MPA', (109, 117))	('SULT1A1', 'Gene', (101, 108))	('SULT1A1', 'Gene', '6817', (63, 70))	('SULT1A1', 'Gene', '6817', (101, 108))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
506462	25493573	Data presented in this review demonstrate the importance of evaluating genetic variation beyond the traditional SULT1A1*1/2 SNP in predicting response to chemicals and therapeutic agents.	('N', 'Chemical', 'MESH:D009584', (125, 126))	('genetic variation', 'Var', (71, 88))	('SULT1A1', 'Gene', (112, 119))	('SULT1A1', 'Gene', '6817', (112, 119))
506465	25493573	Discovering that 4-OHT may upregulate and NF1 knockdown can downregulate SULT1A1 expression affirms that these influences should not be ignored.	('downregulate', 'NegReg', (60, 72))	('knockdown', 'Var', (46, 55))	('SULT1A1', 'Gene', '6817', (73, 80))	('4-OHT', 'Chemical', 'MESH:C032278', (17, 22))	('upregulate', 'PosReg', (27, 37))	('SULT1A1', 'Gene', (73, 80))	('NF1', 'Gene', '4763', (42, 45))	('NF1', 'Gene', (42, 45))	('expression', 'MPA', (81, 91))
506469	25493573	Papers of special note have been highlighted as:   of interest    of considerable interest Most pharmacogenetic studies with tamoxifen (TAM) report no significant associations with SULT1A1 genetic variation and either recurrence-free survival, prognostic clinical or biological markers, breast cancer prevention efficacy, disease-free survival, overall survival, recurrence or pharmacokinetics.	('breast cancer', 'Phenotype', 'HP:0003002', (287, 300))	('recurrence-free survival', 'CPA', (218, 242))	('associations', 'Interaction', (163, 175))	('SULT1A1', 'Gene', (181, 188))	('overall survival', 'CPA', (345, 361))	('SULT1A1', 'Gene', '6817', (181, 188))	('TAM', 'Chemical', 'MESH:D013629', (136, 139))	('tamoxifen', 'Chemical', 'MESH:D013629', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('genetic variation', 'Var', (189, 206))	('breast cancer', 'Disease', 'MESH:D001943', (287, 300))	('breast cancer', 'Disease', (287, 300))
506472	25493573	SULT1A1*1/*1 homozygotes were found to have a decreased risk of recurrence with the CYP2D6*4 variant allele and improved recurrence-free survival with 2 years of TAM treatment.	('recurrence-free survival', 'CPA', (121, 145))	('CYP2D6', 'Gene', (84, 90))	('TAM', 'Chemical', 'MESH:D013629', (162, 165))	('SULT1A1', 'Gene', (0, 7))	('SULT1A1', 'Gene', '6817', (0, 7))	('CYP2D6', 'Gene', '1565', (84, 90))	('decreased', 'NegReg', (46, 55))	('improved', 'PosReg', (112, 120))	('variant', 'Var', (93, 100))
506473	25493573	Pharmacokinetic analyses showed no significant associations between SULT1A1 genotype or copy number with plasma concentrations of TAM and TAM metabolites except when ratios of metabolites were considered in one study.	('TAM', 'Chemical', 'MESH:D013629', (138, 141))	('SULT1A1', 'Gene', (68, 75))	('copy number', 'Var', (88, 99))	('SULT1A1', 'Gene', '6817', (68, 75))	('TAM', 'Chemical', 'MESH:D013629', (130, 133))	('associations', 'Interaction', (47, 59))
506474	25493573	Results from a Phase 1 clinical trial investigating a novel anticancer therapeutic agent, ABT-751, reveals a clear indication for SULT1A1 copy number testing before prescribing this medication.	('SULT1A1', 'Gene', (130, 137))	('copy number testing', 'Var', (138, 157))	('SULT1A1', 'Gene', '6817', (130, 137))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('ABT', 'Chemical', 'MESH:C002502', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
506475	25493573	Patients with high copy number variation of SULT1A1 receiving ABT-751 could potentially exhibit decreased benefit in terms of outcome owing to increased clearance of the active parent compound.	('SULT1A1', 'Gene', (44, 51))	('increased', 'PosReg', (143, 152))	('high copy number variation', 'Var', (14, 40))	('SULT1A1', 'Gene', '6817', (44, 51))	('decreased', 'NegReg', (96, 105))	('clearance of the active parent compound', 'MPA', (153, 192))	('Patients', 'Species', '9606', (0, 8))	('ABT', 'Chemical', 'MESH:C002502', (62, 65))
506476	25493573	Aminoflavone has an allele specific sensitivity toward the SULT1A1 variants *3 > *1 > *2 suggesting that carriers of the low activity *2 allele may not respond to aminoflavone treatment as well as high activity carriers.	('aminoflavone', 'Chemical', 'MESH:C413760', (163, 175))	('respond', 'MPA', (152, 159))	('Aminoflavone', 'Chemical', 'MESH:C413760', (0, 12))	('SULT1A1', 'Gene', (59, 66))	('not', 'NegReg', (148, 151))	('SULT1A1', 'Gene', '6817', (59, 66))	('variants *3 > *1 > *2', 'Var', (67, 88))
506477	25493573	SULT1A1*1/2 and copy number could potentially influence the metabolism of fulvestrant and toremifene adjuvant therapies in that they were significantly associated with substrate sulfation in in vitro assays.	('influence', 'Reg', (46, 55))	('copy number', 'Var', (16, 27))	('SULT1A1', 'Gene', (0, 7))	('SULT1A1', 'Gene', '6817', (0, 7))	('toremifene', 'Chemical', 'MESH:D017312', (90, 100))	('metabolism', 'MPA', (60, 70))	('associated with', 'Reg', (152, 167))	('fulvestrant', 'Chemical', 'MESH:D000077267', (74, 85))	('substrate sulfation', 'MPA', (168, 187))
506480	25493573	No associations were observed for prostate cancer risk between well-done meat consumption and SULT1A1 genotype.	('genotype', 'Var', (102, 110))	('prostate cancer', 'Disease', (34, 49))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('SULT1A1', 'Gene', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (34, 49))	('SULT1A1', 'Gene', '6817', (94, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (34, 49))
506482	25493573	Polycyclic aromatic hydrocarbons found in smoke are carcinogenic, but sulfation from SULT1A1 metabolism is able to intercept the carcinogenic redox cycle, which is a protective benefit.	('carcinogenic', 'Disease', 'MESH:D063646', (129, 141))	('SULT1A1', 'Gene', (85, 92))	('sulfation', 'Var', (70, 79))	('carcinogenic', 'Disease', (129, 141))	('SULT1A1', 'Gene', '6817', (85, 92))	('carcinogenic', 'Disease', 'MESH:D063646', (52, 64))	('carcinogenic', 'Disease', (52, 64))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (0, 32))	('intercept', 'PosReg', (115, 124))
506483	25493573	The *2 variant allele is expected to exhibit a greater risk of cancer due to its lower enzymatic activity in the detoxication of polycyclic aromatic hydrocarbons; however, smoking and SULT1A1 SNP yielded conflicting results in cancer risk at multiple sites.	('N', 'Chemical', 'MESH:D009584', (193, 194))	('lower', 'NegReg', (81, 86))	('detoxication of polycyclic aromatic hydrocarbons', 'MPA', (113, 161))	('SULT1A1', 'Gene', '6817', (184, 191))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (129, 161))	('enzymatic activity', 'MPA', (87, 105))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('variant', 'Var', (7, 14))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('SULT1A1', 'Gene', (184, 191))	('cancer', 'Disease', (63, 69))
506490	25493573	Male breast cancer was associated with a decrease in SULT1A1 copy number and with the BRCA2 mutation.	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('copy', 'MPA', (61, 65))	('BRCA2', 'Gene', (86, 91))	('SULT1A1', 'Gene', '6817', (53, 60))	('mutation', 'Var', (92, 100))	('Male breast cancer', 'Disease', (0, 18))	('Male breast cancer', 'Disease', 'MESH:D018567', (0, 18))	('decrease', 'NegReg', (41, 49))	('BRCA2', 'Gene', '675', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('SULT1A1', 'Gene', (53, 60))
506528	25149542	Results showed that the protein levels of MMP-2 and beta-catenin were increased with ATF3 over-expression (Supplementary Figure S4, Figure 5A).	('increased', 'PosReg', (70, 79))	('protein levels', 'MPA', (24, 38))	('beta-catenin', 'Gene', (52, 64))	('MMP-2', 'Gene', (42, 47))	('beta-catenin', 'Gene', '1499', (52, 64))	('MMP-2', 'Gene', '4313', (42, 47))	('over-expression', 'Var', (90, 105))	('ATF3', 'Gene', (85, 89))
506537	25149542	Results showed that protein level of MMP-2 was recovered in ATF3 over-expression cells when treated with MG132 but did not change when treated with NH4Cl, indicating that ATF3 might affect the degradation of MMP-2 through proteosome pathway (Figure 6A).	('NH4Cl', 'Chemical', 'MESH:D000643', (148, 153))	('MMP-2', 'Gene', '4313', (208, 213))	('degradation', 'MPA', (193, 204))	('over-expression', 'PosReg', (65, 80))	('MMP-2', 'Gene', '4313', (37, 42))	('MG132', 'Var', (105, 110))	('MG132', 'Chemical', 'MESH:C072553', (105, 110))	('recovered', 'MPA', (47, 56))	('ATF3', 'Gene', (60, 64))	('proteosome pathway', 'Pathway', (222, 240))	('MMP-2', 'Gene', (37, 42))	('affect', 'Reg', (182, 188))	('MMP-2', 'Gene', (208, 213))	('protein level', 'MPA', (20, 33))
506540	25149542	Further analysis by employing co-immunoprecipitation (co-IP) showed that the ubiquitination of MMP-2 was increased in MG132-treated cells, but when treated with MDM2 inhibitor or with both MDM2 inhibitor and MG132, the ubiquitination of MMP-2 was abolished and the protein level of MMP-2 was restored (Figure 6D).	('abolished', 'NegReg', (247, 256))	('MMP-2', 'Gene', (95, 100))	('MG132-treated', 'Var', (118, 131))	('ubiquitination', 'MPA', (219, 233))	('protein level', 'MPA', (265, 278))	('MMP-2', 'Gene', (282, 287))	('MMP-2', 'Gene', (237, 242))	('MMP-2', 'Gene', '4313', (95, 100))	('MG132', 'Chemical', 'MESH:C072553', (208, 213))	('increased', 'PosReg', (105, 114))	('MG132', 'Chemical', 'MESH:C072553', (118, 123))	('MMP-2', 'Gene', '4313', (237, 242))	('MMP-2', 'Gene', '4313', (282, 287))	('ubiquitination', 'MPA', (77, 91))
506544	25149542	Treatment of the cells with MG132 resulted in increased formation of the complex whereas treatment with MDM2 inhibitor did the opposite, confirming the existence of ATF3/MDM2/MMP-2 complex (Figure 6E).	('MMP-2', 'Gene', (175, 180))	('MG132', 'Var', (28, 33))	('increased', 'PosReg', (46, 55))	('MG132', 'Chemical', 'MESH:C072553', (28, 33))	('formation', 'MPA', (56, 65))	('MMP-2', 'Gene', '4313', (175, 180))
506551	25149542	We found here that the activity of ERK/MAPK was unchanged while P53 expression was increased upon Cisplatin treatment, suggesting that Cisplatin might induce ATF3 via P53 (Figure 7B, Supplementary Figure S5).	('Cisplatin', 'Var', (135, 144))	('Cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('expression', 'MPA', (68, 78))	('induce', 'Reg', (151, 157))	('Cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('P53', 'Gene', (167, 170))	('activity', 'MPA', (23, 31))	('ATF3', 'Gene', (158, 162))	('ERK', 'Gene', '5594', (35, 38))	('ERK', 'Gene', (35, 38))
506552	25149542	Results of Co-IP assay showed that, when treated with both MG132 and Cisplatin, formation of ATF3/MDM2/MMP-2 complex was increased, whereas MDM2 inhibitor treatment impeded the complex formation (Figure 7C).	('MG132', 'Var', (59, 64))	('MG132', 'Chemical', 'MESH:C072553', (59, 64))	('increased', 'PosReg', (121, 130))	('MMP-2', 'Gene', (103, 108))	('impeded', 'NegReg', (165, 172))	('formation', 'MPA', (80, 89))	('Cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('MMP-2', 'Gene', '4313', (103, 108))
506553	25149542	Moreover, invasiveness assay and MTT assay revealed that Cisplatin inhibited the invasion and growth of ESCC cells, and ATF3 knockdown was able to partially reverse this inhibition (Figure 7D, 7E and 7F).	('knockdown', 'Var', (125, 134))	('inhibited', 'NegReg', (67, 76))	('Cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('MTT', 'Chemical', 'MESH:C070243', (33, 36))
506568	25149542	Consistently, the present study also showed over-expression of ATF3 suppressed the tumor growth in vitro and in vivo while ATF3 silencing did the opposite, supporting an important role for ATF3 in cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('over-expression', 'Var', (44, 59))	('silencing', 'NegReg', (128, 137))	('tumor', 'Disease', (83, 88))	('suppressed', 'NegReg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('ATF3', 'Gene', (63, 67))
506570	25149542	Abnormal expression of ATF3 may mediate multiple aspects of cancer biology by repressing the transcription of certain downstream molecules including Cyclin D1, Id1 and IRS2.	('Cyclin D1', 'Gene', '595', (149, 158))	('Id1', 'Gene', (160, 163))	('Id1', 'Gene', '3397', (160, 163))	('IRS2', 'Gene', (168, 172))	('Cyclin D1', 'Gene', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('transcription', 'MPA', (93, 106))	('cancer', 'Disease', (60, 66))	('ATF3', 'Gene', (23, 27))	('Abnormal', 'Var', (0, 8))	('repressing', 'NegReg', (78, 88))	('IRS2', 'Gene', '8660', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
506571	25149542	Our results suggested that the protein level and activity of MMP-2, a Type IV collagenase which was critical in cancer cell invasion and metastasis, was attenuated in the ATF3-expressing cells, suggesting that MMP-2 might be a downstream molecule of ATF3 function.	('ATF3-expressing', 'Var', (171, 186))	('activity', 'MPA', (49, 57))	('protein level', 'MPA', (31, 44))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('MMP-2', 'Gene', '4313', (61, 66))	('attenuated', 'NegReg', (153, 163))	('MMP-2', 'Gene', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('MMP-2', 'Gene', (61, 66))	('MMP-2', 'Gene', '4313', (210, 215))
506598	25149542	Other four ESCC cell lines, EC109, KYSE150, EC9706 and KYSE510 were provided by professor Ming-Zhou Guo (Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing, China).	('EC9706', 'CellLine', 'CVCL:E307', (44, 50))	('KYSE150', 'CellLine', 'CVCL:1348', (35, 42))	('KYSE150', 'Var', (35, 42))	('KYSE510', 'Var', (55, 62))	('EC9706', 'Var', (44, 50))	('EC109', 'CellLine', 'CVCL:6898', (28, 33))
506608	25149542	After treatment of MG132 (Calbiochem), MDM inhibitor (Santa Cruz) or Cisplatin (Hanson, Jiangshu, China), cells were lysed and the resulting supernatants were incubated on a rocker with 1 mug MMP-2 antibody for 1 h and then with 20 mul protein A/G PLUS Agarose (Santa Cruz) overnight at 4 C. The immunoprecipitates were collected and then subjected to SDS/PAGE analysis.	('MMP-2', 'Gene', (192, 197))	('Cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('Agarose', 'Chemical', 'MESH:D012685', (253, 260))	('MDM', 'Gene', (39, 42))	('MMP-2', 'Gene', '4313', (192, 197))	('MDM', 'Gene', '57152', (39, 42))	('MG132', 'Chemical', 'MESH:C072553', (19, 24))	('MG132', 'Var', (19, 24))	('SDS', 'Chemical', 'MESH:D012967', (352, 355))
506638	24793026	Chronic inflammation is a risk factor for BE and EAC; and NSAIDs exert their anti-inflammatory properties by blocking cyclooxygenase isoenzymes (COX-1 or COX-2) and thus, prostaglandin and thromboxane synthesis.	('EAC', 'Disease', (49, 52))	('Chronic inflammation', 'Disease', (0, 20))	('anti-inflammatory', 'MPA', (77, 94))	('prostaglandin', 'Chemical', 'MESH:D011453', (171, 184))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))	('thromboxane', 'Chemical', 'MESH:D013931', (189, 200))	('COX-2', 'Gene', '4513', (154, 159))	('COX-1', 'Gene', (145, 150))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('cyclooxygenase isoenzymes', 'MPA', (118, 143))	('COX-2', 'Gene', (154, 159))	('blocking', 'NegReg', (109, 117))	('COX-1', 'Gene', '4512', (145, 150))	('thromboxane synthesis', 'MPA', (189, 210))	('BE', 'Phenotype', 'HP:0100580', (42, 44))	('NSAIDs', 'Var', (58, 64))
506639	24793026	NSAIDs are also suggested to induce apoptosis and inhibit angiogenesis and the cell-cycle, resulting in suppression of tumor growth.	('tumor', 'Disease', (119, 124))	('suppression', 'NegReg', (104, 115))	('cell-cycle', 'CPA', (79, 89))	('inhibit', 'NegReg', (50, 57))	('apoptosis', 'CPA', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('induce', 'PosReg', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('angiogenesis', 'CPA', (58, 70))	('NSAIDs', 'Var', (0, 6))
506667	24793026	We planned several stratified analyses: white men only, long-segment (>= 3 cm) BE, GERD symptoms or PPI use, no GERD symptoms or PPI use, GERD symptoms, no GERD symptoms, PPI use, no PPI use, WHR tertiles, being normal weight (BMI <25), overweight (BMI 25-29), or obese (BMI >30), bisphosphonate use, and no bisphosphonate use.	('bisphosphonate', 'Chemical', 'MESH:D004164', (281, 295))	('BMI 25-29', 'Var', (249, 258))	('BE', 'Phenotype', 'HP:0100580', (79, 81))	('bisphosphonate', 'Chemical', 'MESH:D004164', (308, 322))	('men', 'Species', '9606', (46, 49))	('obese', 'Disease', 'MESH:D009765', (264, 269))	('overweight', 'Phenotype', 'HP:0025502', (237, 247))	('men', 'Species', '9606', (64, 67))	('GERD symptoms', 'Disease', (83, 96))	('obese', 'Disease', (264, 269))
506699	24793026	Only high-dose aspirin (>=325mg) was significantly associated with a decreased risk of BE (adjusted OR 0.36; 95% CI 0.20-0.64).	('aspirin', 'Chemical', 'MESH:D001241', (15, 22))	('>=325mg', 'Var', (24, 31))	('decreased', 'NegReg', (69, 78))	('BE', 'Phenotype', 'HP:0100580', (87, 89))
506720	24797725	In contrast to the quiescent nature of non-tumorigenic epithelial cells, human ESCC cells exhibited strikingly hyperactive in intracellular Ca2+ oscillations, which were sensitive to treatments with Orai1 channel blockers and to orai1 silencing.	('intracellular Ca2+ oscillations', 'MPA', (126, 157))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('hyperactive', 'PosReg', (111, 122))	('silencing', 'Var', (235, 244))	('human', 'Species', '9606', (73, 78))	('orai1', 'Gene', (229, 234))	('orai1', 'Gene', '84876', (229, 234))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (126, 157))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
506726	24797725	In particular, a large body of evidence supports the contribution of altered Ca2+ signaling to tumor angiogenesis, progression and metastasis and favors the possibility that genes contributing to such alterations represent novel targets for cancer therapy.	('progression', 'CPA', (115, 126))	('metastasis', 'CPA', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('altered', 'Var', (69, 76))	('Ca2+ signaling', 'MPA', (77, 91))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
506728	24797725	Defects in SOCE resulting from genetic mutations in Orail1 or STIM1 have been linked to several human diseases, e.g.	('SOCE', 'Disease', (11, 15))	('Defects', 'NegReg', (0, 7))	('human', 'Species', '9606', (96, 101))	('linked', 'Reg', (78, 84))	('STIM1', 'Gene', (62, 67))	('Orail1', 'Gene', (52, 58))	('genetic mutations', 'Var', (31, 48))
506730	24797725	Furthermore, reduction of STIM1 and/or Orai1 expression by gene silencing techniques decreases growth and metastasis of breast and cervical tumors in mice.	('decreases', 'NegReg', (85, 94))	('cervical tumors', 'Phenotype', 'HP:0030159', (131, 146))	('Orai1', 'Gene', (39, 44))	('mice', 'Species', '10090', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('decreases growth', 'Phenotype', 'HP:0001510', (85, 101))	('metastasis of breast and cervical tumors', 'Disease', 'MESH:D009362', (106, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('STIM1', 'Gene', (26, 31))	('expression', 'MPA', (45, 55))	('gene silencing', 'Var', (59, 73))	('reduction', 'NegReg', (13, 22))
506734	24797725	Established SOCE blockers, such as skf-96365 and 2-aminoethyl diphenylborate (2-APB), suppress proliferation of various types of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('skf-96365', 'Var', (35, 44))	('suppress', 'NegReg', (86, 94))	('skf-96365', 'Chemical', 'MESH:C063159', (35, 44))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('APB', 'Gene', (80, 83))	('APB', 'Gene', '6051', (80, 83))	('2-aminoethyl diphenylborate', 'Chemical', '-', (49, 76))
506738	24797725	Our attempt is to identify any abnormity in SOCE to be used as diagnostic and/or prognostic biomarker and to provide insights to mechanistic understanding on how such abnormity in SOCE pathway regulates tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('regulates', 'Reg', (193, 202))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('abnormity', 'Var', (167, 176))
506755	24797725	To elucidate the intriguing function of upregulated Orai1 but not STIM1 in esophageal cancer, the Orai1-mediated SOCE activity were examined in epithelial cell lines derived from human ESCC tumors: KYSE-150, KYSE-190, KYSE-30, KYSE-510 and KYSE-790.	('KYSE-510', 'Var', (227, 235))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('human', 'Species', '9606', (179, 184))	('KYSE-150', 'CellLine', 'CVCL:1348', (198, 206))	('KYSE-150', 'Var', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('ESCC tumors', 'Disease', (185, 196))	('KYSE-190', 'Var', (208, 216))	('KYSE-30', 'Var', (218, 225))	('KYSE-790', 'Var', (240, 248))	('ESCC tumors', 'Disease', 'MESH:D004938', (185, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('esophageal cancer', 'Disease', (75, 92))	('upregulated', 'PosReg', (40, 51))
506764	24797725	Delta350/F385 was calculated to represent the activity of SOCE and the findings showed that SOCE was about twice active in KYSE-150 cells than that in HET-1A cells (Fig.	('KYSE-150', 'Var', (123, 131))	('active', 'MPA', (113, 119))	('Delta350/F', 'Mutation', 'rs768046010', (0, 10))	('KYSE-150', 'CellLine', 'CVCL:1348', (123, 131))
506769	24797725	Analyses of Mn2+ quenching slopes indicated that SOCE activities for all ESCC cells examined were significantly higher than that for HET-1A cells; relative activities were: KYSE-150 > KYSE-30 > KYSE-510 > HET-1A cells (Fig.	('KYSE-150', 'CellLine', 'CVCL:1348', (173, 181))	('Mn2+', 'Chemical', '-', (12, 16))	('KYSE-150 > KYSE-30 > KYSE-510', 'Var', (173, 202))	('higher', 'PosReg', (112, 118))
506773	24797725	The presence of SOCE inhibitors skf-96365 (20 muM) or 2-APB (50 muM) completely abolished these intracellular Ca2+ oscillations in KYSE-150 cells (Fig 4,A and B, and Supplementary Video 3).	('KYSE-150', 'CellLine', 'CVCL:1348', (131, 139))	('muM', 'Gene', (64, 67))	('APB', 'Gene', (56, 59))	('muM', 'Gene', '56925', (46, 49))	('abolished', 'NegReg', (80, 89))	('skf-96365', 'Var', (32, 41))	('intracellular Ca2+ oscillations', 'MPA', (96, 127))	('APB', 'Gene', '6051', (56, 59))	('skf-96365', 'Chemical', 'MESH:C063159', (32, 41))	('muM', 'Gene', '56925', (64, 67))	('muM', 'Gene', (46, 49))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (96, 127))
506781	24797725	Following transfection of KYSE-150 cells with shRNA but not with plasmid containing the scrambled sequence, SOCE activity (Delta350/F385) was reduced to almost half of that observed in parental cells (Fig.	('Delta350/F', 'Mutation', 'rs768046010', (123, 133))	('reduced', 'NegReg', (142, 149))	('Delta350/F385', 'Var', (123, 136))	('KYSE-150', 'CellLine', 'CVCL:1348', (26, 34))	('SOCE activity', 'MPA', (108, 121))
506783	24797725	Skf-96365 treatment resulted in almost full suppression of these oscillations, which were present in ~76% of untreated KYSE-150 cells as compared to ~26% of HET-1 cells (Fig.	('Skf-96365', 'Chemical', 'MESH:C063159', (0, 9))	('KYSE-150', 'CellLine', 'CVCL:1348', (119, 127))	('oscillations', 'MPA', (65, 77))	('Skf-96365', 'Var', (0, 9))	('suppression', 'NegReg', (44, 55))
506786	24797725	On the other hand, phosphorylated ERK (p44/42) and pAKT (T308) were elevated in KYSE-150 cells compared with those in HET-1A cells and knocking down of Orai1 resulted in decreased phosphorylation forms of ERK and AKT (Supplementary Fig.	('ERK', 'Gene', '5594', (205, 208))	('KYSE-150', 'CellLine', 'CVCL:1348', (80, 88))	('ERK', 'Gene', (205, 208))	('AKT', 'Gene', (52, 55))	('knocking down', 'Var', (135, 148))	('elevated', 'PosReg', (68, 76))	('ERK', 'Gene', '5594', (34, 37))	('decreased', 'NegReg', (170, 179))	('phosphorylated', 'MPA', (19, 33))	('ERK', 'Gene', (34, 37))	('AKT', 'Gene', '207', (213, 216))	('Orai1', 'Gene', (152, 157))	('phosphorylation', 'MPA', (180, 195))	('AKT', 'Gene', (213, 216))	('AKT', 'Gene', '207', (52, 55))
506793	24797725	The results shown that knockdown of Orai1 did not change the expression of p53, but resulted in upregulation of cdc2, Cyclin B1 and p27, whereas transfection of scramble shRNA had no effects (Fig.	('cdc2', 'Gene', (112, 116))	('Cyclin B1', 'Gene', '891', (118, 127))	('knockdown', 'Var', (23, 32))	('cdc2', 'Gene', '983', (112, 116))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('p27', 'Gene', '3429', (132, 135))	('p27', 'Gene', (132, 135))	('Cyclin B1', 'Gene', (118, 127))	('upregulation', 'PosReg', (96, 108))
506804	24797725	Intraperitoneal injection of skf-96365 (10 mug/g body weight) every other day for 2 weeks significantly retarded tumor growth (Fig.	('retarded tumor', 'Disease', 'MESH:D009369', (104, 118))	('skf-96365', 'Var', (29, 38))	('skf-96365', 'Chemical', 'MESH:C063159', (29, 38))	('retarded tumor', 'Disease', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
506805	24797725	The application of skf-96365 at this dose daily for up to two weeks appeared to be safe for these animals since no obvious abnormality or body weight was observed (not shown).	('obvious abnormality', 'Disease', (115, 134))	('obvious abnormality', 'Disease', 'MESH:D000014', (115, 134))	('skf-96365', 'Var', (19, 28))	('skf-96365', 'Chemical', 'MESH:C063159', (19, 28))
506814	24797725	Moreover, inhibition of Orai1-mediated SOCE by pharmacologic antagonists of the channel or reduction of Orai1 expression by orai1 knockdown impeded the proliferation and migration of ESCC cells in culture, reduced their capacity for invasion, and altered their expression of proteins intimately concerned with migration and invasion (Figs.	('reduced', 'NegReg', (206, 213))	('proteins', 'Protein', (275, 283))	('inhibition', 'NegReg', (10, 20))	('migration', 'CPA', (170, 179))	('migration', 'CPA', (310, 319))	('proliferation', 'CPA', (152, 165))	('impeded', 'NegReg', (140, 147))	('orai1', 'Gene', '84876', (124, 129))	('orai1', 'Gene', (124, 129))	('knockdown', 'Var', (130, 139))	('altered', 'Reg', (247, 254))	('reduction', 'NegReg', (91, 100))	('invasion', 'CPA', (233, 241))	('expression', 'MPA', (110, 120))	('invasion', 'CPA', (324, 332))	('expression of', 'MPA', (261, 274))	('Orai1', 'Gene', (104, 109))
506823	24797725	identified a signaling pathway in which formation of an Orai1-SPCA2 complex elicits constitutive store-independent Ca2+ signaling and promotes tumorigenesis in breast cancer.	('SPCA2', 'Gene', (62, 67))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('promotes', 'PosReg', (134, 142))	('formation', 'Var', (40, 49))	('constitutive store-independent Ca2+ signaling', 'MPA', (84, 129))	('SPCA2', 'Gene', '9914', (62, 67))	('elicits', 'Reg', (76, 83))	('complex', 'Var', (68, 75))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
506825	24797725	found that knockdown of STIM1 had no effect whereas knockdown of Orai1 inhibited migration of breast cancer cells, indicating STIM1 might not be involved in the metastatic process.	('inhibited', 'NegReg', (71, 80))	('Orai1', 'Gene', (65, 70))	('migration of', 'CPA', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('STIM1', 'Gene', (24, 29))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('knockdown', 'Var', (52, 61))	('breast cancer', 'Disease', (94, 107))
506829	24797725	Any perturbation in the stoichiometry may have significant consequence on SOCE properties and intracellular Ca2+ oscillations, and likely tumor progression.	('SOCE', 'MPA', (74, 78))	('intracellular Ca2+ oscillations', 'Phenotype', 'HP:0003575', (94, 125))	('tumor', 'Disease', (138, 143))	('perturbation', 'Var', (4, 16))	('consequence', 'Reg', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('intracellular Ca2+ oscillations', 'MPA', (94, 125))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
506832	24797725	In addition, knockdown of STIM1 in KYSE-150 cells appeared to have no effect on SOCE activity (Supplementary Fig.	('KYSE-150', 'CellLine', 'CVCL:1348', (35, 43))	('SOCE activity', 'CPA', (80, 93))	('knockdown', 'Var', (13, 22))	('STIM1', 'Gene', (26, 31))
506856	24797725	HET-1A cells were maintained in serum-free LHC-9 medium whereas KYSE-150, KYSE-30, KYSE-510, KYSE-790 and other ESCC cell lines were cultured in RPMI-1640/Ham's F12 (1:1) medium supplemented with 5% FBS.	('RPMI-1640', 'Chemical', '-', (145, 154))	('KYSE-510', 'Var', (83, 91))	('KYSE-150', 'CellLine', 'CVCL:1348', (64, 72))	('F12', 'Chemical', 'MESH:C007782', (161, 164))	('KYSE-30', 'Var', (74, 81))
506879	24797725	SOCE activity is presented as DeltaF350/F385, the difference between basal and maximal values of F350/F385 after addition of 2mM CaCl2 in BSS solution.	('F350/F385', 'Var', (97, 106))	('DeltaF350', 'DELETION', 'None', (30, 39))	('CaCl2', 'Chemical', 'MESH:D002122', (129, 134))	('DeltaF350', 'Var', (30, 39))
506966	22417808	Local-regional control and relapse free survival were better in patients who had surgical resection, but there was no statistically significant difference in distant metastatic free survival or overall survival with surgical resection (figure 3).	('relapse free survival', 'CPA', (27, 48))	('patients', 'Species', '9606', (64, 72))	('surgical', 'Var', (81, 89))	('Local-regional control', 'CPA', (0, 22))	('better', 'PosReg', (54, 60))
506973	22417808	In a study comparing protons with X-ray in 5 patients, proton plans were able to spare better all structures (spinal cord, lung, heart and kidneys) and enhances the tumor control probability value by an average of 20%-units (range 2-23% units) using 5% NTCP in any risk organ.	('enhances', 'PosReg', (152, 160))	('NTCP', 'Gene', '6554', (253, 257))	('NTCP', 'Gene', (253, 257))	('proton', 'Var', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
506998	20017917	ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma Cancer cells display widespread changes in DNA methylation that may lead to genetic instability by global hypomethylation and aberrant silencing of tumor suppressor genes by focal hypermethylation.	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('ECRG4', 'Gene', (0, 5))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ECRG4', 'Gene', '84417', (0, 5))	('glioma', 'Disease', (98, 104))	('silencing', 'NegReg', (240, 249))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('Cancer', 'Disease', (105, 111))	('global hypomethylation', 'MPA', (204, 226))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('genetic instability', 'MPA', (181, 200))	('tumor', 'Disease', (253, 258))	('colorectal carcinoma', 'Disease', (73, 93))	('DNA methylation', 'MPA', (148, 163))	('focal hypermethylation', 'Var', (279, 301))	('Cancer', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('changes', 'Reg', (137, 144))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (73, 93))	('lead to', 'Reg', (173, 180))
507006	20017917	Remarkably, aberrant methylation of ECRG4 was also found in primary human tumor tissues, including samples from colorectal carcinoma and from malignant gliomas.	('human', 'Species', '9606', (68, 73))	('methylation', 'MPA', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('ECRG4', 'Gene', '84417', (36, 41))	('malignant gliomas', 'Disease', (142, 159))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('colorectal carcinoma', 'Disease', (112, 132))	('tumor', 'Disease', (74, 79))	('malignant gliomas', 'Disease', 'MESH:D005910', (142, 159))	('aberrant', 'Var', (12, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('found', 'Reg', (51, 56))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (112, 132))	('ECRG4', 'Gene', (36, 41))
507007	20017917	ECRG4 hypermethylation associated strongly with transcriptional silencing and its expression could be re-activated in vitro by demethylating treatment with 5-aza-2'-deoxycytidine.	('hypermethylation', 'Var', (6, 22))	('transcriptional', 'MPA', (48, 63))	('ECRG4', 'Gene', (0, 5))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (156, 178))	('ECRG4', 'Gene', '84417', (0, 5))
507012	20017917	Genetic and epigenetic events work in concert to transform a normal cell into a malignant cancer cell.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('epigenetic', 'Var', (12, 22))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('transform', 'Reg', (49, 58))
507015	20017917	The hypermethylation of these 5'-CpG islands may cause transcriptional silencing of genes, including tumor suppressor genes.	('transcriptional', 'MPA', (55, 70))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('silencing', 'NegReg', (71, 80))	('cause', 'Reg', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('hypermethylation', 'Var', (4, 20))
507016	20017917	Indeed, promoter hypermethylation often acts as second hit in the inactivation of tumor suppressor genes, e.g.	('promoter hypermethylation', 'Var', (8, 33))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('inactivation', 'NegReg', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
507017	20017917	The causes of aberrant DNA methylation in cancer are not fully understood.	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('aberrant', 'Var', (14, 22))
507018	20017917	There are hints that overexpression of DNA methyltransferases (DNMTs) may be involved, such as aberrant activity of DNMT3b promoted de novo methylation.	('DNMT3b', 'Gene', (116, 122))	('promoted', 'PosReg', (123, 131))	('aberrant activity', 'Var', (95, 112))	('de novo methylation', 'MPA', (132, 151))	('DNMT3b', 'Gene', '1789', (116, 122))
507020	20017917	Recently, a model has been proposed to explain the phenomenon why some genes become methylated during carcinogenesis while others do not.	('carcinogenesis', 'Disease', (102, 116))	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('methylated', 'Var', (84, 94))
507021	20017917	A targeting mechanism may predispose genes that are repressed by polycomb proteins in normal cells to aberrant DNA methylation in cancer.	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('aberrant', 'Var', (102, 110))
507024	20017917	Moreover, aberrant DNA methylation patterns in cancer have been used for the discovery of candidate tumor suppressor genes; e.g.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', (100, 105))	('aberrant', 'Var', (10, 18))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
507053	20017917	Methylation of an upstream (-353/-136 relative to transcription start site) and a downstream (-69/+187 relative to transcription start site) fragment from this CpG island was determined by COBRA (combined bisulfite and restriction analysis).	('bisulfite', 'Chemical', 'MESH:C042345', (205, 214))	('-69/+187', 'Var', (94, 102))	('-353/-136', 'Var', (28, 37))
507090	20017917	We therefore analyzed a second promoter fragment by COBRA and found that all three colorectal carcinoma and all three glioblastoma cell lines, as well as HepG2 and MCF7 were methylated whereas A549, HeLa and HT1080 were not (Fig.	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('HT1080', 'CellLine', 'CVCL:0317', (208, 214))	('methylated', 'Var', (174, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (83, 103))	('A549', 'CellLine', 'CVCL:0023', (193, 197))	('HepG2', 'CellLine', 'CVCL:0027', (154, 159))	('MCF7', 'CellLine', 'CVCL:0031', (164, 168))	('glioblastoma', 'Disease', (118, 130))	('colorectal carcinoma', 'Disease', (83, 103))	('HeLa', 'CellLine', 'CVCL:0030', (199, 203))
507096	20017917	As the three analyzed colon cancer cell lines showed ECRG4 hypermethylation, we asked whether ECRG4 methylation also can be found in primary colorectal tumors.	('ECRG4', 'Gene', '84417', (53, 58))	('hypermethylation', 'Var', (59, 75))	('colorectal tumors', 'Disease', 'MESH:D015179', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('colorectal tumors', 'Disease', (141, 158))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('ECRG4', 'Gene', (94, 99))	('colon cancer', 'Disease', (22, 34))	('ECRG4', 'Gene', (53, 58))	('ECRG4', 'Gene', '84417', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
507101	20017917	Of the eight tumor tissues, six were hypermethylated and two were of unknown methylation status.	('tumor', 'Disease', (13, 18))	('hypermethylated', 'Var', (37, 52))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
507106	20017917	Statistical analysis revealed that ECRG4 methylation was significantly more frequent in secondary glioblastomas as compared to diffuse and anaplastic astrocytomas or primary glioblastomas (Fisher's exact test; p = 0.0003 and p = 0.0094, respectively).	('glioblastomas', 'Phenotype', 'HP:0012174', (98, 111))	('more', 'PosReg', (71, 75))	('glioblastomas', 'Disease', 'MESH:D005909', (98, 111))	('glioblastomas', 'Phenotype', 'HP:0012174', (174, 187))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (174, 186))	('ECRG4', 'Gene', (35, 40))	('methylation', 'Var', (41, 52))	('glioblastomas', 'Disease', (98, 111))	('glioblastomas', 'Disease', (174, 187))	('glioblastomas', 'Disease', 'MESH:D005909', (174, 187))	('anaplastic astrocytomas or primary glioblastomas', 'Disease', 'MESH:D001254', (139, 187))	('anaplastic astrocytomas or primary glioblastomas', 'Disease', (139, 187))	('ECRG4', 'Gene', '84417', (35, 40))	('frequent', 'Reg', (76, 84))
507122	20017917	Cancer cells are characterized by extensive epigenetic DNA alterations, including global hypomethylation as well as focal hypermethylation at CpG islands in gene promoters.	('focal hypermethylation', 'Var', (116, 138))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('global hypomethylation', 'MPA', (82, 104))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
507123	20017917	DNA hypermethylation constitutes a major cause of aberrant gene silencing in cancer.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('hypermethylation', 'Var', (4, 20))
507132	20017917	In colorectal carcinomas, we found a high frequency of methylation, but, as the analyzed samples were all from advanced staged tumors, correlations to clinical features were not possible.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (3, 24))	('colorectal carcinomas', 'Disease', (3, 24))	('methylation', 'Var', (55, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
507133	20017917	We also found frequent methylation in astrocytic gliomas, in which the methylation frequency increased with advancing tumor grade, being particularly common in glioblastomas.	('astrocytic gliomas', 'Disease', (38, 56))	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('glioblastomas', 'Disease', (160, 173))	('methylation', 'Var', (23, 34))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('methylation', 'MPA', (71, 82))	('tumor', 'Disease', (118, 123))	('common', 'Reg', (150, 156))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (38, 56))	('glioblastomas', 'Phenotype', 'HP:0012174', (160, 173))	('glioblastomas', 'Disease', 'MESH:D005909', (160, 173))
507134	20017917	This result is consistent with recent reports that ECRG4 methylation is associated with advanced disease and poor prognosis in esophageal and prostate cancer patients.	('methylation', 'Var', (57, 68))	('advanced disease', 'Disease', 'MESH:D020178', (88, 104))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('esophageal and prostate cancer', 'Disease', 'MESH:D011471', (127, 157))	('associated', 'Reg', (72, 82))	('ECRG4', 'Gene', (51, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (142, 157))	('ECRG4', 'Gene', '84417', (51, 56))	('patients', 'Species', '9606', (158, 166))	('advanced disease', 'Disease', (88, 104))
507135	20017917	Our findings of frequent ECRG4 methylation in various cancer cell lines may suggest that ECRG4 might be methylated in even other tumor types.	('ECRG4', 'Gene', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('ECRG4', 'Gene', (25, 30))	('cancer', 'Disease', (54, 60))	('ECRG4', 'Gene', '84417', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('methylation', 'Var', (31, 42))	('ECRG4', 'Gene', '84417', (25, 30))	('tumor', 'Disease', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
507145	20017917	Then again, ECRG4 expression could be reactivated by demethylating treatment, which is a known feature of epigenetically silenced tumor suppressor genes.	('ECRG4', 'Gene', '84417', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('ECRG4', 'Gene', (12, 17))	('expression', 'MPA', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('demethylating', 'Var', (53, 66))
507147	20017917	Using two independent assays of cell viability and cell proliferation, we found reduced growth rates after ECRG4 transfection or culturing of cells in ECRG4 containing medium.	('transfection', 'Var', (113, 125))	('growth', 'MPA', (88, 94))	('reduced growth rates', 'Phenotype', 'HP:0001510', (80, 100))	('reduced', 'NegReg', (80, 87))	('ECRG4', 'Gene', (151, 156))	('ECRG4', 'Gene', (107, 112))	('ECRG4', 'Gene', '84417', (151, 156))	('ECRG4', 'Gene', '84417', (107, 112))
507148	20017917	An additional hint supporting a growth suppressive effect of ECRG4 in tumor cells comes from stabile transfection experiments, in which we observed that the expression of the transgene rapidly declined, presumably by de novo methylation (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('declined', 'NegReg', (193, 201))	('methylation', 'Var', (225, 236))	('expression', 'MPA', (157, 167))	('ECRG4', 'Gene', '84417', (61, 66))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('ECRG4', 'Gene', (61, 66))
507162	20017917	Hypermethylation associates strongly with transcriptional silencing in colorectal carcinomas.	('Hypermethylation', 'Var', (0, 16))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (71, 92))	('colorectal carcinomas', 'Disease', (71, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('transcriptional silencing', 'MPA', (42, 67))
507168	19758438	A substantial proportion of esophageal carcinoma is associated with infection of high-risk HPV type 16 and HPV18, the oncogenic expression of which is controlled by host cell transcription factor Activator Protein-1 (AP-1).	('HPV type 16', 'Gene', (91, 102))	('Activator Protein-1', 'Gene', (196, 215))	('AP-1', 'Gene', '2353', (217, 221))	('esophageal carcinoma', 'Disease', (28, 48))	('associated', 'Reg', (52, 62))	('infection', 'Var', (68, 77))	('Activator Protein-1', 'Gene', '2353', (196, 215))	('HPV', 'Species', '10566', (107, 110))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (28, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('HPV18', 'Gene', (107, 112))	('AP-1', 'Gene', (217, 221))	('HPV', 'Species', '10566', (91, 94))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (28, 48))
507185	19758438	It has been demonstrated that a point mutation in the AP-1 consensus sequence within the binding site of upstream regulatory region (URR) of HPV16/18 leads to complete abolition of E6 and E7 gene expression.	('AP-1', 'Gene', (54, 58))	('rat', 'Species', '10116', (19, 22))	('HPV16/18', 'Gene', (141, 149))	('abolition', 'NegReg', (168, 177))	('AP-1', 'Gene', '2353', (54, 58))	('point mutation', 'Var', (32, 46))	('HPV16', 'Species', '333760', (141, 146))
507250	19758438	Interestingly, unlike in other cancers, Fra-1 expression was diminished or completely lost in tumor tissues infected with HPV16 while HPV-negative tumors showed a very high expression of Fra-1 and also participates in DNA binding as revealed by supershift assay.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('HPV16', 'Species', '333760', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('lost', 'NegReg', (86, 90))	('Fra-1', 'Gene', (40, 45))	('Fra-1', 'Protein', (187, 192))	('participates', 'Reg', (202, 214))	('DNA binding', 'Interaction', (218, 229))	('cancers', 'Disease', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('HPV', 'Species', '10566', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('expression', 'MPA', (173, 183))	('expression', 'MPA', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('diminished', 'NegReg', (61, 71))	('tumor', 'Disease', (94, 99))	('HPV16', 'Var', (122, 127))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('HPV', 'Species', '10566', (134, 137))
507256	19758438	Aberrant AP-1 activity is one of the most frequent mechanisms of tumor promotion in epithelial tissues irrespective of the tumor site and is mediated through activation of its upstream kinases such as ERK, JNK and p38.	('JNK', 'Gene', '5599', (206, 209))	('tumor', 'Disease', (123, 128))	('activity', 'MPA', (14, 22))	('tumor', 'Disease', (65, 70))	('Aberrant', 'Var', (0, 8))	('p38', 'Gene', '1432', (214, 217))	('ERK', 'Enzyme', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('activation', 'PosReg', (158, 168))	('p38', 'Gene', (214, 217))	('AP-1', 'Gene', '2353', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('JNK', 'Gene', (206, 209))	('AP-1', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
507285	19758438	Moreover, change in AP-1 composition resulting in elimination of Fra-1 has been found to be associated with enhanced tumorigenesity.	('AP-1', 'Gene', '2353', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Fra-1', 'Gene', (65, 70))	('tumor', 'Disease', (117, 122))	('AP-1', 'Gene', (20, 24))	('change', 'Var', (10, 16))	('enhanced', 'PosReg', (108, 116))	('elimination', 'NegReg', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
507286	19758438	Thus, lack of Fra-1 appears to contributing to more aggressiveness of the disease, as majority of these patients were infected with HPV and in poorly-differentiated state.	('aggressiveness of the disease', 'Disease', (52, 81))	('Fra-1', 'Gene', (14, 19))	('contributing', 'Reg', (31, 43))	('HPV', 'Species', '10566', (132, 135))	('HPV', 'Gene', (132, 135))	('infected', 'Reg', (118, 126))	('lack', 'Var', (6, 10))	('aggressiveness of the disease', 'Disease', 'MESH:D001523', (52, 81))	('aggressiveness', 'Phenotype', 'HP:0000718', (52, 66))	('patients', 'Species', '9606', (104, 112))
507289	19758438	Considering oncogenic role of HPVs and their co-operative interaction with AP-1 signaling, infection with HPV has been implicated as a possible etiological factor in the development of squamous cell carcinoma of the esophagus.	('HPV', 'Gene', (106, 109))	('squamous cell carcinoma of the esophagus', 'Disease', (185, 225))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('infection', 'Var', (91, 100))	('AP-1', 'Gene', (75, 79))	('rat', 'Species', '10116', (51, 54))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (185, 225))	('etiological', 'Reg', (144, 155))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (199, 225))	('HPV', 'Species', '10566', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('HPV', 'Species', '10566', (106, 109))	('AP-1', 'Gene', '2353', (75, 79))
507297	19758438	Therefore, HPV may significantly influence the disease progression rather than initiation.	('influence', 'Reg', (33, 42))	('rat', 'Species', '10116', (67, 70))	('HPV', 'Species', '10566', (11, 14))	('HPV', 'Var', (11, 14))	('disease progression', 'CPA', (47, 66))
507373	12271166	Long, ulcerated strictures may be observed in patients who have ingested lye or other caustic agents, and in severe cases, diffuse esophageal narrowing may reduce the thoracic esophagus to a thin, filiform stricture (Fig.	('reduce', 'NegReg', (156, 162))	('patients', 'Species', '9606', (46, 54))	('ulcer', 'Disease', (6, 11))	('diffuse', 'Var', (123, 130))	('esophageal narrowing', 'Phenotype', 'HP:0010450', (131, 151))	('thoracic esophagus', 'MPA', (167, 185))	('ulcer', 'Disease', 'MESH:D014456', (6, 11))
507418	32472227	In pancreatic cancer and breast cancer, investigators found that the relationship between blood flow (BF) and glucose metabolism is a potential indicator of the biological status of tumors, especially the low-BF and high-metabolism phenotype (i.e., showing a mismatch between flow and metabolism), which has been shown to be associated with clinically more aggressive tumors, predicting poorer patient outcomes.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('aggressive tumors', 'Disease', 'MESH:D001523', (357, 374))	('tumors', 'Disease', 'MESH:D009369', (368, 374))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumors', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('glucose metabolism', 'Disease', (110, 128))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('patient', 'Species', '9606', (394, 401))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (368, 374))	('pancreatic cancer', 'Disease', (3, 20))	('high-metabolism', 'Var', (216, 231))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('glucose metabolism', 'Disease', 'MESH:D044882', (110, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('tumors', 'Disease', (368, 374))	('low-BF', 'Var', (205, 211))	('aggressive tumors', 'Disease', (357, 374))
507465	32472227	The objective response rate (ORR) was significantly higher in patients with high BF than in those with low BF (71.4% vs 23.1%, p = 0.012).	('patients', 'Species', '9606', (62, 70))	('high BF', 'Var', (76, 83))	('objective', 'MPA', (4, 13))	('higher', 'PosReg', (52, 58))
507498	32472227	Although different from Komar's study, Chen used PET-derived TLG and MRI-derived peaks instead of SUV and BF to quantify tumor metabolism and angiogenesis, and the conclusions were consistent, confirming that the flow-metabolism mismatch was correlated with poorer survival.	('tumor metabolism', 'Disease', 'MESH:D008659', (121, 137))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('poorer', 'NegReg', (258, 264))	('TLG', 'Chemical', '-', (61, 64))	('mismatch', 'Var', (229, 237))	('flow-metabolism', 'MPA', (213, 228))	('tumor metabolism', 'Disease', (121, 137))	('angiogenesis', 'CPA', (142, 154))
507513	32472227	LA ESCC Locally advanced esophageal squamous cell carcinoma dCRT Definitive chemoradiotherapy TNM Tumor, lymph node, metastasis DCE Dynamic contrast-enhanced CT Computed tomography 18F-FDG PET 18F-fluoroglucose glucose positron emission tomography FMR Flow-metabolism ratio BF Blood flow BV Blood volume TTP Time to peak SUVmax Maximum standardized uptake value MTV Metabolic tumor volume TLG Total lesion glycolysis RECIST Revised Response Evaluation Criteria in Solid Tumors CR Complete response PR Partial response SD Stable disease PD Progressive disease ROC Receiver operating characteristic OS Overall survival PFS Progression-free survival AUC Area under the ROC curve ORR Objective response rate HIF Hypoxia-inducing factor ML and JY contributed to the conception and design of the study.	('DCE', 'Gene', '1718', (128, 131))	('HIF', 'Disease', (704, 707))	('MTV', 'Chemical', '-', (362, 365))	('Tumors', 'Disease', (470, 476))	('Progressive disease', 'Disease', 'MESH:D018450', (539, 558))	('CRT', 'Gene', '45841', (61, 64))	('TTP', 'Gene', '7538', (304, 307))	('CR', 'Chemical', '-', (477, 479))	('glucose', 'Chemical', 'MESH:D005947', (211, 218))	('Hypoxia', 'Disease', 'MESH:D000860', (708, 715))	('Area under the ROC curve', 'MPA', (651, 675))	('Hypoxia', 'Disease', (708, 715))	('esophageal squamous cell carcinoma', 'Disease', (25, 59))	('HIF', 'Disease', 'None', (704, 707))	('Tumors', 'Disease', 'MESH:D009369', (470, 476))	('TLG', 'Chemical', '-', (389, 392))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('glucose', 'Chemical', 'MESH:D005947', (203, 210))	('PFS', 'Var', (617, 620))	('DCE', 'Gene', (128, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('CR', 'Chemical', '-', (61, 63))	('FDG', 'Gene', '23583', (185, 188))	('TTP', 'Gene', (304, 307))	('PD', 'Disease', 'MESH:D010300', (536, 538))	('Progressive disease', 'Disease', (539, 558))	('SD', 'Disease', 'MESH:D029461', (518, 520))	('Tumor', 'Phenotype', 'HP:0002664', (98, 103))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (25, 59))	('CRT', 'Gene', (61, 64))	('lesion glycolysis', 'Disease', 'MESH:C564972', (399, 416))	('Tumor', 'Phenotype', 'HP:0002664', (470, 475))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('Tumors', 'Phenotype', 'HP:0002664', (470, 476))	('FDG', 'Gene', (185, 188))	('Metabolic tumor', 'Disease', (366, 381))	('Metabolic tumor', 'Disease', 'MESH:D008659', (366, 381))	('lesion glycolysis', 'Disease', (399, 416))
507539	32308763	Differential phosphorylation of short or long TSC2 splicing variants by AKT and their impacts on mTOR signaling were also examined.	('AKT', 'Gene', '207', (72, 75))	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('AKT', 'Gene', (72, 75))	('TSC2', 'Gene', (46, 50))	('short', 'Var', (32, 37))	('impacts', 'Reg', (86, 93))
507540	32308763	Silencing of DAZAP1 led to the exclusion of TSC2 exon 26 (from Leu947 to Arg988), producing a short TSC2 isoform.	('Arg988', 'Chemical', '-', (73, 79))	('DAZAP1', 'Gene', (13, 19))	('producing', 'Reg', (82, 91))	('Silencing', 'Var', (0, 9))	('TSC2', 'MPA', (100, 104))	('Leu947', 'Chemical', '-', (63, 69))	('Arg988', 'Var', (73, 79))	('TSC2', 'Gene', (44, 48))
507543	32308763	Conclusions: Our data revealed an important physiological function of tumor suppressor DAZAP1 in autophagy regulation and highlighted the potential of controlling mRNA alternative splicing as an effective therapeutic application for cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('mRNA alternative splicing', 'Var', (163, 188))	('autophagy regulation', 'CPA', (97, 117))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('DAZAP1', 'Gene', (87, 93))	('cancers', 'Disease', (233, 240))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
507550	32308763	For example, high CD44 expression is associated with enhanced malignant potential in ESCC.	('high', 'Var', (13, 17))	('CD44', 'Gene', (18, 22))	('malignant potential', 'CPA', (62, 81))	('expression', 'MPA', (23, 33))	('ESCC', 'Disease', (85, 89))	('CD44', 'Gene', '960', (18, 22))	('enhanced', 'PosReg', (53, 61))
507551	32308763	Autophagy facilitates epithelial-mesenchymal transition of transformed esophageal keratinocytes with high CD44 expression via modulation of redox homeostasis and Parkin-dependent mitochondrial clearance.	('epithelial-mesenchymal transition', 'CPA', (22, 55))	('CD44', 'Gene', '960', (106, 110))	('facilitates', 'PosReg', (10, 21))	('redox homeostasis', 'MPA', (140, 157))	('modulation', 'Reg', (126, 136))	('Autophagy', 'CPA', (0, 9))	('CD44', 'Gene', (106, 110))	('high', 'Var', (101, 105))
507560	32308763	Importantly, miR-10b was the first miRNA which was identified to affect invasion and metastasis of human cancers.	('affect', 'Reg', (65, 71))	('miR-10b', 'Var', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (99, 104))
507571	32308763	Strikingly decreased miR-10b expression was observed in ESCC cells after MHY1485 treatment (Figure S1A), indicating that starvation induced nutrient-deprivation may lead to inhibited mTOR, elevated Drosha expression and increased miR-10b biogenesis.	('increased', 'PosReg', (220, 229))	('Drosha', 'Gene', (198, 204))	('mTOR', 'Gene', (183, 187))	('mTOR', 'Gene', '2475', (183, 187))	('elevated', 'PosReg', (189, 197))	('inhibited', 'NegReg', (173, 182))	('MHY1485', 'Chemical', 'MESH:C577756', (73, 80))	('miR-10b', 'Protein', (230, 237))	('decreased', 'NegReg', (11, 20))	('Drosha', 'Gene', '29102', (198, 204))	('miR-10b', 'Gene', (21, 28))	('biogenesis', 'MPA', (238, 248))	('expression', 'MPA', (29, 39))	('MHY1485', 'Var', (73, 80))
507574	32308763	Additionally, miR-10b accelerated degradation of the autophagy receptor, SQSTM1, after starvation (Figure 1B) and significantly enhanced the accumulation of autophagosomes, which were visualized via LC3B-II immunofluorescence staining (both P<0.05) (Figure 1C and 1D).	('accelerated', 'PosReg', (22, 33))	('autophagosomes', 'CPA', (157, 171))	('SQSTM1', 'Gene', '8878', (73, 79))	('LC3B', 'Gene', (199, 203))	('miR-10b', 'Var', (14, 21))	('enhanced', 'PosReg', (128, 136))	('degradation', 'MPA', (34, 45))	('LC3B', 'Gene', '81631', (199, 203))	('SQSTM1', 'Gene', (73, 79))
507575	32308763	As shown in Figure 1E, miR-10b could significantly promote proliferation of both KYSE450 and KYSE510 cells (both P<0.001).	('proliferation', 'CPA', (59, 72))	('KYSE450', 'CPA', (81, 88))	('promote', 'PosReg', (51, 58))	('KYSE510 cells', 'CPA', (93, 106))	('miR-10b', 'Var', (23, 30))	('KYSE510', 'CellLine', 'CVCL:1354', (93, 100))
507576	32308763	Similarly, miR-10b was able to stimulate colony formation of KYSE450 and KYSE510 (Figure 1F), indicating that miR-10b contributes to oncogenic growth of ESCC cells.	('oncogenic growth', 'CPA', (133, 149))	('miR-10b', 'Var', (11, 18))	('miR-10b', 'Var', (110, 117))	('stimulate', 'PosReg', (31, 40))	('colony formation', 'CPA', (41, 57))	('contributes', 'PosReg', (118, 129))	('KYSE510', 'CellLine', 'CVCL:1354', (73, 80))
507580	32308763	We found that the expression levels of TFAP2C, RAP2A, NCOR2, MDGA2, GTF2H1, and DOCK11 were down-regulated in one of the two ESCC cell lines, while the expression of DAZAP1 was inhibited by the ectopic miR-10b in both KYSE450 and KYSE510 cell lines (Figure 2B).	('KYSE510', 'CellLine', 'CVCL:1354', (230, 237))	('NCOR2', 'Gene', (54, 59))	('GTF2H1', 'Gene', '2965', (68, 74))	('RAP2A', 'Gene', '5911', (47, 52))	('NCOR2', 'Gene', '9612', (54, 59))	('MDGA2', 'Gene', (61, 66))	('DOCK11', 'Gene', '139818', (80, 86))	('TFAP2C', 'Gene', (39, 45))	('expression', 'MPA', (152, 162))	('ectopic miR-10b', 'Var', (194, 209))	('down-regulated', 'NegReg', (92, 106))	('inhibited', 'NegReg', (177, 186))	('MDGA2', 'Gene', '161357', (61, 66))	('miR-10b', 'Var', (202, 209))	('GTF2H1', 'Gene', (68, 74))	('TFAP2C', 'Gene', '7022', (39, 45))	('expression levels', 'MPA', (18, 35))	('RAP2A', 'Gene', (47, 52))	('DOCK11', 'Gene', (80, 86))
507585	32308763	However, no significant reduction of luciferase activities caused by miR-10b was observed in ESCC cells that were co-transfected with pGL3-Mut10b and miR-10b mimics or NC RNA (both P>0.05) (Figure 2E).	('activities', 'MPA', (48, 58))	('pGL3', 'Gene', '6391', (134, 138))	('luciferase', 'Enzyme', (37, 47))	('miR-10b', 'Var', (69, 76))	('reduction', 'NegReg', (24, 33))	('pGL3', 'Gene', (134, 138))
507587	32308763	After silencing of DAZAP1 with siRNAs (siDAZ1-1 and siDAZ1-2), we found an increased conversion of LC3B-I to LC3B-II and a significantly decreased SQSTM1 expression after starvation (Figure 2F and Figure S2B-2C).	('DAZ', 'Gene', (41, 44))	('LC3B', 'Gene', (99, 103))	('LC3B', 'Gene', '81631', (109, 113))	('DAZ', 'Gene', (19, 22))	('DAZ', 'Gene', '1617', (19, 22))	('silencing', 'Var', (6, 15))	('DAZ', 'Gene', '1617', (54, 57))	('LC3B', 'Gene', '81631', (99, 103))	('conversion', 'MPA', (85, 95))	('DAZ', 'Gene', '1617', (41, 44))	('SQSTM1', 'Gene', (147, 153))	('DAZ', 'Gene', (54, 57))	('increased', 'PosReg', (75, 84))	('decreased', 'NegReg', (137, 146))	('LC3B', 'Gene', (109, 113))	('SQSTM1', 'Gene', '8878', (147, 153))	('expression', 'MPA', (154, 164))
507588	32308763	In contrast, ectopic expression of DAZAP1 could suppress the conversion of LC3B-I to LC3B-II and the up-regulation of SQSTM1 (Figure 2G and Figure S2D-2E).	('SQSTM1', 'Gene', (118, 124))	('suppress', 'NegReg', (48, 56))	('LC3B', 'Gene', (75, 79))	('LC3B', 'Gene', (85, 89))	('SQSTM1', 'Gene', '8878', (118, 124))	('up-regulation', 'PosReg', (101, 114))	('conversion', 'MPA', (61, 71))	('DAZAP1', 'Gene', (35, 41))	('LC3B', 'Gene', '81631', (85, 89))	('LC3B', 'Gene', '81631', (75, 79))	('ectopic expression', 'Var', (13, 31))
507590	32308763	Ectopic expression of DAZAP1 could rescue starvation-induced autophagy enhanced by miR-10b in KYSE450 and KYSE510 cells (Figure S3), demonstrating that DAZAP1 is a key downstream target of miR-10b in regulating starvation-induced autophagy.	('enhanced', 'PosReg', (71, 79))	('rescue', 'PosReg', (35, 41))	('Ectopic expression', 'Var', (0, 18))	('KYSE510', 'CellLine', 'CVCL:1354', (106, 113))	('miR-10b', 'Gene', (83, 90))	('DAZAP1', 'Gene', (22, 28))	('starvation-induced autophagy', 'CPA', (42, 70))
507593	32308763	ESCC patients with a relatively high DAZAP1 expression exhibited significantly longer survival time compared to cases with a relatively low expression (both log-rank P<0.05) (Figure 3B).	('patients', 'Species', '9606', (5, 13))	('expression', 'Var', (44, 54))	('longer', 'PosReg', (79, 85))	('survival time', 'CPA', (86, 99))	('DAZAP1', 'Gene', (37, 43))
507595	32308763	DAZAP1 significantly suppressed the viability of KYSE450 and KYSE510 cells (Figure 3C and 3D).	('KYSE510', 'Var', (61, 68))	('KYSE510', 'CellLine', 'CVCL:1354', (61, 68))	('suppressed', 'NegReg', (21, 31))	('DAZAP1', 'Gene', (0, 6))	('viability', 'CPA', (36, 45))
507598	32308763	In contrast, the ectopic DAZAP1 expression could inhibit cell proliferation of KYSE450 and KYSE510 cells (Figure 3D).	('KYSE510', 'CellLine', 'CVCL:1354', (91, 98))	('KYSE510 cells', 'CPA', (91, 104))	('DAZAP1', 'Gene', (25, 31))	('ectopic', 'Var', (17, 24))	('inhibit', 'NegReg', (49, 56))
507602	32308763	Consistent with wound-healing assays, miR-10b, siDAZ1-1 or siDAZ1-2 could significantly accelerate migration of ESCC cells (all P<0.001) (Figure 4E).	('DAZ', 'Gene', (49, 52))	('miR-10b', 'Var', (38, 45))	('DAZ', 'Gene', '1617', (61, 64))	('ESCC cells', 'CPA', (112, 122))	('migration', 'CPA', (99, 108))	('accelerate', 'PosReg', (88, 98))	('DAZ', 'Gene', '1617', (49, 52))	('DAZ', 'Gene', (61, 64))
507608	32308763	TSC2 exon 26 codes the peptide fragment from Leu947 to Arg988 and has a Ser981 residue that can be phosphorylated by AKT.	('AKT', 'Gene', '207', (117, 120))	('TSC2', 'Gene', (0, 4))	('Leu947', 'Var', (45, 51))	('Arg988', 'Chemical', '-', (55, 61))	('Ser981', 'Chemical', '-', (72, 78))	('AKT', 'Gene', (117, 120))	('Leu947', 'Chemical', '-', (45, 51))	('Arg988', 'Var', (55, 61))
507611	32308763	We found that silencing DAZAP1 or expression of an ectopic miR-10b could significantly inhibit phosphorylation of TSC2 Ser981 in exon 26 but did not change TCS2 protein expression in KYSE450 and KYSE510 cells (Figure 6A and Figure S6A).	('silencing', 'Var', (14, 23))	('TCS2', 'Gene', '51082', (156, 160))	('DAZAP1', 'Gene', (24, 30))	('Ser981', 'Chemical', '-', (119, 125))	('TCS2', 'Gene', (156, 160))	('KYSE510', 'CellLine', 'CVCL:1354', (195, 202))	('miR-10b', 'Gene', (59, 66))	('phosphorylation', 'MPA', (95, 110))	('inhibit', 'NegReg', (87, 94))
507616	32308763	Collectively, our findings demonstrated that starvation-induced DAZAP1 suppression promotes mTORC1-regulated oncogenic autophagy via controlling TSC2 alternative splicing in ESCC (Figure 6C).	('DAZAP1', 'Gene', (64, 70))	('oncogenic autophagy', 'CPA', (109, 128))	('controlling', 'Reg', (133, 144))	('alternative splicing', 'Var', (150, 170))	('mTORC1', 'Gene', (92, 98))	('promotes', 'PosReg', (83, 91))	('suppression', 'NegReg', (71, 82))	('TSC2', 'Gene', (145, 149))	('mTORC1', 'Gene', '382056', (92, 98))
507618	32308763	Previous studies demonstrate that AKT inhibits TSC2 functions by phosphorylating its Ser981 residue in exon 26.	('TSC2 functions', 'MPA', (47, 61))	('AKT', 'Gene', (34, 37))	('phosphorylating', 'MPA', (65, 80))	('inhibits', 'NegReg', (38, 46))	('Ser981 residue', 'Var', (85, 99))	('AKT', 'Gene', '207', (34, 37))	('Ser981', 'Chemical', '-', (85, 91))
507619	32308763	Consistent with this notion, we observed significantly suppressed phosphorylation of TSC2 Ser981, decreased mTOR phosphorylation and enhanced autophagy in DAZAP1-repressed cells.	('mTOR', 'Gene', (108, 112))	('Ser981', 'Var', (90, 96))	('mTOR', 'Gene', '2475', (108, 112))	('autophagy', 'CPA', (142, 151))	('phosphorylation', 'CPA', (66, 81))	('Ser981', 'Chemical', '-', (90, 96))	('suppressed', 'NegReg', (55, 65))	('decreased', 'NegReg', (98, 107))	('enhanced', 'PosReg', (133, 141))	('TSC2', 'Gene', (85, 89))
507622	32308763	Studies on pathological splicing mutations support the importance for DAZAP1 in RNA splicing of several key tumor suppressors, such as NF1, BRCA1 and ATM .	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('BRCA1', 'Gene', (140, 145))	('NF1', 'Gene', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ATM', 'Gene', (150, 153))	('NF1', 'Gene', '4763', (135, 138))	('RNA splicing', 'MPA', (80, 92))	('DAZAP1', 'Gene', (70, 76))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (33, 42))	('ATM', 'Gene', '472', (150, 153))	('BRCA1', 'Gene', '672', (140, 145))
507623	32308763	We also observed the dysregulated DAZAP1 leads to alternative exon 26 splicing of tumor suppressor TSC2 pre-mRNA in ESCC cells.	('DAZAP1', 'Gene', (34, 40))	('alternative exon 26 splicing', 'MPA', (50, 78))	('leads to', 'Reg', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('dysregulated', 'Var', (21, 33))
507625	32308763	Tumor suppressor TSC2 is a negative regulator upstream of mTOR and its inactivating mutations cause tuberous sclerosis complex, an autosomal dominant syndrome which results in tumor development in multiple organs.	('tuberous sclerosis', 'Disease', (100, 118))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (131, 158))	('mTOR', 'Gene', (58, 62))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('autosomal dominant syndrome', 'Disease', (131, 158))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (100, 118))	('cause', 'Reg', (94, 99))	('inactivating mutations', 'Var', (71, 93))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('mTOR', 'Gene', '2475', (58, 62))
507630	32308763	For example, deletion of Atg5 or Atg7 in Pten-/--driven prostate cancer, KrasG12D- or BrafV600E-driven lung cancer, or KrasG12D-driven pancreatic ductal adenocarcinoma, suppresses tumor growth.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (135, 167))	('Atg7', 'Gene', '74244', (33, 37))	('Atg7', 'Gene', (33, 37))	('lung cancer', 'Disease', (103, 114))	('BrafV600E', 'Mutation', 'rs113488022', (86, 95))	('suppresses', 'NegReg', (169, 179))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('deletion', 'Var', (13, 21))	('Pten', 'Gene', '5728', (41, 45))	('Pten', 'Gene', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('Atg5', 'Gene', '11793', (25, 29))	('Atg5', 'Gene', (25, 29))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (135, 167))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('KrasG12D-driven', 'Var', (119, 134))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('prostate cancer', 'Disease', (56, 71))	('KrasG12D-', 'Var', (73, 82))	('pancreatic ductal adenocarcinoma', 'Disease', (135, 167))	('BrafV600E-driven', 'Var', (86, 102))	('tumor', 'Disease', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))
507631	32308763	Similarly, deletion of Atg13 or Ulk1 in a KrasG12D-driven glioblastoma decreases tumor progression.	('glioblastoma decreases tumor', 'Disease', (58, 86))	('Ulk1', 'Gene', (32, 36))	('glioblastoma decreases tumor', 'Disease', 'MESH:D005909', (58, 86))	('Ulk1', 'Gene', '22241', (32, 36))	('Atg13', 'Gene', '51897', (23, 28))	('glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Atg13', 'Gene', (23, 28))	('deletion', 'Var', (11, 19))
507632	32308763	As a result, a mouse model with tumor-specific deletion of miR-10b in tumors arising spontaneously in mice would be a good tool to stablish the in vivo role of the miR10b/DAZAP1/TSC2 axis in ESCC in the future.	('mice', 'Species', '10090', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('miR10b', 'Gene', (164, 170))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('deletion', 'Var', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('miR-10b', 'Gene', (59, 66))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('miR10b', 'Gene', '387144', (164, 170))	('ESCC', 'Disease', (191, 195))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
507653	32308763	KYSE450 or KYSE510 (4000 cells per well) were seeded into a 6-well cell culture plate and transfected with various small RNAs (20 nmol/L miR-10b mimics, miR-10b inhibitors, siDAZAP1-1, siDAZAP1-2 or NC RNA) or plasmids (the pcDNA3.1 vector or pcDNA-DAZAP1), respectively.	('miR-10b', 'Gene', (153, 160))	('KYSE510', 'CellLine', 'CVCL:1354', (11, 18))	('KYSE510', 'Var', (11, 18))	('miR-10b', 'Gene', (137, 144))
507686	31636653	While genetic alterations initiate tumorigenesis, how they affect the transcriptional program and ultimately drive the malignant phenotype remains elusive.	('affect', 'Reg', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('drive', 'Reg', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('transcriptional', 'CPA', (70, 85))	('initiate', 'Reg', (26, 34))	('genetic alterations', 'Var', (6, 25))
507694	31636653	Four human ESCC cell lines [KYSE140, KYSE510, TE5, and Shantou human embryonic esophageal carcinoma (SHEEC)] and one normal immortalized esophageal squamous epithelial cell line (SHEE) were used in this study.	('KYSE510', 'Var', (37, 44))	('embryonic esophageal carcinoma', 'Disease', (69, 99))	('human', 'Species', '9606', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('ESCC', 'Disease', 'MESH:D018307', (11, 15))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (79, 99))	('embryonic esophageal carcinoma', 'Disease', 'MESH:D004938', (69, 99))	('ESCC', 'Disease', (11, 15))	('human', 'Species', '9606', (5, 10))
507695	31636653	Among the five cell lines in this study, KYSE140, KYSE510, and TE5 are established from the resected specimens of patients with ESCC.	('KYSE510', 'Var', (50, 57))	('KYSE140', 'Var', (41, 48))	('ESCC', 'Disease', 'MESH:D018307', (128, 132))	('ESCC', 'Disease', (128, 132))	('patients', 'Species', '9606', (114, 122))
507696	31636653	We chose these three ESCC patient-derived cell lines as they cover all three types of cell differentiation of primary tumor: KYSE140 is derived from a patient with moderately differentiated squamous cell carcinoma, KYSE510 is derived from a patient with well-differentiated squamous cell carcinoma, and TE5 is derived from a patient with poorly differentiated squamous cell carcinoma.	('patient', 'Species', '9606', (26, 33))	('KYSE510', 'Var', (215, 222))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (374, 383))	('squamous cell carcinoma', 'Disease', (274, 297))	('patient', 'Species', '9606', (325, 332))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (360, 383))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('patient', 'Species', '9606', (151, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('KYSE140', 'Var', (125, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('squamous cell carcinoma', 'Disease', (360, 383))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 213))	('ESCC', 'Disease', 'MESH:D018307', (21, 25))	('patient', 'Species', '9606', (241, 248))	('ESCC', 'Disease', (21, 25))	('tumor', 'Disease', (118, 123))	('squamous cell carcinoma', 'Disease', (190, 213))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (274, 297))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (360, 383))
507703	31636653	RNA was purified according to the following criteria: (1) with concentration >=300 ng/microl, (2) OD260/280 = 2.0-2.2 and OD260/230 = 1.8-2.1, and (3) RNA integrity number (RIN) >=9, which is assessed on the Agilent Bioanalyzer 2100 system.	('N', 'Chemical', 'MESH:D009584', (152, 153))	('OD260/280', 'Var', (98, 107))	('N', 'Chemical', 'MESH:D009584', (175, 176))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('OD260/230', 'Var', (122, 131))
507714	31636653	We also compared the transcription start sites (TSS) of each transcript with the Cap Analysis of Gene Expression (CAGE) promoter tags and epigenetic marks that are typically associated with actively transcribed promoters (H3K4me1, H3K4me3, and H3K27ac).	('H3K4me3', 'Var', (231, 238))	('CAGE', 'Gene', (114, 118))	('H3K27ac', 'Var', (244, 251))	('H3K4me1', 'Var', (222, 229))	('epigenetic marks', 'Var', (138, 154))	('H3K4me1, H3K4me3', 'Chemical', 'MESH:C024755', (222, 238))	('CAGE', 'Gene', '168400', (114, 118))
507736	31636653	Totally, we identified 445,983, 477,033, 491,354, 327,459, 259,482 FLNC reads from KYSE140, KYSE510, SHEE, SHEEC, and TE5 cells, respectively, which cover ~80% of all circular-consensus sequences in each cell line (Table 1).	('KYSE510', 'Var', (92, 99))	('N', 'Chemical', 'MESH:D009584', (69, 70))	('KYSE140', 'Var', (83, 90))
507748	31636653	From current SMRT data, it is clear that, except for the three annotated VIL2 variants in reference genome, other 24 VIL2 variants with different expressions are also transcribed but have not been annotated in KYSE510 cells (Figures 3A, C).	('variants', 'Var', (122, 130))	('VIL2', 'Gene', (117, 121))	('VIL2', 'Gene', (73, 77))	('VIL2', 'Gene', '7430', (73, 77))	('VIL2', 'Gene', '7430', (117, 121))
507750	31636653	For both VIL2 and TPM1 genes, there are plenty of cell-type-specific variants than those shared by multiple cells, suggesting that there may be specific splicing events in each cell (Figures 3C, D).	('variants', 'Var', (69, 77))	('VIL2', 'Gene', (9, 13))	('VIL2', 'Gene', '7430', (9, 13))	('TPM1', 'Gene', (18, 22))
507757	31636653	Under a stringent criterion (see Methods), 5,400, 5,210, 4,883, 4,756, and 2,274 lncRNAs were directly predicted from SHEE, KYSE140, KYSE510, SHEEC, and TE5 cells, respectively (Figure S2A).	('N', 'Chemical', 'MESH:D009584', (85, 86))	('KYSE510', 'Var', (133, 140))	('KYSE140', 'Var', (124, 131))
507790	31636653	During the onset of carcinogenesis, shifted splicing of DNA repair genes has previously been documented in several cancer studies, such as BRCA1 and FANCM in breast cancer and ERCC1 in ovarian cancer.	('shifted splicing', 'Var', (36, 52))	('cancer', 'Disease', (193, 199))	('ovarian cancer', 'Disease', 'MESH:D010051', (185, 199))	('BRCA1', 'Gene', '672', (139, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('ERCC1', 'Gene', '2067', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carcinogenesis', 'Disease', (20, 34))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('BRCA1', 'Gene', (139, 144))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('carcinogenesis', 'Disease', 'MESH:D063646', (20, 34))	('breast cancer', 'Disease', (158, 171))	('FANCM', 'Gene', '57697', (149, 154))	('ERCC1', 'Gene', (176, 181))	('ovarian cancer', 'Disease', (185, 199))	('FANCM', 'Gene', (149, 154))	('ovarian cancer', 'Phenotype', 'HP:0100615', (185, 199))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('cancer', 'Disease', (165, 171))	('DNA repair genes', 'Gene', (56, 72))	('cancer', 'Disease', (115, 121))	('documented', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('N', 'Chemical', 'MESH:D009584', (151, 152))
507795	31636653	Although the altered splicing pattern of this group of genes is not clear in clinical samples currently, several investigations have confirmed that a few regulators of GTPase use different variants in cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('variants', 'Var', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('clinical samples', 'Species', '191496', (77, 93))	('GTPase', 'Gene', (168, 174))
507852	29685377	On FDG-PET/CT, early change in TLG was also associated with pCR, and a 59% decrease in TLG discriminated pCR with optimal sensitivity (specificity) of 1.000 (0.867).	('associated', 'Reg', (44, 54))	('decrease', 'NegReg', (75, 83))	('TLG', 'MPA', (31, 34))	('FDG-PET/CT', 'Var', (3, 13))	('TLG', 'MPA', (87, 90))	('FDG', 'Chemical', 'MESH:C554683', (3, 6))	('pCR', 'Disease', (60, 63))	('pCR', 'Disease', (105, 108))
507980	27725730	Acquired data were auto-calibrated by background ions in positive ion mode (phthalates: m/z 149.0233 and m/z 391.2843) and standard solutions (2-hydroxybenzoic acid: m/z 137.0244 and trioxymethylanthraquinon m/z 269.0455) which were introduced by post-column mixing in negative ion mode.	('2-hydroxybenzoic acid', 'Chemical', 'MESH:D020156', (143, 164))	('m/z', 'Var', (105, 108))	('m/z 149.0233', 'Var', (88, 100))	('m/z 137.0244', 'Var', (166, 178))
507987	27110300	Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC).	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (114, 143))	('ESCC', 'Phenotype', 'HP:0011459', (145, 149))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('esophageal squamous carcinoma', 'Disease', (114, 143))	('cancers', 'Disease', (95, 102))	('Genetic', 'Var', (0, 7))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (114, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (125, 143))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('epigenetic changes', 'Var', (12, 30))
507989	27110300	Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression.	('carcinogenesis', 'Disease', (118, 132))	('tumor', 'Disease', (137, 142))	('roles', 'Reg', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('aberrant epigenetic changes', 'Var', (35, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('rat', 'Species', '10116', (24, 27))
507990	27110300	DNA methylation may occur in the key components of cancer-related signaling pathways.	('occur', 'Reg', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
507991	27110300	Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-beta, and NF-kappaB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382.	('P16', 'Gene', '1029', (141, 144))	('DACH1', 'Gene', '1602', (159, 164))	('Wnt', 'Pathway', (82, 85))	('NF-kappaB signaling', 'Pathway', (101, 120))	('ZNF382', 'Gene', '84911', (170, 176))	('Aberrant', 'Var', (0, 8))	('MGMT', 'Gene', (146, 150))	('methylation', 'Var', (13, 24))	('SFRP2', 'Gene', '6423', (152, 157))	('P16', 'Gene', (141, 144))	('cell', 'CPA', (51, 55))	('DNA', 'Gene', (9, 12))	('TGF-beta', 'Gene', '7040', (87, 95))	('genes', 'Gene', (33, 38))	('affects', 'Reg', (25, 32))	('SFRP2', 'Gene', (152, 157))	('MGMT', 'Gene', '4255', (146, 150))	('TGF-beta', 'Gene', (87, 95))	('DACH1', 'Gene', (159, 164))	('ZNF382', 'Gene', (170, 176))
507992	27110300	Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17.	('HIN1', 'Gene', '54726', (174, 178))	('SOX17', 'Gene', (199, 204))	('TFPI-2', 'Gene', '7980', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('TFPI-2', 'Gene', (180, 186))	('rat', 'Species', '10116', (70, 73))	('DACH1', 'Gene', (188, 193))	('DACH1', 'Gene', '1602', (188, 193))	('HIN1', 'Gene', (174, 178))	('SOX17', 'Gene', '64321', (199, 204))	('esophageal cancer', 'Disease', (109, 126))	('methylation', 'Var', (159, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
507993	27110300	CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC.	('CHFR', 'Gene', (0, 4))	('CHFR', 'Gene', '55743', (0, 4))	('ESCC', 'Phenotype', 'HP:0011459', (94, 98))	('methylation', 'Var', (5, 16))	('taxanes', 'Chemical', 'MESH:D043823', (77, 84))	('human', 'Species', '9606', (88, 93))	('ESCC', 'Disease', (42, 46))	('ESCC', 'Phenotype', 'HP:0011459', (42, 46))
507994	27110300	FHIT methylation is associated with poor prognosis in ESCC.	('methylation', 'Var', (5, 16))	('ESCC', 'Disease', (54, 58))	('ESCC', 'Phenotype', 'HP:0011459', (54, 58))	('FHIT', 'Gene', (0, 4))	('FHIT', 'Gene', '2272', (0, 4))
508000	27110300	Both aberrant genetic and epigenetic changes have been demonstrated to contribute to human ESCC initiation and progression.	('epigenetic changes', 'Var', (26, 44))	('aberrant genetic', 'Var', (5, 21))	('contribute', 'Reg', (71, 81))	('ESCC', 'Disease', (91, 95))	('ESCC', 'Phenotype', 'HP:0011459', (91, 95))	('rat', 'Species', '10116', (62, 65))	('human', 'Species', '9606', (85, 90))
508003	27110300	found that promoter region hypermethylation is associated with tobacco consumption by analyzing a group of tumor suppressor genes in human ESCC.	('hypermethylation', 'Var', (27, 43))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('ESCC', 'Phenotype', 'HP:0011459', (139, 143))	('tobacco', 'Species', '4097', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('human', 'Species', '9606', (133, 138))	('associated', 'Reg', (47, 57))
508020	27110300	Inhibition of methyl group transfer regulates the expression of genes involved in carcinogenesis.	('regulates', 'Reg', (36, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('carcinogenesis', 'Disease', (82, 96))	('Inhibition', 'Var', (0, 10))	('expression of genes', 'MPA', (50, 69))
508023	27110300	Aberrant DNA methylation is involved in the major components of cell cycle, DNA damage repair, and cancer-related signaling pathways.	('Aberrant', 'Var', (0, 8))	('methylation', 'Var', (13, 24))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('involved', 'Reg', (28, 36))	('cancer', 'Disease', (99, 105))	('DNA', 'Gene', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
508025	27110300	P16 is frequently methylated in ESCC, while methylation of p14 and p15 is relatively infrequent in ESCC.	('ESCC', 'Disease', (32, 36))	('ESCC', 'Phenotype', 'HP:0011459', (32, 36))	('P16', 'Gene', (0, 3))	('p14', 'Gene', (59, 62))	('methylated', 'Var', (18, 28))	('p14', 'Gene', '1029', (59, 62))	('P16', 'Gene', '1029', (0, 3))	('ESCC', 'Phenotype', 'HP:0011459', (99, 103))	('p15', 'Gene', (67, 70))	('p15', 'Gene', '1030', (67, 70))
496354	27110300	Methylation of CHFR sensitized ESCC cells to taxanes.	('sensitized', 'Reg', (20, 30))	('Methylation', 'Var', (0, 11))	('CHFR', 'Gene', (15, 19))	('CHFR', 'Gene', '55743', (15, 19))	('ESCC', 'Phenotype', 'HP:0011459', (31, 35))	('taxanes', 'Chemical', 'MESH:D043823', (45, 52))
508038	27110300	Fragile histidine triad (FHIT) is regarded as a "caretaker," and loss of this caretaker function initiates the onset of genome instability and cancer development.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('loss', 'Var', (65, 69))	('genome instability', 'CPA', (120, 138))	('Fragile histidine triad', 'Gene', '2272', (0, 23))	('FHIT', 'Gene', (25, 29))	('FHIT', 'Gene', '2272', (25, 29))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('Fragile histidine triad', 'Gene', (0, 23))
508039	27110300	In some tumors that are associated with environmental carcinogens, alterations in the FHIT gene occur quite early in the development of cancer.	('FHIT', 'Gene', '2272', (86, 90))	('rat', 'Species', '10116', (71, 74))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('alterations', 'Var', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancer', 'Disease', (136, 142))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('FHIT', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
508040	27110300	FHIT is frequently methylated in the early stages of ESCC, and aberrant methylation of FHIT is associated with poor prognosis and tobacco exposure.	('tobacco', 'Species', '4097', (130, 137))	('ESCC', 'Disease', (53, 57))	('ESCC', 'Phenotype', 'HP:0011459', (53, 57))	('FHIT', 'Gene', (0, 4))	('FHIT', 'Gene', (87, 91))	('FHIT', 'Gene', '2272', (0, 4))	('aberrant methylation', 'Var', (63, 83))	('associated', 'Reg', (95, 105))	('FHIT', 'Gene', '2272', (87, 91))
508042	27110300	Defective MMR increases mutation rates up to 1000-fold and leads to microsatellite instability (MSI) to result in carcinogenesis.	('mutation rates', 'MPA', (24, 38))	('carcinogenesis', 'Disease', (114, 128))	('MSI', 'Disease', 'None', (96, 99))	('increases', 'PosReg', (14, 23))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('leads to', 'Reg', (59, 67))	('rat', 'Species', '10116', (33, 36))	('MSI', 'Disease', (96, 99))	('Defective', 'Var', (0, 9))	('microsatellite instability', 'MPA', (68, 94))	('MMR', 'Gene', (10, 13))	('result in', 'Reg', (104, 113))
508043	27110300	Germline MMR mutation gives rise to hereditary nonpolyposis colorectal cancer (CRC) accounts for ~3 % of all CRCs.	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (36, 77))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('MMR', 'Gene', (9, 12))	('mutation', 'Var', (13, 21))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (36, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('hereditary nonpolyposis colorectal cancer', 'Disease', (36, 77))	('gives rise to', 'Reg', (22, 35))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))
508045	27110300	By contrast with HNPCC, sporadic cancers are rarely found to have mutations in the MLH1 or MSH2 genes.	('mutations', 'Var', (66, 75))	('HNPCC', 'Disease', 'None', (17, 22))	('HNPCC', 'Disease', (17, 22))	('MSH2', 'Gene', (91, 95))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('MSH2', 'Gene', '4436', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('MLH1', 'Gene', '4292', (83, 87))	('sporadic cancers', 'Disease', 'MESH:D009369', (24, 40))	('MLH1', 'Gene', (83, 87))	('sporadic cancers', 'Disease', (24, 40))
508047	27110300	Mismatch repair deficiency can be inherited mutations or biallelic MLH1 promoter region hypermethylation.	('MLH1', 'Gene', '4292', (67, 71))	('MLH1', 'Gene', (67, 71))	('biallelic', 'Var', (57, 66))	('hypermethylation', 'Var', (88, 104))	('Mismatch repair', 'Gene', (0, 15))
508048	27110300	Methylation may be served as "second hit" for carcinogenesis.	('Methylation', 'Var', (0, 11))	('carcinogenesis', 'Disease', (46, 60))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))
508049	27110300	MLH1 is frequently methylated in sporadic CRC and other tumors, while MSH2 was not methylated in any of the sporadic CRCs.	('methylated', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('sporadic', 'Disease', (33, 41))	('CRC', 'Phenotype', 'HP:0003003', (42, 45))	('MLH1', 'Gene', '4292', (0, 4))	('tumors', 'Disease', (56, 62))	('MLH1', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('MSH2', 'Gene', (70, 74))	('MSH2', 'Gene', '4436', (70, 74))	('CRC', 'Disease', (42, 45))
508050	27110300	In human esophageal squamous cell carcinoma, MLH1 and MSH2 are methylated in 33-62 % and 29-32 % of cases, irrespectively.	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('MSH2', 'Gene', '4436', (54, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('human', 'Species', '9606', (3, 8))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (9, 43))	('MLH1', 'Gene', '4292', (45, 49))	('MLH1', 'Gene', (45, 49))	('methylated', 'Var', (63, 73))	('esophageal squamous cell carcinoma', 'Disease', (9, 43))	('MSH2', 'Gene', (54, 58))
508051	27110300	The expression of MLH1 and MSH2 were silenced by promoter region hypermethylation.	('hypermethylation', 'Var', (65, 81))	('silenced', 'NegReg', (37, 45))	('expression', 'MPA', (4, 14))	('MSH2', 'Gene', (27, 31))	('MSH2', 'Gene', '4436', (27, 31))	('MLH1', 'Gene', '4292', (18, 22))	('MLH1', 'Gene', (18, 22))
508052	27110300	O6-methylguanine-DNA methyltransferase (MGMT) is a DNA damage repair enzyme that protects cells from G to A mutations by removing methyl or alkyl groups from guanine after chemical modification.	('O6-methylguanine-DNA methyltransferase', 'Gene', (0, 38))	('removing', 'NegReg', (121, 129))	('methyl or alkyl groups', 'MPA', (130, 152))	('mutations', 'Var', (108, 117))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (0, 38))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))	('guanine', 'Chemical', 'MESH:D006147', (9, 16))	('guanine', 'Chemical', 'MESH:D006147', (158, 165))
508053	27110300	MGMT is frequently methylated in human ESCC, and methylation of MGMT sensitized ESCC to temozolomide treatment.	('MGMT', 'Gene', (0, 4))	('ESCC', 'Phenotype', 'HP:0011459', (80, 84))	('sensitized', 'Reg', (69, 79))	('ESCC', 'Phenotype', 'HP:0011459', (39, 43))	('MGMT', 'Gene', (64, 68))	('human', 'Species', '9606', (33, 38))	('methylation', 'Var', (49, 60))	('MGMT', 'Gene', '4255', (64, 68))	('temozolomide', 'Chemical', 'MESH:D000077204', (88, 100))	('MGMT', 'Gene', '4255', (0, 4))	('ESCC', 'Disease', (80, 84))
508059	27110300	SFRP2 is methylated in 83 % of ESCC, and the expression of SFRP2 is regulated by promoter region hypermethylation.	('SFRP2', 'Gene', '6423', (0, 5))	('SFRP2', 'Gene', '6423', (59, 64))	('SFRP2', 'Gene', (0, 5))	('SFRP2', 'Gene', (59, 64))	('hypermethylation', 'Var', (97, 113))	('expression', 'MPA', (45, 55))	('regulated', 'Reg', (68, 77))	('ESCC', 'Phenotype', 'HP:0011459', (31, 35))
508061	27110300	SOX17 is frequently methylated in ESCC, and methylation of SOX17 activated Wnt signaling.	('methylation', 'Var', (44, 55))	('SOX17', 'Gene', (59, 64))	('Wnt signaling', 'Pathway', (75, 88))	('SOX17', 'Gene', '64321', (0, 5))	('activated', 'PosReg', (65, 74))	('SOX17', 'Gene', '64321', (59, 64))	('ESCC', 'Phenotype', 'HP:0011459', (34, 38))	('SOX17', 'Gene', (0, 5))
508062	27110300	SOX17 methylation is an early detection marker and is related to patients' history of alcohol use.	('related', 'Reg', (54, 61))	('alcohol use', 'Phenotype', 'HP:0030955', (86, 97))	('SOX17', 'Gene', '64321', (0, 5))	('alcohol', 'Chemical', 'MESH:D000438', (86, 93))	('methylation', 'Var', (6, 17))	('patients', 'Species', '9606', (65, 73))	('SOX17', 'Gene', (0, 5))
508064	27110300	Wnt inhibitory factor-1 (WIF1), one of the most important Wnt antagonists, is frequently down-regulated by promoter region hypermethylation in various types of cancer.	('down-regulated', 'NegReg', (89, 103))	('WIF1', 'Gene', (25, 29))	('WIF1', 'Gene', '11197', (25, 29))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('Wnt inhibitory factor-1', 'Gene', '11197', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('hypermethylation', 'Var', (123, 139))	('Wnt inhibitory factor-1', 'Gene', (0, 23))
508067	27110300	Adenomatous polyposis coli (APC) is methylated more frequently in human adenocarcinoma than in human ESCC.	('Adenomatous polyposis coli', 'Disease', (0, 26))	('methylated', 'Var', (36, 46))	('human', 'Species', '9606', (95, 100))	('Adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (0, 26))	('Adenomatous polyposis coli', 'Disease', 'MESH:D011125', (0, 26))	('ESCC', 'Phenotype', 'HP:0011459', (101, 105))	('human', 'Species', '9606', (66, 71))	('APC', 'Phenotype', 'HP:0005227', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('APC', 'Disease', 'MESH:D011125', (28, 31))	('adenocarcinoma', 'Disease', (72, 86))	('adenocarcinoma', 'Disease', 'MESH:D000230', (72, 86))	('APC', 'Disease', (28, 31))
508075	27110300	There are only a few reports on the epigenetic regulation of TGF-beta signaling in ESCC.	('epigenetic', 'Var', (36, 46))	('TGF-beta', 'Gene', '7040', (61, 69))	('ESCC', 'Disease', (83, 87))	('TGF-beta', 'Gene', (61, 69))	('ESCC', 'Phenotype', 'HP:0011459', (83, 87))
508076	27110300	The human runt-related transcription factor 3 (RUNX3), an important component of the TGF-beta signaling pathway, is deleted in a variety of human cancers, including ESCC.	('deleted', 'Var', (116, 123))	('TGF-beta', 'Gene', (85, 93))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('human', 'Species', '9606', (140, 145))	('human', 'Species', '9606', (4, 9))	('runt-related transcription factor 3', 'Gene', (10, 45))	('ESCC', 'Disease', (165, 169))	('runt-related transcription factor 3', 'Gene', '864', (10, 45))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('RUNX3', 'Gene', '864', (47, 52))	('TGF-beta', 'Gene', '7040', (85, 93))	('ESCC', 'Phenotype', 'HP:0011459', (165, 169))	('RUNX3', 'Gene', (47, 52))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
508079	27110300	DACH1 expression was regulated by promoter region hypermethylation in esophageal cancer.	('DACH1', 'Gene', (0, 5))	('esophageal cancer', 'Disease', (70, 87))	('DACH1', 'Gene', '1602', (0, 5))	('expression', 'MPA', (6, 16))	('hypermethylation', 'Var', (50, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
508081	27110300	DACH1 methylation is associated with poor differentiation and late tumor stage.	('late tumor', 'Disease', (62, 72))	('DACH1', 'Gene', (0, 5))	('associated', 'Reg', (21, 31))	('DACH1', 'Gene', '1602', (0, 5))	('poor differentiation', 'CPA', (37, 57))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('late tumor', 'Disease', 'MESH:D009369', (62, 72))	('methylation', 'Var', (6, 17))
508084	27110300	FBXO32 is methylated in 52.3 % of human ESCC and methylation of FBXO32 is associated with poor 5-year overall survival.	('ESCC', 'Disease', (40, 44))	('poor', 'NegReg', (90, 94))	('human', 'Species', '9606', (34, 39))	('FBXO32', 'Gene', '114907', (64, 70))	('FBXO32', 'Gene', (64, 70))	('FBXO32', 'Gene', '114907', (0, 6))	('ESCC', 'Phenotype', 'HP:0011459', (40, 44))	('FBXO32', 'Gene', (0, 6))	('methylation', 'Var', (49, 60))	('overall survival', 'CPA', (102, 118))	('associated', 'Reg', (74, 84))
508090	27110300	It has been reported that inhibition of NF-kappaB can increase the chemo-sensitivity of esophageal cancer (EC) cells in vitro.	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('chemo-sensitivity', 'CPA', (67, 84))	('inhibition', 'Var', (26, 36))	('increase', 'PosReg', (54, 62))	('NF-kappaB', 'Protein', (40, 49))	('esophageal cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
508091	27110300	The NF-kappaB inhibitor Bay11-7082 had significant antitumor effects on ESCC xenografts in nude mice by promoting apoptosis and inhibiting proliferation and angiogenesis, as well as reducing the metastasis of ESCC cells to the lungs, without significant toxic effects.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ESCC', 'Phenotype', 'HP:0011459', (72, 76))	('rat', 'Species', '10116', (146, 149))	('promoting', 'PosReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('reducing', 'NegReg', (182, 190))	('Bay11-7082', 'Chemical', 'MESH:C434003', (24, 34))	('nude mice', 'Species', '10090', (91, 100))	('tumor', 'Disease', (55, 60))	('ESCC', 'Disease', (209, 213))	('inhibiting', 'NegReg', (128, 138))	('ESCC', 'Phenotype', 'HP:0011459', (209, 213))	('metastasis', 'CPA', (195, 205))	('Bay11-7082', 'Var', (24, 34))	('apoptosis', 'CPA', (114, 123))
508093	27110300	The best studied epigenetic modification is promoter region hypermethylation in tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('promoter region hypermethylation', 'Var', (44, 76))	('tumor', 'Disease', (80, 85))
508096	27110300	LINE-1 methylation has been shown to be highly variable among ESCC specimens, LINE-1 hypomethylation is a marker of a poor prognosis in patients with early stage tumors, but not in those with advanced stage tumors.	('ESCC', 'Phenotype', 'HP:0011459', (62, 66))	('hypomethylation', 'Var', (85, 100))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('stage tumors', 'Disease', 'MESH:D062706', (156, 168))	('stage tumors', 'Disease', 'MESH:D062706', (201, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('LINE-1', 'Gene', (78, 84))	('patients', 'Species', '9606', (136, 144))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('stage tumors', 'Disease', (156, 168))	('stage tumors', 'Disease', (201, 213))
508099	27110300	Loss of 5-hmC is a poor prognostic marker in kidney cancer.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('kidney cancer', 'Disease', 'MESH:D007680', (45, 58))	('5-hmC', 'Chemical', 'MESH:C011865', (8, 13))	('kidney cancer', 'Phenotype', 'HP:0009726', (45, 58))	('5-hmC', 'Protein', (8, 13))	('kidney cancer', 'Disease', (45, 58))	('Loss', 'Var', (0, 4))
508101	27110300	DNA methylation changes were shown to have a progression tendency during esophageal carcinogenesis and progression, suggesting that DNA methylation is an early event in ESCC.	('changes', 'Var', (16, 23))	('ESCC', 'Disease', (169, 173))	('ESCC', 'Phenotype', 'HP:0011459', (169, 173))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (73, 98))	('esophageal carcinogenesis', 'Disease', (73, 98))
508102	27110300	Our previous studies found that DAPK, p16, MGMT, MLH1, RARbeta2, HIN1, TFPI-2, DACH1, and SOX17 were methylated in the precursor lesions of human esophageal epithelia.	('SOX17', 'Gene', (90, 95))	('DACH1', 'Gene', '1602', (79, 84))	('HIN1', 'Gene', '54726', (65, 69))	('esophageal epithelia', 'Disease', (146, 166))	('TFPI-2', 'Gene', (71, 77))	('MGMT', 'Gene', (43, 47))	('MLH1', 'Gene', (49, 53))	('HIN1', 'Gene', (65, 69))	('SOX17', 'Gene', '64321', (90, 95))	('methylated', 'Var', (101, 111))	('human', 'Species', '9606', (140, 145))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (146, 166))	('TFPI-2', 'Gene', '7980', (71, 77))	('p16', 'Gene', (38, 41))	('esophageal epithelia', 'Disease', 'MESH:D004941', (146, 166))	('DACH1', 'Gene', (79, 84))	('MLH1', 'Gene', '4292', (49, 53))	('MGMT', 'Gene', '4255', (43, 47))	('p16', 'Gene', '1029', (38, 41))
508104	27110300	CHFR methylation is a late stage marker of ESCC.	('CHFR', 'Gene', (0, 4))	('CHFR', 'Gene', '55743', (0, 4))	('methylation', 'Var', (5, 16))	('ESCC', 'Disease', (43, 47))	('ESCC', 'Phenotype', 'HP:0011459', (43, 47))
508106	27110300	Methylation of CDH1 was detected in 14-61 % of ESCC tumors, and it was associated with the recurrence of early stage.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('detected', 'Reg', (24, 32))	('ESCC tumors', 'Disease', (47, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('Methylation', 'Var', (0, 11))	('ESCC tumors', 'Disease', 'MESH:D004938', (47, 58))	('ESCC', 'Phenotype', 'HP:0011459', (47, 51))	('CDH1', 'Gene', (15, 19))	('CDH1', 'Gene', '999', (15, 19))	('associated with', 'Reg', (71, 86))
508107	27110300	RASSF1A hypermethylation was significantly correlated with poorly differentiated tumors and advanced tumor stage.	('RASSF1A', 'Gene', (0, 7))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('hypermethylation', 'Var', (8, 24))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('correlated', 'Reg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('RASSF1A', 'Gene', '11186', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (81, 86))
508108	27110300	P16 methylation was associated with invasiveness and metastasis.	('associated', 'Reg', (20, 30))	('P16', 'Gene', (0, 3))	('metastasis', 'CPA', (53, 63))	('invasiveness', 'CPA', (36, 48))	('methylation', 'Var', (4, 15))	('P16', 'Gene', '1029', (0, 3))
508110	27110300	Our recent study found that DACT2 methylation is frequently methylated in human esophageal squamous dysplasia and ESCC.	('squamous dysplasia', 'Phenotype', 'HP:0002860', (91, 109))	('esophageal squamous dysplasia', 'Disease', 'MESH:D000077277', (80, 109))	('ESCC', 'Disease', (114, 118))	('methylation', 'Var', (34, 45))	('ESCC', 'Phenotype', 'HP:0011459', (114, 118))	('DACT2', 'Gene', '168002', (28, 33))	('esophageal squamous dysplasia', 'Disease', (80, 109))	('human', 'Species', '9606', (74, 79))	('DACT2', 'Gene', (28, 33))
508111	27110300	DACT2 methylation is associated with TNM stage and lymph node metastasis.	('DACT2', 'Gene', '168002', (0, 5))	('associated', 'Reg', (21, 31))	('methylation', 'Var', (6, 17))	('DACT2', 'Gene', (0, 5))	('lymph node metastasis', 'CPA', (51, 72))	('TNM stage', 'Disease', (37, 46))
508112	27110300	These results suggest that DACT2 methylation may serve as ESCC early detective and prognostic markers.	('DACT2', 'Gene', '168002', (27, 32))	('DACT2', 'Gene', (27, 32))	('methylation', 'Var', (33, 44))	('ESCC', 'Phenotype', 'HP:0011459', (58, 62))
508113	27110300	NKD2 is frequently methylated in human ESCC, and methylation of NKD2 is associated with TNM stage and lymph node metastasis (data not shown).	('NKD2', 'Gene', (0, 4))	('TNM', 'Disease', (88, 91))	('associated', 'Reg', (72, 82))	('NKD2', 'Gene', '85409', (0, 4))	('lymph node metastasis', 'CPA', (102, 123))	('ESCC', 'Phenotype', 'HP:0011459', (39, 43))	('human', 'Species', '9606', (33, 38))	('NKD2', 'Gene', (64, 68))	('methylation', 'Var', (49, 60))	('NKD2', 'Gene', '85409', (64, 68))
508117	27110300	In oxaliplatin-treated gastric cancer patients, overall survival was longer in the MLH1 unmethylated group compared to the MLH1 methylated group.	('overall survival', 'MPA', (48, 64))	('gastric cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('MLH1', 'Gene', '4292', (123, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (23, 37))	('MLH1', 'Gene', (123, 127))	('MLH1', 'Gene', '4292', (83, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (23, 37))	('MLH1', 'Gene', (83, 87))	('longer', 'PosReg', (69, 75))	('patients', 'Species', '9606', (38, 46))	('unmethylated', 'Var', (88, 100))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (3, 14))
508124	27110300	The recognition that certain tumors contain activating mutations in driver genes encoding protein kinases has led to the development of small-molecule inhibitor drugs targeting those kinases.	('activating', 'PosReg', (44, 54))	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))
508130	27110300	We are far from having a full understanding of the molecular mechanisms responsible for the initiation and maintenance of the epigenetic abnormalities that help drive tumorigenesis.	('drive', 'PosReg', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('epigenetic', 'Var', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
508131	27110300	Epigenetic regulation of tumor suppressor gene expression plays an important role during esophageal carcinogenesis and progression.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (89, 114))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('esophageal carcinogenesis', 'Disease', (89, 114))	('tumor', 'Disease', (25, 30))	('Epigenetic regulation', 'Var', (0, 21))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
508134	24116107	Increased Risk of Developing Digestive Tract Cancer in Subjects Carrying the PLCE1 rs2274223 A>G Polymorphism: Evidence from a Meta-Analysis To date, the association between phospholipase C epsilon 1 (PLCE1) rs2274223 A>G and risk of digestive tract cancer (DTC) remains inconclusive.	('tract cancer', 'Disease', 'MESH:D014571', (244, 256))	('DTC', 'Chemical', '-', (258, 261))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (234, 256))	('rs2274223', 'Mutation', 'rs2274223', (208, 217))	('tract cancer', 'Disease', (244, 256))	('PLCE1', 'Gene', (77, 82))	('PLCE1', 'Gene', '51196', (77, 82))	('phospholipase C epsilon 1', 'Gene', '51196', (174, 199))	('phospholipase C epsilon 1', 'Gene', (174, 199))	('Tract Cancer', 'Disease', 'MESH:D014571', (39, 51))	('Tract Cancer', 'Disease', (39, 51))	('Digestive Tract Cancer', 'Phenotype', 'HP:0007378', (29, 51))	('DTC', 'Phenotype', 'HP:0007378', (258, 261))	('PLCE1', 'Gene', (201, 206))	('PLCE1', 'Gene', '51196', (201, 206))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('rs2274223 A>G', 'Var', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('rs2274223', 'Mutation', 'rs2274223', (83, 92))	('rs2274223', 'Var', (83, 92))
508135	24116107	A comprehensive search was conducted to identify all eligible studies of PLCE1 rs2274223 polymorphism and digestive tract cancer risk.	('PLCE1', 'Gene', (73, 78))	('tract cancer', 'Disease', (116, 128))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (106, 128))	('PLCE1', 'Gene', '51196', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('rs2274223', 'Mutation', 'rs2274223', (79, 88))	('rs2274223', 'Var', (79, 88))	('tract cancer', 'Disease', 'MESH:D014571', (116, 128))
508136	24116107	Overall, the PLCE1 rs2274223 A>G polymorphism was associated with risk of DTC in all genetic models (GA vs. AA: OR = 1.21, 95% CI = 1.14-1.29, P<0.001; GG vs. AA: OR = 1.30, 95% CI = 1.06-1.60, P = 0.012; GG/GA vs. AA: OR = 1.20, 95% CI = 1.10-1.32, P<0.001; GG vs. GA/AA: OR = 1.21, 95% CI = 1.01-1.46, P = 0.040).	('rs2274223', 'Mutation', 'rs2274223', (19, 28))	('DTC', 'Chemical', '-', (74, 77))	('DTC', 'Disease', (74, 77))	('PLCE1', 'Gene', (13, 18))	('PLCE1', 'Gene', '51196', (13, 18))	('DTC', 'Phenotype', 'HP:0007378', (74, 77))	('rs2274223 A>G', 'Var', (19, 32))
508139	24116107	Our study indicated that PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of DTC, especially among Asian populations.	('DTC', 'Disease', (110, 113))	('DTC', 'Chemical', '-', (110, 113))	('PLCE1', 'Gene', '51196', (25, 30))	('rs2274223 A>G', 'Var', (31, 44))	('DTC', 'Phenotype', 'HP:0007378', (110, 113))	('associated', 'Reg', (76, 86))	('PLCE1', 'Gene', (25, 30))	('rs2274223', 'Mutation', 'rs2274223', (31, 40))
508152	24116107	Rs2274223 (A>G) is a non-synonymous single nucleotide polymorphism (SNP) located in 26th exon of the PLCE1 gene and result in the amino acid change from histidine (His) to arginine (Arg) at codon 1927 of PLCE1.	('histidine', 'Chemical', 'MESH:D006639', (153, 162))	('histidine', 'MPA', (153, 162))	('PLCE1', 'Gene', (204, 209))	('PLCE1', 'Gene', (101, 106))	('Rs2274223', 'Mutation', 'Rs2274223', (0, 9))	('PLCE1', 'Gene', '51196', (204, 209))	('PLCE1', 'Gene', '51196', (101, 106))	('His', 'Chemical', 'MESH:D006639', (164, 167))	('Rs2274223 (A>G', 'Var', (0, 14))	('arginine', 'Chemical', 'MESH:D001120', (172, 180))	('amino acid', 'MPA', (130, 140))	('change', 'Reg', (141, 147))	('Arg', 'Chemical', 'MESH:D001120', (182, 185))
508153	24116107	In 2010, two large-scale genome-wide association studies (GWASs) simultaneously reported that the new and notable low-penetrance susceptibility locus rs2274223 was strongly associated with risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in Chinese population.	('esophageal squamous cell carcinoma', 'Disease', (197, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (243, 272))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('gastric cardia adenocarcinoma', 'Disease', (243, 272))	('rs2274223', 'Mutation', 'rs2274223', (150, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('rs2274223', 'Var', (150, 159))	('associated with', 'Reg', (173, 188))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (197, 231))
508155	24116107	Interestingly, another study proved that rs2274223 was associated with a protective effect against colorectal cancer (CRC) in a Chinese population.	('rs2274223', 'Var', (41, 50))	('colorectal cancer', 'Disease', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CRC', 'Phenotype', 'HP:0003003', (118, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('rs2274223', 'Mutation', 'rs2274223', (41, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
508156	24116107	Otherwise, as reported in a Dutch population and a South African population, it was unlikely that the PLCE1 rs2274223 SNP plays a role in esophageal adenocarcinoma (EAC) or ESCC susceptibility.	('rs2274223', 'Mutation', 'rs2274223', (108, 117))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (138, 163))	('rs2274223', 'Var', (108, 117))	('ESCC', 'Disease', (173, 177))	('EAC', 'Phenotype', 'HP:0011459', (165, 168))	('PLCE1', 'Gene', (102, 107))	('PLCE1', 'Gene', '51196', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (138, 163))	('esophageal adenocarcinoma', 'Disease', (138, 163))
508157	24116107	Besides, there was a study focused on the associations between the rs2274223-G allele and the prognosis of gastric cancer patients, suggesting that individuals carrying rs2274223 AG/GG genotypes had a higher survival rate than those carrying the AA genotype.	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('rs2274223', 'Mutation', 'rs2274223', (169, 178))	('rs2274223', 'Mutation', 'rs2274223', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (122, 130))	('survival rate', 'CPA', (208, 221))	('rs2274223 AG/GG', 'Var', (169, 184))	('gastric cancer', 'Disease', (107, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))	('higher', 'PosReg', (201, 207))
508159	24116107	Hence, we conducted a meta-analysis on all eligible case-control studies involving 8281 cases and 10,532 controls to estimate the overall DTC risk of the rs2274223 (A>G) polymorphism.	('DTC', 'Disease', (138, 141))	('DTC', 'Chemical', '-', (138, 141))	('DTC', 'Phenotype', 'HP:0007378', (138, 141))	('rs2274223', 'Mutation', 'rs2274223', (154, 163))	('rs2274223 (A>G', 'Var', (154, 168))
508160	24116107	We searched PubMed and Embase (updated to 28th February 2013) using the following search terms: "rs2274223", "PLCE1", "10q23", "genetic susceptibility", "SNP", "polymorphism" or "variation", and "cancer" or "carcinoma" or "neoplasia".	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('rs2274223', 'Mutation', 'rs2274223', (97, 106))	('PLCE1', 'Gene', (110, 115))	('variation', 'Var', (179, 188))	('neoplasia', 'Phenotype', 'HP:0002664', (223, 232))	('PLCE1', 'Gene', '51196', (110, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('"carcinoma" or "neoplasia', 'Disease', 'MESH:D009369', (207, 232))	('"cancer', 'Disease', (195, 202))	('"cancer', 'Disease', 'MESH:D009369', (195, 202))	('"carcinoma" or "neoplasia', 'Disease', (207, 232))
508161	24116107	Studies included in our meta-analysis have to meet the following inclusion criteria: (a) evaluated the PLCE1 rs2274223 polymorphism and cancer risk, (b) used a case-control design and (c) contained available genotype frequency.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('rs2274223', 'Mutation', 'rs2274223', (109, 118))	('cancer', 'Disease', (136, 142))	('rs2274223', 'Var', (109, 118))	('PLCE1', 'Gene', (103, 108))	('PLCE1', 'Gene', '51196', (103, 108))
508164	24116107	The strength of the association between the PLCE1 rs2274223 polymorphism and cancer risk was assessed by the odds ratio (OR) and the 95% confidence interval (95% CI).	('rs2274223', 'Mutation', 'rs2274223', (50, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('rs2274223', 'Var', (50, 59))	('PLCE1', 'Gene', (44, 49))	('PLCE1', 'Gene', '51196', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
508168	24116107	The evaluation of the association between the PLCE1 rs2274223 polymorphism and the susceptibility to digestive tract cancer is presented in Table 2.	('rs2274223', 'Var', (52, 61))	('PLCE1', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PLCE1', 'Gene', '51196', (46, 51))	('tract cancer', 'Disease', 'MESH:D014571', (111, 123))	('tract cancer', 'Disease', (111, 123))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (101, 123))	('rs2274223', 'Mutation', 'rs2274223', (52, 61))
508169	24116107	Overall, the variant G allele of rs2274223 A>G could significantly increase the risk of cancer in all genetic models (heterozygote comparison, GA vs. AA: OR = 1.21, 95% CI = 1.14-1.29, P<0.001, I2 = 35.70%; homozygote comparison, GG vs. AA: OR = 1.30, 95% CI = 1.06-1.60, P = 0.012, I2 = 65.60%; dominant model, GG/GA vs. AA: OR = 1.20, 95% CI = 1.10-1.32, P<0.001, I2 = 57.60%; recessive model, GG vs. GA/AA: OR = 1.21, 95% CI = 1.01-1.46, P = 0.040, I2 = 60.00%).	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('rs2274223', 'Mutation', 'rs2274223', (33, 42))	('increase', 'PosReg', (67, 75))	('variant', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('rs2274223 A>G', 'Var', (33, 46))
508170	24116107	Additionally, in the analysis stratified by cancer types (Figure 2), the PLCE1 rs2274223 polymorphism was significantly linked to a higher risk for esophageal cancer (GA vs. AA: OR = 1.22, 95% CI = 1.10-1.34, P<0.001, I2 = 39.60%; GG vs. AA: OR = 1.31, 95% CI = 1.10-1.55, P = 0.002, I2 = 0%; GG/GA vs. AA: OR = 1.24, 95% CI = 1.13-1.36 P<0.001, I2 = 45.20%; GG vs. GA/AA: OR = 1.20, 95% CI = 1.02-1.40, P = 0.027, I2 = 0%).	('cancer', 'Disease', (159, 165))	('PLCE1', 'Gene', (73, 78))	('PLCE1', 'Gene', '51196', (73, 78))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', (148, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('linked', 'Reg', (120, 126))	('rs2274223', 'Mutation', 'rs2274223', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('rs2274223', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
508174	24116107	When evaluating the association between the PLCE1 rs2274223 polymorphism and the susceptibility to DTC, we found that there was significant heterogeneity for the homozygote comparison (GG vs. AA: P heterogeneity = 0.001, I2 = 65.60%), dominant model comparison (GG/GA vs. AA: P heterogeneity = 0.009, I2 = 57.60%) and recessive model comparison (GG vs. GA/AA: P heterogeneity = 0.005, I2 = 60.00%) but not for the heterozygote comparison (GA vs. AA: P heterogeneity = 0.113, I2 = 35.70%).	('rs2274223', 'Mutation', 'rs2274223', (50, 59))	('rs2274223', 'Var', (50, 59))	('PLCE1', 'Gene', (44, 49))	('DTC', 'Chemical', '-', (99, 102))	('PLCE1', 'Gene', '51196', (44, 49))	('DTC', 'Phenotype', 'HP:0007378', (99, 102))
508177	24116107	In the current meta-analysis, we ascertained that the PLCE1 rs2274223 A>G polymorphism was significantly associated with increased DTC risk, especially with gastric cancer and esophageal cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (157, 171))	('DTC', 'Chemical', '-', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('esophageal cancer', 'Disease', (176, 193))	('increased', 'PosReg', (121, 130))	('DTC', 'Disease', (131, 134))	('DTC', 'Phenotype', 'HP:0007378', (131, 134))	('PLCE1', 'Gene', (54, 59))	('gastric cancer', 'Disease', (157, 171))	('esophageal cancer', 'Disease', 'MESH:D004938', (176, 193))	('rs2274223', 'Mutation', 'rs2274223', (60, 69))	('PLCE1', 'Gene', '51196', (54, 59))	('gastric cancer', 'Disease', 'MESH:D013274', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('rs2274223 A>G', 'Var', (60, 73))
508178	24116107	To our knowledge, this is the first study to investigate the association between the PLCE1 rs2274223 A>G polymorphism and the risk of DTC across different ancestries.	('rs2274223 A>G', 'Var', (91, 104))	('DTC', 'Phenotype', 'HP:0007378', (134, 137))	('rs2274223', 'Mutation', 'rs2274223', (91, 100))	('DTC', 'Chemical', '-', (134, 137))	('PLCE1', 'Gene', (85, 90))	('PLCE1', 'Gene', '51196', (85, 90))	('DTC', 'Disease', (134, 137))
508181	24116107	This polymorphism rs2274223 causes an amino acid change from histidine to arginine in the PLCE1 protein calcium-dependent lipid-binding (C2) domain.	('arginine', 'Chemical', 'MESH:D001120', (74, 82))	('rs2274223', 'Var', (18, 27))	('PLCE1', 'Gene', (90, 95))	('lipid', 'Chemical', 'MESH:D008055', (122, 127))	('PLCE1', 'Gene', '51196', (90, 95))	('histidine', 'MPA', (61, 70))	('amino acid change', 'MPA', (38, 55))	('histidine', 'Chemical', 'MESH:D006639', (61, 70))	('calcium-dependent lipid-binding', 'MPA', (104, 135))	('rs2274223', 'Mutation', 'rs2274223', (18, 27))	('calcium', 'Chemical', 'MESH:D002118', (104, 111))
508182	24116107	simultaneously reported the strong association of the new and notable low-penetrance susceptibility locus rs2274223 with the increased risk of ESCC and GCA in the Chinese population by two large-scale GWASs.	('rs2274223', 'Mutation', 'rs2274223', (106, 115))	('GCA', 'Disease', (152, 155))	('rs2274223', 'Var', (106, 115))	('ESCC', 'Disease', (143, 147))
508183	24116107	However, it was unlikely that the PLCE1 rs2274223 SNP played a role in EAC or ESCC susceptibility in American and Dutch.	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('ESCC', 'Disease', (78, 82))	('EAC', 'Disease', (71, 74))	('rs2274223', 'Mutation', 'rs2274223', (40, 49))	('rs2274223', 'Var', (40, 49))	('PLCE1', 'Gene', (34, 39))	('PLCE1', 'Gene', '51196', (34, 39))
508184	24116107	Further observation showed that the rs2274223-G allele had a stronger effect on female and GCA than male and non-cardia GC.	('non-cardia', 'Disease', (109, 119))	('female', 'CPA', (80, 86))	('non-cardia', 'Disease', 'MESH:D004938', (109, 119))	('GCA', 'Disease', (91, 94))	('rs2274223', 'Mutation', 'rs2274223', (36, 45))	('rs2274223-G', 'Var', (36, 47))
508185	24116107	found that individuals carrying PLCE1 rs2274223 AG/GG genotypes had a higher survival rate than those carrying the AA genotype, which suggested that the rs2274223-G allele may be associated with the prognosis of the gastric cancer patients.	('survival rate', 'CPA', (77, 90))	('associated', 'Reg', (179, 189))	('rs2274223', 'Mutation', 'rs2274223', (153, 162))	('patients', 'Species', '9606', (231, 239))	('gastric cancer', 'Phenotype', 'HP:0012126', (216, 230))	('rs2274223 AG/GG', 'Var', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('PLCE1', 'Gene', (32, 37))	('rs2274223-G', 'Var', (153, 164))	('PLCE1', 'Gene', '51196', (32, 37))	('rs2274223', 'Mutation', 'rs2274223', (38, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (216, 230))	('higher', 'PosReg', (70, 76))	('gastric cancer', 'Disease', (216, 230))
508187	24116107	proved that rs2274223 was associated with a decrease risk of CRC in a Chinese population.	('decrease', 'NegReg', (44, 52))	('rs2274223', 'Mutation', 'rs2274223', (12, 21))	('rs2274223', 'Var', (12, 21))	('CRC', 'Disease', (61, 64))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))
508188	24116107	Although many epidemiological studies regarding the PLCE1 rs2274223 polymorphism on the risk of variants of DTC had been conducted, the results were conflicting and inconclusive because of various reasons, such as different ethnicities, resident areas, sample size, environmental factors and diet habits.	('PLCE1', 'Gene', (52, 57))	('PLCE1', 'Gene', '51196', (52, 57))	('variants', 'Var', (96, 104))	('DTC', 'Phenotype', 'HP:0007378', (108, 111))	('DTC', 'Chemical', '-', (108, 111))	('rs2274223', 'Mutation', 'rs2274223', (58, 67))	('rs2274223', 'Var', (58, 67))
508189	24116107	To provide a more comprehensive analysis on the association, we carried out this meta-analysis based on eleven case-control studies with 18,813 participants and indicated that G allele of the PLCE1 rs2274223 A>G polymorphism was associated with increased risk of DTC.	('rs2274223', 'Mutation', 'rs2274223', (198, 207))	('DTC', 'Chemical', '-', (263, 266))	('rs2274223 A>G', 'Var', (198, 211))	('participants', 'Species', '9606', (144, 156))	('DTC', 'Disease', (263, 266))	('PLCE1', 'Gene', (192, 197))	('PLCE1', 'Gene', '51196', (192, 197))	('DTC', 'Phenotype', 'HP:0007378', (263, 266))
508193	24116107	In addition, because of the gene-gene interaction, the influence of the PLCE1 rs2274223 A>G polymorphism might be masked or magnified by the presence of other genes which were unidentified yet in the development of cancer.	('PLCE1', 'Gene', (72, 77))	('PLCE1', 'Gene', '51196', (72, 77))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('rs2274223', 'Mutation', 'rs2274223', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('rs2274223 A>G', 'Var', (78, 91))
508197	24116107	Several previous studies showed that the association between rs2274223 and the risk of gastric cancer was stronger in the cardia than in the non-cardia gastric cancer.	('non-cardia gastric cancer', 'Disease', (141, 166))	('gastric cancer', 'Disease', 'MESH:D013274', (152, 166))	('stronger', 'Reg', (106, 114))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('cardia', 'Disease', (145, 151))	('cardia', 'Disease', 'MESH:D004938', (145, 151))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (141, 166))	('rs2274223', 'Mutation', 'rs2274223', (61, 70))	('cardia', 'Disease', (122, 128))	('rs2274223', 'Var', (61, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cardia', 'Disease', 'MESH:D004938', (122, 128))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))
508203	24116107	First, we estimated the association conclusively between the PLCE1 rs2274223 A>G polymorphism and DTC risk, and further showed the significant association especially among Asians rather than Europeans.	('rs2274223', 'Mutation', 'rs2274223', (67, 76))	('PLCE1', 'Gene', (61, 66))	('PLCE1', 'Gene', '51196', (61, 66))	('DTC', 'Chemical', '-', (98, 101))	('DTC', 'Disease', (98, 101))	('DTC', 'Phenotype', 'HP:0007378', (98, 101))	('rs2274223 A>G', 'Var', (67, 80))
508205	24116107	In conclusion, our meta-analysis suggests that the PLCE1 rs2274223 A>G polymorphism is associated with DTC risk, especially with gastric cancer and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('DTC', 'Disease', (103, 106))	('DTC', 'Chemical', '-', (103, 106))	('PLCE1', 'Gene', '51196', (51, 56))	('gastric cancer', 'Disease', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('rs2274223', 'Mutation', 'rs2274223', (57, 66))	('DTC', 'Phenotype', 'HP:0007378', (103, 106))	('esophageal cancer', 'Disease', (148, 165))	('associated', 'Reg', (87, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))	('rs2274223 A>G', 'Var', (57, 70))	('PLCE1', 'Gene', (51, 56))
508206	24116107	The PLCE1 rs2274223 A>G polymorphism is an independent risk factor for the development of DTC, and will probably be a potential therapeutic target for new drugs.	('DTC', 'Chemical', '-', (90, 93))	('DTC', 'Disease', (90, 93))	('rs2274223 A>G', 'Var', (10, 23))	('DTC', 'Phenotype', 'HP:0007378', (90, 93))	('PLCE1', 'Gene', (4, 9))	('PLCE1', 'Gene', '51196', (4, 9))	('rs2274223', 'Mutation', 'rs2274223', (10, 19))
508209	24116107	should be performed to explore the association between PLCE1 gene polymorphisms and cancer risks.	('PLCE1', 'Gene', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('PLCE1', 'Gene', '51196', (55, 60))	('cancer', 'Disease', (84, 90))	('association', 'Interaction', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('polymorphisms', 'Var', (66, 79))
508248	22529863	PDNF in the cytosol of the host cell apparently activates Akt signaling, leading to a suppression of apoptosis.	('suppression', 'NegReg', (86, 97))	('Akt', 'Gene', '207', (58, 61))	('PDNF', 'Var', (0, 4))	('apoptosis', 'CPA', (101, 110))	('Akt', 'Gene', (58, 61))	('activates', 'PosReg', (48, 57))
508263	22529863	However, a high degree of variability was observed within T. cruzi II, as demonstrated by intense kDNA polymorphism among all clinical forms and also within each of them, irrespective of the intensity of pathological processes.	('polymorphism', 'Var', (103, 115))	('T. cruzi', 'Disease', (58, 66))	('T. cruzi', 'Species', '5693', (58, 66))	('kDNA', 'Gene', (98, 102))
508267	22529863	Two synthetic probes discriminated variants of lineage TcIId.	('TcIId', 'Chemical', '-', (55, 60))	('discriminated', 'Reg', (21, 34))	('variants', 'Var', (35, 43))
508268	22529863	Proportion of TcIId variants encountered were 6/16, 6/16, and 4/16, similar to the distribution of Chagasic populations in Bolivia.	('TcIId', 'Chemical', '-', (14, 19))	('TcIId', 'Gene', (14, 19))	('variants', 'Var', (20, 28))
508288	22529863	PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) studies investigated variants in the promoter region of BAT1 in positions -22 C/G and -348 C/T and LTA in positions -80A3C and -252A3G in CCC and ASY patients.	('LTA', 'Gene', '4049', (177, 180))	('ASY', 'Disease', (224, 227))	('BAT1', 'Gene', '7919', (134, 138))	('variants', 'Var', (99, 107))	('men', 'Species', '9606', (52, 55))	('-22 C/G', 'SUBSTITUTION', 'None', (152, 159))	('patients', 'Species', '9606', (228, 236))	('-22 C/G', 'Var', (152, 159))	('-348 C/T', 'Mutation', 'rs1432986271', (164, 172))	('BAT1', 'Gene', (134, 138))	('LTA', 'Gene', (177, 180))	('CCC', 'Disease', (216, 219))
508289	22529863	Similar results were observed for allele -348 C, suggesting that BAT1 variants, previously associated with reduced expression of HLA-B-1, are predictive of CCC evolution.	('BAT1', 'Gene', '7919', (65, 69))	('CCC', 'Disease', (156, 159))	('variants', 'Var', (70, 78))	('predictive of', 'Reg', (142, 155))	('BAT1', 'Gene', (65, 69))
508296	22529863	Several SNPs in this gene able to affect cytokine production have been described, and five of them with functional significance (-988 C/A; -800 G/A; -509 C/T, 10 T/C; 263 C/T) were investigated.	('10 T/C', 'SUBSTITUTION', 'None', (159, 165))	('10 T/C', 'Var', (159, 165))	('-800 G/A', 'Mutation', 'rs1800468', (139, 147))	('cytokine production', 'MPA', (41, 60))	('-988 C/A; -800 G/A; -509 C/T', 'Var', (129, 157))	('263 C/T', 'Mutation', 'rs370767436', (167, 174))	('-509 C/T', 'Mutation', 'rs1800469', (149, 157))	('-988 C/A', 'Mutation', 'rs551901685', (129, 137))	('affect', 'Reg', (34, 40))
508298	22529863	Additionally, the high frequency of 10 C/C genotype was increased in Chagas disease patients.	('Chagas disease', 'Disease', (69, 83))	('10 C/C', 'Var', (36, 42))	('patients', 'Species', '9606', (84, 92))	('Chagas disease', 'Disease', 'MESH:D014355', (69, 83))
508301	22529863	Chronic Chagas disease patients were haplotyped [208: including 81 indeterminate and 123 symptomatic (76 with cardiac, 19 with digestive, and 28 with cardio-digestive forms)] for six MASP2 polymorphisms using PCR with sequence-specific primers and compared with 300 healthy individuals from Southern Brazil.	('Chronic Chagas disease', 'Disease', (0, 22))	('patients', 'Species', '9606', (23, 31))	('MASP2', 'Gene', (183, 188))	('polymorphisms', 'Var', (189, 202))	('Chronic Chagas disease', 'Disease', 'MESH:D014355', (0, 22))	('MASP2', 'Gene', '10747', (183, 188))
508302	22529863	The g.1961795C, p.371D diplotype occurred at a higher frequency among symptomatic patients, compared with the indeterminate group, as well as genotypes with Chagas disease, but not with the g.1945560A in the promoter in cardiac patients.	('patients', 'Species', '9606', (82, 90))	('patients', 'Species', '9606', (228, 236))	('Chagas disease', 'Disease', (157, 171))	('p.371D', 'Var', (16, 22))	('g.1961795C', 'Var', (4, 14))	('Chagas disease', 'Disease', 'MESH:D014355', (157, 171))
508303	22529863	CD haplotypes linked to the p.P126L and p.V377A variants were associated with reduced MASP-2 levels but not reduced MBL/MASP-2/C4 complexes.	('p.P126L', 'Var', (28, 35))	('MASP-2', 'Gene', (86, 92))	('p.P126L', 'Mutation', 'rs56392418', (28, 35))	('p.V377A', 'Var', (40, 47))	('p.V377A', 'Mutation', 'rs2273346', (40, 47))	('MBL', 'Gene', '4153', (116, 119))	('MBL', 'Gene', (116, 119))	('MASP-2', 'Gene', '10747', (120, 126))	('CD', 'Chemical', 'MESH:D002104', (0, 2))	('reduced', 'NegReg', (78, 85))	('MASP-2', 'Gene', (120, 126))	('MASP-2', 'Gene', '10747', (86, 92))
508304	22529863	The authors concluded that MASP2*CD genotypes, most of them generating low MASP-2 levels, are associated with high risk of chagasic cardiomyopathy.	('low', 'NegReg', (71, 74))	('MASP2', 'Gene', (27, 32))	('CD', 'Chemical', 'MESH:D002104', (33, 35))	('MASP-2', 'Gene', '10747', (75, 81))	('chagasic cardiomyopathy', 'Disease', (123, 146))	('chagasic cardiomyopathy', 'Disease', 'MESH:D009202', (123, 146))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (132, 146))	('MASP2', 'Gene', '10747', (27, 32))	('MASP-2', 'Gene', (75, 81))	('associated', 'Reg', (94, 104))	('genotypes', 'Var', (36, 45))
508306	22529863	Some IL-1B alleles and haplotypes have been associated with susceptibility to inflammatory, autoimmune, and infectious diseases.	('associated', 'Reg', (44, 54))	('susceptibility', 'Reg', (60, 74))	('IL-1B', 'Gene', (5, 10))	('alleles', 'Var', (11, 18))	('infectious diseases', 'Disease', 'MESH:D003141', (108, 127))	('haplotypes', 'Var', (23, 33))	('inflammatory', 'Disease', (78, 90))	('IL-1B', 'Gene', '3553', (5, 10))	('infectious diseases', 'Disease', (108, 127))
508309	22529863	The C allele or CC genotype of this polymorphism was found increased in CCC when compared with IDC and with controls, suggesting an evident association between the IL1RN.4 polymorphism, T. cruzi infection, and CCC development.	('T. cruzi', 'Species', '5693', (186, 194))	('CCC', 'Disease', (210, 213))	('polymorphism', 'Var', (172, 184))	('men', 'Species', '9606', (221, 224))	('CCC', 'Disease', (72, 75))	('cruzi infection', 'Disease', 'MESH:D014355', (189, 204))	('IL1RN.4', 'Gene', (164, 171))	('increased', 'PosReg', (59, 68))	('cruzi infection', 'Disease', (189, 204))
508310	22529863	These studies evidence the association of various polymorphisms in genes of immune response and susceptibility to chagasic cardiopathy, so suggesting that host genetic factors may play a role in the underlying mechanisms of disease pathogenesis.	('cardiopathy', 'Disease', 'MESH:C536187', (123, 134))	('association', 'Interaction', (27, 38))	('polymorphisms', 'Var', (50, 63))	('cardiopathy', 'Disease', (123, 134))
508326	22529863	Idiopathic achalasia and megaesophaus patients, with or without esophageal carcinoma, described changes in expression of proteins such as p53, p16, and MIB (mindbomb homolog), chromosomal aneuploidies, gene deletions in significant (TP53) or marginal levels (TP63, FHIT, PIK3CA, EGFR, CDKN2A, and YES), and gene copy number gain (PIK3CA, TP63, FGFR1, MYC, CDNK2A, and NCOA3) mainly associated with dilation grades III and IV.	('dilation grades III', 'Disease', (398, 417))	('CDKN2A', 'Gene', '1029', (285, 291))	('FHIT', 'Gene', '2272', (265, 269))	('CDNK2A', 'Gene', (356, 362))	('p53', 'Gene', (138, 141))	('PIK3CA', 'Gene', (330, 336))	('PIK3CA', 'Gene', '5290', (271, 277))	('patients', 'Species', '9606', (38, 46))	('MIB', 'Gene', (152, 155))	('Idiopathic achalasia', 'Disease', 'MESH:D004931', (0, 20))	('NCOA3', 'Gene', '8202', (368, 373))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (64, 84))	('EGFR', 'Gene', (279, 283))	('mindbomb homolog', 'Gene', '57534', (157, 173))	('mindbomb homolog', 'Gene', (157, 173))	('MYC', 'Gene', (351, 354))	('associated with', 'Reg', (382, 397))	('gene copy number', 'Var', (307, 323))	('TP63', 'Gene', (338, 342))	('FGFR1', 'Gene', '2260', (344, 349))	('Idiopathic achalasia', 'Disease', (0, 20))	('MIB', 'Gene', '57534', (152, 155))	('TP63', 'Gene', (259, 263))	('TP53', 'Gene', (233, 237))	('PIK3CA', 'Gene', (271, 277))	('aneuploidies', 'Disease', (188, 200))	('p16', 'Gene', (143, 146))	('CD', 'Chemical', 'MESH:D002104', (356, 358))	('NCOA3', 'Gene', (368, 373))	('PIK3CA', 'Gene', '5290', (330, 336))	('CDKN2A', 'Gene', (285, 291))	('FHIT', 'Gene', (265, 269))	('MYC', 'Gene', '4609', (351, 354))	('CD', 'Chemical', 'MESH:D002104', (285, 287))	('TP63', 'Gene', '8626', (338, 342))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (64, 84))	('p16', 'Gene', '1029', (143, 146))	('EGFR', 'Gene', '1956', (279, 283))	('TP63', 'Gene', '8626', (259, 263))	('p53', 'Gene', '7157', (138, 141))	('aneuploidies', 'Disease', 'MESH:D000782', (188, 200))	('achalasia', 'Phenotype', 'HP:0002571', (11, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('gain', 'PosReg', (324, 328))	('esophageal carcinoma', 'Disease', (64, 84))	('FGFR1', 'Gene', (344, 349))	('TP53', 'Gene', '7157', (233, 237))
508327	22529863	A strong immunoreactivity of p53 protein was found in patients with idiopathic and megaesophaus, and two of four cases analyzed showed mutations in TP53 codons 238 and 146 of exons 7 and 5, respectively.	('mutations in', 'Var', (135, 147))	('immunoreactivity', 'MPA', (9, 25))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('patients', 'Species', '9606', (54, 62))	('p53', 'Gene', (29, 32))	('idiopathic', 'Disease', (68, 78))	('megaesophaus', 'Disease', (83, 95))	('p53', 'Gene', '7157', (29, 32))	('protein', 'Protein', (33, 40))
508328	22529863	The authors suggested that changes in TP53 in megaesophagus epithelium might be a useful biomarker for identifying individuals with high risk of carcinoma development.	('carcinoma', 'Disease', 'MESH:D002277', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('TP53', 'Gene', (38, 42))	('men', 'Species', '9606', (162, 165))	('carcinoma', 'Disease', (145, 154))	('changes', 'Var', (27, 34))	('TP53', 'Gene', '7157', (38, 42))
508332	22529863	Chromosomal aneuploidies and deletion of TP53 were also detected in 54% of 40 megaesophaus without ESCC.	('TP53', 'Gene', '7157', (41, 45))	('deletion', 'Var', (29, 37))	('TP53', 'Gene', (41, 45))	('detected', 'Reg', (56, 64))	('aneuploidies', 'Disease', (12, 24))	('aneuploidies', 'Disease', 'MESH:D000782', (12, 24))
508421	21211656	Interestingly, eotaxin-3, IL8, CXCL1, and IL1B were found to be upregulated in our prior studies using microarray analysis; nevertheless, in this study we identified dysregulation of several other genes that were not previously suspected (Table I).	('eotaxin-3', 'Gene', (15, 24))	('IL1B', 'Gene', (42, 46))	('IL1B', 'Gene', '3553', (42, 46))	('IL8', 'Gene', (26, 29))	('IL8', 'Gene', '3576', (26, 29))	('eotaxin-3', 'Gene', '10344', (15, 24))	('CXCL1', 'Gene', '2919', (31, 36))	('dysregulation', 'Var', (166, 179))	('CXCL1', 'Gene', (31, 36))
508512	33450887	There is strong evidence that Helicobacter pylori infection is a risk factor for GC development, therefore Helicobacter pylori has been classified as a class I carcinogen by International Agency for Research on Cancer.	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('the', 'Gene', (97, 100))	('The', 'Gene', (0, 3))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (30, 59))	('as', 'Gene', '112935892', (154, 156))	('Helicobacter pylori', 'Species', '210', (30, 49))	('as', 'Gene', '112935892', (147, 149))	('Cancer', 'Disease', (211, 217))	('Helicobacter pylori', 'Var', (107, 126))	('the', 'Gene', '25085', (97, 100))	('as', 'Gene', '112935892', (138, 140))	('The', 'Gene', '25085', (0, 3))	('Cancer', 'Disease', 'MESH:D009369', (211, 217))	('as', 'Gene', '112935892', (128, 130))	('Helicobacter pylori', 'Species', '210', (107, 126))	('men', 'Species', '9606', (91, 94))	('infection', 'Disease', (50, 59))	('infection', 'Disease', 'MESH:D007239', (50, 59))	('GC development', 'Disease', (81, 95))
508527	33450887	Nutrients are transported through the gastrointestinal tract and nutrient deficiency could be associated with digestive cancer initiation and/or promotion.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('as', 'Gene', '112935892', (94, 96))	('promotion', 'PosReg', (145, 154))	('the', 'Gene', (34, 37))	('cancer', 'Disease', (120, 126))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('as', 'Gene', '112935892', (39, 41))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('n an', 'Gene', '11280', (136, 140))	('n an', 'Gene', (136, 140))	('nutrient deficiency', 'Var', (65, 84))	('the', 'Gene', '25085', (34, 37))
508546	33450887	Along with the modifications of our eating habits and the prevalence of processed foods, it is shown that a large number of adults do not reach the recommended Mg2+ average daily intake.	('Mg2+', 'Var', (160, 164))	('Mg2+', 'Chemical', '-', (160, 164))	('of', 'Gene', '6688', (121, 123))	('the', 'Gene', (54, 57))	('the', 'Gene', '25085', (54, 57))	('men', 'Species', '9606', (153, 156))	('of', 'Gene', '6688', (69, 71))	('the', 'Gene', (11, 14))	('of', 'Gene', '6688', (29, 31))	('the', 'Gene', '25085', (11, 14))	('the', 'Gene', (144, 147))	('the', 'Gene', '25085', (144, 147))
508556	33450887	With the use of a MagFura-2 fluorescent probe in yeast, MRS2 overexpression was shown to enhance mitochondrial Mg2+ influx.	('enhance', 'PosReg', (89, 96))	('of', 'Gene', '6688', (13, 15))	('as', 'Gene', '112935892', (51, 53))	('mitochondrial Mg2+ influx', 'MPA', (97, 122))	('MRS2', 'Gene', (56, 60))	('the', 'Gene', (5, 8))	('as', 'Gene', '112935892', (77, 79))	('the', 'Gene', '25085', (5, 8))	('yeast', 'Species', '4932', (49, 54))	('overexpression', 'Var', (61, 75))	('Mg2+', 'Chemical', '-', (111, 115))
508557	33450887	On the other hand, the mitochondrial Mg2+ influx was abolished upon MRS2 gene deletion.	('the', 'Gene', (8, 11))	('the', 'Gene', '25085', (8, 11))	('deletion', 'Var', (78, 86))	('Mg2+', 'Chemical', '-', (37, 41))	('mitochondrial Mg2+ influx', 'MPA', (23, 48))	('the', 'Gene', (19, 22))	('the', 'Gene', '25085', (3, 6))	('the', 'Gene', '25085', (19, 22))	('as', 'Gene', '112935892', (50, 52))	('the', 'Gene', (3, 6))	('abolished', 'NegReg', (53, 62))	('MRS2', 'Gene', (68, 72))
508571	33450887	The mutated gene is associated with "hypomagnesemia with secondary hypocalcemia" (HSH).	('mutated', 'Var', (4, 11))	('hypocalcemia', 'Phenotype', 'HP:0002901', (67, 79))	('hypomagnesemia', 'Disease', 'MESH:C537153', (37, 51))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (37, 51))	('hypomagnesemia', 'Disease', (37, 51))	('The', 'Gene', (0, 3))	('The', 'Gene', '25085', (0, 3))	('hypocalcemia', 'Disease', (67, 79))	('hypocalcemia', 'Disease', 'MESH:D006996', (67, 79))	('as', 'Gene', '112935892', (20, 22))
508585	33450887	Mg2+ was suspected as a second messenger in the X-linked human immunodeficiency with Mg2+ defect and Epstein-Barr virus infection and neoplasia (XMEN): it appeared that mutations in the MAGT1 gene were actually involved.	('immunodeficiency', 'Phenotype', 'HP:0002721', (63, 79))	('as', 'Gene', '112935892', (6, 8))	('MAGT1', 'Gene', (186, 191))	('mutations', 'Var', (169, 178))	('X-linked human immunodeficiency', 'Disease', 'MESH:D053632', (48, 79))	('as', 'Gene', '112935892', (139, 141))	('the', 'Gene', (182, 185))	('Mg2+', 'Chemical', '-', (0, 4))	('Epstein-Barr virus infection', 'Disease', (101, 129))	('neoplasia', 'Disease', 'MESH:D009369', (134, 143))	('N', 'Chemical', 'MESH:D009584', (148, 149))	('neoplasia', 'Disease', (134, 143))	('as', 'Gene', '112935892', (19, 21))	('the', 'Gene', '25085', (182, 185))	('the', 'Gene', (44, 47))	('Mg2+', 'Chemical', '-', (85, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (134, 143))	('involved', 'Reg', (211, 219))	('Epstein-Barr virus infection', 'Disease', 'MESH:D020031', (101, 129))	('n an', 'Gene', '11280', (128, 132))	('n an', 'Gene', (128, 132))	('the', 'Gene', '25085', (44, 47))	('X-linked human immunodeficiency', 'Disease', (48, 79))
508586	33450887	In disorders like XMEN and congenital disorders of glycosylation (CDG), these mutations caused N-glycosylation defects.	('the', 'Gene', (72, 75))	('the', 'Gene', '25085', (72, 75))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('N-glycosylation defects', 'MPA', (95, 118))	('XMEN', 'Disease', (18, 22))	('mutations', 'Var', (78, 87))	('caused', 'Reg', (88, 94))	('congenital disorders of glycosylation', 'Disease', (27, 64))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('congenital disorders of glycosylation', 'Disease', 'MESH:D018981', (27, 64))	('glycosylation defects', 'Phenotype', 'HP:0012345', (97, 118))
508594	33450887	CNNM2 mRNA was also regulated by Mg2+ deficiency in distal convoluted tubule (MDCT) epithelial cells.	('the', 'Gene', '25085', (87, 90))	('N', 'Chemical', 'MESH:D009584', (2, 3))	('CNNM2', 'Gene', '54805', (0, 5))	('CNNM2', 'Gene', (0, 5))	('Mg2+ deficiency', 'Var', (33, 48))	('as', 'Gene', '112935892', (12, 14))	('Mg2+', 'Chemical', '-', (33, 37))	('regulated', 'Reg', (20, 29))	('mRNA', 'MPA', (6, 10))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('the', 'Gene', (87, 90))	('N', 'Chemical', 'MESH:D009584', (8, 9))
508601	33450887	There is much evidence suggesting an association between Mg2+ intake and digestive cancer risk and/or development.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('development', 'CPA', (102, 113))	('Mg2+', 'Var', (57, 61))	('The', 'Gene', (0, 3))	('as', 'Gene', '112935892', (37, 39))	('Mg2+', 'Chemical', '-', (57, 61))	('The', 'Gene', '25085', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('men', 'Species', '9606', (109, 112))	('cancer', 'Disease', (83, 89))
508605	33450887	In PDAC, a first study from 2012 in a large cohort (142,203 men and 334,999 women) recruited between 1992 and 2000 shows no association between Mg2+ intake and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('n an', 'Gene', '11280', (62, 66))	('as', 'Gene', '112935892', (124, 126))	('cancer', 'Disease', (160, 166))	('men', 'Species', '9606', (60, 63))	('Mg2+', 'Chemical', '-', (144, 148))	('Mg2+', 'Var', (144, 148))	('men', 'Species', '9606', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('women', 'Species', '9606', (76, 81))	('n an', 'Gene', (62, 66))
508610	33450887	Mg2+ intake was associated with a lower risk for CRC, particularly in people with low Ca2+/Mg2+ intake ratio.	('rat', 'Species', '10116', (103, 106))	('people', 'Species', '9606', (70, 76))	('Ca2+', 'Chemical', 'MESH:D000069285', (86, 90))	('Mg2+', 'Chemical', '-', (91, 95))	('Mg2+', 'Chemical', '-', (0, 4))	('as', 'Gene', '112935892', (16, 18))	('Mg2+', 'Var', (0, 4))	('as', 'Gene', '112935892', (13, 15))	('CRC', 'Disease', (49, 52))
508611	33450887	also show that the Thr1482Ile polymorphism in the TRPM7 gene increases the risk for adenomatous and hyperplastic polyps.	('as', 'Gene', '112935892', (66, 68))	('as', 'Gene', '112935892', (107, 109))	('the', 'Gene', (46, 49))	('the', 'Gene', (71, 74))	('the', 'Gene', '25085', (46, 49))	('Thr1482Ile', 'SUBSTITUTION', 'None', (19, 29))	('the', 'Gene', (15, 18))	('the', 'Gene', '25085', (15, 18))	('the', 'Gene', '25085', (71, 74))	('TRPM7', 'Gene', (50, 55))	('Thr1482Ile', 'Var', (19, 29))	('adenomatous and hyperplastic polyps', 'Disease', 'MESH:D018256', (84, 119))
508613	33450887	A meta-analysis from 29 studies published on PubMed, Web of Science and the Chinese National Knowledge Infrastructure confirms that the high intake of Mg2+ is inversely associated with the risk of CRC.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('the', 'Gene', (72, 75))	('as', 'Gene', '112935892', (107, 109))	('the', 'Gene', (132, 135))	('the', 'Gene', '25085', (72, 75))	('the', 'Gene', '25085', (132, 135))	('as', 'Gene', '112935892', (169, 171))	('Mg2+', 'Var', (151, 155))	('of', 'Gene', '6688', (148, 150))	('Mg2+', 'Chemical', '-', (151, 155))	('of', 'Gene', '6688', (57, 59))	('the', 'Gene', (185, 188))	('the', 'Gene', '25085', (185, 188))	('inversely', 'NegReg', (159, 168))	('of', 'Gene', '6688', (194, 196))
508617	33450887	To summarize, these epidemiologic studies suggested that high Mg2+ intake by diet and/or supplemental compounds is inversely associated with CRC, PDAC and possibly ESAC risk, but not with GC risk.	('ESAC', 'Disease', (164, 168))	('as', 'Gene', '112935892', (125, 127))	('the', 'Gene', '25085', (14, 17))	('high Mg2+', 'Var', (57, 66))	('high Mg2+ intake', 'Phenotype', 'HP:0002918', (57, 73))	('men', 'Species', '9606', (95, 98))	('Mg2+', 'Chemical', '-', (62, 66))	('inversely', 'NegReg', (115, 124))	('PDAC', 'Disease', (146, 150))	('CRC', 'Disease', (141, 144))	('the', 'Gene', (14, 17))
508621	33450887	High TRPM7 staining was associated with better 5-year survival in patients with ESAC (Table 1).	('as', 'Gene', '112935892', (21, 23))	('as', 'Gene', '112935892', (24, 26))	('High', 'Var', (0, 4))	('ESAC', 'Disease', (80, 84))	('TRPM7', 'Gene', (5, 10))	('patients', 'Species', '9606', (66, 74))	('better', 'PosReg', (40, 46))
508627	33450887	Evaluation of TRPM6 expression at the mRNA level (by qRT-PCR and in TCGA datasets), it has been found that TRPM6 was downregulated in cancerous colorectal tissues and that a high TRPM6 expression correlates with better survival in patients.	('as', 'Gene', '112935892', (76, 78))	('patients', 'Species', '9606', (231, 239))	('expression', 'MPA', (185, 195))	('as', 'Gene', '112935892', (114, 116))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('cancerous colorectal tissues', 'Disease', (134, 162))	('better', 'PosReg', (212, 218))	('TRPM6', 'Gene', (179, 184))	('high', 'Var', (174, 178))	('cancerous colorectal tissues', 'Disease', 'MESH:D015179', (134, 162))	('of', 'Gene', '6688', (11, 13))	('TRPM6', 'Gene', (14, 19))	('downregulated', 'NegReg', (117, 130))	('TRPM6', 'Gene', (107, 112))	('the', 'Gene', (34, 37))	('as', 'Gene', '112935892', (88, 90))	('the', 'Gene', '25085', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
508651	33450887	For PAAD patients, we observed that high expression MAGT1 and CNNM4 mRNA were associated with shorter patient overall survival, while high TRPM6 mRNA expression was correlated with better outcome in those patients.	('high expression', 'Var', (36, 51))	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (205, 213))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('patient', 'Species', '9606', (102, 109))	('as', 'Gene', '112935892', (162, 164))	('high', 'Var', (134, 138))	('CNNM4', 'Gene', (62, 67))	('shorter', 'NegReg', (94, 101))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('N', 'Chemical', 'MESH:D009584', (147, 148))	('as', 'Gene', '112935892', (78, 80))	('mRNA expression', 'MPA', (145, 160))	('patient', 'Species', '9606', (9, 16))	('patient', 'Species', '9606', (205, 212))	('TRPM6', 'Gene', (139, 144))	('MAGT1', 'Gene', (52, 57))
508653	33450887	For COAD patients, a high expression of MAGT1 mRNA is associated with a better outcome in patient overall survival.	('patients', 'Species', '9606', (9, 17))	('high', 'Var', (21, 25))	('MAGT1', 'Gene', (40, 45))	('as', 'Gene', '112935892', (54, 56))	('patient', 'Species', '9606', (90, 97))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('of', 'Gene', '6688', (37, 39))	('patient', 'Species', '9606', (9, 16))
508677	33450887	Dysregulation of Mg2+ transporters could contribute to cancer hallmarks by regulating malignant cell proliferation, migration or invasion.	('regulating', 'Reg', (75, 85))	('rat', 'Species', '10116', (108, 111))	('Dysregulation', 'Var', (0, 13))	('migration', 'CPA', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('as', 'Gene', '112935892', (132, 134))	('of', 'Gene', '6688', (14, 16))	('rat', 'Species', '10116', (119, 122))	('contribute', 'Reg', (41, 51))	('Mg2+', 'Chemical', '-', (17, 21))	('malignant cell proliferation', 'CPA', (86, 114))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Mg2+ transporters', 'MPA', (17, 34))	('cancer', 'Disease', (55, 61))
508680	33450887	Although the molecular mechanisms involved in TRPM7-mediated ESAC cell proliferation, migration and invasion are far from being fully elucidated, TRPM7 channel expression may prevent the oncogenic properties of ESAC cells.	('the', 'Gene', (183, 186))	('n an', 'Gene', (94, 98))	('as', 'Gene', '112935892', (103, 105))	('TRPM7', 'Gene', (146, 151))	('the', 'Gene', (9, 12))	('the', 'Gene', '25085', (183, 186))	('n an', 'Gene', '11280', (94, 98))	('expression', 'Var', (160, 170))	('prevent', 'NegReg', (175, 182))	('the', 'Gene', '25085', (9, 12))	('rat', 'Species', '10116', (78, 81))	('rat', 'Species', '10116', (89, 92))	('ESAC', 'Disease', (211, 215))	('of', 'Gene', '6688', (208, 210))
508684	33450887	Similar results are found in PDAC cell lines BxPC-3 and PANC-1 where TRPM7 silencing reduces the cell proliferation by accumulating the cells in G0-G1 phases without affecting the number of apoptotic cells.	('TRPM7', 'Gene', (69, 74))	('the', 'Gene', '25085', (93, 96))	('the', 'Gene', (176, 179))	('the', 'Gene', (132, 135))	('the', 'Gene', '25085', (176, 179))	('as', 'Gene', '112935892', (153, 155))	('the', 'Gene', '25085', (132, 135))	('BxPC-3', 'CellLine', 'CVCL:0186', (45, 51))	('rat', 'Species', '10116', (109, 112))	('silencing', 'Var', (75, 84))	('of', 'Gene', '6688', (187, 189))	('accumulating', 'PosReg', (119, 131))	('cell proliferation', 'CPA', (97, 115))	('reduces', 'NegReg', (85, 92))	('PANC-1', 'CellLine', 'CVCL:0480', (56, 62))	('the', 'Gene', (93, 96))
508690	33450887	Importantly, cell migration is also restored by Mg2+ supplementation in TRPM7-deficient BxPC-3, indicating that Mg2+ is essential for PDAC cell migration.	('cell migration', 'CPA', (13, 27))	('TRPM7-deficient', 'Gene', (72, 87))	('Mg2+', 'Chemical', '-', (112, 116))	('BxPC-3', 'CellLine', 'CVCL:0186', (88, 94))	('rat', 'Species', '10116', (21, 24))	('rat', 'Species', '10116', (147, 150))	('restored', 'PosReg', (36, 44))	('Mg2+', 'Chemical', '-', (48, 52))	('Mg2+', 'Var', (48, 52))	('men', 'Species', '9606', (59, 62))
508697	33450887	In a colon carcinoma LoVo cell model, cytosolic Mg2+ levels are higher in doxorubicin-resistant cells when compared to the doxorubicin-sensitive ones.	('colon carcinoma', 'Disease', (5, 20))	('cytosolic Mg2+ levels', 'MPA', (38, 59))	('doxorubicin', 'Chemical', 'MESH:D004317', (74, 85))	('higher', 'PosReg', (64, 70))	('doxorubicin', 'Chemical', 'MESH:D004317', (123, 134))	('doxorubicin-resistant', 'Var', (74, 95))	('the', 'Gene', (119, 122))	('the', 'Gene', '25085', (119, 122))	('colon carcinoma', 'Disease', 'MESH:D003110', (5, 20))	('LoVo', 'CellLine', 'CVCL:0399', (21, 25))	('Mg2+', 'Chemical', '-', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
508699	33450887	TRPM7 silencing induces the acquisition of a more resistant phenotype in sensitive cells, indicating that TRPM7 channel expression is associated with chemoresistance in CRC.	('chemoresistance', 'CPA', (150, 165))	('TRPM7', 'Gene', (0, 5))	('TRPM7', 'Gene', (106, 111))	('as', 'Gene', '112935892', (134, 136))	('the', 'Gene', (24, 27))	('silencing', 'Var', (6, 15))	('of', 'Gene', '6688', (40, 42))	('the', 'Gene', '25085', (24, 27))
508701	33450887	Moreover, MagT1 silencing strongly inhibits resistant cell proliferation without affecting total intracellular Mg2+.	('MagT1', 'Gene', (10, 15))	('inhibits', 'NegReg', (35, 43))	('MagT1', 'Gene', '84061', (10, 15))	('silencing', 'Var', (16, 25))	('rat', 'Species', '10116', (66, 69))	('resistant cell proliferation', 'CPA', (44, 72))	('Mg2+', 'Chemical', '-', (111, 115))
508707	33450887	also show that TRPM7 silencing decreases both HT-29 and SW-480 cell proliferation, migration and invasion.	('HT-29', 'CellLine', 'CVCL:0320', (46, 51))	('SW-480 cell proliferation', 'CPA', (56, 81))	('HT-29', 'CPA', (46, 51))	('as', 'Gene', '112935892', (100, 102))	('rat', 'Species', '10116', (75, 78))	('TRPM7', 'Gene', (15, 20))	('n an', 'Gene', '11280', (91, 95))	('n an', 'Gene', (91, 95))	('SW-480', 'CellLine', 'CVCL:0546', (56, 62))	('as', 'Gene', '112935892', (36, 38))	('rat', 'Species', '10116', (86, 89))	('silencing', 'Var', (21, 30))
508708	33450887	Inhibition of TRPM7 induces the upregulation of E-cadherin and the downregulation of N-cadherin in CRC cells suggesting that this channel may regulate epithelial-to-mesenchymal transition (EMT).	('the', 'Gene', '25085', (28, 31))	('of', 'Gene', '6688', (82, 84))	('downregulation', 'NegReg', (67, 81))	('upregulation', 'PosReg', (32, 44))	('of', 'Gene', '6688', (45, 47))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('the', 'Gene', (154, 157))	('n an', 'Gene', (57, 61))	('of', 'Gene', '6688', (11, 13))	('the', 'Gene', '25085', (154, 157))	('n an', 'Gene', '11280', (57, 61))	('Inhibition', 'Var', (0, 10))	('regulate', 'Reg', (142, 150))	('the', 'Gene', (63, 66))	('TRPM7', 'Gene', (14, 19))	('the', 'Gene', (28, 31))	('the', 'Gene', '25085', (63, 66))
508711	33450887	have demonstrated that CNNM4 deficiency accelerates epithelial colon cell proliferation in mice.	('mice', 'Species', '10090', (91, 95))	('accelerates', 'PosReg', (40, 51))	('rat', 'Species', '10116', (12, 15))	('rat', 'Species', '10116', (46, 49))	('rat', 'Species', '10116', (81, 84))	('epithelial colon', 'Disease', 'MESH:D003110', (52, 68))	('CNNM4', 'Gene', (23, 28))	('deficiency', 'Var', (29, 39))	('epithelial colon', 'Disease', (52, 68))
508717	33450887	These data clearly show a protective role of CNNM4 expression against colon carcinogenesis.	('of', 'Gene', '6688', (42, 44))	('The', 'Gene', (0, 3))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (70, 90))	('CNNM4', 'Gene', (45, 50))	('The', 'Gene', '25085', (0, 3))	('colon carcinogenesis', 'Disease', (70, 90))	('expression', 'Var', (51, 61))
508721	33450887	In cell-based studies, high Mg2+ concentration can cause increased tyrosine-kinases activities.	('as', 'Gene', '112935892', (79, 81))	('increased tyrosine-', 'Phenotype', 'HP:0003231', (57, 76))	('rat', 'Species', '10116', (40, 43))	('activities', 'MPA', (84, 94))	('as', 'Gene', '112935892', (9, 11))	('tyrosine', 'Chemical', 'MESH:D014443', (67, 75))	('Mg2+', 'Var', (28, 32))	('as', 'Gene', '112935892', (62, 64))	('Mg2+', 'Chemical', '-', (28, 32))
508727	33450887	Xie and collaborators were able to show a direct relationship between expression of the SLC41A1 transporter and activation of the AKT/mTOR pathway.	('of', 'Gene', '6688', (81, 83))	('of', 'Gene', '6688', (123, 125))	('rat', 'Species', '10116', (15, 18))	('activation', 'PosReg', (112, 122))	('the', 'Gene', (84, 87))	('the', 'Gene', '25085', (84, 87))	('SLC41A1 transporter', 'Gene', (88, 107))	('AKT', 'Gene', '207', (130, 133))	('the', 'Gene', (126, 129))	('expression', 'Var', (70, 80))	('the', 'Gene', '25085', (126, 129))	('AKT', 'Gene', (130, 133))
508737	33450887	In ApcDelta14/+ mice, which spontaneously form benign polyps in the intestine, deletion of Cnnm4 promoted malignant progression of intestinal polyps to adenocarcinomas.	('intestinal polyps to adenocarcinomas', 'Disease', 'MESH:D007417', (131, 167))	('polyps', 'Disease', (54, 60))	('polyps', 'Disease', 'MESH:D011127', (142, 148))	('polyps in the intestine', 'Phenotype', 'HP:0200008', (54, 77))	('intestinal polyps to adenocarcinomas', 'Disease', (131, 167))	('mice', 'Species', '10090', (16, 20))	('polyps', 'Disease', 'MESH:D011127', (54, 60))	('malignant progression', 'CPA', (106, 127))	('of', 'Gene', '6688', (88, 90))	('the', 'Gene', (64, 67))	('polyps', 'Disease', (142, 148))	('the', 'Gene', '25085', (64, 67))	('of', 'Gene', '6688', (128, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('intestinal polyps', 'Phenotype', 'HP:0005266', (131, 148))	('deletion', 'Var', (79, 87))	('promoted', 'PosReg', (97, 105))	('Cnnm4', 'Gene', (91, 96))
508738	33450887	IHC analyses of tissues from patients with colon cancer demonstrated an inverse relationship between CNNM4 expression and colon cancer malignancy, thereby supporting the notion that CNNM4 suppresses the progression of cancer malignancy in humans.	('cancer malignancy', 'Disease', (218, 235))	('colon cancer', 'Phenotype', 'HP:0003003', (43, 55))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('humans', 'Species', '9606', (239, 245))	('the', 'Gene', (199, 202))	('rat', 'Species', '10116', (63, 66))	('colon cancer malignancy', 'Disease', 'MESH:D015179', (122, 145))	('patients', 'Species', '9606', (29, 37))	('the', 'Gene', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colon cancer', 'Disease', 'MESH:D015179', (43, 55))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('n an', 'Gene', '11280', (116, 120))	('n an', 'Gene', (116, 120))	('of', 'Gene', '6688', (215, 217))	('the', 'Gene', '25085', (199, 202))	('cancer malignancy', 'Disease', 'MESH:D009369', (218, 235))	('the', 'Gene', '25085', (166, 169))	('colon cancer malignancy', 'Disease', (122, 145))	('cancer malignancy', 'Disease', 'MESH:D009369', (128, 145))	('CNNM4', 'Var', (182, 187))	('inverse', 'NegReg', (72, 79))	('CNNM4', 'Gene', (101, 106))	('colon cancer', 'Disease', (43, 55))	('the', 'Gene', (147, 150))	('of', 'Gene', '6688', (13, 15))	('suppresses', 'NegReg', (188, 198))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('the', 'Gene', '25085', (147, 150))
508740	33450887	CNNM4 knockdown is able to increase intracellular Mg2+ levels, and to significantly increase ATP levels in HEK293 cells.	('Mg2+', 'Chemical', '-', (50, 54))	('CNNM4', 'Gene', (0, 5))	('as', 'Gene', '112935892', (32, 34))	('knockdown', 'Var', (6, 15))	('as', 'Gene', '112935892', (89, 91))	('HEK293', 'CellLine', 'CVCL:0045', (107, 113))	('ATP', 'Chemical', 'MESH:D000255', (93, 96))	('ATP levels', 'MPA', (93, 103))	('increase intracellular Mg2+', 'Phenotype', 'HP:0003575', (27, 54))	('intracellular Mg2+ levels', 'MPA', (36, 61))
508741	33450887	Moreover, CNNM4 knockdown (or Mg2+ supplementation) is able to selectively abrogate AMPK hyperphosphorylation (AMPK being phosphorylated and activated under energy-deficient conditions).	('AMPK hyperphosphorylation', 'MPA', (84, 109))	('CNNM4', 'Gene', (10, 15))	('abrogate', 'NegReg', (75, 83))	('knockdown', 'Var', (16, 25))	('Mg2+', 'Chemical', '-', (30, 34))	('men', 'Species', '9606', (41, 44))
508744	33450887	Moreover, it has been shown that Cnnm4 deficiency suppresses Ca2+ signaling and promotes cell proliferation in the colon epithelia.	('the', 'Gene', (124, 127))	('deficiency', 'Var', (39, 49))	('the', 'Gene', (111, 114))	('as', 'Gene', '112935892', (14, 16))	('the', 'Gene', '25085', (124, 127))	('rat', 'Species', '10116', (101, 104))	('Ca2+', 'Chemical', 'MESH:D000069285', (61, 65))	('promotes', 'PosReg', (80, 88))	('Ca2+ signaling', 'MPA', (61, 75))	('suppresses', 'NegReg', (50, 60))	('the', 'Gene', '25085', (111, 114))	('colon epithelia', 'Disease', 'MESH:D003110', (115, 130))	('Cnnm4', 'Gene', (33, 38))	('colon epithelia', 'Disease', (115, 130))	('cell proliferation in', 'CPA', (89, 110))
508749	33450887	Forced expression of MDP1 in the gastric cancer cell line BGC-823 inhibited cell proliferation, whereas the knockdown of MDP1 protein promoted cell growth.	('gastric cancer', 'Disease', 'MESH:D013274', (33, 47))	('rat', 'Species', '10116', (88, 91))	('as', 'Gene', '112935892', (101, 103))	('as', 'Gene', '112935892', (34, 36))	('knockdown', 'Var', (108, 117))	('the', 'Gene', '25085', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('promoted', 'PosReg', (134, 142))	('BGC-823', 'CellLine', 'CVCL:3360', (58, 65))	('of', 'Gene', '6688', (18, 20))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('cell growth', 'CPA', (143, 154))	('inhibited', 'NegReg', (66, 75))	('MDP1', 'Gene', (21, 25))	('the', 'Gene', (29, 32))	('of', 'Gene', '6688', (118, 120))	('gastric cancer', 'Disease', (33, 47))	('cell proliferation', 'CPA', (76, 94))	('the', 'Gene', '25085', (29, 32))	('the', 'Gene', (104, 107))
508752	33450887	TRPM7 has also been linked to Stat3: disrupted expression of Trpm7 in mice causes downregulated expression of Stat3 mRNA.	('downregulated', 'NegReg', (82, 95))	('Trpm7', 'Gene', (61, 66))	('Trpm7', 'Gene', '58800', (61, 66))	('of', 'Gene', '6688', (58, 60))	('of', 'Gene', '6688', (107, 109))	('disrupted', 'Var', (37, 46))	('mice', 'Species', '10090', (70, 74))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('Stat3 mRNA', 'MPA', (110, 120))	('as', 'Gene', '112935892', (7, 9))
508753	33450887	Finally, it has to be mentioned that anti-RTK EGFR antibodies are able to dramatically reduce serum magnesium concentration.	('magnesium', 'Chemical', 'MESH:D008274', (100, 109))	('rat', 'Species', '10116', (117, 120))	('reduce', 'NegReg', (87, 93))	('serum magnesium concentration', 'MPA', (94, 123))	('GFR', 'Gene', (47, 50))	('men', 'Species', '9606', (22, 25))	('reduce serum magnesium concentration', 'Phenotype', 'HP:0002917', (87, 123))	('GFR', 'Gene', '9771', (47, 50))	('as', 'Gene', '112935892', (13, 15))	('anti-RTK', 'Var', (37, 45))	('antibodies', 'Var', (51, 61))
508754	33450887	Although EGFR tyrosine kinase inhibitors can also potentially induce hypomagnesaemia, typical concentrations used in the clinic seem to be insufficient to induce this side-effect.	('hypomagnesaemia', 'Disease', (69, 84))	('GFR', 'Gene', '9771', (10, 13))	('the', 'Gene', (117, 120))	('rat', 'Species', '10116', (101, 104))	('the', 'Gene', '25085', (117, 120))	('induce', 'Reg', (62, 68))	('tyrosine', 'Var', (14, 22))	('as', 'Gene', '112935892', (26, 28))	('hypomagnesaemia', 'Disease', 'None', (69, 84))	('GFR', 'Gene', (10, 13))	('tyrosine', 'Chemical', 'MESH:D014443', (14, 22))
508755	33450887	Inhibition of the EGFR induces a mutated-like TRPM6 syndrome, while stimulation of the EGFR increase current through TRPM6 (but not TRPM7).	('induces', 'Reg', (23, 30))	('the', 'Gene', '25085', (14, 17))	('the', 'Gene', (83, 86))	('the', 'Gene', '25085', (83, 86))	('mutated-like', 'Disease', (33, 45))	('of', 'Gene', '6688', (11, 13))	('GFR', 'Gene', (88, 91))	('as', 'Gene', '112935892', (97, 99))	('GFR', 'Gene', (19, 22))	('GFR', 'Gene', '9771', (19, 22))	('of', 'Gene', '6688', (80, 82))	('current', 'MPA', (101, 108))	('Inhibition', 'Var', (0, 10))	('GFR', 'Gene', '9771', (88, 91))	('TRPM6', 'Gene', (46, 51))	('the', 'Gene', (14, 17))
508758	33450887	Indeed, Li and collaborators have identified mutations in this magnesium transporter gene, in a novel X-linked human immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T lymphocyte activation.	('severe chronic viral infections', 'Phenotype', 'HP:0031691', (168, 199))	('mutations', 'Var', (45, 54))	('X-linked human immunodeficiency', 'Disease', 'MESH:D053632', (102, 133))	('lymphopenia', 'Phenotype', 'HP:0001888', (155, 166))	('immunodeficiency', 'Phenotype', 'HP:0002721', (117, 133))	('defective T lymphocyte activation', 'Phenotype', 'HP:0005419', (205, 238))	('CD4 lymphopenia', 'Phenotype', 'HP:0005407', (151, 166))	('rat', 'Species', '10116', (22, 25))	('magnesium', 'Chemical', 'MESH:D008274', (63, 72))	('lymphopenia', 'Disease', 'MESH:D008231', (155, 166))	('T lymphocyte activation', 'CPA', (215, 238))	('viral infections', 'Disease', 'MESH:D001102', (183, 199))	('viral infections', 'Disease', (183, 199))	('X-linked human immunodeficiency', 'Disease', (102, 133))	('lymphopenia', 'Disease', (155, 166))
508759	33450887	MAGT1 deficiency was shown to abrogate Mg2+ influx, leading to defective activation of phospholipase Cgamma and consequently impaired responses to antigen receptor engagement in patients harboring this XMEN (X-link immunodeficiency with Magnesium defect and EBV infection and Neoplasia) disease.	('impaired', 'NegReg', (125, 133))	('N', 'Chemical', 'MESH:D009584', (205, 206))	('N', 'Chemical', 'MESH:D009584', (276, 277))	('men', 'Species', '9606', (170, 173))	('X-link immunodeficiency', 'Disease', 'MESH:D053632', (208, 231))	('Magnesium defect and EBV infection', 'Disease', 'MESH:D020031', (237, 271))	('X-link immunodeficiency', 'Disease', (208, 231))	('Neoplasia', 'Disease', 'MESH:D009369', (276, 285))	('Mg2+', 'Chemical', '-', (39, 43))	('patients', 'Species', '9606', (178, 186))	('deficiency', 'Var', (6, 16))	('MAGT1', 'Gene', (0, 5))	('defective', 'NegReg', (63, 72))	('as', 'Gene', '112935892', (281, 283))	('responses to antigen receptor engagement', 'MPA', (134, 174))	('as', 'Gene', '112935892', (18, 20))	('as', 'Gene', '112935892', (97, 99))	('abrogate', 'NegReg', (30, 38))	('Mg2+ influx', 'MPA', (39, 50))	('of', 'Gene', '6688', (84, 86))	('Neoplasia', 'Phenotype', 'HP:0002664', (276, 285))	('Neoplasia', 'Disease', (276, 285))	('n an', 'Gene', (270, 274))	('immunodeficiency', 'Phenotype', 'HP:0002721', (215, 231))	('n an', 'Gene', '11280', (270, 274))	('as', 'Gene', '112935892', (291, 293))	('activation', 'MPA', (73, 83))
508777	33450887	Moreover, MAGT1 expression is associated with a poor survival in PDAC patients and with a better survival in CRC patients.	('patients', 'Species', '9606', (70, 78))	('expression', 'Var', (16, 26))	('patients', 'Species', '9606', (113, 121))	('as', 'Gene', '112935892', (30, 32))	('MAGT1', 'Gene', (10, 15))	('PDAC', 'Disease', (65, 69))	('poor', 'NegReg', (48, 52))
508780	33450887	It has been shown that MAGT1 expression can restore TRPM7 deficiency, intracellular Mg2+ homeostasis and cell viability in some cellular models suggesting a possible transcriptomic regulation.	('restore', 'PosReg', (44, 51))	('expression', 'Var', (29, 39))	('as', 'Gene', '112935892', (4, 6))	('MAGT1', 'Gene', (23, 28))	('Mg2+', 'Chemical', '-', (84, 88))	('deficiency', 'NegReg', (58, 68))	('cell viability', 'CPA', (105, 119))	('as', 'Gene', '112935892', (96, 98))	('TRPM7', 'Gene', (52, 57))
508802	33450887	), the "Universite de Picardie Jules Verne (UPJV)" (J.A., P.K., I.D.D., H.O.A., and M.G.	('the', 'Gene', '25085', (3, 6))	('P.K.', 'Var', (58, 62))	('the', 'Gene', (3, 6))
508813	31978896	Results: From the training set, we identified a eight-lncRNA signature (including AP000487, AC011997, LINC01592, LINC01497, LINC01711, FENDRR, AC087045, AC137770) which separated the patients into two groups with significantly different overall survival (hazard ratio, HR = 3.79, 95% confidence interval, 95% CI [2.56-5.62]; P < 0.001).	('AC087045', 'Var', (143, 151))	('LINC01497', 'Gene', '102723487', (113, 122))	('LINC01592', 'Gene', (102, 111))	('LINC01592', 'Gene', '100505718', (102, 111))	('LINC01711', 'Var', (124, 133))	('AC011997', 'Var', (92, 100))	('FENDRR', 'Gene', '400550', (135, 141))	('LINC01497', 'Gene', (113, 122))	('AP000487', 'Var', (82, 90))	('LINC01711', 'Chemical', '-', (124, 133))	('FENDRR', 'Gene', (135, 141))	('AC137770', 'Var', (153, 161))	('patients', 'Species', '9606', (183, 191))
508835	31978896	As above, it was suggested that the lncRNAs in the signature were all risk factors for OS.	('OS', 'Chemical', 'MESH:D009992', (87, 89))	('lncRNAs', 'Var', (36, 43))	('risk factors', 'Reg', (70, 82))
508837	31978896	For example, the influence of LINC01711 was greatest while that of LINC01592 was least.	('LINC01592', 'Gene', (67, 76))	('LINC01592', 'Gene', '100505718', (67, 76))	('LINC01711', 'Chemical', '-', (30, 39))	('LINC01711', 'Var', (30, 39))
508841	31978896	The area under the ROC curve (AUC) for 0.5-, 1-, 3-, and 5-year OS were 0.673, 0.734, 0.798, 0.816, 0.795 and 0.777, 0.644, 0.642, 0.649, 0.765 in the TCGA and GEO cohorts, respectively.	('0.798', 'Var', (86, 91))	('0.795', 'Var', (100, 105))	('0.816', 'Var', (93, 98))	('0.777', 'Var', (110, 115))	('0.734', 'Var', (79, 84))	('OS', 'Chemical', 'MESH:D009992', (64, 66))
508858	31978896	Finally, eight lincRNAs (AP000487, AC011997, LINC01592, LINC01497, LINC01711, FENDRR, AC087045, AC137770) were selected to build a prognostic signature for ESCC.	('FENDRR', 'Gene', (78, 84))	('LINC01497', 'Gene', '102723487', (56, 65))	('AC137770', 'Var', (96, 104))	('LINC01592', 'Gene', (45, 54))	('AC087045', 'Var', (86, 94))	('AP000487', 'Var', (25, 33))	('LINC01711', 'Var', (67, 76))	('ESCC', 'Disease', 'MESH:C562729', (156, 160))	('LINC01592', 'Gene', '100505718', (45, 54))	('LINC01711', 'Chemical', '-', (67, 76))	('LINC01497', 'Gene', (56, 65))	('AC011997', 'Var', (35, 43))	('FENDRR', 'Gene', '400550', (78, 84))	('ESCC', 'Disease', (156, 160))
508887	31851786	TP53 (78% of patients), NOTCH1 (32%), ARID1A (13%), FAT1 (13%), and CDKN2A (13%) were commonly mutated in ESCC patients, while gene amplifications frequently occurred in MCL1 (36%), FGF19 (34%), MYC (32%), CCND1 (27%), ZNF217 (15%), CDKN2A (13%), and YAP1 (11%).	('ESCC', 'Disease', 'MESH:C562729', (106, 110))	('MYC', 'Gene', (195, 198))	('patients', 'Species', '9606', (13, 21))	('FGF19', 'Gene', (182, 187))	('FGF19', 'Gene', '9965', (182, 187))	('CDKN2A', 'Gene', (68, 74))	('CDKN2A', 'Gene', (233, 239))	('NOTCH1', 'Gene', '4851', (24, 30))	('MCL1', 'Gene', (170, 174))	('ZNF217', 'Gene', (219, 225))	('ZNF217', 'Gene', '7764', (219, 225))	('FAT1', 'Gene', (52, 56))	('TP53', 'Gene', '7157', (0, 4))	('YAP1', 'Gene', '10413', (251, 255))	('ESCC', 'Disease', (106, 110))	('CDKN2A', 'Gene', '1029', (68, 74))	('CDKN2A', 'Gene', '1029', (233, 239))	('MYC', 'Gene', '4609', (195, 198))	('MCL1', 'Gene', '4170', (170, 174))	('YAP1', 'Gene', (251, 255))	('ARID1A', 'Gene', (38, 44))	('CCND1', 'Gene', '595', (206, 211))	('CCND1', 'Gene', (206, 211))	('FAT1', 'Gene', '2195', (52, 56))	('TP53', 'Gene', (0, 4))	('ARID1A', 'Gene', '8289', (38, 44))	('NOTCH1', 'Gene', (24, 30))	('mutated', 'Var', (95, 102))	('patients', 'Species', '9606', (111, 119))
508888	31851786	Univariate and multivariate analyses of clinical factors and genetic alterations indicated that sex is an independent prognostic factor, with males tending to have better LRFS (hazard ratio [HR], 0.25; 95%CI, 0.08-0.77, P = .015) and progression-free survival (PFS) (HR, 0.35; 95%CI, 0.13-0.93, P = .030) following dCRT.	('dCRT', 'Gene', '45841', (315, 319))	('alterations', 'Var', (69, 80))	('progression-free survival', 'CPA', (234, 259))	('better', 'PosReg', (164, 170))	('dCRT', 'Gene', (315, 319))	('LRFS', 'CPA', (171, 175))
508890	31851786	In a subgroup analysis, while sex and M-stage were controlled, a much stronger negative effect of YAP1 amplification vs wild-type in LRFS was observed (log-rank P = .0067).	('YAP1', 'Gene', '10413', (98, 102))	('YAP1', 'Gene', (98, 102))	('negative', 'NegReg', (79, 87))	('amplification', 'Var', (103, 116))
508891	31851786	The results suggested that YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored.	('patients', 'Species', '9606', (130, 138))	('YAP1', 'Gene', '10413', (27, 31))	('YAP1', 'Gene', (27, 31))	('amplification', 'Var', (32, 45))
508892	31851786	We found that in patients with nonsurgical esophageal squamous cell carcinoma, YAP1 amplification is an adverse prognostic factor associated with significantly shorter local recurrent-free survival (LRFS) after definitive chemoradiotherapy.	('esophageal squamous cell carcinoma', 'Disease', (43, 77))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (43, 77))	('YAP1', 'Gene', (79, 83))	('YAP1', 'Gene', '10413', (79, 83))	('amplification', 'Var', (84, 97))	('local recurrent-free survival', 'CPA', (168, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('patients', 'Species', '9606', (17, 25))	('shorter', 'NegReg', (160, 167))
508919	31851786	This analysis pipeline is capable of detecting 0.4-fold copy number loss at >=50% tumor cell content, and fourfold amplification at >=10% tumor cell content.	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('loss', 'NegReg', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (82, 87))	('copy number', 'Var', (56, 67))
508932	31851786	Genes that were mutated in more than five cases (>10% patients) included TP53 (79%), NOTCH1 (32%), ARID2A (13%), FAT1 (13%), and CDKN2A (11%), which were consistent with a previous report.23 TP53 mutations were identified in 38 patients, among which 20 patients had frameshift or nonsense mutations (Table S1).	('TP53', 'Gene', '7157', (73, 77))	('NOTCH1', 'Gene', '4851', (85, 91))	('FAT1', 'Gene', '2195', (113, 117))	('patients', 'Species', '9606', (54, 62))	('CDKN2A', 'Gene', (129, 135))	('FAT1', 'Gene', (113, 117))	('TP53', 'Gene', (73, 77))	('TP53', 'Gene', (191, 195))	('NOTCH1', 'Gene', (85, 91))	('TP53', 'Gene', '7157', (191, 195))	('nonsense mutations', 'Var', (280, 298))	('frameshift', 'Var', (266, 276))	('CDKN2A', 'Gene', '1029', (129, 135))	('patients', 'Species', '9606', (253, 261))	('patients', 'Species', '9606', (228, 236))	('mutations', 'Var', (196, 205))
508935	31851786	TERC, which encodes an RNA component of telomerase and serves as the template of the telomere, was amplified in 35 patients (74%), while SOX2, another gene on chromosome 3q26, was amplified in 23 patients (47%), and 23 patients exhibited amplification of both genes (Figure 1).	('patients', 'Species', '9606', (115, 123))	('TERC', 'Gene', (0, 4))	('patients', 'Species', '9606', (196, 204))	('SOX2', 'Gene', '6657', (137, 141))	('patients', 'Species', '9606', (219, 227))	('SOX2', 'Gene', (137, 141))	('amplified', 'Var', (99, 108))	('TERC', 'Gene', '7012', (0, 4))
508937	31851786	Therefore, we examined the association of the top gene alterations in Figure 1 with patients' LRFS, PFS, and OS using the univariate Cox regression model.	('Cox', 'Gene', '1351', (133, 136))	('Cox', 'Gene', (133, 136))	('PFS', 'Disease', (100, 103))	('alterations', 'Var', (55, 66))	('patients', 'Species', '9606', (84, 92))	('association', 'Interaction', (27, 38))	('LRFS', 'Disease', (94, 98))	('Figure 1', 'Gene', (70, 78))
508939	31851786	Multivariate analyses revealed that YAP1 amplification was the only genetic biomarker found to be significantly associated with shorter LRFS (HR 4.06, P = .019).	('YAP1', 'Gene', (36, 40))	('YAP1', 'Gene', '10413', (36, 40))	('amplification', 'Var', (41, 54))	('shorter', 'NegReg', (128, 135))
508940	31851786	A nearly significant association was also found between YAP1 amplification and shorter OS (HR 2.78, P = .062), while a nonsignificant association was observed with PFS (HR 1.56, P = .11, Table 2).	('amplification', 'Var', (61, 74))	('shorter OS', 'Disease', (79, 89))	('YAP1', 'Gene', '10413', (56, 60))	('YAP1', 'Gene', (56, 60))
508945	31851786	Given that both M staging and sex were associated with LRFS in multivariate analyses (Table 2), we compared the survival times of male patients with stage II-III disease between the YAP1 amplification and wt groups.	('patients', 'Species', '9606', (135, 143))	('YAP1', 'Gene', (182, 186))	('YAP1', 'Gene', '10413', (182, 186))	('amplification', 'Var', (187, 200))	('associated', 'Reg', (39, 49))
508951	31851786	The lower impact of sex on OS is consistent with the SCOPE1 trial in which females did not show a pronounced difference in OS from males following dCRT treatment.29 Other reports suggested a longer OS for females than males,30 but under different treatments.31, 32  Genomic profiling of ESCC tumors found 98% patients having amplification in one or more cancer-relevant genes, as well as the co-amplification of genes at adjacent chromosome locations, such as CCND1/FGF19 and TERC/SOX2/PIK3CA.	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('SOX2', 'Gene', (481, 485))	('dCRT', 'Gene', '45841', (147, 151))	('PIK3CA', 'Gene', '5290', (486, 492))	('SOX2', 'Gene', '6657', (481, 485))	('TERC', 'Gene', '7012', (476, 480))	('ESCC', 'Disease', 'MESH:C562729', (287, 291))	('FGF19', 'Gene', (466, 471))	('CCND1', 'Gene', '595', (460, 465))	('FGF19', 'Gene', '9965', (466, 471))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('TERC', 'Gene', (476, 480))	('tumors', 'Disease', (292, 298))	('CCND1', 'Gene', (460, 465))	('PIK3CA', 'Gene', (486, 492))	('ESCC', 'Disease', (287, 291))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('dCRT', 'Gene', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('amplification', 'Var', (325, 338))	('patients', 'Species', '9606', (309, 317))
508952	31851786	The amplification of TERC and SOX2 was frequently observed in a variety of SCC, including oral and oropharyngeal,33 lung, esophagus,34 and cervical.35 However, despite their prevalence in cancers, those genes were not correlated with any of the survival parameters in this study.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('oral', 'Disease', (90, 94))	('observed', 'Reg', (50, 58))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('SCC', 'Disease', 'MESH:D002294', (75, 78))	('cancers', 'Disease', (188, 195))	('TERC', 'Gene', (21, 25))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('SOX2', 'Gene', '6657', (30, 34))	('amplification', 'Var', (4, 17))	('TERC', 'Gene', '7012', (21, 25))	('SOX2', 'Gene', (30, 34))	('SCC', 'Disease', (75, 78))
508954	31851786	In a subgroup of patients (male patients with stage II/III disease), of which the impact of sex and clinical stages was controlled, the difference in LRFS between YAP1 amplification and wt groups was more pronounced, suggesting that YAP1 is an independent prognostic marker for dCRT.	('patients', 'Species', '9606', (32, 40))	('YAP1', 'Gene', (233, 237))	('YAP1', 'Gene', '10413', (233, 237))	('dCRT', 'Gene', '45841', (278, 282))	('dCRT', 'Gene', (278, 282))	('patients', 'Species', '9606', (17, 25))	('YAP1', 'Gene', (163, 167))	('YAP1', 'Gene', '10413', (163, 167))	('amplification', 'Var', (168, 181))
508982	31438645	Most of these are genetic changes that occur in the genomic DNA due to carcinogens, spontaneous mutations or viral infections that integrate mutant oncogenes into genomic DNA.	('carcinogens', 'Disease', 'MESH:D063646', (71, 82))	('mutant', 'Var', (141, 147))	('carcinogens', 'Disease', (71, 82))
509031	31438645	Amplification of genes on chromosome 12 is previously reported in ESCC.	('ESCC', 'Disease', 'MESH:C562729', (66, 70))	('Amplification', 'Var', (0, 13))	('ESCC', 'Disease', (66, 70))
509032	31438645	30 genes where missense mutations were identified in the current study are previously reported to be mutated in ESCC.	('missense mutations', 'Var', (15, 33))	('ESCC', 'Disease', 'MESH:C562729', (112, 116))	('ESCC', 'Disease', (112, 116))
509033	31438645	This included E74 like ETS transcription factor 3 (ELF3), spen family transcriptional repressor (SPEN) and notch receptor 3 (NOTCH3) that are known to be mutated in various cancers.	('ELF3', 'Gene', (51, 55))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancers', 'Disease', (173, 180))	('E74', 'Var', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
509057	31438645	We found that proteins involved in energy pathways including TCA cycle, OXPHOS and fatty acid oxidation were overexpressed in Het1A-8M (Figure 4b-d).	('proteins', 'Protein', (14, 22))	('fatty acid oxidation', 'MPA', (83, 103))	('OXPHOS', 'MPA', (72, 78))	('TCA', 'Chemical', 'MESH:D014233', (61, 64))	('fatty acid', 'Chemical', 'MESH:D005227', (83, 93))	('overexpressed', 'PosReg', (109, 122))	('energy pathways', 'MPA', (35, 50))	('Het1A-8M', 'Var', (126, 134))	('TCA cycle', 'MPA', (61, 70))
509067	31438645	Exome sequencing revealed several single nucleotide variations and amplifications following chewing tobacco treatment.	('tobacco', 'Species', '4097', (100, 107))	('single nucleotide variations', 'Var', (34, 62))	('amplifications', 'MPA', (67, 81))
509118	31333787	The primary antibodies included SNX1 (1:400, SantaCruz, USA) andbeta-actin (1:1000, SantaCruz, USA).	('1:1000', 'Var', (76, 82))	('beta-actin', 'Gene', '728378', (64, 74))	('SNX1', 'Gene', '6642', (32, 36))	('beta-actin', 'Gene', (64, 74))	('SNX1', 'Gene', (32, 36))	('1:400', 'Var', (38, 43))
509161	27456944	This study was conducted to comprehensively evaluate the cytotoxic effects of 83b1 on a series of ESCC cell lines and investigate the mechanisms by which 83b1 suppresses cancer growth based on molecular docking analysis.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('83b1', 'Gene', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('83b1', 'Var', (154, 158))	('suppresses', 'NegReg', (159, 169))
509165	27456944	83b1 showed the significant anti-cancer effects on all ESCC cell lines compared to CDDP; however, 83b1 revealed much lower toxic effects on non-tumor cell lines than CDDP.	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('CDDP', 'Chemical', 'MESH:D002945', (83, 87))	('lower', 'NegReg', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('CDDP', 'Chemical', 'MESH:D002945', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('83b1', 'Var', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
509168	27456944	Furthermore, 83b1 was shown to significantly reduce the tumor size in nude mice xenograft.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('reduce', 'NegReg', (45, 51))	('83b1', 'Var', (13, 17))	('nude mice', 'Species', '10090', (70, 79))
509248	27456944	Our results showed that 83b1 can significantly down-regulate COX-2 mRNA expression in ESCC cell lines.	('COX-2', 'Gene', (61, 66))	('COX-2', 'Gene', '5743', (61, 66))	('83b1', 'Var', (24, 28))	('down-regulate', 'NegReg', (47, 60))
509251	27456944	The in vivo study also showed that 83b1 can significantly suppress tumors in animals within 19 days, and that tumors inside of nude mice almost disappeared.	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('83b1', 'Var', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('nude mice', 'Species', '10090', (127, 136))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (67, 73))	('suppress', 'NegReg', (58, 66))
509260	27099520	Pooled results showed that presence of CTCs was significantly associated with poor overall survival (HR =1.71, 95% CI [1.30, 2.12], P<0.001) and progression-free survival (HR =1.67, 95% CI [1.19, 2.15], P<0.001) in EC patients.	('overall survival', 'CPA', (83, 99))	('CTCs', 'Var', (39, 43))	('patients', 'Species', '9606', (218, 226))	('poor', 'NegReg', (78, 82))	('progression-free survival', 'CPA', (145, 170))	('presence', 'Var', (27, 35))
509261	27099520	Subgroup analysis indicated that presence of CTCs was closely associated with worse overall survival (Asian: HR =1.66, 95% CI [1.24, 2.08], P<0.001; squamous cell carcinoma [SCC]: HR =1.66, 95% CI [1.24, 2.08], P<0.001; no polymerase chain reaction [PCR]: HR =2.08, 95% CI [1.40, 2.76], P<0.001) and progression-free survival (Asian: HR =1.63, 95% CI [1.15, 2.12], P<0.001; SCC: HR =1.63, 95% CI [1.15, 2.12], P<0.001; PCR: HR =1.63, 95% CI [1.15, 2.12], P<0.001).	('SCC', 'Gene', (174, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('SCC', 'Gene', (374, 377))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('SCC', 'Gene', '6317', (174, 177))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (149, 172))	('presence', 'Var', (33, 41))	('squamous cell carcinoma', 'Disease', (149, 172))	('progression-free survival', 'CPA', (300, 325))	('overall survival', 'CPA', (84, 100))	('SCC', 'Gene', '6317', (374, 377))
509284	27099520	The presence of CTCs in pT3/ T4 group was significantly higher than pT1/T2 group (overall: OR =1.77, 95% CI [1.02, 3.06], P=0.04; SCC: OR =2.14, 95% CI [1.56, 2.94], P<0.001, random-effect) (Table 2).	('higher', 'PosReg', (56, 62))	('SCC', 'Gene', (130, 133))	('SCC', 'Gene', '6317', (130, 133))	('pT3/ T4', 'Var', (24, 31))
509285	27099520	We also found that the presence of CTCs was associated with a significantly increased risk of lymph node metastasis (overall: OR =2.41, 95% CI [1.50, 3.86], P<0.001; Asian: OR =2.89, 95% CI [1.80, 4.65], P<0.001; SCC: OR =2.44, 95% CI [1.47, 4.07], P=0.001; PCR: OR =2.89, 95% CI [1.80, 4.65], P<0.001, random-effect) (Table 2).	('SCC', 'Gene', '6317', (213, 216))	('lymph node metastasis', 'CPA', (94, 115))	('presence', 'Var', (23, 31))	('SCC', 'Gene', (213, 216))	('increased risk of lymph node', 'Phenotype', 'HP:0032536', (76, 104))	('CTCs', 'Var', (35, 39))
509286	27099520	We found that the presence of CTCs was correlated with a significantly increased risk of venous invasion in Asian, SCC, and PCR subgroups (overall: OR =2.23, 95% CI [1.46, 3.40], P<0.001; Asian: OR =2.23, 95% CI [1.46, 3.40], P<0.001; SCC: OR =2.23, 95% CI [1.46, 3.40], P<0.001; PCR: OR =2.23, 95% CI [1.46, 3.40], P<0.001, fixed-effect) (Table 2).	('presence', 'Var', (18, 26))	('SCC', 'Gene', '6317', (235, 238))	('Asian', 'Disease', (108, 113))	('venous invasion', 'CPA', (89, 104))	('SCC', 'Gene', (115, 118))	('CTCs', 'Gene', (30, 34))	('SCC', 'Gene', (235, 238))	('SCC', 'Gene', '6317', (115, 118))
509287	27099520	Several studies have indicated that the presence of CTCs could be significantly correlated with distant metastasis and poor prognosis in lung cancer and colorectal cancer.	('correlated', 'Reg', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('presence', 'Var', (40, 48))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('CTCs', 'Var', (52, 56))	('distant metastasis', 'CPA', (96, 114))	('colorectal cancer', 'Disease', (153, 170))
509293	27099520	The survival analysis reveals that patients with presence of CTCs have worse OS and PFS than those who lack CTCs.	('worse', 'NegReg', (71, 76))	('PFS', 'Disease', (84, 87))	('CTCs', 'Var', (61, 65))	('patients', 'Species', '9606', (35, 43))
509298	27099520	Thus, we prove that the presence of CTCs at baseline in PB is significantly correlated with tumor metastasis and poor prognosis of Asian patients with EC.	('tumor metastasis', 'Disease', 'MESH:D009362', (92, 108))	('presence', 'Var', (24, 32))	('tumor metastasis', 'Disease', (92, 108))	('CTCs', 'Var', (36, 40))	('patients', 'Species', '9606', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('correlated', 'Reg', (76, 86))
509303	27099520	In conclusion, our meta-analysis indicates that presence of CTCs is significantly associated with poor prognosis in EC patients, especially in Asian and SCC patients.	('SCC', 'Gene', '6317', (153, 156))	('presence', 'Var', (48, 56))	('patients', 'Species', '9606', (119, 127))	('patients', 'Species', '9606', (157, 165))	('CTCs', 'Gene', (60, 64))	('SCC', 'Gene', (153, 156))	('Asian', 'Disease', (143, 148))
509305	26205887	Heterozygote of TAP1 Codon637 decreases susceptibility to HPV infection but increases susceptibility to esophageal cancer among the Kazakh populations The role of human papillomavirus (HPV) may be involved in the development of esophageal cancer (EC) and the polymorphic immune response gene transporter associated with antigen processing (TAP) may be involved in HPV persistence and subsequent cancer carcinogenesis.	('HPV infection', 'Disease', 'MESH:D030361', (58, 71))	('HPV', 'Species', '10566', (364, 367))	('increases', 'PosReg', (76, 85))	('HPV infection', 'Disease', (58, 71))	('esophageal cancer', 'Disease', (228, 245))	('human papillomavirus', 'Species', '10566', (163, 183))	('susceptibility', 'MPA', (40, 54))	('HPV', 'Species', '10566', (58, 61))	('decreases', 'NegReg', (30, 39))	('TAP1', 'Gene', (16, 20))	('TAP1', 'Gene', '6890', (16, 20))	('susceptibility', 'MPA', (86, 100))	('cancer carcinogenesis', 'Disease', 'MESH:D063646', (395, 416))	('involved', 'Reg', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('HPV', 'Species', '10566', (185, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('men', 'Species', '9606', (220, 223))	('papilloma', 'Phenotype', 'HP:0012740', (169, 178))	('Codon637', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (395, 401))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer carcinogenesis', 'Disease', (395, 416))	('esophageal cancer', 'Disease', (104, 121))	('transporter associated with antigen processing (TAP)', 'Gene', '2317', (292, 344))	('transporter associated with antigen processing (TAP', 'Gene', (292, 343))	('esophageal cancer', 'Disease', 'MESH:D004938', (228, 245))
509306	26205887	The current study aims to provide association evidence for HPV with EC, to investigate TAP1 polymorphisms in EC and assess its association with HPV statuses and EC in Kazakhs.	('HPV', 'Species', '10566', (144, 147))	('association', 'Interaction', (127, 138))	('polymorphisms', 'Var', (92, 105))	('HPV', 'Species', '10566', (59, 62))	('investigate', 'Reg', (75, 86))	('TAP1', 'Gene', (87, 91))	('HPV', 'Disease', (59, 62))	('TAP1', 'Gene', '6890', (87, 91))
509309	26205887	A case-to-case comparison based on the genotyping results was conducted to address the function of TAP1 variants in the involvement of HPV.	('TAP1', 'Gene', (99, 103))	('TAP1', 'Gene', '6890', (99, 103))	('variants', 'Var', (104, 112))	('HPV', 'Species', '10566', (135, 138))	('men', 'Species', '9606', (127, 130))
509310	26205887	The presence of four HPV genotypes in EC tissues : including HPV 16, 18, 31, 45 : was significantly higher at 64.6 % than those in controls at 18.2 % (P < 0.001).	('HPV', 'Species', '10566', (21, 24))	('HPV 16', 'Var', (61, 67))	('HPV 16', 'Species', '333760', (61, 67))	('higher', 'PosReg', (100, 106))	('HPV', 'Species', '10566', (61, 64))
509311	26205887	The infection of HPV16, and multi-infection of 16 and 18 significantly increase the risk for developing EC (OR 4.616, 95 % CI 2.099-10.151; and OR 6.029, 95 % CI 1.395-26.057 respectively).	('HPV16', 'Gene', (17, 22))	('multi-infection', 'Disease', (28, 43))	('HPV16', 'Species', '333760', (17, 22))	('infection', 'Var', (4, 13))	('increase', 'PosReg', (71, 79))	('multi-infection', 'Disease', 'MESH:D015140', (28, 43))
509312	26205887	Heterozygote of TAP1 D637G had a significantly higher risk for developing EC (OR 1.626; 95 % CI 1.080-2.449).	('D637G', 'Mutation', 'rs1135216', (21, 26))	('TAP1', 'Gene', (16, 20))	('TAP1', 'Gene', '6890', (16, 20))	('D637G', 'Var', (21, 26))
509313	26205887	The odds ratio for HPV infection was significantly lower among carriers of TAP1 D637G polymorphism (OR 0.281; 95 % CI 0.144-0.551).	('TAP1', 'Gene', (75, 79))	('HPV infection', 'Disease', (19, 32))	('TAP1', 'Gene', '6890', (75, 79))	('lower', 'NegReg', (51, 56))	('D637G', 'Mutation', 'rs1135216', (80, 85))	('HPV infection', 'Disease', 'MESH:D030361', (19, 32))	('D637G', 'Var', (80, 85))
509315	26205887	Heterozygote of TAP1 D637G decreases susceptibility to HPV infection in patients with EC but increases susceptibility to EC among the Kazakh populations.	('TAP1', 'Gene', (16, 20))	('susceptibility', 'MPA', (103, 117))	('TAP1', 'Gene', '6890', (16, 20))	('D637G', 'Mutation', 'rs1135216', (21, 26))	('decreases', 'NegReg', (27, 36))	('HPV infection', 'Disease', 'MESH:D030361', (55, 68))	('increases', 'PosReg', (93, 102))	('D637G', 'Var', (21, 26))	('susceptibility', 'MPA', (37, 51))	('HPV infection', 'Disease', (55, 68))	('patients', 'Species', '9606', (72, 80))
509332	26205887	Some single nucleotide polymorphisms (SNPs) of TAP gene appear to influence the antigen peptide selection and transport process, and have been confirmed to be susceptible to various human diseases including immune diseases, infectious diseases and tumors.	('infectious diseases and tumors', 'Disease', 'MESH:D003141', (224, 254))	('human', 'Species', '9606', (182, 187))	('susceptible', 'Reg', (159, 170))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('influence', 'Reg', (66, 75))	('antigen peptide selection', 'MPA', (80, 105))	('TAP', 'Gene', '6891', (47, 50))	('single nucleotide polymorphisms', 'Var', (5, 36))	('TAP', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
509335	26205887	The results show no significant difference between the polymorphisms at TAP1 I333V and D637G and EC in Anyang, Henan.	('I333V', 'Var', (77, 82))	('D637G', 'Mutation', 'rs1135216', (87, 92))	('D637G', 'Var', (87, 92))	('TAP1', 'Gene', (72, 76))	('TAP1', 'Gene', '6890', (72, 76))	('I333V', 'Mutation', 'rs1057141', (77, 82))
509336	26205887	Given that TAP1 plays an important role in immune response and the polymorphisms of this gene may result in the conformational and functional change, and thus may affect individual's susceptibility to HPV infection and subsequently the HPV-associated cancer development.	('men', 'Species', '9606', (265, 268))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('affect', 'Reg', (163, 169))	('result in', 'Reg', (98, 107))	('HPV infection', 'Disease', 'MESH:D030361', (201, 214))	('HPV', 'Species', '10566', (201, 204))	('susceptibility', 'MPA', (183, 197))	('HPV', 'Species', '10566', (236, 239))	('TAP1', 'Gene', (11, 15))	('TAP1', 'Gene', '6890', (11, 15))	('HPV-associated', 'Disease', (236, 250))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('functional change', 'MPA', (131, 148))	('HPV infection', 'Disease', (201, 214))	('cancer', 'Disease', (251, 257))	('conformational', 'MPA', (112, 126))	('polymorphisms', 'Var', (67, 80))
509337	26205887	What's more, the distribution of Codon 333 and 637 polymorphisms of TAP1 and its relationship with HPV infection and EC remains unknown among the Kazakh population.	('TAP1', 'Gene', (68, 72))	('TAP1', 'Gene', '6890', (68, 72))	('HPV infection', 'Disease', (99, 112))	('Codon 333', 'Var', (33, 42))	('HPV infection', 'Disease', 'MESH:D030361', (99, 112))
509340	26205887	Additionally, 150 paraffin-embeded tumor specimens and 283 matched cancer-free controls were used to investigate the association between TAP1 polymorphisms and risk of EC in this ethnic and to accumulate evidence regarding the potential role of TAP polymorphisms in the disease.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('TAP1', 'Gene', '6890', (137, 141))	('paraffin', 'Chemical', 'MESH:D010232', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('association', 'Interaction', (117, 128))	('tumor', 'Disease', (35, 40))	('men', 'Species', '9606', (46, 49))	('TAP', 'Gene', '6891', (245, 248))	('polymorphisms', 'Var', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TAP', 'Gene', (245, 248))	('TAP', 'Gene', '6891', (137, 140))	('TAP', 'Gene', (137, 140))	('TAP1', 'Gene', (137, 141))
509341	26205887	Subsequently, a case-to-case comparison based on the genotyping results was conducted to address the possible function of the TAP1 variants in the involvement of HPV in Kazakh patients with EC.	('patients', 'Species', '9606', (176, 184))	('TAP1', 'Gene', (126, 130))	('HPV', 'Species', '10566', (162, 165))	('TAP1', 'Gene', '6890', (126, 130))	('variants', 'Var', (131, 139))	('men', 'Species', '9606', (154, 157))
509372	26205887	The terminator ready sequencin was performed in a total volume of 20 ml containing 8 ml of PCR product, 2.5 ml 10 x PCR buffer, the enzymes used were 7 U of Bcl1 and Acc1 for genotyping Codon 333 and Codon 637 respectively.	('Acc1', 'Gene', '597', (166, 170))	('Acc1', 'Gene', (166, 170))	('Bcl1', 'Gene', (157, 161))	('Codon 637', 'Var', (200, 209))	('Codon 333', 'Var', (186, 195))	('Bcl1', 'Gene', '595', (157, 161))
509377	26205887	To confirm the accuracy of TAP1 I333V and D637G genotyping by PCR, 10 % DNA sequence of the PCR products was then identified by NCBI Blast (Fig.	('D637G', 'Mutation', 'rs1135216', (42, 47))	('I333V', 'Var', (32, 37))	('TAP1', 'Gene', (27, 31))	('TAP1', 'Gene', '6890', (27, 31))	('D637G', 'Var', (42, 47))	('I333V', 'Mutation', 'rs1057141', (32, 37))
509378	26205887	The presence of HPV DNA in case-control study, Clinic pathological characteristics of HPV-positive and HPV-negative patients with ESCC, and the differences in the distributions of genotype of TAP1 I333V and D637G were analyzed by chi-square test.	('D637G', 'Var', (207, 212))	('TAP1', 'Gene', (192, 196))	('HPV', 'Species', '10566', (86, 89))	('TAP1', 'Gene', '6890', (192, 196))	('I333V', 'Var', (197, 202))	('ESCC', 'Disease', (130, 134))	('patients', 'Species', '9606', (116, 124))	('HPV', 'Species', '10566', (103, 106))	('HPV', 'Species', '10566', (16, 19))	('D637G', 'Mutation', 'rs1135216', (207, 212))	('I333V', 'Mutation', 'rs1057141', (197, 202))
509379	26205887	Logistic regression models for genotype were used to examine TAP1 I333V and D637G polymorphisms with risk of Kazakh EC, the effects of TAP1 D637G on risk of ESCC with different tumor depth, histological grade and clinical stage, and the association of HPV infection with TAP1 I333V and D637G polymorphisms in Kazakh EC.	('association', 'Interaction', (237, 248))	('TAP1', 'Gene', (135, 139))	('D637G', 'Mutation', 'rs1135216', (140, 145))	('TAP1', 'Gene', '6890', (135, 139))	('I333V', 'Mutation', 'rs1057141', (66, 71))	('D637G', 'Mutation', 'rs1135216', (76, 81))	('D637G', 'Var', (286, 291))	('tumor', 'Disease', (177, 182))	('TAP1', 'Gene', (61, 65))	('TAP1', 'Gene', '6890', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('I333V', 'Mutation', 'rs1057141', (276, 281))	('HPV infection', 'Disease', 'MESH:D030361', (252, 265))	('Kazakh EC', 'Disease', (109, 118))	('HPV infection', 'Disease', (252, 265))	('TAP1', 'Gene', (271, 275))	('D637G', 'Var', (140, 145))	('D637G', 'Mutation', 'rs1135216', (286, 291))	('ESCC', 'Disease', (157, 161))	('TAP1', 'Gene', '6890', (271, 275))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('D637G', 'Var', (76, 81))	('I333V', 'Var', (276, 281))
509386	26205887	Apart from HPV45, the HPV detected, including HPV16 (OR, 3.941;95 % CI, 1.926-7.955), HPV18 (OR, 3.390;95 % CI, 1.411-8.145) and HPV31 (OR, 3.487; 95 % CI, 1.050-11.582), exhibited a strong positive association with the risk of EC in Kazakhs.	('HPV31', 'Var', (129, 134))	('HPV', 'Species', '10566', (86, 89))	('HPV', 'Species', '10566', (11, 14))	('HPV', 'Species', '10566', (46, 49))	('HPV', 'Species', '10566', (22, 25))	('HPV16', 'Species', '333760', (46, 51))	('HPV18', 'Var', (86, 91))	('HPV', 'Species', '10566', (129, 132))
509389	26205887	The infection of HPV16, 18 and multi-infection of the two types significantly increase the risk for developing EC (OR 4.616, 95 % CI 2.099-10.151; OR 4.522,95 % CI.	('multi-infection', 'Disease', (31, 46))	('HPV16', 'Species', '333760', (17, 22))	('increase', 'PosReg', (78, 86))	('infection', 'Var', (4, 13))	('HPV16', 'Gene', (17, 22))	('multi-infection', 'Disease', 'MESH:D015140', (31, 46))
509393	26205887	The distribution of genotypes and alleles is significantly different between cases and controls at TAP1 D637G (P = 0.040 and P = 0.018 respectively), but not at TAP1 I333V (P = 0.250 and P = 0.118 respectively).	('TAP1', 'Gene', (99, 103))	('TAP1', 'Gene', (161, 165))	('different', 'Reg', (59, 68))	('TAP1', 'Gene', '6890', (99, 103))	('TAP1', 'Gene', '6890', (161, 165))	('D637G', 'Mutation', 'rs1135216', (104, 109))	('I333V', 'Mutation', 'rs1057141', (166, 171))	('D637G', 'Var', (104, 109))
509394	26205887	TAP1 D637G allele (G) is significantly more common in patients than that in controls (P = 0.018), suggesting that the G allele is associated with EC in Kazakh population.	('patients', 'Species', '9606', (54, 62))	('TAP1', 'Gene', (0, 4))	('TAP1', 'Gene', '6890', (0, 4))	('D637G', 'Mutation', 'rs1135216', (5, 10))	('D637G', 'Var', (5, 10))	('associated', 'Reg', (130, 140))
509395	26205887	Logistic regression models for genotype were derived to examine the association between TAP1 polymorphisms and the risk of Kazakh EC.	('association', 'Interaction', (68, 79))	('TAP1', 'Gene', '6890', (88, 92))	('polymorphisms', 'Var', (93, 106))	('Kazakh EC', 'Disease', (123, 132))	('TAP1', 'Gene', (88, 92))
509396	26205887	Only TAP1 D637G polymorphism was found to be associated with cancer risk, which was significantly increased for carriers of at least one G allele (OR, 1.659; 95 % CI, 1.112-2.474) and heterozygote carriers of the variant allele G (OR, 1.626; 95 % CI, 1.080-2.449) (Table 4).	('D637G', 'Mutation', 'rs1135216', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('associated', 'Reg', (45, 55))	('D637G', 'Var', (10, 15))	('increased', 'PosReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TAP1', 'Gene', (5, 9))	('TAP1', 'Gene', '6890', (5, 9))
509397	26205887	To investigate the contribution of confounding factors such as gender and age to the risk for Kazakh ESCC, stratification analyses were conducted to evaluate the potential association of genetic variants of the TAP1 D637G polymorphism with risk of subgroup populations (Table 5).	('association', 'Interaction', (172, 183))	('D637G', 'Var', (216, 221))	('D637G', 'Mutation', 'rs1135216', (216, 221))	('Kazakh ESCC', 'Disease', (94, 105))	('TAP1', 'Gene', (211, 215))	('TAP1', 'Gene', '6890', (211, 215))
509398	26205887	No significant association was found between TAP1 D637G polymorphism and ESCC with respect to age (P > 0.05).	('D637G', 'Var', (50, 55))	('TAP1', 'Gene', (45, 49))	('TAP1', 'Gene', '6890', (45, 49))	('D637G', 'Mutation', 'rs1135216', (50, 55))	('ESCC', 'Disease', (73, 77))
509399	26205887	The association between PLCE1 variants and histologic grade and clinical stage of ESCC was further evaluated (Table 5).	('ESCC', 'Disease', (82, 86))	('PLCE1', 'Gene', (24, 29))	('variants', 'Var', (30, 38))	('PLCE1', 'Gene', '51196', (24, 29))
509400	26205887	When the ESCC patients were divided into 2 subgroups, T1/T2 and T3/T4, according to the AJCC TNM classification of carcinoma of esophagus, the carriers of AG/GG genotypes had a significantly increased risk for T1/T2 ESCC (P = 0.004, OR = 2.040).	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('AG/GG', 'Var', (155, 160))	('carcinoma of esophagus', 'Disease', (115, 137))	('carcinoma of esophagus', 'Disease', 'MESH:D004938', (115, 137))	('patients', 'Species', '9606', (14, 22))	('T1/T2 ESCC', 'Disease', (210, 220))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (115, 137))
509403	26205887	The distribution of genotypes was significantly different between patients with HPV infection and those without at TAP1 D637G (P < 0.001), but not at TAP1 I333V (P = 0.056).	('D637G', 'Mutation', 'rs1135216', (120, 125))	('D637G', 'Var', (120, 125))	('TAP1', 'Gene', (150, 154))	('TAP1', 'Gene', '6890', (150, 154))	('different', 'Reg', (48, 57))	('I333V', 'Mutation', 'rs1057141', (155, 160))	('HPV infection', 'Disease', 'MESH:D030361', (80, 93))	('HPV infection', 'Disease', (80, 93))	('TAP1', 'Gene', (115, 119))	('TAP1', 'Gene', '6890', (115, 119))	('patients', 'Species', '9606', (66, 74))
509404	26205887	To study further, we analyze the association between TAP1 D637G polymorphisms and HPV-associated Kazakh patients with EC.	('D637G', 'Mutation', 'rs1135216', (58, 63))	('D637G', 'Var', (58, 63))	('HPV-associated', 'Disease', (82, 96))	('HPV', 'Species', '10566', (82, 85))	('patients', 'Species', '9606', (104, 112))	('TAP1', 'Gene', (53, 57))	('TAP1', 'Gene', '6890', (53, 57))
509405	26205887	Differing from the wild-type AA homozygote, the combined AG/GG or AG variant genotypes were significantly associated with HPV-positive in EC patients (OR 0.255, 95 % CI 0.127-0.511; and OR 0.281, 95 % CI 0.144-0.551, respectively), although the homozygous mutant type of TAP D637G (GG) exhibited no association with HPV-positive EC patients (P = 0.691).	('variant', 'Var', (69, 76))	('HPV-positive EC', 'Disease', 'MESH:D030361', (316, 331))	('HPV', 'Species', '10566', (122, 125))	('HPV', 'Species', '10566', (316, 319))	('associated', 'Reg', (106, 116))	('D637G', 'Mutation', 'rs1135216', (275, 280))	('HPV-positive EC', 'Disease', (316, 331))	('patients', 'Species', '9606', (141, 149))	('patients', 'Species', '9606', (332, 340))	('HPV-positive', 'Disease', (122, 134))	('D637G', 'Var', (275, 280))	('TAP', 'Gene', (271, 274))	('TAP', 'Gene', '6891', (271, 274))
509406	26205887	We further evaluated the association between the risk of genotypes of TAP1 and risk of HPV-associated ESCC stratified by tumor depth.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ESCC', 'Disease', (102, 106))	('HPV', 'Species', '10566', (87, 90))	('tumor', 'Disease', (121, 126))	('TAP1', 'Gene', (70, 74))	('HPV-associated ESCC', 'Disease', (87, 106))	('TAP1', 'Gene', '6890', (70, 74))	('genotypes', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
509407	26205887	Interestingly, the results showed that differences between the protective effects of heterozygote and combined genotypes of TAP1 D637 were more significantly in T1/T2 subjects (P = 0.004, OR = 0.028 and P = 0.006, OR = 0.283, respectively) than in T3/T4 subjects (P = 0.020, OR = 0.286 and P = 0.026, OR = 0.311 respectively).	('D637', 'Var', (129, 133))	('T1/T2', 'Var', (161, 166))	('TAP1', 'Gene', (124, 128))	('TAP1', 'Gene', '6890', (124, 128))
509410	26205887	The majority of studies have identified HPV in ESCC samples, with infection rates ranging from 17.1 to 78.11 %, detected via amplification of the L1 gene.	('HPV', 'Species', '10566', (40, 43))	('amplification', 'Var', (125, 138))	('ESCC', 'Disease', (47, 51))
509419	26205887	Additionally, our present study showed the incidence of HPV16 infection in Kazakh EC patients (41.1 %) was significantly higher than in the control group (15.2 %), and, it has been proposed that HPV16 infection may play a role in esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (230, 255))	('play', 'Reg', (215, 219))	('esophageal carcinogenesis', 'Disease', (230, 255))	('HPV16', 'Species', '333760', (56, 61))	('HPV16', 'Gene', (195, 200))	('HPV16', 'Species', '333760', (195, 200))	('patients', 'Species', '9606', (85, 93))	('role', 'Reg', (222, 226))	('HPV16', 'Gene', (56, 61))	('infection', 'Var', (62, 71))	('higher', 'PosReg', (121, 127))
509428	26205887	The polymorphisms of TAP1 genes may result in the conformational and functional change of TAP, which can influence the antigen peptide selection and transport process.	('antigen peptide selection', 'MPA', (119, 144))	('TAP', 'Gene', '6891', (90, 93))	('influence', 'Reg', (105, 114))	('TAP1', 'Gene', (21, 25))	('TAP1', 'Gene', '6890', (21, 25))	('TAP', 'Gene', (90, 93))	('transport process', 'MPA', (149, 166))	('result in', 'Reg', (36, 45))	('functional', 'MPA', (69, 79))	('polymorphisms', 'Var', (4, 17))	('conformational', 'MPA', (50, 64))	('TAP', 'Gene', '6891', (21, 24))	('TAP', 'Gene', (21, 24))
509429	26205887	There are several studies on the relationship between TAP (including TAP1 and TAP2) polymorphisms and various carcinoma, and only TAP1 polymorphisms have been confirmed to be susceptible to various tumor types.	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('TAP', 'Gene', (54, 57))	('TAP', 'Gene', '6891', (130, 133))	('TAP', 'Gene', (78, 81))	('TAP', 'Gene', (69, 72))	('TAP1', 'Gene', (69, 73))	('TAP1', 'Gene', '6890', (69, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('TAP2', 'Gene', (78, 82))	('carcinoma', 'Disease', (110, 119))	('susceptible', 'Reg', (175, 186))	('TAP', 'Gene', '6891', (54, 57))	('TAP', 'Gene', '6891', (78, 81))	('tumor', 'Disease', (198, 203))	('polymorphisms', 'Var', (84, 97))	('TAP', 'Gene', (130, 133))	('TAP1', 'Gene', (130, 134))	('TAP', 'Gene', '6891', (69, 72))	('TAP1', 'Gene', '6890', (130, 134))	('TAP2', 'Gene', '6891', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('carcinoma', 'Disease', 'MESH:D002277', (110, 119))
509430	26205887	One study shows that no significant difference in genotype distribution of TAP1 and TAP2 polymorphisms was observed in women with cervical intraepithelial neoplasm (CIN) and controls, and a similar study conducted in India succeeded to reproduce this observation, however, in another similar study, significant differences in allele distribution between women with high-grade cervical neoplasm (CIN II or III) and women without was seen for both TAP1 I333V (P = 0.02) and TAP1 D637G (P = 0.01).	('women', 'Species', '9606', (414, 419))	('TAP2', 'Gene', '6891', (84, 88))	('neoplasm', 'Phenotype', 'HP:0002664', (155, 163))	('CIN', 'Disease', (165, 168))	('CIN', 'Disease', (395, 398))	('cervical intraepithelial neoplasm', 'Disease', 'MESH:D018290', (130, 163))	('cervical neoplasm', 'Disease', 'MESH:D002583', (376, 393))	('neoplasm', 'Phenotype', 'HP:0002664', (385, 393))	('CIN II', 'Disease', 'MESH:D005776', (395, 401))	('cervical intraepithelial neoplasm', 'Phenotype', 'HP:0032242', (130, 163))	('D637G', 'Var', (477, 482))	('women', 'Species', '9606', (119, 124))	('cervical neoplasm', 'Phenotype', 'HP:0032241', (376, 393))	('CIN', 'Phenotype', 'HP:0032242', (395, 398))	('CIN', 'Phenotype', 'HP:0032242', (165, 168))	('cervical neoplasm', 'Disease', (376, 393))	('I333V', 'Mutation', 'rs1057141', (451, 456))	('CIN', 'Disease', 'MESH:D007674', (395, 398))	('CIN', 'Disease', 'MESH:D007674', (165, 168))	('TAP1', 'Gene', (472, 476))	('TAP2', 'Gene', (84, 88))	('TAP1', 'Gene', (75, 79))	('women', 'Species', '9606', (354, 359))	('TAP1', 'Gene', '6890', (472, 476))	('TAP1', 'Gene', '6890', (75, 79))	('D637G', 'Mutation', 'rs1135216', (477, 482))	('cervical intraepithelial neoplasm', 'Disease', (130, 163))	('TAP1', 'Gene', (446, 450))	('TAP1', 'Gene', '6890', (446, 450))	('intraepithelial neoplasm', 'Phenotype', 'HP:0032187', (139, 163))	('I333V', 'Var', (451, 456))	('CIN II', 'Disease', (395, 401))
509431	26205887	In addition, G allele at TAP1 Codon 637 is associated with nasopharyngeal carcinoma (NPC) in Han population in Yunnan, China (OR, 1.88; 95 % CI, 1.35-2.82; P < 0.001), and EBV pathogenesis in NPC might be facilitated by polymorphisms in the TAP1 proteins.	('nasopharyngeal carcinoma', 'Disease', (59, 83))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (59, 83))	('TAP1', 'Gene', (25, 29))	('polymorphisms', 'Var', (220, 233))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (59, 83))	('TAP1', 'Gene', (241, 245))	('TAP1', 'Gene', '6890', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('NPC', 'Phenotype', 'HP:0100630', (85, 88))	('NPC', 'Phenotype', 'HP:0100630', (192, 195))	('TAP1', 'Gene', '6890', (241, 245))	('associated', 'Reg', (43, 53))	('Codon 637', 'Var', (30, 39))
509432	26205887	The present case-control study has analyzed the association between TAP gene polymorphisms and the risk of EC in Kazakh population in Xinjiang, China.	('TAP', 'Gene', (68, 71))	('polymorphisms', 'Var', (77, 90))	('TAP', 'Gene', '6891', (68, 71))
509434	26205887	Another important finding in the present study is that HPV-positive rate is lower for patients carrying allele G at TAP1 D637G, and this provides an illustration to the theory that TAP facilitates the detection of HPV by MHC-I molecules and contributes to detection and eradication of HPV despite various immune evasion mechanisms of the virus.	('TAP', 'Gene', (116, 119))	('TAP1', 'Gene', (116, 120))	('TAP', 'Gene', (181, 184))	('TAP1', 'Gene', '6890', (116, 120))	('detection', 'MPA', (256, 265))	('HPV', 'Species', '10566', (285, 288))	('D637G', 'Mutation', 'rs1135216', (121, 126))	('HPV', 'Species', '10566', (55, 58))	('facilitates', 'PosReg', (185, 196))	('HPV-positive', 'MPA', (55, 67))	('lower', 'NegReg', (76, 81))	('detection', 'MPA', (201, 210))	('D637G', 'Var', (121, 126))	('HPV', 'Species', '10566', (214, 217))	('TAP', 'Gene', '6891', (116, 119))	('TAP', 'Gene', '6891', (181, 184))	('patients', 'Species', '9606', (86, 94))
509435	26205887	Taken together the present study demonstrated that G allele at TAP1 Codon637 decreases susceptibility to HPV infection in patients with EC among the Kazakh populations, however, it is associated with an increased risk of EC in this ethnic.	('susceptibility', 'MPA', (87, 101))	('TAP1', 'Gene', (63, 67))	('TAP1', 'Gene', '6890', (63, 67))	('patients', 'Species', '9606', (122, 130))	('HPV infection', 'Disease', 'MESH:D030361', (105, 118))	('associated with', 'Reg', (184, 199))	('HPV infection', 'Disease', (105, 118))	('Codon637', 'Var', (68, 76))	('decreases', 'NegReg', (77, 86))
509436	26205887	This finding suggests that the polymorphism of TAP1 Codon637 exerts complicated influence on EC in Kazakh population.	('polymorphism', 'Var', (31, 43))	('TAP1', 'Gene', '6890', (47, 51))	('Codon637', 'Var', (52, 60))	('influence', 'Reg', (80, 89))	('TAP1', 'Gene', (47, 51))
509437	26205887	However, given that the mechanisms by which TAP1 polymorphisms may influence the course of HPV infections remains under investigation, further studies need to be conducted to elucidate the influence of TAP1 polymorphisms in HPV-associated EC in the Kazakh population.	('influence', 'Reg', (67, 76))	('HPV infections', 'Disease', (91, 105))	('HPV-associated EC', 'Disease', (224, 241))	('TAP1', 'Gene', (202, 206))	('HPV', 'Species', '10566', (224, 227))	('TAP1', 'Gene', '6890', (202, 206))	('polymorphisms', 'Var', (49, 62))	('HPV', 'Species', '10566', (91, 94))	('polymorphisms', 'Var', (207, 220))	('TAP1', 'Gene', (44, 48))	('HPV infections', 'Disease', 'MESH:D030361', (91, 105))	('TAP1', 'Gene', '6890', (44, 48))
509520	25349582	In particular, metformin has been shown to stimulate adenosine monophosphate-activated protein kinase in cells and to increase FDG uptake by mobilizing GLUT4 from the microsomal membrane to the plasma membrane.	('GLUT4', 'Gene', '6517', (152, 157))	('stimulate', 'PosReg', (43, 52))	('GLUT4', 'Gene', (152, 157))	('metformin', 'Chemical', 'MESH:D008687', (15, 24))	('adenosine monophosphate-activated protein kinase', 'Enzyme', (53, 101))	('increase', 'PosReg', (118, 126))	('FDG uptake', 'MPA', (127, 137))	('metformin', 'Var', (15, 24))	('FDG', 'Chemical', 'MESH:D019788', (127, 130))
509575	24618998	On the other hand, risk factors that are exclusive for noncardia GC include H. pylori infection (at least in Western countries), low socioeconomic status, and perhaps dietary factors such as low consumption of fruits and vegetables and high intake of salty and smoked food.	('salt', 'Chemical', 'MESH:D012492', (251, 255))	('GC', 'Phenotype', 'HP:0012126', (65, 67))	('H. pylori infection', 'Phenotype', 'HP:0005202', (76, 95))	('H. pylori infection', 'Disease', 'MESH:D016481', (76, 95))	('high intake of salty', 'Phenotype', 'HP:0030083', (236, 256))	('H. pylori infection', 'Disease', (76, 95))	('low socioeconomic', 'Var', (129, 146))	('cardia', 'Disease', 'MESH:D004938', (58, 64))	('cardia', 'Disease', (58, 64))
509589	24618998	Significant research over the ensuing two decades established H. pylori as an incontrovertible cause of GC, with relative risks of approximately 6 for noncardia GC.	('cause', 'Reg', (95, 100))	('GC', 'Phenotype', 'HP:0012126', (161, 163))	('GC', 'Phenotype', 'HP:0012126', (104, 106))	('H. pylori', 'Species', '210', (62, 71))	('cardia', 'Disease', (154, 160))	('cardia', 'Disease', 'MESH:D004938', (154, 160))	('H. pylori', 'Var', (62, 71))
509599	24618998	At least since the studies of Villerme and Chadwick in the first half of the 19th century, we have known that lower socioeconomic status is associated with higher risk of total and cause-specific mortality, including mortality from most cancers.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('lower socioeconomic status', 'Var', (110, 136))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (237, 244))	('cancers', 'Disease', 'MESH:D009369', (237, 244))
509633	24618998	Abdominal fat may directly cause GERD, a risk factor for esophageal cancer and cardia GC.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('Abdominal', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cardia', 'Disease', 'MESH:D004938', (79, 85))	('GC', 'Phenotype', 'HP:0012126', (86, 88))	('cardia', 'Disease', (79, 85))	('cause', 'Reg', (27, 32))	('esophageal cancer', 'Disease', (57, 74))	('GERD', 'Disease', (33, 37))	('GERD', 'Disease', 'MESH:D005764', (33, 37))
509656	24618998	Approximately 25% of families with HDGC have inactivating CDH1 germline mutations.	('GC', 'Phenotype', 'HP:0012126', (37, 39))	('CDH1', 'Gene', (58, 62))	('inactivating', 'Var', (45, 57))	('CDH1', 'Gene', '999', (58, 62))
509657	24618998	The penetrance of CDH1 gene mutations is high, with an estimated risk of >80% for both men and women by age 80, and the median age at diagnosis of 38.	('men', 'Species', '9606', (87, 90))	('CDH1', 'Gene', (18, 22))	('men', 'Species', '9606', (97, 100))	('CDH1', 'Gene', '999', (18, 22))	('women', 'Species', '9606', (95, 100))	('mutations', 'Var', (28, 37))
509658	24618998	FAP is an autosomal-dominant colorectal cancer syndrome, caused by a mutation in the adenomatous polyposis coli gene.	('adenomatous polyposis coli', 'Disease', (85, 111))	('FAP', 'Disease', 'MESH:C567782', (0, 3))	('caused by', 'Reg', (57, 66))	('mutation', 'Var', (69, 77))	('autosomal-dominant colorectal cancer syndrome', 'Disease', 'MESH:D015179', (10, 55))	('autosomal-dominant colorectal cancer syndrome', 'Disease', (10, 55))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (85, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (85, 111))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (85, 106))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('FAP', 'Disease', (0, 3))
509661	24618998	Germline mutation of the LKB1 gene, which encodes a serine/threonine kinase that acts as a tumor suppressor, is a cause of PJS.	('LKB1', 'Gene', (25, 29))	('PJS', 'Gene', '6794', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('LKB1', 'Gene', '6794', (25, 29))	('PJS', 'Gene', (123, 126))	('cause', 'Reg', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Germline mutation', 'Var', (0, 17))	('tumor', 'Disease', (91, 96))
509662	24618998	For example, the initially exciting associations found for polymorphisms in inflammatory genes, in particular IL-1B polymorphisms, were not replicated in future studies, including in genome wide association studies.	('IL-1B', 'Gene', (110, 115))	('polymorphisms', 'Var', (59, 72))	('IL-1B', 'Gene', '3553', (110, 115))
509664	24618998	A significant association between SNPs located in the prostate stem cell antigen (PSCA) gene and GC has been reported by three independent GWAS: one in Japanese and Korean and two in Chinese populations.	('PSCA', 'Gene', '8000', (82, 86))	('SNPs located', 'Var', (34, 46))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('PSCA', 'Gene', (82, 86))
509669	24618998	Meta-analysis of the results from Japanese and Korean populations identified several other SNPs in MUC1 that were significantly associated with GC risk.	('GC', 'Phenotype', 'HP:0012126', (144, 146))	('SNPs', 'Var', (91, 95))	('associated with', 'Reg', (128, 143))	('MUC1', 'Gene', (99, 103))	('MUC1', 'Gene', '4582', (99, 103))
509670	24618998	In one of the GWAS in Chinese population positive associations between SNPs in MUC1 and cardia and noncardia cancers were similar.	('SNPs', 'Var', (71, 75))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('MUC1', 'Gene', '4582', (79, 83))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MUC1', 'Gene', (79, 83))	('cardia and noncardia cancers', 'Disease', 'MESH:D004938', (88, 116))
509672	24618998	Two independent GWAS in Chinese reported associations between multiple variants at 10q23, located in gene PLCE1, and cardia GC risk.	('associations', 'Interaction', (41, 53))	('cardia', 'Disease', (117, 123))	('variants', 'Var', (71, 79))	('cardia', 'Disease', 'MESH:D004938', (117, 123))	('GC', 'Phenotype', 'HP:0012126', (124, 126))	('PLCE1', 'Gene', (106, 111))	('PLCE1', 'Gene', '51196', (106, 111))
509699	24618998	These antibodies, which target parietal cells of the stomach, have been recently associated with a substantially higher risk of atrophic gastritis.	('atrophic gastritis', 'Phenotype', 'HP:0002582', (128, 146))	('gastritis', 'Phenotype', 'HP:0005263', (137, 146))	('atrophic gastritis', 'Disease', 'MESH:D005757', (128, 146))	('antibodies', 'Var', (6, 16))	('atrophic gastritis', 'Disease', (128, 146))	('associated', 'Reg', (81, 91))
509719	24618998	Nevertheless, treatment has some effect even after cancer has occurred; treating H. pylori after cancer diagnosis reduces risk of metachronous cancer to almost half.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', (97, 103))	('H. pylori', 'Species', '210', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('reduces', 'NegReg', (114, 121))	('H. pylori', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('men', 'Species', '9606', (19, 22))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
509720	24618998	Despite these findings and guidelines, some have argued that the presence of H. pylori in the stomach may have some benefits, and that a decision to mass eradicate it may be premature.	('benefits', 'PosReg', (116, 124))	('H. pylori', 'Species', '210', (77, 86))	('presence', 'Var', (65, 73))
509830	31516556	These tumors accumulate hundreds to thousands of mutations in the microsatellite regions of DNA during replication, mutations that would normally be repaired if the MMR system was intact.	('DNA', 'Gene', (92, 95))	('mutations', 'Var', (49, 58))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
509831	31516556	MSI is caused by inactivation of at least one of the MMR genes, which include MLH1, MSH2, MSH6, and PMS2.	('MLH1', 'Gene', '4292', (78, 82))	('inactivation', 'Var', (17, 29))	('MLH1', 'Gene', (78, 82))	('MMR genes', 'Gene', (53, 62))	('PMS2', 'Gene', (100, 104))	('MSH6', 'Gene', (90, 94))	('PMS2', 'Gene', '5395', (100, 104))	('MSI', 'Disease', (0, 3))	('MSH6', 'Gene', '2956', (90, 94))	('caused by', 'Reg', (7, 16))	('MSH2', 'Gene', (84, 88))	('MSH2', 'Gene', '4436', (84, 88))
509832	31516556	MSI can also occur by hypermethylation of the MLH1 promoter, leading to functional loss of the protein.	('MLH1', 'Gene', (46, 50))	('hypermethylation', 'Var', (22, 38))	('MSI', 'Disease', (0, 3))	('functional', 'MPA', (72, 82))	('MLH1', 'Gene', '4292', (46, 50))	('protein', 'Protein', (95, 102))	('loss', 'NegReg', (83, 87))
509833	31516556	The frequency of MSI-high (MSI-H) positivity in gastric cancers ranges from 10% to 22%.	('positivity', 'Var', (34, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('MSI-high', 'Protein', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('MSI-H', 'Disease', (27, 32))	('gastric cancers', 'Disease', (48, 63))	('gastric cancers', 'Disease', 'MESH:D013274', (48, 63))	('gastric cancers', 'Phenotype', 'HP:0012126', (48, 63))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('MSI-H', 'Disease', 'MESH:D000848', (27, 32))
509844	31516556	PD-1 pathway blockade inhibits negative T-cell immune regulation caused by PD-1 receptor signaling, thereby reversing T-cell suppression and stimulating an antitumor response.	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', (75, 79))	('T-cell suppression', 'MPA', (118, 136))	('blockade', 'Var', (13, 21))	('PD-1', 'Gene', '5133', (0, 4))	('PD-1', 'Gene', '5133', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('negative T-cell immune regulation', 'MPA', (31, 64))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('reversing', 'PosReg', (108, 117))	('inhibits', 'NegReg', (22, 30))	('tumor', 'Disease', (160, 165))	('stimulating', 'Reg', (141, 152))
509909	31516556	Responses were irrespective of PD-L1 expression, with an ORR of 68.8% (95% CI 41.3-89.0) in PD-L1 positive patients and 37.5% (95% CI 8.5-75.5) in PD-L1 negative patients.	('patients', 'Species', '9606', (162, 170))	('PD-L1', 'Gene', (92, 97))	('patients', 'Species', '9606', (107, 115))	('positive', 'Var', (98, 106))
509914	31516556	Patients with treatment-naive, advanced gastric/GEJ adenocarcinoma with PD-L1 positivity (defined as CPS >=1) were randomized to pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin plus a fluoropyrimidine), or chemotherapy alone (control arm).	('gastric/GEJ adenocarcinoma', 'Disease', 'MESH:D013274', (40, 66))	('positivity', 'Var', (78, 88))	('pembrolizumab', 'Chemical', 'MESH:C582435', (156, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('pembrolizumab', 'Chemical', 'MESH:C582435', (129, 142))	('CPS', 'Chemical', '-', (101, 104))	('gastric/GEJ adenocarcinoma', 'Disease', (40, 66))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', (72, 77))	('fluoropyrimidine', 'Chemical', '-', (206, 222))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))
509917	31516556	In patients CPS >=10 gastric/GEJ adenocarcinoma, pembrolizumab monotherapy was associated with an improved OS by roughly 7 months (17.4 versus 10.8 months; HR 0.69; 95% CI 0.49-0.97).	('pembrolizumab', 'Chemical', 'MESH:C582435', (49, 62))	('OS', 'Gene', '17451', (107, 109))	('gastric/GEJ adenocarcinoma', 'Disease', 'MESH:D013274', (21, 47))	('CPS', 'Chemical', '-', (12, 15))	('CPS >=10', 'Var', (12, 20))	('patients', 'Species', '9606', (3, 11))	('gastric/GEJ adenocarcinoma', 'Disease', (21, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))
509920	31516556	When considering the pembrolizumab with chemotherapy arm, while OS was not improved with the addition of pembrolizumab, there appeared to be a trend toward improved PFS with the addition of pembrolizumab: for CPS >=1 (HR 0.84; 95% CI 0.70-1.02; p = 0.039), and for CPS >=10 (HR 0.74; 95% CI 0.53-1.00).	('CPS', 'Chemical', '-', (265, 268))	('pembrolizumab', 'Chemical', 'MESH:C582435', (21, 34))	('CPS', 'Disease', (209, 212))	('PFS', 'MPA', (165, 168))	('CPS >=10', 'Var', (265, 273))	('improved', 'PosReg', (156, 164))	('pembrolizumab', 'Chemical', 'MESH:C582435', (105, 118))	('pembrolizumab', 'Chemical', 'MESH:C582435', (190, 203))	('CPS', 'Chemical', '-', (209, 212))	('OS', 'Gene', '17451', (64, 66))
509922	31516556	While the results of this study may suggest that single-agent pembrolizumab may be considered noninferior to chemotherapy in patients with advanced gastric/GEJ adenocarcinoma with CPS >=1, one might consider the risk of early progression with pembrolizumab when considering this option if it achieves regulatory approval.	('pembrolizumab', 'Chemical', 'MESH:C582435', (62, 75))	('CPS', 'Chemical', '-', (180, 183))	('pembrolizumab', 'Chemical', 'MESH:C582435', (243, 256))	('gastric/GEJ adenocarcinoma', 'Disease', 'MESH:D013274', (148, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('CPS >=1', 'Var', (180, 187))	('gastric/GEJ adenocarcinoma', 'Disease', (148, 174))	('patients', 'Species', '9606', (125, 133))
509929	31516556	As a prognostic biomarker, PD-L1 expression correlates with poor prognosis and decreased survival in non-small cell lung cancer (NSCLC), melanoma, hepatocellular carcinoma, pancreatic, and renal cell cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('poor', 'NegReg', (60, 64))	('pancreatic', 'Disease', (173, 183))	('renal cell cancers', 'Disease', 'MESH:C538614', (189, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (101, 127))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (147, 171))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('decreased', 'NegReg', (79, 88))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (105, 127))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('survival', 'MPA', (89, 97))	('renal cell cancers', 'Disease', (189, 207))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (147, 171))	('expression', 'Var', (33, 43))	('NSCLC', 'Disease', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('hepatocellular carcinoma', 'Disease', (147, 171))	('pancreatic', 'Disease', 'MESH:D010195', (173, 183))	('cell lung cancer', 'Disease', 'MESH:D008175', (111, 127))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('cell lung cancer', 'Disease', (111, 127))	('PD-L1', 'Gene', (27, 32))
509996	23175214	For example, abnormal expression of oncogenic miRNAs may decrease the translation of target tumor suppressor genes and contribute to the development or progression of cancer.	('miR', 'Gene', (46, 49))	('decrease', 'NegReg', (57, 65))	('men', 'Species', '9606', (144, 147))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('development', 'CPA', (137, 148))	('cancer', 'Disease', (167, 173))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('miR', 'Gene', '220972', (46, 49))	('contribute to', 'Reg', (119, 132))	('abnormal', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('translation', 'MPA', (70, 81))	('expression', 'MPA', (22, 32))	('progression', 'CPA', (152, 163))
510041	23175214	We also examined the expression patterns of miRNAs in noncancerous tissue, and patients with high miR-21 in noncancerous tissue had significantly worse survival prognosis (p = 0.003; Fig.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('cancerous', 'Disease', (111, 120))	('survival prognosis', 'CPA', (152, 170))	('miR', 'Gene', '220972', (98, 101))	('worse', 'NegReg', (146, 151))	('miR', 'Gene', (98, 101))	('cancerous', 'Disease', (57, 66))	('cancerous', 'Disease', 'MESH:D009369', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancerous', 'Disease', 'MESH:D009369', (57, 66))	('high', 'Var', (93, 97))
510046	23175214	Patients with high miRNA risk score had worse overall survival (p = 0.0001; Fig.	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('overall survival', 'MPA', (46, 62))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('worse', 'NegReg', (40, 45))
510064	23175214	Likelihood ratio tests demonstrated that the Cox regression models using both IRS and miRNAs performed significantly better than models with only IRS or miRNA risk score alone (p < 0.001), suggesting that the combination of these classifiers is superior to either alone.	('miR', 'Gene', '220972', (153, 156))	('miR', 'Gene', (153, 156))	('Cox', 'Gene', '1351', (45, 48))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('better', 'PosReg', (117, 123))	('Cox', 'Gene', (45, 48))	('IRS', 'Var', (78, 81))
510074	23175214	Increased expression of miR-21 in the absence of other genetic defects is sufficient at causing malignancies in mice, whereas deletion of miR-21 reduces KRAS-driven oncogenic transformation.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('reduces', 'NegReg', (145, 152))	('KRAS', 'Gene', '16653', (153, 157))	('KRAS', 'Gene', (153, 157))	('miR-21', 'Gene', (138, 144))	('malignancies', 'Disease', (96, 108))	('deletion', 'Var', (126, 134))	('genetic defects', 'Disease', 'MESH:D030342', (55, 70))	('causing', 'Reg', (88, 95))	('genetic defects', 'Disease', (55, 70))	('mice', 'Species', '10090', (112, 116))
510079	23175214	miR-146b was reported to be elevated in thyroid cancer and nonsmall cell lung cancer and can repress SMAD4.	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (59, 84))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('SMAD4', 'Gene', '17128', (101, 106))	('elevated in thyroid', 'Phenotype', 'HP:0008249', (28, 47))	('repress', 'NegReg', (93, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (40, 54))	('thyroid cancer', 'Disease', (40, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('miR-146b', 'Var', (0, 8))	('elevated', 'PosReg', (28, 36))	('SMAD4', 'Gene', (101, 106))	('nonsmall cell lung cancer', 'Disease', (59, 84))	('thyroid cancer', 'Disease', 'MESH:D013964', (40, 54))
510114	30998758	In murine esophageal epithelia, Klf4 overexpression causes chronic inflammation which is mediated by activation of NFkappaB signaling downstream of KLF4, and this esophageal inflammation produces epithelial hyperplasia and subsequent esophageal squamous cell cancer.	('esophageal epithelia', 'Disease', 'MESH:D004941', (10, 30))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (234, 265))	('activation', 'PosReg', (101, 111))	('NFkappaB signaling', 'MPA', (115, 133))	('Klf4', 'Gene', (32, 36))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (163, 186))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (245, 265))	('esophageal squamous cell cancer', 'Disease', (234, 265))	('esophageal epithelia', 'Disease', (10, 30))	('inflammation', 'Disease', 'MESH:D007249', (174, 186))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('inflammation', 'Disease', (67, 79))	('murine', 'Species', '10090', (3, 9))	('epithelial hyperplasia', 'Disease', (196, 218))	('inflammation', 'Disease', (174, 186))	('esophageal inflammation', 'Disease', (163, 186))	('Klf4', 'Gene', '16600', (32, 36))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (196, 218))	('overexpression', 'Var', (37, 51))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (10, 30))	('esophageal inflammation', 'Disease', 'MESH:D007249', (163, 186))
510153	30998758	Two distinct shRNAs against RhoF (Sigma, TRCN0000077678 and TRCN0000447186) were used for knockdown experiments.	('TRCN0000447186', 'Var', (60, 74))	('RhoF', 'Gene', (28, 32))	('RhoF', 'Gene', '23912', (28, 32))
510160	30998758	Consistent with our prior work, we found that primary murine esophageal keratinocytes from ED-L2/Klf4 mice, which overexpress Klf4 in esophageal epithelial cells, had increased expression of the kinases Ikk1, Ikk2, and Ikk3, which activate NFkappaB signaling, compared to control cells (Fig 1A), and in primary murine esophageal keratinocytes from mice with genetic ablation of Klf4 (ED-L2/Cre;Klf4loxp/loxp mice), Ikk1, Ikk2, and Ikk3 expression was decreased (Fig 1B).	('esophageal epithelia', 'Disease', (134, 154))	('mice', 'Species', '10090', (102, 106))	('Ikk1', 'Gene', (203, 207))	('Ikk1', 'Gene', '12675', (203, 207))	('Klf4', 'Gene', (97, 101))	('Klf4', 'Gene', '16600', (126, 130))	('Ikk2', 'Gene', '16150', (209, 213))	('mice', 'Species', '10090', (348, 352))	('expression', 'MPA', (177, 187))	('Ikk2', 'Gene', (209, 213))	('Ikk2', 'Gene', '16150', (421, 425))	('Ikk1', 'Gene', (415, 419))	('murine', 'Species', '10090', (54, 60))	('Ikk1', 'Gene', '12675', (415, 419))	('Ikk2', 'Gene', (421, 425))	('decreased', 'NegReg', (451, 460))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (134, 154))	('Klf4', 'Gene', '16600', (378, 382))	('Klf4', 'Gene', '16600', (394, 398))	('Klf4', 'Gene', (126, 130))	('Ikk3', 'Gene', (431, 435))	('esophageal epithelia', 'Disease', 'MESH:D004941', (134, 154))	('mice', 'Species', '10090', (408, 412))	('expression', 'MPA', (436, 446))	('increased', 'PosReg', (167, 176))	('ablation', 'Var', (366, 374))	('activate', 'PosReg', (231, 239))	('Klf4', 'Gene', '16600', (97, 101))	('Klf4', 'Gene', (378, 382))	('Klf4', 'Gene', (394, 398))	('murine', 'Species', '10090', (311, 317))
510162	30998758	Klf4 overexpression in mice activates NFkappaB, and KLF4 knockdown in primary human esophageal keratinocytes reduced p65 phosphorylation (Fig 1D).	('human', 'Species', '9606', (78, 83))	('Klf4', 'Gene', (0, 4))	('NFkappaB', 'Protein', (38, 46))	('Klf4', 'Gene', '16600', (0, 4))	('knockdown', 'Var', (57, 66))	('KLF4', 'Gene', (52, 56))	('p65', 'Protein', (117, 120))	('reduced', 'NegReg', (109, 116))	('activates', 'PosReg', (28, 37))	('mice', 'Species', '10090', (23, 27))
510165	30998758	Certain Rho GTPases can activate NFkappaB signaling, and both RhoF (also known as Rif) and Argef17, which encodes RhoGEF17, a Rho-specific guanine nucleotide exchange factor (GEF), are differentially expressed by microarray in esophageal epithelia of mice with Klf4 deletion.	('mice', 'Species', '10090', (251, 255))	('RhoF', 'Gene', '23912', (62, 66))	('Klf4', 'Gene', '16600', (261, 265))	('Argef17', 'Gene', (91, 98))	('esophageal epithelia', 'Disease', (227, 247))	('RhoF', 'Gene', (62, 66))	('GEF', 'Gene', (175, 178))	('GEF', 'Gene', '16800', (175, 178))	('deletion', 'Var', (266, 274))	('Rif', 'Gene', (82, 85))	('Rif', 'Gene', '23912', (82, 85))	('Klf4', 'Gene', (261, 265))	('NFkappaB', 'MPA', (33, 41))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (139, 157))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (227, 247))	('GEF', 'Gene', (117, 120))	('esophageal epithelia', 'Disease', 'MESH:D004941', (227, 247))	('GEF', 'Gene', '16800', (117, 120))	('activate', 'PosReg', (24, 32))	('GTP', 'Chemical', 'MESH:D006160', (12, 15))
510172	30998758	In esophageal epithelial cells, expression of constitutively active RHOF promoted actin remodeling and significantly increased single cell migration (S1 Fig).	('esophageal epithelia', 'Disease', (3, 23))	('promoted', 'PosReg', (73, 81))	('increased', 'PosReg', (117, 126))	('expression', 'Var', (32, 42))	('RHOF', 'Gene', (68, 72))	('single cell migration', 'CPA', (127, 148))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (3, 23))	('actin remodeling', 'CPA', (82, 98))	('esophageal epithelia', 'Disease', 'MESH:D004941', (3, 23))
510173	30998758	To define the role of RHOF in esophageal mucosal inflammation, we first knocked down RhoF in esophageal epithelial cells using shRNA and examined the consequences on pro-inflammatory genes.	('esophageal epithelia', 'Phenotype', 'HP:0012859', (93, 113))	('esophageal epithelia', 'Disease', 'MESH:D004941', (93, 113))	('esophageal mucosal inflammation', 'Disease', 'MESH:D007249', (30, 61))	('RhoF', 'Gene', (85, 89))	('esophageal epithelia', 'Disease', (93, 113))	('esophageal mucosal inflammation', 'Disease', (30, 61))	('RhoF', 'Gene', '23912', (85, 89))	('knocked', 'Var', (72, 79))
510174	30998758	RhoF knockdown significantly decreased expression of Ikk1, Ikk2, and Ikk3 (Fig 3A), consistent with a function for RHOF in mediating KLF4 activation of NFkappaB signaling.	('Ikk2', 'Gene', (59, 63))	('Ikk3', 'Gene', (69, 73))	('knockdown', 'Var', (5, 14))	('RhoF', 'Gene', (0, 4))	('RhoF', 'Gene', '23912', (0, 4))	('decreased', 'NegReg', (29, 38))	('Ikk1', 'Gene', '12675', (53, 57))	('expression', 'MPA', (39, 49))	('Ikk1', 'Gene', (53, 57))	('Ikk2', 'Gene', '16150', (59, 63))
510175	30998758	In addition, RhoF knockdown reduced expression of the key pro-inflammatory genes TNFalpha, IL-1alpha, CXCL5, and G-CSF (Fig 3B), each of which is also upregulated in esophageal epithelial cells with Klf4 overexpression.	('reduced', 'NegReg', (28, 35))	('G-CSF', 'Gene', (113, 118))	('RhoF', 'Gene', '23912', (13, 17))	('TNFalpha', 'Gene', (81, 89))	('Klf4', 'Gene', (199, 203))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (166, 186))	('RhoF', 'Gene', (13, 17))	('esophageal epithelia', 'Disease', 'MESH:D004941', (166, 186))	('CXCL5', 'Gene', '20311', (102, 107))	('IL-1alpha', 'Gene', '16175', (91, 100))	('knockdown', 'Var', (18, 27))	('CXCL5', 'Gene', (102, 107))	('G-CSF', 'Gene', '12985', (113, 118))	('IL-1alpha', 'Gene', (91, 100))	('TNFalpha', 'Gene', '21926', (81, 89))	('esophageal epithelia', 'Disease', (166, 186))	('upregulated', 'PosReg', (151, 162))	('expression', 'MPA', (36, 46))	('Klf4', 'Gene', '16600', (199, 203))
510179	30998758	Compared to control esophageal epithelial cells (with endogenous Klf4 expression) and ED-L2/Klf4 cells (that overexpress Klf4), ED-L2/Klf4 cells with RhoF knockdown had dramatically decreased NFkappaB activation (Fig 4A) and decreased expression of Ikk1 and Ikk2 (Fig 4B).	('expression', 'MPA', (235, 245))	('Ikk2', 'Gene', '16150', (258, 262))	('Klf4', 'Gene', (65, 69))	('Ikk2', 'Gene', (258, 262))	('Klf4', 'Gene', (121, 125))	('RhoF', 'Gene', '23912', (150, 154))	('Klf4', 'Gene', '16600', (134, 138))	('Ikk1', 'Gene', '12675', (249, 253))	('Ikk1', 'Gene', (249, 253))	('knockdown', 'Var', (155, 164))	('activation', 'PosReg', (201, 211))	('NFkappaB', 'Protein', (192, 200))	('esophageal epithelia', 'Disease', (20, 40))	('RhoF', 'Gene', (150, 154))	('Klf4', 'Gene', '16600', (92, 96))	('Klf4', 'Gene', (134, 138))	('decreased', 'NegReg', (182, 191))	('Klf4', 'Gene', (92, 96))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (20, 40))	('Klf4', 'Gene', '16600', (65, 69))	('esophageal epithelia', 'Disease', 'MESH:D004941', (20, 40))	('Klf4', 'Gene', '16600', (121, 125))	('decreased', 'NegReg', (225, 234))
510187	30998758	We also showed that, consistent with this, activation of NFkappaB signaling within esophageal keratinocytes by transgenic Ikkbeta expression promotes inflammation and angiogenesis, features of inflammatory diseases and the tumor microenvironment.	('transgenic', 'Var', (111, 121))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('Ikkbeta', 'Gene', (122, 129))	('activation', 'PosReg', (43, 53))	('angiogenesis', 'CPA', (167, 179))	('inflammation', 'Disease', 'MESH:D007249', (150, 162))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('inflammation', 'Disease', (150, 162))	('promotes', 'PosReg', (141, 149))	('Ikkbeta', 'Gene', '16150', (122, 129))
510194	30998758	Of note, global RhoF deletion in mice has no overt phenotype, raising the possibility that other Rho family members may compensate for RHOF function in vivo under normal conditions.	('RhoF', 'Gene', (16, 20))	('RhoF', 'Gene', '23912', (16, 20))	('mice', 'Species', '10090', (33, 37))	('deletion', 'Var', (21, 29))
510195	30998758	Interestingly, KLF4 enhances RHOF protein activation, seemingly to a greater extent than can be explained through KLF4 upregulation of RhoF expression alone.	('RhoF', 'Gene', (135, 139))	('RhoF', 'Gene', '23912', (135, 139))	('activation', 'MPA', (42, 52))	('KLF4', 'Var', (15, 19))	('enhances', 'PosReg', (20, 28))	('RHOF protein', 'Protein', (29, 41))
510198	30998758	shRNA knockdown of RhoF results in a dramatic decrease in phosphorylated p65, some of which is likely related to the effects of KLF4, both endogenous and transgenic, on NFkappaB signaling, although these data also raise the intriguing possibility that RHOF might promote esophageal inflammation and disease independent of KLF4.	('esophageal inflammation', 'Disease', (271, 294))	('promote', 'PosReg', (263, 270))	('RhoF', 'Gene', (19, 23))	('RhoF', 'Gene', '23912', (19, 23))	('disease', 'Disease', (299, 306))	('RHOF', 'Gene', (252, 256))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (271, 294))	('esophageal inflammation', 'Disease', 'MESH:D007249', (271, 294))	('knockdown', 'Var', (6, 15))	('decrease', 'NegReg', (46, 54))	('phosphorylated', 'MPA', (58, 72))
510253	30201005	Significant differences in the clinical stage of initial cancer were observed for patients with re-RT (n = 39) and without re-RT (n = 48) before matching (P = 0.003) (Table 2).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Disease', (57, 63))	('re-RT', 'Var', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
510255	30201005	LN recurrence alone and re-RT were associated with better OS (P = 0.006 and P < 0.001) by Cox univariate analysis.	('Cox', 'Gene', '1351', (90, 93))	('Cox', 'Gene', (90, 93))	('re-RT', 'Var', (24, 29))	('OS', 'Chemical', '-', (58, 60))
510262	30201005	In the matched cohort, failure pattern and re-RT were independently associated with OS for recurrent ESCC (P = 0.025 and P = 0.002, respectively; Table 4).	('OS', 'Chemical', '-', (84, 86))	('ESCC', 'Disease', (101, 105))	('re-RT', 'Var', (43, 48))
510287	30201005	Concurrent CRT was shown to cause severe acute esophagitis in 15-25% of thoracic radiotherapy cases.	('esophagitis', 'Disease', (47, 58))	('esophagitis', 'Disease', 'MESH:D004941', (47, 58))	('cause', 'Reg', (28, 33))	('thoracic radiotherapy', 'Disease', (72, 93))	('CRT', 'Var', (11, 14))	('esophagitis', 'Phenotype', 'HP:0100633', (47, 58))
510348	28695120	As a result of this modification, a less metallic voice was created.	('modification', 'Var', (20, 32))	('metal', 'Chemical', 'MESH:D008670', (41, 46))	('less metallic voice', 'MPA', (36, 55))
510514	28695120	Contact between the esophageal flange and the esophageal mucosa prevented aspiration during swallowing.	('esophageal flange', 'Disease', 'MESH:D004941', (20, 37))	('prevented', 'NegReg', (64, 73))	('esophageal flange', 'Disease', (20, 37))	('aspiration', 'Phenotype', 'HP:0002835', (74, 84))	('aspiration', 'Disease', (74, 84))	('Contact', 'Var', (0, 7))
510565	25815477	All of the plans generated similar dose distributions for PTVs and organs at risk (OARs), except that the 2A- and 3A-VMAT plans yielded a significantly higher conformity index (CI) than the c-IMRT plan.	('higher', 'PosReg', (152, 158))	('PTV', 'Chemical', '-', (58, 61))	('conformity index', 'MPA', (159, 175))	('3A-VMAT', 'Var', (114, 121))	('2A-', 'Var', (106, 109))
510604	25815477	There were minor, but statistically significant, differences in the V93, V95 and V105 values of PTV54 between the VMAT and c-IMRT plans.	('PTV', 'Chemical', '-', (96, 99))	('PTV54', 'Gene', (96, 101))	('V105', 'Var', (81, 85))
510713	25279666	We included the risk factor of alcohol abuse by ICD-9-CM 305.00-305.03, as stated in the "Study sample".	('alcohol abuse', 'Disease', (31, 44))	('alcohol abuse', 'Disease', 'MESH:D000437', (31, 44))	('alcohol abuse', 'Phenotype', 'HP:0030955', (31, 44))	('ICD-9-CM 305.00-305.03', 'Var', (48, 70))
510725	22183866	Moreover, our data suggest that hypermethylation of the promoter region of GNG7 is probably the mechanism of the observed inactivation.	('hypermethylation', 'Var', (32, 48))	('GNG7', 'Gene', (75, 79))	('GNG7', 'Gene', '2788', (75, 79))
510771	22183866	In the remaining samples from group B the Kaplan-Meier test has been used to analyze the difference in survival time depending on GNG7 methylation.	('methylation', 'Var', (135, 146))	('GNG7', 'Gene', (130, 134))	('GNG7', 'Gene', '2788', (130, 134))
510772	22183866	Moreover, the Chi-square crosstabulation test has been used to analyze the correlation between GNG7 methylation and the T, N, G classification and smoking addiction.	('correlation', 'Interaction', (75, 86))	('smoking addiction', 'Disease', (147, 164))	('GNG7', 'Gene', (95, 99))	('methylation', 'Var', (100, 111))	('GNG7', 'Gene', '2788', (95, 99))
510793	22183866	Applying this cut-off to the tumor samples pyrosequencing results we identified hypermethylation of the GNG7 promoter region in 8/13 (62%) laryngeal cancer cell lines and 42/98 (43%) primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('laryngeal cancer', 'Disease', 'MESH:D007822', (139, 155))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('GNG7', 'Gene', '2788', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('laryngeal cancer', 'Disease', (139, 155))	('hypermethylation', 'Var', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (139, 155))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('GNG7', 'Gene', (104, 108))	('tumors', 'Disease', (191, 197))
510796	22183866	GNG7 promoter region hypermethylation was identified in all six cell lines and additionally in the UT-SCC-107 cell line.	('hypermethylation', 'Var', (21, 37))	('GNG7', 'Gene', '2788', (0, 4))	('GNG7', 'Gene', (0, 4))
510802	22183866	Last, we addressed the question if there are differences in the frequency and level of GNG7 methylation between the 44 samples derived from young adult laryngeal cancer patients and the 54 samples from patients age >45.	('laryngeal cancer', 'Disease', 'MESH:D007822', (152, 168))	('patients', 'Species', '9606', (169, 177))	('methylation', 'Var', (92, 103))	('laryngeal cancer', 'Disease', (152, 168))	('GNG7', 'Gene', '2788', (87, 91))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (152, 168))	('patients', 'Species', '9606', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('GNG7', 'Gene', (87, 91))
510803	22183866	We observed in the cohort of young patients a significantly enriched number of cases with GNG7 hypermethylation (29/44 (66%) hypermethylated cases) (chi-square tests p < 0.001) compared to the group of older patients (13/54 (24%) hypermethylated cases) (Table2).	('hypermethylation', 'Var', (95, 111))	('patients', 'Species', '9606', (208, 216))	('GNG7', 'Gene', '2788', (90, 94))	('patients', 'Species', '9606', (35, 43))	('hypermethylated', 'Var', (125, 140))	('GNG7', 'Gene', (90, 94))
510807	22183866	Moreover, in an independent cohort of laryngeal tumor samples we detected recurrent hypermethylation of the GNG7 promoter region in 42/98 (43%) primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('GNG7', 'Gene', '2788', (108, 112))	('laryngeal tumor', 'Disease', 'MESH:D007822', (38, 53))	('laryngeal tumor', 'Disease', (38, 53))	('hypermethylation', 'Var', (84, 100))	('tumors', 'Disease', (152, 158))	('GNG7', 'Gene', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
510808	22183866	It is noteworthy that in a cohort of laryngeal cancer cell lines and 15 primary samples the downregulation of GNG7 gene expression significantly correlates with hypermethylation (p < 0.001).	('hypermethylation', 'Var', (161, 177))	('downregulation', 'NegReg', (92, 106))	('expression', 'MPA', (120, 130))	('GNG7', 'Gene', '2788', (110, 114))	('laryngeal cancer', 'Disease', 'MESH:D007822', (37, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('laryngeal cancer', 'Disease', (37, 53))	('GNG7', 'Gene', (110, 114))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (37, 53))
510809	22183866	This suggests that at least for a subset of cases hypermethylation is the mechanism behind the observed loss of GNG7 expression.	('GNG7', 'Gene', '2788', (112, 116))	('loss', 'NegReg', (104, 108))	('expression', 'MPA', (117, 127))	('hypermethylation', 'Var', (50, 66))	('GNG7', 'Gene', (112, 116))
510816	22183866	It is tempting to speculate that loss of GNG7 protein could be a marker for tumor progression as we detected also a highly significant correlation between GNG7 protein expression and keratinization.	('GNG7', 'Gene', '2788', (41, 45))	('expression', 'MPA', (168, 178))	('GNG7', 'Gene', (155, 159))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('GNG7', 'Gene', '2788', (155, 159))	('GNG7', 'Gene', (41, 45))	('loss', 'Var', (33, 37))	('protein', 'Protein', (46, 53))	('correlation', 'Interaction', (135, 146))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('keratinization', 'MPA', (183, 197))
510818	22183866	In parallel, we show that loss of GNG7 protein was associated with large tumors of pT3/4 stage.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('GNG7', 'Gene', '2788', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('associated', 'Reg', (51, 61))	('pT3/4', 'Gene', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('GNG7', 'Gene', (34, 38))	('tumors', 'Disease', (73, 79))	('loss', 'Var', (26, 30))	('pT3/4', 'Gene', '7694', (83, 88))	('protein', 'Protein', (39, 46))
510820	22183866	Thus, loss of GNG7 defines probably a subgroup of locally advanced tumors with low metastatic potential.	('loss', 'Var', (6, 10))	('GNG7', 'Gene', '2788', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('GNG7', 'Gene', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
510822	22183866	Last, we show that GNG7 promoter methylation is significantly more frequent in young adult patients age <=45 as compared to patients age >45 (p < 0.001).	('methylation', 'Var', (33, 44))	('patients', 'Species', '9606', (91, 99))	('GNG7', 'Gene', (19, 23))	('promoter', 'MPA', (24, 32))	('GNG7', 'Gene', '2788', (19, 23))	('patients', 'Species', '9606', (124, 132))
510824	22183866	Taken together, this might suggest that epigenetic silencing of tumor suppressor genes is more prevalent in young patients and with age shifts toward genomic loss in line with the general observation that genomic instability increases with age.	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('epigenetic silencing', 'Var', (40, 60))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
510825	22183866	In summary we show here that loss of GNG7 protein expression is a frequent event in head and neck cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('protein', 'Protein', (42, 49))	('GNG7', 'Gene', (37, 41))	('head and neck cancer', 'Disease', 'MESH:D006258', (84, 104))	('loss', 'Var', (29, 33))	('head and neck cancer', 'Phenotype', 'HP:0012288', (84, 104))	('GNG7', 'Gene', '2788', (37, 41))	('expression', 'MPA', (50, 60))
510827	22183866	Besides, we suggest epigenetic silencing as the mechanism of GNG7 gene inactivation which might be especially true for young adult patients.	('patients', 'Species', '9606', (131, 139))	('epigenetic silencing', 'Var', (20, 40))	('GNG7', 'Gene', (61, 65))	('inactivation', 'NegReg', (71, 83))	('GNG7', 'Gene', '2788', (61, 65))
510830	21845048	Excellent antibacterial, antifungal, and antiproliferative activities could be demonstrated by both Ag2Ti5O11   xH2O and Ag/titanate (UV light irradiation) due to their unique structures and compositions, which have photocatalytic activities to generate reactive oxygen species and capabilities to continuously release the silver ions.	('antifungal', 'CPA', (25, 35))	('silver', 'Chemical', 'MESH:D012834', (323, 329))	('release', 'MPA', (311, 318))	('antibacterial', 'CPA', (10, 23))	('titanate', 'Chemical', '-', (124, 132))	('antiproliferative activities', 'CPA', (41, 69))	('Ag2Ti5O11   xH2O', 'Chemical', '-', (100, 116))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (254, 277))	('Ag2Ti5O11   xH2O', 'Var', (100, 116))
510882	21845048	Each titanate-based compound was divided into two groups with one group being kept in the dark while the other was exposed to ultraviolet light (lambda = 365 nm, UVA, ENF-280C/FE, Spectroline, Westbury, NY) for 2 hours.	('ENF-280C/FE', 'Var', (167, 178))	('lambda', 'Var', (145, 151))	('titanate', 'Chemical', '-', (5, 13))
510883	21845048	The MIC80 and MIC50 of the target additives (titanate-based compounds or FLC) were defined as an approximately 80% and 50% reduction in terms of the growth of cells compared with the growth of cells with no target additive.	('MIC50', 'Var', (14, 19))	('titanate', 'Chemical', '-', (45, 53))	('growth', 'CPA', (149, 155))	('MIC80', 'Var', (4, 9))	('reduction', 'NegReg', (123, 132))
510915	21845048	Considering the ion balance inside the galleries, the H+ or H3O+ produced by the redox reaction could be exchanged into the galleries in the process of the reaction, resulting in distortion of titanate lattice (see Figure 2).	('distortion', 'MPA', (179, 189))	('H3O+', 'Var', (60, 64))	('titanate', 'Chemical', '-', (193, 201))	('H3O+', 'Chemical', 'MESH:C027727', (60, 64))	('titanate lattice', 'MPA', (193, 209))
510923	21845048	The results for Ag/titanate in the presence of NaBH4 reduction (A), Ag/titanate in the presence of UV light irradiation (B), and Ag2Ti5O11   xH2O (C), and pure H2Ti5O11   H2O (D) tested against E. coli, are presented as images in Figure 5.	('titanate', 'Chemical', '-', (71, 79))	('H2O', 'Chemical', 'MESH:D014867', (171, 174))	('Ag2Ti5O11   xH2O', 'Chemical', '-', (129, 145))	('NaBH4', 'Chemical', 'MESH:C025364', (47, 52))	('H2O', 'Chemical', 'MESH:D014867', (142, 145))	('NaBH4 reduction', 'Gene', (47, 62))	('E. coli', 'Species', '562', (194, 201))	('Ag2Ti5O11', 'Var', (129, 138))	('titanate', 'Chemical', '-', (19, 27))
510924	21845048	The Ag/titanate in the presence of UV light irradiation and Ag2Ti5O11   xH2O showed the highest antibacterial activity.	('Ag2Ti5O11   xH2O', 'Chemical', '-', (60, 76))	('Ag2Ti5O11   xH2O', 'Var', (60, 76))	('titanate', 'Chemical', '-', (7, 15))	('antibacterial activity', 'CPA', (96, 118))
510925	21845048	The fully protonated titanate (H2Ti5O11   H2O) nanofibers showed the least effective antibacterial activity.	('titanate', 'Chemical', '-', (21, 29))	('H2Ti5O11   H2O', 'Var', (31, 45))	('antibacterial activity', 'CPA', (85, 107))	('H2O', 'Chemical', 'MESH:D014867', (42, 45))
510926	21845048	The results in Figure 6A show that both Ag2Ti5O11   xH2O and Ag/titanate (UV light irradiation) have excellent anti-fungal activity, as is revealed by the MIC50 values.	('Ag2Ti5O11   xH2O', 'Chemical', '-', (40, 56))	('Ag2Ti5O11   xH2O', 'Var', (40, 56))	('titanate', 'Chemical', '-', (64, 72))	('anti-fungal activity', 'CPA', (111, 131))
510935	21845048	As indicated in Figure 6B, both Ag2Ti5O11   xH2O and Ag/titanate (UV light irradiation) have better antiproliferative effects than those observed with Ag/titanate (NaBH4 reduction) and plain titanate nanofibers, with the IC50 values being 32.28 and 37.51 mug/mL, respectively, without UV light irradiation.	('Ag2Ti5O11   xH2O', 'Var', (32, 48))	('Ag2Ti5O11   xH2O', 'Chemical', '-', (32, 48))	('titanate', 'Chemical', '-', (56, 64))	('NaBH4', 'Chemical', 'MESH:C025364', (164, 169))	('titanate', 'Chemical', '-', (191, 199))	('antiproliferative effects', 'CPA', (100, 125))	('titanate', 'Chemical', '-', (154, 162))
510940	21845048	From the results, both Ag2Ti5O11   xH2O and Ag/titanate (UV light irradiation) have demonstrated excellent antibacterial, antifungal, and antiproliferative functional activities due to their unique structures and compositions, which include having photocatalytic activity to generate ROS and the ability to release silver ions continuously.	('release', 'MPA', (307, 314))	('titanate', 'Chemical', '-', (47, 55))	('antiproliferative functional activities', 'CPA', (138, 177))	('ROS', 'MPA', (284, 287))	('antibacterial', 'CPA', (107, 120))	('Ag2Ti5O11   xH2O', 'Chemical', '-', (23, 39))	('Ag2Ti5O11   xH2O', 'Var', (23, 39))	('silver', 'Chemical', 'MESH:D012834', (315, 321))	('ROS', 'Chemical', 'MESH:D017382', (284, 287))	('antifungal', 'CPA', (122, 132))
510963	20232121	On a molecular level, BRBs have been shown to influence the mRNA and protein expression levels of multiple genes associated with these cellular effects.	('influence', 'Reg', (46, 55))	('BRBs', 'Chemical', '-', (22, 26))	('BRBs', 'Var', (22, 26))
511078	33390169	Previous studies have shown that short exposure to bile acids and low pH causes oxidative stress and DNA damage in the esophageal tissues and cells.	('oxidative stress', 'MPA', (80, 96))	('bile acids', 'Chemical', 'MESH:D001647', (51, 61))	('DNA damage', 'MPA', (101, 111))	('low', 'Var', (66, 69))	('oxidative stress', 'Phenotype', 'HP:0025464', (80, 96))
511111	33390169	12-LOX over-expression was observed to increase the levels of CCL5, which in turn helped to recruit and repolarize M2 macrophages.	('helped', 'Reg', (82, 88))	('repolarize M2 macrophages', 'CPA', (104, 129))	('CCL5', 'Gene', (62, 66))	('12-LOX', 'Gene', '246', (0, 6))	('12-LOX', 'Gene', (0, 6))	('increase', 'PosReg', (39, 47))	('over-expression', 'Var', (7, 22))	('CCL5', 'Gene', '6352', (62, 66))	('recruit', 'CPA', (92, 99))	('levels', 'MPA', (52, 58))
511121	33390169	Overexpression of IL-1beta has been reported in EC and is involved in increased cell proliferation and associated with poor EC patient prognosis.	('increased', 'PosReg', (70, 79))	('patient', 'Species', '9606', (127, 134))	('reported', 'Reg', (36, 44))	('cell proliferation', 'CPA', (80, 98))	('Overexpression', 'Var', (0, 14))	('IL-1beta', 'Gene', (18, 26))
511122	33390169	Another stromal cell-derived cytokine IL-11 is highly expressed in EC, and its knockdown inhibits EC cell proliferation (Eca109 and KYSE410).	('IL-11', 'Gene', (38, 43))	('knockdown', 'Var', (79, 88))	('IL-11', 'Gene', '3589', (38, 43))	('inhibits', 'NegReg', (89, 97))
511123	33390169	Similarly, overexpression of IL-33 has been reported in EC patients and its knockdown reduced the invasive and metastatic potential in KYSE-450 and Eca-109 cells.	('reduced', 'NegReg', (86, 93))	('knockdown', 'Var', (76, 85))	('IL-33', 'Gene', '90865', (29, 34))	('patients', 'Species', '9606', (59, 67))	('overexpression', 'PosReg', (11, 25))	('IL-33', 'Gene', (29, 34))
511139	33390169	Using both in vitro and in vivo models, knockdown or silencing of CXCR7 was shown to reduce the cell viability and growth of EC.	('cell viability', 'CPA', (96, 110))	('growth', 'CPA', (115, 121))	('reduce', 'NegReg', (85, 91))	('CXCR7', 'Gene', '57007', (66, 71))	('knockdown', 'Var', (40, 49))	('silencing', 'Var', (53, 62))	('CXCR7', 'Gene', (66, 71))
511149	33390169	CCL5 knockdown reduced tumor migration and invasiveness in both the cell lines, and therefore targeting the CCL5/CCR5 axis might act as a novel therapeutic strategy for EC.	('CCL5', 'Gene', (0, 4))	('CCL5', 'Gene', (108, 112))	('knockdown', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('reduced', 'NegReg', (15, 22))	('CCR5', 'Gene', '1234', (113, 117))	('CCL5', 'Gene', '6352', (0, 4))	('CCL5', 'Gene', '6352', (108, 112))	('invasiveness', 'CPA', (43, 55))	('tumor', 'Disease', (23, 28))	('CCR5', 'Gene', (113, 117))
511151	33390169	Overexpression of CCR6 is associated with proliferation, invasion, and EMT in ESCC, while CCL20 overexpression showed a positive correlation with Treg markers (FoxP3 and IL-10) and demonstrated poor patient survival.	('IL-10', 'Gene', (170, 175))	('CCL20', 'Gene', '6364', (90, 95))	('ESCC', 'Disease', (78, 82))	('invasion', 'CPA', (57, 65))	('proliferation', 'CPA', (42, 55))	('patient', 'Species', '9606', (199, 206))	('CCR6', 'Gene', (18, 22))	('EMT', 'CPA', (71, 74))	('IL-10', 'Gene', '3586', (170, 175))	('FoxP3', 'Gene', '50943', (160, 165))	('Overexpression', 'Var', (0, 14))	('Treg', 'Chemical', '-', (146, 150))	('CCR6', 'Gene', '1235', (18, 22))	('CCL20', 'Gene', (90, 95))	('FoxP3', 'Gene', (160, 165))	('associated', 'Reg', (26, 36))
511170	33390169	Besides, the silencing of IL-6 was found to attenuate angiogenesis, reverse EMT, and increase cell death in ESCC.	('attenuate', 'NegReg', (44, 53))	('angiogenesis', 'CPA', (54, 66))	('reverse EMT', 'CPA', (68, 79))	('IL-6', 'Gene', (26, 30))	('IL-6', 'Gene', '3569', (26, 30))	('increase cell death', 'Disease', (85, 104))	('ESCC', 'Disease', (108, 112))	('silencing', 'Var', (13, 22))	('increase cell death', 'Disease', 'MESH:D003643', (85, 104))
511173	33390169	Cells exposed to IL-6 show increased expression of mesenchymal markers such as vimentin, N-cadherin, CXCR4, ZEB1, and SNAI2 and reduced expression of epithelial markers such as E-cadherin, CD24, cytokeratin 19, CD29, ERBB2, and EPCAM, thus disseminating the role of IL-6 in the induction of mesenchymal characteristics in EAC.	('IL-6', 'Gene', '3569', (266, 270))	('ERBB2', 'Gene', '2064', (217, 222))	('CXCR4', 'Var', (101, 106))	('CD24', 'Gene', (189, 193))	('CD29', 'Gene', '3688', (211, 215))	('EPCAM', 'Gene', (228, 233))	('ZEB1', 'Gene', (108, 112))	('IL-6', 'Gene', (266, 270))	('expression', 'MPA', (136, 146))	('reduced', 'NegReg', (128, 135))	('cytokeratin 19', 'Gene', (195, 209))	('SNAI2', 'Gene', (118, 123))	('IL-6', 'Gene', '3569', (17, 21))	('vimentin', 'Gene', '7431', (79, 87))	('vimentin', 'Gene', (79, 87))	('CD29', 'Gene', (211, 215))	('increased', 'PosReg', (27, 36))	('E-cadherin', 'Gene', (177, 187))	('N-cadherin', 'Gene', (89, 99))	('IL-6', 'Gene', (17, 21))	('E-cadherin', 'Gene', '999', (177, 187))	('N-cadherin', 'Gene', '1000', (89, 99))	('cytokeratin 19', 'Gene', '3880', (195, 209))	('CD24', 'Gene', '100133941', (189, 193))	('SNAI2', 'Gene', '6591', (118, 123))	('expression', 'MPA', (37, 47))	('ZEB1', 'Gene', '6935', (108, 112))	('EPCAM', 'Gene', '4072', (228, 233))	('ERBB2', 'Gene', (217, 222))
511174	33390169	Furthermore, the induction of IL-6 is found to increase the expression of ALDH1, a CSC marker, and TWIST, an essential EMT inducer, in a xenograft tumor model.	('expression', 'MPA', (60, 70))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('induction', 'Var', (17, 26))	('ALDH1', 'Gene', (74, 79))	('TWIST', 'Gene', '7291', (99, 104))	('IL-6', 'Gene', (30, 34))	('ALDH1', 'Gene', '216', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('IL-6', 'Gene', '3569', (30, 34))	('increase', 'PosReg', (47, 55))	('TWIST', 'Gene', (99, 104))
511180	33390169	In contrast, the knockdown of IL-33 is found to reduce the expression of EMT-related genes such as vimentin, N-cadherin, slug, and ZEB2, suggesting a role of IL-33 in EMT and metastasis.	('EMT-related genes', 'Gene', (73, 90))	('ZEB2', 'Gene', (131, 135))	('slug', 'Gene', '6591', (121, 125))	('IL-33', 'Gene', (30, 35))	('IL-33', 'Gene', (158, 163))	('N-cadherin', 'Gene', '1000', (109, 119))	('IL-33', 'Gene', '90865', (158, 163))	('IL-33', 'Gene', '90865', (30, 35))	('expression', 'MPA', (59, 69))	('N-cadherin', 'Gene', (109, 119))	('reduce', 'NegReg', (48, 54))	('knockdown', 'Var', (17, 26))	('vimentin', 'Gene', '7431', (99, 107))	('ZEB2', 'Gene', '9839', (131, 135))	('vimentin', 'Gene', (99, 107))	('slug', 'Gene', (121, 125))
511185	33390169	Several studies have reported that microRNA 200a plays a significant role in inhibiting EMT transformation, invasion, and metastasis by specifically targeting E-cadherin's transcriptional repressors, ZEB1, and ZEB2.	('inhibiting', 'NegReg', (77, 87))	('EMT transformation', 'CPA', (88, 106))	('ZEB1', 'Gene', '6935', (200, 204))	('E-cadherin', 'Gene', '999', (159, 169))	('ZEB1', 'Gene', (200, 204))	('ZEB2', 'Gene', '9839', (210, 214))	('targeting', 'NegReg', (149, 158))	('E-cadherin', 'Gene', (159, 169))	('microRNA', 'Var', (35, 43))	('ZEB2', 'Gene', (210, 214))	('invasion', 'CPA', (108, 116))
511193	33390169	Also, STAT3 was downregulated by miR-124 in EC cells.	('miR-124', 'Var', (33, 40))	('STAT3', 'Gene', (6, 11))	('STAT3', 'Gene', '6774', (6, 11))	('downregulated', 'NegReg', (16, 29))
511202	33390169	Furthermore, CXCL12 activates tumor cells' migration to target specific organs via a CXCL12-CXCR4 axis chemotactic gradient.	('CXCL12-CXCR4 axis', 'MPA', (85, 102))	('activates', 'PosReg', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('CXCL12', 'Var', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
511212	33390169	The blockage of the ERK1/2 signaling pathway by CXCR4 or ERK1/2 inhibitors suppressed the ability of ECSCs to invade and metastasize.	('ERK1/2', 'Gene', '5595;5594', (20, 26))	('suppressed', 'NegReg', (75, 85))	('inhibitors', 'Var', (64, 74))	('ERK1/2', 'Gene', (57, 63))	('ERK1/2', 'Gene', '5595;5594', (57, 63))	('blockage', 'NegReg', (4, 12))	('ERK1/2', 'Gene', (20, 26))
511215	33390169	Several studies indicate that high levels of CCR7 are associated with tumor metastasis and a poor clinical outcome in several cancer types, including EC.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CCR7', 'Gene', (45, 49))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor metastasis', 'Disease', 'MESH:D009362', (70, 86))	('tumor metastasis', 'Disease', (70, 86))	('high levels', 'Var', (30, 41))	('associated', 'Reg', (54, 64))
511216	33390169	Accordingly, an in vivo study showed that tumor cells with high expression of CCR7 had higher metastatic potential in the lymph node of the heterotopic transplantation mouse model.	('tumor', 'Disease', (42, 47))	('mouse', 'Species', '10090', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('high expression', 'Var', (59, 74))	('CCR7', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('higher', 'PosReg', (87, 93))
511222	33390169	In addition, the knockdown of MUC1 significantly suppressed the migration and invasion of ESCC cell lines induced by treatment of the cells with CCL21.	('MUC1', 'Gene', (30, 34))	('CCL21', 'Gene', '6366', (145, 150))	('CCL21', 'Gene', (145, 150))	('invasion of ESCC cell lines', 'CPA', (78, 105))	('suppressed', 'NegReg', (49, 59))	('knockdown', 'Var', (17, 26))	('MUC1', 'Gene', '4582', (30, 34))	('migration', 'CPA', (64, 73))
511224	33390169	demonstrated that co-expression of CCR7 and VEGF-C correlated with higher lymphatic metastatic recurrence in patients with pN0 ESCC.	('higher', 'PosReg', (67, 73))	('lymphatic metastatic recurrence', 'CPA', (74, 105))	('patients', 'Species', '9606', (109, 117))	('VEGF-C', 'Gene', '7424', (44, 50))	('co-expression', 'Var', (18, 31))	('CCR7', 'Gene', (35, 39))	('VEGF-C', 'Gene', (44, 50))
511226	33390169	Indeed, several studies have described the close correlation between high VEGF-C expression in tissue and serum samples with tumor differentiation, depth of the tumor, vascular and lymph node metastasis, lymphatic invasion, tumor stage, and a decreased survival rate in ESCC clinical samples.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('ESCC', 'Disease', (270, 274))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('VEGF-C', 'Gene', '7424', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (224, 229))	('lymphatic invasion', 'CPA', (204, 222))	('survival rate', 'CPA', (253, 266))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('high', 'Var', (69, 73))	('VEGF-C', 'Gene', (74, 80))	('decreased', 'NegReg', (243, 252))	('tumor', 'Disease', (161, 166))	('expression', 'MPA', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
511244	33390169	In this context, neutralizing antibodies against CXCR1, CXCR2, or CXCL8 suppressed the migration and invasion in a human ESCC cancer cell model induced by CXCL8.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('CXCL8', 'Gene', '3576', (66, 71))	('CXCL8', 'Gene', (66, 71))	('CXCR1', 'Gene', (49, 54))	('cancer', 'Disease', (126, 132))	('neutralizing', 'Var', (17, 29))	('CXCL8', 'Gene', (155, 160))	('human', 'Species', '9606', (115, 120))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CXCL8', 'Gene', '3576', (155, 160))	('suppressed', 'NegReg', (72, 82))	('CXCR1', 'Gene', '3577', (49, 54))
511258	33390169	Indeed, the expression of IL-6 or IL-8 in ESCC tumor tissues was found to impair NK cell function and positively correlated with tumor progression and poor survival.	('impair', 'NegReg', (74, 80))	('correlated with', 'Reg', (113, 128))	('expression', 'Var', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('IL-6', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('IL-8', 'Gene', '3576', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('IL-6', 'Gene', '3569', (26, 30))	('NK cell function', 'CPA', (81, 97))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('IL-8', 'Gene', (34, 38))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (47, 52))
511277	33390169	More importantly, using a mouse model of ESCC, M2 polarization of TAM increased PD-L2 expression in these cells, resulting in immune evasion and tumor promotion through a PD-1 signaling pathway.	('immune evasion', 'MPA', (126, 140))	('PD-L2', 'Gene', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('PD-1 signaling pathway', 'Pathway', (171, 193))	('increased', 'PosReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('expression', 'MPA', (86, 96))	('tumor', 'Disease', (145, 150))	('TAM', 'Chemical', '-', (66, 69))	('increased PD', 'Phenotype', 'HP:0008151', (70, 82))	('mouse', 'Species', '10090', (26, 31))	('M2 polarization', 'Var', (47, 62))
511288	33390169	Indeed, MDSC with higher CD38 expression displayed a greater capacity to suppress activated T cells and to promote tumor growth than MDSC with lower CD38 expression.	('CD38', 'Gene', (25, 29))	('suppress', 'NegReg', (73, 81))	('CD38', 'Gene', '12494', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('activated T cells', 'CPA', (82, 99))	('CD38', 'Gene', '12494', (25, 29))	('expression', 'Var', (30, 40))	('tumor', 'Disease', (115, 120))	('CD38', 'Gene', (149, 153))	('promote', 'PosReg', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
511298	33390169	Patients with CXCL12 positive tumors had drastically reduced overall survival and disease-free survival rates.	('tumors', 'Disease', (30, 36))	('disease-free survival rates', 'CPA', (82, 109))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('reduced', 'NegReg', (53, 60))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('overall survival', 'CPA', (61, 77))	('CXCL12', 'Var', (14, 20))
511301	33390169	Of these, plerixafor has already been approved for mobilizing hematopoietic stem cells, while a phase II clinical trial is in progress to evaluate its use in combination with standard temozolomide chemo-radiotherapy for patients with glioblastoma (NCT03746080).	('glioblastoma', 'Disease', (234, 246))	('glioblastoma', 'Disease', 'MESH:D005909', (234, 246))	('patients', 'Species', '9606', (220, 228))	('mobilizing', 'MPA', (51, 61))	('NCT03746080', 'Var', (248, 259))	('glioblastoma', 'Phenotype', 'HP:0012174', (234, 246))	('temozolomide', 'Chemical', 'MESH:D000077204', (184, 196))	('plerixafor', 'Chemical', 'MESH:C088327', (10, 20))
511311	33390169	showed that silencing CXCR2, using small interfering RNAs, significantly reduced cell invasion while silencing CXCR7 did not affect cell invasion.	('CXCR7', 'Gene', '57007', (111, 116))	('reduced', 'NegReg', (73, 80))	('small interfering', 'Var', (35, 52))	('CXCR7', 'Gene', (111, 116))	('cell invasion', 'CPA', (81, 94))
511312	33390169	Silencing both chemokines resulted in reducing cancer cell viability and increased induction of apoptosis.	('increased', 'PosReg', (73, 82))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('reducing', 'NegReg', (38, 46))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Silencing', 'Var', (0, 9))
511322	33390169	showed that inhibition of IL-6 using shRNA resulted in a significant reduction in human EC migration and invasion in vitro and reduced tumor xenograft growth in a mouse model.	('inhibition', 'Var', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('IL-6', 'Gene', (26, 30))	('shRNA', 'Gene', (37, 42))	('IL-6', 'Gene', '3569', (26, 30))	('mouse', 'Species', '10090', (163, 168))	('reduction', 'NegReg', (69, 78))	('reduced', 'NegReg', (127, 134))	('human', 'Species', '9606', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
511358	30600672	Esophagectomy has been the standard treatment for T1b esophageal cancer, although with some debate.	('T1b', 'Var', (50, 53))	('Esophagectomy', 'Disease', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))
511363	30600672	We retrospectively identified 208 patients who received treatments for clinical T1N0M0 esophageal cancer between February 2006 and December 2016 at Severance Hospital, Seoul, Korea.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('T1N0M0', 'Var', (80, 86))	('esophageal cancer', 'Disease', (87, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('patients', 'Species', '9606', (34, 42))
511394	30600672	A total of 14 patients were finally diagnosed with pT1b esophageal cancer; half of them received adjuvant RT, and the rest underwent complete esophagectomy.	('esophageal cancer', 'Disease', (56, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('pT1b', 'Var', (51, 55))	('patients', 'Species', '9606', (14, 22))
511400	30600672	There were significantly more tumors in the cervical or upper thoracic area in the CCRT group than in the other groups.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('more', 'PosReg', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('CCRT', 'Var', (83, 87))
511441	30600672	Second, esophagectomy did not improve OS compared with other noninvasive therapies in patients with T1b esophageal cancer.	('T1b', 'Var', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('OS', 'Chemical', '-', (38, 40))	('patients', 'Species', '9606', (86, 94))
511447	30600672	Currently, the National Cancer Institute recommends surgery as the standard treatment for T1b esophageal cancer, and this recommendation is based on the observation that T1b esophageal squamous cell carcinoma has a high incidence of lymph node metastasis.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (174, 208))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('Cancer', 'Disease', (24, 30))	('esophageal cancer', 'Disease', (94, 111))	('esophageal squamous cell carcinoma', 'Disease', (174, 208))	('Cancer', 'Disease', 'MESH:D009369', (24, 30))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('T1b', 'Var', (170, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
511466	30600672	Although the main purpose of this study was to compare each treatment modality in early-stage esophageal cancer, there was a trend to treat patients with T1b disease with esophagectomy unless the patient refused surgery.	('T1b', 'Var', (154, 157))	('patient', 'Species', '9606', (140, 147))	('esophageal cancer', 'Disease', (94, 111))	('patient', 'Species', '9606', (196, 203))	('patients', 'Species', '9606', (140, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
511479	30600672	In conclusion, we assessed the clinical outcomes of clinical T1N0M0 esophageal cancer patients according to each different treatment modality.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('T1N0M0', 'Var', (61, 67))	('esophageal cancer', 'Disease', (68, 85))	('patients', 'Species', '9606', (86, 94))
511492	24759814	Moreover, PPI therapy can lead to partial regression of intestinal metaplasia (IM) in BE patients, as evidenced by the development of macroscopic islands of squamous epithelium and an accompanying shortening of columnar epithelium, albeit inconsistently.	('BE', 'Phenotype', 'HP:0100580', (86, 88))	('intestinal metaplasia', 'Disease', (56, 77))	('patients', 'Species', '9606', (89, 97))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (56, 77))	('regression', 'NegReg', (42, 52))	('shortening', 'NegReg', (197, 207))	('PPI therapy', 'Var', (10, 21))
511534	24759814	With regards to biomarkers, detection of DNA content abnormalities by flow cytometry (aneuploidy or increased 4 N fraction), mutation or loss of heterozygosity of the p53 and p16 genes and methylation-based biomarkers panels have shown promise and may be superior to histology alone for risk stratification, especially in ND-BE and LGD.	('aneuploidy', 'Disease', (86, 96))	('loss of heterozygosity', 'Var', (137, 159))	('p16', 'Gene', (175, 178))	('aneuploidy', 'Disease', 'MESH:D000782', (86, 96))	('ND-BE', 'Disease', (322, 327))	('p53', 'Gene', '7157', (167, 170))	('BE', 'Phenotype', 'HP:0100580', (325, 327))	('LGD', 'Disease', (332, 335))	('p16', 'Gene', '1029', (175, 178))	('p53', 'Gene', (167, 170))	('mutation', 'Var', (125, 133))
511603	24759814	In RFA clinical trials, patients typically receive double-dose PPI without evaluating their actual amount of acid reflux by pH/impedance monitoring.	('PPI', 'Var', (63, 66))	('RFA', 'Disease', (3, 6))	('acid reflux', 'Phenotype', 'HP:0002020', (109, 120))	('patients', 'Species', '9606', (24, 32))
511709	32728033	In many types of human cancer, SOX2 is dysregulated due to gene amplification and protein overexpression.	('SOX2', 'Gene', (31, 35))	('human', 'Species', '9606', (17, 22))	('gene amplification', 'Var', (59, 77))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('overexpression', 'PosReg', (90, 104))	('protein', 'Protein', (82, 89))
511716	32728033	SOX2 deletion in zygotes triggers differentiation of ESCs into trophectoderm (TE)-like cells, leading to failure in embryoblast formation and early embryonic lethality.	('deletion', 'Var', (5, 13))	('failure', 'NegReg', (105, 112))	('triggers', 'Reg', (25, 33))	('embryoblast formation', 'CPA', (116, 137))	('embryonic lethality', 'Disease', (148, 167))	('SOX2', 'Gene', (0, 4))	('embryonic lethality', 'Disease', 'MESH:D020964', (148, 167))
511719	32728033	The SOX2 amplification or overexpression was found in at least 25 different human cancers, and forced SOX2 expression promotes neoplastic progression by accelerating cancer cell proliferation, migration, invasion, and metastasis.	('accelerating', 'PosReg', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (166, 172))	('invasion', 'CPA', (204, 212))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('metastasis', 'CPA', (218, 228))	('migration', 'CPA', (193, 202))	('cancers', 'Disease', (82, 89))	('cancer', 'Disease', (82, 88))	('forced', 'Var', (95, 101))	('promotes', 'PosReg', (118, 126))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('human', 'Species', '9606', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('neoplastic progression', 'CPA', (127, 149))	('SOX2', 'Gene', (102, 106))
511723	32728033	Importantly, zygotic deletion of SOX2 causes the failure in the formation of the pluripotent epiblast, but without affecting the TE formation, and early embryonic lethality.	('formation of the pluripotent epiblast', 'MPA', (64, 101))	('deletion', 'Var', (21, 29))	('SOX2', 'Gene', (33, 37))	('embryonic lethality', 'Disease', 'MESH:D020964', (153, 172))	('embryonic lethality', 'Disease', (153, 172))	('failure', 'NegReg', (49, 56))
511724	32728033	While maternal SOX2 protein expression persists in preimplantation embryos, and depletion of both maternal or embryonic SOX2 via RNAi disrupts the formation of TE or cavity and results in an early arrest of embryos at the morula stage, indicating that SOX2 is essential for the segregation of the ICM and TE.	('disrupts', 'NegReg', (134, 142))	('TE or cavity', 'MPA', (160, 172))	('arrest', 'Disease', 'MESH:D006323', (197, 203))	('formation', 'MPA', (147, 156))	('SOX2', 'Gene', (15, 19))	('preimplantation embryos', 'Phenotype', 'HP:0032479', (51, 74))	('arrest', 'Disease', (197, 203))	('depletion', 'Var', (80, 89))
511727	32728033	For example, SOX2 mutant neural stem cells exhibit morphologically immature beta-tubulin-positive neuronal-like cells, and SOX2 neural knockout mice manifest diminished GABAergic interneurons in newborn cortex and in adult olfactory bulb.	('mice', 'Species', '10090', (144, 148))	('mutant', 'Var', (18, 24))	('diminished', 'NegReg', (158, 168))	('GABAergic interneurons', 'CPA', (169, 191))	('SOX2', 'Gene', (13, 17))
511728	32728033	For example, the anterior part of the foregut with high SOX2 expression differentiates into esophagus and forestomach, while the low SOX2 expression gives rise to trachea and posterior stomach.	('trachea', 'Disease', (163, 170))	('trachea', 'Disease', 'MESH:C557675', (163, 170))	('SOX2', 'Gene', (56, 60))	('esophagus', 'Disease', (92, 101))	('high', 'Var', (51, 55))
511730	32728033	Consistently, the in vivo mouse experiments with osteoblast-specific SOX2 knockout confirm that SOX2 is essential for osteoblast self-renewal, while SOX2 transgenic expression impairs mature osteoblast function.	('knockout', 'Var', (74, 82))	('SOX2', 'Gene', (149, 153))	('mouse', 'Species', '10090', (26, 31))	('transgenic', 'Species', '10090', (154, 164))	('mature osteoblast function', 'CPA', (184, 210))	('impairs', 'NegReg', (176, 183))	('transgenic expression', 'Var', (154, 175))
511735	32728033	Two early identified SOX2 enhancers, SOX regulatory regions (SRR) 1 and 2, are capable of influencing the activity of promoter of SOX2 and specifically exert their functions when cells are in an undifferentiated state.SRR1 displays activity in the promoter constructs expressed in ESCs, but deletion of SRR1 has minimal impact on SOX2 pluripotency.	('SRR1', 'Gene', '70118', (303, 307))	('SRR1', 'Gene', (303, 307))	('deletion', 'Var', (291, 299))	('SOX2 pluripotency', 'MPA', (330, 347))	('activity', 'MPA', (232, 240))	('SRR1', 'Gene', '70118', (218, 222))	('SRR1', 'Gene', (218, 222))
511742	32728033	For example, the methylation of the SOX2 promoter by DNA methyltransferase (DNMT) inhibits SOX2 transcription, and this hypermethylation of SOX2 appears to be a critical epigenetic event, leading to SOX2 silencing in several types of human cancers, including esophageal cancer, gastric cancer (GC), and endometrial cancer.	('silencing', 'NegReg', (204, 213))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('DNA methyltransferase', 'Gene', '1786', (53, 74))	('endometrial cancer', 'Disease', (303, 321))	('transcription', 'MPA', (96, 109))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('endometrial cancer', 'Disease', 'MESH:D016889', (303, 321))	('gastric cancer', 'Disease', 'MESH:D013274', (278, 292))	('cancers', 'Disease', (240, 247))	('cancer', 'Disease', (240, 246))	('SOX2', 'Gene', (91, 95))	('hypermethylation', 'Var', (120, 136))	('cancer', 'Disease', (286, 292))	('DNMT', 'Gene', '1786', (76, 80))	('GC', 'Phenotype', 'HP:0012126', (294, 296))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('DNMT', 'Gene', (76, 80))	('cancer', 'Disease', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('DNA methyltransferase', 'Gene', (53, 74))	('SOX2', 'Gene', (199, 203))	('gastric cancer', 'Phenotype', 'HP:0012126', (278, 292))	('cancer', 'Disease', (315, 321))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('inhibits', 'NegReg', (82, 90))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('human', 'Species', '9606', (234, 239))	('methylation', 'Var', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('endometrial cancer', 'Phenotype', 'HP:0012114', (303, 321))	('gastric cancer', 'Disease', (278, 292))
511750	32728033	As such, MLN4924, a small molecule inhibitor of protein neddylation, significantly downregulated SOX2 transcription by inactivating SCFFBXW2 and subsequently suppressed cancer cell stemness (Fig.	('transcription', 'MPA', (102, 115))	('cancer cell stemness', 'Disease', 'MESH:D009369', (169, 189))	('MLN4924', 'Chemical', 'MESH:C539933', (9, 16))	('suppressed', 'NegReg', (158, 168))	('inactivating', 'NegReg', (119, 131))	('SOX2', 'Gene', (97, 101))	('MLN4924', 'Var', (9, 16))	('cancer cell stemness', 'Disease', (169, 189))	('downregulated', 'NegReg', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('FBXW2', 'Gene', '26190', (135, 140))	('FBXW2', 'Gene', (135, 140))
511751	32728033	A SOX2 NLS mutant acts in a dominant negative manner to form a complex with wild-type SOX2 to retain it in the cytoplasm, thus suppressing its transcription activity and inhibiting expression of its downstream targets such as Fgf4, Oct4, and Nanog.	('mutant', 'Var', (11, 17))	('Fgf4', 'Gene', (226, 230))	('expression', 'MPA', (181, 191))	('Nanog', 'Gene', '79923', (242, 247))	('SOX2 NLS', 'Gene', (2, 10))	('suppressing', 'NegReg', (127, 138))	('Nanog', 'Gene', (242, 247))	('Fgf4', 'Gene', '2249', (226, 230))	('transcription activity', 'MPA', (143, 165))	('Oct4', 'Gene', (232, 236))	('NLS', 'Gene', (7, 10))	('inhibiting', 'NegReg', (170, 180))
511757	32728033	Moreover, miR-9, miR-30a, miR-140, miR-145, and miR-126, are all shown to act as tumor suppressors and negatively regulate the SOX2 expression in human cancers.	('miR-126', 'Gene', '406913', (48, 55))	('SOX2', 'Protein', (127, 131))	('miR-30a', 'Gene', '407029', (17, 24))	('miR-140', 'Gene', (26, 33))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancers', 'Disease', (152, 159))	('miR-140', 'Gene', '406932', (26, 33))	('regulate', 'Reg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('miR-145', 'Gene', '406937', (35, 42))	('tumor', 'Disease', (81, 86))	('negatively', 'NegReg', (103, 113))	('miR-30a', 'Gene', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('miR-126', 'Gene', (48, 55))	('miR-145', 'Gene', (35, 42))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('human', 'Species', '9606', (146, 151))	('miR-9', 'Var', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('expression', 'MPA', (132, 142))
511765	32728033	SOX2 knockdown significantly downregulates miR-181a-5p and miR-30e-5p in breast cancer cells, leading to suppression of cancer cell proliferation, migration, and invasion.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('migration', 'CPA', (147, 156))	('downregulates', 'NegReg', (29, 42))	('knockdown', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('suppression', 'NegReg', (105, 116))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('miR-30e-5p', 'Gene', (59, 69))	('invasion', 'CPA', (162, 170))	('SOX2', 'Gene', (0, 4))	('cancer', 'Disease', (80, 86))	('miR-181a-5p', 'Gene', (43, 54))
511769	32728033	In breast cancer cells, the ectopic expression of SOX2OT significantly promotes SOX2 expression by almost 20-folds, leading to increased anchorage-independent growth, whereas conditional knockdown of SOX2OT inhibits the SOX2 transcription to reduce cancer cell viability and ameliorate cell migration and invasion in bladder and cervical cancer cells.	('promotes', 'PosReg', (71, 79))	('cancer', 'Disease', (249, 255))	('ectopic expression', 'Var', (28, 46))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('cancer', 'Disease', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('SOX2OT', 'Gene', (200, 206))	('SOX2OT', 'Gene', (50, 56))	('ameliorate', 'PosReg', (275, 285))	('reduce', 'NegReg', (242, 248))	('SOX2', 'Gene', (80, 84))	('cell migration', 'CPA', (286, 300))	('SOX2OT', 'Gene', '347689', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('anchorage-independent growth', 'CPA', (137, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('SOX2OT', 'Gene', '347689', (50, 56))	('transcription', 'MPA', (225, 238))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('SOX2', 'Gene', (220, 224))	('expression', 'MPA', (85, 95))	('cancer', 'Disease', (338, 344))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('inhibits', 'NegReg', (207, 215))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('increased', 'PosReg', (127, 136))
511780	32728033	CDK2 directly phosphorylates SOX2 at S39 and S253, which enhances SOX2-mediated pluripotency during deprogramming.	('SOX2-mediated pluripotency', 'MPA', (66, 92))	('CDK2', 'Gene', (0, 4))	('enhances', 'PosReg', (57, 65))	('S253', 'Var', (45, 49))	('CDK2', 'Gene', '1017', (0, 4))	('S39', 'Var', (37, 40))
511781	32728033	AKT phosphorylates SOX2 at T116, which protects SOX2 from ubiquitin-mediated degradation, thus contributing to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('contributing to', 'Reg', (95, 110))	('SOX2', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('ubiquitin-mediated degradation', 'MPA', (58, 88))	('T116', 'Var', (27, 31))	('protects', 'NegReg', (39, 47))
511782	32728033	SOX2 phosphorylation on T118 residue by PKCbeta is associated with its transcriptional activity, as evidenced by the observation that the transcriptional activity is detected in either wild-type or SOX2 phospho-mimic mutant (SOX2-T118D), but not in SOX2 phospho-dead mutant (T118A).	('PKCbeta', 'Gene', (40, 47))	('T118', 'Chemical', '-', (230, 234))	('PKCbeta', 'Gene', '5578', (40, 47))	('T118A', 'Mutation', 'rs1352479562', (275, 280))	('T118D', 'Mutation', 'p.T118D', (230, 235))	('transcriptional activity', 'MPA', (138, 162))	('T118', 'Var', (24, 28))	('SOX2-T118D', 'Var', (225, 235))	('transcriptional activity', 'MPA', (71, 95))	('T118', 'Chemical', '-', (24, 28))	('T118', 'Chemical', '-', (275, 279))
511784	32728033	Human and mouse SOX2 are known to be SUMOylated on K245 or K247, respectively, which causes reduced SOX2 activity to trigger differentiation of ESCs.	('Human', 'Species', '9606', (0, 5))	('mouse', 'Species', '10090', (10, 15))	('K245', 'Var', (51, 55))	('ESCs', 'Disease', (144, 148))	('activity', 'MPA', (105, 113))	('reduced', 'NegReg', (92, 99))	('K247', 'Var', (59, 63))	('SOX2', 'Enzyme', (100, 104))	('trigger', 'Reg', (117, 124))
511785	32728033	Notably, SUMOylation of SOX2 on K245 can be abolished in the SOX2 triplet mutant (S249A-S250A-S251A), suggesting that phosphorylation of the triplet serves as a priming step for subsequent SUMOylation of SOX2.	('SUMOylation', 'MPA', (9, 20))	('S249A', 'Mutation', 'p.S249A', (82, 87))	('S250A', 'Mutation', 'p.S250A', (88, 93))	('K245', 'Var', (32, 36))	('S249A-S250A-S251A', 'Var', (82, 99))	('SOX2', 'Gene', (61, 65))	('abolished', 'NegReg', (44, 53))	('S251A', 'Mutation', 'p.S251A', (94, 99))
511786	32728033	A later study confirms that SOX2 phosphorylation on S251 site by ERK1/2 could promote SOX2 SUMOylation in nasopharyngeal carcinoma (NPC) cells.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('ERK', 'Gene', (65, 68))	('NPC', 'Phenotype', 'HP:0100630', (132, 135))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('promote', 'PosReg', (78, 85))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (106, 130))	('phosphorylation', 'Var', (33, 48))	('carcinoma', 'Disease', (121, 130))	('SOX2 SUMOylation', 'MPA', (86, 102))	('carcinoma', 'Disease', 'MESH:D009369', (121, 130))	('S251', 'Var', (52, 56))	('ERK', 'Gene', '5594', (65, 68))
511788	32728033	The SUMOylated SOX2 has impaired property in its DNA binding and is readily subjected to autophagic degradation, thus SOX2 SUMOylation results in reduced stability and activity of SOX2, thereby reducing the stemness of NPC.	('stability', 'MPA', (154, 163))	('activity', 'MPA', (168, 176))	('SOX2', 'Enzyme', (180, 184))	('DNA binding', 'Interaction', (49, 60))	('NPC', 'Disease', (219, 222))	('reduced', 'NegReg', (146, 153))	('P', 'Chemical', 'MESH:D010758', (220, 221))	('SOX2', 'Gene', (118, 122))	('stemness of', 'CPA', (207, 218))	('reducing', 'NegReg', (194, 202))	('SUMOylation', 'Var', (123, 134))	('NPC', 'Phenotype', 'HP:0100630', (219, 222))
511789	32728033	SOX2 is also monomethylated on lysine 42 and lysine 119 (equivalent to Lys-117 in human SOX2) by methyltransferase SET7, which triggers the ubiquitin-dependent proteolysis of methylated SOX2, thus promoting differentiation of ESCs (Figs.	('SET7', 'Gene', '57108', (115, 119))	('ESCs', 'Disease', (226, 230))	('SET7', 'Gene', (115, 119))	('lysine', 'Chemical', 'MESH:D008239', (31, 37))	('Lys', 'Chemical', 'MESH:D008239', (71, 74))	('triggers', 'Reg', (127, 135))	('lysine 42', 'Var', (31, 40))	('promoting', 'PosReg', (197, 206))	('ubiquitin-dependent proteolysis', 'MPA', (140, 171))	('lysine 119', 'Var', (45, 55))	('human', 'Species', '9606', (82, 87))	('lysine', 'Chemical', 'MESH:D008239', (45, 51))
511795	32728033	Moreover, SOX2 has been shown to be O-glycosylated by O-GlcNAc transferase (OGT) at residues of Ser246/248.	('OGT', 'Gene', '8473', (76, 79))	('Ser246/248', 'Var', (96, 106))	('O-GlcNAc transferase', 'Gene', '8473', (54, 74))	('Ser246', 'Chemical', '-', (96, 102))	('O-GlcNAc transferase', 'Gene', (54, 74))	('OGT', 'Gene', (76, 79))
511799	32728033	The homologous to E6-AP C-terminus (HECT)-type E3 ligase WW domain-containing protein 2 (WWP2) is found to specifically interact with SOX2 through its HECT domain and promote SOX2 ubiquitylation and degradation, which is required for appropriate differentiation of ESCs in development.	('WWP2', 'Gene', (89, 93))	('WWP2', 'Gene', '11060', (89, 93))	('degradation', 'MPA', (199, 210))	('HECT', 'MPA', (151, 155))	('P', 'Chemical', 'MESH:D010758', (91, 92))	('promote', 'PosReg', (167, 174))	('SOX2 ubiquitylation', 'MPA', (175, 194))	('E6-AP', 'Var', (18, 23))	('interact', 'Interaction', (120, 128))	('P', 'Chemical', 'MESH:D010758', (22, 23))
511810	32728033	Inhibition of EGFR signaling, through pharmacological inhibition or genetic inactivation, significantly reduces the SOX2 expression and subsequently suppresses the self-renewal of lung cancer stem-like cells.	('self-renewal of', 'CPA', (164, 179))	('EGFR', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('genetic inactivation', 'Var', (68, 88))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('reduces', 'NegReg', (104, 111))	('SOX2 expression', 'MPA', (116, 131))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('suppresses', 'NegReg', (149, 159))
511811	32728033	On the other hand, ectopic expression of a constitutively active EGFR mutant or ligand exposure induces SOX2 accumulation to further enhance the EGFR-dependent self-renewal capacity of lung cancer cells.	('enhance', 'PosReg', (133, 140))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('EGFR', 'Gene', (65, 69))	('mutant', 'Var', (70, 76))	('induces', 'Reg', (96, 103))	('lung cancer', 'Disease', (185, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('SOX2 accumulation', 'MPA', (104, 121))
511815	32728033	In skin keratinocytes, SOX2 overexpression promotes cell proliferation and migration via activating the EGFR/MEK/ERK pathway to accelerate cutaneous wound healing.	('activating', 'Reg', (89, 99))	('overexpression', 'Var', (28, 42))	('promotes', 'PosReg', (43, 51))	('cell proliferation', 'CPA', (52, 70))	('cutaneous wound healing', 'CPA', (139, 162))	('ERK', 'Gene', '5594', (113, 116))	('ERK', 'Gene', (113, 116))	('SOX2', 'Gene', (23, 27))	('accelerate', 'PosReg', (128, 138))	('migration', 'CPA', (75, 84))	('MEK', 'Gene', (109, 112))	('MEK', 'Gene', '5609', (109, 112))
511819	32728033	Conversely, inhibition of PI3K/AKT directly by PI3K inhibitor duvelisib promotes CSCs differentiation by reducing SOX2.	('P', 'Chemical', 'MESH:D010758', (26, 27))	('inhibition', 'Var', (12, 22))	('SOX2', 'MPA', (114, 118))	('duvelisib', 'Chemical', 'MESH:C586691', (62, 71))	('PI3K/AKT', 'Pathway', (26, 34))	('promotes', 'PosReg', (72, 80))	('CSCs', 'Disease', (81, 85))	('reducing', 'NegReg', (105, 113))	('P', 'Chemical', 'MESH:D010758', (47, 48))
511820	32728033	Finally, during the progression of premalignant squamous lesions in tracheobronchial basal cells, SOX2 amplification cooperates with the PI3K/AKT signaling to promote squamous metaplasia at the expense of normal mucociliary differentiation (Fig.	('P', 'Chemical', 'MESH:D010758', (137, 138))	('squamous metaplasia', 'Disease', (167, 186))	('squamous metaplasia', 'Phenotype', 'HP:0002860', (167, 186))	('SOX2', 'Gene', (98, 102))	('promote', 'PosReg', (159, 166))	('premalignant squamous lesions', 'Disease', (35, 64))	('amplification', 'Var', (103, 116))	('premalignant squamous lesions', 'Disease', 'MESH:D000081483', (35, 64))
511824	32728033	Indeed, SOX2 deletion in adult mice causes hippocampal neurogenesis defect, a phenotype also seen upon Shh loss.	('hippocampal neurogenesis defect', 'Disease', (43, 74))	('SOX2', 'Gene', (8, 12))	('deletion', 'Var', (13, 21))	('mice', 'Species', '10090', (31, 35))	('hippocampal neurogenesis defect', 'Disease', 'MESH:D001750', (43, 74))
511830	32728033	YAP depletion causes reduction of CSCs and tumorigenicity of osteosarcomas.	('YAP', 'Gene', (0, 3))	('osteosarcomas', 'Phenotype', 'HP:0002669', (61, 74))	('osteosarcomas', 'Disease', 'MESH:D012516', (61, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('depletion', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('YAP', 'Gene', '10413', (0, 3))	('reduction', 'NegReg', (21, 30))	('tumor', 'Disease', (43, 48))	('CSCs', 'MPA', (34, 38))	('osteosarcomas', 'Disease', (61, 74))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))
511833	32728033	For instance, SOX2 activity is essential for mouse tooth development, and temporal knockdown of SOX2 terminates the migration of dental epithelium cells, which is attributed to the degradation of Wnt/beta-catenin signaling.	('migration of dental epithelium cells', 'CPA', (116, 152))	('SOX2', 'Gene', (96, 100))	('mouse tooth', 'Phenotype', 'HP:0000698', (45, 56))	('mouse', 'Species', '10090', (45, 50))	('terminates', 'NegReg', (101, 111))	('knockdown', 'Var', (83, 92))
511834	32728033	SOX2 depletion in murine osteosarcoma-derived cells accelerates the differentiation into mature bone-forming cells, and dramatically impairs their ability to form tumors due to inactivation of Wnt/beta-catenin signaling.	('murine', 'Species', '10090', (18, 24))	('depletion', 'Var', (5, 14))	('osteosarcoma', 'Phenotype', 'HP:0002669', (25, 37))	('differentiation into mature bone-forming cells', 'CPA', (68, 114))	('osteosarcoma', 'Disease', (25, 37))	('osteosarcoma', 'Disease', 'MESH:D012516', (25, 37))	('impairs', 'NegReg', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('accelerates', 'PosReg', (52, 63))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('Wnt/beta-catenin signaling', 'Pathway', (193, 219))	('inactivation', 'NegReg', (177, 189))	('SOX2', 'Gene', (0, 4))
511837	32728033	In some cases, however, SOX2 could directly activate beta-catenin expression by binding to its promoter, and also induces translocation of beta-catenin from the cytosol to the nuclei, therefore activating the Wnt pathway to promote tumor metastasis.	('SOX2', 'Var', (24, 28))	('tumor metastasis', 'Disease', (232, 248))	('tumor metastasis', 'Disease', 'MESH:D009362', (232, 248))	('translocation', 'MPA', (122, 135))	('beta-catenin', 'Protein', (53, 65))	('beta-catenin', 'Protein', (139, 151))	('Wnt pathway', 'Pathway', (209, 220))	('expression', 'MPA', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('binding', 'Interaction', (80, 87))	('promote', 'PosReg', (224, 231))	('activating', 'PosReg', (194, 204))	('induces', 'Reg', (114, 121))	('activate', 'PosReg', (44, 52))
511839	32728033	During the process of iPSCs generation, inhibition of TGF-beta signaling appears to increase the reprogramming efficiency via bypassing the requirement for exogenous SOX2 expression.	('inhibition', 'Var', (40, 50))	('bypassing', 'NegReg', (126, 135))	('increase', 'PosReg', (84, 92))	('reprogramming efficiency', 'CPA', (97, 121))	('TGF-beta', 'Gene', (54, 62))	('P', 'Chemical', 'MESH:D010758', (23, 24))	('TGF-beta', 'Gene', '7039', (54, 62))
511840	32728033	In glioma-initiating cells, TGF-beta signaling induces SOX2 expression to maintain cell stemness, whereas inhibition of TGF-beta signal deprives tumor cells of stemness and promotes cell differentiation via decreasing SOX2 expression.	('expression', 'MPA', (60, 70))	('SOX2', 'Gene', (218, 222))	('TGF-beta', 'Gene', '7039', (28, 36))	('glioma', 'Disease', (3, 9))	('cell stemness', 'CPA', (83, 96))	('deprives', 'NegReg', (136, 144))	('promotes', 'PosReg', (173, 181))	('cell differentiation', 'CPA', (182, 202))	('induces', 'Reg', (47, 54))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('TGF-beta', 'Gene', (28, 36))	('expression', 'MPA', (223, 233))	('inhibition', 'Var', (106, 116))	('tumor', 'Disease', (145, 150))	('SOX2', 'Gene', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('TGF-beta', 'Gene', '7039', (120, 128))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('TGF-beta', 'Gene', (120, 128))	('decreasing', 'NegReg', (207, 217))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))
511846	32728033	Ectopic SOX2 expression is also significantly associated with increased population of CSCs in lung and ovarian cancers, whereas SOX2 knockdown dramatically reduces the percentage of CSCs and inhibits the formation of xenograft tumors.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('increased', 'PosReg', (62, 71))	('SOX2', 'Gene', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('SOX2', 'Gene', (8, 12))	('inhibits', 'NegReg', (191, 199))	('knockdown', 'Var', (133, 142))	('expression', 'Var', (13, 23))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('Ectopic', 'Var', (0, 7))	('reduces', 'NegReg', (156, 163))	('lung and ovarian cancers', 'Disease', 'MESH:D055370', (94, 118))	('ovarian cancers', 'Phenotype', 'HP:0100615', (103, 118))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
511847	32728033	Likewise, SOX2 inhibition by a miRNA decreases the breast CSC population and attenuates its tumorigenicity in NOD/SCID nude mice.	('inhibition', 'NegReg', (15, 25))	('SCID', 'Disease', 'MESH:D053632', (114, 118))	('SCID', 'Disease', (114, 118))	('miRNA', 'Var', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('nude mice', 'Species', '10090', (119, 128))	('SOX2', 'Enzyme', (10, 14))	('tumor', 'Disease', (92, 97))	('decreases', 'NegReg', (37, 46))	('breast CSC population', 'CPA', (51, 72))	('attenuates', 'NegReg', (77, 87))
511854	32728033	Dysregulation of SOX2 has been found in over 20 different types of human cancers, and SOX2 overexpression and associated abnormal cross-talks with multiple signaling pathways trigger several malignant features, including uncontrolled proliferation, resistance to apoptosis, altered autophagy, enhanced EMT, and maintenance of CSCs, leading to tumor progression, metastasis, and drug resistance (Figs.	('drug resistance', 'Phenotype', 'HP:0020174', (378, 393))	('EMT', 'CPA', (302, 305))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('enhanced', 'PosReg', (293, 301))	('tumor', 'Disease', (343, 348))	('drug resistance', 'CPA', (378, 393))	('autophagy', 'CPA', (282, 291))	('metastasis', 'CPA', (362, 372))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('leading to', 'Reg', (332, 342))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('uncontrolled proliferation', 'CPA', (221, 247))	('SOX2', 'Gene', (86, 90))	('abnormal', 'Var', (121, 129))	('resistance to apoptosis', 'CPA', (249, 272))	('trigger', 'Reg', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('human', 'Species', '9606', (67, 72))
511856	32728033	SOX2 expression in stem cells maintains a cell self-renewing status by repressing the expression of several proliferative genes, whereas SOX2 depletion promotes cell proliferation by derepression of cyclin D1 to drive cells toward a differentiation state.	('cell self-renewing status', 'CPA', (42, 67))	('cell proliferation', 'CPA', (161, 179))	('cells toward a differentiation', 'CPA', (218, 248))	('drive', 'PosReg', (212, 217))	('derepression', 'Var', (183, 195))	('expression', 'MPA', (86, 96))	('cyclin D1', 'Gene', '595', (199, 208))	('depletion', 'Var', (142, 151))	('SOX2', 'Gene', (137, 141))	('promotes', 'PosReg', (152, 160))	('cyclin D1', 'Gene', (199, 208))	('SOX2', 'Gene', (0, 4))
511859	32728033	Likewise, SOX2 knockdown in prostate cancer cells causes downregulation of cyclin E and upregulation of p27, thereby inhibiting G1 to S transition, while SOX2 overexpression causes the opposite effect.	('SOX2', 'Gene', (10, 14))	('downregulation', 'NegReg', (57, 71))	('p27', 'Gene', '51014', (104, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (28, 43))	('knockdown', 'Var', (15, 24))	('G1 to S transition', 'CPA', (128, 146))	('upregulation', 'PosReg', (88, 100))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('inhibiting', 'NegReg', (117, 127))	('p27', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('prostate cancer', 'Disease', (28, 43))	('cyclin E', 'Protein', (75, 83))
511863	32728033	In contrast, some studies controversially show that SOX2 causes cell-cycle arrest at the G0/G1 phase and suppresses cell proliferation via the mechanisms involving cyclin D1 downregulation, Rb phosphorylation, p27Kip1 increase, and inactivation of mTOR pathway in colorectal and GC cells.	('SOX2', 'Var', (52, 56))	('GC', 'Phenotype', 'HP:0012126', (279, 281))	('downregulation', 'NegReg', (174, 188))	('mTOR', 'Gene', (248, 252))	('suppresses', 'NegReg', (105, 115))	('colorectal', 'Disease', 'MESH:D015179', (264, 274))	('inactivation', 'NegReg', (232, 244))	('arrest', 'Disease', (75, 81))	('mTOR', 'Gene', '2475', (248, 252))	('increase', 'PosReg', (218, 226))	('cyclin D1', 'Gene', (164, 173))	('p27Kip1', 'Gene', (210, 217))	('cell proliferation', 'CPA', (116, 134))	('p27Kip1', 'Gene', '1027', (210, 217))	('arrest', 'Disease', 'MESH:D006323', (75, 81))	('cyclin D1', 'Gene', '595', (164, 173))	('phosphorylation', 'MPA', (193, 208))	('Rb', 'Chemical', 'MESH:D012413', (190, 192))	('colorectal', 'Disease', (264, 274))
511865	32728033	As an oncoprotein, SOX2 expression confers cancer cells resistance to apoptosis.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('SOX2', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('expression', 'Var', (24, 34))	('resistance to apoptosis', 'CPA', (56, 79))
511866	32728033	Inhibition of SOX2 significantly induces apoptosis, and suppresses the metastatic potential in syngeneic mouse models of breast and lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancers', 'Phenotype', 'HP:0100526', (132, 144))	('SOX2', 'Gene', (14, 18))	('breast and lung cancers', 'Disease', 'MESH:D001943', (121, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('metastatic potential', 'CPA', (71, 91))	('Inhibition', 'Var', (0, 10))	('apoptosis', 'CPA', (41, 50))	('suppresses', 'NegReg', (56, 66))	('mouse', 'Species', '10090', (105, 110))	('induces', 'Reg', (33, 40))
511867	32728033	SOX2 knockdown reduces survivin expression, thus activating the caspase-9-related mitochondrial apoptotic pathway to induce apoptosis in neural stem cells, and lung cancer cells, which can be largely rescued by survivin overexpression, indicating a causal role of SOX2 in apoptosis protection.	('SOX2', 'Gene', (0, 4))	('expression', 'MPA', (32, 42))	('caspase-9', 'Gene', '842', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('knockdown', 'Var', (5, 14))	('activating', 'PosReg', (49, 59))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('induce', 'PosReg', (117, 123))	('caspase-9', 'Gene', (64, 73))	('survivin', 'Protein', (23, 31))	('reduces', 'NegReg', (15, 22))	('apoptosis', 'CPA', (124, 133))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
511868	32728033	In Ewing's sarcomas, SOX2 depletion apparently induces apoptosis by activating key proteins controlling both extrinsic death receptor pathways (caspases-8 and Fas) and intrinsic mitochondrial pathways (caspase-9 and Bad), highly suggesting that SOX2 inhibition could activate both apoptotic pathways.	('apoptosis', 'Disease', (55, 64))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (3, 19))	('induces', 'Reg', (47, 54))	('depletion', 'Var', (26, 35))	('activating', 'PosReg', (68, 78))	('intrinsic', 'MPA', (168, 177))	('caspase-9', 'Gene', '842', (202, 211))	('death', 'Disease', 'MESH:D003643', (119, 124))	('sarcomas', 'Phenotype', 'HP:0100242', (11, 19))	('death', 'Disease', (119, 124))	('extrinsic', 'MPA', (109, 118))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (3, 19))	("Ewing's sarcomas", 'Disease', (3, 19))	('SOX2', 'Gene', (21, 25))	('caspase-9', 'Gene', (202, 211))	('apoptotic pathways', 'Pathway', (281, 299))
511886	32728033	SOX2 knockdown in lung cancer cells induces autophagy by enhancing the expression of autophagy marker LC3-II.	('expression', 'MPA', (71, 81))	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('enhancing', 'PosReg', (57, 66))	('LC3-II', 'Protein', (102, 108))	('knockdown', 'Var', (5, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('induces', 'PosReg', (36, 43))	('lung cancer', 'Disease', (18, 29))	('autophagy', 'CPA', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('SOX2', 'Gene', (0, 4))
511891	32728033	SOX2 is an important transcriptional factor required for mouse embryonic development and tissue homeostasis, as revealed by total and conditional SOX2 knockout studies.	('knockout', 'Var', (151, 159))	('mouse', 'Species', '10090', (57, 62))	('SOX2', 'Gene', (146, 150))
511892	32728033	The studies to determine the role of SOX2 in tumorigenesis, using genetically engineered mouse models, were mainly conducted under SOX2 transgenic expression or deletion alone or in combination with oncogene activation or tumor-suppressor inactivation (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('SOX2', 'Gene', (131, 135))	('tumor', 'Disease', (45, 50))	('deletion', 'Var', (161, 169))	('transgenic', 'Species', '10090', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('mouse', 'Species', '10090', (89, 94))
511893	32728033	For example, transgenic overexpression of homozygous SOX2 in lung Clara cells induces hyperplasia of bronchial epithelial cells, eventually leading to lung adenocarcinoma in 50% of mice, implying the oncogenic role of SOX2 during lung tumorigenesis.SOX2 transgenic expression in combination of deletion of three tumor suppressors, TP53, Pten, and Cdkn2A/p16 promotes the formation of LSCCs.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (151, 170))	('mice', 'Species', '10090', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('deletion', 'Var', (294, 302))	('TP53', 'Gene', (331, 335))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (151, 170))	('tumor', 'Disease', (312, 317))	('Pten', 'Gene', (337, 341))	('Pten', 'Gene', '19211', (337, 341))	('hyperplasia', 'Disease', (86, 97))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('hyperplasia', 'Disease', 'MESH:D006965', (86, 97))	('transgenic', 'Species', '10090', (254, 264))	('p16', 'Gene', '12578', (354, 357))	('Cdkn2A', 'Gene', '12578', (347, 353))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('promotes', 'PosReg', (358, 366))	('Cdkn2A', 'Gene', (347, 353))	('lung adenocarcinoma', 'Disease', (151, 170))	('p16', 'Gene', (354, 357))	('tumor', 'Disease', (235, 240))	('formation of LSCCs', 'CPA', (371, 389))	('transgenic', 'Species', '10090', (13, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
511894	32728033	Similarly, SOX2 transgenic expression in combination of Lkb1 deletion leads to mTORC pathway activation to promote LSCC tumorigenesis, and SOX2 also promotes recruitment of tumor-associated neutrophils.	('mTOR', 'Gene', (79, 83))	('mTOR', 'Gene', '2475', (79, 83))	('activation', 'PosReg', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('deletion', 'Var', (61, 69))	('Lkb1', 'Gene', '20869', (56, 60))	('transgenic', 'Species', '10090', (16, 26))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('recruitment', 'MPA', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('LSCC', 'Disease', (115, 119))	('promotes', 'PosReg', (149, 157))	('promote', 'PosReg', (107, 114))	('Lkb1', 'Gene', (56, 60))	('tumor', 'Disease', (120, 125))
511897	32728033	Interestingly, in the KrasG12D mouse lung cancer model, homozygous SOX2 deletion in CC10-positive AT2 cells caused early death, whereas heterozygous SOX2 deletion leads to development of airway papillary adenocarcinoma at 12 weeks after Kras activation and SOX2 reduction.	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Kras', 'Gene', '16653', (22, 26))	('SOX2', 'Gene', (67, 71))	('deletion', 'Var', (72, 80))	('airway papillary adenocarcinoma', 'Disease', (187, 218))	('mouse', 'Species', '10090', (31, 36))	('death', 'Disease', 'MESH:D003643', (121, 126))	('lung cancer', 'Disease', (37, 48))	('CC10', 'Gene', (84, 88))	('papillary adenocarcinoma', 'Phenotype', 'HP:0006774', (194, 218))	('Kras', 'Gene', (237, 241))	('airway papillary adenocarcinoma', 'Disease', 'MESH:D000231', (187, 218))	('CC10', 'Gene', '22287', (84, 88))	('Kras', 'Gene', (22, 26))	('deletion', 'Var', (154, 162))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('death', 'Disease', (121, 126))	('Kras', 'Gene', '16653', (237, 241))
511900	32728033	In ESCC model, Krt-5-driven transgenic SOX2 expression in basal progenitor cells triggers hyperplasia in esophagus and squamous cell carcinomas in the forestomach, particularly when cooperated with inflammation-mediated Stat3 activation in the latter case.	('inflammation', 'Disease', (198, 210))	('esophagus', 'Disease', (105, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('squamous cell carcinomas', 'Disease', (119, 143))	('Stat3', 'Gene', '20848', (220, 225))	('expression', 'Var', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('Krt-5', 'Gene', (15, 20))	('transgenic', 'Var', (28, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('SOX2', 'Gene', (39, 43))	('Stat3', 'Gene', (220, 225))	('hyperplasia', 'Disease', (90, 101))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (119, 143))	('hyperplasia', 'Disease', 'MESH:D006965', (90, 101))	('inflammation', 'Disease', 'MESH:D007249', (198, 210))	('Krt-5', 'Gene', '110308', (15, 20))	('transgenic', 'Species', '10090', (28, 38))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (119, 143))
511901	32728033	In a genetically engineered mouse model of osteosarcoma, induced by dual deletion of RB and p53 in the mouse osteoblast lineage, SOX2 deletion dramatically delays and reduces the tumor formation, along with an extended lifespan.	('reduces', 'NegReg', (167, 174))	('mouse', 'Species', '10090', (28, 33))	('osteosarcoma', 'Disease', 'MESH:D012516', (43, 55))	('mouse', 'Species', '10090', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('SOX2', 'Gene', (129, 133))	('p53', 'Gene', (92, 95))	('deletion', 'Var', (134, 142))	('delays', 'NegReg', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('RB', 'Disease', 'MESH:D012175', (85, 87))	('p53', 'Gene', '22059', (92, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (43, 55))	('osteosarcoma', 'Disease', (43, 55))	('tumor', 'Disease', (179, 184))
511904	32728033	Consistently, SOX2 deficiency suppresses the Shh signaling-induced tumor formation, implying that SOX2 expression in granule cell precursors is required for Shh-induced medulloblastoma (Table 1).	('Shh', 'MPA', (45, 48))	('medulloblastoma', 'Disease', (169, 184))	('SOX2', 'Gene', (14, 18))	('deficiency', 'Var', (19, 29))	('medulloblastoma', 'Disease', 'MESH:D008527', (169, 184))	('suppresses', 'NegReg', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('medulloblastoma', 'Phenotype', 'HP:0002885', (169, 184))
511907	32728033	Indeed, SOX2 overexpression or amplification is often observed in many different types of human cancers, which, importantly, is correlated with poor survival of cancer patients (Fig.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SOX2', 'Gene', (8, 12))	('human', 'Species', '9606', (90, 95))	('poor', 'NegReg', (144, 148))	('overexpression', 'PosReg', (13, 27))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (96, 102))	('amplification', 'Var', (31, 44))
511910	32728033	During lung tumorigenesis, SOX2 amplification is more frequently detected in high-grade bronchial lesions than in low-grade lesions, with the former having a high frequency to progression into cancers.	('detected', 'Reg', (65, 73))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('cancers', 'Disease', (193, 200))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('amplification', 'Var', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Disease', (12, 17))	('SOX2', 'Gene', (27, 31))
511911	32728033	The SOX2 amplification is also seen in lung adenocarcinomas, and serves as an independent poor prognostic marker.	('SOX2', 'Gene', (4, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('amplification', 'Var', (9, 22))	('seen', 'Reg', (31, 35))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('lung adenocarcinomas', 'Disease', (39, 59))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (39, 59))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (39, 59))
511918	32728033	In colorectal cancers, SOX2 expression is associated with cancer stem-like properties, correlates with lymph-node metastases and distant spread, and poor patient prognosis.	('cancer', 'Disease', (14, 20))	('metastases', 'Disease', (114, 124))	('colorectal cancers', 'Disease', 'MESH:D015179', (3, 21))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patient', 'Species', '9606', (154, 161))	('associated', 'Reg', (42, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('colorectal cancers', 'Disease', (3, 21))	('SOX2', 'Gene', (23, 27))	('correlates', 'Reg', (87, 97))	('expression', 'Var', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
511925	32728033	However, the subsequent study showed that patients with SOX2high HNSCCs have markedly longer progression-free survival (51 vs. 16 months) and overall survival (110 vs. 37 months) than those with SOX2low tumors.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('HNSCCs', 'Disease', (65, 71))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('overall survival', 'CPA', (142, 158))	('progression-free survival', 'CPA', (93, 118))	('longer', 'PosReg', (86, 92))	('SOX2high', 'Var', (56, 64))	('HNSCCs', 'Disease', 'MESH:D000077195', (65, 71))	('patients', 'Species', '9606', (42, 50))
511927	32728033	Overall, SOX2 amplification or overexpression is frequently observed in most human cancers, which is highly associated with poor survival of cancer patients.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('patients', 'Species', '9606', (148, 156))	('cancers', 'Disease', (83, 90))	('amplification', 'Var', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('SOX2', 'Gene', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('overexpression', 'PosReg', (31, 45))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', (83, 89))	('human', 'Species', '9606', (77, 82))
511931	32728033	One important mechanism is that SOX2 expression in cancer cells is associated with a CSC state, which is defined as a subpopulation cells within the tumor that are shown to be more resistant toward cancer therapies.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('expression', 'Var', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Disease', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('SOX2', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('associated', 'Reg', (67, 77))	('tumor', 'Disease', (149, 154))	('CSC state', 'Disease', (85, 94))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
511932	32728033	For example, the tamoxifen-resistant breast cancer cells exhibit stem cell-like features with a high SOX2 level, and SOX2 knockdown restores the sensitivity toward tamoxifen, whereas SOX2 overexpression confers tamoxifen resistance.	('breast cancer', 'Disease', (37, 50))	('restores', 'PosReg', (132, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('tamoxifen', 'Chemical', 'MESH:D013629', (211, 220))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('sensitivity toward tamoxifen', 'MPA', (145, 173))	('SOX2', 'Gene', (117, 121))	('tamoxifen', 'Chemical', 'MESH:D013629', (164, 173))	('knockdown', 'Var', (122, 131))	('tamoxifen', 'Chemical', 'MESH:D013629', (17, 26))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('SOX2', 'MPA', (101, 105))
511933	32728033	Importantly, our recent study showed that MLN4924, a small molecular inhibitor of protein neddylation, sensitizes otherwise resistant breast cancer cells to tamoxifen by downregulating SOX2 through inactivation of FBXW2 E3 ligase.	('FBXW2', 'Gene', (214, 219))	('SOX2', 'MPA', (185, 189))	('breast cancer', 'Disease', (134, 147))	('MLN4924', 'Var', (42, 49))	('tamoxifen', 'Chemical', 'MESH:D013629', (157, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('FBXW2', 'Gene', '26190', (214, 219))	('downregulating', 'NegReg', (170, 184))	('inactivation', 'NegReg', (198, 210))	('sensitizes', 'Reg', (103, 113))	('MLN4924', 'Chemical', 'MESH:C539933', (42, 49))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
511936	32728033	For instance, the osimertinib-resistant lung cancer cells express higher SOX2 levels with higher autophagic flux levels, and SOX2 knockdown or autophagy inhibitor treatment resensitizes these resistant cells to osimertinib.	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('autophagic', 'MPA', (97, 107))	('osimertinib', 'Chemical', '-', (18, 29))	('knockdown', 'Var', (130, 139))	('SOX2 levels', 'MPA', (73, 84))	('higher', 'PosReg', (66, 72))	('higher', 'PosReg', (90, 96))	('osimertinib', 'Chemical', '-', (211, 222))	('osimertinib-resistant lung cancer', 'Disease', 'MESH:D008175', (18, 51))	('osimertinib-resistant lung cancer', 'Disease', (18, 51))
511938	32728033	Consistently, SOX2 knockdown confers susceptibility of cancer cells to paclitaxel and cisplatin by inducing autophagy, apoptosis, and mitochondrial abnormalities.	('SOX2', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('knockdown', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('autophagy', 'CPA', (108, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('mitochondrial abnormalities', 'Disease', (134, 161))	('mitochondrial abnormalities', 'Phenotype', 'HP:0012103', (134, 161))	('apoptosis', 'CPA', (119, 128))	('mitochondrial abnormalities', 'Disease', 'MESH:D028361', (134, 161))	('paclitaxel', 'Chemical', 'MESH:D017239', (71, 81))	('susceptibility', 'MPA', (37, 51))	('inducing', 'PosReg', (99, 107))	('cancer', 'Disease', (55, 61))
511943	32728033	In GC stem-like cells, SOX2 knockdown improves the sensitivity of doxorubicin by inhibiting drug efflux.	('sensitivity of doxorubicin', 'MPA', (51, 77))	('GC', 'Phenotype', 'HP:0012126', (3, 5))	('inhibiting', 'NegReg', (81, 91))	('SOX2', 'Gene', (23, 27))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('drug efflux', 'MPA', (92, 103))	('knockdown', 'Var', (28, 37))	('improves', 'PosReg', (38, 46))
511945	32728033	In gliomas, SOX2 expression is associated with temozolomide resistance via activation of the mTOR pathway, and resistance to 1,3-bis(2-chloroethyl)- 1-nitrosourea via upregulation of the ABCC3 and ABCC6 transporters.	('ABCC6', 'Gene', '368', (197, 202))	('1,3-bis(2-chloroethyl)- 1-nitrosourea', 'Chemical', 'MESH:D002330', (125, 162))	('temozolomide', 'Chemical', 'MESH:D000077204', (47, 59))	('mTOR', 'Gene', (93, 97))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('mTOR', 'Gene', '2475', (93, 97))	('temozolomide resistance', 'MPA', (47, 70))	('ABCC6', 'Gene', (197, 202))	('activation', 'PosReg', (75, 85))	('associated', 'Reg', (31, 41))	('ABCC3', 'Gene', (187, 192))	('SOX2', 'Gene', (12, 16))	('expression', 'Var', (17, 27))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('ABCC3', 'Gene', '8714', (187, 192))	('upregulation', 'PosReg', (167, 179))	('gliomas', 'Disease', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))
511946	32728033	In melanoma, SOX2 transactivates the ABCC1 by binding to ABCC1 promoter, which contributes to paclitaxel resistance.	('ABCC1', 'Gene', (57, 62))	('transactivates', 'Var', (18, 32))	('paclitaxel resistance', 'MPA', (94, 115))	('paclitaxel', 'Chemical', 'MESH:D017239', (94, 104))	('ABCC1', 'Gene', '4363', (57, 62))	('ABCC1', 'Gene', '4363', (37, 42))	('contributes', 'Reg', (79, 90))	('binding', 'Interaction', (46, 53))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('ABCC1', 'Gene', (37, 42))
511947	32728033	In head and neck SCCs, SOX2 triggers cisplatin resistance by inducing ABCG2 transporter expression, whereas SOX2 knockdown reestablishes the sensitivity to cisplatin, indicating a causal role of SOX2.	('ABCG2', 'Gene', (70, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('triggers', 'PosReg', (28, 36))	('ABCG2', 'Gene', '9429', (70, 75))	('knockdown', 'Var', (113, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('cisplatin resistance', 'MPA', (37, 57))	('inducing', 'Reg', (61, 69))
511952	32728033	Four distinct ATFs have been engineered with three (ZF-552SKD, ZF-598SKD, and ZF-619SKD) binding to the proximal SOX2 promoter, and one (ZF-4203SKD) binding to the SOX2 enhancer, SRR1.	('binding', 'Interaction', (89, 96))	('ATF', 'Gene', (14, 17))	('ZF-619SKD', 'Var', (78, 87))	('SRR1', 'Gene', (179, 183))	('SRR1', 'Gene', '70118', (179, 183))	('ATF', 'Gene', '2668', (14, 17))	('ZF-552SKD', 'Var', (52, 61))	('binding', 'Interaction', (149, 156))	('ZF-4203SKD', 'Var', (137, 147))	('ZF-598SKD', 'Var', (63, 72))
511953	32728033	Among them, ZF-552SKD and ZF-598SKD are the most potent to reduce SOX2 mRNA levels in MDA-MB-435s cells by 74% and 94%, respectively.	('MDA-MB-435', 'CellLine', 'CVCL:0417', (86, 96))	('ZF-598SKD', 'Var', (26, 35))	('reduce', 'NegReg', (59, 65))	('ZF-552SKD', 'Var', (12, 21))	('SOX2 mRNA levels', 'MPA', (66, 82))
511954	32728033	The in vivo xenograft experiments verified that ZF-598SKD significantly inhibits tumor growth of breast cancers with a long-term effect.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor growth of breast cancers', 'Disease', (81, 111))	('breast cancers', 'Phenotype', 'HP:0003002', (97, 111))	('tumor growth of breast cancers', 'Disease', 'MESH:D001943', (81, 111))	('inhibits', 'NegReg', (72, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ZF-598SKD', 'Var', (48, 57))
511966	32728033	Furthermore, SOX2 is regulated by the EGFR-SRC-AKT and FGFR-ERK1/2 signaling, and inhibitors of their pathways would block self-renewal and expansion of stem-like cells by indirectly targeting SOX2.	('SRC', 'Gene', '6714', (43, 46))	('block', 'NegReg', (117, 122))	('ERK', 'Gene', '5594', (60, 63))	('self-renewal', 'CPA', (123, 135))	('SRC', 'Gene', (43, 46))	('SOX2', 'Gene', (193, 197))	('inhibitors', 'Var', (82, 92))	('ERK', 'Gene', (60, 63))	('targeting', 'Reg', (183, 192))
511968	32728033	Furthermore, in melanoma cells, triphenylmethane gentian violet (GV) inhibits survival and self-renewal capacity by blocking SOX2 induction via the EGFR-STAT3 signaling.	('STAT3', 'Gene', '6774', (153, 158))	('triphenylmethane gentian violet', 'Chemical', '-', (32, 63))	('induction', 'MPA', (130, 139))	('SOX2', 'Gene', (125, 129))	('inhibits', 'NegReg', (69, 77))	('STAT3', 'Gene', (153, 158))	('GV', 'Chemical', 'MESH:D005840', (65, 67))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('triphenylmethane', 'Var', (32, 48))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('blocking', 'NegReg', (116, 124))
511969	32728033	We recently found that neddylation inhibitor MLN4924 effectively blocks SOX2 expression in many types of human cancer cells by targeting the FBXW2-MSX2-SOX2 axis.	('human', 'Species', '9606', (105, 110))	('expression', 'MPA', (77, 87))	('MLN4924', 'Var', (45, 52))	('SOX2', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('MLN4924', 'Chemical', 'MESH:C539933', (45, 52))	('targeting', 'Reg', (127, 136))	('MSX2', 'Gene', '4488', (147, 151))	('MSX2', 'Gene', (147, 151))	('blocks', 'NegReg', (65, 71))	('FBXW2', 'Gene', '26190', (141, 146))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('FBXW2', 'Gene', (141, 146))
511971	32728033	By inactivating FBXW2 E3, MLN4924 causes accumulation of MSX2 to transcriptionally repress SOX2 expression.	('FBXW2', 'Gene', (16, 21))	('MSX2', 'Gene', '4488', (57, 61))	('MSX2', 'Gene', (57, 61))	('accumulation', 'PosReg', (41, 53))	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('MLN4924', 'Var', (26, 33))	('SOX2', 'Gene', (91, 95))	('inactivating', 'Var', (3, 15))	('FBXW2', 'Gene', '26190', (16, 21))
511972	32728033	Biologically, MLN4924, via depleting SOX2, overcomes tamoxifen resistance of breast cancer cells, as demonstrated by both in vitro proliferation and survival assays, and in vivo xenograft tumor model (Fig.	('tumor', 'Disease', (188, 193))	('breast cancer', 'Disease', (77, 90))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('tamoxifen', 'Chemical', 'MESH:D013629', (53, 62))	('overcomes', 'NegReg', (43, 52))	('MLN4924', 'Var', (14, 21))	('SOX2', 'Protein', (37, 41))	('tamoxifen resistance', 'MPA', (53, 73))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('depleting', 'NegReg', (27, 36))
511974	32728033	Furthermore, in most cancer types, SOX2 amplification or overexpression is a frequently occurring event, which is associated with advanced stages of tumorigenesis, poor prognosis, and drug resistance.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('overexpression', 'PosReg', (57, 71))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('SOX2', 'Gene', (35, 39))	('associated with', 'Reg', (114, 129))	('amplification', 'Var', (40, 53))	('tumor', 'Disease', (149, 154))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('drug resistance', 'Phenotype', 'HP:0020174', (184, 199))
511988	31940393	We show by immunohistochemistry that pepsin positivity occurs in a significant proportion of human primary HPSCC specimens, and in many cases matched adjacent uninvolved epithelia are negative for pepsin.	('HPSCC', 'Disease', (107, 112))	('pepsin', 'Protein', (37, 43))	('epithelia', 'Disease', (170, 179))	('HPSCC', 'Disease', 'MESH:D002294', (107, 112))	('human', 'Species', '9606', (93, 98))	('men', 'Species', '9606', (118, 121))	('positivity', 'Var', (44, 54))	('epithelia', 'Disease', 'None', (170, 179))
511989	31940393	Pepsin positivity is associated with nodal involvement, suggesting that pepsin may have a role in metastasis.	('positivity', 'Var', (7, 17))	('Pepsin', 'Protein', (0, 6))	('nodal', 'Gene', (37, 42))	('associated', 'Reg', (21, 31))	('nodal', 'Gene', '4838', (37, 42))	('men', 'Species', '9606', (50, 53))
511997	31940393	In vitro studies have shown that pepsin can induce a dose- and time-dependent increase in proliferation of hypopharyngeal cells in parallel with changes in expression of microRNA and genes known to be involved in tumorigenesis.	('tumor', 'Disease', (213, 218))	('expression', 'MPA', (156, 166))	('proliferation', 'CPA', (90, 103))	('increase', 'PosReg', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('microRNA', 'Protein', (170, 178))	('changes', 'Reg', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('pepsin', 'Var', (33, 39))
512065	31940393	Treating cells with pepsin for 1 hour resulted in a significant decrease in percentage of cells in the G1 phase (P < 0.05), but there was no significant difference in percentage of cells in the S or G2/M phase when compared to controls (Fig 3) To investigate a potential involvement of the endosomes in pepsin reactivation, pepsin-treated FaDu cells were stained with Lysotracker red to track acidic organelles.	('pepsin', 'Var', (20, 26))	('cells in the G1 phase', 'CPA', (90, 111))	('men', 'Species', '9606', (278, 281))	('decrease', 'NegReg', (64, 72))
512082	31940393	Our in vitro studies showed that treatment with pepsin at concentrations of 0.2mg/ml and 0.4mg/ml for 30 min induced proliferation of the FaDu hypopharyngeal cancer cells.	('men', 'Species', '9606', (38, 41))	('FaDu hypopharyngeal cancer', 'Disease', 'MESH:D007012', (138, 164))	('proliferation', 'CPA', (117, 130))	('FaDu hypopharyngeal cancer', 'Disease', (138, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('0.4mg/ml', 'Var', (89, 97))
512090	31940393	In another in vitro study performed by Sasaki el al, weakly acidic-pepsin (pH 5.0) and neutral-pepsin (pH 7.0) were found could induce mild activation of NF-kappaB with increase in TNF-alpha mRNAs in human hypopharyngeal primary cells, that is in accordance with our study, but no oncogenic transcriptional activity was detected in their study.	('NF-kappaB', 'Gene', '4790', (154, 163))	('NF-kappaB', 'Gene', (154, 163))	('TNF-alpha', 'Protein', (181, 190))	('activation', 'PosReg', (140, 150))	('increase', 'PosReg', (169, 177))	('human', 'Species', '9606', (200, 205))	('neutral-pepsin', 'Var', (87, 101))
512093	31940393	NF-kappaB has many cellular functions and targeting NF-kappaB for therapeutic applications may lead to severe side effects.	('NF-kappaB', 'Gene', '4790', (0, 9))	('lead', 'Reg', (95, 99))	('NF-kappaB', 'Gene', (0, 9))	('NF-kappaB', 'Gene', '4790', (52, 61))	('NF-kappaB', 'Gene', (52, 61))	('targeting', 'Var', (42, 51))
512094	31940393	Targeting of TRAIL on the other hand can selectively induce apoptosis in cancer cells without affecting normal cells, indicating that TRAIL may be suitable target for anti-cancer therapy.	('cancer', 'Disease', (73, 79))	('TRAIL', 'Gene', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('TRAIL', 'Gene', '8743', (134, 139))	('TRAIL', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('apoptosis', 'CPA', (60, 69))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('induce', 'Reg', (53, 59))	('cancer', 'Disease', (172, 178))	('TRAIL', 'Gene', '8743', (13, 18))	('Targeting', 'Var', (0, 9))
512105	31940393	Mutations studies in HNSCCs have identified loss-of-function mutations in the NOTCH signaling pathway, consistent with the observation that inactivation of canonical Notch signaling drives head and neck carcinogenesis in mouse models of keratinizing HNSCC.	('inactivation', 'Var', (140, 152))	('neck carcinogenesis', 'Disease', 'MESH:D063646', (198, 217))	('HNSCCs', 'Disease', 'MESH:C535575', (21, 27))	('NOTCH signaling pathway', 'Pathway', (78, 101))	('mouse', 'Species', '10090', (221, 226))	('mutations', 'Var', (61, 70))	('neck carcinogenesis', 'Disease', (198, 217))	('loss-of-function', 'NegReg', (44, 60))	('HNSCCs', 'Disease', (21, 27))
512108	31940393	Results presented in this study suggest that pepsin reflux induces a dose-dependent increase in proliferation of hypopharyngeal cancer cells, and this effect is mediated by the enzymatic activity of pepsin.	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (113, 134))	('pepsin', 'MPA', (45, 51))	('reflux', 'Var', (52, 58))	('proliferation', 'CPA', (96, 109))	('increase', 'PosReg', (84, 92))	('hypopharyngeal cancer', 'Disease', (113, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
512119	30365308	Octahedral, low-spin 5d6 PtIV complexes are usually considered to be prodrugs because they are kinetically more inert than their PtII counterparts under biological conditions.- Photoactivatable PtIV prodrugs can exhibit high dark stability and potential photocytotoxicity;- examples include diazidoplatinum(IV) complexes containing various nonleaving amines and axial substituents.- Among them, trans,trans,trans-[Pt(N3)2(OH)2(py)2] (FM-190) is highly potent, has good aqueous solubility, is relatively stable in cell culture media and toward reactions with abundant intracellular tripeptide glutathione (GSH; gamma-l-Glu-l-Cys-Gly), and can be activated by UVA, blue (420 nm) and green (500 +- 30 nm) light, achieving low micromolar IC50 values even in cisplatin-resistant cell lines, with a high phototoxicity index.	('PtII', 'Chemical', '-', (129, 133))	('trans', 'Var', (395, 400))	('diazidoplatinum', 'Chemical', '-', (291, 306))	('IC50 values', 'MPA', (734, 745))
512120	30365308	Not only does the Pt center become reactive upon photoreduction, but, in addition, azidyl radicals can be released by FM-190 in a manner controllable by the amino acid l-Trp.	('azidyl radicals', 'MPA', (83, 98))	('released', 'MPA', (106, 114))	('FM-190', 'Var', (118, 124))	('azidyl radicals', 'Chemical', '-', (83, 98))	('l-Trp', 'Chemical', '-', (168, 173))
512153	30365308	A number of human cell lines, parental (A2780) and cisplatin-resistant (A2780cis) ovarian carcinoma, esophageal adenocarcinoma (OE19), and normal fibroblast cells (MRC5), were obtained from the European Collection of Animal Cell Culture, Salisbury, U.K. All cell lines used in this work were grown in Roswell Park Memorial Institute media (RPMI-1640), which was supplemented with 10% (v/v) of fetal calf serum, 1% (v/v) of 2 mM glutamine, and 1% (v/v) penicillin/streptomycin.	('A2780cis', 'Var', (72, 80))	('esophageal adenocarcinoma', 'Disease', (101, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (101, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (101, 126))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (82, 99))	('RPMI-1640', 'Chemical', '-', (340, 349))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (82, 99))	('ovarian carcinoma', 'Disease', (82, 99))	('calf', 'Species', '9913', (399, 403))
512176	30365308	The axial bond angles between PtIV and trans donor atoms are <180 , and the Pt-O bond [hydroxide, 1.9857(18) A] is slightly shorter than the Pt-O bond [succinate, 2.0185(18) A], which can be attributed to the steric hindrance caused by the relatively bulky carboxylate groups.	('1.9857', 'Var', (98, 104))	('shorter', 'NegReg', (124, 131))	('axial', 'MPA', (4, 9))	('hydroxide', 'Chemical', 'MESH:C031356', (87, 96))	('donor', 'Species', '9606', (45, 50))
512181	30365308	Upon irradiation with blue light (465 nm, 4.8 mW/cm2, 1 h), complexes 1-4 exhibited photocytotoxicity toward several human cancer cell lines, including A2780 and A2780cis ovarian and OE19 esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('OE19 esophageal cancer', 'Disease', (183, 205))	('photocytotoxicity', 'MPA', (84, 101))	('A2780', 'Var', (152, 157))	('OE19 esophageal cancer', 'Disease', 'MESH:D004938', (183, 205))	('A2780cis ovarian and OE19 esophageal cancer', 'Disease', 'MESH:D010051', (162, 205))
512186	30365308	Plasmid pUC19 linearized by EcoRI (50 mug mL-1) and the Pt complex were irradiated with blue light for 1 h and subsequently incubated in the dark for an additional 23 h in NaClO4 (10 mM) at 310 K. The plasmid was modified to the extent corresponding to the rb values of 0.003 and 0.0006 (in the case of FM-190) or 0.00015 and 0.0003 (in the case of 1 and 4) and analyzed by agarose gel electrophoresis under denaturing conditions (Figure 5C).	('mL-1', 'Gene', (42, 46))	('Plasmid pUC19', 'Species', '31851', (0, 13))	('0.00015', 'Var', (314, 321))	('mL-1', 'Gene', '23961', (42, 46))	('0.0003', 'Var', (326, 332))	('0.0006', 'Var', (280, 286))	('0.003', 'Var', (270, 275))
512198	30212533	Ex vivo drug sensitivity testing may present a viable option for the treatment stratification of esophageal cancer patients and holds the potential to greatly improve patient outcome while reducing treatment toxicity.	('patients', 'Species', '9606', (115, 123))	('drug sensitivity', 'Phenotype', 'HP:0020174', (8, 24))	('patient', 'Species', '9606', (167, 174))	('reducing', 'NegReg', (189, 197))	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('improve', 'PosReg', (159, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('patient', 'Species', '9606', (115, 122))	('toxicity', 'Disease', 'MESH:D064420', (208, 216))	('toxicity', 'Disease', (208, 216))	('drug sensitivity testing', 'Var', (8, 32))
512201	30212533	A number of recent high-throughput investigations revealed histological, genetic and epigenetic changes typical for esophageal adenocarcinoma.	('epigenetic changes', 'Var', (85, 103))	('esophageal adenocarcinoma', 'Disease', (116, 141))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (116, 141))	('genetic', 'Var', (73, 80))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (116, 141))
512242	30212533	In addition to HDAC inhibitors, Flo-1 and EAC47 display sensitivity towards the BET-inhibitors JQ1 and CPI203 (S3 Table).	('Flo-1', 'Chemical', '-', (32, 37))	('CPI203', 'Var', (103, 109))	('sensitivity', 'MPA', (56, 67))
512257	30212533	The impact of epigenetic modifications has recently come into the focus of the esophageal adenocarcinoma community and studies have shown numerous changes in epigenetic marks in patient samples.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('patient', 'Species', '9606', (178, 185))	('changes', 'Reg', (147, 154))	('epigenetic modifications', 'Var', (14, 38))	('esophageal adenocarcinoma', 'Disease', (79, 104))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))
512259	30212533	This suggests that compounds targeting epigenetic modifiers in esophageal adenocarcinoma should be added to the screening library and may present a promising therapeutic option of sensitive patients.	('patients', 'Species', '9606', (190, 198))	('epigenetic modifiers', 'Var', (39, 59))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (63, 88))	('esophageal adenocarcinoma', 'Disease', (63, 88))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (63, 88))
512281	29605977	Even though it is usually a benign disease, GERD can nevertheless lead to complications such as peptic esophagitis and Barrett's esophagus, also known as Barrett's esophagus (BE).	('peptic esophagitis', 'Disease', 'MESH:D004942', (96, 114))	("Barrett's esophagus", 'Disease', (119, 138))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (119, 138))	('BE', 'Phenotype', 'HP:0100580', (175, 177))	("Barrett's esophagus", 'Disease', (154, 173))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (154, 173))	('GERD', 'Var', (44, 48))	('esophagitis', 'Phenotype', 'HP:0100633', (103, 114))	('benign disease', 'Disease', (28, 42))	('lead to', 'Reg', (66, 73))	('benign disease', 'Disease', 'MESH:D009369', (28, 42))	('peptic esophagitis', 'Disease', (96, 114))
512308	29605977	Fragmented peristalsis: peristaltic waves not transmitted in >= 50% of swallows with a large break (DCI > 450 and axial breaks of over 5 cm in the 30 mmHg isobaric contour).	('DCI', 'Chemical', '-', (100, 103))	('axial breaks', 'CPA', (114, 126))	('DCI > 450', 'Var', (100, 109))
512324	29605977	The number of EMD was significantly higher in the GERD + BE group than in the GERD without BE group: respectively 45 (45.9%) vs 15 (14.9%), P < 0.001.	('higher', 'PosReg', (36, 42))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('BE', 'Phenotype', 'HP:0100580', (91, 93))	('GERD + BE', 'Var', (50, 59))	('EMD', 'Disease', (14, 17))	('EMD', 'Disease', 'None', (14, 17))
512343	29605977	The main result of our study is to have demonstrate a significant, independent link between the presence of EMD and BE.	('presence', 'Var', (96, 104))	('BE', 'Phenotype', 'HP:0100580', (116, 118))	('EMD', 'Disease', (108, 111))	('EMD', 'Disease', 'None', (108, 111))
512350	29605977	It has been found that an aggravation of esophageal mucosal lesions with GERD is concomitant with an increase in EMD prevalence (mainly IMS) and a decrease in esophageal clearance.	('esophageal clearance', 'CPA', (159, 179))	('decrease', 'NegReg', (147, 155))	('increase', 'PosReg', (101, 109))	('EMD', 'Disease', (113, 116))	('esophageal mucosal lesions', 'Disease', 'MESH:D009059', (41, 67))	('esophageal mucosal lesions', 'Disease', (41, 67))	('EMD', 'Disease', 'None', (113, 116))	('GERD', 'Var', (73, 77))	('aggravation', 'PosReg', (26, 37))
512451	19578652	Despite the high EUS sensitivity and specificity in T staging of esophageal neoplasias, the presence of tumoral obstruction in the esophageal lumen can prevent the progression of the echoendoscope in up to 30% of the cases, making the performance of the procedure impossible.	('tumoral obstruction', 'Disease', (104, 123))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('esophageal neoplasias', 'Disease', 'MESH:D009369', (65, 86))	('esophageal neoplasias', 'Phenotype', 'HP:0100751', (65, 86))	('neoplasia', 'Phenotype', 'HP:0002664', (76, 85))	('esophageal neoplasias', 'Disease', (65, 86))	('progression', 'MPA', (164, 175))	('neoplasias', 'Phenotype', 'HP:0002664', (76, 86))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (65, 85))	('presence', 'Var', (92, 100))	('prevent', 'NegReg', (152, 159))	('tumoral obstruction', 'Disease', 'MESH:D009369', (104, 123))
512524	32856879	Nowadays, amino acids are one of the most suitable candidates for concentrated metabolomic studies and play important physiological roles in the body (Miyagi et al., 2011) and recent studies have also shown that restrictions on some amino acids play a role in cancer interventions (Kang, 2020).	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (260, 266))	('restrictions', 'Var', (212, 224))	('role', 'Reg', (252, 256))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
512535	32856879	Analysis of the amino acids with normal distribution was dane by t-test (SER, GLN, GLY, ALA, TRP, MET, VAL, ILE).	('GLY', 'Chemical', 'MESH:D005998', (83, 86))	('TRP', 'Chemical', 'MESH:D014364', (93, 96))	('GLN', 'Var', (78, 81))	('MET', 'Gene', (98, 101))	('ILE', 'Chemical', 'MESH:D007532', (108, 111))	('GLY', 'MPA', (83, 86))	('SER', 'Chemical', 'MESH:D012694', (73, 76))	('GLN', 'Chemical', 'MESH:D005973', (78, 81))	('MET', 'Gene', '79811', (98, 101))	('ALA', 'Chemical', 'MESH:D000409', (88, 91))	('VAL', 'Chemical', 'MESH:D014633', (103, 106))
512635	31853280	Hyperproliferation and tissue embedding stimulated by SEPSs were less common than those stimulated by SEMSs.	('tissue embedding', 'CPA', (23, 39))	('SEPSs', 'Var', (54, 59))	('Hyperproliferation', 'Disease', (0, 18))	('rat', 'Species', '10116', (12, 15))
512771	30649642	SMARCB1 deficiency is used to define malignant rhabdoid tumors (MRTs) and some carcinomas with rhabdoid features.	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('carcinomas', 'Disease', (79, 89))	('malignant rhabdoid tumors', 'Disease', (37, 62))	('rhabdoid', 'Disease', 'MESH:D018335', (95, 103))	('rhabdoid', 'Disease', (95, 103))	('rhabdoid', 'Disease', 'MESH:D018335', (47, 55))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (37, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('rhabdoid', 'Disease', (47, 55))	('SMARCB1', 'Gene', '6598', (0, 7))	('deficiency', 'Var', (8, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('SMARCB1', 'Gene', (0, 7))	('carcinomas', 'Disease', 'MESH:D002277', (79, 89))
512786	30649642	According to these diagnostic imaging findings, a preoperative clinical diagnosis of T3N1M0 stage III cancer was made using the Union for International Cancer Control (UICC) classification system.	('Cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Disease', (152, 158))	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('T3N1M0', 'Var', (85, 91))
512801	30649642	A postoperative pathological diagnosis of T3N1M0 stage III cancer was made according to the UICC classification system.	('T3N1M0', 'Var', (42, 48))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
512820	30649642	Most MRTs are characterized by the loss of SMARCB1; however, carcinomas with rhabdoid features do not always involve the loss of SMARCB1.	('MRTs', 'Disease', (5, 9))	('loss', 'NegReg', (35, 39))	('SMARCB1', 'Gene', '6598', (129, 136))	('rhabdoid', 'Disease', 'MESH:D018335', (77, 85))	('loss', 'Var', (121, 125))	('SMARCB1', 'Gene', (129, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('SMARCB1', 'Gene', '6598', (43, 50))	('rhabdoid', 'Disease', (77, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('carcinomas', 'Disease', 'MESH:D002277', (61, 71))	('SMARCB1', 'Gene', (43, 50))	('carcinomas', 'Disease', (61, 71))
512888	21705972	At Week 9, one animal in the control group was assessed as OSCC based on obvious cell heteromorphism, epitheliosis intruding the connective tissues in blocks or streaks, and part of the epithelium exhibiting obvious horny pearls, increased mitotic figures, and polymorphism of cells and nuclei.	('polymorphism', 'Var', (261, 273))	('epitheliosis', 'Disease', (102, 114))	('cell heteromorphism', 'CPA', (81, 100))	('increased', 'PosReg', (230, 239))	('epitheliosis', 'Disease', 'None', (102, 114))	('mitotic figures', 'CPA', (240, 255))
513063	28421162	Details and timing of these modifications are reported, providing other groups with potentially helpful information for the use of the innovation at other tumor sites.	('modifications', 'Var', (28, 41))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))
513104	28204832	In addition, Jesridonin significantly inhibited the proliferation of EC109/Taxol cells, induced apoptosis and arrested the cell cycle at the G2/M phase.	('proliferation', 'CPA', (52, 65))	('induced', 'Reg', (88, 95))	('cell cycle at the G2/M phase', 'CPA', (123, 151))	('Taxol', 'Chemical', 'MESH:D017239', (75, 80))	('inhibited', 'NegReg', (38, 47))	('apoptosis', 'CPA', (96, 105))	('arrested', 'NegReg', (110, 118))	('Jesridonin', 'Chemical', 'MESH:C000606573', (13, 23))	('Jesridonin', 'Var', (13, 23))
513105	28204832	Furthermore, western blot analysis revealed that Jesridonin upregulated the expression of p53, p53 upregulated modulator of apoptosis (PUMA), cleaved-caspase-9 and cleaved-caspase-3 in EC109/Taxol cells, and downregulated the expression of procaspase-3, procaspase-9 and Bcl-2 in the EC109/Taxol cells in a concentration-dependent manner.	('p53', 'Gene', (90, 93))	('Bcl-2', 'Gene', '596', (271, 276))	('Jesridonin', 'Var', (49, 59))	('expression', 'MPA', (226, 236))	('caspase-9', 'Gene', (150, 159))	('PUMA', 'Gene', '27113', (135, 139))	('p53', 'Gene', '7157', (95, 98))	('downregulated', 'NegReg', (208, 221))	('upregulated', 'PosReg', (99, 110))	('upregulated', 'PosReg', (60, 71))	('Taxol', 'Chemical', 'MESH:D017239', (290, 295))	('caspase-9', 'Gene', '842', (257, 266))	('p53', 'Gene', (95, 98))	('caspase-3', 'Gene', '836', (243, 252))	('caspase-3', 'Gene', '836', (172, 181))	('PUMA', 'Gene', (135, 139))	('caspase-3', 'Gene', (243, 252))	('caspase-3', 'Gene', (172, 181))	('caspase-9', 'Gene', (257, 266))	('Bcl-2', 'Gene', (271, 276))	('Taxol', 'Chemical', 'MESH:D017239', (191, 196))	('Jesridonin', 'Chemical', 'MESH:C000606573', (49, 59))	('caspase-9', 'Gene', '842', (150, 159))	('p53', 'Gene', '7157', (90, 93))	('procaspase-3, procaspase-9', 'Gene', '836', (240, 266))	('expression', 'MPA', (76, 86))
513127	28204832	The rabbit monoclonal antibodies against p53 (sc-393031), caspase-9 (sc-8355) and caspase-3 (sc-65497) are the products of Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA).	('p53', 'Gene', '7157', (41, 44))	('sc-393031', 'Var', (46, 55))	('caspase-9', 'Gene', '842', (58, 67))	('caspase-3', 'Gene', (82, 91))	('caspase-3', 'Gene', '836', (82, 91))	('rabbit', 'Species', '9986', (4, 10))	('caspase-9', 'Gene', (58, 67))	('p53', 'Gene', (41, 44))	('sc-8355', 'Var', (69, 76))
513130	28204832	Primary antibody against cleaved caspase-3 (#9661) and cleaved caspase-9 (#9501) was purchased from Cell Signaling Technology (Danvers, MA, USA).	('caspase-3', 'Gene', (33, 42))	('#9501', 'Var', (74, 79))	('caspase-9', 'Gene', '842', (63, 72))	('caspase-3', 'Gene', '836', (33, 42))	('#9661', 'Var', (44, 49))	('caspase-9', 'Gene', (63, 72))
513231	28204832	The dysregulation of the Bcl-2 family has been shown to induce the destruction of the mitochondrial membrane, which is accompanied by the release of intramembranous proteins into the cytosol, such as cytochrome c and other apoptosis-inducing factors, and to subsequently induce the activation of the caspase cascade by activating caspase-9 and caspase-3.	('activating', 'PosReg', (319, 329))	('caspase-3', 'Gene', (344, 353))	('Bcl-2', 'Gene', '596', (25, 30))	('caspase', 'Gene', '841;842', (330, 337))	('dysregulation', 'Var', (4, 17))	('destruction', 'MPA', (67, 78))	('caspase-9', 'Gene', '842', (330, 339))	('mitochondrial membrane', 'MPA', (86, 108))	('cytochrome c', 'Gene', '54205', (200, 212))	('caspase', 'Gene', (344, 351))	('induce', 'Reg', (271, 277))	('caspase', 'Gene', '841;842', (344, 351))	('caspase-9', 'Gene', (330, 339))	('cytochrome c', 'Gene', (200, 212))	('caspase', 'Gene', (300, 307))	('Bcl-2', 'Gene', (25, 30))	('caspase', 'Gene', '841;842', (300, 307))	('caspase-3', 'Gene', '836', (344, 353))	('caspase', 'Gene', (330, 337))
513237	28204832	Therefore, the dysregulation of the Bcl-2 and caspase families and of p53, as well as their respective signaling pathways, has been considered the most important mechanism in the development of apoptotic deficiency and the phenotype of MDR in cancer cells.	('caspase', 'Gene', (46, 53))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('Bcl-2', 'Gene', (36, 41))	('Bcl-2', 'Gene', '596', (36, 41))	('caspase', 'Gene', '841;842', (46, 53))	('MDR', 'Disease', (236, 239))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('dysregulation', 'Var', (15, 28))
513250	26647768	The expression levels of p-ATK, p-PI3K and beta-catenin were markedly decreased.	('expression levels', 'MPA', (4, 21))	('p-PI3K', 'Var', (32, 38))	('decreased', 'NegReg', (70, 79))	('p-ATK', 'Protein', (25, 30))	('beta-catenin', 'Gene', (43, 55))	('beta-catenin', 'Gene', '1499', (43, 55))
513298	26647768	3A-F, the expression levels of p-PI3K, p-AKT and beta-catenin were suppressed significantly in the HB-treated ECA-109 cells, in a dose-dependent manner, compared with the control group.	('beta-catenin', 'Gene', (49, 61))	('expression levels', 'MPA', (10, 27))	('beta-catenin', 'Gene', '1499', (49, 61))	('AKT', 'Gene', '207', (41, 44))	('p-PI3K', 'Var', (31, 37))	('suppressed', 'NegReg', (67, 77))	('AKT', 'Gene', (41, 44))
513310	26647768	The present study further investigated the effects of HB on the adhesion and invasion of ECA-109 cells treated with PI3K activating peptide (740Y-P).	('invasion', 'CPA', (77, 85))	('740Y-P', 'Chemical', '-', (141, 147))	('adhesion', 'CPA', (64, 72))	('740Y-P', 'Var', (141, 147))	('investigated', 'Reg', (26, 38))
513311	26647768	Treatment with 740Y-P for 3 h markedly increased cell adhesion and invasion (Fig.	('740Y-P', 'Chemical', '-', (15, 21))	('invasion', 'CPA', (67, 75))	('cell adhesion', 'CPA', (49, 62))	('740Y-P', 'Var', (15, 21))	('increased', 'PosReg', (39, 48))
513312	26647768	In addition, following pretreatment with 740Y-P for 3 h, cell adhesion and invasion decreased significantly with HB+740Y-P by 29.26+-2.30% and 62.50+-7.09%, respectively (Fig.	('740Y-P', 'Chemical', '-', (116, 122))	('invasion', 'CPA', (75, 83))	('HB+740Y-P', 'Var', (113, 122))	('740Y-P', 'Chemical', '-', (41, 47))	('cell adhesion', 'CPA', (57, 70))	('decreased', 'NegReg', (84, 93))
513317	26647768	These results suggested that HB adjusted the abnormal levels of protein expression, which caused by 740Y-P. Esophageal carcinoma, characterized by a low cure rate is considered a serious disease and a significant threat to human health.	('Esophageal carcinoma', 'Disease', (108, 128))	('human', 'Species', '9606', (223, 228))	('740Y-P.', 'Var', (100, 107))	('levels of protein expression', 'MPA', (54, 82))	('caused', 'Reg', (90, 96))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (108, 128))	('740Y-P', 'Chemical', '-', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (108, 128))
513340	26647768	The results demonstrated that HB effectively suppressed the expression levels of MMP-2 and MMP-9, including the abnormal level of expression induced by 740Y-P. Downregulation of the expression levels of MMP-2 and MMP-9 are mediated by multiple signaling cascades, particularly by the PI3K/AKT pathway.	('AKT', 'Gene', '207', (289, 292))	('expression', 'MPA', (130, 140))	('MMP-9', 'Gene', (213, 218))	('expression', 'MPA', (182, 192))	('MMP-2', 'Gene', (203, 208))	('740Y-P', 'Chemical', '-', (152, 158))	('AKT', 'Gene', (289, 292))	('MMP-2', 'Gene', '4313', (81, 86))	('suppressed', 'NegReg', (45, 55))	('expression levels', 'MPA', (60, 77))	('740Y-P.', 'Var', (152, 159))	('MMP-9', 'Gene', '4318', (91, 96))	('MMP-2', 'Gene', '4313', (203, 208))	('MMP-9', 'Gene', '4318', (213, 218))	('MMP-9', 'Gene', (91, 96))	('MMP-2', 'Gene', (81, 86))	('Downregulation', 'NegReg', (160, 174))
513567	25915159	Additionally, CHP1 and CHP2 can respectively activate and inhibit the phosphatase activity of calcineurin, which induces apoptosis by enhancing BAD heterodimerization with Bcl-xl.	('enhancing', 'PosReg', (134, 143))	('induces', 'Reg', (113, 120))	('heterodimerization', 'MPA', (148, 166))	('CHP1', 'Var', (14, 18))	('CHP1', 'Species', '10857', (14, 18))	('calcineurin', 'Protein', (94, 105))	('activate', 'PosReg', (45, 53))	('phosphatase activity', 'MPA', (70, 90))	('CHP2', 'Var', (23, 27))	('CHP2', 'Species', '105154', (23, 27))	('inhibit', 'NegReg', (58, 65))	('apoptosis', 'CPA', (121, 130))
513570	25915159	The results showed that the IC50 doses of both drugs were significantly higher in the NHE9-overexpressing cells than in the corresponding controls; inversely, NHE9 knockdown obviously reduced the IC50 dose of both cisplatin and vinorelbine (Figure 2A).	('NHE9', 'Gene', (159, 163))	('vinorelbine', 'Chemical', 'MESH:D000077235', (228, 239))	('reduced', 'NegReg', (184, 191))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('knockdown', 'Var', (164, 173))	('IC50 dose', 'MPA', (196, 205))
513575	25915159	Unfortunately, no apparent differences were observed in the cell growth curves (Figure S2A), and the tumor volume was similar between Eca109/NHE and Eca109/Con grafts (Figure S2B).	('NHE', 'Gene', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Eca109/Con', 'Var', (149, 159))	('NHE', 'Gene', '285335', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
513577	25915159	Obviously, Eca109/NHE9 and KYSE30/NHE9 cells exhibited significantly lower rates of apoptosis after anti-cancer drug or X-ray treatments compared with the controls, whereas NHE9 knockdown cell lines displayed a higher apoptosis rate (Figure 3A-3C).	('KYSE30/NHE9', 'Var', (27, 38))	('apoptosis', 'CPA', (84, 93))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('lower', 'NegReg', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
513588	25915159	The western blot results showed that higher levels of phosphorylated Src (Tyr 416) and higher levels of phosphorylated Akt (Ser473) were detected in NHE9-overexpressing cells, whereas lower levels of phosphorylated Src and Akt were observed in NHE9 knockdown cells (Figure 5C).	('Akt', 'Gene', (223, 226))	('NHE9-overexpressing', 'Var', (149, 168))	('Ser473', 'Chemical', '-', (124, 130))	('higher', 'PosReg', (37, 43))	('Akt', 'Gene', '207', (119, 122))	('Tyr', 'Chemical', 'MESH:D014443', (74, 77))	('Akt', 'Gene', (119, 122))	('Akt', 'Gene', '207', (223, 226))	('higher', 'PosReg', (87, 93))
513593	25915159	Phosphorylated Akt was also suggested to be capable of upregulating Bcl-2, a potent anti-apoptotic molecule.	('Phosphorylated', 'Var', (0, 14))	('Akt', 'Gene', '207', (15, 18))	('upregulating', 'PosReg', (55, 67))	('Akt', 'Gene', (15, 18))	('Bcl-2', 'Gene', (68, 73))
513594	25915159	Collectively, our data indicate that NHE9 might induce CRT resistance by upregulating Src/Akt/beta-catenin pathway and Bcl-2 protein expression.	('Akt', 'Gene', (90, 93))	('induce', 'PosReg', (48, 54))	('beta-catenin', 'Gene', (94, 106))	('NHE9', 'Var', (37, 41))	('beta-catenin', 'Gene', '1499', (94, 106))	('CRT resistance', 'Disease', (55, 69))	('upregulating', 'PosReg', (73, 85))	('Akt', 'Gene', '207', (90, 93))	('Bcl-2 protein', 'Protein', (119, 132))
513619	25915159	Although the mechanism underlying the involvement of NHE9 in tumors was unclear, previous studies established an important role for RACK1 in cancer cell apoptosis, which led us to investigate the possibility that NHE9 induced CRT resistance by affecting the RACK1-associated apoptosis pathway.	('NHE9', 'Var', (213, 217))	('CRT resistance', 'MPA', (226, 240))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('induced', 'Reg', (218, 225))	('RACK1', 'Gene', '10399', (258, 263))	('RACK1', 'Gene', (132, 137))	('affecting', 'Reg', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('RACK1', 'Gene', (258, 263))	('cancer', 'Disease', (141, 147))	('RACK1', 'Gene', '10399', (132, 137))
513626	25915159	Phosphorylation of Tyr416 in the kinase domain upregulates enzyme activity and subsequently triggers a series of downstream kinase activation events, such as activation of Akt.	('Phosphorylation', 'Var', (0, 15))	('activity', 'MPA', (66, 74))	('triggers', 'Reg', (92, 100))	('Akt', 'Gene', '207', (172, 175))	('upregulates', 'PosReg', (47, 58))	('Tyr416', 'Chemical', '-', (19, 25))	('enzyme', 'Enzyme', (59, 65))	('Tyr416', 'Var', (19, 25))	('Akt', 'Gene', (172, 175))
513628	25915159	Akt is activated by phosphorylation at Ser473 within its carboxy terminus, and it plays a role in cell survival by activating GSK-3beta and downstream beta-catenin.	('beta-catenin', 'Gene', '1499', (151, 163))	('GSK-3beta', 'Gene', '2932', (126, 135))	('Ser473', 'Chemical', '-', (39, 45))	('Akt', 'Gene', '207', (0, 3))	('activating', 'PosReg', (115, 125))	('activated', 'PosReg', (7, 16))	('phosphorylation', 'Var', (20, 35))	('Akt', 'Gene', (0, 3))	('GSK-3beta', 'Gene', (126, 135))	('beta-catenin', 'Gene', (151, 163))
513653	25915159	Primary antibodies against NHE9 (1:200 dilution, anti-Rabbit, Abcam), phosphor-Src (Tyr416, 1:50 dilution, anti-rabbit, Cell signaling), and Bcl-2 (1:200 dilution, anti-rabbit, Cell signaling) were used in this study.	('rabbit', 'Species', '9986', (169, 175))	('Rabbit', 'Species', '9986', (54, 60))	('Tyr416', 'Var', (84, 90))	('rabbit', 'Species', '9986', (112, 118))	('Tyr416', 'Chemical', '-', (84, 90))	('NHE9', 'Gene', (27, 31))
513668	25915159	Subsequently, we infected the esophageal cancer cell lines Eca109, KYSE30, KYSE180 and KYSE520 with the retrovirus in 6-well plates.	('KYSE520', 'Var', (87, 94))	('infected the esophageal cancer', 'Disease', 'MESH:D004938', (17, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('infected the esophageal cancer', 'Disease', (17, 47))
513692	25915159	106 cells in 150 ul of culture medium were subcutaneously injected into the left (Eca109/NHE) or right flank (Eca109/Con) of five-week old female nu/nu mice maintaining in standard SPF conditions.	('Eca109/Con', 'Var', (110, 120))	('NHE', 'Gene', (89, 92))	('mice', 'Species', '10090', (152, 156))	('NHE', 'Gene', '285335', (89, 92))
513941	32282711	In conclusion, high PFKFB3 protein and gene expression may be associated with the occurrence, development, and prognosis of ESCC.	('high', 'Var', (15, 19))	('PFKFB3', 'Gene', (20, 26))	('protein', 'Protein', (27, 34))	('associated', 'Reg', (62, 72))	('PFKFB3', 'Gene', '5209', (20, 26))	('ESCC', 'Disease', (124, 128))
513983	32282711	After 2 hours of blocking, the gels were incubated with PFKFB3 (1:1000) and beta-actin (1:1000) antibodies overnight at 4  C. Tris-Buffered Saline Tween (TBST) was washed 3 times, for 10 minutes each time.	('TBST', 'Chemical', '-', (154, 158))	('1:1000', 'Var', (88, 94))	('PFKFB3', 'Gene', (56, 62))	('Tris-Buffered Saline Tween', 'Chemical', '-', (126, 152))	('1:1000', 'Var', (64, 70))	('beta-actin', 'Protein', (76, 86))	('PFKFB3', 'Gene', '5209', (56, 62))
513994	32282711	The results revealed a positive rate of PFKFB3 mRNA in ESCC tissues of 86.67% (104/120), which was significantly higher than that in adjacent tissues, of 49.17% (59/120; P < .05; Fig.	('PFKFB3', 'Gene', (40, 46))	('PFKFB3', 'Gene', '5209', (40, 46))	('mRNA', 'Var', (47, 51))	('higher', 'PosReg', (113, 119))
514018	32282711	The pharmacological inhibition of PFKFB3 via PFK15 was found to suppress tumor growth and alleviate metastasis in HNSCC.	('alleviate', 'PosReg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PFKFB3', 'Gene', (34, 40))	('inhibition', 'Var', (20, 30))	('HNSCC', 'Disease', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('suppress', 'NegReg', (64, 72))	('PFK15', 'Gene', (45, 50))	('PFKFB3', 'Gene', '5209', (34, 40))	('tumor', 'Disease', (73, 78))	('HNSCC', 'Disease', 'MESH:D000077195', (114, 119))	('metastasis', 'CPA', (100, 110))
514022	32282711	Furthermore, PRKD and PFKFB3 inhibitor suppressed the viability of GC cells.	('PFKFB3', 'Gene', '5209', (22, 28))	('GC', 'Phenotype', 'HP:0012126', (67, 69))	('inhibitor', 'Var', (29, 38))	('suppressed', 'NegReg', (39, 49))	('PFKFB3', 'Gene', (22, 28))	('viability of GC cells', 'CPA', (54, 75))
514025	32282711	A high expression of PFKFB3 protein was an independent prognostic marker in lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('lung adenocarcinoma', 'Disease', (76, 95))	('PFKFB3', 'Gene', (21, 27))	('high', 'Var', (2, 6))	('protein', 'Protein', (28, 35))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (76, 95))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))	('PFKFB3', 'Gene', '5209', (21, 27))
514039	32282711	The median survival time for patients with high levels of PFKFB3 expression was significantly shorter than patients with lower levels of PFKFB3 expression in ESCC.	('patients', 'Species', '9606', (29, 37))	('PFKFB3', 'Gene', (137, 143))	('high', 'Var', (43, 47))	('PFKFB3', 'Gene', (58, 64))	('survival time', 'CPA', (11, 24))	('shorter', 'NegReg', (94, 101))	('PFKFB3', 'Gene', '5209', (137, 143))	('PFKFB3', 'Gene', '5209', (58, 64))	('patients', 'Species', '9606', (107, 115))
514050	31467173	Association of the vitamin D metabolism gene GC and CYP27B1 polymorphisms with cancer susceptibility: a meta-analysis and trial sequential analysis Nowadays, vitamin D is known to have functions beyond bone formation, including inhibiting angiogenesis and promoting tumor apoptosis.	('polymorphisms', 'Var', (60, 73))	('CYP27B1', 'Gene', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('angiogenesis', 'CPA', (239, 251))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('CYP27B1', 'Gene', '1594', (52, 59))	('vitamin D', 'Chemical', 'MESH:D014807', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('vitamin D', 'Chemical', 'MESH:D014807', (158, 167))	('promoting', 'PosReg', (256, 265))	('Association', 'Interaction', (0, 11))	('tumor', 'Disease', (266, 271))	('cancer', 'Disease', (79, 85))	('inhibiting', 'NegReg', (228, 238))
514053	31467173	We strictly searched EMBASE, PubMed, Web of Science, WanFang and CNKI electronic databases for relevant studies exploring the associations of GC (rs4588 and rs7041) and CYP27B1 (rs4646537, rs3782130) polymorphisms with cancer risks according to search strategy.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('CYP27B1', 'Gene', (169, 176))	('rs3782130', 'Var', (189, 198))	('rs3782130', 'Mutation', 'rs3782130', (189, 198))	('rs4646537', 'Mutation', 'rs4646537', (178, 187))	('rs7041', 'Mutation', 'rs7041', (157, 163))	('CYP27B1', 'Gene', '1594', (169, 176))	('rs4588', 'Mutation', 'rs4588', (146, 152))	('rs4588', 'Var', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))	('rs4646537', 'Var', (178, 187))	('associations', 'Interaction', (126, 138))	('rs7041', 'Var', (157, 163))
514054	31467173	Our analyses suggested that rs4588 and rs7041 polymorphisms were significantly associated with overall cancer risk.	('rs7041', 'Mutation', 'rs7041', (39, 45))	('rs4588', 'Mutation', 'rs4588', (28, 34))	('associated', 'Reg', (79, 89))	('rs4588', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rs7041', 'Var', (39, 45))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
514055	31467173	Stratification analyses of ethnicity indicated that rs4588 polymorphism significantly increased cancer risk in Caucasians and Asians, while rs7041 polymorphism significantly increased cancer risk in Asians.	('cancer', 'Disease', (184, 190))	('rs4588 polymorphism', 'Var', (52, 71))	('polymorphism', 'Var', (59, 71))	('increased', 'PosReg', (86, 95))	('rs4588', 'Mutation', 'rs4588', (52, 58))	('rs7041', 'Mutation', 'rs7041', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('rs7041', 'Var', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (96, 102))
514056	31467173	When studies were stratified by cancer type, our results indicated that rs4588 significantly increased the risk of breast cancer and digestive system tumor, but not in prostate cancer and non-small cell lung cancer, while rs7041 significantly increased the risk of non-small cell lung cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', (208, 214))	('increased', 'PosReg', (93, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('rs7041', 'Var', (222, 228))	('increased', 'PosReg', (243, 252))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('digestive system tumor', 'Phenotype', 'HP:0007378', (133, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (280, 291))	('prostate cancer', 'Disease', 'MESH:D011471', (168, 183))	('non-small cell lung cancer', 'Disease', (265, 291))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (188, 214))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('system tumor', 'Disease', 'MESH:D009423', (143, 155))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('prostate cancer', 'Disease', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (285, 291))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (192, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('rs4588', 'Mutation', 'rs4588', (72, 78))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (265, 291))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (188, 214))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('breast cancer', 'Disease', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (269, 291))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('rs7041', 'Mutation', 'rs7041', (222, 228))	('cancer', 'Disease', (122, 128))	('rs4588', 'Var', (72, 78))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (265, 291))	('non-small cell lung cancer', 'Disease', (188, 214))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('system tumor', 'Disease', (143, 155))
514057	31467173	There were no associations of rs4646537 and rs3782130 with overall cancer risks.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('rs3782130', 'Mutation', 'rs3782130', (44, 53))	('cancer', 'Disease', (67, 73))	('rs4646537', 'Mutation', 'rs4646537', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs4646537', 'Var', (30, 39))	('rs3782130', 'Var', (44, 53))
514067	31467173	Numerous studies have shown that vitamin D deficiency may be the reason why thousands of patients die prematurely from colon, breast, ovarian and other cancers each year.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('colon', 'Disease', (119, 124))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (33, 53))	('vitamin D', 'Chemical', 'MESH:D014807', (33, 42))	('patients', 'Species', '9606', (89, 97))	('vitamin', 'Gene', (33, 40))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('ovarian', 'Disease', 'MESH:D010049', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ovarian', 'Disease', (134, 141))	('deficiency', 'Var', (43, 53))	('breast', 'Disease', (126, 132))
514071	31467173	Both vitamin D metabolites bind to vitamin D-binding proteins, also known as group-specific component (GC), which aid in the transport of vitamin D. Genetic polymorphisms involving the vitamin D pathway may affect its activity, so if vitamin D does play a role in carcinogenesis, it may be associated with cancer.	('vitamin D', 'Chemical', 'MESH:D014807', (185, 194))	('polymorphisms', 'Var', (157, 170))	('vitamin D', 'Chemical', 'MESH:D014807', (35, 44))	('vitamin D', 'Chemical', 'MESH:D014807', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('affect', 'Reg', (207, 213))	('vitamin D pathway', 'Pathway', (185, 202))	('vitamin D', 'Chemical', 'MESH:D014807', (5, 14))	('activity', 'MPA', (218, 226))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('associated', 'Reg', (290, 300))	('vitamin D', 'Chemical', 'MESH:D014807', (234, 243))	('cancer', 'Disease', (306, 312))
514072	31467173	Recently, genome-wide association studies (GWASs) have identified CYP27B1 and GC polymorphisms significantly associated with 25(OH)D concentrations.	('associated', 'Reg', (109, 119))	('polymorphisms', 'Var', (81, 94))	('CYP27B1', 'Gene', '1594', (66, 73))	('25(OH)D', 'Chemical', 'MESH:C101470', (125, 132))	('CYP27B1', 'Gene', (66, 73))
514074	31467173	According to the 1000 Genomes Project Phase 3 allele frequencies, the minor allele frequency (MAF) for rs4646537 is 4% in the combined population, the MAF for rs3782130 is 35% in the combined population, the MAF for rs4588 is 21% in the combined population, and the MAF for rs7041 is 38% in the combined population.	('rs4646537', 'Var', (103, 112))	('rs4588', 'Mutation', 'rs4588', (216, 222))	('rs4588', 'Var', (216, 222))	('rs7041', 'Mutation', 'rs7041', (274, 280))	('rs4646537', 'Mutation', 'rs4646537', (103, 112))	('rs3782130', 'Mutation', 'rs3782130', (159, 168))	('rs3782130', 'Var', (159, 168))
514075	31467173	Up to now, two common CYP27B1 polymorphisms (rs4646537, rs3782130) and two common GC polymorphisms (rs4588 and rs7041) were found to be associated with cancer risks, including breast cancer, non-small cell lung cancer, prostate cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer.	('associated', 'Reg', (136, 146))	('rs7041', 'Var', (111, 117))	('CYP27B1', 'Gene', '1594', (22, 29))	('rs4588', 'Mutation', 'rs4588', (100, 106))	('cancer', 'Disease', (311, 317))	('colorectal cancer', 'Phenotype', 'HP:0003003', (300, 317))	('rs4646537', 'Mutation', 'rs4646537', (45, 54))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (236, 260))	('gastric cancer', 'Phenotype', 'HP:0012126', (281, 295))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (191, 217))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('rs4588', 'Var', (100, 106))	('rs3782130', 'Mutation', 'rs3782130', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (236, 260))	('colorectal cancer', 'Disease', 'MESH:D015179', (300, 317))	('rs4646537', 'Var', (45, 54))	('cancer', 'Disease', (228, 234))	('non-small cell lung cancer', 'Disease', (191, 217))	('CYP27B1', 'Gene', (22, 29))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('rs3782130', 'Var', (56, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('gastric cancer', 'Disease', (281, 295))	('esophageal cancer', 'Disease', 'MESH:D004938', (262, 279))	('rs7041', 'Mutation', 'rs7041', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('colorectal cancer', 'Disease', (300, 317))	('prostate cancer', 'Disease', 'MESH:D011471', (219, 234))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('prostate cancer', 'Phenotype', 'HP:0012125', (219, 234))	('hepatocellular carcinoma', 'Disease', (236, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (273, 279))	('esophageal cancer', 'Disease', (262, 279))	('cancer', 'Disease', (211, 217))	('prostate cancer', 'Disease', (219, 234))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (281, 295))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (195, 217))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (191, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('breast cancer', 'Disease', (176, 189))	('cancer', 'Disease', (289, 295))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
514076	31467173	To better explore the precise relationship, we performed a meta-analysis and trial sequential analysis (TSA) to characterize the associations of GC (rs4588 and rs7041) and CYP27B1 (rs4646537, rs3782130) polymorphisms with cancer susceptibility.	('rs7041', 'Mutation', 'rs7041', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('rs3782130', 'Var', (192, 201))	('cancer', 'Disease', (222, 228))	('rs3782130', 'Mutation', 'rs3782130', (192, 201))	('rs4588', 'Var', (149, 155))	('rs4588', 'Mutation', 'rs4588', (149, 155))	('CYP27B1', 'Gene', '1594', (172, 179))	('rs4646537', 'Mutation', 'rs4646537', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('rs7041', 'Var', (160, 166))	('associations', 'Interaction', (129, 141))	('rs4646537', 'Var', (181, 190))	('CYP27B1', 'Gene', (172, 179))
514077	31467173	We strictly searched EMBASE, PubMed, Web of Science, Wan Fang and CNKI electronic databases (up to 1 December 2018) for relevant studies exploring the associations of GC (rs4588 and rs7041) and CYP27B1 (rs4646537, rs3782130) polymorphisms with cancer risks according to the search strategy (Supplementary Table S1).	('rs4588', 'Var', (171, 177))	('CYP27B1', 'Gene', '1594', (194, 201))	('rs4646537', 'Var', (203, 212))	('associations', 'Interaction', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('rs3782130', 'Mutation', 'rs3782130', (214, 223))	('rs7041', 'Mutation', 'rs7041', (182, 188))	('CYP27B1', 'Gene', (194, 201))	('rs4646537', 'Mutation', 'rs4646537', (203, 212))	('rs4588', 'Mutation', 'rs4588', (171, 177))	('rs3782130', 'Var', (214, 223))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('rs7041', 'Var', (182, 188))
514079	31467173	Enrolled studies should meet the following inclusion criteria: (A) Human-based research; (B) Case-control/cohort studies; (C) Effective data were available to compute odds ratio (OR), 95% confidence interval (CI) and P-value; (D) Involved in the associations of GC (rs4588 and rs7041) or CYP27B1 (rs4646537, rs3782130) polymorphisms (at least one polymorphism involved) with cancer risk; (E) The control group met Hardy-Weinberg equilibrium (HWE).	('rs7041', 'Mutation', 'rs7041', (277, 283))	('rs4646537', 'Mutation', 'rs4646537', (297, 306))	('CYP27B1', 'Gene', '1594', (288, 295))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('associations', 'Interaction', (246, 258))	('rs4588', 'Mutation', 'rs4588', (266, 272))	('rs7041', 'Var', (277, 283))	('rs4646537', 'Var', (297, 306))	('CYP27B1', 'Gene', (288, 295))	('rs3782130', 'Var', (308, 317))	('rs4588', 'Var', (266, 272))	('Human', 'Species', '9606', (67, 72))	('rs3782130', 'Mutation', 'rs3782130', (308, 317))	('cancer', 'Disease', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (375, 381))
514083	31467173	Associations of GC (rs4588 and rs7041) and CYP27B1 (rs4646537, rs3782130) polymorphisms with cancer risks were estimated by OR and 95% CI.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('Associations', 'Interaction', (0, 12))	('rs3782130', 'Var', (63, 72))	('rs4588', 'Var', (20, 26))	('rs4646537', 'Var', (52, 61))	('rs7041', 'Var', (31, 37))	('rs3782130', 'Mutation', 'rs3782130', (63, 72))	('CYP27B1', 'Gene', '1594', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rs7041', 'Mutation', 'rs7041', (31, 37))	('CYP27B1', 'Gene', (43, 50))	('rs4646537', 'Mutation', 'rs4646537', (52, 61))	('rs4588', 'Mutation', 'rs4588', (20, 26))
514085	31467173	After reading full-text, 21 articles were excluded, including 10 that did not describe GC (rs4588 and rs7041) or CYP27B1 (rs4646537, rs3782130) polymorphisms and cancer susceptibility, 2 that did not meet HWE, 4 case only or non-cancer subject only articles, and 5 that not provide detailed genotyping data.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rs4646537', 'Var', (122, 131))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('CYP27B1', 'Gene', '1594', (113, 120))	('rs7041', 'Mutation', 'rs7041', (102, 108))	('rs4646537', 'Mutation', 'rs4646537', (122, 131))	('CYP27B1', 'Gene', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('rs3782130', 'Var', (133, 142))	('rs4588', 'Mutation', 'rs4588', (91, 97))	('rs7041', 'Var', (102, 108))	('rs4588', 'Var', (91, 97))	('rs3782130', 'Mutation', 'rs3782130', (133, 142))
514087	31467173	Ten studies reported the effects of GC polymorphisms in breast cancer, eight reported in digestive system tumor, three in non-small cell lung cancer and two in prostate cancer.	('effects', 'Reg', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('non-small cell lung cancer', 'Disease', (122, 148))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Disease', (56, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('prostate cancer', 'Disease', 'MESH:D011471', (160, 175))	('prostate cancer', 'Phenotype', 'HP:0012125', (160, 175))	('system tumor', 'Disease', (99, 111))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (122, 148))	('polymorphisms', 'Var', (39, 52))	('prostate cancer', 'Disease', (160, 175))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (126, 148))	('digestive system tumor', 'Phenotype', 'HP:0007378', (89, 111))	('system tumor', 'Disease', 'MESH:D009423', (99, 111))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))
514088	31467173	Six studies reported the effects of CYP27B1 polymorphisms in prostate cancer, two reported in non-small cell lung cancer and one in digestive system tumor.	('effects', 'Reg', (25, 32))	('CYP27B1', 'Gene', '1594', (36, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('non-small cell lung cancer', 'Disease', (94, 120))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('system tumor', 'Disease', (142, 154))	('polymorphisms', 'Var', (44, 57))	('prostate cancer', 'Disease', (61, 76))	('CYP27B1', 'Gene', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('digestive system tumor', 'Phenotype', 'HP:0007378', (132, 154))	('system tumor', 'Disease', 'MESH:D009423', (142, 154))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (94, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))
514090	31467173	As shown in Table 2, we found that rs7041 polymorphism significantly increased cancer risk in four models: dominant (OR = 1.22, 95% CI = 1.03-1.44, P=0.019), recessive (OR = 1.27, 95% CI = 1.02-1.58, P=0.030), homozygote (OR = 1.41, 95% CI = 1.06-1.88, P=0.017, Figure 2A), and allele (OR = 1.17, 95% CI = 1.02-1.33, P=0.022) models.	('increased', 'PosReg', (69, 78))	('rs7041', 'Var', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('rs7041', 'Mutation', 'rs7041', (35, 41))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
514091	31467173	Stratification analyses of cancer type indicated that rs7041 polymorphism increased the risk of non-small cell lung cancer (recessive, OR = 1.73, 95% CI = 1.05-2.84, P=0.031, Figure 2B; homozygote, OR = 1.97, 95% CI = 1.38-2.81, P=0.000; allele, OR = 1.32, 95% CI = 1.09-1.60, P=0.004).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('rs7041', 'Mutation', 'rs7041', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (96, 122))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('rs7041', 'Var', (54, 60))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (96, 122))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('non-small cell lung cancer', 'Disease', (96, 122))
514092	31467173	Moreover, our data indicated that rs7041 polymorphism was also significantly associated with an increased risk of cancer in the studies with publication-based controls.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('rs7041', 'Mutation', 'rs7041', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('associated', 'Reg', (77, 87))	('rs7041', 'Var', (34, 40))	('cancer', 'Disease', (114, 120))
514094	31467173	As shown in Figure 3A, although the total number of cases did not exceed the O'Brien-Fleming boundary, the cumulative Z-curve exceeded the test sequence monitoring boundary, which verified that rs7041 was significantly associated with cancer susceptibility.	('associated with', 'Reg', (219, 234))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('rs7041', 'Var', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('rs7041', 'Mutation', 'rs7041', (194, 200))
514095	31467173	Seven publications including ten studies with 4759 cases and 5262 controls examined rs4588 polymorphism.	('rs4588', 'Gene', (84, 90))	('polymorphism', 'Var', (91, 103))	('rs4588', 'Mutation', 'rs4588', (84, 90))
514096	31467173	As shown in Table 3, we found that rs4588 polymorphism significantly increased cancer risk in all five models: dominant (OR = 1.10, 95% CI = 1.02-1.19, P=0.016), recessive (OR = 1.27, 95% CI = 1.11-1.46, P=0.001), homozygote (OR = 1.31, 95% CI = 1.13-1.51, P=0.000, Figure 4A), heterozygote (OR = 1.23, 95% CI = 1.06-1.42, P=0.005), and allele (OR = 1.11, 95% CI = 1.05-1.18, P=0.001) models.	('rs4588 polymorphism', 'Var', (35, 54))	('polymorphism', 'Var', (42, 54))	('increased', 'PosReg', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('rs4588', 'Mutation', 'rs4588', (35, 41))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
514097	31467173	Stratification analyses indicated that rs4588 polymorphism significantly increased cancer risk in Caucasians (dominant, OR = 1.10, 95% CI = 1.01-1.21, P=0.040; recessive, OR = 1.17, 95% CI = 1.00-1.39, P=0.049; homozygote, OR = 1.22, 95% CI = 1.02-1.45, P=0.026; allele, OR = 1.10, 95% CI = 1.02-1.18, P=0.015) and Asians (recessive, OR = 1.51, 95% CI = 1.18-1.94, P=0.001; homozygote, OR = 1.56, 95% CI = 1.06-2.29, P=0.024; heterozygote, OR = 1.51, 95% CI = 1.16-1.96, P=0.002, Figure 4B).	('increased', 'PosReg', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rs4588 polymorphism', 'Var', (39, 58))	('polymorphism', 'Var', (46, 58))	('rs4588', 'Mutation', 'rs4588', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
514102	31467173	Two publications including three studies with 1403 cases and 1325 controls examined rs4646537 polymorphism; five publications including six studies with 2721 cases and 2761 controls examined rs3782130 polymorphism.	('rs4646537', 'Var', (84, 93))	('rs4646537', 'Mutation', 'rs4646537', (84, 93))	('rs3782130', 'Mutation', 'rs3782130', (191, 200))	('rs3782130', 'Var', (191, 200))
514104	31467173	As for rs4646537 and rs3782130, the cumulative number of cases did not exceed the O'Brien-Fleming boundary and test sequence monitoring boundary (Figure 3C,D).	('rs3782130', 'Mutation', 'rs3782130', (21, 30))	('rs3782130', 'Var', (21, 30))	('rs4646537', 'Mutation', 'rs4646537', (7, 16))	('rs4646537', 'Var', (7, 16))
514115	31467173	In addition, there are two common single nucleotide polymorphisms (rs7041 and rs4588) in GC gene.	('rs7041', 'Var', (67, 73))	('rs4588', 'Mutation', 'rs4588', (78, 84))	('rs4588', 'Var', (78, 84))	('rs7041', 'Mutation', 'rs7041', (67, 73))
514116	31467173	In the previous reports, genetic variants in the GC gene, including rs7041 and rs4588, have been investigated in breast cancer, non-small cell lung cancer, prostate cancer and digestive system tumor.	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('prostate cancer', 'Disease', (156, 171))	('breast cancer', 'Disease', (113, 126))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('rs4588', 'Var', (79, 85))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs7041', 'Mutation', 'rs7041', (68, 74))	('digestive system tumor', 'Phenotype', 'HP:0007378', (176, 198))	('non-small cell lung cancer', 'Disease', (128, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('system tumor', 'Disease', (186, 198))	('rs7041', 'Var', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('rs4588', 'Mutation', 'rs4588', (79, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('investigated', 'Reg', (97, 109))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('system tumor', 'Disease', 'MESH:D009423', (186, 198))
514118	31467173	Our data found that rs4588 was significantly associated with an increased risk of cancer susceptibility, and current result was confirmed by FPRP and TSA analyses.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('rs4588', 'Var', (20, 26))	('associated', 'Reg', (45, 55))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (82, 88))	('rs4588', 'Mutation', 'rs4588', (20, 26))
514120	31467173	Stratified analyses by cancer type revealed a significant association between rs4588 and breast cancer and digestive system tumor, but not in prostate cancer and non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', (162, 188))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', (89, 102))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('cancer', 'Disease', (96, 102))	('rs4588', 'Var', (78, 84))	('digestive system tumor', 'Phenotype', 'HP:0007378', (107, 129))	('system tumor', 'Disease', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (162, 188))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', (182, 188))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (166, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (142, 157))	('cancer', 'Disease', (23, 29))	('prostate cancer', 'Phenotype', 'HP:0012125', (142, 157))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (162, 188))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('system tumor', 'Disease', 'MESH:D009423', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('prostate cancer', 'Disease', (142, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('rs4588', 'Mutation', 'rs4588', (78, 84))
514121	31467173	However, our outcomes were different from the results shown by Anderson et al., McCullough et al., Reimers et al., and Deschasaux et al., who demonstrated that rs4588 polymorphism was not associated with breast cancer.	('associated', 'Reg', (188, 198))	('rs4588 polymorphism', 'Var', (160, 179))	('rs4588', 'Mutation', 'rs4588', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('breast cancer', 'Disease', (204, 217))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))
514122	31467173	Previous studies also focused on the relationship between the rs4588 and digestive system tumor.	('rs4588', 'Mutation', 'rs4588', (62, 68))	('rs4588', 'Var', (62, 68))	('system tumor', 'Disease', (83, 95))	('digestive system tumor', 'Phenotype', 'HP:0007378', (73, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('system tumor', 'Disease', 'MESH:D009423', (83, 95))	('focused', 'Reg', (22, 29))
514123	31467173	However, our outcomes were different from previous study, which indicated that rs4588 polymorphism was not associated with hepatocellular carcinoma, esophageal cancer and gastric cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('associated', 'Reg', (107, 117))	('rs4588', 'Mutation', 'rs4588', (79, 85))	('rs4588', 'Var', (79, 85))	('gastric cancer', 'Disease', (171, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (171, 185))	('esophageal cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('hepatocellular carcinoma', 'Disease', (123, 147))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))
514125	31467173	As for rs7041, we found that this polymorphism significantly increased cancer risk.	('rs7041', 'Var', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('rs7041', 'Mutation', 'rs7041', (7, 13))	('increased', 'PosReg', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
514126	31467173	Stratification analyses of ethnicity suggested rs7041 increased cancer risk in Asians, but not in Caucasians.	('rs7041', 'Mutation', 'rs7041', (47, 53))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('increased', 'PosReg', (54, 63))	('rs7041', 'Var', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
514128	31467173	In this meta-analysis, the pooled rs7041 C allele frequency of the controls showed a large difference across ethnicities (Asians: 30.2%; Caucasians: 45.4%), which may possibly affect the relationships between rs7041 polymorphism and cancer risk among different racial subgroups.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('affect', 'Reg', (176, 182))	('relationships', 'Interaction', (187, 200))	('rs7041', 'Mutation', 'rs7041', (34, 40))	('rs7041', 'Mutation', 'rs7041', (209, 215))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('rs7041 C', 'Var', (34, 42))
514129	31467173	Moreover, when studies were stratified by cancer type, we also found that rs7041 polymorphism was significantly associated with an increased risk in the non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (153, 179))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('rs7041', 'Mutation', 'rs7041', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (173, 179))	('non-small cell lung cancer', 'Disease', (153, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('associated', 'Reg', (112, 122))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('rs7041 polymorphism', 'Var', (74, 93))
514130	31467173	Our results were partially consistent with the consequence of the study by Wang et al., which reported that there was no significant association between rs7041 and breast cancer in Asians and Caucasians.	('rs7041', 'Mutation', 'rs7041', (153, 159))	('rs7041', 'Var', (153, 159))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('breast cancer', 'Disease', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
514131	31467173	suggested that rs7041 was associated with an increased risk of breast cancer in Caucasians.	('rs7041', 'Mutation', 'rs7041', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('rs7041', 'Var', (15, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))
514132	31467173	indicated that increased polymorphism may be related to the higher prevalence of estrogen receptor (ER)-negative but not ER-positive breast cancer.	('estrogen receptor', 'Gene', (81, 98))	('polymorphism', 'Var', (25, 37))	('breast cancer', 'Disease', (133, 146))	('ER', 'Gene', '2099', (121, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('ER', 'Gene', '2099', (100, 102))	('estrogen receptor', 'Gene', '2099', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
514134	31467173	Therefore, it is reasonable to hypothesize that rs7041 polymorphism may have a specific effect on the susceptibility to ER-negative breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs7041', 'Mutation', 'rs7041', (48, 54))	('effect', 'Reg', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('ER', 'Gene', '2099', (120, 122))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('rs7041', 'Var', (48, 54))
514135	31467173	Of note, due to limited data, lack of further evaluation between rs7041 and ER-negative and ER-positive breast cancer prevented our comprehensive understanding.	('rs7041', 'Var', (65, 71))	('ER', 'Gene', '2099', (76, 78))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('rs7041', 'Mutation', 'rs7041', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('ER', 'Gene', '2099', (92, 94))
514136	31467173	With respect to the remaining two polymorphisms, we failed to find any associations between rs4646537 and rs3782130 and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs3782130', 'Var', (106, 115))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('rs4646537', 'Var', (92, 101))	('rs4646537', 'Mutation', 'rs4646537', (92, 101))	('rs3782130', 'Mutation', 'rs3782130', (106, 115))
514137	31467173	(3): This system evaluation is the first analysis of reviewing the relationships between CYP27B1 (rs4646537, rs3782130) and GC (rs4588 and rs7041) polymorphisms with cancer susceptibility.	('rs4646537', 'Mutation', 'rs4646537', (98, 107))	('rs3782130', 'Var', (109, 118))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('rs7041', 'Var', (139, 145))	('CYP27B1', 'Gene', '1594', (89, 96))	('rs4588', 'Mutation', 'rs4588', (128, 134))	('rs4646537', 'Var', (98, 107))	('rs4588', 'Var', (128, 134))	('CYP27B1', 'Gene', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('rs7041', 'Mutation', 'rs7041', (139, 145))	('rs3782130', 'Mutation', 'rs3782130', (109, 118))
514138	31467173	(2) The number of studies on rs4646537, rs3782130, rs4588 and rs7041 was relatively small in some subgroups, which may create significant or insignificant results by chance.	('rs3782130', 'Mutation', 'rs3782130', (40, 49))	('rs4588', 'Mutation', 'rs4588', (51, 57))	('rs4646537', 'Var', (29, 38))	('rs4588', 'Var', (51, 57))	('rs7041', 'Mutation', 'rs7041', (62, 68))	('rs4646537', 'Mutation', 'rs4646537', (29, 38))	('rs3782130', 'Var', (40, 49))	('rs7041', 'Var', (62, 68))
514139	31467173	In conclusion, this systematical meta-analysis indicated that rs4588 and rs7041 polymorphisms play important roles in cancer pathogenesis, especially in non-small cell lung cancer, breast cancer and digestive system tumor, which were noteworthy findings as evaluated by FPRP.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (153, 179))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('rs4588', 'Var', (62, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('system tumor', 'Disease', 'MESH:D009423', (209, 221))	('rs7041', 'Var', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('non-small cell lung cancer', 'Disease', (153, 179))	('breast cancer', 'Disease', (181, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('rs7041', 'Mutation', 'rs7041', (73, 79))	('digestive system tumor', 'Phenotype', 'HP:0007378', (199, 221))	('system tumor', 'Disease', (209, 221))	('rs4588', 'Mutation', 'rs4588', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('roles', 'Reg', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
514140	31467173	However, the other two polymorphisms (rs4646537 and rs3782130) are not associated with cancer risk.	('rs4646537', 'Var', (38, 47))	('cancer', 'Disease', (87, 93))	('rs3782130', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rs4646537', 'Mutation', 'rs4646537', (38, 47))	('rs3782130', 'Mutation', 'rs3782130', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
514141	31467173	CI confidence interval CNKI China national knowledge infrastructure EMBASE excerpta medica database ER estrogen receptor FPRP false-positive report probability GC group-specific component HWE Hardy-Weinberg equilibrium MAF minor allele frequency OR odds ratio PCR-RFLP polymerase chain reaction-restrictionfragment length polymorphism SNP single nucleotide polymorphism TSA trial sequential analysis	('estrogen receptor', 'Gene', '2099', (103, 120))	('ER', 'Gene', '2099', (100, 102))	('estrogen receptor', 'Gene', (103, 120))	('single nucleotide polymorphism', 'Var', (339, 369))
514157	31523191	For example, miR-3188 significantly inhibits the development of nasopharyngeal carcinoma by targeting mTOR to inactive the p-PI3K/p-AKT/p-mTOR pathway; and the deficiency of miRNA-150 leads to inhibition of differentiation of intraepithelial lymphocytes.	('mTOR', 'Gene', (138, 142))	('deficiency', 'Var', (160, 170))	('targeting', 'Reg', (92, 101))	('differentiation of intraepithelial lymphocytes', 'CPA', (207, 253))	('PI3', 'Gene', (125, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('miRNA-150', 'Gene', (174, 183))	('nasopharyngeal carcinoma', 'Disease', (64, 88))	('mTOR', 'Gene', '2475', (138, 142))	('AKT', 'Gene', (132, 135))	('inhibits', 'NegReg', (36, 44))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (64, 88))	('inactive', 'NegReg', (110, 118))	('miR-3188', 'Gene', (13, 21))	('mTOR', 'Gene', (102, 106))	('PI3', 'Gene', '5266', (125, 128))	('development of', 'CPA', (49, 63))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (64, 88))	('AKT', 'Gene', '207', (132, 135))	('inhibition', 'NegReg', (193, 203))	('mTOR', 'Gene', '2475', (102, 106))	('miR-3188', 'Gene', '100422833', (13, 21))	('miRNA-150', 'Gene', '406942', (174, 183))
514175	31523191	ESCC cells (1.5x103 cells per well) were seeded in 96-well plates, and cultured for 1-7 days to achieve lentivirus-mediated overexpression or knock-down FGFR2, and for 1-4 days to test the impact of transient transfection with miR-671-5p mimics or miR-671-5p inhibitor, respectively.	('miR-671-5p', 'Gene', '102465990', (248, 258))	('miR-671-5p', 'Gene', (248, 258))	('FGFR2', 'Gene', (153, 158))	('knock-down', 'Var', (142, 152))	('miR-671-5p', 'Gene', '102465990', (227, 237))	('overexpression', 'PosReg', (124, 138))	('miR-671-5p', 'Gene', (227, 237))
514180	31523191	Male 4-5 week-old BALB/c nude mice were subcutaneously injected with 3x106 KYSE180-CTL, KYSE180-shFGFR2-4, EC109-CTL, or EC109-FGFR2 cells to establish their respective ESCC xenografts.	('KYSE180', 'CellLine', 'CVCL:1349', (75, 82))	('KYSE180', 'CellLine', 'CVCL:1349', (88, 95))	('KYSE180-shFGFR2-4', 'Var', (88, 105))	('EC109', 'CellLine', 'CVCL:6898', (121, 126))	('EC109', 'CellLine', 'CVCL:6898', (107, 112))	('EC109-CTL', 'Var', (107, 116))	('EC109-FGFR2', 'Var', (121, 132))	('nude mice', 'Species', '10090', (25, 34))	('KYSE180-CTL', 'Var', (75, 86))
514197	31523191	Results showed that KYSE180 cells infected with shFGFR2 developed dramatically smaller tumors, while EC109 cells overexpressing FGFR2 developed significantly larger tumors as compared with their respective controls (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('EC109', 'CellLine', 'CVCL:6898', (101, 106))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('smaller', 'NegReg', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('KYSE180', 'CellLine', 'CVCL:1349', (20, 27))	('tumors', 'Disease', (87, 93))	('shFGFR2', 'Var', (48, 55))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
514203	31523191	The levels of cyclin D1 and cyclin B1 were reduced in cells lines expressing lower levels of FGFR2 and increased in cells overexpressing FGFR2 (Fig.	('FGFR2', 'Gene', (93, 98))	('levels', 'MPA', (4, 10))	('cyclin B1', 'Gene', (28, 37))	('increased', 'PosReg', (103, 112))	('cyclin D1', 'Gene', '595', (14, 23))	('FGFR2', 'Var', (137, 142))	('reduced', 'NegReg', (43, 50))	('cyclin B1', 'Gene', '891', (28, 37))	('cyclin D1', 'Gene', (14, 23))
514210	31523191	We treated KYSE180 and EC109 cells were treated with either the wild-type or mutant luciferase reporter of miR-671-5p (Fig.	('miR-671-5p', 'Gene', (107, 117))	('mutant', 'Var', (77, 83))	('EC109', 'CellLine', 'CVCL:6898', (23, 28))	('KYSE180', 'CellLine', 'CVCL:1349', (11, 18))	('miR-671-5p', 'Gene', '102465990', (107, 117))
514230	31523191	The FGFR variant was reported to be involved in the development of various cancers.	('variant', 'Var', (9, 16))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('FGFR', 'Gene', (4, 8))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('involved', 'Reg', (36, 44))
514233	31523191	Drugs targeting FGFRs such as dovitinib, AZD4547, lucitanib, BGJ398, and JNJ-42756493 are currently in clinical trials, and may become a new line of treatment for patients with ESCC.	('patients', 'Species', '9606', (163, 171))	('ESCC', 'Disease', (177, 181))	('AZD4547', 'Chemical', 'MESH:C572463', (41, 48))	('dovitinib', 'Chemical', 'MESH:C500007', (30, 39))	('JNJ-42756493', 'Var', (73, 85))	('BGJ398', 'Chemical', 'MESH:C568950', (61, 67))	('BGJ398', 'Gene', (61, 67))	('AZD4547', 'Var', (41, 48))	('lucitanib', 'Chemical', 'MESH:C000595232', (50, 59))
514247	30942438	Esophageal cancer Eca109 cells were exposed to various concentrations of ginsenoside Rg5 (0-32 microMu) for 24 h. Subsequent cell proliferation assays demonstrated that treatment with ginsenoside Rg5 resulted in the dose-dependent inhibition of proliferation, while a significant increase in apoptotic rate and increased activities of caspase-3, -8 and -9 were observed.	('ginsenoside Rg5', 'Var', (184, 199))	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('apoptotic rate', 'CPA', (292, 306))	('inhibition', 'NegReg', (231, 241))	('increase', 'PosReg', (280, 288))	('caspase-3', 'Enzyme', (335, 344))	('proliferation', 'CPA', (245, 258))	('activities', 'MPA', (321, 331))	('Esophageal cancer', 'Disease', (0, 17))	('increased', 'PosReg', (311, 320))	('ginsenoside Rg5', 'Chemical', 'MESH:C572381', (73, 88))	('ginsenoside Rg5', 'Chemical', 'MESH:C572381', (184, 199))
514250	30942438	The specific phosphoinositide-3 kinase (PI3K) inhibitor LY294002 promoted this effect, while insulin-like growth factor-1, a specific PI3K activator, inhibited this action.	('phosphoinositide-3 kinase', 'Gene', '5295', (13, 38))	('LY294002', 'Var', (56, 64))	('promoted', 'PosReg', (65, 73))	('insulin-like growth factor-1', 'Gene', '3479', (93, 121))	('insulin-like growth factor-1', 'Gene', (93, 121))	('phosphoinositide-3 kinase', 'Gene', (13, 38))	('LY294002', 'Chemical', 'MESH:C085911', (56, 64))
514270	30942438	In addition, the inactivation of Akt may contribute to the apoptosis of esophageal cancer cells.	('inactivation', 'Var', (17, 29))	('Akt', 'Gene', '207', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('apoptosis', 'CPA', (59, 68))	('Akt', 'Gene', (33, 36))	('contribute', 'Reg', (41, 51))
514278	30942438	Rabbit polyclonal antibodies specific for cleaved caspase-3 (9661T; 1:800), Bax (5023T; 1:1,000), Bcl-2 (2872S; 1:1,000), Akt (4691S; 1:1,000), phosphorylated (p)-Akt (9611S; 1:1,000), cleaved poly(adenosine diphosphate-ribose) polymerase (PARP) (5625S; 1:1,000) were obtained from Cell Signaling Technology, Inc. (Danvers, MA, USA).	('Bax', 'Gene', (76, 79))	('Akt', 'Gene', (163, 166))	('caspase-3', 'Gene', (50, 59))	('Bax', 'Gene', '581', (76, 79))	('Akt', 'Gene', '207', (122, 125))	('Bcl-2', 'Gene', (98, 103))	('caspase-3', 'Gene', '836', (50, 59))	('Bcl-2', 'Gene', '596', (98, 103))	('9611S;', 'Var', (168, 174))	('Akt', 'Gene', (122, 125))	('Akt', 'Gene', '207', (163, 166))	('9661T;', 'Var', (61, 67))	('Rabbit', 'Species', '9986', (0, 6))
514316	30942438	The results of the current study revealed that, following 24-h treatment with Rg5, the cytoplasmic calcium levels of Eca-109 cells were significantly increased in a dose-dependent manner, compared with the control group levels, as observed by the enhanced fluorescence intensity (Fig.	('fluorescence intensity', 'MPA', (256, 278))	('enhanced', 'PosReg', (247, 255))	('Rg5', 'Var', (78, 81))	('cytoplasmic calcium levels', 'MPA', (87, 113))	('calcium', 'Chemical', 'MESH:D002118', (99, 106))	('increased', 'PosReg', (150, 159))
514318	30942438	Eca-109 cells were treated with the PI3K inhibitor LY294002 or with the PI3K activator IGF-1.	('IGF-1', 'Gene', (87, 92))	('LY294002', 'Var', (51, 59))	('IGF-1', 'Gene', '3479', (87, 92))	('LY294002', 'Chemical', 'MESH:C085911', (51, 59))
514319	30942438	Co-treatment with ginsenoside Rg5 and LY294002 induced apoptosis when compared with the group treated with Rg5 alone (Fig.	('ginsenoside Rg5', 'Chemical', 'MESH:C572381', (18, 33))	('LY294002', 'Chemical', 'MESH:C085911', (38, 46))	('LY294002', 'Var', (38, 46))	('apoptosis', 'CPA', (55, 64))
514321	30942438	In addition, LY294002 significantly lowered the expression levels of p-Akt and Bcl-2.	('lowered', 'NegReg', (36, 43))	('Akt', 'Gene', '207', (71, 74))	('expression levels', 'MPA', (48, 65))	('Akt', 'Gene', (71, 74))	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('LY294002', 'Var', (13, 21))	('Bcl-2', 'Gene', (79, 84))	('Bcl-2', 'Gene', '596', (79, 84))
514323	30942438	The cleavage of caspase-9 and PARP caused by Rg5 was weakened by IGF-1; however, the decline in p-Akt and Bcl-2 protein expression was reversed (Fig.	('weakened', 'NegReg', (53, 61))	('cleavage', 'MPA', (4, 12))	('Akt', 'Gene', '207', (98, 101))	('PARP', 'CPA', (30, 34))	('caspase-9', 'Gene', (16, 25))	('Akt', 'Gene', (98, 101))	('IGF-1', 'Gene', '3479', (65, 70))	('IGF-1', 'Gene', (65, 70))	('Bcl-2', 'Gene', (106, 111))	('Rg5', 'Var', (45, 48))	('Bcl-2', 'Gene', '596', (106, 111))	('caspase-9', 'Gene', '842', (16, 25))
514330	30942438	For instance, it has been reported that ginsenoside Rg3 induces apoptosis in human glioblastoma cells through the mitogen-activated protein kinase kinase signaling pathway.	('apoptosis', 'CPA', (64, 73))	('induces', 'PosReg', (56, 63))	('glioblastoma', 'Disease', (83, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('ginsenoside', 'Chemical', 'MESH:D036145', (40, 51))	('ginsenoside Rg3', 'Var', (40, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))	('human', 'Species', '9606', (77, 82))
514348	30942438	The results of the present study revealed that Rg5 increased the intracellular Ca2+ levels and caused cell apoptosis.	('increased', 'PosReg', (51, 60))	('cell apoptosis', 'CPA', (102, 116))	('Ca2+', 'Chemical', 'MESH:D000069285', (79, 83))	('Rg5', 'Var', (47, 50))	('intracellular Ca2+ levels', 'MPA', (65, 90))	('caused', 'Reg', (95, 101))
514350	30942438	Inhibition of this pathway can decrease the phosphorylation of Akt.	('phosphorylation', 'MPA', (44, 59))	('decrease', 'NegReg', (31, 39))	('Inhibition', 'Var', (0, 10))	('Akt', 'Gene', '207', (63, 66))	('Akt', 'Gene', (63, 66))
514353	30942438	Furthermore, inhibition of PI3K/Akt signaling in lung cancer induces apoptosis and arrests the cell cycle.	('arrests', 'NegReg', (83, 90))	('Akt', 'Gene', '207', (32, 35))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('induces', 'Reg', (61, 68))	('Akt', 'Gene', (32, 35))	('inhibition', 'Var', (13, 23))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('apoptosis', 'CPA', (69, 78))	('cell cycle', 'CPA', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
514354	30942438	The present study further revealed that Rg5 treatment resulted in a concentration-dependent decrease in the level of p-Akt in Eca109 cells.	('Rg5', 'Var', (40, 43))	('Akt', 'Gene', '207', (119, 122))	('Akt', 'Gene', (119, 122))	('decrease', 'NegReg', (92, 100))
514356	30942438	To further determine whether the PI3K/Akt signaling pathway is important in the apoptosis of esophageal cancer cells, Eca-109 cells were co-treated with Rg5 and the PI3K inhibitor LY294002, and the expression levels of apoptosis markers were detected.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('LY294002', 'Var', (180, 188))	('esophageal cancer', 'Disease', (93, 110))	('LY294002', 'Chemical', 'MESH:C085911', (180, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('Akt', 'Gene', '207', (38, 41))	('Akt', 'Gene', (38, 41))
514357	30942438	Compared with Rg5 alone, co-treatment with LY294002 significantly inhibited the level of p-Akt, and in addition, significantly decreased the expression of Bcl2; however, it also induced the expression of cleaved caspase-9.	('Akt', 'Gene', '207', (91, 94))	('decreased', 'NegReg', (127, 136))	('cleaved', 'MPA', (204, 211))	('caspase-9', 'Gene', '842', (212, 221))	('Bcl2', 'Gene', (155, 159))	('Akt', 'Gene', (91, 94))	('LY294002', 'Chemical', 'MESH:C085911', (43, 51))	('induced', 'Reg', (178, 185))	('caspase-9', 'Gene', (212, 221))	('expression', 'MPA', (141, 151))	('LY294002', 'Var', (43, 51))	('inhibited', 'NegReg', (66, 75))	('Bcl2', 'Gene', '596', (155, 159))	('expression', 'MPA', (190, 200))
514359	30942438	The results revealed that IGF-1 treatment reversed the decrease in p-Akt induced by Rg5, while it significantly reversed the decrease in Bcl-2 expression and increase in cleaved caspase-9 expression when compared with Rg5 treatment alone.	('Akt', 'Gene', (69, 72))	('expression', 'MPA', (143, 153))	('expression', 'MPA', (188, 198))	('caspase-9', 'Gene', '842', (178, 187))	('IGF-1', 'Gene', '3479', (26, 31))	('IGF-1', 'Gene', (26, 31))	('Rg5', 'Var', (84, 87))	('Bcl-2', 'Gene', '596', (137, 142))	('decrease', 'NegReg', (55, 63))	('Akt', 'Gene', '207', (69, 72))	('caspase-9', 'Gene', (178, 187))	('decrease', 'NegReg', (125, 133))	('Bcl-2', 'Gene', (137, 142))	('increase', 'PosReg', (158, 166))
514393	29805947	Mean heart dose (MHD), heart V5, V40, and V50, were selected for evaluation based on prior studies showing these constraints as predictors of toxicity and were recalculated for all plans.	('V40', 'Var', (33, 36))	('toxicity', 'Disease', 'MESH:D064420', (142, 150))	('toxicity', 'Disease', (142, 150))	('MHD', 'Disease', 'None', (17, 20))	('MHD', 'Disease', (17, 20))	('V50', 'Var', (42, 45))
514411	29805947	The highest heart dose was in patients treated with 3D CRT (34.8 Gy) and was significantly lower in patients treated with PBT (9.7 Gy), as would be expected with the different dosimetric properties of these treatment modalities (Table 2).	('lower', 'NegReg', (91, 96))	('3D CRT', 'Var', (52, 58))	('heart dose', 'MPA', (12, 22))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (30, 38))
514419	29805947	In this analysis of patients treated with definitive trimodality therapy for esophageal cancer, with a 20 months' median follow-up, the mean heart dose, V5, V40, and V50, were not predictive of local recurrence, distant metastases, or overall survival.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('metastases', 'Disease', 'MESH:D009362', (220, 230))	('V50', 'Var', (166, 169))	('V40', 'Var', (157, 160))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('metastases', 'Disease', (220, 230))	('heart dose', 'MPA', (141, 151))	('local recurrence', 'CPA', (194, 210))
514442	26392415	Immunohistochemistry was performed to analyze epidermal growth factor receptor (EGFR) expression, and the amplified refractory mutation system was used to detect EGFR mutations.	('epidermal growth factor receptor', 'Gene', '1956', (46, 78))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('mutations', 'Var', (167, 176))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('epidermal growth factor receptor', 'Gene', (46, 78))
514446	26392415	Patients with good Eastern Cooperative Oncology Group performance status, never smoking, and EGFR mutated tumors had the best OS (14.0, 14.0, and 17.0 months, respectively).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('EGFR', 'Gene', '1956', (93, 97))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Oncology', 'Phenotype', 'HP:0002664', (39, 47))	('EGFR', 'Gene', (93, 97))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mutated', 'Var', (98, 105))
514460	26392415	Altered EGFR expression or EGFR mutation has been reported in esophageal cancer and correlated with poor patient prognosis and inferior response to therapy.	('EGFR', 'Gene', '1956', (27, 31))	('patient', 'Species', '9606', (105, 112))	('EGFR', 'Gene', (27, 31))	('expression', 'MPA', (13, 23))	('esophageal cancer', 'Disease', (62, 79))	('reported', 'Reg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('EGFR', 'Gene', '1956', (8, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('Altered', 'Reg', (0, 7))	('mutation', 'Var', (32, 40))	('EGFR', 'Gene', (8, 12))
514464	26392415	Previous studies showed that gefitinib treatment of non-small cell lung cancer patients with EGFR exon 19 and 21 mutations achieves a dramatic clinical response.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (56, 78))	('EGFR', 'Gene', '1956', (93, 97))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (52, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('EGFR', 'Gene', (93, 97))	('gefitinib', 'Chemical', 'MESH:D000077156', (29, 38))	('mutations', 'Var', (113, 122))	('patients', 'Species', '9606', (79, 87))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (52, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('non-small cell lung cancer', 'Disease', (52, 78))
514467	26392415	In addition, detection of EGFR mutations is a useful and sensitive biomarker to predict the effect of an EGFR tyrosine kinase inhibitor on non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (139, 165))	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('non-small cell lung cancer', 'Disease', (139, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('EGFR', 'Gene', '1956', (105, 109))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (139, 165))	('EGFR', 'Gene', (105, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('EGFR', 'Gene', '1956', (26, 30))
514468	26392415	Therefore, in the present study, we conducted a phase II clinical trial in elderly Chinese ESCC patients to evaluate concomitant gefitinib and thoracic radiotherapy in terms of both feasibility and efficacy for the treatment of ESCC and to study the impact of EGFR alterations on patient survival.	('alterations', 'Var', (265, 276))	('EGFR', 'Gene', (260, 264))	('patient', 'Species', '9606', (280, 287))	('ESCC', 'Disease', (228, 232))	('ESCC', 'Disease', (91, 95))	('patient', 'Species', '9606', (96, 103))	('gefitinib', 'Chemical', 'MESH:D000077156', (129, 138))	('patients', 'Species', '9606', (96, 104))	('EGFR', 'Gene', '1956', (260, 264))
514480	26392415	In particular, a better OS rate occurred in patients with good ECOG performance status (14 vs. 4 months, p = 0.000), and the OS was marginally better among patients who had never smoked (14 vs. 9 months; p = 0.088) or those with a mutated EGFR tumor (10 vs. 17 months, p = 0.098; Figure 1B, 1C).	('patients', 'Species', '9606', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('ECOG', 'Gene', (63, 67))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', (244, 249))	('mutated', 'Var', (231, 238))	('EGFR', 'Gene', '1956', (239, 243))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('EGFR', 'Gene', (239, 243))
514488	26392415	EGFR protein expression and EGFR mutations were analyzed in 15 patients (5 patient had insufficient tissue material).	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (28, 32))	('insufficient', 'Disease', 'MESH:D000309', (87, 99))	('mutations', 'Var', (33, 42))	('insufficient', 'Disease', (87, 99))	('patient', 'Species', '9606', (63, 70))	('patients', 'Species', '9606', (63, 71))	('EGFR', 'Gene', '1956', (0, 4))	('patient', 'Species', '9606', (75, 82))
514491	26392415	Furthermore, EGFR was mutated in three patients (20%), whereas the rest of the 12 patients did not have EGFR exon 19-21 mutations (Figure 2B).	('patients', 'Species', '9606', (39, 47))	('EGFR', 'Gene', (104, 108))	('patients', 'Species', '9606', (82, 90))	('mutated', 'Var', (22, 29))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('EGFR', 'Gene', '1956', (104, 108))
514492	26392415	After the treatment, patients with a tumor exhibiting EGFR mutation had a median OS of 17 months compared to 10 months in patients whose tumors were without an EGFR mutation (p = 0.098; Table 3 and Figure 1C).	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('EGFR', 'Gene', '1956', (160, 164))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mutation', 'Var', (59, 67))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (160, 164))	('patients', 'Species', '9606', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('EGFR', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
514505	26392415	Moreover, we only obtained 15 of 20 prospectively banked tissues samples from the patients for detection of EGFR alterations.	('EGFR', 'Gene', '1956', (108, 112))	('patients', 'Species', '9606', (82, 90))	('EGFR', 'Gene', (108, 112))	('alterations', 'Var', (113, 124))
514506	26392415	Based on previous studies of non-small cell lung cancer, EGFR mutations occurred more common in non-smoking patients.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (29, 55))	('common', 'Reg', (86, 92))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (33, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('non-small cell lung cancer', 'Disease', (29, 55))	('EGFR', 'Gene', '1956', (57, 61))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (29, 55))	('patients', 'Species', '9606', (108, 116))	('EGFR', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
514508	26392415	In our current study, despite the small number of patients limiting the statistical power to draw a definite conclusion, it is intriguing that an EGFR mutation was associated with a better outcome tendency in gefitinib-treated patients (OS, 17 vs. 10 months in ARMS-positive and -negative patients, respectively).	('gefitinib', 'Chemical', 'MESH:D000077156', (209, 218))	('EGFR', 'Gene', '1956', (146, 150))	('patients', 'Species', '9606', (50, 58))	('mutation', 'Var', (151, 159))	('EGFR', 'Gene', (146, 150))	('patients', 'Species', '9606', (227, 235))	('patients', 'Species', '9606', (289, 297))
514509	26392415	In addition, patients with ESCC expressing high levels of EGFR had a better OS than patients with an ESCC tumor with low EGFR expression, although this difference was not statistically significant.	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', '1956', (121, 125))	('high', 'Var', (43, 47))	('patients', 'Species', '9606', (84, 92))	('EGFR', 'Gene', (58, 62))	('patients', 'Species', '9606', (13, 21))	('EGFR', 'Gene', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('better', 'PosReg', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
514510	26392415	However, a previous phase II study of gefitinib as a second-line treatment for advanced esophageal cancer reported a significantly higher disease control rate (response and SD) in patients with ESCC expressing high levels of EGFR.	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('gefitinib', 'Chemical', 'MESH:D000077156', (38, 47))	('high levels', 'Var', (210, 221))	('SD', 'Disease', 'MESH:D029461', (173, 175))	('EGFR', 'Gene', '1956', (225, 229))	('EGFR', 'Gene', (225, 229))	('esophageal cancer', 'Disease', (88, 105))	('disease control rate', 'CPA', (138, 158))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (180, 188))	('higher', 'PosReg', (131, 137))
514511	26392415	However, to date, the use of an EGFR alteration (overexpression or mutation) as a predictive marker for treatment efficacy is still controversial; thus, the design of a proper multidisciplinary clinical trial will confirm the usefulness of EGFR alteration as a biomarker for EGFR-targeted therapy of ESCC patients.	('EGFR', 'Gene', '1956', (275, 279))	('EGFR', 'Gene', (275, 279))	('EGFR', 'Gene', (240, 244))	('EGFR', 'Gene', '1956', (32, 36))	('patients', 'Species', '9606', (305, 313))	('EGFR', 'Gene', (32, 36))	('alteration', 'Var', (245, 255))	('EGFR', 'Gene', '1956', (240, 244))	('ESCC', 'Disease', (300, 304))
514512	26392415	In addition, our current study also showed that concurrent radiotherapy with gefitinib is effective in elderly patients with ESCC without EGFR overexpression or mutation, indicating that gefitinib could help to sensitize tumor cells to the effect of radiotherapy.	('EGFR', 'Gene', '1956', (138, 142))	('mutation', 'Var', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('EGFR', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('gefitinib', 'Chemical', 'MESH:D000077156', (187, 196))	('gefitinib', 'Chemical', 'MESH:D000077156', (77, 86))	('ESCC', 'Disease', (125, 129))	('patients', 'Species', '9606', (111, 119))
514523	26392415	Thirdly, the incidence of EGFR mutations is different with various sensitivity detection methods.	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))
514524	26392415	In the current study, we detected an EGFR mutation with ARMS, which is a highly sensitive method, and the incidence of EGFR mutations in our patients was relatively higher than that reported previously.	('EGFR', 'Gene', '1956', (37, 41))	('mutation', 'Var', (42, 50))	('EGFR', 'Gene', (119, 123))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (37, 41))	('patients', 'Species', '9606', (141, 149))
514526	26392415	Our study revealed better outcomes in patients with good ECOG performance status, a history of not smoking, and EGFR mutation; however, we did not compare clinical outcomes, including survival rate, local disease control, distant metastasis, and treatment response, directly with those by common treatment modalities, such as chemoradiotherapy.	('mutation', 'Var', (117, 125))	('EGFR', 'Gene', '1956', (112, 116))	('patients', 'Species', '9606', (38, 46))	('EGFR', 'Gene', (112, 116))
514553	26392415	EGFR mutations at exons 19-21 were detected using a Therascreen RGQ PCR kit (Qiagen, Hilden, Germany), which uses the Scorpions technology and the amplified refractory mutation system (ARMS) to detect EGFR mutations after real-time PCR amplification.	('CR', 'Chemical', '-', (233, 235))	('mutations', 'Var', (206, 215))	('EGFR', 'Gene', (0, 4))	('CR', 'Chemical', '-', (69, 71))	('EGFR', 'Gene', '1956', (201, 205))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', (201, 205))	('EGFR', 'Gene', '1956', (0, 4))
514554	26392415	This sensitive method can detect 29 types of EGFR mutations, and the experiments were performed according to the manufacturer's instructions as described previously.	('mutations', 'Var', (50, 59))	('EGFR', 'Gene', '1956', (45, 49))	('EGFR', 'Gene', (45, 49))
514632	24243522	Therefore, the lack of a relationship between urinary total NNN and the risk of lung cancer in the same cohort, as shown in this study, further validates the unique role of urinary total NNN as a predictor of esophageal cancer risk in smokers.	('esophageal cancer', 'Disease', (209, 226))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('urinary', 'Var', (173, 180))	('esophageal cancer', 'Disease', 'MESH:D004938', (209, 226))	('NNN', 'Chemical', 'MESH:C008655', (187, 190))	('lung cancer', 'Disease', (80, 91))	('NNN', 'Chemical', 'MESH:C008655', (60, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
514742	33679976	The inclusion criteria were (1) patients who had undergone radical esophagectomy with two- or three-field lymphadenectomy between January 2009 and December 2011, (2) esophageal squamous cell carcinoma, (3) pN+ and pT2-4 (pT1N+ was eliminated due to less number of cases) and without distant metastasis, (4) no history of other tumors, (5) Karnofsky performance status >=70, and (6) survival time at least one month after surgery.	('tumors', 'Disease', 'MESH:D009369', (327, 333))	('pT1', 'Gene', '58492', (221, 224))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('pN', 'Gene', '79650', (206, 208))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (177, 200))	('tumors', 'Disease', (327, 333))	('squamous cell carcinoma', 'Disease', (177, 200))	('pT1', 'Gene', (221, 224))	('pT2-4', 'Var', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))
514753	33679976	The NLR was calculated by dividing the number of absolute neutrophil count (x109/L) by the number of absolute lymphocyte count (x109/L).	('LR', 'Chemical', '-', (5, 7))	('x109/L', 'Var', (128, 134))	('x109/L', 'Var', (76, 82))
514820	33679976	In the study by Feng et al., ESCC patients with preoperative NLR >= 3.5 had significantly poorer 5-year OS rate compared to those with NLR < 3.5 (35.4% vs 57.7%, respectively).	('ESCC', 'Disease', (29, 33))	('poorer', 'NegReg', (90, 96))	('LR', 'Chemical', '-', (136, 138))	('patients', 'Species', '9606', (34, 42))	('OS rate', 'MPA', (104, 111))	('NLR', 'Var', (61, 64))	('LR', 'Chemical', '-', (62, 64))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))
514822	33679976	In the study by Kosumi et al., high NLR was associated with significantly shorter OS and cancer-specific survival (CSS).	('shorter', 'NegReg', (74, 81))	('LR', 'Chemical', '-', (37, 39))	('NLR', 'Gene', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('high', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
514823	33679976	In the study by Duan et al., the median postoperative CSS and recurrence-free survival (RFS) of patients with NLR <= 3 was 70 and 58 months, respectively, as against 24 and 17 months, respectively, for patients with NLR > 3.	('RFS', 'Disease', (88, 91))	('LR', 'Chemical', '-', (111, 113))	('RFS', 'Disease', 'MESH:D005198', (88, 91))	('NLR <= 3', 'Var', (110, 118))	('patients', 'Species', '9606', (202, 210))	('recurrence-free survival', 'CPA', (62, 86))	('patients', 'Species', '9606', (96, 104))	('LR', 'Chemical', '-', (217, 219))	('CSS', 'CPA', (54, 57))
514824	33679976	In a meta-analysis by Sun and Zhang, high NLR and low LMR were associated with poor OS or CSS and event-free survival of ESCC patients.	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('low', 'Var', (50, 53))	('LMR', 'MPA', (54, 57))	('LR', 'Chemical', '-', (43, 45))	('CSS', 'CPA', (90, 93))	('LMR', 'Chemical', '-', (54, 57))	('poor OS', 'Disease', (79, 86))	('high NLR', 'Var', (37, 45))	('patients', 'Species', '9606', (126, 134))	('ESCC', 'Disease', (121, 125))
514827	33679976	In several studies, low LMR was found to predict shorter DFS and OS in patients with ESCC; patients with low preoperative LMR exhibited significantly worse DFS and OS than those with high preoperative LMR.	('DFS', 'MPA', (156, 159))	('worse', 'NegReg', (150, 155))	('LMR', 'Chemical', '-', (122, 125))	('low', 'Var', (105, 108))	('patients', 'Species', '9606', (91, 99))	('DFS', 'MPA', (57, 60))	('LMR', 'Chemical', '-', (24, 27))	('patients', 'Species', '9606', (71, 79))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('shorter', 'NegReg', (49, 56))	('ESCC', 'Disease', (85, 89))	('LMR', 'Chemical', '-', (201, 204))
514932	31257165	For the CROSS trial cohort as a whole, OS was significantly improved in patients who received nCRT prior to esophagectomy versus esophagectomy alone.	('age', 'Gene', (113, 116))	('age', 'Gene', (134, 137))	('age', 'Gene', '5973', (113, 116))	('nCRT', 'Var', (94, 98))	('age', 'Gene', '5973', (134, 137))	('improved', 'PosReg', (60, 68))	('patients', 'Species', '9606', (72, 80))
514968	31257165	In our study, high NLR was significantly associated with lower RFS survival, supporting this hypothesis.	('RFS', 'Disease', (63, 66))	('high', 'Var', (14, 18))	('RFS', 'Disease', 'MESH:D005198', (63, 66))	('NLR', 'Gene', (19, 22))	('lower', 'NegReg', (57, 62))
515017	32150096	Among them, cardia lymph nodes (0/2), esophageal lymph nodes (0/13); immunohistochemistry (IHC): EGFR (+), P53 (80%+), Ki67 (70%+); Tumor Node Metastasis (TNM) staging was pT1bN0M0, stage I. Twenty months later, he unconsciously found mass on the left neck.	('P53', 'Gene', '7157', (107, 110))	('pT1bN0M0', 'Var', (172, 180))	('cardia lymph', 'Disease', 'MESH:D004938', (12, 24))	('EGFR', 'Gene', '1956', (97, 101))	('EGFR', 'Gene', (97, 101))	('Tumor', 'Phenotype', 'HP:0002664', (132, 137))	('P53', 'Gene', (107, 110))	('cardia lymph', 'Disease', (12, 24))
515018	32150096	Only left cervical lymph nodes (size: 4.7 x 3.7 cm) showed hypermetabolism by whole body Positron Emission Computed Tomography (PET-CT) (February 23, 2017), squamous cell carcinoma was verified by needle biopsy, so it was diagnosed as solitary left cervical lymph node metastasis, at this time, the TNM stage of the patient was cT0N0M1, stage IV.	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (249, 279))	('squamous cell carcinoma', 'Disease', (157, 180))	('cT0N0M1', 'Var', (328, 335))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('patient', 'Species', '9606', (316, 323))	('hypermetabolism', 'Disease', 'MESH:C565498', (59, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (157, 180))	('hypermetabolism', 'Disease', (59, 74))
515031	32150096	The number of insertion mutations and deletion mutations (Indels) is 58, and the ratio of Indels/TMB is 25.66%.	('TMB', 'Chemical', '-', (97, 100))	('deletion mutations', 'Var', (38, 56))	('insertion mutations', 'Var', (14, 33))
515047	32150096	Meanwhile, due to few studies on esophageal cancer, it remains controversial about the prognostic and predictive value of PD-L1 expression in ESCC, as some studies associate high PD-L1 expression with poor differentiation of tumor and poor prognosis, while others postulate better response to PD-1/PD-L1 blockade with high PD-L1 expression.	('poor differentiation', 'CPA', (201, 221))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('expression', 'MPA', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('high', 'Var', (174, 178))	('tumor', 'Disease', (225, 230))	('PD-L1', 'Gene', (179, 184))	('esophageal cancer', 'Disease', (33, 50))	('ESCC', 'Disease', (142, 146))	('PD-1/PD-L1 blockade', 'Disease', (293, 312))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (293, 312))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
515055	32150096	In addition to the common point mutations in cancer cells, insertion mutations, deletion mutations, together is Indels, result in the production of abnormal proteins, which increase the immunogenicity and thus activate the immune system.	('deletion mutations', 'Var', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('activate', 'PosReg', (210, 218))	('proteins', 'Protein', (157, 165))	('immunogenicity', 'MPA', (186, 200))	('insertion mutations', 'Var', (59, 78))	('result in', 'Reg', (120, 129))	('increase', 'PosReg', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('immune system', 'CPA', (223, 236))	('cancer', 'Disease', (45, 51))	('abnormal proteins', 'Protein', (148, 165))
515056	32150096	It showed that the number and percentage of Indels in renal cancer are the highest.	('Indels', 'Var', (44, 50))	('renal cancer', 'Disease', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('renal cancer', 'Disease', 'MESH:D007680', (54, 66))	('renal cancer', 'Phenotype', 'HP:0009726', (54, 66))
515058	32150096	TILs is found to be an independent prognostic factor for prolonging progression free survival (PFS) and overall survival (OS) in tumor immunity, thus indicating the critical role of T cells in tumor immunity.	('overall survival', 'CPA', (104, 120))	('TILs', 'Var', (0, 4))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('progression', 'MPA', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('prolonging', 'PosReg', (57, 67))	('tumor', 'Disease', (193, 198))
515060	32150096	Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent ICIs (PD-1/PD-L1) treatment.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('EGFR', 'Gene', '1956', (48, 52))	('patients', 'Species', '9606', (5, 13))	('MDM2', 'Gene', '4193', (19, 23))	('MDM2', 'Gene', (19, 23))	('tumor', 'Disease', (127, 132))	('EGFR', 'Gene', (48, 52))	('aberrations', 'Var', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('increased', 'PosReg', (109, 118))
515061	32150096	In 2017, European Society for Medical Oncology (ESMO) conducted a comprehensive genetic analysis of patients with hyperprogression on immunotherapy, and found that MDM2/4 amplification, EGFR amplification, and CCND1/FGF3/FGF4/FGF19 amplification were associated with hyperprogression after ICIs treatment.	('CCND1', 'Gene', '595', (210, 215))	('EGFR', 'Gene', (186, 190))	('patients', 'Species', '9606', (100, 108))	('amplification', 'Var', (171, 184))	('FGF3', 'Gene', (216, 220))	('FGF3', 'Gene', '2248', (216, 220))	('MDM2/4', 'Gene', '4193;4194', (164, 170))	('FGF19', 'Gene', (226, 231))	('CCND1', 'Gene', (210, 215))	('FGF19', 'Gene', '9965', (226, 231))	('FGF4', 'Gene', '2249', (221, 225))	('Oncology', 'Phenotype', 'HP:0002664', (38, 46))	('MDM2/4', 'Gene', (164, 170))	('amplification', 'Var', (232, 245))	('EGFR', 'Gene', '1956', (186, 190))	('hyperprogression', 'Disease', (267, 283))	('associated with', 'Reg', (251, 266))	('amplification', 'Var', (191, 204))	('FGF4', 'Gene', (221, 225))
515073	32744314	Investigation of IL-4, IL-10, and HVEM polymorphisms with esophageal squamous cell carcinoma: a case-control study involving 1929 participants It is believed that an individual's hereditary factors may be involved in the development of esophageal cancer (EC).	('esophageal cancer', 'Disease', 'MESH:D004938', (236, 253))	('IL-10', 'Gene', (23, 28))	('involved', 'Reg', (205, 213))	('polymorphisms', 'Var', (39, 52))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (58, 92))	('IL-4', 'Gene', (17, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('esophageal squamous cell carcinoma', 'Disease', (58, 92))	('IL-4', 'Gene', '3565', (17, 21))	('HVEM', 'Gene', (34, 38))	('IL-10', 'Gene', '3586', (23, 28))	('esophageal cancer', 'Disease', (236, 253))	('HVEM', 'Gene', '8764', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
515074	32744314	The present study recruited 721 esophageal squamous cell carcinoma (ESCC) cases and 1208 controls and explored the roles of single nucleotide polymorphisms (SNPs) in the interleukin-4 (IL-4), IL-10, and herpesvirus entry mediator (HVEM) genes in contributing to ESCC risk.	('esophageal squamous cell carcinoma', 'Disease', (32, 66))	('herpesvirus', 'Species', '39059', (203, 214))	('IL-10', 'Gene', '3586', (192, 197))	('HVEM', 'Gene', (231, 235))	('interleukin-4', 'Gene', (170, 183))	('interleukin-4', 'Gene', '3565', (170, 183))	('single nucleotide polymorphisms', 'Var', (124, 155))	('HVEM', 'Gene', '8764', (231, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('IL-4', 'Gene', (185, 189))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (32, 66))	('IL-10', 'Gene', (192, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('ESCC', 'Disease', (262, 266))	('IL-4', 'Gene', '3565', (185, 189))
515076	32744314	After adjustment for body mass index (BMI), smoking, drinking, age and gender, we identified that the rs2070874 T>C locus in IL-4 gene decreased the risk of ESCC (CC vs. TT: P=0.008; CC vs. TT/TC: P=0.010).	('TC', 'Chemical', 'MESH:D013667', (193, 195))	('rs2070874', 'Mutation', 'rs2070874', (102, 111))	('ESCC', 'Disease', (157, 161))	('decreased', 'NegReg', (135, 144))	('IL-4', 'Gene', (125, 129))	('IL-4', 'Gene', '3565', (125, 129))	('rs2070874 T>C', 'Var', (102, 115))
515077	32744314	After a stratified analysis, we suggested that the IL-4 rs2070874 T>C variants might be a protective factor for ESCC in male, >=63 years old, never smoking, drinking and BMI < 24 kg/m2 subgroups.	('ESCC', 'Disease', (112, 116))	('rs2070874 T>C', 'Var', (56, 69))	('IL-4', 'Gene', (51, 55))	('IL-4', 'Gene', '3565', (51, 55))	('rs2070874', 'Mutation', 'rs2070874', (56, 65))
515078	32744314	In addition, we identified that the rs2243263 G>C polymorphism in IL-4 gene was a risk factor for ESCC development in the BMI >= 24 kg/m2 subgroup (GC vs. GG: P=0.030 and GC/CC vs. GG: P=0.018).	('ESCC development', 'Disease', (98, 114))	('risk', 'Reg', (82, 86))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('IL-4', 'Gene', (66, 70))	('rs2243263', 'Mutation', 'rs2243263', (36, 45))	('rs2243263 G>C', 'Var', (36, 49))	('IL-4', 'Gene', '3565', (66, 70))	('GC', 'Phenotype', 'HP:0012126', (171, 173))
515079	32744314	We identified an association of the IL-4 rs2070874 T>C SNP with the decreased susceptibility of ESCC in stage I/II subgroup.	('IL-4', 'Gene', (36, 40))	('decreased', 'NegReg', (68, 77))	('IL-4', 'Gene', '3565', (36, 40))	('ESCC', 'Disease', (96, 100))	('rs2070874', 'Mutation', 'rs2070874', (41, 50))	('rs2070874 T>C', 'Var', (41, 54))
515080	32744314	Finally, we found an association of the IL-10 rs1800872 T>G SNP with a worse differentiation (TG vs. TT: P=0.048 and GG/TG vs. TT: P=0.032).	('association', 'Interaction', (21, 32))	('IL-10', 'Gene', (40, 45))	('rs1800872 T>G', 'Var', (46, 59))	('worse differentiation', 'CPA', (71, 92))	('IL-10', 'Gene', '3586', (40, 45))	('rs1800872', 'Mutation', 'rs1800872', (46, 55))
515081	32744314	In conclusion, the findings indicate a potential importance of IL-4 rs2070874 T>C, IL-4 rs2243263 G>C and IL-10 rs1800872 T>G SNPs in the development of ESCC.	('IL-10', 'Gene', '3586', (106, 111))	('rs1800872', 'Mutation', 'rs1800872', (112, 121))	('rs2070874 T>C', 'Var', (68, 81))	('rs2243263', 'Mutation', 'rs2243263', (88, 97))	('IL-10', 'Gene', (106, 111))	('IL-4', 'Gene', (63, 67))	('IL-4', 'Gene', (83, 87))	('rs2070874', 'Mutation', 'rs2070874', (68, 77))	('rs1800872 T>G', 'Var', (112, 125))	('rs2243263 G>C', 'Var', (88, 101))	('IL-4', 'Gene', '3565', (63, 67))	('IL-4', 'Gene', '3565', (83, 87))	('ESCC', 'Disease', (153, 157))
515090	32744314	IL-4 single nucleotide polymorphisms (SNPs) have also been explored for an association with susceptibility to cancer.	('cancer', 'Disease', (110, 116))	('IL-4', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('single nucleotide polymorphisms', 'Var', (5, 36))	('IL-4', 'Gene', '3565', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('association', 'Interaction', (75, 86))
515091	32744314	The rs2070874 T>C, located in the 5'-UTR region of the IL-4 gene, is an important SNP in cancer development.	('rs2070874 T>C', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('IL-4', 'Gene', (55, 59))	('cancer', 'Disease', (89, 95))	('rs2070874', 'Mutation', 'rs2070874', (4, 13))	('IL-4', 'Gene', '3565', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
515092	32744314	Some meta-analyses have indicated that IL-4 rs2070874 may be associated with cancer development in Asian populations.	('IL-4', 'Gene', (39, 43))	('rs2070874', 'Var', (44, 53))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('IL-4', 'Gene', '3565', (39, 43))	('rs2070874', 'Mutation', 'rs2070874', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('associated', 'Reg', (61, 71))
515093	32744314	reported that IL-4 rs2070874 might affect the role of aspirin in regulating IL-4 expression.	('IL-4', 'Gene', '3565', (76, 80))	('affect', 'Reg', (35, 41))	('rs2070874', 'Mutation', 'rs2070874', (19, 28))	('aspirin', 'Chemical', 'MESH:D001241', (54, 61))	('IL-4', 'Gene', (14, 18))	('IL-4', 'Gene', '3565', (14, 18))	('rs2070874', 'Var', (19, 28))	('IL-4', 'Gene', (76, 80))	('expression', 'MPA', (81, 91))
515094	32744314	Rs2243263 G>C polymorphism is an intron SNP of IL-4 gene.	('Rs2243263', 'Mutation', 'Rs2243263', (0, 9))	('IL-4', 'Gene', '3565', (47, 51))	('IL-4', 'Gene', (47, 51))	('Rs2243263 G>C polymorphism', 'Var', (0, 26))
515095	32744314	Although the exact role of this intron SNP is unknown, the associations of IL-4 rs2243263 G>C SNP with the human disease have been explored.	('associations', 'Interaction', (59, 71))	('IL-4', 'Gene', (75, 79))	('rs2243263', 'Mutation', 'rs2243263', (80, 89))	('human', 'Species', '9606', (107, 112))	('IL-4', 'Gene', '3565', (75, 79))	('rs2243263 G>C', 'Var', (80, 93))
515096	32744314	A previous study suggested that IL-4 rs2243263 was associated with the reverse seroconversion of Hepatitis B virus (HBV).	('rs2243263', 'Var', (37, 46))	('Hepatitis B virus', 'Disease', (97, 114))	('IL-4', 'Gene', '3565', (32, 36))	('HBV', 'Species', '10407', (116, 119))	('rs2243263', 'Mutation', 'rs2243263', (37, 46))	('Hepatitis', 'Phenotype', 'HP:0012115', (97, 106))	('IL-4', 'Gene', (32, 36))
515098	32744314	A previous report investigated the correlation of the IL-4 rs2243263 locus with colorectal cancer.	('IL-4', 'Gene', (54, 58))	('rectal cancer', 'Phenotype', 'HP:0100743', (84, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('IL-4', 'Gene', '3565', (54, 58))	('rs2243263', 'Var', (59, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('rs2243263', 'Mutation', 'rs2243263', (59, 68))
515099	32744314	However, Lan et al., in a large simple size study, found that the IL-4 rs2243263 G>C SNP might increase the susceptibility to non-Hodgkin lymphoma.	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (126, 146))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (130, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (138, 146))	('IL-4', 'Gene', (66, 70))	('rs2243263', 'Mutation', 'rs2243263', (71, 80))	('rs2243263 G>C', 'Var', (71, 84))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (126, 146))	('IL-4', 'Gene', '3565', (66, 70))	('non-Hodgkin lymphoma', 'Disease', (126, 146))
515100	32744314	Currently, the associations of IL-4 the rs2070874 T>C, and rs2243263 G>C polymorphisms with ESCC development are unknown.	('rs2243263 G>C', 'Var', (59, 72))	('rs2070874', 'Mutation', 'rs2070874', (40, 49))	('associations', 'Interaction', (15, 27))	('ESCC development', 'Disease', (92, 108))	('IL-4', 'Gene', (31, 35))	('rs2070874 T>C', 'Var', (40, 53))	('rs2243263', 'Mutation', 'rs2243263', (59, 68))	('IL-4', 'Gene', '3565', (31, 35))
515106	32744314	An investigation found that the up-regulated mRNA expression of the IL-10 gene and higher serum levels of IL-10 were found among subjects who carried the rs1800896 G-allele.	('IL-10', 'Gene', '3586', (106, 111))	('IL-10', 'Gene', '3586', (68, 73))	('rs1800896', 'Mutation', 'rs1800896', (154, 163))	('rs1800896 G-allele', 'Var', (154, 172))	('up-regulated', 'PosReg', (32, 44))	('IL-10', 'Gene', (106, 111))	('IL-10', 'Gene', (68, 73))	('serum levels of', 'MPA', (90, 105))	('mRNA expression', 'MPA', (45, 60))	('higher', 'PosReg', (83, 89))
515107	32744314	The rs1800872 SNP, a promotor variant, could influence the level of IL-10 protein.	('IL-10', 'Gene', '3586', (68, 73))	('rs1800872', 'Mutation', 'rs1800872', (4, 13))	('rs1800872 SNP', 'Var', (4, 17))	('IL-10', 'Gene', (68, 73))	('influence', 'Reg', (45, 54))
515108	32744314	Some investigations have suggested that the IL-10 rs1800896 A>G (-1082) and rs1800872 A>C (-592) variants may influence the susceptibility to ESCC.	('susceptibility', 'MPA', (124, 138))	('IL-10', 'Gene', (44, 49))	('influence', 'Reg', (110, 119))	('rs1800896', 'Mutation', 'rs1800896', (50, 59))	('rs1800872', 'Mutation', 'rs1800872', (76, 85))	('ESCC', 'Disease', (142, 146))	('rs1800872 A>C', 'Var', (76, 89))	('rs1800896 A>G', 'Var', (50, 63))	('IL-10', 'Gene', '3586', (44, 49))
515109	32744314	Of late, a meta-analysis indicated that these IL-10 SNPs increased the risk of EC.	('SNPs', 'Var', (52, 56))	('IL-10', 'Gene', (46, 51))	('IL-10', 'Gene', '3586', (46, 51))
515111	32744314	The association of the IL-10 rs1800896 A>G and rs1800872 A>C polymorphisms with EC development should be further studied.	('EC development', 'Disease', (80, 94))	('IL-10', 'Gene', (23, 28))	('rs1800872 A>C', 'Var', (47, 60))	('rs1800872', 'Mutation', 'rs1800872', (47, 56))	('association', 'Interaction', (4, 15))	('IL-10', 'Gene', '3586', (23, 28))	('rs1800896', 'Mutation', 'rs1800896', (29, 38))	('rs1800896 A>G', 'Var', (29, 42))
515119	32744314	However, the association of HVEM rs2234167 G>A SNP with the expression of HVEM is unknown.	('HVEM', 'Gene', '8764', (28, 32))	('HVEM', 'Gene', (74, 78))	('rs2234167 G>A', 'Var', (33, 46))	('HVEM', 'Gene', '8764', (74, 78))	('HVEM', 'Gene', (28, 32))	('rs2234167', 'Mutation', 'rs2234167', (33, 42))
515121	32744314	To date, investigation has not been performed to identify a relationship of the HVEM rs2234167 G>A polymorphism with ESCC susceptibility.	('HVEM', 'Gene', '8764', (80, 84))	('rs2234167', 'Mutation', 'rs2234167', (85, 94))	('rs2234167 G>A', 'Var', (85, 98))	('ESCC', 'Disease', (117, 121))	('HVEM', 'Gene', (80, 84))
515122	32744314	Therefore, in this investigation, the HVEM rs2234167, IL-4 rs2070874 and rs2243263, and IL-10 rs1800896 and rs1800872 polymorphisms were selected and investigated for their effect on ESCC development in a Chinese Han population.	('rs2234167', 'Var', (43, 52))	('IL-4', 'Gene', (54, 58))	('rs2070874', 'Mutation', 'rs2070874', (59, 68))	('rs1800896', 'Var', (94, 103))	('IL-10', 'Gene', (88, 93))	('rs2243263', 'Mutation', 'rs2243263', (73, 82))	('IL-4', 'Gene', '3565', (54, 58))	('rs2234167', 'Mutation', 'rs2234167', (43, 52))	('rs2070874', 'Var', (59, 68))	('HVEM', 'Gene', (38, 42))	('rs1800896', 'Mutation', 'rs1800896', (94, 103))	('rs2243263', 'Var', (73, 82))	('rs1800872', 'Var', (108, 117))	('ESCC', 'Disease', (183, 187))	('IL-10', 'Gene', '3586', (88, 93))	('rs1800872', 'Mutation', 'rs1800872', (108, 117))	('HVEM', 'Gene', '8764', (38, 42))
515130	32744314	Using an SNPscan  assay (Genesky Biotechologies Inc., Shanghai, China), we determined the genotypes of HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 polymorphisms.	('IL-10', 'Gene', '3586', (154, 159))	('rs2070874', 'Mutation', 'rs2070874', (124, 133))	('IL-4', 'Gene', (119, 123))	('rs1800872', 'Var', (174, 183))	('HVEM', 'Gene', (103, 107))	('rs2243263', 'Mutation', 'rs2243263', (139, 148))	('rs1800896', 'Var', (160, 169))	('rs1800872', 'Mutation', 'rs1800872', (174, 183))	('HVEM', 'Gene', '8764', (103, 107))	('IL-10', 'Gene', (154, 159))	('IL-4', 'Gene', '3565', (119, 123))	('rs1800896', 'Mutation', 'rs1800896', (160, 169))	('rs2234167', 'Var', (108, 117))	('rs2070874', 'Var', (124, 133))	('rs2234167', 'Mutation', 'rs2234167', (108, 117))	('rs2243263', 'Var', (139, 148))
515131	32744314	The genotypes of HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 loci were re-analyzed by another technician.	('IL-10', 'Gene', '3586', (68, 73))	('rs2234167', 'Mutation', 'rs2234167', (22, 31))	('rs2234167', 'Var', (22, 31))	('rs2243263', 'Var', (53, 62))	('IL-4', 'Gene', '3565', (33, 37))	('HVEM', 'Gene', (17, 21))	('rs2070874', 'Var', (38, 47))	('rs2243263', 'Mutation', 'rs2243263', (53, 62))	('IL-10', 'Gene', (68, 73))	('rs1800896', 'Var', (74, 83))	('rs2070874', 'Mutation', 'rs2070874', (38, 47))	('HVEM', 'Gene', '8764', (17, 21))	('rs1800896', 'Mutation', 'rs1800896', (74, 83))	('rs1800872', 'Var', (88, 97))	('rs1800872', 'Mutation', 'rs1800872', (88, 97))	('IL-4', 'Gene', (33, 37))
515132	32744314	The genotypes of HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 SNPs were unchanged.	('IL-10', 'Gene', '3586', (68, 73))	('rs2234167', 'Mutation', 'rs2234167', (22, 31))	('rs2234167', 'Var', (22, 31))	('rs2243263', 'Var', (53, 62))	('IL-4', 'Gene', '3565', (33, 37))	('HVEM', 'Gene', (17, 21))	('rs2070874', 'Var', (38, 47))	('rs2243263', 'Mutation', 'rs2243263', (53, 62))	('IL-10', 'Gene', (68, 73))	('rs1800896', 'Var', (74, 83))	('rs2070874', 'Mutation', 'rs2070874', (38, 47))	('HVEM', 'Gene', '8764', (17, 21))	('rs1800896', 'Mutation', 'rs1800896', (74, 83))	('rs1800872', 'Var', (88, 97))	('rs1800872', 'Mutation', 'rs1800872', (88, 97))	('IL-4', 'Gene', (33, 37))
515134	32744314	We used a Chi-square test (chi2) or Fisher's exact test to determine whether the frequencies of HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 variants in ESCC cases and controls were different.	('rs1800872', 'Var', (167, 176))	('IL-10', 'Gene', '3586', (147, 152))	('rs1800872', 'Mutation', 'rs1800872', (167, 176))	('IL-4', 'Gene', (112, 116))	('rs2243263', 'Var', (132, 141))	('rs2243263', 'Mutation', 'rs2243263', (132, 141))	('rs1800896', 'Var', (153, 162))	('HVEM', 'Gene', '8764', (96, 100))	('IL-4', 'Gene', '3565', (112, 116))	('ESCC', 'Disease', (189, 193))	('IL-10', 'Gene', (147, 152))	('rs1800896', 'Mutation', 'rs1800896', (153, 162))	('rs2070874', 'Var', (117, 126))	('HVEM', 'Gene', (96, 100))	('rs2234167', 'Mutation', 'rs2234167', (101, 110))	('rs2234167', 'Var', (101, 110))	('rs2070874', 'Mutation', 'rs2070874', (117, 126))
515135	32744314	The relationship of HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 polymorphisms with ESCC development was determined by ORs and 95% CIs.	('IL-4', 'Gene', (36, 40))	('rs1800872', 'Var', (91, 100))	('IL-4', 'Gene', '3565', (36, 40))	('rs1800872', 'Mutation', 'rs1800872', (91, 100))	('rs2243263', 'Mutation', 'rs2243263', (56, 65))	('IL-10', 'Gene', (71, 76))	('ESCC', 'Disease', (120, 124))	('rs1800896', 'Var', (77, 86))	('rs2234167', 'Var', (25, 34))	('rs2243263', 'Var', (56, 65))	('rs2070874', 'Var', (41, 50))	('HVEM', 'Gene', (20, 24))	('rs2234167', 'Mutation', 'rs2234167', (25, 34))	('rs1800896', 'Mutation', 'rs1800896', (77, 86))	('rs2070874', 'Mutation', 'rs2070874', (41, 50))	('HVEM', 'Gene', '8764', (20, 24))	('IL-10', 'Gene', '3586', (71, 76))
515136	32744314	An internet-based Hardy-Weinberg equilibrium (HWE) test (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl) was also harnessed to assess whether the distribution of HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 genotypes could represent the included population.	('rs1800896', 'Mutation', 'rs1800896', (209, 218))	('IL-10', 'Gene', '3586', (203, 208))	('rs2234167', 'Mutation', 'rs2234167', (157, 166))	('rs2234167', 'Var', (157, 166))	('rs1800872', 'Var', (223, 232))	('HVEM', 'Gene', '8764', (152, 156))	('IL-4', 'Gene', '3565', (168, 172))	('rs2070874', 'Mutation', 'rs2070874', (173, 182))	('rs1800872', 'Mutation', 'rs1800872', (223, 232))	('rs2243263', 'Var', (188, 197))	('IL-4', 'Gene', (168, 172))	('IL-10', 'Gene', (203, 208))	('rs2070874', 'Var', (173, 182))	('rs2243263', 'Mutation', 'rs2243263', (188, 197))	('rs1800896', 'Var', (209, 218))	('HVEM', 'Gene', (152, 156))
515138	32744314	After genotyping the 1929 participants, the association of HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 genotypes with ESCC risk was assessed.	('rs1800872', 'Var', (130, 139))	('rs2070874', 'Mutation', 'rs2070874', (80, 89))	('rs1800872', 'Mutation', 'rs1800872', (130, 139))	('rs2243263', 'Var', (95, 104))	('IL-4', 'Gene', (75, 79))	('participants', 'Species', '9606', (26, 38))	('rs2234167', 'Mutation', 'rs2234167', (64, 73))	('rs2234167', 'Var', (64, 73))	('IL-10', 'Gene', '3586', (110, 115))	('rs1800896', 'Var', (116, 125))	('IL-4', 'Gene', '3565', (75, 79))	('HVEM', 'Gene', (59, 63))	('rs2070874', 'Var', (80, 89))	('rs2243263', 'Mutation', 'rs2243263', (95, 104))	('HVEM', 'Gene', '8764', (59, 63))	('ESCC', 'Disease', (155, 159))	('IL-10', 'Gene', (110, 115))	('rs1800896', 'Mutation', 'rs1800896', (116, 125))
515139	32744314	The minor allele frequencies (MAFs) of HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 loci are shown in Table 2.	('rs1800896', 'Var', (96, 105))	('rs2243263', 'Var', (75, 84))	('HVEM', 'Gene', (39, 43))	('rs2070874', 'Var', (60, 69))	('rs2234167', 'Mutation', 'rs2234167', (44, 53))	('rs2234167', 'Var', (44, 53))	('rs1800896', 'Mutation', 'rs1800896', (96, 105))	('rs1800872', 'Mutation', 'rs1800872', (110, 119))	('IL-10', 'Gene', '3586', (90, 95))	('IL-4', 'Gene', (55, 59))	('rs1800872', 'Var', (110, 119))	('rs2070874', 'Mutation', 'rs2070874', (60, 69))	('IL-4', 'Gene', '3565', (55, 59))	('rs2243263', 'Mutation', 'rs2243263', (75, 84))	('HVEM', 'Gene', '8764', (39, 43))	('IL-10', 'Gene', (90, 95))
515140	32744314	As presented in Table 2, the HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 genotypes in controls accorded with HWE.	('IL-10', 'Gene', (80, 85))	('HVEM', 'Gene', (29, 33))	('rs2070874', 'Mutation', 'rs2070874', (50, 59))	('rs1800896', 'Var', (86, 95))	('rs2234167', 'Mutation', 'rs2234167', (34, 43))	('rs2234167', 'Var', (34, 43))	('IL-4', 'Gene', (45, 49))	('HVEM', 'Gene', '8764', (29, 33))	('rs1800896', 'Mutation', 'rs1800896', (86, 95))	('IL-10', 'Gene', '3586', (80, 85))	('IL-4', 'Gene', '3565', (45, 49))	('rs2243263', 'Var', (65, 74))	('rs1800872', 'Var', (100, 109))	('rs1800872', 'Mutation', 'rs1800872', (100, 109))	('rs2070874', 'Var', (50, 59))	('rs2243263', 'Mutation', 'rs2243263', (65, 74))
515141	32744314	Table 3 shows the HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872 genotypes.	('rs1800896', 'Mutation', 'rs1800896', (75, 84))	('rs1800872', 'Var', (89, 98))	('rs2070874', 'Var', (39, 48))	('HVEM', 'Gene', '8764', (18, 22))	('rs1800872', 'Mutation', 'rs1800872', (89, 98))	('rs2234167', 'Mutation', 'rs2234167', (23, 32))	('rs2070874', 'Mutation', 'rs2070874', (39, 48))	('IL-10', 'Gene', '3586', (69, 74))	('rs2243263', 'Mutation', 'rs2243263', (54, 63))	('IL-4', 'Gene', (34, 38))	('IL-4', 'Gene', '3565', (34, 38))	('rs1800896', 'Var', (75, 84))	('HVEM', 'Gene', (18, 22))	('IL-10', 'Gene', (69, 74))	('rs2243263', 'Var', (54, 63))
515142	32744314	The frequencies of IL-4 rs2070874 TT, TC, and CC genotypes were 486 (67.88%), 214 (29.89%), and 16 (2.23%) in ESCC cases and 780 (64.95%), 371 (30.89%), and 50 (4.16%) in controls.	('rs2070874 TT', 'Var', (24, 36))	('IL-4', 'Gene', '3565', (19, 23))	('TC', 'Chemical', 'MESH:D013667', (38, 40))	('rs2070874', 'Mutation', 'rs2070874', (24, 33))	('ESCC', 'Disease', (110, 114))	('IL-4', 'Gene', (19, 23))
515143	32744314	When the reference was IL-4 rs2070874 TT genotype, we found the IL-4 rs2070874 CC genotype significantly decreased the risk of ESCC (P=0.023).	('IL-4', 'Gene', (23, 27))	('IL-4', 'Gene', (64, 68))	('ESCC', 'Disease', (127, 131))	('IL-4', 'Gene', '3565', (64, 68))	('IL-4', 'Gene', '3565', (23, 27))	('rs2070874 CC', 'Var', (69, 81))	('rs2070874', 'Mutation', 'rs2070874', (28, 37))	('rs2070874', 'Mutation', 'rs2070874', (69, 78))	('decreased', 'NegReg', (105, 114))
515144	32744314	When the reference was IL-4 rs2070874 TT/TC genotype, the IL-4 rs2070874 CC genotype also significantly decreased the risk of ESCC (P=0.028).	('IL-4', 'Gene', (23, 27))	('rs2070874', 'Var', (28, 37))	('IL-4', 'Gene', '3565', (23, 27))	('decreased', 'NegReg', (104, 113))	('TC', 'Chemical', 'MESH:D013667', (41, 43))	('IL-4', 'Gene', (58, 62))	('ESCC', 'Disease', (126, 130))	('rs2070874 CC', 'Var', (63, 75))	('rs2070874', 'Mutation', 'rs2070874', (28, 37))	('rs2070874', 'Mutation', 'rs2070874', (63, 72))	('IL-4', 'Gene', '3565', (58, 62))
515146	32744314	HVEM rs2234167, IL-4 rs2243263 and IL-10 rs1800896 and rs1800872 genotypes are shown in Table 3.	('rs2243263', 'Mutation', 'rs2243263', (21, 30))	('rs2234167', 'Mutation', 'rs2234167', (5, 14))	('rs1800896', 'Var', (41, 50))	('IL-4', 'Gene', (16, 20))	('HVEM', 'Gene', '8764', (0, 4))	('IL-4', 'Gene', '3565', (16, 20))	('rs1800896', 'Mutation', 'rs1800896', (41, 50))	('rs2243263', 'Var', (21, 30))	('IL-10', 'Gene', '3586', (35, 40))	('HVEM', 'Gene', (0, 4))	('rs1800872', 'Var', (55, 64))	('rs1800872', 'Mutation', 'rs1800872', (55, 64))	('IL-10', 'Gene', (35, 40))
515147	32744314	Both crude and adjusted comparisons indicated that HVEM rs2234167, IL-4 rs2243263, and IL-10 rs1800896 and rs1800872 loci were not associated with the risk of ESCC (Table 4).	('IL-4', 'Gene', (67, 71))	('rs2243263', 'Mutation', 'rs2243263', (72, 81))	('rs1800896', 'Var', (93, 102))	('IL-10', 'Gene', '3586', (87, 92))	('IL-4', 'Gene', '3565', (67, 71))	('rs1800896', 'Mutation', 'rs1800896', (93, 102))	('rs2234167', 'Var', (56, 65))	('rs1800872', 'Var', (107, 116))	('HVEM', 'Gene', (51, 55))	('IL-10', 'Gene', (87, 92))	('rs1800872', 'Mutation', 'rs1800872', (107, 116))	('rs2243263', 'Var', (72, 81))	('rs2234167', 'Mutation', 'rs2234167', (56, 65))	('HVEM', 'Gene', '8764', (51, 55))	('ESCC', 'Disease', (159, 163))
515148	32744314	We identified an association between IL-4 rs2070874 T>C SNP and the decreased susceptibility of ESCC in stage I/II subgroup (CC vs. TT: P=0.022; CC vs. TT/TC: P=0.025, Table 4).	('decreased', 'NegReg', (68, 77))	('IL-4', 'Gene', (37, 41))	('rs2070874 T>C', 'Var', (42, 55))	('IL-4', 'Gene', '3565', (37, 41))	('ESCC', 'Disease', (96, 100))	('TC', 'Chemical', 'MESH:D013667', (155, 157))	('rs2070874', 'Mutation', 'rs2070874', (42, 51))
515149	32744314	In a stratified analysis, the IL-4 rs2070874 genotypes are listed in Table 5.	('IL-4', 'Gene', '3565', (30, 34))	('rs2070874', 'Var', (35, 44))	('IL-4', 'Gene', (30, 34))	('rs2070874', 'Mutation', 'rs2070874', (35, 44))
515150	32744314	After an adjustment, we suggested that IL-4 rs2070874 C allele was a protective factor for ESCC in five subgroups (male subgroup: CC vs. TT: P=0.028; CC vs. TT/TC: P=0.031; >=63 years old subgroup: CC vs. TT: P=0.026; CC vs. TT/TC: P=0.029; never smoking subgroup: CC vs. TT: P=0.041; CC/TC vs. TT: P=0.013 and TC vs. TT: P=0.042; drinking subgroup: CC vs. TT: P=0.025; CC vs. TT/TC: P=0.024 and BMI < 24 kg/m2 subgroup: CC vs. TT: P=0.010; CC vs. TT/TC: P=0.012).	('TC', 'Chemical', 'MESH:D013667', (451, 453))	('TC', 'Chemical', 'MESH:D013667', (380, 382))	('TC', 'Chemical', 'MESH:D013667', (160, 162))	('TC', 'Chemical', 'MESH:D013667', (311, 313))	('IL-4', 'Gene', (39, 43))	('rs2070874', 'Var', (44, 53))	('ESCC', 'Disease', (91, 95))	('TC', 'Chemical', 'MESH:D013667', (288, 290))	('IL-4', 'Gene', '3565', (39, 43))	('rs2070874', 'Mutation', 'rs2070874', (44, 53))	('TC', 'Chemical', 'MESH:D013667', (228, 230))
515151	32744314	In other subgroups, no association of L-4 rs2070874 with ESCC risk was found (Table 5).	('rs2070874', 'Var', (42, 51))	('ESCC', 'Disease', (57, 61))	('rs2070874', 'Mutation', 'rs2070874', (42, 51))
515152	32744314	The IL-4 rs2243263 G>C genotypes in the stratified analysis are listed in Table 6.	('IL-4', 'Gene', (4, 8))	('rs2243263', 'Mutation', 'rs2243263', (9, 18))	('IL-4', 'Gene', '3565', (4, 8))	('rs2243263 G>C', 'Var', (9, 22))
515153	32744314	After adjustment, we identified that IL-4 rs2243263 G>C polymorphism was a risk factor for ESCC development in the BMI >= 24 kg/m2 subgroup (GC vs. GG: P=0.030 and GC/CC vs. GG: P=0.018, Table 6).	('IL-4', 'Gene', (37, 41))	('GC', 'Phenotype', 'HP:0012126', (164, 166))	('rs2243263', 'Mutation', 'rs2243263', (42, 51))	('rs2243263 G>C', 'Var', (42, 55))	('risk', 'Reg', (75, 79))	('IL-4', 'Gene', '3565', (37, 41))	('GC', 'Phenotype', 'HP:0012126', (141, 143))	('ESCC development', 'Disease', (91, 107))
515154	32744314	In other stratified analyses, adjustment comparisons suggested that HVEM rs2234167, and IL-10 rs1800872 and rs1800896 loci did not confer a risk of ESCC (data not shown).	('rs1800872', 'Mutation', 'rs1800872', (94, 103))	('rs1800896', 'Var', (108, 117))	('IL-10', 'Gene', (88, 93))	('HVEM', 'Gene', (68, 72))	('rs1800896', 'Mutation', 'rs1800896', (108, 117))	('HVEM', 'Gene', '8764', (68, 72))	('rs2234167', 'Mutation', 'rs2234167', (73, 82))	('rs2234167', 'Var', (73, 82))	('rs1800872', 'Var', (94, 103))	('IL-10', 'Gene', '3586', (88, 93))	('ESCC', 'Disease', (148, 152))
515156	32744314	As presented in Table 7, we found a null association of HVEM rs2234167, IL-4 rs2070874, rs2243263 and IL-10 rs1800896 and rs1800872 SNPs with different lymph node status.	('rs2070874', 'Var', (77, 86))	('rs2243263', 'Var', (88, 97))	('rs2234167', 'Mutation', 'rs2234167', (61, 70))	('rs1800896', 'Var', (108, 117))	('rs2234167', 'Var', (61, 70))	('rs1800872', 'Mutation', 'rs1800872', (122, 131))	('IL-4', 'Gene', '3565', (72, 76))	('HVEM', 'Gene', '8764', (56, 60))	('IL-10', 'Gene', (102, 107))	('rs2070874', 'Mutation', 'rs2070874', (77, 86))	('rs2243263', 'Mutation', 'rs2243263', (88, 97))	('rs1800896', 'Mutation', 'rs1800896', (108, 117))	('IL-4', 'Gene', (72, 76))	('HVEM', 'Gene', (56, 60))	('IL-10', 'Gene', '3586', (102, 107))	('rs1800872 SNPs', 'Var', (122, 136))
515158	32744314	We found an association of the IL-10 rs1800872 T>G SNP with a worse differentiation (TG vs. TT: P=0.048 and GG/TG vs. TT: P=0.032, Table 8).	('rs1800872', 'Mutation', 'rs1800872', (37, 46))	('IL-10', 'Gene', '3586', (31, 36))	('rs1800872 T>G', 'Var', (37, 50))	('association', 'Interaction', (12, 23))	('IL-10', 'Gene', (31, 36))
515161	32744314	Recently, some studies indicated that the SNPs in inflammation and immune-related genes might influence the risk of EC.	('inflammation', 'Disease', 'MESH:D007249', (50, 62))	('influence', 'Reg', (94, 103))	('inflammation', 'Disease', (50, 62))	('SNPs', 'Var', (42, 46))
515162	32744314	In this study, we explored the role of immune-related gene SNPs (HVEM rs2234167, IL-4 rs2070874, and rs2243263, and IL-10 rs1800896 and rs1800872) to ESCC development.	('rs1800896', 'Mutation', 'rs1800896', (122, 131))	('rs1800872', 'Var', (136, 145))	('rs2070874', 'Mutation', 'rs2070874', (86, 95))	('HVEM', 'Gene', '8764', (65, 69))	('rs2243263', 'Mutation', 'rs2243263', (101, 110))	('rs1800872', 'Mutation', 'rs1800872', (136, 145))	('IL-4', 'Gene', (81, 85))	('IL-10', 'Gene', (116, 121))	('ESCC', 'Disease', (150, 154))	('rs1800896', 'Var', (122, 131))	('IL-4', 'Gene', '3565', (81, 85))	('rs2070874', 'Var', (86, 95))	('HVEM', 'Gene', (65, 69))	('rs2234167', 'Mutation', 'rs2234167', (70, 79))	('rs2234167', 'Var', (70, 79))	('rs2243263', 'Var', (101, 110))	('IL-10', 'Gene', '3586', (116, 121))
515163	32744314	We observed that IL-4 rs2070874 T>C could decrease a risk to ESCC, even in the stage I/II subgroup.	('IL-4', 'Gene', (17, 21))	('ESCC', 'Disease', (61, 65))	('rs2070874', 'Mutation', 'rs2070874', (22, 31))	('IL-4', 'Gene', '3565', (17, 21))	('decrease', 'NegReg', (42, 50))	('rs2070874 T>C', 'Var', (22, 35))
515164	32744314	However, in BMI >= 24 kg/m2 subgroup, IL-4 rs2243263 G>C might increase the risk of ESCC.	('increase', 'PosReg', (63, 71))	('ESCC', 'Disease', (84, 88))	('IL-4', 'Gene', (38, 42))	('rs2243263', 'Mutation', 'rs2243263', (43, 52))	('IL-4', 'Gene', '3565', (38, 42))	('rs2243263 G>C', 'Var', (43, 56))
515165	32744314	We also found an association of the IL-10 rs1800872 T>G SNP with a worse differentiation.	('rs1800872 T>G', 'Var', (42, 55))	('association', 'Interaction', (17, 28))	('worse differentiation', 'CPA', (67, 88))	('IL-10', 'Gene', (36, 41))	('rs1800872', 'Mutation', 'rs1800872', (42, 51))	('IL-10', 'Gene', '3586', (36, 41))
515169	32744314	The IL-4 rs2070874 T>C polymorphism is a 5'-UTR SNP.	('IL-4', 'Gene', (4, 8))	('rs2070874', 'Mutation', 'rs2070874', (9, 18))	('IL-4', 'Gene', '3565', (4, 8))	('rs2070874 T>C', 'Var', (9, 22))
515170	32744314	In a high-risk gastric cancer (GC) region, a previous study suggested that rs2070874 C allele in the IL-4 gene might decrease the susceptibility to GC in a Chinese population.	('IL-4', 'Gene', '3565', (101, 105))	('gastric cancer', 'Disease', (15, 29))	('rs2070874 C', 'Var', (75, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (15, 29))	('GC', 'Phenotype', 'HP:0012126', (31, 33))	('rs2070874', 'Mutation', 'rs2070874', (75, 84))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('decrease', 'NegReg', (117, 125))	('susceptibility', 'MPA', (130, 144))	('IL-4', 'Gene', (101, 105))
515171	32744314	reported that the rs2070874 C allele increased the risk of HCC in a male subgroup.	('rs2070874', 'Mutation', 'rs2070874', (18, 27))	('HCC', 'Disease', (59, 62))	('increased', 'PosReg', (37, 46))	('rs2070874 C', 'Var', (18, 29))
515172	32744314	found that the IL-4 rs2070874 polymorphism might not influence the susceptibility of cancer in Chinese population.	('IL-4', 'Gene', '3565', (15, 19))	('rs2070874', 'Var', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('rs2070874', 'Mutation', 'rs2070874', (20, 29))	('IL-4', 'Gene', (15, 19))
515173	32744314	We found that IL-4 rs2070874 T>C polymorphism seemed to be a protective factor for ESCC development.	('ESCC development', 'Disease', (83, 99))	('rs2070874', 'Mutation', 'rs2070874', (19, 28))	('rs2070874 T>C polymorphism', 'Var', (19, 45))	('IL-4', 'Gene', (14, 18))	('IL-4', 'Gene', '3565', (14, 18))
515174	32744314	Our findings were similar to a previous meta-analysis that suggested that the IL-4 rs2070874 C allele could be associated with a decreased susceptibility of gastrointestinal cancer.	('IL-4', 'Gene', (78, 82))	('rs2070874', 'Mutation', 'rs2070874', (83, 92))	('IL-4', 'Gene', '3565', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (157, 180))	('rs2070874 C', 'Var', (83, 94))	('decreased', 'NegReg', (129, 138))
515175	32744314	A functional study indicated that the IL-4 rs2070874 allele C could promote a higher level of IL-4 in plasma.	('IL-4', 'Gene', '3565', (94, 98))	('promote', 'PosReg', (68, 75))	('higher', 'PosReg', (78, 84))	('rs2070874', 'Mutation', 'rs2070874', (43, 52))	('IL-4', 'Gene', (38, 42))	('IL-4', 'Gene', '3565', (38, 42))	('IL-4', 'Gene', (94, 98))	('rs2070874', 'Var', (43, 52))
515177	32744314	reported that the IL-4 rs2070874 allele C could decrease the risk of prostate cancer specific mortality.	('mortality', 'Disease', (94, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('rs2070874', 'Mutation', 'rs2070874', (23, 32))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('decrease', 'NegReg', (48, 56))	('mortality', 'Disease', 'MESH:D003643', (94, 103))	('IL-4', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('IL-4', 'Gene', '3565', (18, 22))	('prostate cancer', 'Disease', (69, 84))	('rs2070874', 'Var', (23, 32))
515178	32744314	Consistent with that report, we identified an association between the IL-4 rs2070874 T>C SNP and a decreased susceptibility to ESCC in the stage I/II subgroup.	('decreased', 'NegReg', (99, 108))	('ESCC', 'Disease', (127, 131))	('rs2070874 T>C SNP', 'Var', (75, 92))	('rs2070874', 'Mutation', 'rs2070874', (75, 84))	('IL-4', 'Gene', (70, 74))	('susceptibility', 'MPA', (109, 123))	('IL-4', 'Gene', '3565', (70, 74))
515179	32744314	However, we did not find an association of IL-4 rs2070874 T>C polymorphism with lymphatic metastasis.	('IL-4', 'Gene', (43, 47))	('lymphatic', 'Disease', (80, 89))	('rs2070874 T>C', 'Var', (48, 61))	('IL-4', 'Gene', '3565', (43, 47))	('rs2070874', 'Mutation', 'rs2070874', (48, 57))
515180	32744314	In the future, the relationship of the rs2070874 SNP in IL-4 gene with progress and prognosis should be further explored.	('rs2070874 SNP', 'Var', (39, 52))	('IL-4', 'Gene', (56, 60))	('rs2070874', 'Mutation', 'rs2070874', (39, 48))	('IL-4', 'Gene', '3565', (56, 60))
515181	32744314	Rs2243263 G>C, an intron SNP in the IL-4 gene, was studied for the relationship of this SNP to some diseases.	('IL-4', 'Gene', (36, 40))	('Rs2243263 G>C', 'Var', (0, 13))	('IL-4', 'Gene', '3565', (36, 40))	('Rs2243263', 'Mutation', 'Rs2243263', (0, 9))
515183	32744314	reported that the IL-4 rs2243263 C allele was a protective factor for HBV surface antigen reverse seroconversion in non-Hodgkin lymphoma cases undergoing rituximab treatment.	('rs2243263 C', 'Var', (23, 34))	('rituximab', 'Chemical', 'MESH:D000069283', (154, 163))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (120, 136))	('rs2243263', 'Mutation', 'rs2243263', (23, 32))	('HBV', 'Gene', (70, 73))	('HBV', 'Species', '10407', (70, 73))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (116, 136))	('IL-4', 'Gene', (18, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('non-Hodgkin lymphoma', 'Disease', (116, 136))	('IL-4', 'Gene', '3565', (18, 22))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (116, 136))
515184	32744314	A previous study investigated the relationship of IL-4 rs2243263 G>C with colon and rectal cancer risk, but no association was found.	('IL-4', 'Gene', (50, 54))	('IL-4', 'Gene', '3565', (50, 54))	('rectal cancer', 'Phenotype', 'HP:0100743', (84, 97))	('rs2243263', 'Mutation', 'rs2243263', (55, 64))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colon', 'Disease', 'MESH:D003110', (74, 79))	('rs2243263 G>C', 'Var', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colon', 'Disease', (74, 79))
515185	32744314	found that the IL-4 rs2243263 G>C SNP increased the susceptibility to non-Hodgkin lymphoma.	('rs2243263 G>C', 'Var', (20, 33))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (74, 90))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (70, 90))	('IL-4', 'Gene', '3565', (15, 19))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('non-Hodgkin lymphoma', 'Disease', (70, 90))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (70, 90))	('IL-4', 'Gene', (15, 19))	('rs2243263', 'Mutation', 'rs2243263', (20, 29))
515186	32744314	In this study, we found that the IL-4 rs2243263 G>C might increase the risk of ESCC in obese and overweight subjects (Table 6).	('overweight', 'Phenotype', 'HP:0025502', (97, 107))	('rs2243263 G>C', 'Var', (38, 51))	('IL-4', 'Gene', '3565', (33, 37))	('obese', 'Disease', 'MESH:D009765', (87, 92))	('ESCC', 'Disease', (79, 83))	('obese', 'Disease', (87, 92))	('rs2243263', 'Mutation', 'rs2243263', (38, 47))	('IL-4', 'Gene', (33, 37))
515190	32744314	Here, we found that the rs2243263 G>C polymorphism, a SNP in IL-4 intron region, might alter the risk of ESCC.	('ESCC', 'Disease', (105, 109))	('rs2243263 G>C', 'Var', (24, 37))	('IL-4', 'Gene', (61, 65))	('IL-4', 'Gene', '3565', (61, 65))	('alter', 'Reg', (87, 92))	('rs2243263', 'Mutation', 'rs2243263', (24, 33))
515191	32744314	It is presumed that the rs2243263 G>C polymorphism influences the level of IL-4 by regulating gene transcription.	('rs2243263 G>C', 'Var', (24, 37))	('IL-4', 'Gene', (75, 79))	('influences', 'Reg', (51, 61))	('IL-4', 'Gene', '3565', (75, 79))	('gene transcription', 'MPA', (94, 112))	('regulating', 'Reg', (83, 93))	('rs2243263', 'Mutation', 'rs2243263', (24, 33))
515192	32744314	The IL-10 rs1800872 T>G is a promotor SNP.	('IL-10', 'Gene', (4, 9))	('IL-10', 'Gene', '3586', (4, 9))	('rs1800872', 'Mutation', 'rs1800872', (10, 19))	('rs1800872 T>G', 'Var', (10, 23))
515193	32744314	reported that the expression of IL-10 mRNA and the level of serum IL-10 were significantly higher in subjects with the IL-10 rs1800872 T allele.	('IL-10', 'Gene', (32, 37))	('IL-10', 'Gene', '3586', (119, 124))	('higher', 'PosReg', (91, 97))	('IL-10', 'Gene', '3586', (66, 71))	('rs1800872 T', 'Var', (125, 136))	('IL-10', 'Gene', (119, 124))	('expression', 'MPA', (18, 28))	('mRNA', 'MPA', (38, 42))	('IL-10', 'Gene', '3586', (32, 37))	('rs1800872', 'Mutation', 'rs1800872', (125, 134))	('IL-10', 'Gene', (66, 71))
515194	32744314	A recent study found that IL-10 rs1800872 T>G SNP promoted the risk of EC.	('promoted', 'PosReg', (50, 58))	('rs1800872', 'Mutation', 'rs1800872', (32, 41))	('IL-10', 'Gene', (26, 31))	('rs1800872 T>G', 'Var', (32, 45))	('IL-10', 'Gene', '3586', (26, 31))
515195	32744314	In our case-control study, we did not find the association of IL-10 rs1800872 T>G SNP with the development of EC, even in stratified analyses and reviewing different lymph node status.	('IL-10', 'Gene', '3586', (62, 67))	('rs1800872', 'Mutation', 'rs1800872', (68, 77))	('IL-10', 'Gene', (62, 67))	('rs1800872 T>G', 'Var', (68, 81))
515196	32744314	reported that IL-10 rs1800872 GG genotypes predicted the worse survival of diffuse large B-cell lymphoma patients treated with rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).	('vincristine', 'Chemical', 'MESH:D014750', (174, 185))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (89, 104))	('patients', 'Species', '9606', (105, 113))	('CHOP', 'Gene', '1649', (137, 141))	('IL-10', 'Gene', '3586', (14, 19))	('rituximab', 'Chemical', 'MESH:D000069283', (127, 136))	('rs1800872', 'Var', (20, 29))	('doxorubicin', 'Chemical', 'MESH:D004317', (161, 172))	('rs1800872', 'Mutation', 'rs1800872', (20, 29))	('CHOP', 'Gene', (137, 141))	('IL-10', 'Gene', (14, 19))	('prednisone', 'Chemical', 'MESH:D011241', (191, 201))	('lymphoma', 'Phenotype', 'HP:0002665', (96, 104))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (143, 159))	('B-cell lymphoma', 'Disease', (89, 104))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (89, 104))
515197	32744314	In this study, we found that the IL-10 rs1800872 G allele was associated with poorly differentiated tumor.	('rs1800872', 'Mutation', 'rs1800872', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('rs1800872 G', 'Var', (39, 50))	('IL-10', 'Gene', (33, 38))	('associated', 'Reg', (62, 72))	('tumor', 'Disease', (100, 105))	('IL-10', 'Gene', '3586', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
515198	32744314	Thus, in the future, the association of the IL-10 rs1800872 T>G SNP and the survival of ESCC cases should be further studied.	('ESCC', 'Disease', (88, 92))	('IL-10', 'Gene', (44, 49))	('rs1800872 T', 'Var', (50, 61))	('rs1800872', 'Mutation', 'rs1800872', (50, 59))	('IL-10', 'Gene', '3586', (44, 49))
515202	32744314	In summary, the present study suggests that the IL-4 rs2070874 T>C polymorphism is a protective factor for ESCC development, while the IL-4 rs2243263 G>C increases a risk to ESCC in obese and overweight subjects.	('increases', 'PosReg', (154, 163))	('rs2243263 G>C', 'Var', (140, 153))	('rs2070874 T>C', 'Var', (53, 66))	('IL-4', 'Gene', '3565', (135, 139))	('rs2070874', 'Mutation', 'rs2070874', (53, 62))	('ESCC', 'Disease', (174, 178))	('overweight', 'Phenotype', 'HP:0025502', (192, 202))	('obese', 'Disease', 'MESH:D009765', (182, 187))	('IL-4', 'Gene', (48, 52))	('rs2243263', 'Mutation', 'rs2243263', (140, 149))	('obese', 'Disease', (182, 187))	('ESCC', 'Disease', (107, 111))	('IL-4', 'Gene', (135, 139))	('IL-4', 'Gene', '3565', (48, 52))
515203	32744314	Additionally, it is highlighted that the IL-10 rs1800872 G allele is associated with poorly differentiated tumor.	('rs1800872 G', 'Var', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('rs1800872', 'Mutation', 'rs1800872', (47, 56))	('IL-10', 'Gene', '3586', (41, 46))	('associated', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('IL-10', 'Gene', (41, 46))
515225	32533278	As a result, he was diagnosed with middle thoracic esophageal cancer (squamous cell carcinoma) and T3N3M0 in clinical stage III according to the criteria of the Japan Esophageal Society.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('middle thoracic esophageal cancer', 'Disease', 'MESH:D004938', (35, 68))	('middle thoracic esophageal cancer', 'Disease', (35, 68))	('squamous cell carcinoma', 'Disease', (70, 93))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('T3N3M0', 'Var', (99, 105))
515305	30684972	In Her-2-positive patients, high RRBP1 expression is correlated with a poor overall survival, and it can be an independent predictor of survival.	('RRBP1', 'Gene', (33, 38))	('Her-2', 'Gene', (3, 8))	('RRBP1', 'Gene', '6238', (33, 38))	('poor', 'NegReg', (71, 75))	('overall', 'MPA', (76, 83))	('patients', 'Species', '9606', (18, 26))	('expression', 'MPA', (39, 49))	('high', 'Var', (28, 32))	('Her-2', 'Gene', '2064', (3, 8))
515332	30684972	Through log-rank test analysis, we found that high expression of RRBP1 had a strong correlation with poor overall survival (OS) and disease-free survival (DFS) in EC patients (Table 2; Fig.	('poor', 'NegReg', (101, 105))	('RRBP1', 'Gene', (65, 70))	('EC', 'Phenotype', 'HP:0012114', (163, 165))	('disease-free survival', 'CPA', (132, 153))	('RRBP1', 'Gene', '6238', (65, 70))	('overall survival', 'CPA', (106, 122))	('patients', 'Species', '9606', (166, 174))	('high expression', 'Var', (46, 61))
515333	30684972	Through multivariate analysis, we also found that high RRBP1 expression was an independent prognostic factor for both OS and DFS (Table 3; P = 0.033 and P = 0.016).	('high', 'Var', (50, 54))	('expression', 'MPA', (61, 71))	('DFS', 'Disease', (125, 128))	('RRBP1', 'Gene', (55, 60))	('RRBP1', 'Gene', '6238', (55, 60))
515338	30684972	In addition, patients with RRBP1 high expression had a shorter duration of OS than patients with RRBP1 low expression.	('RRBP1', 'Gene', '6238', (97, 102))	('high expression', 'Var', (33, 48))	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (55, 62))	('RRBP1', 'Gene', (27, 32))	('patients', 'Species', '9606', (83, 91))	('RRBP1', 'Gene', (97, 102))	('duration', 'MPA', (63, 71))	('RRBP1', 'Gene', '6238', (27, 32))
515357	30068371	Forty-seven patients (25 patients treated with CDDP/5FU and 22 patients treated with Carb/TAX) were evaluated for the intention-to-treat (ITT) analysis and 41 of 47 patients (23 patients treated with CDDP/5FU and 18 patients treated with Carb/TAX) were evaluated for the PP analysis.	('patients', 'Species', '9606', (12, 20))	('Carb', 'Gene', (238, 242))	('Carb', 'Gene', '9482', (85, 89))	('5FU', 'Chemical', 'MESH:D005472', (52, 55))	('CDDP', 'Chemical', 'MESH:D002945', (200, 204))	('5FU', 'Chemical', 'MESH:D005472', (205, 208))	('CDDP/5FU', 'Var', (47, 55))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (216, 224))	('Carb', 'Gene', (85, 89))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (165, 173))	('patients', 'Species', '9606', (63, 71))	('Carb', 'Gene', '9482', (238, 242))	('CDDP', 'Chemical', 'MESH:D002945', (47, 51))
515369	30068371	Although two retrospective analyses found no significant difference for OS and treatment response between both chemotherapy regimens, nCRT with CDDP/5FU was associated with a significantly increased rate of myelotoxicity.	('OS', 'Chemical', '-', (72, 74))	('myelotoxicity', 'Disease', (207, 220))	('myelotoxicity', 'Disease', 'MESH:D001855', (207, 220))	('CDDP/5FU', 'Var', (144, 152))	('CRT', 'Gene', (135, 138))	('CRT', 'Gene', '45841', (135, 138))	('CDDP', 'Chemical', 'MESH:D002945', (144, 148))	('5FU', 'Chemical', 'MESH:D005472', (149, 152))
515378	30068371	In this study, we compared efficiency and toxicity of dCRT with >=54Gy and either CDDP/5FU or Carb/TAX for patients with SCC.	('Carb', 'Gene', (94, 98))	('Gy', 'Chemical', '-', (68, 70))	('5FU', 'Chemical', 'MESH:D005472', (87, 90))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('SCC', 'Gene', (121, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('toxicity', 'Disease', (42, 50))	('dCRT', 'Chemical', '-', (54, 58))	('Carb', 'Gene', '9482', (94, 98))	('SCC', 'Gene', '6317', (121, 124))	('>=54Gy', 'Var', (64, 70))	('patients', 'Species', '9606', (107, 115))	('CDDP', 'Chemical', 'MESH:D002945', (82, 86))
515417	30068371	In total, >= III  myelotoxicity was seen in 52% (CDDP/5FU) and 55% (Carb/TAX) of patients in the ITT-population and in 52% (CDDP/5FU) and 44% (Carb/TAX) of patients in the PP-population.	('patients', 'Species', '9606', (156, 164))	('CDDP', 'Chemical', 'MESH:D002945', (49, 53))	('III  myelotoxicity', 'Disease', (13, 31))	('Carb', 'Gene', (143, 147))	('Carb', 'Gene', (68, 72))	('CDDP', 'Chemical', 'MESH:D002945', (124, 128))	('patients', 'Species', '9606', (81, 89))	('5FU', 'Chemical', 'MESH:D005472', (54, 57))	('5FU', 'Chemical', 'MESH:D005472', (129, 132))	('CDDP/5FU', 'Var', (124, 132))	('III  myelotoxicity', 'Disease', 'MESH:C536044', (13, 31))	('Carb', 'Gene', '9482', (143, 147))	('Carb', 'Gene', '9482', (68, 72))
515421	30068371	Two patients (8%) who were scheduled for CDDP/5FU and one patient (5%) who was scheduled for Carb/TAX had thrombocytopenia >= III  while anemia >= III  was observed in none of the patients in the CDDP/5FU group and three patients (14%) in the Carb/TAX group.	('patients', 'Species', '9606', (221, 229))	('anemia', 'Disease', (137, 143))	('CDDP/5FU', 'Var', (41, 49))	('thrombocytopenia', 'Disease', 'MESH:D013921', (106, 122))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (106, 122))	('patients', 'Species', '9606', (180, 188))	('CDDP', 'Chemical', 'MESH:D002945', (196, 200))	('5FU', 'Chemical', 'MESH:D005472', (201, 204))	('Carb', 'Gene', '9482', (93, 97))	('patients', 'Species', '9606', (4, 12))	('patient', 'Species', '9606', (221, 228))	('Carb', 'Gene', '9482', (243, 247))	('Carb', 'Gene', (93, 97))	('Carb', 'Gene', (243, 247))	('anemia', 'Disease', 'MESH:D000740', (137, 143))	('patient', 'Species', '9606', (180, 187))	('CDDP', 'Chemical', 'MESH:D002945', (41, 45))	('thrombocytopenia', 'Disease', (106, 122))	('patient', 'Species', '9606', (58, 65))	('5FU', 'Chemical', 'MESH:D005472', (46, 49))	('patient', 'Species', '9606', (4, 11))	('anemia', 'Phenotype', 'HP:0001903', (137, 143))
515422	30068371	Based on all available follow-up information including clinical examination, computed tomography and esophago-gastro-duodenoscopy, 15 patients (60%) treated with CDDP/5FU and 9 patients (41%) treated with Carb/TAX had loco-regional or distant treatment failure (p = 0.248).	('CDDP', 'Chemical', 'MESH:D002945', (162, 166))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (134, 142))	('Carb', 'Gene', '9482', (205, 209))	('5FU', 'Chemical', 'MESH:D005472', (167, 170))	('loco-regional or distant treatment failure', 'CPA', (218, 260))	('CDDP/5FU', 'Var', (162, 170))	('Carb', 'Gene', (205, 209))
515423	30068371	Within the PP-population loco-regional or distant treatment failure was observed in 14 patients (61%) treated with CDDP/5FU and 6 patients (33%) treated with Carb/TAX (p = 0.118).	('Carb', 'Gene', '9482', (158, 162))	('loco-regional or distant treatment failure', 'CPA', (25, 67))	('CDDP', 'Chemical', 'MESH:D002945', (115, 119))	('patients', 'Species', '9606', (130, 138))	('Carb', 'Gene', (158, 162))	('5FU', 'Chemical', 'MESH:D005472', (120, 123))	('patients', 'Species', '9606', (87, 95))	('CDDP/5FU', 'Var', (115, 123))
515424	30068371	The rate of loco-regional recurrence within the first year was 36% in patients treated with CDDP/5FU and 32% in patients treated with Carb/TAX (p = 1.000), while distant treatment failure within the first year was seen in 8% (CDDP/5FU) and 18% (Carb/TAX) (p = 0.398).	('loco-regional recurrence', 'CPA', (12, 36))	('Carb', 'Gene', (245, 249))	('patients', 'Species', '9606', (70, 78))	('Carb', 'Gene', '9482', (134, 138))	('CDDP/5FU', 'Var', (92, 100))	('5FU', 'Chemical', 'MESH:D005472', (97, 100))	('patients', 'Species', '9606', (112, 120))	('Carb', 'Gene', (134, 138))	('5FU', 'Chemical', 'MESH:D005472', (231, 234))	('CDDP', 'Chemical', 'MESH:D002945', (92, 96))	('CDDP', 'Chemical', 'MESH:D002945', (226, 230))	('Carb', 'Gene', '9482', (245, 249))
515428	30068371	For patients treated per protocol, loco-regional recurrence or distant recurrence was the first site of treatment failure in 10 patients (71%) and 4 patients (29%) treated with CDDP/5FU and in 2 patients (33%) and 3 patients (50%) treated with Carb/TAX.	('patients', 'Species', '9606', (149, 157))	('CDDP/5FU', 'Var', (177, 185))	('Carb', 'Gene', '9482', (244, 248))	('distant recurrence', 'CPA', (63, 81))	('patients', 'Species', '9606', (216, 224))	('Carb', 'Gene', (244, 248))	('patients', 'Species', '9606', (195, 203))	('loco-regional recurrence', 'CPA', (35, 59))	('patients', 'Species', '9606', (4, 12))	('5FU', 'Chemical', 'MESH:D005472', (182, 185))	('CDDP', 'Chemical', 'MESH:D002945', (177, 181))	('patients', 'Species', '9606', (128, 136))
515431	30068371	Median follow-up was 49.5 months for patients treated with CDDP/5FU and 18.2 months for patients treated with Carb/TAX.	('CDDP', 'Chemical', 'MESH:D002945', (59, 63))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (88, 96))	('Carb', 'Gene', '9482', (110, 114))	('CDDP/5FU', 'Var', (59, 67))	('5FU', 'Chemical', 'MESH:D005472', (64, 67))	('Carb', 'Gene', (110, 114))
515432	30068371	While median OS was 24.2 months for patients treated with CDDP/FU, median OS was not reached for patients treated with Carb/TAX.	('Carb', 'Gene', '9482', (119, 123))	('CDDP', 'Chemical', 'MESH:D002945', (58, 62))	('patients', 'Species', '9606', (36, 44))	('CDDP/FU', 'Var', (58, 65))	('Carb', 'Gene', (119, 123))	('OS', 'Chemical', '-', (74, 76))	('OS', 'Chemical', '-', (13, 15))	('patients', 'Species', '9606', (97, 105))
515435	30068371	Median FFR was 12.1 months for patients treated with CDDP/5FU and median FFR was not reached for patients treated with Carb/TAX.	('Carb', 'Gene', '9482', (119, 123))	('FFR', 'Gene', '738', (73, 76))	('CDDP/5FU', 'Var', (53, 61))	('Carb', 'Gene', (119, 123))	('CDDP', 'Chemical', 'MESH:D002945', (53, 57))	('patients', 'Species', '9606', (97, 105))	('FFR', 'Gene', (7, 10))	('patients', 'Species', '9606', (31, 39))	('5FU', 'Chemical', 'MESH:D005472', (58, 61))	('FFR', 'Gene', '738', (7, 10))	('FFR', 'Gene', (73, 76))
515452	30068371	In a retrospective trial by Kim et al., high-dose dCRT (median dose 63Gy) was associated with increased OS and loco-regional control than standard-dose dCRT (median dose 50.4Gy).	('high-dose dCRT', 'Var', (40, 54))	('Gy', 'Chemical', '-', (174, 176))	('OS', 'Chemical', '-', (104, 106))	('increased', 'PosReg', (94, 103))	('dCRT', 'Chemical', '-', (152, 156))	('dCRT', 'Chemical', '-', (50, 54))	('Gy', 'Chemical', '-', (70, 72))
515459	30068371	However, when comparing FFR to DFS and PFS our results for patients receiving CDDP/5FU seem to be comparable to the results of Honing et al.	('5FU', 'Chemical', 'MESH:D005472', (83, 86))	('FFR', 'Gene', '738', (24, 27))	('CDDP/5FU', 'Var', (78, 86))	('patients', 'Species', '9606', (59, 67))	('CDDP', 'Chemical', 'MESH:D002945', (78, 82))	('FFR', 'Gene', (24, 27))
515464	30068371	A total of 48 and 20% of patients treated with CDDP/5FU had loco-regional or distant treatment failure.	('5FU', 'Chemical', 'MESH:D005472', (52, 55))	('CDDP/5FU', 'Var', (47, 55))	('patients', 'Species', '9606', (25, 33))	('CDDP', 'Chemical', 'MESH:D002945', (47, 51))	('loco-regional or distant treatment failure', 'CPA', (60, 102))
515471	30068371	Compared to the results presented by Honing et al., the rate of >= III  myelotoxicity in our study was higher for both, patients treated with CDDP/5FU (52% vs. 19%) and patients treated with Carb/TAX (55% vs. 4%).	('5FU', 'Chemical', 'MESH:D005472', (147, 150))	('patients', 'Species', '9606', (169, 177))	('CDDP', 'Chemical', 'MESH:D002945', (142, 146))	('III  myelotoxicity', 'Disease', 'MESH:C536044', (67, 85))	('Carb', 'Gene', '9482', (191, 195))	('patients', 'Species', '9606', (120, 128))	('higher', 'PosReg', (103, 109))	('CDDP/5FU', 'Var', (142, 150))	('III  myelotoxicity', 'Disease', (67, 85))	('Carb', 'Gene', (191, 195))
515475	30068371	Although the rate of >= III  myelotoxicity for patients treated with CDDP/5FU in our analysis is much higher than in the study by Honing et al., it is comparable to other studies.	('CDDP', 'Chemical', 'MESH:D002945', (69, 73))	('III  myelotoxicity', 'Disease', (24, 42))	('patients', 'Species', '9606', (47, 55))	('5FU', 'Chemical', 'MESH:D005472', (74, 77))	('higher', 'PosReg', (102, 108))	('CDDP/5FU', 'Var', (69, 77))	('III  myelotoxicity', 'Disease', 'MESH:C536044', (24, 42))
515493	30068371	Follow-up of patients treated with CDDP/5FU is clearly longer than follow-up of patients treated with Carb/TAX.	('Carb', 'Gene', '9482', (102, 106))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (13, 21))	('5FU', 'Chemical', 'MESH:D005472', (40, 43))	('Carb', 'Gene', (102, 106))	('CDDP/5FU', 'Var', (35, 43))	('CDDP', 'Chemical', 'MESH:D002945', (35, 39))
515494	30068371	The reason for this imbalance is that all patients who received CDDP/5FU were treated between 2011 and 2014 while the first patient who received Carb/TAX was treated at the end of 2014.	('5FU', 'Chemical', 'MESH:D005472', (69, 72))	('Carb', 'Gene', (145, 149))	('imbalance', 'Phenotype', 'HP:0002172', (20, 29))	('CDDP/5FU', 'Var', (64, 72))	('patient', 'Species', '9606', (42, 49))	('patient', 'Species', '9606', (124, 131))	('Carb', 'Gene', '9482', (145, 149))	('patients', 'Species', '9606', (42, 50))	('CDDP', 'Chemical', 'MESH:D002945', (64, 68))
515536	29515136	After at least five passages in culture, the majority of the cells expressed surface markers (Supplemental Table 1) associated with aMSCs, including CD44, CD73, CD90, CD105, and CD146 (>70% of events in live gate, Fig.	('CD90', 'Gene', (161, 165))	('CD44', 'Gene', (149, 153))	('aMSCs', 'Disease', (132, 137))	('CD73', 'Var', (155, 159))	('CD14', 'Gene', (178, 182))	('CD105', 'Var', (167, 172))	('CD44', 'Gene', '100126860', (149, 153))	('CD14', 'Gene', '100620530', (178, 182))	('CD90', 'Gene', '100271931', (161, 165))
515579	29515136	Reshaping the stomach in the form of a tube and rerouting it into the chest carries significant complications namely leakage from the anastomosis which can occur in more than 10% of the patients and major pulmonary complications that can arise in up to 38% of the patients.	('pulmonary complications', 'Phenotype', 'HP:0006532', (205, 228))	('pulmonary complications', 'Disease', (205, 228))	('pulmonary complications', 'Disease', 'MESH:D008171', (205, 228))	('leakage', 'CPA', (117, 124))	('patients', 'Species', '9606', (264, 272))	('Reshaping', 'Var', (0, 9))	('patients', 'Species', '9606', (186, 194))
515669	29113654	Emerging data demonstrate that intestinal bacteria can modulate the efficacy of cancer chemotherapies and novel targeted immunotherapies such as anti-CTLA4 and anti-CD274 therapies, the process of absorption, and the occurrence of complications after gastrointestinal surgery.	('modulate', 'Reg', (55, 63))	('anti-CTLA4', 'Var', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('anti-CD274', 'Var', (160, 170))	('rat', 'Species', '10116', (21, 24))	('complications after gastrointestinal surgery', 'Phenotype', 'HP:0004798', (231, 275))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
515672	29113654	Accumulating evidence indicates that gastrointestinal tract cancers develop through the accumulation of genetic and epigenetic alterations, which are influenced by host immunity, diet, and environmental and microbial exposures.	('rat', 'Species', '10116', (131, 134))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('gastrointestinal tract cancers', 'Disease', 'MESH:D004067', (37, 67))	('epigenetic alterations', 'Var', (116, 138))	('gastrointestinal tract cancers', 'Disease', (37, 67))	('gastrointestinal tract cancer', 'Phenotype', 'HP:0007378', (37, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
515677	29113654	In addition, we describe emerging evidence for roles of intestinal bacteria in the efficacy of cancer chemotherapies and novel targeted immunotherapies such as anti-CTLA4 and anti-CD274 therapies, the process of absorption, and the occurrence of complications after gastrointestinal surgery.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('complications after gastrointestinal surgery', 'Phenotype', 'HP:0004798', (246, 290))	('anti-CD274', 'Var', (175, 185))	('anti-CTLA4', 'Var', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
515692	29113654	Polyamines have been shown to suppress antitumor immunity and potentiate the proliferation of cancer cells, invasion and metastasis.	('Polyamines', 'Var', (0, 10))	('Polyamines', 'Chemical', 'MESH:D011073', (0, 10))	('rat', 'Species', '10116', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('potentiate', 'PosReg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('suppress', 'NegReg', (30, 38))	('tumor', 'Disease', (43, 48))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
515698	29113654	Experimental studies have shown that lithocholic and deoxycholic acid can activate the NFKB signaling pathway in colonic epithelial cells and that deoxycholic acid can potentiate the development of colorectal tumors in rats receiving azoxymethane (AOM), a colorectal carcinogen.	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('colorectal tumors', 'Disease', (198, 215))	('AOM', 'Chemical', 'MESH:D001397', (248, 251))	('potentiate', 'PosReg', (168, 178))	('rats', 'Species', '10116', (219, 223))	('azoxymethane', 'Chemical', 'MESH:D001397', (234, 246))	('NFKB', 'Gene', '81736', (87, 91))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (53, 69))	('colorectal tumors', 'Disease', 'MESH:D015179', (198, 215))	('colorectal carcinogen', 'Disease', (256, 277))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (147, 163))	('lithocholic', 'Chemical', '-', (37, 48))	('NFKB', 'Gene', (87, 91))	('deoxycholic acid', 'Var', (147, 163))	('activate', 'PosReg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('colorectal carcinogen', 'Disease', 'MESH:D015179', (256, 277))
515699	29113654	A study based on a mouse model suggests that deoxycholic acid can promote the development of Barrett's esophagus and esophageal adenocarcinoma by damaging DNA.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (93, 112))	('damaging', 'NegReg', (146, 154))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (117, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('promote', 'PosReg', (66, 73))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (45, 61))	('DNA', 'MPA', (155, 158))	('mouse', 'Species', '10090', (19, 24))	('deoxycholic acid', 'Var', (45, 61))	('esophageal adenocarcinoma', 'Disease', (117, 142))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (117, 142))	("Barrett's esophagus", 'Disease', (93, 112))
515702	29113654	In contrast, emerging data demonstrate that low concentrations of butyrate may promote the growth of colonic tumors that exhibit DNA mismatch repair deficiencies in a mouse model.	('rat', 'Species', '10116', (70, 73))	('butyrate', 'Chemical', 'MESH:D002087', (66, 74))	('colonic tumor', 'Phenotype', 'HP:0100273', (101, 114))	('growth', 'MPA', (91, 97))	('colonic tumors', 'Disease', (101, 115))	('promote', 'PosReg', (79, 86))	('colonic tumors', 'Disease', 'MESH:D015179', (101, 115))	('rat', 'Species', '10116', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('deficiencies', 'Var', (149, 161))	('rat', 'Species', '10116', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mouse', 'Species', '10090', (167, 172))
515731	29113654	A high amount of Campylobacter concisus in esophageal tissues is associated with Barrett's esophagus and increased expression of IL18, which is associated with carcinogenesis.	("Barrett's esophagus", 'Disease', (81, 100))	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (81, 100))	('IL18', 'Gene', (129, 133))	('Campylobacter concisus', 'Var', (17, 39))	('carcinogenesis', 'Disease', (160, 174))	('associated', 'Reg', (65, 75))	('expression', 'MPA', (115, 125))	('Campylobacter concisus', 'Species', '199', (17, 39))	('increased', 'PosReg', (105, 114))
515744	29113654	Several studies have demonstrated that the proportions of colorectal cancers with specific molecular features such as microsatellite instability (MSI)-high, CpG island methylator phenotype (CIMP)-high, and BRAF and PIK3CA mutations gradually increase along the bowel subsites from the rectum to the ascending colon.	('CIMP', 'Chemical', '-', (190, 194))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (58, 75))	('colorectal cancers', 'Disease', 'MESH:D015179', (58, 76))	('PIK3CA', 'Gene', '5290', (215, 221))	('increase', 'PosReg', (242, 250))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rat', 'Species', '10116', (28, 31))	('colorectal cancers', 'Disease', (58, 76))	('MSI', 'Disease', 'None', (146, 149))	('BRAF', 'Gene', '673', (206, 210))	('mutations', 'Var', (222, 231))	('BRAF', 'Gene', (206, 210))	('MSI', 'Disease', (146, 149))	('PIK3CA', 'Gene', (215, 221))
515745	29113654	The proportion of colorectal cancer enriched with Fusobacterium nucleatum increases linearly along the bowel subsites from the rectum to the cecum, suggesting a continuum model of pathogenic influences of intestinal bacteria on colorectal carcinogenesis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('colorectal carcinogenesis', 'Disease', (228, 253))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Fusobacterium nucleatum', 'Species', '851', (50, 73))	('colorectal cancer', 'Disease', (18, 35))	('Fusobacterium', 'Var', (50, 63))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (228, 253))	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))
515746	29113654	Low fiber consumption and high meat intake have been associated with altered bacterial and metagenomic profiles.	('altered', 'Reg', (69, 76))	('fiber', 'Chemical', 'MESH:D004043', (4, 9))	('Low fiber', 'Var', (0, 9))
515762	29113654	The bacterial beta-glucuronidase then deconjugates SN38G to SN38, the active form, in the gut, which can cause severe diarrhea.	('SN38G', 'Var', (51, 56))	('cause', 'Reg', (105, 110))	('diarrhea', 'Phenotype', 'HP:0002014', (118, 126))	('diarrhea', 'Disease', 'MESH:D003967', (118, 126))	('diarrhea', 'Disease', (118, 126))	('SN38', 'Var', (60, 64))	('severe diarrhea', 'Phenotype', 'HP:0002028', (111, 126))
515763	29113654	Bacterial beta-glucuronidase-selective inhibitors have been shown to reduce the incidence of irinotecan-induced diarrhea in mice.	('inhibitors', 'Var', (39, 49))	('diarrhea', 'Disease', (112, 120))	('irinotecan', 'Chemical', 'MESH:D000077146', (93, 103))	('diarrhea', 'Disease', 'MESH:D003967', (112, 120))	('mice', 'Species', '10090', (124, 128))	('reduce', 'NegReg', (69, 75))	('diarrhea', 'Phenotype', 'HP:0002014', (112, 120))
515767	29113654	Therapeutic antibodies specific for immune checkpoint molecules, including CTLA4, PDCD1 (programmed cell death 1; PD-1), and CD274 (programmed cell death 1 ligand 1; PD-L1) can effectively enhance antitumor T-cell activity in various cancers, underscoring an important role of T-cell-mediated adaptive immunity in inhibiting tumor progression.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('PD-L1', 'Gene', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('PDCD1', 'Gene', '100533201', (82, 87))	('enhance', 'PosReg', (189, 196))	('programmed cell death 1 ligand 1', 'Gene', (132, 164))	('tumor', 'Disease', (201, 206))	('CD274', 'Var', (125, 130))	('cancers', 'Disease', 'MESH:D009369', (234, 241))	('PDCD1', 'Gene', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('programmed cell death 1 ligand 1', 'Gene', '574058', (132, 164))	('tumor', 'Disease', (325, 330))	('CTLA4', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('PD-L1', 'Gene', '574058', (166, 171))	('cancers', 'Disease', (234, 241))
515769	29113654	These findings suggest that manipulating the gut microbiota may modulate the efficacy of cancer immunotherapy.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('modulate', 'Reg', (64, 72))	('cancer', 'Disease', (89, 95))	('manipulating', 'Var', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
515804	23053896	LI-cadherin IRS was lower for tumors with poor differentiation than for moderately differentiated tumors, but the difference was not statistically significant.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('lower', 'NegReg', (20, 25))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('poor differentiation', 'Var', (42, 62))	('LI-cadherin', 'Gene', '1015', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('LI-cadherin', 'Gene', (0, 11))
515815	23053896	Abnormalities in adhesion are the most important factors in generating invasive cancer cells.	('invasive cancer', 'Disease', (71, 86))	('Abnormalities', 'Var', (0, 13))	('invasive cancer', 'Disease', 'MESH:D009362', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('adhesion', 'MPA', (17, 25))
515822	23053896	Abnormalities in LI-cadherin expression have been shown to serve as marker for early detection and changes toward development of gastric intestinal metaplasia and well-differentiated gastric adenocarcinomas, and as a marker of other carcinomas.	('LI-cadherin', 'Gene', (17, 28))	('carcinomas', 'Disease', 'MESH:D002277', (233, 243))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('carcinomas', 'Disease', (196, 206))	('carcinomas', 'Disease', 'MESH:D002277', (196, 206))	('Abnormalities', 'Var', (0, 13))	('carcinomas', 'Disease', (233, 243))	('LI-cadherin', 'Gene', '1015', (17, 28))	('men', 'Species', '9606', (121, 124))	('gastric intestinal metaplasia', 'Disease', (129, 158))	('gastric intestinal metaplasia', 'Disease', 'MESH:D013274', (129, 158))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (183, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('expression', 'MPA', (29, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('carcinomas', 'Phenotype', 'HP:0030731', (233, 243))	('gastric adenocarcinomas', 'Disease', (183, 206))
515846	23053896	However, we observed tendency to lower survival of patients with high LI-cadherin expression.	('LI-cadherin', 'Gene', (70, 81))	('LI-cadherin', 'Gene', '1015', (70, 81))	('high', 'Var', (65, 69))	('survival', 'MPA', (39, 47))	('patients', 'Species', '9606', (51, 59))	('lower', 'NegReg', (33, 38))
515876	23053896	Lack of cadherin is one of the factors that may induce metastasis of cancer cells, probably by transduction of signaling pathways and factors that activate tumor cells to invade adjacent cells and tissues.	('cadherin', 'Gene', (8, 16))	('activate', 'PosReg', (147, 155))	('metastasis', 'CPA', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('induce', 'PosReg', (48, 54))	('Lack', 'Var', (0, 4))	('cadherin', 'Gene', '999;1015;1015', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('invade adjacent', 'CPA', (171, 186))
515903	17367523	Seven years prior he was diagnosed with a T1-2, N1 SCCA of the left anterior tonsillar pillar and treated with radiation therapy (XRT) (6660 cyG to the primary tumor).	('left anterior tonsillar pillar', 'Disease', 'MESH:C537775', (63, 93))	('left anterior tonsillar pillar', 'Disease', (63, 93))	('SCCA', 'Phenotype', 'HP:0002860', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('T1-2', 'Var', (42, 46))
515926	17367523	Biopsies at the cancer site 6 weeks after the second cryoablation and bimonthly in the subsequent 12 months of follow-up were completely negative for dysplasia or neoplasia.	('negative', 'NegReg', (137, 145))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('dysplasia or neoplasia', 'Disease', 'MESH:D009369', (150, 172))	('cancer', 'Disease', (16, 22))	('dysplasia or neoplasia', 'Disease', (150, 172))	('neoplasia', 'Phenotype', 'HP:0002664', (163, 172))	('cryoablation', 'Var', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
515931	17367523	CSA induces apoptosis and causes cryonecrosis at super-cold temperatures (-76 C to -158 C), which results in transient ischemia at the CSA site and can cause immune stimulation.	('CSA', 'Chemical', '-', (0, 3))	('transient ischemia', 'Phenotype', 'HP:0002326', (109, 127))	('immune stimulation', 'MPA', (158, 176))	('results in', 'Reg', (98, 108))	('ischemia', 'Disease', (119, 127))	('induces', 'Reg', (4, 11))	('CSA', 'Chemical', '-', (135, 138))	('ischemia', 'Disease', 'MESH:D007511', (119, 127))	('cause', 'Reg', (152, 157))	('cryonecrosis', 'Disease', (33, 45))	('-76', 'Var', (74, 77))	('apoptosis', 'CPA', (12, 21))
515986	32377285	Morphine can inhibit the respiratory and immune functions of the body and lead to the growth and metastasis of residual tumor cells.	('Morphine', 'Chemical', 'MESH:D009020', (0, 8))	('lead to', 'Reg', (74, 81))	('Morphine', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('inhibit', 'NegReg', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
515991	32377285	Studies have shown that the sensory block level of single T6 level paravertebral block can reach 9 to 10 segments after 20 mL mepivacaine injection.	('single T6', 'Var', (51, 60))	('sensory block', 'MPA', (28, 41))	('mepivacaine', 'Chemical', 'MESH:D008619', (126, 137))
516076	30612962	Our data showed that 26% of patients with esophageal cancer had lobar-based defects and that the baseline values were 0.52, 11.2, and 72.5 for the CoV, Vent-RL, and Vent-SI metrics, respectively.	('esophageal cancer', 'Disease', (42, 59))	('Vent-SI', 'Disease', (165, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('lobar-based', 'Var', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Vent-SI', 'Disease', '-', (165, 172))	('patients', 'Species', '9606', (28, 36))
516090	30612962	Hart et al demonstrated how pretreatment to posttreatment changes in standardized uptake value were predictive of clinical radiation pneumonitis in patients with esophageal cancer.	('patients', 'Species', '9606', (148, 156))	('standardized uptake value', 'MPA', (69, 94))	('esophageal cancer', 'Disease', (162, 179))	('changes', 'Var', (58, 65))	('pneumonitis', 'Disease', (133, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('pneumonitis', 'Disease', 'MESH:D011014', (133, 144))
516139	31146370	Gal-9 was shown to induce apoptosis in Th1 and Th17 cells via the Tim-3 pathway and is thought to contribute to the activation of tumor immunity and suppression of the autoimmune response via 4-1BB (CD137).	('induce', 'PosReg', (19, 25))	('autoimmune response', 'Phenotype', 'HP:0002960', (168, 187))	('apoptosis', 'CPA', (26, 35))	('Tim-3', 'Gene', (66, 71))	('Gal-9', 'Var', (0, 5))	('Th1', 'Gene', '51497', (47, 50))	('Th1', 'Gene', '51497', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Tim-3', 'Gene', '84868', (66, 71))	('activation', 'PosReg', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Th1', 'Gene', (39, 42))	('tumor', 'Disease', (130, 135))	('Th1', 'Gene', (47, 50))
516147	31146370	We examined the growth inhibitory effect of Gal-9 on ESCC cells with the cell proliferation assay and found that Gal-9 inhibited the proliferation of human ESCC cell lines KYSE-150 and KYSE-180 in a dose- and time-dependent manner (Figure 1A).	('human', 'Species', '9606', (150, 155))	('Gal-9', 'Var', (113, 118))	('inhibited', 'NegReg', (119, 128))	('proliferation', 'CPA', (133, 146))	('KYSE-150', 'CellLine', 'CVCL:1348', (172, 180))	('ESCC', 'Disease', (156, 160))
516161	31146370	Gal-9 can induce the collapse of mitochondrial potential in KYSE-150 cells.	('mitochondrial potential', 'MPA', (33, 56))	('Gal-9', 'Var', (0, 5))	('KYSE-150', 'CellLine', 'CVCL:1348', (60, 68))	('collapse', 'MPA', (21, 29))
516164	31146370	A significant increase in the expression of miR-222-5p, miR582-5p, miR-6131, and miR-4639-5p was observed (Table 1, GEO, accession no.	('expression', 'MPA', (30, 40))	('miR-222-5p', 'Var', (44, 54))	('increase', 'PosReg', (14, 22))	('miR-4639', 'Gene', '100616269', (81, 89))	('miR-6131', 'Gene', '102465138', (67, 75))	('miR-4639', 'Gene', (81, 89))	('miR582', 'Gene', '693167', (56, 62))	('miR-6131', 'Gene', (67, 75))	('miR582', 'Gene', (56, 62))
516186	31146370	Gal-9 is believed to induce cancer cell death via an apoptosis signal transduction pathway, thereby suppressing the proliferation of various cancerous cells.	('cancerous', 'Disease', (141, 150))	('death', 'Disease', 'MESH:D003643', (40, 45))	('death', 'Disease', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Gal-9', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancerous', 'Disease', 'MESH:D009369', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('suppressing', 'NegReg', (100, 111))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', (141, 147))
516210	31146370	We found a significant increase in the expression of miR-222-5p, miR582-5p, and miR-6131, while the expression of miR-4639-5p was significantly decreased.	('miR582', 'Gene', (65, 71))	('miR-6131', 'Gene', '102465138', (80, 88))	('increase', 'PosReg', (23, 31))	('miR582', 'Gene', '693167', (65, 71))	('miR-4639', 'Gene', '100616269', (114, 122))	('expression', 'MPA', (39, 49))	('miR-4639', 'Gene', (114, 122))	('miR-6131', 'Gene', (80, 88))	('miR-222-5p', 'Var', (53, 63))
516226	31146370	The following antibodies were used: beta-actin (Sigma-Aldrich, St. Louis, MO, USA; A5441), caspase-3 (8G10) (#9665), cleaved caspase-3 (D175) (#1661), caspase-7 (D2Q3L) (#12827), cleaved caspase-7 (Asp198) (D6H1) (#8438), caspase-9 (C9) (#9508), cleaved caspase-9 (Asp330) (#7237), poly (ADP-ribose) polymerase (PARP, #9542), cleaved-PARP (D64E10) (#5625), cytochrome c (D18C7) (#11940), Smac (#2954), HtrA2/Omi (HtrA2) (D20A5) (#9745), stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK, #9252), phospho-SAPK/JNK (Thr183/Tyr185) (81E11) (#4668), p38 mitogen-activated protein kinase (MAPK, D13E1) (#8690), phospho-p38 MAPK (Thr180/Tyr182) (D3F9) (#4511), and secondary horseradish peroxidase (HRP)-linked anti-mouse and anti-rabbit IgG antibodies (Cell Signaling Technology, Danvers, MA, USA).	('JNK', 'Gene', '5599', (501, 504))	('rabbit', 'Species', '9986', (743, 749))	('p38', 'Gene', (632, 635))	('IgG antibodies', 'Phenotype', 'HP:0003237', (750, 764))	('caspase-9', 'Gene', (222, 231))	('Smac', 'Gene', (388, 392))	('HtrA2/Omi', 'Gene', '27429', (402, 411))	('caspase-7', 'Gene', '840', (187, 196))	('cytochrome c', 'Gene', '54205', (357, 369))	('HtrA2', 'Gene', '27429', (402, 407))	('Smac', 'Gene', '56616', (388, 392))	('mouse', 'Species', '10090', (728, 733))	('c-Jun NH2-terminal kinase', 'Gene', '5599', (469, 494))	('beta-actin', 'Gene', (36, 46))	('p38', 'Gene', '1432', (632, 635))	('caspase-3', 'Gene', '836', (125, 134))	('caspase-7', 'Gene', (151, 160))	('HtrA2', 'Gene', (413, 418))	('PARP', 'Gene', '142', (312, 316))	('PARP', 'Gene', '142', (334, 338))	('PARP', 'Gene', (312, 316))	('caspase-3', 'Gene', (125, 134))	('p38', 'Gene', (564, 567))	('caspase-9', 'Gene', '842', (254, 263))	('c-Jun NH2-terminal kinase', 'Gene', (469, 494))	('HtrA2/Omi', 'Gene', (402, 411))	('PARP', 'Gene', (334, 338))	('cytochrome c', 'Gene', (357, 369))	('caspase-7', 'Gene', (187, 196))	('caspase-9', 'Gene', '842', (222, 231))	('caspase-3', 'Gene', '836', (91, 100))	('beta-actin', 'Gene', '728378', (36, 46))	('HtrA2', 'Gene', (402, 407))	('horseradish', 'Species', '3704', (687, 698))	('HtrA2', 'Gene', '27429', (413, 418))	('JNK', 'Gene', (527, 530))	('caspase-3', 'Gene', (91, 100))	('caspase-7', 'Gene', '840', (151, 160))	('p38', 'Gene', '1432', (564, 567))	('JNK', 'Gene', (501, 504))	('caspase-9', 'Gene', (254, 263))	('Thr180/Tyr182', 'Var', (642, 655))	('JNK', 'Gene', '5599', (527, 530))
516256	31182150	Injury of the RLN induces a paresis or palsy of the vocal cords:which can in turn increase the rates of postoperative pulmonary complications and severely impair quality of life.	('pulmonary complications', 'Phenotype', 'HP:0006532', (118, 141))	('Injury', 'Var', (0, 6))	('quality of life', 'CPA', (162, 177))	('palsy', 'Disease', (39, 44))	('impair', 'NegReg', (155, 161))	('paresis', 'Disease', (28, 35))	('increase', 'PosReg', (82, 90))	('palsy', 'Disease', 'MESH:D010243', (39, 44))	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (104, 141))	('postoperative pulmonary complications', 'Disease', (104, 141))	('paresis', 'Disease', 'MESH:D010291', (28, 35))
516296	31182150	Blunt dissection and removal of lymph nodes located around the RLN may cause nerve contusions and heat injuries that can in turn result in postoperative palsy.	('cause', 'Reg', (71, 76))	('result in', 'Reg', (129, 138))	('Blunt dissection', 'Var', (0, 16))	('postoperative palsy', 'Disease', 'MESH:D010149', (139, 158))	('postoperative palsy', 'Disease', (139, 158))	('nerve contusions', 'CPA', (77, 93))	('heat injuries', 'CPA', (98, 111))
516308	31058084	In overall analyses, the presence of metabolic syndrome was associated with a non-significant 19% increased mortality risk for digestive tract cancer (hazard ratio [HR]: 1.19; 95% confidence interval [CI]: 1.45 to 2.520.95 to 1.49, P = 0.130; I2: 94.8%).	('tract cancer', 'Disease', (137, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (127, 149))	('metabolic syndrome', 'Disease', 'MESH:D008659', (37, 55))	('metabolic syndrome', 'Disease', (37, 55))	('tract cancer', 'Disease', 'MESH:D014571', (137, 149))	('presence', 'Var', (25, 33))
516315	31058084	As demonstrated by the Chinese FIESTA cohort, the presence of metabolic syndrome respectively contributed to a 1.45-, 2.30-, and 2.98-fold increase in postsurgical mortality risk of esophageal squamous cell carcinoma, gastric cancer, and colorectal cancer.	('metabolic syndrome', 'Disease', (62, 80))	('colorectal cancer', 'Disease', (238, 255))	('gastric cancer', 'Disease', (218, 232))	('gastric cancer', 'Disease', 'MESH:D013274', (218, 232))	('colorectal cancer', 'Disease', 'MESH:D015179', (238, 255))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (193, 216))	('esophageal squamous cell carcinoma', 'Disease', (182, 216))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('presence', 'Var', (50, 58))	('increase', 'PosReg', (139, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (218, 232))	('colorectal cancer', 'Phenotype', 'HP:0003003', (238, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('metabolic syndrome', 'Disease', 'MESH:D008659', (62, 80))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (182, 216))
516332	31058084	In overall analysis, the presence of metabolic syndrome was associated with a non-significant 19% increased mortality risk in digestive tract cancer (HR: 1.19; 95% CI: 0.95 to 1.49, P = 0.130), and this association was obsessed by significant between-study heterogeneity (I2: 94.8%) (Figure 1: the upper panel).	('tract cancer', 'Disease', (136, 148))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (126, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('metabolic syndrome', 'Disease', 'MESH:D008659', (37, 55))	('metabolic syndrome', 'Disease', (37, 55))	('presence', 'Var', (25, 33))	('tract cancer', 'Disease', 'MESH:D014571', (136, 148))
516344	31058084	Via a comprehensive analysis on 15 publications and 54,656 patients, our findings indicate that the presence of metabolic syndrome was associated with an increased risk of digestive tract cancer mortality in overall analyses, and this association was reinforced under the multivariable model, highlighting the independent role of metabolic reprogramming in carcinogenesis.	('tract cancer', 'Disease', (182, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('increased risk of digestive tract', 'Phenotype', 'HP:0011024', (154, 187))	('carcinogenesis', 'Disease', 'MESH:D063646', (357, 371))	('tract cancer', 'Disease', 'MESH:D014571', (182, 194))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (172, 194))	('metabolic syndrome', 'Disease', 'MESH:D008659', (112, 130))	('metabolic syndrome', 'Disease', (112, 130))	('carcinogenesis', 'Disease', (357, 371))	('patients', 'Species', '9606', (59, 67))	('presence', 'Var', (100, 108))
516501	30071375	The relative anatomic contraindications include obesity, cirrhosis, small bowel obstruction, septic peritonitis, disseminated abdominal cancer, and aberrant anatomy, while the physiologic ones are coagulopathy, pregnancy, shock, or a disease of intracranial, pulmonary or cardiovascular.	('cirrhosis', 'Phenotype', 'HP:0001394', (57, 66))	('pregnancy', 'Disease', (211, 220))	('small bowel obstruction', 'Disease', 'MESH:D007409', (68, 91))	('shock', 'Disease', 'MESH:D012769', (222, 227))	('abdominal cancer', 'Disease', (126, 142))	('coagulopathy', 'Disease', 'MESH:D001778', (197, 209))	('cirrhosis', 'Disease', (57, 66))	('coagulopathy', 'Disease', (197, 209))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('septic peritonitis', 'Disease', (93, 111))	('obesity', 'Phenotype', 'HP:0001513', (48, 55))	('shock', 'Phenotype', 'HP:0031273', (222, 227))	('shock', 'Disease', (222, 227))	('abdominal cancer', 'Disease', 'MESH:D009369', (126, 142))	('aberrant anatomy', 'Var', (148, 164))	('obesity', 'Disease', (48, 55))	('cirrhosis', 'Disease', 'MESH:D005355', (57, 66))	('peritonitis', 'Phenotype', 'HP:0002586', (100, 111))	('small bowel obstruction', 'Disease', (68, 91))	('coagulopathy', 'Phenotype', 'HP:0003256', (197, 209))	('septic peritonitis', 'Disease', 'MESH:D010534', (93, 111))	('obesity', 'Disease', 'MESH:D009765', (48, 55))	('bowel obstruction', 'Phenotype', 'HP:0005214', (74, 91))
516508	30071375	Incomplete myotomy, especially on the gastric side (where myotomy is more difficult), scarring of myotomy, and too-tight anti-reflux bonds are thought to be the cause of treatment failure.	('scarring', 'CPA', (86, 94))	('-reflux', 'Phenotype', 'HP:0002020', (125, 132))	('treatment failure', 'Disease', 'MESH:D016609', (170, 187))	('Incomplete myotomy', 'Disease', (0, 18))	('scar', 'Phenotype', 'HP:0100699', (86, 90))	('treatment failure', 'Disease', (170, 187))	('scarring', 'Phenotype', 'HP:0100699', (86, 94))	('too-tight', 'Var', (111, 120))
516620	26413213	Proteins containing JmjC domain are implicated in the regulation of chromatin remodeling and are predicted to be metallo-enzymes adopting the cupin fold.	('metal', 'Chemical', 'MESH:D008670', (113, 118))	('chromatin', 'MPA', (68, 77))	('implicated', 'Reg', (36, 46))	('Proteins', 'Protein', (0, 8))	('JmjC domain', 'Var', (20, 31))
516622	26413213	MINA (Tyrosine 209C) residue readily cross-links and crystallizes in complex with RPL27A (G37C).	('RPL27A', 'Gene', '6157', (82, 88))	('G37C', 'Mutation', 'c.37G>C', (90, 94))	('RPL27A', 'Gene', (82, 88))	('Tyrosine', 'Chemical', 'MESH:D014443', (6, 14))	('cross-links', 'Interaction', (37, 48))	('Tyrosine 209C', 'Var', (6, 19))
516627	26413213	Tissue distribution of mdig/MINA mRNA in normal human tissues as revealed by northern blot analysis showed the presence of mdig/MINA in liver, skeletal muscle, heart, pancreas and placenta whereas in brain, lung and kidney it was undetectable.	('human', 'Species', '9606', (48, 53))	('mdig/MINA', 'Var', (123, 132))	('pancreas', 'Disease', (167, 175))	('pancreas', 'Disease', 'MESH:D010190', (167, 175))
516651	26413213	It is well-known that genetic aberrations contribute to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('contribute', 'Reg', (42, 52))	('genetic aberrations', 'Var', (22, 41))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
516652	26413213	Emerging evidence in the past decade also suggested important contributions of epigenetic alterations on histone proteins and DNA to carcinogenesis.	('carcinogenesis', 'Disease', (133, 147))	('carcinogenesis', 'Disease', 'MESH:D063646', (133, 147))	('epigenetic alterations', 'Var', (79, 101))	('histone proteins', 'Protein', (105, 121))
516654	26413213	By establishing stably transfected cell lines through overexpressing mdig-GFP protein in A549 cells, we have demonstrated the mdig/MINA's ability in decreasing the heterochromatin conformation of A549 cells and derepressing the transcription of genes present in the tandemly repeated DNA regions.	('A549', 'CellLine', 'CVCL:0023', (196, 200))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('derepressing', 'Reg', (211, 223))	('mdig/MINA', 'Var', (126, 135))	('transcription', 'MPA', (228, 241))	('heterochromatin conformation', 'MPA', (164, 192))	('decreasing', 'NegReg', (149, 159))
516658	26413213	Vice versa, silencing mdig/MINA resulted in a 6.2-fold increase of H19 transcript.	('H19', 'Gene', '283120', (67, 70))	('increase', 'PosReg', (55, 63))	('H19', 'Gene', (67, 70))	('silencing', 'Var', (12, 21))
516670	26413213	Mdig/MINA has also been linked to lymphoma, especially the tumor progression of B cell lymphoma.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (80, 95))	('lymphoma', 'Disease', (34, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('Mdig/MINA', 'Var', (0, 9))	('lymphoma', 'Disease', (87, 95))	('lymphoma', 'Disease', 'MESH:D008223', (34, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (34, 42))	('lymphoma', 'Disease', 'MESH:D008223', (87, 95))	('B cell lymphoma', 'Disease', 'MESH:D016393', (80, 95))	('B cell lymphoma', 'Disease', (80, 95))	('linked', 'Reg', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
516671	26413213	It is overexpressed in gastric carcinoma and has been associated with tumor proliferation and anti-oncogene inactivation.	('gastric carcinoma', 'Disease', (23, 40))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('inactivation', 'Var', (108, 120))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (23, 40))	('gastric carcinoma', 'Disease', 'MESH:D013274', (23, 40))	('associated', 'Reg', (54, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('overexpressed', 'PosReg', (6, 19))
516701	26413213	Similarly, our mdig/MINA gene knockout studies in a model of experimental silicosis revealed that the deficiency of mdig/MINA ameliorated silica-induced lung fibrosis and the infiltration of macrophages and Th17 cells by altering the balance between Th17 and Treg cells in the lung.	('Th1', 'Gene', '51497', (207, 210))	('silica-induced', 'Disease', (138, 152))	('Th1', 'Gene', '51497', (250, 253))	('silica', 'Chemical', 'MESH:D012822', (138, 144))	('altering', 'Reg', (221, 229))	('lung fibrosis', 'Disease', 'MESH:D005355', (153, 166))	('deficiency', 'Var', (102, 112))	('silicosis', 'Disease', 'MESH:D012829', (74, 83))	('silicosis', 'Disease', (74, 83))	('ameliorated', 'PosReg', (126, 137))	('infiltration', 'CPA', (175, 187))	('Th1', 'Gene', (207, 210))	('mdig/MINA', 'Gene', (116, 125))	('lung fibrosis', 'Disease', (153, 166))	('Th1', 'Gene', (250, 253))	('lung fibrosis', 'Phenotype', 'HP:0002206', (153, 166))
516704	26413213	Our studies revealed that the deficiency of mdig/MINA gene attenuated silica-induced lung fibrosis and infiltration of macrophages and Th17 cells.	('silica-induced', 'Disease', (70, 84))	('lung fibrosis', 'Disease', (85, 98))	('Th1', 'Gene', '51497', (135, 138))	('silica', 'Chemical', 'MESH:D012822', (70, 76))	('deficiency', 'Var', (30, 40))	('lung fibrosis', 'Phenotype', 'HP:0002206', (85, 98))	('attenuated', 'NegReg', (59, 69))	('mdig/MINA gene', 'Gene', (44, 58))	('lung fibrosis', 'Disease', 'MESH:D005355', (85, 98))	('Th1', 'Gene', (135, 138))
516706	26413213	Nevertheless both the in vivo studies pertaining to mdig/MINA deficiency revealed an attenuated immune response in murine airways, with our studies indicating this observation might result from an impaired function of Th17 cells.	('mdig/MINA', 'Gene', (52, 61))	('Th1', 'Gene', '51497', (218, 221))	('deficiency', 'Var', (62, 72))	('immune response', 'CPA', (96, 111))	('Th1', 'Gene', (218, 221))	('murine', 'Species', '10090', (115, 121))	('attenuated', 'NegReg', (85, 95))
516712	26413213	In our previous studies using lung cancer cell lines and lung epithelial cell line, we found that mdig/MINA enhanced cell proliferation but repressed migration and invasion in in-vitro assays.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('mdig/MINA', 'Var', (98, 107))	('lung cancer', 'Disease', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cell proliferation', 'CPA', (117, 135))	('enhanced', 'PosReg', (108, 116))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('invasion', 'CPA', (164, 172))	('migration', 'CPA', (150, 159))	('repressed', 'NegReg', (140, 149))
516713	26413213	This might support the notion that mdig/MINA predicts better survival of patients with lymph node positive, an indication of cancer cell metastasis.	('lymph', 'Var', (87, 92))	('survival', 'CPA', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patients', 'Species', '9606', (73, 81))	('better', 'PosReg', (54, 60))
516717	26413213	Using an online database containing gene profiling information from 2,437 cases of lung cancer, we found that high level of mdig/MINA predicts poorer overall survival (OS) of the lung cancer patients who had no lymph node metastasis or had only possible proximal lymph node metastasis.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('patients', 'Species', '9606', (191, 199))	('poorer', 'NegReg', (143, 149))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('overall survival', 'MPA', (150, 166))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))	('mdig/MINA', 'Var', (124, 133))
516727	26413213	revealed that patients who stained negative for mdig/MINA had significantly shorter survival than those who were stained positive for mdig/MINA, especially in stage I or squamous cell carcinoma, indicating that increase of the protein level of mdig/MINA may be associated with a favorable prognosis of lung cancer patients.	('lung cancer', 'Disease', 'MESH:D008175', (302, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('patients', 'Species', '9606', (314, 322))	('protein level', 'MPA', (227, 240))	('increase', 'PosReg', (211, 219))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('survival', 'MPA', (84, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('lung cancer', 'Disease', (302, 313))	('squamous cell carcinoma', 'Disease', (170, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (302, 313))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (170, 193))	('mdig/MINA', 'Var', (244, 253))	('shorter', 'NegReg', (76, 83))	('patients', 'Species', '9606', (14, 22))
516731	26413213	In both H226B cells and A549 cells, overexpression of mdig/MINA inhibited cell migration and invasion, whereas silencing mdig/MINA with shRNA enhanced migration and invasion of these cancer cells.	('migration', 'CPA', (151, 160))	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('cancer', 'Disease', (183, 189))	('silencing', 'Var', (111, 120))	('H226B', 'CellLine', 'CVCL:J621', (8, 13))	('inhibited', 'NegReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('invasion', 'CPA', (165, 173))	('enhanced', 'PosReg', (142, 150))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
516733	26413213	A study evaluated two myc gene-regulated proteins, mdig/MINA and Cap 43, in neuroblastoma revealed that mdig/MINA is a clinico-pathological prognostic predicator of neuroblastoma, one of the common pediatric solid cancers.	('neuroblastoma', 'Disease', (76, 89))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('neuroblastoma', 'Phenotype', 'HP:0003006', (76, 89))	('cancers', 'Disease', (214, 221))	('Cap 43', 'Gene', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('neuroblastoma', 'Disease', 'MESH:D009447', (165, 178))	('Cap 43', 'Gene', '10397', (65, 71))	('neuroblastoma', 'Disease', (165, 178))	('mdig/MINA', 'Var', (104, 113))	('neuroblastoma', 'Phenotype', 'HP:0003006', (165, 178))	('neuroblastoma', 'Disease', 'MESH:D009447', (76, 89))
516742	26413213	Silencing of mdig/MINA by siRNA in human pancreatic cell line, PANC-1, induced cell cycle arrest in G2/M phase and apoptosis, resulting in diminished growth of the cells.	('PANC-1', 'CellLine', 'CVCL:0480', (63, 69))	('Silencing', 'Var', (0, 9))	('human', 'Species', '9606', (35, 40))	('cell cycle arrest in G2/M phase', 'CPA', (79, 110))	('apoptosis', 'CPA', (115, 124))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (79, 96))	('pancreatic', 'Disease', 'MESH:D010195', (41, 51))	('growth', 'CPA', (150, 156))	('pancreatic', 'Disease', (41, 51))	('diminished', 'NegReg', (139, 149))	('mdig/MINA', 'Gene', (13, 22))
516759	26413213	Altogether, high mdig/MINA expression predicted poor prognosis in patients with gastric carcinoma.	('gastric carcinoma', 'Disease', (80, 97))	('high', 'Var', (12, 16))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('gastric carcinoma', 'Disease', 'MESH:D013274', (80, 97))	('patients', 'Species', '9606', (66, 74))	('mdig/MINA', 'Gene', (17, 26))
516769	26413213	Mdig/MINA is a known oncogene that exerts a proliferative effect in several cancer cell lines and abrogation of mdig/MINA inhibits cell proliferation.	('inhibits', 'NegReg', (122, 130))	('abrogation', 'Var', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mdig/MINA', 'Gene', (112, 121))	('cell proliferation', 'CPA', (131, 149))	('proliferative effect', 'MPA', (44, 64))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
516791	26413213	Our earlier reports stated that mdig/MINA predicts poorer overall survival in patients with earlier stages of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('overall survival', 'MPA', (58, 74))	('mdig/MINA', 'Var', (32, 41))	('poorer', 'NegReg', (51, 57))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))
516820	26413213	Recently, studies performed in heterozygous myc knockout mice (myc+/-) revealed that decreased myc expression promoted longevity and benefited multiple organs and physiological process thereby enhancing the health span of the animals.	('mice', 'Species', '10090', (57, 61))	('expression', 'MPA', (99, 109))	('longevity', 'CPA', (119, 128))	('decreased', 'Var', (85, 94))	('benefited', 'PosReg', (133, 142))	('health span of', 'CPA', (207, 221))	('myc', 'Gene', (95, 98))	('enhancing', 'PosReg', (193, 202))	('promoted', 'PosReg', (110, 118))
516821	26413213	Age-related pathologies, notably cardiac fibrosis and immunosenescence were found to be attenuated in the myc+/- mice.	('cardiac fibrosis', 'Disease', (33, 49))	('cardiac fibrosis', 'Disease', 'MESH:D005355', (33, 49))	('attenuated', 'NegReg', (88, 98))	('mice', 'Species', '10090', (113, 117))	('immunosenescence', 'CPA', (54, 70))	('myc+/-', 'Var', (106, 112))
516822	26413213	This is an important finding that further strengthens our mdig/MINA knockout studies reporting that mdig/MINA deficiency ameliorated silica-induced pulmonary fibrosis in mice by altering the balance between Th17 and Treg cells.	('altering', 'Reg', (178, 186))	('Th1', 'Gene', '51497', (207, 210))	('mdig/MINA', 'Gene', (100, 109))	('pulmonary fibrosis', 'Disease', (148, 166))	('Th1', 'Gene', (207, 210))	('deficiency', 'Var', (110, 120))	('ameliorated', 'PosReg', (121, 132))	('mice', 'Species', '10090', (170, 174))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (148, 166))	('silica', 'Chemical', 'MESH:D012822', (133, 139))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (148, 166))	('balance', 'MPA', (191, 198))
516828	26413213	High level of mdig/MINA is an indicator for poor diagnosis of multiple myeloma, possibly due to the enhanced Jak-STAT signaling by mdig/MINA (Wu et al.	('multiple myeloma', 'Disease', 'MESH:D009101', (62, 78))	('STAT', 'Gene', (113, 117))	('STAT', 'Gene', '6774', (113, 117))	('multiple myeloma', 'Phenotype', 'HP:0006775', (62, 78))	('enhanced', 'PosReg', (100, 108))	('multiple myeloma', 'Disease', (62, 78))	('mdig/MINA', 'Var', (131, 140))
516830	25992088	Data Synthesis LPR is associated with symptoms of laryngeal irritation such as throat clearing, coughing, and hoarseness.	('hoarseness', 'Phenotype', 'HP:0001609', (110, 120))	('cough', 'Disease', (96, 101))	('throat clearing', 'Disease', (79, 94))	('hoarseness', 'Disease', (110, 120))	('coughing', 'Phenotype', 'HP:0012735', (96, 104))	('cough', 'Phenotype', 'HP:0012735', (96, 101))	('cough', 'Disease', 'MESH:D003371', (96, 101))	('laryngeal irritation', 'Disease', (50, 70))	('LPR', 'Var', (15, 18))	('laryngeal irritation', 'Disease', 'MESH:D007827', (50, 70))
516852	25992088	The study suggested that bile can cause laryngeal inflammation at both acid and nonacid pH.	('bile', 'Var', (25, 29))	('laryngeal inflammation', 'Disease', 'MESH:D007249', (40, 62))	('laryngeal inflammation', 'Disease', (40, 62))	('cause', 'Reg', (34, 39))
517097	33403048	We found that the patients with high serum exosomal hsa_circ_0026611 expression had a significantly worse survival than those with low expression (for OS, HR [95% CI]: 3.79 [1.27, 11.29], for DFS, HR [95% CI]: 2.77 [1.06, 7.22], Table 2).	('high', 'Var', (32, 36))	('survival', 'CPA', (106, 114))	('hsa_circ_0026611', 'Gene', (52, 68))	('worse', 'NegReg', (100, 105))	('patients', 'Species', '9606', (18, 26))
517112	33403048	In summary, aberrant circRNA expression is associated with prognosis in cancer.	('aberrant', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('associated', 'Reg', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
517119	33403048	indicated that knockdown of ZNF281 expression suppressed cell proliferation, migration, and invasion by inhibiting the Wnt/beta-catenin pathway.	('beta-catenin', 'Gene', '1499', (123, 135))	('knockdown', 'Var', (15, 24))	('ZNF281', 'Gene', '23528', (28, 34))	('invasion', 'CPA', (92, 100))	('migration', 'CPA', (77, 86))	('inhibiting', 'NegReg', (104, 114))	('beta-catenin', 'Gene', (123, 135))	('ZNF281', 'Gene', (28, 34))	('cell proliferation', 'CPA', (57, 75))	('suppressed', 'NegReg', (46, 56))
517291	31855325	Similar to the whole group, the probability of FEV1 reduction was higher in those patients with a V20total lung above the median (= 21%, log rank P-value = 0.102, Fig S4).	('patients', 'Species', '9606', (82, 90))	('V20total', 'Var', (98, 106))	('FEV1', 'Phenotype', 'HP:0032342', (47, 51))	('reduction', 'NegReg', (52, 61))
517292	31855325	In order to detect factors that potentially influence MCID we performed a multivariate analysis (Cox regression, forward stepwise) including patient (gender, age, weight loss, KPS, tumor volume, tumor location, CCI) as well as dosimetric parameters (V20ipsilateral lung, V20total lung, V25total lung, MLD).	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('weight loss', 'Disease', 'MESH:D015431', (163, 174))	('V20ipsilateral', 'Var', (250, 264))	('V25total lung', 'Disease', (286, 299))	('patient', 'Species', '9606', (141, 148))	('Cox', 'Gene', '1351', (97, 100))	('Cox', 'Gene', (97, 100))	('weight loss', 'Disease', (163, 174))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('weight loss', 'Phenotype', 'HP:0001824', (163, 174))	('V20total', 'Var', (271, 279))
517327	27198655	In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001).	('HER2', 'Gene', (77, 81))	('HER2', 'Gene', (120, 124))	('positivity', 'Var', (125, 135))	('HER2', 'Gene', '2064', (77, 81))	('HER2', 'Gene', '2064', (120, 124))	('shorter', 'NegReg', (211, 218))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
517328	27198655	These are the first data in a non-breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2-positive EACs have a predilection for CNS metastases.	('HER2', 'Gene', (86, 90))	('HER2', 'Gene', '2064', (162, 166))	('HER2', 'Gene', (162, 166))	('metastases', 'Disease', 'MESH:D009362', (209, 219))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('HER2', 'Gene', '2064', (86, 90))	('association', 'Interaction', (66, 77))	('non-breast cancer', 'Disease', (30, 47))	('CNS', 'Disease', (113, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('metastases', 'Disease', (209, 219))	('positivity', 'Var', (91, 101))	('non-breast cancer', 'Disease', 'MESH:D001943', (30, 47))
517361	27198655	HER2 positivity was statistically significantly associated with lower T stage, fewer malignant nodes, lower histologic grade, esophageal (vs GEJ) tumor location, the presence of adjacent Barrett's metaplasia, and the absence of signet ring cells.	('lower', 'NegReg', (102, 107))	('positivity', 'Var', (5, 15))	('esophageal', 'Disease', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('malignant nodes', 'CPA', (85, 100))	('histologic grade', 'CPA', (108, 124))	('lower', 'NegReg', (64, 69))	('tumor', 'Disease', (146, 151))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (187, 207))	('T stage', 'CPA', (70, 77))	('HER2', 'Gene', (0, 4))	("Barrett's metaplasia", 'Disease', (187, 207))	('HER2', 'Gene', '2064', (0, 4))	('fewer', 'NegReg', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
517362	27198655	HER2 positivity was not significantly associated with shorter OS (HR 0.84 [95% CI 0.66, 1.08]; p = 0.17 after adjustment for pathologic tumor stage).	('positivity', 'Var', (5, 15))	('shorter OS', 'Disease', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('HER2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('HER2', 'Gene', '2064', (0, 4))	('tumor', 'Disease', (136, 141))
517368	27198655	In multivariable models (Table S1), HER2 amplification was the only variable statistically significantly associated with shorter time to CNS relapse as first recurrence (5-year cumulative incidence: 5.2% vs. 1.5%; multivariate HR 4.11 [95% CI 1.29, 13.14]; p = 0.0171) or CNS relapse at any time (5-year cumulative incidence: 7.8% vs. 2.5%; multivariate HR 3.74 [95% CI 1.51, 9.24]; p = 0.0043).	('HER2', 'Gene', (36, 40))	('HER2', 'Gene', '2064', (36, 40))	('CNS', 'Disease', (137, 140))	('amplification', 'Var', (41, 54))	('CNS', 'Disease', (272, 275))
517376	27198655	Evidence that HER2 overexpression affects brain metastasis was recently reported in an experimental metastasis assay, where HER2 transfection into a brain-trophic clone of triple-negative human breast carcinoma cells increased brain meta-static colonization by 3-fold.	('breast carcinoma', 'Disease', (194, 210))	('HER2', 'Gene', '2064', (14, 18))	('HER2', 'Gene', '2064', (124, 128))	('human', 'Species', '9606', (188, 193))	('transfection', 'Var', (129, 141))	('brain metastasis', 'CPA', (42, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('breast carcinoma', 'Phenotype', 'HP:0003002', (194, 210))	('breast carcinoma', 'Disease', 'MESH:D001943', (194, 210))	('brain meta-static colonization', 'CPA', (227, 257))	('HER2', 'Gene', (14, 18))	('HER2', 'Gene', (124, 128))	('increased', 'PosReg', (217, 226))
517378	27198655	While the precise mechanism remains to be elucidated, both HER2 phosphorylation and increased p21 expression were associated with increased brain metastatic potential.	('p21', 'Gene', (94, 97))	('phosphorylation', 'Var', (64, 79))	('brain metastatic potential', 'CPA', (140, 166))	('increased', 'PosReg', (84, 93))	('HER2', 'Gene', (59, 63))	('p21', 'Gene', '644914', (94, 97))	('increased', 'PosReg', (130, 139))	('HER2', 'Gene', '2064', (59, 63))	('expression', 'MPA', (98, 108))
517382	27198655	However, we demonstrated an association between HER2 positivity and higher CNS relapse even though HER2 was not associated with shorter OS in this cohort or in trial populations of esophagogastric cancer using modern HER2 methodology.	('HER2', 'Gene', '2064', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('esophagogastric cancer', 'Disease', (181, 203))	('higher CNS relapse', 'CPA', (68, 86))	('HER2', 'Gene', (99, 103))	('positivity', 'Var', (53, 63))	('HER2', 'Gene', '2064', (99, 103))	('HER2', 'Gene', (217, 221))	('esophagogastric cancer', 'Disease', 'MESH:C537006', (181, 203))	('HER2', 'Gene', (48, 52))	('HER2', 'Gene', '2064', (217, 221))
517385	27198655	As shown in Table S2, our results are consistent with those from an increasing number of small studies in esophagogastric cancer reporting a correlation between HER2 positivity and CNS metastases.	('esophagogastric cancer', 'Disease', (106, 128))	('HER2', 'Gene', '2064', (161, 165))	('positivity', 'Var', (166, 176))	('HER2', 'Gene', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('metastases', 'Disease', (185, 195))	('esophagogastric cancer', 'Disease', 'MESH:C537006', (106, 128))	('metastases', 'Disease', 'MESH:D009362', (185, 195))
517389	27198655	Another study, involving a multicenter registry, analyzed HER2 expression/amplification in EAC patients with CNS involvement and found HER2 positivity in 36% (36/100) of metastases or primaries, which was higher than expected.	('HER2', 'Gene', (135, 139))	('patients', 'Species', '9606', (95, 103))	('HER2', 'Gene', '2064', (135, 139))	('metastases', 'Disease', (170, 180))	('metastases', 'Disease', 'MESH:D009362', (170, 180))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (58, 62))	('positivity', 'Var', (140, 150))
517417	29563911	The seroprevalence of NAbs against AdC68 was much lower than that against AdHu5 in cancer subjects (43.64 vs. 67.05%, P < 0.01).	('lower', 'NegReg', (50, 55))	('AdHu5', 'Chemical', '-', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('AdC68', 'Chemical', '-', (35, 40))	('seroprevalence', 'MPA', (4, 18))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('AdC68', 'Var', (35, 40))	('cancer', 'Disease', (83, 89))
517422	29563911	The percentage of NAbs against AdC68 was significantly lower than that against AdHu5 (P < 0.05) in stage-I, -II, and -III cancer patients.	('stage-I', 'Disease', (99, 106))	('patients', 'Species', '9606', (129, 137))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('AdC68', 'Chemical', '-', (31, 36))	('AdHu5', 'Chemical', '-', (79, 84))	('lower', 'NegReg', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('AdC68', 'Var', (31, 36))
517426	29563911	Also, the titer of NAbs against AdC68 was significantly lower than that against AdHu5 in the same clinical stage and age group (P < 0.05).	('AdHu5', 'Chemical', '-', (80, 85))	('AdC68', 'Var', (32, 37))	('titer', 'MPA', (10, 15))	('lower', 'NegReg', (56, 61))	('AdC68', 'Chemical', '-', (32, 37))
517427	29563911	Taken together, the present study showed that NAbs against AdC68 is much lower than AdHu5, especially in lung adenocarcinoma, laryngeal cancer, esophageal cancer, and cervical cancer patients.	('laryngeal cancer', 'Phenotype', 'HP:0012118', (126, 142))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cervical cancer', 'Disease', (167, 182))	('cervical cancer', 'Disease', 'MESH:D002583', (167, 182))	('NAbs', 'MPA', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('lung adenocarcinoma', 'Disease', (105, 124))	('AdC68', 'Chemical', '-', (59, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('lower', 'NegReg', (73, 78))	('patients', 'Species', '9606', (183, 191))	('esophageal cancer', 'Disease', (144, 161))	('AdHu5', 'Chemical', '-', (84, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('AdC68', 'Var', (59, 64))	('laryngeal cancer', 'Disease', 'MESH:D007822', (126, 142))	('laryngeal cancer', 'Disease', (126, 142))
517441	29563911	The AdC68-based vaccine could also induce protective effector and memory T-cell responses against malignant melanoma cells in mice.	('AdC68', 'Chemical', '-', (4, 9))	('malignant melanoma', 'Disease', 'MESH:D008545', (98, 116))	('malignant melanoma', 'Disease', (98, 116))	('mice', 'Species', '10090', (126, 130))	('AdC68-based', 'Var', (4, 15))	('induce', 'PosReg', (35, 41))	('malignant melanoma', 'Phenotype', 'HP:0002861', (98, 116))
517481	29563911	The percentages of NAbs against AdC68 were significantly lower than those against AdHu5 (P < 0.05) in subjects of stages I, II, and III.	('AdC68', 'Chemical', '-', (32, 37))	('AdHu5', 'Chemical', '-', (82, 87))	('AdC68', 'Var', (32, 37))	('lower', 'NegReg', (57, 62))
517509	29563911	In addition, the titer of NAbs against AdC68 was significantly lower than that against AdHu5 in the same age groups (P < 0.05, Table 8).	('AdC68', 'Var', (39, 44))	('lower', 'NegReg', (63, 68))	('titer', 'MPA', (17, 22))	('AdC68', 'Chemical', '-', (39, 44))	('AdHu5', 'Chemical', '-', (87, 92))
517522	29563911	The seroprevalence rates of AdC68 NAbs were significantly higher than AdHu5 NAbs in stages I, II, and III.	('AdC68 NAbs', 'Chemical', '-', (28, 38))	('seroprevalence', 'MPA', (4, 18))	('AdHu5 NAbs', 'Chemical', '-', (70, 80))	('higher', 'PosReg', (58, 64))	('AdC68', 'Var', (28, 33))
517523	29563911	Although the seroprevalence rate of AdC68 NAbs was much lower than that of AdHu5 NAbs in stage-IV subjects, there was no significant difference between them.	('seroprevalence', 'MPA', (13, 27))	('AdHu5 NAbs', 'Chemical', '-', (75, 85))	('AdC68', 'Var', (36, 41))	('lower', 'NegReg', (56, 61))	('AdC68 NAbs', 'Chemical', '-', (36, 46))
517582	29221198	Meanwhile, the total of 25 patients with T1-3 status had significantly superior PFS compared to the 26 patients with T4 status (8.9 months versus 3.8 months, P=0.036), and the 19 patients who had N0-2 status had better PFS than the other 32 patients with N3 status (11.2 months versus 4.2 months, P=0.009).	('T1-3 status', 'Var', (41, 52))	('superior', 'PosReg', (71, 79))	('PFS', 'CPA', (219, 222))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (103, 111))	('PFS', 'MPA', (80, 83))	('N0-2 status', 'Var', (196, 207))	('patients', 'Species', '9606', (241, 249))
517678	28111532	Variants of dense SIFT descriptors, extracted at multiple scales, are clustered into visual words and the histograms of these words are treated as descriptions of images.	('Variants', 'Var', (0, 8))	('SIFT', 'Disease', (18, 22))	('visual words', 'Disease', 'MESH:D008569', (85, 97))	('SIFT', 'Disease', 'None', (18, 22))	('visual words', 'Disease', (85, 97))
517691	27422937	Aberrant expression of microRNAs (miRNAs) is responsible for cancer sensitivity to radiation.	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('microRNAs', 'Protein', (23, 32))	('cancer', 'Disease', (61, 67))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (68, 92))	('responsible', 'Reg', (45, 56))
517734	27422937	To select the appropriate cell lines for this experiment, survival fractions along with a series of radiation treatments were evaluated in all six ESCC cell lines (TE1, ECA109, EC9706, KYSE30, KYSE150 and KYSE450) to determine their radiosensitivity.	('EC', 'Phenotype', 'HP:0011459', (169, 171))	('KYSE150', 'Var', (193, 200))	('EC9706', 'Var', (177, 183))	('KYSE30', 'Var', (185, 191))	('EC9706', 'CellLine', 'CVCL:E307', (177, 183))	('EC', 'Phenotype', 'HP:0011459', (177, 179))
517735	27422937	The results showed that the radiosensitivity of the six ESCC cell lines in descending order were as follows: EC9706, KYSE30, KYSE450, TE1, ECA109 and KYSE150 (Fig.	('EC9706', 'CellLine', 'CVCL:E307', (109, 115))	('EC', 'Phenotype', 'HP:0011459', (109, 111))	('KYSE150', 'Var', (150, 157))	('EC9706', 'Var', (109, 115))	('ECA109', 'Var', (139, 145))	('TE1', 'Var', (134, 137))	('KYSE30', 'Var', (117, 123))	('KYSE450', 'Var', (125, 132))	('EC', 'Phenotype', 'HP:0011459', (139, 141))
517738	27422937	As expected, EC9706R cells also exhibited increased proliferation rates compared with EC9706 cells, indicating that they were more radioresistant than their counterparts.	('increased', 'PosReg', (42, 51))	('EC9706', 'CellLine', 'CVCL:E307', (13, 19))	('proliferation rates', 'CPA', (52, 71))	('EC', 'Phenotype', 'HP:0011459', (13, 15))	('EC9706', 'CellLine', 'CVCL:E307', (86, 92))	('EC9706R', 'CellLine', 'CVCL:E307', (13, 20))	('EC9706R', 'Var', (13, 20))	('EC', 'Phenotype', 'HP:0011459', (86, 88))
517758	27422937	Additionally, a mutant reporter was generated in which two nucleotides in the miR-98 seed region's complementary sites were mutated (Fig.	('miR-98', 'Gene', '407054', (78, 84))	('miR-98', 'Gene', (78, 84))	('mutated', 'Var', (124, 131))
517781	27422937	Other miRNAs, such as miRNA-223 and let-7, were also found to have an effect on the progress of ESCC.	('miR', 'Gene', '220972', (22, 25))	('effect', 'Reg', (70, 76))	('let-7', 'Var', (36, 41))	('miR', 'Gene', '220972', (6, 9))	('miR', 'Gene', (6, 9))	('ESCC', 'Disease', (96, 100))	('miRNA-223', 'Gene', (22, 31))	('miR', 'Gene', (22, 25))	('miRNA-223', 'Gene', '407008', (22, 31))
517792	27422937	Based on the differential expression profiles of the miRNAs that were associated with the radioresistance of ESCC, we confirmed the important roles of miRNA in radioresistance and revealed that inhibition of miRNA-98 may promote radioresistance of ESCC in vitro, possibly by directly targeting Bcl-2 protein expression.	('expression', 'MPA', (308, 318))	('miR', 'Gene', (208, 211))	('miR', 'Gene', (53, 56))	('targeting', 'Reg', (284, 293))	('promote', 'PosReg', (221, 228))	('radioresistance', 'CPA', (229, 244))	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', '220972', (208, 211))	('miR', 'Gene', (151, 154))	('Bcl-2', 'Gene', '596', (294, 299))	('ESCC', 'Disease', (248, 252))	('Bcl-2', 'Gene', (294, 299))	('inhibition', 'Var', (194, 204))
517809	26992206	A retrospective study demonstrated that EC patients treated with IMRT had less non cancer-related deaths, better LRC and OS, compared with patients treated with three-dimensional conformal radiotherapy (3DCRT).	('death', 'Disease', 'MESH:D003643', (98, 103))	('death', 'Disease', (98, 103))	('LRC', 'Disease', (113, 116))	('patients', 'Species', '9606', (139, 147))	('less', 'NegReg', (74, 78))	('patients', 'Species', '9606', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('IMRT', 'Var', (65, 69))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
517883	26992206	RT was delivered only when patients fulfilled the following conditions: (a) neutrophils >= 1.0x109/L; (b) blood platelet >= 50x109/L; (c) No grade 4 acute toxicities.	('patients', 'Species', '9606', (27, 35))	('acute toxicities', 'Disease', 'MESH:D000208', (149, 165))	('acute toxicities', 'Disease', (149, 165))	('>= 50x109/L', 'Var', (121, 132))
517887	26992206	Chemotherapy was prescribed only when patients fulfilled the following conditions: (a) neutrophils >= 2.0x109/L or >= 1.5x109/L for appropriate patients without fever; (b) blood platelet >=100x109/L; (c) no grade >= 3 chemotherapy-related toxicities.	('toxicities', 'Disease', 'MESH:D064420', (239, 249))	('>=100x109/L', 'Var', (187, 198))	('fever', 'Disease', 'MESH:D005334', (161, 166))	('fever', 'Disease', (161, 166))	('patients', 'Species', '9606', (144, 152))	('fever', 'Phenotype', 'HP:0001945', (161, 166))	('toxicities', 'Disease', (239, 249))	('patients', 'Species', '9606', (38, 46))
517902	26870996	T2-3N0M0 stage EAC patients with surgery were more likely to be white race, T3 stage.	('EAC', 'Phenotype', 'HP:0011459', (15, 18))	('EAC', 'Disease', (15, 18))	('patients', 'Species', '9606', (19, 27))	('T2-3N0M0 stage', 'Var', (0, 14))
517904	26870996	Significant survival benefit of (neo-)adjuvant radiotherapy is only observed in patients with T3N0M0 stage EAC, but not in those with T2N0M0 stage.	('EAC', 'Phenotype', 'HP:0011459', (107, 110))	('patients', 'Species', '9606', (80, 88))	('T3N0M0 stage', 'Var', (94, 106))	('EAC', 'Disease', (107, 110))
517916	26870996	Young patients with T2N0M0 stage might have a longer survival time, both neoadjuvant and adjuvant radiotherapy prolonged survival time (Table 3).	('longer', 'PosReg', (46, 52))	('survival', 'CPA', (53, 61))	('T2N0M0 stage', 'Var', (20, 32))	('prolonged', 'PosReg', (111, 120))	('patients', 'Species', '9606', (6, 14))
517922	26870996	In this study, we summarized the clinical characteristics of surgical patients with T2-3N0M0 stage EAC, with information provided by the SEER database from 2004 to 2012.	('patients', 'Species', '9606', (70, 78))	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('EAC', 'Disease', (99, 102))	('T2-3N0M0 stage', 'Var', (84, 98))
517923	26870996	We found that operative patients with T2-3N0M0 EAC were more likely to be T3 stage (60.0%), male (88.5%), and white (95.6%) race.	('T2-3N0M0 EAC', 'Var', (38, 50))	('T3 stage', 'CPA', (74, 82))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('patients', 'Species', '9606', (24, 32))
517926	26870996	Death risk of patients in T2N0M0 stage was lower than those in T3N0M0 stage (HR 0.514, 95% CI 0.411-0.641).	('T2N0M0', 'Var', (26, 32))	('patients', 'Species', '9606', (14, 22))	('Death', 'MPA', (0, 5))	('lower', 'NegReg', (43, 48))
517943	27123109	Notably, transwell assays demonstrated that the migratory ability of Eca-109 cells was significantly suppressed following knockdown of the OGT gene.	('OGT', 'Gene', (139, 142))	('OGT', 'Gene', '8473', (139, 142))	('knockdown', 'Var', (122, 131))	('suppressed', 'NegReg', (101, 111))	('migratory ability of Eca-109 cells', 'CPA', (48, 82))
517944	27123109	Correspondingly, western blot analyses demonstrated that OGT knockdown significantly downregulated the expression of matrix metalloproteinase 9 (MMP9) in Eca-109 cells.	('downregulated', 'NegReg', (85, 98))	('expression', 'MPA', (103, 113))	('OGT', 'Gene', (57, 60))	('matrix metalloproteinase 9', 'Gene', '4318', (117, 143))	('OGT', 'Gene', '8473', (57, 60))	('MMP9', 'Gene', (145, 149))	('knockdown', 'Var', (61, 70))	('MMP9', 'Gene', '4318', (145, 149))	('matrix metalloproteinase 9', 'Gene', (117, 143))
517954	27123109	O-GlcNAcylation serves important roles in an array of normal biological processes, and its dysregulation is involved in a variety of human diseases, including diabetes mellitus and various neurological disorders.	('dysregulation', 'Var', (91, 104))	('GlcNAcylation', 'Chemical', '-', (2, 15))	('diabetes mellitus', 'Disease', (159, 176))	('neurological disorders', 'Disease', 'MESH:D009422', (189, 211))	('diabetes mellitus', 'Disease', 'MESH:D003920', (159, 176))	('O-GlcNAc', 'Gene', (0, 8))	('involved', 'Reg', (108, 116))	('O-GlcNAc', 'Gene', '8473', (0, 8))	('human', 'Species', '9606', (133, 138))	('neurological disorders', 'Disease', (189, 211))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (159, 176))
517958	27123109	In the current study, RNA interference (RNAi) was used to knock down OGT in esophageal cancer Eca-109 cells, and the cell proliferation and migration capabilities were subsequently assessed.	('migration capabilities', 'CPA', (140, 162))	('esophageal cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('OGT', 'Gene', (69, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('OGT', 'Gene', '8473', (69, 72))	('knock down', 'Var', (58, 68))
517982	27123109	Therefore, the subsequent functional analyses of OGT knockdown in Eca-109 cells were performed using the RNAi-OGTB construct.	('knockdown', 'Var', (53, 62))	('OGT', 'Gene', (49, 52))	('OGT', 'Gene', '8473', (49, 52))	('OGT', 'Gene', (110, 113))	('OGT', 'Gene', '8473', (110, 113))
517986	27123109	Colony formation assays demonstrated that RNAi-OGTB transfection of Eca-109 cells led to decreased colony formation.	('OGT', 'Gene', (47, 50))	('colony formation', 'CPA', (99, 115))	('OGT', 'Gene', '8473', (47, 50))	('transfection', 'Var', (52, 64))	('decreased', 'NegReg', (89, 98))
517987	27123109	Similarly, cell proliferation assays revealed that RNAi-OGTB transfection of Eca-109 cells did not significantly inhibit cell proliferation when compared with negative control shRNA transfected cells (P=0.728; Fig.	('transfection', 'Var', (61, 73))	('inhibit', 'NegReg', (113, 120))	('cell proliferation', 'CPA', (121, 139))	('OGT', 'Gene', (56, 59))	('OGT', 'Gene', '8473', (56, 59))
517988	27123109	These results indicate that the RNAi knockdown of OGT had no effect on Eca-109 cell viability.	('OGT', 'Gene', (50, 53))	('OGT', 'Gene', '8473', (50, 53))	('knockdown', 'Var', (37, 46))	('Eca-109 cell viability', 'CPA', (71, 93))
517990	27123109	4A), RNAi-OGTB transfection significantly decreased cell migration (P<0.001; Fig.	('decreased', 'NegReg', (42, 51))	('cell migration', 'CPA', (52, 66))	('OGT', 'Gene', (10, 13))	('OGT', 'Gene', '8473', (10, 13))	('transfection', 'Var', (15, 27))
517992	27123109	To investigate the underlying mechanism by which OGT downregulation inhibits cell migration, MMP9 mRNA and protein levels were assessed by RT-qPCR and western blot analysis, respectively, in Eca-109 cells transfected with RNAi-OGTB for 72 h. Compared to the control, RNAi-OGTB transfection significantly downregulated MMP9 mRNA levels (P<0.001; Fig.	('downregulated', 'NegReg', (304, 317))	('transfection', 'Var', (277, 289))	('MMP9', 'Gene', (93, 97))	('MMP9', 'Gene', '4318', (93, 97))	('OGT', 'Gene', (272, 275))	('OGT', 'Gene', (49, 52))	('MMP9', 'Gene', '4318', (318, 322))	('OGT', 'Gene', '8473', (49, 52))	('MMP9', 'Gene', (318, 322))	('OGT', 'Gene', (227, 230))	('OGT', 'Gene', '8473', (272, 275))	('OGT', 'Gene', '8473', (227, 230))
517993	27123109	Correspondingly, western blot analysis also demonstrated the marked downregulation of MMP9 by RNAi-OGTB transfection (P=0.003; Fig.	('OGT', 'Gene', (99, 102))	('OGT', 'Gene', '8473', (99, 102))	('MMP9', 'Gene', '4318', (86, 90))	('downregulation', 'NegReg', (68, 82))	('MMP9', 'Gene', (86, 90))	('transfection', 'Var', (104, 116))
517996	27123109	OGT knockdown did not significantly alter cell viability; however, it did significantly reduce Eca-109 cell migration.	('OGT', 'Gene', (0, 3))	('OGT', 'Gene', '8473', (0, 3))	('Eca-109 cell migration', 'CPA', (95, 117))	('knockdown', 'Var', (4, 13))	('reduce', 'NegReg', (88, 94))
517997	27123109	Moreover, MMP9 mRNA and protein expression was significantly decreased following RNAi knockdown of OGT in Eca-109 cells.	('knockdown', 'Var', (86, 95))	('OGT', 'Gene', (99, 102))	('MMP9', 'Gene', '4318', (10, 14))	('MMP9', 'Gene', (10, 14))	('OGT', 'Gene', '8473', (99, 102))	('decreased', 'NegReg', (61, 70))
518005	27123109	These results led us to hypothesize that elevated OGT expression may promote the tumorigenesis and progression of esophageal cancer.	('OGT', 'Gene', (50, 53))	('expression', 'MPA', (54, 64))	('progression', 'CPA', (99, 110))	('OGT', 'Gene', '8473', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('promote', 'PosReg', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('elevated', 'Var', (41, 49))	('tumor', 'Disease', (81, 86))
518007	27123109	The results of the present study demonstrated that neither the RNAi knockdown of OGT expression nor the decrease of O-GlcNAcylation significantly inhibited cellular proliferation.	('OGT', 'Gene', (81, 84))	('OGT', 'Gene', '8473', (81, 84))	('O-GlcNAc', 'Gene', (116, 124))	('cellular proliferation', 'CPA', (156, 178))	('O-GlcNAc', 'Gene', '8473', (116, 124))	('knockdown', 'Var', (68, 77))	('inhibited', 'NegReg', (146, 155))	('decrease', 'NegReg', (104, 112))	('GlcNAcylation', 'Chemical', '-', (118, 131))
518012	27123109	In accordance with this suggestion, the Transwell assay performed in the current study demonstrated that RNAi knockdown of OGT significantly reduced cell migration.	('knockdown', 'Var', (110, 119))	('reduced', 'NegReg', (141, 148))	('OGT', 'Gene', (123, 126))	('OGT', 'Gene', '8473', (123, 126))	('cell migration', 'CPA', (149, 163))
518014	27123109	This revealed that MMP9 was significantly decreased in the RNAi-OGTB-transfected Eca-109 cells when compared with negative control shRNA transfected cell group, suggesting that knocking down the OGT gene in esophageal cancer may affect cellular migratory ability by decreasing MMP9, a phenomenon which may be predicted to be relative to the level of O-GlcNAcylation.	('GlcNAcylation', 'Chemical', '-', (352, 365))	('OGT', 'Gene', (64, 67))	('cellular migratory ability', 'CPA', (236, 262))	('decreasing', 'NegReg', (266, 276))	('OGT', 'Gene', '8473', (64, 67))	('O-GlcNAc', 'Gene', (350, 358))	('OGT', 'Gene', (195, 198))	('esophageal cancer', 'Disease', (207, 224))	('OGT', 'Gene', '8473', (195, 198))	('MMP9', 'Gene', '4318', (19, 23))	('O-GlcNAc', 'Gene', '8473', (350, 358))	('affect', 'Reg', (229, 235))	('knocking down', 'Var', (177, 190))	('MMP9', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('MMP9', 'Gene', (277, 281))	('esophageal cancer', 'Disease', 'MESH:D004938', (207, 224))	('MMP9', 'Gene', '4318', (277, 281))
518019	27123109	These facts imply a potential mechanism, in which OGT knockdown results in the downregulation of O-GlcNAcylation, which in turn results in the downregulation of MMP9 through the ERK pathway.	('OGT', 'Gene', (50, 53))	('MMP9', 'Gene', (161, 165))	('O-GlcNAc', 'Gene', '8473', (97, 105))	('OGT', 'Gene', '8473', (50, 53))	('knockdown', 'Var', (54, 63))	('GlcNAcylation', 'Chemical', '-', (99, 112))	('downregulation', 'NegReg', (143, 157))	('ERK', 'Gene', '5594', (178, 181))	('downregulation', 'NegReg', (79, 93))	('ERK', 'Gene', (178, 181))	('O-GlcNAc', 'Gene', (97, 105))	('MMP9', 'Gene', '4318', (161, 165))
518021	27123109	OGT knockdown did not affect cell viability; however, it did significantly reduce cell migration.	('cell migration', 'CPA', (82, 96))	('reduce', 'NegReg', (75, 81))	('OGT', 'Gene', (0, 3))	('OGT', 'Gene', '8473', (0, 3))	('knockdown', 'Var', (4, 13))
518022	27123109	Supporting this result, OGT knockdown was accompanied by a decrease in MMP9 expression.	('OGT', 'Gene', (24, 27))	('decrease', 'NegReg', (59, 67))	('OGT', 'Gene', '8473', (24, 27))	('MMP9', 'Gene', '4318', (71, 75))	('knockdown', 'Var', (28, 37))	('MMP9', 'Gene', (71, 75))
518036	23593929	ARPKD is characterized by: 1) non-obstructive fusiform dilatation of the renal collecting tubules (CT) (following an early, transient phase of proximal renal tubular cyst formation; and 2) a ductal plate malformation of the liver ultimately resulting in congenital hepatic fibrosis (CHF).	('fusiform dilatation', 'Phenotype', 'HP:0031056', (46, 65))	('renal tubular cyst formation', 'Phenotype', 'HP:0100611', (152, 180))	('ARPKD', 'Gene', (0, 5))	('malformation of the liver', 'Phenotype', 'HP:0001392', (204, 229))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (265, 281))	('resulting in', 'Reg', (241, 253))	('congenital hepatic fibrosis', 'Disease', 'MESH:C562378', (254, 281))	('dilatation', 'Phenotype', 'HP:0002617', (55, 65))	('congenital hepatic fibrosis', 'Disease', (254, 281))	('CHF', 'Disease', 'MESH:D006333', (283, 286))	('congenital hepatic fibrosis', 'Phenotype', 'HP:0002612', (254, 281))	('CHF', 'Disease', (283, 286))	('ARPKD', 'Gene', '5314', (0, 5))	('malformation', 'Var', (204, 216))
518045	23593929	Other features of hepatobiliary disease include hepatomegaly, malformation of small interlobular bile ducts (congenital hepatic fibrosis), non-obstructive dilation of intrahepatic bile ducts (Caroli syndrome), and dilation of the common bile duct.	('non-obstructive dilation', 'Disease', (139, 163))	('congenital hepatic fibrosis', 'Disease', 'MESH:C562378', (109, 136))	('dilation', 'Disease', (214, 222))	('malformation', 'Var', (62, 74))	('hepatomegaly', 'Disease', (48, 60))	('hepatobiliary disease', 'Disease', (18, 39))	('hepatomegaly', 'Disease', 'MESH:D006529', (48, 60))	('intrahepatic bile ducts', 'Disease', (167, 190))	('Caroli syndrome', 'Disease', (192, 207))	('hepatic fibrosis', 'Phenotype', 'HP:0001395', (120, 136))	('hepatomegaly', 'Phenotype', 'HP:0002240', (48, 60))	('intrahepatic bile ducts', 'Disease', 'MESH:D002780', (167, 190))	('Caroli syndrome', 'Disease', 'MESH:D016767', (192, 207))	('biliary disease', 'Phenotype', 'HP:0001080', (24, 39))	('interlobular bile ducts', 'Phenotype', 'HP:0025344', (84, 107))	('hepatobiliary disease', 'Disease', 'MESH:D004066', (18, 39))	('dilation of intrahepatic bile ducts', 'Phenotype', 'HP:0006571', (155, 190))	('congenital hepatic fibrosis', 'Phenotype', 'HP:0002612', (109, 136))	('congenital hepatic fibrosis', 'Disease', (109, 136))
518047	23593929	Abnormal bile flow may also lead to fat malabsorption and decreased absorption of fat-soluble vitamins (A, D, E, K).	('decreased', 'NegReg', (58, 67))	('absorption of', 'MPA', (68, 81))	('malabsorption', 'Phenotype', 'HP:0002024', (40, 53))	('fat malabsorption', 'Phenotype', 'HP:0002630', (36, 53))	('Abnormal', 'Var', (0, 8))	('lead to', 'Reg', (28, 35))	('bile flow', 'MPA', (9, 18))	('malabsorption', 'Disease', 'MESH:D008286', (40, 53))	('malabsorption', 'Disease', (40, 53))
518230	32545894	Multiple reports have shown that mis-regulation of HOX gene expression plays key roles in the development of cancers.	('roles', 'Reg', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('HOX gene', 'Gene', (51, 59))	('mis-regulation', 'Var', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
518237	32545894	Multiple reports have demonstrated that mis-regulation of HOX genes expression plays key roles in the development of cancers.	('mis-regulation', 'Var', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('roles', 'Reg', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('HOX genes', 'Gene', (58, 67))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
518292	32545894	The expression correlation observed between HOXB5, HOXB6, and HOXB7 in ESCA, is in line with a previous report that showed that expression changes in the three "midcluster" HOXB genes, namely HOXB5, HOXB6, and HOXB7, can trigger changes in the transcriptional program of adult esophageal cells, with implications to the early stages of esophageal carcinogenesis.	('HOXB', 'Gene', (62, 66))	('HOXB7', 'Gene', '3217', (210, 215))	('HOXB7', 'Gene', (210, 215))	('HOXB', 'Gene', (44, 48))	('HOXB', 'Gene', (173, 177))	('HOXB', 'Gene', '3210', (199, 203))	('HOXB', 'Gene', (51, 55))	('HOXB', 'Gene', (210, 214))	('HOXB6', 'Gene', '3216', (51, 56))	('HOXB6', 'Gene', (51, 56))	('HOXB5', 'Gene', (44, 49))	('HOXB', 'Gene', (192, 196))	('HOXB7', 'Gene', '3217', (62, 67))	('HOXB6', 'Gene', '3216', (199, 204))	('trigger changes', 'Reg', (221, 236))	('esophageal carcinogenesis', 'Disease', (336, 361))	('HOXB7', 'Gene', (62, 67))	('HOXB', 'Gene', '3210', (62, 66))	('changes', 'Var', (139, 146))	('HOXB6', 'Gene', (199, 204))	('HOXB', 'Gene', '3210', (44, 48))	('HOXB', 'Gene', '3210', (173, 177))	('transcriptional program', 'MPA', (244, 267))	('HOXB5', 'Gene', '3215', (44, 49))	('HOXB5', 'Gene', (192, 197))	('HOXB', 'Gene', '3210', (51, 55))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (336, 361))	('HOXB', 'Gene', '3210', (210, 214))	('HOXB', 'Gene', (199, 203))	('HOXB', 'Gene', '3210', (192, 196))	('ESCA', 'Phenotype', 'HP:0011459', (71, 75))	('HOXB5', 'Gene', '3215', (192, 197))
518388	30881124	In our in vitro experiment, the expression of hsa_circ_0000337 was higher in TE-1 compared to the normal human esophageal epithelial cell line HET-1A (P<0.001), but was not significantly different in KYSE-150 (P>0.05).	('higher', 'PosReg', (67, 73))	('KYSE-150', 'CellLine', 'CVCL:1348', (200, 208))	('hsa_circ_0000337', 'Var', (46, 62))	('hsa_circ_0000337', 'Chemical', '-', (46, 62))	('human', 'Species', '9606', (105, 110))	('expression', 'MPA', (32, 42))
518392	30881124	hsa_circ_0000337 was found to be an upregulated circRNA that is related to ESCC and promotes the progression of disease by regulating cell proliferation, migration, and invasion.	('cell proliferation', 'CPA', (134, 152))	('invasion', 'CPA', (169, 177))	('regulating', 'Reg', (123, 133))	('ESCC', 'Disease', (75, 79))	('hsa_circ_0000337', 'Var', (0, 16))	('hsa_circ_0000337', 'Chemical', '-', (0, 16))	('migration', 'CPA', (154, 163))	('promotes', 'PosReg', (84, 92))
518401	30881124	The dysregulation of circRNAs in breast cancer, gastric cancer, and colorectal cancer have been reported and implicate the possibility of circRNAs as novel biomarkers.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('colorectal cancer', 'Disease', (68, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('gastric cancer', 'Disease', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (48, 62))	('breast cancer', 'Disease', (33, 46))
518406	30881124	Previous studies have revealed the potential of epigenetic traits as biomarkers for the early diagnosis and therapeutic targeting of human cancers, but the role of circRNAs in ESCC has not been well explored.	('ESCC', 'Disease', (176, 180))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('epigenetic traits', 'Var', (48, 65))	('human', 'Species', '9606', (133, 138))
518408	30881124	hsa_circ_0000337 was one of the top ten upregulated circRNAs with a fold change (FC) =6.255 and P=0.006.	('hsa_circ_0000337', 'Var', (0, 16))	('upregulated', 'PosReg', (40, 51))	('hsa_circ_0000337', 'Chemical', '-', (0, 16))
518425	30881124	We constructed three types of siRNAs targeting hsa_circ_0000337 to inhibit its expression in the TE-1 and KYSE-150 cell lines.	('inhibit', 'NegReg', (67, 74))	('expression', 'MPA', (79, 89))	('hsa_circ_0000337', 'Var', (47, 63))	('hsa_circ_0000337', 'Chemical', '-', (47, 63))	('KYSE-150', 'CellLine', 'CVCL:1348', (106, 114))
518436	30881124	The plasmid with wild-type or mutated hsa_circ_0000337 and miR-670-5p mimics were transfected into TE-1 and KYSE-150 cell lines using Lipofectamine 2000.	('hsa_circ_0000337', 'Gene', (38, 54))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (134, 152))	('mutated', 'Var', (30, 37))	('miR-670', 'Gene', '100313777', (59, 66))	('KYSE-150', 'CellLine', 'CVCL:1348', (108, 116))	('miR-670', 'Gene', (59, 66))	('hsa_circ_0000337', 'Chemical', '-', (38, 54))
518439	30881124	In the chip-based discovery stage, we observed that hsa_circ_0000337 was one of the top ten upregulated miRNAs in ESCC with a fold change of over 6.2 and P=0.006.	('hsa_circ_0000337', 'Var', (52, 68))	('upregulated', 'PosReg', (92, 103))	('hsa_circ_0000337', 'Chemical', '-', (52, 68))	('ESCC', 'Disease', (114, 118))	('miR', 'Gene', '220972', (104, 107))	('miR', 'Gene', (104, 107))
518446	30881124	We then selected the siRNA3 interference cell (si-hsa_circ_0000337) as a competitive inhibitor to observe the function of hsa_circ_0000337 on the proliferation, migration, and invasion of ESCC.	('ESCC', 'Disease', (188, 192))	('proliferation', 'CPA', (146, 159))	('hsa_circ_0000337', 'Chemical', '-', (50, 66))	('hsa_circ_0000337', 'Var', (122, 138))	('hsa_circ_0000337', 'Chemical', '-', (122, 138))	('migration', 'CPA', (161, 170))	('invasion', 'CPA', (176, 184))
518447	30881124	As shown in Figure 3A and B, knockdown of hsa_circ_0000337 significantly inhibited the growth of TE-1 and KYSE-150 cell lines in both the CCK-8 assay and colony formation assay.	('knockdown', 'Var', (29, 38))	('colony formation assay', 'CPA', (154, 176))	('hsa_circ_0000337', 'Gene', (42, 58))	('growth', 'CPA', (87, 93))	('inhibited', 'NegReg', (73, 82))	('KYSE-150', 'CellLine', 'CVCL:1348', (106, 114))	('hsa_circ_0000337', 'Chemical', '-', (42, 58))
518448	30881124	According to the wound healing assay, inhibition of hsa_circ_0000337 could slow the migration rate of the TE-1 and KYSE-150 cell lines (Figure 3C and D).	('hsa_circ_0000337', 'Chemical', '-', (52, 68))	('KYSE-150', 'CellLine', 'CVCL:1348', (115, 123))	('hsa_circ_0000337', 'Gene', (52, 68))	('slow', 'NegReg', (75, 79))	('inhibition', 'Var', (38, 48))
518449	30881124	Silencing of hsa_circ_0000337 significantly limited cell invasion capacity in accordance with the Transwell assay (Figure 3E and F).	('Silencing', 'Var', (0, 9))	('cell invasion capacity', 'CPA', (52, 74))	('hsa_circ_0000337', 'Chemical', '-', (13, 29))	('limited', 'NegReg', (44, 51))	('hsa_circ_0000337', 'Gene', (13, 29))
518462	30881124	Moreover, we performed in vitro experiments, including CCK-8 and colony formation assays, as well as Transwell, wound healing, and luciferase reporter assays and revealed that hsa_circ_0000337 could promote the proliferation, migration, and invasion of ESCC cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('hsa_circ_0000337', 'Var', (176, 192))	('hsa_circ_0000337', 'Chemical', '-', (176, 192))	('promote', 'PosReg', (199, 206))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('proliferation', 'CPA', (211, 224))	('cancer', 'Disease', (258, 264))	('invasion', 'CPA', (241, 249))	('migration', 'CPA', (226, 235))
518465	30881124	For example, hsa_circ_002059, which is downregulated in gastric cancer tissues, has been suggested to be a prognostic biomarker since its expression in plasma was associated with tumor grade and distal metastasis.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('distal metastasis', 'CPA', (195, 212))	('associated', 'Reg', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('expression', 'MPA', (138, 148))	('gastric cancer', 'Disease', (56, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('hsa_circ_002059', 'Var', (13, 28))	('tumor', 'Disease', (179, 184))
518470	30881124	Studies have reported that PPFIA1 amplification was frequently observed in breast cancer, especially, in patients with liver metastasis, and seemed to be a promising prognostic indicator of metastatic relapse.	('liver metastasis', 'Disease', (119, 135))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('patients', 'Species', '9606', (105, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('PPFIA1', 'Gene', (27, 33))	('PPFIA1', 'Gene', '8500', (27, 33))	('amplification', 'Var', (34, 47))	('observed', 'Reg', (63, 71))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('liver metastasis', 'Disease', 'MESH:D009362', (119, 135))
518471	30881124	We hypothesized that hsa_circ_0000337 could bind to specific miRNAs and regulate gene transcription through the circRNA-miRNA-mRNA axis.	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (61, 64))	('miR', 'Gene', (120, 123))	('bind', 'Interaction', (44, 48))	('hsa_circ_0000337', 'Var', (21, 37))	('hsa_circ_0000337', 'Chemical', '-', (21, 37))	('regulate', 'Reg', (72, 80))	('gene transcription', 'MPA', (81, 99))
518475	30881124	hsa_circ_0000337 was observed to be upregulated in ESCC in a chip-based discovery study, and it was also validated in the current study by expanding the sample size.	('upregulated', 'PosReg', (36, 47))	('ESCC', 'Disease', (51, 55))	('hsa_circ_0000337', 'Var', (0, 16))	('hsa_circ_0000337', 'Chemical', '-', (0, 16))
518479	30881124	Therefore, we assumed that hsa_circ_0000337 might be associated with tumor differentiation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('associated', 'Reg', (53, 63))	('hsa_circ_0000337', 'Var', (27, 43))	('hsa_circ_0000337', 'Chemical', '-', (27, 43))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
518480	30881124	In the current study, due to the limited number of samples with poor differentiation, we did not observe a significant relationship between hsa_circ_0000337 and ESCC differentiation.	('hsa_circ_0000337', 'Var', (140, 156))	('ESCC', 'Disease', (161, 165))	('hsa_circ_0000337', 'Chemical', '-', (140, 156))
518485	30881124	Our findings indicate that hsa_circ_0000337 may act as a promising biomarker and provide a new therapeutic target in ESCC.	('ESCC', 'Disease', (117, 121))	('hsa_circ_0000337', 'Var', (27, 43))	('hsa_circ_0000337', 'Chemical', '-', (27, 43))
518494	30508944	As for the genomic alterations, we found 9 gene mutations in all the samples, including checkpoint kinase 2(CHEK2), FAT atypical cadherin 1 (FAT1), tumor protein 53 (TP53), DPYD, ERBB2 interacting protein (ERBB2IP), FBXW7, KMT2D, PPP2R1A, TSC2, whereas amplification of MYC was only in the metastatic example.	('FAT1', 'Gene', (141, 145))	('DPYD', 'Gene', (173, 177))	('FAT atypical cadherin 1', 'Gene', (116, 139))	('CHEK2', 'Gene', (108, 113))	('KMT2D', 'Gene', (223, 228))	('mutations', 'Var', (48, 57))	('ERBB2 interacting protein', 'Gene', '55914', (179, 204))	('FBXW7', 'Gene', '55294', (216, 221))	('PPP2R1A', 'Gene', '5518', (230, 237))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CHEK2', 'Gene', '11200', (108, 113))	('TP53', 'Gene', '7157', (166, 170))	('ERBB2IP', 'Gene', (206, 213))	('checkpoint kinase 2', 'Gene', (88, 107))	('MYC', 'Gene', (270, 273))	('DPYD', 'Gene', '1806', (173, 177))	('FAT1', 'Gene', '2195', (141, 145))	('ERBB2 interacting protein', 'Gene', (179, 204))	('FAT atypical cadherin 1', 'Gene', '2195', (116, 139))	('PPP2R1A', 'Gene', (230, 237))	('tumor protein 53', 'Gene', (148, 164))	('ERBB2IP', 'Gene', '55914', (206, 213))	('tumor protein 53', 'Gene', '7157', (148, 164))	('checkpoint kinase 2', 'Gene', '11200', (88, 107))	('TSC2', 'Gene', '7249', (239, 243))	('KMT2D', 'Gene', '8085', (223, 228))	('MYC', 'Gene', '4609', (270, 273))	('FBXW7', 'Gene', (216, 221))	('TP53', 'Gene', (166, 170))	('TSC2', 'Gene', (239, 243))
518495	30508944	The analysis of clonal evolution and phylogenetic tree showed the propagation and replay of polyclonal esophageal FDC sarcoma.	('esophageal FDC sarcoma', 'Disease', 'MESH:C536231', (103, 125))	('FDC sarcoma', 'Phenotype', 'HP:0031350', (114, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('polyclonal', 'Var', (92, 102))	('esophageal FDC sarcoma', 'Disease', (103, 125))
518496	30508944	At the same time, the detection of biomarkers for immunotherapy revealed microsatellite stable and mismatch repair-proficient (pMMR), which predicted a relatively poor anti-programmed death (PD-1)/programmed death ligand (PD-L1) immunotherapy outcome.	('poor', 'NegReg', (163, 167))	('PD-L1', 'Gene', (222, 227))	('microsatellite', 'Var', (73, 87))	('PD-L1', 'Gene', '29126', (222, 227))	('anti-programmed', 'MPA', (168, 183))	('PD-1', 'Gene', (191, 195))	('PD-1', 'Gene', '5133', (191, 195))
518547	30508944	To date, tumor protein 53 (TP53), PTEN mutations had been identified by NGS in 3 patients with FDCS in 2 studies.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('patients', 'Species', '9606', (81, 89))	('tumor protein 53', 'Gene', (9, 25))	('mutations', 'Var', (39, 48))	('tumor protein 53', 'Gene', '7157', (9, 25))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
518557	30508944	Meanwhile, MYC gene amplification predicts the poorest prognosis in patients with non-small cell lung cancers.DPYD mutation has been reported to be associated with fluorouracil drug toxicity.	('MYC', 'Gene', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('DPYD', 'Gene', '1806', (110, 114))	('toxicity', 'Disease', 'MESH:D064420', (182, 190))	('toxicity', 'Disease', (182, 190))	('patients', 'Species', '9606', (68, 76))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('non-small cell lung cancers', 'Disease', (82, 109))	('associated', 'Reg', (148, 158))	('fluorouracil', 'Chemical', 'MESH:D005472', (164, 176))	('MYC', 'Gene', '4609', (11, 14))	('mutation', 'Var', (115, 123))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (82, 109))	('DPYD', 'Gene', (110, 114))
518563	30508944	To in-depth discuss the heterogeneity of our case, we analyzed the mutation profiles of primary and metastatic tumor specimens and plasma ctDNA mutations and then performed mutation clonal clustering to aggregated 3 clones.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('mutations', 'Var', (144, 153))	('ctDNA', 'Gene', (138, 143))
518566	30508944	The patient was treated with carboplatin and veliparib based on BRCA2 mutation after a failure of frontline surgery and chemoradiotherapy and achieved a durable disease stabilization.	('BRCA2', 'Gene', '675', (64, 69))	('patient', 'Species', '9606', (4, 11))	('BRCA2', 'Gene', (64, 69))	('veliparib', 'Chemical', 'MESH:C521013', (45, 54))	('mutation', 'Var', (70, 78))	('carboplatin', 'Chemical', 'MESH:D016190', (29, 40))
518570	30508944	In our sample, the detection of biomarkers for immunotherapy revealed microsatellite stable (MSS) and mismatch repair-proficient (pMMR), which predicted a relatively poor anti-PD-1/PD-L1 immunotherapy outcome.	('microsatellite', 'Var', (70, 84))	('PD-L1', 'Gene', (181, 186))	('PD-1', 'Gene', (176, 180))	('PD-1', 'Gene', '5133', (176, 180))	('PD-L1', 'Gene', '29126', (181, 186))
518617	28562351	In order to study where there is an age trend of second cancer, the SIRs were stratified according to three age groups (<=50, 50-60 and >60) at initial diagnosis of the primary cancer.	('cancer', 'Disease', (177, 183))	('<=50', 'Var', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('primary cancer', 'Disease', (169, 183))	('primary cancer', 'Disease', 'MESH:D009369', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
518639	28562351	The epigenetic alterations of some genes, such as HOXA9, have been implicated in both oral cancer and esophageal cancer patients as potential biomarkers for the early detection of the field of cancerization.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('HOXA9', 'Gene', (50, 55))	('implicated', 'Reg', (67, 77))	('cancer', 'Disease', (193, 199))	('oral cancer', 'Disease', 'MESH:D009062', (86, 97))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('epigenetic alterations', 'Var', (4, 26))	('oral cancer', 'Disease', (86, 97))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('esophageal cancer', 'Disease', (102, 119))	('HOXA9', 'Gene', '3205', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
518642	28562351	For example, the tumour suppressor gene TP53 plays an important role in the multi-step carcinogenesis for both cancers, and TP53 mutations were found in 93% of esophageal squamous cell carcinoma and 57% of oral squamous cell carcinoma in Chinese patients, particularly those who had alcohol drinking, betel quid chewing or cigarette smoking.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('patients', 'Species', '9606', (246, 254))	('TP53', 'Gene', (124, 128))	('TP53', 'Gene', '7157', (40, 44))	('esophageal squamous cell carcinoma', 'Disease', (160, 194))	('alcohol', 'Chemical', 'MESH:D000438', (283, 290))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (206, 234))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('found', 'Reg', (144, 149))	('oral squamous cell carcinoma', 'Disease', (206, 234))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('alcohol drinking', 'Phenotype', 'HP:0030955', (283, 299))	('cancers', 'Disease', (111, 118))	('TP53', 'Gene', '7157', (124, 128))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (160, 194))	('TP53', 'Gene', (40, 44))	('tumour', 'Disease', (17, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('mutations', 'Var', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
518643	28562351	Recently, genetic polymorphisms of acetaldehyde dehydrogenases (ALDH2) gene is recognized as a key factor regarding the susceptibility to both esophageal and oral squamous cell carcinomas.	('susceptibility', 'Reg', (120, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('ALDH2', 'Gene', '217', (64, 69))	('ALDH2', 'Gene', (64, 69))	('esophageal and oral squamous cell carcinomas', 'Disease', 'MESH:D000077277', (143, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('acetaldehyde', 'Chemical', 'MESH:D000079', (35, 47))	('genetic polymorphisms', 'Var', (10, 31))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (163, 187))
518645	28562351	Inactive heterozygous ALDH2 alleles cause a deficiency of the enzyme and were shown to increase the risk of esophageal squamous cell carcinoma (SCC) and metachronous head and neck cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('ALDH2', 'Gene', (22, 27))	('increase', 'PosReg', (87, 95))	('deficiency of the enzyme', 'Disease', 'MESH:D008661', (44, 68))	('SCC', 'Gene', (144, 147))	('alleles', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (108, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('SCC', 'Gene', '6317', (144, 147))	('head and neck cancer', 'Phenotype', 'HP:0012288', (166, 186))	('neck cancer', 'Disease', 'MESH:D006258', (175, 186))	('ALDH2', 'Gene', '217', (22, 27))	('neck cancer', 'Disease', (175, 186))	('esophageal squamous cell carcinoma', 'Disease', (108, 142))	('deficiency of the enzyme', 'Disease', (44, 68))
518650	28562351	On top of that, the in vitro and animal studies showed that HPV16 E6-E7 can induce cancer stem-like cells phenotypes in esophageal squamous cell carcinoma through activation of the PI3K/Akt signalling pathway.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('Akt', 'Gene', '207', (186, 189))	('activation', 'PosReg', (163, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('HPV16', 'Species', '333760', (60, 65))	('E6-E7', 'Var', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('Akt', 'Gene', (186, 189))	('HPV16', 'Gene', (60, 65))	('induce', 'PosReg', (76, 82))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
518808	26891725	The data showed that RFA for longer BE segments resulted in CE-IM and CE-D of 79 and 83 %, respectively.	('CE-D', 'Disease', (70, 74))	('BE', 'Phenotype', 'HP:0100580', (36, 38))	('CE-IM', 'Disease', (60, 65))	('CE-D', 'Chemical', '-', (70, 74))	('RFA', 'Var', (21, 24))	('CE-IM', 'Chemical', '-', (60, 65))
518837	26891725	Ablation reduced the risk of progression to HGD or EAC by 25.0 % (1.5 % for ablation vs 26.5 % for surveillance).	('Ablation', 'Var', (0, 8))	('HGD', 'Gene', '3081', (44, 47))	('reduced', 'NegReg', (9, 16))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('HGD', 'Gene', (44, 47))	('EAC', 'Disease', (51, 54))
518862	24654646	Herein, we evaluated the relationship of gastric cancer risk-related variants at 1q22, 3q13.3, 5p13.1, and 8q24 with the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population with a case-control study (2139 cases and 2273 controls).	('variants', 'Var', (69, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (129, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('esophageal squamous cell carcinoma', 'Disease', (129, 163))	('gastric cancer', 'Disease', (41, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
518863	24654646	We found that the T allele of rs2294008, an intronic variant of the PSCA gene at 8q24 that was previously associated with an increased risk of gastric cancer, was inversely associated with a decreased risk of ESCC (odds ratio = 0.90; 95% confidence interval, 0.81-0.99; P = 0.034).	('PSCA', 'Gene', (68, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('associated', 'Reg', (106, 116))	('gastric cancer', 'Disease', (143, 157))	('ESCC', 'Disease', (209, 213))	('rs2294008', 'DBSNP_MENTION', 'None', (30, 39))	('PSCA', 'Gene', '8000', (68, 72))	('decreased', 'NegReg', (191, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (125, 157))	('rs2294008', 'Var', (30, 39))
518864	24654646	Of interest, the association of rs2294008 with ESCC was consistent with that observed in esophageal adenocarcinoma and ESCC in Caucasian populations.	('ESCC', 'Disease', (119, 123))	('ESCC', 'Disease', (47, 51))	('rs2294008', 'DBSNP_MENTION', 'None', (32, 41))	('esophageal adenocarcinoma', 'Disease', (89, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (89, 114))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (89, 114))	('rs2294008', 'Var', (32, 41))
518865	24654646	However, no significant associations were observed for the other three variants at 1q22 (rs4072037), 3q13.31 (rs9841504), and 5p13.1 (rs13361707).	('rs4072037', 'Mutation', 'rs4072037', (89, 98))	('rs9841504', 'Mutation', 'rs9841504', (110, 119))	('rs13361707', 'Var', (134, 144))	('rs9841504', 'Var', (110, 119))	('rs4072037', 'Var', (89, 98))	('rs13361707', 'Mutation', 'rs13361707', (134, 144))
518876	24654646	Therefore, we carried out a case-control study including 2139 ESCC cases and 2273 cancer-free controls to investigate the associations of genetic variants at 1q22, 3q13.31, 5p13.1, and 8q24 with the risk of ESCC in a Chinese population.	('ESCC', 'Disease', (207, 211))	('associations', 'Interaction', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('variants', 'Var', (146, 154))	('ESCC', 'Disease', (62, 66))
518881	24654646	Based on reported GWAS on GC, rs4072037 at 1q22, rs9841504 at 3q13.31, rs13361707 at 5p13.1, rs2294008 and rs2976392 at 8q24, rs2274223 at 10q23, and rs13042395 at 20p13 are associated with GC risk at genome-wide significance level or well replicated in independent studies.	('rs4072037', 'Mutation', 'rs4072037', (30, 39))	('rs13042395', 'Var', (150, 160))	('GC', 'Chemical', 'MESH:C057580', (190, 192))	('associated', 'Reg', (174, 184))	('rs2294008', 'DBSNP_MENTION', 'None', (93, 102))	('rs13361707', 'Var', (71, 81))	('rs9841504', 'Mutation', 'rs9841504', (49, 58))	('GC', 'Chemical', 'MESH:C057580', (26, 28))	('rs2294008', 'Var', (93, 102))	('rs2976392', 'Mutation', 'rs2976392', (107, 116))	('rs9841504', 'Var', (49, 58))	('rs13361707', 'Mutation', 'rs13361707', (71, 81))	('rs13042395', 'Mutation', 'rs13042395', (150, 160))	('rs4072037', 'Var', (30, 39))	('rs2274223', 'Mutation', 'rs2274223', (126, 135))	('rs2274223', 'Var', (126, 135))	('rs2976392', 'Var', (107, 116))
518882	24654646	As the two SNPs rs2294008 and rs2976392 at 8q24 are in strong linkage disequilibrium (LD) in Chinese populations, we only selected rs2294008 in the current study.	('rs2294008', 'DBSNP_MENTION', 'None', (131, 140))	('rs2294008', 'Var', (131, 140))	('rs2294008', 'DBSNP_MENTION', 'None', (16, 25))	('rs2976392', 'Var', (30, 39))	('rs2294008', 'Var', (16, 25))	('rs2976392', 'Mutation', 'rs2976392', (30, 39))	('linkage', 'Interaction', (62, 69))
518883	24654646	Finally, we genotyped four SNPs in this study, including rs4072037 at 1q22 associated with the MUC1 gene, rs9841504 at 3q13.31 associated with the ZBTB20 gene, rs13361707 at 5p13.1 associated with the PRKAA1 gene, and rs2294008 at 8q24 associated with the PSCA gene (Table S2).	('rs9841504', 'Var', (106, 115))	('PRKAA1', 'Gene', '5562', (201, 207))	('MUC1', 'Gene', (95, 99))	('MUC1', 'Gene', '4582', (95, 99))	('rs4072037', 'Var', (57, 66))	('associated', 'Reg', (181, 191))	('associated', 'Reg', (127, 137))	('ZBTB20', 'Gene', (147, 153))	('rs2294008', 'DBSNP_MENTION', 'None', (218, 227))	('associated', 'Reg', (236, 246))	('rs13361707', 'Mutation', 'rs13361707', (160, 170))	('PSCA', 'Gene', (256, 260))	('PRKAA1', 'Gene', (201, 207))	('rs2294008', 'Var', (218, 227))	('rs4072037', 'Mutation', 'rs4072037', (57, 66))	('PSCA', 'Gene', '8000', (256, 260))	('ZBTB20', 'Gene', '26137', (147, 153))	('associated', 'Reg', (75, 85))	('rs13361707 at', 'Var', (160, 173))	('rs9841504', 'Mutation', 'rs9841504', (106, 115))
518885	24654646	In the additive model, the T allele of rs2294008 at 8q24 was significantly associated with a decreased risk of ESCC with a per-allele OR of 0.90 (95% CI, 0.81-0.99; P = 0.034).	('decreased', 'NegReg', (93, 102))	('rs2294008', 'DBSNP_MENTION', 'None', (39, 48))	('ESCC', 'Disease', (111, 115))	('rs2294008', 'Var', (39, 48))
518887	24654646	However, no significant associations were observed for the other three SNPs with ESCC risk (P = 0.181, 0.908, and 0.666 for rs4072037 at 1q22, rs9841504 at 3q13.31, and rs13361707 at 5p13.1, respectively).	('rs13361707', 'Var', (169, 179))	('rs9841504', 'Var', (143, 152))	('rs4072037', 'Var', (124, 133))	('rs4072037', 'Mutation', 'rs4072037', (124, 133))	('ESCC', 'Disease', (81, 85))	('rs13361707', 'Mutation', 'rs13361707', (169, 179))	('rs9841504', 'Mutation', 'rs9841504', (143, 152))
518888	24654646	Moreover, in an effort to investigate the association between rs2294008 and ESCC risk in subgroups, we carried out stratification analyses on age, sex, and smoking and drinking status.	('rs2294008', 'DBSNP_MENTION', 'None', (62, 71))	('ESCC', 'Disease', (76, 80))	('rs2294008', 'Var', (62, 71))
518889	24654646	Of interest, a stronger strength of association of rs2294008-T allele with ESCC risk was observed among non-drinkers (OR = 0.81; 95% CI, 0.70-0.93; P = 2.61 x 10-3) compared with that of drinkers (OR = 1.00; 95% CI, 0.86-1.17; P = 0.998) (P = 0.045 for the heterogeneity test).	('association', 'Interaction', (36, 47))	('ESCC', 'Disease', (75, 79))	('rs2294008', 'Var', (51, 60))	('rs2294008', 'DBSNP_MENTION', 'None', (51, 60))
518890	24654646	We carried out a further interactive analysis for rs2294008 genotypes and alcohol drinking on ESCC risk.	('alcohol drinking', 'Phenotype', 'HP:0030955', (74, 90))	('rs2294008', 'DBSNP_MENTION', 'None', (50, 59))	('alcohol', 'Chemical', 'MESH:D000438', (74, 81))	('rs2294008', 'Var', (50, 59))	('ESCC', 'Disease', (94, 98))
518892	24654646	However, no significant interaction between rs22940078 genotypes and alcohol drinking was detected on the risk of ESCC (P = 0.091).	('ESCC', 'Disease', (114, 118))	('rs22940078', 'Var', (44, 54))	('alcohol drinking', 'Phenotype', 'HP:0030955', (69, 85))	('rs22940078', 'Mutation', 'rs22940078', (44, 54))	('alcohol', 'Chemical', 'MESH:D000438', (69, 76))
518893	24654646	In the current study, in an effort to explore the potential roles of genetic loci associated with GC risk in the development of EC, we investigated the associations of genetic variants at 1q22, 3q13.31, 5p13.1, and 8q24 with the risk of ESCC in a Chinese case-control study with 2139 cases and 2273 controls.	('EC', 'Chemical', '-', (128, 130))	('associations', 'Interaction', (152, 164))	('GC', 'Chemical', 'MESH:C057580', (98, 100))	('variants', 'Var', (176, 184))	('investigated', 'Reg', (135, 147))	('ESCC', 'Disease', (237, 241))
518894	24654646	We found that the T allele of rs2294008 was significantly associated with a reduced risk of ESCC, which indicated that genetic variants at 8q24 may be implicated with ESCC susceptibility.	('ESCC', 'Disease', (92, 96))	('ESCC', 'Disease', (167, 171))	('reduced', 'NegReg', (76, 83))	('rs2294008', 'DBSNP_MENTION', 'None', (30, 39))	('rs2294008', 'Var', (30, 39))
518895	24654646	In a two-stage GWAS, genetic variants at 8q24 were identified to be associated with GC risk in Japanese populations, especially for diffuse-type GC with an increased risk for the T allele of the lead SNP rs2294008 (OR = 1.67; 95%CI, 1.47-1.90).	('GC', 'Chemical', 'MESH:C057580', (145, 147))	('rs2294008', 'DBSNP_MENTION', 'None', (204, 213))	('associated', 'Reg', (68, 78))	('GC', 'Chemical', 'MESH:C057580', (84, 86))	('diffuse-type GC', 'Disease', (132, 147))	('variants', 'Var', (29, 37))	('rs2294008', 'Var', (204, 213))
518898	24654646	Of interest, in a population-based case-control study in the USA with individuals of predominantly Caucasian ethnicity, those carrying the rs2294008-T allele were significantly associated with reduced risks of GCA (OR = 0.5; 95% CI, 0.3-0.9), EA (OR = 0.5; 95% CI, 0.3-0.9), and ESCC (OR = 0.4; 95% CI, 0.2-0.9) as compared with those with CC genotype, although the sample size was relatively small (123 GCA, 107 EA, 52 ESCC, and 211 matched controls).	('GCA', 'Gene', '25801', (210, 213))	('GCA', 'Gene', (210, 213))	('rs2294008', 'DBSNP_MENTION', 'None', (139, 148))	('rs2294008', 'Var', (139, 148))	('reduced', 'NegReg', (193, 200))	('ESCC', 'Disease', (279, 283))	('GCA', 'Gene', '25801', (404, 407))	('GCA', 'Gene', (404, 407))
518899	24654646	Consistent with those findings, we also observed a significantly decreased risk of ESCC for those with the rs2294008-T allele in a Chinese population with larger sample size (2139 cases and 2273 controls), which was clearly opposite to that observed in GC.	('rs2294008', 'DBSNP_MENTION', 'None', (107, 116))	('decreased', 'NegReg', (65, 74))	('rs2294008', 'Var', (107, 116))	('GC', 'Chemical', 'MESH:C057580', (253, 255))	('ESCC', 'Disease', (83, 87))
518900	24654646	This discrepancy may reflect the opposing effect of genetic variants at 8q24 in regulating pathogenesis between proximal and distal upper gastroesophageal cancers.	('proximal', 'Disease', (112, 120))	('upper gastroesophageal cancers', 'Disease', (132, 162))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('upper gastroesophageal cancers', 'Disease', 'MESH:D009369', (132, 162))	('variants', 'Var', (60, 68))
518902	24654646	We also conducted an interactive analysis for rs2294008 genotypes and alcohol drinking on ESCC risk.	('rs2294008', 'DBSNP_MENTION', 'None', (46, 55))	('rs2294008', 'Var', (46, 55))	('alcohol', 'Chemical', 'MESH:D000438', (70, 77))	('ESCC', 'Disease', (90, 94))	('alcohol drinking', 'Phenotype', 'HP:0030955', (70, 86))
518903	24654646	However, a significant association between rs2294008 and ESCC risk was only observed among non-drinkers.	('ESCC', 'Disease', (57, 61))	('rs2294008', 'Var', (43, 52))	('rs2294008', 'DBSNP_MENTION', 'None', (43, 52))
518905	24654646	These findings may indicate that rs2294008 acts as an effect modifier of alcohol drinking in the development of ESCC.	('rs2294008', 'DBSNP_MENTION', 'None', (33, 42))	('ESCC', 'Disease', (112, 116))	('rs2294008', 'Var', (33, 42))	('alcohol drinking', 'Phenotype', 'HP:0030955', (73, 89))	('alcohol', 'Chemical', 'MESH:D000438', (73, 80))
518906	24654646	The SNP rs2294008 is located on the 5'-UTR of PSCA at 8q24.	('PSCA', 'Gene', (46, 50))	('rs2294008', 'DBSNP_MENTION', 'None', (8, 17))	('rs2294008', 'Var', (8, 17))	('PSCA', 'Gene', '8000', (46, 50))
518907	24654646	Substitution of the C allele with the T allele at rs2294008 has been shown to reduce transcriptional activity of an upstream fragment of the PSCA gene.	('Substitution', 'Var', (0, 12))	('reduce', 'NegReg', (78, 84))	('transcriptional activity', 'MPA', (85, 109))	('rs2294008', 'DBSNP_MENTION', 'None', (50, 59))	('PSCA', 'Gene', '8000', (141, 145))	('rs2294008', 'Var', (50, 59))	('PSCA', 'Gene', (141, 145))
518908	24654646	According to a web-based SNP analysis tool, SNPinfo (http://snpinfo.niehs.nih.gov/), the SNP rs2294008 may influence an exonic splicing enhancer or exonic splicing silencer and result in disequilibrium for different isoforms of PSCA.	('exonic splicing', 'MPA', (148, 163))	('enhancer', 'PosReg', (136, 144))	('PSCA', 'Gene', (228, 232))	('rs2294008', 'DBSNP_MENTION', 'None', (93, 102))	('result in', 'Reg', (177, 186))	('rs2294008', 'Var', (93, 102))	('PSCA', 'Gene', '8000', (228, 232))	('exonic splicing', 'MPA', (120, 135))	('disequilibrium', 'MPA', (187, 201))	('influence', 'Reg', (107, 116))	('isoforms', 'MPA', (216, 224))
518909	24654646	Moreover, analysis of the Encyclopedia of DNA Elements data as implemented in the online tool, RegulomeDB (http://regulomedb.org/), indicates that several SNPs in LD with rs2294008 (r2 > 0.8) located in motifs may influence the binding of specified transcription factors (Table S4).	('rs2294008', 'Var', (171, 180))	('binding', 'Interaction', (228, 235))	('influence', 'Reg', (214, 223))	('rs2294008', 'DBSNP_MENTION', 'None', (171, 180))
518910	24654646	Two SNPs rs1045574 and rs2976396 are both cis expression quantitative trait loci linked to the expression of LYPD2, whereas the variants rs1045574, rs2976396, and rs2920282 fall into transcription factor binding sites or DNase I peaks.	('fall', 'Phenotype', 'HP:0002527', (173, 177))	('rs2920282', 'Mutation', 'rs2920282', (163, 172))	('rs1045574', 'Var', (137, 146))	('LYPD2', 'Gene', '137797', (109, 114))	('rs2976396', 'Var', (23, 32))	('LYPD2', 'Gene', (109, 114))	('rs1045574', 'Mutation', 'rs1045574', (9, 18))	('rs2976396', 'Mutation', 'rs2976396', (148, 157))	('fall', 'NegReg', (173, 177))	('binding', 'Interaction', (204, 211))	('rs1045574', 'Mutation', 'rs1045574', (137, 146))	('rs2920282', 'Var', (163, 172))	('rs2976396', 'Var', (148, 157))	('rs2976396', 'Mutation', 'rs2976396', (23, 32))	('rs1045574', 'Var', (9, 18))
518915	24654646	Additionally, knockdown of PSCA in a bladder cancer cell line resulted in induction of inflammatory gene expression, accompanied by a reduction in cell growth.	('induction', 'PosReg', (74, 83))	('PSCA', 'Gene', '8000', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('bladder cancer', 'Disease', 'MESH:D001749', (37, 51))	('bladder cancer', 'Disease', (37, 51))	('reduction', 'NegReg', (134, 143))	('PSCA', 'Gene', (27, 31))	('knockdown', 'Var', (14, 23))	('cell growth', 'CPA', (147, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))	('inflammatory gene expression', 'MPA', (87, 115))
518918	24654646	Our findings suggest that genetic variants at 1q22, 3q13.31, and 5p13.1 may not be important in the development of ESCC, though the obvious effects have been implicated in gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (172, 194))	('ESCC', 'Disease', (115, 119))	('variants', 'Var', (34, 42))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (172, 194))	('implicated', 'Reg', (158, 168))	('effects', 'Reg', (140, 147))
518919	24654646	Recently, an exploratory study reported that rs4072037 in MUC1 at 1q22 was associated with a reduced risk of ESCC in Caucasian populations.	('rs4072037', 'Var', (45, 54))	('ESCC', 'Disease', (109, 113))	('rs4072037', 'Mutation', 'rs4072037', (45, 54))	('reduced', 'NegReg', (93, 100))	('MUC1', 'Gene', (58, 62))	('MUC1', 'Gene', '4582', (58, 62))
518921	24654646	In summary, in a relatively large case-control study in a Chinese population, we reported an inverse association for genetic variants at 8q24 with ESCC risk compared with that for GC.	('ESCC', 'Disease', (147, 151))	('inverse', 'NegReg', (93, 100))	('GC', 'Chemical', 'MESH:C057580', (180, 182))	('variants', 'Var', (125, 133))
518925	25154853	FEN1 -69G>A and 4150G>T polymorphisms and cancer risk in Chinese population Previous studies have investigated the associations between FEN1 -69G>A (rs174538) and 4150G>T (rs4246215) polymorphisms and cancer risk in Chinese population.	('FEN1', 'Gene', '2237', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('FEN1', 'Gene', (136, 140))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('-69G>A', 'Mutation', 'rs174538', (5, 11))	('FEN1', 'Gene', (0, 4))	('rs4246215', 'Mutation', 'rs4246215', (172, 181))	('4150G>T', 'Mutation', 'rs4246215', (163, 170))	('rs174538', 'Var', (149, 157))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('4150G>T', 'Mutation', 'rs4246215', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('rs174538', 'Mutation', 'rs174538', (149, 157))	('-69G>A', 'Mutation', 'rs174538', (141, 147))	('FEN1', 'Gene', '2237', (136, 140))
518926	25154853	Crude odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of associations between FEN1 -69G>A and 4150G>T polymorphisms and cancer risk in Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('FEN1', 'Gene', (122, 126))	('4150G>T', 'Mutation', 'rs4246215', (138, 145))	('associations', 'Interaction', (101, 113))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('-69G>A', 'Mutation', 'rs174538', (127, 133))	('4150G>T', 'Var', (138, 145))	('FEN1', 'Gene', '2237', (122, 126))
518930	25154853	In addition, haplotypes consisting of -69G>A and 4150G>T polymorphisms were closely associated with cancer risk.	('4150G>T', 'Mutation', 'rs4246215', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('-69G>A', 'Mutation', 'rs174538', (38, 44))	('associated', 'Reg', (84, 94))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('4150G>T', 'Var', (49, 56))
518936	25154853	Reduced DNA repair capacity (DRC) is reportedly related to an increased risk of cancer, and single nucleotide polymorphisms (SNPs) located in DNA repair genes may affect gene function and thereby debilitate DRC.	('debilitate', 'NegReg', (196, 206))	('affect', 'Reg', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Reduced', 'NegReg', (0, 7))	('gene function', 'MPA', (170, 183))	('single nucleotide polymorphisms', 'Var', (92, 123))	('DNA repair', 'Gene', (142, 152))	('DNA repair capacity', 'MPA', (8, 27))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))	('DRC', 'MPA', (207, 210))
518942	25154853	Among them, -69G>A (rs174538) and 4150G>T (rs4246215) polymorphisms have been gaining great attention.	('rs4246215', 'Mutation', 'rs4246215', (43, 52))	('rs174538', 'Var', (20, 28))	('-69G>A', 'Mutation', 'rs174538', (12, 18))	('4150G>T', 'Mutation', 'rs4246215', (34, 41))	('rs174538', 'Mutation', 'rs174538', (20, 28))	('rs4246215', 'Var', (43, 52))
518943	25154853	Previous studies have suggested that the two polymorphisms in FEN1 may function as biomarkers for cancer risk in Chinese population, including breast cancer, glioma, hepatocellular carcinoma, esophageal cancer, gastric cancer, colorectal cancer, etc.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('breast cancer', 'Disease', (143, 156))	('FEN1', 'Gene', '2237', (62, 66))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (166, 190))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Disease', (98, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (238, 244))	('esophageal cancer', 'Disease', 'MESH:D004938', (192, 209))	('colorectal cancer', 'Phenotype', 'HP:0003003', (227, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('FEN1', 'Gene', (62, 66))	('hepatocellular carcinoma', 'Disease', (166, 190))	('cancer', 'Disease', (150, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('esophageal cancer', 'Disease', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('gastric cancer', 'Disease', (211, 225))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (203, 209))	('glioma', 'Disease', (158, 164))	('cancer', 'Disease', (219, 225))	('colorectal cancer', 'Disease', 'MESH:D015179', (227, 244))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (166, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('colorectal cancer', 'Disease', (227, 244))	('polymorphisms', 'Var', (45, 58))
518944	25154853	However, these studies had relatively small sample sizes, and may lack enough power to assess the associations between FEN1 -69G>A and 4150G>T polymorphisms and cancer risk in Chinese population.	('-69G>A', 'Mutation', 'rs174538', (124, 130))	('FEN1', 'Gene', '2237', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('FEN1', 'Gene', (119, 123))	('4150G>T', 'Var', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('associations', 'Interaction', (98, 110))	('4150G>T', 'Mutation', 'rs4246215', (135, 142))	('cancer', 'Disease', (161, 167))
518945	25154853	Then, 2 articles without FEN1 -69G>A and 4150G>T polymorphisms and cancer risk were excluded.	('FEN1', 'Gene', '2237', (25, 29))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('4150G>T', 'Mutation', 'rs4246215', (41, 48))	('cancer', 'Disease', (67, 73))	('FEN1', 'Gene', (25, 29))	('-69G>A', 'Mutation', 'rs174538', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('4150G>T', 'Var', (41, 48))
518950	25154853	Frequency distribution of the FEN1 -69G>A and 4150G>T haplotypes is shown in Supplement Table S1.	('FEN1', 'Gene', (30, 34))	('4150G>T', 'Var', (46, 53))	('4150G>T', 'Mutation', 'rs4246215', (46, 53))	('-69G>A', 'Mutation', 'rs174538', (35, 41))	('FEN1', 'Gene', '2237', (30, 34))
518953	25154853	Results of FEN1 -69G>A and 4150G>T polymorphisms and cancer risk are presented in Table 2 and Figure 2.	('4150G>T', 'Mutation', 'rs4246215', (27, 34))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('-69G>A', 'Mutation', 'rs174538', (16, 22))	('FEN1', 'Gene', '2237', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('FEN1', 'Gene', (11, 15))	('4150G>T', 'Var', (27, 34))
518954	25154853	For the -69G>A polymorphism, significant association was observed in all cancer type combined study, including breast cancer, glioma, hepatocellular carcinoma, esophageal cancer, gastric cancer, colorectal cancer and lung cancer (A vs. G: OR = 0.73, 95%CI: 0.69-0.77, PH = 0.20; AA vs. GG: OR = 0.54, 95%CI: 0.48-0.61, PH = 0.31; AG vs. GG: OR = 0.76, 95%CI: 0.70-0.82, PH = 0.39; (AA+AG) vs. GG: OR = 0.70, 95%CI: 0.65-0.75, PH = 0.26; AA vs. (AG+GG): OR = 0.62, 95%CI: 0.56-0.69, PH = 0.51).	('gastric cancer', 'Phenotype', 'HP:0012126', (179, 193))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Disease', (111, 124))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (134, 158))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('colorectal cancer', 'Phenotype', 'HP:0003003', (195, 212))	('cancer', 'Disease', (222, 228))	('polymorphism', 'Var', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('gastric cancer', 'Disease', (179, 193))	('cancer', 'Disease', (206, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('cancer', 'Disease', (118, 124))	('hepatocellular carcinoma', 'Disease', (134, 158))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', (217, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (171, 177))	('esophageal cancer', 'Disease', (160, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (179, 193))	('glioma', 'Disease', (126, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('-69G>A', 'Mutation', 'rs174538', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (187, 193))	('colorectal cancer', 'Disease', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (134, 158))
518956	25154853	For the 4150G>T polymorphism, significant associations with cancer risk were observed in all cancer type combined study (T vs. G: OR = 0.77, 95%CI: 0.73-0.81, PH = 0.19; TT vs. GG: OR = 0.59, 95%CI: 0.53-0.67, PH = 0.37; TG vs. GG: OR = 0.79, 95%CI: 0.73-0.86, PH = 0.16; (TT+TG) vs. GG: OR = 0.74, 95%CI: 0.68-0.79, PH = 0.13; TT vs. (TG+GG): OR = 0.67, 95%CI: 0.60-0.75, PH = 0.61).	('associations', 'Interaction', (42, 54))	('cancer', 'Disease', (93, 99))	('4150G>T', 'Var', (8, 15))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', (60, 66))	('4150G>T', 'Mutation', 'rs4246215', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
518958	25154853	In haplotype analysis (Table 3), the FEN1 haplotype (G-69G4150) comprising the major alleles was taken as reference.	('FEN1', 'Gene', (37, 41))	('G-69G4150', 'Var', (53, 62))	('FEN1', 'Gene', '2237', (37, 41))
518959	25154853	The pooled results indicated that G-69T4150, A-69G4150 and A-69T4150 haplotypes were significantly associated with cancer risk (G-69T4150 vs. G-69G4150: OR = 0.68, 95%CI: 0.55-0.83, PH = 0.00; A-69G4150 vs. G-69G4150: OR = 0.41, 95%CI: 0.32-0.51, PH = 0.00; A-69T4150 vs. G-69G4150: OR = 0.76, 95%CI: 0.70-0.82, PH = 0.00).	('A-69T4150', 'Var', (59, 68))	('cancer', 'Disease', (115, 121))	('G-69T4150', 'Var', (34, 43))	('A-69T4150 vs.', 'Var', (258, 271))	('A-69G4150', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('A-69G4150', 'Var', (193, 202))	('associated', 'Reg', (99, 109))
518962	25154853	As shown in Figure 4, the shape of the funnel plot was symmetrical and did not show an obvious publication bias for FEN1 -69G>A or 4150G>T polymorphism.	('4150G>T', 'Var', (131, 138))	('FEN1', 'Gene', (116, 120))	('4150G>T', 'Mutation', 'rs4246215', (131, 138))	('-69G>A', 'Mutation', 'rs174538', (121, 127))	('FEN1', 'Gene', '2237', (116, 120))
518963	25154853	To the best of our knowledge, this is the first meta-analysis providing comprehensive insights into the effects of FEN1 -69G>A and 4150G>T polymorphisms on the risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('4150G>T', 'Var', (131, 138))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('FEN1', 'Gene', '2237', (115, 119))	('-69G>A', 'Mutation', 'rs174538', (120, 126))	('4150G>T', 'Mutation', 'rs4246215', (131, 138))	('cancer', 'Disease', (168, 174))	('FEN1', 'Gene', (115, 119))
518968	25154853	Transient transfection and luciferase assays showed that FEN1, a tumor suppressor gene, -69A or 4150T variant has heightened expression in vitro.	('FEN1', 'Gene', (57, 61))	('tumor', 'Disease', (65, 70))	('or 4150T variant', 'Var', (93, 109))	('heightened', 'PosReg', (114, 124))	('expression', 'MPA', (125, 135))	('FEN1', 'Gene', '2237', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
518971	25154853	Namely, G-69T4150, A-69G4150 and A-69T4150 haplotypes were significantly associated with the decreased risk of cancer in Chinese populations.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('decreased', 'NegReg', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('A-69T4150', 'Var', (33, 42))	('cancer', 'Disease', (111, 117))	('A-69G4150', 'Var', (19, 28))	('G-69T4150', 'Var', (8, 17))
518972	25154853	Interestingly, -69G>A polymorphism is significantly associated with not only cancer risk but also FEN1 mRNA levels in normal tissues.	('-69G>A', 'Var', (15, 21))	('FEN1', 'Gene', (98, 102))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('associated', 'Reg', (52, 62))	('-69G>A', 'Mutation', 'rs174538', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('FEN1', 'Gene', '2237', (98, 102))
518975	25154853	The current research could shed lights on the relationship of FEN1 -69G>A and 4150G>T polymorphisms and the decreased susceptibility to cancer in Chinese population, comprehensively and systematically.	('-69G>A', 'Mutation', 'rs174538', (67, 73))	('FEN1', 'Gene', '2237', (62, 66))	('4150G>T', 'Var', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('FEN1', 'Gene', (62, 66))	('decreased', 'NegReg', (108, 117))	('susceptibility', 'MPA', (118, 132))	('cancer', 'Disease', (136, 142))	('4150G>T', 'Mutation', 'rs4246215', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
518976	25154853	In summary, our meta-analysis suggests that FEN1 -69G>A and 4150G>T polymorphisms and their haplotypes are associated with cancer risk, and FEN1 -69G>A polymorphism are associated with FEN1 mRNA expression in normal tissues.	('FEN1', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('FEN1', 'Gene', '2237', (140, 144))	('FEN1', 'Gene', '2237', (185, 189))	('4150G>T', 'Var', (60, 67))	('FEN1', 'Gene', (140, 144))	('associated', 'Reg', (107, 117))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('FEN1', 'Gene', (185, 189))	('associated', 'Reg', (169, 179))	('cancer', 'Disease', (123, 129))	('4150G>T', 'Mutation', 'rs4246215', (60, 67))	('FEN1', 'Gene', '2237', (44, 48))	('-69G>A', 'Mutation', 'rs174538', (49, 55))	('-69G>A', 'Mutation', 'rs174538', (145, 151))
518977	25154853	We systematically searched literature from PubMed for all relevant studies using the following terms: "flap endonuclease or FNE1" "polymorphism" and "cancer" (up to June 14, 2014).	('"cancer', 'Disease', (149, 156))	('"cancer', 'Disease', 'MESH:D009369', (149, 156))	('polymorphism', 'Var', (131, 143))	('FNE1', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
518978	25154853	Criteria for eligible studies were as follows: (a) case-control studies, (b) evaluating the association between FEN1 -69G>A and/or 4150G>T polymorphisms and cancer risk in Chinese population, (c) and sufficient information for calculating the pooled odds ratios (ORs) with 95% confidence intervals (CIs).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('FEN1', 'Gene', (112, 116))	('4150G>T', 'Var', (131, 138))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('4150G>T', 'Mutation', 'rs4246215', (131, 138))	('cancer', 'Disease', (157, 163))	('-69G>A', 'Mutation', 'rs174538', (117, 123))	('FEN1', 'Gene', '2237', (112, 116))	('association', 'Interaction', (92, 103))
518979	25154853	The following information was collected from each study: first author's name, year of publication, country of origin, cancer type, source of control, genotyping methods, the frequency distribution of -69G>A and 4150G>T genotypes/alleles/haplotypes.	('cancer', 'Disease', (118, 124))	('4150G>T', 'Var', (211, 218))	('-69G>A', 'Mutation', 'rs174538', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('4150G>T', 'Mutation', 'rs4246215', (211, 218))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
518980	25154853	In addition, data of correlations between FEN1 -69G>A polymorphism and FEN1 mRNA expression in normal tissues were also extracted from eligible studies.	('FEN1', 'Gene', (71, 75))	('FEN1', 'Gene', '2237', (42, 46))	('-69G>A', 'Mutation', 'rs174538', (47, 53))	('FEN1', 'Gene', (42, 46))	('polymorphism', 'Var', (54, 66))	('FEN1', 'Gene', '2237', (71, 75))	('mRNA expression', 'MPA', (76, 91))
518981	25154853	The strength of the associations between FEN1 -69G>A and 4150G>T polymorphisms and their haplotypes and cancer risk was measured by ORs with 95% CIs.	('associations', 'Interaction', (20, 32))	('FEN1', 'Gene', '2237', (41, 45))	('-69G>A', 'Mutation', 'rs174538', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('FEN1', 'Gene', (41, 45))	('4150G>T', 'Var', (57, 64))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('4150G>T', 'Mutation', 'rs4246215', (57, 64))
518983	25154853	For FEN1 -69G>A and 4150G>T haplotypes, the pooled ORs were estimated by comparison with G-69G4150 haplotype (G-69T4150 vs. G-69G4150, A-69G4150 vs. G-69G4150, A-69T4150 vs. G-69G4150).	('FEN1', 'Gene', '2237', (4, 8))	('4150G>T', 'Mutation', 'rs4246215', (20, 27))	('FEN1', 'Gene', (4, 8))	('A-69T4150 vs. G-69G4150', 'Var', (160, 183))	('G-69T4150', 'Var', (110, 119))	('A-69G4150 vs. G-69G4150', 'Var', (135, 158))	('G-69G4150', 'Var', (149, 158))	('-69G>A', 'Mutation', 'rs174538', (9, 15))
518987	24813513	First, there are multiple mechanisms whereby PPI-induced acid reduction might benefit patients with EoE.	('PPI-induced', 'Var', (45, 56))	('acid', 'MPA', (57, 61))	('EoE', 'Disease', (100, 103))	('benefit', 'PosReg', (78, 85))	('reduction', 'NegReg', (62, 71))	('patients', 'Species', '9606', (86, 94))
519024	24813513	As discussed above, GERD might contribute to esophageal eosinophilia by inducing the expression of eosinophil chemoattractants.	('expression', 'MPA', (85, 95))	('esophageal eosinophilia', 'Disease', (45, 68))	('inducing', 'PosReg', (72, 80))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (45, 68))	('GERD', 'Var', (20, 24))	('eosinophilia', 'Phenotype', 'HP:0001880', (56, 68))
519032	24813513	PPIs also might help to control esophageal symptoms, even if they do not cause resolution of esophageal eosinophilia.	('esophageal symptoms', 'Disease', (32, 51))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (93, 116))	('esophageal eosinophilia', 'Disease', (93, 116))	('eosinophilia', 'Phenotype', 'HP:0001880', (104, 116))	('esophageal symptoms', 'Disease', 'MESH:D004941', (32, 51))	('PPIs', 'Var', (0, 4))
519034	24813513	It is possible that patients with PPI-REE simply have GERD that is not detected by conventional diagnostic tests, but that benefits from the acid-suppressive effects of PPIs.	('acid-suppressive', 'MPA', (141, 157))	('fits', 'Disease', (127, 131))	('PPI-REE', 'Var', (34, 41))	('patients', 'Species', '9606', (20, 28))	('fits', 'Disease', 'MESH:D012640', (127, 131))	('GERD', 'Disease', (54, 58))
519046	24813513	Two recent studies using esophageal epithelial cells in culture have shown that PPIs inhibit the Th2 cytokine-stimulated secretion of eotaxin-3.	('eotaxin-3', 'Gene', (134, 143))	('PPIs', 'Var', (80, 84))	('eotaxin-3', 'Gene', '10344', (134, 143))	('inhibit', 'NegReg', (85, 92))
519052	24813513	For example, PPIs have anti-oxidant properties including their ability to scavenge hydroxyl radicals, to increase the bioavailability of sulfhydryl compounds, and to induce heme oxygenase 1.	('sulfhydryl compounds', 'Chemical', 'MESH:D013438', (137, 157))	('bioavailability of sulfhydryl compounds', 'MPA', (118, 157))	('scavenge hydroxyl radicals', 'MPA', (74, 100))	('increase', 'PosReg', (105, 113))	('PPIs', 'Var', (13, 17))	('heme oxygenase 1', 'Gene', (173, 189))	('induce', 'PosReg', (166, 172))	('hydroxyl radicals', 'Chemical', 'MESH:D017665', (83, 100))	('anti-oxidant', 'MPA', (23, 35))	('heme oxygenase 1', 'Gene', '3162', (173, 189))
519053	24813513	In epithelial cells and endothelial cells, PPIs can decrease expression of adhesion molecule and pro-inflammatory cytokines (e.g., IL-8, IL-6, tumor necrosis factor-alpha), and inhibit Th2 cytokine-driven STAT6 signaling.	('IL-8', 'Gene', (131, 135))	('inhibit', 'NegReg', (177, 184))	('IL-6, tumor necrosis factor-alpha', 'Gene', '3569;7124', (137, 170))	('adhesion', 'Protein', (75, 83))	('PPIs', 'Var', (43, 47))	('STAT6', 'Gene', (205, 210))	('STAT6', 'Gene', '6778', (205, 210))	('decrease', 'NegReg', (52, 60))	('IL-8', 'Gene', '3576', (131, 135))	('expression', 'MPA', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
519055	24813513	Although PPIs are used to treat esophageal eosinophilia, there are also intriguing data to suggest that PPIs might predispose to the development of celiac disease, food allergies, and EoE.	('food allergies', 'Disease', (164, 178))	('food allergies', 'Phenotype', 'HP:0500093', (164, 178))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (32, 55))	('food allergies', 'Disease', 'MESH:D004342', (164, 178))	('eosinophilia', 'Phenotype', 'HP:0001880', (43, 55))	('celiac disease', 'Disease', 'MESH:D002446', (148, 162))	('celiac disease', 'Disease', (148, 162))	('esophageal eosinophilia', 'Disease', (32, 55))	('allergies', 'Phenotype', 'HP:0012393', (169, 178))	('PPIs', 'Var', (104, 108))	('predispose to', 'Reg', (115, 128))	('EoE', 'Disease', (184, 187))	('celiac disease', 'Phenotype', 'HP:0002608', (148, 162))
519059	24813513	In addition, PPIs have been shown to increase gastric mucosal permeability, which might facilitate the absorption of undigested food allergens and their exposure to the immune cells that mediate allergy development.	('absorption', 'MPA', (103, 113))	('gastric mucosal', 'Disease', (46, 61))	('food allergens', 'Phenotype', 'HP:0500093', (128, 142))	('PPIs', 'Var', (13, 17))	('increase', 'PosReg', (37, 45))	('facilitate', 'PosReg', (88, 98))	('allergy', 'Disease', (195, 202))	('food allergens', 'Disease', 'MESH:D005517', (128, 142))	('gastric mucosal', 'Disease', 'MESH:D013274', (46, 61))	('allergy', 'Phenotype', 'HP:0012393', (195, 202))	('food allergens', 'Disease', (128, 142))	('increase gastric', 'Phenotype', 'HP:0005207', (37, 53))	('allergy', 'Disease', 'MESH:D004342', (195, 202))
519085	21912054	Growing evidence indicates that natural sequence variations in promoters of the MMP genes may result in variable expression of MMPs in different individuals.	('result in', 'Reg', (94, 103))	('expression', 'MPA', (113, 123))	('MMP', 'Gene', (127, 130))	('MMP', 'Gene', '4312;4313;4316;17393;4318;4323', (80, 83))	('variations', 'Var', (49, 59))	('MMP', 'Gene', '4312;4313;4316;17393;4318;4323', (127, 130))	('MMP', 'Gene', (80, 83))
519086	21912054	These polymorphisms have been associated with susceptibility to some diseases including cancers.	('associated', 'Reg', (30, 40))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('polymorphisms', 'Var', (6, 19))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
519087	21912054	In the promoter region of the MMP-7 gene, two single nucleotide polymorphisms (SNPs), an A to G transition at the -181 base pair position (-181A/G) and a C to T transition at the -153 base pair position (-153C/T), have been proved to be functional in vitro and may influence coronary artery dimensions.	('MMP-7', 'Gene', (30, 35))	('-181A/G', 'Mutation', 'rs11568818', (139, 146))	('-153C/T', 'Var', (204, 211))	('MMP-7', 'Gene', '4316', (30, 35))	('-153C/T', 'Mutation', 'rs761682477', (204, 211))	('-181A/G', 'Var', (139, 146))	('influence', 'Reg', (265, 274))	('coronary artery dimensions', 'CPA', (275, 301))
519090	21912054	Most recently, the author and his co-workers reported that the individual living in the Kashmir Valley carrying -181 GG genotype was associated with high risk of gastric cancer, indicating that common MMP-7 (-181A>G) genetic polymorphism may contribute to squamous cell gastric cancer susceptibility in the Kashmir valley.	('gastric cancer', 'Disease', 'MESH:D013274', (162, 176))	('MMP-7', 'Gene', (201, 206))	('squamous cell gastric cancer', 'Disease', (256, 284))	('contribute', 'Reg', (242, 252))	('carrying -181 GG', 'Var', (103, 119))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('MMP-7', 'Gene', '4316', (201, 206))	('high risk of gastric cancer', 'Phenotype', 'HP:0006753', (149, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('gastric cancer', 'Disease', 'MESH:D013274', (270, 284))	('squamous cell gastric cancer', 'Disease', 'MESH:D002294', (256, 284))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (270, 284))	('-181A>G', 'Mutation', 'rs11568818', (208, 215))	('gastric cancer', 'Disease', (162, 176))	('associated', 'Reg', (133, 143))
519093	21912054	All together, these data are very interesting and warrant further large-scale, case-controlled studies of MMP-7 (-181A>G) polymorphism as a biomarker to predict high-risk individuals for the development of EC.	('polymorphism', 'Var', (122, 134))	('MMP-7', 'Gene', (106, 111))	('MMP-7', 'Gene', '4316', (106, 111))	('-181A>G) polymorphism', 'Var', (113, 134))	('-181A>G', 'Mutation', 'rs11568818', (113, 120))
519096	33127962	Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study.	('cancers', 'Disease', (244, 251))	('Gastrointestinal', 'Gene', (216, 232))	('GI', 'Gene', '2770', (59, 61))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('GI', 'Gene', '2770', (234, 236))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutation', 'Var', (195, 203))	('Gastrointestinal', 'Gene', '2770', (216, 232))	('signaling pathways', 'Pathway', (176, 194))	('gastrointestinal (GI) cancers', 'Disease', 'MESH:D004067', (41, 70))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('mutations', 'Var', (28, 37))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
519097	33127962	The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3-8%), 12% (95% CI: 8-18%), 17% (95% CI: 14-20%), and 20% (95% CI: 5-41%), respectively.	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('pancreatic cancer', 'Disease', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('liver cancer', 'Disease', 'MESH:D006528', (90, 102))	('signal transduction pathway', 'Pathway', (33, 60))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('colorectal cancer', 'Disease', (104, 121))	('mutations', 'Var', (61, 70))	('liver cancer', 'Phenotype', 'HP:0002896', (90, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('liver cancer', 'Disease', (90, 102))	('rectal cancer', 'Phenotype', 'HP:0100743', (108, 121))	('gastric cancer', 'Disease', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))
519101	33127962	In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis.	('pancreatic cancer', 'Disease', (13, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (13, 30))	('higher', 'PosReg', (47, 53))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (13, 30))	('mutation', 'Var', (76, 84))
519102	33127962	Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.	('APC', 'Disease', (9, 12))	('associated', 'Reg', (103, 113))	('colorectal cancer', 'Disease', 'MESH:D015179', (26, 43))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('colorectal cancer', 'Disease', (26, 43))	('APC', 'Disease', 'MESH:D011125', (9, 12))	('gastric cancer', 'Disease', (53, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('rectal cancer', 'Phenotype', 'HP:0100743', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (13, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (26, 43))	('KRAS', 'Gene', '3845', (45, 49))	('pancreatic cancer', 'Disease', (73, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('KRAS', 'Gene', (45, 49))
519103	33127962	Distraction of signaling process induce disturbance in cellular mechanisms and may cause diseases, such as cancer, autoimmunity, and diabetes.	('autoimmunity', 'Phenotype', 'HP:0002960', (115, 127))	('autoimmunity', 'Disease', (115, 127))	('cellular mechanisms', 'MPA', (55, 74))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('autoimmunity', 'Disease', 'MESH:D001327', (115, 127))	('cause', 'Reg', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('diabetes', 'Disease', (133, 141))	('disturbance', 'Reg', (40, 51))	('cancer', 'Disease', (107, 113))	('diabetes', 'Disease', 'MESH:D003920', (133, 141))	('Distraction', 'Var', (0, 11))
519111	33127962	Mutations in signaling pathways, such as signal transduction systems, are the basic triggering mechanisms in different types of cancers.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('signaling pathways', 'Pathway', (13, 31))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
519115	33127962	APC mutation and promoter hypermethylation are two important mechanisms in carcinogenesis and colorectal cancer (CRC) progression.	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('carcinogenesis', 'Disease', (75, 89))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('rectal cancer', 'Phenotype', 'HP:0100743', (98, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('mutation', 'Var', (4, 12))	('APC', 'Disease', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))	('carcinogenesis', 'Disease', 'MESH:D063646', (75, 89))
519121	33127962	Mutation analysis of signaling pathway mediators could have prognostic impact on tumor development.	('Mutation analysis', 'Var', (0, 17))	('impact', 'Reg', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
519125	33127962	As EGFR has been a target for anti-tumor drugs, its mutations and related downstream signaling pathway mutations have become important.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mutations', 'Var', (103, 112))	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))
519126	33127962	Indeed, interaction of various signaling pathway mediator mutations and their behavior in cancer development has been a hot topic.	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('interaction', 'Interaction', (8, 19))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
519128	33127962	By considering the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria, we made an attempt to evaluate the prevalence of the signaling pathways mutation rate in the GI tract cancers in a systematic review and meta-analysis setting.	('mutation', 'Var', (177, 185))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('signaling pathways', 'Pathway', (158, 176))	('cancers', 'Disease', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('GI', 'Gene', '2770', (198, 200))
519130	33127962	The numbers of participants for the assessment of the GI cancer mutations induced 17,269, 1056, 2500, 378, 1080 individuals for CRC, LC, GC, PC, and other GI cancers, respectively.	('GI cancers', 'Disease', 'MESH:D009369', (155, 165))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('GI cancer', 'Phenotype', 'HP:0007378', (155, 164))	('LC', 'Phenotype', 'HP:0002896', (133, 135))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancer', 'Disease', (158, 164))	('mutations', 'Var', (64, 73))	('GI', 'Gene', '2770', (54, 56))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('CRC', 'Disease', (128, 131))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('GI', 'Gene', '2770', (155, 157))	('PC', 'Gene', '5091', (141, 143))	('CRC', 'Phenotype', 'HP:0003003', (128, 131))	('GI cancers', 'Disease', (155, 165))	('participants', 'Species', '9606', (15, 27))	('GI cancer', 'Phenotype', 'HP:0007378', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('GC', 'Phenotype', 'HP:0012126', (137, 139))
519133	33127962	Also, the PI3K mutations in the PI3 pathway were 3 to 8.7% and CTNNB1 mutations ranged from 1.7% to 7%.	('mutations', 'Var', (70, 79))	('CTNNB1', 'Gene', '1499', (63, 69))	('mutations', 'Var', (15, 24))	('CTNNB1', 'Gene', (63, 69))	('PI3 pathway', 'Pathway', (32, 43))	('PI3K mutations', 'Var', (10, 24))
519136	33127962	The KRAS mutations in the MAPK pathway were 2.5 to 75% and the BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations ranged from 0 to 78.6%.	('KRAS', 'Gene', '3845', (4, 8))	('B-Raf proto-oncogene', 'Gene', '673', (69, 89))	('mutations', 'Var', (9, 18))	('serine', 'Chemical', 'MESH:D012694', (91, 97))	('mutations', 'Var', (116, 125))	('BRAF', 'Gene', '673', (63, 67))	('B-Raf proto-oncogene', 'Gene', (69, 89))	('KRAS', 'Gene', (4, 8))	('MAPK', 'Gene', '5594', (26, 30))	('BRAF', 'Gene', (63, 67))	('MAPK', 'Gene', (26, 30))
519137	33127962	The Wnt signaling mediator mutations, such as beta-catenin, were reported from 3 to 37.5% and APC mutations ranged from 28.4 to 73%.	('mutations', 'Var', (27, 36))	('Wnt signaling mediator', 'Gene', (4, 26))	('beta-catenin', 'Gene', (46, 58))	('mutations', 'Var', (98, 107))	('beta-catenin', 'Gene', '1499', (46, 58))	('APC', 'Disease', 'MESH:D011125', (94, 97))	('APC', 'Disease', (94, 97))
519141	33127962	In addition, the mutation ranges in p53 were 1.2 to 61% and the JAKs in the JAK signaling pathway were observed to be 1.2 to 16%.	('JAKs', 'Gene', (64, 68))	('p53', 'Gene', (36, 39))	('mutation', 'Var', (17, 25))	('p53', 'Gene', '7157', (36, 39))	('JAK signaling pathway', 'Pathway', (76, 97))	('JAKs', 'Gene', '3716', (64, 68))
519142	33127962	In a total of 9 studies, 392 PC patients were studied with the KRAS and PIK3CA mutations reported 42 to 92% and 2.7 to 12%, respectively.	('patients', 'Species', '9606', (32, 40))	('KRAS', 'Gene', '3845', (63, 67))	('PIK3CA', 'Gene', (72, 78))	('PC', 'Gene', '5091', (29, 31))	('PIK3CA', 'Gene', '5290', (72, 78))	('mutations', 'Var', (79, 88))	('KRAS', 'Gene', (63, 67))
519143	33127962	The results of meta-analysis showed that pooled prevalence of signal transduction pathway mutations in pancreatic cancer was 20% (95% CI: 5-41%) and there was a high heterogeneity between these studies in estimating the prevalence (I-squared = 97.14%, P = 0.0001) (Fig.	('mutations', 'Var', (90, 99))	('signal transduction pathway', 'Pathway', (62, 89))	('pancreatic cancer', 'Disease', (103, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))
519145	33127962	Furthermore, the Subgroup analyses of pooled prevalence signal transduction pathway mutations in pancreatic cancer are summarized in Table 3.	('pancreatic cancer', 'Disease', 'MESH:D010190', (97, 114))	('pancreatic cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (84, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (97, 114))
519150	33127962	Moreover, APC mutations were reported between 9.5 and 47% in different malignancies.	('malignancies', 'Disease', (71, 83))	('APC', 'Disease', 'MESH:D011125', (10, 13))	('APC', 'Disease', (10, 13))	('mutations', 'Var', (14, 23))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))
519152	33127962	As glimpse, the clinic-pathological features statistically significant in association with signaling pathway mutations that they were mentioned in 2 individual studies for gastric cancer and 30, 6, 1 and 2 individual studies for CRC, LC, PC and other GI cancers, respectively.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('GI cancer', 'Phenotype', 'HP:0007378', (251, 260))	('gastric cancer', 'Phenotype', 'HP:0012126', (172, 186))	('gastric cancer', 'Disease', 'MESH:D013274', (172, 186))	('CRC', 'Disease', (229, 232))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('LC', 'Phenotype', 'HP:0002896', (234, 236))	('PC', 'Gene', '5091', (238, 240))	('signaling pathway', 'Pathway', (91, 108))	('GI cancers', 'Disease', (251, 261))	('gastric cancer', 'Disease', (172, 186))	('mutations', 'Var', (109, 118))	('significant', 'Reg', (59, 70))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('CRC', 'Phenotype', 'HP:0003003', (229, 232))	('GI cancers', 'Disease', 'MESH:D009369', (251, 261))
519153	33127962	The survival rate or prognostic feature in association with signaling pathway mutations were mentioned in 1, 6, 1, 1, 0 and 1 included studies for CRC, LC, PC and other GI cancers, respectively.	('CRC', 'Phenotype', 'HP:0003003', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('GI cancers', 'Disease', 'MESH:D009369', (169, 179))	('GI cancer', 'Phenotype', 'HP:0007378', (169, 178))	('mutations', 'Var', (78, 87))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('CRC', 'Disease', (147, 150))	('PC', 'Gene', '5091', (156, 158))	('LC', 'Phenotype', 'HP:0002896', (152, 154))	('GI cancers', 'Disease', (169, 179))
519154	33127962	The aim of the current study was to evaluate the prevalence of the signaling pathway mutation rate in GI tract cancers in a systematic review and meta-analysis setting.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('GI', 'Gene', '2770', (102, 104))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutation', 'Var', (85, 93))	('signaling pathway', 'Pathway', (67, 84))
519159	33127962	Furthermore, the pooled prevalence indices of signal transduction pathway mutations in GC, CRC, LC, and PC were 5% (95% CI: 3-8%), 17% (95% CI: 14-20%), 12% (95% CI: 8-18%), and 20% (95% CI: 5-41%), respectively.	('CRC', 'Disease', (91, 94))	('GC', 'Phenotype', 'HP:0012126', (87, 89))	('mutations', 'Var', (74, 83))	('PC', 'Gene', '5091', (104, 106))	('LC', 'Phenotype', 'HP:0002896', (96, 98))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('signal transduction pathway', 'Pathway', (46, 73))
519160	33127962	The higher rates in pooled prevalence could suggest more association between the signal transduction mutations and GI cancers incidence.	('GI cancer', 'Phenotype', 'HP:0007378', (115, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('mutations', 'Var', (101, 110))	('GI cancers', 'Disease', 'MESH:D009369', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('association', 'Interaction', (57, 68))	('GI cancers', 'Disease', (115, 125))
519166	33127962	Although the nucleotide alterations have critical impacts on cancer initiation, the environmental factors are predisposing elements in cancer induction and are affecting the signaling pathways mutations.	('cancer', 'Disease', (135, 141))	('impacts', 'Reg', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('signaling pathways', 'Pathway', (174, 192))	('cancer', 'Disease', (61, 67))	('nucleotide alterations', 'Var', (13, 35))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('affecting', 'Reg', (160, 169))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
519169	33127962	Moreover, studies on CRC and smoking showed that TGFbeta signaling pathway mutations have significant roles in carcinogenesis.	('carcinogenesis', 'Disease', (111, 125))	('CRC', 'Phenotype', 'HP:0003003', (21, 24))	('TGFbeta', 'Gene', '7039', (49, 56))	('roles', 'Reg', (102, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('mutations', 'Var', (75, 84))	('TGFbeta', 'Gene', (49, 56))
519171	33127962	TLR2 alterations associated with inflammation could lead to the signaling pathways related ERK (extracellular-regulated kinase) and PI3K/AKT mutations.	('extracellular-regulated kinase', 'Gene', (96, 126))	('mutations', 'Var', (141, 150))	('signaling pathways', 'Pathway', (64, 82))	('extracellular-regulated kinase', 'Gene', '5594', (96, 126))	('ERK', 'Gene', '5594', (91, 94))	('AKT', 'Gene', (137, 140))	('inflammation', 'Disease', 'MESH:D007249', (33, 45))	('TLR2', 'Gene', '7097', (0, 4))	('AKT', 'Gene', '207', (137, 140))	('ERK', 'Gene', (91, 94))	('alterations', 'Var', (5, 16))	('inflammation', 'Disease', (33, 45))	('TLR2', 'Gene', (0, 4))	('lead to', 'Reg', (52, 59))
519175	33127962	reported the highest rate (75%) of the KRAS mutations in CRC patients in codon 12 in 1506 individuals.	('CRC', 'Phenotype', 'HP:0003003', (57, 60))	('patients', 'Species', '9606', (61, 69))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))	('KRAS', 'Gene', '3845', (39, 43))
519177	33127962	on 264 metastatic colorectal cancers (mCRC), the KRAS exon 2 mutation was calculated to be 34%, as the highest mutation rate.	('KRAS', 'Gene', '3845', (49, 53))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('rectal cancer', 'Phenotype', 'HP:0100743', (22, 35))	('mutation', 'Var', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('colorectal cancers', 'Disease', 'MESH:D015179', (18, 36))	('colorectal cancers', 'Disease', (18, 36))	('CRC', 'Phenotype', 'HP:0003003', (39, 42))	('KRAS', 'Gene', (49, 53))
519178	33127962	In this study, BRAF mutation rate was reported to be 5.4%.	('BRAF', 'Gene', '673', (15, 19))	('mutation', 'Var', (20, 28))	('BRAF', 'Gene', (15, 19))
519179	33127962	The highest prevalence for the BRAF mutation reported in other studies was 78%.	('BRAF', 'Gene', '673', (31, 35))	('mutation', 'Var', (36, 44))	('BRAF', 'Gene', (31, 35))
519180	33127962	This huge difference in the BRAF mutation rate could be due to the differences in the sample size and the method used for analysis.	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (28, 32))	('mutation', 'Var', (33, 41))
519183	33127962	showed that 37.5% of the 73 CRC patients had mutations in the exon 3 of the beta-catenin gene.	('patients', 'Species', '9606', (32, 40))	('CRC', 'Phenotype', 'HP:0003003', (28, 31))	('beta-catenin', 'Gene', (76, 88))	('beta-catenin', 'Gene', '1499', (76, 88))	('mutations in', 'Var', (45, 57))	('CRC', 'Disease', (28, 31))
519184	33127962	reported the rate of 3% for beta-catenin mutation in exon 3, and 27% in the high-frequency microsatellite instability (MSI-H).	('mutation', 'Var', (41, 49))	('high-frequency microsatellite instability', 'MPA', (76, 117))	('beta-catenin', 'Gene', (28, 40))	('beta-catenin', 'Gene', '1499', (28, 40))
519186	33127962	The previous studies showed that the MSI could be associated with the in/del substitutions in genome hot spots which can initiate CRC tumorogenesis by increasing the mismatches indiscriminately.	('mismatches', 'MPA', (166, 176))	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('initiate', 'Reg', (121, 129))	('MSI', 'Disease', (37, 40))	('CRC tumorogenesis', 'Disease', (130, 147))	('CRC tumorogenesis', 'Disease', 'MESH:D015179', (130, 147))	('increasing', 'PosReg', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('in/del substitutions', 'Var', (70, 90))
519191	33127962	APC gene mutations influence beta-catenin and AXIN protein binding sites.	('influence', 'Reg', (19, 28))	('binding', 'Interaction', (59, 66))	('mutations', 'Var', (9, 18))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('AXIN', 'Gene', (46, 50))	('beta-catenin', 'Gene', (29, 41))	('APC', 'Disease', (0, 3))	('AXIN', 'Gene', '8312', (46, 50))	('beta-catenin', 'Gene', '1499', (29, 41))
519193	33127962	From among the studies which assessed the PI3 signal transduction pathway, the mutation of PIK3CA gene was reported in 20 studies ranging between 0 and 34%.	('PIK3CA', 'Gene', (91, 97))	('PIK3CA', 'Gene', '5290', (91, 97))	('mutation', 'Var', (79, 87))
519195	33127962	the clinic-pathological assessment indicated that, the SMAD4 mutations are more frequent in colon tumors and statistically associated with tumor grade and lymph nodes involvement.	('frequent', 'Reg', (80, 88))	('associated', 'Reg', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('colon tumors', 'Disease', 'MESH:D003110', (92, 104))	('mutations', 'Var', (61, 70))	('SMAD4', 'Gene', '4089', (55, 60))	('tumor', 'Disease', (139, 144))	('colon tumors', 'Phenotype', 'HP:0100273', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (98, 103))	('colon tumors', 'Disease', (92, 104))	('SMAD4', 'Gene', (55, 60))
519196	33127962	Tong and colleagues reports the KRAS mutations are in association with gender and tumor site.	('KRAS', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('KRAS', 'Gene', '3845', (32, 36))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
519197	33127962	points out the BRAF mutations are associated with tumor location, site of metastasis and differentiation pattern.	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('mutations', 'Var', (20, 29))
519198	33127962	Meanwhile, Yang and colleagues reports the association of the KRAS mutations with tumor location, type of tumor, differentiation pattern and gender of the patients.	('KRAS', 'Gene', (62, 66))	('KRAS', 'Gene', '3845', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('association', 'Reg', (43, 54))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (106, 111))
519199	33127962	Furthermore, there were limited data about the association of the mutations in signaling pathways with survival rate in patients.	('mutations', 'Var', (66, 75))	('signaling pathways', 'Pathway', (79, 97))	('patients', 'Species', '9606', (120, 128))
519200	33127962	Some studies suggested BRAF mutations and SMAD4 mutations are association with poor prognosis and survival rate.	('SMAD4', 'Gene', '4089', (42, 47))	('BRAF', 'Gene', '673', (23, 27))	('mutations', 'Var', (48, 57))	('BRAF', 'Gene', (23, 27))	('SMAD4', 'Gene', (42, 47))	('mutations', 'Var', (28, 37))	('survival rate', 'CPA', (98, 111))
519201	33127962	The clinic-pathological features and patients survival association with signaling pathway mutations is one of the current study limitations and needs further investigation.	('patients', 'Species', '9606', (37, 45))	('signaling pathway', 'Pathway', (72, 89))	('mutations', 'Var', (90, 99))
519205	33127962	reported CTNNB1 mutations in 15% of hepatoblastoma patients while the reported prevalence in Ueda's study was 75%.	('CTNNB1', 'Gene', '1499', (9, 15))	('mutations', 'Var', (16, 25))	('hepatoblastoma', 'Disease', 'MESH:D018197', (36, 50))	('patients', 'Species', '9606', (51, 59))	('CTNNB1', 'Gene', (9, 15))	('hepatoblastoma', 'Disease', (36, 50))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (36, 50))
519208	33127962	Moreover, the conducted studies showed that the P53 mutations were mostly associated with the Asian and African countries, while the CTNNB1 mutations were mostly associated with HCC in the Western countries.	('mutations', 'Var', (52, 61))	('CTNNB1', 'Gene', (133, 139))	('HCC', 'Gene', (178, 181))	('associated', 'Reg', (162, 172))	('HCC', 'Gene', '619501', (178, 181))	('P53', 'Gene', (48, 51))	('P53', 'Gene', '7157', (48, 51))	('HCC', 'Phenotype', 'HP:0001402', (178, 181))	('CTNNB1', 'Gene', '1499', (133, 139))	('associated', 'Reg', (74, 84))
519211	33127962	They showed that the AXIN1, KRAS, and PI3CA mutations rate were 5%, 92%, and 4%, respectively.	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('AXIN1', 'Gene', (21, 26))	('mutations', 'Var', (44, 53))	('PI3CA', 'Disease', (38, 43))	('AXIN1', 'Gene', '8312', (21, 26))
519212	33127962	Moreover, the high rate of KRAS mutations in pancreatic cancer patients was confirmed by the other studies.	('KRAS', 'Gene', '3845', (27, 31))	('pancreatic cancer', 'Disease', (45, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (32, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('patients', 'Species', '9606', (63, 71))	('KRAS', 'Gene', (27, 31))
519214	33127962	In GC, mutations were 14% (95% CI: 2-34%) for KRAS, 7% (95% CI: 1-17%) for MAPK, and 6% (95% CI: 2-12%) for PI3 pathways.	('MAPK', 'Gene', (75, 79))	('GC', 'Phenotype', 'HP:0012126', (3, 5))	('PI3 pathways', 'Pathway', (108, 120))	('KRAS', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (46, 50))	('MAPK', 'Gene', '5594', (75, 79))	('mutations', 'Var', (7, 16))
519215	33127962	In the pancreatic and gastric cancers, the most evaluated pathways were PI3 and MAPK.	('gastric cancers', 'Phenotype', 'HP:0012126', (22, 37))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('PI3', 'Var', (72, 75))	('pancreatic and gastric cancers', 'Disease', 'MESH:D013274', (7, 37))	('MAPK', 'Gene', '5594', (80, 84))	('MAPK', 'Gene', (80, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (22, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
519217	33127962	The mutations in KRAS leads to impaired cells activity enhancement and malignancy progression.	('impaired', 'NegReg', (31, 39))	('cells activity enhancement', 'CPA', (40, 66))	('malignancy', 'Disease', 'MESH:D009369', (71, 81))	('KRAS', 'Gene', (17, 21))	('mutations', 'Var', (4, 13))	('malignancy', 'Disease', (71, 81))	('KRAS', 'Gene', '3845', (17, 21))
519219	33127962	studied 100 advanced primary GC cases for the purpose of evaluating PI3K/AKT signaling pathway mutations.	('AKT', 'Gene', (73, 76))	('advanced primary GC', 'Disease', (12, 31))	('GC', 'Phenotype', 'HP:0012126', (29, 31))	('mutations', 'Var', (95, 104))	('AKT', 'Gene', '207', (73, 76))
519222	33127962	The mutations in the PIK3CA and AKT in PI3K/AKT pathway could affect downstream signaling pathway genes, like mTOR (mechanistic target of rapamycin kinase) and caspase 9, which are important in GC progression.	('mTOR', 'Gene', (110, 114))	('downstream signaling pathway', 'Pathway', (69, 97))	('mechanistic target of rapamycin kinase', 'Gene', (116, 154))	('affect', 'Reg', (62, 68))	('mTOR', 'Gene', '2475', (110, 114))	('AKT', 'Gene', '207', (32, 35))	('PIK3CA', 'Gene', (21, 27))	('AKT', 'Gene', '207', (44, 47))	('mechanistic target of rapamycin kinase', 'Gene', '2475', (116, 154))	('AKT', 'Gene', (32, 35))	('PIK3CA', 'Gene', '5290', (21, 27))	('mutations', 'Var', (4, 13))	('AKT', 'Gene', (44, 47))	('GC', 'Phenotype', 'HP:0012126', (194, 196))	('caspase 9', 'Gene', (160, 169))	('caspase 9', 'Gene', '842', (160, 169))
519223	33127962	investigated hedgehog pathway in GC patients and showed that the PTCH1 (patched 1) and SMO (smoothened) genes were mutated in 51.2% and 25.6% of the cases.	('investigated', 'Reg', (0, 12))	('SMO', 'Gene', '6608', (87, 90))	('patients', 'Species', '9606', (36, 44))	('PTCH1', 'Gene', (65, 70))	('mutated', 'Var', (115, 122))	('patched 1', 'Gene', (72, 81))	('SMO', 'Gene', (87, 90))	('GC', 'Phenotype', 'HP:0012126', (33, 35))	('PTCH1', 'Gene', '5727', (65, 70))	('patched 1', 'Gene', '5727', (72, 81))	('smoothened', 'Gene', '6608', (92, 102))	('smoothened', 'Gene', (92, 102))
519224	33127962	Alterations in PTCH1 gene were associated with the basal cell carcinoma and basal cell nevus syndrome.	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (51, 71))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (51, 71))	('basal cell carcinoma', 'Disease', (51, 71))	('nevus', 'Phenotype', 'HP:0003764', (87, 92))	('Alterations', 'Var', (0, 11))	('PTCH1', 'Gene', '5727', (15, 20))	('basal cell nevus syndrome', 'Disease', 'MESH:D001478', (76, 101))	('associated', 'Reg', (31, 41))	('basal cell nevus syndrome', 'Disease', (76, 101))	('basal cell nevus', 'Phenotype', 'HP:0002671', (76, 92))	('PTCH1', 'Gene', (15, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
519230	33127962	In this regard, signal transduction pathway mutations pooled prevalence was higher in PC and lower in GC (20% vs. 5%).	('GC', 'Phenotype', 'HP:0012126', (102, 104))	('prevalence', 'Reg', (61, 71))	('PC', 'Gene', '5091', (86, 88))	('lower', 'NegReg', (93, 98))	('mutations', 'Var', (44, 53))	('signal transduction pathway', 'Pathway', (16, 43))	('higher', 'PosReg', (76, 82))
519231	33127962	Thus, PC is the most common cancer involved by signal transduction mediator's mutations.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('PC', 'Gene', '5091', (6, 8))	('mutations', 'Var', (78, 87))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
519236	33127962	In the present comprehensive study, we assessed all relevant original research studies via the electronic literature search in Web of Science (SCIE), PubMed (Including MEDLINE), Science Direct, Scopus, EMBASE, and Google Scholar databases using the keywords including Polymorphism, Mutation, Mutation Rate, Mutation Prevalence, Silent Mutation, Point Mutation, Missense Mutation, INDEL Mutation, Frameshift Mutation, Synonymous Mutation, Non-synonymous Mutation, Transversion Mutation, Transition Mutation, Insertion Mutation, Deletion Mutation, Digestive System Diseases, Gastrointestinal Neoplasms, Digestive System Abnormalities, Biliary Tract Diseases, Biliary Tract Neoplasms, Gallbladder Diseases, Anorectal Malformations, Colorectal Neoplasms, Pancreatic Neoplasms, Hepatocellular carcinoma, Esophageal cancer, Intestinal Diseases, Stomach Diseases, Stomach cancer, Gastric cancer, Liver Diseases, Liver Neoplasms, Pancreatic Diseases, Signaling Pathways, Signal Transduction, Wnt Signaling Pathway, and MAP Kinase Signaling System between January 1998 and September 28, 2019.	('Biliary Tract Diseases', 'Phenotype', 'HP:0001080', (633, 655))	('Gastrointestinal Neoplasms', 'Disease', 'MESH:D004067', (573, 599))	('Pancreatic Diseases', 'Phenotype', 'HP:0001732', (922, 941))	('Gallbladder Diseases', 'Disease', (682, 702))	('carcinoma', 'Phenotype', 'HP:0030731', (788, 797))	('cancer', 'Disease', (810, 816))	('Liver Neoplasms', 'Phenotype', 'HP:0002896', (905, 920))	('Intestinal Diseases', 'Disease', (818, 837))	('cancer', 'Disease', (865, 871))	('Liver Diseases', 'Disease', (889, 903))	('Liver Diseases', 'Phenotype', 'HP:0001392', (889, 903))	('Neoplasms', 'Disease', 'MESH:D009369', (762, 771))	('Gastrointestinal Neoplasms', 'Disease', (573, 599))	('Signaling', 'Pathway', (943, 952))	('Neoplasms', 'Disease', 'MESH:D009369', (911, 920))	('Neoplasms', 'Phenotype', 'HP:0002664', (671, 680))	('Signal', 'Pathway', (963, 969))	('Neoplasms', 'Disease', (740, 749))	('cancer', 'Phenotype', 'HP:0002664', (810, 816))	('cancer', 'Phenotype', 'HP:0002664', (865, 871))	('Neoplasms', 'Phenotype', 'HP:0002664', (590, 599))	('Colorectal Neoplasms', 'Disease', 'MESH:D015179', (729, 749))	('cancer', 'Disease', (881, 887))	('Anorectal Malformations', 'Phenotype', 'HP:0012732', (704, 727))	('Liver Diseases', 'Disease', 'MESH:D008107', (889, 903))	('Neoplasms', 'Disease', (590, 599))	('cancer', 'Phenotype', 'HP:0002664', (881, 887))	('Gastric cancer', 'Phenotype', 'HP:0012126', (873, 887))	('Pancreatic Diseases', 'Disease', (922, 941))	('Deletion Mutation', 'Var', (527, 544))	('Hepatocellular carcinoma', 'Disease', (773, 797))	('Pancreatic Neoplasms', 'Phenotype', 'HP:0002894', (751, 771))	('Biliary Tract', 'Disease', (657, 670))	('Neoplasms', 'Phenotype', 'HP:0002664', (740, 749))	('Neoplasms', 'Disease', (762, 771))	('Stomach cancer', 'Disease', 'MESH:D013274', (857, 871))	('Gastric cancer', 'Disease', (873, 887))	('Neoplasms', 'Disease', (911, 920))	('Abnormalities, Biliary Tract Diseases', 'Disease', 'MESH:D001660', (618, 655))	('Gastrointestinal Neoplasms', 'Phenotype', 'HP:0007378', (573, 599))	('Anorectal Malformations', 'Disease', (704, 727))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (773, 797))	('Neoplasms', 'Disease', 'MESH:D009369', (671, 680))	('Liver Neoplasms', 'Disease', 'MESH:D008113', (905, 920))	('cancer', 'Disease', 'MESH:D009369', (865, 871))	('cancer', 'Disease', 'MESH:D009369', (810, 816))	('Neoplasms', 'Disease', 'MESH:D009369', (590, 599))	('Gastric cancer', 'Disease', 'MESH:D013274', (873, 887))	('Digestive System Diseases', 'Phenotype', 'HP:0011024', (546, 571))	('Pancreatic Diseases', 'Disease', 'MESH:D010182', (922, 941))	('Liver Neoplasms', 'Disease', (905, 920))	('Pancreatic Neoplasms', 'Disease', (751, 771))	('Frameshift', 'Var', (396, 406))	('Stomach cancer', 'Phenotype', 'HP:0012126', (857, 871))	('cancer', 'Disease', 'MESH:D009369', (881, 887))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (773, 797))	('Neoplasms', 'Phenotype', 'HP:0002664', (762, 771))	('Neoplasms', 'Phenotype', 'HP:0002664', (911, 920))	('Pancreatic Neoplasms', 'Disease', 'MESH:D010190', (751, 771))	('Neoplasms', 'Disease', 'MESH:D009369', (740, 749))	('Colorectal Neoplasms', 'Disease', (729, 749))	('Stomach Diseases', 'Disease', 'MESH:D013272', (839, 855))	('Biliary Tract Neoplasms', 'Phenotype', 'HP:0100574', (657, 680))	('Gallbladder Diseases', 'Disease', 'MESH:D005705', (682, 702))	('Neoplasms', 'Disease', (671, 680))	('Intestinal Diseases', 'Disease', 'MESH:D007410', (818, 837))	('Stomach cancer', 'Disease', (857, 871))	('Stomach Diseases', 'Disease', (839, 855))
519264	32268925	Biological evidence suggests that cisplatin causes the inhibition of the repair of radiation-induced DNA damage via both homologous recombination and nonhomologous end-joining.	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('repair', 'MPA', (73, 79))	('homologous recombination', 'MPA', (121, 145))	('nonhomologous', 'Var', (150, 163))	('inhibition', 'NegReg', (55, 65))
519340	32268925	In the present study, we incorporated DP weekly concurrentwith radiotherapy to treat patients with T4 or M1 LNM esophageal SCC.	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('SCC', 'Gene', '6317', (123, 126))	('patients', 'Species', '9606', (85, 93))	('M1 LNM', 'Var', (105, 111))	('DP', 'Chemical', 'MESH:D004176', (38, 40))	('SCC', 'Gene', (123, 126))
519359	32268925	If LN metastases could be covered by a single radiation field and treated appropriately with a potent radiosensitizer, the survival of patients with M1a and M1b nonvisceral LN disease would be improved.	('M1b', 'Var', (157, 160))	('patients', 'Species', '9606', (135, 143))	('metastases', 'Disease', 'MESH:D009362', (6, 16))	('improved', 'PosReg', (193, 201))	('M1a', 'Var', (149, 152))	('LN disease', 'Disease', (173, 183))	('metastases', 'Disease', (6, 16))	('LN disease', 'Disease', 'MESH:D003141', (173, 183))
519401	32103760	Animal studies show blockade of CCL2-CCR2 axis strongly reduces tumor incidence by hindering TAMs recruitment and thereby potentiates the antitumor efficacy of CD8+ T cells in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('CD8', 'Gene', '925', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (64, 69))	('hindering', 'NegReg', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (180, 185))	('reduces', 'NegReg', (56, 63))	('blockade', 'Var', (20, 28))	('TAMs', 'Chemical', '-', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('TAMs recruitment', 'CPA', (93, 109))	('potentiates', 'PosReg', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('CD8', 'Gene', (160, 163))
519402	32103760	More importantly, M2 polarization increases PD-L2 expression in TAMs, resulting in immune evasion and tumor promotion through PD-1 signaling pathway.	('tumor', 'Disease', (102, 107))	('TAMs', 'Chemical', '-', (64, 68))	('immune evasion', 'MPA', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('increases PD', 'Phenotype', 'HP:0008151', (34, 46))	('polarization', 'Var', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('PD-L2', 'Protein', (44, 49))	('expression', 'MPA', (50, 60))	('increases', 'PosReg', (34, 43))
519412	32103760	On the other hand, accumulating results suggest that the interaction between mutant cells and immune cells in tissue microenvironment directly influences and even determines the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('influences', 'Reg', (143, 153))	('cancer', 'Disease', (193, 199))	('development', 'CPA', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('interaction', 'Interaction', (57, 68))	('mutant', 'Var', (77, 83))	('determines', 'Reg', (163, 173))
519432	32103760	THP-1 cells and TE-1 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, penicillin (100 mug/ml) and streptomycin (100 mug/ml).	('THP-1', 'Gene', (0, 5))	('streptomycin', 'Chemical', 'MESH:D013307', (131, 143))	('RPMI-1640 medium', 'Chemical', '-', (44, 60))	('100 mug/ml', 'Var', (115, 125))	('penicillin', 'Chemical', 'MESH:D010406', (103, 113))	('THP-1', 'Gene', '2736', (0, 5))
519441	32103760	In ESCC cases with higher expression of CCL2, the number of TAMs was significantly elevated (Fig.	('expression', 'MPA', (26, 36))	('higher', 'Var', (19, 25))	('ESCC', 'Disease', 'MESH:C562729', (3, 7))	('CCL2', 'Gene', (40, 44))	('ESCC', 'Disease', (3, 7))	('elevated', 'PosReg', (83, 91))	('TAMs', 'Chemical', '-', (60, 64))
519444	32103760	In the cohort followed up for 4.6 to 6.5 years, expressions of both CCL2 and CD68 were inversely associated with the overall survival of ESCC patients (Fig.	('ESCC', 'Disease', 'MESH:C562729', (137, 141))	('overall', 'MPA', (117, 124))	('ESCC', 'Disease', (137, 141))	('associated with', 'Reg', (97, 112))	('CD68', 'Gene', (77, 81))	('inversely', 'NegReg', (87, 96))	('expressions', 'Var', (48, 59))	('patients', 'Species', '9606', (142, 150))	('CCL2', 'Gene', (68, 72))
519458	32103760	These data further validated our in vivo observations regarding that CCL2 expression triggered TAMs infiltration during esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (120, 145))	('TAMs', 'Chemical', '-', (95, 99))	('esophageal carcinogenesis', 'Disease', (120, 145))	('CCL2', 'Gene', (69, 73))	('TAMs infiltration', 'CPA', (95, 112))	('expression', 'Var', (74, 84))	('rat', 'Species', '10116', (106, 109))	('triggered', 'Reg', (85, 94))
519461	32103760	More importantly, gene knockout of CCL2 dramatically decreased the incidence and number of forestomach tumors in the mouse model (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('forestomach tumors', 'Disease', 'MESH:D013274', (91, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('gene knockout', 'Var', (18, 31))	('mouse', 'Species', '10090', (117, 122))	('CCL2', 'Gene', (35, 39))	('forestomach tumors', 'Disease', (91, 109))	('decreased', 'NegReg', (53, 62))
519463	32103760	Furthermore, we found that deletion of CCL2 significantly inhibited the infiltration of CD11b+CCR2+ monocyte (Fig.	('deletion', 'Var', (27, 35))	('rat', 'Species', '10116', (78, 81))	('inhibited', 'NegReg', (58, 67))	('CCL2', 'Gene', (39, 43))	('infiltration', 'CPA', (72, 84))
519466	32103760	In addition, CCL2 knockout induced marked suppression on TAMs-associated inflammatory cytokines such as IL-10, IL-12b, and IL-13, which were prominently elevated by NMBA-treatment in wild type animals (Fig.	('TAMs', 'Chemical', '-', (57, 61))	('CCL2', 'Gene', (13, 17))	('IL-13', 'Gene', (123, 128))	('suppression', 'NegReg', (42, 53))	('elevated', 'PosReg', (153, 161))	('IL-13', 'Gene', '3596', (123, 128))	('IL-12b', 'Gene', '3593', (111, 117))	('IL-10', 'Gene', '3586', (104, 109))	('NMBA', 'Chemical', 'MESH:C014707', (165, 169))	('IL-10', 'Gene', (104, 109))	('TAMs-associated inflammatory cytokines', 'MPA', (57, 95))	('knockout', 'Var', (18, 26))	('IL-12b', 'Gene', (111, 117))
519469	32103760	In line with our findings with CCL2-/- mouse model, the loss of CCR2 markedly reduced the incidence of mouse forestomach tumors by nearly 60%, as compared with those in CCR2+/+ wild type and CCR2+/- heterozygous animals (Fig.	('forestomach tumors', 'Disease', 'MESH:D013274', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CCR2', 'Gene', (64, 68))	('loss', 'Var', (56, 60))	('mouse', 'Species', '10090', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('forestomach tumors', 'Disease', (109, 127))	('reduced', 'NegReg', (78, 85))	('mouse', 'Species', '10090', (39, 44))
519471	32103760	Flow cytometry analysis showed that CD11b+Ly6Chigh inflammatory monocytes were notably infiltrated in forestomach tumors of CCR2+/+ and CCR2+/- mice after NMBA treatment; however, the infiltration was completely abolished in CCR2-/- mice (Fig.	('forestomach tumors', 'Disease', 'MESH:D013274', (102, 120))	('NMBA', 'Chemical', 'MESH:C014707', (155, 159))	('mice', 'Species', '10090', (233, 237))	('mice', 'Species', '10090', (144, 148))	('CD11b+Ly6Chigh', 'Var', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('rat', 'Species', '10116', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('forestomach tumors', 'Disease', (102, 120))	('infiltrated', 'PosReg', (87, 98))	('rat', 'Species', '10116', (93, 96))
519472	32103760	Furthermore, profiling of tissue cytokines indicated noticeable suppression of inflammatory chemokines including MIP-1alpha (CCL3), RANTES (CCL5), Eotoxin (CCL11), MDC (CCL22), and MIG (CXCL9) by the deletion of CCR2 (Fig.	('CCL22', 'Gene', (169, 174))	('deletion', 'Var', (200, 208))	('CCL11', 'Gene', (156, 161))	('MDC', 'Gene', (164, 167))	('inflammatory chemokines', 'MPA', (79, 102))	('CCL22', 'Gene', '6367', (169, 174))	('MIG', 'Gene', (181, 184))	('suppression', 'NegReg', (64, 75))	('CCL5', 'Gene', (140, 144))	('MIP-1alpha', 'Gene', '6348', (113, 123))	('CCL11', 'Gene', '6356', (156, 161))	('CXCL9', 'Gene', (186, 191))	('CCL3', 'Gene', '6348', (125, 129))	('Eotoxin', 'MPA', (147, 154))	('MIG', 'Gene', '4283', (181, 184))	('CXCL9', 'Gene', '4283', (186, 191))	('MIP-1alpha', 'Gene', (113, 123))	('CCL3', 'Gene', (125, 129))	('CCL5', 'Gene', '6352', (140, 144))	('MDC', 'Gene', '6367', (164, 167))	('CCR2', 'Gene', (212, 216))	('RANTES', 'Gene', (132, 138))	('RANTES', 'Gene', '6352', (132, 138))
519476	32103760	In addition, the expression of genes specifically involved in PD-1 pathway was activated in NMBA-induced carcinogenesis, but notably repressed by the deletion of CCR2 (Fig.	('NMBA', 'Chemical', 'MESH:C014707', (92, 96))	('NMBA-induced carcinogenesis', 'Disease', (92, 119))	('expression of genes', 'MPA', (17, 36))	('carcinogenesis', 'Disease', (105, 119))	('deletion', 'Var', (150, 158))	('activated', 'PosReg', (79, 88))	('CCR2', 'Gene', (162, 166))
519477	32103760	In concert with this, other pathways associated with PD-1 signaling including "CD28 family", "ZAP-70", "Phosphorylation of CD3" and "TCR signaling" were similarly constrained by the absence of CCR2.	('CD3', 'MPA', (123, 126))	('TCR signaling', 'MPA', (133, 146))	('CD28', 'Gene', '940', (79, 83))	('absence', 'Var', (182, 189))	('Phosphorylation', 'MPA', (104, 119))	('CD28', 'Gene', (79, 83))	('ZAP-70', 'Gene', '7535', (94, 100))	('ZAP-70', 'Gene', (94, 100))
519479	32103760	Flow cytometry analysis showed that the proportion of PD-1+ T cells in CD8+ CTLs was decreased from nearly 60% down to 20% by CCR2 deletion (Fig.	('CD8', 'Gene', '925', (71, 74))	('decreased', 'NegReg', (85, 94))	('deletion', 'Var', (131, 139))	('CCR2', 'Gene', (126, 130))	('CD8', 'Gene', (71, 74))
519482	32103760	In comparison with the CCR2+/+ animals, the numbers of F4/80+ TAMs and PD-1+ T cells in tumor microenvironment were markedly decreased in CCR2-/- mice.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('TAMs', 'Chemical', '-', (62, 66))	('F4/80', 'Gene', (55, 60))	('decreased', 'NegReg', (125, 134))	('F4/80', 'Gene', '13733', (55, 60))	('CCR2-/-', 'Var', (138, 145))	('mice', 'Species', '10090', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
519483	32103760	In contrast, distribution of CD8+ CTLs was notably recuperated by the knockout of CCR2 (Fig.	('recuperated', 'NegReg', (51, 62))	('CD8', 'Gene', '925', (29, 32))	('CCR2', 'Gene', (82, 86))	('rat', 'Species', '10116', (57, 60))	('knockout', 'Var', (70, 78))	('CD8', 'Gene', (29, 32))	('distribution', 'MPA', (13, 25))
519485	32103760	Together, the inverse correlation of CD8+ CTLs with CCR2 and PD-1 suggested that TAMs mediate depletion of antitumor T cells and in consequence facilitates tumor cell evasion through PD-1 signaling pathway.	('facilitates', 'PosReg', (144, 155))	('PD-1 signaling pathway', 'Pathway', (183, 205))	('CD8', 'Gene', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('CD8', 'Gene', '925', (37, 40))	('TAMs mediate', 'Chemical', '-', (81, 93))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('TAMs', 'Var', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (156, 161))
519494	32103760	In addition to the decrease of TAMs accumulation by CCR2 knockout, M2-polorization was also dramatically inhibited in the CCR2-/- animals by nearly 70% when compared to the CCR2+/+ and CCR2+/- mice (Fig.	('decrease', 'NegReg', (19, 27))	('CCR2-/-', 'Var', (122, 129))	('inhibited', 'NegReg', (105, 114))	('TAMs accumulation', 'MPA', (31, 48))	('M2-polorization', 'CPA', (67, 82))	('mice', 'Species', '10090', (193, 197))	('TAMs', 'Chemical', '-', (31, 35))	('CCR2', 'Gene', (52, 56))
519495	32103760	Interestingly, we found that the proportion of CD8+ cytotoxic T cells (CTLs) in CD3+ lymphocytes was significantly elevated by the deletion of CCR2 (Fig.	('elevated', 'PosReg', (115, 123))	('CD8', 'Gene', (47, 50))	('CCR2', 'Gene', (143, 147))	('CD8', 'Gene', '925', (47, 50))	('deletion', 'Var', (131, 139))
519500	32103760	Taken together, these data suggested that M2-polorization of infiltrated TAMs facilitates the depletion of antitumor effector T cells in tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('rat', 'Species', '10116', (67, 70))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TAMs', 'Chemical', '-', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('facilitates', 'PosReg', (78, 89))	('M2-polorization', 'Var', (42, 57))
519505	32103760	More importantly, blockade of CCL2 or CCR2 dramatically suppressed the expression of PD-L2 in tumors (Fig.	('expression', 'MPA', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('suppressed', 'NegReg', (56, 66))	('CCR2', 'Gene', (38, 42))	('blockade', 'Var', (18, 26))	('PD-L2', 'Gene', (85, 90))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
519509	32103760	To further validate the impact of M2-polarization, we next conducted esophageal carcinogenesis study using mice with macrophage-specific deletion of peroxisome proliferator activated receptor-gamma (PPARG) which has been shown required for the maturation of M2 macrophages.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (69, 94))	('peroxisome proliferator activated receptor-gamma', 'Gene', '19016', (149, 197))	('esophageal carcinogenesis', 'Disease', (69, 94))	('deletion', 'Var', (137, 145))	('peroxisome proliferator activated receptor-gamma', 'Gene', (149, 197))	('mice', 'Species', '10090', (107, 111))	('rat', 'Species', '10116', (167, 170))	('PPARG', 'Gene', (199, 204))	('rat', 'Species', '10116', (248, 251))
519510	32103760	The results indicated that macrophage-specific PPARG deletion significantly inhibited tumorigenesis in ESCC mouse model (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('ESCC', 'Disease', 'MESH:C562729', (103, 107))	('tumor', 'Disease', (86, 91))	('deletion', 'Var', (53, 61))	('mouse', 'Species', '10090', (108, 113))	('PPARG', 'Gene', (47, 52))	('ESCC', 'Disease', (103, 107))	('inhibited', 'NegReg', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
519511	32103760	The blockade of M2 polarization by PPARG deficiency dramatically decreased expression of PD-L2 in TAMs, but inversely increased the CD8+ antitumor effector T cells in tumors (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('PPARG', 'Gene', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('decreased', 'NegReg', (65, 74))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Disease', (141, 146))	('increased', 'PosReg', (118, 127))	('PD-L2', 'Gene', (89, 94))	('deficiency', 'Var', (41, 51))	('tumor', 'Disease', (167, 172))	('CD8', 'Gene', '925', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('CD8', 'Gene', (132, 135))	('tumors', 'Disease', (167, 173))	('expression', 'MPA', (75, 85))	('TAMs', 'Chemical', '-', (98, 102))
519512	32103760	In summary, these data are in line with our findings on the interaction between TAMs-M2 polarization and PD-1 signaling activation, suggesting that the presentation of PD-L2 by M2-TAMs constitutes an important mechanism underlying immune evasion in ESCC carcinogenesis.	('ESCC', 'Disease', (249, 253))	('PD-L2', 'Var', (168, 173))	('TAMs', 'Chemical', '-', (180, 184))	('TAMs', 'Chemical', '-', (80, 84))	('ESCC', 'Disease', 'MESH:C562729', (249, 253))	('immune evasion', 'MPA', (231, 245))
519517	32103760	We found that tumorigenesis was remarkably suppressed by the blockade of CCL2-CCR2 axis in ESCC animal models.	('CCL2-CCR2', 'Protein', (73, 82))	('tumor', 'Disease', (14, 19))	('ESCC', 'Disease', (91, 95))	('blockade', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('ESCC', 'Disease', 'MESH:C562729', (91, 95))	('suppressed', 'NegReg', (43, 53))
519522	32103760	Increasing studies indicated that inhibition of CCL2 could deplete inflammatory monocytes and macrophages, reduce tumor growth and dissemination in different experimental models such as prostate, melanoma, breast, lung and liver cancer.	('prostate', 'Disease', (186, 194))	('melanoma, breast, lung and liver cancer', 'Disease', 'MESH:D001943', (196, 235))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('inhibition', 'Var', (34, 44))	('liver cancer', 'Phenotype', 'HP:0002896', (223, 235))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CCL2', 'Gene', (48, 52))	('tumor', 'Disease', (114, 119))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('reduce', 'NegReg', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('deplete', 'NegReg', (59, 66))
519536	32103760	Consistent with these studies, our data demonstrated that M2 polarization of TAMs was tightly associated with reduced CD8+ T cells and promoted tumor growth.	('promoted', 'PosReg', (135, 143))	('tumor', 'Disease', (144, 149))	('reduced', 'NegReg', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('TAMs', 'Gene', (77, 81))	('rat', 'Species', '10116', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CD8', 'Gene', (118, 121))	('TAMs', 'Chemical', '-', (77, 81))	('CD8', 'Gene', '925', (118, 121))	('M2 polarization', 'Var', (58, 73))
519552	32103760	Blockade of CCL2-CCR2 axis strongly suppressed cancer development through inhibiting monocyte infiltration and TAMs accumulation in tumor microenvironment.	('inhibiting', 'NegReg', (74, 84))	('suppressed', 'NegReg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Blockade', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Disease', (47, 53))	('TAMs', 'Chemical', '-', (111, 115))	('tumor', 'Disease', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('rat', 'Species', '10116', (100, 103))	('TAMs accumulation', 'CPA', (111, 128))	('monocyte infiltration', 'CPA', (85, 106))
519554	32103760	These findings provide new insights into the mechanism of immune evasion mediated by TAMs in ESCC, which may advance the development of macrophages-based strategies for ESCC prevention and immunotherapy.	('TAMs', 'Chemical', '-', (85, 89))	('advance', 'PosReg', (109, 116))	('ESCC', 'Disease', (169, 173))	('rat', 'Species', '10116', (156, 159))	('immune evasion', 'MPA', (58, 72))	('TAMs', 'Var', (85, 89))	('ESCC', 'Disease', 'MESH:C562729', (93, 97))	('ESCC', 'Disease', 'MESH:C562729', (169, 173))	('ESCC', 'Disease', (93, 97))
519564	32010619	Moreover, Inhibition of PEDF significantly reduced tumor growth and tumor size in vivo.	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('reduced', 'NegReg', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Inhibition', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('PEDF', 'Protein', (24, 28))
519580	32010619	For example, PEDF can promote stem cell growth and self-renewal of glioma stem cells.	('promote', 'PosReg', (22, 29))	('glioma', 'Disease', (67, 73))	('self-renewal', 'CPA', (51, 63))	('PEDF', 'Var', (13, 17))	('stem cell growth', 'CPA', (30, 46))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
519615	32010619	Because PEDF is overexpressed in esophageal carcinoma, we explored the role of PEDF in esophageal carcinoma by knocking down the expression of PEDF in two esophageal carcinoma cell lines EC9706 and KYSE150.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (33, 53))	('expression', 'MPA', (129, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('knocking', 'Var', (111, 119))	('esophageal carcinoma', 'Disease', (155, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (155, 175))	('esophageal carcinoma', 'Disease', (87, 107))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('KYSE150', 'CellLine', 'CVCL:1348', (198, 205))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (155, 175))	('EC9706', 'CellLine', 'CVCL:E307', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('esophageal carcinoma', 'Disease', (33, 53))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (33, 53))	('PEDF', 'Gene', (143, 147))
519616	32010619	The result showed significant reduction of the colony numbers of esophageal carcinoma cells at 7 days after transfection of shRNA (Figure 2A).	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal carcinoma', 'Disease', (65, 85))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (65, 85))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (65, 85))	('reduction', 'NegReg', (30, 39))	('transfection', 'Var', (108, 120))
519617	32010619	The effect of cell migration after knocking down PEDF in esophageal carcinoma cells was also investigated.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (57, 77))	('knocking', 'Var', (35, 43))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (57, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('esophageal carcinoma', 'Disease', (57, 77))
519618	32010619	There were less esophageal carcinoma cells migrated in shRNA-PEDF transfection group than those in control group.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('shRNA-PEDF', 'Var', (55, 65))	('esophageal carcinoma', 'Disease', (16, 36))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (16, 36))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (16, 36))	('less', 'NegReg', (11, 15))
519621	32010619	Because PEDF enhances esophageal carcinoma cell growth, we further investigated whether PEDF affects cell cycle and cell apoptosis.	('PEDF', 'Var', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('enhances', 'PosReg', (13, 21))	('esophageal carcinoma', 'Disease', (22, 42))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (22, 42))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (22, 42))
519624	32010619	The result demonstrated that knocking down PEDF increased early apoptotic cells, late apoptotic cells, and necrotic cells (Figure 3B), suggesting that knocking down PEDF increased apoptosis of esophageal carcinoma cells.	('PEDF', 'Gene', (165, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('knocking down', 'Var', (151, 164))	('necrotic', 'Disease', (107, 115))	('increased', 'PosReg', (170, 179))	('esophageal carcinoma', 'Disease', (193, 213))	('necrotic', 'Disease', 'MESH:D009336', (107, 115))	('knocking', 'Var', (29, 37))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (193, 213))	('PEDF', 'Gene', (43, 47))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (193, 213))	('apoptosis', 'CPA', (180, 189))
519625	32010619	Furthermore, Western blot shows that the levels of caspase 3 and caspase 9 in the shRNA-PEDF group were higher than in control group (Figure 3C).	('caspase 3', 'Gene', (51, 60))	('caspase 3', 'Gene', '836', (51, 60))	('caspase 9', 'Gene', (65, 74))	('caspase 9', 'Gene', '842', (65, 74))	('higher', 'PosReg', (104, 110))	('shRNA-PEDF', 'Var', (82, 92))	('levels', 'MPA', (41, 47))
519628	32010619	Similar to in vitro results, the tumor volume and tumor weight of xenografts in mice inoculated with shRNA-PEDF cells were smaller than that with shRNA control cells, suggesting that PEDF promotes esophageal carcinoma growth in vivo (Figures 4A-C).	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (197, 217))	('promotes', 'PosReg', (188, 196))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('esophageal carcinoma', 'Disease', (197, 217))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (197, 217))	('tumor', 'Disease', (50, 55))	('PEDF', 'Var', (183, 187))
519632	32010619	Moreover, PEDF protects osteoblasts from glucocorticoid-induced apoptosis, and increases vascular permeability of triglycerides by ATGL degradation.	('ATGL', 'Gene', (131, 135))	('vascular permeability of triglycerides', 'MPA', (89, 127))	('increases', 'PosReg', (79, 88))	('ATGL', 'Gene', '57104', (131, 135))	('triglycerides', 'Chemical', 'MESH:D014280', (114, 127))	('PEDF', 'Var', (10, 14))	('osteoblasts', 'CPA', (24, 35))
519633	32010619	Anti-inflammatory and antithrombotic effects of PEDF have been reported, and PEDF can also prevent the adhesion and invasion of liver cancer cells.	('prevent', 'NegReg', (91, 98))	('invasion of liver cancer', 'Disease', 'MESH:D006528', (116, 140))	('antithrombotic effects', 'CPA', (22, 44))	('liver cancer', 'Phenotype', 'HP:0002896', (128, 140))	('PEDF', 'Var', (77, 81))	('Anti-inflammatory', 'CPA', (0, 17))	('invasion of liver cancer', 'Disease', (116, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
519639	32010619	Angiogenesis is inhibited by PEDF via cleaving VEGFR1 and VEGFR2 at the transmembrane region and VEGF-induced phosphorylation.	('VEGFR1', 'Gene', (47, 53))	('VEGF', 'Gene', (58, 62))	('VEGF', 'Gene', '7422', (47, 51))	('inhibited', 'NegReg', (16, 25))	('Angiogenesis', 'CPA', (0, 12))	('VEGF', 'Gene', (97, 101))	('VEGF', 'Gene', '7422', (58, 62))	('VEGFR2', 'Gene', (58, 64))	('phosphorylation', 'MPA', (110, 125))	('VEGF', 'Gene', (47, 51))	('VEGF', 'Gene', '7422', (97, 101))	('VEGFR1', 'Gene', '2321', (47, 53))	('cleaving', 'Var', (38, 46))	('VEGFR2', 'Gene', '3791', (58, 64))
519642	32010619	Previous studies have shown that the abnormal expression of PEDF is closely related to the pathological process of tumor development, including proliferation, migration, invasion, and apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('migration', 'CPA', (159, 168))	('PEDF', 'Gene', (60, 64))	('proliferation', 'CPA', (144, 157))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('abnormal', 'Var', (37, 45))	('expression', 'MPA', (46, 56))	('invasion', 'CPA', (170, 178))	('apoptosis', 'CPA', (184, 193))	('related', 'Reg', (76, 83))
519643	32010619	shRNA-mediated knockdown of PEDF was reported to be effective in inhibiting the growth of melanoma.	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('knockdown', 'Var', (15, 24))	('PEDF', 'Gene', (28, 32))	('growth', 'CPA', (80, 86))	('inhibiting', 'NegReg', (65, 75))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
519646	32010619	In vivo experiments further confirmed that shRNA-mediated PEDF knockdown significantly blocked xenograft esophageal tumor growth.	('esophageal tumor', 'Disease', (105, 121))	('esophageal tumor', 'Phenotype', 'HP:0100751', (105, 121))	('esophageal tumor', 'Disease', 'MESH:D004941', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('knockdown', 'Var', (63, 72))	('blocked', 'NegReg', (87, 94))
519664	31717502	Regarding ROS and ER stress formation associated with apoptosis, we found that Ech increased ROS production, whereas its increase was diminished by NAC treatment.	('increased', 'PosReg', (83, 92))	('increased ROS production', 'Phenotype', 'HP:0025464', (83, 107))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('ROS', 'Chemical', 'MESH:D017382', (93, 96))	('Ech', 'Chemical', 'MESH:C000623341', (79, 82))	('men', 'Species', '9606', (157, 160))	('ROS production', 'MPA', (93, 107))	('ER stress', 'MPA', (18, 27))	('Ech', 'Var', (79, 82))	('NAC', 'Chemical', 'MESH:D000111', (148, 151))
519666	31717502	Moreover, Ech enhanced MMP dysfunction and caspases activity.	('caspases', 'Gene', (43, 51))	('MMP dysfunction', 'Disease', (23, 38))	('activity', 'MPA', (52, 60))	('enhanced', 'PosReg', (14, 22))	('Ech', 'Chemical', 'MESH:C000623341', (10, 13))	('MMP dysfunction', 'Disease', 'MESH:D009461', (23, 38))	('caspases', 'Gene', '841;842', (43, 51))	('Ech', 'Var', (10, 13))
519679	31717502	Ech can induce about a four-fold increase of activity of the nuclear factor erythroid 2-related factor 2, a transcription factor that transcribes antioxidant proteins, thereby protecting mice against hepatoxicity and carbon tetrachloride-induced acute liver injury.	('activity', 'MPA', (45, 53))	('acute liver injury', 'Disease', 'MESH:D056486', (246, 264))	('Ech', 'Chemical', 'MESH:C000623341', (0, 3))	('increase', 'PosReg', (33, 41))	('acute liver injury', 'Disease', (246, 264))	('hepatoxicity', 'Disease', (200, 212))	('mice', 'Species', '10090', (187, 191))	('nuclear factor erythroid 2-related factor 2', 'Gene', '18024', (61, 104))	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (217, 237))	('hepatoxicity', 'Disease', 'None', (200, 212))	('Ech', 'Var', (0, 3))	('nuclear factor erythroid 2-related factor 2', 'Gene', (61, 104))
519691	31717502	The concentration for inhibiting 50% of cell growth (IC50) of Ech was 15 microM for KYSE 30, 15 microM for KYSE 70, 6 microM for KYSE 410, 13 microM for KYSE 450, and 10 microM for KYSE 510.	('KYSE', 'Var', (107, 111))	('KYSE', 'Chemical', '-', (84, 88))	('KYSE', 'Chemical', '-', (129, 133))	('KYSE', 'Var', (84, 88))	('KYSE', 'Var', (129, 133))	('cell growth', 'CPA', (40, 51))	('Ech', 'Chemical', 'MESH:C000623341', (62, 65))	('KYSE', 'Chemical', '-', (181, 185))	('KYSE', 'Chemical', '-', (107, 111))	('KYSE', 'Chemical', '-', (153, 157))	('inhibiting', 'NegReg', (22, 32))
519692	31717502	In the three-dimensional culture of ESCC cells, colony numbers and sizes were decreased by treatment with Ech in KYSE 30 and KYSE 450 cells (Figure 1g).	('Ech', 'Gene', (106, 109))	('men', 'Species', '9606', (96, 99))	('KYSE', 'Var', (125, 129))	('men', 'Species', '9606', (15, 18))	('Ech', 'Chemical', 'MESH:C000623341', (106, 109))	('KYSE', 'Chemical', '-', (125, 129))	('decreased', 'NegReg', (78, 87))	('KYSE', 'Chemical', '-', (113, 117))
519702	31717502	After KYSE 30 and KYSE 450, cells were treated with Ech at 5, 10, or 15 microM for 48 h, expression levels of cell cycle markers p21 and p27 were increased while those of cyclin B1 and cdc2 were decreased compared the control (Figure 3a).	('p27', 'Gene', '10671', (137, 140))	('p21', 'Gene', '644914', (129, 132))	('KYSE', 'Var', (6, 10))	('increased', 'PosReg', (146, 155))	('p27', 'Gene', (137, 140))	('KYSE', 'Var', (18, 22))	('cdc2', 'Gene', (185, 189))	('cell cycle', 'CPA', (110, 120))	('KYSE', 'Chemical', '-', (6, 10))	('KYSE', 'Chemical', '-', (18, 22))	('cdc2', 'Gene', '983', (185, 189))	('p21', 'Gene', (129, 132))	('cyclin B1', 'Gene', '891', (171, 180))	('cyclin B1', 'Gene', (171, 180))	('Ech', 'Chemical', 'MESH:C000623341', (52, 55))	('expression levels', 'MPA', (89, 106))	('decreased', 'NegReg', (195, 204))
519708	31717502	However, Ech significantly decreased the viabilities of KYSE 30 and KYSE 450 cells.	('KYSE', 'Chemical', '-', (68, 72))	('Ech', 'Var', (9, 12))	('decreased', 'NegReg', (27, 36))	('KYSE', 'Chemical', '-', (56, 60))	('viabilities', 'CPA', (41, 52))	('KYSE 450 cells', 'CPA', (68, 82))	('Ech', 'Chemical', 'MESH:C000623341', (9, 12))
519710	31717502	To further determine whether Ech-induced ROS could activate ER stress cascades, thereby inducing apoptosis of ESCC cells, we examined expression levels of ER stress related proteins (Figure 4c).	('ROS', 'Chemical', 'MESH:D017382', (41, 44))	('Ech', 'Chemical', 'MESH:C000623341', (29, 32))	('ROS', 'Var', (41, 44))	('activate', 'PosReg', (51, 59))	('inducing', 'Reg', (88, 96))	('ER stress cascades', 'Pathway', (60, 78))
519712	31717502	Expression levels of GRP78 and CHOP, down-stream targets of DR4 and DR5 proteins, were also increased by Ech in a dose-dependent manner compared to those in the control (DMSO treated).	('Ech', 'Chemical', 'MESH:C000623341', (105, 108))	('GRP78', 'Gene', '3309', (21, 26))	('GRP78', 'Gene', (21, 26))	('DR4', 'Gene', (60, 63))	('Ech', 'Var', (105, 108))	('Expression levels', 'MPA', (0, 17))	('CHOP', 'Gene', '1649', (31, 35))	('increased', 'PosReg', (92, 101))	('DR5', 'Gene', '8795', (68, 71))	('DR4', 'Gene', '3126', (60, 63))	('DR5', 'Gene', (68, 71))	('CHOP', 'Gene', (31, 35))	('DMSO', 'Chemical', 'MESH:D004121', (170, 174))
519714	31717502	Ech at 15 microM obviously induced depolarization of MMP in KYSE 30 and KYSE 450 ESCC cells by 31.01 +- 1.72 and 44.05 +- 0.43%, respectively (Figure 5a).	('depolarization', 'NegReg', (35, 49))	('KYSE', 'Chemical', '-', (60, 64))	('Ech', 'Chemical', 'MESH:C000623341', (0, 3))	('MMP', 'MPA', (53, 56))	('Ech', 'Var', (0, 3))	('KYSE', 'Chemical', '-', (72, 76))
519716	31717502	Ech decreased expression of Bid, and Bcl-2 but increased Bax expression.	('decreased', 'NegReg', (4, 13))	('Bcl-2', 'Gene', (37, 42))	('Bax', 'Gene', (57, 60))	('Bcl-2', 'Gene', '596', (37, 42))	('expression', 'MPA', (14, 24))	('increased', 'PosReg', (47, 56))	('Ech', 'Chemical', 'MESH:C000623341', (0, 3))	('Bid', 'Gene', (28, 31))	('Ech', 'Var', (0, 3))	('Bid', 'Gene', '637', (28, 31))	('Bax', 'Gene', '581', (57, 60))
519717	31717502	In addition, Ech resulted in the release of cyto C from mitochondria to the cytosol in a dose-dependent manner compared to the DMSO control and alpha-tubulin and COX-4 control fraction proteins (Figure 5b).	('alpha-tubulin', 'Gene', '10376', (144, 157))	('Ech', 'Chemical', 'MESH:C000623341', (13, 16))	('COX-4', 'Gene', '1327', (162, 167))	('release of cyto C from mitochondria to the cytosol', 'MPA', (33, 83))	('DMSO', 'Chemical', 'MESH:D004121', (127, 131))	('Ech', 'Var', (13, 16))	('COX-4', 'Gene', (162, 167))	('alpha-tubulin', 'Gene', (144, 157))
519718	31717502	Expression levels of the following signal proteins of apoptosis, Apaf-1 and cleaved Poly (ADP-Ribose) Polymerase (c-PARP), were increased by treatment with Ech in a dose-dependent manner compared to those in the control.	('Apaf-1', 'Gene', '317', (65, 71))	('Ech', 'Var', (156, 159))	('Poly (ADP-Ribose) Polymerase', 'Gene', (84, 112))	('Apaf-1', 'Gene', (65, 71))	('PARP', 'Gene', (116, 120))	('Expression levels', 'MPA', (0, 17))	('increased', 'PosReg', (128, 137))	('Poly (ADP-Ribose) Polymerase', 'Gene', '142', (84, 112))	('men', 'Species', '9606', (146, 149))	('PARP', 'Gene', '142', (116, 120))	('Ech', 'Chemical', 'MESH:C000623341', (156, 159))
519727	31717502	Flow-cytometry analysis results of the present study revealed that Ech induced G2/M phase arrest of cell cycle (Figure 2a).	('arrest', 'Disease', 'MESH:D006323', (90, 96))	('Ech', 'Chemical', 'MESH:C000623341', (67, 70))	('Ech', 'Var', (67, 70))	('arrest', 'Disease', (90, 96))
519746	31717502	ER stress and ROS formation can induce mitochondrial potential disruption and result in apoptosis.	('apoptosis', 'CPA', (88, 97))	('result in', 'Reg', (78, 87))	('ROS', 'Var', (14, 17))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('mitochondrial potential disruption', 'MPA', (39, 73))	('induce', 'Reg', (32, 38))
519748	31717502	In summary, Ech inhibited ESCC cell growth by inducing intrinsic and extrinsic apoptosis pathways through ROS- and ER-stress mediated signaling (Figure 7).	('inhibited', 'NegReg', (16, 25))	('ESCC', 'Disease', (26, 30))	('inducing', 'PosReg', (46, 54))	('Ech', 'Var', (12, 15))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))	('ER-stress mediated signaling', 'MPA', (115, 143))	('ROS-', 'MPA', (106, 110))	('Ech', 'Chemical', 'MESH:C000623341', (12, 15))
519749	31717502	At present, phase I or phase II clinical trials using natural compounds such as resveratrol and grape powder (NCT 00256334, NCT 01370889), ginger root extract (NCT 01344538), and sulforaphane (NCT 01228084) for colorectal cancer or prostate cancer have been conducted or are being conducted.	('NCT 01228084', 'Var', (193, 205))	('sulforaphane', 'Chemical', 'MESH:C016766', (179, 191))	('colorectal cancer', 'Disease', 'MESH:D015179', (211, 228))	('prostate cancer', 'Disease', (232, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('resveratrol', 'Chemical', 'MESH:D000077185', (80, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (211, 228))	('NCT 01370889', 'Var', (124, 136))	('NCT 01344538', 'Var', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('ginger', 'Species', '94328', (139, 145))	('prostate cancer', 'Disease', 'MESH:D011471', (232, 247))	('prostate cancer', 'Phenotype', 'HP:0012125', (232, 247))	('NCT 00256334', 'Var', (110, 122))	('colorectal cancer', 'Disease', (211, 228))	('grape powder', 'Chemical', '-', (96, 108))
519763	31717502	ESCC cells were seeded with optimal cell numbers (KYSE 30: 2.75 x 103/well; KYSE 70: 10 x 103/well; KYSE 410: 2.5 x 103/well; KYSE 450: 3.5 x 103/well; and KYSE 510: 5.5 x 103/well) into 96-well plates and incubated at 37  C overnight.	('KYSE', 'Var', (50, 54))	('KYSE 450', 'Var', (126, 134))	('KYSE', 'Chemical', '-', (126, 130))	('KYSE', 'Chemical', '-', (100, 104))	('KYSE', 'Chemical', '-', (76, 80))	('KYSE', 'Chemical', '-', (50, 54))	('KYSE', 'Chemical', '-', (156, 160))
519861	31019616	Although poor differentiation has been reported to be associated with LVI in esophageal IMAC, it was not associated with LVI in the current study.	('LVI', 'Chemical', '-', (70, 73))	('esophageal IMAC', 'Disease', (77, 92))	('LVI', 'Disease', (70, 73))	('IMAC', 'Chemical', '-', (88, 92))	('poor differentiation', 'Var', (9, 29))	('associated', 'Reg', (54, 64))	('LVI', 'Chemical', '-', (121, 124))
519897	29845226	In addition, aberrant miRNA expression is associated with the development of several types of cancer.	('miR', 'Gene', '220972', (22, 25))	('associated with', 'Reg', (42, 57))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('miR', 'Gene', (22, 25))	('cancer', 'Disease', (94, 100))	('aberrant', 'Var', (13, 21))
519914	29845226	The primer sequences used for PCR were as follows: miR-449a-5p forward, 5'-ATAGTGGCAGTGTATTGTTAG-3'; U6 forward, 5'-GCGCGTCGTGAAGCGTTC-3'; universal reverse primer, 5'-GTGCAGGGTCCGAGGT-3'.	('U6 forward', 'Var', (101, 111))	('miR-449a', 'Gene', '554213', (51, 59))	('miR-449a', 'Gene', (51, 59))
519920	29845226	The sequences were described as following: Cyclin D1-specific siRNA (sense 5'-CCUCGGUGUCCUACUUCAAAUGUGU-3' and anti-sense ACACAUUUGAAGUAGGACACCGAGG-3'); and negative control siRNA (sense 5'-UUCUCCGAACGUGUCACGU-3' and antisense 5'-ACGUGACACGUUCGGAGAA).	('Cyclin D1', 'Gene', '595', (43, 52))	('antisense', 'Var', (217, 226))	('Cyclin D1', 'Gene', (43, 52))
519946	29845226	After 48 h, the expression levels of miR-449a-5p were increased by ~50-fold in Eca-109 cells transfected with 499AM, whereas miR-449a-5p expression was reduced to 40% of that in the NCI group (P<0.01; Fig.	('499AM', 'Var', (110, 115))	('miR-449a', 'Gene', '554213', (37, 45))	('miR-449a', 'Gene', (125, 133))	('increased', 'PosReg', (54, 63))	('expression levels', 'MPA', (16, 33))	('miR-449a', 'Gene', (37, 45))	('miR-449a', 'Gene', '554213', (125, 133))
519951	29845226	Additionally, cyclin D1 protein levels were reduced in Eca-109 cells transfected with 499AM (Fig.	('reduced', 'NegReg', (44, 51))	('cyclin D1', 'Gene', '595', (14, 23))	('499AM', 'Var', (86, 91))	('cyclin D1', 'Gene', (14, 23))
519952	29845226	By contrast, 499AI upregulated cyclin D1 protein levels (Fig.	('upregulated', 'PosReg', (19, 30))	('499AI', 'Var', (13, 18))	('cyclin D1', 'Gene', '595', (31, 40))	('cyclin D1', 'Gene', (31, 40))
519955	29845226	To further determine the role of cyclin D1 in 499AI-induced Eca-109 cell proliferation, small interfering siRNA targeting cyclin D1 mRNA and 499AI were co-transfected into Eca-109 cells.	('small interfering', 'Var', (88, 105))	('cyclin D1', 'Gene', '595', (33, 42))	('cyclin D1', 'Gene', (33, 42))	('499AI-induced', 'Var', (46, 59))	('cyclin D1', 'Gene', '595', (122, 131))	('cyclin D1', 'Gene', (122, 131))
519957	29845226	Downregulation of cyclin D1 expression rescued the effects of 449AI on Eca-109 proliferation (Fig.	('Eca-109', 'Gene', (71, 78))	('cyclin D1', 'Gene', (18, 27))	('Downregulation', 'NegReg', (0, 14))	('449AI', 'Var', (62, 67))	('cyclin D1', 'Gene', '595', (18, 27))
519966	29845226	It has been demonstrated that miRNAs participate in the pathogenesis of various types of cancer by targeting numerous oncogenes, and aberrant expression of miRNAs may contribute to carcinogenesis.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('aberrant expression', 'Var', (133, 152))	('targeting', 'Reg', (99, 108))	('oncogenes', 'Protein', (118, 127))	('contribute', 'Reg', (167, 177))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('carcinogenesis', 'CPA', (181, 195))	('cancer', 'Disease', (89, 95))	('miR', 'Gene', '220972', (156, 159))	('miR', 'Gene', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
519974	29845226	However, 499AI transfection did not alter luciferase activity Cyclin D1.	('Cyclin D1', 'Gene', (62, 71))	('Cyclin D1', 'Gene', '595', (62, 71))	('499AI transfection', 'Var', (9, 27))
519978	29845226	The results of the current study revealed that cyclinD1 was downregulated in ESCC cells transfected with 499AM, whereas cyclin D1 was upregulated in ESCC cells transfected with 499AI.	('cyclinD1', 'Gene', '595', (47, 55))	('499AM', 'Var', (105, 110))	('ESCC', 'Disease', (77, 81))	('upregulated', 'PosReg', (134, 145))	('cyclin D1', 'Gene', '595', (120, 129))	('cyclin D1', 'Gene', (120, 129))	('cyclinD1', 'Gene', (47, 55))	('downregulated', 'NegReg', (60, 73))
519980	29845226	Inhibition of cyclin D1 reversed the effects of 499AI on the proliferation of ESCC cells.	('cyclin D1', 'Gene', '595', (14, 23))	('ESCC', 'Disease', (78, 82))	('499AI', 'Var', (48, 53))	('cyclin D1', 'Gene', (14, 23))
519983	29845226	In addition, inhibition of miR-449a-5p was able to promote the proliferation of ESCC cells by upregulating cyclin D1 expression.	('miR-449a', 'Gene', (27, 35))	('cyclin D1', 'Gene', (107, 116))	('proliferation', 'CPA', (63, 76))	('expression', 'MPA', (117, 127))	('inhibition', 'Var', (13, 23))	('miR-449a', 'Gene', '554213', (27, 35))	('promote', 'PosReg', (51, 58))	('upregulating', 'PosReg', (94, 106))	('cyclin D1', 'Gene', '595', (107, 116))	('ESCC', 'Disease', (80, 84))
520103	28922414	Vitamin D affects genes regulating proliferation, apoptosis, and differentiation and induces the tumor suppressor 15-hydroxyprostaglandin dehydrogenase (PGDH) in other cancers.	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('PGDH', 'Gene', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('PGDH', 'Gene', '3248', (153, 157))	('tumor', 'Disease', (97, 102))	('genes', 'Gene', (18, 23))	('induces', 'PosReg', (85, 92))	('apoptosis', 'CPA', (50, 59))	('15-hydroxyprostaglandin dehydrogenase', 'Gene', '873', (114, 151))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('differentiation', 'CPA', (65, 80))	('affects', 'Reg', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('15-hydroxyprostaglandin dehydrogenase', 'Gene', (114, 151))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('proliferation', 'CPA', (35, 48))	('Vitamin', 'Var', (0, 7))
520113	28922414	Despite improved vitamin D status with supplementation, no significant alterations in gene expression profiles were noted.	('improved', 'PosReg', (8, 16))	('improved vitamin D status', 'Phenotype', 'HP:0100512', (8, 33))	('supplementation', 'Var', (39, 54))	('vitamin D', 'Chemical', 'MESH:D014807', (17, 26))
520133	28922414	Vitamin D deficiency has been associated with insulin resistance, obesity, and increased risk for esophageal cancer.	('associated', 'Reg', (30, 40))	('insulin', 'Gene', (46, 53))	('Vitamin D', 'Gene', (0, 9))	('obesity', 'Disease', (66, 73))	('insulin', 'Gene', '3630', (46, 53))	('obesity', 'Phenotype', 'HP:0001513', (66, 73))	('insulin resistance', 'Phenotype', 'HP:0000855', (46, 64))	('obesity', 'Disease', 'MESH:D009765', (66, 73))	('Vitamin D deficiency', 'Phenotype', 'HP:0100512', (0, 20))	('esophageal cancer', 'Disease', (98, 115))	('deficiency', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
520210	28922414	VDR expression is upregulated in BE compared with normal esophageal mucosa, suggesting that BE may be more sensitive than normal esophageal mucosa to the effects of calcitriol, the active form of vitamin D. Recent data also suggest that genetic variations in VDR are linked to reduced EAC risk.	('VDR', 'Gene', '7421', (0, 3))	('VDR', 'Gene', (259, 262))	('VDR', 'Gene', (0, 3))	('VDR', 'Gene', '7421', (259, 262))	('reduced', 'NegReg', (277, 284))	('calcitriol', 'Chemical', 'MESH:D002117', (165, 175))	('genetic variations', 'Var', (237, 255))	('EAC', 'Disease', (285, 288))	('vitamin D', 'Chemical', 'MESH:D014807', (196, 205))
520212	28922414	Moreover, vitamin D deficiency is associated with an increased risk, as well as worse outcomes, in other cancers.	('vitamin D', 'Chemical', 'MESH:D014807', (10, 19))	('vitamin D', 'Gene', (10, 19))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('deficiency', 'Var', (20, 30))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (10, 30))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
520278	26813745	For instance, some authorities prefer to define BE according to histologic changes that result in an increased risk of cancer and, thus, a need for surveillance, whereas others use a more pragmatic approach and consider BE as present if the esophagus shows columnar metaplasia (even without goblet cells) regardless of whether the cancer risk is increased significantly.	('changes', 'Var', (75, 82))	('columnar metaplasia', 'Disease', (257, 276))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('columnar metaplasia', 'Disease', 'MESH:D008679', (257, 276))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
520308	26813745	Several studies also suggest that metaplastic non-goblet columnar epithelium is at risk for progression to adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('adenocarcinoma', 'Disease', (107, 121))	('metaplastic', 'Var', (34, 45))
520312	26813745	According to more recent large population-based studies, patients with metaplastic non-goblet columnar epithelium have a lower risk of cancer progression than patients with goblet cells, but the risk is greater than the general population.	('cancer', 'Disease', (135, 141))	('patients', 'Species', '9606', (57, 65))	('metaplastic non-goblet', 'Var', (71, 93))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lower', 'NegReg', (121, 126))	('patients', 'Species', '9606', (159, 167))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
520317	26813745	Even if goblet cells are present, recent data shows that the risk of cancer among patients with short-segment BE is significantly lower compared to those with long-segment BE.	('lower', 'NegReg', (130, 135))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('short-segment BE', 'Var', (96, 112))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
520320	26813745	Furthermore, there is some evidence that a significant proportion of "GEJ" cancers actually arise in patients with ultrashort-segments of BE, a condition known to be associated with a low incidence rate of goblet cell metaplasia.	('metaplasia', 'Disease', 'MESH:D008679', (218, 228))	('patients', 'Species', '9606', (101, 109))	('arise', 'Reg', (92, 97))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('ultrashort-segments', 'Var', (115, 134))	('metaplasia', 'Disease', (218, 228))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
520433	26813745	Inactivating mutations of the p53 gene can be detected by IHC, which shows either complete loss (absent protein and negative staining), or more commonly, increased expression and positive staining (due to mutations creating a protein product that is resistant to degradation).	('negative', 'NegReg', (116, 124))	('expression', 'MPA', (164, 174))	('protein', 'Protein', (104, 111))	('mutations', 'Var', (205, 214))	('Inactivating mutations', 'Var', (0, 22))	('absent', 'NegReg', (97, 103))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('loss', 'NegReg', (91, 95))	('protein product', 'MPA', (226, 241))	('increased', 'PosReg', (154, 163))
520434	26813745	The frequency of p53 mutation increases in BE neoplasia.	('neoplasia', 'Disease', (46, 55))	('neoplasia', 'Phenotype', 'HP:0002664', (46, 55))	('mutation', 'Var', (21, 29))	('neoplasia', 'Disease', 'MESH:D009369', (46, 55))	('p53', 'Gene', (17, 20))	('increases', 'PosReg', (30, 39))	('p53', 'Gene', '7157', (17, 20))
520451	26813745	In a recent population-based European study, the risk of progression to adenocarcinoma was five times higher in patients with LGD compared to those with no dysplasia.	('dysplasia', 'Disease', (156, 165))	('LGD', 'Var', (126, 129))	('patients', 'Species', '9606', (112, 120))	('higher', 'PosReg', (102, 108))	('dysplasia', 'Disease', 'MESH:D004476', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('adenocarcinoma', 'Disease', (72, 86))	('adenocarcinoma', 'Disease', 'MESH:D000230', (72, 86))
520461	26813745	Recently, the phosphatidylinositol 3-kinase (PI3K) pathway has been identified by exome and whole-genome sequencing as the most frequently altered oncogenic pathway affected by mutation in esophageal adenocarcinomas.	('mutation', 'Var', (177, 185))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (189, 214))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (189, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('oncogenic pathway', 'Pathway', (147, 164))	('altered', 'Reg', (139, 146))	('esophageal adenocarcinomas', 'Disease', (189, 215))
520462	26813745	Although the role of erbB-2 (also called HER2 or Neu) remains controversial, erbB-2 mutations have been detected in esophageal adenocarcinomas by exome and whole-genome sequencing.	('detected', 'Reg', (104, 112))	('erbB-2', 'Gene', '2064', (21, 27))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (116, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('erbB-2', 'Gene', (77, 83))	('mutations', 'Var', (84, 93))	('Neu', 'Gene', (49, 52))	('HER2', 'Gene', (41, 45))	('erbB-2', 'Gene', '2064', (77, 83))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (116, 141))	('esophageal adenocarcinomas', 'Disease', (116, 142))	('Neu', 'Gene', '2064', (49, 52))	('erbB-2', 'Gene', (21, 27))	('HER2', 'Gene', '2064', (41, 45))
520463	26813745	Inactivation of the tumor suppressor genes p53, p16, p15, p27, and adenomatous polyposis coli (APC), have been implicated in BE's carcinogenesis (Reviewed in ).	('p15', 'Gene', '1030', (53, 56))	('APC', 'Disease', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('p53', 'Gene', (43, 46))	('tumor', 'Disease', (20, 25))	("'s carcinogenesis", 'Disease', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Inactivation', 'Var', (0, 12))	('implicated', 'Reg', (111, 121))	("'s carcinogenesis", 'Disease', 'MESH:D063646', (127, 144))	('p27', 'Gene', '3429', (58, 61))	('p27', 'Gene', (58, 61))	('p16', 'Gene', (48, 51))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (67, 93))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (67, 93))	('adenomatous polyposis coli', 'Disease', (67, 93))	('p16', 'Gene', '1029', (48, 51))	('p15', 'Gene', (53, 56))	('p53', 'Gene', '7157', (43, 46))	('APC', 'Disease', 'MESH:D011125', (95, 98))
520475	26813745	Barrett's cells also use other mechanisms for avoiding autophagy and apoptosis including, inactivation of P53, downregulation of 15-lipoxygenase-1 (15-LOX-1), overexpression of cyclooxygenase-2 (COX-2), expression of nuclear factor kappa B (NF-kappaB), and inactivation of Beclin-I.	('15-lipoxygenase-1', 'Gene', (129, 146))	('15-lipoxygenase-1', 'Gene', '246', (129, 146))	('cyclooxygenase-2', 'Gene', (177, 193))	('Beclin-I', 'Protein', (273, 281))	('NF-kappaB', 'Gene', '4790', (241, 250))	('apoptosis', 'CPA', (69, 78))	('P53', 'Gene', '7157', (106, 109))	('15-LOX-1', 'Gene', (148, 156))	('nuclear factor kappa B', 'Gene', '4790', (217, 239))	('15-LOX-1', 'Gene', '246', (148, 156))	('autophagy', 'CPA', (55, 64))	('COX-2', 'Gene', (195, 200))	('inactivation', 'Var', (90, 102))	('COX-2', 'Gene', '5743', (195, 200))	('nuclear factor kappa B', 'Gene', (217, 239))	('overexpression', 'PosReg', (159, 173))	('P53', 'Gene', (106, 109))	('cyclooxygenase-2', 'Gene', '5743', (177, 193))	('downregulation', 'NegReg', (111, 125))	('NF-kappaB', 'Gene', (241, 250))	('inactivation', 'NegReg', (257, 269))
520494	26813745	Many potential IHC and molecular biomarkers have been evaluated and these include many of the same ones described above for use in diagnosing dysplasia, such as DNA content abnormalities (aneuploidy/tetraploidy), inactivation of tumor suppressor p53 gene by IHC or DNA analysis, methylation markers, alterations in the synthesis of Lewis (Le) antigens and lectin proteins, among many others.	('lectin proteins', 'Protein', (356, 371))	('dysplasia', 'Disease', (142, 151))	('aneuploidy/tetraploidy', 'Disease', (188, 210))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('dysplasia', 'Disease', 'MESH:D004476', (142, 151))	('inactivation', 'Var', (213, 225))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('p53', 'Gene', (246, 249))	('p53', 'Gene', '7157', (246, 249))	('tumor', 'Disease', (229, 234))	('aneuploidy/tetraploidy', 'Disease', 'MESH:D057891', (188, 210))	('synthesis of', 'MPA', (319, 331))	('alterations', 'Reg', (300, 311))
520495	26813745	P53 abnormalities have been studied as an adjunct marker of neoplastic progression and risk stratification in BE.	('P53', 'Gene', '7157', (0, 3))	('P53', 'Gene', (0, 3))	('abnormalities', 'Var', (4, 17))
520496	26813745	In BE progression, p53 function is most often altered or lost by either mutation or loss of heterozygosity (LOH).	('function', 'MPA', (23, 31))	('altered', 'Reg', (46, 53))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('mutation', 'Var', (72, 80))	('loss of heterozygosity', 'Var', (84, 106))	('lost', 'NegReg', (57, 61))
520497	26813745	Several studies have suggested that aberrant p53 expression is associated with an increased risk of neoplastic progression.	('neoplastic progression', 'CPA', (100, 122))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('associated', 'Reg', (63, 73))	('expression', 'MPA', (49, 59))	('aberrant', 'Var', (36, 44))
520499	26813745	In another retrospective case-control study of 16 BE patients, p53 positivity showed 85% sensitivity and 75% specificity for progression of LGD to HGD or adenocarcinoma.	('p53', 'Gene', '7157', (63, 66))	('p53', 'Gene', (63, 66))	('patients', 'Species', '9606', (53, 61))	('LGD to HGD or adenocarcinoma', 'Disease', 'MESH:D000230', (140, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('LGD to HGD or adenocarcinoma', 'Disease', (140, 168))	('positivity', 'Var', (67, 77))
520500	26813745	have shown that patients with diploid baseline biopsies show a significantly lower rate of cancer progression compared to patients with either aneuploidy or tetraploidy.	('lower', 'NegReg', (77, 82))	('cancer', 'Disease', (91, 97))	('patients', 'Species', '9606', (16, 24))	('aneuploidy', 'Disease', 'MESH:D000782', (143, 153))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('diploid', 'Var', (30, 37))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('aneuploidy', 'Disease', (143, 153))
520501	26813745	Some studies show that a combination of biomarkers, such as DNA content and LOH of p53 and p16, are more sensitive and specific indicators of progression compared to either of these individual markers alone.	('p16', 'Gene', (91, 94))	('p53', 'Gene', '7157', (83, 86))	('p53', 'Gene', (83, 86))	('DNA content', 'MPA', (60, 71))	('p16', 'Gene', '1029', (91, 94))	('LOH', 'Var', (76, 79))
520503	26813745	In a recent European case control study of 380 patients, a panel comprising a histologic diagnosis of LGD, abnormal DNA ploidy, and Aspergillus oryzae lectin expression most accurately identified BE patients who progressed to HGD or adenocarcinoma.	('abnormal DNA', 'Var', (107, 119))	('adenocarcinoma', 'Disease', (233, 247))	('patients', 'Species', '9606', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('progressed', 'PosReg', (212, 222))	('Aspergillus oryzae', 'Species', '5062', (132, 150))	('patients', 'Species', '9606', (199, 207))	('adenocarcinoma', 'Disease', 'MESH:D000230', (233, 247))	('LGD', 'Disease', (102, 105))
520522	26813745	Ablation usually results in replacement of columnar epithelium with squamous (neosquamous) epithelium (NSE).	('Ablation', 'Var', (0, 8))	('NSE', 'Gene', '2026', (103, 106))	('results in', 'Reg', (17, 27))	('NSE', 'Gene', (103, 106))
520525	26813745	For example, in a study by Pouw, et al., 100% of pre-RFA BE patients showed abnormal Ki67, p53, and FISH assays (for chromosome 1,9, p16, and p53), but post-RFA NSE showed none of these abnormalities.	('p16', 'Gene', (133, 136))	('NSE', 'Gene', '2026', (161, 164))	('p53', 'Gene', (142, 145))	('pre-RFA BE', 'Disease', (49, 59))	('p53', 'Gene', '7157', (142, 145))	('Ki67', 'Var', (85, 89))	('patients', 'Species', '9606', (60, 68))	('FISH assays', 'CPA', (100, 111))	('NSE', 'Gene', (161, 164))	('p53', 'Gene', (91, 94))	('p16', 'Gene', '1029', (133, 136))	('p53', 'Gene', '7157', (91, 94))
520526	26813745	In another study by Paulson and colleagues in which Post-PPI NSE and adjacent BE were evaluated for p16 and p53 abnormalities, 95% of NSE specimens showed both wild-type p16 and p53 despite the presence of mutations in 1 or both of these genes in adjacent nondysplastic BE.	('mutations', 'Var', (206, 215))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('NSE', 'Gene', '2026', (134, 137))	('NSE', 'Gene', (61, 64))	('p16', 'Gene', '1029', (170, 173))	('p16', 'Gene', (100, 103))	('NSE', 'Gene', (134, 137))	('dysplastic', 'Disease', (259, 269))	('presence', 'Reg', (194, 202))	('dysplastic', 'Disease', 'MESH:D004416', (259, 269))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))	('NSE', 'Gene', '2026', (61, 64))	('p16', 'Gene', (170, 173))	('p16', 'Gene', '1029', (100, 103))
520580	24708624	The eligibility criteria for patients participating in the clinical trial were as follows: (1) they were unresectable ESCC patients with widespread ESCC who refused surgical resection, locally advanced or metastatic disease; (2) they have disease which is possible the evaluation of clinical response ( no limitation with respect to the presence or absence of measurable diseases according to RECIST ); (3) they were HLA-A*2402-positive patients by DNA typing of HLA-A genetic variations; (4) no therapy 4 weeks prior to the initiation of the trial; (5) ECOG performance status was 0-2; (6) their expected survival was at least 3 months; (7) the age of the patients was between >20 and <80 years; and (8) adequate bone-marrow, cardiac, pulmonary, hepatic and renal functions had to be present, including white blood cell count >2000/mm3, platelet count >75000/mm3, total bilirubin < 1.5 times of the institutional normal upper limits, creatinine < 1.5 times of the institutional normal upper limits, AST/ALT/ALP <2.5 times of the institutional normal upper limits.	('HLA-A', 'Gene', '3105', (417, 422))	('patients', 'Species', '9606', (29, 37))	('HLA-A', 'Gene', (417, 422))	('creatinine', 'MPA', (935, 945))	('patients', 'Species', '9606', (657, 665))	('patients', 'Species', '9606', (437, 445))	('HLA-A', 'Gene', '3105', (463, 468))	('AST', 'Gene', (1000, 1003))	('>75000/mm3', 'Var', (853, 863))	('patients', 'Species', '9606', (123, 131))	('platelet count', 'MPA', (838, 852))	('HLA-A', 'Gene', (463, 468))	('total bilirubin', 'MPA', (865, 880))	('AST', 'Gene', '26503', (1000, 1003))
520651	24708624	Because JCOG9906 showed the less grade of lymphopenia as compared with that of other regimen, we selected this regimen for our study (Additional file 3: Table S2).	('lymphopenia', 'Phenotype', 'HP:0001888', (42, 53))	('JCOG9906', 'Var', (8, 16))	('lymphopenia', 'Disease', 'MESH:D008231', (42, 53))	('lymphopenia', 'Disease', (42, 53))
520676	24490085	Low socioeconomic, smoking, snuff use, alcohol, tooth loss, cooking with charcoal and firewood, hot beverage, and use of mursik were independently associated with esophageal cancer (P < 0.05).	('tooth loss', 'Disease', (48, 58))	('Low socioeconomic', 'Var', (0, 17))	('tooth loss', 'Phenotype', 'HP:0006480', (48, 58))	('associated', 'Reg', (147, 157))	('alcohol', 'Chemical', 'MESH:D000438', (39, 46))	('charcoal', 'Chemical', 'MESH:D002606', (73, 81))	('esophageal cancer', 'Disease', (163, 180))	('tooth loss', 'Disease', 'MESH:D016388', (48, 58))	('hot beverage', 'Phenotype', 'HP:0031217', (96, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
520677	24490085	Using logistic regression adjusted for various factors, alcohol consumption was associated with the increased risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('alcohol', 'Chemical', 'MESH:D000438', (56, 63))	('alcohol consumption', 'Var', (56, 75))
520692	24490085	These include the effect of deficiency of trace mineral deficiency, N-nitroso-compounds, contaminated food with mycotoxins, spicy food, tobacco smoking and alcohol, low socioeconomic status, familial nature of this disease, presence of infectious agents, and consumption of hot drinks.	('alcohol', 'Chemical', 'MESH:D000438', (156, 163))	('tobacco', 'Species', '4097', (136, 143))	('presence', 'Reg', (224, 232))	('deficiency of trace mineral deficiency', 'Disease', (28, 66))	('deficiency of trace mineral deficiency', 'Disease', 'MESH:C537337', (28, 66))	('low socioeconomic status', 'Var', (165, 189))	('N-nitroso-compounds', 'MPA', (68, 87))	('familial nature', 'Disease', (191, 206))	('N-nitroso-compounds', 'Chemical', '-', (68, 87))	('hot drinks', 'Phenotype', 'HP:0031217', (274, 284))
520787	24490085	Deficiency of such vitamins results in mucosal inflammation which may predispose the epithelial tissue to malignancy.	('predispose', 'Reg', (70, 80))	('mucosal inflammation', 'Disease', 'MESH:D007249', (39, 59))	('malignancy', 'Disease', (106, 116))	('mucosal inflammation', 'Disease', (39, 59))	('results in', 'Reg', (28, 38))	('malignancy', 'Disease', 'MESH:D009369', (106, 116))	('Deficiency', 'Var', (0, 10))
520812	24490085	Hot drinks were associated with a higher risk of esophageal cancer in a recent study in Iran.	('esophageal cancer', 'Disease', (49, 66))	('Hot drinks', 'Var', (0, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('Hot drinks', 'Phenotype', 'HP:0031217', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
520822	24490085	Polycyclic aromatic hydrocarbons (PAHs) are known to be carcinogenic agents.	('PAHs', 'Chemical', 'MESH:D011084', (34, 38))	('Polycyclic', 'Var', (0, 10))	('carcinogenic', 'Disease', 'MESH:D063646', (56, 68))	('carcinogenic', 'Disease', (56, 68))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (0, 32))
520824	24490085	An additional factor, which may interact with this exposure, is that in people with genetic variation in the enzymes responsible for the metabolism of PAHs there is increased risk of developing squamous dysplasia of the esophagus which may be a predisposing factor to esophageal cancer.	('squamous dysplasia', 'Disease', (194, 212))	('PAHs', 'Chemical', 'MESH:D011084', (151, 155))	('people', 'Species', '9606', (72, 78))	('squamous dysplasia', 'Disease', 'MESH:D002294', (194, 212))	('esophageal cancer', 'Disease', (268, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('genetic variation', 'Var', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (268, 285))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (194, 212))
520840	24490085	In a multivariate logistic regression, adjusting for gender, age, smoking, snuff use, and cooking and sleeping in the same room, alcohol consumption was associated with increased risk of developing oesophagus cancer and OR = 0.449 and 95% CI of the OR was (0.205-0.985).	('alcohol', 'Chemical', 'MESH:D000438', (129, 136))	('oesophagus cancer', 'Disease', (198, 215))	('alcohol consumption', 'Var', (129, 148))	('oesophagus cancer', 'Disease', 'MESH:D009369', (198, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
520845	24490085	Using logistic regression adjusting for gender, age, smoking, snuff use, and cooking with charcoal and firewood, alcohol consumption was associated with increased risk esophageal cancer.	('esophageal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('alcohol', 'Chemical', 'MESH:D000438', (113, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('charcoal', 'Chemical', 'MESH:D002606', (90, 98))	('alcohol consumption', 'Var', (113, 132))
520850	33396321	Multiple papers report dysregulation of miR-194-5p in BE and miR-21-5p, -25-3p, and -93-5p in EAC.	('EAC', 'Disease', (94, 97))	('BE', 'Phenotype', 'HP:0100580', (54, 56))	('miR-21-5p', 'Var', (61, 70))	('miR-194-5p', 'Var', (40, 50))	('EAC', 'Phenotype', 'HP:0011459', (94, 97))	('-3p', 'Chemical', '-', (75, 78))
520870	33396321	Compared with the GERD group, the BE group had significantly higher levels of miR-15a-5p (sensitivity, 75%; specificity, 75%; area under the receiver operating characteristic curve (AUC), 0.68 (0.60-0.86, p = 0.01)) and miR-196a-5p (sensitivity, 70%; specificity, 74%; AUC, 0.72 (0.61-0.89, p = 0.03)).	('higher', 'PosReg', (61, 67))	('GERD', 'Disease', (18, 22))	('GERD', 'Disease', 'MESH:D005764', (18, 22))	('miR-15a', 'Gene', '406948', (78, 85))	('BE', 'Phenotype', 'HP:0100580', (34, 36))	('miR-196a-5p', 'Var', (220, 231))	('miR-15a', 'Gene', (78, 85))
520871	33396321	A combination of miR-15a and miR-196a can be used to distinguish BE patients from GERD patients, with a sensitivity of 75%, a specificity of 85%, and an AUC of 0.79 (0.64-0.95, p = 0.003).	('GERD', 'Disease', (82, 86))	('GERD', 'Disease', 'MESH:D005764', (82, 86))	('patients', 'Species', '9606', (68, 76))	('miR-15a', 'Gene', '406948', (17, 24))	('miR-15a', 'Gene', (17, 24))	('patients', 'Species', '9606', (87, 95))	('BE', 'Phenotype', 'HP:0100580', (65, 67))	('miR-196a', 'Var', (29, 37))
520872	33396321	Further validation in 115 patients and controls showed that miRNA-194-5p and miRNA-451a were up-regulated, and miRNA-136-5p was down-regulated, in BE compared with controls.	('up-regulated', 'PosReg', (93, 105))	('miRNA-451a', 'Gene', (77, 87))	('miRNA-194-5p', 'Var', (60, 72))	('miRNA-136-5p', 'Var', (111, 123))	('patients', 'Species', '9606', (26, 34))	('down-regulated', 'NegReg', (128, 142))	('BE', 'Phenotype', 'HP:0100580', (147, 149))
520874	33396321	Similar to the results from tissues, circulating levels of miR-143-3p, -194-5p, and -215-5p were up-regulated in the serum of patients with BE, and were higher than those in patients with CLE or esophagitis.	('esophagitis', 'Disease', (195, 206))	('higher', 'PosReg', (153, 159))	('esophagitis', 'Phenotype', 'HP:0100633', (195, 206))	('miR-143-3p', 'Var', (59, 69))	('up-regulated', 'PosReg', (97, 109))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (126, 134))	('miR-143-3p', 'Chemical', '-', (59, 69))	('BE', 'Phenotype', 'HP:0100580', (140, 142))	('esophagitis', 'Disease', 'MESH:D004938', (195, 206))
520875	33396321	MiR-194-5p and miR-215-5p were also significantly up-regulated in patients with CLE compared with those with esophagitis, suggesting that CLE is an intermediate condition between BE and esophagitis.	('esophagitis', 'Disease', 'MESH:D004938', (186, 197))	('miR-215', 'Gene', (15, 22))	('CLE', 'Disease', (80, 83))	('MiR-194-5p', 'Var', (0, 10))	('MiR-194-5p', 'Chemical', '-', (0, 10))	('esophagitis', 'Disease', 'MESH:D004938', (109, 120))	('miR-215', 'Gene', '406997', (15, 22))	('up-regulated', 'PosReg', (50, 62))	('esophagitis', 'Phenotype', 'HP:0100633', (109, 120))	('esophagitis', 'Phenotype', 'HP:0100633', (186, 197))	('esophagitis', 'Disease', (186, 197))	('CLE', 'Disease', (138, 141))	('esophagitis', 'Disease', (109, 120))	('BE', 'Phenotype', 'HP:0100580', (179, 181))	('patients', 'Species', '9606', (66, 74))
520876	33396321	investigated expression of plasma miR-223-3p in BE and EAC, and found that expression of miR-223-3p was significantly associated with the degree of intestinal metaplasia in those with atrophic gastritis and LSBE.	('gastritis', 'Phenotype', 'HP:0005263', (193, 202))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (184, 202))	('associated', 'Reg', (118, 128))	('atrophic gastritis', 'Disease', 'MESH:D005757', (184, 202))	('intestinal metaplasia', 'Disease', (148, 169))	('EAC', 'Phenotype', 'HP:0011459', (55, 58))	('BE', 'Phenotype', 'HP:0100580', (48, 50))	('miR-223-3p', 'Var', (89, 99))	('atrophic gastritis', 'Disease', (184, 202))	('BE', 'Phenotype', 'HP:0100580', (209, 211))	('LSBE', 'Disease', (207, 211))	('expression', 'MPA', (75, 85))
520879	33396321	found higher levels of serum miR130a-3p in patients with low-grade and high-grade dysplastic BE than in serum from patients with metaplastic epithelium.	('dysplastic', 'Disease', 'MESH:D004416', (82, 92))	('patients', 'Species', '9606', (115, 123))	('dysplastic', 'Disease', (82, 92))	('patients', 'Species', '9606', (43, 51))	('low-grade', 'Disease', (57, 66))	('BE', 'Phenotype', 'HP:0100580', (93, 95))	('miR130a-3p', 'Var', (29, 39))	('levels', 'MPA', (13, 19))	('higher', 'PosReg', (6, 12))	('-3p', 'Chemical', '-', (36, 39))
520884	33396321	MiR-10b-3p, -144-3p, and -451a in whole saliva, and miR-10b-3p, -144-3p, -21-5p, and -451a in saliva supernatant, were significantly up-regulated in EC patients (sensitivity, 89.7%, 92.3%, 84.6%, 79.5%, 43.6%, 89.7%, and 51.3%, respectively, and specificity, 57.9%, 47.4%, 57.9%, 57.9%, 89.5%, 47.4%, and 84.2%, respectively).	('-3p', 'Chemical', '-', (68, 71))	('-3p', 'Chemical', '-', (7, 10))	('-3p', 'Chemical', '-', (59, 62))	('144-3p', 'Chemical', '-', (65, 71))	('miR-10b-3p', 'Var', (52, 62))	('up-regulated', 'PosReg', (133, 145))	('144-3p', 'Chemical', '-', (13, 19))	('patients', 'Species', '9606', (152, 160))	('-3p', 'Chemical', '-', (16, 19))	('MiR-10b-3p', 'Gene', (0, 10))
520890	33396321	compared BE, EAC, and control plasma miRNAs, and reported that miR-382-5p was significantly up-regulated, and miR-133a-3p was down-regulated, in EAC patients, and that combinations of three or more miRNAs could distinguish EAC from controls (AUC, 0.846) and BE from EAC (AUC, 0.797).	('EAC', 'Disease', (223, 226))	('patients', 'Species', '9606', (149, 157))	('down-regulated', 'NegReg', (126, 140))	('EAC', 'Phenotype', 'HP:0011459', (266, 269))	('combinations', 'Var', (168, 180))	('miR-382', 'Gene', '494331', (63, 70))	('EAC', 'Phenotype', 'HP:0011459', (13, 16))	('BE', 'Phenotype', 'HP:0100580', (9, 11))	('miR-382', 'Gene', (63, 70))	('EAC', 'Phenotype', 'HP:0011459', (223, 226))	('EAC', 'Phenotype', 'HP:0011459', (145, 148))	('up-regulated', 'PosReg', (92, 104))	('miR-133a-3p', 'Var', (110, 121))	('-3p', 'Chemical', '-', (118, 121))	('BE', 'Phenotype', 'HP:0100580', (258, 260))
520894	33396321	compared circulating miRNAs in serum from EAC patients and healthy controls, and found that miR-25-3p and miR-151a-3p were significantly up-regulated, and that miR-100-5p and miR-375-3p were significantly down-regulated in EAC patients.	('EAC', 'Disease', (223, 226))	('patients', 'Species', '9606', (46, 54))	('miR-151a-3p', 'Var', (106, 117))	('-3p', 'Chemical', '-', (98, 101))	('-3p', 'Chemical', '-', (182, 185))	('miR-100-5p', 'Var', (160, 170))	('-3p', 'Chemical', '-', (114, 117))	('EAC', 'Phenotype', 'HP:0011459', (223, 226))	('EAC', 'Phenotype', 'HP:0011459', (42, 45))	('up-regulated', 'PosReg', (137, 149))	('miR-25-3p', 'Var', (92, 101))	('down-regulated', 'NegReg', (205, 219))	('patients', 'Species', '9606', (227, 235))	('miR-375-3p', 'Var', (175, 185))
520895	33396321	isolated exosomes from serum samples from EAC patients and controls, and reported that miR-21-5p, -16-5p, -25-3p, and -155-5p were significantly up-regulated, and miR-192-5p was significantly down-regulated, in EAC patients.	('patients', 'Species', '9606', (215, 223))	('patients', 'Species', '9606', (46, 54))	('EAC', 'Disease', (211, 214))	('up-regulated', 'PosReg', (145, 157))	('down-regulated', 'NegReg', (192, 206))	('miR-192', 'Gene', '406967', (163, 170))	('EAC', 'Phenotype', 'HP:0011459', (42, 45))	('miR-192', 'Gene', (163, 170))	('miR-21-5p', 'Var', (87, 96))	('EAC', 'Phenotype', 'HP:0011459', (211, 214))	('-3p', 'Chemical', '-', (109, 112))
520898	33396321	Compared with the BE group, levels of miR-128-3p and miR-328-3p were higher in the EAC group, and those of miR-143-3p, -144-3p, -15a-5p, -1-3p, and -133b were lower.	('levels', 'MPA', (28, 34))	('miR-128-3p', 'Chemical', '-', (38, 48))	('miR-143-3p', 'Var', (107, 117))	('-3p', 'Chemical', '-', (60, 63))	('BE', 'Phenotype', 'HP:0100580', (18, 20))	('-3p', 'Chemical', '-', (123, 126))	('-3p', 'Chemical', '-', (45, 48))	('lower', 'NegReg', (159, 164))	('144-3p', 'Chemical', '-', (120, 126))	('-3p', 'Chemical', '-', (114, 117))	('miR-328-3p', 'Var', (53, 63))	('miR-128-3p', 'MPA', (38, 48))	('miR-143-3p', 'Chemical', '-', (107, 117))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))	('higher', 'PosReg', (69, 75))	('-3p', 'Chemical', '-', (139, 142))
520899	33396321	Six miRNAs (miR-106b-5p, -146a-5p, -15a-5p, -18a-5p, -21-5p, and -93-5p) were significantly up-regulated and could be used to distinguish EAC patients from healthy subjects (AUC, 0.86).	('miR-106b-5p', 'Var', (12, 23))	('up-regulated', 'PosReg', (92, 104))	('EAC', 'Phenotype', 'HP:0011459', (138, 141))	('patients', 'Species', '9606', (142, 150))	('EAC', 'Disease', (138, 141))
520900	33396321	They found that miR130a-3p was significantly up-regulated in the EAC group, and that expression of miR130a-3p increased gradually from early (I, II) to advanced (III, IV) stage.	('-3p', 'Chemical', '-', (23, 26))	('miR130a-3p', 'Var', (99, 109))	('expression', 'MPA', (85, 95))	('up-regulated', 'PosReg', (45, 57))	('increased', 'PosReg', (110, 119))	('-3p', 'Chemical', '-', (106, 109))	('miR130a-3p', 'Gene', (16, 26))	('EAC', 'Phenotype', 'HP:0011459', (65, 68))	('EAC', 'Disease', (65, 68))
520901	33396321	As we mentioned in the BE section, they also showed that levels of miR130a-3p were significantly higher in patients with LGD and HGD BE than in those with metaplasia (sensitivity, 70.5%; specificity, 62.5%), suggesting that increased miR130a-3p expression in plasma may correlate with early EAC.	('patients', 'Species', '9606', (107, 115))	('higher', 'PosReg', (97, 103))	('LGD', 'Disease', (121, 124))	('-3p', 'Chemical', '-', (74, 77))	('LGD', 'Disease', 'None', (121, 124))	('-3p', 'Chemical', '-', (241, 244))	('EAC', 'Phenotype', 'HP:0011459', (291, 294))	('miR130a-3p', 'Var', (234, 244))	('levels', 'MPA', (57, 63))	('BE', 'Phenotype', 'HP:0100580', (133, 135))	('BE', 'Phenotype', 'HP:0100580', (23, 25))	('increased', 'PosReg', (224, 233))	('men', 'Species', '9606', (6, 9))
520905	33396321	Seven (miR-92a-3p, -151a-5p, -362-3p, -345-3p, -619- 3p, -1260b, and -1276) were up-regulated in the HG-IEN/EAC samples compared with the non-dysplastic BE samples, whereas three (miR-381-3p, -502-3p, and -3615) were down-regulated.	('HG-IEN/EAC', 'Disease', (101, 111))	('EAC', 'Phenotype', 'HP:0011459', (108, 111))	('-3p', 'Chemical', '-', (196, 199))	('BE', 'Phenotype', 'HP:0100580', (153, 155))	('-3p', 'Chemical', '-', (42, 45))	('-3p', 'Chemical', '-', (14, 17))	('dysplastic', 'Disease', (142, 152))	('up-regulated', 'PosReg', (81, 93))	('dysplastic', 'Disease', 'MESH:D004416', (142, 152))	('-3p', 'Chemical', '-', (187, 190))	('miR-92a-3p', 'Var', (7, 17))	('-3p', 'Chemical', '-', (33, 36))
520911	33396321	No serum miRNAs were associated with a therapeutic response, but there was a significant correlation between expression of miR-192-5p and miR-222-3p and T classification, and between expression of miR-302c-3p and miR-222-3p and overall survival (OS).	('expression', 'MPA', (109, 119))	('miR-192', 'Gene', (123, 130))	('miR-302c-3p', 'Var', (197, 208))	('miR-192', 'Gene', '406967', (123, 130))	('-3p', 'Chemical', '-', (220, 223))	('overall survival', 'CPA', (228, 244))	('miR-222-3p', 'Chemical', '-', (213, 223))	('-3p', 'Chemical', '-', (145, 148))	('-3p', 'Chemical', '-', (205, 208))	('miR-222-3p', 'Chemical', '-', (138, 148))	('miR-222-3p', 'Var', (138, 148))
520913	33396321	When comparing miRNAs in the EAC and the control groups, they identified four (miR-126-3p, -142-3p, -331-3p, and -18a-5p) that were specific for EAC (p < 0.05).	('EAC', 'Phenotype', 'HP:0011459', (29, 32))	('EAC', 'Disease', (145, 148))	('-3p', 'Chemical', '-', (86, 89))	('EAC', 'Phenotype', 'HP:0011459', (145, 148))	('-3p', 'Chemical', '-', (104, 107))	('miR-126-3p', 'Var', (79, 89))	('-3p', 'Chemical', '-', (95, 98))
520914	33396321	Also, in cases with high miR-30c-5p expression, the risk of death (HR = 0.28, 95% CI = 0.12-0.65, p = 0.003) and recurrence (HR = 0.49; 95% CI = 0.24-0.99, p = 0.047) was lower than in cases with low expression ("risk of death" was not defined).	('death', 'Disease', 'MESH:D003643', (60, 65))	('death', 'Disease', (60, 65))	('miR-30c-5p', 'Chemical', '-', (25, 35))	('recurrence', 'CPA', (113, 123))	('high miR-30c-5p expression', 'Var', (20, 46))	('death', 'Disease', 'MESH:D003643', (221, 226))	('death', 'Disease', (221, 226))
520915	33396321	Among 118 patients who received chemo/chemoradiation therapy (93% and 84% received 5FU and platinum, respectively), those in both treatment groups with high expression of miR-30c-5p had a reduced risk of mortality.	('miR-30c-5p', 'Chemical', '-', (171, 181))	('5FU', 'Chemical', 'MESH:D005472', (83, 86))	('mortality', 'Disease', 'MESH:D003643', (204, 213))	('mortality', 'Disease', (204, 213))	('platinum', 'Chemical', 'MESH:D010984', (91, 99))	('men', 'Species', '9606', (135, 138))	('miR-30c-5p', 'Var', (171, 181))	('patients', 'Species', '9606', (10, 18))	('reduced', 'NegReg', (188, 195))
520916	33396321	In the platinum group, miR-26a-5p was significantly related to increased risk of death (HR = 5.78; 95% CI = 1.59-21.06, p = 0.008) and recurrence (HR = 7.76; 95% CI = 2.30-26.18, p = 0.001), and miR-142-3p was associated with an increased risk of recurrence (HR = 2.67; 95% CI = 1.09-6.56, p = 0.032).	('death', 'Disease', 'MESH:D003643', (81, 86))	('platinum', 'Chemical', 'MESH:D010984', (7, 15))	('death', 'Disease', (81, 86))	('miR-26a-5p', 'Var', (23, 33))	('miR-26a-5p', 'Chemical', '-', (23, 33))	('miR-142-3p', 'Var', (195, 205))	('miR-142-3p', 'Chemical', '-', (195, 205))	('recurrence', 'CPA', (135, 145))
520917	33396321	By contrast, in the 5FU group, miR-127-3p and miR-486-5p were significantly associated with both survival and recurrence (it is unclear whether high or low expression was important).	('miR-486-5p', 'Var', (46, 56))	('miR-127-3p', 'Gene', '100302165', (31, 41))	('associated', 'Reg', (76, 86))	('survival', 'CPA', (97, 105))	('5FU', 'Chemical', 'MESH:D005472', (20, 23))	('recurrence', 'CPA', (110, 120))	('miR-127-3p', 'Gene', (31, 41))
520922	33396321	This suggests that miRNAs affect the survival rate of those with EAC and may be related to the presence or absence of H. pylori infection.	('infection', 'Disease', (128, 137))	('miRNAs', 'Var', (19, 25))	('affect', 'Reg', (26, 32))	('EAC', 'Phenotype', 'HP:0011459', (65, 68))	('H. pylori infection', 'Phenotype', 'HP:0005202', (118, 137))	('survival rate', 'CPA', (37, 50))	('infection', 'Disease', 'MESH:D007239', (128, 137))	('H. pylori', 'Species', '210', (118, 127))	('EAC', 'Disease', (65, 68))
520926	33396321	MiR-15a-5p, -130-3p, and -451a are also up-regulated in EAC, whereas miR-143 is down-regulated.	('EAC', 'Disease', (56, 59))	('miR-143', 'Gene', (69, 76))	('up-regulated', 'PosReg', (40, 52))	('miR-143', 'Gene', '406935', (69, 76))	('MiR-15a-5p', 'Chemical', '-', (0, 10))	('EAC', 'Phenotype', 'HP:0011459', (56, 59))	('-3p', 'Chemical', '-', (16, 19))	('MiR-15a-5p', 'Var', (0, 10))
520927	33396321	MiR-15a-5p is involved in colon cancer, cervical cancer, and cervical cell cancer, and the main function of miR-130a-3p is to inhibit tumor progression.	('cervical cell cancer', 'Disease', (61, 81))	('cervical cancer', 'Disease', 'MESH:D002583', (40, 55))	('cervical cell cancer', 'Disease', 'MESH:D002583', (61, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cervical cancer', 'Disease', (40, 55))	('involved', 'Reg', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('colon cancer', 'Disease', 'MESH:D015179', (26, 38))	('inhibit', 'NegReg', (126, 133))	('colon cancer', 'Disease', (26, 38))	('MiR-15a-5p', 'Chemical', '-', (0, 10))	('miR-130a-3p', 'Chemical', '-', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('miR-130a-3p', 'Var', (108, 119))
520928	33396321	MiR-143-3p and miR-451a are tumor suppressors that correlate with non-small cell lung cancer (NSCLC) and colorectal cancer.	('tumor', 'Disease', (28, 33))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('miR-451a', 'Gene', '574411', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('NSCLC', 'Disease', (94, 99))	('MiR-143-3p', 'Var', (0, 10))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (66, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('miR-451a', 'Gene', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (81, 92))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('-3p', 'Chemical', '-', (7, 10))	('colorectal cancer', 'Disease', (105, 122))
520929	33396321	MiR-194-5p inhibits cell migration and invasion during gastric cancer progression by down-regulating FoxM1.	('FoxM1', 'Gene', (101, 106))	('gastric cancer', 'Disease', (55, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('MiR-194-5p', 'Chemical', '-', (0, 10))	('MiR-194-5p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('inhibits', 'NegReg', (11, 19))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('down-regulating', 'NegReg', (85, 100))	('FoxM1', 'Gene', '2305', (101, 106))
520936	33396321	Many miRNAs are associated with EAC diagnosis, among which miR-21-5p, -25-3p, and -93-5p are mentioned in more than one paper.	('men', 'Species', '9606', (93, 96))	('-3p', 'Chemical', '-', (73, 76))	('miR-21-5p', 'Var', (59, 68))	('associated', 'Reg', (16, 26))	('EAC diagnosis', 'Disease', (32, 45))	('EAC', 'Phenotype', 'HP:0011459', (32, 35))
520938	33396321	Numerous studies show that miR-21-5p promotes carcinogenesis and tumor progression by targeting genes encoding PDCD4, PTEN, BTG2, FasL, IGFBP3, TGF-beta1, FBXO11, and TIMP3.	('carcinogenesis', 'Disease', (46, 60))	('PTEN', 'Gene', (118, 122))	('promotes', 'PosReg', (37, 45))	('BTG2', 'Gene', '7832', (124, 128))	('FasL', 'Gene', '356', (130, 134))	('FasL', 'Gene', (130, 134))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('TGF-beta1', 'Gene', (144, 153))	('tumor', 'Disease', (65, 70))	('IGFBP3', 'Gene', '3486', (136, 142))	('PTEN', 'Gene', '5728', (118, 122))	('TIMP3', 'Gene', '7078', (167, 172))	('TIMP3', 'Gene', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('PDCD4', 'Gene', (111, 116))	('TGF-beta1', 'Gene', '7040', (144, 153))	('FBXO11', 'Gene', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('PDCD4', 'Gene', '27250', (111, 116))	('targeting', 'Reg', (86, 95))	('miR-21-5p', 'Var', (27, 36))	('IGFBP3', 'Gene', (136, 142))	('FBXO11', 'Gene', '80204', (155, 161))	('BTG2', 'Gene', (124, 128))
520939	33396321	With respect to EAC, miR-21-5p upregulation promotes metastasis of EAC by regulating cancer cell apoptosis; it is also an independent prognostic biomarker for disease-specific survival.	('regulating', 'Reg', (74, 84))	('EAC', 'Disease', (67, 70))	('upregulation promotes', 'PosReg', (31, 52))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('metastasis', 'CPA', (53, 63))	('cancer', 'Disease', (85, 91))	('miR-21-5p', 'Var', (21, 30))	('EAC', 'Phenotype', 'HP:0011459', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('EAC', 'Phenotype', 'HP:0011459', (16, 19))
520940	33396321	More than two papers report upregulation of miR-25-3p and miR-93-5p.	('miR-93-5p', 'Gene', '100126325', (58, 67))	('miR-93-5p', 'Gene', (58, 67))	('miR-25-3p', 'Var', (44, 53))	('upregulation', 'PosReg', (28, 40))
520942	33396321	Mir-93-5p was identified by studies examining EAC tissue miRNA; the combination of miR-25/miR-93 establishes an immunosuppressive microenvironment in breast cancer by inactivating the cGAS pathway, and it also reported to have the promotion function on cervical cancer by targeting THB2/Matrix metalloproteinases (MMPS) pathway MiR-15a-5p is both up-regulated and down-regulated in cancer serum; some reports suggest that it acts as a tumor suppressor, whereas some suggest that it acts as a tumor promoter.	('tumor', 'Phenotype', 'HP:0002664', (492, 497))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('miR-93', 'Gene', '407051', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('inactivating', 'NegReg', (167, 179))	('tumor', 'Disease', 'MESH:D009369', (435, 440))	('Mir-93', 'Gene', '407051', (0, 6))	('EAC', 'Phenotype', 'HP:0011459', (46, 49))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('cancer', 'Disease', (382, 388))	('cervical cancer', 'Disease', (253, 268))	('breast cancer', 'Disease', (150, 163))	('cervical cancer', 'Disease', 'MESH:D002583', (253, 268))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('miR-25', 'Gene', '407014', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (435, 440))	('cancer', 'Disease', (262, 268))	('men', 'Species', '9606', (142, 145))	('tumor', 'Disease', (492, 497))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('MiR-15a-5p', 'Var', (328, 338))	('cancer', 'Disease', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (492, 497))	('Mir-93', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('MiR-15a-5p', 'Chemical', '-', (328, 338))	('miR-93', 'Gene', (90, 96))	('miR-25', 'Gene', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('cGAS pathway', 'Pathway', (184, 196))	('tumor', 'Disease', (435, 440))
520944	33396321	MiR-223-5p inhibits tumor progression, whereas miR-130a-3p expression increases as the tumor stage progresses, suggesting that it promotes tumor growth (Table 4).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('promotes', 'PosReg', (130, 138))	('miR-130a-3p', 'Chemical', '-', (47, 58))	('inhibits', 'NegReg', (11, 19))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('expression', 'MPA', (59, 69))	('miR-130a-3p', 'Var', (47, 58))	('MiR-223', 'Gene', '407008', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('MiR-223', 'Gene', (0, 7))	('tumor', 'Disease', (20, 25))
520945	33396321	The roles of miR-21-5p, -25-3p, and -93-5p in cancer have been reported in multiple papers.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('-3p', 'Chemical', '-', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('miR-21-5p', 'Var', (13, 22))
520947	33396321	Two papers reported that serum levels of miR-331-3p, -30c-5p, 142-3p, 127-3p, 486-5p, and -26a-5p correlate with recurrence of EAC.	('miR-331-3p', 'Var', (41, 51))	('EAC', 'Phenotype', 'HP:0011459', (127, 130))	('-3p', 'Chemical', '-', (65, 68))	('486-5p', 'Var', (78, 84))	('127-3p', 'Var', (70, 76))	('-3p', 'Chemical', '-', (48, 51))	('-3p', 'Chemical', '-', (73, 76))	('EAC', 'Disease', (127, 130))	('142-3p', 'Var', (62, 68))	('miR-331-3p', 'Chemical', '-', (41, 51))
520948	33396321	identified miR-652-5p, -7-2-3p, -3925-3p, and -219-3p as being prognostic for recurrence in patients with stage II/III EAC.	('-3p', 'Chemical', '-', (37, 40))	('stage II/III EAC', 'Disease', (106, 122))	('EAC', 'Phenotype', 'HP:0011459', (119, 122))	('-3p', 'Chemical', '-', (27, 30))	('patients', 'Species', '9606', (92, 100))	('miR-652-5p', 'Var', (11, 21))	('-3p', 'Chemical', '-', (50, 53))
520949	33396321	MiR-142-3p suppresses growth of colorectal cancer and breast cancer cells by targeting CDK4, Beach-1, and CDC25C.	('targeting', 'Reg', (77, 86))	('colorectal cancer', 'Disease', (32, 49))	('breast cancer', 'Disease', (54, 67))	('CDC25C', 'Gene', (106, 112))	('MiR-142-3p', 'Chemical', '-', (0, 10))	('Beach-1', 'Gene', (93, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (32, 49))	('colorectal cancer', 'Disease', 'MESH:D015179', (32, 49))	('MiR-142-3p', 'Var', (0, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('growth', 'CPA', (22, 28))	('CDC25C', 'Gene', '995', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('suppresses', 'NegReg', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('CDK4', 'Gene', '1019', (87, 91))	('CDK4', 'Gene', (87, 91))
520950	33396321	MiR-331-3p is useful for diagnosis of EAC and is known to promote tumor progression.	('EAC', 'Disease', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('promote', 'PosReg', (58, 65))	('MiR-331-3p', 'Chemical', '-', (0, 10))	('EAC', 'Phenotype', 'HP:0011459', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('MiR-331-3p', 'Var', (0, 10))
520951	33396321	As we mentioned in the previous paragraph about EAC recurrence, four (miR-30c-5p, -127-3p, -486-5p, and -26a-5p) serum miRNAs are associated with OS/prognosis (Table 5).	('miR-30c-5p', 'Var', (70, 80))	('-3p', 'Chemical', '-', (86, 89))	('miR-30c-5p', 'Chemical', '-', (70, 80))	('EAC', 'Phenotype', 'HP:0011459', (48, 51))	('OS/prognosis', 'Disease', (146, 158))	('associated with', 'Reg', (130, 145))	('men', 'Species', '9606', (6, 9))
520952	33396321	Among the miRNAs associated with OS or prognosis, miR-30c-5p, -26a-5p, -127-3p, and -486-5p are also associated with recurrence.	('recurrence', 'Disease', (117, 127))	('miR-30c-5p', 'Var', (50, 60))	('associated', 'Reg', (101, 111))	('miR-30c-5p', 'Chemical', '-', (50, 60))	('-3p', 'Chemical', '-', (75, 78))
520953	33396321	Serum miR-222-3p is also associated with T classification.	('miR-222-3p', 'Chemical', '-', (6, 16))	('Serum miR-222-3p', 'Var', (0, 16))	('associated', 'Reg', (25, 35))	('T classification', 'Disease', (41, 57))
520955	33396321	MiR-331-3p regulates cancer growth by targeting HER2, overexpression of which promotes cancer cell proliferation, resistance to apoptosis, angiogenesis, and metastasis.	('cancer', 'Disease', (87, 93))	('HER2', 'Gene', '2064', (48, 52))	('promotes', 'PosReg', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('angiogenesis', 'CPA', (139, 151))	('resistance to apoptosis', 'CPA', (114, 137))	('MiR-331-3p', 'Chemical', '-', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('metastasis', 'CPA', (157, 167))	('MiR-331-3p', 'Var', (0, 10))	('HER2', 'Gene', (48, 52))
520959	33396321	MiR-486-5p stimulates cell proliferation, migration, and invasion by inhibiting PTEN expression and by activating the oncogenic PI3K/AKT pathway, although one study concluded that it works to suppress tumors; further verification is required (Table 5).	('migration', 'CPA', (42, 51))	('expression', 'MPA', (85, 95))	('MiR-486-5p', 'Var', (0, 10))	('PTEN', 'Gene', (80, 84))	('invasion', 'CPA', (57, 65))	('PTEN', 'Gene', '5728', (80, 84))	('activating', 'PosReg', (103, 113))	('AKT', 'Gene', '207', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('inhibiting', 'NegReg', (69, 79))	('tumors', 'Disease', (201, 207))	('stimulates', 'PosReg', (11, 21))	('AKT', 'Gene', (133, 136))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('MiR-486-5p', 'Chemical', '-', (0, 10))	('cell proliferation', 'CPA', (22, 40))
520971	33396321	In particular, several studies identified the same serum miRNAs (miR-21-5p, miR-25-3p, and miR93-5p) as being associated with EAC.	('EAC', 'Phenotype', 'HP:0011459', (126, 129))	('associated', 'Reg', (110, 120))	('miR93', 'Gene', (91, 96))	('miR-25-3p', 'Var', (76, 85))	('miR-21-5p', 'Var', (65, 74))	('miR93', 'Gene', '407051', (91, 96))	('EAC', 'Disease', (126, 129))
521028	28833197	The rate of anastomotic leak was also higher in the solitary LRR group (11%) compared to any patient who developed DR (3%) but the difference was not statistically significant (P = 0.09).	('anastomotic leak', 'MPA', (12, 28))	('patient', 'Species', '9606', (93, 100))	('solitary LRR', 'Var', (52, 64))
521066	28833197	While radiation dose, modality of radiation, and chemotherapy regimen were not associated with LRR in our series, such adjustments in neoadjuvant regimens to increase the incidence of complete pathologic responses may have an indirect, beneficial effect on the rate of locoregional failure.	('regional failure', 'Disease', 'MESH:D006333', (273, 289))	('adjustments', 'Var', (119, 130))	('regional failure', 'Disease', (273, 289))
521138	31114286	The procedures of the modified Sugiura technique are splenectomy, devascularization, transection, and end-to-end anastomosis of the lower esophagus above the gastroesophageal junction, devascularization of the upper 2/3 of the lesser and greater curvatures of the stomach, and pyloroplasty.	('gastroesophageal junction', 'Disease', 'MESH:D008309', (158, 183))	('gastroesophageal junction', 'Disease', (158, 183))	('pyloroplasty', 'Disease', (277, 289))	('devascularization', 'Var', (185, 202))
521149	31114286	High portal pressure can develop into life-threatening complications such as variceal bleeding, intestinal venous occlusion or ischemia, and ascites.	('variceal bleeding', 'Disease', (77, 94))	('intestinal venous occlusion', 'Disease', (96, 123))	('High', 'Var', (0, 4))	('ischemia', 'Disease', (127, 135))	('develop', 'Reg', (25, 32))	('variceal bleeding', 'Disease', 'MESH:D014648', (77, 94))	('ascites', 'Disease', (141, 148))	('venous occlusion', 'Phenotype', 'HP:0025322', (107, 123))	('ascites', 'Phenotype', 'HP:0001541', (141, 148))	('ischemia', 'Disease', 'MESH:D007511', (127, 135))	('ascites', 'Disease', 'MESH:D001201', (141, 148))	('intestinal venous occlusion', 'Disease', 'MESH:D007410', (96, 123))
521169	31114286	We performed devascularization of the upper 2/3 of the lesser and major gastric curvature (Figure 4D) and then pyloroplasty to facilitate gastric emptying (Figure 4E).	('facilitate', 'PosReg', (127, 137))	('gastric curvature', 'Disease', (72, 89))	('gastric emptying', 'Phenotype', 'HP:0002578', (138, 154))	('gastric curvature', 'Disease', 'MESH:D013121', (72, 89))	('gastric emptying', 'MPA', (138, 154))	('devascularization', 'Var', (13, 30))
521226	31114286	Devascularization procedures using modified Sugiura technique are splenectomy; devascularization, transection, and end-to-end anastomosis of lower esophagus above the gastroesophageal junction; devascularization of the upper 2/3 of the lesser and greater curvatures of the stomach; and pyloroplasty.	('gastroesophageal junction', 'Disease', 'MESH:D008309', (167, 192))	('pyloroplasty', 'Disease', (286, 298))	('devascularization', 'Var', (194, 211))	('splenectomy', 'Disease', (66, 77))	('gastroesophageal junction', 'Disease', (167, 192))
521514	27598137	Another study demonstrated that circulating miR-155 was of significant diagnostic value for esophageal cancer (ECa), as evidenced by an ROC curve area of 66%.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR-155', 'Gene', '406947', (44, 51))	('circulating', 'Var', (32, 43))	('esophageal cancer', 'Disease', (92, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))	('miR-155', 'Gene', (44, 51))
521524	27598137	An ROC curve analysis revealed that AUCs using plasma miRNA-718 is 0.715, 0.689, and 0.620 for the detection of ESCC patients, Tis-T1, or TNM 0-I, respectively.	('ESCC patients', 'Disease', (112, 125))	('0.620', 'Var', (85, 90))	('TNM', 'Gene', '10178', (138, 141))	('patients', 'Species', '9606', (117, 125))	('TNM', 'Gene', (138, 141))
521550	27598137	Similarly, other groups have identified several circulating miRNAs as non-invasive diagnostic biomarkers, such as miR-21, miR-122, miR-223, miR-15b, miR-130b, miR-101, miR-483, miR-125, miR-143, miR-215, miR-200, miR-939, and miR-595.	('miR-1', 'Gene', (159, 164))	('miR-939', 'Gene', (213, 220))	('miR-1', 'Gene', '83856', (149, 154))	('miR-122', 'Gene', '406906', (122, 129))	('miR-483', 'Gene', (168, 175))	('miR-1', 'Gene', '83856', (140, 145))	('miR-21', 'Gene', (195, 201))	('miR-939', 'Gene', '100126351', (213, 220))	('miR-21', 'Gene', '406991', (114, 120))	('miR-143', 'Gene', '406935', (186, 193))	('miR-143', 'Gene', (186, 193))	('miR-223', 'Gene', '407008', (131, 138))	('miR-15b', 'Gene', '406949', (140, 147))	('miR-1', 'Gene', (149, 154))	('miR-483', 'Gene', '619552', (168, 175))	('miR-1', 'Gene', '83856', (186, 191))	('miR-1', 'Gene', (140, 145))	('miR-15b', 'Gene', (140, 147))	('miR-122', 'Gene', (122, 129))	('miR-200', 'Var', (204, 211))	('miR-1', 'Gene', '83856', (122, 127))	('miR-1', 'Gene', (186, 191))	('miR-21', 'Gene', (114, 120))	('miR-595', 'Gene', '693180', (226, 233))	('miR-1', 'Gene', '83856', (177, 182))	('miR-1', 'Gene', (122, 127))	('miR-215', 'Gene', '406997', (195, 202))	('miR-130b', 'Gene', '406920', (149, 157))	('miR-1', 'Gene', '83856', (159, 164))	('miR-215', 'Gene', (195, 202))	('miR-130b', 'Gene', (149, 157))	('miR-21', 'Gene', '406991', (195, 201))	('miR-595', 'Gene', (226, 233))	('miR-1', 'Gene', (177, 182))	('miR-223', 'Gene', (131, 138))
521561	27598137	confirmed that seven miRNA-based biomarkers (miR-20a, miR-21, miR-24, miR-25, miR-99a, miR-185, and miR-191) had high sensitivities and specificities for distinguishing the various stages of PCa from cancer-free controls and also accurately discriminated PCa patients from CP patients.	('patients', 'Species', '9606', (276, 284))	('PCa', 'Phenotype', 'HP:0002894', (191, 194))	('miR-191', 'Gene', '406966', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('miR-99a', 'Gene', (78, 85))	('miR-191', 'Gene', (100, 107))	('miR-21', 'Gene', (54, 60))	('sensitivities', 'MPA', (118, 131))	('patients', 'Species', '9606', (259, 267))	('miR-185', 'Gene', '406961', (87, 94))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('miR-25', 'Gene', (70, 76))	('miR-99a', 'Gene', '407055', (78, 85))	('PCa', 'Disease', (255, 258))	('miR-24', 'Var', (62, 68))	('CP', 'Disease', 'MESH:C566991', (273, 275))	('PCa', 'Disease', (191, 194))	('discriminated', 'Reg', (241, 254))	('miR-20a', 'Gene', (45, 52))	('miR-25', 'Gene', '407014', (70, 76))	('miR-20a', 'Gene', '406982', (45, 52))	('miR-21', 'Gene', '406991', (54, 60))	('miR-185', 'Gene', (87, 94))	('PCa', 'Phenotype', 'HP:0002894', (255, 258))	('cancer', 'Disease', (200, 206))	('CP', 'Phenotype', 'HP:0006280', (273, 275))
521576	27598137	We previously demonstrated that the postoperative cause-specific survival rate was significantly poorer in GC patients with high plasma miR-21 levels than in those with low levels.	('GC', 'Phenotype', 'HP:0012126', (107, 109))	('miR-21', 'Gene', '406991', (136, 142))	('poorer', 'NegReg', (97, 103))	('high', 'Var', (124, 128))	('patients', 'Species', '9606', (110, 118))	('miR-21', 'Gene', (136, 142))
521577	27598137	Moreover, the incidence of vascular invasion was also slightly higher in GC patients with high miR-21 levels, and a multivariate analysis revealed that the presence of high miR-21 plasma levels was an independent prognostic factor.	('patients', 'Species', '9606', (76, 84))	('vascular invasion', 'CPA', (27, 44))	('miR-21', 'Gene', '406991', (173, 179))	('miR-21', 'Gene', '406991', (95, 101))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('miR-21', 'Gene', (173, 179))	('high', 'Var', (90, 94))	('higher', 'PosReg', (63, 69))	('miR-21', 'Gene', (95, 101))
521580	27598137	Circulating miR-222 was also identified as an independent prognostic marker in the multivariate analysis.	('Circulating', 'Var', (0, 11))	('miR-222', 'Gene', '407007', (12, 19))	('miR-222', 'Gene', (12, 19))
521586	27598137	demonstrated that plasma miR-141 is a novel biomarker that complements carcinoembryonic antigen (CEA) in the detection of colon cancer with distant metastasis, and that high expression levels of miR-141 in plasma were associated with a poor prognosis.	('CEA', 'Gene', '1048', (97, 100))	('high', 'Var', (169, 173))	('miR-141', 'Gene', '406933', (195, 202))	('miR-141', 'Gene', '406933', (25, 32))	('carcinoembryonic antigen', 'Gene', '1048', (71, 95))	('CEA', 'Gene', (97, 100))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('carcinoembryonic antigen', 'Gene', (71, 95))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('miR-141', 'Gene', (195, 202))	('associated', 'Reg', (218, 228))	('miR-141', 'Gene', (25, 32))	('colon cancer', 'Disease', (122, 134))
521675	27194945	Conversely, knock-down of Cab45-G reduced the expression of the above MMPs.	('reduced', 'NegReg', (34, 41))	('Cab45', 'Gene', (26, 31))	('MMPs', 'Gene', '4313;4316;4318;4322', (70, 74))	('Cab45', 'Gene', '51150', (26, 31))	('MMPs', 'Gene', (70, 74))	('expression', 'MPA', (46, 56))	('knock-down', 'Var', (12, 22))
521713	27194945	HEK-293T or cancer cells were cultured in the lower chamber and transfected with Cab45-G overexpression or silencing vectors.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('silencing', 'Var', (107, 116))	('cancer', 'Disease', (12, 18))	('Cab45', 'Gene', '51150', (81, 86))	('Cab45', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('HEK-293T', 'CellLine', 'CVCL:0063', (0, 8))
521733	27194945	Quantitative real time PCR (qRT-PCR) assay showed that Cab45-G exhibited significantly higher level in B16F10 and MDA-MB-231 than in B16F0 and MCF-7 (Fig.	('Cab45', 'Gene', (55, 60))	('B16F10', 'CellLine', 'CVCL:0159', (103, 109))	('MCF-7', 'CellLine', 'CVCL:0031', (143, 148))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (114, 124))	('level', 'MPA', (94, 99))	('B16F10', 'Var', (103, 109))	('Cab45', 'Gene', '51150', (55, 60))	('higher', 'PosReg', (87, 93))
521737	27194945	B16F0 cells transfected with SP-EGFP (control) accumulated together with more cell-cell contacts, while cells transfected with SP-EGFP-Cab45-G were well scattered in a fibroblast-like morphology throughout the space (Fig.	('Cab45', 'Gene', '51150', (135, 140))	('SP-EGFP', 'Var', (29, 36))	('SP', 'Chemical', 'MESH:D021382', (127, 129))	('SP', 'Chemical', 'MESH:D021382', (29, 31))	('Cab45', 'Gene', (135, 140))	('cell-cell contacts', 'CPA', (78, 96))
521740	27194945	Conversely, knock-down of Cab45-G inhibited the EMT process (Fig.	('Cab45', 'Gene', (26, 31))	('Cab45', 'Gene', '51150', (26, 31))	('inhibited', 'NegReg', (34, 43))	('EMT process', 'CPA', (48, 59))	('knock-down', 'Var', (12, 22))
521744	27194945	HEK-293T cells transfected with SP-EGFP (control) or SP-EGFP-Cab45-G were then plated in the lower chamber and HeLa cells were plated in the upper chamber.	('SP-EGFP', 'Var', (32, 39))	('Cab45', 'Gene', '51150', (61, 66))	('Cab45', 'Gene', (61, 66))	('HEK-293T cells', 'CellLine', 'CVCL:0063', (0, 14))	('SP', 'Chemical', 'MESH:D021382', (53, 55))	('SP', 'Chemical', 'MESH:D021382', (32, 34))	('HeLa', 'CellLine', 'CVCL:0030', (111, 115))
521751	27194945	We then set out to knock down the endogenous expression of Cab45-G to observe its effect on cell migration.	('Cab45', 'Gene', '51150', (59, 64))	('knock down', 'Var', (19, 29))	('Cab45', 'Gene', (59, 64))	('cell migration', 'CPA', (92, 106))
521757	27194945	Moreover, silencing of Cab45-G in Hela and TE-1 cells in the lower chamber also suppressed the migration of co-cultured Hela (Fig.	('Hela', 'CellLine', 'CVCL:0030', (34, 38))	('Cab45', 'Gene', '51150', (23, 28))	('Cab45', 'Gene', (23, 28))	('Hela', 'CellLine', 'CVCL:0030', (120, 124))	('migration', 'CPA', (95, 104))	('suppressed', 'NegReg', (80, 90))	('TE-1', 'CellLine', 'CVCL:1759', (43, 47))	('silencing', 'Var', (10, 19))
521764	27194945	Conversely, knock-down of Cab45-G significantly downregulated the expression of MMP-2 and MMP-7, but not other MMPs (Fig.	('MMP-2', 'Gene', '4313', (80, 85))	('MMP-7', 'Gene', '4316', (90, 95))	('MMPs', 'Gene', '4313;4316;4318;4322', (111, 115))	('Cab45', 'Gene', (26, 31))	('Cab45', 'Gene', '51150', (26, 31))	('downregulated', 'NegReg', (48, 61))	('expression', 'MPA', (66, 76))	('MMP-2', 'Gene', (80, 85))	('MMP-7', 'Gene', (90, 95))	('knock-down', 'Var', (12, 22))	('MMPs', 'Gene', (111, 115))
521796	27194945	The role of Cab45-G in influencing the secretion of extracellular matrix proteins is conceivable as dysregulation of Cab45-G disrupts protein sorting at trans-Golgi network.	('protein sorting at trans-Golgi network', 'MPA', (134, 172))	('Cab45', 'Gene', '51150', (12, 17))	('Cab45', 'Gene', (12, 17))	('secretion of extracellular matrix proteins', 'MPA', (39, 81))	('dysregulation', 'Var', (100, 113))	('Cab45', 'Gene', (117, 122))	('Cab45', 'Gene', '51150', (117, 122))	('disrupts', 'NegReg', (125, 133))	('influencing', 'Reg', (23, 34))
521798	27194945	Recent studies have suggested that the ERK signaling is a promising molecular target to control aberrant MMP-2 and MMP-7 expression, and consequent invasion in the EMT-induced non-small cell lung cancer (NSCLC) cells.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('non-small cell lung cancer', 'Disease', (176, 202))	('NSCLC', 'Phenotype', 'HP:0030358', (204, 209))	('ERK', 'Gene', '5594', (39, 42))	('aberrant', 'Var', (96, 104))	('MMP-2', 'Gene', '4313', (105, 110))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (176, 202))	('NSCLC', 'Disease', (204, 209))	('ERK', 'Gene', (39, 42))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (176, 202))	('NSCLC', 'Disease', 'MESH:D002289', (204, 209))	('MMP-7', 'Gene', (115, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('MMP-2', 'Gene', (105, 110))	('MMP-7', 'Gene', '4316', (115, 120))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (180, 202))
521893	25582499	In hepatocellular carcinomas, SALL4 expression is associated with an unfavorable prognosis and overexpression of proliferative-and metastasis-related genes.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (3, 28))	('hepatocellular carcinomas', 'Disease', (3, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('expression', 'Var', (36, 46))	('overexpression', 'PosReg', (95, 109))	('SALL4', 'Gene', (30, 35))	('associated', 'Reg', (50, 60))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (3, 28))
521928	25337539	Our findings were inconsistent with those of previously published epidemiological studies and a meta-analysis of epidemiological studies, which had reported that people with the highest levels of antioxidant intake such as vitamin C or beta-carotene had an about 50% lower risk compared to those with lower levels of intake.	('vitamin C', 'Chemical', 'MESH:D001205', (223, 232))	('beta-carotene', 'Chemical', 'MESH:D019207', (236, 249))	('people', 'Species', '9606', (162, 168))	('beta-carotene', 'Var', (236, 249))	('lower', 'NegReg', (267, 272))
522015	33490290	The miRNA-target network was associated with (TCCGTCC) MIR-184, (TGCACGA) MIR-517, (GTGGTGA) MIR-197, (CCAGGGG) MIR-331, and (CAGCAGG) MIR-370.	('MIR-331', 'Gene', '442903', (112, 119))	('associated', 'Interaction', (29, 39))	('MIR-197', 'Gene', '406974', (93, 100))	('MIR-331', 'Gene', (112, 119))	('TGCACGA', 'Gene', (65, 72))	('MIR-184', 'Gene', (55, 62))	('MIR-370', 'Gene', (135, 142))	('MIR-184', 'Gene', '406960', (55, 62))	('MIR-370', 'Gene', '442915', (135, 142))	('MIR-197', 'Gene', (93, 100))	('MIR-517', 'Var', (74, 81))
522035	32231765	Genetic modifications can alter the normal control of cell growth and survival, therefore, result in cancer development.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('alter', 'Reg', (26, 31))	('result in', 'Reg', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Genetic modifications', 'Var', (0, 21))
522040	32231765	Different factors such as dental calculus, overhang restorations, tooth position, smoking, nutrition, diabetes mellitus, blood dyscrasia, age and genetic alterations have been considered as predisposing factors of periodontal disease.	('blood dyscrasia', 'Disease', (121, 136))	('periodontal disease', 'Phenotype', 'HP:0000704', (214, 233))	('genetic alterations', 'Var', (146, 165))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (102, 119))	('diabetes mellitus', 'Disease', (102, 119))	('dental calculus', 'Phenotype', 'HP:0000670', (26, 41))	('periodontal disease', 'Disease', (214, 233))	('nutrition', 'Disease', (91, 100))	('dental calculus', 'Disease', (26, 41))	('blood dyscrasia', 'Disease', 'MESH:D006402', (121, 136))	('diabetes mellitus', 'Disease', 'MESH:D003920', (102, 119))
522090	32231765	Some of underlying mechanisms of carcinogenesis in HCV associated liver cancer include increased hepatocyte proliferation, induction of immune and inflammation responses and genomic mutations.	('increased', 'PosReg', (87, 96))	('HCV', 'Species', '11103', (51, 54))	('hepatocyte proliferation', 'CPA', (97, 121))	('carcinogenesis', 'Disease', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('liver cancer', 'Phenotype', 'HP:0002896', (66, 78))	('liver cancer', 'Disease', 'MESH:D006528', (66, 78))	('genomic mutations', 'Var', (174, 191))	('inflammation', 'Disease', 'MESH:D007249', (147, 159))	('liver cancer', 'Disease', (66, 78))	('carcinogenesis', 'Disease', 'MESH:D063646', (33, 47))	('inflammation', 'Disease', (147, 159))
522091	32231765	In the oral cavity, traumatization of oral epithelium during mastication results in HPV infection of oral epithelial basal cells.	('infection of oral', 'Phenotype', 'HP:0100649', (88, 105))	('results in', 'Reg', (73, 83))	('traumatization', 'Var', (20, 34))	('HPV infection', 'Disease', 'MESH:D030361', (84, 97))	('HPV infection', 'Disease', (84, 97))
522094	32231765	In addition, HPV interrupts the initial phases of the immune response, including the expression of TLRs and cytokines which have great impacts on HPV recognition.	('expression', 'MPA', (85, 95))	('HPV', 'Species', '10566', (146, 149))	('interrupts', 'NegReg', (17, 27))	('TLRs', 'Gene', (99, 103))	('HPV', 'Species', '10566', (13, 16))	('HPV', 'Var', (13, 16))
522096	32231765	Besides, the presence of HPV E6/E7 mRNA in periodontium may support the hypothesis that periodontal tissues function as a reservoir for latent HPV infection.	('HPV', 'Species', '10566', (143, 146))	('HPV', 'Species', '10566', (25, 28))	('HPV infection', 'Disease', (143, 156))	('HPV', 'Gene', (25, 28))	('E6/E7 mRNA', 'Var', (29, 39))	('HPV infection', 'Disease', 'MESH:D030361', (143, 156))
522113	32231765	P. gingivalis also activates nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) and MAPK pathways in human oral epithelial cells (Table 2).	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('activates', 'PosReg', (19, 28))	('MAPK pathways', 'Pathway', (107, 120))	('human', 'Species', '9606', (124, 129))	('NFkappaB', 'Gene', (93, 101))	('NFkappaB', 'Gene', '4790', (93, 101))	('nuclear factor kappa-light-chain-enhancer', 'Pathway', (29, 70))
522114	32231765	It is hypothesized that chronic infection by P. gingivalis can establish a microenvironment by targeting CD274 and programmed cell death 1 ligand 2 (PDCD1LG2) via the activation of STAT1.	('CD274', 'Gene', '29126', (105, 110))	('chronic infection', 'Disease', 'MESH:D006505', (24, 41))	('chronic infection', 'Phenotype', 'HP:0031035', (24, 41))	('STAT1', 'Gene', '6772', (181, 186))	('CD274', 'Gene', (105, 110))	('chronic infection', 'Disease', (24, 41))	('P. gingivalis', 'Var', (45, 58))	('P. gingivalis', 'Species', '837', (45, 58))	('PDCD1LG2', 'Gene', '80380', (149, 157))	('PDCD1LG2', 'Gene', (149, 157))	('targeting', 'NegReg', (95, 104))	('STAT1', 'Gene', (181, 186))
522115	32231765	Moreover, P. gingivalis promotes the secretion of cytokines such as IL-6 which in turn activates tumorigenic transcription factors such as STAT1.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('P. gingivalis', 'Var', (10, 23))	('IL-6', 'Gene', (68, 72))	('secretion of cytokines', 'MPA', (37, 59))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('P. gingivalis', 'Species', '837', (10, 23))	('tumor', 'Disease', (97, 102))	('STAT1', 'Gene', (139, 144))	('IL-6', 'Gene', '3569', (68, 72))	('promotes', 'PosReg', (24, 32))	('STAT1', 'Gene', '6772', (139, 144))	('activates', 'PosReg', (87, 96))
522116	32231765	Additionally, P. gingivalis induces the expression of the proenzyme matrix metalloproteinase 9 (proMMP9) and subsequently active form of MMP-9.	('expression', 'MPA', (40, 50))	('MMP-9', 'Gene', '4318', (137, 142))	('MMP-9', 'Gene', (137, 142))	('P. gingivalis', 'Var', (14, 27))	('induces', 'PosReg', (28, 35))	('P. gingivalis', 'Species', '837', (14, 27))	('MMP9', 'Gene', '4318', (99, 103))	('MMP9', 'Gene', (99, 103))
522119	32231765	Besides, the presence of P. gingivalis is related to high serum level of C-reactive protein (CRP).	('C-reactive protein', 'Gene', '1401', (73, 91))	('C-reactive protein', 'Gene', (73, 91))	('P. gingivalis', 'Species', '837', (25, 38))	('P. gingivalis', 'Var', (25, 38))	('high serum level of C-reactive', 'Phenotype', 'HP:0011227', (53, 83))
522122	32231765	Table 3 summarizes the molecular mechanisms by which P. gingivalis may promote periodontitis and oral cancer.	('periodontitis and oral cancer', 'Disease', 'MESH:D009062', (79, 108))	('promote', 'PosReg', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('periodontitis', 'Phenotype', 'HP:0000704', (79, 92))	('P. gingivalis', 'Species', '837', (53, 66))	('P. gingivalis', 'Var', (53, 66))
522141	32231765	P. gingivalis inhibits the synthesis of E-selectin, IL-8 (also known as CXCL8) and ICAM-1 to decrease neutrophil recruitment.	('ICAM-1', 'Gene', '3383', (83, 89))	('inhibits', 'NegReg', (14, 22))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('CXCL8', 'Gene', '3576', (72, 77))	('neutrophil recruitment', 'CPA', (102, 124))	('CXCL8', 'Gene', (72, 77))	('ICAM-1', 'Gene', (83, 89))	('synthesis', 'MPA', (27, 36))	('E-selectin', 'Gene', (40, 50))	('IL-8', 'Gene', '3576', (52, 56))	('decrease', 'NegReg', (93, 101))	('E-selectin', 'Gene', '6401', (40, 50))	('IL-8', 'Gene', (52, 56))
522150	32231765	A previously published study has shown the increased number of CD86+ B cells in the tumor microenvironment of head and neck SCC compared to normal mucosa.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CD86+ B cells', 'Var', (63, 76))	('tumor microenvironment of head and neck', 'Phenotype', 'HP:0012288', (84, 123))	('SCC', 'Gene', (124, 127))	('tumor', 'Disease', (84, 89))	('SCC', 'Gene', '6317', (124, 127))	('CD86', 'Species', '1151276', (63, 67))
522172	32231765	For example, P. gingivalis promotes its own survival and invasion of periodontal tissues by employing the autophagy processes.	('survival', 'CPA', (44, 52))	('invasion', 'CPA', (57, 65))	('P. gingivalis', 'Var', (13, 26))	('autophagy processes', 'CPA', (106, 125))	('P. gingivalis', 'Species', '837', (13, 26))	('promotes', 'PosReg', (27, 35))
522180	32231765	Severe periodontitis have been recorded in Down syndrome (trisomy 21), Chediak-Higashi syndrome and Papillon-Lefevre syndrome.	('Chediak-Higashi syndrome', 'Disease', 'MESH:D002609', (71, 95))	('Papillon-Lefevre syndrome', 'Disease', (100, 125))	('Chediak-Higashi syndrome', 'Disease', (71, 95))	('Severe periodontitis', 'Phenotype', 'HP:0000166', (0, 20))	('periodontitis', 'Disease', 'MESH:D010518', (7, 20))	('Down syndrome', 'Disease', (43, 56))	('periodontitis', 'Phenotype', 'HP:0000704', (7, 20))	('Papillon-Lefevre syndrome', 'Disease', 'MESH:D010214', (100, 125))	('periodontitis', 'Disease', (7, 20))	('trisomy 21', 'Var', (58, 68))	('Severe', 'Disease', (0, 6))
522182	32231765	A previously published systematic review showed that polymorphisms in the IL-1alpha, IL-1beta, IL-6, IL-10, MMP-3, and MMP-9 genes are significantly associated with an increased risk of development of periodontitis.	('MMP-3', 'Gene', (108, 113))	('MMP-9', 'Gene', '4318', (119, 124))	('IL-1beta', 'Gene', '3552', (85, 93))	('IL-6', 'Gene', (95, 99))	('IL-10', 'Gene', '3586', (101, 106))	('IL-1alpha', 'Gene', (74, 83))	('IL-1beta', 'Gene', (85, 93))	('associated with', 'Reg', (149, 164))	('periodontitis', 'Phenotype', 'HP:0000704', (201, 214))	('MMP-9', 'Gene', (119, 124))	('IL-6', 'Gene', '3569', (95, 99))	('periodontitis', 'Disease', 'MESH:D010518', (201, 214))	('IL-1alpha', 'Gene', '3552', (74, 83))	('periodontitis', 'Disease', (201, 214))	('IL-10', 'Gene', (101, 106))	('polymorphisms', 'Var', (53, 66))	('MMP-3', 'Gene', '4314', (108, 113))
522187	32231765	Another published paper has revealed that the earliest cytogenetic alterations in both nonsmokers and smokers are loss of heterozygosity (LOH) and loss of tumor suppressor genes in the oral epithelium.	('loss of tumor', 'Disease', 'MESH:D009369', (147, 160))	('loss of tumor', 'Disease', (147, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('loss', 'Var', (114, 118))
522195	32231765	This finding indicated that miRNA- 146 inhibits pro-inflammatory cytokine secretion via regulating IL-1 receptor-associated kinase 1(IRAK1), IL-1beta, IL-6 and TNF-alpha production.	('IL-1', 'Gene', (141, 145))	('miRNA- 146', 'Chemical', '-', (28, 38))	('TNF-alpha', 'Gene', '7124', (160, 169))	('IL-1', 'Gene', '3552', (141, 145))	('IRAK1', 'Gene', (133, 138))	('TNF-alpha', 'Gene', (160, 169))	('IRAK1', 'Gene', '3654', (133, 138))	('IL-6', 'Gene', (151, 155))	('pro-inflammatory cytokine secretion', 'MPA', (48, 83))	('IL-1beta', 'Gene', '3552', (141, 149))	('miRNA-', 'Var', (28, 34))	('IL-1', 'Gene', '3552', (99, 103))	('inhibits', 'NegReg', (39, 47))	('IL-6', 'Gene', '3569', (151, 155))	('IL-1', 'Gene', (99, 103))	('IL-1beta', 'Gene', (141, 149))
522203	32231765	IL-8 was a target of miR-155 and CXCL2, C-C motif chemokine 3 (CCL3) and IL-6 were the main targets of miR-223.	('C-C motif chemokine 3', 'Gene', (40, 61))	('CCL3', 'Gene', (63, 67))	('miR-223', 'Var', (103, 110))	('CXCL2', 'Gene', '2920', (33, 38))	('miR-155', 'Gene', '387173', (21, 28))	('miR-155', 'Gene', (21, 28))	('IL-8', 'Gene', '3576', (0, 4))	('CCL3', 'Gene', '6348', (63, 67))	('IL-8', 'Gene', (0, 4))	('C-C motif chemokine 3', 'Gene', '6348', (40, 61))	('IL-6', 'Gene', (73, 77))	('CXCL2', 'Gene', (33, 38))	('IL-6', 'Gene', '3569', (73, 77))
522209	32231765	Decreased expression level of miR-100 and miR-125b elevates oral cancer cells proliferation.	('oral cancer', 'Disease', 'MESH:D009062', (60, 71))	('expression level', 'MPA', (10, 26))	('miR-100', 'Gene', '406892', (30, 37))	('elevates', 'PosReg', (51, 59))	('oral cancer', 'Disease', (60, 71))	('Decreased', 'NegReg', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('miR-125b', 'Var', (42, 50))	('miR-100', 'Gene', (30, 37))	('miR-125b', 'Chemical', '-', (42, 50))
522226	32231765	Cisplatin is associated with an increased risk for acute and late toxicities.	('acute', 'CPA', (51, 56))	('toxicities', 'Disease', (66, 76))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('toxicities', 'Disease', 'MESH:D064420', (66, 76))	('Cisplatin', 'Var', (0, 9))
522237	32231765	P. gingivalis is the main cause of periodontitis.	('cause', 'Reg', (26, 31))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('periodontitis', 'Disease', 'MESH:D010518', (35, 48))	('periodontitis', 'Phenotype', 'HP:0000704', (35, 48))	('periodontitis', 'Disease', (35, 48))
522240	32231765	Also, genetic alterations have been considered to be involved in periodontitis and oral cancer.	('periodontitis and oral cancer', 'Disease', 'MESH:D009062', (65, 94))	('involved', 'Reg', (53, 61))	('periodontitis', 'Phenotype', 'HP:0000704', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('genetic alterations', 'Var', (6, 25))
522281	31772719	Cirrhotic patients who underwent EGD for an indication of screening or surveillance of varices were identified using the endoscopy electronic health record system, ProVation , and the ICD-9-CM diagnosis codes 571.2, 571.5, or 571.6.	('Cirrhotic', 'Disease', (0, 9))	('571.5', 'Var', (216, 221))	('571.2', 'Var', (209, 214))	('patients', 'Species', '9606', (10, 18))	('571.6', 'Var', (226, 231))	('Cirrhotic', 'Disease', 'MESH:D005355', (0, 9))
490423	31098822	The 5-year survival rate of patients with pStage IV in UICC classification (including patients with supraclavicular node metastasis) was better than that of patients with pStage IVb in JES classification (not including patients with supraclavicular node metastasis).	('better', 'PosReg', (137, 143))	('supraclavicular node metastasis', 'Disease', 'MESH:D009362', (100, 131))	('supraclavicular node metastasis', 'Disease', (233, 264))	('survival', 'CPA', (11, 19))	('patients', 'Species', '9606', (157, 165))	('pStage', 'Var', (42, 48))	('supraclavicular node metastasis', 'Disease', (100, 131))	('patients', 'Species', '9606', (219, 227))	('patients', 'Species', '9606', (28, 36))	('supraclavicular node metastasis', 'Disease', 'MESH:D009362', (233, 264))	('patients', 'Species', '9606', (86, 94))
522357	22645717	Several studies have evaluated inhibitors of EGFR in combination with radiotherapy, and a strong biologic rationale exists for the use of this combination in certain cancer types, including head and neck squamous cell carcinoma, non-small cell lung cancer, glioblastoma, esophageal cancer, and pancreatic cancer.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (257, 269))	('cancer', 'Disease', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (233, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (229, 255))	('neck squamous cell carcinoma', 'Disease', (199, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('glioblastoma', 'Disease', (257, 269))	('esophageal cancer', 'Disease', 'MESH:D004938', (271, 288))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (294, 311))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (199, 227))	('glioblastoma', 'Phenotype', 'HP:0012174', (257, 269))	('inhibitors', 'Var', (31, 41))	('esophageal cancer', 'Disease', (271, 288))	('cancer', 'Disease', (166, 172))	('non-small cell lung cancer', 'Disease', (229, 255))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('pancreatic cancer', 'Disease', 'MESH:D010190', (294, 311))	('cancer', 'Disease', (282, 288))	('EGFR', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('cancer', 'Disease', (305, 311))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (190, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (229, 255))	('pancreatic cancer', 'Disease', (294, 311))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
522361	22645717	Overexpression of EGFR in tumors often correlates with poor prognosis because of its involvement in tumor progression, angiogenesis, migration, and metastasis (Yarden,).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('metastasis', 'CPA', (148, 158))	('angiogenesis', 'CPA', (119, 131))	('EGFR', 'Gene', (18, 22))	('involvement', 'Reg', (85, 96))	('migration', 'CPA', (133, 142))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('Overexpression', 'Var', (0, 14))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Disease', (26, 32))
522363	22645717	At least a third of tumors exhibit EGFR dysregulation or overexpression, although the expression of EGFR does not always correlate with response to therapeutic EGFR inhibitors (Mendelsohn,; Harari,).	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('overexpression', 'PosReg', (57, 71))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('dysregulation', 'Var', (40, 53))	('EGFR', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
522380	22645717	Erlotinib enhances the radiation response at several levels, including cell cycle arrest, apoptosis induction, accelerated cellular repopulation, and DNA damage repair.	('cellular repopulation', 'CPA', (123, 144))	('accelerated', 'PosReg', (111, 122))	('arrest', 'Disease', (82, 88))	('Erlotinib', 'Var', (0, 9))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (71, 88))	('enhances', 'PosReg', (10, 18))	('DNA damage repair', 'CPA', (150, 167))	('apoptosis', 'CPA', (90, 99))	('arrest', 'Disease', 'MESH:D006323', (82, 88))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))	('radiation response', 'CPA', (23, 41))
522385	22645717	In a second preclinical study involving three human cancer cell lines with low, moderate, and very high EGFR expression, the extent of erlotinib-induced radiosensitization was found to be proportional to the expression and autophosphorylation of EGFR (Kim et al.,).	('low', 'NegReg', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('EGFR', 'Gene', (104, 108))	('erlotinib', 'Chemical', 'MESH:D000069347', (135, 144))	('expression', 'Var', (109, 119))	('autophosphorylation', 'MPA', (223, 242))	('human', 'Species', '9606', (46, 51))	('EGFR', 'Protein', (246, 250))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
522428	22645717	Interestingly, EGFR expression does not seem to correlate with response to EGFR inhibitors, although an increased likelihood of response to EGFR inhibitors was associated with never smoking, adenocarcinoma tumor type, female gender, and acquired EGFR adenosine triphosphate-binding site mutations in an expanded access trial of gefitinib (Kim et al.,).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('adenocarcinoma tumor', 'Disease', (191, 211))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (251, 273))	('mutations', 'Var', (287, 296))	('adenocarcinoma tumor', 'Disease', 'MESH:D000230', (191, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('gefitinib', 'Chemical', 'MESH:D000077156', (328, 337))	('EGFR', 'Gene', (246, 250))
522429	22645717	A recent analysis of data from the BR.21 trial indicated that EGFR mutations and high copy number are predictive of response to erlotinib (Zhu et al.,).	('erlotinib', 'Chemical', 'MESH:D000069347', (128, 137))	('EGFR', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('response', 'MPA', (116, 124))	('high copy number', 'Var', (81, 97))
522463	22645717	In addition, mutations of the EGFR gene may be present in as many as 50-70% of EGFR-overexpressing tumors.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('EGFR', 'Gene', (30, 34))	('EGFR-overexpressing', 'Gene', (79, 98))	('man', 'Species', '9606', (61, 64))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutations', 'Var', (13, 22))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
522574	21533028	Identification of clinically significant subgroups was thought to be disrupted by the disorder of the expression profile through this aiEMT.	('expression', 'MPA', (102, 112))	('EMT', 'Gene', '16428', (136, 139))	('EMT', 'Gene', (136, 139))	('disorder', 'Var', (86, 94))
522620	21533028	Accordingly, over-expression of ZEB2 and TWIST1 in surgical samples of both normal and tumor tissues can induce EMT, resulting in over-expression of representative EMT markers VIM, FN, and COLs (Figures 2, 4, 6, S2, and S3) and membrane signal transducers IL8, CXCL4, CCL5, CXCR4, PDGFRB, and TLR2 (Figure 2).	('induce', 'PosReg', (105, 111))	('TWIST1', 'Gene', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ZEB2', 'Gene', (32, 36))	('EMT', 'Gene', '16428', (112, 115))	('TWIST1', 'Gene', '22160', (41, 47))	('tumor', 'Disease', (87, 92))	('over-expression', 'Var', (13, 28))	('EMT', 'Gene', '16428', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CXCL4', 'Gene', '56744', (261, 266))	('CXCL4', 'Gene', (261, 266))	('over-expression', 'PosReg', (130, 145))	('EMT', 'Gene', (112, 115))	('FN', 'Gene', '14268', (181, 183))	('EMT', 'Gene', (164, 167))
522624	21533028	Recently, the hypoxia-inducible factors (HIF-1A or HIF-2A) have been reported to directly regulate TWIST1 and LOXL2, which reportedly stabilized an EMT regulator, SNAI1/SNAIL, through physical interaction on the SLUG domain and Snail's lysine residues K98 and K137.	('HIF-2A', 'Gene', (51, 57))	('SLUG', 'Gene', '20583', (212, 216))	('SNAI1', 'Gene', (163, 168))	('lysine', 'Chemical', 'MESH:D008239', (236, 242))	('K137', 'Var', (260, 264))	('LOXL2', 'Gene', '94352', (110, 115))	('physical interaction', 'Interaction', (184, 204))	('SLUG', 'Gene', (212, 216))	('Snail', 'Gene', '20613', (228, 233))	('SNAIL', 'Gene', '20613', (169, 174))	('SNAIL', 'Gene', (169, 174))	('hypoxia', 'Disease', (14, 21))	('K98', 'Var', (252, 255))	('LOXL2', 'Gene', (110, 115))	('EMT', 'Gene', '16428', (148, 151))	('TWIST1', 'Gene', (99, 105))	('TWIST1', 'Gene', '22160', (99, 105))	('HIF-2A', 'Gene', '13819', (51, 57))	('HIF-1A', 'Gene', (41, 47))	('EMT', 'Gene', (148, 151))	('hypoxia', 'Disease', 'MESH:D000860', (14, 21))	('SNAI1', 'Gene', '20613', (163, 168))	('HIF-1A', 'Gene', '15251', (41, 47))	('Snail', 'Gene', (228, 233))
522655	21533028	Endogenous peroxidase activity was inhibited with 3% H2O2 in methanol for 30 min.	('methanol', 'Chemical', 'MESH:D000432', (61, 69))	('inhibited', 'NegReg', (35, 44))	('Endogenous', 'MPA', (0, 10))	('H2O2', 'Var', (53, 57))	('activity', 'MPA', (22, 30))	('H2O2', 'Chemical', 'MESH:D006861', (53, 57))
522729	18533990	On EUS, the upper tumor was graded T1N0 and the lower tumor appeared to infiltrate the muscularis propria, without evidence of lymph node involvement.	('tumor', 'Disease', (18, 23))	('muscularis propria', 'Phenotype', 'HP:0030936', (87, 105))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('upper tumor', 'Disease', 'MESH:D009369', (12, 23))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('T1N0', 'Var', (35, 39))	('upper tumor', 'Disease', (12, 23))	('tumor', 'Disease', (54, 59))	('infiltrate', 'Reg', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
522773	18533990	Ultrasound ablation induces a progressive necrosis which allows enough time for inflammation and sclerosis to develop and form an inflammatory barrier against sepsis.	('inflammation', 'Disease', 'MESH:D007249', (80, 92))	('sclerosis', 'Disease', (97, 106))	('necrosis', 'Disease', (42, 50))	('inflammation', 'Disease', (80, 92))	('necrosis', 'Disease', 'MESH:D009336', (42, 50))	('sepsis', 'Disease', (159, 165))	('sclerosis', 'Disease', 'MESH:D012598', (97, 106))	('sepsis', 'Phenotype', 'HP:0100806', (159, 165))	('sepsis', 'Disease', 'MESH:D018805', (159, 165))	('ablation', 'Var', (11, 19))
522809	33347497	These differences retain to expression profiles, mismatch repair (MMR) and p53 status.	('expression profiles', 'MPA', (28, 47))	('mismatch repair', 'Var', (49, 64))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))
522836	33347497	Diffuse, strong nuclear staining (>= 70%) or complete loss of staining were interpreted as aberrant p53 expression, indicating p53 mutation.	('p53', 'Gene', (100, 103))	('loss', 'NegReg', (54, 58))	('p53', 'Gene', '7157', (100, 103))	('expression', 'MPA', (104, 114))	('staining', 'MPA', (62, 70))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))	('mutation', 'Var', (131, 139))
522895	33347497	Field cancerization is a process in which large areas of cells are affected by carcinogenic alterations at the genetic and epigenetic level.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('carcinogenic', 'Disease', 'MESH:D063646', (79, 91))	('alterations', 'Var', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('carcinogenic', 'Disease', (79, 91))	('cancer', 'Disease', (6, 12))
522976	32846794	An important finding of our study was the association between low ALB and the risk of malignancy.	('ALB', 'Gene', '213', (66, 69))	('malignancy', 'Disease', 'MESH:D009369', (86, 96))	('ALB', 'Gene', (66, 69))	('low ALB', 'Phenotype', 'HP:0003282', (62, 69))	('malignancy', 'Disease', (86, 96))	('low', 'Var', (62, 65))
522985	32846794	The OR of 0.349 indicated that the presence of ILD might diminish the risk of coexistent malignancy by 65.1%.	('presence', 'Var', (35, 43))	('malignancy', 'Disease', (89, 99))	('ILD', 'Disease', (47, 50))	('ILD', 'Phenotype', 'HP:0006530', (47, 50))	('diminish', 'NegReg', (57, 65))	('ILD', 'Disease', 'MESH:D017563', (47, 50))	('malignancy', 'Disease', 'MESH:D009369', (89, 99))
522987	32846794	One possible explanation is related to the presence of autoantibodies against aminoacyl-transfer synthetases, which is a common feature of ILD and appears to be protective against malignancies.	('autoantibodies', 'Var', (55, 69))	('aminoacyl-transfer synthetases', 'Enzyme', (78, 108))	('ILD', 'Disease', 'MESH:D017563', (139, 142))	('ILD', 'Disease', (139, 142))	('malignancies', 'Disease', 'MESH:D009369', (180, 192))	('malignancies', 'Disease', (180, 192))	('ILD', 'Phenotype', 'HP:0006530', (139, 142))
523050	32467997	Patients with glioma carrying IDH1 or IDH2 mutations have a relatively favorable survival, when compared to glioma patients with wild-type IDH1/2 genes.	('IDH1/2', 'Gene', (139, 145))	('glioma', 'Disease', (14, 20))	('patients', 'Species', '9606', (115, 123))	('IDH1', 'Gene', (139, 143))	('glioma', 'Disease', (108, 114))	('IDH1', 'Gene', (30, 34))	('IDH2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('IDH1', 'Gene', '3417', (139, 143))	('IDH1/2', 'Gene', '3417;3418', (139, 145))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('IDH2', 'Gene', '3418', (38, 42))	('IDH1', 'Gene', '3417', (30, 34))
523052	32467997	Discriminating between wild-type and mutation status of IDH1 can be challenging.	('IDH1', 'Gene', (56, 60))	('IDH1', 'Gene', '3417', (56, 60))	('mutation', 'Var', (37, 45))
523054	32467997	A traditional CNN approach trained on segmented regions of interest (ROI) of wild-type vs. mutation 2D slices was applied by Grinband et al and a hybrid architecture was proposed by Li et al, including a convolutional network trained with patches of ROI/no ROI, a fisher vector module for encoding the extracted salience maps and a support vector machine classifier for predicting the IDH1 mutation status.	('IDH1', 'Gene', '3417', (385, 389))	('IDH1', 'Gene', (385, 389))	('mutation', 'Var', (91, 99))
523057	32467997	Liang et al, utilized a multi-channel 3D DenseNet architecture for predicting the IDH1 status trained on segmented 3D ROIs with multi-modal [T1, T2, T1Gd and fluid-attenuated inversion recovery (FLAIR)].	('IDH1', 'Gene', '3417', (82, 86))	('T1Gd', 'Var', (149, 153))	('IDH1', 'Gene', (82, 86))
523058	32467997	MGMT is a gene responsible for repairing the mismatched DNA molecules and its methylation status.	('MGMT', 'Gene', (0, 4))	('MGMT', 'Gene', '4255', (0, 4))	('mismatched', 'Var', (45, 55))
523060	32467997	The co-deletion status (the combined loss of the short arm chromosome 1 and the long arm of chromosome 19) of 1p19q in low-grade glioma has been associated with an improved response to therapy and a higher survival rate.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('short arm', 'Phenotype', 'HP:0009824', (49, 58))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('1p19q', 'Gene', (110, 115))	('improved', 'PosReg', (164, 172))	('higher', 'PosReg', (199, 205))	('survival rate', 'CPA', (206, 219))	('co-deletion status', 'Var', (4, 22))	('loss', 'NegReg', (37, 41))	('glioma', 'Disease', (129, 135))
523061	32467997	A proposed multi-kernel CNN predicts the 1p19q chromosomal expression from multi-modal (T1C and T2) low-grade glioma MRI.	('1p19q chromosomal', 'Var', (41, 58))	('glioma', 'Disease', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('T1C', 'Mutation', 'c.1T>C', (88, 91))
523062	32467997	In a previous study, a similar approach was followed to the previously mentioned IDH1 and MGMT by utilizing the same deep architecture to predict the 1p19q codeletion.	('1p19q codeletion', 'Var', (150, 166))	('MGMT', 'Gene', (90, 94))	('MGMT', 'Gene', '4255', (90, 94))	('IDH1', 'Gene', (81, 85))	('IDH1', 'Gene', '3417', (81, 85))
523073	32467997	Yu et al, proposed a 2D CNN trained on CT nodule patches labeled by the mutation state of EGFR.	('mutation state', 'Var', (72, 86))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (90, 94))
523075	32467997	Additionally, fine-tuning was applied with a dataset comprised of approximately 15,000 CT images towards identifying the EGFR mutation status (mutation vs. wild-type).	('EGFR', 'Gene', '1956', (121, 125))	('mutation', 'Var', (126, 134))	('EGFR', 'Gene', (121, 125))
523106	32467997	The differences in pixel-wise labeling (inter-observer variability and bias) for lesion delineation, uncertainty in the examined anatomical areas of malignances (surrounding area, necrosis), disregarding location-based information of the tumor and dependence on morphological features from ROIs may introduce additional variability and misdirection during the convergence process of a fully automated data-driven AI model.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('differences', 'Var', (4, 15))	('necrosis', 'Disease', (180, 188))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (238, 243))	('necrosis', 'Disease', 'MESH:D009336', (180, 188))
523154	32460784	An ultrasonic knife was also used to cut the gastrocolic ligament along the greater curvature of the stomach, cut and ligate the left gastroepiploic artery and vein, and individually cut the short gastric vessels.	('short gastric vessels', 'CPA', (191, 212))	('cut', 'Reg', (183, 186))	('gastrocolic ligament', 'Protein', (45, 65))	('left gastroepiploic artery', 'Disease', 'MESH:D002303', (129, 155))	('cut', 'Var', (110, 113))	('left gastroepiploic artery', 'Disease', (129, 155))	('ligate', 'NegReg', (118, 124))
523232	31389159	Furthermore, the multivariate analysis showed that low pretreatment PLR (hazard ratio (HR) = 1.751; 95% CI: 1.042-2.945; P = 0.035) was an independent predictor of superior survival in PSCCE.	('men', 'Species', '9606', (63, 66))	('PLR', 'MPA', (68, 71))	('PSCCE', 'Disease', (185, 190))	('low', 'Var', (51, 54))	('superior', 'PosReg', (164, 172))
523236	31389159	Moreover, patients diagnosed as PSCCE with low PLR may have superior OS than those with the high PLR.	('superior OS', 'CPA', (60, 71))	('PSCCE', 'Disease', (32, 37))	('patients', 'Species', '9606', (10, 18))	('low PLR', 'Var', (43, 50))
523262	30861255	GLUT1 expression may be a surrogate marker of response to chemotherapy, and inhibition of GLUT1 may be a potential novel therapy for ESCC patients.	('ESCC', 'Disease', (133, 137))	('GLUT1', 'Protein', (0, 5))	('inhibition', 'Var', (76, 86))	('GLUT1', 'Gene', (90, 95))	('patients', 'Species', '9606', (138, 146))
523274	30861255	We also demonstrate that GLUT1 inhibition increases ESCC cellular sensitivity to cisplatin and that GLUT1 expression in clinical biopsy samples correlates with patient response to chemotherapy.	('increases', 'PosReg', (42, 51))	('ESCC cellular sensitivity to cisplatin', 'MPA', (52, 90))	('expression', 'MPA', (106, 116))	('GLUT1', 'Gene', (100, 105))	('inhibition', 'Var', (31, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('GLUT1', 'Protein', (25, 30))	('patient', 'Species', '9606', (160, 167))
523290	30861255	RNA was isolated from the cell lines using an RNeasy Mini Kit (Qiagen, Hilden, Germany), according to the manufacturer's protocol.12 The expression levels of GLUT1, cyclin-dependent kinase 4 (CDK4), CDK6, p21cip1, p27kip, p53, GLUT3, hexokinase 2 (HK2), pyruvate kinase muscle isozyme M2 (PKM2), lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase kinase isozyme-1 (PDK1) were determined by qRT-PCR using TaqMan probes and the reactions were run on a LightCycler 480 System II (Roche Diagnostic, Basel, Schweiz).	('lactate dehydrogenase A', 'Gene', '3939', (296, 319))	('GLUT3', 'Gene', (227, 232))	('p27kip', 'Var', (214, 220))	('cyclin-dependent kinase 4', 'Gene', (165, 190))	('lactate dehydrogenase A', 'Gene', (296, 319))	('p21cip1', 'Gene', '1026', (205, 212))	('CDK4', 'Gene', (192, 196))	('pyruvate dehydrogenase kinase isozyme-1', 'Gene', '5163', (331, 370))	('PDK1', 'Gene', '5163', (372, 376))	('cyclin-dependent kinase 4', 'Gene', '1019', (165, 190))	('p53', 'Gene', '7157', (222, 225))	('pyruvate kinase muscle isozyme M2', 'Gene', (254, 287))	('pyruvate kinase muscle isozyme M2', 'Gene', '5315', (254, 287))	('GLUT3', 'Gene', '6515', (227, 232))	('CDK4', 'Gene', '1019', (192, 196))	('pyruvate dehydrogenase kinase isozyme-1', 'Gene', (331, 370))	('p53', 'Gene', (222, 225))	('hexokinase 2', 'Gene', '3099', (234, 246))	('p21cip1', 'Gene', (205, 212))	('hexokinase 2', 'Gene', (234, 246))	('PDK1', 'Gene', (372, 376))
523301	30861255	Indeed, TE-8, TE-10 and TE-11 cell proliferation was significantly reduced by transfection of GLUT1-targeting siRNA compared with control siRNA (Figure 1E), indicating that GLUT1 is required for ESCC cell proliferation.	('transfection', 'Var', (78, 90))	('GLUT1-targeting', 'Gene', (94, 109))	('reduced', 'NegReg', (67, 74))	('TE-8', 'Chemical', '-', (8, 12))	('TE-11', 'Chemical', '-', (24, 29))
523303	30861255	To clarify the mechanism by which GLUT1 silencing inhibits the proliferation of ESCC cells, we examined cell apoptosis by western blot analysis of cleaved poly (ADP-ribose) polymerase (cleaved PARP) levels and flow cytometric analysis of caspase-3 activity.	('proliferation', 'CPA', (63, 76))	('caspase-3', 'Gene', '836', (238, 247))	('caspase-3', 'Gene', (238, 247))	('GLUT1', 'Protein', (34, 39))	('PARP', 'Gene', '1302', (193, 197))	('silencing', 'Var', (40, 49))	('PARP', 'Gene', (193, 197))	('inhibits', 'NegReg', (50, 58))
523304	30861255	These assays showed that neither PARP expression (Figure 1F) nor caspase-3 activity were influenced by GLUT1 siRNA expression, indicating that the anti-proliferative effect did not result from increased apoptosis.	('GLUT1 siRNA', 'Var', (103, 114))	('caspase-3', 'Gene', '836', (65, 74))	('PARP', 'Gene', '1302', (33, 37))	('activity', 'MPA', (75, 83))	('caspase-3', 'Gene', (65, 74))	('PARP', 'Gene', (33, 37))
523305	30861255	RT-PCR analysis of CDK4, CDK6, p21cip, p27kip and p53 showed that siRNA mediated GLUT1 silencing.	('siRNA', 'MPA', (66, 71))	('p27kip', 'Var', (39, 45))	('p21cip', 'Var', (31, 37))	('CDK4', 'Gene', (19, 23))	('CDK4', 'Gene', '1019', (19, 23))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('silencing', 'NegReg', (87, 96))
523308	30861255	The inhibition of TE-11 proliferation was stronger than that of TE-8 proliferation after using GLUT1 siRNA, as shown by changes to CDK6 and p27kip expression (Figure 1G).	('TE-11 proliferation', 'CPA', (18, 37))	('p27kip', 'Var', (140, 146))	('changes', 'Reg', (120, 127))	('CDK6', 'Protein', (131, 135))	('TE-8', 'Chemical', '-', (64, 68))	('TE-11', 'Chemical', '-', (18, 23))	('inhibition', 'NegReg', (4, 14))
523315	30861255	Moreover, very low doses of cisplatin (0.2 and 0.4 mug/mL) had a strong inhibitory effect on the proliferation of TE11 cells transfected with GLUT1-specific siRNA, but not with control siRNA (Figure 2C), indicating that GLUT1 silencing enhances the potency of cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('potency', 'MPA', (249, 256))	('enhances', 'PosReg', (236, 244))	('proliferation', 'CPA', (97, 110))	('inhibitory', 'NegReg', (72, 82))	('GLUT1', 'Gene', (220, 225))	('silencing', 'Var', (226, 235))	('cisplatin', 'Chemical', 'MESH:D002945', (260, 269))
523317	30861255	Of note, PKM2 and LDHA mRNA levels were highly expressed in both TE-8 and TE-11 cells (Figure 2D).	('PKM2', 'Var', (9, 13))	('TE-8', 'Chemical', '-', (65, 69))	('LDHA mRNA levels', 'MPA', (18, 34))	('TE-11', 'Chemical', '-', (74, 79))
523318	30861255	We detected no effects of GLUT1 silencing on the expression of these genes in TE-8 cells, which express low GLUT1 levels (data not shown).	('silencing', 'Var', (32, 41))	('TE-8', 'Chemical', '-', (78, 82))	('GLUT1', 'Gene', (26, 31))
523320	30861255	We also examined activation of the mitogen-activated protein kinase (MAPK) pathway, which has been reported to be associated with PKM2 and GLUT1 expression.15, 16 We found that phosphorylation of extracellular signal-regulated kinase (ERK)1/2 on Thr202/Tyr204 was reduced in TE-11 cells transfected with GLUT1 siRNA compared with control siRNA, whereas phosphorylation of AKT on Ser473 was unaffected (Figure 2F).	('Ser473', 'Chemical', '-', (379, 385))	('TE-11', 'Chemical', '-', (275, 280))	('Tyr204', 'Chemical', '-', (253, 259))	('reduced', 'NegReg', (264, 271))	('GLUT1 siRNA', 'Var', (304, 315))	('AKT', 'Gene', (372, 375))	('Thr202/Tyr204', 'Var', (246, 259))	('extracellular signal-regulated kinase (ERK)1/2', 'Gene', '5595;5594', (196, 242))	('phosphorylation', 'MPA', (177, 192))	('Thr202', 'Chemical', '-', (246, 252))	('AKT', 'Gene', '207', (372, 375))
523321	30861255	Taken together, these data indicate that GLUT1 knockdown affects signaling through the MAPK pathway and expression of glycolytic enzymes, suggesting that suppression of glycolysis is a potential mechanism for the anti-tumor activity of cisplatin.	('glycolysis', 'MPA', (169, 179))	('MAPK pathway', 'Pathway', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('signaling', 'MPA', (65, 74))	('affects', 'Reg', (57, 64))	('knockdown', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('expression', 'MPA', (104, 114))	('suppression', 'NegReg', (154, 165))	('GLUT1', 'Gene', (41, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (236, 245))	('tumor', 'Disease', (218, 223))
523325	30861255	Thus, addition of 0.5 mumol/L cisplatin, 0.025 nmol/L BAY-876 or 0.025 nmol/L BAY-876 plus 0.5 mumol/L cisplatin reduced the proliferation of TE-8 cells by 79.9% +- 2.3%, 59.9% +- 4.9% and 38.1% +- 3.1% (average +- SD), respectively, and of TE-11 cells by 46.0% +- 6.5%, 51.0% +- 8.2% and 15.4% +- 3.7%, respectively, compared with the vehicle-treated control cells (Figure 2H).	('BAY-876', 'Var', (54, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('TE-8', 'Chemical', '-', (142, 146))	('TE-11', 'Chemical', '-', (241, 246))	('BAY-876', 'Var', (78, 85))	('proliferation', 'CPA', (125, 138))	('0.025 nmol/L', 'Var', (41, 53))	('BAY-876', 'Chemical', 'MESH:C000620175', (54, 61))	('0.025 nmol/L', 'Var', (65, 77))	('BAY-876', 'Chemical', 'MESH:C000620175', (78, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('reduced', 'NegReg', (113, 120))
523327	30861255	Having established that GLUT1 inhibition can enhance the sensitivity of ESCC cells to cisplatin in vitro, we next asked whether tumor levels of GLUT1 could predict the response of patients to platinum-based therapy.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('inhibition', 'Var', (30, 40))	('enhance', 'PosReg', (45, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('GLUT1', 'Protein', (24, 29))	('sensitivity', 'MPA', (57, 68))	('tumor', 'Disease', (128, 133))	('platinum', 'Chemical', 'MESH:D010984', (192, 200))	('patients', 'Species', '9606', (180, 188))
523333	30861255	Silencing of GLUT1 resulted in a significant reduction in CDK6, PKM2, LDHA and phospho-ERK1/2 expression and a significant upregulation of p27kip.	('GLUT1', 'Gene', (13, 18))	('LDHA', 'Gene', (70, 74))	('p27kip', 'Var', (139, 145))	('ERK1/2', 'Gene', '5595', (87, 93))	('ERK1/2', 'Gene', (87, 93))	('upregulation', 'PosReg', (123, 135))	('CDK6', 'Gene', (58, 62))	('expression', 'MPA', (94, 104))	('Silencing', 'Var', (0, 9))	('reduction', 'NegReg', (45, 54))	('PKM2', 'Gene', (64, 68))
523338	30861255	CDK6 overexpression is associated with poor survival and may be a marker of aggressive behavior in esophageal cancer.18 Inhibitors of cyclin D-associated kinases have been proposed as potential cancer therapeutics.19 p27kip also plays a key role in coordinating CDK activity during the cell cycle.	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', (194, 200))	('aggressive behavior', 'Phenotype', 'HP:0000718', (76, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('p27kip', 'Var', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('esophageal cancer', 'Disease', (99, 116))
523339	30861255	In this study, we found that CDK6 and p27kip expression was decreased and increased, respectively, in TE-8 and TE-11 cells after inhibition of GLUT1 expression, suggesting that these proteins may be involved in the anti-proliferative effect of inhibiting GLUT1 expression.	('TE-11', 'Chemical', '-', (111, 116))	('GLUT1', 'Gene', (143, 148))	('p27kip', 'Var', (38, 44))	('increased', 'PosReg', (74, 83))	('expression', 'MPA', (45, 55))	('inhibition', 'NegReg', (129, 139))	('TE-8', 'Chemical', '-', (102, 106))	('CDK6', 'Gene', (29, 33))
523360	30675220	Apatinib enhances the radiosensitivity of the esophageal cancer cell line KYSE-150 by inducing apoptosis and cell cycle redistribution To determine the radiosensitizing effect of apatinib on esophageal cancer cells, and to preliminarily investigate the underlying mechanism, KYSE-150 cells were treated with apatinib, x-ray or apatinib combined with x-ray, and compared with a blank control.	('cell cycle', 'CPA', (109, 119))	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('apatinib', 'Chemical', 'MESH:C553458', (327, 335))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('enhances', 'PosReg', (9, 17))	('apoptosis', 'CPA', (95, 104))	('Apatinib', 'Chemical', 'MESH:C553458', (0, 8))	('KYSE-150', 'CellLine', 'CVCL:1348', (74, 82))	('inducing', 'Reg', (86, 94))	('apatinib', 'Chemical', 'MESH:C553458', (308, 316))	('esophageal cancer', 'Disease', (46, 63))	('radiosensitivity', 'MPA', (22, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Apatinib', 'Var', (0, 8))	('esophageal cancer', 'Disease', (191, 208))	('KYSE-150', 'CellLine', 'CVCL:1348', (275, 283))	('apatinib', 'Chemical', 'MESH:C553458', (179, 187))
523363	30675220	The rate of apoptosis in cells treated with apatinib and x-ray was markedly higher compared with those of the blank control, x-ray and apatinib alone groups (P<0.05).	('apatinib', 'Chemical', 'MESH:C553458', (135, 143))	('apatinib', 'Var', (44, 52))	('apatinib', 'Chemical', 'MESH:C553458', (44, 52))	('higher', 'PosReg', (76, 82))	('apoptosis', 'CPA', (12, 21))
523364	30675220	The proportion of cells in the G2/M phase was significantly increased in the apatinib, x-ray and combination groups compared with the blank control group (P<0.05).	('x-ray', 'Var', (87, 92))	('combination', 'Var', (97, 108))	('apatinib', 'Chemical', 'MESH:C553458', (77, 85))	('apatinib', 'Gene', (77, 85))	('increased', 'PosReg', (60, 69))
523374	30675220	A principle cause of radioresistance in esophageal cancer is the abnormal secretion of radiation-induced vascular endothelial growth factor (VEGF), which contributes to tumor angiogenesis and protects tumor vessels from radiation-associated damage.	('secretion', 'MPA', (74, 83))	('vascular endothelial growth factor', 'Gene', (105, 139))	('abnormal', 'Var', (65, 73))	('contributes', 'PosReg', (154, 165))	('VEGF', 'Gene', (141, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('vascular endothelial growth factor', 'Gene', '7422', (105, 139))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('VEGF', 'Gene', '7422', (141, 145))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', (201, 206))	('cause', 'Reg', (12, 17))	('esophageal cancer', 'Disease', (40, 57))
523444	30675220	By contrast, the expression of pCHK2 in the combination group was lower compared with that in x-ray alone group.	('CHK2', 'Gene', (32, 36))	('CHK2', 'Gene', '11200', (32, 36))	('expression', 'MPA', (17, 27))	('lower', 'NegReg', (66, 71))	('combination', 'Var', (44, 55))
523445	30675220	This indicated that apatinib may not only increase the population of KYSE-150 cells in the G2/M phase, but may also inhibit the DNA repair response (Fig.	('apatinib', 'Var', (20, 28))	('inhibit', 'NegReg', (116, 123))	('KYSE-150', 'CellLine', 'CVCL:1348', (69, 77))	('DNA repair', 'MPA', (128, 138))	('apatinib', 'Chemical', 'MESH:C553458', (20, 28))	('increase', 'PosReg', (42, 50))
523447	30675220	High expression of VEGF is one of the primary causes of radioresistance in esophageal cancer cells.	('High expression', 'Var', (0, 15))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('VEGF', 'Gene', (19, 23))	('esophageal cancer', 'Disease', (75, 92))	('VEGF', 'Gene', '7422', (19, 23))	('causes', 'Reg', (46, 52))
523471	30675220	Furthermore, cell cycle checkpoints remove damaged cells from the actively proliferating population, and halt the cell cycle to temporarily allow for the repair of DSBs, another primary reason for radioresistance in cancer cells.	('allow', 'Reg', (140, 145))	('DSBs', 'Var', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('halt', 'Reg', (105, 109))	('cell cycle', 'CPA', (114, 124))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('DSBs', 'Chemical', '-', (164, 168))
523478	30675220	In the present study, it was demonstrated that apatinib markedly increased radiosensitivity by inhibiting the secretion of VEGF and the proliferation of KYSE-150 cells.	('radiosensitivity', 'MPA', (75, 91))	('increased', 'PosReg', (65, 74))	('inhibiting', 'NegReg', (95, 105))	('VEGF', 'Gene', '7422', (123, 127))	('KYSE-150', 'CellLine', 'CVCL:1348', (153, 161))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (65, 91))	('proliferation of KYSE-150 cells', 'CPA', (136, 167))	('VEGF', 'Gene', (123, 127))	('apatinib', 'Var', (47, 55))	('apatinib', 'Chemical', 'MESH:C553458', (47, 55))
523535	28948043	Shear wave vibrometry measurements were then used to detect changes in esophageal stiffness due to ablation.	('esophageal stiffness', 'Disease', 'MESH:D004941', (71, 91))	('esophageal stiffness', 'Disease', (71, 91))	('ablation', 'Var', (99, 107))	('changes', 'Reg', (60, 67))
523570	28301921	Patients with malignant compared to benign strictures undergoing dilation were more likely to require percutaneous endoscopic gastrostomy or jejunostomy (PEG/J) tube (14.1% vs. 4.5%, p<0.001).	('PEG', 'Chemical', '-', (154, 157))	('J', 'Chemical', '-', (158, 159))	('Patients', 'Species', '9606', (0, 8))	('percutaneous endoscopic gastrostomy', 'Disease', (102, 137))	('malignant', 'Var', (14, 23))
523602	28301921	Even after adjusting for all patient and hospital characteristics by using multivariate regression analysis, as described above, palliative care remained significantly underutilized among those undergoing dilation compared with those who were not dilated (OR, 0.50; CI, 0.36-0.69; p<0.001).	('patient', 'Species', '9606', (29, 36))	('palliative', 'Disease', (129, 139))	('dilation', 'Var', (205, 213))
523610	28301921	Our findings also demonstrated a longer length of stay among patients with malignant stricture.	('length of', 'MPA', (40, 49))	('patients', 'Species', '9606', (61, 69))	('longer', 'PosReg', (33, 39))	('malignant', 'Var', (75, 84))
523631	27635196	Loss of heterozygosity and microsatellite instability as predictive markers among Iranian esophageal cancer patients Variation in microsatellite sequences that are dispersed in the genome has been linked to a deficiency in cellular mismatch repair system and defects in several genes of this system are involved in carcinogenesis.	('Variation', 'Var', (117, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (315, 329))	('deficiency', 'Disease', 'MESH:D007153', (209, 219))	('cellular mismatch', 'Protein', (223, 240))	('defects', 'Var', (259, 266))	('esophageal cancer', 'Disease', (90, 107))	('carcinogenesis', 'Disease', (315, 329))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('linked', 'Reg', (197, 203))	('deficiency', 'Disease', (209, 219))	('microsatellite sequences', 'Gene', (130, 154))
523632	27635196	Our aim in this study was to illustrate microsatellite DNA alteration in esophageal cancer.	('esophageal cancer', 'Disease', (73, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('microsatellite DNA', 'Var', (40, 58))
523634	27635196	Microsatellite instability (MSI) and loss of heterozygosity (LOH) were studied in 50 cases of esophageal squamous cell carcinoma (ESCC) by amplifying six microsatellite markers: D13S260 (13q12.3), D13S267 (13q12.3), D9S171 (9p21), D2S123 (2p), D5S2501 (5q21) and TP53 (17p13.1) analyzed on 6% denaturing polyacrylamide gel electrophoresis.	('D13S260', 'Var', (178, 185))	('D5S2501', 'Var', (244, 251))	('D13S267', 'Var', (197, 204))	('D2S123', 'Var', (231, 237))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (94, 128))	('D9S171', 'Var', (216, 222))	('TP53', 'Gene', '7157', (263, 267))	('polyacrylamide', 'Chemical', 'MESH:C016679', (304, 318))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('TP53', 'Gene', (263, 267))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))
523635	27635196	Specifically, increased LOH in tumor DNA has a significant correlation with increased differentiation from poorly differentiated to well differentiated tumors (P= 0.002 and P= 0.016 respectively).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('poorly', 'Disease', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('increased', 'PosReg', (76, 85))	('tumor', 'Disease', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', (152, 157))	('LOH', 'Var', (24, 27))	('tumors', 'Disease', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
523636	27635196	Microsatellite DNA alterations may be a prognostic tool for detection and the evolution of prognosis in patients with SCC of esophagus.	('SCC of esophagus', 'Disease', (118, 134))	('Microsatellite', 'Var', (0, 14))	('patients', 'Species', '9606', (104, 112))
523646	27635196	As well as MSI, inactivation of tumor suppressor genes appears as another genetic mechanism involved in ESCC development.	('ESCC development', 'Disease', (104, 120))	('involved', 'Reg', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('inactivation', 'Var', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('men', 'Species', '9606', (116, 119))
523648	27635196	Furthermore, LOH in long arm of chromosome 5 containing tumor suppressor genes can affect ESCC development.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('affect', 'Reg', (83, 89))	('LOH', 'Var', (13, 16))	('tumor', 'Disease', (56, 61))	('ESCC', 'Disease', (90, 94))	('men', 'Species', '9606', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
523649	27635196	Interestingly, significant correlations were reported between LOH of MMR system genes and general LOH, as well as MSI status in ESCC patients.	('ESCC', 'Disease', (128, 132))	('LOH', 'Var', (62, 65))	('patients', 'Species', '9606', (133, 141))	('MMR system genes', 'Gene', (69, 85))
523675	27635196	Some markers showed similar instability; D9S171 and TP53 with 18% (9/50), and D13S260 and D13S267 with 10% (5/50) (Table 3).	('D13S260', 'Var', (78, 85))	('D13S267', 'Var', (90, 97))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))	('D9S171', 'Var', (41, 47))
523676	27635196	Specifically, increased LOH in tumor DNA has a significant correlation with increased differentiation from poorly to well differentiated tumors (P=0.002 and P=0.016 respectively).	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('increased', 'PosReg', (76, 85))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('LOH', 'Var', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('poorly', 'CPA', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
523679	27635196	Chromosomal regions which include frequent allelic loss may most likely point to main susceptibility genes which help to understand the involved molecular pathways in esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (167, 192))	('allelic loss', 'Var', (43, 55))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (167, 192))
523684	27635196	It is known that alterations in repeated sequences (microsatellites) are linked to the defects in some critical genes such as mismatch repair genes and tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mismatch repair genes', 'Gene', (126, 147))	('defects', 'MPA', (87, 94))	('linked', 'Reg', (73, 79))	('tumor', 'Disease', (152, 157))	('repeated', 'MPA', (32, 40))	('alterations', 'Var', (17, 28))
523687	27635196	The alterations of BRCA2, p16 and P53 genes are common molecular events in esophageal carcinogenesis, and our results showed LOH in D13S260 and TP53 markers can be common events in ESCC patients.	('esophageal carcinogenesis', 'Disease', (75, 100))	('p16', 'Gene', (26, 29))	('TP53', 'Gene', (144, 148))	('alterations', 'Var', (4, 15))	('TP53', 'Gene', '7157', (144, 148))	('BRCA2', 'Gene', (19, 24))	('P53', 'Gene', (34, 37))	('p16', 'Gene', '1029', (26, 29))	('D13S260', 'Var', (132, 139))	('P53', 'Gene', (145, 148))	('ESCC', 'Disease', (181, 185))	('BRCA2', 'Gene', '675', (19, 24))	('P53', 'Gene', '7157', (34, 37))	('LOH', 'Var', (125, 128))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (75, 100))	('P53', 'Gene', '7157', (145, 148))	('patients', 'Species', '9606', (186, 194))
523688	27635196	A high frequency of replication error (RER) and LOH involving 3p loci in the present study suggests that microsatellite alterations involving 3p loci may be early and frequent events and that multiple tumor suppressor genes harboring these loci may be implicated in esophageal tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('alterations', 'Var', (120, 131))	('LOH', 'Var', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Disease', (201, 206))	('microsatellite', 'Var', (105, 119))	('tumor', 'Disease', (277, 282))
523691	27635196	One of the most frequent LOH loci observed was D9S171 (9p21), where p15INK4b and p16 reside.	('D9S171', 'Var', (47, 53))	('p15INK4b', 'Gene', '1030', (68, 76))	('p15INK4b', 'Gene', (68, 76))	('p16', 'Gene', '1029', (81, 84))	('p16', 'Gene', (81, 84))
523692	27635196	Although LOH at D9S171 was found to be associated with frequent homozygous deletion at p15 INK4b while not showing the same association at p16 INK4a, in our study this LOH was only found in 18% of patients and this may confirm that such alterations are random.	('patients', 'Species', '9606', (197, 205))	('INK4a', 'Gene', (143, 148))	('deletion', 'Var', (75, 83))	('p16', 'Gene', '1029', (139, 142))	('INK4a', 'Gene', '1029', (143, 148))	('p15', 'Gene', (87, 90))	('p15', 'Gene', '1030', (87, 90))	('INK4b', 'Gene', '1030', (91, 96))	('INK4b', 'Gene', (91, 96))	('p16', 'Gene', (139, 142))	('D9S171', 'Var', (16, 22))
523693	27635196	However, inactivation of p16 gene by hypermethylation of its promoter is a frequent event in ESCC as reported by Taghavi et al.	('p16', 'Gene', (25, 28))	('inactivation', 'NegReg', (9, 21))	('hypermethylation', 'Var', (37, 53))	('p16', 'Gene', '1029', (25, 28))	('ESCC', 'Disease', (93, 97))
523712	26934124	To explore the cytotoxic effects of EDHB, esophageal cancer cells with higher (KYSE180) or lower (KYSE510) AKR1C expression levels were evaluated in this study.	('lower', 'NegReg', (91, 96))	('KYSE510', 'Var', (98, 105))	('esophageal cancer', 'Disease', (42, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('KYSE510', 'CellLine', 'CVCL:1354', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('KYSE180', 'CellLine', 'CVCL:1349', (79, 86))	('EDHB', 'Chemical', 'MESH:C018063', (36, 40))
523715	26934124	The sensitivity of esophageal cancer cells to EDHB was significantly attenuated by the siRNA knockdown of AKR1C1/C2.	('knockdown', 'Var', (93, 102))	('attenuated', 'NegReg', (69, 79))	('sensitivity', 'MPA', (4, 15))	('esophageal cancer', 'Disease', (19, 36))	('EDHB', 'Chemical', 'MESH:C018063', (46, 50))	('AKR1C1', 'Gene', '1645', (106, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (19, 36))	('AKR1C1', 'Gene', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
523716	26934124	Moreover, the expression of autophagy inducers (Beclin, LC3II and BNIP3) and NDRG1 was significantly elevated in KYSE180 cells, but not in KYSE510 cells, after EDHB treatment.	('autophagy', 'CPA', (28, 37))	('elevated', 'PosReg', (101, 109))	('KYSE180', 'CellLine', 'CVCL:1349', (113, 120))	('KYSE510', 'CellLine', 'CVCL:1354', (139, 146))	('Beclin', 'Gene', (48, 54))	('KYSE180', 'Var', (113, 120))	('LC3', 'Gene', '84557', (56, 59))	('LC3', 'Gene', (56, 59))	('NDRG1', 'Gene', (77, 82))	('expression', 'MPA', (14, 24))	('BNIP3', 'Gene', (66, 71))	('EDHB', 'Chemical', 'MESH:C018063', (160, 164))	('BNIP3', 'Gene', '664', (66, 71))	('NDRG1', 'Gene', '10397', (77, 82))
523718	26934124	These results indicated that ESCC patients with high AKR1C1/C2 expression may be more sensitive to EDHB, and AKR1C1/C2 may facilitate EDHB-induced autophagy and apoptosis, thus providing potential guidance for the chemoprevention of ESCC.	('ESCC', 'Disease', (29, 33))	('EDHB', 'Chemical', 'MESH:C018063', (99, 103))	('EDHB', 'Chemical', 'MESH:C018063', (134, 138))	('AKR1C1', 'Gene', '1645', (53, 59))	('AKR1C1', 'Gene', (109, 115))	('apoptosis', 'CPA', (161, 170))	('AKR1C1', 'Gene', (53, 59))	('AKR1C1', 'Gene', '1645', (109, 115))	('patients', 'Species', '9606', (34, 42))	('high', 'Var', (48, 52))	('EDHB', 'MPA', (99, 103))	('facilitate', 'PosReg', (123, 133))	('sensitive', 'MPA', (86, 95))
523740	26934124	The most recent study on this topic showed that prostate tumor samples with activated AKR1C1, an androgen-metabolizing enzyme, harbor high Sp1 and c-FLIP expression and low AKR1C1, ERbeta and Sp3 expression.	('AKR1C1', 'Gene', (86, 92))	('AKR1C1', 'Gene', '1645', (86, 92))	('prostate tumor', 'Disease', 'MESH:D011471', (48, 62))	('AKR1C1', 'Gene', (173, 179))	('Sp3', 'Gene', '6670', (192, 195))	('AKR1C1', 'Gene', '1645', (173, 179))	('Sp1', 'MPA', (139, 142))	('activated', 'Var', (76, 85))	('high', 'PosReg', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ERbeta', 'Gene', '2100', (181, 187))	('Sp3', 'Gene', (192, 195))	('prostate tumor', 'Disease', (48, 62))	('ERbeta', 'Gene', (181, 187))	('low', 'NegReg', (169, 172))	('prostate tumor', 'Phenotype', 'HP:0100787', (48, 62))	('c-FLIP', 'Gene', '8837', (147, 153))	('c-FLIP', 'Gene', (147, 153))
523748	26934124	employed this method to quantitate the levels of AKR1A1, AKR1C1/C2, AKR1C3, AKR1C4, AKR1B1, and AKR1B10 in seven different cancer cell lines and to ascertain the absolute quantities of all proteins in each cell line.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('AKR1C3', 'Gene', (68, 74))	('AKR1C3', 'Gene', '8644', (68, 74))	('AKR1C4', 'Gene', (76, 82))	('AKR1C4', 'Gene', '1109', (76, 82))	('AKR1A1', 'Var', (49, 55))	('AKR1B10', 'Gene', (96, 103))	('AKR1B10', 'Gene', '57016', (96, 103))	('AKR1C1', 'Gene', (57, 63))	('AKR1C1', 'Gene', '1645', (57, 63))	('AKR1B1', 'Gene', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
523757	26934124	To examine the role of AKR1C in the EDHB-induced inhibition of ESCC cell proliferation, KYSE 180 and KYSE 510 cells were treated with the same concentration of EDHB for 48 h; the inhibition of cell growth was greater in KYSE 180 cells than in KYSE 510 cells (Figure 1F).	('EDHB', 'Chemical', 'MESH:C018063', (36, 40))	('cell growth', 'CPA', (193, 204))	('KYSE 180', 'Var', (220, 228))	('EDHB', 'Chemical', 'MESH:C018063', (160, 164))
523763	26934124	AKR1C1/C2 expression was elevated in KYSE 180 cells, whereas there was no obvious change in KYSE 510 cells after EDHB treatment.	('EDHB', 'Chemical', 'MESH:C018063', (113, 117))	('expression', 'MPA', (10, 20))	('KYSE', 'Var', (37, 41))	('elevated', 'PosReg', (25, 33))	('AKR1C1', 'Gene', (0, 6))	('AKR1C1', 'Gene', '1645', (0, 6))
523779	26934124	Caspase-3 and caspase-9 expression was lower in KYSE 510 cells than in KYSE 180 cells.	('Caspase-3', 'Gene', (0, 9))	('KYSE 510', 'Var', (48, 56))	('expression', 'MPA', (24, 34))	('caspase-9', 'Gene', '842', (14, 23))	('caspase-9', 'Gene', (14, 23))	('lower', 'NegReg', (39, 44))	('Caspase-3', 'Gene', '836', (0, 9))
523791	26934124	AKR1C inhibitors or other similar drugs are considered promising agents for adjuvant therapy, with the ability to prolong the anticancer efficacy of chemotherapy by two-fold.	('AKR1C', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('prolong', 'PosReg', (114, 121))	('cancer', 'Disease', (130, 136))	('inhibitors', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
523810	26934124	Cell proliferation was inhibited by EDHB in ESCC cells with either higher (KYSE 180) or lower (KYSE 510) AKR1C expression, and this inhibition occurred in a dose- and time-dependent manner.	('lower', 'NegReg', (88, 93))	('higher', 'PosReg', (67, 73))	('inhibited', 'NegReg', (23, 32))	('KYSE 510', 'Var', (95, 103))	('expression', 'MPA', (111, 121))	('KYSE 180', 'Var', (75, 83))	('EDHB', 'Chemical', 'MESH:C018063', (36, 40))	('EDHB', 'Gene', (36, 40))	('AKR1C', 'Gene', (105, 110))	('Cell proliferation', 'CPA', (0, 18))
523811	26934124	The results indicated that AKR1C overexpression increased the sensitivity of ESCC cells to EDHB.	('increased', 'PosReg', (48, 57))	('EDHB', 'Chemical', 'MESH:C018063', (91, 95))	('AKR1C', 'Gene', (27, 32))	('sensitivity', 'MPA', (62, 73))	('overexpression', 'Var', (33, 47))
523848	26934124	These results indicated that esophageal cancer patients with high AKR1C1/C2 expression may be more susceptible to EDHB, thus providing potential guidance for the chemoprevention and clinical treatment of ESCC.	('AKR1C1', 'Gene', (66, 72))	('AKR1C1', 'Gene', '1645', (66, 72))	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (47, 55))	('esophageal cancer', 'Disease', (29, 46))	('EDHB', 'Chemical', 'MESH:C018063', (114, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('susceptible', 'MPA', (99, 110))
523859	26934124	Western blot analysis was performed using the following antibodies: anti-AKR1C, anti-caspase-9, anti-caspase-3, anti-NDRG1, anti-BNIP3, anti-Beclin, and anti-LC3.	('NDRG1', 'Gene', (117, 122))	('LC3', 'Gene', (158, 161))	('caspase-9', 'Gene', '842', (85, 94))	('BNIP3', 'Gene', '664', (129, 134))	('NDRG1', 'Gene', '10397', (117, 122))	('caspase-3', 'Gene', '836', (101, 110))	('LC3', 'Gene', '84557', (158, 161))	('anti-AKR1C', 'Var', (68, 78))	('caspase-9', 'Gene', (85, 94))	('anti-Beclin', 'Var', (136, 147))	('BNIP3', 'Gene', (129, 134))	('caspase-3', 'Gene', (101, 110))
523920	27536141	PTVs were generated by applying 0.5 cm expansions to ITV4D and ITV3D, resulting in PTV4D and PTV3D, respectively.	('PTV', 'Chemical', '-', (0, 3))	('ITV3D', 'Gene', (63, 68))	('PTV', 'Chemical', '-', (83, 86))	('PTV4D', 'Var', (83, 88))	('PTV', 'Chemical', '-', (93, 96))	('PTV3D', 'Disease', (93, 98))
523935	27536141	The median DSCs between PTVconv and PTV4D were 0.80 (mean: 0.79; range: 0.72-0.84) for group A, 0.84 (mean: 0.83; range: 0.72-0.89) for group B, and 0.83 (mean: 0.83; range: 0.78-0.90) for group C. The Kruskal-Wallis H test indicated that the DSC between PTV3D and PTV4D was significantly larger than that between PTVconv and PTV4D for group A (chi2=-3.18; P=0.001) and group B (chi2=-2.98; P=0.003) but smaller for group C (chi2=-3.06; P=0.002).	('PTV3D', 'Var', (255, 260))	('PTV', 'Chemical', '-', (255, 258))	('PTV', 'Chemical', '-', (265, 268))	('PTV', 'Chemical', '-', (24, 27))	('PTV', 'Chemical', '-', (314, 317))	('PTV', 'Chemical', '-', (36, 39))	('PTV4D', 'Var', (265, 270))	('PTV', 'Chemical', '-', (326, 329))
523937	27536141	In the treatment planning based on PTV3D compared with that based on PTVconv, the amount of normal tissue that unnecessarily irradiated was decreased by nearly 11.81% and 11.86% for upper and middle esophageal tumors, respectively.	('decreased', 'NegReg', (140, 149))	('middle esophageal tumors', 'Disease', (192, 216))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('PTV', 'Chemical', '-', (35, 38))	('PTV', 'Chemical', '-', (69, 72))	('PTV3D', 'Var', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('men', 'Species', '9606', (12, 15))	('middle esophageal tumors', 'Disease', 'MESH:D020244', (192, 216))	('esophageal tumors', 'Phenotype', 'HP:0100751', (199, 216))	('amount', 'MPA', (82, 88))	('esophageal tumor', 'Phenotype', 'HP:0100751', (199, 215))
523945	27536141	Compared with upper and middle esophageal cancers, a large intrafractional radial margin (0.36 cm in the lateral direction and 0.47 cm in the AP direction) for distal esophageal cancer would provide tumor motion coverage for 95% of the cases in our study population.	('tumor', 'Disease', (199, 204))	('esophageal cancer', 'Disease', 'MESH:D004938', (167, 184))	('0.36', 'Var', (90, 94))	('middle esophageal cancers', 'Disease', 'MESH:D004938', (24, 49))	('middle esophageal cancers', 'Disease', (24, 49))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('0.47 cm', 'Var', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('distal', 'Disease', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('esophageal cancer', 'Disease', (167, 184))
523956	27536141	PTV3D allows for an average reduction of 2% in the unirradiated target volume compared with PTV4D.	('PTV', 'Chemical', '-', (0, 3))	('unirradiated', 'MPA', (51, 63))	('PTV3D', 'Var', (0, 5))	('reduction', 'NegReg', (28, 37))	('PTV', 'Chemical', '-', (92, 95))
523989	26809870	The occurrence of stricture can cause dysphagia and may severely impair patients' quality of life (QOL).	('dysphagia', 'Disease', (38, 47))	('stricture', 'Var', (18, 27))	('dysphagia', 'Phenotype', 'HP:0002015', (38, 47))	('impair', 'NegReg', (65, 71))	('dysphagia', 'Disease', 'MESH:D003680', (38, 47))	('quality of life', 'CPA', (82, 97))	('cause', 'Reg', (32, 37))	('patients', 'Species', '9606', (72, 80))
524010	26809870	A single-channel upper gastrointestinal endoscope (GIF Q260J; Olympus) with a transparent cap (D-201-10704; Olympus) attached to its tip and a high frequency generator VIO 300D (ERBE; Elektromedizin, Tubingen, Germany) were used during ESD.	('upper gastrointestinal endoscope', 'Disease', (17, 49))	('Q260J', 'SUBSTITUTION', 'None', (55, 60))	('Q260J', 'Var', (55, 60))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (17, 49))
524061	24578608	Genetic Polymorphisms in SLC23A2 as Predictive Biomarkers of Severe Acute Toxicities after Treatment with a Definitive 5-Fluorouracil/Cisplatin-Based Chemoradiotherapy in Japanese Patients with Esophageal Squamous Cell Carcinoma Objective: Definitive chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) is one of the standard therapies for esophageal squamous cell carcinoma (ESCC); however, inter-individual variations in clinical outcomes have yet to be investigated.	('esophageal squamous cell carcinoma', 'Disease', (360, 394))	('CDDP', 'Chemical', 'MESH:D002945', (317, 321))	('SLC23A2', 'Gene', (25, 32))	('Cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (194, 228))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (280, 294))	('5-FU', 'Chemical', 'MESH:D005472', (296, 300))	('Carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('CR', 'Chemical', '-', (270, 272))	('SLC23A2', 'Gene', '9962', (25, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (371, 394))	('Toxicities', 'Disease', 'MESH:D064420', (74, 84))	('Toxicities', 'Disease', (74, 84))	('Polymorphisms', 'Var', (8, 21))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (360, 394))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (119, 133))	('Esophageal Squamous Cell Carcinoma', 'Disease', (194, 228))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (205, 228))	('Patients', 'Species', '9606', (180, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (306, 315))	('carcinoma', 'Phenotype', 'HP:0030731', (385, 394))
524062	24578608	In the present study, single nucleotide polymorphisms (SNPs) in SLC23A2 gene were retrospectively evaluated in 49 Japanese patients with ESCC who were treated with a definitive 5-FU/CDDP-based CRT, and the predictive values for the clinical response, severe acute toxicities, and long-term survival were assessed.	('CDDP', 'Chemical', 'MESH:D002945', (182, 186))	('SLC23A2', 'Gene', (64, 71))	('ESCC', 'Disease', (137, 141))	('patients', 'Species', '9606', (123, 131))	('acute toxicities', 'Disease', (258, 274))	('CR', 'Chemical', '-', (193, 195))	('single nucleotide polymorphisms', 'Var', (22, 53))	('SLC23A2', 'Gene', '9962', (64, 71))	('acute toxicities', 'Disease', 'MESH:D000208', (258, 274))	('5-FU', 'Chemical', 'MESH:D005472', (177, 181))
524064	24578608	The SLC23A2 SNPs rs2681116, rs13037458, rs1715364, rs4987219, and rs1110277 were evaluated.	('rs1715364', 'Var', (40, 49))	('rs2681116', 'Var', (17, 26))	('rs13037458', 'Var', (28, 38))	('SLC23A2', 'Gene', '9962', (4, 11))	('rs4987219', 'Mutation', 'rs4987219', (51, 60))	('rs1110277', 'Mutation', 'rs1110277', (66, 75))	('rs2681116', 'Mutation', 'rs2681116', (17, 26))	('SLC23A2', 'Gene', (4, 11))	('rs13037458', 'Mutation', 'rs13037458', (28, 38))	('rs4987219', 'Var', (51, 60))	('rs1715364', 'Mutation', 'rs1715364', (40, 49))	('rs1110277', 'Var', (66, 75))
524065	24578608	Results: The rs2681116 and rs13037458 had a tendency to predict the clinical response (p=0.144 and 0.085, respectively) and long-term survival (p=0.142 and 0.056, respectively).	('rs2681116', 'Var', (13, 22))	('rs2681116', 'Mutation', 'rs2681116', (13, 22))	('rs13037458', 'Var', (27, 37))	('clinical response', 'CPA', (68, 85))	('rs13037458', 'Mutation', 'rs13037458', (27, 37))	('long-term survival', 'CPA', (124, 142))
524066	24578608	The rs4987219 and rs1110277 correlated with severe acute leukopenia (p=0.025) and stomatitis (p=0.019), respectively.	('leukopenia', 'Phenotype', 'HP:0001882', (57, 67))	('stomatitis', 'Disease', (82, 92))	('rs4987219', 'Mutation', 'rs4987219', (4, 13))	('rs4987219', 'Var', (4, 13))	('acute leukopenia', 'Phenotype', 'HP:0002488', (51, 67))	('rs1110277', 'Mutation', 'rs1110277', (18, 27))	('stomatitis', 'Phenotype', 'HP:0010280', (82, 92))	('leukopenia', 'Disease', 'MESH:D007970', (57, 67))	('leukopenia', 'Disease', (57, 67))	('rs1110277', 'Var', (18, 27))	('stomatitis', 'Disease', 'MESH:D013280', (82, 92))
524067	24578608	Conclusions: Further investigations with a larger number of patients or an in vitro study are needed to confirm the predictive values of genetic polymorphisms in SLC23A2.	('polymorphisms', 'Var', (145, 158))	('patients', 'Species', '9606', (60, 68))	('SLC23A2', 'Gene', (162, 169))	('SLC23A2', 'Gene', '9962', (162, 169))
524078	24578608	Several clinical studies were conducted to identify associations between SLC23A2 SNPs and the risk of cancers such as lymphoma, HPV16-associated head and neck cancer, colorectal cancer, and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('associations', 'Interaction', (52, 64))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (167, 184))	('SLC23A2', 'Gene', (73, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('colorectal cancer', 'Disease', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('neck cancer', 'Disease', 'MESH:D006258', (154, 165))	('neck cancer', 'Disease', (154, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('SLC23A2', 'Gene', '9962', (73, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('head and neck cancer', 'Phenotype', 'HP:0012288', (145, 165))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('HPV16-associated', 'Gene', (128, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (167, 184))	('HPV16', 'Species', '333760', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lymphoma', 'Disease', (118, 126))	('SNPs', 'Var', (81, 85))	('lymphoma', 'Disease', 'MESH:D008223', (118, 126))	('HPV16-associated', 'Reg', (128, 144))	('gastric cancer', 'Disease', (190, 204))
524096	24578608	Five SNPs, rs2681116 in intron 2, rs13037458 in intron 2, rs1715364 in intron 3, rs4987219 in intron 8, and rs1110277 in exon 11 (synonymous), met the criteria above.	('rs1715364', 'Mutation', 'rs1715364', (58, 67))	('rs13037458', 'Var', (34, 44))	('rs4987219', 'Var', (81, 90))	('rs2681116', 'Var', (11, 20))	('rs1715364', 'Var', (58, 67))	('rs1110277 in', 'Var', (108, 120))	('rs13037458', 'Mutation', 'rs13037458', (34, 44))	('rs1110277', 'Mutation', 'rs1110277', (108, 117))	('rs2681116', 'Mutation', 'rs2681116', (11, 20))	('rs4987219', 'Mutation', 'rs4987219', (81, 90))
524097	24578608	To analyze rs13037458, rs1715364, rs4987219, and rs1110277, genomic DNA was isolated from whole blood using a TaqMan  Sample-to-SNPTM kit (Applied Biosystems, Foster City, CA, USA), according to the manufacturer's instructions.	('rs1110277', 'Var', (49, 58))	('rs4987219', 'Mutation', 'rs4987219', (34, 43))	('rs4987219', 'Var', (34, 43))	('rs13037458', 'Var', (11, 21))	('rs13037458', 'Mutation', 'rs13037458', (11, 21))	('rs1110277', 'Mutation', 'rs1110277', (49, 58))	('rs1715364', 'Mutation', 'rs1715364', (23, 32))	('rs1715364', 'Var', (23, 32))
524108	24578608	Table 1 summarizes the data on associations between 5 SLC23A2 SNPs and the clinical response.	('associations', 'Interaction', (31, 43))	('SLC23A2', 'Gene', (54, 61))	('SLC23A2', 'Gene', '9962', (54, 61))	('clinical response', 'CPA', (75, 92))	('SNPs', 'Var', (62, 66))
524109	24578608	No significant correlations were observed between the genotypes examined and the clinical response; however, rs2681116 (p=0.144) and rs13037458 (p=0.085) had a tendency to associate with.	('rs13037458', 'Var', (133, 143))	('rs13037458', 'Mutation', 'rs13037458', (133, 143))	('rs2681116', 'Mutation', 'rs2681116', (109, 118))	('rs2681116', 'Var', (109, 118))
524110	24578608	As shown in Figure 1, these 2 SNPs also showed a tendency to predict long-term survival (p=0.142 for rs2681116, p=0.056 for rs13037458).	('rs2681116', 'Var', (101, 110))	('rs13037458', 'Var', (124, 134))	('long-term survival', 'CPA', (69, 87))	('rs2681116', 'Mutation', 'rs2681116', (101, 110))	('predict', 'Reg', (61, 68))	('rs13037458', 'Mutation', 'rs13037458', (124, 134))
524112	24578608	rs4987219 and rs1110277 significantly correlated with leukopenia (p=0.025) and stomatitis (p=0.019), respectively.	('stomatitis', 'Disease', 'MESH:D013280', (79, 89))	('stomatitis', 'Disease', (79, 89))	('rs4987219', 'Mutation', 'rs4987219', (0, 9))	('rs4987219', 'Var', (0, 9))	('rs1110277', 'Mutation', 'rs1110277', (14, 23))	('leukopenia', 'Phenotype', 'HP:0001882', (54, 64))	('stomatitis', 'Phenotype', 'HP:0010280', (79, 89))	('leukopenia', 'Disease', (54, 64))	('rs1110277', 'Var', (14, 23))	('correlated', 'Reg', (38, 48))	('leukopenia', 'Disease', 'MESH:D007970', (54, 64))
524113	24578608	To the best of our knowledge, this is the first study to investigate associations between genetic polymorphisms in SLC23A2 and the clinical outcomes of definitive 5-FU/CDDP-based CRT.	('polymorphisms', 'Var', (98, 111))	('SLC23A2', 'Gene', '9962', (115, 122))	('associations', 'Interaction', (69, 81))	('CDDP', 'Chemical', 'MESH:D002945', (168, 172))	('5-FU', 'Chemical', 'MESH:D005472', (163, 167))	('CR', 'Chemical', '-', (179, 181))	('SLC23A2', 'Gene', (115, 122))
524114	24578608	There was a tendency for rs2681116 in intron 2 and rs13037458 in intron 2 to predict the clinical response (Table 1).	('rs2681116', 'Var', (25, 34))	('rs13037458', 'Var', (51, 61))	('predict', 'Reg', (77, 84))	('rs2681116', 'Mutation', 'rs2681116', (25, 34))	('rs13037458', 'Mutation', 'rs13037458', (51, 61))
524122	24578608	In the present study, we showed that rs4987219 in intron 8 and the synonymous rs1110277 in exon 11 were associated with the severe acute leukopenia and stomatitis, respectively.	('rs4987219', 'Mutation', 'rs4987219', (37, 46))	('leukopenia', 'Disease', 'MESH:D007970', (137, 147))	('rs4987219', 'Var', (37, 46))	('rs1110277', 'Var', (78, 87))	('acute leukopenia', 'Phenotype', 'HP:0002488', (131, 147))	('leukopenia', 'Phenotype', 'HP:0001882', (137, 147))	('associated', 'Reg', (104, 114))	('stomatitis', 'Disease', 'MESH:D013280', (152, 162))	('stomatitis', 'Disease', (152, 162))	('leukopenia', 'Disease', (137, 147))	('rs1110277', 'Mutation', 'rs1110277', (78, 87))	('stomatitis', 'Phenotype', 'HP:0010280', (152, 162))
524124	24578608	More than 40 variants, including rs4987219 and rs1110277, were found in SLC23A2 gene at that time, but the pattern of linkage disequilibrium across the gene could not be clarified due to large size.	('rs1110277', 'Var', (47, 56))	('SLC23A2', 'Gene', (72, 79))	('rs4987219', 'Mutation', 'rs4987219', (33, 42))	('rs4987219', 'Var', (33, 42))	('rs1110277', 'Mutation', 'rs1110277', (47, 56))	('SLC23A2', 'Gene', '9962', (72, 79))
524125	24578608	It is not surprising that a genetic variant is linked with others and the effect on transport activity varies among variants; however, no associations of rs4987219 with stomatitis and rs1110277 with leukopenia suggested that the effect on transport activity is tissue-dependent.	('leukopenia', 'Disease', 'MESH:D007970', (199, 209))	('rs1110277', 'Var', (184, 193))	('associations', 'Interaction', (138, 150))	('rs4987219', 'Mutation', 'rs4987219', (154, 163))	('rs4987219', 'Var', (154, 163))	('leukopenia', 'Phenotype', 'HP:0001882', (199, 209))	('stomatitis', 'Disease', 'MESH:D013280', (169, 179))	('stomatitis', 'Disease', (169, 179))	('rs1110277', 'Mutation', 'rs1110277', (184, 193))	('leukopenia', 'Disease', (199, 209))	('stomatitis', 'Phenotype', 'HP:0010280', (169, 179))
524126	24578608	The SLC23A2 SNPs rs2681116, rs13037458, rs1715364, rs4987219, and rs1110277 were assessed in terms of the predictability of clinical outcomes following treatment with a definitive 5-FU/CDDP-based CRT in Japanese patients with ESCC.	('rs1715364', 'Var', (40, 49))	('rs2681116', 'Var', (17, 26))	('CDDP', 'Chemical', 'MESH:D002945', (185, 189))	('rs13037458', 'Var', (28, 38))	('ESCC', 'Disease', (226, 230))	('SLC23A2', 'Gene', '9962', (4, 11))	('rs4987219', 'Mutation', 'rs4987219', (51, 60))	('rs1110277', 'Mutation', 'rs1110277', (66, 75))	('patients', 'Species', '9606', (212, 220))	('rs2681116', 'Mutation', 'rs2681116', (17, 26))	('SLC23A2', 'Gene', (4, 11))	('rs13037458', 'Mutation', 'rs13037458', (28, 38))	('5-FU', 'Chemical', 'MESH:D005472', (180, 184))	('rs4987219', 'Var', (51, 60))	('rs1715364', 'Mutation', 'rs1715364', (40, 49))	('rs1110277', 'Var', (66, 75))	('CR', 'Chemical', '-', (196, 198))
524127	24578608	The rs2681116 and rs13037458 had a tendency to predict the clinical response and long-term survival, while rs4987219 and rs1110277 were markers of severe acute leukopenia and stomatitis, respectively.	('rs1110277', 'Var', (121, 130))	('long-term survival', 'CPA', (81, 99))	('leukopenia', 'Disease', (160, 170))	('leukopenia', 'Phenotype', 'HP:0001882', (160, 170))	('acute leukopenia', 'Phenotype', 'HP:0002488', (154, 170))	('stomatitis', 'Phenotype', 'HP:0010280', (175, 185))	('clinical response', 'CPA', (59, 76))	('rs2681116', 'Mutation', 'rs2681116', (4, 13))	('rs4987219', 'Mutation', 'rs4987219', (107, 116))	('rs13037458', 'Var', (18, 28))	('rs1110277', 'Mutation', 'rs1110277', (121, 130))	('leukopenia', 'Disease', 'MESH:D007970', (160, 170))	('rs4987219', 'Var', (107, 116))	('stomatitis', 'Disease', 'MESH:D013280', (175, 185))	('stomatitis', 'Disease', (175, 185))	('rs13037458', 'Mutation', 'rs13037458', (18, 28))	('rs2681116', 'Var', (4, 13))
524128	24578608	Further investigations with a larger number of patients or an in vitro study are needed to confirm the predictive values of genetic polymorphisms in SLC23A2.	('SLC23A2', 'Gene', (149, 156))	('polymorphisms', 'Var', (132, 145))	('patients', 'Species', '9606', (47, 55))	('SLC23A2', 'Gene', '9962', (149, 156))
524225	32072382	Therefore, RAMIE4 is a valuable therapeutic option for patients with resectable esophageal cancer.	('RAMIE4', 'Var', (11, 17))	('esophageal cancer', 'Disease', (80, 97))	('RAMIE4', 'Chemical', '-', (11, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('patients', 'Species', '9606', (55, 63))
524249	32558329	We found that tumors with high NSTMB had a significantly higher percentage of resting natural killer (NK) cells than those with low NSTMB (P = 0.028).	('TMB', 'Chemical', '-', (134, 137))	('higher', 'PosReg', (57, 63))	('high NSTMB', 'Var', (26, 36))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('TMB', 'Chemical', '-', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
524250	32558329	The percentages of regulatory T (Treg) and CD8+ T cells were also higher in those with high NSTMB, although it was not statistically significant (P = 0.064 for Treg cells and P = 0.12 for CD8+ T cells).	('CD8', 'Gene', (43, 46))	('CD8', 'Gene', (188, 191))	('high NSTMB', 'Var', (87, 97))	('CD8', 'Gene', '925', (188, 191))	('CD8', 'Gene', '925', (43, 46))	('TMB', 'Chemical', '-', (94, 97))	('higher', 'PosReg', (66, 72))
524281	32558329	Since NSTMB can affect the immunogenicity of a tumor, 9  which may influence prognosis, we sought to determine whether differences in prognosis existed between the two groups.	('influence', 'Reg', (67, 76))	('TMB', 'Chemical', '-', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('affect', 'Reg', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('NSTMB', 'Var', (6, 11))	('immunogenicity of', 'MPA', (27, 44))	('tumor', 'Disease', (47, 52))
524284	32558329	In stages II and III, patients with high NSTMB had a worse overall survival than patients with low NSTMB (chi2 = 4.134, log-rank P = 0.042 for stage II, and chi2 = 4.914, log-rank P = 0.027 for stage III: see Fig 1[c] and [d]).	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (81, 89))	('worse', 'NegReg', (53, 58))	('overall survival', 'MPA', (59, 75))	('TMB', 'Chemical', '-', (101, 104))	('high', 'Var', (36, 40))	('TMB', 'Chemical', '-', (43, 46))
524302	32558329	The percentages of regulatory T (Treg) and CD8+ T cells were also higher in the NSTMB high group than in the NSTMB low group, although the differences were not statistically significant (P = 0.064 for Treg cells, P = 0.12 for CD8+ T cells: see Fig 4([b]).	('CD8', 'Gene', (43, 46))	('CD8', 'Gene', '925', (43, 46))	('CD8', 'Gene', (226, 229))	('CD8', 'Gene', '925', (226, 229))	('TMB', 'Chemical', '-', (111, 114))	('higher', 'PosReg', (66, 72))	('NSTMB', 'Gene', (80, 85))	('high', 'Var', (86, 90))	('TMB', 'Chemical', '-', (82, 85))
524304	32558329	In this study we first compared the overall survival of patients with different NSTMB and found that patients with high NSTMB had worse overall survival than patients with low NSTMB.	('worse', 'NegReg', (130, 135))	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (101, 109))	('high', 'Var', (115, 119))	('TMB', 'Chemical', '-', (178, 181))	('TMB', 'Chemical', '-', (122, 125))	('overall survival', 'MPA', (136, 152))	('patients', 'Species', '9606', (158, 166))	('TMB', 'Chemical', '-', (82, 85))
524305	32558329	We then compared the overall survival in different pathological stages and found that in stages II and III, patients with high NSTMB had a worse overall survival than that in patients with low NSTMB.	('TMB', 'Chemical', '-', (195, 198))	('high', 'Var', (122, 126))	('overall survival', 'MPA', (145, 161))	('patients', 'Species', '9606', (175, 183))	('worse', 'NegReg', (139, 144))	('patients', 'Species', '9606', (108, 116))	('TMB', 'Chemical', '-', (129, 132))
524315	32558329	Moreover, the proportion of Treg cells was higher in tumors with high NSTMB, although the difference was not statistically significant (P = 0.064).	('higher', 'PosReg', (43, 49))	('NSTMB', 'Gene', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('high', 'Var', (65, 69))	('TMB', 'Chemical', '-', (72, 75))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('Treg cells', 'CPA', (28, 38))	('tumors', 'Disease', (53, 59))
524322	32558329	In addition, we found that the proportion of resting NK cells was higher in tumors with high NSTMB, suggesting that high NSTMB may cause NK cell inactivation to be common in malignant tumors, but more data for other kinds of tumors are needed.	('high', 'Var', (88, 92))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('TMB', 'Chemical', '-', (123, 126))	('inactivation', 'NegReg', (145, 157))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('high', 'Var', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumors', 'Disease', (76, 82))	('higher', 'PosReg', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('TMB', 'Chemical', '-', (95, 98))	('malignant tumors', 'Disease', (174, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('malignant tumors', 'Disease', 'MESH:D009369', (174, 190))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Disease', (225, 231))
524330	32558329	The proportion of resting NK cells was higher in tumors with high NSTMB, suggesting that we may use NK cell activation strategy to obtain a better prognosis.	('higher', 'PosReg', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('high', 'Var', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('NSTMB', 'Gene', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('TMB', 'Chemical', '-', (68, 71))
524337	30807555	Cyclopamine Suppresses Human Esophageal Carcinoma Cell Growth by Inhibiting Glioma-Associated Oncogene Protein-1, a Marker of Human Esophageal Carcinoma Progression Esophageal carcinoma is a common gastrointestinal tumor in humans.	('gastrointestinal tumor', 'Disease', 'MESH:D004067', (198, 220))	('Carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('Carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('Cyclopamine', 'Var', (0, 11))	('Esophageal Carcinoma Cell Growth', 'Disease', 'MESH:D000077277', (29, 61))	('Glioma', 'Phenotype', 'HP:0009733', (76, 82))	('Esophageal carcinoma', 'Disease', (165, 185))	('Human', 'Species', '9606', (23, 28))	('Suppresses', 'NegReg', (12, 22))	('gastrointestinal tumor', 'Disease', (198, 220))	('Human', 'Species', '9606', (126, 131))	('Glioma-Associated Oncogene Protein-1', 'Gene', '2735', (76, 112))	('Inhibiting', 'NegReg', (65, 75))	('Esophageal Carcinoma', 'Disease', 'MESH:D004938', (132, 152))	('Esophageal Carcinoma', 'Disease', 'MESH:D004938', (29, 49))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (29, 49))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (132, 152))	('Cyclopamine', 'Chemical', 'MESH:C000541', (0, 11))	('Esophageal Carcinoma Cell Growth', 'Disease', (29, 61))	('Human', 'CPA', (23, 28))	('gastrointestinal tumor', 'Phenotype', 'HP:0007378', (198, 220))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (165, 185))	('Esophageal Carcinoma', 'Disease', (132, 152))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (165, 185))	('humans', 'Species', '9606', (224, 230))	('Glioma-Associated Oncogene Protein-1', 'Gene', (76, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
524339	30807555	We investigated glioma-associated oncogene protein-1 (Gli-1) expression in human esophageal carcinoma tissue and the inhibition of cyclopamine on EC9706 esophageal carcinoma cell growth.	('Gli-1', 'Gene', '2735', (54, 59))	('esophageal carcinoma', 'Disease', (81, 101))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (153, 173))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (81, 101))	('human', 'Species', '9606', (75, 80))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (81, 101))	('EC9706', 'Var', (146, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (153, 173))	('glioma-associated oncogene protein-1', 'Gene', '2735', (16, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('EC9706', 'CellLine', 'CVCL:E307', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('Gli-1', 'Gene', (54, 59))	('esophageal carcinoma', 'Disease', (153, 173))	('glioma-associated oncogene protein-1', 'Gene', (16, 52))	('cyclopamine', 'Chemical', 'MESH:C000541', (131, 142))
524347	30807555	Morphology of EC9706 cells appeared as round with rough edges, karyopyknosis, and karyorrhexis.	('EC9706', 'Var', (14, 20))	('karyopyknosis', 'CPA', (63, 76))	('karyorrhexis', 'CPA', (82, 94))	('EC9706', 'CellLine', 'CVCL:E307', (14, 20))
524363	30807555	The defect of Hh leads to continuously activating Gli, which is associated with certain types of cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Gli', 'Gene', (50, 53))	('defect', 'Var', (4, 10))	('Gli', 'Gene', '2735', (50, 53))
524409	30807555	The treatment time was 48 h. Apoptotic EC9706 cells appeared rounded with rough edges, karyopyknosis, and karyorrhexis.	('EC9706', 'CellLine', 'CVCL:E307', (39, 45))	('karyopyknosis', 'CPA', (87, 100))	('EC9706', 'Var', (39, 45))
524418	30807555	These results indicated that cyclopamine can downregulate Gli-1 expression and suppress the Hh pathway.	('Gli-1', 'Gene', (58, 63))	('expression', 'MPA', (64, 74))	('Gli-1', 'Gene', '2735', (58, 63))	('downregulate', 'NegReg', (45, 57))	('suppress', 'NegReg', (79, 87))	('cyclopamine', 'Var', (29, 40))	('Hh pathway', 'Pathway', (92, 102))	('cyclopamine', 'Chemical', 'MESH:C000541', (29, 40))
524423	30807555	EC9706 cell proliferation was suppressed but apoptosis was promoted, and the effect was dose-dependent.	('EC9706', 'Var', (0, 6))	('suppressed', 'NegReg', (30, 40))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('rat', 'Species', '10116', (19, 22))	('promoted', 'PosReg', (59, 67))	('apoptosis', 'CPA', (45, 54))
524429	30807555	In normal cells, Ptc suppresses Smo activity, and then inhibits the downstream protein Gli, which suppresses the transcription of targeted genes.	('transcription', 'MPA', (113, 126))	('suppresses', 'NegReg', (98, 108))	('Smo', 'Gene', (32, 35))	('Gli', 'Gene', (87, 90))	('inhibits', 'NegReg', (55, 63))	('Ptc', 'Var', (17, 20))	('suppresses', 'NegReg', (21, 31))	('Smo', 'Gene', '6608', (32, 35))	('Gli', 'Gene', '2735', (87, 90))
524432	30807555	The loss or mutation of Ptc, or the Smo mutation resulting in inhibition of Ptc, can lead to loss of control of Hh, activating Gli and transcription of targeted genes.	('activating', 'PosReg', (116, 126))	('Ptc', 'Gene', (24, 27))	('Gli', 'Gene', '2735', (127, 130))	('loss', 'NegReg', (93, 97))	('Smo', 'Gene', (36, 39))	('transcription', 'MPA', (135, 148))	('control', 'MPA', (101, 108))	('Smo', 'Gene', '6608', (36, 39))	('mutation', 'Var', (12, 20))	('loss', 'NegReg', (4, 8))	('Gli', 'Gene', (127, 130))
524445	30807555	Though measuring EC9706 cell proliferation and apoptosis, we found that inhibiting the Hh pathway significantly suppressed EC9706 proliferation but promoted EC9706 apoptosis, in a dose-dependent manner.	('EC9706', 'CellLine', 'CVCL:E307', (123, 129))	('suppressed', 'NegReg', (112, 122))	('EC9706', 'CellLine', 'CVCL:E307', (17, 23))	('rat', 'Species', '10116', (36, 39))	('EC9706', 'CellLine', 'CVCL:E307', (157, 163))	('inhibiting', 'Var', (72, 82))	('rat', 'Species', '10116', (137, 140))	('Hh pathway', 'Pathway', (87, 97))	('EC9706', 'Gene', (123, 129))	('promoted', 'PosReg', (148, 156))
524448	30807555	found that silencing Gli-1 obviously suppressed EC9706 proliferation and promoted cell apoptosis, which indicated that the expression of Gli-1 influences the growth of esophageal cells.	('silencing', 'Var', (11, 20))	('EC9706', 'MPA', (48, 54))	('Gli-1', 'Gene', (137, 142))	('Gli-1', 'Gene', (21, 26))	('influences', 'Reg', (143, 153))	('growth', 'MPA', (158, 164))	('EC9706', 'CellLine', 'CVCL:E307', (48, 54))	('Gli-1', 'Gene', '2735', (137, 142))	('cell apoptosis', 'CPA', (82, 96))	('Gli-1', 'Gene', '2735', (21, 26))	('rat', 'Species', '10116', (62, 65))	('promoted', 'PosReg', (73, 81))	('suppressed', 'NegReg', (37, 47))
524509	29514688	To this ether vinyl (R1) are attached the saturated (C16:0) and saturated and monounsaturated carbon chains (C18:0 and C18:1, respectively).	('rat', 'Species', '10116', (46, 49))	('C18:1', 'Var', (119, 124))	('rat', 'Species', '10116', (88, 91))	('ether vinyl', 'Chemical', 'MESH:C100195', (8, 19))	('C16:0', 'Var', (53, 58))	('carbon', 'Chemical', 'MESH:D002244', (94, 100))	('rat', 'Species', '10116', (68, 71))	('C18:0', 'Var', (109, 114))
524510	29514688	In the sn-2 (R2) position, plasmalogens are enriched with polyunsaturated fatty acid, specifically docosahexaenoic acids (C22:6 n-3) or arachidonic acid (C20:4 omega-6).	('sn-2', 'Gene', (7, 11))	('C22:6', 'Var', (122, 127))	('docosahexaenoic acids', 'Chemical', 'MESH:D004281', (99, 120))	('polyunsaturated fatty acid', 'Chemical', 'MESH:D005231', (58, 84))	('arachidonic acid', 'Chemical', 'MESH:D016718', (136, 152))	('sn-2', 'Gene', '92745', (7, 11))
524533	29514688	In addition, plasmalogens can act directly in reducing PL surface tension and viscosity, on the synaptic transmission process, on alveolar surfactants, improving membrane dynamics during respiratory cycles, on signal transduction, on membrane vesicle formation, on ion transport, on the platelet activation factor, the regulation of fusion, fission and fluidity of the cell membrane, control of membrane proteins activity, as a reservoir for second lipid messengers and supporting polyunsaturated fatty acids.	('lipid', 'Chemical', 'MESH:D008055', (449, 454))	('PL', 'Chemical', 'MESH:D010743', (55, 57))	('rat', 'Species', '10116', (192, 195))	('plasmalogens', 'Var', (13, 25))	('rat', 'Species', '10116', (491, 494))	('improving', 'PosReg', (152, 161))	('membrane dynamics', 'MPA', (162, 179))	('polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (481, 508))
524574	29514688	The pathogenic impairments conferred by AGPS knockdown in cancer cells are due to the specific depletion of the oncogenic signaling lipid lysophosphatidic acid ether and prostaglandins.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lysophosphatidic acid ether', 'Chemical', '-', (138, 165))	('knockdown', 'Var', (45, 54))	('AGPS', 'Gene', '8540', (40, 44))	('prostaglandins', 'Chemical', 'MESH:D011453', (170, 184))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('lipid', 'Chemical', 'MESH:D008055', (132, 137))	('cancer', 'Disease', (58, 64))	('AGPS', 'Gene', (40, 44))
524584	29514688	Although most of the individual metabolites showed a significant reduction in PC patient serum, the strongest discriminator based on multiple statistical criteria was PC-594.	('patient', 'Species', '9606', (81, 88))	('PC', 'Chemical', 'MESH:D010713', (167, 169))	('PC-594', 'Var', (167, 173))	('PC', 'Chemical', 'MESH:D010713', (78, 80))	('reduction', 'NegReg', (65, 74))
524705	25973684	Furthermore, the knockdown of keratin 18 by small interfering RNAs inhibited the expression of tubulin and increased the metastasis of cancer cells, suggesting that keratin 18 is the upstream signal of tubulin and plays a vital role in metastasis.	('cancer', 'Disease', (135, 141))	('inhibited', 'NegReg', (67, 76))	('keratin', 'Gene', (30, 37))	('small interfering', 'Var', (44, 61))	('increased', 'PosReg', (107, 116))	('RNAs', 'Gene', (62, 66))	('tubulin', 'Protein', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('knockdown', 'Var', (17, 26))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('expression', 'MPA', (81, 91))
524731	25973684	The knockdown of keratin 18 in Eca109 cells was found to partially reverse the effect of OC on metastasis, suggesting that keratin 18 plays an important role on ESCC metastasis.	('ESCC', 'Disease', (161, 165))	('knockdown', 'Var', (4, 13))	('metastasis', 'CPA', (95, 105))	('OC', 'Chemical', 'MESH:C575447', (89, 91))
524772	25973684	Importantly, the silencing of keratin 18 partially attenuated the effect of OC on migration, suggesting that keratin 18 plays a pivotal role on the regulation of migration.	('OC', 'Chemical', 'MESH:C575447', (76, 78))	('attenuated', 'NegReg', (51, 61))	('migration', 'CPA', (82, 91))	('keratin 18', 'Protein', (30, 40))	('silencing', 'Var', (17, 26))
524773	25973684	3E,H, the transwell and matrigel assay results revealed that the silencing of keratin 18 efficiently enhanced Eca109 cell migration and invasion, and the effect of OC on metastasis was partially abolished by keratin 18 siRNA.	('silencing', 'Var', (65, 74))	('keratin 18', 'Gene', (78, 88))	('invasion', 'CPA', (136, 144))	('enhanced', 'PosReg', (101, 109))	('OC', 'Chemical', 'MESH:C575447', (164, 166))	('Eca109 cell migration', 'CPA', (110, 131))
524783	25973684	Importantly, the silencing of keratin 18 diminished the tubulin accumulation upon OC treatment, suggesting the keratin 18 was the key component that mediated the effect of OC on tubulins (Fig.	('keratin', 'Protein', (30, 37))	('tubulin accumulation', 'MPA', (56, 76))	('OC', 'Chemical', 'MESH:C575447', (82, 84))	('diminished', 'NegReg', (41, 51))	('OC', 'Chemical', 'MESH:C575447', (172, 174))	('silencing', 'Var', (17, 26))
524785	25973684	found that the ERK inhibitor U0126 and the AKT inhibitor LY294002 inhibit the expression of keratin 18 in epithelial ovarian cancer.	('expression', 'MPA', (78, 88))	('LY294002', 'Chemical', 'MESH:C085911', (57, 65))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (106, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('U0126', 'Chemical', 'MESH:C113580', (29, 34))	('epithelial ovarian cancer', 'Disease', (106, 131))	('keratin 18', 'Protein', (92, 102))	('inhibit', 'NegReg', (66, 73))	('LY294002', 'Var', (57, 65))
524786	25973684	Furthermore, recent studies have implied the importance of the ERK pathway in cancer cell migration and demonstrated that LY294002 blocks breast cell migration.	('breast cell migration', 'CPA', (138, 159))	('cancer', 'Disease', (78, 84))	('LY294002', 'Chemical', 'MESH:C085911', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('blocks', 'NegReg', (131, 137))	('ERK pathway', 'Pathway', (63, 74))	('LY294002', 'Var', (122, 130))
524787	25973684	In the above study, we showed that knockdown of keratin 18 could not totally eliminate the effect of OC on metastasis, suggesting that OC might target other signaling pathways.	('knockdown', 'Var', (35, 44))	('keratin 18', 'Protein', (48, 58))	('metastasis', 'CPA', (107, 117))	('OC', 'Chemical', 'MESH:C575447', (135, 137))	('OC', 'Chemical', 'MESH:C575447', (101, 103))	('target', 'Reg', (144, 150))
524791	25973684	5B,C, U0126 and LY294002 significantly suppressed Eca109 cell migration.	('LY294002', 'Chemical', 'MESH:C085911', (16, 24))	('LY294002', 'Var', (16, 24))	('U0126', 'Chemical', 'MESH:C113580', (6, 11))	('suppressed', 'NegReg', (39, 49))	('Eca109 cell migration', 'CPA', (50, 71))
524820	25973684	Our study indicated that the knockdown of keratin 18 can enhance tumor cell migration and invasion in esophageal cancer.	('keratin 18', 'Protein', (42, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('knockdown', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('invasion', 'CPA', (90, 98))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('enhance', 'PosReg', (57, 64))
524825	25973684	9, knockdown of keratin 18 could not totally abolish the inhibitory effect of OC on metastasis, suggesting that OC might have other protein targets.	('metastasis', 'CPA', (84, 94))	('OC', 'Chemical', 'MESH:C575447', (112, 114))	('OC', 'Chemical', 'MESH:C575447', (78, 80))	('knockdown', 'Var', (3, 12))	('keratin 18', 'Protein', (16, 26))
524827	25973684	Zhou et al found that the AKT inhibitor LY294002 and the ERK inhibitor U0126 inhibited the expression of keratin 18 in epithelial ovarian cancer.	('expression', 'MPA', (91, 101))	('LY294002', 'Chemical', 'MESH:C085911', (40, 48))	('inhibited', 'NegReg', (77, 86))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (119, 144))	('epithelial ovarian cancer', 'Disease', (119, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('LY294002', 'Var', (40, 48))	('U0126', 'Chemical', 'MESH:C113580', (71, 76))	('keratin 18', 'Protein', (105, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (130, 144))
524828	25973684	We also found LY294002 and U0126 significantly suppressed Eca109 cell migration, consistent with other reports.	('suppressed', 'NegReg', (47, 57))	('U0126', 'Chemical', 'MESH:C113580', (27, 32))	('LY294002', 'Var', (14, 22))	('Eca109 cell migration', 'CPA', (58, 79))	('U0126', 'Var', (27, 32))	('LY294002', 'Chemical', 'MESH:C085911', (14, 22))
524838	25973684	PBS, MTT, DMSO, U0126, LY294002 and crystal violet were purchased from Sigma-Aldrich (St. Louis, MO, USA).	('MTT', 'Chemical', 'MESH:C070243', (5, 8))	('LY294002', 'Chemical', 'MESH:C085911', (23, 31))	('crystal violet', 'Chemical', 'MESH:D005840', (36, 50))	('U0126', 'Chemical', 'MESH:C113580', (16, 21))	('DMSO', 'Chemical', 'MESH:D004121', (10, 14))	('LY294002', 'Var', (23, 31))	('PBS', 'Disease', 'MESH:D011535', (0, 3))	('PBS', 'Disease', (0, 3))
524860	25973684	9154, Cell Signaling), MEK (Cat.9122, Cell Signaling), p-mTOR (Cat.	('Cat.9122', 'Var', (28, 36))	('mTOR', 'Gene', (57, 61))	('mTOR', 'Gene', '2475', (57, 61))	('Cat.9122', 'CellLine', 'CVCL:6F73', (28, 36))	('MEK', 'Gene', (23, 26))	('MEK', 'Gene', '5609', (23, 26))
524861	25973684	5346, Cell Signaling), alpha-tubulin (Cat.sc-5286, Santa Cruz, CA, USA), keratin 8 (Cat.	('Cat.sc-5286', 'Var', (38, 49))	('keratin 8', 'Gene', '3856', (73, 82))	('keratin 8', 'Gene', (73, 82))	('alpha-tubulin', 'Gene', (23, 36))	('alpha-tubulin', 'Gene', '10376', (23, 36))
524953	24312151	Note that k3/(k2 + k3) is the probability that a tracer molecule extracted from blood into tumor will be trapped.	('k3/(k2 + k3', 'Var', (10, 21))	('trapped', 'MPA', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
525042	24312151	Another, simpler approach for tumors with images that appear homogeneous except for the PVE is to erode the VOI boundary within the segmented boundary by a distance based on image resolution.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('erode', 'Var', (98, 103))
525085	24312151	It has been demonstrated in phantom and patient studies that PSF modeling improves image resolution and noise properties, which translates to better tumor detection.	('patient', 'Species', '9606', (40, 47))	('improves', 'PosReg', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('image resolution', 'MPA', (83, 99))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('noise properties', 'MPA', (104, 120))	('tumor', 'Disease', (149, 154))	('better', 'PosReg', (142, 148))	('modeling', 'Var', (65, 73))
525157	23244569	Peroxidase activity was visualized with the DAB Elite kit (K3465, Dako), and the brown coloration of tissues represented positive staining.	('K3465', 'Var', (59, 64))	('activity', 'MPA', (11, 19))	('DAB', 'Chemical', 'MESH:C000469', (44, 47))
525159	23244569	For Immunofluorescent staining, sections were incubated with primary anti-ABCG2 antibodies (1:100, mouse IgG; Santa Cruz, San Diego, CA, USA) and anti-V-ATPase antibodies (1:100, rabbit IgG; Abcam, Cambridge, MA, USA) at 4 C overnight.	('mouse', 'Species', '10090', (99, 104))	('rabbit', 'Species', '9986', (179, 185))	('1:100', 'Var', (92, 97))	('ATPase', 'Gene', '1769', (153, 159))	('ABCG2', 'Gene', (74, 79))	('ABCG2', 'Gene', '9429', (74, 79))	('1:100', 'Var', (172, 177))	('ATPase', 'Gene', (153, 159))
525208	23244569	Our data also supported the notion that ABCG2 expression in esophageal squamous cancer cells associated with TNM staging, particularly in the context of high TNM staging and its association with high expression and enhanced positive staining intensity of ABCG2 expression.	('expression', 'Var', (46, 56))	('ABCG2', 'Gene', '9429', (40, 45))	('ABCG2', 'Gene', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('TNM', 'Gene', (109, 112))	('ABCG2', 'Gene', '9429', (255, 260))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (60, 86))	('squamous cancer', 'Phenotype', 'HP:0002860', (71, 86))	('TNM', 'Gene', (158, 161))	('associated', 'Reg', (93, 103))	('expression', 'MPA', (261, 271))	('TNM', 'Gene', '10178', (109, 112))	('TNM', 'Gene', '10178', (158, 161))	('esophageal squamous cancer', 'Disease', (60, 86))	('high expression', 'MPA', (195, 210))	('ABCG2', 'Gene', (40, 45))	('enhanced', 'PosReg', (215, 223))	('positive staining intensity', 'MPA', (224, 251))
525222	23244569	It was previously shown that over-expression of V-ATPase plays an important role in maintaining the alkaline environment of the cytoplasm by regulating the cytosolic pH as a means to counter the otherwise acidic extracellular environment (15).	('cytosolic pH', 'MPA', (156, 168))	('over-expression', 'Var', (29, 44))	('men', 'Species', '9606', (233, 236))	('ATPase', 'Gene', '1769', (50, 56))	('alkaline environment', 'MPA', (100, 120))	('regulating', 'Reg', (141, 151))	('ATPase', 'Gene', (50, 56))	('men', 'Species', '9606', (116, 119))
525310	22161620	We controlled for a number of known risk factors including age, BMI and cigarette smoking in our analyses; further, the associations we observed between diabetes and EA and GCA did not differ by age and appeared to be more pronounced among subjects with low BMI (<25).	('associations', 'Interaction', (120, 132))	('kin', 'Gene', (85, 88))	('GCA', 'Disease', (173, 176))	('diabetes', 'Disease', (153, 161))	('EA', 'Phenotype', 'HP:0011459', (166, 168))	('diabetes', 'Disease', 'MESH:D003920', (153, 161))	('kin', 'Gene', '22944', (85, 88))	('low BMI', 'Phenotype', 'HP:0045082', (254, 261))	('low', 'Var', (254, 257))
525377	32016515	suggested that the use of electrosurgical instruments is associated with a significant rise in temperature at the tip of the instrument, proportional to the power and length of time of application.	('rise', 'PosReg', (87, 91))	('men', 'Species', '9606', (48, 51))	('electrosurgical instruments', 'Var', (26, 53))	('men', 'Species', '9606', (131, 134))	('temperature at the tip of the instrument', 'MPA', (95, 135))
525402	30863185	Dysregulation of Smurf2 in different cancer types has been described, besides colorectal cancer (CRC).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('Smurf2', 'Gene', (17, 23))	('cancer', 'Disease', (37, 43))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('colorectal cancer', 'Disease', (78, 95))
525411	30863185	Dysregulation in the expression pattern of the substrate-specific E3 ubiquitin ligases is known to contribute to tumorigenesis.	('tumor', 'Disease', (113, 118))	('Dysregulation', 'Var', (0, 13))	('contribute', 'Reg', (99, 109))	('expression', 'MPA', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('E3 ubiquitin', 'Protein', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
525420	30863185	Given its function in the above mentioned signaling pathways, it is not astonishing that Smurf2 silencing diminishes the invasion and migration of breast cancer cells.	('silencing', 'Var', (96, 105))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('diminishes', 'NegReg', (106, 116))	('Smurf2', 'Gene', (89, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('breast cancer', 'Disease', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
525421	30863185	Besides, high-level expressional changes of Smurf2 are associated with poor prognosis in esophageal cancer.	('esophageal cancer', 'Disease', (89, 106))	('Smurf2', 'Gene', (44, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (55, 65))	('high-level', 'Var', (9, 19))
525455	30863185	When looking at the entire cohort, mean overall survival was 58 months for patients displaying high Smurf2 expression, compared to 52.9 months in patients with low tumoral Smurf2 expression (n=98) (P=0.86) (Figure 4A).	('high', 'Var', (95, 99))	('patients', 'Species', '9606', (75, 83))	('low tumoral', 'Disease', (160, 171))	('Smurf2', 'Gene', (100, 106))	('low tumoral', 'Disease', 'MESH:D009800', (160, 171))	('expression', 'Var', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('patients', 'Species', '9606', (146, 154))
525456	30863185	Interestingly, in the subgroup of patients with MSS tumors (n=58), high tumoral expression of Smurf2 was significantly associated with impaired overall survival (mean overall survival high vs low Smurf2 expression 38.3 vs 67.4 months; P=0.044) (Figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('high', 'Var', (67, 71))	('MSS tumors', 'Disease', 'MESH:D013132', (48, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (72, 77))	('impaired', 'NegReg', (135, 143))	('MSS tumors', 'Disease', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('patients', 'Species', '9606', (34, 42))	('Smurf2', 'Gene', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('overall survival', 'MPA', (144, 160))
525460	30863185	Upon knockdown of Smurf2, we observed significantly diminished invasive (P=0.012) and migrative (P=0.011) properties of MSS SW-480 cells (Figure 5 A, B).	('knockdown', 'Var', (5, 14))	('diminished', 'NegReg', (52, 62))	('Smurf2', 'Gene', (18, 24))	('migrative', 'CPA', (86, 95))	('SW-480', 'CellLine', 'CVCL:0546', (124, 130))
525465	30863185	Intriguingly, high-level Smurf2 expression represented an adverse prognostic factor in patients with MSS tumors.	('MSS tumors', 'Disease', (101, 111))	('Smurf2', 'Gene', (25, 31))	('high-level', 'Var', (14, 24))	('MSS tumors', 'Disease', 'MESH:D013132', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('expression', 'MPA', (32, 42))	('patients', 'Species', '9606', (87, 95))
525467	30863185	Expressional changes, dysfunction, and genetic alterations of substrate-specific E3 ubiquitin ligases are known to provoke cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('E3 ubiquitin', 'Protein', (81, 93))	('provoke', 'Reg', (115, 122))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('genetic alterations', 'Var', (39, 58))	('cancer', 'Disease', (123, 129))	('dysfunction', 'Var', (22, 33))
525474	30863185	Hellwinkel et al reported higher Smurf2 expression in T2 than in T3 prostate cancer, indicating that loss of Smurf2 facilitates tumor progression.	('Smurf2', 'Gene', (109, 115))	('expression', 'MPA', (40, 50))	('facilitates', 'PosReg', (116, 127))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('higher', 'PosReg', (26, 32))	('loss', 'Var', (101, 105))	('prostate cancer', 'Disease', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', (128, 133))	('Smurf2', 'Gene', (33, 39))	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))
525477	30863185	In accordance with these findings, David et al observed attenuated proliferative, migrative, and invasive properties after Smurf2 knockdown in MCF-7 (estrogen receptor [ER] positive) and MDA-MB-231 (ER negative) breast cancer cells, which was mediated by the Smurf2 target protein connector enhancer of kinase suppressor of ras 2 (CNKSR2) via PI3K-PTEN-AKT signaling.	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('proliferative', 'CPA', (67, 80))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (187, 197))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('breast cancer', 'Disease', (212, 225))	('MCF-7', 'CellLine', 'CVCL:0031', (143, 148))	('MCF-7', 'Gene', (143, 148))	('attenuated', 'NegReg', (56, 66))	('knockdown', 'Var', (130, 139))	('CNKSR2', 'Gene', (331, 337))	('CNKSR2', 'Gene', '22866', (331, 337))	('estrogen receptor', 'Gene', '2099', (150, 167))	('connector enhancer of kinase suppressor of ras 2', 'Gene', (281, 329))	('connector enhancer of kinase suppressor of ras 2', 'Gene', '22866', (281, 329))	('migrative', 'CPA', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('Smurf2', 'Gene', (123, 129))	('invasive properties', 'CPA', (97, 116))	('estrogen receptor', 'Gene', (150, 167))
525481	30863185	However, Smurf2 expression was significantly elevated and associated with a wider range in MSI as compared to MSS tumors, hinting the fact that MSI tumors of CRC with DNA replication errors and defective mismatch repair have distinct phenotypic features in contrast to MSS tumors.	('MSI tumors', 'Disease', 'MESH:D009369', (144, 154))	('CRC', 'Phenotype', 'HP:0003003', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('associated', 'Reg', (58, 68))	('MSI tumors', 'Disease', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MSS tumors', 'Disease', 'MESH:D013132', (110, 120))	('MSS tumors', 'Disease', 'MESH:D013132', (269, 279))	('defective mismatch repair', 'Var', (194, 219))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('Smurf2', 'Gene', (9, 15))	('elevated', 'PosReg', (45, 53))	('MSS tumors', 'Disease', (269, 279))	('MSS tumors', 'Disease', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('expression', 'MPA', (16, 26))
525484	30863185	In general, better prognosis is reported in patients with MSI compared to those with MSS CRC, but conflicting evidence likewise exists: Shin et al identified MSI as an independent prognostic factor, associated with impaired survival in stage II CRC, and Mohan et al reported reduced disease-specific survival in stage III MSI CRC.	('reduced', 'NegReg', (275, 282))	('MSI CRC', 'Disease', (322, 329))	('patients', 'Species', '9606', (44, 52))	('impaired', 'NegReg', (215, 223))	('stage', 'Disease', (236, 241))	('MSI', 'Disease', (158, 161))	('Shin', 'Var', (136, 140))	('MSI CRC', 'Disease', 'MESH:D015179', (322, 329))	('CRC', 'Phenotype', 'HP:0003003', (245, 248))	('CRC', 'Phenotype', 'HP:0003003', (326, 329))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))	('disease-specific', 'MPA', (283, 299))	('survival', 'MPA', (224, 232))
525486	30863185	Remarkably, in this context, we found that high tumoral expression of Smurf2 was associated with impaired survival in patients with MSS CRC, but not in those with MSI CRC.	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('CRC', 'Phenotype', 'HP:0003003', (167, 170))	('impaired', 'NegReg', (97, 105))	('tumor', 'Disease', (48, 53))	('Smurf2', 'Gene', (70, 76))	('MSS', 'Var', (132, 135))	('MSI CRC', 'Disease', (163, 170))	('MSI CRC', 'Disease', 'MESH:D015179', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('survival', 'MPA', (106, 114))	('patients', 'Species', '9606', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
525489	30863185	Furthermore, migration of the MSI cell line DLD-1 showed no significant difference after Smurf2 knockdown whereas the MSS cell line SW-480 showed both significant differences in invasion and migration.	('knockdown', 'Var', (96, 105))	('Smurf2', 'Gene', (89, 95))	('invasion', 'CPA', (178, 186))	('migration', 'CPA', (191, 200))	('SW-480', 'CellLine', 'CVCL:0546', (132, 138))
525503	30755598	HMGB1 knockdown in ESCC cells resulted in increased radiosensitivity both in vitro and in vivo.	('increased', 'PosReg', (42, 51))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (42, 68))	('HMGB1', 'Gene', '3146', (0, 5))	('HMGB1', 'Gene', (0, 5))	('radiosensitivity', 'MPA', (52, 68))	('knockdown', 'Var', (6, 15))
525504	30755598	Autophagy level was found depressed in HMGB1 inhibition cells and activation of autophagy brought back cell's radioresistance.	('Autophagy level', 'CPA', (0, 15))	('HMGB1', 'Gene', '3146', (39, 44))	('depressed', 'Disease', (26, 35))	('depressed', 'Disease', 'MESH:D000275', (26, 35))	('autophagy', 'CPA', (80, 89))	('inhibition', 'Var', (45, 55))	('radioresistance', 'CPA', (110, 125))	('HMGB1', 'Gene', (39, 44))	('activation', 'PosReg', (66, 76))
525523	30755598	In this work, we showed that high HMGB1 expression in tumor tissue is associated with recurrence after PORT for locally advanced resected ESCC.	('expression', 'MPA', (40, 50))	('high', 'Var', (29, 33))	('HMGB1', 'Gene', (34, 39))	('recurrence', 'Disease', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('associated with', 'Reg', (70, 85))	('HMGB1', 'Gene', '3146', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
525525	30755598	Mechanistically, HMGB1 inhibition induces low autophagy level, which may contribute to such radiosensitization.	('inhibition', 'Var', (23, 33))	('HMGB1', 'Gene', '3146', (17, 22))	('HMGB1', 'Gene', (17, 22))	('autophagy level', 'CPA', (46, 61))	('low', 'NegReg', (42, 45))
525531	30755598	Among the male patients, high HMGB1 expression trended towards higher in-field recurrence rate (P < 0.0001) (Fig.	('patients', 'Species', '9606', (15, 23))	('HMGB1', 'Gene', (30, 35))	('HMGB1', 'Gene', '3146', (30, 35))	('in-field recurrence rate', 'CPA', (70, 94))	('high', 'Var', (25, 29))	('higher', 'PosReg', (63, 69))	('expression', 'MPA', (36, 46))
525534	30755598	Further Kaplan-Meier analyses showed that high HMGB1 associated with shorter relapse-free survival (RFS) (P < 0.0001, Log-rank test, Fig.	('HMGB1', 'Gene', (47, 52))	('HMGB1', 'Gene', '3146', (47, 52))	('shorter', 'NegReg', (69, 76))	('relapse-free survival', 'CPA', (77, 98))	('high', 'Var', (42, 46))
525539	30755598	Based on the result that HMGB1 upregulation was association with recurrence after radiotherapy, we hypothesized that HMGB1 knockdown would sensitize ESCC cells to irradiation (IR).	('ESCC', 'Disease', (149, 153))	('sensitize', 'Reg', (139, 148))	('HMGB1', 'Gene', (117, 122))	('HMGB1', 'Gene', (25, 30))	('HMGB1', 'Gene', '3146', (117, 122))	('HMGB1', 'Gene', '3146', (25, 30))	('knockdown', 'Var', (123, 132))	('upregulation', 'PosReg', (31, 43))
525544	30755598	Clonogenic survival assays showed that HMGB1 knockdown ESCC cells were more sensitive to IR than control (P < 0.05) (Fig.	('HMGB1', 'Gene', '3146', (39, 44))	('HMGB1', 'Gene', (39, 44))	('knockdown', 'Var', (45, 54))	('sensitive to IR', 'MPA', (76, 91))
525549	30755598	In comparison, tumors grew even slower with both IR treatment and HMGB1 depletion in term of tumor weight (P < 0.01) and tumor volume (P < 0.01) (Fig.	('slower', 'NegReg', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('HMGB1', 'Gene', (66, 71))	('tumor', 'Disease', (15, 20))	('HMGB1', 'Gene', '3146', (66, 71))	('depletion', 'Var', (72, 81))	('tumors', 'Disease', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
525550	30755598	3c-e), indicating the additional suppressive effect brought by HMGB1 depletion.	('suppressive', 'NegReg', (33, 44))	('HMGB1', 'Gene', (63, 68))	('HMGB1', 'Gene', '3146', (63, 68))	('depletion', 'Var', (69, 78))
525551	30755598	Together with in vitro experiments, these results proved that HMGB1 knockdown sensitized ESCC cells lines to IR and that HMGB1 inhibitor might be developed as drug to increase radiotherapy effect in ESCC patients.	('patients', 'Species', '9606', (204, 212))	('sensitized', 'Reg', (78, 88))	('HMGB1', 'Gene', (62, 67))	('HMGB1', 'Gene', (121, 126))	('knockdown', 'Var', (68, 77))	('HMGB1', 'Gene', '3146', (62, 67))	('HMGB1', 'Gene', '3146', (121, 126))
525552	30755598	Previous studied reported that endogenous HMGB1 can regulate autophagy in human pancreatic tumor cell, which can protect cells from IR-induced damage.	('pancreatic tumor', 'Disease', (80, 96))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (80, 96))	('HMGB1', 'Gene', (42, 47))	('HMGB1', 'Gene', '3146', (42, 47))	('pancreatic tumor', 'Disease', 'MESH:D010190', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('endogenous', 'Var', (31, 41))	('human', 'Species', '9606', (74, 79))	('autophagy', 'CPA', (61, 70))	('regulate', 'Reg', (52, 60))
525553	30755598	Our hypothesis was that HMGB1 depletion in ESCC may increase the ESCC's radiosensitivity through regulating autophagy.	('regulating', 'Reg', (97, 107))	('increase', 'PosReg', (52, 60))	('depletion', 'Var', (30, 39))	('autophagy', 'CPA', (108, 117))	('HMGB1', 'Gene', (24, 29))	('HMGB1', 'Gene', '3146', (24, 29))	('radiosensitivity', 'CPA', (72, 88))	('ESCC', 'Disease', (65, 69))
525554	30755598	This hypothesis can be tested into two steps, first by investigating whether HMGB1 regulates autophagy in ESCC and second, whether such regulation is the key mechanism of elevated radiosensitivity brought by HMGB1 inhibition.	('inhibition', 'Var', (214, 224))	('HMGB1', 'Gene', '3146', (77, 82))	('elevated radiosensitivity', 'Phenotype', 'HP:0010997', (171, 196))	('autophagy', 'CPA', (93, 102))	('ESCC', 'Disease', (106, 110))	('radiosensitivity', 'CPA', (180, 196))	('elevated', 'PosReg', (171, 179))	('regulates', 'Reg', (83, 92))	('HMGB1', 'Gene', (208, 213))	('HMGB1', 'Gene', (77, 82))	('HMGB1', 'Gene', '3146', (208, 213))
525558	30755598	Further fluorescence assay using tandem fluorescent-tagged LC3 (mRFP-GFP-LC3) also observed reduced autophagy flux after siHMGB1 transfection in both TE-1 cells and Eca-109 cells (Fig.	('transfection', 'Var', (129, 141))	('HMGB1', 'Gene', (123, 128))	('LC3', 'Gene', '84557', (59, 62))	('LC3', 'Gene', (59, 62))	('LC3', 'Gene', '84557', (73, 76))	('HMGB1', 'Gene', '3146', (123, 128))	('LC3', 'Gene', (73, 76))	('reduced', 'NegReg', (92, 99))	('autophagy flux', 'CPA', (100, 114))	('TE-1', 'Gene', '57816', (150, 154))	('TE-1', 'Gene', (150, 154))
525560	30755598	Together our results showed that HMGB1 knockdown reduced the level of autophagy in ESCC cells.	('HMGB1', 'Gene', '3146', (33, 38))	('reduced', 'NegReg', (49, 56))	('autophagy', 'CPA', (70, 79))	('knockdown', 'Var', (39, 48))	('HMGB1', 'Gene', (33, 38))
525565	30755598	Intriguingly, the survival rate of HMGB1 knockdown cells was even higher than controls after EBSS treatment, suggesting that autophagy has a strong regulation effect on radiosensitivity of ESCC.	('autophagy', 'CPA', (125, 134))	('radiosensitivity', 'CPA', (169, 185))	('HMGB1', 'Gene', (35, 40))	('higher', 'PosReg', (66, 72))	('HMGB1', 'Gene', '3146', (35, 40))	('knockdown', 'Var', (41, 50))
525567	30755598	Our cell line-based results showed that inhibiting HMGB1 can increase ESCC's radiosensitivity by downregulating autophagy.	('increase ESCC', 'Phenotype', 'HP:0003565', (61, 74))	('autophagy', 'CPA', (112, 121))	('HMGB1', 'Gene', (51, 56))	('downregulating', 'NegReg', (97, 111))	('HMGB1', 'Gene', '3146', (51, 56))	('increase', 'PosReg', (61, 69))	('ESCC', 'Disease', (70, 74))	('inhibiting', 'Var', (40, 50))	('radiosensitivity', 'CPA', (77, 93))
525584	30755598	Inhibition of autophagy can increase radiosensitivity of several types of cancer including esophageal carcinoma.	('autophagy', 'CPA', (14, 23))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (91, 111))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (28, 53))	('Inhibition', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('esophageal carcinoma', 'Disease', (91, 111))	('radiosensitivity', 'CPA', (37, 53))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (91, 111))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('increase', 'PosReg', (28, 36))
525586	30755598	It is therefore expected that elevated HMGB1 in ESCC may protect cells from IR damage by enhancing autophagy.	('elevated', 'Var', (30, 38))	('HMGB1', 'Gene', '3146', (39, 44))	('enhancing', 'PosReg', (89, 98))	('elevated HMGB1', 'Phenotype', 'HP:0030269', (30, 44))	('HMGB1', 'Gene', (39, 44))	('autophagy', 'CPA', (99, 108))
525589	30755598	Taken together, our results suggested that high-expression of HMGB1 is expected to protect the ESCC's resistant to radiotherapy possibly through upregulating the autophagy.	('autophagy', 'CPA', (162, 171))	('resistant to radiotherapy', 'CPA', (102, 127))	('high-expression', 'Var', (43, 58))	('HMGB1', 'Gene', (62, 67))	('HMGB1', 'Gene', '3146', (62, 67))	('upregulating', 'PosReg', (145, 157))
525596	30755598	HMGB1 knockdown increased the radiosensitivity of ESCC both in vitro and in vivo through decreased autophagy.	('HMGB1', 'Gene', (0, 5))	('HMGB1', 'Gene', '3146', (0, 5))	('radiosensitivity', 'CPA', (30, 46))	('increased', 'PosReg', (16, 25))	('knockdown', 'Var', (6, 15))	('autophagy', 'CPA', (99, 108))	('decreased', 'NegReg', (89, 98))
525598	30755598	HMGB1 inhibitors may be developed as a combination therapy to help these patients improve the efficacy of radiotherapy.	('improve', 'PosReg', (82, 89))	('HMGB1', 'Gene', '3146', (0, 5))	('HMGB1', 'Gene', (0, 5))	('inhibitors', 'Var', (6, 16))	('patients', 'Species', '9606', (73, 81))
525636	29967638	Effect of Esophageal Endoscopic Submucosal Dissection on Motility and Symptoms: A Prospective Study Endoscopic submucosal dissection (ESD) of esophageal tumors can cause stenosis, yet the effect of esophageal ESD on motility remains unclarified.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('stenosis', 'Disease', 'MESH:D003251', (170, 178))	('esophageal tumors', 'Phenotype', 'HP:0100751', (142, 159))	('Endoscopic submucosal dissection', 'Var', (100, 132))	('cause', 'Reg', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('esophageal tumors', 'Disease', 'MESH:D004938', (142, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('esophageal tumors', 'Disease', (142, 159))	('stenosis', 'Disease', (170, 178))
525649	29967638	Exclusion criteria were (1) advanced cancer and/or lesions >= cT1b (lesions thought to involve deep invasion), (2) cases that refused informed consent, (3) patients for whom endoscopic treatment was considered difficult because of serious hepatic, heart, or respiratory diseases, (4) patients in whom a catheter could not be inserted, (5) patients with severe allergy or allergy of unknown cause, (6) patients who needed balloon dilatation due to stenosis after ESD, and (7) patients who needed ESD multiple times on separate days.	('allergy', 'Disease', 'MESH:D004342', (360, 367))	('respiratory diseases', 'Disease', 'MESH:D012131', (258, 278))	('dilatation', 'Phenotype', 'HP:0002617', (429, 439))	('advanced cancer', 'Disease', (28, 43))	('allergy', 'Disease', (371, 378))	('lesions >= cT1b', 'Var', (51, 66))	('allergy', 'Phenotype', 'HP:0012393', (360, 367))	('respiratory diseases', 'Disease', (258, 278))	('allergy', 'Phenotype', 'HP:0012393', (371, 378))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('allergy', 'Disease', (360, 367))	('stenosis', 'MPA', (447, 455))	('allergy', 'Disease', 'MESH:D004342', (371, 378))
525655	29967638	Distal contractile integral (DCI): amplitude x duration x length (mmHg cm s) of the distal esophageal contraction exceeding 20 mmHg from the transition zone to the proximal margin of the LES Contractile front velocity (CFV): slope (cm/s) of the tangent approximation of the 30 mmHg isobaric contour between the proximal pressure trough and the contractile deceleration point (CDP) Intrabolus pressure (IBP): the average compartmentalized pressure (mmHg) below each peristaltic contraction in the 5 cm span above the esophagogastric junction (EGJ) Integrated relaxation pressure (IRP): mean pressure (mmHg) of the 4 s of maximal deglutitive relaxation in the 10 s window beginning at UES relaxation Distal latency (DL): interval (s) between UES relaxation and the CDP Peristaltic breaks (PB): gaps (cm) in the 20 mmHg isobaric contour of the peristaltic contraction between the UES and EGJ (measured in axial length) Based on the Chicago classification categories of esophageal motor dysfunction, HRM results were expressed as follows:  The endoscopes used were mainly GIF Q260J (Olympus Tokyo, Japan).	('dysfunction', 'Disease', 'MESH:D006331', (983, 994))	('esophageal motor dysfunction', 'Disease', 'MESH:D004941', (966, 994))	('dysfunction', 'Disease', (983, 994))	('PB', 'Chemical', '-', (787, 789))	('Q260J', 'Var', (1072, 1077))	('esophageal motor dysfunction', 'Disease', (966, 994))	('Q260J', 'SUBSTITUTION', 'None', (1072, 1077))
525670	29548327	The mediastinal lymphadenectomy of T2 esophageal carcinoma patients who underwent MAE was inferior to those who underwent Ivor Lewis procedure.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('esophageal carcinoma', 'Disease', (38, 58))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (38, 58))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (38, 58))	('patients', 'Species', '9606', (59, 67))	('MAE', 'Chemical', '-', (82, 85))	('MAE', 'Var', (82, 85))
525760	29548327	The mediastinal lymphadenectomy of patients with T2 esophageal cancer who underwent MAE was inferior to those who underwent Ivor Lewis procedure.	('mediastinal lymphadenectomy', 'CPA', (4, 31))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('MAE', 'Chemical', '-', (84, 87))	('MAE', 'Var', (84, 87))	('patients', 'Species', '9606', (35, 43))
525820	27795744	Alterations in DNA methylation, an epigenetic modification that can affect gene expression and that can be influenced by environmental factors, is frequently present in both BE and EAC and is believed to play a role in the formation of BE and its progression to EAC.	('gene expression', 'MPA', (75, 90))	('methylation', 'Var', (19, 30))	('role', 'Reg', (211, 215))	('Alterations', 'Var', (0, 11))	('play', 'Reg', (204, 208))	('men', 'Species', '9606', (128, 131))	('BE', 'Phenotype', 'HP:0100580', (236, 238))	('EAC', 'Disease', (262, 265))	('EAC', 'Phenotype', 'HP:0011459', (181, 184))	('EAC', 'Phenotype', 'HP:0011459', (262, 265))	('DNA', 'Gene', (15, 18))	('BE', 'Phenotype', 'HP:0100580', (174, 176))	('affect', 'Reg', (68, 74))
525823	27795744	We found numerous differentially methylated loci in the esophagus tissues when comparing males to females, obese to lean individuals, and smokers to nonsmokers.	('obese', 'Disease', (107, 112))	('differentially', 'Var', (18, 32))	('obese', 'Disease', 'MESH:D009765', (107, 112))
525830	27795744	Epigenetic alterations, primarily in the form of hypermethylated or hypomethylated CpG dinucleotides in the DNA, have been described in BE and EAC using both candidate gene approaches and microarray-based strategies.	('CpG', 'Gene', (83, 86))	('EAC', 'Phenotype', 'HP:0011459', (143, 146))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (83, 100))	('BE', 'Phenotype', 'HP:0100580', (136, 138))	('hypomethylated', 'Var', (68, 82))	('hypermethylated', 'Var', (49, 64))	('Epigenetic', 'MPA', (0, 10))
525831	27795744	The effects of DNA methylation on the regulation of gene expression have supported the plausibility that alterations in DNA methylation can affect disease processes in people.	('alterations', 'Var', (105, 116))	('people', 'Species', '9606', (168, 174))	('affect', 'Reg', (140, 146))	('disease', 'Disease', (147, 154))
525832	27795744	Aberrant DNA methylation has been shown to occur early in the BE   dysplastic BE   EAC progression sequence.	('Aberrant', 'Var', (0, 8))	('DNA', 'Protein', (9, 12))	('dysplastic', 'Disease', (67, 77))	('BE', 'Phenotype', 'HP:0100580', (78, 80))	('dysplastic', 'Disease', 'MESH:D004416', (67, 77))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))	('BE', 'Phenotype', 'HP:0100580', (62, 64))
525833	27795744	The aberrant methylation of numerous cancer-related genes, such as CDKN2A, as well as global alterations in DNA methylation has been observed in BE, and many of these epigenetic alterations are also found in dysplastic BE and EAC.	('methylation', 'MPA', (13, 24))	('BE', 'Phenotype', 'HP:0100580', (219, 221))	('BE', 'Phenotype', 'HP:0100580', (145, 147))	('CDKN2A', 'Gene', (67, 73))	('numerous cancer', 'Disease', (28, 43))	('alterations', 'Reg', (93, 104))	('EAC', 'Phenotype', 'HP:0011459', (226, 229))	('epigenetic alterations', 'Var', (167, 189))	('dysplastic', 'Disease', (208, 218))	('numerous cancer', 'Disease', 'MESH:D009369', (28, 43))	('DNA methylation', 'MPA', (108, 123))	('EAC', 'Disease', (226, 229))	('dysplastic', 'Disease', 'MESH:D004416', (208, 218))	('found', 'Reg', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
525841	27795744	We also focused on whether epigenetic alterations linked with these demographic features associated with particular molecular or cancer-related pathways in order to assess for possible mechanisms through which alterations in the DNA methylation status may be involved in the formation of BE and/or EAC.	('associated', 'Reg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('alterations', 'Var', (210, 221))	('EAC', 'Phenotype', 'HP:0011459', (298, 301))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('BE and/or', 'Disease', (288, 297))	('BE', 'Phenotype', 'HP:0100580', (288, 290))	('EAC', 'Disease', (298, 301))	('involved', 'Reg', (259, 267))
525842	27795744	While it is likely that both somatic genetic and epigenetic alterations play a role in the pathogenesis of BE and EAC, there is currently very little information about the relationship between Barrett's esophagus and esophageal adenocarcinoma, obesity, and aberrant DNA methylation.	('EAC', 'Disease', (114, 117))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (193, 212))	('obesity', 'Phenotype', 'HP:0001513', (244, 251))	('aberrant', 'Var', (257, 265))	('esophageal adenocarcinoma', 'Disease', (217, 242))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (217, 242))	('obesity', 'Disease', 'MESH:D009765', (244, 251))	('EAC', 'Phenotype', 'HP:0011459', (114, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('obesity', 'Disease', (244, 251))	('BE', 'Phenotype', 'HP:0100580', (107, 109))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (217, 242))
525854	27795744	In contrast to this, DML in the HGD/EAC cases were hypermethylated at all functional regions as well as CpG island shores, shelves, and open seas in the high BMI vs. low BMI cases but not at CpG islands (Fig.	('low BMI', 'Phenotype', 'HP:0045082', (166, 173))	('DML', 'Chemical', '-', (21, 24))	('open sea', 'Disease', 'MESH:D009041', (136, 144))	('open sea', 'Disease', (136, 144))	('hypermethylated', 'Var', (51, 66))	('EAC', 'Phenotype', 'HP:0011459', (36, 39))
525855	27795744	We also looked to see if any of the DML between the high and low BMI BE cases overlapped with any of the DML when comparing BE to EAC, in order to determine if methylation alterations in obese individuals with BE might be associated with progression to HGD/EAC.	('DML', 'Chemical', '-', (105, 108))	('BE', 'Phenotype', 'HP:0100580', (69, 71))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('methylation alterations', 'Var', (160, 183))	('obese', 'Disease', (187, 192))	('low BMI', 'Phenotype', 'HP:0045082', (61, 68))	('EAC', 'Phenotype', 'HP:0011459', (257, 260))	('BE', 'Phenotype', 'HP:0100580', (210, 212))	('HGD/EAC', 'Disease', (253, 260))	('BE', 'Phenotype', 'HP:0100580', (124, 126))	('BMI BE', 'Gene', (65, 71))	('associated', 'Reg', (222, 232))	('DML', 'Chemical', '-', (36, 39))	('obese', 'Disease', 'MESH:D009765', (187, 192))
525857	27795744	Because of the potential for DNA methylation alterations to modify gene expression, we next assessed the methylation status of CpGs located in genes associated with signaling pathways and biological mediators implicated in obesity-associated cancers in the esophageal tissues from the subjects with low vs. high BMI.	('obesity-associated cancers', 'Disease', (223, 249))	('alterations', 'Var', (45, 56))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('obesity-associated cancers', 'Disease', 'MESH:D009765', (223, 249))	('obesity', 'Phenotype', 'HP:0001513', (223, 230))	('modify', 'Reg', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
525858	27795744	We also examined molecular pathways associated with adipose inflammation, which has been shown to mediate obesity-related cancer and found the proinflammatory gene IL-1beta (IL1B) to be hypermethylated in high vs. low BMI cases when we assessed the combined esophageal tissue sets.	('hypermethylated', 'Var', (186, 201))	('obesity', 'Phenotype', 'HP:0001513', (106, 113))	('adipose inflammation', 'Phenotype', 'HP:0012490', (52, 72))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('obesity', 'Disease', 'MESH:D009765', (106, 113))	('low BMI', 'Phenotype', 'HP:0045082', (214, 221))	('adipose inflammation', 'Disease', 'MESH:D007249', (52, 72))	('obesity', 'Disease', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('examined', 'Reg', (8, 16))	('adipose inflammation', 'Disease', (52, 72))	('IL1B', 'Gene', (174, 178))
525865	27795744	We used the NCI Pathway Interaction Database (NCI-PID), Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and the list of Gene Ontology (GO) terms to identify biological processes or pathways that were over- or under-represented based on genes containing DML between the esophageal tissue sets in the subjects with either high or low BMI status.	('biological', 'Pathway', (166, 176))	('low BMI', 'Phenotype', 'HP:0045082', (337, 344))	('DML', 'Chemical', '-', (262, 265))	('under-represented', 'NegReg', (218, 235))	('over-', 'PosReg', (209, 214))	('DML', 'Var', (262, 265))	('pathways', 'Pathway', (190, 198))
525867	27795744	With respect to the HGD/EAC cases, there were no NCI-PID pathways that were significantly associated with methylation differences between high and low BMI status after restricting our analysis to only cancer-related genes.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('methylation', 'MPA', (106, 117))	('cancer', 'Disease', (201, 207))	('NCI-PID pathways', 'Pathway', (49, 65))	('associated', 'Reg', (90, 100))	('low BMI', 'Phenotype', 'HP:0045082', (147, 154))	('low', 'Var', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('EAC', 'Phenotype', 'HP:0011459', (24, 27))	('high', 'Var', (138, 142))
525870	27795744	Using HM450 array analysis of BE, HGD, and EAC esophageal samples from 118 males and 23 females, we found numerous CpG sites that were differentially methylated between the genders after excluding probes on the X and Y chromosomes and after accounting for differences in the age between the men and women in our study.	('methylated', 'Var', (150, 160))	('EAC', 'Phenotype', 'HP:0011459', (43, 46))	('CpG', 'Gene', (115, 118))	('BE', 'Phenotype', 'HP:0100580', (30, 32))	('men', 'Species', '9606', (301, 304))	('women', 'Species', '9606', (299, 304))	('HM450', 'Chemical', '-', (6, 11))	('men', 'Species', '9606', (291, 294))
525873	27795744	These DML were associated with CpGs in genes such as DUSP22, a regulator of estrogen receptor alpha mediated signaling, FRG1B, which is involved in pre-mRNA splicing, and CGREF1, which mediates cell-cell adhesion in a calcium-dependent manner.	('FRG1B', 'Gene', (120, 125))	('CpGs', 'Var', (31, 35))	('calcium', 'Chemical', 'MESH:D002118', (218, 225))	('associated', 'Reg', (15, 25))	('DML', 'Chemical', '-', (6, 9))	('DUSP22', 'Gene', (53, 59))	('CGREF1', 'Gene', (171, 177))
525891	27795744	These DMR were located within the genes TNXB and HOXA4, which are notable because TNXB is a member of the tenascin family and regulates cell-extracellular matrix interactions and HOXA4 is a transcription factor previously shown to inhibit cell motility and to be aberrantly methylated in acute myeloid leukemia (Fig.	('TNXB', 'Gene', (82, 86))	('DMR', 'Chemical', '-', (6, 9))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (288, 310))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (294, 310))	('HOXA4', 'Gene', (49, 54))	('aberrantly', 'Var', (263, 273))	('inhibit', 'NegReg', (231, 238))	('acute myeloid leukemia', 'Disease', (288, 310))	('leukemia', 'Phenotype', 'HP:0001909', (302, 310))	('regulates', 'Reg', (126, 135))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (288, 310))	('HOXA4', 'Gene', (179, 184))	('TNXB', 'Gene', (40, 44))	('cell motility', 'CPA', (239, 252))
525895	27795744	We were interested to see which molecular and cancer-related pathways were associated with the epigenetic differences in the BE and EAC tissues from smokers as compared to nonsmokers.	('BE', 'Phenotype', 'HP:0100580', (125, 127))	('molecular', 'Pathway', (32, 41))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('epigenetic differences', 'Var', (95, 117))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('associated', 'Reg', (75, 85))	('EAC', 'Phenotype', 'HP:0011459', (132, 135))
525911	27795744	We subjected the DML to KEGG, Gene Ontology (GO), and NCI-PID analyses to determine whether particular molecular groups or pathways were associated with the methylation changes in obese individuals with BE, dysplastic BE, or EAC.	('obese', 'Disease', (180, 185))	('associated', 'Reg', (137, 147))	('EAC', 'Disease', (225, 228))	('DML', 'Chemical', '-', (17, 20))	('BE', 'Phenotype', 'HP:0100580', (218, 220))	('methylation', 'Var', (157, 168))	('obese', 'Disease', 'MESH:D009765', (180, 185))	('dysplastic', 'Disease', (207, 217))	('BE', 'Phenotype', 'HP:0100580', (203, 205))	('dysplastic', 'Disease', 'MESH:D004416', (207, 217))	('changes', 'Reg', (169, 176))	('EAC', 'Phenotype', 'HP:0011459', (225, 228))
525912	27795744	This included differentially methylated loci within the RDX gene, which encode a cytoskeletal component that has been shown to inhibit metastasis in gastric cancer.	('gastric cancer', 'Disease', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('metastasis', 'CPA', (135, 145))	('differentially methylated', 'Var', (14, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('inhibit', 'NegReg', (127, 134))	('RDX', 'Gene', (56, 59))
525913	27795744	TP53, the gene for p53, is a well-known tumor suppressor gene that is frequently lost early in BE through mutation or loss of heterozygosity (LOH).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mutation', 'Var', (106, 114))	('BE', 'Phenotype', 'HP:0100580', (95, 97))	('loss', 'Var', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
525914	27795744	TP53 LOH has been shown to identify a subset of BE patients who are at risk for progression to EAC.	('LOH', 'Var', (5, 8))	('EAC', 'Phenotype', 'HP:0011459', (95, 98))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('EAC', 'Disease', (95, 98))	('patients', 'Species', '9606', (51, 59))	('BE', 'Phenotype', 'HP:0100580', (48, 50))
525918	27795744	Obesity was associated with the aberrant methylation of cancer-related genes involved with the immune response, cell growth, and DNA repair.	('methylation', 'MPA', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Obesity', 'Disease', (0, 7))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('associated', 'Reg', (12, 22))	('aberrant', 'Var', (32, 40))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
525928	27795744	The finding of widespread and frequent hypermethylation in BE, dysplastic BE, and EAC tissues of tobacco smokers suggests that tobacco-related epigenetic alterations may be a mechanism through which tobacco affects the development of BE and EAC.	('tobacco', 'Species', '4097', (127, 134))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('dysplastic', 'Disease', (63, 73))	('men', 'Species', '9606', (226, 229))	('tobacco', 'Species', '4097', (199, 206))	('dysplastic', 'Disease', 'MESH:D004416', (63, 73))	('EAC', 'Phenotype', 'HP:0011459', (241, 244))	('BE', 'Phenotype', 'HP:0100580', (74, 76))	('hypermethylation', 'Var', (39, 55))	('EAC', 'Disease', (241, 244))	('BE', 'Phenotype', 'HP:0100580', (234, 236))	('BE', 'Phenotype', 'HP:0100580', (59, 61))	('tobacco', 'Species', '4097', (97, 104))	('affects', 'Reg', (207, 214))
525929	27795744	After enriching the DML (smokers vs. nonsmokers) for cancer-related genes, we found the Trk and Shp2 pathways to be differentially activated between these groups; these differences were driven by hypermethylation of the NTRK2 and NTRK3 genes in smokers.	('Trk', 'Pathway', (88, 91))	('activated', 'PosReg', (131, 140))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('DML', 'Chemical', '-', (20, 23))	('Shp2 pathways', 'Pathway', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('NTRK2', 'Gene', (220, 225))	('NTRK3', 'Gene', (230, 235))	('hypermethylation', 'Var', (196, 212))
525930	27795744	We previously found the aberrant methylation of NTRK3 in 60 % of colon adenomas and 67 % of colon adenocarcinomas, suggesting NTRK3 is a novel conditional tumor suppressor gene that is commonly inactivated in colorectal cancer by both epigenetic and genetic mechanisms.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('colon adenocarcinomas', 'Disease', 'MESH:D003110', (92, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (209, 226))	('NTRK3', 'Gene', (126, 131))	('methylation', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('NTRK3', 'Gene', (48, 53))	('colon adenomas', 'Disease', (65, 79))	('colorectal cancer', 'Disease', (209, 226))	('tumor', 'Disease', (155, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (209, 226))	('aberrant methylation', 'Var', (24, 44))	('colon adenomas', 'Disease', 'MESH:D000236', (65, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('colon adenocarcinomas', 'Disease', (92, 113))
525931	27795744	NTRK2 has also been shown to be hypermethylated in colon cancers as well as prostate cancer cell lines and cancers.	('cancers', 'Disease', (107, 114))	('colon cancers', 'Disease', (51, 64))	('hypermethylated', 'Var', (32, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('colon cancers', 'Disease', 'MESH:D015179', (51, 64))	('colon cancers', 'Phenotype', 'HP:0003003', (51, 64))	('cancers', 'Disease', (57, 64))	('NTRK2', 'Gene', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
525967	27701465	Luciferase assays confirmed that the 3'-UTR of PTEN was a target of miR-20b in esophageal cancer cells.	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('miR-20b', 'Var', (68, 75))	('PTEN', 'Gene', (47, 51))
525975	27701465	Recent data indicate that aberrant miRNA expression is often involved in cancer development from initiation to metastasis in various cancers including esophageal carcinoma.	('cancer', 'Disease', (73, 79))	('esophageal carcinoma', 'Disease', (151, 171))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('aberrant', 'Var', (26, 34))	('miRNA', 'Protein', (35, 40))	('involved', 'Reg', (61, 69))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (151, 171))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (151, 171))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancer', 'Disease', (133, 139))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('initiation to metastasis', 'Disease', 'MESH:D009362', (97, 121))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('initiation to metastasis', 'Disease', (97, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
525978	27701465	Previous studies have demonstrated that miR-20b expression level is higher in the brain metastases of breast cancer patients, compared to primary breast tumors as well as the patients without brain metastasis, and miR-20b can induce colony formation and invasiveness of breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (270, 283))	('induce', 'PosReg', (226, 232))	('expression level', 'MPA', (48, 64))	('miR-20b', 'Var', (214, 221))	('invasiveness of breast cancer', 'Disease', (254, 283))	('patients', 'Species', '9606', (116, 124))	('colony formation', 'CPA', (233, 249))	('brain metastasis', 'Disease', 'MESH:D009362', (192, 208))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('higher', 'PosReg', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('brain metastases of breast cancer', 'Disease', (82, 115))	('brain metastases of breast cancer', 'Disease', 'MESH:D009362', (82, 115))	('breast tumors', 'Disease', 'MESH:D001943', (146, 159))	('breast tumors', 'Disease', (146, 159))	('brain metastasis', 'Disease', (192, 208))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('miR-20b', 'Gene', (40, 47))	('patients', 'Species', '9606', (175, 183))	('breast tumors', 'Phenotype', 'HP:0100013', (146, 159))	('invasiveness of breast cancer', 'Disease', 'MESH:D001943', (254, 283))
526021	27701465	Eca-109 cells transfected with agomir-20b and its negative control (agomir-NC) or KYSE-150 cells transfected with antagomir-20b and its negative control (antagomir-NC) (5 x 106 cells in 0.2 ml PBS) were respectively injected subcutaneously into the right flank of each mouse (5 mice/each group).	('PBS', 'Chemical', '-', (193, 196))	('KYSE-150', 'CellLine', 'CVCL:1348', (82, 90))	('mice', 'Species', '10090', (278, 282))	('mouse', 'Species', '10090', (269, 274))	('agomir-20b', 'Var', (31, 41))	('antagomir-20b', 'Var', (114, 127))
526023	27701465	After 40 days, the mice were sacrificed and the tumor tissues were weighed, and processed for qRT-PCR analysis and immunohistochemistry assays for miR-20b and PTEN expression level, respectively.	('tumor', 'Disease', (48, 53))	('miR-20b', 'Var', (147, 154))	('PTEN', 'MPA', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mice', 'Species', '10090', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
526025	27701465	Based on the clinical information of patients, we found that the aberrant expression of miR-20b was related with the pathological stages including tumor differentiation degree, invasion depth, TNM stage, and lymph node metastasis in esophageal carcinoma patients (P < 0.05), although its expression had not significant correlation with age, gender and tumor size (P > 0.05) (Table 1).	('aberrant', 'Var', (65, 73))	('lymph node metastasis', 'CPA', (208, 229))	('related', 'Reg', (100, 107))	('tumor', 'Disease', (147, 152))	('patients', 'Species', '9606', (37, 45))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (233, 253))	('invasion depth', 'CPA', (177, 191))	('TNM', 'Gene', '10178', (193, 196))	('tumor', 'Disease', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('clinical', 'Species', '191496', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('esophageal carcinoma', 'Disease', (233, 253))	('TNM', 'Gene', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (233, 253))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('miR-20b', 'Gene', (88, 95))	('patients', 'Species', '9606', (254, 262))
526037	27701465	On the contrary, KYSE-150 cells transfected with 100 nM of miR-20b inhibitor dramatically reduced miR-20b expression level as compared with the blank control or negative control (miR-20b inhibitor-NC) (Fig 3B).	('miR-20b', 'Gene', (59, 66))	('reduced', 'NegReg', (90, 97))	('KYSE-150', 'CellLine', 'CVCL:1348', (17, 25))	('miR-20b expression level', 'MPA', (98, 122))	('inhibitor', 'Var', (67, 76))
526038	27701465	In contrast, a marked increase of PTEN protein expression was found in the KYSE-150 cells after transfection with miR-20 inhibitor (P < 0.05).	('increase', 'PosReg', (22, 30))	('PTEN protein', 'Protein', (34, 46))	('transfection', 'Var', (96, 108))	('KYSE-150', 'CellLine', 'CVCL:1348', (75, 83))
526039	27701465	On the other hand, previous studies demonstrated that miR-20b plays an important role in PTEN/Akt signaling pathway carcinogenesis and the progression of esophageal cancer.	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('miR-20b', 'Var', (54, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('Akt', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('carcinogenesis', 'Disease', (116, 130))	('Akt', 'Gene', '207', (94, 97))	('esophageal cancer', 'Disease', (154, 171))
526041	27701465	The results showed that miR-20b mimics and miR-20b inhibitor did not alter the protein level of Akt in the Eca-109 and KYSE-150 cells, but miR-20b mimics significantly up-regulated the level of p-Akt compared with miR-20b mimics-NC in the Eca-109 cells.	('miR-20b mimics', 'Var', (139, 153))	('up-regulated', 'PosReg', (168, 180))	('KYSE-150', 'CellLine', 'CVCL:1348', (119, 127))	('Akt', 'Gene', '207', (196, 199))	('mimics', 'Var', (147, 153))	('Akt', 'Gene', '207', (96, 99))	('Akt', 'Gene', (196, 199))	('Akt', 'Gene', (96, 99))
526052	27701465	However, silenced PTEN expression in the KYSE-150 cells increased their abilities of cell migration and invasion.	('cell migration', 'CPA', (85, 99))	('PTEN', 'Gene', (18, 22))	('increased', 'PosReg', (56, 65))	('KYSE-150', 'CellLine', 'CVCL:1348', (41, 49))	('silenced', 'Var', (9, 17))	('invasion', 'CPA', (104, 112))
526054	27701465	To investigate the effect of miR-20b on tumorigenicity of esophageal carcinoma cells in vivo, Eca-109 cells transfected with agomir-20b or negative control (agomir-NC), and KYSE-150 cells transfected with antagomir-20b and its negative control (antagomir-NC) were subcutaneously inoculated into nude mice, respectively.	('KYSE-150', 'CellLine', 'CVCL:1348', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('esophageal carcinoma', 'Disease', (58, 78))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (58, 78))	('nude mice', 'Species', '10090', (295, 304))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (58, 78))	('antagomir-20b', 'Var', (205, 218))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
526055	27701465	The results demonstrated that Eca-109 cells transfected with agomir-20b promoted tumor formation and growth, produced a significant increase in the tumor size and average weight compared with agomir-NC group (Fig 8A).	('average weight', 'CPA', (163, 177))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('agomir-20b', 'Var', (61, 71))	('increase', 'PosReg', (132, 140))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('growth', 'CPA', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('promoted', 'PosReg', (72, 80))	('tumor', 'Disease', (81, 86))
526056	27701465	On the contrary, KYSE-150 cells transfected with antogomir-20b markedly suppressed tumor growth, and significantly reduced tumor volume and their average weight compared with the antagomir-NC group (Fig 8B and 8C).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', (83, 88))	('reduced', 'NegReg', (115, 122))	('antogomir-20b', 'Var', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('suppressed', 'NegReg', (72, 82))	('KYSE-150', 'CellLine', 'CVCL:1348', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('average weight', 'CPA', (146, 160))
526057	27701465	The results of qRT-PCR showed that miR-20b expression level was significantly up-regulated in the tumor tissues of agomir-20b group (Fig 8D).	('miR-20b', 'Gene', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('expression level', 'MPA', (43, 59))	('up-regulated', 'PosReg', (78, 90))	('tumor', 'Disease', (98, 103))	('agomir-20b', 'Var', (115, 125))
526059	27701465	On the other hand, the level of miR-20b expression was significantly down-regulated in the tumor tissues of antogomir-20b compared with its negative control.	('expression', 'MPA', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('antogomir-20b', 'Var', (108, 121))	('down-regulated', 'NegReg', (69, 83))	('miR-20b', 'Protein', (32, 39))	('level', 'MPA', (23, 28))	('tumor', 'Disease', (91, 96))
526086	27701465	A recent study showed that miR-20b could reduce PTEN protein expression by directly targeting the 3'-UTR of PTEN, and miR-20b was frequently overexpressed in breast cancer tissues and cell lines, and its expression upregulation significantly promoted the proliferation, colony formation and DNA synthesis in breast cancer cells.	('PTEN protein', 'Protein', (48, 60))	('breast cancer', 'Disease', (308, 321))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (308, 321))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('proliferation', 'CPA', (255, 268))	('colony formation', 'CPA', (270, 286))	('upregulation', 'PosReg', (215, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('DNA synthesis', 'CPA', (291, 304))	('reduce', 'NegReg', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('breast cancer', 'Disease', 'MESH:D001943', (308, 321))	('promoted', 'PosReg', (242, 250))	('miR-20b', 'Var', (118, 125))
526089	27701465	Thus, PTEN expression downregulation can activate PI3K-Akt signaling pathway, which is associated with the development of cancers.	('Akt', 'Gene', (55, 58))	('downregulation', 'NegReg', (22, 36))	('activate', 'PosReg', (41, 49))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('Akt', 'Gene', '207', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('expression', 'Var', (11, 21))	('PTEN', 'Gene', (6, 10))
526093	27701465	In conclusion, our data indicate that miR-20b serves as an oncomir, and plays important roles in the regulation of some biological properties of esophageal carcinoma cells possibly by targeting tumor suppressor PTEN protein expression.	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('protein', 'Protein', (216, 223))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('regulation', 'MPA', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('esophageal carcinoma', 'Disease', (145, 165))	('tumor', 'Disease', (194, 199))	('expression', 'MPA', (224, 234))	('targeting', 'Reg', (184, 193))	('miR-20b', 'Var', (38, 45))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (145, 165))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (145, 165))
526102	26021206	Candidate gene and array-based approaches have demonstrated that numerous tumor-suppressor genes exhibit aberrant promoter methylation, and some of these altered genes are associated with the neoplastic progression of BE.	('promoter methylation', 'MPA', (114, 134))	('associated with', 'Reg', (172, 187))	('numerous tumor', 'Disease', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('neoplastic progression', 'CPA', (192, 214))	('numerous tumor', 'Disease', 'MESH:D009369', (65, 79))	('aberrant', 'Var', (105, 113))
526109	26021206	missense mutations), and epigenetic modifications, primarily in the form of DNA hypermethylation and hypomethylation of CpG dinucleotides.	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (120, 137))	('DNA', 'MPA', (76, 79))	('epigenetic modifications', 'Var', (25, 49))	('missense mutations', 'Var', (0, 18))	('hypermethylation', 'Var', (80, 96))	('hypomethylation', 'Var', (101, 116))
526116	26021206	17p and 9p harbor the tumor suppressors TP53 and CDKN2A, respectively, and studies have revealed frequent LOH through mutation (TP53 and CKN2A) or promoter methylation (CDKN2A).	('CDKN2A', 'Gene', (169, 175))	('CDKN2A', 'Gene', '1029', (49, 55))	('TP53', 'Gene', '7157', (128, 132))	('CDKN2A', 'Gene', '1029', (169, 175))	('TP53', 'Gene', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('mutation', 'Var', (118, 126))	('tumor', 'Disease', (22, 27))	('promoter', 'MPA', (147, 155))	('CDKN2A', 'Gene', (49, 55))
526118	26021206	17p LOH was associated with genomic doubling to a 4N state, consistent with the impact of p53 loss upon genomic instability.	('p53', 'Gene', (90, 93))	('p53', 'Gene', '7157', (90, 93))	('loss', 'NegReg', (94, 98))	('genomic', 'MPA', (28, 35))	('17p LOH', 'Var', (0, 7))
526120	26021206	These data contributed to the development of a popular model where CDKN2A loss is thought to be an initiating event in BE progression, while TP53 alterations are later events, associated with neoplastic progression and aneuploidy.	('CDKN2A', 'Gene', (67, 73))	('aneuploidy', 'Disease', 'MESH:D000782', (219, 229))	('alterations', 'Var', (146, 157))	('CDKN2A', 'Gene', '1029', (67, 73))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('associated', 'Reg', (176, 186))	('loss', 'NegReg', (74, 78))	('neoplastic progression', 'CPA', (192, 214))	('aneuploidy', 'Disease', (219, 229))
526126	26021206	They were able to identify the majority of mutations found in EAC in the paired BE tissue, confirming that EAC emerges from BE and showing that many coding mutations are already present in BE, including mutations in the tumor suppressor TP53.	('TP53', 'Gene', '7157', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('TP53', 'Gene', (237, 241))	('mutations', 'Var', (203, 212))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
526132	26021206	While only 2.5% of non-dysplastic BE contained a mutation in TP53, 70% of cases of HGD and EAC were TP53 mutant.	('TP53', 'Gene', '7157', (100, 104))	('HGD', 'Gene', (83, 86))	('TP53', 'Gene', (100, 104))	('non-dysplastic', 'Disease', 'MESH:D004416', (19, 33))	('mutation', 'Var', (49, 57))	('non-dysplastic', 'Disease', (19, 33))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('HGD', 'Gene', '3081', (83, 86))
526134	26021206	As most of these patients likely never progress to cancer, it will be important to determine whether mutations in genes such as ARID1A in BE are markers for increased progression risk.	('mutations', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('patients', 'Species', '9606', (17, 25))	('ARID1A', 'Gene', '8289', (128, 134))	('ARID1A', 'Gene', (128, 134))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
526142	26021206	A key finding from this group was that the predilection for recurrent genomic amplifications was an important feature distinguishing EAC (and gastric cancer) from lower intestinal tumors.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('gastric cancer', 'Disease', (142, 156))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('intestinal tumors', 'Disease', 'MESH:D007414', (169, 186))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('genomic amplifications', 'Var', (70, 92))	('intestinal tumors', 'Disease', (169, 186))
526149	26021206	They demonstrated the occurrence of common TP53 mutations and the absence of Notch family mutations in esophageal squamous cell cancers.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('esophageal squamous cell cancers', 'Disease', (103, 135))	('esophageal squamous cell cancers', 'Disease', 'MESH:D002294', (103, 135))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (114, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
526150	26021206	Canonical oncogene mutations in genes such as KRAS and PIK3CA were uncommon, whereas evidence of oncogene amplification was frequent.	('KRAS', 'Gene', (46, 50))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', '3845', (46, 50))	('PIK3CA', 'Gene', (55, 61))	('PIK3CA', 'Gene', '5290', (55, 61))
526151	26021206	By contrast, there were widespread mutations affecting tumor suppressor genes including TP53 and CDKN2A and chromatin-modifying enzymes including ARID1A, SMARCA4 and PBRM1.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CDKN2A', 'Gene', (97, 103))	('SMARCA4', 'Gene', '6597', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CDKN2A', 'Gene', '1029', (97, 103))	('tumor', 'Disease', (55, 60))	('TP53', 'Gene', '7157', (88, 92))	('PBRM1', 'Gene', (166, 171))	('ARID1A', 'Gene', '8289', (146, 152))	('TP53', 'Gene', (88, 92))	('ARID1A', 'Gene', (146, 152))	('PBRM1', 'Gene', '55193', (166, 171))	('SMARCA4', 'Gene', (154, 161))	('mutations', 'Var', (35, 44))
526153	26021206	The etiology of these mutations is unknown, but it has been hypothesized to be linked to bile acid exposure and the induction of oxidative DNA damage.	('bile acid', 'Chemical', 'MESH:D001647', (89, 98))	('oxidative', 'MPA', (129, 138))	('mutations', 'Var', (22, 31))	('linked', 'Reg', (79, 85))
526160	26021206	Revilla-Nuin et al recently identified 23 miRNAs involved in BE progression using miRNA sequencing analysis, finding four miRNAs (miR-192, miR-194, miR-196a, and miR-196b) had higher expression in BE patients who progressed to cancer compared to those who did not progress.	('miR-192', 'Gene', '406967', (130, 137))	('patients', 'Species', '9606', (200, 208))	('miR-196a', 'Var', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('miR-196b', 'Gene', (162, 170))	('miR-196b', 'Gene', '442920', (162, 170))	('expression', 'MPA', (183, 193))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('higher', 'PosReg', (176, 182))	('miR-194', 'Var', (139, 146))	('miR-192', 'Gene', (130, 137))
526161	26021206	Since the discovery of DNA hypomethylation in colorectal cancer in 1982, epigenetic research has revealed an epigenetic landscape consisting of a complex array of epigenetic regulatory mechanisms that control gene expression in both cancer and normal tissue, where it plays a crucial role in embryonic development, imprinting, and tissue differentiation.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('colorectal cancer', 'Disease', 'MESH:D015179', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('control', 'Reg', (201, 208))	('hypomethylation', 'Var', (27, 42))	('cancer', 'Disease', (57, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('colorectal cancer', 'Disease', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
526167	26021206	CpG methylation can lead to transcriptional inactivation via multiple mechanisms, including directly inhibiting cis-binding elements, including the following transcription factors: AP-2, CREB, E2F, CBF and NF-KB.	('CREB', 'Gene', '1385', (187, 191))	('transcriptional', 'MPA', (28, 43))	('CBF', 'Gene', '10153', (198, 201))	('methylation', 'Var', (4, 15))	('CpG', 'Var', (0, 3))	('inhibiting', 'NegReg', (101, 111))	('lead to', 'Reg', (20, 27))	('cis-binding elements', 'MPA', (112, 132))	('CBF', 'Gene', (198, 201))	('AP-2', 'Gene', '7020', (181, 185))	('CREB', 'Gene', (187, 191))	('AP-2', 'Gene', (181, 185))
526168	26021206	Although this aberrant methylation is traditionally correlated with silencing of gene expression, it appears that decreased gene expression is characteristic of only a subset of methylated genes in most cancers.	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('aberrant', 'Var', (14, 22))	('decreased', 'NegReg', (114, 123))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
526172	26021206	Methylation of CpG island shores is also associated with transcriptional inactivation and splicing alterations and tends to be tissue specific, and has been shown to be altered in colorectal cancer.	('associated', 'Reg', (41, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (180, 197))	('Methylation', 'Var', (0, 11))	('altered', 'Reg', (169, 176))	('colorectal cancer', 'Phenotype', 'HP:0003003', (180, 197))	('transcriptional', 'MPA', (57, 72))	('CpG island', 'Protein', (15, 25))	('colorectal cancer', 'Disease', (180, 197))	('splicing alterations', 'MPA', (90, 110))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
526173	26021206	Feinberg and colleagues observed that two thirds of cancer-associated alterations in DNA methylation can be found in large domains, termed 'large organized chromatin lysine modifications' (LOCKs), as well as in smaller regions immediately adjacent to hypermethylated DNA.	('alterations', 'Var', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lysine', 'Chemical', 'MESH:D008239', (166, 172))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('DNA', 'Gene', (85, 88))
526183	26021206	Aberrant methylation of promoter CpG islands, which leads to gene silencing of a subset of genes, has been shown to occur frequently in BE, dysplastic BE, and EAC.	('methylation', 'Var', (9, 20))	('dysplastic', 'Disease', 'MESH:D004416', (140, 150))	('dysplastic', 'Disease', (140, 150))	('gene', 'MPA', (61, 65))	('Aberrant methylation', 'Var', (0, 20))	('EAC', 'Disease', (159, 162))
526184	26021206	Epigenetic changes involving the promoter regions of several dozen genes have been evaluated using candidate gene approaches based on findings seen in other types of cancers.	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Epigenetic changes', 'Var', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
526186	26021206	CDKN2A promoter hypermethylation combined with 9p21 chromosomal loss leads to inactivation of this gene in some cases of EAC or BE with dysplasia.	('EAC', 'Disease', (121, 124))	('hypermethylation', 'Var', (16, 32))	('dysplasia', 'Disease', (136, 145))	('CDKN2A', 'Gene', (0, 6))	('dysplasia', 'Disease', 'MESH:D004476', (136, 145))	('inactivation', 'NegReg', (78, 90))	('CDKN2A', 'Gene', '1029', (0, 6))
526190	26021206	Similar patterns consistent with clonal expansion in BE have been reported in studies that focused on LOH or mutations of APC, TP53, and CDKN2A.	('APC', 'Disease', 'MESH:D011125', (122, 125))	('CDKN2A', 'Gene', '1029', (137, 143))	('APC', 'Disease', (122, 125))	('CDKN2A', 'Gene', (137, 143))	('mutations', 'Var', (109, 118))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
526191	26021206	Aberrant methylation of APC and CDH1 in BE and EAC has been evaluated by other groups as well.	('APC', 'Disease', (24, 27))	('Aberrant', 'Var', (0, 8))	('CDH1', 'Gene', (32, 36))	('APC', 'Disease', 'MESH:D011125', (24, 27))	('methylation', 'MPA', (9, 20))	('CDH1', 'Gene', '999', (32, 36))
526192	26021206	One group found that hypermethylated APC was found in 39.5% of BE and 92% of EAC cases, but not in matched normal esophagus.	('APC', 'Disease', (37, 40))	('hypermethylated', 'Var', (21, 36))	('EAC', 'Disease', (77, 80))	('APC', 'Disease', 'MESH:D011125', (37, 40))
526193	26021206	Methylated APC could also be detected in the plasma of 25% of EAC patients, and was associated with reduced survival.	('EAC', 'Disease', (62, 65))	('reduced', 'NegReg', (100, 107))	('APC', 'Disease', 'MESH:D011125', (11, 14))	('APC', 'Disease', (11, 14))	('Methylated', 'Var', (0, 10))	('patients', 'Species', '9606', (66, 74))	('survival', 'MPA', (108, 116))
526195	26021206	Other genes implicated in carcinogenesis have been found to be methylated in BE/EAC, including the STAT-induced STAT inhibitors (SSIs), suppressors of cytokine signaling (SOCS-1 and -3) and Reprimo (RPRM) and members of the glutathione S-transferase (GST) and glutathione peroxidase (GPX) family.	('Reprimo', 'Gene', (190, 197))	('Reprimo', 'Gene', '56475', (190, 197))	('methylated', 'Var', (63, 73))	('SOCS-1 and -3', 'Gene', '8651;9021', (171, 184))	('RPRM', 'Gene', (199, 203))	('RPRM', 'Gene', '56475', (199, 203))
526200	26021206	Given features such as TP53 and SMAD4 mutations, chromosomal instability, and genetic diversity are associated with progressive disease, it is highly feasible that assays for such features could be increasingly used to aid the pathological assessment of disease and to select patients for more careful monitoring and/or ablation of their BE.	('patients', 'Species', '9606', (276, 284))	('TP53', 'Gene', (23, 27))	('SMAD4', 'Gene', (32, 37))	('associated', 'Reg', (100, 110))	('mutations', 'Var', (38, 47))	('chromosomal', 'MPA', (49, 60))	('chromosomal instability', 'Phenotype', 'HP:0040012', (49, 72))	('genetic diversity', 'Var', (78, 95))	('TP53', 'Gene', '7157', (23, 27))	('progressive disease', 'Disease', (116, 135))	('SMAD4', 'Gene', '4089', (32, 37))
526201	26021206	The results from the Weaver study, showing common tumor suppressor mutations in non-dysplastic BE, demonstrate the need to carefully assess the specificity of genomic markers that might be associated with increased risk of progression.	('non-dysplastic', 'Disease', (80, 94))	('non-dysplastic', 'Disease', 'MESH:D004416', (80, 94))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mutations', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
526203	26021206	One prospective study of 268 BE patients evaluated whether clonal expansions during the progression of BE lead to homogenous cell populations or result in clonal diversity.	('result in', 'Reg', (145, 154))	('patients', 'Species', '9606', (32, 40))	('clonal', 'MPA', (155, 161))	('clonal expansions', 'Var', (59, 76))	('lead to', 'Reg', (106, 113))	('homogenous', 'MPA', (114, 124))
526205	26021206	Current histologic assessment of EAC is relatively uncomplicated, and no histologic subtype has been shown to be associated with any specific genomic alterations (in contrast to gastric adenocarcinoma, where, for example, loss of CDH1 is associated with diffuse-type tumors).	('CDH1', 'Gene', (230, 234))	('CDH1', 'Gene', '999', (230, 234))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (178, 200))	('loss', 'Var', (222, 226))	('gastric adenocarcinoma', 'Disease', (178, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('associated', 'Reg', (238, 248))	('tumors', 'Disease', (267, 273))	('tumors', 'Disease', 'MESH:D009369', (267, 273))
526206	26021206	Currently, the only standard tests performed in EAC measure changes in HER/ERBB2 using a combination of immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH).	('ERBB2', 'Gene', (75, 80))	('changes', 'Var', (60, 67))	('ERBB2', 'Gene', '2064', (75, 80))
526212	26021206	Genomic studies of BE have revealed that it is not simply a metaplastic tissue, but characterized by frequent somatic alterations, including mutations in TP53 and other genes.	('TP53', 'Gene', '7157', (154, 158))	('mutations', 'Var', (141, 150))	('TP53', 'Gene', (154, 158))
526214	26021206	In general, both genetic and epigenetic abnormalities are seen in BE before the development of dysplasia or EAC.	('EAC', 'Disease', (108, 111))	('epigenetic abnormalities', 'Var', (29, 53))	('dysplasia', 'Disease', (95, 104))	('dysplasia', 'Disease', 'MESH:D004476', (95, 104))
526215	26021206	This has important implications if these molecular alterations are to be used as assays to predict the risk of BE progression, since while it may be true that certain tumor suppressor genes are inactivated in many cases of BE, most individuals with BE will not progress to dysplasia or cancer.	('alterations', 'Var', (51, 62))	('dysplasia or cancer', 'Disease', 'MESH:D009369', (273, 292))	('dysplasia or cancer', 'Disease', (273, 292))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('inactivated', 'NegReg', (194, 205))	('tumor', 'Disease', (167, 172))
526216	26021206	Specific gene mutations, chromosomal instability, and genetic diversity are associated with neoplastic progression, and it is foreseeable that assays to detect these features could be used to support the pathological assessment of disease and to select patients for more intensive surveillance.	('patients', 'Species', '9606', (253, 261))	('chromosomal', 'MPA', (25, 36))	('neoplastic progression', 'CPA', (92, 114))	('chromosomal instability', 'Phenotype', 'HP:0040012', (25, 48))	('associated', 'Reg', (76, 86))	('genetic diversity', 'Var', (54, 71))
526217	26021206	Genetic and epigenetic alterations play a central role in the formation of Barretts esophagus and esophageal adenocarcinoma.	('Barretts esophagus', 'Disease', (75, 93))	('epigenetic alterations', 'Var', (12, 34))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (98, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('Genetic', 'Var', (0, 7))	('esophageal adenocarcinoma', 'Disease', (98, 123))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (98, 123))	('Barretts esophagus', 'Phenotype', 'HP:0100580', (75, 93))
526218	26021206	Global epigenetic alterations occur early in the Barretts esophagus to esophageal adenocarcinoma sequence.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (71, 96))	('esophageal adenocarcinoma', 'Disease', (71, 96))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (71, 96))	('Barretts esophagus', 'Phenotype', 'HP:0100580', (49, 67))	('epigenetic alterations', 'Var', (7, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
526315	31882677	There is evidence that miR-148 is associated with disease-free survival and overall survival (OS) in ESCC patients and could serve as a prognostic biomarker.	('associated', 'Reg', (34, 44))	('overall survival', 'CPA', (76, 92))	('patients', 'Species', '9606', (106, 114))	('miR-148', 'Chemical', '-', (23, 30))	('disease-free survival', 'CPA', (50, 71))	('ESCC', 'Disease', (101, 105))	('miR-148', 'Var', (23, 30))
526321	31882677	Clinical characteristics of all 119 ESCC patients in GSE43732 were shown in Table 1, and underwent uni-and multi-variate Cox regression analysis by using survival package of R. The clinical factors with log-rank p-value < 0.05 in uni-variate Cox regression analysis were further included in multi-variate Cox regression analysis.	('patients', 'Species', '9606', (41, 49))	('GSE43732', 'Var', (53, 61))	('ESCC', 'Disease', (36, 40))
526326	31882677	With parameter lambda of 8.153 obtained by performing 1000 cross-validations, we identified a prognostic panel of five miRNAs (Table 3), including miR-181c-5p, miR-195-5p, miR-203, miR-212-3p and miR-28-5p.	('miR-181c', 'Gene', (147, 155))	('miR-181c', 'Gene', '406957', (147, 155))	('miR-212-3p', 'Var', (181, 191))	('miR-28', 'Gene', (196, 202))	('miR-212-3p', 'Chemical', '-', (181, 191))	('miR-28', 'Gene', '407020', (196, 202))	('miR-195', 'Gene', (160, 167))	('miR-203', 'Gene', '406986', (172, 179))	('miR-203', 'Gene', (172, 179))	('miR-195', 'Gene', '406971', (160, 167))
526330	31882677	Moreover, by using LASSO Cox regression model, five prognostic miRNAs (miR-181c-5p, miR-195-5p, miR-203, miR-212-3p and miR-28-5p) were identified.	('miR-212-3p', 'Var', (105, 115))	('miR-212-3p', 'Chemical', '-', (105, 115))	('miR-28', 'Gene', (120, 126))	('miR-28', 'Gene', '407020', (120, 126))	('miR-203', 'Gene', (96, 103))	('miR-195', 'Gene', (84, 91))	('miR-195', 'Gene', '406971', (84, 91))	('miR-203', 'Gene', '406986', (96, 103))	('miR-181c', 'Gene', (71, 79))	('miR-181c', 'Gene', '406957', (71, 79))
526388	31289589	As shown in Figure 2, the AUC was 0.553, 0.540, 0.532, and 0.521 for SII, NLR, PLR, and MLR, respectively.	('SII', 'Disease', (69, 72))	('SII', 'Disease', 'None', (69, 72))	('0.521', 'Var', (59, 64))	('0.532', 'Var', (48, 53))	('0.540', 'Var', (41, 46))
526389	31289589	The optimal cut-off values for the prediction of survival were 479.72 for SII, 2.27 for NLR, 117.07 for PLR and 0.19 for MLR.	('SII', 'Disease', (74, 77))	('SII', 'Disease', 'None', (74, 77))	('479.72', 'Var', (63, 69))
526404	31289589	The results revealed age (P < 0.001), TNM stage (P < 0.001), operation time (P = 0.030), high SII levels (P = 0.001), high NLR (P = 0.013) and high PLR (P = 0.013) were found to be independently associated with a poor OS or DFS in the multivariate analysis (Table 4).	('high', 'Var', (118, 122))	('poor OS', 'Disease', (213, 220))	('TNM', 'Gene', '10178', (38, 41))	('SII', 'Disease', 'None', (94, 97))	('SII', 'Disease', (94, 97))	('high', 'Var', (143, 147))	('DFS', 'Disease', (224, 227))	('high', 'Var', (89, 93))	('OS', 'Chemical', '-', (218, 220))	('TNM', 'Gene', (38, 41))
526425	31289589	Thirdly, the importance of lymphocytes has been highlighted in several studies in which high TILs (tumor-infiltrating lymphocytes) has been associated with better response to cytotoxic treatment and prognosis in cancer patients.	('response', 'CPA', (163, 171))	('tumor', 'Disease', (99, 104))	('high', 'Var', (88, 92))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('men', 'Species', '9606', (190, 193))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('better', 'PosReg', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
526464	30855489	Immunohistochemistry staining of the stomach showed CK-pan (+), Ki-67 (+50%), P53 (+<5%), and Her-2 (+) (Fig.	('P53', 'Gene', (78, 81))	('Her-2', 'Gene', '2064', (94, 99))	('CK-pan', 'Var', (52, 58))	('Her-2', 'Gene', (94, 99))	('P53', 'Gene', '7157', (78, 81))
526465	30855489	5D), CK-pan (-), CK5/6 (-), P63 (-), Vimentin (-), and Dog-1 (-).	('Vimentin', 'Gene', '477991', (37, 45))	('CK5/6', 'Var', (17, 22))	('Vimentin', 'Gene', (37, 45))	('Dog', 'Species', '9615', (55, 58))
526492	30855489	However, based on our experience with this case, lymph node metastasis is not a decisive factor in prognosis, the double malignancy may have significantly reduced the survival time.	('survival time', 'CPA', (167, 180))	('malignancy', 'Disease', 'MESH:D009369', (121, 131))	('reduced', 'NegReg', (155, 162))	('double', 'Var', (114, 120))	('malignancy', 'Disease', (121, 131))
526533	30544427	A previous retrospective study reported that HVH is associated with a higher cytoreduction rate in primary ovarian cancer operations.	('primary ovarian cancer', 'Disease', 'MESH:D010051', (99, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('primary ovarian cancer', 'Disease', (99, 121))	('cytoreduction', 'MPA', (77, 90))	('higher', 'PosReg', (70, 76))	('HVH', 'Var', (45, 48))
526570	29991888	GCTs can induce pseudoepitheliomatous hyperplasia of overlying squamous epithelium, which can lead to a misdiagnosis of squamous cell carcinoma if the biopsy is superficial.	('pseudoepitheliomatous hyperplasia', 'Disease', 'MESH:D006965', (16, 49))	('induce', 'Reg', (9, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('pseudoepitheliomatous hyperplasia', 'Disease', (16, 49))	('GCTs', 'Var', (0, 4))	('lead to', 'Reg', (94, 101))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 143))	('squamous cell carcinoma', 'Disease', (120, 143))
526658	29991888	These lesions can cause obstruction of the bile duct by concentric narrowing, which may lead to secondary biliary cirrhosis if left untreated, and will possibly require liver transplantation.	('biliary cirrhosis', 'Phenotype', 'HP:0002613', (106, 123))	('biliary cirrhosis', 'Disease', 'MESH:D008105', (106, 123))	('lead to', 'Reg', (88, 95))	('obstruction of the bile', 'Disease', (24, 47))	('lesions', 'Var', (6, 13))	('cause', 'Reg', (18, 23))	('narrowing', 'NegReg', (67, 76))	('biliary cirrhosis', 'Disease', (106, 123))	('cirrhosis', 'Phenotype', 'HP:0001394', (114, 123))	('obstruction of the bile', 'Disease', 'MESH:D002779', (24, 47))
526684	29285832	Through these activities, nimotuzumab is considered to cause cell cycle arrest, apoptosis induction, and inhibition of angiogenesis in tumor tissues.22, 23, 24 Available clinical data for nimotuzumab support an enhanced antitumor effect in patients with head and neck cancer in combination with radiotherapy, and nimotuzumab has been reported not to affect the tolerability of combination therapy.22  With high expression of EGFR, esophageal cancer is considered a potential target for nimotuzumab therapy, and nimotuzumab in combination with CRT is expected to improve the prognosis of esophageal cancer.	('EGFR', 'Gene', (425, 429))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('esophageal cancer', 'Disease', (587, 604))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (598, 604))	('nimotuzumab', 'Chemical', 'MESH:C501466', (313, 324))	('arrest', 'Disease', 'MESH:D006323', (72, 78))	('improve', 'PosReg', (562, 569))	('nimotuzumab', 'Chemical', 'MESH:C501466', (26, 37))	('nimotuzumab', 'Chemical', 'MESH:C501466', (486, 497))	('nimotuzumab', 'Chemical', 'MESH:C501466', (511, 522))	('EGFR', 'Gene', '1956', (425, 429))	('high expression', 'Var', (406, 421))	('esophageal cancer', 'Disease', 'MESH:D004938', (431, 448))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', (135, 140))	('patients', 'Species', '9606', (240, 248))	('cancer', 'Phenotype', 'HP:0002664', (442, 448))	('esophageal cancer', 'Disease', (431, 448))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('esophageal cancer', 'Disease', 'MESH:D004938', (587, 604))	('head and neck cancer', 'Phenotype', 'HP:0012288', (254, 274))	('arrest', 'Disease', (72, 78))	('CRT', 'Gene', '799', (543, 546))	('neck cancer', 'Disease', 'MESH:D006258', (263, 274))	('nimotuzumab', 'Chemical', 'MESH:C501466', (188, 199))	('neck cancer', 'Disease', (263, 274))	('CRT', 'Gene', (543, 546))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))
526716	29285832	Mutations of the K-ras gene, which are associated with resistance against EGFR antibody therapies, were also assessed.	('K-ras', 'Gene', '3845', (17, 22))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', (74, 78))	('K-ras', 'Gene', (17, 22))
526820	29383156	Proliferation ability increased significantly (P < 0.05) after blocking CCR6 in ECA-109 cells compared with CCL20 treated group (Figure 2A).	('CCR6', 'Gene', '1235', (72, 76))	('CCL20', 'Gene', '6364', (108, 113))	('blocking', 'Var', (63, 71))	('increased', 'PosReg', (22, 31))	('CCL20', 'Gene', (108, 113))	('Proliferation ability', 'CPA', (0, 21))	('CCR6', 'Gene', (72, 76))
526822	29383156	ESCC cell lines showed higher migratory potential toward CCL20 gradients, compared to respective untreated cells, which was significantly (P < 0.05) inhibited after CCR6 blockade in ECA-109 cells not in TE-1 cells (Figure 2B).	('CCL20', 'Gene', (57, 62))	('migratory potential', 'CPA', (30, 49))	('higher', 'PosReg', (23, 29))	('CCR6', 'Gene', '1235', (165, 169))	('CCR6', 'Gene', (165, 169))	('CCL20', 'Gene', '6364', (57, 62))	('inhibited', 'NegReg', (149, 158))	('blockade', 'Var', (170, 178))
526839	29383156	Abnormal proliferation of tumor cell promotes the progress of tumor, influence the curative effect of treatment.	('curative effect of treatment', 'CPA', (83, 111))	('Abnormal proliferation of tumor cell', 'Phenotype', 'HP:0031377', (0, 36))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (62, 67))	('Abnormal', 'Var', (0, 8))	('influence', 'Reg', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('promotes', 'PosReg', (37, 45))
526867	29383156	The sections were incubated with 3% H2O2 in PBS for 10 min for blocking endogenous peroxidase, rinsed three times with PBS, blocked with 3% BSA at RT for 20 min, and then incubated with primary antibodies at 4 C overnight in humidity chamber (E-cadherin, 1:500, MAB-0589, Maixin; Vimentin, 1:500, MAB-0178, Maixin; CCR6 antibody, 1:500, MAB195, R&D).	('PBS', 'Disease', 'MESH:D011535', (44, 47))	('MAB195', 'Var', (337, 343))	('PBS', 'Disease', (44, 47))	('E-cadherin', 'Gene', (243, 253))	('CCR6', 'Gene', (315, 319))	('Vimentin', 'Gene', (280, 288))	('PBS', 'Disease', 'MESH:D011535', (119, 122))	('PBS', 'Disease', (119, 122))	('CCR6', 'Gene', '1235', (315, 319))	('E-cadherin', 'Gene', '999', (243, 253))	('H2O2', 'Chemical', 'MESH:D006861', (36, 40))	('Vimentin', 'Gene', '7431', (280, 288))
526870	29383156	The immunostaining intensity of CCR6 and E-cadherin were assessed according to the H-score method described by our previous report: H-score = (% unstained x 0) + (% stained weak x 1) + (% stained moderate x 2) + (% stained strong x 3).	('CCR6', 'Gene', (32, 36))	('CCR6', 'Gene', '1235', (32, 36))	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))	('weak x', 'Var', (173, 179))
526891	29046712	Integration of human papillomavirus 16 in esophageal carcinoma samples Esophageal carcinoma (EC) is one of the major cancers in China.	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (71, 91))	('Integration', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('human papillomavirus 16', 'Species', '333760', (15, 38))	('esophageal carcinoma', 'Disease', (42, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (42, 62))	('Esophageal carcinoma', 'Disease', (71, 91))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (42, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (71, 91))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('EC', 'Phenotype', 'HP:0011459', (93, 95))	('cancers', 'Disease', (117, 124))
526900	29046712	The results verified that the integrated HPV16 E7 in five samples harbored one mutation of viral DNA compared with the HPV16 sequence provided in GenBank (K02718).	('HPV16', 'Species', '333760', (119, 124))	('HPV16', 'Species', '333760', (41, 46))	('mutation', 'Var', (79, 87))	('harbored', 'Reg', (66, 74))	('HPV16', 'Gene', (41, 46))
526944	29046712	High-risk HPV infection (such as HPV types16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58 and HPV59) have been identified as causative agents in cervix cancers.	('HPV56', 'Var', (102, 107))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('HPV45', 'Var', (81, 86))	('HPV infection', 'Disease', (10, 23))	('HPV', 'Species', '10566', (67, 70))	('HPV39', 'Var', (74, 79))	('HPV35', 'Var', (67, 72))	('HPV', 'Species', '10566', (60, 63))	('HPV', 'Species', '10566', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('HPV', 'Species', '10566', (74, 77))	('HPV', 'Species', '10566', (81, 84))	('HPV18', 'Var', (46, 51))	('cervix cancers', 'Disease', 'MESH:D002583', (170, 184))	('HPV31', 'Var', (53, 58))	('HPV', 'Species', '10566', (10, 13))	('HPV52', 'Var', (95, 100))	('HPV33', 'Var', (60, 65))	('HPV58', 'Var', (109, 114))	('HPV', 'Species', '10566', (88, 91))	('HPV35', 'Species', '10587', (67, 72))	('HPV', 'Species', '10566', (33, 36))	('cervix cancers', 'Disease', (170, 184))	('HPV', 'Species', '10566', (95, 98))	('HPV59', 'Var', (119, 124))	('HPV', 'Species', '10566', (119, 122))	('HPV51', 'Var', (88, 93))	('HPV', 'Species', '10566', (46, 49))	('HPV', 'Species', '10566', (109, 112))	('cervix cancers', 'Phenotype', 'HP:0030079', (170, 184))	('HPV', 'Species', '10566', (102, 105))	('HPV infection', 'Disease', 'MESH:D030361', (10, 23))
526948	29046712	study showed that Six HPV genotypes (HPV6, HPV16, HPV33, HPV39, HPV51, and HPV82) were present in at least 51.7% of the esophagealcarcinoma tissues, and combined with other studies, these findings indicate that HPV infection may be a pathogenic factor for esophageal cancers.	('HPV', 'Species', '10566', (211, 214))	('HPV51', 'Var', (64, 69))	('HPV', 'Species', '10566', (75, 78))	('HPV', 'Species', '10566', (37, 40))	('esophageal cancers', 'Disease', (256, 274))	('HPV16', 'Species', '333760', (43, 48))	('HPV', 'Species', '10566', (50, 53))	('esophagealcarcinoma tissues', 'Disease', 'MESH:D009380', (120, 147))	('HPV39', 'Var', (57, 62))	('HPV', 'Species', '10566', (43, 46))	('esophageal cancers', 'Disease', 'MESH:D004938', (256, 274))	('HPV infection', 'Disease', 'MESH:D030361', (211, 224))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('HPV', 'Species', '10566', (57, 60))	('HPV infection', 'Disease', (211, 224))	('HPV', 'Species', '10566', (64, 67))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('HPV', 'Species', '10566', (22, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('esophagealcarcinoma tissues', 'Disease', (120, 147))	('HPV82', 'Var', (75, 80))
526952	29046712	Cleaving the E2 gene increased HPV E6 and E7 gene expression, which disrupts the cell cycle and leads to aberrant proliferation.	('increased', 'PosReg', (21, 30))	('disrupts', 'NegReg', (68, 76))	('HPV', 'Species', '10566', (31, 34))	('leads to', 'Reg', (96, 104))	('Cleaving', 'Var', (0, 8))	('E7 gene', 'Gene', (42, 49))	('HPV E6', 'Gene', (31, 37))	('cell cycle', 'CPA', (81, 91))	('expression', 'MPA', (50, 60))
527084	25554686	Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations Germline mutations in the PTEN tumor-suppressor gene cause autosomal-dominant conditions such as Cowden and Bannayan-Riley-Ruvalcaba syndromes with variable presentations, including hamartomatous gastrointestinal tumors, dermatologic abnormalities, neurologic symptoms, and elevated cancer risk.	('hamartomatous gastrointestinal tumors', 'Disease', 'MESH:C563621', (296, 333))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cause', 'Reg', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Esophageal cancer', 'Disease', (0, 17))	('PTEN', 'Gene', (140, 144))	('PTEN', 'Gene', '5728', (69, 73))	('missense mutations', 'Var', (95, 113))	('hamartomatous gastrointestinal tumors', 'Phenotype', 'HP:0004390', (296, 333))	('tumor', 'Disease', (327, 332))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Disease', (145, 150))	('elevated cancer', 'Disease', (388, 403))	('frameshift', 'Var', (74, 84))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (310, 333))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('PTEN', 'Gene', '5728', (140, 144))	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('SMAD7', 'Gene', (89, 94))	('hamartoma', 'Phenotype', 'HP:0010566', (296, 305))	('hamartoma', 'Phenotype', 'HP:0010566', (35, 44))	('hamartomatous gastrointestinal tumors', 'Disease', (296, 333))	('tumor', 'Disease', (49, 54))	('dermatologic abnormalities', 'Phenotype', 'HP:0000951', (335, 361))	('elevated cancer', 'Disease', 'MESH:D009369', (388, 403))	('hamartomatous tumors', 'Disease', 'MESH:C563621', (35, 55))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('SMAD7', 'Gene', '4092', (89, 94))	('hamartomatous tumors', 'Disease', (35, 55))	('Cowden', 'Disease', (211, 217))	('dermatologic abnormalities, neurologic symptoms', 'Disease', 'MESH:D009422', (335, 382))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))	('PTEN', 'Gene', (69, 73))
527086	25554686	Exome sequencing identified a novel germline PTEN frameshift mutation (c.568_569insC, p.V191S_fs*11).	('c.568_569insC', 'Var', (71, 84))	('c.568_569insC', 'Mutation', 'c.568_569insC', (71, 84))	('p.V191S', 'Mutation', 'p.V191S', (86, 93))	('p.V191S_fs*11', 'Var', (86, 99))
527087	25554686	In addition, a missense mutation of SMAD7 (c.115G>A, p.G39R) with an allele frequency of 0.3% in the Exome Variant Server was detected in both affected individuals.	('c.115G>A', 'Mutation', 'rs144204026', (43, 51))	('c.115G>A', 'Var', (43, 51))	('p.G39R', 'Mutation', 'rs144204026', (53, 59))	('SMAD7', 'Gene', (36, 41))
527090	25554686	Esophageal adenocarcinoma and extensive polyposis/ganglioneuromatosis could represent less-common features of these syndromes, potentially correlating with this novel PTEN frameshift and early protein termination genotype.	('polyposis/ganglioneuromatosis', 'Disease', (40, 69))	('Esophageal adenocarcinoma', 'Disease', (0, 25))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (0, 25))	('polyposis/ganglioneuromatosis', 'Disease', 'MESH:C563519', (40, 69))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('ganglioneuromatosis', 'Phenotype', 'HP:0025151', (50, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('frameshift', 'Var', (172, 182))
527091	25554686	Alternatively, because simultaneous disruption of both the PTEN and TGF-beta/SMAD4 pathways is associated with development of esophageal cancer in a mouse model, and SMAD4 mutations cause gastrointestinal hamartomas in Juvenile Polyposis Syndrome, the SMAD7 mutation may represent an additional modifier of these individuals' PTEN-mutant phenotype.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (172, 181))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('associated', 'Reg', (95, 105))	('TGF-beta/SMAD4', 'Gene', (68, 82))	('cause', 'Reg', (182, 187))	('disruption', 'NegReg', (36, 46))	('Juvenile Polyposis Syndrome', 'Phenotype', 'HP:0004784', (219, 246))	('hamartomas', 'Phenotype', 'HP:0010566', (205, 215))	('mouse', 'Species', '10090', (149, 154))	('gastrointestinal hamartomas in Juvenile Polyposis Syndrome', 'Disease', 'MESH:D006222', (188, 246))	('hamartoma', 'Phenotype', 'HP:0010566', (205, 214))	('gastrointestinal hamartomas', 'Phenotype', 'HP:0004390', (188, 215))	('PTEN', 'Gene', (59, 63))	('esophageal cancer', 'Disease', (126, 143))	('SMAD4', 'Gene', (166, 171))
527093	25554686	Germline loss-of-function PTEN mutations are responsible for Cowden, Bannayan-Riley-Ruvalcaba, and other syndromes, known collectively as the PTEN hamartoma tumor syndrome (PHTS).	('mutations', 'Var', (31, 40))	('PHTS', 'Gene', (173, 177))	('PTEN hamartoma tumor syndrome', 'Disease', 'MESH:D006223', (142, 171))	('hamartoma', 'Phenotype', 'HP:0010566', (147, 156))	('PHTS', 'Gene', '116372', (173, 177))	('PTEN hamartoma tumor syndrome', 'Disease', (142, 171))	('PTEN', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('loss-of-function', 'NegReg', (9, 25))	('Cowden', 'Disease', (61, 67))	('Bannayan-Riley-Ruvalcaba', 'Disease', (69, 93))
527095	25554686	Harmartomatous polyps of the stomach and colorectum define the related but distinct autosomal-dominant Juvenile Polyposis Syndrome (JPS), which results from germline mutations of SMAD4 or BMPR1A disrupting signaling through the bone morphogenetic protein (BMP)/SMAD4 pathway.	('BMPR1A', 'Gene', '657', (188, 194))	('polyps of the stomach and colorectum', 'Phenotype', 'HP:0200008', (15, 51))	('BMP', 'Gene', (188, 191))	('JPS', 'Disease', 'MESH:C537702', (132, 135))	('mutations', 'Var', (166, 175))	('BMP', 'Gene', '649', (256, 259))	('SMAD4', 'Gene', (179, 184))	('JPS', 'Disease', (132, 135))	('Juvenile Polyposis Syndrome', 'Phenotype', 'HP:0004784', (103, 130))	('BMPR1A', 'Gene', (188, 194))	('Harmartomatous polyps of the stomach', 'Disease', (0, 36))	('disrupting', 'NegReg', (195, 205))	('JPS', 'Phenotype', 'HP:0004784', (132, 135))	('signaling', 'MPA', (206, 215))	('BMP', 'Gene', (256, 259))	('dominant Juvenile Polyposis Syndrome', 'Disease', (94, 130))	('bone morphogenetic protein', 'Gene', '649', (228, 254))	('Harmartomatous polyps of the stomach', 'Disease', 'MESH:D011127', (0, 36))	('BMP', 'Gene', '649', (188, 191))	('dominant Juvenile Polyposis Syndrome', 'Disease', 'MESH:C537702', (94, 130))	('bone morphogenetic protein', 'Gene', (228, 254))
527098	25554686	In this report we describe a novel PTEN frameshift mutation and a SMAD7 missense mutation occurring in a father and son who had a syndrome of gastrointestinal hamartomatous and ganglioneuromatous polyposis, and who both developed esophageal adenocarcinoma, which has not previously been reported as a feature of PHTS.	('gastrointestinal hamartomatous', 'Phenotype', 'HP:0004390', (142, 172))	('PHTS', 'Gene', (312, 316))	('PTEN', 'Gene', (35, 39))	('hamartoma', 'Phenotype', 'HP:0010566', (159, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('frameshift mutation', 'Var', (40, 59))	('SMAD7', 'Gene', (66, 71))	('esophageal adenocarcinoma', 'Disease', (230, 255))	('PHTS', 'Gene', '116372', (312, 316))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (230, 255))	('syndrome of gastrointestinal hamartomatous and ganglioneuromatous polyposis', 'Disease', 'MESH:D010580', (130, 205))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (230, 255))	('developed', 'PosReg', (220, 229))
527101	25554686	SMAD4 and BMPR1A were screened for mutations and deletion/duplications as described.	('deletion/duplications', 'Var', (49, 70))	('BMPR1A', 'Gene', (10, 16))	('SMAD4', 'Gene', (0, 5))	('BMPR1A', 'Gene', '657', (10, 16))	('mutations', 'Var', (35, 44))
527118	25554686	The proband's numerous juvenile polyps and lack of PHTS features such as macrocephaly, trichilemmoma, or intellectual disability led to a JPS diagnosis, yet sequencing and multiplex ligation-dependent probe amplification revealed no mutations or deletion/duplications in coding or promoter regions of SMAD4 or BMPR1A.	('macrocephaly', 'Disease', (73, 85))	('SMAD4', 'Gene', (301, 306))	('BMPR1A', 'Gene', (310, 316))	('macrocephaly', 'Disease', 'MESH:D058627', (73, 85))	('led to', 'Reg', (129, 135))	('numerous juvenile polyps', 'Disease', 'MESH:D011127', (14, 38))	('trichilemmoma', 'Disease', (87, 100))	('PHTS', 'Gene', (51, 55))	('intellectual disability', 'Phenotype', 'HP:0001249', (105, 128))	('JPS', 'Disease', 'MESH:C537702', (138, 141))	('juvenile polyps', 'Phenotype', 'HP:0004784', (23, 38))	('macrocephaly', 'Phenotype', 'HP:0000256', (73, 85))	('JPS', 'Disease', (138, 141))	('trichilemmoma', 'Phenotype', 'HP:0012844', (87, 100))	('BMPR1A', 'Gene', '657', (310, 316))	('JPS', 'Phenotype', 'HP:0004784', (138, 141))	('deletion/duplications', 'Var', (246, 267))	('PHTS', 'Gene', '116372', (51, 55))	('numerous juvenile polyps', 'Disease', (14, 38))
527119	25554686	This identified a novel heterozygous single-base insertion in the PTEN gene (c.568_569insC, p.V191S_fs*11), predicted to cause a frameshift with premature termination in the 5th coding exon.	('p.V191S_fs*', 'Var', (92, 103))	('PTEN', 'Gene', (66, 70))	('p.V191S', 'Mutation', 'p.V191S', (92, 99))	('c.568_569insC', 'Var', (77, 90))	('c.568_569insC', 'Mutation', 'c.568_569insC', (77, 90))	('cause', 'Reg', (121, 126))	('frameshift', 'Var', (129, 139))
527121	25554686	While this PTEN mutation was considered likely to be responsible for the proband's symptoms and multiple cancers, the list of candidate mutations was examined for variants occurring in known GI cancer pathways, which might influence the proband's clinical phenotype.	('multiple cancers', 'Disease', 'MESH:D009369', (96, 112))	('mutation', 'Var', (16, 24))	('GI cancer', 'Disease', 'MESH:D009369', (191, 200))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('GI cancer', 'Phenotype', 'HP:0007378', (191, 200))	('influence', 'Reg', (223, 232))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('variants', 'Var', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('multiple cancers', 'Disease', (96, 112))	('GI cancer', 'Disease', (191, 200))
527122	25554686	Out of 72 rare variant candidates (Supplementary Table), a germline missense mutation in SMAD7 (c.115G>A, p.G39R) stood out due to its role in the TGF-beta/SMAD4 pathway, mutations in which are known to cause Juvenile Polyposis Syndrome.	('c.115G>A', 'Mutation', 'rs144204026', (96, 104))	('Juvenile Polyposis Syndrome', 'Disease', (209, 236))	('SMAD7', 'Gene', (89, 94))	('Juvenile Polyposis Syndrome', 'Disease', 'MESH:C537702', (209, 236))	('c.115G>A', 'Var', (96, 104))	('p.G39R', 'Var', (106, 112))	('cause', 'Reg', (203, 208))	('role', 'Reg', (135, 139))	('Juvenile Polyposis Syndrome', 'Phenotype', 'HP:0004784', (209, 236))	('TGF-beta/SMAD4 pathway', 'Pathway', (147, 169))	('p.G39R', 'Mutation', 'rs144204026', (106, 112))
527124	25554686	The SMAD7 G39R mutation is reported in dbSNP (rs144204026), but is rare with an allele frequency of 0.3% (36/10904 chromosomes) in EVS.	('G39R', 'Mutation', 'rs144204026', (10, 14))	('rs144204026', 'Var', (46, 57))	('SMAD7', 'Gene', (4, 9))	('EVS', 'Chemical', '-', (131, 134))	('rs144204026', 'Mutation', 'rs144204026', (46, 57))	('G39R', 'Var', (10, 14))
527129	25554686	Hybridization revealed two PTEN copies in all 200 malignant nuclei examined, suggesting that deletion of the wild-type PTEN allele is not responsible for disrupting PTEN protein expression in this tumor.	('disrupting', 'NegReg', (154, 164))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('expression', 'MPA', (178, 188))	('PTEN', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('deletion', 'Var', (93, 101))	('PTEN', 'Gene', (165, 169))
527130	25554686	The PTEN mutation in this family (c.568_569insC) has not been previously observed, but occurs in a frequently-mutated region of PTEN exon 5, and is similar to several reported mutations.	('mutation', 'Var', (9, 17))	('c.568_569insC', 'Mutation', 'c.568_569insC', (34, 47))	('PTEN', 'Gene', (4, 8))
527131	25554686	Of 290 probands with PTEN mutations causing PHTS reported in a large registry, 13 had termination or frameshift mutations within 20 residues of this V191S_fs*11 mutation.	('PHTS', 'Gene', (44, 48))	('PHTS', 'Gene', '116372', (44, 48))	('frameshift mutations', 'Var', (101, 121))	('mutations', 'Var', (26, 35))	('V191S', 'Mutation', 'p.V191S', (149, 154))	('PTEN', 'Gene', (21, 25))	('V191S_fs*11', 'Var', (149, 160))
527132	25554686	The same registry reported a higher incidence of colorectal cancer among patients with PTEN frameshift mutations compared to missense or promoter mutations, while another registry reported lower rates of thyroid cancer in missense mutation patients.	('PTEN', 'Gene', (87, 91))	('thyroid cancer', 'Phenotype', 'HP:0002890', (204, 218))	('thyroid cancer', 'Disease', (204, 218))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('patients', 'Species', '9606', (73, 81))	('colorectal cancer', 'Disease', (49, 66))	('thyroid cancer', 'Disease', 'MESH:D013964', (204, 218))	('patients', 'Species', '9606', (240, 248))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('frameshift mutations', 'Var', (92, 112))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
527138	25554686	PTEN gene dosage affects tumor susceptibility, with the reduced protein expression in patients with germline mutations predisposing them to develop hamartomas, which may retain PTEN expression.	('hamartomas', 'Disease', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('develop', 'PosReg', (140, 147))	('patients', 'Species', '9606', (86, 94))	('reduced', 'NegReg', (56, 63))	('tumor', 'Disease', (25, 30))	('hamartoma', 'Phenotype', 'HP:0010566', (148, 157))	('hamartomas', 'Disease', 'MESH:D006222', (148, 158))	('hamartomas', 'Phenotype', 'HP:0010566', (148, 158))	('mutations', 'Var', (109, 118))	('PTEN', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('protein expression', 'MPA', (64, 82))
527140	25554686	Recognized PHTS second-hit mechanisms include promoter methylation, chromosomal loss of heterozygosity (LOH), and new somatic mutations.	('chromosomal', 'Var', (68, 79))	('promoter methylation', 'Var', (46, 66))	('loss of', 'NegReg', (80, 87))	('PHTS', 'Gene', (11, 15))	('PHTS', 'Gene', '116372', (11, 15))
527143	25554686	In retrospect, Patient II-2's clinical features at presentation for colectomy give a significant 29% risk of having a PTEN mutation by the Cleveland Clinic Calculator.	('PTEN', 'Gene', (118, 122))	('Patient', 'Species', '9606', (15, 22))	('mutation', 'Var', (123, 131))
527147	25554686	Although somatic PTEN mutations are uncommon in esophageal cancer, alterations in PTEN expression commonly occur in EAC and esophageal squamous cell carcinoma (ESCC).	('esophageal cancer', 'Disease', (48, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('EAC', 'Phenotype', 'HP:0011459', (116, 119))	('occur', 'Reg', (107, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('alterations', 'Var', (67, 78))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (124, 158))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('expression', 'MPA', (87, 97))	('EAC', 'Disease', (116, 119))	('PTEN', 'Gene', (82, 86))	('esophageal squamous cell carcinoma', 'Disease', (124, 158))
527151	25554686	The SMAD7 G39R mutation could represent such a modifier.	('SMAD7', 'Gene', (4, 9))	('G39R', 'Var', (10, 14))	('G39R', 'Mutation', 'rs144204026', (10, 14))
527153	25554686	Although the TGF-beta and BMP pathways both converge on SMAD4 to exert their effects, they have distinct functions, and whereas mutations in BMPR1A and SMAD4 cause JPS, mutations in TGF-beta receptor-associated SMADs (SMAD2-3 and SMAD7), have not been found in hamartomatous tumor syndromes.	('BMP', 'Gene', (141, 144))	('mutations', 'Var', (169, 178))	('hamartoma', 'Phenotype', 'HP:0010566', (261, 270))	('JPS', 'Disease', 'MESH:C537702', (164, 167))	('SMAD2-3', 'Gene', '4087;4088', (218, 225))	('JPS', 'Disease', (164, 167))	('BMPR1A', 'Gene', (141, 147))	('BMP', 'Gene', '649', (26, 29))	('mutations', 'Var', (128, 137))	('cause', 'Reg', (158, 163))	('hamartomatous tumor', 'Disease', (261, 280))	('JPS', 'Phenotype', 'HP:0004784', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('BMP', 'Gene', (26, 29))	('BMP', 'Gene', '649', (141, 144))	('SMAD4', 'Gene', (152, 157))	('hamartomatous tumor', 'Disease', 'MESH:C563621', (261, 280))	('SMAD2-3', 'Gene', (218, 225))	('BMPR1A', 'Gene', '657', (141, 147))
527155	25554686	Loss of SMAD7 protein causes decreased colorectal cancer cell growth in vitro, but in vivo also decreases the ability of tumor infiltrating lymphocytes to induce cancer cell apoptosis, thereby promoting metastasis.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', (121, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('metastasis', 'CPA', (203, 213))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('colorectal cancer', 'Disease', (39, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('protein', 'Protein', (14, 21))	('promoting', 'PosReg', (193, 202))	('decreased', 'NegReg', (29, 38))	('Loss', 'Var', (0, 4))	('SMAD7', 'Gene', (8, 13))	('decreases', 'NegReg', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))
527156	25554686	Smad7 knockout increases rates of hepatocellular carcinoma (HCC) formation after diethylnitrosamine injection in mice, and negative SMAD7 staining by IHC correlates with worse survival in human esophageal squamous and pancreatic cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (34, 58))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (81, 99))	('human', 'Species', '9606', (188, 193))	('pancreatic cancers', 'Disease', 'MESH:D010190', (218, 236))	('pancreatic cancers', 'Disease', (218, 236))	('hepatocellular carcinoma', 'Disease', (34, 58))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('Smad7', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('increases rates of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (15, 58))	('esophageal squamous', 'Disease', 'MESH:D000077277', (194, 213))	('increases', 'PosReg', (15, 24))	('esophageal squamous', 'Disease', (194, 213))	('knockout', 'Var', (6, 14))	('Smad7', 'Gene', '17131', (0, 5))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (218, 236))	('mice', 'Species', '10090', (113, 117))
527157	25554686	IHC results in Patient III-2 esophageal tumor specimen demonstrate intact levels of SMAD7 protein expression, however, whether the function of this protein is affected by the G39R mutation remains unknown.	('esophageal tumor', 'Disease', (29, 45))	('esophageal tumor', 'Phenotype', 'HP:0100751', (29, 45))	('Patient', 'Species', '9606', (15, 22))	('G39R', 'Var', (175, 179))	('esophageal tumor', 'Disease', 'MESH:D004938', (29, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('SMAD7', 'Gene', (84, 89))	('G39R', 'Mutation', 'rs144204026', (175, 179))
527160	25554686	Disruption of two closely-regulated and interacting pathways could explain enhanced tumor development in the dual-knockout mouse.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('enhanced', 'PosReg', (75, 83))	('mouse', 'Species', '10090', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('Disruption', 'Var', (0, 10))
527161	25554686	If loss of SMAD4 promotes cancer, dysfunction of a SMAD4 signaling inhibitor might be expected to have the opposite effect, however, data showing tumorigenic effects of SMAD7 loss, and association of single-nucleotide polymorphisms (SNPs) causing decreased SMAD7 function with colorectal cancer in multiple populations, suggest that perturbation of the TGF-beta pathway at the level of either SMAD7 or SMAD4 promotes tumorigenesis.	('cancer', 'Disease', (26, 32))	('tumor', 'Disease', (146, 151))	('cancer', 'Disease', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', (417, 422))	('function', 'MPA', (263, 271))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('decreased', 'NegReg', (247, 256))	('promotes', 'PosReg', (408, 416))	('tumor', 'Disease', 'MESH:D009369', (417, 422))	('TGF-beta pathway', 'Pathway', (353, 369))	('colorectal cancer', 'Disease', 'MESH:D015179', (277, 294))	('SMAD4', 'Gene', (402, 407))	('SMAD7', 'Gene', (169, 174))	('colorectal cancer', 'Disease', (277, 294))	('single-nucleotide polymorphisms', 'Var', (200, 231))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (417, 422))	('perturbation', 'Var', (333, 345))	('loss', 'NegReg', (175, 179))	('loss', 'Var', (3, 7))	('colorectal cancer', 'Phenotype', 'HP:0003003', (277, 294))
527162	25554686	Perhaps most germane to this family, the microRNA 216a/217, which is upregulated in recurrent HCC specimens, was found to promote HCC recurrence and sorafenib resistance by direct inhibition of both PTEN and SMAD7.	('sorafenib resistance', 'CPA', (149, 169))	('microRNA', 'Var', (41, 49))	('sorafenib', 'Chemical', 'MESH:D000077157', (149, 158))	('promote', 'PosReg', (122, 129))	('HCC', 'Disease', (130, 133))	('inhibition', 'NegReg', (180, 190))	('PTEN', 'Gene', (199, 203))
527163	25554686	Finally, sequencing of SMAD7 in patients with SNP haplotypes deemed at high-risk for colorectal cancer revealed the G39R allele in in 2 of 35 individuals, a frequency significantly higher than in the general population (36 of 10904 chromosomes by EVS, p=0.02 by Fisher exact test).	('patients', 'Species', '9606', (32, 40))	('EVS', 'Chemical', '-', (247, 250))	('G39R', 'Var', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('SMAD7', 'Gene', (23, 28))	('G39R', 'Mutation', 'rs144204026', (116, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
527164	25554686	This suggests the SMAD7 G39R mutation could represent an attenuated allele, which while only weakly tumorigenic by itself, promotes EAC development in this family's PTEN-deficient background, similar to the role proposed for succinate dehydrogenase-family (SDHx) variants in modifying breast cancer risk in PHTS patients.	('G39R', 'Mutation', 'rs144204026', (24, 28))	('mutation', 'Var', (29, 37))	('tumor', 'Disease', (100, 105))	('SDHx', 'Gene', (257, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('PHTS', 'Gene', (307, 311))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('promotes', 'PosReg', (123, 131))	('SMAD7', 'Gene', (18, 23))	('SDHx', 'Chemical', '-', (257, 261))	('breast cancer', 'Disease', 'MESH:D001943', (285, 298))	('variants', 'Var', (263, 271))	('breast cancer', 'Disease', (285, 298))	('EAC', 'Phenotype', 'HP:0011459', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('EAC development', 'CPA', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('patients', 'Species', '9606', (312, 320))	('G39R mutation', 'Var', (24, 37))	('PHTS', 'Gene', '116372', (307, 311))
527165	25554686	In summary, we report novel PTEN and rare SMAD7 mutations in a family with gastrointestinal polyposis and esophageal adenocarcinoma.	('PTEN', 'Gene', (28, 32))	('SMAD7', 'Gene', (42, 47))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (106, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('gastrointestinal polyposis', 'Phenotype', 'HP:0200008', (75, 101))	('mutations', 'Var', (48, 57))	('gastrointestinal polyposis and esophageal adenocarcinoma', 'Disease', 'MESH:D004067', (75, 131))
527166	25554686	Emergence of EAC in these patients is possibly influenced by their coexisting SMAD7 mutation, or may represent a less-common manifestation of PHTS.	('mutation', 'Var', (84, 92))	('EAC', 'Phenotype', 'HP:0011459', (13, 16))	('patients', 'Species', '9606', (26, 34))	('influenced', 'Reg', (47, 57))	('EAC', 'Disease', (13, 16))	('PHTS', 'Gene', (142, 146))	('PHTS', 'Gene', '116372', (142, 146))	('SMAD7', 'Gene', (78, 83))
527170	25398092	In many epithelial malignancies, altered integrin expression is associated with tumor progression and often correlates with unfavorable prognosis.	('associated', 'Reg', (64, 74))	('integrin', 'Protein', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('epithelial malignancies', 'Disease', 'MESH:D002277', (8, 31))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('epithelial malignancies', 'Disease', (8, 31))	('altered', 'Var', (33, 40))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (8, 31))	('expression', 'MPA', (50, 60))
527175	25398092	In contrast, patients with reduced focal alpha6 expression at the tumor invasion front shared a significantly shortened relapse-free survival compared to patients with strong alpha6 expression at their stromal surfaces, as it was regularly observed in normal esophageal epithelium (p = 0.001).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('reduced', 'NegReg', (27, 34))	('alpha6', 'Protein', (41, 47))	('tumor', 'Disease', (66, 71))	('focal', 'Var', (35, 40))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (154, 162))	('relapse-free survival', 'CPA', (120, 141))	('shortened', 'NegReg', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
527176	25398092	Our findings suggest that alterations in both pattern and magnitude of integrin expression may play a major role in the disease progression of ESCC patients.	('patients', 'Species', '9606', (148, 156))	('SCC', 'Gene', (144, 147))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('play', 'Reg', (95, 99))	('alterations', 'Var', (26, 37))	('SCC', 'Gene', '6317', (144, 147))	('integrin', 'Protein', (71, 79))
527235	25398092	Seven (54%) of the 13 pN0 patients had an enhanced beta1 expression at the invasion front of their tumors compared to only two (12%) of 17 of the pN1 patients (p = 0.018).	('pN1', 'Gene', (146, 149))	('expression', 'MPA', (57, 67))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('enhanced', 'PosReg', (42, 50))	('beta1', 'Gene', '3779', (51, 56))	('patients', 'Species', '9606', (26, 34))	('pN0', 'Var', (22, 25))	('patients', 'Species', '9606', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('pN1', 'Gene', '5270', (146, 149))	('beta1', 'Gene', (51, 56))	('tumors', 'Disease', (99, 105))
527240	25398092	Thereby, patients with a down-regulated low to moderate (+/++) alpha6 immunostaining at the invasion front shared a 6.41 times increased risk for tumor relapse (95% CI: 1.88-21.78), a 5.11 times increased risk for shortened tumor-associated survival (95% CI: 1.47-17.81), and a 3.04 times increased risk for shortened overall survival (95% CI: 1.13-8.21) compared to patients with a distinct strong (+++) alpha6 staining.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', (146, 151))	('down-regulated', 'NegReg', (25, 39))	('low to moderate (+/++', 'Var', (40, 61))	('patients', 'Species', '9606', (367, 375))	('overall', 'MPA', (318, 325))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('shortened', 'NegReg', (214, 223))
527270	25398092	Our results indicate that the abrogation of normal integrin expression characteristics, as they are observed in non-malignant squamous epithelium of the esophagus, is a frequent event in esophageal squamous cell carcinoma (ESCC) associated to an unfavorable disease outcome.	('expression', 'MPA', (60, 70))	('SCC', 'Gene', (224, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (198, 221))	('SCC', 'Phenotype', 'HP:0002860', (224, 227))	('abrogation', 'Var', (30, 40))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (187, 221))	('SCC', 'Gene', '6317', (224, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('esophageal squamous cell carcinoma', 'Disease', (187, 221))
527287	25398092	In another study, the loss of polarized alpha6beta4 expression was suggested as a potential early marker of malignancy in oral SCC.	('SCC', 'Gene', (127, 130))	('SCC', 'Phenotype', 'HP:0002860', (127, 130))	('beta4', 'Gene', '10381', (46, 51))	('malignancy', 'Disease', 'MESH:D009369', (108, 118))	('malignancy in oral', 'Phenotype', 'HP:0100649', (108, 126))	('SCC', 'Gene', '6317', (127, 130))	('beta4', 'Gene', (46, 51))	('malignancy', 'Disease', (108, 118))	('loss', 'Var', (22, 26))
527291	25398092	In their in vitro experiments, the authors convincingly show that the molecular interference and down-regulation of alpha6 integrin expression in ESCC cell lines decreases cell proliferation and invasiveness.	('molecular interference', 'Var', (70, 92))	('SCC', 'Gene', (147, 150))	('alpha6 integrin', 'Protein', (116, 131))	('down-regulation', 'NegReg', (97, 112))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('decreases', 'NegReg', (162, 171))	('cell proliferation', 'CPA', (172, 190))	('SCC', 'Gene', '6317', (147, 150))	('invasiveness', 'CPA', (195, 207))
527316	25398092	Particularly the expression of the two alpha6 integrins alpha6beta1 and alpha6beta4 appear to play a critical role in the malignant progression of ESCC reflecting its aggressiveness: The abrogation of a polarized expression pattern in the primary tumor with a loss of the focally enhanced integrin expression along the tumor invasion front represents an amendatory histopathological marker to further assess the malignancy of the individual tumor.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('expression', 'MPA', (298, 308))	('malignancy', 'Disease', 'MESH:D009369', (412, 422))	('enhanced', 'PosReg', (280, 288))	('SCC', 'Gene', (148, 151))	('tumor', 'Disease', (441, 446))	('loss', 'NegReg', (260, 264))	('beta1', 'Gene', (62, 67))	('abrogation', 'Var', (187, 197))	('aggressiveness', 'Disease', (167, 181))	('integrin', 'Protein', (289, 297))	('malignancy', 'Disease', (412, 422))	('tumor', 'Disease', 'MESH:D009369', (441, 446))	('aggressiveness', 'Phenotype', 'HP:0000718', (167, 181))	('beta1', 'Gene', '3779', (62, 67))	('beta4', 'Gene', (78, 83))	('aggressiveness', 'Disease', 'MESH:D001523', (167, 181))	('tumor', 'Disease', (319, 324))	('tumor', 'Disease', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (441, 446))	('beta4', 'Gene', '10381', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('polarized expression pattern', 'MPA', (203, 231))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('SCC', 'Gene', '6317', (148, 151))
527337	25354803	demonstrated that esophageal constructs which had undergone specific ablation of the epithelium subsequently developed severe strictures when introduced into the in vivo environment.	('developed', 'Reg', (109, 118))	('rat', 'Species', '10116', (7, 10))	('ablation', 'Var', (69, 77))	('strictures', 'MPA', (126, 136))
527405	25354803	This suggests that further work is necessary to fully elaborate the implications of CD34 positivity in esophageal epithelial stem cells.	('CD34', 'Gene', (84, 88))	('positivity', 'Var', (89, 99))	('rat', 'Species', '10116', (59, 62))
527419	22877736	TP53 point mutations occur in at least 50% of EC cases.	('point mutations', 'Var', (5, 20))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))
527420	22877736	TP53 mutations have also been detected in early stages of EAC and ESCC tumorigenesis, as well as in benign BE mucosa.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('EAC', 'Disease', (58, 61))	('ESCC', 'Disease', (66, 70))	('detected', 'Reg', (30, 38))	('tumor', 'Disease', (71, 76))	('BE', 'Phenotype', 'HP:0100580', (107, 109))
527429	22877736	We did, however, observe a statistically significant difference between the two tumor types in indels and transversions: A:T>C:G substitutions were more common in EACs, while C:G>G:C transversions and indels were more frequent in ESCCs (p<0.0001, Cochran-Mantel Haenszel test).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ESCCs', 'Disease', (230, 235))	('common', 'Reg', (153, 159))	('tumor', 'Disease', (80, 85))	('EAC', 'Phenotype', 'HP:0011459', (163, 166))	('C:G>G', 'Var', (175, 180))	('A:T>C:G substitutions', 'Var', (121, 142))	('EACs', 'Disease', (163, 167))
527430	22877736	Although tobacco use is associated with a higher risk of ESCC than of EAC, we did not observe a difference between these two tumor types in the C:G>A:T transversions that are typically associated with smoking.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('ESCC', 'Disease', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('C:G>A:T', 'Var', (144, 151))	('tumor', 'Disease', (125, 130))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))	('tobacco', 'Species', '4097', (9, 16))
527435	22877736	Thirty-eight genes were mutated in more than one of the eleven EACs studied, and TP53 was mutated in eight EACs (Supplementary Table 1).	('mutated', 'Var', (24, 31))	('EAC', 'Phenotype', 'HP:0011459', (63, 66))	('EAC', 'Phenotype', 'HP:0011459', (107, 110))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
527436	22877736	Other than TP53, genes (or members of a related pathway) that were mutated in at least three of the 12 ESCCs comprised NOTCH1, NOTCH3, FBXW7, KIF16B, KIF21B, and MYCBP2 (Supplementary Table 2).	('KIF21B', 'Gene', (150, 156))	('KIF21B', 'Gene', '23046', (150, 156))	('MYCBP2', 'Gene', '23077', (162, 168))	('MYCBP2', 'Gene', (162, 168))	('NOTCH3', 'Gene', (127, 133))	('TP53', 'Gene', (11, 15))	('TP53', 'Gene', '7157', (11, 15))	('NOTCH1', 'Gene', (119, 125))	('mutated', 'Var', (67, 74))	('FBXW7', 'Gene', '55294', (135, 140))	('KIF16B', 'Gene', (142, 148))	('NOTCH3', 'Gene', '4854', (127, 133))	('KIF16B', 'Gene', '55614', (142, 148))	('FBXW7', 'Gene', (135, 140))
527442	22877736	Given the potential differences in risk factors and carcinogens between North American and Chinese ESCCs, we analyzed the complete coding sequences of TP53, NOTCH1, NOTCH2, NOTCH3, and FBXW7 in 48 Chinese ESCCs.	('FBXW7', 'Gene', '55294', (185, 190))	('TP53', 'Gene', (151, 155))	('NOTCH3', 'Gene', '4854', (173, 179))	('FBXW7', 'Gene', (185, 190))	('NOTCH2', 'Gene', '4853', (165, 171))	('NOTCH1', 'Var', (157, 163))	('NOTCH3', 'Gene', (173, 179))	('TP53', 'Gene', '7157', (151, 155))	('NOTCH2', 'Gene', (165, 171))
527443	22877736	As in our North American ESCC samples, the incidence of TP53 mutations was high (71%) (Supplementary Table 5) and the fraction of mutant TP53 alleles was large (20% to 90%), suggesting that the neoplastic cell content of the samples used for analysis was sufficient to identify mutations.	('TP53', 'Gene', '7157', (56, 60))	('mutations', 'Var', (61, 70))	('TP53', 'Gene', (56, 60))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', (137, 141))
527448	22877736	In particular, ESO10T had a TP53 mutation in both BE and EAC, while ESO01T did not have a TP53 mutation in either BE or EAC.	('TP53', 'Gene', '7157', (28, 32))	('ESO10T', 'Var', (15, 21))	('mutation', 'Var', (33, 41))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (28, 32))	('EAC', 'Phenotype', 'HP:0011459', (120, 123))	('BE', 'Phenotype', 'HP:0100580', (50, 52))	('TP53', 'Gene', (90, 94))
527449	22877736	These data suggest that the majority of the mutations present in the cancers were already present in their benign precursor lesions, providing very strong molecular evidence that EACs developed from BE epithelium in both of these patients.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('EAC', 'Phenotype', 'HP:0011459', (179, 182))	('patients', 'Species', '9606', (230, 238))	('mutations', 'Var', (44, 53))	('BE', 'Phenotype', 'HP:0100580', (199, 201))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
527450	22877736	Additionally, the data demonstrate that the advent of frank malignancy - i.e., the ability to invade the underlying basement membrane of the esophageal mucosa - was associated with the accumulation of a relatively small number of additional mutations (Table 2).	('malignancy', 'Disease', (60, 70))	('malignancy', 'Disease', 'MESH:D009369', (60, 70))	('mutations', 'Var', (241, 250))
527452	22877736	Our study provides unequivocal evidence that NOTCH1 plays a tumor-suppressive role during ESCC development; we observed 12 mutations, eight of which were inactivating and predicted to result in loss of the majority of amino acids from the translated protein.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('loss', 'NegReg', (194, 198))	('majority of amino acids', 'MPA', (206, 229))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ESCC', 'Disease', (90, 94))	('tumor', 'Disease', (60, 65))	('mutations', 'Var', (123, 132))
240691	22877736	Moreover, loss of epidermal NOTCH1 promotes skin tumorigenesis by impacting the stromal microenvironment.	('epidermal NOTCH1', 'Gene', (18, 34))	('loss', 'Var', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('promotes', 'PosReg', (35, 43))	('tumor', 'Disease', (49, 54))	('impacting', 'Reg', (66, 75))	('stromal microenvironment', 'CPA', (80, 104))
527454	22877736	Nevertheless, a direct connection between NOTCH1 inactivation and human esophageal tumorigenesis had not been established prior to our study.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('inactivation', 'Var', (49, 61))	('human', 'Species', '9606', (66, 71))	('NOTCH1', 'Gene', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
527458	22877736	However, mutations in TP53 and NOTCH genes were not mutually exclusive in esophageal tumors we evaluated; some tumors had mutations in both genes.	('esophageal tumors', 'Phenotype', 'HP:0100751', (74, 91))	('esophageal tumors', 'Disease', 'MESH:D004938', (74, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('esophageal tumors', 'Disease', (74, 91))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (122, 131))	('TP53', 'Gene', '7157', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('TP53', 'Gene', (22, 26))	('tumors', 'Disease', (85, 91))
527459	22877736	NOTCH pathway disruption has also been tied to FBXW7 gene mutation, although FBXW7 also targets other cancer-related proteins for degradation, including c-myc and cyclin E; we observed inactivating FBXW7 gene mutations relatively frequently in our ESCCs, including those which harbored NOTCH mutations.	('FBXW7', 'Gene', '55294', (77, 82))	('FBXW7', 'Gene', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('FBXW7', 'Gene', (77, 82))	('FBXW7', 'Gene', (47, 52))	('cyclin E', 'Gene', (163, 171))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('inactivating', 'NegReg', (185, 197))	('c-myc', 'Gene', '4609', (153, 158))	('mutations', 'Var', (209, 218))	('cyclin E', 'Gene', '34924', (163, 171))	('c-myc', 'Gene', (153, 158))	('FBXW7', 'Gene', '55294', (198, 203))	('FBXW7', 'Gene', '55294', (47, 52))
527467	22877736	From these data, 255 high-quality mutations (for EACs) and 95 (for ESCCs) were chosen for validation by Sanger sequencing of the mutated genes in the same 23 tumors.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutations', 'Var', (34, 43))
527468	22877736	These 255 and 95 high-quality genes were chosen for validation of mutation calling as follows: in EAC, the 8 TP53 mutations, all 117 mutations found in ESO01T and ESO10T, plus 130 randomly selected genes from other samples, were subjected to Sanger sequencing; in ESCC, all 28 mutations in TP53, NOTCH1, NOTCH3, FBXW7, KIF16B, KIF21B and MYCBP2, plus 67 randomly chosen genes, were queried with Sanger sequencing to confirm our mutation calling.	('MYCBP2', 'Gene', (338, 344))	('KIF16B', 'Gene', (319, 325))	('EAC', 'Phenotype', 'HP:0011459', (98, 101))	('FBXW7', 'Gene', (312, 317))	('KIF16B', 'Gene', '55614', (319, 325))	('NOTCH3', 'Gene', '4854', (304, 310))	('MYCBP2', 'Gene', '23077', (338, 344))	('TP53', 'Gene', '7157', (109, 113))	('KIF21B', 'Gene', (327, 333))	('mutations', 'Var', (277, 286))	('TP53', 'Gene', (109, 113))	('TP53', 'Gene', '7157', (290, 294))	('KIF21B', 'Gene', '23046', (327, 333))	('TP53', 'Gene', (290, 294))	('NOTCH1', 'Gene', (296, 302))	('FBXW7', 'Gene', '55294', (312, 317))	('NOTCH3', 'Gene', (304, 310))
527471	22877736	Finally, in the two patients from whom adequate high-quality DNA was available from matched BE epithelium, Sanger sequencing of all 78 genes that were confirmed as mutated in ESO01T and all 39 genes confirmed as mutated in ESO10T was performed in the matching benign BE tissues.	('ESO01T', 'Gene', (175, 181))	('BE', 'Phenotype', 'HP:0100580', (267, 269))	('patients', 'Species', '9606', (20, 28))	('BE', 'Phenotype', 'HP:0100580', (92, 94))	('mutated', 'Var', (164, 171))
527637	32365790	The detection of high-grade dysplasia and early esophageal adenocarcinoma in Barrett's esophagus was significantly higher in the ETMI group compared to SVE alone, but with a huge false-positive rate (71%).	('ETMI', 'Chemical', '-', (129, 133))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (48, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (59, 73))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (77, 96))	('adenocarcinoma', 'Disease', (59, 73))	('dysplasia', 'Disease', 'MESH:C536170', (28, 37))	('higher', 'PosReg', (115, 121))	('ETMI', 'Var', (129, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('dysplasia', 'Disease', (28, 37))
527673	32365790	The positive rate of dysplasia in protruding lesions was significantly higher in low AF than in high AF, while the rate of dysplasia in flat lesions did not differ between low AF and high AF.	('higher', 'PosReg', (71, 77))	('flat lesions', 'Disease', (136, 148))	('AF', 'Disease', 'MESH:D001281', (188, 190))	('flat lesions', 'Disease', 'MESH:D005413', (136, 148))	('low', 'Var', (81, 84))	('AF', 'Disease', 'MESH:D001281', (176, 178))	('dysplasia', 'Disease', 'MESH:C536170', (123, 132))	('dysplasia', 'Disease', 'MESH:C536170', (21, 30))	('AF', 'Disease', 'MESH:D001281', (101, 103))	('dysplasia', 'Disease', (123, 132))	('dysplasia', 'Disease', (21, 30))	('AF', 'Disease', 'MESH:D001281', (85, 87))
527716	32365790	found correlations between SAF and collagen-linked, pentosidine, and Nepsilon-(carboxyethyl)lysine AF for the skin biopsies.	('Nepsilon-(carboxyethyl)lysine', 'Chemical', 'MESH:C054688', (69, 98))	('AF', 'Disease', 'MESH:D001281', (28, 30))	('SAF', 'Chemical', '-', (27, 30))	('pentosidine', 'Chemical', 'MESH:C062187', (52, 63))	('correlations', 'Reg', (6, 18))	('Nepsilon-', 'Var', (69, 78))	('AF', 'Disease', 'MESH:D001281', (99, 101))
527784	32365790	identified the single nucleotide polymorphism rs915895 (located 38188 bp upstream of the AGER gene) as associated with AGE accumulation in the skin.	('AGER', 'Gene', (89, 93))	('rs915895', 'Var', (46, 54))	('associated', 'Reg', (103, 113))	('AGE accumulation', 'Disease', (119, 135))	('AGER', 'Gene', '177', (89, 93))	('rs915895', 'Mutation', 'rs915895', (46, 54))
527836	32365790	found significantly higher PTG detection rates by NIR compared to standard resection under white light in a group of 74 patients undergoing thyroid and parathyroid surgery.	('PTG', 'Gene', (27, 30))	('higher', 'PosReg', (20, 26))	('NIR', 'Var', (50, 53))	('patients', 'Species', '9606', (120, 128))	('PTG', 'Gene', '5507', (27, 30))
527852	32365790	Furthermore, the number of patients with four identified PTGs was higher and parathyroid autotransplantation was less frequent in the NIR AFI group.	('PTG', 'Gene', (57, 60))	('less', 'NegReg', (113, 117))	('AF', 'Disease', 'MESH:D001281', (138, 140))	('patients', 'Species', '9606', (27, 35))	('PTG', 'Gene', '5507', (57, 60))	('higher', 'PosReg', (66, 72))	('parathyroid autotransplantation', 'CPA', (77, 108))	('NIR', 'Var', (134, 137))
527901	32365790	Although clinical AFI uses blue light excitation, experimental studies on AF signals in intestinal tissues found peak excitations at 488 and 561 nm, and the emitted light was detectable at 500-550 or 570-620 nm, respectively.	('excitations', 'MPA', (118, 129))	('488', 'Var', (133, 136))	('561 nm', 'Var', (141, 147))	('AF', 'Disease', 'MESH:D001281', (18, 20))	('AF', 'Disease', 'MESH:D001281', (74, 76))
527990	32365790	AGE advanced glycation end products  AF autofluorescence  AFB  autofluorescence bronchoscopy  AFI autofluorescence imaging  AU arbitrary units  CFOME confocal fiber-optic micro-endoscopy  CI confidence interval   CKD chronic kidney disease  COPD chronic obstructive pulmonary disease  DAFE diagnostic autofluorescence endoscopy  ETMI  endoscopic trimodal imaging  ECM extracellular matrix  FAD flavin adenine dinucleotide  FH functional heartburn  FLIM fluorescence lifetime imaging microscopy  GERD gastroesophageal reflux disease  GOLD global initiative for chronic obstructive lung disease  HRE high resolution endoscopy  LDCT low-dose computed tomography  MPT multiphoton tomography  NAD(P)H reduced nicotinamide adenine dinucleotide phosphate  NBI narrow band imaging  NERD non-erosive reflux disease  NILT near-infrared light transillumination  NIR near-infrared  OTIS overlay tissue imaging system  pCLE probe-based confocal laser endomicroscopy  PTG parathyroid gland  UC ulcerative colitis  RGB red, green and blue  SAF skin autofluorescence  SVE standard white-light video endoscopy  SNP single nucleotide polymorphism  WL white light  WLB white light bronchoscopy  WLE white light endoscopy	('D', 'Chemical', 'MESH:D003903', (244, 245))	('D', 'Chemical', 'MESH:D003903', (498, 499))	('D', 'Chemical', 'MESH:D003903', (285, 286))	('AF', 'Disease', 'MESH:D001281', (58, 60))	('D', 'Chemical', 'MESH:D003903', (690, 691))	('colitis', 'Phenotype', 'HP:0002583', (991, 998))	('reflux disease', 'Phenotype', 'HP:0002020', (791, 805))	('flavin adenine dinucleotide', 'Chemical', 'MESH:D005182', (394, 421))	('AF', 'Disease', 'MESH:D001281', (1026, 1028))	('FAD', 'Chemical', 'MESH:D005182', (390, 393))	('D', 'Chemical', 'MESH:D003903', (536, 537))	('D', 'Chemical', 'MESH:D003903', (392, 393))	('AF', 'Disease', 'MESH:D001281', (286, 288))	('reflux disease', 'Phenotype', 'HP:0002020', (517, 531))	('obstructive lung disease', 'Phenotype', 'HP:0006536', (568, 592))	('lung disease', 'Phenotype', 'HP:0002088', (580, 592))	('SAF', 'Chemical', '-', (1025, 1028))	('MPT multiphoton tomography  NAD(P)H', 'Disease', 'MESH:C000656865', (660, 695))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (217, 239))	('ETMI', 'Chemical', '-', (329, 333))	('AFB', 'Chemical', '-', (58, 61))	('COPD', 'Phenotype', 'HP:0006510', (241, 245))	('CKD', 'Phenotype', 'HP:0012622', (213, 216))	('GERD gastroesophageal reflux disease', 'Disease', (495, 531))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (500, 523))	('chronic obstructive lung disease', 'Disease', (560, 592))	('CKD chronic kidney disease  COPD chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (213, 283))	('AF', 'Disease', 'MESH:D001281', (94, 96))	('PTG', 'Gene', '5507', (954, 957))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (254, 283))	('parathyroid gland  UC ulcerative colitis  RGB red', 'Disease', (958, 1007))	('UC', 'Phenotype', 'HP:0100279', (977, 979))	('AF', 'Disease', 'MESH:D001281', (37, 39))	('kidney disease', 'Phenotype', 'HP:0000112', (225, 239))	('chronic obstructive lung', 'Phenotype', 'HP:0006510', (560, 584))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (980, 998))	('GERD gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (495, 531))	('heartburn', 'Phenotype', 'HP:0002020', (437, 446))	('D', 'Chemical', 'MESH:D003903', (777, 778))	('D', 'Chemical', 'MESH:D003903', (626, 627))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (246, 283))	('parathyroid gland  UC ulcerative colitis  RGB red', 'Disease', 'MESH:D003093', (958, 1007))	('chronic obstructive lung disease', 'Disease', 'MESH:D029424', (560, 592))	('D', 'Chemical', 'MESH:D003903', (215, 216))	('single', 'Var', (1098, 1104))	('PTG', 'Gene', (954, 957))
528020	31906183	The mean age of patients with nodal metastasis was significantly higher than that of the benign group: 64.5 +- 11.3 years vs. 59.4 +- 15.1 years (p = 0.034).	('higher', 'PosReg', (65, 71))	('patients', 'Species', '9606', (16, 24))	('nodal metastasis', 'Var', (30, 46))
528034	31906183	Because F-18 FDG is not a tumor-specific tracer and acts as a basic energy substrate for many tissues, it can also accumulate in a variety of benign processes, including inflammatory conditions and reactive LNs.	('inflammatory conditions', 'Disease', (170, 193))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('accumulate', 'PosReg', (115, 125))	('FDG', 'Chemical', 'MESH:D019788', (13, 16))	('tumor', 'Disease', (26, 31))	('F-18 FDG', 'Var', (8, 16))
528053	30883021	In the 15-year follow-up, moderate tooth loss increased the ESCC mortality risk by 58% (HR 1.58, 95% CI 1.06-2.35), while severe loss increased the GCC mortality risk by 30% (HR 1.30, 95% CI 1.03-1.64).	('tooth loss', 'Phenotype', 'HP:0006480', (35, 45))	('GCC', 'Disease', (148, 151))	('increased', 'PosReg', (46, 55))	('ESCC', 'Disease', (60, 64))	('tooth loss', 'Disease', (35, 45))	('loss', 'NegReg', (129, 133))	('moderate tooth loss', 'Phenotype', 'HP:0006311', (26, 45))	('severe', 'Var', (122, 128))	('tooth loss', 'Disease', 'MESH:D016388', (35, 45))
528055	30883021	In subjects aged < 55 at baseline and men, moderate tooth loss had 53% and 52% higher risks of ESCC mortality (HR<55 years 1.53, 95% CI 1.06-2.05; HRmen 1.52, 95% CI 1.01-2.28).	('men', 'Species', '9606', (38, 41))	('tooth loss', 'Disease', (52, 62))	('tooth loss', 'Phenotype', 'HP:0006480', (52, 62))	('men', 'Species', '9606', (149, 152))	('moderate', 'Var', (43, 51))	('moderate tooth loss', 'Phenotype', 'HP:0006311', (43, 62))	('ESCC mortality', 'Disease', (95, 109))	('tooth loss', 'Disease', 'MESH:D016388', (52, 62))
528057	30883021	Severe tooth loss increased the risk of GCC mortality.	('tooth loss', 'Disease', (7, 17))	('tooth loss', 'Phenotype', 'HP:0006480', (7, 17))	('Severe', 'Var', (0, 6))	('GCC', 'Disease', (40, 43))	('Severe tooth', 'Phenotype', 'HP:0001572', (0, 12))	('tooth loss', 'Disease', 'MESH:D016388', (7, 17))
528099	30883021	Survival curves showed that during most of the 30 years of follow-up, the cumulative mortality rates of patients with moderate and severe tooth loss were higher than those in patients with no tooth loss, which indicated that tooth loss could increase the long-term risk of UGI cancer mortality.	('tooth loss', 'Phenotype', 'HP:0006480', (192, 202))	('UGI cancer', 'Disease', 'MESH:D009369', (273, 283))	('tooth loss', 'Disease', (138, 148))	('tooth loss', 'Disease', 'MESH:D016388', (225, 235))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('tooth loss', 'Phenotype', 'HP:0006480', (138, 148))	('higher', 'PosReg', (154, 160))	('severe tooth', 'Phenotype', 'HP:0001572', (131, 143))	('moderate', 'Var', (118, 126))	('tooth loss', 'Disease', (225, 235))	('tooth loss', 'Disease', 'MESH:D016388', (192, 202))	('patients', 'Species', '9606', (175, 183))	('tooth loss', 'Phenotype', 'HP:0006480', (225, 235))	('UGI cancer', 'Disease', (273, 283))	('tooth loss', 'Disease', 'MESH:D016388', (138, 148))	('patients', 'Species', '9606', (104, 112))	('tooth loss', 'Disease', (192, 202))
528163	29740725	In this classification, grade 1 NETs (mitotic count < 2 per 10 high-power fields [HPFs]), grade 2 NETs (mitotic count 2-20 per 10 HPFs and/or Ki67 index > 20%), NEC (mitotic count > 20 per 10 HPFs and/or Ki67 index > 20%), and MANEC is defined as neoplasms comprised of both adenocarcinoma and NEC components in at least 30% of the tumor.	('NET', 'Gene', '2004', (32, 35))	('neoplasms', 'Disease', 'MESH:D009369', (247, 256))	('NEC', 'Phenotype', 'HP:0100634', (229, 232))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('MANEC', 'Disease', (227, 232))	('neoplasms', 'Disease', (247, 256))	('NET', 'Gene', (98, 101))	('adenocarcinoma', 'Disease', (275, 289))	('neoplasm', 'Phenotype', 'HP:0002664', (247, 255))	('NET', 'Gene', (32, 35))	('NEC', 'Phenotype', 'HP:0100634', (161, 164))	('NETs', 'Phenotype', 'HP:0100634', (98, 102))	('neoplasms', 'Phenotype', 'HP:0002664', (247, 256))	('adenocarcinoma', 'Disease', 'MESH:D000230', (275, 289))	('tumor', 'Disease', (332, 337))	('NETs', 'Phenotype', 'HP:0100634', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('NEC', 'Phenotype', 'HP:0100634', (294, 297))	('NET', 'Gene', '2004', (98, 101))	('mitotic', 'Var', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (332, 337))
528211	23499759	This is a cohort study of patients treated with RFA for BE associated dysplasia from three BE referral centers which are part of a Barrett's Esophagus Translational Research Network (BETRNet) consortium, funded by the National Cancer Institute.	('RFA', 'Var', (48, 51))	('BETRNet', 'Chemical', '-', (183, 190))	('dysplasia', 'Disease', (70, 79))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (131, 150))	('dysplasia', 'Disease', 'MESH:D004476', (70, 79))	('Cancer', 'Disease', (227, 233))	('patients', 'Species', '9606', (26, 34))	('Cancer', 'Disease', 'MESH:D009369', (227, 233))	('Cancer', 'Phenotype', 'HP:0002664', (227, 233))
528339	22855665	Colon Carcinoma with Unusual Metastasis to the Esophagus Manifesting as Multiple Nodules and Dysphagia: Management with Systemic Chemotherapy We present here the rare clinical case of a 44-year-old gentleman with metastasis from colon carcinoma to the esophagus presenting with multiple nodules and dysphagia, which was successfully managed with systemic chemotherapy.	('metastasis', 'Var', (213, 223))	('Colon Carcinoma', 'Disease', (0, 15))	('dysphagia', 'Phenotype', 'HP:0002015', (299, 308))	('Dysphagia', 'Disease', (93, 102))	('Dysphagia', 'Disease', 'MESH:D003680', (93, 102))	('Carcinoma', 'Phenotype', 'HP:0030731', (6, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('dysphagia', 'Disease', 'MESH:D003680', (299, 308))	('colon carcinoma', 'Disease', 'MESH:D015179', (229, 244))	('colon carcinoma', 'Disease', (229, 244))	('Dysphagia', 'Phenotype', 'HP:0002015', (93, 102))	('Colon Carcinoma', 'Disease', 'MESH:D015179', (0, 15))	('dysphagia', 'Disease', (299, 308))
528523	22057498	From the present studies we conclude that HPPH-PDT for precancerous lesions and early intramucosal cancer in BE appears to be safe with promising efficacy, justifying more extensive controlled studies to establish its use for this disease.	('precancerous lesions', 'Disease', (55, 75))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('intramucosal cancer', 'Disease', (86, 105))	('HPPH', 'Chemical', 'MESH:C083998', (42, 46))	('HPPH-PDT', 'Var', (42, 50))	('BE', 'Phenotype', 'HP:0100580', (109, 111))	('intramucosal cancer', 'Disease', 'MESH:D009369', (86, 105))	('precancerous lesions', 'Disease', 'MESH:D011230', (55, 75))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
528546	33927929	Overall classification based on radiological staging was T4 N2 M0 (tracheal invasion and nodal metastases).	('T4 N2 M0', 'Var', (57, 65))	('metastases', 'Disease', 'MESH:D009362', (95, 105))	('metastases', 'Disease', (95, 105))
528682	32368146	The exclusion criteria were as follows: 1) patients with liver diseases, hematology diseases, inflammatory or infectious diseases; 2) combined with other malignant tumor; 3) recurrent tumors; 4) transfusion of albumin or fibrinogen within 1 week before the detection of albumin and fibrinogen concentrations.	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('transfusion', 'Var', (195, 206))	('hematology diseases', 'Disease', 'MESH:D006402', (73, 92))	('albumin', 'Gene', '213', (270, 277))	('liver diseases', 'Phenotype', 'HP:0001392', (57, 71))	('fibrinogen', 'Gene', '2244', (221, 231))	('albumin', 'Gene', (210, 217))	('malignant tumor', 'Disease', (154, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('fibrinogen', 'Gene', '2244', (282, 292))	('liver diseases', 'Disease', 'MESH:D008107', (57, 71))	('patients', 'Species', '9606', (43, 51))	('infectious diseases', 'Disease', 'MESH:D003141', (110, 129))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('albumin', 'Gene', (270, 277))	('liver diseases', 'Disease', (57, 71))	('malignant tumor', 'Disease', 'MESH:D009369', (154, 169))	('infectious diseases', 'Disease', (110, 129))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('fibrinogen', 'Gene', (221, 231))	('albumin', 'Gene', '213', (210, 217))	('tumors', 'Disease', (184, 190))	('hematology diseases', 'Disease', (73, 92))	('fibrinogen', 'Gene', (282, 292))
528828	30416380	Epigenetic alterations of a novel antioxidant gene SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer Esophageal squamous cell carcinoma (ESCC) occurs with the highest frequency in China, especially in the high-risk Northern Chinese.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('predispose', 'Reg', (59, 69))	('SLC22A3', 'Gene', (51, 58))	('SLC22A3', 'Gene', '6581', (51, 58))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (133, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('Esophageal squamous cell carcinoma', 'Disease', (133, 167))
528833	30416380	Moreover, case-control study of Chinese descendants from different risk areas of China revealed that the methylation of the SLC22A3 gene in peripheral blood leukocyte (PBL) DNA samples could be a risk factor for developing ESCC in this high-risk population.	('methylation', 'Var', (105, 116))	('SLC22A3', 'Gene', '6581', (124, 131))	('SLC22A3', 'Gene', (124, 131))	('ESCC', 'Disease', (223, 227))	('risk factor', 'Reg', (196, 207))
528834	30416380	Functional studies showed that SLC22A3 is a novel antioxidant gene, and deregulation of SLC22A3 facilitates heat stress-induced oxidative DNA damage and formation of gamma-H2AX foci in normal esophageal epithelial cells.	('esophageal epithelia', 'Disease', 'MESH:D004941', (192, 212))	('SLC22A3', 'Gene', '6581', (31, 38))	('SLC22A3', 'Gene', (31, 38))	('gamma-H2AX foci', 'MPA', (166, 181))	('deregulation', 'Var', (72, 84))	('facilitates', 'PosReg', (96, 107))	('heat stress-induced oxidative DNA damage', 'MPA', (108, 148))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (192, 212))	('gamma-H2AX', 'Chemical', '-', (166, 176))	('SLC22A3', 'Gene', '6581', (88, 95))	('SLC22A3', 'Gene', (88, 95))	('esophageal epithelia', 'Disease', (192, 212))
528835	30416380	Collectively, we show that epigenetic alterations of SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer.	('esophageal cancer', 'Disease', (117, 134))	('SLC22A3', 'Gene', '6581', (53, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('predispose', 'Reg', (61, 71))	('SLC22A3', 'Gene', (53, 60))	('epigenetic alterations', 'Var', (27, 49))
528875	30416380	Western blot analyses were performed according to the standard protocol with the following antibodies: anti-SLC22A3 (Abmart, 1:1000) anti-gamma-H2AX (Abcam, 1:1000) and GAPDH (Abcam, 1:1000).	('anti-gamma-H2AX', 'Var', (133, 148))	('SLC22A3', 'Gene', '6581', (108, 115))	('SLC22A3', 'Gene', (108, 115))	('GAPDH', 'Gene', '2597', (169, 174))	('gamma-H2AX', 'Chemical', '-', (138, 148))	('GAPDH', 'Gene', (169, 174))
528879	30416380	We selected 114 genetic variants in a ~500-kb region surrounding the SLC22A3 gene on 6q25 from the dataset of a previous esophageal cancer GWAS in 496 cases with a family history of upper gastrointestinal tract cancers and 1056 healthy controls.	('variants', 'Var', (24, 32))	('SLC22A3', 'Gene', '6581', (69, 76))	('SLC22A3', 'Gene', (69, 76))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('upper gastrointestinal tract cancers', 'Disease', (182, 218))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('upper gastrointestinal tract cancers', 'Disease', 'MESH:D004067', (182, 218))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
528880	30416380	One SNP (rs9457930), located at ~45-kb downstream of the SLC22A3 gene, was found to be significantly associated with reduced ESCC risk in high-risk individuals with a family history of ESCC [P = 4.68e-09, odds ratio (OR) = 0.508, 95% confidence interval (CI) 0.504-0.512; Figure 1], indicating that SLC22A3 could be a protective factor and that deregulation of this gene may confer susceptibility to familial ESCC.	('familial ESCC', 'Disease', (400, 413))	('rs9457930', 'Mutation', 'rs9457930', (9, 18))	('reduced', 'NegReg', (117, 124))	('SLC22A3', 'Gene', '6581', (57, 64))	('SLC22A3', 'Gene', '6581', (299, 306))	('SLC22A3', 'Gene', (299, 306))	('deregulation', 'Var', (345, 357))	('susceptibility', 'Reg', (382, 396))	('SLC22A3', 'Gene', (57, 64))	('rs9457930', 'Var', (9, 18))	('ESCC', 'Disease', (125, 129))
528882	30416380	Promoter hypermethylation, especially in tumor suppressor genes, is an important mechanism of transcript silencing in tumourigenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('silencing', 'NegReg', (105, 114))	('transcript', 'MPA', (94, 104))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumourigenesis', 'Disease', (118, 132))	('Promoter hypermethylation', 'Var', (0, 25))
528885	30416380	After 5-Aza treatment, SLC22A3 expression was dramatically restored, suggesting that SLC22A3 methylation was associated with its downregulation in ESCC (Figure 2A).	('5-Aza', 'Chemical', 'MESH:D001374', (6, 11))	('downregulation', 'NegReg', (129, 143))	('ESCC', 'Disease', (147, 151))	('SLC22A3', 'Gene', '6581', (23, 30))	('SLC22A3', 'Gene', (23, 30))	('SLC22A3', 'Gene', '6581', (85, 92))	('SLC22A3', 'Gene', (85, 92))	('methylation', 'Var', (93, 104))
528886	30416380	We next used a CpG-island searcher to study the 5'-region of the SLC22A3 gene (-1000 to +476) and found it was located right in a CpG island (Figure 2B).	('-1000 to +476', 'Var', (79, 92))	('searcher', 'Species', '274808', (26, 34))	('SLC22A3', 'Gene', '6581', (65, 72))	('SLC22A3', 'Gene', (65, 72))
528889	30416380	Intriguingly, SLC22A3 promoter methylation showed a significantly negative correlation with its mRNA level in 76 family history FH+ NT tissues (Spearman r = -0.302, P = 0.008; Figure 2C), suggesting that promoter hypermethylation of SLC22A3 contributes to its gene silencing in familial ESCC.	('SLC22A3', 'Gene', '6581', (233, 240))	('SLC22A3', 'Gene', (233, 240))	('promoter hypermethylation', 'Var', (204, 229))	('SLC22A3', 'Gene', '6581', (14, 21))	('SLC22A3', 'Gene', (14, 21))	('gene', 'MPA', (260, 264))	('NT', 'Chemical', '-', (132, 134))	('familial ESCC', 'Disease', (278, 291))
528890	30416380	Our previous study showed that the SLC22A3 mRNA level was significantly lower in FH+ NT tissues compared with that in FH- NT tissues, indicating that methylation-mediated downregulation of SLC22A3 could be an earlier event in ESCC high-risk individuals.	('methylation-mediated', 'Var', (150, 170))	('NT', 'Chemical', '-', (122, 124))	('downregulation', 'NegReg', (171, 185))	('SLC22A3', 'Gene', (35, 42))	('SLC22A3', 'Gene', '6581', (35, 42))	('SLC22A3', 'Gene', (189, 196))	('SLC22A3', 'Gene', '6581', (189, 196))	('ESCC', 'Disease', (226, 230))	('NT', 'Chemical', '-', (85, 87))	('lower', 'NegReg', (72, 77))	('FH+ NT', 'Var', (81, 87))
528892	30416380	Interestingly, the SLC22A3 proximal promoter showed a distinctly different pattern of methylation in FH+ NT esophageal epithelia compared with that in FH- NT tissues (Figure S1).	('esophageal epithelia', 'Phenotype', 'HP:0012859', (108, 128))	('NT', 'Chemical', '-', (105, 107))	('different', 'Reg', (65, 74))	('methylation', 'MPA', (86, 97))	('esophageal epithelia', 'Disease', (108, 128))	('esophageal epithelia', 'Disease', 'MESH:D004941', (108, 128))	('FH+ NT', 'Var', (101, 107))	('SLC22A3', 'Gene', '6581', (19, 26))	('SLC22A3', 'Gene', (19, 26))	('NT', 'Chemical', '-', (155, 157))
528895	30416380	Similar to the methylation pattern observed in NT esophageal epithelia, the blood DNA samples also showed inter-individual variations of SLC22A3 methylation, of which FH+ blood DNA samples showed a higher degree of methylation than FH- samples (Figure S2).	('esophageal epithelia', 'Phenotype', 'HP:0012859', (50, 70))	('methylation', 'MPA', (145, 156))	('NT', 'Chemical', '-', (47, 49))	('esophageal epithelia', 'Disease', (50, 70))	('esophageal epithelia', 'Disease', 'MESH:D004941', (50, 70))	('FH+', 'Var', (167, 170))	('methylation', 'MPA', (215, 226))	('SLC22A3', 'Gene', '6581', (137, 144))	('SLC22A3', 'Gene', (137, 144))
528896	30416380	To further prove that SLC22A3 hypermethylation is an early event that predisposes high-risk individuals to develop esophageal cancer, we extended the PBL DNA methylation study to case-control sample sets, including 133 cases and 115 controls recruited from an ESCC high-risk region of North China (high-risk cohort), as well as 112 cases and 100 controls from an ESCC low-risk region of South China (low-risk cohort).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('esophageal cancer', 'Disease', (115, 132))	('develop', 'PosReg', (107, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('SLC22A3', 'Gene', '6581', (22, 29))	('SLC22A3', 'Gene', (22, 29))	('hypermethylation', 'Var', (30, 46))
528902	30416380	Moreover, a conditional logistic regression model revealed that SLC22A3 promoter hypermethylation was significantly associated with ESCC risk in the high-risk cohort (OR per 1% increment in SLC22A3 methylation = 1.352, 95% CI = 1.208-1.514) but not in the low-risk cohort (OR = 1.070, 95% CI = 0.9364-1.223; Table 1), indicating that early SLC22A3 hypermethylation contributes to ESCC susceptibility and may serve as an effective marker for earlier screening.	('SLC22A3', 'Gene', '6581', (64, 71))	('SLC22A3', 'Gene', (340, 347))	('ESCC', 'Disease', (380, 384))	('SLC22A3', 'Gene', '6581', (190, 197))	('SLC22A3', 'Gene', (190, 197))	('SLC22A3', 'Gene', '6581', (340, 347))	('contributes', 'Reg', (365, 376))	('ESCC', 'Disease', (132, 136))	('hypermethylation', 'Var', (81, 97))	('SLC22A3', 'Gene', (64, 71))	('associated', 'Reg', (116, 126))
528914	30416380	Collectively, we propose a disease model in which the epigenetic alterations of SLC22A3, predisposed in high-risk individuals with a family history, could accelerate the malignant transformation of normal esophageal epithelial cells under heat stress, leading to the development of ESCC (Figure 6).	('leading to', 'Reg', (252, 262))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (205, 225))	('malignant transformation', 'CPA', (170, 194))	('SLC22A3', 'Gene', '6581', (80, 87))	('epigenetic alterations', 'Var', (54, 76))	('accelerate', 'PosReg', (155, 165))	('esophageal epithelia', 'Disease', 'MESH:D004941', (205, 225))	('SLC22A3', 'Gene', (80, 87))	('esophageal epithelia', 'Disease', (205, 225))	('ESCC', 'Disease', (282, 286))
528917	30416380	A post hoc GWAS analysis revealed that one SNP (rs9457930), located at ~45-kb downstream of the SLC22A3 gene, is significantly associated with reduced ESCC risk in familial ESCC cases.	('SLC22A3', 'Gene', '6581', (96, 103))	('SLC22A3', 'Gene', (96, 103))	('ESCC', 'Disease', (151, 155))	('rs9457930', 'Var', (48, 57))	('rs9457930', 'Mutation', 'rs9457930', (48, 57))	('familial ESCC', 'Disease', (164, 177))	('reduced', 'NegReg', (143, 150))
528918	30416380	This result is in line with our previous finding that SLC22A3 is downregulated in familial ESCC cases, indicating that SLC22A3 could be a protective factor and downregulation of this gene may confer susceptibility to ESCC.	('downregulated', 'NegReg', (65, 78))	('familial ESCC', 'Disease', (82, 95))	('ESCC', 'Disease', (217, 221))	('SLC22A3', 'Gene', '6581', (54, 61))	('SLC22A3', 'Gene', (54, 61))	('SLC22A3', 'Gene', '6581', (119, 126))	('SLC22A3', 'Gene', (119, 126))	('downregulation', 'Var', (160, 174))
528919	30416380	Secondly, epigenetic alterations of the SLC22A3 gene contribute to its significantly lower expression in FH+ ESCCs.	('expression', 'MPA', (91, 101))	('FH+ ESCCs', 'Disease', (105, 114))	('lower', 'NegReg', (85, 90))	('epigenetic alterations', 'Var', (10, 32))	('SLC22A3', 'Gene', '6581', (40, 47))	('SLC22A3', 'Gene', (40, 47))
528920	30416380	Finally, population methylation analyses demonstrate that a gain of SLC22A3 promoter methylation is associated with an increased risk of developing ESCC in a northern Chinese population.	('methylation', 'Var', (85, 96))	('promoter', 'MPA', (76, 84))	('SLC22A3', 'Gene', '6581', (68, 75))	('gain', 'PosReg', (60, 64))	('ESCC', 'Disease', (148, 152))	('SLC22A3', 'Gene', (68, 75))
528922	30416380	With the rapidly developed methylation analysis technologies, cancer-specific hypermethylation events could be detected in more easily accessible biological material, such as sera, feces, urine, and sputum.	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('hypermethylation', 'Var', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
528923	30416380	To date, several studies have reported that the epigenetic alterations detected in peripheral blood cell DNA could be a valuable predictive marker for people with a high risk for cancer.	('people', 'Species', '9606', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))	('epigenetic alterations', 'Var', (48, 70))
528924	30416380	Here, we also provide the first evidence that DNA methylation of the SLC22A3 gene in peripheral blood cells is associated with an increased esophageal cancer risk.	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('SLC22A3', 'Gene', '6581', (69, 76))	('DNA methylation', 'Var', (46, 61))	('SLC22A3', 'Gene', (69, 76))	('associated with', 'Reg', (111, 126))	('esophageal cancer', 'Disease', (140, 157))
528925	30416380	However, to determine the diagnostic value of SLC22A3 methylation in an ESCC high-risk population, large-scale case-control cohorts need to be further investigated.	('methylation', 'Var', (54, 65))	('SLC22A3', 'Gene', '6581', (46, 53))	('SLC22A3', 'Gene', (46, 53))	('ESCC', 'Disease', (72, 76))
528927	30416380	In line with previous observations, methylation heterogeneity or epigenetic mosaicism observed in cancer precursor tissues suggests that this epigenetic variability could reflect a type of genomic instability in the early development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', (237, 243))	('methylation', 'Var', (36, 47))
528933	30416380	DNA damage-related mutagenesis occurs in a wide range of human precancerous lesions, and is associated with early tumourigenesis.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutagenesis', 'Var', (19, 30))	('precancerous lesions', 'Disease', 'MESH:D011230', (63, 83))	('precancerous lesions', 'Disease', (63, 83))	('associated', 'Reg', (92, 102))	('human', 'Species', '9606', (57, 62))
528934	30416380	A recent study revealed that intraepithelial neoplasia (IEN) expressed high levels of gamma-H2AX and shared similar genetic variant spectrum with ESCC, implying that defects in DNA damage repair and accumulation of mutation burden could contribute to the progression from IEN to ESCC.	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (29, 54))	('neoplasia', 'Phenotype', 'HP:0002664', (45, 54))	('intraepithelial neoplasia', 'Disease', (29, 54))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (29, 54))	('IEN', 'Disease', (272, 275))	('defects', 'Var', (166, 173))	('gamma-H2AX', 'Chemical', '-', (86, 96))	('contribute', 'Reg', (237, 247))	('ESCC', 'Disease', (279, 283))	('IEN', 'Phenotype', 'HP:0032187', (272, 275))	('IEN', 'Phenotype', 'HP:0032187', (56, 59))
528936	30416380	Taken together, these results demonstrated that SLC22A3 promoter hypermethylation may directly suppresses its gene transcription, resulting in increased susceptibility to ESCC in high-risk individuals.	('increased', 'PosReg', (143, 152))	('promoter hypermethylation', 'Var', (56, 81))	('suppresses', 'NegReg', (95, 105))	('SLC22A3', 'Gene', (48, 55))	('SLC22A3', 'Gene', '6581', (48, 55))	('ESCC', 'Disease', (171, 175))	('gene transcription', 'MPA', (110, 128))	('susceptibility', 'Reg', (153, 167))
528937	30416380	With the rapid development of methylation analysis technologies, detecting DNA methylation of SLC22A3 in sera, feces, urine, and sputum could be novel diagnostic and prognostic method for familial ESCC in the future.	('SLC22A3', 'Gene', '6581', (94, 101))	('SLC22A3', 'Gene', (94, 101))	('DNA methylation', 'Var', (75, 90))	('familial ESCC', 'Disease', (188, 201))
528939	28487599	miR-195 Regulates Proliferation and Apoptosis through Inhibiting the mTOR/p70s6k Signaling Pathway by Targeting HMGA2 in Esophageal Carcinoma Cells miR-195 is related to tumorigenesis and frequently inhibits cell proliferation and promotes apoptosis in various cancers, including esophageal carcinoma (EC).	('inhibits', 'NegReg', (199, 207))	('tumor', 'Disease', (170, 175))	('miR-195', 'Gene', (148, 155))	('cell proliferation', 'CPA', (208, 226))	('Targeting', 'Var', (102, 111))	('p70s6k', 'Gene', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('HMGA2', 'Gene', '8091', (112, 117))	('Esophageal Carcinoma', 'Disease', (121, 141))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (280, 300))	('Carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cancers', 'Disease', (261, 268))	('miR-195', 'Gene', '406971', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('apoptosis', 'CPA', (240, 249))	('esophageal carcinoma', 'Disease', (280, 300))	('EC', 'Phenotype', 'HP:0011459', (302, 304))	('promotes', 'PosReg', (231, 239))	('Inhibiting', 'NegReg', (54, 64))	('mTOR', 'Gene', (69, 73))	('miR-195', 'Gene', (0, 7))	('Esophageal Carcinoma', 'Disease', 'MESH:D004938', (121, 141))	('HMGA2', 'Gene', (112, 117))	('p70s6k', 'Gene', '6198', (74, 80))	('miR-195', 'Gene', '406971', (148, 155))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (121, 141))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('mTOR', 'Gene', '2475', (69, 73))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (280, 300))
528984	28487599	For reporter assays, 50 pmol miR-195 or miR-control was cotransfected with 50 ng of pMIR-REPORT HMGA2-3'-UTR-wt or pMIR-REPORT HMGA2-3'-UTR-mut into EC109 and EC9706 cells placed in 24-well plates using Lipofectamine 2000 (Invitrogen).	('pMIR-REPORT', 'Var', (115, 126))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('miR', 'Gene', (40, 43))	('miR-195', 'Gene', '406971', (29, 36))	('HMGA2', 'Gene', '8091', (127, 132))	('EC109', 'CellLine', 'CVCL:6898', (149, 154))	('HMGA2', 'Gene', '8091', (96, 101))	('EC9706', 'CellLine', 'CVCL:E307', (159, 165))	('HMGA2', 'Gene', (127, 132))	('Lipofectamine', 'Chemical', 'MESH:C086724', (203, 216))	('miR-195', 'Gene', (29, 36))	('HMGA2', 'Gene', (96, 101))	('EC', 'Phenotype', 'HP:0011459', (159, 161))	('EC', 'Phenotype', 'HP:0011459', (149, 151))
528997	28487599	Furthermore, to confirm whether miR-195 downregulated HMGA2 expression, EC109 and EC9706 cells were transfected with miR-195 mimics, anti-miR-195, or miR-control.	('expression', 'MPA', (60, 70))	('EC9706', 'CellLine', 'CVCL:E307', (82, 88))	('miR-195', 'Gene', (117, 124))	('miR-195', 'Gene', '406971', (138, 145))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', (117, 120))	('EC109', 'CellLine', 'CVCL:6898', (72, 77))	('HMGA2', 'Gene', (54, 59))	('miR-195', 'Gene', (138, 145))	('miR', 'Gene', (138, 141))	('miR-195', 'Gene', '406971', (32, 39))	('miR', 'Gene', '220972', (32, 35))	('miR', 'Gene', '220972', (150, 153))	('downregulated', 'NegReg', (40, 53))	('EC', 'Phenotype', 'HP:0011459', (82, 84))	('mimics', 'Var', (125, 131))	('miR-195', 'Gene', (32, 39))	('EC', 'Phenotype', 'HP:0011459', (72, 74))	('miR', 'Gene', (32, 35))	('miR', 'Gene', (150, 153))	('HMGA2', 'Gene', '8091', (54, 59))	('miR-195', 'Gene', '406971', (117, 124))	('miR', 'Gene', '220972', (117, 120))
529004	28487599	The results indicated that the miR-195 mimic significantly inhibited cell proliferation in both EC109 and EC9706 cells at 24 h and 48 h, whereas the cell proliferation inhibition by miR-195 mimic was alleviated due to the transfection of pcDNA-HMGA2 (Figures 3(c) and 3(d)).	('miR-195', 'Gene', (182, 189))	('mimic', 'Var', (39, 44))	('miR-195', 'Gene', (31, 38))	('miR-195', 'Gene', '406971', (182, 189))	('EC9706', 'CellLine', 'CVCL:E307', (106, 112))	('EC109', 'CellLine', 'CVCL:6898', (96, 101))	('inhibited', 'NegReg', (59, 68))	('miR-195', 'Gene', '406971', (31, 38))	('HMGA2', 'Gene', '8091', (244, 249))	('EC', 'Phenotype', 'HP:0011459', (106, 108))	('cell proliferation', 'CPA', (69, 87))	('EC', 'Phenotype', 'HP:0011459', (96, 98))	('HMGA2', 'Gene', (244, 249))
529011	28487599	In addition, downregulation of miR-195 dramatically promoted the phosphorylation of mTOR and p70s6k, which was inhibited by HMGA2 silencing (Figures 4(c) and 4(d)).	('HMGA2', 'Gene', (124, 129))	('miR-195', 'Gene', (31, 38))	('p70s6k', 'Gene', '6198', (93, 99))	('mTOR', 'Gene', '2475', (84, 88))	('miR-195', 'Gene', '406971', (31, 38))	('downregulation', 'NegReg', (13, 27))	('phosphorylation', 'MPA', (65, 80))	('mTOR', 'Gene', (84, 88))	('p70s6k', 'Gene', (93, 99))	('HMGA2', 'Gene', '8091', (124, 129))	('silencing', 'Var', (130, 139))	('promoted', 'PosReg', (52, 60))
529100	27486337	Elevated TIMP-1 expression was reported to promote cancer cell proliferation and invasion and proved to correlate with cancer progression and unfavorable prognosis in certain tumor types.	('tumor', 'Disease', (175, 180))	('promote', 'PosReg', (43, 50))	('TIMP-1', 'Gene', (9, 15))	('invasion', 'CPA', (81, 89))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('TIMP-1', 'Gene', '7076', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('correlate', 'Reg', (104, 113))	('cancer', 'Disease', (51, 57))	('expression', 'MPA', (16, 26))	('Elevated', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
529101	27486337	In esophageal cancers, Mori et al demonstrated that high TIMP-1 mRNA in esophageal tumor was associated with advanced stage and poor prognosis, but this study only focused on esophageal cancer and the main pathological type of esophageal cancer is squamous carcinoma.	('esophageal cancers', 'Disease', (3, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (227, 244))	('esophageal tumor', 'Disease', (72, 88))	('esophageal cancer', 'Disease', (227, 244))	('esophageal tumor', 'Phenotype', 'HP:0100751', (72, 88))	('esophageal cancers', 'Disease', 'MESH:D004938', (3, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('squamous carcinoma', 'Disease', (248, 266))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('high', 'Var', (52, 56))	('esophageal tumor', 'Disease', 'MESH:D004938', (72, 88))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('esophageal cancer', 'Disease', (175, 192))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (248, 266))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TIMP-1', 'Gene', '7076', (57, 63))	('TIMP-1', 'Gene', (57, 63))	('squamous carcinoma', 'Disease', 'MESH:D002294', (248, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
529104	27486337	Our observation was in concordance with the report by Vegh et al, who found that TIMP-1 expression was lower in positive lymph nodes cases in contrast to those with negative nodes (P<0.0005) in a cohort of 23 adenocarcinoma samples.	('positive', 'Var', (112, 120))	('adenocarcinoma', 'Disease', (209, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('lower', 'NegReg', (103, 108))	('adenocarcinoma', 'Disease', 'MESH:D000230', (209, 223))	('TIMP-1', 'Gene', (81, 87))	('TIMP-1', 'Gene', '7076', (81, 87))	('expression', 'MPA', (88, 98))
529106	27486337	One possible explanation is that in AEG, elevated TIMP-1 is more likely to have a host response to regulate MMP activity and maintain ECM integrity, which control tumor invasion.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('MMP', 'Gene', '4312;4313;282872;4314;4316;4318;282871;9313', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TIMP-1', 'Gene', (50, 56))	('TIMP-1', 'Gene', '7076', (50, 56))	('MMP', 'Gene', (108, 111))	('AEG', 'Chemical', '-', (36, 39))	('tumor', 'Disease', (163, 168))	('elevated', 'Var', (41, 49))
529136	23466464	Ligand binding to the extracellular alpha subunit causes conformational changes in the IGF-1R, which activate the tyrosine kinase domain of the intracellular beta subunit.	('conformational changes', 'MPA', (57, 79))	('binding', 'Interaction', (7, 14))	('IGF-1R', 'Gene', (87, 93))	('Ligand', 'Var', (0, 6))	('activate', 'PosReg', (101, 109))	('IGF-1R', 'Gene', '3480', (87, 93))
529172	23466464	Mean IGFBP-3 was lower in patients with ECA (3076+-s.d.	('ECA', 'Disease', (40, 43))	('lower', 'NegReg', (17, 22))	('IGFBP-3', 'Gene', '3486', (5, 12))	('ECA', 'Chemical', '-', (40, 43))	('patients', 'Species', '9606', (26, 34))	('IGFBP-3', 'Gene', (5, 12))	('3076+-s.d', 'Var', (45, 54))
529193	23466464	Furthermore, the presence of phosphorylated IRS-1 showed weak-to-moderate correlation with the downstream mediators of the insulin/IGF-1 axis, phosphorylated AKT, and mTOR.	('IGF-1', 'Gene', (131, 136))	('mTOR', 'Gene', (167, 171))	('insulin', 'Gene', (123, 130))	('presence', 'Var', (17, 25))	('IRS-1', 'Gene', '3667', (44, 49))	('mTOR', 'Gene', '2475', (167, 171))	('AKT', 'Gene', '207', (158, 161))	('insulin', 'Gene', '3630', (123, 130))	('IRS-1', 'Gene', (44, 49))	('IGF-1', 'Gene', '3479', (131, 136))	('AKT', 'Gene', (158, 161))
529200	23466464	The development of IGF knockout models and identification of patients with IGF-1 gene defects have provided evidence on the important role of circulating and locally produced IGF-1 in growth and development.	('defects', 'Var', (86, 93))	('IGF-1', 'Gene', '3479', (75, 80))	('IGF-1', 'Gene', (75, 80))	('patients', 'Species', '9606', (61, 69))	('IGF-1', 'Gene', '3479', (175, 180))	('IGF-1', 'Gene', (175, 180))
529211	23466464	In addition, specific IGF-1 polymorphisms have been found to be associated with the reflux-metaplasia-dysplasia-cancer progression in another population-based study from Ireland.	('associated with', 'Reg', (64, 79))	('reflux-metaplasia-dysplasia-cancer', 'Disease', 'MESH:D008679', (84, 118))	('IGF-1', 'Gene', '3479', (22, 27))	('IGF-1', 'Gene', (22, 27))	('polymorphisms', 'Var', (28, 41))	('reflux-metaplasia-dysplasia-cancer', 'Disease', (84, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
529245	22866251	We should keep in mind, however, that the presence of ulcer, fibrosis, inflammation and microinvasion can cause over-staging or under-staging with EUS.	('fibrosis', 'Disease', 'MESH:D005355', (61, 69))	('fibrosis', 'Disease', (61, 69))	('cause', 'Reg', (106, 111))	('over-staging', 'MPA', (112, 124))	('inflammation', 'Disease', 'MESH:D007249', (71, 83))	('under-staging', 'Disease', (128, 141))	('inflammation', 'Disease', (71, 83))	('ulcer', 'Disease', (54, 59))	('microinvasion', 'Var', (88, 101))	('ulcer', 'Disease', 'MESH:D014456', (54, 59))
529265	22866251	In a 6-year retrospective cohort study, EUS-FNA of extramesenteric LN resulted in tumor upstaging in 48% of patients with negative findings by CT. Extramesenteric LN metastases outside of standard radiation fields or total mesorectal excision resection margins were detected by EUS-FNA in 41 of 316 patients (13%) with primary rectal cancer.	('primary rectal cancer', 'Disease', 'MESH:D012004', (319, 340))	('rectal cancer', 'Phenotype', 'HP:0100743', (327, 340))	('metastases', 'Disease', (166, 176))	('patients', 'Species', '9606', (108, 116))	('primary rectal cancer', 'Disease', (319, 340))	('EUS-FNA', 'Var', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('metastases', 'Disease', 'MESH:D009362', (166, 176))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('patients', 'Species', '9606', (299, 307))	('upstaging', 'PosReg', (88, 97))	('tumor', 'Disease', (82, 87))
529283	31802892	LINC00152 depletion decreased cell viability and abilities of migration and invasion by regulating miR-107 in vitro and blocked xenograft tumor growth in vivo.	('LINC00152', 'Gene', (0, 9))	('regulating', 'Reg', (88, 98))	('tumor', 'Disease', (138, 143))	('decreased', 'NegReg', (20, 29))	('miR-107', 'Gene', '406901', (99, 106))	('depletion', 'Var', (10, 19))	('blocked', 'NegReg', (120, 127))	('LINC00152', 'Gene', '112597', (0, 9))	('miR-107', 'Gene', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('abilities of migration', 'CPA', (49, 71))	('cell viability', 'CPA', (30, 44))	('invasion', 'CPA', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
529286	31802892	In this study, we found that LINC00152 modulated Rab10 to promote cell proliferation, migration and invasion in ESCC by sponging miR-107.	('migration', 'CPA', (86, 95))	('LINC00152', 'Gene', '112597', (29, 38))	('miR-107', 'Gene', '406901', (129, 136))	('promote', 'PosReg', (58, 65))	('cell proliferation', 'CPA', (66, 84))	('Rab10', 'Gene', (49, 54))	('modulated', 'Var', (39, 48))	('ESCC', 'Disease', (112, 116))	('miR-107', 'Gene', (129, 136))	('Rab10', 'Gene', '10890', (49, 54))	('invasion', 'CPA', (100, 108))	('LINC00152', 'Gene', (29, 38))	('ESCC', 'Disease', 'MESH:C562729', (112, 116))
529293	31802892	Previous documents revealed that lncRNAs closely associated with chromatin remodeling, transcriptional regulation, and post-transcriptional modulation and further affect cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('affect', 'Reg', (163, 169))	('associated', 'Reg', (49, 59))	('lncRNAs', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('nt', 'Chemical', 'MESH:D009711', (15, 17))
529294	31802892	Long intergenic non-coding RNA 152 (LINC00152), an 828 bp lncRNA located on human chromosome 2p11.2, was discovered in the process of demethylation during liver cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('liver cancer', 'Phenotype', 'HP:0002896', (155, 167))	('liver cancer', 'Disease', 'MESH:D006528', (155, 167))	('nt', 'Chemical', 'MESH:D009711', (6, 8))	('demethylation', 'Var', (134, 147))	('human', 'Species', '9606', (76, 81))	('liver cancer', 'Disease', (155, 167))	('LINC00152', 'Gene', '112597', (36, 45))	('LINC00152', 'Gene', (36, 45))
529297	31802892	Actually, another document unraveled that LINC00152 was significantly increased in ESCC tissues and cells (EC109, EC9706, TE-1, TE-3, KYSE150, YSE450 and KYSE30), LINC00152 knockdown inhibited cell proliferation and induced apoptosis via miR-153-3p/FYN axis in ESCC.	('knockdown', 'Var', (173, 182))	('LINC00152', 'Gene', (42, 51))	('induced', 'Reg', (216, 223))	('ESCC', 'Disease', (83, 87))	('cell proliferation', 'CPA', (193, 211))	('EC', 'Disease', 'MESH:D004938', (107, 109))	('LINC00152', 'Gene', '112597', (163, 172))	('miR', 'Gene', '220972', (238, 241))	('LINC00152', 'Gene', '112597', (42, 51))	('FYN', 'Gene', (249, 252))	('ESCC', 'Disease', 'MESH:C562729', (261, 265))	('EC', 'Disease', 'MESH:D004938', (114, 116))	('nt', 'Chemical', 'MESH:D009711', (65, 67))	('apoptosis', 'CPA', (224, 233))	('miR', 'Gene', (238, 241))	('inhibited', 'NegReg', (183, 192))	('ESCC', 'Disease', 'MESH:C562729', (83, 87))	('nt', 'Chemical', 'MESH:D009711', (24, 26))	('FYN', 'Gene', '2534', (249, 252))	('LINC00152', 'Gene', (163, 172))	('EC9706', 'CellLine', 'CVCL:E307', (114, 120))	('ESCC', 'Disease', (261, 265))
529300	31802892	Aberrant expression of miR-107 was found in various cancers including ESCC.	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('Aberrant', 'Var', (0, 8))	('miR-107', 'Gene', '406901', (23, 30))	('ESCC', 'Disease', 'MESH:C562729', (70, 74))	('nt', 'Chemical', 'MESH:D009711', (6, 8))	('miR-107', 'Gene', (23, 30))	('expression', 'MPA', (9, 19))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('ESCC', 'Disease', (70, 74))	('found', 'Reg', (35, 40))
529355	31802892	These data unraveled that LINC00152 knockdown blocked cell proliferation, migration and invasion in ESCC cells.	('LINC00152', 'Gene', (26, 35))	('cell proliferation', 'CPA', (54, 72))	('ESCC', 'Disease', 'MESH:C562729', (100, 104))	('invasion', 'CPA', (88, 96))	('blocked', 'NegReg', (46, 53))	('knockdown', 'Var', (36, 45))	('migration', 'CPA', (74, 83))	('ESCC', 'Disease', (100, 104))	('LINC00152', 'Gene', '112597', (26, 35))
529367	31802892	The transfection of miR-107 contributed to the distinct reduction of cell viability TE-1 and KYSE30 cells related to that in miR-NC group, while the introduction of in-miR-107 showed the opposite trend (Figure 4C and D).	('miR-107', 'Gene', (168, 175))	('nt', 'Chemical', 'MESH:D009711', (150, 152))	('nt', 'Chemical', 'MESH:D009711', (30, 32))	('miR', 'Gene', '220972', (168, 171))	('transfection', 'Var', (4, 16))	('miR', 'Gene', (168, 171))	('miR', 'Gene', '220972', (20, 23))	('miR-107', 'Gene', '406901', (168, 175))	('miR', 'Gene', (20, 23))	('miR-107', 'Gene', '406901', (20, 27))	('miR', 'Gene', '220972', (125, 128))	('reduction', 'NegReg', (56, 65))	('miR', 'Gene', (125, 128))	('miR-107', 'Gene', (20, 27))
529374	31802892	Also, the migration and invasion abilities were suppressed by the LINC00152 knockdown in TE-1 and KYSE30 cells, but the introduction of miR-107 relieved the inhibitory effect (Figure 5E and F).	('knockdown', 'Var', (76, 85))	('miR-107', 'Gene', '406901', (136, 143))	('LINC00152', 'Gene', (66, 75))	('suppressed', 'NegReg', (48, 58))	('nt', 'Chemical', 'MESH:D009711', (121, 123))	('miR-107', 'Gene', (136, 143))	('LINC00152', 'Gene', '112597', (66, 75))
529390	31802892	Similarly, the transfection with Rab10 regained cell viability in TE-1 and KYSE30 cells inhibited by miR-107 mimics (Figure 8C and D).	('miR-107', 'Gene', '406901', (101, 108))	('cell viability', 'CPA', (48, 62))	('miR-107', 'Gene', (101, 108))	('Rab10', 'Gene', (33, 38))	('Rab10', 'Gene', '10890', (33, 38))	('transfection', 'Var', (15, 27))
529408	31802892	Another reporter manifested that LINC00152 was remarkably elevated in ovarian cancer tissues and cell lines, and its silencing inhibited cell proliferation while induced cell apoptosis in ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ovarian cancer', 'Phenotype', 'HP:0100615', (188, 202))	('ovarian cancer', 'Disease', (70, 84))	('cell proliferation', 'CPA', (137, 155))	('silencing', 'Var', (117, 126))	('ovarian cancer', 'Disease', 'MESH:D010051', (188, 202))	('LINC00152', 'Gene', '112597', (33, 42))	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('inhibited', 'NegReg', (127, 136))	('ovarian cancer', 'Disease', (188, 202))	('ovarian cancer', 'Disease', 'MESH:D010051', (70, 84))	('LINC00152', 'Gene', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('elevated', 'PosReg', (58, 66))	('induced', 'Reg', (162, 169))	('cell apoptosis', 'CPA', (170, 184))
529410	31802892	Furthermore, LINC00152 knockdown suppressed cell proliferation, migration and invasion in ESCC.	('cell proliferation', 'CPA', (44, 62))	('LINC00152', 'Gene', (13, 22))	('invasion', 'CPA', (78, 86))	('knockdown', 'Var', (23, 32))	('ESCC', 'Disease', 'MESH:C562729', (90, 94))	('migration', 'CPA', (64, 73))	('ESCC', 'Disease', (90, 94))	('suppressed', 'NegReg', (33, 43))	('LINC00152', 'Gene', '112597', (13, 22))
529414	31802892	The aberrant expression of miR-107 has been reported in various cancers including ESCC.	('miR-107', 'Gene', (27, 34))	('ESCC', 'Disease', (82, 86))	('aberrant', 'Var', (4, 12))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('nt', 'Chemical', 'MESH:D009711', (10, 12))	('cancers', 'Disease', (64, 71))	('reported', 'Reg', (44, 52))	('miR-107', 'Gene', '406901', (27, 34))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
529423	31802892	Rab10 has been known as a member in RAB family of small GTPases, and its aberrant expression was associated with malignancy.	('malignancy', 'Disease', (113, 123))	('Rab10', 'Gene', (0, 5))	('RAB', 'Gene', '10890', (36, 39))	('Rab10', 'Gene', '10890', (0, 5))	('aberrant', 'Var', (73, 81))	('nt', 'Chemical', 'MESH:D009711', (79, 81))	('RAB', 'Gene', (36, 39))	('associated', 'Reg', (97, 107))	('malignancy', 'Disease', 'MESH:D009369', (113, 123))
529424	31802892	For example, a study in osteosarcoma showed that Rab10 knockdown inhibited cell proliferation and migration.	('knockdown', 'Var', (55, 64))	('osteosarcoma', 'Phenotype', 'HP:0002669', (24, 36))	('Rab10', 'Gene', (49, 54))	('osteosarcoma', 'Disease', (24, 36))	('osteosarcoma', 'Disease', 'MESH:D012516', (24, 36))	('Rab10', 'Gene', '10890', (49, 54))	('inhibited', 'NegReg', (65, 74))
529425	31802892	In ESCC, a report indicated that Rab10 depletion blocked cell proliferation, migration and invasion.	('depletion', 'Var', (39, 48))	('ESCC', 'Disease', 'MESH:C562729', (3, 7))	('invasion', 'CPA', (91, 99))	('migration', 'CPA', (77, 86))	('ESCC', 'Disease', (3, 7))	('Rab10', 'Gene', (33, 38))	('Rab10', 'Gene', '10890', (33, 38))	('blocked', 'NegReg', (49, 56))	('cell proliferation', 'CPA', (57, 75))
529428	31802892	The silencing of Rab10 impeded cell growth and metastasis of ESCC cells.	('Rab10', 'Gene', (17, 22))	('impeded', 'NegReg', (23, 30))	('ESCC', 'Disease', (61, 65))	('Rab10', 'Gene', '10890', (17, 22))	('silencing', 'Var', (4, 13))	('ESCC', 'Disease', 'MESH:C562729', (61, 65))
529493	29870260	The Cy5.5-labeled heterodimer QRH*-KSP*-E3-Cy5.5 demonstrated specific binding to each target and showed 3-fold greater fluorescence intensity and 2-fold higher affinity compared with either monomer alone.	('Cy5.5', 'Chemical', 'MESH:C098793', (43, 48))	('fluorescence intensity', 'MPA', (120, 142))	('Cy5.5', 'Chemical', 'MESH:C098793', (4, 9))	('higher', 'PosReg', (154, 160))	('QRH*-KSP*-E3-Cy5', 'Chemical', '-', (30, 46))	('binding', 'Interaction', (71, 78))	('QRH*-KSP', 'Var', (30, 38))	('greater', 'PosReg', (112, 119))
529520	29870260	The heterodimer QRH*-KSP*-E3-Cy5.5 with the triethyleneglycol linker (E3) showed highest signal, and was found to have good hydrophilicity, as well.	('QRH*-KSP*-E3-Cy5', 'Chemical', '-', (16, 32))	('signal', 'MPA', (89, 95))	('triethyleneglycol', 'Chemical', 'MESH:C028914', (44, 61))	('QRH*-KSP*-E3-Cy5.5', 'Var', (16, 34))	('Cy5.5', 'Chemical', 'MESH:C098793', (29, 34))
529523	29870260	We then synthesized QRH*-KSP*-E3-Cy5.5 with >95% purity by analytical HPLC, and measured an experimental mass-to-charge (m/z) ratio by mass spectrometry of 2974.69 that agreed with the expected value, Figure S1C.	('Cy5.5', 'Chemical', 'MESH:C098793', (33, 38))	('QRH*-KSP*-E3-Cy5', 'Chemical', '-', (20, 36))	('2974.69', 'Var', (156, 163))	('QRH*-KSP*-E3-Cy5.5', 'Var', (20, 38))
529536	29870260	On confocal microscopy, QRH*-KSP*-E3-Cy5.5 (red) binds strongly to the surface (arrow) of SKBr3 cells, Figure S6A.	('QRH*-KSP*-E3-Cy5.5', 'Var', (24, 42))	('binds', 'Interaction', (49, 54))	('QRH*-KSP*-E3-Cy5', 'Chemical', '-', (24, 40))	('Cy5.5', 'Chemical', 'MESH:C098793', (37, 42))	('SKBr3', 'CellLine', 'CVCL:0033', (90, 95))
529542	29870260	Western blot shows no change in phosphorylation of either EGFR (p-EGFR) or ErbB2 (p-ErbB2) with addition of up to 20 muM of QRH*-KSP*-E3-Cy5.5, Figure 4.	('EGFR', 'Gene', '1956', (58, 62))	('p-ErbB2', 'Gene', '2064', (82, 89))	('ErbB2', 'Gene', (75, 80))	('ErbB2', 'Gene', '2064', (84, 89))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', (58, 62))	('Cy5.5', 'Chemical', 'MESH:C098793', (137, 142))	('p-EGFR', 'Gene', (64, 70))	('ErbB2', 'Gene', (84, 89))	('muM', 'Gene', '56925', (117, 120))	('p-EGFR', 'Gene', '1956', (64, 70))	('ErbB2', 'Gene', '2064', (75, 80))	('QRH*-KSP*-E3-Cy5.5', 'Var', (124, 142))	('QRH*-KSP*-E3-Cy5', 'Chemical', '-', (124, 140))	('muM', 'Gene', (117, 120))	('phosphorylation', 'MPA', (32, 47))	('p-ErbB2', 'Gene', (82, 89))
529545	29870260	Also, the addition of lapatinib, a tyrosine kinase inhibitor known to disrupt ErbB2 signaling in solid tumors, showed reduced expression of p-ErbB2, p-AKT, and p-ERK.	('p-ErbB2', 'Gene', (140, 147))	('p-AKT', 'Gene', (149, 154))	('p-ErbB2', 'Gene', '2064', (140, 147))	('solid tumors', 'Disease', 'MESH:D009369', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('expression', 'MPA', (126, 136))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('ErbB2', 'Gene', '2064', (78, 83))	('reduced', 'NegReg', (118, 125))	('p-ERK', 'Var', (160, 165))	('ErbB2', 'Gene', (142, 147))	('p-AKT', 'Gene', '207', (149, 154))	('lapatinib', 'Chemical', 'MESH:D000077341', (22, 31))	('solid tumors', 'Disease', (97, 109))	('ErbB2', 'Gene', '2064', (142, 147))	('ErbB2', 'Gene', (78, 83))
529549	29870260	Heterodimer biodistribution was evaluated in nude mice bearing OE33 xenograft tumors following systemic injection (300 muM, 150 muL PBS) of either targeted peptide QRH*-KSP*-E3-Cy5.5 (n=6) or control (GGGAGGG)2KK-Cy5.5 (n=6).	('muM', 'Gene', (119, 122))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('QRH*-KSP*-E3-Cy5.5', 'Var', (164, 182))	('xenograft tumors', 'Disease', (68, 84))	('Cy5.5', 'Chemical', 'MESH:C098793', (213, 218))	('xenograft tumors', 'Disease', 'MESH:D009369', (68, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('QRH*-KSP*-E3-Cy5', 'Chemical', '-', (164, 180))	('muM', 'Gene', '56925', (119, 122))	('Cy5.5', 'Chemical', 'MESH:C098793', (177, 182))	('PBS', 'Chemical', 'MESH:D007854', (132, 135))	('nude mice', 'Species', '10090', (45, 54))
529555	29870260	The same set of specimens was also stained with AF568-labeled anti-EGFR antibody (yellow), and AF488-labeled anti-ErbB2 antibody (green).	('AF488', 'Chemical', '-', (95, 100))	('ErbB2', 'Gene', '2064', (114, 119))	('EGFR', 'Gene', (67, 71))	('AF488-labeled', 'Var', (95, 108))	('EGFR', 'Gene', '1956', (67, 71))	('ErbB2', 'Gene', (114, 119))	('AF568-labeled', 'Var', (48, 61))	('AF568', 'Chemical', '-', (48, 53))
529557	29870260	Co-localization of binding was evaluated between the heterodimer QRH*-KSP*-E3-Cy5.5 (red) and the anti-EGFR-AF568 (yellow) and anti-ErbB2-AF488 (green) antibodies, and a Pearson's correlation coefficient of rho = 0.60 and 0.75, respectively, was measured.	('EGFR', 'Gene', '1956', (103, 107))	('ErbB2', 'Gene', '2064', (132, 137))	('AF568', 'Chemical', '-', (108, 113))	('Cy5.5', 'Chemical', 'MESH:C098793', (78, 83))	('EGFR', 'Gene', (103, 107))	('AF488', 'Chemical', '-', (138, 143))	('binding', 'Interaction', (19, 26))	('ErbB2', 'Gene', (132, 137))	('QRH*-KSP*-E3-Cy5', 'Chemical', '-', (65, 81))	('QRH', 'Var', (65, 68))
529562	29870260	We found that QRH*-KSP*-E3-Cy5.5 with triethyleneglycol (PEG3) consisting of 30 atoms as the linker produced 3-fold greater fluorescence intensity from binding to OE33 cells than either monomer alone.	('greater', 'PosReg', (116, 123))	('PEG3', 'Gene', '5178', (57, 61))	('QRH*-KSP*-E3-Cy5.5', 'Var', (14, 32))	('Cy5.5', 'Chemical', 'MESH:C098793', (27, 32))	('binding', 'Interaction', (152, 159))	('PEG3', 'Gene', (57, 61))	('fluorescence intensity', 'MPA', (124, 146))	('triethyleneglycol', 'Chemical', 'MESH:C028914', (38, 55))	('QRH*-KSP*-E3-Cy5', 'Chemical', '-', (14, 30))
529566	29870260	High T/B ratio was achieved using Cy5.5 to emit NIR fluorescence, which is least affected by hemoglobin absorption, tissue scattering, and autofluorescence background, and provides maximum tumor imaging depth.	('tumor', 'Disease', (189, 194))	('Cy5.5', 'Chemical', 'MESH:C098793', (34, 39))	('Cy5.5', 'Var', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mum', 'Gene', '56925', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('emit NIR fluorescence', 'MPA', (43, 64))	('mum', 'Gene', (185, 188))
529576	29870260	The side-chain protecting groups used the following amino acids: Arg(Nomega-Pbf), Asn(Ngamma-Trt), Glu(O-tBu), His(Nim-Trt), Ser(tBu), Lys(Nepsilon-Alloc), Lys(Nepsilon-Ivdde).	('Arg', 'Chemical', 'MESH:D001120', (65, 68))	('tBu', 'Chemical', '-', (105, 108))	('His', 'Chemical', 'MESH:D006639', (111, 114))	('Pbf', 'Gene', (76, 79))	('tBu', 'Chemical', '-', (129, 132))	('Lys', 'Chemical', 'MESH:D008239', (156, 159))	('Ser', 'Chemical', 'MESH:D012694', (125, 128))	('Lys', 'Chemical', 'MESH:D008239', (135, 138))	('Pbf', 'Gene', '55893', (76, 79))	('O-tBu', 'Chemical', '-', (103, 108))	('Arg', 'Protein', (65, 68))	('Glu', 'Chemical', 'MESH:D018698', (99, 102))	('Lys', 'Var', (156, 159))	('Asn', 'Chemical', 'MESH:D001216', (82, 85))
529592	29870260	For antibody staining, cells were incubated with either anti-EGFR (1:500, #2232S) or anti-ErbB2 (1:500, #29D8) primary antibody from Cell Signaling Inc overnight at 4 C after fixation, and then washed with PBS 3X and processed with secondary antibody staining.	('ErbB2', 'Gene', '2064', (90, 95))	('1:500', 'Var', (97, 102))	('PBS', 'Chemical', 'MESH:D007854', (206, 209))	('ErbB2', 'Gene', (90, 95))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('1:500', 'Var', (67, 72))
529598	29870260	The membranes were incubated with primary rabbit anti-EGFR monoclonal antibody (1:1000, #2232S) and rabbit anti-ErbB2 monoclonal antibody (1:1000, #2165S) from Cell Signaling Inc.	('ErbB2', 'Gene', (112, 117))	('1:1000', 'Var', (80, 86))	('1:1000', 'Var', (139, 145))	('ErbB2', 'Gene', '2064', (112, 117))	('EGFR', 'Gene', '1956', (54, 58))	('rabbit', 'Species', '9986', (42, 48))	('EGFR', 'Gene', (54, 58))	('rabbit', 'Species', '9986', (100, 106))
529604	29870260	ON-TARGETplus human EGFR siRNA (#L-003114-00-0005), ONTARGETplus human ErbB2 siRNA (#L-003126-00-0005) and ON-TARGET plus non-targeting pool (#D-001810-10-05) were used.	('ErbB2', 'Gene', (71, 76))	('human', 'Species', '9606', (65, 70))	('#L-003126-00-0005', 'Var', (84, 101))	('EGFR', 'Gene', (20, 24))	('human', 'Species', '9606', (14, 19))	('ErbB2', 'Gene', '2064', (71, 76))	('#L-003114-00-0005', 'Var', (32, 49))	('EGFR', 'Gene', '1956', (20, 24))
529620	29870260	Lapatinib (CDS022971, Sigma) was diluted to 100 nM in DMSO and PBS from 1 mg/mL stock solution, and was added to the cells incubated with the heterodimer at concentrations of 1, 5, 20 muM in separate wells.	('DMSO', 'Chemical', 'MESH:D004121', (54, 58))	('PBS', 'Chemical', 'MESH:D007854', (63, 66))	('CDS022971', 'Chemical', '-', (11, 20))	('muM', 'Gene', '56925', (184, 187))	('Lapatinib', 'Chemical', 'MESH:D000077341', (0, 9))	('CDS022971', 'Var', (11, 20))	('muM', 'Gene', (184, 187))
529622	29870260	Anti-EGFR antibody (#2232S), anti-HER2 antibody (#2165), anti-phospho-EGFR sampler kit (#9922s), anti-phospho-HER2/ErbB2 (Tyr1248) antibody (#2247), anti-AKT (#4691P), anti-ERK1/2 (#4695P), anti-phospho-AKT (pS473; #4060P), anti-phospho-ERK1/2 (#4370P) were used per manufacturer's instructions (Cell Signaling, Inc).	('#4370P', 'Var', (245, 251))	('ErbB2', 'Gene', (115, 120))	('HER2', 'Gene', '2064', (110, 114))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', '1956', (5, 9))	('HER2', 'Gene', (34, 38))	('#4691P', 'Var', (159, 165))	('AKT', 'Gene', (154, 157))	('#2165', 'Var', (49, 54))	('pS473; #4060P', 'Var', (208, 221))	('#2232S', 'Var', (20, 26))	('ERK1/2', 'Gene', (237, 243))	('AKT', 'Gene', (203, 206))	('ERK1/2', 'Gene', '5595;5594', (237, 243))	('ERK1/2', 'Gene', (173, 179))	('ERK1/2', 'Gene', '5595;5594', (173, 179))	('HER2', 'Gene', (110, 114))	('#9922s', 'Var', (88, 94))	('#2247', 'Var', (141, 146))	('ErbB2', 'Gene', '2064', (115, 120))	('HER2', 'Gene', '2064', (34, 38))	('AKT', 'Gene', '207', (154, 157))	('EGFR', 'Gene', (70, 74))	('#4695P', 'Var', (181, 187))	('EGFR', 'Gene', (5, 9))	('AKT', 'Gene', '207', (203, 206))
529652	30374464	Briefly, while there is widespread chromosomal instability and high mutational load in the EAC genome, presumably due in part to chronic inflammation and oxidative stress in response to acid reflux, only a limited number of recurrent tumor driver genes have been identified, including TP53, SMAD4, ARID1A, and CDKN2A.	('CDKN2A', 'Gene', (310, 316))	('ARID1A', 'Gene', '8289', (298, 304))	('tumor', 'Disease', (234, 239))	('ARID1A', 'Gene', (298, 304))	('TP53', 'Gene', '7157', (285, 289))	('CDKN2A', 'Gene', '1029', (310, 316))	('SMAD4', 'Gene', (291, 296))	('chromosomal instability', 'Phenotype', 'HP:0040012', (35, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (154, 170))	('TP53', 'Gene', (285, 289))	('inflammation', 'Disease', 'MESH:D007249', (137, 149))	('inflammation', 'Disease', (137, 149))	('mutational', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('acid reflux', 'Phenotype', 'HP:0002020', (186, 197))	('SMAD4', 'Gene', '4089', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('EAC', 'Phenotype', 'HP:0011459', (91, 94))
529656	30374464	These tumors and matched normal samples were subjected to whole-genome sequencing (WGS) and profiling for genome-wide mutations, copy number alterations, and structural changes.	('copy number alterations', 'Var', (129, 152))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (118, 127))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
529663	30374464	We identified a median of 7048 mutations per tumor genome for Chinese EAC (range: 2070-53,570), corresponding to a median mutation frequency of 2.56 mutations/Mb (range: 0.75-19.65).	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
529664	30374464	Compared to 9.9 mutations/Mb previously reported and replicated by us in the 16 US EAC, the mutation frequencies in these Chinese EAC tumors were significantly lower (Fig.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('mutation', 'Var', (92, 100))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('to 9', 'Species', '1214577', (9, 13))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))	('lower', 'NegReg', (160, 165))
529666	30374464	Among the six mutation types, C>T transitions have the highest frequency (median 34.37%, range 22.31-38.87%), which has been seen in most epithelial cancers including US EAC.	('EAC', 'Phenotype', 'HP:0011459', (170, 173))	('epithelial cancers', 'Disease', (138, 156))	('C>T transitions', 'Var', (30, 45))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('epithelial cancers', 'Disease', 'MESH:D000077216', (138, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
529669	30374464	2): S3 (27% of samples), a signature with more-or-less equal representation of all 96 tri-nucleotide mutation types, linked to defects in BRCA1/2-led homologous recombination pathway; and S1 (49% of samples), a signature with C>T in a *CG context, likely associated with aging processes.	('BRCA1', 'Gene', (138, 143))	('BRCA1', 'Gene', '672', (138, 143))	('C>T', 'Var', (226, 229))	('defects', 'NegReg', (127, 134))
529670	30374464	The hallmark signature for EAC from the US and UK (S17), that is marked predominantly by A>C substitutions, is completely absent in our analysis of Chinese EAC tumors.	('substitutions', 'Var', (93, 106))	('EAC', 'Phenotype', 'HP:0011459', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('EAC', 'Phenotype', 'HP:0011459', (156, 159))	('EAC', 'Disease', (27, 30))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
529671	30374464	We observed non-silent mutations in 691 genes (including missense, splice site, frameshift, nonsense, in-frame indel), of which 22 were mutated in two or more patients (Supplementary Figure 7).	('in-frame indel', 'Var', (102, 116))	('frameshift', 'Var', (80, 90))	('nonsense', 'Var', (92, 100))	('missense', 'Var', (57, 65))	('patients', 'Species', '9606', (159, 167))
529683	30374464	On the focal level, 17 recurrent copy number gains were detected in Chinese EAC, covering 44.9 Mb of the cancer genome, and 22 recurrent gains were found in US EAC, covering 81.3 Mb of the cancer genome.	('EAC', 'Phenotype', 'HP:0011459', (160, 163))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))	('copy number gains', 'Var', (33, 50))	('cancer', 'Disease', (189, 195))
529686	30374464	The recurrent deletion SCNAs for US EAC (but absent for Chinese EAC) include 16q23.1, which contains a tumor suppressor gene WWOX, whose deregulation is associated with gastric cancer and ESCC; and 18q21.2, which contains SMAD4, a tumor suppressor gene associated with gastrointestinal carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('SMAD4', 'Gene', (222, 227))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('gastrointestinal carcinogenesis', 'Disease', (269, 300))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('tumor', 'Disease', (231, 236))	('deletion', 'Var', (14, 22))	('SMAD4', 'Gene', '4089', (222, 227))	('gastrointestinal carcinogenesis', 'Disease', 'MESH:D063646', (269, 300))	('EAC', 'Phenotype', 'HP:0011459', (36, 39))	('WWOX', 'Gene', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('gastric cancer', 'Disease', (169, 183))	('ESCC', 'Disease', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('associated', 'Reg', (153, 163))	('WWOX', 'Gene', '51741', (125, 129))	('deregulation', 'PosReg', (137, 149))
529689	30374464	A total of 795 candidate variants were identified, with a median of 21 per tumor (range: 8-385), far fewer than observed in the 16 US EAC genomes (median: 172, range: 77-452).	('variants', 'Var', (25, 33))	('EAC', 'Phenotype', 'HP:0011459', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
529690	30374464	4a), including TSC2, a regulatory gene involved in the MTOR signaling pathway; BMPR1A, a receptor serine/threonine kinase, deletion of which may be associated with Juvenile polyposis syndrome, a rare autosomal dominant disorder characterized by multiple gastrointestinal juvenile polyps and an increased risk of colorectal cancer; and two genes, CCSER1 and CNTNAP2 (on the last two rows of Fig.	('colorectal cancer', 'Disease', (312, 329))	('juvenile polyps', 'Phenotype', 'HP:0004784', (271, 286))	('TSC2', 'Gene', (15, 19))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (200, 227))	('BMPR1A', 'Gene', (79, 85))	('CNTNAP2', 'Gene', '26047', (357, 364))	('CCSER1', 'Gene', '401145', (346, 352))	('rectal cancer', 'Phenotype', 'HP:0100743', (316, 329))	('colorectal cancer', 'Phenotype', 'HP:0003003', (312, 329))	('MTOR', 'Gene', (55, 59))	('multiple gastrointestinal juvenile polyps', 'Disease', (245, 286))	('MTOR', 'Gene', '2475', (55, 59))	('CCSER1', 'Gene', (346, 352))	('Juvenile polyposis syndrome', 'Disease', 'MESH:C537702', (164, 191))	('autosomal dominant disorder', 'Disease', (200, 227))	('deletion', 'Var', (123, 131))	('multiple gastrointestinal juvenile polyps', 'Disease', 'MESH:D011127', (245, 286))	('Juvenile polyposis', 'Phenotype', 'HP:0004784', (164, 182))	('Juvenile polyposis syndrome', 'Disease', (164, 191))	('colorectal cancer', 'Disease', 'MESH:D015179', (312, 329))	('TSC2', 'Gene', '7249', (15, 19))	('CNTNAP2', 'Gene', (357, 364))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('associated with', 'Reg', (148, 163))	('BMPR1A', 'Gene', '657', (79, 85))
529691	30374464	4b): translocation of TTC28 in 75% samples, which was the most frequent translocation in colon and rectal cancer; deletion of GMDS in 37.5% samples, which was also found in gastric cancer; and alterations of RBFOX1, SMYD3, or CDK14 in 31% of samples, which were also found in EAC from UK.	('colon and rectal cancer', 'Disease', 'MESH:D012004', (89, 112))	('RBFOX1', 'Gene', '54715', (208, 214))	('translocation', 'Var', (5, 18))	('RBFOX1', 'Gene', (208, 214))	('EAC', 'Phenotype', 'HP:0011459', (276, 279))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gastric cancer', 'Disease', (173, 187))	('alterations', 'Var', (193, 204))	('GMDS', 'Gene', (126, 130))	('TTC28', 'Gene', '23331', (22, 27))	('SMYD3', 'Gene', (216, 221))	('CDK14', 'Gene', '5218', (226, 231))	('gastric cancer', 'Disease', 'MESH:D013274', (173, 187))	('SMYD3', 'Gene', '64754', (216, 221))	('TTC28', 'Gene', (22, 27))	('deletion', 'Var', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('CDK14', 'Gene', (226, 231))	('rectal cancer', 'Phenotype', 'HP:0100743', (99, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (173, 187))
529701	30374464	A recent analysis of WGS data from 129 EAC cases from the UK suggests that EAC is a heterogeneous disease, which may be composed of three distinct molecular subtypes: (i) the dominant A>C mutational pattern, (ii) a C>A/T mutational pattern with evidence of an aging imprint, and (iii) enrichment for BRCA signature.	('EAC', 'Phenotype', 'HP:0011459', (39, 42))	('BRCA', 'Gene', '672', (300, 304))	('EAC', 'Disease', (75, 78))	('BRCA', 'Gene', (300, 304))	('C>A/T mutational', 'Var', (215, 231))	('A>C mutational', 'Var', (184, 198))	('EAC', 'Phenotype', 'HP:0011459', (75, 78))
529702	30374464	Our data in 10 Chinese EAC cases reveal patterns of the two less frequent EAC subtypes in the UK data: high C>A/T mutations and some enrichment for BRCA signatures (Fig.	('EAC', 'Phenotype', 'HP:0011459', (23, 26))	('EAC', 'Phenotype', 'HP:0011459', (74, 77))	('BRCA', 'Gene', '672', (148, 152))	('C>A/T mutations', 'Var', (108, 123))	('BRCA', 'Gene', (148, 152))
529703	30374464	This intriguing finding raises the possibility that tumor subtypes comprising a minority of EAC cases in Western countries, i.e., those potentially arising from aging and defects of DNA damage repair, may constitute the majority of EAC cases in China.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('tumor', 'Disease', (52, 57))	('EAC', 'Disease', (92, 95))	('defects', 'Var', (171, 178))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('EAC', 'Phenotype', 'HP:0011459', (232, 235))
529708	30374464	First, our restricted sample size (10 pairs of tumors and matched normal samples) for WGS did not allow for the detection of recurrent cancer genes and alterations with low recurrent frequencies (e.g., less than 20%).	('tumors', 'Disease', (47, 53))	('cancer', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('alterations', 'Var', (152, 163))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
529723	30374464	Functional annotation of mutations was performed with Oncotator (http://www.broadinstitute.org/cancer/cga/oncotator).	('cga', 'Gene', (102, 105))	('mutations', 'Var', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('cga', 'Gene', '1113', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
529728	29551738	Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE).	('esophageal adenocarcinoma', 'Disease', (221, 246))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (109, 128))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (221, 246))	("Barrett's esophagus", 'Disease', (256, 275))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (256, 275))	('BE', 'Phenotype', 'HP:0100580', (277, 279))	('Variants', 'Var', (29, 37))	('EA', 'Phenotype', 'HP:0011459', (248, 250))	('Esophageal Adenocarcinoma', 'Disease', (79, 104))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (221, 246))
529730	29551738	We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE.	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (132, 155))	('single nucleotide polymorphisms', 'Var', (21, 52))	('gastroesophageal reflux disease', 'Disease', (132, 163))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (132, 163))	('BE', 'Phenotype', 'HP:0100580', (193, 195))	('associations', 'Interaction', (80, 92))	('EA', 'Phenotype', 'HP:0011459', (186, 188))	('modify', 'Reg', (69, 75))
529733	29551738	For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18x10-7).	('rs13429103', 'Var', (8, 18))	('rs13429103', 'Mutation', 'rs13429103', (8, 18))	('EA', 'Phenotype', 'HP:0011459', (4, 6))	('RNF144A-LOC339788', 'Gene', '9781', (50, 67))	('RNF144A-LOC339788', 'Gene', (50, 67))
529735	29551738	Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70x10-7, P = 1.83x10-7, and P = 3.58x10-7, respectively) to affect risk of EA.	('RND3', 'Gene', (78, 82))	('rs13396805', 'Mutation', 'rs13396805', (35, 45))	('rs13396805', 'Var', (35, 45))	('RND3', 'Gene', '390', (78, 82))	('rs2341926', 'Mutation', 'rs2341926', (24, 33))	('rs12465911', 'Var', (12, 22))	('RBM43', 'Gene', '375287', (83, 88))	('affect', 'Reg', (192, 198))	('EA', 'Phenotype', 'HP:0011459', (207, 209))	('rs2341926', 'Var', (24, 33))	('rs12465911', 'Mutation', 'rs12465911', (12, 22))	('RBM43', 'Gene', (83, 88))
529736	29551738	For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44x10-7) and pack-years of smoking history (P = 2.82x10-7), respectively.	('SLC12A6', 'Gene', '9990', (104, 111))	('interacted', 'Reg', (118, 128))	('SLC12A6', 'Gene', (104, 111))	('EIF2C3', 'Gene', '192669', (48, 54))	('rs11631094', 'Mutation', 'rs11631094', (65, 75))	('rs11631094', 'Var', (65, 75))	('EIF2C3', 'Gene', (48, 54))	('rs491603', 'Mutation', 'rs491603', (8, 16))	('BE', 'Phenotype', 'HP:0100580', (4, 6))	('rs491603', 'Var', (8, 16))
529750	29551738	The EA patients in the UK Stomach and Oesophageal Cancer Study had International Classification of Diseases coding of malignant neoplasm of the esophagus (C15) and pathological diagnosis of adenocarcinoma (M8140-8575).	('adenocarcinoma', 'Disease', 'MESH:D000230', (190, 204))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('C15', 'Gene', (155, 158))	('Oesophageal Cancer', 'Disease', 'MESH:D009369', (38, 56))	('Oesophageal Cancer', 'Disease', (38, 56))	('malignant neoplasm of the esophagus', 'Disease', 'MESH:D004938', (118, 153))	('neoplasm', 'Phenotype', 'HP:0002664', (128, 136))	('EA', 'Phenotype', 'HP:0011459', (4, 6))	('M8140-8575', 'Var', (206, 216))	('neoplasm of the esophagus', 'Phenotype', 'HP:0100751', (128, 153))	('adenocarcinoma', 'Disease', (190, 204))	('malignant neoplasm of the esophagus', 'Disease', (118, 153))	('C15', 'Gene', '51316', (155, 158))	('patients', 'Species', '9606', (7, 15))
529767	29551738	At chromosome 2p25.1, rs13429103 (effect allele frequency [EAF] = 15.0%) showed interaction with smoking status (RNF144A-LOC339788, P = 2.18 x 10-7 for interaction).	('EA', 'Phenotype', 'HP:0011459', (59, 61))	('RNF144A-LOC339788', 'Gene', '9781', (113, 130))	('rs13429103', 'Var', (22, 32))	('rs13429103', 'Mutation', 'rs13429103', (22, 32))	('RNF144A-LOC339788', 'Gene', (113, 130))
529768	29551738	We also observed borderline statistically significant interactions between recurrent GERD symptoms and rs12465911 (P = 1.70 x 10-7 for interaction), rs2341926 (P = 1.83 x 10-7 for interaction), and rs13396805 (P = 3.58 x 10-7 for interaction) at chromosome 2q23.3 (RND3-RBM43).	('rs2341926', 'Mutation', 'rs2341926', (149, 158))	('RND3', 'Gene', '390', (265, 269))	('rs12465911', 'Var', (103, 113))	('recurrent', 'Disease', (75, 84))	('rs2341926', 'Var', (149, 158))	('RBM43', 'Gene', '375287', (270, 275))	('rs13396805', 'Mutation', 'rs13396805', (198, 208))	('rs12465911', 'Mutation', 'rs12465911', (103, 113))	('rs13396805', 'Var', (198, 208))	('GERD symptoms', 'Disease', (85, 98))	('RBM43', 'Gene', (270, 275))	('RND3', 'Gene', (265, 269))
529772	29551738	Similarly, the risk for EA associated with recurrent GERD symptoms was higher in individuals with rs12465911-AA genotype (OR, 13.12; 95% CI, 6.21-27.73) than among individuals with rs12465911-GG genotype (OR, 2.80; 95% CI, 2.29-3.41).	('higher', 'PosReg', (71, 77))	('rs12465911', 'Mutation', 'rs12465911', (98, 108))	('GERD symptoms', 'Disease', (53, 66))	('rs12465911', 'Mutation', 'rs12465911', (181, 191))	('rs12465911-AA', 'Var', (98, 111))	('EA', 'Phenotype', 'HP:0011459', (24, 26))
529774	29551738	For BE, at chromosome 1p34.3, we observed an interaction between rs491603 (EAF = 16.5%) and BMI (EIF2C3-LOC100128093, P = 4.44 x 10-7 for interaction) (Table 2, Figure 1C).	('EIF2C3', 'Gene', (97, 103))	('EA', 'Phenotype', 'HP:0011459', (75, 77))	('interaction', 'Interaction', (45, 56))	('rs491603', 'Mutation', 'rs491603', (65, 73))	('EIF2C3', 'Gene', '192669', (97, 103))	('rs491603', 'Var', (65, 73))	('BE', 'Phenotype', 'HP:0100580', (4, 6))
529775	29551738	At chromosome 15p14, rs11631094 (EAF = 28.7%) showed interaction with pack-years of smoking exposure (SLC12A6, P = 2.82 x 10-7 for interaction) (Table 2, Figure 1D).	('rs11631094', 'Mutation', 'rs11631094', (21, 31))	('rs11631094', 'Var', (21, 31))	('interaction', 'Interaction', (53, 64))	('SLC12A6', 'Gene', '9990', (102, 109))	('EA', 'Phenotype', 'HP:0011459', (33, 35))	('SLC12A6', 'Gene', (102, 109))
529777	29551738	Stratified analyses by genotype showed that the risk for BE associated with obesity (BMI >=30 kg/m2) was elevated by over 200% among individuals with rs491603-AA genotype (vs BMI <25 kg/m2; OR, 3.30; 95% CI, 1.90-5.73) but only by approximately 50% among individuals with rs491603-GG genotype (vs BMI <25 kg/m2; OR, 1.52; 95% CI, 1.38-1.67).	('obesity', 'Disease', 'MESH:D009765', (76, 83))	('obesity', 'Disease', (76, 83))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('rs491603', 'Mutation', 'rs491603', (150, 158))	('obesity', 'Phenotype', 'HP:0001513', (76, 83))	('rs491603', 'Mutation', 'rs491603', (272, 280))	('rs491603-AA', 'Var', (150, 161))
529787	29551738	Such preconceived "gene-centric" SNP selection methods fail to capture the large fraction of noncoding intergenic variations that have been linked to altered risk for these 2 conditions, and also artificially restricts the "genic" search space based on limited mechanistic knowledge, a limitation that is overcome by an unbiased comprehensive genome-wide gene-environment interaction assessment.	('restricts', 'NegReg', (209, 218))	('men', 'Species', '9606', (390, 393))	('variations', 'Var', (114, 124))	('linked', 'Reg', (140, 146))	('men', 'Species', '9606', (367, 370))
529809	30108214	A strong genetic association exists between allergy and the IL-33-ST2 axis, as variants in IL33 and IL1RL1 (encodes ST2) confer risk for several allergic diseases.	('ST2', 'Gene', (66, 69))	('IL33', 'Gene', (91, 95))	('ST2', 'Gene', '6761', (116, 119))	('IL33', 'Gene', '90865', (91, 95))	('allergic diseases', 'Disease', (145, 162))	('IL1RL1', 'Gene', '9173', (100, 106))	('allergy', 'Phenotype', 'HP:0012393', (44, 51))	('IL-33-ST2', 'Gene', (60, 69))	('allergy', 'Disease', (44, 51))	('variants', 'Var', (79, 87))	('ST2', 'Gene', '6761', (66, 69))	('allergic diseases', 'Disease', 'MESH:D004342', (145, 162))	('allergy', 'Disease', 'MESH:D004342', (44, 51))	('risk', 'Reg', (128, 132))	('IL1RL1', 'Gene', (100, 106))	('ST2', 'Gene', (116, 119))	('IL-33-ST2', 'Gene', '90865;6761', (60, 69))
529828	30108214	Genome-wide RNA sequencing (RNA-seq) after 48-h treatment with Dox or vehicle revealed that increased IL33 reads were detected after Dox in WT IL-33-overexpressing cells but not in control cells nor in vehicle-treated cells (Fig.	('IL33', 'Gene', (102, 106))	('IL33', 'Gene', '90865', (102, 106))	('Dox', 'Chemical', 'MESH:D004318', (63, 66))	('increased', 'PosReg', (92, 101))	('Dox', 'Var', (133, 136))	('Dox', 'Chemical', 'MESH:D004318', (133, 136))
529841	30108214	Additionally, there was not a statistically significant difference in the co-localization of Hoechst 33342 with truncated IL-33-GFP vs. GFP alone (p = 0.49) within the nucleus.	('Hoechst 33342', 'Chemical', 'MESH:C017807', (93, 106))	('truncated', 'Var', (112, 121))	('IL-33-GFP', 'Gene', (122, 131))
529842	30108214	Because this truncated form of IL-33 is missing a significant amount of the protein in addition to the chromatin binding domain, we also generated IL-33-GFP-fusion proteins (R48A and 47AAA49) with mutations within the chromatin binding domain (Supplementary Fig.	('R48A', 'Mutation', 'p.R48A', (174, 178))	('IL-33', 'Gene', (31, 36))	('mutations', 'Var', (197, 206))	('R48A', 'Var', (174, 178))
529844	30108214	The strength of chromatin binding of these mutant IL-33-GFP-fusion proteins was intermediate compared with WT and truncated IL-33 as assessed by western blot analysis of 0.5% Triton-X 100 cell lysates (Supplementary Fig.	('chromatin binding', 'Interaction', (16, 33))	('mutant', 'Var', (43, 49))	('IL-33-GFP-fusion', 'Gene', (50, 66))	('Triton-X 100', 'Chemical', 'MESH:D017830', (175, 187))
529845	30108214	Importantly, the correlation of Hoechst 33342 and R48A IL-33-GFP or 47AAA49 IL-33-GFP was less than WT IL-33-GFP (Supplementary Fig.	('47AAA49', 'Var', (68, 75))	('less', 'NegReg', (90, 94))	('correlation', 'Interaction', (17, 28))	('R48A', 'Var', (50, 54))	('R48A', 'Mutation', 'p.R48A', (50, 54))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (32, 45))
529848	30108214	In summary, these data demonstrate that chromatin binding causes IL-33 to be enriched in regions of heterochromatin in epithelial cells.	('IL-33', 'Gene', (65, 70))	('epithelia', 'Disease', 'None', (119, 128))	('chromatin', 'Var', (40, 49))	('epithelia', 'Disease', (119, 128))
529849	30108214	In independent experiments, the intranuclear mobilities of R48A IL-33-GFP and 47AAA49 IL-33-GFP were greater than WT IL-33-GFP (Supplementary Fig.	('R48A', 'Mutation', 'p.R48A', (59, 63))	('greater', 'PosReg', (101, 108))	('R48A', 'Var', (59, 63))	('intranuclear mobilities', 'MPA', (32, 55))
529851	30108214	Furthermore, WT IL-33-GFP exhibited a smaller immobile fraction (interpreted as the proportion of the protein that does not change location over the course of the experiment) than H2B-GFP.	('H2B', 'Gene', '8349', (180, 183))	('immobile fraction', 'MPA', (46, 63))	('IL-33-GFP', 'Var', (16, 25))	('smaller', 'NegReg', (38, 45))	('H2B', 'Gene', (180, 183))
529852	30108214	To test this hypothesis, we compared the extracellular release of IL-33 variants after inducing necrosis with a 4-h treatment with calcium ionophore A23187 (20 microM).	('necrosis', 'Disease', (96, 104))	('calcium', 'Chemical', 'MESH:D002118', (131, 138))	('necrosis', 'Disease', 'MESH:D009336', (96, 104))	('variants', 'Var', (72, 80))	('IL-33', 'Gene', (66, 71))	('extracellular release', 'MPA', (41, 62))	('A23187', 'Chemical', 'MESH:D000001', (149, 155))
529853	30108214	Calcium ionophore treatment increased the release of truncated IL-33 compared to WT IL-33 (supernatant/pellet ratio of 1.4 +- 0.5 vs. 0.2 +- 0.1 [mean +- SEM], respectively; two-way ANOVA interaction term p = 0.05), with a 7.8-fold change between truncated and WT IL-33 (Fig.	('release', 'MPA', (42, 49))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	('truncated', 'Var', (53, 62))	('change', 'Reg', (232, 238))
529854	30108214	Furthermore, WT IL-33 was highly cell-associated despite marked necrosis, indicating intracellular retention; a similar rate of necrosis was observed between cells overexpressing truncated and WT IL-33 (p > 0.90) (Fig.	('necrosis', 'Disease', 'MESH:D009336', (64, 72))	('truncated', 'Var', (179, 188))	('necrosis', 'Disease', (128, 136))	('necrosis', 'Disease', (64, 72))	('necrosis', 'Disease', 'MESH:D009336', (128, 136))
529855	30108214	In independent experiments, the supernatant/pellet ratio of R48A IL-33-GFP and 47AAA49-IL-33-GFP was higher than WT IL-33-GFP (Supplementary Fig.	('R48A IL-33-GFP', 'Var', (60, 74))	('supernatant/pellet', 'MPA', (32, 50))	('higher', 'PosReg', (101, 107))	('47AAA49-IL-33-GFP', 'Var', (79, 96))	('R48A', 'Mutation', 'p.R48A', (60, 64))
529859	30108214	In independent experiments, R48A IL-33-GFP and 47AAA49 IL-33-GFP exhibited decreased intracellular retention compared with WT IL-33-GFP (Supplementary Fig.	('intracellular retention', 'MPA', (85, 108))	('R48A IL-33-GFP', 'Var', (28, 42))	('R48A', 'Mutation', 'p.R48A', (28, 32))	('decreased', 'NegReg', (75, 84))
529860	30108214	Notably, a slow, steady decrease in intracellular levels over time was observed for WT IL-33-GFP but not H2B-GFP.	('H2B', 'Gene', '8349', (105, 108))	('intracellular levels', 'MPA', (36, 56))	('decrease', 'NegReg', (24, 32))	('IL-33-GFP', 'Var', (87, 96))	('H2B', 'Gene', (105, 108))
529880	30108214	Our finding that loss of IL-33 chromatin binding increases its extracellular release by mediating intracellular retention is strengthened by the use of multiple independent necrotic stimuli and IL-33 structural variants.	('chromatin', 'Protein', (31, 40))	('intracellular retention', 'MPA', (98, 121))	('increases', 'PosReg', (49, 58))	('IL-33', 'Gene', (25, 30))	('necrotic', 'Disease', (173, 181))	('extracellular release', 'MPA', (63, 84))	('loss', 'Var', (17, 21))	('necrotic', 'Disease', 'MESH:D009336', (173, 181))
529881	30108214	Notably, the changes in IL-33 extracellular release and biochemical properties, including intranuclear mobility, that were identified with the truncated form of IL-33 were reproduced with targeted mutations within the chromatin binding domain (R48A and 47AAA49) that are known to specifically diminish the interaction of IL-33 with the nucleosome acidic patch.	('IL-33', 'Gene', (321, 326))	('diminish', 'NegReg', (293, 301))	('IL-33', 'Gene', (161, 166))	('interaction', 'Interaction', (306, 317))	('R48A', 'Var', (244, 248))	('IL-33', 'Gene', (24, 29))	('R48A', 'Mutation', 'p.R48A', (244, 248))	('mutations', 'Var', (197, 206))	('extracellular release', 'MPA', (30, 51))
529882	30108214	Collectively, these findings build upon a previous elegant study showing that deletion of the chromatin binding domain of IL-33 by an endogenous knock-in approach causes overwhelming lethal eosinophilic inflammation not seen in control mice.	('mice', 'Species', '10090', (236, 240))	('eosinophilic inflammation', 'Disease', (190, 215))	('IL-33', 'Gene', (122, 127))	('eosinophilic inflammation', 'Disease', 'MESH:D004802', (190, 215))	('deletion', 'Var', (78, 86))	('causes', 'Reg', (163, 169))
529917	30108214	In order to generate plasmids encoding proteins with GFP fused to the C-terminus, the Infusion method (Clontech) was used to insert into the peGFP-N1 vector the cDNA for Mus musculus full-length Il1a (NM_010554.4) or the Homo sapiens full-length IL33 (NM_001314044.1) or a truncated form of IL33 that only encodes amino acids 112-270, both with a C-terminal FLAG tag (encoding the amino acid residues DYKDDDDK).	('Mus musculus', 'Species', '10090', (170, 182))	('IL33', 'Gene', (246, 250))	('IL33', 'Gene', (291, 295))	('IL33', 'Gene', '90865', (246, 250))	('Il1a', 'Gene', (195, 199))	('IL33', 'Gene', '90865', (291, 295))	('Homo sapiens', 'Species', '9606', (221, 233))	('NM_010554.4', 'Var', (201, 212))	('Il1a', 'Gene', '16175', (195, 199))	('insert', 'Reg', (125, 131))	('NM_001314044.1', 'Var', (252, 266))
529920	30108214	In order to generate plasmids encoding full-length IL-33 with R48A or 47AAA49 mutations, PCR-mediated mutagenesis was performed using pEGFP-IL33-FL or pINDUCER20-IL33-FL as a template to generate a DNA product inclusive of a restriction fragment (HindIII:BbsI for pEGFP-IL33-FL or BsmBI:BstEII for pINDUCER20-IL33-FL) containing one of the following sets of mutations: (1) c.142C>G; c.143G>C (p.Arg48Ala) or (2) c.139C>G; c.140T>C; c.141C>G; c.142C>G; c.143G>C; c.145T>G; C147T>G (p.Leu47Ala; p.Arg48Ala; p.Ser49Ala).	('IL33', 'Gene', '90865', (309, 313))	('c.140T>C', 'Mutation', 'c.140T>C', (422, 430))	('c.143G>C', 'Mutation', 'c.143G>C', (452, 460))	('IL33', 'Gene', (270, 274))	('c.142C>G; c.143G>C', 'Var', (373, 391))	('IL33', 'Gene', (309, 313))	('mutations', 'Var', (358, 367))	('c.142C>G', 'Mutation', 'rs776800932', (373, 381))	('c.141C>G', 'Mutation', 'c.141C>G', (432, 440))	('p.Leu47Ala', 'Mutation', 'p.L47A', (481, 491))	('c.145T>G', 'Mutation', 'c.145T>G', (462, 470))	('p.Arg48Ala', 'Mutation', 'p.R48A', (393, 403))	('IL33', 'Gene', '90865', (140, 144))	('R48A', 'Mutation', 'p.R48A', (62, 66))	('p.Leu47Ala', 'Var', (481, 491))	('p.Ser49Ala', 'Mutation', 'p.S49A', (505, 515))	('IL33', 'Gene', '90865', (162, 166))	('c.139C>G', 'Mutation', 'c.139C>G', (412, 420))	('p.Arg48Ala', 'Mutation', 'p.R48A', (493, 503))	('IL33', 'Gene', (140, 144))	('c.142C>G', 'Mutation', 'rs776800932', (442, 450))	('p.Arg48Ala; p.Ser49Ala', 'Var', (493, 515))	('p.Ser49Ala', 'Var', (505, 515))	('C147T>G', 'Mutation', 'c.147C>T,G', (472, 479))	('c.143G>C', 'Mutation', 'c.143G>C', (383, 391))	('IL33', 'Gene', (162, 166))	('IL33', 'Gene', '90865', (270, 274))
529924	30108214	In order to generate cells with stable, Dox-inducible overexpression of IL-33, TE-7 cells were transduced with lentivirus pINDUCER20 full-length IL-33-FLAG or truncated (inclusive of a.a. 112-270) IL-33-FLAG, or the empty vector, as described above except that selection was performed with G418.	('IL-33-FLAG', 'Gene', (145, 155))	('TE-7', 'CellLine', 'CVCL:9972', (79, 83))	('truncated', 'Var', (159, 168))	('Dox', 'Chemical', 'MESH:D004318', (40, 43))	('IL-33-FLAG', 'Gene', (197, 207))
529964	30108214	Necrosis was induced by cryoshock in pools of TE-7 cells with Dox-inducible overexpression of WT or truncated IL-33 as described above.	('Necrosis', 'Disease', 'MESH:D009336', (0, 8))	('Necrosis', 'Disease', (0, 8))	('truncated', 'Var', (100, 109))	('shock', 'Phenotype', 'HP:0031273', (28, 33))	('IL-33', 'Gene', (110, 115))	('TE-7', 'CellLine', 'CVCL:9972', (46, 50))	('Dox', 'Chemical', 'MESH:D004318', (62, 65))
529970	30108214	In separate experiments, 4 microg each of recombinant GST-tagged full-length IL-33 (H00090865-P01, Abnova) and acid-purified histones were incubated together in 1 mL of PBS, treated with DNase, and incubated for 1 h with mouse anti-histone H2B (ab52484, Abcam) and rabbit anti-histone H2A (07-146, Millipore) or control IgG for 1 h, and then incubated overnight at 4  C in Protein A/G beads precleared with PBS.	('07-146', 'Var', (290, 296))	('rabbit', 'Species', '9986', (265, 271))	('PBS', 'Chemical', 'MESH:D007854', (407, 410))	('H2B', 'Gene', '8349', (240, 243))	('ab52484', 'Var', (245, 252))	('H2B', 'Gene', (240, 243))	('mouse', 'Species', '10090', (221, 226))	('H00090865-P01, Abnova', 'Disease', 'None', (84, 105))	('PBS', 'Chemical', 'MESH:D007854', (169, 172))
529980	30108214	In separate experiments, necrosis was induced by cryoshock in pools of TE-7 cells with Dox-inducible overexpression of WT IL-33 cultured at 90% confluency in a 150-mm dish as described above in 1.5 mL of PBS.	('necrosis', 'Disease', (25, 33))	('TE-7', 'CellLine', 'CVCL:9972', (71, 75))	('PBS', 'Chemical', 'MESH:D007854', (204, 207))	('necrosis', 'Disease', 'MESH:D009336', (25, 33))	('shock', 'Phenotype', 'HP:0031273', (53, 58))	('Dox', 'Chemical', 'MESH:D004318', (87, 90))	('cryoshock', 'Var', (49, 58))
529990	29343723	Additionally, JQ1 suppressed BRD4, c-MYC, Collagen I, TGF-beta, p-NF-kappaB p65, p-Smad2 and p-Smad3 expressions after irradiation, repressed proliferation and transdifferentiation of lung fibroblasts, and impaired clonogenic survival of thoracic cancer cells.	('p-NF-kappaB', 'MPA', (64, 75))	('proliferation', 'CPA', (142, 155))	('p65', 'Gene', '25716', (76, 79))	('c-MYC', 'Gene', '24577', (35, 40))	('suppressed', 'NegReg', (18, 28))	('p65', 'Gene', (76, 79))	('rat', 'Species', '10116', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('repressed', 'PosReg', (132, 141))	('Smad3', 'Gene', '25631', (95, 100))	('c-MYC', 'Gene', (35, 40))	('BRD4', 'Protein', (29, 33))	('Smad3', 'Gene', (95, 100))	('expressions', 'MPA', (101, 112))	('Smad2', 'Gene', '29357', (83, 88))	('JQ1', 'Var', (14, 17))	('Collagen I', 'MPA', (42, 52))	('thoracic cancer', 'Disease', (238, 253))	('impaired', 'NegReg', (206, 214))	('thoracic cancer', 'Disease', 'MESH:D009369', (238, 253))	('TGF-beta', 'Gene', (54, 62))	('transdifferentiation', 'CPA', (160, 180))	('Smad2', 'Gene', (83, 88))
529999	29343723	These epigenetic readers act as scaffolds and attract components of the transcriptional machinery to these acetylated lysine residues, resulting in modulation of gene transcription.	('attract', 'PosReg', (46, 53))	('modulation', 'Reg', (148, 158))	('lysine', 'Chemical', 'MESH:D008239', (118, 124))	('gene transcription', 'MPA', (162, 180))	('epigenetic readers', 'Var', (6, 24))
530014	29343723	And JQ1 significantly attenuated the histological changes of alveolar structures and pulmonary parenchyma (Fig.	('JQ1', 'Var', (4, 7))	('pulmonary parenchyma', 'Disease', (85, 105))	('pulmonary parenchyma', 'Disease', 'MESH:D010195', (85, 105))	('attenuated', 'NegReg', (22, 32))
530015	29343723	The Masson's trichrome and Sirius red staining demonstrated a lower level of collagen deposition in Radiation + JQ1 group as compared to the Radiation group.	('rat', 'Species', '10116', (54, 57))	('collagen deposition', 'MPA', (77, 96))	('lower', 'NegReg', (62, 67))	('Radiation + JQ1', 'Var', (100, 115))	('Sirius red', 'Chemical', '-', (27, 37))
530017	29343723	Additionally, the fibrosis score, quantitation of the assessment of lung fibrosis, further confirmed the decreased fibrosis after JQ1 treatment in the irradiated animals (P < 0.05; Fig.	('lung fibrosis', 'Disease', (68, 81))	('lung fibrosis', 'Phenotype', 'HP:0002206', (68, 81))	('fibrosis', 'Disease', 'MESH:D005355', (73, 81))	('fibrosis', 'Disease', (73, 81))	('fibrosis', 'Disease', 'MESH:D005355', (18, 26))	('fibrosis', 'Disease', (18, 26))	('JQ1', 'Var', (130, 133))	('fibrosis', 'Disease', 'MESH:D005355', (115, 123))	('fibrosis', 'Disease', (115, 123))	('lung fibrosis', 'Disease', 'MESH:D005355', (68, 81))	('decreased', 'NegReg', (105, 114))
530018	29343723	JQ1, a highly selective BET bromodomain inhibition, has displayed broad antineoplastic effects in a range of tumors carrying different genetic lesions.	('BET', 'Gene', '227325', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('BET', 'Gene', (24, 27))	('genetic lesions', 'Disease', (135, 150))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('JQ1', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('genetic lesions', 'Disease', 'MESH:D020022', (135, 150))	('tumors', 'Disease', (109, 115))	('antineoplastic effects', 'CPA', (72, 94))
530020	29343723	3A and B, treatment with JQ1 and 20 Gy X-ray reduced the expression levels of BRD4 and c-MYC in lung tissues of rats compared with 20 Gy X-ray alone (P < 0.05).	('c-MYC', 'Gene', (87, 92))	('rats', 'Species', '10116', (112, 116))	('reduced', 'NegReg', (45, 52))	('c-MYC', 'Gene', '24577', (87, 92))	('BRD4', 'Protein', (78, 82))	('JQ1', 'Var', (25, 28))	('expression levels', 'MPA', (57, 74))
530022	29343723	JQ1 was able to significantly decreased expressions of Collagen I, TGF-beta and phosphorylation of NF-kappaB p65, p-Smad2 and p-Smad3 increased by irradiation (P < 0.05), indicating its potential role in preventing radiation-induced fibrosis.	('Smad3', 'Gene', (128, 133))	('expressions', 'MPA', (40, 51))	('p65', 'Gene', (109, 112))	('fibrosis', 'Disease', 'MESH:D005355', (233, 241))	('fibrosis', 'Disease', (233, 241))	('Smad2', 'Gene', (116, 121))	('TGF-beta', 'Gene', (67, 75))	('Smad2', 'Gene', '29357', (116, 121))	('JQ1', 'Var', (0, 3))	('Collagen I', 'Protein', (55, 65))	('phosphorylation', 'MPA', (80, 95))	('p65', 'Gene', '25716', (109, 112))	('Smad3', 'Gene', '25631', (128, 133))	('increased', 'PosReg', (134, 143))	('decreased', 'NegReg', (30, 39))
530023	29343723	4A), JQ1 suppressed proliferation of normal human lung fibroblasts (NHLF) after 10 Gy X-ray irradiation in a dose- and time- dependent manner.	('human', 'Species', '9606', (44, 49))	('proliferation', 'CPA', (20, 33))	('JQ1', 'Var', (5, 8))	('rat', 'Species', '10116', (27, 30))	('suppressed', 'NegReg', (9, 19))
530025	29343723	And immunofluorescence staining assay displayed that increased expression of alpha-SMA by irradiation was partially suppressed by JQ1 (P < 0.05; Fig.	('suppressed', 'NegReg', (116, 126))	('alpha-SMA', 'Gene', (77, 86))	('expression', 'MPA', (63, 73))	('JQ1', 'Var', (130, 133))	('increased', 'PosReg', (53, 62))	('alpha-SMA', 'Gene', '25365', (77, 86))
530027	29343723	Our previous study illustrated that JQ1 radiosensitizes non-small cell lung cancer cells (NSCLC) in vitro and in vivo.	('non-small cell lung cancer', 'Disease', (56, 82))	('JQ1', 'Var', (36, 39))	('NSCLC', 'Disease', (90, 95))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (56, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (60, 82))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (56, 82))	('rat', 'Species', '10116', (25, 28))	('radiosensitizes', 'NegReg', (40, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
530029	29343723	The values of SF2, D0, Dq and N decreased after treated with JQ1, indicating the increased radiosensitivity of Eca109 and MCF7 cells.	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (81, 107))	('SF2', 'Gene', '6426', (14, 17))	('SF2', 'Gene', (14, 17))	('JQ1', 'Var', (61, 64))	('radiosensitivity', 'CPA', (91, 107))	('MCF7', 'CellLine', 'CVCL:0031', (122, 126))	('increased', 'PosReg', (81, 90))	('decreased', 'NegReg', (32, 41))
530031	29343723	Meanwhile, JQ1 significantly reduced the surviving colonies (with more than 50 cells per colony) of irradiated Eca109 and MCF7 cells (P < 0.05; Fig.	('MCF7', 'CellLine', 'CVCL:0031', (122, 126))	('reduced', 'NegReg', (29, 36))	('JQ1', 'Var', (11, 14))	('MCF7', 'Gene', (122, 126))
530032	29343723	Collectively, these results suggested that JQ1 enhanced the radiation response of thoracic malignancies including NSCLC, esophageal cancer and breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('enhanced', 'PosReg', (47, 55))	('breast cancer', 'Disease', (143, 156))	('radiation response', 'CPA', (60, 78))	('esophageal cancer', 'Disease', (121, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('NSCLC', 'Disease', (114, 119))	('JQ1', 'Var', (43, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('thoracic malignancies', 'Disease', 'MESH:D009369', (82, 103))	('thoracic malignancies', 'Disease', (82, 103))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
530047	29343723	demonstrated that inhibition of BRD4 by JQ1 can block TGF-beta1 and PDGF-induced migration and proliferation of fibroblasts isolated from lung tissues of patients with idiopathic pulmonary fibrosis.	('block', 'NegReg', (48, 53))	('BRD4', 'Gene', (32, 36))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (179, 197))	('idiopathic pulmonary fibrosis', 'Disease', (168, 197))	('rat', 'Species', '10116', (84, 87))	('PDGF-induced', 'Gene', (68, 80))	('patients', 'Species', '9606', (154, 162))	('rat', 'Species', '10116', (7, 10))	('rat', 'Species', '10116', (102, 105))	('TGF-beta1', 'Gene', (54, 63))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (168, 197))	('inhibition', 'Var', (18, 28))	('proliferation', 'CPA', (95, 108))
530048	29343723	Oral administration of JQ1 was also capable of preventing the development of bleomycin-induced pulmonary fibrosis in murine model.	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (95, 113))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (95, 113))	('JQ1', 'Var', (23, 26))	('preventing', 'NegReg', (47, 57))	('pulmonary fibrosis', 'Disease', (95, 113))	('rat', 'Species', '10116', (13, 16))	('murine', 'Species', '10090', (117, 123))	('bleomycin-induced', 'MPA', (77, 94))	('bleomycin', 'Chemical', 'MESH:D001761', (77, 86))
530049	29343723	found that JQ1 was also effective in blocking activation and proliferation of hepatic stellate cell activation in vitro and in vivo.	('hepatic stellate cell activation', 'CPA', (78, 110))	('activation', 'CPA', (46, 56))	('blocking', 'NegReg', (37, 45))	('rat', 'Species', '10116', (68, 71))	('JQ1', 'Var', (11, 14))	('proliferation', 'CPA', (61, 74))
530052	29343723	Our data showed that JQ1significantly alleviated the presentation of radiation-induced pulmonary injury in rats, as demonstrated by CT films and histological presentations of the lungs, indicating its potential radioprotective role.	('JQ1significantly', 'Var', (21, 37))	('rats', 'Species', '10116', (107, 111))	('radiation-induced', 'Disease', (69, 86))	('rat', 'Species', '10116', (123, 126))	('pulmonary injury', 'Disease', 'MESH:D055370', (87, 103))	('pulmonary injury', 'Disease', (87, 103))	('alleviated', 'NegReg', (38, 48))	('rat', 'Species', '10116', (107, 110))
530057	29343723	Thus, we evaluated the influence of JQ1 on the expressions of TGF-beta, phosphorylation of Smad2 and Smad3 and demonstrated that JQ1 treatment inhibited radiation-induced Smad2 and Smad3 phosphorylation.	('Smad3', 'Gene', '25631', (181, 186))	('TGF-beta', 'Gene', (62, 70))	('rat', 'Species', '10116', (118, 121))	('Smad2', 'Gene', '29357', (91, 96))	('Smad2', 'Gene', (171, 176))	('inhibited', 'NegReg', (143, 152))	('Smad2', 'Gene', (91, 96))	('Smad2', 'Gene', '29357', (171, 176))	('JQ1', 'Var', (129, 132))	('Smad3', 'Gene', (181, 186))	('Smad3', 'Gene', '25631', (101, 106))	('Smad3', 'Gene', (101, 106))
530058	29343723	Therefore, it appears that JQ1 can attenuate radiation-induce fibrosis through suppressing activation of multiple intracellular signaling pathways associated with lung fibroblast activation and proinflammatory responses.	('attenuate', 'NegReg', (35, 44))	('fibrosis', 'Disease', 'MESH:D005355', (62, 70))	('suppressing', 'NegReg', (79, 90))	('fibrosis', 'Disease', (62, 70))	('JQ1', 'Var', (27, 30))	('activation', 'MPA', (91, 101))
530063	29343723	In conclusion, our study demonstrated that JQ1 protected normal lung tissue after radiation, but also exerted a radiosensitizing effect in thoracic cancer cells including NSCLC, esophageal cancer and breast cancer cells.	('esophageal cancer', 'Disease', (178, 195))	('rat', 'Species', '10116', (32, 35))	('radiosensitizing', 'MPA', (112, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('JQ1', 'Var', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancer', 'Disease', (200, 213))	('thoracic cancer', 'Disease', 'MESH:D009369', (139, 154))	('NSCLC', 'Disease', (171, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('thoracic cancer', 'Disease', (139, 154))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
530167	26611860	For example, high birth weight for gestational age is associated with increased risk for all cancers combined in men, while high birth weight or birth length may confer a higher risk of adult cancers in women.	('cancers', 'Disease', (93, 100))	('adult cancers', 'Disease', 'MESH:C535836', (186, 199))	('high birth weight', 'Phenotype', 'HP:0001520', (124, 141))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('men', 'Species', '9606', (205, 208))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('high birth weight for', 'Var', (13, 34))	('cancers', 'Disease', (192, 199))	('women', 'Species', '9606', (203, 208))	('men', 'Species', '9606', (113, 116))	('adult cancers', 'Disease', (186, 199))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('high birth weight', 'Phenotype', 'HP:0001520', (13, 30))
530191	26611860	For analysis, participants were classified into four categories of birth weight (<2500 g, 2500-2999 g, 3000-3999 g, and >=4000 g) and we used the 3000-3999 g group as the referent.	('3000-3999 g', 'Var', (103, 114))	('2500-2999 g', 'Var', (90, 101))	('participants', 'Species', '9606', (14, 26))	('<2500 g', 'Var', (81, 88))
530204	26611860	There were no difference of demographic and endoscopic findings between responders (1,679 patients) and non-responders to the questions pertaining to birth (273 patients); however non-responders were slightly more likely than responders to have a history of GERD symptoms (Supplementary Table 1).	('non-responders', 'Var', (180, 194))	('men', 'Species', '9606', (279, 282))	('patients', 'Species', '9606', (161, 169))	('GERD symptoms', 'Disease', (258, 271))	('patients', 'Species', '9606', (90, 98))
530208	26611860	Conversely, H. pylori positivity was associated with lower risk of BE.	('positivity', 'Var', (22, 32))	('BE', 'Phenotype', 'HP:0100580', (67, 69))	('pylori positivity', 'Phenotype', 'HP:0005202', (15, 32))	('H. pylori', 'Species', '210', (12, 21))	('H. pylori', 'Disease', (12, 21))
530218	26611860	Premature birth and low birth weight are associated with increased risks of coronary heart disease, stroke, type 2 diabetes mellitus, adiposity, the metabolic syndrome, and osteoporosis in adult life.	('stroke', 'Disease', 'MESH:D020521', (100, 106))	('diabetes mellitus', 'Disease', 'MESH:D003920', (115, 132))	('stroke', 'Disease', (100, 106))	('osteoporosis', 'Disease', (173, 185))	('coronary heart disease', 'Disease', (76, 98))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (115, 132))	('osteoporosis', 'Phenotype', 'HP:0000939', (173, 185))	('coronary heart disease', 'Phenotype', 'HP:0001677', (76, 98))	('metabolic syndrome', 'Disease', 'MESH:D008659', (149, 167))	('metabolic syndrome', 'Disease', (149, 167))	('osteoporosis', 'Disease', 'MESH:D010024', (173, 185))	('Premature birth', 'Phenotype', 'HP:0001622', (0, 15))	('low birth weight', 'Phenotype', 'HP:0001518', (20, 36))	('coronary heart disease', 'Disease', 'MESH:D003324', (76, 98))	('low birth weight', 'Var', (20, 36))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (108, 123))	('adiposity', 'Disease', (134, 143))	('diabetes mellitus', 'Disease', (115, 132))	('stroke', 'Phenotype', 'HP:0001297', (100, 106))
530219	26611860	High birth weight also increases the risk of type 2 diabetes in young adult males.	('High birth weight', 'Phenotype', 'HP:0001520', (0, 17))	('diabetes', 'Disease', (52, 60))	('High birth weight', 'Var', (0, 17))	('diabetes', 'Disease', 'MESH:D003920', (52, 60))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (45, 60))
530220	26611860	Furthermore, high birth weight is associated with cancer, especially hormone-related cancer such as breast, prostate, and non-seminoma testicular cancer.	('testicular cancer', 'Phenotype', 'HP:0010788', (135, 152))	('cancer', 'Disease', (146, 152))	('associated', 'Reg', (34, 44))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('breast', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('high birth weight', 'Var', (13, 30))	('non-seminoma testicular cancer', 'Disease', (122, 152))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('non-seminoma testicular cancer', 'Disease', 'MESH:D018239', (122, 152))	('prostate', 'Disease', (108, 116))	('high birth weight', 'Phenotype', 'HP:0001520', (13, 30))
530228	26611860	Furthermore, prematurely birth is a risk for congenital anomalies, including gastroschisis and hiatus hernia.	('hernia', 'Phenotype', 'HP:0100790', (102, 108))	('congenital anomalies', 'Disease', (45, 65))	('prematurely birth', 'Var', (13, 30))	('gastroschisis', 'Phenotype', 'HP:0001543', (77, 90))	('congenital anomalies', 'Disease', 'MESH:D000013', (45, 65))	('hiatus hernia', 'Phenotype', 'HP:0002036', (95, 108))	('prematurely birth', 'Phenotype', 'HP:0001622', (13, 30))	('gastroschisis and hiatus hernia', 'Disease', 'MESH:D006551', (77, 108))
530246	33628033	The five-year overall survival rate of patients with high TMI was significantly lower than that of patients with low TMI (30.8% vs 50.4%, p <0.001).	('TMI', 'Chemical', '-', (58, 61))	('overall survival', 'CPA', (14, 30))	('patients', 'Species', '9606', (39, 47))	('high TMI', 'Var', (53, 61))	('TMI', 'Chemical', '-', (117, 120))	('patients', 'Species', '9606', (99, 107))	('lower', 'NegReg', (80, 85))
530298	33628033	Using these cut-off values, the patients were subdivided into two groups: a low-fibrinogen group (fibrinogen <= 3.42, n=129) and high fibrinogen group (fibrinogen >3.42, n=188); low-NLR group (NLR <= 1.88, n=131) and high NLR group (NLR >1.88, n=186); low-PLR group (PLR <= 119.5, n=158) and high PLR group (PLR >119.5, n=159); low-TMI group (TMI <= 0.53, n=158) and high TMI group (TMI >0.53, n=159).	('patients', 'Species', '9606', (32, 40))	('TMI', 'Var', (343, 346))	('fibrinogen', 'Gene', '2244', (80, 90))	('TMI', 'Chemical', '-', (332, 335))	('fibrinogen', 'Gene', (80, 90))	('low-fibrinogen', 'Phenotype', 'HP:0011900', (76, 90))	('fibrinogen', 'Gene', '2244', (152, 162))	('high fibrinogen', 'Phenotype', 'HP:0011899', (129, 144))	('fibrinogen', 'Gene', (152, 162))	('fibrinogen', 'Gene', '2244', (134, 144))	('fibrinogen', 'Gene', '2244', (98, 108))	('fibrinogen', 'Gene', (134, 144))	('fibrinogen', 'Gene', (98, 108))	('TMI', 'Chemical', '-', (372, 375))	('TMI', 'Chemical', '-', (383, 386))	('TMI', 'Chemical', '-', (343, 346))
530300	33628033	Compared to the low-TMI group, the high-TMI group was associated with larger tumor size (P =0.008), higher NLR level (P=0.027), higher CYFRA 21-1 level (P <0.001), higher SCC level (P<0.001), higher pT status (P=0.008), and higher pN status (P=0.024).	('pN status', 'MPA', (231, 240))	('CYFRA 21-1 level', 'MPA', (135, 151))	('TMI', 'Chemical', '-', (40, 43))	('larger', 'PosReg', (70, 76))	('SCC level', 'MPA', (171, 180))	('TMI', 'Chemical', '-', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('higher', 'PosReg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('NLR level', 'MPA', (107, 116))	('pT status', 'MPA', (199, 208))	('high-TMI', 'Var', (35, 43))	('higher', 'PosReg', (100, 106))	('tumor', 'Disease', (77, 82))	('higher', 'PosReg', (128, 134))
530303	33628033	Similarly, the five-year OS rate of patients in the high TMI group was significantly worse than that in the low TMI group (30.8% vs 50.4%, log-rank, p <0.001, Figure 1B).	('TMI', 'Chemical', '-', (57, 60))	('patients', 'Species', '9606', (36, 44))	('high TMI', 'Var', (52, 60))	('TMI', 'Chemical', '-', (112, 115))	('worse', 'NegReg', (85, 90))
530304	33628033	When the OS rate was evaluated after adjusting for the fibrinogen level, a significant difference was found between the high- and low-TMI groups in the low-fibrinogen patients (36.2% vs 63.3%, log-rank, p < 0.001, Figure 2A), however, there was no significant difference between the two groups in the high-fibrinogen patients (27.6% vs 40.2%, log-rank p=0.063, Figure 2B).	('fibrinogen', 'Gene', '2244', (306, 316))	('fibrinogen', 'Gene', (55, 65))	('fibrinogen', 'Gene', (306, 316))	('TMI', 'Chemical', '-', (134, 137))	('fibrinogen', 'Gene', '2244', (156, 166))	('low-fibrinogen', 'Phenotype', 'HP:0011900', (152, 166))	('fibrinogen', 'Gene', (156, 166))	('patients', 'Species', '9606', (167, 175))	('high-fibrinogen', 'Phenotype', 'HP:0011899', (301, 316))	('low-TMI', 'Var', (130, 137))	('patients', 'Species', '9606', (317, 325))	('fibrinogen', 'Gene', '2244', (55, 65))
530314	33628033	The AUCs for fibrinogen, TMI, and F-TMI were 0.604 (95% CI = 0.538~0.669), 0.627 (95% CI = 0.564~0.691) and 0.668 (95% CI = 0.606~0.731) for all patients.	('patients', 'Species', '9606', (145, 153))	('F-TMI', 'Chemical', '-', (34, 39))	('TMI', 'Chemical', '-', (25, 28))	('0.668', 'Var', (108, 113))	('fibrinogen', 'Gene', '2244', (13, 23))	('0.604', 'Var', (45, 50))	('TMI', 'Chemical', '-', (36, 39))	('fibrinogen', 'Gene', (13, 23))	('0.627', 'Var', (75, 80))
530328	33628033	Our study indicated that high TMI levels were significantly associated with progression and worse survival of ESCC patients, which was consistent with our previous study.	('patients', 'Species', '9606', (115, 123))	('TMI', 'Chemical', '-', (30, 33))	('high', 'Var', (25, 29))	('TMI levels', 'MPA', (30, 40))	('ESCC', 'Disease', (110, 114))	('worse', 'NegReg', (92, 97))	('associated', 'Reg', (60, 70))
530344	33628033	Furthermore, F-TMI was significantly associated with OS.	('F-TMI', 'Chemical', '-', (13, 18))	('F-TMI', 'Var', (13, 18))	('associated', 'Reg', (37, 47))
530348	33628033	Accordingly, our results demonstrated that the F-TMI could increase the prognostic accuracy and compensate for the limitations imposed by using each marker individually.	('prognostic', 'MPA', (72, 82))	('F-TMI', 'Chemical', '-', (47, 52))	('F-TMI', 'Var', (47, 52))	('increase', 'PosReg', (59, 67))
530367	32184622	The results in the present study together confirmed the truth that beta-arrestin1 interference may suppress ESCC cell proliferation, migration, invasion, EMT and tumor growth via AKT/GSK3beta/beta-catenin signaling pathway.	('beta-arrestin1', 'Gene', (67, 81))	('AKT', 'Gene', (179, 182))	('beta-catenin', 'Gene', '1499', (192, 204))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('GSK3beta', 'Gene', (183, 191))	('GSK3beta', 'Gene', '2931', (183, 191))	('ESCC', 'Disease', 'MESH:D000077277', (108, 112))	('tumor', 'Disease', (162, 167))	('beta-arrestin1', 'Gene', '408', (67, 81))	('invasion', 'CPA', (144, 152))	('interference', 'Var', (82, 94))	('migration', 'CPA', (133, 142))	('beta-catenin', 'Gene', (192, 204))	('suppress', 'NegReg', (99, 107))	('ESCC', 'Disease', (108, 112))	('AKT', 'Gene', '207', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
530372	32184622	EMT involves genes changes in tumor cells and epigenetic, which are closely related to tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('epigenetic', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (30, 35))	('related', 'Reg', (76, 83))
530376	32184622	A recent research showed that knockdown of AKT1/2 suppressed cell proliferation and induced cell apoptosis in KYSE70, 450 and 510 ESCC cell lines.	('suppressed', 'NegReg', (50, 60))	('AKT1', 'Gene', (43, 47))	('induced', 'Reg', (84, 91))	('cell apoptosis', 'CPA', (92, 106))	('ESCC', 'Disease', (130, 134))	('ESCC', 'Disease', 'MESH:D000077277', (130, 134))	('knockdown', 'Var', (30, 39))	('AKT1', 'Gene', '207', (43, 47))	('cell proliferation', 'CPA', (61, 79))
530410	32184622	Besides, beta-arrestin1 expression levels were detected in the four ESCC cell lines TE-1, ECA-109, KYSE-410 and KYSE-520, and a normal esophageal epithelial cell line HEEC.	('ESCC', 'Disease', (68, 72))	('KYSE-520', 'Var', (112, 120))	('expression levels', 'MPA', (24, 41))	('ESCC', 'Disease', 'MESH:D000077277', (68, 72))	('beta-arrestin1', 'Gene', '408', (9, 23))	('KYSE-410', 'Var', (99, 107))	('detected', 'Reg', (47, 55))	('beta-arrestin1', 'Gene', (9, 23))
530414	32184622	By contrast, beta-arrestin1 expression was markedly upregulated by transfecting with pcDNA-beta-arrestin1.	('beta-arrestin1', 'Gene', '408', (13, 27))	('beta-arrestin1', 'Gene', (13, 27))	('expression', 'MPA', (28, 38))	('upregulated', 'PosReg', (52, 63))	('beta-arrestin1', 'Gene', '408', (91, 105))	('transfecting', 'Var', (67, 79))	('beta-arrestin1', 'Gene', (91, 105))
530416	32184622	The results revealed that inhibition of beta-arrestin1 decreased the levels of p-AKT, p- GSK3beta and beta-catenin.	('beta-arrestin1', 'Gene', (40, 54))	('beta-catenin', 'Gene', '1499', (102, 114))	('GSK3beta', 'Gene', (89, 97))	('AKT', 'Gene', '207', (81, 84))	('inhibition', 'Var', (26, 36))	('decreased', 'NegReg', (55, 64))	('AKT', 'Gene', (81, 84))	('beta-arrestin1', 'Gene', '408', (40, 54))	('beta-catenin', 'Gene', (102, 114))	('GSK3beta', 'Gene', '2931', (89, 97))
530417	32184622	Also, beta-arrestin1 overexpression significantly promoted AKT/GSK3beta/beta-catenin pathway activation, while LY294002 (a PI3K inhibitor) could reverse the effect of pcDNA-beta-arrestin1.	('activation', 'PosReg', (93, 103))	('promoted', 'PosReg', (50, 58))	('beta-arrestin1', 'Gene', '408', (6, 20))	('AKT', 'Gene', (59, 62))	('beta-catenin', 'Gene', (72, 84))	('LY294002', 'Var', (111, 119))	('beta-catenin', 'Gene', '1499', (72, 84))	('beta-arrestin1', 'Gene', (6, 20))	('overexpression', 'PosReg', (21, 35))	('beta-arrestin1', 'Gene', '408', (173, 187))	('AKT', 'Gene', '207', (59, 62))	('LY294002', 'Chemical', 'MESH:C085911', (111, 119))	('beta-arrestin1', 'Gene', (173, 187))	('GSK3beta', 'Gene', (63, 71))	('GSK3beta', 'Gene', '2931', (63, 71))
530420	32184622	Furthermore, LY294002 inhibited the effect of beta-arrestin1.	('inhibited', 'NegReg', (22, 31))	('beta-arrestin1', 'Gene', (46, 60))	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('LY294002', 'Var', (13, 21))	('beta-arrestin1', 'Gene', '408', (46, 60))
530425	32184622	Relative ratios of wound closures were markedly promoted after transfected with beta-arrestin1 plasmid.	('transfected', 'Var', (63, 74))	('beta-arrestin1', 'Gene', '408', (80, 94))	('beta-arrestin1', 'Gene', (80, 94))	('promoted', 'PosReg', (48, 56))	('wound closures', 'CPA', (19, 33))
530426	32184622	While sh-beta-arrestin1 and LY294002 inhibited the cell migration.	('LY294002', 'Var', (28, 36))	('inhibited', 'NegReg', (37, 46))	('cell migration', 'CPA', (51, 65))	('beta-arrestin1', 'Gene', '408', (9, 23))	('LY294002', 'Chemical', 'MESH:C085911', (28, 36))	('beta-arrestin1', 'Gene', (9, 23))
530430	32184622	Besides, knockdown of beta-arrestin1 inhibited the protein levels of MMP2 and MMP9.	('beta-arrestin1', 'Gene', (22, 36))	('protein levels', 'MPA', (51, 65))	('knockdown', 'Var', (9, 18))	('inhibited', 'NegReg', (37, 46))	('MMP2', 'Gene', (69, 73))	('MMP9', 'Gene', (78, 82))	('MMP2', 'Gene', '4313', (69, 73))	('MMP9', 'Gene', '4318', (78, 82))	('beta-arrestin1', 'Gene', '408', (22, 36))
530431	32184622	All the effects of beta-arrestin1 on cell migration and invasion were reversed by LY294002.	('LY294002', 'Var', (82, 90))	('LY294002', 'Chemical', 'MESH:C085911', (82, 90))	('beta-arrestin1', 'Gene', '408', (19, 33))	('beta-arrestin1', 'Gene', (19, 33))	('cell migration', 'CPA', (37, 51))	('invasion', 'CPA', (56, 64))
530434	32184622	However, knockdown of beta-arrestin1 showed an opposite effect and LY294002 could inhibit the effect of beta-arrestin1 on cell EMT.	('beta-arrestin1', 'Gene', (22, 36))	('knockdown', 'Var', (9, 18))	('LY294002', 'Chemical', 'MESH:C085911', (67, 75))	('beta-arrestin1', 'Gene', '408', (104, 118))	('inhibit', 'NegReg', (82, 89))	('LY294002', 'Var', (67, 75))	('cell EMT', 'CPA', (122, 130))	('beta-arrestin1', 'Gene', (104, 118))	('beta-arrestin1', 'Gene', '408', (22, 36))
530437	32184622	By contrast, beta-arrestin1 expression was markedly upregulated in vivo model of ESCC after transfection with pcDNA-beta-arrestin1.	('beta-arrestin1', 'Gene', '408', (13, 27))	('transfection', 'Var', (92, 104))	('beta-arrestin1', 'Gene', (116, 130))	('beta-arrestin1', 'Gene', (13, 27))	('ESCC', 'Disease', (81, 85))	('expression', 'MPA', (28, 38))	('ESCC', 'Disease', 'MESH:D000077277', (81, 85))	('upregulated', 'PosReg', (52, 63))	('beta-arrestin1', 'Gene', '408', (116, 130))
530440	32184622	Whereas, LY294002 could reduce the expression of beta-arrestin1.	('LY294002', 'Chemical', 'MESH:C085911', (9, 17))	('beta-arrestin1', 'Gene', '408', (49, 63))	('reduce', 'NegReg', (24, 30))	('LY294002', 'Var', (9, 17))	('expression', 'MPA', (35, 45))	('beta-arrestin1', 'Gene', (49, 63))
530442	32184622	In addition, LY294002 inhibited the effect of beta-arrestin1 on promoting tumor growth.	('inhibited', 'NegReg', (22, 31))	('beta-arrestin1', 'Gene', (46, 60))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('LY294002', 'Var', (13, 21))	('beta-arrestin1', 'Gene', '408', (46, 60))
530445	32184622	beta-arrestin1 interference and LY294002 inhibited the tumor migration and invasion in vivo.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('beta-arrestin1', 'Gene', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('LY294002', 'Var', (32, 40))	('inhibited', 'NegReg', (41, 50))	('beta-arrestin1', 'Gene', '408', (0, 14))	('LY294002', 'Chemical', 'MESH:C085911', (32, 40))
530465	31626150	The long-term impact of tumor burden in pT3N0M0 esophageal squamous cell carcinoma The purpose of this study was to assess the impact of tumor burden on the survival of patients with pathologic T3N0M0 (pT3N0M0) esophageal squamous cell carcinoma (ESCC).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('esophageal squamous cell carcinoma', 'Disease', (211, 245))	('patients', 'Species', '9606', (169, 177))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (24, 29))	('ESCC', 'Disease', (247, 251))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (211, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('esophageal squamous cell carcinoma', 'Disease', (48, 82))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (48, 82))	('T3N0M0', 'Var', (194, 200))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('ESCC', 'Disease', 'MESH:C562729', (247, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
530466	31626150	A total of 84 patients with pathologic T3N0M0 ESCC treated with radical esophagectomy and 3-field lymphadenectomy (3-FL) from January 2008 to December 2009 in our center were analyzed.	('ESCC', 'Disease', (46, 50))	('patients', 'Species', '9606', (14, 22))	('T3N0M0', 'Var', (39, 45))	('ESCC', 'Disease', 'MESH:C562729', (46, 50))
530470	31626150	After propensity matching, patients with a tumor volume <=18.6 cc had a better OS than those with a tumor volume >18.6 cc (5-year OS, 85% vs 50%, P = .008).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('<=18.6 cc', 'Var', (56, 65))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
530471	31626150	Tumor volume may serve as a good prognostic factor for patients with pT3N0M0 ESCC treated with radical esophagectomy and 3-FL.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('pT3N0M0', 'Var', (69, 76))	('ESCC', 'Disease', (77, 81))	('patients', 'Species', '9606', (55, 63))	('ESCC', 'Disease', 'MESH:C562729', (77, 81))
530476	31626150	Among pathologic T3N0M0 (pT3N0M0) ESCC cases, cases with grade 2 and 3 tumors in the lower one-third of the esophagus are classified as stage IIa, while cases in which the tumors are located in the upper and middle 3rds of the esophagus are classified as stage IIb.	('ESCC', 'Disease', 'MESH:C562729', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('T3N0M0', 'Var', (17, 23))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ESCC', 'Disease', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
530479	31626150	Here, we analyzed the impact of tumor burden on the long-term prognosis of patients with pT3N0M0 ESCC treated with radical esophagectomy and 3-field lymphadenectomy (3-FL).	('ESCC', 'Disease', 'MESH:C562729', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('pT3N0M0', 'Var', (89, 96))	('tumor', 'Disease', (32, 37))	('ESCC', 'Disease', (97, 101))
530509	31626150	From these results, the OS was significantly better for patients with a maximal esophageal wall thickness <=1.3 cm (chi2 = 6.064, P = .014; Fig.	('patients', 'Species', '9606', (56, 64))	('<=1.3', 'Var', (106, 111))	('better', 'PosReg', (45, 51))
530521	31626150	From these results, the OS was significantly better for patients with a tumor volume <=18.6 cc (chi2 = 13.433, P < .001; Fig.	('patients', 'Species', '9606', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('better', 'PosReg', (45, 51))	('<=18.6', 'Var', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
530523	31626150	For G2/3 cases, for which the average tumor volume was 25.91 +- 18.02 cc (range, 5.0-106.9 cc), patients with a tumor volume <=18.6 cc had a better OS than those with a tumor volume >18.6 cc (chi2 = 14.467, P < .001).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (169, 174))	('patients', 'Species', '9606', (96, 104))	('tumor', 'Disease', (112, 117))	('<=18.6', 'Var', (125, 131))
530524	31626150	Univariate analysis demonstrated that vascular invasion (P < .001), maximal esophageal wall thickness (P = .014), and tumor volume (P < .001) were significantly associated with OS among the patients with pT3N0M0 ESCC.	('ESCC', 'Disease', 'MESH:C562729', (212, 216))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('associated', 'Reg', (161, 171))	('patients', 'Species', '9606', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('pT3N0M0', 'Var', (204, 211))	('ESCC', 'Disease', (212, 216))	('tumor', 'Disease', (118, 123))	('vascular invasion', 'CPA', (38, 55))
530530	31626150	In the present study, we demonstrated that patients with pT3N0M0 ESCC with a small tumor burden based on a maximal esophageal wall thickness <=1.3 cm and tumor volume <=18.6 cc had a better OS than those with a larger tumor volume.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('ESCC', 'Disease', 'MESH:C562729', (65, 69))	('tumor', 'Disease', (83, 88))	('patients', 'Species', '9606', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('pT3N0M0', 'Var', (57, 64))	('ESCC', 'Disease', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (154, 159))
530533	31626150	For patients with pT3N0M0 ESCC, tumor cell grade and tumor location were recommended as staging factors in the 8th AJCC guideline but were found to not be sufficient to predict the prognosis in some studies.	('ESCC', 'Disease', (26, 30))	('pT3N0M0', 'Var', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (32, 37))	('ESCC', 'Disease', 'MESH:C562729', (26, 30))
530534	31626150	Situ et al studied 302 patients with pT3N0M0 ESCC and found that the 5-year OS did not differ among cases with G1 tumor cell differentiation G1 vs G2/3.	('ESCC', 'Disease', 'MESH:C562729', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('ESCC', 'Disease', (45, 49))	('pT3N0M0', 'Var', (37, 44))
530538	31626150	Similarly, in our study, we classified the pT3N0M0 ESCC cases as stage IIa to IIb based on the tumor location and tumor cell grade and found no statistically significant differences in the survival curves between the stage IIa and IIb groups (61% vs 64%).	('ESCC', 'Disease', 'MESH:C562729', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('ESCC', 'Disease', (51, 55))	('pT3N0M0', 'Var', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
530556	31626150	Similarly, Chen et al studied 153 patients with ESCC who received 3D conformal radiotherapy and found that the 5-year survival rates for patients with tumor volumes <20 cc, 20-40 cc, and >40 cc were 41.5%, 18.1%, and 15.4%, respectively.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('ESCC', 'Disease', 'MESH:C562729', (48, 52))	('tumor', 'Disease', (151, 156))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (34, 42))	('ESCC', 'Disease', (48, 52))	('<20 cc', 'Var', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
530559	31626150	Our study focused on the postoperative survival of patients with pT3N0M0 ESCC and found that the best cutoff value for tumor volume was 18.6 cc.	('pT3N0M0', 'Var', (65, 72))	('tumor', 'Disease', (119, 124))	('ESCC', 'Disease', 'MESH:C562729', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('patients', 'Species', '9606', (51, 59))	('ESCC', 'Disease', (73, 77))
530561	31626150	Further subgroup analyses found that for patients with ESCC with tumor cell differentiation G2/G3, the tumor volume <=18.6 cc was associated with a better OS than a tumor volume >18.6 cc.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('<=18.6', 'Var', (116, 122))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (103, 108))	('ESCC', 'Disease', 'MESH:C562729', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('patients', 'Species', '9606', (41, 49))	('ESCC', 'Disease', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('G2/G3', 'Var', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (165, 170))
530563	31626150	After PSM, the patients with a tumor volume <=18.6 cc had a longer 5-year OS than those with a tumor volume >18.6 cc.	('patients', 'Species', '9606', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('longer', 'PosReg', (60, 66))	('tumor', 'Disease', (31, 36))	('<=18.6', 'Var', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', (95, 100))
530564	31626150	Based on the current NCCN guideline, the survival benefit of postoperative radiotherapy for patients with pT3N0M0 ESCC remains controversial.	('pT3N0M0', 'Var', (106, 113))	('ESCC', 'Disease', 'MESH:C562729', (114, 118))	('ESCC', 'Disease', (114, 118))	('patients', 'Species', '9606', (92, 100))
530565	31626150	Yang et al retrospectively studied 678 patients with pT3N0M0 ESCC and found that the 5-year OS rates of those treated with radical surgery only and those treated with radical surgery plus postoperative radiotherapy were 58.8% vs 75.2%, respectively.	('pT3N0M0', 'Var', (53, 60))	('ESCC', 'Disease', (61, 65))	('patients', 'Species', '9606', (39, 47))	('ESCC', 'Disease', 'MESH:C562729', (61, 65))
530566	31626150	Thus, the postoperative radiotherapy showed a survival benefit for patients with pT3N0M0 ESCC.	('ESCC', 'Disease', 'MESH:C562729', (89, 93))	('patients', 'Species', '9606', (67, 75))	('benefit', 'PosReg', (55, 62))	('ESCC', 'Disease', (89, 93))	('pT3N0M0', 'Var', (81, 88))
530579	31626150	Moreover, the number of pT3N0M0 patients treated with postoperative radiotherapy was limited, and the role of the postoperative radiotherapy in patients with pT3N0M0 ESCC with a large tumor volume needs to be elucidated in further studies.	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('ESCC', 'Disease', 'MESH:C562729', (166, 170))	('tumor', 'Disease', (184, 189))	('patients', 'Species', '9606', (144, 152))	('pT3N0M0', 'Var', (158, 165))	('ESCC', 'Disease', (166, 170))
530580	31626150	In conclusion, our study confirmed that the tumor volume is an independent prognostic factor for pT3N0M0 ESCC.	('ESCC', 'Disease', (105, 109))	('pT3N0M0', 'Var', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ESCC', 'Disease', 'MESH:C562729', (105, 109))	('tumor', 'Disease', (44, 49))
530603	31324733	Among them, MMP-2 and MMP-9 of MMP family degrade collagen IV during cancer invasion and metastasis.	('MMP-2', 'Gene', '4313', (12, 17))	('MMP-9', 'Var', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('MMP', 'Var', (31, 34))	('degrade', 'NegReg', (42, 49))	('collagen IV', 'MPA', (50, 61))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('MMP-2', 'Gene', (12, 17))	('cancer', 'Disease', (69, 75))
530610	31324733	At the same time, deacetylation of the NF-kappaB p65 by SIRT1 inhibits NF-kappaB signaling, indicating that SIRT1 can decrease the expression of MMP-9 by deacetylation of NF-kappaB.	('SIRT1', 'Gene', (108, 113))	('deacetylation', 'Var', (154, 167))	('inhibits', 'NegReg', (62, 70))	('NF-kappaB signaling', 'MPA', (71, 90))	('deacetylation', 'Var', (18, 31))	('MMP-9', 'Gene', (145, 150))	('expression', 'MPA', (131, 141))	('decrease', 'NegReg', (118, 126))	('NF-kappaB p65', 'Gene', (39, 52))	('NF-kappaB p65', 'Gene', '5970', (39, 52))	('SIRT1', 'Gene', '23411', (56, 61))	('SIRT1', 'Gene', '23411', (108, 113))	('SIRT1', 'Gene', (56, 61))
530717	27905172	Consensus eliminated location for pT2N0M0 and pT3N0M0G1 SCC groups, and despite similar survival, restricted stage 0 to pTis, excluding pT1aN0M0G1.	('pT2N0M0', 'Var', (34, 41))	('pT1aN0M0G1', 'Gene', (136, 146))	('SCC', 'Gene', (56, 59))	('pT1aN0M0G1', 'Gene', '58492', (136, 146))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('SCC', 'Gene', '6317', (56, 59))	('pT3', 'Gene', '7694', (46, 49))	('pT3', 'Gene', (46, 49))
530720	27905172	Consensus stage IV subgrouping acknowledged pT4N+ and pN3 cancers had poor survival, similar to pM1.	('poor', 'NegReg', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('pT4N+', 'Var', (44, 49))	('pM1', 'Gene', (96, 99))	('pM1', 'Gene', '8834', (96, 99))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('pN3', 'Gene', '6336', (54, 57))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('pN3', 'Gene', (54, 57))	('cancers', 'Disease', (58, 65))
530746	27905172	1); thus, advanced SCC and adenocarcinoma (pT4N0M0, pTanyN + M0, and pM1) shared stage groupings (see Tables 1 and 2).	('SCC', 'Gene', '6317', (19, 22))	('pM1', 'Gene', '8834', (69, 72))	('pT4N0M0', 'Var', (43, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('pM1', 'Gene', (69, 72))	('adenocarcinoma', 'Disease', (27, 41))	('adenocarcinoma', 'Disease', 'MESH:D000230', (27, 41))	('SCC', 'Gene', (19, 22))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))
530754	27905172	Consensus stage group IB was completed by placing data-driven group 2 members pT1N0M0G2-3 and pT2N0M0G1 into consensus group IB.	('pT2N0M0G1', 'Var', (94, 103))	('pT1', 'Gene', (78, 81))	('pT1', 'Gene', '58492', (78, 81))
530756	27905172	These two changes removed location as a category for pT2N0M0 and pT3N0M0G1 cancers.	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('pT3', 'Gene', '7694', (65, 68))	('pT3', 'Gene', (65, 68))	('pT2N0M0', 'Var', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
530758	27905172	pT4bN1-2N0M0 cancer was placed into consensus stage group IVB.	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('pT4bN1-2N0M0', 'Var', (0, 12))
530759	27905172	For any location, if grade is unknown, pT1aN0M0GX is pStage IA, pT1bN0M0GX is pStage IB, pT2N0M0GX is pStage IIA, and pT3N0M0GX is pStage IIB.	('pT1', 'Gene', (39, 42))	('pT1', 'Gene', '58492', (64, 67))	('pT1', 'Gene', '58492', (39, 42))	('pT2N0M0GX', 'Var', (89, 98))	('pT3', 'Gene', '7694', (118, 121))	('pT3', 'Gene', (118, 121))	('pT1', 'Gene', (64, 67))
530768	27905172	pT4aN2M0 and pT4bN1-2M0 were placed into consensus stage group IVA.	('pT4aN2M0', 'Var', (0, 8))	('IVA', 'Disease', 'MESH:C538167', (63, 66))	('pT4bN1-2M0', 'Var', (13, 23))	('IVA', 'Disease', (63, 66))
530769	27905172	If grade is unknown, pT1aN0M0GX is pStage IA, pT1bN0M0GX is pStage IB, and pT2N0M0GX is pStage IIA.	('pT1', 'Gene', '58492', (46, 49))	('pT1', 'Gene', (21, 24))	('pT2N0M0GX', 'Var', (75, 84))	('pT1', 'Gene', '58492', (21, 24))	('pT1', 'Gene', (46, 49))
530778	27905172	Changes were similar for SCC except that pT4aN0M0 in data-driven group 5 was amalgamated with data-driven groups 6 and 7, producing anatomic stage group IIIB after removal of T4aN2M0 (Table 2 and Fig.	('SCC', 'Gene', (25, 28))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('producing', 'Reg', (122, 131))	('SCC', 'Gene', '6317', (25, 28))	('pT4aN0M0', 'Var', (41, 49))	('T4aN2M0', 'Var', (175, 182))
530787	27905172	Consensus removed location as a category for pT2N0M0 and pT3N0M0G1 SCCs.	('pT3', 'Gene', '7694', (57, 60))	('pT2N0M0', 'Var', (45, 52))	('pT3', 'Gene', (57, 60))	('SCC', 'Gene', (67, 70))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('SCC', 'Gene', '6317', (67, 70))
530792	27905172	In contrast, broadening the definition of stage IV acknowledged that pT4N+ and pN3 cancers had dismal survival equivalent to distant metastases.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('pN3', 'Gene', '6336', (79, 82))	('pN3', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pT4N+', 'Var', (69, 74))	('metastases', 'Disease', (133, 143))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('metastases', 'Disease', 'MESH:D009362', (133, 143))
530798	27905172	In the 7th edition, pT2-3N0M0 cancers occupied three subgroups: IB, IIA, and IIB.	('pT2-3N0M0', 'Var', (20, 29))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('IIA', 'Disease', (68, 71))
530799	27905172	In the 8th edition, location is removed as a category for pT2N0M0 cancers, and they are either stage IB (pT2N0M0G1) or stage IIA (pT2N0M0G2-3).	('pT2N0M0', 'Var', (58, 65))	('pT2N0M0G1', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
530804	27905172	7th edition stage IIIA members pT3N1M0 and pT4aN0M0, stage IIIB pT3N2M0 cancers, and stage IIIC pT4aN1M0 cancers form stage IIIB in the 8th edition.	('pT3', 'Gene', '7694', (64, 67))	('pT3', 'Gene', (64, 67))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('pT3', 'Gene', '7694', (31, 34))	('pT3', 'Gene', (31, 34))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('pT4aN1M0', 'Var', (96, 104))
530832	28831761	The clinical diagnosis was T4b (left main bronchus) N2M0 stage IIIC carcinoma, according to the seventh edition of the Union for International Cancer Control TNM Classification of Malignant Tumors.	('IIIC carcinoma', 'Disease', 'MESH:C566891', (63, 77))	('Malignant Tumors', 'Disease', (180, 196))	('TNM', 'Gene', (158, 161))	('T4b', 'Var', (27, 30))	('IIIC carcinoma', 'Disease', (63, 77))	('Cancer', 'Phenotype', 'HP:0002664', (143, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('Malignant Tumors', 'Disease', 'MESH:D018198', (180, 196))	('Tumors', 'Phenotype', 'HP:0002664', (190, 196))	('TNM', 'Gene', '10178', (158, 161))
530865	28831761	Enlargement of the hiatus during esophagectomy is a predisposing factor for hiatal hernia after esophagectomy.	('hiatus during esophagectomy', 'Phenotype', 'HP:0100628', (19, 46))	('Enlargement', 'Var', (0, 11))	('hiatal hernia', 'Disease', 'MESH:D006551', (76, 89))	('hiatal hernia', 'Disease', (76, 89))	('hernia', 'Phenotype', 'HP:0100790', (83, 89))	('hiatal hernia', 'Phenotype', 'HP:0002036', (76, 89))
531001	26599757	The average inpatient stay was shorter and the average hospitalization cost was less in the tegafur group compared with the 5-Fu group, but these differences were not statistically significant (P > 0.05).	('less', 'NegReg', (80, 84))	('tegafur', 'Var', (92, 99))	('5-Fu', 'Chemical', 'MESH:D005472', (124, 128))	('shorter', 'NegReg', (31, 38))	('tegafur', 'Chemical', 'MESH:D005641', (92, 99))	('patient', 'Species', '9606', (14, 21))
531011	26599757	In some cases, even with satisfactory therapeutic effects, combination chemotherapy can cause severe myelosuppression and digestive tract symptoms, resulting in suspension of chemotherapy.	('myelosuppression', 'Disease', 'MESH:D001855', (101, 117))	('combination', 'Var', (59, 70))	('digestive tract', 'Disease', (122, 137))	('myelosuppression', 'Disease', (101, 117))
531032	26599757	The chemotherapeutic side effects observed in the 5-Fu group were mainly myelosuppression and digestive tract symptoms.	('digestive tract symptoms', 'CPA', (94, 118))	('5-Fu', 'Chemical', 'MESH:D005472', (50, 54))	('myelosuppression', 'Disease', 'MESH:D001855', (73, 89))	('5-Fu', 'Var', (50, 54))	('myelosuppression', 'Disease', (73, 89))
531036	26599757	In addition, because the anti-tumor activity of 5-Fu is time-dependent, continuous central venous catheters and intravenous infusion are required, but they can cause inflammation, infection and blood clots within veins, thereby increasing treatment cost and lengthening hospital stays.	('inflammation', 'Disease', 'MESH:D007249', (166, 178))	('cause', 'Reg', (160, 165))	('increasing', 'PosReg', (228, 238))	('5-Fu', 'Chemical', 'MESH:D005472', (48, 52))	('blood clots', 'Phenotype', 'HP:0001907', (194, 205))	('inflammation', 'Disease', (166, 178))	('blood clots', 'CPA', (194, 205))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('5-Fu', 'Var', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('infection', 'Disease', (180, 189))	('infection', 'Disease', 'MESH:D007239', (180, 189))	('tumor', 'Disease', (30, 35))
531064	23531395	HAX-1 and beta-actin primers were designed according to HAX-1 mRNA (NM_006118) and beta-actin mRNA (NM_001101) with Oligo 6.0 software.	('beta-actin', 'Gene', (83, 93))	('NM_001101', 'Var', (100, 109))	('HAX-1', 'Gene', (56, 61))	('beta-actin', 'Gene', (10, 20))	('beta-actin', 'Gene', '728378', (10, 20))	('beta-actin', 'Gene', '728378', (83, 93))
531080	23531395	It has been reported that HAX-1 silencing could induce melanoma cell apoptosis, suggesting that HAX-1 plays an important role in tumorigenesis and tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('HAX-1', 'Gene', (26, 31))	('tumor metastasis', 'Disease', 'MESH:D009362', (147, 163))	('induce', 'PosReg', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor metastasis', 'Disease', (147, 163))	('silencing', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (129, 134))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
531093	21912055	Association of Matrix Metalloproteinase-7 (-181A>G) Polymorphism with Risk of Esophageal Squamous Cell Carcinoma in Kashmir Valley Degradation of the basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be an essential step in the complicated process of hematogenous metastasis.	('-181A>G', 'Mutation', 'rs11568818', (43, 50))	('Esophageal Squamous Cell Carcinoma', 'Disease', (78, 112))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (78, 112))	('-181A>G) Polymorphism', 'Var', (43, 64))	('Polymorphism', 'Var', (52, 64))	('Matrix Metalloproteinase-7', 'Gene', (15, 41))	('Carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('Association', 'Interaction', (0, 11))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('Matrix Metalloproteinase-7', 'Gene', '4316', (15, 41))
531095	21912055	To document the role of MMP-7 polymorphism in esophageal carcinogenesis, a case-control study was performed comprising 135 patients with esophageal cancer (EC) and 195 healthy controls.	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('MMP-7', 'Gene', (24, 29))	('patients', 'Species', '9606', (123, 131))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (46, 71))	('esophageal carcinogenesis', 'Disease', (46, 71))	('MMP-7', 'Gene', '4316', (24, 29))	('polymorphism', 'Var', (30, 42))	('esophageal cancer', 'Disease', (137, 154))
531104	21912055	However, it is clear that aberrant MMP expression can contribute to the pathogenesis of several diseases including rheumatoid arthritis, multiple sclerosis, cerebral hemorrhage, and inflammatory bowel disease.	('arthritis', 'Phenotype', 'HP:0001369', (126, 135))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (115, 135))	('aberrant', 'Var', (26, 34))	('contribute', 'Reg', (54, 64))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (182, 208))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (182, 208))	('cerebral hemorrhage', 'Phenotype', 'HP:0001342', (157, 176))	('multiple sclerosis', 'Disease', (137, 155))	('MMP', 'Protein', (35, 38))	('rheumatoid arthritis', 'Disease', (115, 135))	('inflammatory bowel disease', 'Disease', (182, 208))	('multiple sclerosis', 'Disease', 'MESH:D009103', (137, 155))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (115, 135))	('cerebral hemorrhage', 'Disease', 'MESH:D002543', (157, 176))	('cerebral hemorrhage', 'Disease', (157, 176))
531109	21912055	Two polymorphisms exist in the MMP-7 promoter region, -181A>G and -153C>T, which are known to modify the gene transcription activity.	('modify', 'Reg', (94, 100))	('-181A>G', 'Var', (54, 61))	('-153C>T', 'Mutation', 'c.-153C>T', (66, 73))	('MMP-7', 'Gene', (31, 36))	('-181A>G', 'Mutation', 'rs11568818', (54, 61))	('gene transcription activity', 'MPA', (105, 132))	('MMP-7', 'Gene', '4316', (31, 36))
531110	21912055	Previous studies have shown association of MMP-7 (-181A>G) (rs11568818) polymorphisms with esophageal gastric and other malignancies.	('malignancies', 'Disease', 'MESH:D009369', (120, 132))	('MMP-7', 'Gene', (43, 48))	('rs11568818', 'Mutation', 'rs11568818', (60, 70))	('esophageal gastric', 'Disease', 'MESH:D013274', (91, 109))	('MMP-7', 'Gene', '4316', (43, 48))	('association', 'Interaction', (28, 39))	('malignancies', 'Disease', (120, 132))	('esophageal gastric', 'Disease', (91, 109))	('rs11568818) polymorphisms', 'Var', (60, 85))	('-181A>G', 'Mutation', 'rs11568818', (50, 57))	('polymorphisms', 'Var', (72, 85))
531112	21912055	Therefore, the aim of the present study was to investigate the role of MMP-7 (-181A>G) (rs11568818) in conferring genetic susceptibility to EC in the Kashmir valley.	('MMP-7', 'Gene', (71, 76))	('rs11568818', 'Var', (88, 98))	('MMP-7', 'Gene', '4316', (71, 76))	('rs11568818', 'Mutation', 'rs11568818', (88, 98))	('-181A>G', 'Mutation', 'rs11568818', (78, 85))
531120	21912055	The isolated DNA was stored at -70 C. The MMP-7 polymorphism (-181A>G) was genotyped in subjects by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).	('MMP-7', 'Gene', (42, 47))	('MMP-7', 'Gene', '4316', (42, 47))	('-181A>G', 'Var', (62, 69))	('-181A>G', 'Mutation', 'rs11568818', (62, 69))
531125	21912055	Observed genotype frequencies for MMP-7 (-181A>G) polymorphism (rs17878362) in controls were examined for deviation from HWE by using a goodness-of-fit chi2 -test with one degree of freedom.	('rs17878362', 'Var', (64, 74))	('-181A>G', 'Mutation', 'rs11568818', (41, 48))	('rs17878362', 'Mutation', 'rs17878362', (64, 74))	('MMP-7', 'Gene', (34, 39))	('MMP-7', 'Gene', '4316', (34, 39))
531127	21912055	Binary logistic regression analysis was used to fit statistical models to predict the association of MMP-7 (-181A>G) genotypes with susceptibility to EC.	('MMP-7', 'Gene', '4316', (101, 106))	('MMP-7', 'Gene', (101, 106))	('association', 'Interaction', (86, 97))	('-181A>G', 'Mutation', 'rs11568818', (108, 115))	('-181A>G', 'Var', (108, 115))
531147	21912055	The association of MMP-7 (-181A>G) polymorphism with cancer has been observed in Asians and not in Europeans.	('MMP-7', 'Gene', (19, 24))	('cancer', 'Disease', (53, 59))	('polymorphism', 'Var', (35, 47))	('association', 'Interaction', (4, 15))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('MMP-7', 'Gene', '4316', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('-181A>G', 'Mutation', 'rs11568818', (26, 33))
531159	21912055	These substrates have been known to play important roles in signal transduction, cell-cell adhesion, and apoptosis In addition, elevated expression of MMP-7 induced by the -181G allele may lead to increased activation of other members of the MMP family such as MMP-2.	('MMP-2', 'Gene', '4313', (261, 266))	('expression', 'MPA', (137, 147))	('MMP-2', 'Gene', (261, 266))	('MMP-7', 'Gene', (151, 156))	('increased activation', 'PosReg', (197, 217))	('the -181G', 'Var', (168, 177))	('elevated', 'PosReg', (128, 136))	('MMP-7', 'Gene', '4316', (151, 156))
531161	21912055	reported that the high expression of MMPs in the invasive margin may help degrade the extracellular matrix surrounding ESCC cells, thereby facilitating the invasion or metastasis of this malignancy.	('MMPs', 'Protein', (37, 41))	('facilitating', 'PosReg', (139, 151))	('degrade', 'NegReg', (74, 81))	('SCC', 'Gene', '6317', (120, 123))	('malignancy', 'Disease', 'MESH:D009369', (187, 197))	('high', 'Var', (18, 22))	('malignancy', 'Disease', (187, 197))	('extracellular matrix', 'MPA', (86, 106))	('metastasis', 'CPA', (168, 178))	('invasion', 'CPA', (156, 164))	('SCC', 'Gene', (120, 123))
531167	21912055	However, based on our gene-environment interactions, after Bonferroni correction, we did not find any significant modulation of cancer risk due to interaction of MMP-7 (-181A>G) genotypes with smoking or salted tea consumption.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('interaction', 'Interaction', (147, 158))	('-181A>G', 'Mutation', 'rs11568818', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('MMP-7', 'Gene', (162, 167))	('MMP-7', 'Gene', '4316', (162, 167))	('salted tea', 'Chemical', '-', (204, 214))	('-181A>G', 'Var', (169, 176))	('cancer', 'Disease', (128, 134))
531170	21912055	Determination of MMP-7 (-181A>G) genotype may provide a useful genetic marker in predicating high-risk individuals for the development of EC.	('MMP-7', 'Gene', (17, 22))	('-181A>G', 'Mutation', 'rs11568818', (24, 31))	('MMP-7', 'Gene', '4316', (17, 22))	('-181A>G', 'Var', (24, 31))
531183	19270824	However, the adverse effects of 5-FU, such as esophagitis, which is an additive complication to radiation, or bone marrow suppression, can result in treatment-related hospitalization or mortality, thereby compromising the quality of life and compliance to treatment.	('compromising', 'NegReg', (205, 217))	('result in', 'Reg', (139, 148))	('compliance to treatment', 'CPA', (242, 265))	('bone marrow suppression', 'Disease', (110, 133))	('bone marrow suppression', 'Disease', 'MESH:D001855', (110, 133))	('quality of life', 'CPA', (222, 237))	('5-FU', 'Var', (32, 36))	('esophagitis', 'Phenotype', 'HP:0100633', (46, 57))	('esophagitis', 'Disease', (46, 57))	('5-FU', 'Chemical', 'MESH:D005472', (32, 36))	('esophagitis', 'Disease', 'MESH:D004941', (46, 57))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (110, 133))
531206	19270824	In the presence of myelosuppression (WBC count <4x109/L or platelet count <100x109/L), a persisting fever that exceeded 38C, or other clinically apparent infections, a cycle could be postponed for 1 week or interrupted if this was judged to be necessary in the opinion of the attending physicians.	('fever', 'Phenotype', 'HP:0001945', (100, 105))	('myelosuppression', 'Disease', 'MESH:D001855', (19, 35))	('myelosuppression', 'Disease', (19, 35))	('persisting fever', 'Phenotype', 'HP:0001954', (89, 105))	('<100x109/L', 'Var', (74, 84))	('<4x109/L', 'Var', (47, 55))	('fever', 'Disease', 'MESH:D005334', (100, 105))	('fever', 'Disease', (100, 105))
531244	19270824	also reported that the definitive CRT with 5-FU and cisplatin exhibited a CR rate of 56% and 5-yr overall survival rate of 29% in 139 patients with thoracic esophageal cancer.	('thoracic esophageal cancer', 'Disease', (148, 174))	('5-FU', 'Chemical', 'MESH:D005472', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('patients', 'Species', '9606', (134, 142))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (148, 174))	('cisplatin', 'Var', (52, 61))	('5-FU', 'Var', (43, 47))	('CR', 'Chemical', '-', (74, 76))	('CR', 'Chemical', '-', (34, 36))
531263	33289788	In short, our results demonstrated that miR-196a in tumor tissue or serum/plasma could be used as a prognostic and diagnostic values for cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('miR-196a', 'Var', (40, 48))	('tumor', 'Disease', (52, 57))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('miR-196a', 'Chemical', '-', (40, 48))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
531264	33289788	In the past few decades, aberrant expression of miRNAs has been shown to play roles in tumorigenesis and tumor progression in a variety of cancers.	('play roles', 'Reg', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('expression', 'MPA', (34, 44))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('aberrant', 'Var', (25, 33))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('miRNAs', 'Protein', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (105, 110))
531266	33289788	miR-196a-5p and miR-196a-3p are two molecules produced by pre-MIR196A2.	('miR-196a', 'Chemical', '-', (0, 8))	('MIR196A2', 'Gene', '406973', (62, 70))	('MIR196A2', 'Gene', (62, 70))	('miR-196a', 'Chemical', '-', (16, 24))	('miR-196a-5p', 'Var', (0, 11))	('miR-196a-3p', 'Var', (16, 27))
531267	33289788	Moreover, pre-MIR196A1 also encodes miR-196a-5p.	('MIR196A1', 'Gene', (14, 22))	('MIR196A1', 'Gene', '406972', (14, 22))	('miR-196a-5p', 'Var', (36, 47))	('miR-196a', 'Chemical', '-', (36, 44))
531271	33289788	Meanwhile, polymorphism in miR-196a-2 was reported to confer occurrence risk or progression of cancers, such as it was associated with HCC recurrence after liver transplantation, and we also previously reported that it was associated with occurrence of cancers.	('HCC', 'Gene', '619501', (135, 138))	('associated with', 'Reg', (119, 134))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('polymorphism', 'Var', (11, 23))	('miR-196a-2', 'Gene', (27, 37))	('miR-196a-2', 'Gene', '406973', (27, 37))	('cancers', 'Disease', (253, 260))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('HCC', 'Phenotype', 'HP:0001402', (135, 138))	('HCC', 'Gene', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
531272	33289788	As a regulator, it could be also regulated by non-coding RNAs, such as lncRNA FEZF-AS1, circRNA 101308, H19, lncRNA SNHG1, which were involved in tumorigenesis and tumor progression.	('tumor', 'Disease', (164, 169))	('H19', 'Gene', '283120', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('H19', 'Gene', (104, 107))	('tumor', 'Disease', (146, 151))	('SNHG1', 'Gene', '23642', (116, 121))	('lncRNA', 'Var', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('AS1', 'Gene', '5729', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('SNHG1', 'Gene', (116, 121))	('AS1', 'Gene', (83, 86))
531273	33289788	Additionally, miR-196a was focused on cancers by studies for its biological function in carcinogenesis and potential role in cancer diagnosis or survival prediction.	('miR-196a', 'Chemical', '-', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('carcinogenesis', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('miR-196a', 'Var', (14, 22))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', (125, 131))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))
531276	33289788	Moreover, the level of miR-196a-5p in serum was suggested to be served as a diagnostic biomarker for cancers, including non-small cell lung cancer (NSCLC), prostate cancer and biomarker of cancer metastasis.	('prostate cancer', 'Disease', (156, 171))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (124, 146))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (120, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('miR-196a', 'Chemical', '-', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('NSCLC', 'Disease', (148, 153))	('miR-196a-5p', 'Var', (23, 34))	('non-small cell lung cancer', 'Disease', (120, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('cancer', 'Disease', (189, 195))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (120, 146))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancers', 'Disease', (101, 108))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))
531283	33289788	In the prognostic meta-analysis, the pooled HR with 95% CI was calculated to evaluate the relationship between the level of miR-196a and the prognosis of cancer patients.	('miR-196a', 'Chemical', '-', (124, 132))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('patients', 'Species', '9606', (161, 169))	('miR-196a', 'Var', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
531285	33289788	We accomplished a comprehensive analysis of miR-196a expression profiles in GSE113486 and GSE106817.	('miR-196a', 'Gene', (44, 52))	('miR-196a', 'Chemical', '-', (44, 52))	('GSE113486', 'Var', (76, 85))	('GSE106817', 'Var', (90, 99))
531287	33289788	Seven articles reported the role of miR-196a as a biomarker in cancer diagnosis (Table 1), and all the samples of these studies were collected as serum and plasma.	('miR-196a', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('miR-196a', 'Chemical', '-', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
531288	33289788	In order to assess the diagnostic value of miR-196a for cancer, the pooled SEN and SPE were calculated, and forest plots were also drawn (Figure 1).	('miR-196a', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('miR-196a', 'Chemical', '-', (43, 51))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
531289	33289788	The pooled AUC (AUC = 0.87, 95% CI: 0.84-0.90; SEN = 0.73, 95% CI: 0.64-0.81; SPE = 0.90, 95% CI: 0.81-0.95) (Figure 1, Table 4) indicated that miR-196a is a valuable diagnostic biomarker for cancers.	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('miR-196a', 'Var', (144, 152))	('cancers', 'Disease', (192, 199))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('miR-196a', 'Chemical', '-', (144, 152))
531297	33289788	As shown in Figure 6, the prognostic HR values of miR-196a-5p in patients with adrenocortical carcinoma, esophageal carcinoma, and brain lower grade glioma were 5.70 (P=6.9e-5), 1.93 (P=0.012), 2.91 (P=4.5e-9), respectively.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (105, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('miR-196a-5p', 'Var', (50, 61))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (79, 103))	('glioma', 'Disease', (149, 155))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (79, 103))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('miR-196a', 'Chemical', '-', (50, 58))	('patients', 'Species', '9606', (65, 73))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('adrenocortical carcinoma', 'Disease', (79, 103))	('esophageal carcinoma', 'Disease', (105, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (105, 125))
531298	33289788	In addition, the results of Kaplan-Meier Plotter database showed that high expression of miR-196a predicted unfavorable OS of breast cancer patients (GSE40267: HR = 2.47, 95% CI: 1.2-5.07, P=0.011; TCGA: HR = 1.82, 95% CI: 1.21-2.74, P=0.0034; GSE19783: HR = 4.24, 95% CI: 1-18.06, P=0.033).	('miR-196a', 'Chemical', '-', (89, 97))	('unfavorable OS', 'Disease', (108, 122))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('miR-196a', 'Gene', (89, 97))	('patients', 'Species', '9606', (140, 148))	('high', 'Var', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
531301	33289788	For diagnosis meta-analysis, in the present study, a total of seven diagnosis-related articles were included, the overall and subgroups pooled result showed that miR-196a could be used as a diagnostic marker for cancer.	('miR-196a', 'Chemical', '-', (162, 170))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('miR-196a', 'Var', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
531302	33289788	In fact, the oncogene role of miR-196a in cancer has been reported by studies, and it combined with other miRNAs can improve the efficiency of cancer diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('miR-196a', 'Var', (30, 38))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (143, 149))	('improve', 'PosReg', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('miR-196a', 'Chemical', '-', (30, 38))
531303	33289788	Such as miR-196a and miR-148a could act as candidate biomarkers for early gastric cancer (GC) diagnosis, the combination of miR-10a-5p and miR-196a-5p can serve as non-invasive biomarkers for NSCLC, and miR-196a combined with miR-1202 could serve as biomarkers for evaluating the effectiveness of endometrial cancer treatment.	('NSCLC', 'Disease', (192, 197))	('miR-10a', 'Gene', '406902', (124, 131))	('miR-148a', 'Gene', '406940', (21, 29))	('miR-148a', 'Gene', (21, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('miR-1202', 'Gene', (226, 234))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('endometrial cancer', 'Phenotype', 'HP:0012114', (297, 315))	('miR-10a', 'Gene', (124, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('miR-196a', 'Chemical', '-', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('endometrial cancer', 'Disease', (297, 315))	('miR-196a', 'Chemical', '-', (139, 147))	('endometrial cancer', 'Disease', 'MESH:D016889', (297, 315))	('miR-1202', 'Gene', '100302259', (226, 234))	('miR-196a-5p', 'Var', (139, 150))	('miR-196a', 'Chemical', '-', (8, 16))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('GC', 'Phenotype', 'HP:0012126', (90, 92))	('gastric cancer', 'Disease', (74, 88))
531304	33289788	In addition, results from databases were consistent to the pooled results, indicating miR-196a has promising clinical application in cancer diagnosis.	('miR-196a', 'Chemical', '-', (86, 94))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('miR-196a', 'Var', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
531308	33289788	Regarding the role of miR-196a in the prognosis of cancer, the overall and subgroups pooled results showed that miR-196a could be used as a prognostic marker for cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('miR-196a', 'Var', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('miR-196a', 'Chemical', '-', (112, 120))	('miR-196a', 'Chemical', '-', (22, 30))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
531311	33289788	Moreover, miR-196a promoted tumor progression by down-regulation of SPRR2C, S100A9 and KRT5.	('promoted', 'PosReg', (19, 27))	('tumor', 'Disease', (28, 33))	('down-regulation', 'NegReg', (49, 64))	('S100A9', 'Gene', '6280', (76, 82))	('KRT5', 'Gene', (87, 91))	('miR-196a', 'Var', (10, 18))	('S100A9', 'Gene', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('SPRR2C', 'Gene', '6702', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('SPRR2C', 'Gene', (68, 74))	('miR-196a', 'Chemical', '-', (10, 18))	('KRT5', 'Gene', '3852', (87, 91))
531312	33289788	Additionally, in colorectal cancer (CRC), miR-196 could lead to metastasis by inhibiting HoxB8, and it can also decrease the sensitivity of cancer cells to chemotherapy with FOLFOX4, resulting in unfavorable prognosis, supporting it is a favorable prognostic biomarker.	('CRC', 'Disease', (36, 39))	('inhibiting', 'NegReg', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('CRC', 'Phenotype', 'HP:0003003', (36, 39))	('metastasis', 'CPA', (64, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('miR-196', 'Var', (42, 49))	('colorectal cancer', 'Disease', (17, 34))	('miR-196', 'Chemical', '-', (42, 49))	('CRC', 'Disease', 'MESH:D015179', (36, 39))	('prognosis', 'CPA', (208, 217))	('cancer', 'Disease', (140, 146))	('HoxB8', 'Gene', '3218', (89, 94))	('unfavorable', 'MPA', (196, 207))	('cancer', 'Disease', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('HoxB8', 'Gene', (89, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('decrease', 'NegReg', (112, 120))	('sensitivity', 'MPA', (125, 136))	('FOLFOX4', 'Chemical', '-', (174, 181))	('lead to', 'Reg', (56, 63))
531318	33289788	For example, the prognostic value of miR-196a was assessed in Asian cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('miR-196a', 'Var', (37, 45))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('miR-196a', 'Chemical', '-', (37, 45))	('cancer', 'Disease', (68, 74))
531320	33289788	In addition, compared with the study regarding the polymorphism locates at the coding region of miR-196a, our study discussed the expression of miR-196a, and our previous study has reported the association between the miR-196a polymorphism and cancer risk.	('miR-196a', 'Gene', (218, 226))	('miR-196a', 'Chemical', '-', (96, 104))	('polymorphism', 'Var', (227, 239))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('miR-196a', 'Var', (144, 152))	('miR-196a', 'Chemical', '-', (218, 226))	('association', 'Interaction', (194, 205))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('miR-196a', 'Chemical', '-', (144, 152))
531321	33289788	In short, our study concluded that miR-196a can be used as a diagnostic and prognostic marker for cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('miR-196a', 'Chemical', '-', (35, 43))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('miR-196a', 'Var', (35, 43))	('cancers', 'Disease', (98, 105))
531326	32133283	Methods: Our previous RNA-chip data (GSE53624, GSE53622) for 179 ESCC patients were reanalyzed according to MetS.	('patients', 'Species', '9606', (70, 78))	('MetS', 'Disease', 'MESH:D008659', (108, 112))	('MetS', 'Disease', (108, 112))	('ESCC', 'Disease', 'MESH:C562729', (65, 69))	('GSE53624', 'Var', (37, 45))	('GSE53622', 'Var', (47, 55))	('ESCC', 'Disease', (65, 69))
531331	32133283	A six-lncRNA signature was established by 60 ESCC patients randomly selected from GSE53624 and identified with an effective predictive ability in validation cohorts (59 patients from GSE53624 and 60 patients from GSE53622), subgroup analysis, and ESCC patients from TCGA.	('ESCC', 'Disease', 'MESH:C562729', (45, 49))	('GSE53624', 'Var', (183, 191))	('patients', 'Species', '9606', (169, 177))	('patients', 'Species', '9606', (50, 58))	('ESCC', 'Disease', (247, 251))	('patients', 'Species', '9606', (252, 260))	('ESCC', 'Disease', (45, 49))	('patients', 'Species', '9606', (199, 207))	('ESCC', 'Disease', 'MESH:C562729', (247, 251))
531339	32133283	The presence of MetS can increase the risk and influence the prognosis of various tumors, such as colorectal cancer, breast cancer, and prostate cancer.	('colorectal cancer', 'Disease', (98, 115))	('tumors', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('MetS', 'Disease', 'MESH:D008659', (16, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('influence', 'Reg', (47, 56))	('prostate cancer', 'Disease', (136, 151))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('breast cancer', 'Disease', (117, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('MetS', 'Disease', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('increase', 'PosReg', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('presence', 'Var', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
531357	32133283	The 119 ESCC patients from GSE53624 were randomly divided into 60 ESCC and 59 ESCC patients by caret package of R (set.seed = 1,000, p = 0.50).	('ESCC', 'Disease', (8, 12))	('ESCC', 'Disease', (78, 82))	('ESCC', 'Disease', 'MESH:C562729', (66, 70))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (83, 91))	('GSE53624', 'Var', (27, 35))	('ESCC', 'Disease', (66, 70))	('ESCC', 'Disease', 'MESH:C562729', (8, 12))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))
531361	32133283	The tumor and adjacent normal tissues of 179 ESCC patients (GSE53624, GSE53622) were used for analysis.	('tumor', 'Disease', (4, 9))	('GSE53622', 'Var', (70, 78))	('ESCC', 'Disease', 'MESH:C562729', (45, 49))	('GSE53624', 'Var', (60, 68))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('ESCC', 'Disease', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
531364	32133283	Differences in mRNA and lncRNA expression (GSE53624, GSE53622) classified with MetS of 179 ESCC patients were screened by fold change > 1 and adj p < 0.05.	('MetS', 'Disease', (79, 83))	('ESCC', 'Disease', (91, 95))	('GSE53624', 'Var', (43, 51))	('GSE53622', 'Var', (53, 61))	('patients', 'Species', '9606', (96, 104))	('ESCC', 'Disease', 'MESH:C562729', (91, 95))	('MetS', 'Disease', 'MESH:D008659', (79, 83))
531380	32133283	We also found that age more than 70 years, high N stage, poor grade, and advanced TNM stage were significantly associated with worse OS.	('TNM', 'Gene', '10178', (82, 85))	('high', 'Var', (43, 47))	('TNM', 'Gene', (82, 85))	('poor grade', 'Var', (57, 67))	('OS', 'Chemical', '-', (133, 135))
531386	32133283	Mechanism-related gene sets of MetS were selected from MSigDB and analyzed within our groups, and the results showed that differences in the expression of genes, such as IGF1, IGFALS, CSF1, TGFbeta1, and TGFbeta2, were associated with MetS (Figure 2A, Supplementary Table 1).	('differences', 'Var', (122, 133))	('TGFbeta1', 'Gene', (190, 198))	('men', 'Species', '9606', (258, 261))	('TGFbeta2', 'Gene', '7042', (204, 212))	('associated', 'Reg', (219, 229))	('MetS', 'Disease', 'MESH:D008659', (31, 35))	('MetS', 'Disease', (31, 35))	('MetS', 'Disease', 'MESH:D008659', (235, 239))	('IGF1', 'Gene', '3479', (170, 174))	('TGFbeta2', 'Gene', (204, 212))	('MetS', 'Disease', (235, 239))	('IGFALS', 'Gene', '3483', (176, 182))	('CSF1', 'Gene', '1435', (184, 188))	('expression', 'MPA', (141, 151))	('IGFALS', 'Gene', (176, 182))	('CSF1', 'Gene', (184, 188))	('IGF1', 'Gene', (170, 174))	('TGFbeta1', 'Gene', '7040', (190, 198))
531423	32133283	We know that the high expression of IGF1 and inflammatory factors can promote tumor development by changing the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('high expression', 'Var', (17, 32))	('men', 'Species', '9606', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('promote', 'PosReg', (70, 77))	('changing', 'Reg', (99, 107))	('IGF1', 'Gene', '3479', (36, 40))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (112, 117))	('men', 'Species', '9606', (130, 133))	('IGF1', 'Gene', (36, 40))
531432	32133283	The extracellular matrix (ECM) regulated tissue development and homeostasis, and its dysregulation contributed to tumor progression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tissue development', 'CPA', (41, 59))	('dysregulation', 'Var', (85, 98))	('men', 'Species', '9606', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('homeostasis', 'MPA', (64, 75))	('tumor', 'Disease', (114, 119))	('contributed', 'Reg', (99, 110))
531538	31365299	Furthermore, in the Cancer and Leukemia Group B (CALGB) 80403 phase II trial (ClinicalTrials.gov identifier: NCT00381706), cisplatin plus irinotecan, despite being numerically inferior, had statistically similar efficacy:however was compared with FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) or cisplatin plus infusional fluorouracil.	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('irinotecan', 'Chemical', 'MESH:C051890', (138, 148))	('fluorouracil', 'Chemical', 'MESH:D005472', (338, 350))	('fluorouracil', 'Chemical', 'MESH:D005472', (266, 278))	('Leukemia', 'Disease', 'MESH:D007938', (31, 39))	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Cancer', 'Disease', (20, 26))	('Leukemia', 'Disease', (31, 39))	('Cancer', 'Disease', 'MESH:D009369', (20, 26))	('cisplatin', 'Var', (123, 132))	('Leukemia', 'Phenotype', 'HP:0001909', (31, 39))	('oxaliplatin', 'Chemical', 'MESH:C030110', (296, 307))	('cisplatin', 'Chemical', 'MESH:D002945', (312, 321))	('leucovorin', 'Chemical', 'MESH:D002955', (280, 290))
531577	30987413	This post hoc analysis confirmed the high efficacy of SOF/VEL without ribavirin in patients with cirrhosis and different baseline characteristics including patients with transient elastography (TE) results >=20 KPa.	('patients', 'Species', '9606', (156, 164))	('SOF/VEL', 'Gene', (54, 61))	('>=20 KPa', 'Var', (206, 214))	('ribavirin', 'Chemical', 'MESH:D012254', (70, 79))	('cirrhosis', 'Phenotype', 'HP:0001394', (97, 106))	('cirrhosis', 'Disease', (97, 106))	('patients', 'Species', '9606', (83, 91))	('SOF/VEL', 'Gene', '388588', (54, 61))	('cirrhosis', 'Disease', 'MESH:D005355', (97, 106))
531586	30987413	This recommendation is mostly driven by the risk of Y93H substitution (resistance associated substitutions (RASs)) in the HCV NS5A region associated with resistance to velpatasvir.	('HCV', 'Species', '11103', (122, 125))	('velpatasvir', 'Chemical', 'MESH:C000604171', (168, 179))	('resistance to velpatasvir', 'MPA', (154, 179))	('Y93H', 'Var', (52, 56))	('associated', 'Reg', (138, 148))	('Y93H', 'Mutation', 'p.Y93H', (52, 56))
531609	30987413	Ultrasonographic evidence of portal hypertension was based on the combination of spleen longitudinal diameter >=15 cm and portal vein diameter >=14 mm.	('>=15', 'Var', (110, 114))	('portal hypertension', 'Phenotype', 'HP:0001409', (29, 48))	('hypertension', 'Disease', (36, 48))	('hypertension', 'Phenotype', 'HP:0000822', (36, 48))	('hypertension', 'Disease', 'MESH:D006973', (36, 48))	('>=14', 'Var', (143, 147))
531669	30987413	However, patients with TE >20 KPa are expected to have a less favorable prognosis than patients with lower results, due to the high risk of portal hypertension associated with this TE result.	('patients', 'Species', '9606', (9, 17))	('hypertension', 'Disease', 'MESH:D006973', (147, 159))	('hypertension', 'Disease', (147, 159))	('portal hypertension', 'Phenotype', 'HP:0001409', (140, 159))	('hypertension', 'Phenotype', 'HP:0000822', (147, 159))	('TE >20 KPa', 'Var', (23, 33))	('patients', 'Species', '9606', (87, 95))
531842	30891327	A total of 353 stenoses were dilated in 347 patients, the majority (66%) in anastomoses of the colonic ileum and only 3% in the UGT.	('colonic ileum', 'Disease', (95, 108))	('colonic ileum', 'Disease', 'MESH:D007078', (95, 108))	('patients', 'Species', '9606', (44, 52))	('anastomoses', 'Var', (76, 87))
531867	30456167	Inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate antitumor activity.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('PD-L1', 'Gene', (47, 52))	('PD-1', 'Gene', (38, 42))	('interaction', 'Interaction', (18, 29))	('T-cell responses in vitro', 'CPA', (65, 90))	('Inhibition', 'Var', (0, 10))	('enhance T-cell responses', 'Phenotype', 'HP:0005419', (57, 81))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('enhance', 'PosReg', (57, 64))
531932	30456167	The review of literature highlighting major landmark studies and immunotherapy associated interstitial lung disease and pneumonitis is highlighted in Table 1. Review of literature with summary of recent reports on Anti-PD-1 induced pneumonitis/interstitial lung disease is shown in Table 2.	('pneumonitis', 'Disease', 'MESH:D011014', (120, 131))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (90, 115))	('lung disease', 'Phenotype', 'HP:0002088', (103, 115))	('interstitial lung disease', 'Disease', 'MESH:D017563', (244, 269))	('interstitial lung disease', 'Disease', (244, 269))	('interstitial lung disease', 'Disease', 'MESH:D017563', (90, 115))	('Anti-PD-1', 'Var', (214, 223))	('pneumonitis', 'Disease', (232, 243))	('interstitial lung disease', 'Disease', (90, 115))	('pneumonitis', 'Disease', 'MESH:D011014', (232, 243))	('pneumonitis', 'Disease', (120, 131))	('lung disease', 'Phenotype', 'HP:0002088', (257, 269))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (244, 269))
531941	30456167	in their systematic analysis comparing the toxicity profiles of PD-1 inhibitors showed a twofold rise in the rate of pneumonitis in patients treated with PD-1 inhibitors.	('pneumonitis', 'Disease', (117, 128))	('PD-1', 'Gene', (64, 68))	('toxicity', 'Disease', (43, 51))	('pneumonitis', 'Disease', 'MESH:D011014', (117, 128))	('PD-1', 'Gene', (154, 158))	('rise', 'PosReg', (97, 101))	('inhibitors', 'Var', (159, 169))	('patients', 'Species', '9606', (132, 140))	('toxicity', 'Disease', 'MESH:D064420', (43, 51))
531942	30456167	They reported a 4% complication rate of developing pneumonitis in 3284 patients who received PD-1 inhibitors and 9% developed diarrhea of any grade.	('pneumonitis', 'Disease', (51, 62))	('diarrhea', 'Phenotype', 'HP:0002014', (126, 134))	('inhibitors', 'Var', (98, 108))	('diarrhea', 'Disease', (126, 134))	('patients', 'Species', '9606', (71, 79))	('diarrhea', 'Disease', 'MESH:D003967', (126, 134))	('pneumonitis', 'Disease', 'MESH:D011014', (51, 62))	('PD-1', 'Gene', (93, 97))
532039	30018485	However, a significant decrease in variceal bleeding was noted in patients who underwent band ligation compared to patients administered beta-blockers that was attenuated when the analysis included only studies with adequate randomization and allocation concealment.	('decrease', 'NegReg', (23, 31))	('patients', 'Species', '9606', (115, 123))	('bleeding', 'Disease', 'MESH:D006470', (44, 52))	('band ligation', 'Var', (89, 102))	('bleeding', 'Disease', (44, 52))	('patients', 'Species', '9606', (66, 74))
532105	30018485	A meta-analysis showed a significant reduction in variceal rebleeding episodes and rebleeding-related mortality in patients undergoing TIPS vs endoscopic techniques; although TIPS increased the rate of post-treatment encephalopathy, the overall mortality rate remained the same for both groups.	('encephalopathy', 'Phenotype', 'HP:0001298', (217, 231))	('patients', 'Species', '9606', (115, 123))	('encephalopathy', 'Disease', (217, 231))	('reduction', 'NegReg', (37, 46))	('TIPS', 'Var', (175, 179))	('bleeding', 'Disease', 'MESH:D006470', (61, 69))	('bleeding', 'Disease', 'MESH:D006470', (85, 93))	('variceal', 'Disease', (50, 58))	('bleeding', 'Disease', (61, 69))	('encephalopathy', 'Disease', 'MESH:D001927', (217, 231))	('bleeding', 'Disease', (85, 93))	('bleeding episodes', 'Phenotype', 'HP:0001892', (61, 78))	('bleeding episode', 'Phenotype', 'HP:0001892', (61, 77))
532151	29739952	In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively.	('XPF', 'Gene', (193, 196))	('MUS81', 'Gene', '80198', (201, 206))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (79, 90))	('XPF', 'Gene', '2072', (193, 196))	('depletion', 'MPA', (113, 122))	('knockout', 'Var', (127, 135))	('protein', 'Protein', (139, 146))	('MUS81', 'Gene', (201, 206))
532162	29739952	Such changes, and epigenetic alterations, can cause rapid alterations to gene expression, which are very likely to affect clinical outcomes.	('gene expression', 'MPA', (73, 88))	('changes', 'Var', (5, 12))	('affect', 'Reg', (115, 121))	('cause', 'Reg', (46, 51))	('epigenetic alterations', 'Var', (18, 40))	('alterations', 'Reg', (58, 69))	('clinical', 'Species', '191496', (122, 130))
532185	29739952	High MUS81 protein levels were associated with worse 1-year DFS (OR = 5.00, P = 0.04) and worse OS (median 15.5 months vs. not reached, P = 0.013).	('MUS81', 'Gene', '80198', (5, 10))	('DFS', 'MPA', (60, 63))	('High', 'Var', (0, 4))	('protein', 'Protein', (11, 18))	('MUS81', 'Gene', (5, 10))
532195	29739952	Finally, to obtain mechanistic in vitro corroboration of the observations from the clinical data, we measured the oxaliplatin sensitivity of cell lines deficient in XPF, MUS81 and EME1.	('clinical', 'Species', '191496', (83, 91))	('EME1', 'Gene', (180, 184))	('XPF', 'Gene', '2072', (165, 168))	('oxaliplatin sensitivity', 'MPA', (114, 137))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (114, 125))	('MUS81', 'Gene', (170, 175))	('XPF', 'Gene', (165, 168))	('deficient', 'Var', (152, 161))	('EME1', 'Gene', '146956', (180, 184))	('MUS81', 'Gene', '80198', (170, 175))
532197	29739952	In genetically altered MUS81 and EME1 variants of the HCT116 cell line, oxaliplatin sensitivity of the parental cell line was more than twofold higher than the MUS81 knockout and EME1 haploinsufficient variants (P < 0.05), confirmed by clonogenic survival assays (Fig.	('MUS81', 'Gene', (160, 165))	('EME1', 'Gene', '146956', (33, 37))	('oxaliplatin sensitivity', 'MPA', (72, 95))	('MUS81', 'Gene', '80198', (23, 28))	('MUS81', 'Gene', '80198', (160, 165))	('HCT116', 'CellLine', 'CVCL:0291', (54, 60))	('variants', 'Var', (38, 46))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (72, 83))	('EME1', 'Gene', '146956', (179, 183))	('EME1 haploinsufficient', 'Disease', (179, 201))	('EME1 haploinsufficient', 'Disease', 'MESH:D058495', (179, 201))	('EME1', 'Gene', (33, 37))	('higher', 'PosReg', (144, 150))	('EME1', 'Gene', (179, 183))	('MUS81', 'Gene', (23, 28))
532201	29739952	When association of DNA repair gene expression with clinical endpoints was investigated, high levels of ERCC1 mRNA expression were associated with worse one-year DFS and OS.	('clinical', 'Species', '191496', (52, 60))	('associated', 'Reg', (131, 141))	('ERCC1', 'Gene', '2067', (104, 109))	('ERCC1', 'Gene', (104, 109))	('mRNA expression', 'MPA', (110, 125))	('DFS', 'Disease', (162, 165))	('high levels', 'Var', (89, 100))
532212	29739952	Our findings suggest that high levels of ERCC1 mRNA are associated with poor DFS and OS in a similar subject group.	('ERCC1', 'Gene', '2067', (41, 46))	('ERCC1', 'Gene', (41, 46))	('poor', 'Disease', (72, 76))	('associated', 'Reg', (56, 66))	('high levels', 'Var', (26, 37))
532217	29739952	Polymorphisms of ERCC1 and XPF have been reported in Chinese patients with esophageal cancer, potentially influencing clinical outcomes following platinum-based chemotherapy.	('influencing', 'Reg', (106, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('XPF', 'Gene', '2072', (27, 30))	('clinical', 'Species', '191496', (118, 126))	('ERCC1', 'Gene', '2067', (17, 22))	('ERCC1', 'Gene', (17, 22))	('platinum', 'Chemical', 'MESH:D010984', (146, 154))	('Polymorphisms', 'Var', (0, 13))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('XPF', 'Gene', (27, 30))	('esophageal cancer', 'Disease', (75, 92))
532219	29739952	The somatic sequences observed do not suggest that mutations in XPF, MUS81 and ERCC1 are common in EAC, leading us to conclude that immunodetection of XPF and MUS81 by IHC is a reasonable strategy for detecting protein levels that may impact on repair of platinum-induced DNA damage.	('XPF', 'Gene', '2072', (151, 154))	('ERCC1', 'Gene', (79, 84))	('mutations', 'Var', (51, 60))	('impact', 'Reg', (235, 241))	('ERCC1', 'Gene', '2067', (79, 84))	('XPF', 'Gene', (64, 67))	('XPF', 'Gene', (151, 154))	('MUS81', 'Gene', (69, 74))	('repair', 'MPA', (245, 251))	('MUS81', 'Gene', (159, 164))	('MUS81', 'Gene', '80198', (69, 74))	('MUS81', 'Gene', '80198', (159, 164))	('XPF', 'Gene', '2072', (64, 67))	('platinum', 'Chemical', 'MESH:D010984', (255, 263))
532270	29619059	The distribution of percentage differences between TG-43 and Monte Carlo (MC) in dose volume histogram (DVH) indices for the planning target volume (PTV) presented small median values (about 2%) for both 60Co and 192Ir, with a greater dispersion for 192Ir.	('TG', 'Chemical', '-', (51, 53))	('60Co', 'Var', (204, 208))	('192Ir', 'Var', (213, 218))	('PTV', 'Chemical', '-', (149, 152))
532359	29619059	In Figure 5A, a general TG-43 overestimation of the PTV related indices are observed for both 60Co and 192Ir.	('60Co', 'Var', (94, 98))	('TG', 'Chemical', '-', (24, 26))	('192Ir', 'Var', (103, 108))	('PTV', 'Chemical', '-', (52, 55))
532360	29619059	As shown in this figure, TG-43 overestimates dose to the healthy breast tissue, with median percentage differences from MC results of the order of 3% and 5% for 60Co and 192Ir, respectively.	('TG', 'Chemical', '-', (25, 27))	('60Co', 'Var', (161, 165))	('overestimates', 'PosReg', (31, 44))	('dose', 'MPA', (45, 49))	('192Ir', 'Var', (170, 175))
532361	29619059	Regarding the skin structures studied in this work, although the dose is considerably overestimated by TG-43 for 192Ir (Figure 2), the value of D2cc is determined from the closest source dwell position, leading to comparable median differences for 60Co and 192Ir.	('TG', 'Chemical', '-', (103, 105))	('TG-43', 'Gene', (103, 108))	('dose', 'MPA', (65, 69))	('overestimated', 'PosReg', (86, 99))	('60Co', 'Var', (248, 252))	('D2cc', 'Chemical', '-', (144, 148))	('192Ir', 'Var', (257, 262))
532362	29619059	Median percentage differences in D2cc between TG-43 and MC results are of the order of 4% and 6% for 60Co and 192Ir, respectively, and a larger dispersion is observed for 192Ir, where difference reaches up to 19%.	('192Ir', 'Var', (110, 115))	('D2cc', 'Chemical', '-', (33, 37))	('TG', 'Chemical', '-', (46, 48))	('D2cc', 'MPA', (33, 37))	('60Co', 'Var', (101, 105))
532366	29619059	Regarding the right lung, which is closer to the target, TG-43 deviations are comparable for both treatments showing a median TG-43 underestimation of D10cc on the order of 1%.	('TG', 'Chemical', '-', (57, 59))	('TG', 'Chemical', '-', (126, 128))	('underestimation', 'NegReg', (132, 147))	('D10cc', 'Var', (151, 156))
532370	29619059	For the rectum, TG-43 overestimates D2cc with median differences of about 1% and 2% for 60Co and 192Ir, respectively, demonstrating a wider dispersion for 192Ir.	('D2cc', 'Chemical', '-', (36, 40))	('60Co', 'Var', (88, 92))	('overestimates', 'PosReg', (22, 35))	('TG', 'Chemical', '-', (16, 18))	('D2cc', 'MPA', (36, 40))	('192Ir', 'Var', (97, 102))
532373	29619059	These effects were studied retrospectively in this work, through the comparison of TG-43 based dosimetry with corresponding MC results in groups of clinically equivalent plans with 60Co and 192Ir HDR sources for breast, esophageal, and cervical treatments.	('192Ir', 'Var', (190, 195))	('breast', 'Disease', (212, 218))	('TG', 'Chemical', '-', (83, 85))	('esophageal', 'Disease', (220, 230))
532385	29619059	For the skin, although dose was considerably overestimated by TG-43 for 192Ir, the indices were determined from the closest source dwell position leading to comparable differences between 60Co and 192Ir.	('overestimated', 'PosReg', (45, 58))	('60Co', 'Var', (188, 192))	('192Ir', 'Var', (197, 202))	('TG', 'Chemical', '-', (62, 64))
532386	29619059	For the right lung, which is typically closer to the target, so that the primary radiation dose component prevails, TG-43 differences were comparable for 60Co and 192Ir.	('60Co', 'Var', (154, 158))	('TG', 'Chemical', '-', (116, 118))	('192Ir', 'Var', (163, 168))
532391	29619059	For the lungs, a comparable TG43 dose underestimation was observed for 192Ir and 60Co, which is attributed to the increased contribution of the primary dose component in the low density lung tissue relative to water, assumed by the TG43 dose calculation algorithm.	('TG', 'Chemical', '-', (28, 30))	('TG43', 'Gene', (28, 32))	('192Ir', 'Var', (71, 76))	('underestimation', 'NegReg', (38, 53))	('60Co', 'Var', (81, 85))	('TG', 'Chemical', '-', (232, 234))	('water', 'Chemical', 'MESH:D014867', (210, 215))
532392	29619059	The relative importance of the scatter dose component becomes predominant at greater distance from a source for the 60Co energies (distances greater than one mean free path of about 12 cm in water).	('water', 'Chemical', 'MESH:D014867', (191, 196))	('60Co', 'Var', (116, 120))	('scatter dose', 'MPA', (31, 43))
532399	29619059	For the target, subtle differences (of the order of 2%) were observed in the evaluated DVH indices in all three patient groups for both 60Co and 192Ir, with a greater dispersion however for 192Ir.	('patient', 'Species', '9606', (112, 119))	('differences', 'Reg', (23, 34))	('60Co', 'Var', (136, 140))	('DVH indices', 'MPA', (87, 98))	('192Ir', 'Var', (145, 150))
532400	29619059	For the OARs, errors induced by the TG-43 assumptions were smaller in magnitude and/or range for 60Co relative to 192Ir treatments, with a greater dispersion within the patient groups for the latter.	('smaller', 'NegReg', (59, 66))	('TG', 'Chemical', '-', (36, 38))	('patient', 'Species', '9606', (169, 176))	('TG-43', 'Gene', (36, 41))	('60Co', 'Var', (97, 101))
532401	29619059	Owing to the higher energy of photon emissions, 60Co HDR sources are more amenable to the TG-43 assumptions in clinical treatment planning dosimetry.	('TG', 'Chemical', '-', (90, 92))	('energy', 'MPA', (20, 26))	('60Co', 'Var', (48, 52))
532402	29599931	Association between the Glutathione-S-transferase T1 null genotype and esophageal cancer susceptibility: a meta-analysis involving 11,163 subjects Glutathione-S-Transferase T1 (GSTT1) null genotype has been shown to be associated with the risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('esophageal cancer', 'Disease', (247, 264))	('associated', 'Reg', (219, 229))	('GSTT1', 'Gene', (177, 182))	('GSTT1', 'Gene', '2952', (177, 182))	('esophageal cancer', 'Disease', 'MESH:D004938', (247, 264))	('Glutathione-S-Transferase T1', 'Gene', '2952', (147, 175))	('null', 'Var', (184, 188))	('Glutathione-S-Transferase T1', 'Gene', (147, 175))	('Glutathione-S-transferase T1', 'Gene', (24, 52))	('esophageal cancer', 'Disease', (71, 88))	('Association', 'Interaction', (0, 11))	('Glutathione-S-transferase T1', 'Gene', '2952', (24, 52))
532404	29599931	The strength of correlation between GSTT1 polymorphism and the susceptibility of esophageal cancer was assessed by the crude odds ratios (ORs) with 95% confidence intervals (CIs).	('polymorphism', 'Var', (42, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('GSTT1', 'Gene', (36, 41))	('GSTT1', 'Gene', '2952', (36, 41))	('correlation', 'Interaction', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', (81, 98))
532406	29599931	In a subgroup analysis by ethnicity, GSTT1 null genotype was correlated with a significantly increased risk of esophageal cancer among Asians (OR = 1.33; 95% CI 1.12-1.58; P < 0.05), instead of Caucasians or Africans (OR = 0.91; 95% CI 0.65-1.26; P > 0.05 for Caucasians and OR = 1.32; 95% CI 0.98-1.77; P > 0.05 for Africans).	('GSTT1', 'Gene', '2952', (37, 42))	('GSTT1', 'Gene', (37, 42))	('esophageal cancer', 'Disease', (111, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('null', 'Var', (43, 47))
532407	29599931	In the analysis by histological type, GSTT1 null genotype was correlated with a significantly increased risk of esophageal squamous cell carcinoma (OR = 1.34; 95% CI 1.12-1.61; P < 0.05), particularly among Asians (OR = 1.54; 95% CI 1.30-1.82; P < 0.05), but not among Caucasians or Africans (OR = 0.87; 95% CI 0.48-1.57; P > 0.05 for Caucasians and OR = 1.32; 95% CI 0.98-1.77; P > 0.05 for Africans).	('esophageal squamous cell carcinoma', 'Disease', (112, 146))	('null genotype', 'Var', (44, 57))	('GSTT1', 'Gene', '2952', (38, 43))	('GSTT1', 'Gene', (38, 43))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (112, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('genotype', 'Var', (49, 57))
532408	29599931	In addition, there is no significant correlation between GSTT1 null genotype and the risk of esophageal adenocarcinoma (OR = 0.98; 95% CI 0.71-1.35; P > 0.05).	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (93, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (93, 118))	('GSTT1', 'Gene', (57, 62))	('GSTT1', 'Gene', '2952', (57, 62))	('null genotype', 'Var', (63, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('esophageal adenocarcinoma', 'Disease', (93, 118))
532416	29599931	GSTT1 is genetically polymorphic, and deletion polymorphism of the GSTT1 loci (null genotype) results in the loss of functional activity.	('GSTT1', 'Gene', '2952', (67, 72))	('GSTT1', 'Gene', (67, 72))	('GSTT1', 'Gene', '2952', (0, 5))	('loss', 'NegReg', (109, 113))	('GSTT1', 'Gene', (0, 5))	('functional activity', 'MPA', (117, 136))	('deletion polymorphism', 'Var', (38, 59))
532417	29599931	Several studies have found that GSTT1 null genotype is strongly associated with susceptibility to a number of cancers, such as colorectal, renal and oral cancers et al..	('null', 'Var', (38, 42))	('associated', 'Reg', (64, 74))	('cancers', 'Disease', (110, 117))	('GSTT1', 'Gene', (32, 37))	('GSTT1', 'Gene', '2952', (32, 37))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('colorectal, renal and oral cancers', 'Disease', 'MESH:D015179', (127, 161))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('susceptibility', 'Reg', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
532418	29599931	Previous studies have been published to estimate the association between GSTT1 null genotype and the risk of esophageal cancer, but the results are inconsistent.	('GSTT1', 'Gene', '2952', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('esophageal cancer', 'Disease', (109, 126))	('null genotype', 'Var', (79, 92))	('GSTT1', 'Gene', (73, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
532419	29599931	To date, several meta-analysis studies have reported the association between null GSTT1 genotype and the risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('GSTT1', 'Gene', (82, 87))	('genotype', 'Var', (88, 96))	('GSTT1', 'Gene', '2952', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal cancer', 'Disease', (113, 130))	('null', 'Var', (77, 81))
532420	29599931	Thus, to obtain a conclusive result about this association, we performed current meta-analysis that includes all recent publications to review and summarize the association between the GSTT1 polymorphism and the risk of esophageal cancer.	('esophageal cancer', 'Disease', (220, 237))	('association', 'Interaction', (161, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (220, 237))	('GSTT1', 'Gene', '2952', (185, 190))	('GSTT1', 'Gene', (185, 190))	('polymorphism', 'Var', (191, 203))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
532421	29599931	Characteristics of included studies and the distribution of GSTT1 polymorphism are summarized in Table 1 and Table 2, respectively.	('GSTT1', 'Gene', '2952', (60, 65))	('GSTT1', 'Gene', (60, 65))	('polymorphism', 'Var', (66, 78))
532422	29599931	Table 3 showed the main result of the association between GSTT1 null genotype and the risk of esophageal cancer.	('null genotype', 'Var', (64, 77))	('esophageal cancer', 'Disease', (94, 111))	('GSTT1', 'Gene', '2952', (58, 63))	('GSTT1', 'Gene', (58, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
532423	29599931	Overall, there was a significant correlation of GSTT1 null genotype with esophageal cancer risk (OR = 1.20; 95% CI 1.04-1.40; P < 0.05; Table 3 and Figure 2).	('null genotype', 'Var', (54, 67))	('esophageal cancer', 'Disease', (73, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('GSTT1', 'Gene', '2952', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('GSTT1', 'Gene', (48, 53))	('correlation', 'Interaction', (33, 44))
532424	29599931	In a subgroup analysis by ethnicity, GSTT1 null genotype was correlated with a significantly increased risk of esophageal cancer among Asians (OR = 1.33; 95% CI 1.12-1.58; P < 0.05; Table 3 and Figure 2), but not among Caucasians and Africans (OR = 0.91; 95% CI 0.65-1.26; P > 0.05 for Caucasians and OR = 1.32; 95% CI 0.98-1.77; P > 0.05 for Africans; Table 3 and Figure 2).	('GSTT1', 'Gene', '2952', (37, 42))	('GSTT1', 'Gene', (37, 42))	('esophageal cancer', 'Disease', (111, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('null', 'Var', (43, 47))
532425	29599931	In the analysis by histological type, GSTT1 null genotype were correlated with a significantly increased risk of ESCC (OR = 1.34; 95% CI 1.12-1.61; P < 0.05; Table 3 and Figure 3).	('null genotype', 'Var', (44, 57))	('GSTT1', 'Gene', (38, 43))	('ESCC', 'Disease', (113, 117))	('GSTT1', 'Gene', '2952', (38, 43))
532426	29599931	Moreover, in a subgroup analysis by ethnicity, GSTT1 null genotype was correlated with a significantly increased risk of ESCC among Asians (OR = 1.54; 95% CI 1.30-1.82; P < 0.05; Table 3 and Figure 3), but not among Caucasians and Africans (OR = 0.87; 95% CI 0.48-1.57; P > 0.05 for Caucasians and OR = 1.32; 95% CI 0.98-1.77; P > 0.05 for Africans; Table 3 and Figure 3).	('GSTT1', 'Gene', '2952', (47, 52))	('ESCC', 'Disease', (121, 125))	('null', 'Var', (53, 57))	('GSTT1', 'Gene', (47, 52))
532430	29599931	Although the results showed a significant association between GSTT1 null genotype and esophageal cancer risk, the single Chinese Han population limited the power of the statistical analysis.	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('null genotype', 'Var', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('GSTT1', 'Gene', (62, 67))	('GSTT1', 'Gene', '2952', (62, 67))
532431	29599931	Although the results showed a significant association between GSTT1 null genotype and esophageal cancer risk, the single Asian population limited the power of the statistical analysis.	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('null genotype', 'Var', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('GSTT1', 'Gene', (62, 67))	('GSTT1', 'Gene', '2952', (62, 67))
532433	29599931	However, meta-analysis of adjusted ORs showed a significant association between GSTT1 null genotype and esophageal cancer risk.	('GSTT1', 'Gene', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('null genotype', 'Var', (86, 99))	('GSTT1', 'Gene', '2952', (80, 85))
532434	29599931	Thus we conducted a comprehensive meta-analysis, to investigate not only the strength of association between GSTT1 null genotype and the risk of esophageal cancer, but also the association of GSTT1 null genotype with the risk of different histological types.	('GSTT1', 'Gene', (109, 114))	('GSTT1', 'Gene', '2952', (109, 114))	('GSTT1', 'Gene', (192, 197))	('esophageal cancer', 'Disease', (145, 162))	('GSTT1', 'Gene', '2952', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('null genotype', 'Var', (115, 128))
532435	29599931	This meta-analysis, including 30 case-control studies with 4482 cases and 6681 controls, identified the association between GSTT1 null genotype and esophageal cancer risk.	('null genotype', 'Var', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', (148, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('GSTT1', 'Gene', '2952', (124, 129))	('GSTT1', 'Gene', (124, 129))
532437	29599931	In a subgroup analysis by ethnicity, GSTT1 null genotype was correlated with a significantly increased risk of esophageal cancer among Asians.	('GSTT1', 'Gene', '2952', (37, 42))	('null genotype', 'Var', (43, 56))	('GSTT1', 'Gene', (37, 42))	('esophageal cancer', 'Disease', (111, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
532438	29599931	In the analysis by histological type, GSTT1 null genotype was correlated with a significantly increased risk of ESCC, particularly in Asians.	('GSTT1', 'Gene', (38, 43))	('null genotype', 'Var', (44, 57))	('ESCC', 'Disease', (112, 116))	('GSTT1', 'Gene', '2952', (38, 43))
532442	29599931	GSTT1 is genetically polymorphic, and GSTT1 null genotype results in the loss of functional activity.	('loss', 'NegReg', (73, 77))	('functional activity', 'MPA', (81, 100))	('GSTT1', 'Gene', '2952', (0, 5))	('GSTT1', 'Gene', (0, 5))	('GSTT1', 'Gene', '2952', (38, 43))	('GSTT1', 'Gene', (38, 43))	('null', 'Var', (44, 48))
532445	29599931	GSTT1 null genotype was correlated with a significantly increased risk of ESCC among Asians, but not among Caucasians and Africans.	('ESCC', 'Disease', (74, 78))	('GSTT1', 'Gene', '2952', (0, 5))	('null', 'Var', (6, 10))	('GSTT1', 'Gene', (0, 5))
532455	29599931	In addition, GSTT1 null genotype was correlated with a significantly increased risk of ESCC, particularly among Asians.	('GSTT1', 'Gene', (13, 18))	('ESCC', 'Disease', (87, 91))	('null genotype', 'Var', (19, 32))	('GSTT1', 'Gene', '2952', (13, 18))
532456	29599931	Pubmed, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases (the search was updated in March 31, 2017) were searched using the following terms: 'glutathione S-transferase T1' or 'GSTT1', 'polymorphism' or 'variant', and 'esophageal' or 'esophagus', and 'cancer' or 'carcinoma' or 'tumor' or 'malignancy'.	('GSTT1', 'Gene', '2952', (204, 209))	("'esophagus'", 'Disease', (261, 272))	("'malignancy'", 'Disease', (316, 328))	("'tumor", 'Disease', (305, 311))	('esophageal', 'Disease', 'MESH:D004941', (246, 256))	("'cancer' or 'carcinoma'", 'Disease', (278, 301))	('glutathione S-transferase T1', 'Gene', '2952', (170, 198))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	("'cancer' or 'carcinoma'", 'Disease', 'MESH:D009369', (278, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	("'polymorphism'", 'Var', (212, 226))	("'malignancy'", 'Disease', 'MESH:D009369', (316, 328))	('glutathione S-transferase T1', 'Gene', (170, 198))	('GSTT1', 'Gene', (204, 209))	('esophageal', 'Disease', (246, 256))	("'tumor", 'Disease', 'MESH:D009369', (305, 311))
532458	29599931	The strength of correlation between GSTT1 null genotype and the susceptibility of esophageal cancer was assessed by the crude odds ratios (ORs) with 95% confidence intervals (CIs).	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('GSTT1', 'Gene', (36, 41))	('GSTT1', 'Gene', '2952', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('null genotype', 'Var', (42, 55))	('esophageal cancer', 'Disease', (82, 99))
532459	29599931	Glutathione-S-Transferase T1 GSTT1 China National Knowledge Infrastructure CNKI odds ratios ORs confidence intervals CIs esophageal squamous cell carcinoma ESCC esophageal adenocarcinoma EADC	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('GSTT1', 'Gene', '2952', (29, 34))	('GSTT1', 'Gene', (29, 34))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (121, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (161, 186))	('EADC', 'Phenotype', 'HP:0011459', (187, 191))	('Glutathione-S-Transferase T1', 'Gene', '2952', (0, 28))	('esophageal squamous cell carcinoma', 'Disease', (121, 155))	('esophageal adenocarcinoma', 'Disease', (161, 186))	('Glutathione-S-Transferase T1', 'Gene', (0, 28))	('CIs', 'Var', (117, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (161, 186))
532467	29069758	Our preliminary studies indicated that a small population of octamer-binding transcription factor 4 (OCT4)-positive cancer cells was present in ECC tissues and that ECC with a high percentage of OCT4-positive cells displayed rapid progression, high incidence of lymph node metastasis, and short tumor-free survival and overall survival.	('lymph node metastasis', 'CPA', (262, 283))	('ECC', 'Phenotype', 'HP:0011459', (144, 147))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('ECC', 'Phenotype', 'HP:0011459', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('OCT4-positive', 'Var', (195, 208))	('tumor', 'Disease', (295, 300))
532471	29069758	For ECC tissues, the OCT4-positive rate was approximately 26%, and OCT4 inhibited apoptosis of cancer cells by increasing survivin expression.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('ECC', 'Phenotype', 'HP:0011459', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('expression', 'MPA', (131, 141))	('inhibited', 'NegReg', (72, 81))	('increasing', 'PosReg', (111, 121))	('OCT4', 'Var', (67, 71))	('survivin', 'Protein', (122, 130))
532485	29069758	Both Eca109 cells and TE1 cells were OCT4 positive, but OCT4 expression was significantly stronger in Eca109 cells than in TE1 cells; HET-1A cells did not express OCT4 (Figure 1A).	('OCT4', 'Gene', (56, 60))	('HET-1A', 'CellLine', 'CVCL:3702', (134, 140))	('Eca109', 'Var', (102, 108))	('stronger', 'PosReg', (90, 98))	('expression', 'MPA', (61, 71))
532486	29069758	The Eca109-shOCT4 cells which were transfected with pGen-shOCT4 to knock down OCT4 expression had a significantly decreased invasion ability compared with Eca109 parental cells.	('pGen-shOCT4', 'Chemical', '-', (52, 63))	('knock down', 'Var', (67, 77))	('invasion ability', 'CPA', (124, 140))	('OCT4', 'Gene', (78, 82))	('decreased', 'NegReg', (114, 123))	('expression', 'MPA', (83, 93))
532487	29069758	Both pGen-shOCT4 and pGen-shCtrl vectors possessed an EGFP reporter gene, and we observed phenotypic changes in Eca109-shOCT4 cells which appeared to be more clustered adherent cells with intercellular pseudopodium contact (Figure 2A, left panel).	('pGen-shCtrl', 'Chemical', '-', (21, 32))	('Eca109-shOCT4', 'Var', (112, 125))	('EGFP reporter gene', 'Gene', (54, 72))	('pGen-shOCT4', 'Chemical', '-', (5, 16))
532488	29069758	The results showed that E-cadherin expression was lower in Eca109 cells than in TE1 cells and that N-cadherin and vimentin expression was lower in TE1 cells than in Eca109 cells.	('vimentin', 'Gene', '7431', (114, 122))	('N-cadherin', 'Gene', (99, 109))	('lower', 'NegReg', (50, 55))	('expression', 'MPA', (123, 133))	('vimentin', 'Gene', (114, 122))	('N-cadherin', 'Gene', '1000', (99, 109))	('lower', 'NegReg', (138, 143))	('expression', 'MPA', (35, 45))	('E-cadherin', 'Gene', (24, 34))	('Eca109', 'Var', (59, 65))	('E-cadherin', 'Gene', '999', (24, 34))
532489	29069758	Moreover, E-cadherin expression level was significantly increased in Eca109-shOCT4 cells compared with Eca109 cells, and N-cadherin and vimentin expression was significantly decreased in Eca109-shOCT4 cells compared with Eca109 cells.	('E-cadherin', 'Gene', '999', (10, 20))	('decreased', 'NegReg', (174, 183))	('Eca109-shOCT4', 'Var', (69, 82))	('increased', 'PosReg', (56, 65))	('N-cadherin', 'Gene', (121, 131))	('expression', 'MPA', (145, 155))	('Eca109-shOCT4', 'Var', (187, 200))	('N-cadherin', 'Gene', '1000', (121, 131))	('vimentin', 'Gene', '7431', (136, 144))	('expression level', 'MPA', (21, 37))	('E-cadherin', 'Gene', (10, 20))	('vimentin', 'Gene', (136, 144))
532490	29069758	E-cadherin expression level was decreased and N-cadherin and vimentin expression was increased in TE1-OCT4 cells compared with TE1 cells (Figure 2B).	('N-cadherin', 'Gene', '1000', (46, 56))	('E-cadherin', 'Gene', '999', (0, 10))	('expression', 'MPA', (70, 80))	('vimentin', 'Gene', '7431', (61, 69))	('E-cadherin', 'Gene', (0, 10))	('increased', 'PosReg', (85, 94))	('TE1-OCT4', 'Var', (98, 106))	('vimentin', 'Gene', (61, 69))	('N-cadherin', 'Gene', (46, 56))	('decreased', 'NegReg', (32, 41))
532491	29069758	After OCT4 expression was knocked down with a shRNA vector, we observed a decreased level of VEGF-C and p-VEGFR-3 in Eca109-shOCT4 cells but no significant change in p-VEGFR-1 or p-VEGFR-2 levels.	('VEGFR-2', 'Gene', '3791', (181, 188))	('VEGFR-1', 'Gene', (168, 175))	('knocked', 'Var', (26, 33))	('VEGFR-2', 'Gene', (181, 188))	('VEGF-C', 'MPA', (93, 99))	('decreased', 'NegReg', (74, 83))	('VEGFR-1', 'Gene', '2321', (168, 175))	('p-VEGFR-3', 'Var', (104, 113))	('OCT4', 'Gene', (6, 10))
532498	29069758	After knockdown of OCT expression, the amplified band in the anti-OCT4 antibody immunoprecipitated DNA sample was decreased markedly (Figure 4C).	('OCT', 'Gene', '5362', (66, 69))	('amplified band', 'MPA', (39, 53))	('OCT', 'Gene', (19, 22))	('OCT', 'Gene', '5362', (19, 22))	('decreased', 'NegReg', (114, 123))	('knockdown', 'Var', (6, 15))	('OCT', 'Gene', (66, 69))
532500	29069758	The results showed that the number and weight of intraperitoneal implantation metastatic tumors were significantly decreased in Eca109-shOCT4 cells than in Eca109 parental cells (Figure 5A).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('decreased', 'NegReg', (115, 124))	('Eca109-shOCT4', 'Var', (128, 141))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
532503	29069758	The results demonstrated that tumors weighed significantly more in the Ad5-OCT4 group than in the control group (Figure 5B).	('tumors', 'Disease', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('Ad5-OCT4', 'Var', (71, 79))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('more', 'PosReg', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
532505	29069758	The results showed that Ad5-OCT4-mediated OCT4 overexpression significantly increased the positive levels of VEGF-C and p-VEGFR-3, and decreased the expression level of and E-cadherin, with no significant change in VEGFR-3 expression (Figure 5C), Supplementary Figures 1 and 2 To further investigate the regulation of OCT4 on the activity of VEGF-C/VEGFR-3 signaling pathway and the effect on the biological behaviors of ECC cells, we determined the expression levels of OCT4 and VEGF-C with immunohistochemistry in the primary tumor tissues from 67 cases of surgical ECC specimens.	('tumor', 'Disease', (528, 533))	('E-cadherin', 'Gene', (173, 183))	('E-cadherin', 'Gene', '999', (173, 183))	('increased', 'PosReg', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (528, 533))	('expression level', 'MPA', (149, 165))	('ECC', 'Phenotype', 'HP:0011459', (421, 424))	('ECC', 'Phenotype', 'HP:0011459', (568, 571))	('tumor', 'Disease', 'MESH:D009369', (528, 533))	('positive levels', 'MPA', (90, 105))	('decreased', 'NegReg', (135, 144))	('Ad5-OCT4-mediated', 'Var', (24, 41))
532528	29069758	For malignant tumors, such as breast cancer, gastric cancer, prostate cancer, pancreatic cancer, cervical cancer, non-small cell lung cancer, and throat cancer, high VEGF-C expression promotes lymphatic invasion and lymph node metastasis of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cervical cancer', 'Disease', (97, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('VEGF-C', 'Gene', (166, 172))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (106, 112))	('pancreatic cancer', 'Disease', (78, 95))	('malignant tumors', 'Disease', 'MESH:D018198', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('non-small cell lung cancer', 'Disease', (114, 140))	('cancer', 'Disease', (134, 140))	('lymphatic invasion', 'CPA', (193, 211))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('malignant tumors', 'Disease', (4, 20))	('gastric cancer', 'Disease', (45, 59))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('cancer', 'Disease', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (37, 43))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('breast cancer', 'Disease', (30, 43))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (114, 140))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('prostate cancer', 'Disease', 'MESH:D011471', (61, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (45, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))	('promotes', 'PosReg', (184, 192))	('prostate cancer', 'Disease', (61, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (118, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('high', 'Var', (161, 165))	('cancer', 'Disease', (241, 247))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (114, 140))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('cervical cancer', 'Disease', 'MESH:D002583', (97, 112))
532529	29069758	Moreover, high VEGF-C expression down-regulates the expression of epithelial phenotypic markers of cancer cells and up-regulates the expression of mesenchymal phenotypic markers, thus presumably promoting cancer development by inducing EMT in cancer cells.	('inducing', 'PosReg', (227, 235))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('expression', 'Var', (22, 32))	('EMT', 'CPA', (236, 239))	('VEGF-C', 'Gene', (15, 21))	('promoting', 'PosReg', (195, 204))	('up-regulates', 'PosReg', (116, 128))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('mesenchymal', 'CPA', (147, 158))	('down-regulates', 'NegReg', (33, 47))	('expression', 'MPA', (133, 143))	('cancer', 'Disease', (243, 249))	('expression', 'MPA', (52, 62))	('cancer', 'Disease', (99, 105))	('high', 'Var', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
532534	29069758	We noted that OCT4 overexpression enhanced ECC invasion and metastasis ability, whereas OCT4 knockdown in ECC cells significantly inhibited VEGF-C expression and reduced p-VEGFR-3 level in cancer cells, thereby inhibiting tumor metastasis.	('knockdown', 'Var', (93, 102))	('ECC', 'Phenotype', 'HP:0011459', (43, 46))	('ECC', 'Phenotype', 'HP:0011459', (106, 109))	('tumor metastasis', 'Disease', (222, 238))	('enhanced', 'PosReg', (34, 42))	('expression', 'MPA', (147, 157))	('reduced', 'NegReg', (162, 169))	('ECC invasion', 'CPA', (43, 55))	('OCT4', 'Gene', (88, 92))	('VEGF-C', 'Gene', (140, 146))	('p-VEGFR-3 level', 'MPA', (170, 185))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('inhibiting', 'NegReg', (211, 221))	('inhibited', 'NegReg', (130, 139))	('metastasis ability', 'CPA', (60, 78))	('cancer', 'Disease', (189, 195))	('tumor metastasis', 'Disease', 'MESH:D009362', (222, 238))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))
532535	29069758	ECC nude mouse xenograft experiments also showed that OCT4 overexpression promoted tumor growth and that OCT4 knockdown inhibited intraperitoneal implantation metastasis of cancer cells.	('knockdown', 'Var', (110, 119))	('promoted', 'PosReg', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', (173, 179))	('tumor', 'Disease', (83, 88))	('ECC', 'Phenotype', 'HP:0011459', (0, 3))	('inhibited', 'NegReg', (120, 129))	('mouse', 'Species', '10090', (9, 14))	('OCT4', 'Gene', (105, 109))	('OCT4', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
532549	29069758	ECC cells were seeded in 24-well plates at a density of 1 x 105 cells in each well and cultured for 24 h. The Eca109 cells were transfected with pGen-shOCT4 and pGen-shCtrl at a final concentration of 20 mug/well.	('pGen-shOCT4', 'Var', (145, 156))	('pGen-shOCT4', 'Chemical', '-', (145, 156))	('ECC', 'Phenotype', 'HP:0011459', (0, 3))	('pGen-shCtrl', 'Chemical', '-', (161, 172))	('pGen-shCtrl', 'Gene', (161, 172))	('Eca109', 'Gene', (110, 116))
532550	29069758	The TE1 cells were infected with adenoviruses Ad5-OCT4 and Ad5-EGFP at a viral multiplicity of infection (MOI) of 100 pfu/cell.	('infection', 'Disease', 'MESH:D007239', (95, 104))	('adenovirus', 'Species', '28285', (33, 43))	('Ad5-EGFP', 'Var', (59, 67))	('Ad5-OCT4', 'Var', (46, 54))	('infection', 'Disease', (95, 104))
532566	29069758	Three mice with the largest tumors and two mice with the smallest tumors were excluded, and the remaining 15 mice were randomly divided into 3 groups (Ad5-OCT4 group, Ad5-EGFP group, blank control group).	('mice', 'Species', '10090', (43, 47))	('smallest tumors', 'Disease', 'MESH:D009369', (57, 72))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Ad5-OCT4', 'Var', (151, 159))	('tumors', 'Disease', (28, 34))	('Ad5-EGFP', 'Var', (167, 175))	('mice', 'Species', '10090', (6, 10))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('smallest tumors', 'Disease', (57, 72))	('mice', 'Species', '10090', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
532567	29069758	The Ad5-OCT4 and Ad5-EGFP groups received multi-point intratumor injections with the corresponding adenovirus, at 1 x 108 pfu/100 mul, once a day for 10 days; the control group was injected with saline synchronously at the same volume.	('tumor', 'Disease', (59, 64))	('Ad5-OCT4', 'Var', (4, 12))	('Ad5-EGFP', 'Var', (17, 25))	('adenovirus', 'Species', '28285', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('saline', 'Chemical', 'MESH:D012965', (195, 201))
532576	29069758	According to the TNM staging criteria of malignant tumors developed by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC), 2 patients were in stage 0 (TisN0M0), 6 in stage I (T1N0M0), 18 in stage II (10 in IIA: T2N0M0; 8 in IIB: T1-2N1M0), 29 in stage III (T3N1M0, T4N0-1M0), and 12 in stage IV (IVA: T1-4N0-1M1a; IVB: T1-4N0-1M1b).	('IVA', 'Disease', 'MESH:C538167', (341, 344))	('patients', 'Species', '9606', (170, 178))	('TNM', 'Gene', '10178', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('T3N1M0', 'Var', (302, 308))	('malignant tumors', 'Disease', (41, 57))	('TNM', 'Gene', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('IVA', 'Disease', (341, 344))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))	('T4N0-1M0', 'Var', (310, 318))	('malignant tumors', 'Disease', 'MESH:D018198', (41, 57))	('Cancer', 'Phenotype', 'HP:0002664', (153, 159))
532613	27686535	However, dysregulation in the balance of ROS homeostasis is known to impact keratinocyte differentiation.	('keratinocyte differentiation', 'CPA', (76, 104))	('ROS', 'Chemical', 'MESH:D017382', (41, 44))	('balance', 'MPA', (30, 37))	('impact', 'Reg', (69, 75))	('dysregulation', 'Var', (9, 22))
532615	27686535	Previous studies have shown that ROS signaling induces keratinocyte differentiation through the protein kinase C/activator protein-1 (PKC/AP-1) pathway (Rutberg et al., 1996; Bose et al., 2012).	('induces', 'Reg', (47, 54))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))	('keratinocyte differentiation', 'CPA', (55, 83))	('AP-1', 'Gene', '3727', (138, 142))	('AP-1', 'Gene', (138, 142))	('ROS', 'Var', (33, 36))	('protein kinase C/activator', 'Pathway', (96, 122))
532628	27686535	Mutations in the related gene encoding Cu/Zn superoxide dismutase (SOD1) can affect an inherited form of ALS.	('Cu/Zn superoxide dismutase', 'Gene', '6647', (39, 65))	('ALS', 'Gene', '6647', (105, 108))	('Cu/Zn superoxide dismutase', 'Gene', (39, 65))	('affect', 'Reg', (77, 83))	('Mutations', 'Var', (0, 9))	('ALS', 'Gene', (105, 108))	('SOD1', 'Gene', (67, 71))	('SOD1', 'Gene', '6647', (67, 71))	('ALS', 'Phenotype', 'HP:0007354', (105, 108))
532629	27686535	Note that more than 150 types of SOD1 gene mutations have been described, while most of them are transmitted in an autosomal dominant pattern (Battistini et al., 2005).	('mutations', 'Var', (43, 52))	('SOD1', 'Gene', (33, 37))	('SOD1', 'Gene', '6647', (33, 37))
532630	27686535	The exact mechanism underlying SIRT3-mediated protection against mutant SOD1-induced toxicity remains elusive; however, the co-presence of SIRT3 and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) protects against mitochondrial fragmentation and neuronal cell death (Kong et al., 2010; Kincaid & Bossy-Wetzel, 2013).	('GC', 'Phenotype', 'HP:0012126', (219, 221))	('SOD1', 'Gene', (72, 76))	('toxicity', 'Disease', 'MESH:D064420', (85, 93))	('toxicity', 'Disease', (85, 93))	('mitochondrial fragmentation', 'CPA', (247, 274))	('mutant', 'Var', (65, 71))	('SOD1', 'Gene', '6647', (72, 76))	('neuronal cell death', 'Disease', (279, 298))	('peroxisome proliferator-activated receptor-gamma coactivator-1alpha', 'Gene', '10891', (149, 216))	('neuronal cell death', 'Disease', 'MESH:D009410', (279, 298))
532639	27686535	In addition, the antihypertrophic effects of exogenous NAD+ are also mediated through the activation of SIRT3 instead of SIRT1.	('SIRT1', 'Gene', (121, 126))	('SIRT3', 'Enzyme', (104, 109))	('activation', 'PosReg', (90, 100))	('antihypertrophic effects', 'MPA', (17, 41))	('SIRT1', 'Gene', '23411', (121, 126))	('NAD+', 'Chemical', 'MESH:D009243', (55, 59))	('exogenous', 'Var', (45, 54))
532647	27686535	Mutation of the mitochondrial genome may cause some inherited diseases; remarkable progress has been made from researches in mtDNA mutations with respect to aging and cancer (Taylor & Turnbull, 2005).	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('inherited diseases', 'Disease', (52, 70))	('cancer', 'Disease', (167, 173))	('Mutation', 'Var', (0, 8))	('inherited diseases', 'Disease', 'MESH:D030342', (52, 70))	('cause', 'Reg', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
532656	27686535	Biochemical analysis of HCT116 cells overexpressing a deacetylation mutant demonstrates an overall oxidized intracellular environment compared to overexpression of the wild-type SIRT3 gene, as monitored by increases in intracellular superoxide and oxidized glutathione levels (Wang et al., 2007).	('HCT116', 'CellLine', 'CVCL:0291', (24, 30))	('glutathione', 'Chemical', 'MESH:D005978', (257, 268))	('increases', 'PosReg', (206, 215))	('oxidized glutathione levels', 'MPA', (248, 275))	('oxidized intracellular environment', 'MPA', (99, 133))	('intracellular superoxide', 'MPA', (219, 243))	('superoxide', 'Chemical', 'MESH:D013481', (233, 243))	('deacetylation mutant', 'Var', (54, 74))
532663	27686535	However, SIRT3 is capable of boosting the level of ATP in mitochondria due to the acetylation process.	('boosting', 'PosReg', (29, 37))	('level of ATP in mitochondria', 'MPA', (42, 70))	('ATP', 'Chemical', 'MESH:D000255', (51, 54))	('SIRT3', 'Var', (9, 14))	('acetylation process', 'MPA', (82, 101))
532672	27686535	It was reported that FL SIRT3 may also be present in the nucleus and is capable of activating histone deacetylase (HDAC) against acetylated histone H3 Lys 9 (H3K9ac) and H4K16ac in vivo (Scher et al., 2007; Nakamura et al., 2008; Sundaresan et al., 2008).	('H4K16ac', 'Var', (170, 177))	('HDAC', 'Gene', (115, 119))	('histone deacetylase', 'Gene', '9734', (94, 113))	('HDAC', 'Gene', '9734', (115, 119))	('activating', 'PosReg', (83, 93))	('Lys', 'Chemical', 'MESH:D008239', (151, 154))	('histone deacetylase', 'Gene', (94, 113))
532674	27686535	In HIB1B brown adipocytes, an imposed expression of SIRT3 augments the expression of PGC-1alpha, uncoupling protein 1 (UCP1), and a series of mitochondria-related genes in the presence of both ADP-ribosyltransferase and the deacetylase activity of SIRT3 (Shi et al., 2005).	('expression', 'MPA', (71, 81))	('AD', 'Disease', 'MESH:D000544', (193, 195))	('uncoupling protein 1', 'Gene', (97, 117))	('AD', 'Disease', (193, 195))	('UCP1', 'Gene', (119, 123))	('GC', 'Phenotype', 'HP:0012126', (86, 88))	('SIRT3', 'Gene', (52, 57))	('PGC-1alpha', 'Gene', (85, 95))	('HIB1B', 'Gene', (3, 8))	('expression', 'Var', (38, 48))	('uncoupling protein 1', 'Gene', '7350', (97, 117))	('augments', 'PosReg', (58, 66))	('UCP1', 'Gene', '7350', (119, 123))
532675	27686535	A SIRT3 deacetylase mutant has a synergistic effect with PGC-1alpha to activate UCP1 expression in the mitochondrial inner membrane to mediate the process of adaptive thermogenesis.	('activate', 'PosReg', (71, 79))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('expression in', 'MPA', (85, 98))	('UCP1', 'Gene', '7350', (80, 84))	('UCP1', 'Gene', (80, 84))	('mutant', 'Var', (20, 26))
532680	27686535	LCAD can also be deacetylated under fasting conditions by SIRT3 as hyperacetylation of LCAD reduces its enzymatic activity (Allison & Milner, 2007; Hirschey et al., 2010).	('deacetylate', 'Chemical', '-', (17, 28))	('LCAD', 'Gene', '33', (87, 91))	('LCAD', 'Gene', '33', (0, 4))	('LCAD', 'Gene', (87, 91))	('enzymatic activity', 'MPA', (104, 122))	('hyperacetylation', 'Var', (67, 83))	('reduces', 'NegReg', (92, 99))	('LCAD', 'Gene', (0, 4))
532685	27686535	Thus, SOD-mediated ROS reduction is synergistically increased by SIRT3 co-expression, although it can be negated by SIRT3 depletion.	('SIRT3', 'Gene', (65, 70))	('ROS', 'Protein', (19, 22))	('increased', 'PosReg', (52, 61))	('co-expression', 'Var', (71, 84))	('SOD', 'Gene', '6647', (6, 9))	('reduction', 'NegReg', (23, 32))	('SOD', 'Gene', (6, 9))	('ROS', 'Chemical', 'MESH:D017382', (19, 22))
532687	27686535	However, deletion of SIRT3 removes the requirement for the loss of a tumor suppressor for transformation of primary cells with an oncogene (Kim et al., 2010).	('SIRT3', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('deletion', 'Var', (9, 17))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
532688	27686535	SIRT3 KO mouse embryonic fibroblast (SIRT3-/- MEF) demonstrates genomic instability as well as aberrant mitochondrial physiology.	('aberrant mitochondrial physiology', 'Phenotype', 'HP:0003287', (95, 128))	('MEF', 'Gene', (46, 49))	('MEF', 'Gene', '56501', (46, 49))	('mitochondrial physiology', 'MPA', (104, 128))	('mouse', 'Species', '10090', (9, 14))	('genomic instability', 'CPA', (64, 83))	('aberrant', 'Var', (95, 103))
532705	27686535	Furthermore, cells are susceptible to Tam and apoptotic cell death when SIRT3 expression is knocked down in MTR-3 cells.	('apoptotic cell death', 'CPA', (46, 66))	('knocked down', 'Var', (92, 104))	('SIRT3', 'Gene', (72, 77))	('MTR-3', 'Gene', (108, 113))	('susceptible', 'Reg', (23, 34))	('Tam', 'Chemical', 'MESH:D013629', (38, 41))	('MTR-3', 'Gene', '118460', (108, 113))
532715	27686535	The SIRT3 mechanism should thus be related to ROS levels in the mitochondria (Chen et al., 2011; Park et al., 2011; Schumacker, 2011); however, low SIRT3 expression was reported to act as a poor independent prognostic factor of survival in patients with postsurgical hepatocellular carcinoma (Zhang et al., 2012).	('SIRT3', 'Gene', (148, 153))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (267, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('patients', 'Species', '9606', (240, 248))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (267, 291))	('ROS', 'Chemical', 'MESH:D017382', (46, 49))	('low', 'Var', (144, 147))	('hepatocellular carcinoma', 'Disease', (267, 291))	('expression', 'MPA', (154, 164))
532720	27686535	Accordingly, high expression of SIRT3 was related to a shorter survival time in patients with esophageal cancer, which might be due to the suppression of apoptosis signals that prolonged the survival rate of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('patients', 'Species', '9606', (80, 88))	('survival', 'MPA', (191, 199))	('esophageal cancer', 'Disease', (94, 111))	('high expression', 'Var', (13, 28))	('shorter', 'NegReg', (55, 62))	('apoptosis', 'MPA', (154, 163))	('esophageal cancer', 'Disease', (208, 225))	('suppression', 'NegReg', (139, 150))	('SIRT3', 'Gene', (32, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('prolonged', 'PosReg', (177, 186))	('survival', 'MPA', (63, 71))
532736	27686535	However, it is unclear whether the aberrant expression of SIRT3 in patients with GC is a causal factor, a subsequent effect of tumor progression, or if other mutations play a role in GC (Wang et al., 2015).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('SIRT3', 'Gene', (58, 63))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Disease', (127, 132))	('aberrant', 'Var', (35, 43))	('GC', 'Phenotype', 'HP:0012126', (183, 185))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('GC', 'Phenotype', 'HP:0012126', (81, 83))
532754	27686535	Apolipoprotein E4 (APOE4) is a major genetic factor in late-onset AD, and SIRT3 is known to be downregulated in the frontal cortices of human brain APOE4 carriers compared to noncarriers.	('Apolipoprotein E4', 'Gene', '348', (0, 17))	('APOE4', 'Gene', '348', (19, 24))	('human', 'Species', '9606', (136, 141))	('downregulated', 'NegReg', (95, 108))	('APOE4', 'Gene', (148, 153))	('SIRT3', 'Gene', (74, 79))	('Apolipoprotein E4', 'Gene', (0, 17))	('APOE4', 'Gene', (19, 24))	('APOE4', 'Gene', '348', (148, 153))	('carriers', 'Var', (154, 162))	('AD', 'Disease', 'MESH:D000544', (66, 68))	('AD', 'Disease', (66, 68))
532759	27686535	HD is caused by abnormal polyglutamine expression in the Huntingtin (Htt) protein (Naia & Rego, 2015).	('polyglutamine', 'Chemical', 'MESH:C097188', (25, 38))	('Huntingtin', 'Gene', (57, 67))	('Htt', 'Gene', (69, 72))	('Htt', 'Gene', '3064', (69, 72))	('polyglutamine', 'Var', (25, 38))	('caused by', 'Reg', (6, 15))	('HD', 'Disease', 'MESH:D006816', (0, 2))	('Huntingtin', 'Gene', '3064', (57, 67))
532761	27686535	Nonetheless, as energy-demanding neurons are particularly susceptible to energy deficits and oxidative stress, mitochondrial dysfunction might be a mediating factor for the mutant Htt-induced neurotoxicity (Fu et al., 2012).	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (111, 136))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (111, 136))	('energy deficits', 'Disease', (73, 88))	('energy deficits', 'Disease', 'MESH:D011502', (73, 88))	('mutant', 'Var', (173, 179))	('neurotoxicity', 'Disease', 'MESH:D020258', (192, 205))	('mitochondrial dysfunction', 'Disease', (111, 136))	('Htt', 'Gene', '3064', (180, 183))	('oxidative stress', 'Phenotype', 'HP:0025464', (93, 109))	('Htt', 'Gene', (180, 183))	('neurotoxicity', 'Disease', (192, 205))
532762	27686535	It was previously reported that cells expressing mutant Htt displayed reduced SIRT3 levels, and mutant Htt-induced depletion of SIRT3 protected cells from mutant Htt.	('depletion', 'MPA', (115, 124))	('reduced', 'NegReg', (70, 77))	('mutant', 'Var', (96, 102))	('mutant', 'Var', (49, 55))	('mutant', 'Var', (155, 161))	('Htt', 'Gene', '3064', (103, 106))	('Htt', 'Gene', '3064', (56, 59))	('Htt', 'Gene', '3064', (162, 165))	('Htt', 'Gene', (103, 106))	('Htt', 'Gene', (56, 59))	('SIRT3 levels', 'MPA', (78, 90))	('Htt', 'Gene', (162, 165))	('SIRT3', 'MPA', (128, 133))
532765	27686535	On the other hand, a knockdown significantly inhibited viniferin-mediated AMP-activated kinase activation with diminished neuroprotective effects (Fu et al., 2012).	('viniferin', 'Chemical', '-', (55, 64))	('viniferin-mediated', 'Enzyme', (55, 73))	('inhibited', 'NegReg', (45, 54))	('knockdown', 'Var', (21, 30))	('diminished', 'NegReg', (111, 121))	('neuroprotective effects', 'CPA', (122, 145))
532773	27686535	Calorie restriction induces SIRT3, which prevents or delays age-related hearing loss by protecting cochlear neurons from oxidative damage (Someya et al., 2010; Bell & Guarente, 2011).	('hearing loss', 'Disease', (72, 84))	('protecting', 'Reg', (88, 98))	('SIRT3', 'Gene', (28, 33))	('oxidative damage', 'MPA', (121, 137))	('hearing loss', 'Disease', 'MESH:D034381', (72, 84))	('Calorie restriction', 'Var', (0, 19))	('delays', 'NegReg', (53, 59))	('hearing loss', 'Phenotype', 'HP:0000365', (72, 84))
532830	32175692	This study, for the first time, demonstrates that BRD4 is a critical regulator of YAP1 through direct occupancy on its promoter, while JQ1 decreases YAP1 expression and its transcription output (CTGF, SOX9, and Cyr61), suppresses CSC traits, and decreases ALDH1+ cells, indicating targeting YAP1 can be achieved through BET inhibition, which provides a new therapeutic strategy for EC.	('BRD4', 'Gene', (50, 54))	('JQ1', 'Var', (135, 138))	('ALDH1', 'Gene', '216', (256, 261))	('Cyr61', 'Gene', (211, 216))	('transcription output', 'MPA', (173, 193))	('suppresses', 'NegReg', (219, 229))	('CSC', 'MPA', (230, 233))	('decreases', 'NegReg', (139, 148))	('BET', 'Chemical', '-', (320, 323))	('BRD4', 'Gene', '23476', (50, 54))	('Cyr61', 'Gene', '3491', (211, 216))	('YAP1', 'Gene', (149, 153))	('ALDH1', 'Gene', (256, 261))	('decreases', 'NegReg', (246, 255))	('CTGF', 'Gene', '1490', (195, 199))	('CTGF', 'Gene', (195, 199))	('expression', 'MPA', (154, 164))
532834	32175692	High YAP1 nuclear expression correlates with poor patient outcome in EAC and some other cancers (Kang et al., 2011; Xu et al., 2009).	('EAC', 'Disease', (69, 72))	('High', 'Var', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('EAC', 'Phenotype', 'HP:0011459', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('YAP1', 'Gene', (5, 9))	('patient', 'Species', '9606', (50, 57))
532835	32175692	Overexpression YAP1 in tumor cell lines can induce EMT and enhances in vitro invasion (Overholtzer et al., 2006).	('induce', 'PosReg', (44, 50))	('EMT', 'CPA', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('YAP1', 'Gene', (15, 19))	('Overexpression', 'Var', (0, 14))	('enhances', 'PosReg', (59, 67))	('tumor', 'Disease', (23, 28))
532843	32175692	Overexpression of BRD4 was found in melanoma, and downregulation of BRD4 by genetic knockdown is sufficient to recapitulate the antitumoral effect of BET inhibitors in melanoma cell (Segura et al., 2013).	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('downregulation', 'NegReg', (50, 64))	('melanoma', 'Disease', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('BET', 'Chemical', '-', (150, 153))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('BRD4', 'Gene', (68, 72))	('knockdown', 'Var', (84, 93))	('BRD4', 'Gene', '23476', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('BRD4', 'Gene', '23476', (68, 72))	('tumor', 'Disease', (132, 137))	('BRD4', 'Gene', (18, 22))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
532844	32175692	(2011) showed that inhibition of BRD4 using shRNAs or the small-molecule inhibitor JQ1 led to dramatic antileukemic effects in vitro and in vivo.	('BRD4', 'Gene', (33, 37))	('inhibition', 'Var', (19, 29))	('antileukemic effects', 'CPA', (103, 123))	('JQ1', 'Gene', (83, 86))	('BRD4', 'Gene', '23476', (33, 37))
532849	32175692	We proposed that BRD4 epigenetically regulated YAP1 expression and transcription and targeted aberrant activation of YAP1 in EAC could be reduced by BET inhibition.	('epigenetically', 'Var', (22, 36))	('regulated', 'Reg', (37, 46))	('activation', 'PosReg', (103, 113))	('YAP1', 'Gene', (117, 121))	('BRD4', 'Gene', (17, 21))	('expression', 'MPA', (52, 62))	('BET', 'Chemical', '-', (149, 152))	('EAC', 'Phenotype', 'HP:0011459', (125, 128))	('aberrant', 'Var', (94, 102))	('BRD4', 'Gene', '23476', (17, 21))	('transcription', 'MPA', (67, 80))	('YAP1', 'Gene', (47, 51))
532851	32175692	Remarkably, JQ1 can effectively suppress therapy-resistant EAC cells endowed with CSC traits and decreases ALDH1+ cells (representing CSCs).	('JQ1', 'Var', (12, 15))	('suppress', 'NegReg', (32, 40))	('ALDH1', 'Gene', '216', (107, 112))	('decreases', 'NegReg', (97, 106))	('EAC', 'Phenotype', 'HP:0011459', (59, 62))	('EAC cells', 'Disease', (59, 68))	('ALDH1', 'Gene', (107, 112))
532852	32175692	Furthermore, the effect of JQ1 is amplified when it is combined with docetaxel in vitro and in vivo.	('docetaxel', 'Chemical', 'MESH:D000077143', (69, 78))	('JQ1', 'Var', (27, 30))	('amplified', 'PosReg', (34, 43))	('combined', 'Interaction', (55, 63))
532857	32175692	Antibodies against beta-catenin, EGFR, phosphor-S6, phosphor-70S6K, and c-MYC were from Cell Signaling Technology (Boston, MA 02241-3843).	('phosphor-70S6K', 'Var', (52, 66))	('phosphor-S6', 'Var', (39, 50))	('c-MYC', 'Gene', (72, 77))	('EGFR', 'Gene', '1956', (33, 37))	('beta-catenin', 'Gene', (19, 31))	('EGFR', 'Gene', (33, 37))	('c-MYC', 'Gene', '4609', (72, 77))	('beta-catenin', 'Gene', '1499', (19, 31))
532874	32175692	To determine whether JQ1 suppresses YAP1 expression and transcription, several EAC cell lines SKGT-4, BE3, Flo-1, JHESO, and OACP were treated with JQ1 at relative low concentration as indicated for 48 h, we found that JQ1 suppressed YAP1 and its target SOX9 expression in EAC cell lines (Fig.	('YAP1', 'Gene', (234, 238))	('EAC', 'Phenotype', 'HP:0011459', (273, 276))	('SOX9', 'Gene', (254, 258))	('expression', 'MPA', (41, 51))	('SKGT-4', 'CellLine', 'CVCL:2195', (94, 100))	('expression', 'MPA', (259, 269))	('suppressed', 'NegReg', (223, 233))	('YAP1', 'Gene', (36, 40))	('transcription', 'MPA', (56, 69))	('EAC', 'Phenotype', 'HP:0011459', (79, 82))	('suppresses', 'NegReg', (25, 35))	('JQ1', 'Var', (219, 222))
532875	32175692	Immunofluorescent staining further confirmed the nuclear expression of YAP1 and SOX9 was dramatically reduced upon treatment with JQ1 at 1 mum for 24 h in JHESO and SKGT-4 cells (Fig.	('SKGT-4', 'CellLine', 'CVCL:2195', (165, 171))	('mum', 'Gene', '56925', (139, 142))	('mum', 'Gene', (139, 142))	('SOX9', 'Gene', (80, 84))	('JQ1', 'Var', (130, 133))	('nuclear expression', 'MPA', (49, 67))	('reduced', 'NegReg', (102, 109))	('YAP1', 'Gene', (71, 75))
532878	32175692	To elucidate the molecular mechanisms by which JQ1 suppresses YAP1 expression and transcription, we focused on BRD4, one of BET family members of chromatin reader protein that are highly upregulated in EC tissues (184 cases) compared with normal tissues (11 cases) from TCGA database (Fig.	('transcription', 'MPA', (82, 95))	('YAP1', 'Gene', (62, 66))	('BRD4', 'Gene', '23476', (111, 115))	('JQ1', 'Var', (47, 50))	('suppresses', 'NegReg', (51, 61))	('expression', 'MPA', (67, 77))	('BET', 'Chemical', '-', (124, 127))	('BRD4', 'Gene', (111, 115))	('upregulated', 'PosReg', (187, 198))
532890	32175692	We found that increased BRD4 by transfection of BRD4 cDNA into these cells significantly upregulated mRNA levels of YAP1 and its targets SOX9 and CTGF (Figs 2F,G and S3).	('increased', 'PosReg', (14, 23))	('CTGF', 'Gene', '1490', (146, 150))	('BRD4', 'Gene', '23476', (24, 28))	('mRNA levels', 'MPA', (101, 112))	('upregulated', 'PosReg', (89, 100))	('BRD4', 'Gene', '23476', (48, 52))	('CTGF', 'Gene', (146, 150))	('BRD4', 'Gene', (24, 28))	('BRD4', 'Gene', (48, 52))	('transfection', 'Var', (32, 44))	('YAP1', 'Gene', (116, 120))
532892	32175692	It is known that BRD4 together with its other homologue BRD2 and BRDT is acetylated chromatin readers to epigenetically regulate chromosome remodeling and facilitate gene transcription.	('epigenetically', 'Var', (105, 119))	('BRDT', 'Gene', '676', (65, 69))	('facilitate', 'PosReg', (155, 165))	('regulate', 'Reg', (120, 128))	('gene transcription', 'MPA', (166, 184))	('BRD4', 'Gene', (17, 21))	('BRDT', 'Gene', (65, 69))	('BRD2', 'Gene', (56, 60))	('BRD2', 'Gene', '6046', (56, 60))	('BRD4', 'Gene', '23476', (17, 21))	('chromosome remodeling', 'CPA', (129, 150))
532898	32175692	Consistently, JQ1 significantly reduced YAP/Tead transcriptional activity induced by either mutant or wild-type YAP1 (Fig.	('JQ1', 'Gene', (14, 17))	('YAP', 'Gene', '10413', (40, 43))	('reduced', 'NegReg', (32, 39))	('YAP', 'Gene', '10413', (112, 115))	('mutant', 'Var', (92, 98))	('YAP', 'Gene', (40, 43))	('YAP', 'Gene', (112, 115))
532899	32175692	3E) and decreased YAP1/TEAD transcriptional activity induced by YAP1 and BRD4 cotransfection in JHESO cells and Flo-1 cells (Fig.	('YAP1/TEAD transcriptional activity', 'MPA', (18, 52))	('BRD4', 'Gene', '23476', (73, 77))	('cotransfection', 'Var', (78, 92))	('BRD4', 'Gene', (73, 77))	('decreased', 'NegReg', (8, 17))	('YAP1', 'Gene', (64, 68))
532900	32175692	These data supported that BRD4 as a coactivator enhances YAP1 transcription and downstream signaling in EAC cells and that treatment with JQ1 suppresses BRD4-mediated YAP1 expression and its transcriptional output.	('BRD4', 'Gene', (153, 157))	('YAP1', 'Gene', (167, 171))	('suppresses', 'NegReg', (142, 152))	('BRD4', 'Gene', (26, 30))	('transcription', 'MPA', (62, 75))	('expression', 'MPA', (172, 182))	('transcriptional output', 'MPA', (191, 213))	('BRD4', 'Gene', '23476', (153, 157))	('downstream signaling', 'MPA', (80, 100))	('EAC', 'Phenotype', 'HP:0011459', (104, 107))	('enhances', 'PosReg', (48, 56))	('YAP1', 'Gene', (57, 61))	('BRD4', 'Gene', '23476', (26, 30))	('JQ1', 'Var', (138, 141))
532901	32175692	To further determine whether JQ1 preferentially suppresses YAP1 expression and its transcription, we utilized our established lentiviral-inducible SKGT-4 cells (pIN20YAP1) with (DOX+) or without (DOX-) YAP1 induction.	('expression', 'MPA', (64, 74))	('SKGT-4', 'CellLine', 'CVCL:2195', (147, 153))	('DOX', 'Chemical', 'MESH:D004317', (196, 199))	('YAP1', 'Gene', (59, 63))	('transcription', 'MPA', (83, 96))	('JQ1', 'Var', (29, 32))	('suppresses', 'NegReg', (48, 58))	('DOX', 'Chemical', 'MESH:D004317', (178, 181))
532905	32175692	When we applied JQ1 at 15mg kg-1 three times a week in mice bearing SKGT-4 DOX+ tumors, we found that JQ1 dramatically decreased tumor growth in mice bearing SKGT-4 DOX+ tumors (Fig.	('decreased tumor', 'Disease', 'MESH:D002303', (119, 134))	('tumors', 'Disease', (170, 176))	('DOX', 'Chemical', 'MESH:D004317', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SKGT-4', 'CellLine', 'CVCL:2195', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mice', 'Species', '10090', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('JQ1', 'Var', (102, 105))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('DOX', 'Chemical', 'MESH:D004317', (75, 78))	('mice', 'Species', '10090', (145, 149))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('decreased tumor', 'Disease', (119, 134))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('SKGT-4', 'CellLine', 'CVCL:2195', (158, 164))
532907	32175692	When further analyzing tumors treated with JQ1, we found that the level of proliferation markers Ki67, YAP1, and SOX9 was greatly reduced by treatment of JQ1 (Fig.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('JQ1', 'Var', (154, 157))	('Ki67', 'Gene', '17345', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('reduced', 'NegReg', (130, 137))	('level of proliferation', 'MPA', (66, 88))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('Ki67', 'Gene', (97, 101))
532909	32175692	Furthermore, JQ1 dramatically reduced tumorsphere formation in Flo-1 XTR cells, while Flo-1 parental cells do not form tumorspheres (Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('Flo-1', 'Var', (63, 68))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('JQ1', 'Var', (13, 16))	('reduced', 'NegReg', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
532910	32175692	We have previously demonstrated that Flo-1 XTR cells enrich CSC population compared with Flo-1 parental cells labeled by ALDH1 labeling using ALDEFLUOR detection kit (Stemcell Technologies, Vancouver, BC, Canada) (Wadhwa et al., 2017), while JQ1 suppressed the CSC population (ALDH1+) more than threefold in Flo-1 XTR cells at 1 mum for 48 h (Fig.	('ALDH1', 'Gene', (121, 126))	('mum', 'Gene', '56925', (329, 332))	('JQ1', 'Var', (242, 245))	('ALDH1', 'Gene', '216', (121, 126))	('CSC population', 'CPA', (261, 275))	('mum', 'Gene', (329, 332))	('ALDH1', 'Gene', (277, 282))	('ALDH1', 'Gene', '216', (277, 282))	('suppressed', 'NegReg', (246, 256))
532912	32175692	First, we found that JQ1 decreased cell growth in four EAC cell lines including Flo-1, SKGT-4, JHESO, and BE3 EAC cells with high YAP1 and this became more effective when JQ1 was combined with docetaxel (Fig.	('decreased', 'NegReg', (25, 34))	('SKGT-4', 'CellLine', 'CVCL:2195', (87, 93))	('EAC', 'Phenotype', 'HP:0011459', (55, 58))	('docetaxel', 'Chemical', 'MESH:D000077143', (193, 202))	('EAC', 'Phenotype', 'HP:0011459', (110, 113))	('JQ1', 'Var', (21, 24))	('cell growth', 'CPA', (35, 46))
532913	32175692	More importantly, JQ1 preferentially suppressed radiation-resistant Flo-1 XTR cells compared with Flo-1 parental cells and in combination with docetaxel demonstrated best antiproliferative effects (Fig.	('radiation-resistant Flo-1 XTR cells', 'CPA', (48, 83))	('antiproliferative effects', 'CPA', (171, 196))	('JQ1', 'Var', (18, 21))	('suppressed', 'NegReg', (37, 47))	('docetaxel', 'Chemical', 'MESH:D000077143', (143, 152))
532914	32175692	To investigate the antitumor efficacy of treatment with JQ1 combining with docetaxel in vivo, we tested JQ1 alone and/or in combination with docetaxel in the JHESO xenograft mouse model.	('tested', 'Reg', (97, 103))	('mouse', 'Species', '10090', (174, 179))	('docetaxel', 'Chemical', 'MESH:D000077143', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('docetaxel', 'Chemical', 'MESH:D000077143', (75, 84))	('tumor', 'Disease', (23, 28))	('JQ1', 'Var', (104, 107))
532919	32175692	6C demonstrated JQ1 significantly decreased tumor growth in JHESO xenograft tumors, the combination treatment of JQ1 and docetaxel markedly reduced tumor volumes and showed the best antitumor activity, while body weights of mice among the groups did not differ significantly (Fig.	('docetaxel', 'Chemical', 'MESH:D000077143', (121, 130))	('JQ1', 'Var', (16, 19))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('decreased tumor', 'Disease', 'MESH:D002303', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('decreased tumor', 'Disease', (34, 49))	('mice', 'Species', '10090', (224, 228))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (148, 153))	('JQ1', 'Var', (113, 116))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('reduced', 'NegReg', (140, 147))
532920	32175692	Furthermore, the expression of KI67, YAP1, and its target SOX9 in treated mouse tumors was significantly reduced upon treatment with the combination of JQ1 and docetaxel (Fig.	('KI67', 'Gene', '17345', (31, 35))	('KI67', 'Gene', (31, 35))	('JQ1', 'Var', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('expression', 'MPA', (17, 27))	('docetaxel', 'Chemical', 'MESH:D000077143', (160, 169))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('reduced', 'NegReg', (105, 112))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('mouse', 'Species', '10090', (74, 79))	('YAP1', 'Gene', (37, 41))
532923	32175692	More interestingly, JQ1 can effectively suppress CSC properties and decrease ALDH1+ cells in radiation-resistant EAC cells and this effect is further amplified by the addition of docetaxel in vitro and in vivo.	('EAC', 'Phenotype', 'HP:0011459', (113, 116))	('CSC properties', 'MPA', (49, 63))	('decrease', 'NegReg', (68, 76))	('suppress', 'NegReg', (40, 48))	('ALDH1', 'Gene', (77, 82))	('JQ1', 'Var', (20, 23))	('ALDH1', 'Gene', '216', (77, 82))	('docetaxel', 'Chemical', 'MESH:D000077143', (179, 188))
532924	32175692	Our data indicate that targeting nuclear oncogenic YAP1 can be achieved through BET inhibition in EAC and BET inhibition provides a new therapeutic strategy for EAC with high YAP1 and therapy-resistant tumors (Fig.	('BET', 'MPA', (80, 83))	('inhibition', 'NegReg', (84, 94))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('EAC', 'Phenotype', 'HP:0011459', (98, 101))	('EAC', 'Phenotype', 'HP:0011459', (161, 164))	('tumors', 'Disease', (202, 208))	('high', 'Var', (170, 174))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('BET', 'Chemical', '-', (106, 109))	('BET', 'Chemical', '-', (80, 83))	('YAP1', 'Gene', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
532943	32175692	A recent report by Zhang et al (2017) found that JQ1 negatively regulates c-MYC, Bcl-XL, and YAP1 and induction of p21 and p27; however, how JQ1 suppresses YAP1 is not known.	('JQ1', 'Var', (141, 144))	('p27', 'Gene', (123, 126))	('JQ1', 'Gene', (49, 52))	('Bcl-XL', 'Gene', '598', (81, 87))	('Bcl-XL', 'Gene', (81, 87))	('regulates', 'Reg', (64, 73))	('YAP1', 'Gene', (93, 97))	('c-MYC', 'Gene', (74, 79))	('negatively', 'NegReg', (53, 63))	('p21', 'Gene', (115, 118))	('p21', 'Gene', '644914', (115, 118))	('p27', 'Gene', '10671', (123, 126))	('c-MYC', 'Gene', '4609', (74, 79))	('YAP1', 'MPA', (156, 160))	('suppresses', 'NegReg', (145, 155))
532948	32175692	Our study is clinically relevant and important for EAC patients with YAP1 high expression and/or those with therapy resistance.	('patients', 'Species', '9606', (55, 63))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('YAP1', 'Gene', (69, 73))	('high expression', 'Var', (74, 89))
532951	32175692	Most importantly, YAP1/BET inhibition significantly enhances antitumor effects of conventional cytotoxic (docetaxel) when combined in vitro and in vivo.	('BET', 'Chemical', '-', (23, 26))	('tumor', 'Disease', (65, 70))	('YAP1/BET', 'Gene', (18, 26))	('inhibition', 'Var', (27, 37))	('docetaxel', 'Chemical', 'MESH:D000077143', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('enhances', 'PosReg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
532976	32195923	Staging criteria: According to Tumor Node Metastasis (TNM) Classification for esophageal cancer, 8th ed by Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) in 2017, stage IV esophageal cancer contains T4aN1-2M0, T4bNxM0, TxN3M0, and TxNxM1.	('Cancer', 'Disease', (174, 180))	('Tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Cancer', 'Disease', 'MESH:D009369', (174, 180))	('Cancer', 'Phenotype', 'HP:0002664', (174, 180))	('T4aN1-2M0', 'Var', (238, 247))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('esophageal cancer', 'Disease', (211, 228))	('T4bNxM0', 'Var', (249, 256))	('esophageal cancer', 'Disease', 'MESH:D004938', (211, 228))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('Cancer', 'Disease', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('esophageal cancer', 'Disease', (78, 95))	('Cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
532978	32195923	PNI >=45 meant normal nutritional status for patients.	('nutritional status', 'MPA', (22, 40))	('PNI >=45', 'Var', (0, 8))	('patients', 'Species', '9606', (45, 53))
532979	32195923	In the light of Chinese clinical practise and therapeutic methods, anemia refers to hemoglobin (Hb) <120 g/L in men and Hb <110 g/L in women.	('men', 'Species', '9606', (112, 115))	('anemia', 'Disease', (67, 73))	('<120 g/L', 'Var', (100, 108))	('anemia', 'Disease', 'MESH:D000740', (67, 73))	('anemia', 'Phenotype', 'HP:0001903', (67, 73))	('<110 g/L', 'Var', (123, 131))	('hemoglobin', 'Disease', (84, 94))	('men', 'Species', '9606', (137, 140))	('women', 'Species', '9606', (135, 140))
532984	32195923	Relevant requirements were as follows: 95% of planning target volume (PTV) were irradiated through 100% of the above mentioned prescribed dose, with whole lungs V5 <=55% to 60%, V20 <=25% to 30%, V30 <=18%, heart Dmean <=30 Gy, and spinal cord Dmax <45 Gy.	('men', 'Species', '9606', (117, 120))	('V30 <=18%', 'Var', (196, 205))	('Dmean', 'Chemical', '-', (213, 218))	('V20 <=25% to 30%', 'Var', (178, 194))	('men', 'Species', '9606', (16, 19))	('V5 <=55% to 60%', 'Var', (161, 176))
533027	32195923	In other words, our findings also supported that median survival was obviously lower in stent group than in the group without stent, and that patients' living quality was dramatically decreased in stent group as well.	('median survival', 'CPA', (49, 64))	('lower', 'NegReg', (79, 84))	('stent', 'Var', (88, 93))	('decreased', 'NegReg', (184, 193))	("patients' living quality", 'CPA', (142, 166))	('patients', 'Species', '9606', (142, 150))
533055	31258850	More patients in the Nimo-nCRT and nCRT group developed grade 3 esophagitis compared to those in the nCT group, P = 0.008.	('patients', 'Species', '9606', (5, 13))	('Nimo-nCRT', 'Var', (21, 30))	('nCRT', 'Var', (35, 39))	('esophagitis', 'Phenotype', 'HP:0100633', (64, 75))	('esophagitis', 'Disease', (64, 75))	('esophagitis', 'Disease', 'MESH:D004941', (64, 75))
533061	31258850	The recently published NeoRES trial in a mixed cohort of 181 patients with esophageal squamous cell carcinoma and adenocarcinoma of the distal esophagus, manifested that nCRT increases the pCR and R0 resection rates and decreases the proportion of patients with metastases in regional lymph nodes compared to nCT, though dose not significantly improve overall survival in squamous cell carcinoma patients.	('patients', 'Species', '9606', (396, 404))	('esophageal squamous cell carcinoma', 'Disease', (75, 109))	('decreases', 'NegReg', (220, 229))	('adenocarcinoma', 'Disease', 'MESH:D000230', (114, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('metastases', 'Disease', 'MESH:D009362', (262, 272))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (372, 395))	('patients', 'Species', '9606', (61, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (75, 109))	('metastases', 'Disease', (262, 272))	('increases', 'PosReg', (175, 184))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (386, 395))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (372, 395))	('nCRT', 'Var', (170, 174))	('adenocarcinoma', 'Disease', (114, 128))	('patients', 'Species', '9606', (248, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('squamous cell carcinoma', 'Disease', (372, 395))
533097	31258850	Post-operative pathologic staging determined that 88.2% of the patients were downstaged following Nimo-nCRT, versus 82.4% following nCRT and 67.9% following nCT, a significant difference was found among the three groups (P = 0.000).	('downstaged', 'NegReg', (77, 87))	('Nimo-nCRT', 'Var', (98, 107))	('patients', 'Species', '9606', (63, 71))
533111	31258850	That trial recruited 451 patients of whom 224 were randomly allocated to the nCRT group, and 227 to the surgery alone group, nCRT increased R0 resection rate from 91.2% to 98.4% (P = 0.002) and a 43.2% pCR rate was achieved.	('patients', 'Species', '9606', (25, 33))	('R0 resection', 'CPA', (140, 152))	('nCRT', 'Var', (125, 129))	('increased', 'PosReg', (130, 139))
533132	31258850	The studies above demonstrated that the addition of cetuximab increased treatment-related toxicities, decreased the delivery of all components of standard chemoradiotherapy, and might negatively affect treatment outcomes.	('increased', 'PosReg', (62, 71))	('cetuximab', 'Gene', (52, 61))	('cetuximab', 'Chemical', 'MESH:D000068818', (52, 61))	('toxicities', 'Disease', (90, 100))	('negatively', 'NegReg', (184, 194))	('addition', 'Var', (40, 48))	('toxicities', 'Disease', 'MESH:D064420', (90, 100))	('affect', 'Reg', (195, 201))	('treatment', 'CPA', (202, 211))	('decreased', 'NegReg', (102, 111))
533135	31258850	The rates of pCR and downstaging in patients undergoing Nimo-nCRT were significantly higher than that in those receiving nCRT and nCT.	('downstaging', 'CPA', (21, 32))	('patients', 'Species', '9606', (36, 44))	('higher', 'PosReg', (85, 91))	('Nimo-nCRT', 'Var', (56, 65))	('pCR', 'Disease', (13, 16))
533140	31258850	Required laboratory parameters for inclusion were hemoglobin >= 100g/L, absolute neutrophil count (ANC) >= 1.5x109/L, platelets >= 100x109/L, ALT or AST < 2.5 times the upper limit of normal (ULN), bilirubin <= 1.5 times the ULN, and serum creatinine <= 1.5g/L.	('creatinine', 'Chemical', 'MESH:D003404', (240, 250))	('ALT', 'MPA', (142, 145))	('bilirubin', 'MPA', (198, 207))	('>= 100g/L', 'Var', (61, 70))	('hemoglobin', 'MPA', (50, 60))	('>= 100x109/L', 'Var', (128, 140))	('serum creatinine', 'MPA', (234, 250))
533154	31258850	Radiation was temporarily stopped for any of the following: ANC < 1000/mm3, platelets < 50,000/mm3, grade 3 esophagitis/mucositis, or any grade 4 toxicity.	('esophagitis', 'Phenotype', 'HP:0100633', (108, 119))	('esophagitis', 'Disease', (108, 119))	('esophagitis', 'Disease', 'MESH:D004941', (108, 119))	('ANC < 1000/mm3', 'Var', (60, 74))	('toxicity', 'Disease', 'MESH:D064420', (146, 154))	('mucositis', 'Disease', (120, 129))	('toxicity', 'Disease', (146, 154))	('mucositis', 'Disease', 'MESH:D052016', (120, 129))
533263	22980353	Several retrospective and prospective studies on humans and animals have shown that deficiency in trace elements such as Zn & Mo causes changes in enzymatic pathways producing carcinogenic end products like "nitrosamine and methylbenzylnitrosoamine" (MBN) resulting in EC.	('and', 'MPA', (220, 223))	('men', 'Species', '9606', (107, 110))	('causes', 'Reg', (129, 135))	('methylbenzylnitrosoamine"', 'Chemical', '-', (224, 249))	('Zn & Mo', 'Chemical', '-', (121, 128))	('carcinogenic end', 'Disease', (176, 192))	('MBN', 'Chemical', '-', (251, 254))	('nitrosamine', 'Chemical', 'MESH:D009602', (208, 219))	('deficiency', 'Var', (84, 94))	('carcinogenic end', 'Disease', 'MESH:D007676', (176, 192))	('humans', 'Species', '9606', (49, 55))
533293	22980353	All the statistical evaluations are indicating a deficiency of Zn & Mo in hair among RSA population and the deficiencies of Zn & Mo may play a distinct role for the development of EC in Eastern Cape, RSA (hot spot) and this is also supported by other studies (; Luo et al., 1989).	('the', 'Var', (104, 107))	('Zn & Mo', 'Chemical', '-', (124, 131))	('RSA', 'Chemical', '-', (200, 203))	('Zn & Mo', 'Chemical', '-', (63, 70))	('RSA', 'Chemical', '-', (85, 88))	('deficiency', 'NegReg', (49, 59))	('men', 'Species', '9606', (172, 175))	('development', 'Disease', (165, 176))
533306	25481035	It has long been recognized that dysregulation of Ca2+ homeostasis is associated with a plethora of pathological conditions including immune deficiency, neurodegeneration, muscular and cardiovascular disorders as well as cancer progression.	('dysregulation', 'Var', (33, 46))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('neurodegeneration', 'Phenotype', 'HP:0002180', (153, 170))	('cancer', 'Disease', (221, 227))	('plethora', 'Phenotype', 'HP:0001050', (88, 96))	('neurodegeneration', 'Disease', (153, 170))	('cardiovascular disorders', 'Disease', 'MESH:D002318', (185, 209))	('immune deficiency', 'Phenotype', 'HP:0002721', (134, 151))	('associated', 'Reg', (70, 80))	('immune deficiency', 'Disease', (134, 151))	('immune deficiency', 'Disease', 'MESH:D007153', (134, 151))	('cardiovascular disorders', 'Disease', (185, 209))	('Ca2+', 'Chemical', 'MESH:D000069285', (50, 54))	('neurodegeneration', 'Disease', 'MESH:D019636', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cardiovascular disorders', 'Phenotype', 'HP:0001626', (185, 209))	('Ca2+ homeostasis', 'MPA', (50, 66))
533315	25481035	In this pathway, activation of the G-protein coupled receptor leads to stimulation of PLC to generate IP3; IP3 in turn causes intracellular Ca2+ release that is followed by reduction of Ca2+ concentration inside the ER lumen.	('Ca2+', 'Chemical', 'MESH:D000069285', (140, 144))	('G-protein coupled receptor', 'Protein', (35, 61))	('IP3', 'Var', (107, 110))	('reduction', 'NegReg', (173, 182))	('Ca2+ concentration', 'MPA', (186, 204))	('causes', 'Reg', (119, 125))	('IP3', 'Chemical', 'MESH:D015544', (107, 110))	('IP3', 'MPA', (102, 105))	('Ca2+', 'Chemical', 'MESH:D000069285', (186, 190))	('activation', 'PosReg', (17, 27))	('PLC', 'MPA', (86, 89))	('stimulation', 'PosReg', (71, 82))	('intracellular Ca2+ release', 'MPA', (126, 152))	('IP3', 'Chemical', 'MESH:D015544', (102, 105))
533329	25481035	Using these pharmacological tools, several studies showed that altered function of SOCE might be a general phenomenon associated with cancer progression.	('function', 'MPA', (71, 79))	('SOCE', 'Gene', (83, 87))	('altered', 'Var', (63, 70))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('associated', 'Reg', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
533335	25481035	While genetic mutations in Orai1 or STIM1 were linked to immune disorders, skeletal muscle myopathy and heart hypertrophy, the functions of these genes in various types of cancer have fascinated many investigators.	('heart hypertrophy', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Orai1', 'Gene', '84876', (27, 32))	('myopathy', 'Phenotype', 'HP:0003198', (91, 99))	('heart hypertrophy', 'Disease', 'MESH:D006332', (104, 121))	('STIM1', 'Gene', (36, 41))	('heart hypertrophy', 'Phenotype', 'HP:0001639', (104, 121))	('genetic mutations', 'Var', (6, 23))	('Orai1', 'Gene', (27, 32))	('immune disorders', 'Disease', 'MESH:D007154', (57, 73))	('skeletal muscle myopathy', 'Disease', 'MESH:D009135', (75, 99))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('linked', 'Reg', (47, 53))	('cancer', 'Disease', (172, 178))	('immune disorders', 'Disease', (57, 73))	('STIM1', 'Gene', '6786', (36, 41))	('skeletal muscle myopathy', 'Disease', (75, 99))
533348	25481035	identified a signaling pathway in which formation of an Orai1-SPCA2 complex elicits a constitutive store-independent Ca2+ entry pathway that regulates tumor-igenesis in breast cancer.	('Orai1', 'Gene', '84876', (56, 61))	('SPCA2', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('store-independent Ca2+ entry pathway', 'Pathway', (99, 135))	('Ca2+', 'Chemical', 'MESH:D000069285', (117, 121))	('elicits', 'Reg', (76, 83))	('complex', 'Var', (68, 75))	('SPCA2', 'Gene', '9914', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Orai1', 'Gene', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('regulates', 'Reg', (141, 150))	('breast cancer', 'Disease', (169, 182))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
533350	25481035	showed that knockdown of STIM1 had no effect on, whereas knockdown of Orai1 inhibited, migration of breast cancer cells, indicating STIM1 might not be involved in the metastatic process.	('Orai1', 'Gene', '84876', (70, 75))	('migration', 'CPA', (87, 96))	('STIM1', 'Gene', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('STIM1', 'Gene', '6786', (25, 30))	('knockdown', 'Var', (57, 66))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('STIM1', 'Gene', '6786', (132, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('Orai1', 'Gene', (70, 75))	('breast cancer', 'Disease', (100, 113))	('inhibited', 'NegReg', (76, 85))	('STIM1', 'Gene', (25, 30))
533356	25481035	They proposed that remodeling of Orai1/Orai3 may constitute as an oncogenic switch in prostate cancer.	('Orai1', 'Gene', (33, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('Orai3', 'Gene', (39, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('Orai1', 'Gene', '84876', (33, 38))	('Orai3', 'Gene', '93129', (39, 44))	('remodeling', 'Var', (19, 29))	('prostate cancer', 'Disease', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
533364	25481035	In the same study, we also showed that inhibition of Orai1-mediated SOCE by pharmacologic antagonists of the channel or reduction of Orai1 expression by Orai1 knockdown impeded the proliferation and migration/invasion of ESCC cells in vitro, suppressed the tumor growth in vivo.	('proliferation', 'CPA', (181, 194))	('Orai1', 'Gene', (153, 158))	('Orai1', 'Gene', (53, 58))	('knockdown', 'Var', (159, 168))	('tumor', 'Disease', (257, 262))	('Orai1', 'Gene', '84876', (153, 158))	('Orai1', 'Gene', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('Orai1', 'Gene', '84876', (133, 138))	('inhibition', 'NegReg', (39, 49))	('Orai1', 'Gene', '84876', (53, 58))	('reduction', 'NegReg', (120, 129))	('migration/invasion', 'CPA', (199, 217))	('expression', 'MPA', (139, 149))	('suppressed', 'NegReg', (242, 252))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('impeded', 'NegReg', (169, 176))
533367	25481035	For example, injection of SKF-96365 into xenografted breast, cervical and esophageal cancer mice models suppressed tumor growth, angiogenesis and metastasis in vivo.	('SKF-96365', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('metastasis', 'CPA', (146, 156))	('angiogenesis', 'CPA', (129, 141))	('tumor', 'Disease', (115, 120))	('esophageal cancer', 'Disease', (74, 91))	('SKF-96365', 'Chemical', 'MESH:C063159', (26, 35))	('suppressed', 'NegReg', (104, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mice', 'Species', '10090', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
533398	26370590	According to early epidemiological studies, low levels of IGFBP-3 were independently associated with a high risk of human malignancies, such as colorectal cancer, lung cancer, and breast cancer.	('IGFBP-3', 'Gene', (58, 65))	('malignancies', 'Disease', 'MESH:D009369', (122, 134))	('malignancies', 'Disease', (122, 134))	('IGFBP-3', 'Gene', '3486', (58, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal cancer', 'Disease', (144, 161))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('breast cancer', 'Disease', (180, 193))	('lung cancer', 'Disease', (163, 174))	('associated', 'Reg', (85, 95))	('human', 'Species', '9606', (116, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('low levels', 'Var', (44, 54))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
533422	26370590	2a, b, 45.7% (32 of 70) of ESCC cases were evaluated as having high IGFBP-3 expression, with the remaining ESCC cases (54.3%, 38 of 70) defined as having negative or low IGFBP-3 expression.	('IGFBP-3', 'Gene', '3486', (170, 177))	('high IGFBP', 'Phenotype', 'HP:0030269', (63, 73))	('ESCC', 'Disease', (27, 31))	('IGFBP-3', 'Gene', '3486', (68, 75))	('expression', 'MPA', (76, 86))	('high', 'Var', (63, 67))	('IGFBP-3', 'Gene', (170, 177))	('IGFBP-3', 'Gene', (68, 75))
533428	26370590	Further analysis demonstrated that high IGFBP-3 expression was associated with an improved radiotherapy response in ESCC patients, with 83.3% of patients achieving complete response (CR) after radiotherapy for 3 months.	('radiotherapy response', 'CPA', (91, 112))	('patients', 'Species', '9606', (145, 153))	('ESCC', 'Disease', (116, 120))	('IGFBP-3', 'Gene', '3486', (40, 47))	('high IGFBP', 'Phenotype', 'HP:0030269', (35, 45))	('expression', 'MPA', (48, 58))	('IGFBP-3', 'Gene', (40, 47))	('high', 'Var', (35, 39))	('patients', 'Species', '9606', (121, 129))	('improved', 'PosReg', (82, 90))
533431	26370590	In addition, the median survival time of patients with high expression of IGFBP-3 was 25 months, whereas that of those with low expression of IGFBP-3 was 10 months (P < 0.001, Table 3).	('IGFBP-3', 'Gene', '3486', (142, 149))	('IGFBP-3', 'Gene', (142, 149))	('IGFBP-3', 'Gene', '3486', (74, 81))	('patients', 'Species', '9606', (41, 49))	('high expression', 'Var', (55, 70))	('IGFBP-3', 'Gene', (74, 81))
533443	26370590	ROC analysis was performed for each of the clinicopathologic parameters to set up more sensitive and specific immunohistochemistry cut-off scores for IGFBP-3 positivity.	('positivity', 'Var', (158, 168))	('IGFBP-3', 'Gene', (150, 157))	('IGFBP-3', 'Gene', '3486', (150, 157))
533447	26370590	Furthermore, high expression of IGFBP-3 was found to associate positively with improved radiotherapy response and to enhance radiosensitivity in ESCC patients.	('radiotherapy response', 'CPA', (88, 109))	('improved', 'PosReg', (79, 87))	('radiosensitivity', 'CPA', (125, 141))	('IGFBP-3', 'Gene', '3486', (32, 39))	('high expression', 'Var', (13, 28))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (117, 141))	('enhance', 'PosReg', (117, 124))	('IGFBP-3', 'Gene', (32, 39))	('patients', 'Species', '9606', (150, 158))	('ESCC', 'Disease', (145, 149))
533448	26370590	Univariate survival analysis showed that positive IGFBP-3 expression in ESCC was related to prolonged median survival time (25 vs. 10 months, P < 0.001).	('positive', 'Var', (41, 49))	('IGFBP-3', 'Gene', (50, 57))	('IGFBP-3', 'Gene', '3486', (50, 57))	('prolonged', 'PosReg', (92, 101))
533449	26370590	Moreover, high expression level of IGFBP-3 in ESCC was found to be an independent predictor of OS by Kaplan-Meier curves and multivariable Cox proportional hazards regression analysis.	('IGFBP-3', 'Gene', (35, 42))	('IGFBP-3', 'Gene', '3486', (35, 42))	('expression level', 'MPA', (15, 31))	('high', 'Var', (10, 14))	('Cox', 'Gene', '1351', (139, 142))	('Cox', 'Gene', (139, 142))	('predictor', 'Reg', (82, 91))
533450	26370590	These results suggest that the IGFBP-3 gene potentially facilitates apoptosis, inhibits tumor growth, and prevents cell invasion and/or metastasis in ESCC and that loss of IGFBP-3 expression may cause patients to have a poor prognosis.	('IGFBP-3', 'Gene', (172, 179))	('patients', 'Species', '9606', (201, 209))	('IGFBP-3', 'Gene', (31, 38))	('loss', 'Var', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inhibits', 'NegReg', (79, 87))	('apoptosis', 'CPA', (68, 77))	('facilitates', 'PosReg', (56, 67))	('prevents', 'NegReg', (106, 114))	('ESCC', 'Disease', (150, 154))	('cell invasion', 'CPA', (115, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('IGFBP-3', 'Gene', '3486', (172, 179))	('IGFBP-3', 'Gene', '3486', (31, 38))	('tumor', 'Disease', (88, 93))
533458	26370590	In addition, down-regulation of IGFBP-3 in 86 gastric adenocarcinoma tissues relative to their adjacent non-cancerous tissues by immunohistochemistry was reported, and patients with high expression of IGFBP-3 showed a higher 5-year OS rate.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (46, 68))	('cancerous', 'Disease', (108, 117))	('higher', 'PosReg', (218, 224))	('5-year OS rate', 'CPA', (225, 239))	('IGFBP-3', 'Gene', '3486', (201, 208))	('high expression', 'Var', (182, 197))	('IGFBP-3', 'Gene', '3486', (32, 39))	('cancerous', 'Disease', 'MESH:D009369', (108, 117))	('IGFBP-3', 'Gene', (201, 208))	('down-regulation', 'NegReg', (13, 28))	('IGFBP-3', 'Gene', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('patients', 'Species', '9606', (168, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('gastric adenocarcinoma', 'Disease', (46, 68))
533459	26370590	Knock-down of IGFBP-3 has also been shown to accelerate gastric cancer cell migration and invasion.	('IGFBP-3', 'Gene', '3486', (14, 21))	('accelerate gastric cancer', 'Phenotype', 'HP:0006753', (45, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('IGFBP-3', 'Gene', (14, 21))	('Knock-down', 'Var', (0, 10))	('accelerate', 'PosReg', (45, 55))	('gastric cancer', 'Disease', (56, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('invasion', 'CPA', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
533472	23440684	QGC significantly increased the activities of superoxide dismutase (SOD) and catalase, and also induced the expression of SOD2, while it restored the decrease of catalase expression in cells exposed to acid.	('superoxide dismutase', 'Gene', '39251', (46, 66))	('increased', 'PosReg', (18, 27))	('catalase', 'Gene', '24248', (77, 85))	('QGC', 'Var', (0, 3))	('decrease of catalase', 'Phenotype', 'HP:0012517', (150, 170))	('decrease of catalase expression', 'Phenotype', 'HP:0012517', (150, 181))	('catalase', 'Gene', (162, 170))	('increased the activities of superoxide dismutase', 'Phenotype', 'HP:0031836', (18, 66))	('superoxide dismutase', 'Gene', (46, 66))	('induced', 'Reg', (96, 103))	('catalase', 'Gene', '24248', (162, 170))	('QGC', 'Chemical', 'MESH:C443401', (0, 3))	('expression', 'MPA', (108, 118))	('activities', 'MPA', (32, 42))	('decrease', 'MPA', (150, 158))	('catalase', 'Gene', (77, 85))	('SOD2', 'Gene', (122, 126))
533473	23440684	QGC inhibited NF-kappaB translocation, cyclooxygenase-2 expression and PGE2 secretion in cells exposed to acid, which plays an important role in the pathogenesis of esophagitis.	('esophagitis', 'Phenotype', 'HP:0100633', (165, 176))	('esophagitis', 'Disease', (165, 176))	('QGC', 'Var', (0, 3))	('cat', 'Gene', '24248', (31, 34))	('esophagitis', 'Disease', 'MESH:D004941', (165, 176))	('cyclooxygenase-2', 'Gene', '29527', (39, 55))	('inhibited', 'NegReg', (4, 13))	('expression', 'MPA', (56, 66))	('PGE2 secretion', 'MPA', (71, 85))	('cyclooxygenase-2', 'Gene', (39, 55))	('QGC', 'Chemical', 'MESH:C443401', (0, 3))	('cat', 'Gene', (31, 34))	('PGE2', 'Chemical', 'MESH:D015232', (71, 75))
533476	23440684	But the imbalance between formation and neutralization of ROS causes oxidative stress.	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('ROS', 'Protein', (58, 61))	('imbalance', 'Var', (8, 17))	('imbalance', 'Phenotype', 'HP:0002172', (8, 17))	('oxidative stress', 'Phenotype', 'HP:0025464', (69, 85))	('neutralization', 'MPA', (40, 54))	('oxidative stress', 'MPA', (69, 85))
533483	23440684	ROS can activate NF-kappaB by stimulating IkappaB degradation in a variety of cell types.	('ROS', 'Var', (0, 3))	('IkappaB', 'Protein', (42, 49))	('stimulating', 'PosReg', (30, 41))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('activate', 'PosReg', (8, 16))	('NF-kappaB', 'Protein', (17, 26))
533494	23440684	Many genes and signal pathways are influenced by ROS and antioxidants.	('influenced', 'Reg', (35, 45))	('genes', 'Gene', (5, 10))	('signal pathways', 'Pathway', (15, 30))	('ROS', 'Var', (49, 52))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))
533540	23440684	These results suggest that QGC enhanced viability against acid-induced cytotoxicity.	('viability', 'CPA', (40, 49))	('QGC', 'Var', (27, 30))	('enhanced', 'PosReg', (31, 39))	('cytotoxicity', 'Disease', (71, 83))	('QGC', 'Chemical', 'MESH:C443401', (27, 30))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))
533547	23440684	QGC caused SOD activation at 1 h and reached a maximal response at 6 h (Fig.	('SOD', 'CPA', (11, 14))	('QGC', 'Chemical', 'MESH:C443401', (0, 3))	('QGC', 'Var', (0, 3))	('activation', 'PosReg', (15, 25))
533551	23440684	QGC caused significant increases in SOD expression as compared to the group treated with acid alone.	('increases', 'PosReg', (23, 32))	('SOD expression', 'MPA', (36, 50))	('QGC', 'Var', (0, 3))	('QGC', 'Chemical', 'MESH:C443401', (0, 3))
533573	23440684	In the present study, we demonstrated that QGC acts as non-stressful and non-cytotoxic anti-inflammatory flavonoid since QGC exhibits protective effect against acid-induced cell damage.	('rat', 'Species', '10116', (32, 35))	('QGC', 'Chemical', 'MESH:C443401', (43, 46))	('QGC', 'Var', (121, 124))	('flavonoid', 'Chemical', 'MESH:D005419', (105, 114))	('acid-induced cell damage', 'MPA', (160, 184))	('protective effect', 'CPA', (134, 151))	('QGC', 'Chemical', 'MESH:C443401', (121, 124))
533574	23440684	Our data also suggest that QGC acts as a potent ROS scavenger in EECs since overproduction of intracellular ROS generated by a variety of inflammatory inducers were significantly inhibited by QGC.	('ROS', 'Chemical', 'MESH:D017382', (108, 111))	('inhibited', 'NegReg', (179, 188))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))	('QGC', 'Chemical', 'MESH:C443401', (192, 195))	('QGC', 'Chemical', 'MESH:C443401', (27, 30))	('overproduction of intracellular ROS generated', 'MPA', (76, 121))	('rat', 'Species', '10116', (116, 119))	('QGC', 'Var', (192, 195))
533575	23440684	Overproduction of ROS has been implicated in the generation of esophagitis by depression of MnSOD activity.	('cat', 'Gene', (36, 39))	('esophagitis by depression', 'Disease', (63, 88))	('esophagitis', 'Phenotype', 'HP:0100633', (63, 74))	('esophagitis by depression', 'Disease', 'MESH:D000275', (63, 88))	('rat', 'Species', '10116', (53, 56))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('cat', 'Gene', '24248', (36, 39))	('ROS', 'Protein', (18, 21))	('Overproduction', 'Var', (0, 14))	('MnSOD activity', 'MPA', (92, 106))	('depression', 'Phenotype', 'HP:0000716', (78, 88))
533578	23440684	In this study, QGC up-regulated the decreased SOD and catalase activity and expression in EECs exposed to acid.	('QGC', 'Chemical', 'MESH:C443401', (15, 18))	('expression', 'MPA', (76, 86))	('up-regulated', 'PosReg', (19, 31))	('QGC', 'Var', (15, 18))	('catalase', 'Gene', (54, 62))	('catalase', 'Gene', '24248', (54, 62))	('decreased', 'NegReg', (36, 45))
533580	23440684	ROS can activate NF-kappaB by stimulating IkB degradation in a variety of cell types.	('ROS', 'Var', (0, 3))	('stimulating', 'PosReg', (30, 41))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('IkB degradation', 'MPA', (42, 57))	('activate', 'PosReg', (8, 16))	('NF-kappaB', 'Protein', (17, 26))
533589	23440684	Possible cellular mechanism of anti-inflammatory action of QGC is an inhibition of NF-kappaB translocation, COX2 expression and PGE2 secretion.	('NF-kappaB', 'Protein', (83, 92))	('expression', 'MPA', (113, 123))	('cat', 'Gene', '24248', (100, 103))	('QGC', 'Var', (59, 62))	('PGE2 secretion', 'MPA', (128, 142))	('anti-inflammatory action', 'MPA', (31, 55))	('cat', 'Gene', (100, 103))	('PGE2', 'Chemical', 'MESH:D015232', (128, 132))	('COX2', 'Gene', '29527', (108, 112))	('QGC', 'Chemical', 'MESH:C443401', (59, 62))	('COX2', 'Gene', (108, 112))	('inhibition', 'NegReg', (69, 79))
533590	23440684	These experiments demonstrate that QGC could be a promising drug for the prevention of reflux esophagitis and a scavenger of ROS generated by inflammatory inducers.	('QGC', 'Var', (35, 38))	('esophagitis', 'Phenotype', 'HP:0100633', (94, 105))	('rat', 'Species', '10116', (133, 136))	('ROS', 'Chemical', 'MESH:D017382', (125, 128))	('reflux esophagitis', 'Disease', 'MESH:D005764', (87, 105))	('rat', 'Species', '10116', (25, 28))	('QGC', 'Chemical', 'MESH:C443401', (35, 38))	('reflux esophagitis', 'Disease', (87, 105))
533685	17166272	Several mouse studies have shown that depletion of regulatory T cells improves anti-tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('depletion', 'Var', (38, 47))	('tumor', 'Disease', (84, 89))	('mouse', 'Species', '10090', (8, 13))	('improves', 'PosReg', (70, 78))
533686	17166272	found FOXP3+CD25+CD4+ Tregs predominantly in growing tumors in mice that had not received an agonistic monoclonal antibody against glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), thus suggesting that tumor-infiltrating natural Tregs may hamper effective tumor immunity.	('FOXP3+CD25+CD4+', 'Var', (6, 21))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('Tregs', 'Chemical', '-', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', (154, 159))	('GITR', 'Gene', (209, 213))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumors', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('Tregs', 'Chemical', '-', (22, 27))	('tumor', 'Disease', (237, 242))	('glucocorticoid-induced tumor necrosis factor receptor family-related protein', 'Gene', '21936', (131, 207))	('rat', 'Species', '10116', (249, 252))	('mice', 'Species', '10090', (63, 67))	('hamper', 'NegReg', (274, 280))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (291, 296))	('GITR', 'Gene', '21936', (209, 213))
533711	17166272	HLA-A2-positive patients had been tested for the presence of T cell responses against the HLA-A*0201 presented T cell epitopes Ep-CAM p263-271, her-2/neu p654-662, and CEA p571-579 by ELISPOT assay.	('p263-271', 'Var', (134, 142))	('HLA-A', 'Gene', '3105', (0, 5))	('patients', 'Species', '9606', (16, 24))	('HLA-A', 'Gene', (0, 5))	('presence of T cell', 'Phenotype', 'HP:0100828', (49, 67))	('her-2/neu', 'Gene', '2064', (144, 153))	('CEA', 'Gene', '1048', (168, 171))	('her-2/neu', 'Gene', (144, 153))	('HLA-A', 'Gene', '3105', (90, 95))	('CEA', 'Gene', (168, 171))	('HLA-A', 'Gene', (90, 95))	('Ep-CAM', 'Gene', '4072', (127, 133))	('Ep-CAM', 'Gene', (127, 133))
533761	17166272	While the CD8 infiltration of epithelial tissue was not significantly different between healthy colon (7.9/HPF) and CRC (9.5/HPF), stromal CD8 infiltration was significantly higher in CRC (19.0) than in the lamina propria of healthy colon (3.4/HPF, p < 0.01).	('rat', 'Species', '10116', (149, 152))	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('CD8', 'Gene', (139, 142))	('CD8', 'Gene', '925', (139, 142))	('CRC (19.0', 'Var', (184, 193))	('CD8', 'Gene', (10, 13))	('higher', 'PosReg', (174, 180))	('CD8', 'Gene', '925', (10, 13))	('CRC', 'Phenotype', 'HP:0003003', (184, 187))	('rat', 'Species', '10116', (20, 23))
533824	33566442	Inhibiting chaperone-mediated autophagy can decrease cell growth and increase cisplatin resistance in esophageal squamous cell carcinoma.	('cisplatin resistance', 'MPA', (78, 98))	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('increase', 'PosReg', (69, 77))	('Inhibiting', 'Var', (0, 10))	('decrease', 'NegReg', (44, 52))	('cell growth', 'CPA', (53, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('decrease cell growth', 'Phenotype', 'HP:0001510', (44, 64))
533830	33566442	The first stage is substrate recognition and lysosomal targeting, which means that damaged or misfolded proteins with KEFRQ-like motifs will be recognized by a constitutive chaperone, Hsc70 and translocated to the lysosomal membrane.	('Hsc70', 'Gene', (184, 189))	('Hsc70', 'Gene', '3312', (184, 189))	('KEFRQ-like', 'Var', (118, 128))
533845	33566442	Lentiviral vector harboring a shRNA sequence targeting LAMP2a was used to knockdown LAMP2a in KYSE cell lines.	('LAMP2', 'Gene', (55, 60))	('LAMP2', 'Gene', (84, 89))	('LAMP2', 'Gene', '3920', (55, 60))	('knockdown', 'Var', (74, 83))	('LAMP2', 'Gene', '3920', (84, 89))
533870	33566442	KYSE150 and KYSE150 shLAMP2a cells were typsinized and collected by centrifugation.	('KYSE150', 'Var', (12, 19))	('LAMP2', 'Gene', (22, 27))	('LAMP2', 'Gene', '3920', (22, 27))
533885	33566442	The cell colony formation assay showed that knockdown of LAMP2a decreased the colony formation rate to more than 10% (Figure 3e,f), while overexpression of LAMP2a increased the colony formation rate to more than 10% as compared with the control cell lines (Figure 3g,h).	('colony formation rate', 'CPA', (78, 99))	('LAMP2', 'Gene', (156, 161))	('LAMP2', 'Gene', (57, 62))	('LAMP2', 'Gene', '3920', (57, 62))	('knockdown', 'Var', (44, 53))	('LAMP2', 'Gene', '3920', (156, 161))	('decreased', 'NegReg', (64, 73))
533888	33566442	LAMP2a silencing can increase the expression level of RND3.	('RND3', 'Gene', '390', (54, 58))	('expression level', 'MPA', (34, 50))	('LAMP2', 'Gene', '3920', (0, 5))	('LAMP2', 'Gene', (0, 5))	('increase', 'PosReg', (21, 29))	('silencing', 'Var', (7, 16))	('RND3', 'Gene', (54, 58))
533892	33566442	Previous research showed that inhibition of macroautophagy can increase the sensitivity of ESCC cells to cisplatin as macroautophagy can wipe out the damaged proteins and thus inhibit cell death.	('macroautophagy', 'CPA', (44, 58))	('increase', 'PosReg', (63, 71))	('inhibition', 'Var', (30, 40))	('death', 'Disease', 'MESH:D003643', (189, 194))	('death', 'Disease', (189, 194))	('sensitivity', 'MPA', (76, 87))	('wipe out', 'NegReg', (137, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('macroautophagy', 'CPA', (118, 132))	('inhibit', 'NegReg', (176, 183))
533895	33566442	In a dose-response study, after treatment with various concentrations of cisplatin, the IC50 values of LAMP2a knockdown cell lines KYSE150 shLAMP2a and 510 shLAMP2a were decreased to half of their parental cell lines (Figure 4a,b) and knockdown cell lines showed reduced cell viability when treated by cisplatin as compared with their parental cell lines, which contributes to cisplatin sensitivity (Figure 4c,d).	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (377, 386))	('LAMP2', 'Gene', '3920', (103, 108))	('cell viability', 'CPA', (271, 285))	('KYSE150', 'Var', (131, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (302, 311))	('LAMP2', 'Gene', '3920', (141, 146))	('reduced', 'NegReg', (263, 270))	('decreased', 'NegReg', (170, 179))	('IC50', 'MPA', (88, 92))	('LAMP2', 'Gene', (158, 163))	('LAMP2', 'Gene', (103, 108))	('LAMP2', 'Gene', '3920', (158, 163))	('LAMP2', 'Gene', (141, 146))
533897	33566442	We found the expression of LAMP2a is higher in the 510CDDP cell line compared with the parental 510 cell line (Figure 4e).	('LAMP2', 'Gene', '3920', (27, 32))	('510CDDP', 'Var', (51, 58))	('510CDDP', 'Chemical', '-', (51, 58))	('higher', 'PosReg', (37, 43))	('expression', 'MPA', (13, 23))	('LAMP2', 'Gene', (27, 32))
533898	33566442	We then knocked down LAMP2a in the 510CDDP cell line (Figure 4e) and found that the cisplatin resistance was partially lost in the 510CDDP shLAMP2a cell line as compared with the 510CDDP cell line, and the difference is significant (Figure 4f).	('lost', 'NegReg', (119, 123))	('knocked', 'Var', (8, 15))	('LAMP2', 'Gene', '3920', (21, 26))	('510CDDP', 'Chemical', '-', (179, 186))	('510CDDP', 'Chemical', '-', (35, 42))	('LAMP2', 'Gene', '3920', (141, 146))	('510CDDP', 'Var', (131, 138))	('510CDDP', 'Chemical', '-', (131, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('LAMP2', 'Gene', (21, 26))	('cisplatin resistance', 'MPA', (84, 104))	('LAMP2', 'Gene', (141, 146))
533899	33566442	All these results indicate that inhibition of CMA can decrease cisplatin resistance of ESCC cells.	('decrease', 'NegReg', (54, 62))	('inhibition', 'Var', (32, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('cisplatin resistance', 'MPA', (63, 83))	('CMA', 'Protein', (46, 49))
533900	33566442	We detected whether activating CMA can increase the cisplatin resistance in ESCC cell lines.	('activating', 'Var', (20, 30))	('increase', 'PosReg', (39, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('cisplatin resistance', 'MPA', (52, 72))
533916	33566442	Many cellular pathways that contribute to tumorigenesis were reported to be regulated by CMA.	('regulated', 'Reg', (76, 85))	('cellular pathways', 'Pathway', (5, 22))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CMA', 'Var', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
533919	33566442	At first, we found LAMP2a-mediated CMA affects the proliferation of ESCC cells through knocking down or overexpressing LAMP2a.	('overexpressing', 'PosReg', (104, 118))	('knocking down', 'Var', (87, 100))	('LAMP2', 'Gene', (19, 24))	('affects', 'Reg', (39, 46))	('proliferation', 'CPA', (51, 64))	('LAMP2', 'Gene', '3920', (19, 24))	('LAMP2', 'Gene', (119, 124))	('CMA', 'Disease', (35, 38))	('LAMP2', 'Gene', '3920', (119, 124))	('ESCC cells', 'CPA', (68, 78))
533927	33566442	Only maximal acitivation of CMA by AC220 and spautin-1 can further increase cisplatin resistance of ESCC while mild overexpression of LAMP2a cannot (Figure 5).	('AC220', 'Chemical', 'MESH:C544967', (35, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('LAMP2', 'Gene', (134, 139))	('AC220', 'Var', (35, 40))	('increase', 'PosReg', (67, 75))	('cisplatin resistance', 'MPA', (76, 96))	('LAMP2', 'Gene', '3920', (134, 139))	('spautin-1', 'Gene', (45, 54))
533930	33566442	Of note, AC220 and spautin-1 did not induce cell apoptosis in ESCC cell lines as reported in OCI-AML3 cells in previous research, 18  but they did inhibit ESCC cell proliferation.	('AC220', 'Chemical', 'MESH:C544967', (9, 14))	('OCI-AML3', 'CellLine', 'CVCL:1844', (93, 101))	('ESCC cell proliferation', 'CPA', (155, 178))	('AC220', 'Var', (9, 14))	('inhibit', 'NegReg', (147, 154))
533933	33627431	The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis SIRT2-mediated deacetylation of SMC1A promotes its phosphorylation and overcomes the oncogenic stress for tumor cell survival.	('SIRT2', 'Gene', '22933', (48, 53))	('SIRT2', 'Gene', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('phosphorylation', 'MPA', (181, 196))	('SMC1A', 'Gene', (162, 167))	('promotes', 'PosReg', (168, 176))	('SMC1A', 'Gene', '8243', (54, 59))	('SIRT2', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('deacetylation', 'Var', (145, 158))	('SIRT2', 'Gene', '22933', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (236, 241))	('SMC1A', 'Gene', '8243', (162, 167))	('SMC1A', 'Gene', (54, 59))
533935	33627431	We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents.	('SIRT2', 'Enzyme', (48, 53))	('acetylation', 'MPA', (101, 112))	('mitotic catastrophe', 'CPA', (177, 196))	('SMC1A-K579', 'Gene', (90, 100))	('inhibition', 'Var', (34, 44))	('causes', 'Reg', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('abnormal chromosome segregation', 'Phenotype', 'HP:0002916', (120, 151))	('abnormal chromosome', 'Phenotype', 'HP:0031411', (120, 139))	('abnormal chromosome segregation', 'CPA', (120, 151))	('vulnerability to chemotherapeutic agents', 'CPA', (232, 272))	('enhances', 'PosReg', (217, 225))	('induces', 'Reg', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('K579', 'Chemical', '-', (96, 100))	('cancer', 'Disease', (200, 206))
533936	33627431	Accordingly, the disruption of mitotic catastrophe accelerates tumorigenesis and cancer progression.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('disruption', 'Var', (17, 27))	('accelerates', 'PosReg', (51, 62))	('mitotic', 'CPA', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
533939	33627431	Early studies found that the abnormal expression of SIRT2 is associated with a variety of malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('expression', 'MPA', (38, 48))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('malignant tumors', 'Disease', (90, 106))	('abnormal', 'Var', (29, 37))	('SIRT2', 'Gene', (52, 57))	('malignant tumors', 'Disease', 'MESH:D009369', (90, 106))	('associated', 'Reg', (61, 71))
533941	33627431	A previous study showed that deletion of SIRT2 promotes tumorigenesis due to several mitotic defects.	('deletion', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mitotic defects', 'Disease', (85, 100))	('promotes', 'PosReg', (47, 55))	('mitotic defects', 'Disease', 'MESH:C536987', (85, 100))	('tumor', 'Disease', (56, 61))	('SIRT2', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
533948	33627431	In particular, thiomyristoyl (TM), a SIRT2-specific inhibitor, has obvious inhibitory effects on the growth of various human cancers, further suggesting a tumor-promoter function of SIRT2.	('growth', 'MPA', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('TM', 'Chemical', '-', (30, 32))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('thiomyristoyl', 'Var', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('thiomyristoyl', 'Chemical', '-', (15, 28))	('tumor', 'Disease', (155, 160))	('inhibitory effects', 'MPA', (75, 93))	('human', 'Species', '9606', (119, 124))
533953	33627431	SMC1A mutations lead to chromosomal instability and aneuploidy, suggesting a potential defect in the mitotic checkpoint.	('mitotic checkpoint', 'CPA', (101, 119))	('lead to', 'Reg', (16, 23))	('SMC1A', 'Gene', (0, 5))	('aneuploidy', 'Disease', (52, 62))	('chromosomal instability', 'Phenotype', 'HP:0040012', (24, 47))	('defect', 'NegReg', (87, 93))	('aneuploidy', 'Disease', 'MESH:D000782', (52, 62))	('chromosomal instability', 'MPA', (24, 47))	('mutations', 'Var', (6, 15))
533955	33627431	Overexpression of SMC1A contributes to colorectal cancer development and is a predictor of poor prognosis in late-stage colorectal cancer.	('colorectal cancer', 'Disease', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('SMC1A', 'Gene', (18, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('contributes', 'PosReg', (24, 35))	('Overexpression', 'Var', (0, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('colorectal cancer', 'Disease', (39, 56))
533960	33627431	Aberrant acetylation of nonhistone protein is associated with various diseases, especially cancer.	('nonhistone protein', 'Protein', (24, 42))	('acetylation', 'MPA', (9, 20))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (46, 56))
533963	33627431	SIRT2-mediated deacetylation of K579 in SMC1A promotes its phosphorylation and subsequently overcomes the mitotic catastrophe to allow tumor cell survival, an event associated with various early-stage cancers, particularly colonic carcinoma.	('K579', 'Var', (32, 36))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('overcomes', 'NegReg', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancers', 'Disease', (201, 208))	('K579', 'Chemical', '-', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('tumor', 'Disease', (135, 140))	('mitotic catastrophe', 'MPA', (106, 125))	('allow', 'PosReg', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('phosphorylation', 'MPA', (59, 74))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('promotes', 'PosReg', (46, 54))	('colonic carcinoma', 'Disease', (223, 240))	('colonic carcinoma', 'Disease', 'MESH:D003110', (223, 240))	('SMC1A', 'Gene', (40, 45))
533979	33627431	Treatment with nicotinamide (NAM) alone, an inhibitor of class III histone deacetylases (HDACs) (SIRT family deacetylases), or the combination of NAM and trichostatin A (TSA), class I and II HDAC blockers, enhanced acetylation (fig.	('acetylation', 'MPA', (215, 226))	('NAM', 'Chemical', 'MESH:D009536', (146, 149))	('NAM', 'Var', (146, 149))	('enhanced', 'PosReg', (206, 214))	('trichostatin A', 'Chemical', 'MESH:C012589', (154, 168))	('NAM', 'Chemical', 'MESH:D009536', (29, 32))	('nicotinamide', 'Chemical', 'MESH:D009536', (15, 27))	('TSA', 'Chemical', 'MESH:C012589', (170, 173))
533981	33627431	Furthermore, comparison of the level of endogenous SMC1A acetylation in SIRT2+/+ and SIRT2-/- MEFs showed that SIRT2 deficiency significantly increased SMC1A acetylation (Fig.	('increased', 'PosReg', (142, 151))	('deficiency', 'Var', (117, 127))	('MEFs', 'CellLine', 'CVCL:9115', (94, 98))	('SMC1A acetylation', 'MPA', (152, 169))	('SIRT2', 'Gene', (111, 116))
533984	33627431	We mutated each of the 10 putative acetylation sites to arginine (R, non-acetylatable mutant) using site-directed mutagenesis and then examined acetylation levels.	('acetylation', 'MPA', (144, 155))	('examined', 'Reg', (135, 143))	('mutated', 'Var', (3, 10))	('arginine', 'Chemical', 'MESH:D001120', (56, 64))
533985	33627431	Mutation of each lysine (K) to R variably decreased SMC1A acetylation, whereas only the arginine substitution of K579 caused minimal alteration of SMC1A acetylation with and without SIRT2 overexpression (fig.	('arginine', 'Chemical', 'MESH:D001120', (88, 96))	('decreased', 'NegReg', (42, 51))	('Mutation', 'Var', (0, 8))	('K579', 'Chemical', '-', (113, 117))	('SMC1A acetylation', 'MPA', (52, 69))	('lysine', 'Chemical', 'MESH:D008239', (17, 23))
533986	33627431	Thus, K579 may be a major acetylation site in SMC1A regulated by SIRT2.	('K579', 'Chemical', '-', (6, 10))	('K579', 'Var', (6, 10))	('SMC1A', 'Gene', (46, 51))
533988	33627431	Replacement of K579 with either non-acetylatable arginine (K579R) or acetylmimetic glutamine (K579Q) markedly reduced the overall acetylation of SMC1A when compared with the WT protein, supporting that K579 is a major acetylation site in SMC1A (Fig.	('glutamine', 'Chemical', 'MESH:D005973', (83, 92))	('K579', 'Var', (15, 19))	('K579', 'Chemical', '-', (94, 98))	('acetylation', 'MPA', (130, 141))	('reduced', 'NegReg', (110, 117))	('K579', 'Chemical', '-', (15, 19))	('K579R', 'Var', (59, 64))	('K579R', 'Mutation', 'p.K579R', (59, 64))	('K579Q', 'Var', (94, 99))	('K579Q', 'Mutation', 'p.K579Q', (94, 99))	('arginine', 'Chemical', 'MESH:D001120', (49, 57))	('K579', 'Chemical', '-', (202, 206))	('K579', 'Chemical', '-', (59, 63))
533994	33627431	These findings indicate that CBP is the acetyltransferase that targets SMC1A at K579, which is also a target for SIRT2-dependent deacetylation.	('SMC1A', 'Gene', (71, 76))	('K579', 'Chemical', '-', (80, 84))	('K579', 'Var', (80, 84))
533995	33627431	Phosphorylation of Ser957 and/or Ser966 of SMC1A (SMC1A-p) plays an important role in DNA damage-induced cell cycle checkpoint regulation.	('SMC1A', 'Gene', (43, 48))	('Ser957', 'Chemical', '-', (19, 25))	('Ser966', 'Var', (33, 39))	('Phosphorylation', 'MPA', (0, 15))	('Ser957', 'Var', (19, 25))	('SMC1A-p', 'Gene', '8243', (50, 57))	('DNA damage-induced', 'MPA', (86, 104))	('Ser966', 'Chemical', '-', (33, 39))	('SMC1A-p', 'Gene', (50, 57))	('cell cycle', 'CPA', (105, 115))
533996	33627431	S2A), we hypothesized that SIRT2-dependent deacetylation of K579 may affect mitosis through the regulation of SMC1A phosphorylation.	('K579', 'Gene', (60, 64))	('mitosis', 'CPA', (76, 83))	('affect', 'Reg', (69, 75))	('phosphorylation', 'MPA', (116, 131))	('K579', 'Chemical', '-', (60, 64))	('SMC1A', 'Gene', (110, 115))	('deacetylation', 'Var', (43, 56))
534000	33627431	To further establish the relationship between SIRT2 and SMC1A-p, we used short hairpin RNA (shRNA) to knock down SIRT2 in HCT116 cells (fig.	('HCT116', 'CellLine', 'CVCL:0291', (122, 128))	('SMC1A-p', 'Gene', '8243', (56, 63))	('SMC1A-p', 'Gene', (56, 63))	('SIRT2', 'Gene', (113, 118))	('knock down', 'Var', (102, 112))
534001	33627431	Depletion of SIRT2 led to a notable decrease of SMC1A-p in G2 and mitotic phases (fig.	('SMC1A-p', 'Gene', '8243', (48, 55))	('SMC1A-p', 'Gene', (48, 55))	('Depletion', 'Var', (0, 9))	('SIRT2', 'Gene', (13, 18))	('mitotic phases', 'CPA', (66, 80))	('decrease', 'NegReg', (36, 44))
534002	33627431	We found that oxidative stress generated by H2O2 increased SIRT2 expression and the interaction between SIRT2 and SMC1A (Fig.	('oxidative stress', 'MPA', (14, 30))	('increased', 'PosReg', (49, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (14, 30))	('expression', 'MPA', (65, 75))	('SIRT2', 'Gene', (59, 64))	('H2O2', 'Var', (44, 48))	('SMC1A', 'Gene', (114, 119))	('H2O2', 'Chemical', 'MESH:D006861', (44, 48))	('interaction', 'Interaction', (84, 95))
534005	33627431	SIRT2 deficiency significantly suppressed SMC1A-p under oxidative stress conditions when compared to WT SIRT2 in MEFs (Fig.	('SMC1A-p', 'Gene', '8243', (42, 49))	('MEFs', 'CellLine', 'CVCL:9115', (113, 117))	('SMC1A-p', 'Gene', (42, 49))	('SIRT2', 'Gene', (0, 5))	('deficiency', 'Var', (6, 16))	('oxidative stress', 'Phenotype', 'HP:0025464', (56, 72))	('suppressed', 'NegReg', (31, 41))
534007	33627431	The diminished H2O2-induced SMC1A-p resulting from SIRT2 knockdown in HCT116 cells showed substantial dose-dependent rescue upon expression of WT SIRT2 that is resistant to the SIRT2 shRNA.	('SMC1A-p', 'Gene', '8243', (28, 35))	('rescue', 'PosReg', (117, 123))	('SMC1A-p', 'Gene', (28, 35))	('H2O2', 'Chemical', 'MESH:D006861', (15, 19))	('knockdown', 'Var', (57, 66))	('HCT116', 'CellLine', 'CVCL:0291', (70, 76))	('diminished', 'NegReg', (4, 14))	('H2O2-induced', 'Gene', (15, 27))	('SIRT2', 'Gene', (51, 56))
534010	33627431	SMC1A K579Q mutant significantly impaired SMC1A-p when compared to WT and SMC1A K579R proteins in SMC1A knockdown HCT116 cells (Fig.	('SMC1A-p', 'Gene', '8243', (42, 49))	('SMC1A-p', 'Gene', (42, 49))	('impaired', 'NegReg', (33, 41))	('K579R', 'Mutation', 'p.K579R', (80, 85))	('HCT116', 'CellLine', 'CVCL:0291', (114, 120))	('K579Q', 'Var', (6, 11))	('K579Q', 'Mutation', 'p.K579Q', (6, 11))
534011	33627431	Furthermore, the negative correlation between K579 acetylation and phosphorylation of SMC1A in response to oxidative stress was concentration-dependent (fig.	('K579', 'Var', (46, 50))	('response to oxidative stress', 'MPA', (95, 123))	('K579', 'Chemical', '-', (46, 50))	('negative', 'NegReg', (17, 25))	('SMC1A', 'Gene', (86, 91))	('oxidative stress', 'Phenotype', 'HP:0025464', (107, 123))	('phosphorylation', 'MPA', (67, 82))	('acetylation', 'MPA', (51, 62))
534012	33627431	To further directly test the negative correlation, we analyzed the localizations of SMC1A K579 acetylation and phosphorylation during mitosis by immunofluorescence.	('K579', 'Chemical', '-', (90, 94))	('acetylation', 'MPA', (95, 106))	('SMC1A', 'Gene', (84, 89))	('K579', 'Var', (90, 94))	('phosphorylation', 'MPA', (111, 126))
534016	33627431	Previous studies have shown that Ataxia-Telangiectasia-Mutated (ATM) directly phosphorylates SMC1A at S957 and S966 in mammalian cells after exposure to ionizing irradiation.	('mammalian', 'Species', '9606', (119, 128))	('Ataxia', 'Phenotype', 'HP:0001251', (33, 39))	('Ataxia-Telangiectasia-Mutated', 'Gene', (33, 62))	('Telangiectasia', 'Phenotype', 'HP:0001009', (40, 54))	('ATM', 'Gene', (64, 67))	('S957', 'Var', (102, 106))	('SMC1A', 'Gene', (93, 98))	('ATM', 'Gene', '472', (64, 67))	('S966', 'Var', (111, 115))	('Ataxia-Telangiectasia-Mutated', 'Gene', '472', (33, 62))
534017	33627431	To further explore the mechanism by which acetylation of SMC1A at K579 inhibits its phosphorylation, we asked if acetylation affects the interaction between the main kinase ATM and SMC1A.	('SMC1A', 'Gene', (57, 62))	('acetylation', 'Var', (42, 53))	('inhibits', 'NegReg', (71, 79))	('ATM', 'Gene', '472', (173, 176))	('interaction', 'Interaction', (137, 148))	('K579', 'Var', (66, 70))	('K579', 'Chemical', '-', (66, 70))	('affects', 'Reg', (125, 132))	('phosphorylation', 'MPA', (84, 99))	('ATM', 'Gene', (173, 176))
534020	33627431	Reexpression of the acetylmimetic SMC1A K579Q into HCT116-shSMC1A cells diminished the ATM-SMC1A interaction and the SMC1A-p level in response to oxidative stress (Fig.	('ATM', 'Gene', '472', (87, 90))	('SMC1A-p', 'Gene', '8243', (117, 124))	('response to oxidative stress', 'MPA', (134, 162))	('SMC1A-p', 'Gene', (117, 124))	('HCT116', 'CellLine', 'CVCL:0291', (51, 57))	('K579Q', 'Var', (40, 45))	('diminished', 'NegReg', (72, 82))	('K579Q', 'Mutation', 'p.K579Q', (40, 45))	('oxidative stress', 'Phenotype', 'HP:0025464', (146, 162))	('ATM', 'Gene', (87, 90))
534021	33627431	The data thus far support that SIRT2-dependent SMC1A deacetylation at K579 regulates SMC1A phosphorylation by modulating the ATM-SMC1A interaction.	('phosphorylation', 'MPA', (91, 106))	('ATM', 'Gene', (125, 128))	('K579', 'Chemical', '-', (70, 74))	('regulates', 'Reg', (75, 84))	('ATM', 'Gene', '472', (125, 128))	('modulating', 'Reg', (110, 120))	('interaction', 'Interaction', (135, 146))	('K579', 'Var', (70, 74))	('deacetylation', 'Var', (53, 66))
534023	33627431	SMC1A WT, S957AS966A (AA, a nonphosphorylatable mutant with S957 and S966 replaced by alanine), or S957DS966D (DD, a phosphomimetic mutant created by replacing S957 and S966 with aspartate) mutant was stably reexpressed in HCT116 cell lines with knockdown of SMC1A (fig.	('S966', 'Var', (69, 73))	('S957AS966A', 'Var', (10, 20))	('alanine', 'Chemical', 'MESH:D000409', (86, 93))	('aspartate', 'Chemical', 'MESH:D001224', (179, 188))	('S957', 'Var', (60, 64))	('S957DS966D', 'Var', (99, 109))	('HCT116', 'CellLine', 'CVCL:0291', (223, 229))	('S957AS966A', 'CellLine', 'CVCL:7309', (10, 20))	('SMC1A', 'Gene', (259, 264))
534027	33627431	These data strongly suggest that defects in SMC1A phosphorylation, which is regulated by SIRT2, result in aberrant chromosome segregation and mitotic defects.	('aberrant chromosome segregation', 'CPA', (106, 137))	('SMC1A', 'Gene', (44, 49))	('phosphorylation', 'MPA', (50, 65))	('aberrant chromosome segregation', 'Phenotype', 'HP:0002916', (106, 137))	('defects', 'Var', (33, 40))	('mitotic defects', 'Disease', 'MESH:C536987', (142, 157))	('mitotic defects', 'Disease', (142, 157))	('result in', 'Reg', (96, 105))
534028	33627431	We found that both SMC1A K579R and K579Q mutants colocalized on the mitotic spindles similar to WT and showed no effect on localization of SMC1A (fig.	('K579Q', 'Mutation', 'p.K579Q', (35, 40))	('K579Q', 'Var', (35, 40))	('K579R', 'Var', (25, 30))	('K579R', 'Mutation', 'p.K579R', (25, 30))	('SMC1A', 'Gene', (19, 24))
534029	33627431	SMC1A WT, K579Q (acetylmimetic mutant), or K579Q-DD (K579Q-DD, phosphorylation rescue mutant) mutant was stably reexpressed in HCT116 cell lines with knockdown of SMC1A (fig.	('K579Q-DD', 'Var', (43, 51))	('K579Q', 'Mutation', 'p.K579Q', (53, 58))	('HCT116', 'CellLine', 'CVCL:0291', (127, 133))	('K579Q', 'Mutation', 'p.K579Q', (43, 48))	('SMC1A', 'Gene', (163, 168))	('K579Q', 'Var', (10, 15))	('K579Q', 'Mutation', 'p.K579Q', (10, 15))
534030	33627431	We found that cells expressing the SMC1A K579Q mutant, but not WT or K579Q-DD mutant, had increased spindle multipolarity from mitotic prophase until telophase under normal culture conditions, similar to those expressing the SMC1A AA mutant (Fig.	('K579Q', 'Var', (41, 46))	('K579Q', 'Mutation', 'p.K579Q', (41, 46))	('K579Q', 'Mutation', 'p.K579Q', (69, 74))	('increased', 'PosReg', (90, 99))	('SMC1A', 'Gene', (35, 40))
534031	33627431	Multipolar spindles were significantly rescued in cells expressing the SMC1A K579Q-DD mutant when compared to those expressing the K579Q mutant (Fig.	('SMC1A', 'Gene', (71, 76))	('rescued', 'PosReg', (39, 46))	('K579Q', 'Mutation', 'p.K579Q', (131, 136))	('K579Q-DD', 'Var', (77, 85))	('K579Q', 'Mutation', 'p.K579Q', (77, 82))	('Multipolar spindles', 'CPA', (0, 19))
534032	33627431	We further found that stable expression of the SMC1A K579Q mutant resulted in an increase in the number of multinucleated cells and enlarged cells when compared to the WT and K579Q-DD mutant groups.	('SMC1A', 'Gene', (47, 52))	('K579Q', 'Mutation', 'p.K579Q', (53, 58))	('K579Q', 'Var', (53, 58))	('increase', 'PosReg', (81, 89))	('K579Q', 'Mutation', 'p.K579Q', (175, 180))
534033	33627431	However, the SMC1A K579Q-DD mutant partially rescued the multinucleation phenotype (Fig.	('SMC1A', 'Gene', (13, 18))	('rescued', 'PosReg', (45, 52))	('multinucleation phenotype', 'CPA', (57, 82))	('K579Q', 'Mutation', 'p.K579Q', (19, 24))	('K579Q-DD mutant', 'Var', (19, 34))
534034	33627431	Metaphase chromosome spread analysis showed that stable expression of SMC1A K579Q or K579Q-DD mutant did not cause significant changes in chromosome structure when compared to the WT cells.	('K579Q', 'Var', (76, 81))	('K579Q', 'Mutation', 'p.K579Q', (76, 81))	('K579Q-DD', 'Var', (85, 93))	('SMC1A', 'Gene', (70, 75))	('K579Q', 'Mutation', 'p.K579Q', (85, 90))
534035	33627431	However, ~15% of SMC1A K579Q cells were aneuploid (chromosome numbers ranging from 48 to 90 per cell), whereas <4% of WT and K579Q-DD cells were aneuploid (Fig.	('K579Q', 'Mutation', 'p.K579Q', (125, 130))	('SMC1A', 'Gene', (17, 22))	('aneuploid', 'Disease', 'MESH:D000782', (145, 154))	('aneuploid', 'Disease', (40, 49))	('K579Q', 'Var', (23, 28))	('K579Q', 'Mutation', 'p.K579Q', (23, 28))	('aneuploid', 'Disease', 'MESH:D000782', (40, 49))	('aneuploid', 'Disease', (145, 154))
534036	33627431	These data strongly suggest that enforced K579 acetylation of SMC1A results in abnormal mitotic features and chromosome instability by inhibiting SMC1A phosphorylation.	('chromosome instability', 'Phenotype', 'HP:0040012', (109, 131))	('mitotic features', 'CPA', (88, 104))	('results in', 'Reg', (68, 78))	('chromosome instability', 'CPA', (109, 131))	('SMC1A', 'Gene', (62, 67))	('inhibiting', 'NegReg', (135, 145))	('phosphorylation', 'MPA', (152, 167))	('K579 acetylation', 'Var', (42, 58))	('SMC1A', 'Protein', (146, 151))	('K579', 'Chemical', '-', (42, 46))
534038	33627431	A previous study showed that phosphorylation of Ser957 and Ser966 of SMC1 stimulates binding to RNA export factor 1 (Rae1) during mitosis, which is required for bipolar spindle formation.	('Ser966', 'Var', (59, 65))	('stimulates', 'PosReg', (74, 84))	('SMC1', 'Gene', (69, 73))	('Ser966', 'Chemical', '-', (59, 65))	('Ser957', 'Chemical', '-', (48, 54))	('RNA export factor 1', 'Gene', (96, 115))	('RNA export factor 1', 'Gene', '8480', (96, 115))	('Ser957', 'Var', (48, 54))	('binding', 'Interaction', (85, 92))	('phosphorylation', 'MPA', (29, 44))
534039	33627431	We found that reexpression of acetylmimetic SMC1A K579Q into HCT116-shSMC1A cells significantly reduced SMC1A-Rae1 interaction (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (61, 67))	('K579Q', 'Var', (50, 55))	('K579Q', 'Mutation', 'p.K579Q', (50, 55))	('interaction', 'Interaction', (115, 126))	('reduced', 'NegReg', (96, 103))
534040	33627431	These results support that SIRT2-dependent SMC1A deacetylation at K579 induces mitotic defects by inhibiting SMC1A phosphorylation and thus blocking SMC1A-Rae1 interaction.	('SMC1A', 'Gene', (43, 48))	('blocking', 'NegReg', (140, 148))	('phosphorylation', 'MPA', (115, 130))	('K579', 'Chemical', '-', (66, 70))	('SMC1A', 'Protein', (109, 114))	('mitotic defects', 'Disease', (79, 94))	('deacetylation', 'Var', (49, 62))	('mitotic defects', 'Disease', 'MESH:C536987', (79, 94))	('K579', 'Var', (66, 70))	('interaction', 'Interaction', (160, 171))	('induces', 'Reg', (71, 78))	('inhibiting', 'NegReg', (98, 108))
534042	33627431	In this regard, we found that transient reexpression of the SMC1A K579Q mutant, but not SMC1A WT and the K579Q-DD mutants, in SMC1A-depleted HCT116 cells markedly increased the percentage of apoptotic cells formed in response to oxidative stress, indicating that K579 acetylation of SMC1A may induce cell apoptosis (Fig.	('SMC1A', 'Gene', (60, 65))	('K579Q', 'Var', (66, 71))	('K579 acetylation', 'Var', (263, 279))	('K579Q', 'Mutation', 'p.K579Q', (66, 71))	('K579', 'Chemical', '-', (105, 109))	('increased', 'PosReg', (163, 172))	('K579', 'Chemical', '-', (263, 267))	('K579Q', 'Mutation', 'p.K579Q', (105, 110))	('HCT116', 'CellLine', 'CVCL:0291', (141, 147))	('oxidative stress', 'Phenotype', 'HP:0025464', (229, 245))	('induce', 'PosReg', (293, 299))	('K579', 'Chemical', '-', (66, 70))	('cell apoptosis', 'CPA', (300, 314))
534043	33627431	Furthermore, the cleaved poly(adenosine 5'-diphosphate-ribose) polymerase (C-PARP) and cleaved caspase-3 (C-Cas3) were enhanced in the SMC1A K579Q mutant, but not in WT or the K579Q-DD mutant cells under oxidative stress (fig.	('caspase-3', 'Gene', '836', (95, 104))	('PARP', 'Gene', (77, 81))	('enhanced', 'PosReg', (119, 127))	('PARP', 'Gene', '11545', (77, 81))	('K579Q', 'Var', (141, 146))	('K579Q', 'Mutation', 'p.K579Q', (176, 181))	('K579Q', 'Mutation', 'p.K579Q', (141, 146))	('oxidative stress', 'Phenotype', 'HP:0025464', (204, 220))	('caspase-3', 'Gene', (95, 104))	('SMC1A', 'Gene', (135, 140))	('adenosine', 'Chemical', 'MESH:D000241', (30, 39))	('cleaved', 'MPA', (87, 94))
534044	33627431	SMC1A K579Q mutant also inhibited cell survival at 24 hours under oxidative stress (fig.	('SMC1A', 'Gene', (0, 5))	('inhibited', 'NegReg', (24, 33))	('cell survival at 24 hours', 'CPA', (34, 59))	('oxidative stress', 'Phenotype', 'HP:0025464', (66, 82))	('K579Q', 'Var', (6, 11))	('K579Q', 'Mutation', 'p.K579Q', (6, 11))
534046	33627431	To further clarify the role of SIRT2 regulation of SMC1A in mitosis, we examined whether mutations in SMC1A K579 could rescue SIRT2-deficient phenotypes in response to oxidative stress.	('SMC1A', 'Gene', (102, 107))	('K579', 'Chemical', '-', (108, 112))	('SIRT2-deficient phenotypes', 'MPA', (126, 152))	('oxidative stress', 'Phenotype', 'HP:0025464', (168, 184))	('mutations', 'Var', (89, 98))	('response to oxidative stress', 'MPA', (156, 184))
534048	33627431	Reexpression of the SMC1A K579Q mutant significantly increased the levels of cyclin B1 and H3-p in response to oxidative stress, even in cells lacking SIRT2, suggesting that hyperacetylation of SMC1A at K579 results in mitotic arrest (Fig.	('results in', 'Reg', (208, 218))	('SMC1A', 'Gene', (20, 25))	('mitotic arrest', 'Disease', (219, 233))	('H3-p', 'MPA', (91, 95))	('response to oxidative stress', 'MPA', (99, 127))	('mitotic arrest', 'Disease', 'MESH:D006323', (219, 233))	('K579', 'Var', (203, 207))	('increased', 'PosReg', (53, 62))	('K579Q', 'Var', (26, 31))	('hyperacetylation', 'Var', (174, 190))	('levels of cyclin B1', 'MPA', (67, 86))	('K579Q', 'Mutation', 'p.K579Q', (26, 31))	('K579', 'Chemical', '-', (26, 30))	('oxidative stress', 'Phenotype', 'HP:0025464', (111, 127))	('K579', 'Chemical', '-', (203, 207))
534050	33627431	The K579Q-DD mutant rescued the mitotic block in response to oxidative stress, even in cells lacking SIRT2 (Fig.	('mitotic', 'MPA', (32, 39))	('oxidative stress', 'Phenotype', 'HP:0025464', (61, 77))	('rescued', 'PosReg', (20, 27))	('K579Q-DD', 'Var', (4, 12))	('response to oxidative stress', 'MPA', (49, 77))	('K579Q', 'Mutation', 'p.K579Q', (4, 9))
534051	33627431	Together, the role of SIRT2 in the mitotic stress response, at least in part, can be attributed to SMC1A phosphorylation at Ser957 and Ser966 regulated by SMC1A acetylation.	('Ser966', 'Var', (135, 141))	('SMC1A', 'Gene', (99, 104))	('Ser957', 'Var', (124, 130))	('Ser966', 'Chemical', '-', (135, 141))	('acetylation', 'MPA', (161, 172))	('mitotic', 'CPA', (35, 42))	('Ser957', 'Chemical', '-', (124, 130))
534053	33627431	Our data suggest that K579 acetylation of SMC1A induces mitotic catastrophe characterized by mitotic defects and arrest, and promotes cell death.	('arrest', 'Disease', (113, 119))	('cell death', 'CPA', (134, 144))	('K579 acetylation', 'Var', (22, 38))	('SMC1A', 'Gene', (42, 47))	('K579', 'Chemical', '-', (22, 26))	('induces', 'Reg', (48, 55))	('arrest', 'Disease', 'MESH:D006323', (113, 119))	('mitotic catastrophe', 'CPA', (56, 75))	('mitotic defects', 'Disease', (93, 108))	('mitotic defects', 'Disease', 'MESH:C536987', (93, 108))	('promotes', 'PosReg', (125, 133))
534056	33627431	SMC1A-deficient HCT116 cells with stable reexpression of either WT or the K579R mutant SMC1A were injected subcutaneously into immunodeficient mice.	('HCT116', 'CellLine', 'CVCL:0291', (16, 22))	('immunodeficient', 'Disease', 'MESH:D007153', (127, 142))	('SMC1A', 'Gene', (87, 92))	('immunodeficient', 'Disease', (127, 142))	('K579R', 'Var', (74, 79))	('K579R', 'Mutation', 'p.K579R', (74, 79))	('mice', 'Species', '10090', (143, 147))
534057	33627431	The tumor volume and weight were significantly higher in the SMC1A-K579R-expressing HCT116 xenografts when compared to those derived from HCT116-expressing WT SMC1A (Fig.	('tumor', 'Disease', (4, 9))	('higher', 'PosReg', (47, 53))	('HCT116', 'Gene', (84, 90))	('SMC1A-K579R-expressing', 'Var', (61, 83))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('HCT116', 'CellLine', 'CVCL:0291', (138, 144))	('K579R', 'Mutation', 'p.K579R', (67, 72))	('HCT116', 'CellLine', 'CVCL:0291', (84, 90))
534058	33627431	The growth of AGK2-treated tumors expressing WT SMC1A was significantly inhibited, whereas tumors expressing the K579R mutant SMC1A showed no such effect (Fig.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('growth', 'CPA', (4, 10))	('K579R', 'Var', (113, 118))	('K579R', 'Mutation', 'p.K579R', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('inhibited', 'NegReg', (72, 81))	('SMC1A', 'Var', (48, 53))
534059	33627431	These data confirm that the anticancer effect of SIRT2 inhibition is achieved by regulating SMC1A at K579, and further indicate that Lys579 may be an essential determinant of cell mitotic catastrophe and a potential anticancer target.	('regulating', 'Reg', (81, 91))	('Lys579', 'Chemical', '-', (133, 139))	('SMC1A', 'Gene', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('K579', 'Chemical', '-', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('Lys579', 'Var', (133, 139))	('cancer', 'Disease', (220, 226))	('inhibition', 'NegReg', (55, 65))	('SIRT2', 'Gene', (49, 54))
534060	33627431	Our previous studies have shown that phosphorylation of SMC1A promotes hepatocellular carcinoma cell proliferation and migration.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 95))	('phosphorylation', 'Var', (37, 52))	('hepatocellular carcinoma', 'Disease', (71, 95))	('promotes', 'PosReg', (62, 70))	('SMC1A', 'Gene', (56, 61))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (71, 95))	('migration', 'CPA', (119, 128))
534061	33627431	To explore the biologic significance of SMC1A K579 acetylation in cell proliferation, we examined the proliferation of HCT116 cells stably expressing SMC1A WT, K579Q, or K579Q-DD.	('SMC1A', 'Gene', (150, 155))	('K579', 'Chemical', '-', (170, 174))	('K579', 'Chemical', '-', (160, 164))	('K579', 'Chemical', '-', (46, 50))	('HCT116', 'CellLine', 'CVCL:0291', (119, 125))	('K579Q', 'Mutation', 'p.K579Q', (170, 175))	('K579Q', 'Var', (160, 165))	('K579Q', 'Mutation', 'p.K579Q', (160, 165))	('K579Q-DD', 'Var', (170, 178))
534062	33627431	We found that the SMC1A K579Q mutant, but not WT or the K579Q-DD mutant, significantly inhibited the growth of HCT116 cells (fig.	('K579Q', 'Mutation', 'p.K579Q', (56, 61))	('SMC1A', 'Gene', (18, 23))	('inhibited', 'NegReg', (87, 96))	('HCT116', 'CellLine', 'CVCL:0291', (111, 117))	('growth', 'CPA', (101, 107))	('K579Q', 'Var', (24, 29))	('K579Q', 'Mutation', 'p.K579Q', (24, 29))
534063	33627431	To investigate whether the K579 acetylation of SMC1A also reduces tumor growth in vivo, we performed xenograft experiments and monitored tumor growth over a period of 26 days.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('reduces', 'NegReg', (58, 65))	('SMC1A', 'Gene', (47, 52))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (66, 71))	('K579 acetylation', 'Var', (27, 43))	('K579', 'Chemical', '-', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
534064	33627431	In line with the in vitro observations, the tumor volume and weight were significantly lower in the SMC1A-K579Q-expressing HCT116 xenografts when compared to those derived from HCT116-expressing WT or the SMC1A K579Q-DD mutant, with the latter developing the largest tumors (Fig.	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('K579Q', 'Mutation', 'p.K579Q', (106, 111))	('lower', 'NegReg', (87, 92))	('HCT116', 'CellLine', 'CVCL:0291', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('K579Q', 'Mutation', 'p.K579Q', (211, 216))	('SMC1A-K579Q-expressing', 'Var', (100, 122))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Disease', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('HCT116', 'CellLine', 'CVCL:0291', (177, 183))	('tumors', 'Disease', (267, 273))	('tumor', 'Disease', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('HCT116', 'Gene', (123, 129))
534066	33627431	Moreover, HCT116 SMC1A-K579Q xenografts displayed significantly lower SMC1A-p expression than SMC1A WT xenografts (fig.	('SMC1A-p', 'Gene', '8243', (70, 77))	('HCT116 SMC1A-K579Q', 'Var', (10, 28))	('SMC1A-p', 'Gene', (70, 77))	('lower', 'NegReg', (64, 69))	('K579Q', 'Mutation', 'p.K579Q', (23, 28))	('HCT116', 'CellLine', 'CVCL:0291', (10, 16))
534068	33627431	This result suggests that the tumor suppressor function of K579 acetylation of SMC1A might be achieved through its phosphorylation.	('SMC1A', 'Gene', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('K579 acetylation', 'Var', (59, 75))	('K579', 'Chemical', '-', (59, 63))	('phosphorylation', 'MPA', (115, 130))	('tumor', 'Disease', (30, 35))
534076	33627431	We further examined the effects of different concentrations of 5-FU or oxaliplatin on the survival of cells expressing SMC1A K579 mutants.	('K579', 'Chemical', '-', (125, 129))	('SMC1A', 'Gene', (119, 124))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (71, 82))	('5-FU', 'Chemical', 'MESH:D005472', (63, 67))	('mutants', 'Var', (130, 137))	('K579', 'Var', (125, 129))
534079	33627431	5, K and M) when compared to the SMC1A-WT group, suggesting that K579 acetylation of SMC1A enhances the chemosensitivity of these anticancer drugs by promoting cell apoptosis.	('SMC1A', 'Gene', (85, 90))	('enhances', 'PosReg', (91, 99))	('cell apoptosis', 'CPA', (160, 174))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('K579', 'Var', (65, 69))	('acetylation', 'MPA', (70, 81))	('promoting', 'PosReg', (150, 159))	('K579', 'Chemical', '-', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
534080	33627431	Together, these results demonstrate that the acetylmimetic substitution at Lys579 impairs the ability of SMC1A to promote colon cancer cell survival and tumor growth, suggesting that Lys579 may be a potential anticancer target.	('acetylmimetic substitution', 'Var', (45, 71))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Lys579', 'Gene', (75, 81))	('impairs', 'NegReg', (82, 89))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('promote', 'PosReg', (114, 121))	('tumor', 'Disease', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('cancer', 'Disease', (213, 219))	('colon cancer', 'Disease', (122, 134))	('Lys579', 'Chemical', '-', (183, 189))	('Lys579', 'Chemical', '-', (75, 81))	('cancer', 'Disease', (128, 134))
534081	33627431	Our results indicate that SMC1A acetylation at K579 results in mitotic catastrophe and inhibits tumor cell growth by regulating its phosphorylation.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('inhibits', 'NegReg', (87, 95))	('acetylation at K579', 'Var', (32, 51))	('K579', 'Chemical', '-', (47, 51))	('regulating', 'Reg', (117, 127))	('mitotic catastrophe', 'CPA', (63, 82))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('phosphorylation', 'MPA', (132, 147))	('results in', 'Reg', (52, 62))	('SMC1A', 'Gene', (26, 31))
534091	33627431	Furthermore, the K579-acetylated SMC1A levels were negatively correlated with SIRT2 (r = -0.2716; P = 0.0274; fig.	('negatively', 'NegReg', (51, 61))	('correlated', 'Interaction', (62, 72))	('K579-acetylated', 'Var', (17, 32))	('SIRT2', 'MPA', (78, 83))	('K579', 'Chemical', '-', (17, 21))
534094	33627431	These data indicate that SIRT2 and K579-acetylated SMC1A are potential universal biomarkers for early-stage human cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('K579', 'Chemical', '-', (35, 39))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('SMC1A', 'Gene', (51, 56))	('human', 'Species', '9606', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('K579-acetylated', 'Var', (35, 50))
534096	33627431	SIRT2 directly interacts with and deacetylates SMC1A at Lys579, which, in turn, regulates its phosphorylation under oxidative stress.	('phosphorylation under oxidative stress', 'MPA', (94, 132))	('deacetylates', 'Var', (34, 46))	('SMC1A', 'Gene', (47, 52))	('oxidative stress', 'Phenotype', 'HP:0025464', (116, 132))	('interacts', 'Interaction', (15, 24))	('SIRT2', 'Gene', (0, 5))	('Lys579', 'Chemical', '-', (56, 62))	('regulates', 'Reg', (80, 89))	('Lys579', 'Var', (56, 62))
534097	33627431	Hyperacetylation of SMC1A at K579 induces mitotic catastrophe and inhibits tumor growth, thus ultimately enhancing the effect of anticancer agents.	('Hyperacetylation', 'Var', (0, 16))	('K579', 'Var', (29, 33))	('SMC1A', 'Gene', (20, 25))	('enhancing', 'PosReg', (105, 114))	('K579', 'Chemical', '-', (29, 33))	('inhibits', 'NegReg', (66, 74))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('induces', 'Reg', (34, 41))	('mitotic catastrophe', 'CPA', (42, 61))	('effect', 'MPA', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Disease', (75, 80))
534098	33627431	Reduced K579-acetylated SMC1A expression and elevated SMC1A-p and SIRT2 levels were found in early-stage colorectal, breast, and esophageal carcinomas (Fig.	('expression', 'MPA', (30, 40))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (129, 149))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (129, 150))	('SMC1A', 'Gene', (24, 29))	('breast', 'Disease', (117, 123))	('K579', 'Chemical', '-', (8, 12))	('Reduced', 'NegReg', (0, 7))	('colorectal', 'Disease', (105, 115))	('SMC1A-p', 'Gene', '8243', (54, 61))	('elevated', 'PosReg', (45, 53))	('SMC1A-p', 'Gene', (54, 61))	('esophageal carcinomas', 'Disease', (129, 150))	('K579-acetylated', 'Var', (8, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (129, 150))
534099	33627431	These observations highlight the importance of the SIRT2-SMC1A axis in overcoming oncogenic stress and suggest that SMC1A K579 is a potential therapeutic target for human early-stage cancers.	('human', 'Species', '9606', (165, 170))	('cancers', 'Disease', (183, 190))	('overcoming oncogenic stress', 'MPA', (71, 98))	('K579', 'Var', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('K579', 'Chemical', '-', (122, 126))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
534106	33627431	These results indicate that a higher mitotic index caused by deletion of SIRT2 or SMC1A is only partly due to abnormal SMC1A-p, and that other signal pathways may also be involved.	('SMC1A', 'Gene', (82, 87))	('SIRT2', 'Gene', (73, 78))	('mitotic index', 'CPA', (37, 50))	('higher', 'PosReg', (30, 36))	('deletion', 'Var', (61, 69))	('SMC1A-p', 'Gene', '8243', (119, 126))	('SMC1A-p', 'Gene', (119, 126))
534107	33627431	In this study, we found that cells expressing the SMC1A K579Q mutant, but not WT or the phosphorylation rescue K579Q-S957DS966D mutant, exhibit distinct multipolar spindles during mitosis through a mechanism of SMC1A-p inhibition, suggesting a critical role of this mutant in mitotic spindle multipolarity characteristic of cancer cells.	('multipolar spindles', 'CPA', (153, 172))	('cancer', 'Disease', (324, 330))	('SMC1A', 'Gene', (50, 55))	('K579Q', 'Var', (56, 61))	('K579Q', 'Mutation', 'p.K579Q', (111, 116))	('K579Q', 'Mutation', 'p.K579Q', (56, 61))	('SMC1A-p', 'Gene', '8243', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('SMC1A-p', 'Gene', (211, 218))	('cancer', 'Disease', 'MESH:D009369', (324, 330))
534108	33627431	Previous work showed that phosphorylation of Ser957 and Ser966 of SMC1A stimulates binding to Rae1 during mitosis, which is required for bipolar spindle formation.	('Ser966', 'Var', (56, 62))	('Ser957', 'Var', (45, 51))	('binding', 'Interaction', (83, 90))	('Ser966', 'Chemical', '-', (56, 62))	('Ser957', 'Chemical', '-', (45, 51))	('SMC1A', 'Gene', (66, 71))	('Rae1', 'Protein', (94, 98))	('stimulates', 'PosReg', (72, 82))	('phosphorylation', 'MPA', (26, 41))
534109	33627431	We found that reexpression of acetylmimetic SMC1A K579Q in HCT116-shSMC1A cells significantly reduced SMC1A-Rae1 interaction.	('reduced', 'NegReg', (94, 101))	('HCT116', 'CellLine', 'CVCL:0291', (59, 65))	('K579Q', 'Var', (50, 55))	('K579Q', 'Mutation', 'p.K579Q', (50, 55))	('interaction', 'Interaction', (113, 124))
534111	33627431	Thus, activating the mitotic catastrophe is an attractive anticancer therapy.	('activating', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mitotic catastrophe', 'CPA', (21, 40))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
534112	33627431	Consistent with an early study on mitotic catastrophe characteristics, we have found that hyperacetylation of SMC1A at K579 leads to mitotic arrest with defective mitotic features and ultimately cell apoptosis.	('hyperacetylation', 'Var', (90, 106))	('mitotic arrest', 'Disease', (133, 147))	('mitotic arrest', 'Disease', 'MESH:D006323', (133, 147))	('K579', 'Var', (119, 123))	('cell apoptosis', 'CPA', (195, 209))	('leads to', 'Reg', (124, 132))	('K579', 'Chemical', '-', (119, 123))	('SMC1A', 'Gene', (110, 115))
534113	33627431	Given that SIRT2 deacetylates SMC1A at K579, small-molecule inhibitors of SIRT2 that interfere with mitotic checkpoint signaling may also be of potential clinical use to disrupt tumor cell proliferation.	('SMC1A', 'Gene', (30, 35))	('tumor', 'Disease', (178, 183))	('SIRT2', 'Gene', (74, 79))	('K579', 'Var', (39, 43))	('mitotic checkpoint signaling', 'MPA', (100, 128))	('interfere', 'NegReg', (85, 94))	('inhibitors', 'Var', (60, 70))	('K579', 'Chemical', '-', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
534119	33627431	Under physiological conditions (normal cell), the inhibition of SIRT2 leads to genomic instability and carcinogenesis.	('inhibition', 'Var', (50, 60))	('genomic instability', 'CPA', (79, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('leads to', 'Reg', (70, 78))	('SIRT2', 'Gene', (64, 69))	('carcinogenesis', 'Disease', (103, 117))
534121	33627431	Inhibition of SIRT2 in tumors inevitably leads to gross genomic instability and ultimately tumor cell death.	('gross genomic instability', 'MPA', (50, 75))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('leads to', 'Reg', (41, 49))	('tumor cell death', 'Disease', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('SIRT2', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Inhibition', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor cell death', 'Disease', 'MESH:D003643', (91, 107))
534126	33627431	Mutation and/or up-regulation of SMC1A is commonly observed in human colorectal carcinomas, breast cancers, and gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('breast cancers', 'Phenotype', 'HP:0003002', (92, 106))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (69, 90))	('colorectal carcinomas', 'Disease', (69, 90))	('SMC1A', 'Gene', (33, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('human', 'Species', '9606', (63, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('up-regulation', 'PosReg', (16, 29))	('gliomas', 'Disease', (112, 119))	('observed', 'Reg', (51, 59))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('Mutation', 'Var', (0, 8))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancers', 'Disease', 'MESH:D001943', (92, 106))	('breast cancers', 'Disease', (92, 106))
534131	33627431	We previously reported that phosphorylation of SMC1A promotes hepatocellular carcinoma cell proliferation and migration, a phenomenon in line with the results observed in colorectal cancer.	('phosphorylation', 'Var', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('SMC1A', 'Gene', (47, 52))	('hepatocellular carcinoma', 'Disease', (62, 86))	('promotes', 'PosReg', (53, 61))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (62, 86))	('colorectal cancer', 'Disease', (171, 188))	('migration', 'CPA', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (171, 188))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (62, 86))
534132	33627431	Here, we found that SIRT2-mediated SMC1A deacetylation at K579 promotes phosphorylation of SMC1A that, in turn, enhances cell proliferation and tumor growth.	('SMC1A', 'Gene', (91, 96))	('tumor', 'Disease', (144, 149))	('deacetylation', 'Var', (41, 54))	('enhances', 'PosReg', (112, 120))	('promotes', 'PosReg', (63, 71))	('cell proliferation', 'CPA', (121, 139))	('phosphorylation', 'MPA', (72, 87))	('SMC1A', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('K579', 'Var', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('K579', 'Chemical', '-', (58, 62))
534134	33627431	These findings suggest a potential for combined cytotoxic and SMC1A K579-targeted therapy to achieve a synergistic treatment effect.	('SMC1A', 'Gene', (62, 67))	('K579', 'Chemical', '-', (68, 72))	('K579-targeted', 'Var', (68, 81))
534135	33627431	In addition, K579-acetylated SMC1A expression was significantly decreased, whereas SMC1A-p and SIRT2 levels were significantly increased in early-stage human cancers of various origins, suggesting that the deacetylation-phosphorylation regulation of SIRT2-SMC1A axis is universal in early-stage human cancers.	('human', 'Species', '9606', (295, 300))	('cancers', 'Phenotype', 'HP:0002664', (301, 308))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancers', 'Disease', (301, 308))	('SMC1A-p', 'Gene', '8243', (83, 90))	('cancers', 'Disease', 'MESH:D009369', (301, 308))	('K579-acetylated', 'Var', (13, 28))	('SMC1A-p', 'Gene', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('expression', 'MPA', (35, 45))	('cancers', 'Disease', (158, 165))	('human', 'Species', '9606', (152, 157))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('K579', 'Chemical', '-', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('SMC1A', 'Gene', (29, 34))	('increased', 'PosReg', (127, 136))	('decreased', 'NegReg', (64, 73))
534136	33627431	These findings not only indicate that SIRT2 plays a vital role in early precursor lesions to overcome oncogenic stress but also suggest that K579 acetylation of SMC1A may be a potential novel anticancer target via inhibition of SMC1A phosphorylation.	('K579', 'Chemical', '-', (141, 145))	('SMC1A', 'Gene', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('inhibition', 'NegReg', (214, 224))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('phosphorylation', 'MPA', (234, 249))	('cancer', 'Disease', (196, 202))	('K579 acetylation', 'Var', (141, 157))
534137	33627431	SMC1A acetylation causes mitotic catastrophe and inhibits tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('SMC1A', 'Gene', (0, 5))	('acetylation', 'Var', (6, 17))	('mitotic catastrophe', 'Disease', (25, 44))	('inhibits', 'NegReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('causes', 'Reg', (18, 24))
534139	33627431	These observations further indicate the potential utility of SIRT2 inhibitors or targeting of SMC1A K579 acetylation for early-stage cancer treatment.	('acetylation', 'MPA', (105, 116))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('K579', 'Var', (100, 104))	('cancer', 'Disease', (133, 139))	('SIRT2', 'Enzyme', (61, 66))	('SMC1A', 'Gene', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('K579', 'Chemical', '-', (100, 104))
534148	33627431	AGK2 (S7577), NAM (S1899), and TSA (S1045) were purchased from Selleck.	('NAM', 'Chemical', 'MESH:D009536', (14, 17))	('TSA', 'Chemical', 'MESH:C012589', (31, 34))	('S1045', 'Var', (36, 41))	('S7577', 'Var', (6, 11))
534149	33627431	Flag peptide (F3290), thymidine (T1895), isopropyl-beta-d-thiogalactopyranoside (IPTG; I6758), Giemsa stain (GS500), colchicines (C3915), 5-FU (F6627), and oxaliplatin (O9512) were from Sigma-Aldrich.	('IPTG', 'Chemical', '-', (81, 85))	('colchicines', 'Chemical', 'MESH:D003078', (117, 128))	('5-FU', 'Chemical', 'MESH:D005472', (138, 142))	('F3290', 'Var', (14, 19))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (156, 167))	('T1895', 'Var', (33, 38))	('isopropyl-beta-d-thiogalactopyranoside', 'Chemical', '-', (41, 79))	('thymidine', 'Chemical', 'MESH:D013936', (22, 31))	('Flag peptide', 'Chemical', 'MESH:C085706', (0, 12))	('C3915', 'Var', (130, 135))
534155	33627431	The plasmids containing specific point mutations of SMC1A or SIRT2 were generated using the QuikChange Site-Directed Mutagenesis Kit (Stratagene, CA, USA).	('point mutations', 'Var', (33, 48))	('SIRT2', 'Gene', (61, 66))	('SMC1A', 'Gene', (52, 57))	('Kit', 'Gene', (129, 132))	('Kit', 'Gene', '3815', (129, 132))
534195	33627431	Nude mice (BALB/C, 4-week-old female, N = 10) were injected subcutaneously into the right flank region with 5 x 106 stable HCT116 SMC1A knockdown cells with reexpression of WT, K579Q, or K579Q-S957DS966D (K579Q-DD) mutant SMC1A.	('Nude mice', 'Species', '10090', (0, 9))	('HCT116', 'CellLine', 'CVCL:0291', (123, 129))	('K579Q', 'Mutation', 'p.K579Q', (187, 192))	('K579Q', 'Var', (177, 182))	('K579Q', 'Mutation', 'p.K579Q', (177, 182))	('K579Q', 'Mutation', 'p.K579Q', (205, 210))	('SMC1A', 'Gene', (222, 227))	('K579Q-S957DS966D (K579Q-DD', 'Var', (187, 213))
534351	31550463	Low muscle mass has been associated with chemotherapy-induced toxicity, hospitalization and a prolonged treatment course in various malignancies including esophageal cancer.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('associated', 'Reg', (25, 35))	('Low', 'Var', (0, 3))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('age', 'Gene', '5973', (160, 163))	('malignancies', 'Disease', 'MESH:D009369', (132, 144))	('Low muscle mass', 'Phenotype', 'HP:0003199', (0, 15))	('toxicity', 'Disease', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('malignancies', 'Disease', (132, 144))	('age', 'Gene', (160, 163))
534397	29440962	As he was concerned of the risks of pneumatic dilatation (PD), per oral endoscopic myotomy (POEM) and surgery, he decided for botulinum toxin injections, 25IE botulinum toxin to each quadrant of the LES.	('PD', 'Disease', 'MESH:D010300', (58, 60))	('pneumatic dilatation', 'Disease', (36, 56))	('25IE', 'Var', (154, 158))	('dilatation', 'Phenotype', 'HP:0002617', (46, 56))	('pneumatic dilatation', 'Disease', 'MESH:D002311', (36, 56))
534513	27345473	According to ROC curves, the area under the curve for plasma miRNA-506 was 0.835, indicating statistical significance for ESCC diagnosis by plasma miRNA-506 (P<0.001).	('ESCC', 'Disease', (122, 126))	('plasma miRNA-506', 'Var', (140, 156))	('miRNA-506', 'Chemical', '-', (147, 156))	('miRNA-506', 'Chemical', '-', (61, 70))
534514	27345473	Kaplan-Meier analysis showed that patients with high miRNA-506 expression had significantly shorter survival time than those with low miRNA-506 expression.	('miRNA-506', 'Chemical', '-', (53, 62))	('miRNA-506', 'Chemical', '-', (134, 143))	('high miRNA-506 expression', 'Var', (48, 73))	('patients', 'Species', '9606', (34, 42))	('survival time', 'CPA', (100, 113))	('shorter', 'NegReg', (92, 99))
534516	27345473	miRNA-506 can serve as an important molecular marker for diagnosis and prognostic prediction of ESCC.	('miRNA-506', 'Chemical', '-', (0, 9))	('ESCC', 'Disease', (96, 100))	('miRNA-506', 'Var', (0, 9))
534522	27345473	Factors that lead to postoperative recurrence, invasion, and metastasis include activation of proto-oncogenes, inactivation of tumor suppressor genes, and down-regulation or abnormal expression of multiple proteins.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('invasion', 'CPA', (47, 55))	('metastasis', 'CPA', (61, 71))	('inactivation', 'Var', (111, 123))	('proto-oncogenes', 'Gene', (94, 109))	('expression', 'MPA', (183, 193))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('multiple proteins', 'Protein', (197, 214))	('down-regulation', 'NegReg', (155, 170))	('proteins', 'Protein', (206, 214))	('activation', 'PosReg', (80, 90))
534526	27345473	Approximately 1000 different miRNAs have been identified, of which miRNA-506 is an important regulator of tumorigenesis.	('miRNA-506', 'Chemical', '-', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('miRNA-506', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
534542	27345473	Compared to that of patients with stage I or II ESCC, or with a tumor length of <4 cm, the expression of miRNA-506 was higher in the plasma of patients with stage III ESCC or with a tumor length >4 cm (P<0.001, P=0.031, respectively; Figures 2, 3).	('expression', 'MPA', (91, 101))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (182, 187))	('miRNA-506', 'Chemical', '-', (105, 114))	('ESCC', 'Disease', (167, 171))	('higher', 'PosReg', (119, 125))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (20, 28))	('miRNA-506', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
534544	27345473	We then analyzed the relationship between the expression of plasma miRNA-506 and the clinicopathological features of ESCC; the results indicated that the expression level of plasma miRNA-506 was closely associated with lymph node status (P=0.004), TNM stage (P=0.031), and tumor length (P<0.001).	('plasma miRNA-506', 'Var', (174, 190))	('miRNA-506', 'Chemical', '-', (67, 76))	('associated', 'Reg', (203, 213))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('miRNA-506', 'Chemical', '-', (181, 190))	('lymph node status', 'CPA', (219, 236))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('ESCC', 'Disease', (117, 121))	('TNM stage', 'CPA', (248, 257))	('expression', 'MPA', (154, 164))
534550	27345473	Kaplan-Meier analysis showed that patients with high miRNA-506 expression had significantly shorter survival time (DFS and OS) than that of patients with low miRNA-506 expression.	('miRNA-506', 'Chemical', '-', (53, 62))	('miRNA-506', 'Chemical', '-', (158, 167))	('high miRNA-506 expression', 'Var', (48, 73))	('patients', 'Species', '9606', (34, 42))	('survival time', 'CPA', (100, 113))	('patients', 'Species', '9606', (140, 148))	('shorter', 'NegReg', (92, 99))
534553	27345473	Multivariate analysis using the Cox regression model suggested that high miRNA-506 expression was an independent indicator of poor patient prognosis [DFS: HR=2.647, 95% CI=(1.529-4.582), P=0.001; OS HR=2.351, 95% CI=(1.317-4.195), P=0.004].	('high', 'Var', (68, 72))	('miRNA-506', 'Chemical', '-', (73, 82))	('expression', 'MPA', (83, 93))	('patient', 'Species', '9606', (131, 138))	('miRNA-506', 'Gene', (73, 82))
534556	27345473	An increasing amount of evidence suggests that miRNA-506 inhibits the expression of its target genes through binding to the target mRNAs, and is involved in regulating and controlling cell proliferation, apoptosis, cell cycle arrest, cell aging, cell differentiation, epithelial-mesenchymal transition, cell invasion, and metastasis, as well as initiation and development of tumors.	('cell differentiation', 'CPA', (246, 266))	('cell proliferation', 'CPA', (184, 202))	('tumors', 'Disease', 'MESH:D009369', (375, 381))	('involved', 'Reg', (145, 153))	('apoptosis', 'CPA', (204, 213))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (215, 232))	('cell invasion', 'CPA', (303, 316))	('metastasis', 'CPA', (322, 332))	('miRNA-506', 'Var', (47, 56))	('miRNA-506', 'Chemical', '-', (47, 56))	('expression', 'MPA', (70, 80))	('tumors', 'Phenotype', 'HP:0002664', (375, 381))	('cell aging', 'CPA', (234, 244))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('cell cycle arrest', 'CPA', (215, 232))	('tumors', 'Disease', (375, 381))	('epithelial-mesenchymal transition', 'CPA', (268, 301))	('binding', 'Interaction', (109, 116))	('inhibits', 'NegReg', (57, 65))
534559	27345473	However, there is also research showing that miRNA-506 has an oncogenic role in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('miRNA-506', 'Var', (45, 54))	('miRNA-506', 'Chemical', '-', (45, 54))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
534564	27345473	Subgroup analysis showed that the expression level of miRNA-506 was higher in the plasma of patients with stage III ESCC or those with a tumor length >4 cm.	('tumor', 'Disease', (137, 142))	('ESCC', 'Disease', (116, 120))	('higher', 'PosReg', (68, 74))	('miRNA-506', 'Var', (54, 63))	('patients', 'Species', '9606', (92, 100))	('stage III ESCC', 'Disease', (106, 120))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('miRNA-506', 'Chemical', '-', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('expression level', 'MPA', (34, 50))
534565	27345473	We also discovered that the expression level of miRNA-506 in the plasma was closely associated with clinicopathological features of ESCC patients, such as lymph node status, TNM stage, and tumor length.	('tumor', 'Disease', (189, 194))	('miRNA-506', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('expression', 'MPA', (28, 38))	('patients', 'Species', '9606', (137, 145))	('miRNA-506', 'Chemical', '-', (48, 57))	('associated', 'Reg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('ESCC', 'Disease', (132, 136))
534566	27345473	This suggests that miRNA-506 might promote the growth, proliferation, and invasion of ESCC tumor cells.	('invasion', 'CPA', (74, 82))	('miRNA-506', 'Chemical', '-', (19, 28))	('proliferation', 'CPA', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('miRNA-506', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('promote', 'PosReg', (35, 42))	('growth', 'CPA', (47, 53))	('tumor', 'Disease', (91, 96))
534568	27345473	Multi-factor regression analysis revealed that high miRNA-506 expression was an important, independent indicator for predicting poor prognosis in ESCC patients.	('miRNA-506', 'Var', (52, 61))	('expression', 'MPA', (62, 72))	('patients', 'Species', '9606', (151, 159))	('miRNA-506', 'Chemical', '-', (52, 61))	('ESCC', 'Disease', (146, 150))
534572	27345473	First, miRNA-506 could directly bind to cyclin-dependent kinase4/6 (CDK4/6), and then to cyclinD, regulating cell cycle progression from G1 to S stage.	('miRNA-506', 'Var', (7, 16))	('regulating', 'Reg', (98, 108))	('cyclin-dependent kinase4/6', 'Gene', (40, 66))	('CDK4/6', 'Gene', '1019;1021', (68, 74))	('bind', 'Interaction', (32, 36))	('miRNA-506', 'Chemical', '-', (7, 16))	('cyclin-dependent kinase4/6', 'Gene', '1019;1021', (40, 66))	('CDK4/6', 'Gene', (68, 74))	('cell cycle progression', 'CPA', (109, 131))
534573	27345473	Second, miRNA-506 would inhibit the expression of CDK4/6, which could stimulate proliferation of tumor cells in a feedback-mediated manner.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('miRNA-506', 'Chemical', '-', (8, 17))	('CDK4/6', 'Gene', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('miRNA-506', 'Var', (8, 17))	('tumor', 'Disease', (97, 102))	('inhibit', 'NegReg', (24, 31))	('CDK4/6', 'Gene', '1019;1021', (50, 56))	('stimulate', 'PosReg', (70, 79))	('expression', 'MPA', (36, 46))
534574	27345473	Third, miRNA-506 could inhibit the expression of SNAI2 and consequently increase the expression of E-cadherin, which would confer adhesiveness to mobile tumor cells.	('expression', 'MPA', (85, 95))	('miRNA-506', 'Var', (7, 16))	('increase', 'PosReg', (72, 80))	('mobile tumor', 'Disease', 'MESH:D014086', (146, 158))	('mobile tumor', 'Disease', (146, 158))	('inhibit', 'NegReg', (23, 30))	('miRNA-506', 'Chemical', '-', (7, 16))	('expression', 'MPA', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('SNAI2', 'Gene', '6591', (49, 54))	('E-cadherin', 'Gene', (99, 109))	('SNAI2', 'Gene', (49, 54))	('E-cadherin', 'Gene', '999', (99, 109))	('adhesiveness', 'CPA', (130, 142))
534581	26783961	ALDH1 has three main isotypes, ALDH1A1, ALDH1A2, and ALDH1A3, and is a marker of normal tissue stem cells (SC) and cancer stem cells (CSC), where it is involved in self-renewal, differentiation and self-protection.	('ALDH1A3', 'Gene', (53, 60))	('cancer', 'Disease', (115, 121))	('ALDH1A1', 'Var', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ALDH1', 'Gene', (0, 5))	('ALDH1A2', 'Gene', '8854', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ALDH1A2', 'Gene', (40, 47))
534588	26783961	More than 160 ALDH cDNAs or genes have been isolated and sequenced from various sources (e.g., bacteria, yeast, fungi, plants and animals), and studies report 19 putatively functional genes and many pseudogenes in the human genome (Table 1).	('yeast', 'Species', '4932', (105, 110))	('pseudogenes', 'Var', (199, 210))	('human', 'Species', '9606', (218, 223))	('ALDH', 'Gene', (14, 18))	('ALDH', 'Gene', '216', (14, 18))
534634	26783961	Although ALDH1A1 was first indicated as a marker and a characteristic feature of primitive human hematopoietic stem cells (HSCs) isolated from bone marrow and of neural stem cells, recent studies have reported that other ALDHs (i.e., ALDH1A2, ALDH1A3, ALDH1A7, ALDH2*2, ALDH3A1, ALDH4A1, ALDH5A1, ALDH6A1, and ALDH9A1) are also involved, because ALDH1A1 deficiency does not alter Aldefluor positivity in the analysis of Aldh1a1 -/- mouse.	('ALDH', 'Gene', (288, 292))	('ALDH', 'Gene', (297, 301))	('ALDH', 'Gene', '216', (270, 274))	('ALDH', 'Gene', '216', (9, 13))	('ALDH1A7', 'Gene', '26358', (252, 259))	('ALDH2', 'Gene', '217', (261, 266))	('ALDH4A1', 'Gene', (279, 286))	('ALDH', 'Gene', (279, 283))	('ALDH3A1', 'Gene', '218', (270, 277))	('ALDH', 'Gene', (270, 274))	('ALDH1A2', 'Gene', '8854', (234, 241))	('ALDH', 'Gene', (9, 13))	('ALDH', 'Gene', '216', (221, 225))	('ALDH', 'Gene', '216', (310, 314))	('ALDH3A1', 'Gene', (270, 277))	('ALDH1A2', 'Gene', (234, 241))	('Aldefluor', 'Chemical', '-', (380, 389))	('deficiency', 'Var', (354, 364))	('ALDH', 'Gene', (221, 225))	('ALDH', 'Gene', (310, 314))	('ALDH', 'Gene', '216', (261, 265))	('ALDH', 'Gene', '216', (243, 247))	('ALDH', 'Gene', '216', (252, 256))	('ALDH6A1', 'Gene', '4329', (297, 304))	('ALDH', 'Gene', '216', (346, 350))	('ALDH4A1', 'Gene', '8659', (279, 286))	('ALDH', 'Gene', '216', (234, 238))	('ALDH2', 'Gene', (261, 266))	('ALDH5A1', 'Gene', (288, 295))	('ALDH', 'Gene', (261, 265))	('ALDH9A1', 'Gene', '223', (310, 317))	('ALDH6A1', 'Gene', (297, 304))	('ALDH9A1', 'Gene', (310, 317))	('mouse', 'Species', '10090', (432, 437))	('ALDH', 'Gene', (346, 350))	('ALDH', 'Gene', (243, 247))	('ALDH', 'Gene', (252, 256))	('ALDH', 'Gene', '216', (288, 292))	('ALDH', 'Gene', '216', (297, 301))	('ALDH5A1', 'Gene', '7915', (288, 295))	('ALDH', 'Gene', '216', (279, 283))	('ALDH', 'Gene', (234, 238))	('ALDH1A7', 'Gene', (252, 259))	('human', 'Species', '9606', (91, 96))
534655	26783961	Surprisingly, it has been documented that high ALDH1A1 expression does not always correlate with highly malignant phenotypes and poor clinical outcome in a range of cancers (Table 3).	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('high', 'Var', (42, 46))	('cancers', 'Disease', (165, 172))	('ALDH1A1', 'Gene', (47, 54))
534663	26783961	On the other hand, the role of ALDH1A1 in CSCs was demonstrated in that ALDH1 high cells from breast cancer isolated by Aldeflour assay were the tumor-initiating cells, indicating ALDH1A1 might drive tumor proliferation, differentiation, and maintenance.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('ALDH1 high', 'Gene', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ALDH1A1', 'Var', (180, 187))	('tumor', 'Disease', (200, 205))	('differentiation', 'CPA', (221, 236))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('maintenance', 'CPA', (242, 253))	('drive', 'PosReg', (194, 199))	('breast cancer', 'Disease', (94, 107))
534696	26783961	reported that the stable knockdown of ALDH1A1 dramatically decreased the ability of ovarian cancer cells to form colonies.	('ALDH1A1', 'Gene', (38, 45))	('ovarian cancer', 'Disease', (84, 98))	('colon', 'Disease', (113, 118))	('decreased', 'NegReg', (59, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('colon', 'Disease', 'MESH:D015179', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('knockdown', 'Var', (25, 34))
534703	26783961	Additionally, ALDH1A1-high esophageal squamous cell carcinoma cells possess CSC properties and the expression of ALDH1A1 is associated with esophageal squamous dysplasia and carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (27, 61))	('CSC properties', 'CPA', (76, 90))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (151, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('esophageal squamous dysplasia and carcinoma', 'Disease', 'MESH:D000077277', (140, 183))	('associated', 'Reg', (124, 134))	('expression', 'Var', (99, 109))	('ALDH1A1', 'Gene', (113, 120))	('esophageal squamous cell carcinoma', 'Disease', (27, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))
534709	26783961	In addition, survival times (overall survival and recurrence-free survival) of gastric cancer patients with high ALDH1A1 expression were significantly shorter than for those with low ALDH1A1 expression.	('patients', 'Species', '9606', (94, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('shorter', 'NegReg', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ALDH1A1', 'Gene', (113, 120))	('expression', 'Var', (121, 131))	('high', 'Var', (108, 112))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))	('survival times', 'CPA', (13, 27))
534713	26783961	Collectively, the strong association of high ALDH1A1 expression with gastric cancer aggressiveness suggests that ALDH1A1 could be a feasible target for cancer therapy.	('high', 'Var', (40, 44))	('aggressiveness', 'Phenotype', 'HP:0000718', (84, 98))	('cancer', 'Disease', (152, 158))	('ALDH1A1', 'Gene', (45, 52))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('gastric cancer aggressiveness', 'Disease', (69, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('expression', 'MPA', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gastric cancer aggressiveness', 'Disease', 'MESH:D013274', (69, 98))
534721	26783961	Moreover, ALDH1A1 expression was an independent predictive factor for early metastasis and decreased survival in inflammatory breast cancer.	('ALDH1A1', 'Gene', (10, 17))	('decreased', 'NegReg', (91, 100))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('survival', 'CPA', (101, 109))	('early metastasis', 'CPA', (70, 86))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('expression', 'Var', (18, 28))
534728	26783961	Furthermore, nuclear staining of ALDH1A1 in colon cancer was associated with a dismal prognosis.	('colon cancer', 'Phenotype', 'HP:0003003', (44, 56))	('colon cancer', 'Disease', 'MESH:D015179', (44, 56))	('colon cancer', 'Disease', (44, 56))	('nuclear staining', 'Var', (13, 29))	('ALDH1A1', 'Gene', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('associated', 'Reg', (61, 71))
534746	26783961	The modulation of ALDH1A1 might also play a key role in the regulation of growth and differentiation of both normal and cancer cells, also influencing some aspects of the cancer phenotype and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('modulation', 'Var', (4, 14))	('ALDH1A1', 'Gene', (18, 25))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (171, 177))	('growth', 'CPA', (74, 80))	('influencing', 'Reg', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
534748	26783961	However, for future cancer treatment, further studies are needed that identify specific ALDH1A1 inhibitors or inhibitors of other ALDH involved in CSC regulation without off-target toxicity.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('ALDH', 'Gene', (88, 92))	('toxicity', 'Disease', 'MESH:D064420', (181, 189))	('toxicity', 'Disease', (181, 189))	('ALDH', 'Gene', '216', (88, 92))	('ALDH', 'Gene', (130, 134))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('ALDH', 'Gene', '216', (130, 134))	('cancer', 'Disease', (20, 26))	('inhibitors', 'Var', (96, 106))
534820	20947487	We hypothesized that clonal diversity is associated with the risk of progression to cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('associated', 'Reg', (41, 51))	('cancer', 'Disease', (84, 90))	('clonal diversity', 'Var', (21, 37))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
534821	20947487	We obtained molecular data from a cohort of 239 participants with Barrett's esophagus (BE), including microsatellite shifts and loss of heterozygosity, DNA content tetraploidy and aneuploidy, methylation and sequence mutations.	('aneuploidy', 'Disease', (180, 190))	('microsatellite shifts', 'Var', (102, 123))	('methylation', 'Var', (192, 203))	('tetraploidy', 'Disease', 'MESH:D057891', (164, 175))	('loss of heterozygosity', 'Var', (128, 150))	("Barrett's esophagus", 'Disease', (66, 85))	('aneuploidy', 'Disease', 'MESH:D000782', (180, 190))	('participants', 'Species', '9606', (48, 60))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (66, 85))	('tetraploidy', 'Disease', (164, 175))	('sequence mutations', 'Var', (208, 226))
534825	20947487	Neoplastic progression is an evolutionary process in which genetic instability generates new variants and natural selection leads to expansion of clones containing alterations that increase survival and/or proliferation of the clones.	('proliferation', 'CPA', (206, 219))	('survival', 'CPA', (190, 198))	('Neoplastic', 'Disease', 'MESH:D009369', (0, 10))	('alterations', 'Var', (164, 175))	('increase', 'PosReg', (181, 189))	('Neoplastic', 'Disease', (0, 10))
534828	20947487	We have previously reported that clonal diversity is associated with increased risk of progression to esophageal adenocarcinoma (EA) in patients with Barrett's esophagus (BE).	("Barrett's esophagus", 'Disease', (150, 169))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (150, 169))	('esophageal adenocarcinoma', 'Disease', (102, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (102, 127))	('patients', 'Species', '9606', (136, 144))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))	('clonal diversity', 'Var', (33, 49))
534837	20947487	One fresh, frozen biopsy obtained at every 2cm interval along the entire length of each participant's BE segment at their baseline endoscopy was purified from underlying non-proliferating stroma into proliferating diploid (2N, G1), 4N (G2/tetraploid) and/or aneuploid fractions.	('2N', 'Var', (223, 225))	('aneuploid', 'Var', (258, 267))	('participant', 'Species', '9606', (88, 99))
534840	20947487	The sorted fractions were assayed for 1) loss of heterozygosity and changes in microsatellite lengths (shifts) at 18 microsatellite loci spanning chromosome 17 (ten loci) and chromosome 9 (eight loci), 2) mutations in the TP53 and CDKN2A genes determined by sequencing of exons 5-9, and 2, respectively, and 3) methylation status of the CDKN2A promoter determined by methylation specific PCR performed in a subset of the cohort using bisulfite treated DNA, as previously described.	('CDKN2A', 'Gene', (231, 237))	('mutations', 'Var', (205, 214))	('changes', 'Reg', (68, 75))	('CDKN2A', 'Gene', '1029', (231, 237))	('CDKN2A', 'Gene', (337, 343))	('TP53', 'Gene', '7157', (222, 226))	('TP53', 'Gene', (222, 226))	('loss', 'NegReg', (41, 45))	('CDKN2A', 'Gene', '1029', (337, 343))
534841	20947487	Genotyping was performed using 18 short tandem repeat (STR) microsatellite polymorphisms on chromosome arms 17p (D17S1298, D17S1537, TP53VNTR, D17S786, D17S974, D17S1303, D17S1294, D17S1301), 17q (D17S1290, 17S1293), 9p (D9S935, D9GATA62F03, D9S925, D9S932, D9S1121, D9S1118), and 9q (D9S301, D9S930).	('D17S1303', 'Var', (161, 169))	('D17S786', 'Var', (143, 150))	('D9S930', 'Var', (293, 299))	('D9S1121', 'Var', (258, 265))	('D9S932', 'Var', (250, 256))	('D9S301', 'Var', (285, 291))	('D9S925', 'Var', (242, 248))	('D17S1290', 'Var', (197, 205))	('D9S1118', 'Var', (267, 274))	('D17S1301', 'Var', (181, 189))	('S974', 'CellLine', 'CVCL:U295', (155, 159))	('D9GATA62F03', 'Var', (229, 240))	('TP53', 'Gene', '7157', (133, 137))	('D17S974', 'Var', (152, 159))	('D17S1298', 'Var', (113, 121))	('D9S932', 'CellLine', 'CVCL:BS91', (250, 256))	('D9S935', 'Var', (221, 227))	('D17S1537', 'Var', (123, 131))	('D17S1294', 'Var', (171, 179))	('S1293', 'CellLine', 'CVCL:9F02', (209, 214))	('TP53', 'Gene', (133, 137))
534847	20947487	Clones were distinguished by differences in 1) DNA content, LOH, microsatellite shifts and sequence mutations in CDKN2A and TP53, 2) LOH and DNA content only, 3) selected loci (only LOH and mutation of TP53, and LOH, mutation, and methylation of CDKN2A were considered), and 4) neutral loci.	('mutation', 'Var', (190, 198))	('TP53', 'Gene', (202, 206))	('mutations', 'Var', (100, 109))	('TP53', 'Gene', '7157', (124, 128))	('CDKN2A', 'Gene', (246, 252))	('CDKN2A', 'Gene', '1029', (246, 252))	('CDKN2A', 'Gene', (113, 119))	('TP53', 'Gene', (124, 128))	('CDKN2A', 'Gene', '1029', (113, 119))	('TP53', 'Gene', '7157', (202, 206))
534858	20947487	The best analogy to this functional diversity in a neoplasm may be to define clones based on selected alterations that affect the fitness of a clone.	('neoplasm', 'Disease', (51, 59))	('neoplasm', 'Phenotype', 'HP:0002664', (51, 59))	('fitness', 'MPA', (130, 137))	('neoplasm', 'Disease', 'MESH:D009369', (51, 59))	('affect', 'Reg', (119, 125))	('alterations', 'Var', (102, 113))
534859	20947487	We have previously shown that alterations that inactivate an allele of CDKN2A or TP53 are associated with large clonal expansions and so appear to increase the fitness of a clone.	('inactivate', 'Var', (47, 57))	('CDKN2A', 'Gene', (71, 77))	('increase the fitness', 'Disease', (147, 167))	('CDKN2A', 'Gene', '1029', (71, 77))	('associated', 'Reg', (90, 100))	('alterations', 'Var', (30, 41))	('increase the fitness', 'Disease', 'MESH:D012640', (147, 167))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
534862	20947487	Our results also show that diversity is a robust predictor of progression across all types of genetic alterations, whether LOH alone, selected alterations, neutral alterations, or all genetic alterations were used to define a clone (Table 2, pFigures 3-5, Cox regression <0.001 in all cases).	('Cox', 'Gene', '1351', (256, 259))	('Cox', 'Gene', (256, 259))	('alterations', 'Var', (102, 113))
534891	33788883	GPRC5A, also known as RAI3 or RAIG1, can activate numerous signal transduction cascades, including the NF-kappaB, cAMP-Gs alpha, FAK/Scr, and STAT3 signaling pathways.	('GPRC5A', 'Var', (0, 6))	('RAIG1', 'Gene', (30, 35))	('cAMP', 'Chemical', '-', (114, 118))	('STAT3', 'Gene', (142, 147))	('FAK', 'Gene', '5747', (129, 132))	('activate', 'PosReg', (41, 49))	('NF-kappaB', 'Pathway', (103, 112))	('RAI3', 'Gene', '9052', (22, 26))	('RAIG1', 'Gene', '9052', (30, 35))	('FAK', 'Gene', (129, 132))	('RAI3', 'Gene', (22, 26))	('Gs alpha', 'Gene', (119, 127))	('Gs alpha', 'Gene', '2778', (119, 127))	('STAT3', 'Gene', '6774', (142, 147))	('signal transduction cascades', 'Pathway', (59, 87))
534893	33788883	Previous research indicated that GPRC5A is considered an anti-oncogene in lung cancer and the expression level of GPRC5A in lung cancer tissue is much lower than that in normal lung tissue.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('expression level', 'MPA', (94, 110))	('GPRC5A', 'Var', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('lower', 'NegReg', (151, 156))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
534897	33788883	However, GPRC5A was also found to serve as an oncogene in these cancers, and the high expression of GPRC5A was related to tumorigenesis.	('related', 'Reg', (111, 118))	('GPRC5A', 'Var', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('high', 'PosReg', (81, 85))	('expression', 'MPA', (86, 96))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
534899	33788883	found that lung cancer patients with high expression of GPRC5A tended to have a better prognosis.	('high expression', 'Var', (37, 52))	('patients', 'Species', '9606', (23, 31))	('lung cancer', 'Disease', (11, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('GPRC5A', 'Gene', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
534915	33788883	These results indicated that GPRC5A might be a predictive factor for tumor prognosis and high GPRC5A density is associated with a significantly lower OS rate in cancer patients.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('lower', 'NegReg', (144, 149))	('tumor', 'Disease', (69, 74))	('high', 'Var', (89, 93))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('GPRC5A', 'Gene', (94, 100))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
534920	33788883	High expression level of GPRC5A predicted a worse OS in pancreatic cancer (HR: 1.71 95%CI: 1.29-2.26 I2 = 23.8% p = 0.268), Gastric cancer (HR: 1.97 95%CI: 1.33-2.91 I2 = 0.0% p = 0.381), prostate cancer (HR: 6.13 95%CI:1.02-36.80), hepatocellular cancer (HR: 9.10 95%CI: 2.10-39.46), and esophageal cancer (HR:2.58 95%CI:1.26-5.29).	('HR', 'Phenotype', 'HP:0001402', (140, 142))	('HR', 'Phenotype', 'HP:0001402', (308, 310))	('Gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('pancreatic cancer', 'Disease', (56, 73))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (233, 254))	('Gastric cancer', 'Disease', (124, 138))	('age', 'Gene', '5973', (294, 297))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('Gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('HR', 'Phenotype', 'HP:0001402', (75, 77))	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('cancer', 'Disease', (300, 306))	('HR', 'Phenotype', 'HP:0001402', (256, 258))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('prostate cancer', 'Disease', 'MESH:D011471', (188, 203))	('prostate cancer', 'Phenotype', 'HP:0012125', (188, 203))	('cancer', 'Disease', (132, 138))	('age', 'Gene', (294, 297))	('cancer', 'Disease', (67, 73))	('prostate cancer', 'Disease', (188, 203))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('GPRC5A', 'Gene', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('hepatocellular cancer', 'Disease', (233, 254))	('HR', 'Phenotype', 'HP:0001402', (205, 207))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (233, 254))
534922	33788883	Controversial results observed in lung cancer with pooled HR = 0.73 (95%CI: 0.49-1.11 I2 = 0.0% p = 0.872) and subgroup analysis also showed GPRC5A expression predicted unfavorable prognosis in digestive system (HR: 2.32 95%CI: 1.73-3.11 I2 = 0.0% p = 0.479) (Fig 6), and other systems (HR: 1.29 95%CI:1.09-1.54 I2 = 77.2% p<0.000).	('HR', 'Phenotype', 'HP:0001402', (212, 214))	('GPRC5A', 'Var', (141, 147))	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('HR', 'Phenotype', 'HP:0001402', (58, 60))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('HR', 'Phenotype', 'HP:0001402', (287, 289))	('digestive system', 'Disease', (194, 210))
534934	33788883	found that deletion of GPRC5A can promote tumorigenesis by activating the NF-kappaB signaling pathway, which may lead to the development of acidophilic macrophage pneumonia (AMP) in GPRC5A knockout mice.	('acidophilic macrophage pneumonia', 'Disease', (140, 172))	('tumor', 'Disease', (42, 47))	('GPRC5A', 'Gene', (23, 29))	('lead to', 'Reg', (113, 120))	('activating', 'Reg', (59, 69))	('acidophilic macrophage pneumonia', 'Disease', 'MESH:D055501', (140, 172))	('NF-kappaB signaling pathway', 'Pathway', (74, 101))	('promote', 'PosReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('mice', 'Species', '10090', (198, 202))	('deletion', 'Var', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('pneumonia', 'Phenotype', 'HP:0002090', (163, 172))
534937	33788883	A vivo mouse model found that a lack of GPRC5A inhibited colitis-associated tumorigenesis.	('lack', 'Var', (32, 36))	('inhibited', 'NegReg', (47, 56))	('GPRC5A', 'Protein', (40, 46))	('mouse', 'Species', '10090', (7, 12))	('colitis', 'Phenotype', 'HP:0002583', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('colitis', 'Disease', 'MESH:D003092', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('colitis', 'Disease', (57, 64))
534941	33788883	To assess the specific relationship between the GPRC5A and the OS of each cancer type, subgroup analysis showed high expression of GPRC5A was significantly associated with poor prognosis in the majority of solid cancers studied such as pancreatic, gastric, prostate, hepatocellular and esophageal cancer, but no significant effect was observed in colorectal and ovarian cancer.	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('pancreatic', 'Disease', (236, 246))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('age', 'Gene', (291, 294))	('gastric', 'Disease', (248, 255))	('ovarian cancer', 'Phenotype', 'HP:0100615', (362, 376))	('GPRC5A', 'Var', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('cancer', 'Disease', (370, 376))	('cancer', 'Disease', (212, 218))	('associated', 'Reg', (156, 166))	('prostate', 'Disease', (257, 265))	('age', 'Gene', '5973', (291, 294))	('colorectal and ovarian cancer', 'Disease', 'MESH:D015179', (347, 376))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Disease', (297, 303))	('pancreatic', 'Disease', 'MESH:D010195', (236, 246))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('hepatocellular', 'Disease', (267, 281))
534942	33788883	In lung, as well as head and neck squamous cancer, high GPRC5A expression was associated with favorable prognosis.	('lung', 'Disease', (3, 7))	('neck squamous cancer', 'Disease', (29, 49))	('expression', 'MPA', (63, 73))	('squamous cancer', 'Phenotype', 'HP:0002860', (34, 49))	('GPRC5A', 'Gene', (56, 62))	('high', 'Var', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('neck squamous cancer', 'Disease', 'MESH:D006258', (29, 49))
534958	33788883	From text: "To assess the specific relationship between the GPRC5A and the OS of each cancer type, subgroup analysis showed high expression of GPRC5A was significantly associated with poor prognosis in the majority of solid cancers studied such as pancreatic, gastric, prostate, hepatocellular and esophageal cancer, but no significant effect was observed in colorectal and ovarian cancer.	('age', 'Gene', '5973', (303, 306))	('associated', 'Reg', (168, 178))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('colorectal and ovarian cancer', 'Disease', 'MESH:D015179', (359, 388))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancers', 'Disease', (224, 231))	('cancer', 'Disease', (224, 230))	('GPRC5A', 'Var', (143, 149))	('cancer', 'Disease', (382, 388))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('pancreatic', 'Disease', 'MESH:D010195', (248, 258))	('cancer', 'Disease', (309, 315))	('cancer', 'Disease', (86, 92))	('prostate', 'Disease', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('hepatocellular', 'Disease', (279, 293))	('age', 'Gene', (303, 306))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('gastric', 'Disease', (260, 267))	('ovarian cancer', 'Phenotype', 'HP:0100615', (374, 388))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('pancreatic', 'Disease', (248, 258))	('high expression', 'Var', (124, 139))	('cancer', 'Disease', 'MESH:D009369', (309, 315))
534959	33788883	In lung and head and neck squamous cancer, high GPRC5A expression was associated with favorable prognosis.	('lung', 'Disease', (3, 7))	('neck squamous cancer', 'Disease', 'MESH:D006258', (21, 41))	('high', 'Var', (43, 47))	('squamous cancer', 'Phenotype', 'HP:0002860', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('expression', 'MPA', (55, 65))	('neck squamous cancer', 'Disease', (21, 41))	('GPRC5A', 'Protein', (48, 54))
535062	32351882	Moreover, neutrophils are thought to promote angiogenesis and tumor growth, degrade the extracellular matrix, provide favorable conditions for metastasis, and potentiate genome instability and tumor evolution.	('degrade', 'NegReg', (76, 83))	('neutrophils', 'Var', (10, 21))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('promote', 'PosReg', (37, 44))	('extracellular matrix', 'CPA', (88, 108))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('potentiate', 'PosReg', (159, 169))	('angiogenesis', 'CPA', (45, 57))	('tumor', 'Disease', (193, 198))	('metastasis', 'CPA', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('genome instability', 'CPA', (170, 188))
535064	32351882	In this study, we explored the optimal cutoff value of neutrophil count using the ROC curve analysis to predict CR in ESCC patients treated with radiotherapy and found that patients with high neutrophil count had poor RFS and OS, indicating that increased neutrophil count may be a predictor for poor radiosensitivity.	('RFS', 'Disease', (218, 221))	('ESCC', 'Disease', (118, 122))	('high neutrophil count', 'Var', (187, 208))	('patients', 'Species', '9606', (173, 181))	('RFS', 'Disease', 'MESH:D005198', (218, 221))	('patients', 'Species', '9606', (123, 131))	('CR', 'Chemical', '-', (112, 114))	('increased neutrophil count', 'Phenotype', 'HP:0011897', (246, 272))	('poor', 'NegReg', (213, 217))	('high neutrophil count', 'Phenotype', 'HP:0011897', (187, 208))
535067	32351882	A meta-analysis investigating the prognostic value of the LDH level in solid tumors showed that a high LDH level is associated with poor survival in melanoma, gastric, lung cancer, prostate, and renal cell carcinomas.	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (195, 216))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (195, 215))	('renal cell carcinomas', 'Disease', (195, 216))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('LDH level', 'MPA', (103, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('gastric', 'Disease', (159, 166))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (195, 216))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('prostate', 'Disease', (181, 189))	('tumors', 'Disease', (77, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('carcinomas', 'Phenotype', 'HP:0030731', (206, 216))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('lung cancer', 'Disease', (168, 179))	('high', 'Var', (98, 102))	('poor', 'NegReg', (132, 136))
535107	32070309	The study hypotheses are that: (i) the adjuvant-treatment group (PORT/POCRT) can increase the disease-free survival (DFS) rate compared with the surgery alone (SA) group; (ii) a reduction in the radiation field using POCRT will not increase the out-of-field regional recurrence rate (OoFRRR) compared with that using PORT.	('POCRT', 'Var', (217, 222))	('regional recurrence', 'CPA', (258, 277))	('POCRT', 'Chemical', '-', (217, 222))	('SA', 'Chemical', '-', (160, 162))	('POCRT', 'Chemical', '-', (70, 75))	('disease-free survival', 'CPA', (94, 115))	('increase', 'PosReg', (81, 89))
535121	32070309	The CTV borders will be defined inferiorly as 3-cm below the subcarina or the lower margin of the tumor bed (only for T4 lesions), including the lower cervical and bilateral supraclavicular region and mediastinal stations 1R/L, 2R/L, 3p, 4R/L, and 7 (Fig.	('tumor', 'Disease', (98, 103))	('2R/L', 'SUBSTITUTION', 'None', (228, 232))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('1R/L', 'Var', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('4R/L', 'SUBSTITUTION', 'None', (238, 242))	('1R/L', 'SUBSTITUTION', 'None', (222, 226))	('2R/L', 'Var', (228, 232))	('4R/L', 'Var', (238, 242))
535140	32070309	National Comprehensive Cancer Network guidelines (2016-2019) recommend observation for pathologic T1-4aN0-1 M0 esophageal squamous cell carcinomas.	('esophageal squamous cell carcinomas', 'Disease', 'MESH:C562729', (111, 146))	('esophageal squamous cell carcinomas', 'Disease', (111, 146))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (122, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('T1-4aN0-1 M0', 'Var', (98, 110))
535172	30655768	It was determined that CTPG-W significantly reduced the viability of Eca-109 cells through the induction of apoptosis and cell cycle arrest.	('CTPG-W', 'Var', (23, 29))	('cell cycle arrest', 'CPA', (122, 139))	('Eca', 'Chemical', '-', (69, 72))	('viability', 'CPA', (56, 65))	('CTPG-W', 'Chemical', '-', (23, 29))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('reduced', 'NegReg', (44, 51))	('apoptosis', 'CPA', (108, 117))
535191	30655768	It was determined that CTPG-W could dose-dependently inhibit the viability of Eca-109 cells through the induction of apoptosis via a mitochondrial-dependent pathway.	('CTPG-W', 'Var', (23, 29))	('inhibit', 'NegReg', (53, 60))	('viability', 'CPA', (65, 74))	('CTPG-W', 'Chemical', '-', (23, 29))	('mitochondrial-dependent pathway', 'Pathway', (133, 164))	('apoptosis', 'CPA', (117, 126))	('Eca', 'Chemical', '-', (78, 81))
535247	30655768	These results indicate that CTPG-W suppresses the growth of Eca-109 cells.	('CTPG-W', 'Var', (28, 34))	('CTPG-W', 'Chemical', '-', (28, 34))	('growth', 'CPA', (50, 56))	('Eca', 'Chemical', '-', (60, 63))	('suppresses', 'NegReg', (35, 45))
535254	30655768	The results indicated that CTPG-W primarily inhibited the growth of Eca-109 cells through the induction of apoptosis.	('Eca', 'Chemical', '-', (68, 71))	('CTPG-W', 'Var', (27, 33))	('inhibited', 'NegReg', (44, 53))	('CTPG-W', 'Chemical', '-', (27, 33))	('apoptosis', 'CPA', (107, 116))	('growth', 'CPA', (58, 64))
535255	30655768	Disturbance of the cancer cell cycle will suppress cell growth and promote apoptosis.	('suppress', 'NegReg', (42, 50))	('cell growth', 'CPA', (51, 62))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('apoptosis', 'CPA', (75, 84))	('cancer', 'Disease', (19, 25))	('Disturbance', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('promote', 'PosReg', (67, 74))
535258	30655768	CTPG-W decreases Deltapsim and induces the release of cytochrome c. Apoptosis can be induced by a mitochondrial-dependent pathway.	('Deltapsim', 'MPA', (17, 26))	('decreases', 'NegReg', (7, 16))	('CTPG-W', 'Var', (0, 6))	('induces', 'Reg', (31, 38))	('cytochrome c', 'Gene', (54, 66))	('cytochrome c', 'Gene', '54205', (54, 66))	('CTPG-W', 'Chemical', '-', (0, 6))
535263	30655768	With the increasing concentrations of CTPG-W, the red fluorescence decreased and the green fluorescence increased, which is consistent with the data from flow cytometry.	('green fluorescence', 'MPA', (85, 103))	('red fluorescence', 'MPA', (50, 66))	('W', 'Chemical', 'MESH:D014414', (43, 44))	('increased', 'PosReg', (104, 113))	('W', 'Chemical', 'MESH:D014414', (0, 1))	('CTPG-W', 'Var', (38, 44))	('CTPG-W', 'Chemical', '-', (38, 44))	('decreased', 'NegReg', (67, 76))
535267	30655768	The results indicated that CTPG-W may induce the apoptosis of Eca-109 cells through a mitochondrial-dependent pathway.	('Eca', 'Chemical', '-', (62, 65))	('induce', 'PosReg', (38, 44))	('CTPG-W', 'Var', (27, 33))	('CTPG-W', 'Chemical', '-', (27, 33))	('apoptosis', 'CPA', (49, 58))	('mitochondrial-dependent pathway', 'Pathway', (86, 117))
535275	30655768	6B), which may be associated with the decreased ROS production in Eca-109 cells treated with 800 microg/ml CTPG-W after 12 h. The release of cytochrome c due to Deltapsim reduction could activate the caspase proteases to induce apoptosis.	('caspase', 'Gene', (200, 207))	('apoptosis', 'CPA', (228, 237))	('Eca', 'Chemical', '-', (66, 69))	('cytochrome c', 'Gene', (141, 153))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))	('Deltapsim reduction', 'Var', (161, 180))	('activate', 'PosReg', (187, 195))	('cytochrome c', 'Gene', '54205', (141, 153))	('caspase', 'Gene', '841;842', (200, 207))	('CTPG-W', 'Chemical', '-', (107, 113))
535278	30655768	These results indicated that CTPG-W reduced Deltapsim and promoted cytochrome c release to activate caspases that induce the apoptosis of Eca-109 cells.	('caspases', 'Gene', '841;842', (100, 108))	('CTPG-W', 'Chemical', '-', (29, 35))	('Eca', 'Chemical', '-', (138, 141))	('Deltapsim', 'MPA', (44, 53))	('caspases', 'Gene', (100, 108))	('cytochrome c', 'Gene', (67, 79))	('CTPG-W', 'Var', (29, 35))	('promoted', 'PosReg', (58, 66))	('reduced', 'NegReg', (36, 43))	('apoptosis', 'CPA', (125, 134))	('induce', 'PosReg', (114, 120))	('cytochrome c', 'Gene', '54205', (67, 79))	('activate', 'PosReg', (91, 99))
535281	30655768	In the present study, the antitumor effect of CTPG-W on Eca-109 cells was investigated and it was determined that CTPG-W suppressed the growth of Eca-109 cells, induced apoptosis and cell cycle arrest, reduced Deltapsim, increased the release of cytochrome c and activated caspases.	('reduced', 'NegReg', (202, 209))	('cytochrome c', 'Gene', '54205', (246, 258))	('Eca', 'Chemical', '-', (56, 59))	('cell cycle arrest', 'CPA', (183, 200))	('induced', 'Reg', (161, 168))	('growth', 'CPA', (136, 142))	('CTPG-W', 'Chemical', '-', (114, 120))	('Deltapsim', 'MPA', (210, 219))	('CTPG-W', 'Var', (114, 120))	('activated', 'PosReg', (263, 272))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (183, 200))	('caspases', 'Gene', (273, 281))	('cytochrome c', 'Gene', (246, 258))	('Eca', 'Chemical', '-', (146, 149))	('caspases', 'Gene', '841;842', (273, 281))	('apoptosis', 'CPA', (169, 178))	('increased', 'PosReg', (221, 230))	('CTPG-W', 'Chemical', '-', (46, 52))	('suppressed', 'NegReg', (121, 131))
535282	30655768	CTPG and CTPG-W could induce the apoptosis and cell cycle arrest in cancer cells.	('CTPG-W', 'Chemical', '-', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('apoptosis', 'CPA', (33, 42))	('CTPG', 'Var', (0, 4))	('CTPG', 'Chemical', '-', (0, 4))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('CTPG-W', 'Var', (9, 15))	('cancer', 'Disease', (68, 74))	('CTPG', 'Chemical', '-', (9, 13))	('induce', 'PosReg', (22, 28))	('cell cycle arrest', 'CPA', (47, 64))
535292	30655768	Consistently, the levels of cleaved-caspase-9 were upregulated by CTPG-W treatment.	('caspase-9', 'Gene', '842', (36, 45))	('caspase-9', 'Gene', (36, 45))	('CTPG-W treatment', 'Var', (66, 82))	('CTPG-W', 'Chemical', '-', (66, 72))	('upregulated', 'PosReg', (51, 62))
535294	30655768	The levels of cleaved-caspase-3 were also upregulated by CTPG-W treatment.	('CTPG-W', 'Chemical', '-', (57, 63))	('caspase-3', 'Gene', (22, 31))	('upregulated', 'PosReg', (42, 53))	('caspase-3', 'Gene', '836', (22, 31))	('CTPG-W', 'Var', (57, 63))
535295	30655768	However, caspase-8 was not activated by CTPG-W, indicating that the extrinsic death receptor pathway was not involved in the apoptosis induced by CTPG-W.	('CTPG-W', 'Chemical', '-', (146, 152))	('CTPG-W', 'Chemical', '-', (40, 46))	('caspase-8', 'Gene', (9, 18))	('CTPG-W', 'Var', (146, 152))	('caspase-8', 'Gene', '841', (9, 18))
535296	30655768	These observations indicate that CTPG-W induces apoptosis of Eca-109 cells through the activation of a mitochondrial-dependent pathway.	('CTPG-W', 'Chemical', '-', (33, 39))	('CTPG-W', 'Var', (33, 39))	('apoptosis', 'CPA', (48, 57))	('Eca', 'Chemical', '-', (61, 64))	('mitochondrial-dependent pathway', 'Pathway', (103, 134))
535298	30655768	It was determined that CTPG-W treatment activated caspase-3 and -7, which may cleave PARP to inhibit DNA repair and cause apoptosis.	('inhibit', 'NegReg', (93, 100))	('DNA repair', 'MPA', (101, 111))	('cleave', 'Var', (78, 84))	('cause', 'Reg', (116, 121))	('PARP', 'Gene', (85, 89))	('apoptosis', 'CPA', (122, 131))	('CTPG-W', 'Chemical', '-', (23, 29))	('PARP', 'Gene', '142', (85, 89))	('caspase-3 and -7', 'Gene', '836;840', (50, 66))
535299	30655768	CTPG-W also dose- and time-dependently suppresses the growth of human hepatocellular carcinoma BEL-7404 cells (unpublished data).	('human', 'Species', '9606', (64, 69))	('suppresses', 'NegReg', (39, 49))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (70, 94))	('BEL-7404', 'CellLine', 'CVCL:6568', (95, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 94))	('CTPG-W', 'Var', (0, 6))	('hepatocellular carcinoma', 'Disease', (70, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('growth', 'CPA', (54, 60))	('CTPG-W', 'Chemical', '-', (0, 6))
535302	30655768	In the mouse model, it was determined that CTPG-W significantly increased the spleen index, compared with the control group, but did not affect the body weight and the other organ indexes including heart, liver, kidney and lung (unpublished data), indicating that CTPG-W has no cytotoxic effect on normal cells.	('mouse', 'Species', '10090', (7, 12))	('CTPG-W', 'Chemical', '-', (43, 49))	('spleen index', 'MPA', (78, 90))	('increased', 'PosReg', (64, 73))	('CTPG-W', 'Var', (43, 49))	('CTPG-W', 'Chemical', '-', (264, 270))
535303	30655768	Collectively, the data indicated that CTPG-W inhibits the growth of Eca-109 cells by induction of apoptosis via a mitochondrial-dependent pathway.	('Eca', 'Chemical', '-', (68, 71))	('mitochondrial-dependent pathway', 'Pathway', (114, 145))	('apoptosis', 'CPA', (98, 107))	('inhibits', 'NegReg', (45, 53))	('CTPG-W', 'Var', (38, 44))	('CTPG-W', 'Chemical', '-', (38, 44))	('growth of Eca-109 cells', 'CPA', (58, 81))
535321	30547811	Although standard additional treatments after ESD have not yet been established, CRT would be a new alternative therapeutic approach to esophagectomy in patients with T1a-MM and T1b tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('patients', 'Species', '9606', (153, 161))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (182, 188))	('T1a-MM', 'Var', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
535334	30547811	T1a and T1b tumors were further divided into three subtypes according to the extent of invasion as T1a-EP, mucosal epithelium; T1a-LPM, lamina propria mucosae; and T1a-MM, muscularis mucosa and T1b-SM1, upper-third stratum of the submucosal layer; T1b-SM2, middle-third stratum of the submucosal layer; and T1b-SM3, lower-third stratum of the submucosal layer.	('SM1', 'Gene', '7911', (198, 201))	('T1b-SM3', 'Var', (307, 314))	('SM1', 'Gene', (198, 201))	('b-SM3', 'Species', '578349', (309, 314))	('SM2', 'Gene', '53366', (252, 255))	('T1a-LPM', 'Var', (127, 134))	('-third stratum', 'Phenotype', 'HP:0004691', (263, 277))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('-third stratum', 'Phenotype', 'HP:0004691', (208, 222))	('SM2', 'Gene', (252, 255))	('-third stratum', 'Phenotype', 'HP:0004691', (321, 335))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
535419	27331918	At 4 weeks, only about 60% of patients reported complete resolution of their GERD symptoms with PPIs whereas approximately 40% of patients still complained of persistent symptoms.	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (30, 38))	('PPIs', 'Var', (96, 100))	('GERD symptoms', 'Disease', (77, 90))
535431	27331918	We found that the infiltrating lymphocytes were CD3+ and CD20 -, demonstrating that they were T cells.	('rat', 'Species', '10116', (72, 75))	('CD20', 'Gene', (57, 61))	('rat', 'Species', '10116', (24, 27))	('CD20', 'Gene', '54474', (57, 61))	('CD3+', 'Var', (48, 52))
535433	27331918	In accompanying experiments, we found that cultures of esophageal squamous cells derived from patients with GERD secreted interleukin (IL)-8, a potent pro-inflammatory cytokine, when they were exposed to acidic bile salts, and that secretion of IL-8 induced the migration of lymphocytes and neutrophils.	('patients', 'Species', '9606', (94, 102))	('IL-8', 'Gene', (245, 249))	('interleukin (IL)-8', 'Gene', (122, 140))	('bile salts', 'Chemical', 'MESH:D001647', (211, 221))	('interleukin (IL)-8', 'Gene', '3576', (122, 140))	('induced', 'PosReg', (250, 257))	('IL-8', 'Gene', '3576', (245, 249))	('secretion', 'Var', (232, 241))	('rat', 'Species', '10116', (265, 268))
535447	27331918	Furthermore, high levels of IL-8 in biopsy tissues of NERD patients are a positive predictor of symptomatic recurrence.	('symptomatic recurrence', 'Disease', (96, 118))	('high', 'Var', (13, 17))	('IL-8', 'Gene', '3576', (28, 32))	('NERD', 'Disease', (54, 58))	('patients', 'Species', '9606', (59, 67))	('NERD', 'Disease', 'None', (54, 58))	('IL-8', 'Gene', (28, 32))
535474	27331918	found that NO exposure caused S-nitrosylation of protein kinase B (PKB or Akt), which blocks its phosphorylation to an active state, and that interfering with Akt signaling leads to reductions in esophageal squamous cell expression of SOX2, a transcription factor that promotes stratified squamous epithelia development.	('Akt', 'Gene', '207', (74, 77))	('Akt', 'Gene', (159, 162))	('S-nitrosylation', 'MPA', (30, 45))	('squamous epithelia', 'Disease', (289, 307))	('esophageal squamous cell expression', 'MPA', (196, 231))	('PKB', 'Gene', '207', (67, 70))	('rat', 'Species', '10116', (280, 283))	('Akt', 'Gene', (74, 77))	('protein kinase B', 'Enzyme', (49, 65))	('SOX2', 'Gene', (235, 239))	('PKB', 'Gene', (67, 70))	('reductions', 'NegReg', (182, 192))	('interfering', 'Var', (142, 153))	('phosphorylation', 'MPA', (97, 112))	('Akt', 'Gene', '207', (159, 162))	('squamous epithelia', 'Phenotype', 'HP:0002860', (289, 307))	('squamous epithelia', 'Disease', 'MESH:D002294', (289, 307))
535482	27331918	Acid reflux causes reflux esophagitis, and PPIs are very effective at healing the inflammation caused by acid reflux.	('reflux esophagitis', 'Disease', (19, 37))	('Acid', 'Var', (0, 4))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('Acid reflux', 'Phenotype', 'HP:0002020', (0, 11))	('acid reflux', 'Phenotype', 'HP:0002020', (105, 116))	('esophagitis', 'Phenotype', 'HP:0100633', (26, 37))	('inflammation', 'Disease', (82, 94))	('reflux esophagitis', 'Disease', 'MESH:D005764', (19, 37))
535488	27331918	In all six patients, acid perfusion caused DNA damage, as detected by increases in phospho-H2AX levels by Western blotting, in biopsies of Barrett's metaplasia.	('DNA damage', 'MPA', (43, 53))	('increases', 'PosReg', (70, 79))	('H2AX', 'Gene', '3014', (91, 95))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (139, 159))	('acid perfusion', 'Var', (21, 35))	('Western blotting', 'MPA', (106, 122))	("Barrett's metaplasia", 'Disease', (139, 159))	('patients', 'Species', '9606', (11, 19))	('H2AX', 'Gene', (91, 95))
535489	27331918	Persistent DNA damage can lead to genomic instability and promote cancer formation.	('lead to', 'Reg', (26, 33))	('promote', 'PosReg', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Persistent DNA damage', 'Var', (0, 21))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('genomic instability', 'CPA', (34, 53))	('cancer', 'Disease', (66, 72))
535498	27331918	In Barrett's patients on PPIs, the decrease in gastric acid allows bacteria to grow in the stomach, and these bacteria can metabolize cholic acid into DCA and can deconjugate DCA.	('metabolize cholic acid', 'MPA', (123, 145))	('DCA', 'Chemical', 'MESH:D003840', (175, 178))	('deconjugate', 'Var', (163, 174))	('DCA', 'Chemical', 'MESH:D003840', (151, 154))	('patients', 'Species', '9606', (13, 21))	('decrease', 'NegReg', (35, 43))	('cholic acid', 'Chemical', 'MESH:D019826', (134, 145))	('gastric acid', 'MPA', (47, 59))	('DCA', 'Disease', (175, 178))
535501	27331918	In addition to inducing DNA damage in BAR-T cells, DCA also activates the NF-kappaB pathway, which prevents apoptosis.	('DCA', 'Var', (51, 54))	('NF-kappaB', 'Gene', (74, 83))	('DCA', 'Chemical', 'MESH:D003840', (51, 54))	('inducing', 'Reg', (15, 23))	('DNA damage', 'MPA', (24, 34))	('activates', 'PosReg', (60, 69))	('BAR-T', 'CellLine', 'CVCL:4M95', (38, 43))	('NF-kappaB', 'Gene', '4790', (74, 83))
535515	27331918	A total of 21 patients completed this protocol, and we found that perfusion of the esophagus with DCA, but not UDCA, resulted in a significant increase in DNA damage and NF-kappaB activation.	('DCA', 'Var', (98, 101))	('DNA damage', 'MPA', (155, 165))	('patients', 'Species', '9606', (14, 22))	('UDCA', 'Chemical', 'MESH:D014580', (111, 115))	('NF-kappaB', 'Gene', '4790', (170, 179))	('DCA', 'Chemical', 'MESH:D003840', (112, 115))	('DCA', 'Chemical', 'MESH:D003840', (98, 101))	('increase', 'PosReg', (143, 151))	('activation', 'PosReg', (180, 190))	('NF-kappaB', 'Gene', (170, 179))
535536	26031666	For example, Polyphenols in green tea was found to inhibit esophageal tumorigenesis, whereas mate infusion and caffeine appeared to induce mutagenic effects.	('Polyphenols', 'Chemical', 'MESH:D059808', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('esophageal tumor', 'Disease', 'MESH:D004938', (59, 75))	('esophageal tumor', 'Phenotype', 'HP:0100751', (59, 75))	('caffeine', 'Chemical', 'MESH:D002110', (111, 119))	('mutagenic effects', 'CPA', (139, 156))	('esophageal tumor', 'Disease', (59, 75))	('inhibit', 'NegReg', (51, 58))	('Polyphenols', 'Var', (13, 24))
535568	26031666	This hypothesis is supported by a high rate of somatic G to A transitions in CpG dinucleotides of the TP53 gene in esophageal tumor samples from geographical areas in which drinking hot beverages is considered an important risk factor for EC; these mutations may indicate increased nitric oxide synthase activity in tumors.	('esophageal tumor', 'Phenotype', 'HP:0100751', (115, 131))	('TP53', 'Gene', (102, 106))	('increased', 'PosReg', (272, 281))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('hot', 'Gene', '137872', (182, 185))	('mutations', 'Var', (249, 258))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('hot', 'Gene', (182, 185))	('hot beverage', 'Phenotype', 'HP:0031217', (182, 194))	('tumors', 'Disease', (316, 322))	('tumors', 'Disease', 'MESH:D009369', (316, 322))	('esophageal tumor', 'Disease', 'MESH:D004938', (115, 131))	('TP53', 'Gene', '7157', (102, 106))	('esophageal tumor', 'Disease', (115, 131))	('transitions', 'Var', (62, 73))
535624	25582305	Inclusion criteria were age 75 years or less, histologically verified squamous cell carcinoma or adenocarcinoma of the esophagus or GE-junction, tumor stage T1-3 and N0-1 (according to AJCC TNM staging system 6th edition), WHO performance status 0-1 and no major illness making neoadjuvant treatment unsuitable.	('adenocarcinoma of the esophagus', 'Disease', (97, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('TNM', 'Gene', (190, 193))	('squamous cell carcinoma', 'Disease', (70, 93))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 93))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('tumor', 'Disease', (145, 150))	('N0-1', 'Var', (166, 170))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (97, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('TNM', 'Gene', '10178', (190, 193))
535773	24751580	In addition, iodine solution irritates the mucosa and may cause retrosternal chest pain and discomfort; it is also limited by the occurrence of hypersensitivity and the risk of chemical esophagitis, laryngitis, and bronchopneumonia.	('hypersensitivity', 'Disease', (144, 160))	('retrosternal chest pain', 'Disease', 'MESH:D002637', (64, 87))	('hypersensitivity', 'Disease', 'MESH:D004342', (144, 160))	('bronchopneumonia', 'Disease', 'MESH:D001996', (215, 231))	('laryngitis', 'Disease', (199, 209))	('iodine', 'Chemical', 'MESH:D007455', (13, 19))	('irritates', 'Reg', (29, 38))	('cause', 'Reg', (58, 63))	('laryngitis', 'Disease', 'MESH:D007827', (199, 209))	('iodine solution', 'Var', (13, 28))	('esophagitis', 'Phenotype', 'HP:0100633', (186, 197))	('esophagitis', 'Disease', (186, 197))	('discomfort', 'Disease', (92, 102))	('bronchopneumonia', 'Disease', (215, 231))	('retrosternal chest pain', 'Disease', (64, 87))	('chest pain', 'Phenotype', 'HP:0100749', (77, 87))	('pain', 'Phenotype', 'HP:0012531', (83, 87))	('esophagitis', 'Disease', 'MESH:D004941', (186, 197))
535777	24751580	Therefore, we used propensity score matching to compare the accuracy of the diagnosis of esophageal SCC between NM-NBI and CE-Iodine.	('SCC', 'Gene', (100, 103))	('NM-NBI', 'Chemical', '-', (112, 118))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('NM-NBI', 'Var', (112, 118))	('SCC', 'Gene', '6317', (100, 103))	('CE-Iodine', 'Chemical', '-', (123, 132))
535826	22719211	Her2 positivity is more common in the intestinal type and EGC rather than the diffuse type and pure GC.	('positivity', 'Var', (5, 15))	('intestinal type', 'Disease', (38, 53))	('EGC', 'Disease', (58, 61))	('EGC', 'Chemical', '-', (58, 61))	('Her2', 'Gene', (0, 4))	('common', 'Reg', (24, 30))	('Her2', 'Gene', '2064', (0, 4))
535827	22719211	Her2 amplification on FISH is an independent prognostic factor which correlates with the depth of invasion, nodal/distant metastasis, and poor survival.	('depth of invasion', 'CPA', (89, 106))	('amplification', 'Var', (5, 18))	('poor survival', 'CPA', (138, 151))	('Her2', 'Gene', (0, 4))	('Her2', 'Gene', '2064', (0, 4))	('nodal/distant metastasis', 'CPA', (108, 132))
535841	22719211	The median progression-free survival (PFS) (6.7 versus 5.5 months, hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.59-0.85; P = 0.0002) and OS (13.8 months versus 11.1 months P = 0.0046, HR = 0.74, 95% CI 0.60-0.91) were also in favor of the trastuzumab-containing arm compared with the chemotherapy alone arm.	('trastuzumab-containing', 'Var', (249, 271))	('trastuzumab', 'Chemical', 'MESH:D000068878', (249, 260))	('progression-free survival', 'CPA', (11, 36))	('OS', 'Chemical', '-', (147, 149))
535842	22719211	In an exploratory post-hoc analysis, the OS was longer in patients with high expression of Her2 compared with those with low Her2 expression.	('OS', 'Chemical', '-', (41, 43))	('Her2', 'Gene', '2064', (125, 129))	('Her2', 'Gene', (91, 95))	('high expression', 'Var', (72, 87))	('patients', 'Species', '9606', (58, 66))	('Her2', 'Gene', (125, 129))	('Her2', 'Gene', '2064', (91, 95))
535861	22719211	Abnormal expression and activating mutations of EGFR have been reported in EGC, eg, EGFR overexpression by IHC/SISH occurs in 50%-63% of patients with GC.	('SISH', 'Disease', 'None', (111, 115))	('EGFR', 'Gene', '1956', (48, 52))	('EGC', 'Chemical', '-', (75, 78))	('activating', 'PosReg', (24, 34))	('EGFR', 'Gene', (48, 52))	('SISH', 'Disease', (111, 115))	('overexpression', 'PosReg', (89, 103))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('expression', 'MPA', (9, 19))	('patients', 'Species', '9606', (137, 145))	('EGC', 'Disease', (75, 78))	('mutations', 'Var', (35, 44))
535862	22719211	Overexpression of EGFR is a poor prognostic indicator in EGC with poorly differentiated histology, depth of invasion, and shorter survival.	('EGFR', 'Gene', '1956', (18, 22))	('EGC', 'Chemical', '-', (57, 60))	('EGFR', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('EGC', 'Disease', (57, 60))
535866	22719211	At present, none of the trials evaluating the EGFR-targeted therapies are restricted to patients with wild-type KRAS tumors, as the frequency of KRAS mutations in GC is expected to be low (around 5%), and there are currently no data to suggest that KRAS gene mutation is predictive of lack of response to EGFR-targeted monoclonal antibody therapy in this tumor type.	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('EGFR', 'Gene', '1956', (46, 50))	('KRAS', 'Gene', '3845', (249, 253))	('KRAS tumors', 'Disease', (112, 123))	('EGFR', 'Gene', (305, 309))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('KRAS', 'Gene', (249, 253))	('KRAS', 'Gene', '3845', (145, 149))	('KRAS', 'Gene', '3845', (112, 116))	('KRAS', 'Gene', (145, 149))	('EGFR', 'Gene', (46, 50))	('KRAS', 'Gene', (112, 116))	('EGFR', 'Gene', '1956', (305, 309))	('tumor', 'Disease', (117, 122))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Disease', (355, 360))	('KRAS tumors', 'Disease', 'MESH:D009369', (112, 123))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('mutation', 'Var', (259, 267))	('tumor', 'Disease', 'MESH:D009369', (355, 360))
535883	22719211	In contrast, Han et al in their trial of cetuximab in combination with modified 5-FU/leucovorin/oxaliplatin (mFOLFOX-6), noted that patients with EGFR-positive tumors and low EGF/TGF alpha levels (n = 11) had an ORR of 100% compared with only 37% in the remaining patients (n = 27) with EGFR-negative tumors (P <= 0.001).	('cetuximab', 'Chemical', 'MESH:D000068818', (41, 50))	('EGFR', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('low', 'Var', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('patients', 'Species', '9606', (132, 140))	('mFOLFOX-6', 'Chemical', '-', (109, 118))	('leucovorin', 'Chemical', 'MESH:D002955', (85, 95))	('tumors', 'Disease', (301, 307))	('5-FU', 'Chemical', '-', (80, 84))	('EGFR', 'Gene', (287, 291))	('tumors', 'Disease', 'MESH:D009369', (301, 307))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('TGF alpha', 'Gene', (179, 188))	('EGFR', 'Gene', '1956', (146, 150))	('patients', 'Species', '9606', (264, 272))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (96, 107))	('ORR', 'MPA', (212, 215))	('EGFR', 'Gene', '1956', (287, 291))	('TGF alpha', 'Gene', '7039', (179, 188))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))
535910	22719211	There was a nonsignificant trend towards improved outcome in patients with high EGFR expression compared with low EGFR expression (TTP 5.1 months versus 1.8 months and OS 7.8 months versus 2.8 months).	('improved', 'PosReg', (41, 49))	('high', 'Var', (75, 79))	('patients', 'Species', '9606', (61, 69))	('TTP', 'Gene', (131, 134))	('EGFR', 'Gene', '1956', (114, 118))	('EGFR', 'Gene', (80, 84))	('EGFR', 'Gene', '1956', (80, 84))	('TTP', 'Gene', '7538', (131, 134))	('EGFR', 'Gene', (114, 118))	('OS', 'Chemical', '-', (168, 170))
535913	22719211	From the available evidence, it seems that patients with squamous histology, high EGFR expression, and esophageal/GEJ tumors are more likely to have any meaningful response to TKIs, but these tumors are rarely of squamous type.	('EGFR', 'Gene', (82, 86))	('squamous type', 'Disease', (213, 226))	('high', 'Var', (77, 81))	('tumors', 'Disease', (192, 198))	('patients', 'Species', '9606', (43, 51))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'MPA', (87, 97))	('esophageal/GEJ tumors', 'Disease', 'MESH:D004938', (103, 124))	('tumors', 'Disease', (118, 124))	('EGFR', 'Gene', '1956', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('squamous type', 'Disease', 'MESH:D002294', (213, 226))	('esophageal/GEJ tumors', 'Disease', (103, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
535926	22719211	The toxicity profile of the mDCF was better than the original DCF, with febrile neutropenia rates of 4% versus 29% respectively.	('mDCF', 'Var', (28, 32))	('DCF', 'Chemical', 'MESH:D015649', (62, 65))	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('febrile neutropenia', 'Disease', (72, 91))	('febrile neutropenia', 'Disease', 'MESH:D009503', (72, 91))	('toxicity', 'Disease', (4, 12))	('mDCF', 'Chemical', '-', (28, 32))	('neutropenia', 'Phenotype', 'HP:0001875', (80, 91))	('DCF', 'Chemical', 'MESH:D015649', (29, 32))
536002	32805720	hsa_circRNA6448-14 promoted carcinogenesis in ESCC, suggesting that hsa_circRNA6448-14 could serve as a diagnostic and prognostic biomarker for ESCC.	('ESCC', 'Disease', (46, 50))	('promoted', 'PosReg', (19, 27))	('carcinogenesis', 'Disease', 'MESH:D063646', (28, 42))	('ESCC', 'Disease', (144, 148))	('carcinogenesis', 'Disease', (28, 42))	('hsa_circRNA6448-14', 'Var', (0, 18))	('hsa_circRNA6448-14', 'Var', (68, 86))
536010	32805720	High expression of hsa_circRNA6448-14 was associated with poor differentiation, higher pTNM stage, and poor prognosis in ESCC patients.	('poor', 'NegReg', (58, 62))	('ESCC', 'Disease', (121, 125))	('hsa_circRNA6448-14', 'Var', (19, 37))	('patients', 'Species', '9606', (126, 134))
536011	32805720	In vitro studies suggested that hsa_circRNA6448-14 promoted cell proliferation, migration, and invasion, and acted as a miR-455-3p sponge.	('invasion', 'CPA', (95, 103))	('cell proliferation', 'CPA', (60, 78))	('migration', 'CPA', (80, 89))	('miR-455-3p', 'Chemical', '-', (120, 130))	('hsa_circRNA6448-14', 'Var', (32, 50))	('promoted', 'PosReg', (51, 59))
536013	32805720	The 76 patients were pooled and analyzed, which confirmed that hsa_circRNA6448-14 was significantly up-regulated in ESCC, and ROC curves showed AUC, sensitivity, and specificity of 0.906 (95% CI: 0.899-0.903, p = 0.021), 82.9%, and 85.5%.	('ESCC', 'Disease', (116, 120))	('hsa_circRNA6448-14', 'Var', (63, 81))	('patients', 'Species', '9606', (7, 15))	('up-regulated', 'PosReg', (100, 112))
536016	32805720	Kaplan-Meier analysis revealed that ESCC patients with hsa_circRNA6448-14 high expression had shorter OS and DFS than those with hsa_circRNA6448-14 low expression.	('DFS', 'MPA', (109, 112))	('hsa_circRNA6448-14 high expression', 'Var', (55, 89))	('shorter', 'NegReg', (94, 101))	('patients', 'Species', '9606', (41, 49))	('ESCC', 'Disease', (36, 40))
536018	32805720	hsa_circRNA6448-14 was elevated in ESCC cell lines compared to HEEC (Figure 6A).	('elevated', 'PosReg', (23, 31))	('hsa_circRNA6448-14', 'Var', (0, 18))	('ESCC', 'Disease', (35, 39))	('EC', 'Disease', 'MESH:D005955', (65, 67))
536020	32805720	Expression of hsa_circRNA6448-14 was effectively silenced by si-circRNA6448-1 (si-circ) in KYSE150 cells, and significantly up-regulated by overexpression (over-circ) in TE7 cells (Figure 6B).	('up-regulated', 'PosReg', (124, 136))	('Expression', 'MPA', (0, 10))	('si-circRNA6448-1', 'Var', (61, 77))	('TE7', 'CellLine', 'CVCL:9972', (170, 173))	('silenced', 'NegReg', (49, 57))
536021	32805720	The possible miRNA binding sites of hsa_circRNA6448-14 were predicted to be miR-503-5p, miR-455-3p, miR-4646-5p, miR-382-5p and miR-204-5p, and the hsa_circRNA6448-14-miRNA-mRNA network was constructed (Figure 7).	('miR-4646', 'Gene', '100616230', (100, 108))	('miR-455-3p', 'Chemical', '-', (88, 98))	('miR-204-5p', 'Var', (128, 138))	('miR-382', 'Gene', (113, 120))	('miR-455-3p', 'Var', (88, 98))	('miR-503-5p', 'Var', (76, 86))	('miR-382', 'Gene', '494331', (113, 120))	('miR-4646', 'Gene', (100, 108))
536022	32805720	KEGG pathway analysis showed that hsa_circRNA6448-14 may participate in the regulation of axonal guidance, catalytic activity, adhesion plaques, and tumor proteoglycan pathways (Supplementary Figure 2B).	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('axonal guidance', 'CPA', (90, 105))	('participate', 'Reg', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('catalytic activity', 'CPA', (107, 125))	('tumor', 'Disease', (149, 154))	('adhesion', 'CPA', (127, 135))	('hsa_circRNA6448-14', 'Var', (34, 52))
536024	32805720	Based on the hsa_circRNA6448-14-miRNA-mRNA network, we selected two miRNAs, miR-455-3p and miR-204-5p for pulldown assays.	('miR-455-3p', 'Chemical', '-', (76, 86))	('miR-204-5p', 'Var', (91, 101))	('miR-455-3p', 'Var', (76, 86))
536026	32805720	Furthermore, we analyzed the expression of miR-455-3p in 76 pairs of ESCC tissues, and determined that the expression of miR-455-3p was significantly down-regulated in ESCC tissues compared to adjacent normal tissues (Figure 8B).	('miR-455-3p', 'Chemical', '-', (43, 53))	('down-regulated', 'NegReg', (150, 164))	('expression', 'MPA', (107, 117))	('miR-455-3p', 'Chemical', '-', (121, 131))	('ESCC', 'Disease', (168, 172))	('miR-455-3p', 'Var', (121, 131))
536027	32805720	The expression of miR-455-3p was negatively correlated with that of hsa_circRNA6448-14 in 76 pairs of ESCC tissues (r = -0.701, p < 0.001, Figure 8C).	('negatively', 'NegReg', (33, 43))	('miR-455-3p', 'Chemical', '-', (18, 28))	('expression', 'MPA', (4, 14))	('miR-455-3p', 'Var', (18, 28))
536034	32805720	Patients with high hsa_circRNA6448-14 expression had poor DFS and OS.	('Patients', 'Species', '9606', (0, 8))	('poor', 'NegReg', (53, 57))	('DFS', 'MPA', (58, 61))	('high hsa_circRNA6448-14 expression', 'Var', (14, 48))
536035	32805720	These results suggest that hsa_circRNA6448-14 expression could provide diagnostic and prognostic value for ESCC patients.	('ESCC', 'Disease', (107, 111))	('hsa_circRNA6448-14 expression', 'Var', (27, 56))	('patients', 'Species', '9606', (112, 120))
536037	32805720	RNA pulldown experiments confirmed that hsa_circRNA6448-14 targeted miR-455-3p in ESCC.	('ESCC', 'Disease', (82, 86))	('miR-455-3p', 'Var', (68, 78))	('miR-455-3p', 'Chemical', '-', (68, 78))	('targeted', 'Reg', (59, 67))
536038	32805720	miR-455-3p has been demonstrated to play a role in tumorigenesis and be associated with HCC.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('HCC', 'Disease', (88, 91))	('tumor', 'Disease', (51, 56))	('associated', 'Reg', (72, 82))	('miR-455-3p', 'Chemical', '-', (0, 10))	('miR-455-3p', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
536039	32805720	miR-455-3p, STK17B, and the AKT/GSK-3beta/Snail pathway may operate in combination to regulate epithelial-mesenchymal transition (EMT) and metastasis in HCC.	('epithelial-mesenchymal transition', 'CPA', (95, 128))	('STK17B', 'Gene', '9262', (12, 18))	('HCC', 'Disease', (153, 156))	('AKT', 'Gene', (28, 31))	('metastasis', 'CPA', (139, 149))	('Snail', 'Gene', (42, 47))	('Snail', 'Gene', '6615', (42, 47))	('GSK-3beta', 'Gene', '2931', (32, 41))	('miR-455-3p', 'Chemical', '-', (0, 10))	('regulate', 'PosReg', (86, 94))	('STK17B', 'Gene', (12, 18))	('miR-455-3p', 'Var', (0, 10))	('GSK-3beta', 'Gene', (32, 41))	('AKT', 'Gene', '207', (28, 31))
536040	32805720	miR-455-3p mediates GATA3 tumor suppression in mammary epithelial cells by inhibiting TGF-ss signaling.	('GATA3', 'Gene', '2625', (20, 25))	('inhibiting', 'NegReg', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('suppression', 'NegReg', (32, 43))	('TGF-ss signaling', 'MPA', (86, 102))	('miR-455-3p', 'Chemical', '-', (0, 10))	('miR-455-3p', 'Var', (0, 10))	('GATA3', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
536042	32805720	These results indicate a pro-oncogenic role of miR-455-3p in tumor progression.	('miR-455-3p', 'Chemical', '-', (47, 57))	('miR-455-3p', 'Var', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
536043	32805720	miR-455-3p acts as a prognostic marker and inhibits the proliferation and invasion of ESCC by targeting FAM83F.	('invasion', 'CPA', (74, 82))	('FAM83F', 'Gene', '113828', (104, 110))	('proliferation', 'CPA', (56, 69))	('FAM83F', 'Gene', (104, 110))	('miR-455-3p', 'Chemical', '-', (0, 10))	('miR-455-3p', 'Var', (0, 10))	('inhibits', 'NegReg', (43, 51))	('targeting', 'Reg', (94, 103))	('ESCC', 'Disease', (86, 90))
536044	32805720	We found downregulated miR455-3p in ESCC tissues, and a negative correlation between miR-455-3p and hsa_circRNA6448-14 expression, suggesting that hsa_circRNA6448-14 affects ESCC progression by negatively regulating miR-455-3p.	('affects', 'Reg', (166, 173))	('miR455-3p', 'Gene', (23, 32))	('miR-455-3p', 'Chemical', '-', (85, 95))	('miR-455-3p', 'MPA', (216, 226))	('ESCC', 'Disease', (174, 178))	('negatively', 'NegReg', (194, 204))	('miR-455-3p', 'Chemical', '-', (216, 226))	('downregulated', 'NegReg', (9, 22))	('hsa_circRNA6448-14', 'Var', (147, 165))
536045	32805720	We predicted potential mRNA binding sites for miR-455-3p, and will study their regulatory mechanisms in depth.	('miR-455-3p', 'Chemical', '-', (46, 56))	('mRNA', 'MPA', (23, 27))	('miR-455-3p', 'Var', (46, 56))
536047	32805720	hsa_circRNA6448-14 may promote ESCC carcinogenesis by decreasing miR-455-3p.	('promote', 'PosReg', (23, 30))	('decreasing', 'NegReg', (54, 64))	('carcinogenesis', 'Disease', (36, 50))	('miR-455-3p', 'MPA', (65, 75))	('miR-455-3p', 'Chemical', '-', (65, 75))	('hsa_circRNA6448-14', 'Var', (0, 18))	('carcinogenesis', 'Disease', 'MESH:D063646', (36, 50))
536124	31335710	In esophageal SCC cells, HMG-CoA reductase was found to play an important role in tumorigenecity of esophageal cancer as knockdown of the expression of HMG-CoA reductase could inhibit the growth and migration of esophageal SCC cells, which supported the application of statins as anticancer agents for esophageal cancer.	('HMG-CoA reductase', 'Gene', '3156', (25, 42))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('cancer', 'Disease', (111, 117))	('tumor', 'Disease', (82, 87))	('HMG-CoA reductase', 'Gene', (152, 169))	('esophageal cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('SCC', 'Phenotype', 'HP:0002860', (223, 226))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('HMG-CoA reductase', 'Gene', (25, 42))	('knockdown', 'Var', (121, 130))	('cancer', 'Disease', (284, 290))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('esophageal SCC', 'Disease', 'MESH:C562729', (212, 226))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (302, 319))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('esophageal SCC', 'Disease', (212, 226))	('statins', 'Chemical', 'MESH:D019821', (269, 276))	('esophageal SCC', 'Disease', (3, 17))	('HMG-CoA reductase', 'Gene', '3156', (152, 169))	('esophageal cancer', 'Disease', (302, 319))	('esophageal SCC', 'Disease', 'MESH:C562729', (3, 17))	('cancer', 'Disease', (313, 319))	('inhibit', 'NegReg', (176, 183))
536151	31215094	Moreover, ESCC-DRtca2M cells had additional chromosomal abnormalities in excess of ESCC-DR cells.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (44, 69))	('chromosomal abnormalities', 'Disease', (44, 69))	('ESCC-DRtca2M', 'Var', (10, 22))
536156	31215094	While bile acids are not mutagenic, chronic exposure seems to trigger G6PD overexpression and NF-kappaB (p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression.	('facilitating', 'PosReg', (172, 184))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('G6PD', 'Gene', '24377', (70, 74))	('inducing', 'Reg', (134, 142))	('activation', 'PosReg', (110, 120))	('NF-kappaB', 'Protein', (94, 103))	('overexpression', 'PosReg', (75, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (185, 199))	('genetic', 'Var', (143, 150))	('bile acids', 'Chemical', 'MESH:D001647', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('carcinogenesis', 'Disease', (185, 199))	('G6PD', 'Gene', (70, 74))
536181	31215094	The metabolites were analyzed using a fused silica capillary (50 mum id x 80 cm total length), with commercial electrophoresis buffer (Solution ID: H3301-1001 for cation analysis and H3302-1021 for anion analysis, HMT) as the electrolyte.	('H3301-1001', 'Var', (148, 158))	('H3302-1021', 'Var', (183, 193))	('silica', 'Chemical', 'MESH:D012822', (44, 50))
536191	31215094	Copy number gains and losses were defined as changes in the logarithm to the base 2 of the tumor to reference signal intensity ratio (T/R) more than .3219 and less than -.3219, respectively.	('tumor', 'Disease', (91, 96))	('gains', 'PosReg', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('losses', 'NegReg', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('more than .3219', 'Var', (139, 154))	('rat', 'Species', '10116', (127, 130))	('Copy number', 'Var', (0, 11))	('less', 'Var', (159, 163))
536214	31215094	The PCA plot revealed a clear difference in the metabolome profile, indicating that the PC1 axis mainly comprised the variance information of the K14D group against both the ESCC-DRtca and ESCC-DR groups.	('K14D', 'Var', (146, 150))	('PC1', 'Gene', '85496', (88, 91))	('K14D', 'Mutation', 'p.K14D', (146, 150))	('PC1', 'Gene', (88, 91))
536215	31215094	The PC2 axis contained the variance information of the ESCC-DRtca2M group against the ESCC-DR and K14D groups.	('K14D', 'Mutation', 'p.K14D', (98, 102))	('ESCC-DRtca2M', 'Var', (55, 67))	('PC2', 'Gene', '25121', (4, 7))	('PC2', 'Gene', (4, 7))
536223	31215094	In addition, UDP-GlcNAc levels in ESCC-DRtca2M were lower than in K14D (Figure 6C).	('K14D', 'Mutation', 'p.K14D', (66, 70))	('UDP-GlcNAc', 'Chemical', 'MESH:D014537', (13, 23))	('ESCC-DRtca2M', 'Var', (34, 46))	('lower', 'NegReg', (52, 57))	('UDP-GlcNAc levels', 'MPA', (13, 30))
536243	31215094	They are characterized by an N-terminal Rel-homology domain, which is responsible for DNA binding and dimerization.54 NF-kappaB controls numerous biological processes, including innate immunity, inflammation, cell survival and proliferation, and tumorigenesis.55, 56 Posttranslational modifications such as phosphorylation57, 58, 59, 60, 61, 62 and acetylation63, 64 regulate the transcriptional activity of NF-kappaB.	('phosphorylation57', 'Var', (307, 324))	('regulate', 'Reg', (367, 375))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('acetylation63', 'Var', (349, 362))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('rat', 'Species', '10116', (234, 237))	('inflammation', 'Disease', 'MESH:D007249', (195, 207))	('transcriptional activity', 'MPA', (380, 404))	('tumor', 'Disease', (246, 251))	('inflammation', 'Disease', (195, 207))	('NF-kappaB', 'Protein', (408, 417))
536322	31017739	We previously reported that high PD-L1 expression, mutation load, and potential mutation-associated neoantigen count are associated with a better response.13 In the KEYNOTE-028 trial, six-gene interferon-gamma gene expression signature analysis indicated that higher interferon-gamma composite scores may predict delayed progression and an increased response.12 These preliminary results require further verification and are not readily applicable in real-world clinical practice.	('PD-L1', 'Gene', (33, 38))	('interferon-gamma', 'Gene', (193, 209))	('interferon-gamma', 'Gene', '3458', (267, 283))	('delayed progression', 'CPA', (313, 332))	('PD-L1', 'Gene', '29126', (33, 38))	('interferon-gamma', 'Gene', (267, 283))	('mutation load', 'Var', (51, 64))	('interferon-gamma', 'Gene', '3458', (193, 209))
536351	19651060	Other emergency measures include esophageal balloon tamponade, pharmacologic therapy with various agents, transjugular intrahepatic portal-systemic shunt (TIPS), esophageal devascularization and transection, and emergency portal-systemic shunt.	('esophageal balloon', 'Disease', (33, 51))	('intrahepatic portal-systemic shunt', 'Phenotype', 'HP:0031015', (119, 153))	('esophageal', 'Disease', (162, 172))	('esophageal balloon', 'Disease', 'MESH:D054549', (33, 51))	('systemic shunt', 'Phenotype', 'HP:0001693', (139, 153))	('transection', 'Var', (195, 206))	('systemic shunt', 'Phenotype', 'HP:0001693', (229, 243))
536472	19651060	PCS eliminated portal hypertension in all patients.	('hypertension', 'Disease', 'MESH:D006973', (22, 34))	('PCS', 'Var', (0, 3))	('hypertension', 'Disease', (22, 34))	('portal hypertension', 'Phenotype', 'HP:0001409', (15, 34))	('eliminated', 'NegReg', (4, 14))	('hypertension', 'Phenotype', 'HP:0000822', (22, 34))	('patients', 'Species', '9606', (42, 50))
536551	30022336	Metformin Use and Incidence Cancer Risk: Evidence for a Selective Protective Effect against Liver Cancer Several observational studies suggest that metformin reduces incidence cancer risk; however, many of these studies suffer from time-related biases and several cancer outcomes have not been investigated due to small sample sizes.	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Cancer', 'Disease', (28, 34))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('cancer', 'Disease', (264, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Liver Cancer', 'Disease', (92, 104))	('Cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('reduces', 'NegReg', (158, 165))	('Cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('Liver Cancer', 'Disease', 'MESH:D006528', (92, 104))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('metformin', 'Var', (148, 157))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('Liver Cancer', 'Phenotype', 'HP:0002896', (92, 104))	('cancer', 'Disease', (176, 182))	('metformin', 'Chemical', 'MESH:D008687', (148, 157))
536557	30022336	Metformin was inversely associated with liver cancer (adjusted hazard ratio [aHR] = 0.44, 95% CI 0.31, 0.64) compared to sulfonylurea.	('Metformin', 'Var', (0, 9))	('inversely', 'NegReg', (14, 23))	('associated', 'Interaction', (24, 34))	('sulfonylurea', 'Chemical', 'MESH:D013453', (121, 133))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('liver cancer', 'Phenotype', 'HP:0002896', (40, 52))	('liver cancer', 'Disease', 'MESH:D006528', (40, 52))	('liver cancer', 'Disease', (40, 52))
536558	30022336	We found no association between metformin use and risk of incidence bladder, breast, colorectal, esophageal, gastric, lung, pancreatic, prostate, or renal cancer when compared to sulfonylurea use.	('metformin', 'Var', (32, 41))	('pancreatic', 'Disease', (124, 134))	('breast', 'Disease', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('metformin', 'Chemical', 'MESH:D008687', (32, 41))	('sulfonylurea', 'Chemical', 'MESH:D013453', (179, 191))	('prostate', 'Disease', (136, 144))	('lung', 'Disease', (118, 122))	('renal cancer', 'Disease', (149, 161))	('colorectal', 'Disease', (85, 95))	('renal cancer', 'Phenotype', 'HP:0009726', (149, 161))	('esophageal', 'Disease', (97, 107))	('gastric', 'Disease', (109, 116))	('pancreatic', 'Disease', 'MESH:D010195', (124, 134))	('renal cancer', 'Disease', 'MESH:D007680', (149, 161))
536568	30022336	In many of these studies, metformin use was associated with cancer risk reductions, sometimes as high as 94%.	('metformin', 'Chemical', 'MESH:D008687', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('metformin', 'Var', (26, 35))
536569	30022336	A recent meta-analysis which included the 8 published studies that were free of time-related biases reported a summary risk estimate of 0.90 (95% CI 0.89-0.91) for the association between metformin and any cancer incidence.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('metformin', 'Var', (188, 197))	('association', 'Interaction', (168, 179))	('metformin', 'Chemical', 'MESH:D008687', (188, 197))	('any', 'CPA', (202, 205))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
536587	30022336	Definitions included: bladder (ICD-9-CM codes 188.x); breast (ICD-9-CM codes 174x, 175.x), colorectal (ICD-9-CM codes 153.x, 154.x); esophageal (ICD-9-CM codes 150.x); gastric (ICD-9-CM codes 151.x); liver (ICD-9-CM codes 155.x); lung (ICD-9-CM codes 162.x); pancreas (ICD-9-CM codes 157.x); prostate (ICD-9-CM codes 185.x); and renal (ICD-9-CM codes 189.x).	('gastric', 'Disease', (168, 175))	('esophageal', 'Disease', (133, 143))	('pancreas', 'Disease', 'MESH:D010190', (259, 267))	('colorectal', 'Disease', (91, 101))	('pancreas', 'Disease', (259, 267))	('prostate', 'Disease', (292, 300))	('ICD-9-CM', 'Var', (302, 310))	('renal', 'Disease', (329, 334))
536591	30022336	We constructed separate Cox proportional hazard regression models to estimate the adjusted hazard ratios and 95% two-sided confidence intervals for the association of metformin compared to sulfonylureas and specific incidence cancers.	('metformin', 'Var', (167, 176))	('metformin', 'Chemical', 'MESH:D008687', (167, 176))	('sulfonylureas', 'Chemical', 'MESH:D013453', (189, 202))	('Cox', 'Gene', '1351', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('Cox', 'Gene', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('association', 'Interaction', (152, 163))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
536619	30022336	Allowing additional outcomes, we also found statistically significant associations between metformin compared to sulfonylurea and lung cancer (aHR 0.87; 95% CI 0.79, 0.96) and colorectal cancer (aHR 0.86; 95% CI 0.75, 0.99).	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('metformin', 'Var', (91, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('sulfonylurea and lung cancer', 'Disease', 'MESH:D008175', (113, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('metformin', 'Chemical', 'MESH:D008687', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('significant associations', 'Reg', (58, 82))	('colorectal cancer', 'Disease', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
536625	30022336	In subgroup analysis stratified by cirrhosis at baseline, metformin compared to sulfonylurea was associated with liver cancer both in both patients with (HR 0.32, 95% CI 0.12, 0.89) and without (HR 0.46, 95% CI 0.31, 0.68) baseline cirrhosis (Online Resource Table 4).	('cirrhosis', 'Phenotype', 'HP:0001394', (232, 241))	('liver cancer', 'Disease', (113, 125))	('liver cancer', 'Disease', 'MESH:D006528', (113, 125))	('patients', 'Species', '9606', (139, 147))	('cirrhosis', 'Disease', 'MESH:D005355', (232, 241))	('cirrhosis', 'Disease', (35, 44))	('metformin', 'Var', (58, 67))	('associated with', 'Reg', (97, 112))	('metformin', 'Chemical', 'MESH:D008687', (58, 67))	('sulfonylurea', 'Chemical', 'MESH:D013453', (80, 92))	('liver cancer', 'Phenotype', 'HP:0002896', (113, 125))	('cirrhosis', 'Disease', (232, 241))	('cirrhosis', 'Phenotype', 'HP:0001394', (35, 44))	('cirrhosis', 'Disease', 'MESH:D005355', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
536629	30022336	We found a strong inverse association between metformin use compared to sulfonylurea use and incidence liver cancer.	('liver cancer', 'Phenotype', 'HP:0002896', (103, 115))	('liver cancer', 'Disease', 'MESH:D006528', (103, 115))	('metformin', 'Var', (46, 55))	('liver cancer', 'Disease', (103, 115))	('sulfonylurea', 'Chemical', 'MESH:D013453', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('inverse', 'NegReg', (18, 25))	('metformin', 'Chemical', 'MESH:D008687', (46, 55))
536646	30022336	Indeed, in the unmatched cohort, liver disease was more common in sulfonylurea users than metformin users.	('common', 'Reg', (56, 62))	('liver disease', 'Phenotype', 'HP:0001392', (33, 46))	('liver disease', 'Disease', (33, 46))	('sulfonylurea', 'Chemical', 'MESH:D013453', (66, 78))	('sulfonylurea', 'Var', (66, 78))	('liver disease', 'Disease', 'MESH:D008107', (33, 46))	('metformin', 'Chemical', 'MESH:D008687', (90, 99))
536665	30022336	In conclusion, in a large, nationwide cohort of diabetic patients newly initiated on an oral anti-diabetic agent, we found that metformin use was associated with a 56% reduction in liver cancer risk.	('metformin', 'Chemical', 'MESH:D008687', (128, 137))	('liver cancer', 'Phenotype', 'HP:0002896', (181, 193))	('liver cancer', 'Disease', 'MESH:D006528', (181, 193))	('patients', 'Species', '9606', (57, 65))	('diabetic', 'Disease', 'MESH:D003920', (48, 56))	('liver cancer', 'Disease', (181, 193))	('diabetic', 'Disease', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('diabetic', 'Disease', 'MESH:D003920', (98, 106))	('metformin', 'Var', (128, 137))	('diabetic', 'Disease', (48, 56))	('reduction', 'NegReg', (168, 177))
536674	27759773	In patients with squamous cell carcinoma, poor differentiation histology and tumor size were associated with worse oncology stage, but this was not evidenced in adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('poor differentiation', 'Var', (42, 62))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('oncology', 'Phenotype', 'HP:0002664', (115, 123))	('tumor', 'Disease', (77, 82))	('worse oncology stage', 'CPA', (109, 129))	('squamous cell carcinoma', 'Disease', (17, 40))
536695	21731740	The FACS isolated cell subpopulations with high CD44 expression showed increased colony formation and drug resistance in vitro, as well as significantly enhanced tumorigenicity in NOD/SICD mice, as compared to the low expressing CD44 ESCC cells.	('drug resistance', 'CPA', (102, 117))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('drug resistance', 'Phenotype', 'HP:0020174', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('SICD', 'Disease', 'None', (184, 188))	('high', 'Var', (43, 47))	('SICD', 'Disease', (184, 188))	('mice', 'Species', '10090', (189, 193))	('tumor', 'Disease', (162, 167))	('colony formation', 'CPA', (81, 97))	('increased', 'PosReg', (71, 80))	('enhanced', 'PosReg', (153, 161))	('CD44', 'Gene', (48, 52))
536703	21731740	Based on the previous studies of TICs in other solid carcinomas, the following cell surface proteins were selected: CD44, CD90, CD133, CD271 and CD326.	('solid carcinomas', 'Disease', (47, 63))	('CD44', 'Var', (116, 120))	('CD326', 'Var', (145, 150))	('CD133', 'Gene', (128, 133))	('CD133', 'Gene', '8842', (128, 133))	('CD271', 'Gene', '4804', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('CD90', 'Gene', '7070', (122, 126))	('TIC', 'Phenotype', 'HP:0100033', (33, 36))	('CD90', 'Gene', (122, 126))	('solid carcinomas', 'Disease', 'MESH:D018250', (47, 63))	('TICs', 'Phenotype', 'HP:0100033', (33, 37))	('CD271', 'Gene', (135, 140))
536712	21731740	Beside greater tumorigenicity, tumors generated from ESC1 cells exhibited less differentiation than those derived from ESC2 cells, as shown by light microscopy using H&E staining (Figure 1B).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('differentiation', 'MPA', (79, 94))	('greater', 'PosReg', (7, 14))	('ESC2', 'Gene', '84901', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumors', 'Disease', (31, 37))	('less', 'NegReg', (74, 78))	('tumor', 'Disease', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('ESC1', 'Var', (53, 57))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('ESC2', 'Gene', (119, 123))
536721	21731740	At 1x102 cells, three out of 5 mice displayed visible tumors in the CD44H group at 5 weeks after injection.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mice', 'Species', '10090', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('CD44H', 'Var', (68, 73))
536722	21731740	However, only one out of 5 mice at this cell dose generated visible tumors in the CD44L group (Figure 5A, D).	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('mice', 'Species', '10090', (27, 31))	('CD44L', 'Var', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
536723	21731740	Although all mice injected with higher cell doses of CD44H and CD44L cells (1x103 and 1x104) finally formed visible tumors, those from CD44H cells as compared to CD44L displayed a shorter latency for tumor development, and their tumors were a significantly larger (Figure 5B, C and E, F).	('mice', 'Species', '10090', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Disease', (229, 235))	('tumors', 'Disease', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (229, 234))	('CD44H cells', 'Var', (135, 146))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('larger', 'PosReg', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('latency', 'CPA', (188, 195))	('tumor', 'Disease', (116, 121))
536726	21731740	All the tumors derived from CD44H and unsorted ESC1 cells were pathologically analyzed by H&E staining, and no noticeable differences were observed (Figure S2A, B).	('CD44H', 'Var', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
536727	21731740	Also, the percent and level of expression of CD44 within the tumors derived from either CD44H cells or parental ESC1 cells were similar as determined by flow cytometry (Figure S2D).	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', (61, 67))	('CD44H', 'Var', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CD44', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
536729	21731740	As well as in the first generate xenografts, CD44H cells also shown stronger tumorigenicity in second generate xenografts (Figure S3).	('CD44H', 'Var', (45, 50))	('stronger', 'PosReg', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
536737	21731740	Consistent with the previous reports concerning TICs in other tumors, CD44H cells formed more and larger colonies than CD44L cells (Figure 5G, H).	('CD44H', 'Var', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('TIC', 'Phenotype', 'HP:0100033', (48, 51))	('TICs', 'Phenotype', 'HP:0100033', (48, 52))	('larger', 'PosReg', (98, 104))
536753	21731740	Furthermore, the CD44H cells were more resistant to cell kill by traditional chemotherapeutic drugs, as shown by DDP and 5-FU significantly enriching the CD44H population of both ESC1 and Ec109 cells.	('enriching', 'Reg', (140, 149))	('5-FU', 'Chemical', 'MESH:D005472', (121, 125))	('CD44H', 'Var', (154, 159))	('DDP', 'Var', (113, 116))	('DDP', 'Chemical', '-', (113, 116))
536946	29932307	However, still both PET/CT and EUS miss nodal metastasis detection in more than half of the patients; 84/137 (61.3%) in PET/CT and 80/137 (58.3%) in EUS respectively.	('nodal', 'Gene', '4838', (40, 45))	('PET/CT', 'Var', (120, 126))	('nodal', 'Gene', (40, 45))	('patients', 'Species', '9606', (92, 100))
536990	28866248	When cells have wakened their redox buffering potential or when it is being compromised by overproduction of ROS, cellular redox state shifts more towards oxidation and the cell is likely to be susceptible to oxidative damage.	('cellular redox state', 'MPA', (114, 134))	('oxidation', 'MPA', (155, 164))	('overproduction', 'Var', (91, 105))	('redox buffering potential', 'MPA', (30, 55))	('ROS', 'Chemical', 'MESH:D017382', (109, 112))	('ROS', 'Protein', (109, 112))
536998	28866248	Malignant alterations at genetic level are the main pathological driving force of carcinogenesis, often being associated with oxidative stress.	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('oxidative stress', 'Phenotype', 'HP:0025464', (126, 142))	('carcinogenesis', 'Disease', (82, 96))	('associated', 'Reg', (110, 120))	('Malignant', 'Var', (0, 9))
537001	28866248	There are many examples how genetic mutations (inherited or acquired) lead to increased ROS production, which causes DNA damage and contributes to malignant transformation.	('increased', 'PosReg', (78, 87))	('increased ROS production', 'Phenotype', 'HP:0025464', (78, 102))	('contributes', 'Reg', (132, 143))	('causes', 'Reg', (110, 116))	('genetic mutations', 'Var', (28, 45))	('malignant transformation', 'CPA', (147, 171))	('ROS production', 'MPA', (88, 102))	('ROS', 'Chemical', 'MESH:D017382', (88, 91))	('DNA damage', 'MPA', (117, 127))
537007	28866248	Cumulatively, metabolic phenotype of every tumor is a complex interplay of genetic mutations favoring tumorigenesis, specific metabolic prints of tissue of tumor origin and metabolic "cross talk" between tumor and its microenvironment and nutrient uptake.	('mutations', 'Var', (83, 92))	('favoring', 'PosReg', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
537012	28866248	Increased production of ROS is observed upon activation of many different oncogenes or mutations of tumor suppressor genes further influencing additional DNA mutations.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ROS', 'MPA', (24, 27))	('tumor', 'Disease', (100, 105))	('ROS', 'Chemical', 'MESH:D017382', (24, 27))	('production', 'MPA', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (87, 96))
537028	28866248	Therefore, metabolomic analysis targeting lipid metabolism and oxidative stress in cancer should be complemented by quantitative and qualitative immunochemical analysis for the lipid peroxidation products, notably for HNE-protein adducts, well known already as important biomarker of oxidative stress in various diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('oxidative stress', 'Phenotype', 'HP:0025464', (284, 300))	('lipid', 'Chemical', 'MESH:D008055', (42, 47))	('HNE-protein', 'Protein', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('adducts', 'Var', (230, 237))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('oxidative stress', 'Phenotype', 'HP:0025464', (63, 79))	('cancer', 'Disease', (332, 338))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('HNE', 'Chemical', '-', (218, 221))	('lipid', 'Chemical', 'MESH:D008055', (177, 182))	('cancer', 'Disease', (83, 89))
537042	28866248	The human liver tumor cell line, HepG2 exhibited significant reduction of GSH upon treatment with H2O2, while the same cells pre-treated with vitamin E and GSH showed increased GSH in comparison to control.	('liver tumor', 'Phenotype', 'HP:0002896', (10, 21))	('human', 'Species', '9606', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('HepG2', 'CellLine', 'CVCL:0027', (33, 38))	('GSH', 'Chemical', '-', (156, 159))	('vitamin E', 'Chemical', 'MESH:D014810', (142, 151))	('reduction', 'NegReg', (61, 70))	('GSH', 'Chemical', '-', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('GSH', 'Chemical', '-', (74, 77))	('tumor', 'Disease', (16, 21))	('H2O2', 'Chemical', 'MESH:D006861', (98, 102))	('H2O2', 'Var', (98, 102))	('GSH', 'MPA', (74, 77))
537043	28866248	Another study on non-small-cell lung cancer cells (NSCLC) examined metabolic patterns between three isogenic cell clones harboring different KRAS mutations at most frequently mutated loci, codon-12.	('LC', 'Phenotype', 'HP:0001394', (54, 56))	('mutations', 'Var', (146, 155))	('KRAS', 'Gene', (141, 145))	('KRAS', 'Gene', '3845', (141, 145))	('NSCLC', 'Disease', (51, 56))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('examined', 'Reg', (58, 66))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
537044	28866248	In general, KRAS mutations lead to continuous activation of pathways that increase proliferation and avoid apoptosis such as MAPK and PI3K/AKT7/mTOR pathways.	('proliferation', 'CPA', (83, 96))	('MAPK', 'Pathway', (125, 129))	('activation', 'PosReg', (46, 56))	('increase', 'PosReg', (74, 82))	('KRAS', 'Gene', (12, 16))	('KRAS', 'Gene', '3845', (12, 16))	('mutations', 'Var', (17, 26))	('apoptosis', 'CPA', (107, 116))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))
537045	28866248	The intracellular redox state of the KRAS mutants, measured by GSH, GSSG and the ratio GSH/GSSG was comparable to the wild type.	('GSH', 'Chemical', '-', (63, 66))	('GSSG', 'Chemical', '-', (91, 95))	('mutants', 'Var', (42, 49))	('GSH', 'Chemical', '-', (87, 90))	('GSH', 'MPA', (63, 66))	('KRAS', 'Gene', (37, 41))	('GSSG', 'Chemical', '-', (68, 72))	('KRAS', 'Gene', '3845', (37, 41))
537046	28866248	Despite that, KRAS mutants showed metabolic shift towards an oxidized state.	('metabolic shift towards an oxidized state', 'MPA', (34, 75))	('KRAS', 'Gene', (14, 18))	('mutants', 'Var', (19, 26))	('KRAS', 'Gene', '3845', (14, 18))
537047	28866248	In addition, small but significant differences of redox state could also be observed between different KRAS mutants.	('KRAS', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (103, 107))	('mutants', 'Var', (108, 115))	('redox state', 'MPA', (50, 61))	('differences', 'Reg', (35, 46))
537050	28866248	A highly malignant form of renal cancer is associated with mutations in an enzyme of tricarboxylic cycle (TCA), the fumarate hydratase (FH).	('renal cancer', 'Disease', (27, 39))	('TCA', 'Chemical', '-', (106, 109))	('renal cancer', 'Phenotype', 'HP:0009726', (27, 39))	('fumarate hydratase', 'Gene', (116, 134))	('renal cancer', 'Disease', 'MESH:D007680', (27, 39))	('malignant', 'Reg', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (59, 68))	('associated', 'Reg', (43, 53))	('FH', 'Gene', '2271', (136, 138))	('fumarate hydratase', 'Gene', '2271', (116, 134))
537055	28866248	Persistent oxidative stress elicited by succination of GSH induced cellular senescence in vitro and in vivo and provoked initiation of renal cancer in the mouse model when senescence was bypassed.	('succination', 'Var', (40, 51))	('GSH', 'Chemical', '-', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mouse', 'Species', '10090', (155, 160))	('initiation of renal cancer', 'Disease', (121, 147))	('initiation of renal cancer', 'Disease', 'MESH:D007680', (121, 147))	('oxidative stress', 'Phenotype', 'HP:0025464', (11, 27))	('renal cancer', 'Phenotype', 'HP:0009726', (135, 147))	('GSH', 'Gene', (55, 58))	('cellular senescence', 'CPA', (67, 86))
537082	28866248	Another interesting biomarkers of cancer that can be connected to perturbed GSH metabolism are gamma-glutamyl dipeptides.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('perturbed', 'Var', (66, 75))	('GSH', 'Chemical', '-', (76, 79))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('gamma-glutamyl dipeptides', 'Chemical', '-', (95, 120))	('gamma-glutamyl dipeptides', 'MPA', (95, 120))
537108	28866248	For example, aerobic irradiation of Kyn produces superoxide radical that leads to cytochrome C reduction while increased levels of Kyn have been shown to cause cell death through ROS pathway in natural killer (NK) cells.	('ROS pathway', 'Pathway', (179, 190))	('cell death', 'CPA', (160, 170))	('Kyn', 'Var', (131, 134))	('cause', 'Reg', (154, 159))	('ROS', 'Chemical', 'MESH:D017382', (179, 182))	('cytochrome C', 'Gene', (82, 94))	('superoxide radical', 'MPA', (49, 67))	('cytochrome C', 'Gene', '54205', (82, 94))	('superoxide radical', 'Chemical', 'MESH:D013481', (49, 67))	('Kyn', 'Chemical', 'MESH:D007737', (36, 39))	('Kyn', 'Chemical', 'MESH:D007737', (131, 134))
537202	26699332	Our study demonstrated that cancer patients with endoscopic screening had significantly longer survival time than those without endoscopic screening.	('survival time', 'CPA', (95, 108))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('patients', 'Species', '9606', (35, 43))	('endoscopic screening', 'Var', (49, 69))	('cancer', 'Disease', (28, 34))	('longer', 'PosReg', (88, 94))
537213	26699332	The cost-benefit analysis of screening for esophageal and cardiac cancers showed that the treatment cost savings were RMB 17730 and that the value of prolonged life was RMB 41214-137380, with the ratio of benefit-to-cost of 3.95-11.83.	('RMB', 'Chemical', '-', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cardiac cancers', 'Disease', (58, 73))	('RMB 41214-137380', 'Var', (169, 185))	('esophageal', 'Disease', 'MESH:D004941', (43, 53))	('cardiac cancers', 'Disease', 'MESH:D006338', (58, 73))	('men', 'Species', '9606', (95, 98))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('savings', 'NegReg', (105, 112))	('RMB', 'Chemical', '-', (169, 172))	('esophageal', 'Disease', (43, 53))
537340	18338378	The low-risk HPVs (e.g., types 6, 11, and 33) are associated with the growth of warts and benign lesions.	('warts', 'Disease', (80, 85))	('benign', 'Disease', (90, 96))	('warts', 'Phenotype', 'HP:0200043', (80, 85))	('growth', 'MPA', (70, 76))	('types', 'Var', (25, 30))	('HPV', 'Species', '10566', (13, 16))
537344	18338378	Furthermore, it has been reported that the integration of HPV-DNA into host genomic DNA is associated with chromosomal instability (CIN).	('HPV-DNA', 'Gene', (58, 65))	('integration', 'Var', (43, 54))	('chromosomal instability', 'Phenotype', 'HP:0040012', (107, 130))	('chromosomal instability', 'Disease', (107, 130))	('CIN', 'Disease', 'MESH:D007674', (132, 135))	('HPV', 'Species', '10566', (58, 61))	('CIN', 'Disease', (132, 135))	('associated', 'Reg', (91, 101))
537345	18338378	showed, that integration of E6 and E7 into HeLa cervical carcinoma cells inhibits telomerase activity, increases cyclin-dependent kinase activity and induces expression of c-myc, suggesting that E6 and E7 expressions are required for increased cell proliferation and cell survival.	('increases', 'PosReg', (103, 112))	('cyclin-dependent kinase activity', 'MPA', (113, 145))	('c-myc', 'Gene', '4609', (172, 177))	('HeLa cervical carcinoma', 'Disease', 'MESH:D002575', (43, 66))	('expression', 'MPA', (158, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('HeLa cervical carcinoma', 'Disease', (43, 66))	('inhibits', 'NegReg', (73, 81))	('c-myc', 'Gene', (172, 177))	('telomerase activity', 'MPA', (82, 101))	('integration', 'Var', (13, 24))	('induces', 'Reg', (150, 157))
537360	18338378	Transgenic mice that express JCV T-antigen (T-Ag) can develop tumors of the pituitary gland and malignant peripheral nerve sheath tumors that resemble rare neoplasms that can occur in patients with neurofibromatosis.	('JCV', 'Species', '10632', (29, 32))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (96, 136))	('T-Ag', 'Gene', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('T-antigen', 'Gene', '404663', (33, 42))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (198, 215))	('tumors of the pituitary', 'Disease', 'MESH:D010911', (62, 85))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (96, 136))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('neoplasms', 'Disease', 'MESH:D009369', (156, 165))	('JCV', 'Var', (29, 32))	('neurofibromatosis', 'Disease', 'MESH:C537392', (198, 215))	('malignant peripheral nerve sheath tumors', 'Disease', (96, 136))	('develop', 'PosReg', (54, 61))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('T-antigen', 'Gene', (33, 42))	('neurofibromatosis', 'Disease', (198, 215))	('T-Ag', 'Gene', '404663', (44, 48))	('neoplasms', 'Disease', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Transgenic mice', 'Species', '10090', (0, 15))	('tumors of the pituitary gland', 'Phenotype', 'HP:0040277', (62, 91))	('tumors of the pituitary', 'Disease', (62, 85))	('patients', 'Species', '9606', (184, 192))	('neoplasms', 'Phenotype', 'HP:0002664', (156, 165))
537368	18338378	The inactivation of pRb family members by T-Ag binding leads to the release of E2F, and subsequently the expression of E2F-dependent genes such as c-fos and c-myc, leading to increased cellular proliferation.	('c-myc', 'Gene', (157, 162))	('pRb', 'Gene', '5925', (20, 23))	('inactivation', 'Var', (4, 16))	('c-fos', 'Gene', '2353', (147, 152))	('release', 'MPA', (68, 75))	('increased', 'PosReg', (175, 184))	('c-fos', 'Gene', (147, 152))	('pRb', 'Gene', (20, 23))	('T-Ag', 'Gene', (42, 46))	('cellular proliferation', 'CPA', (185, 207))	('T-Ag', 'Gene', '404663', (42, 46))	('expression', 'MPA', (105, 115))	('c-myc', 'Gene', '4609', (157, 162))	('E2F', 'MPA', (79, 82))	('binding', 'Interaction', (47, 54))
537418	18338378	H. pylori strains are extremely diverse and isolates within an individual can change over time, due to DNA rearrangements, recombination events and endogenous mutations.	('H. pylori', 'Species', '210', (0, 9))	('mutations', 'Var', (159, 168))	('rearrangements', 'Var', (107, 121))	('men', 'Species', '9606', (116, 119))	('recombination', 'Var', (123, 136))
537421	18338378	These gene products seem to interact with each other and their expression represents an increased risk for the development of gastric cancer.	('risk', 'Reg', (98, 102))	('gastric cancer', 'Disease', (126, 140))	('men', 'Species', '9606', (118, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('expression', 'Var', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
537436	18338378	The most extensively studied have been the s1 and m1 vac allele that is strongly correlated with the presence of the cag PAI, and is associated with enhanced epithelial cell injury and distal gastric cancer, compared with VacA m2 strains.	('epithelial cell injury', 'Disease', 'MESH:C567703', (158, 180))	('gastric cancer', 'Phenotype', 'HP:0012126', (192, 206))	('epithelial cell injury', 'Disease', (158, 180))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('presence', 'Var', (101, 109))	('cag PAI', 'Var', (117, 124))	('enhanced', 'PosReg', (149, 157))	('gastric cancer', 'Disease', (192, 206))	('gastric cancer', 'Disease', 'MESH:D013274', (192, 206))
537450	18338378	In this study the authors indicated that transdifferentation of BMDCs to gastric epithelial cells would lead to intraepithelial cancer through metaplasia and dysplasia.	('intraepithelial cancer', 'Disease', (112, 134))	('intraepithelial cancer', 'Disease', 'MESH:D009369', (112, 134))	('transdifferentation', 'Var', (41, 60))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('intraepithelial cancer', 'Phenotype', 'HP:0032187', (112, 134))	('lead to', 'Reg', (104, 111))	('metaplasia and dysplasia', 'Disease', 'MESH:D008679', (143, 167))
537454	18338378	These polymorphisms increase the risk of distal gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('polymorphisms', 'Var', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('gastric cancer', 'Disease', (48, 62))	('gastric cancer', 'Disease', 'MESH:D013274', (48, 62))	('increase', 'PosReg', (20, 28))
537457	18338378	Patients carrying these polymorphisms have a two- to three fold increased risk of developing gastric cancer compared with subjects who have the less proinflammatory genotypes.	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('polymorphisms', 'Var', (24, 37))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Disease', (93, 107))
537460	18338378	Polymorphisms in this gene are correlated to an increased risk of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('Polymorphisms', 'Var', (0, 13))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
537461	18338378	The polymorphism in the IL-10 gene, in association with down-regulation of the proinflammatory cytokine IL-10, results in elevated levels of IL-1beta, TNF-alpha, and interferon-gamma.	('IL-10', 'Gene', '3586', (24, 29))	('IL-1beta', 'Gene', '3553', (141, 149))	('TNF-alpha', 'Gene', '7124', (151, 160))	('down-regulation', 'NegReg', (56, 71))	('interferon-gamma', 'Gene', (166, 182))	('TNF-alpha', 'Gene', (151, 160))	('IL-10', 'Gene', '3586', (104, 109))	('IL-10', 'Gene', (24, 29))	('IL-1beta', 'Gene', (141, 149))	('elevated', 'PosReg', (122, 130))	('IL-10', 'Gene', (104, 109))	('polymorphism', 'Var', (4, 16))	('interferon-gamma', 'Gene', '3458', (166, 182))
537493	18338378	H. pylori has been mainly linked to low-grade MALT lymphomas and even though the exact mechanisms underlying the transition of low-grade to aggressive lymphoma remain unclear, several studies have found genetic alterations associated with this histological transformation, including p53 allelic loss and mutation, hypermethylation of p15 and p16, and chromosomal translocations.	('chromosomal translocations', 'Var', (351, 377))	('H. pylori', 'Species', '210', (0, 9))	('associated', 'Reg', (223, 233))	('MALT lymphomas', 'Disease', (46, 60))	('p15', 'Gene', (334, 337))	('allelic loss', 'Disease', 'MESH:C566065', (287, 299))	('linked', 'Reg', (26, 32))	('mutation', 'Var', (304, 312))	('aggressive lymphoma', 'Disease', 'MESH:D001523', (140, 159))	('p15', 'Gene', '1030', (334, 337))	('lymphoma', 'Phenotype', 'HP:0002665', (151, 159))	('aggressive lymphoma', 'Disease', (140, 159))	('p16', 'Gene', (342, 345))	('MALT lymphomas', 'Disease', 'MESH:D018442', (46, 60))	('lymphomas', 'Phenotype', 'HP:0002665', (51, 60))	('p53', 'Gene', '7157', (283, 286))	('p16', 'Gene', '1029', (342, 345))	('allelic loss', 'Disease', (287, 299))	('H. pylori', 'Disease', (0, 9))	('p53', 'Gene', (283, 286))	('lymphoma', 'Phenotype', 'HP:0002665', (51, 59))	('hypermethylation', 'Var', (314, 330))
537502	18338378	This is either due to germline mutations in an MMR gene, which occurs in Lynch syndrome, or more often, through hypermethylation of the hMLH1 gene promoter, which occurs as an acquired event in sporadic cancers.	('hMLH1', 'Gene', (136, 141))	('MMR gene', 'Gene', (47, 55))	('due', 'Reg', (15, 18))	('sporadic cancers', 'Disease', (194, 210))	('germline mutations', 'Var', (22, 40))	('Lynch syndrome', 'Disease', (73, 87))	('hMLH1', 'Gene', '4292', (136, 141))	('Lynch syndrome', 'Disease', 'MESH:D003123', (73, 87))	('occurs', 'Reg', (63, 69))	('hypermethylation', 'Var', (112, 128))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('sporadic cancers', 'Disease', 'MESH:D009369', (194, 210))
537505	18338378	Methylation of cytosine residues at CpG-rich sequences (CpG islands), present in the promoter regions of many tumor suppressor genes, is a feature of about 35-40% of colorectal CRC.	('cytosine', 'Chemical', 'MESH:D003596', (15, 23))	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('colorectal CRC', 'Disease', (166, 180))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
537506	18338378	The causes and the molecular mechanisms underlying CIN and epigenetic alterations, which occur in approximately 80-85% of all CRCs, are still a matter of controversy.	('CIN', 'Disease', 'MESH:D007674', (51, 54))	('CIN', 'Disease', (51, 54))	('epigenetic alterations', 'Var', (59, 81))	('CRCs', 'Disease', (126, 130))
537514	18338378	Furthermore, demonstrated that JCV T-Ag directly induces CIN in human colonic cells and that interaction of JCV T-Ag with beta-catenin and p53 causes morphological changes and loss of cell-cell contact.	('beta-catenin', 'Gene', '1499', (122, 134))	('T-Ag', 'Gene', '404663', (112, 116))	('p53', 'Gene', (139, 142))	('JCV', 'Var', (108, 111))	('CIN', 'Disease', 'MESH:D007674', (57, 60))	('interaction', 'Interaction', (93, 104))	('T-Ag', 'Gene', (35, 39))	('human', 'Species', '9606', (64, 69))	('loss', 'NegReg', (176, 180))	('T-Ag', 'Gene', (112, 116))	('morphological changes', 'CPA', (150, 171))	('JCV', 'Species', '10632', (31, 34))	('cell-cell contact', 'CPA', (184, 201))	('CIN', 'Disease', (57, 60))	('induces', 'Reg', (49, 56))	('p53', 'Gene', '7157', (139, 142))	('JCV', 'Species', '10632', (108, 111))	('beta-catenin', 'Gene', (122, 134))	('T-Ag', 'Gene', '404663', (35, 39))
537517	18338378	Aberrant methylation in connection to JCV may play a role in early stages of carcinogenesis.	('play', 'Reg', (46, 50))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('Aberrant', 'Var', (0, 8))	('carcinogenesis', 'Disease', (77, 91))	('JCV', 'Species', '10632', (38, 41))	('JCV', 'Disease', (38, 41))	('methylation', 'MPA', (9, 20))
537518	18338378	Taken together, these results indicate that JCV may be involved in two of the principal molecular mechanisms of carcinogenesis in the colon and rectum: abnormal DNA methylation and CIN.	('DNA', 'Protein', (161, 164))	('JCV', 'Species', '10632', (44, 47))	('carcinogenesis in the colon', 'Disease', (112, 139))	('abnormal', 'Var', (152, 160))	('involved', 'Reg', (55, 63))	('CIN', 'Disease', (181, 184))	('CIN', 'Disease', 'MESH:D007674', (181, 184))	('carcinogenesis in the colon', 'Disease', 'MESH:D063646', (112, 139))
537521	18338378	Over the last two decades there has been a rising incidence of anal cancer and studies have identified several risk factors for anal cancer: persistent infection with high-risk genotype human papillomaviruses (HPV), cervical dysplasia or cancer, HIV seropositivity, low CD4 count, cigarette smoking, receptive anal intercourse, and immunosuppression after organ transplant.	('cervical dysplasia', 'Disease', (216, 234))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('anal cancer', 'Phenotype', 'HP:0032186', (128, 139))	('seropositivity', 'Var', (250, 264))	('HIV', 'Disease', (246, 249))	('CD4', 'Gene', (270, 273))	('low', 'Var', (266, 269))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('infection', 'Disease', (152, 161))	('infection', 'Disease', 'MESH:D007239', (152, 161))	('persistent infection', 'Phenotype', 'HP:0031035', (141, 161))	('HPV', 'Species', '10566', (210, 213))	('anal cancer', 'Phenotype', 'HP:0032186', (63, 74))	('cancer', 'Disease', (238, 244))	('cervical dysplasia', 'Disease', 'MESH:D002575', (216, 234))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (216, 234))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('human papillomavirus', 'Species', '10566', (186, 206))	('cancer', 'Disease', (133, 139))	('CD4', 'Gene', '920', (270, 273))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', (68, 74))	('anal intercourse', 'Phenotype', 'HP:0030214', (310, 326))
537522	18338378	Several studies analyzing European, Asian and United States populations detected HPV DNA in 70-100% of anal cancer biopsy specimens.	('anal cancer', 'Phenotype', 'HP:0032186', (103, 114))	('HPV', 'Var', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('HPV', 'Species', '10566', (81, 84))	('men', 'Species', '9606', (127, 130))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
537543	18338378	Another interesting point of anal carcinogenesis is found in the genetic and epigenetic changes of HIV-positive individuals.	('epigenetic changes', 'Var', (77, 95))	('carcinogenesis', 'Disease', (34, 48))	('carcinogenesis', 'Disease', 'MESH:D063646', (34, 48))
537544	18338378	Allelic loss is a key feature of CIN, and certain loci are targets in many gastrointestinal cancers.	('CIN', 'Disease', (33, 36))	('gastrointestinal cancers', 'Disease', (75, 99))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (75, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('CIN', 'Disease', 'MESH:D007674', (33, 36))	('Allelic loss', 'Var', (0, 12))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (75, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('targets', 'Reg', (59, 66))
537549	18338378	In those two studies, the frequency of microsatellite alterations in the HIV-positive group was six fold greater than in the negative group, suggesting that MSI may be important in HIV-associated tumors.	('MSI', 'Disease', 'None', (157, 160))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('HIV-associated tumors', 'Disease', (181, 202))	('MSI', 'Disease', (157, 160))	('microsatellite alterations', 'Var', (39, 65))	('HIV-associated tumors', 'Disease', 'MESH:D016263', (181, 202))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
537559	18338378	The fact that H. pylori eradication has the potential to reduce the risk of gastric cancer development, is an indication of how basic research can be translated into medical practice, and this has major implications for the future directions of public health.	('H. pylori', 'Gene', (14, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('reduce', 'NegReg', (57, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('eradication', 'Var', (24, 35))	('H. pylori', 'Species', '210', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('men', 'Species', '9606', (98, 101))	('gastric cancer', 'Disease', (76, 90))
537561	33214570	Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort PARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Disease', (123, 129))	('BRCA', 'Gene', '672', (222, 226))	('BRCA', 'Gene', (222, 226))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('mutations', 'Var', (34, 43))	('tumors', 'Disease', (235, 241))
537566	33214570	We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.	('human', 'Species', '9606', (165, 170))	('HR deficiency', 'Disease', 'MESH:D001919', (306, 319))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('mutations', 'Var', (43, 52))	('HR deficiency', 'Disease', (306, 319))	('cancers', 'Disease', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
537568	33214570	For example, Tyrosine kinase inhibitors such as imatinib, bosutinib, and dasatinib targeting the BCR-ABL fusion protein have improved outcomes in Philadelphia chromosome positive leukemia, and similar approaches have made a considerable impact in breast cancer, non-small cell lung cancer (NSCLC), and several other cancer types.	('imatinib', 'Chemical', 'MESH:D000068877', (48, 56))	('BCR-ABL', 'Gene', '25', (97, 104))	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('breast cancer', 'Disease', (247, 260))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (266, 288))	('cancer', 'Disease', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (262, 288))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('Philadelphia chromosome positive leukemia', 'Disease', 'MESH:D010677', (146, 187))	('bosutinib', 'Var', (58, 67))	('non-small cell lung cancer', 'Disease', (262, 288))	('cancer', 'Disease', (316, 322))	('Philadelphia chromosome positive leukemia', 'Disease', (146, 187))	('BCR-ABL', 'Gene', (97, 104))	('NSCLC', 'Disease', 'MESH:D002289', (290, 295))	('leukemia', 'Phenotype', 'HP:0001909', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('improved', 'PosReg', (125, 133))	('NSCLC', 'Disease', (290, 295))	('bosutinib', 'Chemical', 'MESH:C471992', (58, 67))	('cancer', 'Disease', (282, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('NSCLC', 'Phenotype', 'HP:0030358', (290, 295))	('Philadelphia chromosome positive leukemia', 'Phenotype', 'HP:0004848', (146, 187))	('dasatinib', 'Chemical', 'MESH:D000069439', (73, 82))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (262, 288))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('Tyrosine', 'Var', (13, 21))
537571	33214570	This approach has strong scientific rationale, as patients with BRCA mutations are thought to have homologous recombination deficiency (HRD), thereby limiting their ability to repair double stranded DNA breaks.	('mutations', 'Var', (69, 78))	('HRD', 'Disease', 'None', (136, 139))	('patients', 'Species', '9606', (50, 58))	('deficiency', 'Disease', (124, 134))	('BRCA', 'Gene', '672', (64, 68))	('deficiency', 'Disease', 'MESH:D007153', (124, 134))	('ability', 'MPA', (165, 172))	('BRCA', 'Gene', (64, 68))	('HRD', 'Disease', (136, 139))	('limiting', 'NegReg', (150, 158))
537575	33214570	For instance, in metastatic prostate cancer, mutations to genes more modestly associated with the pathway such as ATM, CHEK2, and PALB2 are strongly associated with clinical responses to olaparib.	('mutations', 'Var', (45, 54))	('prostate cancer', 'Disease', 'MESH:D011471', (28, 43))	('CHEK2', 'Gene', (119, 124))	('PALB2', 'Gene', '79728', (130, 135))	('ATM', 'Gene', '472', (114, 117))	('PALB2', 'Gene', (130, 135))	('associated with', 'Reg', (149, 164))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('CHEK2', 'Gene', '11200', (119, 124))	('clinical responses to olaparib', 'MPA', (165, 195))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('olaparib', 'Chemical', 'MESH:C531550', (187, 195))	('prostate cancer', 'Disease', (28, 43))	('ATM', 'Gene', (114, 117))
537577	33214570	Likewise, 88% of prostate cancer patients with CHECK2 mutations showed clinical responses to PARP inhibition, with similar results observed in other studies, many including additional cancer histologies.	('cancer', 'Disease', (184, 190))	('prostate cancer', 'Phenotype', 'HP:0012125', (17, 32))	('patients', 'Species', '9606', (33, 41))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('inhibition', 'NegReg', (98, 108))	('prostate cancer', 'Disease', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('CHECK2', 'Gene', (47, 53))	('PARP', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('prostate cancer', 'Disease', 'MESH:D011471', (17, 32))
537578	33214570	Similarly, PALB2 mutated breast cancer also appears to be highly sensitive to PARP inhibition.	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('PALB2', 'Gene', (11, 16))	('PALB2', 'Gene', '79728', (11, 16))	('mutated', 'Var', (17, 24))
537584	33214570	For instance, though loss of POLQ appears to upregulate HR activity in HR-proficient cells, loss of POLQ is also seemingly central to PARP inhibitor sensitivity in the setting of topoisomerase, ATR, or FANCD2-deficiency.	('loss', 'Var', (21, 25))	('POLQ', 'Gene', (100, 104))	('POLQ', 'Gene', '10721', (100, 104))	('ATR', 'Gene', (194, 197))	('POLQ', 'Gene', (29, 33))	('FANCD2-deficiency', 'Disease', (202, 219))	('loss', 'Var', (92, 96))	('FANCD2-deficiency', 'Disease', 'OMIM:227646', (202, 219))	('POLQ', 'Gene', '10721', (29, 33))	('upregulate', 'PosReg', (45, 55))	('ATR', 'Gene', '545', (194, 197))
537585	33214570	Hence, it is clear that stratifying patients based solely BRCA mutations will likely under predict for those who will derive clinical benefit from PARP inhibition.	('mutations', 'Var', (63, 72))	('BRCA', 'Gene', (58, 62))	('BRCA', 'Gene', '672', (58, 62))	('patients', 'Species', '9606', (36, 44))
537587	33214570	We then identified the individual cancer types in which these alterations are most frequent.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('frequent', 'Reg', (83, 91))	('cancer', 'Disease', (34, 40))	('alterations', 'Var', (62, 73))
537588	33214570	Though many of the observed mutations are currently of unknown significance, these newly identified genomic alterations warrant further investigation, particularly in the setting of homologous recombination deficiency and PARP inhibition.	('deficiency', 'Disease', 'MESH:D007153', (207, 217))	('mutations', 'Var', (28, 37))	('deficiency', 'Disease', (207, 217))
537598	33214570	HR pathway mutations were common in this cohort, affecting 7117 (13.4%) of patients.	('mutations', 'Var', (11, 20))	('patients', 'Species', '9606', (75, 83))	('HR pathway', 'Pathway', (0, 10))
537599	33214570	ATM and BRCA2 mutations were most common, affecting 2160 (4.1%) and 1452 (2.7%) of patients respectively, followed by BRCA1 (822 or 1.5%), CDK12 (805 or 1.5%), and POLQ (634 or 1.19%).	('POLQ', 'Gene', (164, 168))	('POLQ', 'Gene', '10721', (164, 168))	('BRCA2', 'Gene', (8, 13))	('CDK12', 'Gene', (139, 144))	('BRCA1', 'Gene', '672', (118, 123))	('affecting', 'Reg', (42, 51))	('ATM', 'Gene', (0, 3))	('BRCA2', 'Gene', '675', (8, 13))	('CDK12', 'Gene', '51755', (139, 144))	('patients', 'Species', '9606', (83, 91))	('BRCA1', 'Gene', (118, 123))	('mutations', 'Var', (14, 23))	('ATM', 'Gene', '472', (0, 3))
537601	33214570	Of these 33,633 patients, 4472 (13.3%) had an identifiable mutation to the queried HR genes, whereas 29,161 (86.7%) did not.	('mutation', 'Var', (59, 67))	('patients', 'Species', '9606', (16, 24))	('HR genes', 'Gene', (83, 91))
537604	33214570	While these data suggest that as a whole, HR pathway mutations may have prognostic value, these results may be skewed should HR mutations be more frequently observed in more aggressive cancers.	('aggressive cancers', 'Disease', (174, 192))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (53, 62))	('observed', 'Reg', (157, 165))	('HR pathway', 'Pathway', (42, 52))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('aggressive cancers', 'Disease', 'MESH:D009369', (174, 192))
537608	33214570	Using this new sample set, we determined the rate of mutations to the HR pathway both overall and by by cancer type (Fig.	('HR pathway', 'Pathway', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
537609	33214570	HR pathway mutations were particularly common among diffuse large B cell lymphomas and melanoma patients, with combined mutation rates of 37.5 and 37.33%, respectively (Fig.	('melanoma', 'Disease', (87, 95))	('mutations', 'Var', (11, 20))	('lymphomas', 'Disease', 'MESH:D008223', (73, 82))	('HR pathway', 'Pathway', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('large B cell', 'Phenotype', 'HP:0005404', (60, 72))	('lymphomas', 'Phenotype', 'HP:0002665', (73, 82))	('common', 'Reg', (39, 45))	('B cell lymphoma', 'Disease', 'MESH:D016393', (66, 81))	('B cell lymphoma', 'Disease', (66, 81))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (66, 81))	('patients', 'Species', '9606', (96, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (66, 82))	('lymphomas', 'Disease', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
537612	33214570	Once again, mutations affecting the combined gene set were associated with poor outcomes in the combined cancer cohort (Fig.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
537614	33214570	With respect to ATM, we observed a total of 485 mutations, 339 of which were missense, 142 truncating, and 4 in-frame mutations of unknown significance (Fig.	('missense', 'Var', (77, 85))	('ATM', 'Gene', '472', (16, 19))	('ATM', 'Gene', (16, 19))	('mutations', 'Var', (48, 57))
537616	33214570	While mutations to POLQ, FANCM, CHECK2, CDK12, and FANCD2 were among the most heterogeneous, these had a relatively low frequency, most effecting only one patient (Fig.	('CDK12', 'Gene', '51755', (40, 45))	('FANCD2', 'Gene', (51, 57))	('FANCM', 'Gene', (25, 30))	('CDK12', 'Gene', (40, 45))	('FANCD2', 'Gene', '2177', (51, 57))	('POLQ', 'Gene', (19, 23))	('patient', 'Species', '9606', (155, 162))	('effecting', 'Reg', (136, 145))	('POLQ', 'Gene', '10721', (19, 23))	('CHECK2', 'Gene', (32, 38))	('mutations', 'Var', (6, 15))	('FANCM', 'Gene', '57697', (25, 30))
537617	33214570	While the majority of mutations identified in this study have yet to be uncharacterized, a sizeable fraction was analogous to those reported previously to have a role in PARP inhibitor sensitivity and/or HRD and likely to have oncogenic function, though this requires further exploration (Supplementary Table S3).	('role', 'Reg', (162, 166))	('HRD', 'Disease', (204, 207))	('mutations', 'Var', (22, 31))	('HRD', 'Disease', 'None', (204, 207))	('PARP', 'Protein', (170, 174))
537618	33214570	Interestingly, several HR-associated mutations often co-occurred in the same patients, suggesting patients with select HR-associated mutations are likely to incur additional HR-associated mutations (Supplementary Table S4).	('HR-associated', 'Gene', (119, 132))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (77, 85))	('mutations', 'Var', (133, 142))	('HR-associated', 'Disease', (174, 187))	('mutations', 'Var', (188, 197))
537619	33214570	Additionally, patients with HR-associated mutations also harbored mutations to several non-HR genes with higher frequency than those without HR associated mutations (Supplementary Table S5), several of which were also independent predictors of poor clinical outcomes (Supplementary Table S6).	('mutations', 'Var', (66, 75))	('HR-associated', 'Disease', (28, 41))	('non-HR genes', 'Gene', (87, 99))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (42, 51))
537621	33214570	As mentioned previously, HR mutations were observed most frequently in diffuse large B cell lymphoma, affecting roughly 38% of patients, though this may be inflated given the small sample size of the study (N = 47).	('B cell lymphoma', 'Disease', 'MESH:D016393', (85, 100))	('B cell lymphoma', 'Disease', (85, 100))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (85, 100))	('observed', 'Reg', (43, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (92, 100))	('patients', 'Species', '9606', (127, 135))	('large B cell', 'Phenotype', 'HP:0005404', (79, 91))	('mutations', 'Var', (28, 37))
537623	33214570	Also as mentioned, HR mutations were also common in cutaneous melanomas (37.5%), though this represented data from 288 patients.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (52, 71))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (52, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('patients', 'Species', '9606', (119, 127))	('cutaneous melanomas', 'Disease', (52, 71))	('mutations', 'Var', (22, 31))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('common', 'Reg', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
537624	33214570	In this group, BRCA mutations were observed in 11.5% of patients, though mutations to ATM, BRIP1, FANCM, and other genes were also common (Table 3).	('patients', 'Species', '9606', (56, 64))	('ATM', 'Gene', '472', (86, 89))	('FANCM', 'Gene', '57697', (98, 103))	('BRIP1', 'Gene', (91, 96))	('mutations', 'Var', (73, 82))	('BRCA', 'Gene', (15, 19))	('BRCA', 'Gene', '672', (15, 19))	('ATM', 'Gene', (86, 89))	('observed', 'Reg', (35, 43))	('BRIP1', 'Gene', '83990', (91, 96))	('mutations', 'Var', (20, 29))	('FANCM', 'Gene', (98, 103))
537627	33214570	ATM, BRCA, CHECK2, and CDK12 mutations were frequent in cholangiocarcinoma (Supplementary Table S8, N = 34) with similar results in uterine carcinoma (Supplementary Table S9, N = 57), though the significance of these results is limited by small sample sizes.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('carcinoma', 'Disease', (65, 74))	('CDK12', 'Gene', (23, 28))	('carcinoma', 'Disease', 'MESH:D009369', (140, 149))	('BRCA', 'Gene', '672', (5, 9))	('ATM', 'Gene', (0, 3))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (132, 149))	('carcinoma', 'Disease', 'MESH:D009369', (65, 74))	('BRCA', 'Gene', (5, 9))	('CDK12', 'Gene', '51755', (23, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('cholangiocarcinoma', 'Disease', (56, 74))	('mutations', 'Var', (29, 38))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinoma', 'Disease', (140, 149))	('CHECK2', 'Gene', (11, 17))	('frequent', 'Reg', (44, 52))	('ATM', 'Gene', '472', (0, 3))
537628	33214570	In esophageal cancers, HR mutations were common to both adenocarcinoma (N = 89) and squamous (N = 96) cancers, though they were more frequent to the former (Table 5).	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('esophageal cancers', 'Disease', (3, 21))	('esophageal cancers', 'Disease', 'MESH:D004938', (3, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('mutations', 'Var', (26, 35))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('adenocarcinoma', 'Disease', (56, 70))	('squamous', 'Disease', (84, 92))	('cancers', 'Disease', (102, 109))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('common', 'Reg', (41, 47))
537629	33214570	While ATM, BRCA, and POLQ mutations were similarly prevalent in both cancer types, adenocarcinoma patients had a high frequency to mutations effecting FANCM (8.9%) and FANCD2 (5.6%), comprising a majority of the difference between the two cancers in overall HR mutation rate (Table 5).	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('ATM', 'Gene', '472', (6, 9))	('FANCM', 'Gene', '57697', (151, 156))	('POLQ', 'Gene', '10721', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('FANCM', 'Gene', (151, 156))	('adenocarcinoma', 'Disease', (83, 97))	('cancers', 'Disease', (239, 246))	('cancer', 'Disease', (239, 245))	('effecting', 'Reg', (141, 150))	('FANCD2', 'Gene', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('BRCA', 'Gene', '672', (11, 15))	('patients', 'Species', '9606', (98, 106))	('ATM', 'Gene', (6, 9))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('FANCD2', 'Gene', '2177', (168, 174))	('cancer', 'Disease', (69, 75))	('POLQ', 'Gene', (21, 25))	('mutations', 'Var', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BRCA', 'Gene', (11, 15))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('cancer', 'Disease', 'MESH:D009369', (239, 245))
537631	33214570	For instance, in the four subtypes represented in the TCGA stomach adenocarcinoma cohort, HR mutations were most common in mucinous adenocarcinoma by percent at 41%, though this represents a very small sample size of only 21 patients (Table 6).	('adenocarcinoma', 'Disease', (67, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (132, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (225, 233))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('mucinous adenocarcinoma', 'Disease', (123, 146))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (123, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('common', 'Reg', (113, 119))	('adenocarcinoma', 'Disease', (132, 146))
537633	33214570	However, the relative distribution of HR mutation among subtypes were varied, though all subtypes had relatively high rates of ATM, BRCA, and POLQ mutations, with FANCM mutations common to mucinous and non-specified carcinomas (Table 6).	('ATM', 'Gene', '472', (127, 130))	('mutations', 'Var', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('carcinomas', 'Disease', (216, 226))	('BRCA', 'Gene', '672', (132, 136))	('POLQ', 'Gene', (142, 146))	('FANCM', 'Gene', '57697', (163, 168))	('POLQ', 'Gene', '10721', (142, 146))	('mucinous', 'Disease', (189, 197))	('BRCA', 'Gene', (132, 136))	('ATM', 'Gene', (127, 130))	('FANCM', 'Gene', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('carcinomas', 'Disease', 'MESH:D009369', (216, 226))
537636	33214570	The efficacy of PARP inhibitors in BRCA-mutated tumors stems largely from the known roles for PARP in mediating single stranded break repair.	('PARP', 'Gene', (16, 20))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('BRCA', 'Gene', (35, 39))	('inhibitors', 'Var', (21, 31))	('BRCA', 'Gene', '672', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
537637	33214570	Thus, initial trials were based on the hypothesis that inhibiting the repair of single stranded breaks will cause synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination.	('tumors', 'Disease', (137, 143))	('repair', 'MPA', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('loss', 'NegReg', (149, 153))	('synthetic lethality', 'CPA', (114, 133))	('single stranded breaks', 'Var', (80, 102))	('inhibiting', 'NegReg', (55, 65))	('cause', 'Reg', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
537644	33214570	While mutations of these and other HR genes are certainly less established indicators of HRD, those affecting ATM and PALB2 have already been shown to associate with responsiveness to PARP inhibition.	('HRD', 'Disease', 'None', (89, 92))	('associate', 'Reg', (151, 160))	('PALB2', 'Gene', '79728', (118, 123))	('responsiveness to PARP inhibition', 'MPA', (166, 199))	('PALB2', 'Gene', (118, 123))	('ATM', 'Gene', '472', (110, 113))	('HRD', 'Disease', (89, 92))	('ATM', 'Gene', (110, 113))	('mutations', 'Var', (6, 15))
537646	33214570	This is consistent to results observed in a similar study, which also found that expanding criteria identifies a larger group of patients who potentially harbor defects to the HR pathway.	('patients', 'Species', '9606', (129, 137))	('defects', 'Var', (161, 168))	('HR pathway', 'Pathway', (176, 186))
537650	33214570	While we cannot conclusively state that the entirety of these patients are in fact HR deficient and would derive clinical benefit from PARP inhibition, as mutations to BARD1, CDK12, DMC1, PALB2, and POLQ seem to predict for poor outcomes in this cohort, their predictive value for PARP inhibition is not established and warrants continued exploration.	('DMC1', 'Gene', (182, 186))	('POLQ', 'Gene', '10721', (199, 203))	('CDK12', 'Gene', '51755', (175, 180))	('mutations', 'Var', (155, 164))	('HR deficient', 'Disease', (83, 95))	('DMC1', 'Gene', '11144', (182, 186))	('PALB2', 'Gene', '79728', (188, 193))	('BARD1', 'Gene', '580', (168, 173))	('PALB2', 'Gene', (188, 193))	('CDK12', 'Gene', (175, 180))	('BARD1', 'Gene', (168, 173))	('patients', 'Species', '9606', (62, 70))	('HR deficient', 'Disease', 'MESH:D001919', (83, 95))	('POLQ', 'Gene', (199, 203))
537652	33214570	For instance, though limited by a small sample size, we found that nearly 40% of diffuse large B cell lymphoma patients harbor mutations to genes associated with the HR pathway, though BRCA mutations were only observed in 6.38%.	('B cell lymphoma', 'Disease', 'MESH:D016393', (95, 110))	('B cell lymphoma', 'Disease', (95, 110))	('BRCA', 'Gene', '672', (185, 189))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (95, 110))	('BRCA', 'Gene', (185, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('HR pathway', 'Pathway', (166, 176))	('large B cell', 'Phenotype', 'HP:0005404', (89, 101))	('mutations', 'Var', (127, 136))	('patients', 'Species', '9606', (111, 119))
537654	33214570	Still, recent evidence points to additional predictive criteria expanding beyond BRCA mutations, with less-studied HR-associated genes such as LMO2 appearing to predict for sensitivity to PARP inhibition.	('BRCA', 'Gene', (81, 85))	('predict', 'Reg', (161, 168))	('mutations', 'Var', (86, 95))	('LMO2', 'Gene', '4005', (143, 147))	('LMO2', 'Gene', (143, 147))	('sensitivity', 'MPA', (173, 184))	('BRCA', 'Gene', '672', (81, 85))
537655	33214570	As discussed, we also identified a high frequency in HR mutations in cutaneous melanoma patients.	('mutations', 'Var', (56, 65))	('cutaneous melanoma', 'Disease', (69, 87))	('patients', 'Species', '9606', (88, 96))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (69, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))
537658	33214570	A 2013 phase II study suggests that the PARP inhibitor rucaparib cooperates with temozolomide in metastatic melanoma, though there are a relatively small number of subsequent clinical studies, likely as BRCA1/2 mutations are not typically considered a cause of malignant melanoma.	('temozolomide', 'Chemical', 'MESH:D000077204', (81, 93))	('BRCA1/2', 'Gene', (203, 210))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('malignant melanoma', 'Phenotype', 'HP:0002861', (261, 279))	('BRCA1/2', 'Gene', '672;675', (203, 210))	('mutations', 'Var', (211, 220))	('malignant melanoma', 'Disease', 'MESH:D008545', (261, 279))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('malignant melanoma', 'Disease', (261, 279))	('melanoma', 'Disease', (271, 279))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('rucaparib', 'Chemical', 'MESH:C531549', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
537659	33214570	However, in the TCGA cohort examined in our study, we found that BRCA mutations are represented in as many as 11.5% of cutaneous melanoma patients, with many patients also harboring mutations to ATM, BRIP1, CHECK2, DMC1, FANCD2, FANCM, and POLQ.	('FANCM', 'Gene', '57697', (229, 234))	('harboring', 'Reg', (172, 181))	('FANCD2', 'Gene', '2177', (221, 227))	('CHECK2', 'Gene', (207, 213))	('FANCM', 'Gene', (229, 234))	('patients', 'Species', '9606', (158, 166))	('cutaneous melanoma', 'Disease', (119, 137))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (119, 137))	('POLQ', 'Gene', (240, 244))	('BRIP1', 'Gene', (200, 205))	('DMC1', 'Gene', '11144', (215, 219))	('patients', 'Species', '9606', (138, 146))	('ATM', 'Gene', '472', (195, 198))	('mutations', 'Var', (182, 191))	('mutations', 'Var', (70, 79))	('BRCA', 'Gene', '672', (65, 69))	('DMC1', 'Gene', (215, 219))	('BRCA', 'Gene', (65, 69))	('POLQ', 'Gene', '10721', (240, 244))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('BRIP1', 'Gene', '83990', (200, 205))	('FANCD2', 'Gene', (221, 227))	('ATM', 'Gene', (195, 198))
537660	33214570	As 37.5% of this patient cohort had at least one mutation affecting the HR pathway, the use of these and other mutations warrant consideration when exploring PARP inhibitors in subsequent clinical trials.	('mutation', 'Var', (49, 57))	('patient', 'Species', '9606', (17, 24))	('HR pathway', 'Pathway', (72, 82))	('affecting', 'Reg', (58, 67))
537663	33214570	However, we must note that an inherent limitation of our study is though we identified several mutations in HR associated genes, relatively few have been characterized, particularly with respect to either HRD or PARP inhibition.	('PARP', 'MPA', (212, 216))	('HRD', 'Disease', (205, 208))	('mutations', 'Var', (95, 104))	('HRD', 'Disease', 'None', (205, 208))	('HR associated genes', 'Gene', (108, 127))
537668	33214570	Further, should PARP inhibitors be combined with other DNA-damaging agents such as chemo or radiotherapy, a patient's HRD status may become less relevant, as early evidence suggests that such approaches may have efficacy in multiple TP53 mutated but HR-intact tumor types.	('tumor', 'Disease', (260, 265))	('HRD', 'Disease', (118, 121))	('TP53', 'Gene', (233, 237))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('mutated', 'Var', (238, 245))	('HRD', 'Disease', 'None', (118, 121))	('patient', 'Species', '9606', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('TP53', 'Gene', '7157', (233, 237))
537672	31962291	Identification of key genes by integrating DNA methylation and next-generation transcriptome sequencing for esophageal squamous cell carcinoma Aberrant DNA methylation leads to abnormal gene expression, making it a significant regulator in the progression of cancer and leading to the requirement for integration of gene expression with DNA methylation.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('Aberrant', 'Var', (143, 151))	('abnormal gene expression', 'MPA', (177, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('DNA', 'Gene', (152, 155))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (108, 142))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('esophageal squamous cell carcinoma', 'Disease', (108, 142))	('cancer', 'Disease', (259, 265))
537684	31962291	Epigenetic alterations have been suggested as underlying mechanisms of cancer progression.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
537685	31962291	DNA methylation is one of the major epigenetic mechanisms involved in cancer, with global DNA hypomethylation accompanied by hypermethylation of tumor suppressor genes being recognized as an epigenetic hallmark of cancer.	('hallmark of cancer', 'Disease', (202, 220))	('tumor suppressor', 'Gene', (145, 161))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('hypermethylation', 'Var', (125, 141))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('hallmark of cancer', 'Disease', 'MESH:D009369', (202, 220))	('hypomethylation', 'Var', (94, 109))	('tumor suppressor', 'Gene', '7248', (145, 161))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
537687	31962291	In 1999, the feasibility of detecting tumor-associated abnormal ctDNA methylation was initially described.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('abnormal', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('ctDNA', 'Gene', (64, 69))
537689	31962291	In addition, posttranslational modifications of histones also regulate gene activity in tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('posttranslational modifications', 'Var', (13, 44))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('regulate', 'Reg', (62, 70))	('tumors', 'Disease', (88, 94))	('gene activity', 'MPA', (71, 84))	('histones', 'Protein', (48, 56))
537696	31962291	Then we found that these candidate genes were cancer-associated, by DAVID enrichment analysis, which suggested that abnormal methylation also plays an important role in esophageal squamous cell carcinoma (Figure 1H).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (169, 203))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('cancer', 'Disease', (46, 52))	('methylation', 'MPA', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('abnormal', 'Var', (116, 124))	('esophageal squamous cell carcinoma', 'Disease', (169, 203))
537706	31962291	The expression of hypermethylated genes increased in seven ESCC cell lines after 5-aza-dC treatment (Figure 3B).	('ESCC', 'Disease', 'MESH:C562729', (59, 63))	('5-aza-dC', 'Var', (81, 89))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (81, 89))	('expression', 'MPA', (4, 14))	('ESCC', 'Disease', (59, 63))	('increased', 'PosReg', (40, 49))
537708	31962291	The efficiency of cell colony formation in the presence of 5-aza-dC was significantly decreased, suggesting that aberrant hypermethylation of these key genes could promote cell colony formation and proliferation of ESCC cells (Figure 3C).	('ESCC', 'Disease', (215, 219))	('promote', 'PosReg', (164, 171))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (59, 67))	('aberrant hypermethylation', 'Var', (113, 138))	('decreased', 'NegReg', (86, 95))	('cell colony formation', 'CPA', (18, 39))	('proliferation', 'CPA', (198, 211))	('cell colony formation', 'CPA', (172, 193))	('ESCC', 'Disease', 'MESH:C562729', (215, 219))
537734	31962291	This shows epigenetically modified regions of CRABP2 may affect histone binding and correlates with expression silencing.	('CRABP2', 'Gene', '1382', (46, 52))	('affect', 'Reg', (57, 63))	('expression', 'MPA', (100, 110))	('epigenetically modified', 'Var', (11, 34))	('CRABP2', 'Gene', (46, 52))	('histone', 'MPA', (64, 71))
537736	31962291	We found frequent hypomethylation of the CpG loci at the promoter region in ESCC samples, but not in EAC samples.	('EAC', 'Disease', 'MESH:D004941', (101, 104))	('EAC', 'Disease', (101, 104))	('hypomethylation', 'Var', (18, 33))	('ESCC', 'Disease', 'MESH:C562729', (76, 80))	('ESCC', 'Disease', (76, 80))
537738	31962291	This indicates that abnormal hypomethylation of the SIX4 promoter was most prominently associated with aberrantly high SIX4 expression in ESCC.	('aberrantly', 'Var', (103, 113))	('SIX4', 'Gene', '51804', (119, 123))	('ESCC', 'Disease', 'MESH:C562729', (138, 142))	('SIX4', 'Gene', (119, 123))	('associated', 'Reg', (87, 97))	('abnormal hypomethylation', 'Var', (20, 44))	('SIX4', 'Gene', '51804', (52, 56))	('expression', 'MPA', (124, 134))	('hypomethylation', 'Var', (29, 44))	('ESCC', 'Disease', (138, 142))	('SIX4', 'Gene', (52, 56))
537759	31962291	GPX3 can catalyze the reduction of peroxides and protect cells against oxidative damage and its hypermethylation has been found in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (131, 156))	('esophageal adenocarcinoma', 'Disease', (131, 156))	('reduction of peroxides', 'MPA', (22, 44))	('peroxides', 'Chemical', 'MESH:D010545', (35, 44))	('GPX3', 'Gene', (0, 4))	('GPX3', 'Gene', '2878', (0, 4))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (131, 156))	('found', 'Reg', (122, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('hypermethylation', 'Var', (96, 112))
537761	31962291	These results suggest that the present analysis has identified some potential key genes in ESCC, and their aberrant DNA methylation may affect the function of super-enhancers to lead to abnormal gene expression and influence tumor progression.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('function', 'MPA', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('ESCC', 'Disease', (91, 95))	('lead to', 'Reg', (178, 185))	('influence', 'Reg', (215, 224))	('abnormal gene expression', 'MPA', (186, 210))	('tumor', 'Disease', (225, 230))	('aberrant', 'Var', (107, 115))	('affect', 'Reg', (136, 142))	('ESCC', 'Disease', 'MESH:C562729', (91, 95))
537764	31962291	Our study reveals many genes with aberrant DNA methylation, which may help to understand the tumor progression of ESCC and to develop novel treatment strategies for patients with ESCC.	('ESCC', 'Disease', 'MESH:C562729', (179, 183))	('ESCC', 'Disease', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('aberrant', 'Var', (34, 42))	('tumor', 'Disease', (93, 98))	('ESCC', 'Disease', (179, 183))	('ESCC', 'Disease', 'MESH:C562729', (114, 118))	('patients', 'Species', '9606', (165, 173))	('help', 'Reg', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
537765	31962291	The eleven genes regulated by methylation are correlated with OS and DFS of ESCC patients and may be potential prognostic biomarkers.	('methylation', 'Var', (30, 41))	('correlated', 'Reg', (46, 56))	('patients', 'Species', '9606', (81, 89))	('ESCC', 'Disease', 'MESH:C562729', (76, 80))	('DFS', 'Disease', (69, 72))	('ESCC', 'Disease', (76, 80))
537771	31962291	ChIP-seq data from 5 ESCC cell lines (KYSE510, KYSE140, TE5, TT and TE7) and WGBS data of 7 ESCC tumor tissues were generated previously, by Lin et.al., and visualized in R with bigWig files.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('ESCC', 'Disease', 'MESH:C562729', (21, 25))	('ESCC', 'Disease', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ESCC', 'Disease', (21, 25))	('tumor', 'Disease', (97, 102))	('KYSE510', 'Var', (38, 45))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))
537778	31962291	The GEO accession numbers of the five ESCC datasets were GSE53622, GSE53624, GSE20347, GSE17351, and GSE23400, and the GEO accession numbers of the other cancers were GSE15471, GSE19826, GSE32323, GSE27262 and GSE1420.	('GSE23400', 'Var', (101, 109))	('ESCC', 'Disease', 'MESH:C562729', (38, 42))	('GSE53624', 'Var', (67, 75))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('ESCC', 'Disease', (38, 42))	('GSE53622', 'Var', (57, 65))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('GSE1420', 'Chemical', '-', (210, 217))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('GSE17351', 'Var', (87, 95))	('GSE20347', 'Var', (77, 85))
537788	30609930	Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCepsilon-NF-kappaB signaling pathway and VEGF-C/ Bcl-2 expression Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies.	('NF-kappaB', 'Gene', '4790', (137, 146))	('upregulated', 'PosReg', (15, 26))	('PLCE1', 'Gene', (39, 44))	('PLCE1', 'Gene', '51196', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('Epigenetically', 'Var', (0, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (205, 228))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (52, 72))	('malignancies', 'Disease', 'MESH:D009369', (262, 274))	('oncoprotein', 'Protein', (27, 38))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (194, 228))	('malignancies', 'Disease', (262, 274))	('esophageal carcinoma', 'Disease', (52, 72))	('VEGF-C', 'Gene', (169, 175))	('drives', 'PosReg', (45, 51))	('Bcl-2', 'Gene', (177, 182))	('activating', 'PosReg', (108, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('VEGF-C', 'Gene', '7424', (169, 175))	('proliferation', 'CPA', (90, 103))	('NF-kappaB', 'Gene', (137, 146))	('Bcl-2', 'Gene', '596', (177, 182))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (52, 72))	('Esophageal squamous cell carcinoma', 'Disease', (194, 228))
537792	30609930	We report that hypomethylation-associated up-regulation of PLCE1 expression was correlated with tumor angiogenesis and poor prognosis in ESCC cohorts.	('hypomethylation-associated', 'Var', (15, 41))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ESCC', 'Disease', (137, 141))	('tumor', 'Disease', (96, 101))	('expression', 'MPA', (65, 75))	('PLCE1', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('up-regulation', 'PosReg', (42, 55))
537795	30609930	Consequently, phosphorylated IkappaBalpha promotes nuclear translocation of p50/p65 and p65, as a transcription factor, can bind vascular endothelial growth factor-C and bcl-2 promoters, enhancing angiogenesis and inhibiting apoptosis in vitro.	('p65', 'Gene', '5970', (80, 83))	('phosphorylated', 'Var', (14, 28))	('vascular endothelial growth factor-C', 'Gene', (129, 165))	('nuclear translocation', 'MPA', (51, 72))	('IkappaBalpha', 'Gene', (29, 41))	('angiogenesis', 'CPA', (197, 209))	('apoptosis', 'CPA', (225, 234))	('p65', 'Gene', (88, 91))	('p50', 'Gene', '4790', (76, 79))	('IkappaBalpha', 'Gene', '4792', (29, 41))	('promotes', 'PosReg', (42, 50))	('bcl-2', 'Gene', (170, 175))	('vascular endothelial growth factor-C', 'Gene', '7424', (129, 165))	('enhancing', 'PosReg', (187, 196))	('inhibiting', 'NegReg', (214, 224))	('p50', 'Gene', (76, 79))	('p65', 'Gene', (80, 83))	('bind', 'Interaction', (124, 128))	('p65', 'Gene', '5970', (88, 91))	('bcl-2', 'Gene', '596', (170, 175))
537797	30609930	Our findings not only provide evidence that hypomethylation-induced PLCE1 confers angiogenesis and proliferation in ESCC by activating PI-PLCepsilon-NF-kappaB signaling pathway and VEGF-C/Bcl-2 expression, but also suggest that modulation of PLCE1 by epigenetic modification or a selective inhibitor may be a promising therapeutic approach for the treatment of ESCC.	('PLC', 'Gene', (68, 71))	('angiogenesis', 'CPA', (82, 94))	('PLC', 'Gene', (138, 141))	('confers', 'PosReg', (74, 81))	('Bcl-2', 'Gene', (188, 193))	('VEGF-C', 'Gene', (181, 187))	('ESCC', 'Disease', (361, 365))	('PLC', 'Gene', '5336', (242, 245))	('VEGF-C', 'Gene', '7424', (181, 187))	('PLC', 'Gene', '5336', (68, 71))	('Bcl-2', 'Gene', '596', (188, 193))	('PLC', 'Gene', '5336', (138, 141))	('activating', 'PosReg', (124, 134))	('proliferation', 'CPA', (99, 112))	('hypomethylation-induced', 'Var', (44, 67))	('modulation', 'Var', (228, 238))	('epigenetic modification', 'Var', (251, 274))	('expression', 'MPA', (194, 204))	('PLC', 'Gene', (242, 245))
537804	30609930	Similarly, we demonstrated that SNPs (rs12263737 and rs2274223) in PLCE1 are associated with esophageal cancer via promoting gene expression in a Chinese-Kazakh population, and the heterozygote of PLCE1 rs2274223 increases susceptibility to human papillomavirus infection in Kazakh patients with ESCC.	('susceptibility', 'MPA', (223, 237))	('esophageal cancer', 'Disease', (93, 110))	('human', 'Species', '9606', (241, 246))	('papillomavirus infection', 'Disease', (247, 271))	('gene expression', 'MPA', (125, 140))	('papillomavirus infection', 'Disease', 'MESH:D030361', (247, 271))	('promoting', 'PosReg', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('PLCE1', 'Gene', (197, 202))	('patients', 'Species', '9606', (282, 290))	('associated', 'Reg', (77, 87))	('PLCE1', 'Gene', (67, 72))	('papillomavirus infection', 'Phenotype', 'HP:0012740', (247, 271))	('rs2274223', 'Mutation', 'rs2274223', (53, 62))	('rs2274223', 'Var', (203, 212))	('rs2274223', 'Var', (53, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('rs2274223', 'Mutation', 'rs2274223', (203, 212))	('rs12263737', 'Var', (38, 48))	('rs12263737', 'Mutation', 'rs12263737', (38, 48))
537807	30609930	Zhai's study showed that using CRISPR/Cas9 genome editing technology to knockdown PLCE1, cell migration, and invasion were significantly inhibited by decreasing transcriptional activity of snail in ESCC.	('transcriptional activity', 'MPA', (161, 185))	('invasion', 'CPA', (109, 117))	('snail', 'Gene', (189, 194))	('inhibited', 'NegReg', (137, 146))	('snail', 'Gene', '6615', (189, 194))	('PLCE1', 'Gene', (82, 87))	('decreasing', 'NegReg', (150, 160))	('knockdown', 'Var', (72, 81))	('cell migration', 'CPA', (89, 103))
537808	30609930	PLCE1 knockout mice are resistant to 9,10-dimethylbenzanthracene/phorbol 12-myristate 13-acetate-induced two-stage skin chemical carcinogenesis and to intestinal tumorigenesis, which are caused by loss-of-function mutations of adenomatous polyposis coli tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (227, 253))	('tumor', 'Disease', (254, 259))	('adenomatous polyposis coli tumor', 'Disease', 'MESH:D011125', (227, 259))	('9,10-dimethylbenzanthracene', 'Chemical', '-', (37, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', (162, 167))	('mutations', 'Var', (214, 223))	('carcinogenesis', 'Disease', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('loss-of-function', 'NegReg', (197, 213))	('phorbol 12-myristate 13-acetate', 'Chemical', 'MESH:D013755', (65, 96))	('mice', 'Species', '10090', (15, 19))	('adenomatous polyposis coli tumor', 'Disease', (227, 259))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
537821	30609930	Here, we confirmed that hypomethylation of PLCE1 promoter significantly up-regulated PLCE1 protien expression and the overexpressed PLCE1 was correlated with tumor angiogenesis and poor overall survival for ESCC patients.	('ESCC', 'Disease', (207, 211))	('tumor', 'Disease', (158, 163))	('expression', 'MPA', (99, 109))	('up-regulated', 'PosReg', (72, 84))	('correlated', 'Reg', (142, 152))	('PLCE1', 'Gene', (43, 48))	('patients', 'Species', '9606', (212, 220))	('hypomethylation', 'Var', (24, 39))	('PLCE1', 'Gene', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('protien', 'Protein', (91, 98))
537841	30609930	U73122 was also used to inhibit PLCE1, and our results indicated that U73122 exerted time-dependent and dose-dependent inhibition effects on PLCE1 in human esophageal cancer cells.	('human', 'Species', '9606', (150, 155))	('U73122', 'Chemical', 'MESH:C060229', (70, 76))	('esophageal cancer', 'Disease', (156, 173))	('U73122', 'Var', (70, 76))	('inhibition', 'NegReg', (119, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('U73122', 'Chemical', 'MESH:C060229', (0, 6))	('PLCE1', 'Gene', (141, 146))
537888	30609930	Kaplan-Meier analysis established that in the cohort, 27 months was the median disease-specific survival time for patients with high expressing PLCE1 compared with the 34 months for patients with low expressing PLCE1 (P = 0.002, log-rank test; Fig.	('patients', 'Species', '9606', (114, 122))	('high expressing', 'Var', (128, 143))	('PLCE1', 'Gene', (144, 149))	('patients', 'Species', '9606', (182, 190))
537892	30609930	Data from the Oncomine database (https://www.oncomine.com/) also confirmed that PLCE1 expression was increased in esophageal carcinoma, hepatocellular carcinoma, glioblastoma and renal cell carcinoma in the four published datasets, GSE92396, GSE98383, GSE90886, and GSE6357 (Fig.	('GSE90886', 'Var', (252, 260))	('PLCE1', 'Gene', (80, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (136, 160))	('increased', 'PosReg', (101, 110))	('renal cell carcinoma', 'Disease', (179, 199))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (179, 199))	('glioblastoma', 'Disease', 'MESH:D005909', (162, 174))	('hepatocellular carcinoma', 'Disease', (136, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('GSE92396', 'Var', (232, 240))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (114, 134))	('oncomine', 'Chemical', '-', (45, 53))	('glioblastoma', 'Disease', (162, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('glioblastoma', 'Phenotype', 'HP:0012174', (162, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('esophageal carcinoma', 'Disease', (114, 134))	('expression', 'MPA', (86, 96))	('GSE6357', 'Var', (266, 273))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (136, 160))	('GSE98383', 'Var', (242, 250))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (179, 199))	('GSE6357', 'Chemical', '-', (266, 273))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (114, 134))	('Oncomine', 'Chemical', '-', (14, 22))
537894	30609930	Importantly, CpGs residing within PLCE1 were strongly hypomethylated in tumor tissues compared to adjacent normal tissues (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('hypomethylated', 'Var', (54, 68))	('PLCE1', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
537896	30609930	In TCGA Illumina 450 k infinium methylation beadchip, we found that the methylation status of 6 CpG site (cg03088791; cg06539629; cg24553184; cg13506485; cg14741153; cg16986921) was all negatively correlated with PLCE1 expression (Fig.	('cg03088791', 'Var', (106, 116))	('cg16986921', 'Chemical', '-', (166, 176))	('cg24553184', 'Var', (130, 140))	('methylation', 'MPA', (72, 83))	('expression', 'MPA', (219, 229))	('negatively', 'NegReg', (186, 196))	('correlated', 'Reg', (197, 207))	('cg16986921', 'Var', (166, 176))	('cg13506485', 'Var', (142, 152))	('cg06539629', 'Var', (118, 128))	('PLCE1', 'Gene', (213, 218))	('cg24553184', 'Chemical', '-', (130, 140))	('cg14741153', 'Chemical', '-', (154, 164))	('cg03088791', 'Chemical', '-', (106, 116))	('cg14741153; cg16986921', 'Var', (154, 176))	('cg06539629', 'Chemical', '-', (118, 128))	('cg13506485', 'Chemical', '-', (142, 152))
537897	30609930	Furthermore, Kaplan-Meier analysis showed that esophageal carcinoma patients with CpG_5.6 hypomethylation have significantly shorter overall survival than those with relative hypermethylation (log rank P = 0.046) (Fig.	('esophageal carcinoma', 'Disease', (47, 67))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (47, 67))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (47, 67))	('hypomethylation', 'Var', (90, 105))	('patients', 'Species', '9606', (68, 76))	('CpG_5.6', 'Gene', (82, 89))	('shorter', 'NegReg', (125, 132))	('overall survival', 'MPA', (133, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
537905	30609930	Colony formation assays revealed that the transfection of Eca109 and EC9706 cells with shR-PLCE1 or U73122 reduced growth compared with controls or blanks (Additional file 2: Figure S1a, b).	('U73122', 'Chemical', 'MESH:C060229', (100, 106))	('reduced', 'NegReg', (107, 114))	('shR-PLCE1', 'Gene', (87, 96))	('U73122', 'Var', (100, 106))	('EC9706', 'CellLine', 'CVCL:E307', (69, 75))	('growth', 'MPA', (115, 121))
537906	30609930	Annexin V (AV)- FITC and TUNEL assays demonstrated that silencing PLCE1 promoted apoptosis in ESCC cells (Fig.	('PLCE1', 'Gene', (66, 71))	('silencing', 'Var', (56, 65))	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('apoptosis', 'CPA', (81, 90))	('AV', 'Disease', 'MESH:D054537', (11, 13))	('ESCC', 'Disease', (94, 98))	('promoted', 'PosReg', (72, 80))
537907	30609930	In Eca109 and EC9706 cells, after treatment with shR-PLCE1 or U73122, red fluorescence emitted by JC-1 was reduced, but green fluorescence was elevated, indicating PLCE1 induced mitochondrial dysfunction in ESCC cells (Additional file 2: Figure S1f).	('U73122', 'Chemical', 'MESH:C060229', (62, 68))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (178, 203))	('mitochondrial dysfunction', 'Disease', (178, 203))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (178, 203))	('shR-PLCE1', 'Var', (49, 58))	('U73122', 'Var', (62, 68))	('reduced', 'NegReg', (107, 114))	('elevated', 'PosReg', (143, 151))	('EC9706', 'CellLine', 'CVCL:E307', (14, 20))	('red fluorescence emitted', 'MPA', (70, 94))	('JC-1', 'Gene', (98, 102))	('green fluorescence', 'MPA', (120, 138))
537911	30609930	We also observed that silencing PLCE1 strongly inhibits Eca109 and EC9706 ESCC cell induction of human umbilical vein endothelial cells (HUVECs) proliferation (Additional file 3: Figure S2a-c).	('PLCE1', 'Gene', (32, 37))	('human', 'Species', '9606', (97, 102))	('EC9706', 'Var', (67, 73))	('silencing', 'Var', (22, 31))	('EC9706', 'CellLine', 'CVCL:E307', (67, 73))	('inhibits', 'NegReg', (47, 55))
537920	30609930	When the ESCC cells were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA), a regular substitution of diacylglycerol (DAG), results showed it could rescue the side effect of PLCE1 knockdown in NF-kappaB-related proteins, phosphorylated-IKK-alpha/beta, -p65, and-IkappaBalpha protein.	('knockdown', 'Var', (186, 195))	('IKK-alpha', 'Gene', (242, 251))	('diacylglycerol', 'Chemical', 'MESH:D004075', (108, 122))	('IkappaBalpha', 'Gene', '4792', (268, 280))	('p65', 'Gene', (259, 262))	('IkappaBalpha', 'Gene', (268, 280))	('p65', 'Gene', '5970', (259, 262))	('IKK-alpha', 'Gene', '1147', (242, 251))	('DAG', 'Chemical', 'MESH:D004075', (124, 127))	('TPA', 'Chemical', 'MESH:D013755', (76, 79))	('12-O-tetradecanoylphorbol 13-acetate', 'Chemical', 'MESH:D013755', (38, 74))	('NF-kappaB-related proteins', 'Protein', (199, 225))	('PLCE1', 'Gene', (180, 185))
537925	30609930	PLCE1 knockdown also triggers the downregulation of Ca2+ content as well (Fig.	('Ca2+', 'Chemical', 'MESH:D000069285', (52, 56))	('downregulation', 'NegReg', (34, 48))	('PLCE1', 'Gene', (0, 5))	('Ca2+ content', 'MPA', (52, 64))	('knockdown', 'Var', (6, 15))
537926	30609930	Silencing of PLCE1 after bay-11-7082 treatment (individually or in combination) reduced NF-kappaB luciferase reporter gene activity (Fig.	('NF-kappaB luciferase reporter', 'Enzyme', (88, 117))	('Silencing', 'Var', (0, 9))	('reduced', 'NegReg', (80, 87))	('PLCE1', 'Gene', (13, 18))	('activity', 'MPA', (123, 131))	('bay-11-7082', 'Chemical', 'MESH:C434003', (25, 36))
537928	30609930	However, silencing PLCE1 expression significantly decreased expression of IkappaBalpha-S32 phosphorylation (Fig.	('expression', 'MPA', (60, 70))	('PLCE1', 'Gene', (19, 24))	('silencing', 'Var', (9, 18))	('IkappaBalpha', 'Gene', '4792', (74, 86))	('decreased', 'NegReg', (50, 59))	('IkappaBalpha', 'Gene', (74, 86))
537929	30609930	Consistently, typical NF-kappaB signaling gene protein and the phosphorylation of p65 in ESCC cells were downregulated by U73122 (Fig.	('U73122', 'Var', (122, 128))	('p65', 'Gene', (82, 85))	('NF-kappaB signaling gene', 'Gene', (22, 46))	('phosphorylation', 'MPA', (63, 78))	('p65', 'Gene', '5970', (82, 85))	('U73122', 'Chemical', 'MESH:C060229', (122, 128))	('downregulated', 'NegReg', (105, 118))
537931	30609930	Immunoprecipitation (IP) assay shows that anti-PLCE1 bound to a band in p65 and IkappaBalpha IPs, which migrated together with PLCE1 protein in cell lysates (Fig.	('anti-PLCE1', 'Var', (42, 52))	('IkappaBalpha', 'Gene', '4792', (80, 92))	('p65', 'Gene', '5970', (72, 75))	('IkappaBalpha', 'Gene', (80, 92))	('bound', 'Interaction', (53, 58))	('p65', 'Gene', (72, 75))
537936	30609930	To test this hypothesis, we first used NF-kappaB inhibitor Bay11-7082 to inhibit the NF-kappaB signaling pathway.	('Bay11-7082', 'Var', (59, 69))	('NF-kappaB', 'Protein', (39, 48))	('NF-kappaB signaling pathway', 'Pathway', (85, 112))	('Bay11-7082', 'Chemical', 'MESH:C434003', (59, 69))	('inhibit', 'NegReg', (73, 80))
537937	30609930	Data show that bay11-7082 exerted time- and dose-dependent inhibition of NF-kappaB signaling pathway in human ESCC (Fig.	('inhibition', 'NegReg', (59, 69))	('bay11-7082', 'Var', (15, 25))	('NF-kappaB signaling pathway', 'Pathway', (73, 100))	('human', 'Species', '9606', (104, 109))	('ESCC', 'Disease', (110, 114))
537938	30609930	PLCE1 knockdown in infected Eca109 and EC9706 ESCC cells increased the effects of NF-kappaB inhibitor, reducing proliferation and increased apoptosis (P < 0.05, Fig.	('apoptosis', 'CPA', (140, 149))	('EC9706', 'Var', (39, 45))	('NF-kappaB', 'Protein', (82, 91))	('reducing', 'NegReg', (103, 111))	('PLCE1', 'Gene', (0, 5))	('increased', 'PosReg', (57, 66))	('increased', 'PosReg', (130, 139))	('knockdown', 'Var', (6, 15))	('effects', 'MPA', (71, 78))	('proliferation', 'CPA', (112, 125))	('EC9706', 'CellLine', 'CVCL:E307', (39, 45))
537939	30609930	PLCE1 knockdown in infected Eca109 and EC9706 ESCC cells increased the effects of NF-kappaB inhibitor, reducing HUVEC proliferation and ESCC cells' ability to induce tubule formation and migration by HUVECs in vitro (P < 0.05, Fig.	('migration', 'CPA', (187, 196))	('EC9706', 'Var', (39, 45))	('tubule formation', 'CPA', (166, 182))	('induce', 'PosReg', (159, 165))	('reducing', 'NegReg', (103, 111))	('PLCE1', 'Gene', (0, 5))	('increased', 'PosReg', (57, 66))	('knockdown', 'Var', (6, 15))	('effects', 'MPA', (71, 78))	('EC9706', 'CellLine', 'CVCL:E307', (39, 45))
537942	30609930	Tumor-bearing mice treated with Bay11-7082 had reduced tumor volume and weight compared with controls (P < 0.05, Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mice', 'Species', '10090', (14, 18))	('Bay11-7082', 'Chemical', 'MESH:C434003', (32, 42))	('Bay11-7082', 'Var', (32, 42))	('tumor', 'Disease', (55, 60))	('reduced', 'NegReg', (47, 54))
537950	30609930	Previous work confirmed a greater expression of PLCE1 protein in homozygous mutant types of rs12263737 and rs2274223 carriers than in homozygous wild-type control carriers.	('rs2274223', 'Mutation', 'rs2274223', (107, 116))	('rs2274223', 'Var', (107, 116))	('expression', 'MPA', (34, 44))	('rs12263737', 'Var', (92, 102))	('rs12263737', 'Mutation', 'rs12263737', (92, 102))	('PLCE1', 'Gene', (48, 53))	('protein', 'Protein', (54, 61))	('greater', 'PosReg', (26, 33))
537952	30609930	Thus, epigenetically upregulated PLCE1 is essential for its transcription, which can cause epigenetic activation, enzyme activity, and augmentation of inflammation esophageal epithelia.	('enzyme activity', 'MPA', (114, 129))	('PLCE1', 'Gene', (33, 38))	('cause', 'Reg', (85, 90))	('upregulated', 'PosReg', (21, 32))	('epigenetically', 'Var', (6, 20))	('inflammation esophageal epithelia', 'Disease', (151, 184))	('epigenetic activation', 'MPA', (91, 112))	('inflammation esophageal epithelia', 'Disease', 'MESH:D007249', (151, 184))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (164, 184))
537953	30609930	Zhai's group showed that CRISPR/Cas9-mediated mutations of PLCE1 decreased transcriptional activity of snails, thereby inhibiting cell migration and invasion in vitro and in vivo.	('snail', 'Gene', (103, 108))	('mutations', 'Var', (46, 55))	('decreased', 'NegReg', (65, 74))	('inhibiting', 'NegReg', (119, 129))	('snail', 'Gene', '6615', (103, 108))	('transcriptional activity', 'MPA', (75, 99))	('PLCE1', 'Gene', (59, 64))	('cell migration', 'CPA', (130, 144))	('invasion', 'CPA', (149, 157))
537957	30609930	Overall, the induction of PLCE1 degradation by hypermethylation may be a therapeutic strategy for preventing PLCE1 activity and treating esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('preventing', 'NegReg', (98, 108))	('activity', 'MPA', (115, 123))	('PLCE1', 'Gene', (109, 114))	('degradation', 'MPA', (32, 43))	('PLCE1', 'Gene', (26, 31))	('esophageal cancer', 'Disease', (137, 154))	('hypermethylation', 'Var', (47, 63))
537977	30609930	Our data suggest, after knockdown of PLCE1, the levels of PI-PLCepsilon-signaling-pathway-related proteins, DAG, IP3, and PKCalpha, were downregulated, which suggests PLCE1 plays an important role in PIP2 cleavage.	('downregulated', 'NegReg', (137, 150))	('levels', 'MPA', (48, 54))	('DAG', 'MPA', (108, 111))	('IP3', 'MPA', (113, 116))	('PLC', 'Gene', (37, 40))	('PLC', 'Gene', (167, 170))	('PLC', 'Gene', (61, 64))	('PIP2', 'Chemical', 'MESH:D019269', (200, 204))	('DAG', 'Chemical', 'MESH:D004075', (108, 111))	('PLC', 'Gene', '5336', (37, 40))	('PLC', 'Gene', '5336', (167, 170))	('IP3', 'Chemical', 'MESH:D015544', (113, 116))	('PKCalpha', 'Gene', '5578', (122, 130))	('PKCalpha', 'Gene', (122, 130))	('knockdown', 'Var', (24, 33))	('PLC', 'Gene', '5336', (61, 64))
537980	30609930	IP3, on the other hand, mobilizes internal Ca2+ stores.	('Ca2+', 'Chemical', 'MESH:D000069285', (43, 47))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))	('mobilizes internal Ca2+ stores', 'MPA', (24, 54))	('IP3', 'Var', (0, 3))
537990	30609930	Guo revealed that compared with the wild-type mouse esophagus, the mRNA of cytokines (e.g., TNFalpha, NF-kappaB, IL-1beta, IFN-gamma, and IL-6) was significantly decreased in PLCE1-/- mouse esophagus.	('NF-kappaB', 'MPA', (102, 111))	('IL-1beta', 'Gene', '16176', (113, 121))	('PLCE1-/-', 'Var', (175, 183))	('mRNA of cytokines', 'MPA', (67, 84))	('IL-1beta', 'Gene', (113, 121))	('decreased', 'NegReg', (162, 171))	('mouse', 'Species', '10090', (46, 51))	('IFN-gamma', 'Gene', '15978', (123, 132))	('mouse', 'Species', '10090', (184, 189))	('TNFalpha', 'MPA', (92, 100))	('IFN-gamma', 'Gene', (123, 132))
538002	30609930	In conclusion, the hypomethylation-associated upregulation of PLCE1 expression is closely correlated with tumor angiogenesis and poor prognosis in ESCC cohorts.	('hypomethylation-associated', 'Var', (19, 45))	('upregulation', 'PosReg', (46, 58))	('expression', 'MPA', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('ESCC', 'Disease', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PLCE1', 'Gene', (62, 67))	('tumor', 'Disease', (106, 111))
538005	30609930	Consequently, phosphorylated IkappaBalpha promotes translocation of p50/p65 to the nucleus and the p65, as a transcription factor, can directly bind vascular endothelial growth factor-C and bcl-2 promoters, thereby enhancing angiogenesis and inhibiting apoptosis in vitro.	('angiogenesis', 'CPA', (225, 237))	('apoptosis', 'CPA', (253, 262))	('p65', 'Gene', (99, 102))	('p65', 'Gene', '5970', (72, 75))	('vascular endothelial growth factor-C', 'Gene', '7424', (149, 185))	('phosphorylated', 'Var', (14, 28))	('bcl-2', 'Gene', (190, 195))	('inhibiting', 'NegReg', (242, 252))	('enhancing', 'PosReg', (215, 224))	('p65', 'Gene', '5970', (99, 102))	('p50', 'Gene', '4790', (68, 71))	('IkappaBalpha', 'Gene', (29, 41))	('translocation', 'MPA', (51, 64))	('bind', 'Interaction', (144, 148))	('bcl-2', 'Gene', '596', (190, 195))	('IkappaBalpha', 'Gene', '4792', (29, 41))	('p50', 'Gene', (68, 71))	('vascular endothelial growth factor-C', 'Gene', (149, 185))	('p65', 'Gene', (72, 75))
538006	30609930	bcl-2 B-cell lymphoma-2 BIM Bisindolylmaleimide CRISPR/Cas9 Clustered regularly interspaced short palindromic repeats/Cas9 DAG Diacylglycerol ESCC Esophageal squamous cell carcinoma FLIP FLICE inhibitory protein GWAS Genome-wide association studies IKK IkB kinase IP3 Inositol trisphosphate MALDI-TOF MS Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry MMP Mitochondrial membrane potential MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MVD Microvessel density NF-kappaB Nuclear factor-kappaB PIP2 Phosphatidylinositol 4,5-bisphosphate PI-PLC Phosphoinositide-phospholipase C PKC Protein kinase C PLCE1 Phospholipase C epsilon 1 SNPs Single-nucleotide polymorphisms VEGF-C Vascular Endothelial Growth Factor C YZC, DDW, HP made conception and designed this study.	('Phospholipase C epsilon 1', 'Gene', (650, 675))	('Ionization', 'Disease', 'MESH:D004194', (338, 348))	('Ionization', 'Disease', (338, 348))	('FLICE', 'Gene', (187, 192))	('Esophageal squamous cell carcinoma', 'Disease', (147, 181))	('bcl-2', 'Gene', (0, 5))	('PIP2', 'Chemical', 'MESH:D019269', (540, 544))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('Phospholipase C epsilon 1', 'Gene', '51196', (650, 675))	('VEGF-C', 'Gene', (713, 719))	('PKC', 'Gene', '112476', (623, 626))	('PLC', 'Gene', '5336', (586, 589))	('Phosphatidylinositol 4,5-bisphosphate', 'Chemical', 'MESH:D019269', (545, 582))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (6, 21))	('Bisindolylmaleimide', 'Chemical', 'MESH:C088060', (28, 47))	('VEGF-C', 'Gene', '7424', (713, 719))	('bcl-2', 'Gene', '596', (0, 5))	('PKC', 'Gene', (623, 626))	('PLC', 'Gene', (644, 647))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (147, 181))	('Diacylglycerol', 'Chemical', 'MESH:D004075', (127, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (13, 21))	('MTT', 'Chemical', 'MESH:C070243', (419, 422))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('Single-nucleotide polymorphisms', 'Var', (681, 712))	('BIM', 'Chemical', 'MESH:C088060', (24, 27))	('IP3', 'Chemical', 'MESH:D015544', (264, 267))	('DAG', 'Chemical', 'MESH:D004075', (123, 126))	('FLICE', 'Gene', '841', (187, 192))	('Inositol trisphosphate', 'Chemical', '-', (268, 290))	('PLC', 'Gene', (586, 589))	('PLC', 'Gene', '5336', (644, 647))	('3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (423, 483))
538015	28627618	HIF-1alpha promoted EC109 cell autophagy via positively modulating p27, whereas silencing of p27 abolished the autophagy induced by hypoxia.	('silencing', 'Var', (80, 89))	('hypoxia', 'Disease', 'MESH:D000860', (132, 139))	('promoted', 'PosReg', (11, 19))	('modulating', 'Reg', (56, 66))	('p27', 'Gene', '3429', (93, 96))	('EC109 cell autophagy', 'CPA', (20, 40))	('p27', 'Gene', '3429', (67, 70))	('p27', 'Gene', (93, 96))	('EC109', 'CellLine', 'CVCL:6898', (20, 25))	('p27', 'Gene', (67, 70))	('hypoxia', 'Disease', (132, 139))	('HIF-1alpha', 'Gene', (0, 10))
538035	28627618	As HIF-1alpha can be degraded through the ubiquitin-proteasome pathway upon normoxia by von Hippel-Lindau (VHL) protein and VHL protein binds to HIF-1alpha by recognizing two highly conserved proline residues (Pro-402 and Pro-564) for polyubitylation, so let alanine to substitute the conserved proline will keep HIF-1alpha constitutively active.	('ubiquitin-proteasome pathway', 'Pathway', (42, 70))	('VHL', 'Gene', '7428', (124, 127))	('alanine', 'Var', (259, 266))	('von Hippel-Lindau', 'Gene', (88, 105))	('degraded', 'NegReg', (21, 29))	('proline', 'Chemical', 'MESH:D011392', (192, 199))	('proline', 'Chemical', 'MESH:D011392', (295, 302))	('von Hippel-Lindau', 'Gene', '7428', (88, 105))	('VHL', 'Gene', '7428', (107, 110))	('Pro', 'Chemical', 'MESH:D011392', (222, 225))	('Pro', 'Chemical', 'MESH:D011392', (210, 213))	('alanine', 'Chemical', 'MESH:D000409', (259, 266))	('VHL', 'Gene', (107, 110))	('VHL', 'Gene', (124, 127))
538047	28627618	In the experiment, NOD/SCID mice at age of 6 weeks were injected with 1x106 cells in 100 microl PBS into left and right flanks, respectively.	('mice', 'Species', '10090', (28, 32))	('SCID', 'Gene', '19090', (23, 27))	('PBS', 'Chemical', 'MESH:D007854', (96, 99))	('1x106 cells', 'Var', (70, 81))	('SCID', 'Gene', (23, 27))
538066	28627618	While E2F1 and p62 presented an opposite expression profile with p27 (Fig.	('p27', 'Gene', '3429', (65, 68))	('p27', 'Gene', (65, 68))	('p62', 'Gene', '23636', (15, 18))	('E2F1', 'Var', (6, 10))	('p62', 'Gene', (15, 18))
538072	28627618	As expected, silencing p27 in EC109 cells decreased HIF-1alpha mediated processing of formation of LC3-II and increased p62 expression (Fig.	('LC3', 'Gene', (99, 102))	('p27', 'Gene', (23, 26))	('LC3', 'Gene', '379556', (99, 102))	('p62', 'Gene', (120, 123))	('decreased', 'NegReg', (42, 51))	('increased', 'PosReg', (110, 119))	('silencing', 'Var', (13, 22))	('expression', 'MPA', (124, 134))	('EC109', 'CellLine', 'CVCL:6898', (30, 35))	('p27', 'Gene', '3429', (23, 26))	('processing of formation', 'MPA', (72, 95))	('p62', 'Gene', '23636', (120, 123))	('HIF-1alpha', 'Protein', (52, 62))
538075	28627618	Here we showed that repression of p27 lead to up-modulating of Bcl-2 and cleavage of PARP (Fig.	('p27', 'Gene', '3429', (34, 37))	('p27', 'Gene', (34, 37))	('up-modulating', 'PosReg', (46, 59))	('PARP', 'Protein', (85, 89))	('cleavage', 'CPA', (73, 81))	('repression', 'Var', (20, 30))	('Bcl-2', 'Protein', (63, 68))
538090	28627618	Here, we found HIF-1alpha can induce autophagy through p27-E2F1 pathway under hypoxia which could degrade cell constituents and supply energy for cell survival.	('supply', 'Reg', (128, 134))	('induce', 'PosReg', (30, 36))	('degrade', 'NegReg', (98, 105))	('hypoxia', 'Disease', (78, 85))	('hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('p27', 'Gene', '3429', (55, 58))	('HIF-1alpha', 'Var', (15, 25))	('p27', 'Gene', (55, 58))	('autophagy', 'CPA', (37, 46))	('cell constituents', 'MPA', (106, 123))
538101	28627618	Ablation of p27 inhibits HIF-1alpha induced autophagy and promotes E2F1 induced apoptosis.	('Ablation', 'Var', (0, 8))	('promotes', 'PosReg', (58, 66))	('E2F1', 'Gene', (67, 71))	('p27', 'Gene', '3429', (12, 15))	('inhibits', 'NegReg', (16, 24))	('autophagy', 'CPA', (44, 53))	('HIF-1alpha', 'Protein', (25, 35))	('apoptosis', 'CPA', (80, 89))	('p27', 'Gene', (12, 15))
538103	26862830	Alcohol consumption and the aldehyde dehydrogenase 2 (ALDH2) polymorphism are associated with the risk of upper aerodigestive tract cancer, and a significant gene-environment interaction between the two has been confirmed in a Japanese population.	('associated', 'Reg', (78, 88))	('ALDH2', 'Gene', (54, 59))	('upper aerodigestive tract cancer', 'Disease', (106, 138))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (106, 138))	('as', 'Chemical', 'MESH:D001151', (47, 49))	('as', 'Chemical', 'MESH:D001151', (78, 80))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('men', 'Species', '9606', (170, 173))	('aldehyde dehydrogenase 2', 'Gene', '217', (28, 52))	('aldehyde dehydrogenase 2', 'Gene', (28, 52))	('ALDH2', 'Gene', '217', (54, 59))	('as', 'Chemical', 'MESH:D001151', (204, 206))	('polymorphism', 'Var', (61, 73))
538104	26862830	To aid the development of a personalized prevention strategy, we developed a risk-prediction model and estimated absolute risks stratified by a combination of the ALDH2 genotype and alcohol consumption.	('ALDH2', 'Gene', (163, 168))	('genotype', 'Var', (169, 177))	('men', 'Species', '9606', (18, 21))	('alcohol', 'Chemical', 'MESH:D000438', (182, 189))	('ALDH2', 'Gene', '217', (163, 168))
538107	26862830	The risk model, including a combination of the ALDH2 genotype and alcohol consumption, provided high discriminatory accuracy and good calibration in both the derivation and the validation studies: C statistics were 0.82 (95% confidence interval 0.80-0.84) and 0.83 (95% confidence interval 0.81-0.85), respectively, and the calibration plots of both studies remained close to the ideal calibration line.	('alcohol', 'Chemical', 'MESH:D000438', (66, 73))	('ALDH2', 'Gene', (47, 52))	('ALDH2', 'Gene', '217', (47, 52))	('genotype', 'Var', (53, 61))
538110	26862830	In conclusion, modification of alcohol consumption according to the ALDH2 genotype will have a major impact on upper aerodigestive tract cancer prevention.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('impact', 'Reg', (101, 107))	('ALDH2', 'Gene', '217', (68, 73))	('modification', 'Var', (15, 27))	('ALDH2', 'Gene', (68, 73))	('alcohol', 'Chemical', 'MESH:D000438', (31, 38))	('upper aerodigestive tract cancer', 'Disease', (111, 143))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (111, 143))
538120	26862830	In East Asian populations, the ALDH2 gene shows a polymorphism (rs671, Glu504Lys) that modulates individual differences in acetaldehyde-oxidizing capacity.	('rs671', 'Var', (64, 69))	('Glu504Lys', 'Var', (71, 80))	('Glu504Lys', 'SUBSTITUTION', 'None', (71, 80))	('rs671', 'Mutation', 'rs671', (64, 69))	('acetaldehyde', 'Chemical', 'MESH:D000079', (123, 135))	('modulates', 'Reg', (87, 96))	('ALDH2', 'Gene', '217', (31, 36))	('acetaldehyde-oxidizing capacity', 'MPA', (123, 154))	('as', 'Chemical', 'MESH:D001151', (4, 6))	('ALDH2', 'Gene', (31, 36))
538121	26862830	As the ALDH2 Lys allele encodes a catalytically inactive subunit, individuals with the Lys allele show a marked increase in blood acetaldehyde after alcohol ingestion, and as a result carry a high risk of UATC.	('Lys', 'Chemical', 'MESH:D008239', (87, 90))	('ALDH2', 'Gene', '217', (7, 12))	('acetaldehyde', 'Chemical', 'MESH:D000079', (130, 142))	('acetaldehyde after alcohol ingestion', 'Phenotype', 'HP:0003533', (130, 166))	('UATC', 'Disease', (205, 209))	('as', 'Chemical', 'MESH:D001151', (172, 174))	('increase', 'PosReg', (112, 120))	('UATC', 'Chemical', '-', (205, 209))	('as', 'Chemical', 'MESH:D001151', (117, 119))	('ALDH2', 'Gene', (7, 12))	('blood acetaldehyde', 'MPA', (124, 142))	('Lys allele', 'Var', (87, 97))	('Lys', 'Chemical', 'MESH:D008239', (13, 16))	('alcohol ingestion', 'Phenotype', 'HP:0030955', (149, 166))	('alcohol', 'Chemical', 'MESH:D000438', (149, 156))
538122	26862830	Moreover, the Lys allele has been confirmed to increase susceptibility to UATC among drinkers, particularly heavy drinkers.	('Lys', 'Chemical', 'MESH:D008239', (14, 17))	('as', 'Chemical', 'MESH:D001151', (26, 28))	('susceptibility', 'Reg', (56, 70))	('as', 'Chemical', 'MESH:D001151', (52, 54))	('Lys', 'Var', (14, 17))	('UATC', 'Disease', (74, 78))	('UATC', 'Chemical', '-', (74, 78))
538123	26862830	We previously showed for the first time a strong gene-environment interaction between the ALDH2 genotype and alcohol drinking on the risk of esophageal cancer, and subsequent studies, including our own, showed the same phenomenon in UATC.	('men', 'Species', '9606', (224, 227))	('alcohol drinking', 'Phenotype', 'HP:0030955', (109, 125))	('alcohol', 'Chemical', 'MESH:D000438', (109, 116))	('esophageal cancer', 'Disease', (141, 158))	('UATC', 'Chemical', '-', (233, 237))	('ALDH2', 'Gene', '217', (90, 95))	('genotype', 'Var', (96, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('men', 'Species', '9606', (61, 64))	('ALDH2', 'Gene', (90, 95))
538131	26862830	By evaluating a combination of the ALDH2 genotype and alcohol drinking, we would be able to encourage individuals to modify their drinking behavior, specifically on the basis of their genotype.	('alcohol', 'Chemical', 'MESH:D000438', (54, 61))	('ALDH2', 'Gene', '217', (35, 40))	('genotype', 'Var', (41, 49))	('alcohol drinking', 'Phenotype', 'HP:0030955', (54, 70))	('ALDH2', 'Gene', (35, 40))	('as', 'Chemical', 'MESH:D001151', (170, 172))
538135	26862830	(ICD-O-3): oral cavity and oropharynx (C00.3-C00.9, C01.9, C02.0-C02.4, C03, C04, C05.0-C05.2, C06, C09, C10), hypopharynx (C12, C13), oral cavity-oropharynx-hypopharynx not otherwise specified (C02.8, C02.9, C05.8, C05.9, C14), larynx (C32), and esophagus (C15).	('C05.9', 'Var', (216, 221))	('C13', 'Gene', (129, 132))	('C15', 'Gene', '51316', (258, 261))	('C14', 'Var', (223, 226))	('C15', 'Gene', (258, 261))	('C02.8', 'Var', (195, 200))	('C32', 'Gene', (237, 240))	('C13', 'Gene', '3229', (129, 132))	('C05.8', 'Var', (209, 214))	('C02.0-C02.4', 'Var', (59, 70))	('C03', 'Var', (72, 75))	('C32', 'Gene', '51192', (237, 240))	('C00.3-C00.9', 'Var', (39, 50))	('C05.0-C05.2', 'Var', (82, 93))	('C01.9', 'Var', (52, 57))	('C10', 'Gene', '113246', (105, 108))	('C10', 'Gene', (105, 108))	('C01.9', 'CellLine', 'CVCL:E303', (52, 57))	('C02.9', 'Var', (202, 207))
538136	26862830	Malignant neoplasms of the salivary glands (C07, C08), nasopharynx (C11), nasal (C30), and paranasal sinuses (C31) were excluded as they have quite distinct etiologies.	('Malignant neoplasms of the salivary glands', 'Disease', 'MESH:D012468', (0, 42))	('neoplasms of the salivary glands', 'Phenotype', 'HP:0100684', (10, 42))	('as', 'Chemical', 'MESH:D001151', (75, 77))	('as', 'Chemical', 'MESH:D001151', (129, 131))	('as', 'Chemical', 'MESH:D001151', (15, 17))	('C11', 'Gene', '1109', (68, 71))	('Malignant neoplasms of the salivary glands', 'Disease', (0, 42))	('as', 'Chemical', 'MESH:D001151', (56, 58))	('as', 'Chemical', 'MESH:D001151', (96, 98))	('neoplasms', 'Phenotype', 'HP:0002664', (10, 19))	('C11', 'Gene', (68, 71))	('C07', 'Var', (44, 47))
538145	26862830	Genotyping for rs671 (ALDH2 Glu504Lys) was based on TaqMan Assays (Applied Biosystems, Foster City, California, USA).	('as', 'Chemical', 'MESH:D001151', (40, 42))	('ALDH2', 'Gene', (22, 27))	('as', 'Chemical', 'MESH:D001151', (44, 46))	('Glu504Lys', 'Var', (28, 37))	('Glu504Lys', 'SUBSTITUTION', 'None', (28, 37))	('ALDH2', 'Gene', '217', (22, 27))	('rs671', 'Mutation', 'rs671', (15, 20))
538156	26862830	The categories of cumulative smoking (never, light-moderate, and heavy), alcohol consumption (never, moderate, high-moderate, and heavy), and the ALDH2 genotype (Glu/Glu, Glu/Lys, and Lys/Lys) were introduced as dummy variables.	('Glu/Lys', 'Var', (171, 178))	('Lys', 'Chemical', 'MESH:D008239', (184, 187))	('Glu', 'Chemical', 'MESH:D018698', (166, 169))	('Glu/Glu', 'Var', (162, 169))	('Lys/Lys', 'Var', (184, 191))	('as', 'Chemical', 'MESH:D001151', (209, 211))	('Glu', 'Chemical', 'MESH:D018698', (162, 165))	('ALDH2', 'Gene', '217', (146, 151))	('Lys', 'Chemical', 'MESH:D008239', (188, 191))	('Lys', 'Chemical', 'MESH:D008239', (175, 178))	('alcohol', 'Chemical', 'MESH:D000438', (73, 80))	('ALDH2', 'Gene', (146, 151))	('Glu', 'Chemical', 'MESH:D018698', (171, 174))
538164	26862830	The two case-control studies were combined to stratify patients into different risk groups by a combination of the ALDH2 genotype and alcohol drinking.	('as', 'Chemical', 'MESH:D001151', (9, 11))	('alcohol', 'Chemical', 'MESH:D000438', (134, 141))	('ALDH2', 'Gene', '217', (115, 120))	('alcohol drinking', 'Phenotype', 'HP:0030955', (134, 150))	('patients', 'Species', '9606', (55, 63))	('ALDH2', 'Gene', (115, 120))	('genotype', 'Var', (121, 129))
538182	26862830	Table 4 shows the OR and cumulative risk by age 80 for a combination of the ALDH2 genotype and alcohol consumption in combined data sets of derivation and validation studies.	('alcohol', 'Chemical', 'MESH:D000438', (95, 102))	('combination', 'Interaction', (57, 68))	('genotype', 'Var', (82, 90))	('ALDH2', 'Gene', '217', (76, 81))	('ALDH2', 'Gene', (76, 81))
538183	26862830	The cumulative risk for heavy drinkers with the Glu/Lys genotype by age 80 was very high: risks for UATC, head and neck cancer, and esophageal cancer were 20.2, 6.1, and 15.9%, respectively, versus respective values for the other subgroups of <4.6, <2.0, and <4.1%, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('head and neck cancer', 'Phenotype', 'HP:0012288', (106, 126))	('neck cancer', 'Disease', 'MESH:D006258', (115, 126))	('neck cancer', 'Disease', (115, 126))	('esophageal cancer', 'Disease', (132, 149))	('UATC', 'Disease', (100, 104))	('Lys', 'Chemical', 'MESH:D008239', (52, 55))	('Glu', 'Chemical', 'MESH:D018698', (48, 51))	('UATC', 'Chemical', '-', (100, 104))	('Glu/Lys', 'Var', (48, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('as', 'Chemical', 'MESH:D001151', (76, 78))
538184	26862830	Figure 3 shows the marked increase in the cumulative risk for heavy drinkers with the Glu/Lys genotype in comparison with the other subgroups, particularly after the age of around 50 (the graph of cumulative risk by cancer site; Supplementary Fig.	('Glu', 'Chemical', 'MESH:D018698', (86, 89))	('Lys', 'Chemical', 'MESH:D008239', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Glu/Lys', 'Var', (86, 93))	('as', 'Chemical', 'MESH:D001151', (31, 33))	('men', 'Species', '9606', (235, 238))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('increase', 'PosReg', (26, 34))
538190	26862830	In the analysis, we found that heavy drinkers with the ALDH2 Glu/Lys genotype had a very high cumulative risk by the age of 80 years at 20.2% for UATC, 6.1% for head and neck cancer, and 15.9% for esophageal cancer.	('Lys', 'Chemical', 'MESH:D008239', (65, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('head and neck cancer', 'Phenotype', 'HP:0012288', (161, 181))	('Glu/Lys', 'Var', (61, 68))	('neck cancer', 'Disease', 'MESH:D006258', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('UATC', 'Disease', (146, 150))	('neck cancer', 'Disease', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('UATC', 'Chemical', '-', (146, 150))	('ALDH2', 'Gene', '217', (55, 60))	('esophageal cancer', 'Disease', (197, 214))	('Glu', 'Chemical', 'MESH:D018698', (61, 64))	('ALDH2', 'Gene', (55, 60))
538192	26862830	Animal studies suggest that circulating ethanol-derived acetaldehyde causes esophageal DNA damage and that the extent of damage is influenced by ALDH2 gene impairment.	('esophageal DNA damage', 'Disease', (76, 97))	('men', 'Species', '9606', (162, 165))	('ethanol', 'Chemical', 'MESH:D000431', (40, 47))	('impairment', 'Var', (156, 166))	('ALDH2', 'Gene', '217', (145, 150))	('acetaldehyde', 'Chemical', 'MESH:D000079', (56, 68))	('causes', 'Reg', (69, 75))	('ALDH2', 'Gene', (145, 150))	('influenced', 'Reg', (131, 141))
538193	26862830	reported that individuals with the Lys/Lys genotype showed markedly higher acetaldehyde levels after ethanol intake than those with the Glu/Lys genotype, who in turn showed about six times the level of those with the Glu/Glu genotype.	('Glu', 'Chemical', 'MESH:D018698', (136, 139))	('Lys', 'Chemical', 'MESH:D008239', (35, 38))	('acetaldehyde', 'Chemical', 'MESH:D000079', (75, 87))	('Glu', 'Chemical', 'MESH:D018698', (217, 220))	('higher', 'PosReg', (68, 74))	('ethanol', 'Chemical', 'MESH:D000431', (101, 108))	('Glu', 'Chemical', 'MESH:D018698', (221, 224))	('Lys', 'Chemical', 'MESH:D008239', (39, 42))	('acetaldehyde levels', 'MPA', (75, 94))	('Lys', 'Chemical', 'MESH:D008239', (140, 143))	('Lys/Lys', 'Var', (35, 42))
538194	26862830	Interestingly, however, individuals with the Lys/Lys genotype had a relatively low risk of UATC because the Lys/Lys genotype is strongly associated with nondrinking.	('Lys', 'Chemical', 'MESH:D008239', (45, 48))	('associated', 'Reg', (137, 147))	('UATC', 'Disease', (91, 95))	('Lys', 'Chemical', 'MESH:D008239', (49, 52))	('Lys', 'Chemical', 'MESH:D008239', (108, 111))	('UATC', 'Chemical', '-', (91, 95))	('nondrinking', 'Disease', (153, 164))	('as', 'Chemical', 'MESH:D001151', (137, 139))	('Lys', 'Chemical', 'MESH:D008239', (112, 115))	('Lys/Lys', 'Var', (108, 115))
538204	26862830	Even though the combined effect of the ALDH2 genotype and alcohol drinking is relatively low in head and neck cancer (Tables 2-4, Supplementary Figs 1-3, Supplemental digital content 2, http://links.lww.com/EJCP/A47, Supplemental digital content 4, http://links.lww.com/EJCP/A49, Supplemental digital content 5, http://links.lww.com/EJCP/A50), this study showed that the risk was nevertheless highest for heavy drinkers with the Glu/Lys genotype.	('Lys', 'Chemical', 'MESH:D008239', (433, 436))	('Glu', 'Chemical', 'MESH:D018698', (429, 432))	('men', 'Species', '9606', (223, 226))	('ALDH2', 'Gene', (39, 44))	('head and neck cancer', 'Phenotype', 'HP:0012288', (96, 116))	('men', 'Species', '9606', (286, 289))	('Glu/Lys', 'Var', (429, 436))	('alcohol', 'Chemical', 'MESH:D000438', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('neck cancer', 'Disease', 'MESH:D006258', (105, 116))	('neck cancer', 'Disease', (105, 116))	('alcohol drinking', 'Phenotype', 'HP:0030955', (58, 74))	('as', 'Chemical', 'MESH:D001151', (377, 379))	('men', 'Species', '9606', (160, 163))	('ALDH2', 'Gene', '217', (39, 44))	('men', 'Species', '9606', (136, 139))
538205	26862830	In addition, among moderate drinkers with the Glu/Glu genotype, ORs of less than one were observed in both head and neck and esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('esophageal cancers', 'Disease', (125, 143))	('Glu', 'Chemical', 'MESH:D018698', (46, 49))	('esophageal cancers', 'Disease', 'MESH:D004938', (125, 143))	('Glu', 'Chemical', 'MESH:D018698', (50, 53))	('Glu/Glu', 'Var', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
538209	26862830	In addition, our evaluation of cumulative risk highlighted the very high risk for heavy drinkers with the Glu/Lys genotype.	('Glu', 'Chemical', 'MESH:D018698', (106, 109))	('Lys', 'Chemical', 'MESH:D008239', (110, 113))	('heavy drinkers', 'Disease', (82, 96))	('Glu/Lys', 'Var', (106, 113))
538213	26862830	Our study showed that a risk model developed using established predictors, including a combination of the ALDH2 genotype and alcohol drinking, had high discriminatory accuracy and good calibration.	('ALDH2', 'Gene', '217', (106, 111))	('genotype', 'Var', (112, 120))	('ALDH2', 'Gene', (106, 111))	('alcohol drinking', 'Phenotype', 'HP:0030955', (125, 141))	('alcohol', 'Chemical', 'MESH:D000438', (125, 132))
538214	26862830	On the basis of their surprisingly high cumulative risk, heavy drinkers with the ALDH2 Glu/Lys genotype should be targeted for prevention efforts aimed at reducing alcohol consumption.	('ALDH2', 'Gene', '217', (81, 86))	('ALDH2', 'Gene', (81, 86))	('Glu', 'Chemical', 'MESH:D018698', (87, 90))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('Lys', 'Chemical', 'MESH:D008239', (91, 94))	('Glu/Lys', 'Var', (87, 94))	('as', 'Chemical', 'MESH:D001151', (8, 10))
538221	26862830	ri is relative risk for the ith subgroup of the ALDH2 genotype stratified by alcohol consumption (step 1), where the subgroups are 1=Glu/Glu and never drinker; 2=Glu/Glu and moderate drinker; 3=Glu/Glu and high-moderate drinker; 4=Glu/Glu and heavy drinker; 5=Glu/Lys and never drinker; 6=Glu/Lys and moderate drinker; 7=Glu/Lys and high-moderate drinker; 8=Glu/Lys and heavy drinker; 9=Lys/Lys and never drinker; 10=Lys/Lys and moderate drinker; 11=Lys/Lys and high-moderate drinker; and 12=Lys/Lys and heavy drinker.	('Glu', 'Chemical', 'MESH:D018698', (358, 361))	('Glu', 'Chemical', 'MESH:D018698', (231, 234))	('11=Lys/Lys', 'Var', (447, 457))	('Lys', 'Chemical', 'MESH:D008239', (391, 394))	('10=Lys/Lys', 'Var', (414, 424))	('Lys', 'Chemical', 'MESH:D008239', (454, 457))	('alcohol', 'Chemical', 'MESH:D000438', (77, 84))	('Lys', 'Chemical', 'MESH:D008239', (264, 267))	('Glu', 'Chemical', 'MESH:D018698', (166, 169))	('Lys', 'Chemical', 'MESH:D008239', (421, 424))	('Lys', 'Chemical', 'MESH:D008239', (325, 328))	('ALDH2', 'Gene', (48, 53))	('Glu', 'Chemical', 'MESH:D018698', (198, 201))	('Glu', 'Chemical', 'MESH:D018698', (260, 263))	('Glu', 'Chemical', 'MESH:D018698', (133, 136))	('Lys', 'Chemical', 'MESH:D008239', (492, 495))	('Lys', 'Chemical', 'MESH:D008239', (293, 296))	('Glu', 'Chemical', 'MESH:D018698', (321, 324))	('Lys', 'Chemical', 'MESH:D008239', (387, 390))	('Glu', 'Chemical', 'MESH:D018698', (235, 238))	('Lys', 'Chemical', 'MESH:D008239', (450, 453))	('ALDH2', 'Gene', '217', (48, 53))	('Glu', 'Chemical', 'MESH:D018698', (289, 292))	('Lys', 'Chemical', 'MESH:D008239', (417, 420))	('Lys', 'Chemical', 'MESH:D008239', (362, 365))	('Glu', 'Chemical', 'MESH:D018698', (162, 165))	('Lys', 'Chemical', 'MESH:D008239', (496, 499))	('Glu', 'Chemical', 'MESH:D018698', (194, 197))	('Glu', 'Chemical', 'MESH:D018698', (137, 140))
538224	26862830	In our study, relative risks of upper aerodigestive tract cancer were estimated by means of the odds ratios using conditional logistic regression, with the Glu/Glu genotype and never drinkers forming the reference subgroup.	('upper aerodigestive tract cancer', 'Disease', (32, 64))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (32, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Glu', 'Chemical', 'MESH:D018698', (156, 159))	('Glu', 'Chemical', 'MESH:D018698', (160, 163))	('Glu/Glu', 'Var', (156, 163))
538234	26862830	They used a similar approach to develop a risk model for esophageal cancer at screening in a clinical setting, on the basis of alcohol drinking, ALDH2 genotype, smoking, and intake of vegetables and fruit.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('alcohol', 'Chemical', 'MESH:D000438', (127, 134))	('as', 'Chemical', 'MESH:D001151', (119, 121))	('alcohol drinking', 'Phenotype', 'HP:0030955', (127, 143))	('genotype', 'Var', (151, 159))	('ALDH2', 'Gene', '217', (145, 150))	('esophageal cancer', 'Disease', (57, 74))	('ALDH2', 'Gene', (145, 150))
538273	27775643	For instance, though wound complications are no different between groups (10% 3DCRT vs. 11% IMRT (p = 0.36)), pulmonary complications are increased with 3DCRT (30% vs. 24%, p = 0.02).	('increased', 'PosReg', (138, 147))	('pulmonary complications', 'Disease', 'MESH:D008171', (110, 133))	('pulmonary complications', 'Phenotype', 'HP:0006532', (110, 133))	('3DCRT', 'Var', (153, 158))	('pulmonary complications', 'Disease', (110, 133))
538296	27775643	Of note, the 72 patients who received PBT (versus the 164 and 208 patients receiving IMRT and 3DCRT, respectively) displayed a strong trend towards fewer postoperative pulmonary complications.	('fewer', 'NegReg', (148, 153))	('patients', 'Species', '9606', (16, 24))	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (154, 191))	('pulmonary complications', 'Phenotype', 'HP:0006532', (168, 191))	('postoperative pulmonary complications', 'Disease', (154, 191))	('patients', 'Species', '9606', (66, 74))	('PBT', 'Var', (38, 41))
538298	27775643	This indicated that PBT in itself may not be associated with fewer pulmonary complications, but its primary effect (e.g., decreasing mean lung dose) is indeed associated.	('pulmonary complications', 'Phenotype', 'HP:0006532', (67, 90))	('pulmonary complications', 'Disease', (67, 90))	('decreasing', 'NegReg', (122, 132))	('pulmonary complications', 'Disease', 'MESH:D008171', (67, 90))	('PBT', 'Var', (20, 23))
538307	27775643	Next, because the Bragg peak needs to be spread out and placed within the target volume, fluctuations in heterodensities and/or thickness of matter may lead to under-dosing the tumor volume and/or overdosing areas proximal or distal to this volume.	('lead', 'Reg', (152, 156))	('fluctuations', 'Var', (89, 101))	('overdosing', 'Disease', 'MESH:D062787', (197, 207))	('heterodensities', 'MPA', (105, 120))	('overdosing', 'Disease', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('under-dosing', 'NegReg', (160, 172))	('tumor', 'Disease', (177, 182))
538319	27472962	Single nucleotide polymorphism rs13042395 in the SLC52A3 gene as a biomarker for regional lymph node metastasis and relapse-free survival of esophageal squamous cell carcinoma patients SLC52A3 was recently identified as a susceptibility gene for esophageal squamous cell carcinoma (ESCC).	('Single nucleotide polymorphism rs13042395', 'Var', (0, 41))	('rs13042395', 'Mutation', 'rs13042395', (31, 41))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (141, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('SLC52A3', 'Gene', (185, 192))	('SLC52A3', 'Gene', (49, 56))	('SLC52A3', 'Gene', '113278', (185, 192))	('SLC52A3', 'Gene', '113278', (49, 56))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (246, 280))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (257, 280))	('esophageal squamous cell carcinoma', 'Disease', (246, 280))
538320	27472962	However, associations between the single nucleotide polymorphisms (SNPs) rs13042395 (C > T) and rs3746803 (G > A) in SLC52A3 and risk, tumor characteristics and survival of ESCC patients remain inconclusive and of unknown prognostic significance.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('ESCC', 'Disease', (173, 177))	('patients', 'Species', '9606', (178, 186))	('tumor', 'Disease', (135, 140))	('rs13042395', 'Mutation', 'rs13042395', (73, 83))	('SLC52A3', 'Gene', (117, 124))	('associations', 'Interaction', (9, 21))	('rs13042395 (C > T', 'Var', (73, 90))	('rs3746803', 'Mutation', 'rs3746803', (96, 105))	('rs3746803 (G > A', 'Var', (96, 112))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
538322	27472962	No association was found between SLC52A3 rs3746803 and susceptibility, tumor characteristics or survival of ESCC patients.	('patients', 'Species', '9606', (113, 121))	('rs3746803', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('rs3746803', 'Mutation', 'rs3746803', (41, 50))	('ESCC', 'Disease', (108, 112))	('tumor', 'Disease', (71, 76))	('SLC52A3', 'Gene', (33, 40))
538323	27472962	For rs13042395, TT genotype carriers were likely to have reduced lymph node metastasis (odds ratio (OR) = 0.55, 95 % confidence interval (CI), 0.31-0.98) and longer relapse-free survival time (P = 0.03) .	('rs13042395', 'Mutation', 'rs13042395', (4, 14))	('longer', 'PosReg', (158, 164))	('rs13042395', 'Var', (4, 14))	('relapse-free survival time', 'CPA', (165, 191))	('reduced lymph node', 'Phenotype', 'HP:0002732', (57, 75))	('reduced', 'NegReg', (57, 64))	('lymph node metastasis', 'CPA', (65, 86))
538324	27472962	Also, both rs13042395 (hazard ratio (HR) = 0.62, 95 % CI, 0.38-0.99) and regional lymph node metastasis (HR = 2.06, 95 % CI, 1.36-3.13 for N1 vs. N0; HR = 2.88, 95 % CI, 1.70-4.86 for N2 vs. N0; HR = 2.08, 95 % CI, 1.01-4.30 for N3 vs. N0) were independent factors affecting relapse-free survival for ESCC patients who underwent surgery.	('rs13042395', 'Mutation', 'rs13042395', (11, 21))	('ESCC', 'Disease', (301, 305))	('relapse-free', 'Disease', (275, 287))	('rs13042395', 'Var', (11, 21))	('affecting', 'Reg', (265, 274))	('patients', 'Species', '9606', (306, 314))
538325	27472962	Dual luciferase reporter assays and EMSAs suggested that the CC genotype of rs13042395 enhanced SLC52A3 expression, probably via binding with specific transcription factors.	('rs13042395', 'Mutation', 'rs13042395', (76, 86))	('SLC52A3', 'Gene', (96, 103))	('rs13042395', 'Var', (76, 86))	('expression', 'MPA', (104, 114))	('enhanced', 'PosReg', (87, 95))	('binding', 'Interaction', (129, 136))
538326	27472962	The rs13042395 polymorphism in SLC52A3 is associated with regional lymph node metastasis and relapse-free survival in ESCC patients.	('relapse-free survival', 'CPA', (93, 114))	('ESCC', 'Disease', (118, 122))	('rs13042395', 'Mutation', 'rs13042395', (4, 14))	('associated', 'Reg', (42, 52))	('rs13042395', 'Var', (4, 14))	('patients', 'Species', '9606', (123, 131))	('SLC52A3', 'Gene', (31, 38))	('regional lymph node metastasis', 'CPA', (58, 88))
538331	27472962	Single nucleotide polymorphisms (SNPs) are regarded as stable and effective biomarkers for prediction of onset and susceptibility, and prognosis of various cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
538337	27472962	A recent GWAS study and smaller studies have shown that some SNP loci, such as rs13042395 (C > T), rs3746802 (T > C), rs3746803 (G > A) and rs3746804 (G > A) in SLC52A3, are associated with ESCC risk.	('ESCC', 'Disease', (190, 194))	('rs13042395', 'Mutation', 'rs13042395', (79, 89))	('rs3746803', 'Mutation', 'rs3746803', (118, 127))	('associated', 'Reg', (174, 184))	('rs3746802 (T > C', 'Var', (99, 115))	('SLC52A3', 'Gene', (161, 168))	('rs13042395 (C > T', 'Var', (79, 96))	('rs3746804', 'Mutation', 'rs3746804', (140, 149))	('rs3746804 (G > A', 'Var', (140, 156))	('rs3746802', 'Mutation', 'rs3746802', (99, 108))
538338	27472962	The rs13042395 is a SNP locus, located at the 5' flanking region of the SLC52A3 gene, with a minor allele frequency (MAF) ranging from 9.30 to 36.4 % in ESCC vs. 8.28 % to 36.5 % in controls.	('rs13042395', 'Mutation', 'rs13042395', (4, 14))	('rs13042395', 'Var', (4, 14))	('ESCC', 'Disease', (153, 157))	('SLC52A3', 'Gene', (72, 79))
538339	27472962	However, according to other GWAS studies and smaller sample replication studies, associations between rs13042395 and ESCC are inconclusive.	('ESCC', 'Disease', (117, 121))	('rs13042395', 'Mutation', 'rs13042395', (102, 112))	('associations', 'Interaction', (81, 93))	('rs13042395', 'Var', (102, 112))
538340	27472962	The rs3746803, located in the coding region of SLC52A3, is a functional polymorphism (missense) and site of modification by protein kinase C. The reported MAF of rs3746803 in the PubMed SNP database is 9.05 %.	('SLC52A3', 'Gene', (47, 54))	('rs3746803', 'Var', (4, 13))	('rs3746803', 'Mutation', 'rs3746803', (4, 13))	('rs3746803', 'Var', (162, 171))	('rs3746803', 'Mutation', 'rs3746803', (162, 171))
538341	27472962	So far, only one study demonstrates that no relationship exists between rs3746803 and risk of ESCC.	('rs3746803', 'Var', (72, 81))	('ESCC', 'Disease', (94, 98))	('rs3746803', 'Mutation', 'rs3746803', (72, 81))
538342	27472962	Moreover, neither rs13042395 nor rs3746803 have been validated in regard to whether they are related to ESCC in the Chaoshan area of China, a coastal high-risk area for EC, and it has yet to be reported whether SNPs rs13042395 and rs3746803 are associated with tumor characteristics and survival in ESCC patients.	('rs13042395', 'Mutation', 'rs13042395', (216, 226))	('patients', 'Species', '9606', (304, 312))	('tumor', 'Disease', (261, 266))	('rs13042395', 'Mutation', 'rs13042395', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('rs13042395', 'Var', (216, 226))	('rs13042395', 'Var', (18, 28))	('rs3746803', 'Var', (231, 240))	('ESCC', 'Disease', (104, 108))	('associated', 'Reg', (245, 255))	('ESCC', 'Disease', (299, 303))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('rs3746803', 'Mutation', 'rs3746803', (33, 42))	('rs3746803', 'Mutation', 'rs3746803', (231, 240))
538343	27472962	In the present study, we investigated the association between rs13042395 or rs3746803, in SLC52A3, and ESCC risk, tumor characteristics and survival.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('investigated', 'Reg', (25, 37))	('rs13042395', 'Mutation', 'rs13042395', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('rs3746803', 'Var', (76, 85))	('tumor', 'Disease', (114, 119))	('rs13042395', 'Var', (62, 72))	('SLC52A3', 'Gene', (90, 97))	('ESCC', 'Disease', (103, 107))	('rs3746803', 'Mutation', 'rs3746803', (76, 85))
538349	27472962	We prepared a 400 bp genomic DNA fragment containing the human rs13042395 locus located 5622 nt upstream of the transcriptional starting site in the human SLC52A3 gene.	('rs13042395', 'Mutation', 'rs13042395', (63, 73))	('SLC52A3', 'Gene', (155, 162))	('human', 'Species', '9606', (149, 154))	('rs13042395', 'Var', (63, 73))	('human', 'Species', '9606', (57, 62))
538359	27472962	The observed genotype frequencies for the two polymorphisms of SLC52A3 in the controls conformed to the Hardy-Weinberg equilibrium (P = 0.06 and 0.80 for rs13042395 and rs3746803, respectively).	('rs13042395', 'Var', (154, 164))	('rs3746803', 'Var', (169, 178))	('SLC52A3', 'Gene', (63, 70))	('rs13042395', 'Mutation', 'rs13042395', (154, 164))	('rs3746803', 'Mutation', 'rs3746803', (169, 178))
538360	27472962	No significant associations were observed between rs13042395 or SNP 3746803 and ESCC risk (P > 0.05, Table 2).	('rs13042395', 'Var', (50, 60))	('ESCC', 'Disease', (80, 84))	('SNP 3746803', 'Var', (64, 75))	('rs13042395', 'Mutation', 'rs13042395', (50, 60))
538362	27472962	For rs13042395, TT genotype carriers were less likely to have regional lymph node metastasis (OR = 0.55, 95 % CI, 0.31-0.98) than CC genotype carriers.	('rs13042395', 'Mutation', 'rs13042395', (4, 14))	('less', 'NegReg', (42, 46))	('rs13042395', 'Var', (4, 14))	('regional lymph node metastasis', 'CPA', (62, 92))
538364	27472962	No association was found between rs13042395 and other tumor characteristics such as tumor size, depth of tumor invasion, distant metastasis and TNM classification.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (105, 110))	('TNM', 'Gene', '10178', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('rs13042395', 'Mutation', 'rs13042395', (33, 43))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('TNM', 'Gene', (144, 147))	('tumor', 'Disease', (54, 59))	('rs13042395', 'Var', (33, 43))	('distant metastasis', 'CPA', (121, 139))
538365	27472962	For rs3746803, no associations were observed with ESCC tumor characteristics.	('ESCC tumor', 'Disease', (50, 60))	('rs3746803', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('rs3746803', 'Mutation', 'rs3746803', (4, 13))	('ESCC tumor', 'Disease', 'MESH:D004938', (50, 60))
538367	27472962	This result suggests that the relative risk of relapse after surgery for TT genotype carriers is 0.60-fold less than that for the (CC + CT) genotype carriers in ESCC patients.	('ESCC', 'Disease', (161, 165))	('carriers', 'Var', (85, 93))	('less', 'NegReg', (107, 111))	('patients', 'Species', '9606', (166, 174))
538369	27472962	In multivariate Cox regression models, gender, age, rs13042395, rs3746803, tumor size, depth of tumor invasion, regional lymph node metastasis, tumor location, TNM classification, radiotherapy after surgery and chemotherapy after surgery were adjusted for each other.	('rs3746803', 'Var', (64, 73))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TNM', 'Gene', (160, 163))	('rs13042395', 'Mutation', 'rs13042395', (52, 62))	('rs3746803', 'Mutation', 'rs3746803', (64, 73))	('tumor', 'Disease', (96, 101))	('rs13042395', 'Var', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('regional lymph node metastasis', 'CPA', (112, 142))	('TNM', 'Gene', '10178', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', (75, 80))
538370	27472962	Multivariate analysis showed that rs13042395 (HR = 0.62, 95 % CI, 0.38-0.99 for TT vs. (CC + CT)), depth of tumor invasion, regional lymph node metastasis (HR = 2.06, 95 % CI, 1.36-3.13 for N1 vs. N0; HR = 2.88, 95 % CI, 1.70-4.86 for N2 vs. N0; HR = 2.08, 95 % CI, 1.01-4.30 for N3 vs. N0) and radiotherapy after surgery (HR = 1.68, 95 % CI, 1.16-2.43) were linked with ESCC relapse (Table 4).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('rs13042395', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('linked', 'Reg', (359, 365))	('ESCC relapse', 'Disease', (371, 383))	('tumor', 'Disease', (108, 113))	('rs13042395', 'Mutation', 'rs13042395', (34, 44))
538371	27472962	Cox regression analysis in 84 patients who had radiotherapy after surgery showed that TT genotype carriers were more likely to have relapse-free survival (HR = 0.46, 95 % CI, 0.21-0.98) compared with (CC + CT) genotype carriers (Additional file 1: Table S1).	('relapse-free survival', 'CPA', (132, 153))	('carriers', 'Var', (98, 106))	('patients', 'Species', '9606', (30, 38))
538372	27472962	However, rs3746803 was not shown to be associated with ESCC relapse-free survival either by univariate or multivariate analysis (Table 4, Additional file 2: Figure S1A).	('ESCC relapse-free', 'Disease', (55, 72))	('rs3746803', 'Var', (9, 18))	('rs3746803', 'Mutation', 'rs3746803', (9, 18))
538375	27472962	Univariate Cox regression analysis showed that neither rs13042395 nor rs3746803 was associated with ESCC overall survival after surgery (Additional file 3: Table S2).	('rs13042395', 'Mutation', 'rs13042395', (55, 65))	('rs3746803', 'Var', (70, 79))	('ESCC', 'Disease', (100, 104))	('rs13042395', 'Var', (55, 65))	('rs3746803', 'Mutation', 'rs3746803', (70, 79))
538379	27472962	This suggests that the CC genotype of rs13042395 has stronger transcription activity for the down-stream gene (SLC52A3) and promotes SLC52A3 expression.	('stronger', 'PosReg', (53, 61))	('rs13042395', 'Mutation', 'rs13042395', (38, 48))	('rs13042395', 'Var', (38, 48))	('SLC52A3', 'Gene', (133, 140))	('promotes', 'PosReg', (124, 132))	('transcription activity', 'MPA', (62, 84))	('SLC52A3', 'Gene', (111, 118))	('expression', 'MPA', (141, 151))
538380	27472962	In order to identify whether DNA-binding activity on rs13042395 plays an important role in SLC52A3 overexpression, we used an EMSA assay to search for potential factors that could interact with rs13042395 (Fig.	('rs13042395', 'Mutation', 'rs13042395', (53, 63))	('rs13042395', 'Var', (194, 204))	('rs13042395', 'Var', (53, 63))	('rs13042395', 'Mutation', 'rs13042395', (194, 204))
538386	27472962	These results are consistent with the above results demonstrating that the CC genotype of rs13042395 in humans promotes SLC52A3 gene expression, probably via binding with additional transcription factors.	('expression', 'MPA', (133, 143))	('SLC52A3', 'Gene', (120, 127))	('rs13042395', 'Mutation', 'rs13042395', (90, 100))	('rs13042395', 'Var', (90, 100))	('promotes', 'PosReg', (111, 119))	('humans', 'Species', '9606', (104, 110))	('binding', 'Interaction', (158, 165))
538387	27472962	In recent years, the role of rs13042395 in ESCC susceptibility has been controversial.	('ESCC', 'Disease', (43, 47))	('rs13042395', 'Var', (29, 39))	('rs13042395', 'Mutation', 'rs13042395', (29, 39))
538388	27472962	In 2010, rs13042395 was initially found to be related to ESCC by Wang et al..	('ESCC', 'Disease', (57, 61))	('rs13042395', 'Var', (9, 19))	('rs13042395', 'Mutation', 'rs13042395', (9, 19))	('related', 'Reg', (46, 53))
538389	27472962	The present study shows that neither rs13042395 nor rs3746803 is related to ESCC risk.	('rs3746803', 'Var', (52, 61))	('rs13042395', 'Mutation', 'rs13042395', (37, 47))	('rs3746803', 'Mutation', 'rs3746803', (52, 61))	('rs13042395', 'Var', (37, 47))	('ESCC', 'Disease', (76, 80))
538390	27472962	For rs13042395, TT genotype carriers were less likely to have regional lymph node metastasis (compared with CC genotype carriers) and more likely to have better relapse-free survival (compared with (CC + CT) genotype carriers).	('rs13042395', 'Mutation', 'rs13042395', (4, 14))	('better', 'PosReg', (154, 160))	('rs13042395', 'Var', (4, 14))	('relapse-free survival', 'CPA', (161, 182))	('less', 'NegReg', (42, 46))	('regional lymph node metastasis', 'CPA', (62, 92))
538391	27472962	The CC genotype of rs13042395 likely promotes down-stream SLC52A3 gene expression in human ESCC, probably by binding with specific transcription factors.	('rs13042395', 'Var', (19, 29))	('expression', 'MPA', (71, 81))	('SLC52A3 gene', 'Gene', (58, 70))	('down-stream', 'NegReg', (46, 57))	('human', 'Species', '9606', (85, 90))	('rs13042395', 'Mutation', 'rs13042395', (19, 29))	('binding', 'Interaction', (109, 116))	('promotes', 'PosReg', (37, 45))
538392	27472962	According to our study, rs13042395 in SLC52A3 plays an important role in regional lymph node metastasis.	('regional lymph node metastasis', 'CPA', (73, 103))	('rs13042395', 'Mutation', 'rs13042395', (24, 34))	('SLC52A3', 'Gene', (38, 45))	('rs13042395', 'Var', (24, 34))
538393	27472962	This is supported by our demonstration that rs13042395 and regional lymph node metastasis status are independent prognostic factors for relapse-free survival.	('rs13042395', 'Mutation', 'rs13042395', (44, 54))	('rs13042395', 'Var', (44, 54))	('relapse-free', 'Disease', (136, 148))
538394	27472962	Moreover, we show that the CC genotype of rs13042395 could act by promoting SLC52A3 expression by causing the binding of additional transcription factors.	('rs13042395', 'Mutation', 'rs13042395', (42, 52))	('promoting', 'PosReg', (66, 75))	('rs13042395', 'Var', (42, 52))	('binding', 'Interaction', (110, 117))	('SLC52A3', 'Gene', (76, 83))	('causing', 'Reg', (98, 105))	('expression', 'MPA', (84, 94))
538397	27472962	Therefore, it is reasonable to conclude that the CC genotype of rs13042395 in humans leads to SLC52A3 overexpression, which promotes ESCC cell proliferation and protects against cell death.	('rs13042395', 'Var', (64, 74))	('ESCC', 'Disease', (133, 137))	('overexpression', 'PosReg', (102, 116))	('humans', 'Species', '9606', (78, 84))	('SLC52A3', 'Gene', (94, 101))	('promotes', 'PosReg', (124, 132))	('rs13042395', 'Mutation', 'rs13042395', (64, 74))
538398	27472962	All evidence indicates that rs13042395 plays an essential role in ESCC prognosis and is a potential predictive marker for progression and prognosis of ESCC.	('rs13042395', 'Var', (28, 38))	('rs13042395', 'Mutation', 'rs13042395', (28, 38))	('ESCC', 'Disease', (151, 155))	('ESCC', 'Disease', (66, 70))
538404	27472962	Our study shows that the CC genotype of rs13042395 can promote SLC52A3 expression.	('expression', 'MPA', (71, 81))	('SLC52A3', 'Gene', (63, 70))	('promote', 'PosReg', (55, 62))	('rs13042395', 'Mutation', 'rs13042395', (40, 50))	('rs13042395', 'Var', (40, 50))
538409	27472962	Regarding rs3746803, we found rs3746803 had no association with susceptibility, tumor characteristics and survival of ESCC patients, consistent with a previous study.	('ESCC', 'Disease', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('rs3746803', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('rs3746803', 'Mutation', 'rs3746803', (30, 39))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', (80, 85))	('rs3746803', 'Mutation', 'rs3746803', (10, 19))	('rs3746803', 'Var', (30, 39))
538411	27472962	Replicating studies with larger sample size and with a prospective design is necessary to clarify the association between rs13042395 and rs3746803 and ESCC.	('rs13042395', 'Var', (122, 132))	('rs3746803', 'Mutation', 'rs3746803', (137, 146))	('ESCC', 'Disease', (151, 155))	('rs3746803', 'Var', (137, 146))	('rs13042395', 'Mutation', 'rs13042395', (122, 132))
538412	27472962	Second, our study indicates that the CC genotype of rs13042395 promotes SLC52A3 expression, probably via binding with specific transcription factors that generated complexes II and III.	('rs13042395', 'Mutation', 'rs13042395', (52, 62))	('promotes', 'PosReg', (63, 71))	('rs13042395', 'Var', (52, 62))	('SLC52A3', 'Gene', (72, 79))	('expression', 'MPA', (80, 90))	('binding', 'Interaction', (105, 112))
538413	27472962	The present study demonstrates that rs13042395 polymorphisms in the SLC52A3 gene play an important role in regional lymph node metastasis and relapse-free survival of ESCC patients.	('SLC52A3', 'Gene', (68, 75))	('rs13042395 polymorphisms', 'Var', (36, 60))	('ESCC', 'Disease', (167, 171))	('rs13042395', 'Mutation', 'rs13042395', (36, 46))	('patients', 'Species', '9606', (172, 180))	('relapse-free survival', 'CPA', (142, 163))	('regional lymph node metastasis', 'CPA', (107, 137))
538414	27472962	The rs13042395 could enhance SLC52A3 expression in humans, and this enhancement is probably due to additional transcription factor binding.	('rs13042395', 'Mutation', 'rs13042395', (4, 14))	('enhance', 'PosReg', (21, 28))	('rs13042395', 'Var', (4, 14))	('binding', 'Interaction', (131, 138))	('expression', 'MPA', (37, 47))	('humans', 'Species', '9606', (51, 57))	('SLC52A3', 'Gene', (29, 36))
538437	19309775	In these studies, Dkk1 overexpression lead to a substantial reduction of the villus structure in the small bowel and decreased crypts in the colon concomitant with a reduction of the progenitor cells.	('small bowel', 'Disease', 'MESH:D015212', (101, 112))	('reduction', 'NegReg', (166, 175))	('Dkk1', 'Gene', '22943', (18, 22))	('decreased', 'NegReg', (117, 126))	('crypts in the colon', 'CPA', (127, 146))	('overexpression', 'Var', (23, 37))	('reduction', 'NegReg', (60, 69))	('small bowel', 'Disease', (101, 112))	('Dkk1', 'Gene', (18, 22))
538521	19309775	The presence of canonical Wnt 3 in the LP in juxtaposition to the BC layer found in this study may also contribute to proliferation of this layer.	('Wnt 3', 'Gene', (26, 31))	('Wnt 3', 'Gene', '7473', (26, 31))	('BC', 'Chemical', '-', (66, 68))	('proliferation', 'CPA', (118, 131))	('presence', 'Var', (4, 12))	('contribute', 'Reg', (104, 114))
538538	19309775	The role of Dkk3 is not well understood but its levels have been shown to be suppressed in malignant tissues and its ectopic expression has been reported to lead to suppressed growth of cultured cells suggesting that it may be involved in cell proliferation.	('levels', 'MPA', (48, 54))	('Dkk3', 'Gene', (12, 16))	('growth', 'CPA', (176, 182))	('Dkk3', 'Gene', '27122', (12, 16))	('suppressed', 'NegReg', (165, 175))	('involved', 'Reg', (227, 235))	('ectopic', 'Var', (117, 124))
538773	31231980	Additionally, tumor cells or tumor-associated macrophages (TAMs) could also secrete CCL17 and CCL22 which are able to recruit CCR4+ regulatory T cells (Treg).	('secrete', 'Var', (76, 83))	('CCL22', 'Gene', (94, 99))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('recruit', 'PosReg', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CCL17', 'Gene', (84, 89))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('CCL22', 'Gene', '6367', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('CCL17', 'Gene', '6361', (84, 89))
538778	31231980	The main risks for ESCC are smoking and alcohol abuse which may induce gene mutations which can be easily recognized by the immune system.	('induce', 'Reg', (64, 70))	('alcohol abuse', 'Disease', 'MESH:D000437', (40, 53))	('ESCC', 'Disease', (19, 23))	('alcohol abuse', 'Phenotype', 'HP:0030955', (40, 53))	('gene mutations', 'Var', (71, 85))	('alcohol abuse', 'Disease', (40, 53))
538779	31231980	The well-established association of precursor chronic inflammatory lesions and high gene mutation rates with approximately 3000-300 000 mutations per tumor gives the rationale for developing immunotherapy in esophageal cancer.18 Currently, pembrolizumab was recommended for the treatment of esophageal and esophagogastric junction (EGJ) adenocarcinoma with high microsatellite instability or deficient mismatch repair or PD-L1-positive.	('esophageal', 'Disease', 'MESH:D004941', (208, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('gastric', 'Disease', (314, 321))	('deficient', 'NegReg', (392, 401))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('esophageal', 'Disease', (291, 301))	('gastric', 'Disease', 'MESH:D013274', (314, 321))	('adenocarcinoma', 'Disease', (337, 351))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('esophageal', 'Disease', 'MESH:D004941', (291, 301))	('esophageal cancer', 'Disease', (208, 225))	('adenocarcinoma', 'Disease', 'MESH:D000230', (337, 351))	('esophageal', 'Disease', (208, 218))	('tumor', 'Disease', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mismatch repair', 'MPA', (402, 417))	('high microsatellite instability', 'Var', (357, 388))	('pembrolizumab', 'Chemical', 'MESH:C582435', (240, 253))
538840	31231980	However, two studies included in this analysis showed PD-L1 expression to be a favorable prognostic factor for OS in EC.	('expression', 'Var', (60, 70))	('PD-L1', 'Gene', (54, 59))	('OS', 'Gene', '17451', (111, 113))
538843	31231980	The mutations or epigenetic inactivation of the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 could cause microsatellite instability (MSI),62 which means that the microsatellite sequences of DNA cannot be repaired,resulting in a replication error.	('PMS2', 'Gene', '5395', (98, 102))	('MSI', 'Disease', 'None', (143, 146))	('MSH2', 'Gene', (82, 86))	('epigenetic inactivation', 'Var', (17, 40))	('cause', 'Reg', (109, 114))	('microsatellite instability', 'MPA', (115, 141))	('MSH2', 'Gene', '4436', (82, 86))	('MSH6', 'Gene', '2956', (88, 92))	('MSI', 'Disease', (143, 146))	('MSH6', 'Gene', (88, 92))	('replication', 'MPA', (238, 249))	('mutations', 'Var', (4, 13))	('MLH1', 'Gene', '4292', (76, 80))	('PMS2', 'Gene', (98, 102))	('MLH1', 'Gene', (76, 80))
538902	30380687	In response to H. pylori infection, gastric stem cells that have the longest lifetime are susceptible to acquire genetic or epigenetic modifications that can lead to CSC formation.	('lead to', 'Reg', (158, 165))	('infection', 'Disease', (25, 34))	('infection', 'Disease', 'MESH:D007239', (25, 34))	('CSC formation', 'Disease', (166, 179))	('epigenetic modifications', 'Var', (124, 148))	('H. pylori infection', 'Phenotype', 'HP:0005202', (15, 34))	('H. pylori', 'Species', '210', (15, 24))
538912	30380687	In vitro studies demonstrated that cancer cells expressing CD44 and ALDH initiate more tumorspheres than CD44- and ALDH- cancer cells.	('ALDH', 'Gene', '11670', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('more', 'PosReg', (82, 86))	('CD44', 'Var', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ALDH', 'Gene', (68, 72))	('ALDH- cancer', 'Disease', 'MESH:D009369', (115, 127))	('ALDH', 'Gene', '11670', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('ALDH- cancer', 'Disease', (115, 127))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumors', 'Disease', (87, 93))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', (35, 41))	('ALDH', 'Gene', (115, 119))
538913	30380687	Xenograft experiments using extreme limiting dilution analysis mathematical models demonstrated that CD44+ and ALDH+ cells initiate more tumors in vivo than cells expressing other biomarkers such as CD133.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('CD44+', 'Var', (101, 106))	('CD133', 'Gene', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ALDH', 'Gene', '11670', (111, 115))	('ALDH', 'Gene', (111, 115))	('CD133', 'Gene', '8842', (199, 204))
538976	30380687	It has also been shown that high expression of RARbeta is correlated with favorable patient prognosis.	('high', 'Var', (28, 32))	('RARbeta', 'Gene', (47, 54))	('patient', 'Species', '9606', (84, 91))
538993	30380687	Furthermore, it was recently demonstrated that the association of gamma-secretase inhibitors to ATRA increases its growth inhibition and apoptosis enhancement properties.	('growth inhibition', 'CPA', (115, 132))	('gamma-secretase', 'Protein', (66, 81))	('increases', 'PosReg', (101, 110))	('association', 'Interaction', (51, 62))	('inhibitors', 'Var', (82, 92))	('ATRA', 'Chemical', 'MESH:D014212', (96, 100))	('apoptosis enhancement properties', 'CPA', (137, 169))
539024	30380687	Consequently, inhibitors of cytochrome P450 (CYP450), such as Liarozole, can increase a patient's ATRA plasmatic concentrations.	('patient', 'Species', '9606', (88, 95))	('Liarozole', 'Chemical', 'MESH:C061121', (62, 71))	('cytochrome P450', 'Gene', (28, 43))	('ATRA', 'Chemical', 'MESH:D014212', (98, 102))	('cytochrome P450', 'Gene', '4051', (28, 43))	('increase', 'PosReg', (77, 85))	('inhibitors', 'Var', (14, 24))	('CYP450', 'Gene', '4051', (45, 51))	('ATRA plasmatic concentrations', 'MPA', (98, 127))	('CYP450', 'Gene', (45, 51))
539026	30380687	Indeed, R116010 is a CYP26 inhibitor and has a 100-fold increased potency compared to that of Liarozole in human T47D breast cancer cells.	('CYP26', 'Gene', '1592', (21, 26))	('increased', 'PosReg', (56, 65))	('human', 'Species', '9606', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('R116010', 'Var', (8, 15))	('CYP26', 'Gene', (21, 26))	('potency', 'MPA', (66, 73))	('Liarozole', 'Chemical', 'MESH:C061121', (94, 103))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('T47D', 'CellLine', 'CVCL:0553', (113, 117))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
539029	30380687	On the other hand, some studies suggest that 4-hydroxy RA, 18-hydroxy RA, 4-oxo RA, and 5,6-epoxy RA, four metabolites of ATRA, can activate RAR and RXR.	('4-oxo RA', 'Chemical', 'MESH:C002202', (74, 82))	('4-hydroxy', 'Var', (45, 54))	('RXR', 'Gene', (149, 152))	('RAR', 'Gene', (141, 144))	('ATRA', 'Chemical', 'MESH:D014212', (122, 126))	('18-hydroxy RA', 'Chemical', '-', (59, 72))	('RAR', 'Gene', '5914', (141, 144))	('activate', 'PosReg', (132, 140))	('5,6-epoxy RA', 'Chemical', 'MESH:C018058', (88, 100))	('4-hydroxy RA', 'Chemical', 'MESH:C019429', (45, 57))	('RXR', 'Gene', '6256', (149, 152))
539036	30380687	Translational studies on myeloid leukemia cells and clinical studies on APL patients demonstrated that, point mutations in the ligand-binding domain (E domain) of RAR is, as well, another possible resistance mechanism.	('patients', 'Species', '9606', (76, 84))	('APL', 'Phenotype', 'HP:0004836', (72, 75))	('myeloid leukemia', 'Disease', (25, 41))	('point mutations in', 'Var', (104, 122))	('APL', 'Disease', (72, 75))	('APL', 'Disease', 'MESH:D015473', (72, 75))	('myeloid leukemia', 'Disease', 'MESH:D007951', (25, 41))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (25, 41))	('RAR', 'Gene', (163, 166))	('RAR', 'Gene', '5914', (163, 166))	('leukemia', 'Phenotype', 'HP:0001909', (33, 41))
539037	30380687	In conclusion, ATRA resistance seems to be due, at least partly, to drug efflux systems, an increased expression of CRABPs and point mutation in RARE.	('ATRA', 'Chemical', 'MESH:D014212', (15, 19))	('RAR', 'Gene', (145, 148))	('ATRA resistance', 'Disease', (15, 30))	('point mutation', 'Var', (127, 141))	('expression', 'MPA', (102, 112))	('CRABP', 'Gene', '1381', (116, 121))	('drug efflux systems', 'MPA', (68, 87))	('increased', 'PosReg', (92, 101))	('RAR', 'Gene', '5914', (145, 148))	('CRABP', 'Gene', (116, 121))
539042	30380687	According to Jiang Sy et al., 13cisRA has a stronger effect than ATRA on the regression of subcutaneous tumor xenografts derived from GC cell line SC-M1.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('subcutaneous tumor', 'Disease', (91, 109))	('13cisRA', 'Chemical', 'MESH:D015474', (30, 37))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (91, 109))	('subcutaneous tumor', 'Disease', 'MESH:D013352', (91, 109))	('ATRA', 'Chemical', 'MESH:D014212', (65, 69))	('regression', 'CPA', (77, 87))	('13cisRA', 'Var', (30, 37))	('GC', 'Phenotype', 'HP:0012126', (134, 136))
539046	30380687	It was demonstrated that 13cisRA decreased expression of the N-MYC oncogene in neuroblastoma cells in vitro.	('N-MYC', 'Gene', (61, 66))	('neuroblastoma', 'Phenotype', 'HP:0003006', (79, 92))	('13cisRA', 'Chemical', 'MESH:D015474', (25, 32))	('13cisRA', 'Var', (25, 32))	('N-MYC', 'Gene', '4613', (61, 66))	('neuroblastoma', 'Disease', 'MESH:D009447', (79, 92))	('decreased', 'NegReg', (33, 42))	('neuroblastoma', 'Disease', (79, 92))	('expression', 'MPA', (43, 53))
539050	30380687	However, 13cisRA has less activity than ATRA in mammal tumors derived from human mammary carcinoma cells xenografted in athymic mice.	('ATRA', 'Chemical', 'MESH:D014212', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('13cisRA', 'Chemical', 'MESH:D015474', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mice', 'Species', '10090', (128, 132))	('mammal', 'Species', '9606', (48, 54))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('carcinoma', 'Disease', 'MESH:D002277', (89, 98))	('13cisRA', 'Var', (9, 16))	('human', 'Species', '9606', (75, 80))	('activity', 'MPA', (26, 34))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (81, 98))	('carcinoma', 'Disease', (89, 98))
539051	30380687	Biochemical studies demonstrate that 13cisRA has very low affinity for RARs in comparison with ATRA or 9cisRA.	('affinity', 'Interaction', (58, 66))	('13cisRA', 'Var', (37, 44))	('ATRA', 'Chemical', 'MESH:D014212', (95, 99))	('9cisRA', 'Chemical', 'MESH:D000077556', (103, 109))	('13cisRA', 'Chemical', 'MESH:D015474', (37, 44))	('RAR', 'Gene', (71, 74))	('RAR', 'Gene', '5914', (71, 74))
539058	30380687	In GC cell lines it has been demonstrated that, through the activation of RXR, 9cisRA can potentiate the ligand-activated transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma)'s activity, which contributes to the inhibition of cell growth and tissue invasion ability, and enhances apoptosis.	('GC', 'Phenotype', 'HP:0012126', (3, 5))	('RXR', 'Gene', '6256', (74, 77))	('PPARgamma', 'Gene', (193, 202))	('9cisRA', 'Var', (79, 85))	('PPARgamma', 'Gene', '5468', (193, 202))	('9cisRA', 'Chemical', 'MESH:D000077556', (79, 85))	('apoptosis', 'CPA', (309, 318))	('peroxisome proliferator-activated receptor gamma', 'Gene', (143, 191))	('tissue invasion ability', 'CPA', (271, 294))	('potentiate', 'PosReg', (90, 100))	('RXR', 'Gene', (74, 77))	('cell growth', 'CPA', (255, 266))	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (143, 191))	('enhances', 'PosReg', (300, 308))	('inhibition', 'NegReg', (241, 251))	('activity', 'MPA', (206, 214))
539067	30380687	Exogenous RARbeta2 expression restores RII induced growth inhibition, suggesting that RII acts, at least in part, via the RARbeta2 receptor.	('RII', 'Chemical', 'MESH:C045860', (39, 42))	('Exogenous', 'Var', (0, 9))	('RII', 'Chemical', 'MESH:C045860', (86, 89))	('RARbeta2', 'Gene', (10, 18))	('growth inhibition', 'MPA', (51, 68))
539069	30380687	According to Formelli et al., RII seems to be effective against human ovarian carcinoma xenograft in mice and potentiates cisplatin activity.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (70, 87))	('RII', 'Var', (30, 33))	('human', 'Species', '9606', (64, 69))	('cisplatin activity', 'MPA', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ovarian carcinoma xenograft', 'Disease', 'MESH:D010051', (70, 97))	('ovarian carcinoma xenograft', 'Disease', (70, 97))	('mice', 'Species', '10090', (101, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('potentiates', 'PosReg', (110, 121))	('RII', 'Chemical', 'MESH:C045860', (30, 33))
539097	27557504	Patients with CRP/PNI ratio <=0.10 had a significantly better 5-year CSS compared to CRP/PNI ratio >0.10 (44.5% vs. 15.7%, P<0.001).	('CRP/PNI', 'Gene', (85, 92))	('<=0.10', 'Var', (28, 34))	('CSS', 'CPA', (69, 72))	('CRP/PNI', 'Gene', '1401;5270', (14, 21))	('CRP/PNI', 'Gene', (14, 21))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (55, 61))	('CRP/PNI', 'Gene', '1401;5270', (85, 92))	('CSS', 'Chemical', '-', (69, 72))
539129	27557504	Patients with CRP/PNI ratio <= 0.10 had a significantly better 5-year CSS than patients with CRP/PNI ratio > 0.10 (44.5% vs. 15.7%, P <0.001) (Figure 3A).	('CRP/PNI', 'Gene', '1401;5270', (14, 21))	('CSS', 'Chemical', '-', (70, 73))	('CRP/PNI', 'Gene', '1401;5270', (93, 100))	('CRP/PNI', 'Gene', (14, 21))	('CSS', 'CPA', (70, 73))	('better', 'PosReg', (56, 62))	('Patients', 'Species', '9606', (0, 8))	('CRP/PNI', 'Gene', (93, 100))	('patients', 'Species', '9606', (79, 87))	('<= 0.10', 'Var', (28, 35))
539138	27557504	The areas under the curve (AUC) was 0.671 (95% CI: 0.606-0.736, P <0.001) for CRP/PNI ratio, 0.632 (95% CI: 0.567-0.696, P <0.001) for CRP, 0.622 (95% CI: 0.556-0.687, P = 0.001) for GPS and 0.569 (95% CI: 0.501-0.638, P =0.053) for PNI.	('CRP', 'Gene', (135, 138))	('CRP', 'Gene', '1401', (135, 138))	('PNI', 'Gene', '5270', (82, 85))	('CRP', 'Gene', (78, 81))	('0.632', 'Var', (93, 98))	('CRP', 'Gene', '1401', (78, 81))	('PNI', 'Gene', (82, 85))	('PNI', 'Gene', (233, 236))	('GPS', 'Disease', (183, 186))	('CRP/PNI', 'Gene', '1401;5270', (78, 85))	('PNI', 'Gene', '5270', (233, 236))	('CRP/PNI', 'Gene', (78, 85))
539224	27433035	Chronic inflammation (esophagitis) resulting from GERD leads to the development of Barrett's esophagus, which is metaplasia of native squamous epithelium to intestinal-like columnar epithelium following chronic exposure to gastric acid.	('Chronic inflammation', 'Disease', (0, 20))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))	('GERD', 'Var', (50, 54))	('esophagitis', 'Disease', (22, 33))	('esophagitis', 'Disease', 'MESH:D004941', (22, 33))	('esophagitis', 'Phenotype', 'HP:0100633', (22, 33))	("Barrett's esophagus", 'Disease', (83, 102))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (83, 102))
539257	22253528	Therefore, many investigators believe that the potential for making significant progress lies in exploiting the molecular biology of tumors to investigate new therapeutic strategies: such as epithelial growth factor receptor (EGFR) inhibitors, antiangiogenic agents, apoptosis promoters, and specific immunotherapy.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('inhibitors', 'Var', (232, 242))	('epithelial growth factor receptor', 'Gene', '1956', (191, 224))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('epithelial growth factor receptor', 'Gene', (191, 224))	('EGFR', 'Gene', '1956', (226, 230))	('EGFR', 'Gene', (226, 230))
539264	22253528	However, the cancer also developed a number of different strategies to escape immune surveillance such as loss of tumor antigen expression, MHC downregulation, expression of Fas-L that can induce apoptosis in activated T cells, secretion of cytokines such as IL-10 (Interleukin-10) and/or TGF-ss (Tumor grow factor-beta) and generation of regulatory T cells (Treg).	('MHC', 'Gene', '3107', (140, 143))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Fas-L', 'Gene', (174, 179))	('tumor', 'Disease', (114, 119))	('IL-10', 'Gene', '3586', (259, 264))	('apoptosis', 'CPA', (196, 205))	('Interleukin-10', 'Gene', (266, 280))	('secretion', 'MPA', (228, 237))	('IL-10', 'Gene', (259, 264))	('TGF-ss', 'Gene', (289, 295))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Interleukin-10', 'Gene', '3586', (266, 280))	('cancer', 'Disease', (13, 19))	('regulatory T cells', 'CPA', (339, 357))	('MHC', 'Gene', (140, 143))	('Fas-L', 'Gene', '356', (174, 179))	('Tumor', 'Phenotype', 'HP:0002664', (297, 302))	('loss', 'Var', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('expression', 'Var', (160, 170))	('induce', 'Reg', (189, 195))	('downregulation', 'NegReg', (144, 158))
539275	22253528	About the gastric cancer, it was demonstrated that patients with many DCs infiltration had lower lymph node metastases and lymphatic invasion than patients with fewer DCs infiltration.	('metastases', 'Disease', (108, 118))	('lower', 'NegReg', (91, 96))	('gastric cancer', 'Phenotype', 'HP:0012126', (10, 24))	('metastases', 'Disease', 'MESH:D009362', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (51, 59))	('DCs infiltration', 'Var', (70, 86))	('gastric cancer', 'Disease', (10, 24))	('lower lymph node', 'Phenotype', 'HP:0002732', (91, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (10, 24))
539284	22253528	Vaccinations with DCs pulsed with HER-2 (p369) peptide were performed at 2-week intervals.	('p369', 'Var', (41, 45))	('HER-2', 'Gene', '2064', (34, 39))	('HER-2', 'Gene', (34, 39))
539289	22253528	Most recently, Kim improved the potency of a DC vaccine with a small interfering RNA (siRNA) targeting phosphatase and tensin homologue (PTEN), which is known to be a central negative regulator of the PI3K/AKT signal transduction cascade.	('potency', 'MPA', (32, 39))	('AKT', 'Gene', (206, 209))	('phosphatase and tensin homologue', 'Gene', '5728', (103, 135))	('AKT', 'Gene', '207', (206, 209))	('PTEN', 'Gene', (137, 141))	('PTEN', 'Gene', '5728', (137, 141))	('improved', 'PosReg', (19, 27))	('Kim', 'Var', (15, 18))
539290	22253528	Downregulation of PTEN in DCs resulted in AKT-dependent maturation, which in turn caused a significant upregulation of surface expression in costimulatory molecules and the chemokine receptor, CCR7, leading to an increase of in vitro T cell activation activity and in vivo migration to a draining lymph node, respectively.	('upregulation', 'PosReg', (103, 115))	('PTEN', 'Gene', (18, 22))	('in vitro T cell activation activity', 'CPA', (225, 260))	('AKT', 'Gene', (42, 45))	('PTEN', 'Gene', '5728', (18, 22))	('Downregulation', 'Var', (0, 14))	('CCR7', 'Gene', '1236', (193, 197))	('CCR7', 'Gene', (193, 197))	('surface expression', 'MPA', (119, 137))	('increase', 'PosReg', (213, 221))	('AKT', 'Gene', '207', (42, 45))	('maturation', 'CPA', (56, 66))
539293	22253528	In conclusion, these results indicate that manipulation of the PI3K/AKT pathway via siRNA system could improve the efficacy of a DC-based tumor vaccine, for example, in gastric cancer therapy.	('gastric cancer', 'Disease', (169, 183))	('efficacy', 'MPA', (115, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('tumor', 'Disease', (138, 143))	('manipulation', 'Var', (43, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('AKT', 'Gene', '207', (68, 71))	('improve', 'PosReg', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('AKT', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
539295	22253528	In recent times, the same group demonstrated that by blocking the immunosuppressive axis with small interfering RNA targeting IL-10 receptor, it is possible to enhance dendritic cell-based vaccine potency providing the groundwork for future clinical translation of siRNA-mediated to enhance DC-based vaccine immunotherapy.	('IL-10', 'Gene', '3586', (126, 131))	('RNA', 'Gene', (112, 115))	('IL-10', 'Gene', (126, 131))	('blocking', 'NegReg', (53, 61))	('dendritic', 'MPA', (168, 177))	('enhance', 'PosReg', (160, 167))	('small interfering', 'Var', (94, 111))
539296	22253528	Most promising are also the data obtained by He and colleagues about the possibility of enhancing antitumor immunity in vitro using granulocyte-macrophage colony stimulating factor (GM-CSF) gene-modified DCs.	('gene-modified', 'Var', (190, 203))	('GM-CSF', 'Gene', (182, 188))	('granulocyte-macrophage colony stimulating factor', 'Gene', '1437', (132, 180))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('GM-CSF', 'Gene', '1437', (182, 188))	('granulocyte-macrophage colony stimulating factor', 'Gene', (132, 180))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('enhancing', 'PosReg', (88, 97))
539297	22253528	They demonstrated that after GM-CSF gene modification, DCs can produce high level of GM-CSF, which tend to be more maturated, and the capacity of activating the proliferation of allogenic T lymphocytes is enhanced greatly.	('GM-CSF', 'Gene', (85, 91))	('GM-CSF', 'Gene', '1437', (85, 91))	('activating', 'MPA', (146, 156))	('gene modification', 'Var', (36, 53))	('GM-CSF', 'Gene', (29, 35))	('enhanced', 'PosReg', (205, 213))	('GM-CSF', 'Gene', '1437', (29, 35))	('proliferation', 'CPA', (161, 174))
539338	22253528	However, should technical limitations of current tissue culture approaches be overcome, recent studies indicate that the presence of TILs positively correlate with patients survival in ovarian and colorectal cancer, thus prompting the use of this protocol for other commonly encountered epithelial neoplasias.	('neoplasias', 'Phenotype', 'HP:0002664', (298, 308))	('presence', 'Var', (121, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))	('epithelial neoplasias', 'Phenotype', 'HP:0031492', (287, 308))	('epithelial neoplasias', 'Disease', (287, 308))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('epithelial neoplasias', 'Disease', 'MESH:D009369', (287, 308))	('patients', 'Species', '9606', (164, 172))	('TILs', 'Var', (133, 137))	('ovarian and colorectal cancer', 'Disease', 'MESH:D015179', (185, 214))
539346	22253528	These studies have laid the groundwork for a possible vaccination of GC patients with specific peptides of tumor-associated antigens able to raise an effective immune response to gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (179, 193))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('peptides', 'Var', (95, 103))	('raise', 'PosReg', (141, 146))	('tumor', 'Disease', (107, 112))	('GC', 'Phenotype', 'HP:0012126', (69, 71))	('gastric cancer', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('gastric cancer', 'Disease', 'MESH:D013274', (179, 193))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (72, 80))
539364	22253528	In addition, it is now well established that the mutational status of K-ras, an oncogene downstream of the EGFR which is involved in an intricate array of signal transduction pathways, dictates responsiveness to anti-EGFR therapies in colorectal cancer (CRC) and patients whose tumors were found to have K-ras mutations derived no benefit from anti-EGFR antibodies treatment.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumors', 'Disease', (278, 284))	('EGFR', 'Gene', (107, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (235, 252))	('EGFR', 'Gene', (217, 221))	('mutations', 'Var', (310, 319))	('K-ras', 'Gene', (304, 309))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('EGFR', 'Gene', (349, 353))	('mutational', 'Var', (49, 59))	('EGFR', 'Gene', '1956', (107, 111))	('K-ras', 'Gene', '3845', (70, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (235, 252))	('responsiveness', 'MPA', (194, 208))	('colorectal cancer', 'Disease', (235, 252))	('EGFR', 'Gene', '1956', (217, 221))	('CR', 'Chemical', 'MESH:D002857', (254, 256))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('dictates', 'Reg', (185, 193))	('patients', 'Species', '9606', (263, 271))	('CRC', 'Phenotype', 'HP:0003003', (254, 257))	('K-ras', 'Gene', '3845', (304, 309))	('EGFR', 'Gene', '1956', (349, 353))	('K-ras', 'Gene', (70, 75))
539365	22253528	In EGCs, relatively little is known about the incidence of mutated K-ras status, much less its predictive value for anti-EGFR therapy.	('EGFR', 'Gene', '1956', (121, 125))	('GC', 'Phenotype', 'HP:0012126', (4, 6))	('EGFR', 'Gene', (121, 125))	('K-ras', 'Gene', (67, 72))	('K-ras', 'Gene', '3845', (67, 72))	('mutated', 'Var', (59, 66))	('EGCs', 'Chemical', '-', (3, 7))
539366	22253528	In recent studies, 0 of 3824 and 2 of 23 patients (8.7%) were found to have mutated K-ras.	('patients', 'Species', '9606', (41, 49))	('K-ras', 'Gene', (84, 89))	('mutated', 'Var', (76, 83))	('K-ras', 'Gene', '3845', (84, 89))
539426	22253528	Studies in SCCs have indicated that expression of VEGF in tumors correlates with more advanced tumor stage, the presence of nodal and distant metastases, and a poorer survival outcome.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('SCC', 'Gene', (11, 14))	('SCC', 'Phenotype', 'HP:0002860', (11, 14))	('tumors', 'Disease', (58, 64))	('metastases', 'Disease', (142, 152))	('VEGF', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('expression', 'Var', (36, 46))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('SCC', 'Gene', '6317', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('VEGF', 'Gene', '7422', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
539451	22253528	Moreover, the recent results about the enhancing of the antitumor immunity by (GM-CSF) gene-modified DCs and blocking the immunosuppressive axis with small interfering RNA targeting IL-10 receptor give hope for the immediate future in a more effective of GC immunotherapy DC-based.	('enhancing', 'PosReg', (39, 48))	('gene-modified', 'Var', (87, 100))	('GC', 'Phenotype', 'HP:0012126', (255, 257))	('IL-10', 'Gene', '3586', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('GM-CSF', 'Gene', (79, 85))	('IL-10', 'Gene', (182, 187))	('DCs', 'Gene', (101, 104))	('immunosuppressive', 'MPA', (122, 139))	('tumor', 'Disease', (60, 65))	('GM-CSF', 'Gene', '1437', (79, 85))
539467	22206016	Individually, CYP1A1*2A polymorphism was significantly associated with increased lung cancer risk (OR = 1.69;95%CI = 1.11-2.59,p = 0.01), whereas EPHX1 Tyr113His and SULT1A1 Arg213His conferred reduced risk (OR = 0.40;95%CI = 0.25-0.65,p<0.001 and OR = 0.51;95%CI = 0.33-0.78,p = 0.002 respectively).	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('CYP1A1', 'Gene', (14, 20))	('polymorphism', 'Var', (24, 36))	('Tyr113His', 'Var', (152, 161))	('Arg213His', 'Var', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CYP1A1', 'Gene', '1543', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('Arg213His', 'SUBSTITUTION', 'None', (174, 183))	('SULT1A1', 'Gene', (166, 173))	('Tyr113His', 'Chemical', '-', (152, 161))
539468	22206016	In smokers, EPHX1 Tyr113His and SULT1A1 Arg213His polymorphisms reduced the risk of lung cancer, whereas CYP1A1*2A, CYP1A1*2C and GSTP1 Ile105Val imparted increased risk in non-smokers only.	('lung cancer', 'Disease', (84, 95))	('CYP1A1', 'Gene', '1543', (116, 122))	('GSTP1', 'Gene', (130, 135))	('Arg213His', 'Var', (40, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('Ile105Val', 'Chemical', '-', (136, 145))	('CYP1A1', 'Gene', (116, 122))	('CYP1A1', 'Gene', (105, 111))	('Arg213His', 'SUBSTITUTION', 'None', (40, 49))	('GSTP1', 'Gene', '2950', (130, 135))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('Tyr113His', 'Chemical', '-', (18, 27))	('reduced', 'NegReg', (64, 71))	('CYP1A1', 'Gene', '1543', (105, 111))	('SULT1A1', 'Gene', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
539469	22206016	While exploring non-linear interactions through CART analysis, smokers carrying the combination of EPHX1 113TC (Tyr/His), SULT1A1 213GG (Arg/Arg) or AA (His/His) and GSTM1 null genotypes showed the highest risk for lung cancer (OR = 3.73;95%CI = 1.33-10.55,p = 0.006), whereas combined effect of CYP1A1*2A 6235CC or TC, SULT1A1 213GG (Arg/Arg) and betel quid chewing showed maximum risk in non-smokers (OR = 2.93;95%CI = 1.15-7.51,p = 0.01).	('lung cancer', 'Disease', (215, 226))	('EPHX1', 'Gene', (99, 104))	('GSTM1', 'Gene', (166, 171))	('Arg', 'Chemical', 'MESH:D001120', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('CYP1A1', 'Gene', '1543', (296, 302))	('lung cancer', 'Disease', 'MESH:D008175', (215, 226))	('Arg', 'Chemical', 'MESH:D001120', (137, 140))	('TC', 'Chemical', 'MESH:D013667', (316, 318))	('Arg', 'Chemical', 'MESH:D001120', (335, 338))	('TC', 'Chemical', 'MESH:D013667', (108, 110))	('Arg', 'Chemical', 'MESH:D001120', (339, 342))	('SULT1A1 213GG', 'Var', (320, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('CYP1A1', 'Gene', (296, 302))
539470	22206016	MDR analysis identified two distinct predictor models for the risk of lung cancer in smokers (tobacco chewing, EPHX1 Tyr113His, and SULT1A1 Arg213His) and non-smokers (CYP1A1*2A, GSTP1 Ile105Val and SULT1A1 Arg213His) with testing balance accuracy (TBA) of 0.6436 and 0.6677 respectively.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('CYP1A1', 'Gene', '1543', (168, 174))	('TBA', 'Chemical', '-', (249, 252))	('Arg213His', 'Var', (207, 216))	('Tyr113His', 'Var', (117, 126))	('GSTP1', 'Gene', (179, 184))	('Arg213His', 'SUBSTITUTION', 'None', (207, 216))	('Arg213His', 'Var', (140, 149))	('Ile105Val', 'Chemical', '-', (185, 194))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Arg213His', 'SUBSTITUTION', 'None', (140, 149))	('Tyr113His', 'Chemical', '-', (117, 126))	('tobacco', 'Species', '4097', (94, 101))	('GSTP1', 'Gene', '2950', (179, 184))	('CYP1A1', 'Gene', (168, 174))
539471	22206016	Interaction entropy interpretations of MDR results showed non-additive interactions of tobacco chewing with SULT1A1 Arg213His and EPHX1 Tyr113His in smokers and SULT1A1 Arg213His with GSTP1 Ile105Val and CYP1A1*2C in nonsmokers.	('Arg213His', 'Var', (169, 178))	('tobacco', 'Species', '4097', (87, 94))	('interactions', 'Interaction', (71, 83))	('GSTP1', 'Gene', '2950', (184, 189))	('Arg213His', 'SUBSTITUTION', 'None', (169, 178))	('CYP1A1', 'Gene', (204, 210))	('Arg213His', 'Var', (116, 125))	('Tyr113His', 'Chemical', '-', (136, 145))	('CYP1A1', 'Gene', '1543', (204, 210))	('Arg213His', 'SUBSTITUTION', 'None', (116, 125))	('SULT1A1', 'Gene', (108, 115))	('Ile105Val', 'Chemical', '-', (190, 199))	('Tyr113His', 'Var', (136, 145))	('GSTP1', 'Gene', (184, 189))
539481	22206016	Single nucleotide polymorphisms (SNPs) in xenobiotic metabolizing genes have been studied extensively with risk of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
539492	22206016	The deletion variants in GSTM1 and GSTT1 were determined by multiplex polymerase chain reaction protocol and SNPs in CYP1A1, EPHX1, GSTP1, SULT1A1 were determined by polymerase chain reaction-restriction fragment length polymorphism assays as previously described.	('GSTM1', 'Gene', (25, 30))	('CYP1A1', 'Gene', '1543', (117, 123))	('GSTP1', 'Gene', '2950', (132, 137))	('deletion variants', 'Var', (4, 21))	('GSTT1', 'Gene', (35, 40))	('GSTP1', 'Gene', (132, 137))	('CYP1A1', 'Gene', (117, 123))
539497	22206016	The distribution of all SNPs in control was in agreement with HWE (p>0.05), however alleles of EPHX1 Tyr113His and SULT1A1 Arg213His polymorphisms in cases did not follow HWE (p<0.001 and p = 0.004 respectively).	('Tyr113His', 'Var', (101, 110))	('EPHX1', 'Gene', (95, 100))	('Arg213His', 'Var', (123, 132))	('Arg213His', 'SUBSTITUTION', 'None', (123, 132))	('SULT1A1', 'Gene', (115, 122))	('Tyr113His', 'Chemical', '-', (101, 110))
539500	22206016	Genotype distribution of CYP1A1*2A, EPHX1 Tyr113His, SULT1A1 Arg213His and GSTT1 null polymorphism were significantly different in cases from controls (p = 0.014, p<0.001, p = 0.01 and p = 0.04 respectively).	('Tyr113His', 'Var', (42, 51))	('EPHX1', 'Gene', (36, 41))	('CYP1A1', 'Gene', '1543', (25, 31))	('GSTT1', 'Gene', (75, 80))	('Arg213His', 'Var', (61, 70))	('Arg213His', 'SUBSTITUTION', 'None', (61, 70))	('different', 'Reg', (118, 127))	('Tyr113His', 'Chemical', '-', (42, 51))	('SULT1A1', 'Gene', (53, 60))	('CYP1A1', 'Gene', (25, 31))
539502	22206016	Heterozygous genotype in CYP1A1*2A was associated with increased risk (OR = 1.69,95% CI = 1.11-2.59; p = 0.01) whereas heterozygous genotypes in EPHX1 Tyr113His and SULT1A1 Arg213His imparted reduced risk towards lung cancer (OR = 0.40;95%C.I = 0.25-0.65,p<0.001 and OR = 0.51;p = 0.33x-0.78,p = 0.002 respectively).	('Tyr113His', 'Var', (151, 160))	('Arg213His', 'Var', (173, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('CYP1A1', 'Gene', '1543', (25, 31))	('Arg213His', 'SUBSTITUTION', 'None', (173, 182))	('SULT1A1', 'Gene', (165, 172))	('lung cancer', 'Disease', (213, 224))	('EPHX1', 'Gene', (145, 150))	('lung cancer', 'Disease', 'MESH:D008175', (213, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('Tyr113His', 'Chemical', '-', (151, 160))	('reduced', 'NegReg', (192, 199))	('CYP1A1', 'Gene', (25, 31))
539503	22206016	CYP1A1*2A and EPHX1 His139Arg polymorphisms were associated with increased risk to lung cancer in dominant genetic model, whereas EPHX1 Tyr113His and SULT1A1 Arg213His imparted reduced risk in recessive genetic model (Table S2).	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('CYP1A1', 'Gene', '1543', (0, 6))	('His139Arg', 'Var', (20, 29))	('Tyr113His', 'Chemical', '-', (136, 145))	('His139Arg', 'SUBSTITUTION', 'None', (20, 29))	('Arg213His', 'Var', (158, 167))	('Arg213His', 'SUBSTITUTION', 'None', (158, 167))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Tyr113His', 'Var', (136, 145))	('CYP1A1', 'Gene', (0, 6))
539504	22206016	Table 2 summarizes the associations between the frequency distributions of the haplotypes in CYP1A1 and EPHX1 genes and the risk of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CYP1A1', 'Gene', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('CYP1A1', 'Gene', '1543', (93, 99))	('lung cancer', 'Disease', (132, 143))	('haplotypes', 'Var', (79, 89))	('EPHX1', 'Gene', (104, 109))	('associations', 'Interaction', (23, 35))
539509	22206016	Heterozygous and homozygous variant genotypes of CYP1A1*2A polymorphism imparted significant risk in non-smokers (OR = 2.88;95%CI = 1.22-6.81,p = 0.016 and OR = 4.35;95%CI = 1.47-12.84,p = 0.008).	('CYP1A1', 'Gene', (49, 55))	('CYP1A1', 'Gene', '1543', (49, 55))	('polymorphism', 'Var', (59, 71))	('variant', 'Var', (28, 35))
539510	22206016	Also, CYP1A1*2C variant genotype and GSTP1 Ile105Val heterozygous genotype were significantly associated with increased risk in non-smokers (OR = 11.81;95%CI = 1.24-111.98,p = 0.03 and OR = 2.40;95%CI = 1.15-5.03,p = 0.01).	('variant', 'Var', (16, 23))	('CYP1A1', 'Gene', '1543', (6, 12))	('GSTP1', 'Gene', '2950', (37, 42))	('CYP1A1', 'Gene', (6, 12))	('Ile105Val', 'Var', (43, 52))	('GSTP1', 'Gene', (37, 42))	('Ile105Val', 'Chemical', '-', (43, 52))
539511	22206016	Heterozygous genotypes in EPHX1 Tyr113His and SULT1A1 Arg213His were associated with 66% and 55% reduced risk in smokers (OR = 0.34;95%CI = 0.18-0.63,p = 0.001 and OR = 0.45;95%CI = 0.25-0.80,p = 0.007 respectively).	('Arg213His', 'SUBSTITUTION', 'None', (54, 63))	('EPHX1', 'Gene', (26, 31))	('Tyr113His', 'Chemical', '-', (32, 41))	('reduced', 'NegReg', (97, 104))	('smokers', 'Disease', (113, 120))	('Tyr113His', 'Var', (32, 41))	('Arg213His', 'Var', (54, 63))	('SULT1A1', 'Gene', (46, 53))
539512	22206016	However heterozygous genotype in EPHX1 His139Arg conferred significant risk in smokers (OR = 1.92;95%CI = 1.07-3.45,p = 0.02).	('EPHX1', 'Gene', (33, 38))	('His139Arg', 'Var', (39, 48))	('smokers', 'Disease', (79, 86))	('His139Arg', 'SUBSTITUTION', 'None', (39, 48))
539514	22206016	Among smokers, the subsequent splits showed interactions between EPHX1 Tyr113His, SULT1A1 Arg213His and GSTM1.	('GSTM1', 'Gene', (104, 109))	('Arg213His', 'SUBSTITUTION', 'None', (90, 99))	('SULT1A1', 'Gene', (82, 89))	('Tyr113His', 'Chemical', '-', (71, 80))	('EPHX1', 'Gene', (65, 70))	('Tyr113His', 'Var', (71, 80))	('Arg213His', 'Var', (90, 99))	('interactions', 'Interaction', (44, 56))
539516	22206016	Further interactions were predicted by SULT1A1 Arg213His polymorphism and betel quid status.	('SULT1A1', 'Gene', (39, 46))	('Arg213His', 'Var', (47, 56))	('Arg213His', 'SUBSTITUTION', 'None', (47, 56))	('interactions', 'Interaction', (8, 20))	('betel quid status', 'Disease', (74, 91))
539517	22206016	Among smokers maximum risk was observed for terminal node1 consisting of EPHX1 113TT (Tyr/Tyr) or -113CC (His/His) genotypes (OR = 4.38;95%CI = 2.12-9.15) and for terminal node 2 with combination of EPHX1 113TC (Tyr/His), SULT1A1 213GG (Arg/Arg) or AA (His/His) and GSTM1 null genotypes (OR =  3.73;95%CI = 1.33-10.55, p = 0.006).	('Arg', 'Chemical', 'MESH:D001120', (241, 244))	('EPHX1 113TC (Tyr/His', 'Var', (199, 219))	('terminal node1', 'Disease', (44, 58))	('SULT1A1 213GG (Arg/Arg', 'Var', (222, 244))	('GSTM1', 'Gene', (266, 271))	('EPHX1 113TT', 'Var', (73, 84))	('Arg', 'Chemical', 'MESH:D001120', (237, 240))	('TC', 'Chemical', 'MESH:D013667', (208, 210))
539518	22206016	In non-smokers high risk was seen for terminal node 5 comprising of CYP1A1*2A 6235CC or TC, SULT1A1 213GG (Arg/Arg) and betel quid chewing (OR = 2.93;95%CI = 1.15-7.51, p =  0.01).	('CYP1A1', 'Gene', '1543', (68, 74))	('SULT1A1 213GG', 'Var', (92, 105))	('Arg', 'Chemical', 'MESH:D001120', (107, 110))	('TC', 'Chemical', 'MESH:D013667', (88, 90))	('terminal node', 'Disease', (38, 51))	('Arg', 'Chemical', 'MESH:D001120', (111, 114))	('CYP1A1', 'Gene', (68, 74))
539520	22206016	For a 2-locus interaction, combination of smoking and EPHX1 Tyr113His was most significant with CVC of 10/10 and TBA of 0.6407 (p<0.001).	('Tyr113His', 'Chemical', '-', (60, 69))	('EPHX1', 'Gene', (54, 59))	('TBA', 'Chemical', '-', (113, 116))	('Tyr113His', 'Var', (60, 69))
539522	22206016	The 4 loci interaction model of smoking, EPHX1 Tyr113His, EPHX1 His139Arg and SULT1A1 Arg213His, was the best model identified, with maximum CVC (10/10) and TBA (0.6503, p<0.001).	('His139Arg', 'SUBSTITUTION', 'None', (64, 73))	('TBA', 'Chemical', '-', (157, 160))	('Tyr113His', 'Chemical', '-', (47, 56))	('Tyr113His', 'Var', (47, 56))	('His139Arg', 'Var', (64, 73))	('Arg213His', 'Var', (86, 95))	('CVC', 'MPA', (141, 144))	('Arg213His', 'SUBSTITUTION', 'None', (86, 95))
539523	22206016	In smokers the best interaction model was the three loci model consisting of tobacco chewing, EPHX1 Tyr113His and SULT1A1 Arg213His having maximum CVC (10/10) and TBA (0.6436, p<0.001) among all models identified.	('tobacco', 'Species', '4097', (77, 84))	('CVC', 'MPA', (147, 150))	('Tyr113His', 'Var', (100, 109))	('Arg213His', 'Var', (122, 131))	('interaction', 'Interaction', (20, 31))	('Arg213His', 'SUBSTITUTION', 'None', (122, 131))	('TBA', 'Chemical', '-', (163, 166))	('EPHX1', 'Gene', (94, 99))	('Tyr113His', 'Chemical', '-', (100, 109))
539525	22206016	In non-smokers the best model was the three loci model comprising of CYP1A1*2A, GSTP1 Ile105Val and SULT1A1 Arg213His with CVC of 10/10 and TBA of 0.6677 (p<0.005) and an OR of 7.32 (95%CI = 3.24-16.53).	('CYP1A1', 'Gene', (69, 75))	('GSTP1', 'Gene', '2950', (80, 85))	('CYP1A1', 'Gene', '1543', (69, 75))	('TBA', 'Chemical', '-', (140, 143))	('Ile105Val', 'Chemical', '-', (86, 95))	('GSTP1', 'Gene', (80, 85))	('Arg213His', 'Var', (108, 117))	('Arg213His', 'SUBSTITUTION', 'None', (108, 117))
539527	22206016	In smokers, EPHX1 Tyr113His had a large independent effect (4.64%) and a non-additive interaction with tobacco chewing (entropy 1.79%).	('Tyr113His', 'Var', (18, 27))	('EPHX1', 'Gene', (12, 17))	('Tyr113His', 'Chemical', '-', (18, 27))	('tobacco', 'Species', '4097', (103, 110))
539528	22206016	Considerable entropy was associated with SULT1A1 Arg213His (1.88%) and its interaction with tobacco chewing further removed 1.49% of entropy from case-control group.	('tobacco', 'Species', '4097', (92, 99))	('entropy', 'MPA', (13, 20))	('entropy', 'MPA', (133, 140))	('SULT1A1', 'Gene', (41, 48))	('removed', 'NegReg', (116, 123))	('Arg213His', 'Var', (49, 58))	('interaction', 'Interaction', (75, 86))	('Arg213His', 'SUBSTITUTION', 'None', (49, 58))
539531	22206016	GSTP1 Ile105Val too had a strong independent effect (entropy removal = 3.28%) and its interaction with SULT1A1 Arg213His further removed 3.02% of entropy.	('entropy', 'MPA', (53, 60))	('GSTP1', 'Gene', (0, 5))	('interaction', 'Interaction', (86, 97))	('Ile105Val', 'Chemical', '-', (6, 15))	('removed', 'NegReg', (129, 136))	('GSTP1', 'Gene', '2950', (0, 5))	('Ile105Val', 'Var', (6, 15))	('Arg213His', 'Var', (111, 120))	('entropy', 'MPA', (146, 153))	('Arg213His', 'SUBSTITUTION', 'None', (111, 120))
539532	22206016	A strong synergistic interaction was observed between SULT1A1 Arg213His and CYP1A1*2C as the combination removed an additional 2.61% of the total entropy.	('CYP1A1', 'Gene', (76, 82))	('CYP1A1', 'Gene', '1543', (76, 82))	('removed', 'NegReg', (105, 112))	('total entropy', 'MPA', (140, 153))	('Arg213His', 'Var', (62, 71))	('Arg213His', 'SUBSTITUTION', 'None', (62, 71))
539535	22206016	Interaction of EPHX1 Tyr113His and SULT1A1 Arg213His was consistently identified in smokers.	('Tyr113His', 'Var', (21, 30))	('Interaction', 'Interaction', (0, 11))	('Arg213His', 'Var', (43, 52))	('identified', 'Reg', (70, 80))	('Arg213His', 'SUBSTITUTION', 'None', (43, 52))	('SULT1A1', 'Gene', (35, 42))	('Tyr113His', 'Chemical', '-', (21, 30))	('EPHX1', 'Gene', (15, 20))
539536	22206016	Both EPHX1 Tyr113His and SULT1A1 Arg213His conferred reduced risk in smoker subset in LR.	('EPHX1', 'Gene', (5, 10))	('Arg213His', 'Var', (33, 42))	('Arg213His', 'SUBSTITUTION', 'None', (33, 42))	('Tyr113His', 'Var', (11, 20))	('smoker subset', 'Disease', (69, 82))	('reduced', 'NegReg', (53, 60))	('Tyr113His', 'Chemical', '-', (11, 20))
539537	22206016	The two polymorphisms along with EPHX1 His139Arg formed the best predictor model in MDR analysis in smokers and also formed subsequent splits within smokers in CART.	('MDR analysis', 'MPA', (84, 96))	('His139Arg', 'Var', (39, 48))	('His139Arg', 'SUBSTITUTION', 'None', (39, 48))
539540	22206016	Studies on lung cancer suggest protective effect for His113 (slow type) as compared to Tyr113 (fast type) which imparts increased lung caner risk.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))	('lung cancer', 'Disease', (11, 22))	('His113', 'Chemical', '-', (53, 59))	('Tyr113', 'Chemical', '-', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('Tyr113', 'Var', (87, 93))	('lung caner', 'CPA', (130, 140))	('His113', 'Var', (53, 59))
539541	22206016	The variant allele has also been suggested to decrease the risk of ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('ovarian cancer', 'Disease', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('variant', 'Var', (4, 11))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('decrease', 'NegReg', (46, 54))
539542	22206016	We have earlier reported similar results from the same population in esophageal cancer showing His113 allele to be associated with a significantly reduced risk in smokers.	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('His113', 'Chemical', '-', (95, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('His113 allele', 'Var', (95, 108))	('reduced', 'NegReg', (147, 154))
539545	22206016	In vitro model studies suggest that substitution of histidine at position 213 in the amino acid sequence is associated with decreased substrate affinity and a lower level of protein which might protect against chemical carcinogenesis of PAHs in lung cancer.	('lung cancer', 'Disease', (245, 256))	('lung cancer', 'Phenotype', 'HP:0100526', (245, 256))	('substitution', 'Var', (36, 48))	('substrate affinity', 'MPA', (134, 152))	('carcinogenesis', 'Disease', 'MESH:D063646', (219, 233))	('lung cancer', 'Disease', 'MESH:D008175', (245, 256))	('PAHs', 'Chemical', 'MESH:D011084', (237, 241))	('level of protein', 'MPA', (165, 181))	('decreased', 'NegReg', (124, 133))	('lower', 'NegReg', (159, 164))	('protect', 'Reg', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('carcinogenesis', 'Disease', (219, 233))	('histidine at', 'Var', (52, 64))	('histidine', 'Chemical', 'MESH:D006639', (52, 61))
539546	22206016	Results on association of SULT1A1 Arg213His and risk of cancer are inconsistent, from null association with risk of colorectal cancer and prostate cancer to increase in risk of breast cancer associated with His213 allele.	('cancer', 'Disease', (184, 190))	('His213 allele', 'Var', (207, 220))	('breast cancer', 'Disease', (177, 190))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('prostate cancer', 'Disease', 'MESH:D011471', (138, 153))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Arg213His', 'Var', (34, 43))	('Arg213His', 'SUBSTITUTION', 'None', (34, 43))	('increase', 'PosReg', (157, 165))	('cancer', 'Disease', (56, 62))	('prostate cancer', 'Disease', (138, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('colorectal cancer', 'Disease', (116, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (147, 153))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('SULT1A1', 'Gene', (26, 33))
539547	22206016	Another study on colorectal cancer showed a significantly reduced risk for individuals carrying His213 allele.	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('His213 allele', 'Var', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('colorectal cancer', 'Disease', (17, 34))	('reduced', 'NegReg', (58, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))
539548	22206016	A Meta-analysis by Kotnis et al showed a significant protective effect of the polymorphism in seven studies of genitourinary cancers.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('genitourinary cancers', 'Disease', (111, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('protective', 'NegReg', (53, 63))	('genitourinary cancers', 'Disease', 'MESH:D014565', (111, 132))	('polymorphism', 'Var', (78, 90))
539549	22206016	Among non-smokers CYP1A1*2A and GSTP1 Ile105Val were the most important polymorphisms identified for lung cancer development.	('CYP1A1', 'Gene', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('GSTP1', 'Gene', '2950', (32, 37))	('Ile105Val', 'Chemical', '-', (38, 47))	('CYP1A1', 'Gene', '1543', (18, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('GSTP1', 'Gene', (32, 37))	('lung cancer', 'Disease', (101, 112))	('Ile105Val', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
539550	22206016	Similarly, MDR 3 loci model of CYP1A1*2A, GSTP1 Ile105Val and SULT1A1Arg213His polymorphisms was the best predictor of risk in non-smokers.	('SULT1A1Arg213His', 'Gene', (62, 78))	('Arg', 'Chemical', 'MESH:D001120', (69, 72))	('CYP1A1', 'Gene', '1543', (31, 37))	('GSTP1', 'Gene', (42, 47))	('polymorphisms', 'Var', (79, 92))	('Ile105Val', 'Chemical', '-', (48, 57))	('GSTP1', 'Gene', '2950', (42, 47))	('CYP1A1', 'Gene', (31, 37))	('Ile105Val', 'Var', (48, 57))
539552	22206016	Investigations on association between CYP1A1 polymorphisms and lung cancer have yielded equivocal results.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('CYP1A1', 'Gene', '1543', (38, 44))	('association', 'Interaction', (18, 29))	('lung cancer', 'Disease', (63, 74))	('polymorphisms', 'Var', (45, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('CYP1A1', 'Gene', (38, 44))
539553	22206016	reported association of CYP1A1*2A variant allele with lung cancer, however after stratification by smoking the association remained confined to non-smokers only.	('lung cancer', 'Disease', (54, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('variant', 'Var', (34, 41))	('association', 'Interaction', (9, 20))	('CYP1A1', 'Gene', (24, 30))	('CYP1A1', 'Gene', '1543', (24, 30))
539554	22206016	Further, in a pooled analysis of 11 studies on CYP1A1*2C polymorphism in lung cancer, Le Marchand et al found it to be associated with risk in non-smokers, a finding which corroborates our results.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('CYP1A1', 'Gene', (47, 53))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('polymorphism', 'Var', (57, 69))	('CYP1A1', 'Gene', '1543', (47, 53))	('associated', 'Reg', (119, 129))
539555	22206016	Another study by Jose et al on lung cancer found no association of any CYP1A1 polymorphism with smokers.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('CYP1A1', 'Gene', (71, 77))	('lung cancer', 'Disease', (31, 42))	('association', 'Interaction', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('CYP1A1', 'Gene', '1543', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('polymorphism', 'Var', (78, 90))
539557	22206016	In vitro cDNA expression study suggests that GSTP1 with 105Val variant results in a protein with reduced enzyme activity, however it is reported to play an unlikely role for smoking-related cancers.	('variant', 'Var', (63, 70))	('GSTP1', 'Gene', '2950', (45, 50))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('reduced', 'NegReg', (97, 104))	('enzyme activity', 'MPA', (105, 120))	('GSTP1', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
539560	22206016	High risk for smoking related lung cancer has been reported in individuals deficient in GSTM1 .	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('lung cancer', 'Disease', (30, 41))	('deficient', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('GSTM1', 'Gene', (88, 93))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))
539561	22206016	Smokers with the GSTM1 enzyme have approximately one-third of the risk for lung carcinoma than smokers without the enzyme.	('lung carcinoma', 'Disease', 'MESH:D008175', (75, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('GSTM1', 'Var', (17, 22))	('lung carcinoma', 'Disease', (75, 89))
539562	22206016	There are numerous reports of association between GSTM1 null genotype and smoking in various cancers including esophageal, bladder colorectal and oral.	('cancers', 'Disease', (93, 100))	('bladder colorectal', 'Disease', (123, 141))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('bladder colorectal', 'Disease', 'MESH:D001749', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('GSTM1', 'Gene', (50, 55))	('esophageal', 'Disease', (111, 121))	('association', 'Interaction', (30, 41))	('null genotype', 'Var', (56, 69))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('oral', 'Disease', (146, 150))
539569	22206016	The previously documented main effects of EPHX1 Tyr113His and SULT1A1 Arg213His in smokers and CYP1A1*2A and GSTP1 Ile105Val in non-smokers were evident.	('Tyr113His', 'Var', (48, 57))	('Arg213His', 'SUBSTITUTION', 'None', (70, 79))	('GSTP1', 'Gene', (109, 114))	('SULT1A1', 'Gene', (62, 69))	('EPHX1', 'Gene', (42, 47))	('CYP1A1', 'Gene', (95, 101))	('GSTP1', 'Gene', '2950', (109, 114))	('Arg213His', 'Var', (70, 79))	('Ile105Val', 'Chemical', '-', (115, 124))	('Tyr113His', 'Chemical', '-', (48, 57))	('CYP1A1', 'Gene', '1543', (95, 101))
539570	22206016	Further, synergistic interactions of SULT1A1 Arg213His with GSTP1 Ile105Val and with CYP1A1*2C were observed in non-smokers.	('GSTP1', 'Gene', (60, 65))	('SULT1A1', 'Gene', (37, 44))	('GSTP1', 'Gene', '2950', (60, 65))	('Ile105Val', 'Chemical', '-', (66, 75))	('CYP1A1', 'Gene', (85, 91))	('Arg213His', 'Var', (45, 54))	('Arg213His', 'SUBSTITUTION', 'None', (45, 54))	('CYP1A1', 'Gene', '1543', (85, 91))
539572	22206016	CG haplotype in CYP1A1 was significantly associated with risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('associated with', 'Reg', (41, 56))	('lung cancer', 'Disease', (65, 76))	('CYP1A1', 'Gene', (16, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('haplotype', 'Var', (3, 12))	('CYP1A1', 'Gene', '1543', (16, 22))
539575	22206016	Role of CYP1A1*2A polymorphism is evident only among non smokers in all the three methods.	('CYP1A1', 'Gene', (8, 14))	('CYP1A1', 'Gene', '1543', (8, 14))	('polymorphism', 'Var', (18, 30))
539576	22206016	LR and CART analyses even showed a gene-dosage effect for the increased lung cancer risk with the increasing number of variant allele in the CYP1A1*2A polymorphism.	('CYP1A1', 'Gene', (141, 147))	('polymorphism', 'Var', (151, 163))	('CYP1A1', 'Gene', '1543', (141, 147))	('variant', 'Var', (119, 126))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
539577	22206016	MDR and CART analysis show epitasis between EPHX1 Tyr113His and SULT1A1 Arg213His polymorphisms exclusively among smokers.	('SULT1A1', 'Gene', (64, 71))	('EPHX1', 'Gene', (44, 49))	('Tyr113His', 'Var', (50, 59))	('Arg213His', 'Var', (72, 81))	('Tyr113His', 'Chemical', '-', (50, 59))	('Arg213His', 'SUBSTITUTION', 'None', (72, 81))
539581	22206016	Polymorphisms of EPHX1 Tyr113His and SULT1A1 Arg213His in cases showed deviation from HWE.	('SULT1A1', 'Gene', (37, 44))	('Tyr113His', 'Chemical', '-', (23, 32))	('HWE', 'Disease', (86, 89))	('EPHX1', 'Gene', (17, 22))	('Tyr113His', 'Var', (23, 32))	('Arg213His', 'Var', (45, 54))	('Arg213His', 'SUBSTITUTION', 'None', (45, 54))
539642	18686719	Compared with <0.5 mg/L, ORs for stomach cancer (adjusted for age, gender, and duration of farming) were elevated for 0.5-4.5mg/L (OR=4.7, 95% CI 0.5-41; 7 cases, 18 controls), and >4.5mg/L (OR=5.1, 95% CI 0.5-52; 4 cases, 13 controls); whereas, ORs were non-significantly inverse for esophagus cancer (>4.5mg/ L OR=0.5, 95% CI 0.1-2.9; 8 cases; 13 controls).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('elevated', 'PosReg', (105, 113))	('esophagus cancer', 'Disease', 'MESH:D004938', (285, 301))	('stomach cancer', 'Disease', 'MESH:D013274', (33, 47))	('stomach cancer', 'Phenotype', 'HP:0012126', (33, 47))	('stomach cancer', 'Disease', (33, 47))	('>4.5mg/L', 'Var', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('0.5-4.5mg/L', 'Var', (118, 129))	('esophagus cancer', 'Disease', (285, 301))
539656	18686719	A cohort study in the Netherlands found increased risk for stomach cancer associated with the highest quartile of dietary nitrite ingestion, although risk was attenuated after adjustment for vitamin C and intake of other nutrients.	('increased risk for stomach cancer', 'Phenotype', 'HP:0006753', (40, 73))	('stomach cancer', 'Phenotype', 'HP:0012126', (59, 73))	('stomach cancer', 'Disease', (59, 73))	('dietary', 'Var', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('vitamin C', 'Chemical', 'MESH:D001205', (191, 200))	('men', 'Species', '9606', (182, 185))	('nitrite', 'Chemical', 'MESH:D009573', (122, 129))	('stomach cancer', 'Disease', 'MESH:D013274', (59, 73))
539684	19430607	ESD creates larger artificial ulcers with greater risks of bleeding, but whether the stronger acid suppressant, PPIs would reduce incidence of the complication is unknown.	('artificial ulcers', 'Disease', 'MESH:D014456', (19, 36))	('bleeding', 'Disease', 'MESH:D006470', (59, 67))	('ESD', 'Var', (0, 3))	('artificial ulcers', 'Disease', (19, 36))	('artificial ulcers', 'Phenotype', 'HP:0012399', (19, 36))	('bleeding', 'Disease', (59, 67))
539732	19430607	ESD creates larger artificial ulcers with greater risks of bleeding, but there is little information on whether PPIs would reduce incidence of the complication.	('artificial ulcers', 'Disease', 'MESH:D014456', (19, 36))	('bleeding', 'Disease', 'MESH:D006470', (59, 67))	('ESD', 'Var', (0, 3))	('artificial ulcers', 'Disease', (19, 36))	('artificial ulcers', 'Phenotype', 'HP:0012399', (19, 36))	('bleeding', 'Disease', (59, 67))
539735	19430607	Bleeding occurred in 4 patients in the PPI group and 11 in the H2RA group; multivariate analysis revealed that treatment with the PPI significantly reduced the risk of bleeding (adjusted hazard ratio 0.47, 95% confidence interval, 0.22-0.92).	('patients', 'Species', '9606', (23, 31))	('reduced', 'NegReg', (148, 155))	('PPI', 'Var', (130, 133))	('bleeding', 'Disease', 'MESH:D006470', (168, 176))	('bleeding', 'Disease', (168, 176))
539859	32021845	In our study, prone CT did not improve the detectability of upper esophageal lesions, but 19% (12/63) the mid or lower esophageal malignancies were better identified by prone CT when compared to that of supine CT.	('esophageal malignancies', 'Phenotype', 'HP:0100751', (119, 142))	('upper esophageal lesions', 'Disease', 'MESH:D004941', (60, 84))	('prone', 'Var', (169, 174))	('upper esophageal lesions', 'Disease', (60, 84))	('esophageal malignancies', 'Disease', (119, 142))	('esophageal malignancies', 'Disease', 'MESH:D004941', (119, 142))
539865	32021845	The patient group with esophagectomy had a relatively low grade stage and a statistically higher confidence score for preoperative prone CT than supine CT, which means that the preoperative predictability of local invasion was statistically higher for prone CT than supine CT, especially for the early stages of esophageal cancer.	('higher', 'PosReg', (90, 96))	('patient', 'Species', '9606', (4, 11))	('prone', 'Var', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('higher', 'PosReg', (241, 247))	('local invasion', 'CPA', (208, 222))	('esophageal cancer', 'Disease', (312, 329))	('esophageal cancer', 'Disease', 'MESH:D004938', (312, 329))
539885	31393754	The CMAC group had a higher rate of tumor in situ (two of 11 patients) compared with the other groups.	('patients', 'Species', '9606', (61, 69))	('CMAC', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
539948	31393754	Along this line and in accordance with a previous report, we observed a high prevalence of active alcohol consumption and smoking in patients with CMAC, indicating that these factors may potentiate the carcinogenic effect of achalasia.	('carcinogenic effect of achalasia', 'Disease', (202, 234))	('patients', 'Species', '9606', (133, 141))	('alcohol', 'Chemical', 'MESH:D000431', (98, 105))	('carcinogenic effect of achalasia', 'Disease', 'MESH:D004931', (202, 234))	('active', 'MPA', (91, 97))	('smoking', 'Var', (122, 129))	('potentiate', 'PosReg', (187, 197))	('achalasia', 'Phenotype', 'HP:0002571', (225, 234))	('CMAC', 'Disease', (147, 151))	('active alcohol consumption', 'Phenotype', 'HP:0030955', (91, 117))
539977	31286978	Cell numbers were adjusted depending on radiation quality and dose (OE19: 400-8000, OE33: 400-8000, KYSE270: 500-9000, KYSE410: 300-4000).	('OE19: 400-8000', 'Var', (68, 82))	('OE33', 'Chemical', '-', (84, 88))	('KYSE410: 300-4000', 'Var', (119, 136))	('OE33: 400-8000', 'Var', (84, 98))	('KYSE270: 500-9000', 'Var', (100, 117))
539990	31286978	Survival curves after exposure to conventional photon radiation were comparable for OE19, KYSE270 and KYSE410, while OE33 were markedly more sensitive, as demonstrated by a significantly stronger dose-dependent decrease in clonogenic survival (p = 0.001 for OE33 vs. OE19, p = 0.54 for OE33 vs. KYSE270, p < 0.001 for OE33 vs. KYSE410, two-sided paired Student's t-test, (Additional file 1: Figure S1).	('OE33', 'Chemical', '-', (318, 322))	('clonogenic survival', 'CPA', (223, 242))	('KYSE410', 'Var', (102, 109))	('OE33', 'Chemical', '-', (258, 262))	('OE33', 'Chemical', '-', (117, 121))	('OE33', 'Chemical', '-', (286, 290))	('decrease', 'NegReg', (211, 219))
539992	31286978	1), whereas treatment with 12C and 16O particles resulted in significantly reduced survival in both cell lines compared to photon radiation (12C vs. X: p = 0.004 for OE19, p = 0.002 for OE33; 16O vs. X: p = 0.003 for OE19, p = 0.001 for OE33).	('12C', 'Chemical', 'MESH:C039599', (141, 144))	('12C', 'Chemical', 'MESH:C039599', (27, 30))	('survival', 'CPA', (83, 91))	('reduced', 'NegReg', (75, 82))	('16O', 'Chemical', '-', (192, 195))	('OE33', 'Chemical', '-', (186, 190))	('OE33', 'Chemical', '-', (237, 241))	('16O particles', 'Var', (35, 48))	('16O', 'Chemical', '-', (35, 38))
539993	31286978	The tested SCC cell lines showed considerable heterogeneity regarding their response to photon and particle irradiation: KYSE270 presented the highest sensitivities towards all particle irradiation modalities compared to photon treatment (p = 0.005 for 1H vs. X; p = 0.002 for 12C vs. X; p = 0.005 for 16O vs. X), while there were only marginal survival differences after photon and particle irradiation in KYSE410 cells (p = 0.82 for 1H vs. X; p = 0.65 for 12C vs. X; p = 0.01 for 16O vs. X).	('1H', 'Chemical', '-', (435, 437))	('16O', 'Chemical', '-', (302, 305))	('SCC', 'Gene', (11, 14))	('16O', 'Chemical', '-', (482, 485))	('12C', 'Chemical', 'MESH:C039599', (458, 461))	('SCC', 'Gene', '6317', (11, 14))	('sensitivities', 'MPA', (151, 164))	('KYSE270', 'Var', (121, 128))	('12C', 'Chemical', 'MESH:C039599', (277, 280))	('1H', 'Chemical', '-', (253, 255))
539999	31286978	In comparison to photons, 1H, 12C and 16O irradiation induced a significantly stronger G2 arrest within 24 h in both AC cell lines and at both dose levels (at the high dose level X: 37%, 1H: 59%, 12C: 58%, 16O: 65% for OE19; X: 42%, 1H: 63%, 12C: 65%, 16O: 62% for OE33) (Fig.	('stronger', 'PosReg', (78, 86))	('1H', 'Chemical', '-', (233, 235))	('16O', 'Chemical', '-', (252, 255))	('OE19', 'Var', (219, 223))	('12C', 'Chemical', 'MESH:C039599', (242, 245))	('12C', 'Chemical', 'MESH:C039599', (196, 199))	('12C', 'Chemical', 'MESH:C039599', (30, 33))	('G2 arrest', 'CPA', (87, 96))	('16O', 'Chemical', '-', (206, 209))	('1H', 'Chemical', '-', (187, 189))	('1H', 'Chemical', '-', (26, 28))	('16O', 'Chemical', '-', (38, 41))	('OE33', 'Var', (265, 269))	('OE33', 'Chemical', '-', (265, 269))
540000	31286978	In the SCC cell lines, a comparable to even stronger G2 phase block was observed at 24 h after treatment with either radiation modality at the high dose level, but there were no clear differences between photon and particle irradiation (X: 86%, 1H: 89%, 12C: 88%, 16O: 93% for KYSE270; X: 77%, 1H: 72%, 12C: 74%, 16O: 77% for KYSE410).	('SCC', 'Gene', (7, 10))	('16O', 'Chemical', '-', (313, 316))	('1H', 'Chemical', '-', (294, 296))	('KYSE270', 'Var', (277, 284))	('12C', 'Chemical', 'MESH:C039599', (254, 257))	('12C', 'Chemical', 'MESH:C039599', (303, 306))	('SCC', 'Gene', '6317', (7, 10))	('G2 phase', 'CPA', (53, 61))	('KYSE410', 'Var', (326, 333))	('16O', 'Chemical', '-', (264, 267))	('1H', 'Chemical', '-', (245, 247))
540001	31286978	At 96 h after treatment, both SCC cell lines demonstrated lower levels of G2 phase cells after photon (30% for KYSE270, 27% for KYSE410) than after 1H, 12C or 16O irradiation (1H: 48%, p = 0.092; 12C: 43%, p = 0.110; 16O: 42%, p = 0.038 for KYSE270; 1H: 42%, p = 0.008; 12C: 35%, p = 0.112; 16O: 34%, p = 0.006 for KYSE410).	('SCC', 'Gene', '6317', (30, 33))	('G2 phase cells', 'CPA', (74, 88))	('lower', 'NegReg', (58, 63))	('KYSE270', 'Var', (241, 248))	('1H', 'Chemical', '-', (176, 178))	('12C', 'Chemical', 'MESH:C039599', (152, 155))	('12C', 'Chemical', 'MESH:C039599', (270, 273))	('12C', 'Chemical', 'MESH:C039599', (196, 199))	('1H', 'Chemical', '-', (148, 150))	('16O', 'Chemical', '-', (291, 294))	('SCC', 'Gene', (30, 33))	('1H', 'Chemical', '-', (250, 252))	('16O', 'Chemical', '-', (217, 220))	('16O', 'Chemical', '-', (159, 162))
540005	31286978	Considerable heterogeneity regarding apoptosis induction was noted for the SCC cell lines: KYSE270 demonstrated higher apoptosis levels after 12C (p < 0.05) and 16O (p < 0.01) irradiation than after photon treatment as measured by caspase-3 activation, whereas KYSE410 demonstrated lower apoptosis rates for 12C and 16O particle radiation compared to conventional photons, although statistical significance was not reached (p = 0,095 for 12C, p = 0,44 for 16O); this correlated well with the clonogenic survival data observed after photon and particle irradiation in these cell lines.	('SCC', 'Gene', '6317', (75, 78))	('12C', 'Chemical', 'MESH:C039599', (142, 145))	('16O', 'Chemical', '-', (161, 164))	('higher', 'PosReg', (112, 118))	('caspase-3', 'Gene', (231, 240))	('apoptosis levels', 'MPA', (119, 135))	('12C', 'Chemical', 'MESH:C039599', (438, 441))	('12C', 'Chemical', 'MESH:C039599', (308, 311))	('caspase-3', 'Gene', '836', (231, 240))	('SCC', 'Gene', (75, 78))	('KYSE270', 'Var', (91, 98))	('16O', 'Chemical', '-', (316, 319))	('16O', 'Chemical', '-', (456, 459))
540016	31286978	Clinically available ion beam radiation with protons or heavier ions like 12C or 16O may make use of the particles' physical advantages like their inverted dose-depth profile, resulting in the ability to increase treatment doses while sparing surrounding organs-at-risk, or their increased RBE values.	('increase', 'PosReg', (204, 212))	('16O', 'Chemical', '-', (81, 84))	('16O', 'Var', (81, 84))	('12C', 'Chemical', 'MESH:C039599', (74, 77))	('RBE', 'MPA', (290, 293))	('sparing', 'NegReg', (235, 242))	('treatment doses', 'CPA', (213, 228))
540027	31286978	Resistance to proton and particle irradiation is linked to effective homologous recombination (HR) DSB repair, and previous studies have shown the important role of HR for esophageal AC and SCC such as OE33 and KYSE410.	('KYSE410', 'Var', (211, 218))	('esophageal AC', 'Disease', (172, 185))	('OE33', 'Var', (202, 206))	('OE33', 'Chemical', '-', (202, 206))	('SCC', 'Gene', (190, 193))	('SCC', 'Gene', '6317', (190, 193))
540031	31286978	Additionally, response to particle irradiation was found to correlate with the level of apoptosis induction in all tested esophageal cancer samples, and the cell lines most sensitive to 12C and 16O irradiation exhibited the highest levels of caspase-3 induction at 96 h after treatment.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('apoptosis', 'MPA', (88, 97))	('caspase-3', 'Gene', (242, 251))	('16O', 'Chemical', '-', (194, 197))	('12C', 'Chemical', 'MESH:C039599', (186, 189))	('caspase-3', 'Gene', '836', (242, 251))	('16O', 'Var', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
540040	28546524	Two authors independently reviewed and selected cohort studies on the association between very light (<= 0.5 drink/day), light (<= 1 drink/day), or moderate drinking (1-2 drinks/day) and the risk of cancer incidence and mortality.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('<= 1', 'Var', (128, 132))	('<= 0.5', 'Var', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('mortality', 'CPA', (220, 229))	('cancer', 'Disease', (199, 205))
540043	28546524	Conversely, light drinking was associated with a decreased incidence of both female and male lung cancer significantly and both female and male thyroid cancer marginally significantly.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('male thyroid cancer', 'Disease', (139, 158))	('male lung cancer', 'Disease', (88, 104))	('light drinking', 'Var', (12, 26))	('male thyroid cancer', 'Disease', 'MESH:D013964', (139, 158))	('decreased', 'NegReg', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('male lung cancer', 'Disease', 'MESH:D008175', (88, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('thyroid cancer', 'Phenotype', 'HP:0002890', (144, 158))
540063	28546524	We investigated the risk of each type of cancer in both incidence and mortality according to different levels of alcohol drinking: very light drinking (<= 0.5 drink/day), light drinking (<= 1 drink/day), and moderate drinking (1-2 drinks /day).	('<=', 'Var', (187, 189))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('alcohol drinking', 'Phenotype', 'HP:0030955', (113, 129))	('alcohol', 'Chemical', 'MESH:D000438', (113, 120))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('<= 0.5', 'Var', (152, 158))
540085	28546524	However, light drinking was significantly associated with a decreased incidence of both female and male lung cancer (RR, 0.91; 95% CI, 0.90 to 0.94; I2=0.0%; n=10), male lung cancer (RR, 0.91; 95% CI, 0.90 to 0.95; I2=0.0%; n=3), and female lung cancer (RR, 0.90; 95% CI, 0.87 to 0.94; I2=0.0%; n=4), whereas it increased the incidence of female breast cancer (RR, 1.09; 95% CI, 1.06 to 1.12; I2=32.8%; n=25) (Fig.	('decreased', 'NegReg', (60, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (241, 252))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('male lung cancer', 'Disease', 'MESH:D008175', (165, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (346, 359))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('male lung cancer', 'Disease', 'MESH:D008175', (99, 115))	('male lung cancer', 'Disease', 'MESH:D008175', (236, 252))	('female', 'Disease', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (346, 359))	('breast cancer', 'Disease', (346, 359))	('light drinking', 'Var', (9, 23))	('male lung cancer', 'Disease', (165, 181))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('male lung cancer', 'Disease', (99, 115))	('male lung cancer', 'Disease', (236, 252))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))
540089	28546524	Also, light drinking was marginally associated with a decreased incidence of both female and male thyroid cancer (RR, 0.89; 95% CI, 0.79 to 1.00; I2=0.0%; n=6).	('light drinking', 'Var', (6, 20))	('male thyroid cancer', 'Disease', (93, 112))	('female', 'Disease', (82, 88))	('male thyroid cancer', 'Disease', 'MESH:D013964', (93, 112))	('thyroid cancer', 'Phenotype', 'HP:0002890', (98, 112))	('decreased', 'NegReg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
540144	28852939	Poor HRQOL at 6 months after surgery for esophageal or gastroesophageal junction cancer is associated with increased long-term mortality, as is poor HRQOL up to 10 years postoperatively.	('esophageal or gastroesophageal junction cancer', 'Disease', (41, 87))	('Poor', 'Var', (0, 4))	('esophageal or gastroesophageal junction cancer', 'Disease', 'MESH:D004938', (41, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
540227	29344287	For example, microRNA-483 (miR-483) aberrant expression plays a pivotal part in tumor biology in a variety of human cancer, including DTCs.	('aberrant expression', 'Var', (36, 55))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('miR-483', 'Gene', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('DTCs', 'Disease', (134, 138))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', (80, 85))	('human', 'Species', '9606', (110, 115))	('microRNA-483', 'Gene', '619552', (13, 25))	('miR-483', 'Gene', '619552', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('microRNA-483', 'Gene', (13, 25))
540231	29344287	Particularly, emerging evidence suggests that abnormalities in the expression of miRNA are associated with a variety of cancers, including DTCs.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('abnormalities', 'Var', (46, 59))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('miRNA', 'Gene', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('expression', 'MPA', (67, 77))	('DTCs', 'Disease', (139, 143))	('associated', 'Reg', (91, 101))
540261	29344287	Furthermore, epigenetic features, including DNA methylation, histone modifications, and miRNAs, have been described as early events in carcinogenesis recently.	('carcinogenesis', 'Disease', (135, 149))	('miRNAs', 'CPA', (88, 94))	('DNA methylation', 'Var', (44, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (135, 149))	('histone', 'MPA', (61, 68))
540270	29344287	It has been reported that miR-483-3p is over-expressed in hepatocellular carcinoma that carry mutations in Wnt/beta-catenin signaling pathway genes and in hepatocellular carcinoma with wild-type TP53 gene.	('hepatocellular carcinoma', 'Disease', (58, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('TP53', 'Gene', (195, 199))	('hepatocellular carcinoma', 'Disease', (155, 179))	('miR-483', 'Gene', '619552', (26, 33))	('mutations', 'Var', (94, 103))	('beta-catenin', 'Gene', (111, 123))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('miR-483', 'Gene', (26, 33))	('beta-catenin', 'Gene', '1499', (111, 123))	('over-expressed', 'PosReg', (40, 54))	('TP53', 'Gene', '7157', (195, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
540273	29344287	In another research by this author, researchers found that O-GlcNAc transferase(OGT) is an important factor which meditates numeral cellular processes and repression of its activity brings about low-expression of miR-483-3p.	('low-expression', 'MPA', (195, 209))	('OGT', 'Gene', '8473', (80, 83))	('miR-483', 'Gene', '619552', (213, 220))	('miR-483', 'Gene', (213, 220))	('repression', 'Var', (155, 165))	('OGT', 'Gene', (80, 83))
540284	29344287	Compared with side normal tissue, miR-483-3p is aberrantly over-active in pancreatic cancer tissues as a member of miR-483 family, indicating that aberrant expression of miR-483-3p is an important indicator in pancreatic cancer in the early stage and is related to tumor distinction and prognosis.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('miR-483', 'Gene', (170, 177))	('miR-483', 'Gene', (115, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (210, 227))	('miR-483', 'Gene', '619552', (115, 122))	('miR-483', 'Gene', (34, 41))	('miR-483', 'Gene', '619552', (170, 177))	('tumor', 'Disease', (265, 270))	('miR-483', 'Gene', '619552', (34, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('pancreatic cancer', 'Disease', 'MESH:D010190', (210, 227))	('pancreatic cancer', 'Disease', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('aberrant', 'Var', (147, 155))	('pancreatic cancer', 'Disease', (210, 227))	('related', 'Reg', (254, 261))
540291	29344287	In esophageal cancer, high expression of miR-483 had a poorer overall survival and a less median survival, and it may predict less sensitivity to chemotherapy.	('high expression', 'Var', (22, 37))	('miR-483', 'Gene', (41, 48))	('overall survival', 'CPA', (62, 78))	('median survival', 'CPA', (90, 105))	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('less', 'NegReg', (85, 89))	('poorer', 'NegReg', (55, 61))	('less', 'NegReg', (126, 130))	('miR-483', 'Gene', '619552', (41, 48))
540356	28694664	Western blotting results showed that miR-382 inhibited the phosphorylation of mTOR and 4E-BP1.	('miR-382', 'Var', (37, 44))	('miR-382', 'Chemical', '-', (37, 44))	('phosphorylation', 'MPA', (59, 74))	('inhibited', 'NegReg', (45, 54))	('mTOR and 4E-BP1', 'Gene', '21977;13685', (78, 93))
540358	28694664	Core tip: Our previous study revealed that miR-382 was significantly down-regulated in esophageal squamous cell carcinoma (ESCC) patients with short-term motility, implying that miR-382 may display antitumor function in ESCC development and metastasis.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('tumor', 'Disease', (202, 207))	('miR-382', 'Var', (178, 185))	('patients', 'Species', '9606', (129, 137))	('miR-382', 'Gene', (43, 50))	('miR-382', 'Chemical', '-', (43, 50))	('ESCC', 'Disease', (220, 224))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('miR-382', 'Chemical', '-', (178, 185))	('down-regulated', 'NegReg', (69, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
540360	28694664	Inhibitory influence on protein translation mediated by mTOR/4E-BP1 signaling might be involved in the antitumor activity of miR-382 against ESCC.	('miR-382', 'Chemical', '-', (125, 132))	('4E-BP1', 'Gene', '1978', (61, 67))	('mTOR', 'Gene', (56, 60))	('tumor', 'Disease', (107, 112))	('mTOR', 'Gene', '2475', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('4E-BP1', 'Gene', (61, 67))	('protein translation', 'MPA', (24, 43))	('miR-382', 'Var', (125, 132))	('ESCC', 'Disease', (141, 145))
540361	28694664	Thus, manipulation of miR-382 level can be a potentially therapeutic intervention for ESCC.	('manipulation', 'Var', (6, 18))	('ESCC', 'Disease', (86, 90))	('miR-382', 'Chemical', '-', (22, 29))
540401	28694664	As shown in Figure 1A, endogenous miR-382 in Eca109 was 7.69-fold lower than that in Het-1A cells (P < 0.01).	('endogenous miR-382', 'MPA', (23, 41))	('miR-382', 'Chemical', '-', (34, 41))	('lower', 'NegReg', (66, 71))	('Eca109', 'Var', (45, 51))
540403	28694664	As indicated in Figure 1B, miR-382 levels of LV-miR-382 infected Eca109 cells were 24153.06-fold higher than that of LV-Con control cells.	('higher', 'PosReg', (97, 103))	('miR-382 levels', 'MPA', (27, 41))	('LV-miR-382', 'Var', (45, 55))	('miR-382', 'Chemical', '-', (27, 34))	('miR-382', 'Chemical', '-', (48, 55))
540405	28694664	As the expression of endogenous miR-382 in Eca109 cells was down-regulated, we speculated that miR-382 might affect the proliferation rate of ESCC cells.	('miR-382', 'Chemical', '-', (32, 39))	('down-regulated', 'NegReg', (60, 74))	('miR-382', 'Var', (95, 102))	('expression', 'MPA', (7, 17))	('miR-382', 'Chemical', '-', (95, 102))	('affect', 'Reg', (109, 115))	('ESCC', 'Disease', (142, 146))	('proliferation rate', 'CPA', (120, 138))
540410	28694664	To elucidate the possible mechanisms by which miR-382 inhibited the proliferation of ESCC cells, we studied the impact of miR-382 on Eca109 cell cycle progression and apoptosis.	('inhibited', 'NegReg', (54, 63))	('proliferation', 'CPA', (68, 81))	('miR-382', 'Chemical', '-', (46, 53))	('miR-382', 'Chemical', '-', (122, 129))	('miR-382', 'Var', (46, 53))
540420	28694664	As shown in Figure 5A and B, in the group infected with LV-miR-382 the rate of cell migration into the bottom chamber was significantly reduced by 32% compared with that of the scrambled control cells (LV-Con vs LV-miR-382, 433.50 +- 20.72 vs 292.25 +- 18.02, P < 0.05).	('LV-miR-382', 'Var', (56, 66))	('miR-382', 'Chemical', '-', (215, 222))	('cell migration into the bottom chamber', 'CPA', (79, 117))	('infected', 'Var', (42, 50))	('reduced', 'NegReg', (136, 143))	('miR-382', 'Chemical', '-', (59, 66))
540422	28694664	The result shown in Figure 5C and D demonstrates that miR-382 significantly suppressed invasion of Eca109 cells by 54% (LV-Con vs LV-miR-382, 603.80 +- 64.46 vs 273.80 +- 54.99, P < 0.01).	('miR-382', 'Var', (54, 61))	('miR-382', 'Chemical', '-', (54, 61))	('suppressed', 'NegReg', (76, 86))	('miR-382', 'Chemical', '-', (133, 140))	('invasion of Eca109 cells', 'CPA', (87, 111))
540425	28694664	Interestingly, miR-382 attenuated expressions of three mesenchymal markers (beta-catenin, vimentin and snail).	('vimentin', 'Gene', '7431', (90, 98))	('snail', 'Gene', (103, 108))	('miR-382', 'Var', (15, 22))	('expressions', 'MPA', (34, 45))	('vimentin', 'Gene', (90, 98))	('miR-382', 'Chemical', '-', (15, 22))	('beta-catenin', 'Gene', (76, 88))	('snail', 'Gene', '6615', (103, 108))	('beta-catenin', 'Gene', '1499', (76, 88))	('attenuated', 'NegReg', (23, 33))
540433	28694664	As shown in Figure 6, increased levels of either LC3-I or LC3-II were detected in LV-miR-382 cells compared to control cells, indicating that miR-382 activated the autophagy process.	('miR-382', 'Chemical', '-', (142, 149))	('LV-miR-382', 'Var', (82, 92))	('LC3', 'Gene', (58, 61))	('LC3', 'Gene', '84557', (49, 52))	('autophagy process', 'CPA', (164, 181))	('activated', 'PosReg', (150, 159))	('miR-382', 'Chemical', '-', (85, 92))	('LC3', 'Gene', (49, 52))	('increased', 'PosReg', (22, 31))	('miR-382', 'Var', (142, 149))	('LC3', 'Gene', '84557', (58, 61))
540438	28694664	Human miR-382 (has-mir-382, MIMAT0000737, 5'-GAAGUUGUUCGUGGUGGAUUCG-3') resides in a miRNA cluster in the imprinted DLK1-DIO3 region on the 14q32 locus, which hosts one of the largest miRNA clusters in the genome.	('Human', 'Species', '9606', (0, 5))	('DLK1', 'Gene', (116, 120))	('DIO3', 'Gene', '1735', (121, 125))	('miR-382', 'Gene', (6, 13))	('DIO3', 'Gene', (121, 125))	('miR-382', 'Chemical', '-', (6, 13))	('DLK1', 'Gene', '8788', (116, 120))	('MIMAT0000737', 'Var', (28, 40))
540443	28694664	This indicates that miR-382 may play antitumor functions in esophageal carcinogenesis, and could be a potential predictive biomarker for ESCC prognosis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('ESCC', 'Disease', (137, 141))	('miR-382', 'Var', (20, 27))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (60, 85))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('miR-382', 'Chemical', '-', (20, 27))	('esophageal carcinogenesis', 'Disease', (60, 85))
540447	28694664	These findings together with our previous result suggest that miR-382 functions as a tumor suppressor in ESCC.	('tumor', 'Disease', (85, 90))	('ESCC', 'Disease', (105, 109))	('miR-382', 'Var', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('miR-382', 'Chemical', '-', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
540456	28694664	Accordingly, these data indicated that miR-382 might suppress the EMT process, so that Eca109 cell invasion and metastasis may be restrained.	('miR-382', 'Var', (39, 46))	('EMT process', 'CPA', (66, 77))	('miR-382', 'Chemical', '-', (39, 46))	('suppress', 'NegReg', (53, 61))	('restrained', 'NegReg', (130, 140))
540459	28694664	Our data revealed that overexpression of miR-382 was able to up-regulate the expression of two distinctive hallmarks of autophagy, LC3-I and LC3-II, in Eca109 cells, implying that miR-382 could induce autophagy in Eca109 cells.	('expression', 'MPA', (77, 87))	('miR-382', 'Chemical', '-', (180, 187))	('autophagy', 'CPA', (201, 210))	('LC3', 'Gene', '84557', (141, 144))	('miR-382', 'Chemical', '-', (41, 48))	('LC3', 'Gene', (141, 144))	('miR-382', 'Var', (41, 48))	('LC3', 'Gene', '84557', (131, 134))	('LC3', 'Gene', (131, 134))	('up-regulate', 'PosReg', (61, 72))	('induce', 'PosReg', (194, 200))	('miR-382', 'Var', (180, 187))
540463	28694664	Our results showed that miR-382 dramatically inhibited the phosphorylation of mTOR as well as 4E-BP1.	('4E-BP1', 'Gene', (94, 100))	('phosphorylation', 'MPA', (59, 74))	('mTOR', 'Gene', (78, 82))	('miR-382', 'Var', (24, 31))	('mTOR', 'Gene', '2475', (78, 82))	('4E-BP1', 'Gene', '1978', (94, 100))	('miR-382', 'Chemical', '-', (24, 31))	('inhibited', 'NegReg', (45, 54))
540464	28694664	These results indicated that miR-382 might suppress the overall protein translation process through mTOR/4E-BP1, and could potentially function as a tumor suppressor against ESCC.	('4E-BP1', 'Gene', '1978', (105, 111))	('miR-382', 'Var', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('miR-382', 'Chemical', '-', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('ESCC', 'Disease', (174, 178))	('suppress', 'NegReg', (43, 51))	('4E-BP1', 'Gene', (105, 111))	('protein translation process', 'MPA', (64, 91))	('tumor', 'Disease', (149, 154))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
540476	28694664	Previous literature indicates that miR-382 was reduced and associated with poor survival in osteosarcoma patients.	('osteosarcoma', 'Disease', 'MESH:D012516', (92, 104))	('patients', 'Species', '9606', (105, 113))	('poor', 'NegReg', (75, 79))	('survival', 'MPA', (80, 88))	('miR-382', 'Var', (35, 42))	('miR-382', 'Chemical', '-', (35, 42))	('osteosarcoma', 'Disease', (92, 104))	('reduced', 'NegReg', (47, 54))	('osteosarcoma', 'Phenotype', 'HP:0002669', (92, 104))
540482	28694664	Thus, manipulation of miR-382 level is a potential therapeutic strategy for ESCC.	('manipulation', 'Var', (6, 18))	('miR-382', 'Chemical', '-', (22, 29))	('ESCC', 'Disease', (76, 80))
540490	24931169	Moreover, Notch1 appears to mediate replicative senescence as well as TGF-beta-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor suppressor attribute of endogenous Notch1.	('TGF-beta', 'Gene', '7040', (70, 78))	('Notch1', 'Gene', (10, 16))	('HPV', 'Species', '10566', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('TGF-beta', 'Gene', (70, 78))	('Notch1', 'Gene', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('mediate', 'Reg', (28, 35))	('inactivation', 'Var', (170, 182))	('senescence', 'MPA', (194, 204))	('E6/E7', 'Gene', '25479186', (145, 150))	('tumor', 'Disease', (218, 223))	('E6/E7', 'Gene', (145, 150))
540492	24931169	Common genetic lesions associated with ESCC include p53 mutations, p16INK4A loss, cyclin D1 overexpression, EGFR overexpression and telomerase activation .	('mutations', 'Var', (56, 65))	('telomerase', 'CPA', (132, 142))	('SCC', 'Gene', '6317', (40, 43))	('loss', 'NegReg', (76, 80))	('overexpression', 'PosReg', (92, 106))	('p16INK4A', 'Gene', (67, 75))	('EGFR', 'Gene', (108, 112))	('p53', 'Gene', (52, 55))	('overexpression', 'PosReg', (113, 127))	('EGFR', 'Gene', '1956', (108, 112))	('cyclin D1', 'Gene', (82, 91))	('p16INK4A', 'Gene', '1029', (67, 75))	('cyclin D1', 'Gene', '595', (82, 91))	('activation', 'PosReg', (143, 153))	('SCC', 'Gene', (40, 43))
540494	24931169	Oncogenes induce senescence in immortalized esophageal keratinocytes .	('Oncogenes', 'Var', (0, 9))	('induce', 'Reg', (10, 16))	('senescence', 'MPA', (17, 27))	('rat', 'Species', '10116', (57, 60))
540507	24931169	Multiple lines of evidence indicate a tumor suppressor role of Notch in SCCs.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('SCC', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('SCCs', 'Phenotype', 'HP:0002860', (72, 76))	('SCC', 'Gene', '6317', (72, 75))	('Notch', 'Var', (63, 68))
540508	24931169	They include loss-of-function mutations identified in primary SCCs including ESCC  and tumor-prone phenotypes in genetically engineered mouse models targeting the Notch pathway .	('loss-of-function', 'NegReg', (13, 29))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SCC', 'Gene', '6317', (78, 81))	('SCC', 'Gene', '6317', (62, 65))	('SCCs', 'Phenotype', 'HP:0002860', (62, 66))	('tumor', 'Disease', (87, 92))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mouse', 'Species', '10090', (136, 141))	('SCC', 'Gene', (78, 81))	('SCC', 'Gene', (62, 65))
540514	24931169	The activated form of Notch1 (ICN1Val1744) was upregulated at 43 PDs in cells with senescent characteristics corroborated by Rb dephosphorylation, upregulation of p53, p16INK4A and p21 (CDKN1A), flat and enlarged cell morphology and the increased senescenceassociated beta-galactosidase (SABG) activity (Figure 1, c-e).	('increased', 'PosReg', (237, 246))	('flat', 'CPA', (195, 199))	('ICN', 'Chemical', '-', (30, 33))	('upregulated', 'PosReg', (47, 58))	('senescenceassociated', 'MPA', (247, 267))	('activity', 'MPA', (294, 302))	('Rb', 'Chemical', 'MESH:D012413', (125, 127))	('SABG', 'Chemical', '-', (288, 292))	('beta-galactosidase', 'Gene', '2720', (268, 286))	('p16INK4A', 'Gene', (168, 176))	('p16INK4A', 'Gene', '1029', (168, 176))	('beta-galactosidase', 'Gene', (268, 286))	('Notch1', 'Gene', (22, 28))	('rat', 'Species', '10116', (116, 119))	('upregulation', 'PosReg', (147, 159))	('p21', 'Var', (181, 184))	('PDs', 'Chemical', '-', (65, 68))	('CDKN1A', 'Gene', (186, 192))	('CDKN1A', 'Gene', '1026', (186, 192))	('p53', 'Var', (163, 166))
540523	24931169	CSL knockdown prevented ICN1 from activating CSL-dependent transcription, allowing continued cell proliferation with antagonized Rb dephosphorylation and decreased SABG activation in EPC2-hTERT and EPC1-hTERT cells (Figure 3 and Supplementary Figures S3), suggesting that CSL-dependent transcription may mediate ICN1-induced senescence since.	('decreased', 'NegReg', (154, 163))	('CSL', 'Gene', (45, 48))	('SABG', 'Chemical', '-', (164, 168))	('knockdown', 'Var', (4, 13))	('EPC2', 'Gene', (183, 187))	('activation', 'PosReg', (169, 179))	('CSL', 'Gene', '3516', (272, 275))	('hTERT', 'Gene', '7015', (188, 193))	('hTERT', 'Gene', '7015', (203, 208))	('EPC1', 'Gene', (198, 202))	('EPC1', 'Gene', '80314', (198, 202))	('ICN', 'Chemical', '-', (312, 315))	('CSL', 'Gene', (272, 275))	('CSL', 'Gene', '3516', (0, 3))	('EPC2', 'Gene', '26122', (183, 187))	('CSL', 'Gene', (0, 3))	('Rb', 'Chemical', 'MESH:D012413', (129, 131))	('hTERT', 'Gene', (188, 193))	('CSL', 'Gene', '3516', (45, 48))	('rat', 'Species', '10116', (105, 108))	('hTERT', 'Gene', (203, 208))	('ICN', 'Chemical', '-', (24, 27))
540525	24931169	EPC2-T is a derivative of EPC2-hTERT carrying EGFR, cyclin D1 and p53R175H transgenes and that has been further modified to express either DNMAML1, a genetic pan-Notch inhibitor, or GFP as a control .	('MAML1', 'Gene', (141, 146))	('cyclin D1', 'Gene', (52, 61))	('p53R175H', 'Var', (66, 74))	('hTERT', 'Gene', '7015', (31, 36))	('hTERT', 'Gene', (31, 36))	('EGFR', 'Gene', '1956', (46, 50))	('EPC2', 'Gene', '26122', (26, 30))	('MAML1', 'Gene', '103806', (141, 146))	('EGFR', 'Gene', (46, 50))	('EPC2', 'Gene', (26, 30))	('EPC2', 'Gene', '26122', (0, 4))	('EPC2', 'Gene', (0, 4))	('cyclin D1', 'Gene', '595', (52, 61))
540526	24931169	The p14ARF-p53 and p16INK4A-Rb pathways are compromised in EN60 cells carrying HPV E6 and E7, which target p53 and Rb for degradation or sequestration, respectively.	('p14ARF', 'Gene', '1029', (4, 10))	('Rb', 'Chemical', 'MESH:D012413', (115, 117))	('HPV E6', 'Var', (79, 85))	('p53', 'Protein', (107, 110))	('HPV', 'Species', '10566', (79, 82))	('p16INK4A', 'Gene', (19, 27))	('p16INK4A', 'Gene', '1029', (19, 27))	('p14ARF', 'Gene', (4, 10))	('Rb', 'Chemical', 'MESH:D012413', (28, 30))	('degradation', 'MPA', (122, 133))	('rat', 'Species', '10116', (144, 147))	('sequestration', 'MPA', (137, 150))
540527	24931169	TE11 cells show biallelic p53 inactivation and INK4A deletion.	('p53', 'Protein', (26, 29))	('deletion', 'Var', (53, 61))	('INK4A', 'Gene', '1029', (47, 52))	('INK4A', 'Gene', (47, 52))	('inactivation', 'NegReg', (30, 42))
540529	24931169	Likewise, CSL knockdown prevented ICN1 from activating CSL-dependent transcription and SABG induction in EPC2-T cells (data not shown).	('CSL', 'Gene', (55, 58))	('CSL', 'Gene', '3516', (10, 13))	('EPC2', 'Gene', '26122', (105, 109))	('EPC2', 'Gene', (105, 109))	('ICN', 'Chemical', '-', (34, 37))	('CSL', 'Gene', '3516', (55, 58))	('SABG induction', 'Gene', (87, 101))	('knockdown', 'Var', (14, 23))	('SABG', 'Chemical', '-', (87, 91))	('CSL', 'Gene', (10, 13))
540530	24931169	In the absence of DNMAML1, ICN1 induced p16INK4A and Rb dephosphorylation to inhibit cell proliferation (Supplementary Figure S4b - e).	('rat', 'Species', '10116', (97, 100))	('cell proliferation', 'CPA', (85, 103))	('p16INK4A', 'Gene', (40, 48))	('inhibit', 'NegReg', (77, 84))	('ICN1', 'Var', (27, 31))	('MAML1', 'Gene', '103806', (20, 25))	('dephosphorylation', 'CPA', (56, 73))	('ICN', 'Chemical', '-', (27, 30))	('p16INK4A', 'Gene', '1029', (40, 48))	('MAML1', 'Gene', (20, 25))	('Rb', 'Chemical', 'MESH:D012413', (53, 55))
540532	24931169	When tested in EN60 and TE11, ICN1 activated CSL-dependent transcription and induced Notch target genes; however, ICN1 affected little, if any, Rb phosphorylation, cell proliferation or SABG activity (Supplementary Figures S5), suggesting that oncogenic genetic alterations that limit cellular senescence check point functions may suppress ICN1-induced senescence without affecting CSL-dependent transcriptional activity.	('SABG', 'Chemical', '-', (186, 190))	('CSL', 'Gene', (45, 48))	('ICN', 'Chemical', '-', (30, 33))	('rat', 'Species', '10116', (176, 179))	('CSL', 'Gene', (382, 385))	('ICN', 'Chemical', '-', (114, 117))	('CSL', 'Gene', '3516', (45, 48))	('suppress', 'NegReg', (331, 339))	('Rb', 'Chemical', 'MESH:D012413', (144, 146))	('ICN', 'Chemical', '-', (340, 343))	('rat', 'Species', '10116', (266, 269))	('CSL', 'Gene', '3516', (382, 385))	('ICN1-induced', 'Disease', (340, 352))	('genetic alterations', 'Var', (254, 273))
540534	24931169	p53 and p14ARF proteins, the latter a p53 stabilizing tumor suppressor, were unaffected or rather downregulated in EPC2-hTERT, EPC1 and EPC1-hTERT with ectopically expressed ICN1 (Figure 2b; Supplementary Figure S2a).	('downregulated', 'NegReg', (98, 111))	('EPC2', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('p53', 'Protein', (0, 3))	('hTERT', 'Gene', (120, 125))	('EPC1', 'Gene', '80314', (127, 131))	('EPC1', 'Gene', '80314', (136, 140))	('EPC1', 'Gene', (127, 131))	('EPC1', 'Gene', (136, 140))	('hTERT', 'Gene', '7015', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('EPC2', 'Gene', '26122', (115, 119))	('rat', 'Species', '10116', (91, 94))	('p14ARF', 'Gene', '1029', (8, 14))	('ICN1', 'Gene', (174, 178))	('hTERT', 'Gene', (141, 146))	('ectopically', 'Var', (152, 163))	('ICN', 'Chemical', '-', (174, 177))	('p14ARF', 'Gene', (8, 14))	('hTERT', 'Gene', '7015', (120, 125))	('tumor', 'Disease', (54, 59))
540538	24931169	Moreover, ICN1 induced neither p21 nor BAX mRNA in EPC2-T cells expressing p53R175H (Supplementary Figure S6c).	('BAX', 'Gene', (39, 42))	('BAX', 'Gene', '581', (39, 42))	('ICN', 'Chemical', '-', (10, 13))	('p53R175H', 'Var', (75, 83))	('EPC2', 'Gene', '26122', (51, 55))	('EPC2', 'Gene', (51, 55))
540539	24931169	Finally, p53R175H did not prevent ICN1-induced senescence in EPC2-hTERT and EPC2-T (Supplementary Figures S7 and S4).	('hTERT', 'Gene', '7015', (66, 71))	('p53R175H', 'Var', (9, 17))	('EPC2', 'Gene', (76, 80))	('ICN', 'Chemical', '-', (34, 37))	('hTERT', 'Gene', (66, 71))	('EPC2', 'Gene', '26122', (61, 65))	('EPC2', 'Gene', (61, 65))	('senescence', 'MPA', (47, 57))	('EPC2', 'Gene', '26122', (76, 80))
540540	24931169	Thus, p53 inactivation may be insufficient to negate ICN1-induced senescence; however, the above findings do not exclude the requirement of p14ARF at the onset of ICN1-induced senescence.	('ICN', 'Chemical', '-', (53, 56))	('insufficient', 'Disease', 'MESH:D000309', (30, 42))	('p14ARF', 'Gene', (140, 146))	('insufficient', 'Disease', (30, 42))	('inactivation', 'Var', (10, 22))	('ICN', 'Chemical', '-', (163, 166))	('p14ARF', 'Gene', '1029', (140, 146))
540556	24931169	In agreement, TGF-beta target genes PAI1 and JAG1 were found to be elevated in the presence of E7 siRNA (Figure 5b and g).	('TGF-beta', 'Gene', (14, 22))	('JAG1', 'Gene', (45, 49))	('elevated', 'PosReg', (67, 75))	('E7 siRNA', 'Var', (95, 103))	('PAI1', 'Gene', (36, 40))	('PAI1', 'Gene', '5054', (36, 40))	('TGF-beta', 'Gene', '7040', (14, 22))
540557	24931169	Moreover, E7 knockdown resulted in the activation of both TGF-beta and Notch reporter constructs in transfection assays (Figure 5h).	('TGF-beta', 'Gene', (58, 66))	('activation', 'PosReg', (39, 49))	('knockdown', 'Var', (13, 22))	('Notch reporter', 'Gene', (71, 85))	('TGF-beta', 'Gene', '7040', (58, 66))	('E7 knockdown', 'Var', (10, 22))
540565	24931169	Nevertheless, GSI or Notch1 knockdown reversed G0/G1 cell-cycle arrest to a partial extent (Figure 6e; and data not shown) as corroborated by the limited antagonistic effect upon Rb dephosphorylation and cell proliferation in the presence of TGF-beta (Figure 6b and d; Supplementary Figure S12b).	('G0/G1 cell-cycle arrest', 'CPA', (47, 70))	('Notch1', 'Gene', (21, 27))	('GSI', 'Gene', (14, 17))	('TGF-beta', 'Gene', '7040', (242, 250))	('GSI', 'Chemical', '-', (14, 17))	('TGF-beta', 'Gene', (242, 250))	('Rb', 'Chemical', 'MESH:D012413', (179, 181))	('rat', 'Species', '10116', (133, 136))	('cell proliferation', 'CPA', (204, 222))	('knockdown', 'Var', (28, 37))	('rat', 'Species', '10116', (216, 219))
540566	24931169	TGF-beta induced p16INK4A and p21 prior to full induction of ICN1Val1744 (Figure 6a) although Notch1 knockdown delayed Rb dephosphorylation (Supplementary Figure S12b).	('ICN', 'Chemical', '-', (61, 64))	('knockdown', 'Var', (101, 110))	('Rb', 'Chemical', 'MESH:D012413', (119, 121))	('Notch1', 'Gene', (94, 100))	('p16INK4A', 'Gene', (17, 25))	('p21', 'Var', (30, 33))	('delayed', 'NegReg', (111, 118))	('TGF-beta', 'Gene', '7040', (0, 8))	('p16INK4A', 'Gene', '1029', (17, 25))	('TGF-beta', 'Gene', (0, 8))
540572	24931169	In nude mice, ICN1 greatly enhanced tumor growth by EN60 and TE11 cells (Figure 7b).	('enhanced', 'PosReg', (27, 35))	('ICN1', 'Var', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ICN', 'Chemical', '-', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('nude mice', 'Species', '10090', (3, 12))	('tumor', 'Disease', (36, 41))
540573	24931169	Interestingly, histopathological analysis of xenograft tumors revealed a significantly increased number of less differentiated, smaller and proliferative ESCC cells upon ICN1 expression (Figure 7c and Supplementary Fig.	('increased', 'PosReg', (87, 96))	('xenograft tumors', 'Disease', 'MESH:D009369', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SCC', 'Gene', (155, 158))	('ICN1 expression', 'Var', (170, 185))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('less differentiated', 'CPA', (107, 126))	('xenograft tumors', 'Disease', (45, 61))	('SCC', 'Gene', '6317', (155, 158))	('rat', 'Species', '10116', (147, 150))	('ICN', 'Chemical', '-', (170, 173))
540575	24931169	Notch1 has been implicated in replicative senescence in endothelial cells; however, this is the first study demonstrating in epithelial cells that Notch1 activates cellular senescence defined by cell-cycle arrest, morphological changes, SABG induction and molecular changes including Rb dephosphorylation.	('dephosphorylation', 'MPA', (287, 304))	('Rb', 'Chemical', 'MESH:D012413', (284, 286))	('rat', 'Species', '10116', (115, 118))	('cellular senescence', 'CPA', (164, 183))	('cell-cycle arrest', 'CPA', (195, 212))	('activates', 'PosReg', (154, 163))	('SABG', 'Chemical', '-', (237, 241))	('Notch1', 'Var', (147, 153))	('SABG', 'Gene', (237, 241))
540584	24931169	Unlike squamous-cell differentiation, our data suggest that Notch1 may induce senescence independent of Notch3 (Supplementary Figures S14).	('senescence', 'MPA', (78, 88))	('Notch3', 'Gene', '4854', (104, 110))	('Notch1', 'Var', (60, 66))	('Notch3', 'Gene', (104, 110))	('induce', 'Reg', (71, 77))
540586	24931169	Cell-cycle arrest can be mediated by p16INK4A and p21.	('p16INK4A', 'Gene', '1029', (37, 45))	('p21', 'Var', (50, 53))	('p16INK4A', 'Gene', (37, 45))	('Cell-cycle arrest', 'CPA', (0, 17))
540597	24931169	Besides loss-of-function Notch1 mutations, tumor suppressor activities of Notch have been suggested by Notch downregulation via p53 dysfunction and EGFR overexpression.	('p53', 'Protein', (128, 131))	('overexpression', 'PosReg', (153, 167))	('Notch', 'MPA', (103, 108))	('downregulation', 'NegReg', (109, 123))	('Notch1', 'Gene', (25, 31))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('dysfunction', 'Var', (132, 143))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('loss-of-function', 'NegReg', (8, 24))	('tumor', 'Disease', (43, 48))
540606	24931169	Thus, a pre-existing dysfunctional p16INK4A/Rb-mediated cell-cycle regulatory machinery may nullify Notch-mediated senescence in transformed cells.	('Rb', 'Chemical', 'MESH:D012413', (44, 46))	('dysfunctional', 'Var', (21, 34))	('p16INK4A', 'Gene', (35, 43))	('nullify', 'NegReg', (92, 99))	('Notch-mediated senescence', 'MPA', (100, 125))	('p16INK4A', 'Gene', '1029', (35, 43))
540607	24931169	Although our data show an accelerated growth and altered differentiation in tumors expressing ICN1 (Figure 7), ICN1 suppressed tumor growth by oral SCC cell lines carrying loss-of-function Notch1 mutations  where ICN1 induced SABG, but not morphological features of senescent cells in vitro.	('altered', 'Reg', (49, 56))	('rat', 'Species', '10116', (32, 35))	('tumor', 'Disease', (76, 81))	('SABG', 'Chemical', '-', (226, 230))	('loss-of-function', 'NegReg', (172, 188))	('SCC', 'Gene', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('suppressed', 'NegReg', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('mutations', 'Var', (196, 205))	('Notch1', 'Gene', (189, 195))	('tumor', 'Disease', (127, 132))	('accelerated', 'PosReg', (26, 37))	('ICN', 'Chemical', '-', (213, 216))	('growth', 'MPA', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('differentiation', 'MPA', (57, 72))	('ICN', 'Chemical', '-', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('SCC', 'Gene', '6317', (148, 151))	('ICN', 'Chemical', '-', (111, 114))
540622	24931169	Cells were incubated in the presence or absence of 1 microg/ml DOX to induce ICN1 in cells expressing ICN1TetOn for 48 hours before cell lysis.	('ICN', 'Chemical', '-', (77, 80))	('Tet', 'Chemical', 'MESH:C010349', (106, 109))	('ICN', 'Chemical', '-', (102, 105))	('ICN1', 'Gene', (77, 81))	('DOX', 'Chemical', 'MESH:D004318', (63, 66))	('ICN1TetOn', 'Var', (102, 111))
540627	24931169	Real-time RT-PCR was done with SYBR  Green and TaqMan  Gene Expression Assays (Applied Biosystems) for NOTCH1 (Hs01062014_m1), NOTCH3 (Hs00166432_m1), IVL (Hs00846307_s1), CK13 (Hs00999762_m1), CSL (Hs01068138_m1), JAG1 (Hs00164982_m1), HES5 (Hs01387463_g1), HES1(Hs00172878_m1), HEY1 (Hs00232618_m1), HEY2 (Hs00232622_m1), CDKN2A/p16INK4a (Hs99999189_m1), CDKN2B/p15INK4b (Hs00394703_m1), CDKN1A/p21 (Hs00355782_m1), CDKN1B/p27 (Hs00153277_m1), CDKN1C/p57 (Hs00175938_m1), PAI-1 (Hs01126606_m1) using the StepOnePlus  Real-Time PCR System (Applied Biosystems).	('CDKN1B', 'Gene', (418, 424))	('HES5', 'Gene', (237, 241))	('CDKN2A', 'Gene', '1029', (324, 330))	('p15INK4b', 'Gene', '1030', (364, 372))	('CDKN1C', 'Gene', '1028', (446, 452))	('CK13', 'Gene', (172, 176))	('Hs00355782_m1', 'Var', (402, 415))	('CDKN2B', 'Gene', (357, 363))	('Hs01126606_m1', 'Var', (481, 494))	('p15INK4b', 'Gene', (364, 372))	('CK13', 'Gene', '3860', (172, 176))	('CSL', 'Gene', '3516', (194, 197))	('HEY2', 'Gene', '23493', (302, 306))	('PAI-1', 'Gene', '5054', (474, 479))	('p16INK4a', 'Gene', (331, 339))	('PAI-1', 'Gene', (474, 479))	('CSL', 'Gene', (194, 197))	('p57', 'Gene', (453, 456))	('CDKN1B', 'Gene', '1027', (418, 424))	('HES5', 'Gene', '388585', (237, 241))	('CDKN1C', 'Gene', (446, 452))	('CDKN2B', 'Gene', '1030', (357, 363))	('HES1', 'Gene', (259, 263))	('CDKN1A', 'Gene', (390, 396))	('p16INK4a', 'Gene', '1029', (331, 339))	('p27', 'Gene', '3429', (425, 428))	('p27', 'Gene', (425, 428))	('CDKN1A', 'Gene', '1026', (390, 396))	('HEY1', 'Gene', (280, 284))	('HEY1', 'Gene', '23462', (280, 284))	('HEY2', 'Gene', (302, 306))	('CDKN2A', 'Gene', (324, 330))	('Hs00153277_m1', 'Var', (430, 443))	('HES1', 'Gene', '3280', (259, 263))	('p57', 'Gene', '1028', (453, 456))	('Hs00394703_m1', 'Var', (374, 387))	('Hs00175938_m1', 'Var', (458, 471))
540785	21225343	After four weeks of treatment with proton pump inhibitors, patients underwent endoscopy of the upper gastrointestinal tract with the detailed examination of columnar mucosa in esophagus using optical magnification up to 115 times (Olympus GIF Q160Z).	('Q160Z', 'SUBSTITUTION', 'None', (243, 248))	('Q160Z', 'Var', (243, 248))	('upper gastrointestinal tract', 'Disease', (95, 123))	('patients', 'Species', '9606', (59, 67))	('upper gastrointestinal tract', 'Disease', 'MESH:D004067', (95, 123))	('men', 'Species', '9606', (25, 28))
540869	33889297	The assay detects single nucleotide variants (SNV), indels, focal copy number alterations (CNA), TERT promoter region, as well as tumor mutation burden (TMB) and microsatellite instability (MSI) status.	('tumor', 'MPA', (130, 135))	('microsatellite instability', 'MPA', (162, 188))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('TERT', 'Gene', (97, 101))	('indels', 'Var', (52, 58))	('TMB', 'Chemical', '-', (153, 156))	('TERT', 'Gene', '7015', (97, 101))	('single nucleotide variants', 'Var', (18, 44))
540870	33889297	Additionally, the assay incorporates whole transcriptome sequencing of the tumor sample that allows for the detection of gene fusions and select special transcripts, including AR-V7, EGFR vIII, EGFRvIV, and MET exon 14 skipping events.	('gene', 'Protein', (121, 125))	('vIII', 'Gene', (188, 192))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('AR-V7', 'Gene', (176, 181))	('skipping events', 'Var', (219, 234))	('MET', 'Gene', '79811', (207, 210))	('AR', 'Chemical', 'MESH:D001128', (176, 178))	('EGFR', 'Gene', '1956', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('EGFR', 'Gene', (194, 198))	('vIII', 'Gene', '1351', (188, 192))	('MET', 'Gene', (207, 210))
540877	33889297	We estimate microsatellite instability by scanning the tumor-specific indels for mono-, di-, or tri-nucleotide repeats.	('mono-, di-, or tri-nucleotide', 'Chemical', '-', (81, 110))	('di-', 'Var', (88, 91))	('mono-', 'Var', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('microsatellite', 'MPA', (12, 26))	('tri-nucleotide repeats', 'Var', (96, 118))
540879	33889297	Tumor types with the highest frequency of microsatellite instability were endometrial (9.4%), gynecologic (7.1%), stomach (6.1%), colorectal (4.4%), prostate (3.5%), ovarian (2.5%), and sarcomas (1.9%).	('prostate', 'Disease', (149, 157))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('gynecologic', 'Disease', (94, 105))	('sarcoma', 'Disease', 'MESH:D012509', (186, 193))	('sarcomas', 'Disease', 'MESH:D012509', (186, 194))	('stomach', 'Disease', (114, 121))	('sarcoma', 'Disease', (186, 193))	('colorectal', 'Disease', (130, 140))	('endometrial', 'Disease', (74, 85))	('ovarian', 'Disease', (166, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (186, 193))	('sarcomas', 'Disease', (186, 194))	('microsatellite', 'Var', (42, 56))
540884	33889297	Tumors with highest number of actionable mutations included skin (4.9 +- 2.2), endometrial (4.5 +- 3.9), and colorectal (4.1 +- 3.5).	('endometrial', 'Disease', (79, 90))	('mutations', 'Var', (41, 50))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('skin', 'Disease', (60, 64))	('Tumors', 'Disease', (0, 6))	('colorectal', 'Disease', (109, 119))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
540885	33889297	For example, approximately 45% of driver events in esophageal cancer included focal amplifications in cell cycle genes such as CCND1/2/3 and CDK4/6/9, in addition to amplifications in ERBB2, KRAS, MYC.	('ERBB2', 'Gene', (184, 189))	('MYC', 'Gene', '4609', (197, 200))	('KRAS', 'Gene', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('CCND1/2/3', 'Gene', '595;894;896', (127, 136))	('esophageal cancer', 'Disease', (51, 68))	('CDK4/6/9', 'Gene', '1019;1021;1025', (141, 149))	('KRAS', 'Gene', '3845', (191, 195))	('MYC', 'Gene', (197, 200))	('amplifications', 'Var', (166, 180))	('cell cycle genes', 'Gene', (102, 118))	('CDK4/6/9', 'Gene', (141, 149))	('ERBB2', 'Gene', '2064', (184, 189))	('CCND1/2/3', 'Gene', (127, 136))
540887	33889297	Alternative transcripts were recurrently identified in EGFR (i.e., vIII, vIVb) within CNS tumors in AR (e.g., v7) within prostate tumors, and in MET (e.g., exon 14 skipping) within breast and lung (data not shown) tumors.	('CNS tumors', 'Disease', (86, 96))	('prostate tumors', 'Disease', 'MESH:D011471', (121, 136))	('MET', 'Var', (145, 148))	('EGFR', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('prostate tumors', 'Disease', (121, 136))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CNS tumors', 'Disease', 'MESH:D016543', (86, 96))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
540888	33889297	Finally, point mutations in BRAF/NRAS/PTEN/TP53 are key driver events in Thyroid cancer, and were identified in approximately 80% of thyroid tumors in this study.	('PTEN', 'Gene', '5728', (38, 42))	('thyroid tumors', 'Disease', (133, 147))	('BRAF', 'Gene', '673', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('NRAS', 'Gene', (33, 37))	('TP53', 'Gene', '7157', (43, 47))	('Thyroid cancer', 'Disease', (73, 87))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('NRAS', 'Gene', '4893', (33, 37))	('identified', 'Reg', (98, 108))	('thyroid tumors', 'Disease', 'MESH:D013964', (133, 147))	('BRAF', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TP53', 'Gene', (43, 47))	('point mutations', 'Var', (9, 24))	('PTEN', 'Gene', (38, 42))	('Thyroid cancer', 'Phenotype', 'HP:0002890', (73, 87))
540889	33889297	In fact, 80% of KRAS alterations in esophageal tumors were amplifications, which correlated with the TCGA dataset.	('esophageal tumors', 'Disease', 'MESH:D004938', (36, 53))	('esophageal tumors', 'Phenotype', 'HP:0100751', (36, 53))	('esophageal tumors', 'Disease', (36, 53))	('KRAS', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('alterations', 'Var', (21, 32))
540890	33889297	In addition, GEM ExTra identified KRAS alterations in approximately 77% of pancreatic tumors which generally correlates with previous estimates in this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (75, 92))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic tumors', 'Disease', 'MESH:D010190', (75, 92))	('alterations', 'Var', (39, 50))	('pancreatic tumors', 'Disease', (75, 92))	('KRAS', 'Gene', (34, 38))
540891	33889297	Pancreatic tumors with KRAS actionable alterations were mainly driven by G12 codon alterations.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('KRAS', 'Gene', (23, 27))	('alterations', 'Var', (39, 50))	('Pancreatic tumors', 'Disease', (0, 17))	('Pancreatic tumors', 'Disease', 'MESH:D010190', (0, 17))	('Pancreatic tumors', 'Phenotype', 'HP:0002894', (0, 17))	('G12 codon alterations', 'Var', (73, 94))
540892	33889297	Of the 65 KRAS-mutant tumors 57 (87.6%) harbored a G12A/C/D/R/S/V mutation.	('harbored', 'Reg', (40, 48))	('G12A', 'SUBSTITUTION', 'None', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('G12A', 'Var', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('KRAS-mutant', 'Var', (10, 21))
540893	33889297	Although the tumor samples received for sequencing encompass a wide spectrum of pre-, and post-treatment primary and metastatic tumors with complex histopathology, GEM ExTra assay findings generally correlated with previously reported driver gene frequencies including but not limited to CDKN2A alterations in melanoma, EGFR in lung and CNS tumors, PIK3CA hotspot in breast and endometrial tumors, and PTEN loss of function alterations in endometrial tumors, suggesting the clinical utility of the GEM ExTra assay in the detection and reporting of clinically relevant somatic alterations in a wide spectrum of sample types.	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('endometrial tumors', 'Disease', 'MESH:D016889', (378, 396))	('tumor', 'Phenotype', 'HP:0002664', (451, 456))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (390, 395))	('tumors', 'Phenotype', 'HP:0002664', (451, 457))	('endometrial tumors', 'Disease', (378, 396))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('endometrial tumors', 'Disease', 'MESH:D016889', (439, 457))	('CDKN2A', 'Gene', (288, 294))	('PIK3CA', 'Gene', '5290', (349, 355))	('alterations', 'Var', (424, 435))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('endometrial tumors', 'Disease', (439, 457))	('loss of function', 'NegReg', (407, 423))	('CDKN2A', 'Gene', '1029', (288, 294))	('alterations', 'Var', (295, 306))	('PIK3CA', 'Gene', (349, 355))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (390, 396))
540895	33889297	As expected, lung tumors with driver fusions harbored mostly EML4/ALK fusions, sarcomas were driven mostly by EWSR1-related and PAX3/FOXO1 fusions, while hematologic malignancies with a spectrum of BCR/ABL1, KMT2A-related, and IGH/MYC fusions.	('FOXO1', 'Gene', '2308', (133, 138))	('sarcomas', 'Phenotype', 'HP:0100242', (79, 87))	('EWSR1', 'Gene', (110, 115))	('sarcomas', 'Disease', (79, 87))	('fusions', 'Var', (70, 77))	('FOXO1', 'Gene', (133, 138))	('EML4', 'Gene', (61, 65))	('KMT2A', 'Gene', (208, 213))	('ALK', 'Gene', '238', (66, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('EML4', 'Gene', '27436', (61, 65))	('fusions', 'Var', (37, 44))	('ALK', 'Gene', (66, 69))	('IGH', 'Gene', (227, 230))	('fusions', 'Var', (139, 146))	('lung tumors', 'Phenotype', 'HP:0100526', (13, 24))	('EWSR1', 'Gene', '2130', (110, 115))	('ABL1', 'Gene', (202, 206))	('PAX3', 'Gene', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('lung tumors', 'Disease', (13, 24))	('KMT2A', 'Gene', '4297', (208, 213))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('ABL1', 'Gene', '25', (202, 206))	('IGH', 'Gene', '3492', (227, 230))	('PAX3', 'Gene', '5077', (128, 132))
540896	33889297	We also identified recurrent KIAA1549/BRAF fusions in Pilomyxoid astrocytoma tumors which is an emerging diagnostic and prognostic marker in pediatric low-grade gliomas that predicts positive response to certain MEK inhibitors.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('astrocytoma tumors', 'Disease', 'MESH:D001254', (65, 83))	('MEK', 'Gene', (212, 215))	('gliomas', 'Phenotype', 'HP:0009733', (161, 168))	('MEK', 'Gene', '5609', (212, 215))	('fusions', 'Var', (43, 50))	('astrocytoma', 'Phenotype', 'HP:0009592', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('gliomas', 'Disease', (161, 168))	('KIAA1549', 'Gene', '57670', (29, 37))	('astrocytoma tumors', 'Disease', (65, 83))	('gliomas', 'Disease', 'MESH:D005910', (161, 168))	('KIAA1549', 'Gene', (29, 37))
540897	33889297	Finally, several lung and breast cancer cases have been identified harboring MET exon 14 skipping detected by GEM ExTra tumor RNA sequencing, suggesting FDA-approved therapeutic options such as MET-inhibitors in these tumor types as recommended by NCCN (data not shown).	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('MET exon 14 skipping', 'Var', (77, 97))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('lung', 'Disease', (17, 21))
540900	33889297	The test was utilized in over 1400 patient samples during a period of April 2018 and December 2019 across cancer centers to detect multiple actionable alterations in a variety of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('2019 across cancer', 'Disease', 'MESH:C000657245', (94, 112))	('2019 across cancer', 'Disease', (94, 112))	('alterations', 'Var', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
540901	33889297	22Rv1 cell line (Sigma Aldrich) - well established prostate cell line that expresses high levels of the ARv7 variant, which is known to confer resistance to AR-targeted therapies.	('22Rv1', 'CellLine', 'CVCL:1045', (0, 5))	('variant', 'Var', (109, 116))	('ARv7', 'Gene', (104, 108))
540904	33889297	EGFR vIII mutation is seen in glioblastoma multifoma, breast cancer, and head and neck squamous cell carcinoma, and is relatively resistant to treatment with conventional anti-EGFR treatments.	('breast cancer', 'Disease', (54, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('glioblastoma multifoma', 'Disease', (30, 52))	('EGFR', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('mutation', 'Var', (10, 18))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (73, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('seen', 'Reg', (22, 26))	('glioblastoma multifoma', 'Disease', 'MESH:D005909', (30, 52))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (73, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
540905	33889297	MET exon 14 skipping events are seen in lung cancer and are known to respond to MET/ALK inhibitors.	('skipping events', 'Var', (12, 27))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('MET exon 14', 'Gene', (0, 11))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('lung cancer', 'Disease', (40, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))
540914	33889297	Each of these variant callers produces a VCF file which can then be inserted into the ashionMarkers01 variant database.	('VCF', 'Gene', (41, 44))	('variant', 'Var', (14, 21))	('VCF', 'Gene', '1714', (41, 44))
540943	33353561	We found combined administration of AFCNC with cisplatin or radiation therapy significantly inhibited tumor growth rates in the human ESCC mice xenograft model compared with cisplatin or radiation treatment alone.	('inhibited', 'NegReg', (92, 101))	('AFCNC', 'Var', (36, 41))	('AFCNC', 'Chemical', '-', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('human', 'Species', '9606', (128, 133))	('mice', 'Species', '10090', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (174, 183))
540988	33353561	Irradiation was administered to the mice xenografts zone at a dose of 5 Gy with SARRP small animal irradiator (Xstrahl Ltd. UK) at a dose rate of 4 Gy per minute using a range of custom collimators depending on the tumour geometry (220-kV, 13 mA X-ray, 10mm x 10 mm).	('tumour', 'Disease', 'MESH:D009369', (215, 221))	('tumour', 'Disease', (215, 221))	('mice', 'Species', '10090', (36, 40))	('220-kV', 'Var', (232, 238))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))
540991	33353561	Standard IHC analysis was performed with the primary antibodies against human Cox-2 (Proteintech 12375-1-AP), YAP (13584-1-AP) at a dilution in 1:100.	('13584-1-AP', 'Var', (115, 125))	('Cox-2', 'Gene', '4513', (78, 83))	('human', 'Species', '9606', (72, 77))	('Cox-2', 'Gene', (78, 83))
541011	33353561	We found Hippo signaling pathway is strongly affected by arsenic sulfide treatment, which has the highest enrichment score among all the signaling pathways analyzed in the gene microarray, and the p value of the differentially expressed genes affected by arsenic treatment in the Hippo pathway is 0.0047.	('arsenic', 'Var', (57, 64))	('arsenic', 'Chemical', 'MESH:D001151', (255, 262))	('Hippo signaling pathway', 'Pathway', (9, 32))	('affected', 'Reg', (45, 53))	('arsenic sulfide', 'Chemical', 'MESH:C045816', (57, 72))	('arsenic', 'Chemical', 'MESH:D001151', (57, 64))
541035	33353561	We observed combinatory administration of AFCNC with cisplatin or after radiation therapy significantly reduced the growth rates and tumor volumes of the KYSE-450 ESCC xenograft tumors in nude mice compared with cisplatin treatment or radiation alone, without observable side effects (Fig.	('tumor', 'Disease', (178, 183))	('reduced', 'NegReg', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('KYSE-450', 'CellLine', 'CVCL:1353', (154, 162))	('nude mice', 'Species', '10090', (188, 197))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('tumor', 'Disease', (133, 138))	('AFCNC', 'Var', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('AFCNC', 'Chemical', '-', (42, 47))	('growth rates', 'CPA', (116, 128))
541040	33353561	Collectively, these findings suggested combined administration of AFCNC sensitized ESCC cancer cells to radiation therapy and cisplatin based chemotherapy in the mice xenograft model.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('sensitized', 'Reg', (72, 82))	('mice', 'Species', '10090', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ESCC', 'Disease', (83, 87))	('AFCNC', 'Var', (66, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('AFCNC', 'Chemical', '-', (66, 71))
541059	33353561	We found AFCNC is a more potent inducer of ROS compared with unconjugated arsenic or ferrosoferric oxide nano particles in KYSE-450 cells with DCFH-DA ROS detection assay.	('DCFH-DA', 'Chemical', 'MESH:C029569', (143, 150))	('AFCNC', 'Chemical', '-', (9, 14))	('ROS', 'Chemical', 'MESH:D017382', (151, 154))	('KYSE-450', 'CellLine', 'CVCL:1353', (123, 131))	('inducer', 'PosReg', (32, 39))	('ROS', 'Disease', (43, 46))	('ferrosoferric oxide', 'Chemical', 'MESH:D052203', (85, 104))	('ROS', 'Chemical', 'MESH:D017382', (43, 46))	('AFCNC', 'Var', (9, 14))	('arsenic', 'Chemical', 'MESH:D001151', (74, 81))
541082	31270960	High linc00152 expression levels are associated with chemoresistance as well as poor prognosis and shorter survival.	('High', 'Var', (0, 4))	('chemoresistance', 'CPA', (53, 68))	('linc00152', 'Gene', (5, 14))	('expression levels', 'MPA', (15, 32))	('associated', 'Reg', (37, 47))	('linc00152', 'Gene', '112597', (5, 14))
541103	31270960	Their qRT-PCR and transwell assay results indicated that the knockdown of linc00152 prevents PDAC cell proliferation and invasion, thereby verifying the oncogenic property of linc00152.	('linc00152', 'Gene', '112597', (74, 83))	('prevents', 'NegReg', (84, 92))	('linc00152', 'Gene', '112597', (175, 184))	('knockdown', 'Var', (61, 70))	('linc00152', 'Gene', (74, 83))	('invasion', 'CPA', (121, 129))	('PDAC', 'Disease', (93, 97))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('linc00152', 'Gene', (175, 184))
541113	31270960	Specifically, Zhang et al 41 determined the knockdown of linc00152 can inhibit the cell cycle (especially the G1 phase) to delay cell proliferation.	('cell proliferation', 'CPA', (129, 147))	('linc00152', 'Gene', '112597', (57, 66))	('inhibit', 'NegReg', (71, 78))	('delay', 'NegReg', (123, 128))	('linc00152', 'Gene', (57, 66))	('knockdown', 'Var', (44, 53))
541126	31270960	Additionally, downregulated linc00152 expression decreases cell proliferation and shortens the S phase, possibly because of the epigenetic suppression of P16 and inhibition of miR-205.	('inhibition', 'NegReg', (162, 172))	('S phase', 'CPA', (95, 102))	('epigenetic', 'Var', (128, 138))	('miR-205', 'Gene', '406988', (176, 183))	('linc00152', 'Gene', (28, 37))	('P16', 'Gene', '1029', (154, 157))	('downregulated', 'NegReg', (14, 27))	('cell proliferation', 'CPA', (59, 77))	('decreases', 'NegReg', (49, 58))	('linc00152', 'Gene', '112597', (28, 37))	('shortens', 'NegReg', (82, 90))	('miR-205', 'Gene', (176, 183))	('P16', 'Gene', (154, 157))
541128	31270960	A cell viability assay indicated that inhibited linc00152 expression can disrupt cell proliferation.	('cell proliferation', 'CPA', (81, 99))	('inhibited', 'Var', (38, 47))	('linc00152', 'Gene', (48, 57))	('disrupt', 'NegReg', (73, 80))	('expression', 'MPA', (58, 68))	('linc00152', 'Gene', '112597', (48, 57))
541136	31270960	When we investigated the relationship between linc00152 and gastric carcinogenesis, we observed that linc00152 can specifically recognize the EGFR-binding site and activate the PI3K/AKT signaling pathway to promote the proliferation of gastric cancer cells.31 Moreover, PI3K signals help regulate many cellular functions such as proliferation, differentiation, apoptosis, and glucose transport.	('EGFR', 'Gene', '1956', (142, 146))	('linc00152', 'Gene', (101, 110))	('gastric carcinogenesis', 'Disease', (60, 82))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (60, 82))	('gastric cancer', 'Disease', (236, 250))	('differentiation', 'CPA', (344, 359))	('cellular functions', 'CPA', (302, 320))	('AKT', 'Gene', '207', (182, 185))	('PI3K', 'Var', (270, 274))	('apoptosis', 'CPA', (361, 370))	('glucose', 'Chemical', 'MESH:D005947', (376, 383))	('regulate', 'Reg', (288, 296))	('EGFR', 'Gene', (142, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('linc00152', 'Gene', '112597', (46, 55))	('proliferation', 'CPA', (329, 342))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('linc00152', 'Gene', (46, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('glucose transport', 'CPA', (376, 393))	('linc00152', 'Gene', '112597', (101, 110))	('AKT', 'Gene', (182, 185))
541137	31270960	The signaling pathway comprising type IA PI3K and its downstream molecular protein kinase B (PKB or AKT) was recently determined to be closely related to the development and progression of human tumors.32 This pathway regulates the proliferation and survival of tumor cells, and its abnormal activity can lead to the development of malignant cells, while also facilitating cellular migration, adhesion, tumor angiogenesis, and the degradation of the extracellular matrix (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (403, 408))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('lead to', 'Reg', (305, 312))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('regulates', 'Reg', (218, 227))	('AKT', 'Gene', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (403, 408))	('facilitating', 'PosReg', (360, 372))	('abnormal', 'Var', (283, 291))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (195, 201))	('cellular migration', 'CPA', (373, 391))	('human', 'Species', '9606', (189, 194))	('tumor', 'Disease', (262, 267))	('adhesion', 'CPA', (393, 401))	('AKT', 'Gene', '207', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('survival', 'CPA', (250, 258))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('development of malignant cells', 'CPA', (317, 347))	('PKB', 'Gene', '207', (93, 96))	('degradation of the extracellular matrix', 'MPA', (431, 470))	('proliferation', 'CPA', (232, 245))	('PKB', 'Gene', (93, 96))	('tumor', 'Disease', (403, 408))
541142	31270960	Therefore, inhibiting linc00152 activity may be a viable strategy for treating esophageal cancer.	('esophageal cancer', 'Disease', (79, 96))	('inhibiting', 'Var', (11, 21))	('linc00152', 'Gene', '112597', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('activity', 'MPA', (32, 40))	('linc00152', 'Gene', (22, 31))
541170	30736860	ChIRP-MS data indicate that FMR1-AS1 could be packaged into exosomes and released into tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('men', 'Species', '9606', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('FMR1-AS1', 'Var', (28, 36))
541174	30736860	Our results highlighted exosomal FMR1-AS1 in maintaining CSC dynamic interconversion state through the mechanism of activating TLR7-NFkappaB signaling, upregulating c-Myc level in recipient cells, which may be taken as an attractive target approach for advancing current precision cancer therapeutics in female patients.	('c-Myc', 'Gene', (165, 170))	('activating', 'PosReg', (116, 126))	('NFkappaB', 'Gene', '4790', (132, 140))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('maintaining CSC dynamic interconversion state', 'MPA', (45, 90))	('cancer', 'Disease', (281, 287))	('TLR7', 'Gene', (127, 131))	('FMR1-AS1', 'Var', (33, 41))	('patients', 'Species', '9606', (311, 319))	('TLR7', 'Gene', '51284', (127, 131))	('upregulating', 'PosReg', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('c-Myc', 'Gene', '4609', (165, 170))	('NFkappaB', 'Gene', (132, 140))	('exosomal FMR1-AS1', 'Var', (24, 41))
541196	30736860	The following antibodies were used in the followed western-blotting: anti-TLR7 (ab45371, Abcam), anti-hnRNPK (ab39975, Abcam), anti-PRDX1 (ab41906, Abcam), anti-PRDX2 (ab109367, Abcam), anti-ECM1 (ab126629, Abcam) and anti-beta-actin (ab8227, Abcam).	('beta-actin', 'Gene', (223, 233))	('TLR7', 'Gene', (74, 78))	('ECM1', 'Gene', '1893', (191, 195))	('hnRNPK', 'Gene', '3190', (102, 108))	('TLR7', 'Gene', '51284', (74, 78))	('beta-actin', 'Gene', '728378', (223, 233))	('PRDX1', 'Gene', (132, 137))	('ab109367', 'Var', (168, 176))	('ECM1', 'Gene', (191, 195))	('PRDX2', 'Gene', '7001', (161, 166))	('hnRNPK', 'Gene', (102, 108))	('PRDX1', 'Gene', '5052', (132, 137))	('ab126629', 'Var', (197, 205))	('PRDX2', 'Gene', (161, 166))	('ab41906', 'Var', (139, 146))
541204	30736860	We found that female patients from the discovery set (Suzhou: 206) in the high FMR1-AS1 subgroup had a lower OS than those in the low FMR1-AS1 subgroup (HR = 1.618; 95%CI = 1.117-2.345; P = 0.009).	('patients', 'Species', '9606', (21, 29))	('high FMR1-AS1', 'Var', (74, 87))	('lower', 'NegReg', (103, 108))
541205	30736860	And this result was confirmed in the validation set (Guangzhou: 188, HR = 1.768; 95%CI = 1.189-2.631; P = 0.0031) and the pooled set (HR = 1.679; 95%CI = 1.28-2.202; P = 0.0001), the high FMR1-AS1 group showed a lower OS of female ESCC patients (Fig.	('female ESCC patients', 'Disease', (224, 244))	('lower', 'NegReg', (212, 217))	('patients', 'Species', '9606', (236, 244))	('high FMR1-AS1', 'Var', (183, 196))
541219	30736860	Interestingly, more sXCI patients were found in the high FMR1-AS1 expression group than in the low FMR1-AS1 expression group (CR >= 3: 48.60% versus 25.14%; CR >= 10: 17.88% versus 5.03%) (Fig.	('sXCI', 'Disease', (20, 24))	('CR', 'Chemical', 'MESH:D002857', (126, 128))	('patients', 'Species', '9606', (25, 33))	('high FMR1-AS1 expression', 'Var', (52, 76))	('CR', 'Chemical', 'MESH:D002857', (157, 159))
541231	30736860	Further consistent with FMR1-AS1 ChIRP-MS data, a strong signal for TLR7 could be detected in the proteins that were pulled-down with the sense strand of FMR1-AS1 (Fig.	('FMR1-AS1', 'Var', (154, 162))	('proteins', 'Protein', (98, 106))	('TLR7', 'Gene', (68, 72))	('TLR7', 'Gene', '51284', (68, 72))
541233	30736860	The results showed a significant enrichment of FMR1-AS1 bound to TLR7, compared with the non-specific IgG control (Fig.	('TLR7', 'Gene', '51284', (65, 69))	('bound', 'Interaction', (56, 61))	('TLR7', 'Gene', (65, 69))	('FMR1-AS1', 'Var', (47, 55))	('men', 'Species', '9606', (39, 42))
541241	30736860	Interestingly, GSEA indicated that several classic stemness-associated signaling pathways, such as Wnt and Notch signaling, were significantly enriched in the cells with aberrantly expressed FMR1-AS1 (Additional file 9: Figure S4a and Additional file 4).	('aberrantly expressed', 'Var', (170, 190))	('enriched', 'PosReg', (143, 151))	('GSEA', 'Chemical', '-', (15, 19))	('FMR1-AS1', 'Gene', (191, 199))	('Wnt', 'Pathway', (99, 102))	('Notch signaling', 'Pathway', (107, 122))
541242	30736860	Moreover, GSEA results also indicated four putative NFkappaB associated gene signatures that were significantly enriched in both FMR1-AS1 overexpressed and knocked-down cells (Additional file 9: Figure S3d and Additional file 4).	('GSEA', 'Chemical', '-', (10, 14))	('FMR1-AS1', 'Gene', (129, 137))	('NFkappaB', 'Gene', (52, 60))	('NFkappaB', 'Gene', '4790', (52, 60))	('knocked-down', 'Var', (156, 168))
541243	30736860	The EMSA, luciferase reporter assays and western-blotting demonstrated that NFkappaB activity in ESCC cells was significantly increased by exogenous FMR1-AS1 and suppressed upon FMR1-AS1 silencing (Fig.	('NFkappaB', 'Gene', '4790', (76, 84))	('FMR1-AS1', 'Var', (149, 157))	('silencing', 'NegReg', (187, 196))	('NFkappaB', 'Gene', (76, 84))	('FMR1-AS1', 'Var', (178, 186))	('suppressed', 'NegReg', (162, 172))	('increased', 'PosReg', (126, 135))	('activity', 'MPA', (85, 93))
541244	30736860	4k-m), strongly suggested that FMR1-AS1 is involved in NFkappaB activation.	('FMR1-AS1', 'Var', (31, 39))	('NFkappaB', 'Gene', (55, 63))	('activation', 'PosReg', (64, 74))	('NFkappaB', 'Gene', '4790', (55, 63))
541246	30736860	Reasonably, c-Myc level was also increased by exogenous FMR1-AS1 and suppressed upon FMR1-AS1 silencing (Fig.	('FMR1-AS1', 'Var', (56, 64))	('silencing', 'Var', (94, 103))	('FMR1-AS1', 'Gene', (85, 93))	('c-Myc', 'Gene', '4609', (12, 17))	('increased', 'PosReg', (33, 42))	('c-Myc', 'Gene', (12, 17))	('suppressed', 'NegReg', (69, 79))
541256	30736860	We found that female patients from the discovery set (Suzhou: 146) in the high serum FMR1-AS1 subgroup had a lower OS than those in the low FMR1-AS1 subgroup (HR = 1.942; 95%CI = 1.246-3.027; P = 0.0029).	('patients', 'Species', '9606', (21, 29))	('lower', 'NegReg', (109, 114))	('FMR1-AS1', 'Gene', (85, 93))	('high serum', 'Var', (74, 84))
541257	30736860	And this result was confirmed in the validation set (Guangzhou: 107, HR = 1.784; 95%CI = 1.06-3.004; P = 0.0163) and the pooled set (HR = 1.761; 95%CI = 1.259-2.462; P = 0.0006), the high serum FMR1-AS1 group showed a lower OS of female ESCC patients (Fig.	('patients', 'Species', '9606', (242, 250))	('high serum', 'Var', (183, 193))	('female ESCC patients', 'Disease', (230, 250))	('lower', 'NegReg', (218, 223))	('FMR1-AS1', 'Gene', (194, 202))
541270	30736860	Collectively, these findings demonstrated that exosomes from the FMR1-AS1 overexpressed cells could endow the basal cells with stem-like phenotypes via intercellular transfer of FMR1-AS1, through activating NFkappaB-dependent pathways, thus contributing to ESCC intratumorally stemness dynamic transition.	('NFkappaB', 'Gene', '4790', (207, 215))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('contributing', 'Reg', (241, 253))	('activating', 'PosReg', (196, 206))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (267, 272))	('FMR1-AS1', 'Var', (178, 186))	('NFkappaB', 'Gene', (207, 215))
541272	30736860	Therefore, by stably silencing TLR7 in ESCC cells, we found that the inhibition of TLR7 could block the activation of NFkappaB-c-Myc signaling pathway and suppressed the xenografts growth phenotypes by FMR1-AS1 exosome incubation (Fig.	('c-Myc', 'Gene', (127, 132))	('block', 'NegReg', (94, 99))	('TLR7', 'Gene', (83, 87))	('xenografts growth phenotypes', 'CPA', (170, 198))	('NFkappaB', 'Gene', (118, 126))	('TLR7', 'Gene', (31, 35))	('suppressed', 'NegReg', (155, 165))	('c-Myc', 'Gene', '4609', (127, 132))	('inhibition', 'Var', (69, 79))	('NFkappaB', 'Gene', '4790', (118, 126))	('TLR7', 'Gene', '51284', (83, 87))	('silencing', 'Var', (21, 30))	('TLR7', 'Gene', '51284', (31, 35))
541273	30736860	Moreover, the silencing of MyD88 could also hinder the NFkappaB-c-Myc signaling cascades and phenotype transition through FMR1-AS1 exosome incubation in the ESCC cells (Fig.	('silencing', 'Var', (14, 23))	('hinder', 'NegReg', (44, 50))	('MyD88', 'Gene', (27, 32))	('MyD88', 'Gene', '4615', (27, 32))	('phenotype transition', 'CPA', (93, 113))	('NFkappaB', 'Gene', (55, 63))	('NFkappaB', 'Gene', '4790', (55, 63))	('c-Myc', 'Gene', '4609', (64, 69))	('c-Myc', 'Gene', (64, 69))
541274	30736860	6g), indicating exosomal FMR1-AS1 could induce ESCC tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('ESCC', 'Disease', (47, 51))	('FMR1-AS1', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('induce', 'PosReg', (40, 46))
541275	30736860	Together, these results suggest that exosomal FMR1-AS1 induces ESCC cancer stem-like phenotypes by activating TLR7-NFkappaB signaling pathway, thus promoting c-Myc expression level.	('NFkappaB', 'Gene', '4790', (115, 123))	('activating', 'PosReg', (99, 109))	('TLR7', 'Gene', '51284', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('c-Myc', 'Gene', (158, 163))	('promoting', 'PosReg', (148, 157))	('induces', 'PosReg', (55, 62))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('TLR7', 'Gene', (110, 114))	('exosomal', 'Var', (37, 45))	('cancer', 'Disease', (68, 74))	('FMR1-AS1', 'Gene', (46, 54))	('c-Myc', 'Gene', '4609', (158, 163))	('NFkappaB', 'Gene', (115, 123))
541291	30736860	Our study also showed that sXCI may contribute to the FMR1-AS1-dependent TLR7 responses in female ESCC cells.	('TLR7', 'Gene', '51284', (73, 77))	('FMR1-AS1-dependent', 'Var', (54, 72))	('TLR7', 'Gene', (73, 77))
541298	30736860	In sum, the sex-dependent FMR1-AS1 within exosomes secreted by ESCC cancer stem-like cells can bind to endosomal TLR7 and activate TLR7-NFkappaB signaling, thus promoting the expression of downstream CSC-linked gene, c-Myc, in the recipient non-CSCs (Fig.	('TLR7', 'Gene', (131, 135))	('expression', 'MPA', (175, 185))	('activate', 'PosReg', (122, 130))	('c-Myc', 'Gene', (217, 222))	('TLR7', 'Gene', (113, 117))	('c-Myc', 'Gene', '4609', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('NFkappaB', 'Gene', (136, 144))	('TLR7', 'Gene', '51284', (131, 135))	('TLR7', 'Gene', '51284', (113, 117))	('NFkappaB', 'Gene', '4790', (136, 144))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('bind', 'Interaction', (95, 99))	('cancer', 'Disease', (68, 74))	('FMR1-AS1', 'Var', (26, 34))	('promoting', 'PosReg', (161, 170))
541338	30717684	In addition, if cyanoacrylate extravasates and gets stuck to the endoscope, it will cause permanent damage to its working channel.	('extravasates', 'PosReg', (30, 42))	('cyanoacrylate', 'Var', (16, 29))	('damage', 'Reg', (100, 106))	('cyanoacrylate', 'Chemical', 'MESH:D003487', (16, 29))	('working channel', 'MPA', (114, 129))	('cause', 'Reg', (84, 89))
541348	30717684	Control of active bleeding was significantly higher in cyanoacrylate (98.25%) compared to sclerotherapy (83.93%) groups, P = 0.007 as shown in Table 3.	('cyanoacrylate', 'Var', (55, 68))	('Control', 'MPA', (0, 7))	('cyanoacrylate', 'Chemical', 'MESH:D003487', (55, 68))	('active bleeding', 'Disease', 'MESH:D006470', (11, 26))	('active bleeding', 'Disease', (11, 26))	('higher', 'PosReg', (45, 51))
541364	30717684	Regarding control of active bleeding, the current study showed that the initial hemostasis was significantly higher in cyanoacrylate versus sclerotherapy groups (P = 0.007).	('active bleeding', 'Disease', 'MESH:D006470', (21, 36))	('higher', 'PosReg', (109, 115))	('active bleeding', 'Disease', (21, 36))	('cyanoacrylate', 'Var', (119, 132))	('cyanoacrylate', 'Chemical', 'MESH:D003487', (119, 132))
541371	30717684	In this study, rebleeding rate was higher in sclerotherapy group (26.79%) than that in cyanoacrylate group (19.30%), but without significant difference (P = 0.344).	('cyanoacrylate', 'Chemical', 'MESH:D003487', (87, 100))	('sclerotherapy', 'Var', (45, 58))	('bleeding', 'Disease', 'MESH:D006470', (17, 25))	('bleeding', 'Disease', (17, 25))	('higher', 'PosReg', (35, 41))
541463	28819556	Previous studies have confirmed the association between high BMI and risk of several cancers including, esophageal adenocarcinoma, colon, rectal, kidney, thyroid, pancreas, gallbladder (women only), postmenopausal breast, ovarian, and endometrial cancers.	('endometrial cancers', 'Disease', 'MESH:D016889', (235, 254))	('postmenopausal breast', 'Disease', (199, 220))	('men', 'Species', '9606', (203, 206))	('endometrial cancers', 'Disease', (235, 254))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('colon', 'Disease', (131, 136))	('cancers', 'Disease', (247, 254))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('rectal', 'Disease', (138, 144))	('pancreas', 'Disease', (163, 171))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (104, 129))	('men', 'Species', '9606', (188, 191))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (104, 129))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('women', 'Species', '9606', (186, 191))	('thyroid', 'Disease', (154, 161))	('high BMI', 'Var', (56, 64))	('pancreas', 'Disease', 'MESH:D010190', (163, 171))	('gallbladder', 'Disease', (173, 184))	('esophageal adenocarcinoma', 'Disease', (104, 129))	('kidney', 'Disease', (146, 152))	('ovarian', 'Disease', (222, 229))
541520	28404900	This suggested that at the tumor level, high FDG uptake zones might exhibit residual metabolic activity and increased risk for LF.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('high FDG', 'Var', (40, 48))	('FDG', 'Chemical', 'MESH:D019788', (45, 48))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('metabolic', 'MPA', (85, 94))
541526	28404900	We hypothesized that high FDG uptake areas would be more prone to LF.	('prone', 'Reg', (57, 62))	('high', 'Var', (21, 25))	('FDG', 'Chemical', 'MESH:D019788', (26, 29))
541550	28404900	For the 19 patients who had LF in initial PET/CT high uptake regions, the average OF of the failure regions with Pre40%, Pre50%, Pre60%, and Pre70% were 78.6%, 66.3%, 54.5%, and 42.8%, respectively.	('Pre70%', 'Var', (141, 147))	('Pre40%', 'Var', (113, 119))	('Pre50%', 'Var', (121, 127))	('patients', 'Species', '9606', (11, 19))	('Pre60%', 'Var', (129, 135))
541610	28404900	On initial PET/CT images, the pre-subvolume was delineated using a relative threshold method (40%, 50%, 60%, and 70% of primary tumor SUVmax) as Pre40%, Pre50%, Pre60%, and Pre70%, respectively.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Pre60%', 'Var', (161, 167))	('Pre70%', 'Var', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('Pre40%', 'Var', (145, 151))	('Pre50%', 'Var', (153, 159))
541626	28642830	She received six cycles of Cisplatin, 5-Fluorouracil, and Herceptin and subsequently developed symptomatic anemia and hematuria.	('Cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('hematuria', 'Disease', 'MESH:D006417', (118, 127))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (38, 52))	('anemia', 'Phenotype', 'HP:0001903', (107, 113))	('Herceptin', 'Chemical', 'MESH:D000068878', (58, 67))	('hematuria', 'Phenotype', 'HP:0000790', (118, 127))	('5-Fluorouracil', 'Var', (38, 52))	('hematuria', 'Disease', (118, 127))	('anemia', 'Disease', 'MESH:D000740', (107, 113))	('anemia', 'Disease', (107, 113))
541685	26959879	Furthermore, flurbiprofen exerted a similar analgesic effect and brought a significantly less sufentanil consumption compared to group C. Taken together, flurbiprofen provided a short-term increase of postoperative naturally circulating DCs in ESCC patients.	('flurbiprofen', 'Chemical', 'MESH:D005480', (154, 166))	('naturally circulating DCs', 'MPA', (215, 240))	('patients', 'Species', '9606', (249, 257))	('flurbiprofen', 'Chemical', 'MESH:D005480', (13, 25))	('flurbiprofen', 'Var', (154, 166))	('postoperative', 'MPA', (201, 214))	('ESCC', 'Disease', (244, 248))	('sufentanil', 'Chemical', 'MESH:D017409', (94, 104))	('less', 'NegReg', (89, 93))	('increase', 'PosReg', (189, 197))	('sufentanil consumption', 'MPA', (94, 116))
541723	26959879	The tumor-specific COX ablation stimulated tumor-infiltrating CD11c+ MHC-II+ DCs displayed higher levels of co-stimulatory molecules, and over-production of PGE2 impaired accumulation of DCs within melanoma and suppress their activation, including IL-12-producing activity.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (43, 48))	('levels of co-stimulatory molecules', 'MPA', (98, 132))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('CD11c', 'Gene', (62, 67))	('CD11c', 'Gene', '3687', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('impaired accumulation of DCs within melanoma', 'Disease', (162, 206))	('activation', 'MPA', (226, 236))	('higher', 'PosReg', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('IL-12-producing activity', 'MPA', (248, 272))	('PGE2', 'Chemical', 'MESH:D015232', (157, 161))	('suppress', 'NegReg', (211, 219))	('PGE2', 'Gene', (157, 161))	('impaired accumulation of DCs within melanoma', 'Disease', 'MESH:D001929', (162, 206))	('over-production', 'Var', (138, 153))
541783	26142034	Variceal ligation results in ischemic necrosis of banded tissue and thrombosis of varices (24-48 hours).	('ischemic necrosis', 'Disease', (29, 46))	('ligation', 'Var', (9, 17))	('thrombosis', 'Disease', 'MESH:D013927', (68, 78))	('ischemic necrosis', 'Disease', 'MESH:D007511', (29, 46))	('ischemic necrosis', 'Phenotype', 'HP:0010885', (29, 46))	('thrombosis', 'Disease', (68, 78))
541796	26142034	On the other hand, stricture formation was higher after EIS compared to EVBL alone.	('EIS', 'Var', (56, 59))	('stricture formation', 'CPA', (19, 38))	('EVBL', 'Chemical', '-', (72, 76))	('higher', 'PosReg', (43, 49))
541913	26364162	We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus (BE).	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (107, 132))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (107, 132))	("Barrett's esophagus", 'Disease', (156, 175))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (156, 175))	('cancers', 'Disease', (71, 78))	('variants', 'Var', (45, 53))	('BE', 'Phenotype', 'HP:0100580', (177, 179))	('associated', 'Reg', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal adenocarcinoma', 'Disease', (107, 132))	('EA', 'Phenotype', 'HP:0011459', (134, 136))
541915	26364162	Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or BE.	('variants', 'Var', (13, 21))	('BE', 'Phenotype', 'HP:0100580', (110, 112))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('EA', 'Phenotype', 'HP:0011459', (104, 106))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
541919	26364162	Motivated by studies investigating pleiotropic associations of GWAS-identified variants, some of which work has identified additional risk-associated loci for colorectal, endometrial, and pancreatic cancers (see references in), we investigated in BEAGESS whether cancer-GWAS-identified variants could also influence the risk of EA and BE.	('EA', 'Phenotype', 'HP:0011459', (328, 330))	('cancer', 'Disease', (263, 269))	('EA', 'Phenotype', 'HP:0011459', (248, 250))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Disease', (199, 205))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (188, 206))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colorectal', 'Disease', (159, 169))	('pancreatic cancers', 'Disease', (188, 206))	('BE', 'Phenotype', 'HP:0100580', (335, 337))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('BE', 'Phenotype', 'HP:0100580', (247, 249))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('variants', 'Var', (286, 294))	('pancreatic cancers', 'Disease', 'MESH:D010190', (188, 206))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('colorectal', 'Disease', 'MESH:D015179', (159, 169))	('influence', 'Reg', (306, 315))
541921	26364162	We identified 407 single nucleotide polymorphisms (SNPs) that have previously been associated with one or more cancer sites at a P-value<5x10-8 in the National Human Genome Research Institute (NHGRI) GWAS catalog as of March 2014.	('single nucleotide polymorphisms', 'Var', (18, 49))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (83, 93))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('Human', 'Species', '9606', (160, 165))
541923	26364162	Studies investigating pleiotropic effects of GWAS-identified risk variants have revealed additional risk loci for endometrial, colorectal, and pancreatic cancer, but not for estrogen-receptor (ER)-negative breast cancer (ER-positive cancers were not investigated), prostate cancer, or non-Hodgkin lymphoma.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('endometrial', 'Disease', (114, 125))	('non-Hodgkin lymphoma', 'Disease', (285, 305))	('prostate cancer', 'Disease', 'MESH:D011471', (265, 280))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (285, 305))	('prostate cancer', 'Phenotype', 'HP:0012125', (265, 280))	('lymphoma', 'Phenotype', 'HP:0002665', (297, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('prostate cancer', 'Disease', (265, 280))	('estrogen-receptor', 'Gene', (174, 191))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (285, 305))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('variants', 'Var', (66, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('ER', 'Gene', '2099', (221, 223))	('breast cancer', 'Disease', (206, 219))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('colorectal', 'Disease', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('estrogen-receptor', 'Gene', '2099', (174, 191))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))	('colorectal', 'Disease', 'MESH:D015179', (127, 137))	('ER', 'Gene', '2099', (193, 195))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (289, 305))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
541937	25440267	Tri-modality treatment with pre-operative chemoradiotherapy has been shown to improve survival rates versus surgery alone and is accepted as a standard of care for esophageal cancer patients.Neoadjuvant chemoradiation treatment (NCRT) has been shown to decrease locoregional failure control (14.1% with NCRT vs. 33.5% with surgery alone at 45 months) as well as distant failure rates (31.5% vs. 47.8%, respectively), therefore improving outcomes.	('esophageal cancer', 'Disease', (164, 181))	('decrease', 'NegReg', (253, 261))	('NCRT', 'Var', (303, 307))	('improving', 'PosReg', (427, 436))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('distant failure rates', 'CPA', (362, 383))	('patients', 'Species', '9606', (182, 190))	('locoregional failure control', 'CPA', (262, 290))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
541988	25440267	Our findings were consistent with the literature as patients achieving a pCR had an improved OS versus those with residual or microscopic disease.	('pCR', 'Var', (73, 76))	('improved', 'PosReg', (84, 92))	('patients', 'Species', '9606', (52, 60))
542007	25440267	Although patients completing NCRT are typically presumed to have worse perioperative outcomes, a recent study demonstrated that patients who completed NCRT followed by esophagectomy were more likely to have a reduced length of stay compared with patients who only underwent surgery.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (246, 254))	('NCRT', 'Var', (151, 155))	('reduced', 'NegReg', (209, 216))	('esophagectomy', 'Disease', (168, 181))	('length of stay', 'MPA', (217, 231))	('patients', 'Species', '9606', (128, 136))
542178	26992210	Patients with 11-71 RLNs had better CSS (hazard ratio [HR] = 0.694, 95% confidence interval [CI]: 0.603-0.799, P < 0.001) and OS (HR = 0.724, 95% CI: 0.636-0.824, P < 0.001) than patients with 1-10 RLNs.	('CSS', 'Chemical', '-', (36, 39))	('RLNs', 'Var', (20, 24))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (179, 187))	('CSS', 'CPA', (36, 39))	('OS', 'Chemical', '-', (126, 128))	('better', 'PosReg', (29, 35))
542185	26992210	Additionally, studies have indicated that nCRT affects the mode of EC recurrence, the recurrence rate of mediastinal lymph nodes is significantly lower in patients who receive nCRT combined with surgery than in patients who receive surgery only.	('patients', 'Species', '9606', (211, 219))	('nCRT', 'Var', (176, 180))	('lower', 'NegReg', (146, 151))	('patients', 'Species', '9606', (155, 163))	('recurrence', 'CPA', (86, 96))
542213	26992210	In patients with N0, N1, N2, and N3 stage disease, a higher number of RLNs correlated with better CSS (P < 0.001 for N0 stage, P < 0.001 for N1 stage, P < 0.001 for N2 stage, and P = 0.037 for N3 stage) and OS (P < 0.001 for N0 stage, P = 0.001 for N1 stage, P < 0.001 for N2 stage, and P = 0.018 for N3 stage) (Figures 5-8).	('better', 'PosReg', (91, 97))	('N3 stage', 'Var', (33, 41))	('OS', 'Chemical', '-', (207, 209))	('patients', 'Species', '9606', (3, 11))	('CSS', 'Chemical', '-', (98, 101))	('CSS', 'CPA', (98, 101))
542218	26992210	A phase III randomized controlled trial revealed that the number of RLNs in EC was lower in nCRT-treated patients than in non-nCRT-treated counterparts (16.0 vs. 22.0, P = 0.001).	('patients', 'Species', '9606', (105, 113))	('nCRT-treated', 'Var', (92, 104))	('RLNs', 'Var', (68, 72))	('lower', 'NegReg', (83, 88))
542252	26989293	Clinical data indicated that plasma miRNA-216a/b were inversely correlated with lymph node metastasis and TNM stage.	('inversely', 'NegReg', (54, 63))	('TNM', 'Gene', '10178', (106, 109))	('lymph node metastasis', 'CPA', (80, 101))	('miRNA-216a/b', 'Var', (36, 48))	('TNM', 'Gene', (106, 109))	('miRNA-216a', 'Chemical', '-', (36, 46))	('correlated', 'Reg', (64, 74))
542254	26989293	Our study, for the first time, demonstrated that plasma miRNA-216a/b might serve as potential biomarkers for the diagnosis of ESCC and dysregulation of miRNA-216a/b might be involved in the progression of ESCC.	('involved', 'Reg', (174, 182))	('miRNA-216a', 'Chemical', '-', (56, 66))	('miRNA-216a/b', 'Var', (152, 164))	('ESCC', 'Disease', (126, 130))	('miRNA-216a', 'Chemical', '-', (152, 162))	('dysregulation', 'Var', (135, 148))	('ESCC', 'Disease', (205, 209))
542263	26989293	found that miRNAs could be clearly detectable in serum samples and that the dysregulation of miRNAs was correlated with the diagnosis and prognosis of diffuse large B-cell lymphoma patients, which initiated the investigations on the role of circulating miRNAs in the diagnosis of human diseases.	('miRNAs', 'Gene', (93, 99))	('correlated', 'Reg', (104, 114))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (165, 180))	('lymphoma', 'Disease', (172, 180))	('patients', 'Species', '9606', (181, 189))	('lymphoma', 'Disease', 'MESH:D008223', (172, 180))	('dysregulation', 'Var', (76, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (172, 180))	('human', 'Species', '9606', (280, 285))
542267	26989293	What is more, the diagnostic value of miRNA-216a/b was also demonstrated in several diseases including acute pancreatitis, pancreatic cancer (PCA), and HCC.	('miRNA-216a', 'Chemical', '-', (38, 48))	('PCA', 'Phenotype', 'HP:0002894', (142, 145))	('pancreatic cancer', 'Disease', (123, 140))	('pancreatitis', 'Phenotype', 'HP:0001733', (109, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('HCC', 'Phenotype', 'HP:0001402', (152, 155))	('pancreatitis', 'Disease', 'MESH:D010195', (109, 121))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (103, 121))	('pancreatitis', 'Disease', (109, 121))	('HCC', 'Disease', (152, 155))	('miRNA-216a/b', 'Var', (38, 50))
542268	26989293	Despite these findings, the role of miRNA-216a/b in ESCC has never been reported previously.	('miRNA-216a/b', 'Var', (36, 48))	('miRNA-216a', 'Chemical', '-', (36, 46))	('ESCC', 'Disease', (52, 56))
542269	26989293	The present study was designed to examine the expression of plasma miRNA-216a/b in ESCC patients and evaluate their diagnostic value, hoping to provide some valuable information in the early diagnosis of ESCC.	('ESCC', 'Disease', (204, 208))	('patients', 'Species', '9606', (88, 96))	('miRNA-216a', 'Chemical', '-', (67, 77))	('miRNA-216a/b', 'Var', (67, 79))	('ESCC', 'Disease', (83, 87))
542281	26989293	As shown in Figure 1, the expression level of miRNA-216a/b was significantly downregulated in ESCC patients compared with that of healthy controls (0.068 +- 0.052 versus 0.179 +- 0.098, P < 0.0001; 0.091 +- 0.087 versus 0.199 +- 0.161, P < 0.0001) (Figures 1(a) and 1(b)).	('downregulated', 'NegReg', (77, 90))	('miRNA-216a/b', 'Var', (46, 58))	('expression level', 'MPA', (26, 42))	('patients', 'Species', '9606', (99, 107))	('miRNA-216a', 'Chemical', '-', (46, 56))	('ESCC', 'Disease', (94, 98))
542290	26989293	ROC curve analysis was performed to evaluate the diagnostic value of plasma miRNA-216a/b for ESCC.	('plasma miRNA-216a/b', 'Var', (69, 88))	('ESCC', 'Disease', (93, 97))	('miRNA-216a', 'Chemical', '-', (76, 86))
542291	26989293	We found that plasma miRNA-216a/b could differentiate ESCC patients from healthy controls, with an AUC of 0.877 (95% CI: 0.818-0.922) for miRNA-216a and 0.756 (95% CI: 0.685-0.819) for miRNA-216b, respectively.	('miRNA-216', 'Gene', '406998', (138, 147))	('miRNA-216a', 'Chemical', '-', (21, 31))	('ESCC', 'Disease', (54, 58))	('miRNA-216', 'Gene', '406998', (185, 194))	('0.756', 'Var', (153, 158))	('miRNA-216a', 'Chemical', '-', (138, 148))	('miRNA-216', 'Gene', (185, 194))	('patients', 'Species', '9606', (59, 67))	('miRNA-216', 'Gene', (138, 147))	('miRNA-216', 'Gene', (21, 30))	('differentiate', 'Reg', (40, 53))	('miRNA-216', 'Gene', '406998', (21, 30))
542300	26989293	In fact, accumulating evidence demonstrated that circulating miRNAs could serve as potential diagnostic biomarkers for a wide range of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('miRNAs', 'Var', (61, 67))	('human', 'Species', '9606', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
542305	26989293	Decreased expression of miRNA-216a was found in NSCLC patients' specimens and by directly targeting eIF4B and ZEB1, miRNA-216a could inhibit NSCLC cell growth and metastasis.	('miRNA-216a', 'Chemical', '-', (24, 34))	('NSCLC', 'Disease', (48, 53))	('patients', 'Species', '9606', (54, 62))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('miRNA-216a', 'Gene', (24, 34))	('Decreased', 'NegReg', (0, 9))	('NSCLC', 'Disease', (141, 146))	('expression', 'MPA', (10, 20))	('inhibit', 'NegReg', (133, 140))	('eIF4B', 'Gene', '1975', (100, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('targeting', 'Reg', (90, 99))	('miRNA-216a', 'Chemical', '-', (116, 126))	('eIF4B', 'Gene', (100, 105))	('ZEB1', 'Gene', '6935', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('miRNA-216a', 'Var', (116, 126))	('ZEB1', 'Gene', (110, 114))
542308	26989293	miRNA-216a was significantly upregulated and contributed to early hepatocarcinogenesis through suppressing the gene expression of tumor suppressor in lung cancer-1 (TSLC1), which was in accordance with Xia et al.	('contributed', 'Reg', (45, 56))	('TSLC1', 'Gene', (165, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('suppressing', 'NegReg', (95, 106))	('miRNA-216a', 'Chemical', '-', (0, 10))	('upregulated', 'PosReg', (29, 40))	('tumor suppressor in lung cancer-1', 'Gene', (130, 163))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (66, 86))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor suppressor in lung cancer-1', 'Gene', '23705', (130, 163))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('hepatocarcinogenesis', 'Disease', (66, 86))	('miRNA-216a', 'Var', (0, 10))	('gene expression', 'MPA', (111, 126))	('TSLC1', 'Gene', '23705', (165, 170))
542310	26989293	Additionally, miRNA-216a/b might influence the therapeutic effect of different treatments, thus providing candidate therapeutic methods for different cancers.	('influence', 'Reg', (33, 42))	('miRNA-216a/b', 'Var', (14, 26))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('miRNA-216a', 'Chemical', '-', (14, 24))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('therapeutic effect', 'CPA', (47, 65))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
542311	26989293	For example, overexpression of miRNA-216a could induce resistance of sorafenib in HCC cells.	('resistance', 'MPA', (55, 65))	('sorafenib', 'Chemical', 'MESH:D000077157', (69, 78))	('induce', 'PosReg', (48, 54))	('miRNA-216a', 'Chemical', '-', (31, 41))	('sorafenib', 'Gene', (69, 78))	('overexpression', 'PosReg', (13, 27))	('HCC', 'Phenotype', 'HP:0001402', (82, 85))	('miRNA-216a', 'Var', (31, 41))
542314	26989293	Plasma miRNA-216a/b were found to be considerably upregulated in the model of acute pancreatitis and were more specific than amylase and lipase in the detection of acute pancreatitis, providing novel biomarkers for pancreatic injury.	('upregulated', 'PosReg', (50, 61))	('miRNA-216a/b', 'Var', (7, 19))	('miRNA-216a', 'Chemical', '-', (7, 17))	('pancreatitis', 'Phenotype', 'HP:0001733', (170, 182))	('pancreatitis', 'Phenotype', 'HP:0001733', (84, 96))	('pancreatitis', 'Disease', 'MESH:D010195', (84, 96))	('pancreatitis', 'Disease', 'MESH:D010195', (170, 182))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (78, 96))	('pancreatic injury', 'Disease', (215, 232))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (164, 182))	('pancreatitis', 'Disease', (170, 182))	('pancreatic injury', 'Disease', 'MESH:D010195', (215, 232))	('pancreatitis', 'Disease', (84, 96))
542319	26989293	ROC curve analysis showed that plasma miRNA-216a/b exhibited satisfactory diagnostic value for ESCC, with AUC of 0.877 (95% CI: 0.818-0.922) for miRNA-216a and 0.756 (95% CI: 0.685-0.819) for miRNA-216b, which were higher than conventional biomarkers such as SCC-Ag (AUC: 0.665) and CEA (AUC: 0.549) reported in other studies.	('miRNA-216', 'Gene', (145, 154))	('miRNA-216a', 'Chemical', '-', (38, 48))	('miRNA-216', 'Gene', '406998', (192, 201))	('miRNA-216a', 'Chemical', '-', (145, 155))	('ESCC', 'Disease', (95, 99))	('0.756', 'Var', (160, 165))	('miRNA-216', 'Gene', '406998', (145, 154))	('miRNA-216', 'Gene', (38, 47))	('miRNA-216', 'Gene', (192, 201))	('CEA', 'Gene', (283, 286))	('CEA', 'Gene', '1084', (283, 286))	('miRNA-216', 'Gene', '406998', (38, 47))
542321	26989293	Further analysis revealed that plasma miRNA-216a/b were inversely correlated with lymph node metastasis and TNM stage, indicating that miRNA-216a/b might be involved in the progression of ESCC.	('miRNA-216a', 'Chemical', '-', (38, 48))	('involved', 'Reg', (157, 165))	('ESCC', 'Disease', (188, 192))	('TNM', 'Gene', '10178', (108, 111))	('miRNA-216a/b', 'Var', (135, 147))	('miRNA-216a', 'Chemical', '-', (135, 145))	('lymph node metastasis', 'CPA', (82, 103))	('inversely', 'NegReg', (56, 65))	('TNM', 'Gene', (108, 111))
542322	26989293	Therefore, it seems important and valuable to investigate the exact mechanism of miRNA-216a/b in the development and progression of ESCC.	('ESCC', 'Disease', (132, 136))	('miRNA-216a/b', 'Var', (81, 93))	('miRNA-216a', 'Chemical', '-', (81, 91))
542327	26989293	In our study, the expression level of plasma miRNA-216a in postoperative samples was indeed upregulated compared with that of preoperative samples (0.118 +- 0.028 versus 0.101 +- 0.056), although it was insignificant (P = 0.2619).	('miRNA-216a', 'Var', (45, 55))	('upregulated', 'PosReg', (92, 103))	('miRNA-216a', 'Chemical', '-', (45, 55))	('expression level', 'MPA', (18, 34))
542328	26989293	If we expanded the sample size, miRNA-216a would probably exhibit significant upregulation.	('miRNA-216a', 'Var', (32, 42))	('upregulation', 'PosReg', (78, 90))	('miRNA-216a', 'Chemical', '-', (32, 42))
542334	26989293	In conclusion, our study demonstrated that plasma miRNA-216a/b might act as potential diagnostic biomarkers for ESCC.	('ESCC', 'Disease', (112, 116))	('miRNA-216a/b', 'Var', (50, 62))	('miRNA-216a', 'Chemical', '-', (50, 60))
542335	26989293	Dysregulation of miRNA-216a/b was correlated with the lymph node metastasis and TNM stage of ESCC patients, thus indicating that they might be involved in the progression of ESCC.	('TNM', 'Gene', (80, 83))	('miRNA-216a', 'Chemical', '-', (17, 27))	('Dysregulation', 'Var', (0, 13))	('lymph node metastasis', 'CPA', (54, 75))	('involved', 'Reg', (143, 151))	('ESCC', 'Disease', (174, 178))	('patients', 'Species', '9606', (98, 106))	('ESCC', 'Disease', (93, 97))	('TNM', 'Gene', '10178', (80, 83))	('correlated', 'Reg', (34, 44))	('miRNA-216a/b', 'Gene', (17, 29))
542336	26989293	In order to have a better understanding of the role of miRNA-216a/b in ESCC, further efforts are recommended to reveal the exact mechanism of miRNA-216a/b in the carcinogenesis of ESCC.	('miRNA-216a/b', 'Var', (142, 154))	('miRNA-216a', 'Chemical', '-', (55, 65))	('ESCC', 'Disease', (71, 75))	('miRNA-216a', 'Chemical', '-', (142, 152))	('ESCC', 'Disease', (180, 184))
542349	25452763	Changes at the genetic level causing modifications in cellular phenotype could explain some of the variability in response and toxicity to cisplatin-included chemotherapy.	('toxicity', 'Disease', 'MESH:D064420', (127, 135))	('toxicity', 'Disease', (127, 135))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('modifications', 'Reg', (37, 50))	('Changes', 'Var', (0, 7))	('cellular phenotype', 'MPA', (54, 72))
542350	25452763	In this review, we discuss associations between genetic variants in the germ line and in outcomes following cisplatin-based chemotherapy.	('associations', 'Interaction', (27, 39))	('genetic variants', 'Var', (48, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))
542355	25452763	Cisplatin distorts the structure of the DNA that generate intrastrand 1, 2:crosslinks binding proteins into shallow minor groove [high-mobility group (HMG) box proteins, repair proteins, transcription factors, histone H1] (Kartalou and Essigmann,; Wozniak and Blasiak,; Zdraveski et al.,).	('crosslinks', 'Var', (75, 85))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('distorts', 'Var', (10, 18))
542360	25452763	Studies have shown that disruption or suppression of expression of both REV3L, the gene encoding the catalytic subunit of Pol zeta, or REV1 modifies sensitivity to cisplatin (Lin et al.,; Doles et al.,).	('REV1', 'Gene', (135, 139))	('REV3L', 'Gene', (72, 77))	('disruption', 'Var', (24, 34))	('REV3L', 'Gene', '5980', (72, 77))	('modifies', 'Reg', (140, 148))	('sensitivity to cisplatin', 'MPA', (149, 173))	('suppression', 'NegReg', (38, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
542361	25452763	recently determined in patients with malignant mesothelioma that the mutant allele in REV1 rs3087403 and REV1 TGT haplotype associated with increased risk for leukopenia and neutropenia.	('REV1', 'Gene', (86, 90))	('rs3087403', 'Mutation', 'rs3087403', (91, 100))	('neutropenia', 'Disease', 'MESH:D009503', (174, 185))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (37, 59))	('leukopenia', 'Disease', (159, 169))	('rs3087403', 'Var', (91, 100))	('REV1', 'Gene', (105, 109))	('patients', 'Species', '9606', (23, 31))	('neutropenia', 'Phenotype', 'HP:0001875', (174, 185))	('leukopenia', 'Disease', 'MESH:D007970', (159, 169))	('malignant mesothelioma', 'Disease', (37, 59))	('associated', 'Reg', (124, 134))	('neutropenia', 'Disease', (174, 185))	('leukopenia', 'Phenotype', 'HP:0001882', (159, 169))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (37, 59))
542362	25452763	REV3L rs465646, rs462779, and REV3L CCGG haplotype associated with longer overall survival (Goricar et al.,).	('rs462779', 'Mutation', 'rs462779', (16, 24))	('REV3L', 'Gene', '5980', (30, 35))	('overall survival', 'MPA', (74, 90))	('rs462779', 'Var', (16, 24))	('REV3L', 'Gene', '5980', (0, 5))	('longer', 'PosReg', (67, 73))	('rs465646', 'Mutation', 'rs465646', (6, 14))	('rs465646', 'Var', (6, 14))	('REV3L', 'Gene', (30, 35))	('REV3L', 'Gene', (0, 5))
542364	25452763	Excision repair cross-complementary 1 (ERCC1) is a key protein involved in the process of NER and ERCC1-xeroderma pigmentosum (ERCC1-XPF) catalyzes incision on the incision 50 side to the site of DNA damage (Parker et al.,; Bessho,).	('ERCC1', 'Gene', (127, 132))	('ERCC1-xeroderma pigmentosum', 'Disease', (98, 125))	('XPF', 'Gene', (133, 136))	('ERCC1', 'Gene', '2067', (127, 132))	('ERCC1-xeroderma pigmentosum', 'Disease', 'MESH:D014983', (98, 125))	('ERCC1', 'Gene', (39, 44))	('incision', 'Var', (148, 156))	('ERCC1', 'Gene', '2067', (39, 44))	('ERCC1', 'Gene', '2067', (98, 103))	('ERCC1', 'Gene', (98, 103))	('XPF', 'Gene', '2072', (133, 136))
542366	25452763	Mutations destroying the enzymatic function of XPD protein are manifested clinically in combinations of three severe syndromes, including xeroderma pigmentosum, XP combined with Cockayne Syndrome and trichothiodystrophy (Lehmann,; Clarkson and Wood,).	('XPD', 'Gene', (47, 50))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (138, 159))	('xeroderma pigmentosum', 'Disease', (138, 159))	('XPD', 'Gene', '2068', (47, 50))	('trichothiodystrophy', 'Disease', 'MESH:D054463', (200, 219))	('Mutations', 'Var', (0, 9))	('Cockayne Syndrome', 'Disease', (178, 195))	('trichothiodystrophy', 'Disease', (200, 219))	('enzymatic function', 'MPA', (25, 43))
542370	25452763	Polymorphisms in ERCC1 include mainly rs3212986 and rs11615.	('rs11615', 'Mutation', 'rs11615', (52, 59))	('rs3212986', 'Mutation', 'rs3212986', (38, 47))	('ERCC1', 'Gene', (17, 22))	('ERCC1', 'Gene', '2067', (17, 22))	('rs3212986', 'Var', (38, 47))	('rs11615', 'Var', (52, 59))
542371	25452763	The polymorphism rs3212986 is located in the 3' untranslated region and therefore may affect mRNA stability resulting in a decreased expression levels (Chen et al.,).	('affect', 'Reg', (86, 92))	('decreased', 'NegReg', (123, 132))	('rs3212986', 'Mutation', 'rs3212986', (17, 26))	('expression levels', 'MPA', (133, 150))	('mRNA stability', 'MPA', (93, 107))	('rs3212986', 'Var', (17, 26))
542374	25452763	showed that in esophageal cancer, patients with A/A or A/C genotype had improved outcomes compared with patients carrying wild-type genotypes.	('A/A', 'Var', (48, 51))	('outcomes', 'MPA', (81, 89))	('improved', 'PosReg', (72, 80))	('esophageal cancer', 'Disease', (15, 32))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (15, 32))	('patients', 'Species', '9606', (104, 112))
542378	25452763	The polymorphism C T at codon 118 located on exon 4 of ERCC1 gene (rs11615) is expected to have the same effect.	('rs11615', 'Var', (67, 74))	('ERCC1', 'Gene', '2067', (55, 60))	('rs11615', 'Mutation', 'rs11615', (67, 74))	('ERCC1', 'Gene', (55, 60))
542379	25452763	This polymorphism is associated with clinical response to platinum-based chemotherapy in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('associated', 'Reg', (21, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('polymorphism', 'Var', (5, 17))	('NSCLC', 'Disease', (89, 94))	('platinum', 'Chemical', 'MESH:D010984', (58, 66))
542381	25452763	Nephrotoxicity has been related to the C allele in rs3212986 ERCC1 (Tzvetkov et al.,), T allele in rs11615 ERCC1 (Tzvetkov et al.,) and C/T genotype in rs3212986 ERCC1 (Khrunin et al.,), independent of cancer type.	('ERCC1', 'Gene', '2067', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Nephrotoxicity', 'Disease', 'MESH:D007674', (0, 14))	('cancer type', 'Disease', (202, 213))	('ERCC1', 'Gene', '2067', (107, 112))	('ERCC1', 'Gene', (107, 112))	('ERCC1', 'Gene', '2067', (162, 167))	('ERCC1', 'Gene', (162, 167))	('rs11615', 'Mutation', 'rs11615', (99, 106))	('rs3212986', 'Mutation', 'rs3212986', (51, 60))	('cancer type', 'Disease', 'MESH:D009369', (202, 213))	('rs3212986', 'Mutation', 'rs3212986', (152, 161))	('C/T', 'Var', (136, 139))	('ERCC1', 'Gene', (61, 66))	('rs3212986', 'Var', (51, 60))	('Nephrotoxicity', 'Disease', (0, 14))	('rs3212986', 'Var', (152, 161))
542383	25452763	The presence of a variation in ERCC2 gene (rs13181 and rs1799793) reduces repair capacity, and results in greater efficacy of cisplatin treatment due to increased DNA damage and an enhanced cytotoxic effect.	('rs1799793', 'Var', (55, 64))	('ERCC2', 'Gene', '2068', (31, 36))	('greater', 'PosReg', (106, 113))	('reduces', 'NegReg', (66, 73))	('DNA damage', 'MPA', (163, 173))	('increased', 'PosReg', (153, 162))	('enhanced', 'PosReg', (181, 189))	('ERCC2', 'Gene', (31, 36))	('repair', 'MPA', (74, 80))	('cytotoxic effect', 'CPA', (190, 206))	('rs13181', 'Var', (43, 50))	('rs1799793', 'Mutation', 'rs1799793', (55, 64))	('efficacy', 'MPA', (114, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('rs13181', 'Mutation', 'rs13181', (43, 50))
542384	25452763	rs1799793 generates a positive effect in overall survival and progression free survival (Gurubhagavatula et al.,; Bradbury et al.,; Biason et al.,).	('rs1799793', 'Mutation', 'rs1799793', (0, 9))	('Gurubhagavatula', 'Disease', 'None', (89, 104))	('progression free survival', 'CPA', (62, 87))	('rs1799793', 'Var', (0, 9))	('Gurubhagavatula', 'Disease', (89, 104))	('overall survival', 'CPA', (41, 57))
542385	25452763	found that G/G genotype is related to an increase in various types of toxicity (Erculj et al.,) while nephrotoxicity has been shown by Joerger et al.	('genotype', 'Var', (15, 23))	('toxicity', 'Disease', 'MESH:D064420', (108, 116))	('toxicity', 'Disease', (108, 116))	('nephrotoxicity', 'Disease', (102, 116))	('toxicity', 'Disease', (70, 78))	('toxicity', 'Disease', 'MESH:D064420', (70, 78))	('nephrotoxicity', 'Disease', 'MESH:D007674', (102, 116))	('G/G genotype', 'Var', (11, 23))	('increase', 'PosReg', (41, 49))
542386	25452763	The A allele in the mutation rs13181 increases overall survival (Park et al.,; Quintela-Fandino et al.,; Caronia et al.,; Chew et al.,).	('rs13181', 'Mutation', 'rs13181', (29, 36))	('increases', 'PosReg', (37, 46))	('rs13181', 'Var', (29, 36))	('overall survival', 'CPA', (47, 63))
542389	25452763	Nonetheless, the majority of the results support an association between both rs1799793 and rs13181 and clinical outcomes in patients with NSCLC, osteosarcoma, breast cancer, ovarian cancer, and colorectal cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (174, 188))	('rs1799793', 'Mutation', 'rs1799793', (77, 86))	('rs1799793', 'Var', (77, 86))	('rs13181', 'Var', (91, 98))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('osteosarcoma', 'Phenotype', 'HP:0002669', (145, 157))	('breast cancer', 'Disease', (159, 172))	('patients', 'Species', '9606', (124, 132))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('colorectal cancer', 'Phenotype', 'HP:0003003', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('NSCLC', 'Disease', (138, 143))	('ovarian cancer', 'Disease', 'MESH:D010051', (174, 188))	('association', 'Interaction', (52, 63))	('osteosarcoma', 'Disease', (145, 157))	('osteosarcoma', 'Disease', 'MESH:D012516', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('colorectal cancer', 'Disease', 'MESH:D015179', (194, 211))	('ovarian cancer', 'Disease', (174, 188))	('rs13181', 'Mutation', 'rs13181', (91, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('colorectal cancer', 'Disease', (194, 211))
542390	25452763	These significant associations in ERCC2 polymorphisms and clinical outcomes have included studies with a larger number of patients and differing patient populations.	('polymorphisms', 'Var', (40, 53))	('ERCC2', 'Gene', (34, 39))	('patient', 'Species', '9606', (122, 129))	('patient', 'Species', '9606', (145, 152))	('patients', 'Species', '9606', (122, 130))	('ERCC2', 'Gene', '2068', (34, 39))
542391	25452763	Other studies found associations between ERCC5 mutations (rs1047768 and rs751402), PFS (progression free survival) (Sun et al.,) and OS (overall survival) (He et al.,).	('PFS', 'Disease', (83, 86))	('rs1047768', 'Var', (58, 67))	('associations', 'Interaction', (20, 32))	('ERCC5', 'Gene', (41, 46))	('rs1047768', 'Mutation', 'rs1047768', (58, 67))	('rs751402', 'Var', (72, 80))	('ERCC5', 'Gene', '2073', (41, 46))	('rs751402', 'Mutation', 'rs751402', (72, 80))
542392	25452763	These studies have indicated that ERCC5 polymorphisms are involved in the efficacy of cisplatin neoadjuvant chemotherapy.	('polymorphisms', 'Var', (40, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('involved', 'Reg', (58, 66))	('ERCC5', 'Gene', (34, 39))	('ERCC5', 'Gene', '2073', (34, 39))
542393	25452763	Also, ototoxicity has related to rs2228001 mutation in the Xeroderma Pigmentosum Complementation group C (XPC) gene (Caronia et al.,).	('Xeroderma Pigmentosum Complementation group C', 'Gene', (59, 104))	('XPC', 'Gene', '7508', (106, 109))	('Xeroderma Pigmentosum Complementation group C', 'Gene', '7508', (59, 104))	('rs2228001', 'Mutation', 'rs2228001', (33, 42))	('ototoxicity', 'Disease', (6, 17))	('ototoxicity', 'Disease', 'MESH:D006311', (6, 17))	('XPC', 'Gene', (106, 109))	('rs2228001', 'Var', (33, 42))
542396	25452763	Among the mutations, we highlight rs25487 and rs1799782 mutations.	('rs1799782', 'Var', (46, 55))	('rs25487', 'Mutation', 'rs25487', (34, 41))	('rs25487', 'Var', (34, 41))	('rs1799782', 'Mutation', 'rs1799782', (46, 55))
542397	25452763	In relation to rs25487, the mutant G variant has been associated with decreased treatment response (Gurubhagavatula et al.,; Giachino et al.,; Pacetti et al.,; Khrunin et al.,; Joerger et al.,; Ke et al.,; Miao et al.,), although opposite results exist (Quintela-Fandino et al.,; Sakano et al.,).	('mutant', 'Var', (28, 34))	('rs25487', 'Mutation', 'rs25487', (15, 22))	('Gurubhagavatula', 'Disease', (100, 115))	('decreased', 'NegReg', (70, 79))	('treatment response', 'CPA', (80, 98))	('Gurubhagavatula', 'Disease', 'None', (100, 115))
542399	25452763	T allele in rs1799782 mutation is related with an increase (Miao et al.,; Li and Li,) and decrease in overall survival (Li et al.,; Shim et al.,).	('rs1799782', 'Mutation', 'rs1799782', (12, 21))	('increase', 'PosReg', (50, 58))	('decrease', 'NegReg', (90, 98))	('overall survival', 'CPA', (102, 118))	('rs1799782', 'Var', (12, 21))
542405	25452763	With respect to X-ray repair cross complementing protein 3 (XRCC3), a protein involved in DNA double-strand breaks, the rs861539 mutation is the only one that relates to treatment outcome.	('XRCC3', 'Gene', (60, 65))	('XRCC3', 'Gene', '7517', (60, 65))	('rs861539', 'Var', (120, 128))	('rs861539', 'Mutation', 'rs861539', (120, 128))	('X-ray repair cross complementing protein 3', 'Gene', (16, 58))	('X-ray repair cross complementing protein 3', 'Gene', '7517', (16, 58))
542408	25452763	In summary, studies of association between genetic variants in the DNA repair system and clinical results show that these variants can be potential biomarkers for outcomes in the cisplatin-based therapies (Table 1).	('association', 'Interaction', (23, 34))	('variants', 'Var', (122, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('variants', 'Var', (51, 59))
542409	25452763	Despite race and treatment regimen, associations testing the polymorphism in ERCC1 appear to follow a consistent direction.	('ERCC1', 'Gene', (77, 82))	('polymorphism', 'Var', (61, 73))	('associations', 'Interaction', (36, 48))	('ERCC1', 'Gene', '2067', (77, 82))
542410	25452763	rs3212986 and rs11615 polymorphisms should be considered in a future genetic panel because results were obtained in several researches with different treatment and demographic characteristics.	('rs3212986', 'Var', (0, 9))	('rs3212986', 'Mutation', 'rs3212986', (0, 9))	('rs11615', 'Var', (14, 21))	('rs11615', 'Mutation', 'rs11615', (14, 21))
542411	25452763	Additional research should be performed in order to replicate results found with polymorphisms in ERCC2, XRCC1, and XRCC3.	('polymorphisms', 'Var', (81, 94))	('XRCC1', 'Gene', (105, 110))	('XRCC3', 'Gene', (116, 121))	('XRCC3', 'Gene', '7517', (116, 121))	('ERCC2', 'Gene', '2068', (98, 103))	('XRCC1', 'Gene', '7515', (105, 110))	('ERCC2', 'Gene', (98, 103))
542416	25452763	Recent studies have demonstrated that mutation or deletion of the CTR1 gene results in increased cisplatin resistance and reduction of platinum levels (Ishida et al.,).	('increased', 'PosReg', (87, 96))	('deletion', 'Var', (50, 58))	('platinum', 'Chemical', 'MESH:D010984', (135, 143))	('CTR1', 'Gene', '1317', (66, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('cisplatin resistance', 'MPA', (97, 117))	('reduction', 'NegReg', (122, 131))	('mutation', 'Var', (38, 46))	('CTR1', 'Gene', (66, 70))	('platinum levels', 'MPA', (135, 150))
542420	25452763	found that rs4148416 was associated with low survival.	('rs4148416', 'DBSNP_MENTION', 'None', (11, 20))	('rs4148416', 'Var', (11, 20))	('low', 'NegReg', (41, 44))
542421	25452763	In addition, the ABCB1 gene that is well-known and encodes P-glycoprotein, contains three polymorphisms (rs2032582, rs1045642, and rs1128503) that have been studied individually and as a haplotype, however, the results have been inconsistent (Caronia et al.,).	('rs1045642', 'Var', (116, 125))	('P-glycoprotein', 'Gene', (59, 73))	('rs1128503', 'Var', (131, 140))	('rs1128503', 'Mutation', 'rs1128503', (131, 140))	('ABCB1', 'Gene', (17, 22))	('rs2032582', 'Var', (105, 114))	('ABCB1', 'Gene', '5243', (17, 22))	('rs2032582', 'Mutation', 'rs2032582', (105, 114))	('rs1045642', 'Mutation', 'rs1045642', (116, 125))	('P-glycoprotein', 'Gene', '5243', (59, 73))
542423	25452763	Genetic variations in GSTs have been implicated in cellular resistance to cancer chemotherapy and in outcomes of cisplatin-based treatments.	('GSTs', 'Gene', '373156', (22, 26))	('implicated', 'Reg', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('GSTs', 'Gene', (22, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('Genetic variations', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
542426	25452763	Several studies have shown significant association between polymorphic GSTs genes and cisplatin treatment response suggesting these polymorphisms as potential biomarkers (Table 2).	('GSTs', 'Gene', '373156', (71, 75))	('polymorphic', 'Var', (59, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('GSTs', 'Gene', (71, 75))	('cisplatin', 'MPA', (86, 95))
542430	25452763	A single nucleotide substitution (A G) at position 313 (rs1695) of the GSTP1 gene, results in replacement of isoleucine with valine at codon 105 of the enzyme, substantially diminishes GSTP1 enzyme activity.	('diminishes', 'NegReg', (174, 184))	('GSTP1', 'Gene', (71, 76))	('GSTP1', 'Gene', (185, 190))	('GSTP1', 'Gene', '2950', (185, 190))	('GSTP1', 'Gene', '2950', (71, 76))	('isoleucine with valine at codon 105', 'Mutation', 'rs1695', (109, 144))	('replacement', 'Var', (94, 105))	('activity', 'MPA', (198, 206))	('isoleucine', 'MPA', (109, 119))	('valine', 'MPA', (125, 131))	('rs1695', 'Mutation', 'rs1695', (56, 62))
542433	25452763	Some investigations have shown that patients with G/G genotype present less toxicity (Oldenburg et al.,; Goekkurt et al.,; Kim et al.,) with more survival (Goekkurt et al.,; Ruzzo et al.,; Ji et al.,) and better therapy response (Sun et al.,; Yang et al.,).	('therapy response', 'CPA', (212, 228))	('patients', 'Species', '9606', (36, 44))	('less', 'NegReg', (71, 75))	('toxicity', 'Disease', 'MESH:D064420', (76, 84))	('toxicity', 'Disease', (76, 84))	('survival', 'CPA', (146, 154))	('G/G', 'Var', (50, 53))	('more', 'PosReg', (141, 145))	('better', 'PosReg', (205, 211))
542434	25452763	On the other hand, the G allele has been associated with a risk of myelosuppression, polyneuropathy, and toxicity (Yokomizo et al.,; Joerger et al.,; Windsor et al.,; Rednam et al.,).	('myelosuppression', 'Disease', (67, 83))	('polyneuropathy', 'Disease', 'MESH:D011115', (85, 99))	('neuropathy', 'Phenotype', 'HP:0009830', (89, 99))	('polyneuropathy', 'Disease', (85, 99))	('polyneuropathy', 'Phenotype', 'HP:0001271', (85, 99))	('G allele', 'Var', (23, 31))	('toxicity', 'Disease', 'MESH:D064420', (105, 113))	('toxicity', 'Disease', (105, 113))	('myelosuppression', 'Disease', 'MESH:D001855', (67, 83))
542437	25452763	The influence of rs1695 GSTP1 on toxicity to taxane-and platinum-based chemotherapy is in debate (Kim et al.,).	('platinum', 'Chemical', 'MESH:D010984', (56, 64))	('GSTP1', 'Gene', (24, 29))	('taxane', 'Chemical', 'MESH:C080625', (45, 51))	('rs1695', 'Var', (17, 23))	('rs1695', 'Mutation', 'rs1695', (17, 23))	('GSTP1', 'Gene', '2950', (24, 29))	('toxicity', 'Disease', 'MESH:D064420', (33, 41))	('toxicity', 'Disease', (33, 41))
542438	25452763	Polymorphism of GSTM1 and GSTT1 genes is associated with cisplatin-based treatments.	('Polymorphism', 'Var', (0, 12))	('associated', 'Reg', (41, 51))	('cisplatin-based treatments', 'Disease', (57, 83))	('GSTT1', 'Gene', '2952', (26, 31))	('GSTM1', 'Gene', '2944', (16, 21))	('GSTT1', 'Gene', (26, 31))	('GSTM1', 'Gene', (16, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))
542439	25452763	GSTM1 null has been specifically related to an increase of OS and PFS (Medeiros et al.,; Petros et al.,; Beeghly et al.,; Ott et al.,).	('PFS', 'Disease', (66, 69))	('null', 'Var', (6, 10))	('GSTM1', 'Gene', '2944', (0, 5))	('GSTM1', 'Gene', (0, 5))	('increase', 'PosReg', (47, 55))
542443	25452763	Moreover, the null allele has also associated with an increase in ototoxicity (Jurajda et al.,; Choeyprasert et al.,).	('increase', 'PosReg', (54, 62))	('null', 'Var', (14, 18))	('ototoxicity', 'Disease', (66, 77))	('ototoxicity', 'Disease', 'MESH:D006311', (66, 77))
542444	25452763	Finally, additional studies examining the GSTA1 gene showed the T/T genotype (rs3957357) associates with an increase of overall survival (Khrunin et al.,).	('increase', 'PosReg', (108, 116))	('GSTA1', 'Gene', '2938', (42, 47))	('rs3957357', 'Var', (78, 87))	('overall survival', 'MPA', (120, 136))	('GSTA1', 'Gene', (42, 47))	('T/T', 'Var', (64, 67))	('rs3957357', 'Mutation', 'rs3957357', (78, 87))
542445	25452763	Regarding to GSTM3 gene, the AGG/AGG haplotype (rs1799735) is related to less thrombocytopenia, anemia and neuropathy (Khrunin et al.,).	('AGG/AGG', 'Gene', (29, 36))	('thrombocytopenia', 'Disease', (78, 94))	('anemia', 'Phenotype', 'HP:0001903', (96, 102))	('neuropathy', 'Phenotype', 'HP:0009830', (107, 117))	('rs1799735', 'Var', (48, 57))	('GSTM3', 'Gene', (13, 18))	('thrombocytopenia', 'Disease', 'MESH:D013921', (78, 94))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (78, 94))	('rs1799735', 'Mutation', 'rs1799735', (48, 57))	('GSTM3', 'Gene', '2947', (13, 18))	('anemia and neuropathy', 'Disease', 'MESH:D000740', (96, 117))
542447	25452763	Polymorphisms in the GSTP1 gene have shown controversial results among different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Polymorphisms', 'Var', (0, 13))	('GSTP1', 'Gene', (21, 26))	('GSTP1', 'Gene', '2950', (21, 26))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
542448	25452763	Some studies found the polymorphic allele related to less toxicity, better therapy response and more survival but others found the opposite regarding to toxicity (Rednam et al.,).	('therapy response', 'CPA', (75, 91))	('better', 'PosReg', (68, 74))	('less', 'NegReg', (53, 57))	('more', 'PosReg', (96, 100))	('toxicity', 'Disease', 'MESH:D064420', (58, 66))	('toxicity', 'Disease', (58, 66))	('survival', 'CPA', (101, 109))	('toxicity', 'Disease', 'MESH:D064420', (153, 161))	('toxicity', 'Disease', (153, 161))	('polymorphic allele', 'Var', (23, 41))
542452	25452763	Regarding OS and PFS it appears that null allele is related to decreased OS and PFS, although one author showed the opposite (Ruzzo et al.,; Goekkurt et al.,).	('null allele', 'Var', (37, 48))	('decreased OS', 'Disease', 'MESH:C567932', (63, 75))	('decreased OS', 'Disease', (63, 75))	('PFS', 'Disease', (80, 83))
542454	25452763	Together, the evidence appears to indicate a strong association between GSTs polymorphisms and clinical response (overall survival and disease progression).	('GSTs', 'Gene', (72, 76))	('disease progression', 'CPA', (135, 154))	('polymorphisms', 'Var', (77, 90))	('clinical response', 'CPA', (95, 112))	('GSTs', 'Gene', '373156', (72, 76))
542456	25452763	Despite this, with the data presented we can conclude that the GSTP1 polymorphic allele and the GSTM1 and GSTT1 null alleles appear to result in enhanced overall survival and progression free survival, particularly in gastric cancer where the data have been more consistent.	('overall survival', 'CPA', (154, 170))	('GSTM1', 'Gene', (96, 101))	('progression free survival', 'CPA', (175, 200))	('gastric cancer', 'Disease', (218, 232))	('GSTP1', 'Gene', (63, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (218, 232))	('polymorphic', 'Var', (69, 80))	('GSTT1', 'Gene', '2952', (106, 111))	('GSTT1', 'Gene', (106, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (218, 232))	('GSTP1', 'Gene', '2950', (63, 68))	('enhanced', 'PosReg', (145, 153))	('GSTM1', 'Gene', '2944', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
542467	25452763	For example, recent studies showed a relationship between rs12201199 in thiopurine S-methyltransferase gene (TPMT) and rs9332377 in the catechol-O-methyltransferase gene (COMPT) with cisplatin-induced hearing loss in children (Ross et al.,).	('children', 'Species', '9606', (217, 225))	('hearing loss', 'Disease', (201, 213))	('rs9332377', 'Var', (119, 128))	('TPMT', 'Gene', '7172', (109, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (183, 192))	('COMPT', 'Gene', (171, 176))	('thiopurine S-methyltransferase', 'Gene', '7172', (72, 102))	('thiopurine S-methyltransferase', 'Gene', (72, 102))	('catechol-O-methyltransferase', 'Gene', '1312', (136, 164))	('hearing loss', 'Disease', 'MESH:D034381', (201, 213))	('rs12201199', 'Mutation', 'rs12201199', (58, 68))	('catechol-O-methyltransferase', 'Gene', (136, 164))	('hearing loss', 'Phenotype', 'HP:0000365', (201, 213))	('TPMT', 'Gene', (109, 113))	('rs12201199', 'Var', (58, 68))	('rs9332377', 'Mutation', 'rs9332377', (119, 128))
542475	25238263	Blockade of IL-6 prevented induction of MDSCs and the incidence of 4-NQO- induced invasive tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('IL-6', 'Gene', (12, 16))	('Blockade', 'Var', (0, 8))	('invasive tumors', 'Disease', (82, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('4-NQO', 'Chemical', 'MESH:D015112', (67, 72))	('invasive tumors', 'Disease', 'MESH:D009369', (82, 97))
542477	25238263	Moreover, we suggest inhibition of IL-6 as a potential strategy for the treatment of esophageal SCC.	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('inhibition', 'Var', (21, 31))	('esophageal SCC', 'Disease', (85, 99))	('esophageal SCC', 'Disease', 'MESH:D004941', (85, 99))
542532	25238263	Figure 5b showed that the absence of IL-6 decreased the SUVR in PET images of the esophageal lesions of the IL-6 KO mice compared to that of the C57 mice with IL-6 stimulation.	('mice', 'Species', '10090', (116, 120))	('decreased', 'NegReg', (42, 51))	('IL-6', 'Gene', (37, 41))	('esophageal lesions', 'Disease', (82, 100))	('absence', 'Var', (26, 33))	('IL-6 KO', 'Var', (108, 115))	('mice', 'Species', '10090', (149, 153))	('SUVR in', 'MPA', (56, 63))	('esophageal lesions', 'Disease', 'MESH:D004935', (82, 100))
542537	25238263	MDSCs have been reported to inhibit T cell effector function via a range of mechanisms including reactive oxygen species (ROS) production and increased arginase 1 (ARG1) levels.	('MDSCs', 'Var', (0, 5))	('ROS', 'Chemical', 'MESH:D017382', (122, 125))	('increased', 'PosReg', (142, 151))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (97, 120))	('increased arginase', 'Phenotype', 'HP:0500153', (142, 160))	('arginase 1', 'Gene', (152, 162))	('arginase 1', 'Gene', '383', (152, 162))	('T cell effector function', 'CPA', (36, 60))	('ARG1', 'Gene', '383', (164, 168))	('ARG1', 'Gene', (164, 168))	('inhibit', 'NegReg', (28, 35))
542542	25238263	MDSC are thought to promote cancer progression and present an important barrier limiting the full potential of immune-based cancer therapies or the endogenous host response against tumor development.	('MDSC', 'Var', (0, 4))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('promote', 'PosReg', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('cancer', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
542545	25238263	To date, MDSCs have been defined mainly as HLA-DR-, CD11b+, CD33+, and CD15+ lineages in human cancers.	('human', 'Species', '9606', (89, 94))	('CD11b+', 'Var', (52, 58))	('CD15', 'Gene', (71, 75))	('CD15', 'Gene', '2526', (71, 75))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('CD33', 'Gene', '945', (60, 64))	('CD33', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
542560	25238263	The expansion of MDSCs induced by intravenous infusion was associated with a higher SUVR in esophageal lesions and an increased incidence of invasive esophageal tumor formation.	('esophageal lesions', 'Disease', (92, 110))	('invasive', 'CPA', (141, 149))	('esophageal tumor', 'Disease', (150, 166))	('higher', 'PosReg', (77, 83))	('esophageal tumor', 'Phenotype', 'HP:0100751', (150, 166))	('esophageal lesions', 'Disease', 'MESH:D004935', (92, 110))	('MDSCs', 'Gene', (17, 22))	('expansion', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('SUVR', 'MPA', (84, 88))	('esophageal tumor', 'Disease', 'MESH:D004938', (150, 166))
542566	25238263	Activation of STAT3 has been shown to enhanced the expression of IDO, a key factor maintaining immune tolerance in myeloid cells, and is the main transcription factor that regulates the expansion of MDSC.	('STAT3', 'Gene', (14, 19))	('enhanced', 'PosReg', (38, 46))	('IDO', 'Gene', '3620', (65, 68))	('STAT3', 'Gene', '6774', (14, 19))	('expression', 'MPA', (51, 61))	('Activation', 'Var', (0, 10))	('IDO', 'Gene', (65, 68))
542585	25238263	Conversely, blocking IL-6 abrogated the induction of MDSCs and the incidence of 4-NQO-induced invasive tumors.	('invasive tumors', 'Disease', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('invasive tumors', 'Disease', 'MESH:D009369', (94, 109))	('4-NQO', 'Chemical', 'MESH:D015112', (80, 85))	('MDSCs', 'MPA', (53, 58))	('abrogated', 'NegReg', (26, 35))	('IL-6', 'Gene', (21, 25))	('blocking', 'Var', (12, 20))
542608	25238263	The mice were allowed access to the drinking water containing 4-NQO (tumor-induced group) or the solvent only (control group) at all times during the treatment.	('4-NQO', 'Var', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('4-NQO', 'Chemical', 'MESH:D015112', (62, 67))	('drinking water', 'Chemical', 'MESH:D060766', (36, 50))	('mice', 'Species', '10090', (4, 8))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
542637	24686850	We identified novel significantly mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to previously discovered ones (TP53, PIK3CA and NOTCH1).	('NOTCH1', 'Gene', '4851', (146, 152))	('FAT1', 'Gene', (56, 60))	('NOTCH1', 'Gene', (146, 152))	('ZNF750', 'Gene', (68, 74))	('TP53', 'Gene', '7157', (129, 133))	('FAT2', 'Gene', (62, 66))	('PIK3CA', 'Gene', (135, 141))	('KMT2D', 'Gene', (79, 84))	('KMT2D', 'Gene', '8085', (79, 84))	('TP53', 'Gene', (129, 133))	('ZNF750', 'Gene', '79755', (68, 74))	('PIK3CA', 'Gene', '5290', (135, 141))	('mutated', 'Var', (34, 41))	('FAT1', 'Gene', '2195', (56, 60))
542639	24686850	Moreover, our approaches uncovered many novel druggable candidates, and XPO1 was further explored as a therapeutic target because of its mutation and protein overexpression.	('XPO1', 'Gene', '7514', (72, 76))	('XPO1', 'Gene', (72, 76))	('overexpression', 'PosReg', (158, 172))	('mutation', 'Var', (137, 145))
542643	24686850	We and others have revealed frequent somatic copy number variations (SCNV) involving 3q26, 9p21, 11q13.3 and 8q24.3, as well as somatic mutations in PIK3CA, TP53and NOTCH1 in ESCC.	('TP53', 'Gene', (157, 161))	('copy number variations', 'Var', (45, 67))	('NOTCH1', 'Gene', '4851', (165, 171))	('PIK3CA', 'Gene', (149, 155))	('mutations', 'Var', (136, 145))	('NOTCH1', 'Gene', (165, 171))	('PIK3CA', 'Gene', '5290', (149, 155))	('TP53', 'Gene', '7157', (157, 161))
542648	24686850	Cross comparing the WES with RNA-seq data from the same tumors revealed that 61% of the mutated genes were transcribed (Supplementary Table 4), which is comparable to the value reported on breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('tumors', 'Disease', (56, 62))	('breast cancer', 'Disease', (189, 202))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutated', 'Var', (88, 95))
542653	24686850	To identify mutations conferring selective growth advantages ("Driver Mutations"), we applied the algorithm MutSigCV, which corrects for variation by incorporating patient-specific mutational spectrum, gene-specific background mutational burden and also by measuring gene expression level and replication time.	('growth', 'MPA', (43, 49))	('patient', 'Species', '9606', (164, 171))	('mutations', 'Var', (12, 21))	('advantages', 'PosReg', (50, 60))	('gene expression level', 'MPA', (267, 288))
542655	24686850	We focused on focal SCNV, defined as narrow regions (typically <100 kb) exhibiting high-amplitude of copy number changes (Online Methods), which has more probability to contain cancer genes.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('copy number changes', 'Var', (101, 120))	('contain', 'Reg', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
542661	24686850	Given that FGFR amplification predicts for sensitivity to targeted inhibitors in several other solid tumors, our results suggest that FGFR1 is a potential therapeutic target in ESCC.	('solid tumors', 'Disease', (95, 107))	('FGFR1', 'Gene', (134, 139))	('ESCC', 'Disease', (177, 181))	('solid tumors', 'Disease', 'MESH:D009369', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('amplification', 'Var', (16, 29))	('FGFR1', 'Gene', '2260', (134, 139))	('predicts', 'Reg', (30, 38))	('FGFR', 'Gene', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('sensitivity', 'MPA', (43, 54))
542662	24686850	2d, P = 0.0005, Supplementary Table 9a, Online Methods) and phosphatidylinositol 3-kinase (PI3K)pathways (P = 0.0004) are augmented by multiple mechanisms: i) amplification and overexpression of RTKs, KRAS and PIK3CA; ii) activation mutations of ERBB4 and PIK3CA; iii) inactivation mutations of PTEN, MAP3K13 and MAP3K15.	('ERBB4', 'Gene', '2066', (246, 251))	('ERBB4', 'Gene', (246, 251))	('overexpression', 'PosReg', (177, 191))	('inactivation mutations', 'Var', (269, 291))	('MAP3K13', 'Gene', (301, 308))	('PIK3CA', 'Gene', '5290', (256, 262))	('KRAS', 'Gene', (201, 205))	('MAP3K15', 'Gene', '389840', (313, 320))	('activation', 'PosReg', (222, 232))	('MAP3K13', 'Gene', '9175', (301, 308))	('KRAS', 'Gene', '3845', (201, 205))	('PIK3CA', 'Gene', (210, 216))	('PTEN', 'Gene', (295, 299))	('PTEN', 'Gene', '5728', (295, 299))	('PIK3CA', 'Gene', '5290', (210, 216))	('MAP3K15', 'Gene', (313, 320))	('PIK3CA', 'Gene', (256, 262))
542663	24686850	In addition, IL7R amplification and JAK1 mutations were identified, which will likely activate JAK-STAT3 signaling (P=0.0006).	('mutations', 'Var', (41, 50))	('JAK1', 'Gene', (36, 40))	('IL7R', 'Gene', (13, 17))	('JAK1', 'Gene', '3716', (36, 40))	('STAT3', 'Gene', '6774', (99, 104))	('activate', 'PosReg', (86, 94))	('STAT3', 'Gene', (99, 104))	('amplification', 'Var', (18, 31))	('IL7R', 'Gene', '3575', (13, 17))
542665	24686850	2e, P = 1.63E-05) is altered mostly by CCND1 amplification, CDKN2A deletion/mutation and TP53 mutation.	('deletion/mutation', 'Var', (67, 84))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('CCND1', 'Gene', (39, 44))	('mutation', 'Var', (94, 102))	('CDKN2A', 'Gene', (60, 66))	('CDKN2A', 'Gene', '1029', (60, 66))	('CCND1', 'Gene', '595', (39, 44))	('altered', 'Reg', (21, 28))	('amplification', 'Var', (45, 58))
542666	24686850	As a negative regulator of c-Myc, frequent FBXW7 mutations were observed in our investigation (Fig.	('FBXW7', 'Gene', (43, 48))	('mutations', 'Var', (49, 58))	('c-Myc', 'Gene', (27, 32))	('c-Myc', 'Gene', '4609', (27, 32))	('FBXW7', 'Gene', '55294', (43, 48))
542667	24686850	Importantly, we next examined FBXW7 protein expression with IHC and found its mutation led to loss of the protein (Fig.	('FBXW7', 'Gene', '55294', (30, 35))	('loss', 'NegReg', (94, 98))	('mutation', 'Var', (78, 86))	('FBXW7', 'Gene', (30, 35))
542671	24686850	We observed that ZNF750 was significantly mutated in ESCC (q = 1.24E-06, Fig.	('mutated', 'Var', (42, 49))	('ZNF750', 'Gene', (17, 23))	('ESCC', 'Disease', (53, 57))	('ZNF750', 'Gene', '79755', (17, 23))
542673	24686850	Supportively, ESCC harbors a much higher mutational burden affecting ZNF750 than esophageal adenocarcinoma.	('ZNF750', 'Gene', '79755', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('esophageal adenocarcinoma', 'Disease', (81, 106))	('ZNF750', 'Gene', (69, 75))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (81, 106))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (81, 106))	('mutational', 'Var', (41, 51))
542677	24686850	In addition, we identified that ZNF750 was focally deleted in 3.4% ESCC tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ESCC tumors', 'Disease', 'MESH:D004938', (67, 78))	('ZNF750', 'Gene', '79755', (32, 38))	('deleted', 'Var', (51, 58))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('ESCC tumors', 'Disease', (67, 78))	('ZNF750', 'Gene', (32, 38))
542683	24686850	Notably, ectopic expression of ZNF750 further promoted the TPA-induced growth-suppression (Fig.3g).	('promoted', 'PosReg', (46, 54))	('ectopic expression', 'Var', (9, 27))	('ZNF750', 'Gene', (31, 37))	('TPA', 'Chemical', 'MESH:D013755', (59, 62))	('growth-suppression', 'Disease', (71, 89))	('growth-suppression', 'Disease', 'MESH:D006130', (71, 89))	('ZNF750', 'Gene', '79755', (31, 37))
542688	24686850	Our data revealed that ESCC harbored very frequent, mutually-exclusive truncating mutations affecting FAT1, FAT2 and FAT3 compared to other solid tumors (Figs.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('truncating mutations', 'Var', (71, 91))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ESCC', 'Disease', (23, 27))	('solid tumors', 'Disease', (140, 152))	('FAT1', 'Gene', '2195', (102, 106))	('FAT1', 'Gene', (102, 106))	('FAT2', 'Gene', (108, 112))	('FAT3', 'Gene', (117, 121))	('solid tumors', 'Disease', 'MESH:D009369', (140, 152))	('FAT3', 'Gene', '120114', (117, 121))
542690	24686850	We next found that homozygous deletions ofFAT1 occurred in 3.4% ESCCs (Fig.	('deletions', 'Var', (30, 39))	('ESCCs', 'Disease', (64, 69))	('occurred', 'Reg', (47, 55))	('FAT1', 'Gene', '2195', (42, 46))	('FAT1', 'Gene', (42, 46))
542693	24686850	On the other hand, ectopic expression of FAT1 cDNA significantly inhibited both cell proliferation and colony formation in soft agar (Supplementary Fig.	('ectopic expression', 'Var', (19, 37))	('colony formation in soft agar', 'CPA', (103, 132))	('cell proliferation', 'CPA', (80, 98))	('inhibited', 'NegReg', (65, 74))	('FAT1', 'Gene', '2195', (41, 45))	('FAT1', 'Gene', (41, 45))
542695	24686850	In mammalian cells, the chief mediator of protein nuclear export is exportin 1 (XPO1).Due to its ability to export a number of tumor suppressors, targeting XPO1 has been considered as an anti-neoplastic approach.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('exportin 1', 'Gene', '7514', (68, 78))	('tumor', 'Disease', (127, 132))	('exportin 1', 'Gene', (68, 78))	('targeting', 'Var', (146, 155))	('XPO1', 'Gene', '7514', (80, 84))	('XPO1', 'Gene', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('XPO1', 'Gene', (156, 160))	('XPO1', 'Gene', '7514', (156, 160))	('mammalian', 'Species', '9606', (3, 12))
542696	24686850	We found one missense mutation D624G affecting XPO1.	('D624G', 'Mutation', 'rs750215195', (31, 36))	('XPO1', 'Gene', '7514', (47, 51))	('D624G', 'Var', (31, 36))	('XPO1', 'Gene', (47, 51))
542699	24686850	D624G mutation presumably reduces the affinity of interactions due to loss of the salt bridge.	('reduces', 'NegReg', (26, 33))	('loss', 'NegReg', (70, 74))	('D624G', 'Var', (0, 5))	('salt bridge', 'MPA', (82, 93))	('D624G', 'Mutation', 'rs750215195', (0, 5))	('interactions', 'Interaction', (50, 62))	('affinity', 'MPA', (38, 46))
542700	24686850	This alteration may accelerate the turnover of XPO1 from "bound" to "unbound" state and enhance its exporting efficiency.	('XPO1', 'Gene', '7514', (47, 51))	('alteration', 'Var', (5, 15))	('XPO1', 'Gene', (47, 51))	('accelerate', 'PosReg', (20, 30))	('turnover', 'MPA', (35, 43))	('exporting efficiency', 'MPA', (100, 120))	('enhance', 'PosReg', (88, 95))
542707	24686850	Inhibition of XPO1 with either shRNA or KPT-330 altered the expression of its known cargos (such as P53), as well as indirect targets including Cyclin D1, c-Myc, PUMA and BIM, which might be due to various novel mechanisms that we and others have recently identified (Figs.	('expression', 'MPA', (60, 70))	('c-Myc', 'Gene', '4609', (155, 160))	('KPT-330', 'Chemical', 'MESH:C585161', (40, 47))	('altered', 'Reg', (48, 55))	('shRNA', 'Gene', (31, 36))	('XPO1', 'Gene', '7514', (14, 18))	('XPO1', 'Gene', (14, 18))	('c-Myc', 'Gene', (155, 160))	('P53', 'Gene', (100, 103))	('Inhibition', 'Var', (0, 10))	('Cyclin D1', 'MPA', (144, 153))	('KPT-330', 'Gene', (40, 47))
542708	24686850	Given that frequent overexpression of XPO1 protein is clinically relevant and functionally contributes to the cellular malignant phenotype, targeting XPO1 in those patients with XPO1 up-regulation might offer potential benefits in ESCC.	('ESCC', 'Disease', (231, 235))	('XPO1', 'Gene', (38, 42))	('targeting', 'Var', (140, 149))	('XPO1', 'Gene', (150, 154))	('up-regulation', 'PosReg', (183, 196))	('XPO1', 'Gene', (178, 182))	('XPO1', 'Gene', '7514', (38, 42))	('XPO1', 'Gene', '7514', (150, 154))	('XPO1', 'Gene', '7514', (178, 182))	('benefits', 'PosReg', (219, 227))	('patients', 'Species', '9606', (164, 172))
542711	24686850	A number of novel mutated/altered genes and pathways were identified with statistical and biological evidence of growth selection, indicating that they likely contribute to esophageal tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('mutated/altered', 'Var', (18, 33))	('tumor', 'Disease', (184, 189))	('contribute', 'Reg', (159, 169))
542719	24686850	ESCC cell lines KYSE30, KYSE50, KYSE70, KYSE110, KYSE150, KYSE450, KYSE510 and YES2 were kindly shared by Yutaka Shimada (Faculty of medicine, Kyoto University).	('KYSE70', 'Var', (32, 38))	('KYSE450', 'Var', (58, 65))	('KYSE150', 'CellLine', 'CVCL:1348', (49, 56))	('KYSE110', 'Var', (40, 47))	('YES2', 'Gene', '7526', (79, 83))	('KYSE50', 'Var', (24, 30))	('YES2', 'Gene', (79, 83))	('KYSE510', 'Var', (67, 74))	('KYSE150', 'Var', (49, 56))
542720	24686850	KYSE140 and KYSE180 were generously provided by Dr. Xin-Yuan Guan.	('Xin', 'Gene', (52, 55))	('Xin', 'Gene', '165904', (52, 55))	('KYSE180', 'Var', (12, 19))
542740	24686850	In addition, the following nucleotide positions were eliminated from further analysis, including those positions at which the depth is less than 10 in either tumor or control, or the most frequent SNV or indel accounts for less than 7% of all reads in the tumor.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('SNV', 'Var', (197, 200))
542741	24686850	Finally, a list of candidate somatic mutations was generated by excluding synonymous SNVs and other variants registered in dbSNP131, 1,000 genomes, or our in-house SNP database constructed from 180 patients.	('variants', 'Var', (100, 108))	('dbSNP131', 'Gene', (123, 131))	('patients', 'Species', '9606', (198, 206))
542742	24686850	To make a more rigorous somatic mutation calling with the TDS approach of Frequency Cohort, the following nucleotide positions were further removed: the supporting depth from both directions was less than 5 in either tumor or control, or the most frequent SNV or indel accounts for less than 8% of all reads in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('SNV', 'Var', (256, 259))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('indel', 'Var', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', (315, 320))
542743	24686850	To detect probable somatic mutations of ESCC cell lines which do not have paired germline controls, the following nucleotide positions were further removed: the supporting depth from both directions is less than 5, or the most frequent SNV or indel accounts for less than 8% of all reads, or the frequency of the SNV or indel is between 45% and 55% without copy number abnormalities.	('mutations', 'Var', (27, 36))	('indel', 'Var', (243, 248))	('number abnormalities', 'Disease', 'MESH:D007674', (362, 382))	('number abnormalities', 'Disease', (362, 382))	('SNV', 'Var', (236, 239))
542749	24686850	Antibodies specific for cyclin B1 (4135), cleaved-PARP (9541), p21WAF1(2947) and BIM (2933) were purchased from Cell Signaling Technology.	('cyclin B1', 'Gene', '891', (24, 33))	('cyclin B1', 'Gene', (24, 33))	('9541', 'Var', (56, 60))	('p21WAF1(2947', 'Var', (63, 75))	('PARP', 'Gene', '1302', (50, 54))	('PARP', 'Gene', (50, 54))	('4135', 'Var', (35, 39))
542759	24686850	These values were converted based on the following presumptions: (i) for amplifications, copy number > 6 was present in more than 70% cancer cell populations; (ii) for deletions, loss of both alleles was present in more than 70% cancer cell populations, and (iii) normal cell contamination was less than 30%.	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('deletions', 'Var', (168, 177))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('loss', 'NegReg', (179, 183))
542769	24686850	All of the fluorescent images were captured with individual single-band-pass filters specific for visualizing DAPI, Green, Cy3 fluorochromes.	('DAPI', 'Chemical', '-', (110, 114))	('Cy3', 'Var', (123, 126))	('Green', 'MPA', (116, 121))
542771	24686850	The statistical analyses of the following assays were conducted using the two tailed Student's t-test upon verification of the assumptions (e.g., normality), otherwise the non-parametric test was applied: short-term cell proliferation, xenografts proliferation, q-PCR, apoptosis induction, mRNA levels examined from GSE20347, GSE23400 and CCLE.	('q-PCR', 'CPA', (262, 267))	('GSE23400', 'Var', (326, 334))	('CCLE', 'Chemical', '-', (339, 343))	('GSE20347', 'Var', (316, 324))	('apoptosis induction', 'CPA', (269, 288))	('mRNA levels', 'MPA', (290, 301))	('xenografts proliferation', 'CPA', (236, 260))
542824	25009751	Other potential protective mechanisms of EA include shielding of DNA from attack and subsequent mutation by its direct association with this macromolecule, inhibition of ROS production, and chelation of metal ions, such as copper.	('association', 'Interaction', (119, 130))	('inhibition', 'NegReg', (156, 166))	('metal', 'Chemical', 'MESH:D008670', (203, 208))	('chelation', 'MPA', (190, 199))	('DNA', 'Gene', (65, 68))	('mutation', 'Var', (96, 104))	('EA', 'Chemical', 'MESH:D004610', (41, 43))	('ROS production', 'MPA', (170, 184))	('ROS', 'Chemical', 'MESH:D017382', (170, 173))	('copper', 'Chemical', 'MESH:D003300', (223, 229))
542836	25009751	For example, the formation of O6-methylguanine (O6-meGua) adducts and their persistence are closely linked to esophageal tumor induction in rats.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('rats', 'Species', '10116', (140, 144))	('linked', 'Reg', (100, 106))	('esophageal tumor', 'Disease', 'MESH:D004938', (110, 126))	('adducts', 'Var', (58, 65))	('persistence', 'MPA', (76, 87))	('esophageal tumor', 'Disease', (110, 126))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (30, 46))	('esophageal tumor', 'Phenotype', 'HP:0100751', (110, 126))	('O6-meGua', 'Chemical', 'MESH:C008449', (48, 56))
542837	25009751	The detection of O6-meGua adducts in the DNA of normal esophageal tissue taken from esophageal cancer patients in China also substantiates the function of methylating nitrosamines in esophageal cancer development.	('patients', 'Species', '9606', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('esophageal cancer', 'Disease', (183, 200))	('nitrosamines', 'Chemical', 'MESH:D009602', (167, 179))	('esophageal cancer', 'Disease', (84, 101))	('O6-meGua', 'Var', (17, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('O6-meGua', 'Chemical', 'MESH:C008449', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (183, 200))
542907	25009751	Inhibiting GST overexpression has been suggested as an approach to combat GST-induced resistance.	('GST', 'Gene', (11, 14))	('Inhibiting', 'Var', (0, 10))	('GST', 'Gene', '373156', (11, 14))	('GST', 'Gene', (74, 77))	('GST', 'Gene', '373156', (74, 77))
542934	20151048	The average concentration in the patients with CR was 0.122+-0.035 mug/mL, and was significantly higher than that in non-CR patients, 0.102+-0.023 mug/mL (p = 0.029).	('higher', 'PosReg', (97, 103))	('patients', 'Species', '9606', (33, 41))	('CR', 'Chemical', '-', (121, 123))	('0.122+-0.035 mug/mL', 'Var', (54, 73))	('CR', 'Chemical', '-', (47, 49))	('patients', 'Species', '9606', (124, 132))
542954	20151048	The plasma concentrations of 5-FU in the high dose group, 0.137+-0.031 mug/mL, were higher than those in the standard dose group, 0.112+-0.030 mug/mL, but with no statistical significance (p = 0.052), presumably due to great differences between individuals.	('0.137+-0.031 mug/mL', 'Var', (58, 77))	('5-FU', 'Chemical', 'MESH:D005472', (29, 33))	('plasma concentrations', 'MPA', (4, 25))	('higher', 'PosReg', (84, 90))
542955	20151048	In Stage IVa, the plasma concentrations of 5-FU in the high dose group, 0.144+-0.029 mug/mL, were significantly higher than those in the standard dose group, 0.101+-0.027 mug/mL (p = 0.028), and tended to be still higher after the dose-normalization (0.116+-0.012 mug/mL).	('5-FU', 'Chemical', 'MESH:D005472', (43, 47))	('0.144+-0.029 mug/mL', 'Var', (72, 91))	('plasma concentrations', 'MPA', (18, 39))	('higher', 'PosReg', (112, 118))
542958	20151048	In the standard dose group, the plasma concentrations of 5-FU at 5:00 AM (0.069+-0.031 mug/mL) were significantly lower than those at 5:00 PM (0.109+-0.059 mug/mL) in the 1st cycle/1st course (P < 0.05, beta = 0.882) and a similar tendency was observed in the 2nd cycle/1st course (P = 0.438, beta = 0.179), not significantly.	('0.069+-0.031 mug/mL', 'Var', (74, 93))	('5-FU', 'Chemical', 'MESH:D005472', (57, 61))	('plasma concentrations', 'MPA', (32, 53))	('lower', 'NegReg', (114, 119))
543050	33856574	Gastrobronchial fistulas caused by leakage from a staple line differ from fistulas caused by anastomotic leakage.	('anastomotic leakage', 'Disease', 'MESH:D057868', (93, 112))	('leakage', 'Var', (35, 42))	('fistula', 'Disease', 'MESH:D005402', (16, 23))	('anastomotic leakage', 'Disease', (93, 112))	('fistula', 'Disease', (16, 23))	('fistula', 'Disease', 'MESH:D005402', (74, 81))	('fistula', 'Disease', (74, 81))
543052	33856574	Therefore, leakage from the staple line causes lower mediastinitis, which can lead to fistulas developing in the lower lung or bronchus.	('leakage', 'Var', (11, 18))	('lead', 'Reg', (78, 82))	('fistula', 'Disease', (86, 93))	('lower mediastinitis', 'Disease', (47, 66))	('fistula', 'Disease', 'MESH:D005402', (86, 93))
543055	33856574	To the best of our knowledge, this is the first reported case in which lobectomy was used to manage a gastrobronchial fistula caused by leakage from the staple line of a gastric tube.	('gastrobronchial fistula', 'Phenotype', 'HP:0002575', (102, 125))	('fistula', 'Disease', 'MESH:D005402', (118, 125))	('fistula', 'Disease', (118, 125))	('leakage', 'Var', (136, 143))
543072	33554099	In vitro and in vivo studies have respectively shown that ASI inhibits the proliferation of esophageal cancer cells via blockade of the G0 to G1 cell transition, whereas intraperitoneal injection of an ASI in mice leads to a significant reduction in tumor growth and altered miRNA expression.	('proliferation', 'CPA', (75, 88))	('tumor growth', 'CPA', (250, 262))	('mice', 'Species', '10090', (209, 213))	('blockade', 'NegReg', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('inhibits', 'NegReg', (62, 70))	('G0 to G1 cell transition', 'CPA', (136, 160))	('ASI', 'Var', (58, 61))	('esophageal cancer', 'Disease', (92, 109))	('miRNA expression', 'MPA', (275, 291))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('altered', 'Reg', (267, 274))	('reduction', 'NegReg', (237, 246))
543116	32026048	The dietician measured body composition such as arm circumference, triceps skinfolds, calf circumference, and measured lean body mass using bioelectrical impedance analysis and diagnosed patients with skeletal muscle less than 7.0 kg/m2 for men and 5.7 kg/m2 for women as sarcopenia according to the Asian Working Group on Sarcopenia.	('patients', 'Species', '9606', (187, 195))	('less than', 'Var', (217, 226))	('men', 'Species', '9606', (241, 244))	('women', 'Species', '9606', (263, 268))	('men', 'Species', '9606', (265, 268))	('Sarcopenia', 'Disease', (323, 333))	('Sarcopenia', 'Disease', 'MESH:D055948', (323, 333))	('sarcopenia', 'Disease', 'MESH:D055948', (272, 282))	('calf', 'Species', '9913', (86, 90))	('sarcopenia', 'Disease', (272, 282))
543283	32415055	showed that DNAJB1 knockdown is associated with apoptosis in lung cancer.	('lung cancer', 'Disease', (61, 72))	('DNAJB1', 'Gene', '3337', (12, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('knockdown', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('DNAJB1', 'Gene', (12, 18))	('associated', 'Reg', (32, 42))	('apoptosis', 'CPA', (48, 57))
543290	32415055	TBK1 is upregulated in bladder cancer tissue and cell lines, and knockdown of TBK1 inhibits cell migration.	('bladder cancer', 'Disease', 'MESH:D001749', (23, 37))	('bladder cancer', 'Disease', (23, 37))	('TBK1', 'Gene', '29110', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('inhibits', 'NegReg', (83, 91))	('TBK1', 'Gene', (0, 4))	('TBK1', 'Gene', '29110', (78, 82))	('cell migration', 'CPA', (92, 106))	('knockdown', 'Var', (65, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (23, 37))	('upregulated', 'PosReg', (8, 19))	('TBK1', 'Gene', (78, 82))
543295	32415055	also showed that inhibiting VAMP7 function reduces cell migration and invasion.	('VAMP7', 'Gene', '6845', (28, 33))	('VAMP7', 'Gene', (28, 33))	('inhibiting', 'Var', (17, 27))	('reduces', 'NegReg', (43, 50))
543337	27230238	Many researchers have reported that the use of rhBMP-2 in bone surgery is definitely related to a cancer risk, although they did not show incontrovertible evidence of the function of rhBMP-2 for promoting tumorigenesis or metastasis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('BMP-2', 'Gene', (185, 190))	('use', 'Var', (40, 43))	('rhBMP', 'Chemical', '-', (47, 52))	('related', 'Reg', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('BMP-2', 'Gene', (49, 54))	('BMP-2', 'Gene', '650', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('metastasis', 'CPA', (222, 232))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cancer', 'Disease', (98, 104))	('rhBMP', 'Chemical', '-', (183, 188))	('BMP-2', 'Gene', '650', (49, 54))	('promoting', 'PosReg', (195, 204))
543344	27230238	Because the increase of many genetic alterations drives cancer development, the Hippo pathway, which has been recently identified in Drosophila, has come under special scrutiny.	('genetic alterations', 'Var', (29, 48))	('increase', 'PosReg', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Drosophila', 'Species', '7227', (133, 143))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('Hippo pathway', 'Pathway', (80, 93))
543345	27230238	Because of overgrowth of cells and tissues when Hippo pathway components become mutated, the Hippo pathway has been postulated to be an important regulator of human cancer.	('overgrowth', 'PosReg', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Hippo', 'Gene', (48, 53))	('human', 'Species', '9606', (159, 164))	('mutated', 'Var', (80, 87))	('overgrowth', 'Phenotype', 'HP:0001548', (11, 21))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
543350	27230238	Deregulation of the Hippo pathway has been reported many times in human carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('Deregulation', 'Var', (0, 12))	('carcinomas', 'Disease', 'MESH:D002277', (72, 82))	('human', 'Species', '9606', (66, 71))	('carcinomas', 'Disease', (72, 82))	('Hippo pathway', 'Pathway', (20, 33))
543371	27230238	The growth rate of the TE-8 and TE-12 cells transfected with YAP siRNA were significantly inhibited compared with the cells transfected with the empty vector.	('inhibited', 'NegReg', (90, 99))	('growth rate', 'CPA', (4, 15))	('YAP', 'Var', (61, 64))	('TE-12', 'CellLine', 'CVCL:1762', (32, 37))
543372	27230238	In addition, silencing of YAP plus rhBMP-2 treatment in TE-8 and TE-12 cell lines resulted in significantly decreased cellular proliferation compared with cells transfected with the empty vector or YAP siRNA, respectively.	('cellular proliferation', 'CPA', (118, 140))	('TE-12', 'CellLine', 'CVCL:1762', (65, 70))	('decreased', 'NegReg', (108, 117))	('BMP-2', 'Gene', (37, 42))	('rhBMP', 'Chemical', '-', (35, 40))	('YAP', 'Gene', (26, 29))	('silencing', 'Var', (13, 22))	('BMP-2', 'Gene', '650', (37, 42))
543379	27230238	The expression of p-YAP was increased in TE-8 and TE-12 cells, whereas the expression of YAP was not changed after the treatment with rhBMP-2.	('increased', 'PosReg', (28, 37))	('rhBMP', 'Chemical', '-', (134, 139))	('BMP-2', 'Gene', '650', (136, 141))	('expression', 'MPA', (4, 14))	('p-YAP', 'Var', (18, 23))	('TE-12', 'CellLine', 'CVCL:1762', (50, 55))	('BMP-2', 'Gene', (136, 141))
543385	27230238	We found that the direct interaction between Akt and RASSF1 was significantly diminished by rhBMP-2 treatment in the TE-12 cell line, whereas the interaction between Akt and RASSF1 was not affected in the TE-8 cell line.	('TE-12', 'CellLine', 'CVCL:1762', (117, 122))	('Akt', 'Gene', (45, 48))	('diminished', 'NegReg', (78, 88))	('RASSF1', 'Gene', (53, 59))	('BMP-2', 'Gene', (94, 99))	('treatment', 'Var', (100, 109))	('BMP-2', 'Gene', '650', (94, 99))	('direct interaction', 'Interaction', (18, 36))	('rhBMP', 'Chemical', '-', (92, 97))
543419	27230238	In addition, dysregulation of the Hippo pathway has been implicated in many types of cancers.	('implicated', 'Reg', (57, 67))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('dysregulation', 'Var', (13, 26))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('Hippo pathway', 'Pathway', (34, 47))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
543423	27230238	In addition, silencing of YAP significantly inhibited the growth rate of TE-8 and TE-12 cells.	('YAP', 'Gene', (26, 29))	('inhibited', 'NegReg', (44, 53))	('TE-12', 'CellLine', 'CVCL:1762', (82, 87))	('silencing', 'Var', (13, 22))
543424	27230238	Moreover, the silencing of YAP plus rhBMP-2 treatment in TE-8 and TE-12 cells resulted in significantly decreased cellular proliferation compared with cells transfected with an empty vector or with YAP siRNA, respectively.	('YAP', 'Gene', (27, 30))	('cellular proliferation', 'CPA', (114, 136))	('BMP-2', 'Gene', (38, 43))	('silencing', 'Var', (14, 23))	('rhBMP', 'Chemical', '-', (36, 41))	('TE-12', 'CellLine', 'CVCL:1762', (66, 71))	('decreased', 'NegReg', (104, 113))	('BMP-2', 'Gene', '650', (38, 43))
543431	27230238	In addition, the induced expression of p-YAP in TE-8 and TE-12 cells by rhBMP-2 was inhibited by the RASSF1 silencing.	('silencing', 'NegReg', (108, 117))	('BMP-2', 'Gene', '650', (74, 79))	('p-YAP', 'Var', (39, 44))	('expression', 'MPA', (25, 35))	('RASSF1', 'Gene', (101, 107))	('BMP-2', 'Gene', (74, 79))	('rhBMP', 'Chemical', '-', (72, 77))	('TE-12', 'CellLine', 'CVCL:1762', (57, 62))	('inhibited', 'NegReg', (84, 93))
543482	27230238	TE-8 and TE-12 cells (2 x 105 cells/well) were cultured in a six-well tissue plate were transiently transfected with 100 pM of RASSF1 small interfering RNA (siRNA), YAP siRNA, or control siRNA (Santa Cruz biotechnology) according to the manufacturer's instructions.	('small interfering', 'Var', (134, 151))	('RASSF1', 'Gene', (127, 133))	('TE-12', 'CellLine', 'CVCL:1762', (9, 14))
543525	26537271	The effect of weight gain on the GERD is important, it is estimated that the increase of 3.5 points in BMI increases by approximately three times the risk of developing symptoms of reflux.	('weight gain', 'Disease', (14, 25))	('BMI increase', 'Phenotype', 'HP:0031418', (103, 115))	('increase', 'Var', (77, 85))	('BMI', 'Gene', (103, 106))	('weight gain', 'Disease', 'MESH:D015430', (14, 25))	('weight gain', 'Phenotype', 'HP:0004324', (14, 25))
543543	26294209	Production of inducible nitric oxide synthase (iNOS) and arginase, as well as other suppressive mechanisms, allow MDSCs to suppress T cell-mediated tumor clearance and foster tumor progression.	('tumor', 'Disease', (175, 180))	('inducible nitric oxide synthase', 'Gene', '18126', (14, 45))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('foster', 'PosReg', (168, 174))	('MDSCs', 'Var', (114, 119))	('inducible nitric oxide synthase', 'Gene', (14, 45))	('suppress', 'NegReg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
543545	26294209	We find that CD38 expression in MDSCs is evident in other mouse tumor models of esophageal carcinogenesis, and CD38high MDSCs are more immature than MDSCs lacking CD38 expression, suggesting a potential role for CD38 in the maturation halt found in MDSC populations.	('mouse', 'Species', '10090', (58, 63))	('tumor', 'Disease', (64, 69))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (80, 105))	('esophageal carcinogenesis', 'Disease', (80, 105))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CD38high', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
543546	26294209	CD38high MDSCs also possess a greater capacity to suppress activated T cells, and promote tumor growth to a greater degree than CD38low MDSCs, likely as a result of increased iNOS production.	('promote', 'PosReg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CD38high', 'Var', (0, 8))	('tumor', 'Disease', (90, 95))	('suppress', 'NegReg', (50, 58))	('activated T cells', 'CPA', (59, 76))	('increased', 'PosReg', (165, 174))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
543558	26294209	Foxp3+CD25+CD4+ Tregs expressing high CD38 levels possess a greater immunosuppressive activity than CD38low Tregs.	('high', 'Var', (33, 37))	('CD4', 'Gene', '12504', (11, 14))	('immunosuppressive activity', 'CPA', (68, 94))	('Foxp3', 'Gene', '20371', (0, 5))	('CD25', 'Gene', (6, 10))	('CD25', 'Gene', '16184', (6, 10))	('CD38', 'MPA', (38, 42))	('Foxp3', 'Gene', (0, 5))	('CD4', 'Gene', (11, 14))
543565	26294209	In both mouse and human myeloid cells, ligation of CD38 receptor leads to suppressed growth and survival resulting in loss of the most differentiated immune populations.	('CD38', 'Gene', (51, 55))	('suppressed', 'NegReg', (74, 84))	('ligation', 'Var', (39, 47))	('human', 'Species', '9606', (18, 23))	('survival', 'CPA', (96, 104))	('loss', 'NegReg', (118, 122))	('growth', 'CPA', (85, 91))	('mouse', 'Species', '10090', (8, 13))
543568	26294209	Finally, we have demonstrated that administration of an anti-CD38 monoclonal antibody slows disease progression in tumor-bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('slows', 'NegReg', (86, 91))	('tumor', 'Disease', (115, 120))	('anti-CD38', 'Gene', (56, 65))	('anti-CD38', 'Var', (56, 65))	('mice', 'Species', '10090', (129, 133))	('disease progression', 'CPA', (92, 111))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
543572	26294209	We have propagated cells from frozen stocks of the original vials that were authenticated by short tandem repeat analysis for highly polymorphic microsatellites FES/FPS, vWA31, D22S417, D10S526 and D5S592 so as to validate the identity of cells by comparing cells from the earliest stocks and those grown >8-12 passages.	('stocks', 'Species', '3724', (37, 43))	('D10S526', 'Var', (186, 193))	('D22S417', 'Var', (177, 184))	('stocks', 'Species', '3724', (282, 288))	('D5S592', 'Var', (198, 204))	('FES/FPS', 'Gene', (161, 168))
543589	26294209	C57BL/6J recipient mice from Jackson Labs were injected subcutaneously with a mixture of 2.5x105 syngeneic HNM007 tumor cells with either 2.5x105 CD38low or CD38hi MDSCs obtained from HNM007 tumor-bearing C57BL/6J mice.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('HNM007 tumor', 'Disease', (107, 119))	('HNM007 tumor', 'Disease', 'MESH:D009369', (107, 119))	('HNM007 tumor', 'Disease', (184, 196))	('CD38low', 'Var', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('HNM007 tumor', 'Disease', 'MESH:D009369', (184, 196))	('CD38hi', 'Var', (157, 163))	('mice', 'Species', '10090', (214, 218))	('mice', 'Species', '10090', (19, 23))
543591	26294209	For antibody treatment experiments, anti-CD38 monoclonal antibody or IgG2a isotype control antibody were administered intraperitoneally every 48 hours starting on day 5 post-injection.	('anti-CD38', 'Var', (36, 45))	('IgG2a', 'Gene', '668478', (69, 74))	('IgG2a', 'Gene', (69, 74))
543594	26294209	We have previously demonstrated that MDSCs play a fundamental role in tumor initiation and progression in a spontaneous genetic mouse model of ESCC (L2-Cre;p120f/f; referred to hereafter as p120-/-).	('p120f/f', 'Var', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor initiation', 'Disease', 'MESH:D009369', (70, 86))	('ESCC', 'Disease', (143, 147))	('mouse', 'Species', '10090', (128, 133))	('tumor initiation', 'Disease', (70, 86))	('p120-/-', 'Gene', (190, 197))	('p120-/-)', 'Gene', '12388', (190, 198))
543601	26294209	CD11b+Gr-1+ cells were slightly more abundant in spleens of non-diseased p120-/- mice and markedly elevated in spleens of tumor-bearing p120-/- mice, compared to control mice (Fig 2A).	('mice', 'Species', '10090', (81, 85))	('p120-/-', 'Var', (73, 80))	('mice', 'Species', '10090', (144, 148))	('CD11b+Gr-1+', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('elevated', 'PosReg', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mice', 'Species', '10090', (170, 174))	('p120-/-', 'Var', (136, 143))	('tumor', 'Disease', (122, 127))
543607	26294209	There also was a trend of M-MDSC (CD11b+Ly-6C+) expansion, accompanied by a significant increase in mature monocytes (CD11b+Ly-6C-Ly-6G-) in HNM007, compared to AKR tumor-bearing and control mice (p=0.02).	('Ly-6G', 'Gene', '546644', (130, 135))	('Ly-6G', 'Gene', (130, 135))	('HNM007', 'Var', (141, 147))	('Ly-6C', 'Gene', (40, 45))	('Ly-6C', 'Gene', '17067', (124, 129))	('increase', 'PosReg', (88, 96))	('mature monocytes', 'CPA', (100, 116))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Ly-6C', 'Gene', '17067', (40, 45))	('Ly-6C', 'Gene', (124, 129))	('mice', 'Species', '10090', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
543609	26294209	Since the CD38high MDSC population expands in tumor-bearing mice, we hypothesized that CD38high MDSCs possess greater immunosuppressive potential than CD38low MDSCs.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('CD38high', 'Var', (87, 95))	('mice', 'Species', '10090', (60, 64))	('immunosuppressive potential', 'CPA', (118, 145))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
543610	26294209	To test this, we sorted CD38high and CD38low MDSCs from HNM007 tumor-bearing mice and assessed their capacity to suppress OT-1 T cell growth following antigen stimulation.	('mice', 'Species', '10090', (77, 81))	('HNM007 tumor', 'Disease', (56, 68))	('suppress', 'NegReg', (113, 121))	('CD38high', 'Var', (24, 32))	('HNM007 tumor', 'Disease', 'MESH:D009369', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('OT-1 T cell growth', 'MPA', (122, 140))	('CD38low', 'Var', (37, 44))
543611	26294209	Next we evaluated the impact of co-injection of CD38high MDSCs with HNM007 cells on tumor growth.	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('CD38high', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
543612	26294209	Tumor volumes in CD38high group were significantly larger than CD38low tumors on days 6 and 10 (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('larger', 'PosReg', (51, 57))	('CD38high', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('Tumor volumes', 'CPA', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
543614	26294209	No difference in size was detected between the CD38low and control HNM007 tumors.	('CD38low', 'Var', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('HNM007 tumors', 'Disease', 'MESH:D009369', (67, 80))	('HNM007 tumors', 'Disease', (67, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
543618	26294209	These results suggest that CD38high MDSCs may possess greater tumor-promoting capacity than CD38low MDSCs in vivo.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CD38high', 'Var', (27, 35))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
543621	26294209	Next we analyzed CD38high and CD38low splenic MDSCs from tumor-bearing p120-/- mice via microarray (Supplementary Fig.5; GEO accession number GSE71706) and detected differential expression of 498 genes (Fig.	('differential', 'Reg', (165, 177))	('expression', 'MPA', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mice', 'Species', '10090', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('CD38low', 'Var', (30, 37))
543623	26294209	qPCR analysis further revealed that iNos expression was significantly elevated in CD38high MDSCs compared to CD38low MDSCs, while expression of arginase 1 (Arg1) and NADPH oxidase subunit (Nox2) , two additional mediators of MDSC suppressive function, was comparable in these subpopulations (Fig.	('iNos', 'Gene', '18126', (36, 40))	('CD38high', 'Var', (82, 90))	('elevated', 'PosReg', (70, 78))	('Nox2', 'Gene', '13058', (189, 193))	('expression', 'MPA', (41, 51))	('arginase 1', 'Gene', '11846', (144, 154))	('Nox2', 'Gene', (189, 193))	('iNos', 'Gene', (36, 40))	('Arg1', 'Gene', '11846', (156, 160))	('arginase 1', 'Gene', (144, 154))	('Arg1', 'Gene', (156, 160))
543624	26294209	Since iNos is a target of NFkappaB transactivation, we evaluated the levels of total and phosphorylated NFkappaB in CD38high and CD38low MDSCs and found increased phosphoNFkappaB-to-totalNFkappaB ratio in the CD38high population (Fig.	('phosphoNFkappaB-to-totalNFkappaB ratio', 'MPA', (163, 201))	('CD38high', 'Var', (209, 217))	('increased', 'PosReg', (153, 162))	('iNos', 'Gene', '18126', (6, 10))	('iNos', 'Gene', (6, 10))
543625	26294209	To test whether iNOS contributes to the increased immunosuppressive capacity of CD38high MDSCs, we used an iNOS inhibitor (L-NMMA), and found that it completely abrogated OT-1 T cell suppression mediated by CD38high MDSCs (Fig.	('CD38high MDSCs', 'Var', (207, 221))	('abrogated', 'NegReg', (161, 170))	('OT-1 T cell', 'MPA', (171, 182))	('L-NMMA', 'Chemical', 'MESH:D019323', (123, 129))
543629	26294209	A cytokine array using CM from ex vivo differentiation experiments revealed several factors, including CXCL16 and IGFBP-3 that were present at higher levels in HNM007 cultures as compared to AKR cultures (Fig.5B).	('CXCL16', 'Gene', (103, 109))	('IGFBP-3', 'Gene', (114, 121))	('HNM007', 'Var', (160, 166))	('IGFBP-3', 'Gene', '16009', (114, 121))	('CXCL16', 'Gene', '66102', (103, 109))
543630	26294209	In addition, the pro-inflammatory cytokine IL-6, a predicted activator of CD38 transcription, was elevated in HNM007 cultures, albeit not as dramatically as CXCL16 or IGFBP-3 (Fig.	('CXCL16', 'Gene', (157, 163))	('IGFBP-3', 'Gene', '16009', (167, 174))	('IL-6', 'Gene', (43, 47))	('HNM007', 'Var', (110, 116))	('elevated', 'PosReg', (98, 106))	('IL-6', 'Gene', '16193', (43, 47))	('CXCL16', 'Gene', '66102', (157, 163))	('CD38', 'Gene', (74, 78))	('IGFBP-3', 'Gene', (167, 174))
543633	26294209	To test whether cross-linking of CD38 with a monoclonal antibody has an effect on MDSC function(s), MDSCs from spleens of tumor-bearing p120-/- mice were cultured in methylcellulose-based medium in the presence of an anti-CD38 monoclonal antibody (NIM-R5) or isotype control (IgG2a).	('IgG2a', 'Gene', '668478', (276, 281))	('effect', 'Reg', (72, 78))	('mice', 'Species', '10090', (144, 148))	('IgG2a', 'Gene', (276, 281))	('anti-CD38', 'Var', (217, 226))	('anti-CD38', 'Gene', (217, 226))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('MDSC', 'MPA', (82, 86))	('methylcellulose', 'Chemical', 'MESH:D008747', (166, 181))	('CD38', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
543634	26294209	Addition of anti-CD38 antibody inhibited growth of colonies from splenic MDSCs, and the effect of anti- CD38 antibody remained unchanged regardless of whether splenocytes were pre-sorted (Fig.	('colon', 'Disease', 'MESH:D015179', (51, 56))	('growth', 'CPA', (41, 47))	('colon', 'Disease', (51, 56))	('inhibited', 'NegReg', (31, 40))	('anti-CD38', 'Var', (12, 21))
543635	26294209	Lastly, anti-CD38 antibody treatment resulted in decreased tumor growth rate in vivo in a subcutaneous HNM007 transplant ESCC model (Fig.	('anti-CD38', 'Var', (8, 17))	('decreased tumor', 'Disease', 'MESH:D009369', (49, 64))	('decreased tumor', 'Disease', (49, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
543640	26294209	Expansion of the CD11b+Gr-1+CD38high cell population occurs after initial splenic MDSC accumulation is evident, which likely indicates a requirement of threshold levels of tumor-derived signals for induction of CD38 by MDSCs (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('CD11b+Gr-1+CD38high', 'Var', (17, 36))
543643	26294209	Furthermore, our data suggest that the tumor-derived signals do not promote enhanced proliferation of CD38high MDSCs (RB1 pathway was activated in CD38high MDSCs (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CD38high', 'Var', (147, 155))	('activated', 'PosReg', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
543645	26294209	Interestingly, CD38 can induce iNOS upregulation in murine activated microglia (resident monocytes of the brain).	('murine', 'Species', '10090', (52, 58))	('upregulation', 'PosReg', (36, 48))	('iNOS', 'MPA', (31, 35))	('CD38', 'Var', (15, 19))
543648	26294209	This is consistent with observations made in murine B cells, where CD38 ligation activates NFkappaB.	('ligation', 'Var', (72, 80))	('activates', 'PosReg', (81, 90))	('NFkappaB', 'Protein', (91, 99))	('murine', 'Species', '10090', (45, 51))	('CD38', 'Protein', (67, 71))
543652	26294209	In fact, TNFalpha inhibition can impair immunosuppressive capacity of MDSCs and induce differentiation in a murine model of chronic inflammation, while MDSCs from Tnf-/- mice have reduced iNOS levels.	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('immunosuppressive capacity', 'MPA', (40, 66))	('iNOS levels', 'MPA', (188, 199))	('differentiation', 'CPA', (87, 102))	('inflammation', 'Disease', (132, 144))	('Tnf', 'Gene', (163, 166))	('induce', 'Reg', (80, 86))	('reduced', 'NegReg', (180, 187))	('Tnf', 'Gene', '21926', (163, 166))	('TNFalpha', 'Gene', (9, 17))	('impair', 'NegReg', (33, 39))	('inhibition', 'Var', (18, 28))	('mice', 'Species', '10090', (170, 174))	('murine', 'Species', '10090', (108, 114))
543660	26294209	These data are in agreement with our observation that IL-6 can promote CD38 expression on MDSCs generated ex vivo, since CD38high MDSCs are less differentiated than CD38low MDSCs (Fig.	('IL-6', 'Gene', (54, 58))	('IL-6', 'Gene', '16193', (54, 58))	('CD38high', 'Var', (121, 129))	('CD38', 'Gene', (71, 75))	('promote', 'PosReg', (63, 70))
543662	26294209	Recently, an anti-CD38 monoclonal antibody (Daratumumab) was shown to be efficient in treatment of multiple myeloma in pre-clinical studies.	('anti-CD38', 'Var', (13, 22))	('multiple myeloma', 'Phenotype', 'HP:0006775', (99, 115))	('multiple myeloma', 'Disease', 'MESH:D009101', (99, 115))	('Daratumumab', 'Chemical', 'MESH:C556306', (44, 55))	('multiple myeloma', 'Disease', (99, 115))
543725	26098420	Preparation of the stomach for gastric pull-up requires ligation of the left gastric, left gastroepiploic, and short gastric arteries.	('left gastroepiploic', 'Disease', (86, 105))	('left gastroepiploic', 'Disease', 'MESH:D018487', (86, 105))	('ligation', 'Var', (56, 64))	('rat', 'Species', '10116', (5, 8))
543744	26098420	First, 64Cu-ATSM is very lipophilic with low molecular weight, therefore is more permeable to high cell membrane than other imidazole-ring group hypoxia agents such as 18F-fluoromisonidazole (fMISO).	('fMISO', 'Chemical', 'MESH:C031843', (192, 197))	('permeable', 'MPA', (81, 90))	('64Cu-ATSM', 'Chemical', '-', (7, 16))	('18F-fluoromisonidazole', 'Chemical', 'MESH:C031843', (168, 190))	('hypoxia', 'Disease', 'MESH:D000860', (145, 152))	('hypoxia', 'Disease', (145, 152))	('imidazole', 'Chemical', 'MESH:C029899', (124, 133))	('more', 'PosReg', (76, 80))	('64Cu-ATSM', 'Var', (7, 16))
543750	26098420	The gastric fundus is the area most susceptible to ischemia after ligation of the left gastric and short gastric arteries.	('ligation', 'Var', (66, 74))	('ischemia', 'Disease', (51, 59))	('ischemia', 'Disease', 'MESH:D007511', (51, 59))
543765	26098420	However, 64Cu-ATSM has been accepted as a safe radiopharmaceutical that can be used to obtain high-quality images of tumor hypoxia in human cancers and other non-tumor conditions.	('human', 'Species', '9606', (134, 139))	('64Cu-ATSM', 'Chemical', '-', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('non-tumor', 'Disease', 'MESH:D009369', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('64Cu-ATSM', 'Var', (9, 18))	('tumor hypoxia', 'Disease', (117, 130))	('tumor hypoxia', 'Disease', 'MESH:D000860', (117, 130))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('non-tumor', 'Disease', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
543766	26098420	In conclusion, we showed that 64Cu-ATSM hypoxia PET imaging could detect ischemia of a gastric conduit after devascularization in a rat esophagectomy model.	('hypoxia', 'Disease', (40, 47))	('hypoxia', 'Disease', 'MESH:D000860', (40, 47))	('ischemia', 'Disease', 'MESH:D007511', (73, 81))	('rat', 'Species', '10116', (132, 135))	('detect', 'Reg', (66, 72))	('64Cu-ATSM', 'Chemical', '-', (30, 39))	('64Cu-ATSM', 'Var', (30, 39))	('ischemia', 'Disease', (73, 81))
543789	26060647	The NDD guideline proposed viscosity to range from thin (1-50 cP), nectar-thick (51-350 cP), honey-thick (351-1750 cP) to spoon thick (>1750 cP) foodstuffs.	('viscosity', 'MPA', (27, 36))	('51-350 cP', 'Var', (81, 90))	('NDD', 'Chemical', '-', (4, 7))	('351-1750', 'Var', (106, 114))
544009	18923929	Analysis of R213R and 13494 g a polymorphisms of the p53 gene in individuals with esophagitis, intestinal metaplasia of the cardia and Barrett's Esophagus compared with a control group Protein p53 is the tumor suppressor involved in cell cycle control and apoptosis.	('esophagitis', 'Disease', 'MESH:D004941', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('intestinal metaplasia of the cardia', 'Disease', 'MESH:D008679', (95, 130))	('p53', 'Gene', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('intestinal metaplasia of the cardia', 'Disease', (95, 130))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (135, 154))	('p53', 'Gene', '7157', (193, 196))	('tumor', 'Disease', (204, 209))	('p53', 'Gene', (53, 56))	('R213R', 'Mutation', 'rs1800372', (12, 17))	('p53', 'Gene', '7157', (53, 56))	('13494 g a', 'Var', (22, 31))	('esophagitis', 'Phenotype', 'HP:0100633', (82, 93))	('R213R', 'Var', (12, 17))	('esophagitis', 'Disease', (82, 93))
544010	18923929	There are several polymorphisms reported for p53 which can affect important regions involved in protein tumor suppressor activity.	('affect', 'Reg', (59, 65))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('protein tumor', 'Disease', 'MESH:D009369', (96, 109))	('polymorphisms', 'Var', (18, 31))	('protein tumor', 'Disease', (96, 109))	('regions involved', 'MPA', (76, 92))
544011	18923929	Amongst the polymorphisms described, R213R and 13949 g a are rarely studied, with an estimate frequency not yet available for the Brazilian population.	('R213R', 'Mutation', 'rs1800372', (37, 42))	('R213R', 'Var', (37, 42))	('13949 g a', 'Var', (47, 56))
544013	18923929	A total of 35 patients for R213R and 45 for 13494 g a polymorphisms analysis with gastroesophageal reflux disease (GERD) symptoms diagnosed by upper digestive endoscopy and confirmed by biopsy were studied.	('R213R', 'Mutation', 'rs1800372', (27, 32))	('gastroesophageal reflux disease', 'Disease', (82, 113))	('R213R', 'Var', (27, 32))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (82, 105))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (82, 113))	('GERD', 'Disease', (115, 119))	('GERD', 'Disease', 'MESH:D005764', (115, 119))	('patients', 'Species', '9606', (14, 22))
544015	18923929	There was one patient with Barrett's Esophagus (BE) showing LOH for R213R out of two heterozygous samples analyzed and two patients (esophagitis and BE) for 13494 g a polymorphism.	('esophagitis', 'Disease', (133, 144))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (27, 46))	('esophagitis', 'Disease', 'MESH:D004941', (133, 144))	('patient', 'Species', '9606', (123, 130))	("Barrett's Esophagus", 'Disease', (27, 46))	('BE', 'Phenotype', 'HP:0100580', (149, 151))	('R213R', 'Var', (68, 73))	('patients', 'Species', '9606', (123, 131))	('patient', 'Species', '9606', (14, 21))	('R213R', 'Mutation', 'rs1800372', (68, 73))	('BE', 'Phenotype', 'HP:0100580', (48, 50))	('esophagitis', 'Phenotype', 'HP:0100633', (133, 144))
544027	18923929	Gene mutations in the tumor-suppressing p53 gene were the abnormalities most commonly reported.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('p53', 'Gene', (40, 43))	('p53', 'Gene', '7157', (40, 43))	('tumor', 'Disease', (22, 27))	('Gene mutations', 'Var', (0, 14))
544028	18923929	The incidence of mutations tends to increase with the metaplasia-dysplasia-adenocarcinoma progression, ranging from rare in non-dysplastic epithelium to up to 90% in adenocarcinoma (Neshat et al.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('non-dysplastic', 'Disease', (124, 138))	('non-dysplastic', 'Disease', 'MESH:D004416', (124, 138))	('increase', 'PosReg', (36, 44))	('adenocarcinoma', 'Disease', 'MESH:D000230', (75, 89))	('adenocarcinoma', 'Disease', 'MESH:D000230', (166, 180))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', 'MESH:D008679', (54, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('adenocarcinoma', 'Disease', (166, 180))	('mutations', 'Var', (17, 26))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', (54, 89))	('adenocarcinoma', 'Disease', (75, 89))
544029	18923929	More than 90% of the mutations described for the p53 gene occur between exons 4 and 9, which encompass protein domains II-V.	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (49, 52))	('mutations', 'Var', (21, 30))
544031	18923929	p53 gene mutations can damage its DNA-binding or transactivation functions, thereby inhibiting its key role in the cell cycle control.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('transactivation', 'MPA', (49, 64))	('mutations', 'Var', (9, 18))	('damage', 'NegReg', (23, 29))	('DNA-binding', 'Interaction', (34, 45))	('inhibiting', 'NegReg', (84, 94))	('cell cycle control', 'CPA', (115, 133))
544032	18923929	In the majority of these cases where the mutation is recessive, tumor cells often retained only the mutated allele and lose the wild type, while blood cells harbor both alleles.	('mutated', 'Var', (100, 107))	('tumor', 'Disease', (64, 69))	('wild type', 'MPA', (128, 137))	('lose', 'NegReg', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
544034	18923929	Mutations in tumor suppressor p53 gene have been detected in more than 25% of patients with Barrett's metaplasia submitted to endoscopy and in more than 75% of Barrett's adenocarcinomas (Aldulaimi and Jankowski).	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('detected', 'Reg', (49, 57))	('patients', 'Species', '9606', (78, 86))	("Barrett's adenocarcinomas", 'Disease', 'MESH:D001471', (160, 185))	("Barrett's adenocarcinomas", 'Disease', (160, 185))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (92, 112))	("Barrett's metaplasia", 'Disease', (92, 112))
544038	18923929	The R213R polymorphism retains the arginine amino acid, the most frequent codon being CGA and the polymorphic, CGG.	('CGA', 'Gene', (86, 89))	('R213R', 'Var', (4, 9))	('arginine amino acid', 'MPA', (35, 54))	('arginine amino acid', 'Chemical', '-', (35, 54))	('CGA', 'Gene', '1113', (86, 89))	('frequent', 'Reg', (65, 73))	('R213R', 'Mutation', 'rs1800372', (4, 9))
544040	18923929	Our study aimed to estimate the frequency of R213R and 13494 g a polymorphisms in control individuals, who represent the population of Porto Alegre, and in individuals with alterations in the esophageal tissue from the southernmost region of Brazil.	('13494 g a', 'Var', (55, 64))	('R213R', 'Mutation', 'rs1800372', (45, 50))	('R213R', 'Var', (45, 50))
544042	18923929	Furthermore, it also purports to build a haplotype for both polymorphisms collectively analyzed with the R27P polymorphism of exon 4 of the TP53, previously analyzed by our group (Leistner-Segal et al.).	('R27P', 'Mutation', 'p.R27P', (105, 109))	('TP53', 'Gene', '7157', (140, 144))	('R27P', 'Var', (105, 109))	('TP53', 'Gene', (140, 144))
544045	18923929	A total of 35 patients (17 female and 18 male; ages ranging between 23 years and 82 years; average of 51.1 years) with gastroesophageal reflux disease (GERD) symptoms diagnosed by upper digestive endoscopy and confirmed by biopsy were analyzed for the R213R polymorphism, while for the 13494 g a polymorphism analysis a total of 45 individuals (22 female and 23 male; ages ranging between 23  years and 82 years; average of 51.4 years) were used.	('R213R', 'Var', (252, 257))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (119, 142))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (119, 150))	('gastroesophageal reflux disease', 'Disease', (119, 150))	('R213R', 'Mutation', 'rs1800372', (252, 257))	('GERD', 'Disease', (152, 156))	('GERD', 'Disease', 'MESH:D005764', (152, 156))	('patients', 'Species', '9606', (14, 22))
544053	18923929	R213R (exon 6) polymorphism: to identify the R213R polymorphism, digestion of the long PCR product was carried out using TaqI (New England BioLabs ) enzyme to cleave the T'CGA site, according to the manufacturer's instructions.	('R213R', 'Mutation', 'rs1800372', (45, 50))	('CGA', 'Gene', '1113', (172, 175))	('R213R', 'Var', (45, 50))	('R213R', 'Mutation', 'rs1800372', (0, 5))	('CGA', 'Gene', (172, 175))
544057	18923929	Only individuals who presented a heterozygous pattern in their blood were considered (n = 2 for the R213R polymorphism and n = 12 for the 13494 g a polymorphism), respectively 8% and 33% of the sample for each polymorphism.	('13494 g a', 'Var', (138, 147))	('R213R', 'Mutation', 'rs1800372', (100, 105))	('R213R', 'Var', (100, 105))
544059	18923929	For R213R polymorphism analysis, 20% (7/35) showed esophagitis, 37.1% (13/45) showed IMC and 42.9% (15/35) showed BE.	('esophagitis', 'Phenotype', 'HP:0100633', (51, 62))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('esophagitis', 'Disease', (51, 62))	('IMC', 'Disease', (85, 88))	('R213R', 'Var', (4, 9))	('esophagitis', 'Disease', 'MESH:D004941', (51, 62))	('R213R', 'Mutation', 'rs1800372', (4, 9))
544060	18923929	For the 13494 g a polymorphism, 27% (12/45) showed esophagitis, 37.8% (17/45) IMC and 35.6% (16/45) BE.	('BE', 'Phenotype', 'HP:0100580', (100, 102))	('esophagitis', 'Phenotype', 'HP:0100633', (51, 62))	('esophagitis', 'Disease', (51, 62))	('esophagitis', 'Disease', 'MESH:D004941', (51, 62))	('13494 g a', 'Var', (8, 17))
544067	18923929	The patients that present the polymorphic allele (A) showed esophagitis (4/45), IMC (5/45) and BE (3/45).	('polymorphic', 'Var', (30, 41))	('esophagitis', 'Disease', 'MESH:D004941', (60, 71))	('BE', 'Phenotype', 'HP:0100580', (95, 97))	('patients', 'Species', '9606', (4, 12))	('esophagitis', 'Disease', (60, 71))	('esophagitis', 'Phenotype', 'HP:0100633', (60, 71))	('IMC', 'Disease', (80, 83))
544072	18923929	The R213R and 13494 g a polymorphisms were jointly analyzed with the R27P polymorphism, previously reported by us using the same group of patients (Leistner-Segal et al.).	('13494 g a', 'Var', (14, 23))	('R213R', 'Var', (4, 9))	('R27P', 'Mutation', 'p.R27P', (69, 73))	('R213R', 'Mutation', 'rs1800372', (4, 9))	('patients', 'Species', '9606', (138, 146))
544075	18923929	In the allele frequency analysis there were no significant difference between the three histological types (esophagitis, IMC and BE) for none of the polymorphisms, R213R, 13494 g a and R72P (P = 0.7600, P = 0.8438 and P = 0.8557, respectively).	('esophagitis', 'Phenotype', 'HP:0100633', (108, 119))	('esophagitis', 'Disease', (108, 119))	('R213R', 'Var', (164, 169))	('R72P', 'Var', (185, 189))	('BE', 'Phenotype', 'HP:0100580', (129, 131))	('R213R', 'Mutation', 'rs1800372', (164, 169))	('R72P', 'Mutation', 'rs1042522', (185, 189))	('esophagitis', 'Disease', 'MESH:D004941', (108, 119))	('13494 g a', 'Var', (171, 180))	('IMC', 'Disease', (121, 124))
544078	18923929	A consistent association between these polymorphisms and several types of human neoplasias may serve as argument supporting such sites as susceptibility determiners (IARC).	('polymorphisms', 'Var', (39, 52))	('neoplasia', 'Phenotype', 'HP:0002664', (80, 89))	('neoplasias', 'Phenotype', 'HP:0002664', (80, 90))	('neoplasias', 'Disease', 'MESH:D009369', (80, 90))	('human', 'Species', '9606', (74, 79))	('neoplasias', 'Disease', (80, 90))
544080	18923929	We thus investigated the relationship linking the R213R and 13494 g a polymorphisms of the p53 gene and the premalignant esophageal alterations (esophagitis, IMC and BE).	('premalignant esophageal alterations', 'Disease', (108, 143))	('premalignant esophageal alterations', 'Disease', 'MESH:D004941', (108, 143))	('R213R', 'Var', (50, 55))	('IMC', 'Disease', (158, 161))	('esophagitis', 'Phenotype', 'HP:0100633', (145, 156))	('BE', 'Phenotype', 'HP:0100580', (166, 168))	('investigated', 'Reg', (8, 20))	('esophagitis', 'Disease', (145, 156))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('esophagitis', 'Disease', 'MESH:D004941', (145, 156))	('R213R', 'Mutation', 'rs1800372', (50, 55))	('13494 g a', 'Var', (60, 69))
544081	18923929	Also, countless studies indicate an association between the R72P polymorphism at exon 4 of TP53 and the increased risk of developing neoplasias (Malcolm et al.	('TP53', 'Gene', (91, 95))	('R72P', 'Var', (60, 64))	('neoplasias', 'Disease', 'MESH:D009369', (133, 143))	('neoplasias', 'Disease', (133, 143))	('neoplasias', 'Phenotype', 'HP:0002664', (133, 143))	('neoplasia', 'Phenotype', 'HP:0002664', (133, 142))	('TP53', 'Gene', '7157', (91, 95))	('R72P', 'Mutation', 'rs1042522', (60, 64))
544082	18923929	In the present study the genotypic distribution of the R213R and 13494 g a polymorphisms are in agreement with the Hardy-Weinberg equilibrium in the patient group as well as in the control group.	('R213R', 'Mutation', 'rs1800372', (55, 60))	('R213R', 'Var', (55, 60))	('13494 g', 'Var', (65, 72))	('patient', 'Species', '9606', (149, 156))
544094	18923929	Abnormalities involving the TP53 are common with esophageal adenocarcinoma and have been detected in pre-malignant tissues surrounding the esophageal cancer (Prevo et al.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('TP53', 'Gene', '7157', (28, 32))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (49, 74))	('Abnormalities', 'Var', (0, 13))	('TP53', 'Gene', (28, 32))	('common', 'Reg', (37, 43))	('esophageal cancer', 'Disease', (139, 156))	('esophageal adenocarcinoma', 'Disease', (49, 74))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (49, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
544095	18923929	reported molecular and genomic alterations identifying LOH in 94% of Barrett cancers and 88% of mutations in the TP53.	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('Barrett cancers', 'Disease', 'MESH:D001471', (69, 84))	('Barrett cancers', 'Disease', (69, 84))	('TP53', 'Gene', '7157', (113, 117))	('LOH', 'Var', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TP53', 'Gene', (113, 117))	('mutations', 'Var', (96, 105))
544096	18923929	Allelic loss of 17p has been detected in initial stages of high-degree metaplasia and dysplasia, leading to aneuploidy and suggesting that inactivation of the TP53 is a first step in carcinogenesis.	('aneuploidy', 'Disease', (108, 118))	('carcinogenesis', 'Disease', (183, 197))	('Allelic loss', 'Var', (0, 12))	('leading', 'Reg', (97, 104))	('metaplasia and dysplasia', 'Disease', 'MESH:D008679', (71, 95))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (159, 163))	('aneuploidy', 'Disease', 'MESH:D000782', (108, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (183, 197))	('inactivation', 'Var', (139, 151))
544098	18923929	Identification of these alterations may help select patients with a higher risk of developing cancer, allowing optimization of treatments (Lacerda et al.).	('alterations', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('patients', 'Species', '9606', (52, 60))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
544099	18923929	Considering our data regarding the incidence of alleles, genotypes and haplotypes of the R213R, 13494 g a and R72P polymorphisms of the p53 gene in patients and controls, we can suggest that these three sites do not represent genetic susceptibility determiners to esophagitis, intestinal metaplasia of the cardia and BE.	('BE', 'Phenotype', 'HP:0100580', (317, 319))	('patients', 'Species', '9606', (148, 156))	('13494 g a', 'Var', (96, 105))	('intestinal metaplasia of the cardia', 'Disease', 'MESH:D008679', (277, 312))	('R213R', 'Var', (89, 94))	('p53', 'Gene', '7157', (136, 139))	('esophagitis', 'Phenotype', 'HP:0100633', (264, 275))	('esophagitis', 'Disease', (264, 275))	('esophagitis', 'Disease', 'MESH:D004941', (264, 275))	('R72P', 'Mutation', 'rs1042522', (110, 114))	('intestinal metaplasia of the cardia', 'Disease', (277, 312))	('R72P', 'Var', (110, 114))	('R213R', 'Mutation', 'rs1800372', (89, 94))	('p53', 'Gene', (136, 139))
544111	33902648	There was also a significant correlation between MAEL expression and depth of invasion in which tumor with T1/2 had higher levels of MAEL expression compared with T3/4 tumors (p=0.017).	('MAEL', 'Gene', '84944', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (168, 173))	('higher', 'PosReg', (116, 122))	('MAEL', 'Gene', (49, 53))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('MAEL', 'Gene', '84944', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('levels', 'MPA', (123, 129))	('T1/2', 'Var', (107, 111))	('MAEL', 'Gene', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
544120	33902648	Genetic aberrations have also an important role during ESCC progression among Iranians through deregulation of various cell and molecular processes such as cell cycle, DNA repair, and developmental signaling pathways.	('deregulation', 'Reg', (95, 107))	('cell', 'CPA', (119, 123))	('DNA repair', 'Pathway', (168, 178))	('SCC', 'Gene', (56, 59))	('developmental signaling pathways', 'Pathway', (184, 216))	('Genetic aberrations', 'Var', (0, 19))	('SCC', 'Gene', '6317', (56, 59))	('cell cycle', 'CPA', (156, 166))
544174	33902648	In the case of tumor depth of invasion, there was also a significant correlation between MAEL expression and depth of invasion in which tumor with T1/2 had higher levels of MAEL expression compared with T3/4 tumors (1.54 +- 0.87 VS. -0.29 +- 0.42 fold changes) (p = 0.017).	('higher', 'PosReg', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('MAEL', 'Gene', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('T1/2', 'Var', (147, 151))	('MAEL', 'Gene', '84944', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumors', 'Disease', (208, 214))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (208, 213))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('MAEL', 'Gene', (173, 177))	('tumor', 'Disease', (136, 141))	('MAEL', 'Gene', '84944', (173, 177))
544201	33902648	Therefore, every aberration in such processes will be resulted in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('aberration', 'Var', (17, 27))	('resulted in', 'Reg', (54, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
544229	33503901	A meta-analysis showed that the postoperative symptoms of constipation, speech problems and insomnia increased for a long time after MIE.	('constipation', 'Disease', (58, 70))	('speech problems', 'Disease', (72, 87))	('insomnia', 'Disease', 'MESH:D007319', (92, 100))	('MIE', 'Var', (133, 136))	('insomnia', 'Disease', (92, 100))	('insomnia', 'Phenotype', 'HP:0100785', (92, 100))	('constipation', 'Phenotype', 'HP:0002019', (58, 70))	('speech problems', 'Phenotype', 'HP:0000750', (72, 87))	('constipation', 'Disease', 'MESH:D003248', (58, 70))
544230	33503901	The use of MIE was associated with modestly improved perioperative outcomes comparing with OE in western esophageal cancer patients.	('cancer', 'Disease', (116, 122))	('perioperative outcomes', 'CPA', (53, 75))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('patients', 'Species', '9606', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('improved', 'PosReg', (44, 52))	('MIE', 'Var', (11, 14))
544251	33503901	Both intraoperative bleeding volume and incidence of pneumonia of MIE group were significantly lower than OE group (Table 1).	('MIE', 'Var', (66, 69))	('lower', 'NegReg', (95, 100))	('intraoperative bleeding', 'Disease', 'MESH:D016063', (5, 28))	('intraoperative bleeding', 'Disease', (5, 28))	('pneumonia', 'Phenotype', 'HP:0002090', (53, 62))	('pneumonia', 'Disease', (53, 62))	('pneumonia', 'Disease', 'MESH:D011014', (53, 62))
544254	33503901	Six months later, global health status, role function, social function, fatigue, pain and economic difficulties in MIE group were better than OE group.	('pain', 'Disease', (81, 85))	('better', 'PosReg', (130, 136))	('fatigue', 'Disease', (72, 79))	('social function', 'CPA', (55, 70))	('fatigue', 'Disease', 'MESH:D005221', (72, 79))	('economic difficulties', 'CPA', (90, 111))	('MIE', 'Var', (115, 118))	('fatigue', 'Phenotype', 'HP:0012378', (72, 79))	('pain', 'Phenotype', 'HP:0012531', (81, 85))	('global health status', 'CPA', (18, 38))	('role function', 'CPA', (40, 53))	('pain', 'Disease', 'MESH:D010146', (81, 85))
544267	33503901	Consistent with previous studies, we reported that the intraoperative bleeding volume of MIE group was significantly lower than OE group, because of the clearer operative vision on vascular anatomy due to the magnifying effect thoracoscope.	('MIE', 'Var', (89, 92))	('intraoperative bleeding', 'Disease', (55, 78))	('intraoperative bleeding', 'Disease', 'MESH:D016063', (55, 78))	('lower', 'NegReg', (117, 122))
544275	33503901	It was suggested that the quality of life of MIE group patients was better than OE group which was consist with previous study in western patients.	('better', 'PosReg', (68, 74))	('quality of life', 'CPA', (26, 41))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (138, 146))	('MIE', 'Var', (45, 48))
544280	33503901	According to OES-18, the score of troublesome feeding, pain and troublesome taste of MIE group were lower than OE group, which meant the quality of life was better in MIE group.	('troublesome taste', 'MPA', (64, 81))	('pain', 'Disease', 'MESH:D010146', (55, 59))	('troublesome feeding', 'MPA', (34, 53))	('pain', 'Disease', (55, 59))	('better', 'PosReg', (157, 163))	('lower', 'NegReg', (100, 105))	('MIE', 'Var', (85, 88))	('troublesome feeding', 'Phenotype', 'HP:0011968', (34, 53))	('pain', 'Phenotype', 'HP:0012531', (55, 59))
544293	31558183	In an in vitro assay, knockdown of FOXD2-AS1 noticeably inhibited cell invasion and growth, triggered cell death, and repressed the stimulation of the Akt/mTOR axis in cisplatin-resistant ESCC cells (TE-1/DDP).	('cisplatin', 'Chemical', 'MESH:D002945', (168, 177))	('mTOR', 'Gene', '2475', (155, 159))	('stimulation', 'PosReg', (132, 143))	('mTOR', 'Gene', (155, 159))	('cell death', 'CPA', (102, 112))	('triggered', 'Reg', (92, 101))	('FOXD2-AS1', 'Gene', (35, 44))	('Akt', 'Gene', '207', (151, 154))	('ESCC', 'Phenotype', 'HP:0011459', (188, 192))	('knockdown', 'Var', (22, 31))	('TE', 'Chemical', 'MESH:D013691', (200, 202))	('inhibited', 'NegReg', (56, 65))	('Akt', 'Gene', (151, 154))
544294	31558183	Conversely, the overexpression of FOXD2-AS1 remarkably increased cell invasion and growth, repressed cell death, and triggered the stimulation of the Akt/mTOR axis in TE-1/DDP cells.	('Akt', 'Gene', '207', (150, 153))	('FOXD2-AS1', 'Var', (34, 43))	('overexpression', 'PosReg', (16, 30))	('cell invasion', 'CPA', (65, 78))	('increased', 'PosReg', (55, 64))	('growth', 'CPA', (83, 89))	('Akt', 'Gene', (150, 153))	('TE', 'Chemical', 'MESH:D013691', (167, 169))	('mTOR', 'Gene', (154, 158))	('mTOR', 'Gene', '2475', (154, 158))	('stimulation', 'PosReg', (131, 142))
544337	31558183	The tumor volume was assessed every 3 days in the FOXD2-AS1-, Vector-, siFOXD2-AS1-, and siNC-transfected groups (n = 6 each).	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('FOXD2-AS1-', 'Var', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (4, 9))
544346	31558183	FOXD2-AS1 expression was upregulated in TE-1/DDP cells compared to the parent TE-1 cells (Fig.	('TE-1/DDP', 'Var', (40, 48))	('FOXD2-AS1', 'Gene', (0, 9))	('expression', 'MPA', (10, 20))	('upregulated', 'PosReg', (25, 36))	('TE', 'Chemical', 'MESH:D013691', (40, 42))	('TE', 'Chemical', 'MESH:D013691', (78, 80))
544350	31558183	2A), and qRT-PCR showed that repression of FOXD2-AS1 expression remarkably upregulated miR-195, while an increase in FOXD2-AS1 expression noticeably downregulated miR-195 (Fig.	('FOXD2-AS1', 'Gene', (43, 52))	('upregulated', 'PosReg', (75, 86))	('expression', 'MPA', (127, 137))	('repression', 'Var', (29, 39))	('miR-195', 'Gene', (87, 94))	('miR-195', 'Gene', '406971', (87, 94))	('miR-195', 'Gene', (163, 170))	('miR-195', 'Gene', '406971', (163, 170))	('FOXD2-AS1', 'Gene', (117, 126))	('downregulated', 'NegReg', (149, 162))
544359	31558183	A CCK-8 survival assay showed that cell proliferation was dose-dependently inhibited by DDP.	('cell proliferation', 'CPA', (35, 53))	('CCK-8', 'Chemical', 'MESH:D012844', (2, 7))	('DDP', 'Var', (88, 91))	('inhibited', 'NegReg', (75, 84))
544360	31558183	FOXD2-AS1 KD markedly inhibited the growth of DDP-supplemented cells when compared with control siRNA-transfected DDP-supplemented cells.	('inhibited', 'NegReg', (22, 31))	('men', 'Species', '9606', (124, 127))	('men', 'Species', '9606', (56, 59))	('growth', 'CPA', (36, 42))	('FOXD2-AS1 KD', 'Var', (0, 12))
544361	31558183	The above findings indicated that FOXD2-AS1 aggravated cisplatin resistance in ESCC cells.	('ESCC', 'Phenotype', 'HP:0011459', (79, 83))	('FOXD2-AS1', 'Var', (34, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('cisplatin resistance', 'MPA', (55, 75))	('aggravated', 'PosReg', (44, 54))
544365	31558183	WB showed that KD of FOXD2-AS1 markedly inhibited MMP-9 expression in TE-1/DDP cells, whereas the overexpression of FOXD2-AS1 upregulated MMP-9 (Fig.	('FOXD2-AS1', 'Var', (116, 125))	('MMP-9', 'Gene', '4318', (138, 143))	('FOXD2-AS1', 'Gene', (21, 30))	('inhibited', 'NegReg', (40, 49))	('MMP-9', 'Gene', (138, 143))	('TE', 'Chemical', 'MESH:D013691', (70, 72))	('expression', 'MPA', (56, 66))	('MMP-9', 'Gene', '4318', (50, 55))	('MMP-9', 'Gene', (50, 55))
544368	31558183	FOXD2-AS1 KD remarkably downregulated p-AKT and p-mTOR in TE-1/DDP cells, whereas overexpression of FOXD2-AS1 upregulated p-AKT and p-mTOR (Fig.	('TE', 'Chemical', 'MESH:D013691', (58, 60))	('downregulated', 'NegReg', (24, 37))	('AKT', 'Gene', (124, 127))	('mTOR', 'Gene', (50, 54))	('AKT', 'Gene', '207', (40, 43))	('mTOR', 'Gene', '2475', (50, 54))	('FOXD2-AS1', 'Var', (100, 109))	('upregulated', 'PosReg', (110, 121))	('AKT', 'Gene', (40, 43))	('FOXD2-AS1 KD', 'Var', (0, 12))	('mTOR', 'Gene', (134, 138))	('mTOR', 'Gene', '2475', (134, 138))	('AKT', 'Gene', '207', (124, 127))
544369	31558183	The above findings suggested that FOXD2-AS1 upregulated the AKT/mTOR axis in TE-1/DDP cells, which could be the mechanism underlying FOXD2-AS1-mediated resistance to cisplatin in ESCC cells.	('FOXD2-AS1', 'Var', (34, 43))	('upregulated', 'PosReg', (44, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('AKT', 'Gene', '207', (60, 63))	('mTOR', 'Gene', (64, 68))	('mTOR', 'Gene', '2475', (64, 68))	('TE', 'Chemical', 'MESH:D013691', (77, 79))	('AKT', 'Gene', (60, 63))	('ESCC', 'Phenotype', 'HP:0011459', (179, 183))
544374	31558183	Tumor growth markedly decreased in the FOXD2-AS1-siRNA group treated with cisplatin (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FOXD2-AS1-siRNA', 'Var', (39, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('Tumor growth', 'CPA', (0, 12))	('decreased', 'NegReg', (22, 31))
544384	31558183	We confirmed, via gain-of-function and loss-of-function assays, that FOXD2-AS1 overexpression increased the inhibitory impact of cisplatin, increased migration, and repressed cell death in ESCC cells, whereas FOXD2-AS1 KD reduced the inhibitory impact of cisplatin, repressed migration, and triggered cell death.	('inhibitory impact of cisplatin', 'MPA', (108, 138))	('overexpression increased', 'PosReg', (79, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (255, 264))	('FOXD2-AS1', 'Gene', (69, 78))	('cell', 'CPA', (175, 179))	('inhibitory impact', 'MPA', (234, 251))	('migration', 'CPA', (276, 285))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('FOXD2-AS1 KD', 'Var', (209, 221))	('gain-of-function', 'PosReg', (18, 34))	('increased', 'PosReg', (140, 149))	('reduced', 'NegReg', (222, 229))	('migration', 'CPA', (150, 159))	('ESCC', 'Phenotype', 'HP:0011459', (189, 193))
544385	31558183	KD of FOXD2-AS1 obviously reduced tumorigenicity as well as tumor volume and weight, and overexpression of FOXD2-AS1 markedly increased tumor volume and weight.	('FOXD2-AS1', 'Gene', (6, 15))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('reduced', 'NegReg', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('FOXD2-AS1', 'Var', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', (60, 65))	('increased', 'PosReg', (126, 135))	('tumor', 'Disease', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
544406	33158037	The World Health Organization (WHO) provides guidelines for the minimal daily consumption of B vitamins in the adult diet (B1: 1.1-1.2 mg, B2: 1.0-1.3 mg, B3: 11-12 mg, B5: 5 mg, B6: 1.3-1.7 mg, B7: 30 mug, B9: 400 mug and B12: 2.4 mug).	('B6', 'Var', (179, 181))	('B9', 'Chemical', 'MESH:C014499', (207, 209))	('B5: 5 mg', 'Var', (169, 177))	('B2', 'Chemical', 'MESH:C023970', (139, 141))	('B6', 'Chemical', '-', (179, 181))	('B7: 30 mug', 'Var', (195, 205))	('B12', 'Gene', (223, 226))	('B12', 'Gene', '4709', (223, 226))	('B9: 400 mug', 'Var', (207, 218))	('B3', 'Var', (155, 157))
544408	33158037	Notably, vitamin B12 is not produced by plants, placing vegans and vegetarians solely reliant on microbial sources, thereby placing them at risk for B12 deficiency in the absence of supplementation.	('B12', 'Gene', (17, 20))	('B12', 'Gene', '4709', (17, 20))	('men', 'Species', '9606', (188, 191))	('B12 deficiency', 'Phenotype', 'HP:0100502', (149, 163))	('deficiency', 'Var', (153, 163))	('B12', 'Gene', (149, 152))	('B12', 'Gene', '4709', (149, 152))
544443	33158037	Thiamine deficiency in this model shows congruent patterns of neuronal death occurring in brain regions displaying reduced thiamine-dependent enzyme activities.	('Thiamine', 'Chemical', 'MESH:D013831', (0, 8))	('reduced thiamine', 'Phenotype', 'HP:0100503', (115, 131))	('activities', 'MPA', (149, 159))	('reduced', 'NegReg', (115, 122))	('neuronal death occurring in brain', 'Phenotype', 'HP:0002529', (62, 95))	('neuronal death', 'Disease', (62, 76))	('Thiamine deficiency', 'Phenotype', 'HP:0100503', (0, 19))	('deficiency', 'Var', (9, 19))	('neuronal death', 'Disease', 'MESH:D009410', (62, 76))	('thiamine', 'Chemical', 'MESH:D013831', (123, 131))
544444	33158037	Thiamine deficiency induced ferritin expression in activated microglia in vulnerable regions of the brain.	('Thiamine', 'Chemical', 'MESH:D013831', (0, 8))	('Thiamine deficiency', 'Phenotype', 'HP:0100503', (0, 19))	('deficiency', 'Var', (9, 19))	('expression', 'MPA', (37, 47))	('induced', 'Reg', (20, 27))	('ferritin', 'Protein', (28, 36))
544448	33158037	In macrophages, thiamine suppresses oxidative stress-induced activation of NF-kappaB and pro-inflammatory cytokine release.	('thiamine', 'Var', (16, 24))	('pro-inflammatory cytokine release', 'MPA', (89, 122))	('oxidative stress-induced', 'MPA', (36, 60))	('activation', 'PosReg', (61, 71))	('NF-kappaB', 'Protein', (75, 84))	('suppresses', 'NegReg', (25, 35))	('thiamine', 'Chemical', 'MESH:D013831', (16, 24))	('oxidative stress', 'Phenotype', 'HP:0025464', (36, 52))
544451	33158037	Thiamine deficiency in septic patients is prevalent (20-70%) and thought to contribute to a variety of phenotypes associated with septic shock including decreased ATP production and increased Reactive Oxygen Species (ROS).	('increased', 'PosReg', (182, 191))	('increased Reactive Oxygen Species', 'Phenotype', 'HP:0025464', (182, 215))	('septic', 'Disease', 'MESH:D001170', (23, 29))	('ROS', 'Chemical', 'MESH:D017382', (217, 220))	('Thiamine deficiency', 'Phenotype', 'HP:0100503', (0, 19))	('decreased', 'NegReg', (153, 162))	('septic shock', 'Disease', (130, 142))	('ATP', 'Chemical', 'MESH:D000255', (163, 166))	('septic shock', 'Phenotype', 'HP:0100806', (130, 142))	('shock', 'Phenotype', 'HP:0031273', (137, 142))	('Thiamine', 'Gene', (0, 8))	('Reactive Oxygen Species', 'MPA', (192, 215))	('septic shock', 'Disease', 'MESH:D012772', (130, 142))	('septic', 'Disease', 'MESH:D001170', (130, 136))	('patients', 'Species', '9606', (30, 38))	('Thiamine', 'Chemical', 'MESH:D013831', (0, 8))	('septic', 'Disease', (23, 29))	('Oxygen', 'Chemical', 'MESH:D010100', (201, 207))	('deficiency', 'Var', (9, 19))	('septic', 'Disease', (130, 136))	('ATP production', 'MPA', (163, 177))
544465	33158037	PDK is over-expressed in tumor cells and phosphorylation of PDH drives aerobic glycolysis to complement TCA cycle energy generation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('P', 'Chemical', 'MESH:D010758', (60, 61))	('PDH', 'Gene', (60, 63))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('aerobic glycolysis', 'MPA', (71, 89))	('TCA cycle energy generation', 'MPA', (104, 131))	('tumor', 'Disease', (25, 30))	('drives', 'Reg', (64, 70))	('TCA', 'Chemical', 'MESH:D014233', (104, 107))	('PDH', 'Gene', '54704', (60, 63))	('men', 'Species', '9606', (99, 102))	('phosphorylation', 'Var', (41, 56))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
544473	33158037	A study conducted in rats examined the effect of a reduced thiamine diet and found that thiamine deficiency was associated with increased frequency of aberrant crypt foci in the colon.	('thiamine', 'Chemical', 'MESH:D013831', (59, 67))	('thiamine', 'Gene', (88, 96))	('rats', 'Species', '10116', (21, 25))	('deficiency', 'Var', (97, 107))	('thiamine', 'Chemical', 'MESH:D013831', (88, 96))	('reduced thiamine', 'Phenotype', 'HP:0100503', (51, 67))	('thiamine deficiency', 'Phenotype', 'HP:0100503', (88, 107))	('reduced thiamine diet', 'Phenotype', 'HP:0100503', (51, 72))	('aberrant crypt foci in', 'CPA', (151, 173))
544480	33158037	Riboflavin activates phagocytosis and proliferation of macrophages and neutrophils.	('activates', 'PosReg', (11, 20))	('Riboflavin', 'Var', (0, 10))	('Riboflavin', 'Chemical', 'MESH:D012256', (0, 10))	('phagocytosis', 'CPA', (21, 33))
544520	33158037	Niacin deficiency can result in Pellagra, a rare disease in developed countries resulting in inflamed skin, diarrhea and/or dementia.	('inflamed skin', 'Phenotype', 'HP:0011123', (93, 106))	('Niacin', 'Chemical', 'MESH:D009525', (0, 6))	('diarrhea', 'Phenotype', 'HP:0002014', (108, 116))	('result in', 'Reg', (22, 31))	('deficiency', 'Var', (7, 17))	('Niacin', 'Protein', (0, 6))	('Pellagra', 'Disease', (32, 40))	('diarrhea', 'Disease', (108, 116))	('diarrhea', 'Disease', 'MESH:D003967', (108, 116))	('dementia', 'Phenotype', 'HP:0000726', (124, 132))	('inflamed skin', 'Disease', (93, 106))	('dementia', 'Disease', (124, 132))	('P', 'Chemical', 'MESH:D010758', (32, 33))	('dementia', 'Disease', 'MESH:D003704', (124, 132))
544525	33158037	In high-fat diet-fed mice, niacin increased adiponectin (hormone regulating fatty acid catabolism) gene and protein expression and decreased MCP-1, IL-1beta and the frequency of activated M1 macrophage.	('increased adiponectin', 'Phenotype', 'HP:0030686', (34, 55))	('fatty acid', 'Chemical', 'MESH:D005227', (76, 86))	('mice', 'Species', '10090', (21, 25))	('IL-1beta', 'Gene', '16175', (148, 156))	('decreased', 'NegReg', (131, 140))	('frequency of activated M1 macrophage', 'CPA', (165, 201))	('adiponectin', 'Gene', '11450', (44, 55))	('IL-1beta', 'Gene', (148, 156))	('niacin', 'Chemical', 'MESH:D009525', (27, 33))	('decreased MCP', 'Phenotype', 'HP:0025066', (131, 144))	('MCP-1', 'Gene', (141, 146))	('adiponectin', 'Gene', (44, 55))	('increased', 'PosReg', (34, 43))	('niacin', 'Var', (27, 33))
544544	33158037	GPR109A influences physiology in a tissue-dependent manner; in colonocytes, its activation is anti-inflammatory and induces apoptosis, whereas in keratinocytes niacin induces flushing via COX-2 inflammatory pathways.	('anti-inflammatory', 'MPA', (94, 111))	('induces', 'Reg', (116, 123))	('GPR109A', 'Var', (0, 7))	('niacin', 'Chemical', 'MESH:D009525', (160, 166))	('flushing', 'Phenotype', 'HP:0031284', (175, 183))	('flushing', 'Disease', (175, 183))	('COX-2', 'Gene', '4513', (188, 193))	('influences', 'Reg', (8, 18))	('flushing', 'Disease', 'MESH:D005483', (175, 183))	('apoptosis', 'CPA', (124, 133))	('COX-2', 'Gene', (188, 193))	('activation', 'PosReg', (80, 90))
544545	33158037	GPR109A is expressed in normal mammary tissue but is shut off in human primary breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('human', 'Species', '9606', (65, 70))	('GPR109A', 'Var', (0, 7))	('breast tumors', 'Phenotype', 'HP:0100013', (79, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('breast tumors', 'Disease', 'MESH:D001943', (79, 92))	('breast tumors', 'Disease', (79, 92))
544546	33158037	Furthermore, GPR109A deletion triggers earlier onset of tumors and lung metastases in an mouse mammary tumor virus (MMTV)-Neu mouse model of breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('lung metastases', 'Disease', 'MESH:D009362', (67, 82))	('tumors', 'Disease', (56, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('MMTV', 'Species', '11757', (116, 120))	('mouse', 'Species', '10090', (126, 131))	('earlier', 'PosReg', (39, 46))	('mouse mammary tumor virus', 'Species', '11757', (89, 114))	('lung metastases', 'Disease', (67, 82))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('Neu', 'Gene', (122, 125))	('Neu', 'Gene', '2064', (122, 125))	('breast cancer', 'Disease', (141, 154))	('GPR109A deletion', 'Var', (13, 29))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mouse', 'Species', '10090', (89, 94))
544567	33158037	Intestinal deletion of SMVT results in stunted growth, spontaneous and severe inflammation, increased gut permeability and early death.	('death', 'Disease', 'MESH:D003643', (129, 134))	('death', 'Disease', (129, 134))	('stunted', 'NegReg', (39, 46))	('SMVT', 'Gene', '8884', (23, 27))	('inflammation', 'Disease', 'MESH:D007249', (78, 90))	('gut permeability', 'CPA', (102, 118))	('increased', 'PosReg', (92, 101))	('inflammation', 'Disease', (78, 90))	('increased gut permeability', 'Phenotype', 'HP:0410204', (92, 118))	('stunted growth', 'Phenotype', 'HP:0001510', (39, 53))	('deletion', 'Var', (11, 19))	('growth', 'CPA', (47, 53))	('SMVT', 'Gene', (23, 27))
544574	33158037	Mice deficient in vanin-1 are resistant to apoptotic oxidative tissue injury caused by gamma-irradiation or paraquot.	('vanin-1', 'Gene', (18, 25))	('Mice', 'Species', '10090', (0, 4))	('deficient', 'Var', (5, 14))
544580	33158037	Cysteamine breaks disulfide bonds that inactivate proteins and directly inhibits gamma-glutamylcysteine synthase, the rate-limiting step in glutathione synthesis.	('inactivate', 'NegReg', (39, 49))	('disulfide', 'Chemical', 'MESH:D004220', (18, 27))	('glutathione', 'Chemical', 'MESH:D005978', (140, 151))	('Cysteamine', 'Var', (0, 10))	('Cysteamine', 'Chemical', 'MESH:D003543', (0, 10))	('proteins', 'Protein', (50, 58))	('inhibits', 'NegReg', (72, 80))	('gamma-glutamylcysteine', 'MPA', (81, 103))	('cysteine', 'Chemical', 'MESH:D003545', (95, 103))
544601	33158037	In an examination of bile acids that are a risk factor for developing colorectal cancer (CRC), B6 supplementation increased fecal mucin levels and reduced the ratio of lithocholic acid to deoxycholic acid in a dose-dependent manner.	('mucin', 'Gene', (130, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mucin', 'Gene', '100508689', (130, 135))	('B6', 'Chemical', '-', (95, 97))	('men', 'Species', '9606', (104, 107))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (188, 204))	('CRC', 'Disease', (89, 92))	('B6 supplementation', 'Var', (95, 113))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))	('ratio of lithocholic acid to deoxycholic acid', 'MPA', (159, 204))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('increased', 'PosReg', (114, 123))	('supplementation', 'Var', (98, 113))	('colorectal cancer', 'Disease', (70, 87))	('CRC', 'Disease', 'MESH:D015179', (89, 92))	('lithocholic acid', 'Chemical', 'MESH:D008095', (168, 184))	('bile acids', 'Chemical', 'MESH:D001647', (21, 31))	('reduced', 'NegReg', (147, 154))
544602	33158037	A study of rats exposed to 1,2-dimethylhydrazine to induce intestinal damage observed that vitamin B6 supplementation reduced the expression of alkaline phosphatase, a marker of intestinal damage and reduced cell proliferation.	('expression', 'MPA', (130, 140))	('intestinal damage', 'Disease', (178, 195))	('intestinal damage', 'Disease', (59, 76))	('vitamin B6', 'Gene', (91, 101))	('men', 'Species', '9606', (108, 111))	('vitamin B6', 'Chemical', 'MESH:D025101', (91, 101))	('reduced', 'NegReg', (118, 125))	('1,2-dimethylhydrazine', 'Chemical', 'MESH:D019813', (27, 48))	('reduced', 'NegReg', (200, 207))	('alkaline phosphatase', 'Gene', (144, 164))	('supplementation', 'Var', (102, 117))	('rats', 'Species', '10116', (11, 15))	('cell proliferation', 'CPA', (208, 226))	('intestinal damage', 'Disease', 'MESH:D007410', (178, 195))	('intestinal damage', 'Disease', 'MESH:D007410', (59, 76))
544628	33158037	Biotin deficiency stems primarily from genetic changes in biotinidase which is required for cleavage from BCCP and recycling, resulting in alopecia, delays in development, seizures, aciduria and others neurological conditions.	('P', 'Chemical', 'MESH:D010758', (109, 110))	('stems', 'Reg', (18, 23))	('aciduria', 'Disease', (182, 190))	('seizures', 'Disease', 'MESH:D012640', (172, 180))	('alopecia', 'Disease', (139, 147))	('cyclin', 'Gene', '5111', (117, 123))	('seizures', 'Phenotype', 'HP:0001250', (172, 180))	('genetic changes', 'Var', (39, 54))	('aciduria', 'Disease', 'MESH:C537358', (182, 190))	('delays', 'CPA', (149, 155))	('aciduria', 'Phenotype', 'HP:0012072', (182, 190))	('cyclin', 'Gene', (117, 123))	('men', 'Species', '9606', (166, 169))	('Biotin', 'Chemical', 'MESH:D001710', (0, 6))	('biotinidase', 'Gene', '686', (58, 69))	('alopecia', 'Phenotype', 'HP:0001596', (139, 147))	('Biotin', 'Gene', (0, 6))	('neurological conditions', 'Disease', (202, 225))	('biotinidase', 'Gene', (58, 69))	('seizures', 'Disease', (172, 180))
544629	33158037	Biotin deficiency is also associated with elevated inflammation.	('Biotin', 'Protein', (0, 6))	('elevated inflammation', 'Disease', (42, 63))	('deficiency', 'Var', (7, 17))	('elevated inflammation', 'Disease', 'MESH:D006973', (42, 63))	('Biotin', 'Chemical', 'MESH:D001710', (0, 6))
544642	33158037	Both folate and vitamin B12 deficiency are associated with the reduction in glutathione, a major antioxidant protein in the cell.	('glutathione', 'MPA', (76, 87))	('folate', 'Gene', (5, 11))	('B12 deficiency', 'Phenotype', 'HP:0100502', (24, 38))	('folate and vitamin B12 deficiency', 'Phenotype', 'HP:0100507', (5, 38))	('deficiency', 'Var', (28, 38))	('vitamin B12 deficiency', 'Phenotype', 'HP:0100502', (16, 38))	('glutathione', 'Chemical', 'MESH:D005978', (76, 87))	('B12', 'Gene', (24, 27))	('reduction', 'NegReg', (63, 72))	('folate', 'Chemical', 'MESH:D005492', (5, 11))	('B12', 'Gene', '4709', (24, 27))
544646	33158037	Folate deficiency has been shown to have negative consequences for some immune functions.	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('Folate deficiency', 'Phenotype', 'HP:0100507', (0, 17))	('Folate', 'MPA', (0, 6))	('deficiency', 'Var', (7, 17))	('immune functions', 'CPA', (72, 88))
544649	33158037	Folate deficiency in primary human lymphocytes reduced cell proliferation and resulted in increased DNA strand breaks, apoptosis and cell cycle arrest.	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('Folate deficiency', 'Phenotype', 'HP:0100507', (0, 17))	('increased', 'PosReg', (90, 99))	('increased DNA strand breaks', 'Phenotype', 'HP:0040012', (90, 117))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (133, 150))	('apoptosis', 'CPA', (119, 128))	('deficiency', 'Var', (7, 17))	('cell proliferation', 'CPA', (55, 73))	('DNA strand', 'MPA', (100, 110))	('arrest', 'Disease', 'MESH:D006323', (144, 150))	('human', 'Species', '9606', (29, 34))	('lymphocytes reduced', 'Phenotype', 'HP:0001888', (35, 54))	('Folate', 'Protein', (0, 6))	('reduced', 'NegReg', (47, 54))	('arrest', 'Disease', (144, 150))
544650	33158037	Folate deficiency has also been linked to reduced DC maturation and effector functions including: reduced IL-2, TNF-alpha, IL-6 and IL1-beta in response to LPS stimulation.	('P', 'Chemical', 'MESH:D010758', (157, 158))	('reduced', 'NegReg', (42, 49))	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('IL1-beta', 'Gene', (132, 140))	('IL-6', 'MPA', (123, 127))	('TNF-alpha', 'MPA', (112, 121))	('Folate deficiency', 'Phenotype', 'HP:0100507', (0, 17))	('IL-2', 'Gene', '3558', (106, 110))	('deficiency', 'Var', (7, 17))	('DC maturation', 'CPA', (50, 63))	('IL1-beta', 'Gene', '3552', (132, 140))	('reduced', 'NegReg', (98, 105))	('Folate', 'Protein', (0, 6))	('IL-2', 'Gene', (106, 110))	('response to LPS stimulation', 'MPA', (144, 171))
544661	33158037	Low folate intake has been associated with increased expression of immune-related genes, urokinase and iNOS, and the downregulation of genes encoding adhesion proteins:protocadherin-4, nidogen and integrin alphaV.	('urokinase', 'Gene', (89, 98))	('iNOS', 'Gene', '4843', (103, 107))	('iNOS', 'Gene', (103, 107))	('folate', 'Chemical', 'MESH:D005492', (4, 10))	('downregulation', 'NegReg', (117, 131))	('increased', 'PosReg', (43, 52))	('expression', 'MPA', (53, 63))	('Low folate', 'Var', (0, 10))	('Low folate intake', 'Phenotype', 'HP:0100507', (0, 17))
544669	33158037	Other studies come to an opposing conclusion indicating a protective effect of folic acid supplementation in women with BRCA1 mutation.	('men', 'Species', '9606', (96, 99))	('BRCA1', 'Gene', (120, 125))	('men', 'Species', '9606', (111, 114))	('folic acid', 'Chemical', 'MESH:D005492', (79, 89))	('mutation', 'Var', (126, 134))	('women', 'Species', '9606', (109, 114))	('BRCA1', 'Gene', '672', (120, 125))
544673	33158037	High serum folate in men with prostate cancer was associated with elevated cell proliferation.	('High', 'Var', (0, 4))	('folate', 'Chemical', 'MESH:D005492', (11, 17))	('prostate cancer', 'Disease', (30, 45))	('High serum folate', 'Phenotype', 'HP:0032164', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('prostate cancer', 'Disease', 'MESH:D011471', (30, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (30, 45))	('men', 'Species', '9606', (21, 24))	('elevated', 'PosReg', (66, 74))	('cell proliferation', 'CPA', (75, 93))
544678	33158037	Similarly, folate deprivation of cultured epithelial colon cancer cells enhanced cell migration and invasion resembling an epithelial-mesencymal transition, associated with snail gene expression and E-cadherin repression with increased expression of beta1 integrin and proteolysis activity of MMP2.	('colon cancer', 'Disease', 'MESH:D015179', (53, 65))	('beta1 integrin', 'Gene', '3688', (250, 264))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('increased', 'PosReg', (226, 235))	('epithelial-mesencymal transition', 'CPA', (123, 155))	('folate', 'Chemical', 'MESH:D005492', (11, 17))	('snail', 'Gene', (173, 178))	('enhanced', 'PosReg', (72, 80))	('colon cancer', 'Disease', (53, 65))	('repression', 'NegReg', (210, 220))	('cell migration', 'CPA', (81, 95))	('MMP2', 'Gene', (293, 297))	('E-cadherin', 'Gene', (199, 209))	('E-cadherin', 'Gene', '999', (199, 209))	('expression', 'MPA', (236, 246))	('colon cancer', 'Phenotype', 'HP:0003003', (53, 65))	('deprivation', 'Var', (18, 29))	('invasion', 'CPA', (100, 108))	('beta1 integrin', 'Gene', (250, 264))	('MMP2', 'Gene', '4313', (293, 297))	('snail', 'Gene', '6615', (173, 178))
544679	33158037	These patterns were abolished by the inhibition of sonic hedgehog due to the hypomethylation of its promoter or NFkappaB.	('NFkappaB', 'Gene', (112, 120))	('inhibition', 'NegReg', (37, 47))	('NFkappaB', 'Gene', '4790', (112, 120))	('sonic hedgehog', 'Gene', (51, 65))	('hypomethylation', 'Var', (77, 92))	('sonic hedgehog', 'Gene', '6469', (51, 65))
544683	33158037	These outcomes were associated with folate receptor alpha gene amplification and hypermethylation of the reduced folate carrier.	('folate', 'Chemical', 'MESH:D005492', (113, 119))	('associated', 'Reg', (20, 30))	('reduced folate carrier', 'Phenotype', 'HP:0100507', (105, 127))	('folate receptor alpha', 'Gene', (36, 57))	('reduced', 'Protein', (105, 112))	('folate receptor alpha', 'Gene', '2348', (36, 57))	('folate', 'Chemical', 'MESH:D005492', (36, 42))	('hypermethylation', 'Var', (81, 97))
544685	33158037	Knock down of folate receptor alpha or over-expression of the reduced folate carrier negated these effects.	('reduced folate carrier', 'Protein', (62, 84))	('folate receptor alpha', 'Gene', '2348', (14, 35))	('folate', 'Chemical', 'MESH:D005492', (70, 76))	('reduced folate carrier', 'Phenotype', 'HP:0100507', (62, 84))	('folate', 'Chemical', 'MESH:D005492', (14, 20))	('folate receptor alpha', 'Gene', (14, 35))	('negated', 'NegReg', (85, 92))	('Knock down', 'Var', (0, 10))	('over-expression', 'PosReg', (39, 54))
544695	33158037	Folate and cobalamin deficiency can alter the balance of one-carbon metabolism pathways.	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('alter', 'Reg', (36, 41))	('deficiency', 'Var', (21, 31))	('balance of one-carbon metabolism pathways', 'MPA', (46, 87))	('cobalamin', 'Chemical', 'MESH:D014805', (11, 20))	('Folate and cobalamin deficiency', 'Phenotype', 'HP:0100507', (0, 31))	('carbon', 'Chemical', 'MESH:D002244', (61, 67))	('cobalamin', 'Protein', (11, 20))
544703	33158037	B12 deficiency leads to the trapping and accumulation of methyltetrahydrofolate disrupting the normal cycling of cofactors.	('methyltetrahydrofolate', 'Chemical', '-', (57, 79))	('B12 deficiency', 'Phenotype', 'HP:0100502', (0, 14))	('accumulation', 'PosReg', (41, 53))	('cyclin', 'Gene', '5111', (102, 108))	('cyclin', 'Gene', (102, 108))	('deficiency', 'Var', (4, 14))	('methyltetrahydrofolate', 'MPA', (57, 79))	('B12', 'Gene', (0, 3))	('B12', 'Gene', '4709', (0, 3))	('disrupting', 'NegReg', (80, 90))	('leads to', 'Reg', (15, 23))	('trapping', 'MPA', (28, 36))
544714	33158037	In another meta-analysis study examining methylenetetrahydrofolate reductase polymorphisms (MTHFR C677T) and B9 and B12 intake concluded that low intake of folate was associated with increased risk of breast cancer, whereas no association were found for B12.	('folate', 'Chemical', 'MESH:D005492', (60, 66))	('C677T', 'Mutation', 'rs1801133', (98, 103))	('MTHFR', 'Gene', (92, 97))	('methylenetetrahydrofolate reductase', 'Gene', (41, 76))	('B12', 'Gene', (116, 119))	('B12', 'Gene', '4709', (116, 119))	('B9', 'Chemical', 'MESH:C014499', (109, 111))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (41, 76))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('folate', 'Chemical', 'MESH:D005492', (156, 162))	('B12', 'Gene', '4709', (254, 257))	('B12', 'Gene', (254, 257))	('breast cancer', 'Disease', (201, 214))	('low', 'Var', (142, 145))	('MTHFR', 'Gene', '4524', (92, 97))	('low intake of folate', 'Phenotype', 'HP:0100507', (142, 162))
544716	33158037	A study of B vitamins involved in one-carbon metabolism in the setting of esophageal cancer found that vitamin B2 and B12 were positively correlated with cancer risk, whereas vitamin B6 and B9 were inversely correlated.	('B12', 'Gene', (118, 121))	('B12', 'Gene', '4709', (118, 121))	('B9', 'Chemical', 'MESH:C014499', (190, 192))	('vitamin', 'Var', (103, 110))	('carbon', 'Chemical', 'MESH:D002244', (38, 44))	('vitamin B6', 'Chemical', 'MESH:D025101', (175, 185))	('correlated', 'Interaction', (138, 148))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('vitamin B2', 'Chemical', 'MESH:D012256', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
544718	33158037	In a large meta-analysis of patients (757,185 subjects) for all cancers, elevated B12 was identified as a risk factor for cancer; this was particularly evident in liver, pancreatic and myeloid malignancies.	('elevated', 'Var', (73, 81))	('B12', 'Gene', (82, 85))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('pancreatic and myeloid malignancies', 'Disease', 'MESH:D010190', (170, 205))	('B12', 'Gene', '4709', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('patients', 'Species', '9606', (28, 36))	('liver', 'Disease', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
544719	33158037	Finally, a meta-analysis of prostate cancer risk found that both vitamin B9 and B12 were positively associated.	('B12', 'Gene', (80, 83))	('B12', 'Gene', '4709', (80, 83))	('prostate cancer', 'Disease', 'MESH:D011471', (28, 43))	('prostate cancer', 'Disease', (28, 43))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('associated', 'Interaction', (100, 110))	('vitamin', 'Var', (65, 72))	('vitamin B9', 'Chemical', 'MESH:D005492', (65, 75))
544726	33158037	In aged rats, B12 deficiency was associated with a decline in NK cell activity and a reduction in a subset of B lymphocytes.	('decline', 'NegReg', (51, 58))	('activity', 'MPA', (70, 78))	('NK cell', 'CPA', (62, 69))	('reduction', 'NegReg', (85, 94))	('B12', 'Gene', '4709', (14, 17))	('B12 deficiency', 'Phenotype', 'HP:0100502', (14, 28))	('deficiency', 'Var', (18, 28))	('B12', 'Gene', (14, 17))	('rats', 'Species', '10116', (8, 12))
544816	31289600	Low-quality drinking water might raise the risk of having EPLs.	('Low-quality', 'Var', (0, 11))	('drinking water', 'Chemical', 'MESH:D060766', (12, 26))	('EPLs', 'Disease', (58, 62))
544860	31080835	Twenty (44%) patients with a Polyflex SEPS stent and 18 (33%) with an Ultraflex SEMS stent had recurrent dysphagia because of tumor overgrowth, stent migration, hyperplastic granulomatous reaction, or food bolus impaction.	('dysphagia', 'Phenotype', 'HP:0002015', (105, 114))	('SEPS', 'Chemical', '-', (38, 42))	('tumor overgrowth', 'Disease', (126, 142))	('dysphagia', 'Disease', 'MESH:D003680', (105, 114))	('patients', 'Species', '9606', (13, 21))	('hyperplastic granulomatous reaction', 'Disease', (161, 196))	('stent migration', 'CPA', (144, 159))	('food bolus', 'CPA', (201, 211))	('hyperplastic granulomatous reaction', 'Disease', 'MESH:D004342', (161, 196))	('granulomatous reaction', 'Phenotype', 'HP:0002955', (174, 196))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('dysphagia', 'Disease', (105, 114))	('tumor overgrowth', 'Disease', 'MESH:D019214', (126, 142))	('food bolus impaction', 'Phenotype', 'HP:0031984', (201, 221))	('overgrowth', 'Phenotype', 'HP:0001548', (132, 142))	('Polyflex', 'Var', (29, 37))
544900	31080835	Although the function of the 3D-printed flexible polymer stent has not been proved in vivo, the in vitro study showed that the 3D-printed esophageal stent has promising potential to treat malignant esophageal diseases.	('polymer', 'Chemical', 'MESH:D011108', (49, 56))	('esophageal diseases', 'Disease', (198, 217))	('3D-printed', 'Var', (127, 137))	('esophageal diseases', 'Disease', 'MESH:D004935', (198, 217))
545001	30555257	STAT1 was reported to decrease the expression of STAT3 after STAT1C transfection into ESCC cells, and siRNA knockdown of STAT1 substantially increases the expression level of STAT3 and p-STAT3.	('STAT1', 'Gene', '6772', (61, 66))	('expression level', 'MPA', (155, 171))	('knockdown', 'Var', (108, 117))	('STAT3', 'Gene', (49, 54))	('STAT1', 'Gene', '6772', (0, 5))	('decrease', 'NegReg', (22, 30))	('STAT3', 'Gene', '6774', (187, 192))	('increases', 'PosReg', (141, 150))	('STAT1', 'Gene', (121, 126))	('STAT3', 'Gene', (187, 192))	('expression', 'MPA', (35, 45))	('STAT1', 'Gene', '6772', (121, 126))	('STAT3', 'Gene', '6774', (175, 180))	('STAT3', 'Gene', (175, 180))	('STAT1', 'Gene', (61, 66))	('STAT3', 'Gene', '6774', (49, 54))	('STAT1', 'Gene', (0, 5))
545021	30555257	As shown in Figure 2B, STAT3 knockdown increased the transcriptional activity of STAT1 (P<0.05) as compared to that of empty vector.	('STAT1', 'Gene', '6772', (81, 86))	('knockdown', 'Var', (29, 38))	('STAT3', 'Gene', '6774', (23, 28))	('STAT3', 'Gene', (23, 28))	('increased', 'PosReg', (39, 48))	('STAT1', 'Gene', (81, 86))	('transcriptional activity', 'MPA', (53, 77))
545022	30555257	Again, to test whether the increased transcriptional activity of STAT1 mediated by STAT3 transfection was caused by an increase in STAT1-DNA binding, a pull-down experiment using a biotinylated probe containing the STAT1 DNA-binding consensus sequence was performed.	('STAT1', 'Gene', (65, 70))	('increased', 'PosReg', (27, 36))	('STAT3', 'Gene', (83, 88))	('transfection', 'Var', (89, 101))	('STAT1', 'Gene', '6772', (65, 70))	('biotin', 'Chemical', 'MESH:D001710', (181, 187))	('STAT1', 'Gene', (131, 136))	('STAT1', 'Gene', '6772', (131, 136))	('STAT1', 'Gene', (215, 220))	('STAT1', 'Gene', '6772', (215, 220))	('STAT3', 'Gene', '6774', (83, 88))	('transcriptional activity', 'MPA', (37, 61))
545129	29946425	Another study in Denmark also suggested that PLWHAs are at higher risk of esophageal cancer (IR/100,000 PY = 8.0) compared with uninfected individuals .	('infected', 'Disease', 'MESH:D007239', (130, 138))	('infected', 'Disease', (130, 138))	('esophageal cancer', 'Disease', (74, 91))	('PLWHAs', 'Var', (45, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
545162	29108269	Copy number variant analyses indicated that overexpression of ECT2 and other five genes were correlated with copy number amplification.	('ECT2', 'Gene', (62, 66))	('ECT2', 'Gene', '1894', (62, 66))	('overexpression', 'PosReg', (44, 58))	('copy number amplification', 'Var', (109, 134))
545177	29108269	Additionally, knockdown of ECT2 and ITGA6 expression suppressed esophageal cancer cell growth and proliferation (Table 1).	('ECT2', 'Gene', '1894', (27, 31))	('ITGA6', 'Gene', (36, 41))	('ITGA6', 'Gene', '3655', (36, 41))	('ECT2', 'Gene', (27, 31))	('esophageal cancer', 'Disease', (64, 81))	('knockdown', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('proliferation', 'CPA', (98, 111))	('suppressed', 'NegReg', (53, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
545194	29108269	By bivariate analysis, 6 up-regulated genes, ECT2, ITGA6, TFRC, NETO2, TOPBP1 and PTDSS1 (Figure 9) revealed positive correlation with amplified in copy number.	('up-regulated', 'PosReg', (25, 37))	('TFRC', 'Gene', '7037', (58, 62))	('PTDSS1', 'Gene', '9791', (82, 88))	('ECT2', 'Gene', (45, 49))	('NETO2', 'Gene', '81831', (64, 69))	('TFRC', 'Gene', (58, 62))	('amplified in copy number', 'Var', (135, 159))	('ECT2', 'Gene', '1894', (45, 49))	('TOPBP1', 'Gene', (71, 77))	('ITGA6', 'Gene', '3655', (51, 56))	('PTDSS1', 'Gene', (82, 88))	('ITGA6', 'Gene', (51, 56))	('TOPBP1', 'Gene', '11073', (71, 77))	('NETO2', 'Gene', (64, 69))
545196	29108269	Finally, we found that up-regulated of ECT2 and other five genes were correlated with amplification of copy number.	('up-regulated', 'PosReg', (23, 35))	('amplification', 'Var', (86, 99))	('ECT2', 'Gene', (39, 43))	('ECT2', 'Gene', '1894', (39, 43))
545201	29108269	TFRC was identified as a prognostic factor in patients with ESCC and correlated with amplification of the chromosome 3q.	('patients', 'Species', '9606', (46, 54))	('ESCC', 'Disease', (60, 64))	('TFRC', 'Gene', (0, 4))	('amplification', 'Var', (85, 98))	('TFRC', 'Gene', '7037', (0, 4))
545239	29108269	ESCC esophageal squamous cell carcinoma TCGA The Cancer Genome Atlas GEO Gene Expression Omnibus CNV copy number variant GO Gene Ontology KEGG Kyoto Encyclopedia of Genes and Genomes NCCR National Central Cancer Registry of China	('Cancer', 'Phenotype', 'HP:0002664', (205, 211))	('Central Cancer', 'Disease', 'MESH:D009369', (197, 211))	('variant', 'Var', (113, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (5, 39))	('Cancer Genome Atlas', 'Disease', (49, 68))	('Central Cancer', 'Disease', (197, 211))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (49, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('esophageal squamous cell carcinoma', 'Disease', (5, 39))
545247	28042390	Core tip: Endoscopic eradication therapy (EET) is reported as safe and effective for low risk T1b esophageal adenocarcinomas (EAC), but overall data is lacking.	('EET', 'Chemical', '-', (42, 45))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (98, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('T1b', 'Var', (94, 97))	('esophageal adenocarcinomas', 'Disease', (98, 124))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (98, 123))
545249	28042390	EET of T1b EAC may be a reasonable treatment strategy for a subset of these patients.	('patients', 'Species', '9606', (76, 84))	('EET', 'Chemical', '-', (0, 3))	('EET', 'Var', (0, 3))	('T1b', 'Gene', (7, 10))
545255	28042390	A study from two referral centers in the Netherlands examined EET of deep T1a and T1b EAC (n = 75) with an overall recurrence rate of 9%.	('T1a', 'Gene', '10630', (74, 77))	('T1a', 'Gene', (74, 77))	('EET', 'Chemical', '-', (62, 65))	('T1b', 'Var', (82, 85))
545269	28042390	A T1b esophageal cancer was defined as tumor extending beyond the muscularis mucosa and into tissue which contains submucosal glands or tumor adjacent to large caliber arteries which would not be present in the mucosa.	('esophageal cancer', 'Disease', (6, 23))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (6, 23))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (39, 44))	('T1b', 'Var', (2, 5))	('tumor', 'Disease', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
545300	28042390	Our lower survival rate is likely reflected in our patient population, as we evaluated all patients with T1b EAC and not only those with "low risk" disease.	('patients', 'Species', '9606', (91, 99))	('EAC', 'Var', (109, 112))	('T1b', 'Gene', (105, 108))	('patient', 'Species', '9606', (51, 58))	('patient', 'Species', '9606', (91, 98))
545307	28042390	Specifically, a previous meta-analysis showed good accuracy with area under the curve > 0.93 for both T1a and T1b esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('T1a', 'Gene', '10630', (102, 105))	('T1a', 'Gene', (102, 105))	('esophageal cancers', 'Disease', (114, 132))	('T1b', 'Var', (110, 113))	('esophageal cancers', 'Disease', 'MESH:D004938', (114, 132))
545319	28042390	For patients with T1b esophageal cancer and treated with EET alone, the recurrence rate was 38%; therefore treatment with adjuvant therapy in conjunction with EET seems reasonable in patients that are either unable to or refuse to undergo esophagectomy.	('EET', 'Chemical', '-', (159, 162))	('T1b', 'Var', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('patients', 'Species', '9606', (4, 12))	('EET', 'Chemical', '-', (57, 60))	('esophageal cancer', 'Disease', (22, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))	('patients', 'Species', '9606', (183, 191))
545349	27400987	We also reviewed diagnostic upper gastrointestinal endoscopy reports to collect information pertaining to the site of suspicious esophageal lesions i.e., upper third (15-24 cm), middle third (24-32 cm), and lower third (32-40 cm) esophageal lesions.	('15-24', 'Var', (167, 172))	('24-32', 'Var', (192, 197))	('upper gastrointestinal', 'Disease', 'MESH:D005767', (28, 50))	('esophageal lesions', 'Disease', (129, 147))	('esophageal lesions', 'Disease', (230, 248))	('upper gastrointestinal', 'Disease', (28, 50))	('esophageal lesions', 'Disease', 'MESH:D004935', (129, 147))	('esophageal lesions', 'Disease', 'MESH:D004935', (230, 248))
545470	24529029	A third possible mechanism is shared genetic mutations, such as those in tumor suppressor gene p53 .	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))
545559	18677478	To overcome these limitations, approaches to cancer immunotherapy have been developed based on the genetic modification of normal PBL.	('genetic modification', 'Var', (99, 119))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('PBL', 'Gene', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
545589	18677478	The H1299 small cell lung carcinoma line was transduced with retroviral construct to express HLA-A*0201 as previously described, and was designated H1299-A2.	('H1299', 'CellLine', 'CVCL:0060', (148, 153))	('HLA-A*0201', 'Var', (93, 103))	('H1299 small cell lung carcinoma', 'Disease', 'MESH:D055752', (4, 35))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (10, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('H1299', 'CellLine', 'CVCL:0060', (4, 9))	('H1299 small cell lung carcinoma', 'Disease', (4, 35))
545594	18677478	The sequences of the peptide used in this study are as follows: NY-ESO-1 p157-165 (SLLMWITQC), gp100 209-217, Mart-1 27-35.	('Mart-1', 'Gene', '2315', (110, 116))	('p157-165', 'Var', (73, 81))	('Mart-1', 'Gene', (110, 116))	('gp100', 'Gene', (95, 100))	('NY-ESO-1', 'Gene', '246100', (64, 72))	('NY-ESO-1', 'Gene', (64, 72))	('gp100', 'Gene', '6490', (95, 100))
545637	18677478	Antigen-specific IFN-gamma release was detected in co-cultures of peptide-pulsed T2 cells for all constructs, with a higher level of cytokine secretion for PBL transduced with the constructs incorporating the 2A linker peptides (Fig.	('IFN-gamma', 'Gene', '3458', (17, 26))	('IFN-gamma', 'Gene', (17, 26))	('peptides', 'Chemical', 'MESH:D010455', (219, 227))	('cytokine secretion', 'MPA', (133, 151))	('higher', 'PosReg', (117, 123))	('transduced', 'Var', (160, 170))
545645	18677478	Transduction with constructs incorporating the cysteine-modified 1G4 TCR demonstrated a modest increase in expression of the TCR, both by Vbeta13.1 staining and NY-ESO-1 tetramer (Fig.	('TCR', 'Gene', (125, 128))	('cysteine-modified', 'Var', (47, 64))	('increase', 'PosReg', (95, 103))	('expression', 'MPA', (107, 117))	('TCR', 'Gene', '6962', (69, 72))	('cysteine', 'Chemical', 'MESH:D003545', (47, 55))	('NY-ESO-1', 'Gene', '246100', (161, 169))	('TCR', 'Gene', '6962', (125, 128))	('NY-ESO-1', 'Gene', (161, 169))	('TCR', 'Gene', (69, 72))
545646	18677478	There was also a slight increase in recognition of tumor targets in CysfrnSGSGP2A-transduced PBL that was consistent with our previous results (Fig.	('CysfrnSGSGP2A-transduced', 'Var', (68, 92))	('increase', 'PosReg', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('recognition', 'MPA', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
545656	18677478	Transduction efficiency was 60% by Vbeta13.1 and 50% by NY-ESO-1 tetramer staining (data not shown).	('NY-ESO-1', 'Gene', (56, 64))	('NY-ESO-1', 'Gene', '246100', (56, 64))	('Transduction', 'MPA', (0, 12))	('Vbeta13.1', 'Var', (35, 44))
545674	18677478	Furthermore, modifications utilizing targeted mutations in the CDR2 or CDR3 regions of TCR can significantly enhance antigen-specific recognition, and confer this recognition to both CD4 and CD8+ T lymphocytes.	('enhance', 'PosReg', (109, 116))	('TCR', 'Gene', (87, 90))	('antigen-specific recognition', 'MPA', (117, 145))	('CD8', 'Gene', '925', (191, 194))	('mutations', 'Var', (46, 55))	('CDR2', 'Gene', '1039', (63, 67))	('CDR3', 'Gene', (71, 75))	('CD4', 'Gene', (183, 186))	('CD4', 'Gene', '920', (183, 186))	('TCR', 'Gene', '6962', (87, 90))	('CD8', 'Gene', (191, 194))	('CDR3', 'Gene', '8163', (71, 75))	('CDR2', 'Gene', (63, 67))	('modifications', 'Var', (13, 26))
545682	18677478	We also confirmed our previous findings that addition of cysteine modifications to TCRs results in improved expression in PBL, perhaps by facilitating pairing of the introduced alpha and beta.	('improved', 'PosReg', (99, 107))	('TCR', 'Gene', (83, 86))	('PBL', 'Gene', (122, 125))	('cysteine', 'Chemical', 'MESH:D003545', (57, 65))	('TCR', 'Gene', '6962', (83, 86))	('pairing', 'Interaction', (151, 158))	('expression', 'MPA', (108, 118))	('alpha', 'Protein', (177, 182))	('facilitating', 'PosReg', (138, 150))	('cysteine modifications', 'Var', (57, 79))
545692	18677478	These findings have significant implications as we move forward with TCR-based genetic immunotherapy for melanoma as well as non-melanoma epithelial malignancies, and suggest that a combination of immunotherapy and epigenetic modulation may be a useful clinical strategy.	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('epigenetic modulation', 'Var', (215, 236))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('non-melanoma epithelial malignancies', 'Disease', (125, 161))	('TCR', 'Gene', '6962', (69, 72))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (138, 161))	('non-melanoma epithelial malignancies', 'Disease', 'MESH:D008545', (125, 161))	('TCR', 'Gene', (69, 72))
545797	33300112	GATA6 amplification was detectable in 49 (9.9%) EACs of our cohort.	('amplification', 'Var', (6, 19))	('EACs', 'Chemical', 'MESH:D015119', (48, 52))	('GATA6', 'Gene', (0, 5))	('GATA6', 'Gene', '2627', (0, 5))
545815	33300112	Being a transcriptional factor, dysregulation of GATA6 can also result in pathological changes and it was demonstrated that GATA6 alterations implicated in several malignancies such as non-small lung cancer (NSCLC), gastric cancer, cholangiocarcinoma, pancreatic adenocarcinoma or colorectal adenocarcinoma (Zhong et al.	('non-small lung cancer', 'Disease', (185, 206))	('cholangiocarcinoma, pancreatic adenocarcinoma or colorectal adenocarcinoma', 'Disease', 'MESH:D000230', (232, 306))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('alterations', 'Var', (130, 141))	('gastric cancer', 'Disease', 'MESH:D013274', (216, 230))	('small lung', 'Phenotype', 'HP:0002089', (189, 199))	('non-small lung cancer', 'Disease', 'MESH:D002289', (185, 206))	('result', 'Reg', (64, 70))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (252, 277))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (232, 250))	('GATA6', 'Gene', (49, 54))	('GATA6', 'Gene', '2627', (124, 129))	('gastric cancer', 'Phenotype', 'HP:0012126', (216, 230))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('non-small lung cancer', 'Phenotype', 'HP:0030358', (185, 206))	('dysregulation', 'Var', (32, 45))	('implicated', 'Reg', (142, 152))	('malignancies', 'Disease', 'MESH:D009369', (164, 176))	('malignancies', 'Disease', (164, 176))	('NSCLC', 'Disease', (208, 213))	('GATA6', 'Gene', '2627', (49, 54))	('gastric cancer', 'Disease', (216, 230))	('GATA6', 'Gene', (124, 129))
545816	33300112	For esophageal adenocarcinoma, it has been shown in a study including 85 EACs that gene amplification of GATA6 affected the patients' survival in a negative manner (Lin et al.).	('gene amplification', 'Var', (83, 101))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (4, 29))	('GATA6', 'Gene', (105, 110))	('survival', 'CPA', (134, 142))	('affected', 'Reg', (111, 119))	('GATA6', 'Gene', '2627', (105, 110))	('EACs', 'Chemical', 'MESH:D015119', (73, 77))	('esophageal adenocarcinoma', 'Disease', (4, 29))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (4, 29))	('patients', 'Species', '9606', (124, 132))
545818	33300112	Aim of the current study was to analyze the relevance and frequency of GATA6 amplification in a large cohort of EAC patients and the consecutively correlation with clinical, pathological and molecular parameters as well as the patients' survival.	('GATA6', 'Gene', (71, 76))	('patients', 'Species', '9606', (116, 124))	('GATA6', 'Gene', '2627', (71, 76))	('amplification', 'Var', (77, 90))	('EAC', 'Disease', (112, 115))	('patients', 'Species', '9606', (227, 235))
545828	33300112	Amplification of GATA6 (via FISH) was correlated with molecular profiles of these EAC samples including assessments of ARIDA 1A loss, TP53 mutations as well as ERBB2, c-MYC, KRAS and PIK3CA amplifications.	('KRAS', 'Gene', '3845', (174, 178))	('ERBB2', 'Gene', '2064', (160, 165))	('TP53', 'Gene', (134, 138))	('loss', 'NegReg', (128, 132))	('c-MYC', 'Gene', '4609', (167, 172))	('mutations', 'Var', (139, 148))	('ERBB2', 'Gene', (160, 165))	('GATA6', 'Gene', (17, 22))	('GATA6', 'Gene', '2627', (17, 22))	('PIK3CA', 'Gene', '5290', (183, 189))	('c-MYC', 'Gene', (167, 172))	('PIK3CA', 'Gene', (183, 189))	('TP53', 'Gene', '7157', (134, 138))	('KRAS', 'Gene', (174, 178))
545832	33300112	Cases were further evaluated only when normal tissue nuclei displayed one or two clearly distinct signals of green GATA6 and orange CEN18.	('orange CEN18', 'Var', (125, 137))	('GATA6', 'Gene', '2627', (115, 120))	('GATA6', 'Gene', (115, 120))
545844	33300112	However, GATA6 amplification was correlated with the status of neoadjuvant treatment (p = 0.044).	('GATA6', 'Gene', (9, 14))	('correlated', 'Reg', (33, 43))	('GATA6', 'Gene', '2627', (9, 14))	('amplification', 'Var', (15, 28))
545848	33300112	However, we identified co-amplification of GATA6 together with PIK3CA in 9 (1.8%) patients of the entire cohort (p < 0.001) divided into 2 (0.3%) patients of the pretreated subgroup (p < 0.001) and 7 (1.4%) patients with primary surgery (p = 0.174).	('patients', 'Species', '9606', (207, 215))	('co-amplification', 'Var', (23, 39))	('GATA6', 'Gene', (43, 48))	('patients', 'Species', '9606', (82, 90))	('GATA6', 'Gene', '2627', (43, 48))	('PIK3CA', 'Gene', (63, 69))	('PIK3CA', 'Gene', '5290', (63, 69))	('patients', 'Species', '9606', (146, 154))
545852	33300112	In this subgroup, postsurgical survival was comparable between patients with and those without GATA6 amplification (median survival without GATA6 amplification: 22.3 months (95% CI 18.2-26.4 months) versus median survival with GATA6 amplification: 31.9 months (95% CI 28.2-35.6 months, p = 0.699) (Fig.	('amplification', 'Var', (101, 114))	('GATA6', 'Gene', (95, 100))	('GATA6', 'Gene', (140, 145))	('GATA6', 'Gene', '2627', (95, 100))	('GATA6', 'Gene', '2627', (140, 145))	('GATA6', 'Gene', (227, 232))	('patients', 'Species', '9606', (63, 71))	('GATA6', 'Gene', '2627', (227, 232))
545853	33300112	However, in patients without neoadjuvant therapy, intratumoral GATA6 amplification was associated with a prolonged overall survival (OS) compared to those tumors without this amplification (Fig.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('patients', 'Species', '9606', (12, 20))	('prolonged', 'PosReg', (105, 114))	('overall survival', 'MPA', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (55, 60))	('GATA6', 'Gene', (63, 68))	('tumors', 'Disease', (155, 161))	('GATA6', 'Gene', '2627', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('amplification', 'Var', (69, 82))
545857	33300112	We identified gene amplification of GATA6 in up to 12,6% of patients.	('GATA6', 'Gene', '2627', (36, 41))	('gene amplification', 'Var', (14, 32))	('GATA6', 'Gene', (36, 41))	('patients', 'Species', '9606', (60, 68))
545858	33300112	Interestingly, there was a positive correlation between the amplification of GATA6 and multimodal treatment since patients after neoadjuvant therapy more frequently showed corresponding amplification compared to patients who primarily underwent surgical resection (p = 0.044).	('amplification', 'Var', (60, 73))	('GATA6', 'Gene', (77, 82))	('GATA6', 'Gene', '2627', (77, 82))	('patients', 'Species', '9606', (212, 220))	('amplification', 'MPA', (186, 199))	('patients', 'Species', '9606', (114, 122))
545860	33300112	GATA6 amplification had no effect on the OS in those patients who received neoadjuvant treatment while in patients without neoadjuvant procedures, GATA6-positive patients had a significantly prolonged OS.	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (53, 61))	('GATA6', 'Gene', (0, 5))	('GATA6', 'Gene', '2627', (0, 5))	('GATA6', 'Gene', '2627', (147, 152))	('patients', 'Species', '9606', (106, 114))	('GATA6', 'Gene', (147, 152))	('amplification', 'Var', (6, 19))	('prolonged', 'PosReg', (191, 200))
545862	33300112	Our current results considering the frequency of amplified GATA6 is consistent with previous publications by recent large genetic studies (14%) (n = 551) (Frankell et al.)	('GATA6', 'Gene', '2627', (59, 64))	('GATA6', 'Gene', (59, 64))	('amplified', 'Var', (49, 58))
545865	33300112	Using the fluorescence in-situ technique (FISH; gold standard for determining gene amplification) we have the possibility of a direct and reliable visualization of gene copy alterations in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('gene copy alterations', 'Var', (164, 185))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
545867	33300112	In our cohort there is an accumulation of GATA6 amplified tumors in the group of neoadjuvant treated tumors, which has not been considered in all studies so far.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('amplified', 'Var', (48, 57))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('GATA6', 'Gene', (42, 47))	('GATA6', 'Gene', '2627', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
545877	33300112	demonstrated that ectopic expression of GATA6 increased anchorage-independent growth in immortalized Barrett's esophageal cells (Lin et al.).	('ectopic expression', 'Var', (18, 36))	('increased', 'PosReg', (46, 55))	('GATA6', 'Gene', '2627', (40, 45))	('GATA6', 'Gene', (40, 45))	('anchorage-independent growth', 'CPA', (56, 84))
545881	33300112	Interestingly, a large genome-wide association study (GWAS) on EAC performed by the German Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) including about 1065 EAC cases and 1019 controls identified variants of GATA6 to be strongly associated with the disease reflecting its central role within the tumor development (Becker et al.).	('disease', 'Disease', (264, 271))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('associated with', 'Reg', (244, 259))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (105, 130))	('variants', 'Var', (211, 219))	('GATA6', 'Gene', '2627', (223, 228))	('GATA6', 'Gene', (223, 228))	('tumor', 'Disease', (311, 316))	('Adenocarcinoma', 'Disease', (116, 130))
545882	33300112	The reasons for the higher frequency of GATA6 amplification among patients with neoadjuvant therapy in the current analysis are unsolved.	('patients', 'Species', '9606', (66, 74))	('GATA6', 'Gene', '2627', (40, 45))	('GATA6', 'Gene', (40, 45))	('amplification', 'Var', (46, 59))
545898	33300112	In summary, our study identified GATA6 amplification to be significantly associated with multimodal treatment concepts in EAC and to be of prognostic impact for at least those patients with primary surgery.	('patients', 'Species', '9606', (176, 184))	('GATA6', 'Gene', (33, 38))	('GATA6', 'Gene', '2627', (33, 38))	('amplification', 'Var', (39, 52))	('associated with', 'Reg', (73, 88))	('EAC', 'Disease', (122, 125))
545902	33300112	Finally, mechanistic approaches for further investigation of the biological functions/interactions related to GATA6 amplification in EAC via in-vitro, respectively, in vivo experiments should gain more knowledge about how this molecular alteration might be a target for future treatment concepts.	('GATA6', 'Gene', (110, 115))	('EAC', 'Disease', (133, 136))	('amplification', 'Var', (116, 129))	('GATA6', 'Gene', '2627', (110, 115))
545914	29884612	Inhibition of PTPN13 expression in EAC cells promoted several hallmark behaviors of EAC including proliferation, colony formation and migration, and further, resulted in increased phosphorylation of ERBB2/EGFR/Src kinase pathways.	('EGFR', 'Gene', '1956', (205, 209))	('ERBB2', 'Gene', (199, 204))	('migration', 'CPA', (134, 143))	('ERBB2', 'Gene', '2064', (199, 204))	('increased', 'PosReg', (170, 179))	('promoted', 'PosReg', (45, 53))	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('phospho', 'Chemical', 'MESH:C033601', (180, 187))	('colony formation', 'CPA', (113, 129))	('EGFR', 'Gene', (205, 209))	('EAC', 'Phenotype', 'HP:0011459', (35, 38))	('Src', 'Gene', (210, 213))	('PTPN13', 'Gene', '5783', (14, 20))	('Inhibition', 'Var', (0, 10))	('phosphorylation', 'MPA', (180, 195))	('proliferation', 'CPA', (98, 111))	('EAC', 'Disease', (84, 87))	('Src', 'Gene', '6714', (210, 213))	('PTPN13', 'Gene', (14, 20))
545921	29884612	Recently, studies of the genome of BE and EAC have revealed that mutations in multiple genes, including TP53, CDKN2A, SMAD4, ERBB2, PIK3CA, and ELMO1, are common in EAC and also present in BE, although at a lower frequency.	('CDKN2A', 'Gene', (110, 116))	('BE', 'Phenotype', 'HP:0100580', (189, 191))	('SMAD4', 'Gene', (118, 123))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('BE', 'Phenotype', 'HP:0100580', (35, 37))	('CDKN2A', 'Gene', '1029', (110, 116))	('mutations', 'Var', (65, 74))	('EAC', 'Phenotype', 'HP:0011459', (165, 168))	('SMAD4', 'Gene', '4089', (118, 123))	('EAC', 'Phenotype', 'HP:0011459', (42, 45))	('ELMO1', 'Gene', '9844', (144, 149))	('ERBB2', 'Gene', (125, 130))	('ERBB2', 'Gene', '2064', (125, 130))	('PIK3CA', 'Gene', '5290', (132, 138))	('PIK3CA', 'Gene', (132, 138))	('EAC', 'Disease', (165, 168))	('ELMO1', 'Gene', (144, 149))
545922	29884612	Of particular note, TP53 mutations appear to play a role in BE progression presumably by affecting genomic stability .	('mutations', 'Var', (25, 34))	('role', 'Reg', (52, 56))	('TP53', 'Gene', (20, 24))	('affecting', 'Reg', (89, 98))	('BE', 'Phenotype', 'HP:0100580', (60, 62))	('play', 'Reg', (45, 49))	('genomic stability', 'CPA', (99, 116))	('TP53', 'Gene', '7157', (20, 24))
545924	29884612	CpG island DNA methylation in the promoter regions, a specific type of epigenetic modification, can lead to the silencing of a subset of tumor suppressor genes and presumably drive cancer formation.	('methylation', 'Var', (15, 26))	('tumor', 'Disease', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('drive', 'Reg', (175, 180))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('lead to', 'Reg', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Disease', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('silencing', 'MPA', (112, 121))
545925	29884612	A recently published paper by TCGA found molecular features including DNA hypermethylation in esophageal carcinoma, including EAC.	('esophageal carcinoma', 'Disease', (94, 114))	('EAC', 'Phenotype', 'HP:0011459', (126, 129))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (94, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (94, 114))	('EAC', 'Disease', (126, 129))	('DNA hypermethylation', 'Var', (70, 90))
545949	29884612	Clustering using RPMM revealed four methylation subtypes among EAC samples (Figure 1A), denoted as high (HM), intermediate (IM), low (LM) and minimal (MM) methylator based on the underlying MVP methylation patterns.	('low', 'Var', (129, 132))	('MVP', 'Gene', '9961', (190, 193))	('methylator', 'Var', (155, 165))	('EAC', 'Phenotype', 'HP:0011459', (63, 66))	('MVP', 'Gene', (190, 193))
545955	29884612	We then conducted survival analyses in independent data sets from TCGA (87 EACs) and the Gene Expression Omnibus (GSE72872, 123 EACs), but found no significant correlation either with or without adjustment for pathologic stage of the tumor (P > 0.1, Cox Proportional Hazard testing) (Supplemental Figure 4).	('Cox', 'Gene', (250, 253))	('tumor', 'Disease', (234, 239))	('GSE72872', 'Var', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('Cox', 'Gene', '1351', (250, 253))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('EAC', 'Phenotype', 'HP:0011459', (75, 78))
545960	29884612	We identified frequent TP53 mutations in all of the methylation subtypes.	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('TP53', 'Gene', '7157', (23, 27))
545965	29884612	Overall likely ERBB2 activating genomic alterations (recurrent COSMIC mutations or amplifications) occurred in 7/25 (28%) of HM subtype, 8/26 (31%) of IM subtype, 1/20 (5%) of LM subtype, and 2/16 (12.5%) of MM subtype (Supplemental Table 6).	('ERBB2', 'Gene', (15, 20))	('genomic alterations', 'Var', (32, 51))	('ERBB2', 'Gene', '2064', (15, 20))	('activating', 'PosReg', (21, 31))
545966	29884612	We observed a trend for increased loss of function ARID1A mutations in the HM subtype (6/25, 24%) compared to the IM (2/26, 8%), LM (1/20, 5%), and MM (1/16, 6%) subtypes (P = 0.1 - 0.2, Fisher's exact test).	('mutations', 'Var', (58, 67))	('ARID1A', 'Gene', '8289', (51, 57))	('ARID1A', 'Gene', (51, 57))
545967	29884612	Amplifications in CDK6 were found in 5/26 (19%) of IM samples, while only in <=1 sample for all other subtypes.	('CDK6', 'Gene', '1021', (18, 22))	('Amplifications', 'Var', (0, 14))	('found', 'Reg', (28, 33))	('CDK6', 'Gene', (18, 22))
545968	29884612	High-level MDM2 amplifications were rare but found exclusively within the MM subtype (3/16, 19%).	('MDM2', 'Gene', '4193', (11, 15))	('amplifications', 'Var', (16, 30))	('MDM2', 'Gene', (11, 15))
545969	29884612	We observed that recurrent COSMIC ERBB2 mutations were enriched in the HM subtype, with a higher number of mutated samples (6/32, 19%) compared to the IM (3/31, 10%), the MM subtype (0/20) or LM subtype (0/26) (Fisher's exact test, P = 0.03 for both HM vs. LM and HM vs. MM).	('mutations', 'Var', (40, 49))	('ERBB2', 'Gene', (34, 39))	('ERBB2', 'Gene', '2064', (34, 39))
545974	29884612	Gene enrichment analysis of DETGs repressed by miRNAs in HM cases compared to MM casesn (Binomial test, p-adj < 0.05, Supplemental Table 11-14) revealed subtype-specific repression of cancer pathways in the HM subtype, including the WNT pathway and cell adhesion and signaling (see details in Supplemental Results and Methods).	('cancer', 'Disease', (184, 190))	('WNT pathway', 'Pathway', (233, 244))	('repression', 'NegReg', (170, 180))	('miRNAs', 'Var', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cell adhesion', 'CPA', (249, 262))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('signaling', 'Pathway', (267, 276))
545981	29884612	Using the relative methylation level >0.1 as a cutoff threshold for methylated PTPN13, it was methylated in 56% of EAC samples (Figure 3A).	('methylated', 'Var', (68, 78))	('EAC', 'Disease', (115, 118))	('PTPN13', 'Gene', '5783', (79, 85))	('methylated', 'Var', (94, 104))	('PTPN13', 'Gene', (79, 85))	('EAC', 'Phenotype', 'HP:0011459', (115, 118))
545985	29884612	We observed 75% of PTPN13 methylated EAC samples showed low mRNA level (relative expression <0.5), while 67% of unmethylated EAC samples showed high mRNA level (relative expression > 8).	('EAC', 'Phenotype', 'HP:0011459', (37, 40))	('PTPN13', 'Gene', (19, 25))	('methylated', 'Var', (26, 36))	('mRNA level', 'MPA', (149, 159))	('EAC', 'Phenotype', 'HP:0011459', (125, 128))	('mRNA level', 'MPA', (60, 70))	('PTPN13', 'Gene', '5783', (19, 25))	('low', 'NegReg', (56, 59))
545986	29884612	To determine the role of DNA methylation in regulation PTPN13 gene expression, we treated ESO26 and OE33 cell lines, which have methylated PTPN13 and no detectable mRNA level, with 5-azacytidine (5-Aza).	('mRNA level', 'MPA', (164, 174))	('5-azacytidine', 'Chemical', 'MESH:D001374', (181, 194))	('5-Aza', 'Chemical', 'MESH:D001372', (196, 201))	('PTPN13', 'Gene', '5783', (55, 61))	('PTPN13', 'Gene', '5783', (139, 145))	('methylated', 'Var', (128, 138))	('PTPN13', 'Gene', (55, 61))	('PTPN13', 'Gene', (139, 145))	('ESO26', 'CellLine', 'CVCL:2035', (90, 95))
545989	29884612	We found PTPN13 was methylated with no detectable mRNA level in 4 EAC cell lines (ESO26, FLO-1, OE33 and ESO51) and that SK-GT-4 had higher PTPN13 mRNA level than any other cell line (Figure 4A).	('PTPN13', 'Gene', '5783', (140, 146))	('PTPN13', 'Gene', (140, 146))	('methylated', 'MPA', (20, 30))	('SK-GT-4', 'Var', (121, 128))	('ESO26', 'CellLine', 'CVCL:2035', (82, 87))	('higher', 'PosReg', (133, 139))	('EAC', 'Phenotype', 'HP:0011459', (66, 69))	('PTPN13', 'Gene', '5783', (9, 15))	('PTPN13', 'Gene', (9, 15))	('mRNA level', 'MPA', (50, 60))
545994	29884612	SK-GT-4 shRNA-PTPN13 clones also had increased capacity to form colonies compared to SK-GT-4 -NSC control cells (Figure 4C).	('PTPN13', 'Gene', '5783', (14, 20))	('form colonies', 'CPA', (59, 72))	('increased', 'PosReg', (37, 46))	('PTPN13', 'Gene', (14, 20))	('SK-GT-4', 'Var', (0, 7))
545996	29884612	Taken together, these results suggest that inhibition of PTPN13 in EAC cells promoted cell growth, colony formation and migration.	('cell growth', 'CPA', (86, 97))	('PTPN13', 'Gene', (57, 63))	('inhibition', 'Var', (43, 53))	('promoted', 'PosReg', (77, 85))	('colony formation', 'CPA', (99, 115))	('migration', 'CPA', (120, 129))	('EAC', 'Phenotype', 'HP:0011459', (67, 70))	('PTPN13', 'Gene', '5783', (57, 63))
545998	29884612	Thus, we determined if inhibition of PTPN13 in EAC cells would affect the tyrosine phosphorylation status of a panel of key kinases implicated in EAC.	('PTPN13', 'Gene', (37, 43))	('affect', 'Reg', (63, 69))	('tyrosine', 'Chemical', 'None', (74, 82))	('inhibition', 'Var', (23, 33))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('PTPN13', 'Gene', '5783', (37, 43))	('EAC', 'Phenotype', 'HP:0011459', (146, 149))	('phospho', 'Chemical', 'MESH:C033601', (83, 90))
546000	29884612	These data demonstrate that inhibition of PTPN13 enhanced EGFR/ERBB2 and Src kinase signaling.	('EGFR', 'Gene', '1956', (58, 62))	('enhanced', 'PosReg', (49, 57))	('EGFR', 'Gene', (58, 62))	('ERBB2', 'Gene', '2064', (63, 68))	('PTPN13', 'Gene', '5783', (42, 48))	('inhibition', 'Var', (28, 38))	('ERBB2', 'Gene', (63, 68))	('PTPN13', 'Gene', (42, 48))	('Src', 'Gene', (73, 76))	('Src', 'Gene', '6714', (73, 76))
546002	29884612	With a limited sample size (N=14), we observed activation of EGFR at Tyr1068 in 2 EACs with methylated PTPN13 and reduced gene/protein expression (Supplemental Figure 14).	('reduced', 'NegReg', (114, 121))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('PTPN13', 'Gene', '5783', (103, 109))	('activation', 'PosReg', (47, 57))	('PTPN13', 'Gene', (103, 109))	('Tyr1068', 'Chemical', 'MESH:C056418', (69, 76))	('EGFR', 'Gene', '1956', (61, 65))	('gene/protein expression', 'MPA', (122, 145))	('at Tyr1068', 'Var', (66, 76))	('EGFR', 'Gene', (61, 65))
546003	29884612	Further, we examined the expression of PTPN13 and phospho-ERBB2 (Tyr1248) in EAC tissue microarrays.	('Tyr1248', 'Chemical', 'MESH:C103625', (65, 72))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('phospho', 'Chemical', 'MESH:C033601', (50, 57))	('Tyr1248', 'Var', (65, 72))	('ERBB2', 'Gene', '2064', (58, 63))	('ERBB2', 'Gene', (58, 63))	('PTPN13', 'Gene', '5783', (39, 45))	('PTPN13', 'Gene', (39, 45))
546004	29884612	The immunohistochemical analyses revealed that 7.7% cases (3/39 EAC cores) had strong pERBB2 expression (Tyr1248) (score 2+) with weak or absent PTPN13 (score <= 60).	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('Tyr1248', 'Chemical', 'MESH:C103625', (105, 112))	('PTPN13', 'Gene', '5783', (145, 151))	('ERBB2', 'Gene', (87, 92))	('Tyr1248', 'Var', (105, 112))	('ERBB2', 'Gene', '2064', (87, 92))	('PTPN13', 'Gene', (145, 151))
546005	29884612	In contrast, 41% cases (16/39) with weak or absent pERBB2 (Tyr1248) (score <=2) had strong PTPN13 expression (IS>60) (Supplemental Table 16).	('Tyr1248', 'Chemical', 'MESH:C103625', (59, 66))	('PTPN13', 'Gene', (91, 97))	('Tyr1248', 'Var', (59, 66))	('ERBB2', 'Gene', '2064', (52, 57))	('ERBB2', 'Gene', (52, 57))	('absent', 'NegReg', (44, 50))	('PTPN13', 'Gene', '5783', (91, 97))	('expression', 'MPA', (98, 108))
546015	29884612	Furthermore, our integrative analysis identified a list of candidate genes that are epigenetically silenced specifically in the HM subtype, including the candidate tumor suppressor gene, PTPN13, a non-receptor type tyrosine phosphatase.	('tumor', 'Disease', (164, 169))	('tyrosine', 'Chemical', 'None', (215, 223))	('epigenetically silenced', 'Var', (84, 107))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('PTPN13', 'Gene', '5783', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('PTPN13', 'Gene', (187, 193))
546018	29884612	To further elucidate the biological relevance of this HM subtype specific feature, we investigated the consequences of PTPN13 loss on several hallmark behaviors of EAC cells and showed PTNP13 suppressed cell proliferation, colony formation and migration.	('PTPN13', 'Gene', '5783', (119, 125))	('cell proliferation', 'CPA', (203, 221))	('suppressed', 'NegReg', (192, 202))	('PTPN13', 'Gene', (119, 125))	('EAC', 'Phenotype', 'HP:0011459', (164, 167))	('colony formation', 'CPA', (223, 239))	('loss', 'NegReg', (126, 130))	('migration', 'CPA', (244, 253))	('PTNP13', 'Var', (185, 191))
546019	29884612	Furthermore, inhibition of PTPN13 led to increased phosphorylation in critical tyrosine sites of EGFR/Erbb2 and Src kinases at basal level, with further increases upon EGF stimulation (Figure 4).	('Src', 'Gene', (112, 115))	('increased', 'PosReg', (41, 50))	('EGFR', 'Gene', '1956', (97, 101))	('Src', 'Gene', '6714', (112, 115))	('PTPN13', 'Gene', '5783', (27, 33))	('inhibition', 'Var', (13, 23))	('phosphorylation in critical tyrosine sites', 'MPA', (51, 93))	('Erbb2', 'Gene', (102, 107))	('PTPN13', 'Gene', (27, 33))	('increases', 'PosReg', (153, 162))	('EGFR', 'Gene', (97, 101))	('Erbb2', 'Gene', '2064', (102, 107))	('tyrosine', 'Chemical', 'None', (79, 87))	('phospho', 'Chemical', 'MESH:C033601', (51, 58))
546020	29884612	Additionally, western blotting of EAC biopsy samples reveals increased EGFR-Tyr1068 phosphorylation in a subset that harbor aberrant PTPN13 hypermethylation and silenced expression at both mRNA and protein levels (Supplemental Figure 14).	('PTPN13', 'Gene', '5783', (133, 139))	('phospho', 'Chemical', 'MESH:C033601', (84, 91))	('PTPN13', 'Gene', (133, 139))	('hypermethylation', 'Var', (140, 156))	('EAC', 'Phenotype', 'HP:0011459', (34, 37))	('increased', 'PosReg', (61, 70))	('EGFR', 'Gene', '1956', (71, 75))	('silenced', 'NegReg', (161, 169))	('EGFR', 'Gene', (71, 75))	('Tyr1068', 'Chemical', 'MESH:C056418', (76, 83))	('phosphorylation', 'MPA', (84, 99))	('expression', 'MPA', (170, 180))
546024	29884612	Collectively, our data on methylated PTPN13 and EGFR/ERBB2 alterations reveals a novel molecular mechanism of activating oncogenic ERBB2/EGFR signaling in a subset of EAC, which highlights the importance of ERBB2/EGFR signaling pathways in the pathophysiology of a subset of EAC.	('EGFR', 'Gene', '1956', (48, 52))	('EAC', 'Phenotype', 'HP:0011459', (167, 170))	('EGFR', 'Gene', '1956', (213, 217))	('EGFR', 'Gene', (137, 141))	('ERBB2', 'Gene', (207, 212))	('alterations', 'Var', (59, 70))	('EAC', 'Phenotype', 'HP:0011459', (275, 278))	('activating', 'PosReg', (110, 120))	('EAC', 'Disease', (167, 170))	('PTPN13', 'Gene', '5783', (37, 43))	('ERBB2', 'Gene', (53, 58))	('ERBB2', 'Gene', '2064', (207, 212))	('EGFR', 'Gene', (48, 52))	('EGFR', 'Gene', '1956', (137, 141))	('ERBB2', 'Gene', (131, 136))	('PTPN13', 'Gene', (37, 43))	('ERBB2', 'Gene', '2064', (53, 58))	('EGFR', 'Gene', (213, 217))	('ERBB2', 'Gene', '2064', (131, 136))
546025	29884612	Our experiments assessing EAC cell culture susceptibility to two topoisomerase I inhibitors as well as palbociclib (Figure 5, Supplemental Figure 15) suggest that the methylation subtypes may have distinct susceptibilities to conventional and targeted therapies.	('EAC', 'Phenotype', 'HP:0011459', (26, 29))	('susceptibilities', 'Reg', (206, 222))	('Supplemental Figure 15', 'Disease', (126, 148))	('methylation', 'Var', (167, 178))	('Supplemental Figure 15', 'Disease', 'MESH:C567193', (126, 148))
546029	29884612	We further observed no significant correlations between methylation subtype membership and important histologic (tumor nuclei percent, tumor necrosis percent, and tumor weight) or clinical features (age, gender, tobacco use and survival) (P > 0.1).	('tumor', 'Disease', (113, 118))	('tumor weight', 'Disease', (163, 175))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('clinical', 'Species', '191496', (180, 188))	('tumor necrosis', 'Disease', 'MESH:D009336', (135, 149))	('tobacco', 'Species', '4097', (212, 219))	('tumor weight', 'Disease', 'MESH:D015431', (163, 175))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('methylation', 'Var', (56, 67))	('tumor necrosis', 'Disease', (135, 149))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
546031	29884612	Our integrative analysis combined with functional in vitro studies uncovers a novel molecular mechanism by which EAC cells activates the oncogenic kinase pathways via epigenetically silencing the tyrosine phosphatase, specifically in the HM subtype.	('epigenetically', 'Var', (167, 181))	('EAC', 'Phenotype', 'HP:0011459', (113, 116))	('tyrosine', 'Chemical', 'None', (196, 204))	('oncogenic kinase pathways', 'Pathway', (137, 162))	('silencing', 'NegReg', (182, 191))	('activates', 'PosReg', (123, 132))	('tyrosine', 'Enzyme', (196, 204))
546038	27219912	On multivariate analysis, increasing HV5-HV50, LV5-LV50, MHD, and MLD were associated with greater risk of PlEf.	('HV5-HV50', 'Var', (37, 45))	('LV5-LV50', 'Var', (47, 55))	('MHD', 'Disease', 'None', (57, 60))	('MLD', 'Disease', (66, 69))	('MHD', 'Disease', (57, 60))	('MLD', 'Disease', 'MESH:D007966', (66, 69))	('PlEf', 'Disease', (107, 111))	('PlEf', 'Phenotype', 'HP:0002202', (107, 111))
546073	27219912	DM parameters were collected in increasing increments of 10 for heart V10-V60 (HV), and lung V10-V60 (LV), in addition to HV5, LV5, mean heart dose (MHD), and MLD.	('MLD', 'Disease', (159, 162))	('MHD', 'Disease', 'None', (149, 152))	('MHD', 'Disease', (149, 152))	('DM', 'Disease', 'MESH:D009223', (0, 2))	('lung V10-V60', 'Var', (88, 100))	('MLD', 'Disease', 'MESH:D007966', (159, 162))	('heart V10-V60', 'Disease', 'MESH:D006331', (64, 77))	('heart V10-V60', 'Disease', (64, 77))
546093	27219912	On univariate analysis, factors significantly associated with increased risk of PlEf were HV5,-HV60, LV5-LV50, MHD, and MLD (Supplemental Table, available online at http://www.informahealthcare.com).	('PlEf', 'Phenotype', 'HP:0002202', (80, 84))	('LV5-LV50', 'Var', (101, 109))	('HV5', 'Var', (90, 93))	('MHD', 'Disease', 'None', (111, 114))	('MHD', 'Disease', (111, 114))	('MLD', 'Disease', 'MESH:D007966', (120, 123))	('MLD', 'Disease', (120, 123))	('PlEf', 'Disease', (80, 84))
546094	27219912	On multivariate analysis (Table 3), HV5 -HV50, LV5-LV50, MHD and MLD were all associated with increased risk of PlEf when adjusted for PI and TVol.	('PlEf', 'Disease', (112, 116))	('LV5-LV50', 'Var', (47, 55))	('PlEf', 'Phenotype', 'HP:0002202', (112, 116))	('HV5 -HV50', 'Var', (36, 45))	('MHD', 'Disease', 'None', (57, 60))	('MHD', 'Disease', (57, 60))	('MLD', 'Disease', 'MESH:D007966', (65, 68))	('MLD', 'Disease', (65, 68))
546097	27219912	DM parameters greater than LV30 did not correlate with any grade PlEf.	('LV30', 'Var', (27, 31))	('DM', 'Disease', 'MESH:D009223', (0, 2))	('grade PlEf', 'Disease', (59, 69))	('PlEf', 'Phenotype', 'HP:0002202', (65, 69))
546098	27219912	However, HV5-HV60 and well as MHD were associated with development of grade one, two and three PlEf (Figure 1-3).	('associated with', 'Reg', (39, 54))	('PlEf', 'Phenotype', 'HP:0002202', (95, 99))	('MHD', 'Disease', 'None', (30, 33))	('grade one', 'CPA', (70, 79))	('MHD', 'Disease', (30, 33))	('HV5-HV60', 'Var', (9, 17))
546107	27219912	From a pathological standpoint, irradiation of cardiac tissue can result in long-term injury including accelerated atherosclerosis, pericardial and myocardial fibrosis, conduction abnormalities, injury to cardiac valves, and possibly radiation pneumonitis.	('myocardial fibrosis', 'Disease', 'MESH:D005355', (148, 167))	('pneumonitis', 'Disease', (244, 255))	('atherosclerosis', 'Disease', (115, 130))	('myocardial fibrosis', 'Disease', (148, 167))	('pneumonitis', 'Disease', 'MESH:D011014', (244, 255))	('accelerated atherosclerosis', 'Phenotype', 'HP:0004943', (103, 130))	('conduction abnormalities, injury to cardiac valves', 'Disease', 'MESH:D006349', (169, 219))	('irradiation', 'Var', (32, 43))	('myocardial fibrosis', 'Phenotype', 'HP:0001685', (148, 167))	('atherosclerosis', 'Disease', 'MESH:D050197', (115, 130))	('atherosclerosis', 'Phenotype', 'HP:0002621', (115, 130))
546108	27219912	Also, lung irradiation can cause pneumonitis, fibrosis, and vascular remodeling leading to pulmonary hypertension and cardiopulmonary dysfunction.	('lung irradiation', 'Var', (6, 22))	('vascular remodeling', 'CPA', (60, 79))	('pneumonitis', 'Disease', (33, 44))	('cardiopulmonary dysfunction', 'Disease', (118, 145))	('pulmonary hypertension', 'Disease', (91, 113))	('cause', 'Reg', (27, 32))	('pulmonary hypertension', 'Disease', 'MESH:D006976', (91, 113))	('cardiopulmonary dysfunction', 'Disease', 'MESH:D006323', (118, 145))	('fibrosis', 'Disease', 'MESH:D005355', (46, 54))	('pneumonitis', 'Disease', 'MESH:D011014', (33, 44))	('fibrosis', 'Disease', (46, 54))	('hypertension', 'Phenotype', 'HP:0000822', (101, 113))	('leading to', 'Reg', (80, 90))
546109	27219912	demonstrated that CRT in esophageal cancer is associated with acute cardiac toxicity before treatment completion.	('CRT', 'Var', (18, 21))	('esophageal cancer', 'Disease', (25, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (25, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cardiac toxicity', 'Disease', 'MESH:D066126', (68, 84))	('cardiac toxicity', 'Disease', (68, 84))
546220	28253360	The result indicated that PEMSs caused epithelial denudation, mucin hypersecretion and epithelial metaplasia.	('epithelial metaplasia', 'Disease', (87, 108))	('mucin', 'MPA', (62, 67))	('epithelial denudation', 'Disease', (39, 60))	('PEMSs', 'Var', (26, 31))	('epithelial metaplasia', 'Disease', 'MESH:D008679', (87, 108))
546270	28169357	Integrative analysis of copy number and transcriptional expression profiles in esophageal cancer to identify a novel driver gene for therapy An increasing amount of evidence has highlighted the critical roles that copy number variants play in cancer progression.	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('copy number variants', 'Var', (214, 234))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
546273	28169357	We subsequently showed that silencing of FAM60A could inhibit esophageal carcinoma tumor cell growth, migration and invasion in vitro.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('FAM60A', 'Gene', (41, 47))	('inhibit', 'NegReg', (54, 61))	('invasion', 'CPA', (116, 124))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (62, 82))	('esophageal carcinoma tumor', 'Disease', 'MESH:D009369', (62, 88))	('esophageal carcinoma tumor', 'Disease', (62, 88))	('silencing', 'Var', (28, 37))	('FAM60A', 'Gene', '58516', (41, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
546280	28169357	In oral cavity squamous cell carcinoma, amplifications of FGFR1 and PIK3CA were identified and were shown to be independent risk factors for prognosis.	('PIK3CA', 'Gene', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('PIK3CA', 'Gene', '5290', (68, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('FGFR1', 'Gene', (58, 63))	('FGFR1', 'Gene', '2260', (58, 63))	('squamous cell carcinoma', 'Disease', (15, 38))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (15, 38))	('amplifications', 'Var', (40, 54))
546289	28169357	Collectively, up-regulation of FAM60A expression may result from amplification of the copy number alterations.	('FAM60A', 'Gene', '58516', (31, 37))	('up-regulation', 'PosReg', (14, 27))	('FAM60A', 'Gene', (31, 37))	('expression', 'MPA', (38, 48))	('copy number alterations', 'Var', (86, 109))
546304	28169357	Additionally, the homozygous loss-of- function germline mutation in the NTHL1 gene is related to a new subtype of base-excision repair-associated adenomatous polyposis and colorectal cancer.	('adenomatous polyposis', 'Disease', (146, 167))	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (146, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('base-excision', 'Var', (114, 127))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (146, 167))	('germline mutation', 'Var', (47, 64))	('loss-of- function', 'NegReg', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('colorectal cancer', 'Disease', (172, 189))	('NTHL1', 'Gene', '4913', (72, 77))	('NTHL1', 'Gene', (72, 77))
546328	28169357	First, we observed that knockdown of FAM60A expression had a significant effect on cell cycle (Fig.	('effect', 'Reg', (73, 79))	('FAM60A', 'Gene', '58516', (37, 43))	('cell cycle', 'CPA', (83, 93))	('FAM60A', 'Gene', (37, 43))	('knockdown', 'Var', (24, 33))
546331	28169357	The results showed that inhibition of FAM60A expression suppressed the expression levels of p21 and p27, which is in accordance with the above results.	('FAM60A', 'Gene', (38, 44))	('p21', 'Gene', '644914', (92, 95))	('p27', 'Gene', '3429', (100, 103))	('p27', 'Gene', (100, 103))	('suppressed', 'NegReg', (56, 66))	('inhibition', 'Var', (24, 34))	('FAM60A', 'Gene', '58516', (38, 44))	('expression levels', 'MPA', (71, 88))	('p21', 'Gene', (92, 95))
546346	28169357	In the aforementioned experimental results, knock-down of FAM60A expression decreased the percentage of cells at G1 phase and arrested cancer cells at G2/M phase.	('arrest', 'Disease', (126, 132))	('FAM60A', 'Gene', (58, 64))	('cancer', 'Disease', (135, 141))	('FAM60A', 'Gene', '58516', (58, 64))	('decreased', 'NegReg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('arrest', 'Disease', 'MESH:D006323', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('knock-down', 'Var', (44, 54))
546353	28169357	In this study, we comprehensively analyzed the copy number alterations in esophageal carcinoma as well as the differential transcriptional gene expression between normal and tumor specimens.	('tumor', 'Disease', (174, 179))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (74, 94))	('copy number', 'Var', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('esophageal carcinoma', 'Disease', (74, 94))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (74, 94))
546359	28169357	The function assay revealed that knock-down of FAM60A expression could decrease the percentage of G1 phase cells, arrest cells at G2/M phase, suppress cell proliferation and increase apoptosis.	('FAM60A', 'Gene', (47, 53))	('decrease', 'NegReg', (71, 79))	('arrest', 'Disease', 'MESH:D006323', (114, 120))	('cell proliferation', 'CPA', (151, 169))	('arrest', 'Disease', (114, 120))	('increase', 'PosReg', (174, 182))	('FAM60A', 'Gene', '58516', (47, 53))	('cells at G2/M phase', 'CPA', (121, 140))	('knock-down', 'Var', (33, 43))	('apoptosis', 'CPA', (183, 192))	('percentage of G1 phase cells', 'CPA', (84, 112))	('suppress', 'NegReg', (142, 150))
546362	28169357	It has been demonstrated that copy number variations affect larger fractions of the genome in cancer than do other type of somatic genetic alterations.	('affect', 'Reg', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('copy number variations', 'Var', (30, 52))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
546366	28169357	A single-nucleotide polymorphism array-based copy number profile was performed and revealed that focal amplifications of YAPA and loss-of-function mutations in FAT1 and AJUBA may contribute to the activation of WNT signaling in ESCC.	('mutations', 'Var', (147, 156))	('FAT1', 'Gene', '2195', (160, 164))	('loss-of-function', 'NegReg', (130, 146))	('ESCC', 'Disease', (228, 232))	('YAPA', 'Gene', (121, 125))	('activation', 'PosReg', (197, 207))	('FAT1', 'Gene', (160, 164))	('AJUBA', 'Gene', (169, 174))	('WNT signaling', 'Pathway', (211, 224))	('AJUBA', 'Gene', '84962', (169, 174))
546367	28169357	Whole-genome sequencing and whole-exome sequencing of patients with different stages of ESCC were performed and revealed that somatic amplifications at 8q were enriched in stage I tumors, and deletions of 4p-q and 5q were specifically identified in stage III tumors.	('III tumors', 'Disease', 'MESH:D009369', (255, 265))	('I tumors', 'Disease', (178, 186))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('I tumors', 'Disease', 'MESH:D009369', (178, 186))	('patients', 'Species', '9606', (54, 62))	('I tumors', 'Disease', 'MESH:D009369', (257, 265))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('III tumors', 'Disease', (255, 265))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('deletions', 'Var', (192, 201))	('amplifications at', 'Var', (134, 151))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('identified', 'Reg', (235, 245))
546369	28169357	Copy number alterations were also analyzed among esophageal adenocarcinoma, which showed that SKI and PRKCZ, biomarkers involved in transforming growth factor-beta pathway, were located at a deletion region, suggesting the potential utility of novel biomarkers for EA.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('SKI', 'Gene', '6497', (94, 97))	('SKI', 'Gene', (94, 97))	('deletion', 'Var', (191, 199))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (49, 74))	('esophageal adenocarcinoma', 'Disease', (49, 74))	('PRKCZ', 'Gene', (102, 107))	('PRKCZ', 'Gene', '5590', (102, 107))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (49, 74))
546370	28169357	Genome-wide copy number variation analysis was performed on ESCC samples and identified that amplification of ABCC4 located at 13q32.1 was significantly correlated with ESCC risk, which was an independent poor prognostic factor for ESCC.	('amplification', 'Var', (93, 106))	('ABCC4', 'Gene', '10257', (110, 115))	('ESCC', 'Disease', (169, 173))	('correlated with', 'Reg', (153, 168))	('ABCC4', 'Gene', (110, 115))
546376	28169357	Overall, this study provides important insights into copy number variants of esophageal carcinoma, and FAM60A was demonstrated as a driver gene in esophageal carcinoma that acts as a new therapeutic target.	('FAM60A', 'Gene', '58516', (103, 109))	('FAM60A', 'Gene', (103, 109))	('copy number', 'Var', (53, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (77, 97))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (77, 97))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (147, 167))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (147, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('esophageal carcinoma', 'Disease', (77, 97))	('esophageal carcinoma', 'Disease', (147, 167))
546377	28169357	This comprehensive analysis of genomic and transcriptional data emphasized that copy number variations play important roles in the progression of cancer which provides a novel approach for the treatment of esophageal carcinoma.	('cancer', 'Disease', (146, 152))	('roles', 'Reg', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('esophageal carcinoma', 'Disease', (206, 226))	('copy number variations', 'Var', (80, 102))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (206, 226))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (206, 226))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
546441	27957019	Patients on medication such as those enhancing gastric emptying (metoclopramide, erythromycine, domperidone, tegaserod) and opiate analgesic (morphine, codeine, demerol) and anticholinergic antispasmotic were asked to stop medications 2 days prior to scanning.	('enhancing', 'PosReg', (37, 46))	('tegaserod', 'Chemical', 'MESH:C105050', (109, 118))	('demerol', 'Chemical', 'MESH:D008614', (161, 168))	('metoclopramide', 'Chemical', 'MESH:D008787', (65, 79))	('codeine', 'Chemical', 'MESH:D003061', (152, 159))	('opiate', 'Chemical', 'MESH:D053610', (124, 130))	('metoclopramide', 'Var', (65, 79))	('morphine', 'Chemical', 'MESH:D009020', (142, 150))	('Patients', 'Species', '9606', (0, 8))	('enhancing gastric emptying', 'Phenotype', 'HP:0002578', (37, 63))	('gastric emptying', 'Phenotype', 'HP:0002578', (47, 63))	('erythromycine', 'Chemical', 'MESH:C058417', (81, 94))	('gastric emptying', 'MPA', (47, 63))	('domperidone', 'Chemical', 'MESH:D004294', (96, 107))
546541	23008529	The high-fat, low-fiber food in the West is related to risk of cancers of the colon, pancreas, breast, prostate, ovary and endometrium.	('ovary', 'Disease', (113, 118))	('high-fat', 'Var', (4, 12))	('pancreas', 'Disease', (85, 93))	('cancers of the colon', 'Disease', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('prostate', 'Disease', (103, 111))	('cancers of the colon', 'Disease', 'MESH:D015179', (63, 83))	('fiber', 'Chemical', 'MESH:D004043', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('endometrium', 'Disease', (123, 134))	('breast', 'Disease', (95, 101))
546556	23008529	The omega-6 polyunsaturated lipids, effective in lowering serum cholesterol, are more efficient promoters than saturated fats such as lard or beef fat.	('fats', 'Gene', (121, 125))	('omega-6 polyunsaturated lipids', 'Chemical', '-', (4, 34))	('cholesterol', 'Chemical', 'MESH:D002784', (64, 75))	('fats', 'Gene', '118611', (121, 125))	('serum cholesterol', 'MPA', (58, 75))	('omega-6', 'Var', (4, 11))	('lowering', 'NegReg', (49, 57))
546572	23008529	Though most international and national studies identified a protective association between dietary fiber and the risk of colon cancer, other studies show no association, and a few studies indicate increased risk.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('dietary fiber', 'Var', (91, 104))	('colon cancer', 'Disease', (121, 133))	('fiber', 'Chemical', 'MESH:D004043', (99, 104))	('protective', 'NegReg', (60, 70))	('colon cancer', 'Phenotype', 'HP:0003003', (121, 133))	('colon cancer', 'Disease', 'MESH:D015179', (121, 133))
546580	23008529	Recent studies show that high alcohol intake is associated with an increased risk of several types of cancer, such as cancer of the esophagus, pharynx, larynx, and mouth.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('alcohol', 'Chemical', 'MESH:D000438', (30, 37))	('high alcohol', 'Var', (25, 37))	('mouth', 'Disease', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('larynx', 'Disease', (152, 158))	('cancer', 'Disease', (102, 108))	('pharynx', 'Disease', (143, 150))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
546626	23008529	Dietary restriction reduces cell cycling in major organs and depresses cancer development.	('depresses cancer', 'Disease', 'MESH:D000275', (61, 77))	('Dietary restriction', 'Var', (0, 19))	('cell cycling in major organs', 'CPA', (28, 56))	('depresses cancer', 'Disease', (61, 77))	('reduces', 'NegReg', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
546661	22891079	We excluded those subjects with esophageal cancer or any other cancer (ICD-9 codes 140-208 and A-code A08x-A14x) before the index date.	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('A-code A08x-A14x', 'Var', (95, 111))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('esophageal cancer', 'Disease', (32, 49))	('cancer', 'Disease', (63, 69))
546662	22891079	To enumerate the effects of potential co-morbidities and medications on the risk of esophageal cancer, the following co-morbidities were included before the index date: obesity (ICD-9 codes 278.00, 278.01, and A-code A183), esophageal diseases (ICD-9 codes 530.x and 947.2), H. pylori infection (ICD-9 codes 041.86), alcoholism (ICD-9 codes 303, 305.00, 305.01, 305.02, 305.03, V11.3, and A-code A215), and tobacco use (ICD-9 codes 305.1).	('esophageal diseases', 'Disease', (224, 243))	('obesity', 'Disease', (169, 176))	('H. pylori infection', 'Phenotype', 'HP:0005202', (275, 294))	('alcoholism', 'Disease', (317, 327))	('obesity', 'Phenotype', 'HP:0001513', (169, 176))	('esophageal diseases', 'Disease', 'MESH:D004935', (224, 243))	('A-code A215', 'Var', (389, 400))	('esophageal cancer', 'Disease', (84, 101))	('alcoholism', 'Disease', 'MESH:D000437', (317, 327))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('pylori infection', 'Disease', 'MESH:D016481', (278, 294))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('alcoholism', 'Phenotype', 'HP:0030955', (317, 327))	('pylori infection', 'Disease', (278, 294))	('obesity', 'Disease', 'MESH:D009765', (169, 176))	('tobacco', 'Species', '4097', (407, 414))
546696	21167162	Altered tumor susceptibilities can result also from gene polymorphisms.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('gene polymorphisms', 'Var', (52, 70))	('tumor', 'Disease', (8, 13))	('result', 'Reg', (35, 41))
546709	21167162	These cells colonized the germ line with useful efficiency and were capable of transmitting transgenes with generational stability.	('transgenes', 'Var', (92, 102))	('colon', 'Disease', (12, 17))	('colon', 'Disease', 'MESH:D015179', (12, 17))
546714	21167162	Combination of the Cre/LoxP recombinase system with another recombination system from yeast (Flip/FRT) increases the complexity of conditional gene alterations that can occur.	('conditional', 'Var', (131, 142))	('yeast', 'Species', '4932', (86, 91))	('increases', 'PosReg', (103, 112))
546716	21167162	Inherited mutations are often the initiators that establish conditions for additional mutations that then direct the tissue prevalence and progression pathway for tumorigenesis.	('progression', 'CPA', (139, 150))	('mutations', 'Var', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tissue', 'CPA', (117, 123))	('direct', 'Reg', (106, 112))	('tumor', 'Disease', (163, 168))	('mutations', 'Var', (10, 19))
546718	21167162	Most human cancers are sporadic in that they involve an initiating mutation in a cell, with subsequent accumulation of other genetic changes that drive pathways of progression to malignancy.	('malignancy', 'Disease', (179, 189))	('mutation', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('malignancy', 'Disease', 'MESH:D009369', (179, 189))	('cancers', 'Disease', (11, 18))	('human', 'Species', '9606', (5, 10))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
546722	21167162	When combined with inactivations of Pten, p53, and E2f1 and transgenic Kras activation in astrocytes, prostate, breast, brain, and ovarian cells, a variety of progression pathways for tumorigenesis in each of these cell types was delineated.	('p53', 'Gene', (42, 45))	('Pten', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('ovarian cells', 'Disease', (131, 144))	('E2f1', 'Gene', '13555', (51, 55))	('p53', 'Gene', '22059', (42, 45))	('Kras', 'Gene', (71, 75))	('Kras', 'Gene', '16653', (71, 75))	('Pten', 'Gene', '19211', (36, 40))	('ovarian cells', 'Disease', 'MESH:D010051', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('transgenic', 'Species', '10090', (60, 70))	('inactivations', 'Var', (19, 32))	('tumor', 'Disease', (184, 189))	('E2f1', 'Gene', (51, 55))	('activation', 'PosReg', (76, 86))
546727	21167162	Combination with a p53 deficiency led to invasive oral-esophageal cancer.	('deficiency', 'Var', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '22059', (19, 22))	('led to', 'Reg', (34, 40))	('oral-esophageal cancer', 'Disease', 'MESH:D004938', (50, 72))	('oral-esophageal cancer', 'Disease', (50, 72))
546730	21167162	It was found that loss of either of these genes leads to columnar metaplasia, but only loss of p53 and p27, but not APC, supports tumorigenesis in some of these mice.	('columnar metaplasia', 'Disease', 'MESH:D008679', (57, 76))	('mice', 'Species', '10090', (161, 165))	('loss', 'Var', (87, 91))	('loss', 'Var', (18, 22))	('APC', 'Disease', 'MESH:D011125', (116, 119))	('leads to', 'Reg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('APC', 'Disease', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('p53', 'Gene', (95, 98))	('p27', 'Gene', (103, 106))	('p53', 'Gene', '22059', (95, 98))	('columnar metaplasia', 'Disease', (57, 76))	('tumor', 'Disease', (130, 135))	('p27', 'Gene', '12576', (103, 106))
546737	21167162	Noggin (inhibitor of BMP) transgenics and doubly transgenic Cox2 and Pmes mice (both genes in PGE2 synthetic pathway) did not develop gastric cancer until triply combined.	('Noggin', 'Gene', (0, 6))	('transgenics', 'Var', (26, 37))	('Noggin', 'Gene', '18121', (0, 6))	('Cox2', 'Gene', (60, 64))	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('transgenic', 'Species', '10090', (26, 36))	('BMP', 'Gene', '649', (21, 24))	('PGE2', 'Chemical', 'MESH:D015232', (94, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('mice', 'Species', '10090', (74, 78))	('Cox2', 'Gene', '17709', (60, 64))	('transgenic', 'Species', '10090', (49, 59))	('BMP', 'Gene', (21, 24))
546740	21167162	The role of inflammation in gastric apoptosis and preneoplasia has been investigated using ionizing radiation and Helicobacter infection in GEMs with epithelial-specific disruption of I-kappaB-kinase beta/nuclear factor kappaB signaling.	('inflammation', 'Disease', 'MESH:D007249', (12, 24))	('gastric apoptosis and preneoplasia', 'Disease', 'MESH:D013274', (28, 62))	('disruption', 'Var', (170, 180))	('inflammation', 'Disease', (12, 24))	('Helicobacter infection', 'Disease', 'MESH:D016481', (114, 136))	('Helicobacter infection', 'Phenotype', 'HP:0005202', (114, 136))	('neoplasia', 'Phenotype', 'HP:0002664', (53, 62))	('Helicobacter infection', 'Disease', (114, 136))
546753	21167162	Mutations in the human APC gene are found in nearly 90% of human colon tumors.	('colon tumors', 'Disease', 'MESH:D015179', (65, 77))	('human', 'Species', '9606', (59, 64))	('APC', 'Disease', (23, 26))	('colon tumors', 'Disease', (65, 77))	('human', 'Species', '9606', (17, 22))	('found', 'Reg', (36, 41))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('colon tumors', 'Phenotype', 'HP:0100273', (65, 77))	('APC', 'Disease', 'MESH:D011125', (23, 26))
546755	21167162	Mice heterozygous for an N-ethyl-N-nitrosourea-mediated mutation in the mouse Apc gene have multiple intestinal neoplasia (Apcmin/+ mice), and tumorigenesis in these mice is independent of colitis.	('N-ethyl-N-nitrosourea', 'Chemical', 'MESH:D005038', (25, 46))	('colitis', 'Disease', 'MESH:D003092', (189, 196))	('tumor', 'Disease', (143, 148))	('colitis', 'Disease', (189, 196))	('mouse', 'Species', '10090', (72, 77))	('neoplasia', 'Phenotype', 'HP:0002664', (112, 121))	('neoplasia', 'Disease', (112, 121))	('multiple intestinal neoplasia', 'Phenotype', 'HP:0200008', (92, 121))	('Apc', 'Gene', (78, 81))	('colitis', 'Phenotype', 'HP:0002583', (189, 196))	('mice', 'Species', '10090', (132, 136))	('mice', 'Species', '10090', (166, 170))	('neoplasia', 'Disease', 'MESH:D009369', (112, 121))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutation', 'Var', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
546759	21167162	TGF-beta pathway disruptions are found in up to 30% of human colon tumors and have been modeled in several GEM strains.	('colon tumors', 'Disease', (61, 73))	('human', 'Species', '9606', (55, 60))	('disruptions', 'Var', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('colon tumors', 'Phenotype', 'HP:0100273', (61, 73))	('colon tumors', 'Disease', 'MESH:D015179', (61, 73))	('TGF-beta', 'Gene', (0, 8))
546769	21167162	Mice with a TGF-beta type 2 receptor (Tgfbr2) inactivation in which a Tgfbr2flox allele is combined with a Villin promoter-driven Cre transgene (Villin-Cre; expressed only in intestinal epithelium) develop duodenal adenomas and few intestinal tumors.	('develop', 'Reg', (198, 205))	('intestinal tumors', 'Disease', (232, 249))	('adenomas', 'Disease', 'MESH:D000236', (215, 223))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('Tgfbr2', 'Gene', '21813', (38, 44))	('adenomas', 'Disease', (215, 223))	('intestinal tumors', 'Disease', 'MESH:D007414', (232, 249))	('Tgfbr2', 'Gene', '21813', (70, 76))	('Mice', 'Species', '10090', (0, 4))	('inactivation', 'Var', (46, 58))	('Tgfbr2', 'Gene', (38, 44))	('Tgfbr2', 'Gene', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
546770	21167162	However, when genetically combined with mice harboring an Apc truncation mutation (Apc1638N/+), the intestinal epithelial-specific loss of TGF-betaR2 increased progression of intestinal Apc1638N/+ adenomas to invasive adenocarcinomas.	('adenomas to invasive adenocarcinomas', 'Disease', 'MESH:D000236', (197, 233))	('adenomas to invasive adenocarcinomas', 'Disease', (197, 233))	('loss', 'Var', (131, 135))	('increased', 'PosReg', (150, 159))	('mice', 'Species', '10090', (40, 44))	('TGF-betaR2', 'Gene', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))
546772	21167162	Finally, conditional ablation of Smad4 in the T-cell compartment through genetic combination of Smad4flox/flox and Cd4-Cre transgenic mice led to epithelial tumors throughout the GI tract from the oral cavity to the rectum, whereas conditional ablation in the intestinal epithelial compartment using a Transthyretin-Cre transgenic mouse did not.	('epithelial tumors', 'Disease', 'MESH:D002277', (146, 163))	('Smad4', 'Gene', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('led to', 'Reg', (139, 145))	('Cd4', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('Smad4', 'Gene', '17128', (96, 101))	('Smad4', 'Gene', '17128', (33, 38))	('mouse', 'Species', '10090', (331, 336))	('Smad4', 'Gene', (33, 38))	('ablation', 'Var', (21, 29))	('transgenic', 'Species', '10090', (123, 133))	('transgenic mice', 'Species', '10090', (123, 138))	('epithelial tumors', 'Disease', (146, 163))	('Cd4', 'Gene', '12504', (115, 118))	('transgenic', 'Species', '10090', (320, 330))
546773	21167162	Both this and a previous study in which the G protein subunit alpha i2 was knocked out, causing a thymocyte deficiency, which led to mucinous adenocarcinoma of the colon, indicate the importance of the immunomodulatory microenvironment in tumorigenesis.	('adenocarcinoma of the colon', 'Phenotype', 'HP:0040276', (142, 169))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('mucinous adenocarcinoma of the colon', 'Disease', (133, 169))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('knocked out', 'Var', (75, 86))	('tumor', 'Disease', (239, 244))	('mucinous adenocarcinoma of the colon', 'Disease', 'MESH:D002288', (133, 169))	('led to', 'Reg', (126, 132))	('causing', 'Reg', (88, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
546774	21167162	Because human APC or TGFbeta mutations usually occur in combination with other mutations, GEMs are also modeling this complexity.	('human', 'Species', '9606', (8, 13))	('mutations', 'Var', (29, 38))	('TGFbeta', 'Gene', (21, 28))	('APC', 'Disease', 'MESH:D011125', (14, 17))	('APC', 'Disease', (14, 17))	('TGFbeta', 'Gene', '7040', (21, 28))
546778	21167162	With the increasing complexity of these models, colon cancer researchers should be able to better correlate specific gene mutation with phenotypic aspects of colon tumors.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('colon tumors', 'Disease', 'MESH:D015179', (158, 170))	('colon tumors', 'Disease', (158, 170))	('colon cancer', 'Disease', (48, 60))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('mutation', 'Var', (122, 130))	('colon cancer', 'Phenotype', 'HP:0003003', (48, 60))	('colon tumors', 'Phenotype', 'HP:0100273', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('colon cancer', 'Disease', 'MESH:D015179', (48, 60))
546788	19263437	Histopathological analyses of the tongue revealed significantly higher severity of dysplasia in the cyclin D1 overexpression mice, compared with non-transgenic controls and with untreated controls.	('transgenic', 'Species', '10090', (149, 159))	('cyclin D1', 'Gene', (100, 109))	('dysplasia', 'Disease', 'MESH:D004476', (83, 92))	('higher', 'PosReg', (64, 70))	('overexpression', 'Var', (110, 124))	('mice', 'Species', '10090', (125, 129))	('dysplasia', 'Disease', (83, 92))
546799	19263437	There is strong evidence that dysregulation of cyclin D1 plays an important role in oral SCC development.	('dysregulation', 'Var', (30, 43))	('SCC', 'Gene', '6317', (89, 92))	('cyclin D1', 'Protein', (47, 56))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
546801	19263437	These aberrations are also noted in precancerous oral epithelial dysplastic lesions, suggesting that cyclin D1 deregulation is an early event in the neoplastic process.	('epithelial dysplastic lesions', 'Phenotype', 'HP:0031492', (54, 83))	('cyclin D1', 'Gene', (101, 110))	('neoplastic process', 'Phenotype', 'HP:0002664', (149, 167))	('deregulation', 'Var', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('precancerous oral epithelial dysplastic lesions', 'Disease', (36, 83))	('precancerous oral epithelial dysplastic lesions', 'Disease', 'MESH:D011230', (36, 83))
546805	19263437	When crossbred with constitutive p53-deficient mice, the L2-D1 mice develop invasive oro-esophageal SCC.	('p53', 'Gene', '22060', (33, 36))	('SCC', 'Gene', (100, 103))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('SCC', 'Gene', '6317', (100, 103))	('mice', 'Species', '10090', (63, 67))	('p53', 'Gene', (33, 36))	('L2-D1', 'Var', (57, 62))	('mice', 'Species', '10090', (47, 51))
546808	19263437	4NQO is a quinoline derivative and causes a wide range of DNA damage, including DNA adducts, single-strand breaks, abasic sites, pyrimidine dimers, and oxidized bases.	('pyrimidine', 'Chemical', 'MESH:C030986', (129, 139))	('single-strand', 'MPA', (93, 106))	('pyrimidine', 'Var', (129, 139))	('quinoline', 'Chemical', 'MESH:C037219', (10, 19))	('4NQO', 'Chemical', 'MESH:D015112', (0, 4))	('abasic sites', 'Var', (115, 127))	('DNA damage', 'MPA', (58, 68))	('causes', 'Reg', (35, 41))	('DNA adducts', 'MPA', (80, 91))	('4NQO', 'Var', (0, 4))
546809	19263437	Depending upon the dose and duration of treatment, 4NQO induces a spectrum of dysplastic and neoplastic lesions in the oro-esophageal epithelium, with morphological and molecular alterations that mimic those occurring in human oral epithelial preneoplastic and neoplastic lesions.	('neoplastic lesion', 'Phenotype', 'HP:0002664', (93, 110))	('4NQO', 'Var', (51, 55))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (261, 278))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (261, 279))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (93, 111))	('4NQO', 'Chemical', 'MESH:D015112', (51, 55))	('human', 'Species', '9606', (221, 226))	('induces', 'Reg', (56, 63))	('neoplastic lesions', 'Disease', 'MESH:D051437', (93, 111))	('neoplastic lesions', 'Disease', (261, 279))	('dysplastic and neoplastic lesions', 'Disease', 'MESH:D021782', (78, 111))	('neoplastic lesions', 'Disease', (93, 111))	('neoplastic lesions', 'Disease', 'MESH:D051437', (261, 279))
546825	19263437	Adult L2-D1 transgenic mice and non-transgenic littermates (approximately 5 months of age) were treated with 4NQO (Sigma, St. Louis, MO) in their drinking water at a concentration of 20 parts per million (ppm) or 50 ppm for a period of 8 weeks.	('transgenic mice', 'Species', '10090', (12, 27))	('transgenic', 'Species', '10090', (12, 22))	('transgenic', 'Species', '10090', (36, 46))	('L2-D1', 'Gene', (6, 11))	('drinking water', 'Chemical', 'MESH:D060766', (146, 160))	('4NQO', 'Var', (109, 113))	('4NQO', 'Chemical', 'MESH:D015112', (109, 113))
546846	19263437	To determine the difference in severity of 4NQO-induced dysplasia between L2-D1 and wild-type mice, we used the nonparametric Mann-Whitney test.	('4NQO', 'Chemical', 'MESH:D015112', (43, 47))	('dysplasia', 'Disease', 'MESH:D004476', (56, 65))	('mice', 'Species', '10090', (94, 98))	('L2-D1', 'Var', (74, 79))	('dysplasia', 'Disease', (56, 65))
546852	19263437	Although it is not a natural tobacco-derived product, 4NQO induces several types of DNA damage, similar to those occurring as a result of tobacco exposure and is a potent oral carcinogen in rodents.	('tobacco', 'Species', '4097', (29, 36))	('DNA damage', 'MPA', (84, 94))	('induces', 'Reg', (59, 66))	('4NQO', 'Var', (54, 58))	('tobacco', 'Species', '4097', (138, 145))	('4NQO', 'Chemical', 'MESH:D015112', (54, 58))
546862	19263437	However, the degree of dysplastic change was significantly influenced by the cyclin D1 genotype and the carcinogenic dose (Figure 2B).	('dysplastic', 'Disease', 'MESH:D004416', (23, 33))	('dysplastic', 'Disease', (23, 33))	('cyclin D1', 'Gene', (77, 86))	('carcinogenic', 'Disease', 'MESH:D063646', (104, 116))	('carcinogenic', 'Disease', (104, 116))	('genotype', 'Var', (87, 95))	('influenced', 'Reg', (59, 69))
546866	19263437	Notably, at this dose, 50% of the L2D1 mice developed SCC of the tongue and/or esophagus.	('SCC', 'Gene', '6317', (54, 57))	('L2D1', 'Var', (34, 38))	('SCC', 'Gene', (54, 57))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('mice', 'Species', '10090', (39, 43))
546867	19263437	By contrast, wild-type mice treated with 50 ppm of 4NQO showed lesser degrees of epithelial dysplastic change and none of the wild-type mice developed neoplastic changes (Table I).	('4NQO', 'Var', (51, 55))	('mice', 'Species', '10090', (136, 140))	('epithelial dysplastic change', 'Disease', (81, 109))	('4NQO', 'Chemical', 'MESH:D015112', (51, 55))	('neoplastic changes', 'Phenotype', 'HP:0002664', (151, 169))	('epithelial dysplastic change', 'Phenotype', 'HP:0031492', (81, 109))	('epithelial dysplastic change', 'Disease', 'MESH:C536444', (81, 109))	('mice', 'Species', '10090', (23, 27))
546880	19263437	We next examined the molecular alterations occurring in 4NQO-induced dysplastic and neoplasia lesions in the L2-D1 mice.	('neoplasia lesions', 'Disease', (84, 101))	('dysplastic', 'Disease', (69, 79))	('neoplasia lesions', 'Disease', 'MESH:D009369', (84, 101))	('dysplastic', 'Disease', 'MESH:D004416', (69, 79))	('4NQO-induced', 'Var', (56, 68))	('neoplasia', 'Phenotype', 'HP:0002664', (84, 93))	('4NQO', 'Chemical', 'MESH:D015112', (56, 60))	('mice', 'Species', '10090', (115, 119))
546882	19263437	Inactivation of p16 by gene deletion, mutation or promoter hypermethylation is a frequent event in oral epithelial dysplasia and SCC.	('oral epithelial dysplasia', 'Disease', 'MESH:D017573', (99, 124))	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('SCC', 'Gene', '6317', (129, 132))	('oral epithelial dysplasia', 'Disease', (99, 124))	('p16', 'Gene', '12578', (16, 19))	('mutation', 'Var', (38, 46))	('promoter', 'MPA', (50, 58))	('gene deletion', 'Var', (23, 36))	('SCC', 'Gene', (129, 132))	('p16', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))
546889	19263437	Although the role of Cox2 in this process is not understood fully, inhibition of Cox2 has gained considerable attention as a potential target for chemopreventive agents.	('inhibition', 'Var', (67, 77))	('Cox2', 'Gene', '17709', (81, 85))	('Cox2', 'Gene', '17709', (21, 25))	('Cox2', 'Gene', (81, 85))	('Cox2', 'Gene', (21, 25))
546901	19263437	It is accepted generally that oral SCC develops by a multistep process with accumulation of mutations in key growth-regulating genes.	('SCC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('SCC', 'Gene', '6317', (35, 38))	('mutations', 'Var', (92, 101))
546907	19263437	The severity of carcinogen-induced dysplasia was significantly higher in the cyclin D1 mice, compared with their wild-type littermates.	('dysplasia', 'Disease', (35, 44))	('dysplasia', 'Disease', 'MESH:D004476', (35, 44))	('mice', 'Species', '10090', (87, 91))	('cyclin D1', 'Var', (77, 86))	('higher', 'PosReg', (63, 69))
546912	19263437	Taken together, our findings and previous studies strongly imply that cyclin D1 enhances carcinogenic effects.	('cyclin', 'Var', (70, 76))	('carcinogenic', 'Disease', (89, 101))	('enhances', 'PosReg', (80, 88))	('carcinogenic', 'Disease', 'MESH:D063646', (89, 101))
546913	19263437	Our findings have important implications for human oral SCC: deregulation of cyclin D1 and other components in the cyclin D1 pathway is a frequent and early event in human oral SCC development.	('SCC', 'Gene', (56, 59))	('human', 'Species', '9606', (166, 171))	('SCC', 'Gene', (177, 180))	('human', 'Species', '9606', (45, 50))	('cyclin D1', 'Gene', (77, 86))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('SCC', 'Gene', '6317', (56, 59))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))	('SCC', 'Gene', '6317', (177, 180))	('deregulation', 'Var', (61, 73))
546916	19263437	It is also possible that cyclin D1 may more directly modulate the cell's response to the DNA damaging effects of 4NQO:for example, cyclin D1 overexpression may permit the epithelial cells to override 4NQO damage-induced apoptotic signals and thus, favor accumulation of mutations necessary for development of dysplasia and neoplasia.	('cyclin', 'Gene', (131, 137))	('neoplasia', 'Phenotype', 'HP:0002664', (323, 332))	('favor accumulation', 'PosReg', (248, 266))	('mutations', 'Var', (270, 279))	('override', 'PosReg', (191, 199))	('dysplasia and neoplasia', 'Disease', 'MESH:D009369', (309, 332))	('overexpression', 'PosReg', (141, 155))	('4NQO', 'Chemical', 'MESH:D015112', (200, 204))	('4NQO', 'Chemical', 'MESH:D015112', (113, 117))
546918	19263437	Notably, there is increasing evidence that a specific polymorphism of cyclin D1 (G/A870) influences the risk of oral SCC development.	('influences', 'Reg', (89, 99))	('G/A870', 'Gene', (81, 87))	('SCC', 'Gene', (117, 120))	('polymorphism', 'Var', (54, 66))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('SCC', 'Gene', '6317', (117, 120))	('G/A870', 'Mutation', 'rs9344', (81, 87))
546919	19263437	This polymorphism results in an alternatively spliced protein product that lacks the threonine 286 phosphorylation site required for nuclear export and ubiqutin-mediated degradation.	('threonine 286 phosphorylation site required', 'MPA', (85, 128))	('polymorphism', 'Var', (5, 17))	('ubiqutin-mediated degradation', 'MPA', (152, 181))	('threonine', 'Chemical', 'MESH:D013912', (85, 94))	('lacks', 'NegReg', (75, 80))	('results in', 'Reg', (18, 28))
546921	19263437	Indeed, transgenic mice that overexpress of a mutant form of cyclin D1 (D1T286A) that lacks nuclear export, develop mammary adenocarcinomas at an increased rate relative to mice that overexpress wild-type cyclin D1.	('transgenic mice', 'Species', '10090', (8, 23))	('develop', 'PosReg', (108, 115))	('adenocarcinomas', 'Disease', 'MESH:D000230', (124, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('lacks', 'NegReg', (86, 91))	('mutant', 'Var', (46, 52))	('mammary', 'CPA', (116, 123))	('nuclear export', 'MPA', (92, 106))	('adenocarcinomas', 'Disease', (124, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('mice', 'Species', '10090', (19, 23))	('mice', 'Species', '10090', (173, 177))
546922	19263437	Furthermore, inactivating mutations of Fbx4, a factor that directs cyclin D1 ubiquitination, are frequent in human cancers.	('inactivating mutations', 'Var', (13, 35))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('Fbx4', 'Gene', (39, 43))	('human cancers', 'Disease', 'MESH:D009369', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('human cancers', 'Disease', (109, 122))
546945	33758229	Its identity has been verified by short tandem repeat analysis, p53 mutation and xenograft histology against the original tumors.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('mutation', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
546946	33758229	The whole-genome sequencing of FLO-1 cell line confirmed the presence of many of the known mutations that drive esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('FLO-1', 'Chemical', '-', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', (123, 129))
547108	33758229	Immature tight junctions were more frequently seen in the cells maintained in A-DMEM than in DMEM (Fig.	('DMEM', 'Chemical', '-', (93, 97))	('DMEM', 'Chemical', '-', (80, 84))	('seen', 'Reg', (46, 50))	('A-DMEM', 'Chemical', '-', (78, 84))	('A-DMEM', 'Var', (78, 84))
547242	33287147	According to the main international guidelines, patients with Siewert III type tumors were treated as gastric cancers, while patients with SC cervical tumors were assigned to definitive chemo-radiotherapy and therefore excluded from the analysis.	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (125, 133))	('Siewert', 'Var', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('SC cervical tumors', 'Disease', 'MESH:D000755', (139, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('gastric cancers', 'Disease', 'MESH:D013274', (102, 117))	('SC cervical tumors', 'Disease', (139, 157))	('gastric cancers', 'Disease', (102, 117))	('gastric cancers', 'Phenotype', 'HP:0012126', (102, 117))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cervical tumors', 'Phenotype', 'HP:0030159', (142, 157))
547283	31737702	Immunohistochemically, the cancer cells were positive for cytokeratin 34betaE12 and p63, but negative for in situ hybridization for the Epstein-Barr virus encoded small RNA (EBER-1) transcript, and tumor nests were observed in a scattered manner with infiltration of CD3-positive T-lymphocytes (Figure 4).	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('man', 'Species', '9606', (239, 242))	('N', 'Chemical', 'MESH:D009584', (170, 171))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('p63', 'Var', (84, 87))	('positive', 'Reg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', (27, 33))	('tumor', 'Disease', (198, 203))	('Epstein-Barr virus', 'Species', '10376', (136, 154))
547317	31490413	Decision curve analysis yielded a range of threshold probabilities (0.020-0.177 and 0.021-0.133 for patients with esophageal adenocarcinoma and squamous cell carcinoma, respectively) at which the clinical net benefit of the risk model was larger than those of hypothetical all-screening and no-screening scenarios.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (114, 139))	('esophageal adenocarcinoma', 'Disease', (114, 139))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (114, 139))	('patients', 'Species', '9606', (100, 108))	('larger', 'PosReg', (239, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('squamous cell carcinoma', 'Disease', (144, 167))	('0.021-0.133', 'Var', (84, 95))
547385	30540749	These mutations are caused by environmental factors accumulated during an individual's lifetime; this accumulation of mutational events results in a large degree of genetic heterogeneity among cancer cells.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('results in', 'Reg', (136, 146))	('genetic heterogeneity', 'MPA', (165, 186))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('mutations', 'Var', (6, 15))
547389	30540749	It states that all tumor cells descend from a single founder cell, and cells with some advantageous mutations become more competitive than normal cells for growth and clonal expansion.	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor cells', 'Disease', (19, 30))	('tumor cells', 'Disease', 'MESH:D005935', (19, 30))
547397	30540749	Single-nucleotide variants (SNVs) and copy number aberrations (CNAs) are widely used data types to study tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Single-nucleotide variants', 'Var', (0, 26))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('copy number aberrations', 'Var', (38, 61))
547399	30540749	This approach applies a Dirichlet process prior on group mutations and infers the posterior distribution to estimate the cellular prevalence, which is the fraction of cancer cells harboring a mutation.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cellular', 'MPA', (121, 129))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
547403	30540749	Furthermore, PyLOH resolves the identifiability problem by integrating CNAs and loss of heterozygosity (LOH) within a unified probabilistic model.	('CNAs', 'MPA', (71, 75))	('loss of heterozygosity', 'Var', (80, 102))	('PyLOH', 'Chemical', '-', (13, 18))
547409	30540749	The novel subclonal CNAs have also been identified, and their subclonal structure has been shown to facilitate the discovery of driver mutations for advanced tumor progression.	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (158, 163))	('mutations', 'Var', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
547427	30540749	We also applied CloneDeMix on head and neck cancer data from TCGA and serial biopsies of esophageal cancer to infer genomic evolution based on copy number change.	('esophageal cancer', 'Disease', (89, 106))	('copy', 'Var', (143, 147))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('neck cancer', 'Disease', 'MESH:D006258', (39, 50))	('neck cancer', 'Disease', (39, 50))	('head and neck cancer', 'Phenotype', 'HP:0012288', (30, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
547428	30540749	It has been reported that CNAs affect a larger fraction of the genome in cancers than any other type of somatic genetic mutation does.	('affect', 'Reg', (31, 37))	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('CNAs', 'Var', (26, 30))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
547437	30540749	If, for example, an abnormal copy number is found to be k, the raw read depth of this locus would be divided by k to provide the estimate of abase,i for tumor modeling.	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('copy number', 'Var', (29, 40))
547456	30540749	The heterogeneity and mortality in head and neck cancer was also investigated by a different approach, and it also concluded that high-heterogeneity in tumors had doubled the hazard of death.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('head and neck cancer', 'Phenotype', 'HP:0012288', (35, 55))	('high-heterogeneity', 'Var', (130, 148))	('death', 'Disease', 'MESH:D003643', (185, 190))	('death', 'Disease', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('neck cancer', 'Disease', 'MESH:D006258', (44, 55))	('neck cancer', 'Disease', (44, 55))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
547462	30540749	That is, the mutation of PIK3CA occurs early in the tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('mutation', 'Var', (13, 21))	('PIK3CA', 'Gene', (25, 31))	('PIK3CA', 'Gene', '5290', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
547465	30540749	For example, we identified structure variation of TP53 only in a few patients, and these few MCPs are not enough to construct a powerful P-score.	('patients', 'Species', '9606', (69, 77))	('structure variation', 'Var', (27, 46))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))
547468	30540749	The genes above the diagonal line of the plot are more likely to acquire mutations at an earlier stage of tumor formation and occupy a significant proportion of the tumor at its advanced stage.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', (165, 170))
547470	30540749	Several studies have shown that the inhibition of HAS2 reduced the invasion of oral squamous cell carcinoma.	('HAS2', 'Gene', (50, 54))	('HAS2', 'Gene', '3037', (50, 54))	('inhibition', 'Var', (36, 46))	('reduced', 'NegReg', (55, 62))	('invasion', 'CPA', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('oral squamous cell carcinoma', 'Disease', (79, 107))
547506	30540749	We next analyzed SNV data of head and neck cancer to identify the additional subclones induced by nonsynonymous substitution in tumors.	('nonsynonymous substitution', 'Var', (98, 124))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('head and neck cancer', 'Phenotype', 'HP:0012288', (29, 49))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (128, 134))	('neck cancer', 'Disease', 'MESH:D006258', (38, 49))	('neck cancer', 'Disease', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
547508	30540749	In S4 Fig, the distribution of subclone numbers induced by different variant types varies across samples, and it could be evidence of the complexity of tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('variant', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))
547514	30540749	Most existing methods for cancer evolution discuss the history of single-nucleotide changes and derive the potential driver genes.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('single-nucleotide changes', 'Var', (66, 91))
547518	30540749	For instance, the MCPs of early mutations in cancer must exceed those of other mutations, but no such structural relationship exists for SCPs.	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
547522	30540749	The deletions observed on chromosomes 3p, 18q, and 21p and the amplifications on chromosomes 3q, 5p, and 8q are consistent with most cancer studies on copy number identification.	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('deletions', 'Var', (4, 13))
547527	30540749	By comparing the P scores of a somatic variant between different clinical groups, we could identify the copy number mutations that occur early in the tumor stage and expand the accompanied subclones with time.	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mutations', 'Var', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('copy', 'Var', (104, 108))	('tumor', 'Disease', (150, 155))
547544	29288243	Silencing Cav1 decreased PY14Cav1 expression in TE1 and TE13 cells, as well as suppressing the migration and invasion of all ECSS cells, and these differences were significant (P<0.05).	('expression', 'MPA', (34, 44))	('Cav1', 'Gene', (29, 33))	('Cav1', 'Gene', '857', (10, 14))	('Cav1', 'Gene', '857', (29, 33))	('suppressing', 'NegReg', (79, 90))	('decreased', 'NegReg', (15, 24))	('Silencing', 'Var', (0, 9))	('Cav1', 'Gene', (10, 14))
547607	29288243	The results of silencing Cav1 are shown in Figure 2A-2D.	('silencing', 'Var', (15, 24))	('Cav1', 'Gene', '857', (25, 29))	('Cav1', 'Gene', (25, 29))
547609	29288243	In TE1 and TE13 cells, PY14Cav1 levels were significantly (P<0.05) reduced compared to the NC and BC groups after silencing Cav1.	('Cav1', 'Gene', (124, 128))	('BC', 'Chemical', '-', (98, 100))	('Cav1', 'Gene', '857', (27, 31))	('silencing', 'Var', (114, 123))	('Cav1', 'Gene', '857', (124, 128))	('reduced', 'NegReg', (67, 74))	('Cav1', 'Gene', (27, 31))
547610	29288243	After silencing Cav1, the number of migrating EC109, Eca109, TE1, and TE13 cells decreased significantly (P<0.05) compared to the NC and BC groups.	('decreased', 'NegReg', (81, 90))	('BC', 'Chemical', '-', (137, 139))	('Cav1', 'Gene', '857', (16, 20))	('Cav1', 'Gene', (16, 20))	('silencing', 'Var', (6, 15))
547611	29288243	Before and after silencing Cav1, there were significantly (P<0.05) fewer migrating EC109 and Eca109 cells than migrating TE1 and TE13 cells, and fewer migrating TE1 cells than migrating TE13 cells.	('migrating', 'CPA', (151, 160))	('Cav1', 'Gene', '857', (27, 31))	('fewer', 'NegReg', (67, 72))	('Cav1', 'Gene', (27, 31))	('silencing', 'Var', (17, 26))	('migrating EC109', 'CPA', (73, 88))
547612	29288243	After silencing Cav1, the numbers of invasive EC109, Eca109, TE1, and TE13 cells decreased significantly (P<0.05) compared to NC and BC groups.	('decreased', 'NegReg', (81, 90))	('invasive EC109', 'CPA', (37, 51))	('Cav1', 'Gene', '857', (16, 20))	('BC', 'Chemical', '-', (133, 135))	('Cav1', 'Gene', (16, 20))	('silencing', 'Var', (6, 15))
547613	29288243	Before and after silencing Cav1, there were significantly (P<0.05) fewer invasive EC109 and Eca109 cells than TE13 cells.	('Cav1', 'Gene', '857', (27, 31))	('Eca109', 'CPA', (92, 98))	('fewer', 'NegReg', (67, 72))	('Cav1', 'Gene', (27, 31))	('silencing', 'Var', (17, 26))
547615	29288243	Compared to the control group, after suppressing the Rho/ROCK pathway with Y-27632 (10 muM), Cav1 expression in EC109 (Figure 3A), Eca109 (Figure 3B), TE1 (Figure 3C), and TE13 (Figure 3-D) cells were all significantly (P<0.05) inhibited, as was PY14Cav1 expression in TE1 (Figure 3C) and TE13 (Figure 3D) cells.	('Cav1', 'Gene', (93, 97))	('EC109', 'Var', (112, 117))	('Cav1', 'Gene', '857', (250, 254))	('suppressing', 'NegReg', (37, 48))	('inhibited', 'NegReg', (228, 237))	('Rho/ROCK pathway', 'Pathway', (53, 69))	('expression', 'MPA', (255, 265))	('Cav1', 'Gene', (250, 254))	('Cav1', 'Gene', '857', (93, 97))	('Y-27632', 'Chemical', 'MESH:C108830', (75, 82))	('Eca109', 'Var', (131, 137))	('expression', 'MPA', (98, 108))
547633	29288243	Silencing Cav1 expression in ESCC cells not only decreased Cav1 and PY14Cav1 levels, but also suppressed ESCC cell migration and invasion.	('ESCC', 'Disease', (105, 109))	('Cav1', 'Gene', (72, 76))	('Cav1', 'Gene', '857', (59, 63))	('Cav1', 'Gene', '857', (10, 14))	('invasion', 'CPA', (129, 137))	('decreased', 'NegReg', (49, 58))	('suppressed', 'NegReg', (94, 104))	('Cav1', 'Gene', '857', (72, 76))	('Cav1', 'Gene', (59, 63))	('Silencing', 'Var', (0, 9))	('Cav1', 'Gene', (10, 14))
547638	29288243	showed that hypermethylation of the Cav1 promoter led to gene silencing, which is common in human early esophageal cancer during Barrett's-associated EAC, but this is inconsistent with a previous study, as well with as our research.	('Cav1', 'Gene', (36, 40))	("Barrett's-associated", 'Disease', (129, 149))	('hypermethylation', 'Var', (12, 28))	('EAC', 'Disease', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gene', 'MPA', (57, 61))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('Cav1', 'Gene', '857', (36, 40))	('human', 'Species', '9606', (92, 97))
547640	29288243	showed that Cav1 expression inhibits tumor growth during the early stage of cancer progression, while promoting tumor invasion and metastasis during the later stages.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Cav1', 'Gene', (12, 16))	('inhibits', 'NegReg', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('expression', 'Var', (17, 27))	('promoting', 'PosReg', (102, 111))	('tumor', 'Disease', (112, 117))	('Cav1', 'Gene', '857', (12, 16))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
547647	29288243	Thirdly, we did not detect the activity of Rho/ROCK pathway after silencing Cav1, so their co-interaction is still unclear.	('Cav1', 'Gene', '857', (76, 80))	('silencing', 'Var', (66, 75))	('Rho/ROCK pathway', 'Pathway', (43, 59))	('Cav1', 'Gene', (76, 80))
547759	27975019	Recurrent laryngeal nerve resection caused comorbid and recurrent nerve paralysis (RNP) in 8 patients.	('nerve paralysis', 'Disease', (66, 81))	('nerve paralysis', 'Disease', 'MESH:D010243', (66, 81))	('resection', 'Var', (26, 35))	('patients', 'Species', '9606', (93, 101))	('paralysis', 'Phenotype', 'HP:0003470', (72, 81))
547875	27292876	Stable clones with either overexpression or shRNA knockdown of MT3-MMP were examined by Western blot analysis (see below in Fig.	('MT3-MMP', 'Gene', '4325', (63, 70))	('knockdown', 'Var', (50, 59))	('MT3-MMP', 'Gene', (63, 70))
547879	27292876	Moreover, shRNA knockdown of MT3-MMP markedly increased proliferation of EC9706 cells, compared to shRNA control (P < 0.05 for days 3-6, Fig.	('increased', 'PosReg', (46, 55))	('proliferation', 'CPA', (56, 69))	('knockdown', 'Var', (16, 25))	('MT3-MMP', 'Gene', '4325', (29, 36))	('EC9706', 'CellLine', 'CVCL:E307', (73, 79))	('MT3-MMP', 'Gene', (29, 36))
547881	27292876	Next, colony formation assays with or without soft agar were then carried out in human ESCC cells with either shRNA knockdown or ectopic overexpression of MT3-MMP, as described above.	('MT3-MMP', 'Gene', '4325', (155, 162))	('MT3-MMP', 'Gene', (155, 162))	('agar', 'Chemical', 'MESH:D000362', (51, 55))	('shRNA', 'Gene', (110, 115))	('knockdown', 'Var', (116, 125))	('human', 'Species', '9606', (81, 86))
547890	27292876	Conversely, shRNA knockdown of MT3-MMP in either EC109 (shMT3-MMP1,) or EC9706 (shMT3-MMP2) substantially decreased about 70% and 90% in expression MT3-MMP, respectively (Fig.	('MT3-MMP', 'Gene', (82, 89))	('EC9706', 'Var', (72, 78))	('decreased', 'NegReg', (106, 115))	('MT3-MMP', 'Gene', (58, 65))	('shMT3-MMP1', 'Gene', '4312', (56, 66))	('MT3-MMP', 'Gene', '4325', (31, 38))	('EC109', 'CellLine', 'CVCL:6898', (49, 54))	('MT3-MMP', 'Gene', (31, 38))	('MT3-MMP', 'Gene', '4325', (148, 155))	('EC9706', 'CellLine', 'CVCL:E307', (72, 78))	('MMP2', 'Gene', (86, 90))	('MT3-MMP', 'Gene', (148, 155))	('shMT3-MMP1', 'Gene', (56, 66))	('MT3-MMP', 'Gene', '4325', (82, 89))	('MT3-MMP', 'Gene', '4325', (58, 65))	('MMP2', 'Gene', '4313', (86, 90))
547897	27292876	To this end, expression of MMPs is generally considered as an adverse factor for prognosis of cancer patients.	('MMPs', 'Gene', '4312;4313;4317;17394;4318;4320;4321;4322;4323;4324;4325;4327', (27, 31))	('patients', 'Species', '9606', (101, 109))	('MMPs', 'Gene', (27, 31))	('expression', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
547918	27292876	While the exact mechanism(s) for regulation of p21Cip1 and p27Kip1 by MT3-MMP remains to be defined, one possibility is that it may up-regulate p21Cip1 and p27Kip1 via inactivation of MEK/ERK as MMPs belong to the ADAMTS family that antagonizes the EGFR/MEK/ERK signaling pathway 21.	('MEK', 'Gene', (254, 257))	('p21Cip1', 'Gene', '1026', (144, 151))	('EGFR', 'Gene', (249, 253))	('MMPs', 'Gene', '4312;4313;4317;17394;4318;4320;4321;4322;4323;4324;4325;4327', (195, 199))	('ERK', 'Gene', (258, 261))	('p21Cip1', 'Gene', (144, 151))	('p21Cip1', 'Gene', '1026', (47, 54))	('p21Cip1', 'Gene', (47, 54))	('p27Kip1', 'Gene', (156, 163))	('MT3-MMP', 'Gene', '4325', (70, 77))	('ERK', 'Gene', '5594', (188, 191))	('p27Kip1', 'Gene', (59, 66))	('MMPs', 'Gene', (195, 199))	('EGFR', 'Gene', '1956', (249, 253))	('p27Kip1', 'Gene', '1027', (156, 163))	('MEK', 'Gene', '5609', (184, 187))	('p27Kip1', 'Gene', '1027', (59, 66))	('inactivation', 'Var', (168, 180))	('MT3-MMP', 'Gene', (70, 77))	('up-regulate', 'PosReg', (132, 143))	('MEK', 'Gene', '5609', (254, 257))	('MEK', 'Gene', (184, 187))	('ERK', 'Gene', (188, 191))	('ERK', 'Gene', '5594', (258, 261))
547928	26735535	In the analysis of data from all participants, the OR (95% CI) for the association between SHS and ESCC was (OR = 1.02; 95% CI, 0.53-1.93) for SHS <=14 h/wk and (OR = 1.91; 95% CI, 0.75-4.89) for SHS >14 h/wk in the models adjusted for tobacco use and several other potential confounding factors.	('tobacco', 'Species', '4097', (236, 243))	('SHS', 'Gene', (91, 94))	('ESCC', 'Disease', (99, 103))	('SHS <=14', 'Var', (143, 151))	('participants', 'Species', '9606', (33, 45))
547935	26735535	However, because SHS contains many carcinogenic compounds existing in the mainstream smoke, it may cause some other smoking-related cancers.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('SHS', 'Var', (17, 20))	('cause', 'Reg', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('carcinogenic', 'Disease', 'MESH:D063646', (35, 47))	('carcinogenic', 'Disease', (35, 47))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
547959	26735535	Overall, SHS in the unadjusted model increased ESCC risk (OR = 1.64; 95% CI, 1.14-2.36); however, the association was attenuated and the 95% CI included unity (OR = 1.23; 95% CI, 0.72-2.11) in the models adjusted for tobacco smoking and chewing and other potential confounding factors.	('tobacco', 'Species', '4097', (217, 224))	('ESCC', 'Disease', (47, 51))	('increased ESCC', 'Phenotype', 'HP:0003565', (37, 51))	('increased', 'PosReg', (37, 46))	('SHS', 'Var', (9, 12))
547973	26735535	The constituents of nass, such as polycyclic aromatic hydrocarbons from ash, may have carcinogenic effects on the esophageal epithelium.	('nass', 'Chemical', '-', (20, 24))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (34, 66))	('carcinogenic', 'Disease', 'MESH:D063646', (86, 98))	('carcinogenic', 'Disease', (86, 98))	('polycyclic aromatic hydrocarbons', 'Var', (34, 66))
547978	26735535	Although low SES is not a biological cause of cancer, it may influence the risk through behavior, lifestyle, environmental exposure, and diet.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('low SES', 'Var', (9, 16))	('cancer', 'Disease', (46, 52))	('influence', 'Reg', (61, 70))	('risk', 'MPA', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('men', 'Species', '9606', (116, 119))
547987	22583970	While loss of Eph B3 is linked to colorectal cancer initiation, overexpression of Eph B3 in cancer cell lines inhibits growth and induces functional changes with decreased mesenchymal and increased epithelial markers.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('inhibits', 'NegReg', (110, 118))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('functional', 'MPA', (138, 148))	('increased', 'PosReg', (188, 197))	('Eph B3', 'Gene', (82, 88))	('mesenchymal and', 'CPA', (172, 187))	('loss', 'Var', (6, 10))	('colorectal cancer initiation', 'Disease', (34, 62))	('colorectal cancer initiation', 'Disease', 'MESH:D015179', (34, 62))	('induces', 'Reg', (130, 137))	('growth', 'CPA', (119, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('cancer', 'Disease', (92, 98))	('epithelial markers', 'CPA', (198, 216))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Eph B3', 'Gene', (14, 20))	('decreased', 'NegReg', (162, 171))	('overexpression', 'PosReg', (64, 78))
547998	22583970	Even patients with early disease (for example, with a T1b-category) have lymph node metastases in up to 20% of the cases.	('lymph node metastases', 'Disease', (73, 94))	('patients', 'Species', '9606', (5, 13))	('lymph node metastases', 'Disease', 'MESH:D009362', (73, 94))	('T1b-category', 'Var', (54, 66))
548003	22583970	Analysis of E-cadherin and Eph B3 indicate that their coexpression suppresses cancer progression by cell-cell contacts and compartmentalization of the tumor cells.	('Eph B3', 'Gene', (27, 33))	('coexpression', 'Var', (54, 66))	('suppresses', 'NegReg', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cell-cell contacts', 'CPA', (100, 118))	('cancer', 'Disease', (78, 84))	('tumor', 'Disease', (151, 156))	('compartmentalization', 'CPA', (123, 143))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('men', 'Species', '9606', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
548053	22583970	The Ki-67 IHC had a significantly higher activity in tumor samples compared to the Barrett`s epithelium (P = 0.001).	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('higher', 'PosReg', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('activity', 'MPA', (41, 49))	('Ki-67', 'Var', (4, 9))
548060	22583970	According to the literature, lymph node metastases can be found in approximately 25% of patients with a T1-category.	('lymph node metastases', 'Disease', (29, 50))	('patients', 'Species', '9606', (88, 96))	('lymph node metastases', 'Disease', 'MESH:D009362', (29, 50))	('T1-category', 'Var', (104, 115))
548076	22583970	Pathologically, loss of the Eph B3 allele induces the development of colon adenomas as the first morphological step towards colon cancer, whereas Eph B-mediated compartmentalization could be demonstrated to be a mechanism suppressing colorectal cancer progression.	('colon cancer', 'Disease', (124, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (234, 251))	('Eph B3', 'Gene', (28, 34))	('men', 'Species', '9606', (61, 64))	('colorectal cancer', 'Disease', (234, 251))	('colon adenomas', 'Disease', (69, 83))	('induces', 'Reg', (42, 49))	('loss', 'Var', (16, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colon cancer', 'Disease', 'MESH:D015179', (124, 136))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('colon cancer', 'Phenotype', 'HP:0003003', (124, 136))	('men', 'Species', '9606', (168, 171))	('colon adenomas', 'Disease', 'MESH:D000236', (69, 83))
548101	21435900	PCA identified six patterns: meat/nitrite, fruit/vegetable, smoking/alcohol, legume/meat alternate, GERD/BMI, and fish/vitamin C. Risk of each cancer under study increased with rising meat/nitrite score.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('vitamin C', 'Chemical', 'MESH:D001205', (119, 128))	('nitrite', 'Chemical', 'MESH:D009573', (34, 41))	('alcohol', 'Chemical', 'MESH:D000438', (68, 75))	('nitrite', 'Chemical', 'MESH:D009573', (189, 196))	('GERD', 'Disease', (100, 104))	('GERD', 'Disease', 'MESH:D005764', (100, 104))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('meat/nitrite', 'Var', (184, 196))
548105	21435900	The analyses suggest that meat/nitrite intake is associated with elevated risk of each cancer under study, while fruit/vegetable intake reduces risk of EA, ESCC, and GCA.	('cancer', 'Disease', (87, 93))	('meat/nitrite', 'Var', (26, 38))	('nitrite', 'Chemical', 'MESH:D009573', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('GCA', 'Gene', '25801', (166, 169))	('GCA', 'Gene', (166, 169))	('EA', 'Phenotype', 'HP:0011459', (152, 154))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('ESCC', 'Disease', (156, 160))
548110	21435900	While epidemiologic studies have found that fruits and vegetables are associated with a decreased risk of gastric and esophageal cancers without regard to subsite or histologic type, evidence linking dietary factors to subtypes of these cancers is more limited.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (237, 244))	('fruits', 'Var', (44, 50))	('decreased', 'NegReg', (88, 97))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('gastric and esophageal cancers', 'Disease', 'MESH:D013274', (106, 136))
548149	21435900	The meat/nitrite pattern was significantly associated with increased risk of OGA (ORQ4 vs. Q1 = 2.40, 95% CI: 1.25, 4.62; PTrend = 0.01, Table 3).	('OGA', 'Disease', (77, 80))	('meat/nitrite', 'Var', (4, 16))	('nitrite', 'Chemical', 'MESH:D009573', (9, 16))
548157	21435900	This principal component loaded high for red meats, high-nitrite meats, and nitrite, but also for high-fat dairy products, poultry, refined grains, dietary fiber, vitamin C, and starchy vegetables, so that inferences cannot be made regarding meats or any specific food product.	('high-nitrite', 'Var', (52, 64))	('nitrite', 'Chemical', 'MESH:D009573', (76, 83))	('vitamin C', 'Chemical', 'MESH:D001205', (163, 172))	('nitrite', 'MPA', (76, 83))	('nitrite', 'Chemical', 'MESH:D009573', (57, 64))
548183	33976727	The initial locoregional failure rate was 17.9 % in ENI arm and 20.7% in IFI arm respectively (p=0.085).	('ENI', 'Var', (52, 55))	('IFI', 'Chemical', '-', (73, 76))	('locoregional failure', 'CPA', (12, 32))	('ENI', 'Chemical', '-', (52, 55))
548186	33976727	Acute radiation pneumonitis (p=0.005) and hematological toxicities (p =0.029) also showed statistical differences between groups, ENI arm was more than IFI arm.	('ENI', 'Chemical', '-', (130, 133))	('hematological toxicities', 'Disease', (42, 66))	('hematological toxicities', 'Disease', 'MESH:D006402', (42, 66))	('IFI', 'Chemical', '-', (152, 155))	('ENI arm', 'Var', (130, 137))	('Acute radiation pneumonitis', 'Disease', (0, 27))	('Acute radiation pneumonitis', 'Disease', 'MESH:D017564', (0, 27))
548187	33976727	Conclusions: The results indicated that IFI tended to improve survival and reduce toxicities for patients with operative ESCC and did not increase locoregional failure compared to ENI.	('survival', 'MPA', (62, 70))	('IFI', 'Chemical', '-', (40, 43))	('reduce', 'NegReg', (75, 81))	('increase locoregional failure', 'Disease', 'MESH:D006333', (138, 167))	('toxicities', 'Disease', 'MESH:D064420', (82, 92))	('ENI', 'Chemical', '-', (180, 183))	('increase locoregional failure', 'Disease', (138, 167))	('IFI', 'Var', (40, 43))	('toxicities', 'Disease', (82, 92))	('ESCC', 'Disease', (121, 125))	('improve', 'PosReg', (54, 61))	('patients', 'Species', '9606', (97, 105))
548203	33976727	No significant differences in local control or OS were noted between ENI and IFI, and the incidences of >=grade 3 acute esophagitis and pneumonitis were significantly lower in the IFI group.	('esophagitis', 'Phenotype', 'HP:0100633', (120, 131))	('lower', 'NegReg', (167, 172))	('esophagitis', 'Disease', (120, 131))	('IFI', 'Chemical', '-', (77, 80))	('ENI', 'Chemical', '-', (69, 72))	('IFI', 'Var', (180, 183))	('pneumonitis', 'Disease', (136, 147))	('esophagitis', 'Disease', 'MESH:D004938', (120, 131))	('pneumonitis', 'Disease', 'MESH:D011014', (136, 147))	('IFI', 'Chemical', '-', (180, 183))
548254	33976727	Furthermore, the PFS was significantly superior in the IFI group than that of the ENI group.	('IFI', 'Var', (55, 58))	('PFS', 'CPA', (17, 20))	('superior', 'PosReg', (39, 47))	('IFI', 'Chemical', '-', (55, 58))	('ENI', 'Chemical', '-', (82, 85))
548259	33976727	The incidences of acute radiation pneumonitis (p=0.005) and hematological toxicities (p=0.029) were significantly higher in the ENI group than in those receiving IFI.	('hematological toxicities', 'Disease', 'MESH:D006402', (60, 84))	('acute radiation pneumonitis', 'Disease', (18, 45))	('ENI', 'Chemical', '-', (128, 131))	('acute radiation pneumonitis', 'Disease', 'MESH:D017564', (18, 45))	('hematological toxicities', 'Disease', (60, 84))	('ENI', 'Var', (128, 131))	('IFI', 'Chemical', '-', (162, 165))	('higher', 'PosReg', (114, 120))
548264	33976727	There were statistical differences between the groups in terms of PTV (p=0.014), GTV (p=0.038), maximum dose of spinal cord (p=0.024), and MLD (p=0.049), V5 (p =0.005), V10 (p=0.042), V20 (p=0.018), V30 (p =0.035) of the lungs, the ENI group demonstrated higher values than the IFI group.	('GTV', 'Chemical', '-', (81, 84))	('MLD', 'Disease', 'MESH:D007966', (139, 142))	('PTV', 'Chemical', '-', (66, 69))	('MLD', 'Disease', (139, 142))	('ENI', 'Chemical', '-', (232, 235))	('higher', 'PosReg', (255, 261))	('ENI', 'Var', (232, 235))	('IFI', 'Chemical', '-', (278, 281))
548301	33976727	Conversely, in the ENI group, the incidence of grade 3-5 acute and late radiation related adverse events were higher, with 3 related deaths.	('ENI', 'Var', (19, 22))	('deaths', 'Disease', 'MESH:D003643', (133, 139))	('deaths', 'Disease', (133, 139))	('ENI', 'Chemical', '-', (19, 22))
548309	33976727	In the current study, there were statistical differences between the fields in terms of may parameters including PTV, GTV, MLD, V5, V10, V20, and V30 of the lungs, and the maximum dose to the spinal cord.	('MLD', 'Disease', 'MESH:D007966', (123, 126))	('MLD', 'Disease', (123, 126))	('V30', 'Var', (146, 149))	('V20', 'Var', (137, 140))	('PTV', 'Chemical', '-', (113, 116))	('GTV', 'Chemical', '-', (118, 121))
548310	33976727	All of these were higher in the ENI group.	('ENI', 'Var', (32, 35))	('higher', 'PosReg', (18, 24))	('ENI', 'Chemical', '-', (32, 35))
548311	33976727	In the current study, adjuvant chemotherapy was administered to 85.7% and 75.8% in ENI and IFI groups, respectively; the number of chemotherapy cycles were higher in ENI group than that of IFI group (3.1 vs. 2.4); this also could explain the higher incidence of toxicities in the former.	('higher', 'PosReg', (156, 162))	('IFI', 'Chemical', '-', (91, 94))	('ENI', 'Chemical', '-', (83, 86))	('toxicities', 'Disease', 'MESH:D064420', (262, 272))	('ENI', 'Chemical', '-', (166, 169))	('IFI', 'Chemical', '-', (189, 192))	('ENI', 'Var', (166, 169))	('toxicities', 'Disease', (262, 272))
548405	33847651	The laboratory tests for iron deficiency anemia and vitamin B12 deficiency have been conducted routinely since 2015 and selectively performed in high-risk patients before 2015.	('iron deficiency anemia', 'Disease', 'MESH:D018798', (25, 47))	('vitamin B12 deficiency', 'Phenotype', 'HP:0100502', (52, 74))	('deficiency', 'Var', (64, 74))	('anemia', 'Phenotype', 'HP:0001903', (41, 47))	('vitamin B12', 'Chemical', 'MESH:D014805', (52, 63))	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (25, 47))	('patients', 'Species', '9606', (155, 163))	('vitamin B12', 'Gene', (52, 63))	('iron deficiency anemia', 'Disease', (25, 47))
548415	31110179	Our findings suggest that clinical management of microenvironmental stressor-mediated microscopic injury may be important in delaying tumor initiation from foregut basal progenitor cells expressing pre-existing tumorigenic mutation(s) and genetic alteration(s).	('tumor initiation', 'Disease', (134, 150))	('genetic alteration', 'Var', (239, 257))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('delaying', 'NegReg', (125, 133))	('tumor initiation', 'Disease', 'MESH:D009369', (134, 150))	('tumor', 'Disease', (134, 139))
548419	31110179	As genetically engineered animal models have been widely developed and used to model biological processes such as cancer, the role of stem/progenitor cells with oncogenic mutation(s) and/or alteration(s) have been well described.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutation', 'Var', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('alteration', 'Var', (190, 200))	('cancer', 'Disease', (114, 120))
548422	31110179	It is also important to note that although stem cell division rate appears to play a crucial role in the development of driver mutations for tumors, cellular extrinsic stressors can often prove to be the tipping point for whether or not genetically prone cells become tumorigenic.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (268, 273))	('tumors', 'Disease', (141, 147))	('tumor', 'Disease', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
548431	31110179	Therefore, using genetically engineered mouse models, we investigated if microenvironmental gastric acid stress can act as a co-promoting factor, which may significantly accelerate early tumor formation from foregut squamous epithelia, particularly from mutant long-lived basal progenitor cells expressing a pre-existing oncogenic load.	('accelerate', 'PosReg', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('squamous epithelia', 'Disease', (216, 234))	('squamous epithelia', 'Phenotype', 'HP:0002860', (216, 234))	('tumor', 'Disease', (187, 192))	('squamous epithelia', 'Disease', 'MESH:D002294', (216, 234))	('mouse', 'Species', '10090', (40, 45))	('mutant', 'Var', (254, 260))
548435	31110179	This study further reveals that gastric acid stress-induced acceleration of tumor formation from mutant foregut basal progenitors is dependent on epithelial-specific prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as cyclooxygenase-2, Cox-2) expression.	('prostaglandin-endoperoxide synthase 2', 'Gene', (166, 203))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutant', 'Var', (97, 103))	('prostaglandin-endoperoxide synthase 2', 'Gene', '19225', (166, 203))	('cyclooxygenase-2', 'Gene', '19225', (226, 242))	('acceleration', 'PosReg', (60, 72))	('Ptgs2', 'Gene', '19225', (205, 210))	('cyclooxygenase-2', 'Gene', (226, 242))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('Ptgs2', 'Gene', (205, 210))
548438	31110179	Unlike p53, mutations are not frequently found in Kras or Pten; however, enhanced RTK/Ras/PI3K/Akt signaling and p53 mutations are characteristic of altered signaling pathways found in human ESCC and are hypothesized to be sufficient to induce murine foregut tumor formation from basal progenitors.	('mutations', 'Var', (117, 126))	('tumor', 'Disease', (259, 264))	('human', 'Species', '9606', (185, 190))	('Akt', 'Gene', '207', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('induce', 'PosReg', (237, 243))	('Akt', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('enhanced', 'PosReg', (73, 81))	('p53', 'Gene', (113, 116))	('murine', 'Species', '10090', (244, 250))
548454	31110179	Since murine foregut tumor formation induced by oncogenic Ras/p53 expression is more frequently found in the region adjacent to the SCJ within the forestomach tissues (Fig.	('tumor', 'Disease', (21, 26))	('Ras/p53', 'Gene', (58, 65))	('oncogenic', 'Var', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('murine', 'Species', '10090', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
548462	31110179	In addition, since conditional expression of oncogenic Kras mutation using the LSL-KrasG12D genetic allele can cause significant health concerns in Krt5-CreER mice due to tumor susceptibility throughout the body (i.e., significant hyperplasia from oral and palm tissues), using the Krt15-CrePR genetic allele may minimize this experimental limitation.	('mutation', 'Var', (60, 68))	('Krt15', 'Gene', (282, 287))	('Krt5', 'Gene', '110308', (148, 152))	('PR', 'Gene', '18667', (291, 293))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('hyperplasia', 'Disease', (231, 242))	('Krt15', 'Gene', '16665', (282, 287))	('Krt5', 'Gene', (148, 152))	('Kras', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('cause', 'Reg', (111, 116))	('hyperplasia', 'Disease', 'MESH:D006965', (231, 242))
548465	31110179	Similar to progenitors labeled by Krt5-CreER, mice expressing these mutant alleles (LSL-KrasG12D with/without p53flox/flox), showed high susceptibility to foregut tumor formation from Krt15+ progenitors at regions adjacent to the SCJ (Fig.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('susceptibility', 'Reg', (137, 151))	('Krt15', 'Gene', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Krt5', 'Gene', (34, 38))	('Krt5', 'Gene', '110308', (34, 38))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Disease', (163, 168))	('Krt15', 'Gene', '16665', (184, 189))	('mutant', 'Var', (68, 74))
548470	31110179	One possible explanation for higher tumorigenic preference at the adjacent region is simply due to an increase in the number of tumor-prone cells expressing both oncogenic Ras/p53 and Ras/Pten.	('higher', 'PosReg', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Ras/Pten', 'Var', (184, 192))	('increase', 'PosReg', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', (36, 41))
548488	31110179	To test this hypothesis, we administered low-pH acidified (<=pH 3) drinking water and compared regional tumor incidence to control animals supplied with normal drinking water.	('drinking water', 'Chemical', 'MESH:D060766', (67, 81))	('low-pH', 'Var', (41, 47))	('drinking water', 'Chemical', 'MESH:D060766', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
548495	31110179	In our mouse model, one notable well-observed histological phenotype was an increased inflammation burden during tumor formation at the SCJ-adjacent region, and expression of inflammatory markers following PPI treatment was decreased (Supplementary Fig.	('tumor', 'Disease', (113, 118))	('inflammation', 'Disease', (86, 98))	('increased', 'PosReg', (76, 85))	('decreased', 'NegReg', (224, 233))	('expression of inflammatory markers', 'MPA', (161, 195))	('mouse', 'Species', '10090', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('PPI', 'Var', (206, 209))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('inflammation', 'Disease', 'MESH:D007249', (86, 98))
548499	31110179	Since it has also been reported that low-pH can significantly induce the activation of pathways related to NF-kappaB and Cox-2 in the esophageal tissues, we determined if Cox-2 could be an underlying mediator of inflammation and foregut tumor development.	('activation', 'PosReg', (73, 83))	('tumor', 'Disease', (237, 242))	('NF-kappaB', 'Protein', (107, 116))	('low-pH', 'Var', (37, 43))	('pathways', 'Pathway', (87, 95))	('inflammation', 'Disease', 'MESH:D007249', (212, 224))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('inflammation', 'Disease', (212, 224))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
548505	31110179	While oncogenic Ras/p53 expression significantly induced tumor formation from Krt15+ cells within the SCJ-adjacent region, loss of Ptgs2 function in Krt15+ cells significantly suppressed tumor development from tumor-competent Krt15+ basal progenitors (Fig.	('Krt15', 'Gene', '16665', (78, 83))	('Krt15', 'Gene', (78, 83))	('tumor', 'Disease', (187, 192))	('Krt15', 'Gene', '16665', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('Krt15', 'Gene', '16665', (226, 231))	('Krt15', 'Gene', (149, 154))	('tumor', 'Disease', (210, 215))	('Ptgs2', 'Gene', '19225', (131, 136))	('Krt15', 'Gene', (226, 231))	('loss', 'Var', (123, 127))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('suppressed', 'NegReg', (176, 186))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Ptgs2', 'Gene', (131, 136))
548506	31110179	Consistent with known functions of Cox-2 enzymatic activity, Cox-2-knockout tissue demonstrated a decreased inflammation burden (Supplementary Fig.	('decreased inflammation burden', 'Disease', 'MESH:D007249', (98, 127))	('Cox-2-knockout', 'Var', (61, 75))	('decreased inflammation burden', 'Disease', (98, 127))	('Cox-2-knockout', 'Gene', (61, 75))
548508	31110179	5e-j), epithelial-specific Cox-2 deletion increased cellular differentiation, as indicated by significantly higher expression of Lor, a marker for terminally differentiated cells (Fig.	('increased', 'PosReg', (42, 51))	('deletion', 'Var', (33, 41))	('Lor', 'Gene', '16939', (129, 132))	('cellular differentiation', 'CPA', (52, 76))	('expression', 'MPA', (115, 125))	('epithelial-specific', 'Gene', (7, 26))	('Lor', 'Gene', (129, 132))	('higher', 'PosReg', (108, 114))
548511	31110179	These results further show that inhibition of cellular extrinsic stress factors to the foregut epithelia, in this case through PPI use, can suppress the process of tumor formation from tumor-competent Krt15+ progenitors and may increase the latency of tumor initiation (Fig.	('tumor', 'Disease', (164, 169))	('PPI', 'Var', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor initiation', 'Disease', (252, 268))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('latency', 'CPA', (241, 248))	('tumor', 'Disease', (185, 190))	('process', 'CPA', (153, 160))	('increase', 'PosReg', (228, 236))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('inhibition', 'Var', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('Krt15', 'Gene', '16665', (201, 206))	('Krt15', 'Gene', (201, 206))	('tumor initiation', 'Disease', 'MESH:D009369', (252, 268))	('tumor', 'Disease', (252, 257))	('suppress', 'NegReg', (140, 148))
548512	31110179	Together with maintenance of physiological stressors, inhibition of cellular intrinsic Cox-2 pathways may significantly delay tumor initiation from tumor-competent long-lived basal progenitors (Fig.	('delay', 'NegReg', (120, 125))	('inhibition', 'Var', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor initiation', 'Disease', (126, 142))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor initiation', 'Disease', 'MESH:D009369', (126, 142))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (126, 131))
548515	31110179	Both smoking and alcohol lead to DNA mutations, and the combination of both risk factors is known to further increase the incidence rate of ESCC.	('increase', 'PosReg', (109, 117))	('ESCC', 'Disease', (140, 144))	('alcohol', 'Chemical', 'MESH:D000438', (17, 24))	('lead to', 'Reg', (25, 32))	('mutations', 'Var', (37, 46))	('DNA', 'Gene', (33, 36))
548516	31110179	These stress factors may facilitate esophageal tumor initiation from cancer cells of origin expressing pre-existing genetic mutations and/or alterations known to be sufficient for ESCC development.	('facilitate', 'PosReg', (25, 35))	('esophageal tumor', 'Disease', (36, 52))	('esophageal tumor', 'Phenotype', 'HP:0100751', (36, 52))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('genetic mutations', 'Var', (116, 133))	('tumor initiation', 'Disease', 'MESH:D009369', (47, 63))	('esophageal tumor', 'Disease', 'MESH:D004938', (36, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor initiation', 'Disease', (47, 63))	('cancer', 'Disease', (69, 75))
548517	31110179	The current studies aimed to understand the early steps of tumor initiation from basal progenitors containing a pre-existing mutational load, oncogenic Ras/p53 or Ras/Pten, and how the low-pH microenvironment may influence tumor initiation.	('tumor initiation', 'Disease', 'MESH:D009369', (223, 239))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor initiation', 'Disease', (59, 75))	('mutational load', 'Var', (125, 140))	('tumor initiation', 'Disease', (223, 239))	('influence', 'Reg', (213, 222))	('Ras/Pten', 'Var', (163, 171))	('tumor initiation', 'Disease', 'MESH:D009369', (59, 75))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
548525	31110179	For instance, PPI treatment is known to beneficially control esophagitis and provide a significant reduction of Cox-1 and Cox-2 expression.	('control', 'PosReg', (53, 60))	('esophagitis', 'Disease', (61, 72))	('reduction', 'NegReg', (99, 108))	('Cox-1', 'Gene', '17708', (112, 117))	('Cox-1', 'Gene', (112, 117))	('expression', 'MPA', (128, 138))	('esophagitis', 'Phenotype', 'HP:0100633', (61, 72))	('PPI treatment', 'Var', (14, 27))	('Cox-2', 'Gene', (122, 127))	('esophagitis', 'Disease', 'MESH:D004941', (61, 72))
548526	31110179	Our experimental results using genetically engineered mice further demonstrate the potential benefit of PPI treatment in tumor initiation from tumor-competent Krt15+ foregut basal progenitors.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (143, 148))	('Krt15', 'Gene', (159, 164))	('tumor initiation', 'Disease', 'MESH:D009369', (121, 137))	('tumor', 'Disease', (121, 126))	('tumor initiation', 'Disease', (121, 137))	('Krt15', 'Gene', '16665', (159, 164))	('PPI', 'Var', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mice', 'Species', '10090', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
548532	31110179	Mice were acquired from Jackson Labs (Krt5-CreER, Krt15-CrePR, LSL-tdTomato, Ptenflox/flox and Ptgs2flox/flox) or the National Cancer Institute Mouse Models of Human Cancers Consortium repository (p53flox/flox and LSL-KrasG12D).	('Ptgs2', 'Gene', '19225', (95, 100))	('Krt5', 'Gene', '110308', (38, 42))	('Cancer', 'Disease', 'MESH:D009369', (127, 133))	('Mice', 'Species', '10090', (0, 4))	('Cancers', 'Phenotype', 'HP:0002664', (166, 173))	('Human Cancers', 'Disease', 'MESH:D009369', (160, 173))	('Cancer', 'Disease', 'MESH:D009369', (166, 172))	('Krt5', 'Gene', (38, 42))	('PR', 'Gene', '18667', (59, 61))	('Ptgs2', 'Gene', (95, 100))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('p53flox/flox', 'Var', (197, 209))	('Human Cancers', 'Disease', (160, 173))	('Krt15', 'Gene', '16665', (50, 55))	('Cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Cancer', 'Disease', (127, 133))	('Krt15', 'Gene', (50, 55))	('Cancer', 'Disease', (166, 172))	('Mouse', 'Species', '10090', (144, 149))
548541	31110179	Antibodies against Ki-67 (#14-5698, 1:300) were obtained from eBioscience, ph-H3 (#3377, 1:400) from Cell Signaling, Cox-2 (#160106, 1:200) from Cayman Chemical, Krt7 (#ab181598, 1:600) from Abcam, and Krt5 (#PRB-160P and # SIG-3475, 1:600), Krt6 (#PRB-169P, 1:600), Krt15 (#PCK-153P, 1:400), CD324 (#147306, 1:300), CD45 (#103101, 1:400), Gr-1 (#108417, 1:400), Ly-6G (#127625, 1:400), F4/80 (#123101, 1:600), and CD3 (#100201, 1:400) from BioLegend.	('#147306', 'Var', (300, 307))	('#127625', 'Var', (370, 377))	('#123101', 'Var', (394, 401))	('Ly-6G', 'Gene', '546644', (363, 368))	('CD45', 'Gene', '19264', (317, 321))	('Krt15', 'Gene', '16665', (267, 272))	('CD3', 'Gene', (415, 418))	('Krt15', 'Gene', (267, 272))	('Krt7', 'Gene', '110310', (162, 166))	('Krt5', 'Gene', '110308', (202, 206))	('PR', 'Gene', '18667', (209, 211))	('Ly-6G', 'Gene', (363, 368))	('#108417', 'Var', (346, 353))	('CD45', 'Gene', (317, 321))	('Krt7', 'Gene', (162, 166))	('Krt5', 'Gene', (202, 206))	('PR', 'Gene', '18667', (249, 251))	('CD3', 'Gene', (293, 296))	('CD3', 'Gene', '12501', (415, 418))	('Krt6', 'Gene', (242, 246))	('#100201', 'Var', (420, 427))	('F4/80', 'Gene', '13733', (387, 392))	('Krt6', 'Gene', '110309', (242, 246))	('#103101', 'Var', (323, 330))	('F4/80', 'Gene', (387, 392))	('CD3', 'Gene', '12501', (293, 296))
548546	31110179	Antibodies against Krt5 (#PRB-160P, 1:2000), Krt6 (#PRB-169P, 1:2000), and Lor (#905104, 1:1000) were obtained from BioLegend, and alpha-tubulin (#NB600-506, 1:5000) from Novus.	('Lor', 'Gene', '16939', (75, 78))	('Krt6', 'Gene', (45, 49))	('Krt5', 'Gene', '110308', (19, 23))	('PR', 'Gene', '18667', (26, 28))	('Lor', 'Gene', (75, 78))	('Krt6', 'Gene', '110309', (45, 49))	('PR', 'Gene', '18667', (52, 54))	('#905104', 'Var', (80, 87))	('#NB600-506', 'Var', (146, 156))	('Krt5', 'Gene', (19, 23))
548610	30949298	Both of them show limited coverage, being higher in DCE-MR compared to PWI.	('higher', 'PosReg', (42, 48))	('mi', 'Chemical', 'MESH:C011506', (20, 22))	('DCE', 'Chemical', 'MESH:C024565', (52, 55))	('DCE-MR', 'Var', (52, 58))
548698	30949298	As well as thymic NETs, low ADC values suggest aggressiveness and poor differentiation, and DCE-MRI with a TTP > 2 min indicates a high-grade tumor (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('ADC values', 'MPA', (28, 38))	('mi', 'Chemical', 'MESH:C011506', (14, 16))	('tumor', 'Disease', (142, 147))	('DCE', 'Chemical', 'MESH:C024565', (92, 95))	('aggressiveness', 'Phenotype', 'HP:0000718', (47, 61))	('mi', 'Chemical', 'MESH:C011506', (115, 117))	('NETs', 'Phenotype', 'HP:0100634', (18, 22))	('low', 'Var', (24, 27))	('aggressiveness', 'Disease', 'MESH:D001523', (47, 61))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('aggressiveness', 'Disease', (47, 61))
548712	30949298	RECIL criteria are aligned with response evaluation criteria in solid tumors, in as much as it suggests a uni-dimensional measurement method, but introduce tumor metabolic evaluation with 18FDG-PET/CT.	('solid tumors', 'Disease', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (70, 75))	('18FDG-PET/CT', 'Var', (188, 200))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('18FDG', 'Chemical', 'MESH:D019788', (188, 193))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('men', 'Species', '9606', (129, 132))	('tumor', 'Disease', (156, 161))	('men', 'Species', '9606', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
548717	30949298	The study by Mosavi et al showed a difference in ADC values between indolent NHL, aggressive NHL and HL using whole-body DWI, with ADC values being lower in indolent NHL (597 +- 115 mm2/s) rather than aggressive NHL (822 +- 266 mm2/s) and HL (1020 +- 547 mm2/s) (Figure 5).	('NHL', 'Phenotype', 'HP:0012539', (93, 96))	('HL', 'Phenotype', 'HP:0012189', (167, 169))	('mm2', 'Gene', '10687', (255, 258))	('mm2', 'Gene', '10687', (182, 185))	('indolent', 'Var', (157, 165))	('HL', 'Phenotype', 'HP:0012189', (213, 215))	('mm2', 'Gene', (255, 258))	('HL', 'Phenotype', 'HP:0012189', (94, 96))	('mm2', 'Gene', '10687', (228, 231))	('HL', 'Phenotype', 'HP:0012189', (78, 80))	('NHL', 'Phenotype', 'HP:0012539', (166, 169))	('ADC', 'MPA', (131, 134))	('mm2', 'Gene', (182, 185))	('NHL', 'Phenotype', 'HP:0012539', (77, 80))	('lower', 'NegReg', (148, 153))	('HL', 'Phenotype', 'HP:0012189', (101, 103))	('mm2', 'Gene', (228, 231))	('NHL', 'Phenotype', 'HP:0012539', (212, 215))	('ADC', 'MPA', (49, 52))
548756	30949298	In addition, DWI has a potential impact on lung cancer differentiation.	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('DWI', 'Var', (13, 16))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('impact', 'Reg', (33, 39))
548813	30542481	Additionally, the recurrence time of esophageal stenosis was significantly shorter in the >16-mm subgroup compared with that of the <16-mm subgroup (P<0.001).	('esophageal stenosis', 'Disease', (37, 56))	('esophageal stenosis', 'Disease', 'MESH:D004940', (37, 56))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (37, 56))	('shorter', 'NegReg', (75, 82))	('>16-mm', 'Var', (90, 96))
548816	30542481	Recently, more and more studies have indicated that surgeries can also lead to benign esophageal stenosis, including endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD).	('lead to', 'Reg', (71, 78))	('endoscopic submucosal dissection', 'Disease', (156, 188))	('endoscopic mucosal resection', 'Disease', (117, 145))	('benign esophageal stenosis', 'Disease', (79, 105))	('surgeries', 'Var', (52, 61))	('benign esophageal stenosis', 'Disease', 'MESH:D004940', (79, 105))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (86, 105))
548862	29915165	S1P produced a concentration-dependent increase in [Ca2+]i in the cells.	('Ca2', 'Gene', '760', (52, 55))	('rat', 'Species', '10116', (22, 25))	('Ca2', 'Gene', (52, 55))	('increase', 'PosReg', (39, 47))	('S1P', 'Var', (0, 3))	('S1P', 'Chemical', 'MESH:C060506', (0, 3))
548866	29915165	Treatment with pertussis toxin (PTX), an inhibitor of Gi-protein, suppressed the increase in [Ca2+]i evoked by S1P.	('Ca2', 'Gene', (94, 97))	('S1P', 'Chemical', 'MESH:C060506', (111, 114))	('S1P', 'Var', (111, 114))	('suppressed', 'NegReg', (66, 76))	('increase', 'PosReg', (81, 89))	('Ca2', 'Gene', '760', (94, 97))
548886	29915165	S1P was reported to decrease the length of smooth muscle cells isolated from the esophagus of the cat.	('S1P', 'Var', (0, 3))	('decrease', 'NegReg', (20, 28))	('length of smooth muscle cells isolated', 'CPA', (33, 71))	('S1P', 'Chemical', 'MESH:C060506', (0, 3))
548899	29915165	The lipophilicity of fura-2 promotes the formation of micelles in aqueous media, which may impede the passage of the probe across cell membranes.	('passage of the probe across cell membranes', 'MPA', (102, 144))	('fura-2', 'Gene', (21, 27))	('impede', 'NegReg', (91, 97))	('formation', 'MPA', (41, 50))	('fura-2', 'Chemical', 'MESH:D016257', (21, 27))	('micelles in aqueous', 'MPA', (54, 73))	('lipophilicity', 'Var', (4, 17))
548910	29915165	It is known that S1P induces contraction in smooth muscle cells.	('S1P', 'Chemical', 'MESH:C060506', (17, 20))	('S1P', 'Var', (17, 20))	('contraction', 'MPA', (29, 40))
548913	29915165	S1P increased [Ca2+]i in a concentration-dependent manner, the maximal response was observed at 10-7 M (Fig.	('Ca2', 'Gene', '760', (15, 18))	('Ca2', 'Gene', (15, 18))	('rat', 'Species', '10116', (34, 37))	('S1P', 'Var', (0, 3))	('increased', 'PosReg', (4, 13))	('S1P', 'Chemical', 'MESH:C060506', (0, 3))
548914	29915165	To evaluate whether the increase in [Ca2+]i induced by S1P occurred because of an influx of Ca2+ from an extracellular source, EGTA, an extracellular Ca2+ chelator, was used.	('increase', 'PosReg', (24, 32))	('S1P', 'Chemical', 'MESH:C060506', (55, 58))	('Ca2', 'Gene', '760', (150, 153))	('Ca2', 'Gene', '760', (92, 95))	('Ca2', 'Gene', '760', (37, 40))	('Ca2', 'Gene', (37, 40))	('EGTA', 'Chemical', 'MESH:D004533', (127, 131))	('Ca2', 'Gene', (150, 153))	('Ca2', 'Gene', (92, 95))	('S1P', 'Var', (55, 58))
548917	29915165	Preincubation for 5 min with nimodipine (100 nM) reduced the immediate [Ca2+]i response induced by S1P (10-7 M) (Fig.	('Ca2', 'Gene', '760', (72, 75))	('reduced', 'NegReg', (49, 56))	('Ca2', 'Gene', (72, 75))	('nimodipine', 'Chemical', 'MESH:D009553', (29, 39))	('S1P', 'Var', (99, 102))	('S1P', 'Chemical', 'MESH:C060506', (99, 102))
548922	29915165	Thapsigargin nearly abolished the increase in the [Ca2+]i response evoked by S1P (10-7 M) (Fig.	('Thapsigargin', 'Chemical', 'MESH:D019284', (0, 12))	('abolished', 'NegReg', (20, 29))	('Ca2', 'Gene', (51, 54))	('S1P', 'Chemical', 'MESH:C060506', (77, 80))	('S1P', 'Var', (77, 80))	('Ca2', 'Gene', '760', (51, 54))
548924	29915165	6, 2-APB significantly inhibited S1P-induced Ca2+ mobilization, indicating that S1P caused the release of Ca2+ from the SR through InsP3 receptors (Fig.	('Ca2', 'Gene', (106, 109))	('InsP3', 'Protein', (131, 136))	('Ca2', 'Gene', (45, 48))	('inhibited', 'NegReg', (23, 32))	('S1P', 'Var', (80, 83))	('S1P', 'Chemical', 'MESH:C060506', (80, 83))	('Ca2', 'Gene', '760', (106, 109))	('APB', 'Gene', (5, 8))	('S1P', 'Chemical', 'MESH:C060506', (33, 36))	('Ca2', 'Gene', '760', (45, 48))	('APB', 'Gene', '6051', (5, 8))
548934	29915165	S1P (10-10-10-5 M) was found to produce a concentration-dependent increase in [Ca2+]i in cat esophageal smooth muscle cells.	('increase', 'PosReg', (66, 74))	('rat', 'Species', '10116', (49, 52))	('Ca2', 'Gene', (79, 82))	('Ca2', 'Gene', '760', (79, 82))	('S1P', 'Var', (0, 3))	('S1P', 'Chemical', 'MESH:C060506', (0, 3))
548937	29915165	S1P has been previously suggested to mobilize [Ca2+]i by stimulating L-type Ca2+ channels in renovascular cells.	('Ca2', 'Gene', '760', (76, 79))	('Ca2', 'Gene', (76, 79))	('Ca2', 'Gene', '760', (47, 50))	('S1P', 'Var', (0, 3))	('Ca2', 'Gene', (47, 50))	('stimulating', 'PosReg', (57, 68))	('S1P', 'Chemical', 'MESH:C060506', (0, 3))
548940	29915165	Thus, it is reasonable to assume that the S1P-induced increase in [Ca2+]i in the esophageal smooth muscle cells is linked to opening of the L-type Ca2+ channels in the sarcolemmal membrane.	('S1P-induced', 'Var', (42, 53))	('Ca2', 'Gene', '760', (67, 70))	('S1P', 'Chemical', 'MESH:C060506', (42, 45))	('Ca2', 'Gene', (67, 70))	('increase', 'PosReg', (54, 62))	('Ca2', 'Gene', '760', (147, 150))	('Ca2', 'Gene', (147, 150))
548963	29967357	(NCT03347903) Gastroesophageal reflux disease (GERD) is suggested to be involved in the induction of a novel hypercontractile condition that is not observed in healthy volunteers and was nicknamed Jackhammer esophagus (JE).	('NCT03347903', 'Var', (1, 12))	('Gastroesophageal reflux disease', 'Disease', (14, 45))	('Gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (14, 45))	('hypercontractile condition', 'Disease', (109, 135))	('Jackhammer esophagus', 'Disease', (197, 217))	('Gastroesophageal reflux', 'Phenotype', 'HP:0002020', (14, 37))	('hypercontractile condition', 'Disease', 'MESH:D009135', (109, 135))
548979	29967357	Patients experienced PPI mediated complete resolution of heartburn and or/regurgitation in 10% (n = 2) and partial resolution in 90% (n = 18).	('heartburn', 'Phenotype', 'HP:0002020', (57, 66))	('or/regurgitation', 'Disease', (71, 87))	('Patients', 'Species', '9606', (0, 8))	('PPI', 'Var', (21, 24))	('heartburn', 'Disease', (57, 66))
548982	29967357	JE-GERDpos patients had significantly higher counts of total reflux episodes (p = 0.027), which was mainly credited to acidic reflux episodes (p = 0.022) and not to non-acidic (p = 0.852) or gas containing (p = 0.583) reflux.	('acidic reflux', 'Phenotype', 'HP:0002020', (119, 132))	('reflux episodes', 'Phenotype', 'HP:0002020', (61, 76))	('higher', 'PosReg', (38, 44))	('reflux episodes', 'Phenotype', 'HP:0002020', (126, 141))	('patients', 'Species', '9606', (11, 19))	('JE-GERDpos', 'Var', (0, 10))	('acidic reflux', 'MPA', (119, 132))
548993	29967357	Early acid perfusion studies have demonstrated that acid was able to provoke spasms, motility changes and the perception of non-cardiac chest pain, a symptom frequently observed in JE.	('spasms', 'Disease', (77, 83))	('spasms', 'Disease', 'MESH:D013035', (77, 83))	('pain', 'Phenotype', 'HP:0012531', (142, 146))	('chest pain', 'Disease', 'MESH:D002637', (136, 146))	('chest pain', 'Disease', (136, 146))	('acid', 'Var', (52, 56))	('motility changes', 'CPA', (85, 101))	('chest pain', 'Phenotype', 'HP:0100749', (136, 146))
549033	28241446	DNA Methylation Status of PAX1 and ZNF582 in Esophageal Squamous Cell Carcinoma Hypermethylation of specific gene promoters is an important mechanism of carcinogenesis.	('carcinogenesis', 'Disease', (153, 167))	('PAX1', 'Gene', '5075', (26, 30))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (45, 79))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('Carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('ZNF582', 'Gene', '147948', (35, 41))	('Esophageal Squamous Cell Carcinoma', 'Disease', (45, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (153, 167))	('Hypermethylation', 'Var', (80, 96))	('ZNF582', 'Gene', (35, 41))	('PAX1', 'Gene', (26, 30))
549042	28241446	The sensitivities and specificities of PAX1 and ZNF582 methylation for the detection of cancer were 100% and 85.7%, and 78.6% and 100%, respectively.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('ZNF582', 'Gene', '147948', (48, 54))	('PAX1', 'Gene', (39, 43))	('methylation', 'Var', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ZNF582', 'Gene', (48, 54))	('PAX1', 'Gene', '5075', (39, 43))
549044	28241446	DNA methylation status of these two genes showed a relatively good sensitivity and specificity for the detection of ESCC tumors.	('ESCC tumors', 'Disease', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('ESCC tumors', 'Disease', 'MESH:D004938', (116, 127))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('methylation status', 'Var', (4, 22))
549052	28241446	The hypermethylation of CpG islands in the promoter region of tumor suppressor genes, a key mechanism in tumorigenesis, could impede gene transcription and result in a decrease or loss of gene function, a key mechanism in tumorigenesis.	('gene transcription', 'MPA', (133, 151))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('loss', 'NegReg', (180, 184))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('impede', 'NegReg', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('decrease', 'NegReg', (168, 176))	('gene function', 'MPA', (188, 201))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('hypermethylation', 'Var', (4, 20))
549053	28241446	Similar to other cancers, epigenetic silencing of tumor suppressor genes by promoter hypermethylation is a common molecular alteration in ESCC.	('promoter hypermethylation', 'Var', (76, 101))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('epigenetic silencing', 'Var', (26, 46))	('ESCC', 'Disease', (138, 142))	('tumor', 'Disease', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
549054	28241446	Methylation of CpG islands in the tumor suppressor genes prevents the binding of transcription factors to the corresponding DNA response elements, resulting in a decrease in gene transcription, and ultimately, a loss of tumor suppressing function, leading to an uncontrolled cell growth and tumor development.	('gene transcription', 'MPA', (174, 192))	('leading to', 'Reg', (248, 258))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (34, 39))	('binding', 'Interaction', (70, 77))	('prevents', 'NegReg', (57, 65))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (220, 225))	('decrease', 'NegReg', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('uncontrolled cell growth', 'CPA', (262, 286))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('loss', 'NegReg', (212, 216))	('tumor', 'Disease', (291, 296))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
549055	28241446	It has been shown that aberrant methylation of some tumor suppressor genes such as PTEN, SFRP1, RASSF1A, DAPK, RUNX3, UCHL1, CDH1, p16INK, FHIT, APC and MGMT occurs frequently in esophageal cancer.	('SFRP1', 'Gene', (89, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('tumor', 'Disease', (52, 57))	('UCHL1', 'Gene', (118, 123))	('p16INK', 'Gene', (131, 137))	('CDH1', 'Gene', '999', (125, 129))	('RUNX3', 'Gene', (111, 116))	('MGMT', 'Gene', '4255', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('PTEN', 'Gene', (83, 87))	('DAPK', 'Gene', (105, 109))	('UCHL1', 'Gene', '7345', (118, 123))	('esophageal cancer', 'Disease', (179, 196))	('occurs', 'Reg', (158, 164))	('CDH1', 'Gene', (125, 129))	('RASSF1A', 'Gene', '11186', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('SFRP1', 'Gene', '6422', (89, 94))	('aberrant', 'Var', (23, 31))	('FHIT', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('DAPK', 'Gene', '1612', (105, 109))	('PTEN', 'Gene', '5728', (83, 87))	('RASSF1A', 'Gene', (96, 103))	('RUNX3', 'Gene', '864', (111, 116))	('MGMT', 'Gene', (153, 157))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('methylation', 'MPA', (32, 43))	('APC', 'Disease', (145, 148))	('FHIT', 'Gene', '2272', (139, 143))
549056	28241446	It is therefore the case that alterations in DNA methylation of specific genes may be a useful biomarker for early esophageal cancer detection.	('esophageal cancer', 'Disease', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('alterations', 'Var', (30, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))
549059	28241446	have reported that DNA methylation of PAX1 gene is a prognostic indicator for oral squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('PAX1', 'Gene', '5075', (38, 42))	('PAX1', 'Gene', (38, 42))	('oral squamous cell carcinoma', 'Disease', (78, 106))	('DNA methylation', 'Var', (19, 34))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 106))
549061	28241446	Based on these facts, we hypothesized that alterations in DNA methylation of PAX1 and ZNF582 genes were associated with ESCC development and progression, which may serve as a potential biomarker for early ESCC detection.	('ZNF582', 'Gene', (86, 92))	('SCC', 'Phenotype', 'HP:0002860', (206, 209))	('PAX1', 'Gene', '5075', (77, 81))	('ESCC', 'Disease', (120, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('associated with', 'Reg', (104, 119))	('DNA methylation', 'MPA', (58, 73))	('progression', 'CPA', (141, 152))	('ZNF582', 'Gene', '147948', (86, 92))	('alterations', 'Var', (43, 54))	('PAX1', 'Gene', (77, 81))
549079	28241446	For each sample, the PCR allows to detect simultaneously the methylated strands of ZNF582 or PAX1 using a FAM-labeled probe, while a probe labeled with VIC amplifies a CpG free region of the COL2A gene as internal control, therefore normalizing for the DNA quantity.	('methylated', 'Var', (61, 71))	('detect', 'Reg', (35, 41))	('PAX1', 'Gene', (93, 97))	('COL2A', 'Gene', (191, 196))	('PAX1', 'Gene', '5075', (93, 97))	('ZNF582', 'Gene', '147948', (83, 89))	('ZNF582', 'Gene', (83, 89))
549087	28241446	Along the lines, log (meth-index) >= -2.376 for PAX1 or log (meth-index) >= -0.597 for ZNF582 were considered to be methylation positivity.	('log', 'Var', (17, 20))	('ZNF582', 'Gene', (87, 93))	('PAX1', 'Gene', (48, 52))	('PAX1', 'Gene', '5075', (48, 52))	('>= -2.376', 'Var', (34, 43))	('ZNF582', 'Gene', '147948', (87, 93))
549088	28241446	The frequency of PAX1 methylation was 100% (14/14) in the tumor tissues, which is significantly higher than that (21.4%, 3/14) in the paracancerous tissues.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('PAX1', 'Gene', '5075', (17, 21))	('higher', 'PosReg', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('paracancerous tissues', 'Disease', (134, 155))	('paracancerous tissues', 'Disease', 'MESH:D009380', (134, 155))	('PAX1', 'Gene', (17, 21))	('methylation', 'Var', (22, 33))
549091	28241446	The frequency of PAX1 methylation was 80.7% (151/187) in the tumor samples, which is significantly higher than that (25%, 4/16) in the paracancerous samples.	('paracancerous', 'Disease', (135, 148))	('PAX1', 'Gene', '5075', (17, 21))	('higher', 'PosReg', (99, 105))	('paracancerous', 'Disease', 'None', (135, 148))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PAX1', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('methylation', 'Var', (22, 33))
549092	28241446	The frequency of ZNF582 methylation was 88.2% (165/187) in the tumor samples, which is significantly higher than that (18.8%, 3/16) in the paracancerous samples.	('tumor', 'Disease', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('higher', 'PosReg', (101, 107))	('ZNF582', 'Gene', '147948', (17, 23))	('paracancerous', 'Disease', 'None', (139, 152))	('methylation', 'Var', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ZNF582', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('paracancerous', 'Disease', (139, 152))
549096	28241446	The accuracies of PAX1 and ZNF582 methylation testing were 0.893 and 0.954, respectively (Table 2).	('methylation', 'Var', (34, 45))	('PAX1', 'Gene', '5075', (18, 22))	('PAX1', 'Gene', (18, 22))	('ZNF582', 'Gene', '147948', (27, 33))	('ZNF582', 'Gene', (27, 33))
549097	28241446	As shown in Figure 2 and Table 2, the sensitivity and specificity of PAX1 methylation testing achieved 100% and 78.6% at the best meth-index cut-off value of -2.376, respectively.	('PAX1', 'Gene', (69, 73))	('PAX1', 'Gene', '5075', (69, 73))	('methylation', 'Var', (74, 85))
549098	28241446	At the best meth-index cut-off value of -0.597, the sensitivity and specificity of ZNF582 methylation testing were 85.7% and 100%, respectively.	('methylation', 'Var', (90, 101))	('ZNF582', 'Gene', '147948', (83, 89))	('ZNF582', 'Gene', (83, 89))
549099	28241446	Additionally, as shown in Figure 3C, the results of the accuracies of PAX1 and ZNF582 methylation testing using TCGA datasets were 0.760 and 0.806, respectively (Table 2).	('PAX1', 'Gene', (70, 74))	('methylation', 'Var', (86, 97))	('PAX1', 'Gene', '5075', (70, 74))	('ZNF582', 'Gene', '147948', (79, 85))	('ZNF582', 'Gene', (79, 85))
549100	28241446	The sensitivity and specificity of PAX1 methylation testing achieved 80.7% and 75.0%, respectively, and the sensitivity and specificity of ZNF582 methylation testing were 88.2% and 81.2%, respectively.	('ZNF582', 'Gene', (139, 145))	('methylation', 'Var', (40, 51))	('PAX1', 'Gene', (35, 39))	('PAX1', 'Gene', '5075', (35, 39))	('ZNF582', 'Gene', '147948', (139, 145))
549102	28241446	However, there is a tendency that PAX1 methylation level was associated with TNM stage and lymph node metastasis with a p value of 0.068 and 0.073, respectively, while ZNF582 methylation level was associated with carcino-embryonic antigen (CEA) concentration with a p value of 0.076 (Table 4).	('CEA', 'Gene', '1084', (240, 243))	('PAX1', 'Gene', (34, 38))	('methylation', 'Var', (39, 50))	('PAX1', 'Gene', '5075', (34, 38))	('TNM', 'Gene', (77, 80))	('ZNF582', 'Gene', '147948', (168, 174))	('lymph node metastasis', 'CPA', (91, 112))	('TNM', 'Gene', '10178', (77, 80))	('ZNF582', 'Gene', (168, 174))	('carcino-embryonic antigen', 'Gene', '1084', (213, 238))	('associated', 'Reg', (197, 207))	('associated', 'Reg', (61, 71))	('CEA', 'Gene', (240, 243))	('carcino-embryonic antigen', 'Gene', (213, 238))
549103	28241446	However, there is no association between methylation occurrence frequency of PAX1 and ZNF582 and any clinical features as shown in Table 3.	('ZNF582', 'Gene', (86, 92))	('PAX1', 'Gene', '5075', (77, 81))	('methylation', 'Var', (41, 52))	('ZNF582', 'Gene', '147948', (86, 92))	('PAX1', 'Gene', (77, 81))
549105	28241446	Previous studies have shown that the methylation status of PAX1 and ZNF582 genes is a useful testing to distinguish tumor and non-tumor tissues in cervical and oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (160, 188))	('tumor', 'Disease', (116, 121))	('cervical', 'Disease', (147, 155))	('PAX1', 'Gene', (59, 63))	('PAX1', 'Gene', '5075', (59, 63))	('methylation', 'Var', (37, 48))	('ZNF582', 'Gene', '147948', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (160, 188))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ZNF582', 'Gene', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('tumor', 'Disease', (130, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))
549106	28241446	In the present study, we have for the first time demonstrated that the levels and frequencies of PAX1 and ZNF582 methylation are markedly higher in the tumor tissues compared to non-tumor tissues from ESCC patients, and methylation testing of these two genes has an excellent accuracy and great sensitivity and specificity to detect ESCC tumors, suggesting that PAX1 and ZNF582 methylation testing may be a promising biomarker for the detection of ESCC.	('SCC', 'Phenotype', 'HP:0002860', (334, 337))	('tumor', 'Disease', (338, 343))	('ESCC tumors', 'Disease', 'MESH:D004938', (333, 344))	('PAX1', 'Gene', (97, 101))	('PAX1', 'Gene', '5075', (362, 366))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('ZNF582', 'Gene', '147948', (371, 377))	('tumor', 'Disease', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (338, 344))	('ZNF582', 'Gene', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('ESCC tumors', 'Disease', (333, 344))	('PAX1', 'Gene', (362, 366))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('PAX1', 'Gene', '5075', (97, 101))	('higher', 'PosReg', (138, 144))	('SCC', 'Phenotype', 'HP:0002860', (449, 452))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('methylation', 'Var', (113, 124))	('SCC', 'Phenotype', 'HP:0002860', (202, 205))	('ZNF582', 'Gene', '147948', (106, 112))	('patients', 'Species', '9606', (206, 214))	('ZNF582', 'Gene', (371, 377))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
549110	28241446	On the other hand, PAX1 and PAX4 are silenced by DNA methylation in ovarian and cervical cancers and in melanoma, and may function as tumor suppressors.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('ovarian and cervical cancers', 'Disease', 'MESH:D010051', (68, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('silenced', 'NegReg', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('PAX4', 'Gene', (28, 32))	('PAX4', 'Gene', '5078', (28, 32))	('PAX1', 'Gene', (19, 23))	('PAX1', 'Gene', '5075', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('DNA methylation', 'Var', (49, 64))	('tumor', 'Disease', (134, 139))	('methylation', 'Var', (53, 64))
549112	28241446	Previous studies have reported that PAX1 methylation testing is a potential biomarker for the screening of cervical cancer with a sensitivity and specificity greater than 80% in the detection of grade III or higher cervical intraepithelial neoplasia (CIN3+) lesions.	('cervical cancer', 'Disease', (107, 122))	('higher', 'PosReg', (208, 214))	('methylation', 'Var', (41, 52))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (215, 249))	('cervical intraepithelial neoplasia', 'Disease', 'MESH:D018290', (215, 249))	('PAX1', 'Gene', (36, 40))	('cervical intraepithelial neoplasia', 'Disease', (215, 249))	('PAX1', 'Gene', '5075', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (107, 122))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (224, 249))	('neoplasia', 'Phenotype', 'HP:0002664', (240, 249))
549113	28241446	The efficacy of PAX1 methylation testing in detecting cervical cancer is significantly improved with a combination of cervical cell cytology or HPV 16, 18 genotyping.	('cervical cancer', 'Disease', (54, 69))	('cervical cancer', 'Disease', 'MESH:D002583', (54, 69))	('improved', 'PosReg', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation testing', 'Var', (21, 40))	('HPV 16', 'Species', '333760', (144, 150))	('PAX1', 'Gene', (16, 20))	('PAX1', 'Gene', '5075', (16, 20))
549114	28241446	Consistent with the reports in cervical cancers, we observed in the current study that PAX1 methylation testing had a 100% sensitivity and a 78.6% specificity in the detection of ESCC tumors, indicating that PAX1 methylation is a valuable biomarker for ESCC diagnosis.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('methylation', 'Var', (92, 103))	('ESCC tumors', 'Disease', (179, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('PAX1', 'Gene', (87, 91))	('cervical cancers', 'Disease', (31, 47))	('PAX1', 'Gene', '5075', (87, 91))	('SCC', 'Phenotype', 'HP:0002860', (254, 257))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('ESCC tumors', 'Disease', 'MESH:D004938', (179, 190))	('PAX1', 'Gene', (208, 212))	('PAX1', 'Gene', '5075', (208, 212))	('cervical cancers', 'Disease', 'MESH:D002583', (31, 47))	('SCC', 'Phenotype', 'HP:0002860', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
549118	28241446	Consistent with the concept that ZNF582 is a tumor suppressor, ZNF582 hypermethylation has been reported in acute myeloid leukemia and various invasive cancers.	('acute myeloid leukemia', 'Disease', (108, 130))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ZNF582', 'Gene', '147948', (33, 39))	('ZNF582', 'Gene', (33, 39))	('reported', 'Reg', (96, 104))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('hypermethylation', 'Var', (70, 86))	('tumor', 'Disease', (45, 50))	('invasive cancers', 'Disease', 'MESH:D009362', (143, 159))	('invasive cancers', 'Disease', (143, 159))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (108, 130))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (108, 130))	('ZNF582', 'Gene', '147948', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (114, 130))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('ZNF582', 'Gene', (63, 69))
549119	28241446	reported that ZNF582 methylation testing had a 70% sensitivity and an 82% specificity for the detection of cervical cancer CIN3+ lesions, and a great sensitivity and specificity in the classification of low-grade squamous intraepithelial lesion (LSIL).	('cervical cancer', 'Disease', (107, 122))	('ZNF582', 'Gene', (14, 20))	('squamous intraepithelial lesion', 'Disease', 'MESH:D000081483', (213, 244))	('methylation', 'Var', (21, 32))	('CIN3+', 'Var', (123, 128))	('ZNF582', 'Gene', '147948', (14, 20))	('squamous intraepithelial lesion', 'Disease', (213, 244))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (107, 122))
549120	28241446	In the present study, we demonstrated that ZNF582 gene was much more frequently methylated in ESCC tumor tissues compared to non-tumor paracancerous tissues.	('ESCC tumor', 'Disease', 'MESH:D004938', (94, 104))	('more', 'PosReg', (64, 68))	('non-tumor paracancerous', 'Disease', (125, 148))	('paracancerous tissues', 'Disease', (135, 156))	('ZNF582', 'Gene', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('non-tumor paracancerous', 'Disease', 'MESH:D009369', (125, 148))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ESCC tumor', 'Disease', (94, 104))	('methylated', 'Var', (80, 90))	('paracancerous tissues', 'Disease', 'MESH:D009380', (135, 156))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('ZNF582', 'Gene', '147948', (43, 49))
549121	28241446	ZNF582 methylation testing reaches a 100% specificity and an 85.7% sensitivity for the detection of ESCC tumors (see Table 2), suggesting that it is a useful biomarker for screening ESCC.	('ESCC tumors', 'Disease', (100, 111))	('methylation', 'Var', (7, 18))	('SCC', 'Phenotype', 'HP:0002860', (183, 186))	('ZNF582', 'Gene', '147948', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('ESCC tumors', 'Disease', 'MESH:D004938', (100, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('ZNF582', 'Gene', (0, 6))
549122	28241446	Moreover, a combination of PAX1 and ZNF582 methylation testing could reach a 100% sensitivity and specificity in the detection of ESCC tumors.	('PAX1', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('methylation testing', 'Var', (43, 62))	('PAX1', 'Gene', '5075', (27, 31))	('ESCC tumors', 'Disease', 'MESH:D004938', (130, 141))	('ZNF582', 'Gene', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('SCC', 'Phenotype', 'HP:0002860', (131, 134))	('ESCC tumors', 'Disease', (130, 141))	('ZNF582', 'Gene', '147948', (36, 42))
549123	28241446	To further evaluate the clinical significance of PAX1 and ZNF582 methylation in ESCC development and progression, the association of PAX1/ZNF582 methylation to the clinicopathological features of ESCC patients was analyzed, as a previous report indicated a significant association between PAX6 methylation and TNM stage of non-small cell lung cancer (NSCLC).	('PAX1', 'Gene', (49, 53))	('methylation', 'Var', (294, 305))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (323, 349))	('ZNF582', 'Gene', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('ZNF582', 'Gene', (138, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (327, 349))	('SCC', 'Phenotype', 'HP:0002860', (197, 200))	('PAX1', 'Gene', (133, 137))	('patients', 'Species', '9606', (201, 209))	('PAX1', 'Gene', '5075', (49, 53))	('ZNF582', 'Gene', '147948', (58, 64))	('cell lung cancer', 'Disease', 'MESH:D008175', (333, 349))	('NSCLC', 'Disease', 'MESH:D002289', (351, 356))	('ZNF582', 'Gene', '147948', (138, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (338, 349))	('ESCC', 'Disease', (80, 84))	('cell lung cancer', 'Disease', (333, 349))	('NSCLC', 'Disease', (351, 356))	('PAX6', 'Gene', (289, 293))	('TNM', 'Gene', '10178', (310, 313))	('PAX6', 'Gene', '5080', (289, 293))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('PAX1', 'Gene', '5075', (133, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (351, 356))	('TNM', 'Gene', (310, 313))
549125	28241446	However, the associations of PAX1 methylation with TNM stage (p = 0.068) and LN metastasis (p = 0.073) and ZNF582 methylation with CEA concentration (p = 0.076) appear to be interesting.	('LN metastasis', 'CPA', (77, 90))	('TNM', 'Gene', '10178', (51, 54))	('methylation', 'Var', (34, 45))	('CEA', 'Gene', (131, 134))	('CEA', 'Gene', '1084', (131, 134))	('ZNF582', 'Gene', '147948', (107, 113))	('PAX1', 'Gene', (29, 33))	('PAX1', 'Gene', '5075', (29, 33))	('methylation', 'Var', (114, 125))	('associations', 'Interaction', (13, 25))	('TNM', 'Gene', (51, 54))	('ZNF582', 'Gene', (107, 113))
549130	28241446	The methylation of PAX1 and ZNF582 detected in these cells could act as biomarkers for esophageal cancer screening in the future, which could replace traditional endoscopy as an equally effective but less invasive way of diagnosing for esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (236, 253))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('esophageal cancer', 'Disease', (87, 104))	('ZNF582', 'Gene', '147948', (28, 34))	('methylation', 'Var', (4, 15))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('PAX1', 'Gene', (19, 23))	('PAX1', 'Gene', '5075', (19, 23))	('esophageal cancer', 'Disease', (236, 253))	('ZNF582', 'Gene', (28, 34))
549133	28241446	PAX1 and ZNF582 methylation testing has an excellent accuracy, sensitivity and specificity in distinguishing ESCC tumor tissues from non-tumor tissues.	('ESCC tumor', 'Disease', (109, 119))	('ZNF582', 'Gene', (9, 15))	('PAX1', 'Gene', (0, 4))	('PAX1', 'Gene', '5075', (0, 4))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ESCC tumor', 'Disease', 'MESH:D004938', (109, 119))	('tumor', 'Disease', (114, 119))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('ZNF582', 'Gene', '147948', (9, 15))	('methylation', 'Var', (16, 27))
549134	28241446	The combination of PAX1 and ZNF582 methylation testing could reach a 100% sensitivity and specificity in detecting ESCC tumors, providing a promising biomarker for ESCC screening and diagnosis, although further studies with larger sample size or population-based investigation are necessary to confirm this intriguing finding.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('ZNF582', 'Gene', '147948', (28, 34))	('ESCC', 'Disease', (164, 168))	('PAX1', 'Gene', (19, 23))	('methylation', 'Var', (35, 46))	('PAX1', 'Gene', '5075', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('ESCC tumors', 'Disease', (115, 126))	('ZNF582', 'Gene', (28, 34))	('ESCC tumors', 'Disease', 'MESH:D004938', (115, 126))
549142	26935396	Overexpression of lncRNA-LET was observed to inhibit the migration and invasion of ESCC cells, and modulate p53 expression levels in human ESCC cell lines in vitro.	('modulate', 'Reg', (99, 107))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('lncRNA-LET', 'Gene', (18, 28))	('invasion of ESCC cells', 'CPA', (71, 93))	('lncRNA-LET', 'Gene', '101241892', (18, 28))	('migration', 'CPA', (57, 66))	('inhibit', 'NegReg', (45, 52))	('Overexpression', 'Var', (0, 14))	('expression levels', 'MPA', (112, 129))	('human', 'Species', '9606', (133, 138))
549147	26935396	Although previous studies have demonstrated that alterations of numerous oncogenes and tumor-suppressor genes are involved in ESCC, the underlying molecular and genetic mechanism of esophageal carcinogenesis remains largely unknown.	('alterations', 'Var', (49, 60))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (182, 207))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('esophageal carcinogenesis', 'Disease', (182, 207))	('tumor', 'Disease', (87, 92))	('ESCC', 'Disease', (126, 130))	('involved', 'Reg', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
549195	26935396	To investigate the biological role of lncRNA-LET in ESCC progression, Eca109 and TE-1 cells were transfected with PLL3.7-EF-1a-SV40pA-LET.	('TE-1', 'CellLine', 'CVCL:1759', (81, 85))	('lncRNA-LET', 'Gene', '101241892', (38, 48))	('SV40pA', 'Chemical', '-', (127, 133))	('PLL3.7-EF-1a-SV40pA-LET', 'Var', (114, 137))	('EF-1a-SV4', 'CellLine', 'CVCL:S576', (121, 130))	('ESCC', 'Disease', (52, 56))	('lncRNA-LET', 'Gene', (38, 48))
549203	26935396	The apoptotic rate of Eca109 and TE-1 cells transfected with PLL3.7-EF-1a-SV40pA-LET was identified to be significantly increased when compared with those of the wild-type ESCC cells (Fig.	('EF-1a-SV4', 'CellLine', 'CVCL:S576', (68, 77))	('apoptotic rate', 'CPA', (4, 18))	('PLL3.7-EF-1a-SV40pA-LET', 'Var', (61, 84))	('SV40pA', 'Chemical', '-', (74, 80))	('TE-1', 'CellLine', 'CVCL:1759', (33, 37))	('increased', 'PosReg', (120, 129))
549205	26935396	To further investigate whether, and the mechanism by which, LET induces ESCC cell growth arrest and apoptosis, the protein level of p53 was examined following transfection of PLL3.7-EF-1a-SV40pA-LET in wild-type ESCC cells.	('arrest', 'Disease', (89, 95))	('induces', 'Reg', (64, 71))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('LET', 'Var', (60, 63))	('EF-1a-SV4', 'CellLine', 'CVCL:S576', (182, 191))	('growth arrest', 'Phenotype', 'HP:0001510', (82, 95))	('arrest', 'Disease', 'MESH:D006323', (89, 95))	('SV40pA', 'Chemical', '-', (188, 194))	('apoptosis', 'CPA', (100, 109))
549206	26935396	The results of western blot analysis indicated that the expression level of p53 was significantly increased in ESCC cells transfected with PLL3.7-EF-1a-SV40pA-LET when compared with that of wild-type ESCC cells (Fig.	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('expression level', 'MPA', (56, 72))	('PLL3.7-EF-1a-SV40pA-LET', 'Var', (139, 162))	('EF-1a-SV4', 'CellLine', 'CVCL:S576', (146, 155))	('SV40pA', 'Chemical', '-', (152, 158))	('increased', 'PosReg', (98, 107))
549208	26935396	In addition, previous studies have demonstrated that dysregu-lation of lncRNAs may also affect epigenetic information and provide a cellular growth advantage, resulting in a wide range of diseases, particularly in progressive and uncontrolled tumor growth.	('lncRNAs', 'Gene', (71, 78))	('affect', 'Reg', (88, 94))	('progressive', 'CPA', (214, 225))	('diseases', 'Disease', (188, 196))	('resulting in', 'Reg', (159, 171))	('cellular growth advantage', 'CPA', (132, 157))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('dysregu-lation', 'Var', (53, 67))	('epigenetic information', 'MPA', (95, 117))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
549282	25580368	For given values of SUVR50 and gamma50, the probability of tumor recurrence for each patient I is expressed as:  The log-likelihood (LL) can be calculated as: where Ri=1 if the patient is a nonresponder and Ri=0 if he or she is a responder.	('patient', 'Species', '9606', (85, 92))	('tumor', 'Disease', (59, 64))	('gamma50', 'Var', (31, 38))	('SUVR50', 'Var', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('patient', 'Species', '9606', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
549358	25001061	The ESCC cell lines Eca-109, Kyse30, Kyse140, Kyse180, Kyse510 and Kyse520 (Chinese Academy of Sciences, Shanghai, China) were grown in RPMI 1640 (Invitrogen, USA) supplemented with 10% fetal bovine serum.	('Kyse180', 'Var', (46, 53))	('Kyse520', 'Var', (67, 74))	('bovine', 'Species', '9913', (192, 198))	('Kyse510', 'Var', (55, 62))	('Kyse140', 'Var', (37, 44))	('Kyse30', 'Var', (29, 35))
549384	25001061	To investigate the expression of YKL-40 in ESCC, the YKL-40 mRNA and protein levels were detected by real-time RT-PCR and Western Blotting, respectively, in several esophageal carcinoma cell lines (Eca-109, Kyse180, Kyse510, Kyse30, Kyse140 and Kyse520) and the immortalized esophageal epithelial cell line NE-3.	('Kyse180', 'Var', (207, 214))	('esophageal carcinoma', 'Disease', (165, 185))	('YKL-40', 'Gene', (33, 39))	('YKL-40', 'Gene', (53, 59))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (165, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (165, 185))	('YKL-40', 'Gene', '1116', (33, 39))	('YKL-40', 'Gene', '1116', (53, 59))	('NE-3', 'CellLine', 'CVCL:3554', (307, 311))
549405	25001061	The cut-off values that we applied for CEA, CYFRA21-1 and SCCA were 5.0 ng/ml, 3.3 ng/ml and 1.5 ng/ml, respectively, according to the manufacturer's protocols.	('CYFRA21-1', 'Var', (44, 53))	('CEA', 'Gene', '1048', (39, 42))	('CEA', 'Gene', (39, 42))
549443	25001061	In the present study, the addition of YKL-40 to CEA (74.00%), CYFRA21-1(82.00%) or SCCA (82.00%) increased the diagnostic sensitivity compared with CEA (8.00%), CYFRA21-1 (40.00%) or SCCA (32.67%) alone, but the diagnostic specificity did not significantly decrease.	('CEA', 'Gene', '1048', (148, 151))	('CEA', 'Gene', (48, 51))	('CYFRA21-1', 'Var', (62, 71))	('increased', 'PosReg', (97, 106))	('diagnostic sensitivity', 'MPA', (111, 133))	('YKL-40', 'Gene', '1116', (38, 44))	('CEA', 'Gene', (148, 151))	('YKL-40', 'Gene', (38, 44))	('CEA', 'Gene', '1048', (48, 51))
549449	25001061	Although an analysis of additional patients is needed to verify and expand the present results, our data indicate that the addition of YKL-40 to the traditional ESCC tumor marker SCCA may significantly improve the sensitivity of the detection of ESCC.	('YKL-40', 'Gene', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('ESCC', 'Disease', (246, 250))	('ESCC tumor', 'Disease', (161, 171))	('improve', 'PosReg', (202, 209))	('YKL-40', 'Gene', '1116', (135, 141))	('patients', 'Species', '9606', (35, 43))	('addition', 'Var', (123, 131))	('ESCC tumor', 'Disease', 'MESH:D004938', (161, 171))
549454	21258768	Among them, the heat shock protein B2 (HSPB2) was methylated in 95.7% (67/70) of primary ESCCs, whereas no methylation was found in normal esophageal tissues from ESCC patients (0%, 0/20).	('methylated', 'Var', (50, 60))	('primary ESCCs', 'Disease', (81, 94))	('heat shock protein B2', 'Gene', (16, 37))	('patients', 'Species', '9606', (168, 176))	('HSPB2', 'Gene', (39, 44))	('HSPB2', 'Gene', '3316', (39, 44))	('shock', 'Phenotype', 'HP:0031273', (21, 26))	('heat shock protein B2', 'Gene', '3316', (16, 37))
549463	21258768	It is also known as heat shock 27-kDa protein 2 (HSP27), located at chromosome 11q22-q23 which is a frequent target for deletion during the development of many solid tumor types.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('heat shock 27-kDa protein 2', 'Gene', '3316', (20, 47))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('HSP27', 'Gene', (49, 54))	('heat shock 27-kDa protein 2', 'Gene', (20, 47))	('tumor', 'Disease', (166, 171))	('deletion', 'Var', (120, 128))	('shock', 'Phenotype', 'HP:0031273', (25, 30))
549472	21258768	Hypermethylation of gene promoters and the corresponding loss of gene expression are now recognized as a hallmark of human cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (117, 122))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('gene expression', 'MPA', (65, 80))	('cancer', 'Disease', (123, 129))	('loss', 'NegReg', (57, 61))
549476	21258768	In this study, we examined the methylation status of the HSPB2 gene promoter in human ESCC, and report for the first time that HSPB2 is frequently methylated in primary ESCC but not in normal esophageal tissues.	('HSPB2', 'Gene', (127, 132))	('HSPB2', 'Gene', '3316', (127, 132))	('methylated', 'Var', (147, 157))	('human', 'Species', '9606', (80, 85))	('HSPB2', 'Gene', (57, 62))	('HSPB2', 'Gene', '3316', (57, 62))
549490	21258768	We examined promoter methylation status of these 19 genes by bisulfite-sequencing in three ESCC cell lines (KYSE30, KYSE410, KYSE520) and four tumor tissue samples (PT).	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (143, 148))	('bisulfite', 'Chemical', 'MESH:C042345', (61, 70))	('ESCC', 'Disease', (91, 95))	('examined', 'Reg', (3, 11))	('KYSE410', 'Var', (116, 123))	('KYSE520', 'Var', (125, 132))	('KYSE30', 'Var', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
549492	21258768	As a result, we found that heat shock protein B2 (HSPB2), Rho GTPase activating protein 4 (ARHGAP4), alpha2 hemoglobin (HBA2), a hypothetical protein (LOC254531), potassium large conductance calcium-activated channel (KCNMA1) and ADP-ribosylation factor related protein 1 (ARFRP1) were methylated in ESCC cell lines and tissues, but not in 4 normal esophageal tissues (Table II).	('ESCC', 'Disease', (300, 304))	('Rho GTPase activating protein 4', 'Gene', '393', (58, 89))	('methylated', 'Var', (286, 296))	('heat shock protein B2', 'Gene', (27, 48))	('ADP-ribosylation factor related protein 1', 'Gene', (230, 271))	('ARFRP1', 'Gene', '10139', (273, 279))	('HBA2', 'Gene', (120, 124))	('shock', 'Phenotype', 'HP:0031273', (32, 37))	('HSPB2', 'Gene', (50, 55))	('HSPB2', 'Gene', '3316', (50, 55))	('ARHGAP4', 'Gene', (91, 98))	('Rho GTPase activating protein 4', 'Gene', (58, 89))	('KCNMA1', 'Gene', '3778', (218, 224))	('ADP-ribosylation factor related protein 1', 'Gene', '10139', (230, 271))	('KCNMA1', 'Gene', (218, 224))	('heat shock protein B2', 'Gene', '3316', (27, 48))	('ARHGAP4', 'Gene', '393', (91, 98))	('ARFRP1', 'Gene', (273, 279))	('HBA2', 'Gene', '3040', (120, 124))
549496	21258768	In addition, HSPB2, LOC254531 and ARHGAP4 were methylated in <20% of the 20 normal matched esophageal tissues, indicating that the methylation was cancer-specific (Fig.	('LOC254531', 'Var', (20, 29))	('HSPB2', 'Gene', '3316', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('ARHGAP4', 'Gene', (34, 41))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('ARHGAP4', 'Gene', '393', (34, 41))	('HSPB2', 'Gene', (13, 18))
549505	21258768	Taken together, the overall HSPB2 methylation was observed in a total of 67 out of 70 ESCC cases (95.7%, P=0.02).	('methylation', 'Var', (34, 45))	('HSPB2', 'Gene', (28, 33))	('observed', 'Reg', (50, 58))	('HSPB2', 'Gene', '3316', (28, 33))	('ESCC', 'Disease', (86, 90))
549508	21258768	Unexpectedly, HSPB2 was expressed in KYSE70 and KYSE520, two cell lines which harbored HSPB2 promoter methylation.	('HSPB2', 'Gene', (14, 19))	('HSPB2', 'Gene', (87, 92))	('HSPB2', 'Gene', '3316', (14, 19))	('HSPB2', 'Gene', '3316', (87, 92))	('KYSE520', 'Var', (48, 55))
549509	21258768	However, the mRNA level of HSPB2 was reactivated by treatment with 5-aza-dC, and/or trichostatin A (TSA) in all ESCC cell lines (Fig.	('mRNA level', 'MPA', (13, 23))	('HSPB2', 'Gene', (27, 32))	('5-aza-dC', 'Chemical', '-', (67, 75))	('HSPB2', 'Gene', '3316', (27, 32))	('TSA', 'Chemical', 'MESH:C012589', (100, 103))	('reactivated', 'PosReg', (37, 48))	('5-aza-dC', 'Var', (67, 75))	('trichostatin A', 'Chemical', 'MESH:C012589', (84, 98))
549518	21258768	We undertook pharmacological unmasking of ESCC cell lines with 5-aza-dC and TSA followed by microarray analysis to comprehensively identify epigenetically inactivated genes in ESCC.	('ESCC', 'Disease', (176, 180))	('5-aza-dC', 'Chemical', '-', (63, 71))	('TSA', 'Chemical', 'MESH:C012589', (76, 79))	('epigenetically inactivated', 'Var', (140, 166))
549519	21258768	Among the large number of genes identified by the microarray analysis, we selected in this study candidate genes of which expression was initially absent and then reactivated by treatment with 5-aza-dC.	('expression', 'MPA', (122, 132))	('5-aza-dC', 'Chemical', '-', (193, 201))	('absent', 'NegReg', (147, 153))	('5-aza-dC', 'Var', (193, 201))
549520	21258768	We evaluated the methylation status of the promoter regions in 19 genes by bisulfite-sequencing, and discovered that three genes (HSPB2, LOC254531 and ARHGAP4) harbored methylation in >80% of ESCC tissues.	('HSPB2', 'Gene', (130, 135))	('HSPB2', 'Gene', '3316', (130, 135))	('bisulfite', 'Chemical', 'MESH:C042345', (75, 84))	('ESCC', 'Disease', (192, 196))	('ARHGAP4', 'Gene', (151, 158))	('methylation', 'Var', (169, 180))	('ARHGAP4', 'Gene', '393', (151, 158))	('LOC254531', 'Gene', (137, 146))
549535	21258768	In conclusion, we have found that HSPB2 was methylated in human ESCC in a cancer-specific manner.	('methylated', 'Var', (44, 54))	('HSPB2', 'Gene', (34, 39))	('ESCC', 'Disease', (64, 68))	('human', 'Species', '9606', (58, 63))	('HSPB2', 'Gene', '3316', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
549675	22191081	NSAIDs may occasionally cause small intestinal perforation, ulcers, and strictures that require surgery.	('strictures', 'Disease', (72, 82))	('small intestinal perforation', 'Disease', (30, 58))	('cause', 'Reg', (24, 29))	('ulcers', 'Disease', (60, 66))	('small intestinal perforation', 'Phenotype', 'HP:0031370', (30, 58))	('ulcers', 'Disease', 'MESH:D014456', (60, 66))	('intestinal perforation', 'Phenotype', 'HP:0031368', (36, 58))	('NSAIDs', 'Var', (0, 6))
549697	30598588	TEF can lead to significant respiratory distress that may result in lethal respiratory compromise, often due to recurrent and intractable infections.	('recurrent and intractable infections', 'Phenotype', 'HP:0002719', (112, 148))	('infections', 'Disease', 'MESH:D007239', (138, 148))	('respiratory distress', 'Phenotype', 'HP:0002098', (28, 48))	('lethal', 'Disease', (68, 74))	('infections', 'Disease', (138, 148))	('respiratory', 'Disease', (28, 39))	('TEF', 'Var', (0, 3))	('result in', 'Reg', (58, 67))	('lead to', 'Reg', (8, 15))
549813	28912889	Next, we used two pairs of small hairpin RNAs (shRNAs) to dramatically reduce endogenous CBX8 expression in TE-1 cells, which endogenously express a high level of CBX8, and this knockdown significantly enhanced the migration and invasion of TE-1 cells (Fig.	('reduce', 'NegReg', (71, 77))	('CBX8', 'Gene', (163, 167))	('enhanced', 'PosReg', (202, 210))	('invasion of TE-1 cells', 'CPA', (229, 251))	('CBX8', 'Gene', '57332', (89, 93))	('TE-1', 'CellLine', 'CVCL:1759', (241, 245))	('TE-1', 'CellLine', 'CVCL:1759', (108, 112))	('CBX8', 'Gene', (89, 93))	('knockdown', 'Var', (178, 187))	('expression', 'MPA', (94, 104))	('CBX8', 'Gene', '57332', (163, 167))	('endogenous', 'MPA', (78, 88))
549815	28912889	However, as demonstrated by the MTT assay, the knockdown of CBX8 impaired the viability of TE-1 cells (Fig.	('CBX8', 'Gene', '57332', (60, 64))	('TE-1', 'CellLine', 'CVCL:1759', (91, 95))	('CBX8', 'Gene', (60, 64))	('knockdown', 'Var', (47, 56))	('viability of TE-1 cells', 'CPA', (78, 101))	('impaired', 'NegReg', (65, 73))	('MTT', 'Chemical', 'MESH:C070243', (32, 35))
549818	28912889	Furthermore, knocking down CBX8 increased the tumor size, the number of metastatic nodules and the lung weight (Fig.	('knocking down', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('CBX8', 'Gene', '57332', (27, 31))	('CBX8', 'Gene', (27, 31))	('increased', 'PosReg', (32, 41))	('lung weight', 'CPA', (99, 110))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
549823	28912889	We noticed that the morphology of stable CBX8-shRNAs TE-1 cells have been changed from the tight cell-to-cell adhesion into the spindle-like and fibroblastic phenotype, suggesting that TE-1 cells knockdown of CBX8 occur EMT.	('EMT', 'CPA', (220, 223))	('TE-1', 'CellLine', 'CVCL:1759', (53, 57))	('CBX8', 'Gene', '57332', (41, 45))	('TE-1', 'CellLine', 'CVCL:1759', (185, 189))	('CBX8', 'Gene', '57332', (209, 213))	('CBX8', 'Gene', (41, 45))	('CBX8', 'Gene', (209, 213))	('knockdown', 'Var', (196, 205))
549844	28912889	Using two pairs of shRNAs to stably knock down Snail in the CBX8-silenced TE-1 cells, we found that the down-regulation of Snail abrogated the increase of cell migration and invasion in TE-1 cells induced by knocking down CBX8 (Fig.	('down-regulation', 'NegReg', (104, 119))	('CBX8', 'Gene', '57332', (60, 64))	('CBX8', 'Gene', '57332', (222, 226))	('Snail', 'Gene', '6615', (47, 52))	('Snail', 'Gene', (47, 52))	('CBX8', 'Gene', (60, 64))	('cell migration', 'CPA', (155, 169))	('CBX8', 'Gene', (222, 226))	('Snail', 'Gene', (123, 128))	('knocking down', 'Var', (208, 221))	('abrogated', 'NegReg', (129, 138))	('Snail', 'Gene', '6615', (123, 128))	('TE-1', 'CellLine', 'CVCL:1759', (186, 190))	('increase', 'PosReg', (143, 151))	('TE-1', 'CellLine', 'CVCL:1759', (74, 78))
549846	28912889	Moreover, using the tail vein-lung metastasis model, the inhibition of ESCC metastasis to the lungs by CBX8 was abolished in the cells bearing stably knocking down of both CBX8 and Snail (Fig.	('ESCC', 'Disease', (71, 75))	('Snail', 'Gene', '6615', (181, 186))	('Snail', 'Gene', (181, 186))	('inhibition', 'NegReg', (57, 67))	('CBX8', 'Gene', '57332', (172, 176))	('CBX8', 'Gene', '57332', (103, 107))	('abolished', 'NegReg', (112, 121))	('CBX8', 'Gene', (172, 176))	('CBX8', 'Gene', (103, 107))	('knocking down', 'Var', (150, 163))
549856	28912889	CBX8 is one of the five human homologs of the Drosophila Pc protein, and participates in the PRC1 complex and drives the PRC1 complex to the promoter regions of CBX8 target genes to mediate epigenetic gene silencing.	('Drosophila', 'Species', '7227', (46, 56))	('human', 'Species', '9606', (24, 29))	('CBX8', 'Gene', '57332', (161, 165))	('CBX8', 'Gene', '57332', (0, 4))	('CBX8', 'Gene', (161, 165))	('CBX8', 'Gene', (0, 4))	('epigenetic gene', 'Var', (190, 205))
549859	28912889	In fact, the regulation of CBX8 on cancer metastasis have been also reported in CRC, showing that the knockdown of CBX8 releases its inhibition on the ITGB4 promoter, which in turn reduces active RhoA and enhances CRC metastasis.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CRC', 'Phenotype', 'HP:0030731', (80, 83))	('CBX8', 'Gene', (27, 31))	('CRC', 'Phenotype', 'HP:0030731', (214, 217))	('RhoA', 'Gene', (196, 200))	('CBX8', 'Gene', (115, 119))	('ITGB4', 'Gene', '3691', (151, 156))	('active', 'MPA', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('inhibition', 'MPA', (133, 143))	('RhoA', 'Gene', '387', (196, 200))	('enhances', 'PosReg', (205, 213))	('ITGB4', 'Gene', (151, 156))	('reduces', 'NegReg', (181, 188))	('knockdown', 'Var', (102, 111))	('CRC', 'Disease', (214, 217))	('CBX8', 'Gene', '57332', (27, 31))	('CBX8', 'Gene', '57332', (115, 119))	('cancer', 'Disease', (35, 41))
549879	27941559	In mice, cse1 is essential for early embryonic growth and development; when mutated, it induces death.	('induces', 'Reg', (88, 95))	('cse1', 'Gene', (9, 13))	('mice', 'Species', '10090', (3, 7))	('embryonic growth', 'Disease', (37, 53))	('mutated', 'Var', (76, 83))	('embryonic growth', 'Disease', 'MESH:D006130', (37, 53))	('death', 'Disease', 'MESH:D003643', (96, 101))	('cse1', 'Gene', '852612', (9, 13))	('death', 'Disease', (96, 101))
549883	27941559	Furthermore, its expression seems associated with an adverse patient outcome in certain tumors, such as colorectal cancer, in which, CAS/CSE1L affects cellular proliferation, apoptosis, cell-cell adhesion, and invasion, thus promoting the progression of colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('invasion', 'CPA', (210, 218))	('cellular proliferation', 'CPA', (151, 173))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('CAS/CSE1L', 'Var', (133, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (254, 271))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('colorectal cancer', 'Disease', (254, 271))	('promoting', 'PosReg', (225, 234))	('colorectal cancer', 'Disease', (104, 121))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('associated', 'Reg', (34, 44))	('patient', 'Species', '9606', (61, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (254, 271))	('apoptosis', 'CPA', (175, 184))	('affects', 'Reg', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cell-cell adhesion', 'CPA', (186, 204))	('tumors', 'Disease', (88, 94))
549884	27941559	have reported a close association between K-Ras mutation and CAS/CSE1L expression, providing a rational strategy for targeting CAS/CSE1L in K-Ras-mutated colorectal cancer.	('colorectal cancer', 'Disease', (154, 171))	('K-Ras', 'Gene', '3845', (140, 145))	('CAS/CSE1L', 'Gene', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('K-Ras', 'Gene', '3845', (42, 47))	('K-Ras', 'Gene', (140, 145))	('mutation', 'Var', (48, 56))	('K-Ras', 'Gene', (42, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))	('association', 'Interaction', (22, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))
549928	27941559	For example, in colonic adenocarcinoma, cytoplasmic CAS/CSE1L was reported to correlate with cancer stage, depth of tumor penetration, and lymph node metastasis.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('colonic adenocarcinoma', 'Disease', (16, 38))	('lymph node metastasis', 'CPA', (139, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('cytoplasmic', 'Var', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('colonic adenocarcinoma', 'Disease', 'MESH:D003110', (16, 38))	('tumor', 'Disease', (116, 121))
549952	25289046	Therefore, in the present study, the effects of ECRG2 in combination with DDP on EC9706 esophageal cell proliferation and apoptosis were investigated and compared with those of ECRG2 alone.	('EC9706', 'CellLine', 'CVCL:E307', (81, 87))	('ECRG2', 'Gene', (177, 182))	('ECRG2', 'Gene', '84651', (48, 53))	('ECRG2', 'Gene', (48, 53))	('EC9706', 'Var', (81, 87))	('DDP', 'Chemical', '-', (74, 77))	('ECRG2', 'Gene', '84651', (177, 182))
549975	25289046	The primers for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were 5'-TCATGGGTGTGAACCATGAGAA-3' (forward) and 5'-GGCATGGACTGTGGTCATGAG-3' (reverse).	("5'-TCATGGGTGTGAACCATGAGAA-3", 'Var', (70, 97))	('GAPDH', 'Gene', '2597', (58, 63))	('GAPDH', 'Gene', (58, 63))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (16, 56))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (16, 56))
549982	25289046	As shown in Table I, EC9706 cell growth was inhibited by different concentrations of the ECRG2 protein in a time- and concentration-dependent manner within a certain range of concentrations.	('ECRG2', 'Gene', '84651', (89, 94))	('inhibited', 'NegReg', (44, 53))	('EC9706', 'CellLine', 'CVCL:E307', (21, 27))	('ECRG2', 'Gene', (89, 94))	('EC9706', 'Var', (21, 27))
549984	25289046	The proliferation rate of EC9706 cells exhibited a time-and concentration-dependent reduction as the concentration of ECRG2 protein increased.	('ECRG2', 'Gene', (118, 123))	('reduction', 'NegReg', (84, 93))	('EC9706', 'Var', (26, 32))	('proliferation rate', 'CPA', (4, 22))	('EC9706', 'CellLine', 'CVCL:E307', (26, 32))	('ECRG2', 'Gene', '84651', (118, 123))
549990	25289046	When the ECRG2 protein was combined with DDP, the expression levels of Bax mRNA were significantly increased compared with those observed when the ECRG2 protein was used alone (Fig.	('DDP', 'Var', (41, 44))	('DDP', 'Chemical', '-', (41, 44))	('Bax', 'Gene', (71, 74))	('ECRG2', 'Gene', '84651', (147, 152))	('expression levels', 'MPA', (50, 67))	('ECRG2', 'Gene', (147, 152))	('increased', 'PosReg', (99, 108))	('ECRG2', 'Gene', (9, 14))	('ECRG2', 'Gene', '84651', (9, 14))
549992	25289046	When ECRG2 protein was combined with DDP, the expression level of Bax protein was significantly increased compared with that observed when the ECRG2 protein was used alone.	('ECRG2', 'Gene', '84651', (5, 10))	('increased', 'PosReg', (96, 105))	('expression level', 'MPA', (46, 62))	('ECRG2', 'Gene', (143, 148))	('Bax protein', 'Protein', (66, 77))	('ECRG2', 'Gene', '84651', (143, 148))	('DDP', 'Var', (37, 40))	('DDP', 'Chemical', '-', (37, 40))	('ECRG2', 'Gene', (5, 10))
550025	24952744	The most appropriate therapeutic targets are therefore those mutations that occur early in the development of disease and are thus clonal in the resulting malignancy.	('malignancy', 'Disease', 'MESH:D009369', (155, 165))	('malignancy', 'Disease', (155, 165))	('mutations', 'Var', (61, 70))
550026	24952744	In this context mutations occurring at disease-stage boundaries, for example, the transition from non-dysplastic epithelium to dysplasia, and then to cancer would be most informative.	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (16, 25))	('cancer', 'Disease', (150, 156))	('non-dysplastic epithelium to dysplasia', 'Disease', 'MESH:C536309', (98, 136))	('non-dysplastic epithelium to dysplasia', 'Disease', (98, 136))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
550033	24952744	Intriguingly, the majority of mutations were found to be present even in apparently normal Barrett's esophagus  similar to the observation in colorectal adenocarcinoma.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (91, 110))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (142, 167))	('colorectal adenocarcinoma', 'Disease', (142, 167))	('mutations', 'Var', (30, 39))
550034	24952744	This raises the possibility that prior to the progression to malignancy mutations that predict the risk of progression may be detectable within cytologically benign tissue.	('mutations', 'Var', (72, 81))	('malignancy', 'Disease', (61, 71))	('malignancy', 'Disease', 'MESH:D009369', (61, 71))
550040	24952744	As observed by Dulak et al in the intervening time since our study commenced, the most frequent mutation type across the discovery cohort was T:A>G:C transversions with a striking enrichment at CTT trinucleotides (Supplementary Figure 1).	('CTT trinucleotides', 'Chemical', '-', (194, 212))	('CTT', 'Disease', (194, 197))	('T:A>G:C transversions', 'Var', (142, 163))
550041	24952744	This enrichment for T:A>G:C transversions differentiates EAC from other cancers that have been studied by WGS, including breast, colorectal and hepatocellular.	('colorectal', 'Disease', 'MESH:D015179', (129, 139))	('breast', 'Disease', (121, 127))	('hepatocellular', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('differentiates', 'Reg', (42, 56))	('T:A>G:C transversions', 'Var', (20, 41))	('transversions', 'Var', (28, 41))	('EAC', 'Disease', (57, 60))	('colorectal', 'Disease', (129, 139))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
550042	24952744	The findings confirmed and extended those of our discovery cohort and previous work from others, including the identification of recurrent mutations in the SWI/SNF complex, such as ARID1A (Supplementary Figure 2).	('mutations', 'Var', (139, 148))	('ARID1A', 'Gene', (181, 187))	('ARID1A', 'Gene', '8289', (181, 187))	('SWI/SNF', 'Gene', (156, 163))
550046	24952744	SEMA5A and ABCB1 mutations occurred more commonly in the same tumor than would be expected by chance (Benjamini-Hochberg-adjusted p-value = 0.0021) although the reason for this association remains unclear.	('SEMA5A', 'Gene', (0, 6))	('SEMA5A', 'Gene', '9037', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('ABCB1', 'Gene', (11, 16))	('ABCB1', 'Gene', '5243', (11, 16))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
550047	24952744	The stage specificity of mutations can be derived from patients at discrete stages of Barrett's esophagus carcinogenesis.	('mutations', 'Var', (25, 34))	('patients', 'Species', '9606', (55, 63))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (86, 105))	("Barrett's esophagus carcinogenesis", 'Disease', (86, 120))	("Barrett's esophagus carcinogenesis", 'Disease', 'MESH:D001471', (86, 120))
550052	24952744	For the never-dysplastic Barrett's esophagus cohort, 21/40 (53%) patients were found to have mutations within their Barrett's esophagus segment (Figure 3a), with several biopsies containing multiple mutations (Supplementary Table 5).	('mutations', 'Var', (93, 102))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (116, 135))	("dysplastic Barrett's esophagus", 'Disease', (14, 44))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (14, 44))	('patients', 'Species', '9606', (65, 73))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (25, 44))
550053	24952744	Importantly, the mutations identified in never-dysplastic Barrett's esophagus occurred in several genes previously identified as drivers in EAC and other cancers, including SMARCA4, ARID1A, and CNTNAP5 (Figure 3b).	("dysplastic Barrett's esophagus", 'Disease', (47, 77))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (47, 77))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('ARID1A', 'Gene', '8289', (182, 188))	('ARID1A', 'Gene', (182, 188))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (58, 77))	('SMARCA4', 'Gene', (173, 180))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('CNTNAP5', 'Gene', '129684', (194, 201))	('occurred', 'Reg', (78, 86))	('cancers', 'Disease', (154, 161))	('EAC', 'Disease', (140, 143))	('SMARCA4', 'Gene', '6597', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('mutations', 'Var', (17, 26))	('CNTNAP5', 'Gene', (194, 201))
550057	24952744	Only TP53 (p<0.0001) and SMAD4 p=0.0061) (Figure 3b and c) exhibited mutational frequencies that would distinguish between disease stages and thus identify progression towards malignancy.	('mutational', 'Var', (69, 79))	('malignancy', 'Disease', 'MESH:D009369', (176, 186))	('SMAD4', 'Gene', '4089', (25, 30))	('malignancy', 'Disease', (176, 186))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('SMAD4', 'Gene', (25, 30))	('distinguish', 'Reg', (103, 114))
550069	24952744	From the aforementioned sequencing data, TP53 mutations fit the criteria of a good risk stratification candidate marker, since TP53 mutations discriminate between patients with and without high grade dysplasia, the key point of therapeutic intervention.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('patients', 'Species', '9606', (163, 171))	('mutations', 'Var', (46, 55))	('dysplasia', 'Disease', (200, 209))	('discriminate', 'Reg', (142, 154))	('mutations', 'Var', (132, 141))	('dysplasia', 'Disease', 'MESH:D004476', (200, 209))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
550070	24952744	This situation is analogous to the detection of tumor cell-free DNA in blood as a biomarker in advanced malignant disease: sensitive assays have been developed to detect extremely low levels of mutant DNA against normal background.	('tumor', 'Disease', (48, 53))	('mutant', 'Var', (194, 200))	('DNA', 'Gene', (201, 204))	('malignant disease', 'Disease', 'MESH:D009369', (104, 121))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('malignant disease', 'Disease', (104, 121))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
550071	24952744	Four patients with HGD dysplasia had TP53 mutations and had also swallowed the Cytosponge  (twice in patient 4).	('HGD dysplasia', 'Disease', (19, 32))	('patient', 'Species', '9606', (5, 12))	('patients', 'Species', '9606', (5, 13))	('HGD dysplasia', 'Disease', 'MESH:D004476', (19, 32))	('TP53', 'Gene', '7157', (37, 41))	('patient', 'Species', '9606', (101, 108))	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
550072	24952744	For all four patients, the specific TP53 mutations were detected at an allele fraction (proportion of variant reads) of between 0.04 and 0.24 (Table 2).	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (13, 21))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
550073	24952744	We then tested whether we could detect unknown TP53 mutations within material collected using the Cytosponge  as this would be required for a clinical test.	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))
550075	24952744	TP53 mutations were called de novo using TAm-Seq on samples from control patients (no Barrett's esophagus), Barrett's esophagus patients with no dysplasia as well as Barrett's esophagus patients with high grade dysplasia.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (166, 185))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('dysplasia', 'Disease', (145, 154))	('mutations', 'Var', (5, 14))	('dysplasia', 'Disease', (211, 220))	('patients', 'Species', '9606', (73, 81))	('dysplasia', 'Disease', 'MESH:D004476', (145, 154))	('dysplasia', 'Disease', 'MESH:D004476', (211, 220))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (86, 105))	('patients', 'Species', '9606', (128, 136))	("Barrett's esophagus", 'Disease', (108, 127))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (108, 127))	('patients', 'Species', '9606', (186, 194))
550077	24952744	In contrast, TP53 mutations were identified in 19/22 (86%) HGD patients (details of individual mutations can be found in Supplementary table 8).	('TP53', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (13, 17))	('patients', 'Species', '9606', (63, 71))	('HGD', 'Disease', (59, 62))	('mutations', 'Var', (18, 27))
550078	24952744	The allele fractions of the TP53 mutations varied widely (between 0.006 to 0.357) but anything in this range can be called successfully and mutations were mostly clustered in the DNA binding domain, as expected (Figure 4b).	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
550083	24952744	Surprisingly we identified numerous mutations occurring in never-dysplastic Barrett's esophagus at detectable allele fractions (>10%).	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (65, 95))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (76, 95))	("dysplastic Barrett's esophagus", 'Disease', (65, 95))	('mutations', 'Var', (36, 45))
550084	24952744	Intriguingly the most prevalent gene mutations in EAC were also present at a similar frequency in Barrett's esophagus and HGD samples, including mutations within cancer-associated genes, for example ARID1A and SMARCA4, members of the SWI/SNF complex.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('ARID1A', 'Gene', '8289', (199, 205))	('cancer', 'Disease', (162, 168))	('ARID1A', 'Gene', (199, 205))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (98, 117))	('SMARCA4', 'Gene', (210, 217))	('SMARCA4', 'Gene', '6597', (210, 217))	('mutations', 'Var', (37, 46))	('EAC', 'Gene', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
550087	24952744	Our result has substantial implications for the specificity of tests aiming to use highly sensitive detection of mutations for the early diagnosis of malignancy.	('malignancy', 'Disease', (150, 160))	('mutations', 'Var', (113, 122))	('malignancy', 'Disease', 'MESH:D009369', (150, 160))
550090	24952744	Only mutation in TP53 and SMAD4 accurately defined the boundaries of disease states.	('SMAD4', 'Gene', (26, 31))	('TP53', 'Gene', '7157', (17, 21))	('mutation', 'Var', (5, 13))	('TP53', 'Gene', (17, 21))	('SMAD4', 'Gene', '4089', (26, 31))
550091	24952744	The fact that mutation of SMAD4 was only found in EAC provides a clear genetic distinction between EAC and HGD.	('SMAD4', 'Gene', (26, 31))	('mutation', 'Var', (14, 22))	('EAC', 'Disease', (99, 102))	('SMAD4', 'Gene', '4089', (26, 31))
550092	24952744	However, the low frequency of SMAD4 mutation (13%) makes it a sub-optimal candidate for biomarker development.	('SMAD4', 'Gene', '4089', (30, 35))	('SMAD4', 'Gene', (30, 35))	('mutation', 'Var', (36, 44))
550095	24952744	In addition, since genetic diversity has been shown to predict progression to Barrett's esophagus it may be possible to perform somatic mutation testing looking at both presence and relative proportions of mutations in a panel of genes, to identify patients with high-risk disease.	('patients', 'Species', '9606', (249, 257))	("Barrett's esophagus", 'Disease', (78, 97))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (78, 97))	('genetic diversity', 'Var', (19, 36))
550096	24952744	In conclusion, never-dysplastic Barrett's esophagus harbours frequent mutations affecting recurrently-mutated genes in EAC.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (32, 51))	('mutations', 'Var', (70, 79))	("dysplastic Barrett's esophagus", 'Disease', (21, 51))	('EAC', 'Disease', (119, 122))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (21, 51))
550098	24952744	It is generally accepted that the mutations observed in a tumor are accrued in a linear progression with each step bringing the clone closer to the invasive endpoint.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (34, 43))
550099	24952744	Our observation of mutations in almost all of the recurrently-mutated genes in the tissue of patients who have not gone on to develop malignancy argues against a major role of these mutations in the progression towards cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))	('malignancy', 'Disease', 'MESH:D009369', (134, 144))	('patients', 'Species', '9606', (93, 101))	('malignancy', 'Disease', (134, 144))
550100	24952744	Furthermore, our systematic molecular approach to identify key mutations involved in the steps distinguishing pre-inasive from invasive disease has applicability to other epithelial cancers amenable to early detection.	('mutations', 'Var', (63, 72))	('epithelial cancers', 'Disease', 'MESH:D000077216', (171, 189))	('pre-inasive', 'Disease', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('epithelial cancers', 'Disease', (171, 189))	('invasive disease', 'Disease', (127, 143))
550151	24602313	Because of the high rate of #106 rec R and L lymph nodes with cancer involvement, complete lymphadenectomy along bilateral recurrent laryngeal nerve is desirable, but it often cause recurrent laryngeal nerve palsy leading dysphagia or aspiration pneumonia.	('laryngeal nerve palsy', 'Disease', 'MESH:D014826', (192, 213))	('dysphagia', 'Phenotype', 'HP:0002015', (222, 231))	('dysphagia', 'Disease', 'MESH:D003680', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('pneumonia', 'Phenotype', 'HP:0002090', (246, 255))	('men', 'Species', '9606', (76, 79))	('#106', 'Var', (28, 32))	('aspiration pneumonia', 'Disease', (235, 255))	('aspiration', 'Phenotype', 'HP:0002835', (235, 245))	('cancer', 'Disease', (62, 68))	('cause', 'Reg', (176, 181))	('dysphagia', 'Disease', (222, 231))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (235, 255))	('laryngeal nerve palsy', 'Disease', (192, 213))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (235, 255))
550207	24649251	Numerous risk factors for esophageal cancer have been identified, including tobacco smoking, alcohol intake, hot beverage intake, family history of cancer and low fruit and vegetable intake, the first two are considered to be the most significant factors.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('tobacco', 'Species', '4097', (76, 83))	('alcohol intake', 'Disease', (93, 107))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('hot beverage', 'Phenotype', 'HP:0031217', (109, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (26, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('hot beverage intake', 'Disease', (109, 128))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('low', 'Var', (159, 162))	('alcohol', 'Chemical', 'MESH:D000438', (93, 100))	('esophageal cancer', 'Disease', (26, 43))
550209	24649251	Several studies investigating the effects of smoking and alcohol intake on the risk of esophageal cancer have demonstrated that long duration, high consumption and the interaction of these habits may increase the risk of ESCC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('interaction', 'Interaction', (168, 179))	('esophageal cancer', 'Disease', (87, 104))	('increase', 'PosReg', (200, 208))	('alcohol', 'Chemical', 'MESH:D000438', (57, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('high consumption', 'Var', (143, 159))
550227	24649251	Five combined categories were created for alcohol intake: no alcohol intake, <=53.3 g ethanol/day for <=20 years, <=53.3 g ethanol/day for >20 years, >53.3 g ethanol/day for <=20 years and >53.3 g ethanol/day for >20 years.	('alcohol', 'Chemical', 'MESH:D000438', (61, 68))	('<=53.3', 'Var', (114, 120))	('ethanol', 'Chemical', 'MESH:D000431', (197, 204))	('alcohol', 'Chemical', 'MESH:D000438', (42, 49))	('ethanol', 'Chemical', 'MESH:D000431', (158, 165))	('ethanol', 'Chemical', 'MESH:D000431', (123, 130))	('<=53.3', 'Var', (77, 83))	('>53.3', 'Var', (150, 155))	('ethanol', 'Chemical', 'MESH:D000431', (86, 93))
550270	23175176	We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity.	('people', 'Species', '9606', (110, 116))	('PAH', 'Gene', (74, 77))	('variation', 'Var', (61, 70))	('PAH', 'Gene', '5053', (74, 77))
550271	23175176	In 111 randomly-selected female never-smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in 8 DNA repair genes.	('xenobiotic metabolism', 'Disease', 'MESH:D008659', (130, 151))	('xenobiotic metabolism', 'Disease', (130, 151))	('SNPs', 'Var', (102, 106))
550273	23175176	DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non risk-allele genotype, and was higher in the MPO homozygote risk-allele genotype.	('MPO', 'Gene', (136, 139))	('NAT2', 'Gene', (60, 64))	('higher', 'PosReg', (122, 128))	('ERCC5', 'Gene', (82, 87))	('MPO', 'Gene', '4353', (136, 139))	('lower', 'NegReg', (35, 40))	('ERCC5', 'Gene', '2073', (82, 87))	('slow alleles', 'Var', (65, 77))	('NAT2', 'Gene', '10', (60, 64))	('DNA adduct level', 'MPA', (0, 16))
550275	23175176	NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes.	('MTHFR', 'Gene', (50, 55))	('NER capacity', 'CPA', (0, 12))	('affected', 'Reg', (17, 25))	('polymorphisms', 'Var', (29, 42))	('MTHFR', 'Gene', '4524', (50, 55))	('ERCC1', 'Gene', '2067', (60, 65))	('ERCC1', 'Gene', (60, 65))
550286	23175176	While differences in environmental exposures are partly responsible for variations in DNA adduct formation, inter-individual variations among people with similar exposures may be explained partially by polymorphisms in genes that code for metabolizing or repair enzymes , and accumulating evidence suggests a role for genetic polymorphisms in PAH-related DNA adduct formation .	('DNA adduct formation', 'MPA', (86, 106))	('PAH', 'Gene', (343, 346))	('PAH', 'Gene', '5053', (343, 346))	('men', 'Species', '9606', (28, 31))	('people', 'Species', '9606', (142, 148))	('variations', 'Var', (72, 82))
550322	23175176	For GSTM1 and GSTT1, deletion, which results in the absence of the enzyme, was coded 2 (as opposed to 0 for those with the enzyme present).	('deletion', 'Var', (21, 29))	('GSTT1', 'Gene', '2952', (14, 19))	('GSTM1', 'Gene', '2944', (4, 9))	('GSTT1', 'Gene', (14, 19))	('GSTM1', 'Gene', (4, 9))	('absence', 'NegReg', (52, 59))
550333	23175176	As Table 3 shows, the homozygote non-risk-allele MTHFR genotype was significantly associated with lower NER capacity.	('MTHFR', 'Gene', '4524', (49, 54))	('MTHFR', 'Gene', (49, 54))	('non-risk-allele', 'Var', (33, 48))	('lower', 'NegReg', (98, 103))
550334	23175176	MTHFR CA haplotype also showed a significant association with NER capacity (Supplementary table 2).	('haplotype', 'Var', (9, 18))	('MTHFR', 'Gene', '4524', (0, 5))	('MTHFR', 'Gene', (0, 5))	('NER capacity', 'CPA', (62, 74))	('men', 'Species', '9606', (82, 85))
550335	23175176	Also, homozygotes for risk-allele genotype in ERCC1 had a higher NER capacity.	('risk-allele genotype', 'Var', (22, 42))	('ERCC1', 'Gene', '2067', (46, 51))	('ERCC1', 'Gene', (46, 51))	('NER capacity', 'CPA', (65, 77))	('higher', 'PosReg', (58, 64))
550347	23175176	As in our study, however, SNPs in some individual genes may not show significant associations with DNA adduct levels, in spite of the crucial role of these genes in coding enzymes which metabolize PAHs.	('associations', 'Interaction', (81, 93))	('SNPs', 'Var', (26, 30))	('PAHs', 'Chemical', 'MESH:D011084', (197, 201))	('DNA adduct levels', 'MPA', (99, 116))
550350	23175176	showed that although a GSTP1 polymorphism alone was not associated with a change in DNA adduct level, when combined with GSTM1 deletion, it was associated with increased adduct formation.	('GSTM1', 'Gene', (121, 126))	('adduct formation', 'MPA', (170, 186))	('increased', 'PosReg', (160, 169))	('GSTP1', 'Gene', '2950', (23, 28))	('deletion', 'Var', (127, 135))	('polymorphism', 'Var', (29, 41))	('DNA adduct level', 'MPA', (84, 100))	('GSTM1', 'Gene', '2944', (121, 126))	('GSTP1', 'Gene', (23, 28))
550354	23175176	They showed that adding phase I polymorphisms to environmental exposures increased the ability of the model to predict 1-OHPG concentration by 12%.	('increased', 'PosReg', (73, 82))	('polymorphisms', 'Var', (32, 45))	('men', 'Species', '9606', (56, 59))	('1-OHPG concentration', 'MPA', (119, 139))	('1-OHPG', 'Chemical', '-', (119, 125))
550357	23175176	In our study, 1-OHPG was not associated with the adduct level and did not improve adduct formation model fit.	('1-OHPG', 'Var', (14, 20))	('adduct', 'MPA', (49, 55))	('1-OHPG', 'Chemical', '-', (14, 20))
550359	23175176	showed that BPDE-DNA adduct formation was decreased in the skin of coal-tar treated patients carrying the MPO mutant allele.	('MPO', 'Gene', (106, 109))	('decreased', 'NegReg', (42, 51))	('patients', 'Species', '9606', (84, 92))	('BPDE', 'Chemical', '-', (12, 16))	('mutant', 'Var', (110, 116))	('MPO', 'Gene', '4353', (106, 109))	('BPDE-DNA adduct formation', 'MPA', (12, 37))
550360	23175176	In another study, this polymorphism was shown to reduce DNA adduct levels in bronchoalveolar lavage specimens from smokers .	('men', 'Species', '9606', (105, 108))	('DNA adduct levels', 'MPA', (56, 73))	('reduce', 'NegReg', (49, 55))	('polymorphism', 'Var', (23, 35))
550363	23175176	showed that slow acetylation was associated with increased DNA adducts in the lung, but a non-significant reduction of adducts in the blood monocytes of lung cancer patients.	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('increased', 'PosReg', (49, 58))	('acetylation', 'MPA', (17, 28))	('lung cancer', 'Disease', (153, 164))	('DNA adducts', 'MPA', (59, 70))	('patients', 'Species', '9606', (165, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('slow', 'Var', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
550367	23175176	We also showed that NER capacity itself is increased in individuals with MTHFR and ERCC1 polymorphisms.	('ERCC1', 'Gene', (83, 88))	('NER capacity', 'CPA', (20, 32))	('polymorphisms', 'Var', (89, 102))	('ERCC1', 'Gene', '2067', (83, 88))	('MTHFR', 'Gene', '4524', (73, 78))	('increased', 'PosReg', (43, 52))	('MTHFR', 'Gene', (73, 78))
550368	23175176	Two of the SNPs we studied in the ERCC1 gene (rs11615 T allele and rs3212986 C allele) have been shown to increase DNA adduct levels , but this is the first study to show the association between this gene and NER capacity.	('rs3212986 C', 'Var', (67, 78))	('ERCC1', 'Gene', (34, 39))	('ERCC1', 'Gene', '2067', (34, 39))	('NER capacity', 'CPA', (209, 221))	('rs11615 T', 'Var', (46, 55))	('rs11615', 'Mutation', 'rs11615', (46, 53))	('increase', 'PosReg', (106, 114))	('DNA adduct levels', 'MPA', (115, 132))	('rs3212986', 'Mutation', 'rs3212986', (67, 76))
550369	23175176	Although the role of MTHFR in DNA repair may not be straightforward, it has been shown that the rs1801133 MTHFR T allele could increase 5,10-methylenetetrahydrofolate levels, which are necessary for DNA repair .	('MTHFR', 'Gene', '4524', (21, 26))	('MTHFR', 'Gene', (106, 111))	('5,10-methylenetetrahydrofolate', 'Chemical', 'MESH:C013123', (136, 166))	('rs1801133', 'Mutation', 'rs1801133', (96, 105))	('MTHFR', 'Gene', (21, 26))	('increase', 'PosReg', (127, 135))	('rs1801133', 'Var', (96, 105))	('MTHFR', 'Gene', '4524', (106, 111))
550394	20122192	These disease families include genetically heterogeneous disorders in which mutations in distinct genes are associated with similar or even indistinguishable phenotypes; cancer syndromes comprising genes associated with hereditary cancer, increased risk, or somatic mutation in a given cancer type; and complex (polygenic) disorders known to be influenced by variation in multiple genes.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('mutations', 'Var', (76, 85))	('hereditary cancer', 'Disease', (220, 237))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('associated', 'Reg', (108, 118))	('cancer syndromes', 'Disease', (170, 186))	('cancer syndromes', 'Disease', 'MESH:D009369', (170, 186))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('hereditary cancer', 'Disease', 'MESH:D009369', (220, 237))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Disease', (286, 292))
550450	33793074	Based on mechanism analyses, we show that miR-493 inhibits the activity of c-JUN and p-PI3K/p-AKT with enhanced p21 and directly regulates Wnt5A expression and function, whereas c-JUN binds the promoter region of miR-493 and suppressed the expression of miR-493, forming a negative feedback loop.	('suppressed', 'NegReg', (225, 235))	('Wnt5A', 'Gene', (139, 144))	('miR-493', 'Var', (42, 49))	('AKT', 'Gene', (94, 97))	('expression', 'MPA', (145, 155))	('miR-493', 'Gene', (254, 261))	('function', 'MPA', (160, 168))	('p21', 'Gene', (112, 115))	('regulates', 'Reg', (129, 138))	('activity', 'MPA', (63, 71))	('p21', 'Gene', '644914', (112, 115))	('binds', 'Interaction', (184, 189))	('expression', 'MPA', (240, 250))	('enhanced', 'PosReg', (103, 111))	('AKT', 'Gene', '207', (94, 97))	('Wnt5A', 'Gene', '7474', (139, 144))	('inhibits', 'NegReg', (50, 58))	('c-JUN', 'Gene', '3725', (75, 80))	('c-JUN', 'Gene', '3725', (178, 183))	('c-JUN', 'Gene', (75, 80))	('c-JUN', 'Gene', (178, 183))
550454	33793074	MicroRNA (MiRNA) dysregulation has been implicated in cancer development.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('dysregulation', 'Var', (17, 30))	('cancer', 'Disease', (54, 60))	('implicated', 'Reg', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('MicroRNA', 'MPA', (0, 8))
550460	33793074	13 ,  14 ,  15  Moreover, miR-493 promotes proliferation, invasion, and chemo-resistance in gastric cancer cells.	('miR-493', 'Var', (26, 33))	('gastric cancer', 'Disease', (92, 106))	('promotes', 'PosReg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('invasion', 'CPA', (58, 66))	('proliferation', 'CPA', (43, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('chemo-resistance', 'CPA', (72, 88))
550475	33793074	Levels of c-JUN, p-PI3K, and p-AKT were significantly reduced whereas p21 was enhanced after overexpression of miR-493 in EC9706 and TE13 cells (Figure 1(g)).	('EC9706', 'CellLine', 'CVCL:E307', (122, 128))	('Levels', 'MPA', (0, 6))	('c-JUN', 'Gene', '3725', (10, 15))	('AKT', 'Gene', (31, 34))	('p21', 'Gene', (70, 73))	('p-PI3K', 'MPA', (17, 23))	('TE13', 'Chemical', '-', (133, 137))	('reduced', 'NegReg', (54, 61))	('p21', 'Gene', '644914', (70, 73))	('c-JUN', 'Gene', (10, 15))	('miR-493', 'Var', (111, 118))	('AKT', 'Gene', '207', (31, 34))	('overexpression', 'PosReg', (93, 107))	('enhanced', 'PosReg', (78, 86))
550478	33793074	We found that tumor developed from miR-493 overexpressed cells were significantly smaller than control tumor (Figure 1(h)).	('smaller', 'NegReg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('miR-493', 'Gene', (35, 42))	('overexpressed', 'Var', (43, 56))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
550479	33793074	To evaluate the effects of miR-493 on tumor metastasis in vivo, nude mice were injected intravenously into the tail vein with EC9706/TE13-miR-493 or control cells, respectively, and then assessed lung metastasis by bioluminescence imaging.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('EC9706', 'CellLine', 'CVCL:E307', (126, 132))	('tumor metastasis', 'Disease', 'MESH:D009362', (38, 54))	('nude mice', 'Species', '10090', (64, 73))	('lung metastasis', 'CPA', (196, 211))	('TE13', 'Chemical', '-', (133, 137))	('tumor metastasis', 'Disease', (38, 54))	('EC9706/TE13-miR-493', 'Var', (126, 145))
550481	33793074	Together, these data indicate that miR-493 plays a pivotal role in esophageal cancer in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal cancer', 'Disease', (67, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('miR-493', 'Var', (35, 42))
550482	33793074	Using TargetScan bioinformatics algorithms for target gene prediction, we found that Wnt5A was predicted to be a direct target of miR-493 (Figure 2(a)).	('miR-493', 'Var', (130, 137))	('Wnt5A', 'Gene', (85, 90))	('Wnt5A', 'Gene', '7474', (85, 90))
550485	33793074	Consistent with binding data, there was a decrease in relative luciferase activity when the Wnt5A 3'UTR was co-transfected in EC9706 and TE13 cells with the miR-493, however, there was no difference in relative luciferase activity for mutant Wnt5A 3'UTR transfection (Figure 2(c)).	('Wnt5A', 'Gene', (242, 247))	('Wnt5A', 'Gene', (92, 97))	('EC9706', 'CellLine', 'CVCL:E307', (126, 132))	('Wnt5A', 'Gene', '7474', (242, 247))	('Wnt5A', 'Gene', '7474', (92, 97))	('TE13', 'Chemical', '-', (137, 141))	('activity', 'MPA', (74, 82))	('decrease', 'NegReg', (42, 50))	('activity', 'MPA', (222, 230))	('mutant', 'Var', (235, 241))	('luciferase', 'Enzyme', (63, 73))
550488	33793074	The ectopic expression of Wnt5A increased cell proliferation ability (Figure 3(a)).	('Wnt5A', 'Gene', (26, 31))	('Wnt5A', 'Gene', '7474', (26, 31))	('cell proliferation ability', 'CPA', (42, 68))	('increased', 'PosReg', (32, 41))	('ectopic expression', 'Var', (4, 22))
550496	33793074	Next, dual-luciferase reporter assay indicated c-JUN reduced the luciferase activities of the wild-type compared with the mutant miR-493 promoter after co-transfection with c-JUN in EC9706 and TE13 cells (Figure 4(d)).	('c-JUN', 'Gene', (173, 178))	('TE13', 'Chemical', '-', (193, 197))	('activities', 'MPA', (76, 86))	('EC9706', 'CellLine', 'CVCL:E307', (182, 188))	('c-JUN', 'Gene', (47, 52))	('miR-493', 'Gene', (129, 136))	('reduced', 'NegReg', (53, 60))	('c-JUN', 'Gene', '3725', (173, 178))	('luciferase', 'Enzyme', (65, 75))	('mutant', 'Var', (122, 128))	('c-JUN', 'Gene', '3725', (47, 52))
550510	33793074	Notably, a reverse correlation was observed between relative miR-493 and Wnt5A expressions (Figure 7(d)).	('miR-493', 'Var', (61, 68))	('Wnt5A', 'Gene', (73, 78))	('Wnt5A', 'Gene', '7474', (73, 78))
550515	33793074	Next, PD-L1 was knocked down in EC cells (Figure 8(c)).	('knocked', 'Var', (16, 23))	('PD-L1', 'Gene', (6, 11))	('PD-L1', 'Gene', '29126', (6, 11))
550516	33793074	We found that the inhibition of PD-L1 enhanced the sensitivity of EC cells to DDP (Figure 8(d)).	('DDP', 'Chemical', 'MESH:D002945', (78, 81))	('PD-L1', 'Gene', (32, 37))	('enhanced', 'PosReg', (38, 46))	('sensitivity', 'MPA', (51, 62))	('PD-L1', 'Gene', '29126', (32, 37))	('inhibition', 'Var', (18, 28))
550517	33793074	These findings suggest miR-493 is a critical regulator of PD-L1 expression by c-JUN and a potential therapeutic target to enhance antitumor activity.	('miR-493', 'Var', (23, 30))	('PD-L1', 'Gene', '29126', (58, 63))	('c-JUN', 'Gene', (78, 83))	('enhance', 'PosReg', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('PD-L1', 'Gene', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('c-JUN', 'Gene', '3725', (78, 83))	('tumor', 'Disease', (134, 139))
550518	33793074	MiR-493 dysregulation has been linked with several types of cancer.	('dysregulation', 'Var', (8, 21))	('MiR-493', 'Gene', '574450', (0, 7))	('linked', 'Reg', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('MiR-493', 'Gene', (0, 7))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
550519	33793074	These results suggest that miR-493 functions as a potential tumor suppressor in EC.	('miR-493', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))
550521	33793074	After profoundly studying the underlying mechanisms, we show that miR-493 inhibited the activity of c-JUN and p-PI3K/p-AKT with enhanced p21 and directly regulates Wnt5A expression and function, whereas c-JUN binds the promoter region of miR-493 and suppressed the expression of miR-493, forming a negative feedback loop.	('p21', 'Gene', '644914', (137, 140))	('function', 'MPA', (185, 193))	('activity', 'MPA', (88, 96))	('enhanced', 'PosReg', (128, 136))	('expression', 'MPA', (265, 275))	('expression', 'MPA', (170, 180))	('inhibited', 'NegReg', (74, 83))	('regulates', 'Reg', (154, 163))	('AKT', 'Gene', '207', (119, 122))	('Wnt5A', 'Gene', '7474', (164, 169))	('c-JUN', 'Gene', '3725', (203, 208))	('c-JUN', 'Gene', '3725', (100, 105))	('c-JUN', 'Gene', (203, 208))	('c-JUN', 'Gene', (100, 105))	('suppressed', 'NegReg', (250, 260))	('miR-493', 'Var', (66, 73))	('Wnt5A', 'Gene', (164, 169))	('AKT', 'Gene', (119, 122))	('miR-493', 'Gene', (279, 286))	('p21', 'Gene', (137, 140))
550524	33793074	The inhibiting effect of miR-493 on EC growth might be because of the arrest of G1 to S transit by miR-493.	('miR-493', 'Var', (99, 106))	('inhibiting', 'NegReg', (4, 14))	('arrest', 'Disease', (70, 76))	('G1 to S transit', 'CPA', (80, 95))	('arrest', 'Disease', 'MESH:D006323', (70, 76))
550526	33793074	24 ,  25  Furthermore, we also observed that increased miR-493 induced the sensitivity of EC cells to DDP.	('increased', 'PosReg', (45, 54))	('DDP', 'Chemical', 'MESH:D002945', (102, 105))	('miR-493', 'Var', (55, 62))	('sensitivity', 'MPA', (75, 86))	('induced', 'Reg', (63, 70))
550530	33793074	31  In this study, ectopic expression of Wnt5A as the target of miR-493 mitigates miR-493 suppression of EC proliferation, migration, and invasion.	('miR-493', 'Var', (82, 89))	('suppression', 'NegReg', (90, 101))	('mitigates', 'NegReg', (72, 81))	('Wnt5A', 'Gene', (41, 46))	('invasion', 'CPA', (138, 146))	('migration', 'CPA', (123, 132))	('Wnt5A', 'Gene', '7474', (41, 46))	('EC proliferation', 'CPA', (105, 121))
550534	33793074	Together, these results indicate that miR-493 can induce its own expression through a miR-493/Wnt5A/c-JUN loop in EC pathogenesis.	('Wnt5A', 'Gene', '7474', (94, 99))	('miR-493', 'Var', (38, 45))	('c-JUN', 'Gene', '3725', (100, 105))	('expression', 'MPA', (65, 75))	('c-JUN', 'Gene', (100, 105))	('Wnt5A', 'Gene', (94, 99))	('induce', 'PosReg', (50, 56))
550542	33793074	38 ,  39 ,  40  Here, we examined the effect of miR-493 on PD-L1 and found that miR-493 regulates the expression of PD-L1 by c-JUN and then the sensitivity of EC cells to DDP.	('regulates', 'Reg', (88, 97))	('sensitivity', 'CPA', (144, 155))	('expression', 'MPA', (102, 112))	('DDP', 'Chemical', 'MESH:D002945', (171, 174))	('PD-L1', 'Gene', (116, 121))	('c-JUN', 'Gene', '3725', (125, 130))	('PD-L1', 'Gene', (59, 64))	('PD-L1', 'Gene', '29126', (116, 121))	('PD-L1', 'Gene', '29126', (59, 64))	('miR-493', 'Var', (80, 87))	('c-JUN', 'Gene', (125, 130))
550565	32561638	Programmed cell death-1 (PD-1) is a cell surface receptor that is expressed on activated T cells as part of the adaptive immune response and which inhibits T-cell signaling when it binds to its ligands, PD-L1 and PD-L2.	('binds', 'Interaction', (181, 186))	('T-cell signaling', 'MPA', (156, 172))	('PD-1', 'Gene', (25, 29))	('PD-1', 'Gene', '5133', (25, 29))	('PD-L2', 'Gene', (213, 218))	('PD-L1', 'Var', (203, 208))	('PD-L2', 'Gene', '574057', (213, 218))	('inhibits', 'NegReg', (147, 155))
550568	32561638	In clinical trials, monoclonal antibodies against the immune checkpoint inhibitory receptor PD-1 have demonstrated objective responses in patients with multiple malignancies.	('PD-1', 'Gene', (92, 96))	('PD-1', 'Gene', '5133', (92, 96))	('malignancies', 'Disease', (161, 173))	('monoclonal', 'Var', (20, 30))	('patients', 'Species', '9606', (138, 146))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
550663	32561638	Based on the data from this study and other additional clinical trials, three phase 3 studies of tislelizumab as treatment for NSCLC have been initiated (NCT03358875, NCT03594747, and NCT03663205).	('NSCLC', 'Disease', (127, 132))	('NCT03663205', 'Var', (184, 195))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('NCT03358875', 'Var', (154, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('NCT03594747', 'Var', (167, 178))
550673	32561638	Although the underlying mechanisms remain unclear, emerging data suggest anti-PD-1 monotherapy may have increased antitumor activity in ESCC when compared with esophageal adenocarcinoma.	('PD-1', 'Gene', (78, 82))	('adenocarcinoma', 'Disease', (171, 185))	('PD-1', 'Gene', '5133', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('adenocarcinoma', 'Disease', 'MESH:D000230', (171, 185))	('increased', 'PosReg', (104, 113))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (160, 185))	('ESCC', 'Disease', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('monotherapy', 'Var', (83, 94))	('tumor', 'Disease', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
550675	32561638	In the KEYNOTE-181 study, the median OS for patients with CPS>=10 ESCC was 10.3 months compared with 6.7 months for those receiving standard-of-care chemotherapy; median OS for patients with CPS>=10 esophageal adenocarcinoma was 6.3 months for those receiving pembrolizumab versus 6.9 months for those receiving standard-of-care chemotherapy.	('patients', 'Species', '9606', (44, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (210, 224))	('patients', 'Species', '9606', (177, 185))	('CPS>=10', 'Var', (191, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('adenocarcinoma', 'Disease', (210, 224))	('pembrolizumab', 'Chemical', 'MESH:C582435', (260, 273))	('pembrolizumab', 'Var', (260, 273))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (199, 224))
550679	32561638	Three phase 3 trials have been initiated to evaluate the efficacy and safety of tislelizumab alone and in combination with chemotherapy/chemoradiotherapy in patients with ESCC (NCT03783442, NCT03430843, and NCT03957590).	('NCT03430843', 'Var', (190, 201))	('NCT03783442', 'Var', (177, 188))	('patients', 'Species', '9606', (157, 165))	('ESCC', 'Disease', (171, 175))	('NCT03957590', 'Var', (207, 218))
550698	31740710	Histological studies revealed that RAN + lime induced cancer in all the mice and interestingly only 20% developed cancer when PRE/EA-mixture was provided along with RAN + lime.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('lime', 'Species', '159033', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('EA', 'Chemical', 'MESH:C007650', (130, 132))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mice', 'Species', '10090', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('RAN + lime', 'Var', (35, 45))	('lime', 'Species', '159033', (171, 175))	('cancer', 'Disease', (114, 120))
550705	31740710	It has also been reported that Helicobactor pylori infection enhances development of gastric cancers caused by chewing and swallowing RAN and lime.	('gastric cancers', 'Disease', 'MESH:D013274', (85, 100))	('gastric cancers', 'Disease', (85, 100))	('gastric cancers', 'Phenotype', 'HP:0012126', (85, 100))	('Helicobactor', 'Disease', (31, 43))	('pylori', 'Species', '210', (44, 50))	('enhances', 'PosReg', (61, 69))	('development', 'CPA', (70, 81))	('lime', 'Species', '159033', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Helicobactor pylori infection', 'Phenotype', 'HP:0005202', (31, 60))	('infection', 'Var', (51, 60))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
550728	31740710	However, two out of 10 mice treated with PRE + RAN + lime showed carcinoma whereas 5 showed hyperplasia, a precancerous lesion in stomach.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('precancerous lesion', 'Disease', 'MESH:D011230', (107, 126))	('precancerous lesion', 'Disease', (107, 126))	('carcinoma', 'Disease', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('PRE + RAN + lime', 'Var', (41, 57))	('lesion in stomach', 'Phenotype', 'HP:0006753', (120, 137))	('hyperplasia', 'Disease', 'MESH:D006965', (92, 103))	('hyperplasia', 'Disease', (92, 103))	('carcinoma', 'Disease', 'MESH:D002277', (65, 74))	('lime', 'Species', '159033', (53, 57))	('mice', 'Species', '10090', (23, 27))
550730	31740710	After 260 days of treatment, cancer was observed to be induced in all the ten mice treated with RAN + lime whereas only 20% mice developed cancer after treatment with PRE + RAN + lime.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('lime', 'Species', '159033', (102, 106))	('cancer', 'Disease', (29, 35))	('lime', 'Species', '159033', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mice', 'Species', '10090', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('RAN + lime', 'Var', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('mice', 'Species', '10090', (78, 82))	('cancer', 'Disease', (139, 145))
550772	31740710	Further, transition metal ions such as Cu-2+, Mn++, Fe2+ and Fe3+ present in RAN and betel-leaf, facilitate the production of more reactive oxygen species which in turn contributes to initiation and promotion of cancer.	('promotion', 'PosReg', (199, 208))	('oxygen', 'Chemical', 'MESH:D010100', (140, 146))	('Fe3+', 'Chemical', 'MESH:D007501', (61, 65))	('Cu-2+', 'Chemical', 'MESH:D003300', (39, 44))	('production of more reactive oxygen species', 'MPA', (112, 154))	('Mn++', 'Var', (46, 50))	('Fe3+', 'Var', (61, 65))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('facilitate', 'PosReg', (97, 107))	('contributes', 'Reg', (169, 180))	('Fe2+', 'Chemical', 'MESH:D007501', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
550786	31740710	Overexpression of Securin has been associated with the aneuploidy formation due to chromatid mis-segregation and is demonstrated in multiple cancer types.	('Securin', 'Gene', '30939', (18, 25))	('aneuploidy', 'Disease', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('associated', 'Reg', (35, 45))	('chromatid mis-segregation', 'CPA', (83, 108))	('Securin', 'Gene', (18, 25))	('aneuploidy', 'Disease', 'MESH:D000782', (55, 65))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
550798	31740710	This in vivo study thus demonstrated that the presence of either PRE or ECGU mitigates the RAN + lime induced tumor-initiating processes.	('RAN + lime', 'MPA', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mitigates', 'NegReg', (77, 86))	('lime', 'Species', '159033', (97, 101))	('ECGU', 'Var', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
550801	31740710	Further in-depth studies are needed to identify the driver pathways targeted by PRE or ECGU in inflammation-induced tumorigenesis.	('inflammation', 'Disease', 'MESH:D007249', (95, 107))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('inflammation', 'Disease', (95, 107))	('ECGU', 'Var', (87, 91))	('tumor', 'Disease', (116, 121))
550836	31740710	Then the proteins were transferred to a polyvinylidene difluoride membrane (Sigma) and probed with 1:1000 dilution of a mouse monoclonal antibody against p53 (PAb 240; ab-26; Abcam, USA), Securin (DCS-280; ab3305; Abcam, USA) and beta-actin (AC-15; ab6276; Abcam, USA).	('polyvinylidene difluoride', 'Chemical', 'MESH:C024865', (40, 65))	('DCS-280', 'Var', (197, 204))	('Securin', 'Gene', (188, 195))	('p53', 'Gene', '22060', (154, 157))	('beta-actin', 'Gene', '11461', (230, 240))	('Securin', 'Gene', '30939', (188, 195))	('p53', 'Gene', (154, 157))	('beta-actin', 'Gene', (230, 240))	('mouse', 'Species', '10090', (120, 125))
550854	31612012	Recently, the application of next-generation sequencing in ESCC allowed for the identification of several processes that may contribute to carcinogenesis and disease prognosis, including driver gene mutations, changes in molecular and protein dynamics, dysregulation of cellular signaling pathways and alterations of the tumor microenvironment.	('dysregulation', 'Var', (253, 266))	('carcinogenesis', 'Disease', (139, 153))	('contribute', 'Reg', (125, 135))	('ESCC', 'Disease', 'MESH:C562729', (59, 63))	('tumor', 'Disease', (321, 326))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('changes', 'Reg', (210, 217))	('ESCC', 'Disease', (59, 63))	('mutations', 'Var', (199, 208))	('carcinogenesis', 'Disease', 'MESH:D063646', (139, 153))	('cellular signaling pathways', 'Pathway', (270, 297))
550874	31612012	The use of anti-PD-1 and anti-PD-L1 monoclonal antibodies (mAbs) is therefore an effective way to maintain the activation of the effector function of CD8+ T cells, and to improve the clinical outcome of patients with ESCC.	('CD8', 'Gene', (150, 153))	('PD-1', 'Gene', '5133', (16, 20))	('CD8', 'Gene', '925', (150, 153))	('ESCC', 'Disease', 'MESH:C562729', (217, 221))	('improve', 'PosReg', (171, 178))	('ESCC', 'Disease', (217, 221))	('patients', 'Species', '9606', (203, 211))	('anti-PD-L1', 'Var', (25, 35))	('PD-1', 'Gene', (16, 20))
550876	31612012	The majority of these studies reported that high expression of PD-L1 is associated with poor prognosis in these patients.	('high', 'Var', (44, 48))	('PD-L1', 'Gene', (63, 68))	('patients', 'Species', '9606', (112, 120))
550877	31612012	Wang et al recruited 180 patients with ESCC and reported that patients with high expression of PD-L1 exhibited worse clinical outcome compared with patients with low expression (P=0.0010).	('patients', 'Species', '9606', (148, 156))	('ESCC', 'Disease', (39, 43))	('PD-L1', 'Gene', (95, 100))	('patients', 'Species', '9606', (25, 33))	('high expression', 'Var', (76, 91))	('ESCC', 'Disease', 'MESH:C562729', (39, 43))	('patients', 'Species', '9606', (62, 70))
550893	31612012	The results revealed that the median PFS was 2 months (95% CI, 1.9-2.1) and the ORR was 14% (95% CI, 5-17%) in patients with high PD-L1 expression.	('high', 'Var', (125, 129))	('PD-L1', 'Gene', (130, 135))	('patients', 'Species', '9606', (111, 119))
550921	31612012	In addition, the median percentage of the lesion volume was reduced to a greater extent following anti-PD-L1 treatment compared with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) treatment.	('CTLA-4', 'Gene', (183, 189))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (138, 181))	('anti-PD-L1', 'Var', (98, 108))	('reduced', 'NegReg', (60, 67))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (138, 181))	('CTLA-4', 'Gene', '1493', (183, 189))
550934	31612012	Patients with high PD-L1 expression tend to respond well to anti-PD1/PD-L1 mAbs and exhibit a significant increase in OS rate.	('PD1', 'Gene', (65, 68))	('PD-L1', 'Gene', (19, 24))	('PD1', 'Gene', '5133', (65, 68))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('increase', 'PosReg', (106, 114))	('OS rate', 'MPA', (118, 125))
550972	31598372	An LATG was indicated for tumors with cT1, cN0 (or recently, due to the improved skill, cT1, 2, or 3 without esophageal invasion and lymph node metastasis confined to the perigastric nodes), according to the Japanese Classification of Gastric Carcinoma, 3rd English edition.	('Carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('cT1', 'Gene', (38, 41))	('cN0', 'Var', (43, 46))	('cT1', 'Gene', '1489', (88, 91))	('Gastric Carcinoma', 'Disease', 'MESH:D013274', (235, 252))	('cT1, 2', 'Gene', '266740;1489;30848', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('cT1', 'Gene', (88, 91))	('Gastric Carcinoma', 'Phenotype', 'HP:0012126', (235, 252))	('cT1', 'Gene', '1489', (38, 41))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('Gastric Carcinoma', 'Disease', (235, 252))	('tumors', 'Disease', (26, 32))
550973	31598372	As previously described, an LAPG was indicated for tumors with cT1, cN0 if the distal half of the stomach could be preserved.	('cN0', 'Var', (68, 71))	('cT1', 'Gene', (63, 66))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('cT1', 'Gene', '1489', (63, 66))	('LAPG', 'Chemical', 'MESH:C068451', (28, 32))
551100	30828566	Accumulated clinical studies demonstrated a closely association with high lymphocytes and better patient outcomes in several types of human cancer.	('high lymphocytes', 'Var', (69, 85))	('human', 'Species', '9606', (134, 139))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patient', 'Species', '9606', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
551130	30372581	LR004-VC-MMAE showed a potent antitumor effect against ESCC and other EGFR-positive cells with IC 50 values of nM concentrations in vitro.	('LR004', 'Chemical', '-', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('ESCC', 'Disease', (55, 59))	('LR004-VC-MMAE', 'Var', (0, 13))	('MMAE', 'Chemical', 'MESH:C495575', (9, 13))
551131	30372581	The in vivo antitumor effects of LR004-VC-MMAE were investigated in ESCC KYSE520 and A431 xenograft nude mice models.	('nude mice', 'Species', '10090', (100, 109))	('A431', 'CellLine', 'CVCL:0037', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('LR004-VC-MMAE', 'Var', (33, 46))	('MMAE', 'Chemical', 'MESH:C495575', (42, 46))	('tumor', 'Disease', (16, 21))	('LR004', 'Chemical', '-', (33, 38))
551134	30372581	In addition, the tumors also remained responsive to LR004-VC-MMAE for large tumor experiments (tumor volume 400-500 mm3).	('LR004-VC-MMAE', 'Var', (52, 65))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('MMAE', 'Chemical', 'MESH:C495575', (61, 65))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('LR004', 'Chemical', '-', (52, 57))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (95, 100))
551135	30372581	The study results demonstrated that LR004-VC-MMAE could be a potential therapeutic agent for ESCC and other EGFR-expressing malignancies.	('LR004', 'Chemical', '-', (36, 41))	('MMAE', 'Chemical', 'MESH:C495575', (45, 49))	('malignancies', 'Disease', 'MESH:D009369', (124, 136))	('LR004-VC-MMAE', 'Var', (36, 49))	('malignancies', 'Disease', (124, 136))	('ESCC', 'Disease', (93, 97))
551140	30372581	Anti-EGFR antibodies exert antitumor effects by binding the receptor at the cell surface to interfere with ligand binding, which leads to the inhibition of its downstream signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('inhibition', 'NegReg', (142, 152))	('interfere', 'NegReg', (92, 101))	('tumor', 'Disease', (31, 36))	('downstream signaling pathway', 'Pathway', (160, 188))	('ligand', 'MPA', (107, 113))	('binding', 'Interaction', (48, 55))	('Anti-EGFR', 'Gene', (0, 9))	('receptor', 'Protein', (60, 68))	('antibodies', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
551144	30372581	ABT-414, which is composed of the monomethyl auristatin F attached to an anti-EGFRvIII antibody via a cleavable linker, has shown significant efficacy against tumors expressing amplified EGFR and EGFRvIII in phase III (van den Bent et al., 2017).	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('monomethyl', 'Chemical', '-', (34, 44))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('EGFR', 'Gene', (187, 191))	('EGFRvIII', 'Gene', (196, 204))	('amplified', 'Var', (177, 186))	('ABT', 'Chemical', 'MESH:C002502', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('auristatin F', 'Chemical', '-', (45, 57))
551151	30372581	LR004 is an anti-EGFR antibody, with the advantages of improved safety and fewer hypersensitivity reactions (Eric, 2016).	('LR004', 'Chemical', '-', (0, 5))	('hypersensitivity reactions', 'Disease', (81, 107))	('improved', 'PosReg', (55, 63))	('hypersensitivity reactions', 'Disease', 'MESH:D004342', (81, 107))	('LR004', 'Var', (0, 5))
551153	30372581	In addition, LR004 also demonstrates a long serum half-life and high thermostability.	('thermostability', 'MPA', (69, 84))	('LR004', 'Chemical', '-', (13, 18))	('LR004', 'Var', (13, 18))
551154	30372581	When used as a single agent, LR004 hampers the growth of several tumor xenografts, such as epidermoid carcinoma (A431), colon cancer (GEO), and breast cancer (MDA-MB-468).	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('breast cancer', 'Disease', (144, 157))	('A431', 'CellLine', 'CVCL:0037', (113, 117))	('tumor', 'Disease', (65, 70))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('epidermoid carcinoma', 'Disease', 'MESH:D002294', (91, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('growth', 'CPA', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('LR004', 'Var', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('LR004', 'Chemical', '-', (29, 34))	('colon cancer', 'Disease', (120, 132))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (159, 169))	('hampers', 'NegReg', (35, 42))	('epidermoid carcinoma', 'Disease', (91, 111))
551158	30372581	Then, we screened various types of tumor cells with different EGFR expression levels and assessed the antitumor activities of LR004-VC-MMAE in vitro.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('LR004', 'Chemical', '-', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('LR004-VC-MMAE', 'Var', (126, 139))	('MMAE', 'Chemical', 'MESH:C495575', (135, 139))	('tumor', 'Disease', (106, 111))
551159	30372581	Moreover, we mainly evaluated the functional characterization and antitumor activities of LR004-VC-MMAE in ESCC cell lines and A431 cells in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('LR004-VC-MMAE', 'Var', (90, 103))	('MMAE', 'Chemical', 'MESH:C495575', (99, 103))	('A431', 'CellLine', 'CVCL:0037', (127, 131))	('tumor', 'Disease', (70, 75))	('LR004', 'Chemical', '-', (90, 95))	('ESCC', 'Disease', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
551160	30372581	Based on these findings, the ADC of LR004-VC-MMAE could be an enlightened EGFR-targeted therapy for ESCC and other tumors, with its potent effectiveness.	('LR004', 'Chemical', '-', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('MMAE', 'Chemical', 'MESH:C495575', (45, 49))	('tumors', 'Disease', (115, 121))	('ESCC', 'Disease', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('LR004-VC-MMAE', 'Var', (36, 49))
551161	30372581	The preliminary PK profile would provide the basis for further studies of LR004-VC-MMAE with cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('LR004-VC-MMAE', 'Var', (74, 87))	('MMAE', 'Chemical', 'MESH:C495575', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('LR004', 'Chemical', '-', (74, 79))
551182	30372581	Size-exclusion chromatography analyses were used to detect purity of LR004 and LR004-VC-MMAE.	('LR004', 'Var', (69, 74))	('LR004', 'Chemical', '-', (79, 84))	('LR004', 'Chemical', '-', (69, 74))	('LR004-VC-MMAE', 'Var', (79, 92))	('MMAE', 'Chemical', 'MESH:C495575', (88, 92))
551186	30372581	A total of 3 x 105 cells were incubated with various concentrations (3, 1, 0.3, 0.1, 0.03, 0.01, and 0.003 mug mL-1) of LR004 and LR004-VC-MMAE in PBS/1% FBS for 1 h at 4  C. The cells were then washed three times with PBS and incubated with 1 : 100 FITC-labeled goat anti-human IgG for 1 h at 4  C. The labeled cells were washed, resuspended in PBS, and analyzed by a FACSCalibur (BD Biosciences, San Jose, CA, USA).	('LR004', 'Chemical', '-', (120, 125))	('FBS', 'Disease', 'MESH:D005198', (154, 157))	('goat', 'Species', '9925', (263, 267))	('mL-1', 'Gene', (111, 115))	('human', 'Species', '9606', (273, 278))	('PBS', 'Chemical', 'MESH:D007854', (147, 150))	('FITC', 'Chemical', 'MESH:D016650', (250, 254))	('PBS', 'Chemical', 'MESH:D007854', (346, 349))	('PBS', 'Chemical', 'MESH:D007854', (219, 222))	('mL-1', 'Gene', '16728', (111, 115))	('FBS', 'Disease', (154, 157))	('LR004-VC-MMAE', 'Var', (130, 143))	('LR004', 'Var', (120, 125))	('MMAE', 'Chemical', 'MESH:C495575', (139, 143))	('LR004', 'Chemical', '-', (130, 135))
551187	30372581	The CM5 sensor chip was pre-immobilized with LR004 and LR004-VC-MMAE at a concentration of 1 mug mL-1.	('MMAE', 'Chemical', 'MESH:C495575', (64, 68))	('mL-1', 'Gene', (97, 101))	('LR004-VC-MMAE', 'Var', (55, 68))	('LR004', 'Chemical', '-', (45, 50))	('mL-1', 'Gene', '16728', (97, 101))	('LR004', 'Chemical', '-', (55, 60))
551190	30372581	The KYSE520 cells were seeded at a density of 1 x 104 cells well-1 and incubated for 24 h; they were then treated with 5 mug mL-1 LR004 and LR004-VC-MMAE for 30 min at 4  C or for 0.5 and 10 h at 37  C. After washing the wells with PBS, the cells were exposed on the chamber coverslip by the cytospin, fixed with 4% paraformaldehyde for 10 min, and permeabilized with 0.2% Triton X-100 for 5 min.	('Triton X-100', 'Chemical', 'MESH:D017830', (373, 385))	('LR004', 'Chemical', '-', (140, 145))	('mL-1', 'Gene', (125, 129))	('MMAE', 'Chemical', 'MESH:C495575', (149, 153))	('mL-1', 'Gene', '16728', (125, 129))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (316, 332))	('LR004-VC-MMAE', 'Var', (140, 153))	('PBS', 'Chemical', 'MESH:D007854', (232, 235))	('LR004', 'Chemical', '-', (130, 135))
551197	30372581	Nascent DNA synthesis was detected with anti-BrdUrd FITC, and total DNA content was detected with PI.	('FITC', 'Chemical', 'MESH:D016650', (52, 56))	('detected', 'Reg', (26, 34))	('anti-BrdUrd', 'Var', (40, 51))
551209	30372581	Therapy was started on the seventh day, when the tumor volumes reached approximately 100 mm3; the mice were randomly divided into 7 groups (n = 6 per group) and were treated with LR004 (15 mg kg-1), LR004-VC-MMAE (1, 5, 10, 15 mg kg-1), and MMAE (0.3 mg kg-1) every 4 days for a total of six injections.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('MMAE', 'Chemical', 'MESH:C495575', (208, 212))	('LR004', 'Chemical', '-', (179, 184))	('LR004', 'Chemical', '-', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('MMAE', 'Chemical', 'MESH:C495575', (241, 245))	('LR004', 'Var', (179, 184))	('mice', 'Species', '10090', (98, 102))	('LR004-VC-MMAE', 'Var', (199, 212))
551210	30372581	Meanwhile, a large tumor group for the A431 tumor xenograft model was established on the tenth day, when the tumor volume reached a size of 400-500 mm3; the mice were given an intravenous injection (LR004-VC-MMAE 15 mg kg-1) every 4 days for a total of six injections.	('A431', 'CellLine', 'CVCL:0037', (39, 43))	('MMAE', 'Chemical', 'MESH:C495575', (208, 212))	('LR004', 'Chemical', '-', (199, 204))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (109, 114))	('LR004-VC-MMAE', 'Var', (199, 212))
551235	30372581	The SEC-HPLC comparison of the conjugate to the LR004 demonstrated a slight increase in both retention time (LR004,RT = 3.998 s;LR004-VC-MMAE, RT = 4.031 s) and peak tailing for the ADC (Fig.	('LR004', 'Chemical', '-', (109, 114))	('MMAE', 'Chemical', 'MESH:C495575', (137, 141))	('increase', 'PosReg', (76, 84))	('retention time', 'MPA', (93, 107))	('LR004-VC-MMAE', 'Var', (128, 141))	('LR004', 'Chemical', '-', (48, 53))	('peak tailing', 'MPA', (161, 173))	('LR004', 'Var', (109, 114))	('LR004', 'Chemical', '-', (128, 133))
551238	30372581	The binding characteristics of LR004 and LR004-VC-MMAE were assessed by ELISA, Biacore, and FACS analysis.	('binding', 'Interaction', (4, 11))	('LR004', 'Chemical', '-', (41, 46))	('LR004', 'Chemical', '-', (31, 36))	('LR004-VC-MMAE', 'Var', (41, 54))	('MMAE', 'Chemical', 'MESH:C495575', (50, 54))
551240	30372581	The ELISA-based binding assay revealed that LR004 and LR004-VC-MMAE could bind to the recombinant human EGFR antigen in a concentration-dependent manner, and the binding ability of LR004-VC-MMAE showed a minimal decrease compared to LR004 (Fig.	('LR004', 'Chemical', '-', (181, 186))	('LR004', 'Chemical', '-', (54, 59))	('LR004', 'Chemical', '-', (233, 238))	('MMAE', 'Chemical', 'MESH:C495575', (63, 67))	('bind', 'Interaction', (74, 78))	('binding', 'Interaction', (162, 169))	('LR004-VC-MMAE', 'Var', (181, 194))	('human', 'Species', '9606', (98, 103))	('MMAE', 'Chemical', 'MESH:C495575', (190, 194))	('LR004', 'Chemical', '-', (44, 49))
551243	30372581	The binding of LR004 and LR004-VC-MMAE to the cell surface EGFR antigen was tested by FACS.	('LR004-VC-MMAE', 'Var', (25, 38))	('MMAE', 'Chemical', 'MESH:C495575', (34, 38))	('binding', 'Interaction', (4, 11))	('LR004', 'Chemical', '-', (25, 30))	('LR004', 'Chemical', '-', (15, 20))
551247	30372581	2D), suggesting that the LR004 conjugated with MMAE did not alter the binding ability.	('MMAE', 'Chemical', 'MESH:C495575', (47, 51))	('LR004', 'Chemical', '-', (25, 30))	('LR004', 'Var', (25, 30))	('binding', 'Interaction', (70, 77))
551248	30372581	LR004-VC-MMAE and MMAE displayed significant cytotoxicity against various tumor cells expressing EGFR, with IC50 values of 0.01-8 nm (Table 1).	('LR004', 'Chemical', '-', (0, 5))	('cytotoxicity', 'Disease', 'MESH:D064420', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('EGFR', 'Gene', (97, 101))	('MMAE', 'Chemical', 'MESH:C495575', (18, 22))	('tumor', 'Disease', (74, 79))	('cytotoxicity', 'Disease', (45, 57))	('LR004-VC-MMAE', 'Var', (0, 13))	('MMAE', 'Chemical', 'MESH:C495575', (9, 13))
551250	30372581	In the NSCLC cell lines, LR004-VC-MMAE inhibited the viability of the HCC827 and A549 with the IC50 of 0.302 +- 0.088 nm and 5.259 +- 1.127 nm, respectively.	('LR004-VC-MMAE', 'Var', (25, 38))	('inhibited', 'NegReg', (39, 48))	('NSCLC', 'Disease', (7, 12))	('MMAE', 'Chemical', 'MESH:C495575', (34, 38))	('NSCLC', 'Disease', 'MESH:D002289', (7, 12))	('LR004', 'Chemical', '-', (25, 30))	('HCC827', 'CellLine', 'CVCL:2063', (70, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (7, 12))	('viability', 'CPA', (53, 62))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
551251	30372581	In the breast cancer cell lines, LR004-VC-MMAE inhibited the viability of the MDA-MB-468 and MCF-7 with the IC50 of 0.340 +- 0.252 nm and 2.935 +- 0.983 nm, respectively.	('inhibited', 'NegReg', (47, 56))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (78, 88))	('LR004-VC-MMAE', 'Var', (33, 46))	('breast cancer', 'Disease', (7, 20))	('MCF-7', 'CellLine', 'CVCL:0031', (93, 98))	('MMAE', 'Chemical', 'MESH:C495575', (42, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('LR004', 'Chemical', '-', (33, 38))	('viability', 'CPA', (61, 70))
551254	30372581	3A, LR004-VC-MMAE inhibited the viability of the KYSE520 and KYSE150 cells in a concentration-dependent manner, and the IC50 values were 1.852 +- 0.617 nm and 4.440 +- 0.208 nm, respectively.	('viability', 'CPA', (32, 41))	('LR004', 'Chemical', '-', (4, 9))	('MMAE', 'Chemical', 'MESH:C495575', (13, 17))	('inhibited', 'NegReg', (18, 27))	('LR004-VC-MMAE', 'Var', (4, 17))	('KYSE150', 'CellLine', 'CVCL:1348', (61, 68))
551255	30372581	However, LR004 had a weak inhibitory effect (IC50 > 6 nm), implying that the cytotoxicity of LR004-VC-MMAE in vitro results from the delivery of MMAE rather than from the efficacy of the antibody.	('LR004-VC-MMAE', 'Var', (93, 106))	('MMAE', 'Chemical', 'MESH:C495575', (102, 106))	('cytotoxicity', 'Disease', (77, 89))	('LR004', 'Chemical', '-', (93, 98))	('LR004', 'Chemical', '-', (9, 14))	('cytotoxicity', 'Disease', 'MESH:D064420', (77, 89))	('MMAE', 'Chemical', 'MESH:C495575', (145, 149))
551256	30372581	To confirm the on-target killing by LR004-VC-MMAE, rituximab-VC-MMAE (CD20-targeting ADC) was used as a negative control, and its minimal cytotoxic activity was observed in the KYSE520 and KYSE150 cells.	('LR004', 'Chemical', '-', (36, 41))	('MMAE', 'Chemical', 'MESH:C495575', (64, 68))	('rituximab-VC-MMAE', 'Chemical', '-', (51, 68))	('MMAE', 'Chemical', 'MESH:C495575', (45, 49))	('KYSE150', 'CellLine', 'CVCL:1348', (189, 196))	('CD20', 'Gene', (70, 74))	('CD20', 'Gene', '931', (70, 74))	('LR004-VC-MMAE', 'Var', (36, 49))
551258	30372581	These results demonstrated that LR004-VC-MMAE had selectivity for EGFR-positive or EGFR-negative cells.	('MMAE', 'Chemical', 'MESH:C495575', (41, 45))	('LR004-VC-MMAE', 'Var', (32, 45))	('EGFR-positive', 'Gene', (66, 79))	('LR004', 'Chemical', '-', (32, 37))
551261	30372581	The internalization and lysosomal localization of LR004 and LR004-VC-MMAE were detected in the KYSE520 cells by laser scanning confocal microscope.	('LR004', 'Chemical', '-', (50, 55))	('LR004-VC-MMAE', 'Var', (60, 73))	('LR004', 'Var', (50, 55))	('MMAE', 'Chemical', 'MESH:C495575', (69, 73))	('LR004', 'Chemical', '-', (60, 65))
551262	30372581	LR004 and LR004-VC-MMAE were bound to the cell peripheral membrane of KYSE520 cells at 4  C for 30 min, while the anti-EGFR-IgG staining (green) was not localized inside the cells or colocalized with the lysosomal markers.	('LR004', 'Chemical', '-', (0, 5))	('LR004', 'Var', (0, 5))	('LR004', 'Chemical', '-', (10, 15))	('LR004-VC-MMAE', 'Var', (10, 23))	('MMAE', 'Chemical', 'MESH:C495575', (19, 23))
551263	30372581	4A), with LR004 and LR004-VC-MMAE colocalized within Lamp-1.	('Lamp-1', 'Gene', (53, 59))	('LR004-VC-MMAE', 'Var', (20, 33))	('LR004', 'Chemical', '-', (20, 25))	('LR004', 'Chemical', '-', (10, 15))	('Lamp-1', 'Gene', '3916', (53, 59))	('LR004', 'Var', (10, 15))	('MMAE', 'Chemical', 'MESH:C495575', (29, 33))
551264	30372581	At 10 h, internalized LR004 and LR004-VC-MMAE was still present in the lysosomes, indicating that both LR004 and LR004-VC-MMAE were rapidly internalized into the cells and continuously transported to the lysosomes in KYSE520 cells.	('LR004', 'Chemical', '-', (113, 118))	('MMAE', 'Chemical', 'MESH:C495575', (122, 126))	('LR004', 'Chemical', '-', (22, 27))	('MMAE', 'Chemical', 'MESH:C495575', (41, 45))	('LR004', 'Chemical', '-', (103, 108))	('LR004-VC-MMAE', 'Var', (113, 126))	('LR004', 'Chemical', '-', (32, 37))	('LR004', 'Var', (103, 108))
551265	30372581	The in vivo tissue distribution and targeting accumulation capability of LR004, LR004-VC-MMAE, and rituximab-VC-MMAE were evaluated in a nude mice KYSE520 xenograft model via an optical molecular imaging system.	('MMAE', 'Chemical', 'MESH:C495575', (112, 116))	('nude mice', 'Species', '10090', (137, 146))	('LR004', 'Var', (73, 78))	('MMAE', 'Chemical', 'MESH:C495575', (89, 93))	('LR004', 'Chemical', '-', (80, 85))	('rituximab-VC-MMAE', 'Chemical', '-', (99, 116))	('LR004', 'Chemical', '-', (73, 78))	('targeting accumulation', 'MPA', (36, 58))
551266	30372581	After IV administration to the mice in the three Dylight 680-labeled groups at a dosage of 20 mg kg-1 each, LR004 and LR004-VC-MMAE showed a higher fluorescence than rituximab-VC-MMAE within 24 h. Then, the fluorescence signal of LR004 and LR004-VC-MMAE was initially visualized in the tumor sites within 48 h, and the tumor-located image was clearly maintained for 6 days (Fig.	('tumor', 'Disease', (319, 324))	('LR004', 'Chemical', '-', (230, 235))	('MMAE', 'Chemical', 'MESH:C495575', (127, 131))	('rituximab-VC-MMAE', 'Chemical', '-', (166, 183))	('tumor', 'Disease', (286, 291))	('LR004', 'Chemical', '-', (240, 245))	('MMAE', 'Chemical', 'MESH:C495575', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('mice', 'Species', '10090', (31, 35))	('LR004', 'Chemical', '-', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('LR004', 'Var', (230, 235))	('LR004', 'Chemical', '-', (118, 123))	('fluorescence', 'MPA', (207, 219))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('LR004-VC-MMAE', 'Var', (240, 253))	('MMAE', 'Chemical', 'MESH:C495575', (249, 253))
551268	30372581	As described above, there was strong selective tumor accumulation and localization in the EGFR-positive KYSE520 tumors with LR004 and LR004-VC-MMAE.	('LR004', 'Chemical', '-', (134, 139))	('tumor', 'Disease', (47, 52))	('MMAE', 'Chemical', 'MESH:C495575', (143, 147))	('localization', 'MPA', (70, 82))	('EGFR-positive KYSE520', 'Gene', (90, 111))	('LR004', 'Var', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('KYSE520', 'Gene', (104, 111))	('LR004', 'Chemical', '-', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('LR004-VC-MMAE', 'Var', (134, 147))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
551269	30372581	The EGFR-overexpressing ESCC KYSE520 xenograft model was designed to assess the ability of LR004-VC-MMAE to mediate antitumor activity.	('MMAE', 'Chemical', 'MESH:C495575', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (120, 125))	('LR004-VC-MMAE', 'Var', (91, 104))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('LR004', 'Chemical', '-', (91, 96))
551277	30372581	In addition, we assessed the toxicity of LR004 and LR004-VC-MMAE at a dosage of 15 mg kg-1.	('LR004', 'Var', (41, 46))	('LR004-VC-MMAE', 'Var', (51, 64))	('LR004', 'Chemical', '-', (41, 46))	('LR004', 'Chemical', '-', (51, 56))	('toxicity', 'Disease', 'MESH:D064420', (29, 37))	('toxicity', 'Disease', (29, 37))	('MMAE', 'Chemical', 'MESH:C495575', (60, 64))
551279	30372581	These results confirmed that LR004 and its ADC has a low systemic toxicity in the mice model.	('mice', 'Species', '10090', (82, 86))	('LR004', 'Var', (29, 34))	('toxicity', 'Disease', 'MESH:D064420', (66, 74))	('LR004', 'Chemical', '-', (29, 34))	('toxicity', 'Disease', (66, 74))
551281	30372581	LR004-VC-MMAE significantly delayed tumor growth at the 5, 10, and 15 mg kg-1 dose levels compared with the control group on day 40 (P < 0.0001).	('LR004', 'Chemical', '-', (0, 5))	('delayed', 'NegReg', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('LR004-VC-MMAE', 'Var', (0, 13))	('MMAE', 'Chemical', 'MESH:C495575', (9, 13))
551282	30372581	From days 40 to 60, all the animals treated with LR004-VC-MMAE in the three dose groups possessed tumors less than 33 mm3 in size and even appeared tumor complete regressions.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('LR004-VC-MMAE', 'Var', (49, 62))	('less', 'NegReg', (105, 109))	('tumor', 'Disease', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('LR004', 'Chemical', '-', (49, 54))	('MMAE', 'Chemical', 'MESH:C495575', (58, 62))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
551284	30372581	In contrast, LR004 (15 mg kg-1), as a single agent, suppressed tumor growth in this model on day 60 but had a limited therapeutic effect compared with LR004-VC-MMAE (average tumor volume 399 +- 246 mm3; P < 0.01 compared with the three ADC groups), indicating that the conjugation of MMAE significantly increased potency.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', (63, 68))	('MMAE', 'Chemical', 'MESH:C495575', (284, 288))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('LR004', 'Chemical', '-', (13, 18))	('LR004', 'Chemical', '-', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('suppressed', 'NegReg', (52, 62))	('MMAE', 'Chemical', 'MESH:C495575', (160, 164))	('potency', 'MPA', (313, 320))	('LR004', 'Var', (13, 18))
551285	30372581	By H&E, no toxico-pathological changes were found in various organs after treatment with LR004 and LR004-VC-MMAE at the maximum tolerated dosage of 15 mg kg-1 after six injections (Fig.	('LR004', 'Chemical', '-', (99, 104))	('and', 'Var', (95, 98))	('LR004', 'Chemical', '-', (89, 94))	('MMAE', 'Chemical', 'MESH:C495575', (108, 112))	('with', 'Var', (84, 88))
551286	30372581	For the second study, mice were treated with either a dose of 15 mg kg-1 of LR004-VC-MMAE or a control when the tumor volume reached a size of 400-500 mm3.	('LR004-VC-MMAE', 'Var', (76, 89))	('MMAE', 'Chemical', 'MESH:C495575', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('LR004', 'Chemical', '-', (76, 81))	('tumor', 'Disease', (112, 117))	('mice', 'Species', '10090', (22, 26))
551287	30372581	The control group showed progressive tumor growth, with an average TV of more than 2500 mm3 within 40 days, whereas LR004-VC-MMAE suppressed tumor growth or even reduced tumor size, and the tumor inhibition rate increased to 87.2% (average tumor volume 370 +- 62 mm3; P < 0.0001).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('reduced', 'NegReg', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (170, 175))	('LR004-VC-MMAE', 'Var', (116, 129))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (190, 195))	('MMAE', 'Chemical', 'MESH:C495575', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('suppressed', 'NegReg', (130, 140))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (37, 42))	('LR004', 'Chemical', '-', (116, 121))
551290	30372581	The PK profile of total antibody of LR004-VC-MMAE had the elimination half-life (t1/2) of 113.61 +- 20.07 h (~ 5 days) and the clearance (CL) at rates of 0.88 +- 0.05 mL h-1 kg-1 in vivo.	('LR004', 'Chemical', '-', (36, 41))	('elimination half-life', 'MPA', (58, 79))	('MMAE', 'Chemical', 'MESH:C495575', (45, 49))	('clearance', 'MPA', (127, 136))	('LR004-VC-MMAE', 'Var', (36, 49))
551292	30372581	Observed free MMAE concentrations were generally very low, the pharmacokinetics data revealed that concentrations of free MMAE declined to 2.4 +- 1.84 ng mL-1 over 24 h. However, LR004-VC-MMAE showed a higher concentration of conjugated MMAE at time points ranging from 0.5 h to 5 days.	('LR004', 'Chemical', '-', (179, 184))	('MMAE', 'Chemical', 'MESH:C495575', (188, 192))	('mL-1', 'Gene', '16728', (154, 158))	('MMAE', 'Chemical', 'MESH:C495575', (122, 126))	('MMAE', 'Chemical', 'MESH:C495575', (14, 18))	('MMAE', 'Chemical', 'MESH:C495575', (237, 241))	('conjugated', 'MPA', (226, 236))	('higher', 'PosReg', (202, 208))	('mL-1', 'Gene', (154, 158))	('LR004-VC-MMAE', 'Var', (179, 192))	('concentration', 'MPA', (209, 222))
551293	30372581	The PK profile of conjugated MMAE of LR004-VC-MMAE had the elimination half-life (t1/2) of 33.31 +- 6.15 h and the clearance (CL) at rates of 3.67 +- 0.50 L h-1 kg-1 in vivo.	('elimination half-life', 'MPA', (59, 80))	('LR004-VC-MMAE', 'Var', (37, 50))	('clearance', 'MPA', (115, 124))	('MMAE', 'Chemical', 'MESH:C495575', (46, 50))	('LR004', 'Chemical', '-', (37, 42))	('MMAE', 'Chemical', 'MESH:C495575', (29, 33))
551298	30372581	First, LR004 was bound to various forms of the EGFR antigen with a high affinity.	('LR004', 'Chemical', '-', (7, 12))	('LR004', 'Var', (7, 12))	('bound', 'Interaction', (17, 22))
551300	30372581	Second, LR004 was rapidly internalized into the cell followed by localization in the lysosomes.	('LR004', 'Chemical', '-', (8, 13))	('LR004', 'Var', (8, 13))	('localization', 'MPA', (65, 77))
551301	30372581	Therefore, we hypothesized that LR004 could directly delivery the highly potent antitubulin drug MMAE to display a potential antitumor activity.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('LR004', 'Var', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MMAE', 'Chemical', 'MESH:C495575', (97, 101))	('tumor', 'Disease', (129, 134))	('LR004', 'Chemical', '-', (32, 37))
551306	30372581	LR004-VC-MMAE had a theoretical DAR distribution of 0, 2, 4, 6, and 8 isoforms (average DAR is approximately 4.0), and the coupling technology was shown to be stable and controllable.	('LR004', 'Chemical', '-', (0, 5))	('DAR', 'Gene', (32, 35))	('DAR', 'Gene', (88, 91))	('DAR', 'Gene', '146', (32, 35))	('DAR', 'Gene', '146', (88, 91))	('LR004-VC-MMAE', 'Var', (0, 13))	('MMAE', 'Chemical', 'MESH:C495575', (9, 13))
551309	30372581	In this study, we evaluated the functional characterization and antitumor activities of LR004-VC-MMAE on ESCC cell lines in vitro and in vivo.	('tumor', 'Disease', (68, 73))	('ESCC', 'Disease', (105, 109))	('LR004-VC-MMAE', 'Var', (88, 101))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('MMAE', 'Chemical', 'MESH:C495575', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('LR004', 'Chemical', '-', (88, 93))
551311	30372581	We further explored whether LR004-conjugated MMAE could significantly improve the antitumor activity in A431 model.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('LR004', 'Chemical', '-', (28, 33))	('A431', 'CellLine', 'CVCL:0037', (104, 108))	('tumor', 'Disease', (86, 91))	('LR004-conjugated', 'Var', (28, 44))	('MMAE', 'Chemical', 'MESH:C495575', (45, 49))	('improve', 'PosReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
551312	30372581	In vitro, LR004-VC-MMAE showed a promising cytotoxicity on ESCC cells, while the cytotoxicity of LR004 was nearly undetectable.	('cytotoxicity', 'Disease', (81, 93))	('cytotoxicity', 'Disease', (43, 55))	('LR004', 'Chemical', '-', (10, 15))	('ESCC', 'Disease', (59, 63))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('LR004', 'Chemical', '-', (97, 102))	('cytotoxicity', 'Disease', 'MESH:D064420', (43, 55))	('LR004-VC-MMAE', 'Var', (10, 23))	('MMAE', 'Chemical', 'MESH:C495575', (19, 23))
551314	30372581	The result from the cell cycle arrest and apoptosis analysis to ESCC cells and A431 cells demonstrated that the LR004-VC-MMAE caused G2/M arrest and induced significant apoptosis.	('MMAE', 'Chemical', 'MESH:C495575', (121, 125))	('apoptosis', 'CPA', (169, 178))	('A431', 'CellLine', 'CVCL:0037', (79, 83))	('LR004-VC-MMAE', 'Var', (112, 125))	('G2/M arrest', 'CPA', (133, 144))	('LR004', 'Chemical', '-', (112, 117))
551317	30372581	The antitumor activity of LR004-VC-MMAE in the ESCC KYSE520 tumor model was evaluated in these experiments.	('LR004', 'Chemical', '-', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('LR004-VC-MMAE', 'Var', (26, 39))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (8, 13))	('MMAE', 'Chemical', 'MESH:C495575', (35, 39))	('tumor', 'Disease', (60, 65))
551318	30372581	LR004-VC-MMAE effectively eliminated the tumors and prevented recurrence.	('LR004', 'Chemical', '-', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('eliminated', 'NegReg', (26, 36))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('recurrence', 'CPA', (62, 72))	('LR004-VC-MMAE', 'Var', (0, 13))	('MMAE', 'Chemical', 'MESH:C495575', (9, 13))
551320	30372581	However, LR004 showed little effect on the inhibition of tumor growth at the 15 mg kg-1 dose level.	('LR004', 'Var', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('LR004', 'Chemical', '-', (9, 14))	('tumor', 'Disease', (57, 62))
551321	30372581	Interestingly, both LR004 and LR004-VC-MMAE presented tumor accumulation and localization by the in vivo fluorescence imaging experiment.	('LR004', 'Chemical', '-', (20, 25))	('MMAE', 'Chemical', 'MESH:C495575', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('LR004-VC-MMAE', 'Var', (30, 43))	('localization', 'CPA', (77, 89))	('tumor', 'Disease', (54, 59))	('LR004', 'Var', (20, 25))	('LR004', 'Chemical', '-', (30, 35))
551322	30372581	For the anti-EGFR antibody, it is reported that the antibody, as a single agent, has minimal clinical activity in patients with ESCC (Chan et al., 2011).	('ESCC', 'Disease', (128, 132))	('anti-EGFR', 'Gene', (8, 17))	('anti-EGFR', 'Var', (8, 17))	('patients', 'Species', '9606', (114, 122))
551323	30372581	The main reason for this may be that the key mechanism of the EGFR antibody is achieved by blocking the EGFR signaling pathway when accumulating around the tumor, whereas gene mutations and amplifications of the EGFR downstream signaling pathways are frequently noted in ESCC (Song et al., 2014; Zhou et al., 2017).	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('ESCC', 'Disease', (271, 275))	('blocking', 'NegReg', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('EGFR signaling pathway', 'Pathway', (104, 126))	('tumor', 'Disease', (156, 161))	('gene mutations', 'Var', (171, 185))	('amplifications', 'Var', (190, 204))
551324	30372581	It suggests that the low response rate to LR004 in the ESCC KYSE520 tumor model might be due to high frequency of gene alteration of EGFR downstream signaling pathways.	('tumor', 'Disease', (68, 73))	('LR004', 'Chemical', '-', (42, 47))	('EGFR downstream signaling pathways', 'Pathway', (133, 167))	('gene alteration', 'Var', (114, 129))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('LR004', 'Gene', (42, 47))
551328	30372581	Therefore, our data suggest that the LR004-conjugated MMAE may provide promising support for new agent development against ESCC.	('LR004', 'Chemical', '-', (37, 42))	('ESCC', 'Disease', (123, 127))	('MMAE', 'Chemical', 'MESH:C495575', (54, 58))	('LR004-conjugated', 'Var', (37, 53))
551330	30372581	The activity of LR004-VC-MMAE was still significant compared with MMAE.	('MMAE', 'Chemical', 'MESH:C495575', (25, 29))	('MMAE', 'Chemical', 'MESH:C495575', (66, 70))	('LR004-VC-MMAE', 'Var', (16, 29))	('LR004', 'Chemical', '-', (16, 21))	('activity', 'MPA', (4, 12))
551332	30372581	In the large TV (400-500 mm3) group for the A431 models, LR004-VC-MMAE, at 15 mg kg-1, led to a significant inhibition of tumor volume, demonstrating that the tumors remained responsive to LR004-VC-MMAE in the large tumor experiments.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('MMAE', 'Chemical', 'MESH:C495575', (66, 70))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('MMAE', 'Chemical', 'MESH:C495575', (198, 202))	('LR004', 'Chemical', '-', (57, 62))	('inhibition', 'NegReg', (108, 118))	('tumor', 'Disease', (159, 164))	('LR004-VC-MMAE', 'Var', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('LR004', 'Chemical', '-', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('A431', 'CellLine', 'CVCL:0037', (44, 48))
551334	30372581	The FACS binding analyses of the cells highly expressing EGFR confirmed the kinetic binding affinity of LR004-VC-MMAE for the cell surface receptor, with binding characteristics that were essentially indistinguishable from LR004.	('LR004-VC-MMAE', 'Var', (104, 117))	('LR004', 'Chemical', '-', (223, 228))	('LR004', 'Chemical', '-', (104, 109))	('binding', 'Interaction', (84, 91))	('EGFR', 'Gene', (57, 61))	('MMAE', 'Chemical', 'MESH:C495575', (113, 117))
551340	30372581	Therefore, our study suggested that LR004-VC-MMAE might be one such promising treatment for EGFR-positive malignancies.	('LR004', 'Chemical', '-', (36, 41))	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('MMAE', 'Chemical', 'MESH:C495575', (45, 49))	('EGFR-positive', 'Gene', (92, 105))	('malignancies', 'Disease', (106, 118))	('LR004-VC-MMAE', 'Var', (36, 49))
551342	30372581	In mouse experimental model, LR004-VC-MMAE total antibody presented a longer half-life and a lower clearance.	('mouse', 'Species', '10090', (3, 8))	('clearance', 'MPA', (99, 108))	('LR004-VC-MMAE', 'Var', (29, 42))	('MMAE', 'Chemical', 'MESH:C495575', (38, 42))	('longer', 'PosReg', (70, 76))	('lower', 'NegReg', (93, 98))	('LR004', 'Chemical', '-', (29, 34))	('half-life', 'MPA', (77, 86))
551343	30372581	The result indicated that LR004 with MMAE has not compromised the characteristics of the antibody in vivo and supported the LR004 as a suitable delivery vehicle for an ADC carrier.	('characteristics', 'MPA', (66, 81))	('MMAE', 'Chemical', 'MESH:C495575', (37, 41))	('LR004', 'Chemical', '-', (26, 31))	('LR004', 'Var', (124, 129))	('LR004', 'Chemical', '-', (124, 129))
551350	30372581	According to the result of intracellular trafficking and in vivo fluorescence imaging analysis, on the other hand, it indicated that LR004-VC-MMAE could effectively release MMAE in target tumor cells.	('tumor', 'Disease', (188, 193))	('release MMAE', 'MPA', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('LR004-VC-MMAE', 'Var', (133, 146))	('MMAE', 'Chemical', 'MESH:C495575', (142, 146))	('LR004', 'Chemical', '-', (133, 138))	('MMAE', 'Chemical', 'MESH:C495575', (173, 177))
551351	30372581	Overall, the preliminary pharmacokinetic evaluation can provide some guidance for LR004-VC-MMAE ADC in malignancies.	('MMAE', 'Chemical', 'MESH:C495575', (91, 95))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('LR004-VC-MMAE', 'Var', (82, 95))	('malignancies', 'Disease', (103, 115))	('LR004', 'Chemical', '-', (82, 87))
551352	30372581	In conclusion, the ADC of LR004-VC-MMAE could be a potential therapeutic agent for ESCC and other EGFR-expressing malignancies, with a combination of antitumor activity and a desirable PK and safety profile in the mice model.	('LR004', 'Chemical', '-', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('malignancies', 'Disease', 'MESH:D009369', (114, 126))	('LR004-VC-MMAE', 'Var', (26, 39))	('MMAE', 'Chemical', 'MESH:C495575', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('ESCC', 'Disease', (83, 87))	('malignancies', 'Disease', (114, 126))	('mice', 'Species', '10090', (214, 218))	('tumor', 'Disease', (154, 159))
551365	30619750	demonstrated that deep sequencing of ctDNA KRAS mutations sensitively detects pancreatic ductal adenocarcinoma and correlates with therapeutic response and disease progression.	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('pancreatic ductal adenocarcinoma', 'Disease', (78, 110))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (78, 110))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (78, 110))	('KRAS', 'Gene', (43, 47))	('detects', 'Reg', (70, 77))	('KRAS', 'Gene', '3845', (43, 47))	('mutations', 'Var', (48, 57))
551381	30619750	To date, the only FDA approved tests include methylation-based test of SEPT9 for colorectal cancer and qPCR-based test for EGFR in non-small cell lung cancer.	('EGFR', 'Gene', (123, 127))	('non-small cell lung cancer', 'Disease', (131, 157))	('SEPT9', 'Gene', '10801', (71, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (135, 157))	('colorectal cancer', 'Disease', (81, 98))	('methylation-based', 'Var', (45, 62))	('SEPT9', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (131, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('EGFR', 'Gene', '1956', (123, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (131, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))
551389	30619750	Particularly, the tumor suppressors TP53 and CDKN2A are mutated in ~72 and 12% of EAC cases, respectively.	('tumor', 'Disease', (18, 23))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('mutated', 'Var', (56, 63))	('TP53', 'Gene', '7157', (36, 40))	('EAC', 'Disease', (82, 85))	('TP53', 'Gene', (36, 40))	('CDKN2A', 'Gene', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('CDKN2A', 'Gene', '1029', (45, 51))
551394	30619750	Many of the described mutations that characterize EAC, such as TP53 and CDKN2A, also occur in precursor lesions such as BE and HGD, lowering the specificity of such testing for established cancer.	('EAC', 'Phenotype', 'HP:0011459', (50, 53))	('occur', 'Reg', (85, 90))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('CDKN2A', 'Gene', '1029', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('specificity', 'MPA', (145, 156))	('BE', 'Phenotype', 'HP:0100580', (120, 122))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('CDKN2A', 'Gene', (72, 78))	('lowering', 'NegReg', (132, 140))	('cancer', 'Disease', (189, 195))
551398	30619750	The study demonstrated that non-progressing BE lesions had small localized deletions at fragile sites, such as FHIT, WWOX, CDKN2A, and 9p arm loss/copy neutral loss of heterozygosity (LOH).	('WWOX', 'Gene', (117, 121))	('FHIT', 'Gene', '2272', (111, 115))	('CDKN2A, and 9p', 'Gene', '1029', (123, 137))	('deletions', 'Var', (75, 84))	('WWOX', 'Gene', '51741', (117, 121))	('BE', 'Phenotype', 'HP:0100580', (44, 46))	('loss of', 'NegReg', (160, 167))	('FHIT', 'Gene', (111, 115))	('non-progressing BE lesions', 'Disease', (28, 54))	('loss/copy', 'NegReg', (142, 151))
551399	30619750	Progressors showed significant mutation of SMAD4 and were universally more heterogenetic with progressive diversity and genome doublings.	('SMAD4', 'Gene', '4089', (43, 48))	('SMAD4', 'Gene', (43, 48))	('mutation', 'Var', (31, 39))
551406	30619750	Similarly, in a study investigating the utility of ctDNA to monitor non-small cell lung cancer (NSCLC) patients, tumor and blood samples before and after surgical resection demonstrated that the presence of ctDNA had a higher positive predictive value than six currently utilized clinical tumor biomarkers.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (68, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (72, 94))	('NSCLC', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('tumor', 'Disease', (289, 294))	('ctDNA', 'Gene', (207, 212))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (68, 94))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('non-small cell lung cancer', 'Disease', (68, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('patients', 'Species', '9606', (103, 111))	('presence', 'Var', (195, 203))
551414	30619750	In a third study for lung cancer, ctDNA mutations predicted recurrence with 94% sensitivity with a median clinical lead-time of 5.2 months.	('recurrence', 'Disease', (60, 70))	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('mutations', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('predicted', 'Reg', (50, 59))	('ctDNA', 'Gene', (34, 39))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))
551417	30619750	also confirmed this finding in addition to TT>CT changes, and acquired mutations in SF3B1, TAF1, and CCND2.	('CCND2', 'Gene', (101, 106))	('SF3B1', 'Gene', '23451', (84, 89))	('CCND2', 'Gene', '894', (101, 106))	('TAF1', 'Gene', '6872', (91, 95))	('mutations', 'Var', (71, 80))	('TAF1', 'Gene', (91, 95))	('SF3B1', 'Gene', (84, 89))
551418	30619750	described an increasing mutation burden correlating with progression in metastatic colorectal cancer, while CT imaging showed stable disease.	('colorectal cancer', 'Disease', 'MESH:D015179', (83, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('mutation burden', 'Var', (24, 39))	('colorectal cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))
551435	30619750	demonstrated increased ctDNA detection of variants of unknown significance correlated with statistically significant improved PFS and OS in patients with diverse malignancies receiving immunotherapy.	('variants', 'Var', (42, 50))	('improved', 'PosReg', (117, 125))	('malignancies', 'Disease', 'MESH:D009369', (162, 174))	('patients', 'Species', '9606', (140, 148))	('malignancies', 'Disease', (162, 174))	('PFS', 'Disease', (126, 129))
551438	30619750	Moreover, many patients with EAC are resistant to first line chemoradiotherapy, and therapeutic monitoring of ctDNA mutations throughout the course of treatment may allow for more efficient adjustments of personalized therapy.	('patients', 'Species', '9606', (15, 23))	('EAC', 'Phenotype', 'HP:0011459', (29, 32))	('ctDNA', 'Gene', (110, 115))	('EAC', 'Disease', (29, 32))	('mutations', 'Var', (116, 125))
551494	27053957	Overexpression of EGFR has been found in many human malignancies, including cancers of the head and neck, lung cancer, breast cancer, colorectal cancer, and esophageal cancer.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('Overexpression', 'Var', (0, 14))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('EGFR', 'Gene', (18, 22))	('human', 'Species', '9606', (46, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('cancers of the head and neck', 'Phenotype', 'HP:0012288', (76, 104))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('colorectal cancer', 'Disease', (134, 151))	('found', 'Reg', (32, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('lung cancer', 'Disease', (106, 117))	('EGFR', 'Gene', '1956', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('malignancies', 'Disease', 'MESH:D009369', (52, 64))	('malignancies', 'Disease', (52, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('esophageal cancer', 'Disease', (157, 174))
551533	27053957	There were no other significant differences in baseline clinical characteristics between ESCC with high EGFR expression and those with low expression or negative EGFR expression (Table S1).	('expression', 'MPA', (109, 119))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('high', 'Var', (99, 103))	('EGFR', 'Gene', '1956', (104, 108))
551535	27053957	The proportions of patients who received chemotherapy and radiotherapy were not significantly different between high EGFR expression or low/negative EGFR expression groups (46.5 % vs. 41.8 % for chemotherapy [P = 0.548] and 52.5 % vs. 48.1% for radiotherapy [P = 0.652]).	('patients', 'Species', '9606', (19, 27))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('high', 'Var', (112, 116))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'Gene', (149, 153))
551544	27053957	Patients with high expression of both EGFR and c-Met had significantly worse OS compared with those with high expression of either EGFR or c-Met alone, or high expression of neither (P = 0.000; Figure 4).	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (131, 135))	('c-Met', 'Gene', (139, 144))	('EGFR', 'Gene', (131, 135))	('Patients', 'Species', '9606', (0, 8))	('c-Met', 'Gene', '4233', (139, 144))	('high expression', 'Var', (14, 29))	('OS', 'Chemical', '-', (77, 79))	('c-Met', 'Gene', (47, 52))	('worse', 'NegReg', (71, 76))	('c-Met', 'Gene', '4233', (47, 52))
551548	27053957	Univariate Cox proportional hazards analysis revealed that high c-Met expression was a significant prognostic factor for OS (P = 0.003).	('c-Met', 'Gene', '4233', (64, 69))	('high', 'Var', (59, 63))	('OS', 'Chemical', '-', (121, 123))	('c-Met', 'Gene', (64, 69))
551549	27053957	Multivariate Cox proportional hazards analysis revealed that high c-Met expression was the only significant prognostic factor for OS among the covariates analyzed (HR: 0.459 [95 % CI, 0.287-0.733]; P = 0.001; Table 1).	('c-Met', 'Gene', (66, 71))	('high', 'Var', (61, 65))	('c-Met', 'Gene', '4233', (66, 71))	('OS', 'Chemical', '-', (130, 132))
551560	27053957	Similarly, Delektorskaya and associates reported that amplification of EGFR gene (>=2.2) correlated with low degree of tumor differentiation (P = 0.006).	('tumor', 'Disease', (119, 124))	('amplification', 'Var', (54, 67))	('EGFR', 'Gene', '1956', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('EGFR', 'Gene', (71, 75))
551562	27053957	Ozawa and associates examined 104 surgically obtained ESCC specimens and reported that patients with high c-Met expression had significantly worse survival; this is in agreement with our study.	('c-Met', 'Gene', '4233', (106, 111))	('worse', 'NegReg', (141, 146))	('c-Met', 'Gene', (106, 111))	('high', 'Var', (101, 105))	('patients', 'Species', '9606', (87, 95))	('survival', 'MPA', (147, 155))	('expression', 'MPA', (112, 122))
551565	27053957	Our study showed that high expression of c-Met was significantly correlated with worse survival, but its role in ESCC needs to be further verified with prospective study.	('c-Met', 'Gene', (41, 46))	('high', 'Var', (22, 26))	('ESCC', 'Disease', (113, 117))	('c-Met', 'Gene', '4233', (41, 46))
551568	27053957	We observed a non-significant trend for HER2 positivity to be a prognostic factor for OS in ESCC patients (P = 0.061).	('HER2', 'Gene', (40, 44))	('ESCC', 'Disease', (92, 96))	('HER2', 'Gene', '2064', (40, 44))	('OS', 'Chemical', '-', (86, 88))	('positivity', 'Var', (45, 55))	('patients', 'Species', '9606', (97, 105))
551570	27053957	There was a statistically significant different in the proportions of patients who received postoperative radiotherapy between the HER2 positive group and HER2 negative group, which may confound our results.	('patients', 'Species', '9606', (70, 78))	('HER2', 'Gene', '2064', (155, 159))	('HER2', 'Gene', (131, 135))	('positive', 'Var', (136, 144))	('HER2', 'Gene', '2064', (131, 135))	('HER2', 'Gene', (155, 159))
551577	27053957	Patients with high EGFR expression had higher rates of HER2 positivity, but there was no significant difference in HER2 positivity between high c-Met expressing and low/negative c-Met expressing patients.	('c-Met', 'Gene', '4233', (178, 183))	('HER2', 'Gene', (115, 119))	('higher', 'PosReg', (39, 45))	('HER2', 'Gene', '2064', (115, 119))	('EGFR', 'Gene', '1956', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (195, 203))	('EGFR', 'Gene', (19, 23))	('HER2', 'Gene', (55, 59))	('c-Met', 'Gene', (144, 149))	('c-Met', 'Gene', (178, 183))	('HER2', 'Gene', '2064', (55, 59))	('c-Met', 'Gene', '4233', (144, 149))
551661	24667142	Patients who had high expression of HLA class I in their initial biopsies showed a significant better overall survival compared to those with low expression of HLA class I, or those with negative expression.	('overall survival', 'CPA', (102, 118))	('high expression', 'Var', (17, 32))	('Patients', 'Species', '9606', (0, 8))	('HLA class I', 'Protein', (36, 47))	('better', 'PosReg', (95, 101))
551666	24667142	Among female patients included in this study, poor response to preoperative chemotherapy together with metastatic stage at time of diagnosis were associated significantly with shorter overall and disease-free survival when compared to male patients, localized stage at presentation and good response to preoperative chemotherapy.	('disease-free survival', 'CPA', (196, 217))	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (176, 183))	('patients', 'Species', '9606', (240, 248))	('poor', 'Var', (46, 50))
551676	24667142	It is well known that abnormality of HLA class I molecules and APM in tumor cells is one of the major reasons for escape from CD8(+) cytotoxic T cells, resulting in disease progression.	('APM', 'Gene', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('HLA class I molecules', 'Protein', (37, 58))	('tumor', 'Disease', (70, 75))	('disease', 'MPA', (165, 172))	('resulting in', 'Reg', (152, 164))	('APM', 'Gene', '290', (63, 66))	('abnormality', 'Var', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
292503	24667142	investigated HLA class I expression in breast cancer using a HC-10 antibody, and demonstrated that HLA class I negativity correlated with a better postoperative outcome.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('negativity', 'Var', (111, 121))	('breast cancer', 'Disease', (39, 52))
551684	24667142	The only research work, in addition to this research, that performed osteosarcoma tissue blocks by immunohistochemistry is in agreement consistently with our findings as the researchers declared that patients with osteosarcoma exhibiting high expression of HLA class I showed significantly better overall and event-free survival compared to those with HLA class I-negative osteosarcoma.	('HLA', 'Protein', (257, 260))	('osteosarcoma', 'Disease', (373, 385))	('overall', 'CPA', (297, 304))	('osteosarcoma', 'Disease', 'MESH:D012516', (214, 226))	('better', 'PosReg', (290, 296))	('patients', 'Species', '9606', (200, 208))	('osteosarcoma', 'Phenotype', 'HP:0002669', (373, 385))	('osteosarcoma', 'Disease', 'MESH:D012516', (373, 385))	('osteosarcoma', 'Phenotype', 'HP:0002669', (69, 81))	('osteosarcoma', 'Disease', (69, 81))	('osteosarcoma', 'Disease', 'MESH:D012516', (69, 81))	('event-free survival', 'CPA', (309, 328))	('high expression', 'Var', (238, 253))	('osteosarcoma', 'Disease', (214, 226))	('osteosarcoma', 'Phenotype', 'HP:0002669', (214, 226))
551685	24667142	Another recent study showed that osteosarcoma tissues with high expression of SOX9, a developmental transcription factor, tend to have shorter overall survival and disease-free survival.	('SOX9', 'Gene', (78, 82))	('SOX9', 'Gene', '6662', (78, 82))	('osteosarcoma', 'Disease', (33, 45))	('disease-free survival', 'CPA', (164, 185))	('high expression', 'Var', (59, 74))	('osteosarcoma', 'Phenotype', 'HP:0002669', (33, 45))	('shorter', 'NegReg', (135, 142))	('overall survival', 'CPA', (143, 159))	('osteosarcoma', 'Disease', 'MESH:D012516', (33, 45))
551705	23691442	The overall hospitalization and chest tube duration were shorter in the VATS lobectomy group (n=949) than in the open thoracotomy (OT) lobectomy group (n=753).	('VATS', 'Var', (72, 76))	('chest tube duration', 'CPA', (32, 51))	('hospitalization', 'MPA', (12, 27))	('OT', 'Chemical', '-', (131, 133))	('shorter', 'NegReg', (57, 64))
551707	23691442	In the thymoma patients, there was no significant difference in the chest tube duration, morbidity rate, mortality rate, and hospital length of stay between the VATS thymectomy group (n=41) and open thymectomy group (n=41).	('patients', 'Species', '9606', (15, 23))	('thymoma', 'Disease', 'MESH:D013945', (7, 14))	('thymoma', 'Disease', (7, 14))	('thymoma', 'Phenotype', 'HP:0100522', (7, 14))	('VATS', 'Var', (161, 165))
551745	23691442	The postoperative LOS and chest tube duration were shorter in the VATS lobectomy group than in the OT lobectomy group, comparable with previous reports.	('VATS', 'Var', (66, 70))	('OT', 'Chemical', '-', (99, 101))	('shorter', 'NegReg', (51, 58))
551830	23426899	P53 gene mutations exist in both the sarcomatous and carcinomatous components, but the type of mutation differs.	('carcinomatous', 'Disease', (53, 66))	('sarcomatous', 'Disease', 'MESH:D018316', (37, 48))	('mutations', 'Var', (9, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('sarcomatous', 'Disease', (37, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('carcinomatous', 'Disease', 'MESH:D055756', (53, 66))
551870	31978054	FLI >=60 was significantly associated with the development of esophageal (HR 2.10, 95% CI 1.88-2.35), stomach (HR 1.18, 95% CI 1.14-1.22), and colon cancer (HR, 1.23, 95% CI 1.19-1.26) after multivariable adjustment.	('colon cancer', 'Phenotype', 'HP:0003003', (143, 155))	('associated with', 'Reg', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('esophageal', 'Disease', (62, 72))	('colon cancer', 'Disease', 'MESH:D015179', (143, 155))	('men', 'Species', '9606', (211, 214))	('colon cancer', 'Disease', (143, 155))	('men', 'Species', '9606', (54, 57))	('FLI >=60', 'Var', (0, 8))	('stomach', 'Disease', (102, 109))
551908	31978054	Hypertension was defined with the ICD-10 codes I10-I13 and I15 and treatment with anti-hypertensive agents or systolic or diastolic blood pressure >=140 mmHg or >=90 mmHg, respectively.	('hypertensive', 'Disease', 'MESH:D006973', (87, 99))	('I10-I13', 'Var', (47, 54))	('I15', 'Var', (59, 62))	('men', 'Species', '9606', (72, 75))	('hypertensive', 'Disease', (87, 99))	('Hypertension', 'Phenotype', 'HP:0000822', (0, 12))	('Hypertension', 'Disease', 'MESH:D006973', (0, 12))	('Hypertension', 'Disease', (0, 12))
551912	31978054	The primary outcome was newly diagnosed esophageal, stomach, or colon cancer (ICD-10 codes of C16, C18-20, or C15, respectively), a reimbursement code for severe disease, or censoring for death.	('men', 'Species', '9606', (141, 144))	('esophageal', 'Disease', (40, 50))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('colon cancer', 'Disease', 'MESH:D015179', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('death', 'Disease', 'MESH:D003643', (188, 193))	('C16', 'Var', (94, 97))	('death', 'Disease', (188, 193))	('C15', 'Gene', (110, 113))	('stomach', 'Disease', (52, 59))	('colon cancer', 'Disease', (64, 76))	('C18-20', 'Chemical', 'MESH:C456584', (99, 105))	('C15', 'Gene', '51316', (110, 113))	('C18-20', 'Var', (99, 105))
551934	31978054	Thus, BMI was stratified into normal (BMI <23 kg/m2), overweight (23-<25 kg/m2), and obese (>=25 kg/m2) populations across each GI cancer.	('cancer', 'Disease', (131, 137))	('overweight', 'Phenotype', 'HP:0025502', (54, 64))	('23-<25', 'Var', (66, 72))	('GI cancer', 'Phenotype', 'HP:0007378', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
551940	31978054	The GGT upper quartile (>=36 IU/mL) was associated with an increased risk of esophageal, stomach, and colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('GGT', 'Gene', '728441', (4, 7))	('colorectal cancers', 'Disease', (102, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('GGT', 'Gene', (4, 7))	('>=36 IU/mL', 'Var', (24, 34))	('stomach', 'Disease', (89, 96))	('colorectal cancers', 'Disease', 'MESH:D015179', (102, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('esophageal', 'Disease', (77, 87))
551943	31978054	The all-cause mortality rates were significantly higher in the FLI >=60 group compared to the FLI <60 group (24.3 vs. 26.0 in esophageal cancer, 6.75 vs. 6.12 in stomach cancer, and 7.06 vs. 7.06 per 1,000 patient-years in colorectal cancer, respectively (Table 4).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('stomach cancer', 'Phenotype', 'HP:0012126', (162, 176))	('stomach cancer', 'Disease', (162, 176))	('patient', 'Species', '9606', (206, 213))	('colorectal cancer', 'Phenotype', 'HP:0003003', (223, 240))	('esophageal cancer', 'Disease', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Disease', (223, 240))	('colorectal cancer', 'Disease', 'MESH:D015179', (223, 240))	('higher', 'PosReg', (49, 55))	('FLI >=60', 'Var', (63, 71))	('stomach cancer', 'Disease', 'MESH:D013274', (162, 176))
551966	31978054	Poor diet, commonly observed in individuals who are underweight, can lead to malnutrition and have been implicated as high-risk factors for esophageal cancer, especially in Asian populations.	('malnutrition', 'Disease', (77, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('malnutrition', 'Disease', 'MESH:D044342', (77, 89))	('Poor diet', 'Phenotype', 'HP:0011968', (0, 9))	('malnutrition', 'Phenotype', 'HP:0004395', (77, 89))	('lead to', 'Reg', (69, 76))	('esophageal cancer', 'Disease', (140, 157))	('Poor diet', 'Var', (0, 9))
551974	31978054	Based on a retrospective study performed in 447 patients with esophageal squamous cell carcinoma, higher GGT might predict worse overall survival than normal GGT.	('GGT', 'Gene', (105, 108))	('worse', 'NegReg', (123, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('GGT', 'Gene', (158, 161))	('higher', 'Var', (98, 104))	('esophageal squamous cell carcinoma', 'Disease', (62, 96))	('GGT', 'Gene', '728441', (105, 108))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (62, 96))	('overall', 'MPA', (129, 136))	('GGT', 'Gene', '728441', (158, 161))	('patients', 'Species', '9606', (48, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
551976	31978054	Clinical data from 8,388,256 Korean individuals aged 40 years and over who received national healthcare check-ups in 2007 and 2008 showed an increased risk of esophageal cancer in subjects with serum GGT values >18 IU/L, regardless of age, sex, smoking status, or alcohol consumption.	('alcohol', 'Chemical', 'MESH:D000431', (264, 271))	('esophageal cancer', 'Disease', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('GGT', 'Gene', '728441', (200, 203))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('>18 IU/L', 'Var', (211, 219))	('GGT', 'Gene', (200, 203))
552002	30621632	Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies.	('malignancies', 'Disease', 'MESH:D009369', (81, 93))	('HER2', 'Gene', (32, 36))	('HER2', 'Gene', '2064', (32, 36))	('malignancies', 'Disease', (81, 93))	('Overexpression/amplification', 'Var', (0, 28))
552021	30621632	According to the current literature, the rate of HER2 positivity in EAC varies, ranging from 15 to 29%.	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('EAC', 'Disease', (68, 71))	('HER2', 'Gene', (49, 53))	('HER2', 'Gene', '2064', (49, 53))	('positivity', 'Var', (54, 64))
552033	30621632	The reading strategy followed the recommendations HER2/CEN17 ratio >= 2.0 or HER2 signals >=6.0 and negative ratio (< 2.0).	('HER2', 'Gene', (50, 54))	('HER2', 'Gene', (77, 81))	('HER2', 'Gene', '2064', (50, 54))	('HER2', 'Gene', '2064', (77, 81))	('>=6.0', 'Var', (90, 95))	('CEN17', 'Chemical', '-', (55, 60))
552059	30621632	Consequently, dysregulated HER2 may cause tumorigenesis by suppressing apoptosis and by other effects.	('tumor', 'Disease', (42, 47))	('dysregulated', 'Var', (14, 26))	('apoptosis', 'CPA', (71, 80))	('cause', 'Reg', (36, 41))	('suppressing', 'NegReg', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('HER2', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('HER2', 'Gene', '2064', (27, 31))
552063	30621632	We found HER2 positivity in 14.9% (multi-spot TMA) and 12.2% (single-spot TMA) in our tumor cohort.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TMA', 'Chemical', '-', (74, 77))	('TMA', 'Chemical', '-', (46, 49))	('HER2', 'Gene', (9, 13))	('tumor', 'Disease', (86, 91))	('HER2', 'Gene', '2064', (9, 13))	('positivity', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
552069	30621632	In their sequencing study, they identified HER2 mutation in 3% and HER2 amplification in 19% of the cases.	('HER2', 'Gene', (43, 47))	('HER2', 'Gene', (67, 71))	('HER2', 'Gene', '2064', (43, 47))	('HER2', 'Gene', '2064', (67, 71))	('amplification', 'MPA', (72, 85))	('mutation', 'Var', (48, 56))
552070	30621632	Within their comprehensive molecular analysis of upper gastrointestinal adenocarcinomas, including 77 EAC tumors from patients who underwent primary resection, the authors demonstrated that HER2 amplifications took place in 19 cases (24.68%), while HER2 mutations occurred in three patients (3.9%).	('HER2', 'Gene', (190, 194))	('upper gastrointestinal adenocarcinomas', 'Disease', (49, 87))	('amplifications', 'Var', (195, 209))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('HER2', 'Gene', '2064', (190, 194))	('tumors', 'Disease', (106, 112))	('HER2', 'Gene', (249, 253))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('EAC', 'Phenotype', 'HP:0011459', (102, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('HER2', 'Gene', '2064', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('upper gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (49, 87))	('patients', 'Species', '9606', (282, 290))	('patients', 'Species', '9606', (118, 126))
552075	30621632	Furthermore, the authors described HER2 alterations in eight cases (14.5%) of their study cohort.	('HER2', 'Gene', '2064', (35, 39))	('HER2', 'Gene', (35, 39))	('alterations', 'Var', (40, 51))
552087	30621632	Multivariate analysis in those irresectable patients revealed that detectable HER2 mutations within circulating tumor DNA were significantly associated with a poor overall survival compared to patients with the HER2 wild-type (p = 0.003).	('poor', 'NegReg', (159, 163))	('mutations', 'Var', (83, 92))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (44, 52))	('HER2', 'Gene', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('HER2', 'Gene', '2064', (211, 215))	('HER2', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('HER2', 'Gene', '2064', (78, 82))	('tumor', 'Disease', (112, 117))	('overall survival', 'MPA', (164, 180))
552089	30621632	In a published genomic characterization, the Cancer Genome Atlas Research Network identified no prognostic difference (p = 0.781) between those patients with HER2 amplification/alteration in upper gastrointestinal adenocarcinomas compared to those without (median overall survival: 31.28 vs. 28.75 months).	('upper gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (191, 229))	('upper gastrointestinal adenocarcinomas', 'Disease', (191, 229))	('patients', 'Species', '9606', (144, 152))	('HER2', 'Gene', (158, 162))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('HER2', 'Gene', '2064', (158, 162))	('amplification/alteration', 'Var', (163, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))
552092	30621632	In contrast, another study, currently the largest one, considered an EAC cohort of 713 patients analyzed by Yoon et al., identifying HER2 positivity to be associated with better disease-specific survival and overall survival.	('HER2', 'Gene', (133, 137))	('disease-specific survival', 'CPA', (178, 203))	('overall survival', 'CPA', (208, 224))	('HER2', 'Gene', '2064', (133, 137))	('EAC', 'Phenotype', 'HP:0011459', (69, 72))	('positivity', 'Var', (138, 148))	('patients', 'Species', '9606', (87, 95))	('better', 'PosReg', (171, 177))
552108	30621632	In conclusion, this study indicates the positive biological effects of HER2 positivity in EAC, being associated with better prognosis, earlier tumor stages, and a lower rate of lymphatic metastasis, representing a hitherto insufficiently characterized subtype of EAC.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('EAC', 'Phenotype', 'HP:0011459', (263, 266))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HER2', 'Gene', (71, 75))	('positivity', 'Var', (76, 86))	('lymphatic metastasis', 'CPA', (177, 197))	('HER2', 'Gene', '2064', (71, 75))	('better', 'PosReg', (117, 123))	('EAC', 'Phenotype', 'HP:0011459', (90, 93))	('insufficiently', 'Disease', 'MESH:D000309', (223, 237))	('insufficiently', 'Disease', (223, 237))	('lower', 'NegReg', (163, 168))	('EAC', 'Disease', (90, 93))
552117	29892933	The recovery of gastrointestinal function regarding flatus, defecation, and oral intake showed no significant between-group differences, but postoperative bowel symptoms tended to be rare in the TJ-100 group.	('TJ-100', 'Var', (195, 201))	('postoperative bowel', 'Disease', 'MESH:D010149', (141, 160))	('postoperative bowel symptoms', 'Disease', 'MESH:D019106', (141, 169))	('recovery of gastrointestinal function', 'Phenotype', 'HP:0012719', (4, 41))	('postoperative bowel symptoms', 'Phenotype', 'HP:0002607', (141, 169))	('postoperative bowel symptoms', 'Disease', (141, 169))	('postoperative bowel symptom', 'Phenotype', 'HP:0002607', (141, 168))
552147	27672288	In this review we provide a comprehensive overview of the current state-of-knowledge of HER2 alterations in the most common tumors of the digestive system and discuss the operational implications of HER2 testing.	('rat', 'Species', '10116', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('alterations', 'Var', (93, 104))	('HER2', 'Gene', (88, 92))	('HER2', 'Gene', '2064', (88, 92))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('rat', 'Species', '10116', (174, 177))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('HER2', 'Gene', (199, 203))	('tumors of the digestive system', 'Phenotype', 'HP:0007378', (124, 154))	('HER2', 'Gene', '2064', (199, 203))
552161	27672288	Massively parallel sequencing studies have recently revealed that a substantial proportion of DSC are genetically characterized by HER2 alterations (Figure 2).	('HER2', 'Gene', (131, 135))	('HER2', 'Gene', '2064', (131, 135))	('DSC', 'Disease', (94, 97))	('alterations', 'Var', (136, 147))	('rat', 'Species', '10116', (140, 143))
552169	27672288	Due to the increasing importance of HER2 testing in cancer and the new exciting challenges that precision medicine is providing, in this review we seek to describe the current state of knowledge of HER2 alterations in the most common DSC, to discuss the operational issues of HER2 testing, and to outline forthcoming clinical perspectives, in particular focusing on the cutting-edge tools available for HER2 characterization and targeting in the digestive system.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('rat', 'Species', '10116', (207, 210))	('HER2', 'Gene', '2064', (276, 280))	('HER2', 'Gene', (36, 40))	('HER2', 'Gene', (198, 202))	('DSC', 'Disease', (234, 237))	('HER2', 'Gene', (276, 280))	('HER2', 'Gene', (403, 407))	('HER2', 'Gene', '2064', (36, 40))	('HER2', 'Gene', '2064', (198, 202))	('HER2', 'Gene', '2064', (403, 407))	('cancer', 'Disease', (52, 58))	('rat', 'Species', '10116', (257, 260))	('alterations', 'Var', (203, 214))
552173	27672288	In the largest meta-analysis of the prognostic significance of erbB2 overexpression and gene amplification in EC patients, 22% of tumors were HER2-positive, regardless of histotype.	('overexpression', 'PosReg', (69, 83))	('HER2', 'Gene', (142, 146))	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('erbB2', 'Gene', '2064', (63, 68))	('HER2', 'Gene', '2064', (142, 146))	('erbB2', 'Gene', (63, 68))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('gene amplification', 'Var', (88, 106))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
552177	27672288	Interestingly, the prognostic influence of HER2 amplification as a biomarker is slightly greater in SCC compared to ADC.	('HER2', 'Gene', (43, 47))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('HER2', 'Gene', '2064', (43, 47))	('SCC', 'Disease', (100, 103))	('amplification', 'Var', (48, 61))
552181	27672288	Indeed, it has recently been reported that possible alterations in epidermal growth factor receptor (EGFR), telomerase reverse transcriptase (TERT), and HER2 are bona fide predictor of response to HER2-target therapy in EC, particularly in SCCs.	('epidermal growth factor receptor', 'Gene', '1956', (67, 99))	('alterations', 'Var', (52, 63))	('rat', 'Species', '10116', (56, 59))	('HER2', 'Gene', (153, 157))	('telomerase reverse transcriptase', 'Gene', (108, 140))	('HER2', 'Gene', (197, 201))	('EGFR', 'Gene', (101, 105))	('HER2', 'Gene', '2064', (153, 157))	('telomerase reverse transcriptase', 'Gene', '7015', (108, 140))	('EGFR', 'Gene', '1956', (101, 105))	('HER2', 'Gene', '2064', (197, 201))	('epidermal growth factor receptor', 'Gene', (67, 99))	('SCC', 'Phenotype', 'HP:0002860', (240, 243))	('TERT', 'Gene', (142, 146))	('TERT', 'Gene', '7015', (142, 146))	('SCCs', 'Disease', (240, 244))
552189	27672288	Overall, GCs overexpressing erbB2 and/or showing HER2 amplification, range from 13% to 22% of cases.	('erbB2', 'Gene', '2064', (28, 33))	('erbB2', 'Gene', (28, 33))	('overexpressing', 'Var', (13, 27))	('GC', 'Phenotype', 'HP:0012126', (9, 11))	('HER2', 'Gene', (49, 53))	('HER2', 'Gene', '2064', (49, 53))
552190	27672288	Meta-analysis data suggest that GC harboring HER2 amplification fares worse; however, the prognostic value of HER2 remains controversial in the stomach.	('amplification', 'Var', (50, 63))	('HER2', 'Gene', (45, 49))	('HER2', 'Gene', (110, 114))	('GC', 'Phenotype', 'HP:0012126', (32, 34))	('HER2', 'Gene', '2064', (45, 49))	('HER2', 'Gene', '2064', (110, 114))
552200	27672288	In accordance to this notion, a recent comprehensive genomic characterization of CRC revealed a recurrent amplicon at 17q21.1 in 4% of these tumors.	('amplicon', 'Var', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))
552202	27672288	The operational implications of HER2 amplification in CRC, however, remain elusive, with a number of studies reporting contradictory links to prognosis.	('HER2', 'Gene', (32, 36))	('HER2', 'Gene', '2064', (32, 36))	('amplification', 'Var', (37, 50))	('CRC', 'Disease', (54, 57))	('rat', 'Species', '10116', (7, 10))	('CRC', 'Phenotype', 'HP:0003003', (54, 57))
552206	27672288	This observation is not trivial, raising the hypothesis that HER2 amplification might be a bona fide alternative driver of Ras-Raf-MEK-ERK pathway activation in CRC.	('ERK', 'Gene', '5594', (135, 138))	('Raf', 'Gene', '22882', (127, 130))	('amplification', 'Var', (66, 79))	('MEK', 'Gene', '5609', (131, 134))	('CRC', 'Phenotype', 'HP:0003003', (161, 164))	('ERK', 'Gene', (135, 138))	('HER2', 'Gene', '2064', (61, 65))	('Raf', 'Gene', (127, 130))	('HER2', 'Gene', (61, 65))	('MEK', 'Gene', (131, 134))	('CRC', 'Disease', (161, 164))	('activation', 'PosReg', (147, 157))
552208	27672288	For these reasons, and given the homogeneity in erbB2 expression, it has recently been proposed that HER2 status should be assessed as a putative biomarker of resistance to anti-EGFR therapy in KRAS wild-type patients and, if further studies confirm that TOP2A amplifications are associated with anthracycline sensitivity, as a predictor to response.	('anthracycline sensitivity', 'Disease', (296, 321))	('EGFR', 'Gene', '1956', (178, 182))	('HER2', 'Gene', (101, 105))	('anthracycline', 'Chemical', 'MESH:D018943', (296, 309))	('HER2', 'Gene', '2064', (101, 105))	('erbB2', 'Gene', '2064', (48, 53))	('EGFR', 'Gene', (178, 182))	('erbB2', 'Gene', (48, 53))	('amplifications', 'Var', (261, 275))	('TOP2A', 'Gene', (255, 260))	('patients', 'Species', '9606', (209, 217))	('associated', 'Reg', (280, 290))
552213	27672288	Amplification of HER2 gene and/or overexpression of its product have been implicated in the development of PC.	('Amplification', 'Var', (0, 13))	('HER2', 'Gene', (17, 21))	('overexpression', 'PosReg', (34, 48))	('implicated', 'Reg', (74, 84))	('HER2', 'Gene', '2064', (17, 21))	('men', 'Species', '9606', (99, 102))	('PC', 'Phenotype', 'HP:0002894', (107, 109))
552215	27672288	Furthermore, the prognostic role of HER2 amplification in PC has been investigated in numerous studies, again, with heterogeneous results.	('PC', 'Phenotype', 'HP:0002894', (58, 60))	('HER2', 'Gene', '2064', (36, 40))	('amplification', 'Var', (41, 54))	('HER2', 'Gene', (36, 40))
552216	27672288	As a consequence, the diagnostic criteria and prevalence of HER2 amplification in pancreatic ductal ADC remain unclear.	('HER2', 'Gene', (60, 64))	('HER2', 'Gene', '2064', (60, 64))	('pancreatic ductal', 'Disease', (82, 99))	('amplification', 'Var', (65, 78))	('pancreatic ductal', 'Disease', 'MESH:D021441', (82, 99))
552218	27672288	In one phase II trial, 17 patients showing HER2 amplification were treated with capecitabine combined with trastuzumab.	('HER2', 'Gene', (43, 47))	('HER2', 'Gene', '2064', (43, 47))	('patients', 'Species', '9606', (26, 34))	('capecitabine', 'Chemical', 'MESH:D000069287', (80, 92))	('trastuzumab', 'Chemical', 'MESH:D000068878', (107, 118))	('amplification', 'Var', (48, 61))
552228	27672288	Among these few cases, only a minority of tumors is reported to harbor HER2 amplification.	('tumors', 'Disease', (42, 48))	('HER2', 'Gene', (71, 75))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('HER2', 'Gene', '2064', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('amplification', 'Var', (76, 89))
552238	27672288	However, 51% of cases in a small cohort study showed erbB2 positivity using 50% of positive tumor cells as a threshold, suggesting the presence of heterogeneous protein expression.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('positivity', 'Var', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('erbB2', 'Gene', '2064', (53, 58))	('erbB2', 'Gene', (53, 58))
552242	27672288	Taking into account overall and disease-free survival, HER2 amplification seems not to have a prognostic role in BTC.	('amplification', 'Var', (60, 73))	('BTC', 'Disease', (113, 116))	('BTC', 'Phenotype', 'HP:0100574', (113, 116))	('HER2', 'Gene', (55, 59))	('HER2', 'Gene', '2064', (55, 59))
552261	27672288	Indeed, there are several molecular evidences that genetic heterogeneity is not restricted to passenger genes but that also bona fide driver genetic alterations such as HER2 gene amplification can be heterogeneously distributed within a given tumor.	('gene amplification', 'Var', (174, 192))	('HER2', 'Gene', (169, 173))	('rat', 'Species', '10116', (153, 156))	('HER2', 'Gene', '2064', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
552264	27672288	In addition, somatic mutations in HER2 have been described in a small subset of DSC and there are functional evidences that at least a subset of mutations targeting HER2 might be responsible for the development of resistance to trastuzumab therapy, in a way akin to breast cancer.	('breast cancer', 'Disease', (266, 279))	('breast cancer', 'Disease', 'MESH:D001943', (266, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (266, 279))	('described', 'Reg', (49, 58))	('mutations', 'Var', (145, 154))	('responsible', 'Reg', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('HER2', 'Gene', (34, 38))	('HER2', 'Gene', (165, 169))	('trastuzumab', 'Chemical', 'MESH:D000068878', (228, 239))	('HER2', 'Gene', '2064', (165, 169))	('HER2', 'Gene', '2064', (34, 38))	('DSC', 'Disease', (80, 83))	('men', 'Species', '9606', (206, 209))
552265	27672288	For example, alterations leading to increased heterodimerization of HER2 with EGFR or HER3 are thought to induce resistance to trastuzumab therapy.	('induce', 'Reg', (106, 112))	('trastuzumab', 'Chemical', 'MESH:D000068878', (127, 138))	('heterodimerization', 'MPA', (46, 64))	('HER2', 'Gene', (68, 72))	('rat', 'Species', '10116', (17, 20))	('HER3', 'Gene', (86, 90))	('HER2', 'Gene', '2064', (68, 72))	('HER3', 'Gene', '2065', (86, 90))	('increased', 'PosReg', (36, 45))	('EGFR', 'Gene', '1956', (78, 82))	('alterations', 'Var', (13, 24))	('EGFR', 'Gene', (78, 82))
552266	27672288	Furthermore, cleavage of the full-length erbB2 protein produces a truncated membrane-associated fragment called p95HER2 with increased kinase activity in GC cell lines.	('HER2', 'Gene', (115, 119))	('men', 'Species', '9606', (100, 103))	('increased', 'PosReg', (125, 134))	('kinase activity', 'MPA', (135, 150))	('HER2', 'Gene', '2064', (115, 119))	('erbB2', 'Gene', '2064', (41, 46))	('erbB2', 'Gene', (41, 46))	('cleavage', 'Var', (13, 21))	('GC', 'Phenotype', 'HP:0012126', (154, 156))
552268	27672288	Furthermore, 11% of HCC but none of BTC have been found to harbor HER2 (H878Y) somatic mutation occurring in the tyrosine kinase domain, resulting in c.2632C>T.	('BTC', 'Phenotype', 'HP:0100574', (36, 39))	('HER2', 'Gene', '2064', (66, 70))	('c.2632C>T', 'Mutation', 'c.2632C>T', (150, 159))	('H878Y', 'Mutation', 'p.H878Y', (72, 77))	('tyrosine', 'Chemical', 'MESH:D014443', (113, 121))	('HCC', 'Phenotype', 'HP:0001402', (20, 23))	('c.2632C>T', 'Var', (150, 159))	('HER2', 'Gene', (66, 70))
552270	27672288	Interestingly, a phase II trial observed that the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib was active in HCC but not in BTC, suggesting that mutations in the tyrosine kinase domain of HER2 in HCC may underlie responsiveness to agents that target HER2 and/or EGFR.	('tyrosine', 'Chemical', 'MESH:D014443', (168, 176))	('tyrosine', 'Chemical', 'MESH:D014443', (65, 73))	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', '1956', (268, 272))	('HCC', 'Phenotype', 'HP:0001402', (115, 118))	('EGFR', 'Gene', (55, 59))	('HER2', 'Gene', (60, 64))	('HER2', 'Gene', (194, 198))	('HER2', 'Gene', (256, 260))	('EGFR', 'Gene', (268, 272))	('HER2', 'Gene', '2064', (194, 198))	('HER2', 'Gene', '2064', (60, 64))	('HER2', 'Gene', '2064', (256, 260))	('BTC', 'Phenotype', 'HP:0100574', (130, 133))	('mutations in', 'Var', (151, 163))	('HCC', 'Phenotype', 'HP:0001402', (202, 205))	('lapatinib', 'Chemical', 'MESH:D000077341', (91, 100))
552271	27672288	Generally, erbB2-directed therapy appears to be beneficial in erbB2-positive gallbladder cancers; however, tumors harboring HER2 mutation (V777L), in the kinase domain, followed into the non-responders category.	('HER2', 'Gene', '2064', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('erbB2', 'Gene', '2064', (11, 16))	('V777L', 'Mutation', 'rs121913471', (139, 144))	('erbB2', 'Gene', '2064', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumors', 'Disease', (107, 113))	('erbB2', 'Gene', (11, 16))	('V777L', 'Var', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('gallbladder cancers', 'Disease', (77, 96))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('gallbladder cancers', 'Disease', 'MESH:D005706', (77, 96))	('erbB2', 'Gene', (62, 67))	('HER2', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
552272	27672288	In addition to the alterations in erbB2 receptors, mutations in genes involved in the signaling pathways activated by these receptors are also correlated with failure of therapeutic response to erbB2 inhibitors.	('mutations', 'Var', (51, 60))	('erbB2', 'Gene', '2064', (34, 39))	('rat', 'Species', '10116', (23, 26))	('erbB2', 'Gene', (34, 39))	('erbB2', 'Gene', '2064', (194, 199))	('erbB2', 'Gene', (194, 199))
552274	27672288	Moreover, PIK3CA mutations and PTEN inactivation could affect the effectiveness of erbB2-targeting therapy.	('PTEN', 'Gene', (31, 35))	('affect', 'Reg', (55, 61))	('PTEN', 'Gene', '5728', (31, 35))	('PIK3CA', 'Gene', (10, 16))	('erbB2', 'Gene', '2064', (83, 88))	('erbB2', 'Gene', (83, 88))	('PIK3CA', 'Gene', '5290', (10, 16))	('inactivation', 'Var', (36, 48))	('mutations', 'Var', (17, 26))
552283	27672288	In this setting, PIK3CA mutation or PTEN loss has been evaluated as a possible predictive biomarker and has also been used as one of the inclusion criteria.	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', '5728', (36, 40))	('mutation', 'Var', (24, 32))	('loss', 'NegReg', (41, 45))
552284	27672288	Understanding the interplay between HER2 and the PI3K-Akt pathway alterations would be pivotal in the development of new therapeutic strategies.	('rat', 'Species', '10116', (70, 73))	('rat', 'Species', '10116', (135, 138))	('Akt', 'Gene', '207', (54, 57))	('HER2', 'Gene', (36, 40))	('HER2', 'Gene', '2064', (36, 40))	('Akt', 'Gene', (54, 57))	('men', 'Species', '9606', (109, 112))	('alterations', 'Var', (66, 77))
552304	21839994	In China, intraepithelial squamous neoplasia of the esophagus is graded according to the proportion of the epithelial thickness containing neoplasia: 1/3 (low-grade intraepithelial neoplasia, LGIN, mild dysplasia), 2/3 (moderate-grade, MGIN, moderate dysplasia), or 3/3 (high-grade, HGIN, severe dysplasia).	('dysplasia', 'Disease', 'MESH:D004476', (203, 212))	('intraepithelial squamous neoplasia', 'Disease', 'MESH:D019048', (10, 44))	('dysplasia', 'Disease', 'MESH:D004476', (251, 260))	('LGIN', 'Disease', (192, 196))	('low-grade', 'Var', (155, 164))	('neoplasia', 'Phenotype', 'HP:0002664', (139, 148))	('neoplasia', 'Disease', 'MESH:D009369', (181, 190))	('dysplasia', 'Disease', (296, 305))	('dysplasia', 'Disease', 'MESH:D004476', (296, 305))	('neoplasia', 'Phenotype', 'HP:0002664', (35, 44))	('intraepithelial squamous neoplasia', 'Disease', (10, 44))	('neoplasia', 'Disease', (181, 190))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (165, 190))	('neoplasia of the esophagus', 'Phenotype', 'HP:0100751', (35, 61))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (165, 190))	('neoplasia', 'Disease', 'MESH:D009369', (139, 148))	('MGIN', 'Disease', (236, 240))	('epithelial neoplasia', 'Phenotype', 'HP:0031492', (170, 190))	('squamous neoplasia', 'Phenotype', 'HP:0002860', (26, 44))	('neoplasia', 'Phenotype', 'HP:0002664', (181, 190))	('neoplasia', 'Disease', (139, 148))	('neoplasia', 'Disease', (35, 44))	('neoplasia', 'Disease', 'MESH:D009369', (35, 44))	('intraepithelial neoplasia', 'Disease', (165, 190))	('dysplasia', 'Disease', (203, 212))	('dysplasia', 'Disease', (251, 260))
552308	21839994	A randomized, sham-controlled trial showed that RFA resulted in a high rate of complete eradication of neoplasia and a reduction in the rate of neoplastic progression.	('rate', 'MPA', (136, 140))	('RFA', 'Var', (48, 51))	('neoplastic progression', 'MPA', (144, 166))	('reduction', 'NegReg', (119, 128))	('neoplasia', 'Phenotype', 'HP:0002664', (103, 112))	('neoplasia', 'Disease', 'MESH:D009369', (103, 112))	('neoplasia', 'Disease', (103, 112))
552317	21839994	Endoscopy procedures were performed with Olympus GIF-H260, GIF-H260Z, or GIF-H260J (Olympus, Tokyo, Japan) high-resolution endoscopes (Lucera systems).	('H260Z', 'SUBSTITUTION', 'None', (63, 68))	('H260J', 'SUBSTITUTION', 'None', (77, 82))	('H260Z', 'Var', (63, 68))	('H260J', 'Var', (77, 82))
552374	21839994	In conclusion, in this prospective study of RFA in patients with early flat-type esophageal squamous cell neoplasia (MGIN, HGIN, ESCC), RFA was associated with a high rate of histological complete response (97% of patients), no neoplastic progression, and an acceptable adverse event profile.	('squamous cell neoplasia', 'Phenotype', 'HP:0002860', (92, 115))	('patients', 'Species', '9606', (214, 222))	('neoplasia', 'Phenotype', 'HP:0002664', (106, 115))	('flat-type esophageal squamous cell neoplasia', 'Disease', (71, 115))	('patients', 'Species', '9606', (51, 59))	('RFA', 'Var', (136, 139))	('flat-type esophageal squamous cell neoplasia', 'Disease', 'MESH:D000077277', (71, 115))
552376	19620936	Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes Genetic variations or polymorphisms within genes of the nucleotide excision repair (NER) pathway alter DNA repair capacity.	('DNA repair capacity', 'MPA', (188, 207))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('variations', 'Var', (93, 103))	('alter', 'Reg', (182, 187))	('polymorphisms', 'Var', (107, 120))
552378	19620936	We investigated the potential predictive significance of functional NER single nucleotide polymorphisms in esophageal cancer patients treated with (n = 262) or without (n = 108) cisplatin.	('patients', 'Species', '9606', (125, 133))	('single nucleotide polymorphisms', 'Var', (72, 103))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('NER', 'Gene', (68, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))
552379	19620936	Four NER polymorphisms XPD Asp312Asn; XPD Lys751Gln, ERCC1 8092C/A, and ERCC1 codon 118C/T were each assessed in polymorphism-cisplatin treatment interactions for overall survival (OS), with progression-free survival (PFS) as a secondary endpoint.	('118C/T', 'SUBSTITUTION', 'None', (84, 90))	('Asp312Asn', 'Var', (27, 36))	('XPD', 'Gene', (38, 41))	('ERCC1', 'Gene', '2067', (72, 77))	('ERCC1', 'Gene', (72, 77))	('8092C/A', 'Var', (59, 66))	('XPD', 'Gene', '2068', (38, 41))	('Lys751Gln', 'SUBSTITUTION', 'None', (42, 51))	('Asp312Asn', 'SUBSTITUTION', 'None', (27, 36))	('Lys751Gln', 'Var', (42, 51))	('ERCC1', 'Gene', (53, 58))	('interactions', 'Interaction', (146, 158))	('118C/T', 'Var', (84, 90))	('8092C/A', 'Mutation', 'rs3212986', (59, 66))	('ERCC1', 'Gene', '2067', (53, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('XPD', 'Gene', (23, 26))	('XPD', 'Gene', '2068', (23, 26))
552382	19620936	In cisplatin-treated patients, variant alleles of XPD 312, XPD 751, and ERCC1 8092 were each associated with significantly improved OS (and PFS): adjusted hazard ratios of homozygous variants versus wild-type ranged from 0.22 [95% confidence interval (CI): 0.1-0.5] to 0.31 (95% CI: 0.1-0.7).	('cisplatin', 'Chemical', 'MESH:D002945', (3, 12))	('XPD', 'Gene', (59, 62))	('ERCC1', 'Gene', '2067', (72, 77))	('ERCC1', 'Gene', (72, 77))	('variants', 'Var', (183, 191))	('XPD', 'Gene', '2068', (59, 62))	('XPD', 'Gene', (50, 53))	('improved', 'PosReg', (123, 131))	('XPD', 'Gene', '2068', (50, 53))	('patients, variant', 'Species', '9606', (21, 38))
552383	19620936	In contrast, in patients who did not receive cisplatin, variant alleles of XPD 751 and ERCC1 8092 had significantly worse survival, with adjusted hazard ratios of homozygous variants ranging from 2.47 (95% CI: 1.1-5.5) to 3.73 (95% CI: 1.6-8.7).	('worse', 'NegReg', (116, 121))	('variant', 'Var', (56, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('ERCC1', 'Gene', (87, 92))	('patients', 'Species', '9606', (16, 24))	('ERCC1', 'Gene', '2067', (87, 92))	('survival', 'MPA', (122, 130))	('XPD', 'Gene', (75, 78))	('XPD', 'Gene', '2068', (75, 78))
552384	19620936	DNA repair polymorphisms are associated with OS and PFS, and if validated may predict for benefit from cisplatin therapy in patients with esophageal cancer.	('esophageal cancer', 'Disease', (138, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('PFS', 'Disease', (52, 55))	('DNA repair', 'Gene', (0, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('polymorphisms', 'Var', (11, 24))	('associated', 'Reg', (29, 39))	('patients', 'Species', '9606', (124, 132))
552388	19620936	NER capacity is, therefore, important to the efficacy of cisplatin, and suboptimal NER capacity may render esophageal cancers more sensitive to cisplatin treatment.	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('esophageal cancers', 'Disease', (107, 125))	('more', 'PosReg', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancers', 'Disease', 'MESH:D004938', (107, 125))	('render', 'Reg', (100, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('sensitive', 'MPA', (131, 140))	('suboptimal', 'Var', (72, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))
552389	19620936	In preclinical studies, the variant alleles of the Xeroderma pigmentosum group D-complementing gene (XPD) polymorphisms XPD Asp312Asn (rs1799793) and XPD Lys751Gln (rs13181) are associated with decreased lymphocyte mRNA levels compared with the more common, wild-type allele.	('XPD', 'Gene', (120, 123))	('Lys751Gln', 'SUBSTITUTION', 'None', (154, 163))	('XPD', 'Gene', '2068', (150, 153))	('Xeroderma pigmentosum group D-complementing gene', 'Gene', (51, 99))	('rs13181', 'Mutation', 'rs13181', (165, 172))	('XPD', 'Gene', '2068', (120, 123))	('rs1799793', 'Mutation', 'rs1799793', (135, 144))	('lymphocyte mRNA levels', 'MPA', (204, 226))	('Lys751Gln', 'Var', (154, 163))	('Asp312Asn', 'Var', (124, 133))	('XPD', 'Gene', '2068', (101, 104))	('Asp312Asn', 'SUBSTITUTION', 'None', (124, 133))	('decreased lymphocyte', 'Phenotype', 'HP:0001888', (194, 214))	('XPD', 'Gene', (101, 104))	('decreased', 'NegReg', (194, 203))	('XPD', 'Gene', (150, 153))	('Xeroderma pigmentosum group D-complementing gene', 'Gene', '2068', (51, 99))	('rs1799793', 'Var', (135, 144))
552390	19620936	Excision repair cross-complementing 1 (ERCC1) codon 118C/T (rs11615) is associated with cisplatin sensitivity in ovarian cancer cell lines, and ERCC1 8092C/A (rs3212986) may be associated with altered mRNA stability.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('associated', 'Reg', (72, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('Excision repair cross-complementing 1', 'Gene', (0, 37))	('rs11615', 'Var', (60, 67))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('ERCC1', 'Gene', '2067', (144, 149))	('ERCC1', 'Gene', '2067', (39, 44))	('118C/T', 'Var', (52, 58))	('ERCC1', 'Gene', (144, 149))	('rs11615', 'Mutation', 'rs11615', (60, 67))	('ovarian cancer', 'Disease', (113, 127))	('ERCC1', 'Gene', (39, 44))	('rs3212986', 'Mutation', 'rs3212986', (159, 168))	('mRNA stability', 'MPA', (201, 215))	('cisplatin sensitivity', 'MPA', (88, 109))	('Excision repair cross-complementing 1', 'Gene', '2067', (0, 37))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('8092C/A', 'Mutation', 'rs3212986', (150, 157))	('118C/T', 'SUBSTITUTION', 'None', (52, 58))
552392	19620936	In a study of patients with advanced squamous cancer of the head and neck treated with cisplatin regimens, the variant alleles of XPD Asp312Asn and XPD Lys751Gln were associated with an improved overall survival (OS).	('Asp312Asn', 'SUBSTITUTION', 'None', (134, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('cancer of the head and neck', 'Phenotype', 'HP:0012288', (46, 73))	('XPD', 'Gene', '2068', (130, 133))	('XPD', 'Gene', (148, 151))	('squamous cancer', 'Phenotype', 'HP:0002860', (37, 52))	('Lys751Gln', 'SUBSTITUTION', 'None', (152, 161))	('improved', 'PosReg', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('overall survival', 'MPA', (195, 211))	('squamous cancer', 'Disease', 'MESH:D002294', (37, 52))	('XPD', 'Gene', '2068', (148, 151))	('Asp312Asn', 'Var', (134, 143))	('squamous cancer', 'Disease', (37, 52))	('Lys751Gln', 'Var', (152, 161))	('XPD', 'Gene', (130, 133))	('patients', 'Species', '9606', (14, 22))
552393	19620936	It was hypothesized that reduced DNA repair associated with the variant genotype provided a therapeutic advantage from cisplatin chemotherapy.	('reduced', 'NegReg', (25, 32))	('variant', 'Var', (64, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('DNA repair', 'MPA', (33, 43))
552396	19620936	We hypothesized that four NER polymorphisms, XPD Asp312Asn; XPD Lys751Gln, ERCC1 8092C/A, and ERCC1 codon 118C/T, are independent pharmacogenetic predictors of cisplatin therapy in esophageal cancer patients, which we evaluated in cisplatin and non-cisplatin-treated patients.	('ERCC1', 'Gene', '2067', (75, 80))	('esophageal cancer', 'Disease', (181, 198))	('118C/T', 'Var', (106, 112))	('XPD', 'Gene', '2068', (60, 63))	('Lys751Gln', 'Var', (64, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (231, 240))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('ERCC1', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('patients', 'Species', '9606', (267, 275))	('XPD', 'Gene', (45, 48))	('118C/T', 'SUBSTITUTION', 'None', (106, 112))	('XPD', 'Gene', (60, 63))	('Lys751Gln', 'SUBSTITUTION', 'None', (64, 73))	('8092C/A', 'Mutation', 'rs3212986', (81, 88))	('Asp312Asn', 'SUBSTITUTION', 'None', (49, 58))	('ERCC1', 'Gene', '2067', (94, 99))	('8092C/A', 'Var', (81, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (249, 258))	('Asp312Asn', 'Var', (49, 58))	('XPD', 'Gene', '2068', (45, 48))	('ERCC1', 'Gene', (94, 99))	('patients', 'Species', '9606', (199, 207))
552405	19620936	The four NER SNPs, XPD Asp312Asn, rs1799793; XPD Lys751Gln, rs13181; ERCC1 8092C/A, rs3212986; and ERCC1 codon 118C/T, rs11615, were selected based on the following criteria:    DNA was extracted from whole blood using the Puregene DNA Isolation Kit (Gentra Systems, Minneapolis, Minnesota, USA).	('ERCC1', 'Gene', '2067', (99, 104))	('118C/T', 'Var', (111, 117))	('rs13181', 'Var', (60, 67))	('rs11615', 'Mutation', 'rs11615', (119, 126))	('ERCC1', 'Gene', (99, 104))	('XPD', 'Gene', '2068', (19, 22))	('XPD', 'Gene', (45, 48))	('8092C/A', 'Mutation', 'rs3212986', (75, 82))	('rs1799793', 'Mutation', 'rs1799793', (34, 43))	('rs1799793', 'Var', (34, 43))	('Lys751Gln', 'SUBSTITUTION', 'None', (49, 58))	('118C/T', 'SUBSTITUTION', 'None', (111, 117))	('ERCC1', 'Gene', '2067', (69, 74))	('XPD', 'Gene', (19, 22))	('Asp312Asn', 'SUBSTITUTION', 'None', (23, 32))	('rs3212986', 'Var', (84, 93))	('ERCC1', 'Gene', (69, 74))	('XPD', 'Gene', '2068', (45, 48))	('rs13181', 'Mutation', 'rs13181', (60, 67))	('Asp312Asn', 'Var', (23, 32))	('Lys751Gln', 'Var', (49, 58))	('rs3212986', 'Mutation', 'rs3212986', (84, 93))
552408	19620936	By convention, the T allele of ERCC1 codon 118C/T has the greater allele frequency; therefore, this allele was treated as wild-type in analyses.	('118C/T', 'SUBSTITUTION', 'None', (43, 49))	('ERCC1', 'Gene', '2067', (31, 36))	('ERCC1', 'Gene', (31, 36))	('allele frequency', 'MPA', (66, 82))	('118C/T', 'Var', (43, 49))
552414	19620936	Exploratory haplotype analyses were performed to assess the combined effect of all four NER polymorphisms, which are in linkage disequilibrium (Lewontin D' for XPD Lys751Gln-XPD Asp312Asn-ERCC1 8092C/A-ERCC1 Codon 118C/T were 0.73-0.44-0.84).	('118C/T', 'SUBSTITUTION', 'None', (214, 220))	('XPD', 'Gene', '2068', (160, 163))	('ERCC1', 'Gene', '2067', (188, 193))	('ERCC1', 'Gene', (188, 193))	('Asp312Asn', 'Var', (178, 187))	('Lys751Gln', 'SUBSTITUTION', 'None', (164, 173))	('Asp312Asn', 'SUBSTITUTION', 'None', (178, 187))	('XPD', 'Gene', '2068', (174, 177))	('ERCC1', 'Gene', '2067', (202, 207))	('ERCC1', 'Gene', (202, 207))	('8092C/A', 'Mutation', 'rs3212986', (194, 201))	('Lys751Gln', 'Var', (164, 173))	('118C/T', 'Var', (214, 220))	('XPD', 'Gene', (160, 163))	('XPD', 'Gene', (174, 177))
552418	19620936	No-cisplatin-treated patients were older (P = 0.0002, t-test) and had significantly less nodal disease (P < 0.0001) than cisplatin-treated patients.	('cisplatin', 'Chemical', 'MESH:D002945', (3, 12))	('patients', 'Species', '9606', (139, 147))	('less', 'NegReg', (84, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('patients', 'Species', '9606', (21, 29))	('nodal disease', 'Disease', 'MESH:D013611', (89, 102))	('nodal disease', 'Disease', (89, 102))	('No-cisplatin-treated', 'Var', (0, 20))
552421	19620936	The genotype frequencies in the entire sample for homozygous wild-type, heterozygous, and homozygous variants, respectively, were as follows: XPD Asp312Asn (rs1799793) 40%, 51%, and 9%; XPD Lys751Gln (rs13181) 38%, 52%, and 10%; ERCC1 8092C/A (rs3212986) 50%, 44%, and 6%; and for ERCC1 codon 118C/T (rs11615) 13%, 52%, and 36%.	('ERCC1', 'Gene', '2067', (281, 286))	('Lys751Gln', 'Var', (190, 199))	('rs11615', 'Mutation', 'rs11615', (301, 308))	('XPD', 'Gene', (142, 145))	('Asp312Asn', 'SUBSTITUTION', 'None', (146, 155))	('rs13181', 'Mutation', 'rs13181', (201, 208))	('ERCC1', 'Gene', (281, 286))	('XPD', 'Gene', '2068', (186, 189))	('Asp312Asn', 'Var', (146, 155))	('8092C/A', 'Mutation', 'rs3212986', (235, 242))	('Lys751Gln', 'SUBSTITUTION', 'None', (190, 199))	('ERCC1', 'Gene', '2067', (229, 234))	('118C/T', 'Var', (293, 299))	('rs3212986', 'Var', (244, 253))	('ERCC1', 'Gene', (229, 234))	('XPD', 'Gene', '2068', (142, 145))	('XPD', 'Gene', (186, 189))	('rs11615', 'Var', (301, 308))	('118C/T', 'SUBSTITUTION', 'None', (293, 299))	('rs1799793', 'Mutation', 'rs1799793', (157, 166))	('rs1799793', 'Var', (157, 166))	('rs3212986', 'Mutation', 'rs3212986', (244, 253))
552423	19620936	For XPD Asp312Asn, the variant Asn allele was protective in cisplatin-treated patients, but had no effect on no-cisplatin patients.	('XPD', 'Gene', (4, 7))	('Asn', 'Chemical', 'MESH:D001216', (14, 17))	('Asn', 'Chemical', 'MESH:D001216', (31, 34))	('XPD', 'Gene', '2068', (4, 7))	('patients', 'Species', '9606', (78, 86))	('cisplatin-treated', 'Disease', (60, 77))	('patients', 'Species', '9606', (122, 130))	('Asp312Asn', 'SUBSTITUTION', 'None', (8, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('Asp312Asn', 'Var', (8, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
552424	19620936	For both XPD Lys751Gln and ERCC1 8092C/A, the protective effects of the variant Gln and A alleles, respectively, in cisplatin-treated patients were reversed, with increased risks of the variant allele conferred onto the no-cisplatin patients.	('cisplatin', 'Chemical', 'MESH:D002945', (223, 232))	('ERCC1', 'Gene', (27, 32))	('8092C/A', 'Mutation', 'rs3212986', (33, 40))	('Lys751Gln', 'SUBSTITUTION', 'None', (13, 22))	('ERCC1', 'Gene', '2067', (27, 32))	('patients', 'Species', '9606', (134, 142))	('Gln', 'Chemical', 'MESH:D005973', (80, 83))	('Lys751Gln', 'Var', (13, 22))	('XPD', 'Gene', (9, 12))	('Gln', 'Chemical', 'MESH:D005973', (19, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('patients', 'Species', '9606', (233, 241))	('XPD', 'Gene', '2068', (9, 12))
552425	19620936	No significant results were found with ERCC1 codon 118C/T.	('118C/T', 'Var', (51, 57))	('ERCC1', 'Gene', '2067', (39, 44))	('ERCC1', 'Gene', (39, 44))	('118C/T', 'SUBSTITUTION', 'None', (51, 57))
552426	19620936	Statistically significant interactions were observed for XPD Asp312Asn, XPD Lys751Gln, and ERCC1 8092C/A for outcome (OS and PFS), using both additive (Table 3) and codominant (Supplementary Table 1) models of inheritance.	('interactions', 'Interaction', (26, 38))	('8092C/A', 'Mutation', 'rs3212986', (97, 104))	('XPD', 'Gene', '2068', (57, 60))	('ERCC1', 'Gene', (91, 96))	('XPD', 'Gene', (72, 75))	('Lys751Gln', 'SUBSTITUTION', 'None', (76, 85))	('XPD', 'Gene', '2068', (72, 75))	('Asp312Asn', 'Var', (61, 70))	('Lys751Gln', 'Var', (76, 85))	('XPD', 'Gene', (57, 60))	('ERCC1', 'Gene', '2067', (91, 96))	('Asp312Asn', 'SUBSTITUTION', 'None', (61, 70))
552430	19620936	Supplementary Table 2 presents the results from these subgroup analyses for the three polymorphisms that yielded significant main associations, XPD Asp312Asn, XPD Lys751Gln, and ERCC1 codon 8092C/A, assuming an additive model of genetic inheritance.	('8092C/A', 'Var', (190, 197))	('XPD', 'Gene', (144, 147))	('ERCC1', 'Gene', '2067', (178, 183))	('ERCC1', 'Gene', (178, 183))	('XPD', 'Gene', (159, 162))	('Asp312Asn', 'Var', (148, 157))	('Asp312Asn', 'SUBSTITUTION', 'None', (148, 157))	('XPD', 'Gene', '2068', (144, 147))	('XPD', 'Gene', '2068', (159, 162))	('8092C/A', 'SUBSTITUTION', 'None', (190, 197))	('Lys751Gln', 'SUBSTITUTION', 'None', (163, 172))	('Lys751Gln', 'Var', (163, 172))
552438	19620936	As the four NER polymorphisms evaluated are in linkage disequilibrium, haplotype analysis was performed to assess the combined effect of XPD Lys751Gln (A/C), XPD Asp312Asn (G/A), ERCC1 8092C/A, ERCC1 codon 118C/T together, in cisplatin-treated and no-cisplatin groups.	('XPD', 'Gene', (137, 140))	('ERCC1', 'Gene', (179, 184))	('ERCC1', 'Gene', '2067', (179, 184))	('XPD', 'Gene', '2068', (137, 140))	('118C/T', 'Var', (206, 212))	('cisplatin', 'Chemical', 'MESH:D002945', (251, 260))	('XPD', 'Gene', '2068', (158, 161))	('Asp312Asn', 'Var', (162, 171))	('Asp312Asn', 'SUBSTITUTION', 'None', (162, 171))	('8092C/A', 'Var', (185, 192))	('ERCC1', 'Gene', '2067', (194, 199))	('ERCC1', 'Gene', (194, 199))	('Lys751Gln', 'SUBSTITUTION', 'None', (141, 150))	('118C/T', 'SUBSTITUTION', 'None', (206, 212))	('8092C/A', 'Mutation', 'rs3212986', (185, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (226, 235))	('Lys751Gln', 'Var', (141, 150))	('XPD', 'Gene', (158, 161))
552442	19620936	In this study, three of four NER polymorphisms, XPD Asp312Asn (rs1799793), XPD Lys751Gln (rs13181), and ERCC1 8092C/A (rs3212986), were strongly associated with OS and PFS in cisplatin-treated patients with esophageal cancer.	('XPD', 'Gene', (48, 51))	('Asp312Asn', 'SUBSTITUTION', 'None', (52, 61))	('rs13181', 'Mutation', 'rs13181', (90, 97))	('associated with', 'Reg', (145, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('rs13181', 'Var', (90, 97))	('Lys751Gln', 'SUBSTITUTION', 'None', (79, 88))	('Asp312Asn', 'Var', (52, 61))	('ERCC1', 'Gene', '2067', (104, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (207, 224))	('XPD', 'Gene', (75, 78))	('patients', 'Species', '9606', (193, 201))	('ERCC1', 'Gene', (104, 109))	('esophageal cancer', 'Disease', (207, 224))	('XPD', 'Gene', '2068', (48, 51))	('rs1799793', 'Var', (63, 72))	('rs1799793', 'Mutation', 'rs1799793', (63, 72))	('rs3212986', 'Var', (119, 128))	('PFS', 'Disease', (168, 171))	('rs3212986', 'Mutation', 'rs3212986', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('Lys751Gln', 'Var', (79, 88))	('XPD', 'Gene', '2068', (75, 78))	('8092C/A', 'Mutation', 'rs3212986', (110, 117))
552443	19620936	Our results are suggestive of a predictive effect through highly significant polymorphism-cisplatin treatment interactions, even after correction for multiple polymorphism comparisons.	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('polymorphism-cisplatin', 'Var', (77, 99))	('interactions', 'Interaction', (110, 122))
552444	19620936	Exploring further, the nature of these interactions through subgroup analyses, cisplatin-treated patients carrying variant alleles of XPD Asp312Asn, XPD Lys751Gln, and ERCC1 8092C/A had improved outcomes compared with patients carrying the wild-type genotypes of each of these polymorphisms.	('XPD', 'Gene', (134, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('ERCC1', 'Gene', (168, 173))	('patients', 'Species', '9606', (218, 226))	('Asp312Asn', 'Var', (138, 147))	('XPD', 'Gene', (149, 152))	('Asp312Asn', 'SUBSTITUTION', 'None', (138, 147))	('ERCC1', 'Gene', '2067', (168, 173))	('outcomes', 'MPA', (195, 203))	('XPD', 'Gene', '2068', (134, 137))	('improved', 'PosReg', (186, 194))	('patients', 'Species', '9606', (97, 105))	('XPD', 'Gene', '2068', (149, 152))	('Lys751Gln', 'SUBSTITUTION', 'None', (153, 162))	('8092C/A', 'Mutation', 'rs3212986', (174, 181))	('Lys751Gln', 'Var', (153, 162))
552446	19620936	Although we hypothesized that NER polymorphisms predict outcome for cisplatin-treated patients, we anticipated that the same polymorphisms might not have an association with survival in the no-cisplatin group.	('predict', 'Reg', (48, 55))	('polymorphisms', 'Var', (34, 47))	('NER', 'Gene', (30, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('patients', 'Species', '9606', (86, 94))
552447	19620936	This was indeed what was found for XPD Asp312Asn.	('Asp312Asn', 'SUBSTITUTION', 'None', (39, 48))	('Asp312Asn', 'Var', (39, 48))	('XPD', 'Gene', (35, 38))	('XPD', 'Gene', '2068', (35, 38))
552451	19620936	This was also the finding in a randomized controlled trial of cisplatin-based adjuvant chemotherapy in non-small-cell lung cancer (NSCLC), where the absence of intratumoral ERCC1 protein expression conferred a poorer prognosis in patients randomized to surgery alone.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('protein', 'Protein', (179, 186))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('NSCLC', 'Disease', (131, 136))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('patients', 'Species', '9606', (230, 238))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('ERCC1', 'Gene', '2067', (173, 178))	('ERCC1', 'Gene', (173, 178))	('lung cancer', 'Disease', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('absence', 'Var', (149, 156))	('tumor', 'Disease', (165, 170))
552453	19620936	One theory postulates that in the absence of cisplatin therapy, poor DNA repair may result in more biologically aggressive tumors through susceptibility to greater genetic aberrations over time, resulting in worse outcome.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('aggressive tumors', 'Disease', 'MESH:D001523', (112, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('result in', 'Reg', (84, 93))	('poor', 'NegReg', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('aggressive tumors', 'Disease', (112, 129))	('DNA', 'MPA', (69, 72))	('genetic aberrations', 'Var', (164, 183))	('more', 'PosReg', (94, 98))
552454	19620936	The results of our cisplatin-treated arm are consistent with prior studies evaluating DNA repair polymorphisms in malignancies of the aerodigestive tract.	('malignancies', 'Disease', (114, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('malignancies', 'Disease', 'MESH:D009369', (114, 126))	('polymorphisms', 'Var', (97, 110))
552455	19620936	In a study of DNA repair polymorphisms in patients with head and neck cancer, the variant alleles of XPD Lys751Gln and XPD Asp312Asn were associated with improved survival.	('Asp312Asn', 'Var', (123, 132))	('neck cancer', 'Disease', 'MESH:D006258', (65, 76))	('improved', 'PosReg', (154, 162))	('neck cancer', 'Disease', (65, 76))	('XPD', 'Gene', '2068', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Asp312Asn', 'SUBSTITUTION', 'None', (123, 132))	('Lys751Gln', 'Var', (105, 114))	('XPD', 'Gene', '2068', (101, 104))	('head and neck cancer', 'Phenotype', 'HP:0012288', (56, 76))	('XPD', 'Gene', (101, 104))	('survival', 'CPA', (163, 171))	('patients', 'Species', '9606', (42, 50))	('Lys751Gln', 'SUBSTITUTION', 'None', (105, 114))	('XPD', 'Gene', (119, 122))
552456	19620936	In a recent study evaluating the association of NER polymorphisms in NSCLC patients treated with a gemcitabine and docetaxel combination, the variant allele of XPD Lys751Gln was unfavorable, which is in keeping with the finding in our no-cisplatin cohort.	('XPD', 'Gene', '2068', (160, 163))	('Lys751Gln', 'SUBSTITUTION', 'None', (164, 173))	('NSCLC', 'Disease', (69, 74))	('patients', 'Species', '9606', (75, 83))	('docetaxel', 'Chemical', 'MESH:D000077143', (115, 124))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (238, 247))	('Lys751Gln', 'Var', (164, 173))	('XPD', 'Gene', (160, 163))	('gemcitabine', 'Chemical', 'MESH:C056507', (99, 110))
552458	19620936	However, in a study of cisplatin-treated patients with esophageal cancer, no independent association was found for either ERCC1 8092C/A or XPD Lys751Gln.	('ERCC1', 'Gene', (122, 127))	('8092C/A', 'Mutation', 'rs3212986', (128, 135))	('Lys751Gln', 'SUBSTITUTION', 'None', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (55, 72))	('patients', 'Species', '9606', (41, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('Lys751Gln', 'Var', (143, 152))	('cisplatin', 'Chemical', 'MESH:D002945', (23, 32))	('XPD', 'Gene', (139, 142))	('XPD', 'Gene', '2068', (139, 142))	('ERCC1', 'Gene', '2067', (122, 127))
552459	19620936	This study included 136 cisplatin-treated patients with a median follow-up time of 18.6 months, and may have been underpowered to detect an independent association for XPD Lys751Gln or ERCC1 8092C/A.	('XPD', 'Gene', (168, 171))	('ERCC1', 'Gene', (185, 190))	('ERCC1', 'Gene', '2067', (185, 190))	('XPD', 'Gene', '2068', (168, 171))	('8092C/A', 'Mutation', 'rs3212986', (191, 198))	('Lys751Gln', 'SUBSTITUTION', 'None', (172, 181))	('Lys751Gln', 'Var', (172, 181))	('patients', 'Species', '9606', (42, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))
552461	19620936	This compares with our study with almost double the number of cisplatin-treated patients, and 31 patients carrying the homozygous variant genotype for XPD Lys751Gln and 14 for ERCC1 8092C/A.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('XPD', 'Gene', (151, 154))	('patients', 'Species', '9606', (80, 88))	('XPD', 'Gene', '2068', (151, 154))	('ERCC1', 'Gene', '2067', (176, 181))	('ERCC1', 'Gene', (176, 181))	('Lys751Gln', 'SUBSTITUTION', 'None', (155, 164))	('8092C/A', 'Mutation', 'rs3212986', (182, 189))	('Lys751Gln', 'Var', (155, 164))	('patients', 'Species', '9606', (97, 105))
552469	19620936	Finally, XPD Lys751Gln has also been associated with altered paclitaxel cytotoxicity in cell line studies.	('cytotoxicity', 'Disease', 'MESH:D064420', (72, 84))	('Lys751Gln', 'SUBSTITUTION', 'None', (13, 22))	('Lys751Gln', 'Var', (13, 22))	('paclitaxel', 'Chemical', 'MESH:D017239', (61, 71))	('altered', 'Reg', (53, 60))	('XPD', 'Gene', (9, 12))	('associated', 'Reg', (37, 47))	('cytotoxicity', 'Disease', (72, 84))	('XPD', 'Gene', '2068', (9, 12))
552527	19862357	For example, as compared with cf (cisplatin, 5fu) in advanced gastric cancer, dcf yields a longer median survival (9.2 months vs. 8.6 months) and a better 2-year survival rate (18% vs. 9%), which led to its approval by the U.S. Food and Drug Administration for gastric and gastroesophageal junction cancers.	('dcf', 'Chemical', 'MESH:D015649', (78, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('longer', 'PosReg', (91, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('dcf', 'Var', (78, 81))	('median survival', 'MPA', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('gastric and gastroesophageal junction cancers', 'Disease', 'MESH:D013274', (261, 306))	('5fu', 'Chemical', 'MESH:D005472', (45, 48))	('gastric cancer', 'Disease', (62, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))
552531	19862357	Overall survival after ecf (epirubicin, cisplatin, 5fu) chemotherapy was longer than that with famtx (doxorubicin, 5fu, leucovorin, methotrexate: 8.9 months vs. 5.7 months) at the cost of more nausea, vomiting, and alopecia, and fewer episodes of neutropenia and infection.	('epirubicin', 'Var', (28, 38))	('nausea', 'Disease', (193, 199))	('epirubicin', 'Chemical', 'MESH:D015251', (28, 38))	('methotrexate', 'Chemical', 'MESH:D008727', (132, 144))	('alopecia', 'Disease', (215, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('5fu', 'Chemical', 'MESH:D005472', (51, 54))	('neutropenia and infection', 'Disease', 'MESH:D009503', (247, 272))	('vomiting', 'Disease', 'MESH:D014839', (201, 209))	('nausea', 'Disease', 'MESH:D009325', (193, 199))	('5fu', 'Chemical', 'MESH:D005472', (115, 118))	('more', 'PosReg', (188, 192))	('ecf', 'Var', (23, 26))	('doxorubicin', 'Chemical', 'MESH:D004317', (102, 113))	('vomiting', 'Phenotype', 'HP:0002013', (201, 209))	('famtx', 'Chemical', 'MESH:C059764', (95, 100))	('Overall', 'MPA', (0, 7))	('longer', 'PosReg', (73, 79))	('vomiting', 'Disease', (201, 209))	('leucovorin', 'Chemical', 'MESH:D002955', (120, 130))	('neutropenia', 'Phenotype', 'HP:0001875', (247, 258))	('alopecia', 'Phenotype', 'HP:0001596', (215, 223))	('nausea', 'Phenotype', 'HP:0002018', (193, 199))
552532	19862357	Survival after folfiri was equivalent to that after cf, but more grade 3+ diarrhea occurred with folfiri (22% vs. 7%) and more grade 3 neutropenia occurred with cf (52% vs. 25%).	('diarrhea', 'Disease', 'MESH:D003967', (74, 82))	('folfiri', 'Chemical', '-', (15, 22))	('neutropenia', 'Phenotype', 'HP:0001875', (135, 146))	('folfiri', 'Var', (97, 104))	('neutropenia', 'Disease', (135, 146))	('folfiri', 'Chemical', '-', (97, 104))	('diarrhea', 'Phenotype', 'HP:0002014', (74, 82))	('neutropenia', 'Disease', 'MESH:D009503', (135, 146))	('diarrhea', 'Disease', (74, 82))
552563	33671266	Although it remains unclear if additional chemotherapy should be provided in the adjuvant setting, subgroups such as patients with ERCC1 negativity, could potentially benefit from this treatment option based on our exploratory biomarker research.	('benefit', 'PosReg', (167, 174))	('ERCC1', 'Gene', (131, 136))	('negativity', 'Var', (137, 147))	('ERCC1', 'Gene', '2067', (131, 136))	('patients', 'Species', '9606', (117, 125))
552573	33671266	Although the question remains whether additional treatment with chemotherapy should be provided in the adjuvant setting, subgroups such as patients with ERCC1 negativity could potentially benefit from adjuvant SOX based on our exploratory biomarker research.	('patients', 'Species', '9606', (139, 147))	('ERCC1', 'Gene', '2067', (153, 158))	('ERCC1', 'Gene', (153, 158))	('negativity', 'Var', (159, 169))	('benefit', 'PosReg', (188, 195))
552608	33671266	In primary tumor biopsies, ERCC1 negativity did not correlate to survival (p = 0.656).	('negativity', 'Var', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('ERCC1', 'Gene', (27, 32))	('tumor', 'Disease', (11, 16))	('ERCC1', 'Gene', '2067', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
552613	33671266	Higher Cmax and AUC0-  of 5-FU correlated with higher toxicity grades of diarrhea (p = 0.05, p = 0.001 respectively), nausea (p = 0.03, p = 0.04 respectively) and vomiting (p = 0.02, p = 0.04 respectively).	('5-FU', 'Chemical', 'MESH:D005472', (26, 30))	('toxicity', 'Disease', (54, 62))	('Cmax', 'Var', (7, 11))	('vomiting', 'Disease', 'MESH:D014839', (163, 171))	('diarrhea', 'Phenotype', 'HP:0002014', (73, 81))	('diarrhea', 'Disease', 'MESH:D003967', (73, 81))	('AUC0-  of', 'Var', (16, 25))	('nausea', 'Phenotype', 'HP:0002018', (118, 124))	('diarrhea', 'Disease', (73, 81))	('nausea', 'Disease', (118, 124))	('nausea', 'Disease', 'MESH:D009325', (118, 124))	('toxicity', 'Disease', 'MESH:D064420', (54, 62))	('vomiting', 'Phenotype', 'HP:0002013', (163, 171))	('vomiting', 'Disease', (163, 171))
552635	33671266	In the validation cohort including patients treated with nCRT only, no correlation between ERCC1 negativity and survival benefit was observed.	('ERCC1', 'Gene', (91, 96))	('negativity', 'Var', (97, 107))	('ERCC1', 'Gene', '2067', (91, 96))	('patients', 'Species', '9606', (35, 43))
552638	33671266	Although immunohistochemistry analyses were performed on a small cohort, these findings suggest that the absence of ERCC1 tumor expression holds a prognostic and potentially predictive value as biomarker in response to adjuvant SOX.	('absence', 'Var', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('ERCC1', 'Gene', '2067', (116, 121))	('ERCC1', 'Gene', (116, 121))
552675	33671266	In the assay, oligonucleotide-labeled antibody pairs can bind to target proteins.	('oligonucleotide-labeled', 'Var', (14, 37))	('bind', 'Interaction', (57, 61))	('oligonucleotide', 'Chemical', 'MESH:D009841', (14, 29))	('proteins', 'Protein', (72, 80))
552679	33671266	Further research should focus on providing four cycles of adjuvant treatment to specific subgroups of patients with most benefit based on biomarker research, such as patients with ERCC1 negativity.	('negativity', 'Var', (186, 196))	('patients', 'Species', '9606', (102, 110))	('ERCC1', 'Gene', (180, 185))	('ERCC1', 'Gene', '2067', (180, 185))	('patients', 'Species', '9606', (166, 174))
552685	30886542	Identification of DNA methylation-driven genes in esophageal squamous cell carcinoma: a study based on The Cancer Genome Atlas Aberrant DNA methylations are significantly associated with esophageal squamous cell carcinoma (ESCC).	('DNA', 'Gene', (136, 139))	('associated with', 'Reg', (171, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (198, 221))	('methylations', 'Var', (140, 152))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (187, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))	('esophageal squamous cell carcinoma', 'Disease', (187, 221))
552695	30886542	Epigenetic changes are identified as significant contributors to cancer progression.	('cancer', 'Disease', (65, 71))	('Epigenetic changes', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
552696	30886542	Selective hypermethylation or hypomethylation of genes to regulate the expression of genes and form specific tissue types during development are considered to be a hallmark in developing many carcinomas.	('carcinomas', 'Disease', (192, 202))	('carcinomas', 'Disease', 'MESH:D002277', (192, 202))	('hyper', 'Disease', (10, 15))	('hyper', 'Disease', 'MESH:D053307', (10, 15))	('expression of genes', 'MPA', (71, 90))	('hypomethylation', 'Var', (30, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))
552702	30886542	stated out the function of epigenetic changes on malignant mesothelioma cell.	('epigenetic changes', 'Var', (27, 45))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (49, 71))	('mesothelioma', 'Disease', (59, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))
552727	30886542	Aberrant DNA methylation of genes can be served as noninvasive biomarkers for the diagnosis and detection of cancer.	('Aberrant DNA methylation', 'Var', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
552728	30886542	Several reports have shown that the aberrant methylation of DNA affects genes involved in DNA damage, cell cycle, Wnt, NF-kappaB signaling pathways, including MGMT, P16, DACH1 and ZNF382.	('cell', 'CPA', (102, 106))	('aberrant methylation', 'Var', (36, 56))	('NF-kappaB signaling pathways', 'Pathway', (119, 147))	('affects', 'Reg', (64, 71))	('MGMT', 'Gene', '4255', (159, 163))	('P16', 'Gene', (165, 168))	('MGMT', 'Gene', (159, 163))	('methylation', 'Var', (45, 56))	('ZNF382', 'Gene', (180, 186))	('P16', 'Gene', '1029', (165, 168))	('ZNF382', 'Gene', '84911', (180, 186))	('DACH1', 'Gene', (170, 175))	('DNA', 'Gene', (60, 63))	('DACH1', 'Gene', '1602', (170, 175))
552729	30886542	Also, other studies have shown that methylated FHIT is correlated with poor prognosis in early ESCC.	('methylated', 'Var', (36, 46))	('FHIT', 'Gene', (47, 51))	('early ESCC', 'Disease', (89, 99))	('FHIT', 'Gene', '2272', (47, 51))
552737	30886542	Previous studies have suggested CCDC8 (coiled-coil domain containing 8) was frequently epigenetically dysregulated in renal cell carcinoma and in breast carcinomas that metastasis to the brain.	('renal cell carcinoma', 'Disease', (118, 138))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (118, 138))	('CCDC8', 'Gene', (32, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('coiled-coil domain containing 8', 'Gene', (39, 70))	('breast carcinomas', 'Disease', 'MESH:D001943', (146, 163))	('breast carcinomas', 'Disease', (146, 163))	('epigenetically dysregulated', 'Var', (87, 114))	('CCDC8', 'Gene', '83987', (32, 37))	('coiled-coil domain containing 8', 'Gene', '83987', (39, 70))	('breast carcinomas', 'Phenotype', 'HP:0003002', (146, 163))
552739	30886542	The result may due to aberrant methylation of the sites leading to the dysregulation of the expression, which affects the generation and progression of cancers and the prognosis of patients.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('aberrant methylation', 'Var', (22, 42))	('dysregulation', 'MPA', (71, 84))	('methylation', 'Var', (31, 42))	('patients', 'Species', '9606', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('affects', 'Reg', (110, 117))	('expression', 'MPA', (92, 102))
552740	30886542	Growing evidence demonstrated that the aberrant DNA methylation was associated tumors generation and progression via the bioinformatics analysis.	('associated', 'Reg', (68, 78))	('DNA', 'Protein', (48, 51))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('aberrant', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
552742	30886542	used GEO database to study aberrant methylation genes as biomarkers for hepatocellular cancer.	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (72, 93))	('aberrant', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (72, 93))	('hepatocellular cancer', 'Disease', (72, 93))
552797	29600230	A recent randomized clinical trial comparing surgery alone with chemoradiation followed by surgery in patients with T1N1 or T2-3N0-1 esophageal cancer showed that preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric junction tumor.	('survival', 'MPA', (203, 211))	('T1N1', 'Var', (116, 120))	('junction tumor', 'Disease', (282, 296))	('esophageal', 'Disease', (133, 143))	('patients', 'Species', '9606', (218, 226))	('patients', 'Species', '9606', (102, 110))	('esophageal', 'Disease', 'MESH:D004941', (252, 262))	('T2-3N0-1', 'Var', (124, 132))	('esophagogastric junction tumor', 'Phenotype', 'HP:0100751', (266, 296))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('esophageal', 'Disease', 'MESH:D004941', (133, 143))	('improved', 'PosReg', (194, 202))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('junction tumor', 'Disease', 'MESH:D009369', (282, 296))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('esophageal', 'Disease', (252, 262))
552814	27793030	Four of the five microRNAs (miR-652-5p, miR-7-2-3p, miR-3925-3p, and miR-219-3p) were validated by qRT-PCR.	('miR-7-2-3p', 'Var', (40, 50))	('miR-21', 'Gene', (69, 75))	('miR-652-5p', 'Var', (28, 38))	('miR-3925-3p', 'Var', (52, 63))	('miR-21', 'Gene', '406991', (69, 75))
552816	27793030	The highest area under receiver operating characteristic (ROC) curve was 0.8212 for the combination of miR-652-5p and miR-7-2-3p.	('rat', 'Species', '10116', (35, 38))	('miR-7-2-3p', 'Var', (118, 128))	('miR-652-5p', 'Var', (103, 113))
552817	27793030	Collectively, our findings demonstrated that the miR-652-5p/miR-7-2-3p signature may serve as a promising prognostic marker in patients with locally advanced EAC.	('patients', 'Species', '9606', (127, 135))	('miR-652-5p/miR-7-2-3p', 'Var', (49, 70))	('EAC', 'Disease', (158, 161))	('rat', 'Species', '10116', (34, 37))
552823	27793030	MiRNAs significantly influence numerous cancer-relevant processes such as differentiation, proliferation, migration, and apoptosis by targeting developmental pathways.	('MiRNAs', 'Var', (0, 6))	('targeting', 'Reg', (134, 143))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('developmental pathways', 'Pathway', (144, 166))	('cancer', 'Disease', (40, 46))	('rat', 'Species', '10116', (98, 101))	('rat', 'Species', '10116', (109, 112))	('influence', 'Reg', (21, 30))	('proliferation', 'CPA', (91, 104))	('differentiation', 'CPA', (74, 89))	('migration', 'CPA', (106, 115))	('apoptosis', 'CPA', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
552824	27793030	Furthermore, accumulating studies have shown that aberrant miRNA expression is involved in the initiation and development of various types of cancers, including esophageal cancer.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancers', 'Disease', (142, 149))	('miRNA expression', 'Protein', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('involved', 'Reg', (79, 87))	('esophageal cancer', 'Disease', (161, 178))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('aberrant', 'Var', (50, 58))
552826	27793030	Liu et al, have demonstrated that silencing of miR-143 and miR-145 are linked with risk of development of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('silencing', 'Var', (34, 43))	('miR-143', 'Gene', '406935', (47, 54))	('rat', 'Species', '10116', (23, 26))	('miR-145', 'Gene', '406937', (59, 66))	('miR-143', 'Gene', (47, 54))	('linked', 'Reg', (71, 77))	('miR-145', 'Gene', (59, 66))	('esophageal cancer', 'Disease', (106, 123))
552836	27793030	Importantly, these networks were all regulated by three miRNAs within the list of 12: 1) miR-652-5p, 2) miR-7-2-3p and 3) miR-520h.	('miR-520h', 'Gene', '574493', (122, 130))	('regulated', 'Reg', (37, 46))	('miR-652-5p', 'Var', (89, 99))	('miR-520h', 'Gene', (122, 130))	('miR-7-2-3p', 'Var', (104, 114))
552838	27793030	A panel of the top five candidate miRNAs related to disease progression were selected based on 1) regulation of the main pathways identified by DIANA-mirPath analysis (miR-652-5p, miR-7-2-3p, miR-520h), 2) downregulation in the metastatic group compared to Stage I Non-Progressors (miR-3925-3p), and 3) correlation with an EAC metastatic rat model in our recent study (miR-219b-3p).	('miR-520h', 'Gene', (192, 200))	('rat', 'Species', '10116', (338, 341))	('miR-7-2-3p', 'Var', (180, 190))	('downregulation', 'NegReg', (206, 220))	('miR-652-5p', 'Var', (168, 178))	('miR-520h', 'Gene', '574493', (192, 200))
552840	27793030	Early identification of EAC and a reliable prediction of prognosis are essential to the development of individualized therapeutic strategies, and there is increasing evidence that aberrant expressions of miRNAs are closely associated with disease progression and carcinogenesis.	('carcinogenesis', 'Disease', (263, 277))	('rat', 'Species', '10116', (132, 135))	('associated', 'Reg', (223, 233))	('expressions', 'MPA', (189, 200))	('aberrant', 'Var', (180, 188))	('carcinogenesis', 'Disease', 'MESH:D063646', (263, 277))	('miRNAs', 'Gene', (204, 210))
552841	27793030	The present study demonstrates a discovery phase experiment that identifies and validates four miRNAs (miR-652-5p, miR-7-2-3p, miR-3925-3p, and miR-219-3p) that are significant and functionally relevant to EAC progression in Stage I EAC patients.	('Stage', 'Disease', (225, 230))	('miR-21', 'Gene', (144, 150))	('miR-3925-3p', 'Var', (127, 138))	('miR-21', 'Gene', '406991', (144, 150))	('miR-7-2-3p', 'Var', (115, 125))	('rat', 'Species', '10116', (25, 28))	('miR-652-5p', 'Var', (103, 113))	('EAC', 'Disease', (233, 236))	('EAC', 'Disease', (206, 209))	('patients', 'Species', '9606', (237, 245))
552846	27793030	The four miRNAs (miR-652-5p, miR-7-2-3p, miR-3925-3p, and miR-219-3p) that passed validation by qRT-PCR were consistent with several studies of other solid tumor types.	('miR-21', 'Gene', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('miR-652-5p', 'Var', (17, 27))	('miR-3925-3p', 'Var', (41, 52))	('tumor', 'Disease', (156, 161))	('miR-21', 'Gene', '406991', (58, 64))	('miR-7-2-3p', 'Var', (29, 39))
552853	27793030	In fact, the results of our study demonstrated that patients with downregulated miR-652-5p and/or miR-7-2-3p expression level have a significantly lower progression-free survival time.	('miR-7-2-3p', 'Var', (98, 108))	('progression-free survival time', 'CPA', (153, 183))	('lower', 'NegReg', (147, 152))	('downregulated', 'NegReg', (66, 79))	('rat', 'Species', '10116', (41, 44))	('miR-652-5p', 'Var', (80, 90))	('patients', 'Species', '9606', (52, 60))
552854	27793030	Consequently, patients with significantly downregulated miR-652-5p and miR-7-2-3p expression may benefit by the addition of adjuvant systemic therapy in order to more aggressively combat recurrence.	('expression', 'MPA', (82, 92))	('miR-7-2-3p', 'Gene', (71, 81))	('downregulated', 'NegReg', (42, 55))	('benefit', 'PosReg', (97, 104))	('miR-652-5p', 'Var', (56, 66))	('patients', 'Species', '9606', (14, 22))
552855	27793030	The National Comprehensive Cancer Network (NCCN) recommends adjuvant chemoradiation, or only adjuvant chemotherapy if induction radiation was administered, for patients who have had resection of adenocarcinoma with either residual disease, node-positive disease, or T2-T4a.	('patients', 'Species', '9606', (160, 168))	('adenocarcinoma', 'Disease', (195, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('Cancer', 'Disease', (27, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (195, 209))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('T2-T4a', 'Var', (266, 272))
552857	27793030	Moreover, miR-652-5p and miR-7-2-3p could be key therapeutic targets for patients with resectable EAC in an adjuvant therapeutic setting helping to identify high-risk patients.	('miR-7-2-3p', 'Var', (25, 35))	('patients', 'Species', '9606', (167, 175))	('patients', 'Species', '9606', (73, 81))	('EAC', 'Disease', (98, 101))	('miR-652-5p', 'Var', (10, 20))
552867	27793030	In conclusion, the present study identified a unique miRNA signature that was relevant to EAC progression and metastasis within the primary tumor, and subsequently, we demonstrated miR-652-5p/miR-7-2-3p signature might have clinical utility as a prognostic marker for surgically resectable EAC patients who could benefit from more aggressive adjuvant chemotherapy.	('metastasis within the primary tumor', 'Disease', (110, 145))	('miRNA', 'MPA', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (294, 302))	('EAC', 'Disease', (290, 293))	('metastasis within the primary tumor', 'Disease', 'MESH:D001929', (110, 145))	('rat', 'Species', '10116', (175, 178))	('miR-652-5p/miR-7-2-3p', 'Var', (181, 202))	('EAC', 'Disease', (90, 93))
552902	27506957	Kaplan-Meier method and Cox regression model were used to investigate the relationships between WIF-1, RASSF1A, and CDH13 promoter methylations and the prognosis of EC.	('methylations', 'Var', (131, 143))	('WIF-1', 'Gene', (96, 101))	('Cox', 'Gene', '1351', (24, 27))	('CDH13', 'Gene', (116, 121))	('RASSF1A', 'Gene', (103, 110))	('Cox', 'Gene', (24, 27))	('WIF-1', 'Gene', '11197', (96, 101))	('RASSF1A', 'Gene', '11186', (103, 110))	('CDH13', 'Gene', '1012', (116, 121))
552904	27506957	WIF-1 and CDH13 promoter methylations were associated with the degree of tumor differentiation and WIF-1 and RASSF1A promoter methylations were associated with age (all P<0.05).	('WIF-1', 'Gene', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('RASSF1A', 'Gene', '11186', (109, 116))	('associated', 'Reg', (144, 154))	('WIF-1', 'Gene', '11197', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('WIF-1', 'Gene', '11197', (0, 5))	('tumor', 'Disease', (73, 78))	('methylations', 'Var', (25, 37))	('associated', 'Reg', (43, 53))	('CDH13', 'Gene', '1012', (10, 15))	('CDH13', 'Gene', (10, 15))	('RASSF1A', 'Gene', (109, 116))	('WIF-1', 'Gene', (0, 5))
552905	27506957	The survival rates of patients with WIF-1, RASSF1A, and CDH13 methylations were significantly lower than those of patients without methylation (all P<0.05).	('survival rates', 'CPA', (4, 18))	('WIF-1', 'Gene', '11197', (36, 41))	('RASSF1A', 'Gene', '11186', (43, 50))	('CDH13', 'Gene', '1012', (56, 61))	('patients', 'Species', '9606', (22, 30))	('WIF-1', 'Gene', (36, 41))	('lower', 'NegReg', (94, 99))	('patients', 'Species', '9606', (114, 122))	('methylations', 'Var', (62, 74))	('CDH13', 'Gene', (56, 61))	('RASSF1A', 'Gene', (43, 50))
552911	27506957	Epigenetic silencing attributable to aberrant methylation of promoter regions was suggested as one of the main genetic alterations in the development and progression of cancers, including EC.	('methylation', 'Var', (46, 57))	('cancers', 'Disease', (169, 176))	('aberrant methylation', 'Var', (37, 57))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('alterations', 'Reg', (119, 130))	('Epigenetic', 'MPA', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
552913	27506957	The higher frequency of ras-association domain family member 1A (RASSF1A) gene methylation has been observed in many malignant tumor patients, indicating that RASSF1A inactivation is related to cancer pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('malignant tumor', 'Disease', (117, 132))	('cancer', 'Disease', (194, 200))	('RASSF1A', 'Gene', (65, 72))	('patients', 'Species', '9606', (133, 141))	('ras-association domain family member 1A', 'Gene', (24, 63))	('malignant tumor', 'Disease', 'MESH:D018198', (117, 132))	('ras-association domain family member 1A', 'Gene', '11186', (24, 63))	('RASSF1A', 'Gene', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('RASSF1A', 'Gene', '11186', (65, 72))	('methylation', 'Var', (79, 90))	('RASSF1A', 'Gene', '11186', (159, 166))	('related', 'Reg', (183, 190))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
552915	27506957	Furthermore, promoter methylation of the WIF-1 gene is involved in the EC process, and the abnormal expression of WIF-1 mRNA might be related to EC oncogenesis.	('WIF-1', 'Gene', (41, 46))	('related', 'Reg', (134, 141))	('involved', 'Reg', (55, 63))	('expression', 'MPA', (100, 110))	('WIF-1', 'Gene', (114, 119))	('abnormal', 'Var', (91, 99))	('WIF-1', 'Gene', '11197', (41, 46))	('WIF-1', 'Gene', '11197', (114, 119))	('promoter', 'MPA', (13, 21))
552916	27506957	RASSF1A was suggested to be one of the EC-related tumor suppressor genes, and hypermethylation of RASSF1A gene was associated with EC progression.	('RASSF1A', 'Gene', (0, 7))	('RASSF1A', 'Gene', '11186', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('RASSF1A', 'Gene', '11186', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('hypermethylation', 'Var', (78, 94))	('tumor', 'Disease', (50, 55))	('associated with', 'Reg', (115, 130))	('RASSF1A', 'Gene', (98, 105))
552917	27506957	A previous study showed that CDH1 gene silencing contributed to by promoter hypermethylation might have a considerable impact on the development of EC, and CDH1 methylation predicted post-surgery survival status of EC patients.	('patients', 'Species', '9606', (218, 226))	('impact', 'Reg', (119, 125))	('CDH1', 'Gene', (156, 160))	('CDH1', 'Gene', (29, 33))	('silencing', 'NegReg', (39, 48))	('methylation', 'Var', (161, 172))	('CDH1', 'Gene', '999', (29, 33))	('predicted', 'Reg', (173, 182))	('promoter', 'MPA', (67, 75))	('CDH1', 'Gene', '999', (156, 160))
552964	27506957	There were significant differences in the mRNA expression levels of WIF-1, RASSF1A, and CDH13 genes between tissues with methylation and tissues without methylation, and expression levels in the methylation group were significantly lower than those in the non-methylation group (all P<0.05) (Figure 3).	('WIF-1', 'Gene', (68, 73))	('RASSF1A', 'Gene', '11186', (75, 82))	('CDH13', 'Gene', (88, 93))	('differences', 'Reg', (23, 34))	('methylation', 'Var', (195, 206))	('WIF-1', 'Gene', '11197', (68, 73))	('expression levels', 'MPA', (170, 187))	('CDH13', 'Gene', '1012', (88, 93))	('mRNA expression levels', 'MPA', (42, 64))	('methylation', 'Var', (121, 132))	('RASSF1A', 'Gene', (75, 82))	('lower', 'NegReg', (232, 237))
552969	27506957	Prognostic outcomes and the overall survival (OS) status were significantly better in EC patients without WIF-1, RASSF1A, or CDH13 methylation compared to those in patients with methylation (all P<0.05).	('WIF-1', 'Gene', (106, 111))	('CDH13', 'Gene', (125, 130))	('overall survival', 'CPA', (28, 44))	('WIF-1', 'Gene', '11197', (106, 111))	('RASSF1A', 'Gene', '11186', (113, 120))	('CDH13', 'Gene', '1012', (125, 130))	('Prognostic outcomes', 'CPA', (0, 19))	('better', 'PosReg', (76, 82))	('OS', 'Chemical', '-', (46, 48))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (164, 172))	('RASSF1A', 'Gene', (113, 120))	('without', 'Var', (98, 105))	('methylation', 'Var', (131, 142))
552973	27506957	One of the main changes resulting from DNA methylation is transcriptional silencing of tumor suppressor genes, which is caused by hypermethylation of CpG islands in the promoter regions.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('methylation', 'Var', (43, 54))	('tumor', 'Disease', (87, 92))	('silencing', 'NegReg', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('transcriptional', 'MPA', (58, 73))
552975	27506957	Our study demonstrates that WIF-1, RASSF1A, and CDH13 promoter region methylations are associated with EC.	('CDH13', 'Gene', '1012', (48, 53))	('WIF-1', 'Gene', (28, 33))	('RASSF1A', 'Gene', (35, 42))	('associated', 'Reg', (87, 97))	('WIF-1', 'Gene', '11197', (28, 33))	('RASSF1A', 'Gene', '11186', (35, 42))	('CDH13', 'Gene', (48, 53))	('methylations', 'Var', (70, 82))
552977	27506957	The obtained results indicate that WIF-1, RASSF1A, and CDH13 gene methylations are associated with the progression of EC.	('CDH13', 'Gene', (55, 60))	('CDH13', 'Gene', '1012', (55, 60))	('RASSF1A', 'Gene', (42, 49))	('WIF-1', 'Gene', (35, 40))	('RASSF1A', 'Gene', '11186', (42, 49))	('associated with', 'Reg', (83, 98))	('WIF-1', 'Gene', '11197', (35, 40))	('methylations', 'Var', (66, 78))
552979	27506957	Studies have determined that the epigenetic silencing of WIF-1 is a common mechanism of promoter hypermethylation and it causes aberrant activation of the Wnt/b-catenin pathway in EC.	('WIF-1', 'Gene', '11197', (57, 62))	('promoter', 'MPA', (88, 96))	('Wnt', 'Gene', '7474', (155, 158))	('activation', 'PosReg', (137, 147))	('Wnt', 'Gene', (155, 158))	('b-catenin', 'Gene', '1499', (159, 168))	('epigenetic silencing', 'Var', (33, 53))	('WIF-1', 'Gene', (57, 62))	('b-catenin', 'Gene', (159, 168))
552981	27506957	As suggested by Dammann et al., the expression of RASSF1A in tumor cell lines can decrease the colony formation in vitro and tumorigenicity in vivo.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('RASSF1A', 'Gene', '11186', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('decrease', 'NegReg', (82, 90))	('expression', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (125, 130))	('RASSF1A', 'Gene', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
552982	27506957	In addition, DNA methylation of RASSF1A is expected to trigger the loss of function along with an increase in both spontaneous and induced tumor formation.	('RASSF1A', 'Gene', '11186', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('increase', 'PosReg', (98, 106))	('RASSF1A', 'Gene', (32, 39))	('DNA methylation', 'Var', (13, 28))	('loss of function', 'NegReg', (67, 83))
552985	27506957	proposed that the aberrant methylation of CDH13 gene is common in oesophageal and gastric cancers.	('common', 'Reg', (56, 62))	('CDH13', 'Gene', '1012', (42, 47))	('gastric cancers', 'Disease', 'MESH:D013274', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gastric cancers', 'Disease', (82, 97))	('gastric cancers', 'Phenotype', 'HP:0012126', (82, 97))	('methylation', 'Var', (27, 38))	('oesophageal', 'Disease', (66, 77))	('CDH13', 'Gene', (42, 47))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('aberrant methylation', 'Var', (18, 38))
552986	27506957	Additionally, the abnormal methylation could be found in patients with gastric cancers at all clinical stages, which means that both oesophageal and gastric cancers can be methylated at an early stage.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gastric cancers', 'Disease', (71, 86))	('gastric cancers', 'Phenotype', 'HP:0012126', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (57, 65))	('oesophageal', 'Disease', (133, 144))	('methylation', 'Var', (27, 38))	('gastric cancers', 'Disease', 'MESH:D013274', (149, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('found', 'Reg', (48, 53))	('gastric cancers', 'Disease', (149, 164))	('gastric cancers', 'Phenotype', 'HP:0012126', (149, 164))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('gastric cancers', 'Disease', 'MESH:D013274', (71, 86))
552987	27506957	Therefore, CDH13 methylation could act as a tumor marker for early detection of digestive tract cancers.	('CDH13', 'Gene', '1012', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tract cancers', 'Disease', (90, 103))	('methylation', 'Var', (17, 28))	('tract cancers', 'Disease', 'MESH:D014571', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('tumor', 'Disease', (44, 49))	('CDH13', 'Gene', (11, 16))
552988	27506957	These studies confirmed that WIF-1, RASSF1A, and CDH13 gene methylations exert functions in the formation and development of EC.	('CDH13', 'Gene', (49, 54))	('WIF-1', 'Gene', '11197', (29, 34))	('methylations', 'Var', (60, 72))	('CDH13', 'Gene', '1012', (49, 54))	('RASSF1A', 'Gene', '11186', (36, 43))	('functions', 'Reg', (79, 88))	('WIF-1', 'Gene', (29, 34))	('RASSF1A', 'Gene', (36, 43))
552990	27506957	It has been verified that the aberrant DNA methylations of some particular genes were related to the clinicopathologic features and clinical outcomes of cancer cancers.	('cancer cancers', 'Disease', 'MESH:D009369', (153, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('aberrant DNA', 'Var', (30, 42))	('cancer cancers', 'Disease', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('related', 'Reg', (86, 93))
552991	27506957	Another result in our study was that the overall survival rates of patients with WIF-1, RASSF1A, and CDH13 methylations were significantly lower than those of the patients with non-methylations.	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (67, 75))	('WIF-1', 'Gene', '11197', (81, 86))	('RASSF1A', 'Gene', '11186', (88, 95))	('CDH13', 'Gene', '1012', (101, 106))	('WIF-1', 'Gene', (81, 86))	('lower', 'NegReg', (139, 144))	('RASSF1A', 'Gene', (88, 95))	('methylations', 'Var', (107, 119))	('CDH13', 'Gene', (101, 106))
552993	27506957	Methylation profile can predict responses to radiotherapy and chemotherapy agents, and thus affects the prognosis of cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Methylation', 'Var', (0, 11))	('affects', 'Reg', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('predict', 'Reg', (24, 31))
552994	27506957	This study indicates that the OS time is substantially reduced with the methylation of WIF-1; therefore, WIF-1 gene methylation could be used as a biomarker for predicting the prognosis of EC patients.	('WIF-1', 'Gene', '11197', (105, 110))	('WIF-1', 'Gene', (87, 92))	('reduced', 'NegReg', (55, 62))	('patients', 'Species', '9606', (192, 200))	('methylation', 'Var', (72, 83))	('OS', 'Chemical', '-', (30, 32))	('WIF-1', 'Gene', '11197', (87, 92))	('WIF-1', 'Gene', (105, 110))
552995	27506957	Inactivation of RASSF1A is closely associated with poor outcomes of some cancers, including advanced-stage tumors.	('cancers', 'Disease', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('associated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('RASSF1A', 'Gene', '11186', (16, 23))	('RASSF1A', 'Gene', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('Inactivation', 'Var', (0, 12))
552996	27506957	suggested that hyper-methylated RASSF1A is related to less favorable OS.	('RASSF1A', 'Gene', '11186', (32, 39))	('hyper-methylated', 'Var', (15, 31))	('OS', 'Chemical', '-', (69, 71))	('RASSF1A', 'Gene', (32, 39))	('less', 'Disease', (54, 58))
552997	27506957	It has been reported that patients with CDH13 methylation had worse progression-free survival time and shorter recurrence-free survival when compared to patients without CDH13 methylation.	('methylation', 'Var', (46, 57))	('CDH13', 'Gene', (170, 175))	('patients', 'Species', '9606', (153, 161))	('worse', 'NegReg', (62, 67))	('CDH13', 'Gene', (40, 45))	('progression-free survival time', 'CPA', (68, 98))	('shorter', 'NegReg', (103, 110))	('patients', 'Species', '9606', (26, 34))	('CDH13', 'Gene', '1012', (170, 175))	('CDH13', 'Gene', '1012', (40, 45))	('recurrence-free survival', 'CPA', (111, 135))
552998	27506957	Therefore, CDH13 methylation might be used to assess the severity of disease in order to tailor appropriate therapeutic approaches.	('CDH13', 'Gene', '1012', (11, 16))	('methylation', 'Var', (17, 28))	('CDH13', 'Gene', (11, 16))
552999	27506957	Our study provides strong evidence that WIF-1, RASSF1A, and CDH13 promoter region methylations are associated with EC.	('RASSF1A', 'Gene', (47, 54))	('WIF-1', 'Gene', '11197', (40, 45))	('methylations', 'Var', (82, 94))	('RASSF1A', 'Gene', '11186', (47, 54))	('CDH13', 'Gene', (60, 65))	('CDH13', 'Gene', '1012', (60, 65))	('WIF-1', 'Gene', (40, 45))	('associated', 'Reg', (99, 109))
553001	27506957	Therefore, WIF-1, RASSF1A, and CDH13 gene methylations may be considered as biomarkers for predicting the prognosis of EC patients.	('WIF-1', 'Gene', (11, 16))	('CDH13', 'Gene', '1012', (31, 36))	('RASSF1A', 'Gene', (18, 25))	('patients', 'Species', '9606', (122, 130))	('WIF-1', 'Gene', '11197', (11, 16))	('methylations', 'Var', (42, 54))	('RASSF1A', 'Gene', '11186', (18, 25))	('CDH13', 'Gene', (31, 36))
553049	32547096	The expression levels of FAM83D in the esophageal cancer tissues and paracarcinoma tissues of the sixty-nine patients were measured.	('paracarcinoma', 'Disease', (69, 82))	('patients', 'Species', '9606', (109, 117))	('paracarcinoma', 'Disease', 'None', (69, 82))	('expression', 'MPA', (4, 14))	('esophageal cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('FAM83D', 'Var', (25, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
553051	32547096	In addition, we also examined changes in the expression of metastasis-related molecules at the protein and mRNA levels by qRT-PCR and Western blotting after silencing FAM83D expression, and we detected the expression of PI3K/Akt signaling-related proteins by Western blotting.	('FAM83D', 'Gene', (167, 173))	('Akt', 'Gene', '207', (225, 228))	('Akt', 'Gene', (225, 228))	('expression', 'MPA', (45, 55))	('silencing', 'Var', (157, 166))	('metastasis-related molecules', 'Gene', (59, 87))
553053	32547096	FAM83D overexpression was positively associated with tumor size, tumor-node-metastasis (TNM) stage, T classification, N classification, distant metastasis and relapse and was negatively associated with patient survival rates.	('T classification', 'CPA', (100, 116))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('distant metastasis', 'CPA', (136, 154))	('N classification', 'CPA', (118, 134))	('patient', 'Species', '9606', (202, 209))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('overexpression', 'PosReg', (7, 21))	('tumor', 'Disease', (53, 58))	('associated', 'Reg', (37, 47))	('negatively', 'NegReg', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('FAM83D', 'Var', (0, 6))	('relapse', 'CPA', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
553054	32547096	Compared to that in the control group, the proliferation of tumor cells in the FAM83D shRNA group was hindered after exposure to radiation in vitro and in vivo; in addition, FAM83D knockdown inhibited cell invasion, induced apoptosis and regulated apoptosis-related protein expression.	('hindered', 'NegReg', (102, 110))	('inhibited', 'NegReg', (191, 200))	('regulated', 'Reg', (238, 247))	('cell invasion', 'CPA', (201, 214))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('apoptosis-related protein', 'Gene', '23591', (248, 273))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('induced', 'Reg', (216, 223))	('apoptosis', 'CPA', (224, 233))	('apoptosis-related protein', 'Gene', (248, 273))	('tumor', 'Disease', (60, 65))	('FAM83D knockdown', 'Var', (174, 190))
553055	32547096	Moreover, the radiosensitivity of esophageal cancer cells was increased after depletion of FAM83D.	('increased', 'PosReg', (62, 71))	('esophageal cancer', 'Disease', (34, 51))	('depletion', 'Var', (78, 87))	('radiosensitivity', 'CPA', (14, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('FAM83D', 'Var', (91, 97))
553056	32547096	In addition, FAM83D silencing was associated with the reversion of EMT, as reflected by an increase in the epithelial marker E-cadherin and a decrease in the mesenchymal markers N-cadherin and vimentin.	('mesenchymal markers', 'CPA', (158, 177))	('E-cadherin', 'Gene', '999', (125, 135))	('vimentin', 'Gene', '7431', (193, 201))	('N-cadherin', 'Gene', (178, 188))	('EMT', 'CPA', (67, 70))	('increase', 'PosReg', (91, 99))	('FAM83D', 'Var', (13, 19))	('vimentin', 'Gene', (193, 201))	('decrease', 'NegReg', (142, 150))	('N-cadherin', 'Gene', '1000', (178, 188))	('silencing', 'NegReg', (20, 29))	('reversion', 'CPA', (54, 63))	('E-cadherin', 'Gene', (125, 135))
553057	32547096	Further study showed that FAM83D depletion suppressed the signaling pathway involving p-Akt, p-GSK-3beta and Snail.	('Akt', 'Gene', '207', (88, 91))	('signaling pathway', 'Pathway', (58, 75))	('Snail', 'Gene', '6615', (109, 114))	('Snail', 'Gene', (109, 114))	('FAM83D depletion', 'Var', (26, 42))	('GSK-3beta', 'Gene', '2931', (95, 104))	('Akt', 'Gene', (88, 91))	('GSK-3beta', 'Gene', (95, 104))	('suppressed', 'NegReg', (43, 53))
553058	32547096	The results reveal that FAM83D may be a potential therapeutic target for esophageal squamous cell carcinoma (ESCC) and that lower expression of FAM83D in coordination with irradiation promotes the radiosensitization of ESCC by inducing EMT through the Akt/GSK-3beta/Snail signaling pathway.	('Akt', 'Gene', '207', (252, 255))	('inducing', 'PosReg', (227, 235))	('Snail', 'Gene', (266, 271))	('radiosensitization', 'CPA', (197, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (73, 107))	('Snail', 'Gene', '6615', (266, 271))	('Akt', 'Gene', (252, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('GSK-3beta', 'Gene', '2931', (256, 265))	('FAM83D', 'Var', (144, 150))	('EMT', 'CPA', (236, 239))	('lower', 'NegReg', (124, 129))	('esophageal squamous cell carcinoma', 'Disease', (73, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('ESCC', 'Disease', (219, 223))	('GSK-3beta', 'Gene', (256, 265))	('promotes', 'PosReg', (184, 192))
553062	32547096	More importantly, it was recently demonstrated that FAM83D exhibits oncogenic properties and acts as a novel oncogene in various human tumors, including gynecological, gastrointestinal and respiratory cancers.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('gynecological', 'Disease', (153, 166))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('human', 'Species', '9606', (129, 134))	('FAM83D', 'Var', (52, 58))	('gastrointestinal and respiratory cancers', 'Disease', 'MESH:D012818', (168, 208))	('oncogenic properties', 'CPA', (68, 88))
553063	32547096	A recent study indicated that FAM83D participates in the development of colorectal cancer by downregulating the tumor suppressor gene FBXW7 and has prognostic value for patients with colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('tumor', 'Disease', (112, 117))	('patients', 'Species', '9606', (169, 177))	('FBXW7', 'Gene', (134, 139))	('downregulating', 'NegReg', (93, 107))	('FAM83D', 'Var', (30, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (183, 200))	('participates', 'Reg', (37, 49))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (183, 200))	('colorectal cancer', 'Disease', (72, 89))	('FBXW7', 'Gene', '55294', (134, 139))	('colorectal cancer', 'Disease', (183, 200))
553065	32547096	However, the biological role of FAM83D and its molecular mechanism in regulating radiosensitization is still unknown in human ESCC.	('FAM83D', 'Var', (32, 38))	('human', 'Species', '9606', (120, 125))	('ESCC', 'Disease', (126, 130))	('radiosensitization', 'MPA', (81, 99))
553067	32547096	Given the crucial role of FAM83D in ionizing radiation-induced DNA damage response (DDR), we assume that knockdown of FAM83D may bring about DNA damage pathway defects and thus increase radiosensitivity.	('FAM83D', 'Var', (118, 124))	('damage pathway defects', 'Disease', (145, 167))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (177, 202))	('knockdown', 'Var', (105, 114))	('increase', 'PosReg', (177, 185))	('radiosensitivity', 'CPA', (186, 202))	('damage pathway defects', 'Disease', 'MESH:D000014', (145, 167))	('bring about', 'Reg', (129, 140))
553068	32547096	In this research, we attempted to verify the above hypothesis by using different types of cells in vitro to explore the regulatory mechanisms of FAM83D-induced carcinogenesis and tumor progression.	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('FAM83D-induced', 'Var', (145, 159))	('carcinogenesis', 'Disease', (160, 174))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
553085	32547096	The tumor cells in the control, NC, and FAM83D shRNA groups were irradiated by graded single doses (0-8 Gy) and seeded in petri dishes with complete RPMI-1640 medium.	('tumor', 'Disease', (4, 9))	('FAM83D', 'Var', (40, 46))	('RPMI-1640 medium', 'Chemical', '-', (149, 165))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
553094	32547096	As summarized in Table 1, the accumulation of FAM83D in esophageal cancer was significantly associated with tumor size (P=0.029), TNM stage (P=0.034), T classification (P=0.020), N classification (P=0.048), distant metastasis (P=0.024), and relapse (P=0.011), indicating a correlation between FAM83D expression and esophageal cancer invasion, and metastasis.	('accumulation', 'PosReg', (30, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (315, 332))	('tumor', 'Disease', (108, 113))	('esophageal cancer', 'Disease', (315, 332))	('metastasis', 'CPA', (347, 357))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('distant metastasis', 'CPA', (207, 225))	('relapse', 'CPA', (241, 248))	('associated', 'Reg', (92, 102))	('T classification', 'CPA', (151, 167))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('N classification', 'CPA', (179, 195))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('TNM stage', 'CPA', (130, 139))	('FAM83D', 'Var', (293, 299))	('FAM83D', 'Var', (46, 52))	('esophageal cancer', 'Disease', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('invasion', 'CPA', (333, 341))
553096	32547096	Furthermore, Kaplan-Meier analysis indicated that patients with lower FAM83D protein levels had a significantly longer overall survival than patients with higher levels of FAM83D expression (P<0.001, Log rank test; Figure 1A-e).	('patients', 'Species', '9606', (50, 58))	('lower', 'NegReg', (64, 69))	('overall survival', 'CPA', (119, 135))	('FAM83D', 'Var', (70, 76))	('patients', 'Species', '9606', (141, 149))	('longer', 'PosReg', (112, 118))
553101	32547096	The results revealed that the volume and weight (Figure 2C) of tumors in the FAM83D depletion group were significantly smaller than those in the NC group before and after irradiation (P<0.01).	('smaller', 'NegReg', (119, 126))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('FAM83D depletion', 'Var', (77, 93))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
553102	32547096	The apoptosis rate in the FAM83D shRNA group was higher than that in the control and NC groups before IR, as evidenced by both annexin V and 7-AAD staining.	('annexin V', 'Gene', (127, 136))	('FAM83D', 'Var', (26, 32))	('annexin V', 'Gene', '308', (127, 136))	('7-AAD', 'Chemical', 'MESH:C025942', (141, 146))	('apoptosis rate', 'CPA', (4, 18))	('higher', 'PosReg', (49, 55))
553104	32547096	Significant downregulation of Bid and Mcl-1 and upregulation of the active form of caspase-3, but not total caspase-3, were observed in the FAM83D shRNA group before IR (Figure 3A).	('downregulation', 'NegReg', (12, 26))	('caspase-3', 'Gene', (108, 117))	('Bid', 'Gene', '637', (30, 33))	('caspase-3', 'Gene', '836', (83, 92))	('Bid', 'Gene', (30, 33))	('caspase-3', 'Gene', '836', (108, 117))	('active form', 'MPA', (68, 79))	('FAM83D', 'Var', (140, 146))	('Mcl-1', 'Gene', (38, 43))	('caspase-3', 'Gene', (83, 92))	('Mcl-1', 'Gene', '4170', (38, 43))	('upregulation', 'PosReg', (48, 60))
553108	32547096	Our data demonstrated that silencing FAM83D can upregulate the expression of an epithelial marker (E-cadherin) and downregulate mesenchymal markers (N-cadherin and vimentin) at the RNA and protein levels before IR in both ECA109 and KYSE30 cells (Figure 5A and C).	('silencing', 'Var', (27, 36))	('mesenchymal', 'CPA', (128, 139))	('vimentin', 'Gene', (164, 172))	('EC', 'Phenotype', 'HP:0011459', (222, 224))	('expression', 'MPA', (63, 73))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))	('downregulate', 'NegReg', (115, 127))	('N-cadherin', 'Gene', (149, 159))	('upregulate', 'PosReg', (48, 58))	('vimentin', 'Gene', '7431', (164, 172))	('N-cadherin', 'Gene', '1000', (149, 159))	('FAM83D', 'Gene', (37, 43))
553110	32547096	To further elucidate the potential signaling pathways involved in FAM83D-mediated EMT, we explored the main effects of FAM83D depletion on the Akt/GSK-3beta/Snail signaling pathway.	('Snail', 'Gene', (157, 162))	('GSK-3beta', 'Gene', (147, 156))	('Snail', 'Gene', '6615', (157, 162))	('Akt', 'Gene', '207', (143, 146))	('FAM83D', 'Var', (119, 125))	('Akt', 'Gene', (143, 146))	('FAM83D-mediated', 'Var', (66, 81))	('GSK-3beta', 'Gene', '2931', (147, 156))
553111	32547096	Our results suggested that the protein levels of phosphorylated Akt (Ser473) and phosphorylated GSK-3beta (Ser9), but not total Akt or total GSK-3beta, were significantly decreased after silencing FAM83D.	('Ser473', 'Chemical', '-', (69, 75))	('protein levels', 'MPA', (31, 45))	('FAM83D', 'Gene', (197, 203))	('GSK-3beta', 'Gene', (96, 105))	('decreased', 'NegReg', (171, 180))	('GSK-3beta', 'Gene', '2931', (141, 150))	('Ser9', 'Chemical', '-', (107, 111))	('Akt', 'Gene', (128, 131))	('GSK-3beta', 'Gene', (141, 150))	('Akt', 'Gene', '207', (64, 67))	('silencing', 'Var', (187, 196))	('Akt', 'Gene', (64, 67))	('Akt', 'Gene', '207', (128, 131))	('GSK-3beta', 'Gene', '2931', (96, 105))
553112	32547096	Additionally, the expression level of Snail was also downregulated by FAM83D depletion before (Figure 6A) and after IR (Figure 6B).	('FAM83D depletion', 'Var', (70, 86))	('expression level', 'MPA', (18, 34))	('Snail', 'Gene', (38, 43))	('Snail', 'Gene', '6615', (38, 43))	('downregulated', 'NegReg', (53, 66))
553113	32547096	These findings suggest that FAM83D knockdown acts through the Akt/GSK-3beta/Snail signaling pathway to hinder the progression of EMT in ESCC.	('FAM83D knockdown', 'Var', (28, 44))	('progression of EMT in', 'CPA', (114, 135))	('GSK-3beta', 'Gene', (66, 75))	('ESCC', 'Disease', (136, 140))	('Akt', 'Gene', '207', (62, 65))	('hinder', 'NegReg', (103, 109))	('Snail', 'Gene', (76, 81))	('GSK-3beta', 'Gene', '2931', (66, 75))	('Snail', 'Gene', '6615', (76, 81))	('Akt', 'Gene', (62, 65))
553120	32547096	A recent study showed that FAM83D overexpression exerts oncogenic effects and promotes the interaction of FAM83D and FBXW7 in breast cancer cells.	('oncogenic effects', 'CPA', (56, 73))	('promotes', 'PosReg', (78, 86))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('FBXW7', 'Gene', '55294', (117, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('overexpression', 'PosReg', (34, 48))	('FAM83D', 'Var', (106, 112))	('FBXW7', 'Gene', (117, 122))	('FAM83D', 'Gene', (27, 33))	('interaction', 'Interaction', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
553121	32547096	Moreover, FAM83D overexpression is significantly correlated with poor disease-free survival in patients with breast cancer.	('breast cancer', 'Disease', (109, 122))	('patients', 'Species', '9606', (95, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('disease-free survival', 'CPA', (70, 91))	('overexpression', 'PosReg', (17, 31))	('FAM83D', 'Var', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('poor', 'NegReg', (65, 69))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
553122	32547096	However, studies elucidating the role and mechanism of FAM83D in esophageal carcinoma have not yet been conducted.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal carcinoma', 'Disease', (65, 85))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (65, 85))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (65, 85))	('FAM83D', 'Var', (55, 61))
553124	32547096	Our results indicate that FAM83D expression is obviously elevated in esophageal carcinoma tissues and cell lines, which suggests that FAM83D may act as an oncogene.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('FAM83D', 'Gene', (26, 32))	('elevated', 'PosReg', (57, 65))	('esophageal carcinoma', 'Disease', (69, 89))	('FAM83D', 'Var', (134, 140))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (69, 89))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (69, 89))	('expression', 'MPA', (33, 43))
553125	32547096	Similar to a previous study, our data demonstrated that overexpression of FAM83D is positively associated with tumor size, TNM stage, distant metastasis and relapse and negatively associated with a poor survival rate.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('FAM83D', 'Var', (74, 80))	('tumor', 'Disease', (111, 116))	('negatively', 'NegReg', (169, 179))	('relapse', 'CPA', (157, 164))	('distant metastasis', 'CPA', (134, 152))	('overexpression', 'PosReg', (56, 70))	('TNM stage', 'CPA', (123, 132))	('associated', 'Reg', (95, 105))
553129	32547096	We found similar results: silencing FAM83D obviously inhibited the proliferation of tumor cells exposed to radiation or not in vitro and in vivo, and the effect of FAM83D knockdown combined with irradiation on their suppression was more obvious.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('FAM83D', 'Gene', (36, 42))	('inhibited', 'NegReg', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('silencing', 'Var', (26, 35))
553134	32547096	Consistent with our results, a recent study demonstrated that FAM83D modulates the migration of hepatocellular carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('hepatocellular carcinoma', 'Disease', (96, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('modulates', 'Reg', (69, 78))	('FAM83D', 'Var', (62, 68))	('migration', 'CPA', (83, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))
553135	32547096	Shi et al suggested that knockdown of FAM83D markedly suppressed the metastasis of lung adenocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('metastasis of', 'CPA', (69, 82))	('suppressed', 'NegReg', (54, 64))	('lung adenocarcinoma', 'Disease', (83, 102))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('FAM83D', 'Var', (38, 44))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))
553139	32547096	Similar to the above study, we found that FAM83D depletion in ESCC inhibited EMT by increasing of E-cadherin expression and reducing of N-cadherin and vimentin expression before IR; the alteration was more obvious after IR, implying that FAM83D may play an important role in regulating radiosensitivity by inducing EMT to mediate the invasion and migration of cells.	('increasing', 'PosReg', (84, 94))	('expression', 'MPA', (160, 170))	('N-cadherin', 'Gene', (136, 146))	('inhibited', 'NegReg', (67, 76))	('expression', 'MPA', (109, 119))	('E-cadherin', 'Gene', (98, 108))	('E-cadherin', 'Gene', '999', (98, 108))	('inducing', 'PosReg', (306, 314))	('N-cadherin', 'Gene', '1000', (136, 146))	('depletion', 'Var', (49, 58))	('reducing', 'NegReg', (124, 132))	('EMT', 'CPA', (77, 80))	('EMT', 'CPA', (315, 318))	('vimentin', 'Gene', '7431', (151, 159))	('FAM83D depletion', 'Var', (42, 58))	('vimentin', 'Gene', (151, 159))
553143	32547096	Recently, published studies have demonstrated that overexpression of FAM83D enhances the proliferation, motility and invasiveness of non-small-cell lung cancer cells, facilitates concurrent EMT-like molecular changes and is associated with the activation of the Akt/mTOR signaling pathway; however, repression of FAM83D reverses the expression of EMT markers and inhibits the Akt/mTOR pathway.	('proliferation', 'CPA', (89, 102))	('Akt', 'Gene', (262, 265))	('motility', 'CPA', (104, 112))	('mTOR', 'Gene', '2475', (266, 270))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (137, 159))	('reverses', 'NegReg', (320, 328))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Akt', 'Gene', '207', (262, 265))	('FAM83D', 'Var', (313, 319))	('inhibits', 'NegReg', (363, 371))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (133, 159))	('EMT-like molecular changes', 'CPA', (190, 216))	('lung cancer', 'Disease', (148, 159))	('expression', 'MPA', (333, 343))	('Akt', 'Gene', (376, 379))	('mTOR', 'Gene', (380, 384))	('Akt', 'Gene', '207', (376, 379))	('invasiveness', 'CPA', (117, 129))	('facilitates', 'PosReg', (167, 178))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('mTOR', 'Gene', (266, 270))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('mTOR', 'Gene', '2475', (380, 384))	('FAM83D', 'Var', (69, 75))	('enhances', 'PosReg', (76, 84))
553144	32547096	Consistent with the above report, our data showed that suppression of FAM83D led to an obvious decrease in p-AKT, p-GSK-3beta and Snail expression before and after IR, especially after IR, compared to that in the control group indicating that FAM83D helps to trigger EMT through the Akt/GSK-3beta/Snail signaling pathway, which leads to radioresistance in ESCC.	('leads to', 'Reg', (328, 336))	('FAM83D', 'Var', (243, 249))	('trigger', 'PosReg', (259, 266))	('GSK-3beta', 'Gene', (116, 125))	('AKT', 'Gene', (109, 112))	('Snail', 'Gene', (130, 135))	('Snail', 'Gene', (297, 302))	('GSK-3beta', 'Gene', '2931', (287, 296))	('EMT', 'CPA', (267, 270))	('Akt', 'Gene', (283, 286))	('AKT', 'Gene', '207', (109, 112))	('Akt', 'Gene', '207', (283, 286))	('GSK-3beta', 'Gene', (287, 296))	('FAM83D', 'Var', (70, 76))	('decrease', 'NegReg', (95, 103))	('suppression', 'Var', (55, 66))	('Snail', 'Gene', '6615', (130, 135))	('Snail', 'Gene', '6615', (297, 302))	('ESCC', 'Disease', (356, 360))	('GSK-3beta', 'Gene', '2931', (116, 125))
553145	32547096	In conclusion, the present study determined the expression and prognostic significance of FAM83D in esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('esophageal carcinoma', 'Disease', (100, 120))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (100, 120))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (100, 120))	('FAM83D', 'Var', (90, 96))
553146	32547096	Our findings demonstrated that FAM83D is overexpressed in esophageal carcinoma tissues and cell lines and correlated with poor prognosis of patients with esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('overexpressed', 'PosReg', (41, 54))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (154, 174))	('esophageal carcinoma', 'Disease', (58, 78))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (58, 78))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (58, 78))	('patients', 'Species', '9606', (140, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('FAM83D', 'Var', (31, 37))	('esophageal carcinoma', 'Disease', (154, 174))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (154, 174))
553147	32547096	In addition, we found that FAM83D and radiation coordinately affect the invasion of ESCC cells by inducing EMT at least partially through the Akt/GSK-3beta/Snail signaling pathway.	('Snail', 'Gene', (156, 161))	('Akt', 'Gene', (142, 145))	('ESCC', 'Disease', (84, 88))	('Snail', 'Gene', '6615', (156, 161))	('EMT', 'CPA', (107, 110))	('GSK-3beta', 'Gene', (146, 155))	('Akt', 'Gene', '207', (142, 145))	('affect', 'Reg', (61, 67))	('inducing', 'PosReg', (98, 106))	('FAM83D', 'Var', (27, 33))	('invasion', 'CPA', (72, 80))	('GSK-3beta', 'Gene', '2931', (146, 155))
553148	32547096	Moreover, the characterization of FAM83D may support its exploration as a valuable biomarker target for the diagnosis and treatment of patients with ESCC.	('ESCC', 'Disease', (149, 153))	('patients', 'Species', '9606', (135, 143))	('FAM83D', 'Var', (34, 40))
553152	32256975	The aim of our study was to evaluate the prognostic role of p16 expression and CDKN2A deletion in esophageal cancer (EC).	('CDKN2A', 'Gene', '1029', (79, 85))	('p16', 'Gene', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))	('p16', 'Gene', '1029', (60, 63))	('esophageal cancer', 'Disease', (98, 115))	('CDKN2A', 'Gene', (79, 85))	('deletion', 'Var', (86, 94))
553153	32256975	Therefore, we analyzed p16 and KI67 expression by immunohistochemistry and 9p21 deletion by fluorescence in-situ hybridization on a tissue microarray including 398 adenocarcinomas (AC) and 293 squamous cell carcinomas (SCC) with clinical follow up-data.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (193, 217))	('adenocarcinomas', 'Disease', 'MESH:D000230', (164, 179))	('deletion', 'Var', (80, 88))	('p16', 'Gene', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (193, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('SCC', 'Phenotype', 'HP:0002860', (219, 222))	('adenocarcinomas', 'Disease', (164, 179))	('p21', 'Gene', (76, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('p16', 'Gene', '1029', (23, 26))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (193, 217))	('p21', 'Gene', '644914', (76, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('squamous cell carcinomas', 'Disease', (193, 217))
553154	32256975	p16 positivity was found in 30.2% of AC and 13.9% of SCC and CDKN2A deletion in 32.1% of AC and 33.5% of SCC.	('SCC', 'Disease', (53, 56))	('found', 'Reg', (19, 24))	('CDKN2A', 'Gene', (61, 67))	('p16', 'Gene', (0, 3))	('deletion', 'Var', (68, 76))	('CDKN2A', 'Gene', '1029', (61, 67))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('p16', 'Gene', '1029', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))
553156	32256975	In AC Ki67 positivity was associated with high tumor stage (P = 0.001), presence of lymph node metastasis (P = 0.009), high UICC stage (P = 0.001) and poor grading (P = 0.005).	('lymph node metastasis', 'CPA', (84, 105))	('high tumor', 'Disease', 'MESH:D009369', (42, 52))	('positivity', 'Var', (11, 21))	('Ki67', 'Chemical', '-', (6, 10))	('Ki67 positivity', 'Var', (6, 21))	('high UICC stage', 'CPA', (119, 134))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('poor grading', 'CPA', (151, 163))	('high tumor', 'Disease', (42, 52))
553157	32256975	Overall survival (OS) was shorter for patients with high Ki67 labeling index (Ki67LI; P = 0.009) and negative p16 immunostaining (P = 0.026).	('Ki67', 'Chemical', '-', (78, 82))	('Ki67', 'Var', (57, 61))	('p16', 'Gene', '1029', (110, 113))	('shorter', 'NegReg', (26, 33))	('patients', 'Species', '9606', (38, 46))	('p16', 'Gene', (110, 113))	('Overall', 'MPA', (0, 7))	('negative', 'NegReg', (101, 109))	('Ki67', 'Chemical', '-', (57, 61))
553158	32256975	In both histological tumor types, CDKN2A deletion showed no association with phenotype or outcome.	('tumor', 'Disease', (21, 26))	('deletion', 'Var', (41, 49))	('CDKN2A', 'Gene', '1029', (34, 40))	('CDKN2A', 'Gene', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
553161	32256975	In summary, our study shows that loss of p16 expression and high Ki67LI is linked to shortened OS in AC.	('loss', 'NegReg', (33, 37))	('p16', 'Gene', (41, 44))	('Ki67', 'Chemical', '-', (65, 69))	('expression', 'MPA', (45, 55))	('high Ki67LI', 'Var', (60, 71))	('shortened OS in AC', 'Disease', (85, 103))	('p16', 'Gene', '1029', (41, 44))
553162	32256975	CDKN2A deletion shows no relevant association with tumor phenotype and patient outcome.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('CDKN2A', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('patient', 'Species', '9606', (71, 78))	('deletion', 'Var', (7, 15))	('CDKN2A', 'Gene', '1029', (0, 6))
553174	32256975	In EC, different types of p16 inactivation have been described, such as homozygous and heterozygous CDKN2A deletions, deleterious point mutations and p16 promoter methylation.	('p16', 'Gene', (26, 29))	('p16', 'Gene', (150, 153))	('point mutations', 'Var', (130, 145))	('p16', 'Gene', '1029', (26, 29))	('p16', 'Gene', '1029', (150, 153))	('deletions', 'Var', (107, 116))	('CDKN2A', 'Gene', (100, 106))	('inactivation', 'NegReg', (30, 42))	('CDKN2A', 'Gene', '1029', (100, 106))
553175	32256975	Previous studies additionally suggest, that alterations of p16 occur early during tumorigenesis as they are commonly seen in Barret's dysplasia and peritumoral mucosa.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('p16', 'Gene', '1029', (59, 62))	("Barret's dysplasia", 'Phenotype', 'HP:0100580', (125, 143))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	("Barret's dysplasia", 'Disease', (125, 143))	("Barret's dysplasia", 'Disease', 'MESH:D010300', (125, 143))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (152, 157))	('p16', 'Gene', (59, 62))	('alterations', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
553176	32256975	To elucidate the potential role of both p16 expression and CDKN2A deletion as prognostic biomarkers we examined our preexisting EC tissue microarray (TMA) built from tumor samples of more than 690 individual EC patients.	('p16', 'Gene', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('TMA', 'Disease', (150, 153))	('patients', 'Species', '9606', (211, 219))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('p16', 'Gene', '1029', (40, 43))	('TMA', 'Disease', 'MESH:D000783', (150, 153))	('CDKN2A', 'Gene', (59, 65))	('deletion', 'Var', (66, 74))	('CDKN2A', 'Gene', '1029', (59, 65))
553185	32256975	Association with clinical data was found in AC between high-level Ki67 staining and high tumor stage (P = 0.001), presence of lymph node metastasis (P = 0.009), high UICC stage (P = 0.001) and poor grading (P = 0.005, Table 1).	('high tumor', 'Disease', (84, 94))	('poor grading', 'CPA', (193, 205))	('high-level', 'Var', (55, 65))	('Ki67', 'Chemical', '-', (66, 70))	('lymph node metastasis', 'CPA', (126, 147))	('high tumor', 'Disease', 'MESH:D009369', (84, 94))	('high UICC stage', 'CPA', (161, 176))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
553188	32256975	Homozygous CDKN2A deletions were detectable in 13 samples (6.4%) and heterozygous deletions in 52 samples (25.7%) of AC.	('deletions', 'Var', (18, 27))	('CDKN2A', 'Gene', '1029', (11, 17))	('CDKN2A', 'Gene', (11, 17))
553190	32256975	In AC no links were evident between deletion rates and clinico-pathological parameters (Table 1), while in SCC CDKN2A deletions were associated with patients' age (P = 0.033) and tumor stage (P = 0.024, Table 2).	('patients', 'Species', '9606', (149, 157))	('CDKN2A', 'Gene', '1029', (111, 117))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('CDKN2A', 'Gene', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('deletions', 'Var', (118, 127))	('associated', 'Reg', (133, 143))	('tumor', 'Disease', (179, 184))
553191	32256975	A correlation between p16 immunostaining and CDKN2A deletion was found for AC (P = 0.039) but not for SCC (P = 0.610).	('deletion', 'Var', (52, 60))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('p16', 'Gene', '1029', (22, 25))	('CDKN2A', 'Gene', (45, 51))	('p16', 'Gene', (22, 25))	('CDKN2A', 'Gene', '1029', (45, 51))
553192	32256975	However, in both histological tumor types, all cases with homozygous gene deletion were negative for p16 immunostaining (data not shown).	('negative', 'NegReg', (88, 96))	('gene deletion', 'Var', (69, 82))	('p16', 'Gene', '1029', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('p16', 'Gene', (101, 104))	('tumor', 'Disease', (30, 35))
553193	32256975	Since a correlation between p16 immunostaining and CDKN2A deletion was found for AC a combined analysis of IHC and FISH was performed.	('p16', 'Gene', '1029', (28, 31))	('CDKN2A', 'Gene', '1029', (51, 57))	('p16', 'Gene', (28, 31))	('deletion', 'Var', (58, 66))	('CDKN2A', 'Gene', (51, 57))
553194	32256975	Data on both p16 immunostaining and CDKN2A deletion were available from 172 AC and 142 SCC.	('CDKN2A', 'Gene', (36, 42))	('deletion', 'Var', (43, 51))	('p16', 'Gene', (13, 16))	('CDKN2A', 'Gene', '1029', (36, 42))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('p16', 'Gene', '1029', (13, 16))
553196	32256975	There was no correlation detectable between clinical parameters and the combination of p16 expression with CDKN2A deletion.	('CDKN2A', 'Gene', '1029', (107, 113))	('p16', 'Gene', '1029', (87, 90))	('p16', 'Gene', (87, 90))	('CDKN2A', 'Gene', (107, 113))	('deletion', 'Var', (114, 122))
553198	32256975	In addition, links between Ki67 immunostaining and CDKN2A deletion status were also not detectable (AC: P = 0.172; SCC: P = 0.712).	('CDKN2A', 'Gene', '1029', (51, 57))	('Ki67', 'Chemical', '-', (27, 31))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('CDKN2A', 'Gene', (51, 57))	('deletion status', 'Var', (58, 73))
553199	32256975	Kaplan-Meier survival analysis for OS in AC showed shortened survival rates for patients with high Ki67 labeling index (P = 0.009, Figure 3A).	('high Ki67', 'Var', (94, 103))	('Ki67', 'Chemical', '-', (99, 103))	('patients', 'Species', '9606', (80, 88))	('Ki67', 'Var', (99, 103))	('survival', 'MPA', (61, 69))	('shortened', 'NegReg', (51, 60))
553201	32256975	CDKN2A deletions had no influence on the OS in AC (P = 0.679, Figure 3C).	('CDKN2A', 'Gene', '1029', (0, 6))	('deletions', 'Var', (7, 16))	('CDKN2A', 'Gene', (0, 6))
553202	32256975	Combined analysis of Ki67 and p16 IHC suggested a superior prognostic value as compared to analysis of Ki67 and p16 expression alone, revealing favorable prognosis for patients with a combination of positive p16 immunostaining and low Ki67LI (P = 0.004, Figure 3D).	('p16', 'Gene', (30, 33))	('p16', 'Gene', (112, 115))	('Ki67', 'Chemical', '-', (21, 25))	('Ki67LI', 'Var', (235, 241))	('Ki67', 'Chemical', '-', (103, 107))	('low Ki67LI', 'Var', (231, 241))	('p16', 'Gene', '1029', (208, 211))	('p16', 'Gene', '1029', (30, 33))	('p16', 'Gene', '1029', (112, 115))	('patients', 'Species', '9606', (168, 176))	('p16', 'Gene', (208, 211))	('Ki67', 'Chemical', '-', (235, 239))
553204	32256975	Multivariate Analyses were performed evaluation the prognostic relevance of Ki67LI, p16 expression and CDKN2A deletion in relationship to patients' age, sex and clinic-pathological parameters (pT, pN, pM, UICC stage, Grade, resection margin) in AC and SCC.	('CDKN2A', 'Gene', '1029', (103, 109))	('p16', 'Gene', '1029', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (252, 255))	('Ki67', 'Chemical', '-', (76, 80))	('CDKN2A', 'Gene', (103, 109))	('SCC', 'Disease', (252, 255))	('deletion', 'Var', (110, 118))	('patients', 'Species', '9606', (138, 146))	('p16', 'Gene', (84, 87))
553205	32256975	For AC, the proportional cox-regression model revealed higher patients' age (P = 0.0050), lymph node metastasis (P = 0.0070), resection margin (P = 0.0010) and the Ki67LI (P = 0.0040) as independent prognostic markers.	('lymph node metastasis', 'CPA', (90, 111))	('patients', 'Species', '9606', (62, 70))	('Ki67', 'Chemical', '-', (164, 168))	('Ki67LI', 'Var', (164, 170))
553207	32256975	The results of our study show that loss of p16 expression - but not 9p21 deletion - and high Ki67LI are prognosticators of poor survival in AC of the esophagus.	('p16', 'Gene', (43, 46))	('Ki67LI', 'Var', (93, 99))	('p21', 'Gene', (69, 72))	('loss', 'Var', (35, 39))	('poor', 'NegReg', (123, 127))	('p21', 'Gene', '644914', (69, 72))	('Ki67', 'Chemical', '-', (93, 97))	('AC of the esophagus', 'Disease', (140, 159))	('p16', 'Gene', '1029', (43, 46))
553208	32256975	Aim of the present study was to assess whether p16 alterations are associated with adverse clinical outcome in patients with EC.	('alterations', 'Var', (51, 62))	('p16', 'Gene', (47, 50))	('associated', 'Reg', (67, 77))	('p16', 'Gene', '1029', (47, 50))	('patients', 'Species', '9606', (111, 119))
553214	32256975	Our deletion rate in AC is somewhat lower than reported in other studies, which is partially caused by more stringent criteria for defining CDKN2A deletions.	('lower', 'NegReg', (36, 41))	('CDKN2A', 'Gene', (140, 146))	('deletions', 'Var', (147, 156))	('CDKN2A', 'Gene', '1029', (140, 146))	('deletion', 'Var', (4, 12))
553217	32256975	p16 is known to be a major tumor suppressor protein and its alteration has been associated with tumor progression in different entities.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('alteration', 'Var', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (27, 32))	('p16', 'Gene', (0, 3))	('tumor', 'Disease', (96, 101))	('associated', 'Reg', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('p16', 'Gene', '1029', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
553221	32256975	Almost 50% of all tumors show p16 inactivation as one of the main drivers during carcinogenesis including pancreatic and biliary, head and neck, lung, bladder and colon carcinoma.	('p16', 'Gene', (30, 33))	('inactivation', 'Var', (34, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('lung', 'Disease', (145, 149))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('pancreatic', 'Disease', 'MESH:D010195', (106, 116))	('p16', 'Gene', '1029', (30, 33))	('bladder and colon carcinoma', 'Disease', 'MESH:D001749', (151, 178))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('pancreatic', 'Disease', (106, 116))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
553222	32256975	Different mechanisms of p16 inactivation have been described earlier including promoter hypermethylation, point and missense mutations, loss of heterozygosity (LOH) and genetic deletions.	('missense mutations', 'Var', (116, 134))	('p16', 'Gene', '1029', (24, 27))	('loss of heterozygosity', 'Var', (136, 158))	('inactivation', 'NegReg', (28, 40))	('p16', 'Gene', (24, 27))	('genetic deletions', 'Var', (169, 186))	('promoter hypermethylation', 'MPA', (79, 104))	('point', 'Var', (106, 111))
553223	32256975	As p16 is considered a tumor suppressor and negative regulator for cell proliferation we correlated p16 expression with the cell proliferation marker Ki67 to analyze whether the loss of p16 was associated with increased cell proliferation.	('loss', 'Var', (178, 182))	('Ki67', 'Chemical', '-', (150, 154))	('increased', 'PosReg', (210, 219))	('p16', 'Gene', (3, 6))	('cell proliferation', 'CPA', (220, 238))	('p16', 'Gene', '1029', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('p16', 'Gene', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('p16', 'Gene', '1029', (3, 6))	('p16', 'Gene', (186, 189))	('p16', 'Gene', '1029', (100, 103))
553224	32256975	Ki67 is a known index marker for aggressive tumor behavior, including dedifferentiation.	('Ki67', 'Chemical', '-', (0, 4))	('aggressive tumor behavior', 'Disease', (33, 58))	('dedifferentiation', 'Disease', (70, 87))	('Ki67', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (33, 58))
553225	32256975	In line with the results of our analysis, high Ki67 indices have been linked to advanced tumor stages in EC.	('Ki67', 'Chemical', '-', (47, 51))	('linked', 'Reg', (70, 76))	('Ki67', 'Var', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
553226	32256975	That Ki67 had independent prognostic value in our multivariate analysis, but not p16, suggests that Ki67 may be more promising candidate for clinical testing than p16.	('p16', 'Gene', '1029', (163, 166))	('Ki67', 'Var', (100, 104))	('Ki67', 'Chemical', '-', (100, 104))	('p16', 'Gene', '1029', (81, 84))	('p16', 'Gene', (163, 166))	('Ki67', 'Chemical', '-', (5, 9))	('p16', 'Gene', (81, 84))
553228	32256975	Although, possibly, the high rate of cancers with low Ki67LI experienced in our study may be misleading in this context rendering some results insignificant.	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('Ki67LI', 'Var', (54, 60))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Ki67', 'Chemical', '-', (54, 58))
553230	32256975	Another aim was to assess the relationship between CDKN2A deletions and p16 expression.	('CDKN2A', 'Gene', '1029', (51, 57))	('p16', 'Gene', '1029', (72, 75))	('deletions', 'Var', (58, 67))	('p16', 'Gene', (72, 75))	('CDKN2A', 'Gene', (51, 57))
553232	32256975	Inactivation of CDKN2A involves four types of genetic alterations: homozygous deletion, promoter hypermethylation, loss of heterozygosity and point mutation.	('promoter hypermethylation', 'MPA', (88, 113))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('point mutation', 'Var', (142, 156))	('loss of heterozygosity', 'Var', (115, 137))	('Inactivation', 'Var', (0, 12))
553233	32256975	Homozygous deletion and promoter hypermethylation constitute the majority of p16 alterations, but some cancers are known to prefer specific types of alterations.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('p16', 'Gene', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('promoter', 'MPA', (24, 32))	('p16', 'Gene', '1029', (77, 80))	('alterations', 'Var', (81, 92))	('Homozygous deletion', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
553235	32256975	Deletions are a common mechanism of gene inactivation for numerous tumor suppressor genes.	('numerous tumor', 'Disease', (58, 72))	('Deletions', 'Var', (0, 9))	('numerous tumor', 'Disease', 'MESH:D009369', (58, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))
553236	32256975	As expected, all cancers with bi-allelic (homozygous) CDKN2A deletion completely lacked p16 expression, which indirectly validates our experimental approaches both for FISH and IHC.	('p16', 'Gene', (88, 91))	('lacked', 'NegReg', (81, 87))	('deletion', 'Var', (61, 69))	('CDKN2A', 'Gene', (54, 60))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('p16', 'Gene', '1029', (88, 91))	('cancers', 'Disease', (17, 24))	('CDKN2A', 'Gene', '1029', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('expression', 'MPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
553237	32256975	Differences in p16 expression levels in samples with or without heterozygous CDKN2A deletion demonstrate that EC cells have the ability to compensate the loss of one p16 (CDKN2A) allele, either by increased transcriptional activation of the remaining allele or by increased stabilization of p16 protein or mRNA (reviewed in).	('p16', 'Gene', (15, 18))	('expression', 'MPA', (19, 29))	('mRNA', 'MPA', (306, 310))	('increased', 'PosReg', (264, 273))	('deletion', 'Var', (84, 92))	('p16', 'Gene', (291, 294))	('CDKN2A', 'Gene', (77, 83))	('p16', 'Gene', '1029', (166, 169))	('transcriptional', 'MPA', (207, 222))	('CDKN2A', 'Gene', (171, 177))	('stabilization', 'MPA', (274, 287))	('p16', 'Gene', '1029', (15, 18))	('CDKN2A', 'Gene', '1029', (77, 83))	('increased', 'PosReg', (197, 206))	('CDKN2A', 'Gene', '1029', (171, 177))	('activation', 'PosReg', (223, 233))	('p16', 'Gene', '1029', (291, 294))	('p16', 'Gene', (166, 169))
553238	32256975	This also explained the absent of significant associations between CDKN2A deletions and clinic-pathological parameters as well as overall survival in our study.	('deletions', 'Var', (74, 83))	('CDKN2A', 'Gene', '1029', (67, 73))	('CDKN2A', 'Gene', (67, 73))
553239	32256975	However, rare (5-6% depending on the histological subtype) biallelic CDKN2A deletions lead to catastrophic events for the cell with total loss of p16 expression.	('loss', 'NegReg', (138, 142))	('expression', 'MPA', (150, 160))	('deletions', 'Var', (76, 85))	('CDKN2A', 'Gene', '1029', (69, 75))	('p16', 'Gene', '1029', (146, 149))	('lead to', 'Reg', (86, 93))	('p16', 'Gene', (146, 149))	('CDKN2A', 'Gene', (69, 75))
553244	32256975	Rare homozygous 9p21 deletions can be considered as catastrophic events leading to complete loss of p16 expression.	('p21', 'Gene', '644914', (17, 20))	('deletions', 'Var', (21, 30))	('p16', 'Gene', (100, 103))	('loss', 'NegReg', (92, 96))	('p21', 'Gene', (17, 20))	('p16', 'Gene', '1029', (100, 103))
553273	32256975	These thresholds are based on our previous study analyzing PTEN deletions on a prostate cancer TMA where our approach resulted in a 100% concordance with aCGH data.	('prostate cancer TMA', 'Disease', (79, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('deletions', 'Var', (64, 73))	('prostate cancer TMA', 'Disease', 'MESH:D011471', (79, 98))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))
553299	19399912	Recently, 1849G 1849T point mutation (V617F) of the tyrosine kinase Janus kinase 2 (JAK2) gene in myeloid cells has proved a highly specific and easily detectable marker for myeloproliferative disease.	('Janus kinase 2', 'Gene', '3717', (68, 82))	('JAK2', 'Gene', (84, 88))	('V617F', 'Var', (38, 43))	('1849G 1849T', 'Mutation', 'c.1849,1849G>T', (10, 21))	('myeloproliferative disease', 'Phenotype', 'HP:0005547', (174, 200))	('myeloproliferative disease', 'Disease', (174, 200))	('myeloproliferative disease', 'Disease', 'MESH:D009196', (174, 200))	('Janus kinase 2', 'Gene', (68, 82))	('V617F', 'SUBSTITUTION', 'None', (38, 43))	('JAK2', 'Gene', '3717', (84, 88))
553326	19399912	Rapid and complete obstruction of the portal vein or mesenteric veins, without involvement of mesenteric venous arches, induces intestinal congestion, manifested by severe continuous colicky abdominal pain and occasionally nonbloody diarrhea.	('venous arches', 'Disease', (105, 118))	('nonbloody diarrhea', 'Disease', 'MESH:D003967', (223, 241))	('induces', 'Reg', (120, 127))	('nonbloody diarrhea', 'Disease', (223, 241))	('intestinal congestion', 'Disease', (128, 149))	('colicky abdominal pain', 'Disease', 'MESH:D003085', (183, 205))	('diarrhea', 'Phenotype', 'HP:0002014', (233, 241))	('bloody diarrhea', 'Phenotype', 'HP:0025085', (226, 241))	('pain', 'Phenotype', 'HP:0012531', (201, 205))	('colicky abdominal pain', 'Disease', (183, 205))	('abdominal pain', 'Phenotype', 'HP:0002027', (191, 205))	('intestinal congestion', 'Phenotype', 'HP:0005214', (128, 149))	('obstruction', 'Var', (19, 30))	('venous arches', 'Disease', 'MESH:D001015', (105, 118))
553393	19399912	Complete occlusion of the portal vein trunk, or of its two main branches is virtually always associated with portal hypertension and the development of portosystemic collaterals.	('hypertension', 'Disease', 'MESH:D006973', (116, 128))	('hypertension', 'Disease', (116, 128))	('portal hypertension', 'Phenotype', 'HP:0001409', (109, 128))	('hypertension', 'Phenotype', 'HP:0000822', (116, 128))	('Complete occlusion', 'Var', (0, 18))	('associated', 'Reg', (93, 103))	('portosystemic collaterals', 'Phenotype', 'HP:0025154', (152, 177))
553464	19399912	In cirrhotic patients with PVT, compared with those without PVT, however, molecular testing shows an increased prevalence of the factor V Leiden, MTHFR, and prothrombin gene mutations, the latter being particularly common.	('prothrombin', 'Gene', (157, 168))	('prothrombin', 'Gene', '2147', (157, 168))	('mutations', 'Var', (174, 183))	('patients', 'Species', '9606', (13, 21))	('MTHFR', 'Gene', '4524', (146, 151))	('PVT', 'Phenotype', 'HP:0030242', (60, 63))	('factor V Leiden', 'Gene', (129, 144))	('PVT', 'Phenotype', 'HP:0030242', (27, 30))	('cirrhotic', 'Disease', 'MESH:D005355', (3, 12))	('prevalence', 'Reg', (111, 121))	('MTHFR', 'Gene', (146, 151))	('factor V Leiden', 'Gene', '2153', (129, 144))	('cirrhotic', 'Disease', (3, 12))
553496	19399912	In this model monocrotaline induces rounding up of sinusoidal endothelial cells, which leads to dissection of sinusoidal lining cells that embolize and block the sinusoids.	('rounding up', 'CPA', (36, 47))	('leads to', 'Reg', (87, 95))	('monocrotaline', 'Chemical', 'MESH:D016686', (14, 27))	('induces', 'Reg', (28, 35))	('monocrotaline', 'Var', (14, 27))
553560	19399912	Substituting fludarabine for cyclophosphamide (a busulfan/fludarabine conditioning regimen) results in a low incidence of SOS with improved transplant outcome.	('SOS', 'Disease', 'MESH:D006504', (122, 125))	('busulfan', 'Chemical', 'MESH:D002066', (49, 57))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (29, 45))	('fludarabine', 'Chemical', 'MESH:C024352', (13, 24))	('fludarabine', 'Chemical', 'MESH:C024352', (58, 69))	('improved', 'PosReg', (131, 139))	('SOS', 'Disease', (122, 125))	('Substituting', 'Var', (0, 12))
553575	19399912	However the largest randomized trial, which did not find any benefit for SOS, did find that prophylactic use of ursodeoxycholate decreased the frequency of jaundice and lowered peak alanine aminotransferase levels.	('jaundice', 'Disease', (156, 164))	('jaundice', 'Phenotype', 'HP:0000952', (156, 164))	('peak alanine aminotransferase levels', 'MPA', (177, 213))	('ursodeoxycholate', 'Var', (112, 128))	('SOS', 'Disease', 'MESH:D006504', (73, 76))	('ursodeoxycholate', 'Chemical', 'MESH:D014580', (112, 128))	('lowered peak alanine', 'Phenotype', 'HP:0500154', (169, 189))	('jaundice', 'Disease', 'MESH:D007565', (156, 164))	('lowered', 'NegReg', (169, 176))	('decreased', 'NegReg', (129, 138))	('SOS', 'Disease', (73, 76))
553610	19399912	Although TIPS in SOS does reduce ascites, there is no benefit in survival and this is therefore not considered an appropriate indication for TIPS.	('reduce', 'NegReg', (26, 32))	('SOS', 'Disease', 'MESH:D006504', (17, 20))	('ascites', 'Disease', 'MESH:D001201', (33, 40))	('ascites', 'Phenotype', 'HP:0001541', (33, 40))	('SOS', 'Disease', (17, 20))	('ascites', 'Disease', (33, 40))	('TIPS', 'Var', (9, 13))
553634	19399912	Clusters of dystrophic megakaryocytes at bone marrow biopsy, endogenous erythroid colony formation in culture of bone marrow or circulating progenitors and, recently, detection of V617F activating mutation of JAK2 tyrosine kinase in blood cells have been used as sensitive markers.	('V617F', 'SUBSTITUTION', 'None', (180, 185))	('JAK2', 'Gene', '3717', (209, 213))	('V617F', 'Var', (180, 185))	('dystrophic', 'Disease', 'MESH:D020388', (12, 22))	('JAK2', 'Gene', (209, 213))	('dystrophic', 'Disease', (12, 22))
553636	19399912	Factor V Leiden mutation and G20210A prothrombin gene mutation are associated with odds ratio for BCS of about 12 and 2, respectively.	('BCS', 'Phenotype', 'HP:0002639', (98, 101))	('BCS', 'Disease', (98, 101))	('Factor V Leiden', 'Gene', (0, 15))	('rat', 'Species', '10116', (88, 91))	('G20210A', 'Var', (29, 36))	('BCS', 'Disease', 'MESH:D006502', (98, 101))	('G20210A', 'Mutation', 'rs1799963', (29, 36))	('prothrombin', 'Gene', (37, 48))	('prothrombin', 'Gene', '2147', (37, 48))	('Factor V Leiden', 'Gene', '2153', (0, 15))
553641	19399912	Studies on the prevalence of C677T homozygous state for MTHFR are limited and their results are not consistent.	('C677T', 'Var', (29, 34))	('MTHFR', 'Gene', '4524', (56, 61))	('C677T', 'Mutation', 'rs1801133', (29, 34))	('MTHFR', 'Gene', (56, 61))
553653	19399912	Do not regard relatively weak thrombotic risk factors (factor V Leiden mutation, prothrombin gene mutation, hyperhomocysteinemia, or oral contraceptive use) as the only risk factor for BCS until other causes have been ruled out (Class I, Level B).	('factor V Leiden', 'Gene', (55, 70))	('hyperhomocysteinemia', 'Disease', (108, 128))	('thrombotic', 'Disease', (30, 40))	('mutation', 'Var', (98, 106))	('mutation', 'Var', (71, 79))	('BCS', 'Phenotype', 'HP:0002639', (185, 188))	('factor V Leiden', 'Gene', '2153', (55, 70))	('BCS', 'Disease', (185, 188))	('hyperhomocysteinemia', 'Disease', 'MESH:D020138', (108, 128))	('prothrombin', 'Gene', (81, 92))	('thrombotic', 'Disease', 'MESH:D013927', (30, 40))	('BCS', 'Disease', 'MESH:D006502', (185, 188))	('prothrombin', 'Gene', '2147', (81, 92))
553788	19399912	Moreover, PTFE covered stents appear to be associated with a lower incidence of clinically significant events than uncovered stents.	('clinically significant events', 'MPA', (80, 109))	('lower', 'NegReg', (61, 66))	('PTFE', 'Chemical', 'MESH:D011138', (10, 14))	('PTFE covered', 'Var', (10, 22))
553835	19399912	There are, however, isolated case reports of an association with factor V Leiden or prothrombin gene mutation, antiphopholipid syndrome, or celiac disease.	('celiac disease', 'Disease', (140, 154))	('mutation', 'Var', (101, 109))	('factor V Leiden', 'Gene', '2153', (65, 80))	('association', 'Interaction', (48, 59))	('celiac disease', 'Phenotype', 'HP:0002608', (140, 154))	('prothrombin', 'Gene', (84, 95))	('antiphopholipid syndrome', 'Disease', (111, 135))	('prothrombin', 'Gene', '2147', (84, 95))	('factor V Leiden', 'Gene', (65, 80))	('celiac disease', 'Disease', 'MESH:D002446', (140, 154))
553856	19399912	In most HHT families, there is a mutation in one of two genes, endoglin (ENG) and activin receptor-like kinase tpe 1 (ALK-1 and ACVRL1), that encode for transmembrane proteins involved in the transforming growth factor-beta (TGF-beta) signaling pathway and are expressed predominantly on vascular endothelium.	('ACVRL1', 'Gene', (128, 134))	('mutation', 'Var', (33, 41))	('ENG', 'Gene', '2022', (73, 76))	('ENG', 'Gene', (73, 76))	('HHT', 'Disease', (8, 11))	('ALK-1', 'Gene', (118, 123))	('ACVRL1', 'Gene', '94', (128, 134))	('ALK-1', 'Gene', '94', (118, 123))	('endoglin', 'Gene', (63, 71))	('HHT', 'Disease', 'MESH:D013683', (8, 11))
553861	19399912	LVMs are more common and are more often symptomatic in families of patients with the ALK-1 mutation Symptoms of LVMs in HHT appear around age 30 and occur predominantly in females.	('HHT', 'Disease', (120, 123))	('LVMs', 'Disease', (112, 116))	('mutation', 'Var', (91, 99))	('LVMs', 'Disease', 'MESH:D056486', (0, 4))	('patients', 'Species', '9606', (67, 75))	('LVMs', 'Disease', (0, 4))	('LVMs', 'Phenotype', 'HP:0006576', (112, 116))	('HHT', 'Disease', 'MESH:D013683', (120, 123))	('LVMs', 'Phenotype', 'HP:0006576', (0, 4))	('ALK-1', 'Gene', '94', (85, 90))	('ALK-1', 'Gene', (85, 90))	('LVMs', 'Disease', 'MESH:D056486', (112, 116))
553943	31338011	Investigations have been revealed that a significant association between deregulation of lncRNAs and cancerogenesis, such as colorectal, breast, lung, and hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('colorectal', 'Disease', (125, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('hepatocellular carcinoma', 'Disease', (155, 179))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('cancer', 'Disease', (101, 107))	('lncRNAs', 'Protein', (89, 96))	('deregulation', 'Var', (73, 85))	('lung', 'Disease', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal', 'Disease', 'MESH:D015179', (125, 135))	('breast', 'Disease', (137, 143))
553989	31338011	In addition, the lncRNA-PCAT-1 played as a ceRNA against miR-122, and that inhibition of lncRNA-PCAT-1 suppressed the advancement of ECC by decreasing Wnt/beta-catenin signaling pathway by miR-122 repression and Wnt group member 1 (WNT1) expression (Zhang et al., 2017).	('miR-122', 'Gene', (189, 196))	('Wnt', 'Gene', '7471', (151, 154))	('inhibition', 'Var', (75, 85))	('decreasing', 'NegReg', (140, 150))	('suppressed', 'NegReg', (103, 113))	('Wnt', 'Gene', (212, 215))	('WNT1', 'Gene', (232, 236))	('WNT1', 'Gene', '7471', (232, 236))	('Wnt', 'Gene', '7471', (212, 215))	('ECC', 'Disease', (133, 136))	('PCAT-1', 'Gene', '100750225', (24, 30))	('PCAT-1', 'Gene', '100750225', (96, 102))	('miR-122', 'Gene', '406906', (57, 64))	('PCAT-1', 'Gene', (24, 30))	('beta-catenin', 'Gene', (155, 167))	('PCAT-1', 'Gene', (96, 102))	('beta-catenin', 'Gene', '1499', (155, 167))	('miR-122', 'Gene', (57, 64))	('miR-122', 'Gene', '406906', (189, 196))	('Wnt', 'Gene', (151, 154))
553992	31338011	Because of lncRNA-PCAT-1 knockdown leads to suppression of cell growth and proliferation.	('suppression', 'NegReg', (44, 55))	('PCAT-1', 'Gene', (18, 24))	('PCAT-1', 'Gene', '100750225', (18, 24))	('knockdown', 'Var', (25, 34))
553993	31338011	In addition, lncRNA-PCAT-1 knockdown increased the chemosensitivity of esophageal cells on cisplatin by inhibiting tumor cell expansion and proliferation and promoting tumor cell apoptosis.	('PCAT-1', 'Gene', (20, 26))	('knockdown', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (115, 120))	('PCAT-1', 'Gene', '100750225', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('inhibiting', 'NegReg', (104, 114))	('increased', 'PosReg', (37, 46))	('chemosensitivity', 'MPA', (51, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('promoting', 'PosReg', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
553994	31338011	Findings from in vivo xenograft model demonstrated that knockdown of lncRNA-PCAT-1 significantly suppressed tumor expansion and evolution.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PCAT-1', 'Gene', (76, 82))	('tumor', 'Disease', (108, 113))	('PCAT-1', 'Gene', '100750225', (76, 82))	('suppressed', 'NegReg', (97, 107))	('knockdown', 'Var', (56, 65))
553999	31338011	Our investigation is a preliminary observational study that could open to new questions regarding the effect of aberrant expression of -PCAT-1 on ESCC development of Iranian patients.	('aberrant', 'Var', (112, 120))	('ESCC development', 'Disease', (146, 162))	('PCAT-1', 'Gene', '100750225', (136, 142))	('patients', 'Species', '9606', (174, 182))	('PCAT-1', 'Gene', (136, 142))
554101	28658650	CONCLUSION: In PDAC patients, positive CAF grading was identified as a negative prognostic parameter correlating with positive N status, high LNR, positive M status, and smaller tumor size.	('PDAC', 'Phenotype', 'HP:0006725', (15, 19))	('tumor', 'Disease', (178, 183))	('PDAC', 'Chemical', '-', (15, 19))	('patients', 'Species', '9606', (20, 28))	('positive', 'Var', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
554108	28658650	As recently demonstrated, high expression of ZEB1 qualified as a negative prognostic factor in patients with PDAC or other adenocarcinoma.	('PDAC', 'Disease', (109, 113))	('high', 'Var', (26, 30))	('adenocarcinoma', 'Disease', (123, 137))	('patients', 'Species', '9606', (95, 103))	('PDAC', 'Phenotype', 'HP:0006725', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('negative', 'NegReg', (65, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (123, 137))	('ZEB1', 'Gene', (45, 49))	('PDAC', 'Chemical', '-', (109, 113))
554200	28658650	In a study by Brentnell et al., Vimentin expression in CAF was associated with enhanced cancer cell invasion.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('enhanced', 'PosReg', (79, 87))	('Vimentin', 'Protein', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('expression', 'Var', (41, 51))
554221	28658650	In the patients showing portal vein invasion, the authors demonstrated higher rates of margin positive resections.	('higher', 'PosReg', (71, 77))	('portal vein', 'Disease', (24, 35))	('patients', 'Species', '9606', (7, 15))	('margin', 'Var', (87, 93))
554263	27736796	As shown in Figure 2, patients with high infiltrating density of CD57+ NK cells in the tumor nest had significantly better overall survival (OS) than those with low infiltration (median OS: 2.95 vs. 1.45 years, P = 0.0187).	('better', 'PosReg', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('patients', 'Species', '9606', (22, 30))	('overall survival', 'MPA', (123, 139))	('CD57', 'Gene', (65, 69))	('CD57', 'Gene', '27087', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('high infiltrating density', 'Var', (36, 61))
554265	27736796	Moreover, the patients with high infiltrating density of CD68+ macrophages in the tumor nest had a significantly worse OS than those with low infiltration (median OS: 1.40 vs. 3.10 years, P = 0.0332).	('CD68', 'Gene', '968', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('CD68', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('high infiltrating density', 'Var', (28, 53))	('tumor', 'Disease', (82, 87))	('patients', 'Species', '9606', (14, 22))
554270	27736796	As shown in Table 3, patients with high infiltrating density of CD57+ NK cells in tumor nest had significant reduced death risk (HR = 0.597, 95% CI: 0.392-0.908, P = 0.016) compared with the reference group (patients with low infiltrating density of CD57+ NK cells) after adjusting for gender, age, tumor size, TNM stage and treatment.	('CD57', 'Gene', (250, 254))	('men', 'Species', '9606', (330, 333))	('CD57', 'Gene', (64, 68))	('CD57', 'Gene', '27087', (64, 68))	('patients', 'Species', '9606', (208, 216))	('tumor', 'Disease', (299, 304))	('CD57', 'Gene', '27087', (250, 254))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('death', 'Disease', 'MESH:D003643', (117, 122))	('death', 'Disease', (117, 122))	('reduced', 'NegReg', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('high infiltrating density', 'Var', (35, 60))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))
554274	27736796	In addition, after adjusting for gender, age, tumor size, TNM stage and treatment, the death risk was increased by 48.8% (HR = 1.488, 95% CI: 0.996-2.221, P = 0.052) in patients with high infiltrating density of CD68+ macrophages in the tumor nest compared with patients with low infiltrating density of these macrophages, as shown in Table 6.	('tumor', 'Disease', (237, 242))	('patients', 'Species', '9606', (169, 177))	('patients', 'Species', '9606', (262, 270))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('death', 'Disease', 'MESH:D003643', (87, 92))	('men', 'Species', '9606', (77, 80))	('CD68', 'Gene', (212, 216))	('death', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('high infiltrating density', 'Var', (183, 208))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('CD68', 'Gene', '968', (212, 216))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
554275	27736796	Conversely, high infiltrating density of CD68+ macrophages in tumor stroma indicated a decreased death risk (HR = 0.586, 95% CI: 0.378-0.908, P = 0.017) compared with patients with low infiltrating density (Table 7).	('CD68', 'Gene', '968', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('high infiltrating', 'Var', (12, 29))	('patients', 'Species', '9606', (167, 175))	('decreased death', 'Disease', (87, 102))	('tumor stroma', 'Disease', 'MESH:D009369', (62, 74))	('tumor stroma', 'Disease', (62, 74))	('CD68', 'Gene', (41, 45))	('decreased death', 'Disease', 'MESH:D003643', (87, 102))
554305	27736796	demonstrated that the overall survival and recurrence free survival of the patients with hilar cholangiocarcinoma were significantly improved in patients with low infiltration of TAMs in tumor invasive front in contrast to those with a high infiltration.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('TAMs', 'Chemical', '-', (179, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('patients', 'Species', '9606', (75, 83))	('low infiltration', 'Var', (159, 175))	('overall survival', 'CPA', (22, 38))	('tumor', 'Disease', (187, 192))	('recurrence free survival', 'CPA', (43, 67))	('hilar cholangiocarcinoma', 'Disease', 'MESH:D018285', (89, 113))	('hilar cholangiocarcinoma', 'Disease', (89, 113))	('improved', 'PosReg', (133, 141))
554354	24392231	Thrombotic risk profile was negative for factor V Leiden, prothrombin gene G20210A, hyperhomocysteinemia, antithrombin III deficiency, protein C or S deficiency, and antiphospholipid antibodies.	('protein C or S deficiency', 'Disease', (135, 160))	('Thrombotic', 'Disease', 'MESH:D013927', (0, 10))	('prothrombin', 'Gene', (58, 69))	('factor V Leiden', 'Gene', '2153', (41, 56))	('Thrombotic', 'Disease', (0, 10))	('prothrombin', 'Gene', '2147', (58, 69))	('G20210A', 'Var', (75, 82))	('hyperhomocysteinemia', 'Disease', (84, 104))	('protein C or S deficiency', 'Disease', 'MESH:D018455', (135, 160))	('antithrombin III deficiency', 'Phenotype', 'HP:0001976', (106, 133))	('hyperhomocysteinemia', 'Disease', 'MESH:D020138', (84, 104))	('antiphospholipid antibodies', 'Phenotype', 'HP:0003613', (166, 193))	('III deficiency', 'Disease', (119, 133))	('factor V Leiden', 'Gene', (41, 56))	('G20210A', 'Mutation', 'rs1799963', (75, 82))	('III deficiency', 'Disease', 'MESH:C536044', (119, 133))
554462	22761039	In regenerating cirrhotic livers, GCTM-5 marked an expanded population of ductal cells with the appearance of biliary ductular reaction (Fig.	('cirrhotic liver', 'Disease', (16, 31))	('GCTM-5', 'Var', (34, 40))	('GCTM-5', 'Chemical', '-', (34, 40))	('cirrhotic liver', 'Disease', 'MESH:D008103', (16, 31))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (16, 31))	('biliary ductular reaction', 'Disease', (110, 135))	('cirrhotic livers', 'Phenotype', 'HP:0001394', (16, 32))
554576	22761039	Antibodies to the GCTM-5 epitope may find application in the diagnosis or treatment of pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Antibodies', 'Var', (0, 10))	('pancreatic cancer', 'Disease', (87, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('GCTM-5', 'Gene', (18, 24))	('GCTM-5', 'Chemical', '-', (18, 24))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))
554584	22872778	Both univariate and multivariate analysis revealed the survival rate was significantly higher in patients who received IORT than in those who did not (P = 0.033 univariate; 0.026 multivariate).	('IORT', 'Var', (119, 123))	('patients', 'Species', '9606', (97, 105))	('survival', 'CPA', (55, 63))	('higher', 'PosReg', (87, 93))
554602	22872778	Our concern was that microscopic residual tumor in the upper abdominal area might cause abdominal recurrence, though it was performed with curative resection.	('cause', 'Reg', (82, 87))	('tumor', 'Disease', (42, 47))	('abdominal recurrence', 'Disease', (88, 108))	('microscopic', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
554626	22872778	The incidence of first recurrence in the upper abdominal lymph node area was lower in the IORT group (2.8%, 2 patients) than in the non-IORT group (13.3%, 6 patients).	('lower', 'NegReg', (77, 82))	('IORT', 'Var', (90, 94))	('patients', 'Species', '9606', (110, 118))	('patients', 'Species', '9606', (157, 165))
554627	22872778	The incidence rates of other locoregional recurrence (including local recurrence and recurrence in the cervical lymph node area or mediastinal lymph node area) were not much different between the IORT group (18.1%, 13 patients) and the non-IORT group (20.0%, 9 patients).	('patients', 'Species', '9606', (218, 226))	('patients', 'Species', '9606', (261, 269))	('local', 'CPA', (64, 69))	('IORT', 'Var', (196, 200))
554640	22872778	IORT, chemotherapy, external radiotherapy, age, and performance status (PS)) revealed that the 5-year overall survival rate was significantly higher in patients with PS 0 than in those with PS 1-4 (P = 0.0029).	('patients', 'Species', '9606', (152, 160))	('overall survival', 'CPA', (102, 118))	('higher', 'PosReg', (142, 148))	('PS 0', 'Var', (166, 170))
554643	22872778	In addition, in this subgroup of patients, the 5-year abdominal control rate was 88.8% in the IORT group and 62.7% in the non-IORT group.	('patients', 'Species', '9606', (33, 41))	('IORT', 'Var', (94, 98))	('abdominal control', 'CPA', (54, 71))
554655	22872778	Both univariate and multivariate analysis revealed that, within this subgroup, the survival rates were high in patients with PS 0 and in those who received IORT.	('PS 0', 'Var', (125, 129))	('survival rates', 'CPA', (83, 97))	('high', 'PosReg', (103, 107))	('patients', 'Species', '9606', (111, 119))
554665	22872778	A temporary elevation in the serum amylase level was reported in patients who underwent IORT targeted to the stomach, probably due to radiation to the pancreas, but this was absent in all patients in the present study.	('IORT targeted', 'Var', (88, 101))	('elevation', 'PosReg', (12, 21))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (65, 73))	('serum amylase level', 'MPA', (29, 48))
554686	22142693	The inhibition of ceramide production could lead to reduced apoptosis and survival of DNA-damaged cells, stimulation of cell division and increased regeneration and thereby, encourage carcinogenesis.	('encourage', 'PosReg', (174, 183))	('carcinogenesis', 'Disease', (184, 198))	('survival', 'CPA', (74, 82))	('ceramide', 'Protein', (18, 26))	('stimulation', 'PosReg', (105, 116))	('increased', 'PosReg', (138, 147))	('regeneration', 'CPA', (148, 160))	('reduced', 'NegReg', (52, 59))	('ceramide', 'Chemical', 'MESH:D002518', (18, 26))	('apoptosis', 'CPA', (60, 69))	('cell division', 'CPA', (120, 133))	('inhibition', 'Var', (4, 14))	('carcinogenesis', 'Disease', 'MESH:D063646', (184, 198))
554974	29430188	The survival rate of ESCC patients with high ROR expression levels was lower than that of patients with low ROR expression levels (p<0.001).	('high', 'Var', (40, 44))	('ROR', 'Gene', (45, 48))	('survival rate', 'CPA', (4, 17))	('ROR', 'Gene', (108, 111))	('ESCC', 'Disease', (21, 25))	('ROR', 'Gene', '100885779', (45, 48))	('patients', 'Species', '9606', (26, 34))	('ROR', 'Gene', '100885779', (108, 111))	('patients', 'Species', '9606', (90, 98))	('lower', 'NegReg', (71, 76))
554998	29430188	It is proposed that ROR can accelerate the development of ESCC by sponging miR-145 and upregulating FSCN1.	('accelerate', 'PosReg', (28, 38))	('ROR', 'Gene', '100885779', (20, 23))	('miR-145', 'Gene', (75, 82))	('sponging', 'Var', (66, 74))	('miR-145', 'Gene', '406937', (75, 82))	('FSCN1', 'Gene', (100, 105))	('FSCN1', 'Gene', '6624', (100, 105))	('upregulating', 'PosReg', (87, 99))	('ESCC', 'Disease', (58, 62))	('ROR', 'Gene', (20, 23))
555048	29430188	The high ROR level could increase the risk of ESCC.	('ESCC', 'Disease', (46, 50))	('high', 'Var', (4, 8))	('ROR', 'Gene', '100885779', (9, 12))	('ROR', 'Gene', (9, 12))
555082	29430188	The mechanisms could be regulating tumor invasion and metastasis-related gene FSCN1 by sponging miR-145.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('sponging', 'Var', (87, 95))	('miR-145', 'Gene', '406937', (96, 103))	('tumor', 'Disease', (35, 40))	('miR-145', 'Gene', (96, 103))	('FSCN1', 'Gene', (78, 83))	('FSCN1', 'Gene', '6624', (78, 83))
555106	29430188	The DLR assay was used to prove that the novel site 805-828 effectively bound to miR-145, meaning that this site could be a new target for ESCC molecular therapy.	('805-828', 'Var', (52, 59))	('bound', 'Interaction', (72, 77))	('miR-145', 'Gene', (81, 88))	('miR-145', 'Gene', '406937', (81, 88))	('ESCC', 'Disease', (139, 143))
555121	28903408	Derlin-1 depletion inhibited cell growth while its overexpression facilitated cell growth.	('inhibited', 'NegReg', (19, 28))	('cell growth', 'CPA', (29, 40))	('cell growth', 'CPA', (78, 89))	('Derlin-1', 'Gene', (0, 8))	('facilitated', 'PosReg', (66, 77))	('Derlin-1', 'Gene', '79139', (0, 8))	('depletion', 'Var', (9, 18))
555125	28903408	Blockage of AKT signaling attenuated the role of Derlin-1 on radioresistance.	('radioresistance', 'CPA', (61, 76))	('Blockage', 'Var', (0, 8))	('AKT', 'Gene', '207', (12, 15))	('AKT', 'Gene', (12, 15))	('attenuated', 'NegReg', (26, 36))	('Derlin-1', 'Gene', (49, 57))	('Derlin-1', 'Gene', '79139', (49, 57))
555140	28903408	There was one report identifying microRNA-181d as a tumor suppressor in human esophageal squamous cell carcinoma by downregulating Derlin-1.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Derlin-1', 'Gene', (131, 139))	('esophageal squamous cell carcinoma', 'Disease', (78, 112))	('tumor', 'Disease', (52, 57))	('Derlin-1', 'Gene', '79139', (131, 139))	('human', 'Species', '9606', (72, 77))	('microRNA-181d', 'Var', (33, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (78, 112))	('downregulating', 'NegReg', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
555151	28903408	We found that patients with a high expression of Derlin-1 tended to have a advanced TNM stage and T stage than other patients (Table 1).	('TNM', 'Gene', (84, 87))	('advanced', 'PosReg', (75, 83))	('T stage', 'CPA', (98, 105))	('high expression', 'Var', (30, 45))	('TNM', 'Gene', '10178', (84, 87))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (14, 22))	('Derlin-1', 'Gene', (49, 57))	('Derlin-1', 'Gene', '79139', (49, 57))
555156	28903408	The patients with a high Derlin-1 expression exhibited a significantly lower overall survival (p = 0.0003, Log-Rank test).	('expression', 'MPA', (34, 44))	('high', 'Var', (20, 24))	('overall survival', 'MPA', (77, 93))	('patients', 'Species', '9606', (4, 12))	('Derlin-1', 'Gene', (25, 33))	('Derlin-1', 'Gene', '79139', (25, 33))	('lower', 'NegReg', (71, 76))
555161	28903408	As shown in Table 3 and Table 4, high Derlin-1 status serves as independent risk factors for postoperative survival in the both groups.	('Derlin-1', 'Gene', (38, 46))	('high', 'Var', (33, 37))	('postoperative survival', 'CPA', (93, 115))	('Derlin-1', 'Gene', '79139', (38, 46))
555166	28903408	The effect of siRNA knockdown was confirmed in TE-1 cells (Figure 2B).	('knockdown', 'Var', (20, 29))	('siRNA', 'Gene', (14, 19))	('TE-1', 'CellLine', 'CVCL:1759', (47, 51))
555167	28903408	CCK-8 demonstrated that Derlin-1 transfection facilitated cell proliferation while its siRNA blocked proliferation (Figure 3A).	('blocked', 'NegReg', (93, 100))	('transfection', 'Var', (33, 45))	('facilitated', 'PosReg', (46, 57))	('cell proliferation', 'CPA', (58, 76))	('Derlin-1', 'Gene', (24, 32))	('Derlin-1', 'Gene', '79139', (24, 32))
555176	28903408	Derlin-1 depletion dramatically reduced the proportion of apoptotic TE-1 cells induced by radiation (Figure 4A).	('reduced', 'NegReg', (32, 39))	('Derlin-1', 'Gene', (0, 8))	('Derlin-1', 'Gene', '79139', (0, 8))	('TE-1', 'CellLine', 'CVCL:1759', (68, 72))	('depletion', 'Var', (9, 18))
555177	28903408	Consistent with previous results, Derlin-1 depletion induced significant upregulation in cleaved caspase3 in TE-1 cells treated with 4 Gy IR.	('depletion', 'Var', (43, 52))	('caspase3', 'Gene', (97, 105))	('caspase3', 'Gene', '836', (97, 105))	('Derlin-1', 'Gene', (34, 42))	('TE-1', 'CellLine', 'CVCL:1759', (109, 113))	('Derlin-1', 'Gene', '79139', (34, 42))	('upregulation', 'PosReg', (73, 85))
555181	28903408	In addition, Derlin-1 overexpression also upregulated p-PI3K p85, p-GSK3beta and p -ERK.	('p85', 'Gene', (61, 64))	('ERK', 'Gene', '5594', (84, 87))	('overexpression', 'PosReg', (22, 36))	('p-GSK3beta', 'Var', (66, 76))	('ERK', 'Gene', (84, 87))	('Derlin-1', 'Gene', (13, 21))	('p-PI3K', 'Protein', (54, 60))	('Derlin-1', 'Gene', '79139', (13, 21))	('upregulated', 'PosReg', (42, 53))	('p85', 'Gene', '5296', (61, 64))
555188	28903408	Cells transfected with either Derlin-1 plasmid or siRNA were treated with LY294005 (5 mumol/L).	('Derlin-1', 'Gene', '79139', (30, 38))	('LY294005', 'Chemical', 'MESH:C477931', (74, 82))	('LY294005', 'Var', (74, 82))	('Derlin-1', 'Gene', (30, 38))
555189	28903408	LY294002 effectively blocked AKT phosphorylation in both cell lines.	('LY294002', 'Var', (0, 8))	('AKT', 'Gene', '207', (29, 32))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('blocked', 'NegReg', (21, 28))	('AKT', 'Gene', (29, 32))
555190	28903408	CCK-8 assay demonstrated that LY294002 dramatically reduced the effect of Derlin-1 on cell viability (Figure 5A).	('Derlin-1', 'Gene', (74, 82))	('reduced', 'NegReg', (52, 59))	('cell viability', 'CPA', (86, 100))	('LY294002', 'Chemical', 'MESH:C085911', (30, 38))	('effect', 'MPA', (64, 70))	('Derlin-1', 'Gene', '79139', (74, 82))	('LY294002', 'Var', (30, 38))
555191	28903408	Annexin V/PI staining showed that LY294002 treatment significantly upregulated the percentage of apoptosis.	('LY294002', 'Var', (34, 42))	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('LY294002', 'Chemical', 'MESH:C085911', (34, 42))	('upregulated', 'PosReg', (67, 78))
555192	28903408	In LY294002 treated Eca-109 cells, the effect of Derlin-1 was not significant as that in untreated group.	('LY294002 treated', 'Var', (3, 19))	('Derlin-1', 'Gene', (49, 57))	('LY294002', 'Chemical', 'MESH:C085911', (3, 11))	('Derlin-1', 'Gene', '79139', (49, 57))
555194	28903408	Next, we examined the effect of LY294002 on caspase3 cleavage and Bcl-2.	('cleavage', 'MPA', (53, 61))	('Bcl-2', 'Gene', (66, 71))	('Bcl-2', 'Gene', '596', (66, 71))	('caspase3', 'Gene', (44, 52))	('LY294002', 'Var', (32, 40))	('caspase3', 'Gene', '836', (44, 52))	('LY294002', 'Chemical', 'MESH:C085911', (32, 40))
555223	28903408	PI3K functions upstream of AKT and was composed of a catalytic subunit (p110) and a regulatory subunit.	('PI3K', 'Var', (0, 4))	('AKT', 'Gene', (27, 30))	('p110', 'Gene', (72, 76))	('p110', 'Gene', '100616443', (72, 76))	('AKT', 'Gene', '207', (27, 30))
555225	28903408	Moreover, LY294002, an AKT inhibitor, blocked the effects of Derlin-1 on Bcl-2 and IR resistance, indicating that PI3K/AKT/Bcl-2 signaling mediated the biological effects of Derlin-1.	('Bcl-2', 'Gene', (123, 128))	('Derlin-1', 'Gene', '79139', (174, 182))	('LY294002', 'Var', (10, 18))	('Bcl-2', 'Gene', (73, 78))	('Bcl-2', 'Gene', '596', (73, 78))	('AKT', 'Gene', '207', (23, 26))	('AKT', 'Gene', '207', (119, 122))	('Derlin-1', 'Gene', (174, 182))	('Derlin-1', 'Gene', (61, 69))	('LY294002', 'Chemical', 'MESH:C085911', (10, 18))	('Derlin-1', 'Gene', '79139', (61, 69))	('AKT', 'Gene', (23, 26))	('IR resistance', 'MPA', (83, 96))	('AKT', 'Gene', (119, 122))	('blocked', 'NegReg', (38, 45))	('Bcl-2', 'Gene', '596', (123, 128))
555227	28903408	Inhibition of the PI3K/AKT pathway could also induce mitotic catastrophe.	('AKT', 'Gene', '207', (23, 26))	('Inhibition', 'Var', (0, 10))	('AKT', 'Gene', (23, 26))	('induce', 'Reg', (46, 52))	('mitotic catastrophe', 'CPA', (53, 72))
555232	28903408	High Derlin-1 status might be a predictor of cancer aggressiveness and serve as an independent prognostic factor for ESCC patients with chemoradiotherapy.	('aggressiveness', 'Phenotype', 'HP:0000718', (52, 66))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Derlin-1', 'Gene', (5, 13))	('cancer aggressiveness', 'Disease', (45, 66))	('Derlin-1', 'Gene', '79139', (5, 13))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (45, 66))	('patients', 'Species', '9606', (122, 130))	('ESCC', 'Disease', (117, 121))	('predictor', 'Reg', (32, 41))
555332	23266093	There may be a link between CFLD and increased insulin resistance leading to a higher incidence of CF related diabetes.	('CFLD', 'Var', (28, 32))	('diabetes', 'Disease', (110, 118))	('insulin', 'Gene', (47, 54))	('insulin resistance', 'Phenotype', 'HP:0000855', (47, 65))	('diabetes', 'Disease', 'MESH:D003920', (110, 118))	('insulin', 'Gene', '3630', (47, 54))	('increased', 'PosReg', (37, 46))
555350	23266093	Hepatic steatosis has been associated with malnutrition, and deficiencies of essential fatty acid, carnitine and choline.	('malnutrition', 'Disease', (43, 55))	('Hepatic steatosis', 'Phenotype', 'HP:0001397', (0, 17))	('Hepatic steatosis', 'Disease', 'MESH:D005234', (0, 17))	('essential fatty acid', 'MPA', (77, 97))	('choline', 'MPA', (113, 120))	('essential fatty acid', 'Chemical', 'MESH:D005228', (77, 97))	('associated', 'Reg', (27, 37))	('Hepatic steatosis', 'Disease', (0, 17))	('malnutrition', 'Phenotype', 'HP:0004395', (43, 55))	('carnitine', 'Chemical', 'MESH:D002331', (99, 108))	('steatosis', 'Phenotype', 'HP:0001397', (8, 17))	('carnitine', 'MPA', (99, 108))	('choline', 'Chemical', 'MESH:D002794', (113, 120))	('deficiencies', 'Var', (61, 73))
555356	23266093	Magnetic resonance cholangiography (MRC) demonstrates abnormalities in the intrahepatic bile ducts in a significant number of CF patients, with structuring, beading, and areas of narrowing and dilatation similar to primary sclerosing cholangitis.	('intrahepatic bile', 'Disease', 'MESH:D002780', (75, 92))	('intrahepatic bile', 'Disease', (75, 92))	('MRC', 'CellLine', 'CVCL:0440', (36, 39))	('patients', 'Species', '9606', (129, 137))	('cholangitis', 'Phenotype', 'HP:0030151', (234, 245))	('cholangitis', 'Disease', (234, 245))	('abnormalities', 'Var', (54, 67))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (223, 245))	('dilatation', 'Phenotype', 'HP:0002617', (193, 203))	('cholangitis', 'Disease', 'MESH:D002761', (234, 245))
555366	23266093	Coinheritance of the Gilbert syndrome associated UGT1A1 mutation appears to increase the risk for gallstones in CF.	('gallstones', 'Disease', (98, 108))	('gallstones', 'Phenotype', 'HP:0001081', (98, 108))	('gallstones', 'Disease', 'MESH:D042882', (98, 108))	('Gilbert syndrome', 'Disease', (21, 37))	('UGT1A1', 'Gene', '54658', (49, 55))	('UGT1A1', 'Gene', (49, 55))	('increase', 'Reg', (76, 84))	('Gilbert syndrome', 'Disease', 'MESH:D005878', (21, 37))	('mutation', 'Var', (56, 64))
555379	23266093	Cirrhosis occurs predominantly in those individuals with more severe class 1, 2, and 3 mutations and pancreatic insufficiency, but no specific genotype/phenotype correlation exists.	('pancreatic insufficiency', 'Disease', (101, 125))	('Cirrhosis', 'Disease', 'MESH:D005355', (0, 9))	('pancreatic insufficiency', 'Phenotype', 'HP:0001738', (101, 125))	('Cirrhosis', 'Phenotype', 'HP:0001394', (0, 9))	('class', 'Gene', (69, 74))	('Cirrhosis', 'Disease', (0, 9))	('mutations', 'Var', (87, 96))	('pancreatic insufficiency', 'Disease', 'MESH:D010188', (101, 125))
555381	23266093	Other factors inconsistently associated with cirrhosis have been male sex, meconium ileus and TGF-B1 polymorphisms.	('ileus', 'Phenotype', 'HP:0002595', (84, 89))	('meconium ileus', 'Disease', (75, 89))	('cirrhosis', 'Disease', (45, 54))	('TGF-B1', 'Gene', (94, 100))	('cirrhosis', 'Phenotype', 'HP:0001394', (45, 54))	('cirrhosis', 'Disease', 'MESH:D005355', (45, 54))	('meconium ileus', 'Phenotype', 'HP:0004401', (75, 89))	('polymorphisms', 'Var', (101, 114))	('TGF-B1', 'Gene', '7040', (94, 100))
555406	23266093	The presence of abnormalities in ALT or GGT is not predictive of ultrasound findings, although abnormal ultrasound findings were associated with abnormalities in ALT or GGT.	('GGT', 'Gene', (40, 43))	('abnormalities', 'Var', (145, 158))	('GGT', 'Gene', '728441', (169, 172))	('GGT', 'Gene', (169, 172))	('GGT', 'Gene', '728441', (40, 43))
555408	23266093	MRI, when combined with MRCP, has the advantage of being able to detect abnormalities in intra and extraheptic bile ducts as well as significant periportal fibrosis and nodularity in the liver parenchyma.	('portal fibrosis', 'Phenotype', 'HP:0006580', (149, 164))	('nodularity', 'CPA', (169, 179))	('abnormalities', 'Var', (72, 85))	('fibrosis', 'Disease', 'MESH:D005355', (156, 164))	('fibrosis', 'Disease', (156, 164))	('liver parenchyma', 'Disease', (187, 203))	('periportal fibrosis', 'Phenotype', 'HP:0001405', (145, 164))	('MRC', 'CellLine', 'CVCL:0440', (24, 27))	('liver parenchyma', 'Disease', 'MESH:D010195', (187, 203))
555453	23266093	Some authors have used partial splenic embolization or partial or total splenectomy in an attempt to reduce portal venous flow and improve thrombocytopenia.	('reduce', 'NegReg', (101, 107))	('splenic embolization', 'Disease', 'MESH:D013158', (31, 51))	('splenic embolization', 'Phenotype', 'HP:0012223', (31, 51))	('thrombocytopenia', 'Disease', 'MESH:D013921', (139, 155))	('portal venous flow', 'MPA', (108, 126))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (139, 155))	('partial', 'Var', (55, 62))	('thrombocytopenia', 'Disease', (139, 155))	('splenic embolization', 'Disease', (31, 51))	('improve', 'PosReg', (131, 138))
555476	23266093	Short term improvements in lung function are reported in pediatric patients following liver transplant, and poorer lung function prior to surgery has been positively associated with mortality risk.	('patients', 'Species', '9606', (67, 75))	('lung function', 'MPA', (27, 40))	('poorer lung function', 'Phenotype', 'HP:0005952', (108, 128))	('poorer', 'Var', (108, 114))	('associated', 'Reg', (166, 176))	('improvements', 'PosReg', (11, 23))
555540	20080098	In adult cells, alterations in homeobox genes might alter cellular phenotypic features.	('homeobox genes', 'Gene', (31, 45))	('alterations', 'Var', (16, 27))	('alter', 'Reg', (52, 57))	('cellular phenotypic features', 'CPA', (58, 86))	('rat', 'Species', '10116', (20, 23))
555549	20080098	In addition, deoxycholic acid (a bile acid) induces DNA damage in a dose-dependent, but nonlinear fashion.	('deoxycholic acid', 'Chemical', 'MESH:D003840', (13, 29))	('bile acid', 'Chemical', 'MESH:D001647', (33, 42))	('DNA damage', 'MPA', (52, 62))	('deoxycholic acid', 'Var', (13, 29))
555551	20080098	In addition to its potential role in initiating tumor development, GERD might also promote the growth of established neoplasms in Barrett's esophagus (a process called tumor promotion).	('tumor', 'Disease', (48, 53))	('growth', 'MPA', (95, 101))	('tumor', 'Disease', (168, 173))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (130, 149))	('neoplasms', 'Disease', 'MESH:D009369', (117, 126))	('neoplasms', 'Disease', (117, 126))	('GERD', 'Var', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('promote', 'PosReg', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('neoplasms', 'Phenotype', 'HP:0002664', (117, 126))
555553	20080098	For example, the farnesoid X receptor (FXR), a nuclear receptor that regulates inflammation, is up-regulated by deoxycholic acid in vitro.	('X receptor', 'Gene', (27, 37))	('X receptor', 'Gene', '9213', (27, 37))	('FXR', 'Gene', (39, 42))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (112, 128))	('deoxycholic acid', 'Var', (112, 128))	('FXR', 'Gene', '9971', (39, 42))	('inflammation', 'Disease', 'MESH:D007249', (79, 91))	('inflammation', 'Disease', (79, 91))	('up-regulated', 'PosReg', (96, 108))
555570	20080098	There is considerable genetic heterogeneity among the adenocarcinomas that develop in patients with Barrett's esophagus, which frequently involve alterations in tumor suppressor genes.	('adenocarcinomas', 'Disease', (54, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('alterations', 'Var', (146, 157))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('rat', 'Species', '10116', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	("Barrett's esophagus", 'Disease', (100, 119))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (100, 119))	('adenocarcinomas', 'Disease', 'MESH:D000230', (54, 69))	('involve', 'Reg', (138, 145))	('tumor', 'Disease', (161, 166))	('patients', 'Species', '9606', (86, 94))
555573	20080098	Methylation of DNA cytosine residues in the gene promoter region is another common gene silencing mechanism.	('Methylation', 'Var', (0, 11))	('silencing', 'NegReg', (88, 97))	('cytosine', 'Chemical', 'MESH:D003596', (19, 27))
555574	20080098	Alterations in genes that encode the tumor suppressors p16 (CDKN2A) and TP53 are frequently found in cells from Barrett's esophagus samples.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (112, 131))	('TP53', 'Gene', '7157', (72, 76))	('found', 'Reg', (92, 97))	('Alterations', 'Var', (0, 11))	('CDKN2A', 'Gene', (60, 66))	('p16', 'Gene', (55, 58))	('TP53', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('CDKN2A', 'Gene', '1029', (60, 66))	('rat', 'Species', '10116', (4, 7))	('p16', 'Gene', '1029', (55, 58))
555575	20080098	Loss of expression of a CDKN2A allele, usually through methylation of its promoter, is found in non-dysplastic Barrett's metaplasia in 85% of cases (Figure, panel B).	('Loss of', 'NegReg', (0, 7))	('CDKN2A', 'Gene', (24, 30))	("non-dysplastic Barrett's metaplasia", 'Disease', 'MESH:D001471', (96, 131))	('CDKN2A', 'Gene', '1029', (24, 30))	('expression', 'MPA', (8, 18))	('methylation', 'Var', (55, 66))	("non-dysplastic Barrett's metaplasia", 'Disease', (96, 131))
555576	20080098	The CDKN2A mutations found in Barrett's metaplasia appear to have been caused by oxidative damage in areas of chronic inflammation.	('oxidative damage', 'MPA', (81, 97))	('mutations', 'Var', (11, 20))	('inflammation', 'Disease', 'MESH:D007249', (118, 130))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (30, 50))	('inflammation', 'Disease', (118, 130))	('caused by', 'Reg', (71, 80))	('CDKN2A', 'Gene', '1029', (4, 10))	('CDKN2A', 'Gene', (4, 10))	("Barrett's metaplasia", 'Disease', (30, 50))
555578	20080098	CDKN2A abnormalities do not always alter esophageal cell proliferation and the affected cells can remain diploid, so these defects might cause not histological abnormalities.	('histological abnormalities', 'Phenotype', 'HP:0002664', (147, 173))	('abnormalities', 'Var', (7, 20))	('rat', 'Species', '10116', (64, 67))	('esophageal cell proliferation', 'CPA', (41, 70))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))
555585	20080098	The loss of p14ARF expression appears to occur primarily as the result of CpG or histone methylation, rather than LOH.	('p14ARF', 'Gene', (12, 18))	('expression', 'MPA', (19, 29))	('CpG', 'Var', (74, 77))	('histone', 'Protein', (81, 88))	('methylation', 'Var', (89, 100))	('p14ARF', 'Gene', '1029', (12, 18))	('rat', 'Species', '10116', (102, 105))	('loss', 'NegReg', (4, 8))
555586	20080098	The appearance of low-grade dysplasia in Barrett's esophagus often coincides with the loss of TP53 expression, through methylation of the gene promoter, mutations, or LOH in cells that have already lost p16 expression (Fig.	('expression', 'MPA', (99, 109))	('dysplasia', 'Disease', 'MESH:D004476', (28, 37))	('loss', 'NegReg', (86, 90))	('LOH', 'Var', (167, 170))	('mutations', 'Var', (153, 162))	('methylation', 'Var', (119, 130))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('p16', 'Gene', (203, 206))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (41, 60))	('expression', 'MPA', (207, 217))	('dysplasia', 'Disease', (28, 37))	('p16', 'Gene', '1029', (203, 206))
555587	20080098	LOH at TP53 is associated with a 16-fold increase in the rate of progression to cancer.	('TP53', 'Gene', '7157', (7, 11))	('LOH at', 'Var', (0, 6))	('TP53', 'Gene', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('rat', 'Species', '10116', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('increase', 'PosReg', (41, 49))	('cancer', 'Disease', (80, 86))
555588	20080098	Certain mutations in TP53 result in nuclear accumulation of the resulting non-functional p53 protein that can be detected by immunohistochemistry.	('TP53', 'Gene', (21, 25))	('protein', 'Protein', (93, 100))	('nuclear accumulation', 'MPA', (36, 56))	('mutations', 'Var', (8, 17))	('p53', 'Gene', (89, 92))	('non-functional', 'MPA', (74, 88))	('p53', 'Gene', '7157', (89, 92))	('TP53', 'Gene', '7157', (21, 25))
555593	20080098	Widespread LOH at TP53 and cytogenetic abnormalities are associated with increased cancer risk, perhaps because these changes increase sensitivity to mutagens.	('increased cancer', 'Disease', 'MESH:D009369', (73, 89))	('TP53', 'Gene', '7157', (18, 22))	('LOH', 'Var', (11, 14))	('cytogenetic abnormalities', 'Var', (27, 52))	('increased cancer', 'Disease', (73, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Widespread LOH', 'Var', (0, 14))	('TP53', 'Gene', (18, 22))	('sensitivity', 'MPA', (135, 146))	('increase', 'PosReg', (126, 134))
555595	20080098	Chromosomal copy number changes (a manifestation of aneuploidy) do not appear to be random events in Barrett's cells.	('aneuploidy', 'Disease', (52, 62))	('Chromosomal copy number changes', 'Var', (0, 31))	('aneuploidy', 'Disease', 'MESH:D000782', (52, 62))
555597	20080098	The presence of ploidy abnormalities in esophageal cells increases the risk for cancer among patients with Barrett's esophagus (relative risks (RR)=4.4 and 11 for tetraploidy and aneuploidy, respectively; RR=20 when both are present).	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (107, 126))	('aneuploidy', 'Disease', 'MESH:D000782', (179, 189))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tetraploidy', 'Disease', (163, 174))	('ploidy abnormalities', 'Disease', 'MESH:D000014', (16, 36))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	("Barrett's esophagus", 'Disease', (107, 126))	('presence', 'Var', (4, 12))	('ploidy abnormalities', 'Disease', (16, 36))	('aneuploidy', 'Disease', (179, 189))	('patients', 'Species', '9606', (93, 101))	('tetraploidy', 'Disease', 'MESH:D057891', (163, 174))	('cancer', 'Disease', (80, 86))
555600	20080098	This genomic heterogeneity results from local variations in the microenvironment of different regions of the esophagus (so-called microenvironmental niches) or from genetic instability.	('variations', 'Reg', (46, 56))	('iron', 'Chemical', 'MESH:D007501', (138, 142))	('results from', 'Reg', (27, 39))	('iron', 'Chemical', 'MESH:D007501', (72, 76))	('genetic instability', 'Var', (165, 184))
555601	20080098	However, microsatellite instability, which often underlies colorectal carcinomas, does not seem to contribute importantly to carcinogenesis in Barrett's esophagus.	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('microsatellite instability', 'Var', (9, 35))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (59, 80))	('colorectal carcinomas', 'Disease', (59, 80))	("Barrett's esophagus", 'Disease', (143, 162))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (143, 162))	('carcinogenesis', 'Disease', (125, 139))
555602	20080098	The number of molecular abnormalities identified in Barrett's esophagus has greatly increased with advances in high-throughput screening techniques for genomic and epigenetic alterations.	('molecular abnormalities', 'Disease', (14, 37))	('molecular abnormalities', 'Disease', 'MESH:C567116', (14, 37))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (52, 71))	('epigenetic', 'Var', (164, 174))	('rat', 'Species', '10116', (179, 182))
555654	20080098	In the aforementioned sham-controlled trial of RFA for dysplasia in Barrett's esophagus, the frequency of buried metaplasia decreased in the group treated with RFA and PPIs (from 25% to 5%) and increased in the control group who received sham therapy and PPIs (from 25% to 40%).	('dysplasia', 'Disease', (55, 64))	('buried', 'Disease', (106, 112))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (68, 87))	('dysplasia', 'Disease', 'MESH:D004476', (55, 64))	('decreased', 'NegReg', (124, 133))	('RFA', 'Var', (160, 163))	('PPIs', 'Var', (168, 172))
555685	27075367	Initially, SMYD2 was characterized as methylating H3 lysine 36 and lysine 4 when interacting with HSP90a.	('HSP90', 'Gene', (98, 103))	('HSP90', 'Gene', '3320', (98, 103))	('interacting', 'Interaction', (81, 92))	('H3', 'Chemical', 'MESH:C012616', (50, 52))	('HSP90a', 'Gene', (98, 104))	('methylating', 'Var', (38, 49))	('HSP90a', 'Gene', '3324', (98, 104))
555688	27075367	In the same study, a knockdown of SMYD2 and treatment with doxorubicin led to an increase in p53-mediated cell-cycle arrest and apoptosis.	('p53-mediated', 'Protein', (93, 105))	('arrest', 'Disease', (117, 123))	('doxorubicin', 'Chemical', 'MESH:D004317', (59, 70))	('SMYD2', 'Gene', (34, 39))	('increase', 'PosReg', (81, 89))	('knockdown', 'Var', (21, 30))	('apoptosis', 'CPA', (128, 137))	('arrest', 'Disease', 'MESH:D006323', (117, 123))
555719	27075367	The 4-chlorophenyl substituent inserts into the lysine binding channel and is engaged in pi-stacking interactions with Phe184 and Tyr240.	('Phe184', 'Chemical', '-', (119, 125))	('inserts', 'Reg', (31, 38))	('Phe184', 'Var', (119, 125))	('engaged', 'Reg', (78, 85))	('Tyr240', 'Var', (130, 136))	('lysine', 'Protein', (48, 54))	('Tyr240', 'Chemical', '-', (130, 136))
555737	27075367	The KYSE-150 cell line model was selected based on a described SMYD2 gene amplification and a heterozygous R248Q mutation in p53 (COSMIC), leading to p53 protein accumulation without a stress stimulus.	('R248Q', 'Var', (107, 112))	('p53', 'Gene', (125, 128))	('SMYD2', 'Gene', (63, 68))	('R248Q', 'Mutation', 'rs11540652', (107, 112))	('p53 protein accumulation', 'MPA', (150, 174))
555783	27075367	Assays were conducted in 384-well microtiter plates in a buffer containing 50 mM Tris/HCl pH 9.0, 1 mM DTT, 0.01% (w/v) BSA, and 0.0022% (v/v) Pluronic, and a final volume of 5 muL.	('DTT', 'Chemical', 'MESH:D004229', (103, 106))	('Tris', 'Chemical', '-', (81, 85))	('Pluronic', 'Chemical', 'MESH:D020442', (143, 151))	('0.0022', 'Var', (129, 135))	('0.01', 'Var', (108, 112))
555817	25937890	In this study, it was investigated whether ESE-16 is capable of inducing apoptosis in vitro in the esophageal carcinoma SNO cell line via the intrinsic pathway at a concentration of 0.2 muM with an exposure time of 24 hours.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (99, 119))	('ESE-16', 'Chemical', 'MESH:C588027', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('esophageal carcinoma SNO', 'Disease', (99, 123))	('muM', 'Gene', '56925', (186, 189))	('inducing', 'PosReg', (64, 72))	('apoptosis', 'CPA', (73, 82))	('ESE-16', 'Var', (43, 49))	('esophageal carcinoma SNO', 'Disease', 'MESH:D004938', (99, 123))	('muM', 'Gene', (186, 189))
555820	25937890	Cell death via apoptosis in the ESE-16-treated cells was confirmed by studying the internal ultrastructure of the cells via transmission electron microscopy, while confocal microscopy revealed abnormal spindle formation and condensed chromatin in ESE-16-treated cells, thus confirming metaphase block.	('tap', 'Gene', (287, 290))	('ESE-16', 'Chemical', 'MESH:C588027', (32, 38))	('tap', 'Gene', '2317', (287, 290))	('ESE-16-treated', 'Var', (247, 261))	('spindle formation', 'CPA', (202, 219))	('ESE-16', 'Chemical', 'MESH:C588027', (247, 253))	('condensed chromatin', 'CPA', (224, 243))
555822	25937890	Flow cytometry and spectrophotometry revealed dissipation of mitochondrial membrane potential and an increase in superoxide levels in the ESE-16-treated cells when compared to the relevant controls.	('ESE-16', 'Chemical', 'MESH:C588027', (138, 144))	('dissipation', 'NegReg', (46, 57))	('superoxide levels', 'MPA', (113, 130))	('increase', 'PosReg', (101, 109))	('superoxide', 'Chemical', 'MESH:D013481', (113, 123))	('ESE-16-treated', 'Var', (138, 152))	('mitochondrial membrane potential', 'MPA', (61, 93))
555823	25937890	Both initiator caspase 9 and effector caspase 3 activities were increased, which demonstrates that ESE-16 causes cell death in a caspase-dependent manner.	('caspase 3', 'Gene', (38, 47))	('caspase 3', 'Gene', '836', (38, 47))	('activities', 'MPA', (48, 58))	('caspase 9', 'Gene', '842', (15, 24))	('caspase 9', 'Gene', (15, 24))	('ESE-16', 'Chemical', 'MESH:C588027', (99, 105))	('increased', 'PosReg', (64, 73))	('ESE-16', 'Var', (99, 105))
555841	25937890	Previous studies have shown sulphamoylated analogues with modifications on the 3- and 17-position of the molecule revealed significant anticancer potency and prolonged half-life and bioavailability.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('half-life', 'MPA', (168, 177))	('prolonged', 'PosReg', (158, 167))	('modifications', 'Var', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('bioavailability', 'MPA', (182, 197))	('cancer', 'Disease', (139, 145))
555844	25937890	Studies have also revealed ESE-16 to be more potent than its source compound, 2ME.	('ESE-16', 'Var', (27, 33))	('ESE-16', 'Chemical', 'MESH:C588027', (27, 33))	('potent', 'MPA', (45, 51))	('2ME', 'Chemical', 'MESH:D000077584', (78, 81))
555854	25937890	The staining was used to visualize morphological changes in SNO cells after exposure to ESE-16 and the appropriate controls.	('ESE-16', 'Chemical', 'MESH:C588027', (88, 94))	('ESE-16', 'Var', (88, 94))	('SNO', 'Gene', '55206', (60, 63))	('SNO', 'Gene', (60, 63))
555861	25937890	Confocal microscopy was used to determine the influence of ESE-16 on the cytoskeletal microtubule architecture of SNO cells after exposure to ESE-16 and the appropriate controls.	('ESE-16', 'Chemical', 'MESH:C588027', (142, 148))	('ESE-16', 'Var', (142, 148))	('SNO', 'Gene', (114, 117))	('SNO', 'Gene', '55206', (114, 117))	('ESE-16', 'Chemical', 'MESH:C588027', (59, 65))
555864	25937890	The ESE-16-treated cells (Figure 4D) also showed a decrease in cell density and revealed abnormal spindle formation, indicating cells being blocked in metaphase.	('spindle formation', 'CPA', (98, 115))	('cell density', 'CPA', (63, 75))	('tap', 'Gene', '2317', (153, 156))	('decrease', 'NegReg', (51, 59))	('ESE-16', 'Chemical', 'MESH:C588027', (4, 10))	('ESE-16-treated', 'Var', (4, 18))	('tap', 'Gene', (153, 156))
555876	25937890	Thus, flow cytometry was used to measure O2 - levels in the SNO cells after exposure to ESE-16 and the various controls (Figure 7).	('SNO', 'Gene', (60, 63))	('ESE-16', 'Chemical', 'MESH:C588027', (88, 94))	('SNO', 'Gene', '55206', (60, 63))	('ESE-16', 'Var', (88, 94))	('O2 - levels', 'MPA', (41, 52))	('O2', 'Chemical', 'MESH:D013481', (41, 43))
555880	25937890	Results indicate that ESE-16 does cause an increase in O2 - levels, which may lead to mitochondrial degradation and cell death.	('cell death', 'CPA', (116, 126))	('O2', 'Chemical', 'MESH:D013481', (55, 57))	('mitochondrial degradation', 'MPA', (86, 111))	('lead to', 'Reg', (78, 85))	('ESE-16', 'Chemical', 'MESH:C588027', (22, 28))	('increase', 'PosReg', (43, 51))	('ESE-16', 'Var', (22, 28))	('O2 - levels', 'MPA', (55, 66))
555883	25937890	The initiator caspase 9 results (Figure 8) showed that ESE-16-treated cells had a ratio to medium value of 1.2188, while the vehicle control had a value of 1.0625.	('ESE-16', 'Chemical', 'MESH:C588027', (55, 61))	('caspase 9', 'Gene', (14, 23))	('caspase 9', 'Gene', '842', (14, 23))	('ESE-16-treated', 'Var', (55, 69))	('ratio', 'MPA', (82, 87))
555885	25937890	The effector caspase 3 results (Figure 9) showed ESE-16-treated cells had an average ratio to medium value of 2.9772 while the vehicle control had a value of 1.0681.	('caspase 3', 'Gene', (13, 22))	('caspase 3', 'Gene', '836', (13, 22))	('ESE-16', 'Chemical', 'MESH:C588027', (49, 55))	('ESE-16-treated', 'Var', (49, 63))
555887	25937890	The caspase activity results show that ESE-16 causes the activation of caspases and reveals that ESE-16 causes cell death in a caspase-dependent manner.	('ESE-16', 'Chemical', 'MESH:C588027', (97, 103))	('caspases', 'Gene', (71, 79))	('activation', 'PosReg', (57, 67))	('ESE-16', 'Chemical', 'MESH:C588027', (39, 45))	('ESE-16', 'Var', (97, 103))	('caspases', 'Gene', '842', (71, 79))	('ESE-16', 'Var', (39, 45))	('cell death', 'CPA', (111, 121))
555889	25937890	These two targets were chosen because: 1) several studies have shown that inhibition of CAIX can lead to decreased invasiveness and may cause cell death under hypoxic conditions and 2) by binding to microtubules there is interference during cell division, which may lead to cell death.	('cell', 'CPA', (274, 278))	('binding', 'Interaction', (188, 195))	('inhibition', 'Var', (74, 84))	('lead', 'Reg', (266, 270))	('cause', 'Reg', (136, 141))	('CAIX', 'Gene', (88, 92))	('invasiveness', 'CPA', (115, 127))	('CAIX', 'Gene', '768', (88, 92))	('microtubules', 'Protein', (199, 211))	('decreased', 'NegReg', (105, 114))	('cell death', 'CPA', (142, 152))
555890	25937890	In this study ESE-16 was shown to induce apoptosis in vitro in the esophageal carcinoma SNO cell line via the intrinsic pathway at a concentration of 0.2 muM with an exposure time of 24 hours.	('esophageal carcinoma SNO', 'Disease', (67, 91))	('esophageal carcinoma SNO', 'Disease', 'MESH:D004938', (67, 91))	('ESE-16', 'Var', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('apoptosis', 'CPA', (41, 50))	('muM', 'Gene', '56925', (154, 157))	('intrinsic pathway', 'Pathway', (110, 127))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (67, 87))	('ESE-16', 'Chemical', 'MESH:C588027', (14, 20))	('muM', 'Gene', (154, 157))
555893	25937890	The H&E results revealed the presence of apoptotic morphological characteristics, such as membrane blebbing and apoptotic bodies in the ESE-16-treated.	('as membrane', 'CPA', (87, 98))	('the', 'Var', (132, 135))	('and apoptotic', 'CPA', (108, 121))	('H&E', 'Chemical', '-', (4, 7))	('ESE-16', 'Chemical', 'MESH:C588027', (136, 142))	('of apoptotic', 'CPA', (38, 50))
555897	25937890	Results from the Annexin V-FITC apoptosis-detection assay revealed a statistically insignificant increase in MFI (P-value of 0.0614) of the ESE-16-treated cells when compared to the appropriate controls.	('Annexin V', 'Gene', '308', (17, 26))	('increase', 'PosReg', (97, 105))	('Annexin V', 'Gene', (17, 26))	('ESE-16-treated', 'Var', (140, 154))	('ESE-16', 'Chemical', 'MESH:C588027', (140, 146))	('MFI', 'MPA', (109, 112))	('FITC', 'Chemical', 'MESH:D016650', (27, 31))
555902	25937890	An increase in the percentage of cells in the sub G1 (indicative of apoptosis) in the ESE-16-treated cells was observed when compared to the relevant controls.	('ESE-16-treated', 'Var', (86, 100))	('ESE-16', 'Chemical', 'MESH:C588027', (86, 92))	('increase', 'PosReg', (3, 11))
555911	25937890	ESE-16 has a similar mechanism to that of 2ME, its source compound, and thus also binds to the colchicine binding site situated between the alpha - and beta-dimers of the tubulin protein.	('ESE-16', 'Var', (0, 6))	('colchicine', 'Chemical', 'MESH:D003078', (95, 105))	('ESE-16', 'Chemical', 'MESH:C588027', (0, 6))	('binds', 'Interaction', (82, 87))	('2ME', 'Chemical', 'MESH:D000077584', (42, 45))
555912	25937890	It was hypothesized that ESE-16 would, like its source compound, cause abnormal spindle formation and activate the SAC, causing metaphase arrest.	('activate', 'PosReg', (102, 110))	('ESE-16', 'Var', (25, 31))	('arrest', 'Disease', 'MESH:D006323', (138, 144))	('SAC', 'CPA', (115, 118))	('tap', 'Gene', (130, 133))	('arrest', 'Disease', (138, 144))	('cause', 'Reg', (65, 70))	('tap', 'Gene', '2317', (130, 133))	('ESE-16', 'Chemical', 'MESH:C588027', (25, 31))	('spindle formation', 'CPA', (80, 97))	('causing', 'Reg', (120, 127))
555916	25937890	The observed effect of ESE-16 on the microtubules was qualitatively confirmed via confocal microscopy, which also showed hypercondensed chromatin and abnormal spindle formation in the ESE-16-treated cells when compared to the appropriate controls.	('ESE-16-treated', 'Var', (184, 198))	('hypercondensed', 'PosReg', (121, 135))	('ESE-16', 'Chemical', 'MESH:C588027', (23, 29))	('spindle formation', 'CPA', (159, 176))	('ESE-16', 'Chemical', 'MESH:C588027', (184, 190))
555918	25937890	The increased potency of ESE-16 can once again be seen, since it was able to cause metaphase block in the SNO cell line after 24 hours' exposure at a much lower concentration of 0.2 muM.	('ESE-16', 'Var', (25, 31))	('tap', 'Gene', (85, 88))	('muM', 'Gene', (182, 185))	('tap', 'Gene', '2317', (85, 88))	('SNO', 'Gene', (106, 109))	('SNO', 'Gene', '55206', (106, 109))	('ESE-16', 'Chemical', 'MESH:C588027', (25, 31))	('muM', 'Gene', '56925', (182, 185))
555921	25937890	These findings illustrate that ESE-16 caused a decrease in  Psim, which may have led to the degradation of the mitochondrial membrane and apoptosis.	('ESE-16', 'Var', (31, 37))	('degradation of the mitochondrial membrane', 'MPA', (92, 133))	('Psim', 'Disease', (60, 64))	('decrease', 'NegReg', (47, 55))	('ESE-16', 'Chemical', 'MESH:C588027', (31, 37))
555922	25937890	The decrease of  Psim due to ESE-16 exposure was also found by Stander et al.	('ESE-16', 'Chemical', 'MESH:C588027', (29, 35))	('ESE-16', 'Var', (29, 35))	('decrease', 'NegReg', (4, 12))	('Psim', 'Disease', (17, 21))
555924	25937890	showed that ESE-16 had a more pronounced effect on the tumorigenic cell lines when compared to the non-tumorigenic MCF-12 cell line.	('ESE-16', 'Var', (12, 18))	('MCF-12', 'CellLine', 'CVCL:3744', (115, 121))	('ESE-16', 'Chemical', 'MESH:C588027', (12, 18))	('tumorigenic cell lines', 'CPA', (55, 77))
555930	25937890	Results revealed an increase in O2 - levels in the ESE-16-treated cells when compared to the relevant controls.	('ESE-16', 'Chemical', 'MESH:C588027', (51, 57))	('O2 - levels', 'MPA', (32, 43))	('O2', 'Chemical', 'MESH:D013481', (32, 34))	('ESE-16-treated', 'Var', (51, 65))	('increase', 'PosReg', (20, 28))
555931	25937890	This increase shows that ESE-16 causes oxidative stress after 24 hours' exposure and confirms previously discussed results of  Psim dissipitation, since it is believed that ROS can cause  Psim dissipation.	('oxidative stress', 'Phenotype', 'HP:0025464', (39, 55))	('ESE-16', 'Var', (25, 31))	('Psim dissipation', 'MPA', (188, 204))	('oxidative stress', 'MPA', (39, 55))	('ROS', 'Chemical', 'MESH:D017382', (173, 176))	('ESE-16', 'Chemical', 'MESH:C588027', (25, 31))	('causes', 'Reg', (32, 38))
555944	25937890	Results revealed a statistically insignificant (P-value of 0.238) increase in caspase 9 activity in ESE-16-treated cells when compared to the relevant controls.	('increase', 'PosReg', (66, 74))	('caspase 9', 'Gene', '842', (78, 87))	('activity', 'MPA', (88, 96))	('ESE-16-treated', 'Var', (100, 114))	('ESE-16', 'Chemical', 'MESH:C588027', (100, 106))	('caspase 9', 'Gene', (78, 87))
555947	25937890	The caspase activity results show that ESE-16 causes the activation of caspases and induces cell death in a caspase-dependent manner.	('caspases', 'Gene', (71, 79))	('activation', 'PosReg', (57, 67))	('ESE-16', 'Chemical', 'MESH:C588027', (39, 45))	('caspases', 'Gene', '842', (71, 79))	('ESE-16', 'Var', (39, 45))	('cell death', 'CPA', (92, 102))
556074	33330444	LncRNA MAGI2-AS3 Overexpression Sensitizes Esophageal Cancer Cells to Irradiation Through Down-Regulation of HOXB7 via EZH2 Accumulating evidence has suggested that aberrant expression of long non-coding RNAs (lncRNAs) may contribute to cancer progression in association with radioresistance.	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('aberrant', 'Var', (165, 173))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (7, 16))	('lncRNAs', 'Gene', (210, 217))	('radioresistance', 'Disease', (276, 291))	('contribute', 'Reg', (223, 233))	('Down-Regulation', 'NegReg', (90, 105))	('MAGI2-AS3', 'Gene', (7, 16))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('HOXB7', 'Gene', '3217', (109, 114))	('cancer', 'Disease', (237, 243))	('HOXB7', 'Gene', (109, 114))
556089	33330444	For instance, lncRNA-p21 was indicated to promote the radiotherapy sensitivity of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('radiotherapy sensitivity', 'CPA', (54, 78))	('promote', 'PosReg', (42, 49))	('gastric cancer', 'Disease', (82, 96))	('lncRNA-p21', 'Var', (14, 24))
556101	33330444	The Affy installation package of R software was applied to normalize the microarray data and the Limma package was used to screen the DEGs with   log2FoldChange  > 2.0 and p-value < 0.05 serving as the threshold.	('DEGs', 'Gene', (134, 138))	('DEGs', 'Gene', '8560', (134, 138))	('log2FoldChange', 'Var', (146, 160))
556124	33330444	The esophageal cancer cell line with highest radio-resistance was identified as KYSE150R.	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal cancer', 'Disease', (4, 21))	('KYSE150R', 'Var', (80, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))
556128	33330444	When reaching approximately 50% confluence, the KYSE150 and KYSE150R cells were infected with lentiviral vectors carrying overexpression (oe)-MAGI2-AS, sh-MAGI2-AS3, oe-HOXB7 or the corresponding NC sequences (oe-M-NC, sh-M-NC, sh-NC and oe-NC), respectively.	('KYSE150R', 'Var', (60, 68))	('MAGI2-AS3', 'Gene', (155, 164))	('overexpression', 'PosReg', (122, 136))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (155, 164))	('infected', 'Disease', 'MESH:D007239', (80, 88))	('infected', 'Disease', (80, 88))
556137	33330444	The membrane was blocked with 5% bovine serum albumin (BSA) at room temperature for 1 h and then incubated at 4 C overnight with diluted primary rabbit antibodies to HOXB7 (ab196007, dilution ratio of 1:1000), Ki67 (ab92742, 1: 5000), proliferating cell nuclear antigen (PCNA) (ab92552, 1: 1000), Cyclin D1 (ab16663, 1: 200), CDK4 (ab68266, 1: 1000), caspase 3 (ab13847, 1: 500), Bcl-2-associated X protein (Bax) (ab18283, 1: 1000), B-cell lymphoma 2 (Bcl-2) (ab59348, 1: 500), and GAPDH (ab181602, 1:10,000).	('GAPDH', 'Gene', (482, 487))	('Bax', 'Gene', '581', (408, 411))	('caspase 3', 'Gene', (351, 360))	('caspase 3', 'Gene', '836', (351, 360))	('PCNA', 'Gene', (271, 275))	('B-cell lymphoma 2', 'Gene', '596', (433, 450))	('serum albumin', 'Gene', '213', (40, 53))	('Bcl-2', 'Gene', '596', (452, 457))	('Bcl-2', 'Gene', '596', (380, 385))	('proliferating cell nuclear antigen', 'Gene', '5111', (235, 269))	('PCNA', 'Gene', '5111', (271, 275))	('B-cell lymphoma 2', 'Gene', (433, 450))	('serum albumin', 'Gene', (40, 53))	('Bcl-2-associated X protein', 'Gene', '581', (380, 406))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (433, 448))	('ab13847', 'Var', (362, 369))	('CDK4', 'Gene', (326, 330))	('proliferating cell nuclear antigen', 'Gene', (235, 269))	('GAPDH', 'Gene', '2597', (482, 487))	('Bcl-2-associated X protein', 'Gene', (380, 406))	('ab18283', 'Var', (414, 421))	('Cyclin D1', 'Gene', '595', (297, 306))	('Bax', 'Gene', (408, 411))	('Cyclin D1', 'Gene', (297, 306))	('ab181602', 'Var', (489, 497))	('lymphoma', 'Phenotype', 'HP:0002665', (440, 448))	('Bcl-2', 'Gene', (452, 457))	('Bcl-2', 'Gene', (380, 385))	('CDK4', 'Gene', '1019', (326, 330))
556162	33330444	The supernatant was collected by centrifugation at 13,000 rpm and 4 C, sub-packed into 3 tubes, and incubated with the normal mouse antibody to IgG or the target protein specific rabbit antibody to EZH2 (ab195409, Abcam Inc., Cambridge, United Kingdom) or trimethylated lysine-27 of histone H3 (H3K27me3) (ab192985, Abcam Inc., Cambridge, United Kingdom) at 4 C overnight.	('mouse', 'Species', '10090', (126, 131))	('antibody to IgG', 'Phenotype', 'HP:0003237', (132, 147))	('histone H3', 'Gene', (283, 293))	('ab192985', 'Var', (306, 314))	('lysine', 'Chemical', 'MESH:D008239', (270, 276))	('trimethylated lysine-27', 'Var', (256, 279))	('histone H3', 'Gene', '260423', (283, 293))
556178	33330444	KYSE150R cells infected with sh-MAGI2-AS3, oe-MAGI2-AS3, oe-HOXB7 or oe-MAGI2-AS3 + oe-HOXB7 along with corresponding NC (sh-M-NC or oe-M-NC) were detached, rinsed 2-3 times with PBS, and formulated into a single cell suspension at a density of 1 x 107 cells/mL.	('infected', 'Disease', (15, 23))	('MAGI2-AS3', 'Gene', (72, 81))	('MAGI2-AS3', 'Gene', (46, 55))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (72, 81))	('PBS', 'Chemical', '-', (179, 182))	('MAGI2-AS3', 'Gene', (32, 41))	('infected', 'Disease', 'MESH:D007239', (15, 23))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (46, 55))	('oe-HOXB7', 'Var', (57, 65))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (32, 41))
556194	33330444	The KYSE30, KYSE150, and KYSE450 cell lines presented with significantly high mRNA and protein expression of HOXB7 compared to the HEEC cell lines, among which the KYSE150 cell line exhibited the highest HOXB7 expression (p < 0.05, Figures 2A-C), and was therefore selected for subsequent experimentation.	('KYSE450', 'Var', (25, 32))	('expression', 'MPA', (210, 220))	('KYSE150', 'Var', (164, 171))	('high', 'PosReg', (73, 77))	('HOXB7', 'Enzyme', (204, 209))	('HEEC', 'CellLine', 'None', (131, 135))
556196	33330444	Taken together, these findings suggested that esophageal cancer cells with HOXB7 silencing were more susceptible to X-ray irradiation and HOXB7 enhanced radioresistance of the cancer cells in vitro.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('enhanced', 'PosReg', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('silencing', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('HOXB7', 'Gene', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('HOXB7', 'Var', (138, 143))
556199	33330444	The results demonstrated that the protein expression of Ki67, PCNA, cyclin D1, CDK4 and Bcl-2 was increased, while that of Bax and caspase 3 was decreased in KYSE150 (Figures 3G,H) and KYSE150R cells (Figures 3I,J) over-expressing HOXB7, while silencing HOXB7 brought about opposite results (p < 0.05).	('Bax', 'Gene', '581', (123, 126))	('HOXB7', 'Gene', (231, 236))	('decreased', 'NegReg', (145, 154))	('cyclin D1', 'Gene', '595', (68, 77))	('Ki67', 'Gene', (56, 60))	('protein expression', 'MPA', (34, 52))	('over-expressing', 'PosReg', (215, 230))	('increased', 'PosReg', (98, 107))	('KYSE150R', 'Var', (185, 193))	('Bcl-2', 'Gene', (88, 93))	('PCNA', 'Gene', (62, 66))	('CDK4', 'Gene', (79, 83))	('caspase 3', 'Gene', (131, 140))	('caspase 3', 'Gene', '836', (131, 140))	('Bax', 'Gene', (123, 126))	('Bcl-2', 'Gene', '596', (88, 93))	('cyclin D1', 'Gene', (68, 77))	('PCNA', 'Gene', '5111', (62, 66))	('CDK4', 'Gene', '1019', (79, 83))
556208	33330444	The results revealed that the expression of MAGI2-AS3 was much lower in KYSE30, KYSE150, and KYSE450 cell lines than that in HEEC cell lines.	('expression', 'MPA', (30, 40))	('lower', 'NegReg', (63, 68))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (44, 53))	('KYSE150', 'Var', (80, 87))	('KYSE450', 'Var', (93, 100))	('KYSE30', 'Var', (72, 78))	('HEEC', 'CellLine', 'None', (125, 129))	('MAGI2-AS3', 'Gene', (44, 53))
556213	33330444	As a stemness factor, histone methyltransferase EZH2 has the ability to regulate cell differentiation, embryonic development, and cancer development, and EZH2 silencing has been confirmed to downregulate different genes in ESCC.	('downregulate', 'NegReg', (191, 203))	('embryonic development', 'Disease', 'MESH:D002658', (103, 124))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('EZH2', 'Gene', (154, 158))	('silencing', 'Var', (159, 168))	('cancer', 'Disease', (130, 136))	('histone methyltransferase', 'Gene', '56979', (22, 47))	('embryonic development', 'Disease', (103, 124))	('ESCC', 'Disease', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('histone methyltransferase', 'Gene', (22, 47))	('cell differentiation', 'CPA', (81, 101))
556214	33330444	H3K27me3 is required for EZH2-mediated repression of various genes essential for tumorigenesis and tumor development, while the expression of H3K27me3 and EZH2 could serve as biomarkers in the prediction of ESCC patients' survival and ESCC metastasis.	('ESCC', 'Disease', (207, 211))	('tumor', 'Disease', (99, 104))	('patients', 'Species', '9606', (212, 220))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('EZH2', 'Gene', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('H3K27me3', 'Var', (142, 150))	('tumor', 'Disease', (81, 86))
556219	33330444	Meanwhile, EZH2 and H3K27me3 showed lower enrichment in the HOXB7 promoter region in the presence of MAGI2-AS3-MUT than MAGI2-AS3-WT (Figure 5E).	('lower', 'NegReg', (36, 41))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (120, 129))	('MAGI2-AS3', 'Gene', (101, 110))	('enrichment in the HOXB7 promoter region', 'MPA', (42, 81))	('H3K27me3', 'Var', (20, 28))	('MAGI2-AS3', 'Gene', (120, 129))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (101, 110))
556225	33330444	Additionally, Western blot analysis of HOXB7 protein revealed that over-expression of MAGI2-AS3 suppressed its expression and conversely, MAGI2-AS3 silencing enhanced the expression in mouse tumor tissues (p < 0.05, Figures 6B,C).	('expression', 'MPA', (171, 181))	('mouse', 'Species', '10090', (185, 190))	('MAGI2-AS3', 'Gene', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('MAGI2-AS3', 'Gene', (86, 95))	('silencing', 'Var', (148, 157))	('enhanced', 'PosReg', (158, 166))	('expression', 'MPA', (111, 121))	('suppressed', 'NegReg', (96, 106))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (138, 147))	('tumor', 'Disease', (191, 196))	('over-expression', 'PosReg', (67, 82))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))
556227	33330444	Moreover, tumor size was much smaller (Figure 6D), tumor weight was much lighter (Figure 6E) in mice after inoculation of cells with over-expressed MAGI2-AS3 than after inoculation of cells treated with oe-M-NC (p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Disease', (10, 15))	('MAGI2-AS3', 'Gene', (148, 157))	('tumor', 'Disease', (51, 56))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (148, 157))	('over-expressed', 'Var', (133, 147))	('lighter', 'NegReg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('smaller', 'NegReg', (30, 37))
556229	33330444	To conclude, MAGI2-AS3 silencing promoted the resistance of esophageal cancer cells to radiotherapy in vivo.	('MAGI2-AS3', 'Gene', (13, 22))	('promoted', 'PosReg', (33, 41))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (13, 22))	('silencing', 'Var', (23, 32))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('resistance', 'CPA', (46, 56))
556231	33330444	KYSE150 and KYSE150R cells were, respectively, infected with lentivirus expressing oe-M-NC, oe-MAGI2-AS3, oe-HOXB7, or oe-MAGI2-AS3 + oe-HOXB7.	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (122, 131))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (95, 104))	('oe-M-NC', 'Var', (83, 90))	('infected', 'Disease', (47, 55))	('MAGI2-AS3', 'Gene', (95, 104))	('MAGI2-AS3', 'Gene', (122, 131))	('infected', 'Disease', 'MESH:D007239', (47, 55))
556236	33330444	Results indicated that restoring MAGI2-AS3 suppressed the proliferation of KYSE150 and KYSE150R cells (Figures 7C,D) and resistance to radiotherapy (Figures 7E-J), decreased PE and SF and promoted apoptosis (Figures 7M,N) with more cells arrested at the G0/G1 phase and fewer cells arrested at the S and G2/M phases (p < 0.05) (Figures 7K,L).	('apoptosis', 'CPA', (197, 206))	('proliferation', 'CPA', (58, 71))	('decreased', 'NegReg', (164, 173))	('promoted', 'PosReg', (188, 196))	('MAGI2-AS3', 'Gene', (33, 42))	('KYSE150R', 'Var', (87, 95))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (33, 42))	('suppressed', 'NegReg', (43, 53))
556239	33330444	Consistently, the expressions of Ki67, PCNA, Bcl-2, cyclin D1, and CDK4 were all decreased, while those of Bax and caspase 3 were increased in KYSE150 and KYSE150R cells infected with oe-MAGI2-AS3, whereas KYSE150 and KYSE150R cells infected with oe-HOXB7 presented with opposite results (p < 0.05) (Figures 7O-R).	('Ki67', 'Gene', (33, 37))	('Bax', 'Gene', '581', (107, 110))	('KYSE150R', 'Var', (155, 163))	('decreased', 'NegReg', (81, 90))	('Bcl-2', 'Gene', (45, 50))	('CDK4', 'Gene', (67, 71))	('infected', 'Disease', 'MESH:D007239', (170, 178))	('KYSE150', 'Var', (143, 150))	('increased', 'PosReg', (130, 139))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (187, 196))	('infected', 'Disease', (170, 178))	('PCNA', 'Gene', (39, 43))	('infected', 'Disease', 'MESH:D007239', (233, 241))	('Bcl-2', 'Gene', '596', (45, 50))	('CDK4', 'Gene', '1019', (67, 71))	('infected', 'Disease', (233, 241))	('cyclin D1', 'Gene', (52, 61))	('caspase 3', 'Gene', (115, 124))	('caspase 3', 'Gene', '836', (115, 124))	('PCNA', 'Gene', '5111', (39, 43))	('MAGI2-AS3', 'Gene', (187, 196))	('expressions', 'MPA', (18, 29))	('Bax', 'Gene', (107, 110))	('cyclin D1', 'Gene', '595', (52, 61))
556240	33330444	Moreover, the results were more pronounced in cells infected with both oe-MAGI2-AS3 and oe-HOXB7 than oe-HOXB7 alone (p < 0.05).	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (74, 83))	('infected', 'Disease', 'MESH:D007239', (52, 60))	('MAGI2-AS3', 'Gene', (74, 83))	('infected', 'Disease', (52, 60))	('oe-HOXB7', 'Var', (88, 96))
556243	33330444	KYSE150R cells infected with lentivirus carrying oe-M-NC, oe-MAGI2-AS3, oe-HOXB7 or oe-MAGI2-AS3 + oe-HOXB7 were inoculated into the nude mice.	('infected', 'Disease', (15, 23))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (61, 70))	('MAGI2-AS3', 'Gene', (87, 96))	('nude mice', 'Species', '10090', (133, 142))	('oe-HOXB7', 'Var', (72, 80))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (87, 96))	('infected', 'Disease', 'MESH:D007239', (15, 23))	('MAGI2-AS3', 'Gene', (61, 70))	('oe-M-NC', 'Var', (49, 56))
556248	33330444	In agreement with our initial assumption, irradiation led to a more pronounced shrinkage of the tumor, as evidenced by reduced tumor volume (Figure 8D) and tumor weight (Figure 8E) in mice injected with KYSE150R cells over-expressing MAGI2-AS3, while mice injected with KYSE150R cells over-expressing HOXB7 presented with opposite trends (p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mice', 'Species', '10090', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (234, 243))	('shrinkage', 'NegReg', (79, 88))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('KYSE150R', 'Var', (203, 211))	('mice', 'Species', '10090', (184, 188))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('reduced', 'NegReg', (119, 126))	('MAGI2-AS3', 'Gene', (234, 243))
556256	33330444	Our findings revealed that restoration of MAGI2-AS3 could function as a tumor suppressor by down-regulating its target gene HOXB7, thus attenuating radio-resistance in esophageal cancer cells.	('restoration', 'Var', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('esophageal cancer', 'Disease', (168, 185))	('MAGI2-AS3', 'Gene', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', (72, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('radio-resistance', 'CPA', (148, 164))	('attenuating', 'NegReg', (136, 147))	('MAGI2-AS3', 'Gene', '100505881;9863;23047', (42, 51))	('down-regulating', 'NegReg', (92, 107))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
556262	33330444	have highlighted the capability of HOXB7 silencing in suppressing tumorigenicity f in ESCC as well.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('silencing', 'Var', (41, 50))	('suppressing', 'NegReg', (54, 65))	('tumor', 'Disease', (66, 71))	('HOXB7', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('ESCC', 'Disease', (86, 90))
556263	33330444	Our findings further illustrated that HOXB7 knockdown led to suppression of KYSE150 cancer cell growth in vitro and tumor growth in nude mice.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('HOXB7', 'Gene', (38, 43))	('nude mice', 'Species', '10090', (132, 141))	('cancer', 'Disease', (84, 90))	('KYSE150', 'Gene', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('suppression', 'NegReg', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('knockdown', 'Var', (44, 53))	('tumor', 'Disease', (116, 121))
556271	33330444	The indispensable role of H3K27me3 in EZH2-mediated repression of genes in tumorigenesis and tumor progression has also been documented, while expression of H3K27me3 and EZH2 are indicative of poor prognosis of patients with ESCC.	('ESCC', 'Disease', (225, 229))	('patients', 'Species', '9606', (211, 219))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('H3K27me3', 'Var', (26, 34))	('H3K27me3', 'Var', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('repression', 'NegReg', (52, 62))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
556331	29568867	For instance, chloroquine, an inhibitor of autophagy, has been shown to notably enhance the sensitivity of tumor cells to chemotherapeutic drugs.	('sensitivity', 'CPA', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('chloroquine', 'Chemical', 'MESH:D002738', (14, 25))	('enhance', 'PosReg', (80, 87))	('chloroquine', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
556333	29568867	The dysregulation of miRNA expression may lead to the destruction of the equilibrium between tumor suppression and promotion.	('miRNA expression', 'Protein', (21, 37))	('promotion', 'PosReg', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('dysregulation', 'Var', (4, 17))	('destruction', 'NegReg', (54, 65))	('tumor', 'Disease', (93, 98))	('equilibrium', 'MPA', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
556350	29568867	The cells were transfected with antagomiR-NC (800 nM), antagomiR-503 (800 nM), agomiR-NC (600 nM), agomiR-503 (600 nM) or negative control (100 ng), or co-transfected with agomiR-503 (600 nM) and PRKACA expression vector (100 ng), respectively.	('PRKACA', 'Gene', (196, 202))	('miR-503', 'Gene', (61, 68))	('miR-503', 'Gene', (102, 109))	('miR-503', 'Gene', (175, 182))	('PRKACA', 'Gene', '5566', (196, 202))	('miR-503', 'Gene', '574506', (61, 68))	('800 nM', 'Var', (70, 76))	('miR-503', 'Gene', '574506', (102, 109))	('miR-503', 'Gene', '574506', (175, 182))
556355	29568867	Ad-mRFP (red fluorescent protein)-GFP (green fluorescent protein)-LC3B was transfected into the indicated cells at a multiplicity of infection (MOI) of 20, and cultured for 72 h in an environment at 37 C and 5% CO2.	('CO2', 'Chemical', '-', (211, 214))	('LC3B', 'Gene', (66, 70))	('Ad-mRFP', 'Var', (0, 7))	('infection', 'Disease', (133, 142))	('LC3B', 'Gene', '81631', (66, 70))	('infection', 'Disease', 'MESH:D007239', (133, 142))
556364	29568867	For the in vivo pulmonary metastasis assays, 1x106 Eca109 cells transfected with agomiR-NC (600 nM) or agomiR-503 (600 nM) were suspended in 200 microl of PBS for each mouse.	('600 nM', 'Var', (115, 121))	('mouse', 'Species', '10090', (168, 173))	('miR-503', 'Gene', (106, 113))	('pulmonary metastasis', 'Disease', (16, 36))	('miR-503', 'Gene', '574506', (106, 113))	('PBS', 'Chemical', '-', (155, 158))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (16, 36))
556380	29568867	In brief, the DNA oligonucleotides containing the wild-type 3'-UTR of PRKACA or the mutant 3'-UTR of PRKACA were synthesized with flanking SpeI and HindIII restriction enzyme digestion sites, respectively.	('PRKACA', 'Gene', '5566', (101, 107))	('PRKACA', 'Gene', (70, 76))	('mutant', 'Var', (84, 90))	('PRKACA', 'Gene', '5566', (70, 76))	('PRKACA', 'Gene', (101, 107))	('oligonucleotides', 'Chemical', 'MESH:D009841', (18, 34))
556388	29568867	The 293T cells (The Cell Bank of Type Culture Collection of Chinese Academy of Sciences, Shanghai, China) were transfected with 0.5 microg reporter plasmid harboring wild-type PRKACA-3'-UTR or mutant PRKACA-3'-UTR, or Renilla luciferase control vector (pRL-TK; Promega, Madison, WI, USA) using Lipofectamine  2000 (Thermo Fisher Scientific, Inc.).	('293T', 'CellLine', 'CVCL:0063', (4, 8))	('Lipofectamine', 'Chemical', 'MESH:C086724', (294, 307))	('PRKACA', 'Gene', (176, 182))	('Renilla luciferase', 'Disease', (218, 236))	('PRKACA', 'Gene', (200, 206))	('mutant', 'Var', (193, 199))	('PRKACA', 'Gene', '5566', (176, 182))	('Renilla luciferase', 'Disease', 'None', (218, 236))	('PRKACA', 'Gene', '5566', (200, 206))
556389	29568867	The indicated cells were transfected with agomiR-NC (600 nM) or agomiR-503 (600 nM), respectively.	('600 nM', 'Var', (53, 59))	('miR-503', 'Gene', '574506', (67, 74))	('miR-503', 'Gene', (67, 74))	('600 nM', 'Var', (76, 82))
556397	29568867	The primary incubation was followed by incubation with goat anti rabbit or mouse HRP-conjugated secondary antibodies (dilution, 1:4,000; A0208 and A0216; Beyotime Institute of Biotechnology) for 1 h at room temperature.	('rabbit', 'Species', '9986', (65, 71))	('A0208', 'Var', (137, 142))	('mouse', 'Species', '10090', (75, 80))	('goat', 'Species', '9925', (55, 59))	('A0216', 'Var', (147, 152))
556408	29568867	Specifically, Eca9706 and TE-1 exhibited a >2-fold increase in miR-503 expression.	('increase', 'PosReg', (51, 59))	('expression', 'MPA', (71, 81))	('miR-503', 'Gene', '574506', (63, 70))	('Eca9706', 'CellLine', 'CVCL:E307', (14, 21))	('Eca9706', 'Var', (14, 21))	('miR-503', 'Gene', (63, 70))
556414	29568867	Moreover, a cell cycle array performed by flow cytometry revealed that the overexpression of miR-503 markedly increased the percentages of cells in the G1 phase (by 19.05 and 12.20% in the Eca109 and Eca9706 cells, respectively) and decreased the proportions cells in the S phase (by 19.9 and 4.59% in the Eca109 and Eca9706, respectively) (Fig.	('miR-503', 'Gene', '574506', (93, 100))	('cells in the G1 phase', 'CPA', (139, 160))	('overexpression', 'PosReg', (75, 89))	('increased', 'PosReg', (110, 119))	('decreased', 'NegReg', (233, 242))	('Eca9706', 'CellLine', 'CVCL:E307', (317, 324))	('Eca9706', 'CellLine', 'CVCL:E307', (200, 207))	('Eca9706', 'Var', (317, 324))	('miR-503', 'Gene', (93, 100))
556416	29568867	As expected, transfection with agomiR-503 effectively attenuated the propensity of Eca109 and Eca9706 cells to invade the Matrigel.	('Eca9706', 'CellLine', 'CVCL:E307', (94, 101))	('miR-503', 'Gene', (34, 41))	('Eca9706', 'Var', (94, 101))	('attenuated', 'NegReg', (54, 64))	('miR-503', 'Gene', '574506', (34, 41))
556423	29568867	As expected, the injected ESCC cells transfected with miR-503 grew into smaller tumors compared with those in the NC group.	('miR-503', 'Gene', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('smaller', 'NegReg', (72, 79))	('miR-503', 'Gene', '574506', (54, 61))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('transfected', 'Var', (37, 48))
556425	29568867	The volumes of the tumors formed by ESCC cells transfected with agomiR-503 were significantly smaller than those in the NC group (Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('miR-503', 'Gene', (67, 74))	('miR-503', 'Gene', '574506', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('smaller', 'NegReg', (94, 101))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('transfected', 'Var', (47, 58))
556444	29568867	We then examined whether PRKACA was downstream of miR-503, and found that PRKACA mRNA and protein expression levels both decreased in the presence of ectopic miR-503 expression (agomiR-503); this effect was reversed by transfection with antagomiR-503 in vitro (Fig.	('PRKACA', 'Gene', (74, 80))	('miR-503', 'Gene', (50, 57))	('ectopic', 'Var', (150, 157))	('miR-503', 'Gene', (158, 165))	('PRKACA', 'Gene', '5566', (74, 80))	('PRKACA', 'Gene', (25, 31))	('miR-503', 'Gene', (243, 250))	('miR-503', 'Gene', '574506', (50, 57))	('decreased', 'NegReg', (121, 130))	('miR-503', 'Gene', (181, 188))	('PRKACA', 'Gene', '5566', (25, 31))	('miR-503', 'Gene', '574506', (243, 250))	('miR-503', 'Gene', '574506', (158, 165))	('miR-503', 'Gene', '574506', (181, 188))
556445	29568867	To further confirm that PRKACA is a target gene of miR-503, we constructed vectors harboring the wild-type or mutant 3'-UTR of PRKACA mRNA, individually fused directly downstream of the firefly luciferase gene for luciferase assays.	('miR-503', 'Gene', '574506', (51, 58))	('PRKACA', 'Gene', (24, 30))	('PRKACA', 'Gene', (127, 133))	('PRKACA', 'Gene', '5566', (24, 30))	('mutant', 'Var', (110, 116))	('PRKACA', 'Gene', '5566', (127, 133))	('miR-503', 'Gene', (51, 58))
556450	29568867	First, we evaluated whether the silencing or overexpression of PRKACA could mimic the biological effects of miR-503 on the growth and metastasis of ESCC cells.	('miR-503', 'Gene', '574506', (108, 115))	('PRKACA', 'Gene', (63, 69))	('silencing', 'Var', (32, 41))	('miR-503', 'Gene', (108, 115))	('PRKACA', 'Gene', '5566', (63, 69))	('ESCC', 'Disease', (148, 152))	('overexpression', 'PosReg', (45, 59))
556497	29568867	Moreover, mutant PRKACA has been reported to promote the development of adrenal adenomas.	('PRKACA', 'Gene', (17, 23))	('mutant', 'Var', (10, 16))	('adrenal adenomas', 'Disease', (72, 88))	('PRKACA', 'Gene', '5566', (17, 23))	('promote', 'PosReg', (45, 52))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (72, 88))	('adrenal adenomas', 'Disease', 'MESH:D018246', (72, 88))
556517	28190659	Among patients with gastric cancer, the mortality risk was higher in underweight patients versus patients of normal weight (multivariable HR = 1.66, 95% CI: 1.34, 2.05).	('underweight', 'Var', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('patients', 'Species', '9606', (81, 89))	('gastric cancer', 'Disease', (20, 34))	('patients', 'Species', '9606', (6, 14))	('gastric cancer', 'Disease', 'MESH:D013274', (20, 34))	('higher', 'PosReg', (59, 65))	('gastric cancer', 'Phenotype', 'HP:0012126', (20, 34))	('patients', 'Species', '9606', (97, 105))
556587	28190659	Among ESCC patients in a cohort study in China, alcohol drinkers were more likely to experience poor survival compared to nondrinkers (HR = 1.372, 95% CI = 1.2, 1.6).	('alcohol drinkers', 'Var', (48, 64))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (48, 64))	('ESCC', 'Disease', (6, 10))	('poor survival', 'CPA', (96, 109))	('patients', 'Species', '9606', (11, 19))	('alcohol', 'Chemical', 'MESH:D000438', (48, 55))
556593	28190659	In the Japanese population, lower BMI has been observed to be associated with an increased risk of mortality among gastric cancer patients, with a linear inverse association.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lower BMI', 'Phenotype', 'HP:0045082', (28, 37))	('lower BMI', 'Var', (28, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('patients', 'Species', '9606', (130, 138))	('gastric cancer', 'Disease', (115, 129))
556598	28190659	A meta-analysis of seven cohort and nine case-control studies demonstrated that physical exercise is associated with a reduced risk of gastric cancer in the general population.	('gastric cancer', 'Disease', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('physical exercise', 'Var', (80, 97))	('reduced risk of gastric cancer', 'Phenotype', 'HP:0006753', (119, 149))	('reduced', 'NegReg', (119, 126))
556698	25701083	MicroRNAs (miRNAs) are approximately 21 to 25 nucleotides long and regulate many cellular processes; their alteration has been associated with the pathogenesis of many diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('regulate', 'Reg', (67, 75))	('associated', 'Reg', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('alteration', 'Var', (107, 117))
556706	25701083	Tests have been developed to screen for potential upper gastrointestinal malignancies as well as for colonic neoplasms that detect DNA, methylation, and protein markers unique to cancerous cells.	('methylation', 'Var', (136, 147))	('cancerous', 'Disease', 'MESH:D009369', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('neoplasms', 'Phenotype', 'HP:0002664', (109, 118))	('colonic neoplasms', 'Disease', 'MESH:D003110', (101, 118))	('protein', 'Protein', (153, 160))	('upper gastrointestinal malignancies', 'Disease', 'MESH:D005767', (50, 85))	('colonic neoplasms', 'Phenotype', 'HP:0100273', (101, 118))	('cancerous', 'Disease', (179, 188))	('colonic neoplasms', 'Disease', (101, 118))	('upper gastrointestinal malignancies', 'Disease', (50, 85))	('DNA', 'MPA', (131, 134))
556707	25701083	Assays that detect changes in DNA methylation patterns are particularly well studied for detection of esophageal cancers and hold promise for minimally invasive screening.	('esophageal cancers', 'Disease', (102, 120))	('esophageal cancers', 'Disease', 'MESH:D004938', (102, 120))	('changes', 'Var', (19, 26))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
556743	26166121	The tumor was a superficial (0 - Ip + IIc type), well-differentiated squamous cell carcinoma with invasion into 2/3 of the depth of the submucosal layer (500 mum) from the inferior border of the muscularis mucosae, and it had negative surgical margins, no intramural metastasis and no LN metastases (pN0; #1: right cardiac LNs [0/3]; #3: LNs along the lesser curvature [0/9]; #7: LNs along the left gastric artery [0/3]; #101L: left cervical paraesophageal LN [0/5]; #105: upper thoracic paraesophageal LNs [0/5]; #106recL: left recurrent nerve LNs [0/3]; #106tbL: left tracheobronchial LNs [0/0]; #107: subcarinal LNs [0/4]; #108: middle thoracic paraesophageal LNs [0/2]; #109L: left main bronchus LNs [0/2]; #109R: right main bronchus LNs [0/8]; #110: lower thoracic paraesophageal LNs [0/1]; and #112: posterior mediastinal LNs [0/0]).	('tumor', 'Disease', (4, 9))	('#109R', 'Var', (711, 716))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('squamous cell carcinoma', 'Disease', (69, 92))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('metastases', 'Disease', (288, 298))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('metastases', 'Disease', 'MESH:D009362', (288, 298))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
556757	26166121	Moreover, when P1 = P2 = P3, it is possible for particles, such as cancer cells, in the fluid to move through the valve by random Brownian diffusion.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('P1 = P2 = P3', 'Var', (15, 27))	('cancer', 'Disease', (67, 73))
556773	26029176	The etiological factors involved in the development of both cardia cancers and EACs are associated with high animal fat intake, which causes severe obesity.	('obesity', 'Disease', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('high animal fat intake', 'Var', (104, 126))	('cardia cancers', 'Disease', 'MESH:D004938', (60, 74))	('cardia cancers', 'Disease', (60, 74))	('obesity', 'Phenotype', 'HP:0001513', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('EAC', 'Phenotype', 'HP:0011459', (79, 82))	('EACs', 'Disease', (79, 83))	('men', 'Species', '9606', (47, 50))	('obesity', 'Disease', 'MESH:D009765', (148, 155))
556826	26029176	Furthermore, detected the endogenous DNA adducts produced from N-nitroso bile acid conjugates, such as N-nitrosoglycocholic acid and N-nitrosotaurocholic acid, in the glandular stomach of the duodenal contents reflux rats.	('N-nitroso bile acid', 'Chemical', '-', (63, 82))	('N-nitrosotaurocholic acid', 'Chemical', 'MESH:C034936', (133, 158))	('N-nitrosotaurocholic acid', 'Var', (133, 158))	('N-nitrosoglycocholic acid', 'Chemical', 'MESH:C034937', (103, 128))	('rats', 'Species', '10116', (217, 221))	('N-nitrosoglycocholic acid', 'Var', (103, 128))
556844	26029176	Although most studies of Western populations found no association or an inverse association, few studies of Asian populations have found a positive association between H. pylori seropositivity and cardia cancer.	('H. pylori', 'Gene', (168, 177))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (171, 192))	('cardia cancer', 'Disease', 'MESH:D004938', (197, 210))	('seropositivity', 'Var', (178, 192))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('H. pylori', 'Species', '210', (168, 177))	('cardia cancer', 'Disease', (197, 210))
556855	26029176	We recently proposed the mechanism of how the long-term use of PPIs exacerbates corpus atrophic gastritis in H. pylori-positive patients with GERD that includes interactions among bile acids, pH, and H. pylori.	('H. pylori', 'Species', '210', (109, 118))	('GER', 'Gene', '59330', (142, 145))	('interactions', 'Interaction', (161, 173))	('atrophic gastritis', 'Disease', 'MESH:D005757', (87, 105))	('H. pylori', 'Species', '210', (200, 209))	('GER', 'Gene', (142, 145))	('bile acids', 'Chemical', 'MESH:D001647', (180, 190))	('atrophic gastritis', 'Disease', (87, 105))	('gastritis', 'Phenotype', 'HP:0005263', (96, 105))	('exacerbates', 'PosReg', (68, 79))	('GER', 'Phenotype', 'HP:0002020', (142, 145))	('patients', 'Species', '9606', (128, 136))	('PPIs', 'Var', (63, 67))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (87, 105))
556881	33976728	Ten metabolites (dopamine, L-histidine, 5-hydroxyindoleacetate, L-tryptophan, 2'-O-methylcytidine, PC (14:0/0:0), PC (O-16:1/0:0), PE (18:0/0:0), PC (16:1/0:0), PC (18:2/0:0)) were associated with decreased risk of developing ESCC.	('5-hydroxyindoleacetate', 'Chemical', 'MESH:D006897', (40, 62))	('L-histidine', 'Chemical', 'MESH:D006639', (27, 38))	('L-histidine', 'Var', (27, 38))	('5-hydroxyindoleacetate', 'Var', (40, 62))	('L-tryptophan', 'Chemical', 'MESH:D014364', (64, 76))	('PC', 'Gene', '5091', (161, 163))	('ESCC', 'Disease', (226, 230))	('PC', 'Gene', '5091', (99, 101))	('PC', 'Gene', '5091', (114, 116))	('dopamine', 'Var', (17, 25))	('PC', 'Gene', '5091', (146, 148))	('decreased', 'NegReg', (197, 206))	('L-tryptophan', 'Var', (64, 76))	("2'-O-methylcytidine", 'Chemical', 'MESH:C052203', (78, 97))	('PE (18:0/0:0', 'Var', (131, 143))	('dopamine', 'Chemical', 'MESH:D004298', (17, 25))
556957	33976728	Compared to the healthy controls, the concentration of tryptophan is down-regulated in both ESCC and metastatic ESCC patients, further analysis showed that disturbed tryptophan metabolism correlating to progression and metastasis of ESCC.	('concentration of tryptophan', 'MPA', (38, 65))	('ESCC', 'Disease', (92, 96))	('disturbed', 'Var', (156, 165))	('tryptophan', 'Chemical', 'MESH:D014364', (55, 65))	('tryptophan', 'Chemical', 'MESH:D014364', (166, 176))	('down-regulated', 'NegReg', (69, 83))	('tryptophan metabolism', 'MPA', (166, 187))	('ESCC', 'Disease', (233, 237))	('metastasis', 'CPA', (219, 229))	('patients', 'Species', '9606', (117, 125))
556961	33976728	In this study, L-histidine also has a down-regulated trend in the development of ESCC.	('down-regulated', 'NegReg', (38, 52))	('ESCC', 'Disease', (81, 85))	('development', 'CPA', (66, 77))	('L-histidine', 'Chemical', 'MESH:D006639', (15, 26))	('L-histidine', 'Var', (15, 26))
556979	32087941	Hemoglobin levels on admission were lower in patients with Child-Pugh B/C cirrhosis than in those with Child-Pugh A (p <0.001).	('lower', 'NegReg', (36, 41))	('Hemoglobin levels', 'MPA', (0, 17))	('cirrhosis', 'Phenotype', 'HP:0001394', (74, 83))	('patients', 'Species', '9606', (45, 53))	('C cirrhosis', 'Disease', (72, 83))	('C cirrhosis', 'Disease', 'MESH:D005355', (72, 83))	('Child-Pugh', 'Var', (59, 69))
556994	32087941	Codes for cirrhosis and LGIB were as follow: (ICD-9) 455.0, 456.20, 569.3, 571.2, 571.5, 572.2, 572.4, 578.1, 578.9, and 789.59; (ICD-10) I85.00, I85.11, K62.5, K64.8, K92.1, K92.2, K70.30, K70.31, K72.91, K74.60, K74.69, K76.7, and R18.8.	('K70.30', 'Var', (182, 188))	('K64.8', 'Var', (161, 166))	('GI', 'Gene', '2770', (25, 27))	('cirrhosis', 'Phenotype', 'HP:0001394', (10, 19))	('K62.5', 'Var', (154, 159))	('K92.2', 'Var', (175, 180))	('K74.60', 'Var', (206, 212))	('I85.11', 'Var', (146, 152))	('K76.7', 'Var', (222, 227))	('R18.8', 'Var', (233, 238))	('K72.91', 'Var', (198, 204))	('cirrhosis', 'Disease', 'MESH:D005355', (10, 19))	('K70.31', 'Var', (190, 196))	('I85.00', 'Var', (138, 144))	('K74.69', 'Var', (214, 220))	('K92.1', 'Var', (168, 173))	('cirrhosis', 'Disease', (10, 19))
557073	32087941	Our study showed a significant positive correlation between the severity of bleeding as reflected by hemoglobin level, and the severity of liver disease (measured by CP score) (p < 0.001 for patients with CP score B/C [mean hemoglobin of 7.5 gm/dl] vs. CP score A [mean hemoglobin 9.2 gm/dl]).	('hemoglobin level', 'MPA', (101, 117))	('bleeding', 'Disease', 'MESH:D006470', (76, 84))	('bleeding', 'Disease', (76, 84))	('patients', 'Species', '9606', (191, 199))	('CP score B/C', 'Var', (205, 217))	('liver disease', 'Phenotype', 'HP:0001392', (139, 152))	('liver disease', 'Disease', (139, 152))	('liver disease', 'Disease', 'MESH:D008107', (139, 152))
557138	27904837	Given its ability to quantitatively detect tumor glucose metabolic change, 18F-FDG PET/CT can be potentially used for early treatment response to chemoradiotherapy, usually after the first cycle in one or 2 weeks.	('glucose', 'Chemical', 'MESH:D005947', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('18F-FDG', 'Var', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('18F-FDG', 'Chemical', 'MESH:D019788', (75, 82))
557167	27904837	Changes in attenuation in contrast-enhanced CT (CECT) have been shown to correlate better with response than changes in tumor size in hepatocellular carcinoma and gastrointestinal stromal tumor.	('tumor', 'Disease', (188, 193))	('attenuation', 'MPA', (11, 22))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (134, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('Changes', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (163, 193))	('tumor', 'Disease', (120, 125))	('hepatocellular carcinoma and gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (134, 193))
557188	26947069	By integrating the siRNA screen data with molecular profiling data, including exome sequencing data, we show how vulnerabilities/genetic dependencies that are associated with mutations in specific cancer driver genes can be identified.	('cancer', 'Disease', (197, 203))	('mutations', 'Var', (175, 184))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
557190	26947069	We demonstrate the utility of this resource by using it to predict the drug sensitivity of genetically or histologically defined subsets of tumor cell lines, including an increased sensitivity of osteosarcoma cell lines to FGFR inhibitors and SMAD4 mutant tumor cells to mitotic inhibitors.	('osteosarcoma', 'Phenotype', 'HP:0002669', (196, 208))	('SMAD4', 'Gene', '4089', (243, 248))	('sensitivity', 'MPA', (181, 192))	('osteosarcoma cell lines', 'Disease', 'MESH:D012516', (196, 219))	('drug sensitivity', 'Phenotype', 'HP:0020174', (71, 87))	('SMAD4', 'Gene', (243, 248))	('FGFR', 'Gene', (223, 227))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutant', 'Var', (249, 255))	('osteosarcoma cell lines', 'Disease', (196, 219))	('increased', 'PosReg', (171, 180))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', (140, 145))
557191	26947069	Kinome-wide (714 gene) siRNA screens in 117 cell lines from ten cancer histotypes Integrating genotype data reveals cancer driver gene dependencies Integrating protein interaction data aids the interpretation of genetic dependencies Identified dependencies enable prediction of mutant cell line responses to drugs  Campbell et al.	('mutant', 'Var', (278, 284))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
557202	26947069	Building on our previous work, we extend our analytical approach to describe how this data set may be used as a hypothesis-generating tool for identifying candidate therapeutic targets associated with specific tumor histotypes or mutations in cancer driver genes.	('associated', 'Reg', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('mutations', 'Var', (230, 239))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
557214	26947069	Testing a set of 58 tumor cell lines for FGFR inhibitor sensitivity, we found AZD4547 and PD173074 to be more selective for osteosarcoma models (AZD4547, p = 7.6 x 10-3, PD173074 p = 3.9 x 10-2; Figures 2C and 2D; Table S1E) and to have minimal effects in two non-tumor epithelial models (Figure S1).	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', (264, 269))	('osteosarcoma', 'Disease', (124, 136))	('AZD4547', 'Chemical', 'MESH:C572463', (145, 152))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('AZD4547', 'Var', (78, 85))	('osteosarcoma', 'Disease', 'MESH:D012516', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('PD173074', 'Var', (90, 98))	('PD173074', 'Chemical', 'MESH:C115711', (170, 178))	('PD173074', 'Chemical', 'MESH:C115711', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('PD173074', 'Var', (170, 178))	('tumor', 'Disease', (20, 25))	('AZD4547', 'Chemical', 'MESH:C572463', (78, 85))
557215	26947069	This osteosarcoma selective effect was independent of FGFR1 or FGFR2 amplification status and was also apparent when FGFR1 or FGFR2 amplified tumor cell lines were excluded from the analysis (AZD4572, p = 7.2 x 10-3 and PD173074, p = 4.3 x 10-2; Figures 2C and 2D).	('osteosarcoma', 'Disease', 'MESH:D012516', (5, 17))	('FGFR2', 'Gene', '2263', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FGFR1', 'Gene', (54, 59))	('tumor', 'Disease', (142, 147))	('FGFR1', 'Gene', '2260', (54, 59))	('PD173074', 'Chemical', 'MESH:C115711', (220, 228))	('PD173074', 'Var', (220, 228))	('FGFR1', 'Gene', (117, 122))	('FGFR1', 'Gene', '2260', (117, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (5, 17))	('FGFR2', 'Gene', '2263', (63, 68))	('osteosarcoma', 'Disease', (5, 17))	('FGFR2', 'Gene', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('FGFR2', 'Gene', (63, 68))
557222	26947069	By integrating the siRNA data with exome sequencing and copy number profiling data, we identified KGDs associated with mutations in each of 200 candidate cancer driver genes (see Supplemental Information; Table S1G).	('associated', 'Reg', (103, 113))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('mutations', 'Var', (119, 128))
557223	26947069	As the large number of tests performed using these 200 driver genes prohibited correction for multiple hypothesis testing, we focused our subsequent analysis on 21 key cancer driver genes (12 tumor suppressor genes and nine oncogenes) (Figure 3A) mutated in at least seven tumor cell lines in our panel.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('mutated', 'Var', (247, 254))
557224	26947069	This approach reconfirmed the well-established ERBB2 oncogene addiction in models of breast cancer, but also established ERBB2 addiction/KGD in models of esophageal cancer (Figures 3B and 3C), where ERBB2 is recurrently amplified/overexpressed in 20% of tumors.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('tumors', 'Disease', (254, 260))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('ERBB2', 'Gene', (47, 52))	('esophageal cancer', 'Disease', (154, 171))	('ERBB2', 'Gene', '2064', (47, 52))	('breast cancer', 'Disease', (85, 98))	('addiction/KGD', 'Var', (127, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('ERBB2', 'Gene', '2064', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('ERBB2', 'Gene', (199, 204))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('ERBB2', 'Gene', '2064', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ERBB2', 'Gene', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
557226	26947069	ERBB2 amplification was also associated with dependency upon other members of the ERBB2 signaling network including the ERBB2 binding partner ERBB3 (p = 2 x 10-3), JAK2 (p = 1 x 10-2), and the downstream effector of ERBB2, PIK3CA (p = 4 x 10-3; Figure 3D).	('dependency', 'MPA', (45, 55))	('ERBB2', 'Gene', '2064', (82, 87))	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB2', 'Gene', '2064', (120, 125))	('ERBB2', 'Gene', (82, 87))	('ERBB2', 'Gene', (216, 221))	('ERBB2', 'Gene', '2064', (216, 221))	('ERBB2', 'Gene', (0, 5))	('ERBB2', 'Gene', (120, 125))	('JAK2', 'Gene', '3717', (164, 168))	('ERBB3', 'Gene', '2065', (142, 147))	('PIK3CA', 'Gene', (223, 229))	('ERBB3', 'Gene', (142, 147))	('JAK2', 'Gene', (164, 168))	('PIK3CA', 'Gene', '5290', (223, 229))	('associated', 'Reg', (29, 39))	('amplification', 'Var', (6, 19))
557228	26947069	We assessed the possibility that some KGDs associated with cancer driver gene mutations might be private to or more profound in particular histotypes.	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (78, 87))
557229	26947069	For example, BRAF p.V600E mutant melanomas are extremely sensitive to BRAF inhibition, whereas colorectal cancers with the same mutation show little response.	('p.V600E', 'Var', (18, 25))	('BRAF', 'Gene', (70, 74))	('BRAF', 'Gene', '673', (13, 17))	('colorectal cancers', 'Disease', (95, 113))	('sensitive', 'MPA', (57, 66))	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('BRAF', 'Gene', (13, 17))	('BRAF', 'Gene', '673', (70, 74))	('p.V600E', 'Mutation', 'rs113488022', (18, 25))	('colorectal cancers', 'Disease', 'MESH:D015179', (95, 113))	('melanomas', 'Disease', (33, 42))
557230	26947069	As an example of this, we selected for validation one of the KGDs associated with RB1 mutation in osteosarcoma, DYRK1A (p = 6.8 x 10-3; Figure S3A), a component of the DREAM complex previously identified as a protein interaction partner of RB1.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('RB1', 'Gene', (240, 243))	('RB1', 'Gene', '5925', (82, 85))	('osteosarcoma', 'Disease', 'MESH:D012516', (98, 110))	('RB1', 'Gene', (82, 85))	('DYRK1A', 'Gene', '1859', (112, 118))	('RB1', 'Gene', '5925', (240, 243))	('mutation', 'Var', (86, 94))	('DYRK1A', 'Gene', (112, 118))	('osteosarcoma', 'Disease', (98, 110))
557233	26947069	We also noted from our analysis of the siRNA data that some genetic dependencies associated with cancer driver gene mutations were observed independently in multiple histotypes.	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
557236	26947069	In both osteosarcoma (p = 1.4 x 10-3) and lung cancer models (p = 3.5 x 10-2; Figure S1C), we identified an association between mutation/deletion of CDKN2A and dependency upon the cyclin dependent kinase gene CDK11A, which encodes a CDKN2A interacting protein.	('CDKN2A', 'Gene', '1029', (149, 155))	('CDK11A', 'Gene', '728642', (209, 215))	('CDKN2A interacting protein', 'Gene', '55602', (233, 259))	('CDKN2A', 'Gene', (233, 239))	('osteosarcoma', 'Phenotype', 'HP:0002669', (8, 20))	('osteosarcoma', 'Disease', (8, 20))	('dependency', 'Disease', (160, 170))	('CDKN2A interacting protein', 'Gene', (233, 259))	('lung cancer', 'Disease', (42, 53))	('CDKN2A', 'Gene', '1029', (233, 239))	('CDK11A', 'Gene', (209, 215))	('CDKN2A', 'Gene', (149, 155))	('mutation/deletion', 'Var', (128, 145))	('osteosarcoma', 'Disease', 'MESH:D012516', (8, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
557237	26947069	The set of KGDs associated with cancer driver gene alterations can be used to frame testable hypotheses, such as "mutation in gene A drives dependency upon a gene B."	('alterations', 'Var', (51, 62))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('gene A', 'Gene', (126, 132))	('drives', 'Reg', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutation', 'Var', (114, 122))	('dependency upon a gene B', 'MPA', (140, 164))
557239	26947069	For example, mutation/amplification of EGFR in lung cancer cell lines was associated with an increased dependency upon FES (p = 3 x 10-2; Figure 3F), previously identified as an EGFR binding partner.	('dependency upon FES', 'MPA', (103, 122))	('EGFR', 'Gene', '1956', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('increased', 'PosReg', (93, 102))	('EGFR', 'Gene', (178, 182))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('mutation/amplification', 'Var', (13, 35))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
557240	26947069	Similarly, in esophageal cancer models, we identified a significant association between mutation of the chromatin remodeling factor gene SMARCA4 and dependency upon the bromodomain protein BRD4 (p = 6 x 10-3; Figure 3F), previously identified as a protein interaction partner of SMARCA4.	('mutation', 'Var', (88, 96))	('SMARCA4', 'Gene', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('SMARCA4', 'Gene', '6597', (137, 144))	('BRD4', 'Gene', '23476', (189, 193))	('esophageal cancer', 'Disease', (14, 31))	('SMARCA4', 'Gene', (279, 286))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('SMARCA4', 'Gene', '6597', (279, 286))	('dependency', 'MPA', (149, 159))	('BRD4', 'Gene', (189, 193))
557241	26947069	Among the dependencies associated with a kinase-substrate interaction, we found that mutation of STK11 (LKB1) in ovarian cancer models was associated with an increased dependency upon MARK2 (p = 2 x 10-3; Figure 3G), an LKB1 substrate.	('STK11', 'Gene', '6794', (97, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('LKB1', 'Gene', (220, 224))	('LKB1', 'Gene', (104, 108))	('MARK2', 'Gene', '2011', (184, 189))	('MARK2', 'Gene', (184, 189))	('mutation', 'Var', (85, 93))	('LKB1', 'Gene', '6794', (220, 224))	('ovarian cancer', 'Disease', (113, 127))	('LKB1', 'Gene', '6794', (104, 108))	('STK11', 'Gene', (97, 102))	('increased', 'PosReg', (158, 167))
557244	26947069	In lung cancer models, we found that MYC amplification was associated with an increased dependency upon CDKL5 (5.6 x 10-3; Figure 3H), a gene whose expression is regulated by MYC.	('MYC', 'Gene', (175, 178))	('CDKL5', 'Gene', (104, 109))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('MYC', 'Gene', '4609', (37, 40))	('MYC', 'Gene', '4609', (175, 178))	('CDKL5', 'Gene', '6792', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('increased', 'PosReg', (78, 87))	('amplification', 'Var', (41, 54))	('MYC', 'Gene', (37, 40))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
557245	26947069	Similarly, in esophageal models, we found MYC amplification to be associated with an increased dependency upon the MYC transcriptional target PRKCH (p = 6.7 x 10-3; Figure 3H).	('amplification', 'Var', (46, 59))	('MYC', 'Gene', (42, 45))	('PRKCH', 'Gene', (142, 147))	('MYC', 'Gene', (115, 118))	('dependency upon the', 'MPA', (95, 114))	('increased', 'PosReg', (85, 94))	('MYC', 'Gene', '4609', (42, 45))	('PRKCH', 'Gene', '5583', (142, 147))	('MYC', 'Gene', '4609', (115, 118))
557248	26947069	In esophageal cancer models, we found that ERBB2 amplification is associated with MASTL and NEK9 KGDs (Figure 3I).	('MASTL', 'Gene', '84930', (82, 87))	('amplification', 'Var', (49, 62))	('NEK9', 'Gene', (92, 96))	('ERBB2', 'Gene', '2064', (43, 48))	('esophageal cancer', 'Disease', (3, 20))	('ERBB2', 'Gene', (43, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('MASTL', 'Gene', (82, 87))	('associated', 'Reg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('NEK9', 'Gene', '91754', (92, 96))
557254	26947069	In the case of the network associated with ERBB2 amplification, this suggested that ERBB2 amplification might induce dependencies on direct binding partners and substrates of ERBB2 (JAK2, ERBB3, and PIK3CA), but also a network of genes involved in MAPK signaling (e.g., MAP2K3, MAP3K4, and MAP3K2) and inositol phosphate metabolism (including PIP5K1A, PIK3CA, and PIK3CD) (Figure 4A).	('PIK3CA', 'Gene', '5290', (352, 358))	('ERBB2', 'Gene', '2064', (43, 48))	('ERBB2', 'Gene', (175, 180))	('MAP3K2', 'Gene', '10746', (290, 296))	('PIK3CD', 'Gene', (364, 370))	('PIK3CA', 'Gene', '5290', (199, 205))	('PIP5K1A', 'Gene', '8394', (343, 350))	('ERBB3', 'Gene', '2065', (188, 193))	('binding', 'Interaction', (140, 147))	('JAK2', 'Gene', '3717', (182, 186))	('ERBB2', 'Gene', '2064', (175, 180))	('dependencies', 'MPA', (117, 129))	('PIK3CA', 'Gene', (352, 358))	('amplification', 'Var', (90, 103))	('ERBB2', 'Gene', (84, 89))	('MAP3K4', 'Gene', '4216', (278, 284))	('PIK3CA', 'Gene', (199, 205))	('MAP2K3', 'Gene', (270, 276))	('inositol phosphate', 'Chemical', 'MESH:D007295', (302, 320))	('induce', 'Reg', (110, 116))	('PIP5K1A', 'Gene', (343, 350))	('ERBB2', 'Gene', '2064', (84, 89))	('JAK2', 'Gene', (182, 186))	('MAP3K2', 'Gene', (290, 296))	('ERBB3', 'Gene', (188, 193))	('ERBB2', 'Gene', (43, 48))	('MAP3K4', 'Gene', (278, 284))	('PIK3CD', 'Gene', '5293', (364, 370))	('MAP2K3', 'Gene', '5606', (270, 276))
557255	26947069	Similarly, we found significantly more functional interactions among the kinases identified as dependencies associated with mutation of the tumor suppressor SMAD4, a member of the TGF-beta pathway that is frequently mutated or homozygously deleted in colorectal, pancreatic, and esophageal cancers (Figure 4B).	('pancreatic', 'Disease', 'MESH:D010195', (263, 273))	('TGF-beta', 'Gene', '7040', (180, 188))	('cancers', 'Phenotype', 'HP:0002664', (290, 297))	('TGF-beta', 'Gene', (180, 188))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('more', 'PosReg', (34, 38))	('pancreatic', 'Disease', (263, 273))	('functional interactions', 'MPA', (39, 62))	('esophageal cancers', 'Disease', (279, 297))	('SMAD4', 'Gene', (157, 162))	('colorectal', 'Disease', 'MESH:D015179', (251, 261))	('SMAD4', 'Gene', '4089', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mutation', 'Var', (124, 132))	('esophageal cancers', 'Disease', 'MESH:D004938', (279, 297))	('colorectal', 'Disease', (251, 261))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('tumor', 'Disease', (140, 145))
557256	26947069	The integrated network we constructed from SMAD4 KGDs revealed that AKT1 and a number of its substrates (FGR, MAP3K3, PIKFYVE, CHEK1, and WEE1) were SMAD4 mutation associated KGDs.	('WEE1', 'Gene', (138, 142))	('WEE1', 'Gene', '7465', (138, 142))	('CHEK1', 'Gene', '1111', (127, 132))	('AKT1', 'Gene', (68, 72))	('SMAD4', 'Gene', (149, 154))	('MAP3K3', 'Gene', '4215', (110, 116))	('SMAD4', 'Gene', (43, 48))	('PIKFYVE', 'Gene', '200576', (118, 125))	('CHEK1', 'Gene', (127, 132))	('MAP3K3', 'Gene', (110, 116))	('PIKFYVE', 'Gene', (118, 125))	('SMAD4', 'Gene', '4089', (149, 154))	('mutation', 'Var', (155, 163))	('AKT1', 'Gene', '207', (68, 72))	('SMAD4', 'Gene', '4089', (43, 48))
557257	26947069	Consistent with this, loss of SMAD4 has been shown to be associated with increased AKT activation in colorectal and pancreatic tumor cell lines.	('AKT', 'Gene', '207', (83, 86))	('increased', 'PosReg', (73, 82))	('activation', 'PosReg', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('SMAD4', 'Gene', '4089', (30, 35))	('AKT', 'Gene', (83, 86))	('pancreatic tumor', 'Disease', (116, 132))	('SMAD4', 'Gene', (30, 35))	('colorectal', 'Disease', (101, 111))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (116, 132))	('pancreatic tumor', 'Disease', 'MESH:D010190', (116, 132))	('loss', 'Var', (22, 26))	('colorectal', 'Disease', 'MESH:D015179', (101, 111))
557259	26947069	In addition to AKT1 and its substrates, we found a densely connected group of kinases that regulate the mitotic cell cycle in the SMAD4 dependency network (Figure 4B), suggesting that SMAD4 mutant tumor cell lines may have an increased sensitivity to perturbation of this process.	('SMAD4', 'Gene', (184, 189))	('AKT1', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('SMAD4', 'Gene', (130, 135))	('SMAD4', 'Gene', '4089', (184, 189))	('mutant', 'Var', (190, 196))	('AKT1', 'Gene', '207', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('SMAD4', 'Gene', '4089', (130, 135))	('tumor', 'Disease', (197, 202))
557260	26947069	To test this hypothesis, we analyzed a compendium of drug sensitivity profiles and found that SMAD4 mutant cell lines have increased sensitivity to the Aurora Kinase inhibitor VX-680 (p = 4 x 10-3; Figure 4C).	('increased', 'PosReg', (123, 132))	('mutant', 'Var', (100, 106))	('drug sensitivity', 'Phenotype', 'HP:0020174', (53, 69))	('SMAD4', 'Gene', '4089', (94, 99))	('VX-680', 'Chemical', 'MESH:C484810', (176, 182))	('sensitivity to the Aurora Kinase inhibitor VX-680', 'MPA', (133, 182))	('SMAD4', 'Gene', (94, 99))
557261	26947069	Furthermore, we found that SMAD4 mutant cell lines also exhibited an increased sensitivity to the mitotic inhibitors paclitaxel (p = 8.3 x 10-5) and epothilone B (p = 3 x 10-3; Figure 4C), suggesting a general sensitivity to drugs that target the mitotic checkpoint.	('paclitaxel', 'Chemical', 'MESH:D017239', (117, 127))	('increased', 'PosReg', (69, 78))	('SMAD4', 'Gene', '4089', (27, 32))	('mitotic inhibitors paclitaxel', 'MPA', (98, 127))	('sensitivity', 'MPA', (79, 90))	('mutant', 'Var', (33, 39))	('SMAD4', 'Gene', (27, 32))	('epothilone B', 'Chemical', 'MESH:C093788', (149, 161))
557263	26947069	With this in mind, we considered whether we could identify candidate "pathway level" dependencies by grouping tumor cell lines according to mutations in any one of a set of driver genes belonging to the same pathway or complex.	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mutations', 'Var', (140, 149))
557264	26947069	For each pathway, tumor cell lines were grouped using a logical OR argument, i.e., if a cell line possessed a functional mutation of any gene member of the pathway then that cell line was considered mutated in that pathway.	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('mutation', 'Var', (121, 129))	('tumor', 'Disease', (18, 23))
557267	26947069	This suggested that mutation of one pathway may induce dependency on a second pathway, consistent with observations from yeast where it has been shown genetic dependencies can often be best explained as occurring between pairs of pathways.	('induce', 'Reg', (48, 54))	('mutation', 'Var', (20, 28))	('dependency', 'MPA', (55, 65))	('yeast', 'Species', '4932', (121, 126))
557268	26947069	For example, alteration in the mTOR signaling pathway (mutation in TSC1 OR TSC2 OR STK11) was associated with an increased dependency upon the signal recognition particle SRP72 gene (rho = -0.40), but mutation of STK11 alone better explained the relative sensitivity of mutant and non-mutant cell lines in this regard (rho = -0.44).	('TSC2', 'Gene', (75, 79))	('TSC1', 'Gene', '7248', (67, 71))	('SRP72', 'Gene', '6731', (171, 176))	('STK11', 'Gene', (213, 218))	('TOR', 'Gene', '6097', (32, 35))	('TSC1', 'Gene', (67, 71))	('TOR', 'Gene', (32, 35))	('STK11', 'Gene', (83, 88))	('STK11', 'Gene', '6794', (213, 218))	('alteration', 'Reg', (13, 23))	('mutation', 'Var', (55, 63))	('TSC2', 'Gene', '7249', (75, 79))	('STK11', 'Gene', '6794', (83, 88))	('dependency', 'MPA', (123, 133))	('SRP72', 'Gene', (171, 176))
557269	26947069	One example of a pathway dependency involved loss-of-function mutations in the genes encoding components of the SWI/SNF complex, mutated in ~20% of all human cancers.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('loss-of-function', 'NegReg', (45, 61))	('cancers', 'Disease', (158, 165))	('mutated', 'Var', (129, 136))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('human', 'Species', '9606', (152, 157))	('mutations', 'Var', (62, 71))
557270	26947069	By grouping all tumor cell lines that had a loss-of-function mutation or homozygous deletion of any member of the SWI/SNF complex (including the genes ARID1A, SMARCA1, SMARCA4, ARID2, ARID1B, and PBRM1) and then carrying out MP tests on the siRNA data as before, we identified ten KGDs including TWF2 (Figure 5A), a gene encoding a protein that affects the stability of the actin cytoskeleton through interaction with G-actin.	('TWF2', 'Gene', (296, 300))	('SMARCA4', 'Gene', (168, 175))	('mutation', 'Var', (61, 69))	('ARID2', 'Gene', '196528', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('SMARCA1', 'Gene', (159, 166))	('ARID2', 'Gene', (177, 182))	('affects', 'Reg', (345, 352))	('interaction', 'Interaction', (401, 412))	('deletion', 'Var', (84, 92))	('SMARCA4', 'Gene', '6597', (168, 175))	('ARID1A', 'Gene', (151, 157))	('tumor', 'Disease', (16, 21))	('SMARCA1', 'Gene', '6594', (159, 166))	('PBRM1', 'Gene', '55193', (196, 201))	('TWF2', 'Gene', '11344', (296, 300))	('ARID1B', 'Gene', (184, 190))	('stability', 'MPA', (357, 366))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('ARID1A', 'Gene', '8289', (151, 157))	('PBRM1', 'Gene', (196, 201))	('ARID1B', 'Gene', '57492', (184, 190))	('loss-of-function', 'NegReg', (44, 60))
557272	26947069	We also investigated MAPK gene alterations (including RAS gene or BRAF mutations) as a pathway and found a CDK6 KGD (Figure 5D).	('MAPK', 'Gene', (21, 25))	('mutations', 'Var', (71, 80))	('BRAF', 'Gene', '673', (66, 70))	('CDK6', 'Gene', (107, 111))	('CDK6', 'Gene', '1021', (107, 111))	('BRAF', 'Gene', (66, 70))
557273	26947069	The dependency of KRAS mutant tumor cell lines upon CDK6 was readily apparent (rho = -0.38), but was stronger when KRAS, HRAS, NRAS, or BRAF mutant tumor cell line models were combined as a group (rho = -0.43).	('BRAF', 'Gene', '673', (136, 140))	('KRAS', 'Gene', '3845', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BRAF', 'Gene', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('KRAS', 'Gene', '3845', (18, 22))	('KRAS', 'Gene', (115, 119))	('NRAS', 'Gene', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('HRAS', 'Gene', '3265', (121, 125))	('KRAS', 'Gene', (18, 22))	('mutant', 'Var', (141, 147))	('HRAS', 'Gene', (121, 125))	('CDK6', 'Gene', '1021', (52, 56))	('stronger', 'PosReg', (101, 109))	('tumor', 'Disease', (148, 153))	('CDK6', 'Gene', (52, 56))	('NRAS', 'Gene', '4893', (127, 131))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
557275	26947069	Our results suggest that CDK6 might be a non-oncogene addiction not just for KRAS mutant models, but also for cell lines with any one of a variety of MAPK activating mutations (NRAS, HRAS, and BRAF).	('BRAF', 'Gene', (193, 197))	('BRAF', 'Gene', '673', (193, 197))	('mutations', 'Var', (166, 175))	('HRAS', 'Gene', '3265', (183, 187))	('NRAS', 'Gene', (177, 181))	('CDK6', 'Gene', (25, 29))	('HRAS', 'Gene', (183, 187))	('CDK6', 'Gene', '1021', (25, 29))	('KRAS', 'Gene', (77, 81))	('NRAS', 'Gene', '4893', (177, 181))	('KRAS', 'Gene', '3845', (77, 81))	('mutant', 'Var', (82, 88))
557276	26947069	We tested this hypothesis using published drug screening results for a CDK4/6 inhibitor (PD0332991) in 628 cell lines and found a significant association between mutation of the MAPK pathway and sensitivity to this inhibitor (p = 2.5 x 10-3, Mann-Whitney U [MW U]-test).	('sensitivity', 'MPA', (195, 206))	('CDK4/6', 'Gene', (71, 77))	('mutation', 'Var', (162, 170))	('PD0332991', 'Chemical', 'MESH:C500026', (89, 98))	('CDK4/6', 'Gene', '1019;1021', (71, 77))	('MAPK pathway', 'Pathway', (178, 190))
557278	26947069	A key challenge in the study of cancer biology is to understand how driver mutations alter the cellular state to promote tumor progression and how these altered states may be exploited in the development of targeted therapeutic approaches to the disease.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cellular state', 'MPA', (95, 109))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('promote', 'PosReg', (113, 120))	('cancer', 'Disease', (32, 38))	('alter', 'Reg', (85, 90))	('tumor', 'Disease', (121, 126))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
557280	26947069	By integrating our siRNA data with molecular and histotype classifications, we have identified KGDs associated with particular cancer histologies or the presence of particular driver gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('associated', 'Reg', (100, 110))	('particular cancer', 'Disease', (116, 133))	('mutations', 'Var', (188, 197))	('particular cancer', 'Disease', 'MESH:D009369', (116, 133))
557353	26576348	Neutralizing CCR9-CCL25 interactions resulted in impaired cellular migration and invasion of breast cancer cells.	('CCL25', 'Gene', '6370', (18, 23))	('cellular migration', 'CPA', (58, 76))	('invasion', 'CPA', (81, 89))	('interactions', 'Interaction', (24, 36))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('CCL25', 'Gene', (18, 23))	('CCR9', 'Gene', (13, 17))	('CCR9', 'Gene', '10803', (13, 17))	('breast cancer', 'Disease', (93, 106))	('Neutralizing', 'Var', (0, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('impaired', 'NegReg', (49, 57))
557367	26576348	Neutralization of chemokine receptors in vivo by antibodies, inhibitory peptide, or siRNA may attenuate the progress of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('progress of', 'CPA', (108, 119))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('attenuate', 'NegReg', (94, 103))	('Neutralization', 'Var', (0, 14))	('chemokine receptor', 'Gene', '7852', (18, 36))	('chemokine receptor', 'Gene', (18, 36))
557368	26023713	Dysregulation of PAK1 Is Associated with DNA Damage and Is of Prognostic Importance in Primary Esophageal Small Cell Carcinoma Primary esophageal small cell carcinoma (PESCC) is a rare, but fatal subtype of esophageal carcinoma.	('Dysregulation', 'Var', (0, 13))	('PAK1', 'Gene', (17, 21))	('Primary esophageal small cell carcinoma', 'Disease', 'MESH:D018288', (127, 166))	('Carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('Small Cell Carcinoma', 'Phenotype', 'HP:0030357', (106, 126))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (207, 227))	('Primary Esophageal Small Cell Carcinoma', 'Disease', 'MESH:D018288', (87, 126))	('PAK1', 'Gene', '5058', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('Primary Esophageal Small Cell Carcinoma', 'Disease', (87, 126))	('DNA Damage', 'MPA', (41, 51))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (207, 227))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (146, 166))	('esophageal small cell carcinoma', 'Phenotype', 'HP:0011459', (135, 166))	('Associated', 'Reg', (25, 35))	('Esophageal Small Cell Carcinoma', 'Phenotype', 'HP:0011459', (95, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('esophageal carcinoma', 'Disease', (207, 227))	('Primary esophageal small cell carcinoma', 'Disease', (127, 166))
557373	26023713	Overexpression of PAK1 was significantly associated with tumor location (p = 0.011), lymph node metastasis (p = 0.026) and patient survival (p = 0.032).	('associated', 'Reg', (41, 51))	('patient', 'Species', '9606', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('PAK1', 'Gene', '5058', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('Overexpression', 'Var', (0, 14))	('lymph node metastasis', 'CPA', (85, 106))	('PAK1', 'Gene', (18, 22))	('patient survival', 'CPA', (123, 139))
557384	26023713	gammaH2AX, a key regulator of DNA damage response (DDR), has been recently demonstrated to be significantly correlated with lymphatic infiltration in non-small cell lung cancer.	('lymphatic infiltration', 'Disease', (124, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (150, 176))	('gammaH2AX', 'Chemical', '-', (0, 9))	('gammaH2AX', 'Var', (0, 9))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (154, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('non-small cell lung cancer', 'Disease', (150, 176))	('correlated with', 'Reg', (108, 123))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (150, 176))
557385	26023713	In addition, gammaH2AX was a poor prognostic indicator in non-small cell lung cancer, endometrial carcinomas and triple-negative breast cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (58, 84))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (86, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('gammaH2AX', 'Chemical', '-', (13, 22))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (86, 108))	('gammaH2AX', 'Var', (13, 22))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (58, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('non-small cell lung cancer', 'Disease', (58, 84))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('endometrial carcinomas', 'Disease', (86, 108))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (62, 84))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
557386	26023713	More recently, another study has demonstrated that gammaH2AX was significantly enriched in metastatic renal cell carcinoma, and measurements of gammaH2AX was a potentially useful mean in clinical diagnosis of metastatic renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('clinical', 'Species', '191496', (187, 195))	('gammaH2AX', 'Chemical', '-', (144, 153))	('metastatic renal cell carcinoma', 'Disease', (91, 122))	('metastatic renal cell carcinoma', 'Disease', (209, 240))	('measurements', 'Var', (128, 140))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (91, 122))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (209, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (220, 240))	('gammaH2AX', 'Chemical', '-', (51, 60))	('gammaH2AX', 'Var', (51, 60))
557388	26023713	PAK1 acts as a convergence point in a composite oncogenic signaling pathway and its dysregulation possibly influences oncogenic transformation and survival.	('dysregulation', 'Var', (84, 97))	('survival', 'CPA', (147, 155))	('influences', 'Reg', (107, 117))	('PAK1', 'Gene', '5058', (0, 4))	('PAK1', 'Gene', (0, 4))	('oncogenic transformation', 'CPA', (118, 142))
557439	26023713	Overexpression of kinase active T423E mutant caused anchorage independent growth in breast epithelial cells and mammary oncogenesis and tumor promotion in mouse model.	('T423E', 'Var', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('mouse', 'Species', '10090', (155, 160))	('mammary oncogenesis', 'CPA', (112, 131))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('anchorage independent growth', 'CPA', (52, 80))	('tumor', 'Disease', (136, 141))	('T423E', 'Mutation', 'p.T423E', (32, 37))
557452	26023713	Functional studies showed that in vitro knock down of endogenous PAK1 by siRNA reduced the motility of cancer cells.	('reduced', 'NegReg', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('endogenous', 'Var', (54, 64))	('PAK1', 'Gene', (65, 69))	('PAK1', 'Gene', '5058', (65, 69))	('knock down', 'Var', (40, 50))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
557459	26023713	In gastroesophageal junction adenocarcinoma, shorter survival in patients was associated with overexpression of PAK1.	('PAK1', 'Gene', '5058', (112, 116))	('shorter', 'NegReg', (45, 52))	('PAK1', 'Gene', (112, 116))	('overexpression', 'Var', (94, 108))	('gastroesophageal junction adenocarcinoma', 'Disease', (3, 43))	('gastroesophageal junction adenocarcinoma', 'Disease', 'MESH:D008309', (3, 43))	('esophageal junction adenocarcinoma', 'Phenotype', 'HP:0011459', (9, 43))	('patients', 'Species', '9606', (65, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
557466	26023713	Moreover, we investigated the correlation between PAK1 and DNA damage in clinical specimens for the first time, and found that PAK1 expression was positively associated with gammaH2AX, a DNA damage marker, indicating that PAK1 expression may reflect endogenous genomic instability in tissues.	('PAK1', 'Gene', (50, 54))	('PAK1', 'Gene', '5058', (127, 131))	('PAK1', 'Gene', '5058', (222, 226))	('clinical', 'Species', '191496', (73, 81))	('PAK1', 'Gene', (222, 226))	('PAK1', 'Gene', (127, 131))	('associated', 'Interaction', (158, 168))	('gammaH2AX', 'Chemical', '-', (174, 183))	('gammaH2AX', 'Var', (174, 183))	('PAK1', 'Gene', '5058', (50, 54))	('expression', 'MPA', (132, 142))
557468	26023713	Moreover, gammaH2AX has been recently revealed as a prognostic indicator in non-small cell lung cancer, endometrial carcinomas and triple-negative breast cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('non-small cell lung cancer', 'Disease', (76, 102))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (147, 160))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (104, 126))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('gammaH2AX', 'Var', (10, 19))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (104, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('gammaH2AX', 'Chemical', '-', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (76, 102))	('endometrial carcinomas', 'Disease', (104, 126))
557494	26023713	A volume of 100 microL of 3,3-diaminibenzidine tetrahydrochloride (DAB) was applied on sections for chromogenic detection of PAK1 or gammaH2AX, then counterstained with Hematoxylin.	('3,3-diaminibenzidine tetrahydrochloride', 'Chemical', '-', (26, 65))	('gammaH2AX', 'Chemical', '-', (133, 142))	('gammaH2AX', 'Var', (133, 142))	('DAB', 'Chemical', '-', (67, 70))	('PAK1', 'Gene', '5058', (125, 129))	('PAK1', 'Gene', (125, 129))	('Hematoxylin', 'Chemical', 'MESH:D006416', (169, 180))
557500	26023713	We show for the first time that PAK1 was frequently overexpressed in PESCC and in addition, overexpression of PAK1 was significantly associated with tumor location, metastasis and reduced overall survival, and gammaH2AX, a DNA damage marker.	('PAK1', 'Gene', (32, 36))	('metastasis', 'CPA', (165, 175))	('gammaH2AX', 'Var', (210, 219))	('PAK1', 'Gene', '5058', (32, 36))	('associated with', 'Reg', (133, 148))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('overexpression', 'PosReg', (92, 106))	('overexpressed', 'PosReg', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('reduced', 'NegReg', (180, 187))	('PAK1', 'Gene', '5058', (110, 114))	('PAK1', 'Gene', (110, 114))	('overall survival', 'CPA', (188, 204))	('tumor', 'Disease', (149, 154))	('PESCC', 'Disease', (69, 74))	('gammaH2AX', 'Chemical', '-', (210, 219))
557730	31651855	Additionally, patients with MPLNM had a lower 5-year survival rate (15.6%) than those with LNM at other sites.	('patients', 'Species', '9606', (14, 22))	('MPLNM', 'Var', (28, 33))	('lower', 'NegReg', (40, 45))
557768	31651855	Patients with MPLNM had a 5-year cumulative survival rate of 15.6%, which was significantly lower than the 46.7% survival rate in those without MPLNM (P < .001, Fig.	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (92, 97))	('MPLNM', 'Var', (14, 19))
557769	31651855	Interestingly, the 5-year survival of patients with MPLNM was also lower than those with LNM in other regions (Table 2).	('MPLNM', 'Var', (52, 57))	('lower', 'NegReg', (67, 72))	('patients', 'Species', '9606', (38, 46))
557782	31651855	In addition, LNM near the celiac trunk was found to be associated with adverse prognosis in ESCC.	('LNM near', 'Var', (13, 21))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))	('ESCC', 'Disease', (92, 96))	('celiac trunk', 'Phenotype', 'HP:0012327', (26, 38))
557785	31651855	It is notable that the 5-year cumulative survival of patients with MPLNM was much worse than those with LNM in other sites.	('worse', 'NegReg', (82, 87))	('patients', 'Species', '9606', (53, 61))	('MPLNM', 'Var', (67, 72))
557787	31651855	In conclusion, MPLNM is an independent prognostic factor for patients with resectable ESCC and receiving surgery.	('ESCC', 'Disease', 'MESH:C562729', (86, 90))	('MPLNM', 'Var', (15, 20))	('patients', 'Species', '9606', (61, 69))	('ESCC', 'Disease', (86, 90))
557795	31059681	Mutations in plasma DNA were detected using custom, barcoded, patient-specific sequencing libraries.	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (62, 69))	('plasma DNA', 'Gene', (13, 23))
557810	31059681	Novel technologies, such as our sequencing approach, enable detection of these rare tumor mutations in an abundance of normal ccfDNA.	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('mutations', 'Var', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
557834	31059681	If sufficient DNA was available, selected mutations were verified in the tumor using SiMSen-Seq as described below.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('mutations', 'Var', (42, 51))
557836	31059681	SiMSen-Seq assays were designed to selected tumor mutations, tested, and validated as described previously.	('mutations', 'Var', (50, 59))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
557838	31059681	Custom libraries were created using specific assays designed to capture each tumor's selected mutations.	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutations', 'Var', (94, 103))
557843	31059681	Of the remaining 47 patients, 29 had sufficient tumor DNA for verification of selected mutations using SiMSen-Seq while 18 did not.	('tumor', 'Disease', (48, 53))	('mutations', 'Var', (87, 96))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
557857	31059681	Similarly, for tumors with mutations verified by SiMSen-Seq, 12/21(57%) plasma samples were positive versus 6/17(35%) for those in which DNA was not available for tumor verification (Table 1).	('mutations', 'Var', (27, 36))	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (163, 168))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
557858	31059681	Longitudinal samples were available from eight patients with verified mutations in their tumor.	('mutations', 'Var', (70, 79))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
557863	31059681	One patient (LA15, Figure 2) was diagnosed with cT3N1Mx EAC and two tumor mutations (TP53, ARID1A) were identified.	('tumor', 'Disease', (68, 73))	('TP53', 'Gene', (85, 89))	('ARID1A', 'Gene', '8289', (91, 97))	('ARID1A', 'Gene', (91, 97))	('EAC', 'Disease', (56, 59))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('TP53', 'Gene', '7157', (85, 89))	('EAC', 'Phenotype', 'HP:0011459', (56, 59))	('cT3N1Mx', 'Var', (48, 55))
557868	31059681	A second patient (LA15, Figure 3) was diagnosed with cT3N1M0 EAC and two tumor mutations (TP53, ERBB4) were identified.	('cT3N1M0 EAC', 'Var', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('EAC', 'Phenotype', 'HP:0011459', (61, 64))	('TP53', 'Gene', '7157', (90, 94))	('ERBB4', 'Gene', '2066', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('TP53', 'Gene', (90, 94))	('ERBB4', 'Gene', (96, 101))	('patient', 'Species', '9606', (9, 16))
557871	31059681	Plasma DNA showed mutations present 30 days into palliative therapy, while a CT showed stable peritoneal disease and worse ascites.	('worse ascites', 'Disease', (117, 130))	('worse ascites', 'Disease', 'MESH:D001201', (117, 130))	('ascites', 'Phenotype', 'HP:0001541', (123, 130))	('mutations', 'Var', (18, 27))
557885	31059681	Additionally, although all tumor sequence data was reviewed in IGV, we discovered a relatively high failure rate when verifying the selected mutations.	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (141, 150))
557987	30563041	Cell viability assay revealed that B11 significantly inhibited the proliferation of human cervical (HeLa), human hepatocellular carcinoma (HepG2), and human esophageal cancer (EC109) cancer cell lines, but not normal liver cell lines (T-antigen-immortalized human liver epithelial (THLE) cells or THLE-3), by inducing morphological changes, nuclear condensation, and margination, features which are indicative of apoptosis.	('inhibited', 'NegReg', (53, 62))	('EC109', 'CellLine', 'CVCL:6898', (176, 181))	('THLE', 'Chemical', '-', (297, 301))	('THLE-3', 'CellLine', 'CVCL:3804', (297, 303))	('cancer', 'Disease', (168, 174))	('margination', 'CPA', (367, 378))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (183, 189))	('morphological changes', 'CPA', (318, 339))	('inducing', 'Reg', (309, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (113, 137))	('nuclear condensation', 'CPA', (341, 361))	('human', 'Species', '9606', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('proliferation', 'CPA', (67, 80))	('human', 'Species', '9606', (84, 89))	('HeLa', 'CellLine', 'CVCL:0030', (100, 104))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (113, 137))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('human', 'Species', '9606', (258, 263))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('HepG2', 'CellLine', 'CVCL:0027', (139, 144))	('B11', 'Var', (35, 38))	('human', 'Species', '9606', (107, 112))	('hepatocellular carcinoma', 'Disease', (113, 137))	('esophageal cancer', 'Disease', (157, 174))	('THLE', 'Chemical', '-', (282, 286))
557988	30563041	Besides, peptide B11-induced apoptosis was confirmed by isothiocyanate-labeled Annexin V/propidium iodide (Annexin V-FITC/PI) double staining of HeLa cells.	('Annexin V', 'Gene', '308', (79, 88))	('HeLa', 'CellLine', 'CVCL:0030', (145, 149))	('Annexin V', 'Gene', '308', (107, 116))	('Annexin V', 'Gene', (79, 88))	('peptide B11-induced', 'Var', (9, 28))	('propidium iodide', 'Chemical', 'MESH:D011419', (89, 105))	('Annexin V', 'Gene', (107, 116))	('isothiocyanate', 'Chemical', 'MESH:C037152', (56, 70))
557989	30563041	Moreover, cell uptake studies, confocal microscopy, and Western blot analysis revealed that rhodamine-labeled B11 permeated HeLa cells and localized to the mitochondria, causing mitochondria dysfunction through lost mitochondrial membrane potential, which consequently triggered the induction of apoptosis.	('mitochondrial membrane potential', 'MPA', (216, 248))	('mitochondria dysfunction', 'Disease', (178, 202))	('mitochondria dysfunction', 'Disease', 'MESH:C564925', (178, 202))	('B11', 'Var', (110, 113))	('rhodamine', 'Chemical', 'MESH:D012235', (92, 101))	('causing', 'Reg', (170, 177))	('apoptosis', 'CPA', (296, 305))	('lost', 'NegReg', (211, 215))	('HeLa', 'CellLine', 'CVCL:0030', (124, 128))
557990	30563041	Increased expression levels of caspase-9, caspase-3, and Bax (Bcl-2-associated X) proteins, coupled with a decrease in Bcl-2 (B-cell lymphoma 2) protein, confirmed that peptide B11 induced apoptosis via the mitochondrial pathway.	('Bcl-2', 'Gene', (62, 67))	('apoptosis', 'CPA', (189, 198))	('B-cell lymphoma 2', 'Gene', (126, 143))	('Bcl-2', 'Gene', '596', (119, 124))	('peptide B11', 'Var', (169, 180))	('caspase-9', 'Gene', (31, 40))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (126, 141))	('Bcl-2', 'Gene', '596', (62, 67))	('mitochondrial pathway', 'Pathway', (207, 228))	('Bax', 'Gene', (57, 60))	('decrease', 'NegReg', (107, 115))	('Bcl-2-associated X', 'Gene', '581', (62, 80))	('Bax', 'Gene', '581', (57, 60))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('Increased', 'PosReg', (0, 9))	('expression levels', 'MPA', (10, 27))	('caspase-3', 'Gene', '836', (42, 51))	('B-cell lymphoma 2', 'Gene', '596', (126, 143))	('caspase-9', 'Gene', '842', (31, 40))	('Bcl-2-associated X', 'Gene', (62, 80))	('Bcl-2', 'Gene', (119, 124))	('caspase-3', 'Gene', (42, 51))
557991	30563041	Thus, the hemocyanin-derived peptide, B11, inhibits the proliferation of cancer cells by causing mitochondrial dysfunction and inducing apoptotic cell death, for which reason it could be explored as an anticancer peptide.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (97, 122))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (97, 122))	('B11', 'Var', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('apoptotic cell death', 'CPA', (136, 156))	('mitochondrial dysfunction', 'Disease', (97, 122))	('inhibits', 'NegReg', (43, 51))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('inducing', 'NegReg', (127, 135))	('causing', 'Reg', (89, 96))
558007	30563041	Peptide B11 could inhibit the proliferation of three cancer cell lines by permeabilizing, entering, and inducing apoptotic cell death.	('inhibit', 'NegReg', (18, 25))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('permeabilizing', 'CPA', (74, 88))	('apoptotic cell death', 'CPA', (113, 133))	('inducing', 'Reg', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Peptide B11', 'Var', (0, 11))	('entering', 'CPA', (90, 98))	('proliferation', 'CPA', (30, 43))
558011	30563041	When the cell proliferation or viability following treatment with peptide B11, 5-fluorouracil (5-FU), or PBS (Phosphate-buffered saline) was determined using the MTS assay (Figure 2), it was observed that the proliferation of all three cancer cell types was significantly decreased 24 h post-treatment with peptide B11 or with the anticancer drug 5-FU compared with PBS.	('proliferation', 'CPA', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('peptide B11', 'Var', (307, 318))	('5-FU', 'Chemical', 'MESH:D005472', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('PBS', 'Chemical', '-', (105, 108))	('decreased', 'NegReg', (272, 281))	('cancer', 'Disease', (236, 242))	('cancer', 'Disease', (335, 341))	('5-FU', 'Chemical', 'MESH:D005472', (347, 351))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('PBS', 'Chemical', '-', (366, 369))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('Phosphate-buffered saline', 'Chemical', '-', (110, 135))
558012	30563041	For instance, peptide B11 significantly (p < 0.05) decreased HeLa cells viability by 20.0% (Figure 2A), while that of HepG2 cells decreased by 23.0% (Figure 2B) and EC109 cells decreased by 13.0% (Figure 2C) relative to PBS treatment.	('HepG2', 'CellLine', 'CVCL:0027', (118, 123))	('decreased', 'NegReg', (51, 60))	('HeLa', 'CellLine', 'CVCL:0030', (61, 65))	('decreased', 'NegReg', (177, 186))	('PBS', 'Chemical', '-', (220, 223))	('EC109', 'CellLine', 'CVCL:6898', (165, 170))	('peptide B11', 'Var', (14, 25))	('decreased', 'NegReg', (130, 139))
558014	30563041	Thus, these results suggest that peptide B11 selectively inhibits the in vitro proliferation of only cancer cell lines, and could potentially be used as an antitumor agent.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('peptide B11', 'Var', (33, 44))	('cancer', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (160, 165))	('inhibits', 'NegReg', (57, 65))
558017	30563041	In addition, the typical characteristics of apoptosis, including nuclei shrinkage, condensation, margination and the formation of apoptotic body-like vesicles were observed in cells 24 h post-treatment with peptide B11 and 5-FU, but not in PBS (Figure 3B).	('5-FU', 'Var', (223, 227))	('peptide B11', 'Var', (207, 218))	('apoptosis', 'CPA', (44, 53))	('margination', 'CPA', (97, 108))	('5-FU', 'Chemical', 'MESH:D005472', (223, 227))	('nuclei shrinkage', 'CPA', (65, 81))	('PBS', 'Chemical', '-', (240, 243))	('condensation', 'CPA', (83, 95))
558018	30563041	Moreover, flow cytometry analysis with Annexin V/propidium iodide (Annexin V/PI) staining revealed that the ratio of viable cells to total cells gradually decreased in peptide B11-treated cells, while there was a time-dependent gradual increase in the percentage of late apoptotic cells (Figure 3C).	('Annexin V/PI', 'Gene', (67, 79))	('Annexin V/PI', 'Gene', '308', (67, 79))	('decreased', 'NegReg', (155, 164))	('Annexin V', 'Gene', '308', (67, 76))	('increase', 'PosReg', (236, 244))	('peptide B11-treated', 'Var', (168, 187))	('Annexin V', 'Gene', '308', (39, 48))	('propidium iodide', 'Chemical', 'MESH:D011419', (49, 65))	('Annexin V', 'Gene', (39, 48))
558019	30563041	In fact, the average percentage of apoptotic cells in peptide B11-treated cells was 40.4% at 48 h post-treatment, which is similar to that observed in the 5-FU treated cells (41.1%) at the same time point.	('peptide B11-treated', 'Var', (54, 73))	('5-FU', 'Chemical', 'MESH:D005472', (155, 159))	('apoptotic cells', 'CPA', (35, 50))
558020	30563041	These results suggest that peptide B11 exerts a proapoptotic effect on cancer cells, which is synonymous with 5-FU, and that this might account for the antiproliferative effects of peptide B11 on HeLa cells.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('5-FU', 'Chemical', 'MESH:D005472', (110, 114))	('HeLa', 'CellLine', 'CVCL:0030', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('peptide B11', 'Var', (27, 38))	('proapoptotic effect', 'MPA', (48, 67))
558023	30563041	Thus, given the size of peptide B11, its net positive charge, alpha-helix, and beta-sheet structure, as well as other features that are typical of therapeutic peptides and/or AMPs, it should be able to permeable cells.	('peptide B11', 'Var', (24, 35))	('peptides', 'Chemical', 'MESH:D010455', (159, 167))	('AMPs', 'Chemical', '-', (175, 179))	('alpha-helix', 'MPA', (62, 73))
558026	30563041	Moreover, peptide B11 not only localized to the mitochondria, but was able to cause mitochondrial dysfunction in the form of a loss in mitochondrial membrane potential (Figure 5B).	('cause', 'Reg', (78, 83))	('mitochondrial membrane potential', 'MPA', (135, 167))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (84, 109))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (84, 109))	('loss', 'NegReg', (127, 131))	('peptide B11', 'Var', (10, 21))	('mitochondrial dysfunction', 'Disease', (84, 109))
558029	30563041	All of these results indicate that peptide B11 was able to cause mitochondrial dysfunction and induced apoptosis via the mitochondrial-dependent pathway.	('mitochondrial-dependent pathway', 'Pathway', (121, 152))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (65, 90))	('mitochondrial dysfunction', 'Disease', (65, 90))	('induced', 'Reg', (95, 102))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (65, 90))	('cause', 'Reg', (59, 64))	('apoptosis', 'CPA', (103, 112))	('peptide B11', 'Var', (35, 46))
558035	30563041	The antiproliferative effect of peptide B11 is because it causes mitochondrial dysfunction and induces apoptosis, therefore suggesting its anticancer potential.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (65, 90))	('peptide B11', 'Var', (32, 43))	('mitochondrial dysfunction', 'Disease', (65, 90))	('causes', 'Reg', (58, 64))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (65, 90))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('apoptosis', 'CPA', (103, 112))	('antiproliferative effect', 'MPA', (4, 28))	('induces', 'Reg', (95, 102))
558040	30563041	In this study, the antitumor potential of a 15 amino acids hydrophobic cationic antimicrobial peptide, peptide B11, which is derived from the large molecular weight hemocyanin protein of L. vannamei, and has alpha-helical and beta-sheet structure, was explored.	('L. vannamei', 'Species', '6689', (187, 198))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('peptide', 'Var', (103, 110))	('tumor', 'Disease', (23, 28))
558043	30563041	On the other hand, AMPs rich in hydrophobic amino acids are able to insert into cell membranes to form a stable structure, thereby disrupting the cell membrane and forming pores, leading to changes in cell membrane charge and therefore interfering with cell death pathways.	('cell death', 'CPA', (253, 263))	('changes', 'Reg', (190, 197))	('forming', 'Reg', (164, 171))	('hydrophobic amino acids', 'Var', (32, 55))	('cell membrane', 'MPA', (146, 159))	('cell membrane charge', 'MPA', (201, 221))	('AMPs', 'Chemical', '-', (19, 23))	('interfering', 'NegReg', (236, 247))	('disrupting', 'NegReg', (131, 141))
558046	30563041	In the current study, rhodamine-labeled B11 was able to permeate HeLa cells (Figure 4D), just as other anticancer peptides, and localized to the mitochondria (Figure 5A), where it induced a loss of mitochondrial membrane potential (Figure 5B), and consequently mitochondrial dysfunction.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (261, 286))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (261, 286))	('rhodamine', 'Chemical', 'MESH:D012235', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mitochondrial dysfunction', 'Disease', (261, 286))	('loss', 'NegReg', (190, 194))	('rhodamine-labeled B11', 'Var', (22, 43))	('peptides', 'Chemical', 'MESH:D010455', (114, 122))	('mitochondrial membrane potential', 'MPA', (198, 230))	('B11', 'Var', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('HeLa', 'CellLine', 'CVCL:0030', (65, 69))	('cancer', 'Disease', (107, 113))
558054	30563041	Interestingly, peptide B11 treatment caused a decrease in antiapoptotic Bcl-2 protein, but an increase in proapototic Bax in HeLa cells (Figure 5C(ii),(iii)).	('Bax', 'Gene', (118, 121))	('Bcl-2', 'Gene', (72, 77))	('Bcl-2', 'Gene', '596', (72, 77))	('increase', 'PosReg', (94, 102))	('peptide B11', 'Var', (15, 26))	('Bax', 'Gene', '581', (118, 121))	('decrease', 'NegReg', (46, 54))	('HeLa', 'CellLine', 'CVCL:0030', (125, 129))
558058	30563041	The studies presented thus far provide evidence that suggest peptide B11 exerts an antiproliferative effect in cancer cells by targeting the mitochondria, causing mitochondrial dysfunction through a loss in membrane potential, and consequently inducing mitochondrial-dependent apoptosis.	('antiproliferative effect', 'CPA', (83, 107))	('peptide B11', 'Var', (61, 72))	('causing', 'Reg', (155, 162))	('inducing', 'Reg', (244, 252))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (163, 188))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mitochondrial-dependent apoptosis', 'CPA', (253, 286))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (163, 188))	('targeting', 'Reg', (127, 136))	('membrane potential', 'MPA', (207, 225))	('mitochondrial dysfunction', 'Disease', (163, 188))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('loss', 'NegReg', (199, 203))	('mitochondria', 'MPA', (141, 153))
558205	27861146	In general, metformin may exert its anticancer effect through the inhibition of tumor angiogenesis, suppressing cancer cell metabolism, activation of apoptosis and autophagy, inhibition of mammalian target of rapamycin (mTOR), immunomodulation by increasing the number of CD8+ tumor-infiltrating lymphocytes, and impairing one-carbon metabolism acting like an antifolate drug.	('mTOR', 'Gene', '2475', (220, 224))	('cancer', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('apoptosis', 'CPA', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('mammalian target of rapamycin', 'Gene', '2475', (189, 218))	('suppressing', 'NegReg', (100, 111))	('metformin', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('metformin', 'Chemical', 'MESH:D008687', (12, 21))	('cancer', 'Disease', (40, 46))	('activation', 'PosReg', (136, 146))	('mammalian target of rapamycin', 'Gene', (189, 218))	('CD8', 'Gene', (272, 275))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('autophagy', 'CPA', (164, 173))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', (80, 85))	('one-carbon metabolism acting', 'MPA', (323, 351))	('tumor', 'Disease', (277, 282))	('inhibition', 'NegReg', (66, 76))	('impairing', 'NegReg', (313, 322))	('mTOR', 'Gene', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('increasing', 'PosReg', (247, 257))	('inhibition', 'NegReg', (175, 185))	('carbon', 'Chemical', 'MESH:D002244', (327, 333))	('CD8', 'Gene', '925', (272, 275))
558307	25996101	Patient with Siewert II and III adenocarcinomas are less likely to have upper and middle mediastinal lymph node metastasis making surgery using the transabdominal approach by the diaphragmatic hiatus feasible.	('mediastinal lymph node metastasis', 'Phenotype', 'HP:0100721', (89, 122))	('Siewert', 'Var', (13, 20))	('adenocarcinomas', 'Disease', 'MESH:D000230', (32, 47))	('adenocarcinomas', 'Disease', (32, 47))	('Patient', 'Species', '9606', (0, 7))
558351	26135095	The depths of field of the BLI prototype scope, GIF-H260Z, and CF-H260AZI were 6 - 100 mm, 7 - 100 mm, and 7 - 100 mm without magnification, and 2 - 3 mm, 1.5 - 3 mm, and 2 - 3 mm with magnification, respectively.	('CF-H260AZI', 'Var', (63, 73))	('H260Z', 'Var', (52, 57))	('H260Z', 'SUBSTITUTION', 'None', (52, 57))
558388	24060519	The study population was comprised of patients with a first primary esophageal cancer [International Classification of Diseases for Oncology (ICD-O-3 codes): C150-C155, C158-C159)], microscopically confirmed, and diagnosed from 1998 - 2009.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('ICD', 'Disease', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('C150-C155', 'Var', (158, 167))	('patients', 'Species', '9606', (38, 46))	('esophageal cancer', 'Disease', (68, 85))	('ICD', 'Disease', 'OMIM:252500', (142, 145))	('Oncology', 'Phenotype', 'HP:0002664', (132, 140))
558418	24060519	Although the proportion of deaths attributed to esophageal cancer was comparable between the two groups (10.5% vs. 12.7%, p=0.27), patients receiving endoscopic eradication therapies were more likely to die of other causes (predominantly heart disease) compared with patients receiving esophagectomy (11.1% vs. 5.4%, p<0.001).	('patients', 'Species', '9606', (131, 139))	('esophageal cancer', 'Disease', (48, 65))	('heart disease', 'Disease', 'MESH:D006331', (238, 251))	('patients', 'Species', '9606', (267, 275))	('endoscopic', 'Var', (150, 160))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('death', 'Disease', 'MESH:D003643', (27, 32))	('death', 'Disease', (27, 32))	('heart disease', 'Disease', (238, 251))
558424	24060519	Higher mortality related to other causes was noted in the endoscopic eradication therapies arm compared to esophagectomy (10.4% vs. 5%, p=0.002) with no difference in esophageal cancer specific mortality (10% vs. 11.1%, p=0.64).	('esophageal cancer', 'Disease', (167, 184))	('esophageal cancer', 'Disease', 'MESH:D004938', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('endoscopic', 'Var', (58, 68))
558435	24060519	Comparable 2-year and 5-year esophageal cancer related mortality rates (p=0.8 and p=0.2, respectively) were noted when endoscopic eradication therapies were compared to surgery in patients with T1b esophageal cancer (n=724), including subgroup of patients with EAC (n=530) and non-EAC (n=194).	('esophageal cancer', 'Disease', 'MESH:D004938', (198, 215))	('EAC', 'Gene', '1540', (261, 264))	('EAC', 'Gene', (261, 264))	('esophageal cancer', 'Disease', (29, 46))	('patients', 'Species', '9606', (247, 255))	('EAC', 'Gene', '1540', (281, 284))	('esophageal cancer', 'Disease', (198, 215))	('EAC', 'Gene', (281, 284))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('patients', 'Species', '9606', (180, 188))	('T1b', 'Var', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
558559	23267382	Depending on the types and number of repeat regions including R1 (15 bp), R2 (42 bp) and R3 (147 bp), four types (motifs) of A, B, C, and D are contributed to the 3' end variability of cagA.	('cagA', 'Gene', (185, 189))	('cagA', 'Gene', '6279', (185, 189))	('R3 (147 bp', 'Var', (89, 99))
558567	23267382	Furthermore, the presence of anti-CagA antibodies showed an association with clinical manifestations when categorized in three groups of NUD, PUD, and GC.	('CagA', 'Gene', (34, 38))	('CagA', 'Gene', '6279', (34, 38))	('association', 'Reg', (60, 71))	('presence', 'Var', (17, 25))
558576	23267382	Applying PCR-based methodology, different combinations of allelic variations such as s1m1, s1m2, and s2m2 were detected from dyspeptic patients who underwent upper gastrointestinal endoscopy.	('dyspeptic', 'Disease', (125, 134))	('patients', 'Species', '9606', (135, 143))	('dyspeptic', 'Disease', 'None', (125, 134))	('s2m2', 'Var', (101, 105))	('s1m2', 'Var', (91, 95))	('s1m1', 'Var', (85, 89))
558581	23267382	However, the collective assessment of the vacA genotype signal sequence and middle region determined a majority of s1m2 genotype in patients with PUD which was significantly correlated with the disease (p < 0.05) in two other studies (Table 1).	('s1m2', 'Gene', (115, 119))	('correlated with', 'Reg', (174, 189))	('genotype', 'Var', (120, 128))	('disease', 'Disease', (194, 201))	('PUD', 'Disease', (146, 149))	('men', 'Species', '9606', (30, 33))	('patients', 'Species', '9606', (132, 140))
558610	23267382	GC was associated with vacA s1 allele (p < 0.05), cagA (p < 0.005), and m1 allele (p < 0.05) compared to the NUD group as control.	('vacA s1', 'Var', (23, 30))	('cagA', 'Gene', '6279', (50, 54))	('cagA', 'Gene', (50, 54))
558638	23267382	On the other hand, possession of this gene appeared to be protective against gastric adenocarcinoma.	('possession', 'Var', (19, 29))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (77, 99))	('gastric adenocarcinoma', 'Disease', (77, 99))
558639	23267382	The presence of the jhp0917 and jhp0918 genes was assessed in 157 H. pylori infected patients with DU, gastric ulcer (GU), gastritis, and GC using gene specific PCR.	('gastritis', 'Disease', 'MESH:D005756', (123, 132))	('jhp0918', 'Var', (32, 39))	('gastric ulcer', 'Disease', 'MESH:D013276', (103, 116))	('gastritis', 'Phenotype', 'HP:0005263', (123, 132))	('gastric ulcer', 'Disease', (103, 116))	('patients', 'Species', '9606', (85, 93))	('H. pylori', 'Species', '210', (66, 75))	('infected', 'Disease', 'MESH:D007239', (76, 84))	('gastritis', 'Disease', (123, 132))	('gastric ulcer', 'Phenotype', 'HP:0002592', (103, 116))	('infected', 'Disease', (76, 84))
558641	23267382	However, the presence of dupA gene was inversely associated with dysplasia (p < 0.05) as the final stage towards GC and 83.3% of dysplasia-positive strains were colonized with dupA-negative strains.	('dysplasia', 'Disease', (65, 74))	('dupA gene', 'Gene', (25, 34))	('dupA', 'Chemical', '-', (176, 180))	('dysplasia', 'Disease', 'MESH:D004476', (65, 74))	('associated', 'Reg', (49, 59))	('dysplasia', 'Disease', (129, 138))	('dysplasia', 'Disease', 'MESH:D004476', (129, 138))	('presence', 'Var', (13, 21))	('dupA', 'Chemical', '-', (25, 29))
558644	23267382	It has been suggested that the number of homB genes affects the number of bacteria adhering to host cells and that the presence of homB is associated with secretion of the pro-inflammatory cytokine IL-8, PUD, and GC.	('homB', 'Gene', (131, 135))	('homB', 'Chemical', '-', (41, 45))	('associated', 'Reg', (139, 149))	('presence', 'Var', (119, 127))	('homB', 'Chemical', '-', (131, 135))	('homB', 'Gene', (41, 45))	('secretion of', 'MPA', (155, 167))	('affects', 'Reg', (52, 59))
558658	23267382	We found a significant association of cagA genotype with chronic gastritis, PUD, and GC.	('genotype', 'Var', (43, 51))	('cagA', 'Gene', (38, 42))	('gastritis', 'Disease', 'MESH:D005756', (65, 74))	('chronic gastritis', 'Phenotype', 'HP:0005231', (57, 74))	('gastritis', 'Phenotype', 'HP:0005263', (65, 74))	('cagA', 'Gene', '6279', (38, 42))	('PUD', 'Disease', (76, 79))	('gastritis', 'Disease', (65, 74))
558665	23267382	The variations in the three regions of vacA gene of H. pylori s, m, and i region are known to cause the differences in vacuolating activity.	('H. pylori', 'Gene', (52, 61))	('variations', 'Var', (4, 14))	('vacuolating activity', 'MPA', (119, 139))	('H. pylori', 'Species', '210', (52, 61))	('differences', 'Reg', (104, 115))	('cause', 'Reg', (94, 99))
558669	23267382	Overall, unlike the cagA status, the majority of studies emphasized the implication of vacA polymorphic structure in increasing risk of gastroduodenal diseases.	('vacA', 'Gene', (87, 91))	('gastroduodenal disease', 'Phenotype', 'HP:0011024', (136, 158))	('cagA', 'Gene', '6279', (20, 24))	('cagA', 'Gene', (20, 24))	('gastroduodenal diseases', 'Phenotype', 'HP:0011024', (136, 159))	('gastroduodenal diseases', 'Disease', (136, 159))	('gastroduodenal diseases', 'Disease', 'MESH:D010437', (136, 159))	('polymorphic structure', 'Var', (92, 113))
558670	23267382	Looking at the association between vacA genotypes and disease status, a significant association was observed between s1 genotype and gastritis, PUD, and GC.	('gastritis', 'Phenotype', 'HP:0005263', (133, 142))	('gastritis', 'Disease', (133, 142))	('genotype', 'Var', (120, 128))	('PUD', 'Disease', (144, 147))	('gastritis', 'Disease', 'MESH:D005756', (133, 142))
558673	23267382	Mixed polymorphic determinant of vacA genotype s1m1i1 indicated a significant prevalence in subjects with GC and IM, while s2m2i2 genotyping was most prevalent in NUD patients.	('s1m1i1', 'Var', (47, 53))	('patients', 'Species', '9606', (167, 175))	('prevalence', 'Reg', (78, 88))
558731	32450791	Of note, both ropivacaine and bupivacaine at 100 muM resulted in ~ 80% inhibition of migration.	('bupivacaine', 'Chemical', 'MESH:D002045', (30, 41))	('bupivacaine', 'Var', (30, 41))	('inhibition', 'NegReg', (71, 81))	('ropivacaine', 'Chemical', 'MESH:D000077212', (14, 25))	('migration', 'CPA', (85, 94))
558803	31199600	Overall, approximately 20% of all resected esophageal cancers are early lesions limited to the mucosa and submucosa.2  The National Comprehensive Cancer Network (NCCN) guidelines recommend the following treatment for early esophageal cancer: in patients with Tis and T1a esophageal cancer, endoscopic therapy (ET) is the preferred therapeutic approach; in patients with T1b esophageal cancer, esophagectomy (ES) is currently the preferred therapy or ET may be an alternative strategy to ES, especially in patients who are poor surgical candidates.	('esophagectomy', 'Disease', (393, 406))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('patients', 'Species', '9606', (245, 253))	('cancer', 'Phenotype', 'HP:0002664', (385, 391))	('ET', 'Chemical', '-', (450, 452))	('patients', 'Species', '9606', (356, 364))	('patients', 'Species', '9606', (505, 513))	('esophageal cancers', 'Disease', 'MESH:D004938', (43, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('Cancer', 'Phenotype', 'HP:0002664', (146, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (271, 288))	('Cancer', 'Disease', (146, 152))	('esophageal cancer', 'Disease', (271, 288))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('T1b', 'Var', (370, 373))	('esophageal cancer', 'Disease', 'MESH:D004938', (374, 391))	('ET', 'Chemical', '-', (310, 312))	('esophageal cancer', 'Disease', 'MESH:D004938', (223, 240))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', 'MESH:D009369', (146, 152))	('esophageal cancer', 'Disease', (374, 391))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('esophageal cancer', 'Disease', (223, 240))	('esophageal cancers', 'Disease', (43, 61))
558841	31199600	In addition, after PSM (Table 4), Cox proportional hazards regression revealed that ES did not improve five-year OS (HR 0.756, 95% CI 0.419-1.366; P = 0.354) or CSS (HR 0.89, 95% CI 0.394-2.013; P = 0.78) compared to ET.	('CSS', 'CPA', (161, 164))	('improve', 'PosReg', (95, 102))	('ET', 'Chemical', '-', (217, 219))	('PSM', 'Var', (19, 22))	('CSS', 'Chemical', '-', (161, 164))	('OS', 'Chemical', '-', (113, 115))
558843	31199600	Multivariate Cox regression analysis revealed that radiotherapy, older age at diagnosis, low grade or undifferentiated, T1b staging, unmarried, and early year of diagnosis were independent risk predictors for five-year OS, while RT, older age at diagnosis, low grade or undifferentiated, and T1b staging were independent risk predictors for CSS (Table 6).	('low grade', 'Var', (89, 98))	('OS', 'Chemical', '-', (219, 221))	('CSS', 'Chemical', '-', (341, 344))	('T1b', 'Gene', (120, 123))	('CSS', 'Disease', (341, 344))
558898	31139564	However, patients with post-CCRT sarcopenia showed shorter OS and PFS than patients without it (median OS: 73 months vs. 28 months; median PFS: 34 months vs. 25 months, respectively).	('patients', 'Species', '9606', (9, 17))	('sarcopenia', 'Disease', 'MESH:D055948', (33, 43))	('OS', 'Chemical', '-', (59, 61))	('OS', 'Chemical', '-', (103, 105))	('shorter', 'NegReg', (51, 58))	('patients', 'Species', '9606', (75, 83))	('PFS', 'CPA', (66, 69))	('sarcopenia', 'Disease', (33, 43))	('post-CCRT', 'Var', (23, 32))
559079	26641256	Our study showed NY-ESO-1 positivity in 38 of 274 (14%) of metastatic tumors and 2 of 40 (5%) primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('NY-ESO-1', 'Gene', '246100', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('NY-ESO-1', 'Gene', (17, 25))	('positivity', 'Var', (26, 36))
559080	26641256	Aung and colleagues, demonstrated NY-ESO-1 positivity was found in 58 of 206 (28.2%) metastatic tumors and 0 of 16 (0%) primary tumors.	('NY-ESO-1', 'Gene', '246100', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('positivity', 'Var', (43, 53))	('found', 'Reg', (58, 63))	('NY-ESO-1', 'Gene', (34, 42))
559097	26641256	MAGE-A positivity was found in 51% of a panel of 57 primary head and neck squamous cell cancer.	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (69, 94))	('neck squamous cell cancer', 'Disease', (69, 94))	('positivity', 'Var', (7, 17))	('MAGE-A', 'Chemical', '-', (0, 6))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (60, 94))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (74, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
559124	25928282	Diagnostic and prognostic potential of miR-21, miR-29c, miR-148 and miR-203 in adenocarcinoma and squamous cell carcinoma of esophagus Esophageal cancer is the malignant tumor with very poor prognosis and increasing incidence often diagnosed at very late stage, so the prognosis of affected patients is unsatisfactory, despite the development of therapeutic option such as surgery, chemotherapy and radiotherapy.	('miR-203', 'Gene', (68, 75))	('miR-148', 'Var', (56, 63))	('miR-29c', 'Gene', '407026', (47, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Esophageal cancer', 'Disease', (135, 152))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 121))	('miR-29c', 'Gene', (47, 54))	('patients', 'Species', '9606', (291, 299))	('miR-203', 'Gene', '406986', (68, 75))	('miR-21', 'Gene', '406991', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('Esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('carcinoma of esophagus Esophageal cancer', 'Phenotype', 'HP:0011459', (112, 152))	('malignant tumor', 'Disease', (160, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('miR-21', 'Gene', (39, 45))	('malignant tumor', 'Disease', 'MESH:D018198', (160, 175))
559132	25928282	MiR-203 and miR-148 were linked to disease-free survival and overall survival in esophageal adenocarcinoma patients, and miR-148 also in esophageal squamous cell carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('linked', 'Reg', (25, 31))	('esophageal squamous cell carcinoma', 'Disease', (137, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('esophageal adenocarcinoma', 'Disease', (81, 106))	('disease-free', 'Disease', (35, 47))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (137, 171))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (81, 106))	('MiR-203', 'Gene', '406986', (0, 7))	('miR-148', 'Var', (121, 128))	('MiR-203', 'Gene', (0, 7))	('miR-148', 'Chemical', '-', (121, 128))	('miR-148', 'Chemical', '-', (12, 19))	('patients', 'Species', '9606', (172, 180))	('miR-148', 'Gene', (12, 19))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (81, 106))	('patients', 'Species', '9606', (107, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
559133	25928282	Our data suggest that altered expression of miR-21, miR-29c, miR-148 and miR-203 are related to neoplastic transformation and progression of the disease and these microRNAs could serve as a potential diagnostic and prognostic biomarkers in esophageal cancer.	('miR-203', 'Gene', '406986', (73, 80))	('miR-29c', 'Gene', (52, 59))	('miR-203', 'Gene', (73, 80))	('expression', 'MPA', (30, 40))	('esophageal cancer', 'Disease', (240, 257))	('miR-148', 'Var', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('related', 'Reg', (85, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (240, 257))	('miR-21', 'Gene', '406991', (44, 50))	('progression', 'CPA', (126, 137))	('neoplastic transformation', 'Disease', (96, 121))	('neoplastic transformation', 'Disease', 'MESH:D002471', (96, 121))	('altered', 'Reg', (22, 29))	('miR-148', 'Chemical', '-', (61, 68))	('miR-29c', 'Gene', '407026', (52, 59))	('miR-21', 'Gene', (44, 50))
559154	25928282	To determine whether the selected miRNAs (miR-200c, miR-25, miR-27a, miR-7a, miR-29c, miR-203, miR-148a, miR-21 a miR-31) have a diagnostic potential, expression levels were analyzed for each miRNA in 17 EAC samples and 17 paired adjacent mucosa.	('miR-148a', 'Gene', (95, 103))	('miR-31', 'Gene', '407035', (114, 120))	('miR-148a', 'Gene', '406940', (95, 103))	('EAC', 'Phenotype', 'HP:0011459', (204, 207))	('miR-200c', 'Gene', '406985', (42, 50))	('miR-29c', 'Gene', (77, 84))	('miR-29c', 'Gene', '407026', (77, 84))	('miR-21', 'Gene', '406991', (105, 111))	('miR-25', 'Gene', '407014', (52, 58))	('miR-27a', 'Gene', (60, 67))	('miR-31', 'Gene', (114, 120))	('miR-25', 'Gene', (52, 58))	('miR-27a', 'Gene', '407018', (60, 67))	('miR-203', 'Gene', (86, 93))	('miR-200c', 'Gene', (42, 50))	('miR-7a', 'Var', (69, 75))	('miR-21', 'Gene', (105, 111))	('miR-203', 'Gene', '406986', (86, 93))
559157	25928282	To determine whether different expression levels of analyzed miRNAs exist in EAC and ESCC tissues, we performed qPCR analysis of selected miRNAs (miR-200c, miR-25, miR-27a, miR-7a, miR-29c, miR-203, miR-148a, miR-21 a miR-31) in 22 ESCC samples and 22 EAC samples.	('miR-31', 'Gene', '407035', (218, 224))	('miR-203', 'Gene', '406986', (190, 197))	('miR-27a', 'Gene', (164, 171))	('miR-21', 'Gene', '406991', (209, 215))	('miR-29c', 'Gene', '407026', (181, 188))	('EAC', 'Phenotype', 'HP:0011459', (252, 255))	('miR-25', 'Gene', '407014', (156, 162))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('miR-200c', 'Gene', '406985', (146, 154))	('miR-29c', 'Gene', (181, 188))	('miR-21', 'Gene', (209, 215))	('miR-200c', 'Gene', (146, 154))	('miR-31', 'Gene', (218, 224))	('miR-27a', 'Gene', '407018', (164, 171))	('miR-7a', 'Var', (173, 179))	('miR-25', 'Gene', (156, 162))	('miR-203', 'Gene', (190, 197))	('miR-148a', 'Gene', '406940', (199, 207))	('miR-148a', 'Gene', (199, 207))
559158	25928282	We found that miR-148 and miR-29c were decreased in ESCC when compared to EAC and have ability to significantly distinguish ESCC and EAC tissues (fold change 0,32; p = 0,0014; fold change 0,62; p = 0,0446), respectively (Figure 1C,D).	('EAC', 'Phenotype', 'HP:0011459', (74, 77))	('EAC', 'Phenotype', 'HP:0011459', (133, 136))	('miR-148', 'Chemical', '-', (14, 21))	('miR-29c', 'Gene', '407026', (26, 33))	('miR-29c', 'Gene', (26, 33))	('miR-148', 'Var', (14, 21))	('ESCC', 'Disease', (52, 56))	('decreased', 'NegReg', (39, 48))	('ESCC', 'Disease', (124, 128))
559178	25928282	Further, miR-29c and miR-148 have ability to distinguish between EAC and ESCC histological subtypes of esophageal cancer.	('miR-29c', 'Gene', (9, 16))	('miR-29c', 'Gene', '407026', (9, 16))	('esophageal cancer', 'Disease', (103, 120))	('miR-148', 'Var', (21, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('EAC', 'Phenotype', 'HP:0011459', (65, 68))	('distinguish', 'Reg', (45, 56))	('ESCC', 'Disease', (73, 77))	('miR-148', 'Chemical', '-', (21, 28))	('EAC', 'Disease', (65, 68))
559179	25928282	Moreover miR-203 and miR-148 could serve as prognostic biomarker in EAC, and miR-148 also in ESCC patients.	('miR-203', 'Gene', '406986', (9, 16))	('miR-148', 'Var', (21, 28))	('miR-203', 'Gene', (9, 16))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('patients', 'Species', '9606', (98, 106))	('miR-148', 'Var', (77, 84))	('miR-148', 'Chemical', '-', (77, 84))	('EAC', 'Disease', (68, 71))	('ESCC', 'Disease', (93, 97))	('miR-148', 'Chemical', '-', (21, 28))
559268	32083013	Survival at 12 months was almost doubled for nivolumab treated patients; this being 26.6% for nivolumab and 10.9% for patients treated with placebo.	('Survival', 'MPA', (0, 8))	('nivolumab', 'Var', (94, 103))	('nivolumab', 'Chemical', 'MESH:D000077594', (45, 54))	('patients', 'Species', '9606', (63, 71))	('doubled', 'PosReg', (33, 40))	('patients', 'Species', '9606', (118, 126))	('nivolumab', 'Chemical', 'MESH:D000077594', (94, 103))
559273	32083013	Similar results to nivolumab in gastric and gastroesophageal cancer have been demonstrated for pembrolizumab, which is a humanized immunoglobulin G4 monoclonal antibody targeting PD-1 which is licensed to treat melanoma, NSCLC and microsatellite unstable cancers of any tumor site.	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('PD-1', 'Gene', (179, 183))	('NSCLC', 'Disease', (221, 226))	('PD-1', 'Gene', '5133', (179, 183))	('human', 'Species', '9606', (121, 126))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('cancers', 'Disease', (255, 262))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('pembrolizumab', 'Chemical', 'MESH:C582435', (95, 108))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('microsatellite', 'Var', (231, 245))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancers', 'Disease', 'MESH:D009369', (255, 262))	('tumor', 'Disease', (270, 275))	('nivolumab', 'Chemical', 'MESH:D000077594', (19, 28))	('gastric and gastroesophageal cancer', 'Disease', 'MESH:D013274', (32, 67))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))
559303	32083013	Total bilirubin within normal limits (if the patient has documented Gilbert's disease <= 1.5 * ULN or direct bilirubin <= ULN).	('bilirubin', 'Chemical', 'MESH:D001663', (6, 15))	("Gilbert's disease", 'Disease', (68, 85))	('direct bilirubin', 'MPA', (102, 118))	('<= 1.5 *', 'Var', (86, 94))	('patient', 'Species', '9606', (45, 52))	('Total bilirubin', 'MPA', (0, 15))	('bilirubin', 'Chemical', 'MESH:D001663', (109, 118))
559339	32083013	Folic acid: multivitamin supplements containing folic acid should be avoided as it could potentially increase capecitabine toxicity.	('toxicity', 'Disease', (123, 131))	('folic acid', 'Chemical', 'MESH:D005492', (48, 58))	('capecitabine', 'Chemical', 'MESH:D000069287', (110, 122))	('increase', 'PosReg', (101, 109))	('Folic acid', 'Chemical', 'MESH:D005492', (0, 10))	('folic acid', 'Var', (48, 58))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))
559483	31516586	Human PRC1 includes polycomb (PC), polyhomeotic (PH), B-cell-specific Moloney murine leukemia virus integration site-1 (BMI1), RING1a and RING1b.	('Human', 'Species', '9606', (0, 5))	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('polycomb', 'Gene', (20, 28))	('RING1a', 'Var', (127, 133))	('Moloney murine leukemia virus', 'Species', '11801', (70, 99))	('BMI1', 'Gene', (120, 124))	('polycomb', 'Gene', '12416', (20, 28))	('RING1b', 'Gene', '6045', (138, 144))	('polyhomeotic', 'Disease', (35, 47))	('RING1b', 'Gene', (138, 144))	('BMI1', 'Gene', '648', (120, 124))
559487	31516586	A previous biological study revealed that silencing Ring finger protein 2 (RNF2) in esophageal cancer cells may lead to defects in DNA damage pathways, and therefore increase sensitivity to radiotherapy.	('silencing', 'Var', (42, 51))	('increase', 'PosReg', (166, 174))	('sensitivity to radiotherapy', 'MPA', (175, 202))	('lead to', 'Reg', (112, 119))	('DNA damage pathways', 'Pathway', (131, 150))	('RNF2', 'Gene', (75, 79))	('increase sensitivity to radiotherapy', 'Phenotype', 'HP:0011133', (166, 202))	('esophageal cancer', 'Disease', (84, 101))	('RNF2', 'Gene', '6045', (75, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('defects', 'NegReg', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Ring finger protein 2', 'Gene', (52, 73))	('Ring finger protein 2', 'Gene', '6045', (52, 73))
559541	31516586	In a previous study, it was revealed that the knockdown of BMI1 resulted in a DNA-damage response defect, and that the PI3K/AKT pathway could be perturbed to increase sensitivity to radiotherapy.	('defect', 'NegReg', (98, 104))	('sensitivity', 'MPA', (167, 178))	('increase sensitivity to radiotherapy', 'Phenotype', 'HP:0011133', (158, 194))	('perturbed', 'Reg', (145, 154))	('BMI1', 'Gene', '648', (59, 63))	('knockdown', 'Var', (46, 55))	('AKT', 'Gene', (124, 127))	('BMI1', 'Gene', (59, 63))	('DNA-damage response', 'MPA', (78, 97))	('increase', 'PosReg', (158, 166))	('AKT', 'Gene', '207', (124, 127))
559542	31516586	Therefore, it was hypothesized that RNF2 overexpression may increase radiotherapeutic resistance by activating the PI3K/AKT pathway.	('RNF2', 'Gene', (36, 40))	('AKT', 'Gene', (120, 123))	('activating', 'Reg', (100, 110))	('overexpression', 'Var', (41, 55))	('RNF2', 'Gene', '6045', (36, 40))	('radiotherapeutic resistance', 'CPA', (69, 96))	('increase', 'PosReg', (60, 68))	('AKT', 'Gene', '207', (120, 123))
559692	29933761	Approximately 50-70% of esophageal cancers harbor mutations in the TP53 gene (p53 protein) which is the most commonly mutated gene in cancer.	('esophageal cancers', 'Disease', (24, 42))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', (134, 140))	('esophageal cancers', 'Disease', 'MESH:D004938', (24, 42))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('p53', 'Gene', (78, 81))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('p53', 'Gene', '7157', (78, 81))	('cancer', 'Disease', (35, 41))
559694	29933761	EAC patients with p53 mutations respond poorly to chemotherapy and have worse outcomes after either surgery alone or nCRT.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('poorly', 'NegReg', (40, 46))	('mutations', 'Var', (22, 31))	('patients', 'Species', '9606', (4, 12))
559695	29933761	Evaluation of p53 mutations will help determine whether patients need different treatment strategies based on p53 status.	('patients', 'Species', '9606', (56, 64))	('p53', 'Gene', (110, 113))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', '7157', (110, 113))	('mutations', 'Var', (18, 27))
559701	29933761	To explore whether specific p53 mutations correlate with metabolomic signatures or BH3 profiles.	('p53', 'Gene', (28, 31))	('mutations', 'Var', (32, 41))	('BH3', 'Chemical', '-', (83, 86))	('p53', 'Gene', '7157', (28, 31))
559726	29933761	The secondary outcomes will be the association of overall survival (OS), disease-free survival (DFS), pathological stage (ypStage), and p53 mutational status with a metabolic signature.	('p53', 'Gene', '7157', (136, 139))	('p53', 'Gene', (136, 139))	('mutational status', 'Var', (140, 157))
559754	29933761	Mutations in the TP53 gene are detected in greater than 50% of esophageal cancers whereas the next most common mutations occur in less than 12% of esophageal cancers.	('detected', 'Reg', (31, 39))	('esophageal cancers', 'Disease', (147, 165))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('esophageal cancers', 'Disease', (63, 81))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('esophageal cancers', 'Disease', 'MESH:D004938', (147, 165))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Mutations', 'Var', (0, 9))	('esophageal cancers', 'Disease', 'MESH:D004938', (63, 81))	('TP53', 'Gene', '7157', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('TP53', 'Gene', (17, 21))
559755	29933761	Wild-type p53 has multiple functions including the induction of apoptosis whereas p53 mutations may block apoptosis and therefore 'unprime' a tumor cell.	('mutations', 'Var', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('p53', 'Gene', '7157', (10, 13))	("'unprime", 'PosReg', (130, 138))	('block', 'NegReg', (100, 105))	('tumor', 'Disease', (142, 147))	('apoptosis', 'CPA', (106, 115))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('p53', 'Gene', (10, 13))
559756	29933761	p53 mutations may affect both metabolomic signatures as well as BH3 profiling.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('metabolomic signatures', 'MPA', (30, 52))	('affect', 'Reg', (18, 24))	('BH3 profiling', 'MPA', (64, 77))	('BH3', 'Chemical', '-', (64, 67))	('mutations', 'Var', (4, 13))
559757	29933761	Therefore, all tumors will be sequenced for TP53 gene mutations and data analysis will account for the mutation type.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
559762	29933761	Alternatively, if p53 mutational status blocks apoptosis, inhibition of p53 may be required to increase the efficacy of standard nCRT.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('apoptosis', 'CPA', (47, 56))	('p53', 'Gene', (72, 75))	('inhibition', 'Var', (58, 68))	('p53', 'Gene', '7157', (72, 75))	('mutational status', 'Var', (22, 39))
559799	29379981	A total of seven cell lines, including six ESCC cell lines (KYSE30, KYSE70, KYSE150, KYSE180, KYSE450, and KYSE510) and the immortalized normal human esophageal epithelial cell line Het-1a, were used in this study.	('KYSE30', 'Var', (60, 66))	('KYSE180', 'CellLine', 'CVCL:1349', (85, 92))	('human', 'Species', '9606', (144, 149))	('KYSE150', 'Var', (76, 83))	('KYSE450', 'Var', (94, 101))	('KYSE180', 'Var', (85, 92))	('KYSE70', 'Var', (68, 74))	('KYSE510', 'Var', (107, 114))	('Het-1', 'CellLine', 'CVCL:3702', (182, 187))
559801	29379981	To inhibit TGF-beta and NF-kappaB signaling, we added 10 muM JSH-23 (Selleck, USA) or 5 muM SB505124 (Selleck, USA) to the cell culture media 30 min prior to the specified treatments.	('TGF-beta', 'Gene', '7040', (11, 19))	('TGF-beta', 'Gene', (11, 19))	('SB505124', 'Chemical', 'MESH:C519132', (92, 100))	('NF-kappaB', 'Gene', '4790', (24, 33))	('JSH-23', 'Gene', (61, 67))	('inhibit', 'NegReg', (3, 10))	('NF-kappaB', 'Gene', (24, 33))	('SB505124', 'Var', (92, 100))
559824	29379981	The results showed that SB505124 completely inhibited TGF-beta1-induced NKILA expression in KYSE30 and KYSE180 cells but not JSH-23 (Fig.	('SB505124', 'Var', (24, 32))	('inhibited', 'NegReg', (44, 53))	('NKILA', 'Gene', '105416157', (72, 77))	('NKILA', 'Gene', (72, 77))	('TGF-beta1', 'Gene', '7040', (54, 63))	('TGF-beta1', 'Gene', (54, 63))	('SB505124', 'Chemical', 'MESH:C519132', (24, 32))	('KYSE180', 'CellLine', 'CVCL:1349', (103, 110))
559852	29379981	Furthermore, we found that ectopic NKILA expression markedly inhibited TNF-alpha-induced p65 nuclear translocation in KYSE30 and KYSE180 cells compared with mock-vehicle control-transfected cells, while NKILA silencing significantly prolonged p65 translocation (to 24 h) in KYSE30 and KYSE180 cells compared with mock-vehicle control-transfected cells, results consistent with those mentioned above (Fig.	('KYSE180', 'CellLine', 'CVCL:1349', (129, 136))	('inhibited', 'NegReg', (61, 70))	('NKILA', 'Gene', '105416157', (203, 208))	('p65', 'Gene', (89, 92))	('prolonged', 'PosReg', (233, 242))	('p65', 'Gene', (243, 246))	('NKILA', 'Gene', '105416157', (35, 40))	('KYSE180', 'CellLine', 'CVCL:1349', (285, 292))	('TNF-alpha', 'Gene', '7124', (71, 80))	('NKILA', 'Gene', (203, 208))	('p65', 'Gene', '5970', (89, 92))	('p65', 'Gene', '5970', (243, 246))	('NKILA', 'Gene', (35, 40))	('TNF-alpha', 'Gene', (71, 80))	('silencing', 'Var', (209, 218))
559856	29379981	We found that MMP14 expression levels were remarkably attenuated by ectopic NKILA expression.	('ectopic', 'Var', (68, 75))	('attenuated', 'NegReg', (54, 64))	('NKILA', 'Gene', '105416157', (76, 81))	('MMP14', 'Gene', '4323', (14, 19))	('MMP14', 'Gene', (14, 19))	('NKILA', 'Gene', (76, 81))	('expression levels', 'MPA', (20, 37))
559857	29379981	In contrast, silencing NKILA elevated MMP14 expression levels in KYSE30 and KYSE180 cells (Fig.	('NKILA', 'Gene', (23, 28))	('elevated', 'PosReg', (29, 37))	('MMP14', 'Gene', '4323', (38, 43))	('NKILA', 'Gene', '105416157', (23, 28))	('MMP14', 'Gene', (38, 43))	('expression levels', 'MPA', (44, 61))	('KYSE180', 'CellLine', 'CVCL:1349', (76, 83))	('silencing', 'Var', (13, 22))
559869	29379981	In our study, we found that the lncRNA NKILA was dramatically induced by TGF-beta1 in KYSE30 and KYSE180 ESCC cells via RNA-seq, findings that were validated by RT-qPCR.	('NKILA', 'Gene', (39, 44))	('induced', 'PosReg', (62, 69))	('KYSE180', 'Var', (97, 104))	('TGF-beta1', 'Gene', '7040', (73, 82))	('TGF-beta1', 'Gene', (73, 82))	('NKILA', 'Gene', '105416157', (39, 44))	('KYSE30', 'Var', (86, 92))	('KYSE180', 'CellLine', 'CVCL:1349', (97, 104))
559967	29255373	Overexpression of parathyroid hormone-related protein (PTHrP) is associated with increased risk of bone metastases in small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('bone metastases', 'Disease', (99, 114))	('small cell lung cancer', 'Disease', 'MESH:D055752', (118, 140))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (118, 140))	('PTHrP', 'Gene', (55, 60))	('parathyroid hormone-related protein', 'Gene', '5744', (18, 53))	('Overexpression', 'Var', (0, 14))	('PTHrP', 'Gene', '5744', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('small cell lung cancer', 'Disease', (118, 140))	('parathyroid hormone-related protein', 'Gene', (18, 53))	('bone metastases', 'Disease', 'MESH:D009362', (99, 114))
560059	24013949	The -842G/C Polymorphisms of PIN1 Contributes to Cancer Risk: A Meta-Analysis of 10 Case-Control Studies Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) plays an important role in cancer development.	('Polymorphisms', 'Var', (12, 25))	('PIN1', 'Gene', (29, 33))	('cancer', 'Disease', (194, 200))	('PIN1', 'Gene', '5300', (161, 165))	('PIN1', 'Gene', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancer', 'Disease', (49, 55))	('-842G/C', 'Mutation', 'rs2233678', (4, 11))	('Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1', 'Gene', '5300', (105, 159))	('PIN1', 'Gene', '5300', (29, 33))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
560061	24013949	Overall, individuals with the variant CG (OR = 0.728, 95% CI: 0.585,0.906; Pheterogeneity<0.01) and CG/CC (OR = 0.731, 95% CI: 0.602,0.888; Pheterogeneity<0.01) genotypes were associated with a significantly reduced cancer risk compared with those with wild GG genotype.	('CG', 'Chemical', 'MESH:C028505', (38, 40))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('CG', 'Chemical', 'MESH:C028505', (100, 102))	('variant CG', 'Var', (30, 40))	('reduced', 'NegReg', (208, 215))	('CG/CC', 'Var', (100, 105))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))
560062	24013949	Sub-group analysis revealed that the variant CG (OR = 0.635, 95% CI: 0.548,0.735; Pheterogeneity = 0.240) and CG/CC (OR = 0.645, 95% CI: 0.559,0.744, Pheterogeneity = 0.258) genotypes still showed an reduced risk of cancer in Asians; while no significant association was observed in Caucasians (CG vs.GG: OR = 0.926, 95% CI: 0.572,1.499, Pheterogeneity<0.01; CG/CC vs. GG: OR = 0.892, 95% CI: 0.589,1.353; Pheterogeneity<0.01).	('CG', 'Chemical', 'MESH:C028505', (295, 297))	('CG', 'Chemical', 'MESH:C028505', (45, 47))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('reduced', 'NegReg', (200, 207))	('CG', 'Chemical', 'MESH:C028505', (359, 361))	('variant', 'Var', (37, 44))	('CG', 'Chemical', 'MESH:C028505', (110, 112))	('CG/CC', 'Var', (359, 364))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))
560064	24013949	It has been demonstrated that the deregulation of this mechanism can lead to cell transformation and tumorigenesis.	('deregulation', 'Var', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('lead to', 'Reg', (69, 76))	('cell transformation', 'CPA', (77, 96))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
560071	24013949	Several studies have investigated the relationship between the single nucleotide polymorphisms (SNP, -842G/C, rs2233678) in the PIN1 promoter region and risk of cancers, such as breast cancer, lung cancer, esophageal carcinoma, hepatocellular carcinoma, nasopharyngeal carcinoma, laryngeal squamous cell carcinoma, and squamous cell carcinoma of the head and neck.	('esophageal carcinoma', 'Disease', (206, 226))	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (228, 252))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (280, 313))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (319, 342))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('rs2233678', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('nasopharyngeal carcinoma', 'Disease', (254, 278))	('hepatocellular carcinoma', 'Disease', (228, 252))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (206, 226))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))	('squamous cell carcinoma', 'Disease', (319, 342))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (254, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('PIN1', 'Gene', '5300', (128, 132))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (333, 363))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (290, 313))	('laryngeal squamous cell carcinoma', 'Disease', (280, 313))	('rs2233678', 'Mutation', 'rs2233678', (110, 119))	('lung cancer', 'Disease', (193, 204))	('-842G/C', 'Mutation', 'rs2233678', (101, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (228, 252))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (254, 278))	('single nucleotide polymorphisms', 'Var', (63, 94))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (206, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('breast cancer', 'Disease', (178, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (319, 342))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (290, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('PIN1', 'Gene', (128, 132))
560073	24013949	Search terms included: "PIN1" or "rs2233678" in combination with "polymorphism" or "variant" and "cancer" or "neoplasm" or "malignancy".	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('"cancer', 'Disease', (97, 104))	('"cancer', 'Disease', 'MESH:D009369', (97, 104))	('"neoplasm" or "malignancy', 'Disease', 'MESH:D009369', (109, 134))	('PIN1', 'Gene', '5300', (24, 28))	('neoplasm', 'Phenotype', 'HP:0002664', (110, 118))	('rs2233678', 'Mutation', 'rs2233678', (34, 43))	('PIN1', 'Gene', (24, 28))	('rs2233678', 'Var', (34, 43))	('"neoplasm" or "malignancy', 'Disease', (109, 134))
560074	24013949	Studies were selected according to the following inclusion criteria: (1) case-control studies; (2) investigating the association between PIN1 rs2233678 (G>C) polymorphism and cancer risks; (3)cancers diagnosed by histopathology; (4) providing detail genotype frequencies.	('polymorphism', 'Var', (158, 170))	('PIN1', 'Gene', '5300', (137, 141))	('cancer', 'Disease', (175, 181))	('PIN1', 'Gene', (137, 141))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('rs2233678 (G>C) polymorphism', 'Var', (142, 170))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancer', 'Disease', (192, 198))	('cancers', 'Disease', (192, 199))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('rs2233678', 'Mutation', 'rs2233678', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
560079	24013949	The association strength between -842G>C (rs2233678) polymorphism and cancer risks was measured by odds ratio (OR) with 95% confidence intervals (95% CI).	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('rs2233678', 'Mutation', 'rs2233678', (42, 51))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('-842G>C', 'Mutation', 'rs2233678', (33, 40))	('rs2233678', 'Var', (42, 51))
560087	24013949	The association strength between -842G/C polymorphisms in the PIN1 promoter region and cancer risk was shown in Table 2.	('cancer', 'Disease', (87, 93))	('-842G/C', 'Mutation', 'rs2233678', (33, 40))	('polymorphisms', 'Var', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('PIN1', 'Gene', '5300', (62, 66))	('PIN1', 'Gene', (62, 66))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
560091	24013949	In the sub-group analyses of squamous cancer, and other cancers, we did find any significant association between -842G/C polymorphisms in the PIN1 promoter region and cancer risk.	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('-842G/C', 'Mutation', 'rs2233678', (113, 120))	('cancer', 'Disease', (167, 173))	('polymorphisms', 'Var', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (56, 62))	('PIN1', 'Gene', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (38, 44))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancers', 'Disease', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('squamous cancer', 'Phenotype', 'HP:0002860', (29, 44))	('squamous cancer', 'Disease', (29, 44))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('squamous cancer', 'Disease', 'MESH:D002294', (29, 44))	('PIN1', 'Gene', '5300', (142, 146))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
560093	24013949	However, for hospital-based studies, significant association between -842G/C polymorphisms in the PIN1 promoter region and reduced risks of cancers was found only in heterozygote comparison (CG vs GG: OR = 0.651, 95% CI: 0.572, 0.742; Pheterogeneity = 0.214), dominant model (CC/CG vs GG: OR = 0.671, 95% CI: 0.592, 0.762; Pheterogeneity = 0.194).	('PIN1', 'Gene', '5300', (98, 102))	('polymorphisms', 'Var', (77, 90))	('PIN1', 'Gene', (98, 102))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('CG', 'Chemical', 'MESH:C028505', (279, 281))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('-842G/C', 'Mutation', 'rs2233678', (69, 76))	('CG', 'Chemical', 'MESH:C028505', (191, 193))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('reduced', 'NegReg', (123, 130))
560102	24013949	This finding indicates that the genetic variant in PIN1 promoter region may crucially modify the susceptibility of cancers.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('genetic variant', 'Var', (32, 47))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('PIN1', 'Gene', '5300', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('PIN1', 'Gene', (51, 55))	('modify', 'Reg', (86, 92))
560105	24013949	Lu J et al found that the change from G to C may cause loss of the known gene-binding site that may regulate the PIN1 expression, and thereby deregulate its target protein leading to cancer development.	('protein', 'Protein', (164, 171))	('deregulate', 'NegReg', (142, 152))	('change', 'Var', (26, 32))	('cancer', 'Disease', (183, 189))	('loss', 'NegReg', (55, 59))	('gene-binding', 'Protein', (73, 85))	('PIN1', 'Gene', '5300', (113, 117))	('PIN1', 'Gene', (113, 117))	('regulate', 'Reg', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('leading to', 'Reg', (172, 182))	('expression', 'MPA', (118, 128))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
560108	24013949	However, we did not observe any significant association between the genetic variant and the susceptibility of other cancers.	('genetic variant', 'Var', (68, 83))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
560115	24013949	However, for hospital-based studies, no significant association between -842G/C polymorphisms in the PIN1 promoter region and risk of cancers was found in homozygote model, and recessive model.	('PIN1', 'Gene', (101, 105))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('-842G/C', 'Mutation', 'rs2233678', (72, 79))	('polymorphisms', 'Var', (80, 93))	('PIN1', 'Gene', '5300', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
560131	23476110	All procedures were performed by using EVIS LUCERA SPECTRUM system (Olympus, Tokyo, Japan) and high-resolution upper gastrointestinal endoscopes, either GIF-Q240Z or GIF-H260Z (Olympus) by 4 endoscopists (S.K., S.O., K.N., and S.M.)	('H260Z', 'SUBSTITUTION', 'None', (170, 175))	('Q240Z', 'Var', (157, 162))	('H260Z', 'Var', (170, 175))	('Q240Z', 'SUBSTITUTION', 'None', (157, 162))
560136	23476110	At the same time, esophageal iodine staining can lead to a transient dysphagia related to an esophagospasm, esophagitis, and gastritis.	('dysphagia', 'Disease', (69, 78))	('esophageal iodine staining', 'Var', (18, 44))	('dysphagia', 'Phenotype', 'HP:0002015', (69, 78))	('esophagitis', 'Phenotype', 'HP:0100633', (108, 119))	('esophagitis', 'Disease', (108, 119))	('gastritis', 'Disease', 'MESH:D005756', (125, 134))	('dysphagia', 'Disease', 'MESH:D003680', (69, 78))	('esophagitis', 'Disease', 'MESH:D004941', (108, 119))	('esophagospasm', 'Disease', (93, 106))	('lead to', 'Reg', (49, 56))	('gastritis', 'Phenotype', 'HP:0005263', (125, 134))	('gastritis', 'Disease', (125, 134))
560140	22759597	We report a case of advanced-stage SDP esophageal and gastric adenocarcinoma in which a complete response to treatment was obtained with S-1 and cis-diamminedichloroplatinum (CDDP).	('CDDP', 'Chemical', 'MESH:D002945', (175, 179))	('S-1', 'Gene', '5707', (137, 140))	('gastric adenocarcinoma', 'Disease', (54, 76))	('cis-diamminedichloroplatinum', 'Chemical', 'MESH:D002945', (145, 173))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (54, 76))	('cis-diamminedichloroplatinum', 'Var', (145, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('S-1', 'Gene', (137, 140))	('esophageal', 'Disease', (39, 49))
560213	22792097	Studies also suggest a higher risk for patients with long-segment Barrett's esophagus and a greater risk in men compared with women.	('women', 'Species', '9606', (126, 131))	('long-segment', 'Var', (53, 65))	("Barrett's esophagus", 'Disease', (66, 85))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (66, 85))
560215	22792097	Mutation in p53 gene was first described as a marker of poor prognosis, regardless of TNM status.	('p53', 'Gene', '7157', (12, 15))	('Mutation', 'Var', (0, 8))	('p53', 'Gene', (12, 15))
560227	22792097	Although well-differentiated tumors were less frequent in EGFR positive patients (44%) as opposed to 76% in EGFR negative, the difference was not statistically significant.	('tumors', 'Disease', (29, 35))	('EGFR', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('positive', 'Var', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('less', 'NegReg', (41, 45))	('tumors', 'Disease', 'MESH:D009369', (29, 35))
560230	22792097	Secondary findings included a relation between EGFR positivity and older age and predominance of GEJ compromising in spite of esophageal lesions.	('esophageal lesions', 'Disease', (126, 144))	('positivity', 'Var', (52, 62))	('GEJ compromising', 'Disease', (97, 113))	('esophageal lesions', 'Disease', 'MESH:D004935', (126, 144))	('EGFR', 'Gene', (47, 51))
560291	22760900	Thus, the SV diameters in patients with varices associated with PV-IVC shunts may be smaller than in those without shunts.	('smaller', 'NegReg', (85, 92))	('varices', 'Disease', (40, 47))	('patients', 'Species', '9606', (26, 34))	('shunts', 'Var', (71, 77))	('SV diameters', 'MPA', (10, 22))	('-IVC shunts', 'Phenotype', 'HP:0001693', (66, 77))
560352	32300688	In particular, low birth weight, seems to be interwoven with reduced muscle mass and strength in adult life and in this way with sarcopenia too.	('low birth weight', 'Var', (15, 31))	('reduced muscle mass', 'Phenotype', 'HP:0003199', (61, 80))	('sarcopenia', 'Disease', 'MESH:D055948', (129, 139))	('low birth weight', 'Phenotype', 'HP:0001518', (15, 31))	('sarcopenia', 'Disease', (129, 139))	('muscle mass', 'CPA', (69, 80))	('reduced', 'NegReg', (61, 68))
560355	32300688	Additionally, due to malfunctioned swallowing, patients show depressive symptoms and poor quality of life.	('malfunctioned swallowing', 'Phenotype', 'HP:0002015', (21, 45))	('depressive', 'Disease', 'MESH:D000275', (61, 71))	('malfunctioned', 'Var', (21, 34))	('depressive symptoms', 'Phenotype', 'HP:0000716', (61, 80))	('patients', 'Species', '9606', (47, 55))	('depressive', 'Disease', (61, 71))
560438	31632466	High-CLDN4 cells harbored stemness and cisplatin/concurrent chemoradiation therapy (CCRT) resistance properties and a high level of CLDN4 was correlated with poor prognosis and poor CCRT response in ESCC patients.	('patients', 'Species', '9606', (204, 212))	('ESCC', 'Disease', 'MESH:C562729', (199, 203))	('stemness', 'CPA', (26, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('High-CLDN4', 'Var', (0, 10))	('ESCC', 'Disease', (199, 203))
560461	31632466	Combinations of CCRT and TTFD provide a novel therapeutic strategy to improve the clinical outcome for ESCC patients in the future.	('ESCC', 'Disease', 'MESH:C562729', (103, 107))	('patients', 'Species', '9606', (108, 116))	('TTFD', 'Gene', (25, 29))	('Combinations', 'Var', (0, 12))	('improve', 'PosReg', (70, 77))	('TTFD', 'Chemical', 'MESH:D005666', (25, 29))	('ESCC', 'Disease', (103, 107))
560480	31632466	To investigate the role of CSCs in ESCC, the KYSE70, CE48T, and KYSE170 cell lines were cultured in ultra-low attachment plates to establish tumorspheres.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('ESCC', 'Disease', 'MESH:C562729', (35, 39))	('ESCC', 'Disease', (35, 39))	('CE48T', 'Var', (53, 58))
560514	31632466	Among these genes, CLDN4 exhibited high level in KYSE70, CE48T, and KYSE170-derived spheroid cells, and was correlated with poor survival in esophagus and breast cancers (Figure 3(a) and Supplemental Data 3(a)).	('CE48T', 'Var', (57, 62))	('CLDN4', 'Gene', (19, 24))	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('esophagus', 'Disease', (141, 150))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('breast cancers', 'Disease', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('KYSE70', 'Var', (49, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('correlated with', 'Reg', (108, 123))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('poor', 'NegReg', (124, 128))
560518	31632466	The tumorsphere assay was also performed to examine stemness in both high-CLDN4 and low-CLDN4 cells.	('high-CLDN4', 'Var', (69, 79))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('low-CLDN4', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
560519	31632466	High-CLDN4, but not low-CLDN4 cells showed 40-50% tumorsphere formation ability and maintained stemness in the first and second passage in 3D culture (Figure 3(e)).	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('High-CLDN4', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('stemness', 'CPA', (95, 103))
560520	31632466	Limiting dilution cell transplantation assays were used to determine the tumor initiation ability of high-CLDN4 and low-CLDN4 cells.	('low-CLDN4', 'Var', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('high-CLDN4', 'Var', (101, 111))	('tumor initiation ability', 'Disease', (73, 97))	('tumor initiation ability', 'Disease', 'MESH:D009369', (73, 97))
560521	31632466	The results demonstrated that 10 high-CLDN4 cells can initiate tumor formation in 1 out of 3 mice.	('tumor', 'Disease', (63, 68))	('high-CLDN4 cells', 'Var', (33, 49))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mice', 'Species', '10090', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
560522	31632466	Tumor formation was also observed in mice injected with 100-10,000 high-CLDN4 cells, suggesting that high-CLDN4 cells, exhibit tumor initiation ability.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor initiation ability', 'Disease', (127, 151))	('high-CLDN4', 'Var', (101, 111))	('tumor initiation ability', 'Disease', 'MESH:D009369', (127, 151))	('mice', 'Species', '10090', (37, 41))
560529	31632466	In combination, the data indicates that CLDN4 can serve as a biomarker for cancer stem-like ESCC cells, and high-CLDN4 cells carry tumor initiation and CCRT resistance properties.	('high-CLDN4', 'Var', (108, 118))	('ESCC', 'Disease', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('tumor initiation', 'Disease', 'MESH:D009369', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Disease', (75, 81))	('tumor initiation', 'Disease', (131, 147))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))	('CCRT resistance properties', 'CPA', (152, 178))
560531	31632466	The results demonstrated that patients with high levels of CLDN4 generally had poor survival and early recurrence, even if they had the early-stage disease, suggesting that CLDN4 can serve as a prognostic biomarker for ESCC patients.	('high', 'Var', (44, 48))	('ESCC', 'Disease', 'MESH:C562729', (219, 223))	('patients', 'Species', '9606', (30, 38))	('ESCC', 'Disease', (219, 223))	('patients', 'Species', '9606', (224, 232))	('poor', 'NegReg', (79, 83))	('survival', 'CPA', (84, 92))
560533	31632466	This would explain why and how ESCC patients with high CLDN4 expression showed high recurrence rates after CCRT treatment.	('patients', 'Species', '9606', (36, 44))	('ESCC', 'Disease', 'MESH:C562729', (31, 35))	('ESCC', 'Disease', (31, 35))	('high', 'Var', (50, 54))	('CLDN4', 'Gene', (55, 60))
560543	31632466	CLDN4 mRNA and protein levels were also downregulated by TTFD treatment, but not other small molecules (Figure 5(c) and Supplemental Data 6(b) and (c).	('downregulated', 'NegReg', (40, 53))	('treatment', 'Var', (62, 71))	('TTFD', 'Gene', (57, 61))	('TTFD', 'Chemical', 'MESH:D005666', (57, 61))
560549	31632466	The tumor burden was significantly decreased in the TTFD treatment group (100 mm3, TTFD + CCRT) compared with the control group (300 mm3, CCRT only) after treatment for 4 weeks (Figure 5(g)).	('tumor', 'Disease', (4, 9))	('100 mm3', 'Var', (74, 81))	('TTFD', 'Var', (52, 56))	('decreased', 'NegReg', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TTFD', 'Chemical', 'MESH:D005666', (83, 87))	('TTFD', 'Chemical', 'MESH:D005666', (52, 56))
560550	31632466	Overall the authors demonstrated that TTFD can diminish stemness and enhance CCRT efficacy in ESCC.	('TTFD', 'Var', (38, 42))	('enhance', 'PosReg', (69, 76))	('TTFD', 'Chemical', 'MESH:D005666', (38, 42))	('ESCC', 'Disease', 'MESH:C562729', (94, 98))	('diminish', 'NegReg', (47, 55))	('stemness', 'CPA', (56, 64))	('CCRT efficacy', 'CPA', (77, 90))	('ESCC', 'Disease', (94, 98))
560552	31632466	CSCs are known to promote tumor initiation, metastasis, and drug resistance in a number of cancers.	('CSCs', 'Var', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('drug resistance', 'Phenotype', 'HP:0020174', (60, 75))	('cancers', 'Disease', (91, 98))	('tumor initiation', 'Disease', 'MESH:D009369', (26, 42))	('metastasis', 'CPA', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor initiation', 'Disease', (26, 42))	('drug resistance', 'CPA', (60, 75))	('promote', 'PosReg', (18, 25))
560555	31632466	This data also revealed that CLDN4, a surface protein, was significantly increased in spheroid cells, which suggests that CLDN4 can serve as a marker of stem-like ESCC cells.	('increased', 'PosReg', (73, 82))	('ESCC', 'Disease', (163, 167))	('CLDN4', 'Gene', (29, 34))	('CLDN4', 'Var', (122, 127))	('ESCC', 'Disease', 'MESH:C562729', (163, 167))
560558	31632466	Overall the authors' data reveals that high-CLDN4 cancer stem-like ESCC cells are responsible for tumor initiation, metastasis, and drug resistance properties in vitro and in vivo.	('ESCC', 'Disease', (67, 71))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('high-CLDN4', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor initiation', 'Disease', 'MESH:D009369', (98, 114))	('drug resistance', 'Phenotype', 'HP:0020174', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ESCC', 'Disease', 'MESH:C562729', (67, 71))	('tumor initiation', 'Disease', (98, 114))
560561	31632466	In combination, the authors demonstrated that high-CLDN4 cancer stem-like ESCC cells harbored tumor initiation, metastasis, and CCRT resistance properties and that TTFD can diminish stemness as well as improve CCRT response in ESCC.	('harbored tumor initiation', 'Disease', 'MESH:C537062', (85, 110))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('TTFD', 'Var', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', (57, 63))	('ESCC', 'Disease', (74, 78))	('ESCC', 'Disease', 'MESH:C562729', (227, 231))	('improve', 'PosReg', (202, 209))	('metastasis', 'CPA', (112, 122))	('high-CLDN4', 'Var', (46, 56))	('diminish', 'NegReg', (173, 181))	('harbored tumor initiation', 'Disease', (85, 110))	('stemness', 'CPA', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('ESCC', 'Disease', 'MESH:C562729', (74, 78))	('CCRT response', 'CPA', (210, 223))	('TTFD', 'Chemical', 'MESH:D005666', (164, 168))	('ESCC', 'Disease', (227, 231))
560572	31632466	In addition, the authors found that high-CLDN4 cells were shown to harbor tumor initiation, metastasis, and CCRT resistance capabilities (Figures 3 and 4).	('harbor tumor initiation', 'Disease', (67, 90))	('metastasis', 'CPA', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('high-CLDN4', 'Var', (36, 46))	('harbor tumor initiation', 'Disease', 'MESH:C537062', (67, 90))	('CCRT resistance capabilities', 'CPA', (108, 136))
560573	31632466	Moreover, high-CLDN4 cells were enriched under the selective pressure of CCRT treatment, and CLDN4 was correlated with poor prognosis and early recurrence, even in early disease ESCC.	('ESCC', 'Disease', (178, 182))	('ESCC', 'Disease', 'MESH:C562729', (178, 182))	('CLDN4', 'Var', (93, 98))
560584	31632466	This theory is consistent with this study's results that show high-CLDN4 cancer stem-like ESCC cells cause treatment failure.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ESCC', 'Disease', 'MESH:C562729', (90, 94))	('ESCC', 'Disease', (90, 94))	('high-CLDN4', 'Var', (62, 72))
560586	31632466	The authors' revealed that TTFD, a disulfide derivative of thiamine, can reverse the stemness gene profile, downregulate CLDN4 levels, and diminish stemness potential (Figure 5).	('thiamine', 'Chemical', 'MESH:D013831', (59, 67))	('TTFD', 'Var', (27, 31))	('reverse', 'NegReg', (73, 80))	('disulfide', 'Chemical', 'MESH:D004220', (35, 44))	('CLDN4 levels', 'MPA', (121, 133))	('diminish', 'NegReg', (139, 147))	('stemness potential', 'CPA', (148, 166))	('downregulate', 'NegReg', (108, 120))	('TTFD', 'Chemical', 'MESH:D005666', (27, 31))	('stemness gene profile', 'Gene', (85, 106))
560614	29163691	As inhibition of the Akt/mTOR signaling pathway is known to activate autophagy, it is hypothesized that there is an association between autophagy and Endostar treatment in ESCC therapy.	('association', 'Interaction', (116, 127))	('autophagy', 'CPA', (69, 78))	('inhibition', 'Var', (3, 13))	('Akt', 'Gene', '207', (21, 24))	('ESCC', 'Disease', (172, 176))	('Akt', 'Gene', (21, 24))	('mTOR', 'Gene', '2475', (25, 29))	('activate', 'PosReg', (60, 68))	('mTOR', 'Gene', (25, 29))
560702	28143873	Within the context of cancer, particularly GI malignancies, 'epigenetic' alterations together with genetic events, have emerged as key drivers of disease development and progression.	("'epigenetic' alterations", 'Var', (60, 84))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('GI malignancies', 'Disease', (43, 58))	('GI malignancies', 'Disease', 'MESH:D009369', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
560703	28143873	In cancer, the most well-investigated epigenetic alterations include aberrant DNA methylation, histone modifications, and dysregulated expression of non-coding RNAs.	('aberrant', 'Var', (69, 77))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('histone modifications', 'MPA', (95, 116))	('expression', 'MPA', (135, 145))	('DNA', 'Protein', (78, 81))	('dysregulated', 'Var', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
560704	28143873	Epigenetic alterations manifest far more frequently than genetic mutations and often appear in early stages of tumorigenesis.	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('appear', 'Reg', (85, 91))
560708	28143873	Among noncoding RNAs (ncRNAs), dysregulated expression of microRNAs (miRNAs) have been most widely studied over the last decade, and they appear to be promising diagnostic biomarkers for a variety of human cancers, including GI malignancies.	('dysregulated', 'Var', (31, 43))	('GI malignancies', 'Disease', (225, 240))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('GI malignancies', 'Disease', 'MESH:D009369', (225, 240))	('miR', 'Gene', '220972', (69, 72))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('miR', 'Gene', (69, 72))	('human', 'Species', '9606', (200, 205))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))
560710	28143873	From a clinical standpoint, dysregulated expression of miRNAs have been readily detected in a variety of biological fluids in cancer patients, highlighting their stability in these biofluids and providing a rationale for developing them as 'liquid biopsy' biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('dysregulated', 'Var', (28, 40))	('clinical', 'Species', '191496', (7, 15))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))
560811	23741270	Although, stenosis of the central airway can deteriorate the functional and clinical statuses of patients, and lead to severe morbidity with impending respiratory failure, the available definite therapeutic options are limited.	('stenosis', 'Var', (10, 18))	('deteriorate', 'NegReg', (45, 56))	('respiratory failure', 'Disease', (151, 170))	('respiratory failure', 'Disease', 'MESH:D012131', (151, 170))	('functional', 'CPA', (61, 71))	('respiratory failure', 'Phenotype', 'HP:0002878', (151, 170))	('lead to', 'Reg', (111, 118))	('morbidity', 'MPA', (126, 135))	('patients', 'Species', '9606', (97, 105))
560906	33575873	This virus and the related virus, ONYX-015, can replicate effectively in cancer cells with a dysfunctional (absent or mutated) p53 tumor suppressor gene.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('dysfunctional', 'Disease', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('mutated', 'Var', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (131, 136))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))	('dysfunctional', 'Disease', 'MESH:D009461', (93, 106))
560934	33575873	Deletion of these genes or others targeting various mechanisms within the NF-kappaB pathway can influence NF-kappaB activation and downstream neutrophil recruitment.	('NF-kappaB', 'Gene', '4790', (106, 115))	('NF-kappaB', 'Gene', (74, 83))	('NF-kappaB', 'Gene', (106, 115))	('activation', 'PosReg', (116, 126))	('men', 'Species', '9606', (160, 163))	('influence', 'Reg', (96, 105))	('NF-kappaB', 'Gene', '4790', (74, 83))	('Deletion', 'Var', (0, 8))
560954	33575873	Overall, Ad-p53 gene transfer is well tolerated by patients, with minimal side effects but no change in survival.	('gene transfer', 'Var', (16, 29))	('p53', 'Gene', '7157', (12, 15))	('patients', 'Species', '9606', (51, 59))	('p53', 'Gene', (12, 15))
560979	33575873	Four copies of the miRNA145 target sequence were incorporated into the 3'-untranslated region of ICP27 to create an AP27i145 amplicon virus.	('AP27i145', 'Chemical', '-', (116, 124))	('AP27i145', 'Var', (116, 124))	('miRNA145', 'Gene', (19, 27))	('miRNA145', 'Gene', '406937', (19, 27))
560981	33575873	The cytotoxicity of AP27i145 was significantly stronger than that of 5dl1.2, at an MOI of 0.01 in A549 and H460 cells (p < 0.05 in both comparisons).	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('AP27i145', 'Var', (20, 28))	('stronger', 'PosReg', (47, 55))	('AP27i145', 'Chemical', '-', (20, 28))	('cytotoxicity', 'Disease', (4, 16))	('H460', 'CellLine', 'CVCL:0459', (107, 111))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
560983	33575873	These findings suggest that AP27i145 may have selective cytotoxicity in NSCLC cell lines and may be of potential value.	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('NSCLC', 'Disease', (72, 77))	('AP27i145', 'Var', (28, 36))	('SCLC', 'Phenotype', 'HP:0030357', (73, 77))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('AP27i145', 'Chemical', '-', (28, 36))	('cytotoxicity', 'Disease', (56, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
560984	33575873	Many studies have used oncolytic adenovirus (oAdv) variants in lung cancer models, and several strategies have been used to improve the efficacy of these viruses.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('adenovirus', 'Species', '10508', (33, 43))	('variants', 'Var', (51, 59))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))
560987	33575873	In vitro, CVB3 induced cell apoptosis and cell survival, signaling pathways associated with phosphoinositide 3-kinase/Akt and mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) pathways, leading to cytotoxicity and regulation of CVB3 replication.	('cell apoptosis', 'CPA', (23, 37))	('cytotoxicity', 'Disease', (229, 241))	('CVB3', 'Species', '12072', (10, 14))	('MEK', 'Gene', (203, 206))	('cell survival', 'CPA', (42, 55))	('leading to', 'Reg', (218, 228))	('regulation', 'MPA', (246, 256))	('Akt', 'Gene', (118, 121))	('extracellular signal-regulated (ERK) kinase', 'Gene', 'None', (158, 201))	('cytotoxicity', 'Disease', 'MESH:D064420', (229, 241))	('MEK', 'Gene', '5609', (203, 206))	('CVB3', 'Gene', (260, 264))	('replication', 'MPA', (265, 276))	('CVB3', 'Species', '12072', (260, 264))	('Akt', 'Gene', '207', (118, 121))	('CVB3', 'Var', (10, 14))
560991	33575873	Some investigators have used thymidine kinase (TK) deletion alone, whereas others have used viruses with dual deletion of viral genes encoding both TK and the viral growth factor B18R- or dual deletion of viral genes encoding TK- and viral growth factor (VGF).	('VGF', 'Gene', '7425', (255, 258))	('B18R', 'SUBSTITUTION', 'None', (179, 183))	('dual deletion', 'Var', (188, 201))	('thymidine kinase', 'Gene', (29, 45))	('thymidine kinase', 'Gene', '3707550', (29, 45))	('deletion', 'Var', (51, 59))	('B18R', 'Var', (179, 183))	('VGF', 'Gene', (255, 258))
560992	33575873	These genetic modifications aim to enhance tumor selectivity while retaining potency when infecting tumor but not normal cells.	('modifications', 'Var', (14, 27))	('potency', 'MPA', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('enhance', 'PosReg', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
560994	33575873	An oncolytic VV mutant (TK-/B18R-/INFbeta +) (VV.mIFNbeta) was used in subcutaneous murine models of the NSCLC cell lines, TC-1 and LKRM2.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('B18R', 'Var', (28, 32))	('murine', 'Species', '10090', (84, 90))	('VV', 'Species', '10245', (13, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('B18R', 'SUBSTITUTION', 'None', (28, 32))	('IFNbeta', 'Gene', '3439', (50, 57))	('VV', 'Species', '10245', (46, 48))	('IFNbeta', 'Gene', (50, 57))	('TC-1', 'CellLine', 'CVCL:1F93', (123, 127))	('NSCLC', 'Disease', (105, 110))	('SCLC', 'Phenotype', 'HP:0030357', (106, 110))
561012	33575873	Intraperitoneal injection with vvDD-IL-2 but no linker led to IL-2 toxicity, with serum IL-2 levels 100 times higher than mice treated with membrane-bound forms.	('mice', 'Species', '10090', (122, 126))	('vvDD-IL-2', 'Var', (31, 40))	('IL-2', 'Gene', (62, 66))	('serum IL-2 levels', 'MPA', (82, 99))	('higher', 'PosReg', (110, 116))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))	('toxicity', 'Disease', (67, 75))
561021	33575873	Recently, a preclinical study using a murine orthotopic esophageal cancer xenograft model demonstrated that intra-tumoral injection of the adenovirus telomelysin plus regional irradiation induced tumor cell-specific radiosensitization, which has prompted phases 1 and 2 clinical trials.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('murine', 'Species', '10090', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (196, 201))	('adenovirus', 'Species', '10508', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('telomelysin', 'Var', (150, 161))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
561028	33575873	Intra-tumoral injection of NV1066 decreased progression of subcutaneous tumors by 77% at 4 weeks compared with PBS-treated mice (p < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PBS', 'Chemical', '-', (111, 114))	('progression', 'CPA', (44, 55))	('decreased', 'NegReg', (34, 43))	('tumor', 'Disease', (72, 77))	('tumors', 'Disease', (72, 78))	('NV1066', 'Chemical', '-', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('NV1066', 'Var', (27, 33))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (59, 78))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('mice', 'Species', '10090', (123, 127))
561029	33575873	Intraperitoneal injection of NV1066 decreased tumor burden by 73% after 4 weeks versus treatment with PBS alone (p < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PBS', 'Chemical', '-', (102, 105))	('NV1066', 'Chemical', '-', (29, 35))	('decreased tumor', 'Disease', (36, 51))	('men', 'Species', '9606', (92, 95))	('NV1066', 'Var', (29, 35))	('decreased tumor', 'Disease', 'MESH:D002303', (36, 51))
561043	33575873	Oncorine (H101) in combination with chemotherapy is approved for patients with nasopharyngeal carcinoma in China, and Imlygic(T-VEC) is approved to treat stage 3b IVM1c melanoma in the United States, Europe, and Australia.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (79, 103))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('H101', 'Chemical', '-', (10, 14))	('carcinoma', 'Disease', (94, 103))	('patients', 'Species', '9606', (65, 73))	('Oncorine', 'Chemical', '-', (0, 8))	('IVM1c', 'Var', (163, 168))	('carcinoma', 'Disease', 'MESH:D009369', (94, 103))
561051	33435156	The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer Cancer is a global health concern, and the prognosis of patients with cancer is associated with metastasis.	('Cancer', 'Disease', 'MESH:D009369', (92, 98))	('Cancer', 'Disease', (92, 98))	('cancer', 'Disease', (169, 175))	('Cancer', 'Disease', 'MESH:D009369', (99, 105))	('Cancer', 'Disease', (99, 105))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Anchorage-Independent', 'CPA', (60, 81))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Noncoding', 'Var', (12, 21))	('patients', 'Species', '9606', (155, 163))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
561073	33435156	Also, knockdown of Beclin-1 (BECN1), a mediator of autophagy, attenuates anoikis resistance, thereby inhibiting the spheroid formation of cancer cells under anchorage-independent conditions.	('Beclin-1', 'Gene', (19, 27))	('BECN1', 'Gene', (29, 34))	('cancer', 'Disease', (138, 144))	('Beclin-1', 'Gene', '8678', (19, 27))	('attenuates', 'NegReg', (62, 72))	('BECN1', 'Gene', '8678', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('knockdown', 'Var', (6, 15))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('anoikis resistance', 'CPA', (73, 91))	('inhibiting', 'NegReg', (101, 111))
561075	33435156	Inhibition of FAK using genetic and pharmacological approaches weakens anoikis resistance as well as metastasis.	('weakens', 'NegReg', (63, 70))	('anoikis resistance', 'CPA', (71, 89))	('FAK', 'Gene', '5747', (14, 17))	('metastasis', 'CPA', (101, 111))	('Inhibition', 'Var', (0, 10))	('FAK', 'Gene', (14, 17))
561084	33435156	A recent study also demonstrated that high expression of miR-21-5p is associated with poor overall survival and lymph node metastasis in patients with esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('high expression', 'Var', (38, 53))	('lymph node metastasis', 'CPA', (112, 133))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('rat', 'Species', '10116', (27, 30))	('expression', 'Species', '29278', (43, 53))	('overall survival', 'CPA', (91, 107))	('miR-21-5p', 'Gene', (57, 66))	('miR-21-5p', 'Gene', '406997', (57, 66))	('poor', 'NegReg', (86, 90))
561086	33435156	It was also found that the overexpression or knockdown of miR-21-5p promotes or impedes liver metastases in vivo, respectively.	('liver metastases', 'Disease', 'MESH:D009362', (88, 104))	('impedes', 'NegReg', (80, 87))	('miR-21-5p', 'Gene', (58, 67))	('promotes', 'PosReg', (68, 76))	('miR-21-5p', 'Gene', '406997', (58, 67))	('expression', 'Species', '29278', (31, 41))	('liver metastases', 'Disease', (88, 104))	('overexpression', 'PosReg', (27, 41))	('knockdown', 'Var', (45, 54))
561087	33435156	In retinoblastoma, PTEN is also targeted by miR-25-3p (a member of the miR-106b-25 cluster), thereby activating PI3K/Akt signaling and anchorage-independent cell growth.	('miR-25-3p', 'Var', (44, 53))	('Akt', 'Gene', (117, 120))	('miR-106', 'Gene', (71, 78))	('retinoblastoma', 'Disease', 'MESH:D012175', (3, 17))	('PTEN', 'Gene', (19, 23))	('retinoblastoma', 'Phenotype', 'HP:0009919', (3, 17))	('PTEN', 'Gene', '5728', (19, 23))	('miR-106', 'Gene', '406899', (71, 78))	('anchorage-independent cell growth', 'CPA', (135, 168))	('Akt', 'Gene', '207', (117, 120))	('activating', 'PosReg', (101, 111))	('miR-25-3p', 'Chemical', '-', (44, 53))	('retinoblastoma', 'Disease', (3, 17))
561088	33435156	Knockdown of miR-25-3p increases the expression of cleaved caspase-3 as well as the induction of apoptosis in vitro.	('caspase-3', 'Gene', '836', (59, 68))	('miR-25-3p', 'Var', (13, 22))	('expression', 'Species', '29278', (37, 47))	('cleaved', 'MPA', (51, 58))	('caspase-3', 'Gene', (59, 68))	('expression', 'MPA', (37, 47))	('increases', 'PosReg', (23, 32))	('apoptosis', 'CPA', (97, 106))	('miR-25-3p', 'Chemical', '-', (13, 22))
561089	33435156	Moreover, it was observed that miR-25-3p accelerates cancer growth, which can be abolished by PTEN restoration or PI3K inhibition in vivo (Figure 1 and Table 1).	('PTEN', 'Gene', (94, 98))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('PTEN', 'Gene', '5728', (94, 98))	('miR-25-3p', 'Chemical', '-', (31, 40))	('miR-25-3p', 'Var', (31, 40))	('rat', 'Species', '10116', (47, 50))	('accelerates', 'PosReg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('rat', 'Species', '10116', (104, 107))
561093	33435156	The relationship between miR-141-3p and metastasis has been explored in cancer.	('miR-141-3p', 'Chemical', '-', (25, 35))	('miR-141-3p', 'Var', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
561094	33435156	For example, exosomal miR-141-3p derived from prostate cancer cells activates osteogenesis, thus facilitating the bone metastasis of prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('prostate cancer', 'Disease', (46, 61))	('facilitating', 'PosReg', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('bone metastasis of prostate cancer', 'Disease', 'MESH:D011471', (114, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('osteogenesis', 'Disease', (78, 90))	('osteogenesis', 'Disease', 'MESH:D010013', (78, 90))	('exosomal', 'Var', (13, 21))	('miR-141-3p', 'Chemical', '-', (22, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (46, 61))	('activates', 'PosReg', (68, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (46, 61))	('bone metastasis of prostate cancer', 'Disease', (114, 148))	('prostate cancer', 'Disease', 'MESH:D011471', (133, 148))
561096	33435156	In addition, miR-141-3p is overexpressed in ovarian cancer tissues, and this miRNA can augment anchorage-independent cell growth and anoikis resistance by suppressing the expression of Kruppel-like factor 12 (KLF12), which interferes with Sp1-activated transcription of the survivin gene.	('expression', 'MPA', (171, 181))	('miR-141-3p', 'Chemical', '-', (13, 23))	('KLF12', 'Gene', '11278', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian cancer', 'Disease', 'MESH:D010051', (44, 58))	('anoikis resistance', 'CPA', (133, 151))	('augment', 'PosReg', (87, 94))	('survivin gene', 'Gene', (274, 287))	('KLF12', 'Gene', (209, 214))	('suppressing', 'NegReg', (155, 166))	('ovarian cancer', 'Disease', (44, 58))	('miR-141-3p', 'Var', (13, 23))	('anchorage-independent cell growth', 'CPA', (95, 128))	('expression', 'Species', '29278', (171, 181))	('ovarian cancer', 'Phenotype', 'HP:0100615', (44, 58))
561097	33435156	It was also observed that miR-141-3p stimulates the growth of metastatic ovarian cancer cells in vivo (Figure 1 and Table 1).	('metastatic ovarian cancer', 'Disease', 'MESH:D018223', (62, 87))	('miR-141-3p', 'Var', (26, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('miR-141-3p', 'Chemical', '-', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('metastatic ovarian cancer', 'Disease', (62, 87))	('stimulates', 'PosReg', (37, 47))
561104	33435156	In that study, it was also denoted that human papillomavirus E6/E7 oncoproteins increase the level of miR-146-3p, which targets HPGD and supports the anchorage-independent growth of cancer cells (Figure 1 and Table 1).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('anchorage-independent growth', 'CPA', (150, 178))	('supports', 'PosReg', (137, 145))	('increase', 'PosReg', (80, 88))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('miR-146-3p', 'Var', (102, 112))	('cancer', 'Disease', (182, 188))	('E6/E7', 'Var', (61, 66))	('human papillomavirus', 'Species', '10566', (40, 60))
561128	33435156	Anchorage-independent cell growth resulted from the knockdown of NFKB2 can be reversed by miR-494 inhibition, supporting that miR-494 undeviatingly promotes cancer progression (Figure 1 and Table 1).	('miR-494', 'Gene', '574452', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('miR-494', 'Gene', (126, 133))	('miR-494', 'Gene', '574452', (90, 97))	('miR-494', 'Gene', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('NFKB2', 'Gene', (65, 70))	('cancer', 'Disease', (157, 163))	('promotes', 'PosReg', (148, 156))	('knockdown', 'Var', (52, 61))
561129	33435156	Screening of miRNAs identified that miR-645 is one of the upregulated miRNAs in colorectal cancer tissues.	('rectal cancer', 'Phenotype', 'HP:0100743', (84, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('upregulated', 'PosReg', (58, 69))	('miR-645', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))
561132	33435156	In line with this, another study also denoted that miR-645 facilitates liver metastasis of colorectal cancer in a mouse xenograft model (Figure 1 and Table 1).	('miR-645', 'Var', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('metastasis of colorectal cancer', 'Disease', 'MESH:D015179', (77, 108))	('facilitates', 'PosReg', (59, 70))	('rectal cancer', 'Phenotype', 'HP:0100743', (95, 108))	('metastasis of colorectal cancer', 'Disease', (77, 108))	('mouse', 'Species', '10090', (114, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('liver metastasis', 'Disease', 'MESH:D009362', (71, 87))	('liver metastasis', 'Disease', (71, 87))
561133	33435156	Several studies demonstrated that miR-27-3p promotes and suppresses the metastasis of pancreatic cancer and hepatocellular carcinoma, respectively, suggesting the dual role of this miRNA in a cellular context-dependent manner.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (108, 132))	('promotes', 'PosReg', (44, 52))	('metastasis', 'CPA', (72, 82))	('hepatocellular carcinoma', 'Disease', (108, 132))	('suppresses', 'NegReg', (57, 67))	('miR-27-3p', 'Var', (34, 43))	('pancreatic cancer', 'Disease', (86, 103))	('miR-27-3p', 'Chemical', '-', (34, 43))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (108, 132))	('rat', 'Species', '10116', (23, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
561134	33435156	Another study showed that the anchorage-independent growth of osteosarcoma cells is accelerated by miR-27-3p, whose expression is upregulated in cancer cells in comparison with normal osteocyte cells.	('upregulated', 'PosReg', (130, 141))	('cancer', 'Disease', (145, 151))	('expression', 'MPA', (116, 126))	('miR-27-3p', 'Var', (99, 108))	('miR-27-3p', 'Chemical', '-', (99, 108))	('accelerated', 'PosReg', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('osteosarcoma', 'Phenotype', 'HP:0002669', (62, 74))	('osteosarcoma', 'Disease', (62, 74))	('osteosarcoma', 'Disease', 'MESH:D012516', (62, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('expression', 'Species', '29278', (116, 126))	('rat', 'Species', '10116', (90, 93))
561135	33435156	A further study on the mechanism of miR-27-3p indicated that G1-S cell cycle progression is promoted by miR-27-3p that targets the inhibitor of growth family member 5 (ING5).	('miR-27-3p', 'Chemical', '-', (36, 45))	('inhibitor of growth family member 5', 'Gene', (131, 166))	('ING5', 'Gene', (168, 172))	('promoted', 'PosReg', (92, 100))	('inhibitor of growth family member 5', 'Gene', '84289', (131, 166))	('miR-27-3p', 'Var', (104, 113))	('miR-27-3p', 'Chemical', '-', (104, 113))	('G1-S cell cycle progression', 'CPA', (61, 88))	('ING5', 'Gene', '84289', (168, 172))
561139	33435156	Additional evidence showed that miR-141-3p expression is repressed by tumor protein P63 alpha containing the transactivation domain (TAp63alpha), leading to a reduction of CCND1.	('reduction', 'NegReg', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CCND1', 'Gene', '595', (172, 177))	('tumor', 'Disease', (70, 75))	('miR-141-3p', 'Var', (32, 42))	('miR-141-3p', 'Chemical', '-', (32, 42))	('expression', 'Species', '29278', (43, 53))	('CCND1', 'Gene', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
561140	33435156	Besides, TAp63alpha diminishes in vitro anchorage-independent growth and in vivo tumorigenic growth of bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('TAp63alpha', 'Var', (9, 19))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('bladder cancer', 'Disease', (103, 117))	('diminishes', 'NegReg', (20, 30))
561141	33435156	TAp63alpha and CCND1 are considered to suppress metastasis and anoikis, respectively.	('CCND1', 'Gene', (15, 20))	('anoikis', 'CPA', (63, 70))	('TAp63alpha', 'Var', (0, 10))	('suppress', 'NegReg', (39, 47))	('CCND1', 'Gene', '595', (15, 20))	('metastasis', 'CPA', (48, 58))
561142	33435156	The TAp63alpha/miR-141-3p/AUF1/CCND1 axis can support the finding that TAp63alpha inhibits cancer metastasis and that miR-141-3p serves as an anoikis-resistant factor in cancer (also see Section 2.1.2) (Figure 1 and Table 1).	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer metastasis', 'Disease', (91, 108))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('2.1', 'Gene', (195, 198))	('TAp63alpha', 'Var', (71, 81))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer metastasis', 'Disease', 'MESH:D009362', (91, 108))	('miR-141-3p', 'Var', (118, 128))	('miR-141-3p', 'Chemical', '-', (15, 25))	('CCND1', 'Gene', '595', (31, 36))	('inhibits', 'NegReg', (82, 90))	('CCND1', 'Gene', (31, 36))	('AUF1', 'Gene', (26, 30))	('cancer', 'Disease', (91, 97))	('2.1', 'Gene', '6700', (195, 198))	('miR-141-3p', 'Chemical', '-', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('AUF1', 'Gene', '3184', (26, 30))
561156	33435156	It was also denoted that miR-1288-3p is upregulated in glioblastoma tissues and cell lines compared to normal brain tissues and astrocyte cells, respectively.	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))	('miR-1288-3p', 'Var', (25, 36))	('glioblastoma', 'Disease', (55, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (55, 67))	('upregulated', 'PosReg', (40, 51))	('miR-1288-3p', 'Chemical', '-', (25, 36))
561157	33435156	Ectopic expression of miR-1288-3p boosts the anchorage-independent growth of glioblastoma cells by targeting CYLD (Figure 1 and Table 1).	('CYLD', 'Gene', '1540', (109, 113))	('boosts', 'PosReg', (34, 40))	('glioblastoma', 'Disease', (77, 89))	('targeting', 'Reg', (99, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('expression', 'Species', '29278', (8, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('miR-1288-3p', 'Chemical', '-', (22, 33))	('CYLD', 'Gene', (109, 113))	('miR-1288-3p', 'Var', (22, 33))
561159	33435156	Additionally, a recent study found that the overexpression or knockdown of miR-362-3p increases or decreases the anchorage-independent growth of hepatocellular carcinoma cells, respectively, through targeting TOB2.	('decreases', 'NegReg', (99, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('miR-362-3p', 'Var', (75, 85))	('miR-362-3p', 'Chemical', '-', (75, 85))	('expression', 'Species', '29278', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('anchorage-independent growth', 'CPA', (113, 141))	('hepatocellular carcinoma', 'Disease', (145, 169))	('increases', 'PosReg', (86, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('targeting', 'Reg', (199, 208))	('TOB2', 'Gene', (209, 213))	('overexpression', 'PosReg', (44, 58))	('TOB2', 'Gene', '10766', (209, 213))
561162	33435156	It was illustrated that miR-376c-3p augments the anchorage-independent growth of gastric cancer cells via repressing AT-rich interactive domain-containing protein 4A (ARID4A, also called RBP-1), which negatively regulates E2F-mediated transcription (Figure 1 and Table 1).	('augments', 'PosReg', (36, 44))	('RBP-1', 'Gene', '5947', (187, 192))	('miR-376c-3p', 'Chemical', '-', (24, 35))	('AT-rich interactive domain-containing protein 4A', 'Gene', (117, 165))	('RBP-1', 'Gene', (187, 192))	('AT-rich interactive domain-containing protein 4A', 'Gene', '5926', (117, 165))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('ARID4A', 'Gene', '5926', (167, 173))	('gastric cancer', 'Disease', (81, 95))	('miR-376c-3p', 'Var', (24, 35))	('anchorage-independent growth', 'CPA', (49, 77))	('rat', 'Species', '10116', (13, 16))	('repressing', 'PosReg', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ARID4A', 'Gene', (167, 173))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
561163	33435156	Additionally, miR-376c-3p was validated to promote metastasis of hepatocellular carcinoma cells in vivo.	('metastasis', 'CPA', (51, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('hepatocellular carcinoma', 'Disease', (65, 89))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (65, 89))	('promote', 'PosReg', (43, 50))	('miR-376c-3p', 'Chemical', '-', (14, 25))	('miR-376c-3p', 'Var', (14, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))
561165	33435156	Functional experiments showed that the anchorage-independent growth ability of cancer cells is enhanced by overexpressing either miR-527 or miR-760, in company with an increase in CCND1 levels (Figure 1 and Table 1).	('increase', 'PosReg', (168, 176))	('miR-7', 'Gene', '10859', (140, 145))	('overexpressing', 'PosReg', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CCND1', 'Gene', '595', (180, 185))	('miR-527', 'Var', (129, 136))	('anchorage-independent growth ability', 'CPA', (39, 75))	('miR-7', 'Gene', (140, 145))	('enhanced', 'PosReg', (95, 103))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('CCND1', 'Gene', (180, 185))
561169	33435156	Recent investigations showed that APC is directly regulated by miR-582-5p and miR-3607 in colorectal and lung cancer, respectively.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('miR-3607', 'Gene', '100500805', (78, 86))	('colorectal and lung cancer', 'Disease', 'MESH:D015179', (90, 116))	('regulated', 'Reg', (50, 59))	('miR-3607', 'Gene', (78, 86))	('APC', 'Phenotype', 'HP:0005227', (34, 37))	('APC', 'Disease', 'MESH:D011125', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('APC', 'Disease', (34, 37))	('miR-582-5p', 'Var', (63, 73))
561172	33435156	Recently, it was reported that the inhibition of miR-766-5p blocks cell proliferation, invasion, and survival of SW480 colorectal cancer cells.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('blocks', 'NegReg', (60, 66))	('miR-766', 'Gene', '768218', (49, 56))	('SW480', 'CellLine', 'CVCL:0546', (113, 118))	('miR-766', 'Gene', (49, 56))	('colorectal cancer', 'Disease', (119, 136))	('rat', 'Species', '10116', (79, 82))	('rectal cancer', 'Phenotype', 'HP:0100743', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('invasion', 'CPA', (87, 95))	('inhibition', 'Var', (35, 45))	('cell proliferation', 'CPA', (67, 85))	('survival', 'CPA', (101, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))
561183	33435156	The expression of miR-10b is transcriptionally activated by BRAFV600E-mediated upregulation of Twist family BHLH transcription factor 1 (TWIST1) in melanoma cells.	('BRAFV600E-mediated', 'Var', (60, 78))	('TWIST1', 'Gene', (137, 143))	('TWIST1', 'Gene', '7291', (137, 143))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('expression', 'Species', '29278', (4, 14))	('activated', 'PosReg', (47, 56))	('expression', 'MPA', (4, 14))	('miR-10b', 'Gene', '406903', (18, 25))	('upregulation', 'PosReg', (79, 91))	('BRAFV600E', 'Mutation', 'rs113488022', (60, 69))	('miR-10b', 'Gene', (18, 25))
561185	33435156	The levels of both miR-139-5p and miR-483-5p are upregulated in adrenocortical cancer tissues and inversely correlated with the overall survival of patients.	('patients', 'Species', '9606', (148, 156))	('correlated', 'Reg', (108, 118))	('inversely', 'NegReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miR-139-5p', 'Var', (19, 29))	('adrenocortical cancer', 'Disease', (64, 85))	('upregulated', 'PosReg', (49, 60))	('miR-483', 'Gene', '619552', (34, 41))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (64, 85))	('miR-483', 'Gene', (34, 41))
561187	33435156	Evidence provided indicated that miR-139-5p and miR-483-5p target N-Myc downstream-regulated gene 4 (NDRG4) and NDRG2, respectively, and that overexpression of either NDRG4 or NDRG2 inhibits the invasive capacity of cancer cells (Figure 1 and Table 1).	('overexpression', 'PosReg', (142, 156))	('cancer', 'Disease', (216, 222))	('NDRG4', 'Gene', (101, 106))	('inhibits', 'NegReg', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('N-Myc downstream-regulated gene 4', 'Gene', (66, 99))	('NDRG2', 'Gene', '57447', (176, 181))	('miR-483', 'Gene', (48, 55))	('NDRG4', 'Gene', '65009', (167, 172))	('NDRG2', 'Gene', '57447', (112, 117))	('expression', 'Species', '29278', (146, 156))	('N-Myc downstream-regulated gene 4', 'Gene', '65009', (66, 99))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('miR-483', 'Gene', '619552', (48, 55))	('miR-139-5p', 'Var', (33, 43))	('NDRG4', 'Gene', (167, 172))	('NDRG2', 'Gene', (176, 181))	('NDRG2', 'Gene', (112, 117))	('NDRG4', 'Gene', '65009', (101, 106))
561191	33435156	For example, CPEB2A and CPEB2B act as a tumor suppressor and an oncogene, respectively, and a high CPEB2B/CPEB2A ratio leads to anoikis resistance and metastasis of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('CPEB2', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('CPEB2', 'Gene', '132864', (13, 18))	('leads to', 'Reg', (119, 127))	('CPEB2', 'Gene', (99, 104))	('CPEB2', 'Gene', (106, 111))	('CPEB2', 'Gene', '132864', (99, 104))	('CPEB2', 'Gene', '132864', (106, 111))	('anoikis resistance', 'CPA', (128, 146))	('high', 'Var', (94, 98))	('CPEB2', 'Gene', (24, 29))	('metastasis of breast cancer', 'Disease', (151, 178))	('tumor', 'Disease', (40, 45))	('CPEB2', 'Gene', '132864', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('metastasis of breast cancer', 'Disease', 'MESH:D001943', (151, 178))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('rat', 'Species', '10116', (113, 116))
561193	33435156	Further, both miR-526b-5p and miR-655-3p were identified to directly target CPEB2, suggesting a possibility that these miRNAs can serve as anoikis-resistant factors (Figure 1 and Table 1), even though more investigation on the effect of these miRNAs especially on the regulation of CPEB2B/CPEB2A ratio is warranted.	('CPEB2', 'Gene', '132864', (282, 287))	('rat', 'Species', '10116', (296, 299))	('CPEB2', 'Gene', '132864', (76, 81))	('CPEB2', 'Gene', '132864', (289, 294))	('CPEB2', 'Gene', (289, 294))	('CPEB2', 'Gene', (282, 287))	('miR-526b-5p', 'Var', (14, 25))	('CPEB2', 'Gene', (76, 81))	('miR-655-3p', 'Var', (30, 40))
561194	33435156	Deep sequencing analysis of GRSF1-bound miRNAs identified that miR-G-10 is one of the most abundant miRNAs in cervical cancer.	('miR-G-10', 'Var', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('abundant', 'Reg', (91, 99))	('GRSF1', 'Gene', '2926', (28, 33))	('miR-G-10', 'Chemical', '-', (63, 71))	('GRSF1', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
561195	33435156	A further investigation on the molecular mechanism of miR-G-10 indicated that the malignant phenotypes of cancer cells, such as EMT and anoikis resistance, are promoted by miR-G-10 that increases the expression of phosphatidylinositol 3-kinase regulatory subunit gamma (PIK3R3), an upstream activator of NF-kappaB.	('promoted', 'PosReg', (160, 168))	('NF-kappaB', 'Gene', (304, 313))	('EMT', 'CPA', (128, 131))	('anoikis resistance', 'CPA', (136, 154))	('PIK3R3', 'Gene', (270, 276))	('miR-G-10', 'Var', (172, 180))	('miR-G-10', 'Chemical', '-', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('increases', 'PosReg', (186, 195))	('expression', 'Species', '29278', (200, 210))	('cancer', 'Disease', (106, 112))	('expression', 'MPA', (200, 210))	('miR-G-10', 'Chemical', '-', (172, 180))	('NF-kappaB', 'Gene', '4790', (304, 313))	('PIK3R3', 'Gene', '8503', (270, 276))
561196	33435156	Indeed, lung metastasis of cervical cancer is accelerated by miR-G-10 in vivo (Figure 1 and Table 1).	('lung metastasis', 'CPA', (8, 23))	('rat', 'Species', '10116', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('accelerated', 'PosReg', (46, 57))	('cancer', 'Disease', (36, 42))	('miR-G-10', 'Chemical', '-', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('miR-G-10', 'Var', (61, 69))
561204	33435156	Tumor-suppressive miR-22-3p is underexpressed in rhabdomyosarcoma tissues, and the reconstitution of miR-22-3p was observed to induce apoptosis and subdue anchorage-independent growth of cancer cells.	('subdue', 'NegReg', (148, 154))	('miR-22-3p', 'Gene', '407008', (18, 27))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-22-3p', 'Gene', '407008', (101, 110))	('cancer', 'Disease', (187, 193))	('induce', 'PosReg', (127, 133))	('apoptosis', 'CPA', (134, 143))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (49, 65))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (49, 65))	('miR-22-3p', 'Gene', (18, 27))	('rhabdomyosarcoma', 'Disease', (49, 65))	('reconstitution', 'Var', (83, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('miR-22-3p', 'Gene', (101, 110))
561206	33435156	Huntingtin-interacting protein 1-related (HIP1R) is involved in the encouragement of cell survival via stabilizing receptor tyrosine kinases; therefore, loss-of-function mutants of HIP1R are able to induce cell death.	('Huntingtin-interacting protein 1-related', 'Gene', (0, 40))	('HIP1R', 'Gene', '9026', (181, 186))	('HIP1R', 'Gene', (42, 47))	('HIP1R', 'Gene', (181, 186))	('HIP1R', 'Gene', '9026', (42, 47))	('mutants', 'Var', (170, 177))	('cell death', 'CPA', (206, 216))	('loss-of-function', 'NegReg', (153, 169))	('Huntingtin-interacting protein 1-related', 'Gene', '9026', (0, 40))
561211	33435156	Additional studies provided evidence that miR-30-5p and miR-33a target MTA1 and METTL3, respectively, hence contributing to attenuated anchorage-independent growth of cancer cells (Figure 2 and Table 2).	('miR-30-5p', 'Var', (42, 51))	('miR-33a', 'Gene', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('miR-33a', 'Gene', '407039', (56, 63))	('cancer', 'Disease', (167, 173))	('MTA1', 'Gene', (71, 75))	('attenuated', 'NegReg', (124, 134))	('METTL3', 'Gene', '56339', (80, 86))	('MTA1', 'Gene', '9112', (71, 75))	('METTL3', 'Gene', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('miR-30-5p', 'Chemical', '-', (42, 51))
561213	33435156	Knockdown of ME1 increases the level of reactive oxygen species (ROS), leading to the inhibition of cell growth and the induction of anoikis.	('anoikis', 'CPA', (133, 140))	('cell growth', 'CPA', (100, 111))	('increases', 'PosReg', (17, 26))	('level of reactive oxygen species', 'MPA', (31, 63))	('Knockdown', 'Var', (0, 9))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (40, 63))	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('ME1', 'Gene', (13, 16))	('ME1', 'Gene', '4199', (13, 16))	('induction', 'Reg', (120, 129))	('inhibition', 'NegReg', (86, 96))
561214	33435156	In the case of miR-30-5p, this miRNA also targets ME1, promotes apoptosis, and attenuates the anchorage-independent growth of colorectal cancer cells (Figure 2 and Table 2).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('attenuates', 'NegReg', (79, 89))	('miR-30-5p', 'Chemical', '-', (15, 24))	('colorectal cancer', 'Disease', (126, 143))	('rectal cancer', 'Phenotype', 'HP:0100743', (130, 143))	('apoptosis', 'CPA', (64, 73))	('ME1', 'Gene', (50, 53))	('promotes', 'PosReg', (55, 63))	('miR-30-5p', 'Var', (15, 24))	('ME1', 'Gene', '4199', (50, 53))	('anchorage-independent growth', 'CPA', (94, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('targets', 'Reg', (42, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
561215	33435156	The expression of miR-133-3p is downregulated in prostate cancer and further reduced in metastatic prostate cancer, suggesting that miR-133-3p may affect cellular events/signaling associated with metastasis.	('miR-133-3p', 'Gene', (18, 28))	('downregulated', 'NegReg', (32, 45))	('miR-133-3p', 'Chemical', '-', (18, 28))	('cellular events/signaling', 'MPA', (154, 179))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('expression', 'Species', '29278', (4, 14))	('miR-133-3p', 'Var', (132, 142))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('miR-133-3p', 'Chemical', '-', (132, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('expression', 'MPA', (4, 14))	('prostate cancer', 'Disease', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('reduced', 'NegReg', (77, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (99, 114))	('prostate cancer', 'Disease', (49, 64))	('affect', 'Reg', (147, 153))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))
561216	33435156	Investigations of miR-133-3p in relation to anoikis and metastasis showed that this miRNA diminishes the level of anti-apoptotic factors (e.g., BCL-2) and the activity of PI3K/Akt signaling via targeting multiple genes (e.g., EGFR), eventually alleviating anoikis resistance and bone metastasis of prostate cancer (Figure 2 and Table 2).	('miR-133-3p', 'Var', (18, 28))	('targeting', 'Reg', (194, 203))	('miR-133-3p', 'Chemical', '-', (18, 28))	('BCL-2', 'Gene', '596', (144, 149))	('activity', 'MPA', (159, 167))	('bone metastasis of prostate cancer', 'Disease', 'MESH:D011471', (279, 313))	('anoikis resistance', 'CPA', (256, 274))	('Akt', 'Gene', (176, 179))	('prostate cancer', 'Phenotype', 'HP:0012125', (298, 313))	('diminishes', 'NegReg', (90, 100))	('BCL-2', 'Gene', (144, 149))	('level of anti-apoptotic factors', 'MPA', (105, 136))	('Akt', 'Gene', '207', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('bone metastasis of prostate cancer', 'Disease', (279, 313))	('EGFR', 'Gene', '1956', (226, 230))	('alleviating', 'NegReg', (244, 255))	('EGFR', 'Gene', (226, 230))
561218	33435156	The silencing of SESN2 leads to anoikis in vitro and restricts distant metastasis in vivo.	('SESN2', 'Gene', (17, 22))	('anoikis', 'CPA', (32, 39))	('SESN2', 'Gene', '83667', (17, 22))	('silencing', 'Var', (4, 13))	('restricts', 'NegReg', (53, 62))	('distant metastasis', 'CPA', (63, 81))	('leads to', 'Reg', (23, 31))
561233	33435156	Ectopic expression of miR-451 facilitates anoikis induction, and the overexpression of Ras-related protein Rab-14 (RAB14), a target of miR-451, substantially abrogates the effect of miR-451 on anoikis.	('overexpression', 'PosReg', (69, 83))	('RAB14', 'Gene', (115, 120))	('miR-451', 'Gene', '574411', (135, 142))	('anoikis induction', 'CPA', (42, 59))	('RAB14', 'Gene', '51552', (115, 120))	('expression', 'Species', '29278', (73, 83))	('Ectopic expression', 'Var', (0, 18))	('miR-451', 'Gene', '574411', (182, 189))	('miR-451', 'Gene', (135, 142))	('expression', 'Species', '29278', (8, 18))	('miR-451', 'Gene', (22, 29))	('anoikis', 'CPA', (193, 200))	('abrogates', 'NegReg', (158, 167))	('facilitates', 'PosReg', (30, 41))	('miR-451', 'Gene', (182, 189))	('miR-451', 'Gene', '574411', (22, 29))
561236	33435156	Liver metastasis of colorectal cancer is restrained by miR-487b-3p that inhibits the KRAS/Akt signaling pathway.	('miR-487b-3p', 'Var', (55, 66))	('restrained', 'NegReg', (41, 51))	('Akt', 'Gene', (90, 93))	('-487b', 'Chemical', '-', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('inhibits', 'NegReg', (72, 80))	('Liver metastasis of colorectal cancer', 'Disease', (0, 37))	('rectal cancer', 'Phenotype', 'HP:0100743', (24, 37))	('Akt', 'Gene', '207', (90, 93))	('Liver metastasis of colorectal cancer', 'Disease', 'MESH:D015179', (0, 37))
561237	33435156	In another study, miR-487b-3p was also demonstrated to dampen colorectal cancer tumorigenesis by diminishing anchorage-independent growth and Akt activity.	('Akt', 'Gene', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('dampen', 'NegReg', (55, 61))	('-487b', 'Chemical', '-', (21, 26))	('anchorage-independent growth', 'CPA', (109, 137))	('rat', 'Species', '10116', (46, 49))	('miR-487b-3p', 'Var', (18, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('diminishing', 'NegReg', (97, 108))	('tumor', 'Disease', (80, 85))	('colorectal cancer', 'Disease', (62, 79))	('Akt', 'Gene', '207', (142, 145))	('rectal cancer', 'Phenotype', 'HP:0100743', (66, 79))
561238	33435156	In this study, glutamate metabotropic receptor 3 (GRM3) was confirmed as a target gene of miR-487b-3p.	('glutamate metabotropic receptor 3', 'Gene', (15, 48))	('-487b', 'Chemical', '-', (93, 98))	('GRM3', 'Gene', '2913', (50, 54))	('GRM3', 'Gene', (50, 54))	('glutamate metabotropic receptor 3', 'Gene', '2913', (15, 48))	('miR-487b-3p', 'Var', (90, 101))
561253	33435156	Lately, it was also demonstrated that the knockdown of LGALS1 reduces anchorage-independent growth and lung metastasis of hepatocellular carcinoma cells.	('LGALS1', 'Gene', '3956', (55, 61))	('reduces', 'NegReg', (62, 69))	('lung metastasis of hepatocellular carcinoma', 'Disease', (103, 146))	('LGALS1', 'Gene', (55, 61))	('anchorage-independent growth', 'CPA', (70, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('rat', 'Species', '10116', (27, 30))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (122, 146))	('lung metastasis of hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 146))	('knockdown', 'Var', (42, 51))
561257	33435156	As stated in Section 3.1.4, miR-133-3p serves as an anoikis-promoting factor by targeting, for example, EGFR.	('EGFR', 'Gene', (104, 108))	('miR-133-3p', 'Chemical', '-', (28, 38))	('miR-133-3p', 'Var', (28, 38))	('targeting', 'Reg', (80, 89))	('EGFR', 'Gene', '1956', (104, 108))
561259	33435156	Indeed, it was reported that miR-133-3p suppresses EMT, eventually restricting anoikis resistance, anchorage-independent growth, and lung metastasis of esophageal cancer cells (Figure 2 and Table 2).	('EMT', 'CPA', (51, 54))	('miR-133-3p', 'Var', (29, 39))	('anchorage-independent growth', 'CPA', (99, 127))	('miR-133-3p', 'Chemical', '-', (29, 39))	('lung metastasis', 'CPA', (133, 148))	('suppresses', 'NegReg', (40, 50))	('restricting', 'NegReg', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('anoikis resistance', 'CPA', (79, 97))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
561266	33435156	The silencing of SET reduces the level of EMT markers such as vimentin (VIM) and represses the migration and invasion of cancer cells.	('level of EMT markers', 'MPA', (33, 53))	('VIM', 'Gene', (72, 75))	('vimentin', 'Gene', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('SET', 'Gene', (17, 20))	('rat', 'Species', '10116', (98, 101))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('silencing', 'Var', (4, 13))	('VIM', 'Gene', '7431', (72, 75))	('vimentin', 'Gene', '7431', (62, 70))	('cancer', 'Disease', (121, 127))	('represses', 'NegReg', (81, 90))	('reduces', 'NegReg', (21, 28))
561268	33435156	Moreover, SET is targeted by miR-199-5p, which is downregulated in colorectal cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rectal cancer', 'Phenotype', 'HP:0100743', (71, 84))	('miR-199-5p', 'Var', (29, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('downregulated', 'NegReg', (50, 63))	('colorectal cancer', 'Disease', (67, 84))
561269	33435156	These results suggest that low miR-199-5p expression is one of the causes of high SET levels in colorectal cancer and that miR-199-5p can negatively modulate anchorage-independent growth via targeting SET (Figure 2 and Table 2).	('modulate', 'Reg', (149, 157))	('high SET levels', 'MPA', (77, 92))	('expression', 'Species', '29278', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('anchorage-independent growth', 'CPA', (158, 186))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('low', 'NegReg', (27, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))	('colorectal cancer', 'Disease', (96, 113))	('miR-199-5p', 'Var', (123, 133))	('rectal cancer', 'Phenotype', 'HP:0100743', (100, 113))	('miR-199-5p expression', 'MPA', (31, 52))
561272	33435156	A recent study further demonstrated that TDO2 is targeted by miR-200 in breast cancer and that the overexpression of TDO2 brings about enhanced anchorage-independent growth, suggesting that miR-200 can inhibit anchorage-independent cell growth through repressing EMT process mediated by the TDO2/kynurenine/AHR signaling (Figure 2 and Table 2).	('TDO2', 'Gene', (117, 121))	('AHR', 'Gene', (307, 310))	('TDO2', 'Gene', '6999', (41, 45))	('TDO2', 'Gene', (291, 295))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('miR-200', 'Var', (190, 197))	('rat', 'Species', '10116', (30, 33))	('kynurenine', 'Chemical', 'MESH:D007737', (296, 306))	('enhanced', 'PosReg', (135, 143))	('TDO2', 'Gene', (41, 45))	('AHR', 'Gene', '196', (307, 310))	('anchorage-independent cell growth', 'CPA', (210, 243))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TDO2', 'Gene', '6999', (117, 121))	('inhibit', 'NegReg', (202, 209))	('EMT process', 'CPA', (263, 274))	('expression', 'Species', '29278', (103, 113))	('TDO2', 'Gene', '6999', (291, 295))	('repressing', 'NegReg', (252, 262))	('anchorage-independent growth', 'CPA', (144, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
561276	33435156	In addition, the knockdown of XIAP attenuates anchorage-independent cell growth, suggesting that the anchorage-independent growth of bladder cancer can be modulated by the XIAP/miR-200/EGFR/EMT axis (see Section 3.3.2 for EGFR/EMT relationship) (Figure 2 and Table 2).	('anchorage-independent growth', 'CPA', (101, 129))	('XIAP', 'Gene', '331', (30, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('XIAP', 'Gene', (172, 176))	('EGFR', 'Gene', (185, 189))	('attenuates', 'NegReg', (35, 45))	('XIAP', 'Gene', '331', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('anchorage-independent cell growth', 'CPA', (46, 79))	('EGFR', 'Gene', '1956', (222, 226))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('bladder cancer', 'Disease', (133, 147))	('knockdown', 'Var', (17, 26))	('XIAP', 'Gene', (30, 34))	('EGFR', 'Gene', (222, 226))	('modulated', 'Reg', (155, 164))	('EGFR', 'Gene', '1956', (185, 189))
561277	33435156	Accumulating evidence reveals that miR-204-5p hinders EMT, stemness, invasion, and metastasis in multiple types of cancer.	('miR-204-5p', 'Var', (35, 45))	('cancer', 'Disease', (115, 121))	('metastasis', 'CPA', (83, 93))	('hinders', 'NegReg', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('stemness', 'CPA', (59, 67))	('invasion', 'CPA', (69, 77))	('EMT', 'CPA', (54, 57))	('miR-204-5p', 'Chemical', '-', (35, 45))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
561278	33435156	In gastric cancer, low levels of miR-204-5p are correlated with lymph node metastasis, and this miRNA negatively regulates C-X-C motif chemokine receptor 4 (CXCR4), which can provoke metastasis by blocking anoikis.	('provoke', 'PosReg', (175, 182))	('C-X-C motif chemokine receptor 4', 'Gene', '7852', (123, 155))	('miRNA', 'Var', (96, 101))	('miR-204-5p', 'Chemical', '-', (33, 43))	('CXCR4', 'Gene', '7852', (157, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('anoikis', 'CPA', (206, 213))	('miR-204-5p', 'Var', (33, 43))	('metastasis', 'CPA', (183, 193))	('regulates', 'Reg', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('lymph node metastasis', 'CPA', (64, 85))	('CXCR4', 'Gene', (157, 162))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('negatively', 'NegReg', (102, 112))	('C-X-C motif chemokine receptor 4', 'Gene', (123, 155))
561279	33435156	Also, miR-204-5p interrupts EMT process by targeting POU class 2 homeobox 1 (POU2F1, also called OCT1), which is proposed to protect cells from anoikis.	('POU2F1', 'Gene', '5451', (77, 83))	('targeting', 'Reg', (43, 52))	('POU class 2 homeobox 1', 'Gene', '5451', (53, 75))	('OCT1', 'Gene', (97, 101))	('OCT1', 'Gene', '5451', (97, 101))	('miR-204-5p', 'Chemical', '-', (6, 16))	('POU2F1', 'Gene', (77, 83))	('POU class 2 homeobox 1', 'Gene', (53, 75))	('miR-204-5p', 'Var', (6, 16))
561280	33435156	Further, there is consistent evidence that miR-204-5p negatively regulates EMT process and dampens anoikis resistance in gastric cancer.	('EMT process', 'CPA', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('anoikis resistance', 'CPA', (99, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('miR-204-5p', 'Chemical', '-', (43, 53))	('miR-204-5p', 'Var', (43, 53))	('dampens', 'NegReg', (91, 98))	('regulates', 'Reg', (65, 74))	('negatively', 'NegReg', (54, 64))	('gastric cancer', 'Disease', (121, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
561281	33435156	In this study, sirtuin 1 (SIRT1) was validated as a target of miR-204-5p.	('SIRT1', 'Gene', '23411', (26, 31))	('SIRT1', 'Gene', (26, 31))	('sirtuin 1', 'Gene', '23411', (15, 24))	('miR-204-5p', 'Chemical', '-', (62, 72))	('sirtuin 1', 'Gene', (15, 24))	('miR-204-5p', 'Var', (62, 72))
561283	33435156	Therefore, it is feasible that miR-204-5p acts as an anoikis-promoting miRNA by regulating CXCR4, OCT1, etcetera, rather than SIRT1, in gastric cancer (Figure 2 and Table 2).	('CXCR4', 'Gene', '7852', (91, 96))	('OCT1', 'Gene', (98, 102))	('rat', 'Species', '10116', (114, 117))	('OCT1', 'Gene', '5451', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('miR-204-5p', 'Chemical', '-', (31, 41))	('SIRT1', 'Gene', '23411', (126, 131))	('CXCR4', 'Gene', (91, 96))	('gastric cancer', 'Disease', (136, 150))	('etcetera', 'MPA', (104, 112))	('SIRT1', 'Gene', (126, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('regulating', 'Reg', (80, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('miR-204-5p', 'Var', (31, 41))
561286	33435156	In addition, it was found that UBE2C knockdown leads to the reduction of anchorage-independent growth of rectal carcinoma cells and that UBE2C is targeted by miR-381, suggesting that miR-381 can modulate anchorage-independent growth partly via UBE2C.	('rectal carcinoma', 'Disease', (105, 121))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (105, 121))	('UBE2C', 'Gene', '11065', (137, 142))	('UBE2C', 'Gene', '11065', (244, 249))	('UBE2C', 'Gene', (137, 142))	('knockdown', 'Var', (37, 46))	('UBE2C', 'Gene', '11065', (31, 36))	('UBE2C', 'Gene', (244, 249))	('miR-381', 'Gene', '494330', (183, 190))	('miR-381', 'Gene', (158, 165))	('reduction', 'NegReg', (60, 69))	('UBE2C', 'Gene', (31, 36))	('rectal carcinoma', 'Disease', 'MESH:D012004', (105, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('modulate', 'Reg', (195, 203))	('miR-381', 'Gene', '494330', (158, 165))	('miR-381', 'Gene', (183, 190))	('anchorage-independent growth', 'CPA', (204, 232))
561292	33435156	Further tests showed that the restoration of miR-450 forcefully increases the rate of anoikis in vitro and cancer growth in vivo (Figure 2 and Table 2).	('anoikis', 'CPA', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('miR-450', 'Chemical', '-', (45, 52))	('rat', 'Species', '10116', (78, 81))	('restoration', 'Var', (30, 41))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('rat', 'Species', '10116', (35, 38))	('miR-450', 'Gene', (45, 52))	('cancer', 'Disease', (107, 113))	('increases', 'PosReg', (64, 73))
561299	33435156	In pancreatic cancer, miR-29-3p sensitizes cancer cells to gemcitabine and diminishes the ability of cancer cells to grow under anchorage-independent conditions.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('pancreatic cancer', 'Disease', (3, 20))	('miR-29-3p', 'Chemical', '-', (22, 31))	('cancer', 'Disease', (101, 107))	('sensitizes', 'Reg', (32, 42))	('cancer', 'Disease', (43, 49))	('gemcitabine', 'Chemical', 'MESH:C056507', (59, 70))	('miR-29-3p', 'Var', (22, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('diminishes', 'NegReg', (75, 85))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
561300	33435156	The mechanism underlying these tumor-suppressive activities of miR-29-3p involves the downregulation of autophagy-related 9A (ATG9A) and transcription factor EB (TFEB), which control the trafficking of autophagosome and lysosomal function.	('autophagy-related 9A', 'Gene', (104, 124))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('ATG9A', 'Gene', (126, 131))	('miR-29-3p', 'Chemical', '-', (63, 72))	('downregulation', 'NegReg', (86, 100))	('ATG9A', 'Gene', '79065', (126, 131))	('TFEB', 'Gene', '7942', (162, 166))	('miR-29-3p', 'Var', (63, 72))	('autophagy-related 9A', 'Gene', '79065', (104, 124))	('TFEB', 'Gene', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
561301	33435156	Therefore, the overexpression of miR-29-3p causes the impairment of autophagic flux resulting from the blockage of autophagosome-lysosome fusion (Figure 2 and Table 2).	('overexpression', 'PosReg', (15, 29))	('miR-29-3p', 'Var', (33, 42))	('miR-29-3p', 'Chemical', '-', (33, 42))	('autophagic flux', 'CPA', (68, 83))	('autophagosome-lysosome fusion', 'CPA', (115, 144))	('impairment', 'NegReg', (54, 64))	('blockage', 'NegReg', (103, 111))	('expression', 'Species', '29278', (19, 29))
561302	33435156	Several studies have highlighted the role of miR-30-5p in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', (58, 82))	('miR-30-5p', 'Var', (45, 54))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('miR-30-5p', 'Chemical', '-', (45, 54))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
561303	33435156	For instance, through targeting SNAI1, miR-30-5p impedes EMT.	('targeting', 'Reg', (22, 31))	('miR-30-5p', 'Chemical', '-', (39, 48))	('SNAI1', 'Gene', '6615', (32, 37))	('SNAI1', 'Gene', (32, 37))	('impedes', 'NegReg', (49, 56))	('miR-30-5p', 'Var', (39, 48))	('EMT', 'CPA', (57, 60))
561304	33435156	In addition, miR-30-5p induces apoptotic cell death and retards proliferation, as well as invasion.	('induces', 'Reg', (23, 30))	('retards proliferation', 'Disease', (56, 77))	('miR-30-5p', 'Var', (13, 22))	('apoptotic cell death', 'CPA', (31, 51))	('retards proliferation', 'Disease', 'MESH:C565054', (56, 77))	('miR-30-5p', 'Chemical', '-', (13, 22))	('invasion', 'CPA', (90, 98))
561305	33435156	Moreover, it has been recently demystified that miR-30-5p abates anoikis resistance and lung metastasis in hepatocellular carcinoma cells through targeting autophagy-inducing factors, namely, ATG5 and BECN1 (Figure 2 and Table 2).	('abates', 'NegReg', (58, 64))	('miR-30-5p', 'Var', (48, 57))	('ATG5', 'Gene', (192, 196))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (107, 131))	('BECN1', 'Gene', (201, 206))	('hepatocellular carcinoma', 'Disease', (107, 131))	('lung metastasis', 'CPA', (88, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (107, 131))	('targeting', 'Reg', (146, 155))	('BECN1', 'Gene', '8678', (201, 206))	('ATG5', 'Gene', '9474', (192, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('anoikis resistance', 'CPA', (65, 83))	('miR-30-5p', 'Chemical', '-', (48, 57))
561306	33435156	These findings suggest the therapeutic benefit of miR-30-5p overexpression for hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('hepatocellular carcinoma', 'Disease', (79, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('miR-30-5p', 'Var', (50, 59))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))	('expression', 'Species', '29278', (64, 74))	('miR-30-5p', 'Chemical', '-', (50, 59))
561307	33435156	The expression of miR-204-5p is epigenetically silenced in medulloblastoma, and low levels of this miRNA are correlated with the dismal prognosis of patients.	('miR-204-5p', 'Var', (18, 28))	('miR-204-5p', 'Chemical', '-', (18, 28))	('patients', 'Species', '9606', (149, 157))	('expression', 'Species', '29278', (4, 14))	('expression', 'MPA', (4, 14))	('medulloblastoma', 'Disease', 'MESH:D008527', (59, 74))	('correlated', 'Reg', (109, 119))	('medulloblastoma', 'Phenotype', 'HP:0002885', (59, 74))	('silenced', 'NegReg', (47, 55))	('medulloblastoma', 'Disease', (59, 74))
561308	33435156	The evaluation of miR-204-5p activity denoted that miR-204-5p reduces the number of cells growing anchorage-independently, at least in part owing to its capability to inhibit autophagy via targeting microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B, also called LC3B) (Figure 2 and Table 2).	('LC3B', 'Gene', (257, 261))	('miR-204-5p', 'Chemical', '-', (18, 28))	('reduces', 'NegReg', (62, 69))	('LC3B', 'Gene', (275, 279))	('microtubule-associated proteins 1A/1B light chain 3B', 'Gene', '81631', (199, 251))	('miR-204-5p', 'Var', (51, 61))	('MAP1LC3B', 'Gene', (253, 261))	('number of cells growing anchorage-independently', 'CPA', (74, 121))	('inhibit', 'NegReg', (167, 174))	('MAP1LC3B', 'Gene', '81631', (253, 261))	('LC3B', 'Gene', '81631', (257, 261))	('LC3B', 'Gene', '81631', (275, 279))	('miR-204-5p', 'Chemical', '-', (51, 61))	('autophagy', 'CPA', (175, 184))
561309	33435156	In hepatocellular carcinoma, miR-26-5p has been perceived to suppress metastasis by regulating several cellular events, such as apoptosis and EMT.	('metastasis', 'CPA', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('miR-26-5p', 'Var', (29, 38))	('miR-26-5p', 'Chemical', '-', (29, 38))	('EMT', 'CPA', (142, 145))	('suppress', 'NegReg', (61, 69))	('regulating', 'Reg', (84, 94))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('apoptosis', 'CPA', (128, 137))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
561310	33435156	Moreover, miR-26-5p stimulates the anoikis of hepatocellular carcinoma cells by directly suppressing ITGA5.	('anoikis of hepatocellular carcinoma', 'Disease', (35, 70))	('suppressing', 'NegReg', (89, 100))	('stimulates', 'PosReg', (20, 30))	('ITGA5', 'Gene', (101, 106))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('miR-26-5p', 'Var', (10, 19))	('miR-26-5p', 'Chemical', '-', (10, 19))	('ITGA5', 'Gene', '3678', (101, 106))	('anoikis of hepatocellular carcinoma', 'Disease', 'MESH:D006528', (35, 70))
561311	33435156	These observations demonstrate that miR-26-5p is a bona fide metastasis-suppressing miRNA in hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (93, 117))	('miR-26-5p', 'Chemical', '-', (36, 45))	('hepatocellular carcinoma', 'Disease', (93, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (93, 117))	('rat', 'Species', '10116', (26, 29))	('miR-26-5p', 'Var', (36, 45))
561313	33435156	In that study, it was also shown that ITGA3 levels are positively correlated with poor prognosis of patients with colorectal cancer and that knockdown of ITGA3 augments anoikis induction and reduces metastasis.	('rectal cancer', 'Phenotype', 'HP:0100743', (118, 131))	('knockdown', 'Var', (141, 150))	('ITGA3', 'Gene', (38, 43))	('augments', 'PosReg', (160, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('ITGA3', 'Gene', '3675', (154, 159))	('ITGA3', 'Gene', '3675', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('patients', 'Species', '9606', (100, 108))	('reduces', 'NegReg', (191, 198))	('metastasis', 'CPA', (199, 209))	('anoikis induction', 'CPA', (169, 186))	('colorectal cancer', 'Disease', (114, 131))	('ITGA3', 'Gene', (154, 159))
561314	33435156	Moreover, anoikis resistance is attenuated by the overexpression of miR-363-3p, which is downregulated in papillary thyroid carcinoma.	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (106, 133))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (116, 133))	('overexpression', 'PosReg', (50, 64))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (106, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('miR-363-3p', 'Var', (68, 78))	('anoikis resistance', 'CPA', (10, 28))	('downregulated', 'NegReg', (89, 102))	('attenuated', 'NegReg', (32, 42))	('papillary thyroid carcinoma', 'Disease', (106, 133))	('expression', 'Species', '29278', (54, 64))
561325	33435156	LncRNA-ANRIL knockdown increases miR-203a levels and abates the expression of several cellular factors, such as BCL-2, CDK2, c-Myc, and Akt.	('CDK2', 'Gene', (119, 123))	('BCL-2', 'Gene', (112, 117))	('expression', 'MPA', (64, 74))	('c-Myc', 'Gene', '4609', (125, 130))	('ANRIL', 'Gene', '100048912', (7, 12))	('ncRNA', 'Gene', '220202', (1, 6))	('c-Myc', 'Gene', (125, 130))	('miR-203', 'Gene', (33, 40))	('Akt', 'Gene', (136, 139))	('Akt', 'Gene', '207', (136, 139))	('miR-203', 'Gene', '406986', (33, 40))	('abates', 'NegReg', (53, 59))	('ANRIL', 'Gene', (7, 12))	('BCL-2', 'Gene', '596', (112, 117))	('increases', 'PosReg', (23, 32))	('knockdown', 'Var', (13, 22))	('ncRNA', 'Gene', (1, 6))	('expression', 'Species', '29278', (64, 74))
561326	33435156	The knockdown of miR-203a partially reverses the effect of lncRNA-ANRIL silencing, certainly indicating that the ability of lncRNA-ANRIL to regulate anoikis is mediated by miR-203a (Figure 3 and Table 3).	('ANRIL', 'Gene', (131, 136))	('anoikis', 'Disease', (149, 156))	('ncRNA', 'Gene', '220202', (125, 130))	('miR-203', 'Gene', (172, 179))	('ncRNA', 'Gene', (60, 65))	('ANRIL', 'Gene', '100048912', (66, 71))	('ANRIL', 'Gene', '100048912', (131, 136))	('miR-203', 'Gene', (17, 24))	('miR-203', 'Gene', '406986', (17, 24))	('ncRNA', 'Gene', '220202', (60, 65))	('miR-203', 'Gene', '406986', (172, 179))	('ncRNA', 'Gene', (125, 130))	('knockdown', 'Var', (4, 13))	('ANRIL', 'Gene', (66, 71))
561345	33435156	Also, it was demonstrated that lncRNA-MEG3 impedes the metastasis of gastric cancer, at least partly via sponging miR-21.	('MEG3', 'Gene', '55384', (38, 42))	('miR-21', 'Gene', '406991', (114, 120))	('gastric cancer', 'Disease', (69, 83))	('ncRNA', 'Gene', (32, 37))	('metastasis', 'CPA', (55, 65))	('impedes', 'NegReg', (43, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('ncRNA', 'Gene', '220202', (32, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('sponging', 'Var', (105, 113))	('miR-21', 'Gene', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rat', 'Species', '10116', (20, 23))	('MEG3', 'Gene', (38, 42))
561348	33435156	Ectopic expression of lncRNA-MEG3 brings about the retarded growth of cancer cells in the absence of anchorage.	('ncRNA', 'Gene', (23, 28))	('MEG3', 'Gene', (29, 33))	('retarded growth', 'Phenotype', 'HP:0001510', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Ectopic expression', 'Var', (0, 18))	('ncRNA', 'Gene', '220202', (23, 28))	('expression', 'Species', '29278', (8, 18))	('MEG3', 'Gene', '55384', (29, 33))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
561349	33435156	The expression of lncRNA-MEG3 can be derepressed by miR-29-3p that negatively regulates the levels of DNA Methyltransferase 1 (DNMT1) and DNMT3B.	('regulates', 'Reg', (78, 87))	('DNMT3B', 'Gene', (138, 144))	('levels of', 'MPA', (92, 101))	('DNMT3B', 'Gene', '1789', (138, 144))	('ncRNA', 'Gene', (19, 24))	('expression', 'Species', '29278', (4, 14))	('ncRNA', 'Gene', '220202', (19, 24))	('expression', 'MPA', (4, 14))	('miR-29-3p', 'Chemical', '-', (52, 61))	('negatively', 'NegReg', (67, 77))	('MEG3', 'Gene', (25, 29))	('miR-29-3p', 'Var', (52, 61))	('MEG3', 'Gene', '55384', (25, 29))
561350	33435156	These findings suggest that miR-29-3p can modulate anchorage-independent growth by affecting lncRNA levels and autophagy processes (see Section 3.4.1) (Figure 3 and Table 3).	('ncRNA', 'Gene', '220202', (94, 99))	('miR-29-3p', 'Chemical', '-', (28, 37))	('affecting', 'Reg', (83, 92))	('miR-29-3p', 'Var', (28, 37))	('anchorage-independent growth', 'CPA', (51, 79))	('autophagy processes', 'CPA', (111, 130))	('modulate', 'Reg', (42, 50))	('ncRNA', 'Gene', (94, 99))
561353	33435156	Further, it was shown that the knockdown of lncRNA-MEG3 abrogates TGF-beta-induced EMT marker levels.	('abrogates', 'NegReg', (56, 65))	('ncRNA', 'Gene', '220202', (45, 50))	('TGF-beta', 'Gene', (66, 74))	('MEG3', 'Gene', '55384', (51, 55))	('MEG3', 'Gene', (51, 55))	('TGF-beta', 'Gene', '7039', (66, 74))	('ncRNA', 'Gene', (45, 50))	('knockdown', 'Var', (31, 40))
561362	33435156	Also, the knockdown of lncRNA-SNHG12 inactivates Wnt/beta-catenin signaling and decreases CCND1 expression, eventually limiting the metastasis of thyroid cancer in vivo.	('CCND1', 'Gene', '595', (90, 95))	('SNHG12', 'Gene', (30, 36))	('limiting', 'NegReg', (119, 127))	('CCND1', 'Gene', (90, 95))	('thyroid cancer', 'Disease', (146, 160))	('expression', 'MPA', (96, 106))	('inactivates', 'NegReg', (37, 48))	('knockdown', 'Var', (10, 19))	('SNHG12', 'Gene', '85028', (30, 36))	('metastasis', 'CPA', (132, 142))	('beta-catenin', 'Gene', (53, 65))	('ncRNA', 'Gene', (24, 29))	('thyroid cancer', 'Disease', 'MESH:D013964', (146, 160))	('beta-catenin', 'Gene', '1499', (53, 65))	('ncRNA', 'Gene', '220202', (24, 29))	('expression', 'Species', '29278', (96, 106))	('thyroid cancer', 'Phenotype', 'HP:0002890', (146, 160))	('decreases', 'NegReg', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
561367	33435156	The silencing of lncRNA-TINCR suppresses the cell survival, migration, invasion, anchorage-independent growth, and in vivo growth of breast cancer cells (Figure 3 and Table 3).	('breast cancer', 'Disease', (133, 146))	('anchorage-independent growth', 'CPA', (81, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('cell survival', 'CPA', (45, 58))	('suppresses', 'NegReg', (30, 40))	('invasion', 'CPA', (71, 79))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('migration', 'CPA', (60, 69))	('ncRNA', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('rat', 'Species', '10116', (63, 66))	('ncRNA', 'Gene', '220202', (18, 23))	('silencing', 'Var', (4, 13))
561379	33435156	EVs secreted from gemcitabine-resistant cells contain miR-222-3p, and this miRNA confers anoikis resistance in EV-receiving cells.	('miR-222-3p', 'Var', (54, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (18, 29))	('anoikis resistance', 'CPA', (89, 107))
561466	32850451	In a recent study, poor tumor differentiation (HR, 2.28; P = 0.022) and an advanced clinical stage (HR, 1.89; P = 0.042) were predictors of recurrence in the esophageal adenocarcinoma subgroup, and poor tumor differentiation was the only risk factor predicting recurrence (HR, 2.28, P = 0.009) in the total cohort of patients with EC achieving pCR after nCRT and surgery.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('poor', 'Var', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('adenocarcinoma', 'Disease', 'MESH:D000230', (169, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('adenocarcinoma', 'Disease', (169, 183))	('patients', 'Species', '9606', (317, 325))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (158, 183))
561618	29863142	Gram-negative organisms, which predominate in reflux esophagitis and Barrett's esophagus, produce specific constituents such as lipopolysaccharide (LPS) that activate the innate immune responses.46 Either directly or indirectly, LPS may stimulate the innate immune system's Toll-like receptor (TLR) 4 in the epithelial or inflammatory cells, leading to nuclear factor kappa B (NF-kappaB) activation.	('reflux esophagitis', 'Disease', 'MESH:D005764', (46, 64))	('reflux esophagitis', 'Disease', (46, 64))	('NF-kappaB', 'Gene', '4790', (377, 386))	('nuclear factor kappa B', 'Gene', '4790', (353, 375))	('esophagitis', 'Phenotype', 'HP:0100633', (53, 64))	('stimulate', 'PosReg', (237, 246))	('NF-kappaB', 'Gene', (377, 386))	('activation', 'PosReg', (388, 398))	('LPS', 'Var', (229, 232))	('nuclear factor kappa B', 'Gene', (353, 375))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (69, 88))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (128, 146))
561624	29863142	Campylobacter were significantly more enriched in GERD and Barrett's esophagus than in the controls and esophageal adenocarcinoma.	('Campylobacter', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('esophageal adenocarcinoma', 'Disease', (104, 129))	("Barrett's esophagus", 'Disease', (59, 78))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (59, 78))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (104, 129))	('GERD', 'Disease', (50, 54))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (104, 129))	('GERD', 'Disease', 'MESH:D005764', (50, 54))
561634	29863142	The presence of Porphyromonas gingivalis was also positively correlated with the severity (ie cancer cell differentiation and metastasis) of esophageal squamous cell carcinoma and with poor clinical outcome.	('Porphyromonas gingivalis', 'Species', '837', (16, 40))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (141, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('correlated', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('metastasis', 'CPA', (126, 136))	('Porphyromonas gingivalis', 'Gene', (16, 40))	('presence', 'Var', (4, 12))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
561644	29863142	Importantly, the presence of Fusobacterium nucleatum in cancer tissue was associated with significantly shorter survival time.	('survival time', 'CPA', (112, 125))	('shorter', 'NegReg', (104, 111))	('Fusobacterium nucleatum', 'Species', '851', (29, 52))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('presence', 'Var', (17, 25))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
561658	29863142	Immunotherapy (eg antibodies to PD-L1) ranks among the most exciting and successful developments in cancer care over the past decade.	('PD-L1', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PD-L1', 'Gene', '29126', (32, 37))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('antibodies', 'Var', (18, 28))
561660	29863142	If correct, the relationship between Fusobacterium nucleatum and poor clinical outcome identified in our previous work will have clinical implications.65  Accumulating evidence suggests that imbalanced gut microbiota induces changes in the enteric environment that lead to esophageal mucosal inflammation or tumorigenesis.	('changes', 'Reg', (225, 232))	('esophageal mucosal inflammation', 'Disease', (273, 304))	('esophageal mucosal inflammation', 'Disease', 'MESH:D007249', (273, 304))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('biota', 'Species', '131567', (211, 216))	('lead to', 'Reg', (265, 272))	('Fusobacterium nucleatum', 'Species', '851', (37, 60))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('enteric environment', 'MPA', (240, 259))	('imbalanced', 'Var', (191, 201))	('tumor', 'Disease', (308, 313))
561670	29563809	In univariate analysis, IKBKE expression was closely associated with decreased 3-year disease-free survival (HR 1.804, 95% CI 1.076-3.027; p=0.023) and overall survival (HR 2.118, 95% CI 1.189-3.773; p=0.009).	('IKBKE', 'Gene', (24, 29))	('IKBKE', 'Gene', '9641', (24, 29))	('decreased', 'NegReg', (69, 78))	('expression', 'Var', (30, 40))	('overall survival', 'CPA', (152, 168))	('disease-free survival', 'CPA', (86, 107))
561759	29563809	Patients with high preoperative IKBKE had a significant worse prognosis for DFS (p=0.023) and OS (p=0.009) than those with no IKBKE.	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('IKBKE', 'Gene', (32, 37))	('IKBKE', 'Gene', (126, 131))	('IKBKE', 'Gene', '9641', (32, 37))	('DFS', 'Disease', (76, 79))	('IKBKE', 'Gene', '9641', (126, 131))
561793	29563809	IkappaBalpha degradation was not affected, but IKKepsilon-mediated phosphorylation of cRel would result in dissociation of the IkappaBalpha-cRel complex, in a manner which was independent of IkappaBalpha Ser32 and Ser36 phosphorylation.	('IkappaBalpha', 'Gene', (0, 12))	('cRel', 'Gene', (140, 144))	('dissociation', 'MPA', (107, 119))	('result in', 'Reg', (97, 106))	('Ser32', 'Chemical', '-', (204, 209))	('phosphorylation', 'Var', (67, 82))	('IkappaBalpha', 'Gene', '4792', (191, 203))	('cRel', 'Gene', '5966', (140, 144))	('IKKepsilon', 'Gene', (47, 57))	('IkappaBalpha', 'Gene', (191, 203))	('IkappaBalpha', 'Gene', '4792', (127, 139))	('cRel', 'Gene', (86, 90))	('IkappaBalpha', 'Gene', '4792', (0, 12))	('cRel', 'Gene', '5966', (86, 90))	('Ser36', 'Chemical', '-', (214, 219))	('IkappaBalpha', 'Gene', (127, 139))	('IKKepsilon', 'Gene', '9641', (47, 57))
561806	29563809	Furthermore, researchers also found that IKKepsilon can functionally replace the AKT oncogene to promote malignant transformation by phosphorylating Akt-Thr308 and Ser473, with AKT activation.	('Akt', 'Gene', (149, 152))	('AKT', 'Gene', '207', (177, 180))	('AKT', 'Gene', '207', (81, 84))	('IKKepsilon', 'Gene', '9641', (41, 51))	('AKT', 'Gene', (177, 180))	('malignant transformation', 'CPA', (105, 129))	('Ser473', 'Var', (164, 170))	('AKT', 'Gene', (81, 84))	('Thr308', 'Chemical', '-', (153, 159))	('Akt', 'Gene', '207', (149, 152))	('IKKepsilon', 'Gene', (41, 51))	('Ser473', 'Chemical', '-', (164, 170))	('promote', 'PosReg', (97, 104))
561919	24766770	We seeded 5 x 104 cells/well TE4 or TE4CCR7+ and incubated for 10 min at 37 C with or without human recombinant CCL21/SLC (R&D Systems).	('TE4CCR7+', 'Var', (36, 44))	('TE4', 'Var', (29, 32))	('CCL21', 'Gene', '6366', (112, 117))	('human', 'Species', '9606', (94, 99))	('CCL21', 'Gene', (112, 117))
561939	24766770	The CCL21/SLC facilitated cell adhesion in the presence of HMVEC-LLy, but only a small difference was found between the two cell lines in its absence (10.3 +- 9.7 versus 3.0 +- 2.1, p = 0.012).	('HMVEC-LLy', 'Var', (59, 68))	('CCL21', 'Gene', '6366', (4, 9))	('cell adhesion', 'CPA', (26, 39))	('facilitated', 'PosReg', (14, 25))	('CCL21', 'Gene', (4, 9))
561982	23904462	Dichotomized at the median in controls, a significantly increased risk for EAC was observed in association with high gamma-H2AX ratio (odds ratio=2.94, 95% confidence interval=1.83-4.72).	('high', 'Var', (112, 116))	('EAC', 'Disease', (75, 78))	('H2AX', 'Gene', '3014', (123, 127))	('H2AX', 'Gene', (123, 127))	('EAC', 'Phenotype', 'HP:0011459', (75, 78))
562055	23904462	Our data showed that the association between high radiation-induced gamma-H2AX and increased EAC risk was significant in never and former smokers, but not in current smokers.	('EAC', 'Disease', (93, 96))	('H2AX', 'Gene', '3014', (74, 78))	('high', 'Var', (45, 49))	('H2AX', 'Gene', (74, 78))	('EAC', 'Phenotype', 'HP:0011459', (93, 96))
562156	19643189	Furthermore, patients with additional anxiety related to improper or unadjusted anchors may further overweight risks based on the recurrent mental image of esophageal cancer.	('anxiety', 'Disease', (38, 45))	('anxiety', 'Phenotype', 'HP:0000739', (38, 45))	('patients', 'Species', '9606', (13, 21))	('overweight', 'PosReg', (100, 110))	('esophageal cancer', 'Disease', (156, 173))	('anxiety', 'Disease', 'MESH:D001008', (38, 45))	('overweight', 'Phenotype', 'HP:0025502', (100, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('improper', 'Var', (57, 65))
562190	17576439	The hypothesis is that gerd results in acute mucosal injury (esophagitis), thereby promoting cellular proliferation and inducing specialized columnar metaplasia of the normal squamous epithelium lining the esophagus.	('promoting', 'PosReg', (83, 92))	('acute mucosal injury', 'Disease', (39, 59))	('columnar metaplasia', 'Disease', (141, 160))	('gerd', 'Var', (23, 27))	('acute mucosal injury', 'Disease', 'MESH:D058186', (39, 59))	('columnar metaplasia', 'Disease', 'MESH:D008679', (141, 160))	('esophagitis', 'Phenotype', 'HP:0100633', (61, 72))	('inducing', 'PosReg', (120, 128))	('esophagitis', 'Disease', (61, 72))	('cellular proliferation', 'CPA', (93, 115))	('esophagitis', 'Disease', 'MESH:D004941', (61, 72))
562204	17576439	In esophageal intestinal metaplasia, CK7 positivity is found in superficial and deep glands, and CK20 positivity is limited to superficial glands ("Barrett CK 7/20 pattern").	('CK20', 'Gene', (97, 101))	('esophageal intestinal metaplasia', 'Disease', (3, 35))	('CK7', 'Var', (37, 40))	('CK 7', 'Gene', '3855', (156, 160))	('CK20', 'Gene', '54474', (97, 101))	('esophageal intestinal metaplasia', 'Phenotype', 'HP:0012859', (3, 35))	('esophageal intestinal metaplasia', 'Disease', 'MESH:D008679', (3, 35))	('CK 7', 'Gene', (156, 160))
562216	17576439	Although the natural history of dysplasia is not known, it was recently reported that the presence of low-grade dysplasia in Barrett epithelia conferred an increased risk of progression to malignancy.	('malignancy', 'Disease', 'MESH:D009369', (189, 199))	('dysplasia in Barrett epithelia', 'Disease', (112, 142))	('dysplasia in Barrett epithelia', 'Disease', 'MESH:D001471', (112, 142))	('dysplasia', 'Disease', (32, 41))	('malignancy', 'Disease', (189, 199))	('dysplasia', 'Disease', 'MESH:D004476', (32, 41))	('dysplasia', 'Disease', (112, 121))	('dysplasia', 'Disease', 'MESH:D004476', (112, 121))	('low-grade', 'Var', (102, 111))
562247	17576439	The hypothesis is that gerd leads to acute mucosal injury, promotes cellular proliferation, and induces specialized intestinal metaplasia of the esophagus.	('intestinal metaplasia', 'Disease', 'MESH:D008679', (116, 137))	('acute mucosal injury', 'Disease', (37, 57))	('induces', 'Reg', (96, 103))	('cellular proliferation', 'CPA', (68, 90))	('promotes', 'PosReg', (59, 67))	('acute mucosal injury', 'Disease', 'MESH:D058186', (37, 57))	('gerd', 'Var', (23, 27))	('intestinal metaplasia', 'Disease', (116, 137))
562257	17576439	A number of molecular alterations have been reported in Barrett esophagus, and these molecular alterations are implicated in the molecular pathogenesis of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (155, 180))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (155, 180))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (56, 73))	('alterations', 'Var', (22, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('Barrett esophagus', 'Disease', (56, 73))	('esophageal adenocarcinoma', 'Disease', (155, 180))	('implicated', 'Reg', (111, 121))
562264	17576439	A recently published and ongoing phase 4 study, which has used a well-established endoscopic biopsy protocol to prospectively evaluate more than 300 patients for 15 years, has provided further convincing evidence for using flow cytometry to determine tissue ploidy in Barrett epithelia.	('Barrett epithelia', 'Disease', (268, 285))	('patients', 'Species', '9606', (149, 157))	('Barrett epithelia', 'Disease', 'MESH:D001471', (268, 285))	('tissue ploidy', 'Var', (251, 264))
562267	17576439	Patients whose baseline biopsies had aneuploidy, tetraploidy (4N), or hgd had 5-year cancer incidences of 43%, 56%, and 59% respectively, prompting a recommendation for more frequent surveillance for that group.	('tetraploidy', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('aneuploidy', 'Disease', (37, 47))	('cancer', 'Disease', (85, 91))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('aneuploidy', 'Disease', 'MESH:D000782', (37, 47))
562269	17576439	Subsequent analysis of study data has determined specific ploidy variables that appear to be even more highly predictive of cancer progression:namely, aneuploid content greater than 2.7N, and a 4N fraction greater than 6%.	('cancer', 'Disease', (124, 130))	('4N fraction', 'MPA', (194, 205))	('aneuploid content', 'Var', (151, 168))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('predictive', 'Reg', (110, 120))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
562275	17576439	Point mutations leading to loss of function of TP53 is a common mechanism of inactivation, and more than 90% of TP53 mutations have been located in the conserved dna binding domain (exons 5-8).	('mutations', 'Var', (117, 126))	('loss of function', 'NegReg', (27, 43))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', '7157', (112, 116))	('Point mutations', 'Var', (0, 15))	('TP53', 'Gene', (47, 51))	('TP53', 'Gene', (112, 116))
562277	17576439	Mutations in the TP53 gene were initially reported in primary esophageal adenocarcinomas and associated Barrett epithelium in 1991.	('esophageal adenocarcinomas', 'Disease', (62, 88))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (62, 87))	('Barrett epithelium', 'Disease', (104, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('reported', 'Reg', (42, 50))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (62, 88))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
562278	17576439	These findings were subsequently confirmed in several phase 1 and 2 studies, and the spectrum of TP53 alterations in Barrett esophagus has been extensively characterized.	('TP53', 'Gene', '7157', (97, 101))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (117, 134))	('TP53', 'Gene', (97, 101))	('alterations', 'Var', (102, 113))	('Barrett esophagus', 'Disease', (117, 134))
562279	17576439	The finding of TP53 mutations in non-dysplastic Barrett epithelia suggests that TP53 may be altered early in the metaplasia-dysplasia-carcinoma sequence, and it may therefore be a useful biomarker in endoscopic surveillance programs.	('non-dysplastic Barrett epithelia', 'Disease', 'MESH:D001471', (33, 65))	('TP53', 'Gene', '7157', (80, 84))	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (113, 143))	('TP53', 'Gene', (80, 84))	('metaplasia-dysplasia-carcinoma', 'Disease', (113, 143))	('TP53', 'Gene', '7157', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('TP53', 'Gene', (15, 19))	('non-dysplastic Barrett epithelia', 'Disease', (33, 65))	('altered', 'Reg', (92, 99))	('mutations', 'Var', (20, 29))
562280	17576439	In a 10-year prospective study of surgically resected esophageal adenocarcinomas, TP53 mutations were associated with poor tumour differentiation and with reduced disease-free and overall survival following surgical resection.	('TP53', 'Gene', (82, 86))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (54, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('reduced', 'NegReg', (155, 162))	('poor', 'NegReg', (118, 122))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('tumour', 'Disease', (123, 129))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (54, 79))	('esophageal adenocarcinomas', 'Disease', (54, 80))	('TP53', 'Gene', '7157', (82, 86))	('mutations', 'Var', (87, 96))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
562281	17576439	Of particular biologic interest was the observation that patterns of TP53 mutation in esophageal adenocarcinomas were predominantly G:C to A:T transitions at CpG dinucleotides, suggesting that TP53 mutations result from endogenous mechanisms that likely involve spontaneous deamination into thymine of the 5'-methylated cytosine that frequently occurs at CpG di-nucleotides.	('result from', 'Reg', (208, 219))	('esophageal adenocarcinomas', 'Disease', (86, 112))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (86, 111))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('TP53', 'Gene', '7157', (193, 197))	('di-nucleotides', 'Chemical', 'MESH:D015226', (359, 373))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (158, 175))	('thymine', 'Chemical', 'MESH:D013941', (291, 298))	('mutations', 'Var', (198, 207))	('TP53', 'Gene', (193, 197))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (86, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('deamination', 'MPA', (274, 285))	('cytosine', 'Chemical', 'MESH:D003596', (320, 328))
562282	17576439	Because this mechanism is enhanced by exposure to oxy-radicals and nitro-radicals, we hypothesized that local overproduction of nitric oxide, a consequence of chronic gerd, may enhance the rate of formation of spontaneous TP53 mutations in Barrett esophagus.	('nitric oxide', 'Chemical', 'MESH:D009569', (128, 140))	('nitro-radicals', 'Chemical', '-', (67, 81))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (240, 257))	('overproduction', 'PosReg', (110, 124))	('oxy-radicals', 'Chemical', '-', (50, 62))	('enhance', 'PosReg', (177, 184))	('TP53', 'Gene', '7157', (222, 226))	('TP53', 'Gene', (222, 226))	('formation', 'MPA', (197, 206))	('mutations', 'Var', (227, 236))
562283	17576439	Although no phase 4 studies have evaluated TP53 mutations or protein overexpression in Barrett epithelia as predictors of malignant progression, loss of heterozygosity (loh) of 17p (inclusive of TP53) was evaluated in one ongoing phase 4 study in conjunction with flow cytometry.	('TP53', 'Gene', (195, 199))	('loss', 'Var', (145, 149))	('Barrett epithelia', 'Disease', (87, 104))	('Barrett epithelia', 'Disease', 'MESH:D001471', (87, 104))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('TP53', 'Gene', '7157', (195, 199))	('mutations', 'Var', (48, 57))
562290	17576439	As a result of a single base polymorphism (G870A) of CCND1, alternative gene splicing is thought to give rise to two functional transcripts.	('result', 'Reg', (5, 11))	('G870A', 'Var', (43, 48))	('CCND1', 'Gene', (53, 58))	('CCND1', 'Gene', '595', (53, 58))	('give', 'Reg', (100, 104))	('G870A', 'Mutation', 'rs9344', (43, 48))
562292	17576439	The variant transcript (cyclin D1b), a consequence of the polymorphic A-allele, encodes a truncated protein isoform with an altered C-terminal domain that has been implicated in neoplastic transformation.	('variant', 'Var', (4, 11))	('C-terminal', 'MPA', (132, 142))	('cyclin D1', 'Gene', (24, 33))	('cyclin D1', 'Gene', '595', (24, 33))
562293	17576439	A report from a prospective case-control (phase 4) study said that individuals with the CCND1 A/A genotype were at increased risk for gerd, Barrett esophagus, and esophageal adenocarcinoma, supporting the hypothesis that this polymorphism is an individual susceptibility factor in the molecular progression of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (163, 188))	('esophageal adenocarcinoma', 'Disease', (310, 335))	('esophageal adenocarcinoma', 'Disease', (163, 188))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (140, 157))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (310, 335))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (310, 335))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (163, 188))	('A/A', 'Var', (94, 97))	('CCND1', 'Gene', (88, 93))	('Barrett esophagus', 'Disease', (140, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('CCND1', 'Gene', '595', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('gerd', 'Disease', (134, 138))
562297	17576439	Alterations of CDKN2A are reported frequently in various human malignancies, but mechanisms of CDKN2A inactivation appear to vary between tumour types.	('CDKN2A', 'Gene', (15, 21))	('human', 'Species', '9606', (57, 62))	('Alterations', 'Var', (0, 11))	('CDKN2A', 'Gene', (95, 101))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('CDKN2A', 'Gene', '1029', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('CDKN2A', 'Gene', '1029', (95, 101))	('malignancies', 'Disease', (63, 75))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', (138, 144))
562298	17576439	Point mutations in Barrett esophagus and esophageal adenocarcinoma are relatively uncommon, but 9p loh and promoter hypermethylation appear to be frequent mechanisms of CDKN2A inactivation.	('CDKN2A', 'Gene', (169, 175))	('CDKN2A', 'Gene', '1029', (169, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('esophageal adenocarcinoma', 'Disease', (41, 66))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (41, 66))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (41, 66))	('Point mutations', 'Var', (0, 15))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (19, 36))
562299	17576439	Although CDKN2A alterations have been the subject of phase 1 and 2 studies only, they are increasingly recognized as critical early molecular lesions associated with clonal proliferation within Barrett epithelia.	('CDKN2A', 'Gene', '1029', (9, 15))	('alterations', 'Var', (16, 27))	('Barrett epithelia', 'Disease', (194, 211))	('Barrett epithelia', 'Disease', 'MESH:D001471', (194, 211))	('CDKN2A', 'Gene', (9, 15))
562303	17576439	Currently, hgd remains the most reliable predictor of progression to invasive esophageal adenocarcinoma, but potentially promising biomarkers include aneuploidy (dna content greater than 2.7N, or 4N fraction greater than 6%, or both), 17p loh and TP53 mutations, cyclin D1 protein overexpression, and CDKN2A alterations.	('17p', 'Gene', (235, 238))	('TP53', 'Gene', (247, 251))	('aneuploidy', 'Disease', 'MESH:D000782', (150, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('invasive esophageal adenocarcinoma', 'Disease', (69, 103))	('cyclin D1', 'Gene', '595', (263, 272))	('CDKN2A', 'Gene', (301, 307))	('CDKN2A', 'Gene', '1029', (301, 307))	('cyclin D1', 'Gene', (263, 272))	('overexpression', 'PosReg', (281, 295))	('invasive esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (69, 103))	('alterations', 'Reg', (308, 319))	('mutations', 'Var', (252, 261))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (78, 103))	('aneuploidy', 'Disease', (150, 160))	('TP53', 'Gene', '7157', (247, 251))
562306	34046198	miR-1299 has mainly been investigated in cancers.	('miR-1299', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
562309	34046198	This article discusses how the microRNA miR-1299 plays a role as a tumor suppressor and participates in the regulation of tumor pathogenesis.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('participates', 'Reg', (88, 100))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (67, 72))	('miR-1299', 'Var', (40, 48))	('tumor', 'Disease', (122, 127))
562326	34046198	Here we discuss the regulatory mechanism of dysregulated miRNAs in cancer and what biological functions they perform.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('dysregulated', 'Var', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
562329	34046198	As a tumor suppressor, miR-1299 inhibits tumor cell proliferation, invasion and metastasis, improves chemotherapeutic sensitivity and regulates the development and progression of tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('men', 'Species', '9606', (155, 158))	('regulates', 'Reg', (134, 143))	('improves', 'PosReg', (92, 100))	('tumors', 'Disease', (179, 185))	('tumor', 'Disease', (41, 46))	('chemotherapeutic sensitivity', 'MPA', (101, 129))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('inhibits', 'NegReg', (32, 40))	('tumor', 'Disease', (5, 10))	('miR-1299', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (179, 184))
562342	34046198	miR-1299 contains a hsa_circ_0136666 binding site; thus miR-1299 may function as a downstream RNA of hsa_circ_0136666 to act as a tumor suppressor in breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (150, 163))	('miR-1299', 'Var', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
562344	34046198	Moreover, miR-1299 inhibits cell cycle progression by binding to the transcript of one of its targets, CDK6.	('miR-1299', 'Var', (10, 18))	('cell cycle progression', 'CPA', (28, 50))	('CDK6', 'Gene', (103, 107))	('CDK6', 'Gene', '1021', (103, 107))	('inhibits', 'NegReg', (19, 27))	('binding', 'Interaction', (54, 61))
562345	34046198	These results indicate that miR-1299 can act as a tumor suppressor in breast cancer cells and regulate the growth and metastasis of breast cancer through the hsa_circ_0136666/miR-1299/CDK6 axis.	('regulate', 'Reg', (94, 102))	('miR-1299', 'Var', (28, 36))	('growth', 'CPA', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('CDK6', 'Gene', '1021', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('metastasis of breast cancer', 'Disease', 'MESH:D001943', (118, 145))	('CDK6', 'Gene', (184, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('tumor', 'Disease', (50, 55))	('metastasis of breast cancer', 'Disease', (118, 145))
562349	34046198	The results showed that miR-1299 is regulated by the upstream molecular sponge circ_0006528; knocking down circ_0006528 increased the expression of miR-1299, which decreased the IC50 value of PTX as well as hindering cell proliferation, migration, invasion and autophagy and induced apoptosis in breast cancer cells in vitro.	('cell proliferation', 'CPA', (217, 235))	('PTX', 'Chemical', 'MESH:D017239', (192, 195))	('migration', 'CPA', (237, 246))	('autophagy', 'CPA', (261, 270))	('apoptosis', 'CPA', (283, 292))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('IC50 value', 'MPA', (178, 188))	('hindering', 'NegReg', (207, 216))	('invasion', 'CPA', (248, 256))	('miR-1299', 'Gene', (148, 156))	('circ_0006528', 'Var', (107, 119))	('expression', 'MPA', (134, 144))	('induced', 'Reg', (275, 282))	('breast cancer', 'Phenotype', 'HP:0003002', (296, 309))	('increased', 'PosReg', (120, 129))	('decreased', 'NegReg', (164, 173))	('knocking down circ_0006528', 'Var', (93, 119))	('breast cancer', 'Disease', 'MESH:D001943', (296, 309))	('breast cancer', 'Disease', (296, 309))
562350	34046198	Interestingly, miR-1299 is able to target the 3'-UTR of CDK8; in vivo experiments showed that circ_0006528 knockdown downregulated CDK8 expression via reducing the sponging of miR-1299.	('knockdown', 'Var', (107, 116))	('expression', 'MPA', (136, 146))	('CDK8', 'Gene', (131, 135))	('CDK8', 'Gene', (56, 60))	('reducing', 'NegReg', (151, 159))	('CDK8', 'Gene', '1024', (56, 60))	('men', 'Species', '9606', (76, 79))	('downregulated', 'NegReg', (117, 130))	('CDK8', 'Gene', '1024', (131, 135))	('sponging of miR-1299', 'MPA', (164, 184))	('circ_0006528', 'Var', (94, 106))
562353	34046198	As miR-1299 is a tumor suppressor, its downregulation maintains the high migration and invasion characteristics of TNBC cells.	('miR-1299', 'Var', (3, 11))	('tumor', 'Disease', (17, 22))	('invasion characteristics', 'CPA', (87, 111))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('high migration', 'CPA', (68, 82))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('downregulation', 'NegReg', (39, 53))
562354	34046198	On this basis, miR-1299 was found to inhibit the migration and invasion of TNBC cells at least in part by inhibiting the expression of MMPs, providing new potential therapeutic targets for TNBC treatment.	('men', 'Species', '9606', (199, 202))	('TNBC', 'Gene', (75, 79))	('migration', 'CPA', (49, 58))	('inhibiting', 'NegReg', (106, 116))	('inhibit', 'NegReg', (37, 44))	('expression', 'MPA', (121, 131))	('miR-1299', 'Var', (15, 23))	('invasion', 'CPA', (63, 71))	('MMPs', 'Protein', (135, 139))
562363	34046198	PI003, as a novel synthesized pan-PIM inhibitor, could induce the death-receptor and mitochondrial apoptosis involved in some miRNA regulation, and also possesses remarkable antitumor activity and apoptosis-inducing capacity in vivo.	('mitochondrial apoptosis', 'CPA', (85, 108))	('tumor', 'Disease', (178, 183))	('PI003', 'Chemical', '-', (0, 5))	('PIM', 'Gene', (34, 37))	('PIM', 'Gene', '5292', (34, 37))	('apoptosis-inducing', 'CPA', (197, 215))	('death', 'Disease', 'MESH:D003643', (66, 71))	('death', 'Disease', (66, 71))	('induce', 'PosReg', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('miRNA regulation', 'MPA', (126, 142))	('PI003', 'Var', (0, 5))
562364	34046198	found that PI003 induces apoptosis via the death-receptor and mitochondrial pathways in HeLa cells.	('death', 'Disease', 'MESH:D003643', (43, 48))	('PI003', 'Var', (11, 16))	('death', 'Disease', (43, 48))	('HeLa', 'CellLine', 'CVCL:0030', (88, 92))	('PI003', 'Chemical', '-', (11, 16))	('apoptosis', 'CPA', (25, 34))	('mitochondrial pathways', 'Pathway', (62, 84))
562365	34046198	The authors used miRNA microarray analysis to identify miRNAs expressed in HeLa cells when PI003 induced apoptosis.	('apoptosis', 'CPA', (105, 114))	('PI003', 'Chemical', '-', (91, 96))	('HeLa', 'CellLine', 'CVCL:0030', (75, 79))	('PI003', 'Var', (91, 96))
562366	34046198	The results showed that miR-1299 was upregulated during PI003-induced apoptosis in HeLa cells compared with control cells and that a miR-1299 mimic markedly decreased the expression level of PIM1, suggesting that miR-1299 negatively regulates PIM1 and possesses remarkable antitumor activity and apoptosis-inducing effects in vitro.	('PIM1', 'Gene', (191, 195))	('upregulated', 'PosReg', (37, 48))	('PIM1', 'Gene', '5292', (191, 195))	('miR-1299', 'Var', (213, 221))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('PIM1', 'Gene', (243, 247))	('PI003-induced', 'Var', (56, 69))	('negatively', 'NegReg', (222, 232))	('PIM1', 'Gene', '5292', (243, 247))	('regulates', 'Reg', (233, 242))	('PI003', 'Chemical', '-', (56, 61))	('miR-1299', 'Gene', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('apoptosis', 'CPA', (70, 79))	('expression level', 'MPA', (171, 187))	('tumor', 'Disease', (277, 282))	('decreased', 'NegReg', (157, 166))	('HeLa', 'CellLine', 'CVCL:0030', (83, 87))
562374	34046198	The data from qRT-PCR revealed that circ_0005230 expression was enhanced in CCA specimens compared with healthy tissues.	('CCA', 'Disease', (76, 79))	('expression', 'MPA', (49, 59))	('CCA', 'Phenotype', 'HP:0030153', (76, 79))	('men', 'Species', '9606', (85, 88))	('circ_0005230', 'Var', (36, 48))	('enhanced', 'PosReg', (64, 72))
562375	34046198	After validating the elevation of circ_0005230 in CCA specimens, its clinical implication was investigated; analysis indicated that circ_0005230 expression is related to larger tumor size, positive lymph node invasion and advanced tumor node metastasis stages for CCA patients.	('patients', 'Species', '9606', (268, 276))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('larger', 'PosReg', (170, 176))	('CCA', 'Phenotype', 'HP:0030153', (264, 267))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('CCA', 'Phenotype', 'HP:0030153', (50, 53))	('circ_0005230', 'Var', (132, 144))	('positive lymph node invasion', 'CPA', (189, 217))	('tumor', 'Disease', (177, 182))	('CCA', 'Disease', (264, 267))	('related', 'Reg', (159, 166))	('men', 'Species', '9606', (59, 62))
562376	34046198	Both functional assays and in vivo research experiments showed that si-circ_0005230 cotransfected with an miR-1299 inhibitor partially rescued the tumor-suppressing effects of si-circ_0005230 in CCA cells.	('rescued', 'PosReg', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('CCA', 'Phenotype', 'HP:0030153', (195, 198))	('si-circ_0005230', 'Var', (176, 191))	('men', 'Species', '9606', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('CCA', 'Disease', (195, 198))
562377	34046198	In general, miR-1299 inhibits the proliferation and migration of CCA tumor cells by negatively regulating its molecular sponge circ_0005230, thereby exerting a tumor-suppressive effect.	('proliferation', 'CPA', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('inhibits', 'NegReg', (21, 29))	('migration', 'CPA', (52, 61))	('CCA tumor', 'Disease', 'MESH:C536211', (65, 74))	('tumor', 'Disease', (69, 74))	('negatively', 'NegReg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('CCA tumor', 'Disease', (65, 74))	('CCA', 'Phenotype', 'HP:0030153', (65, 68))	('miR-1299', 'Var', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
562382	34046198	found that miR-1299 is expressed at low levels in ESCC tissues compared with normal tissues and that it can inhibit the autophagy of ESCC cells induced by starvation or rapamycin.	('miR-1299', 'Var', (11, 19))	('rapamycin', 'Chemical', 'MESH:D020123', (169, 178))	('inhibit', 'NegReg', (108, 115))	('autophagy of', 'CPA', (120, 132))
562383	34046198	In order to further study the regulation mechanism of miR-1299, dual luciferase reporter gene detection showed that miR-1299 significantly reduced the luciferase activity of EGFR 3'-UTR.	('EGFR', 'Gene', (174, 178))	('activity', 'MPA', (162, 170))	('luciferase', 'Enzyme', (151, 161))	('reduced', 'NegReg', (139, 146))	('miR-1299', 'Var', (116, 124))	('EGFR', 'Gene', '1956', (174, 178))
562384	34046198	At the same time, the EGFR mRNA expression level detected by qRT-PCR showed that, miR-1299 significantly reduces the expression of EGFR.	('expression', 'MPA', (117, 127))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (22, 26))	('miR-1299', 'Var', (82, 90))	('reduces', 'NegReg', (105, 112))	('EGFR', 'Gene', (22, 26))
562385	34046198	miR-1299 has a binding sequence in the 3'-UTR of EGFR that regulates the downstream Akt-mTOR pathway, thereby promoting the autophagy of ESCC cells.	('EGFR', 'Gene', '1956', (49, 53))	('miR-1299', 'Var', (0, 8))	('Akt', 'Gene', '207', (84, 87))	('EGFR', 'Gene', (49, 53))	('ESCC', 'Disease', (137, 141))	('mTOR', 'Gene', (88, 92))	('regulates', 'Reg', (59, 68))	('Akt', 'Gene', (84, 87))	('promoting', 'PosReg', (110, 119))	('mTOR', 'Gene', '2475', (88, 92))	('autophagy of', 'CPA', (124, 136))
562389	34046198	This finding provides a basis for miR-1299 to act as a tumor suppressor to regulate ESCC.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miR-1299', 'Var', (34, 42))	('ESCC', 'Disease', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))
562395	34046198	Researchers also found that the cell cycle regulator CDK6 is a target of miR-1299, and that miR-1299 can bind to the 3'-UTR of CDK6.	('CDK6', 'Gene', (53, 57))	('CDK6', 'Gene', '1021', (53, 57))	('miR-1299', 'Var', (73, 81))	('CDK6', 'Gene', (127, 131))	('bind', 'Interaction', (105, 109))	('CDK6', 'Gene', '1021', (127, 131))	('miR-1299', 'Var', (92, 100))
562396	34046198	The simultaneous downregulation of CDK6 and miR-1299 increased the proliferation ability of HCC cells, indicating that miR-1299 inhibits the proliferation of HCC cells by downregulating the expression of CDK6.	('CDK6', 'Gene', '1021', (35, 39))	('CDK6', 'Gene', (204, 208))	('CDK6', 'Gene', '1021', (204, 208))	('proliferation ability of HCC cells', 'CPA', (67, 101))	('inhibits', 'NegReg', (128, 136))	('proliferation', 'CPA', (141, 154))	('downregulation', 'NegReg', (17, 31))	('increased', 'PosReg', (53, 62))	('HCC', 'Phenotype', 'HP:0001402', (92, 95))	('miR-1299', 'Var', (44, 52))	('downregulating', 'NegReg', (171, 185))	('expression', 'MPA', (190, 200))	('miR-1299', 'Var', (119, 127))	('HCC', 'Phenotype', 'HP:0001402', (158, 161))	('CDK6', 'Gene', (35, 39))
562397	34046198	At the same time, they revealed a negative correlation between miR-1299 and CTNND1 expression levels; miR-1299 inhibition significantly increased CTNND1 protein levels, and miR-1299 mimics reduced the expression of CTNND1 to promote CTNND1-induced proliferation and invasion of HCC cells.	('invasion of HCC cells', 'CPA', (266, 287))	('CTNND1', 'Gene', (146, 152))	('CTNND1', 'Gene', '1500', (146, 152))	('expression', 'MPA', (201, 211))	('HCC', 'Phenotype', 'HP:0001402', (278, 281))	('miR-1299', 'Gene', (102, 110))	('CTNND1', 'Gene', (215, 221))	('CTNND1', 'Gene', '1500', (215, 221))	('mimics', 'Var', (182, 188))	('miR-1299', 'Var', (173, 181))	('increased', 'PosReg', (136, 145))	('CTNND1', 'Gene', (76, 82))	('CTNND1', 'Gene', '1500', (76, 82))	('proliferation', 'CPA', (248, 261))	('reduced', 'NegReg', (189, 196))	('CTNND1', 'Gene', (233, 239))	('CTNND1', 'Gene', '1500', (233, 239))	('promote', 'PosReg', (225, 232))	('inhibition', 'NegReg', (111, 121))
562398	34046198	The above results indicate that miR-1299 can be used as a tumor suppressor to inhibit the proliferation and migration of liver cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('proliferation', 'CPA', (90, 103))	('inhibit', 'NegReg', (78, 85))	('liver cancer', 'Disease', 'MESH:D006528', (121, 133))	('miR-1299', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('liver cancer', 'Phenotype', 'HP:0002896', (121, 133))	('liver cancer', 'Disease', (121, 133))
562406	34046198	Hence, ETS1 was selected for further study, and luciferase reporter gene detection showed that it directly binds to miR-1299.	('miR-1299', 'Var', (116, 124))	('binds', 'Interaction', (107, 112))	('ETS1', 'Gene', '2113', (7, 11))	('ETS1', 'Gene', (7, 11))
562407	34046198	In addition, the ectopic expression of miR-1299 resulted in a decrease in the expression of ETS1 at the mRNA and protein levels, which proved that ETS1 is the downstream target of miR-1299.	('expression', 'MPA', (78, 88))	('ETS1', 'Gene', '2113', (147, 151))	('ETS1', 'Gene', (147, 151))	('ectopic expression', 'MPA', (17, 35))	('decrease', 'NegReg', (62, 70))	('miR-1299', 'Var', (39, 47))	('ETS1', 'Gene', '2113', (92, 96))	('ETS1', 'Gene', (92, 96))
562408	34046198	Thus miR-1299 can act as a tumor suppressor of GC through the miR-1299/ETS1 pathway.	('ETS1', 'Gene', '2113', (71, 75))	('ETS1', 'Gene', (71, 75))	('GC', 'Phenotype', 'HP:0012126', (47, 49))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('miR-1299', 'Var', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
562417	34046198	Furthermore, abnormality of NEK2 has been found to be linked to the incidence and development of many malignant tumors.	('abnormality', 'Var', (13, 24))	('malignant tumors', 'Disease', (102, 118))	('development', 'CPA', (82, 93))	('malignant tumors', 'Disease', 'MESH:D009369', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('NEK2', 'Gene', (28, 32))	('NEK2', 'Gene', '4751', (28, 32))	('men', 'Species', '9606', (89, 92))	('linked', 'Reg', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
562420	34046198	To confirm the effect of the miR-1299/NEK2 pathway on the proliferation and migration of prostate cancer cells, MTT assays, flow cytometry and Transwell assays were conducted; overexpression of miR-1299 was found to significantly inhibit the expression of NEK2, reduce the relative viability of PCa cells and reduce their proliferation and migration rates.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('PCa', 'Disease', (295, 298))	('NEK2', 'Gene', (256, 260))	('migration of prostate cancer', 'Disease', 'MESH:D011471', (76, 104))	('relative viability', 'CPA', (273, 291))	('NEK2', 'Gene', '4751', (256, 260))	('NEK2', 'Gene', (38, 42))	('overexpression', 'PosReg', (176, 190))	('MTT', 'Chemical', 'MESH:C070243', (112, 115))	('PCa', 'Phenotype', 'HP:0012125', (295, 298))	('NEK2', 'Gene', '4751', (38, 42))	('miR-1299', 'Var', (194, 202))	('inhibit', 'NegReg', (230, 237))	('reduce', 'NegReg', (309, 315))	('reduce', 'NegReg', (262, 268))	('migration of prostate cancer', 'Disease', (76, 104))	('expression', 'MPA', (242, 252))
562421	34046198	These results indicate that miR-1299 is a novel tumor suppressor in PCa through its negative regulation of NEK2.	('PCa', 'Disease', (68, 71))	('tumor', 'Disease', (48, 53))	('miR-1299', 'Var', (28, 36))	('PCa', 'Phenotype', 'HP:0012125', (68, 71))	('NEK2', 'Gene', (107, 111))	('NEK2', 'Gene', '4751', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('negative regulation', 'NegReg', (84, 103))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
562424	34046198	found that miR-1299 is downregulated in melanin deposition diseases, including chloasma, and its expression level is inversely proportional to that of ARG2.	('chloasma', 'Disease', (79, 87))	('melanin deposition diseases', 'Disease', (40, 67))	('downregulated', 'NegReg', (23, 36))	('ARG2', 'Gene', (151, 155))	('ARG2', 'Gene', '384', (151, 155))	('chloasma', 'Phenotype', 'HP:0025272', (79, 87))	('melanin', 'Chemical', 'MESH:D008543', (40, 47))	('miR-1299', 'Var', (11, 19))	('expression', 'MPA', (97, 107))
562432	34046198	Studies have shown that miR-1299 can inhibit cell proliferation, colony formation and 5-ethynyl 2'-deoxyuridine (EdU) incorporation and induce G0/G1 cell cycle arrest in OC cells.	('induce', 'PosReg', (136, 142))	('OC', 'Phenotype', 'HP:0100615', (170, 172))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (149, 166))	('miR-1299', 'Var', (24, 32))	('EdU', 'Chemical', 'MESH:C031086', (113, 116))	('inhibit', 'NegReg', (37, 44))	('cell proliferation', 'CPA', (45, 63))	('arrest', 'Disease', 'MESH:D006323', (160, 166))	("5-ethynyl 2'-deoxyuridine", 'Chemical', 'MESH:C031086', (86, 111))	('arrest', 'Disease', (160, 166))	('colony formation', 'CPA', (65, 81))
562433	34046198	After transfection into a constructed ovarian cancer model via liposomes, miR-1299 significantly reduced the tumor volume and weight, confirming the tumor-suppressive function of miR-1299 in OC tumorigenesis.	('miR-1299', 'Gene', (74, 82))	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('miR-1299', 'Var', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('ovarian cancer', 'Disease', 'MESH:D010051', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('reduced', 'NegReg', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ovarian cancer', 'Disease', (38, 52))	('tumor', 'Disease', (109, 114))	('OC', 'Phenotype', 'HP:0100615', (191, 193))
562434	34046198	The authors also proposed that miR-1299 is a novel negative regulator of NOTCH3, which is downregulated in OC.	('NOTCH3', 'Gene', '4854', (73, 79))	('miR-1299', 'Var', (31, 39))	('negative', 'NegReg', (51, 59))	('downregulated', 'NegReg', (90, 103))	('OC', 'Phenotype', 'HP:0100615', (107, 109))	('NOTCH3', 'Gene', (73, 79))
562438	34046198	The lncRNA TUG1 acts as a sponge for miR-1299 and promotes cell proliferation by upregulating NOTCH3.	('TUG1', 'Gene', '55000', (11, 15))	('upregulating', 'PosReg', (81, 93))	('TUG1', 'Gene', (11, 15))	('cell proliferation', 'CPA', (59, 77))	('NOTCH3', 'Gene', (94, 100))	('miR-1299', 'Var', (37, 45))	('promotes', 'PosReg', (50, 58))	('NOTCH3', 'Gene', '4854', (94, 100))
562441	34046198	The proposed mechanism was that circTNPO3 acted as a sponge for miR-1299, and downregulation of circTNPO3 significantly promoted miR-1299 expression.	('downregulation', 'Var', (78, 92))	('circTNPO3', 'Gene', (96, 105))	('miR-1299', 'Gene', (129, 137))	('promoted', 'PosReg', (120, 128))	('circTNPO3', 'Chemical', '-', (32, 41))	('expression', 'MPA', (138, 148))	('circTNPO3', 'Chemical', '-', (96, 105))
562443	34046198	Functionally, knockdown of circTNPO3 enhanced cell sensitivity to PTX by promoting PTX-induced apoptosis in vitro and in vivo by upregulating the expression of miR-1299.	('upregulating', 'PosReg', (129, 141))	('PTX', 'Chemical', 'MESH:D017239', (83, 86))	('circTNPO3', 'Gene', (27, 36))	('promoting', 'PosReg', (73, 82))	('miR-1299', 'Var', (160, 168))	('circTNPO3', 'Chemical', '-', (27, 36))	('knockdown', 'Var', (14, 23))	('enhanced', 'PosReg', (37, 45))	('expression', 'MPA', (146, 156))	('PTX', 'Chemical', 'MESH:D017239', (66, 69))	('cell sensitivity to PTX', 'MPA', (46, 69))	('PTX-induced', 'MPA', (83, 94))
562448	34046198	More importantly, miR-1299 inhibitors rescued the proliferation, migration and invasion of OC cells via silencing of its molecular sponge RHPN1-AS1.	('migration', 'CPA', (65, 74))	('silencing', 'NegReg', (104, 113))	('OC', 'Phenotype', 'HP:0100615', (91, 93))	('proliferation', 'CPA', (50, 63))	('RHPN1', 'Gene', (138, 143))	('inhibitors', 'Var', (27, 37))	('invasion', 'CPA', (79, 87))	('rescued', 'PosReg', (38, 45))	('miR-1299', 'Gene', (18, 26))	('AS1', 'Gene', (144, 147))	('RHPN1', 'Gene', '114822', (138, 143))	('AS1', 'Gene', '5729', (144, 147))
562451	34046198	demonstrated, by analyzing and comparing the tissues of 60 colon cancer patients with adjacent normal tissues, that miR-1299 was significantly downregulated, inhibited tumor size and was correlated with tumor node metastasis stage in colon cancer.	('tumor', 'Disease', (203, 208))	('correlated', 'Reg', (187, 197))	('colon cancer', 'Disease', 'MESH:D015179', (234, 246))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('downregulated', 'NegReg', (143, 156))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colon cancer', 'Disease', (234, 246))	('colon cancer', 'Disease', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('miR-1299', 'Var', (116, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('inhibited', 'NegReg', (158, 167))	('colon cancer', 'Phenotype', 'HP:0003003', (234, 246))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('patients', 'Species', '9606', (72, 80))
562454	34046198	To further study the regulatory mechanism of miR-1299 in colon cancer, a luciferase reporter gene assay was performed; the report stated that miR-1299 inhibited the expression of STAT3 at the transcriptional level.	('miR-1299', 'Var', (142, 150))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('expression', 'MPA', (165, 175))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('inhibited', 'NegReg', (151, 160))	('STAT3', 'Gene', '6774', (179, 184))	('colon cancer', 'Disease', (57, 69))	('STAT3', 'Gene', (179, 184))
562455	34046198	On the other hand, the researchers found by real-time PCR that the expression of miR-1299 was negatively correlated with the expression of STAT3 in colon cancer tissue: overexpression of miR-1299 can significantly inhibit the expression of STAT3, and when the expression of miR-1299 decreases, the expression of STAT3 increases, which is further evidence that miR-1299 can regulate STAT3.	('expression', 'MPA', (298, 308))	('expression', 'MPA', (226, 236))	('decreases', 'NegReg', (283, 292))	('colon cancer', 'Disease', (148, 160))	('inhibit', 'NegReg', (214, 221))	('increases', 'PosReg', (318, 327))	('miR-1299', 'Var', (187, 195))	('STAT3', 'Gene', (139, 144))	('STAT3', 'Gene', (312, 317))	('miR-1299', 'Var', (274, 282))	('colon cancer', 'Phenotype', 'HP:0003003', (148, 160))	('STAT3', 'Gene', (240, 245))	('STAT3', 'Gene', '6774', (139, 144))	('STAT3', 'Gene', (382, 387))	('STAT3', 'Gene', '6774', (312, 317))	('STAT3', 'Gene', '6774', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('colon cancer', 'Disease', 'MESH:D015179', (148, 160))	('STAT3', 'Gene', '6774', (382, 387))
562458	34046198	The above research confirmed that miR-1299 can inhibit the proliferation and promote the apoptosis of colon cancer cells by reducing the expression of STAT3, the phosphorylation level of STAT3 and the expression of its downstream proteins.	('STAT3', 'Gene', (151, 156))	('proliferation', 'CPA', (59, 72))	('promote', 'PosReg', (77, 84))	('miR-1299', 'Var', (34, 42))	('expression', 'MPA', (137, 147))	('STAT3', 'Gene', '6774', (187, 192))	('apoptosis', 'CPA', (89, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('STAT3', 'Gene', (187, 192))	('inhibit', 'NegReg', (47, 54))	('reducing', 'NegReg', (124, 132))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', (102, 114))	('expression', 'MPA', (201, 211))	('STAT3', 'Gene', '6774', (151, 156))	('phosphorylation level', 'MPA', (162, 183))
562461	34046198	Aberrations in the regulation of a restricted number of key pathways that control cell proliferation and cell survival are a prerequisite for the establishment of all tumors.	('men', 'Species', '9606', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('Aberrations in', 'Var', (0, 14))
562463	34046198	A disruption in the balance of pro- and anti-apoptotic proteins contributes to carcinogenesis by reducing the apoptosis of malignant cells.	('apoptosis of malignant cells', 'CPA', (110, 138))	('disruption', 'Var', (2, 12))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('reducing', 'NegReg', (97, 105))	('carcinogenesis', 'Disease', (79, 93))	('balance', 'MPA', (20, 27))
562464	34046198	For example, disequilibrium between pro- and anti-apoptotic BCL2 proteins can promote cancer cell survival.	('promote', 'PosReg', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('disequilibrium', 'Var', (13, 27))	('BCL2', 'Gene', '596', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('BCL2', 'Gene', (60, 64))	('cancer', 'Disease', (86, 92))
562466	34046198	There is evidence that dysregulation of miRNAs is associated with different human cancers and that miRNAs can function as oncogenes and tumor suppressors.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('dysregulation', 'Var', (23, 36))	('miRNAs', 'Protein', (40, 46))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('associated', 'Reg', (50, 60))	('tumor', 'Disease', (136, 141))
562467	34046198	Their modulation (overexpression or downregulation according to the specific miRNA) in cancer cells often sensitizes cells to apoptotic and antiproliferative treatments and then participates in regulating cell apoptosis and proliferation, which suggests that targeting miRNAs to modulate apoptosis or the proliferation of cancer cells can be utilized for cancer treatment.	('cancer', 'Disease', (87, 93))	('cell apoptosis', 'CPA', (205, 219))	('proliferation', 'CPA', (224, 237))	('modulation', 'Var', (6, 16))	('downregulation', 'NegReg', (36, 50))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('men', 'Species', '9606', (163, 166))	('cancer', 'Disease', (322, 328))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('participates', 'Reg', (178, 190))	('cancer', 'Disease', 'MESH:D009369', (355, 361))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('sensitizes', 'Reg', (106, 116))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', (355, 361))	('men', 'Species', '9606', (367, 370))
562472	34046198	In the tissues of patients with prostate cancer, low expression of miR-1299 leads to a decrease in tumor proliferation and migration rate, which inhibits tumor growth.	('tumor', 'Disease', (99, 104))	('prostate cancer', 'Disease', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('inhibits', 'NegReg', (145, 153))	('decrease', 'NegReg', (87, 95))	('low', 'NegReg', (49, 52))	('miR-1299', 'Var', (67, 75))	('expression', 'MPA', (53, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('tumor', 'Disease', (154, 159))
562473	34046198	In addition, high miR-1299 levels in tumor cells can lead to high levels of prolactin synthesis and secretion and poor control of serum prolactin levels.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('miR-1299', 'Var', (18, 26))	('poor', 'NegReg', (114, 118))	('prolactin', 'Gene', (136, 145))	('prolactin', 'Gene', '5617', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('secretion', 'MPA', (100, 109))	('high levels of prolactin', 'Phenotype', 'HP:0000870', (61, 85))	('prolactin', 'Gene', (76, 85))	('prolactin', 'Gene', '5617', (76, 85))	('high levels', 'MPA', (61, 72))
562474	34046198	In these tumor patients, miR-1299 does exert antitumor activity by regulating different genes.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('regulating', 'Reg', (67, 77))	('patients', 'Species', '9606', (15, 23))	('miR-1299', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (9, 14))
562477	34046198	As a tumor suppressor, miR-1299 targets multiple relevant genes and forms several signaling pathways to exert its synergistic effects.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('signaling pathways', 'Pathway', (82, 100))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('forms', 'Reg', (68, 73))	('tumor', 'Disease', (5, 10))	('miR-1299', 'Var', (23, 31))
562481	34046198	In the next 5-10 years, the mechanism of miR-1299 in other diseases, such as cardiovascular and endocrine diseases, also merits further research, to study whether miR-1299 participates in cell apoptosis, proliferation, migration and so on in other diseases by regulating particular genes.	('miR-1299', 'Var', (41, 49))	('regulating', 'Reg', (260, 270))	('cardiovascular and endocrine diseases', 'Disease', 'MESH:D002318', (77, 114))	('migration', 'CPA', (219, 228))	('genes', 'MPA', (282, 287))	('proliferation', 'CPA', (204, 217))	('cell apoptosis', 'CPA', (188, 202))	('miR-1299', 'Var', (163, 171))	('participates', 'Reg', (172, 184))
562488	34046198	miR-1299 could be used as a tumor suppressor to regulate tumor cell proliferation, invasion and metastasis, improve chemotherapy sensitivity and regulate tumor development and progression.	('metastasis', 'CPA', (96, 106))	('miR-1299', 'Var', (0, 8))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('regulate', 'PosReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('invasion', 'CPA', (83, 91))	('improve', 'PosReg', (108, 115))	('progression', 'CPA', (176, 187))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (57, 62))	('chemotherapy sensitivity', 'CPA', (116, 140))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('regulate', 'Reg', (145, 153))	('men', 'Species', '9606', (167, 170))	('tumor', 'Disease', (154, 159))
562527	31050823	Esophageal cancer included topography ICD-O codes C15.0-C15.9; EA was categorized as (ICD-O morphological codes: 8140, 8141, 8190-8231, 8260-8263, 8310, 8430, 8480-8490, 8560, 8570-8572) and ESCC was categorized as (ICD-O morphological codes: 8050-8076).	('C15', 'Gene', '51316', (56, 59))	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('C15', 'Gene', '51316', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('8430', 'Var', (153, 157))	('C15', 'Gene', (56, 59))	('EA', 'Phenotype', 'HP:0011459', (63, 65))	('ESCC', 'Disease', 'MESH:C562729', (191, 195))	('C15', 'Gene', (50, 53))	('8310', 'Var', (147, 151))	('Esophageal cancer', 'Disease', (0, 17))	('8480-8490', 'Var', (159, 168))	('ESCC', 'Disease', (191, 195))	('8190-8231', 'Var', (125, 134))
562533	31050823	BMI was classified according to World Health Organization (WHO) categories: underweight (BMI < 18.5 kg/m2), normal weight (18.5 <= BMI < 25 kg/m2), overweight (25 <= BMI < 30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', (186, 191))	('25 <= BMI <', 'Var', (160, 171))	('obese', 'Disease', 'MESH:D009765', (186, 191))	('overweight', 'Phenotype', 'HP:0025502', (148, 158))	('18.5 <=', 'Var', (123, 130))
562699	27015363	Silencing of MALAT1 expression inhibited cell proliferation, migration and tumor sphere formation, while increasing cell apoptosis of esophageal cancer in vitro.	('increasing', 'PosReg', (105, 115))	('MALAT1', 'Gene', (13, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('cell apoptosis', 'CPA', (116, 130))	('cell proliferation', 'CPA', (41, 59))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('migration', 'CPA', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('inhibited', 'NegReg', (31, 40))	('Silencing', 'Var', (0, 9))	('esophageal cancer', 'Disease', (134, 151))	('tumor', 'Disease', (75, 80))
562701	27015363	Animal experiments showed that knockdown of MALAT1 decreased tumor formation and improved survival.	('improved', 'PosReg', (81, 89))	('MALAT1', 'Gene', (44, 50))	('decreased', 'NegReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('survival', 'CPA', (90, 98))	('tumor', 'Disease', (61, 66))	('knockdown', 'Var', (31, 40))
562708	27015363	Increasing evidences have shown that the aberrant expression of MALAT1 plays a crucial role in cancinogenesis.	('si', 'Chemical', 'MESH:D012825', (6, 8))	('aberrant expression', 'Var', (41, 60))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('cancinogenesis', 'CPA', (95, 109))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('MALAT1', 'Gene', (64, 70))
562723	27015363	Results revealed that patients with MALAT1 high-expression level had a significantly poorer overall survival than those with low-expression level (P=0.0294, Figure 1D).	('poorer', 'NegReg', (85, 91))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('patients', 'Species', '9606', (22, 30))	('overall survival', 'MPA', (92, 108))	('high-expression level', 'Var', (43, 64))	('MALAT1', 'Gene', (36, 42))
562725	27015363	As shown in Figure 2A, cells transfected with si-MALAT1 showed a significant decreased (more than 70%) mRNA expression of MALAT1 compared to the si-NC group (P=0.0015).	('si', 'Chemical', 'MESH:D012825', (145, 147))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('decreased', 'NegReg', (77, 86))	('si-MALAT1', 'Var', (46, 55))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('mRNA expression', 'MPA', (103, 118))	('MALAT1', 'Gene', (122, 128))
562726	27015363	CCK-8 assays revealed that cell growth was suppressed in TE7 cells transfected with si-MALAT1 compared with si-NC group (24 hr: P = 0.0011, 48 hr: P=0.0015, 72 hr P=0.0002, Figure 2B).	('si', 'Chemical', 'MESH:D012825', (84, 86))	('CCK-8', 'Chemical', 'MESH:D012844', (0, 5))	('TE7', 'CellLine', 'CVCL:9972', (57, 60))	('cell growth', 'CPA', (27, 38))	('si-MALAT1', 'Var', (84, 93))	('si', 'Chemical', 'MESH:D012825', (108, 110))	('suppressed', 'NegReg', (43, 53))
562727	27015363	Apoptotic rate of cells transfected with si-MALAT1 was notably elevated compared with si-NC group (P=0.0043, Figure 2C).	('Apoptotic rate', 'CPA', (0, 14))	('si-MALAT1', 'Var', (41, 50))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('elevated', 'PosReg', (63, 71))	('si', 'Chemical', 'MESH:D012825', (86, 88))
562728	27015363	Sphere formation assay also revealed that cells transfected with si-MALAT1 formed fewer and smaller spheres than si-NC group (P=0.0008, Figure 2D).	('fewer', 'NegReg', (82, 87))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('si-MALAT1', 'Var', (65, 74))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('smaller', 'NegReg', (92, 99))
562729	27015363	We also investigated the effect of tumor stemness genes after cells transfected with si-MALAT1 by qRT-PCR, we found that silencing MALAT1 down-regulated the expression of OCT4 and Nanog genes (P=0.0022, P=0.0005, Figure 2E).	('Nanog', 'Gene', '71950', (180, 185))	('silencing', 'Var', (121, 130))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('expression', 'MPA', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Nanog', 'Gene', (180, 185))	('tumor stemness', 'Disease', (35, 49))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('down-regulated', 'NegReg', (138, 152))	('MALAT1', 'Gene', (131, 137))	('tumor stemness', 'Disease', 'MESH:D020295', (35, 49))	('OCT4', 'Gene', (171, 175))	('OCT4', 'Gene', '18999', (171, 175))	('si', 'Chemical', 'MESH:D012825', (121, 123))
562730	27015363	In addition, transwell assay was performed to analyze the role of MALAT1 in cell migration, results presented that TE7 cells transfected with si-MALAT1 was distinctively less migratory than the cells transfected with si-NC (P=0.0005, Figure 2F).	('less', 'NegReg', (170, 174))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('TE7', 'CellLine', 'CVCL:9972', (115, 118))	('si', 'Chemical', 'MESH:D012825', (217, 219))	('migratory', 'CPA', (175, 184))	('si-MALAT1', 'Var', (142, 151))
562731	27015363	It was reported that resveratrol decreased nuclear localization of beta-catenin thus attenuated beta-catenin signaling after silencing MALAT1 in colorectal cancer cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('resveratrol', 'Chemical', 'MESH:D000077185', (21, 32))	('beta-catenin', 'Gene', '12387', (67, 79))	('silencing', 'Var', (125, 134))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('beta-catenin', 'Gene', '12387', (96, 108))	('MALAT1', 'Gene', (135, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('nuclear localization', 'MPA', (43, 63))	('beta-catenin', 'Gene', (67, 79))	('decreased', 'NegReg', (33, 42))	('colorectal cancer', 'Disease', (145, 162))	('attenuated', 'NegReg', (85, 95))	('si', 'Chemical', 'MESH:D012825', (125, 127))	('beta-catenin', 'Gene', (96, 108))
562733	27015363	As expected, the mRNA level of beta-catenin (P=0.0014, Figure 3A) and Lin28 (P=0.0026, Figure 3A) and the protein level of beta-catenin (P=0.0311, Figure 3B), Lin28 (P=0.0178, Figure 3B) and OCT4 (P=0.0016, Figure 3B) were significantly decreased and E-cadherin mRNA (P=0.0011, Figure 3A) and protein (P=0.0037, Figure 3B) expression level were dramatically increased in si-MALAT1-treated esophageal cancer cells.	('Lin28', 'Gene', (159, 164))	('OCT4', 'Gene', (191, 195))	('Lin28', 'Gene', '83557', (159, 164))	('beta-catenin', 'Gene', '12387', (31, 43))	('E-cadherin', 'Gene', (251, 261))	('cancer', 'Phenotype', 'HP:0002664', (400, 406))	('si', 'Chemical', 'MESH:D012825', (223, 225))	('beta-catenin', 'Gene', (31, 43))	('Lin28', 'Gene', (70, 75))	('OCT4', 'Gene', '18999', (191, 195))	('Lin28', 'Gene', '83557', (70, 75))	('E-cadherin', 'Gene', '12550', (251, 261))	('decreased', 'NegReg', (237, 246))	('beta-catenin', 'Gene', '12387', (123, 135))	('expression level', 'MPA', (323, 339))	('si-MALAT1-treated', 'Var', (371, 388))	('si', 'Chemical', 'MESH:D012825', (371, 373))	('esophageal cancer', 'Disease', 'MESH:D004938', (389, 406))	('beta-catenin', 'Gene', (123, 135))	('protein level', 'MPA', (106, 119))	('mRNA level', 'MPA', (17, 27))	('esophageal cancer', 'Disease', (389, 406))	('si', 'Chemical', 'MESH:D012825', (329, 331))	('increased', 'PosReg', (358, 367))
562748	27015363	There was no significant difference in the body weights of mice between MALAT1-shRNA group and control group (P>0.05, Figure 6A), while there were significant differences in tumor volume between MALAT1-shRNA group and control group (P<0.05, Figure 6B).	('tumor', 'Disease', (174, 179))	('mice', 'Species', '10090', (59, 63))	('MALAT1-shRNA', 'Var', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('si', 'Chemical', 'MESH:D012825', (147, 149))
562750	27015363	We also investigated the images of tumors in nude mice formed by MALAT1-shRNA group and control group stably transfected TE7 cells were shown in Figure 6D.	('TE7', 'CellLine', 'CVCL:9972', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('MALAT1-shRNA', 'Var', (65, 77))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('nude mice', 'Species', '10090', (45, 54))
562751	27015363	Immunohistochemistry analysis showed that beta-catenin expression was distributed in the membrane of cancer cells and significantly decreased in MALAT1-shRNA group compared with control group, and Ezh2 expression demonstrated the lower expression level in cell nucleus after MALAT1 knockdown (Figure 6E).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('beta-catenin', 'Gene', (42, 54))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('si', 'Chemical', 'MESH:D012825', (208, 210))	('lower', 'NegReg', (230, 235))	('Ezh2', 'Gene', (197, 201))	('cancer', 'Disease', (101, 107))	('si', 'Chemical', 'MESH:D012825', (242, 244))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('expression level in', 'MPA', (236, 255))	('expression', 'MPA', (55, 65))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('MALAT1', 'Gene', (275, 281))	('beta-catenin', 'Gene', '12387', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('decreased', 'NegReg', (132, 141))	('knockdown', 'Var', (282, 291))
562754	27015363	It was reported that lncRNA LOC285194 was associated with larger tumor size, advanced TNM stage, more lymph node metastases and distant metastases, etc.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('lncRNA', 'Gene', (21, 27))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('LOC285194', 'Var', (28, 37))	('metastases', 'Disease', (113, 123))	('metastases', 'Disease', (136, 146))	('more', 'PosReg', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('metastases', 'Disease', 'MESH:D009362', (113, 123))
562760	27015363	After MALAT1 specific siRNA (si-MALAT1) was transfected in TE7 cells, we noted that the down-regulation of MALAT1 expression inhibited cell proliferation, migration, tumor sphere formation, while increasing esophageal cancer cell apoptosis in vitro, as the results reported by Wang et al, in which the abilities of migration and invasion of ESCC cells were inhibited after silencing MALAT1.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('down-regulation', 'NegReg', (88, 103))	('silencing', 'Var', (373, 382))	('invasion', 'CPA', (329, 337))	('si', 'Chemical', 'MESH:D012825', (333, 335))	('si', 'Chemical', 'MESH:D012825', (373, 375))	('increasing', 'PosReg', (196, 206))	('cell proliferation', 'CPA', (135, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (207, 224))	('TE7', 'CellLine', 'CVCL:9972', (59, 62))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('migration', 'CPA', (155, 164))	('si', 'Chemical', 'MESH:D012825', (236, 238))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('tumor', 'Disease', (166, 171))	('MALAT1', 'Gene', (107, 113))	('esophageal cancer', 'Disease', (207, 224))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('inhibited', 'NegReg', (357, 366))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('MALAT1', 'Gene', (383, 389))	('inhibited', 'NegReg', (125, 134))	('si', 'Chemical', 'MESH:D012825', (202, 204))
562766	27015363	Vassallo et al revealed that the Wnt inhibitory factor 1 (WIF1), which was a secreted inhibitor of WNTs, suppressed the expression of MALAT1 in glioblastoma and loss of WIF1 enhanced the migratory potential of glioblastoma through Wnt5A that activated the Wnt/Ca2+ pathway and MALAT1.	('suppressed', 'NegReg', (105, 115))	('Ca2+', 'Chemical', 'MESH:D000069285', (260, 264))	('glioblastoma', 'Disease', 'MESH:D005909', (210, 222))	('Wnt5A', 'Gene', (231, 236))	('MALAT1', 'Gene', (134, 140))	('enhanced', 'PosReg', (174, 182))	('expression', 'MPA', (120, 130))	('activated', 'PosReg', (242, 251))	('WIF1', 'Gene', '24117', (58, 62))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('Wnt/Ca2+ pathway', 'Pathway', (256, 272))	('glioblastoma', 'Disease', (210, 222))	('WIF1', 'Gene', '24117', (169, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (210, 222))	('Wnt5A', 'Gene', '22418', (231, 236))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('loss', 'Var', (161, 165))	('migratory potential', 'CPA', (187, 206))	('WIF1', 'Gene', (58, 62))	('WIF1', 'Gene', (169, 173))	('glioblastoma', 'Disease', (144, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('Wnt inhibitory factor 1', 'Gene', (33, 56))	('Wnt inhibitory factor 1', 'Gene', '24117', (33, 56))
562772	27015363	After MALAT1 silencing, E-cadherin expression was increased, whereas beta-catenin expression was decreased through Ezh2.	('si', 'Chemical', 'MESH:D012825', (13, 15))	('beta-catenin', 'Gene', (69, 81))	('increased', 'PosReg', (50, 59))	('MALAT1', 'Gene', (6, 12))	('expression', 'MPA', (35, 45))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('E-cadherin', 'Gene', (24, 34))	('decreased', 'NegReg', (97, 106))	('E-cadherin', 'Gene', '12550', (24, 34))	('beta-catenin', 'Gene', '12387', (69, 81))	('silencing', 'Var', (13, 22))
562833	27376780	In ESCC cell lines, silencing of Nm23H1 expression markedly enhanced cell invasiveness, accompanied by increased Akt phosphorylation and decreased CLDN1 expression.	('Nm23H1', 'Gene', '4830', (33, 39))	('CLDN1', 'Gene', '9076', (147, 152))	('increased', 'PosReg', (103, 112))	('expression', 'Species', '29278', (40, 50))	('Akt', 'Gene', '207', (113, 116))	('CLDN1', 'Gene', (147, 152))	('cell invasiveness', 'CPA', (69, 86))	('Akt', 'Gene', (113, 116))	('expression', 'Species', '29278', (153, 163))	('expression', 'MPA', (153, 163))	('decreased', 'NegReg', (137, 146))	('silencing', 'Var', (20, 29))	('enhanced', 'PosReg', (60, 68))	('Nm23H1', 'Gene', (33, 39))
562850	27376780	However, the connection between dysregulation of Nm23H1 and tumor invasion has not been well established.	('dysregulation', 'Var', (32, 45))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Nm23H1', 'Gene', '4830', (49, 55))	('Nm23H1', 'Gene', (49, 55))	('tumor', 'Disease', (60, 65))
562875	27376780	Not surprisingly, the degree of difference between these two kinds of clones was more remarkable in the CE48T cells, which gained more suppression of Nm23H1 expression after gene silencing.	('expression', 'Species', '29278', (157, 167))	('Nm23H1', 'Gene', (150, 156))	('expression', 'MPA', (157, 167))	('Nm23H1', 'Gene', '4830', (150, 156))	('gene silencing', 'Var', (174, 188))	('suppression', 'NegReg', (135, 146))	('CE48T', 'Chemical', '-', (104, 109))
562879	27376780	These results documented that silencing Nm23H1 expression would negatively regulate the expression of CLDN1, CLDN7 and resulted in the cadherin switch.	('Nm23H1', 'Gene', (40, 46))	('CLDN7', 'Gene', '1366', (109, 114))	('CLDN1', 'Gene', '9076', (102, 107))	('Nm23H1', 'Gene', '4830', (40, 46))	('CLDN1', 'Gene', (102, 107))	('resulted in', 'Reg', (119, 130))	('cadherin switch', 'MPA', (135, 150))	('expression', 'Species', '29278', (88, 98))	('expression', 'Species', '29278', (47, 57))	('silencing', 'Var', (30, 39))	('expression', 'MPA', (88, 98))	('CLDN7', 'Gene', (109, 114))	('negatively', 'NegReg', (64, 74))
562882	27376780	In addition to decreased CLDN1 expression after Nm23H1 silencing, the localization of the CLDN1 protein also moved from cell-cell contact sites to the cytoplasm and nucleus of the ESCC-shNm23 cells.	('protein', 'Protein', (96, 103))	('localization', 'MPA', (70, 82))	('silencing', 'Var', (55, 64))	('Nm23H1', 'Gene', (48, 54))	('expression', 'Species', '29278', (31, 41))	('Nm23', 'Gene', '4830', (48, 52))	('CLDN1', 'Gene', '9076', (25, 30))	('CLDN1', 'Gene', '9076', (90, 95))	('expression', 'MPA', (31, 41))	('Nm23', 'Gene', (48, 52))	('Nm23', 'Gene', '4830', (187, 191))	('decreased', 'NegReg', (15, 24))	('CLDN1', 'Gene', (25, 30))	('Nm23H1', 'Gene', '4830', (48, 54))	('CLDN1', 'Gene', (90, 95))	('Nm23', 'Gene', (187, 191))	('moved', 'Reg', (109, 114))
562902	27376780	As shown in Figure 4b, CLDN1 expression was recovered in a dose-dependent manner in the CE48T-shNm23 cells after the treatment of MK2206.	('Nm23', 'Gene', '4830', (96, 100))	('MK2206', 'Var', (130, 136))	('CE48T', 'Chemical', '-', (88, 93))	('Nm23', 'Gene', (96, 100))	('CLDN1', 'Gene', '9076', (23, 28))	('expression', 'Species', '29278', (29, 39))	('expression', 'MPA', (29, 39))	('MK2206', 'Chemical', 'MESH:C548887', (130, 136))	('CLDN1', 'Gene', (23, 28))
562903	27376780	Moreover, MK2206 markedly reduced the migration and invasion of the CE48T-shNm23 cells (Figure 4c).	('MK2206', 'Chemical', 'MESH:C548887', (10, 16))	('CE48T', 'Chemical', '-', (68, 73))	('reduced', 'NegReg', (26, 33))	('Nm23', 'Gene', (76, 80))	('Nm23', 'Gene', '4830', (76, 80))	('invasion', 'CPA', (52, 60))	('MK2206', 'Var', (10, 16))	('migration', 'CPA', (38, 47))
562906	27376780	Consistent with the results of the CE48T cells, silencing of Nm23H1 expression by shRNA caused increased pAkt levels and reduced CLDN1 expression in both the CE146T and the CETE2 cells.	('expression', 'Species', '29278', (68, 78))	('silencing', 'Var', (48, 57))	('Nm23H1', 'Gene', '4830', (61, 67))	('Nm23H1', 'Gene', (61, 67))	('CE48T', 'Chemical', '-', (35, 40))	('Akt', 'Gene', '207', (106, 109))	('reduced', 'NegReg', (121, 128))	('expression', 'Species', '29278', (135, 145))	('expression', 'MPA', (135, 145))	('CLDN1', 'Gene', '9076', (129, 134))	('CE146', 'CellLine', 'CVCL:Y008', (158, 163))	('increased', 'PosReg', (95, 104))	('Akt', 'Gene', (106, 109))	('CLDN1', 'Gene', (129, 134))
562925	27376780	Our previous studies have shown that the expression of Nm23H1 was associated with better survival in patients with ESCC and oral squamous cell carcinoma.	('ESCC', 'Disease', (115, 119))	('expression', 'Species', '29278', (41, 51))	('patients', 'Species', '9606', (101, 109))	('better', 'PosReg', (82, 88))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('Nm23H1', 'Gene', '4830', (55, 61))	('Nm23H1', 'Gene', (55, 61))	('expression', 'Var', (41, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('survival', 'MPA', (89, 97))	('oral squamous cell carcinoma', 'Disease', (124, 152))
562930	27376780	Cell line studies also demonstrated that modulation of Nm23H1 influences expression of multiple proteins that were accompanied by changes in cell-to-cell adhesion, migration and invasion.	('proteins', 'Protein', (96, 104))	('modulation', 'Var', (41, 51))	('cell-to-cell adhesion', 'CPA', (141, 162))	('changes', 'Reg', (130, 137))	('influences', 'Reg', (62, 72))	('expression', 'Species', '29278', (73, 83))	('invasion', 'CPA', (178, 186))	('expression of multiple', 'MPA', (73, 95))	('Nm23H1', 'Gene', '4830', (55, 61))	('Nm23H1', 'Gene', (55, 61))	('migration', 'CPA', (164, 173))
562938	27376780	Furthermore, we demonstrated that enhanced CLDN1 expression by gene transfection markedly diminished their migration and invasion without changing either Nm23H1 expression or Akt phosphorylation, and was independent of Nm23H1 expression (Figures 4e and f).	('expression', 'Species', '29278', (161, 171))	('expression', 'Species', '29278', (226, 236))	('CLDN1', 'Gene', (43, 48))	('enhanced', 'PosReg', (34, 42))	('Nm23H1', 'Gene', (154, 160))	('Nm23H1', 'Gene', (219, 225))	('expression', 'Species', '29278', (49, 59))	('Nm23H1', 'Gene', '4830', (154, 160))	('gene transfection', 'Var', (63, 80))	('expression', 'MPA', (49, 59))	('Nm23H1', 'Gene', '4830', (219, 225))	('Akt', 'Gene', '207', (175, 178))	('diminished', 'NegReg', (90, 100))	('Akt', 'Gene', (175, 178))	('CLDN1', 'Gene', '9076', (43, 48))
562945	27376780	Previously, it has been reported that silencing of CLDN7 by genetic approaches leads to reduced E-cadherin expression, impairment of homotypic adhesion and increased cell invasion.	('impairment', 'NegReg', (119, 129))	('expression', 'Species', '29278', (107, 117))	('CLDN7', 'Gene', (51, 56))	('increased', 'PosReg', (156, 165))	('expression', 'MPA', (107, 117))	('cell invasion', 'CPA', (166, 179))	('CLDN7', 'Gene', '1366', (51, 56))	('homotypic adhesion', 'CPA', (133, 151))	('E-cadherin', 'Gene', (96, 106))	('reduced', 'NegReg', (88, 95))	('silencing', 'Var', (38, 47))	('E-cadherin', 'Gene', '999', (96, 106))
562951	27376780	Moreover, in our current study, application of the Akt inhibitor MK2206 was able to abrogate the invasiveness of Nm23H1-depleted ESCC cells significantly.	('Akt', 'Gene', (51, 54))	('ESCC', 'Disease', (129, 133))	('invasiveness', 'CPA', (97, 109))	('Nm23H1', 'Gene', (113, 119))	('abrogate', 'NegReg', (84, 92))	('Nm23H1', 'Gene', '4830', (113, 119))	('MK2206', 'Chemical', 'MESH:C548887', (65, 71))	('Akt', 'Gene', '207', (51, 54))	('MK2206', 'Var', (65, 71))
562960	27376780	The human esophageal cancer cell lines, CE48T, CE146T and CETE2 (obtained from the Food Industry Research and Development Institute, Hsinchu, Taiwan), were grown in monolayer cultures and maintained in a high-glucose Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 100 mug/ml streptomycin, 100 units/ml penicillin G and 3.75 mug/ml sodium bicarbonate at 37  C in a 5% CO2 environment.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (4, 9))	('esophageal cancer', 'Disease', (10, 27))	('CE48T', 'Chemical', '-', (40, 45))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (217, 251))	('CO2', 'Chemical', '-', (404, 407))	('penicillin G', 'Chemical', 'MESH:D010400', (339, 351))	('sodium bicarbonate', 'Chemical', 'MESH:D017693', (368, 386))	('esophageal cancer', 'Disease', 'MESH:D004938', (10, 27))	('glucose', 'Chemical', 'MESH:D005947', (209, 216))	('high-glucose', 'Phenotype', 'HP:0003074', (204, 216))	('CE146T', 'Var', (47, 53))	('CE146', 'CellLine', 'CVCL:Y008', (47, 52))	('streptomycin', 'Chemical', 'MESH:D013307', (312, 324))	('bovine', 'Species', '9913', (287, 293))	('DMEM', 'Chemical', '-', (253, 257))
562979	26334393	Loss of miR-200b promotes invasion via activating the Kindlin-2/integrin beta1/AKT pathway in esophageal squamous cell carcinoma: An E-cadherin-independent mechanism Our previous studies have shown that loss of miR-200b enhances the invasiveness of esophageal squamous cell carcinoma (ESCC) cells.	('AKT', 'Gene', (79, 82))	('E-cadherin', 'Gene', (133, 143))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (94, 128))	('E-cadherin', 'Gene', '999', (133, 143))	('activating', 'PosReg', (39, 49))	('integrin beta1', 'Gene', '3688', (64, 78))	('invasiveness of esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (233, 283))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (260, 283))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (249, 283))	('invasiveness of esophageal squamous cell carcinoma', 'Disease', (233, 283))	('miR-200b', 'Gene', '406984', (8, 16))	('AKT', 'Gene', '207', (79, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('loss', 'Var', (203, 207))	('Kindlin-2', 'Gene', (54, 63))	('miR-200b', 'Gene', (211, 219))	('integrin beta1', 'Gene', (64, 78))	('enhances', 'PosReg', (220, 228))	('Loss', 'Var', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))	('Kindlin-2', 'Gene', '10979', (54, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('miR-200b', 'Gene', '406984', (211, 219))	('miR-200b', 'Gene', (8, 16))
562981	26334393	Here, we show that miR-200b represses ESCC cell invasion in vivo without altering the expression of E-cadherin and vimentin, two surrogate markers of EMT.	('represses', 'NegReg', (28, 37))	('vimentin', 'Gene', '7431', (115, 123))	('miR-200b', 'Var', (19, 27))	('ESCC cell invasion', 'CPA', (38, 56))	('vimentin', 'Gene', (115, 123))	('E-cadherin', 'Gene', (100, 110))	('E-cadherin', 'Gene', '999', (100, 110))
562983	26334393	Methylation of E-cadherin gene was found to block the regulation of E-cadherin by the miR-200b-ZEB1/2 axis, indicating that an E-cadherin-independent mechanism can mediate the biological function of miR-200b in ESCC.	('ESCC', 'Disease', (211, 215))	('E-cadherin', 'Gene', (15, 25))	('E-cadherin', 'Gene', '999', (15, 25))	('Methylation', 'Var', (0, 11))	('miR-200b-ZEB1/2', 'Gene', (86, 101))	('miR-200b-ZEB1/2', 'Gene', '406984;6935;9839', (86, 101))	('regulation', 'MPA', (54, 64))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', (127, 137))	('E-cadherin', 'Gene', '999', (68, 78))	('E-cadherin', 'Gene', '999', (127, 137))	('block', 'NegReg', (44, 49))
562984	26334393	We revealed that miR-200b suppresses the integrin beta1-AKT pathway via targeting Kindlin-2 to mitigate ESCC cell invasiveness.	('AKT', 'Gene', '207', (56, 59))	('Kindlin-2', 'Gene', (82, 91))	('suppresses', 'NegReg', (26, 36))	('AKT', 'Gene', (56, 59))	('mitigate', 'NegReg', (95, 103))	('Kindlin-2', 'Gene', '10979', (82, 91))	('miR-200b', 'Var', (17, 25))	('ESCC', 'Disease', (104, 108))	('integrin beta1', 'Gene', (41, 55))	('integrin beta1', 'Gene', '3688', (41, 55))
562986	26334393	These data highlight that suppression of the Kindlin-2-integrin beta1-AKT regulatory axis is an alternative mechanism underlying the tumor suppressor function of miR-200b in ESCC.	('miR-200b', 'Var', (162, 170))	('Kindlin-2', 'Gene', '10979', (45, 54))	('integrin beta1', 'Gene', '3688', (55, 69))	('AKT', 'Gene', '207', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('AKT', 'Gene', (70, 73))	('suppression', 'NegReg', (26, 37))	('ESCC', 'Disease', (174, 178))	('tumor', 'Disease', (133, 138))	('Kindlin-2', 'Gene', (45, 54))	('integrin beta1', 'Gene', (55, 69))
562991	26334393	the miR-200b/200a/429 cluster on Chr.1p36 and the miR-200c-141 cluster on Chr.12p13.	('miR-200c', 'Gene', '406985', (50, 58))	('miR-200c', 'Gene', (50, 58))	('miR-200b/200a/429', 'Var', (4, 21))
562992	26334393	Deregulation of miR-200 has been shown to suppress invasion/metastasis in various cancer types, mainly by preventing epithelial-to-mesenchymal transition (EMT).	('suppress', 'NegReg', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Deregulation', 'Var', (0, 12))	('invasion/metastasis', 'CPA', (51, 70))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('miR', 'Gene', '220972', (16, 19))	('preventing', 'NegReg', (106, 116))	('miR', 'Gene', (16, 19))	('epithelial-to-mesenchymal transition', 'CPA', (117, 153))
562996	26334393	Our previous studies have reported that miR-200b suppresses the invasiveness of ESCC in vitro via repressing the cytoskeletal and the adhesive machinery, and Kindlin-2 was identified as a direct target and functional mediator of miR-200b.	('miR-200b', 'Var', (40, 48))	('cytoskeletal', 'MPA', (113, 125))	('repressing', 'NegReg', (98, 108))	('Kindlin-2', 'Gene', (158, 167))	('invasiveness', 'CPA', (64, 76))	('Kindlin-2', 'Gene', '10979', (158, 167))	('suppresses', 'NegReg', (49, 59))	('ESCC', 'Disease', (80, 84))
562999	26334393	In this study, we asked if miR-200b also affects the tumor invasiveness of ESCC in vivo using a previously described mouse model.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ESCC', 'Disease', (75, 79))	('mouse', 'Species', '10090', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('miR-200b', 'Var', (27, 35))	('affects', 'Reg', (41, 48))	('tumor', 'Disease', (53, 58))
563002	26334393	As shown in Figure 1D-1E, despite the inhibitory effect of miR-200b in the tumor invasion of ESCC, the expression of neither E-cadherin nor vimentin was appreciably altered by the miR-200b mimic in the xenografts.	('E-cadherin', 'Gene', '999', (125, 135))	('expression', 'MPA', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('ESCC', 'Disease', (93, 97))	('miR-200b mimic', 'Var', (180, 194))	('miR-200b', 'Gene', (59, 67))	('vimentin', 'Gene', '7431', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('E-cadherin', 'Gene', (125, 135))	('vimentin', 'Gene', (140, 148))	('tumor', 'Disease', (75, 80))
563003	26334393	We then asked whether the tumor suppressor effects of miR-200b were mediated via the miR-200b-ZEB1/ 2-E-cadherin axis.	('miR-200b-ZEB1/ 2-E-cadherin', 'Gene', (85, 112))	('miR-200b', 'Var', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('miR-200b-ZEB1/ 2-E-cadherin', 'Gene', '406984', (85, 112))	('tumor', 'Disease', (26, 31))
563006	26334393	Correlating with our previous finding that a low expression of miR-200b was associated with a poor prognosis in ESCC patients, we found that a high expression of ZEB2 significantly correlated with a shorter overall survival (P = 0.034), although the correlation between ZEB1 and survival just fell short of statistical significance (P = 0.078) (Figure 2E).	('overall survival', 'MPA', (207, 223))	('shorter', 'NegReg', (199, 206))	('ZEB1', 'Gene', (270, 274))	('ZEB1', 'Gene', '6935', (270, 274))	('high', 'Var', (143, 147))	('ESCC', 'Disease', (112, 116))	('ZEB2', 'Gene', '9839', (162, 166))	('miR-200b', 'Gene', (63, 71))	('patients', 'Species', '9606', (117, 125))	('ZEB2', 'Gene', (162, 166))
563007	26334393	These data suggest that deregulation of the miR-200b-ZEB1/2 axis is involved in the pathobiology of ESCC.	('miR-200b-ZEB1/2', 'Gene', '406984;6935;9839', (44, 59))	('involved', 'Reg', (68, 76))	('deregulation', 'Var', (24, 36))	('ESCC', 'Disease', (100, 104))	('miR-200b-ZEB1/2', 'Gene', (44, 59))
563008	26334393	We then determined whether E-cadherin, a key downstream mediator of the miR-200b-ZEB1/2 axis, mediates the biological function of miR-200b in ESCC.	('miR-200b-ZEB1/2', 'Gene', '406984;6935;9839', (72, 87))	('miR-200b-ZEB1/2', 'Gene', (72, 87))	('miR-200b', 'Var', (130, 138))	('ESCC', 'Disease', (142, 146))	('E-cadherin', 'Gene', (27, 37))	('E-cadherin', 'Gene', '999', (27, 37))
563011	26334393	This lack of correlation between E-cadherin and miR-200b or ZEB1/2 is probably due to the fact that E-cadherin has been reported to be frequently silenced via gene methylation in ESCC.	('silenced', 'NegReg', (146, 154))	('E-cadherin', 'Gene', (33, 43))	('E-cadherin', 'Gene', '999', (33, 43))	('ESCC', 'Gene', (179, 183))	('E-cadherin', 'Gene', (100, 110))	('E-cadherin', 'Gene', '999', (100, 110))	('gene methylation', 'Var', (159, 175))
563012	26334393	EC109 and EC9706) with 5-aza-dC, a DNA methyltransferase inhibitor, restored the expression of E-cadherin (Figure 3B).	('5-aza-dC', 'Chemical', 'MESH:D000077209', (23, 31))	('E-cadherin', 'Gene', (95, 105))	('EC9706', 'CellLine', 'CVCL:E307', (10, 16))	('EC9706', 'Var', (10, 16))	('E-cadherin', 'Gene', '999', (95, 105))	('expression', 'MPA', (81, 91))	('restored', 'PosReg', (68, 76))
563014	26334393	In comparison, in an immortalized esophageal epithelial cell line NE2, in which the loss of E-cadherin has been shown to be unassociated with DNA hypermethylation, miR-200b mimic transfection could effectively induce E-cadherin expression (Figure 3A).	('miR-200b mimic transfection', 'Var', (164, 191))	('NE2', 'CellLine', 'CVCL:3554', (66, 69))	('E-cadherin', 'Gene', (92, 102))	('E-cadherin', 'Gene', '999', (92, 102))	('induce', 'PosReg', (210, 216))	('E-cadherin', 'Gene', (217, 227))	('E-cadherin', 'Gene', '999', (217, 227))	('expression', 'MPA', (228, 238))
563015	26334393	Overall, these data suggests that an E-cadherin-independent mechanism may mediate the tumor suppressive effects of miR-200b in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR-200b', 'Var', (115, 123))	('E-cadherin', 'Gene', (37, 47))	('ESCC', 'Disease', (127, 131))	('tumor', 'Disease', (86, 91))	('E-cadherin', 'Gene', '999', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
563016	26334393	As shown in Figure 4A, enforced expression of miR-200b decreased the expression of phospho-AKTSer473 (pAKT), a key downstream mediator of the PI3K pathway, in both EC109 and EC9706 cells.	('AKT', 'Gene', '207', (103, 106))	('miR-200b', 'Var', (46, 54))	('EC9706', 'CellLine', 'CVCL:E307', (174, 180))	('AKT', 'Gene', '207', (91, 94))	('AKT', 'Gene', (103, 106))	('expression', 'MPA', (69, 79))	('decreased', 'NegReg', (55, 64))	('AKT', 'Gene', (91, 94))
563017	26334393	In comparison, miR-200b inhibition in KYSE150, an ESCC cell line that expressed a relatively high level of miR-200b, substantially increased pAKT.	('miR-200b', 'Gene', (15, 23))	('increased', 'PosReg', (131, 140))	('KYSE150', 'CellLine', 'CVCL:1348', (38, 45))	('AKT', 'Gene', (142, 145))	('inhibition', 'NegReg', (24, 34))	('AKT', 'Gene', '207', (142, 145))	('miR-200b', 'Var', (107, 115))
563018	26334393	Then, we assessed whether inhibition of the PI3K pathway using LY294002 can mimic the biological function of miR-200b in ESCC cells.	('LY294002', 'Chemical', 'MESH:C085911', (63, 71))	('ESCC', 'Disease', (121, 125))	('LY294002', 'Var', (63, 71))	('PI3K pathway', 'Pathway', (44, 56))
563019	26334393	As shown in Figure 4B-4C, LY294002 induced cell rounding and inhibited invasiveness in a dose-dependent manner in both EC109 and EC9706 cells.	('EC9706', 'CellLine', 'CVCL:E307', (129, 135))	('inhibited', 'NegReg', (61, 70))	('cell rounding', 'CPA', (43, 56))	('invasiveness', 'CPA', (71, 83))	('induced', 'Reg', (35, 42))	('LY294002', 'Chemical', 'MESH:C085911', (26, 34))	('LY294002', 'Var', (26, 34))
563022	26334393	myristoylated AKT (myr-AKT), significantly restored invasiveness that was suppressed by miR-200b in both EC109 and EC9706 cells (P < 0.05).	('invasiveness', 'CPA', (52, 64))	('AKT', 'Gene', (14, 17))	('AKT', 'Gene', '207', (23, 26))	('miR-200b', 'Var', (88, 96))	('myristoylated', 'Var', (0, 13))	('EC9706', 'CellLine', 'CVCL:E307', (115, 121))	('AKT', 'Gene', (23, 26))	('AKT', 'Gene', '207', (14, 17))	('restored', 'PosReg', (43, 51))
563023	26334393	The mechanism underlying the suppression of the PI3K-AKT pathway by miR-200b remains unclear in ESCC.	('AKT', 'Gene', '207', (53, 56))	('suppression', 'NegReg', (29, 40))	('miR-200b', 'Var', (68, 76))	('ESCC', 'Disease', (96, 100))	('AKT', 'Gene', (53, 56))
563024	26334393	Since Kindlin-2, a target of miR-200b, is one of the key molecules mediating the inside-out activation of integrin beta1, and integrin beta1 has been shown to activate the PI3K-AKT pathway, we hypothesized that the miR-200b can repress the Kindlin-2-integrin beta1-AKT axis.	('Kindlin-2', 'Gene', '10979', (6, 15))	('AKT', 'Gene', '207', (177, 180))	('miR-200b', 'Var', (215, 223))	('AKT', 'Gene', (265, 268))	('integrin beta1', 'Gene', (250, 264))	('activate', 'PosReg', (159, 167))	('integrin beta1', 'Gene', (106, 120))	('integrin beta1', 'Gene', (126, 140))	('integrin beta1', 'Gene', '3688', (250, 264))	('AKT', 'Gene', '207', (265, 268))	('AKT', 'Gene', (177, 180))	('repress', 'NegReg', (228, 235))	('integrin beta1', 'Gene', '3688', (106, 120))	('Kindlin-2', 'Gene', (240, 249))	('Kindlin-2', 'Gene', (6, 15))	('integrin beta1', 'Gene', '3688', (126, 140))	('Kindlin-2', 'Gene', '10979', (240, 249))
563025	26334393	First, as shown in Figure 5A, knockdown of Kindlin-2 dramatically decreased the expression of pAKT, and re-expression of Kindlin-2 restored the pAKT expression that was suppressed by miR-200b mimic transfection.	('Kindlin-2', 'Gene', '10979', (121, 130))	('AKT', 'Gene', (145, 148))	('AKT', 'Gene', '207', (95, 98))	('Kindlin-2', 'Gene', (43, 52))	('decreased', 'NegReg', (66, 75))	('Kindlin-2', 'Gene', '10979', (43, 52))	('AKT', 'Gene', (95, 98))	('knockdown', 'Var', (30, 39))	('restored', 'PosReg', (131, 139))	('expression', 'MPA', (80, 90))	('AKT', 'Gene', '207', (145, 148))	('Kindlin-2', 'Gene', (121, 130))
563026	26334393	Second, as shown in Figure 5B-5C, both enforced expression of miR-200b and Kindlin-2 knockdown significantly decreased the percentage of cells with active integrin beta1, detected by flow cytometry.	('decreased', 'NegReg', (109, 118))	('integrin beta1', 'Gene', '3688', (155, 169))	('cells', 'CPA', (137, 142))	('Kindlin-2', 'Gene', (75, 84))	('knockdown', 'Var', (85, 94))	('Kindlin-2', 'Gene', '10979', (75, 84))	('miR-200b', 'Gene', (62, 70))	('integrin beta1', 'Gene', (155, 169))
563028	26334393	Taken together, these data suggest that miR-200b suppresses the PI3K-AKT pathway via inhibiting the Kindlin-2-integrin beta1 axis.	('integrin beta1', 'Gene', '3688', (110, 124))	('AKT', 'Gene', (69, 72))	('inhibiting', 'NegReg', (85, 95))	('Kindlin-2', 'Gene', '10979', (100, 109))	('miR-200b', 'Var', (40, 48))	('integrin beta1', 'Gene', (110, 124))	('AKT', 'Gene', '207', (69, 72))	('suppresses', 'NegReg', (49, 59))	('Kindlin-2', 'Gene', (100, 109))
563030	26334393	As shown in Figure 6A-6B, Kindlin-2 expression was positively correlated with the activation of both the integrin signaling pathway and the PI3K-AKT signaling pathway in two independent cohorts of ESCC patients (both P < 0.01, n = 20 and n = 53, respectively).	('AKT', 'Gene', (145, 148))	('ESCC', 'Disease', (197, 201))	('expression', 'Var', (36, 46))	('Kindlin-2', 'Gene', (26, 35))	('activation', 'PosReg', (82, 92))	('patients', 'Species', '9606', (202, 210))	('Kindlin-2', 'Gene', '10979', (26, 35))	('integrin signaling pathway', 'Pathway', (105, 131))	('AKT', 'Gene', '207', (145, 148))
563032	26334393	Collectively, these data suggest that miR-200b suppresses the integrin beta1-AKT pathway via targeting Kindlin-2, which may mediate the role of miR-200b in mitigating ESCC cell invasiveness.	('Kindlin-2', 'Gene', '10979', (103, 112))	('integrin beta1', 'Gene', (62, 76))	('targeting', 'Reg', (93, 102))	('AKT', 'Gene', '207', (77, 80))	('suppresses', 'NegReg', (47, 57))	('miR-200b', 'Var', (38, 46))	('AKT', 'Gene', (77, 80))	('Kindlin-2', 'Gene', (103, 112))	('ESCC cell', 'Disease', (167, 176))	('integrin beta1', 'Gene', '3688', (62, 76))
563037	26334393	Deregulation of the miR-200-ZEB1/2 axis was found to contribute to the pathobiology of ESCC, as manifested by their prognostic values in ESCC patients.	('contribute', 'Reg', (53, 63))	('Deregulation', 'Var', (0, 12))	('ESCC', 'Disease', (137, 141))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('ESCC', 'Disease', (87, 91))	('patients', 'Species', '9606', (142, 150))
563039	26334393	We revealed that epigenetic silencing of E-cadherin (i.e.	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))	('epigenetic silencing', 'Var', (17, 37))
563041	26334393	This finding suggests that miR-200b can suppress ESCC cell invasion via E-cadherin or EMT independent pathways.	('EMT independent pathways', 'CPA', (86, 110))	('suppress', 'NegReg', (40, 48))	('miR-200b', 'Var', (27, 35))	('ESCC', 'Disease', (49, 53))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))
563042	26334393	In keeping with our hypothesis, we uncovered the Kindlin-2-integrin beta1-AKT pathway as an important mediator of the biological function of miR-200b in ESCC cells (Figure 6C).	('Kindlin-2', 'Gene', (49, 58))	('miR-200b', 'Var', (141, 149))	('Kindlin-2', 'Gene', '10979', (49, 58))	('AKT', 'Gene', '207', (74, 77))	('integrin beta1', 'Gene', '3688', (59, 73))	('AKT', 'Gene', (74, 77))	('integrin beta1', 'Gene', (59, 73))	('ESCC', 'Disease', (153, 157))
563044	26334393	Specifically, miR-200b mitigated ESCC cell invasiveness and dramatically altered the cytoskeletal structure and morphology without affecting the expression of E-cadherin and vimentin.	('E-cadherin', 'Gene', '999', (159, 169))	('ESCC', 'Disease', (33, 37))	('altered', 'Reg', (73, 80))	('mitigated', 'NegReg', (23, 32))	('vimentin', 'Gene', '7431', (174, 182))	('miR-200b', 'Var', (14, 22))	('E-cadherin', 'Gene', (159, 169))	('vimentin', 'Gene', (174, 182))
563048	26334393	For instance, the reciprocal stimulation between the tyrosine kinase Src and Kindlin-2 has been shown to enhance cancer cell spreading and migration.	('reciprocal', 'Var', (18, 28))	('Kindlin-2', 'Gene', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('Kindlin-2', 'Gene', '10979', (77, 86))	('Src', 'Gene', (69, 72))	('Src', 'Gene', '6714', (69, 72))	('enhance', 'PosReg', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
563054	26334393	Pharmacological blockade of the PI3K-AKT pathway or siRNA knockdown of AKT have been shown to mitigate ESCC cell invasiveness.	('AKT', 'Gene', '207', (71, 74))	('AKT', 'Gene', '207', (37, 40))	('mitigate', 'NegReg', (94, 102))	('AKT', 'Gene', (37, 40))	('AKT', 'Gene', (71, 74))	('ESCC', 'Disease', (103, 107))	('knockdown', 'Var', (58, 67))
563055	26334393	In this study, we revealed miR-200b as an upstream suppressor of the PI3K-AKT pathway via blocking the Kindlin-2-integrin beta1 axis.	('Kindlin-2', 'Gene', '10979', (103, 112))	('AKT', 'Gene', '207', (74, 77))	('blocking', 'NegReg', (90, 98))	('integrin beta1', 'Gene', (113, 127))	('miR-200b', 'Var', (27, 35))	('integrin beta1', 'Gene', '3688', (113, 127))	('AKT', 'Gene', (74, 77))	('Kindlin-2', 'Gene', (103, 112))
563056	26334393	Thus, restoring miR-200b expression can be a promising approach to attenuate the PI3K-AKT pathway, hence, suppressing tumor aggressiveness in ESCC.	('AKT', 'Gene', (86, 89))	('suppressing', 'NegReg', (106, 117))	('expression', 'MPA', (25, 35))	('miR-200b', 'Gene', (16, 24))	('aggressiveness', 'Phenotype', 'HP:0000718', (124, 138))	('restoring', 'Var', (6, 15))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor aggressiveness', 'Disease', (118, 138))	('ESCC', 'Disease', (142, 146))	('AKT', 'Gene', '207', (86, 89))	('attenuate', 'NegReg', (67, 76))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (118, 138))
563059	26334393	Our previous study has identified Kindlin-2, a significant prognostic marker in ESCC, as a target and mediator of the function of miR-200b in ESCC.	('miR-200b', 'Var', (130, 138))	('Kindlin-2', 'Gene', (34, 43))	('ESCC', 'Disease', (142, 146))	('Kindlin-2', 'Gene', '10979', (34, 43))	('ESCC', 'Disease', (80, 84))
563060	26334393	In this study, we revealed that miR-200b inhibits the inside-out activation of integrin beta1 via targeting Kindlin-2.	('miR-200b', 'Var', (32, 40))	('inhibits', 'NegReg', (41, 49))	('targeting', 'Reg', (98, 107))	('Kindlin-2', 'Gene', '10979', (108, 117))	('inside-out activation', 'MPA', (54, 75))	('integrin beta1', 'Gene', (79, 93))	('integrin beta1', 'Gene', '3688', (79, 93))	('Kindlin-2', 'Gene', (108, 117))
563062	26334393	Moreover, miR-200b has been shown to inhibit the activation of FAK and Rho GTPases via targeting Kindlin-2.	('Rho', 'Protein', (71, 74))	('Kindlin-2', 'Gene', '10979', (97, 106))	('inhibit', 'NegReg', (37, 44))	('activation', 'MPA', (49, 59))	('targeting', 'Reg', (87, 96))	('FAK', 'Gene', (63, 66))	('FAK', 'Gene', '5747', (63, 66))	('miR-200b', 'Var', (10, 18))	('Kindlin-2', 'Gene', (97, 106))
563064	26334393	To conclude, our data suggest that deregulation of the miR-200-ZEB1/2 axis contributes to the pathobiology of ESCC, which can serve as prognostic markers in ESCC patients.	('patients', 'Species', '9606', (162, 170))	('deregulation', 'Var', (35, 47))	('ESCC', 'Disease', (157, 161))	('miR', 'Gene', '220972', (55, 58))	('ESCC', 'Disease', (110, 114))	('miR', 'Gene', (55, 58))
563065	26334393	DNA methylation of the E-cadherin gene may block the control of E-cadherin expression by the miR-200b-ZEB1/2 axis in ESCC, whereas miR-200b can suppress invasiveness via inhibiting the Kindlin-2-integrin beta1-AKT signaling cascade.	('E-cadherin', 'Gene', (23, 33))	('E-cadherin', 'Gene', '999', (23, 33))	('Kindlin-2', 'Gene', (185, 194))	('invasiveness', 'CPA', (153, 165))	('miR-200b-ZEB1/2', 'Gene', (93, 108))	('Kindlin-2', 'Gene', '10979', (185, 194))	('integrin beta1', 'Gene', '3688', (195, 209))	('suppress', 'NegReg', (144, 152))	('block', 'NegReg', (43, 48))	('inhibiting', 'NegReg', (170, 180))	('AKT', 'Gene', (210, 213))	('methylation', 'Var', (4, 15))	('control', 'MPA', (53, 60))	('miR-200b', 'Var', (131, 139))	('E-cadherin', 'Gene', (64, 74))	('integrin beta1', 'Gene', (195, 209))	('E-cadherin', 'Gene', '999', (64, 74))	('AKT', 'Gene', '207', (210, 213))	('ESCC', 'Disease', (117, 121))	('miR-200b-ZEB1/2', 'Gene', '406984;6935;9839', (93, 108))
563091	26334393	The membranes were blocked with 5% non-fat milk and incubated with antibodies against E-cadherin (1:400, Santa Cruz Biotechnology, Santa Cruz, CA), vimentin (1:500, Dako, Carpinteria, CA), Kindlin-2 (1:2000, Millipore), phospho-AKTS473 (1:1000, Cell Signaling), AKT (1:1000, Cell Signaling), and beta-actin (1:10000, Sigma, St. Louis, MO, USA).	('AKT', 'Gene', (262, 265))	('AKT', 'Gene', '207', (228, 231))	('vimentin', 'Gene', '7431', (148, 156))	('1:10000', 'Var', (308, 315))	('1:400', 'Var', (98, 103))	('AKT', 'Gene', '207', (262, 265))	('vimentin', 'Gene', (148, 156))	('Kindlin-2', 'Gene', '10979', (189, 198))	('1:1000', 'Var', (267, 273))	('AKT', 'Gene', (228, 231))	('Kindlin-2', 'Gene', (189, 198))	('E-cadherin', 'Gene', (86, 96))	('E-cadherin', 'Gene', '999', (86, 96))
563101	26334393	The cells incubated with antibody against total integrin beta1 were then incubated with FITC-conjugated secondary antibody (goat-anti-mouse, Santa Cruz Biotechnology) for 30 min on ice.	('FITC', 'Chemical', 'MESH:D016650', (88, 92))	('mouse', 'Species', '10090', (134, 139))	('goat', 'Species', '9925', (124, 128))	('antibody', 'Var', (25, 33))	('integrin beta1', 'Gene', (48, 62))	('integrin beta1', 'Gene', '3688', (48, 62))
563104	25909284	This study characterized the therapeutic efficacy and action mechanism of a novel natural macrolide compound F806 in human ESCC xenograft models and cell lines.	('human', 'Species', '9606', (117, 122))	('ESCC', 'Disease', (123, 127))	('F806', 'Var', (109, 113))	('macrolide', 'Chemical', 'MESH:D018942', (90, 99))	('F806', 'Chemical', '-', (109, 113))
563105	25909284	F806 inhibited growth of ESCC, most importantly, it displayed fewer undesirable side effects on normal tissues in two human ESCC xenograft models.	('F806', 'Chemical', '-', (0, 4))	('F806', 'Var', (0, 4))	('inhibited', 'NegReg', (5, 14))	('ESCC', 'Disease', (25, 29))	('growth', 'CPA', (15, 21))	('human', 'Species', '9606', (118, 123))
563106	25909284	F806 inhibited proliferation of six ESCC cells lines, with the half maximal inhibitory concentration (IC50) ranging from 9.31 to 16.43 muM.	('F806', 'Chemical', '-', (0, 4))	('rat', 'Species', '10116', (94, 97))	('F806', 'Var', (0, 4))	('inhibited', 'NegReg', (5, 14))	('rat', 'Species', '10116', (22, 25))	('proliferation', 'CPA', (15, 28))
563107	25909284	Furthermore, F806 induced apoptosis of ESCC cells, contributing to its growth-inhibitory effect.	('F806', 'Var', (13, 17))	('growth-inhibitory', 'CPA', (71, 88))	('apoptosis', 'CPA', (26, 35))	('F806', 'Chemical', '-', (13, 17))
563108	25909284	Also, F806 inhibited cell adhesion resulting in anoikis.	('F806', 'Var', (6, 10))	('cell adhesion', 'CPA', (21, 34))	('F806', 'Chemical', '-', (6, 10))	('anoikis', 'CPA', (48, 55))	('inhibited', 'NegReg', (11, 20))
563109	25909284	Mechanistic studies revealed that F806 inhibited the activation of beta1 integrin in part by binding to a novel site Arg610 of beta1 integrin, suppressed focal adhesion formation, decreased cell adhesion to extracellular matrix and eventually triggered apoptosis.	('focal adhesion formation', 'CPA', (154, 178))	('F806', 'Chemical', '-', (34, 38))	('inhibited', 'NegReg', (39, 48))	('beta1 integrin', 'Gene', (127, 141))	('suppressed', 'NegReg', (143, 153))	('beta1 integrin', 'Gene', '3688', (67, 81))	('triggered', 'Reg', (243, 252))	('binding', 'Interaction', (93, 100))	('decreased', 'NegReg', (180, 189))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (180, 203))	('beta1 integrin', 'Gene', '3688', (127, 141))	('Arg610', 'Var', (117, 123))	('activation', 'MPA', (53, 63))	('beta1 integrin', 'Gene', (67, 81))	('Arg610', 'Chemical', '-', (117, 123))	('F806', 'Var', (34, 38))	('cell adhesion to extracellular matrix', 'CPA', (190, 227))
563110	25909284	We concluded that F806 would potentially be a well-tolerated anticancer drug by targeting beta1 integrin, resulting in anoikis in ESCC cells.	('rat', 'Species', '10116', (55, 58))	('beta1 integrin', 'Gene', '3688', (90, 104))	('F806', 'Var', (18, 22))	('resulting in', 'Reg', (106, 118))	('F806', 'Chemical', '-', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('anoikis', 'Disease', (119, 126))	('beta1 integrin', 'Gene', (90, 104))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
563122	25909284	Our previous study has been reported that F806 exhibited potent activity against human cancer cells.	('cancer', 'Disease', (87, 93))	('F806', 'Var', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('F806', 'Chemical', '-', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('human', 'Species', '9606', (81, 86))
563123	25909284	In the current study, we investigated the anti-cancer effect of F806 in ESCC cells in vivo and in vitro, and the biological activity of F806 against ESCC cells by blocking beta1 integrin activation.	('F806', 'Chemical', '-', (136, 140))	('F806', 'Chemical', '-', (64, 68))	('beta1 integrin', 'Gene', (172, 186))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('blocking', 'NegReg', (163, 171))	('activation', 'MPA', (187, 197))	('F806', 'Var', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('F806', 'Var', (136, 140))	('beta1 integrin', 'Gene', '3688', (172, 186))
563124	25909284	To assess the antitumor potential of F806 in xenograft models, EC109 and KYSE510 esophageal squamous cell carcinoma (ESCC) cells were inoculated subcutaneously into nude mice.	('esophageal squamous cell carcinoma', 'Disease', (81, 115))	('tumor', 'Disease', (18, 23))	('nude mice', 'Species', '10090', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (81, 115))	('F806', 'Var', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('KYSE510', 'CellLine', 'CVCL:1354', (73, 80))	('F806', 'Chemical', '-', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
563126	25909284	The data showed that tumors from both of F806-treated groups grew more slowly than the control group (Figure 1A and 1B).	('F806-treated', 'Var', (41, 53))	('F806', 'Chemical', '-', (41, 45))	('slowly', 'NegReg', (71, 77))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('grew', 'CPA', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
563128	25909284	However, a significant (P < 0.05) antitumor effect of F806 was displayed in EC109 and KYSE510 xenograft models beginning at day 8/9 after the start of treatment.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('F806', 'Var', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('F806', 'Chemical', '-', (54, 58))	('KYSE510', 'CellLine', 'CVCL:1354', (86, 93))
563129	25909284	At the end of treatment, 4 mg/kg or 8 mg/kg F806 reduced tumor growth by 55.0% (P = 0.015) or 47.2% (P = 0.035) in EC109 cells, and 62.2% (P = 0.003) or 75.9% (P = 0.000) in KYSE510 cells, as compared to the control group.	('reduced', 'NegReg', (49, 56))	('F806', 'Chemical', '-', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('KYSE510', 'CellLine', 'CVCL:1354', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('F806', 'Var', (44, 48))	('tumor', 'Disease', (57, 62))
563133	25909284	No effect on complete blood count including white blood, red blood, hemoglobin and blood platelet count, was observed between F806-treated and control mice (Supplementary Table 4).	('F806', 'Chemical', '-', (126, 130))	('mice', 'Species', '10090', (151, 155))	('red blood', 'MPA', (57, 66))	('hemoglobin', 'MPA', (68, 78))	('F806-treated', 'Var', (126, 138))
563134	25909284	In addition, no histological abnormality was shown in lungs, brains, liver, heart and kidneys of mice between F806-treated and control groups at the end of drug treatment (Figure 1C).	('F806-treated', 'Var', (110, 122))	('F806', 'Chemical', '-', (110, 114))	('kidney', 'Disease', 'MESH:D007674', (86, 92))	('mice', 'Species', '10090', (97, 101))	('kidney', 'Disease', (86, 92))	('histological abnormality', 'Phenotype', 'HP:0002664', (16, 40))
563135	25909284	Together, these data suggest that F806 effectively inhibits tumor growth in the absence of drug-induced adverse effects.	('F806', 'Chemical', '-', (34, 38))	('inhibits', 'NegReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('F806', 'Var', (34, 38))
563137	25909284	Meanwhile, as a positive control, the growth of MTLn3 rat mammary adenocarcinoma cell was inhibited by F806 with 72 hr IC50 value of 9.60 muM, which is consistent with a previous report.	('F806', 'Var', (103, 107))	('F806', 'Chemical', '-', (103, 107))	('rat', 'Species', '10116', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('adenocarcinoma', 'Disease', (66, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (66, 80))	('inhibited', 'NegReg', (90, 99))	('growth', 'CPA', (38, 44))
563138	25909284	Shown in cell viability assays on ESCC cells, rounding and detachment of cultured cells increased in a dose- (0-40 muM) and time-dependent (0-72 h) manner after treatment with F806 (the morphology features of EC109 cells as shown in Supplementary Figure 2).	('F806', 'Var', (176, 180))	('F806', 'Chemical', '-', (176, 180))	('increased', 'PosReg', (88, 97))	('detachment', 'CPA', (59, 69))	('rounding', 'CPA', (46, 54))
563140	25909284	Notably F806 demonstrated potent growth-inhibitory effects against ESCC cells.	('ESCC cells', 'Disease', (67, 77))	('F806', 'Var', (8, 12))	('rat', 'Species', '10116', (20, 23))	('F806', 'Chemical', '-', (8, 12))	('growth-inhibitory effects', 'CPA', (33, 58))
563141	25909284	We next examined whether the growth-inhibitory effect of F806 was due to apoptosis.	('growth-inhibitory', 'MPA', (29, 46))	('F806', 'Var', (57, 61))	('F806', 'Chemical', '-', (57, 61))
563142	25909284	Transmission electron microscopy revealed condensation and margination of nuclear chromatin surrounding in the nucleus of EC109 cells treated with F806 for 24 hr, which is strongly suggestive of apoptotic cell death (Figure 2B).	('condensation', 'CPA', (42, 54))	('margination', 'CPA', (59, 70))	('F806', 'Var', (147, 151))	('F806', 'Chemical', '-', (147, 151))
563143	25909284	An apoptotic phenotype was further supported by DNA laddering, a specific marker for cell apoptosis (Figure 2C) in F806-treated EC109 cells.	('F806', 'Chemical', '-', (115, 119))	('F806-treated', 'Var', (115, 127))	('DNA laddering', 'CPA', (48, 61))
563144	25909284	On the other hand, cell cycle analysis presented the presence of a sub-G1 DNA peak in F806-treated EC109 cells (Figure 2D).	('sub-G1 DNA peak', 'MPA', (67, 82))	('F806', 'Chemical', '-', (86, 90))	('F806-treated', 'Var', (86, 98))
563145	25909284	Furthermore, the apoptosis precursor (ADP-ribose) polymerase (PARP) was cleaved, along with the reduction of PARP and the increase of cleaved PARP in F806-treated ESCC cells (Figure 2E).	('F806', 'Chemical', '-', (150, 154))	('cleaved', 'MPA', (134, 141))	('increase', 'PosReg', (122, 130))	('PARP', 'MPA', (109, 113))	('F806-treated', 'Var', (150, 162))	('reduction', 'NegReg', (96, 105))	('PARP', 'Protein', (142, 146))
563146	25909284	To further confirm the F806-induced apoptosis in ESCC cells, tumor sections from xenograft models were stained for nuclear apoptosis using the DeadEnd Fluorometric TUNEL reagent staining (Figure 2F).	('tumor', 'Disease', (61, 66))	('F806-induced', 'Var', (23, 35))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('F806', 'Chemical', '-', (23, 27))
563148	25909284	Thus, F806 would induce apoptosis, contributing to growth inhibition and cell death in ESCC cells.	('induce', 'Reg', (17, 23))	('growth inhibition', 'CPA', (51, 68))	('F806', 'Var', (6, 10))	('F806', 'Chemical', '-', (6, 10))	('apoptosis', 'CPA', (24, 33))	('cell death', 'CPA', (73, 83))
563149	25909284	Interestingly, we noted that ESCC cells began to round up and detach after 24 hr of F806-treatment, however, visible inhibition of growth was not observed until 48 hr after treatment.	('F806-treatment', 'Var', (84, 98))	('F806', 'Chemical', '-', (84, 88))	('detach', 'NegReg', (62, 68))
563150	25909284	These results clued that F806 inhibited cell adhesion, resulting in the induction of apoptosis in a process named 'anoikis'.	('F806', 'Chemical', '-', (25, 29))	('inhibited', 'NegReg', (30, 39))	('apoptosis', 'CPA', (85, 94))	('induction', 'Reg', (72, 81))	('F806', 'Var', (25, 29))	('cell adhesion', 'CPA', (40, 53))
563151	25909284	When EC109 and KYSE510 cells were cultured in poly-HEMA plates in presence of F806, a significant induction of anoikis in a dose-dependent manner was found (Figure 3A).	('poly-HEMA', 'Chemical', 'MESH:D011102', (46, 55))	('KYSE510', 'CellLine', 'CVCL:1354', (15, 22))	('anoikis', 'CPA', (111, 118))	('F806', 'Var', (78, 82))	('F806', 'Chemical', '-', (78, 82))	('induction', 'Reg', (98, 107))
563153	25909284	As shown in Figure 3B, F806 significantly inhibited cell adhesion, while there was no selectivity on fibronectin (FN), collagen (COL) or laminin (LAM).	('cell adhesion', 'CPA', (52, 65))	('fibronectin', 'Gene', (101, 112))	('inhibited', 'NegReg', (42, 51))	('F806', 'Var', (23, 27))	('fibronectin', 'Gene', '2335', (101, 112))	('FN', 'Gene', '2335', (114, 116))	('F806', 'Chemical', '-', (23, 27))
563154	25909284	Furthermore, when EC109 and KYSE510 cells were kept in FN or COL-coated plates for 30 min and treated with F806 for another 24 h (Figure 3C), or kept for 24 h prior to 30 min of F806 stimulation (Figure 3D), cell adhesion was still significantly inhibited.	('inhibited', 'NegReg', (246, 255))	('F806', 'Chemical', '-', (178, 182))	('F806', 'Var', (107, 111))	('F806', 'Chemical', '-', (107, 111))	('FN', 'Gene', '2335', (55, 57))	('cell adhesion', 'CPA', (208, 221))	('KYSE510', 'CellLine', 'CVCL:1354', (28, 35))
563155	25909284	These data indicated that F806 clearly inhibited cell adhesion, indicating anoikis.	('inhibited', 'NegReg', (39, 48))	('cell adhesion', 'CPA', (49, 62))	('anoikis', 'CPA', (75, 82))	('F806', 'Var', (26, 30))	('F806', 'Chemical', '-', (26, 30))
563156	25909284	The results of anoikis led us to the hypothesis that adhesion complex formation might be inhibited in ESCC cells by F806.	('ESCC', 'Disease', (102, 106))	('inhibited', 'NegReg', (89, 98))	('F806', 'Var', (116, 120))	('adhesion complex formation', 'MPA', (53, 79))	('F806', 'Chemical', '-', (116, 120))
563158	25909284	After cells on FN, COL or LAM-coated coverslips treated with F806 for 24 hr, focal adhesion were clearly observed in the basal layer of cells and the cell shapes remained normal in the control group, however, focal adhesion formation were obviously inhibited in F806-treated group (Figure 4A and 4B, left panel).	('inhibited', 'NegReg', (249, 258))	('F806-treated', 'Var', (262, 274))	('F806', 'Chemical', '-', (61, 65))	('FN', 'Gene', '2335', (15, 17))	('F806', 'Chemical', '-', (262, 266))	('focal adhesion formation', 'CPA', (209, 233))	('focal adhesion', 'CPA', (77, 91))	('F806', 'Var', (61, 65))
563160	25909284	Additionally, the effect of F806 on expression of Paxillin and Kindlin-2 were evaluated by Western blot.	('F806', 'Var', (28, 32))	('Paxillin', 'Gene', (50, 58))	('F806', 'Chemical', '-', (28, 32))	('Kindlin-2', 'Gene', (63, 72))	('Paxillin', 'Gene', '5829', (50, 58))	('Kindlin-2', 'Gene', '10979', (63, 72))
563161	25909284	As shown in Figure 4A and 4B, right panel, compared to the control, no difference on expression of Paxillin and Kindlin-2 were found in F806-treated cells.	('F806', 'Chemical', '-', (136, 140))	('Paxillin', 'Gene', '5829', (99, 107))	('Paxillin', 'Gene', (99, 107))	('Kindlin-2', 'Gene', (112, 121))	('Kindlin-2', 'Gene', '10979', (112, 121))	('F806-treated', 'Var', (136, 148))
563162	25909284	Therefore, F806 inhibited focal adhesion formation of ESCC cells and consequently inhibited cells to attach to ECM.	('focal adhesion formation', 'CPA', (26, 50))	('inhibited', 'NegReg', (16, 25))	('inhibited', 'NegReg', (82, 91))	('F806', 'Var', (11, 15))	('F806', 'Chemical', '-', (11, 15))	('cells to attach to ECM', 'CPA', (92, 114))
563163	25909284	We next investigated the potential mechanism of F806 involved in the inhibition of cell adhesion.	('cell adhesion', 'CPA', (83, 96))	('F806', 'Chemical', '-', (48, 52))	('F806', 'Var', (48, 52))
563165	25909284	Western blot analysis revealed that no apparent effect on the total protein level of beta1 integrin, beta4 integrin and alpha5 integrin was observed; nevertheless, F806 inhibited beta1 integrin activation in KYSE510 and EC109 cells by immunoprecipitation (Figure 5A).	('F806', 'Var', (164, 168))	('beta1 integrin', 'Gene', (179, 193))	('beta4', 'Gene', '10381', (101, 106))	('F806', 'Chemical', '-', (164, 168))	('KYSE510', 'CellLine', 'CVCL:1354', (208, 215))	('beta4', 'Gene', (101, 106))	('beta1 integrin', 'Gene', '3688', (85, 99))	('beta1 integrin', 'Gene', '3688', (179, 193))	('activation', 'MPA', (194, 204))	('inhibited', 'NegReg', (169, 178))	('beta1 integrin', 'Gene', (85, 99))
563168	25909284	Decreases in levels of activated FAK (p-FAK), AKT (p-AKT) and ERK1/2 (p-ERK1/2) were observed in F806-treated ESCC cells (Figure 5C).	('p-AKT', 'Gene', (51, 56))	('FAK', 'Gene', '5747', (33, 36))	('AKT', 'Gene', '207', (46, 49))	('FAK', 'Gene', (40, 43))	('F806-treated', 'Var', (97, 109))	('FAK', 'Gene', '5747', (40, 43))	('FAK', 'Gene', (33, 36))	('ERK1/2', 'MPA', (62, 68))	('F806', 'Chemical', '-', (97, 101))	('AKT', 'Gene', '207', (53, 56))	('AKT', 'Gene', (46, 49))	('levels', 'MPA', (13, 19))	('AKT', 'Gene', (53, 56))	('Decreases', 'NegReg', (0, 9))	('p-AKT', 'Gene', '207', (51, 56))
563169	25909284	To determine whether F806 inhibited the activation of beta1 integrin, resulting in inhibition of cell adhesion and inducing anoikis, the blockade of the activation of beta1 integrin using specific antibody JB1A and down-regulation of beta1 integrin by siRNA were examined to mimic the effect of F806.	('F806', 'Var', (21, 25))	('F806', 'Chemical', '-', (295, 299))	('inhibition', 'NegReg', (83, 93))	('F806', 'Chemical', '-', (21, 25))	('inhibited', 'NegReg', (26, 35))	('anoikis', 'CPA', (124, 131))	('beta1 integrin', 'Gene', '3688', (167, 181))	('beta1 integrin', 'Gene', (234, 248))	('cell adhesion', 'CPA', (97, 110))	('beta1 integrin', 'Gene', '3688', (54, 68))	('inducing', 'Reg', (115, 123))	('beta1 integrin', 'Gene', (167, 181))	('beta1 integrin', 'Gene', (54, 68))	('beta1 integrin', 'Gene', '3688', (234, 248))
563170	25909284	As shown in Figure 5D, the blockade of the activation of beta1 integrin inhibited cell adhesion in KYSE510 cells; however, F806 was more effective and the combination of anti-beta1 integrin with F806 caused the most suppression of cell adhesion.	('beta1 integrin', 'Gene', (175, 189))	('F806', 'Chemical', '-', (195, 199))	('F806', 'Var', (123, 127))	('KYSE510', 'CellLine', 'CVCL:1354', (99, 106))	('beta1 integrin', 'Gene', '3688', (57, 71))	('F806', 'Chemical', '-', (123, 127))	('beta1 integrin', 'Gene', '3688', (175, 189))	('cell adhesion', 'CPA', (231, 244))	('beta1 integrin', 'Gene', (57, 71))	('cell adhesion', 'CPA', (82, 95))	('inhibited', 'NegReg', (72, 81))	('F806', 'Var', (195, 199))	('suppression', 'NegReg', (216, 227))
563171	25909284	Furthermore, knockdown of beta1 integrin by siRNA certainly decreased the number of cell adhesion; nevertheless, F806 still was more effective.	('decreased', 'NegReg', (60, 69))	('beta1 integrin', 'Gene', '3688', (26, 40))	('F806', 'Var', (113, 117))	('F806', 'Chemical', '-', (113, 117))	('knockdown', 'Var', (13, 22))	('beta1 integrin', 'Gene', (26, 40))	('number of cell adhesion', 'CPA', (74, 97))
563172	25909284	Importantly, after the knockdown of beta1 integrin, mounting inhibition ratio of cell adhesion was found in F806-treated KYSE510 cells (Figure 5E).	('rat', 'Species', '10116', (72, 75))	('KYSE510', 'CellLine', 'CVCL:1354', (121, 128))	('inhibition', 'NegReg', (61, 71))	('knockdown', 'Var', (23, 32))	('F806', 'Chemical', '-', (108, 112))	('beta1 integrin', 'Gene', '3688', (36, 50))	('beta1 integrin', 'Gene', (36, 50))	('cell adhesion', 'CPA', (81, 94))
563173	25909284	Collectively, it can be concluded that F806 would inhibit the activation of beta1 integrin, leading to inhibition of focal adhesion formation and cell adhesion, finally triggering apoptosis.	('beta1 integrin', 'Gene', '3688', (76, 90))	('inhibit', 'NegReg', (50, 57))	('cell adhesion', 'CPA', (146, 159))	('activation', 'MPA', (62, 72))	('beta1 integrin', 'Gene', (76, 90))	('focal adhesion formation', 'CPA', (117, 141))	('F806', 'Var', (39, 43))	('F806', 'Chemical', '-', (39, 43))	('triggering', 'Reg', (169, 179))	('inhibition', 'NegReg', (103, 113))
563174	25909284	This study reported on the efficacy and mechanism of action of a novel macrolide analog F806 in preclinical models of esophageal squamous cell carcinoma (ESCC).	('macrolide', 'Chemical', 'MESH:D018942', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (118, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('F806', 'Var', (88, 92))	('F806', 'Chemical', '-', (88, 92))	('esophageal squamous cell carcinoma', 'Disease', (118, 152))
563175	25909284	Anticancer activity of F806 was evaluated in two human ESCC xenograft models and in six ESCC cell lines.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('human', 'Species', '9606', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('F806', 'Var', (23, 27))	('cancer', 'Disease', (4, 10))	('F806', 'Chemical', '-', (23, 27))
563176	25909284	Our data showed principle mechanisms for how F806 inhibited the growth in ESCC cells: F806 decreased the activation of beta1 integrin, prevented cancer cells away from the ECM, and eventually initiated apoptosis (Figure 6).	('cancer', 'Disease', (145, 151))	('F806', 'Chemical', '-', (45, 49))	('decreased', 'NegReg', (91, 100))	('F806', 'Var', (86, 90))	('initiated', 'Reg', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('F806', 'Chemical', '-', (86, 90))	('beta1 integrin', 'Gene', '3688', (119, 133))	('apoptosis', 'CPA', (202, 211))	('prevented', 'NegReg', (135, 144))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('F806', 'Var', (45, 49))	('activation', 'MPA', (105, 115))	('beta1 integrin', 'Gene', (119, 133))
563179	25909284	In the present study, F806 displays promising antitumor activity in ESCC cells and showed very low toxicity to the non-cancerous cells.	('toxicity', 'Disease', 'MESH:D064420', (99, 107))	('toxicity', 'Disease', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Disease', (119, 125))	('F806', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('F806', 'Chemical', '-', (22, 26))	('tumor', 'Disease', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
563180	25909284	Notably, F806 reduced the volume of ESCC xenografts at a 4 mg/kg/d dose by intraperitoneal administration, which is far below the reported minimal dose of 50 mg/kg.	('reduced', 'NegReg', (14, 21))	('volume', 'CPA', (26, 32))	('rat', 'Species', '10116', (99, 102))	('F806', 'Var', (9, 13))	('F806', 'Chemical', '-', (9, 13))	('ESCC', 'Disease', (36, 40))
563182	25909284	Indeed, F806 exhibited good safety during the treatment in ESCC xenografts: no abnormality in body weight, daily diet, liver and renal function, hematological indices, and histological characteristics in the lungs, brain, heart, kidney and liver tissue, were observed (Figure 1C, Supplementary Tables 3 and 4).	('kidney', 'Disease', (229, 235))	('abnormality in body weight', 'Phenotype', 'HP:0004323', (79, 105))	('F806', 'Var', (8, 12))	('kidney', 'Disease', 'MESH:D007674', (229, 235))	('F806', 'Chemical', '-', (8, 12))
563184	25909284	Our previous study reported that F806, could bind to the N-terminal of Hsp90 and inhibit Hsp90/Cdc37 interaction, resulting in the disassociation of Hsp90/Cdc37/client complexes and the degradation of Hsp90 client proteins in breast cancer cells.	('Hsp90', 'Gene', '3320', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Cdc37', 'Gene', (95, 100))	('Cdc37', 'Gene', '11140', (155, 160))	('Hsp90', 'Gene', (201, 206))	('Hsp90', 'Gene', (89, 94))	('disassociation', 'MPA', (131, 145))	('Hsp90', 'Gene', '3320', (71, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('interaction', 'Interaction', (101, 112))	('Hsp90', 'Gene', '3320', (149, 154))	('F806', 'Chemical', '-', (33, 37))	('Cdc37', 'Gene', (155, 160))	('Hsp90', 'Gene', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))	('breast cancer', 'Disease', (226, 239))	('degradation', 'MPA', (186, 197))	('Hsp90', 'Gene', (149, 154))	('bind', 'Interaction', (45, 49))	('Cdc37', 'Gene', '11140', (95, 100))	('inhibit', 'NegReg', (81, 88))	('F806', 'Var', (33, 37))	('Hsp90', 'Gene', '3320', (201, 206))
563185	25909284	Here our observations suggested that another novel anti-cancer mechanism of F806 would exist in ESCC cells.	('F806', 'Var', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('F806', 'Chemical', '-', (76, 80))	('ESCC', 'Disease', (96, 100))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
563187	25909284	Indeed, anoikis induction contributed to the potent antitumor effects of F806, as evidenced by inhibition of cell adhesion to the ECM components including FN, COL and LAM.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('F806', 'Var', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('F806', 'Chemical', '-', (73, 77))	('tumor', 'Disease', (56, 61))	('inhibition', 'NegReg', (95, 105))	('FN', 'Gene', '2335', (155, 157))	('anoikis induction', 'CPA', (8, 25))	('cell adhesion', 'CPA', (109, 122))
563188	25909284	These results strongly supported the notion that F806 attenuated cell adhesion, contributing to the inhibition of cell growth, i.e., anoikis.	('cell adhesion', 'CPA', (65, 78))	('cell growth', 'CPA', (114, 125))	('F806', 'Var', (49, 53))	('F806', 'Chemical', '-', (49, 53))	('anoikis', 'Disease', (133, 140))	('attenuated', 'NegReg', (54, 64))	('inhibition', 'NegReg', (100, 110))
563190	25909284	In our present study, no apparent effect on the protein level of beta1 integrin, beta4 integrin and alpha5 integrin was observed; nevertheless, the activation of beta1 integrin was inhibited by F806 both in vitro and in vivo.	('beta1 integrin', 'Gene', '3688', (162, 176))	('beta1 integrin', 'Gene', '3688', (65, 79))	('beta1 integrin', 'Gene', (162, 176))	('beta1 integrin', 'Gene', (65, 79))	('activation', 'PosReg', (148, 158))	('inhibited', 'NegReg', (181, 190))	('F806', 'Chemical', '-', (194, 198))	('F806', 'Var', (194, 198))	('beta4', 'Gene', '10381', (81, 86))	('beta4', 'Gene', (81, 86))
563192	25909284	Therefore, the inactivation of beta1 integrin would in part inhibit the affinity of integrins for their ligands, resulting in anoikis.	('affinity', 'Interaction', (72, 80))	('beta1 integrin', 'Gene', '3688', (31, 45))	('inhibit', 'NegReg', (60, 67))	('beta1 integrin', 'Gene', (31, 45))	('integrins', 'Protein', (84, 93))	('anoikis', 'Disease', (126, 133))	('inactivation', 'Var', (15, 27))
563194	25909284	These roles of beta1 integrin prompt us to identify it as a potential target of F806 in ESCC cells.	('ESCC', 'Disease', (88, 92))	('beta1 integrin', 'Gene', '3688', (15, 29))	('F806', 'Var', (80, 84))	('F806', 'Chemical', '-', (80, 84))	('beta1 integrin', 'Gene', (15, 29))
563195	25909284	The decrease in the downstream signal molecules (such as p-FAK, p-AKT and p-ERK1/2) of integrin signaling confirmed the suppression of beta1 integrin activation by F806 in ESCC cells.	('F806', 'Var', (164, 168))	('beta1 integrin', 'Gene', '3688', (135, 149))	('F806', 'Chemical', '-', (164, 168))	('decrease', 'NegReg', (4, 12))	('p-AKT', 'Gene', '207', (64, 69))	('p-AKT', 'Gene', (64, 69))	('beta1 integrin', 'Gene', (135, 149))	('FAK', 'Gene', '5747', (59, 62))	('integrin signaling', 'MPA', (87, 105))	('FAK', 'Gene', (59, 62))	('suppression', 'NegReg', (120, 131))
563196	25909284	The specific blockade of beta1 integrin antibody was performed to determine whether the inhibition of beta1 integrin activation by F806 resulted in suppression of cell adhesion and inducing anoikis.	('inducing', 'Reg', (181, 189))	('beta1 integrin', 'Gene', (25, 39))	('beta1 integrin', 'Gene', '3688', (25, 39))	('suppression', 'NegReg', (148, 159))	('F806', 'Var', (131, 135))	('beta1 integrin', 'Gene', '3688', (102, 116))	('cell adhesion', 'CPA', (163, 176))	('F806', 'Chemical', '-', (131, 135))	('anoikis', 'CPA', (190, 197))	('activation', 'PosReg', (117, 127))	('beta1 integrin', 'Gene', (102, 116))
563197	25909284	It was showed that F806 revealed greater inhibitory effect on cell adhesion in ESCC cells, in contrast to specific anti-beta1 integrin JB1A.	('cell adhesion', 'CPA', (62, 75))	('inhibitory effect', 'NegReg', (41, 58))	('beta1 integrin', 'Gene', '3688', (120, 134))	('F806', 'Chemical', '-', (19, 23))	('F806', 'Var', (19, 23))	('beta1 integrin', 'Gene', (120, 134))
563198	25909284	Nevertheless, the combination of F806 with JB1A could cause the most suppression of cell adhesion in ESCC cells (Figure 5D).	('JB1A', 'Gene', (43, 47))	('suppression', 'NegReg', (69, 80))	('F806', 'Var', (33, 37))	('F806', 'Chemical', '-', (33, 37))	('cell adhesion in', 'CPA', (84, 100))	('combination', 'Interaction', (18, 29))	('ESCC', 'Disease', (101, 105))
563199	25909284	The potential synergistic effect of F806 and JB1A on the inhibition of cell adhesion hinted different binding site between F806 and JB1A.	('binding', 'Interaction', (102, 109))	('F806', 'Var', (36, 40))	('inhibition', 'NegReg', (57, 67))	('F806', 'Chemical', '-', (36, 40))	('F806', 'Var', (123, 127))	('cell adhesion', 'CPA', (71, 84))	('F806', 'Chemical', '-', (123, 127))
563201	25909284	Based on these observations, docking computation model was performed to predict possible F806-binding site of beta1 integrin.	('F806', 'Chemical', '-', (89, 93))	('F806-binding', 'Var', (89, 101))	('beta1 integrin', 'Gene', '3688', (110, 124))	('beta1 integrin', 'Gene', (110, 124))
563202	25909284	Indeed, it was presented that F806 would interact with Arg610 site of beta1 integrin by pi bond (pi bond) (Supplementary Figure 3).	('F806', 'Chemical', '-', (30, 34))	('Arg610', 'Chemical', '-', (55, 61))	('beta1 integrin', 'Gene', '3688', (70, 84))	('interact', 'Reg', (41, 49))	('beta1 integrin', 'Gene', (70, 84))	('pi bond', 'MPA', (88, 95))	('F806', 'Var', (30, 34))	('Arg610', 'Var', (55, 61))
563203	25909284	However, detailed investigation might be necessary to clarify the mechanism of the interaction between F806 and Arg610 site of beta1 integrin.	('F806', 'Var', (103, 107))	('beta1 integrin', 'Gene', (127, 141))	('F806', 'Chemical', '-', (103, 107))	('Arg610', 'Chemical', '-', (112, 118))	('Arg610 site', 'Var', (112, 123))	('beta1 integrin', 'Gene', '3688', (127, 141))
563204	25909284	Our study also showed that the knockdown of beta1 integrin indeed decreased cell adhesion in KYSE510 cells, while F806 still was more effective than si-beta1 integrin.	('beta1 integrin', 'Gene', (44, 58))	('beta1 integrin', 'Gene', '3688', (152, 166))	('decreased', 'NegReg', (66, 75))	('F806', 'Var', (114, 118))	('beta1 integrin', 'Gene', (152, 166))	('beta1 integrin', 'Gene', '3688', (44, 58))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (66, 89))	('F806', 'Chemical', '-', (114, 118))	('cell adhesion in KYSE510 cells', 'CPA', (76, 106))	('KYSE510', 'CellLine', 'CVCL:1354', (93, 100))	('knockdown', 'Var', (31, 40))
563205	25909284	Intriguingly, after the remarkable knockdown of beta1 integrin, mounting inhibition ratio of cell adhesion was found in F806-treated KYSE510 cells (Figure 5E).	('knockdown', 'Var', (35, 44))	('F806', 'Chemical', '-', (120, 124))	('inhibition', 'NegReg', (73, 83))	('beta1 integrin', 'Gene', (48, 62))	('rat', 'Species', '10116', (84, 87))	('cell adhesion', 'CPA', (93, 106))	('KYSE510', 'CellLine', 'CVCL:1354', (133, 140))	('beta1 integrin', 'Gene', '3688', (48, 62))
563206	25909284	Obviously, after the loss of the target molecule beta1 integrin by si-RNA, F806 still could suppress KYSE510 cells binding to ECM.	('F806', 'Chemical', '-', (75, 79))	('KYSE510', 'CellLine', 'CVCL:1354', (101, 108))	('beta1 integrin', 'Gene', (49, 63))	('suppress', 'NegReg', (92, 100))	('beta1 integrin', 'Gene', '3688', (49, 63))	('KYSE510 cells binding', 'CPA', (101, 122))	('F806', 'Var', (75, 79))	('si-RNA', 'Gene', (67, 73))
563207	25909284	It hinted that beta1 integrin would not be the only potential target of F806 in ESCC cells.	('F806', 'Var', (72, 76))	('beta1 integrin', 'Gene', '3688', (15, 29))	('F806', 'Chemical', '-', (72, 76))	('beta1 integrin', 'Gene', (15, 29))	('ESCC', 'Disease', (80, 84))
563209	25909284	Therefore, F806 might also direct or indirect against other integrin subunit and further investigations would be warranted to verify the detailed mechanism.	('F806', 'Var', (11, 15))	('integrin subunit', 'Protein', (60, 76))	('F806', 'Chemical', '-', (11, 15))
563210	25909284	Mounting experimental evidence supports that drug resistance of a targeted therapeutic agent can be acquired, because inhibition of one key pathway in a tumor may not completely turn off other parallel signaling pathways, allowing some cancer cells to survive and propagate.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('drug resistance', 'Phenotype', 'HP:0020174', (45, 60))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('inhibition', 'Var', (118, 128))
563213	25909284	Furthermore, targeting beta1 integrin inhibits tumor growth in bevacizumab-resistant glioblastoma.	('beta1 integrin', 'Gene', '3688', (23, 37))	('inhibits', 'NegReg', (38, 46))	('glioblastoma', 'Disease', (85, 97))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('targeting', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('beta1 integrin', 'Gene', (23, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('bevacizumab', 'Chemical', 'MESH:D000068258', (63, 74))	('tumor', 'Disease', (47, 52))
563214	25909284	In this study, it was clearly demonstrated that F806 could induce apoptosis and inhibit cell growth via blocking the activation of beta1 integrin.	('F806', 'Var', (48, 52))	('blocking', 'NegReg', (104, 112))	('inhibit', 'NegReg', (80, 87))	('F806', 'Chemical', '-', (48, 52))	('rat', 'Species', '10116', (37, 40))	('activation', 'MPA', (117, 127))	('beta1 integrin', 'Gene', (131, 145))	('cell growth', 'CPA', (88, 99))	('apoptosis', 'CPA', (66, 75))	('beta1 integrin', 'Gene', '3688', (131, 145))
563216	25909284	In summary, our data indicate that the novel drug F806 revealed promising antitumor activity in ESCC models and showed very low toxicity to the non-cancerous cells.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('F806', 'Var', (50, 54))	('toxicity', 'Disease', 'MESH:D064420', (128, 136))	('toxicity', 'Disease', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('F806', 'Chemical', '-', (50, 54))	('ESCC', 'Disease', (96, 100))	('tumor', 'Disease', (78, 83))
563217	25909284	In addition, this study highlights the inhibition of beta1 integrin activation as a potential mechanism of F806, contributing to the suppression of focal adhesion formation, the prevention of further tumor growth and survival from the ECM, and the eventual initiation of apoptosis (i.e., anoikis) in ESCC cells.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('focal adhesion', 'Protein', (148, 162))	('F806', 'Var', (107, 111))	('inhibition', 'NegReg', (39, 49))	('beta1 integrin', 'Gene', '3688', (53, 67))	('tumor', 'Disease', (200, 205))	('survival', 'CPA', (217, 225))	('F806', 'Chemical', '-', (107, 111))	('suppression', 'NegReg', (133, 144))	('prevention', 'NegReg', (178, 188))	('apoptosis', 'CPA', (271, 280))	('beta1 integrin', 'Gene', (53, 67))
563224	25909284	Mice were inoculated subcutaneously with 1.0 x 106 EC109 or 1.0 x 106 KYSE510 human esophageal squamous cell carcinoma (ESCC) cells on the right flank.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (84, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('KYSE510', 'CellLine', 'CVCL:1354', (70, 77))	('EC109', 'Var', (51, 56))	('Mice', 'Species', '10090', (0, 4))	('human', 'Species', '9606', (78, 83))	('esophageal squamous cell carcinoma', 'Disease', (84, 118))
563238	25909284	Inhibition of growth was expressed as an inhibition ratio (%) = (1 - OD490Treated/OD490Control) x 100 or a growth ratio (%) = OD490Treated/OD490Control x 100.	('rat', 'Species', '10116', (52, 55))	('rat', 'Species', '10116', (114, 117))	('OD490Treated/OD490Control', 'Var', (126, 151))	('growth', 'MPA', (107, 113))	('growth', 'MPA', (14, 20))	('inhibition', 'NegReg', (41, 51))
563273	24966803	Positive staining for the proliferation markers Ki67 and PCNA (proliferating cell nuclear antigen) was detected in 56.9% and 60.2% of ESCC specimens, respectively, and was strongly correlated with the nestin phenotype.	('proliferating cell nuclear antigen', 'Gene', (63, 97))	('detected', 'Reg', (103, 111))	('PCNA', 'Gene', (57, 61))	('nestin', 'Gene', (201, 207))	('ESCC', 'Disease', (134, 138))	('PCNA', 'Gene', '5111', (57, 61))	('proliferating cell nuclear antigen', 'Gene', '5111', (63, 97))	('Ki67', 'Var', (48, 52))	('correlated', 'Reg', (181, 191))	('nestin', 'Gene', '10763', (201, 207))
563287	24966803	Subsequent studies have revealed that nestin knockdown inhibits cell proliferation and G1/S arrest in human non-small cell lung cancer cells, possibly via downregulation of AKT-GSK3beta-cyclin D signaling.	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('inhibits', 'NegReg', (55, 63))	('AKT', 'Gene', (173, 176))	('S arrest', 'Disease', (90, 98))	('knockdown', 'Var', (45, 54))	('GSK3beta', 'Gene', (177, 185))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('downregulation', 'NegReg', (155, 169))	('S arrest', 'Disease', 'MESH:D006323', (90, 98))	('human', 'Species', '9606', (102, 107))	('AKT', 'Gene', '207', (173, 176))	('cell proliferation', 'CPA', (64, 82))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('nestin', 'Gene', '10763', (38, 44))	('GSK3beta', 'Gene', '2932', (177, 185))	('nestin', 'Gene', (38, 44))
563325	24966803	As shown in Figure 5 (A and B) and Table 1, a subsequent Pearson's correlation analysis revealed a significant relationship between the nestin phenotype and Ki67 and PCNA optical density (Ki67: r = 0.223, P = 0.036; PCNA: r = 0.328, P = 0.003).	('PCNA', 'Gene', '5111', (166, 170))	('nestin', 'Gene', '10763', (136, 142))	('Ki67', 'Var', (157, 161))	('PCNA', 'Gene', (216, 220))	('nestin', 'Gene', (136, 142))	('PCNA', 'Gene', '5111', (216, 220))	('PCNA', 'Gene', (166, 170))
563348	24966803	Moreover, a quantitative analysis revealed that Ki67 and PCNA expression were positively correlated with nestin expression.	('correlated', 'Interaction', (89, 99))	('PCNA', 'Gene', (57, 61))	('nestin', 'Gene', '10763', (105, 111))	('nestin', 'Gene', (105, 111))	('PCNA', 'Gene', '5111', (57, 61))	('Ki67', 'Var', (48, 52))	('expression', 'MPA', (112, 122))
563372	24966803	Targeted regulation of nestin may thus have therapeutic applications in the treatment of human esophageal cancer.	('human', 'Species', '9606', (89, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('nestin', 'Gene', '10763', (23, 29))	('nestin', 'Gene', (23, 29))	('Targeted regulation', 'Var', (0, 19))	('esophageal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
563407	24955303	Similarly, rebleeding rates were significantly lower in Child A and B patients that received restrictive transfusion strategy (11%) compared to those randomized to liberal strategy (21%), but no significant differences in rebleeding rates were observed among Child C patients.	('patients', 'Species', '9606', (70, 78))	('lower', 'NegReg', (47, 52))	('patients', 'Species', '9606', (267, 275))	('bleeding', 'Disease', 'MESH:D006470', (13, 21))	('Child', 'Species', '9606', (56, 61))	('bleeding', 'Disease', (13, 21))	('bleeding', 'Disease', 'MESH:D006470', (224, 232))	('restrictive', 'Var', (93, 104))	('bleeding', 'Disease', (224, 232))	('Child', 'Species', '9606', (259, 264))
563413	24955303	A more recent meta-analysis including 12 trials (1,241 patients with cirrhosis and GI hemorrhage) confirming that antibiotic prophylaxis is associated with a significant reduction in all-cause mortality and in the development of bacterial infections but also showing a significant reduction in mortality from bacterial infections, rebleeding and days of hospitalization.	('bacterial infections', 'Disease', 'MESH:D001424', (229, 249))	('reduction', 'NegReg', (170, 179))	('bacterial infections', 'Disease', (309, 329))	('GI hemorrhage', 'Disease', (83, 96))	('cirrhosis', 'Disease', (69, 78))	('all-cause mortality', 'MPA', (183, 202))	('GI hemorrhage', 'Phenotype', 'HP:0002239', (83, 96))	('bleeding', 'Disease', 'MESH:D006470', (333, 341))	('bacterial infections', 'Disease', (229, 249))	('patients', 'Species', '9606', (55, 63))	('GI hemorrhage', 'Disease', 'MESH:D006471', (83, 96))	('development', 'MPA', (214, 225))	('reduction', 'NegReg', (281, 290))	('cirrhosis', 'Disease', 'MESH:D005355', (69, 78))	('cirrhosis', 'Phenotype', 'HP:0001394', (69, 78))	('bacterial infections', 'Disease', 'MESH:D001424', (309, 329))	('bleeding', 'Disease', (333, 341))	('antibiotic', 'Var', (114, 124))
563449	24955303	A total of 63 patients were randomized and, in a median followup of 16 months, rebleeding or failure to control hemorrhage occurred in 3% (1/32) of early TIPS group compared to 45% (14/31) of the standard therapy group (p=0.001).	('bleeding', 'Disease', 'MESH:D006470', (81, 89))	('hemorrhage', 'Disease', (112, 122))	('bleeding', 'Disease', (81, 89))	('early TIPS', 'Var', (148, 158))	('patients', 'Species', '9606', (14, 22))	('hemorrhage', 'Disease', 'MESH:D006470', (112, 122))
563450	24955303	Importantly, mortality was significantly lower in the early TIPS group (12%) compared to standard therapy (39%)(p=0.01), without differences in hepatic encephalopathy.	('early TIPS', 'Var', (54, 64))	('encephalopathy', 'Disease', 'MESH:D001927', (152, 166))	('encephalopathy', 'Phenotype', 'HP:0001298', (152, 166))	('lower', 'NegReg', (41, 46))	('encephalopathy', 'Disease', (152, 166))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (144, 166))	('mortality', 'MPA', (13, 22))
563476	24955303	The rate of rebleeding from varices was significantly lower among those who received combination therapy, whether compared to drug therapy alone or EVL alone, without differences in survival.	('EVL', 'Chemical', '-', (148, 151))	('bleeding', 'Disease', 'MESH:D006470', (14, 22))	('bleeding', 'Disease', (14, 22))	('lower', 'NegReg', (54, 59))	('combination', 'Var', (85, 96))
563554	24090770	Shorter telomeres have also been reported in esophageal squamous cell carcinoma, and in these cases, telomere shortening has been shown to associate with genomic instability.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('telomere shortening', 'Phenotype', 'HP:0031413', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (45, 79))	('associate', 'Reg', (139, 148))	('esophageal squamous cell carcinoma', 'Disease', (45, 79))	('telomere shortening', 'Var', (101, 120))	('reported', 'Reg', (33, 41))	('Shorter', 'NegReg', (0, 7))	('genomic instability', 'CPA', (154, 173))
563556	24090770	Other independent studies have also confirmed the association of shorter telomeres with the etiology of esophageal cancer.	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('shorter telomeres', 'Var', (65, 82))
563557	24090770	In a study in which telomere length was measured by quantitative PCR, short telomeres in the leukocytes of Barrett's esophagus patients with premalignant disease were significantly associated with progression to esophageal cancer.	('premalignant disease', 'Disease', (141, 161))	('short telomeres', 'Phenotype', 'HP:0031413', (70, 85))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (107, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('short telomeres', 'Var', (70, 85))	('premalignant disease', 'Disease', 'MESH:D004194', (141, 161))	('associated with', 'Reg', (181, 196))	('patients', 'Species', '9606', (127, 135))	('esophageal cancer', 'Disease', (212, 229))
563558	24090770	Similarly, another study demonstrated that reduction of both the average telomere length as well the telomere length of chromosomes 17p and 12q as compared to control individuals were associated with a significantly elevated risk of esophageal cancer.	('esophageal cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('reduction', 'NegReg', (43, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (233, 250))	('telomere', 'Var', (101, 109))	('telomere length', 'MPA', (73, 88))
563562	24090770	Acid exposure is probably the reason that certain types of mutations are observed at higher frequency in carcinomas of esophagus compared to other solid tumors.	('carcinomas of esophagus', 'Disease', (105, 128))	('solid tumors', 'Disease', (147, 159))	('carcinomas of esophagus', 'Disease', 'MESH:D004938', (105, 128))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('solid tumors', 'Disease', 'MESH:D009369', (147, 159))	('mutations', 'Var', (59, 68))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))
563567	24090770	Although the consumption of very hot liquids does not appear to have a definitive association with telomere shortening, it has been indicated as a risk fatcor for esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('telomere shortening', 'Phenotype', 'HP:0031413', (99, 118))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (163, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('esophageal squamous cell carcinoma', 'Disease', (163, 197))	('telomere', 'Var', (99, 107))
563572	24090770	We have found that inhibitors of homologous recombination (HR) reduce telomere length in telomerase positive Barrett's esophageal adenocarcinoma cells.	("Barrett's esophageal adenocarcinoma", 'Disease', 'MESH:D001471', (109, 144))	("Barrett's esophageal adenocarcinoma", 'Phenotype', 'HP:0100580', (109, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('reduce telomere length', 'Phenotype', 'HP:0031413', (63, 85))	('inhibitors', 'Var', (19, 29))	('telomere length', 'MPA', (70, 85))	("Barrett's esophageal adenocarcinoma", 'Disease', (109, 144))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (119, 144))	('reduce', 'NegReg', (63, 69))
563574	24090770	Genomic instability is further increased upon restriction endonuclease-induced DSBs in hTERT-knockdown BAC cells.	('Genomic instability', 'CPA', (0, 19))	('increased', 'PosReg', (31, 40))	('hTERT', 'Gene', (87, 92))	('DSBs', 'Var', (79, 83))	('hTERT', 'Gene', '7015', (87, 92))	('restriction endonuclease-induced DSBs', 'Var', (46, 83))
563576	24090770	The induction of HR and PML bodies seen following telomerase inhibition increases the possibility of telomere elongation through the ALT pathway.	('inhibition', 'Var', (61, 71))	('PML', 'Gene', '5371', (24, 27))	('ALT pathway', 'Pathway', (133, 144))	('telomere elongation', 'CPA', (101, 120))	('PML', 'Gene', (24, 27))
563606	24260045	MFH has a significant antitumor effect by confining the heat within the tumor site without damaging the adjacent normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('MFH', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('MFH', 'Var', (0, 3))
563694	24260045	However, MFH was able to greatly inhibit the in vivo tumor growth (P<0.001).	('MFH', 'Chemical', '-', (9, 12))	('inhibit', 'NegReg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('MFH', 'Var', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
563695	24260045	MFH was able to significantly increase the life span of the tumor-bearing rabbits over that of the control and MNP injection groups.	('rabbits', 'Species', '9986', (74, 81))	('life span', 'CPA', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MFH', 'Chemical', '-', (0, 3))	('increase', 'PosReg', (30, 38))	('tumor', 'Disease', (60, 65))	('MFH', 'Var', (0, 3))
563726	24260045	MFH is able to induce heat that is confined within the tumor site.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('MFH', 'Chemical', '-', (0, 3))	('heat', 'MPA', (22, 26))	('induce', 'Reg', (15, 21))	('MFH', 'Var', (0, 3))
563728	24260045	The results of the present study indicate that MFH at a thermal dose of 48 C for 30 min may effectively inhibit the tumor growth and significantly prolong the life-span of the tumor-bearing rabbits without any harm to the nearby tissue or organs.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('rabbits', 'Species', '9986', (190, 197))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('life-span', 'CPA', (159, 168))	('MFH', 'Chemical', '-', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('MFH', 'Var', (47, 50))	('inhibit', 'NegReg', (104, 111))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('prolong', 'NegReg', (147, 154))
563799	23063415	Cossrow and Falkner stated that the biggest rise in obesity rates was observed among NHB women, followed by USH and NHW women.	('obesity', 'Disease', (52, 59))	('NHB', 'Var', (85, 88))	('women', 'Species', '9606', (89, 94))	('women', 'Species', '9606', (120, 125))	('obesity', 'Phenotype', 'HP:0001513', (52, 59))	('rise', 'PosReg', (44, 48))	('obesity', 'Disease', 'MESH:D009765', (52, 59))
563805	23063415	Researches have found that larger VAT levels are more likely related to European genetic admixtures than to African genetic admixtures (P < 0.013 and P < 0.001, respectively), which could be responsible for the higher risks of AC in the PR population than NHB but lower than NHW and USH.	('VAT', 'Disease', 'None', (34, 37))	('larger', 'PosReg', (27, 33))	('VAT', 'Disease', (34, 37))	('genetic admixtures', 'Var', (81, 99))
563840	33753766	However, when more than three-fourths of the esophageal luminal circumference is defected after ER, it can cause stricture in spite of steroid injection or intake and require repeated balloon dilation for several months.	('defected', 'Var', (81, 89))	('intake', 'Disease', 'MESH:D000855', (156, 162))	('intake', 'Disease', (156, 162))	('stricture', 'MPA', (113, 122))	('cause', 'Reg', (107, 112))	('steroid', 'Chemical', 'MESH:D013256', (135, 142))
563866	33753766	After ER, all patients received standard follow-up, which included EGD with NBI and iodine staining every 6-12 months, and blood tests including tumor marker and computed tomographic scans of the neck, chest, and abdomen, performed every 6 months in patients with pT1a-MM or pT1b-SM invasion for lymph node and distant metastasis screening.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('pT1b-SM invasion', 'Var', (275, 291))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('patients', 'Species', '9606', (250, 258))	('tumor', 'Disease', (145, 150))	('iodine', 'Chemical', 'MESH:D007455', (84, 90))	('T1a', 'Gene', '10630', (265, 268))	('T1a', 'Gene', (265, 268))	('patients', 'Species', '9606', (14, 22))
563899	33753766	The efficacy and safety of ER combined with CRT for treating T1a-MM and T1b-SM ESCC have been reported.	('T1a', 'Gene', '10630', (61, 64))	('ESCC', 'Disease', (79, 83))	('T1a', 'Gene', (61, 64))	('T1b-SM', 'Var', (72, 78))
563900	33753766	The favorable outcome of esophagectomy for pT1a-MM with LVI and T1b-SM after ER has also been reported.	('T1a', 'Gene', '10630', (44, 47))	('T1b-SM', 'Var', (64, 70))	('esophagectomy', 'Disease', (25, 38))	('T1a', 'Gene', (44, 47))
563940	32895915	EAC was defined by a combination of the diagnosis code for esophageal cancer (C15) in the International Classification of Diseases, 10th version (ICD-10), and the histological codes for adenocarcinoma (8140-8141, 8143-8145, 8190-8231, 8260-8263, 8310, 8401, 8480-8490, 8550-8551, 8570-8574 or 8576) in the International Classification of Diseases for Oncology, Third Edition (ICD-O-3).	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('8310', 'Var', (246, 250))	('age', 'Gene', '5973', (64, 67))	('8190-8231', 'Var', (224, 233))	('8570-8574 or 8576', 'Var', (280, 297))	('adenocarcinoma', 'Disease', (186, 200))	('8550-8551', 'Var', (269, 278))	('cancer', 'Disease', (70, 76))	('EAC', 'Disease', (0, 3))	('8143-8145', 'Var', (213, 222))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('8260-8263', 'Var', (235, 244))	('8140-8141', 'Var', (202, 211))	('adenocarcinoma', 'Disease', 'MESH:D000230', (186, 200))	('age', 'Gene', (64, 67))	('8480-8490', 'Var', (258, 267))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('Oncology', 'Phenotype', 'HP:0002664', (351, 359))	('8401', 'Var', (252, 256))
564042	32846986	In their preliminary series, high ADC entropy combined with low SUV entropy were associated with a higher prevalence of metastases and a promising initial signature for future study.	('high', 'Var', (29, 33))	('low', 'NegReg', (60, 63))	('metastases', 'Disease', (120, 130))	('ADC entropy', 'MPA', (34, 45))	('SUV entropy', 'MPA', (64, 75))	('metastases', 'Disease', 'MESH:D009362', (120, 130))
564077	32846986	also retrospectively looked at the relationship between parameters derived from texture analysis of FDG PET imaging and biological characteristics of 151 newly diagnosed primary colorectal carcinoma and found that SUVmax, mean, standard deviation, and coefficient of variation as well as skewness proved significantly associated with the presence of RAS mutations (p values ranging between 0.049 and 0.001).	('RAS', 'Gene', (350, 353))	('mutations', 'Var', (354, 363))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (182, 198))	('FDG', 'Gene', (100, 103))	('SUVmax', 'MPA', (214, 220))	('FDG', 'Gene', '23583', (100, 103))	('colorectal carcinoma', 'Disease', (178, 198))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (178, 198))	('associated', 'Reg', (318, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
564146	32368307	Our study showed a significant association between high CD34 expression in tumoral tissue and a poorer prognosis in patients affected by esophageal cancer (HR 2.10; 95%CI 1.41-3.14; I2 56%; p=0.0003) (Figure 2A).	('tumoral', 'Disease', (75, 82))	('tumoral', 'Disease', 'MESH:D009369', (75, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('CD34', 'Gene', (56, 60))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CD34', 'Gene', '947', (56, 60))	('high', 'Var', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('esophageal cancer', 'Disease', (137, 154))	('expression', 'MPA', (61, 71))
564150	32368307	The meta-analysis showed a significant association between high expression of CD133 in tumoral tissue and poor prognosis in patients affected by esophageal cancer (HR 1.91; 95%CI 1.15-3.19; I2 55%; p=0.01) (Figure 2B).	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('esophageal cancer', 'Disease', (145, 162))	('CD133', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CD133', 'Gene', '8842', (78, 83))	('high expression', 'Var', (59, 74))	('tumoral', 'Disease', (87, 94))	('tumoral', 'Disease', 'MESH:D009369', (87, 94))	('patients', 'Species', '9606', (124, 132))
564152	32368307	The meta-analysis that we carried out showed a significant association between high expression of Nucleostemin in tumoral tissue and poor prognosis in patients affected by esophageal cancer (HR 2.97; 95%CI 1.11-7.98; I2 0%; p=0.03) (Figure 2C).	('esophageal cancer', 'Disease', (172, 189))	('Nucleostemin', 'Gene', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('patients', 'Species', '9606', (151, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Nucleostemin', 'Gene', '26354', (98, 110))	('high', 'Var', (79, 83))	('poor prognosis', 'CPA', (133, 147))	('tumoral', 'Disease', (114, 121))	('tumoral', 'Disease', 'MESH:D009369', (114, 121))
564158	32368307	Two studies were excluded from the meta-analysis of CD34 and the sub-analysis showed a significant association between high CD34 expression in tumoral tissue and a poorer prognosis in patients affected by esophageal cancer (HR 2.02; 95%CI 1.22-3.33; I2 65%; p=0.006) (Figure 3A).	('CD34', 'Gene', '947', (124, 128))	('expression', 'MPA', (129, 139))	('patients', 'Species', '9606', (184, 192))	('high', 'Var', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumoral', 'Disease', (143, 150))	('esophageal cancer', 'Disease', (205, 222))	('tumoral', 'Disease', 'MESH:D009369', (143, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (205, 222))	('CD34', 'Gene', (124, 128))	('CD34', 'Gene', (52, 56))	('CD34', 'Gene', '947', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
564159	32368307	Two studies were excluded from the meta-analysis of CD133 and the sub-analysis showed a tendentially significant association between high CD133 expression in tumoral tissue and a poorer prognosis in patients affected by esophageal cancer (HR 1.61; 95%CI 0.99-2.62; I2 59%; p=0.05) (Figure 3B).	('esophageal cancer', 'Disease', (220, 237))	('CD133', 'Gene', (138, 143))	('CD133', 'Gene', (52, 57))	('CD133', 'Gene', '8842', (138, 143))	('CD133', 'Gene', '8842', (52, 57))	('tumoral', 'Disease', (158, 165))	('tumoral', 'Disease', 'MESH:D009369', (158, 165))	('expression', 'MPA', (144, 154))	('high', 'Var', (133, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (220, 237))	('patients', 'Species', '9606', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
564168	32368307	This result suggests that high MVD has a prognostic value in esophageal cancer, as recently concluded in another meta-analysis.	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('esophageal cancer', 'Disease', (61, 78))	('high MVD', 'Var', (26, 34))
564198	31274653	Based on the available data, endoscopic treatment for T1N0 esophageal cancer has become integrated in national guidelines as a possible option, although there is variability in the specific tumors and patients that are eligible.	('patients', 'Species', '9606', (201, 209))	('T1N0', 'Var', (54, 58))	('esophageal cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
564252	31274653	Although we adjusted for comorbid conditions and other important clinical variables, the observed long-term survival benefit in our study may be because of overall healthier patients being treated with esophagectomy, or may be because of the impact of 13.5% occult nodal disease and improved long-term locoregional cancer control particularly for the T1bN0 patients with deeper invasion.	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('occult nodal disease', 'Disease', 'MESH:D005596', (258, 278))	('benefit', 'PosReg', (117, 124))	('cancer', 'Disease', (315, 321))	('occult nodal disease', 'Disease', (258, 278))	('patients', 'Species', '9606', (357, 365))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('improved', 'PosReg', (283, 291))	('T1bN0', 'Var', (351, 356))	('esophagectomy', 'Disease', (202, 215))
564289	31274653	This is clearly an important contribution to our knowledge of the treatment of early-stage esophageal cancer, and I think the key points you have made are that, first of all, the increasing use of endoscopic resection for T1N0 and particularly for the T1a subgroup and the decreasing use of esophagectomy for that group.	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('T1N0', 'Var', (222, 226))	('T1a', 'Gene', (252, 255))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('T1a', 'Gene', '10630', (252, 255))	('esophageal cancer', 'Disease', (91, 108))
564290	31274653	You also pointed out that survival with endoscopic resection for T1aN0 is similar to that with esophagectomy but lower in the T1b group.	('T1b', 'Var', (126, 129))	('T1a', 'Gene', '10630', (65, 68))	('T1a', 'Gene', (65, 68))	('lower', 'NegReg', (113, 118))
564293	31274653	For the T1b patients, a lot of patients are now being offered endoscopic treatment as an alternative to esophagectomy because it is viewed as a lower risk procedure, and yet the survival is inferior with endoscopic resection, and you have shown that the rate of esophagectomy is similar over the years despite increasing use of endoscopic resection.	('inferior', 'NegReg', (190, 198))	('T1b', 'Var', (8, 11))	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (31, 39))
564368	31897236	ESCC cell lines (HKESC, Eca109, KYSE30, KYSE140, KYSE410, KYSE510, KYSE150, EC9706) used in this study were obtained from the Shanghai Cell Institute Country Cell Bank and maintained in Dulbecco's modified Eagle's medium (Gibco BRL, Grand Island, NY, USA), supplemented with 10% heat-inactivated fetal bovine serum (ThermoFisher Scientific, Carlsbad, California, USA), penicillin and streptomycin in a humidified atmosphere of 5% CO2 at 37C.	('penicillin', 'Chemical', 'MESH:D010406', (369, 379))	('KYSE510', 'Var', (58, 65))	('ESCC', 'Disease', 'MESH:C562729', (0, 4))	('bovine', 'Species', '9913', (302, 308))	('CO2', 'Chemical', 'MESH:D002245', (430, 433))	('EC9706', 'CellLine', 'CVCL:E307', (76, 82))	('ESCC', 'Disease', (0, 4))	('streptomycin', 'Chemical', 'MESH:D013307', (384, 396))
564382	31897236	As shown in Figure 1D-F, the expression of SPARC was significantly inhibited with transfected SPARC siRNAs both in protein and mRNA levels.	('transfected', 'Var', (82, 93))	('inhibited', 'NegReg', (67, 76))	('SPARC', 'Gene', (43, 48))	('SPARC', 'Gene', '6678', (94, 99))	('expression', 'MPA', (29, 39))	('SPARC', 'Gene', (94, 99))	('SPARC', 'Gene', '6678', (43, 48))
564395	31897236	Thus, p-FAK and p-ERK are potential components of the SPARC intracellular signaling pathway.	('SPARC', 'Gene', (54, 59))	('p-ERK', 'Var', (16, 21))	('FAK', 'Gene', (8, 11))	('SPARC', 'Gene', '6678', (54, 59))	('FAK', 'Gene', '5747', (8, 11))
564397	31897236	There were 50% and 70% decrease in the ability of SPARC-expressing Eca109 and HKESC cells to invade through the Matrigel with the transfection of FAK siRNA, respectively (Figure 4B-D).	('FAK', 'Gene', (146, 149))	('decrease', 'NegReg', (23, 31))	('Eca109', 'Gene', (67, 73))	('SPARC', 'Gene', (50, 55))	('transfection', 'Var', (130, 142))	('invade through the Matrigel', 'CPA', (93, 120))	('FAK', 'Gene', '5747', (146, 149))	('SPARC', 'Gene', '6678', (50, 55))
564407	31897236	revealed that siRNA-mediated knockdown of SPARC in MGC803 and HGC27 gastric cancer cells dramatically decreased their invasion.	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('SPARC', 'Gene', '6678', (42, 47))	('knockdown', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('SPARC', 'Gene', (42, 47))	('gastric cancer', 'Disease', (68, 82))	('HGC27', 'CellLine', 'CVCL:1279', (62, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('invasion', 'CPA', (118, 126))	('decreased', 'NegReg', (102, 111))
564409	31897236	showed that compared to the controlled groups, knockdown of SPARC could significantly inhibit the growth and increase the apoptosis of MGC803 and HGC 27 gastric cancer cells.	('SPARC', 'Gene', '6678', (60, 65))	('gastric cancer', 'Disease', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('gastric cancer', 'Disease', 'MESH:D013274', (153, 167))	('SPARC', 'Gene', (60, 65))	('apoptosis', 'CPA', (122, 131))	('increase', 'PosReg', (109, 117))	('knockdown', 'Var', (47, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (153, 167))	('inhibit', 'NegReg', (86, 93))	('growth', 'CPA', (98, 104))
564410	31897236	Moreover, they suggested that the induction of apoptosis was partially attributed to mitochondrial pathway such as activation of the caspase pathway and cleavage of PARP.	('PARP', 'Gene', '1302', (165, 169))	('activation', 'PosReg', (115, 125))	('PARP', 'Gene', (165, 169))	('caspase pathway', 'Pathway', (133, 148))	('cleavage', 'Var', (153, 161))
564417	31897236	In addition, the successful control of melanomas by targeting SPARC expression further suggested that knockdown of SPARC in some malignancies, such as ESCC, may be one of the effective strategies for cancer therapy.	('melanomas', 'Disease', (39, 48))	('ESCC', 'Disease', 'MESH:C562729', (151, 155))	('malignancies', 'Disease', (129, 141))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('SPARC', 'Gene', '6678', (62, 67))	('ESCC', 'Disease', (151, 155))	('knockdown', 'Var', (102, 111))	('SPARC', 'Gene', '6678', (115, 120))	('melanomas', 'Disease', 'MESH:D008545', (39, 48))	('SPARC', 'Gene', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('SPARC', 'Gene', (115, 120))	('malignancies', 'Disease', 'MESH:D009369', (129, 141))	('cancer', 'Disease', (200, 206))
564435	30829906	Although LCE increases the sensitivity of WLI to >95%, it is uncomfortable for most patients and can cause inflammation of the esophageal mucosa.	('patients', 'Species', '9606', (84, 92))	('inflammation of the esophageal mucosa', 'Disease', 'MESH:D007249', (107, 144))	('inflammation of the esophageal mucosa', 'Disease', (107, 144))	('sensitivity', 'MPA', (27, 38))	('inflammation of the esophageal mucosa', 'Phenotype', 'HP:0100633', (107, 144))	('LCE', 'Var', (9, 12))	('cause', 'Reg', (101, 106))
564549	29896397	Furthermore, the cells were CK7(+), CK18(+), CK20(-) and Ki-67(+) (80-90% of the cells) (Fig.	('CK20', 'Gene', (45, 49))	('CK20', 'Gene', '54474', (45, 49))	('CK7(+', 'Var', (28, 33))	('CK18', 'Gene', (36, 40))	('Ki-67', 'Var', (57, 62))	('CK18', 'Gene', '3875', (36, 40))
564552	29896397	Thus, the TNM classification was T2N1M0 according to the European Neuroendocrine Tumor Society, and T2N3M0 stage IIIA according to the American Joint Committee on Cancer (AJCC).	('TNM', 'Gene', '10178', (10, 13))	('Cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Neuroendocrine Tumor', 'Disease', 'MESH:D018358', (66, 86))	('TNM', 'Gene', (10, 13))	('Neuroendocrine Tumor', 'Phenotype', 'HP:0100634', (66, 86))	('Cancer', 'Disease', 'MESH:D009369', (163, 169))	('T2N3M0', 'Var', (100, 106))	('Cancer', 'Disease', (163, 169))	('Tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Neuroendocrine Tumor', 'Disease', (66, 86))
564565	29896397	K-Ras mutations (0.17 and 0% respectively) are rare and the loss of p16 expression (33 and 10% respectively) is infrequent.	('K-Ras', 'Gene', '3845', (0, 5))	('p16', 'Gene', (68, 71))	('K-Ras', 'Gene', (0, 5))	('expression', 'MPA', (72, 82))	('p16', 'Gene', '1029', (68, 71))	('mutations', 'Var', (6, 15))
564590	29782621	DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKalpha-dependent cell migration Lung cancer is the leading cause of cancer-related death worldwide.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('DARPP-32', 'Gene', (0, 8))	('Lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (29, 55))	('DARPP-32', 'Gene', '84152', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('Lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (33, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Lung cancer', 'Disease', (119, 130))	('promote', 'PosReg', (21, 28))	('IKKalpha', 'Gene', '1147', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('t-DARPP', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('IKKalpha', 'Gene', (85, 93))
564591	29782621	Here we demonstrate that elevated expression of dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant t-DARPP promote lung tumor growth, while abrogation of DARPP-32 expression in human non-small-cell lung cancer (NSCLC) cells reduces tumor growth in orthotopic mouse models.	('expression', 'MPA', (34, 44))	('lung tumor', 'Disease', 'MESH:D008175', (188, 198))	('lung cancer', 'Disease', 'MESH:D008175', (271, 282))	('tumor', 'Disease', (305, 310))	('NSCLC', 'Disease', 'MESH:D002289', (284, 289))	('mouse', 'Species', '10090', (332, 337))	('lung cancer', 'Phenotype', 'HP:0100526', (271, 282))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('NSCLC', 'Disease', (284, 289))	('tumor', 'Disease', (193, 198))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (260, 282))	('NSCLC', 'Phenotype', 'HP:0030358', (284, 289))	('dopamine', 'Chemical', 'MESH:D004298', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('lung tumor', 'Disease', (188, 198))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('promote', 'PosReg', (180, 187))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (256, 282))	('lung tumor', 'Phenotype', 'HP:0100526', (188, 198))	('lung cancer', 'Disease', (271, 282))	('phosphate', 'Chemical', 'MESH:D010710', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('DARPP-32', 'Gene', (128, 136))	('reduces', 'NegReg', (297, 304))	('t-DARPP', 'Gene', (172, 179))	('abrogation', 'Var', (213, 223))	('human', 'Species', '9606', (250, 255))
564601	29782621	Despite administration of standard chemotherapeutic agents with evolving systemic cancer therapies directed at driver mutations (epidermal growth factor receptor (EGFR), BRAF and ALK), inhibiting angiogenesis (anti-vascular endothelial growth factor therapy) and immune-checkpoint blockade (anti-programmed death-1 antibody), these statistics remain dismal due to the large number of patients diagnosed with advanced-stage disease and the primary and secondary resistance to current therapies.	('epidermal growth factor receptor', 'Gene', (129, 161))	('ALK', 'Gene', '238', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('systemic cancer', 'Disease', (73, 88))	('inhibiting', 'NegReg', (185, 195))	('BRAF', 'Gene', (170, 174))	('BRAF', 'Gene', '673', (170, 174))	('epidermal growth factor receptor', 'Gene', '1956', (129, 161))	('vascular endothelial growth factor', 'Gene', '7422', (215, 249))	('mutations', 'Var', (118, 127))	('EGFR', 'Gene', '1956', (163, 167))	('angiogenesis', 'CPA', (196, 208))	('patients', 'Species', '9606', (384, 392))	('ALK', 'Gene', (179, 182))	('EGFR', 'Gene', (163, 167))	('systemic cancer', 'Disease', 'MESH:D009369', (73, 88))	('vascular endothelial growth factor', 'Gene', (215, 249))
564605	29782621	Phosphorylation at threonine-34 (T34) by PKA causes DARPP-32-mediated inhibition of protein phosphatase-1 (PP-1), hence DARPP-32 is also called phosphoprotein phosphatase-1 regulatory subunit 1B (PPP1R1B).	('phosphoprotein phosphatase-1 regulatory subunit 1B', 'Gene', (144, 194))	('inhibition', 'NegReg', (70, 80))	('protein phosphatase-1', 'Gene', '5540', (84, 105))	('PPP1R1B', 'Gene', (196, 203))	('Phosphorylation', 'Var', (0, 15))	('phosphoprotein phosphatase-1 regulatory subunit 1B', 'Gene', '84152', (144, 194))	('threonine', 'Chemical', 'MESH:D013912', (19, 28))	('PP-1', 'Gene', (107, 111))	('PPP1R1B', 'Gene', '84152', (196, 203))	('protein phosphatase-1', 'Gene', '5540', (151, 172))	('protein phosphatase-1', 'Gene', (84, 105))	('PP-1', 'Gene', '5540', (107, 111))
564614	29782621	Several studies have demonstrated that DARPP-32 and t-DARPP protect cancer cells from drug-induced apoptosis, which is dependent upon their T75 phosphorylation residue and involves upregulation of Akt and Bcl2 proteins.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Akt', 'Gene', '207', (197, 200))	('Akt', 'Gene', (197, 200))	('drug-induced apoptosis', 'CPA', (86, 108))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Bcl2', 'Gene', (205, 209))	('cancer', 'Disease', (68, 74))	('upregulation', 'PosReg', (181, 193))	('T75', 'MPA', (140, 143))	('t-DARPP', 'Var', (52, 59))	('Bcl2', 'Gene', '596', (205, 209))	('DARPP-32', 'Gene', (39, 47))
564620	29782621	The family of NF-kappaB proteins is comprised of structurally homologous transcription factors, including NF-kappaB1 (p105/50), NF-kappaB2 (p100/52), RelA (p65), RelB and c-Rel.	('NF-kappaB', 'Gene', '4790', (106, 115))	('c-Rel', 'Gene', (171, 176))	('p65', 'Gene', (156, 159))	('NF-kappaB', 'Gene', (128, 137))	('p65', 'Gene', '5970', (156, 159))	('RelA', 'Gene', (150, 154))	('RelB', 'Gene', (162, 166))	('NF-kappaB', 'Gene', (106, 115))	('RelB', 'Gene', '5971', (162, 166))	('NF-kappaB', 'Gene', '4790', (14, 23))	('RelA', 'Gene', '5970', (150, 154))	('NF-kappaB', 'Gene', (14, 23))	('c-Rel', 'Gene', '5966', (171, 176))	('p100/52', 'Var', (140, 147))	('p105', 'Gene', '4790', (118, 122))	('p105', 'Gene', (118, 122))	('NF-kappaB', 'Gene', '4790', (128, 137))
564622	29782621	When a cell receives appropriate stimuli, IkappaB kinase (IKK) phosphorylation is initiated, leading to proteasome-mediated processing of p105 and p100.	('p100', 'Var', (147, 151))	('leading to', 'Reg', (93, 103))	('p105', 'Gene', (138, 142))	('p105', 'Gene', '4790', (138, 142))	('proteasome-mediated processing', 'MPA', (104, 134))
564627	29782621	Dysregulation of the IKK complex can initiate constitutive activation of the NF-kappaB1 pathway in cancer cells.	('Dysregulation', 'Var', (0, 13))	('NF-kappaB', 'Gene', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('IKK', 'Protein', (21, 24))	('cancer', 'Disease', (99, 105))	('activation', 'PosReg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('NF-kappaB', 'Gene', '4790', (77, 86))
564630	29782621	Ablation of constitutive IKK activity by small molecule inhibitor reduces cellular NF-kappaB1 activity and melanoma cell survival in vitro and in vivo.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('reduces', 'NegReg', (66, 73))	('Ablation', 'Var', (0, 8))	('NF-kappaB', 'Gene', '4790', (83, 92))	('activity', 'MPA', (94, 102))	('IKK', 'Protein', (25, 28))	('NF-kappaB', 'Gene', (83, 92))	('cellular', 'MPA', (74, 82))
564637	29782621	To determine the role of DARPP-32 in regulation of cell survival, we first assessed apoptosis upon DARPP-32 knockdown using flow cytometry-based annexin V assays and detection of apoptosis-associated proteins by immunoblotting.	('knockdown', 'Var', (108, 117))	('apoptosis', 'CPA', (84, 93))	('DARPP-32', 'Gene', (99, 107))	('annexin V', 'Gene', '308', (145, 154))	('annexin V', 'Gene', (145, 154))
564638	29782621	We observed increased annexin V-positive cells, along with elevated expression of cleaved poly(ADP-ribose) polymerase (PARP) and caspase-3 proteins, in DARPP-32 knockdown cell lines compared to controls (Fig.	('expression', 'MPA', (68, 78))	('PARP', 'Gene', (119, 123))	('cleaved', 'MPA', (82, 89))	('caspase-3', 'Gene', (129, 138))	('poly(ADP-ribose) polymerase', 'Gene', '142', (90, 117))	('increased', 'PosReg', (12, 21))	('annexin V', 'Gene', '308', (22, 31))	('PARP', 'Gene', '142', (119, 123))	('elevated', 'PosReg', (59, 67))	('annexin V', 'Gene', (22, 31))	('knockdown', 'Var', (161, 170))	('poly(ADP-ribose) polymerase', 'Gene', (90, 117))	('caspase-3', 'Gene', '836', (129, 138))
564650	29782621	Ablation of DARPP-32 decreased phosphorylated Akt (p-Akt) and phosphorylated Erk (p-Erk) levels substantially, while corresponding total Akt and Erk1/2 protein expression remained unchanged by immunoblotting (Fig.	('Akt', 'Gene', '207', (46, 49))	('Erk', 'Gene', (145, 148))	('Akt', 'Gene', '207', (53, 56))	('Erk1/2', 'Gene', '5595;5594', (145, 151))	('decreased', 'NegReg', (21, 30))	('Ablation', 'Var', (0, 8))	('Akt', 'Gene', (46, 49))	('Akt', 'Gene', '207', (137, 140))	('Erk', 'Gene', (77, 80))	('Erk', 'Gene', '5594', (145, 148))	('Erk', 'Gene', (84, 87))	('Erk1/2', 'Gene', (145, 151))	('DARPP-32', 'Gene', (12, 20))	('Akt', 'Gene', (53, 56))	('Akt', 'Gene', (137, 140))	('Erk', 'Gene', '5594', (77, 80))	('Erk', 'Gene', '5594', (84, 87))
564652	29782621	We found exogenous overexpression of t-DARPP and mutant DARPP-32 (T34A) proteins also elevates p-Akt and p-Erk1/2 levels, suggesting PP-1 activation by DARPP-32 T34 phosphorylation is not directly involved in stimulation of Akt and Erk signaling (Fig.	('PP-1', 'Gene', (133, 137))	('Erk1/2', 'Gene', '5595;5594', (107, 113))	('Erk', 'Gene', (107, 110))	('mutant', 'Var', (49, 55))	('Akt', 'Gene', (97, 100))	('proteins', 'Protein', (72, 80))	('Erk', 'Gene', (232, 235))	('Erk1/2', 'Gene', (107, 113))	('PP-1', 'Gene', '5540', (133, 137))	('elevates', 'PosReg', (86, 94))	('Erk', 'Gene', '5594', (107, 110))	('DARPP-32', 'Gene', (56, 64))	('Akt', 'Gene', '207', (224, 227))	('Erk', 'Gene', '5594', (232, 235))	('Akt', 'Gene', '207', (97, 100))	('Akt', 'Gene', (224, 227))	('T34A', 'Mutation', 'c.34T>A', (66, 70))
564654	29782621	DARPP-32 is upregulated in various cancers including breast and gastric cancer, in which expression of DARPP-32 is associated with increased migration and invasion.	('migration', 'CPA', (141, 150))	('DARPP-32', 'Gene', (0, 8))	('increased', 'PosReg', (131, 140))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (53, 78))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('expression', 'Var', (89, 99))	('DARPP-32', 'Gene', (103, 111))	('invasion', 'CPA', (155, 163))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('upregulated', 'PosReg', (12, 23))
564658	29782621	DARPP-32, as well as t-DARPP and the T34A DARPP-32 mutant, promoted increased migration in A549 and H1650 cells (Fig.	('T34A', 'Mutation', 'c.34T>A', (37, 41))	('T34A', 'Var', (37, 41))	('DARPP-32', 'Gene', (42, 50))	('promoted increased', 'PosReg', (59, 77))	('migration', 'CPA', (78, 87))	('H1650', 'CellLine', 'CVCL:1483', (100, 105))	('A549', 'CellLine', 'CVCL:0023', (91, 95))
564661	29782621	Similar to our previous findings, DARPP-32 knockdown substantially decreased tumor cell migration in A549 and H1650 cells (Supplementary Fig.	('decreased', 'NegReg', (67, 76))	('DARPP-32', 'Gene', (34, 42))	('knockdown', 'Var', (43, 52))	('A549', 'CellLine', 'CVCL:0023', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('men', 'Species', '9606', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('H1650', 'CellLine', 'CVCL:1483', (110, 115))	('tumor', 'Disease', (77, 82))
564662	29782621	Moreover, A549 and H1650 cells stably overexpressing DARPP-32, t-DARPP or mutant DARPP-32 (T34A) increased cell migration compared to control (Supplementary Fig.	('A549', 'CellLine', 'CVCL:0023', (10, 14))	('H1650', 'CellLine', 'CVCL:1483', (19, 24))	('increased', 'PosReg', (97, 106))	('men', 'Species', '9606', (149, 152))	('DARPP-32', 'Gene', (53, 61))	('cell migration', 'CPA', (107, 121))	('T34A', 'Mutation', 'c.34T>A', (91, 95))	('t-DARPP', 'Protein', (63, 70))	('mutant', 'Var', (74, 80))	('DARPP-32', 'Gene', (81, 89))
564667	29782621	By immunoblotting, we found DARPP-32 ablation in A549 and H1650 human lung adenocarcinoma cells reduced the NF-kB2 p52 to p100 ratio, suggesting DARPP-32 positively regulates non-canonical NF-kB2 signaling (Supplementary Fig.	('human', 'Species', '9606', (64, 69))	('p52', 'Gene', '4791', (115, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('NF-kB2', 'Gene', '4791', (189, 195))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (70, 89))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('DARPP-32', 'Gene', (28, 36))	('ablation', 'Var', (37, 45))	('H1650', 'CellLine', 'CVCL:1483', (58, 63))	('NF-kB2', 'Gene', '4791', (108, 114))	('NF-kB2', 'Gene', (189, 195))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('p52', 'Gene', (115, 118))	('NF-kB2', 'Gene', (108, 114))	('men', 'Species', '9606', (213, 216))	('lung adenocarcinoma', 'Disease', (70, 89))	('reduced', 'NegReg', (96, 103))
564668	29782621	Correspondingly, we found DARPP-32 knockdown decreased cytosolic phosphorylated NF-kB2 p100 and nuclear NF-kB2 p52 protein expression in A549 and H1650 cells (Fig.	('knockdown', 'Var', (35, 44))	('DARPP-32', 'Gene', (26, 34))	('NF-kB2', 'Gene', '4791', (80, 86))	('NF-kB2', 'Gene', '4791', (104, 110))	('decreased', 'NegReg', (45, 54))	('NF-kB2', 'Gene', (80, 86))	('cytosolic phosphorylated', 'MPA', (55, 79))	('protein', 'Protein', (115, 122))	('p52', 'Gene', (111, 114))	('NF-kB2', 'Gene', (104, 110))	('H1650', 'CellLine', 'CVCL:1483', (146, 151))	('p52', 'Gene', '4791', (111, 114))	('A549', 'CellLine', 'CVCL:0023', (137, 141))
564670	29782621	Indeed, we observed greater nuclear localization of p52 in A549 and H1650 lung cancer cells overexpressing DARPP-32, t-DARPP or DARPP-32 T34A relative to controls (Fig.	('nuclear localization', 'MPA', (28, 48))	('lung cancer', 'Disease', (74, 85))	('A549', 'CellLine', 'CVCL:0023', (59, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('greater', 'PosReg', (20, 27))	('H1650', 'CellLine', 'CVCL:1483', (68, 73))	('DARPP-32', 'Var', (107, 115))	('T34A', 'Mutation', 'c.34T>A', (137, 141))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('p52', 'Gene', (52, 55))	('p52', 'Gene', '4791', (52, 55))	('DARPP-32 T34A', 'Var', (128, 141))	('t-DARPP', 'Var', (117, 124))
564676	29782621	The interaction of DARPP-32 and IKKalpha was substantially decreased upon DARPP-32 ablation (Fig.	('interaction', 'Interaction', (4, 15))	('IKKalpha', 'Gene', '1147', (32, 40))	('decreased', 'NegReg', (59, 68))	('IKKalpha', 'Gene', (32, 40))	('DARPP-32', 'Gene', (74, 82))	('ablation', 'Var', (83, 91))
564677	29782621	To determine whether DARPP-32 isoforms regulate transcriptional effectors of non-canonical NF-kB2 signaling, we assessed the messenger RNA (mRNA) expression of EZH2 and BIRC3 transcriptional targets upon DARPP-32 isoform modulation in A549 and H1650 human NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('NF-kB2', 'Gene', (91, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (256, 261))	('BIRC3', 'Gene', (169, 174))	('H1650', 'CellLine', 'CVCL:1483', (244, 249))	('BIRC3', 'Gene', '330', (169, 174))	('modulation', 'Var', (221, 231))	('A549', 'CellLine', 'CVCL:0023', (235, 239))	('EZH2', 'Gene', '2146', (160, 164))	('NF-kB2', 'Gene', '4791', (91, 97))	('human', 'Species', '9606', (250, 255))	('EZH2', 'Gene', (160, 164))	('NSCLC', 'Disease', (256, 261))
564678	29782621	We observed decreased expression of EZH2 and BIRC3 transcripts upon knockdown of DARPP-32 (Supplementary Fig.	('BIRC3', 'Gene', '330', (45, 50))	('men', 'Species', '9606', (97, 100))	('knockdown', 'Var', (68, 77))	('expression', 'MPA', (22, 32))	('decreased', 'NegReg', (12, 21))	('DARPP-32', 'Gene', (81, 89))	('EZH2', 'Gene', '2146', (36, 40))	('EZH2', 'Gene', (36, 40))	('BIRC3', 'Gene', (45, 50))
564679	29782621	7a, b, c, d), whereas these NF-kB2 signaling targets increased upon overexpression of DARPP-32 or t-DARPP in NSCLC cells relative to controls (Supplementary Fig.	('NF-kB2', 'Gene', '4791', (28, 34))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('men', 'Species', '9606', (149, 152))	('t-DARPP', 'Var', (98, 105))	('NF-kB2', 'Gene', (28, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('overexpression', 'PosReg', (68, 82))	('increased', 'PosReg', (53, 62))	('DARPP-32', 'Protein', (86, 94))	('NSCLC', 'Disease', (109, 114))
564686	29782621	Next, we examined migration in A549 and H1650 cells upon shRNA-mediated NF-kB2 knockdown (Fig.	('H1650', 'CellLine', 'CVCL:1483', (40, 45))	('NF-kB2', 'Gene', '4791', (72, 78))	('A549', 'CellLine', 'CVCL:0023', (31, 35))	('NF-kB2', 'Gene', (72, 78))	('knockdown', 'Var', (79, 88))	('examined', 'Reg', (9, 17))
564688	29782621	NF-kappaB2 depletion decreased tumor cell migration in the scratch wound healing assay (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('NF-kappaB', 'Gene', '4790', (0, 9))	('decreased', 'NegReg', (21, 30))	('NF-kappaB', 'Gene', (0, 9))	('tumor', 'Disease', (31, 36))	('depletion', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
564693	29782621	Migration was not altered in IKKalpha- or NF-kB2-depleted NSCLC cells upon overexpression of DARPP-32, but migration was substantially increased when DARPP-32 was overexpressed in the absence of IKKalpha or NF-kB2 knockdown (Fig.	('NSCLC', 'Disease', (58, 63))	('migration', 'CPA', (107, 116))	('NF-kB2', 'Gene', '4791', (42, 48))	('IKKalpha', 'Gene', '1147', (29, 37))	('IKKalpha', 'Gene', (29, 37))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('knockdown', 'Var', (214, 223))	('NF-kB2', 'Gene', (42, 48))	('NF-kB2', 'Gene', '4791', (207, 213))	('increased', 'PosReg', (135, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('IKKalpha', 'Gene', '1147', (195, 203))	('IKKalpha', 'Gene', (195, 203))	('NF-kB2', 'Gene', (207, 213))
564696	29782621	To this end, we tested whether DARPP-32 ablation reduces lung tumor growth in an orthotopic xenograft mouse model.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('ablation', 'Var', (40, 48))	('DARPP-32', 'Gene', (31, 39))	('reduces', 'NegReg', (49, 56))	('lung tumor', 'Disease', 'MESH:D008175', (57, 67))	('lung tumor', 'Disease', (57, 67))	('lung tumor', 'Phenotype', 'HP:0100526', (57, 67))	('mouse', 'Species', '10090', (102, 107))
564698	29782621	We observed a substantial decrease in lung tumor growth in mice challenged with DARPP-32 ablated A549 cells compared to mice challenged with cells transduced with control LacZ shRNA (Fig.	('ablated', 'Var', (89, 96))	('mice', 'Species', '10090', (59, 63))	('mice', 'Species', '10090', (120, 124))	('lung tumor', 'Phenotype', 'HP:0100526', (38, 48))	('decrease', 'NegReg', (26, 34))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('lung tumor', 'Disease', (38, 48))	('lung tumor', 'Disease', 'MESH:D008175', (38, 48))	('DARPP-32 ablated', 'Var', (80, 96))
564699	29782621	Correspondingly, we found decreased tumor growth in mice orthotopically injected with DARPP-32 ablated H1650 (Fig.	('ablated', 'Var', (95, 102))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('DARPP-32', 'Gene', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('H1650', 'Gene', (103, 108))	('H1650', 'CellLine', 'CVCL:1483', (103, 108))	('decreased', 'NegReg', (26, 35))	('tumor', 'Disease', (36, 41))
564701	29782621	These findings support our hypothesis that DARPP-32 depletion inhibits human lung tumor growth.	('DARPP-32', 'Protein', (43, 51))	('inhibits', 'NegReg', (62, 70))	('lung tumor', 'Disease', 'MESH:D008175', (77, 87))	('lung tumor', 'Disease', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('depletion', 'Var', (52, 61))	('lung tumor', 'Phenotype', 'HP:0100526', (77, 87))	('human', 'Species', '9606', (71, 76))
564703	29782621	To address this question, we injected luciferase-labeled human A549 NSCLC cells stably overexpressing exogenous DARPP-32 or t-DARPP into the left thorax of anesthetized SCID mice.	('DARPP-32', 'Gene', (112, 120))	('SCID', 'Disease', 'MESH:D053632', (169, 173))	('SCID', 'Disease', (169, 173))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('mice', 'Species', '10090', (174, 178))	('A549', 'CellLine', 'CVCL:0023', (63, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('t-DARPP', 'Var', (124, 131))	('human', 'Species', '9606', (57, 62))	('NSCLC', 'Disease', (68, 73))
564705	29782621	Taken together, our data suggest DARPP-32 proteins drive lung tumorigenesis and inhibition of DARPP-32 reduces lung cancer growth.	('DARPP-32', 'Protein', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lung tumor', 'Disease', 'MESH:D008175', (57, 67))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('lung tumor', 'Disease', (57, 67))	('reduces', 'NegReg', (103, 110))	('lung cancer', 'Disease', (111, 122))	('DARPP-32', 'Gene', (94, 102))	('lung tumor', 'Phenotype', 'HP:0100526', (57, 67))	('inhibition', 'Var', (80, 90))	('drive', 'PosReg', (51, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
564718	29782621	As assessed by Kaplan-Meier survival curve, we observed that patients with high t-DARPP to DARPP-32 ratio showed substantially decreased survival relative to lung adenocarcinoma patients with low t-DARPP expression (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('decreased', 'NegReg', (127, 136))	('high', 'Var', (75, 79))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (61, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (158, 177))	('survival', 'MPA', (137, 145))	('lung adenocarcinoma', 'Disease', (158, 177))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (158, 177))
564723	29782621	Our results reveal decreased survival in the patients with high expression of NF-kB2 and IKKalpha transcripts compared to low expressers of those mRNAs (Fig.	('NF-kB2', 'Gene', (78, 84))	('survival', 'MPA', (29, 37))	('patients', 'Species', '9606', (45, 53))	('IKKalpha', 'Gene', '1147', (89, 97))	('high expression', 'Var', (59, 74))	('IKKalpha', 'Gene', (89, 97))	('decreased', 'NegReg', (19, 28))	('NF-kB2', 'Gene', '4791', (78, 84))
564727	29782621	For example, alternations in expression of DARPP-32 and t-DARPP have been implicated in schizophrenia, bipolar disorder and Alzheimer's disease as well as numerous types of tumors, including breast, gastric, prostate, esophageal and colon cancers.	('colon cancers', 'Phenotype', 'HP:0003003', (233, 246))	('esophageal and colon cancers', 'Disease', 'MESH:D004938', (218, 246))	('prostate', 'Disease', (208, 216))	('alternations', 'Var', (13, 25))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('bipolar disorder', 'Phenotype', 'HP:0007302', (103, 119))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('implicated', 'Reg', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	("Alzheimer's disease", 'Disease', (124, 143))	('tumors', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('gastric', 'Disease', (199, 206))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (124, 143))	('schizophrenia, bipolar disorder', 'Disease', 'MESH:D001714', (88, 119))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('expression', 'MPA', (29, 39))	('t-DARPP', 'Gene', (56, 63))	('DARPP-32', 'Gene', (43, 51))	('breast', 'Disease', (191, 197))	('schizophrenia', 'Phenotype', 'HP:0100753', (88, 101))
564728	29782621	Since investigation of the frequent amplification at the 17q12 locus in gastric cancers implicated DARPP-32 and t-DARPP in oncogenesis, numerous studies have demonstrated the role of these proteins in cancer cell survival, drug resistance, migration, invasion and angiogenesis.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('drug resistance', 'CPA', (223, 238))	('drug resistance', 'Phenotype', 'HP:0020174', (223, 238))	('cancer', 'Disease', (201, 207))	('DARPP-32', 'Gene', (99, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('gastric cancers', 'Disease', 'MESH:D013274', (72, 87))	('amplification', 'Var', (36, 49))	('invasion', 'CPA', (251, 259))	('gastric cancers', 'Disease', (72, 87))	('gastric cancers', 'Phenotype', 'HP:0012126', (72, 87))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('migration', 'CPA', (240, 249))	('angiogenesis', 'CPA', (264, 276))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
564729	29782621	Our results suggest DARPP-32 and t-DARPP promote NSCLC cell survival through activation of Akt and Erk1/2 signaling by protecting cells from apoptotic cell death (Figs.	('Erk1/2', 'Gene', (99, 105))	('Akt', 'Gene', '207', (91, 94))	('DARPP-32', 'Gene', (20, 28))	('NSCLC', 'Disease', (49, 54))	('t-DARPP', 'Var', (33, 40))	('activation', 'PosReg', (77, 87))	('Akt', 'Gene', (91, 94))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('promote', 'PosReg', (41, 48))	('Erk1/2', 'Gene', '5595;5594', (99, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))
564731	29782621	Correspondingly, overexpression of DARPP-32 and t-DARPP in human gastrointestinal adenocarcinoma cells was shown to cause a fourfold reduction in apoptosis.	('human', 'Species', '9606', (59, 64))	('gastrointestinal adenocarcinoma', 'Disease', 'MESH:D004067', (65, 96))	('reduction', 'NegReg', (133, 142))	('DARPP-32', 'Protein', (35, 43))	('overexpression', 'PosReg', (17, 31))	('gastrointestinal adenocarcinoma', 'Disease', (65, 96))	('apoptosis', 'CPA', (146, 155))	('t-DARPP', 'Var', (48, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
564732	29782621	The T75 phosphorylation residue shared by DARPP-32 and t-DARPP was attributed to promoting cell survival, and a follow-up report by the same group suggested increased activation of Akt and Bcl2 is mechanistically responsible for t-DARPP-mediated cancer cell survival.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('Bcl2', 'Gene', (189, 193))	('cancer', 'Disease', (246, 252))	('T75', 'Var', (4, 7))	('DARPP-32', 'Gene', (42, 50))	('activation', 'PosReg', (167, 177))	('Akt', 'Gene', '207', (181, 184))	('Bcl2', 'Gene', '596', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('promoting', 'PosReg', (81, 90))	('Akt', 'Gene', (181, 184))	('cell survival', 'CPA', (91, 104))
564737	29782621	Collectively, these studies demonstrated that t-DARPP drives breast cancer cell resistance to trastuzumab through inhibition of apoptotic caspase-3 and activation of pro-survival Akt signaling through its T75 residue, common among both DARPP-32 isoforms.	('caspase-3', 'Gene', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('inhibition', 'NegReg', (114, 124))	('t-DARPP', 'Var', (46, 53))	('activation', 'PosReg', (152, 162))	('drives', 'PosReg', (54, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('caspase-3', 'Gene', '836', (138, 147))	('trastuzumab', 'Chemical', 'MESH:D000068878', (94, 105))	('Akt', 'Gene', '207', (179, 182))	('T75', 'Var', (205, 208))	('Akt', 'Gene', (179, 182))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('resistance to trastuzumab', 'MPA', (80, 105))
564757	29782621	However, studies suggest the NF-kB2 pathway is activated in cancer through viral oncogenes, mutations in pathway components and upregulation of upstream components of the pathway, the latter of which is supported by our results, suggesting DARPP-32 promotes activation of non-canonical NF-kB2 signaling in lung cancer through an interaction with IKKalpha.	('NF-kB2', 'Gene', '4791', (286, 292))	('cancer', 'Disease', (311, 317))	('NF-kB2', 'Gene', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('NF-kB2', 'Gene', '4791', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('lung cancer', 'Disease', (306, 317))	('NF-kB2', 'Gene', (29, 35))	('interaction', 'Interaction', (329, 340))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('mutations', 'Var', (92, 101))	('IKKalpha', 'Gene', '1147', (346, 354))	('lung cancer', 'Disease', 'MESH:D008175', (306, 317))	('DARPP-32', 'Gene', (240, 248))	('cancer', 'Disease', (60, 66))	('IKKalpha', 'Gene', (346, 354))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))	('activation', 'PosReg', (258, 268))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
564761	29782621	Using a similar xenograft mouse model, they have subsequently demonstrated shRNA-mediated knockdown of DARPP-32 reduces gastric tumorigenesis and overexpression of DARPP-32 in AGS human gastric adenocarcinoma cells promotes in vivo tumor growth.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('knockdown', 'Var', (90, 99))	('human', 'Species', '9606', (180, 185))	('gastric tumor', 'Disease', (120, 133))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Disease', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('DARPP-32', 'Gene', (103, 111))	('gastric tumor', 'Disease', 'MESH:D013274', (120, 133))	('tumor', 'Disease', (128, 133))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (186, 208))	('gastric adenocarcinoma', 'Disease', (186, 208))	('mouse', 'Species', '10090', (26, 31))	('gastric tumor', 'Phenotype', 'HP:0006753', (120, 133))	('reduces', 'NegReg', (112, 119))	('promotes', 'PosReg', (215, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
564762	29782621	To the best of our knowledge, our study is the first to assess DARPP-32 knockdown as well as DARPP-32 and t-DARPP overexpression in an orthotopic cancer xenograft mouse model.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('DARPP-32', 'Gene', (63, 71))	('mouse', 'Species', '10090', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('knockdown', 'Var', (72, 81))
564763	29782621	Importantly, our in vivo results showing DARPP-32 and t-DARPP promote NSCLC oncogenesis coincide with similar findings in esophageal and gastric cancer subcutaneous xenograft models.	('DARPP-32', 'Gene', (41, 49))	('t-DARPP', 'Var', (54, 61))	('esophageal', 'Disease', (122, 132))	('NSCLC', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('gastric cancer', 'Disease', (137, 151))	('promote', 'PosReg', (62, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('esophageal', 'Disease', 'MESH:D004941', (122, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
564778	29782621	The Flag-tagged coding sequence of DARPP-32, t-DARPP and T34A DARPP-32 were subcloned into the retroviral (pMMP) vector.	('DARPP-32', 'Gene', (35, 43))	('T34A', 'Mutation', 'c.34T>A', (57, 61))	('T34A', 'Var', (57, 61))	('DARPP-32', 'Gene', (62, 70))
564801	29782621	: 9662; dilution 1:1000), cleaved caspase-3 (cat no.	('caspase-3', 'Gene', (34, 43))	('caspase-3', 'Gene', '836', (34, 43))	('cleaved', 'Var', (26, 33))
564802	29782621	: 9664; dilution 1:1000), phosphorylated Akt (S473; cat no.	('Akt', 'Gene', (41, 44))	('S473;', 'Var', (46, 51))	('Akt', 'Gene', '207', (41, 44))
564804	29782621	: 4691; dilution 1:1000), phosphorylated p44/42 MAPK (T202/Y204; cat no.	('p44', 'Gene', (41, 44))	('p44', 'Gene', '2966', (41, 44))	('T202/Y204;', 'Var', (54, 64))
564806	29782621	: 4695; dilution 1:1000), phosphorylated NF-kappaB2 p100 (S866/870; cat no.	('S866/870;', 'Var', (58, 67))	('NF-kappaB', 'Gene', '4790', (41, 50))	('NF-kappaB', 'Gene', (41, 50))	('p100 (S866/870', 'Var', (52, 66))
564808	29782621	: 4882; dilution 1:1000), phosphorylated IKKalpha/beta (S176/180; cat no.	('IKKalpha/beta', 'Gene', '1147;3551', (41, 54))	('IKKalpha/beta', 'Gene', (41, 54))	('S176/180;', 'Var', (56, 65))
564891	29642180	The TaqMan Gene expression assay IDs for the genes used in this study are as follows: CSTA, Hs00193257_m1; GAPDH, Hs00266705_g1.	('CSTA', 'Gene', (86, 90))	('Hs00266705_g1', 'Var', (114, 127))	('GAPDH', 'Gene', '2597', (107, 112))	('GAPDH', 'Gene', (107, 112))	('Hs00193257_m1', 'Var', (92, 105))	('CSTA', 'Gene', '1475', (86, 90))
564914	29642180	In the CSTA-positive group, Ki67 was often expressed in cells that were CSTA-positive, which was in sharp contrast to normal mucosa, where proliferating cells that expressed Ki67 were limited to the basal layer and did not express CSTA (Fig.	('CSTA', 'Gene', (72, 76))	('CSTA', 'Gene', (231, 235))	('Ki67', 'Var', (174, 178))	('expressed', 'Reg', (43, 52))	('CSTA', 'Gene', '1475', (7, 11))	('CSTA', 'Gene', (7, 11))	('CSTA', 'Gene', '1475', (72, 76))	('CSTA', 'Gene', '1475', (231, 235))
564927	29642180	In human keratinocytes, knockdown of CSTA led to decreased cell-cell adhesion by disrupting the desmosomal structures.	('CSTA', 'Gene', '1475', (37, 41))	('disrupting', 'NegReg', (81, 91))	('desmosomal structures', 'CPA', (96, 117))	('human', 'Species', '9606', (3, 8))	('CSTA', 'Gene', (37, 41))	('cell-cell adhesion', 'CPA', (59, 77))	('decreased', 'NegReg', (49, 58))	('knockdown', 'Var', (24, 33))
564929	29642180	We also observed that PPL expression facilitated tumor cell growth in vivo, probably due to PPL-promoted cell-cell adhesion.	('cell-cell adhesion', 'CPA', (105, 123))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PPL', 'Gene', '5493', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('expression', 'Var', (26, 36))	('PPL', 'Gene', '5493', (92, 95))	('tumor', 'Disease', (49, 54))	('facilitated', 'PosReg', (37, 48))	('PPL', 'Gene', (22, 25))	('PPL', 'Gene', (92, 95))
564964	28900326	Zn deficiency adversely affects the immune system, increases oxidative stress, increases the generation of inflammatory cytokines, and also potentiates the effects of certain nitrosamines that act as esophageal carcinogens.	('deficiency adversely affects the immune system', 'Phenotype', 'HP:0002721', (3, 49))	('increases', 'PosReg', (79, 88))	('oxidative stress', 'Phenotype', 'HP:0025464', (61, 77))	('generation of inflammatory cytokines', 'MPA', (93, 129))	('immune system', 'CPA', (36, 49))	('increases', 'PosReg', (51, 60))	('deficiency', 'Var', (3, 13))	('potentiates', 'PosReg', (140, 151))	('esophageal carcinogens', 'Disease', 'MESH:D004941', (200, 222))	('oxidative stress', 'MPA', (61, 77))	('nitrosamines', 'Chemical', 'MESH:D009602', (175, 187))	('affects', 'Reg', (24, 31))	('effects of', 'MPA', (156, 166))	('esophageal carcinogens', 'Disease', (200, 222))	('Zn', 'Chemical', 'MESH:D015032', (0, 2))
565022	25519497	The patient was clinically diagnosed with T1b N2 M0 G2, stage IIIA cancer (according to the American Joint Committee on Cancer (AJCC) staging system) and treated with concurrent chemoradiotherapy.	('Cancer', 'Disease', (120, 126))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('patient', 'Species', '9606', (4, 11))	('stage IIIA cancer', 'Disease', (56, 73))	('stage IIIA cancer', 'Disease', 'MESH:D009369', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('T1b N2 M0 G2', 'Var', (42, 54))
565025	25519497	After chemoradiotherapy, the patient showed a sufficient response to be clinically down-staged to T1a/T1b N0 M0 G2, stage IA (according to the AJCC staging system).	('patient', 'Species', '9606', (29, 36))	('down-staged', 'NegReg', (83, 94))	('T1a/T1b', 'Var', (98, 105))
565055	22406828	Epigenetic Biomarkers in Esophageal Cancer The aberrant DNA methylation of tumor suppressor genes is well documented in esophageal cancer, including adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) as well as in Barrett's esophagus (BE), a pre-malignant condition that is associated with chronic acid reflux.	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Esophageal Cancer', 'Disease', (25, 42))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (219, 238))	('adenocarcinoma', 'Disease', (149, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('tumor', 'Disease', (75, 80))	('EAC', 'Phenotype', 'HP:0011459', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('BE', 'Phenotype', 'HP:0100580', (240, 242))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (174, 197))	('aberrant', 'Var', (47, 55))	('adenocarcinoma', 'Disease', 'MESH:D000230', (149, 163))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (25, 42))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('esophageal cancer', 'Disease', (120, 137))	('squamous cell carcinoma', 'Disease', (174, 197))	('acid reflux', 'Phenotype', 'HP:0002020', (303, 314))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	("Barrett's esophagus", 'Disease', (219, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))
565071	22406828	In addition, epigenetic modifications, primarily in the form of DNA hypermethylation of tumor suppressor genes, have been demonstrated to occur frequently in both ESCC and EAC, as well as in the EAC precursor lesion BE.	('epigenetic modifications', 'Var', (13, 37))	('ESCC', 'Disease', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('DNA', 'MPA', (64, 67))	('occur', 'Reg', (138, 143))	('EAC', 'Phenotype', 'HP:0011459', (195, 198))	('EAC', 'Phenotype', 'HP:0011459', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('EAC', 'Disease', (172, 175))	('BE', 'Phenotype', 'HP:0100580', (216, 218))	('tumor', 'Disease', (88, 93))
565072	22406828	A subset of these aberrantly methylated tumor suppressor genes are predicted to play an important role in the pathogenesis of these esophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('esophageal cancers', 'Disease', (132, 150))	('esophageal cancers', 'Disease', 'MESH:D004938', (132, 150))	('tumor', 'Disease', (40, 45))	('aberrantly methylated', 'Var', (18, 39))
565078	22406828	Hypermethylation of this gene promoter combined with loss of heterozygosity (LOH) of 9p21 (which contains the p16INK4a locus) leads to CDKN2A inactivation in some individuals with EAC or BE with dysplasia.	('CDKN2A', 'Gene', (135, 141))	('CDKN2A', 'Gene', '1029', (135, 141))	('p21', 'Gene', (86, 89))	('p16INK4a', 'Gene', '1029', (110, 118))	('EAC', 'Disease', (180, 183))	('BE', 'Phenotype', 'HP:0100580', (187, 189))	('Hypermethylation', 'Var', (0, 16))	('p21', 'Gene', '644914', (86, 89))	('inactivation', 'NegReg', (142, 154))	('p16INK4a', 'Gene', (110, 118))	('dysplasia', 'Disease', (195, 204))	('loss of heterozygosity', 'Var', (53, 75))	('dysplasia', 'Disease', 'MESH:D004476', (195, 204))	('EAC', 'Phenotype', 'HP:0011459', (180, 183))
565080	22406828	Methylation of the CDKN2A promoter was also found to be associated with other established genetic biomarkers in BE, including 17p (p53) LOH and increased aneuploidy/tetraploidy, which together are thought to promote the clonal expansion of BE at high risk of transformation and to drive the process of carcinogenesis.	('promote', 'PosReg', (208, 215))	('aneuploidy', 'Disease', 'MESH:D000782', (154, 164))	('Methylation', 'Var', (0, 11))	('CDKN2A', 'Gene', (19, 25))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('associated', 'Reg', (56, 66))	('CDKN2A', 'Gene', '1029', (19, 25))	('carcinogenesis', 'Disease', 'MESH:D063646', (302, 316))	('BE', 'Phenotype', 'HP:0100580', (112, 114))	('aneuploidy', 'Disease', (154, 164))	('BE', 'Phenotype', 'HP:0100580', (240, 242))	('carcinogenesis', 'Disease', (302, 316))
565081	22406828	Hypermethylation of CDKN2A appears to occur early in the metaplasia-dysplasia-carcinoma sequence, with various studies reporting promoter methylation in 3-77% of BE cases.	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (57, 87))	('metaplasia-dysplasia-carcinoma', 'Disease', (57, 87))	('BE', 'Phenotype', 'HP:0100580', (162, 164))	('Hypermethylation', 'Var', (0, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('CDKN2A', 'Gene', (20, 26))	('promoter', 'MPA', (129, 137))	('CDKN2A', 'Gene', '1029', (20, 26))
565082	22406828	These studies suggest that methylated CDKN2A might be a useful marker in a noninvasive assay for the diagnosis of BE.	('CDKN2A', 'Gene', '1029', (38, 44))	('methylated', 'Var', (27, 37))	('CDKN2A', 'Gene', (38, 44))	('BE', 'Phenotype', 'HP:0100580', (114, 116))
565084	22406828	They found a high incidence of methylation of ESR1, APC and CDKN2A in BE, BE with dysplasia, and EAC in a pattern suggesting clonal expansion of those cells that had acquired methylated alleles of these genes; in contrast, CDH1 was unmethylated in almost all of the samples.	('methylated', 'Var', (175, 185))	('BE', 'Phenotype', 'HP:0100580', (70, 72))	('CDH1', 'Gene', (223, 227))	('ESR1', 'Gene', '2099', (46, 50))	('CDH1', 'Gene', '999', (223, 227))	('dysplasia', 'Disease', (82, 91))	('CDKN2A', 'Gene', (60, 66))	('BE', 'Phenotype', 'HP:0100580', (74, 76))	('methylation', 'Var', (31, 42))	('ESR1', 'Gene', (46, 50))	('CDKN2A', 'Gene', '1029', (60, 66))	('APC', 'Disease', 'MESH:D011125', (52, 55))	('EAC', 'Phenotype', 'HP:0011459', (97, 100))	('dysplasia', 'Disease', 'MESH:D004476', (82, 91))	('APC', 'Disease', (52, 55))
526190	22406828	Similar patterns consistent with clonal expansion in BE have been reported in studies that focused on LOH or mutations of APC, TP53, and CDKN2A.	('BE', 'Phenotype', 'HP:0100580', (53, 55))	('APC', 'Disease', 'MESH:D011125', (122, 125))	('CDKN2A', 'Gene', '1029', (137, 143))	('APC', 'Disease', (122, 125))	('CDKN2A', 'Gene', (137, 143))	('mutations', 'Var', (109, 118))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
565086	22406828	Hypermethylated APC was found frequently in both EAC and ESCC cases (N=48/52 cases (92%) and N=16/32 cases (50%), respectively) as well as in N=17/34 (39.5%) BE patients, but not in matched normal esophageal tissues.	('EAC', 'Disease', (49, 52))	('ESCC', 'Disease', (57, 61))	('Hypermethylated', 'Var', (0, 15))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('patients', 'Species', '9606', (161, 169))	('BE', 'Phenotype', 'HP:0100580', (158, 160))	('APC', 'Disease', 'MESH:D011125', (16, 19))	('APC', 'Disease', (16, 19))
565087	22406828	Interestingly, Kawakami et al detected methylated APC in the plasma of 25% of EAC patients (N=13/52) and 6.3% ESCC patients (N=2/32).	('patients', 'Species', '9606', (115, 123))	('APC', 'Disease', (50, 53))	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('patients', 'Species', '9606', (82, 90))	('EAC', 'Disease', (78, 81))	('methylated', 'Var', (39, 49))	('APC', 'Disease', 'MESH:D011125', (50, 53))
565089	22406828	The methylation status of REPRIMO, a tumor suppressor gene that regulates p53-mediated cell cycle arrest, was evaluated in 175 endoscopic biopsy specimens and was found to be methylated infrequently in ESCC (13%), and more frequently in BE (36%), BE with high-grade dysplasia (HGD; 64%) and EAC cases (63%) suggesting this might be a useful biomarker for the early detection of esophageal neoplasia.	('methylated', 'Var', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('REPRIMO', 'Gene', '56475', (26, 33))	('ESCC', 'Disease', (202, 206))	('p53', 'Gene', (74, 77))	('dysplasia', 'Disease', (266, 275))	('dysplasia', 'Disease', 'MESH:D004476', (266, 275))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (378, 398))	('REPRIMO', 'Gene', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('BE', 'Phenotype', 'HP:0100580', (247, 249))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))	('EAC', 'Phenotype', 'HP:0011459', (291, 294))	('neoplasia', 'Phenotype', 'HP:0002664', (389, 398))	('BE', 'Phenotype', 'HP:0100580', (237, 239))	('tumor', 'Disease', (37, 42))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (378, 398))	('p53', 'Gene', '7157', (74, 77))	('esophageal neoplasia', 'Disease', (378, 398))
565090	22406828	This group found frequent hypermethylation of GPX3 (62%), GXP7 (67%), and GSTM2 (69%) (N=75) that was associated with reduced levels of the corresponding mRNA and which was reversible following treatment with the DNA methyltransferase 1 (DNMT1) inhibitor 5-aza-2'-deoxycytidine.	('DNA methyltransferase 1', 'Gene', '1786', (213, 236))	('GSTM2', 'Gene', '2946', (74, 79))	('DNMT1', 'Gene', (238, 243))	('reduced', 'NegReg', (118, 125))	('DNMT1', 'Gene', '1786', (238, 243))	('hypermethylation', 'Var', (26, 42))	('mRNA', 'MPA', (154, 158))	('levels', 'MPA', (126, 132))	('GSTM2', 'Gene', (74, 79))	('GPX3', 'Gene', (46, 50))	('DNA methyltransferase 1', 'Gene', (213, 236))	('GPX3', 'Gene', '2878', (46, 50))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (255, 277))
565092	22406828	SOCS-3, and to a lesser degree SOCS-1, was found to be hypermethylated and associated with a subsequent reduction in mRNA transcript levels in BE (SOCS-3: N=4/30 (13%), SOCS-1: N=0/30 (0%)), BE with low-grade dysplasia (SOCS-3: N=6/27 (22%), SOCS-1: N=1/27 (4%)), BE with high-grade dysplasia (SOCS-3: N=20/29 (69%), SOCS-1: N=6/29 (21%)), and EAC cases (SOCS-3: N=14/19 (74%), SOCS-1: N=8/19 (42%)).	('SOCS-1', 'Gene', '8651', (378, 384))	('SOCS-3', 'Gene', (147, 153))	('mRNA transcript levels', 'MPA', (117, 139))	('dysplasia', 'Disease', (209, 218))	('SOCS-1', 'Gene', '8651', (242, 248))	('SOCS-1', 'Gene', (31, 37))	('dysplasia', 'Disease', 'MESH:D004476', (209, 218))	('low-grade dysplasia', 'Disease', (199, 218))	('SOCS-1', 'Gene', (317, 323))	('SOCS-1', 'Gene', '8651', (169, 175))	('SOCS-3', 'Gene', '9021', (294, 300))	('SOCS-1', 'Gene', (378, 384))	('SOCS-3', 'Gene', '9021', (0, 6))	('SOCS-3', 'Gene', (294, 300))	('SOCS-1', 'Gene', (242, 248))	('SOCS-3', 'Gene', '9021', (355, 361))	('BE', 'Phenotype', 'HP:0100580', (264, 266))	('SOCS-3', 'Gene', (0, 6))	('BE', 'Phenotype', 'HP:0100580', (191, 193))	('SOCS-3', 'Gene', (355, 361))	('low-grade dysplasia', 'Disease', 'MESH:D008228', (199, 218))	('EAC', 'Phenotype', 'HP:0011459', (344, 347))	('BE', 'Phenotype', 'HP:0100580', (143, 145))	('hypermethylated', 'Var', (55, 70))	('reduction', 'NegReg', (104, 113))	('SOCS-1', 'Gene', (169, 175))	('SOCS-3', 'Gene', '9021', (220, 226))	('SOCS-1', 'Gene', '8651', (31, 37))	('SOCS-3', 'Gene', (220, 226))	('dysplasia', 'Disease', (283, 292))	('SOCS-1', 'Gene', '8651', (317, 323))	('dysplasia', 'Disease', 'MESH:D004476', (283, 292))	('SOCS-3', 'Gene', '9021', (147, 153))
565096	22406828	Additional genes that have previously been reported to demonstrate hypermethylation in BE and/or EAC, including DAPK, SFRP1, 2, 4, and 5, EYA4, p14ARF, MGMT, and TIMP-3 are also listed in Table 1.	('DAPK', 'Gene', (112, 116))	('DAPK', 'Gene', '1612', (112, 116))	('TIMP-3', 'Gene', '7078', (162, 168))	('BE', 'Phenotype', 'HP:0100580', (87, 89))	('p14ARF', 'Gene', (144, 150))	('MGMT', 'Gene', (152, 156))	('EYA4', 'Gene', (138, 142))	('MGMT', 'Gene', '4255', (152, 156))	('hypermethylation', 'Var', (67, 83))	('EYA4', 'Gene', '2070', (138, 142))	('SFRP1, 2, 4, and 5', 'Gene', '6422;6423;6424;6425', (118, 136))	('TIMP-3', 'Gene', (162, 168))	('EAC', 'Phenotype', 'HP:0011459', (97, 100))	('p14ARF', 'Gene', '1029', (144, 150))
565099	22406828	For example, in a retrospective study which compared BE patients who progressed to HGD or EAC to those who did not, hypermethylation of the genes CDKN2A (OR 1.74, 95% CI 1.33 - 2.20), RUNX3 (OR 1.80, 95% CI 1.08 - 2.81), and HPP1 (OR 1.77, 95% CI 1.06 - 2.81) was associated with an increased risk of progression.	('CDKN2A', 'Gene', (146, 152))	('patients', 'Species', '9606', (56, 64))	('HPP1', 'Gene', '780897', (225, 229))	('associated', 'Reg', (264, 274))	('CDKN2A', 'Gene', '1029', (146, 152))	('BE', 'Phenotype', 'HP:0100580', (53, 55))	('HPP1', 'Gene', (225, 229))	('RUNX3', 'Gene', (184, 189))	('RUNX3', 'Gene', '864', (184, 189))	('EAC', 'Phenotype', 'HP:0011459', (90, 93))	('hypermethylation', 'Var', (116, 132))
565100	22406828	Age, BE segment length, and hypermethylation of other genes (TIMP-3, APC, or CRBP1) were not found to be independent risk factors.	('CRBP1', 'Gene', (77, 82))	('hypermethylation', 'Var', (28, 44))	('TIMP-3', 'Gene', '7078', (61, 67))	('BE', 'Phenotype', 'HP:0100580', (5, 7))	('APC', 'Disease', 'MESH:D011125', (69, 72))	('CRBP1', 'Gene', '5947', (77, 82))	('APC', 'Disease', (69, 72))	('TIMP-3', 'Gene', (61, 67))
565104	22406828	Other reports have also noted that methylated APC and CDKN2A are associated with an increased risk of BE progression to EAC.	('APC', 'Disease', (46, 49))	('CDKN2A', 'Gene', (54, 60))	('EAC', 'Phenotype', 'HP:0011459', (120, 123))	('associated', 'Reg', (65, 75))	('methylated', 'Var', (35, 45))	('CDKN2A', 'Gene', '1029', (54, 60))	('EAC', 'Disease', (120, 123))	('BE', 'Phenotype', 'HP:0100580', (102, 104))	('APC', 'Disease', 'MESH:D011125', (46, 49))
565105	22406828	Although ESCC is not as well characterized as EAC from an epigenetic standpoint, several putative tumor suppressor genes have been shown to be frequently hypermethylated in ESCC.	('ESCC', 'Disease', (9, 13))	('ESCC', 'Disease', (173, 177))	('hypermethylated', 'Var', (154, 169))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('EAC', 'Phenotype', 'HP:0011459', (46, 49))
565106	22406828	CDKN2A/p16INK4a, a tumor suppressor that demonstrates DNA promoter hypermethylation in many BE and EAC cases (as outlined above), also exhibits hypermethylation in ESCC.	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('p16INK4a', 'Gene', '1029', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('hypermethylation', 'Var', (67, 83))	('ESCC', 'Disease', (164, 168))	('p16INK4a', 'Gene', (7, 15))	('tumor', 'Disease', (19, 24))	('CDKN2A', 'Gene', (0, 6))	('hypermethylation', 'MPA', (144, 160))	('BE', 'Phenotype', 'HP:0100580', (92, 94))	('CDKN2A', 'Gene', '1029', (0, 6))
565107	22406828	Hypermethylation of CDKN2A is relatively common in ESCC cases, ranging from 40-62%, and is frequently associated with loss of expression and an advanced histological grade of cancer.	('associated', 'Reg', (102, 112))	('expression', 'MPA', (126, 136))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('loss of', 'NegReg', (118, 125))	('CDKN2A', 'Gene', (20, 26))	('ESCC', 'Disease', (51, 55))	('CDKN2A', 'Gene', '1029', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
565109	22406828	For this reason, inactivation of MGMT by aberrant DNA methylation might favor the progression of esophageal squamous epithelium to ESCC.	('inactivation', 'Var', (17, 29))	('favor', 'PosReg', (72, 77))	('aberrant', 'Var', (41, 49))	('progression', 'CPA', (82, 93))	('MGMT', 'Gene', (33, 37))	('esophageal squamous', 'Disease', 'MESH:D000077277', (97, 116))	('MGMT', 'Gene', '4255', (33, 37))	('esophageal squamous', 'Disease', (97, 116))	('DNA', 'Protein', (50, 53))	('ESCC', 'Disease', (131, 135))
565110	22406828	In fact, methylated MGMT has been shown in 33-39% of ESCC cases, and can be associated with a reduction in MGMT protein levels.	('MGMT', 'Gene', (20, 24))	('ESCC', 'Disease', (53, 57))	('reduction', 'NegReg', (94, 103))	('MGMT', 'Gene', '4255', (107, 111))	('MGMT', 'Gene', (107, 111))	('methylated', 'Var', (9, 19))	('MGMT', 'Gene', '4255', (20, 24))
565112	22406828	Methylated TFF1 was also identified as a potential early marker for ESCC in this analysis.	('ESCC', 'Disease', (68, 72))	('TFF1', 'Gene', '7031', (11, 15))	('TFF1', 'Gene', (11, 15))	('Methylated', 'Var', (0, 10))
565114	22406828	Just as some individuals with EAC have hypermethylated APC detectable in their plasma, a minority of ESCC patients (N=2/32; 6.3%) had quantifiable methylated APC detected in their plasma.	('EAC', 'Phenotype', 'HP:0011459', (30, 33))	('APC', 'Disease', 'MESH:D011125', (158, 161))	('APC', 'Disease', (158, 161))	('hypermethylated', 'Var', (39, 54))	('APC', 'Disease', 'MESH:D011125', (55, 58))	('patients', 'Species', '9606', (106, 114))	('APC', 'Disease', (55, 58))	('ESCC', 'Disease', (101, 105))
565115	22406828	In another study, 23% of patients (N=7/31) who had methylated CDKN2A in their ESCC also had this same methylation change detected in DNA isolated from their serum.	('methylation', 'MPA', (102, 113))	('methylated', 'Var', (51, 61))	('CDKN2A', 'Gene', (62, 68))	('patients', 'Species', '9606', (25, 33))	('CDKN2A', 'Gene', '1029', (62, 68))
565119	22406828	Individuals with >50% of their gene profile showing aberrant methylation had significantly reduced survival (p = 0.04) and earlier tumor recurrence (p = 0.05) compared to those individuals with <50% of their genes showing aberrant methylation.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('survival', 'CPA', (99, 107))	('tumor', 'Disease', (131, 136))	('reduced', 'NegReg', (91, 98))	('aberrant methylation', 'Var', (52, 72))
565120	22406828	A positive methylation status was a better predictor of survival than either age or tumor stage.	('tumor', 'Disease', (84, 89))	('positive methylation status', 'Var', (2, 29))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
565121	22406828	Other methylated genes that have been associated with a poor prognosis in EAC include methylated NELL1 and TAC1.	('EAC', 'Phenotype', 'HP:0011459', (74, 77))	('TAC1', 'Gene', '6863', (107, 111))	('NELL1', 'Gene', '4745', (97, 102))	('EAC', 'Disease', (74, 77))	('methylated', 'Var', (86, 96))	('TAC1', 'Gene', (107, 111))	('NELL1', 'Gene', (97, 102))
565122	22406828	The APC gene, which demonstrates frequent methylation in both EAC and ESCC cases, has been associated with reduced survival in ESCC patients following treatment of their disease.	('survival', 'MPA', (115, 123))	('ESCC', 'Disease', (127, 131))	('reduced', 'NegReg', (107, 114))	('APC', 'Disease', 'MESH:D011125', (4, 7))	('EAC', 'Phenotype', 'HP:0011459', (62, 65))	('APC', 'Disease', (4, 7))	('methylation', 'Var', (42, 53))	('EAC', 'Disease', (62, 65))	('ESCC', 'Disease', (70, 74))	('patients', 'Species', '9606', (132, 140))
565123	22406828	In a cohort of ESCC patients (N=45), 44.4% had hypermethylated APC detected in their cancers, and this group showed reduced two-year survival rates as compared to those with unmethylated APC present in the cancers.	('reduced', 'NegReg', (116, 123))	('ESCC', 'Disease', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('hypermethylated', 'Var', (47, 62))	('APC', 'Disease', 'MESH:D011125', (63, 66))	('cancers', 'Disease', (85, 92))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('patients', 'Species', '9606', (20, 28))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('APC', 'Disease', (63, 66))	('APC', 'Disease', 'MESH:D011125', (187, 190))	('cancers', 'Disease', (206, 213))	('APC', 'Disease', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
565124	22406828	Methylated FHIT has also been associated with a poor outcome.	('FHIT', 'Gene', (11, 15))	('FHIT', 'Gene', '2272', (11, 15))	('Methylated', 'Var', (0, 10))
565125	22406828	In a study of ESCC patients (N=257), 33% had methylated FHIT present in their cancers, and these cases were associated with a greater rate of disease recurrence after esophagectomy (HR = 5.81 (CI = 1.15-14.07) versus controls), as well as reduced survival after recurrence (HR = 2.31 (CI = 1.18-7.92) versus controls).	('FHIT', 'Gene', '2272', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('disease', 'Disease', (142, 149))	('patients', 'Species', '9606', (19, 27))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('methylated', 'Var', (45, 55))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('reduced', 'NegReg', (239, 246))	('survival', 'MPA', (247, 255))	('FHIT', 'Gene', (56, 60))
565127	22406828	Patients with the highest PGP9.5 methylation levels had poorer five-year survival rates (p = 0.01) and also an increased incidence of lymph nodes metastases (p = 0.03) versus those with lower methylation values.	('lymph nodes metastases', 'Disease', 'MESH:D009362', (134, 156))	('poorer', 'NegReg', (56, 62))	('Patients', 'Species', '9606', (0, 8))	('increased incidence of lymph nodes', 'Phenotype', 'HP:0032536', (111, 145))	('PGP9.5', 'Gene', '7345', (26, 32))	('lymph nodes metastases', 'Disease', (134, 156))	('methylation levels', 'Var', (33, 51))	('PGP9.5', 'Gene', (26, 32))
565128	22406828	Additionally, the tumor suppressor gene TSLC1 is frequently methylated in ESCC cases, and methylated TLSC1 has been associated with loss of TSLC1 mRNA expression and aggressive tumor behavior.	('mRNA expression', 'MPA', (146, 161))	('aggressive tumor behavior', 'Disease', (166, 191))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', (18, 23))	('loss', 'NegReg', (132, 136))	('ESCC', 'Disease', (74, 78))	('TSLC1', 'Gene', '23705', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('TLSC1', 'Gene', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (166, 191))	('methylated', 'Var', (90, 100))	('TSLC1', 'Gene', '23705', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('TSLC1', 'Gene', (140, 145))	('TSLC1', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
565130	22406828	Methylation of the Wnt antagonists SFRP1, DKK3, and RUNX3 in DNA isolated from the plasma of ESCC patients has been associated with an increased risk of recurrent disease.	('associated with', 'Reg', (116, 131))	('SFRP1', 'Gene', '6422', (35, 40))	('RUNX3', 'Gene', (52, 57))	('Methylation', 'Var', (0, 11))	('DKK3', 'Gene', '27122', (42, 46))	('RUNX3', 'Gene', '864', (52, 57))	('DKK3', 'Gene', (42, 46))	('patients', 'Species', '9606', (98, 106))	('SFRP1', 'Gene', (35, 40))	('recurrent disease', 'Disease', (153, 170))
565132	22406828	In another report, recurrence of Stage I ESCC was associated with CDH1 methylation (OR = 5.26, 95% CI = 1.48-18.67) and the risk of recurrence was elevated in those with methylated WIF1 detected in their ESCCs (HR = 13.17, 95% CI = 2.46-70.41).	('methylation', 'Var', (71, 82))	('WIF1', 'Gene', '11197', (181, 185))	('CDH1', 'Gene', (66, 70))	('CDH1', 'Gene', '999', (66, 70))	('associated', 'Reg', (50, 60))	('methylated', 'Var', (170, 180))	('WIF1', 'Gene', (181, 185))
565133	22406828	For Stage II cancers, methylated ITGA4 (the gene for integrin-alpha4) was associated with an increased risk of cancer recurrence (OR = 3.03, 95% CI = 1.09-8.37) and reduced recurrence-free survival (HR = 2.12, 95% CI=1.13-3.98) compared to those without methylated ITGA4.	('II cancers', 'Disease', 'MESH:D009369', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('ITGA4', 'Gene', (265, 270))	('recurrence-free survival', 'CPA', (173, 197))	('ITGA4', 'Gene', (33, 38))	('II cancers', 'Disease', (10, 20))	('ITGA4', 'Gene', '3676', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ITGA4', 'Gene', '3676', (33, 38))	('cancer', 'Disease', (13, 19))	('integrin-alpha4', 'Gene', (53, 68))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('integrin-alpha4', 'Gene', '3676', (53, 68))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('methylated', 'Var', (22, 32))	('reduced', 'NegReg', (165, 172))
565137	22406828	The authors detected CIMP in 54% (N=27/50) of ESCC and 8% (N=4/50) of dysplastic tissues.	('ESCC', 'Disease', (46, 50))	('dysplastic', 'Disease', (70, 80))	('CIMP', 'Var', (21, 25))	('dysplastic', 'Disease', 'MESH:D004416', (70, 80))	('CIMP', 'Chemical', '-', (21, 25))
565140	22406828	Furthermore, patients with ESCC with CIMP were found to have a worse four-year survival rate compared to patients with non-CIMP ESCC.	('patients', 'Species', '9606', (105, 113))	('worse', 'NegReg', (63, 68))	('patients', 'Species', '9606', (13, 21))	('CIMP', 'Chemical', '-', (37, 41))	('ESCC', 'Disease', (27, 31))	('CIMP', 'Chemical', '-', (123, 127))	('CIMP', 'Var', (37, 41))
565143	22406828	Methylated genes are likely to alter a tumor's response to treatment as many of these genes are known to regulate DNA damage repair (e.g.	('regulate', 'Reg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('alter', 'Reg', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('Methylated', 'Var', (0, 10))	('DNA damage repair', 'MPA', (114, 131))
565149	22406828	With respect to individual genes, in one study, methylated REPRIMO was detected at significantly lower levels (and less frequently) in chemoradiotherapy responders versus nonresponders.	('methylated', 'Var', (48, 58))	('REPRIMO', 'Gene', '56475', (59, 66))	('lower', 'NegReg', (97, 102))	('REPRIMO', 'Gene', (59, 66))
565151	22406828	In this study, BE progressors were more likely to demonstrate hypomethylation of growth-promoting genes (as opposed to hypermethylation of tumor suppressor genes) compared to non-progressors, including genes involved in insulin signaling pathways.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('hypomethylation', 'Var', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('BE', 'Phenotype', 'HP:0100580', (15, 17))	('insulin', 'Gene', (220, 227))	('insulin', 'Gene', '3630', (220, 227))	('growth-promoting genes', 'Gene', (81, 103))
565155	22406828	Global hypomethylation cooperated with gene amplification, leading to upregulation of CXCL1, CXCL3, GATA6, and DMBT1, which might be functionally important cancer-related proteins and which have the potential to be biomarkers used to screen patients with BE for neoplastic progression.	('upregulation', 'PosReg', (70, 82))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('CXCL3', 'Gene', '2921', (93, 98))	('DMBT1', 'Gene', '1755', (111, 116))	('BE', 'Phenotype', 'HP:0100580', (255, 257))	('Global hypomethylation', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CXCL1', 'Gene', '2919', (86, 91))	('GATA6', 'Gene', (100, 105))	('CXCL1', 'Gene', (86, 91))	('CXCL3', 'Gene', (93, 98))	('GATA6', 'Gene', '2627', (100, 105))	('patients', 'Species', '9606', (241, 249))	('DMBT1', 'Gene', (111, 116))
565163	22406828	In summary, there are a myriad of published studies of aberrantly methylated genes in BE, EAC, and ESCC in the literature to date (N=311, PubMed search terms "DNA methylation" and "esophageal cancer").	('esophageal cancer', 'Disease', (181, 198))	('BE', 'Phenotype', 'HP:0100580', (86, 88))	('aberrantly methylated genes', 'Var', (55, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('ESCC', 'Disease', (99, 103))	('EAC', 'Phenotype', 'HP:0011459', (90, 93))	('EAC', 'Disease', (90, 93))
565164	22406828	Although many of these studies involve the analysis of relatively few patients and are generally not prospective in nature, hypermethylated tumor suppressor genes appear to be associated with Barrett's esophagus and esophageal cancer and thus show considerable potential to be used as diagnostic biomarkers.	('patients', 'Species', '9606', (70, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (216, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	("Barrett's esophagus", 'Disease', (192, 211))	('associated', 'Reg', (176, 186))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (192, 211))	('hypermethylated', 'Var', (124, 139))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('esophageal cancer', 'Disease', (216, 233))	('tumor', 'Disease', (140, 145))
565198	21716646	A multitude of new PET analogs are applied, whereas [68Ga-DOTA0, Tyr3] octreotide or [68Ga-DOTA0, Tyr3] octreotate is likely to become the new standard for somatostatin receptor imaging with PET.	('Tyr3] octreotate', 'Chemical', 'MESH:C470036', (98, 114))	('Tyr3] octreotide', 'Chemical', 'MESH:C045210', (65, 81))	('[68Ga-DOTA0', 'Var', (85, 96))	('DOTA0', 'Chemical', '-', (91, 96))	('DOTA0', 'Chemical', '-', (58, 63))	('[68Ga-DOTA0', 'Var', (52, 63))
565200	21716646	While the objective responses for chemotherapy with the median time to progression is reported to be less than 18 months, PRRT with 90Y-octreotide or 177Lu-octreotate performs considerably better with a median time to progression of 30 and 40 months, respectively, and significantly improved quality of life.	('quality of life', 'CPA', (292, 307))	('177Lu-octreotate', 'Var', (150, 166))	('90Y-octreotide', 'Chemical', '-', (132, 146))	('improved', 'PosReg', (283, 291))	('90Y-octreotide', 'Var', (132, 146))	('177Lu-octreotate', 'Chemical', 'MESH:C554548', (150, 166))
565209	20598162	Furthermore, overexpression inhibited cell migration and invasion in transwell and Boyden chamber experiments and retarded the cell cycle progression from G1 to S phase by FACSCaliber cytometry.	('cell migration', 'CPA', (38, 52))	('cell cycle progression', 'CPA', (127, 149))	('retarded', 'Disease', (114, 122))	('inhibited', 'NegReg', (28, 37))	('retarded', 'Disease', 'MESH:D008607', (114, 122))	('overexpression', 'Var', (13, 27))
565218	20598162	Hypermethylation of CpG islands of gene promoter often causes transcriptional silencing of genes, including tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', (108, 113))	('causes', 'Reg', (55, 61))	('transcriptional', 'MPA', (62, 77))
565219	20598162	Previous studies reported promoter hypermethylation and reduced expression of ECRG4 in advanced esophageal, prostate carcinomas, colorectal carcinoma, and glioma Together with a study in esophageal cancer cell lines, these reports suggest that ECRG4 may play a tumor suppressor role in certain cancers including glioma.	('promoter hypermethylation', 'Var', (26, 51))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('prostate carcinomas', 'Disease', 'MESH:D011472', (108, 127))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Disease', (294, 301))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('glioma', 'Disease', (312, 318))	('esophageal cancer', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('ECRG4', 'Gene', (78, 83))	('expression', 'MPA', (64, 74))	('glioma', 'Disease', 'MESH:D005910', (312, 318))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('reduced', 'NegReg', (56, 63))	('ECRG4', 'Gene', (244, 249))	('ECRG4', 'Gene', '84417', (78, 83))	('prostate carcinomas', 'Disease', (108, 127))	('colorectal carcinoma', 'Disease', (129, 149))	('ECRG4', 'Gene', '84417', (244, 249))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (129, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('glioma', 'Phenotype', 'HP:0009733', (312, 318))	('tumor', 'Disease', (261, 266))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('glioma', 'Disease', (155, 161))
565262	20598162	Further, ECRG4 promoter hypermethylation has been attributed to decreased expression in esophageal, prostatic, and colorectal cancers.	('hypermethylation', 'Var', (24, 40))	('expression', 'MPA', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostatic', 'Disease', (100, 109))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('colorectal cancers', 'Disease', 'MESH:D015179', (115, 133))	('ECRG4', 'Gene', (9, 14))	('colorectal cancers', 'Disease', (115, 133))	('esophageal', 'Disease', (88, 98))	('ECRG4', 'Gene', '84417', (9, 14))	('decreased', 'NegReg', (64, 73))
565286	33613750	DNA methylation integratedly modulates the expression of Pit-Oct-Unt transcription factors in esophageal squamous cell carcinoma Background: Dysregulation of Pit-Oct-Unc family transcription factors has been implicated in esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', (222, 256))	('Pit-Oct-Unc family transcription factors', 'Gene', (158, 198))	('implicated', 'Reg', (208, 218))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (94, 128))	('Dysregulation', 'Var', (141, 154))	('modulates', 'Reg', (29, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (222, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))
565320	33613750	OCT1 protein level was detected by western blotting (antibody from Abcam, Cambridge, UK; ab51363), with GAPDH serving as a loading control.	('ab51363', 'Var', (89, 96))	('OCT1 protein level', 'MPA', (0, 18))	('GAPDH', 'Gene', '2597', (104, 109))	('GAPDH', 'Gene', (104, 109))
565340	33613750	There was no association between the methylation status of the OCT4 gene promoter and T stage or histologic grade (Figure 6C, D).	('OCT4', 'Gene', (63, 67))	('T stage', 'CPA', (86, 93))	('OCT4', 'Gene', '5460', (63, 67))	('methylation', 'Var', (37, 48))
565341	33613750	OCT1 was highly expressed in KYSE70, KYSE140, and KYSE450 ESCC cell lines and three patient-derived cell lines (Nos.	('KYSE140', 'Var', (37, 44))	('KYSE450', 'Var', (50, 57))	('patient', 'Species', '9606', (84, 91))	('OCT1', 'Gene', (0, 4))
565349	33613750	OCT1 knockdown decreased proliferation in KYSE70, KYSE140, and KYSE450 cells and patient-derived ESCC cell line Nos.	('patient', 'Species', '9606', (81, 88))	('proliferation', 'CPA', (25, 38))	('OCT1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (15, 24))
565354	33613750	Drug treatment reduced ESCC cell colony formation in a dose-dependent manner, whereas OCT1 knockdown via siRNA-1 or siRNA-2 enhanced the antitumor effect of cisplatin (Supplemental Figure 3A, B and Table 2).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('men', 'Species', '9606', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('knockdown', 'Var', (91, 100))	('enhanced', 'PosReg', (124, 132))	('tumor', 'Disease', (141, 146))	('reduced', 'NegReg', (15, 22))	('OCT1', 'Gene', (86, 90))	('ESCC cell colony formation', 'CPA', (23, 49))	('siRNA-2', 'Gene', (116, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('men', 'Species', '9606', (174, 177))
565355	33613750	The IC50 values for KYSE70, KYSE140, and KYSE450 cells and three patient-derived ESCC cell lines with high endogenous OCT1 expression are shown in Table 2.	('KYSE140', 'Var', (28, 35))	('patient', 'Species', '9606', (65, 72))	('KYSE70', 'Var', (20, 26))
565369	33613750	It was also suggested that high OCT1 expression enhances drug resistance in prostate cancer cells.	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('high', 'Var', (27, 31))	('OCT1', 'Protein', (32, 36))	('drug resistance', 'CPA', (57, 72))	('drug resistance', 'Phenotype', 'HP:0020174', (57, 72))	('enhances', 'PosReg', (48, 56))	('expression', 'MPA', (37, 47))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
565376	33613750	For instance, hypermethylation of tumor suppressor gene promoters in tumor tissues results in the loss of gene expression, whereas hypomethylation of oncogene promoters leads to their aberrant activation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('hypermethylation', 'Var', (14, 30))	('tumor', 'Disease', (34, 39))	('activation', 'PosReg', (193, 203))	('tumor', 'Disease', (69, 74))	('gene expression', 'MPA', (106, 121))	('hypomethylation', 'Var', (131, 146))	('loss', 'NegReg', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
565406	33457096	The mutated genes that promote the growth and proliferation of cancer cells are called cancer-driving genes, which can cause selective growth of tumor cells.	('mutated', 'Var', (4, 11))	('cancer', 'Disease', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('promote', 'PosReg', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('growth', 'CPA', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('proliferation', 'CPA', (46, 59))	('tumor', 'Disease', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', (63, 69))
565466	33457096	The mutation of TP53 can acquire carcinogenic characteristics and promote the invasion, metastasis, proliferation, and survival of cancer cells.	('cancer', 'Disease', (131, 137))	('carcinogenic', 'Disease', 'MESH:D063646', (33, 45))	('carcinogenic', 'Disease', (33, 45))	('invasion', 'CPA', (78, 86))	('metastasis', 'CPA', (88, 98))	('proliferation', 'CPA', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutation', 'Var', (4, 12))	('promote', 'PosReg', (66, 73))	('TP53', 'Gene', '7157', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('TP53', 'Gene', (16, 20))
565469	33457096	CASP8 is involved in exogenous apoptotic signaling pathway, and its genetic variation can affect cancer susceptibility.	('affect', 'Reg', (90, 96))	('CASP8', 'Gene', (0, 5))	('cancer', 'Disease', (97, 103))	('CASP8', 'Gene', '841', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('genetic variation', 'Var', (68, 85))	('involved', 'Reg', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
565492	32547209	The results of animal experiments showed that knocking down KIF2A can significantly reduce the tumor volume of mice.	('reduce', 'NegReg', (84, 90))	('KIF2A', 'Gene', (60, 65))	('knocking down', 'Var', (46, 59))	('mice', 'Species', '10090', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
565499	32547209	For example, aberrant expression of KIF2A is associated with the prognosis of gastric cancer, breast cancer, and glioma.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('KIF2A', 'Gene', (36, 41))	('aberrant expression', 'Var', (13, 32))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('associated', 'Reg', (45, 55))	('gastric cancer', 'Disease', (78, 92))	('glioma', 'Disease', (113, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
565501	32547209	We have revealed that knocking down KIF2A could significantly inhibit the proliferation of ESCC in both cell lines and mice.	('mice', 'Species', '10090', (119, 123))	('KIF2A', 'Gene', (36, 41))	('ESCC', 'Disease', (91, 95))	('knocking down', 'Var', (22, 35))	('proliferation', 'CPA', (74, 87))	('inhibit', 'NegReg', (62, 69))
565533	32547209	However, there were no significant differences between the high and low KIF2A groups in other aspects of clinicopathological features, such as age, gender, tumor grade, and lymph node metastasis.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('lymph node metastasis', 'CPA', (173, 194))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('low', 'Var', (68, 71))	('high', 'Var', (59, 63))	('tumor', 'Disease', (156, 161))	('KIF2A', 'Gene', (72, 77))
565534	32547209	To investigate the role of KIF2A in ESCC, we used shRNA vectors to establish CaEs-17 and EC-109 cell lines that knock down KIF2A.	('KIF2A', 'Gene', (123, 128))	('knock down', 'Var', (112, 122))	('EC-109', 'CellLine', 'CVCL:6898', (89, 95))
565536	32547209	The results showed that Ki67 and PCNA were significantly decreased in the knockdown group, indicating that proliferation was inhibited after knockdown of KIF2A.	('knockdown', 'Var', (141, 150))	('Ki67', 'Gene', '17345', (24, 28))	('proliferation', 'CPA', (107, 120))	('KIF2A', 'Gene', (154, 159))	('Ki67', 'Gene', (24, 28))	('inhibited', 'NegReg', (125, 134))	('decreased', 'NegReg', (57, 66))
565537	32547209	To investigate the effect of KIF2A on ESCC proliferation in vivo, we divided 6-week-old BALB/c mice into two groups and subcutaneously injected KIF2A shRNA or shRNA to attenuate lentiviral cells.	('lentiviral cells', 'CPA', (178, 194))	('attenuate', 'NegReg', (168, 177))	('mice', 'Species', '10090', (95, 99))	('KIF2A', 'Var', (144, 149))
565541	32547209	We also used IHC to detect mouse tumor proliferation markers Ki67 and PCNA, and the results showed that both Ki67 and PCNA were significantly reduced in the knockdown group compared to the control group (Figure 4C).	('Ki67', 'Gene', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('reduced', 'NegReg', (142, 149))	('mouse', 'Species', '10090', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Ki67', 'Gene', (61, 65))	('knockdown', 'Var', (157, 166))	('tumor', 'Disease', (33, 38))	('Ki67', 'Gene', '17345', (109, 113))	('Ki67', 'Gene', '17345', (61, 65))
565548	32547209	Wang et al reported that KIF2A silencing inhibits the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and leads to increased apoptosis.	('silencing', 'Var', (31, 40))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (54, 83))	('inhibits', 'NegReg', (41, 49))	('AKT', 'Gene', '207', (91, 94))	('apoptosis', 'CPA', (126, 135))	('phosphatidylinositol 3-kinase', 'Gene', (54, 83))	('AKT', 'Gene', (91, 94))	('KIF2A', 'Gene', (25, 30))	('increased', 'PosReg', (116, 125))
565549	32547209	Xie et al showed that the expression levels of phosphorylated AKT and phosphorylated ERK1/2 in the KIF2A knockout group were significantly reduced.	('AKT', 'Gene', (62, 65))	('knockout', 'Var', (105, 113))	('KIF2A', 'Gene', (99, 104))	('reduced', 'NegReg', (139, 146))	('ERK1/2', 'Gene', (85, 91))	('AKT', 'Gene', '207', (62, 65))	('expression levels', 'MPA', (26, 43))
565550	32547209	Sheng et al reported that miR-206 inhibited the overexpression of KIF2A and Uchida et al showed that the regulation of KIF2A by anti-tumor miR-451a can inhibit the aggressiveness of cancer cells.	('inhibit', 'NegReg', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('regulation', 'Var', (105, 115))	('miR-206', 'Gene', '406989', (26, 33))	('overexpression', 'MPA', (48, 62))	('inhibited', 'NegReg', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('KIF2A', 'Gene', (119, 124))	('aggressiveness of cancer', 'Disease', (164, 188))	('aggressiveness', 'Phenotype', 'HP:0000718', (164, 178))	('tumor', 'Disease', (133, 138))	('miR-451a', 'Gene', '574411', (139, 147))	('miR-451a', 'Gene', (139, 147))	('miR-206', 'Gene', (26, 33))	('aggressiveness of cancer', 'Disease', 'MESH:D009369', (164, 188))
565689	31045906	Silent RE might progress to asymptomatic injures in esophagus and may do more harm to patients by delaying seeking medical help.	('esophagus', 'Disease', (52, 61))	('delaying', 'NegReg', (98, 106))	('seeking medical help', 'MPA', (107, 127))	('progress', 'Reg', (16, 24))	('Silent', 'Var', (0, 6))	('patients', 'Species', '9606', (86, 94))
565739	31045906	However, strong evidence was found that eradicating H. pylori infection may increase the prevalence of RE.	('increase', 'PosReg', (76, 84))	('H. pylori infection', 'Phenotype', 'HP:0005202', (52, 71))	('infection', 'Disease', (62, 71))	('infection', 'Disease', 'MESH:D007239', (62, 71))	('H. pylori', 'Protein', (52, 61))	('H. pylori', 'Species', '210', (52, 61))	('eradicating', 'Var', (40, 51))
565759	28851377	Dysregulation of miRNAs in CAFs can affect the secretory phenotype of the latter cells.	('secretory phenotype', 'MPA', (47, 66))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('CAF', 'Gene', (27, 30))	('affect', 'Reg', (36, 42))	('CAF', 'Gene', '8850', (27, 30))
565765	28851377	Previous studies reported that miRNAs might serve as a tool for cancer diagnosis, and dysregulation of miRNA expression could be used for patient prognosis.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('dysregulation', 'Var', (86, 99))	('miR', 'Gene', '220972', (103, 106))	('patient', 'Species', '9606', (138, 145))	('miR', 'Gene', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
565775	28851377	The dysregulation of miRNAs and exosomal miRNAs can influence the crosstalk between cancer cells and the tumor microenvironment.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('dysregulation', 'Var', (4, 17))	('crosstalk', 'Interaction', (66, 75))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('miR', 'Gene', (41, 44))	('miR', 'Gene', '220972', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('influence', 'Reg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
565777	28851377	We also demonstrated that miRNA dysregulation mediates functional changes in CAFs.	('dysregulation', 'Var', (32, 45))	('miR', 'Gene', '220972', (26, 29))	('CAF', 'Gene', (77, 80))	('miR', 'Gene', (26, 29))	('rat', 'Species', '10116', (15, 18))	('CAF', 'Gene', '8850', (77, 80))
565796	28851377	MicroRNA-211 inhibits the tumor suppressor IGF2R, thereby hyper-activating the IGF1R/MAPK signaling pathway.	('IGF2R', 'Gene', '3482', (43, 48))	('hyper-activating', 'PosReg', (58, 74))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('IGF1R', 'Gene', (79, 84))	('IGF2R', 'Gene', (43, 48))	('MicroRNA-211', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('IGF1R', 'Gene', '3480', (79, 84))	('inhibits', 'NegReg', (13, 21))
565805	28851377	Here, we focused on miRNA dysregulation in CAFs in association with their formation and activation.	('dysregulation', 'Var', (26, 39))	('CAF', 'Gene', (43, 46))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('CAF', 'Gene', '8850', (43, 46))
565816	28851377	Over-expression of miR-21 or Smad7 depletion promotes CAF formation, even without TGF-beta1 stimulation.	('CAF', 'Gene', (54, 57))	('Smad7', 'Gene', (29, 34))	('miR-21', 'Gene', '406991', (19, 25))	('CAF', 'Gene', '8850', (54, 57))	('Smad7', 'Gene', '4092', (29, 34))	('promotes', 'PosReg', (45, 53))	('TGF-beta1', 'Gene', '7040', (82, 91))	('TGF-beta1', 'Gene', (82, 91))	('depletion', 'Var', (35, 44))	('miR-21', 'Gene', (19, 25))
565831	28851377	In addition, GW4869, an inhibitor of exosome release, significantly reduces survival in co-cultured epithelial cells, suggesting that drug-induced exosome miRNAs may be closely associated with drug resistance after treatment with chemotherapeutic agents.	('GW4869', 'Var', (13, 19))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', (155, 158))	('drug resistance', 'Phenotype', 'HP:0020174', (193, 208))	('associated with', 'Reg', (177, 192))	('drug resistance', 'Disease', (193, 208))	('survival in co-cultured epithelial', 'CPA', (76, 110))	('GW4869', 'Chemical', 'MESH:C468773', (13, 19))	('reduces', 'NegReg', (68, 75))
565835	28851377	Dysregulation of miRNAs in CAFs results in drug resistance.	('results in', 'Reg', (32, 42))	('drug resistance', 'Phenotype', 'HP:0020174', (43, 58))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('drug resistance', 'MPA', (43, 58))	('CAF', 'Gene', (27, 30))	('CAF', 'Gene', '8850', (27, 30))
565855	28851377	MiRNA dysregulation often indicates an invasive phenotype in several cancer types through different signaling pathways.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('dysregulation', 'Var', (6, 19))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('indicates', 'Reg', (26, 35))	('cancer', 'Disease', (69, 75))	('MiRNA', 'MPA', (0, 5))
565857	28851377	In addition, miR-21 and two other miRNAs (378e and 143) are increased in exosomes released from CAFs, and promote the aggressive ability of breast cancer cells, increasing stem cell amounts and inducing EMT.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('miR', 'Gene', (13, 16))	('promote', 'PosReg', (106, 113))	('inducing', 'PosReg', (194, 202))	('aggressive ability', 'Phenotype', 'HP:0000718', (118, 136))	('stem cell amounts', 'CPA', (172, 189))	('miR-21', 'Gene', (13, 19))	('aggressive ability', 'CPA', (118, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('miR', 'Gene', '220972', (34, 37))	('378e', 'Var', (42, 46))	('CAF', 'Gene', '8850', (96, 99))	('EMT', 'CPA', (203, 206))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('breast cancer', 'Disease', (140, 153))	('CAF', 'Gene', (96, 99))	('miR', 'Gene', (34, 37))	('miR', 'Gene', '220972', (13, 16))	('increasing', 'PosReg', (161, 171))	('miR-21', 'Gene', '406991', (13, 19))
565867	28851377	Most related reports demonstrated that dysregulated miRNAs are associated with tumor invasion, migration, proliferation, metastasis, and drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (137, 152))	('metastasis', 'CPA', (121, 131))	('tumor', 'Disease', (79, 84))	('associated', 'Reg', (63, 73))	('rat', 'Species', '10116', (113, 116))	('migration', 'CPA', (95, 104))	('rat', 'Species', '10116', (98, 101))	('dysregulated', 'Var', (39, 51))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('miR', 'Gene', '220972', (52, 55))	('proliferation', 'CPA', (106, 119))	('miR', 'Gene', (52, 55))	('rat', 'Species', '10116', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('drug resistance', 'CPA', (137, 152))
565868	28851377	In addition, abnormal expression of miRNAs was found to be associated with poor prognosis, and could change the secretory phenotype of CAFs.	('CAF', 'Gene', '8850', (135, 138))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (36, 39))	('secretory phenotype', 'MPA', (112, 131))	('abnormal', 'Var', (13, 21))	('CAF', 'Gene', (135, 138))	('expression', 'MPA', (22, 32))	('change', 'Reg', (101, 107))
565874	28851377	MiR-335 is up-regulated by COX-2; conversely, COX-2 inhibition by celecoxib reduces miR-335 expression and restores PTEN production.	('COX-2', 'Gene', '4513', (46, 51))	('COX-2', 'Gene', (46, 51))	('MiR-335', 'Gene', '442904', (0, 7))	('miR-335', 'Gene', (84, 91))	('celecoxib', 'Chemical', 'MESH:D000068579', (66, 75))	('PTEN', 'Gene', '5728', (116, 120))	('reduces', 'NegReg', (76, 83))	('inhibition', 'Var', (52, 62))	('COX-2', 'Gene', '4513', (27, 32))	('MiR-335', 'Gene', (0, 7))	('PTEN', 'Gene', (116, 120))	('miR-335', 'Gene', '442904', (84, 91))	('restores', 'PosReg', (107, 115))	('COX-2', 'Gene', (27, 32))	('expression', 'MPA', (92, 102))
565875	28851377	Similarly, miR-7 overexpression induces a functional conversion of NFs into CAFs through RASSF2 down-regulation, dramatically decreasing PAR-4 secretion from CAFs.	('miR-7', 'Gene', (11, 16))	('overexpression', 'Var', (17, 31))	('CAF', 'Gene', '8850', (76, 79))	('decreasing', 'NegReg', (126, 136))	('secretion from', 'MPA', (143, 157))	('CAF', 'Gene', (76, 79))	('CAF', 'Gene', (158, 161))	('RASSF2', 'Gene', '9770', (89, 95))	('miR-7', 'Gene', '10859', (11, 16))	('CAF', 'Gene', '8850', (158, 161))	('PAR-4', 'Gene', '5074', (137, 142))	('RASSF2', 'Gene', (89, 95))	('PAR-4', 'Gene', (137, 142))	('down-regulation', 'NegReg', (96, 111))
565906	28851377	Secondly, miRNA dysregulation is closely related to CAF activation and formation, and affects the tumor-supportive capability of CAFs in vitro and in vivo.	('CAF', 'Gene', '8850', (52, 55))	('CAF', 'Gene', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CAF', 'Gene', '8850', (129, 132))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))	('affects', 'Reg', (86, 93))	('CAF', 'Gene', (52, 55))	('tumor', 'Disease', (98, 103))	('dysregulation', 'Var', (16, 29))
565928	27974696	Inhibition of miR-205 expression may be a new strategy for radiotherapy in ESCC.	('ESCC', 'Disease', (75, 79))	('Inhibition', 'Var', (0, 10))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('expression', 'MPA', (22, 32))
565953	27974696	Thus, we identified the important role and mechanism of miR-205 as a key regulator of radioresistance and showed that downregulation of miR-205 could sensitize ESCC cells to irradiation.	('ESCC', 'Disease', (160, 164))	('sensitize', 'Reg', (150, 159))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('miR', 'Gene', '220972', (56, 59))	('downregulation', 'Var', (118, 132))	('miR', 'Gene', (56, 59))
565956	27974696	The number of gamma-H2AX foci in the KYSE450 cells was approximately 3 times higher than that in KYSE450/RR cells at 24-48 h after IR (Figure 1B).	('higher', 'PosReg', (77, 83))	('H2AX', 'Gene', '3014', (20, 24))	('KYSE450', 'Var', (37, 44))	('H2AX', 'Gene', (20, 24))
565961	27974696	First, we compared miR-205 expression in ESCC/RR and their parental cell lines, and the results showed that miR-205 expression was increased by 2.1- and 1.6-fold in KYSE30/RR and KYSE450/RR cells, respectively (Figure 2A).	('miR', 'Gene', '220972', (19, 22))	('expression', 'MPA', (116, 126))	('miR', 'Gene', (19, 22))	('increased', 'PosReg', (131, 140))	('KYSE30/RR', 'Var', (165, 174))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))
565968	27974696	Cell survival upon IR showed that miR-205 overexpression induced radioresistance in parental cells (Figure 2C), while miR-205 depletion significantly decreased the surviving fraction of RR cells post-IR (Figure 2D).	('depletion', 'Var', (126, 135))	('induced', 'Reg', (57, 64))	('miR', 'Gene', '220972', (34, 37))	('radioresistance', 'CPA', (65, 80))	('miR', 'Gene', (34, 37))	('surviving fraction of RR cells post-IR', 'CPA', (164, 202))	('overexpression', 'PosReg', (42, 56))	('miR', 'Gene', '220972', (118, 121))	('miR', 'Gene', (118, 121))	('decreased', 'NegReg', (150, 159))
565973	27974696	In the absence of IR, tumor growth was slightly decreased upon miR-205 depletion.	('depletion', 'Var', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('decreased', 'NegReg', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('tumor', 'Disease', (22, 27))
565976	27974696	These data suggest that miR-205 depletion sensitizes ESCC cells to irradiation treatment both in vitro and in vivo.	('ESCC', 'Disease', (53, 57))	('depletion', 'Var', (32, 41))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('sensitizes', 'Reg', (42, 52))
565980	27974696	However, a decrease in foci number was clearly observed in miR-205 agomir-transfected KYSE450 cells compared with the control cells 24 h after IR.	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))	('decrease', 'NegReg', (11, 19))	('agomir-transfected', 'Var', (67, 85))	('foci number', 'CPA', (23, 34))
565981	27974696	In contrast, the number of foci in miR-205 antagomir-transfected KYSE450/RR cells was 3-5 times higher than that in the control cells 24h after IR (Figure 3A), suggesting that DSB repair was inhibited after miR-205 depletion.	('inhibited', 'NegReg', (191, 200))	('depletion', 'Var', (215, 224))	('DSB repair', 'CPA', (176, 186))	('antagomir-transfected', 'Var', (43, 64))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('higher', 'PosReg', (96, 102))	('miR', 'Gene', '220972', (207, 210))	('miR', 'Gene', (207, 210))
565983	27974696	In contrast, miR-205 depletion caused 37.1% and 40.6% increases in apoptotic cells in KYSE30/RR and KYSE450/RR cells, respectively.	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('increases', 'PosReg', (54, 63))	('apoptotic cells', 'CPA', (67, 82))	('KYSE30/RR', 'Var', (86, 95))	('depletion', 'MPA', (21, 30))
565984	27974696	Moreover, miR-205 depletion slightly increased the apoptotic rate of KYSE30/RR and KYSE450/RR cells in the absence of IR.	('apoptotic rate', 'CPA', (51, 65))	('miR', 'Gene', '220972', (10, 13))	('depletion', 'Var', (18, 27))	('increased', 'PosReg', (37, 46))	('miR', 'Gene', (10, 13))
565987	27974696	Furthermore, overexpression of miR-205 in KYSE450 cells promoted cell migration and invasion, while inhibition of miR-205 in KYSE450/RR cells decreased their migratory and invasive potentials (Figure 3F).	('invasion', 'CPA', (84, 92))	('cell migration', 'CPA', (65, 79))	('decreased', 'NegReg', (142, 151))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('overexpression', 'PosReg', (13, 27))	('inhibition', 'Var', (100, 110))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', (114, 117))	('promoted', 'PosReg', (56, 64))
565999	27974696	To verify the importance of Sp1 in miR-205 upregulation, we used three types of siRNAs to knock down Sp1 expression (Supplementary Figure S5).	('Sp1', 'Gene', (101, 104))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('knock', 'Var', (90, 95))
566000	27974696	The qRT-PCR results showed that the three types of siRNA-induced silencing of Sp1 all decreased the basal expression of miR-205 and abolished IR-induced upregulation of miR-205 (Figure 5A).	('silencing', 'Var', (65, 74))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (120, 123))	('basal expression', 'MPA', (100, 116))	('miR', 'Gene', (169, 172))	('decreased', 'NegReg', (86, 95))	('abolished', 'NegReg', (132, 141))	('IR-induced upregulation', 'MPA', (142, 165))	('miR', 'Gene', '220972', (169, 172))	('Sp1', 'Gene', (78, 81))
566001	27974696	Luciferase reporter assays revealed that silence of Sp1 significantly reduced miR-205 promoter activities and abolished IR-induced activation of miR-205 promoter (Figure 5B).	('reduced', 'NegReg', (70, 77))	('silence', 'Var', (41, 48))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('Sp1', 'Gene', (52, 55))	('abolished', 'NegReg', (110, 119))	('miR', 'Gene', '220972', (145, 148))	('IR-induced activation', 'MPA', (120, 141))	('miR', 'Gene', (145, 148))
566006	27974696	To determine the role of Sp1-RE1 and Sp1-RE2 in the transcriptional activation of miR-205, we separately generated deletion mutations of the two sites by site-directed mutagenesis.	('Sp1-RE1', 'Gene', '6667', (25, 32))	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))	('deletion mutations', 'Var', (115, 133))	('Sp1-RE1', 'Gene', (25, 32))
566007	27974696	The Sp1-RE1 mutation resulted in a significant functional change compared with the wild-type promoter, suggesting a critical role of the putative Sp1-RE1 in the transcription of miR-205 (Figure 5F).	('miR', 'Gene', '220972', (178, 181))	('Sp1-RE1', 'Gene', (4, 11))	('miR', 'Gene', (178, 181))	('Sp1-RE1', 'Gene', '6667', (146, 153))	('Sp1-RE1', 'Gene', (146, 153))	('mutation', 'Var', (12, 20))	('Sp1-RE1', 'Gene', '6667', (4, 11))
566014	27974696	In contrast, the engineered deletion mutation of the miR-205 binding site antagonized this effect (Figure 6B).	('deletion mutation', 'Var', (28, 45))	('antagonized', 'NegReg', (74, 85))	('miR', 'Gene', (53, 56))	('miR', 'Gene', '220972', (53, 56))
566026	27974696	Log-rank test showed that ESCC patients with high miR-205 expression had poorer overall survival (OS) than patients with low miR-205 expression (median survival time, 35 months vs. 53 months; P = 0.024; Figure 7A).	('miR', 'Gene', '220972', (50, 53))	('patients', 'Species', '9606', (107, 115))	('miR', 'Gene', (50, 53))	('ESCC', 'Disease', (26, 30))	('overall survival', 'MPA', (80, 96))	('poorer', 'NegReg', (73, 79))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('OS', 'Chemical', '-', (98, 100))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (125, 128))
566041	27974696	Accumulating evidence has shown that the cellular miRNA expression profile can be notably altered post-IR and that there is a strong relationship between dysregulated miRNAs and tumor sensitivity to radiotherapy.	('dysregulated', 'Var', (154, 166))	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('tumor', 'Disease', (178, 183))	('miR', 'Gene', '220972', (167, 170))	('miR', 'Gene', (167, 170))	('altered', 'Reg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
566052	27974696	Importantly, high miR-205 expression was significantly associated with poor survival of ESCC patients and could potentially serve as a prognostic indicator for patients with ESCC.	('expression', 'MPA', (26, 36))	('ESCC', 'Disease', (88, 92))	('patients', 'Species', '9606', (160, 168))	('high', 'Var', (13, 17))	('poor', 'NegReg', (71, 75))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('patients', 'Species', '9606', (93, 101))
566063	27974696	Inhibition of miR-205 may be the attractive target for new therapeutic strategy in radiotherapy for ESCC patients.	('patients', 'Species', '9606', (105, 113))	('ESCC', 'Disease', (100, 104))	('miR', 'Gene', '220972', (14, 17))	('Inhibition', 'Var', (0, 10))	('miR', 'Gene', (14, 17))
566096	27974696	The deletion mutants of PTEN 3'-UTR were generated by performing site-directed deletion of the binding sequence of miR-205.	('PTEN', 'Gene', '5728', (24, 28))	('deletion', 'Var', (79, 87))	('miR', 'Gene', '220972', (115, 118))	('PTEN', 'Gene', (24, 28))	('miR', 'Gene', (115, 118))
566098	27974696	Lentiviral particles expressing miR-205 inhibitors and control lentiviral were purchased from GenePharma (Shanghai, China).	('miR', 'Gene', (32, 35))	('inhibitors', 'Var', (40, 50))	('miR', 'Gene', '220972', (32, 35))
566125	25737442	Obesity is now well recognized as a state of low grade inflammation, and adipocyte dysfunction with increased secretion of inflammatory cytokines and adipokines has been associated with esophageal cancer and other cancers.	('secretion of inflammatory cytokines', 'MPA', (110, 145))	('increased', 'PosReg', (100, 109))	('increased secretion of inflammatory cytokines', 'Phenotype', 'HP:0012649', (100, 145))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancers', 'Disease', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('Obesity', 'Disease', (0, 7))	('dysfunction', 'Var', (83, 94))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('esophageal cancer', 'Disease', (186, 203))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('associated', 'Reg', (170, 180))	('inflammation', 'Disease', (55, 67))
566138	25737442	Levels of serum total adiponectin have either shown no evidence of association with BE, or demonstrated a protective effect for LMW adiponectin.	('LMW', 'Chemical', '-', (128, 131))	('adiponectin', 'Gene', (132, 143))	('adiponectin', 'Gene', '9370', (22, 33))	('adiponectin', 'Gene', (22, 33))	('association', 'Interaction', (67, 78))	('LMW', 'Var', (128, 131))	('adiponectin', 'Gene', '9370', (132, 143))
566258	26338060	Finally, we have to admit that patients selected for minimally invasive surgery are more likely to be in early stages of cancer, with smaller tumors and less risk of complications occurrence than patients in late stages.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (196, 204))	('minimally invasive surgery', 'Var', (53, 79))	('patients', 'Species', '9606', (31, 39))	('tumors', 'Disease', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', (121, 127))
566299	28783764	Specifically speaking, mid- and low-thoracic tumor (aHR = 2.20, 95% CI = 1.03, 4.72), abdominal and retroperitoneal lymph node metastasis (aHR = 1.62, 95% CI = 1.00, 2.64) and low albumin (aHR = 2.81, 95% CI = 1.24, 6.41) were statistically significantly related to lower survival; while lymphatic metastasis (aHR = 2.36, 95% CI = 0.93, 5.98) and distant metastasis (aHR = 1.61, 95% CI = 0.97, 2.69) were marginally significant.	('low-thoracic tumor', 'Disease', 'MESH:D013899', (32, 50))	('aHR', 'Gene', '196', (189, 192))	('aHR', 'Gene', (310, 313))	('aHR', 'Gene', (189, 192))	('low albumin', 'Phenotype', 'HP:0003073', (176, 187))	('lymphatic metastasis', 'CPA', (288, 308))	('albumin', 'Gene', (180, 187))	('lower', 'NegReg', (266, 271))	('retroperitoneal lymph node metastasis', 'Disease', (100, 137))	('aHR', 'Gene', '196', (52, 55))	('aHR', 'Gene', '196', (139, 142))	('distant metastasis', 'CPA', (347, 365))	('aHR', 'Gene', '196', (367, 370))	('low', 'Var', (176, 179))	('aHR', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('aHR', 'Gene', (139, 142))	('aHR', 'Gene', (367, 370))	('low-thoracic tumor', 'Disease', (32, 50))	('retroperitoneal lymph node metastasis', 'Disease', 'MESH:D009362', (100, 137))	('albumin', 'Gene', '213', (180, 187))	('survival', 'CPA', (272, 280))	('aHR', 'Gene', '196', (310, 313))
566329	28526815	PARD3 overexpression promoted apoptosis, impaired proliferation, and inhibited cell migration and invasion in Eca109 cells, while PARD3 silencing promoted proliferation and increased migration and invasion.	('PARD3', 'Gene', (0, 5))	('invasion', 'CPA', (197, 205))	('cell migration', 'CPA', (79, 93))	('apoptosis', 'CPA', (30, 39))	('proliferation', 'CPA', (155, 168))	('PARD3', 'Gene', '56288', (130, 135))	('PARD3', 'Gene', '56288', (0, 5))	('promoted', 'PosReg', (21, 29))	('increased', 'PosReg', (173, 182))	('impaired', 'NegReg', (41, 49))	('inhibited', 'NegReg', (69, 78))	('PARD3', 'Gene', (130, 135))	('silencing', 'Var', (136, 145))	('promoted', 'PosReg', (146, 154))
566331	28526815	Overexpression of PARD3 could be a promising new therapeutic intervention against ESCC.	('ESCC', 'Disease', (82, 86))	('PARD3', 'Gene', '56288', (18, 23))	('PARD3', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))
566376	28526815	On the other hand, PARD3 silencing did not significantly affect apoptosis (2.7+-0.4% compared with 2.2+-0.5% in controls; P>0.05, Table 4, Figure 3).	('silencing', 'Var', (25, 34))	('PARD3', 'Gene', '56288', (19, 24))	('apoptosis', 'CPA', (64, 73))	('PARD3', 'Gene', (19, 24))
566379	28526815	On the other hand, PARD3 overexpression significantly reduced cell migration compared to control cells (P<0.05, Figure 4B).	('cell migration', 'CPA', (62, 76))	('overexpression', 'Var', (25, 39))	('reduced', 'NegReg', (54, 61))	('PARD3', 'Gene', '56288', (19, 24))	('PARD3', 'Gene', (19, 24))
566380	28526815	PARD3 silencing resulted in a significant promotion of Eca109 cell invasion (P<0.01, Figure 4C), while PARD3 overexpression significantly decreased cell invasion by approximately 50% compared to the control cells (P<0.05, Figure 4D).	('PARD3', 'Gene', (0, 5))	('promotion', 'PosReg', (42, 51))	('PARD3', 'Gene', (103, 108))	('PARD3', 'Gene', '56288', (103, 108))	('decreased', 'NegReg', (138, 147))	('cell invasion', 'CPA', (148, 161))	('PARD3', 'Gene', '56288', (0, 5))	('silencing', 'Var', (6, 15))	('Eca109 cell invasion', 'CPA', (55, 75))
566387	28526815	observed that PARD3 deletions were limited to 2 distinct types of cancer: (1) squamous carcinomas including the esophagus, lung, and head and neck, and (2) glioblastoma, as supported by other studies.	('PARD3', 'Gene', '56288', (14, 19))	('squamous carcinomas', 'Disease', 'MESH:D002294', (78, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (156, 168))	('PARD3', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('deletions', 'Var', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('lung', 'Disease', (123, 127))	('squamous carcinomas', 'Disease', (78, 97))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('esophagus', 'Disease', (112, 121))	('glioblastoma', 'Disease', (156, 168))	('cancer', 'Disease', (66, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (156, 168))
566388	28526815	Recurrent tumor-specific inactivating alterations of PARD3 were observed in 8% of lung squamous cell cancer (LSCC).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('lung squamous cell cancer', 'Disease', (82, 107))	('LSCC', 'Phenotype', 'HP:0030359', (109, 113))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (87, 107))	('tumor', 'Disease', (10, 15))	('observed', 'Reg', (64, 72))	('PARD3', 'Gene', (53, 58))	('PARD3', 'Gene', '56288', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (82, 107))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('inactivating alterations', 'Var', (25, 49))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (82, 107))
566393	28526815	These findings are in accordance with those of Rothenberg et al., who reported that shRNA-mediated knockdown of PARD3 in some cancer cells with a disrupted wild type endogenous gene reduced the localization of ZO-1.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ZO-1', 'Gene', '7082', (210, 214))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('ZO-1', 'Gene', (210, 214))	('localization', 'MPA', (194, 206))	('knockdown', 'Var', (99, 108))	('PARD3', 'Gene', (112, 117))	('PARD3', 'Gene', '56288', (112, 117))	('reduced', 'NegReg', (182, 189))
566394	28526815	Loss of PARD3 in mammary epithelial cells promotes proliferation.	('proliferation', 'CPA', (51, 64))	('promotes', 'PosReg', (42, 50))	('PARD3', 'Gene', '56288', (8, 13))	('PARD3', 'Gene', (8, 13))	('Loss', 'Var', (0, 4))
566572	22805987	1)  where Yij was the PAH concentration in a given medium (air, food, or urine) for the i-th subject on the j-th day; beta0 was the overall mean concentration in the study population; beta1 was the regression coefficient for the variable X1ij; X1ij was the PAH concentration for a given medium (air or food) for the i-th subject on the j-th day; bi was the random effect for i-th subject; and epsilonij was the residual error associated with i-th subject on the j-th day.	('X1ij', 'Var', (244, 248))	(' PAH', 'Gene', '5053', (21, 25))	(' PAH', 'Gene', (21, 25))	(' PAH', 'Gene', '5053', (256, 260))	(' PAH', 'Gene', (256, 260))
566602	22805987	In contrast, the relative contribution to total daily PAH intake was greater from food sources for pyrene and total PAH, with the percentage of total intake from inhalation of 21% (2-73%) and 46 % (11-80%), respectively (data not shown).	(' PAH', 'Gene', '5053', (115, 119))	(' PAH', 'Gene', (115, 119))	('pyrene', 'Chemical', 'MESH:C030984', (99, 105))	('pyrene', 'Var', (99, 105))	(' PAH', 'Gene', '5053', (53, 57))	(' PAH', 'Gene', (53, 57))
566652	21637674	Moreover, this positioning revealed no association with either gene amplification or the protein over-expression status of these genes, although, in esophageal carcinoma, Kappa statistics showed a moderate agreement between amplification of the CCND1 gene (Kappa = 0.400) and its location within the CT, as well as with over-expression of the corresponding protein (Kappa = 0.444).	('CCND1', 'Gene', (245, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (149, 169))	('over-expression', 'PosReg', (320, 335))	('esophageal carcinoma', 'Disease', (149, 169))	('CCND1', 'Gene', '595', (245, 250))	('amplification', 'Var', (224, 237))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (149, 169))
566692	21637674	According to Kappa statistics, no exact association between these parameters was found in either esophageal or gastric cancers, but only a moderate agreement between amplification of the CCND1 gene and internal or peripheral positioning of this gene within its respective CT in esophageal carcinoma (Kappa = 0.400; p = 0.088).	('gastric cancers', 'Disease', (111, 126))	('amplification', 'Var', (166, 179))	('gastric cancers', 'Phenotype', 'HP:0012126', (111, 126))	('CCND1', 'Gene', (187, 192))	('gastric cancers', 'Disease', 'MESH:D013274', (111, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('esophageal carcinoma', 'Disease', (278, 298))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (278, 298))	('CCND1', 'Gene', '595', (187, 192))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (278, 298))	('esophageal', 'Disease', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
566708	21637674	In their previous report on breast tumor cell lines, Park and De Boni (1998) did not even relate the positioning of the HER-2/neu gene with alterations in the copy number of chromosome 17.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('HER-2/neu', 'Gene', '2064', (120, 129))	('breast tumor', 'Disease', (28, 40))	('breast tumor', 'Phenotype', 'HP:0100013', (28, 40))	('alterations', 'Var', (140, 151))	('breast tumor', 'Disease', 'MESH:D001943', (28, 40))	('HER-2/neu', 'Gene', (120, 129))
566709	21637674	As in our sample, tumors with amplification of the HER-2/neu gene presented non-uniformity in signal size, thereby suggesting possible clustering.	('HER-2/neu', 'Gene', (51, 60))	('amplification', 'Var', (30, 43))	('signal size', 'MPA', (94, 105))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('non-uniformity', 'MPA', (76, 90))	('HER-2/neu', 'Gene', '2064', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
566739	19920957	All patients underwent the four test procedures: US +- FNA, EUS +- FNA, CT, and PET (see Table 1).	('US +- FNA', 'Var', (49, 58))	('PET', 'Disease', (80, 83))	('PET', 'Species', '9606', (80, 83))	('patients', 'Species', '9606', (4, 12))	('EUS +- FNA', 'Var', (60, 70))
566771	19920957	In a subgroup analysis of patients with or without a FNA in US and EUS, there was a significant higher perceived total burden for US with FNA (n = 14, mean 5.1, SD 2.2) versus US without FNA (n = 68, mean 4.0 SD 1.9) (P = 0.02), which was due to difference in perceived discomfort (1.7 versus 1.3, respectively; P = 0.004).	('higher', 'PosReg', (96, 102))	('FNA', 'Var', (138, 141))	('patients', 'Species', '9606', (26, 34))
566801	19826638	Silencing of Tumor Necrosis Factor Receptor 1 by siRNA in EC109 Cells Affects Cell Proliferation and Apoptosis Tumor necrosis factor receptor 1 (TNFR1) is a membrane receptor able to bind TNF-alpha or TNF-beta.	('bind', 'Interaction', (183, 187))	('TNFR1', 'Gene', '7132', (145, 150))	('Affects', 'Reg', (70, 77))	('Apoptosis', 'CPA', (101, 110))	('TNF-alpha', 'Gene', (188, 197))	('Cell Proliferation', 'CPA', (78, 96))	('Tumor Necrosis Factor Receptor 1', 'Gene', '7132', (13, 45))	('EC109', 'CellLine', 'CVCL:6898', (58, 63))	('TNFR1', 'Gene', (145, 150))	('TNF-beta', 'Gene', '4049', (201, 209))	('Tumor necrosis factor receptor 1', 'Gene', '7132', (111, 143))	('Tumor Necrosis Factor Receptor 1', 'Gene', (13, 45))	('Tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Tumor necrosis factor receptor 1', 'Gene', (111, 143))	('Silencing', 'Var', (0, 9))	('TNF-beta', 'Gene', (201, 209))	('TNF-alpha', 'Gene', '7124', (188, 197))	('Tumor', 'Phenotype', 'HP:0002664', (13, 18))
566847	19826638	In contrast, the rate of apoptosis in the experimental group after transfection with TNFR1-siRNA was 4.64 +- 1.59%, which is significantly lower than in the control groups (P < .05) (Figure 4).	('TNFR1', 'Gene', (85, 90))	('transfection', 'Var', (67, 79))	('TNFR1', 'Gene', '7132', (85, 90))	('lower', 'NegReg', (139, 144))	('apoptosis', 'CPA', (25, 34))
566863	19826638	The reduction of apoptosis rate after silencing of TNFR1 may be due to  inhibition of the FADD-dependent complex II.	('FADD-dependent complex II', 'Enzyme', (90, 115))	('TNFR1', 'Gene', (51, 56))	('silencing', 'Var', (38, 47))	('apoptosis rate', 'CPA', (17, 31))	('reduction', 'NegReg', (4, 13))	('TNFR1', 'Gene', '7132', (51, 56))	('inhibition', 'NegReg', (72, 82))
566867	19826638	Then a report showed that tumor cells with high NF-kappaB expression had a higher tolerance to ionizing radiation and anti-tumor   drugs, and that inhibition of NF-kappaB activity could significantly increase the therapeutic sensitivity  and induce apoptosis.	('apoptosis', 'CPA', (249, 258))	('tumor', 'Disease', (123, 128))	('tolerance', 'CPA', (82, 91))	('high', 'Var', (43, 47))	('increase', 'PosReg', (200, 208))	('higher', 'PosReg', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('higher tolerance to ionizing radiation', 'Phenotype', 'HP:0011133', (75, 113))	('NF-kappaB', 'Protein', (161, 170))	('inhibition', 'Var', (147, 157))	('tumor', 'Disease', (26, 31))	('therapeutic sensitivity', 'CPA', (213, 236))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('induce', 'Reg', (242, 248))	('activity', 'MPA', (171, 179))	('NF-kappaB', 'Protein', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
566892	33034409	Several studies have validated that the RNP is a novel prognostic predictor in colon cancer and gastric cancer patients post-surgery.	('colon cancer', 'Disease', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('RNP', 'Var', (40, 43))	('gastric cancer', 'Disease', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('patients', 'Species', '9606', (111, 119))
566903	33034409	The tumor-node-metastasis (TNM) staging system is as follows: IIB, T1N1M0; IIIA, T1N2M0, T2N1M0; IIIB, T2N2M0, T3N1M0, T3N2M0, T4aN1M0; IVA, T1N3M0, T2N3M0, T3N3M0, T4aN2M0, T4aN3M0.	('tumor', 'Disease', (4, 9))	('T4aN3M0', 'Var', (174, 181))	('IVA', 'Disease', (136, 139))	('T2N2M0', 'Var', (103, 109))	('T3N2M0', 'Var', (119, 125))	('T3N1M0', 'Var', (111, 117))	('IVA', 'Disease', 'MESH:C538167', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('T3N3M0', 'Var', (157, 163))	('T1N3M0', 'Var', (141, 147))	('T2N3M0', 'Var', (149, 155))	('T4aN2M0', 'Var', (165, 172))	('T4aN1M0', 'Var', (127, 134))
566908	33034409	The TRNPM staging system is as follows: IIB, T1RNP1M0; IIIA, T1RNP2M0, T2RNP1M0; IIIB, T2RNP2M0, T3RNP1M0, T3RNP2M0, T4aRNP1M0; IVA, T1RNP3M0, T2RNP3M0, T3RNP3M0, T4aRNP2M0, T4aRNP3M0.	('T4aRNP2M0', 'Var', (163, 172))	('T3RNP1M0', 'Var', (97, 105))	('T1RNP3M0', 'Var', (133, 141))	('T3RNP3M0', 'Var', (153, 161))	('IVA', 'Disease', (128, 131))	('T3RNP2M0', 'Var', (107, 115))	('T2RNP2M0', 'Var', (87, 95))	('T4aRNP1M0', 'Var', (117, 126))	('IVA', 'Disease', 'MESH:C538167', (128, 131))	('T1RNP2M0', 'Var', (61, 69))	('T4aRNP3M0', 'Var', (174, 183))	('T2RNP3M0', 'Var', (143, 151))
566939	33034409	Our study analyzed the OS of two random cohorts of EC patients who underwent radical surgery and assessed the prognostic prediction performance of N, NLN and RNP.	('RNP', 'Var', (158, 161))	('EC', 'Disease', 'MESH:D005955', (51, 53))	('NLN', 'Gene', '57486', (150, 153))	('patients', 'Species', '9606', (54, 62))	('NLN', 'Gene', (150, 153))
566947	33034409	14 ,  23  it was demonstrated that RNP could help improve the accuracy of prognostic evaluation when compared with other prognostic factors, and was recommended for use in predicting OS of GC patients.	('improve', 'PosReg', (50, 57))	('accuracy', 'MPA', (62, 70))	('patients', 'Species', '9606', (192, 200))	('RNP', 'Var', (35, 38))
566965	32319613	The present study aimed to determine the role of circRNA_001275 in cisplatin-resistant esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('cancer', 'Disease', (98, 104))	('circRNA_001275', 'Var', (49, 63))
566969	32319613	The results showed that circRNA_001275 was significantly upregulated in cisplatin-resistant esophageal cancer tissues and cells (P<0.05).	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('circRNA_001275', 'Var', (24, 38))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('upregulated', 'PosReg', (57, 68))
566970	32319613	Overexpression of circRNA_001275 promoted the proliferation and invasion, and decreased the apoptosis of cisplatin-resistant cells.	('circRNA_001275', 'Var', (18, 32))	('promoted', 'PosReg', (33, 41))	('apoptosis of', 'CPA', (92, 104))	('invasion', 'CPA', (64, 72))	('proliferation', 'CPA', (46, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('decreased', 'NegReg', (78, 87))
566971	32319613	Dual-luciferase reporter assays revealed that circRNA_001275 directly binds to miR-370-3p, and that Wnt family member 7A (Wnt7a) is targeted by miR-370-3p.	('miR-370-3p', 'Chemical', '-', (144, 154))	('Wnt7a', 'Gene', '7476', (122, 127))	('miR-370-3p', 'Chemical', '-', (79, 89))	('binds', 'Interaction', (70, 75))	('miR-370-3p', 'Protein', (79, 89))	('miR-370-3p', 'Var', (144, 154))	('Wnt7a', 'Gene', (122, 127))
566972	32319613	RT-qPCR and western blotting further demonstrated that circRNA_001275 serves as an miR-370-3p sponge to upregulate Wnt7a expression.	('circRNA_001275', 'Var', (55, 69))	('Wnt7a', 'Gene', (115, 120))	('expression', 'MPA', (121, 131))	('miR-370-3p', 'Chemical', '-', (83, 93))	('Wnt7a', 'Gene', '7476', (115, 120))	('upregulate', 'PosReg', (104, 114))
566973	32319613	In conclusion, the present study revealed that circRNA_001275 was upregulated in cisplatin-resistant esophageal cancer and promoted cisplatin resistance by sponging miR-370-3p to upregulate Wnt7a expression.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('promoted', 'PosReg', (123, 131))	('upregulated', 'PosReg', (66, 77))	('expression', 'MPA', (196, 206))	('Wnt7a', 'Gene', (190, 195))	('circRNA_001275', 'Var', (47, 61))	('upregulate', 'PosReg', (179, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('miR-370-3p', 'Chemical', '-', (165, 175))	('cisplatin resistance', 'MPA', (132, 152))	('Wnt7a', 'Gene', '7476', (190, 195))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))
566974	32319613	Therefore circRNA_001275 may serve as a potential diagnostic biomarker and therapeutic target for patients with cisplatin-resistant esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('circRNA_001275', 'Var', (10, 24))	('patients', 'Species', '9606', (98, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
566979	32319613	circRNAs are conserved and stable, and may therefore serve as suitable markers for disease diagnosis and treatment; previous studies have shown that circRNAs serve important roles in various tumors, and the abnormal expression of circRNAs may be involved in the occurrence and development of cancer.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('involved', 'Reg', (246, 254))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('abnormal', 'Var', (207, 215))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('cancer', 'Disease', (292, 298))	('tumors', 'Disease', (191, 197))
566982	32319613	A circRNA chip assay revealed that circRNA_001275 was significantly upregulated in cisplatin-resistant esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('upregulated', 'PosReg', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('circRNA_001275', 'Var', (35, 49))	('cancer', 'Disease', (114, 120))
566992	32319613	mRNA levels were quantified using the 2-Delta Cq method; circRNA_001275 and Wnt7a were normalized to GAPDH, whereas miR-370-3p was normalized to U6.	('GAPDH', 'Gene', '2597', (101, 106))	('Wnt7a', 'Gene', (76, 81))	('GAPDH', 'Gene', (101, 106))	('circRNA_001275', 'Var', (57, 71))	('Wnt7a', 'Gene', '7476', (76, 81))	('miR-370-3p', 'Chemical', '-', (116, 126))
566993	32319613	The circRNA_001275 overexpression (OE) vector (circRNA_001275 OE), pcDNA3.1 empty vector, small interfering (si)RNA targeting circRNA_001275 (si-circRNA_001275), si-negative control (NC), miR-370-3p mimic, miR-370-3p inhibitor and miR-370-3p NC labeled with green fluorescent protein were designed and synthesized by Shanghai GeneChem Co., Ltd. Sequences were as follows: si-circRNA_001275, 5'-GTT GAA GGG GGA GCT CCT GTC ATA AAA GCC AA-3'; si-NC, 5'-GAG CCC CAG CCT TCT CCA TG-3'.	('miR-370-3p', 'Chemical', '-', (188, 198))	('GAA', 'Gene', '2548', (398, 401))	('si-circRNA_001275', 'Var', (372, 389))	('CCT', 'Gene', (463, 466))	('miR-370-3p', 'Chemical', '-', (231, 241))	('miR-370-3p', 'Chemical', '-', (206, 216))	('CCT', 'Gene', '907', (414, 417))	('GAA', 'Gene', (398, 401))	('CCT', 'Gene', '907', (463, 466))	('CCT', 'Gene', (414, 417))
567002	32319613	Cells were co-transfected with the miR-370-3p mimic or miR-370-3p NC along with wild-type (wt) or mutated (mut) circRNA_001275-3'-UTR or Wnt7a-3'-UTR using Lipofectamine 2000 at a final concentration of 50 nM for each RNA/plasmid.	('miR-370-3p', 'Var', (35, 45))	('Wnt7a', 'Gene', '7476', (137, 142))	('miR-370-3p', 'Var', (55, 65))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (156, 174))	('miR-370-3p', 'Chemical', '-', (35, 45))	('miR-370-3p', 'Chemical', '-', (55, 65))	('mutated', 'Var', (98, 105))	('Wnt7a', 'Gene', (137, 142))
567017	32319613	A schematic representation of the potential binding sites between miR-370-3p and the circRNA_001275-3'-UTR is presented in Fig.	('binding', 'Interaction', (44, 51))	('miR-370-3p', 'Chemical', '-', (66, 76))	('miR-370-3p', 'Var', (66, 76))
567018	32319613	miR-370-3p NC, mimic or inhibitor were transfected into KYSE30/DDP and ECA109/DDP cells.	('DDP', 'Gene', (78, 81))	('miR-370-3p', 'Chemical', '-', (0, 10))	('DDP', 'Gene', (63, 66))	('DDP', 'Gene', '1678', (78, 81))	('DDP', 'Gene', '1678', (63, 66))	('miR-370-3p', 'Var', (0, 10))
567019	32319613	RT-qPCR results confirmed that miR-370-3p were significantly increased in the miR-370-3p mimic group, and significantly reduced in miR-370-3p inhibitor group, compared with the miR-370-3p NC group (both P<0.05; Fig.	('miR-370-3p', 'Chemical', '-', (78, 88))	('miR-370-3p', 'Var', (131, 141))	('miR-370-3p', 'Chemical', '-', (31, 41))	('miR-370-3p', 'Chemical', '-', (131, 141))	('miR-370-3p', 'Var', (78, 88))	('increased', 'PosReg', (61, 70))	('miR-370-3p', 'Chemical', '-', (177, 187))	('reduced', 'NegReg', (120, 127))	('miR-370-3p', 'MPA', (31, 41))
567020	32319613	A luciferase assay revealed that the relative luciferase activity in the circRNA_001275-wt and miR-370-3p mimic co-transfection group was significantly decreased compared with the circRNA_001275-mut or miR-370-3p NC groups (both P<0.05; Fig.	('miR-370-3p', 'Chemical', '-', (202, 212))	('luciferase', 'Enzyme', (46, 56))	('decreased', 'NegReg', (152, 161))	('miR-370-3p mimic', 'Var', (95, 111))	('activity', 'MPA', (57, 65))	('miR-370-3p', 'Chemical', '-', (95, 105))
567021	32319613	RT-qPCR revealed that miR-370-3p was downregulated in cisplatin-resistant cells compared with corresponding sensitive cells (P<0.05; Fig.	('downregulated', 'NegReg', (37, 50))	('miR-370-3p', 'Var', (22, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('miR-370-3p', 'Chemical', '-', (22, 32))	('cisplatin-resistant', 'Disease', (54, 73))
567023	32319613	Furthermore, the expression of miR-370-3p was significantly decreased in the circRNA_001275 OE group, and significantly increased in the si-circRNA_001275 group, compared with the corresponding control groups (both P<0.05; Fig.	('miR-370-3p', 'Var', (31, 41))	('decreased', 'NegReg', (60, 69))	('circRNA_001275 OE', 'Var', (77, 94))	('expression', 'MPA', (17, 27))	('miR-370-3p', 'Chemical', '-', (31, 41))	('si-circRNA_001275', 'Var', (137, 154))	('increased', 'PosReg', (120, 129))
567025	32319613	The potential binding sites of miR-370-3p with Wnt7a-wt and Wnt7a-mut were predicted.	('miR-370-3p', 'Var', (31, 41))	('Wnt7a', 'Gene', '7476', (60, 65))	('miR-370-3p', 'Chemical', '-', (31, 41))	('binding', 'Interaction', (14, 21))	('Wnt7a', 'Gene', (47, 52))	('Wnt7a', 'Gene', (60, 65))	('Wnt7a', 'Gene', '7476', (47, 52))
567026	32319613	The results indicated a potential binding site for miR-370-3p in the Wnt7a 3'-UTR (Fig.	('miR-370-3p', 'Var', (51, 61))	('Wnt7a', 'Gene', (69, 74))	('binding', 'Interaction', (34, 41))	('miR-370-3p', 'Chemical', '-', (51, 61))	('Wnt7a', 'Gene', '7476', (69, 74))
567027	32319613	A luciferase assay revealed that the relative luciferase activity in the Wnt7a-3'-UTR-wt and miR-370-3p mimic co-transfection group was significantly decreased compared with the miR-370-3p NC or Wnt7a-3'-UTR-mut groups (both P<0.05; Fig.	('miR-370-3p', 'Chemical', '-', (178, 188))	('Wnt7a', 'Gene', '7476', (195, 200))	('luciferase', 'Enzyme', (46, 56))	('miR-370-3p', 'Var', (93, 103))	('Wnt7a', 'Gene', (73, 78))	('Wnt7a', 'Gene', '7476', (73, 78))	('miR-370-3p', 'Chemical', '-', (93, 103))	('activity', 'MPA', (57, 65))	('decreased', 'NegReg', (150, 159))	('Wnt7a', 'Gene', (195, 200))
567030	32319613	Furthermore, Wnt7a mRNA was significantly decreased in the miR-370-3p mimic group, and significantly increased in the miR-370-3p inhibitor group, compared with the miR-370-3p NC group (both P<0.05; Fig.	('miR-370-3p', 'Var', (59, 69))	('miR-370-3p', 'Chemical', '-', (164, 174))	('decreased', 'NegReg', (42, 51))	('Wnt7a', 'Gene', '7476', (13, 18))	('increased', 'PosReg', (101, 110))	('miR-370-3p', 'Chemical', '-', (59, 69))	('miR-370-3p', 'Chemical', '-', (118, 128))	('Wnt7a', 'Gene', (13, 18))
567031	32319613	Additionally, the Wnt7a protein level was significantly decreased in the miR-370-3p mimic group, and significantly increased in the miR-370-3p inhibitor group, compared with the miR-370-3p NC group (both P<0.05; Fig.	('Wnt7a', 'Gene', (18, 23))	('miR-370-3p', 'Chemical', '-', (178, 188))	('miR-370-3p', 'Var', (73, 83))	('increased', 'PosReg', (115, 124))	('decreased', 'NegReg', (56, 65))	('Wnt7a', 'Gene', '7476', (18, 23))	('miR-370-3p', 'Chemical', '-', (73, 83))	('miR-370-3p', 'Chemical', '-', (132, 142))
567032	32319613	Therefore, the results revealed that Wnt7a is a direct target gene of miR-370-3p.	('miR-370-3p', 'Var', (70, 80))	('Wnt7a', 'Gene', (37, 42))	('Wnt7a', 'Gene', '7476', (37, 42))	('miR-370-3p', 'Chemical', '-', (70, 80))
567034	32319613	RT-qPCR revealed that Wnt7a mRNA expression was significantly increased in the circRNA_001275 OE group and significantly decreased in the si-circRNA_001275 group; however, these effects were attenuated by miR-370-3p mimic and inhibitor, respectively (P<0.05; Fig.	('increased', 'PosReg', (62, 71))	('Wnt7a', 'Gene', '7476', (22, 27))	('decreased', 'NegReg', (121, 130))	('Wnt7a', 'Gene', (22, 27))	('miR-370-3p', 'Chemical', '-', (205, 215))	('circRNA_001275', 'Var', (79, 93))
567035	32319613	Furthermore, MTT results showed that overexpression of circRNA_141539 increased cell viability, and that circRNA_001275 silencing decreased cell viability; these effects were abrogated by miR-370-3p mimic and inhibitor, respectively (P<0.05; Fig.	('cell viability', 'CPA', (140, 154))	('miR-370-3p', 'Chemical', '-', (188, 198))	('overexpression', 'PosReg', (37, 51))	('MTT', 'Chemical', 'MESH:C070243', (13, 16))	('circRNA_141539', 'Var', (55, 69))	('increased', 'PosReg', (70, 79))	('silencing decreased', 'NegReg', (120, 139))	('circRNA_001275', 'Var', (105, 119))	('cell viability', 'CPA', (80, 94))
567037	32319613	For example, Xie et al revealed that circ_001569 is upregulated in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('circ_001569', 'Var', (37, 48))	('upregulated', 'PosReg', (52, 63))	('colorectal cancer', 'Disease', (67, 84))
567038	32319613	Similarly, Zhong et al demonstrated that circRNA transcription factor 25 (circTCF25) is upregulated in bladder carcinoma, and that circTCF25 down-regulates miR-103a-3p, increases cyclin-dependent kinase 6 expression and promotes proliferation.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (103, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('miR', 'Gene', '22877', (156, 159))	('upregulated', 'PosReg', (88, 99))	('3p', 'Chemical', '-', (165, 167))	('promotes', 'PosReg', (220, 228))	('bladder carcinoma', 'Disease', 'MESH:D001749', (103, 120))	('proliferation', 'CPA', (229, 242))	('increases', 'PosReg', (169, 178))	('bladder carcinoma', 'Disease', (103, 120))	('circTCF25', 'Var', (131, 140))	('down-regulates', 'NegReg', (141, 155))	('cyclin-dependent kinase 6', 'Gene', (179, 204))	('expression', 'MPA', (205, 215))	('cyclin-dependent kinase 6', 'Gene', '1021', (179, 204))	('miR', 'Gene', (156, 159))
567045	32319613	Furthermore, circRNA_001275 was found to promote the proliferation of cisplatin-resistant cells.	('promote', 'PosReg', (41, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('proliferation', 'CPA', (53, 66))	('circRNA_001275', 'Var', (13, 27))
567046	32319613	To the best of the authors' knowledge, circRNA_001275 has only been investigated in a study by Zhao, who reported that circRNA_001275 was significantly upregulated in post-menopausal osteoporosis and may serve as a novel potential diagnostic biomarker.	('upregulated', 'PosReg', (152, 163))	('osteoporosis', 'Disease', 'MESH:D010024', (183, 195))	('osteoporosis', 'Disease', (183, 195))	('circRNA_001275', 'Var', (119, 133))	('osteoporosis', 'Phenotype', 'HP:0000939', (183, 195))
567047	32319613	The present study revealed that circRNA_001275 may function as an oncogenic factor and serve as a promising biomarker for patients with cisplatin-resistant esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('circRNA_001275', 'Var', (32, 46))	('cancer', 'Disease', (167, 173))	('patients', 'Species', '9606', (122, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
567048	32319613	The present study revealed that circRNA_001275 may act as an miR-370-3p sponge to upregulate Wnt7a expression.	('expression', 'MPA', (99, 109))	('Wnt7a', 'Gene', (93, 98))	('circRNA_001275', 'Var', (32, 46))	('Wnt7a', 'Gene', '7476', (93, 98))	('upregulate', 'PosReg', (82, 92))	('miR-370-3p', 'Chemical', '-', (61, 71))
567050	32319613	Several reports have shown that miR-370-3p may promote the progression of bladder cancer and glioma, and affect temozolomide sensitivity in glioblastoma.	('temozolomide', 'Chemical', 'MESH:D000077204', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('glioma', 'Disease', (93, 99))	('miR-370-3p', 'Var', (32, 42))	('promote', 'PosReg', (47, 54))	('glioblastoma', 'Disease', (140, 152))	('bladder cancer', 'Disease', 'MESH:D001749', (74, 88))	('progression', 'CPA', (59, 70))	('glioblastoma', 'Disease', 'MESH:D005909', (140, 152))	('affect', 'Reg', (105, 111))	('temozolomide sensitivity', 'MPA', (112, 136))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('bladder cancer', 'Disease', (74, 88))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('miR-370-3p', 'Chemical', '-', (32, 42))
567056	32319613	Therefore, miR-370-3p-induced Wnt7a upregulation may be one of the mechanisms underlying cisplatin resistance.	('Wnt7a', 'Gene', '7476', (30, 35))	('miR-370-3p', 'Chemical', '-', (11, 21))	('upregulation', 'PosReg', (36, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('miR-370-3p-induced', 'Var', (11, 29))	('Wnt7a', 'Gene', (30, 35))
567058	32319613	To the best of our knowledge, the present study was the first to determine that circRNA_001275 was upregulated in cispl-atin-resistant esophageal cancer, and that circRNA_001275 may promote cisplatin resistance by sponging miR-370-3p to upregulate Wnt7a expression.	('cancer', 'Disease', (146, 152))	('circRNA_001275', 'Var', (163, 177))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('Wnt7a', 'Gene', (248, 253))	('upregulated', 'PosReg', (99, 110))	('Wnt7a', 'Gene', '7476', (248, 253))	('circRNA_001275', 'Gene', (80, 94))	('expression', 'MPA', (254, 264))	('miR-370-3p', 'Chemical', '-', (223, 233))	('promote', 'PosReg', (182, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (190, 199))	('cispl', 'Chemical', '-', (114, 119))	('cispl', 'Chemical', '-', (190, 195))	('upregulate', 'PosReg', (237, 247))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cisplatin resistance', 'MPA', (190, 210))
567065	31308045	Overexpression of a redox-defective mutant, C65A, abrogated the pro-invasive phenotype of APE1.	('pro-invasive', 'CPA', (64, 76))	('expression', 'Species', '29278', (4, 14))	('abrogated', 'NegReg', (50, 59))	('APE1', 'Gene', (90, 94))	('APE1', 'Gene', '328', (90, 94))	('C65A', 'SUBSTITUTION', 'None', (44, 48))	('C65A', 'Var', (44, 48))
567075	31308045	The N-terminal Cys65 residue in the APE1 has been identified to mediate the redox function of APE1.	('redox function', 'MPA', (76, 90))	('APE1', 'Gene', (94, 98))	('mediate', 'Reg', (64, 71))	('APE1', 'Gene', '328', (94, 98))	('APE1', 'Gene', (36, 40))	('APE1', 'Gene', '328', (36, 40))	('Cys65', 'Var', (15, 20))	('Cys65', 'Chemical', '-', (15, 20))
567098	31308045	E3330 (APE1 redox-specific inhibitor) was purchased from Novus Biologicals (Littleton, CO, USA), and APE1-i3 (APE1 DNA repair-specific inhibitor) was purchased from MilliporeSigma (Burlington, MA, USA).	('APE1', 'Gene', (7, 11))	('APE1', 'Gene', '328', (7, 11))	('MilliporeSigma', 'Disease', 'None', (165, 179))	('APE1', 'Gene', '328', (110, 114))	('E3330', 'Var', (0, 5))	('APE1', 'Gene', (101, 105))	('APE1-i3', 'Gene', (101, 108))	('APE1', 'Gene', '328', (101, 105))	('MilliporeSigma', 'Disease', (165, 179))	('E3330', 'Chemical', 'MESH:C075569', (0, 5))	('APE1', 'Gene', (110, 114))	('APE1-i3', 'Gene', '328', (101, 108))
567099	31308045	The usage of inhibitors were following pharmacological studies with recommended doses for the E3330 and APE1-i3.	('APE1-i3', 'Gene', '328', (104, 111))	('E3330', 'Var', (94, 99))	('APE1-i3', 'Gene', (104, 111))	('E3330', 'Chemical', 'MESH:C075569', (94, 99))
567103	31308045	APE1 redox-deficient mutant, C65A, and DNA-repair-deficient mutant, H309N, were generated by the QuickChange Lightning Site-Directed Mutagenesis Kit (Agilent Technologies, Santa Clara, CA, USA).	('rat', 'Species', '10116', (84, 87))	('C65A', 'SUBSTITUTION', 'None', (29, 33))	('H309N', 'Mutation', 'p.H309N', (68, 73))	('APE1', 'Gene', (0, 4))	('C65A', 'Var', (29, 33))	('APE1', 'Gene', '328', (0, 4))
567105	31308045	To overexpress APE1 and its relevant mutants in APE1-knockdown (shAPE1) cells, the mutation has been introduced into APE1, C65A and H309N expression vectors to avoid APE1-shRNA targeting, but not change protein sequence.	('C65A', 'Var', (123, 127))	('APE1', 'Gene', (48, 52))	('expression vectors', 'Species', '29278', (138, 156))	('APE1', 'Gene', '328', (66, 70))	('APE1', 'Gene', '328', (117, 121))	('H309N', 'Mutation', 'p.H309N', (132, 137))	('APE1', 'Gene', '328', (48, 52))	('APE1', 'Gene', (15, 19))	('APE1', 'Gene', '328', (166, 170))	('APE1', 'Gene', (166, 170))	('APE1', 'Gene', '328', (15, 19))	('mutation', 'Var', (83, 91))	('C65A', 'SUBSTITUTION', 'None', (123, 127))	('APE1', 'Gene', (66, 70))	('APE1', 'Gene', (117, 121))
567111	31308045	3D organotypic cultures of APE1 knockdown cells (shAPE1) and control cells (shCtrl) in CPB or FLO-1 cells were performed, as previously described.	('APE1', 'Gene', '328', (51, 55))	('CPB', 'Gene', '1360', (87, 90))	('knockdown', 'Var', (32, 41))	('APE1', 'Gene', (27, 31))	('APE1', 'Gene', (51, 55))	('CPB', 'Gene', (87, 90))	('APE1', 'Gene', '328', (27, 31))
567121	31308045	Total 106 cells were washed with DMEM and seeded on DQ gelatin fluorescein conjugate (Thermo Fisher Scientific) coated cover glass and cultured with serum-free media for 16 h. The fluorescence release resulting from MMP cleavage of the matrix was visualized by fluorescence microscopy.	('fluorescence release', 'MPA', (180, 200))	('fluorescein', 'Chemical', 'MESH:D019793', (63, 74))	('DMEM', 'Chemical', '-', (33, 37))	('MMP cleavage', 'Var', (216, 228))
567145	31308045	Interestingly, we observed that APE1 knockdown (shAPE1 cells) changed the cellular shape from spindle-like to a cobblestone-like shape (Figure1B).	('cellular shape', 'CPA', (74, 88))	('APE1', 'Gene', (32, 36))	('knockdown', 'Var', (37, 46))	('APE1', 'Gene', (50, 54))	('APE1', 'Gene', '328', (32, 36))	('APE1', 'Gene', '328', (50, 54))	('spindle-like', 'CPA', (94, 106))	('changed', 'Reg', (62, 69))
567148	31308045	Additionally, APE1 knockdown by siRNA confirmed that APE1 is required for FLO-1 cell invasion (Supplementary Figure S1A &B).	('knockdown', 'Var', (19, 28))	('APE1', 'Gene', '328', (53, 57))	('APE1', 'Gene', (53, 57))	('APE1', 'Gene', (14, 18))	('APE1', 'Gene', '328', (14, 18))
567150	31308045	To determine which function of APE1 is involved in APE1-dependent cell invasion capabilities, we treated CPB, FLO-1, OE19, and ESO26 cells with specific APE1 inhibitors, E3330 or APE1-i3, respectively.	('APE1', 'Gene', (31, 35))	('APE1', 'Gene', '328', (51, 55))	('E3330', 'Var', (170, 175))	('E3330', 'Chemical', 'MESH:C075569', (170, 175))	('CPB', 'Gene', (105, 108))	('APE1', 'Gene', '328', (31, 35))	('APE1', 'Gene', '328', (179, 183))	('APE1', 'Gene', (153, 157))	('APE1-i3', 'Gene', '328', (179, 186))	('CPB', 'Gene', '1360', (105, 108))	('APE1', 'Gene', '328', (153, 157))	('ESO26', 'CellLine', 'CVCL:2035', (127, 132))	('APE1', 'Gene', (179, 183))	('APE1-i3', 'Gene', (179, 186))	('APE1', 'Gene', (51, 55))
567151	31308045	E3330, is a known APE1 redox-specific inhibitor, whereas APE1-i3 is mainly an inhibitor of DNA damage repair function of APE1.	('APE1', 'Gene', (121, 125))	('APE1', 'Gene', (18, 22))	('APE1-i3', 'Gene', '328', (57, 64))	('E3330', 'Var', (0, 5))	('APE1', 'Gene', '328', (121, 125))	('APE1', 'Gene', '328', (18, 22))	('E3330', 'Chemical', 'MESH:C075569', (0, 5))	('APE1-i3', 'Gene', (57, 64))	('APE1', 'Gene', (57, 61))	('APE1', 'Gene', '328', (57, 61))
567152	31308045	By using in vitro matrigel invasion assays, we found that E3330 treatment significantly diminished cell invasion (p < 0.01), whereas APE1-i3 treatment had no significant effect on invasion, as compared to control cells (Figure 2A, and Supplementary Figure S2A).	('cell invasion', 'CPA', (99, 112))	('APE1-i3', 'Gene', '328', (133, 140))	('E3330', 'Var', (58, 63))	('APE1-i3', 'Gene', (133, 140))	('E3330', 'Chemical', 'MESH:C075569', (58, 63))	('diminished', 'NegReg', (88, 98))
567153	31308045	Interestingly, we also observed that E3330 treatment changed FLO-1 cell morphology (spindle-like) to a less invasive shape (cobblestone-like), whereas, APE1-i3 didn't induce these changes (Supplementary Figure S2B).	('APE1-i3', 'Gene', (152, 159))	('FLO-1', 'Gene', (61, 66))	('E3330', 'Chemical', 'MESH:C075569', (37, 42))	('changed', 'Reg', (53, 60))	('E3330 treatment', 'Var', (37, 52))	('APE1-i3', 'Gene', '328', (152, 159))
567154	31308045	To verify the inhibitors' functions, we reconstituted APE1 expression in APE1-knockdown (shAPE1) FLO-1 cells by overexpression of control vector (Ctrl), FLAG-tagged wild-type APE1, APE1-C65A (redox-defective mutant) or APE1-H309N (DNA-repair-defective mutant).	('APE1', 'Gene', (73, 77))	('APE1', 'Gene', '328', (219, 223))	('expression', 'Species', '29278', (116, 126))	('APE1', 'Gene', '328', (73, 77))	('C65A', 'SUBSTITUTION', 'None', (186, 190))	('expression', 'Species', '29278', (59, 69))	('APE1', 'Gene', (54, 58))	('H309N', 'Mutation', 'p.H309N', (224, 229))	('APE1', 'Gene', '328', (54, 58))	('APE1', 'Gene', (91, 95))	('C65A', 'Var', (186, 190))	('APE1', 'Gene', (181, 185))	('APE1', 'Gene', '328', (91, 95))	('APE1', 'Gene', (175, 179))	('APE1', 'Gene', (219, 223))	('APE1', 'Gene', '328', (175, 179))	('APE1', 'Gene', '328', (181, 185))
567156	31308045	More importantly, we detected a significant rescue of cell invasion by reconstitution of wild-type APE1 or H309N mutant, as compared to the control vector (Ctrl) (p < 0.05).	('APE1', 'Gene', (99, 103))	('H309N mutant', 'Var', (107, 119))	('H309N', 'Mutation', 'p.H309N', (107, 112))	('cell invasion', 'CPA', (54, 67))	('rescue', 'PosReg', (44, 50))	('APE1', 'Gene', '328', (99, 103))
567157	31308045	However, unlike wild-type APE1 or H309N mutant, redox-defective C65A mutant failed to rescue cell invasion (p < 0.01).	('C65A', 'Var', (64, 68))	('cell invasion', 'CPA', (93, 106))	('C65A', 'SUBSTITUTION', 'None', (64, 68))	('H309N', 'Mutation', 'p.H309N', (34, 39))	('APE1', 'Gene', (26, 30))	('APE1', 'Gene', '328', (26, 30))
567158	31308045	The ectopic expression of flag-tagged wild-type APE1 or relevant mutants was confirmed by Western blot analysis (Figure 2B).	('APE1', 'Gene', (48, 52))	('mutants', 'Var', (65, 72))	('APE1', 'Gene', '328', (48, 52))	('ectopic expression', 'MPA', (4, 22))	('expression', 'Species', '29278', (12, 22))
567159	31308045	Additionally, we found that the C65A mutant did not promote cell invasion as wild-type APE1 or H309N mutant in OE33 and SK-GT-4 cells (Supplementary Figure S2D).	('APE1', 'Gene', (87, 91))	('SK-GT-4', 'CellLine', 'CVCL:2195', (120, 127))	('APE1', 'Gene', '328', (87, 91))	('H309N', 'Var', (95, 100))	('C65A', 'SUBSTITUTION', 'None', (32, 36))	('H309N', 'Mutation', 'p.H309N', (95, 100))	('C65A', 'Var', (32, 36))	('cell invasion', 'CPA', (60, 73))
567161	31308045	Overexpression of MMP-14 is known to mediate invasion in several cancer types.	('MMP-14', 'Gene', '4323', (18, 24))	('expression', 'Species', '29278', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Overexpression', 'Var', (0, 14))	('MMP-14', 'Gene', (18, 24))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
567164	31308045	We also observed similar results in transient APE1 knockdown by siRNA in FLO-1 cells (Supplementary Figure S1B).	('APE1', 'Gene', (46, 50))	('APE1', 'Gene', '328', (46, 50))	('knockdown', 'Var', (51, 60))
567173	31308045	APE1 silencing significantly decreased MMP-14 protein levels on the cell surface in CPB and FLO-1 cells, as compared to control cells (p < 0.05, Figure 4A).	('CPB', 'Gene', (84, 87))	('MMP-14', 'Gene', (39, 45))	('MMP-14', 'Gene', '4323', (39, 45))	('silencing', 'Var', (5, 14))	('CPB', 'Gene', '1360', (84, 87))	('decreased', 'NegReg', (29, 38))	('APE1', 'Gene', (0, 4))	('APE1', 'Gene', '328', (0, 4))
567175	31308045	Immunofluorescence data indicated that inhibition of APE1 redox activity by E3330 had no effect on APE1 protein levels or cellular localization, as expected, but significantly diminished MMP-14 on cell surface in CPB and FLO-1 cells, relative to control cells (p < 0.05, Figure 4B).	('E3330', 'Chemical', 'MESH:C075569', (76, 81))	('MMP-14', 'Gene', '4323', (187, 193))	('diminished MMP-14 on cell surface', 'Phenotype', 'HP:0041048', (176, 209))	('CPB', 'Gene', (213, 216))	('inhibition', 'NegReg', (39, 49))	('APE1', 'Gene', '328', (53, 57))	('APE1', 'Gene', (53, 57))	('CPB', 'Gene', '1360', (213, 216))	('E3330', 'Var', (76, 81))	('APE1', 'Gene', (99, 103))	('diminished', 'NegReg', (176, 186))	('MMP-14', 'Gene', (187, 193))	('APE1', 'Gene', '328', (99, 103))
567176	31308045	Moreover, Western blot analysis (Supplementary Figure S3A) and immunofluorescence staining (Supplementary Figure S3B) showed C65A mutant could not rescue MMP-14 expression as wild-type APE1 or H309N in APE1-knockdown (shAPE1) FLO-1 cells.	('APE1', 'Gene', '328', (185, 189))	('C65A', 'SUBSTITUTION', 'None', (125, 129))	('expression', 'Species', '29278', (161, 171))	('H309N', 'Mutation', 'p.H309N', (193, 198))	('APE1', 'Gene', '328', (202, 206))	('expression', 'MPA', (161, 171))	('MMP-14', 'Gene', (154, 160))	('MMP-14', 'Gene', '4323', (154, 160))	('C65A', 'Var', (125, 129))	('APE1', 'Gene', (202, 206))	('APE1', 'Gene', (220, 224))	('APE1', 'Gene', (185, 189))	('APE1', 'Gene', '328', (220, 224))
567184	31308045	Western blot results indicated that APE1 knockdown decreased protein levels of MMP-2 (pro-form, 72 kDa), as well as MMP-14 in CPB and FLO-1 cells, as compared to the relevant control cells (Figure 5A).	('CPB', 'Gene', '1360', (126, 129))	('MMP-14', 'Gene', (116, 122))	('MMP-2', 'Gene', (79, 84))	('MMP-14', 'Gene', '4323', (116, 122))	('APE1', 'Gene', (36, 40))	('protein levels', 'MPA', (61, 75))	('decreased', 'NegReg', (51, 60))	('CPB', 'Gene', (126, 129))	('APE1', 'Gene', '328', (36, 40))	('MMP-2', 'Gene', '4313', (79, 84))	('knockdown', 'Var', (41, 50))
567188	31308045	Furthermore, in situ zymography assay data indicated that APE-1 knockdown or inhibition of APE1-specific redox function by E3330 significantly reduced ECM degradation activities, as demonstrated by levels of quenched fluorescein-labeled gelatin (DQ-gelatin), in CPB and FLO-1 cells, as compared to control cells, respectively (p < 0.01, Figure 5C & D).	('APE-1', 'Gene', '328', (58, 63))	('ECM degradation activities', 'MPA', (151, 177))	('APE1', 'Gene', (91, 95))	('CPB', 'Gene', '1360', (262, 265))	('E3330', 'Var', (123, 128))	('inhibition', 'NegReg', (77, 87))	('CPB', 'Gene', (262, 265))	('E3330', 'Chemical', 'MESH:C075569', (123, 128))	('knockdown', 'Var', (64, 73))	('fluorescein', 'Chemical', 'MESH:D019793', (217, 228))	('rat', 'Species', '10116', (189, 192))	('APE1', 'Gene', '328', (91, 95))	('APE-1', 'Gene', (58, 63))	('reduced', 'NegReg', (143, 150))
567193	31308045	Additionally, inhibition of APE1 redox activity by E3330 significantly decreased MMP-14 protein half-life from ~10 h to ~4 h in FLO-1 cells as compared to control cells (Supplementary Figure S4B).	('APE1', 'Gene', (28, 32))	('MMP-14', 'Gene', (81, 87))	('half-life', 'MPA', (96, 105))	('APE1', 'Gene', '328', (28, 32))	('MMP-14', 'Gene', '4323', (81, 87))	('E3330', 'Chemical', 'MESH:C075569', (51, 56))	('E3330', 'Var', (51, 56))	('decreased', 'NegReg', (71, 80))	('inhibition', 'NegReg', (14, 24))
567200	31308045	The results strongly suggested that APE1 silencing significantly slowed down the rate of MMP-14 endocytosis in EAC cells.	('rate', 'MPA', (81, 85))	('silencing', 'Var', (41, 50))	('MMP-14', 'Gene', (89, 95))	('rat', 'Species', '10116', (81, 84))	('APE1', 'Gene', (36, 40))	('slowed down', 'NegReg', (65, 76))	('MMP-14', 'Gene', '4323', (89, 95))	('APE1', 'Gene', '328', (36, 40))
567201	31308045	Moreover, consistent with APE1 knockdown data, inhibition of APE1 redox function by E3330 significantly enhanced endocytic MMP-14 at 5 min (p < 0.01) and at 7.5 min (p < 0.05) in FLO-1 cells, relative to control cells (Figure 6B).	('E3330', 'Chemical', 'MESH:C075569', (84, 89))	('MMP-14', 'Gene', (123, 129))	('inhibition', 'NegReg', (47, 57))	('enhanced', 'PosReg', (104, 112))	('APE1', 'Gene', (61, 65))	('APE1', 'Gene', '328', (26, 30))	('MMP-14', 'Gene', '4323', (123, 129))	('APE1', 'Gene', (26, 30))	('APE1', 'Gene', '328', (61, 65))	('E3330', 'Var', (84, 89))
567203	31308045	Notably, recycling assay data indicated that APE1-knockdown, as well as APE1 redox function inhibition (E3330), significantly diminished MMP-14 recycling at 7.5 min (p < 0.05) and 15 min (p < 0.01) in FLO-1 cells, as compared to control cells, respectively (Figure 6C & D).	('APE1', 'Gene', '328', (45, 49))	('APE1', 'Gene', (72, 76))	('MMP-14', 'Gene', (137, 143))	('diminished', 'NegReg', (126, 136))	('APE1', 'Gene', '328', (72, 76))	('MMP-14', 'Gene', '4323', (137, 143))	('E3330', 'Var', (104, 109))	('APE1', 'Gene', (45, 49))	('E3330', 'Chemical', 'MESH:C075569', (104, 109))
567210	31308045	Both stable shRNA knockdown (Figure 7C) and transient siRNA knockdown (Supplementary Figure S5C) of APE1 significantly attenuated ARF6 activities (p < 0.05) in CPB and FLO-1 cells relative to control cells, respectively.	('CPB', 'Gene', (160, 163))	('APE1', 'Gene', '328', (100, 104))	('ARF6', 'Gene', (130, 134))	('knockdown', 'Var', (60, 69))	('ARF6', 'Gene', '382', (130, 134))	('CPB', 'Gene', '1360', (160, 163))	('attenuated', 'NegReg', (119, 129))	('APE1', 'Gene', (100, 104))
567211	31308045	In addition, APE1 redox inhibition (E3330) significantly decreased active-ARF6 levels (p < 0.05) in CPB and FLO-1 cells as compared to control cells, respectively (Figure 7C).	('CPB', 'Gene', '1360', (100, 103))	('E3330', 'Var', (36, 41))	('ARF6', 'Gene', (74, 78))	('ARF6', 'Gene', '382', (74, 78))	('E3330', 'Chemical', 'MESH:C075569', (36, 41))	('CPB', 'Gene', (100, 103))	('APE1', 'Gene', '328', (13, 17))	('APE1', 'Gene', (13, 17))	('decreased', 'NegReg', (57, 66))
567212	31308045	However, E3330 treatment or FLAG-tagged APE1-C65A (redox-defective) mutant had no significant effect on APE1-ARF6 interaction (Supplementary Figure S5D & E).	('APE1', 'Gene', '328', (104, 108))	('E3330', 'Chemical', 'MESH:C075569', (9, 14))	('ARF6', 'Gene', (109, 113))	('C65A', 'Var', (45, 49))	('APE1', 'Gene', (40, 44))	('ARF6', 'Gene', '382', (109, 113))	('interaction', 'Interaction', (114, 125))	('APE1', 'Gene', '328', (40, 44))	('E3330 treatment', 'Var', (9, 24))	('C65A', 'SUBSTITUTION', 'None', (45, 49))	('APE1', 'Gene', (104, 108))	('mutant', 'Var', (68, 74))
567213	31308045	Interestingly, ARF6 specific activity inhibitor, NAV-2729, inhibited active ARF6 (GTP-ARF6) and abolished MMP-14 protein elevation induced by APE1-overexpression (Ad-APE1) in OE33 and SK-GT-4 cells (Figure 7D), suggesting that APE1 upregulates MMP-14 in an ARF6-dependent manner.	('ARF6', 'Gene', (15, 19))	('ARF6', 'Gene', '382', (86, 90))	('expression', 'Species', '29278', (151, 161))	('APE1', 'Gene', (166, 170))	('inhibited', 'NegReg', (59, 68))	('GTP-ARF6', 'Gene', (82, 90))	('ARF6', 'Gene', '382', (257, 261))	('MMP-14', 'Gene', '4323', (244, 250))	('ARF6', 'Gene', (86, 90))	('ARF6', 'Gene', '382', (76, 80))	('abolished', 'NegReg', (96, 105))	('APE1', 'Gene', '328', (227, 231))	('ARF6', 'Gene', (257, 261))	('MMP-14', 'Gene', (244, 250))	('elevation', 'PosReg', (121, 130))	('NAV-2729', 'Chemical', 'MESH:C000623233', (49, 57))	('ARF6', 'Gene', (76, 80))	('APE1', 'Gene', (227, 231))	('MMP-14', 'Gene', '4323', (106, 112))	('SK-GT-4', 'CellLine', 'CVCL:2195', (184, 191))	('APE1', 'Gene', '328', (142, 146))	('APE1', 'Gene', '328', (166, 170))	('ARF6', 'Gene', '382', (15, 19))	('MMP-14', 'Gene', (106, 112))	('GTP-ARF6', 'Gene', '382;92170', (82, 90))	('NAV-2729', 'Var', (49, 57))	('APE1', 'Gene', (142, 146))
567214	31308045	Further, we found NAV-2729 or MMPs inhibitor, GM6001, abolished APE1-elevated invasion capability (p < 0.05) in SK-GT-4 cells (Figure 7E).	('GM6001', 'Var', (46, 52))	('APE1', 'Gene', (64, 68))	('MMPs', 'Gene', (30, 34))	('APE1', 'Gene', '328', (64, 68))	('invasion capability', 'CPA', (78, 97))	('abolished', 'NegReg', (54, 63))	('MMPs', 'Gene', '4313;4316;4318;4323', (30, 34))	('GM6001', 'Chemical', 'MESH:C078131', (46, 52))	('NAV-2729', 'Chemical', 'MESH:C000623233', (18, 26))	('SK-GT-4', 'CellLine', 'CVCL:2195', (112, 119))
567220	31308045	We consistently found that knockdown of APE1 or inhibition of its redox function remarkably diminished invasion.	('redox function', 'MPA', (66, 80))	('knockdown', 'Var', (27, 36))	('diminished', 'NegReg', (92, 102))	('APE1', 'Gene', (40, 44))	('APE1', 'Gene', '328', (40, 44))	('inhibition', 'NegReg', (48, 58))	('invasion', 'CPA', (103, 111))
567222	31308045	Unlike wild-type APE1 or H309N (DNA-repair-deficient mutant), overexpression of a redox-deficient APE1 mutant (C65A) failed to promote invasion in our models of EAC, confirming that APE1 redox activity is required for APE1 pro-invasion function.	('APE1', 'Gene', '328', (182, 186))	('C65A', 'SUBSTITUTION', 'None', (111, 115))	('promote', 'PosReg', (127, 134))	('expression', 'Species', '29278', (66, 76))	('APE1', 'Gene', (218, 222))	('C65A', 'Var', (111, 115))	('APE1', 'Gene', (17, 21))	('EAC', 'Disease', (161, 164))	('APE1', 'Gene', (98, 102))	('APE1', 'Gene', '328', (218, 222))	('APE1', 'Gene', '328', (17, 21))	('APE1', 'Gene', '328', (98, 102))	('APE1', 'Gene', (182, 186))	('H309N', 'Mutation', 'p.H309N', (25, 30))
567239	31308045	Genetic knockdown or redox-specific inhibition (E3330) of APE1 repressed ARF6 activity and consequently decelerated MMP-14 endocytosis/recycling, suggesting that overexpression of APE1 activates ARF6 through its redox-function in cancer cells.	('MMP-14', 'Gene', '4323', (116, 122))	('APE1', 'Gene', '328', (180, 184))	('E3330', 'Var', (48, 53))	('expression', 'Species', '29278', (166, 176))	('ARF6', 'Gene', '382', (195, 199))	('rat', 'Species', '10116', (110, 113))	('APE1', 'Gene', (180, 184))	('MMP-14', 'Gene', (116, 122))	('ARF6', 'Gene', (195, 199))	('redox-function', 'MPA', (212, 226))	('cancer', 'Disease', (230, 236))	('activity', 'MPA', (78, 86))	('ARF6', 'Gene', '382', (73, 77))	('APE1', 'Gene', '328', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('decelerated', 'NegReg', (104, 115))	('activates', 'PosReg', (185, 194))	('ARF6', 'Gene', (73, 77))	('APE1', 'Gene', (58, 62))	('E3330', 'Chemical', 'MESH:C075569', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
567268	31470870	The T4N1M0 tumors had highest levels of eIF4E expression.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('eIF4E', 'Gene', '1977', (40, 45))	('T4N1M0', 'Var', (4, 10))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('eIF4E', 'Gene', (40, 45))	('expression', 'MPA', (46, 56))
567285	31470870	Levels of nine MUC1 variants mRNA expression were assessed in tumor and corresponding normal margins in ESCC patients.	('variants', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mRNA expression', 'MPA', (29, 44))	('MUC1', 'Gene', (15, 19))	('MUC1', 'Gene', '4582', (15, 19))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', (62, 67))	('ESCC', 'Disease', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
567294	31470870	Although, the role of MMP-2 (-1306C/T), MMP-9 (-1562C/T), and MMP-12 (-82A/G) polymorphisms were analyzed among Iranian ESCC patients, they were not useful prognostic markers in the identification of susceptible ESCC cases.	('-1306C/T', 'Mutation', 'rs243865', (29, 37))	('-82A/G', 'Mutation', 'rs2276109', (70, 76))	('MMP-12', 'Gene', (62, 68))	('ESCC', 'Disease', (120, 124))	('ESCC', 'Disease', (212, 216))	('MMP-2', 'Gene', '4313', (22, 27))	('-1562C/T', 'Mutation', 'rs3918242', (47, 55))	('MMP-12', 'Gene', '4321', (62, 68))	('MMP-9', 'Gene', '4318', (40, 45))	('-1306C/T', 'Var', (29, 37))	('-1562C/T', 'Var', (47, 55))	('MMP-9', 'Gene', (40, 45))	('MMP-2', 'Gene', (22, 27))	('patients', 'Species', '9606', (125, 133))
567299	31470870	Moreover, the levels of MMP-21 were significantly correlated with lymph node metastasis, TNM stage, and overall survival.	('overall survival', 'CPA', (104, 120))	('TNM', 'Gene', (89, 92))	('MMP-21', 'Gene', (24, 30))	('levels', 'Var', (14, 20))	('correlated', 'Reg', (50, 60))	('MMP-21', 'Gene', '118856', (24, 30))	('TNM', 'Gene', '10178', (89, 92))	('lymph node metastasis', 'CPA', (66, 87))
567306	31470870	Methylation of p16INK4a promoter sequence is a critical mechanism for its inactivation and promotes the ESCC progression.	('p16INK4a', 'Gene', (15, 23))	('promotes', 'PosReg', (91, 99))	('Methylation', 'Var', (0, 11))	('p16INK4a', 'Gene', '1029', (15, 23))	('ESCC', 'Disease', (104, 108))	('inactivation', 'MPA', (74, 86))
567311	31470870	P16 hypermethylation was observed in 73% of Iranian cases.	('P16', 'Gene', (0, 3))	('P16', 'Gene', '1029', (0, 3))	('observed', 'Reg', (25, 33))	('hypermethylation', 'Var', (4, 20))
567312	31470870	Moreover, p16 hypermethylated ESCC patients had 59 and 36% of p16 hypermethylation in their blood and serum samples, respectively.	('hypermethylation', 'Var', (66, 82))	('p16', 'Gene', (62, 65))	('p16', 'Gene', (10, 13))	('ESCC', 'Disease', (30, 34))	('patients', 'Species', '9606', (35, 43))	('p16', 'Gene', '1029', (62, 65))	('p16', 'Gene', '1029', (10, 13))
567315	31470870	Golestan province has the highest rate of somatic TP53 mutations with at least one mutation in 89.9% of the cases.	('TP53', 'Gene', (50, 54))	('TP53', 'Gene', '7157', (50, 54))	('mutations', 'Var', (55, 64))
567318	31470870	Majority of these missense mutations results in accumulation of mutant p53 protein.	('accumulation', 'PosReg', (48, 60))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('protein', 'Protein', (75, 82))	('missense mutations', 'Var', (18, 36))	('mutant', 'Var', (64, 70))
567329	31470870	Three out of four detected variants included amino acid changes within KCNJ12/KCNJ18 gene.	('KCNJ12', 'Gene', (71, 77))	('KCNJ18', 'Gene', (78, 84))	('KCNJ18', 'Gene', '100134444', (78, 84))	('KCNJ12', 'Gene', '3768', (71, 77))	('amino acid changes', 'Var', (45, 63))	('included', 'Reg', (36, 44))
567336	31470870	It has been shown that there was a correlation between rs10811661 and rs1333049 in CDKN2A/B loci and poor prognosis in Iranian ESCC patients in which the CC genotype carriers had a lower survival rates.	('CDKN2A/B', 'Gene', '1029;1030', (83, 91))	('CDKN2A/B', 'Gene', (83, 91))	('lower', 'NegReg', (181, 186))	('survival rates', 'CPA', (187, 201))	('rs1333049', 'Mutation', 'rs1333049', (70, 79))	('rs10811661', 'Mutation', 'rs10811661', (55, 65))	('rs1333049', 'Var', (70, 79))	('rs10811661', 'Var', (55, 65))	('Iranian ESCC', 'Disease', (119, 131))	('patients', 'Species', '9606', (132, 140))
567337	31470870	Therefore, aberrant NOTCH pathway can be observed in developmental malignancies and cancers.	('NOTCH pathway', 'Pathway', (20, 33))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('developmental malignancies and cancers', 'Disease', 'MESH:D009369', (53, 91))	('aberrant', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('observed', 'Reg', (41, 49))
567345	31470870	MAML1 and TWIST1 over expressions have been reported among a sub population of Iranian ESCC samples in which aberrant expressions of MAML1/TWIST1 were correlated with depth of invasion, node metastasis, and surgical stage.	('depth of invasion', 'CPA', (167, 184))	('aberrant expressions', 'Var', (109, 129))	('over expressions', 'PosReg', (17, 33))	('TWIST1', 'Gene', (10, 16))	('TWIST1', 'Gene', '7291', (10, 16))	('node metastasis', 'CPA', (186, 201))	('MAML1', 'Gene', (133, 138))	('MAML1', 'Gene', '9794', (133, 138))	('TWIST1', 'Gene', (139, 145))	('TWIST1', 'Gene', '7291', (139, 145))	('MAML1', 'Gene', (0, 5))	('MAML1', 'Gene', '9794', (0, 5))	('correlated', 'Reg', (151, 161))
567347	31470870	In another study on Korean ESCC cases, the TWIST1 expression was associated with poor prognosis and EMT in ESCC tissues.	('EMT', 'Gene', (100, 103))	('EMT', 'Gene', '3702', (100, 103))	('expression', 'Var', (50, 60))	('TWIST1', 'Gene', (43, 49))	('TWIST1', 'Gene', '7291', (43, 49))
567348	31470870	Deregulation of WNT signaling pathway is commonly observed in malignancies.	('WNT signaling pathway', 'Pathway', (16, 37))	('malignancies', 'Disease', (62, 74))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('Deregulation', 'Var', (0, 12))
567365	31470870	In contrast, it has been shown that the high SOX2 expression was correlated with negative lymph node metastasis in Taiwanese ESCC cases.	('high', 'Var', (40, 44))	('negative lymph node metastasis', 'CPA', (81, 111))	('Taiwanese ESCC', 'Disease', (115, 129))	('SOX2', 'Gene', '6657', (45, 49))	('expression', 'MPA', (50, 60))	('SOX2', 'Gene', (45, 49))
567402	31470870	Pattern of linc-ROR splice variants (2 to 5) expression were assessed in Iranian ESCC cases, showing an over expression of variants 2 and 4 in tumors compared with normal margins.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('Iranian ESCC', 'Disease', (73, 85))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('linc-ROR', 'Gene', (11, 19))	('over expression', 'PosReg', (104, 119))	('linc-ROR', 'Gene', '100885779', (11, 19))	('variants', 'Var', (123, 131))
567403	31470870	There was also a significant correlation between variant 4 and grade of tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('grade', 'CPA', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('variant', 'Var', (49, 56))
567409	31470870	Germline DNA of 197 Turkmen ESCC cases have been assessed for the BRCA2 mutations.	('BRCA2', 'Gene', (66, 71))	('mutations', 'Var', (72, 81))	('BRCA2', 'Gene', '675', (66, 71))
567417	31470870	However, aberrant CTAs expressions have been reported in a variety of cancers.	('CTAs expressions', 'Protein', (18, 34))	('reported', 'Reg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('aberrant', 'Var', (9, 17))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
567454	30538491	Moreover, expression of DKK1 and CKAP4 was associated with poor prognosis and relapse-free survival.	('poor prognosis', 'CPA', (59, 73))	('CKAP4', 'Gene', (33, 38))	('relapse-free survival', 'CPA', (78, 99))	('DKK1', 'Gene', (24, 28))	('CKAP4', 'Gene', '10970', (33, 38))	('DKK1', 'Gene', '22943', (24, 28))	('associated', 'Reg', (43, 53))	('expression', 'Var', (10, 20))
567459	30538491	Furthermore, the sensitivity of serum CKAP4 was higher than that of other markers for lung cancer.	('CKAP4', 'Gene', '10970', (38, 43))	('sensitivity', 'MPA', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('serum', 'Var', (32, 37))	('lung cancer', 'Disease', (86, 97))	('higher', 'PosReg', (48, 54))	('CKAP4', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
567489	30538491	Recent research has reported that the expression of CKAP4 presented associations with clinical outcome and prognosis of intrahepatic cholangiocarcinoma and hepatocellular carcinoma.	('CKAP4', 'Gene', '10970', (52, 57))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (133, 151))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (156, 180))	('expression', 'Var', (38, 48))	('intrahepatic cholangiocarcinoma and hepatocellular carcinoma', 'Disease', 'MESH:D018281', (120, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('CKAP4', 'Gene', (52, 57))	('associations', 'Reg', (68, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
567575	26396004	However, a recent study investigated the relationship between ghrelin and Barrett's esophagus and found a positive association with high levels of ghrelin, which is difficult to reconcile with the reported relationships between ghrelin and some of the known risk factors for Barrett's esophagus.	('ghrelin', 'Chemical', 'MESH:D054439', (62, 69))	('ghrelin', 'Chemical', 'MESH:D054439', (228, 235))	("Barrett's esophagus", 'Disease', (74, 93))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (74, 93))	("Barrett's esophagus", 'Disease', (275, 294))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (275, 294))	('high', 'Var', (132, 136))	('ghrelin', 'Chemical', 'MESH:D054439', (147, 154))
567587	26396004	The first was a GERD control group of KPNC members who had all of the following characteristics: a GERD-related ICD-9 code (530.11 [reflux esophagitis] or 530.81 [gastroesophageal reflux]); a prescription sufficient for at least 90 days use of H2RB or a PPI within the year previous to the index date; no prior diagnosis of Barrett's esophagus in electronic coding; and an esophagogastroduodenoscopy (EGD) performed in close proximity to the index date that did not show esophageal columnar metaplasia of any type.	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (163, 186))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (324, 343))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (163, 186))	('gastroesophageal reflux', 'Disease', (163, 186))	('esophageal columnar metaplasia', 'Disease', 'MESH:D008679', (471, 501))	('esophageal columnar metaplasia', 'Disease', (471, 501))	('530.11', 'Var', (124, 130))	('esophagitis', 'Phenotype', 'HP:0100633', (139, 150))	('esophagitis', 'Disease', (139, 150))	('esophagitis', 'Disease', 'MESH:D004941', (139, 150))	('530.81', 'Var', (155, 161))
567648	26396004	that ghrelin had both a positive relationship and an inverse relationship with Barrett's esophagus, whereby ghrelin may be associated with a reduced risk of GERD itself, but an increased risk of abnormal healing of mucosal injury into esophageal intestinal metaplasia (i.e., Barrett's esophagus).	('abnormal healing', 'CPA', (195, 211))	('ghrelin', 'Chemical', 'MESH:D054439', (108, 115))	('esophageal intestinal metaplasia', 'Phenotype', 'HP:0012859', (235, 267))	('esophageal intestinal metaplasia', 'Disease', (235, 267))	('ghrelin', 'Var', (108, 115))	('reduced', 'NegReg', (141, 148))	('esophageal intestinal metaplasia', 'Disease', 'MESH:D008679', (235, 267))	('mucosal injury', 'Disease', (215, 229))	('GERD itself', 'Disease', (157, 168))	('mucosal injury', 'Disease', 'MESH:D052016', (215, 229))	('ghrelin', 'Chemical', 'MESH:D054439', (5, 12))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (275, 294))	('increased risk of abnormal healing', 'Phenotype', 'HP:0001058', (177, 211))	("Barrett's esophagus", 'Disease', (79, 98))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (79, 98))
567699	20069112	H. pylori infection may be associated with either increased acid secretion or achlorydria with resultant atrophic gastritis, depending on the species of the bacterium and the inflammatory response induced.	('pylori infection', 'Phenotype', 'HP:0005202', (3, 19))	('H. pylori', 'Disease', (0, 9))	('achlorydria', 'Disease', (78, 89))	('increased', 'PosReg', (50, 59))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (105, 123))	('infection', 'Var', (10, 19))	('acid', 'Disease', (60, 64))	('atrophic gastritis', 'Disease', 'MESH:D005757', (105, 123))	('gastritis', 'Phenotype', 'HP:0005263', (114, 123))	('atrophic gastritis', 'Disease', (105, 123))
567727	20069112	Putative mechanisms for failure of PPI treatment include compliance, improper dosing time, weakly acidic reflux, DGER, delayed gastric emptying, esophageal hypersensitivity, eosinophilic esophagitis nocturnal reflux, residual acid reflux reduced PPI bioavailability, and psychological comorbidity.	('DGER', 'Disease', (113, 117))	('residual acid reflux', 'MPA', (217, 237))	('hypersensitivity,', 'Disease', 'MESH:D004342', (156, 173))	('acidic reflux', 'Phenotype', 'HP:0002020', (98, 111))	('eosinophilic esophagitis nocturnal reflux', 'Disease', 'MESH:D004802', (174, 215))	('improper', 'Var', (69, 77))	('reduced', 'NegReg', (238, 245))	('hypersensitivity', 'Disease', (156, 172))	('hypersensitivity', 'Disease', 'MESH:D004342', (156, 172))	('eosinophilic esophagitis nocturnal reflux', 'Disease', (174, 215))	('PPI bioavailability', 'MPA', (246, 265))	('esophagitis', 'Phenotype', 'HP:0100633', (187, 198))	('eosinophilic esophagitis', 'Phenotype', 'HP:0410151', (174, 198))	('delayed gastric emptying', 'MPA', (119, 143))	('gastric emptying', 'Phenotype', 'HP:0002578', (127, 143))	('nocturnal reflux', 'Phenotype', 'HP:0002020', (199, 215))	('weakly acidic reflux', 'MPA', (91, 111))	('acid reflux', 'Phenotype', 'HP:0002020', (226, 237))
567903	31409002	During clonal evolution, only a few "jackpot" mutations that activate oncogenic pathways and/or inactivate tumor suppressors are selectively advantageous, allowing the mutant clones to achieve selective sweeps.	('activate', 'PosReg', (61, 69))	('mutant', 'Var', (168, 174))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('oncogenic pathways', 'Pathway', (70, 88))	('inactivate', 'NegReg', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
567904	31409002	These mutations are so-called "passengers" and are mainly responsible for intratumor heterogeneity.	('tumor', 'Disease', (79, 84))	('responsible', 'Reg', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mutations', 'Var', (6, 15))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
567906	31409002	Moreover, given the fact that the Darwinian selection is context-specific, and the evolutionary dynamics of tumor microenvironment and epigenomic events could translate into heterogeneous selective pressures experienced by tumor cells, the selective effect of given mutations (either driver or passenger) can change substantially at different stages of tumor progression.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (353, 358))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (266, 275))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))
567909	31409002	proposed that approximately 40% of driver mutations were spatially heterogeneous, including oncogenes such as KIT, and members of the PI3K/MTOR (PIK3CA and MTOR) and NFE2L2 pathways (NFE2L2 and KEAP1).	('NFE2L2', 'Gene', (166, 172))	('NFE2L2', 'Gene', (183, 189))	('MTOR', 'Gene', (139, 143))	('MTOR', 'Gene', (156, 160))	('MTOR', 'Gene', '2475', (156, 160))	('KEAP1', 'Gene', '9817', (194, 199))	('NFE2L2', 'Gene', '4780', (183, 189))	('MTOR', 'Gene', '2475', (139, 143))	('PIK3CA', 'Gene', (145, 151))	('NFE2L2', 'Gene', '4780', (166, 172))	('KEAP1', 'Gene', (194, 199))	('PIK3CA', 'Gene', '5290', (145, 151))	('mutations', 'Var', (42, 51))
567910	31409002	In addition, significant spatial heterogeneity was observed in copy number alterations, including EGFR amplification and CDKN2A/B deletions.	('EGFR', 'Gene', (98, 102))	('CDKN2A/B', 'Gene', '1029;1030', (121, 129))	('deletions', 'Var', (130, 139))	('CDKN2A/B', 'Gene', (121, 129))	('EGFR', 'Gene', '1956', (98, 102))	('amplification', 'Var', (103, 116))
567921	31409002	Lung cancers initially containing rare mutations of EGFR, e.g., T790M, or low frequency of MET amplification, are capable of rendering resistance to targeted therapy.	('e.g.', 'Var', (58, 62))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('Lung cancers', 'Disease', 'MESH:D008175', (0, 12))	('T790M', 'Mutation', 'rs121434569', (64, 69))	('T790M', 'Var', (64, 69))	('Lung cancers', 'Phenotype', 'HP:0100526', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancers', 'Disease', (0, 12))	('resistance', 'MPA', (135, 145))
567922	31409002	Another well-understood case is chronic myeloid leukemia, in which mutant forms of the BCR-ABL fusion protein have been implicated in the relapse of disease under imatinib treatment.	('myeloid leukemia', 'Disease', 'MESH:D007951', (40, 56))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (32, 56))	('imatinib', 'Chemical', 'MESH:D000068877', (163, 171))	('implicated', 'Reg', (120, 130))	('leukemia', 'Phenotype', 'HP:0001909', (48, 56))	('myeloid leukemia', 'Disease', (40, 56))	('mutant', 'Var', (67, 73))	('BCR-ABL', 'Gene', '25', (87, 94))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (40, 56))	('BCR-ABL', 'Gene', (87, 94))
567925	31409002	In addition to genomic alterations, epigenomic dysregulation also contributes to spatial diversity within a tumor.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('contributes', 'Reg', (66, 77))	('tumor', 'Disease', (108, 113))	('epigenomic dysregulation', 'Var', (36, 60))	('spatial', 'MPA', (81, 88))
567926	31409002	These alterations potentially provide fitness benefit, leading to intratumor heterogeneity either independently or in conjunction with genomic alterations.	('alterations', 'Var', (6, 17))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('leading to', 'Reg', (55, 65))
567928	31409002	Dynamic changes of mutational status and promoter DNA methylation were also observed in the SWI/SNF chromatin remodeling complex and were shown to involve in ESCC carcinogenesis.	('promoter', 'MPA', (41, 49))	('ESCC carcinogenesis', 'Disease', (158, 177))	('mutational', 'Var', (19, 29))	('changes', 'Reg', (8, 15))	('involve', 'Reg', (147, 154))	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (158, 177))	('SWI/SNF', 'Gene', (92, 99))
567933	31409002	observed a tight association between genomic heterogeneity and variation of T cell repertoire in ESCC primary tumors.	('primary tumor', 'Disease', 'MESH:D009369', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('variation', 'Var', (63, 72))	('tumors', 'Disease', (110, 116))	('T cell repertoire', 'Protein', (76, 93))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('primary tumor', 'Disease', (102, 115))
567941	31409002	Importantly, the majority of driver mutations in tumor suppressors (including TP53, KMT2D, ZNF750, etc.)	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('KMT2D', 'Gene', (84, 89))	('KMT2D', 'Gene', '8085', (84, 89))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (49, 54))	('ZNF750', 'Gene', '79755', (91, 97))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('ZNF750', 'Gene', (91, 97))
567943	31409002	In contrast, half of the driver mutations in the branches were in oncogenes, including potential actionable targets, PIK3CA and MTOR, suggesting that they are late events in ESCC.	('MTOR', 'Gene', '2475', (128, 132))	('ESCC', 'Disease', (174, 178))	('PIK3CA', 'Gene', (117, 123))	('mutations', 'Var', (32, 41))	('PIK3CA', 'Gene', '5290', (117, 123))	('MTOR', 'Gene', (128, 132))
567948	31409002	also reported early emergence of copy number alterations in precursor lesions of ESCC and highlighted this phenomenon as a prominent genomic feature distinct from the development of esophageal adenocarcinoma, another pathological subtype of esophageal cancer.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (182, 207))	('esophageal cancer', 'Disease', (241, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('ESCC', 'Disease', (81, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (241, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('esophageal adenocarcinoma', 'Disease', (182, 207))	('copy number alterations', 'Var', (33, 56))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (182, 207))
567969	31409002	Specific driver and passenger mutations could be introduced by the CRISPR-Cas9 genome-editing system with the resultant organoids valuable for dissecting tumor progression mechanisms.	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
567982	31409002	Current promising therapeutics include targeting epigenetic modifications of cancer cells (e.g., histone deacetylase inhibitors), modulating the tumor microenvironment (e.g., anti-angiogenic therapy, immune therapy), as well as multiplex-targeted therapy and adaptive therapy.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('epigenetic modifications', 'Var', (49, 73))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('histone deacetylase inhibitors', 'Protein', (97, 127))	('modulating', 'Reg', (130, 140))
567995	30626422	Knocking down endogenous IGFBP2 in FLO1 cells (with constitutive high levels of IGFBP2) led to a significant increase in DNA double-strand breaks and apoptosis, following transient exposure to ABS.	('DNA double-strand breaks', 'MPA', (121, 145))	('IGFBP2', 'Gene', (80, 86))	('IGFBP2', 'Gene', '3485', (80, 86))	('Knocking down', 'Var', (0, 13))	('apoptosis', 'CPA', (150, 159))	('increase', 'PosReg', (109, 117))	('IGFBP2', 'Gene', '3485', (25, 31))	('IGFBP2', 'Gene', (25, 31))
568009	30626422	Phosphorylation at Thr2609 of DNA-PKcs plays a key role in NHEJ.	('role', 'Reg', (51, 55))	('NHEJ', 'Disease', (59, 63))	('Phosphorylation', 'Var', (0, 15))	('DNA-PKcs', 'Gene', '5591', (30, 38))	('Thr2609', 'Chemical', '-', (19, 26))	('DNA-PKcs', 'Gene', (30, 38))
568037	30626422	The primer sequences for EGFR are CCAGTATTGATCGGGAGAGC (forward) and TGCCTTGGCAAACTTTCTTT (reverse).	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', (25, 29))	('TGCCTTGGCAAACTTTCTTT', 'Var', (69, 89))
568054	30626422	FLO1 cells with IGFBP2 knockdown and control cells were treated with or without ABS for 20 min and then recovered in full medium with 50 mug/ml CHX.	('IGFBP2', 'Gene', (16, 22))	('CHX', 'Chemical', 'MESH:D003513', (144, 147))	('knockdown', 'Var', (23, 32))	('IGFBP2', 'Gene', '3485', (16, 22))
568075	30626422	Data shows that IGFBP2 levels were clearly enhanced by ABS in both FLO1 (Fig.	('FLO1', 'Gene', (67, 71))	('enhanced', 'PosReg', (43, 51))	('IGFBP2', 'Gene', '3485', (16, 22))	('IGFBP2', 'Gene', (16, 22))	('ABS', 'Var', (55, 58))
568081	30626422	3b, ABS induced higher levels of gammaH2AX, cleaved-PARP and cleaved-caspase 3 in IGFBP2 knockdown cells, as compared with the control cells.	('higher', 'PosReg', (16, 22))	('gammaH2AX', 'Chemical', '-', (33, 42))	('PARP', 'Gene', '1302', (52, 56))	('cleaved-caspase 3', 'MPA', (61, 78))	('PARP', 'Gene', (52, 56))	('levels', 'MPA', (23, 29))	('IGFBP2', 'Gene', '3485', (82, 88))	('knockdown', 'Var', (89, 98))	('gammaH2AX', 'MPA', (33, 42))	('IGFBP2', 'Gene', (82, 88))
568084	30626422	We also performed flow cytometry analyses of annexin V, confirming that knockdown of IGFBP2 significantly promoted ABS-induced apoptotic cell death in FLO1 cells (Fig.	('annexin V', 'Gene', '308', (45, 54))	('promoted', 'PosReg', (106, 114))	('annexin V', 'Gene', (45, 54))	('IGFBP2', 'Gene', '3485', (85, 91))	('IGFBP2', 'Gene', (85, 91))	('knockdown', 'Var', (72, 81))
568085	30626422	To determine whether EGFR-DNA-PKcs pathway is involved in ABS-induced DNA damage repair, we examined the levels of phosphorylated EGFR (Tyr1068) and phosphorylated DNA-PKcs (Thr2609), which are representatives of enzymatic activity of EGFR and DNA-PKcs, respectively.	('EGFR', 'Gene', '1956', (21, 25))	('DNA-PKcs', 'Gene', (244, 252))	('EGFR', 'Gene', (21, 25))	('DNA-PKcs', 'Gene', (164, 172))	('Tyr1068', 'Chemical', '-', (136, 143))	('DNA-PKcs', 'Gene', (26, 34))	('DNA-PKcs', 'Gene', '5591', (26, 34))	('EGFR', 'Gene', '1956', (235, 239))	('EGFR', 'Gene', (235, 239))	('DNA-PKcs', 'Gene', '5591', (164, 172))	('DNA-PKcs', 'Gene', '5591', (244, 252))	('Tyr1068', 'Var', (136, 143))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('Thr2609', 'Chemical', '-', (174, 181))
568086	30626422	Our data showed that phosphorylation of EGFR (Tyr1068) and DNA-PKcs (Thr2609) was markedly induced by ABS in FLO1 and OE33 cells (Additional file 2: Figure S8).	('DNA-PKcs', 'Gene', '5591', (59, 67))	('Tyr1068', 'Chemical', '-', (46, 53))	('Thr2609', 'Var', (69, 76))	('phosphorylation', 'MPA', (21, 36))	('Thr2609', 'Chemical', '-', (69, 76))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('Tyr1068', 'Var', (46, 53))	('induced', 'PosReg', (91, 98))	('DNA-PKcs', 'Gene', (59, 67))
568087	30626422	To determine the role of IGFBP2 in regulating the EGFR-DNA-PKcs DNA damage repair pathways, we knocked down IGFBP2 in FLO1 cells and exposed cells to ABS.	('DNA-PKcs', 'Gene', (55, 63))	('IGFBP2', 'Gene', '3485', (108, 114))	('IGFBP2', 'Gene', (108, 114))	('knocked', 'Var', (95, 102))	('EGFR', 'Gene', '1956', (50, 54))	('IGFBP2', 'Gene', '3485', (25, 31))	('EGFR', 'Gene', (50, 54))	('DNA-PKcs', 'Gene', '5591', (55, 63))	('IGFBP2', 'Gene', (25, 31))
568088	30626422	4a, knockdown of IGFBP2 attenuated ABS-induced phosphorylation of EGFR and DNA-PKcs, indicating reduced DNA repair activity of DNA-PKcs.	('attenuated', 'NegReg', (24, 34))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('phosphorylation', 'MPA', (47, 62))	('DNA-PKcs', 'Gene', '5591', (127, 135))	('DNA-PKcs', 'Gene', '5591', (75, 83))	('DNA-PKcs', 'Gene', (75, 83))	('IGFBP2', 'Gene', '3485', (17, 23))	('IGFBP2', 'Gene', (17, 23))	('DNA repair activity', 'MPA', (104, 123))	('knockdown', 'Var', (4, 13))	('DNA-PKcs', 'Gene', (127, 135))	('reduced', 'NegReg', (96, 103))
568091	30626422	Immunofluorescence staining assay further confirmed a decrease in nuclear phospho-DNA-PKcs, following ABS exposure in IGFBP2 knockdown FLO1 cells, as compared to control cells (Fig.	('decrease', 'NegReg', (54, 62))	('knockdown', 'Var', (125, 134))	('IGFBP2', 'Gene', '3485', (118, 124))	('IGFBP2', 'Gene', (118, 124))	('nuclear', 'MPA', (66, 73))	('DNA-PKcs', 'Gene', '5591', (82, 90))	('DNA-PKcs', 'Gene', (82, 90))
568097	30626422	To find whether IGFBP2 mediates EGFR nuclear translocation and, thus, activates DNA-PKcs, we knocked down IGFBP2 in FLO1 cells and treated cells with ABS.	('DNA-PKcs', 'Gene', '5591', (80, 88))	('activates', 'PosReg', (70, 79))	('IGFBP2', 'Gene', '3485', (16, 22))	('EGFR', 'Gene', '1956', (32, 36))	('DNA-PKcs', 'Gene', (80, 88))	('IGFBP2', 'Gene', (16, 22))	('EGFR', 'Gene', (32, 36))	('IGFBP2', 'Gene', '3485', (106, 112))	('IGFBP2', 'Gene', (106, 112))	('knocked', 'Var', (93, 100))
568098	30626422	5b, IGFBP2 knockdown attenuated ABS-induced nuclear accumulation of total and phospho-EGFR and DNA-PKcs.	('IGFBP2', 'Gene', (4, 10))	('attenuated', 'NegReg', (21, 31))	('DNA-PKcs', 'Gene', '5591', (95, 103))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', (86, 90))	('nuclear accumulation', 'MPA', (44, 64))	('DNA-PKcs', 'Gene', (95, 103))	('IGFBP2', 'Gene', '3485', (4, 10))	('knockdown', 'Var', (11, 20))
568100	30626422	Nuclear EGFR was hardly visible, following knockdown of IGFBP2.	('IGFBP2', 'Gene', (56, 62))	('knockdown', 'Var', (43, 52))	('EGFR', 'Gene', '1956', (8, 12))	('EGFR', 'Gene', (8, 12))	('IGFBP2', 'Gene', '3485', (56, 62))
568111	30626422	To prove that IGFBP2 is required for the interaction between EGFR and DNA-PKcs, under ABS exposure conditions, we repeated co-IP for EGFR, following IGFBP2 knockdown and ABS treatment.	('IGFBP2', 'Gene', '3485', (149, 155))	('DNA-PKcs', 'Gene', '5591', (70, 78))	('knockdown', 'Var', (156, 165))	('IGFBP2', 'Gene', (14, 20))	('IGFBP2', 'Gene', (149, 155))	('DNA-PKcs', 'Gene', (70, 78))	('IGFBP2', 'Gene', '3485', (14, 20))	('EGFR', 'Gene', '1956', (133, 137))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (133, 137))	('EGFR', 'Gene', (61, 65))
568112	30626422	6c, IGFBP2 knockdown in FLO1 cells led to a remarkable reduction in the interaction between EGFR and DNA-PKcs, as compared with control cells.	('IGFBP2', 'Gene', (4, 10))	('DNA-PKcs', 'Gene', '5591', (101, 109))	('reduction', 'NegReg', (55, 64))	('interaction', 'Interaction', (72, 83))	('DNA-PKcs', 'Gene', (101, 109))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('IGFBP2', 'Gene', '3485', (4, 10))	('knockdown', 'Var', (11, 20))
568113	30626422	Because we observed that ABS induced a significant upregulation of EGFR protein, whereas the EGFR induction was impaired in cells with IGFBP2 knockdown (Fig.	('upregulation', 'PosReg', (51, 63))	('IGFBP2', 'Gene', '3485', (135, 141))	('EGFR', 'Gene', '1956', (93, 97))	('IGFBP2', 'Gene', (135, 141))	('EGFR', 'Gene', (93, 97))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('knockdown', 'Var', (142, 151))
568114	30626422	4), we examined mRNA levels of EGFR in control and IGFBP2 knockdown FLO1 cells.	('EGFR', 'Gene', '1956', (31, 35))	('IGFBP2', 'Gene', (51, 57))	('EGFR', 'Gene', (31, 35))	('knockdown', 'Var', (58, 67))	('IGFBP2', 'Gene', '3485', (51, 57))
568115	30626422	Knockdown of IGFBP2 did not affect mRNA levels of EGFR without or with ABS treatment (Additional file 2: Figure S10).	('mRNA levels', 'MPA', (35, 46))	('Knockdown', 'Var', (0, 9))	('S1', 'CellLine', 'CVCL:Z231', (112, 114))	('EGFR', 'Gene', '1956', (50, 54))	('IGFBP2', 'Gene', '3485', (13, 19))	('EGFR', 'Gene', (50, 54))	('IGFBP2', 'Gene', (13, 19))
568117	30626422	To confirm this, FLO1 cells with IGFBP2 knockdown and control cells were treated with or without ABS, and then recovered in full medium with cycloheximide (CHX, 50 mug/ml) for 0, 1, 24 and 48 h to block protein synthesis.	('CHX', 'Chemical', 'MESH:D003513', (156, 159))	('cycloheximide', 'Chemical', 'MESH:D003513', (141, 154))	('IGFBP2', 'Gene', '3485', (33, 39))	('knockdown', 'Var', (40, 49))	('IGFBP2', 'Gene', (33, 39))	('protein synthesis', 'MPA', (203, 220))
568139	30626422	We found that phosphorylation of DNA-PKcs at Thr2609, following ABS, was regulated by levels of IGFBP2.	('IGFBP2', 'Gene', (96, 102))	('Thr2609', 'Var', (45, 52))	('Thr2609', 'Chemical', '-', (45, 52))	('DNA-PKcs', 'Gene', '5591', (33, 41))	('DNA-PKcs', 'Gene', (33, 41))	('phosphorylation', 'MPA', (14, 29))	('IGFBP2', 'Gene', '3485', (96, 102))	('regulated', 'Reg', (73, 82))
568155	30626422	A number of experimental DNA-PK inhibitors, such as NU7026, are also under investigation for various cancers.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('DNA-PK', 'Gene', (25, 31))	('cancers', 'Disease', (101, 108))	('NU7026', 'Var', (52, 58))	('DNA-PK', 'Gene', '5591', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('NU7026', 'Chemical', 'MESH:C479235', (52, 58))
568168	29029460	Silencing c-MYC abolished the c-Jun-mediated CDDP resistance of ESCC cells.	('c-Jun', 'Gene', '3725', (30, 35))	('c-MYC', 'Gene', '4609', (10, 15))	('c-Jun', 'Gene', (30, 35))	('Silencing', 'Var', (0, 9))	('CDDP', 'Chemical', '-', (45, 49))	('c-MYC', 'Gene', (10, 15))	('abolished', 'NegReg', (16, 25))
568178	29029460	In addition, VRK1 promotes the formation of 53BP1 foci in response to ionizing radiation-induced DNA damage and participates in the DNA damage response (DDR) by phosphorylating H2AX and NBS1.	('53BP1', 'Gene', (44, 49))	('53BP1', 'Gene', '7158', (44, 49))	('H2AX', 'Gene', '3014', (177, 181))	('phosphorylating', 'Var', (161, 176))	('participates', 'Reg', (112, 124))	('response to ionizing radiation-induced DNA damage', 'MPA', (58, 107))	('NBS1', 'Gene', '4683', (186, 190))	('promotes', 'PosReg', (18, 26))	('H2AX', 'Gene', (177, 181))	('NBS1', 'Gene', (186, 190))	('VRK1', 'Gene', (13, 17))
568181	29029460	In breast cancer, VRK1 depletion can inhibit cancer cell proliferation in vitro as well as growth and metastasis in vivo.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('depletion', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('inhibit', 'NegReg', (37, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('VRK1', 'Protein', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', (10, 16))
568184	29029460	In cells, c-Jun phosphorylation is rapidly and transiently induced by numerous extracellular stress stimuli, which are mediated and relayed by mitogen-activated protein kinases (MAPKs), such as ERK1/2, p38K and c-Jun N-terminal kinase (JNK).	('c-Jun', 'Gene', '3725', (211, 216))	('JNK', 'Gene', (236, 239))	('p38K', 'Var', (202, 206))	('JNK', 'Gene', '5599', (236, 239))	('c-Jun', 'Gene', '3725', (10, 15))	('ERK1/2', 'Gene', (194, 200))	('c-Jun', 'Gene', (211, 216))	('ERK1/2', 'Gene', '5595;5594', (194, 200))	('c-Jun', 'Gene', (10, 15))
568187	29029460	Thus, aberrant VRK1 expression might induce constitutive c-Jun activity independent of extracellular stress or upstream signals and eventually contribute to oncogenesis.	('c-Jun', 'Gene', '3725', (57, 62))	('aberrant', 'Var', (6, 14))	('oncogenesis', 'CPA', (157, 168))	('contribute', 'Reg', (143, 153))	('c-Jun', 'Gene', (57, 62))	('VRK1', 'Gene', (15, 19))	('induce', 'PosReg', (37, 43))
568195	29029460	Consistent with this observation, statistical analysis revealed that aberrant VRK1 protein levels were significantly correlated with the depth of invasion, lymphatic involvement and TNM stage (Table 1).	('TNM', 'Gene', (182, 185))	('aberrant', 'Var', (69, 77))	('lymphatic involvement', 'CPA', (156, 177))	('VRK1 protein', 'Protein', (78, 90))	('depth of invasion', 'CPA', (137, 154))	('correlated', 'Reg', (117, 127))	('TNM', 'Gene', '10178', (182, 185))
568196	29029460	Furthermore, Kaplan-Meier and log-rank analyses indicated that patients with high levels of VRK1 expression (SI >= 8) had worse overall survival (OS) or disease-free survival (DFS) than patients with low levels of VRK1 (SI < 8) expression (Figure 1G, 1H).	('worse', 'NegReg', (122, 127))	('overall survival', 'CPA', (128, 144))	('VRK1', 'Gene', (92, 96))	('OS', 'Chemical', '-', (146, 148))	('SI', 'Disease', 'None', (220, 222))	('patients', 'Species', '9606', (63, 71))	('disease-free survival', 'CPA', (153, 174))	('high levels', 'Var', (77, 88))	('SI', 'Disease', 'None', (109, 111))	('expression', 'MPA', (97, 107))	('patients', 'Species', '9606', (186, 194))
568200	29029460	In contrast, ectopic expression of VRK1 in Ec9706 cells led to a significant increase in cell proliferation (Figure 2B, Supplementary Figure 1) and colony formation (Figure 2C).	('cell proliferation', 'CPA', (89, 107))	('Ec9706', 'CellLine', 'CVCL:E307', (43, 49))	('VRK1', 'Gene', (35, 39))	('increase', 'PosReg', (77, 85))	('ectopic expression', 'Var', (13, 31))	('colony formation', 'CPA', (148, 164))
568204	29029460	Because VRK1 can enhance the proliferative and anti-apoptotic abilities of ESCC, we assessed the association between VRK1 expression and CDDP resistance in ESCC cells.	('CDDP', 'Chemical', '-', (137, 141))	('enhance', 'PosReg', (17, 24))	('VRK1', 'Var', (8, 12))	('anti-apoptotic abilities', 'CPA', (47, 71))
568206	29029460	Conversely, knockdown of endogenous VRK1 markedly sensitized Eca109 and Kyse150 cells to CDDP (Figure 3A, Supplementary Figure 2A).	('knockdown', 'Var', (12, 21))	('endogenous', 'Var', (25, 35))	('VRK1', 'Gene', (36, 40))	('CDDP', 'Chemical', '-', (89, 93))	('sensitized', 'Reg', (50, 60))
568207	29029460	Concordantly, overexpression of VRK1 inhibited ESCC cell apoptosis in response to CDDP, whereas silencing VRK1 promoted apoptosis (Figure 3B).	('VRK1', 'Gene', (106, 110))	('silencing', 'Var', (96, 105))	('inhibited', 'NegReg', (37, 46))	('response to CDDP', 'MPA', (70, 86))	('ESCC', 'Disease', (47, 51))	('VRK1', 'Gene', (32, 36))	('CDDP', 'Chemical', '-', (82, 86))	('overexpression', 'PosReg', (14, 28))	('promoted', 'PosReg', (111, 119))
568208	29029460	In parallel with the observed VRK1-mediated CDDP resistance in vitro, a xenograft model showed that tumors formed by OEVRK1-Ec9706 cells were larger than those formed by Blank-Ec9706 cells in both the normal saline (NS) and CDDP administration groups.	('Ec9706', 'CellLine', 'CVCL:E307', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Ec9706', 'CellLine', 'CVCL:E307', (124, 130))	('OEVRK1-Ec9706', 'Var', (117, 130))	('larger', 'PosReg', (142, 148))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('CDDP', 'Chemical', '-', (44, 48))	('CDDP', 'Chemical', '-', (224, 228))	('OEVRK1-Ec9706', 'CellLine', 'CVCL:E307', (117, 130))
568209	29029460	In contrast, tumors formed by shVRK1-Ec9706 cells exhibited a smaller size and lower mass than control tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mass', 'MPA', (85, 89))	('shVRK1-Ec9706', 'Var', (30, 43))	('tumors', 'Disease', (13, 19))	('smaller', 'NegReg', (62, 69))	('Ec9706', 'CellLine', 'CVCL:E307', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('lower', 'NegReg', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
568214	29029460	A previous study showed that c-Jun could be phosphorylated by VRK1 at Ser63 and Ser73.	('c-Jun', 'Gene', '3725', (29, 34))	('VRK1', 'Gene', (62, 66))	('Ser73', 'Chemical', '-', (80, 85))	('c-Jun', 'Gene', (29, 34))	('Ser73', 'Var', (80, 85))	('Ser63', 'Chemical', '-', (70, 75))	('phosphorylated', 'MPA', (44, 58))	('Ser63', 'Var', (70, 75))
568217	29029460	As predicted, silencing c-Jun in Eca109 and Kyse150 cells sensitized these cells to CDDP, decreased cell proliferation (Figure 4C, Supplementary Figure 3) and promoted cell apoptosis (Figure 4B).	('silencing', 'Var', (14, 23))	('sensitized', 'Reg', (58, 68))	('CDDP', 'Chemical', '-', (84, 88))	('decreased', 'NegReg', (90, 99))	('c-Jun', 'Gene', '3725', (24, 29))	('cell proliferation', 'CPA', (100, 118))	('cell apoptosis', 'CPA', (168, 182))	('promoted', 'PosReg', (159, 167))	('c-Jun', 'Gene', (24, 29))
568223	29029460	Among these molecules, the protein levels of c-MYC were the most reduced in Eca109 and Kyse150 cells with c-Jun knockdown.	('c-Jun', 'Gene', '3725', (106, 111))	('reduced', 'NegReg', (65, 72))	('c-MYC', 'Gene', (45, 50))	('knockdown', 'Var', (112, 121))	('c-MYC', 'Gene', '4609', (45, 50))	('c-Jun', 'Gene', (106, 111))
568225	29029460	Moreover, down-regulation of c-MYC was observed in Eca109 and Kyse150 cells with stable VRK1 knockdown, confirming that VRK1 could regulate c-MYC levels by activating c-Jun (Figure 5B).	('knockdown', 'Var', (93, 102))	('VRK1', 'Gene', (120, 124))	('c-Jun', 'Gene', '3725', (167, 172))	('c-MYC', 'Gene', '4609', (140, 145))	('c-MYC', 'Gene', '4609', (29, 34))	('c-MYC', 'Gene', (29, 34))	('c-Jun', 'Gene', (167, 172))	('activating', 'PosReg', (156, 166))	('c-MYC', 'Gene', (140, 145))	('regulate', 'Reg', (131, 139))
568227	29029460	As shown in Figure 5D, knockdown of c-Jun inhibited the luciferase activity of the c-MYC promoter in ESCC cells, indicating that c-Jun regulated the expression of c-MYC at the transcriptional level.	('c-Jun', 'Gene', '3725', (129, 134))	('c-Jun', 'Gene', '3725', (36, 41))	('c-MYC', 'Gene', (83, 88))	('knockdown', 'Var', (23, 32))	('c-Jun', 'Gene', (129, 134))	('c-MYC', 'Gene', (163, 168))	('c-MYC', 'Gene', '4609', (83, 88))	('inhibited', 'NegReg', (42, 51))	('activity', 'MPA', (67, 75))	('c-Jun', 'Gene', (36, 41))	('luciferase', 'Enzyme', (56, 66))	('c-MYC', 'Gene', '4609', (163, 168))
568229	29029460	The results showed that knockdown of c-MYC significantly sensitized Eca109 and Kyse150 ESCC cells to CDDP (Figure 5E, 5F, and Supplementary Figure 4), while Ec9706 cells with constitutive c-MYC overexpression exhibited significantly superior cell viability (Supplementary Figure 5E and Supplementary Figure 4) and less apoptosis (Figure 5F) after CDDP treatment.	('c-MYC', 'Gene', '4609', (37, 42))	('CDDP', 'Chemical', '-', (347, 351))	('c-MYC', 'Gene', (188, 193))	('CDDP', 'Chemical', '-', (101, 105))	('c-MYC', 'Gene', (37, 42))	('apoptosis', 'CPA', (319, 328))	('c-MYC', 'Gene', '4609', (188, 193))	('Ec9706', 'CellLine', 'CVCL:E307', (157, 163))	('cell viability', 'CPA', (242, 256))	('sensitized', 'Reg', (57, 67))	('knockdown', 'Var', (24, 33))	('superior', 'PosReg', (233, 241))
568230	29029460	In addition, silencing c-MYC strongly blocked c-Jun-enhanced CDDP resistance in Eca109 and Kyse150 cells (Figure 5G, 5H).	('c-MYC', 'Gene', '4609', (23, 28))	('c-Jun', 'Gene', (46, 51))	('c-MYC', 'Gene', (23, 28))	('CDDP resistance', 'MPA', (61, 76))	('CDDP', 'Chemical', '-', (61, 65))	('c-Jun', 'Gene', '3725', (46, 51))	('blocked', 'NegReg', (38, 45))	('silencing', 'Var', (13, 22))
568233	29029460	Thus, we examined whether luteolin could simulate the anticancer effect of VRK1 depletion in ESCC.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('luteolin', 'Chemical', 'MESH:D047311', (26, 34))	('VRK1', 'Protein', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('ESCC', 'Disease', (93, 97))	('depletion', 'Var', (80, 89))
568255	29029460	Consistent with this, in a xenograft mouse model, overexpression of VRK1 enhanced ESCC tumorigenicity, whereas knockdown of VRK1 reduced this activity.	('knockdown', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('overexpression', 'PosReg', (50, 64))	('ESCC', 'Disease', (82, 86))	('tumor', 'Disease', (87, 92))	('mouse', 'Species', '10090', (37, 42))	('enhanced', 'PosReg', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('VRK1', 'Gene', (68, 72))
568259	29029460	In support of our hypothesis, VRK1 inhibition sensitized ESCC cells to CDDP both in vitro and in vivo; conversely, reconstituting VRK1 made cells refractory to CDDP in vitro and in vivo.	('CDDP', 'Chemical', '-', (160, 164))	('CDDP', 'Chemical', '-', (71, 75))	('reconstituting', 'Var', (115, 129))	('VRK1', 'Gene', (130, 134))
568271	29029460	In our experiments, we confirmed that c-MYC was regulated by c-Jun at the transcriptional level and that inhibition of c-Jun led to a dramatic reduction in c-MYC at the mRNA and protein level.	('c-Jun', 'Gene', '3725', (61, 66))	('inhibition', 'Var', (105, 115))	('c-MYC', 'Gene', '4609', (156, 161))	('c-Jun', 'Gene', '3725', (119, 124))	('c-MYC', 'Gene', '4609', (38, 43))	('c-Jun', 'Gene', (61, 66))	('c-MYC', 'Gene', (156, 161))	('reduction', 'NegReg', (143, 152))	('c-Jun', 'Gene', (119, 124))	('c-MYC', 'Gene', (38, 43))
568276	29029460	Here, we used luteolin, a VRK1inhibitor, to mimic the inhibitory effect of VRK1 knockdown in both in vitro and in vivo assays.	('VRK1', 'Gene', (75, 79))	('knockdown', 'Var', (80, 89))	('luteolin', 'Chemical', 'MESH:D047311', (14, 22))
568278	29029460	Taken together, we suggest that some undefined stress in the nucleus causes the levels of nuclear c-Jun to increase and that c-Jun is phosphorylated by aberrant VRK1 overexpression to become transcriptionally active.	('c-Jun', 'Gene', (125, 130))	('c-Jun', 'Gene', '3725', (98, 103))	('increase', 'PosReg', (107, 115))	('VRK1', 'Protein', (161, 165))	('aberrant', 'Var', (152, 160))	('c-Jun', 'Gene', (98, 103))	('c-Jun', 'Gene', '3725', (125, 130))	('overexpression', 'PosReg', (166, 180))
568296	29029460	The human esophageal squamous carcinoma cell lines Eca109, Kyse150, Kyse410, Kyse450, TE-1, and EC9706 and the normal esophageal epithelial cell line Het-1a, and HECC were purchased from Chinese Academy of Science cell bank (Shanghai, China).	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (10, 39))	('human', 'Species', '9606', (4, 9))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (10, 39))	('esophageal squamous carcinoma', 'Disease', (10, 39))	('Kyse410', 'Var', (68, 75))	('Kyse450', 'Var', (77, 84))	('EC9706', 'CellLine', 'CVCL:E307', (96, 102))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (21, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))
568333	29029460	To control the variation in cell proliferation after VRK1 alteration, Nocodazole was added to arrest cell cycle in M-phase.	('Nocodazole', 'Chemical', 'MESH:D015739', (70, 80))	('VRK1', 'Gene', (53, 57))	('cell cycle', 'CPA', (101, 111))	('alteration', 'Var', (58, 68))
568511	27558656	In our case, tumor cells at the gastroesophageal junction and rectum had positivity for CK7, supporting the primary gastric site.	('tumor', 'Disease', (13, 18))	('CK7', 'Gene', (88, 91))	('positivity', 'Var', (73, 83))	('CK7', 'Gene', '3855', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
568530	27082574	Patients who drink alcohol, chew betel nut, smoke cigarettes and have a prior history of head and neck squamous cell carcinoma have been reported to be predisposed to developing ESCNs.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (98, 126))	('nut', 'Gene', '256646', (39, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('alcohol', 'Chemical', 'MESH:D000438', (19, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('chew', 'Var', (28, 32))	('developing ESCNs', 'Disease', (167, 183))	('nut', 'Gene', (39, 42))	('Patients', 'Species', '9606', (0, 8))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (89, 126))	('neck squamous cell carcinoma', 'Disease', (98, 126))
568584	27082574	We thus tried to analyze the risk factors for the development of circumferential lesions by logistic regression analysis, and found that alcohol drinking tended to be associated with circumferential neoplasias with borderline statistical significance (odds ratio: 4.81; P = 0.15).	('neoplasia', 'Phenotype', 'HP:0002664', (199, 208))	('neoplasias', 'Disease', 'MESH:D009369', (199, 209))	('neoplasias', 'Phenotype', 'HP:0002664', (199, 209))	('alcohol drinking', 'Phenotype', 'HP:0030955', (137, 153))	('alcohol', 'Chemical', 'MESH:D000438', (137, 144))	('neoplasias', 'Disease', (199, 209))	('alcohol drinking', 'Var', (137, 153))	('associated', 'Reg', (167, 177))
568624	26504869	Current theories suggest the irritation or aberrant activation of a vagal reflex, resulting in cerebral hypoperfusion.	('vagal reflex', 'Phenotype', 'HP:0002886', (68, 80))	('irritation', 'Disease', 'MESH:D001523', (29, 39))	('cerebral hypoperfusion', 'Disease', (95, 117))	('vagal reflex', 'MPA', (68, 80))	('cerebral hypoperfusion', 'Disease', 'MESH:D002543', (95, 117))	('aberrant', 'Var', (43, 51))	('irritation', 'Disease', (29, 39))	('activation', 'PosReg', (52, 62))
568687	26221076	The disruption of apoptosis is implicated in tumors development, neurodegeneration and auto-immune diseases.	('implicated', 'Reg', (31, 41))	('neurodegeneration', 'Disease', (65, 82))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('neurodegeneration', 'Disease', 'MESH:D019636', (65, 82))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('apoptosis', 'Gene', (18, 27))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('neurodegeneration', 'Phenotype', 'HP:0002180', (65, 82))	('disruption', 'Var', (4, 14))
568713	26221076	The modulation of Bcl-2 family proteins results in dissipation of mitochondrial membrane potential (MMP) and subsequent release of many pro-apoptotic proteins such as cytochrome c, apoptosis inducing factor (AIF), and second mitochondrial activator of caspases (Smac/DIABLO) from the mitochondrial inter-membrane space into the cytosol.	('cytochrome c', 'Gene', '54205', (167, 179))	('mitochondrial membrane potential', 'MPA', (66, 98))	('caspases', 'Gene', (252, 260))	('apoptosis inducing factor', 'Gene', (181, 206))	('Bcl-2', 'Gene', (18, 23))	('modulation', 'Var', (4, 14))	('dissipation', 'MPA', (51, 62))	('DIABLO', 'Gene', (267, 273))	('AIF', 'Gene', '9131', (208, 211))	('DIABLO', 'Gene', '56616', (267, 273))	('release', 'MPA', (120, 127))	('AIF', 'Gene', (208, 211))	('cytochrome c', 'Gene', (167, 179))	('Smac', 'Gene', '56616', (262, 266))	('apoptosis inducing factor', 'Gene', '9131', (181, 206))	('caspases', 'Gene', '841;842', (252, 260))	('Smac', 'Gene', (262, 266))	('Bcl-2', 'Gene', '596', (18, 23))
568723	26221076	Modulation of Bcl-2 family proteins leads to the opening of mitochondrial permeability transition pores (PTP).	('Bcl-2', 'Gene', (14, 19))	('Modulation', 'Var', (0, 10))	('Bcl-2', 'Gene', '596', (14, 19))	('opening', 'PosReg', (49, 56))	('mitochondrial permeability transition pores', 'MPA', (60, 103))
568733	26221076	Other studies have shown that ROS eliminate cancer cells by arresting the cell cycle at various check points and thereby inducing apoptosis.	('apoptosis', 'CPA', (130, 139))	('cancer', 'Disease', (44, 50))	('inducing', 'Reg', (121, 129))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('ROS', 'Var', (30, 33))	('cell cycle', 'CPA', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
568734	26221076	An increasing body of literature evidence indicated that phytochemical targeting ROS metabolism can selectively kill cancer cells.	('ROS', 'Gene', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('phytochemical', 'Var', (57, 70))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))
568740	26221076	Pretreatment of cells with NAC (ROS inhibitors), SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor) effectively abrogated the apoptotic effects of Icariside II, indicating the potential involvement of ROS/MAPK pathway in Icariside II -mediated apoptosis in A549 cells.	('Icariside II', 'Chemical', 'MESH:C060988', (224, 236))	('A549', 'CellLine', 'CVCL:0023', (260, 264))	('p38', 'Gene', (59, 62))	('abrogated', 'NegReg', (115, 124))	('NAC', 'Gene', '6622', (27, 30))	('JNK', 'Gene', (88, 91))	('ROS', 'Chemical', 'MESH:D017382', (204, 207))	('NAC', 'Gene', (27, 30))	('SB203580', 'Var', (49, 57))	('p38', 'Gene', '5594', (59, 62))	('SP600125', 'Var', (78, 86))	('SB203580', 'Chemical', 'MESH:C093642', (49, 57))	('SP600125', 'Chemical', 'MESH:C432165', (78, 86))	('JNK', 'Gene', '5599', (88, 91))	('Icariside II', 'Chemical', 'MESH:C060988', (150, 162))	('ROS', 'Chemical', 'MESH:D017382', (32, 35))	('apoptotic effects', 'CPA', (129, 146))
568743	26221076	The extrinsic pathways is triggered by the activation and ligation of cell surface receptors (death receptors) of the tumor necrosis factor (TNF) receptor superfamily, such as fibroblast associated antigen (Fas) also called CD95 or TNF-related apoptosis-inducing ligand (TRAIL) receptors.	('CD95', 'Gene', '355', (224, 228))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (232, 269))	('TRAIL', 'Gene', '8743', (271, 276))	('activation', 'PosReg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor necrosis', 'Disease', 'MESH:D009336', (118, 132))	('TNF-related apoptosis-inducing ligand', 'Gene', (232, 269))	('TRAIL', 'Gene', (271, 276))	('CD95', 'Gene', (224, 228))	('tumor necrosis', 'Disease', (118, 132))	('extrinsic pathways', 'Pathway', (4, 22))	('ligation', 'Var', (58, 66))
568746	26221076	Activated caspase-8 then directly activates the downstream effector caspase-3, resulting in cell death via the type I extrinsic apoptotic pathway, or cleaves Bid, a pro-apoptotic member of the Bcl-2 family, leading to activation of the type II extrinsic apoptotic pathway.	('caspase-8', 'Gene', (10, 19))	('caspase-3', 'Gene', '836', (68, 77))	('type I extrinsic apoptotic pathway', 'Pathway', (111, 145))	('activation', 'PosReg', (218, 228))	('activates', 'PosReg', (34, 43))	('Bid', 'Gene', '637', (158, 161))	('caspase-8', 'Gene', '841', (10, 19))	('Bid', 'Gene', (158, 161))	('Bcl-2', 'Gene', '596', (193, 198))	('caspase-3', 'Gene', (68, 77))	('type II extrinsic apoptotic pathway', 'Pathway', (236, 271))	('Bcl-2', 'Gene', (193, 198))	('cleaves', 'Var', (150, 157))	('cell death', 'CPA', (92, 102))
568754	26221076	Checkpoint failure often causes mutations and genomic arrangements resulting in genetic instability which is the major cause of cancer development.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('resulting in', 'Reg', (67, 79))	('causes', 'Reg', (25, 31))	('mutations', 'Var', (32, 41))	('Checkpoint failure', 'Disease', (0, 18))	('Checkpoint failure', 'Disease', 'MESH:D017093', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('genetic instability', 'MPA', (80, 99))	('cancer', 'Disease', (128, 134))
568771	26221076	STAT3 is activated by phosphorylation at tyrosine 705 (Y705) or serine 727 (S727).	('Y705', 'Var', (55, 59))	('activated', 'PosReg', (9, 18))	('serine', 'Chemical', 'MESH:D012694', (64, 70))	('phosphorylation', 'Var', (22, 37))	('S727', 'Var', (76, 80))	('STAT3', 'Gene', '6774', (0, 5))	('serine 727 (S727', 'Var', (64, 80))	('STAT3', 'Gene', (0, 5))	('tyrosine', 'Chemical', 'MESH:D014443', (41, 49))
568795	26221076	The most common genetic alteration in PI3k/AKT signaling is inactivation of phosphatase and tensin homologue (PTEN) protein.	('PTEN', 'Gene', '5728', (110, 114))	('AKT', 'Gene', '207', (43, 46))	('AKT', 'Gene', (43, 46))	('PTEN', 'Gene', (110, 114))	('inactivation', 'Var', (60, 72))	('phosphatase and tensin homologue', 'Gene', '5728', (76, 108))
568805	26221076	Abnormal signaling of this pathway leads to tumorigenesis, senescence, and drug resistance.	('senescence', 'CPA', (59, 69))	('leads to', 'Reg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Abnormal signaling', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('drug resistance', 'CPA', (75, 90))	('drug resistance', 'Phenotype', 'HP:0020174', (75, 90))	('tumor', 'Disease', (44, 49))
568817	26221076	Aberrant signaling of Wnt/beta-catenin pathway can lead to a variety of human diseases ranging from birth defects to cancer.	('beta-catenin', 'Gene', '1499', (26, 38))	('human diseases', 'Disease', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Aberrant signaling', 'Var', (0, 18))	('human', 'Species', '9606', (72, 77))	('lead to', 'Reg', (51, 58))	('beta-catenin', 'Gene', (26, 38))	('birth defects to cancer', 'Disease', (100, 123))	('birth defects to cancer', 'Disease', 'MESH:D009369', (100, 123))
568819	26221076	Perturbations of beta-catenin signaling are associated with many cancers, including hepatocellular carcinoma, colorectal carcinoma, lung cancer, malignant breast tumors, ovarian cancer, endometrial cancer and esophageal cancer.	('colorectal carcinoma', 'Disease', (110, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('beta-catenin', 'Gene', '1499', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (110, 130))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (84, 108))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian cancer', 'Disease', (170, 184))	('esophageal cancer', 'Disease', 'MESH:D004938', (209, 226))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('endometrial cancer', 'Phenotype', 'HP:0012114', (186, 204))	('malignant breast tumors', 'Disease', (145, 168))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (170, 184))	('lung cancer', 'Disease', (132, 143))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (84, 108))	('esophageal cancer', 'Disease', (209, 226))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('endometrial cancer', 'Disease', (186, 204))	('hepatocellular carcinoma', 'Disease', (84, 108))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('endometrial cancer', 'Disease', 'MESH:D016889', (186, 204))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('associated', 'Reg', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('malignant breast tumors', 'Disease', 'MESH:D001943', (145, 168))	('breast tumors', 'Phenotype', 'HP:0100013', (155, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('Perturbations', 'Var', (0, 13))	('ovarian cancer', 'Disease', 'MESH:D010051', (170, 184))	('beta-catenin', 'Gene', (17, 29))
568832	26221076	Inhibition of AKT activation results in activation of GSK-3beta, which then triggered phosphorylation-mediated degradation of beta-catenin.	('phosphorylation-mediated degradation', 'MPA', (86, 122))	('beta-catenin', 'Gene', '1499', (126, 138))	('AKT', 'Gene', (14, 17))	('triggered', 'Reg', (76, 85))	('GSK-3beta', 'Gene', '2932', (54, 63))	('GSK-3beta', 'Gene', (54, 63))	('activation', 'PosReg', (40, 50))	('Inhibition', 'Var', (0, 10))	('AKT', 'Gene', '207', (14, 17))	('beta-catenin', 'Gene', (126, 138))
568839	26221076	As HIF-1 has been documented to regulate the expression of a wide range of essential genes associated with tumorigenesis and cancer progression, the inhibition of HIF-1 may be a useful strategy in the treatment of cancer.	('regulate', 'Reg', (32, 40))	('HIF-1', 'Gene', (3, 8))	('cancer', 'Disease', (214, 220))	('tumor', 'Disease', (107, 112))	('HIF-1', 'Gene', '3091', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('HIF-1', 'Gene', '3091', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('HIF-1', 'Gene', (163, 168))	('expression', 'MPA', (45, 55))	('inhibition', 'Var', (149, 159))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
568845	26221076	In the presence of molecular oxygen, PHDs induces proline hydroxylation of HIF-1alpha which facilitates its interaction with VHL resulting in ubiquitination and subsequent proteasomal degradation of HIF-1alpha.	('proline', 'Chemical', 'MESH:D011392', (50, 57))	('HIF-1alpha', 'Gene', '3091', (75, 85))	('PHDs', 'Var', (37, 41))	('proteasomal degradation', 'MPA', (172, 195))	('proline hydroxylation', 'MPA', (50, 71))	('PHDs', 'Chemical', 'MESH:D013929', (37, 41))	('HIF-1alpha', 'Gene', '3091', (199, 209))	('interaction', 'Interaction', (108, 119))	('induces', 'Reg', (42, 49))	('ubiquitination', 'MPA', (142, 156))	('HIF-1alpha', 'Gene', (75, 85))	('VHL', 'Disease', 'MESH:D006623', (125, 128))	('oxygen', 'Chemical', 'MESH:D010100', (29, 35))	('VHL', 'Disease', (125, 128))	('HIF-1alpha', 'Gene', (199, 209))	('facilitates', 'PosReg', (92, 103))
568854	26221076	It is widely accepted now that deregulation of COX-2 expression leads to an increased abundance of its enzymatic product prostaglandin E2 (PGE2), the most abundant prostaglandin in human body.	('human', 'Species', '9606', (181, 186))	('deregulation', 'Var', (31, 43))	('abundance', 'MPA', (86, 95))	('increased', 'PosReg', (76, 85))	('prostaglandin', 'Chemical', 'MESH:D011453', (164, 177))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (121, 137))	('COX-2', 'Gene', (47, 52))	('prostaglandin', 'Chemical', 'MESH:D011453', (121, 134))	('PGE2', 'Chemical', 'MESH:D015232', (139, 143))	('COX-2', 'Gene', '5743', (47, 52))
568862	26221076	Addition of exogenous PGE2 attenuated Icariside II -mediated PARP cleavage while COX-2 siRNA transfection augmented Icariside II -mediated PARP cleavage.	('attenuated', 'NegReg', (27, 37))	('PARP', 'Gene', '1302', (61, 65))	('PGE2', 'Gene', (22, 26))	('PARP', 'Gene', (61, 65))	('PARP', 'Gene', '1302', (139, 143))	('COX-2', 'Gene', (81, 86))	('COX-2', 'Gene', '5743', (81, 86))	('Icariside II', 'Chemical', 'MESH:C060988', (116, 128))	('transfection', 'Var', (93, 105))	('Icariside II', 'Chemical', 'MESH:C060988', (38, 50))	('PARP', 'Gene', (139, 143))	('PGE2', 'Chemical', 'MESH:D015232', (22, 26))	('augmented', 'PosReg', (106, 115))
568866	26221076	A number of research reports from different laboratories indicate that paclitaxel induces the activation of EGFR and toll like receptors-4 (TLR4) signaling cascades which are functionally associated with cell survival, tumor growth and drug resistance.	('TLR4', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('toll like receptors-4', 'Gene', '7099', (117, 138))	('tumor', 'Disease', (219, 224))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('drug resistance', 'Phenotype', 'HP:0020174', (236, 251))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('paclitaxel', 'Chemical', 'MESH:D017239', (71, 81))	('TLR4', 'Gene', '7099', (140, 144))	('toll like receptors-4', 'Gene', (117, 138))	('paclitaxel', 'Var', (71, 81))	('activation', 'PosReg', (94, 104))
568971	23837030	Ki67 staining was classified according to the protocols reported by Yi: + represents <25% positively-stained cells, ++ indicates 26-50% positive cells, +++ indicates 51-75% positive cells and ++++ indicates >76% positively-stained cells in ten randomly selected fields under a microscope with x400 magnification.	('+++', 'Var', (152, 155))	('++++', 'Var', (192, 196))	('Ki67', 'Chemical', '-', (0, 4))
568976	23837030	Another finding of the present study was the co-expression of the Ki67 protein in GCA and the corresponding IM, which further supports our above hypothesis.	('Ki67', 'Var', (66, 70))	('protein', 'Protein', (71, 78))	('Ki67', 'Chemical', '-', (66, 70))	('co-expression', 'Reg', (45, 58))
569040	31261874	The low-dose group tended to have smaller tumor volume than the control group, but not significantly so.	('low-dose', 'Var', (4, 12))	('tumor', 'Disease', (42, 47))	('smaller', 'NegReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
569051	31261874	Telmisartan has been shown to inhibit cell proliferation of OE19, OE33, and SK-GT4 on EAC, which is the predominant type of esophageal cancer in North America and Europe.	('OE19', 'Var', (60, 64))	('SK-GT4', 'Var', (76, 82))	('esophageal cancer', 'Disease', (124, 141))	('cell proliferation', 'CPA', (38, 56))	('inhibit', 'NegReg', (30, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('OE33', 'Var', (66, 70))	('SK-GT4', 'Chemical', '-', (76, 82))	('Telmisartan', 'Chemical', 'MESH:D000077333', (0, 11))
569052	31261874	In accordance with this finding, our results show the anti-tumor effect of telmisartan in the KYSE150, KYSE180, KYSE850 ESCC cell lines.	('KYSE180', 'Var', (103, 110))	('tumor', 'Disease', (59, 64))	('telmisartan', 'Chemical', 'MESH:D000077333', (75, 86))	('KYSE850', 'Var', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
569062	31261874	Previous studies have shown that telmisartan inhibits cell proliferation by inducing apoptosis in endometrial, ovarian, urological, lung, and colon cancer cells; other studies have shown that telmisartan induces cell-cycle arrest, but not apoptosis, in EAC and cholangiocarcinoma.	('colon cancer', 'Disease', (142, 154))	('telmisartan', 'Chemical', 'MESH:D000077333', (33, 44))	('cell-cycle arrest', 'CPA', (212, 229))	('inhibits', 'NegReg', (45, 53))	('apoptosis', 'CPA', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('EAC', 'Disease', (253, 256))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (261, 279))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('telmisartan', 'Var', (192, 203))	('cell proliferation', 'CPA', (54, 72))	('cholangiocarcinoma', 'Disease', (261, 279))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (261, 279))	('telmisartan', 'Chemical', 'MESH:D000077333', (192, 203))	('ovarian', 'Disease', (111, 118))	('inducing', 'Reg', (76, 84))	('ovarian', 'Disease', 'MESH:D010051', (111, 118))
569069	31261874	In addition, ErbB3 downregulation or knockdown induces cell-cycle arrest and apoptosis in colon cancer cell lines.	('colon cancer', 'Disease', 'MESH:D015179', (90, 102))	('induces', 'Reg', (47, 54))	('colon cancer', 'Disease', (90, 102))	('ErbB3', 'Gene', (13, 18))	('apoptosis', 'CPA', (77, 86))	('ErbB3', 'Gene', '2065', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('knockdown', 'Var', (37, 46))	('colon cancer', 'Phenotype', 'HP:0003003', (90, 102))	('cell-cycle arrest', 'CPA', (55, 72))	('downregulation', 'NegReg', (19, 33))
569074	31261874	Overexpression of TSP-1 has been associated with TMN stage and regional lymph node involvement in ESCC, and with poor survival for ESCC patients in one study; whereas another study associated low TSP-1 expression with shorter progression-free survival after surgery in ESCC patients.	('TMN', 'Disease', 'MESH:C562476', (49, 52))	('TSP-1', 'Gene', (18, 23))	('regional lymph node involvement', 'CPA', (63, 94))	('low', 'NegReg', (192, 195))	('patients', 'Species', '9606', (274, 282))	('TSP-1', 'Gene', (196, 201))	('ESCC', 'Disease', (98, 102))	('expression', 'MPA', (202, 212))	('TSP-1', 'Gene', '7057', (196, 201))	('TSP-1', 'Gene', '7057', (18, 23))	('patients', 'Species', '9606', (136, 144))	('Overexpression', 'Var', (0, 14))	('TMN', 'Disease', (49, 52))	('progression-free', 'MPA', (226, 242))	('shorter', 'NegReg', (218, 225))
569086	31261874	The stock solution was stored at -20  C. We used three human ESCC cell lines, KYSE150 (Lot.12112008), KYSE180 (Lot.8012008), KYSE850 (Lot.8252001), which were obtained from Japanese Collection of Research Bioresources Cell Bank (Osaka, Japan) on 28 May 2013.	('Lot.8012008', 'Var', (111, 122))	('Lot.12112008', 'Var', (87, 99))	('human', 'Species', '9606', (55, 60))
569126	31277104	The results showed that the expression of PVT1 was closely related to the overall survival rate of cancers (HR = 1.64, 95% confidence interval [CI]: 1.50-1.78, P < .000001).	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('PVT1', 'Gene', (42, 46))	('cancers', 'Disease', (99, 106))	('expression', 'Var', (28, 38))	('related', 'Reg', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
569128	31277104	In addition, the high expression of PVT1 was positively correlated with tumor size (OR = 1.50, 95% CI: 1.14-1.96, P = .004), TNM stage (OR = 3.39, 95% CI: 2.73-4.20, P < .00001), lymph node metastasis (OR = 2.60, 95% CI: 1.76-3.84, P < .00001), and distant metastasis (OR = 2.94, 95% CI: 1.90-4.56, P < .00001).	('TNM stage', 'CPA', (125, 134))	('distant metastasis', 'CPA', (249, 267))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('high', 'Var', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('lymph node metastasis', 'CPA', (179, 200))	('PVT1', 'Gene', (36, 40))	('correlated', 'Reg', (56, 66))
569131	31277104	Abnormal lncRNA expression is believed to be closely related to the occurrence of a variety of human diseases, including various cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('human', 'Species', '9606', (95, 100))	('related', 'Reg', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('lncRNA expression', 'Protein', (9, 26))	('cancers', 'Disease', (129, 136))	('Abnormal', 'Var', (0, 8))
569138	31277104	It is reported that the high expression of PVT1 increased the expression of autophagy related 7 (Atg7) and Beclin1 (BECN1) by targeting miRNA-186, thereby inducing the protective autophagy of glioma cells and promoting the proliferation, migration and angiogenesis of vascular endothelial cells.	('angiogenesis of vascular endothelial cells', 'CPA', (252, 294))	('Atg7', 'Gene', (97, 101))	('proliferation', 'CPA', (223, 236))	('BECN1', 'Gene', (116, 121))	('protective autophagy', 'CPA', (168, 188))	('migration', 'CPA', (238, 247))	('Atg7', 'Gene', '10533', (97, 101))	('Beclin1', 'Gene', (107, 114))	('autophagy related 7', 'Gene', (76, 95))	('glioma', 'Disease', (192, 198))	('promoting', 'PosReg', (209, 218))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('autophagy related 7', 'Gene', '10533', (76, 95))	('targeting', 'Var', (126, 135))	('expression', 'MPA', (62, 72))	('miR', 'Gene', '220972', (136, 139))	('increased', 'PosReg', (48, 57))	('Beclin1', 'Gene', '8678', (107, 114))	('inducing', 'PosReg', (155, 163))	('PVT1', 'Gene', (43, 47))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('miR', 'Gene', (136, 139))	('BECN1', 'Gene', '8678', (116, 121))
569174	31277104	The subgroup analysis based on different tumor types showed that the high expression of PVT1 was related to the poor overall survival rate of patients with clear cell renal cell carcinoma, breast cancer, cervical cancer, colon cancer, epithelial ovarian cancer, gastric cancer, lung cancer, osteosarcoma and others (including: bladder cancer, nasopharyngeal carcinoma, pancreatic cancer, melanoma, prostate cancer) respectively.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (369, 386))	('colon cancer', 'Disease', (221, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('lung cancer', 'Disease', (278, 289))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (343, 367))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (156, 187))	('gastric cancer', 'Disease', 'MESH:D013274', (262, 276))	('prostate cancer', 'Disease', 'MESH:D011471', (398, 413))	('osteosarcoma', 'Disease', (291, 303))	('cervical cancer', 'Disease', (204, 219))	('cervical cancer', 'Disease', 'MESH:D002583', (204, 219))	('prostate cancer', 'Phenotype', 'HP:0012125', (398, 413))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('bladder cancer', 'Disease', 'MESH:D001749', (327, 341))	('bladder cancer', 'Disease', (327, 341))	('melanoma', 'Disease', 'MESH:D008545', (388, 396))	('osteosarcoma', 'Disease', 'MESH:D012516', (291, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (358, 367))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (235, 260))	('breast cancer', 'Disease', (189, 202))	('prostate cancer', 'Disease', (398, 413))	('high', 'Var', (69, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (369, 386))	('melanoma', 'Phenotype', 'HP:0002861', (388, 396))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('melanoma', 'Disease', (388, 396))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (327, 341))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (343, 367))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('lung cancer', 'Disease', 'MESH:D008175', (278, 289))	('gastric cancer', 'Phenotype', 'HP:0012126', (262, 276))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (156, 187))	('tumor', 'Disease', (41, 46))	('epithelial ovarian cancer', 'Disease', (235, 260))	('pancreatic cancer', 'Disease', (369, 386))	('lung cancer', 'Phenotype', 'HP:0100526', (278, 289))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('osteosarcoma', 'Phenotype', 'HP:0002669', (291, 303))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('colon cancer', 'Disease', 'MESH:D015179', (221, 233))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (235, 260))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('clear cell renal cell carcinoma', 'Disease', (156, 187))	('gastric cancer', 'Disease', (262, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('nasopharyngeal carcinoma', 'Disease', (343, 367))	('patients', 'Species', '9606', (142, 150))	('ovarian cancer', 'Phenotype', 'HP:0100615', (246, 260))	('PVT1', 'Gene', (88, 92))
569177	31277104	Although no significant association was found, patients exhibiting high PVT1 expression levels demonstrated a trend for poor prognoses.	('high', 'Var', (67, 71))	('expression', 'MPA', (77, 87))	('PVT1', 'Gene', (72, 76))	('patients', 'Species', '9606', (47, 55))
569193	31277104	To sum up, although there are some limitations, our meta-analysis showed that high expression of PVT1 was significantly associated with tumor size, TNM stage, lymph node metastasis, distant metastasis, and overall survival time and so on, especially in breast cancer, liver cancer, lung cancer, indicating meaning is more apparent, but in bladder cancer, renal cell carcinoma and nasopharyngeal carcinoma, the indication is relatively weak as the fewer samples.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('associated', 'Reg', (120, 130))	('renal cell carcinoma', 'Disease', (355, 375))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (355, 375))	('lung cancer', 'Disease', 'MESH:D008175', (282, 293))	('liver cancer', 'Phenotype', 'HP:0002896', (268, 280))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (366, 375))	('liver cancer', 'Disease', (268, 280))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('lung cancer', 'Phenotype', 'HP:0100526', (282, 293))	('nasopharyngeal carcinoma', 'Disease', (380, 404))	('breast cancer', 'Disease', (253, 266))	('high', 'Var', (78, 82))	('lymph node metastasis', 'CPA', (159, 180))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (380, 404))	('distant metastasis', 'CPA', (182, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (395, 404))	('tumor', 'Disease', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (355, 375))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('lung cancer', 'Disease', (282, 293))	('bladder cancer', 'Disease', (339, 353))	('bladder cancer', 'Disease', 'MESH:D001749', (339, 353))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (380, 404))	('bladder cancer', 'Phenotype', 'HP:0009725', (339, 353))	('liver cancer', 'Disease', 'MESH:D006528', (268, 280))	('PVT1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
569201	30816485	The effect of OIP5 knockdown on tumorigenesis was also detected in nude mice, and differentially-expressed genes (DEGs) were identified and their biological functions were identified.	('knockdown', 'Var', (19, 28))	('nude mice', 'Species', '10090', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('OIP5', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
569205	30816485	Finally, OIP5 knockdown in Huh7 cells dysregulated bone morphogenetic protein receptor type 2/JUN/checkpoint kinase 1/Rac family small GTPase 1 expression.	('Huh7', 'Gene', (27, 31))	('expression', 'MPA', (144, 154))	('bone morphogenetic protein receptor type 2', 'Gene', (51, 93))	('checkpoint kinase 1', 'Gene', '1111', (98, 117))	('bone morphogenetic protein receptor type 2', 'Gene', '659', (51, 93))	('Rac', 'Gene', (118, 121))	('Huh7', 'Gene', '284424', (27, 31))	('checkpoint kinase 1', 'Gene', (98, 117))	('dysregulated', 'Reg', (38, 50))	('knockdown', 'Var', (14, 23))	('GTPase 1', 'Protein', (135, 143))	('Rac', 'Gene', '6035;5879', (118, 121))	('OIP5', 'Gene', (9, 13))
569216	30816485	Ectopic OIP5 expression is identified in a number of cancer types.	('identified', 'Reg', (27, 37))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Ectopic', 'Var', (0, 7))
569301	30816485	Briefly, Huh7 cells successfully transfected with pGCSIL-shOIP5 or pGCSIL-pGCSIL-shCtrl lentivirus were subcutaneously injected into the mice abdomen at a single site.	('Huh7', 'Gene', '284424', (9, 13))	('pGCSIL-shOIP5', 'Var', (50, 63))	('Huh7', 'Gene', (9, 13))	('mice', 'Species', '10090', (137, 141))
569313	30816485	It was observed that the survival rate of patients with high OIP5 expression was significantly reduced, compared with those with low OIP5 expression (P<0.01, Fig.	('survival rate', 'CPA', (25, 38))	('patients', 'Species', '9606', (42, 50))	('high OIP5 expression', 'Var', (56, 76))	('reduced', 'NegReg', (95, 102))
569316	30816485	Huh7 and HepG2 cell lines were infected with lentivirus-pGCSIL-shOIP5 and lentivirus-pGCSIL-shCtrl.	('lentivirus-pGCSIL-shCtrl', 'Var', (74, 98))	('Huh7', 'Gene', '284424', (0, 4))	('HepG2', 'CellLine', 'CVCL:0027', (9, 14))	('Huh7', 'Gene', (0, 4))
569319	30816485	OIP5 mRNA expression was significantly decreased by pGCSIL-shOIP5 lentivirus transfection in Huh7 and HepG2 cell lines, compared with pGCSIL-shCtrl lentivirus transfection (P<0.01; Fig.	('transfection', 'Var', (77, 89))	('pGCSIL-shOIP5', 'Var', (52, 65))	('Huh7', 'Gene', (93, 97))	('OIP5', 'Gene', (0, 4))	('Huh7', 'Gene', '284424', (93, 97))	('HepG2', 'CellLine', 'CVCL:0027', (102, 107))	('decreased', 'NegReg', (39, 48))
569321	30816485	4B, the number of Huh7 cells transfected with pGCSIL-shCtrl lentivirus significantly increased over the 5 days of observation, while the number of pGCSIL-shOIP5-transfected Huh7 cells remained almost the same.	('Huh7', 'Gene', (18, 22))	('Huh7', 'Gene', '284424', (18, 22))	('increased', 'PosReg', (85, 94))	('Huh7', 'Gene', '284424', (173, 177))	('Huh7', 'Gene', (173, 177))	('pGCSIL-shCtrl', 'Var', (46, 59))
569323	30816485	4C, the proliferative effect of Huh7 cells transfected with pGCSIL-shCtrl was increased, compared with Huh7 cells transfected with pGCSIL-shOIP5 (P<0.01).	('pGCSIL-shCtrl', 'Var', (60, 73))	('Huh7', 'Gene', (103, 107))	('proliferative effect', 'CPA', (8, 28))	('Huh7', 'Gene', (32, 36))	('Huh7', 'Gene', '284424', (103, 107))	('increased', 'PosReg', (78, 87))	('Huh7', 'Gene', '284424', (32, 36))
569325	30816485	These data indicated that the proliferation of Huh7 or HepG2 cells could be significantly suppressed by OIP5 knockdown.	('HepG2', 'CellLine', 'CVCL:0027', (55, 60))	('knockdown', 'Var', (109, 118))	('OIP5', 'Gene', (104, 108))	('suppressed', 'NegReg', (90, 100))	('Huh7', 'Gene', (47, 51))	('Huh7', 'Gene', '284424', (47, 51))	('proliferation', 'CPA', (30, 43))
569327	30816485	Furthermore, when counted, OIP5-knockdown Huh7 cells colony numbers were significantly reduced, compared with the number in the controls with functional OIP5 (P<0.01; Fig.	('colony numbers', 'CPA', (53, 67))	('Huh7', 'Gene', (42, 46))	('reduced', 'NegReg', (87, 94))	('Huh7', 'Gene', '284424', (42, 46))	('OIP5-knockdown', 'Var', (27, 41))
569328	30816485	Similarly, OIP5 knockdown significantly affected the colony formation of HepG2 cells (P<0.01; Fig.	('affected', 'Reg', (40, 48))	('HepG2', 'CellLine', 'CVCL:0027', (73, 78))	('colony formation', 'CPA', (53, 69))	('knockdown', 'Var', (16, 25))	('OIP5', 'Gene', (11, 15))
569329	30816485	These data indicated that silencing of OIP5 expression could inhibit colony forming in liver cancer cells.	('OIP5', 'Gene', (39, 43))	('liver cancer', 'Phenotype', 'HP:0002896', (87, 99))	('liver cancer', 'Disease', 'MESH:D006528', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('inhibit', 'NegReg', (61, 68))	('liver cancer', 'Disease', (87, 99))	('silencing', 'Var', (26, 35))
569330	30816485	OIP5 knockdown significantly decreased the number of cells in the S phase, and significantly increased the number of cells in the G0/G1 phases in HepG2 and Huh7 cells (P<0.05, Fig.	('increased', 'PosReg', (93, 102))	('knockdown', 'Var', (5, 14))	('OIP5', 'Gene', (0, 4))	('Huh7', 'Gene', (156, 160))	('decreased', 'NegReg', (29, 38))	('Huh7', 'Gene', '284424', (156, 160))	('HepG2', 'CellLine', 'CVCL:0027', (146, 151))
569331	30816485	These data indicated that silencing OIP5 promoted the apoptosis of liver cancer cells, including HepG2 and Huh7 cells.	('apoptosis', 'CPA', (54, 63))	('liver cancer', 'Disease', (67, 79))	('HepG2', 'CellLine', 'CVCL:0027', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('promoted', 'PosReg', (41, 49))	('Huh7', 'Gene', (107, 111))	('Huh7', 'Gene', '284424', (107, 111))	('silencing', 'Var', (26, 35))	('liver cancer', 'Phenotype', 'HP:0002896', (67, 79))	('liver cancer', 'Disease', 'MESH:D006528', (67, 79))	('OIP5', 'Gene', (36, 40))
569332	30816485	A total number of 628 genes were differentially expressed in OIP5 knockdown Huh7 cells, compared with control Huh7 cells (+-2.0-fold change; P<0.05), 87 of which were upregulated, whilst the remaining 541 were downregulated.	('upregulated', 'PosReg', (167, 178))	('OIP5', 'Gene', (61, 65))	('Huh7', 'Gene', (110, 114))	('Huh7', 'Gene', '284424', (110, 114))	('Huh7', 'Gene', (76, 80))	('Huh7', 'Gene', '284424', (76, 80))	('knockdown', 'Var', (66, 75))
569336	30816485	RT-qPCR analyses were further performed to evaluate downstream gene expression, and it was determined that JUN, RAC1, MAD2L1, HNRNPU and EEF1A1 mRNA expression was significantly decreased following OIP5 knockdown, while BMPR2 and CHEK1 were significantly upregulated.	('MAD2L1', 'Gene', (118, 124))	('JUN', 'Gene', (107, 110))	('decreased', 'NegReg', (178, 187))	('HNRNPU', 'Gene', '3192', (126, 132))	('mRNA expression', 'MPA', (144, 159))	('BMPR2', 'Gene', (220, 225))	('CHEK1', 'Gene', (230, 235))	('RAC1', 'Gene', '5879', (112, 116))	('MAD2L1', 'Gene', '4085', (118, 124))	('EEF1A1', 'Gene', (137, 143))	('OIP5 knockdown', 'Var', (198, 212))	('BMPR2', 'Gene', '659', (220, 225))	('HNRNPU', 'Gene', (126, 132))	('RAC1', 'Gene', (112, 116))	('EEF1A1', 'Gene', '1915', (137, 143))	('CHEK1', 'Gene', '1111', (230, 235))	('knockdown', 'Var', (203, 212))
569337	30816485	Furthermore, it was identified via western blotting that OIP5 knockdown markedly altered the expression of proteins, including as JUN, RAC1, BMPR2 and CHEK1 (Fig.	('CHEK1', 'Gene', '1111', (151, 156))	('proteins', 'Protein', (107, 115))	('OIP5', 'Gene', (57, 61))	('RAC1', 'Gene', (135, 139))	('BMPR2', 'Gene', (141, 146))	('RAC1', 'Gene', '5879', (135, 139))	('expression of', 'MPA', (93, 106))	('CHEK1', 'Gene', (151, 156))	('BMPR2', 'Gene', '659', (141, 146))	('JUN', 'Gene', (130, 133))	('altered', 'Reg', (81, 88))	('knockdown', 'Var', (62, 71))
569338	30816485	Collectively, these results indicated that OIP5 was involved in the growth and apoptosis of liver cancer cells via dysregulation of RAC1/JUN/BMPR2/CHEK1.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('liver cancer', 'Disease', (92, 104))	('CHEK1', 'Gene', '1111', (147, 152))	('RAC1', 'Gene', (132, 136))	('BMPR2', 'Gene', (141, 146))	('CHEK1', 'Gene', (147, 152))	('dysregulation', 'Var', (115, 128))	('involved', 'Reg', (52, 60))	('apoptosis', 'CPA', (79, 88))	('BMPR2', 'Gene', '659', (141, 146))	('liver cancer', 'Phenotype', 'HP:0002896', (92, 104))	('liver cancer', 'Disease', 'MESH:D006528', (92, 104))	('growth', 'CPA', (68, 74))	('RAC1', 'Gene', '5879', (132, 136))
569344	30816485	Thus, these data indicated that OIP5 knockdown could have an inhibitory effect on liver cancer cell growth and tumorigenicity, suggesting a potential therapeutic approach against liver cancer in which OIP5 is overexpressed.	('OIP5', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('liver cancer', 'Phenotype', 'HP:0002896', (179, 191))	('liver cancer', 'Disease', (82, 94))	('liver cancer', 'Disease', 'MESH:D006528', (179, 191))	('inhibitory effect', 'NegReg', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('liver cancer', 'Disease', (179, 191))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('knockdown', 'Var', (37, 46))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('liver cancer', 'Phenotype', 'HP:0002896', (82, 94))	('liver cancer', 'Disease', 'MESH:D006528', (82, 94))
569354	30816485	OY-YES-1, a CTAs homolog of human OIP5, is overexpressed in HCC and its inhibition weakens malignant behaviors of liver cancer cells, including cell growth, cell apoptosis, cell migration and cell metastasis, and then results in cell cycle arrest by regulating caspase-3, matrix metallopeptidase 2 (MMP2), MMP9 and reducing cyclic E expression.	('results in', 'Reg', (218, 228))	('liver cancer', 'Disease', 'MESH:D006528', (114, 126))	('cell growth', 'CPA', (144, 155))	('MMP2', 'Gene', '4313', (299, 303))	('cell cycle arrest', 'CPA', (229, 246))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('matrix metallopeptidase 2', 'Gene', (272, 297))	('liver cancer', 'Phenotype', 'HP:0002896', (114, 126))	('caspase-3', 'Gene', '836', (261, 270))	('inhibition', 'Var', (72, 82))	('liver cancer', 'Disease', (114, 126))	('matrix metallopeptidase 2', 'Gene', '4313', (272, 297))	('cell metastasis', 'CPA', (192, 207))	('caspase-3', 'Gene', (261, 270))	('weakens', 'NegReg', (83, 90))	('regulating', 'Reg', (250, 260))	('HCC', 'Gene', '619501', (60, 63))	('YES-1', 'Gene', (3, 8))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (229, 246))	('MMP9', 'Gene', '4318', (306, 310))	('MMP9', 'Gene', (306, 310))	('HCC', 'Phenotype', 'HP:0001402', (60, 63))	('cyclic E expression', 'MPA', (324, 343))	('YES-1', 'Gene', '7525', (3, 8))	('HCC', 'Gene', (60, 63))	('reducing', 'NegReg', (315, 323))	('human', 'Species', '9606', (28, 33))	('MMP2', 'Gene', (299, 303))	('cell apoptosis', 'CPA', (157, 171))	('cell migration', 'CPA', (173, 187))
569355	30816485	OIP5 aberrant expression is common in various types of cancer, including glioblastoma, bladder cancer, acute myeloid leukemia, lung, esophageal and breast cancer, clear cell renal cell carcinoma, gastric and colorectal cancer, and HCC.	('gastric', 'Disease', 'MESH:D013274', (196, 203))	('HCC', 'Gene', '619501', (231, 234))	('colorectal cancer', 'Disease', 'MESH:D015179', (208, 225))	('HCC', 'Phenotype', 'HP:0001402', (231, 234))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (163, 194))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('HCC', 'Gene', (231, 234))	('lung', 'Disease', (127, 131))	('colorectal cancer', 'Disease', (208, 225))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (109, 125))	('common', 'Reg', (28, 34))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (103, 125))	('esophageal', 'Disease', (133, 143))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('cancer', 'Disease', (95, 101))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (103, 125))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('breast cancer', 'Disease', (148, 161))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (73, 85))	('cancer', 'Disease', (55, 61))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (163, 194))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('glioblastoma', 'Disease', (73, 85))	('esophageal', 'Disease', 'MESH:D004941', (133, 143))	('colorectal cancer', 'Phenotype', 'HP:0003003', (208, 225))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (174, 194))	('cancer', 'Disease', (219, 225))	('cancer', 'Disease', (155, 161))	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('gastric', 'Disease', (196, 203))	('clear cell renal cell carcinoma', 'Disease', (163, 194))	('aberrant expression', 'Var', (5, 24))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('OIP5', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('acute myeloid leukemia', 'Disease', (103, 125))
569361	30816485	The present data demonstrated that OIP5 is also highly expressed in liver cancer tissues, based on bioinformatics and IHC staining, and patients with liver cancer with a high expression of OIP5 exhibited a markedly decreased overall survival rate, compared with those with low OIP5 expression.	('overall survival rate', 'CPA', (225, 246))	('liver cancer', 'Disease', 'MESH:D006528', (150, 162))	('liver cancer', 'Phenotype', 'HP:0002896', (150, 162))	('liver cancer', 'Disease', (68, 80))	('liver cancer', 'Disease', (150, 162))	('OIP5', 'Gene', (189, 193))	('patients', 'Species', '9606', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('decreased', 'NegReg', (215, 224))	('high expression', 'Var', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('liver cancer', 'Phenotype', 'HP:0002896', (68, 80))	('liver cancer', 'Disease', 'MESH:D006528', (68, 80))
569363	30816485	Silencing of OIP5 expression suppressed the colony-forming ability and inhibited tumor cell growth in bladder cancer.	('colony-forming ability', 'CPA', (44, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('inhibited', 'NegReg', (71, 80))	('OIP5', 'Gene', (13, 17))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (81, 86))	('suppressed', 'NegReg', (29, 39))
569365	30816485	Silencing OIP5 expression also inhibits proliferation of gastric and colorectal cancer cells in vitro.	('gastric', 'Disease', 'MESH:D013274', (57, 64))	('inhibits', 'NegReg', (31, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colorectal cancer', 'Disease', (69, 86))	('OIP5', 'Gene', (10, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('Silencing', 'Var', (0, 9))	('proliferation', 'CPA', (40, 53))	('gastric', 'Disease', (57, 64))
569367	30816485	In the present study, it was identified that OIP5 knockdown inhibited cell proliferation, reduced colony formation and also arrested the cell cycle at the G0/G1 or G2/M phases in liver cancer cells.	('liver cancer', 'Phenotype', 'HP:0002896', (179, 191))	('liver cancer', 'Disease', 'MESH:D006528', (179, 191))	('reduced', 'NegReg', (90, 97))	('cell cycle at the G0/G1', 'CPA', (137, 160))	('G2/M phases', 'CPA', (164, 175))	('liver cancer', 'Disease', (179, 191))	('knockdown', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cell proliferation', 'CPA', (70, 88))	('inhibited', 'NegReg', (60, 69))	('OIP5', 'Gene', (45, 49))	('colony formation', 'CPA', (98, 114))	('arrested', 'NegReg', (124, 132))
569370	30816485	In order to identify the molecular mechanisms of OIP5-mediated liver cancer progression, the expression profiles of 20,000 genes following OIP5 knockdown in Huh7 cells was determined.	('Huh7', 'Gene', (157, 161))	('OIP5-mediated liver cancer', 'Disease', 'MESH:D006528', (49, 75))	('liver cancer', 'Phenotype', 'HP:0002896', (63, 75))	('Huh7', 'Gene', '284424', (157, 161))	('OIP5-mediated liver cancer', 'Disease', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('knockdown', 'Var', (144, 153))
569371	30816485	OIP5 knockdown in Huh7 cells resulted in the deregulation of 628 genes, 87 of which were upregulated while the remaining 541 were downregulated.	('downregulated', 'NegReg', (130, 143))	('upregulated', 'PosReg', (89, 100))	('Huh7', 'Gene', (18, 22))	('knockdown', 'Var', (5, 14))	('Huh7', 'Gene', '284424', (18, 22))	('OIP5', 'Gene', (0, 4))	('deregulation', 'MPA', (45, 57))
569372	30816485	Expression data integration at the mRNA and protein levels demonstrated that OIP5 knockdown decreased the expression levels of RAC1.	('OIP5', 'Gene', (77, 81))	('knockdown', 'Var', (82, 91))	('RAC1', 'Gene', '5879', (127, 131))	('RAC1', 'Gene', (127, 131))	('decreased', 'NegReg', (92, 101))	('expression levels', 'MPA', (106, 123))
569433	29492432	The following abnormal coagulation parameters during the perioperative period have been identified as risk factors for epidural hematoma occurrence: APTT >35 s, international normalized ratio of PT >1.5, and platelet count <10 x 104/muL.	('epidural hematoma', 'Phenotype', 'HP:0100310', (119, 136))	('hematoma', 'Disease', (128, 136))	('APTT', 'Phenotype', 'HP:0003645', (149, 153))	('international normalized ratio of PT', 'MPA', (161, 197))	('abnormal coagulation', 'Phenotype', 'HP:0001928', (14, 34))	('hematoma', 'Disease', 'MESH:D006406', (128, 136))	('<10 x 104/muL', 'Var', (223, 236))
569483	26046353	Two randomized controlled trials (RCTs) confirmed that CCRT rather than sequential chemoradiotherapy resulted in improved patient survival rate in advanced esophageal cancer.	('patient survival', 'CPA', (122, 138))	('CR', 'Chemical', '-', (56, 58))	('patient', 'Species', '9606', (122, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('esophageal cancer', 'Disease', (156, 173))	('CCRT', 'Var', (55, 59))	('improved', 'PosReg', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
569515	26046353	The occurrence of acute toxicities was higher in the CCRT group than in the RT alone group (Fig 3A), with an RR value of 2.34 (95% CI: 1.90-2.90, P <0.001), and no publication bias was found (t = 0.13, P = 0.903).	('CCRT', 'Var', (53, 57))	('higher', 'PosReg', (39, 45))	('CR', 'Chemical', '-', (54, 56))	('acute toxicities', 'Disease', (18, 34))	('acute toxicities', 'Disease', 'MESH:D000208', (18, 34))
569541	26046353	However, 5- FU has prominent side effects such as mucosal inflammation and ulceration, leading to severe vomiting or esophageal injury, as previously reported.	('ulceration', 'Disease', (75, 85))	('mucosal inflammation', 'Disease', 'MESH:D007249', (50, 70))	('esophageal injury', 'Disease', 'MESH:D004941', (117, 134))	('vomiting', 'Disease', (105, 113))	('vomiting', 'Disease', 'MESH:D014839', (105, 113))	('5- FU', 'Chemical', 'MESH:D005472', (9, 14))	('mucosal inflammation', 'Disease', (50, 70))	('5- FU', 'Var', (9, 14))	('vomiting', 'Phenotype', 'HP:0002013', (105, 113))	('esophageal injury', 'Disease', (117, 134))
569629	24240108	Primary tumors and in vitro GC cell models with overexpression or knockdown of AURKA were used.	('AURKA', 'Gene', (79, 84))	('GC', 'Phenotype', 'HP:0012126', (28, 30))	('Primary tumors', 'Disease', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('Primary tumors', 'Disease', 'MESH:D009369', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('knockdown', 'Var', (66, 75))
569644	24240108	Frequent amplification and/or overexpression of AURKA have been reported in breast, colon, esophageal, gastric, liver, ovarian, and pancreatic cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('liver', 'Disease', (112, 117))	('pancreatic cancers', 'Disease', (132, 150))	('pancreatic cancers', 'Disease', 'MESH:D010190', (132, 150))	('reported', 'Reg', (64, 72))	('amplification', 'Var', (9, 22))	('AURKA', 'Gene', (48, 53))	('breast', 'Disease', (76, 82))	('overexpression', 'PosReg', (30, 44))	('gastric', 'Disease', (103, 110))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (132, 150))	('ovarian', 'Disease', (119, 126))	('colon', 'Disease', (84, 89))	('esophageal', 'Disease', (91, 101))
569648	24240108	Nonetheless, AURKA overexpression has been shown to mediate resistance against Taxol and Cisplatin and can thereby undermine the therapeutic outcome of the DCF regimen in GCs.	('AURKA', 'Gene', (13, 18))	('resistance against Taxol', 'MPA', (60, 84))	('GCs', 'Disease', (171, 174))	('therapeutic outcome', 'MPA', (129, 148))	('overexpression', 'Var', (19, 33))	('Taxol', 'Chemical', 'MESH:D017239', (79, 84))	('undermine', 'NegReg', (115, 124))	('mediate', 'Reg', (52, 59))	('DCF', 'Chemical', 'MESH:D015649', (156, 159))	('Cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('GC', 'Phenotype', 'HP:0012126', (171, 173))
569652	24240108	HDM2 has been shown to inhibit P53 by blocking P53 transcriptional activity, promoting cytosolic translocation of P53 from the nucleus and tagging it with ubiquitin for proteasomal degradation.	('blocking', 'NegReg', (38, 46))	('cytosolic translocation', 'MPA', (87, 110))	('tagging', 'Var', (139, 146))	('HDM2', 'Gene', '4193', (0, 4))	('transcriptional activity', 'MPA', (51, 75))	('inhibit', 'NegReg', (23, 30))	('P53', 'Gene', (47, 50))	('HDM2', 'Gene', (0, 4))	('P53', 'Gene', (31, 34))	('promoting', 'PosReg', (77, 86))	('ubiquitin', 'MPA', (155, 164))
569687	24240108	Conversely, siRNA mediated knockdown of endogenous AURKA increased P53, P21, and BAX expression in AGS cells.	('BAX', 'Gene', '581', (81, 84))	('expression', 'MPA', (85, 95))	('knockdown', 'Var', (27, 36))	('endogenous', 'Var', (40, 50))	('P21', 'Gene', (72, 75))	('P53', 'Protein', (67, 70))	('AURKA', 'Gene', (51, 56))	('increased', 'PosReg', (57, 66))	('P21', 'Gene', '644914', (72, 75))	('BAX', 'Gene', (81, 84))
569688	24240108	AURKA overexpression and knockdown exhibited similar effects on HDM2, P53, and P21 in SNU-1 cells (Figure 1B).	('P21', 'Gene', (79, 82))	('P53', 'Var', (70, 73))	('effects', 'Reg', (53, 60))	('P21', 'Gene', '644914', (79, 82))	('HDM2', 'Gene', '4193', (64, 68))	('SNU-1', 'CellLine', 'CVCL:0099', (86, 91))	('knockdown', 'Var', (25, 34))	('HDM2', 'Gene', (64, 68))
569690	24240108	To investigate whether AURKA-mediated increase in HDM2 protein level was dependent on its serine/threonine kinase activity, we utilized kinase-dead mutant AURKA (D274A).	('D274A', 'Mutation', 'p.D274A', (162, 167))	('AURKA', 'Gene', (155, 160))	('HDM2', 'Gene', (50, 54))	('HDM2', 'Gene', '4193', (50, 54))	('D274A', 'Var', (162, 167))
569691	24240108	The Western blot analysis revealed that, unlike wild-type AURKA, kinase-dead mutant AURKA (D274A) did not significantly affect HDM2 expression in the AGS cells (Figure 1C).	('HDM2', 'Gene', '4193', (127, 131))	('HDM2', 'Gene', (127, 131))	('D274A', 'Var', (91, 96))	('D274A', 'Mutation', 'p.D274A', (91, 96))	('affect', 'Reg', (120, 126))	('AURKA', 'Gene', (84, 89))	('expression', 'MPA', (132, 142))
569693	24240108	The Western blot data confirmed that inhibition of AURKA led to a significant decrease in HDM2 protein level coupled with upregulation of P53 and P21 expression in both cell lines (Figure 1D).	('inhibition', 'Var', (37, 47))	('decrease', 'NegReg', (78, 86))	('P21', 'Gene', (146, 149))	('AURKA', 'Gene', (51, 56))	('HDM2', 'Gene', (90, 94))	('upregulation', 'PosReg', (122, 134))	('P21', 'Gene', '644914', (146, 149))	('HDM2', 'Gene', '4193', (90, 94))	('P53', 'MPA', (138, 141))
569714	24240108	Genetic knockdown of HDM2 by siRNA abrogated AURKA-induced suppression of P53 and P21 in AGS cells, confirming the results obtained by Nutlin3A (Supplemental Figure 3C).	('suppression', 'NegReg', (59, 70))	('P21', 'Gene', '644914', (82, 85))	('abrogated', 'NegReg', (35, 44))	('HDM2', 'Gene', '4193', (21, 25))	('HDM2', 'Gene', (21, 25))	('knockdown', 'Var', (8, 17))	('P53', 'Protein', (74, 77))	('P21', 'Gene', (82, 85))
569724	24240108	Collectively, our data clearly indicated that AURKA can directly interact and phosphorylate HDM2.	('phosphorylate', 'Var', (78, 91))	('interact', 'Interaction', (65, 73))	('HDM2', 'Gene', '4193', (92, 96))	('HDM2', 'Gene', (92, 96))
569731	24240108	In accordance with the in vitro data, the xenograft results clearly show that AURKA inhibition induces P53 through down-regulation of HDM2 in vivo.	('P53', 'Protein', (103, 106))	('HDM2', 'Gene', (134, 138))	('down-regulation', 'NegReg', (115, 130))	('HDM2', 'Gene', '4193', (134, 138))	('AURKA', 'Gene', (78, 83))	('inhibition', 'Var', (84, 94))	('induces', 'Reg', (95, 102))
569747	24240108	In addition, AURKA-mediated phosphorylation of P53 at Ser215 inhibits P53 transcriptional activity and suppresses expression of its downstream targets.	('phosphorylation', 'Var', (28, 43))	('P53', 'Protein', (70, 73))	('Ser215', 'Var', (54, 60))	('Ser215', 'Chemical', '-', (54, 60))	('suppresses', 'NegReg', (103, 113))	('transcriptional activity', 'MPA', (74, 98))	('expression', 'MPA', (114, 124))	('inhibits', 'NegReg', (61, 69))
569751	24240108	Additionally, mutant AURKA failed to affect expression of HDM2, indicating that AURKA function is dependent on its kinase activity.	('HDM2', 'Gene', (58, 62))	('mutant', 'Var', (14, 20))	('AURKA', 'Gene', (21, 26))	('HDM2', 'Gene', '4193', (58, 62))
569759	24240108	We further validated this novel finding and demonstrated that inhibition of AURKA with alisertib blocks AURKA/HDM2 interaction in vitro.	('alisertib', 'Gene', (87, 96))	('alisertib', 'Chemical', 'MESH:C550258', (87, 96))	('HDM2', 'Gene', '4193', (110, 114))	('HDM2', 'Gene', (110, 114))	('AURKA', 'Gene', (76, 81))	('inhibition', 'Var', (62, 72))	('interaction', 'Interaction', (115, 126))	('blocks', 'NegReg', (97, 103))
569765	24240108	This could be an important mechanism that mediates resistance to chemotherapeutic drugs whereby activation of HDM2 prevents apoptosis by down-regulating P53 expression.	('P53', 'Gene', (153, 156))	('expression', 'MPA', (157, 167))	('activation', 'Var', (96, 106))	('HDM2', 'Gene', '4193', (110, 114))	('HDM2', 'Gene', (110, 114))	('down-regulating', 'NegReg', (137, 152))	('apoptosis', 'CPA', (124, 133))
569769	24240108	In line with the in vitro data, the tumor xenograft data and molecular analysis indicated that inhibition of AURKA with alisertib significantly reduced tumor growth coupled with down-regulation of HDM2 and induction of P53 and its downstream transcriptional targets.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('AURKA', 'Gene', (109, 114))	('reduced', 'NegReg', (144, 151))	('HDM2', 'Gene', '4193', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('inhibition', 'Var', (95, 105))	('tumor', 'Disease', (152, 157))	('P53', 'Gene', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('down-regulation', 'NegReg', (178, 193))	('induction', 'PosReg', (206, 215))	('alisertib', 'Chemical', 'MESH:C550258', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('HDM2', 'Gene', (197, 201))	('tumor', 'Disease', (36, 41))
569790	18703277	This report reviews the risk factors for Barrett esophagus and esophageal adenocarcinoma, the mechanisms by which genetic alterations might contribute to carcinogenesis in Barrett esophagus, and the role of stem cells in the development of Barrett metaplasia and adenocarcinoma.	('genetic alterations', 'Var', (114, 133))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (41, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (154, 168))	('contribute', 'Reg', (140, 150))	('carcinogenesis', 'Disease', (154, 168))	('rat', 'Species', '10116', (126, 129))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (172, 189))	('Barrett metaplasia and adenocarcinoma', 'Disease', 'MESH:D001471', (240, 277))	('Barrett esophagus', 'Disease', (41, 58))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (63, 88))	('esophageal adenocarcinoma', 'Disease', (63, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (63, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))
569801	18703277	GERD is thought to be the factor that both injures the esophageal squamous epithelium and provides the abnormal milieu necessary for healing of the reflux esophagitis through metaplasia rather than through the regeneration of squamous epithelium.	('reflux esophagitis', 'Disease', (148, 166))	('reflux esophagitis', 'Disease', 'MESH:D005764', (148, 166))	('GERD', 'Disease', (0, 4))	('rat', 'Species', '10116', (186, 189))	('GERD', 'Disease', 'MESH:D005764', (0, 4))	('metaplasia', 'Var', (175, 185))	('esophagitis', 'Phenotype', 'HP:0100633', (155, 166))	('rat', 'Species', '10116', (216, 219))	('injures', 'NegReg', (43, 50))
569804	18703277	Adenocarcinomas in Barrett esophagus develop through a sequence of genetic alterations which eventually endow cells with unlimited proliferative capacity.	('rat', 'Species', '10116', (138, 141))	('Adenocarcinomas', 'Disease', (0, 15))	('Adenocarcinomas', 'Disease', 'MESH:D000230', (0, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('carcinomas', 'Phenotype', 'HP:0030731', (5, 15))	('alterations', 'Var', (75, 86))	('rat', 'Species', '10116', (79, 82))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (19, 36))
569836	18703277	Although the metaplastic cells may be more resistant to the inflammatory insult than the native cells, the metaplasia also may predispose to malignancy.	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('predispose', 'Reg', (127, 137))	('metaplasia', 'Var', (107, 117))	('malignancy', 'Disease', (141, 151))
569840	18703277	These alterations eventually endow the cells with the essential physiological hallmarks of cancer cells including the ability to proliferate without exogenous stimulation, to resist growth-inhibitory signals, to avoid triggering apoptosis, to resist cell senescence, to develop new vascular supplies (angiogenesis), and to invade and metastasize.	('resist', 'NegReg', (243, 249))	('alterations', 'Var', (6, 17))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cell senescence', 'CPA', (250, 265))	('invade', 'CPA', (323, 329))	('develop', 'PosReg', (270, 277))	('rat', 'Species', '10116', (136, 139))	('proliferate', 'CPA', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rat', 'Species', '10116', (10, 13))	('resist', 'NegReg', (175, 181))
569841	18703277	The sections below focus on how genetic alterations acquired during the neoplastic progression of Barrett esophagus result in the acquisition of each of the cancer hallmarks (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer hallmarks', 'Disease', (157, 173))	('cancer hallmarks', 'Disease', 'MESH:D009369', (157, 173))	('result in', 'Reg', (116, 125))	('genetic alterations', 'Var', (32, 51))	('rat', 'Species', '10116', (44, 47))	('Barrett esophagus', 'Disease', (98, 115))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (98, 115))
569849	18703277	In addition to the direct activation of oncogenes, alterations in growth factors, growth factor receptors, or the signaling pathways that mediate growth factor-receptor interactions can also allow cells to proliferate without exogenous stimulation.	('rat', 'Species', '10116', (213, 216))	('alterations', 'Var', (51, 62))	('rat', 'Species', '10116', (55, 58))	('allow', 'Reg', (191, 196))
569853	18703277	However recent data suggest that HER2 amplification may be associated with a worse outcome for esophageal adenocarcinoma .	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('HER2', 'Gene', (33, 37))	('HER2', 'Gene', '2064', (33, 37))	('esophageal adenocarcinoma', 'Disease', (95, 120))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (95, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (95, 120))	('amplification', 'Var', (38, 51))
569855	18703277	K-ras mutations have been reported in 11-40% of esophageal adenocarcinomas .	('reported', 'Reg', (26, 34))	('esophageal adenocarcinomas', 'Disease', (48, 74))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (48, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (48, 74))	('K-ras', 'Gene', (0, 5))	('K-ras', 'Gene', '3845', (0, 5))	('mutations', 'Var', (6, 15))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))
569856	18703277	Cells can acquire the ability to resist growth inhibitory signals by inactivating tumor suppressor genes through one or a combination of three mechanisms including mutation of the gene, loss of heterozygosity (LOH, which is a deletion of the chromosomal region containing the gene), or promoter methylation (attachment of methyl groups to the promoter region of genes).	('loss', 'NegReg', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('promoter', 'MPA', (286, 294))	('mutation', 'Var', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('inactivating', 'NegReg', (69, 81))
569859	18703277	p16 and p53 proteins normally act to block cell cycle progression at the G1 to S transition and, therefore, inactivation of the p16 or p53 gene enables unregulated cell growth.	('p53', 'Gene', (8, 11))	('p16', 'Gene', '1029', (128, 131))	('p16', 'Gene', (0, 3))	('enables', 'PosReg', (144, 151))	('block', 'NegReg', (37, 42))	('inactivation', 'Var', (108, 120))	('p53', 'Gene', '7157', (8, 11))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('cell cycle progression', 'CPA', (43, 65))	('p16', 'Gene', (128, 131))	('p16', 'Gene', '1029', (0, 3))
569860	18703277	Allelic loss of 9p21, the chromosomal locus for p16, and methylation of the p16 promoter have been reported in 45-54% of esophageal adenocarcinomas .	('p16', 'Gene', '1029', (48, 51))	('methylation', 'Var', (57, 68))	('esophageal adenocarcinomas', 'Disease', (121, 147))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (121, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('p16', 'Gene', '1029', (76, 79))	('Allelic loss', 'Var', (0, 12))	('p16', 'Gene', (48, 51))	('9p21', 'Gene', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (121, 147))	('p16', 'Gene', (76, 79))
569861	18703277	Moreover, p16 mutation, LOH or promoter methylation has been detected in non-dysplastic, Barrett metaplasia in approximately 80% of cases, suggesting that genetic alterations of p16 are among the earliest events in the neoplastic progression of Barrett esophagus.	('genetic alterations', 'Var', (155, 174))	('p16', 'Gene', '1029', (10, 13))	('non-dysplastic', 'Disease', 'MESH:D004416', (73, 87))	('Barrett metaplasia', 'Disease', (89, 107))	('Barrett esophagus', 'Disease', (245, 262))	('p16', 'Gene', (178, 181))	('non-dysplastic', 'Disease', (73, 87))	('p16', 'Gene', (10, 13))	('rat', 'Species', '10116', (167, 170))	('p16', 'Gene', '1029', (178, 181))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (245, 262))	('Barrett metaplasia', 'Disease', 'MESH:D001471', (89, 107))
569862	18703277	Inactivation of p53 by LOH at its 17p locus along with mutation of the remaining allele has been found in approximately 50-90% of esophageal adenocarcinomas  Non-malignant cells of specialized intestinal metaplasia also can develop p53 LOH and mutation, but rarely in the absence of a preexisting alteration of p16.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('p16', 'Gene', (311, 314))	('LOH', 'NegReg', (236, 239))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (193, 214))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (130, 156))	('rat', 'Species', '10116', (301, 304))	('p53', 'Gene', (16, 19))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (130, 155))	('p53', 'Gene', (232, 235))	('p53', 'Gene', '7157', (232, 235))	('p16', 'Gene', '1029', (311, 314))	('p53', 'Gene', '7157', (16, 19))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('mutation', 'Var', (244, 252))	('esophageal adenocarcinomas', 'Disease', (130, 156))	('intestinal metaplasia', 'Disease', (193, 214))	('Inactivation', 'Var', (0, 12))
569865	18703277	Methylation of APC has been found in over 80% of cases of Barrett esophagus with high grade dysplasia or adenocarcinoma, and in approximately 40 % of patients with non-dysplastic Barrett metaplasia .	('dysplasia or adenocarcinoma', 'Disease', 'MESH:D000230', (92, 119))	('APC', 'Gene', '324', (15, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('Methylation', 'Var', (0, 11))	('non-dysplastic Barrett metaplasia', 'Disease', 'MESH:D001471', (164, 197))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (58, 75))	('patients', 'Species', '9606', (150, 158))	('dysplasia or adenocarcinoma', 'Disease', (92, 119))	('APC', 'Gene', (15, 18))	('non-dysplastic Barrett metaplasia', 'Disease', (164, 197))	('found', 'Reg', (28, 33))	('APC', 'Phenotype', 'HP:0005227', (15, 18))	('Barrett esophagus', 'Disease', (58, 75))
569869	18703277	Esophageal adenocarcinoma cells can avoid apoptosis by inactivating p53.	('inactivating', 'Var', (55, 67))	('Esophageal adenocarcinoma', 'Disease', (0, 25))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (0, 25))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('p53', 'Gene', '7157', (68, 71))	('p53', 'Gene', (68, 71))
569964	33925512	The best results are reported after neoadjuvant treatment and surgery (NATS), followed by upfront surgery and DCRT; indeed, surgery compared to non-surgical treatment increased median OS from 5-10 to 18-22 months, and 5-year OS from 3% to 23%.	('DCRT', 'Chemical', '-', (110, 114))	('increased', 'PosReg', (167, 176))	('surgery', 'Var', (124, 131))
569974	33925512	(22 vs. 13 months), although in this study EP treated with DCRT seemed to have more advanced disease (cT4 tumors) than those treated with surgery.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('EP', 'Gene', '2069', (43, 45))	('DCRT', 'Var', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('DCRT', 'Chemical', '-', (59, 63))
570049	33925512	performed a multivariate analysis and identified as poor prognosticators for long-term survival after DCRT the following; low baseline performance status, advanced tumor stage, and radiation dose <60 Gy.	('tumor', 'Disease', (164, 169))	('age', 'Gene', (172, 175))	('low', 'Var', (122, 125))	('DCRT', 'Chemical', '-', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('age', 'Gene', '5973', (172, 175))
570094	33925512	assessed patients > 65 years and found that by omitting docetaxel from the FLOT regimen, toxicity and postoperative morbidity were significantly reduced, with only a trend towards shorter progression-free survival.	('patients', 'Species', '9606', (9, 17))	('omitting', 'Var', (47, 55))	('docetaxel', 'Chemical', 'MESH:D000077143', (56, 65))	('reduced', 'NegReg', (145, 152))	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('toxicity', 'Disease', (89, 97))
570138	33925512	; Original draft preparation: all authors; Review and editing: S.M., H.T.F., M.S., N.D., G.P.	('H.T', 'Disease', 'MESH:D000848', (69, 72))	('H.T', 'Disease', (69, 72))	('M.S.', 'Var', (77, 81))
570160	33029095	Moreover, P.gingivalis was found to be correlated with the differentiation, metastasis and clinical stage of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('metastasis', 'CPA', (76, 86))	('P.gingivalis', 'Var', (10, 22))	('age', 'Gene', '5973', (114, 117))	('age', 'Gene', (102, 105))	('differentiation', 'CPA', (59, 74))	('correlated', 'Reg', (39, 49))	('P.gingivalis', 'Species', '837', (10, 22))	('age', 'Gene', '5973', (102, 105))	('age', 'Gene', (114, 117))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
570172	33029095	Diagnosis codes for the 5 cancers, such as ICD-9-CM 150 (esophageal cancer), ICD-10-CM C61 (prostate cancer); Records on cancer registries or death certificates where cancer was the underlying cause of death.	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('prostate cancer', 'Disease', (92, 107))	('cancer', 'Disease', (167, 173))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('death', 'Disease', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('death', 'Disease', 'MESH:D003643', (202, 207))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('death', 'Disease', 'MESH:D003643', (142, 147))	('esophageal cancer', 'Disease', (57, 74))	('ICD-10-CM C61', 'Var', (77, 90))	('cancer', 'Disease', (101, 107))	('death', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))	('cancer', 'Disease', (121, 127))
570227	33029095	In esophageal cancer tissues, periodontal microorganisms were found, including P.gingivalis , T. denticola  and F. nucleatum , which might induce inflammation of the esophagus.	('inflammation', 'Disease', 'MESH:D007249', (146, 158))	('F. nucleatum', 'Species', '851', (112, 124))	('esophageal cancer', 'Disease', (3, 20))	('inflammation', 'Disease', (146, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('P.gingivalis', 'Species', '837', (79, 91))	('inflammation of the esophagus', 'Phenotype', 'HP:0100633', (146, 175))	('induce', 'Reg', (139, 145))	('T. denticola', 'Species', '158', (94, 106))	('P.gingivalis', 'Var', (79, 91))
570233	33029095	In addition, P.gingivalis could interfere with tumor suppressor p53 and promote carcinogenesis.	('interfere', 'NegReg', (32, 41))	('P.gingivalis', 'Species', '837', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('promote', 'PosReg', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('P.gingivalis', 'Var', (13, 25))	('tumor', 'Disease', (47, 52))	('carcinogenesis', 'Disease', (80, 94))
570240	33029095	Studies showed that the citrullination of neutrophils and joint tissue proteins caused by periodontal pathogens (P.gingivalis and Actinobacillus gingivalis) might trigger autoimmune responses.	('P.gingivalis', 'Species', '837', (113, 125))	('autoimmune response', 'Phenotype', 'HP:0002960', (171, 190))	('Actinobacillus gingivalis', 'Disease', 'MESH:D000189', (130, 155))	('autoimmune', 'CPA', (171, 181))	('Actinobacillus gingivalis', 'Disease', (130, 155))	('citrullination', 'MPA', (24, 38))	('P.gingivalis', 'Var', (113, 125))	('Actinobacillus gingivalis', 'Phenotype', 'HP:0000169', (130, 155))	('trigger', 'Reg', (163, 170))
570292	29507463	On the basis of clinical, immunological, and histopathological observations, three pathways have been proposed as being involved in scleroderma: vascular alterations, an abnormal immune response, and disturbances in the regulation of connective tissue metabolism.	('scleroderma', 'Disease', (132, 143))	('scleroderma', 'Phenotype', 'HP:0100324', (132, 143))	('vascular alterations', 'Phenotype', 'HP:0002597', (145, 165))	('immune response', 'CPA', (179, 194))	('scleroderma', 'Disease', 'MESH:D012595', (132, 143))	('regulation of connective tissue metabolism', 'MPA', (220, 262))	('vascular alterations', 'CPA', (145, 165))	('disturbances', 'Var', (200, 212))
570341	29507463	Moreover, there is some concern over safety issues, as domperidone has been associated with cases of sudden death due to its cardiac side effects.	('sudden death', 'Disease', 'MESH:D003645', (101, 113))	('associated', 'Reg', (76, 86))	('domperidone', 'Var', (55, 66))	('sudden death', 'Disease', (101, 113))	('domperidone', 'Chemical', 'MESH:D004294', (55, 66))
570353	29507463	Indeed, 38-71% of patients who underwent fundoplication developed postoperative dysphagia, even though an improvement in the severity of reflux symptoms and in esophageal acid exposure has been reported after surgical intervention.	('esophageal acid exposure', 'MPA', (160, 184))	('reflux symptoms', 'Phenotype', 'HP:0002020', (137, 152))	('postoperative dysphagia', 'Disease', 'MESH:D003680', (66, 89))	('postoperative dysphagia', 'Disease', (66, 89))	('dysphagia', 'Phenotype', 'HP:0002015', (80, 89))	('developed', 'Reg', (56, 65))	('patients', 'Species', '9606', (18, 26))	('fundoplication', 'Var', (41, 55))
570380	28805741	Emerging evidence indicates that the imbalance in ethanol metabolism may be markedly involved in alcohol-associated cancer (Figure 1).	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('involved', 'Reg', (85, 93))	('imbalance', 'Var', (37, 46))	('imbalance', 'Phenotype', 'HP:0002172', (37, 46))	('ethanol', 'Chemical', 'MESH:D000431', (50, 57))	('ethanol metabolism', 'MPA', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('alcohol', 'Chemical', 'MESH:D000438', (97, 104))
570390	28805741	Although rare, HCC in non-cirrhotic liver has also been reported and mostly occurs due to hepatitis B virus (HBV) infection, contamination with aflatoxin B1, mutations of certain genes such as telomerase reverse transcriptase (TERT) and catenin beta 1 (CTNNB1), encoding beta-catenin.	('occurs due', 'Reg', (76, 86))	('CTNNB1', 'Gene', (253, 259))	('HCC', 'Gene', '619501', (15, 18))	('HCC', 'Phenotype', 'HP:0001402', (15, 18))	('cirrhotic liver', 'Disease', (26, 41))	('beta-catenin', 'Gene', '12387', (271, 283))	('hepatitis', 'Phenotype', 'HP:0012115', (90, 99))	('cirrhotic liver', 'Disease', 'MESH:D008103', (26, 41))	('hepatitis B virus (HBV) infection', 'Disease', 'MESH:D006509', (90, 123))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (26, 41))	('TERT', 'Gene', (227, 231))	('mutations', 'Var', (158, 167))	('HCC', 'Gene', (15, 18))	('beta-catenin', 'Gene', (271, 283))
570395	28805741	In the Danish prospective cohort study, variant allele carriers of peroxisome proliferator-activated receptor gamma (PPARG2) Pro12Ala (rs1801282) polymorphism had a 20% increased risk of breast cancer per 10 g of alcohol consumed per day.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('peroxisome proliferator-activated receptor gamma', 'Gene', (67, 115))	('PPARG2', 'Gene', (117, 123))	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (67, 115))	('Pro12Ala', 'SUBSTITUTION', 'None', (125, 133))	('alcohol', 'Chemical', 'MESH:D000438', (213, 220))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('PPARG2', 'Gene', '5468', (117, 123))	('Pro12Ala', 'Var', (125, 133))	('rs1801282', 'Var', (135, 144))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('rs1801282', 'Mutation', 'rs1801282', (135, 144))	('breast cancer', 'Disease', (187, 200))
570403	28805741	Under certain circumstances errors in the altered- or initiated-cell could confer a selective growth advantage leading to tumor progression.	('growth advantage', 'CPA', (94, 110))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('errors', 'Var', (28, 34))
570424	28805741	Furthermore, synergism between chronic alcohol abuse and hepatitis C infection are frequently related to hepatocarcinoma in Western countries.	('alcohol abuse and hepatitis C infection', 'Disease', 'MESH:D006526', (39, 78))	('alcohol abuse', 'Phenotype', 'HP:0030955', (39, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('hepatocarcinoma', 'Disease', (105, 120))	('hepatocarcinoma', 'Disease', 'None', (105, 120))	('hepatitis', 'Phenotype', 'HP:0012115', (57, 66))	('related', 'Reg', (94, 101))	('synergism', 'Var', (13, 22))
570425	28805741	Exome sequencing analysis of liver tumors identified association between specific risk factor, including alcohol consumption and mutational signatures.	('liver tumors', 'Disease', (29, 41))	('alcohol', 'Chemical', 'MESH:D000438', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('liver tumor', 'Phenotype', 'HP:0002896', (29, 40))	('mutational', 'Var', (129, 139))	('association', 'Interaction', (53, 64))	('liver tumors', 'Disease', 'MESH:D008113', (29, 41))	('liver tumors', 'Phenotype', 'HP:0002896', (29, 41))
570427	28805741	More than 100 empirical studies have established a positive correlation between moderate or chronic ethanol consumption and the incidence of breast cancer in pre- and post-menopausal women.	('moderate', 'Var', (80, 88))	('men', 'Species', '9606', (185, 188))	('ethanol', 'Chemical', 'MESH:D000431', (100, 107))	('women', 'Species', '9606', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('men', 'Species', '9606', (172, 175))
570444	28805741	These effects predispose to gastroesophageal reflux, esophagitis, and intestinal metaplasia.	('predispose', 'Reg', (14, 24))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (28, 51))	('intestinal metaplasia', 'Disease', (70, 91))	('gastroesophageal reflux', 'Disease', (28, 51))	('effects', 'Var', (6, 13))	('esophagitis', 'Phenotype', 'HP:0100633', (53, 64))	('esophagitis', 'Disease', (53, 64))	('esophagitis', 'Disease', 'MESH:D004941', (53, 64))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (70, 91))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (28, 51))
570459	28805741	Disturbances between ADH and ALDH activities in cancer cells might be attributed to the polymorphism in the associated genes which has been dealt in detail in the following section.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('ALDH', 'Enzyme', (29, 33))	('ADH', 'Gene', (21, 24))	('ADH', 'Gene', '10327', (21, 24))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('polymorphism', 'Var', (88, 100))	('activities', 'MPA', (34, 44))
570461	28805741	A multitude of studies suggest an association between genetic variants and alcohol consumption on cancer risk in humans.	('association', 'Interaction', (34, 45))	('genetic variants', 'Var', (54, 70))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('humans', 'Species', '9606', (113, 119))	('cancer', 'Disease', (98, 104))	('alcohol', 'Chemical', 'MESH:D000438', (75, 82))
570462	28805741	Here we summarize the published studies on the combined effects of alcohol drinking and polymorphisms in genes for ADH, ALDH, CYP2E1, and methylene-tetrahydrofolate reductase (MTHFR) on the risk of alcohol-related cancer.	('alcohol', 'Chemical', 'MESH:D000438', (67, 74))	('ADH', 'Gene', '10327', (115, 118))	('polymorphisms', 'Var', (88, 101))	('cancer', 'Disease', (214, 220))	('alcohol', 'Chemical', 'MESH:D000438', (198, 205))	('MTHFR', 'Gene', '4524', (176, 181))	('methylene-tetrahydrofolate reductase', 'Gene', (138, 174))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('ALDH', 'Gene', (120, 124))	('methylene-tetrahydrofolate reductase', 'Gene', '4524', (138, 174))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('CYP2E1', 'Gene', (126, 132))	('MTHFR', 'Gene', (176, 181))	('alcohol drinking', 'Phenotype', 'HP:0030955', (67, 83))	('ADH', 'Gene', (115, 118))
570466	28805741	Another polymorphism in ADH1C modifies breast cancer risk.	('ADH1C', 'Gene', (24, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('polymorphism', 'Var', (8, 20))	('modifies', 'Reg', (30, 38))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('ADH1C', 'Gene', '126', (24, 29))	('breast cancer', 'Disease', (39, 52))
570467	28805741	Premenopausal women carrying ADH1C*1 variant are found to be at a 1.8 times greater risk for breast cancer than women with other two genotypes.	('women', 'Species', '9606', (112, 117))	('men', 'Species', '9606', (114, 117))	('ADH1C', 'Gene', '126', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('men', 'Species', '9606', (16, 19))	('variant', 'Var', (37, 44))	('ADH1C', 'Gene', (29, 34))	('breast cancer', 'Disease', (93, 106))	('women', 'Species', '9606', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('men', 'Species', '9606', (3, 6))
570469	28805741	The effect of ADH1C genotype and chronic alcohol consumption was noted on the risk of liver cancer in Caucasians.	('ADH1C', 'Gene', (14, 19))	('chronic alcohol consumption', 'Phenotype', 'HP:0030955', (33, 60))	('liver cancer', 'Disease', 'MESH:D006528', (86, 98))	('liver cancer', 'Phenotype', 'HP:0002896', (86, 98))	('alcohol', 'Chemical', 'MESH:D000438', (41, 48))	('liver cancer', 'Disease', (86, 98))	('genotype', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ADH1C', 'Gene', '126', (14, 19))
570471	28805741	One of the recent meta-analysis study among Japanese population indicated Glu504Lys polymorphism of ALDH2 gene as a candidate for susceptibility to esophageal cancer.	('Glu504Lys', 'Var', (74, 83))	('susceptibility', 'Reg', (130, 144))	('Glu504Lys', 'SUBSTITUTION', 'None', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', (148, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('ALDH2', 'Gene', (100, 105))
570472	28805741	Several other studies show a significantly increased risk of esophageal cancer for Asian individuals who are heavy or moderate drinkers and carry ALDH2*1/*2 or ALDH2*2/*2 genotype compared to those who have an ALDH2*1/*1 genotype.	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('ALDH2', 'Gene', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ALDH2*1/*2', 'Var', (146, 156))	('esophageal cancer', 'Disease', (61, 78))
570475	28805741	Most of the studies revealed inconsistent findings on the effects of CYP2E1 polymorphism and alcohol consumption on various cancer risks.	('cancer', 'Disease', (124, 130))	('CYP2E1', 'Gene', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('polymorphism', 'Var', (76, 88))	('alcohol', 'Chemical', 'MESH:D000438', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
570476	28805741	A meta-analysis of published reports showed that PstI/RsaI polymorphism of CYP2E1 may increase the risk of HCC and, alcohol consumption increases the probability of developing HCC.	('HCC', 'Gene', '619501', (107, 110))	('HCC', 'Phenotype', 'HP:0001402', (107, 110))	('polymorphism', 'Var', (59, 71))	('increase', 'PosReg', (86, 94))	('HCC', 'Phenotype', 'HP:0001402', (176, 179))	('CYP2E1', 'Gene', (75, 81))	('alcohol', 'Chemical', 'MESH:D000438', (116, 123))	('PstI', 'Gene', '6690', (49, 53))	('HCC', 'Gene', (107, 110))	('HCC', 'Gene', (176, 179))	('PstI', 'Gene', (49, 53))	('increases', 'PosReg', (136, 145))	('HCC', 'Gene', '619501', (176, 179))
570477	28805741	No risk associated with CYP2E1 polymorphisms and esophageal squamous cell carcinoma with alcohol consumption was reported in Brazilian population, however, significant increased risk was noted for Asians with heavy alcohol intake who carry CYP2E1c1/c1 or CYP2E1c1/c2 genotypes, compared with non-drinkers.	('alcohol', 'Chemical', 'MESH:D000438', (89, 96))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (49, 83))	('alcohol', 'Chemical', 'MESH:D000438', (215, 222))	('CYP2E1c1/c1', 'Var', (240, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('esophageal squamous cell carcinoma', 'Disease', (49, 83))	('heavy alcohol intake', 'Phenotype', 'HP:0030955', (209, 229))
570480	28805741	An increase in breast cancer risk has been reported among postmenopausal women who were homozygote TT for MTHFR C677T and were heavy drinkers, compared with non-drinkers who were homozygote CC.	('men', 'Species', '9606', (62, 65))	('C677T', 'Mutation', 'rs1801133', (112, 117))	('women', 'Species', '9606', (73, 78))	('C677T', 'Var', (112, 117))	('MTHFR', 'Gene', (106, 111))	('men', 'Species', '9606', (75, 78))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('MTHFR', 'Gene', '4524', (106, 111))	('increase', 'PosReg', (3, 11))
570483	28805741	ROS produced by CYP2E1 results in the accumulation of lipid peroxidation products such as malondialdehyde and 4-hydroxynonenal (4-HNE) which in turn forms exocyclic DNA adducts.	('lipid', 'Chemical', 'MESH:D008055', (54, 59))	('exocyclic DNA adducts', 'MPA', (155, 176))	('4-HNE', 'Chemical', 'MESH:C027576', (128, 133))	('lipid peroxidation products', 'MPA', (54, 81))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('accumulation', 'PosReg', (38, 50))	('malondialdehyde', 'MPA', (90, 105))	('malondialdehyde', 'Chemical', 'MESH:D008315', (90, 105))	('4-hydroxynonenal', 'Chemical', 'MESH:C027576', (110, 126))	('CYP2E1', 'Var', (16, 22))	('4-hydroxynonenal', 'MPA', (110, 126))
570488	28805741	ROS mediated DNA damage and other effects of ROS are widely accepted as a cause for initiation and progression of breast cancer, HCC, lung cancer, and prostate cancer.	('lung cancer', 'Disease', (134, 145))	('HCC', 'Gene', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))	('ROS', 'Var', (0, 3))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('prostate cancer', 'Disease', (151, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('cause', 'Reg', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('HCC', 'Gene', '619501', (129, 132))	('HCC', 'Phenotype', 'HP:0001402', (129, 132))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Disease', (114, 127))
570491	28805741	Excessive alcohol is known to hinder retinoid metabolism in multiple ways: (1) acts as a competitive inhibitor of vitamin A oxidation to retinoic acid; (2) enhances catabolism of retinoic acid by alcohol-induced CYP2E1; and (3) increases vitamin A mobilization from liver to extrahepatic tissues.	('hinder', 'NegReg', (30, 36))	('enhances', 'PosReg', (156, 164))	('vitamin A', 'Chemical', 'MESH:D014801', (114, 123))	('retinoic acid', 'Chemical', 'MESH:D014212', (137, 150))	('Excessive alcohol', 'Phenotype', 'HP:0030955', (0, 17))	('retinoid', 'Chemical', 'MESH:D012176', (37, 45))	('retinoic acid', 'Chemical', 'MESH:D014212', (179, 192))	('vitamin A mobilization', 'MPA', (238, 260))	('increases', 'PosReg', (228, 237))	('alcohol', 'Chemical', 'MESH:D000438', (196, 203))	('alcohol', 'Chemical', 'MESH:D000438', (10, 17))	('CYP2E1', 'Var', (212, 218))	('vitamin A', 'Chemical', 'MESH:D014801', (238, 247))	('catabolism of retinoic acid', 'MPA', (165, 192))
570512	28805741	Both AOM and DMH undergo metabolic activation by CYP2E1 to form reactive intermediates that elicit tumorigenesis.	('tumor', 'Disease', (99, 104))	('CYP2E1', 'Var', (49, 55))	('elicit', 'Reg', (92, 98))	('reactive intermediates', 'MPA', (64, 86))	('DMH', 'Chemical', 'MESH:D004127', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('AOM', 'Disease', (5, 8))	('AOM', 'Disease', 'MESH:C537492', (5, 8))
570514	28805741	Chronic ethanol feeding in rats treated with DMH has been shown to significantly increase the number of aberrant crypt foci in colons.	('DMH', 'Var', (45, 48))	('ethanol', 'Chemical', 'MESH:D000431', (8, 15))	('rats', 'Species', '10116', (27, 31))	('DMH', 'Chemical', 'MESH:D004127', (45, 48))	('increase', 'PosReg', (81, 89))
570517	28805741	The common genetically engineered models of pancreatic cancer are based on Kras mutations and also include PDX-1-Cre/Lox-Stop-Lox (LSL)-Kras or p48/LSL-Kras mice, which have been modified by deletions or mutations of Ink4, p53, Mist, Smad4 or TGF-beta.	('mice', 'Species', '10090', (157, 161))	('Ink4', 'Gene', (217, 221))	('Kras', 'Gene', (75, 79))	('Mist', 'Gene', '27278', (228, 232))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('TGF-beta', 'Gene', (243, 251))	('PDX-1-Cre', 'Gene', (107, 116))	('p48', 'Gene', (144, 147))	('Smad4', 'Gene', (234, 239))	('mutations', 'Var', (80, 89))	('Mist', 'Gene', (228, 232))	('p48', 'Gene', '16391', (144, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('p53', 'Gene', (223, 226))	('TGF-beta', 'Gene', '21803', (243, 251))	('mutations', 'Var', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PDX-1-Cre', 'Gene', '18609', (107, 116))	('p53', 'Gene', '22060', (223, 226))	('pancreatic cancer', 'Disease', (44, 61))	('deletions', 'Var', (191, 200))	('Smad4', 'Gene', '17128', (234, 239))
570521	28805741	One study reported the use of TALEN-approach to edit the beta-catenin gene in mouse liver to generate an efficient and physiologic liver cancer mouse model.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mouse', 'Species', '10090', (144, 149))	('beta-catenin', 'Gene', '12387', (57, 69))	('liver cancer', 'Phenotype', 'HP:0002896', (131, 143))	('edit', 'Var', (48, 52))	('liver cancer', 'Disease', 'MESH:D006528', (131, 143))	('mouse', 'Species', '10090', (78, 83))	('beta-catenin', 'Gene', (57, 69))	('liver cancer', 'Disease', (131, 143))
570562	28805741	In another study, alcohol consuming mice that were inoculated with B16BL6 melanoma showed marked reduction in the number of CD8+ T cells that specifically recognize a melanoma-specific antigen (i.e., gp100) compared with water-drinking control mice.	('reduction', 'NegReg', (97, 106))	('B16BL6', 'Var', (67, 73))	('water', 'Chemical', 'MESH:D014867', (221, 226))	('gp100', 'Gene', '20431', (200, 205))	('mice', 'Species', '10090', (244, 248))	('B16BL6', 'CellLine', 'CVCL:0157', (67, 73))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('CD8', 'Gene', (124, 127))	('melanoma', 'Disease', (167, 175))	('CD8', 'Gene', '925', (124, 127))	('mice', 'Species', '10090', (36, 40))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('alcohol', 'Chemical', 'MESH:D000438', (18, 25))	('gp100', 'Gene', (200, 205))
570568	28805741	They also showed that depletion of B cells enhanced B16 melanoma metastasis to the lung by inhibiting CD8+ T cell proliferation and Th1 cytokine production.	('inhibiting', 'NegReg', (91, 101))	('enhanced', 'PosReg', (43, 51))	('Th1', 'Gene', '51497', (132, 135))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('CD8', 'Gene', (102, 105))	('melanoma metastasis to the lung', 'Disease', 'MESH:D009362', (56, 87))	('CD8', 'Gene', '925', (102, 105))	('depletion', 'Var', (22, 31))	('melanoma metastasis to the lung', 'Disease', (56, 87))	('Th1', 'Gene', (132, 135))
570569	28805741	On contrary, there are evidences suggesting that B-cell depletion could therapeutically enhance anti-tumor immune responses by decreasing IL-10 production from B cells.	('IL-10', 'Gene', '3586', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('decreasing', 'NegReg', (127, 137))	('depletion', 'Var', (56, 65))	('IL-10', 'Gene', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('enhance', 'PosReg', (88, 95))
570613	28652774	Among the cells that comprise the immune microenvironment, polymorphonuclear neutrophils (PMNs) have recently been shown to play pivotal roles by altering the immune responses, which are also correlated with patient survival in various cancers.	('patient', 'Species', '9606', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('cancers', 'Disease', (236, 243))	('immune responses', 'CPA', (159, 175))	('altering', 'Reg', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('polymorphonuclear', 'Var', (59, 76))
570695	28652774	According to the correlation between EMT and TIN in a previous study, and the relation between VM and EMT, we speculated that TIN might develop VM formation through inducing EMT progression in tumor microenvironment.	('VM formation', 'CPA', (144, 156))	('inducing', 'Reg', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('TIN', 'Chemical', '-', (126, 129))	('TIN', 'Var', (126, 129))	('TIN', 'Chemical', '-', (45, 48))	('tumor', 'Disease', (193, 198))	('develop', 'PosReg', (136, 143))
570706	28521398	Effect of SATB1 silencing on the proliferation, invasion and apoptosis of TE-1 esophageal cancer cells The aim of the present study was to investigate the effect of special AT-rich sequence-binding protein-1 (SATB1)-targeted small interfering RNA (siRNA) on the proliferation, invasion and apoptosis of TE-1 human esophageal cancer cells.	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('SATB1', 'Gene', (209, 214))	('SATB1', 'Gene', '6304', (209, 214))	('apoptosis', 'CPA', (290, 299))	('invasion', 'CPA', (277, 285))	('SATB1', 'Gene', (10, 15))	('esophageal cancer', 'Disease', (314, 331))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('SATB1', 'Gene', '6304', (10, 15))	('silencing', 'Var', (16, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (314, 331))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('human', 'Species', '9606', (308, 313))
570708	28521398	Therefore, the present study constructed and transfected SATB1-siRNA into TE-1 cells in order to knockdown the expression of the SATB1 gene.	('knockdown', 'Var', (97, 106))	('expression', 'Species', '29278', (111, 121))	('SATB1', 'Gene', '6304', (57, 62))	('expression', 'MPA', (111, 121))	('SATB1', 'Gene', (129, 134))	('SATB1', 'Gene', (57, 62))	('SATB1', 'Gene', '6304', (129, 134))
570777	28521398	The results of the present study were consistent with those of previous studies, demonstrating that the proliferation of esophageal cancer cells was significantly decreased following transfection with SATBB1 siRNA.	('proliferation of', 'CPA', (104, 120))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('SATBB1', 'Gene', (201, 207))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('transfection', 'Var', (183, 195))	('decreased', 'NegReg', (163, 172))
570790	25373392	In addition, FSEER inhibited the growth of esophageal cancer cells in xenograft models and no detectable toxicity was present in the lung or liver tissues.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('inhibited', 'NegReg', (19, 28))	('FSEER', 'Var', (13, 18))	('growth', 'CPA', (33, 39))	('esophageal cancer', 'Disease', (43, 60))	('toxicity', 'Disease', 'MESH:D064420', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('toxicity', 'Disease', (105, 113))
570842	25373392	Following treatment with 0.251 mg/ml FSEER for 24, 48 and 72 h, the growth of TE-13 cells was inhibited in a dose- and time-dependent manner (Fig.	('growth of TE-13 cells', 'CPA', (68, 89))	('inhibited', 'NegReg', (94, 103))	('0.251 mg/ml', 'Var', (25, 36))	('TE', 'Chemical', 'MESH:D013691', (78, 80))
570861	25373392	The JAK/STAT3 and ERK signaling pathways are important pathways in cell growth and apoptosis and the inactivity of these pathways may regulate the Bcl2 family resulting in growth arrest and apoptosis in certain tumor cells.	('Bcl2', 'Gene', (147, 151))	('ERK', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('inactivity', 'Var', (101, 111))	('Bcl', 'Phenotype', 'HP:0012191', (147, 150))	('regulate', 'Reg', (134, 142))	('STAT3', 'Gene', '6774', (8, 13))	('Bcl2', 'Gene', '596', (147, 151))	('growth arrest', 'Disease', (172, 185))	('STAT3', 'Gene', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('growth arrest', 'Disease', 'MESH:D006323', (172, 185))	('ERK', 'Gene', '5594', (18, 21))	('growth arrest', 'Phenotype', 'HP:0001510', (172, 185))	('apoptosis', 'CPA', (190, 199))
570867	25373392	AG490 is a member of the typhostin family of tyrosine kinase inhibitors, which inhibit the JAK/STAT3 signaling pathway in several types of cancer cell, including esophageal carcinoma cells.	('inhibit', 'NegReg', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('AG490', 'Var', (0, 5))	('esophageal carcinoma', 'Disease', (162, 182))	('STAT3', 'Gene', '6774', (95, 100))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (162, 182))	('STAT3', 'Gene', (95, 100))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (162, 182))	('cancer', 'Disease', (139, 145))
570868	25373392	Beales and Ogunwobi demonstrated that the P4244 MAP kinase inhibitor PD98059 enhanced the activity of leptin-mediated esophageal adenocarcinoma cell apoptosis.	('enhanced', 'PosReg', (77, 85))	('esophageal adenocarcinoma', 'Disease', (118, 143))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (118, 143))	('activity', 'MPA', (90, 98))	('leptin', 'Gene', '3952', (102, 108))	('PD98059', 'Gene', (69, 76))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (118, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('leptin', 'Gene', (102, 108))	('PD98059', 'Chemical', 'MESH:C093973', (69, 76))	('P4244', 'Var', (42, 47))
570869	25373392	The present study revealed that, although AG490 (5 mumol/l) and PD98059 (10 mumol/l) alone were not able to inhibit the proliferation of TE-13 cells, they significantly enhanced the inhibitory effect of FSEER (0.5 mg/ml) on the proliferation of TE-13 cells by ~25 and 35%, respectively (Fig.	('TE', 'Chemical', 'MESH:D013691', (137, 139))	('PD98059', 'Var', (64, 71))	('PD98059', 'Chemical', 'MESH:C093973', (64, 71))	('AG490', 'Var', (42, 47))	('inhibitory effect', 'MPA', (182, 199))	('proliferation', 'CPA', (228, 241))	('TE', 'Chemical', 'MESH:D013691', (245, 247))	('enhanced', 'PosReg', (169, 177))
570894	25373392	In addition, mitochondrial outer membrane permeabilization and disruption of the MMP are independent triggers of the mitochondrial cell death cascade, resulting in the release of Cyt-c from the intermembrane space of the mitochondria into the cytoplasm.	('disruption', 'Var', (63, 73))	('Cyt-c', 'Gene', (179, 184))	('Cyt-c', 'Gene', '54205', (179, 184))
570905	25373392	The results revealed that levels of p-JAK/STAT3 and pERK were significantly decreased by FSEER in vitro, which contributed to the decreases in survival rate and induction of apoptosis in TE-13 cells.	('STAT3', 'Gene', (42, 47))	('induction', 'Reg', (161, 170))	('FSEER', 'Var', (89, 94))	('apoptosis', 'CPA', (174, 183))	('levels', 'MPA', (26, 32))	('decreased', 'NegReg', (76, 85))	('pERK', 'Gene', (52, 56))	('pERK', 'Gene', '9451', (52, 56))	('TE', 'Chemical', 'MESH:D013691', (187, 189))	('STAT3', 'Gene', '6774', (42, 47))	('decreases', 'NegReg', (130, 139))	('survival rate', 'CPA', (143, 156))
570911	25373392	The compounds quercetin, phillyrin and pinoresinol, which are present in the fruit of Forsythia suspensa, have been shown to induce apoptosis in cancer cells.	('apoptosis', 'CPA', (132, 141))	('cancer', 'Disease', (145, 151))	('pinoresinol', 'Chemical', 'MESH:C103298', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('induce', 'PosReg', (125, 131))	('phillyrin', 'Var', (25, 34))	('quercetin', 'Chemical', 'MESH:D011794', (14, 23))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('Forsythia suspensa', 'Species', '126418', (86, 104))	('phillyrin', 'Chemical', 'MESH:C075528', (25, 34))
570954	32664098	Then cutoff the left gastric vessels and preserve the gastroepiploic vascular arch.	('gastroepiploic vascular arch', 'Disease', (54, 82))	('left gastric vessels', 'CPA', (16, 36))	('gastroepiploic vascular arch', 'Disease', 'MESH:D001015', (54, 82))	('cutoff', 'Var', (5, 11))
570957	32664098	After operation, all patients were treated with parenteral nutrition, anti-infection, inhibition of gastric acid, and others.	('infection', 'Disease', 'MESH:D007239', (75, 84))	('gastric', 'Protein', (100, 107))	('patients', 'Species', '9606', (21, 29))	('inhibition', 'Var', (86, 96))	('infection', 'Disease', (75, 84))
570986	32664098	Previous studies have shown that LNM was an independent prognostic factor in patients with esophageal squamous cell carcinoma.	('LNM', 'Var', (33, 36))	('esophageal squamous cell carcinoma', 'Disease', (91, 125))	('patients', 'Species', '9606', (77, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (91, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))
570988	32664098	The present study found that patients with LNM had shorter OS time than that of without LNM.	('OS time', 'MPA', (59, 66))	('patients', 'Species', '9606', (29, 37))	('shorter', 'NegReg', (51, 58))	('LNM', 'Var', (43, 46))
571146	31391032	In a survey from Tehran University of Medical Sciences, opium use (odds ratio 1.9; 95% CI, 1.1-3.4) and alcohol consumption (odds ratio 4.2; 95% CI: 1.9 to 9.3) were significantly associated with increased risks of pancreatic cancer.	('alcohol consumption', 'Var', (104, 123))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (215, 232))	('to 9', 'Species', '1214577', (153, 157))	('increased risks of pancreatic cancer', 'Phenotype', 'HP:0002894', (196, 232))	('associated', 'Reg', (180, 190))	('pancreatic cancer', 'Disease', (215, 232))	('opium', 'Var', (56, 61))	('pancreatic cancer', 'Disease', 'MESH:D010190', (215, 232))	('alcohol', 'Chemical', 'MESH:D000438', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
571170	29225860	A 59-year-old otherwise healthy woman presented with dysphagia to solids and was diagnosed with stage III T4N0M0 invasive squamous cell carcinoma of the mid-esophagus with concern for involvement of the aorta (Fig.	('dysphagia', 'Disease', 'MESH:D003680', (53, 62))	('woman', 'Species', '9606', (32, 37))	('dysphagia', 'Disease', (53, 62))	('T4N0M0', 'Var', (106, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('squamous cell carcinoma', 'Disease', (122, 145))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 145))	('dysphagia', 'Phenotype', 'HP:0002015', (53, 62))
571214	29170450	Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia.	('drive', 'PosReg', (129, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('Notch3', 'Gene', (119, 125))	('tumor initiation in squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 96))	('Notch3', 'Gene', (29, 35))	('promotes', 'PosReg', (36, 44))	('transactivates', 'Var', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('Notch1', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Notch1', 'Gene', (97, 103))	('rat', 'Species', '10116', (165, 168))	('Notch3', 'Gene', '18131', (119, 125))	('terminal differentiation', 'CPA', (135, 159))	('Notch3', 'Gene', '18131', (29, 35))	('squamous epithelia', 'Disease', (174, 192))	('tumor initiation in squamous cell carcinoma', 'Disease', (53, 96))	('squamous epithelia', 'Phenotype', 'HP:0002860', (174, 192))	('squamous epithelia', 'Disease', 'MESH:D002294', (174, 192))	('Notch1', 'Gene', '18128', (18, 24))	('Notch1', 'Gene', '18128', (97, 103))
571222	29170450	In this manuscript, the authors reveal that Notch1 activation and EMT promote tumor initiation and cancer cell heterogeneity in squamous cell carcinoma, while the repression of Notch3 by ZEB1 limits Notch1-induced differentiation, permitting Notch1-mediated EMT.	('limits', 'NegReg', (192, 198))	('ZEB1', 'Gene', (187, 191))	('repression', 'Var', (163, 173))	('EMT', 'CPA', (66, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('Notch1', 'Gene', (44, 50))	('squamous cell carcinoma', 'Disease', (128, 151))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Disease', (99, 105))	('promote', 'PosReg', (70, 77))	('tumor initiation', 'Disease', 'MESH:D009369', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Notch3', 'Gene', (177, 183))	('activation', 'PosReg', (51, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('tumor initiation', 'Disease', (78, 94))
571227	29170450	Loss-of-function Notch1 mutations are found in SCCs, suggesting a tumor suppressor role for Notch1.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Loss-of-function', 'NegReg', (0, 16))	('Notch1', 'Gene', (17, 23))	('SCCs', 'Phenotype', 'HP:0002860', (47, 51))	('SCC', 'Gene', '6317', (47, 50))	('tumor', 'Disease', (66, 71))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('SCC', 'Gene', (47, 50))
571229	29170450	Many human SCC cell lines express ICN1 and ectopic ICN1 expression promotes xenograft tumor growth.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('promotes', 'PosReg', (67, 75))	('SCC', 'Gene', (11, 14))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('tumor', 'Disease', (86, 91))	('ectopic', 'Var', (43, 50))	('SCC', 'Gene', '6317', (11, 14))	('ICN1', 'Gene', (51, 55))	('human', 'Species', '9606', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
571230	29170450	While pharmacological modulation of Notch paralogs represents an attractive strategy for cancer therapy, a more detailed understanding of the functional role of the Notch pathway as it relates to tissue biology in the context of health and disease is necessary to guide such approaches.	('N', 'Chemical', 'MESH:D009584', (36, 37))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('N', 'Chemical', 'MESH:D009584', (165, 166))	('rat', 'Species', '10116', (78, 81))	('cancer', 'Disease', (89, 95))	('modulation', 'Var', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
571236	29170450	While emerging lines of evidence support Notch1 as a positive effector of EMT, Notch3 limits the expansion of EMT-competent esophageal keratinocytes.	('limits', 'NegReg', (86, 92))	('rat', 'Species', '10116', (137, 140))	('Notch3', 'Var', (79, 85))
571267	29170450	Mice with p53 deletion did, however, display frequent metastases (Supplementary Fig.	('p53', 'Gene', '22060', (10, 13))	('metastases', 'Disease', (54, 64))	('metastases', 'Disease', 'MESH:D009362', (54, 64))	('Mice', 'Species', '10090', (0, 4))	('deletion', 'Var', (14, 22))	('p53', 'Gene', (10, 13))
571270	29170450	Both express ICN1 and form tumors upon xenograft transplantation in immunodeficient mice where doxycycline (DOX)-inducible ectopic ICN1 augments tumor growth.	('N', 'Chemical', 'MESH:D009584', (133, 134))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('DOX', 'Chemical', 'MESH:D004318', (108, 111))	('mice', 'Species', '10090', (84, 88))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('ICN1', 'Gene', (13, 17))	('immunodeficient', 'Disease', 'MESH:D007153', (68, 83))	('immunodeficient', 'Disease', (68, 83))	('doxycycline', 'Chemical', 'MESH:D004318', (95, 106))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (27, 33))	('ectopic', 'Var', (123, 130))	('augments', 'PosReg', (136, 144))	('ICN1', 'Gene', (131, 135))
571273	29170450	A functional role for Notch activity in ESCC tumor growth is evident as dominant negative mutant MAML1 (DNMAML1) prevented DOX-induced ectopic ICN1 from stimulating tumor growth (Fig.	('prevented', 'NegReg', (113, 122))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('mutant', 'Var', (90, 96))	('tumor', 'Disease', (45, 50))	('MAML1', 'Gene', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('DOX', 'Chemical', 'MESH:D004318', (123, 126))	('MAML1', 'Gene', (97, 102))	('DOX-induced ectopic ICN1', 'MPA', (123, 147))	('SCC', 'Gene', '6317', (41, 44))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('SCC', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MAML1', 'Gene', '103806', (106, 111))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('MAML1', 'Gene', '103806', (97, 102))	('stimulating', 'PosReg', (153, 164))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (165, 170))
571275	29170450	CRISPR/Cas9-mediated NOTCH1 deletion dramatically impaired tumor formation by TE11 cells in immunodeficient mice (Fig.	('impaired tumor', 'Disease', 'MESH:D015417', (50, 64))	('immunodeficient', 'Disease', 'MESH:D007153', (92, 107))	('immunodeficient', 'Disease', (92, 107))	('mice', 'Species', '10090', (108, 112))	('NOTCH1', 'Gene', (21, 27))	('impaired tumor', 'Disease', (50, 64))	('deletion', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
571278	29170450	Moreover, the ability of esophageal neoplastic cells to form single-cell-derived 3D organoids was attenuated upon Cre-mediated ex vivo Notch1 deletion in single-cell suspensions prepared from dysplastic lesions or ESCC tumors of 4NQO-treated Notch1 loxP/loxp mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('4NQO', 'Chemical', 'MESH:D015112', (229, 233))	('dysplastic lesions', 'Disease', 'MESH:D021782', (192, 210))	('Notch1', 'Gene', (135, 141))	('ESCC tumors', 'Disease', 'MESH:D004938', (214, 225))	('esophageal neoplastic', 'Disease', 'MESH:D004938', (25, 46))	('dysplastic lesions', 'Disease', (192, 210))	('mice', 'Species', '10090', (259, 263))	('D', 'Chemical', 'MESH:D003903', (82, 83))	('deletion', 'Var', (142, 150))	('attenuated', 'NegReg', (98, 108))	('ESCC tumors', 'Disease', (214, 225))	('esophageal neoplastic', 'Disease', (25, 46))
571287	29170450	CD44L cells purified from EN60 and TE11 tumors showed low (<30%) spontaneous tumor formation efficiency; however, ICN1 dramatically stimulated tumor initiation by CD44L cells to 80-90%.	('tumor initiation', 'Disease', (143, 159))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('N', 'Chemical', 'MESH:D009584', (116, 117))	('stimulated', 'PosReg', (132, 142))	('tumor', 'Disease', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor initiation', 'Disease', 'MESH:D009369', (143, 159))	('ICN1', 'Var', (114, 118))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (77, 82))	('tumors', 'Disease', (40, 46))
571288	29170450	In TE11 CD44L cells, DNMAML1 not only antagonized ICN1-mediated tumorigenicity, but also suppressed spontaneous tumor formation.	('tumor', 'Disease', (64, 69))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('suppressed', 'NegReg', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('DNMAML1', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (112, 117))	('antagonized', 'NegReg', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
571291	29170450	Cre-mediated ex vivo Notch1 deletion in 3D ESCC organoids generated from 4NQO-induced Notch1 loxP/loxP murine tumors resulted in a diminished expression of Zeb1 (Fig.	('SCC', 'Gene', '6317', (44, 47))	('Notch1', 'Gene', (21, 27))	('D', 'Chemical', 'MESH:D003903', (41, 42))	('Notch1', 'Gene', (86, 92))	('rat', 'Species', '10116', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('Zeb1', 'Protein', (156, 160))	('4NQO', 'Chemical', 'MESH:D015112', (73, 77))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('loxP/loxP', 'NegReg', (93, 102))	('SCC', 'Gene', (44, 47))	('expression', 'MPA', (142, 152))	('diminished', 'NegReg', (131, 141))	('deletion', 'Var', (28, 36))	('murine', 'Species', '10090', (103, 109))
571292	29170450	Moreover, DOX-induced ectopic ICN1 augmented intratumoral EpCAMneg cell content in TE11 xenograft tumors (Supplementary Fig.	('N', 'Chemical', 'MESH:D009584', (32, 33))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('ectopic', 'Var', (22, 29))	('xenograft tumors', 'Disease', (88, 104))	('DOX', 'Chemical', 'MESH:D004318', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('augmented', 'PosReg', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('ICN1', 'Gene', (30, 34))	('xenograft tumors', 'Disease', 'MESH:D009369', (88, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (50, 55))	('rat', 'Species', '10116', (48, 51))
571297	29170450	In the context of 4NQO-mediated carcinogenesis, the percentage of esophageal mucosa occupied by neoplastic lesions classified as intraepithelial neoplasia (IEN) or ESCC was diminished upon treatment with 1D11 (26.0% +- 8.1 s.e.m.	('1D11', 'Var', (204, 208))	('SCC', 'Gene', (165, 168))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (129, 154))	('D', 'Chemical', 'MESH:D003903', (205, 206))	('IEN', 'Phenotype', 'HP:0032187', (156, 159))	('neoplastic lesions', 'Disease', (96, 114))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('neoplasia', 'Phenotype', 'HP:0002664', (145, 154))	('intraepithelial neoplasia', 'Disease', (129, 154))	('neoplastic lesions', 'Disease', 'MESH:D051437', (96, 114))	('esophageal mucosa', 'Disease', (66, 83))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (96, 114))	('esophageal mucosa', 'Disease', 'MESH:D004941', (66, 83))	('4NQO', 'Chemical', 'MESH:D015112', (18, 22))	('diminished', 'NegReg', (173, 183))	('carcinogenesis', 'Disease', (32, 46))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (129, 154))	('SCC', 'Gene', '6317', (165, 168))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('carcinogenesis', 'Disease', 'MESH:D063646', (32, 46))
571303	29170450	5a), indicating that Notch activity may be augmented transiently during the CD44L-to-CD44H transition.	('N', 'Chemical', 'MESH:D009584', (21, 22))	('CD44L-to-CD44H', 'Var', (76, 90))	('Notch activity', 'MPA', (21, 35))	('augmented', 'PosReg', (43, 52))
571305	29170450	Ectopic ICN1 augmented CD44H cell expansion from TGFbeta-stimulated purified CD44L cells where ICN1 failed to influence spontaneous CD44H cell expansion in the absence of TGFbeta (Fig.	('augmented', 'PosReg', (13, 22))	('ICN1', 'Gene', (8, 12))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('Ectopic', 'Var', (0, 7))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('CD44H cell expansion', 'CPA', (23, 43))
571313	29170450	Gene array analysis in EPC2T cells revealed further that ectopic ICN1 expression induced a gene expression pattern compatible with squamous-cell differentiation.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('squamous-cell differentiation', 'Disease', (131, 160))	('EPC2T', 'CellLine', 'CVCL:4361', (23, 28))	('ectopic', 'Var', (57, 64))	('induced', 'Reg', (81, 88))	('ICN1', 'Gene', (65, 69))	('gene expression pattern', 'MPA', (91, 114))
571319	29170450	TE11 serial transplantation experiments revealed that DOX-induced ectopic ICN3 suppressed tumor initiation by CD44L cells (Fig.	('tumor initiation', 'Disease', 'MESH:D009369', (90, 106))	('ICN3', 'Gene', (74, 78))	('suppressed', 'NegReg', (79, 89))	('tumor initiation', 'Disease', (90, 106))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ectopic', 'Var', (66, 73))	('DOX', 'Chemical', 'MESH:D004318', (54, 57))	('N', 'Chemical', 'MESH:D009584', (76, 77))
571320	29170450	In EPC2T cells, ectopic ICN3 induced IVL in the presence or absence of TGFbeta stimulation (Supplementary Fig.	('N', 'Chemical', 'MESH:D009584', (26, 27))	('EPC2T', 'CellLine', 'CVCL:4361', (3, 8))	('IVL', 'MPA', (37, 40))	('ICN3', 'Gene', (24, 28))	('ectopic', 'Var', (16, 23))
571332	29170450	Within tumors invading into submucosa or muscularis propria, most SCC cells (>80%) did not express ICN1 with or without NOTCH1 mutations; however, a small subset of SCC cells expressed ICN1 in the invasive tumor front (35.3% for HNSCC, n = 17; 37.0% for ESCC, n = 227) (Fig.	('SCC', 'Gene', (165, 168))	('SCC', 'Gene', '6317', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('invasive tumor', 'Disease', 'MESH:D009369', (197, 211))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('N', 'Chemical', 'MESH:D009584', (187, 188))	('SCC', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('SCC', 'Gene', '6317', (255, 258))	('tumors', 'Disease', (7, 13))	('mutations', 'Var', (127, 136))	('SCC', 'Gene', (255, 258))	('SCC', 'Gene', '6317', (231, 234))	('muscularis propria', 'Phenotype', 'HP:0030936', (41, 59))	('N', 'Chemical', 'MESH:D009584', (230, 231))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('SCC', 'Gene', (231, 234))	('NOTCH1', 'Gene', (120, 126))	('SCC', 'Gene', '6317', (165, 168))	('invasive tumor', 'Disease', (197, 211))	('N', 'Chemical', 'MESH:D009584', (101, 102))
571356	29170450	While our own published findings and those of others have implicated Notch1 as a tumor promoter in SCCs, the current study is the first to demonstrate in vivo that Notch1 facilitates tumor initiation by converting CD44L cells to highly tumorigenic CD44H cells with mesenchymal traits, complementing the earlier studies implicating EMT and ZEB1 in the CD44L-to-CD44H transition.	('tumor initiation', 'Disease', 'MESH:D009369', (183, 199))	('SCC', 'Gene', '6317', (99, 102))	('facilitates', 'PosReg', (171, 182))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('SCC', 'Gene', (99, 102))	('rat', 'Species', '10116', (146, 149))	('SCCs', 'Phenotype', 'HP:0002860', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor initiation', 'Disease', (183, 199))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Notch1', 'Var', (164, 170))	('tumor', 'Disease', (236, 241))	('tumor', 'Disease', (81, 86))
571365	29170450	Indeed, genetic Notch inhibition via DNMAML1 expression accelerates carcinogen-mediated esophageal tumor initiation, growth and invasion in vivo.	('esophageal tumor initiation', 'Disease', (88, 115))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('esophageal tumor', 'Phenotype', 'HP:0100751', (88, 104))	('Notch', 'Var', (16, 21))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('DNMAML1', 'Gene', (37, 44))	('rat', 'Species', '10116', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('accelerates', 'PosReg', (56, 67))	('invasion', 'CPA', (128, 136))	('esophageal tumor initiation', 'Disease', 'MESH:D004938', (88, 115))
571367	29170450	Interestingly, Notch inhibition by DNMAML1 permits clonal immortalization and expansion of murine esophageal epithelial cells.	('esophageal epithelia', 'Disease', (98, 118))	('Notch inhibition', 'Var', (15, 31))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('murine', 'Species', '10090', (91, 97))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (98, 118))	('esophageal epithelia', 'Disease', 'MESH:D004941', (98, 118))	('DNMAML1', 'Gene', (35, 42))	('N', 'Chemical', 'MESH:D009584', (15, 16))
571371	29170450	Notably, the observed inhibitory effects of anti-TGFbeta antibody upon tumor progression in mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('anti-TGFbeta', 'Gene', (44, 56))	('anti-TGFbeta', 'Var', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('inhibitory effects', 'NegReg', (22, 40))	('mice', 'Species', '10090', (92, 96))
571378	29170450	We have also successfully performed ex vivo Cre-mediated recombination in 3D organoids generated from neoplastic esophageal keratinocytes of 4NQO-treated Notch1 loxP/loxP mice, demonstrating that Notch1 is required for organoid formation and EMT-like features in neoplastic 3D organoids (Figs.	('mice', 'Species', '10090', (171, 175))	('neoplastic esophageal', 'Disease', (102, 123))	('rat', 'Species', '10116', (91, 94))	('rat', 'Species', '10116', (184, 187))	('D', 'Chemical', 'MESH:D003903', (275, 276))	('neoplastic esophageal', 'Disease', 'MESH:D004938', (102, 123))	('loxP/loxP', 'Var', (161, 170))	('rat', 'Species', '10116', (126, 129))	('4NQO', 'Chemical', 'MESH:D015112', (141, 145))	('D', 'Chemical', 'MESH:D003903', (75, 76))	('Notch1', 'Gene', (154, 160))
571379	29170450	Notch1 deletion in the murine skin promotes SCC development in a non-cell autonomous fashion due to inflammation associated with epidermal barrier defects, limiting the assessment of the cell-autonomous oncogenic role of Notch1 in vivo.	('inflammation', 'Disease', (100, 112))	('SCC', 'Gene', '6317', (44, 47))	('Notch1', 'Gene', (0, 6))	('promotes', 'PosReg', (35, 43))	('murine', 'Species', '10090', (23, 29))	('SCC', 'Gene', (44, 47))	('inflammation', 'Disease', 'MESH:D007249', (100, 112))	('deletion', 'Var', (7, 15))
571383	29170450	Once an appropriate window of 4NQO-induced malignant transformation is determined, our cell-lineage traceable mice can be utilized for genetic ablation of Notch1 following 4NQO administration to elucidate how Notch1 may exert its oncogenic role by promoting EMT and tumor initiation and/or progression in vivo.	('promoting', 'PosReg', (248, 257))	('4NQO', 'Chemical', 'MESH:D015112', (30, 34))	('progression', 'CPA', (290, 301))	('Notch1', 'Gene', (155, 161))	('mice', 'Species', '10090', (110, 114))	('tumor initiation', 'Disease', 'MESH:D009369', (266, 282))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('4NQO', 'Chemical', 'MESH:D015112', (172, 176))	('Notch1', 'Var', (209, 215))	('rat', 'Species', '10116', (185, 188))	('tumor initiation', 'Disease', (266, 282))
571391	29170450	Samples with NOTCH1 mutations (n = 4; E755*, D469Y, R1279D, and D1457G) and wild-type NOTCH1 (n = 15) were identified by DNA sequencing (SRP072948).	('D1457G', 'Var', (64, 70))	('E755*', 'Var', (38, 43))	('D469Y', 'Mutation', 'p.D469Y', (45, 50))	('NOTCH1', 'Gene', (13, 19))	('R1279D', 'Var', (52, 58))	('E755*', 'SUBSTITUTION', 'None', (38, 43))	('D1457G', 'Mutation', 'p.D1457G', (64, 70))	('R1279D', 'Mutation', 'p.R1279D', (52, 58))	('D469Y', 'Var', (45, 50))
571397	29170450	R26tdTomato lsl/lsl mice were also crossed with p53 loxP/loxP to generate R26tdTomato lsl/wt ;p53 loxP/wt mice, which were then crossed to generate R26tdTomato lsl/lsl ;p53 loxP/loxP mice.	('p53', 'Gene', (48, 51))	('mice', 'Species', '10090', (106, 110))	('p53', 'Gene', (94, 97))	('p53', 'Gene', (169, 172))	('mice', 'Species', '10090', (20, 24))	('mice', 'Species', '10090', (183, 187))	('p53', 'Gene', '22060', (48, 51))	('rat', 'Species', '10116', (143, 146))	('p53', 'Gene', '22060', (94, 97))	('R26tdTomato', 'Var', (74, 85))	('p53', 'Gene', '22060', (169, 172))	('rat', 'Species', '10116', (69, 72))
571398	29170450	The K5Cre ERT2 ;p53 loxP/loxP mice were further crossed with R26tdTomato lsl/lsl ;p53 loxP/loxP mice to generate K5Cre ERT2 ;R26tdTomato lsl/wt ;p53 loxP/loxP.	('rat', 'Species', '10116', (108, 111))	('mice', 'Species', '10090', (30, 34))	('p53', 'Gene', '22060', (82, 85))	('mice', 'Species', '10090', (96, 100))	('p53', 'Gene', (145, 148))	('ERT2', 'Gene', '26417', (119, 123))	('p53', 'Gene', (16, 19))	('ERT2', 'Gene', '26417', (10, 14))	('K5Cre', 'Var', (113, 118))	('p53', 'Gene', '22060', (145, 148))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '22060', (16, 19))	('ERT2', 'Gene', (119, 123))	('ERT2', 'Gene', (10, 14))
571400	29170450	The L2Cre transgenic mouse strain was intercrossed with p53 R172H/R172H mice to generate L2Cre;p53 R172H/wt mice.	('L2Cre', 'Chemical', '-', (4, 9))	('R172H', 'SUBSTITUTION', 'None', (66, 71))	('mice', 'Species', '10090', (108, 112))	('R172H', 'Mutation', 'p.R172H', (60, 65))	('R172H', 'Mutation', 'p.R172H', (99, 104))	('p53', 'Gene', (95, 98))	('R172H', 'Mutation', 'p.R172H', (66, 71))	('p53', 'Gene', '22060', (95, 98))	('L2Cre', 'Chemical', '-', (89, 94))	('p53', 'Gene', (56, 59))	('mouse', 'Species', '10090', (21, 26))	('rat', 'Species', '10116', (84, 87))	('p53', 'Gene', '22060', (56, 59))	('R172H', 'Var', (60, 65))	('R172H', 'SUBSTITUTION', 'None', (99, 104))	('mice', 'Species', '10090', (72, 76))	('R172H', 'Var', (99, 104))	('R172H', 'SUBSTITUTION', 'None', (60, 65))	('R172H', 'Var', (66, 71))
571403	29170450	To inhibit TGFbeta receptor-mediated signaling, mice were treated for 2 weeks with either anti-TGFbeta antibody 1D11 (intra-peritoneally), neutralizing all three isoforms of TGFbeta (a gift of Dr. Singhal, University of Pennsylvania; 3 mg/kg, three times per week) or control IgG (intra-peritoneally) with injections initiated 4 weeks following 4NQO withdrawal.	('neutralizing', 'Var', (139, 151))	('TGFbeta', 'Gene', (174, 181))	('mice', 'Species', '10090', (48, 52))	('TGFbeta', 'Protein', (11, 18))	('inhibit', 'NegReg', (3, 10))	('D', 'Chemical', 'MESH:D003903', (193, 194))	('4NQO', 'Chemical', 'MESH:D015112', (345, 349))	('D', 'Chemical', 'MESH:D003903', (113, 114))
571417	29170450	Other shRNA sequences in pGIPZ (GE Dharmacon) targeting NOTCH3 (Notch3-A; V2LHS_229748 and Notch3-B; V2LHS_93017), ZEB1 (ZEB1-A; V2LHS_116663 and ZEB1-B; V2LHS_116659), and a non-silencing scrambled sequence (RHS4348) were used as described previously.	('Notch3-A', 'Gene', '18131', (64, 72))	('V2LHS_93017', 'Var', (101, 112))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('D', 'Chemical', 'MESH:D003903', (35, 36))	('V2LHS_229748', 'Var', (74, 86))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('Notch3-A', 'Gene', (64, 72))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('N', 'Chemical', 'MESH:D009584', (56, 57))
571423	29170450	To delete human NOTCH1 via Crispr/Cas9-mediated gene editing, five candidate guide RNA (gRNA) sequences were subcloned into lentiCRISPR v1 (gift of a gift from Feng Zhang; Addgene, plasmid #52961) at its BsmBI sites and used as described.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('human', 'Species', '9606', (10, 15))	('NOTCH1', 'Gene', (16, 22))	('delete', 'Var', (3, 9))	('N', 'Chemical', 'MESH:D009584', (90, 91))
571424	29170450	gRNAs 1, 2, and 5 targeting chromosome 9 NOTCH1 exon 14 (EGF-like region at 139,407,894-139,407,913) or exon 19 (EGF-like region at 139,403,465-139,403,484) and exon 34 (PEST domain at 139,390,539-139,390,558), respectively, were found to be equally effective to delete NOTCH1.	('N', 'Chemical', 'MESH:D009584', (2, 3))	('N', 'Chemical', 'MESH:D009584', (270, 271))	('NOTCH1', 'Gene', (270, 276))	('delete', 'Var', (263, 269))	('N', 'Chemical', 'MESH:D009584', (41, 42))
571432	29170450	Cells transduced with GFP (pGIPZ) or tRFP (pTR-tRFP) were selected for the brightest level of fluorescence (top 20%) by FACS.	('pTR-tRFP', 'Gene', '56771', (43, 51))	('pTR-tRFP', 'Gene', (43, 51))	('tRFP', 'Gene', (37, 41))	('fluorescence', 'MPA', (94, 106))	('GFP', 'Var', (22, 25))
571445	29170450	Esophageal keratinocytes were isolated from vehicle-treated or 4NQO-treated K5Cre ERT2 ;R26tdTomato lsl/lsl or Notch1 loxP/loxP (Jacskon Laboratories) mice under an IACUC-approved protocol as described previously.	('Notch1', 'Var', (111, 117))	('mice', 'Species', '10090', (151, 155))	('ERT2', 'Gene', '26417', (82, 86))	('4NQO', 'Chemical', 'MESH:D015112', (63, 67))	('rat', 'Species', '10116', (13, 16))	('ERT2', 'Gene', (82, 86))	('rat', 'Species', '10116', (141, 144))	('loxP/loxP', 'NegReg', (118, 127))
571460	29170450	Following centrifugation, residual tissue pieces were digested in 0.05% trypsin-EDTA (Invitrogen) at 37  C for 10 min and then with 1 U/ml Dispase (BD Biosciences) and 100 mug/ml DNase I (#10104159001, Roche) at 37  C for 10 min.	('D', 'Chemical', 'MESH:D003903', (179, 180))	('DNase I', 'Gene', '13419', (179, 186))	('EDTA', 'Chemical', 'MESH:D004492', (80, 84))	('DNase I', 'Gene', (179, 186))	('#10104159001', 'Var', (188, 200))	('D', 'Chemical', 'MESH:D003903', (139, 140))	('D', 'Chemical', 'MESH:D003903', (149, 150))	('D', 'Chemical', 'MESH:D003903', (81, 82))
571481	29170450	Cells were incubated in the presence or absence of 1 microg/ml DOX to induce ICN1 in cells expressing ICN1 TetOn for 48 h before cell lysis.	('ICN1', 'Gene', (77, 81))	('DOX', 'Chemical', 'MESH:D004318', (63, 66))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('ICN1 TetOn', 'Var', (102, 112))	('N', 'Chemical', 'MESH:D009584', (104, 105))	('TetOn', 'Chemical', '-', (107, 112))
571496	29170450	M.N., S.K., K.T., P.M.C., and V.S.	('N', 'Chemical', 'MESH:D009584', (2, 3))	('K.T.', 'Var', (12, 16))	('S.K.', 'Var', (6, 10))	('P.M.C.', 'Var', (18, 24))
571507	29170450	J.A.D., A.J.B., K.-K.W., and A.K.R.	('K.-K.W.', 'Var', (16, 23))	('D', 'Chemical', 'MESH:D003903', (4, 5))	('A.J.B.', 'Var', (8, 14))
571617	27247259	Using a nude mouse xenograft model, we confirmed that the re-expression of miR-1 significantly inhibited ESCC tumor growth.	('mouse', 'Species', '10090', (13, 18))	('ESCC', 'Disease', (105, 109))	('inhibited', 'NegReg', (95, 104))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('miR-1', 'Gene', (75, 80))	('re-expression', 'Var', (58, 71))	('miR-1', 'Gene', '83856', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
571618	27247259	A tetrazolium assay and a trypan blue exclusion assay revealed that miR-1 suppressed ESCC cell proliferation and increased apoptosis, whereas the silencing of miR-1 promoted cell proliferation and decreased apoptosis, suggesting that miR-1 is a novel tumor suppressor.	('tumor', 'Disease', (251, 256))	('suppressed', 'NegReg', (74, 84))	('apoptosis', 'CPA', (207, 216))	('miR-1', 'Gene', (159, 164))	('ESCC', 'Disease', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('miR-1', 'Gene', '83856', (234, 239))	('promoted', 'PosReg', (165, 173))	('miR-1', 'Gene', (234, 239))	('miR-1', 'Gene', '83856', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('cell proliferation', 'CPA', (174, 192))	('silencing', 'Var', (146, 155))	('tetrazolium', 'Chemical', 'MESH:D013778', (2, 13))	('trypan blue', 'Chemical', 'MESH:D014343', (26, 37))	('apoptosis', 'CPA', (123, 132))	('increased', 'PosReg', (113, 122))	('decreased', 'NegReg', (197, 206))	('miR-1', 'Gene', (68, 73))	('miR-1', 'Gene', '83856', (159, 164))
571628	27247259	Tumor growth can be facilitated by genetic alterations in cancer cells that regulate the phenotypic changes.	('genetic alterations', 'Var', (35, 54))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('facilitated', 'PosReg', (20, 31))	('Tumor growth', 'CPA', (0, 12))
571629	27247259	Genetic alterations play an important role in EC, and alterations in a large number of oncogenes and tumor suppressor genes have previously been described in patients with EC.	('described', 'Reg', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('alterations', 'Var', (54, 65))	('patients', 'Species', '9606', (158, 166))	('oncogenes', 'Gene', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
571641	27247259	However, the roles of miR-1 deregulation in carcinogenesis and cancer progression remain largely elusive.	('deregulation', 'Var', (28, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('carcinogenesis', 'Disease', (44, 58))	('miR-1', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('miR-1', 'Gene', '83856', (22, 27))	('cancer', 'Disease', (63, 69))
571668	27247259	The miR-1 gain-of-function experiments using KYSE-150 cells were performed using miR-1 mimics (100 nM) purchased from Shanghai GenePharma Co., Ltd., (Shanghai, China) and its negative control (NC, 100 nM).	('KYSE-150', 'CellLine', 'CVCL:1348', (45, 53))	('miR-1', 'Gene', (81, 86))	('Shanghai', 'Var', (150, 158))	('miR-1', 'Gene', (4, 9))	('miR-1', 'Gene', '83856', (81, 86))	('miR-1', 'Gene', '83856', (4, 9))
571669	27247259	The loss-of-function experiments using KYSE-150 cells were performed using miR-1 inhibitor (100 nM) and its NC (100 nM).	('KYSE-150', 'CellLine', 'CVCL:1348', (39, 47))	('loss-of-function', 'NegReg', (4, 20))	('100 nM', 'Var', (92, 98))	('100 nM', 'Var', (112, 118))	('miR-1', 'Gene', (75, 80))	('miR-1', 'Gene', '83856', (75, 80))
571677	27247259	KYSE-150 cells (5x103/well) were plated in 96-well plates in a final volume of 100 ml and transfected with the miRNAs.	('miR', 'Gene', (111, 114))	('miR', 'Gene', '220972', (111, 114))	('transfected', 'Var', (90, 101))	('KYSE-150', 'CellLine', 'CVCL:1348', (0, 8))
571680	27247259	The KYSE-150 cells (5x103/well) were plated in 96-well plates in a final volume of 100 ml and transfected with miR-1 mimics, inhibitors and their respective NCs.	('miR-1', 'Gene', (111, 116))	('miR-1', 'Gene', '83856', (111, 116))	('KYSE-150', 'CellLine', 'CVCL:1348', (4, 12))	('transfected', 'Reg', (94, 105))	('inhibitors', 'Var', (125, 135))
571712	27247259	The number of Annexin V-FITC(+) apoptotic cells was significantly increased in the miR-1 mimics-transfected group compared to the mimics-NC-transfected group.	('miR-1', 'Gene', (83, 88))	('Annexin V', 'Gene', '308', (14, 23))	('increased', 'PosReg', (66, 75))	('miR-1', 'Gene', '83856', (83, 88))	('mimics-transfected', 'Var', (89, 107))	('Annexin V', 'Gene', (14, 23))	('FITC', 'Chemical', '-', (24, 28))
571713	27247259	The percentage of apoptotic cells in the group treated with miR-1 inhibitor was higher than that of the inhibitor-NC group (Fig.	('inhibitor', 'Var', (66, 75))	('apoptotic cells', 'CPA', (18, 33))	('miR-1', 'Gene', (60, 65))	('higher', 'PosReg', (80, 86))	('miR-1', 'Gene', '83856', (60, 65))
571723	27247259	By contrast, the protein expression of MET, cyclin D1, and CDK4 was increased in the loss-of-function experiments following transection with miR-1 inhibitor compared to transfection with miR-1 inhibitor-NC (Fig.	('transection', 'Var', (124, 135))	('protein expression', 'MPA', (17, 35))	('miR-1', 'Gene', (141, 146))	('CDK4', 'Gene', '1019', (59, 63))	('loss-of-function', 'NegReg', (85, 101))	('miR-1', 'Gene', '83856', (141, 146))	('miR-1', 'Gene', (187, 192))	('cyclin D1', 'Gene', '595', (44, 53))	('miR-1', 'Gene', '83856', (187, 192))	('CDK4', 'Gene', (59, 63))	('cyclin D1', 'Gene', (44, 53))	('increased', 'PosReg', (68, 77))	('MET', 'Gene', (39, 42))
571751	27247259	The results of the present study demonstrate that miR-1 overexpression inhibits ESCC cell proliferation and promotes apoptosis, whereas miR-1 silencing promotes cell proliferation and inhibits apoptosis, suggesting that miR-1 may influence the formation and progression of ESCC by regulating cell proliferation and apoptosis.	('silencing', 'Var', (142, 151))	('influence', 'Reg', (230, 239))	('promotes', 'PosReg', (108, 116))	('apoptosis', 'CPA', (117, 126))	('inhibits', 'NegReg', (71, 79))	('ESCC', 'Disease', (273, 277))	('miR-1', 'Gene', '83856', (220, 225))	('cell proliferation', 'CPA', (161, 179))	('apoptosis', 'CPA', (315, 324))	('miR-1', 'Gene', (220, 225))	('regulating', 'Reg', (281, 291))	('cell proliferation', 'CPA', (292, 310))	('miR-1', 'Gene', '83856', (50, 55))	('promotes', 'PosReg', (152, 160))	('ESCC', 'Disease', (80, 84))	('miR-1', 'Gene', '83856', (136, 141))	('apoptosis', 'CPA', (193, 202))	('inhibits', 'NegReg', (184, 192))	('miR-1', 'Gene', (136, 141))	('miR-1', 'Gene', (50, 55))
571766	27247259	A key protein in the HGF/MET signaling pathway involved with tyrosine kinase activity, MET affects cell proliferation, apoptosis, invasion, migration and angiogenesis via interactions with critical molecules of the Wnt and phosphatidylinositol-3-kinase (PI3K) signaling pathways.	('affects', 'Reg', (91, 98))	('interactions', 'Interaction', (171, 183))	('cell proliferation', 'CPA', (99, 117))	('MET', 'Var', (87, 90))	('HGF', 'Gene', (21, 24))	('invasion', 'CPA', (130, 138))	('apoptosis', 'CPA', (119, 128))	('HGF', 'Gene', '3082', (21, 24))	('angiogenesis', 'CPA', (154, 166))	('migration', 'CPA', (140, 149))
571869	15906956	Abnormality of the mechanorecepters of the lower esophagus or its abnormal reaction to stimuli may be involved in the mechanism of swallow syncope.	('syncope', 'Disease', (139, 146))	('Abnormality', 'Var', (0, 11))	('involved', 'Reg', (102, 110))	('syncope', 'Phenotype', 'HP:0001279', (139, 146))	('syncope', 'Disease', 'MESH:D013575', (139, 146))	('reaction to stimuli', 'MPA', (75, 94))
571958	20801121	Prenatal CSL deletion impairs squamous differentiation with loss of early and late differentiation markers such as CK1/CK10 and filaggrin, causing barrier defects and death at birth due to severe dehydration.	('CK1', 'Species', '2498238', (119, 122))	('death', 'Disease', 'MESH:D003643', (167, 172))	('squamous differentiation', 'CPA', (30, 54))	('death', 'Disease', (167, 172))	('dehydration', 'Phenotype', 'HP:0001944', (196, 207))	('dehydration', 'Disease', 'MESH:D003681', (196, 207))	('loss', 'NegReg', (60, 64))	('deletion', 'Var', (13, 21))	('CSL', 'Gene', (9, 12))	('filaggrin', 'Gene', (128, 137))	('barrier', 'Disease', (147, 154))	('causing', 'Reg', (139, 146))	('filaggrin', 'Gene', '14246', (128, 137))	('dehydration', 'Disease', (196, 207))	('CK1', 'Species', '2498238', (115, 118))	('CK1/CK10', 'Protein', (115, 123))	('impairs', 'NegReg', (22, 29))
571966	20801121	Notch inhibition not only impairs squamous differentiation, but leads to basal cell hyperplasia and dysplasia in the mouse esophagus, providing novel insight into the role of Notch signaling in squamous epithelial biology.	('squamous epithelia', 'Phenotype', 'HP:0002860', (194, 212))	('impairs', 'NegReg', (26, 33))	('squamous epithelia', 'Disease', 'MESH:D002294', (194, 212))	('mouse', 'Species', '10090', (117, 122))	('squamous epithelia', 'Disease', (194, 212))	('Notch inhibition', 'Var', (0, 16))	('squamous differentiation', 'CPA', (34, 58))	('basal cell hyperplasia and dysplasia', 'Disease', 'MESH:D002280', (73, 109))	('leads to', 'Reg', (64, 72))
571976	20801121	Lentiviral pGIPZ vector (Open Biosystems, Huntsville, AL) was used to express short hairpin RNA (shRNA) directed against N3 (N3-A, V2LHS_229748 and N3-B, V2LHS_93017), or a non-silencing scramble control sequence (RHS4346).	('N3', 'Gene', '18131', (148, 150))	('V2LHS_229748', 'Var', (131, 143))	('N3-B', 'Gene', '18131', (148, 152))	('N3-B', 'Gene', (148, 152))	('V2LHS_93017', 'Var', (154, 165))	('N3', 'Gene', '18131', (121, 123))	('N3', 'Gene', '18131', (125, 127))
571979	20801121	Small interfering RNA (siRNA) directed against N1 (N1-A, HSS181550 and N1-B, HSS107249), or a non-silencing scramble control sequence (12935-300)(Invitrogen) was transfected transiently using the Lipofectamine  RNAiMAX reagent (Invitrogen), following manufacturer's instructions.	('N1-A', 'Gene', '18128', (51, 55))	('N1', 'Gene', '18128', (47, 49))	('HSS181550', 'Var', (57, 66))	('N1', 'Gene', '18128', (51, 53))	('HSS107249', 'Var', (77, 86))	('N1-A', 'Gene', (51, 55))	('Lipofectamine', 'Chemical', 'MESH:C086724', (196, 209))	('N1', 'Gene', '18128', (71, 73))
571980	20801121	Briefly, 400 ng of 8xCBF1-luc (designated as 8xCSL-luc), a reporter plasmid containing eight copies of the CSL DNA binding consensus sequence or INV2.5-pGL3 containing a 2.5 kb IVL promoter (-2466 to +41)(IVL-luc) was transfected along with or without ICN expression plasmids or a control empty vector (p3XFLAG-CMV-7).	('IVL', 'Gene', (205, 208))	('-2466 to +41', 'Var', (191, 203))	('IVL', 'Gene', '16447', (205, 208))	('IVL', 'Gene', '16447', (177, 180))	('ICN', 'Chemical', '-', (252, 255))	('IVL', 'Gene', (177, 180))
571983	20801121	Briefly, chromatin samples were prepared from fixed 2.5 million cells and immunoprecipitated with rabbit IgG (#sc-3888, Santa Cruz), anti-N1, anti-CSL/RBP-jkappa (#AB5790, Millipore), or anti-Histone H3 (#ab1791-100 Abcam) antibody.	('RBP-jkappa', 'Gene', (151, 161))	('rabbit', 'Species', '9986', (98, 104))	('RBP-jkappa', 'Gene', '19664', (151, 161))	('N1', 'Gene', '18128', (138, 140))	('#ab1791-100 Abcam', 'Var', (204, 221))
571993	20801121	In the esophageal epithelium reconstituted in organotypic 3D culture, Notch inhibition suppressed sharply epithelial stratification as well as early (i.e.	('Notch inhibition', 'Var', (70, 86))	('rat', 'Species', '10116', (119, 122))	('suppressed', 'NegReg', (87, 97))
572002	20801121	Ca2+ increased N1 and N3, but not N2 and N4 mRNA (Figure 4A and Supplementary Figure 6), and that was reflected by the HES5, IVL and CK13 mRNA levels (Figure 1, Supplementary Figures 2).	('HES5', 'MPA', (119, 123))	('CK13', 'Gene', (133, 137))	('CK13', 'Gene', '16663', (133, 137))	('increased', 'PosReg', (5, 14))	('IVL', 'Gene', '16447', (125, 128))	('N1 and N3', 'Gene', '18128', (15, 24))	('Ca2+', 'Var', (0, 4))	('IVL', 'Gene', (125, 128))
572013	20801121	Consistent with this premise, DNMAML1 prevented Ca2+ from inducing N3 mRNA and FL-N3 protein (Figure 4D and E).	('FL-N3', 'Chemical', '-', (79, 84))	('DNMAML1', 'Var', (30, 37))	('inducing', 'PosReg', (58, 66))	('N3', 'Gene', '18131', (67, 69))	('N3', 'Gene', '18131', (82, 84))
572015	20801121	Moreover, repression of DNMAML1 by doxycycline in the Tet-Off system augmented N3 mRNA and ICN3 induction (Supplementary Figure 7C and D), reinforcing the notion of direct CSL-mediated induction and nuclear translocation of the activated N3.	('ICN', 'Chemical', '-', (91, 94))	('N3', 'Gene', '18131', (93, 95))	('N3', 'Gene', '18131', (238, 240))	('doxycycline', 'Chemical', 'MESH:D004318', (35, 46))	('augmented', 'PosReg', (69, 78))	('N3', 'Gene', '18131', (79, 81))	('DNMAML1', 'Gene', (24, 31))	('Tet', 'Chemical', 'MESH:C010349', (54, 57))	('repression', 'Var', (10, 20))
572026	20801121	N1 knockdown compromised Ca2+-mediated induction and activation of N3 as well as Notch target genes (Figure 5C and D, Supplementary Figure 11), implying N1 in N3-mediated squamous differentiation.	('Ca2+-mediated induction', 'MPA', (25, 48))	('compromised', 'NegReg', (13, 24))	('N1', 'Gene', '18128', (0, 2))	('N3', 'Gene', '18131', (67, 69))	('N1', 'Gene', '18128', (153, 155))	('knockdown', 'Var', (3, 12))	('activation', 'MPA', (53, 63))	('N3', 'Gene', '18131', (159, 161))
572030	20801121	N3 knockdown resulted in suppression of the IVL promoter activation as well as IVL mRNA and IVL protein induction (Figure 6B-D, and supplementary Figure 13B and C).	('suppression', 'NegReg', (25, 36))	('IVL', 'Gene', (44, 47))	('IVL', 'Gene', '16447', (79, 82))	('IVL', 'Gene', (92, 95))	('N3', 'Gene', '18131', (0, 2))	('IVL', 'Gene', (79, 82))	('knockdown', 'Var', (3, 12))	('IVL', 'Gene', '16447', (44, 47))	('IVL', 'Gene', '16447', (92, 95))
572031	20801121	Additionally, N3 knockdown suppressed HES5 and CK13 induction (Supplementary Figure 13D and E), implying N3 is involved in their transcriptional regulation.	('CK13', 'Gene', (47, 51))	('CK13', 'Gene', '16663', (47, 51))	('N3', 'Gene', '18131', (105, 107))	('suppressed', 'NegReg', (27, 37))	('HES5', 'Protein', (38, 42))	('knockdown', 'Var', (17, 26))	('N3', 'Gene', '18131', (14, 16))
572032	20801121	Moreover, in organotypic 3D culture, N3 knockdown impaired squamous epithelial stratification and IVL expression without affecting basal cell proliferation (Figure 6E).	('rat', 'Species', '10116', (149, 152))	('IVL', 'Gene', '16447', (98, 101))	('N3', 'Gene', '18131', (37, 39))	('squamous epithelia', 'Disease', (59, 77))	('rat', 'Species', '10116', (81, 84))	('impaired', 'NegReg', (50, 58))	('knockdown', 'Var', (40, 49))	('IVL', 'Gene', (98, 101))	('basal cell proliferation', 'Phenotype', 'HP:0002671', (131, 155))	('squamous epithelia', 'Disease', 'MESH:D002294', (59, 77))	('squamous epithelia', 'Phenotype', 'HP:0002860', (59, 77))
572049	20801121	In mouse, Notch inhibition not only impaired esophageal squamous differentiation, but caused basal cell hyperplasia and dysplasia (Figure 7).	('mouse', 'Species', '10090', (3, 8))	('impaired esophageal squamous differentiation', 'Disease', (36, 80))	('caused', 'Reg', (86, 92))	('impaired esophageal squamous differentiation', 'Disease', 'MESH:D000077277', (36, 80))	('Notch inhibition', 'Var', (10, 26))	('basal cell hyperplasia and dysplasia', 'Disease', 'MESH:D002280', (93, 129))
572050	20801121	These findings establish a novel model whereby crosstalk between N1 and N3 regulates squamous differentiation (Supplementary Figure 14).	('squamous differentiation', 'CPA', (85, 109))	('crosstalk', 'Var', (47, 56))	('N1 and N3', 'Gene', '18128', (65, 74))	('regulates', 'Reg', (75, 84))
572054	20801121	GSI induces goblet cell metaplasia in the rat intestine without affecting normal esophageal squamous epithelium after five daily intraperitoneal injections.	('goblet cell metaplasia', 'CPA', (12, 34))	('induces', 'Reg', (4, 11))	('GSI', 'Chemical', '-', (0, 3))	('esophageal squamous', 'Disease', 'MESH:D000077277', (81, 100))	('esophageal squamous', 'Disease', (81, 100))	('GSI', 'Var', (0, 3))	('rat', 'Species', '10116', (42, 45))
572062	20801121	We suspect mosaicism in the K14Cre;DNMAML1 mouse esophagus as a possible explanation.	('K14', 'Gene', '16664', (28, 31))	('K14', 'Gene', (28, 31))	('mouse', 'Species', '10090', (43, 48))	('mosaicism', 'Var', (11, 20))
572066	20801121	Similar to CK13 expression in esophageal cells, Ca2+ induces skin-specific suprabasal cytokeratins CK1 and CK10 in a Csl-dependent fashion.	('CK1', 'Species', '2498238', (99, 102))	('Ca2+', 'Var', (48, 52))	('Csl', 'Gene', '71832', (117, 120))	('CK1', 'Species', '2498238', (11, 14))	('CK10', 'Gene', (107, 111))	('rat', 'Species', '10116', (92, 95))	('CK1', 'Gene', (99, 102))	('CK13', 'Gene', (11, 15))	('CK1', 'Species', '2498238', (107, 110))	('CK13', 'Gene', '16663', (11, 15))	('Csl', 'Gene', (117, 120))	('induces', 'Reg', (53, 60))
572085	20801121	Reminiscent of our K14Cre;DNMAML1 mouse phenotypes, esophageal hyperplasia has been noted when N3 was deleted in the N1N2 compound knockout mice, phenocopying the gamma-secretase deficient skin.	('gamma-secretase deficient skin', 'Disease', (163, 193))	('esophageal hyperplasia', 'Disease', 'MESH:D006965', (52, 74))	('deleted', 'Var', (102, 109))	('mice', 'Species', '10090', (140, 144))	('mouse', 'Species', '10090', (34, 39))	('N3', 'Gene', '18131', (95, 97))	('K14', 'Gene', '16664', (19, 22))	('N1', 'Gene', '18128', (117, 119))	('esophageal hyperplasia', 'Disease', (52, 74))	('K14', 'Gene', (19, 22))	('gamma-secretase deficient skin', 'Disease', 'MESH:D012871', (163, 193))	('deficient skin', 'Phenotype', 'HP:0000973', (179, 193))
572094	33607850	In this study, we focused on identifying independent prognostic miRNA signatures in tumor and tumor-adjacent tissues in EC.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (84, 89))	('miRNA', 'Var', (64, 69))
572106	33607850	Dysregulation of miRNAs is closely associated with the occurrence and development of tumors by regulating the expression of target genes.	('regulating', 'Reg', (95, 105))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('Dysregulation', 'Var', (0, 13))	('miRNAs', 'Protein', (17, 23))	('associated', 'Reg', (35, 45))	('expression', 'MPA', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
572128	33607850	In TCGA dataset, 3 miRNAs (hsa-miR-197-3p, hsa-miR-186-5p, and hsa-miR-191-5p) were identified as independent risk factors for predicting the OS (all with P < .05) and 6 miRNAs (hsa-miR-150-5p, hsa-miR-29c-3p, hsa-miR-29a-3p, hsa-miR-23b-3p, hsa-miR-27b-3p, and hsa-let-7b-5p) were identified as independent protective factors for OS (all with P < .05).	('hsa-miR-191', 'Gene', (63, 74))	('hsa-miR-29c-3p', 'Var', (194, 208))	('hsa-miR-27b-3p', 'Var', (242, 256))	('hsa-miR-23b-3p', 'Var', (226, 240))	('hsa-miR-197-3p', 'Gene', '100302290', (27, 41))	('hsa-let-7b', 'Gene', '406884', (262, 272))	('hsa-miR-197-3p', 'Gene', (27, 41))	('hsa-let-7b', 'Gene', (262, 272))	('hsa-miR-186', 'Gene', '406962', (43, 54))	('hsa-miR-191', 'Gene', '406966', (63, 74))	('hsa-miR-186', 'Gene', (43, 54))	('hsa-miR-29a-3p', 'Var', (210, 224))	('hsa-miR-150-5p', 'Var', (178, 192))
572129	33607850	In the GSE13937 dataset, multivariate Cox analyses with adjustment for TNM stage and chemoradiation therapy showed that hsa-miR-186-5p and hsa-miR-27b-3p were independent risk factors for predicting the OS (HR = 7.53, 95% CI = 1.47-38.58, P = .015; HR = 2.49, 95% CI = 1.04-5.98, P = .041, respectively).	('age', 'Gene', (77, 80))	('hsa-miR-27b-3p', 'Var', (139, 153))	('age', 'Gene', '5973', (77, 80))	('hsa-miR-186', 'Gene', '406962', (120, 131))	('hsa-miR-186', 'Gene', (120, 131))
572133	33607850	In TCGA dataset, 4 miRNAs (hsa-miR-126-3p, hsa-miR-340-3p, hsa-let-7d-5p, and hsa-miR-192-5p) were identified as independent risk factors for predicting the OS (all P < .05), and six miRNAs (hsa-miR-105-5p, hsa-miR-200b-3p, hsa-miR-429, hsa-miR-494-3p, hsa-miR-376b-3p, and hsa-miR-320a) were identified as independent protective factors for OS (all P < .05).	('hsa-miR-320a', 'Gene', (274, 286))	('hsa-miR-200b-3p', 'Var', (207, 222))	('hsa-miR-429', 'Gene', (224, 235))	('hsa-let-7d', 'Gene', '406886', (59, 69))	('hsa-miR-192', 'Gene', (78, 89))	('hsa-miR-320a', 'Gene', '407037', (274, 286))	('hsa-miR-494-3p', 'Var', (237, 251))	('hsa-miR-126-3p', 'Gene', '100302148', (27, 41))	('hsa-miR-376b-3p', 'Var', (253, 268))	('hsa-let-7d', 'Gene', (59, 69))	('hsa-miR-126-3p', 'Gene', (27, 41))	('hsa-miR-340-3p', 'Var', (43, 57))	('hsa-miR-192', 'Gene', '406967', (78, 89))	('hsa-miR-429', 'Gene', '554210', (224, 235))	('hsa-miR-105-5p', 'Var', (191, 205))
572159	33607850	For instance, in the GSE13937 dataset, hsa-miR-150-5p in the EADC-adjacent tissues was significantly associated with EADC prognosis in both univariate and multivariate analyses, which suggested that the tumor-adjacent tissues may be linked to EC.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('EADC', 'Phenotype', 'HP:0011459', (117, 121))	('EADC', 'Disease', (117, 121))	('hsa-miR-150-5p', 'Var', (39, 53))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('EADC', 'Phenotype', 'HP:0011459', (61, 65))	('associated with', 'Reg', (101, 116))
572194	32046072	If the medium is mostly liquid and can freely move, then liquid movement can lead to the production of microscopic streaming, which can cause cell apoptosis.	('microscopic streaming', 'MPA', (103, 124))	('lead to', 'Reg', (77, 84))	('production', 'MPA', (89, 99))	('cause', 'Reg', (136, 141))	('men', 'Species', '9606', (68, 71))	('cell apoptosis', 'CPA', (142, 156))	('liquid movement', 'Var', (57, 72))
572252	32046072	Transurethral resection of the prostate before HIFU treatment have been reported to mitigate urinary retention and significantly reduces indwelling catheter-required time from 40 to 7 days.	('to 7', 'Species', '1214577', (179, 183))	('Transurethral', 'Var', (0, 13))	('indwelling catheter-required time', 'MPA', (137, 170))	('urinary retention', 'Phenotype', 'HP:0000016', (93, 110))	('urinary', 'MPA', (93, 100))	('mitigate', 'NegReg', (84, 92))	('men', 'Species', '9606', (57, 60))	('reduces', 'NegReg', (129, 136))
572315	32046072	Disruption of key motor nuclei can lead to significant improvement in motor symptoms.	('improvement', 'PosReg', (55, 66))	('men', 'Species', '9606', (62, 65))	('motor symptoms', 'MPA', (70, 84))	('Disruption', 'Var', (0, 10))
572391	32012474	Finally, only one patient (2.9%) experienced a transient delayed conduit emptying due to a mechanical obstruction caused by an acute angle that developed in an abnormally long gastric conduit as it lay in the chest cavity, and as confirmed by upper gastrointestinal radiography.	('acute angle', 'Var', (127, 138))	('mechanical obstruction', 'Disease', 'MESH:D006930', (91, 113))	('mechanical obstruction', 'Disease', (91, 113))	('gastrointestinal', 'Disease', (249, 265))	('patient', 'Species', '9606', (18, 25))	('delayed conduit emptying', 'CPA', (57, 81))	('gastrointestinal', 'Disease', 'MESH:D005767', (249, 265))
572441	32025392	Genes involved in the pathogenesis of iron deficiency anemia associated with PVS include a mutation in the TMPRSS6 gene.	('mutation', 'Var', (91, 99))	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (38, 60))	('PVS', 'Disease', 'MESH:D011004', (77, 80))	('TMPRSS6', 'Gene', '164656', (107, 114))	('iron deficiency anemia', 'Disease', 'MESH:D018798', (38, 60))	('iron deficiency anemia', 'Disease', (38, 60))	('anemia', 'Phenotype', 'HP:0001903', (54, 60))	('TMPRSS6', 'Gene', (107, 114))	('PVS', 'Disease', (77, 80))
572482	31620505	Infection with HPV may also be associated with an increased risk of having esophageal squamous cell papillomas based on some observational studies.	('esophageal squamous cell papillomas', 'Disease', (75, 110))	('squamous cell papillomas', 'Phenotype', 'HP:0031021', (86, 110))	('associated', 'Reg', (31, 41))	('papillomas', 'Phenotype', 'HP:0012740', (100, 110))	('HPV', 'Species', '10566', (15, 18))	('Infection', 'Var', (0, 9))	('HPV', 'Gene', (15, 18))	('esophageal squamous cell papillomas', 'Phenotype', 'HP:0031463', (75, 110))	('papilloma', 'Phenotype', 'HP:0012740', (100, 109))	('esophageal squamous cell papillomas', 'Disease', 'MESH:D010212', (75, 110))
572524	29707153	Finally, the kallikreins can activate one another, and cross-activation of kallikreins may be related to malignancies.	('malignancies', 'Disease', (105, 117))	('kallikrein', 'Gene', (75, 85))	('kallikrein', 'Gene', (13, 23))	('kallikrein', 'Gene', '9622', (75, 85))	('kallikrein', 'Gene', '9622', (13, 23))	('cross-activation', 'Var', (55, 71))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))	('activate', 'PosReg', (29, 37))	('related', 'Reg', (94, 101))
572598	29707153	Thyroid hormones regulate kallikrein levels, and the dysfunction of thyroid hormones during thyroid carcinoma may lead to the dramatic changes in the kallikreins' expression.	('changes', 'Reg', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (92, 109))	('kallikrein', 'Gene', (26, 36))	('kallikrein', 'Gene', '9622', (150, 160))	('dysfunction of thyroid hormones', 'Phenotype', 'HP:0002930', (53, 84))	('kallikrein', 'Gene', (150, 160))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (92, 109))	('kallikrein', 'Gene', '9622', (26, 36))	('expression', 'MPA', (163, 173))	('dysfunction', 'Var', (53, 64))	('thyroid carcinoma', 'Disease', (92, 109))	('lead to', 'Reg', (114, 121))
572605	29707153	Increased KLK8 has been associated with a favorable clinical outcome in lung adenocarcinoma by suppressing tumor invasiveness through inhibition of integrin signaling and cell adhesion; however we could not confirm this finding in our study.	('suppressing', 'NegReg', (95, 106))	('tumor invasiveness', 'Disease', (107, 125))	('lung adenocarcinoma', 'Disease', (72, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Increased', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('inhibition', 'NegReg', (134, 144))	('tumor invasiveness', 'Disease', 'MESH:D009369', (107, 125))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('KLK8', 'Gene', '11202', (10, 14))	('integrin signaling', 'MPA', (148, 166))	('KLK8', 'Gene', (10, 14))	('cell adhesion', 'CPA', (171, 184))
572661	29344225	In conclusion, metformin can inhibit the proliferation, promote apoptosis and enhance the chemosensitivity of hepatocarcinoma cells to cisplatin through AMPK pathway.	('enhance', 'PosReg', (78, 85))	('AMPK', 'Gene', (153, 157))	('metformin', 'Chemical', 'MESH:D008687', (15, 24))	('chemosensitivity', 'CPA', (90, 106))	('hepatocarcinoma cells', 'Disease', 'MESH:C538614', (110, 131))	('apoptosis', 'CPA', (64, 73))	('inhibit', 'NegReg', (29, 36))	('hepatocarcinoma cells', 'Disease', (110, 131))	('promote', 'PosReg', (56, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('AMPK', 'Gene', '5563', (153, 157))	('metformin', 'Var', (15, 24))	('proliferation', 'CPA', (41, 54))
572696	29344225	After incubation for 48 h, apoptosis rate of cisplatin (8 microM) + metformin (10 mmol/l) was significantly higher than that of cisplatin group (P<0.05) (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('cisplatin', 'Var', (45, 54))	('metformin', 'Chemical', 'MESH:D008687', (68, 77))	('apoptosis rate', 'CPA', (27, 41))	('higher', 'PosReg', (108, 114))
572703	29344225	Ratio of p-AMPK/AMPK in cisplatin + metformin was significantly higher than that in cisplatin group (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))	('metformin', 'Chemical', 'MESH:D008687', (36, 45))	('AMPK', 'Gene', (16, 20))	('higher', 'PosReg', (64, 70))	('cisplatin', 'Var', (24, 33))	('AMPK', 'Gene', '5563', (11, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('AMPK', 'Gene', '5563', (16, 20))	('AMPK', 'Gene', (11, 15))
572714	29344225	Cisplatin can also bind to purine and pyrimidine bases of DNA in nucleus to form cisplatin and DNA complex to cause DNA breakage and error code, which in turn inhibit DNA replication and transcription, thereby inducing tumor cell apoptosis to play a role in treating tumors.	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('error code', 'Var', (133, 143))	('transcription', 'CPA', (187, 200))	('DNA', 'MPA', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('cause', 'Reg', (110, 115))	('tumors', 'Disease', (267, 273))	('purine', 'Chemical', 'MESH:C030985', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('inducing', 'Reg', (210, 218))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('pyrimidine', 'Chemical', 'MESH:C030986', (38, 48))	('tumor', 'Disease', (267, 272))	('inhibit', 'NegReg', (159, 166))
572723	29344225	A prospective study on patients with endometrial cancer showed a significant correlation between metformin intake and increased recurrence-free survival and overall survival.	('metformin', 'Chemical', 'MESH:D008687', (97, 106))	('patients', 'Species', '9606', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('increased', 'PosReg', (118, 127))	('endometrial cancer', 'Disease', (37, 55))	('metformin', 'Var', (97, 106))	('recurrence-free survival', 'CPA', (128, 152))	('overall survival', 'CPA', (157, 173))	('endometrial cancer', 'Phenotype', 'HP:0012114', (37, 55))	('endometrial cancer', 'Disease', 'MESH:D016889', (37, 55))
572729	29344225	This study found that metformin can enhance the chemosensitivity of drug-resistant hepatocarcinoma cell lines to chemotherapeutic drugs cisplatin, and the possible molecular mechanism of the function of metformin was also explored.	('metformin', 'Var', (22, 31))	('metformin', 'Chemical', 'MESH:D008687', (22, 31))	('metformin', 'Chemical', 'MESH:D008687', (203, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('hepatocarcinoma', 'Disease', 'None', (83, 98))	('enhance', 'PosReg', (36, 43))	('chemosensitivity', 'MPA', (48, 64))	('hepatocarcinoma', 'Disease', (83, 98))
572730	29344225	Results showed that cisplatin could inhibit the proliferation and promote apoptosis of HepG2 and Huh-7 hepatocarcinoma cells.	('Huh-7', 'Gene', (97, 102))	('apoptosis', 'CPA', (74, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('Huh-7', 'Gene', '284424', (97, 102))	('hepatocarcinoma cells', 'Disease', 'MESH:C538614', (103, 124))	('proliferation', 'CPA', (48, 61))	('inhibit', 'NegReg', (36, 43))	('hepatocarcinoma cells', 'Disease', (103, 124))	('promote', 'PosReg', (66, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cisplatin', 'Var', (20, 29))	('HepG2', 'CellLine', 'CVCL:0027', (87, 92))
572736	29344225	Studies have shown that metformin can activate AMPK, thereby inhibiting signal transduction of mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B and inhibiting the growth of breast cancer, lymphoma and other cancers.	('mitogen-activated', 'MPA', (95, 112))	('inhibiting', 'NegReg', (61, 71))	('signal transduction', 'MPA', (72, 91))	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('growth', 'CPA', (198, 204))	('protein kinase B', 'Gene', '2185', (162, 178))	('lymphoma', 'Phenotype', 'HP:0002665', (223, 231))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('AMPK', 'Gene', '5563', (47, 51))	('protein kinase B', 'Gene', (162, 178))	('metformin', 'Var', (24, 33))	('metformin', 'Chemical', 'MESH:D008687', (24, 33))	('inhibiting', 'NegReg', (183, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancers', 'Disease', (242, 249))	('AMPK', 'Gene', (47, 51))	('lymphoma', 'Disease', (223, 231))	('lymphoma', 'Disease', 'MESH:D008223', (223, 231))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('breast cancer', 'Disease', (208, 221))
572751	29093644	The cell proliferation significantly decreased and cell apoptosis was induced with combined crocetin and cisplatin, compared with either crocetin only or cisplatin only.	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('cell proliferation', 'CPA', (4, 22))	('cisplatin', 'Var', (105, 114))	('crocetin', 'Chemical', 'MESH:C010561', (92, 100))	('crocetin', 'Chemical', 'MESH:C010561', (137, 145))	('induced', 'Reg', (70, 77))	('cell apoptosis', 'CPA', (51, 65))	('decreased', 'NegReg', (37, 46))
572800	29093644	However, after the cells were treated with crocetin or cisplatin for 48 h, the cell morphology markedly changed: the cells were significantly reduced in number, appeared shrunk and round, and became loosely arranged.	('changed', 'Reg', (104, 111))	('reduced', 'NegReg', (142, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('crocetin', 'Chemical', 'MESH:C010561', (43, 51))	('cell morphology', 'CPA', (79, 94))	('cisplatin', 'Var', (55, 64))
572840	29093644	The results we obtained indicated that the combination of crocetin and cisplatin significantly inhibited cell proliferation and induced cell apoptosis in KYSE-150 cells.	('crocetin', 'Chemical', 'MESH:C010561', (58, 66))	('cisplatin', 'Var', (71, 80))	('cell apoptosis', 'CPA', (136, 150))	('inhibited', 'NegReg', (95, 104))	('combination', 'Interaction', (43, 54))	('KYSE-150', 'CellLine', 'CVCL:1348', (154, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))	('induced', 'Reg', (128, 135))	('cell proliferation', 'CPA', (105, 123))
572846	29093644	The phosphorylated PI3K can activate AKT.	('PI3', 'Gene', '5266', (19, 22))	('AKT', 'Gene', '207', (37, 40))	('activate', 'PosReg', (28, 36))	('PI3', 'Gene', (19, 22))	('phosphorylated', 'Var', (4, 18))	('AKT', 'Gene', (37, 40))
572861	29093644	The expression of Aquaporin 5 was positively correlated with drug resistance in colon cancer, and silencing of Aquaporin 5 suppressed p38 MAPK signaling and improved drug resistance in colon cancer cells.	('colon cancer', 'Disease', (80, 92))	('colon cancer', 'Phenotype', 'HP:0003003', (185, 197))	('MAPK', 'Gene', (138, 142))	('Aquaporin 5', 'Gene', '362', (18, 29))	('p38', 'Gene', '5594', (134, 137))	('colon cancer', 'Disease', 'MESH:D015179', (185, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('improved', 'PosReg', (157, 165))	('colon cancer', 'Phenotype', 'HP:0003003', (80, 92))	('p38', 'Gene', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('silencing', 'Var', (98, 107))	('Aquaporin 5', 'Gene', '362', (111, 122))	('Aquaporin 5', 'Gene', (18, 29))	('colon cancer', 'Disease', (185, 197))	('colon cancer', 'Disease', 'MESH:D015179', (80, 92))	('drug resistance', 'MPA', (166, 181))	('suppressed', 'NegReg', (123, 133))	('MAPK', 'Gene', '5595;5594;5595', (138, 142))	('drug resistance', 'Phenotype', 'HP:0020174', (166, 181))	('drug resistance', 'Phenotype', 'HP:0020174', (61, 76))	('Aquaporin 5', 'Gene', (111, 122))	('drug resistance', 'Disease', (61, 76))	('correlated', 'Reg', (45, 55))
572869	29093644	Activated p21 could induce the arrest of cell growth.	('induce', 'Reg', (20, 26))	('p21', 'Gene', (10, 13))	('Activated', 'Var', (0, 9))	('arrest of cell growth', 'CPA', (31, 52))	('p21', 'Gene', '1026', (10, 13))
572871	29093644	An increasing number of evidence confirmed that the occurrence of EC exhibits a close correlation with high mutant p53 expression and low p21 expression.	('expression', 'MPA', (119, 129))	('p21', 'Gene', '1026', (138, 141))	('p21', 'Gene', (138, 141))	('high mutant', 'Var', (103, 114))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('low', 'NegReg', (134, 137))
572872	29093644	However, mutant p53 lost it normal function.	('normal function', 'MPA', (28, 43))	('lost', 'NegReg', (20, 24))	('p53', 'Gene', (16, 19))	('mutant', 'Var', (9, 15))	('p53', 'Gene', '7157', (16, 19))
572936	27818592	As shown in Table 5, the areas of ROC curves for the combination of the three biomarkers were 0.837, 0.740, 0.590 and 0.562 in the ESCC, HGD, LGD and BCH groups, respectively.	('0.740', 'Var', (101, 106))	('BCH', 'Chemical', '-', (150, 153))	('0.590', 'Var', (108, 113))	('0.562', 'Var', (118, 123))	('ESCC', 'Disease', (131, 135))
572946	27818592	Bagaria et al reported that with the specificity set at 100%, the sensitivity for esophageal cancer was 28%, 18% and 42% for CEA, CA19-9 and their combination, respectively.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('CEA', 'Gene', (125, 128))	('CA19-9', 'Var', (130, 136))	('CEA', 'Gene', '1084', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('esophageal cancer', 'Disease', (82, 99))
572967	27818592	CA19-9 is a high-molecular-mass mucin glycoprotein complex and is used as a tumor marker for cancers of the colon, stomach, pancreas and bile duct.	('pancreas', 'Disease', 'MESH:D010190', (124, 132))	('bile duct', 'Disease', (137, 146))	('tumor', 'Disease', (76, 81))	('cancers of the colon', 'Disease', (93, 113))	('stomach', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('pancreas', 'Disease', (124, 132))	('cancers of the colon', 'Disease', 'MESH:D015179', (93, 113))	('CA19-9', 'Var', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
572970	28174712	From its origins in the study of gastrointestinal hormones, the section's membership has interests representing many areas of cutting-edge science, including growth factors and stem cells, cellular differentiation in the gastrointestinal (GI) tract, epigenetics, mechanisms of receptor function, basic physiology and cell biology, luminal chemosensing, intestinal inflammation, and mucosal injury and healing.	('mucosal injury', 'Disease', 'MESH:D052016', (382, 396))	('mucosal injury', 'Disease', (382, 396))	('cellular differentiation', 'CPA', (189, 213))	('intestinal inflammation', 'Disease', 'MESH:D007249', (353, 376))	('intestinal inflammation', 'Disease', (353, 376))	('epigenetics', 'Var', (250, 261))
572972	28174712	Sunday, May 22, 2016: "Transcriptional and Epigenetic Regulation of GI Cancers."	('GI Cancers', 'Disease', 'MESH:D009369', (68, 78))	('Cancers', 'Phenotype', 'HP:0002664', (71, 78))	('Epigenetic', 'Var', (43, 53))	('GI Cancers', 'Disease', (68, 78))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
572974	28174712	Saturday, May 21, 2016: "Genetic and Epigenetic Drivers of Colorectal Cancer."	('Colorectal Cancer', 'Disease', 'MESH:D015179', (59, 76))	('Epigenetic', 'Var', (37, 47))	('Colorectal Cancer', 'Disease', (59, 76))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (59, 76))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))
572992	28174712	Other topics will include the role of gene fusions in esophageal adenocarcinoma and circulating neuroendocrine gene transcripts that predict the progression and recurrence of these tumors after surgery.	('gene fusions', 'Var', (38, 50))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (54, 79))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('esophageal adenocarcinoma', 'Disease', (54, 79))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (54, 79))	('neuroendocrine', 'Disease', 'MESH:D018358', (96, 110))	('neuroendocrine', 'Disease', (96, 110))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
573104	28174712	This collaborative symposium will cover the emerging study of variations in genes involved in carbohydrate digestion/absorption to guide dietary therapy in IBS, the role of dietary nutrients and dietary supplements in IBD treatment, the role of enteral nutrition in the treatment of intestinal failure, and the role of diet in the management of obesity, metabolic syndrome, and nonalcoholic fatty liver disease.	('nonalcoholic fatty liver disease', 'Disease', 'MESH:D065626', (378, 410))	('obesity', 'Disease', (345, 352))	('intestinal failure', 'Phenotype', 'HP:0005214', (283, 301))	('variations', 'Var', (62, 72))	('metabolic syndrome', 'Disease', 'MESH:D008659', (354, 372))	('liver disease', 'Phenotype', 'HP:0001392', (397, 410))	('metabolic syndrome', 'Disease', (354, 372))	('intestinal failure', 'Disease', (283, 301))	('obesity', 'Phenotype', 'HP:0001513', (345, 352))	('fatty liver', 'Phenotype', 'HP:0001397', (391, 402))	('carbohydrate', 'Chemical', 'MESH:D002241', (94, 106))	('IBS', 'Disease', (156, 159))	('nonalcoholic fatty liver disease', 'Disease', (378, 410))	('IBS', 'Disease', 'MESH:D043183', (156, 159))	('intestinal failure', 'Disease', 'MESH:D007410', (283, 301))	('obesity', 'Disease', 'MESH:D009765', (345, 352))
573131	28174712	Topics include the following: "Introductory Case: Sporadic PRSS1 Mutation in Patient With Single Attack of Pancreatitis (Matthew DiMagno), "Presentation of Research Mentor Award: David C. Whitcomb, MD, PhD, AGAF" (Matthew DiMagno and Santhi Vege), "View of the Geneticist-Classifying the Significance of Mutations" (Randall Brand), "Pro and Con of Genetic Screening in Chronic Pancreatitis" (David C. Whitcomb), "Genomic Analysis in Chronic Pancreatitis" (Andrew Rhim), and "Epigenetics at the Intersection of Chronic Pancreatitis and Pancreatic Cancer" (Raul Urrutia).	('Pancreatitis', 'Phenotype', 'HP:0001733', (377, 389))	('Pancreatitis', 'Disease', 'MESH:D010195', (441, 453))	('PRSS1', 'Gene', (59, 64))	('Pancreatitis', 'Phenotype', 'HP:0001733', (107, 119))	('Patient', 'Species', '9606', (77, 84))	('Chronic Pancreatitis', 'Phenotype', 'HP:0006280', (510, 530))	('Pancreatitis', 'Disease', 'MESH:D010195', (377, 389))	('Chronic Pancreatitis', 'Phenotype', 'HP:0006280', (369, 389))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (535, 552))	('Pancreatitis', 'Phenotype', 'HP:0001733', (518, 530))	('PRSS1', 'Gene', '5644', (59, 64))	('Pancreatitis', 'Disease', 'MESH:D010195', (107, 119))	('Pancreatitis', 'Disease', (441, 453))	('Chronic Pancreatitis', 'Disease', (433, 453))	('Pancreatitis', 'Disease', 'MESH:D010195', (518, 530))	('Pancreatitis', 'Disease', (377, 389))	('Chronic Pancreatitis', 'Disease', 'MESH:D050500', (433, 453))	('Pancreatitis', 'Disease', (107, 119))	('Chronic Pancreatitis', 'Disease', (510, 530))	('Pancreatic Cancer', 'Disease', (535, 552))	('Chronic Pancreatitis', 'Disease', (369, 389))	('Pancreatitis', 'Disease', (518, 530))	('Chronic Pancreatitis', 'Disease', 'MESH:D050500', (510, 530))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (535, 552))	('Chronic Pancreatitis', 'Disease', 'MESH:D050500', (369, 389))	('Mutation', 'Var', (65, 73))	('Cancer', 'Phenotype', 'HP:0002664', (546, 552))	('Pancreatitis', 'Phenotype', 'HP:0001733', (441, 453))	('Chronic Pancreatitis', 'Phenotype', 'HP:0006280', (433, 453))
573161	21943206	Blood examination showed leucocytosis (12430/mm3), but normal level of C-reactive protein.	('leucocytosis', 'Disease', (25, 37))	('12430/mm3', 'Var', (39, 48))	('leucocytosis', 'Disease', 'None', (25, 37))
573191	15831992	M1a disease is further classified by tumor location; M1a tumors of the upper thoracic esophagus metastatic to cervical nodes and M1a tumors of the lower thoracic esophagus metastatic to celiac lymph nodes.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('M1a', 'Var', (53, 56))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumor', 'Disease', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
573194	15831992	We report our surgical results of M1a and M1b esophageal squamous cell carcinoma and evaluate the clinical relevance of the M1a and M1b subclassification.	('M1b', 'Var', (42, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (46, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('M1a', 'Var', (34, 37))	('esophageal squamous cell carcinoma', 'Disease', (46, 80))
573210	15831992	Patients with M1a disease showed better survival than those with M1b disease by the log rank test (p=0.0488) as shown in Fig.	('M1a', 'Var', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (33, 39))	('survival', 'CPA', (40, 48))
573214	15831992	Multivariate analysis was performed using likelihood-ratio statistics based on the conditional parameter estimate, and M1b disease was found to be the only significant risk factor in the prognosis of stage IV esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (220, 243))	('esophageal squamous cell carcinoma', 'Disease', (209, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (209, 243))	('M1b', 'Var', (119, 122))
573230	31031863	Meanwhile, 8 studies with 1862 cases revealed that elevated XIAP level predicted shorter disease-free survival (DFS) (HR=2.17, 95% CI: 1.03-4.59).	('elevated', 'Var', (51, 59))	('disease-free survival', 'CPA', (89, 110))	('XIAP', 'Gene', (60, 64))	('XIAP', 'Gene', '331', (60, 64))	('shorter', 'NegReg', (81, 88))
573272	31031863	Dealing with different ethnicities, high XIAP expression was a negative prognostic marker for both Caucasian patients (HR=1.29, 95% CI: 1.05-1.59, P heterogeneity<0.001) and Asian patients (HR=2.07, 95% CI: 1.47-2.92, P heterogeneity<0.001).	('XIAP', 'Gene', (41, 45))	('XIAP', 'Gene', '331', (41, 45))	('high', 'Var', (36, 40))	('patients', 'Species', '9606', (109, 117))	('negative', 'NegReg', (63, 71))	('patients', 'Species', '9606', (180, 188))
573282	31031863	Although most studies demonstrated that expression of XIAP was associated with poor prognosis in cancer, some researchers reported contradictory predictive value of XIAP or even found no significant relationship between its level and clinical survival.	('XIAP', 'Gene', '331', (165, 169))	('cancer', 'Disease', (97, 103))	('expression', 'Var', (40, 50))	('associated', 'Reg', (63, 73))	('XIAP', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('XIAP', 'Gene', '331', (54, 58))	('XIAP', 'Gene', (165, 169))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
573350	30543139	Despite the patient's advanced age, extensive adhesion from the first surgery, and the gravity of the intervention, the patient showed no more complications after RAMIE4.	('RAMIE4', 'Var', (163, 169))	('patient', 'Species', '9606', (120, 127))	('adhesion', 'CPA', (46, 54))	('patient', 'Species', '9606', (12, 19))
573361	27698800	High expression of lncRNA PVT1 promotes invasion by inducing epithelial-to-mesenchymal transition in esophageal cancer The long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) has been identified as an oncogene in numerous diseases, and aberrant lncRNA PVT1 expression has been associated with the development of cancer.	('PVT1', 'Gene', (26, 30))	('cancer', 'Disease', (112, 118))	('PVT1', 'Gene', '5820', (26, 30))	('esophageal cancer', 'Disease', (101, 118))	('plasmacytoma', 'Phenotype', 'HP:0011857', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PVT1', 'Gene', (190, 194))	('PVT1', 'Gene', '5820', (190, 194))	('cancer', 'Disease', (333, 339))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('numerous diseases', 'Disease', (234, 251))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('associated', 'Reg', (298, 308))	('PVT1', 'Gene', (273, 277))	('aberrant', 'Var', (257, 265))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('PVT1', 'Gene', '5820', (273, 277))	('numerous diseases', 'Disease', 'MESH:D004194', (234, 251))	('inducing', 'Reg', (52, 60))	('epithelial-to-mesenchymal transition', 'CPA', (61, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))
573406	27698800	The aberrant expression level of lncRNA PVT1 in the cancer tissues suggested that lncRNA PVT1 may play an important role in the development of esophageal cancer.	('lncRNA', 'Gene', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('PVT1', 'Gene', '5820', (40, 44))	('aberrant', 'Var', (4, 12))	('cancer', 'Disease', (154, 160))	('play', 'Reg', (98, 102))	('PVT1', 'Gene', (89, 93))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('expression level', 'MPA', (13, 29))	('role', 'Reg', (116, 120))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('PVT1', 'Gene', '5820', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('esophageal cancer', 'Disease', (143, 160))	('PVT1', 'Gene', (40, 44))
573410	27698800	To explore the mechanism of lncRNA PVT1 and cell invasion in esophageal cancer, lncRNA PVT1 expression was upregulated in TE-1 cells by transfection with lentivirus (named LV-lncRNA), and downregulated in Eca-10 cells by siRNA interference (named lncRNA-siRNA).	('downregulated', 'NegReg', (188, 201))	('PVT1', 'Gene', '5820', (35, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('upregulated', 'PosReg', (107, 118))	('PVT1', 'Gene', (87, 91))	('Eca-10', 'CellLine', 'CVCL:6898', (205, 211))	('lentivirus', 'Var', (154, 164))	('PVT1', 'Gene', (35, 39))	('esophageal cancer', 'Disease', (61, 78))	('expression', 'MPA', (92, 102))	('PVT1', 'Gene', '5820', (87, 91))
573427	27698800	In the current study, it was also discovered that abnormal expression of lncRNA PVT1 could regulate markers of EMT.	('regulate', 'Reg', (91, 99))	('PVT1', 'Gene', '5820', (80, 84))	('expression', 'MPA', (59, 69))	('abnormal', 'Var', (50, 58))	('PVT1', 'Gene', (80, 84))	('markers of EMT', 'CPA', (100, 114))
573434	25644061	Recently, a strong link between microRNA dysregulation and human cancers has been established.	('microRNA', 'Var', (32, 40))	('human', 'Species', '9606', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Disease', (65, 72))
573441	25644061	Though implicated in carcinogenesis, it is not clear how miRNAs promote tumorigenesis and metastasis or what networks regulate miRNAs expression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('promote', 'PosReg', (64, 71))	('metastasis', 'CPA', (90, 100))	('tumor', 'Disease', (72, 77))	('miRNAs', 'Var', (57, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (21, 35))	('carcinogenesis', 'Disease', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
573445	25644061	Overexpression of miR-31 has been linked to disease progression in colorectal cancer, head-and-neck squamous cell carcinoma (HNSCC) and lung cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('head-and-neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (86, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (125, 130))	('linked to', 'Reg', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('miR-31', 'Gene', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('colorectal cancer', 'Disease', (67, 84))	('Overexpression', 'Var', (0, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('neck squamous cell carcinoma', 'Disease', (95, 123))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('lung cancer', 'Disease', (136, 147))
573459	25644061	The histone methyltransferase EZH2 (enhancer of zeste homolog 2) epigenetically regulates genes involved in cell fate determination.	('EZH2', 'Gene', (30, 34))	('enhancer of zeste homolog 2', 'Gene', '2146', (36, 63))	('epigenetically', 'Var', (65, 79))	('regulates', 'Reg', (80, 89))	('genes', 'Gene', (90, 95))	('enhancer of zeste homolog 2', 'Gene', (36, 63))
573464	25644061	Genetic and epigenetic loss of miR-31 is associated with EZH2 overexpression in melanoma, suggesting that miR-31 directly or indirectly regulates EZH2 expression.	('epigenetic loss', 'Var', (12, 27))	('EZH2', 'Gene', (57, 61))	('associated', 'Reg', (41, 51))	('miR-31', 'Gene', (31, 37))	('regulates', 'Reg', (136, 145))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('expression', 'MPA', (151, 161))	('overexpression', 'PosReg', (62, 76))
573471	25644061	Comparing esophageal squamous cell carcinoma cell lines, TE11 is less motile than TE8 and displays an epithelial phenotype (Figure 1A).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (10, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('esophageal squamous cell carcinoma', 'Disease', (10, 44))	('TE11', 'Var', (57, 61))	('less', 'NegReg', (65, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))
573472	25644061	The esophageal adenocarcinoma cell lines OE33 and FLO1 differ in that FLO1 is more mesenchymal and therefore more motile than the OE33 (Figure 1B).	('more', 'PosReg', (78, 82))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (4, 29))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (4, 29))	('esophageal adenocarcinoma', 'Disease', (4, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('motile', 'CPA', (114, 120))	('FLO1', 'Var', (70, 74))	('more', 'PosReg', (109, 113))
573473	25644061	After miR-200a and 200b, which are known for their roles in EMT, miR-31 was the most downregulated miRNA in invasive FLO1 cells compared to their less invasive OE33 counterparts by qPCR screen (Figure 1C).	('miR-31', 'Var', (65, 71))	('downregulated', 'NegReg', (85, 98))	('miRNA', 'MPA', (99, 104))	('miR-200a', 'Gene', (6, 14))	('miR-200a', 'Gene', '406983', (6, 14))
573477	25644061	In FLO1 cells, however, miR-31 suppressed proliferation and colony formation (Figure 2D, E, respectively), indicating miR-31 regulates esophageal carcinoma cell growth in some cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('proliferation', 'CPA', (42, 55))	('miR-31', 'Var', (118, 124))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (135, 155))	('colony formation', 'CPA', (60, 76))	('miR-31', 'Var', (24, 30))	('esophageal carcinoma', 'Disease', (135, 155))	('suppressed', 'NegReg', (31, 41))	('regulates', 'Reg', (125, 134))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (135, 155))
573479	25644061	We therefore speculated that loss of miR-31 in invasive esophageal cancer cells could be mediated, in part, by DNA and histone methylation.	('invasive esophageal cancer', 'Disease', 'MESH:D004938', (47, 73))	('methylation', 'Var', (127, 138))	('invasive esophageal cancer', 'Disease', (47, 73))	('loss', 'NegReg', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('histone', 'Reg', (119, 126))	('miR-31', 'Gene', (37, 43))
573493	25644061	SOX4 knockdown (Figure 5A) using shRNA led to significant upregulation of miR-31 in TE8 and FLO1 cells, while miR-191 and miR-423-5p, used as controls, did not show any significant change (Figure 5B and C).	('miR-423', 'Gene', '494335', (122, 129))	('miR-191', 'Gene', '406966', (110, 117))	('knockdown', 'Var', (5, 14))	('miR-191', 'Gene', (110, 117))	('miR-31', 'Gene', (74, 80))	('miR-423', 'Gene', (122, 129))	('SOX4', 'Gene', (0, 4))	('upregulation', 'PosReg', (58, 70))
573494	25644061	We next investigated if loss of SOX4 functionally mimics overexpression of miR-31 in esophageal cancer cells.	('loss', 'Var', (24, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('miR-31', 'Gene', (75, 81))	('esophageal cancer', 'Disease', (85, 102))
573499	25644061	HDAC3 and H3K27me3 were equally enriched at the MYT1 promoter, which was used as a positive control as EZH2 has been shown to bind and regulate MYT1 promoter activity.	('regulate', 'Reg', (135, 143))	('MYT1', 'Gene', '4661', (48, 52))	('MYT1', 'Gene', (144, 148))	('MYT1', 'Gene', (48, 52))	('bind', 'Interaction', (126, 130))	('H3K27me3', 'Var', (10, 18))	('MYT1', 'Gene', '4661', (144, 148))
573519	25644061	A number of studies argue that epithelial-mesenchymal transition (EMT) plays a crucial role in cancer metastasis and progression, and loss of miR-200 family members drives EMT in multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer metastasis', 'Disease', 'MESH:D009362', (95, 112))	('multiple cancers', 'Disease', 'MESH:D009369', (179, 195))	('drives', 'PosReg', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('epithelial-mesenchymal transition', 'CPA', (31, 64))	('miR-200', 'Gene', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer metastasis', 'Disease', (95, 112))	('multiple cancers', 'Disease', (179, 195))	('loss', 'Var', (134, 138))	('EMT', 'CPA', (172, 175))
573525	25644061	Therefore, we propose a key role for Polycomb/EZH2, HDAC and DNMT for survival and metastasis of esophageal cancers.	('metastasis of esophageal cancers', 'Disease', (83, 115))	('HDAC', 'Gene', (52, 56))	('HDAC', 'Gene', '9734', (52, 56))	('metastasis of esophageal cancers', 'Disease', 'MESH:D009362', (83, 115))	('DNMT', 'Gene', '1786', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Polycomb/EZH2', 'Var', (37, 50))	('DNMT', 'Gene', (61, 65))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))
573529	25644061	Additional studies will aim to identify a subset of patients with concomitant high SOX4, EZH2 and HDAC3 and low miR-31 to demonstrate the mechanistic and clinical correlation between these pathways.	('high', 'Var', (78, 82))	('EZH2', 'Gene', (89, 93))	('miR-31', 'Gene', (112, 118))	('low', 'NegReg', (108, 111))	('HDAC3', 'Gene', (98, 103))	('SOX4', 'Gene', (83, 87))	('patients', 'Species', '9606', (52, 60))
573551	25644061	Equal volumes of chromatin were immunoprecipitated with anti-HDAC3, anti-SOX4, anti-EZH2, anti-trimethyl-Histone H3 Lys27 or normal IgG as a negative control (Millipore).	('anti-EZH2', 'Var', (79, 88))	('anti-trimethyl-Histone H3 Lys27', 'Var', (90, 121))	('trimethyl-Histone', 'Chemical', '-', (95, 112))	('anti-SOX4', 'Var', (68, 77))	('IgG', 'Gene', '16059', (132, 135))	('IgG', 'Gene', (132, 135))	('anti-HDAC3', 'Var', (56, 66))	('Lys27', 'Chemical', '-', (116, 121))
573587	32677925	Based on EORTC multi-center clinical trials and tests, the combination of QLQ-C30 and QLQ-OESl8 was found to more accurately reflect the degree of association between the symptoms of esophageal cancer patients and their QOL.	('patients', 'Species', '9606', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('QLQ-OESl8', 'Var', (86, 95))	('esophageal cancer', 'Disease', (183, 200))	('reflect', 'Reg', (125, 132))	('QLQ-C30', 'Var', (74, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (183, 200))
573671	31786674	This increased risk of death observed for alcohol consumers was more evident in patients with normal p53 expression, GLUT-1 positive or CD-8 positive tumors.	('tumors', 'Disease', (150, 156))	('GLUT-1', 'Gene', (117, 123))	('GLUT-1', 'Gene', '6513', (117, 123))	('death', 'Disease', (23, 28))	('patients', 'Species', '9606', (80, 88))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('CD-8', 'Gene', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('normal', 'Var', (94, 100))	('death', 'Disease', 'MESH:D003643', (23, 28))	('expression', 'MPA', (105, 115))	('CD-8', 'Gene', '925', (136, 140))	('alcohol', 'Chemical', 'MESH:D000431', (42, 49))
573674	31786674	However, in some biomarker-selected subgroups, ever-alcohol consumption was associated with a worsened survival in comparison with never drinkers.	('survival', 'MPA', (103, 111))	('alcohol', 'Chemical', 'MESH:D000431', (52, 59))	('worsened', 'NegReg', (94, 102))	('ever-alcohol consumption', 'Var', (47, 71))	('ever-alcohol consumption', 'Phenotype', 'HP:0030955', (47, 71))
573696	31786674	In esophageal squamous cell carcinoma, heavy smokers have been shown to have a two-times higher odds of P53 mutation than non-smokers, and in lung cancer, frequent alcohol drinkers had a 4.6-fold increased odds of having a P53 mutation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (164, 180))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('alcohol drinker', 'Phenotype', 'HP:0030955', (164, 179))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (3, 37))	('lung cancer', 'Disease', (142, 153))	('P53', 'Gene', (104, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('mutation', 'Var', (108, 116))	('alcohol', 'Chemical', 'MESH:D000431', (164, 171))	('P53', 'Gene', (223, 226))	('P53', 'Gene', '7157', (223, 226))	('P53', 'Gene', '7157', (104, 107))
573705	31786674	Relevant ethical approvals were obtained from the Northern Ireland Biobank (NIB12-0032 and NIB12-0062) and the Office for Research Ethics Committees Northern Ireland (ORECNI, 13/NI/0149).	('NIB12-0032', 'Var', (76, 86))	('NIB12-0032', 'Chemical', 'MESH:C102275', (76, 86))	('NIB12-0062', 'Chemical', 'MESH:C102275', (91, 101))	('NIB12-0062', 'Var', (91, 101))
573706	31786674	The staining and study of the biomarker CD8 was performed under the accelerator grant from Cancer Research UK (C11512/A20256 to PWH/MS-T).	('C11512', 'Chemical', 'MESH:D002244', (111, 117))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CD8', 'Gene', '925', (40, 43))	('C11512/A20256', 'Var', (111, 124))	('CD8', 'Gene', (40, 43))
573753	31786674	The previously observed increased risk of death for alcohol consumers was more evident in patients within the normal tertile of p53 expression (HR 11.8 95% CI 1.55-89.7), GLUT-1-positive (HR 2.40 95% CI 1.31-4.41), CD 8-positive (HR 2.77 95% CI 1.26-6.09), and HER 2-positive tumors (HR 7.00 95% CI 0.85-57.6), although the latter did not reach statistical significance.	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('CD 8-positive', 'Var', (215, 228))	('alcohol', 'Chemical', 'MESH:D000431', (52, 59))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('death', 'Disease', 'MESH:D003643', (42, 47))	('death', 'Disease', (42, 47))	('GLUT-1', 'Gene', '6513', (171, 177))	('HER 2', 'Gene', (261, 266))	('GLUT-1', 'Gene', (171, 177))	('patients', 'Species', '9606', (90, 98))	('tumors', 'Disease', (276, 282))	('HER 2', 'Gene', '2064', (261, 266))
573777	31786674	To date, there has only been one study (performed on the same cohort of patients as this study) which has investigated the role of GLUT1 as a biomarker in esophageal adenocarcinoma, and positive expression was associated with a poorer prognosis.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (155, 180))	('positive expression', 'Var', (186, 205))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (155, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('GLUT1', 'Gene', (131, 136))	('GLUT1', 'Gene', '6513', (131, 136))	('esophageal adenocarcinoma', 'Disease', (155, 180))	('patients', 'Species', '9606', (72, 80))
573779	31786674	The poorer outcomes in ever drinkers with CD8 positive, or normal p53, tumor expression indicate that further mechanistic studies are warranted to verify the biological plausibility of a potential underlying interaction with alcohol intake in relation to prognosis.	('p53', 'Gene', '7157', (66, 69))	('alcohol', 'Chemical', 'MESH:D000431', (225, 232))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('CD8', 'Gene', (42, 45))	('normal', 'Var', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CD8', 'Gene', '925', (42, 45))	('tumor', 'Disease', (71, 76))	('p53', 'Gene', (66, 69))
573806	30624916	On the other hand, we recently demonstrated that contrast-enhanced Raman imaging using surface-enhanced resonance Raman scattering nanoparticles (SERRS-NPs) provides femtomolar sensitivity in vivo as a result of the unparalleled signal specificity of SERRS-NPs' Raman spectral "fingerprint", which is virtually nonexistent in biological tissues.	('rat', 'Species', '10116', (38, 41))	('signal specificity', 'MPA', (229, 247))	('SERRS-NPs', 'Var', (251, 260))
573822	30624916	Furthermore, we assessed the distribution of intravenously administrated SERRS-NPs in situ and in normal tissues of the upper GI tract of healthy control mice and found no nonspecific accumulation of SERRS-NPs at the gastroesophageal junction (GEJ), in the stomach, or in the intestines (n = 4; Supplementary Figure S3a-c).	('rat', 'Species', '10116', (67, 70))	('mice', 'Species', '10090', (154, 158))	('gastroesophageal junction', 'Disease', (217, 242))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (217, 242))	('SERRS-NPs', 'Var', (200, 209))
573836	30624916	ApcMin/+ mice harbor a chemically induced mutation in the Apc gene resulting in a premature truncation of its gene product, which predisposes these animals to the formation of intestinal adenoma formation.	('adenoma', 'Disease', (187, 194))	('truncation', 'MPA', (92, 102))	('predisposes', 'Reg', (130, 141))	('mutation', 'Var', (42, 50))	('adenoma', 'Disease', 'MESH:D000236', (187, 194))	('Apc', 'Gene', (58, 61))	('Apc', 'Gene', (0, 3))	('Apc', 'Gene', '11789', (58, 61))	('mice', 'Species', '10090', (9, 13))	('Apc', 'Gene', '11789', (0, 3))
573839	30624916	Cyclin D1 (CCND1) was used as a marker, since its nuclear overexpression is found in intestinal lesions of ApcMin/+ mice due to abnormal beta-catenin translocation resulting from the Apc gene mutation.	('Apc', 'Gene', (107, 110))	('mice', 'Species', '10090', (116, 120))	('Apc', 'Gene', (183, 186))	('beta-catenin', 'Gene', '12387', (137, 149))	('Apc', 'Gene', '11789', (107, 110))	('Cyclin D1', 'Gene', '12443', (0, 9))	('Apc', 'Gene', '11789', (183, 186))	('mutation', 'Var', (192, 200))	('overexpression', 'PosReg', (58, 72))	('beta-catenin', 'Gene', (137, 149))	('Cyclin D1', 'Gene', (0, 9))	('CCND1', 'Gene', (11, 16))	('CCND1', 'Gene', '12443', (11, 16))
573859	30624916	The white-light video provided the relevant anatomical context (Figure 7b); the presence of SERRS signal was associated with colorectal polyps (Figure 7b,c; 1), while lack of SERRS signal was associated with normal appearance of the colonic surface (Figure 7b,c; 2).	('associated', 'Reg', (109, 119))	('colorectal polyps', 'Phenotype', 'HP:0200063', (125, 142))	('colonic', 'Disease', (233, 240))	('colorectal polyps', 'Disease', (125, 142))	('presence', 'Var', (80, 88))	('colorectal polyps', 'Disease', 'MESH:D003111', (125, 142))	('SERRS', 'MPA', (92, 97))	('colonic', 'Disease', 'MESH:D015179', (233, 240))
573869	30624916	The retention is largely attributed to abnormalities in the draining lymphatic vessels, which remain relatively intact in infection or inflammation.	('infection or inflammation', 'Disease', (122, 147))	('abnormalities', 'Var', (39, 52))	('infection or inflammation', 'Disease', 'MESH:D007249', (122, 147))
573884	30624916	Consequently, approaches involving targeted SERS nanoparticles may lead to an increase in false negatives (i.e., miss rate) relative to strategies involving systemically administered nontargeted SERRS nanoparticles.	('rat', 'Species', '10116', (138, 141))	('nanoparticles', 'Var', (49, 62))	('rat', 'Species', '10116', (118, 121))	('false negatives', 'MPA', (90, 105))	('SERS', 'Gene', (44, 48))	('SERS', 'Gene', '54938', (44, 48))
573950	28977982	Dysregulated expression of miRNA-100 is correlated with cancer diagnosis and prognosis.	('miRNA-100', 'Gene', (27, 36))	('expression', 'MPA', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('miRNA-100', 'Chemical', '-', (27, 36))	('correlated', 'Reg', (40, 50))	('Dysregulated', 'Var', (0, 12))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
573976	28977982	MiRNA-100 could suppress the related proteins of the IGF/mTOR signaling cascade in different cancers.	('cancers', 'Disease', (93, 100))	('MiRNA-100', 'Chemical', '-', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('suppress', 'NegReg', (16, 24))	('proteins', 'Protein', (37, 45))	('mTOR', 'Gene', (57, 61))	('MiRNA-100', 'Var', (0, 9))	('mTOR', 'Gene', '2475', (57, 61))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
573978	28977982	And, miRNA-100 can also exert as a tumor suppressor in many cancers by targeting polo-like kinase 1 (PLK1).	('targeting', 'Reg', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('PLK1', 'Gene', (101, 105))	('polo-like kinase 1', 'Gene', '5347', (81, 99))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancers', 'Disease', (60, 67))	('polo-like kinase 1', 'Gene', (81, 99))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('tumor', 'Disease', (35, 40))	('PLK1', 'Gene', '5347', (101, 105))	('miRNA-100', 'Chemical', '-', (5, 14))	('miRNA-100', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
573979	28977982	MiRNA-100 was found to significantly inhibit the expression of PLK1 and other proteins, which has a vital effect on cell growth, apoptosis, development and drug resistance.	('MiRNA-100', 'Chemical', '-', (0, 9))	('PLK1', 'Gene', '5347', (63, 67))	('inhibit', 'NegReg', (37, 44))	('expression', 'MPA', (49, 59))	('drug resistance', 'Phenotype', 'HP:0020174', (156, 171))	('MiRNA-100', 'Var', (0, 9))	('proteins', 'Protein', (78, 86))	('PLK1', 'Gene', (63, 67))
573980	28977982	In addition, several studies reported that miR-100 regulated apoptosis in gastric tumor cells and breast cancer cells, and they declared miR-100 antagonism triggers apoptosis by inhibiting ubiquitination-mediated p53 degradation.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('gastric tumor', 'Disease', (74, 87))	('apoptosis', 'CPA', (61, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('inhibiting', 'NegReg', (178, 188))	('apoptosis', 'CPA', (165, 174))	('miR-100', 'Gene', '406892', (137, 144))	('miR-100', 'Gene', '406892', (43, 50))	('gastric tumor', 'Disease', 'MESH:D013274', (74, 87))	('gastric tumor', 'Phenotype', 'HP:0006753', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('p53', 'Gene', (213, 216))	('p53', 'Gene', '7157', (213, 216))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('miR-100', 'Gene', (43, 50))	('antagonism', 'Var', (145, 155))	('miR-100', 'Gene', (137, 144))
573988	28977982	Some studies on EOC, SCCC and NSCLC found miR-100 was significantly decreased in cancer tissues in comparison to healthy people, which appeared that low miR-100 was a poor prognostic biomarker by targeting PLK1 in patients and some researches in HCC, CRC and ESCC hold the similar view.	('SCC', 'Gene', (21, 24))	('decreased', 'NegReg', (68, 77))	('people', 'Species', '9606', (121, 127))	('patients', 'Species', '9606', (214, 222))	('miR-100', 'Gene', (153, 160))	('cancer', 'Disease', (81, 87))	('targeting', 'Reg', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('miR-100', 'Gene', (42, 49))	('PLK1', 'Gene', (206, 210))	('NSCLC', 'Disease', (30, 35))	('miR-100', 'Gene', '406892', (153, 160))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('miR-100', 'Gene', '406892', (42, 49))	('low', 'Var', (149, 152))	('PLK1', 'Gene', '5347', (206, 210))	('SCC', 'Gene', '6317', (260, 263))	('SCC', 'Gene', '6317', (21, 24))	('SCC', 'Gene', (260, 263))
573995	28977982	They suggested that patients with lower expression of miRNA-100 in cancer tissue had poorer survival in a variety of carcinomas, which was similar to our result in prognostic meta-analysis.	('expression', 'MPA', (40, 50))	('poorer', 'NegReg', (85, 91))	('carcinomas', 'Disease', 'MESH:D002277', (117, 127))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('cancer', 'Disease', (67, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('carcinomas', 'Disease', (117, 127))	('lower', 'NegReg', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (20, 28))	('miRNA-100', 'Chemical', '-', (54, 63))	('miRNA-100', 'Var', (54, 63))
574009	28977982	We collect HRs and their 95% CIs preferentially from multivariate or univariate analyses in the original article, and HR>1 means higher expression of miRNA-100 in tumor tissues that may have a poorer prognosis in cancer patients.	('HR>1', 'Var', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('expression', 'MPA', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('miRNA-100', 'Protein', (150, 159))	('higher', 'PosReg', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (220, 228))	('tumor', 'Disease', (163, 168))	('cancer', 'Disease', (213, 219))	('miRNA-100', 'Chemical', '-', (150, 159))
574016	25214541	Following meta-analysis, significant associations were seen for six tumor variants (mutant TP53 and PIK3CA, copy number gain of ERBB2/HER2, CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms: ERCC1 rs3212986, ERCC2 rs1799793, TP53 rs1042522, MDM2 rs2279744, TYMS rs34743033, ABCB1 rs1045642 and MTHFR rs1801133.	('ERCC2', 'Gene', (243, 248))	('ERCC1', 'Gene', (226, 231))	('rs1045642', 'Var', (315, 324))	('PIK3CA', 'Gene', (100, 106))	('rs1045642', 'Mutation', 'rs1045642', (315, 324))	('ERCC2', 'Gene', '2068', (243, 248))	('rs34743033', 'Mutation', 'rs34743033', (297, 307))	('rs2279744', 'Var', (281, 290))	('rs1799793', 'Mutation', 'rs1799793', (249, 258))	('chromosomal instability', 'Phenotype', 'HP:0040012', (160, 183))	('ERBB2', 'Gene', (128, 133))	('TP53', 'Gene', (260, 264))	('tumor', 'Disease', (68, 73))	('rs1799793', 'Var', (249, 258))	('rs34743033', 'Var', (297, 307))	('rs3212986', 'Var', (232, 241))	('rs1042522', 'Var', (265, 274))	('ABCB1', 'Gene', (309, 314))	('ABCB1', 'Gene', '5243', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('rs1801133', 'Mutation', 'rs1801133', (335, 344))	('TYMS', 'Gene', '7298', (292, 296))	('HER2', 'Gene', '2064', (134, 138))	('MTHFR', 'Gene', '4524', (329, 334))	('gain', 'PosReg', (120, 124))	('rs1042522', 'Mutation', 'rs1042522', (265, 274))	('ERBB2', 'Gene', '2064', (128, 133))	('TP53', 'Gene', (91, 95))	('rs3212986', 'Mutation', 'rs3212986', (232, 241))	('FGF3', 'Gene', (150, 154))	('mutant', 'Var', (84, 90))	('rs2279744', 'Mutation', 'rs2279744', (281, 290))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PIK3CA', 'Gene', '5290', (100, 106))	('TP53', 'Gene', '7157', (260, 264))	('CCND1', 'Gene', '595', (140, 145))	('FGF3', 'Gene', '2248', (150, 154))	('MDM2', 'Gene', (276, 280))	('ERCC1', 'Gene', '2067', (226, 231))	('TYMS', 'Gene', (292, 296))	('MTHFR', 'Gene', (329, 334))	('rs1801133', 'Var', (335, 344))	('CCND1', 'Gene', (140, 145))	('HER2', 'Gene', (134, 138))	('TP53', 'Gene', '7157', (91, 95))	('MDM2', 'Gene', '4193', (276, 280))
574018	25214541	Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487.	('rs11615', 'Mutation', 'rs11615', (79, 86))	('rs25487', 'Mutation', 'rs25487', (97, 104))	('associations', 'Interaction', (25, 37))	('XRCC1', 'Gene', (91, 96))	('rs11615', 'Var', (79, 86))	('ERCC1', 'Gene', (73, 78))	('XRCC1', 'Gene', '7515', (91, 96))	('ERCC1', 'Gene', '2067', (73, 78))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('mutant', 'Var', (60, 66))	('rs25487', 'Var', (97, 104))
574029	25214541	Markers included germline SNPs, tumor mutations, copy number variants (CNVs), loss of heterozygosity (LOH), microsatellite instability (MSI) and chromosomal instability (CIN; alterations in ploidy).	('chromosomal instability', 'MPA', (145, 168))	('CIN', 'Disease', 'MESH:D007674', (170, 173))	('microsatellite instability', 'MPA', (108, 134))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('MSI', 'Disease', 'None', (136, 139))	('MSI', 'Disease', (136, 139))	('loss of heterozygosity', 'MPA', (78, 100))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('copy number', 'Var', (49, 60))	('chromosomal instability', 'Phenotype', 'HP:0040012', (145, 168))	('tumor', 'Disease', (32, 37))	('CIN', 'Disease', (170, 173))	('germline SNPs', 'Disease', (17, 30))
574034	25214541	The following term was used: (esophageal OR esophagus OR gastroesophageal) AND (cancer OR carcinoma or adenocarcinoma OR SCC) AND (genomic OR genetic OR genome OR pharmacogenetic OR pharmacogenomic OR amplification OR copy OR mutation OR polymorphism OR polymorphic OR variant OR deletion OR insertion OR locus OR loci OR allele) AND (outcome OR prognosis OR survival OR response OR stage OR surgery OR chemotherapy OR radiotherapy OR marker OR biomarker OR complication).	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinoma or adenocarcinoma', 'Disease', 'MESH:D000230', (90, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('SCC', 'Gene', (121, 124))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('SCC', 'Gene', '6317', (121, 124))	('carcinoma or adenocarcinoma', 'Disease', (90, 117))	('variant OR deletion', 'Var', (269, 288))	('esophageal OR esophagus OR gastroesophageal', 'Disease', 'MESH:D004938', (30, 73))	('cancer', 'Disease', (80, 86))	('esophageal OR esophagus OR gastroesophageal', 'Disease', (30, 73))
574043	25214541	There were 65 reported markers of survival or recurrence: 24 tumor (Table 1; 3 mutations, 16 CNV, 2 LOH regions, 1 telomere length ratio, CIN, heterogeneous ploidy) and 40 germline polymorphisms (Table 2).	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CIN', 'Disease', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CIN', 'Disease', 'MESH:D007674', (138, 141))	('tumor', 'Disease', (61, 66))	('mutations', 'Var', (79, 88))
574047	25214541	Following correction for likely publication bias, a significant negative survival association was demonstrated for mutant TP53 tumors: HR 1.27 (1.01-1.59; P = 0.04; n = 21 studies; supplementary Figures S1 and S2, available at Annals of Oncology online).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('TP53', 'Gene', (122, 126))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('mutant', 'Var', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('Oncology', 'Phenotype', 'HP:0002664', (237, 245))	('TP53', 'Gene', '7157', (122, 126))	('negative', 'NegReg', (64, 72))
574049	25214541	An association with DFS was demonstrated for mutant PIK3CA SCC tumors [HR 0.42 (0.21-0.85); n = 2; P = 0.02], but not OS.	('SCC tumors', 'Disease', 'MESH:D009369', (59, 69))	('mutant', 'Var', (45, 51))	('SCC tumors', 'Disease', (59, 69))	('OS', 'Chemical', '-', (118, 120))	('PIK3CA', 'Gene', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('DFS', 'Disease', (20, 23))	('PIK3CA', 'Gene', '5290', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
574061	25214541	1q22-23 LOH was associated with worse OS in one study (LOE IV).	('OS', 'Chemical', '-', (38, 40))	('1q22-23 LOH', 'Var', (0, 11))	('worse OS', 'Disease', (32, 40))
574067	25214541	Significant associations were demonstrated for six SNPs: ERCC1 rs3212986 (cisplatin treatment; LOE II; Caucasian ethnicity), ERCC2 rs1799793 (cisplatin; Caucasian) TP53 rs1042522 (Caucasian), MDM2 rs2279744 (Caucasian), TYMS rs34743033 (Japanese; LOE III) ABCB1 rs1045642 (Caucasian and Japanese; LOE IV).	('rs1799793', 'Mutation', 'rs1799793', (131, 140))	('rs1799793', 'Var', (131, 140))	('ERCC1', 'Gene', '2067', (57, 62))	('ABCB1', 'Gene', (256, 261))	('TP53', 'Gene', (164, 168))	('ABCB1', 'Gene', '5243', (256, 261))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('rs2279744', 'Mutation', 'rs2279744', (197, 206))	('MDM2', 'Gene', (192, 196))	('rs1042522', 'Var', (169, 178))	('rs3212986', 'Var', (63, 72))	('TYMS', 'Gene', '7298', (220, 224))	('ERCC1', 'Gene', (57, 62))	('rs34743033', 'Mutation', 'rs34743033', (225, 235))	('rs1042522', 'Mutation', 'rs1042522', (169, 178))	('rs34743033', 'Var', (225, 235))	('ERCC2', 'Gene', (125, 130))	('MDM2', 'Gene', '4193', (192, 196))	('rs3212986', 'Mutation', 'rs3212986', (63, 72))	('rs1045642', 'Var', (262, 271))	('rs1045642', 'Mutation', 'rs1045642', (262, 271))	('ERCC2', 'Gene', '2068', (125, 130))	('TP53', 'Gene', '7157', (164, 168))	('TYMS', 'Gene', (220, 224))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('rs2279744', 'Var', (197, 206))
574068	25214541	An association was demonstrated for VEGFA rs2010963, but combining two studies with East Asian ethnicities (Taiwanese and Japanese).	('rs2010963', 'Var', (42, 51))	('VEGFA', 'Gene', '7422', (36, 41))	('rs2010963', 'Mutation', 'rs2010963', (42, 51))	('VEGFA', 'Gene', (36, 41))
574069	25214541	One association with recurrence was demonstrated: MTHFR rs1801133 (Caucasian; LOE III).	('MTHFR', 'Gene', (50, 55))	('rs1801133', 'Var', (56, 65))	('MTHFR', 'Gene', '4524', (50, 55))	('rs1801133', 'Mutation', 'rs1801133', (56, 65))
574072	25214541	Two tumor variants (mutant TP53 and CIN) and 15 germline polymorphisms were reported to be associated with clinical or pathological response to chemo +- radiotherapy (Table 3); 11 polymorphisms were excluded due to multiple comparisons).	('tumor', 'Disease', (4, 9))	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('CIN', 'Disease', 'MESH:D007674', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CIN', 'Disease', (36, 39))	('mutant', 'Var', (20, 26))	('associated', 'Reg', (91, 101))
574073	25214541	Mutant TP53 was assessed by six studies; three for pathological and three for clinical response.	('Mutant', 'Var', (0, 6))	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))
574074	25214541	Following meta-analysis, two polymorphisms were associated with a major pathological response to platinum-based chemo/radiotherapy in Caucasians: wild-type XRCC1 rs25487 [GG genotype, LOE III; OR 1.91 (1.30-2.81), n = 3, P = 0.001], and variant ERCC1 rs11615 [TT/CT; OR 4.57 (3.01-6.94); n = 3; P < 1 x 10-5].	('rs11615 [', 'Var', (251, 260))	('XRCC1', 'Gene', (156, 161))	('platinum', 'Chemical', 'MESH:D010984', (97, 105))	('rs25487 [', 'Var', (162, 171))	('XRCC1', 'Gene', '7515', (156, 161))	('ERCC1', 'Gene', (245, 250))	('rs11615', 'Mutation', 'rs11615', (251, 258))	('ERCC1', 'Gene', '2067', (245, 250))	('rs25487', 'Mutation', 'rs25487', (162, 169))
574075	25214541	The AA variant of ERCC1 rs3212986 (LOE III) was associated with radiological response to palliative cisplatin-based chemotherapy in one study (Chinese ethnicity), but not major pathological response to neoadjuvant chemotherapy in two (Caucasian).	('ERCC1', 'Gene', (18, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('rs3212986', 'Mutation', 'rs3212986', (24, 33))	('associated', 'Reg', (48, 58))	('ERCC1', 'Gene', '2067', (18, 23))	('rs3212986', 'Var', (24, 33))
574076	25214541	Twenty-four tumor markers were reported: 2 mutations, 12 CNV, 7 LOH, 2 MSI and CIN; 15 were excluded.	('MSI', 'Disease', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CIN', 'Disease', (79, 82))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('MSI', 'Disease', 'None', (71, 74))	('CIN', 'Disease', 'MESH:D007674', (79, 82))	('tumor', 'Disease', (12, 17))
574078	25214541	Following meta-analysis, mutant TP53 tumors were associated with more advanced T (T3/T4) and N (>=N1) stages, but not overall TNM stage (III/IV), grade (G3/4) or positive resection margin (R1).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('mutant', 'Var', (25, 31))	('TNM', 'Gene', '10178', (126, 129))	('TP53', 'Gene', '7157', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('TNM', 'Gene', (126, 129))	('TP53', 'Gene', (32, 36))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
574083	25214541	One marker (GNAS1 rs7172) underwent meta-analysis, without significance.	('GNAS1', 'Gene', '2778', (12, 17))	('GNAS1', 'Gene', (12, 17))	('rs7172', 'Mutation', 'rs7172', (18, 24))	('rs7172', 'Var', (18, 24))
574084	25214541	Visual inspection of plots identified asymmetry for nine outcome analyses: mutant TP53 (OS overall, adjusted HR, SCC and unspecified cell types, neoadjuvant therapy and SSCP/direct sequencing analyses; supplementary Tables S2 and S3, available at Annals of Oncology online), ERRBB2/HER2 (OS) and FGF3 (OS), and three stage analyses: EGFR (overall) and ERBB2/HER2 (N and grade).	('ERBB2', 'Gene', (352, 357))	('HER2', 'Gene', '2064', (358, 362))	('FGF3', 'Gene', (296, 300))	('OS', 'Chemical', '-', (288, 290))	('HER2', 'Gene', (282, 286))	('ERBB2', 'Gene', '2064', (352, 357))	('EGFR', 'Gene', '1956', (333, 337))	('SCC', 'Gene', '6317', (113, 116))	('OS', 'Chemical', '-', (302, 304))	('FGF3', 'Gene', '2248', (296, 300))	('unspecified', 'Species', '32644', (121, 132))	('OS', 'Chemical', '-', (88, 90))	('SCC', 'Gene', (113, 116))	('HER2', 'Gene', (358, 362))	('TP53', 'Gene', (82, 86))	('Oncology', 'Phenotype', 'HP:0002664', (257, 265))	('HER2', 'Gene', '2064', (282, 286))	('EGFR', 'Gene', (333, 337))	('mutant', 'Var', (75, 81))	('TP53', 'Gene', '7157', (82, 86))
574088	25214541	These demonstrated a small number of associations of DNA sequence markers with worse survival (mutant TP53, HER2, CCND1 and FGF3 copy number gain and CIN) and resistance to chemo-radio +- therapy (TP53).	('HER2', 'Gene', (108, 112))	('CIN', 'Disease', (150, 153))	('TP53', 'Gene', (102, 106))	('HER2', 'Gene', '2064', (108, 112))	('CCND1', 'Gene', (114, 119))	('CIN', 'Disease', 'MESH:D007674', (150, 153))	('FGF3', 'Gene', '2248', (124, 128))	('copy number', 'Var', (129, 140))	('gain', 'PosReg', (141, 145))	('CCND1', 'Gene', '595', (114, 119))	('TP53', 'Gene', '7157', (102, 106))	('TP53', 'Gene', '7157', (197, 201))	('associations', 'Interaction', (37, 49))	('FGF3', 'Gene', (124, 128))	('TP53', 'Gene', (197, 201))
574094	25214541	We also found TP53 mutant tumors to be less chemo(radio)sensitive.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mutant', 'Var', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
574098	25214541	TP53 as an esophageal tumor biomarker is often considered in terms of TP53 status: aberrant expression, with or without mutation.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (70, 74))	('aberrant', 'Var', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('TP53', 'Gene', (70, 74))	('esophageal tumor', 'Disease', 'MESH:D004938', (11, 27))	('esophageal tumor', 'Disease', (11, 27))	('esophageal tumor', 'Phenotype', 'HP:0100751', (11, 27))
574100	25214541	However, TP53 mutational and expression statuses may be discordant particularly in the case of high-impact mutations precluding expression, or dramatically reducing half-life.	('mutations', 'Var', (107, 116))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('reducing', 'NegReg', (156, 164))	('expression', 'MPA', (128, 138))	('half-life', 'MPA', (165, 174))
574102	25214541	While such tumors appear to be disproportionately TP53 mutated, deep re-sequencing and clonal studies comparing the prevalence and associations of pre- and post-treatment tumor are required to establish the true pretreatment predictive utility of TP53 mutations in this regard.	('TP53', 'Gene', (247, 251))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('TP53', 'Gene', '7157', (50, 54))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('mutations', 'Var', (252, 261))	('TP53', 'Gene', '7157', (247, 251))	('TP53', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
574112	25214541	We also demonstrated survival associations for six common germline polymorphisms by meta-analysis: ERCC1 rs3212986 (for cisplatin treatment and Caucasian ethnicity), ERCC2 rs1799793 (cisplatin and Caucasian), TP53 rs1042522 (Caucasian), MDM2 rs2279744 (Caucasian), TYMS rs34743033 (Japanese) ABCB1 rs1045642 (both Caucasian and Japanese).	('TYMS', 'Gene', '7298', (265, 269))	('ERCC1', 'Gene', '2067', (99, 104))	('rs1799793', 'Mutation', 'rs1799793', (172, 181))	('MDM2', 'Gene', '4193', (237, 241))	('rs1799793', 'Var', (172, 181))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('ERCC1', 'Gene', (99, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (183, 192))	('rs3212986', 'Var', (105, 114))	('rs1045642', 'Var', (298, 307))	('ERCC2', 'Gene', (166, 171))	('TYMS', 'Gene', (265, 269))	('rs1045642', 'Mutation', 'rs1045642', (298, 307))	('rs3212986', 'Mutation', 'rs3212986', (105, 114))	('TP53', 'Gene', (209, 213))	('ERCC2', 'Gene', '2068', (166, 171))	('rs2279744', 'Mutation', 'rs2279744', (242, 251))	('ABCB1', 'Gene', (292, 297))	('ABCB1', 'Gene', '5243', (292, 297))	('rs1042522', 'Var', (214, 223))	('rs34743033', 'Mutation', 'rs34743033', (270, 280))	('rs1042522', 'Mutation', 'rs1042522', (214, 223))	('rs34743033', 'Var', (270, 280))	('TP53', 'Gene', '7157', (209, 213))	('MDM2', 'Gene', (237, 241))
574113	25214541	The association of VEGFA rs2010963 was evident only on combining Taiwanese and Japanese study populations.	('VEGFA', 'Gene', '7422', (19, 24))	('rs2010963', 'Var', (25, 34))	('rs2010963', 'Mutation', 'rs2010963', (25, 34))	('VEGFA', 'Gene', (19, 24))
574114	25214541	MTHFR rs1801133 was associated with recurrence in Caucasians.	('associated', 'Reg', (20, 30))	('MTHFR', 'Gene', '4524', (0, 5))	('MTHFR', 'Gene', (0, 5))	('rs1801133', 'Var', (6, 15))	('recurrence', 'Disease', (36, 46))	('rs1801133', 'Mutation', 'rs1801133', (6, 15))
574115	25214541	XRCC1 rs25487 and ERCC1 rs11615 were associated with response to chemotherapy in Caucasians.	('ERCC1', 'Gene', (18, 23))	('XRCC1', 'Gene', (0, 5))	('ERCC1', 'Gene', '2067', (18, 23))	('rs25487', 'Var', (6, 13))	('rs11615', 'Var', (24, 31))	('associated', 'Reg', (37, 47))	('rs25487', 'Mutation', 'rs25487', (6, 13))	('XRCC1', 'Gene', '7515', (0, 5))	('rs11615', 'Mutation', 'rs11615', (24, 31))
574116	25214541	rs3212986 modifies ERCC1 mRNA stability, a component of the nucleotide excision repair (NER) pathway, variants of which are associated with platinum sensitivity and survival in pancreatic, gastric, colorectal and lung cancers.	('variants', 'Var', (102, 110))	('rs3212986', 'Mutation', 'rs3212986', (0, 9))	('pancreatic', 'Disease', 'MESH:D010195', (177, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('colorectal and lung cancers', 'Disease', 'MESH:D015179', (198, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('survival', 'CPA', (165, 173))	('pancreatic', 'Disease', (177, 187))	('gastric', 'Disease', (189, 196))	('associated with', 'Reg', (124, 139))	('rs3212986', 'Var', (0, 9))	('ERCC1', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('lung cancers', 'Phenotype', 'HP:0100526', (213, 225))	('modifies', 'Reg', (10, 18))	('ERCC1', 'Gene', '2067', (19, 24))	('platinum', 'Chemical', 'MESH:D010984', (140, 148))	('platinum', 'Disease', (140, 148))
574117	25214541	The missense rs1799793 SNP results in an aspartate-asparagine substitution at codon 312 of the ERCC2 component of the NER pathway, and has been similarly associated with survival in gastric and other cancers.	('ERCC2', 'Gene', (95, 100))	('asparagine', 'Chemical', 'MESH:D001216', (51, 61))	('associated with', 'Reg', (154, 169))	('NER pathway', 'Pathway', (118, 129))	('missense rs1799793 SNP', 'Var', (4, 26))	('gastric', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('aspartate-asparagine', 'MPA', (41, 61))	('aspartate', 'Chemical', 'MESH:D001224', (41, 50))	('rs1799793', 'Mutation', 'rs1799793', (13, 22))	('cancers', 'Disease', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('ERCC2', 'Gene', '2068', (95, 100))	('results in', 'Reg', (27, 37))
574118	25214541	The rs10456402 SNP in exon 26 of ABCB1 (Multi Drug Resistance 1) reduces expression (and consequent platinum-analogue membrane transportation), and is similarly associated with colorectal cancer prognosis.	('rs10456402', 'Mutation', 'rs10456402', (4, 14))	('colorectal cancer', 'Disease', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('associated with', 'Reg', (161, 176))	('Drug Resistance', 'Phenotype', 'HP:0020174', (46, 61))	('reduces', 'NegReg', (65, 72))	('rs10456402 SNP', 'Var', (4, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('Multi Drug Resistance 1', 'Gene', '5243', (40, 63))	('Multi Drug Resistance 1', 'Gene', (40, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('ABCB1', 'Gene', (33, 38))	('ABCB1', 'Gene', '5243', (33, 38))	('platinum', 'Chemical', 'MESH:D010984', (100, 108))
574119	25214541	rs2279744 increases mRNA expression of MDM2, which suppresses TP53 activity, and is associated with increased susceptibility to a number of cancers (including gastric).	('increases', 'PosReg', (10, 19))	('TP53', 'Gene', '7157', (62, 66))	('number of cancers', 'Disease', 'MESH:D009369', (130, 147))	('MDM2', 'Gene', '4193', (39, 43))	('MDM2', 'Gene', (39, 43))	('TP53', 'Gene', (62, 66))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('mRNA expression', 'MPA', (20, 35))	('associated', 'Reg', (84, 94))	('susceptibility', 'Reg', (110, 124))	('number of cancers', 'Disease', (130, 147))	('rs2279744', 'Mutation', 'rs2279744', (0, 9))	('suppresses', 'NegReg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('rs2279744', 'Var', (0, 9))
574120	25214541	rs34743033 is a 28-bp variable number tandem repeat in TYMS (thymidylate synthase), with enhancer function correlating with increased TYMS expression, and survival in platinum-treatment nonsmall-cell lung carcinoma.	('enhancer', 'PosReg', (89, 97))	('nonsmall-cell lung carcinoma', 'Disease', (186, 214))	('TYMS', 'Gene', (134, 138))	('TYMS', 'Gene', (55, 59))	('increased', 'PosReg', (124, 133))	('rs34743033', 'Mutation', 'rs34743033', (0, 10))	('nonsmall-cell lung carcinoma', 'Disease', 'MESH:D002289', (186, 214))	('TYMS', 'Gene', '7298', (134, 138))	('thymidylate synthase', 'Gene', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('nonsmall-cell lung carcinoma', 'Phenotype', 'HP:0030358', (186, 214))	('platinum', 'Chemical', 'MESH:D010984', (167, 175))	('expression', 'MPA', (139, 149))	('rs34743033', 'Var', (0, 10))	('TYMS', 'Gene', '7298', (55, 59))	('thymidylate synthase', 'Gene', '7298', (61, 81))
574121	25214541	The rs1801133 missense SNP induces an alanine-valine substitution at codon 222, with reduced activity of methylenetetrahydrofolate reductase, and increased susceptibility to gastric cancer.	('methylenetetrahydrofolate reductase', 'Gene', (105, 140))	('susceptibility', 'Reg', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('alanine', 'Chemical', 'MESH:D000409', (38, 45))	('alanine-valine', 'Var', (38, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (174, 188))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (105, 140))	('activity', 'MPA', (93, 101))	('increased', 'PosReg', (146, 155))	('valine', 'Chemical', 'MESH:D014633', (46, 52))	('induces', 'Reg', (27, 34))	('gastric cancer', 'Disease', (174, 188))	('rs1801133', 'Mutation', 'rs1801133', (4, 13))	('gastric cancer', 'Disease', 'MESH:D013274', (174, 188))	('increased susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (146, 188))	('reduced', 'NegReg', (85, 92))	('rs1801133 missense', 'Var', (4, 22))
574122	25214541	rs25487 induces a glutamine-arginine substation in codon 399, with resultant reduction in function of the DNA repair gene XRCC1, and an association with survival of lung cancer.	('rs25487', 'Var', (0, 7))	('lung cancer', 'Disease', (165, 176))	('association with', 'Reg', (136, 152))	('XRCC1', 'Gene', (122, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('glutamine-arginine substation', 'MPA', (18, 47))	('arginine', 'Chemical', 'MESH:D001120', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('function', 'MPA', (90, 98))	('reduction in', 'NegReg', (77, 89))	('rs25487', 'Mutation', 'rs25487', (0, 7))	('XRCC1', 'Gene', '7515', (122, 127))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('glutamine', 'Chemical', 'MESH:D005973', (18, 27))
574123	25214541	rs11615 reduces ERCC1 expression, and increases likelihood of response to platinum chemotherapy in gastric and colorectal cancer.	('increases', 'PosReg', (38, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('rs11615', 'Var', (0, 7))	('ERCC1', 'Gene', '2067', (16, 21))	('platinum', 'Chemical', 'MESH:D010984', (74, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('reduces', 'NegReg', (8, 15))	('rs11615', 'Mutation', 'rs11615', (0, 7))	('colorectal cancer', 'Disease', (111, 128))	('ERCC1', 'Gene', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('expression', 'MPA', (22, 32))	('gastric', 'Disease', (99, 106))
574144	23229199	Phosphorylation of stathmin led to a loss of the microtubule-destabilizing activity.	('Phosphorylation', 'Var', (0, 15))	('stathmin', 'Gene', (19, 27))	('microtubule-destabilizing activity', 'MPA', (49, 83))	('loss', 'NegReg', (37, 41))	('stathmin', 'Gene', '3925', (19, 27))
574145	23229199	Inhibition of stathmin phosphorylation produced strong mitotic phenotypes characterized by disassembly and disorganization of mitotic spindles and abnormal chromosome distributions.	('stathmin', 'Gene', '3925', (14, 22))	('abnormal chromosome', 'Phenotype', 'HP:0031411', (147, 166))	('Inhibition', 'Var', (0, 10))	('phosphorylation', 'Protein', (23, 38))	('disorganization', 'CPA', (107, 122))	('mitotic', 'CPA', (55, 62))	('stathmin', 'Gene', (14, 22))
574149	23229199	Wang et al demonstrated that knockdown of stathmin by antisense oligonucleotide can inhibit the proliferation of ECa109 cells.	('stathmin', 'Gene', '3925', (42, 50))	('knockdown', 'Var', (29, 38))	('proliferation', 'CPA', (96, 109))	('inhibit', 'NegReg', (84, 91))	('antisense oligonucleotide', 'Var', (54, 79))	('ECa109', 'CellLine', 'CVCL:6898', (113, 119))	('oligonucleotide', 'Chemical', 'MESH:D009841', (64, 79))	('stathmin', 'Gene', (42, 50))
574176	23229199	KYSE30, KYSE410 or EC0156 cells were incubated overnight yielding confluent monolayer for wounding.	('KYSE410', 'Var', (8, 15))	('EC0156', 'CellLine', 'CVCL:K425', (19, 25))	('EC0156', 'Var', (19, 25))
574186	23229199	SiRNA was employed to knockdown stathmin, and western blotting to detect the effect of siRNA.	('stathmin', 'Gene', (32, 40))	('knockdown', 'Var', (22, 31))	('stathmin', 'Gene', '3925', (32, 40))
574187	23229199	The results showed that the expression of stathmin was reduced after transfection of siRNA oligonucleotide for 72 h in KYSE30 and KYSE410 (Fig.	('stathmin', 'Gene', '3925', (42, 50))	('KYSE410', 'Var', (130, 137))	('reduced', 'NegReg', (55, 62))	('expression', 'MPA', (28, 38))	('KYSE30', 'Var', (119, 125))	('oligonucleotide', 'Chemical', 'MESH:D009841', (91, 106))	('stathmin', 'Gene', (42, 50))
574189	23229199	The results revealed that cell migration was impaired when deficient of stathmin.	('stathmin', 'Gene', (72, 80))	('stathmin', 'Gene', '3925', (72, 80))	('deficient', 'Var', (59, 68))	('impaired', 'NegReg', (45, 53))	('cell migration', 'CPA', (26, 40))
574211	23229199	We demonstrated that the speed of wound recovery in stathmin knockdown cells was much slower than the scramble in both KYSE30 and KYSE410 cells, suggesting cell migration was impaired when deficient of stathmin.	('stathmin', 'Gene', '3925', (202, 210))	('stathmin', 'Gene', '3925', (52, 60))	('stathmin', 'Gene', (52, 60))	('knockdown', 'Var', (61, 70))	('slower', 'NegReg', (86, 92))	('wound recovery', 'CPA', (34, 48))	('cell migration', 'CPA', (156, 170))	('stathmin', 'Gene', (202, 210))
574213	23229199	Stathmin depletion with siRNA caused significant inhibition of lamellipodia formation, which directed by Pak1-WAVE2-kinesin complex.	('Stathmin', 'Gene', (0, 8))	('Pak1', 'Gene', (105, 109))	('WAVE2', 'Gene', '10163', (110, 115))	('Pak1', 'Gene', '5058', (105, 109))	('lamellipodia formation', 'CPA', (63, 85))	('Stathmin', 'Gene', '3925', (0, 8))	('inhibition', 'NegReg', (49, 59))	('WAVE2', 'Gene', (110, 115))	('depletion', 'Var', (9, 18))
574214	23229199	Thus, stathmin depletion might inactivate lamellipodia formation leading to reduction of cell migration.	('depletion', 'Var', (15, 24))	('stathmin', 'Gene', (6, 14))	('reduction', 'NegReg', (76, 85))	('lamellipodia formation', 'CPA', (42, 64))	('stathmin', 'Gene', '3925', (6, 14))	('inactivate', 'NegReg', (31, 41))	('cell migration', 'CPA', (89, 103))
574215	23229199	We demonstrated that the band at 19 kDa of stathmin was decreased when EC0156 was treated by paclitaxel.	('EC0156', 'Var', (71, 77))	('band at 19 kDa', 'MPA', (25, 39))	('decreased', 'NegReg', (56, 65))	('paclitaxel', 'Chemical', 'MESH:D017239', (93, 103))	('EC0156', 'CellLine', 'CVCL:K425', (71, 77))	('stathmin', 'Gene', '3925', (43, 51))	('stathmin', 'Gene', (43, 51))
574220	23229199	Phosphorylation at Ser-16 and Ser-63 strongly reduced stathmin-tubulin complex formation.	('Phosphorylation', 'Var', (0, 15))	('stathmin', 'Gene', (54, 62))	('Ser-63', 'Var', (30, 36))	('stathmin', 'Gene', '3925', (54, 62))	('reduced', 'NegReg', (46, 53))	('Ser', 'Chemical', 'MESH:D012694', (19, 22))	('Ser', 'Chemical', 'MESH:D012694', (30, 33))
574221	23229199	The effects of stathmin on dynamic instability were strongly attenuated by phosphorylation at Ser-16-and Ser-63.	('dynamic instability', 'MPA', (27, 46))	('phosphorylation', 'Var', (75, 90))	('Ser', 'Chemical', 'MESH:D012694', (94, 97))	('stathmin', 'Gene', (15, 23))	('Ser-63', 'Var', (105, 111))	('Ser', 'Chemical', 'MESH:D012694', (105, 108))	('stathmin', 'Gene', '3925', (15, 23))	('attenuated', 'NegReg', (61, 71))	('Ser-16-and', 'Var', (94, 104))
574223	23229199	Stathmin is known to undergo phosphorylation at Ser16 upon cell stimulation, such as paclitaxel at low concentration.	('Stathmin', 'Gene', (0, 8))	('Ser16', 'Var', (48, 53))	('Stathmin', 'Gene', '3925', (0, 8))	('Ser16', 'Chemical', '-', (48, 53))	('paclitaxel', 'Chemical', 'MESH:D017239', (85, 95))	('phosphorylation', 'MPA', (29, 44))
574226	23229199	Through microscopic analysis, rounded cells were observed in most of EC0156 after the treatment with paclitaxel.	('EC0156', 'Var', (69, 75))	('observed', 'Reg', (49, 57))	('paclitaxel', 'Chemical', 'MESH:D017239', (101, 111))	('EC0156', 'CellLine', 'CVCL:K425', (69, 75))
574228	23229199	Besides, the wound recovery speed of EC0156 treated with paclitaxel was diminished compared to the control, suggesting that cell migration may be impaired after stathmin phophorylation.	('impaired', 'NegReg', (146, 154))	('EC0156', 'Var', (37, 43))	('wound recovery speed', 'CPA', (13, 33))	('cell migration', 'CPA', (124, 138))	('phophorylation', 'Var', (170, 184))	('EC0156', 'CellLine', 'CVCL:K425', (37, 43))	('diminished', 'NegReg', (72, 82))	('paclitaxel', 'Chemical', 'MESH:D017239', (57, 67))	('stathmin', 'Gene', (161, 169))	('stathmin', 'Gene', '3925', (161, 169))
574229	23229199	It is possibly that stabilized phosphorylation of stathmin may disrupt microtubule dynamics and finally impaired the motility of EC0156, which were supported by other reports.	('impaired', 'NegReg', (104, 112))	('motility', 'CPA', (117, 125))	('disrupt', 'NegReg', (63, 70))	('stathmin', 'Gene', '3925', (50, 58))	('stabilized', 'Var', (20, 30))	('stathmin', 'Gene', (50, 58))	('EC0156', 'CellLine', 'CVCL:K425', (129, 135))	('phosphorylation', 'Var', (31, 46))	('microtubule dynamics', 'MPA', (71, 91))
574232	23229199	Di Paolo et al revealed that phosphorylation at three sites (Ser-16, Ser-25, Ser-63) completely inhibited the tubulin binding capacity of stathmin.	('Ser-25', 'Var', (69, 75))	('stathmin', 'Gene', (138, 146))	('stathmin', 'Gene', '3925', (138, 146))	('Ser', 'Chemical', 'MESH:D012694', (69, 72))	('Ser-16', 'Var', (61, 67))	('tubulin', 'MPA', (110, 117))	('Ser-63', 'Var', (77, 83))	('inhibited', 'NegReg', (96, 105))	('Ser', 'Chemical', 'MESH:D012694', (77, 80))	('Ser', 'Chemical', 'MESH:D012694', (61, 64))	('phosphorylation', 'MPA', (29, 44))
574234	23229199	Belletti et al revealed that Ser-16 phosphorylation of stathmin enhanced sarcoma cell adhesion and inhibited sarcoma cell motility by mutant methods.	('Ser-16', 'Var', (29, 35))	('stathmin', 'Gene', '3925', (55, 63))	('stathmin', 'Gene', (55, 63))	('phosphorylation', 'Var', (36, 51))	('inhibited', 'NegReg', (99, 108))	('sarcoma', 'Disease', (73, 80))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('sarcoma cell motility', 'Disease', (109, 130))	('sarcoma', 'Disease', (109, 116))	('Ser', 'Chemical', 'MESH:D012694', (29, 32))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('sarcoma cell motility', 'Disease', 'MESH:D012509', (109, 130))	('enhanced', 'PosReg', (64, 72))
574257	21760843	re-evaluated those features and also the role of EUS-FNA in patients with lung, esophageal, and pancreatic cancer, showing that FNA increases the accuracy of EUS.	('pancreatic cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('EUS', 'Var', (158, 161))	('patients', 'Species', '9606', (60, 68))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('increases', 'PosReg', (132, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))
574337	33847642	The primary site (Site recode: ICD-O-3/2008) was the esophagus, and 4 histopathological types, namely, small cell cancer (8041/2, 8041/3, 8042/3, 8043/3, 8044/3, 8045/3), were included.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('small cell cancer', 'Phenotype', 'HP:0030357', (103, 120))	('8041/2', 'Var', (122, 128))	('cancer', 'Disease', (114, 120))
574587	24829906	Furthermore, p53 in human hepG2 cells and ovarian cancer cells arrests the cell cycle in the G2/M phase.	('ovarian cancer', 'Phenotype', 'HP:0100615', (42, 56))	('p53', 'Var', (13, 16))	('ovarian cancer', 'Disease', 'MESH:D010051', (42, 56))	('cell cycle in the G2/M phase', 'CPA', (75, 103))	('ovarian cancer', 'Disease', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('arrests', 'NegReg', (63, 70))
574589	24829906	The activation of MPF is controlled through the dephosphorylation of CDC2 at tyrosine15.	('dephosphorylation', 'MPA', (48, 65))	('tyrosine15', 'Chemical', '-', (77, 87))	('tyrosine15', 'Var', (77, 87))	('CDC2', 'Gene', (69, 73))
574620	23304125	Of note, the offspring of women exposed to undernutrition during early pregnancy were more likely to develop metabolic syndrome in adulthood compared with offspring of women who were pregnant either before or after the famine.	('undernutrition', 'Var', (43, 57))	('women', 'Species', '9606', (26, 31))	('early pregnancy', 'Phenotype', 'HP:0001622', (65, 80))	('develop', 'PosReg', (101, 108))	('metabolic syndrome', 'Disease', 'MESH:D008659', (109, 127))	('women', 'Species', '9606', (168, 173))	('metabolic syndrome', 'Disease', (109, 127))
574622	23304125	Nutritional imbalance (over- or undernutrition) and exposure to environmental chemicals during development can also increase the risk of these diseases, possibly through common pathways.	('undernutrition', 'Var', (32, 46))	('over-', 'Var', (23, 28))	('men', 'Species', '9606', (71, 74))	('imbalance', 'Phenotype', 'HP:0002172', (12, 21))	('increase', 'PosReg', (116, 124))	('men', 'Species', '9606', (102, 105))
574623	23304125	Disruption of epigenetic mechanisms can result in oxidative stress, obesity, insulin resistance, diabetes, and vascular dysfunction in animals and humans.	('obesity', 'Phenotype', 'HP:0001513', (68, 75))	('insulin', 'Gene', (77, 84))	('epigenetic', 'Var', (14, 24))	('obesity', 'Disease', 'MESH:D009765', (68, 75))	('vascular dysfunction', 'Disease', 'MESH:D002561', (111, 131))	('result in', 'Reg', (40, 49))	('diabetes', 'Disease', (97, 105))	('oxidative stress', 'MPA', (50, 66))	('insulin', 'Gene', '3630', (77, 84))	('obesity', 'Disease', (68, 75))	('insulin resistance', 'Phenotype', 'HP:0000855', (77, 95))	('diabetes', 'Disease', 'MESH:D003920', (97, 105))	('humans', 'Species', '9606', (147, 153))	('oxidative stress', 'Phenotype', 'HP:0025464', (50, 66))	('vascular dysfunction', 'Disease', (111, 131))	('Disruption', 'Var', (0, 10))
574642	23304125	Subjects with IGF-1 levels in the highest quintile were more likely to develop colorectal cancer compared with subjects with IGF-1 levels in the lowest quintile.	('levels', 'Var', (20, 26))	('IGF-1', 'Gene', (125, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colorectal cancer', 'Disease', (79, 96))	('develop', 'PosReg', (71, 78))	('IGF-1', 'Gene', '3479', (14, 19))	('rectal cancer', 'Phenotype', 'HP:0100743', (83, 96))	('IGF-1', 'Gene', (14, 19))	('IGF-1', 'Gene', '3479', (125, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))
574645	23304125	Genetic polymorphisms of IGF-1 may also increase the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('increase', 'PosReg', (40, 48))	('Genetic polymorphisms', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('IGF-1', 'Gene', '3479', (25, 30))	('IGF-1', 'Gene', (25, 30))
574646	23304125	Polymorphisms of IGF-1 (rs1520220 and rs2195239) were reported to decrease the risk of disease recurrence in Japanese patients with gastric cancer who had undergone curative gastrectomy.	('decrease', 'NegReg', (66, 74))	('rs1520220', 'Mutation', 'rs1520220', (24, 33))	('gastric cancer', 'Disease', (132, 146))	('rs2195239', 'Mutation', 'rs2195239', (38, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('disease recurrence', 'CPA', (87, 105))	('rs1520220', 'Var', (24, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('IGF-1', 'Gene', '3479', (17, 22))	('IGF-1', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('rs2195239', 'Var', (38, 47))	('patients', 'Species', '9606', (118, 126))
574647	23304125	An earlier study revealed that metformin, a commonly used oral antihyperglycemic agent belonging to the biguanide family, may reduce the risk of cancer, and improve its prognosis.	('cancer', 'Disease', (145, 151))	('prognosis', 'CPA', (169, 178))	('reduce', 'NegReg', (126, 132))	('biguanide', 'Chemical', 'MESH:D001645', (104, 113))	('improve', 'PosReg', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('metformin', 'Var', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('metformin', 'Chemical', 'MESH:D008687', (31, 40))
574648	23304125	One explanation for this finding is that metformin reduces the phosphorylation of epidermal growth factor receptor and IGF-1 receptor in vitro and in vivo.	('epidermal growth factor receptor', 'Gene', (82, 114))	('reduces', 'NegReg', (51, 58))	('metformin', 'Var', (41, 50))	('epidermal growth factor receptor', 'Gene', '1956', (82, 114))	('IGF-1', 'Gene', '3479', (119, 124))	('phosphorylation', 'MPA', (63, 78))	('IGF-1', 'Gene', (119, 124))	('metformin', 'Chemical', 'MESH:D008687', (41, 50))
574658	23304125	Mice with disruptions in the adiponectin gene are more likely to develop intestinal tumors, with decreased activation (i.e., phosphorylation) of AMP-activated protein kinase and increased PAI-1 levels compared with wild-type mice.	('develop', 'PosReg', (65, 72))	('AMP-activated protein kinase', 'MPA', (145, 173))	('adiponectin gene', 'Gene', (29, 45))	('PAI-1', 'Gene', '18787', (188, 193))	('PAI-1', 'Gene', (188, 193))	('intestinal tumors', 'Disease', 'MESH:D007414', (73, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('activation', 'MPA', (107, 117))	('decreased', 'NegReg', (97, 106))	('intestinal tumors', 'Disease', (73, 90))	('phosphorylation', 'MPA', (125, 140))	('Mice', 'Species', '10090', (0, 4))	('mice', 'Species', '10090', (225, 229))	('disruptions', 'Var', (10, 21))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('increased', 'PosReg', (178, 187))
574679	23304125	Overweight and high BMI are associated with an increased risk of esophageal adenocarcinoma and adenocarcinoma of the gastric cardia, even in subjects with a normal BMI.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (65, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('high BMI', 'Var', (15, 23))	('Overweight', 'Var', (0, 10))	('esophageal adenocarcinoma and adenocarcinoma of the gastric cardia', 'Disease', 'MESH:D004938', (65, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))
574698	23304125	Colorectal cancer and adenoma disease are associated with dietary factors, such as red meat, high fat content, and inadequate fiber intake.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('adenoma disease', 'Disease', 'MESH:D000236', (22, 37))	('rectal cancer', 'Phenotype', 'HP:0100743', (4, 17))	('Colorectal cancer', 'Disease', (0, 17))	('high fat content', 'Var', (93, 109))	('adenoma disease', 'Disease', (22, 37))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))
574702	23304125	It is also becoming apparent that adiposity is the factor that is most strongly associated with the risk of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('adiposity', 'Var', (34, 43))	('rectal cancer', 'Phenotype', 'HP:0100743', (112, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('associated', 'Reg', (80, 90))	('colorectal cancer', 'Disease', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
574712	23304125	It is likely that NAFLD causes HCC via cirrhosis, although the exact pathogenesis is unclear.	('HCC', 'Phenotype', 'HP:0001402', (31, 34))	('cirrhosis', 'Phenotype', 'HP:0001394', (39, 48))	('cirrhosis', 'Disease', 'MESH:D005355', (39, 48))	('causes', 'Reg', (24, 30))	('HCC', 'Gene', (31, 34))	('cirrhosis', 'Disease', (39, 48))	('HCC', 'Gene', '619501', (31, 34))	('NAFLD', 'Var', (18, 23))
574721	23304125	Several studies have revealed a link between high body mass, lack of physical activity, and pancreatic cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('high body mass', 'Var', (45, 59))	('pancreatic cancer', 'Disease', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))
574724	23304125	It was also reported that high BMI is associated with decreased survival in patients with pancreatic cancer, although the mechanism for this association was not determined.	('BMI', 'MPA', (31, 34))	('patients', 'Species', '9606', (76, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('high', 'Var', (26, 30))	('pancreatic cancer', 'Disease', (90, 107))	('survival', 'MPA', (64, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('decreased', 'NegReg', (54, 63))
574726	23304125	Metabolic syndrome represents a cluster of metabolic abnormalities and is defined as the presence of three or more of the following factors: abdominal obesity (i.e., increased waist circumference), elevated triglycerides, low HDL cholesterol, high blood pressure, and high fasting glucose.	('increased waist circumference', 'Phenotype', 'HP:0031819', (166, 195))	('metabolic abnormalities', 'Disease', (43, 66))	('abdominal obesity', 'Disease', 'MESH:D056128', (141, 158))	('triglycerides', 'MPA', (207, 220))	('high', 'Disease', (243, 247))	('low HDL cholesterol', 'Phenotype', 'HP:0003233', (222, 241))	('obesity', 'Phenotype', 'HP:0001513', (151, 158))	('cholesterol', 'Chemical', 'MESH:D002784', (230, 241))	('elevated triglycerides', 'Phenotype', 'HP:0002155', (198, 220))	('abdominal obesity', 'Phenotype', 'HP:0012743', (141, 158))	('Metabolic syndrome', 'Disease', 'MESH:D008659', (0, 18))	('high fasting glucose', 'Phenotype', 'HP:0003074', (268, 288))	('glucose', 'Chemical', 'MESH:D005947', (281, 288))	('waist', 'MPA', (176, 181))	('high fasting glucose', 'MPA', (268, 288))	('high blood pressure', 'Phenotype', 'HP:0000822', (243, 262))	('elevated', 'PosReg', (198, 206))	('triglycerides', 'Chemical', 'MESH:D014280', (207, 220))	('increased', 'PosReg', (166, 175))	('metabolic abnormalities', 'Phenotype', 'HP:0001939', (43, 66))	('low', 'Var', (222, 225))	('metabolic abnormalities', 'Disease', 'MESH:D008659', (43, 66))	('Metabolic syndrome', 'Disease', (0, 18))	('abdominal obesity', 'Disease', (141, 158))
574736	31922357	Further verification experiment from qRT-PCR indicated that miR-128-3p, miR-140-3p, miR-340-5p, miR-452-5p, miR-769-5p and miR-1304-p5 were significantly upregulated in EVs from hypoxia TE-13 cells while miR-340-5p was significantly upregulated in two other ESCC cells, ECA109 and TE-1.	('miR-140-3p', 'Var', (72, 82))	('miR-452-5p', 'Gene', '100616196', (96, 106))	('miR-769-5p', 'Var', (108, 118))	('upregulated', 'PosReg', (154, 165))	('miR-340-5p', 'Var', (84, 94))	('miR-128-3p', 'Var', (60, 70))	('TE', 'Chemical', 'MESH:D013691', (281, 283))	('ESCC', 'Disease', 'MESH:C562729', (258, 262))	('hypoxia', 'Disease', (178, 185))	('hypoxia', 'Disease', 'MESH:D000860', (178, 185))	('TE', 'Chemical', 'MESH:D013691', (186, 188))	('miR-340-5p', 'Chemical', '-', (204, 214))	('miR-1304-p5', 'Var', (123, 134))	('ESCC', 'Disease', (258, 262))	('miR-452-5p', 'Gene', (96, 106))	('ESCC', 'Phenotype', 'HP:0011459', (258, 262))	('miR-340-5p', 'Chemical', '-', (84, 94))
574768	31922357	Differentially expressed miRNAs and their target mRNAs were determined to be mostly involved in cancer-related pathways, phospholipase D signaling pathway (Fig.	('phospholipase D signaling pathway', 'Pathway', (121, 154))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('miRNAs', 'Var', (25, 31))	('involved', 'Reg', (84, 92))
574771	31922357	The results showed that miR-128-3p, miR-140-3p, miR-340-5p, miR-452-5p, miR-769-5p and miR-1304-p5 were significantly upregulated in hypoxic EVs (Fig.5(a)).	('miR-1304-p5', 'Var', (87, 98))	('hypoxic EVs', 'Disease', (133, 144))	('miR-128-3p', 'Var', (24, 34))	('miR-452-5p', 'Gene', (60, 70))	('miR-140-3p', 'Var', (36, 46))	('miR-340-5p', 'Chemical', '-', (48, 58))	('miR-452-5p', 'Gene', '100616196', (60, 70))	('miR-340-5p', 'Var', (48, 58))	('upregulated', 'PosReg', (118, 129))	('miR-769-5p', 'Var', (72, 82))
574772	31922357	We further verified these seven miRNAs in EVs of TE1 and ECA109 cells and found that miR-340-5p was overexpressed in hypoxic EVs of all three types of cells (Fig.5(b) and 5(c)).	('TE', 'Chemical', 'MESH:D013691', (49, 51))	('miR-340-5p', 'Chemical', '-', (85, 95))	('overexpressed', 'PosReg', (100, 113))	('miR-340-5p', 'Var', (85, 95))
574784	31922357	Therefore, blockade of overactivated cancer pathways can be an important target for cancer therapy.30, 31 For instance, tyrosine kinase inhibitors have been successfully used to treat mutant EGFR non-small cell lung cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('mutant', 'Var', (184, 190))	('cancer', 'Disease', (216, 222))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (200, 222))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (196, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('blockade of overactivated cancer', 'Disease', 'MESH:D009369', (11, 43))	('EGFR', 'Gene', (191, 195))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (37, 43))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (196, 222))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('blockade of overactivated cancer', 'Disease', (11, 43))	('EGFR', 'Gene', '1956', (191, 195))	('non-small cell lung cancer', 'Disease', (196, 222))
574792	31922357	In colorectal and oral cancer, silencing AGE-RAGE signaling can repress cancer cells from proliferation and migration.	('repress', 'NegReg', (64, 71))	('silencing', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('RAGE', 'Gene', (45, 49))	('RAGE', 'Gene', '101669765', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('colorectal and oral cancer', 'Disease', 'MESH:D015179', (3, 29))	('cancer', 'Disease', (72, 78))
574794	31922357	Further verification experiment from RT-PCR indicated that miR-128-3p, miR-140-3p, miR-340-5p, miR-452-5p, miR-769-5p and miR-1304-p5 were significantly upregulated in EVs from hypoxia TE-13 cells while miR-340-5p was significantly upregulated in two other ESCC cells, ECA109 and TE-1.	('miR-769-5p', 'Var', (107, 117))	('miR-340-5p', 'Var', (83, 93))	('ESCC', 'Disease', 'MESH:C562729', (257, 261))	('TE', 'Chemical', 'MESH:D013691', (185, 187))	('miR-452-5p', 'Gene', (95, 105))	('miR-128-3p', 'Var', (59, 69))	('miR-340-5p', 'Chemical', '-', (203, 213))	('miR-140-3p', 'Var', (71, 81))	('miR-452-5p', 'Gene', '100616196', (95, 105))	('ESCC', 'Disease', (257, 261))	('upregulated', 'PosReg', (153, 164))	('TE', 'Chemical', 'MESH:D013691', (280, 282))	('miR-1304-p5', 'Var', (122, 133))	('hypoxia', 'Disease', 'MESH:D000860', (177, 184))	('ESCC', 'Phenotype', 'HP:0011459', (257, 261))	('miR-340-5p', 'Chemical', '-', (83, 93))	('hypoxia', 'Disease', (177, 184))
574920	28422823	Association between ALDH2 Glu487Lys polymorphism and the risk of esophageal cancer A meta-analysis was carried out to further evaluate the relationship between ALDH2 Glu487Lys polymorphism and esophageal cancer risk.	('ALDH2', 'Gene', '217', (20, 25))	('Glu487Lys', 'Var', (166, 175))	('Glu487Lys', 'SUBSTITUTION', 'None', (26, 35))	('esophageal cancer', 'Disease', (65, 82))	('ALDH2', 'Gene', (160, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('ALDH2', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Glu487Lys', 'SUBSTITUTION', 'None', (166, 175))	('Glu487Lys', 'Var', (26, 35))	('esophageal cancer', 'Disease', (193, 210))	('Association', 'Interaction', (0, 11))	('ALDH2', 'Gene', '217', (160, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))
574921	28422823	Our findings indicated that individuals with the combination of Glu/Lys and Lys/Lys genotype had an increased risk of getting esophageal cancer (GA + AA vs. GG: odds ratio [OR] 1.36, 95% confidence interval [CI] 0.93-2.00, P = 0.113) with a shift pattern.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('Lys', 'Chemical', 'MESH:D008239', (76, 79))	('Lys/Lys', 'Var', (76, 83))	('Lys', 'Chemical', 'MESH:D008239', (80, 83))	('GA', 'Chemical', 'MESH:D005708', (145, 147))	('GG', 'Chemical', 'MESH:C094686', (157, 159))	('Lys', 'Chemical', 'MESH:D008239', (68, 71))	('esophageal cancer', 'Disease', (126, 143))	('Glu', 'Chemical', 'MESH:D018698', (64, 67))	('Glu/Lys', 'Var', (64, 71))
574922	28422823	Although Lys/Lys genotype carriers showed areduced esophageal cancer risk (AA vs. GA + GG: OR 0.41, 95% CI 0.23-0.72, P = 0.002).	('GA', 'Chemical', 'MESH:D005708', (82, 84))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Lys/Lys', 'Var', (9, 16))	('esophageal cancer', 'Disease', (51, 68))	('Lys', 'Chemical', 'MESH:D008239', (9, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('Lys', 'Chemical', 'MESH:D008239', (13, 16))	('GG', 'Chemical', 'MESH:C094686', (87, 89))
574924	28422823	This meta-analysis concluded that there was a strong association between ALDH2 Glu487Lys polymorphism and the risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('ALDH2', 'Gene', (73, 78))	('Glu487Lys', 'SUBSTITUTION', 'None', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('ALDH2', 'Gene', '217', (73, 78))	('esophageal cancer', 'Disease', (118, 135))	('Glu487Lys', 'Var', (79, 88))
574925	28422823	It further confirmed that ALDH2 Glu487Lys polymorphism was a -risk factor for esophageal cancer.	('ALDH2', 'Gene', '217', (26, 31))	('ALDH2', 'Gene', (26, 31))	('Glu487Lys', 'Var', (32, 41))	('Glu487Lys', 'SUBSTITUTION', 'None', (32, 41))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
574934	28422823	ALDH2 displays a polymorphism that may affect alcohol-oxidizing capacity.	('alcohol-oxidizing capacity', 'MPA', (46, 72))	('alcohol', 'Chemical', 'MESH:D000438', (46, 53))	('affect', 'Reg', (39, 45))	('ALDH2', 'Gene', (0, 5))	('polymorphism', 'Var', (17, 29))	('ALDH2', 'Gene', '217', (0, 5))
574935	28422823	A single point mutation of a lysine amino acid has been found at residue 487 instead of glutamic acid in ALDH2 gene (ALDH2 Glu487Lys), resulting in a reduced enzyme activity.	('Glu487Lys', 'SUBSTITUTION', 'None', (123, 132))	('enzyme activity', 'MPA', (158, 173))	('ALDH2', 'Gene', (105, 110))	('ALDH2', 'Gene', '217', (117, 122))	('glutamic acid', 'Chemical', 'MESH:D018698', (88, 101))	('lysine amino acid', 'Chemical', '-', (29, 46))	('reduced', 'NegReg', (150, 157))	('Glu487Lys', 'Var', (123, 132))	('ALDH2', 'Gene', (117, 122))	('ALDH2', 'Gene', '217', (105, 110))
574936	28422823	Individuals with the ALDH2 Lys allele have a high concentration of blood acetaldehyde after drinking alcohol, thus enhances the risk for esophageal cancer.	('alcohol', 'Chemical', 'MESH:D000438', (101, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('blood acetaldehyde', 'Phenotype', 'HP:0003533', (67, 85))	('ALDH2', 'Gene', '217', (21, 26))	('Lys', 'Var', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('ALDH2', 'Gene', (21, 26))	('acetaldehyde', 'Chemical', 'MESH:D000079', (73, 85))	('esophageal cancer', 'Disease', (137, 154))	('Lys', 'Chemical', 'MESH:D008239', (27, 30))	('enhances', 'PosReg', (115, 123))
574937	28422823	The polymorphisms of ALDH2 associated with the risk of esophageal cancer have been described in several studies, but the results are still inconsistent.	('ALDH2', 'Gene', '217', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('associated', 'Reg', (27, 37))	('esophageal cancer', 'Disease', (55, 72))	('polymorphisms', 'Var', (4, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('ALDH2', 'Gene', (21, 26))
574938	28422823	To assess the association between ALDH2 Glu487Lys polymorphism and the risk of esophageal cancer, we performed a meta-analysis based on 3812 cases and 7376 controls.	('esophageal cancer', 'Disease', (79, 96))	('ALDH2', 'Gene', '217', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('Glu487Lys', 'Var', (40, 49))	('ALDH2', 'Gene', (34, 39))	('Glu487Lys', 'SUBSTITUTION', 'None', (40, 49))
574939	28422823	Fifteen case-control studies related to ALDH2 Glu487Lys polymorphism and esophageal cancer risk were covered in this meta-analysis.	('Glu487Lys', 'Var', (46, 55))	('ALDH2', 'Gene', (40, 45))	('esophageal cancer', 'Disease', (73, 90))	('Glu487Lys', 'SUBSTITUTION', 'None', (46, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ALDH2', 'Gene', '217', (40, 45))
574940	28422823	Only case-control studies that investigated the relationship between ALDH2 polymorphisms and EC were included in the meta-analysis.	('ALDH2', 'Gene', (69, 74))	('ALDH2', 'Gene', '217', (69, 74))	('polymorphisms', 'Var', (75, 88))	('EC', 'Phenotype', 'HP:0011459', (93, 95))
574941	28422823	For the first-round exclusion, articles were searched with NCBI Global Cross-database, including PubMed, PMC, Gene, PubChem, among others, as well as Google Scholar by using "ALDH2 polymorphism?	('ALDH2', 'Gene', (175, 180))	('ALDH2', 'Gene', '217', (175, 180))	('polymorphism', 'Var', (181, 193))
574942	28422823	"ALDH2 Glu487Lys polymorphism?	('Glu487Lys', 'Var', (7, 16))	('Glu487Lys', 'SUBSTITUTION', 'None', (7, 16))	('ALDH2', 'Gene', (1, 6))	('ALDH2', 'Gene', '217', (1, 6))
574943	28422823	"ALDH2 rs671 polymorphism?	('polymorphism', 'Var', (13, 25))	('ALDH2', 'Gene', (1, 6))	('rs671 polymorphism', 'Var', (7, 25))	('rs671', 'Mutation', 'rs671', (7, 12))	('ALDH2', 'Gene', '217', (1, 6))
574945	28422823	For the second-round selection, we excluded the articles that were not aimed at investigating the association between ALDH2 Glu487Lys polymorphisms and esophageal cancer risk, and then 61 articles were identified.	('association', 'Interaction', (98, 109))	('Glu487Lys', 'Var', (124, 133))	('ALDH2', 'Gene', (118, 123))	('Glu487Lys', 'SUBSTITUTION', 'None', (124, 133))	('esophageal cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('ALDH2', 'Gene', '217', (118, 123))
574950	28422823	In this meta-analysis, 15 studies were included in the final analysis for ALDH2 Glu487Lys polymorphism.	('Glu487Lys', 'Var', (80, 89))	('ALDH2', 'Gene', (74, 79))	('Glu487Lys', 'SUBSTITUTION', 'None', (80, 89))	('ALDH2', 'Gene', '217', (74, 79))
574951	28422823	To get a reasonable statistical conclusion, association between ALDH2 Glu487Lys polymorphism and the risk of EC was evaluated using odds ratio (OR) derived from different analysis models.	('Glu487Lys', 'Var', (70, 79))	('ALDH2', 'Gene', '217', (64, 69))	('EC', 'Phenotype', 'HP:0011459', (109, 111))	('ALDH2', 'Gene', (64, 69))	('Glu487Lys', 'SUBSTITUTION', 'None', (70, 79))	('association', 'Interaction', (44, 55))
574952	28422823	In our study, we just utilized previous articles to review the association between ALDH2 Glu487Lys polymorphism and the risk of esophageal cancer, and it did not include clinical trials and animal experiments.	('Glu487Lys', 'SUBSTITUTION', 'None', (89, 98))	('esophageal cancer', 'Disease', (128, 145))	('ALDH2', 'Gene', '217', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('association', 'Interaction', (63, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('Glu487Lys', 'Var', (89, 98))	('ALDH2', 'Gene', (83, 88))
574953	28422823	All the data in these studies were related to association between ALDH2 Glu487Lys polymorphism and human esophageal cancer risk.	('Glu487Lys', 'SUBSTITUTION', 'None', (72, 81))	('ALDH2', 'Gene', '217', (66, 71))	('esophageal cancer', 'Disease', (105, 122))	('association', 'Interaction', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ALDH2', 'Gene', (66, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('Glu487Lys', 'Var', (72, 81))	('human', 'Species', '9606', (99, 104))
574956	28422823	For dominant model, the overall OR was 1.36 (95% CI 0.93-2.00, P = 0.113), indicating that an increased EC risk was associated with ALDH2 Glu487Lys polymorphisms in the dominant model (GA+AA vs GG, Figure 2A) even though a shift pattern was detected (P > 0.05).	('Glu487Lys', 'Var', (138, 147))	('ALDH2', 'Gene', (132, 137))	('GG', 'Chemical', 'MESH:C094686', (194, 196))	('Glu487Lys', 'SUBSTITUTION', 'None', (138, 147))	('ALDH2', 'Gene', '217', (132, 137))	('EC', 'Phenotype', 'HP:0011459', (104, 106))	('GA+AA', 'Chemical', '-', (185, 190))
574957	28422823	The overall OR for recessive model (AA vs. GA + GG) was 0.41 (95% CI 0.23-0.72, P = 0.002), suggesting that AA genotype of ALDH2 Glu487Lys polymorphisms had the association with the reduced EC risk (Fig.	('ALDH2', 'Gene', '217', (123, 128))	('Glu487Lys', 'Var', (129, 138))	('ALDH2', 'Gene', (123, 128))	('Glu487Lys', 'SUBSTITUTION', 'None', (129, 138))	('GA', 'Chemical', 'MESH:D005708', (43, 45))	('GG', 'Chemical', 'MESH:C094686', (48, 50))	('EC', 'Phenotype', 'HP:0011459', (190, 192))	('reduced', 'NegReg', (182, 189))
574959	28422823	In this article, we presented a meta-analysis to investigate the association between ALDH2 Glu487Lys polymorphisms and the risk of human esophageal cancer.	('ALDH2', 'Gene', '217', (85, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('human', 'Species', '9606', (131, 136))	('ALDH2', 'Gene', (85, 90))	('Glu487Lys', 'Var', (91, 100))	('esophageal cancer', 'Disease', (137, 154))	('Glu487Lys', 'SUBSTITUTION', 'None', (91, 100))
574960	28422823	According to our knowledge, this is the first meta-analysis generated to summarize the effects of the specific single-nucleotide polymorphism (SNP) (ALDH2 Glu487Lys) on human esophageal cancer.	('esophageal cancer', 'Disease', (175, 192))	('Glu487Lys', 'Var', (155, 164))	('ALDH2', 'Gene', (149, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('Glu487Lys', 'SUBSTITUTION', 'None', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('human', 'Species', '9606', (169, 174))	('ALDH2', 'Gene', '217', (149, 154))
574962	28422823	The data from this meta-analysis showed that there was a significant association between ALDH2 Glu487Lys polymorphism and the risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('ALDH2', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Glu487Lys', 'Var', (95, 104))	('Glu487Lys', 'SUBSTITUTION', 'None', (95, 104))	('esophageal cancer', 'Disease', (134, 151))	('ALDH2', 'Gene', '217', (89, 94))
574963	28422823	The combination of Glu/Lys and Lys/Lys genotype showed an increased risk of esophageal cancer even though a shift pattern was detected (P > 0.05).	('Lys', 'Chemical', 'MESH:D008239', (31, 34))	('Lys/Lys', 'Var', (31, 38))	('Lys', 'Chemical', 'MESH:D008239', (35, 38))	('esophageal cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('Lys', 'Chemical', 'MESH:D008239', (23, 26))	('Glu', 'Chemical', 'MESH:D018698', (19, 22))	('Glu/Lys', 'Var', (19, 26))
574964	28422823	However, compared to Glu/Glu genotype, we observed that individuals with Lys/Lys genotype presented a decreased risk of esophageal cancer.	('Glu', 'Chemical', 'MESH:D018698', (21, 24))	('Lys/Lys', 'Var', (73, 80))	('Glu', 'Chemical', 'MESH:D018698', (25, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('Lys', 'Chemical', 'MESH:D008239', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Lys', 'Chemical', 'MESH:D008239', (77, 80))	('esophageal cancer', 'Disease', (120, 137))	('decreased', 'NegReg', (102, 111))
574968	28422823	Previous studies have shown that ADH1B and ALDH2 polymorphism was one of risk-conferring factors for alcohol dependence.	('ADH1B', 'Gene', (33, 38))	('polymorphism', 'Var', (49, 61))	('ADH1B', 'Gene', '125', (33, 38))	('ALDH2', 'Gene', (43, 48))	('alcohol dependence', 'Disease', 'MESH:D000437', (101, 119))	('alcohol dependence', 'Phenotype', 'HP:0030955', (101, 119))	('alcohol dependence', 'Disease', (101, 119))	('ALDH2', 'Gene', '217', (43, 48))
574969	28422823	ALDH 487Lys allele encodes an inactive subunit of ALDH2, leading to large amounts of acetaldehyde accumulation after alcohol consumption.	('acetaldehyde accumulation', 'MPA', (85, 110))	('Lys', 'Chemical', 'MESH:D008239', (8, 11))	('leading to', 'Reg', (57, 67))	('acetaldehyde', 'Chemical', 'MESH:D000079', (85, 97))	('ALDH2', 'Gene', (50, 55))	('acetaldehyde accumulation', 'Phenotype', 'HP:0003533', (85, 110))	('alcohol', 'Chemical', 'MESH:D000438', (117, 124))	('ALDH', 'Gene', (0, 4))	('487Lys', 'Var', (5, 11))	('ALDH2', 'Gene', '217', (50, 55))
574970	28422823	The concentration of blood acetaldehyde was 6-fold in individuals with inactive ALDH2 than those with active ALDH2.	('ALDH2', 'Gene', '217', (109, 114))	('inactive', 'Var', (71, 79))	('acetaldehyde', 'Chemical', 'MESH:D000079', (27, 39))	('ALDH2', 'Gene', (109, 114))	('concentration of blood acetaldehyde', 'MPA', (4, 39))	('ALDH2', 'Gene', '217', (80, 85))	('blood acetaldehyde', 'Phenotype', 'HP:0003533', (21, 39))	('ALDH2', 'Gene', (80, 85))
574971	28422823	Our dominant model results in this study suggest the hypothesis that ALDH2 Lys allele may increase the susceptibility to EC because of longer exposure to alcohol and high concentration of acetaldehyde.	('Lys', 'Var', (75, 78))	('EC', 'Phenotype', 'HP:0011459', (121, 123))	('acetaldehyde', 'Chemical', 'MESH:D000079', (188, 200))	('alcohol', 'Chemical', 'MESH:D000438', (154, 161))	('ALDH2', 'Gene', '217', (69, 74))	('Lys', 'Chemical', 'MESH:D008239', (75, 78))	('ALDH2', 'Gene', (69, 74))	('exposure', 'MPA', (142, 150))
574973	28422823	It may be very important to avoid alcohol to prevent EC for those carriers with ALDH2 Lys allele.	('ALDH2', 'Gene', (80, 85))	('EC', 'Phenotype', 'HP:0011459', (53, 55))	('ALDH2', 'Gene', '217', (80, 85))	('alcohol', 'Chemical', 'MESH:D000438', (34, 41))	('Lys allele', 'Var', (86, 96))	('Lys', 'Chemical', 'MESH:D008239', (86, 89))
574975	28422823	Third, there was heterogeneity between studies of ALDH2 polymorphisms.	('polymorphisms', 'Var', (56, 69))	('ALDH2', 'Gene', (50, 55))	('ALDH2', 'Gene', '217', (50, 55))
574976	28422823	Based on the results of our meta-analysis, we concluded that a strong association was existed between ALDH2 Glu487Lys polymorphism and the risk of esophageal cancer.	('esophageal cancer', 'Disease', (147, 164))	('Glu487Lys', 'Var', (108, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('ALDH2', 'Gene', (102, 107))	('Glu487Lys', 'SUBSTITUTION', 'None', (108, 117))	('ALDH2', 'Gene', '217', (102, 107))
574977	28422823	The combination of ALDH2 Glu/Lys and Lys/Lys genotypes was associated with the increased risk of esophageal cancer with a shift pattern.	('Glu', 'Chemical', 'MESH:D018698', (25, 28))	('ALDH2', 'Gene', (19, 24))	('Glu/Lys', 'Var', (25, 32))	('esophageal cancer', 'Disease', (97, 114))	('Lys', 'Chemical', 'MESH:D008239', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Lys', 'Chemical', 'MESH:D008239', (37, 40))	('Lys/Lys', 'Var', (37, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('ALDH2', 'Gene', '217', (19, 24))	('Lys', 'Chemical', 'MESH:D008239', (41, 44))
574978	28422823	When compared to Glu/Lys and Glu/Glu or Glu/Glu genotypes, individuals with Lys/Lys genotype had a reduced risk of getting esophageal cancer.	('esophageal cancer', 'Disease', (123, 140))	('Lys', 'Chemical', 'MESH:D008239', (76, 79))	('Lys/Lys', 'Var', (76, 83))	('Lys', 'Chemical', 'MESH:D008239', (80, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('Glu', 'Chemical', 'MESH:D018698', (40, 43))	('Glu', 'Chemical', 'MESH:D018698', (44, 47))	('Glu', 'Chemical', 'MESH:D018698', (33, 36))	('Glu', 'Chemical', 'MESH:D018698', (29, 32))	('reduced', 'NegReg', (99, 106))	('Lys', 'Chemical', 'MESH:D008239', (21, 24))	('Glu', 'Chemical', 'MESH:D018698', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
575054	28280360	Therefore, dysregulation of this process can promote tumor progression and chemoresistance during cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('chemoresistance', 'CPA', (75, 90))	('promote', 'PosReg', (45, 52))	('dysregulation', 'Var', (11, 24))	('cancer', 'Disease', (98, 104))	('tumor', 'Disease', (53, 58))
575059	28280360	As shown in Figure 5A, transfection of cells with p53 siRNA significantly inhibited the ArBu-induced p53 phosphorylation and the overall cell apoptosis by measuring the sub-G1 cell population (Figure 5B), whereas transfection with the negative control siRNA showed no effects in the earlier events.	('inhibited', 'NegReg', (74, 83))	('p53 siRNA', 'Var', (50, 59))	('cell apoptosis', 'CPA', (137, 151))	('ArBu-induced p53 phosphorylation', 'MPA', (88, 120))	('ArBu', 'Chemical', 'MESH:C055393', (88, 92))
575110	15327696	It is possible that patients with anastomotic strictures may be at increased risk of recurrent Barrett's esophagus because of worse reflux although their swallowing symptoms may, alternatively, be related to other factors such as anastomotic ischemia or surgical sutures.	('swallowing symptoms', 'Phenotype', 'HP:0002015', (154, 173))	('worse reflux', 'MPA', (126, 138))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (95, 114))	('anastomotic ischemia', 'Disease', 'MESH:D007511', (230, 250))	('patients', 'Species', '9606', (20, 28))	('anastomotic strictures', 'Var', (34, 56))	("recurrent Barrett's esophagus", 'Disease', (85, 114))	('anastomotic ischemia', 'Disease', (230, 250))
575120	15327696	Three other patients developed recurrent Barrett's disease after curative resection of esophageal T2 or T3N0M0 adenocarcinoma.	("Barrett's disease", 'Disease', 'MESH:D001471', (41, 58))	('patients', 'Species', '9606', (12, 20))	('developed', 'Reg', (21, 30))	('adenocarcinoma', 'Disease', (111, 125))	('T3N0M0', 'Var', (104, 110))	("Barrett's disease", 'Phenotype', 'HP:0100580', (41, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	("Barrett's disease", 'Disease', (41, 58))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))
575128	15327696	Repeat resection confirmed the tumor histologic grade of T2N1M0 adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('adenocarcinoma', 'Disease', (64, 78))	('tumor', 'Disease', (31, 36))	('T2N1M0', 'Var', (57, 63))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
575178	27515178	The results showed that patients harboring NOTCH1 mutations had a longer lifespan after surgery than those without mutations.	('NOTCH1', 'Gene', '4851', (43, 49))	('NOTCH1', 'Gene', (43, 49))	('mutations', 'Var', (50, 59))	('longer', 'PosReg', (66, 72))	('patients', 'Species', '9606', (24, 32))
575184	27515178	Both the gene copy number and expression of MYBL2 showed negative effects on individuals' survival.	('gene copy number', 'Var', (9, 25))	('MYBL2', 'Gene', '4605', (44, 49))	('MYBL2', 'Gene', (44, 49))	('negative', 'NegReg', (57, 65))
575187	27515178	In our study, a CNV-harbored microRNA, miR-4707-5p, was found to be significantly overexpressed in tumors, and individuals with high miR-4707-5p levels exhibited worse prognosis than those with low miR-4707-5p levels.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('overexpressed', 'PosReg', (82, 95))	('high miR-4707-5p levels', 'Var', (128, 151))
575188	27515178	The pro-metastasis ability of miR-4707-5p was confirmed in two different mouse tumor metastasis models.	('tumor', 'Disease', (79, 84))	('mouse', 'Species', '10090', (73, 78))	('miR-4707-5p', 'Var', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
575189	27515178	Furthermore, through mechanism studies, we found that miR-4707-5p can decrease E-cadherin by targeting adenosine deaminase, RNA specific B1 (ADARB1), in turn promoting cell metastasis.	('adenosine deaminase, RNA specific B1', 'Gene', '104;100', (103, 139))	('decrease', 'NegReg', (70, 78))	('E-cadherin', 'Gene', (79, 89))	('miR-4707-5p', 'Var', (54, 65))	('E-cadherin', 'Gene', '999', (79, 89))	('ADARB1', 'Gene', (141, 147))	('targeting', 'Reg', (93, 102))	('ADARB1', 'Gene', '104', (141, 147))	('promoting', 'PosReg', (158, 167))	('cell metastasis', 'CPA', (168, 183))
575192	27515178	Thus, VANGL1 mutation might play a role only at early stages of the neoplastic process.	('VANGL1', 'Gene', '81839', (6, 12))	('mutation', 'Var', (13, 21))	('VANGL1', 'Gene', (6, 12))	('neoplastic process', 'Phenotype', 'HP:0002664', (68, 86))
575194	27515178	We showed that at least two of them, MYBL2 and miR-4707-5p, are involved in ESCC cell malignant transformation and might be a basis for poor ESCC prognosis.	('involved', 'Reg', (64, 72))	('MYBL2', 'Gene', '4605', (37, 42))	('miR-4707-5p', 'Var', (47, 58))	('MYBL2', 'Gene', (37, 42))	('ESCC', 'Disease', (76, 80))	('ESCC', 'Disease', (141, 145))
575214	26972225	BE cases were excluded if they had one or more instances of the non-specific "Barrett's ulcer" (J102500) prior to BE or if BE was reported by the patient at an initial GP visit (i.e.	('J102500', 'Var', (96, 103))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('ulcer', 'Disease', 'MESH:D014456', (88, 93))	('patient', 'Species', '9606', (146, 153))	('BE', 'Phenotype', 'HP:0100580', (123, 125))	('ulcer', 'Disease', (88, 93))	('BE', 'Phenotype', 'HP:0100580', (0, 2))
575221	26972225	Potential population control subjects for the BE and EA case groups were excluded if they had any instance of BE (J101611) or "Barrett's ulcer" of the esophagus (J102500) prior to their index date or if BE was reported by the patient and documented at an initial GP visit (i.e.	('ulcer', 'Disease', 'MESH:D014456', (137, 142))	('ulcer', 'Disease', (137, 142))	('Barrett\'s ulcer" of the esophagus', 'Phenotype', 'HP:0100580', (127, 160))	('BE', 'Phenotype', 'HP:0100580', (110, 112))	('J102500', 'Var', (162, 169))	('patient', 'Species', '9606', (226, 233))	('BE', 'Phenotype', 'HP:0100580', (46, 48))	('J101611', 'Var', (114, 121))	('ulcer" of the esophagus', 'Phenotype', 'HP:0004791', (137, 160))	('EA', 'Phenotype', 'HP:0011459', (53, 55))	('BE', 'Phenotype', 'HP:0100580', (203, 205))
575234	26972225	We also conducted multivariable logistic regression analyses stratified by presence of GERD and/or sex to assess effect-modification, since GERD may be associated with MetS and sex may modify the effect of obesity .	('MetS', 'Disease', (168, 172))	('obesity', 'Phenotype', 'HP:0001513', (206, 213))	('obesity', 'Disease', 'MESH:D009765', (206, 213))	('GERD', 'Var', (140, 144))	('associated', 'Reg', (152, 162))	('obesity', 'Disease', (206, 213))	('modify', 'Reg', (185, 191))
575246	26972225	In addition, high cholesterol and hypertension were independently associated with risk of BE in the absence of GERD, even after adjusting for all other metabolic conditions.	('BE', 'Phenotype', 'HP:0100580', (90, 92))	('high cholesterol', 'Phenotype', 'HP:0003124', (13, 29))	('hypertension', 'Disease', 'MESH:D006973', (34, 46))	('hypertension', 'Disease', (34, 46))	('high cholesterol', 'Var', (13, 29))	('cholesterol', 'Chemical', 'MESH:D002784', (18, 29))	('hypertension', 'Phenotype', 'HP:0000822', (34, 46))
575273	27171439	High ACSL3 expression predicted a better prognosis in ovarian cancer; in contrast, high ACSL3 predicted a worse prognosis in melanoma.	('ovarian cancer', 'Disease', 'MESH:D010051', (54, 68))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('ACSL3', 'Gene', (88, 93))	('High', 'Var', (0, 4))	('ACSL3', 'Gene', (5, 10))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('ovarian cancer', 'Disease', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (54, 68))	('ACSL3', 'Gene', '2181', (5, 10))	('ACSL3', 'Gene', '2181', (88, 93))
575275	27171439	High expression of ACSL4 predicted a worse prognosis in colorectal cancer, but predicted better prognosis in breast, brain and lung cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('High', 'Var', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('brain and lung cancer', 'Disease', 'MESH:D008175', (117, 138))	('ACSL4', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('breast', 'Disease', (109, 115))
575277	27171439	High expression of ACSL5 predicted good prognosis in breast, ovarian, and lung cancers.	('High', 'Var', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancers', 'Disease', 'MESH:D008175', (74, 86))	('lung cancers', 'Phenotype', 'HP:0100526', (74, 86))	('ACSL5', 'Gene', (19, 24))	('breast', 'Disease', (53, 59))	('ACSL5', 'Gene', '51703', (19, 24))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('lung cancers', 'Disease', (74, 86))	('ovarian', 'Disease', (61, 68))
575285	27171439	Altered fatty acid has been observed in varieties of cancers and is recognized as a marker of cancer.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('fatty acid', 'Chemical', 'MESH:D005227', (8, 18))	('Altered', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('observed', 'Reg', (28, 36))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
575288	27171439	Overexpression of fatty acid synthase (FASN) in breast and prostate cancer is associated with the poor prognosis and inhibition of FASN attenuates the lipogenesis and serves as the therapeutic approach.	('FASN', 'Gene', '2194', (39, 43))	('fatty acid synthase', 'Gene', '2194', (18, 37))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('lipogenesis', 'MPA', (151, 162))	('fatty acid synthase', 'Gene', (18, 37))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (48, 74))	('inhibition', 'Var', (117, 127))	('FASN', 'Gene', (131, 135))	('FASN', 'Gene', '2194', (131, 135))	('attenuates', 'NegReg', (136, 146))	('FASN', 'Gene', (39, 43))
575296	27171439	ACSL3 is present in brain and shows preference for myristate, arachidonate and eicosapentaenoate.	('eicosapentaenoate', 'Var', (79, 96))	('arachidonate', 'MPA', (62, 74))	('eicosapentaenoate', 'Chemical', 'MESH:D015118', (79, 96))	('myristate', 'MPA', (51, 60))	('ACSL3', 'Gene', (0, 5))	('myristate', 'Chemical', 'MESH:D019814', (51, 60))	('arachidonate', 'Chemical', 'MESH:D016718', (62, 74))	('ACSL3', 'Gene', '2181', (0, 5))
575299	27171439	ACSL6 is found in plasma membrane and displays a high activity with fatty acid with C16-C20 saturated and polyunsaturated.	('C16-C20', 'Var', (84, 91))	('fatty acid', 'MPA', (68, 78))	('ACSL6', 'Gene', (0, 5))	('ACSL6', 'Gene', '23305', (0, 5))	('C16-C20', 'Chemical', '-', (84, 91))	('activity', 'MPA', (54, 62))	('polyunsaturated', 'MPA', (106, 121))	('fatty acid', 'Chemical', 'MESH:D005227', (68, 78))
575339	27171439	Hepatocytic deletion of Pten in mice develops hepatocellular carcinoma and increased acsl5:acsl1 ratio.	('deletion', 'Var', (12, 20))	('acsl5', 'Gene', '433256', (85, 90))	('acsl1', 'Gene', '14081', (91, 96))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('increased', 'PosReg', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('hepatocellular carcinoma', 'Disease', (46, 70))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (46, 70))	('Pten', 'Gene', (24, 28))	('acsl1', 'Gene', (91, 96))	('mice', 'Species', '10090', (32, 36))	('Pten', 'Gene', '19211', (24, 28))	('acsl5', 'Gene', (85, 90))	('develops', 'PosReg', (37, 45))
575350	27171439	Loss of ACSL1 favors the ABCA1 expression, contributing to the apoA-I-mediated cholesterol efflux in macrophage.	('cholesterol', 'Chemical', 'MESH:D002784', (79, 90))	('ACSL1', 'Gene', (8, 13))	('ABCA1', 'Gene', '19', (25, 30))	('apoA-I', 'Gene', '335', (63, 69))	('expression', 'MPA', (31, 41))	('apoA-I', 'Gene', (63, 69))	('ABCA1', 'Gene', (25, 30))	('Loss', 'Var', (0, 4))	('contributing', 'Reg', (43, 55))
575351	27171439	Lacking ACSL1 in heart-specific tissue drives the reduction of beta-oxidation and results in the heart dysfunction.	('beta-oxidation', 'MPA', (63, 77))	('reduction', 'NegReg', (50, 59))	('ACSL1', 'Gene', (8, 13))	('Lacking', 'Var', (0, 7))	('results in', 'Reg', (82, 92))	('heart dysfunction', 'Disease', (97, 114))	('heart dysfunction', 'Disease', 'MESH:D006331', (97, 114))
575352	27171439	In addition, miR-205 blocks the lipogenesis in liver cancer and anti-miR-205 promotes the increase of triglyceride by ACSL1.	('anti-miR-205', 'Var', (64, 76))	('liver cancer', 'Disease', 'MESH:D006528', (47, 59))	('increase', 'PosReg', (90, 98))	('liver cancer', 'Disease', (47, 59))	('triglyceride', 'MPA', (102, 114))	('increase of triglyceride', 'Phenotype', 'HP:0002155', (90, 114))	('blocks', 'NegReg', (21, 27))	('triglyceride', 'Chemical', 'MESH:D014280', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('liver cancer', 'Phenotype', 'HP:0002896', (47, 59))	('lipogenesis', 'MPA', (32, 43))
575353	27171439	The negative-correlation of miR-205 and ACSL1 expression in hepatitis B virus X protein (HBx)-transgenic mice suggests that miR-205 leads to the dysregulation of lipid metabolism by ACSL1 and the cancer progression.	('HBx', 'Gene', '944566', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('transgenic mice', 'Species', '10090', (94, 109))	('dysregulation', 'MPA', (145, 158))	('negative-correlation', 'NegReg', (4, 24))	('HBx', 'Gene', (89, 92))	('ACSL1', 'Gene', (40, 45))	('miR-205', 'Var', (124, 131))	('lipid', 'Chemical', 'MESH:D008055', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('hepatitis B virus', 'Species', '10407', (60, 77))	('leads to', 'Reg', (132, 140))	('cancer', 'Disease', (196, 202))	('miR-205', 'Gene', (28, 35))	('lipid metabolism', 'MPA', (162, 178))	('hepatitis', 'Phenotype', 'HP:0012115', (60, 69))
575372	27171439	In contrast, ACSL1 shRNA enhanced the anchorage-independent growth and cell migration in A549 (Fig 3C and 3D).	('ACSL1 shRNA', 'Var', (13, 24))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('enhanced', 'PosReg', (25, 33))	('anchorage-independent growth', 'CPA', (38, 66))	('cell migration', 'CPA', (71, 85))
575376	27171439	ACSL1 knockdown cell exhibited a reduced cell proliferation, which was demonstrated by MTT assay (Fig 3B, right panel).	('cell proliferation', 'CPA', (41, 59))	('ACSL1', 'Gene', (0, 5))	('MTT', 'Chemical', 'MESH:C070243', (87, 90))	('reduced', 'NegReg', (33, 40))	('knockdown', 'Var', (6, 15))
575377	27171439	Downregulation of ACSL1 also inhibited anchorage-independent growth and cell migration of the MDA-MB-231 cells with soft agar assay and Boyden chamber assay (Fig 3C and 3D, right panel).	('inhibited', 'NegReg', (29, 38))	('anchorage-independent growth', 'CPA', (39, 67))	('cell migration', 'CPA', (72, 86))	('Downregulation', 'Var', (0, 14))	('agar', 'Chemical', 'MESH:D000362', (121, 125))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (94, 104))	('ACSL1', 'Gene', (18, 23))
575404	27171439	The deficiency of ACSL4 is correlated with the mental retardation and Alport syndrome.	('mental retardation', 'Disease', (47, 65))	('Alport syndrome', 'Disease', 'MESH:D009394', (70, 85))	('mental retardation', 'Phenotype', 'HP:0001249', (47, 65))	('deficiency', 'Var', (4, 14))	('Alport syndrome', 'Disease', (70, 85))	('mental retardation', 'Disease', 'MESH:D008607', (47, 65))	('correlated', 'Reg', (27, 37))	('ACSL4', 'Gene', (18, 23))
575407	27171439	The expression of ACSL4 mRNA is correlated with the estrogen receptor alpha expression and ACSL4 is sensitive to the triacsin C treatment, indicating that ACSL4 affects the steroid hormone-sensitivity in breast and prostate cancer.	('steroid hormone-sensitivity', 'MPA', (173, 200))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('affects', 'Reg', (161, 168))	('estrogen receptor alpha', 'Gene', (52, 75))	('triacsin C', 'Chemical', 'MESH:C034613', (117, 127))	('prostate cancer', 'Phenotype', 'HP:0012125', (215, 230))	('steroid hormone', 'Chemical', 'MESH:D013256', (173, 188))	('estrogen receptor alpha', 'Gene', '2099', (52, 75))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (204, 230))	('ACSL4', 'Var', (155, 160))
575414	27171439	The prognostic analysis indicated that the colorectal patient with higher ACSL4 expression had poor survival; in contrast, the brain, breast, and lung cancer patient with lower ACSL4 expression had poor survival (Fig 5B and S6 Table).	('patient', 'Species', '9606', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('patient', 'Species', '9606', (158, 165))	('colorectal', 'Disease', (43, 53))	('poor', 'NegReg', (95, 99))	('ACSL4', 'Gene', (74, 79))	('brain', 'Disease', (127, 132))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('breast', 'Disease', (134, 140))	('expression', 'Var', (80, 90))
575424	27171439	ACSL5 is located on mitochondria and involved in the enterocyte apoptosis by alternative splicing.	('enterocyte apoptosis', 'CPA', (53, 73))	('alternative splicing', 'Var', (77, 97))	('ACSL5', 'Gene', (0, 5))	('involved', 'Reg', (37, 45))	('ACSL5', 'Gene', '51703', (0, 5))
575428	27171439	The lower expression of ACSL5 is observed in the colorectal cancer tissue and the patient with the lower ACSL5 has a longer disease-free interval (DFI).	('ACSL5', 'Gene', '51703', (24, 29))	('lower', 'NegReg', (4, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('patient', 'Species', '9606', (82, 89))	('lower', 'Var', (99, 104))	('expression', 'MPA', (10, 20))	('ACSL5', 'Gene', (105, 110))	('colorectal cancer', 'Disease', (49, 66))	('disease-free interval', 'CPA', (124, 145))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('ACSL5', 'Gene', '51703', (105, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('ACSL5', 'Gene', (24, 29))
575448	27171439	The schizophrenia is correlated with the single nucleotide polymorphism of ACSL6.	('schizophrenia', 'Phenotype', 'HP:0100753', (4, 17))	('single nucleotide polymorphism', 'Var', (41, 71))	('ACSL6', 'Gene', '23305', (75, 80))	('schizophrenia', 'Disease', 'MESH:D012559', (4, 17))	('schizophrenia', 'Disease', (4, 17))	('correlated', 'Reg', (21, 31))	('ACSL6', 'Gene', (75, 80))
575466	27171439	The alteration of PTEN and activation of PI3K pathway contribute to cell proliferation and metastasis in ovarian and breast cancer.	('PTEN', 'Gene', (18, 22))	('metastasis in ovarian and breast cancer', 'Disease', 'MESH:D009362', (91, 130))	('PTEN', 'Gene', '5728', (18, 22))	('contribute', 'Reg', (54, 64))	('cell proliferation', 'CPA', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('alteration', 'Var', (4, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('PI3K pathway', 'Pathway', (41, 53))
575478	27171439	Our data indicated that ACSL1 shRNA decreased cell growth and migration in HCT116, but increased cell growth and migration in A549 cells.	('A549', 'CellLine', 'CVCL:0023', (126, 130))	('increased', 'PosReg', (87, 96))	('HCT116', 'CellLine', 'CVCL:0291', (75, 81))	('cell growth', 'CPA', (97, 108))	('cell growth', 'CPA', (46, 57))	('ACSL1', 'Var', (24, 29))	('decreased', 'NegReg', (36, 45))
575498	26945412	After adjusting for esophagitis, esophagus stricture, esophageal reflux, and primary sites, the PEG cohort had a higher adjusted hazard ratio (2.31, 95% confidence interval [CI] = 1.09-4.09) of developing esophageal cancer than the controls.	('esophagitis', 'Phenotype', 'HP:0100633', (20, 31))	('esophagitis', 'Disease', (20, 31))	('PEG', 'Var', (96, 99))	('esophageal cancer', 'Disease', (205, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('esophagitis', 'Disease', 'MESH:D004941', (20, 31))	('PEG', 'Chemical', '-', (96, 99))	('esophagus stricture', 'Phenotype', 'HP:0002043', (33, 52))	('esophageal reflux', 'Disease', (54, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (205, 222))	('esophageal reflux', 'Phenotype', 'HP:0002020', (54, 71))	('esophageal reflux', 'Disease', 'MESH:D005764', (54, 71))
575516	26945412	This study excluded patients with any other cancer (ICD-9-CM150-159,162-239) before the index date and patients aged <20 years.	('ICD-9-CM150-159,162-239', 'Var', (52, 75))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('patients', 'Species', '9606', (20, 28))	('patients', 'Species', '9606', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
575529	26945412	The primary tumor sites of the head and neck included the lips (ICD-9-CM 140), oral cavity (ICD-9-CM 141, 143-145), major salivary glands (ICD-9-CM 142), oropharynx (ICD-9-CM 146), nasopharynx (ICD-9-CM 147), hypopharynx (ICD-9-CM 148), nasal cavity and sinuses (ICD-9-CM 160), larynx (ICD-9-CM 161), and others (ICD-9-CM 149).	('nasopharynx', 'Disease', (181, 192))	('ICD-9-CM', 'Var', (194, 202))	('larynx', 'Disease', (278, 284))	('ICD-9-CM', 'Var', (139, 147))	('hypopharynx', 'Disease', (209, 220))	('ICD-9-CM', 'Var', (92, 100))	('nasal cavity', 'Disease', (237, 249))	('ICD-9-CM 160', 'Var', (263, 275))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor sites of the head and neck', 'Phenotype', 'HP:0012288', (12, 44))	('ICD-9-CM 148', 'Var', (222, 234))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('ICD-9-CM 161', 'Var', (286, 298))
575539	26945412	After adjusting for the possible confounding factors, the incidence of esophageal cancer in the PEG cohort was nearly 2.31-fold higher than that in the control cohort (HR = 2.31, 95% CI = 1.09-4.09).	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PEG', 'Var', (96, 99))	('PEG', 'Chemical', '-', (96, 99))	('esophageal cancer', 'Disease', (71, 88))	('higher', 'PosReg', (128, 134))
575541	26945412	In the study population without any comorbidity, the PEG cohort still had a 2.13-fold higher risk of developing esophageal cancer than the control cohort (adjusted HR = 2.13, 95% CI = 0.86-4.12).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PEG', 'Var', (53, 56))	('PEG', 'Chemical', '-', (53, 56))	('esophageal cancer', 'Disease', (112, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
575542	26945412	Patients with esophagitis, stricture and stenosis of the esophagus, and esophageal reflux showed higher risks of developing esophageal cancer, with adjusted HRs of 1.98 (95% CI = 1.09-2.88), 3.49 (95% CI = 1.12-4.01), and 5.67 (95% CI = 2.01-8.76), respectively.	('esophageal cancer', 'Disease', (124, 141))	('stricture', 'Var', (27, 36))	('stricture and stenosis of the esophagus', 'Phenotype', 'HP:0002043', (27, 66))	('esophagitis', 'Disease', (14, 25))	('esophagitis', 'Phenotype', 'HP:0100633', (14, 25))	('esophagitis', 'Disease', 'MESH:D004941', (14, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('stenosis of the esophagus', 'Phenotype', 'HP:0010450', (41, 66))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('esophageal reflux', 'Phenotype', 'HP:0002020', (72, 89))	('esophageal reflux', 'Disease', (72, 89))	('Patients', 'Species', '9606', (0, 8))	('esophageal reflux', 'Disease', 'MESH:D005764', (72, 89))	('stenosis', 'Var', (41, 49))
575544	26945412	Lastly, we also used sensitivity analyses to assess the associations between PEG insertion and the risk of developing esophageal cancer according to different follow-up durations (Table 3).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('PEG', 'Chemical', '-', (77, 80))	('associations', 'Interaction', (56, 68))	('PEG insertion', 'Var', (77, 90))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))
575546	26945412	Especially, patients treated with PEG had a significantly greater incidence of developing esophageal cancer when the follow-up period was longer than 3 years; the adjusted HRs were 2.44 (95% CI = 1.00-4.86) for follow-up periods of 2 to 3 years and 5.24 (95% CI = 2.06-8.15) for follow-up periods of >3 years.	('patients', 'Species', '9606', (12, 20))	('PEG', 'Var', (34, 37))	('PEG', 'Chemical', '-', (34, 37))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))
575564	26945412	Our results showed that hypopharyngeal, oropharyngeal, and laryngeal cancer patients treated with PEG had a higher incidence of subsequent esophageal cancer compared with in the control cohort (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('PEG', 'Var', (98, 101))	('patients', 'Species', '9606', (76, 84))	('hypopharyngeal', 'Disease', 'MESH:D007012', (24, 38))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (59, 75))	('PEG', 'Chemical', '-', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', (139, 156))	('laryngeal cancer', 'Disease', 'MESH:D007822', (59, 75))	('laryngeal cancer', 'Disease', (59, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (139, 156))	('hypopharyngeal', 'Disease', (24, 38))
575588	26079040	Gastric intrinsic factor which is necessary for vitamin B12 absorption, is produced in parietal cells and over many years their destruction typically leads to vitamin B12 deficiency.	('leads to', 'Reg', (150, 158))	('B12 deficiency', 'Disease', 'MESH:D014806', (167, 181))	('Gastric intrinsic factor', 'Phenotype', 'HP:0005219', (0, 24))	('B12 deficiency', 'Disease', (167, 181))	('B12', 'Gene', (167, 170))	('vitamin B12 deficiency', 'Phenotype', 'HP:0100502', (159, 181))	('B12', 'Gene', '4709', (167, 170))	('B12', 'Gene', '4709', (56, 59))	('destruction', 'Var', (128, 139))	('Gastric intrinsic factor', 'Gene', (0, 24))	('B12', 'Gene', (56, 59))	('Gastric intrinsic factor', 'Gene', '2694', (0, 24))
575591	26079040	Such an association is plausible, as a less acidic stomach (hypochlorhydria) as well as chronic inflammation are among the mechanisms by which H.pylori is thought to cause gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (172, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('hypochlorhydria', 'Disease', 'MESH:D000126', (60, 75))	('H.pylori', 'Var', (143, 151))	('H.pylori', 'Species', '210', (143, 151))	('gastric cancer', 'Disease', (172, 186))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('cause', 'Reg', (166, 171))	('gastric cancer', 'Disease', 'MESH:D013274', (172, 186))	('hypochlorhydria', 'Disease', (60, 75))	('inflammation', 'Disease', (96, 108))
575673	26079040	Our prevalence estimate (1.5% of controls) is lower than other population based estimates such as the National Health and Nutrition Examination Survey (NHANES; 4.1% of adults 67 years and over) and the Framingham study (5.3% of adults 67 years and older), which might be explained by their use of a biochemical definition (serologic vitamin B12 deficiency (<= 200pg/mL) that would include patients with vitamin B12 deficiency due to other causes.	('<= 200pg/mL', 'Var', (357, 368))	('B12 deficiency', 'Disease', 'MESH:D014806', (411, 425))	('B12 deficiency', 'Disease', (411, 425))	('vitamin B12 deficiency', 'Phenotype', 'HP:0100502', (403, 425))	('B12 deficiency', 'Disease', 'MESH:D014806', (341, 355))	('lower', 'NegReg', (46, 51))	('patients', 'Species', '9606', (389, 397))	('B12 deficiency', 'Disease', (341, 355))	('vitamin B12 deficiency', 'Phenotype', 'HP:0100502', (333, 355))
575748	21950831	In the majority of studies, chemical carcinogens have been used to induce esophageal cancer in surgically manipulated animals models, most notably 2,6-dimethylnitrosamine and methyl-n-amylnitrosamine.	('methyl-n-amylnitrosamine', 'Chemical', 'MESH:C025033', (175, 199))	('methyl-n-amylnitrosamine', 'Var', (175, 199))	('esophageal cancer', 'Disease', (74, 91))	('induce', 'Reg', (67, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('2,6-dimethylnitrosamine', 'Chemical', '-', (147, 170))
575749	21950831	In studies using the nitrosamine carcinogens, EAC comprised half of the tumors in rats with DER, while only ESCC was induced in those with GER.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('rats', 'Species', '10116', (82, 86))	('nitrosamine', 'Chemical', 'MESH:D009602', (21, 32))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('DER', 'Var', (92, 95))	('EAC', 'Phenotype', 'HP:0011459', (46, 49))
575764	21950831	It has also been reported that duodenal contents reflux has great potential for malignant initiation, and refluxed duodenal contents cause gastric and esophageal carcinoma in rats without exposure to carcinogens.	('esophageal carcinoma', 'Disease', (151, 171))	('rats', 'Species', '10116', (175, 179))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (151, 171))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (151, 171))	('malignant initiation', 'CPA', (80, 100))	('refluxed', 'Var', (106, 114))	('duodenal contents reflux', 'MPA', (31, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('cause', 'Reg', (133, 138))
575782	21950831	Recently, we modified a previously reported animal model and introduced ligation through a serosal suture at the esophago-jejunal junction to increase the animals' survival rate and reduce the volume of reflux.	('ligation', 'Var', (72, 80))	('increase', 'PosReg', (142, 150))	('rat', 'Species', '10116', (173, 176))	('survival rate', 'CPA', (164, 177))	('volume of reflux', 'MPA', (193, 209))	('jejunal junction', 'Phenotype', 'HP:0004786', (122, 138))	('reduce', 'NegReg', (182, 188))	('esophago-jejunal junction', 'Phenotype', 'HP:0100628', (113, 138))
575784	21950831	Our hypothesis is as follows: high animal fat dietary intake causes severe obesity, resulting in the development of increased abdominal pressure and increased refluxate, particularly of the duodenal contents.	('high animal', 'Var', (30, 41))	('obesity', 'Disease', (75, 82))	('increased', 'PosReg', (149, 158))	('men', 'Species', '9606', (108, 111))	('obesity', 'Phenotype', 'HP:0001513', (75, 82))	('increased', 'PosReg', (116, 125))	('abdominal pressure', 'MPA', (126, 144))	('refluxate', 'MPA', (159, 168))	('obesity', 'Disease', 'MESH:D009765', (75, 82))
575788	21950831	At 30 weeks after surgery, the rats with duodenal contents reflux in the high-fat group showed a significantly higher incidence of BE and Barrett's dysplasia than those in the soybean oil group.	('BE', 'Phenotype', 'HP:0100580', (131, 133))	('soybean', 'Species', '3847', (176, 183))	('oil', 'Chemical', 'MESH:D009821', (184, 187))	('duodenal contents reflux', 'MPA', (41, 65))	("Barrett's dysplasia", 'Disease', (138, 157))	('high-fat', 'Var', (73, 81))	("Barrett's dysplasia", 'Disease', 'MESH:D001471', (138, 157))	('rats', 'Species', '10116', (31, 35))	('higher', 'PosReg', (111, 117))
575814	21950831	Urinary concentration of N-nitrosothioproline in the thioproline-treated group was much higher than in the control group; but in another experiment, nitrate concentration was not different between the two groups.	('higher', 'PosReg', (88, 94))	('Urinary concentration', 'MPA', (0, 21))	('rat', 'Species', '10116', (15, 18))	('rat', 'Species', '10116', (152, 155))	('thioproline', 'Chemical', 'MESH:C003438', (34, 45))	('N-nitrosothioproline', 'Chemical', 'MESH:C039001', (25, 45))	('thioproline-treated', 'Var', (53, 72))	('nitrate', 'Chemical', 'MESH:D009566', (149, 156))	('rat', 'Species', '10116', (164, 167))	('thioproline', 'Chemical', 'MESH:C003438', (53, 64))	('men', 'Species', '9606', (143, 146))
575819	21950831	Incidences of BE and EAC in the CXB group were 12% and 0%, respectively, while they were 89% and 47% in the control group (Table 3).	('BE', 'Phenotype', 'HP:0100580', (14, 16))	('EAC', 'Phenotype', 'HP:0011459', (21, 24))	('CXB', 'Var', (32, 35))	('CXB', 'Chemical', '-', (32, 35))	('EAC', 'Disease', (21, 24))
575827	21950831	Incidences of BE and EAC in the UDCA group were 20% and 10%, respectively, while they were 60% and 60% in the control group.	('BE', 'Phenotype', 'HP:0100580', (14, 16))	('EAC', 'Phenotype', 'HP:0011459', (21, 24))	('UDCA', 'Var', (32, 36))	('EAC', 'Disease', (21, 24))	('DCA', 'Chemical', 'MESH:D003840', (33, 36))
575830	21950831	Deoxycholic acid (DCA) and chenodeoxycholic (CDCA) acid strongly induce COX-2 through several pathways, such as NF-kappaB and AP-1 pathway; UDCA stimulates these pathways less and reduces the volume of DCA and CDCA by changing bile acid proportion.	('Deoxycholic acid', 'Chemical', 'MESH:D003840', (0, 16))	('bile acid', 'Chemical', 'MESH:D001647', (227, 236))	('COX-2', 'Gene', (72, 77))	('DCA', 'Chemical', 'MESH:D003840', (202, 205))	('CDCA', 'Chemical', 'MESH:D002635', (45, 49))	('volume', 'MPA', (192, 198))	('stimulates', 'PosReg', (145, 155))	('UDCA', 'Var', (140, 144))	('CDCA', 'Chemical', 'MESH:D002635', (210, 214))	('DCA', 'Chemical', 'MESH:D003840', (18, 21))	('induce', 'PosReg', (65, 71))	('AP-1 pathway', 'Pathway', (126, 138))	('COX-2', 'Gene', '29527', (72, 77))	('DCA', 'Chemical', 'MESH:D003840', (141, 144))	('DCA', 'Chemical', 'MESH:D003840', (46, 49))	('NF-kappaB', 'Pathway', (112, 121))	('reduces', 'NegReg', (180, 187))	('DCA', 'Chemical', 'MESH:D003840', (211, 214))	('chenodeoxycholic', 'Chemical', '-', (27, 43))
575871	23671646	Combined misexpression of MTA3, Snail and E-cadherin had stronger correlation with malignant properties.	('Snail', 'Gene', '6615', (32, 37))	('misexpression', 'Var', (9, 22))	('MTA3', 'Protein', (26, 30))	('E-cadherin', 'Gene', (42, 52))	('E-cadherin', 'Gene', '999', (42, 52))	('malignant properties', 'CPA', (83, 103))	('Snail', 'Gene', (32, 37))
575885	23671646	Disregulation of MTA3 has been correlated with poor differentiation in endometrial cancer and poor prognosis in uterine carcinoma  .	('carcinoma', 'Disease', (120, 129))	('Disregulation', 'Var', (0, 13))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('endometrial cancer', 'Disease', (71, 89))	('MTA3', 'Protein', (17, 21))	('carcinoma', 'Disease', 'MESH:D002277', (120, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('endometrial cancer', 'Disease', 'MESH:D016889', (71, 89))	('endometrial cancer', 'Phenotype', 'HP:0012114', (71, 89))
575915	23671646	Accordingly, these results consistently indicate that MTA3 is downregulated in tumorous tissues, and underexpression of MTA3 is related with stronger metastasis tendency in tumor cells, supporting the hypothesis that MTA3 may act as a tumor suppressor and metastasis inhibitor in GEJ adenocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('MTA3', 'Gene', (54, 58))	('GEJ adenocarcinoma', 'Disease', 'MESH:D000230', (280, 298))	('underexpression', 'Var', (101, 116))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('GEJ adenocarcinoma', 'Disease', (280, 298))	('tumorous', 'Disease', 'MESH:D009369', (79, 87))	('tumor', 'Disease', (79, 84))	('downregulated', 'NegReg', (62, 75))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('stronger', 'PosReg', (141, 149))	('tumorous', 'Disease', (79, 87))	('metastasis tendency', 'CPA', (150, 169))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (235, 240))	('MTA3', 'Gene', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
575929	23671646	In summary, our results demonstrate that misexpression of MTA3-pathway components is closely associated with parameters involving invasion/metastasis, and tumor advancement.	('tumor advancement', 'Disease', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('associated', 'Reg', (93, 103))	('MTA3-pathway', 'Pathway', (58, 70))	('invasion/metastasis', 'CPA', (130, 149))	('misexpression', 'Var', (41, 54))	('tumor advancement', 'Disease', 'MESH:D020178', (155, 172))
575930	23671646	Thus, these data provide favorable evidence that the altered MTA3 pathway contributes to the EMT and tumor metastasis, and thereby the tumorigenic process of GEJ adenocarcinoma.	('contributes', 'Reg', (74, 85))	('GEJ adenocarcinoma', 'Disease', (158, 176))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('altered', 'Var', (53, 60))	('MTA3 pathway', 'Pathway', (61, 73))	('tumor metastasis', 'Disease', 'MESH:D009362', (101, 117))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor metastasis', 'Disease', (101, 117))	('GEJ adenocarcinoma', 'Disease', 'MESH:D000230', (158, 176))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
575932	23671646	The OS rate of patients with tumors that expressed MTA3 was significantly higher than that of patients with tumors that did not express MTA3 (P<0.001; Figure 3A).	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (94, 102))	('higher', 'PosReg', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('OS rate', 'MPA', (4, 11))	('MTA3', 'Var', (51, 55))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumors', 'Disease', (29, 35))
575958	23671646	The results of the present study suggest that the MTA3 inhibition of Snail and the subsequent regulation of E-cadherin expression also occur in hormone-independent cancers.	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('MTA3', 'Var', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('regulation', 'MPA', (94, 104))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('Snail', 'Gene', '6615', (69, 74))	('cancers', 'Disease', (164, 171))	('Snail', 'Gene', (69, 74))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('inhibition', 'NegReg', (55, 65))
575968	31684858	We found that copy number alterations underpinning transcriptional dysregulation of JAK-STAT pathway genes differ within and between cancer types.	('cancer type', 'Disease', (133, 144))	('JAK-STAT pathway genes', 'Gene', (84, 106))	('cancer type', 'Disease', 'MESH:D009369', (133, 144))	('copy number', 'Var', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
575970	31684858	High JAK-STAT scores were associated with increased mortality rates in brain and renal cancers, but not in lung and endometrial cancers where hyperactive JAK-STAT signaling is a positive prognostic factor.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('renal cancer', 'Phenotype', 'HP:0009726', (81, 93))	('lung and endometrial cancers', 'Disease', 'MESH:D016889', (107, 135))	('High', 'Var', (0, 4))	('brain', 'Disease', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('renal cancers', 'Disease', 'MESH:D007680', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('JAK-STAT', 'Gene', (5, 13))	('renal cancers', 'Disease', (81, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))
575971	31684858	Patients with aberrant JAK-STAT signaling demonstrated pan-cancer molecular features associated with misexpression of genes in other oncogenic pathways (Wnt, MAPK, TGF-beta, PPAR and VEGF).	('VEGF', 'Gene', (183, 187))	('PPAR', 'Gene', (174, 178))	('TGF-beta', 'Gene', '7040', (164, 172))	('TGF-beta', 'Gene', (164, 172))	('MAPK', 'Gene', (158, 162))	('misexpression', 'Var', (101, 114))	('VEGF', 'Gene', '7422', (183, 187))	('PPAR', 'Gene', '5465', (174, 178))	('aberrant', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
575974	31684858	Providing a pan-cancer perspective of clinically-relevant JAK-STAT alterations, this study could serve as a framework for future research investigating anti-tumor immunity using combination therapy involving JAK-STAT and immune checkpoint inhibitors.	('tumor', 'Disease', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('alterations', 'Var', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
576002	31684858	Lung squamous cell carcinoma (LUSC) and papillary renal cell carcinoma (KIRP) had the highest and lowest fraction of samples with deleted JAK-STAT pathway genes respectively (Additional file 2).	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (40, 70))	('JAK-STAT pathway', 'Pathway', (138, 154))	('papillary renal cell carcinoma', 'Disease', (40, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (50, 70))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('squamous cell carcinoma', 'Disease', (5, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))	('deleted', 'Var', (130, 137))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (40, 70))
576005	31684858	We identified 71 and 49 genes that were recurrently deleted and amplified respectively in at least 20% of samples within each cancer type and at least 7 cancer types (Additional file 2).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer type', 'Disease', (126, 137))	('deleted', 'Var', (52, 59))	('cancer type', 'Disease', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer type', 'Disease', 'MESH:D009369', (126, 137))	('cancer type', 'Disease', 'MESH:D009369', (153, 164))
576006	31684858	Esophageal carcinoma (ESCA) had 70 genes that were recurrently deleted while only four recurrently deleted genes were found in papillary renal cell carcinoma (KIRP).	('Esophageal carcinoma', 'Disease', (0, 20))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (127, 157))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (0, 20))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (127, 157))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (0, 20))	('papillary renal cell carcinoma', 'Disease', (127, 157))	('deleted', 'Var', (63, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
576022	31684858	Kaplan-Meier analyses and log-rank tests revealed that patients with high scores (4th quartile) had higher death risks in glioma (P < 0.0001), pan-kidney (consisting of chromophobe renal cell, clear cell renal cell and papillary renal cell cancers; P < 0.0001) and clear cell renal cell (P < 0.0001) cohorts (Fig.	('papillary renal cell cancers', 'Disease', (219, 247))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('pan-kidney', 'Disease', (143, 153))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('glioma', 'Disease', (122, 128))	('chromophobe renal cell', 'Disease', 'MESH:D002292', (169, 191))	('clear cell renal cell', 'Disease', (265, 286))	('high scores', 'Var', (69, 80))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('patients', 'Species', '9606', (55, 63))	('chromophobe renal cell', 'Disease', (169, 191))	('renal cell cancer', 'Phenotype', 'HP:0005584', (229, 246))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('papillary renal cell cancers', 'Disease', 'MESH:D002292', (219, 247))
576023	31684858	In contrast, high expression of signature genes was linked to improved survival rates in lung (P = 0.025) and endometrial (P = 0.032) cancers (Fig.	('endometrial', 'Disease', (110, 121))	('lung', 'Disease', (89, 93))	('survival', 'CPA', (71, 79))	('improved', 'PosReg', (62, 70))	('high', 'Var', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
576027	31684858	Lastly, multidimensional scaling analyses of signature genes in the five cohorts revealed significant differences between tumor and non-tumor samples, implying that dysregulated JAK-STAT signaling may serve as a diagnostic marker for early detection in pre-cancerous lesions (Fig.	('dysregulated', 'Var', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancerous lesions', 'Disease', (257, 274))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('non-tumor', 'Disease', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('non-tumor', 'Disease', 'MESH:C580335', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', (122, 127))	('cancerous lesions', 'Disease', 'MESH:D009369', (257, 274))
576030	31684858	High JAK-STAT scores were associated with decreased survival rates in glioma patients.	('survival rates', 'CPA', (52, 66))	('glioma', 'Disease', (70, 76))	('decreased', 'NegReg', (42, 51))	('High', 'Var', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('patients', 'Species', '9606', (77, 85))
576035	31684858	3), we reasoned that patients from diverse cancer types might harbor similar transcriptional defects caused by aberrant activation of JAK-STAT.	('cancer type', 'Disease', (43, 54))	('JAK-STAT', 'Gene', (134, 142))	('cancer type', 'Disease', 'MESH:D009369', (43, 54))	('activation', 'PosReg', (120, 130))	('patients', 'Species', '9606', (21, 29))	('aberrant', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
576043	31684858	For instance, except for THBS1 and THBS2, a vast majority of TGF-beta DEGs exhibited somatic gains (Fig.	('DEGs', 'Var', (70, 74))	('DEGs', 'Chemical', 'MESH:C062694', (70, 74))	('THBS1', 'Gene', (25, 30))	('somatic gains', 'CPA', (85, 98))	('THBS2', 'Gene', (35, 40))	('TGF-beta', 'Gene', '7040', (61, 69))	('THBS1', 'Gene', '7057', (25, 30))	('TGF-beta', 'Gene', (61, 69))	('THBS2', 'Gene', '7058', (35, 40))
576047	31684858	IRF8 was among one of the most enriched TFs implicated in the regulation of transcriptional outputs of patients with dysregulated JAK-STAT signaling (Fig.	('patients', 'Species', '9606', (103, 111))	('JAK-STAT signaling', 'MPA', (130, 148))	('IRF8', 'Gene', (0, 4))	('dysregulated', 'Var', (117, 129))
576050	31684858	To evaluate the combined relationship between JAK-STAT signaling and IRF8 expression, patients were categorized into four groups based on median IRF8 and JAK-STAT scores: 1) high-high, 2) low-low, 3) high IRF8 and low 28-gene score and 4) low IRF8 and high 28-gene score.	('low', 'NegReg', (239, 242))	('low', 'NegReg', (214, 217))	('low-low', 'Var', (188, 195))	('28-gene score', 'MPA', (218, 231))	('high', 'Var', (200, 204))	('patients', 'Species', '9606', (86, 94))
576053	31684858	Our results support a model in which IRF8 influences the behavior of tumors with aberrant JAK-STAT signaling.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('aberrant', 'Var', (81, 89))	('influences', 'Reg', (42, 52))	('behavior', 'CPA', (57, 65))	('IRF8', 'Gene', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('JAK-STAT signaling', 'MPA', (90, 108))
576059	31684858	Tumor-promoting and tumor-suppressing roles of JAK-STAT signaling is very much cell type-dependent (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('JAK-STAT', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Tumor-promoting', 'CPA', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
576063	31684858	In contrast, phosphorylated STAT5 promotes cellular differentiation and inhibits invasive properties in breast cancer cells (Sultan et al.,; Sultan et al.,).	('invasive properties', 'CPA', (81, 100))	('STAT5', 'Gene', (28, 33))	('promotes', 'PosReg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('phosphorylated', 'Var', (13, 27))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('inhibits', 'NegReg', (72, 80))	('breast cancer', 'Disease', (104, 117))	('STAT5', 'Gene', '6776', (28, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cellular differentiation', 'CPA', (43, 67))
576065	31684858	Similarly, in rectal cancers, patients with tumors positive for phosphorylated STAT3 had improved survival outcomes (Monnien et al.,).	('improved', 'PosReg', (89, 97))	('rectal cancers', 'Disease', (14, 28))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('phosphorylated', 'Var', (64, 78))	('survival outcomes', 'CPA', (98, 115))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('patients', 'Species', '9606', (30, 38))	('STAT3', 'Gene', '6774', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('rectal cancers', 'Disease', 'MESH:D012004', (14, 28))	('STAT3', 'Gene', (79, 84))
576066	31684858	In contrast, high levels of phosphorylated STAT3 is associated with reduced survival rates in glioblastoma (Birner et al.,) and renal cancer (Horiguchi et al.,), which independently corroborates our findings on the tumor-promoting effects of JAK-STAT signaling in these cancer types (Figs.	('phosphorylated', 'Var', (28, 42))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('glioblastoma', 'Disease', (94, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer type', 'Disease', (270, 281))	('high levels', 'Var', (13, 24))	('survival rates', 'CPA', (76, 90))	('cancer type', 'Disease', 'MESH:D009369', (270, 281))	('renal cancer', 'Disease', (128, 140))	('renal cancer', 'Phenotype', 'HP:0009726', (128, 140))	('STAT3', 'Gene', (43, 48))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('STAT3', 'Gene', '6774', (43, 48))	('reduced', 'NegReg', (68, 75))	('renal cancer', 'Disease', 'MESH:D007680', (128, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))
576071	31684858	Patients with aberrant JAK-STAT signaling exhibited interactions with other major oncogenic pathways, including MAPK, Wnt, TGF-beta, PPAR and VEGF (Fig.	('VEGF', 'Gene', (142, 146))	('JAK-STAT', 'Var', (23, 31))	('PPAR', 'Gene', '5465', (133, 137))	('MAPK', 'Disease', (112, 116))	('PPAR', 'Gene', (133, 137))	('interactions', 'Interaction', (52, 64))	('oncogenic pathways', 'Pathway', (82, 100))	('VEGF', 'Gene', '7422', (142, 146))	('TGF-beta', 'Gene', '7040', (123, 131))	('Patients', 'Species', '9606', (0, 8))	('aberrant JAK-STAT', 'Var', (14, 31))	('TGF-beta', 'Gene', (123, 131))
576072	31684858	We demonstrated that hyperactivation of JAK-STAT signaling promotes the loss of anti-tumor immunity in glioma and renal cancer patients (Fig.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', (85, 90))	('loss', 'NegReg', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('renal cancer', 'Disease', (114, 126))	('JAK-STAT signaling', 'MPA', (40, 58))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('renal cancer', 'Phenotype', 'HP:0009726', (114, 126))	('patients', 'Species', '9606', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('renal cancer', 'Disease', 'MESH:D007680', (114, 126))	('hyperactivation', 'Var', (21, 36))	('glioma', 'Disease', (103, 109))
576074	31684858	Furthermore, hyperactivation of STAT3 is linked to abnormal differentiation of dendritic cells in colon cancer cells (Nefedova et al.,).	('linked', 'Reg', (41, 47))	('STAT3', 'Gene', '6774', (32, 37))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('STAT3', 'Gene', (32, 37))	('hyperactivation', 'Var', (13, 28))	('colon cancer', 'Disease', (98, 110))
576079	31684858	Promoter hypermethylation and gene silencing of IRF8 abrogates cellular response to interferon stimulation and overexpression of IRF8 in nasopharyngeal, esophageal and colon cancer cell lines could inhibit clonogenicity (Lee et al.,).	('colon cancer', 'Disease', (168, 180))	('gene silencing', 'Var', (30, 44))	('IRF8', 'Gene', (129, 133))	('inhibit', 'NegReg', (198, 205))	('clonogenicity', 'CPA', (206, 219))	('abrogates', 'NegReg', (53, 62))	('colon cancer', 'Phenotype', 'HP:0003003', (168, 180))	('colon cancer', 'Disease', 'MESH:D015179', (168, 180))	('cellular response to interferon stimulation', 'MPA', (63, 106))	('overexpression', 'PosReg', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('IRF8', 'Gene', (48, 52))	('Promoter hypermethylation', 'Var', (0, 25))
576082	31684858	Importantly, loss of IRF8 may further suppress tumor immunity in patients with hyperactive JAK-STAT signaling.	('tumor', 'Disease', (47, 52))	('JAK-STAT signaling', 'MPA', (91, 109))	('hyperactive', 'PosReg', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('patients', 'Species', '9606', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('IRF8', 'Gene', (21, 25))	('loss', 'Var', (13, 17))	('suppress', 'NegReg', (38, 46))
576095	31490264	Meanwhile, six miRNAs (including miR-200b-3p, miR-31-5p, miR-15b-5p, miR-141-3p, miR-135b-5p, and miR-195-5p) were correlated with overall survival of ESCC patients (log-rank, P < 0.05).	('patients', 'Species', '9606', (156, 164))	('ESCC', 'Disease', 'MESH:C562729', (151, 155))	('miR-195', 'Gene', '406971', (98, 105))	('miR-15b', 'Gene', '406949', (57, 64))	('miR-135b-5p', 'Var', (81, 92))	('miR-141-3p', 'Var', (69, 79))	('correlated', 'Reg', (115, 125))	('miR-31', 'Gene', '407035', (46, 52))	('overall survival', 'CPA', (131, 147))	('ESCC', 'Disease', (151, 155))	('miR-15b', 'Gene', (57, 64))	('miR-31', 'Gene', (46, 52))	('miR-200b-3p', 'Var', (33, 44))	('miR-195', 'Gene', (98, 105))
576096	31490264	MiR-135b-5p, miR-15b-5p, and miR-195-5p were selected for verification of the expression levels in 51 ESCC patients' tissue samples by using qRT-PCR.	('ESCC', 'Disease', (102, 106))	('miR-15b', 'Gene', '406949', (13, 20))	('MiR-135b-5p', 'Var', (0, 11))	('miR-15b', 'Gene', (13, 20))	('miR-195', 'Gene', (29, 36))	('miR-195', 'Gene', '406971', (29, 36))	('patients', 'Species', '9606', (107, 115))	('ESCC', 'Disease', 'MESH:C562729', (102, 106))
576097	31490264	The results also suggested that miR-135b-5p, miR-15b-5p, and miR-195-5p were significantly correlated with tumor differentiation degrees (P < 0.05), miR-195-5p was significantly correlated with tumor TNM stage (P < 0.05), and miR-135b-5p was significantly correlated with lymph-node metastasis (P < 0.05).	('tumor', 'Disease', (107, 112))	('correlated', 'Reg', (91, 101))	('miR-15b', 'Gene', '406949', (45, 52))	('tumor', 'Disease', (194, 199))	('correlated', 'Reg', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('miR-195', 'Gene', (61, 68))	('miR-15b', 'Gene', (45, 52))	('miR-135b-5p', 'Var', (32, 43))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('correlated', 'Reg', (256, 266))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('miR-195', 'Gene', '406971', (149, 156))	('TNM', 'Gene', '10178', (200, 203))	('TNM', 'Gene', (200, 203))	('lymph-node metastasis', 'CPA', (272, 293))	('miR-195', 'Gene', (149, 156))	('miR-135b-5p', 'Var', (226, 237))	('miR-195', 'Gene', '406971', (61, 68))
576098	31490264	MiR-135b-5p, miR-15b-5p, and miR-195-5p expression levels, ESCC patient clinical features association analysis results and the aforementioned TCGA bioinformatics analyses were similar.	('ESCC', 'Disease', 'MESH:C562729', (59, 63))	('patient', 'Species', '9606', (64, 71))	('miR-15b', 'Gene', '406949', (13, 20))	('MiR-135b-5p', 'Var', (0, 11))	('ESCC', 'Disease', (59, 63))	('miR-15b', 'Gene', (13, 20))	('miR-195', 'Gene', (29, 36))	('miR-195', 'Gene', '406971', (29, 36))
576112	31490264	Further evidence suggested that aberrantly expressed miRNAs in ESCC tissues have a clinical influence on disease diagnosis and prognosis.	('influence', 'Reg', (92, 101))	('aberrantly expressed', 'Var', (32, 52))	('ESCC', 'Disease', 'MESH:C562729', (63, 67))	('ESCC', 'Disease', (63, 67))	('miRNAs', 'Protein', (53, 59))
576148	31490264	In addition, pathway analysis was performed for all 72 mRNAs, and the results suggested that the enriched pathways targeted by upregulated mRNAs transcripts were 'microRNAs in cancer, human T-cell leukaemia virus type I (HTLV-I) infection, cell cycle and hepatitis B.'	('hepatitis', 'Phenotype', 'HP:0012115', (255, 264))	('upregulated', 'PosReg', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('T-cell leukaemia virus type I (HTLV-I) infection', 'Disease', 'MESH:D015459', (190, 238))	('mRNAs', 'Var', (139, 144))	('hepatitis B', 'Disease', 'MESH:D006509', (255, 266))	('hepatitis B', 'Disease', (255, 266))	('human', 'Species', '9606', (184, 189))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
576152	31490264	We showed that miR-32-5p, miR-330-5p, miR-135b-5p, miR-195-5p, and miR-145-5p were associated with ESCC patients' tumor grade, miR-16-5p, miR-32-5p, miR-93-5p, miR-185-5p, miR-15b-5p, miR-135b-5p, miR133a-3p, miR-28-5p, and miR-195-5p were associated with TNM stages, and miR-32-5p, miR-93-5p, miR-15b-5p, miR-135b-5p, miR-330-5p, miR-106b-5p, miR-182-5p, miR-20b-5p, miR-141-3p, miR-28-5p, miR-195-5p, and miR-320a were associated with lymphatic metastasis.	('miR-141-3p', 'Var', (368, 378))	('miR-15b', 'Gene', '406949', (172, 179))	('miR-195', 'Gene', '406971', (51, 58))	('associated', 'Reg', (240, 250))	('miR-20b-5p', 'Var', (356, 366))	('miR-15b', 'Gene', (172, 179))	('associated', 'Reg', (421, 431))	('miR-135b-5p', 'Var', (184, 195))	('miR-32-5p', 'Gene', '442899', (15, 24))	('miR-32-5p', 'Gene', (138, 147))	('miR-195', 'Gene', (51, 58))	('miR-195', 'Gene', '406971', (391, 398))	('miR-195', 'Gene', '406971', (224, 231))	('miR-28', 'Gene', (209, 215))	('miR-28', 'Gene', '407020', (380, 386))	('miR-93-5p', 'Gene', (149, 158))	('lymphatic metastasis', 'CPA', (437, 457))	('miR-185-5p', 'Var', (160, 170))	('miR-182-5p', 'Gene', (344, 354))	('tumor', 'Disease', (114, 119))	('ESCC', 'Disease', (99, 103))	('miR-145', 'Gene', '406937', (67, 74))	('miR-93-5p', 'Gene', (283, 292))	('TNM', 'Gene', '10178', (256, 259))	('miR133a-3p', 'Var', (197, 207))	('miR-32-5p', 'Gene', (272, 281))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('TNM', 'Gene', (256, 259))	('miR-145', 'Gene', (67, 74))	('miR-106', 'Gene', (331, 338))	('miR-330-5p', 'Var', (319, 329))	('miR-195', 'Gene', (391, 398))	('miR-195', 'Gene', (224, 231))	('miR-320a', 'Gene', (407, 415))	('miR-32-5p', 'Gene', '442899', (138, 147))	('miR-135b-5p', 'Var', (306, 317))	('patients', 'Species', '9606', (104, 112))	('miR-15b', 'Gene', '406949', (294, 301))	('miR-28', 'Gene', (380, 386))	('miR-32-5p', 'Gene', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('miR-28', 'Gene', '407020', (209, 215))	('miR-106', 'Gene', '406899', (331, 338))	('miR-93-5p', 'Gene', '100126325', (149, 158))	('miR-15b', 'Gene', (294, 301))	('miR-182-5p', 'Gene', '100302183', (344, 354))	('associated', 'Reg', (83, 93))	('miR-93-5p', 'Gene', '100126325', (283, 292))	('miR-32-5p', 'Gene', '442899', (272, 281))	('miR-320a', 'Gene', '407037', (407, 415))	('miR-16-5p', 'Var', (127, 136))	('ESCC', 'Disease', 'MESH:C562729', (99, 103))
576156	31490264	Among these six miRNAs, there were five miRNAs (miR-200b-3p, miR-31-5p, miR-15b-5p, miR-141-3p, and miR-135b-5p) that were negatively related with ESCC patient overall survival time (P < 0.05), and miR-195-5p was positively correlated with ESCC patient overall survival time (P < 0.05) [Figure 5].	('correlated', 'Reg', (224, 234))	('miR-195', 'Gene', (198, 205))	('miR-195', 'Gene', '406971', (198, 205))	('miR-141-3p', 'Var', (84, 94))	('miR-31', 'Gene', '407035', (61, 67))	('ESCC', 'Disease', 'MESH:C562729', (240, 244))	('ESCC', 'Disease', 'MESH:C562729', (147, 151))	('related', 'Reg', (134, 141))	('miR-15b', 'Gene', '406949', (72, 79))	('ESCC', 'Disease', (147, 151))	('miR-200b-3p', 'Var', (48, 59))	('ESCC', 'Disease', (240, 244))	('miR-135b-5p', 'Var', (100, 111))	('miR-31', 'Gene', (61, 67))	('negatively', 'NegReg', (123, 133))	('patient', 'Species', '9606', (152, 159))	('patient', 'Species', '9606', (245, 252))	('miR-15b', 'Gene', (72, 79))
576157	31490264	Based on the above bioinformatics analyses, three miRNAs (miR-135b-5p, miR-15b-5p, and miR-195-5p) were randomly selected.	('miR-15b', 'Gene', (71, 78))	('miR-195', 'Gene', (87, 94))	('miR-195', 'Gene', '406971', (87, 94))	('miR-135b-5p', 'Var', (58, 69))	('miR-15b', 'Gene', '406949', (71, 78))
576159	31490264	The expression levels of miR-135b-5p and miR-15b-5p were consistently upregulated in 51 ESCC patient tumor tissue samples compared with normal esophageal epithelial tissues (P < 0.05); however, miR-195-5p expression levels were consistently downregulated (P < 0.05) [Table 2].	('expression levels', 'MPA', (4, 21))	('ESCC', 'Disease', (88, 92))	('miR-15b', 'Gene', '406949', (41, 48))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('expression levels', 'MPA', (205, 222))	('downregulated', 'NegReg', (241, 254))	('miR-135b-5p', 'Var', (25, 36))	('patient', 'Species', '9606', (93, 100))	('ESCC', 'Disease', 'MESH:C562729', (88, 92))	('upregulated', 'PosReg', (70, 81))	('miR-195', 'Gene', '406971', (194, 201))	('miR-195', 'Gene', (194, 201))	('miR-15b', 'Gene', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
576162	31490264	We found that miR-135b-5p, miR-15b-5p, and miR-195-5p expression levels were significantly related with the 51 ESCC patients tumor differentiation degrees (P < 0.05) [Table 3]; miR-195-5p was significantly related with tumor TNM stage (P < 0.05), and miR-135b-5p was significantly related with lymph-node metastasis (P < 0.05).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (219, 224))	('miR-195', 'Gene', '406971', (177, 184))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('miR-195', 'Gene', '406971', (43, 50))	('related', 'Reg', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('patients', 'Species', '9606', (116, 124))	('ESCC', 'Disease', 'MESH:C562729', (111, 115))	('miR-15b', 'Gene', '406949', (27, 34))	('miR-195', 'Gene', (177, 184))	('TNM', 'Gene', '10178', (225, 228))	('miR-15b', 'Gene', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('miR-195', 'Gene', (43, 50))	('TNM', 'Gene', (225, 228))	('related', 'Reg', (281, 288))	('miR-135b-5p', 'Var', (251, 262))	('ESCC', 'Disease', (111, 115))	('related', 'Reg', (206, 213))	('tumor', 'Disease', (125, 130))	('lymph-node metastasis', 'CPA', (294, 315))
576178	31490264	In addition, upregulated miR-20b-5p, miR-93-5p, miR-16-5p, miR-330-5p, miR-106b-5p, and miR-484 were reported in esophageal cancer and were involved in regulating the progression of this disease.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('miR-106', 'Gene', (71, 78))	('upregulated', 'PosReg', (13, 24))	('miR-484', 'Gene', (88, 95))	('miR-330-5p', 'Var', (59, 69))	('miR-106', 'Gene', '406899', (71, 78))	('miR-93-5p', 'Gene', '100126325', (37, 46))	('miR-93-5p', 'Gene', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal cancer', 'Disease', (113, 130))	('miR-484', 'Gene', '619553', (88, 95))	('miR-20b-5p', 'Var', (25, 35))	('miR-16-5p', 'Var', (48, 57))
576181	31490264	MiR-143-3p, miR-125a-5p, and miR-101-3p levels also were reported to be significantly different in esophageal cancer tissues and cell lines.	('MiR-143-3p', 'Chemical', 'MESH:C103046', (0, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MiR-143-3p', 'Var', (0, 10))	('different', 'Reg', (86, 95))	('miR-101-3p', 'MPA', (29, 39))	('miR-125a-5p', 'Var', (12, 23))	('esophageal cancer', 'Disease', (99, 116))
576185	31490264	In the miRNAs-mRNAs co-expression network, we also found some of these 28 key miRNAs were reported as potential diagnostic and prognostic biomarkers in ESCC, including miR-101-3p, miR-125a-5p, miR-16-5p, and miR-20b-5p.	('miR-101-3p', 'Var', (168, 178))	('miR-20b-5p', 'Var', (208, 218))	('miR-16-5p', 'Var', (193, 202))	('miR-125a-5p', 'Var', (180, 191))	('ESCC', 'Disease', 'MESH:C562729', (152, 156))	('ESCC', 'Disease', (152, 156))
576188	31490264	Ishibashi et al also reported that the overexpressed miR-141-3p targeted PHLPP-2 gene expression and affected the activity of the PI3K/AKT pathway in ESCC.	('PHLPP-2', 'Gene', (73, 80))	('AKT', 'Gene', '207', (135, 138))	('activity', 'MPA', (114, 122))	('miR-141-3p', 'Var', (53, 63))	('AKT', 'Gene', (135, 138))	('expression', 'MPA', (86, 96))	('ESCC', 'Disease', (150, 154))	('PHLPP-2', 'Gene', '23035', (73, 80))	('overexpressed', 'PosReg', (39, 52))	('targeted', 'Reg', (64, 72))	('affected', 'Reg', (101, 109))	('ESCC', 'Disease', 'MESH:C562729', (150, 154))
576190	31490264	To investigate the correlation between the 28 key miRNA expression levels and the 161 ESCC patients' clinical pathology features, we identified 17 miRNAs that were related with 161 ESCC patients' clinical pathology features, including miR-32-5p, miR-16-5p, miR-32-5p, and miR-183-5p.	('miR-32-5p', 'Gene', (257, 266))	('miR-32-5p', 'Gene', '442899', (235, 244))	('patients', 'Species', '9606', (91, 99))	('miR-32-5p', 'Gene', (235, 244))	('patients', 'Species', '9606', (186, 194))	('miR-183-5p', 'Var', (272, 282))	('miR-16-5p', 'Var', (246, 255))	('ESCC', 'Disease', 'MESH:C562729', (86, 90))	('related', 'Reg', (164, 171))	('ESCC', 'Disease', (181, 185))	('miR-32-5p', 'Gene', '442899', (257, 266))	('ESCC', 'Disease', (86, 90))	('ESCC', 'Disease', 'MESH:C562729', (181, 185))
576192	31490264	Among these 17 miRNAs, miR-16-5p, miR-330-5p, miR-145-5p, miR-93-5p, miR-93-5p, miR133a-3p, miR-28-5p, miR-15b-5p, miR-20b-5p, miR-141-3p, and miR-320a were previously reported to be important indicators in lymphatic metastasis, invasion, and as diagnostic biomarkers of ESCC.	('ESCC', 'Disease', 'MESH:C562729', (271, 275))	('miR-15b', 'Gene', (103, 110))	('miR-145', 'Gene', '406937', (46, 53))	('miR133a-3p', 'Var', (80, 90))	('miR-93-5p', 'Gene', '100126325', (58, 67))	('miR-93-5p', 'Gene', (69, 78))	('miR-330-5p', 'Var', (34, 44))	('miR-145', 'Gene', (46, 53))	('lymphatic metastasis', 'CPA', (207, 227))	('ESCC', 'Disease', (271, 275))	('miR-141-3p', 'Var', (127, 137))	('miR-20b-5p', 'Var', (115, 125))	('miR-28', 'Gene', '407020', (92, 98))	('miR-320a', 'Gene', (143, 151))	('miR-93-5p', 'Gene', '100126325', (69, 78))	('miR-93-5p', 'Gene', (58, 67))	('invasion', 'CPA', (229, 237))	('miR-16-5p', 'Var', (23, 32))	('miR-15b', 'Gene', '406949', (103, 110))	('miR-28', 'Gene', (92, 98))	('miR-320a', 'Gene', '407037', (143, 151))
576198	31490264	Finally, miR-135b-5p, miR-15b-5p, and miR-195-5p were selected and validated using TCGA bioinformatics analysis results from 51 newly collected ESCC patients' tissue samples.	('miR-15b', 'Gene', '406949', (22, 29))	('patients', 'Species', '9606', (149, 157))	('ESCC', 'Disease', 'MESH:C562729', (144, 148))	('miR-135b-5p', 'Var', (9, 20))	('miR-195', 'Gene', (38, 45))	('miR-195', 'Gene', '406971', (38, 45))	('miR-15b', 'Gene', (22, 29))	('ESCC', 'Disease', (144, 148))
576204	31490264	We found that miRNAs (miR-16-5p, miR-183-5p, miR-32-5p, miR-330-5p, miR-135b-5p, miR-195-5p, miR-145-5p, miR-93-5p, miR-185-5p, miR133a-3p, miR-28-5p, miR-15b-5p, miR-106b-5p, miR-182-5p, miR-20b-5p, miR-141-3p, and miR-320a) and (miR-200b-3p, miR-31-5p, miR-15b-5p, miR-141-3p, miR-135b-5p and miR-195-5p) were related with ESCC patients' clinical pathology features and patients' overall survival time, respectively.	('miR-28', 'Gene', (140, 146))	('patients', 'Species', '9606', (330, 338))	('miR-135b-5p', 'Var', (279, 290))	('miR-32-5p', 'Gene', (45, 54))	('miR-195', 'Gene', '406971', (81, 88))	('miR-145', 'Gene', '406937', (93, 100))	('miR-182-5p', 'Gene', (176, 186))	('miR-195', 'Gene', (81, 88))	('miR-93-5p', 'Gene', '100126325', (105, 114))	('miR-320a', 'Gene', (216, 224))	('miR-200b-3p', 'Var', (231, 242))	('ESCC', 'Disease', 'MESH:C562729', (325, 329))	('miR-145', 'Gene', (93, 100))	('miR-106', 'Gene', (163, 170))	('miR-195', 'Gene', '406971', (295, 302))	('related', 'Reg', (312, 319))	('miR-141-3p', 'Var', (267, 277))	('miR-28', 'Gene', '407020', (140, 146))	('miR-31', 'Gene', (244, 250))	('miR-15b', 'Gene', '406949', (255, 262))	('miR-32-5p', 'Gene', '442899', (45, 54))	('miR-15b', 'Gene', (255, 262))	('miR-320a', 'Gene', '407037', (216, 224))	('miR-195', 'Gene', (295, 302))	('miR-106', 'Gene', '406899', (163, 170))	('ESCC', 'Disease', (325, 329))	('miR-182-5p', 'Gene', '100302183', (176, 186))	('miR-15b', 'Gene', '406949', (151, 158))	('miR-15b', 'Gene', (151, 158))	('miR-93-5p', 'Gene', (105, 114))	('patients', 'Species', '9606', (372, 380))	('miR-31', 'Gene', '407035', (244, 250))
576242	28787442	After ruling out significant batch effects (S1 Fig), we discovered that the greatest component driving gene expression variation (PC1) accounted for significantly more variation (34% of total) than other components (Fig 1B).	('variation', 'MPA', (168, 177))	('PC1', 'Gene', '3868', (130, 133))	('variation', 'Var', (119, 128))	('gene expression', 'MPA', (103, 118))	('PC1', 'Gene', (130, 133))
576250	28787442	Other notable genes relatively upregulated in SCCs were keratins KRT14 and KRT17; DSC3, a member of the desmocollin family (a component of intercellular desmosomes); FAT2, an atypical cadherin found to be induced by DeltaNp63alpha (isoform of TP63) and promote invasion in LUSC; EGFR, a key growth factor receptor in many cancers; CCNA1, which encodes for cyclin A1, a cell cycle regulator; and WNT3A, a member of the Wnt family of signaling proteins, which also may have a role in SCCs.	('WNT3A', 'Gene', '89780', (395, 400))	('Wnt', 'Gene', (418, 421))	('DSC3', 'Gene', '1825', (82, 86))	('CCNA1', 'Gene', '8900', (331, 336))	('SCCs', 'Phenotype', 'HP:0002860', (46, 50))	('EGFR', 'Gene', (279, 283))	('cancers', 'Disease', 'MESH:D009369', (322, 329))	('KRT17', 'Gene', '3872', (75, 80))	('Wnt', 'Gene', '89780', (418, 421))	('KRT14', 'Gene', '3861', (65, 70))	('WNT3A', 'Gene', (395, 400))	('DSC3', 'Gene', (82, 86))	('SCCs', 'Phenotype', 'HP:0002860', (482, 486))	('KRT14', 'Gene', (65, 70))	('promote', 'PosReg', (253, 260))	('cyclin A1', 'Gene', '8900', (356, 365))	('TP63', 'Gene', (243, 247))	('invasion', 'CPA', (261, 269))	('FAT2', 'Gene', '2196', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('KRT17', 'Gene', (75, 80))	('SCC', 'Gene', '6317', (482, 485))	('cyclin A1', 'Gene', (356, 365))	('SCC', 'Gene', '6317', (46, 49))	('EGFR', 'Gene', '1956', (279, 283))	('TP63', 'Gene', '8626', (243, 247))	('cancers', 'Phenotype', 'HP:0002664', (322, 329))	('CCNA1', 'Gene', (331, 336))	('cancers', 'Disease', (322, 329))	('SCC', 'Gene', (482, 485))	('upregulated', 'PosReg', (31, 42))	('SCC', 'Gene', (46, 49))	('DeltaNp63alpha', 'Var', (216, 230))	('FAT2', 'Gene', (166, 170))
576257	28787442	Genes that were downregulated and hypermethylated in ADCs were squamous markers such as DSC3 and KRT5, as well as transcription factors such as FOXE1 and TP73, whose isoforms have demonstrated both tumor suppressor and oncogenic properties.	('ADC', 'Gene', '113451', (53, 56))	('KRT5', 'Gene', '3852', (97, 101))	('oncogenic properties', 'CPA', (219, 239))	('FOXE1', 'Gene', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('FOXE1', 'Gene', '2304', (144, 149))	('DSC3', 'Gene', '1825', (88, 92))	('ADC', 'Gene', (53, 56))	('hypermethylated', 'Var', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('KRT5', 'Gene', (97, 101))	('DSC3', 'Gene', (88, 92))	('tumor', 'Disease', (198, 203))	('TP73', 'Gene', '7161', (154, 158))	('TP73', 'Gene', (154, 158))	('downregulated', 'NegReg', (16, 29))
576259	28787442	The predominant isoform of TP63 in squamous epithelia and SCCs is DeltaNp63, which has been demonstrated previously to reversibly inhibit TP73-dependent transcription by direct promoter binding or physical interaction with the p73 protein, leading to decreased apoptosis.	('SCC', 'Gene', (58, 61))	('TP73', 'Gene', '7161', (138, 142))	('TP73', 'Gene', (138, 142))	('p73', 'Gene', (227, 230))	('inhibit', 'NegReg', (130, 137))	('p73', 'Gene', '7161', (227, 230))	('squamous epithelia', 'Disease', (35, 53))	('decreased', 'NegReg', (251, 260))	('physical interaction', 'Interaction', (197, 217))	('SCC', 'Gene', '6317', (58, 61))	('SCCs', 'Phenotype', 'HP:0002860', (58, 62))	('TP63', 'Gene', '8626', (27, 31))	('apoptosis', 'CPA', (261, 270))	('TP63', 'Gene', (27, 31))	('squamous epithelia', 'Phenotype', 'HP:0002860', (35, 53))	('DeltaNp63', 'Var', (66, 75))	('squamous epithelia', 'Disease', 'MESH:D002294', (35, 53))
576261	28787442	By contrast, genes that were upregulated and hypomethylated included mucins like MUC1; SERPINA1, a serine protease inhibitor that acts in the liver and lung; HNF1B, a transcription factor that regulates in renal and pancreatic development; and ME3, a mitochondrial malic enzyme whose deletion was shown recently to confer lethality in SMAD4-deleted pancreatic adenocarcinoma.	('SERPINA1', 'Gene', (87, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (365, 374))	('deletion', 'Var', (284, 292))	('upregulated', 'PosReg', (29, 40))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (349, 374))	('SMAD4', 'Gene', (335, 340))	('HNF1B', 'Gene', (158, 163))	('MUC1', 'Gene', (81, 85))	('MUC1', 'Gene', '4582', (81, 85))	('HNF1B', 'Gene', '6928', (158, 163))	('SERPINA1', 'Gene', '5265', (87, 95))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (349, 374))	('ME3', 'Gene', (244, 247))	('pancreatic adenocarcinoma', 'Disease', (349, 374))	('SMAD4', 'Gene', '4089', (335, 340))	('ME3', 'Gene', '10873', (244, 247))
576284	28787442	Furthermore, aberrant Wnt signaling and non-canonical Wnt/PCP signaling, which normally regulates cell shape via the cytoskeleton, have been hypothesized to have a unique role in SCCs, and may represent a functional distinction between SCCs and ADCs.	('SCC', 'Gene', '6317', (236, 239))	('SCCs', 'Phenotype', 'HP:0002860', (236, 240))	('Wnt', 'Gene', (22, 25))	('SCCs', 'Phenotype', 'HP:0002860', (179, 183))	('SCC', 'Gene', (179, 182))	('Wnt', 'Gene', (54, 57))	('Wnt', 'Gene', '89780', (22, 25))	('Wnt', 'Gene', '89780', (54, 57))	('ADC', 'Gene', (245, 248))	('SCC', 'Gene', '6317', (179, 182))	('SCC', 'Gene', (236, 239))	('ADC', 'Gene', '113451', (245, 248))	('role', 'Reg', (171, 175))	('aberrant', 'Var', (13, 21))
576285	28787442	Notably upregulated in ADCs relative to SCCs was STK11 (or LKB1), loss of which has been previously shown to induce adeno-to-squamous differentiation of lung tumors in mice; GATA4 and GATA6, important for cell differentiation and commonly amplified in EAC and gastric cancers; and NKX2-1, a commonly used marker for lung adenocarcinomas.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('lung tumors', 'Phenotype', 'HP:0100526', (153, 164))	('LKB1', 'Gene', '20869', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('carcinomas', 'Phenotype', 'HP:0030731', (326, 336))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (316, 335))	('NKX2-1', 'Gene', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('lung tumors', 'Disease', (153, 164))	('GATA6', 'Gene', (184, 189))	('GATA4', 'Gene', '14463', (174, 179))	('LKB1', 'Gene', (59, 63))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (316, 336))	('lung adenocarcinomas', 'Disease', (316, 336))	('ADC', 'Gene', '113451', (23, 26))	('SCC', 'Gene', '6317', (40, 43))	('EAC', 'Disease', (252, 255))	('ADC', 'Gene', (23, 26))	('STK11', 'Gene', (49, 54))	('adeno-to-squamous differentiation', 'CPA', (116, 149))	('SCC', 'Gene', (40, 43))	('upregulated', 'PosReg', (8, 19))	('induce', 'Reg', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('GATA4', 'Gene', (174, 179))	('gastric cancers', 'Disease', (260, 275))	('gastric cancers', 'Disease', 'MESH:D013274', (260, 275))	('gastric cancers', 'Phenotype', 'HP:0012126', (260, 275))	('loss', 'Var', (66, 70))	('NKX2-1', 'Gene', '21869', (281, 287))	('mice', 'Species', '10090', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('lung tumors', 'Disease', 'MESH:D008175', (153, 164))	('SCCs', 'Phenotype', 'HP:0002860', (40, 44))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (316, 336))
576313	28787442	In fact, one study utilized an inverse agonist SR9243 to inhibit LXR activity, suppressing tumor growth in several colon, prostate, lung and pancreatic adenocarcinoma cell lines.	('activity', 'MPA', (69, 77))	('LXR', 'Enzyme', (65, 68))	('inhibit', 'NegReg', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (141, 166))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (141, 166))	('suppressing', 'NegReg', (79, 90))	('pancreatic adenocarcinoma', 'Disease', (141, 166))	('SR9243', 'Var', (47, 53))	('SR9243', 'Chemical', 'MESH:C000602007', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('colon', 'Disease', (115, 120))	('tumor', 'Disease', (91, 96))
576330	28787442	Another finding with potential therapeutic relevance is TP73 methylation and low expression in ADCs.	('low', 'NegReg', (77, 80))	('methylation', 'Var', (61, 72))	('TP73', 'Gene', '7161', (56, 60))	('TP73', 'Gene', (56, 60))	('ADC', 'Gene', (95, 98))	('ADC', 'Gene', '113451', (95, 98))	('expression', 'MPA', (81, 91))
576331	28787442	TP73 is a known tumor suppressor, and its methylation could contribute to reduced apoptosis in response to chemo- or radiotherapy relative to SCCs.	('TP73', 'Gene', '7161', (0, 4))	('TP73', 'Gene', (0, 4))	('apoptosis', 'CPA', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('SCC', 'Gene', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('SCCs', 'Phenotype', 'HP:0002860', (142, 146))	('SCC', 'Gene', '6317', (142, 145))	('tumor', 'Disease', (16, 21))	('methylation', 'Var', (42, 53))	('reduced', 'NegReg', (74, 81))
576335	28787442	These findings are consistent with other reports: while loss of STK11 has been associated with lung, skin, and head and neck SCCs, inherited loss of STK11, as in Peutz-Jeghers syndrome, has been associated with endometrial adenocarcinoma and a rare variant of endocervical carcinoma, minimal deviation adenocarcinoma of the endocervix.	('associated', 'Reg', (79, 89))	('loss', 'Var', (56, 60))	('SCC', 'Gene', (125, 128))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (162, 184))	('adenocarcinoma', 'Disease', 'MESH:D000230', (223, 237))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (211, 237))	('adenocarcinoma', 'Disease', 'MESH:D000230', (302, 316))	('endometrial adenocarcinoma', 'Disease', (211, 237))	('endocervical carcinoma', 'Disease', (260, 282))	('loss', 'Var', (141, 145))	('SCCs', 'Phenotype', 'HP:0002860', (125, 129))	('endocervical carcinoma', 'Disease', 'MESH:D002277', (260, 282))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (211, 237))	('lung', 'Disease', (95, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('associated', 'Reg', (195, 205))	('skin', 'Disease', (101, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('Peutz-Jeghers syndrome', 'Disease', (162, 184))	('STK11', 'Gene', (64, 69))	('adenocarcinoma', 'Disease', (223, 237))	('adenocarcinoma', 'Disease', (302, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('SCC', 'Gene', '6317', (125, 128))	('STK11', 'Gene', (149, 154))
576371	27613842	Taken together, PTPN22 was hypermethylationed in ESCC.	('hypermethylationed', 'Var', (27, 45))	('PTPN22', 'Gene', '26191', (16, 22))	('ESCC', 'Disease', (49, 53))	('PTPN22', 'Gene', (16, 22))
576377	27613842	In particular, hypermethylation of cytosine-guanine dinucleotide (CpG) islands in promoter regions has been strongly implicated in the onset and progression of cancer.	('cytosine-guanine dinucleotide', 'Chemical', 'MESH:C015772', (35, 64))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('hypermethylation', 'Var', (15, 31))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('implicated', 'Reg', (117, 127))
576378	27613842	Aberrant methylation of the gene promoter has become widely recognized as a mechanism of gene inactivation in cancer.	('cancer', 'Disease', (110, 116))	('inactivation', 'NegReg', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Aberrant methylation', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
576401	27613842	For other analyzed elements, including age, alcohol habit, nerve invasion, vessel invasion and TNM stage, there was no significant association with the methylation change in ESCC (Table 2).	('TNM', 'Gene', (95, 98))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('ESCC', 'Gene', (174, 178))	('alcohol habit', 'Phenotype', 'HP:0030955', (44, 57))	('TNM', 'Gene', '10178', (95, 98))	('methylation change', 'Var', (152, 170))
576410	27613842	Patients with high PAX4 expression levels demonstrated lower 5-year survival rates in HNSCC, gastric cancer and breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('HNSCC', 'Disease', (86, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('breast cancer', 'Disease', (112, 125))	('expression', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('PAX4', 'Gene', (19, 23))	('PAX4', 'Gene', '5078', (19, 23))	('gastric cancer', 'Disease', (93, 107))
576420	27613842	Combined with the hypermethylation in tumor tissue, the current results suggest that aberrant PTPN22 methylation may suppress the expression of PTPN22 mRNA in esophageal cancer.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('expression', 'MPA', (130, 140))	('aberrant', 'Var', (85, 93))	('PTPN22', 'Gene', '26191', (144, 150))	('esophageal cancer', 'Disease', (159, 176))	('PTPN22', 'Gene', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mRNA', 'MPA', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('PTPN22', 'Gene', '26191', (94, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('methylation', 'Var', (101, 112))	('PTPN22', 'Gene', (144, 150))	('suppress', 'NegReg', (117, 125))
576422	27613842	Combined with the higher methylation level in N1-3 and III stage patients, these phenomena were also consistent with the notion that gene hypermethylation down-regulates gene expression.	('methylation level', 'MPA', (25, 42))	('down-regulates', 'NegReg', (155, 169))	('patients', 'Species', '9606', (65, 73))	('higher', 'PosReg', (18, 24))	('gene expression', 'MPA', (170, 185))	('gene hypermethylation', 'Var', (133, 154))
576429	27613842	Studies have demonstrated that tobacco smoking is associated with aberrant gene methylation in several cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aberrant gene methylation', 'Var', (66, 91))	('tobacco', 'Species', '4097', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
576431	27613842	The results revealed that the difference in the methylation level of tumor tissue and ANT was larger in non-smoking and N0 patients than in smoking and N1-3 patients.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('methylation level', 'MPA', (48, 65))	('tumor', 'Disease', (69, 74))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (157, 165))	('non-smoking', 'Var', (104, 115))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
576435	27613842	With respect to the relationship between methylation and differentiation, studies have hypothesized that two potential mechanisms, loss of cell fate-determining transcription factors by methylation and functional inactivation of corresponding genomic-binding sites by DNA methylation, can promote cellular differentiation defects, thus enhancing the ability of tumor progenitor cells to transition toward ESCC.	('transition', 'CPA', (387, 397))	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('enhancing', 'PosReg', (336, 345))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('inactivation', 'Var', (213, 225))	('loss', 'NegReg', (131, 135))	('tumor', 'Disease', (361, 366))	('cellular differentiation defects', 'CPA', (297, 329))	('methylation', 'Var', (272, 283))	('promote', 'PosReg', (289, 296))	('methylation', 'Var', (186, 197))
576438	27613842	No significant correlation has been observed between PTPN22 methylation and prognosis.	('methylation', 'Var', (60, 71))	('PTPN22', 'Gene', (53, 59))	('PTPN22', 'Gene', '26191', (53, 59))
576439	27613842	In other malignancies, gene-specific DNA hypermethylation can predict PFS and OS and is always associated with unfavorable clinical outcomes, lower survival rates and aggressive behavior.	('malignancies', 'Disease', (9, 21))	('DNA hypermethylation', 'Var', (37, 57))	('PFS', 'Disease', (70, 73))	('survival rates', 'CPA', (148, 162))	('lower', 'NegReg', (142, 147))	('aggressive behavior', 'Phenotype', 'HP:0000718', (167, 186))	('malignancies', 'Disease', 'MESH:D009369', (9, 21))	('associated', 'Reg', (95, 105))	('predict', 'Reg', (62, 69))
576440	27613842	However, in the current study, a quantitative research was used to investigate the clinical significance of aberrant methylation of PTPN22.	('aberrant', 'Var', (108, 116))	('PTPN22', 'Gene', '26191', (132, 138))	('PTPN22', 'Gene', (132, 138))
576446	27613842	In conclusion, hypermethylation of the PTPN22 gene was observed in ESCC.	('ESCC', 'Disease', (67, 71))	('PTPN22', 'Gene', (39, 45))	('hypermethylation', 'Var', (15, 31))	('observed', 'Reg', (55, 63))	('PTPN22', 'Gene', '26191', (39, 45))
576468	27613842	The expression level of PTPN22 was analyzed using the 2-DeltaDeltaCT method, where DeltaCt = Ct (PTPN22)-Ct (GAPDH) and DeltaDeltaCt = DeltaCt (Tumor)-DeltaCt (ANT).	('GAPDH', 'Gene', (109, 114))	('Tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PTPN22', 'Gene', '26191', (24, 30))	('PTPN22', 'Gene', (97, 103))	('DeltaDeltaCt', 'Var', (120, 132))	('PTPN22', 'Gene', '26191', (97, 103))	('PTPN22', 'Gene', (24, 30))	('GAPDH', 'Gene', '2597', (109, 114))
576636	25922660	This research investigated the prevalence of SIRT1 protein expression and its prognostic influence with the aim of validating its potential role in lymphangiogenesis and lymphovascular invasion (LVI) in pN0 esophageal squamous cell carcinoma (ESCC).	('pN0', 'Var', (203, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (218, 241))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (207, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('SIRT1', 'Gene', (45, 50))	('esophageal squamous cell carcinoma', 'Disease', (207, 241))
576640	25922660	Patients with SIRT1 positive expression, high LVD and positive LVI had a significantly unfavorable 5-year disease free survival (P < 0.001, P = 0.030, and P < 0.001, respectively) and overall survival (P < 0.001, P = 0.017, and P < 0.001, respectively).	('high LVD', 'Var', (41, 49))	('overall survival', 'CPA', (184, 200))	('unfavorable', 'NegReg', (87, 98))	('Patients', 'Species', '9606', (0, 8))	('positive', 'PosReg', (20, 28))	('SIRT1', 'Gene', (14, 19))	('disease free survival', 'CPA', (106, 127))
576650	25922660	Thus, identification of prognostic molecular markers for pN0 ESCC may help to identify patients with poor prognosis who would benefit from further clinical treatment, provide possible therapeutic targets and improve the long-term survival rate.	('improve', 'PosReg', (208, 215))	('patients', 'Species', '9606', (87, 95))	('pN0', 'Var', (57, 60))	('men', 'Species', '9606', (161, 164))
576674	25922660	We found that patients with SIRT1 positive expression had a significantly shorter 5-year overall survival (OS) than patients who lacked SIRT1 expression (48.4% vs 78.4%; P < 0.001, Figure 2d).	('shorter', 'NegReg', (74, 81))	('patients', 'Species', '9606', (116, 124))	('positive expression', 'Var', (34, 53))	('overall survival', 'MPA', (89, 105))	('SIRT1', 'Gene', (28, 33))	('patients', 'Species', '9606', (14, 22))
576679	25922660	Recent reports have indicated that deacetylation of FOXO-1 by SIRT1 could enhance VEGF-C transcription in the nuclei of prostate cancer cells and facilitate the growth of endothelial cells in mice.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('FOXO-1', 'Gene', '56458', (52, 58))	('mice', 'Species', '10090', (192, 196))	('transcription', 'MPA', (89, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('growth of endothelial cells', 'CPA', (161, 188))	('prostate cancer', 'Disease', (120, 135))	('facilitate', 'PosReg', (146, 156))	('deacetylation', 'Var', (35, 48))	('FOXO-1', 'Gene', (52, 58))	('SIRT1', 'Gene', (62, 67))	('VEGF-C', 'Gene', (82, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))	('enhance', 'PosReg', (74, 81))
576680	25922660	Additionally, our results showed a significantly high LVD and positive LVI in patients with SIRT1 positive expression, indicating an important role for SIRT1 in promoting tumor lymphangiogenesis and lymphatic metastasis.	('lymphatic metastasis', 'CPA', (199, 219))	('SIRT1', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('patients', 'Species', '9606', (78, 86))	('positive expression', 'Var', (98, 117))	('LVD', 'MPA', (54, 57))	('tumor', 'Disease', (171, 176))	('high', 'PosReg', (49, 53))	('promoting', 'PosReg', (161, 170))
576682	25922660	Previous studies have shown that ESCC patients with high LVD have a significantly worse prognosis, while Schoppmann showed a significant prognostic impact in adenocarcinomas only.	('adenocarcinomas', 'Disease', 'MESH:D000230', (158, 173))	('ESCC', 'Disease', (33, 37))	('adenocarcinomas', 'Disease', (158, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('high LVD', 'Var', (52, 60))	('patients', 'Species', '9606', (38, 46))
576684	25922660	Our research demonstrated higher rates of tumor recurrence and worse OS in patients with high LVD, positive LVI and SIRT1 positive expression.	('tumor', 'Disease', (42, 47))	('positive', 'Var', (99, 107))	('LVI', 'Gene', (108, 111))	('patients', 'Species', '9606', (75, 83))	('SIRT1', 'Gene', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('worse OS', 'CPA', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
576739	24522517	Abnormal expression of Myc family genes has long been known to be associated with neoplastic diseases in a wide range of vertebrates, including humans.	('neoplastic diseases', 'Disease', (82, 101))	('Myc', 'Gene', (23, 26))	('associated', 'Reg', (66, 76))	('humans', 'Species', '9606', (144, 150))	('neoplastic diseases', 'Disease', 'MESH:D009386', (82, 101))	('Abnormal', 'Var', (0, 8))	('Myc', 'Gene', '4609', (23, 26))
576773	24522517	The membranes were blocked using 5 % nonfat dry milk and incubated overnight at 4  C with primary antibodies (anti-Mina53 or anti-actin; both from Santa Cruz Biotechnology, Santa Cruz, CA, USA), followed by incubation with HRP-conjugated secondary antibodies for 1 h at room temperature.	('Mina53', 'Gene', (115, 121))	('Mina53', 'Gene', '84864', (115, 121))	('anti-actin', 'Var', (125, 135))
576790	24522517	The siRNA silencing led to a decrease of Mina53 mRNA levels of 35.1 +- 2.7 % (P < 0.01 vs. blank control group; Fig.	('Mina53', 'Gene', '84864', (41, 47))	('siRNA', 'Gene', (4, 9))	('Mina53', 'Gene', (41, 47))	('decrease', 'NegReg', (29, 37))	('silencing', 'Var', (10, 19))
576796	24522517	By contrast, silencing of Mina53 significantly suppressed proliferation in PANC-1 cells (Fig.	('Mina53', 'Gene', (26, 32))	('suppressed', 'NegReg', (47, 57))	('proliferation', 'CPA', (58, 71))	('PANC-1', 'CellLine', 'CVCL:0480', (75, 81))	('Mina53', 'Gene', '84864', (26, 32))	('silencing', 'Var', (13, 22))
576832	22939994	Agonists such as rifampicin, SR12813, pregnenolone 16alpha carbonitrile (PCN), anticancer drugs, and environmental chemicals bind to PXR and induce conformational changes that lead to dissociation of corepressors and recruitment of coactivators such as steroid receptor coactivator 1 (SRC-1) and SRC-3 which have intrinsic histone acetyltransferase activity, (Fig.	('steroid receptor coactivator 1', 'Gene', '8648', (253, 283))	('recruitment', 'PosReg', (217, 228))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('conformational changes', 'MPA', (148, 170))	('rifampicin', 'Chemical', 'MESH:D012293', (17, 27))	('pregnenolone 16alpha carbonitrile', 'Chemical', 'MESH:D011285', (38, 71))	('SRC-3', 'Gene', (296, 301))	('SRC-1', 'Gene', (285, 290))	('SR12813', 'Var', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('steroid receptor coactivator 1', 'Gene', (253, 283))	('dissociation', 'MPA', (184, 196))	('PCN', 'Chemical', 'MESH:D011285', (73, 76))	('SRC-1', 'Gene', '8648', (285, 290))	('SRC-3', 'Gene', '8202', (296, 301))	('bind', 'Interaction', (125, 129))	('SR12813', 'Chemical', 'MESH:C100355', (29, 36))	('corepressors', 'MPA', (200, 212))	('cancer', 'Disease', (83, 89))
576851	22939994	Conversely, inhibition of PXR with A-792611 or knockdown of PXR with siRNA, resulted in downregulation of OATP1A2 expression as well as OATP1A2-mediated estrogen uptake.	('OATP1A2', 'Gene', (106, 113))	('downregulation', 'NegReg', (88, 102))	('A-792611', 'Var', (35, 43))	('knockdown', 'Var', (47, 56))	('OATP1A2', 'Gene', '6579', (136, 143))	('expression', 'MPA', (114, 124))	('OATP1A2', 'Gene', (136, 143))	('OATP1A2', 'Gene', '6579', (106, 113))
576867	22939994	For instance, in MDA-MB-231 and MCF-7 human breast cancer cells, preactivation of PXR by SR12813, led to an increased resistance to Taxol as well as an increased expression of CYP3A4 and MDR1.	('MDR1', 'Gene', '5243', (187, 191))	('Taxol', 'Chemical', 'MESH:D017239', (132, 137))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('human', 'Species', '9606', (38, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (17, 27))	('increased', 'PosReg', (152, 161))	('increased', 'PosReg', (108, 117))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('SR12813', 'Chemical', 'MESH:C100355', (89, 96))	('expression', 'MPA', (162, 172))	('CYP3A4', 'Gene', (176, 182))	('MDR1', 'Gene', (187, 191))	('SR12813', 'Var', (89, 96))	('CYP3A4', 'Gene', '1576', (176, 182))	('MCF-7', 'CellLine', 'CVCL:0031', (32, 37))	('resistance to Taxol', 'MPA', (118, 137))
576868	22939994	Conversely, knockdown of PXR using small hairpin RNA (shRNA) sensitized MDA-MB-231 and MCF-7 cells to the treatment of Taxol, vinblastine or tamoxifen.	('vinblastine', 'Chemical', 'MESH:D014747', (126, 137))	('knockdown', 'Var', (12, 21))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (72, 82))	('MCF-7', 'CellLine', 'CVCL:0031', (87, 92))	('Taxol', 'Chemical', 'MESH:D017239', (119, 124))	('Taxol', 'MPA', (119, 124))	('tamoxifen', 'Chemical', 'MESH:D013629', (141, 150))	('sensitized', 'Reg', (61, 71))
576879	22939994	In PC3 cells, activation of PXR with SR12813 enhanced the expression of both CYP3A4 and MDR1 and increased the resistance of PC-3 cells to anticancer drugs, paclitaxel and vinblastine, suggesting that PXR activation confers prostate cancer cells with increased resistance toward chemotherapy.	('paclitaxel', 'Chemical', 'MESH:D017239', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('expression', 'MPA', (58, 68))	('MDR1', 'Gene', '5243', (88, 92))	('prostate cancer', 'Disease', 'MESH:D011471', (224, 239))	('prostate cancer', 'Phenotype', 'HP:0012125', (224, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('SR12813', 'Var', (37, 44))	('cancer', 'Disease', (143, 149))	('prostate cancer', 'Disease', (224, 239))	('vinblastine', 'Chemical', 'MESH:D014747', (172, 183))	('MDR1', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CYP3A4', 'Gene', '1576', (77, 83))	('increased', 'PosReg', (97, 106))	('enhanced', 'PosReg', (45, 53))	('PC3', 'CellLine', 'CVCL:0035', (3, 6))	('CYP3A4', 'Gene', (77, 83))	('resistance', 'MPA', (111, 121))	('PC-3', 'CellLine', 'CVCL:0035', (125, 129))	('cancer', 'Disease', (233, 239))	('SR12813', 'Chemical', 'MESH:C100355', (37, 44))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
576880	22939994	On the other hand, the targeted knockdown of PXR using shRNA increased the sensitivity of PC3 cells to paclitaxel and vinblastine, suggesting that downregulation of PXR sensitizes prostate cancer cells toward chemotherapy.	('prostate cancer', 'Disease', (180, 195))	('paclitaxel', 'Chemical', 'MESH:D017239', (103, 113))	('downregulation', 'Var', (147, 161))	('vinblastine', 'Chemical', 'MESH:D014747', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('knockdown', 'Var', (32, 41))	('prostate cancer', 'Disease', 'MESH:D011471', (180, 195))	('increased', 'PosReg', (61, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (180, 195))	('PC3', 'CellLine', 'CVCL:0035', (90, 93))	('sensitivity', 'MPA', (75, 86))
576890	22939994	showed that PXR activation induced proliferation, invasion, and migration of LS174T human colon cancer cells in vitro and mouse xenografts of LS174T cells.	('LS174T', 'CellLine', 'CVCL:1384', (77, 83))	('invasion', 'CPA', (50, 58))	('colon cancer', 'Disease', 'MESH:D015179', (90, 102))	('colon cancer', 'Disease', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('proliferation', 'CPA', (35, 48))	('PXR', 'Enzyme', (12, 15))	('human', 'Species', '9606', (84, 89))	('LS174T', 'CellLine', 'CVCL:1384', (142, 148))	('migration', 'CPA', (64, 73))	('colon cancer', 'Phenotype', 'HP:0003003', (90, 102))	('mouse', 'Species', '10090', (122, 127))	('LS174T', 'Var', (77, 83))
576891	22939994	In contrast, PXR knockdown inhibited proliferation and metastasis to liver from spleen, suggesting that PXR activation can enhance tumor growth and metastasis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('enhance', 'PosReg', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('inhibited', 'NegReg', (27, 36))	('knockdown', 'Var', (17, 26))
576901	22939994	Similarly, the PXR promoter is significantly silenced by methylation in normal colon cells as opposed to tumor cells.	('methylation', 'Var', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('silenced', 'NegReg', (45, 53))
576925	22939994	Dog PXR has been shown to be similar to human PXR in terms of ligand-binding, that is, dog PXR is activated by both rifampicin and SR 12813 but not PCN.	('activated', 'PosReg', (98, 107))	('SR 12813', 'Chemical', 'MESH:C100355', (131, 139))	('rifampicin', 'Var', (116, 126))	('dog', 'MPA', (87, 90))	('PCN', 'Chemical', 'MESH:D011285', (148, 151))	('Dog', 'Species', '9615', (0, 3))	('rifampicin', 'Chemical', 'MESH:D012293', (116, 126))	('human', 'Species', '9606', (40, 45))	('dog', 'Species', '9615', (87, 90))
576943	22939994	reported that MCF cells, with a low metastatic potential, expressed PXR.1 but not PXR.2 mRNA.	('PXR.1', 'Var', (68, 73))	('PXR.2', 'Gene', (82, 87))	('PXR.2', 'Gene', '51555', (82, 87))	('MCF', 'CellLine', 'CVCL:E778', (14, 17))
576951	22939994	Receptor cross-talk (e.g., PXR and AhR or LXR/FXR or CAR) should also be given consideration, especially for those receptors that share common ligands (e.g., T1317 activates both PXR and LXR).	('FXR', 'Gene', (46, 49))	('AhR', 'Gene', '196', (35, 38))	('CAR', 'Gene', (53, 56))	('T1317', 'Var', (158, 163))	('CAR', 'Gene', '9970', (53, 56))	('FXR', 'Gene', '9971', (46, 49))	('PXR', 'MPA', (179, 182))	('activates', 'PosReg', (164, 173))	('AhR', 'Gene', (35, 38))
576966	22939994	For example, while PXR induces prostate cancer drug resistance, it has also been shown to be a favorable prognostic marker.	('induces', 'Reg', (23, 30))	('PXR', 'Var', (19, 22))	('prostate cancer', 'Disease', 'MESH:D011471', (31, 46))	('drug resistance', 'Phenotype', 'HP:0020174', (47, 62))	('prostate cancer', 'Phenotype', 'HP:0012125', (31, 46))	('prostate cancer', 'Disease', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
577011	21537872	found in 48 patients that even though clinicopathological findings did not correlate with FDG uptake, patients with a high SUV had a poorer prognosis compared with those with low FDG uptake (55% 2-year disease-free survival vs 30%).	('high', 'Var', (118, 122))	('patients', 'Species', '9606', (12, 20))	('FDG', 'Chemical', 'MESH:D019788', (179, 182))	('FDG', 'Chemical', 'MESH:D019788', (90, 93))	('at', 'Gene', '36849', (103, 105))	('disease-free survival', 'CPA', (202, 223))	('patients', 'Species', '9606', (102, 110))	('at', 'Gene', '36849', (46, 48))	('at', 'Gene', '36849', (81, 83))	('at', 'Gene', '36849', (23, 25))	('at', 'Gene', '36849', (13, 15))
577015	21537872	The 2-year survival rate in patients with high FDG uptake (48%) was lower than in patients with low FDG uptake (91%).	('FDG', 'Chemical', 'MESH:D019788', (100, 103))	('at', 'Gene', '36849', (21, 23))	('lower', 'NegReg', (68, 73))	('patients', 'Species', '9606', (82, 90))	('at', 'Gene', '36849', (83, 85))	('at', 'Gene', '36849', (29, 31))	('high FDG uptake', 'Var', (42, 57))	('FDG', 'Chemical', 'MESH:D019788', (47, 50))	('patients', 'Species', '9606', (28, 36))
577032	21537872	Cerfolio and Bryant showed in a multivariate analysis that patients with high FDG uptake were more likely to have poorly differentiated tumors and advanced stage using a retrospective cohort of 89 patients.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('at', 'Gene', '36849', (41, 43))	('at', 'Gene', '36849', (131, 133))	('patients', 'Species', '9606', (197, 205))	('at', 'Gene', '36849', (56, 58))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('at', 'Gene', '36849', (60, 62))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('at', 'Gene', '36849', (198, 200))	('high', 'Var', (73, 77))	('FDG', 'Chemical', 'MESH:D019788', (78, 81))	('advanced stage', 'CPA', (147, 161))
577037	21537872	The survival advantage for patients with low FDG uptake was even seen in a subset of patients with clinically and pathologically early-stage disease.	('FDG', 'Chemical', 'MESH:D019788', (45, 48))	('at', 'Gene', '36849', (28, 30))	('at', 'Gene', '36849', (86, 88))	('at', 'Gene', '36849', (115, 117))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (27, 35))	('low', 'Var', (41, 44))	('FDG', 'Protein', (45, 48))
577148	21694826	Mutations of the tumor suppression antigen p53 are among the most commonly detected genetic abnormalities in human neoplasia in general and in squamous cell carcinomas in particular.	('neoplasia', 'Disease', (115, 124))	('genetic abnormalities', 'Disease', (84, 105))	('tumor', 'Disease', (17, 22))	('squamous cell carcinomas', 'Disease', (143, 167))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (143, 167))	('human', 'Species', '9606', (109, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('neoplasia', 'Disease', 'MESH:D009369', (115, 124))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (143, 167))	('neoplasia', 'Phenotype', 'HP:0002664', (115, 124))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('genetic abnormalities', 'Disease', 'MESH:D030342', (84, 105))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
577152	21694826	DNA ploidy is known to indicate prognosis in squamous cell carcinoma of the esophagus through the detection of aneuploid peaks in flow cytometric analysis.	('squamous cell carcinoma of the esophagus', 'Disease', (45, 85))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (59, 85))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (45, 85))	('aneuploid peaks', 'Var', (111, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))
577199	21694826	Most of the 28 analyzed tumors were aneuploid (n = 25).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('aneuploid', 'Var', (36, 45))
577485	21116340	sDNA: Adenoma and CRC that contained altered DNA are shed and passed in feces.	('Adenoma', 'Disease', (6, 13))	('sDNA', 'Chemical', '-', (0, 4))	('Adenoma', 'Disease', 'MESH:D000236', (6, 13))	('altered DNA', 'Var', (37, 48))
577590	32151057	We hypothesized that aberrant expression and function of FoxAs are involved in CCA progression via induction of stem-like cell and tumorigenic properties of the cancer cells.	('involved', 'Reg', (67, 75))	('induction', 'PosReg', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('aberrant expression', 'Var', (21, 40))	('function', 'MPA', (45, 53))	('CCA', 'Phenotype', 'HP:0030153', (79, 82))	('tumor', 'Disease', (131, 136))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('CCA', 'Disease', 'MESH:D018281', (79, 82))	('cancer', 'Disease', (161, 167))	('CCA', 'Disease', (79, 82))	('FoxAs', 'Gene', (57, 62))
577607	32151057	The median survival of CCA patients with high FoxA1 expression was 364 days and the median survival of CCA patients with low FoxA1 expression was 256 days.	('high FoxA1', 'Var', (41, 51))	('CCA', 'Disease', (103, 106))	('CCA', 'Disease', 'MESH:D018281', (23, 26))	('CCA', 'Disease', (23, 26))	('patients', 'Species', '9606', (27, 35))	('CCA', 'Phenotype', 'HP:0030153', (103, 106))	('CCA', 'Disease', 'MESH:D018281', (103, 106))	('CCA', 'Phenotype', 'HP:0030153', (23, 26))	('patients', 'Species', '9606', (107, 115))
577610	32151057	According to the data analysis, low FoxA1 expression was related with short survival rates and high FoxA3 expression was correlated with metastasis status of CCA patients.	('low', 'NegReg', (32, 35))	('correlated', 'Reg', (121, 131))	('patients', 'Species', '9606', (162, 170))	('CCA', 'Phenotype', 'HP:0030153', (158, 161))	('CCA', 'Disease', 'MESH:D018281', (158, 161))	('expression', 'MPA', (42, 52))	('FoxA3', 'Gene', (100, 105))	('expression', 'MPA', (106, 116))	('high', 'Var', (95, 99))	('FoxA1', 'Gene', (36, 41))	('metastasis status', 'CPA', (137, 154))	('CCA', 'Disease', (158, 161))
577618	32151057	The stem cell marker (CD133 and Oct3/4) expression levels were also significantly increased in KKU-213 cells compared to KKU-100 cells, as shown in Figure 3I,J, respectively.	('KKU-213 cells', 'Var', (95, 108))	('Oct3/4', 'Gene', '5460', (32, 38))	('CD133', 'Gene', (22, 27))	('stem cell', 'CPA', (4, 13))	('Oct3/4', 'Gene', (32, 38))	('CD133', 'Gene', '8842', (22, 27))	('increased', 'PosReg', (82, 91))	('expression levels', 'MPA', (40, 57))
577639	32151057	Additionally, high FoxA3 expression CCA cell line (KKU-213) was increased in cell proliferation rate, cell invasion activity, and stem-like cell properties compared to the low FoxA3 expression CCA cell line (KKU-100).	('CCA', 'Disease', (193, 196))	('CCA', 'Disease', (36, 39))	('FoxA3', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('cell invasion activity', 'CPA', (102, 124))	('CCA', 'Phenotype', 'HP:0030153', (193, 196))	('CCA', 'Phenotype', 'HP:0030153', (36, 39))	('increased', 'PosReg', (64, 73))	('CCA', 'Disease', 'MESH:D018281', (193, 196))	('stem-like cell properties', 'CPA', (130, 155))	('cell proliferation rate', 'CPA', (77, 100))	('CCA', 'Disease', 'MESH:D018281', (36, 39))
577669	32151057	The mRNA levels of FoxA1, FoxA3, CD133, Oct3/4 and GAPDH were detected by TaqMan gene expression assay using TaqMan probes (Hs00270129_m1 FoxA1, Hs00270130_m1 FoxA3, Hs01009257_m1 PROM1 (CD133), Hs04260367_gH POU5F1 (Oct3/4) and GAPDH).	('CD133', 'Gene', (33, 38))	('GAPDH', 'Gene', '2597', (51, 56))	('CD133', 'Gene', '8842', (33, 38))	('POU5F1', 'Gene', (209, 215))	('Oct3/4', 'Gene', '5460', (40, 46))	('Oct3/4', 'Gene', (40, 46))	('GAPDH', 'Gene', (51, 56))	('GAPDH', 'Gene', '2597', (229, 234))	('Hs00270129_m1', 'Var', (124, 137))	('Hs01009257_m1', 'Var', (166, 179))	('PROM1', 'Gene', (180, 185))	('PROM1', 'Gene', '8842', (180, 185))	('Hs00270130_m1', 'Var', (145, 158))	('POU5F1', 'Gene', '5460', (209, 215))	('GAPDH', 'Gene', (229, 234))	('Oct3/4', 'Gene', '5460', (217, 223))	('Oct3/4', 'Gene', (217, 223))	('CD133', 'Gene', (187, 192))	('CD133', 'Gene', '8842', (187, 192))
577713	29496425	With the MBCEA applicator, the contours of the target (tumor plus margin), non-target esophagus, heart, gastroesophageal junction (GEJ) are drawn on the CT scan dataset and a plan is generated using Brachyvision software (Varian Brachytherapy, Charlottesville, VA) with following planning criteria: target V100 (volume receiving 100% of dose) > 90%, D0.3cc (maximum dose to 0.3cc of volume) <=12 Gy/fraction.	('GEJ', 'Disease', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('D0.3cc', 'Var', (350, 356))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('gastroesophageal junction', 'Disease', (104, 129))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (104, 129))	('tumor', 'Disease', (55, 60))	('GEJ', 'Disease', 'MESH:D008309', (131, 134))
577829	30083328	Thirty-five patients (median age 68 years) were included: 17 low-risk (submucosal invasion <500 microns, G1-G2, no lymphovascular invasion (LVI)), and 18 high-risk (submucosal invasion >500 microns, and/or G3-G4, and/or LVI, and/or a tumor-positive deep resection margin (R1)) EACs.	('patients', 'Species', '9606', (12, 20))	('tumor', 'Disease', (234, 239))	('EAC', 'Phenotype', 'HP:0011459', (277, 280))	('LVI', 'CPA', (220, 223))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('G3-G4', 'Var', (206, 211))	('G1-G2', 'Var', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
577857	30083328	For each case a desmin stain was performed to determine the deepest point of invasion and a D2-40 or CD31 when LVI was suspected.	('CD31', 'Gene', (101, 105))	('CD31', 'Gene', '5175', (101, 105))	('D2-40', 'Var', (92, 97))
577957	25734919	Aberrant Methylation Inactivates Somatostatin and Somatostatin Receptor Type 1 in Head and Neck Squamous Cell Carcinoma The aim of this study was to define somatostatin (SST) and somatostatin receptor type 1 (SSTR1) methylation profiles for head and neck squamous cell carcinoma (HNSCC) tumors at diagnosis and follow up and to evaluate their prognostic significance and value as a biomarker.	('somatostatin receptor type 1', 'Gene', (179, 207))	('Aberrant Methylation', 'Var', (0, 20))	('somatostatin receptor type 1', 'Gene', '6751', (179, 207))	('Carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('Methylation', 'Var', (9, 20))	('Inactivates', 'NegReg', (21, 32))	('Head and Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (82, 119))	('Somatostatin', 'Gene', '6750', (50, 62))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('neck squamous cell carcinoma (HNSCC) tumors', 'Disease', 'MESH:D000077195', (250, 293))	('Somatostatin', 'Gene', (50, 62))	('HNSCC', 'Phenotype', 'HP:0012288', (280, 285))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (241, 278))	('Somatostatin', 'Gene', '6750', (33, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('Somatostatin', 'Gene', (33, 45))	('Somatostatin Receptor Type 1', 'Gene', '6751', (50, 78))	('Somatostatin Receptor Type 1', 'Gene', (50, 78))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('SSTR1', 'Gene', (209, 214))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (82, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
577958	25734919	SST methylation in 81% of HNSCC tumor specimens significantly correlated with tumor size (P = 0.043), stage (P = 0.008), galanin receptor type 2 (GALR2) methylation (P = 0.041), and tachykinin-1 (TAC1) (P = 0.040).	('HNSCC tumor', 'Disease', 'MESH:D000077195', (26, 37))	('SST', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('men', 'Species', '9606', (43, 46))	('tachykinin-1', 'Gene', (182, 194))	('GALR2', 'Gene', '8811', (146, 151))	('HNSCC', 'Phenotype', 'HP:0012288', (26, 31))	('TAC1', 'Gene', (196, 200))	('tachykinin-1', 'Gene', '6863', (182, 194))	('HNSCC tumor', 'Disease', (26, 37))	('galanin receptor type 2', 'Gene', '8811', (121, 144))	('methylation', 'Var', (4, 15))	('galanin receptor type 2', 'Gene', (121, 144))	('tumor', 'Disease', (78, 83))	('methylation', 'Var', (153, 164))	('tumor', 'Disease', (32, 37))	('correlated', 'Reg', (62, 72))	('GALR2', 'Gene', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('TAC1', 'Gene', '6863', (196, 200))
577959	25734919	SSTR1 hypermethylation in 64% of cases was correlated with tumor size (P = 0.037), stage (P = 0.037), SST methylation (P < 0.001), and expression of galanin (P = 0.03), GALR2 (P = 0.014), TAC1 (P = 0.023), and tachykinin receptor type 1 (TACR1) (P = 0.003).	('TACR1', 'Gene', (238, 243))	('hypermethylation', 'Var', (6, 22))	('tumor', 'Disease', (59, 64))	('tachykinin receptor type 1', 'Gene', (210, 236))	('TAC1', 'Gene', (188, 192))	('TACR1', 'Gene', '6869', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('correlated', 'Reg', (43, 53))	('GALR2', 'Gene', '8811', (169, 174))	('GALR2', 'Gene', (169, 174))	('SSTR1', 'Gene', (0, 5))	('tachykinin receptor type 1', 'Gene', '6869', (210, 236))	('TAC1', 'Gene', '6863', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
577960	25734919	Among patients with oral cavity and oropharynx cancer, methylation of both SST and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.028).	('oral cavity', 'Disease', (20, 31))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('reduced', 'NegReg', (115, 122))	('disease-free survival', 'CPA', (123, 144))	('cancer', 'Disease', (47, 53))	('patients', 'Species', '9606', (6, 14))	('methylation', 'Var', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('SST', 'Gene', (75, 78))	('SSTR1', 'Gene', (83, 88))
577961	25734919	CpG hypermethylation is a likely mechanism of SST and SSTR1 gene inactivation, supporting the hypothesis that SST and SSTR1 play a role in the tumorigenesis of HNSCC and that this hypermethylation may serve as an important biomarker.	('inactivation', 'NegReg', (65, 77))	('tumor', 'Disease', (143, 148))	('role', 'Reg', (131, 135))	('SSTR1', 'Gene', (118, 123))	('SSTR1', 'Gene', (54, 59))	('HNSCC', 'Disease', (160, 165))	('HNSCC', 'Phenotype', 'HP:0012288', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('SST', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('hypermethylation', 'Var', (4, 20))
577966	25734919	Our findings suggest that simultaneous methylation of galanin, galanin receptor type 1 (GALR1), and GALR2 genes occurs in a subset of HNSCC and may be used as a prognostic marker.	('occurs', 'Reg', (112, 118))	('methylation', 'Var', (39, 50))	('GALR2', 'Gene', (100, 105))	('HNSCC', 'Disease', (134, 139))	('GALR1', 'Gene', '2587', (88, 93))	('GALR2', 'Gene', '8811', (100, 105))	('galanin receptor type 1', 'Gene', '2587', (63, 86))	('galanin receptor type 1', 'Gene', (63, 86))	('GALR1', 'Gene', (88, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (134, 139))
577971	25734919	Hypermethylation of SST has been described in esophageal cancer, gastric cancer, colon cancer, and renal cancer.	('renal cancer', 'Disease', 'MESH:D007680', (99, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (81, 93))	('Hypermethylation', 'Var', (0, 16))	('SST', 'Gene', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colon cancer', 'Disease', 'MESH:D015179', (81, 93))	('described', 'Reg', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('esophageal cancer', 'Disease', (46, 63))	('colon cancer', 'Disease', (81, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('gastric cancer', 'Disease', (65, 79))	('renal cancer', 'Disease', (99, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))	('renal cancer', 'Phenotype', 'HP:0009726', (99, 111))
577979	25734919	Therefore, detection of aberrant expression of SST/SSTR1 may be of potential use as a marker for selecting HNSCC patients who could benefit from additional targeted therapies.	('HNSCC', 'Disease', (107, 112))	('SST/SSTR1', 'Gene', (47, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (107, 112))	('patients', 'Species', '9606', (113, 121))	('aberrant', 'Var', (24, 32))
577981	25734919	More recently, data from our laboratory have shown that the galanin, GALR1, GALR2, TAC1, and TACR1 promoters are methylated in HNSCC.	('methylated', 'Var', (113, 123))	('TAC1', 'Gene', '6863', (83, 87))	('GALR1', 'Gene', (69, 74))	('TAC1', 'Gene', (83, 87))	('GALR2', 'Gene', (76, 81))	('GALR2', 'Gene', '8811', (76, 81))	('TACR1', 'Gene', (93, 98))	('GALR1', 'Gene', '2587', (69, 74))	('TACR1', 'Gene', '6869', (93, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))
577982	25734919	Therefore, we hypothesized that neuropeptide genes and receptor genes might be inactivated via promoter hypermethylation in human head and neck cancers, and that hypermethylation of these genes is an important event in the genesis of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (234, 239))	('head and neck cancers', 'Phenotype', 'HP:0012288', (130, 151))	('inactivated', 'NegReg', (79, 90))	('hypermethylation', 'Var', (162, 178))	('human', 'Species', '9606', (124, 129))	('promoter hypermethylation', 'Var', (95, 120))	('neck cancers', 'Disease', (139, 151))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('head and neck cancer', 'Phenotype', 'HP:0012288', (130, 150))	('neuropeptide genes', 'Gene', (32, 50))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('HNSCC', 'Disease', (234, 239))	('neck cancers', 'Disease', 'MESH:D006258', (139, 151))
577996	25734919	Q-MSP primers for methylated DNA were Q-MSP-SST-F (5'- GGG GCG TTT TTT AGT TTG ACG T-3') and Q-MSP-SST-R (5'-AAC AAC GAT AAC TCC GAA CCT CG-3'), Q-MSP-SSTR1-F (5'- CGG GTG CGC GAG GAG AAA GTT-3') and Q-MSP-SSTR1-R (5'- TAG TTC GGG TAG TTG CGG CGA A-3'), and Q-MSP-ACTB-F (5'-TGG TGA TGG AGG AGG TTT AGT AAG T-3') and Q-MSP-ACTB-R (5'-AAC CAA TAA AAC CTA CTC CTC CCT TAA-3').	('CCT', 'Gene', (133, 136))	('CCT', 'Gene', '907', (362, 365))	('TGG AGG AGG', 'Phenotype', 'HP:0003237', (283, 294))	('CCT', 'Gene', '907', (133, 136))	('CCT', 'Gene', (362, 365))	('Q-MSP-ACTB-F', 'Var', (258, 270))
578010	25734919	Methylation of SST was associated with several clinicopathologic factors, including tumor size (P = 0.043), stage (P = 0.008), GALR2 methylation (P = 0.041), TAC1 methylation (P = 0.040), and DAPK methylation (P = 0.012) (Table 1and S1 Table).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('GALR2', 'Gene', (127, 132))	('GALR2', 'Gene', '8811', (127, 132))	('DAPK', 'Gene', (192, 196))	('Methylation', 'Var', (0, 11))	('DAPK', 'Gene', '1612', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TAC1', 'Gene', (158, 162))	('tumor', 'Disease', (84, 89))	('SST', 'Gene', (15, 18))	('associated', 'Reg', (23, 33))	('TAC1', 'Gene', '6863', (158, 162))
578011	25734919	SSTR1 methylation was significantly correlated with tumor size (P = 0.037), stage (P = 0.037), galanin (P = 0.030), GALR2 methylation (P = 0.014), TAC1 methylation (P = 0.023), TAC1R methylation (P = 0.003), H-cadherin methylation (P = 0.007), MGMT methylation (P = 0.001), DAPK methylation (P = 0.001) and DCC methylation (P = 0.045) (Table 1and S1 Table).	('DCC', 'Gene', '1630', (307, 310))	('tumor', 'Disease', (52, 57))	('correlated', 'Reg', (36, 46))	('SSTR1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('GALR2', 'Gene', '8811', (116, 121))	('DAPK', 'Gene', '1612', (274, 278))	('TAC1', 'Gene', (177, 181))	('TAC1', 'Gene', '6863', (147, 151))	('DCC', 'Gene', (307, 310))	('methylation', 'Var', (6, 17))	('TAC1R', 'Gene', '6869', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('MGMT', 'Gene', '4255', (244, 248))	('H-cadherin', 'Protein', (208, 218))	('TAC1R', 'Gene', (177, 182))	('GALR2', 'Gene', (116, 121))	('TAC1', 'Gene', '6863', (177, 181))	('TAC1', 'Gene', (147, 151))	('MGMT', 'Gene', (244, 248))	('DAPK', 'Gene', (274, 278))
578015	25734919	Hypermethylation of MI was significantly associated with tumor size (P = 0.022), lymph-node status (P = 0.019), stage (P = 0.004), and recurrence events (P = 0.036).	('recurrence events', 'CPA', (135, 152))	('associated', 'Reg', (41, 51))	('lymph-node', 'Disease', (81, 91))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
578018	25734919	Kaplan-Meier plots indicated that methylation of SST, SSTR1, and other genes in the patients' tumors were related to the duration of DFS.	('methylation', 'Var', (34, 45))	('DFS', 'Disease', (133, 136))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('SST', 'Gene', (49, 52))	('related', 'Reg', (106, 113))	('SSTR1', 'Gene', (54, 59))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
578019	25734919	Among patients with oral cavity and oropharynx cancer, the disease-free survival rate in the group of patients with both SST and SSTR1 methylation was 48.1% as compared with 81.4% in the other groups (log-rank test, P = 0.028) (Fig.	('methylation', 'Var', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('patients', 'Species', '9606', (102, 110))	('SSTR1', 'Gene', (129, 134))	('disease-free survival', 'CPA', (59, 80))	('cancer', 'Disease', (47, 53))	('SST', 'Gene', (121, 124))	('patients', 'Species', '9606', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
578020	25734919	The DFS of the both TAC1 and SSTR1 methylation group was significantly higher than that of the no methylation group (log-rank test, P = 0.011) (S2A Fig.).	('higher', 'PosReg', (71, 77))	('TAC1', 'Gene', '6863', (20, 24))	('TAC1', 'Gene', (20, 24))	('SSTR1', 'Gene', (29, 34))	('DFS', 'MPA', (4, 7))	('methylation', 'Var', (35, 46))
578022	25734919	The DFS of the both SSTR1 and GALR1 methylation group was significantly higher than that of the no methylation group (log-rank test, P = 0.022) (S2D Fig.).	('GALR1', 'Gene', (30, 35))	('DFS', 'MPA', (4, 7))	('GALR1', 'Gene', '2587', (30, 35))	('higher', 'PosReg', (72, 78))	('SSTR1', 'Gene', (20, 25))	('methylation', 'Var', (36, 47))
578023	25734919	Patients with SSTR1 and galanin methylation had a highest odds ratio for recurrence (OR = 12.53, 95% CI, 2.62 to 59.81; P = 0.002) (Fig.	('recurrence', 'CPA', (73, 83))	('methylation', 'Var', (32, 43))	('galanin', 'Protein', (24, 31))	('Patients', 'Species', '9606', (0, 8))	('SSTR1', 'Gene', (14, 19))
578034	25734919	reported that ectopic expression of SSTR1 in gastric cancer cell lines, which exhibit hypermethylation and express no SSTR1 mRNA, significantly suppressed cell growth in culture conditions and reduced tumor size in nude mice.	('hypermethylation', 'Var', (86, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('SSTR1', 'Gene', (118, 123))	('suppressed', 'NegReg', (144, 154))	('cell growth in culture conditions', 'CPA', (155, 188))	('SSTR1', 'Gene', (36, 41))	('nude mice', 'Species', '10090', (215, 224))	('reduced', 'NegReg', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('gastric cancer', 'Disease', (45, 59))	('tumor', 'Disease', (201, 206))	('ectopic expression', 'Var', (14, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (45, 59))
578037	25734919	Hypermethylation of TAC1 has been described in esophageal cancer, gastric cancer, colon cancer, and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (82, 94))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('TAC1', 'Gene', '6863', (20, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('colon cancer', 'Disease', 'MESH:D015179', (82, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('described', 'Reg', (34, 43))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('colon cancer', 'Disease', (82, 94))	('breast cancer', 'Disease', (100, 113))	('gastric cancer', 'Disease', (66, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TAC1', 'Gene', (20, 24))	('esophageal cancer', 'Disease', (47, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
578038	25734919	Overall patient survival is correlated with TAC1 methylation status in esophageal squamous cell carcinoma, but not in esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('TAC1', 'Gene', (44, 48))	('esophageal adenocarcinoma', 'Disease', (118, 143))	('methylation status', 'Var', (49, 67))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (118, 143))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (118, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('patient', 'Species', '9606', (8, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('TAC1', 'Gene', '6863', (44, 48))
578039	25734919	Our preliminary analysis showed that silencing of the TAC1 gene by methylation may be a critical event in tumor progression of HNSCC and that TAC1 promoter methylation was associated with reduced overall survival rates.	('TAC1', 'Gene', '6863', (142, 146))	('TAC1', 'Gene', (54, 58))	('silencing', 'NegReg', (37, 46))	('overall survival rates', 'CPA', (196, 218))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))	('TAC1', 'Gene', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TAC1', 'Gene', '6863', (54, 58))	('reduced', 'NegReg', (188, 195))	('HNSCC', 'Disease', (127, 132))	('tumor', 'Disease', (106, 111))	('methylation', 'Var', (67, 78))
578041	25734919	The methylation of the gene pair of galanin and GALR1 in the primary tumor was associated with the most significant odds ratio of recurrence, while another study concluded that GALR1 induces cell cycle arrest, and GALR2 induces both cell cycle arrest and apoptosis in HNSCC following galanin treatment.	('GALR2', 'Gene', '8811', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('arrest', 'Disease', 'MESH:D006323', (244, 250))	('HNSCC', 'Phenotype', 'HP:0012288', (268, 273))	('tumor', 'Disease', (69, 74))	('GALR1', 'Gene', (48, 53))	('induces', 'Reg', (220, 227))	('arrest', 'Disease', (202, 208))	('GALR1', 'Gene', '2587', (177, 182))	('methylation', 'Var', (4, 15))	('men', 'Species', '9606', (297, 300))	('arrest', 'Disease', (244, 250))	('GALR2', 'Gene', (214, 219))	('GALR1', 'Gene', '2587', (48, 53))	('apoptosis', 'CPA', (255, 264))	('GALR1', 'Gene', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('arrest', 'Disease', 'MESH:D006323', (202, 208))
578044	25734919	reported that methylation of p16 and H-cadherin was associated with early recurrence of stage I non-small cell lung cancer.	('p16', 'Gene', (29, 32))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('cell lung cancer', 'Disease', (106, 122))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (96, 122))	('associated', 'Reg', (52, 62))	('H-cadherin', 'Protein', (37, 47))	('cell lung cancer', 'Disease', 'MESH:D008175', (106, 122))	('p16', 'Gene', '1029', (29, 32))	('methylation', 'Var', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
578045	25734919	However, gene silencing via hypermethylation is still a relatively important idea in the development of HNSCC, and little is known about the contribution of epigenetics to disease progression in HNSCC.	('men', 'Species', '9606', (96, 99))	('hypermethylation', 'Var', (28, 44))	('HNSCC', 'Disease', (104, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('gene', 'Var', (9, 13))	('HNSCC', 'Phenotype', 'HP:0012288', (195, 200))
578050	25734919	Patients who had hypermethylation of both genes had lower survival rates than did patients without methylation of both genes; however, this was not statistically significant.	('patients', 'Species', '9606', (82, 90))	('lower', 'NegReg', (52, 57))	('Patients', 'Species', '9606', (0, 8))	('survival rates', 'CPA', (58, 72))	('hypermethylation', 'Var', (17, 33))
578051	25734919	In multivariate logistic-regression analyses, adjusted for stage, age, sex, alcohol exposure, and smoking status, methylation of both SST and SSTR1 was associated with an elevation in the odds of recurrence that was not significant.	('alcohol', 'Chemical', 'MESH:D000438', (76, 83))	('SST', 'Gene', (134, 137))	('SSTR1', 'Gene', (142, 147))	('elevation', 'PosReg', (171, 180))	('methylation', 'Var', (114, 125))
578052	25734919	When both SSTR1 and galanin were methylated in the primary tumors, the adjusted odds ratio for recurrence was higher than in tumors with other methylation patterns at these two loci.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('galanin', 'Protein', (20, 27))	('primary tumors', 'Disease', (51, 65))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('primary tumors', 'Disease', 'MESH:D009369', (51, 65))	('higher', 'PosReg', (110, 116))	('methylated', 'Var', (33, 43))	('SSTR1', 'Gene', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
578053	25734919	In another model of logistic regression with GMI, age, sex, alcohol exposure, and smoking status, SSTR1 and galanin methylation has the highest odds ratio as an independent biomarker on its own.	('methylation', 'Var', (116, 127))	('SSTR1', 'Gene', (98, 103))	('alcohol', 'Chemical', 'MESH:D000438', (60, 67))	('GMI', 'Chemical', '-', (45, 48))
578054	25734919	Our study indicates that methylation of the promoter regions of neuropeptide genes in a resected HNSCC specimen is associated with tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('men', 'Species', '9606', (108, 111))	('tumor', 'Disease', (131, 136))	('methylation', 'Var', (25, 36))	('associated with', 'Reg', (115, 130))	('neuropeptide genes', 'Gene', (64, 82))
578061	24260056	Significant loss of DUSP6 was observed in EC9706 and KYSE150 ESCC cell lines by immunoblotting assay.	('EC9706', 'CellLine', 'CVCL:E307', (42, 48))	('loss', 'NegReg', (12, 16))	('EC9706', 'Var', (42, 48))	('DUSP6', 'Gene', '1848', (20, 25))	('KYSE150', 'CellLine', 'CVCL:1348', (53, 60))	('DUSP6', 'Gene', (20, 25))
578065	24260056	The presence of cleaved PARP product, a marker of caspase-mediated apoptosis, expressed in the two pCMV-DUSP6 transfectants in marked contrast to the parental and pCMV-transfected EC9706 and KYSE150 cells, was observed by immunoblotting.	('PARP', 'Gene', '1302', (24, 28))	('DUSP6', 'Gene', '1848', (104, 109))	('DUSP6', 'Gene', (104, 109))	('PARP', 'Gene', (24, 28))	('EC9706', 'CellLine', 'CVCL:E307', (180, 186))	('KYSE150', 'CellLine', 'CVCL:1348', (191, 198))	('transfectants', 'Var', (110, 123))
578072	24260056	The downregulation of DUSP6 was caused by the hypermethylation of CpG sequences in intron 1 of the DUSP6 gene in the progression of pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('pancreatic cancer', 'Disease', (132, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('DUSP6', 'Gene', (22, 27))	('hypermethylation', 'Var', (46, 62))	('downregulation', 'NegReg', (4, 18))	('DUSP6', 'Gene', '1848', (22, 27))	('DUSP6', 'Gene', (99, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))	('DUSP6', 'Gene', '1848', (99, 104))
578078	24260056	Overexpression of DUSP6 causes estrogen receptor-positive breast cancer cells to become resistant to the growth inhibitory effects of tamoxifen.	('DUSP6', 'Gene', '1848', (18, 23))	('tamoxifen', 'Chemical', 'MESH:D013629', (134, 143))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('Overexpression', 'Var', (0, 14))	('DUSP6', 'Gene', (18, 23))
578079	24260056	Furthermore, methylation of DUSP6 is infrequent in endometrial cancer.	('DUSP6', 'Gene', (28, 33))	('DUSP6', 'Gene', '1848', (28, 33))	('methylation', 'Var', (13, 24))	('endometrial cancer', 'Disease', (51, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('endometrial cancer', 'Phenotype', 'HP:0012114', (51, 69))	('endometrial cancer', 'Disease', 'MESH:D016889', (51, 69))
578080	24260056	Therefore, silencing of DUSP6 may not be involved in the constitutive activation of the ERK kinase cascade in endometrial cancer.	('silencing', 'Var', (11, 20))	('ERK', 'Gene', '5594', (88, 91))	('endometrial cancer', 'Disease', (110, 128))	('ERK', 'Gene', (88, 91))	('endometrial cancer', 'Disease', 'MESH:D016889', (110, 128))	('endometrial cancer', 'Phenotype', 'HP:0012114', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('DUSP6', 'Gene', '1848', (24, 29))	('DUSP6', 'Gene', (24, 29))
578094	24260056	The ESCC cells, EC9706 and KYSE150, were transiently transfected with pCMV-AC or pCMV-DUSP6, using Lipofectamine  2000 according to the manufacturer's instructions (Invitrogen Life Technologies, Carlsbad, CA, USA).	('DUSP6', 'Gene', (86, 91))	('DUSP6', 'Gene', '1848', (86, 91))	('Lipofectamine  2000', 'Chemical', 'MESH:C086724', (99, 118))	('KYSE150', 'CellLine', 'CVCL:1348', (27, 34))	('pCMV-AC', 'Var', (70, 77))	('EC9706', 'CellLine', 'CVCL:E307', (16, 22))
578111	24260056	After the EC9706 and KYSE150 cells were transiently transfected with plasmid constructs, the two cell lines and their transfectants were collected by trypsinization and washed with PBS, and subsequently stained with annexin/PI.	('KYSE150', 'CellLine', 'CVCL:1348', (21, 28))	('EC9706', 'CellLine', 'CVCL:E307', (10, 16))	('PBS', 'Disease', 'MESH:D011535', (181, 184))	('PBS', 'Disease', (181, 184))	('EC9706', 'Var', (10, 16))
578128	24260056	Forced expression of DUSP6 in EC9706 significantly suppressed the p-ERK expression, indicating that increased DUSP6 expression is associated with downregulation of p-ERK in vitro in ESCC.	('EC9706', 'CellLine', 'CVCL:E307', (30, 36))	('downregulation', 'NegReg', (146, 160))	('expression', 'MPA', (116, 126))	('ERK', 'Gene', '5594', (166, 169))	('DUSP6', 'Gene', '1848', (21, 26))	('increased', 'PosReg', (100, 109))	('ERK', 'Gene', (166, 169))	('DUSP6', 'Gene', (110, 115))	('DUSP6', 'Gene', '1848', (110, 115))	('ERK', 'Gene', '5594', (68, 71))	('suppressed', 'NegReg', (51, 61))	('EC9706', 'Var', (30, 36))	('ESCC', 'Disease', (182, 186))	('ERK', 'Gene', (68, 71))	('DUSP6', 'Gene', (21, 26))
578137	24260056	The results indicated that the hypermethylation of the promoter was important in pathological suppression of DUSP6 transcription in ESCCs.	('ESCCs', 'Disease', (132, 137))	('hypermethylation', 'Var', (31, 47))	('suppression', 'NegReg', (94, 105))	('transcription', 'MPA', (115, 128))	('DUSP6', 'Gene', (109, 114))	('DUSP6', 'Gene', '1848', (109, 114))
578141	24260056	In this case, it was demonstrated that the hypermethylation of CpG islands in intron 1 may be one main mechanism leading to the silencing of DUSP6 in esophageal squamous cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('DUSP6', 'Gene', (141, 146))	('silencing', 'NegReg', (128, 137))	('esophageal squamous cancers', 'Disease', 'MESH:D004938', (150, 177))	('DUSP6', 'Gene', '1848', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('leading', 'Reg', (113, 120))	('hypermethylation', 'Var', (43, 59))	('esophageal squamous cancers', 'Disease', (150, 177))
578144	24260056	It was found that both pCMV-DUSP6 transfectants displayed a marked increased in early and total apoptosis by annexin/PI assay.	('DUSP6', 'Gene', (28, 33))	('transfectants', 'Var', (34, 47))	('increased', 'PosReg', (67, 76))	('DUSP6', 'Gene', '1848', (28, 33))
578148	24260056	The presence of cleaved PARP product, a marker of caspase-mediated apoptosis, was found to be expressed in both pCMV-DUSP6 transfectants, in marked contrast to the parental and pCMV transfected EC9706 and KYSE150 cells, further confirming the induction of apoptosis by DUSP6 expression in these cells (Fig.	('DUSP6', 'Gene', (117, 122))	('PARP', 'Gene', '1302', (24, 28))	('DUSP6', 'Gene', '1848', (117, 122))	('DUSP6', 'Gene', (269, 274))	('PARP', 'Gene', (24, 28))	('transfectants', 'Var', (123, 136))	('DUSP6', 'Gene', '1848', (269, 274))	('KYSE150', 'CellLine', 'CVCL:1348', (205, 212))	('EC9706', 'CellLine', 'CVCL:E307', (194, 200))
578156	24260056	Overall, these results implied that DUSP6 may serve as a tumor suppressor gene in ESCC, and loss of DUSP6 may be important in ESCC tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('DUSP6', 'Gene', '1848', (100, 105))	('ESCC', 'Disease', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('DUSP6', 'Gene', (36, 41))	('ESCC', 'Disease', (126, 130))	('loss', 'Var', (92, 96))	('DUSP6', 'Gene', '1848', (36, 41))	('tumor', 'Disease', (57, 62))	('DUSP6', 'Gene', (100, 105))
578170	24260056	The crucial mechanisms inactivating tumor suppressor genes are gene promoter hypermethylation, coding exon mutation and loss of heterozygosity (LOH).	('loss of heterozygosity', 'Var', (120, 142))	('inactivating', 'NegReg', (23, 35))	('coding exon mutation', 'Var', (95, 115))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
578171	24260056	Previous studies have demonstrated that DUSP6 was downregulated by hypermethylation of intron 1, LOH or ubiquitination/proteasome degradation.	('ubiquitination/proteasome degradation', 'MPA', (104, 141))	('intron', 'Protein', (87, 93))	('LOH', 'MPA', (97, 100))	('hypermethylation', 'Var', (67, 83))	('DUSP6', 'Gene', (40, 45))	('DUSP6', 'Gene', '1848', (40, 45))	('downregulated', 'NegReg', (50, 63))
578172	24260056	In ESCC, tumor suppressor genes, such as FHIT, ECRG4 and DIRAS1, are downregulated by gene promoter hypermethylation.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('gene promoter hypermethylation', 'Var', (86, 116))	('ECRG4', 'Gene', '84417', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('DIRAS1', 'Gene', '148252', (57, 63))	('downregulated', 'NegReg', (69, 82))	('DIRAS1', 'Gene', (57, 63))	('FHIT', 'Gene', (41, 45))	('tumor', 'Disease', (9, 14))	('FHIT', 'Gene', '2272', (41, 45))	('ECRG4', 'Gene', (47, 52))
578173	24260056	In the current study, our preliminary investigation of the DUSP6 downregulation focused on the epigenetic gene silencing, which is important in the initiation and progression of cancer.	('DUSP6', 'Gene', '1848', (59, 64))	('epigenetic gene silencing', 'Var', (95, 120))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('downregulation', 'NegReg', (65, 79))	('DUSP6', 'Gene', (59, 64))
578176	24260056	Consistent with our results, a previous study showed that hypermethylation was also pivotal in downregulation of DUSP6 in ESCC in Hong Kong.	('hypermethylation', 'Var', (58, 74))	('ESCC', 'Disease', (122, 126))	('downregulation', 'NegReg', (95, 109))	('DUSP6', 'Gene', '1848', (113, 118))	('DUSP6', 'Gene', (113, 118))
578181	24260056	Consistent with a previous study, our data showed that exogenous DUSP6 expression markedly increased early and total apoptosis in vitro, further supporting the fact that DUSP6 may be an important candidate tumor suppressor gene in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('DUSP6', 'Gene', '1848', (65, 70))	('ESCC', 'Disease', (231, 235))	('DUSP6', 'Gene', (170, 175))	('tumor', 'Disease', (206, 211))	('exogenous', 'Var', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('DUSP6', 'Gene', '1848', (170, 175))	('increased', 'PosReg', (91, 100))	('DUSP6', 'Gene', (65, 70))
578190	23731957	Functional polymorphisms in the genes coding for GSTs alter their enzyme activity in vitro, and were reported to modify EC risk in Asians.	('alter', 'Reg', (54, 59))	('modify', 'Reg', (113, 119))	('GSTs', 'Gene', '373156', (49, 53))	('polymorphisms', 'Var', (11, 24))	('GSTs', 'Gene', (49, 53))	('enzyme activity', 'MPA', (66, 81))
578195	23731957	Low or intermediate activity enzyme genotypes for GSTM1, GSTA1, GSTP1 I105V and A114V as well as for GSTT1, did not significantly modify the risk for ESCC or EAC in our Dutch population.	('GSTP1', 'Gene', (64, 69))	('modify', 'Reg', (130, 136))	('GSTM1', 'Gene', '2944', (50, 55))	('EAC', 'Phenotype', 'HP:0011459', (158, 161))	('A114V', 'Mutation', 'rs1138272', (80, 85))	('I105V', 'Var', (70, 75))	('GSTA1', 'Gene', (57, 62))	('ESCC', 'Disease', (150, 154))	('GSTM1', 'Gene', (50, 55))	('EAC', 'Disease', (158, 161))	('GSTP1', 'Gene', '2950', (64, 69))	('GSTA1', 'Gene', '2938', (57, 62))	('I105V', 'Mutation', 'rs1695', (70, 75))	('GSTT1', 'Gene', '2952', (101, 106))	('A114V', 'Var', (80, 85))	('GSTT1', 'Gene', (101, 106))
578215	23731957	GSTM1*a and GSTM11*b differ only at base position 519 by a G > C replacement which results in a K > N substitution at codon 173.	('GSTM1', 'Gene', '2944', (12, 17))	('GSTM11', 'Gene', (12, 18))	('K > N', 'Var', (96, 101))	('K > N substitution at codon 173', 'Mutation', 'rs1065411', (96, 127))	('GSTM1', 'Gene', (12, 17))	('GSTM1', 'Gene', '2944', (0, 5))	('GSTM11', 'Gene', '2944', (12, 18))	('GSTM1', 'Gene', (0, 5))
578218	23731957	A base pair (A > G) substitution at nucleotide 313 results in the amino-acid substitution Isoleucine (I) to Valine (V) at codon 105.	('Isoleucine', 'Var', (90, 100))	('Isoleucine', 'Chemical', 'MESH:D007532', (90, 100))	('(A > G) substitution at nucleotide 313', 'Mutation', 'rs1695', (12, 50))	('substitution', 'Var', (20, 32))	('Valine', 'Chemical', 'MESH:D014633', (108, 114))	('results in', 'Reg', (51, 61))
578219	23731957	In addition, the C > T substitution at nucleotide 341 creates a change in amino-acid transcription at codon 114: Alanine (A) to Valine (V).	('change', 'Reg', (64, 70))	('Alanine', 'MPA', (113, 120))	('C > T substitution at nucleotide 341', 'Mutation', 'rs1138272', (17, 53))	('Valine', 'Chemical', 'MESH:D014633', (128, 134))	('C > T', 'Var', (17, 22))	('amino-acid transcription at codon 114', 'MPA', (74, 111))	('Alanine', 'Chemical', 'MESH:D000409', (113, 120))
578220	23731957	The GSTP1 variant alleles express a protein with an altered enzyme activity and substrate specificity.	('GSTP1', 'Gene', (4, 9))	('altered', 'Reg', (52, 59))	('enzyme activity', 'MPA', (60, 75))	('GSTP1', 'Gene', '2950', (4, 9))	('variant', 'Var', (10, 17))
578222	23731957	The intensity of the mutant probe signal (HEX) was plotted against the wild type probe signal.	('HEX', 'Gene', (42, 45))	('mutant', 'Var', (21, 27))	('HEX', 'Gene', '3087', (42, 45))
578225	23731957	However, due to the nature of the polymorphism in GSTM1 and GSTT1, the distinction between heterozygous and homozygous functional genotypes cannot be made by our analyses.	('polymorphism', 'Var', (34, 46))	('GSTT1', 'Gene', '2952', (60, 65))	('GSTM1', 'Gene', '2944', (50, 55))	('GSTT1', 'Gene', (60, 65))	('GSTM1', 'Gene', (50, 55))
578238	23731957	For GSTM1, GSTA1, GSTP1 I105V and A114V as well as for GSTT1, the low or intermediate activity enzyme genotypes did not significantly modify the risk for ESCC or EAC in our population.	('GSTA1', 'Gene', (11, 16))	('EAC', 'Disease', (162, 165))	('GSTA1', 'Gene', '2938', (11, 16))	('I105V', 'Var', (24, 29))	('A114V', 'Var', (34, 39))	('ESCC', 'Disease', (154, 158))	('GSTP1', 'Gene', (18, 23))	('GSTM1', 'Gene', '2944', (4, 9))	('I105V', 'Mutation', 'rs1695', (24, 29))	('GSTM1', 'Gene', (4, 9))	('GSTP1', 'Gene', '2950', (18, 23))	('GSTT1', 'Gene', (55, 60))	('EAC', 'Phenotype', 'HP:0011459', (162, 165))	('A114V', 'Mutation', 'rs1138272', (34, 39))	('GSTT1', 'Gene', '2952', (55, 60))
578241	23731957	The genotypes of predicted low and intermediate GSTP1 105 & low and intermediate GSTA1 enzyme activity, and of low and intermediate GSTP1 105 & low GSTT1 were combined and set off against their corresponding predicted high activity genotypes, but the associations for ESCC risk failed to reach significance; OR 0.62; 95%CI 0.36 - 1.08 and 0.46; 0.20 - 1.07, respectively (Figure 2).	('associations', 'Disease', (251, 263))	('GSTP1', 'Gene', '2950', (132, 137))	('GSTP1', 'Gene', (48, 53))	('GSTP1', 'Gene', '2950', (48, 53))	('low', 'Var', (27, 30))	('GSTA1', 'Gene', (81, 86))	('GSTP1', 'Gene', (132, 137))	('GSTT1', 'Gene', '2952', (148, 153))	('GSTA1', 'Gene', '2938', (81, 86))	('enzyme', 'MPA', (87, 93))	('GSTT1', 'Gene', (148, 153))	('intermediate', 'Gene', (68, 80))
578242	23731957	Only GSTA1 low or intermediate genoytpe was associated with a non-significant protective effect for both tumour types, whereas the remaining GST classes showed contradictory effect sizes for EAC and ESCC.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('EAC', 'Disease', (191, 194))	('tumour', 'Disease', (105, 111))	('GSTA1', 'Gene', (5, 10))	('GSTA1', 'Gene', '2938', (5, 10))	('low', 'Var', (11, 14))	('ESCC', 'Disease', (199, 203))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('EAC', 'Phenotype', 'HP:0011459', (191, 194))
578243	23731957	that the GSTP1 Ile105Val and GSTT1*1*1 genotype increased EAC risk, ORs are 2.5; 1.0 - 6.3 and 13.3; 1.7 - 106.9, respectively.	('increased', 'PosReg', (48, 57))	('GSTT1', 'Gene', '2952', (29, 34))	('GSTP1', 'Gene', '2950', (9, 14))	('GSTT1', 'Gene', (29, 34))	('Ile105Val', 'SUBSTITUTION', 'None', (15, 24))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('Ile105Val', 'Var', (15, 24))	('GSTP1', 'Gene', (9, 14))	('EAC', 'Disease', (58, 61))
578245	23731957	So although results differ globally, our finding is in accordance with several meta-analyses, concluding that GST genotypes do not seem EC risk factors, the variant GSTP1 105 genotypes excluded.	('variant', 'Var', (157, 164))	('GSTP1', 'Gene', '2950', (165, 170))	('GSTP1', 'Gene', (165, 170))
578246	23731957	Interestingly, this meta-analysis consisted of the Caucasian studies mentioned above and found that the GSTP1 I105V polymorphism was associated with an increased risk for ESCC (1.4; 1.0 - 2.2) and not for EAC (1.2; 0.9 - 1.6).	('GSTP1', 'Gene', '2950', (104, 109))	('ESCC', 'Disease', (171, 175))	('GSTP1', 'Gene', (104, 109))	('I105V', 'Var', (110, 115))	('I105V', 'Mutation', 'rs1695', (110, 115))	('EAC', 'Phenotype', 'HP:0011459', (205, 208))
578248	23731957	So according to the literature so far, only the GSTP1 Ile105Val polymorphism seems involved in ESCC etiology.	('Ile105Val', 'SUBSTITUTION', 'None', (54, 63))	('ESCC', 'Disease', (95, 99))	('GSTP1', 'Gene', (48, 53))	('involved', 'Reg', (83, 91))	('Ile105Val', 'Var', (54, 63))	('GSTP1', 'Gene', '2950', (48, 53))
578249	23731957	Our genotype-genotype interaction analyses confirmed this premise, as combinations of low and intermediate GSTA1, or low GSTT1, with low and intermediate GSTP1 105 genotypes showed a trend for a decreased ESCC risk.	('low', 'Var', (117, 120))	('GSTA1', 'Gene', (107, 112))	('GSTP1', 'Gene', (154, 159))	('GSTA1', 'Gene', '2938', (107, 112))	('GSTP1', 'Gene', '2950', (154, 159))	('decreased ESCC', 'Phenotype', 'HP:0025022', (195, 209))	('GSTT1', 'Gene', (121, 126))	('low', 'Var', (86, 89))	('GSTT1', 'Gene', '2952', (121, 126))	('ESCC', 'Disease', (205, 209))	('decreased', 'NegReg', (195, 204))
578253	23731957	Moreover, GSTP1 is the main GST enzyme expressed in the esophagus and the genetic variants express proteins with a large reduction of enzyme activity.	('variants', 'Var', (82, 90))	('proteins', 'Protein', (99, 107))	('activity', 'MPA', (141, 149))	('GSTP1', 'Gene', (10, 15))	('GSTP1', 'Gene', '2950', (10, 15))	('reduction', 'NegReg', (121, 130))
578261	23731957	For instance, interactions with the GSTP1 variants showed a tendency to modify ESCC risk, but genotype combinations failed to reach statistical significance, which mainly may be a power issue as the especially the ESCC group is small in our Dutch Caucasian population.	('GSTP1', 'Gene', (36, 41))	('variants', 'Var', (42, 50))	('interactions', 'Interaction', (14, 26))	('GSTP1', 'Gene', '2950', (36, 41))	('ESCC', 'Disease', (79, 83))	('modify', 'Reg', (72, 78))
578264	23731957	We conducted the largest case-control study so far on GST variant genotypes and esophageal cancer risk in a Western population of Caucasian ethnicity.	('esophageal cancer', 'Disease', (80, 97))	('GST', 'Gene', (54, 57))	('variant', 'Var', (58, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
578265	23731957	Although this study did not detect significant associations between altered predicted enzyme activity GST genotypes and EAC or ESCC risk, our results indicate that gene-gene interactions between GSTP1 variants could play a role in EC susceptibility.	('interactions', 'Interaction', (174, 186))	('GSTP1', 'Gene', (195, 200))	('ESCC', 'Disease', (127, 131))	('EAC', 'Phenotype', 'HP:0011459', (120, 123))	('play', 'Reg', (216, 220))	('variants', 'Var', (201, 209))	('GSTP1', 'Gene', '2950', (195, 200))	('EAC', 'Disease', (120, 123))
578297	22690876	Transgenic ED-L2-rtTA founder lines were generated with a construct consisting of the ED-L2 promoter cloned in front of the reverse tetracycline transactivator rtTA2-M2, previously described as an improved rtTA variant ('Tet-On') with strongly reduced background activity and a 10-fold increased sensitivity for doxycycline-driven induction (Figure 1A).	('variant', 'Var', (211, 218))	('Transgenic', 'Species', '10090', (0, 10))	('increased', 'PosReg', (286, 295))	('background activity', 'MPA', (252, 271))	('ED-L2', 'Gene', (86, 91))	('tetracycline', 'Chemical', 'MESH:D013752', (132, 144))	('sensitivity for doxycycline-driven induction', 'MPA', (296, 340))	('doxycycline', 'Chemical', 'MESH:D004318', (312, 323))	('Tet', 'Chemical', 'MESH:C010349', (221, 224))	('rat', 'Species', '10116', (45, 48))
578318	22690876	In the intestine, loss of function mutations at the Apc tumor suppressor gene have been shown to trigger tumor formation exclusively from cycling stem cellsthough not from progenitor, transient amplifying cells.	('trigger', 'Reg', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('loss of function', 'NegReg', (18, 34))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('mutations', 'Var', (35, 44))
578324	22690876	Future studies should be directed to the identification of esophageal stem cell-specific genes and their promoters to allow lineage tracing and the introduction of specific gene mutations to assess their potential as cell of origin of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (235, 252))	('mutations', 'Var', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('esophageal cancer', 'Disease', (235, 252))
578329	22690876	The PCR product was then subcloned downstream of the ED-L2 promoter (ED-L2 vector kind gift from Joanna B. Wilson, Glasgow) by digesting both PCR product and vector with the restriction enzymes XhoI and MluI, and ligating both fragments.	('Wilson', 'Disease', 'MESH:D006527', (107, 113))	('digesting', 'Var', (127, 136))	('Wilson', 'Disease', (107, 113))
578339	22690876	Immunohistochemistry was performed according to standard procedures using the following antibodies: GFP (1:800, A11222, Invitrogen), CK4 (1:100, ab11215, Abcam), CK13 (1:100, ab16112, Abcam), CK14 (1:10000, PRB-155B, Covance) and Ki-67 (1:50, M7249, DAKO).	('PRB', 'Gene', '19645', (207, 210))	('CK14', 'Gene', '16664', (192, 196))	('1:10000', 'Var', (198, 205))	('CK13', 'Gene', '16663', (162, 166))	('CK13', 'Gene', (162, 166))	('CK14', 'Gene', (192, 196))	('Ki-67', 'Gene', '17345', (230, 235))	('CK4', 'Gene', '16682', (133, 136))	('1:100', 'Var', (168, 173))	('1:100', 'Var', (138, 143))	('PRB', 'Gene', (207, 210))	('Ki-67', 'Gene', (230, 235))	('CK4', 'Gene', (133, 136))
578531	30484263	TRIM28 protein was mainly distributed in the nucleus of ESCC.	('ESCC', 'Disease', (56, 60))	('TRIM28', 'Var', (0, 6))	('ESCC', 'Disease', 'MESH:C562729', (56, 60))
578543	30484263	TRIM28, also known as transcription intermediary factor 1(TIF1beta) or Kruppel associated box (KRAB)-associated protein 1(KAP1), is a universal co-repressor for a family of KRAB domain containing zinc finger proteins (KRAB-ZFPs), which constitute the single largest group of transcriptional repressors encoded by the genomes of higher organisms.	('TIF1beta', 'Gene', (58, 66))	('KAP1', 'Gene', (122, 126))	('TIF1beta', 'Gene', '10155', (58, 66))	('TRIM28', 'Var', (0, 6))	('KAP1', 'Gene', '10155', (122, 126))
578544	30484263	As one of the evolutionarily conserved TRIM family proteins, TRIM28 has been proved to accelerate cell proliferation and metastasis in a variety of human cancers.	('cell proliferation', 'CPA', (98, 116))	('metastasis', 'CPA', (121, 131))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('TRIM28', 'Var', (61, 67))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('human', 'Species', '9606', (148, 153))	('accelerate', 'PosReg', (87, 97))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
578545	30484263	Studies have shown, for example, that TRIM28 knockdown may be effective against NSCLC, and the knockdown of TRIM28 expression by lenti-siRNA/TRIM28 may inhibit tumor growth and induce cell apoptosis in vivo.	('TRIM28', 'Gene', (38, 44))	('inhibit', 'NegReg', (152, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('NSCLC', 'Disease', (80, 85))	('TRIM28', 'Gene', (108, 114))	('knockdown', 'Var', (95, 104))	('N', 'Chemical', 'MESH:D009584', (80, 81))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('induce', 'PosReg', (177, 183))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('N', 'Chemical', 'MESH:D009584', (138, 139))	('tumor', 'Disease', (160, 165))	('knockdown', 'Var', (45, 54))	('cell apoptosis', 'CPA', (184, 198))
578593	30484263	Moreover, the abnormal expression of TRIM28 was related to pTNM stage, invasive depth and lymph node metastasis (P < 0.05) (Table 2).	('invasive depth', 'CPA', (71, 85))	('lymph node metastasis', 'CPA', (90, 111))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('abnormal', 'Var', (14, 22))	('pTNM stage', 'Disease', (59, 69))	('related', 'Reg', (48, 55))	('TRIM28', 'Gene', (37, 43))	('expression', 'MPA', (23, 33))
578597	30484263	However, the results of statistical analysis showed that TRIM28 may not be a prognostic factor of patients with ESCC.	('ESCC', 'Disease', 'MESH:C562729', (112, 116))	('ESCC', 'Disease', (112, 116))	('TRIM28', 'Var', (57, 63))	('patients', 'Species', '9606', (98, 106))
578603	30484263	Our results showed that cells in ESCC can express TRIM28 while there was no expression of TRIM28 in cells of NEE (Fig.	('TRIM28', 'Var', (50, 56))	('ESCC', 'Disease', 'MESH:C562729', (33, 37))	('ESCC', 'Disease', (33, 37))	('N', 'Chemical', 'MESH:D009584', (109, 110))
578607	30484263	Analysis of the fluorescence intensity revealed that the expression of TRIM28 in ESCC was noticeably higher than that of NEE (F = 1417.061, P = 0.000; Fig.	('ESCC', 'Disease', 'MESH:C562729', (81, 85))	('expression', 'MPA', (57, 67))	('TRIM28', 'Var', (71, 77))	('higher', 'PosReg', (101, 107))	('ESCC', 'Disease', (81, 85))	('N', 'Chemical', 'MESH:D009584', (121, 122))
578610	30484263	They are considered important regulators of carcinogenesis and participate in many cellular processes, such as cell growth, development and cellular differentiation and alteration of them can affect transcriptional regulation, cell proliferation, autophagy and apoptosis.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('transcriptional regulation', 'MPA', (199, 225))	('men', 'Species', '9606', (131, 134))	('carcinogenesis', 'Disease', (44, 58))	('cell proliferation', 'CPA', (227, 245))	('apoptosis', 'CPA', (261, 270))	('affect', 'Reg', (192, 198))	('autophagy', 'CPA', (247, 256))	('alteration', 'Var', (169, 179))
578615	30484263	Their results also showed that the TRIM28-overexpressing tumors grew at a much higher rate, as determined by size and weight, than the control tumors, whereas the tumors formed by TRIM28-silenced cells were smaller and had lower tumor weights than those formed from shRNA-vector control cells.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (163, 168))	('TRIM28-overexpressing', 'Var', (35, 56))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumors', 'Disease', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Disease', (57, 62))	('TRIM28-overexpressing', 'PosReg', (35, 56))	('lower', 'NegReg', (223, 228))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (229, 234))	('tumors', 'Disease', (163, 169))	('higher rate', 'PosReg', (79, 90))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (143, 148))	('grew', 'CPA', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('N', 'Chemical', 'MESH:D009584', (269, 270))
578618	30484263	Furthermore, TRIM28 expression was significantly correlated with several clinicopathological characteristics of patients with breast cancer (BC), such as p53 mutation, tumor recurrence and Elston grade of the tumor.	('TRIM28', 'Protein', (13, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('tumor', 'Disease', (209, 214))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Disease', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('BC', 'Disease', 'MESH:D001943', (141, 143))	('correlated', 'Reg', (49, 59))	('tumor', 'Disease', (168, 173))	('BC', 'Phenotype', 'HP:0003002', (141, 143))	('p53', 'Gene', '7157', (154, 157))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('expression', 'MPA', (20, 30))	('patients', 'Species', '9606', (112, 120))	('mutation', 'Var', (158, 166))	('p53', 'Gene', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
578620	30484263	Research into the correlation between TRIM28 expression and prognosis in patients with cancer, Hao L demonstrated that high expression of TRIM28 is a predictor of poor prognosis in patients with breast cancer.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('high', 'Var', (119, 123))	('breast cancer', 'Disease', (195, 208))	('TRIM28', 'Gene', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('patients', 'Species', '9606', (181, 189))	('cancer', 'Disease', (202, 208))	('patients', 'Species', '9606', (73, 81))
578626	30484263	The above results indicate that the abnormal expression of TRIM28 may play an important role for development and metastasis in ESCC.	('play', 'Reg', (70, 74))	('TRIM28', 'Gene', (59, 65))	('men', 'Species', '9606', (104, 107))	('ESCC', 'Disease', (127, 131))	('role', 'Reg', (88, 92))	('abnormal', 'Var', (36, 44))	('expression', 'MPA', (45, 55))	('metastasis', 'CPA', (113, 123))	('development', 'CPA', (97, 108))	('ESCC', 'Disease', 'MESH:C562729', (127, 131))
578777	28848771	Prior studies have suggested that both etoposide and cisplatin can exacerbate radiation effects on the esophagus.	('cisplatin', 'Var', (53, 62))	('radiation effects', 'CPA', (78, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('exacerbate', 'PosReg', (67, 77))	('etoposide', 'Chemical', 'MESH:D005047', (39, 48))
578788	28388588	More and more evidence has shown that non-coding RNAs play an important role in the development and progression of multiple human cancers, including esophageal cancer.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('human', 'Species', '9606', (124, 129))	('esophageal cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('non-coding RNAs', 'Var', (38, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))
578802	28388588	Other miRNAs like miR-138, miR-375, miR-593, miR-133a were down-regulated in esophageal cancer tissue, serving as tumor suppressors, while miR-34b, miR-16, miR-208, miR-423, miR-21, miR-31, miR-223 and miR-373 could have oncogenic actions (Figure 1).	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('miR-21', 'Gene', (174, 180))	('miR-208', 'Gene', (156, 163))	('miR-423', 'Gene', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('miR-138', 'Var', (18, 25))	('miR-31', 'Gene', (182, 188))	('tumor', 'Disease', (114, 119))	('miR-16', 'Gene', (148, 154))	('miR-223', 'Gene', (190, 197))	('oncogenic actions', 'CPA', (221, 238))	('miR-593', 'Gene', '693178', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('miR-34b', 'Gene', '407041', (139, 146))	('miR-31', 'Gene', '407035', (182, 188))	('miR-21', 'Gene', '406991', (174, 180))	('miR-375', 'Gene', '494324', (27, 34))	('miR-373', 'Gene', (202, 209))	('miR-16', 'Gene', '51573', (148, 154))	('miR-375', 'Gene', (27, 34))	('miR-423', 'Gene', '494335', (165, 172))	('miR-34b', 'Gene', (139, 146))	('miR-223', 'Gene', '407008', (190, 197))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('miR-593', 'Gene', (36, 43))	('down-regulated', 'NegReg', (59, 73))	('miR-208', 'Gene', '406990', (156, 163))	('miR-373', 'Gene', '442918', (202, 209))	('miR-133a', 'Var', (45, 53))
578804	28388588	In order to better clarify the expression profiling of non-coding RNAs in esophageal cancer, the database on such patients and tissue collection should be expanded.	('non-coding RNAs', 'Var', (55, 70))	('esophageal cancer', 'Disease', (74, 91))	('patients', 'Species', '9606', (114, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
578805	28388588	The molecular contributions of non-coding RNAs in the carcinogenesis of esophageal cancer have been widely determined (Table 1).	('carcinogenesis of esophageal cancer', 'Disease', 'MESH:D063646', (54, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('non-coding RNAs', 'Var', (31, 46))	('carcinogenesis of esophageal cancer', 'Disease', (54, 89))
578806	28388588	These miRNAs variants may function in a different manner, which lead to the development of esophageal cancer.	('variants', 'Var', (13, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lead to', 'Reg', (64, 71))	('esophageal cancer', 'Disease', (91, 108))
578814	28388588	miR-101, miR-217 and MALAT1 siRNA have common downstream genes like MIA2, HNF4G, ROBO1, CCT4 and CTHRC1, and miR-101 or miR-217 and MALAT1 were negatively correlated in 42 pairs of esophageal cancer tissue samples and adjacent normal tissues.	('esophageal cancer', 'Disease', (181, 198))	('ROBO1', 'Gene', (81, 86))	('MIA2', 'Gene', (68, 72))	('CCT4', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('miR-217', 'Gene', '406999', (9, 16))	('miR-217', 'Gene', '406999', (120, 127))	('negatively', 'NegReg', (144, 154))	('HNF4G', 'Gene', (74, 79))	('MALAT1', 'Gene', (21, 27))	('miR-101', 'Gene', (0, 7))	('miR-217', 'Gene', (9, 16))	('CTHRC1', 'Gene', (97, 103))	('MIA2', 'CellLine', 'CVCL:0428', (68, 72))	('MALAT1', 'Gene', (132, 138))	('miR-217', 'Gene', (120, 127))	('MALAT1', 'Gene', '378938', (21, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('MALAT1', 'Gene', '378938', (132, 138))	('miR-101', 'Var', (109, 116))
578816	28388588	lncRNA PEG10 silencing could decrease cell proliferation and migration, induce cell apoptosis in two esophageal cancer EC9706 and KYSE150 cells.	('cell proliferation', 'CPA', (38, 56))	('PEG10', 'Gene', '23089', (7, 12))	('EC9706', 'CellLine', 'CVCL:E307', (119, 125))	('PEG10', 'Gene', (7, 12))	('induce', 'Reg', (72, 78))	('esophageal cancer', 'Disease', (101, 118))	('cell apoptosis', 'CPA', (79, 93))	('KYSE150', 'CellLine', 'CVCL:1348', (130, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('decrease', 'NegReg', (29, 37))	('silencing', 'Var', (13, 22))
578820	28388588	STAT3 can directly increase miR-181b transcription, which targets CYLD gene and miR-181b can enhance the p-STAT3 activity.	('miR-181b', 'Gene', (28, 36))	('STAT3', 'Gene', (107, 112))	('transcription', 'MPA', (37, 50))	('increase', 'PosReg', (19, 27))	('enhance', 'PosReg', (93, 100))	('STAT3', 'Gene', '6774', (0, 5))	('CYLD', 'Gene', (66, 70))	('CYLD', 'Gene', '1540', (66, 70))	('STAT3', 'Gene', (0, 5))	('STAT3', 'Gene', '6774', (107, 112))	('miR-181b', 'Var', (80, 88))
578824	28388588	MALAT1 silencing could inhibit proliferation-enhanced apoptosis, cell migration/invasion, and reduce colony formation and induce G2/M arrest.	('colony formation', 'CPA', (101, 117))	('induce', 'PosReg', (122, 128))	('MALAT1', 'Gene', '378938', (0, 6))	('proliferation-enhanced apoptosis', 'CPA', (31, 63))	('inhibit', 'NegReg', (23, 30))	('MALAT1', 'Gene', (0, 6))	('cell migration/invasion', 'CPA', (65, 88))	('G2/M arrest', 'CPA', (129, 140))	('reduce', 'NegReg', (94, 100))	('silencing', 'Var', (7, 16))
578827	28388588	CASC9 knockdown could significantly suppress cell migration and invasion, and increased CASC9 expression was associated with cell differentiation in vitro, indicating that CASC9 may be identified as a new promising biomarker for poor prognosis and a potential therapeutic target for treating esophageal cancer.	('esophageal cancer', 'Disease', (292, 309))	('CASC9', 'Gene', (172, 177))	('CASC9', 'Gene', '101805492', (172, 177))	('suppress', 'NegReg', (36, 44))	('cell differentiation', 'CPA', (125, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (292, 309))	('CASC9', 'Gene', (88, 93))	('CASC9', 'Gene', '101805492', (88, 93))	('increased', 'PosReg', (78, 87))	('CASC9', 'Gene', '101805492', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('expression', 'MPA', (94, 104))	('knockdown', 'Var', (6, 15))	('CASC9', 'Gene', (0, 5))
578828	28388588	lncRNA LOC100130476 up-regulation could suppress cell proliferation and invasion, and hypermethylation of CpG sites in exon 1 could down-regulate LOC100130476 expression in esophageal cancer, which could predict the clinical TNM stage and pathological differentiation.	('LOC100130476', 'Gene', '100130476', (146, 158))	('TNM', 'Gene', (225, 228))	('hypermethylation', 'Var', (86, 102))	('esophageal cancer', 'Disease', 'MESH:D004938', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('suppress', 'NegReg', (40, 48))	('predict', 'Reg', (204, 211))	('cell proliferation', 'CPA', (49, 67))	('expression', 'MPA', (159, 169))	('LOC100130476', 'Gene', (7, 19))	('esophageal cancer', 'Disease', (173, 190))	('TNM', 'Gene', '10178', (225, 228))	('LOC100130476', 'Gene', (146, 158))	('LOC100130476', 'Gene', '100130476', (7, 19))	('invasion', 'CPA', (72, 80))	('down-regulate', 'NegReg', (132, 145))	('up-regulation', 'PosReg', (20, 33))
578830	28388588	H19 overexpression could promote cell proliferation and invasion and induce epithelial-to-mesenchymal transition, whereas H19 knockdown could inhibit cell proliferation and invasion and reverse epithelial-to-mesenchymal transition in vitro.	('H19', 'Gene', (122, 125))	('H19', 'Gene', (0, 3))	('invasion', 'CPA', (173, 181))	('inhibit', 'NegReg', (142, 149))	('cell proliferation', 'CPA', (150, 168))	('epithelial-to-mesenchymal transition', 'CPA', (76, 112))	('reverse', 'NegReg', (186, 193))	('promote', 'PosReg', (25, 32))	('epithelial-to-mesenchymal transition', 'CPA', (194, 230))	('induce', 'PosReg', (69, 75))	('overexpression', 'PosReg', (4, 18))	('cell proliferation', 'CPA', (33, 51))	('knockdown', 'Var', (126, 135))	('H19', 'Gene', '283120', (122, 125))	('H19', 'Gene', '283120', (0, 3))	('invasion', 'CPA', (56, 64))
578837	28388588	BDH2 modulation could partially rescue the effect of lncRNA TP73-AS1 on cell proliferation and apoptosis.	('apoptosis', 'CPA', (95, 104))	('cell proliferation', 'CPA', (72, 90))	('TP73', 'Gene', '7161', (60, 64))	('BDH2', 'Gene', '56898', (0, 4))	('TP73', 'Gene', (60, 64))	('BDH2', 'Gene', (0, 4))	('AS1', 'Gene', '5729', (65, 68))	('AS1', 'Gene', (65, 68))	('modulation', 'Var', (5, 15))
578838	28388588	lncRNA AFAP1-AS1 was hypomethylated and overexpressed in Barrett's esophagus and esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	("Barrett's esophagus", 'Disease', (57, 76))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (57, 76))	('AS1', 'Gene', '5729', (13, 16))	('AS1', 'Gene', (13, 16))	('AFAP1', 'Gene', '60312', (7, 12))	('hypomethylated', 'Var', (21, 35))	('AFAP1', 'Gene', (7, 12))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('overexpressed', 'PosReg', (40, 53))	('esophageal cancer', 'Disease', (81, 98))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (57, 76))
578839	28388588	AFAP1-AS1 silencing by siRNA could inhibit cell proliferation, migration and invasion, suppress colony-forming ability and induce cell apoptosis, but the protein-coding counterpart AFAP1 was not affected.	('suppress', 'NegReg', (87, 95))	('induce', 'Reg', (123, 129))	('inhibit', 'NegReg', (35, 42))	('cell apoptosis', 'CPA', (130, 144))	('colony-forming ability', 'CPA', (96, 118))	('AFAP1', 'Gene', (181, 186))	('AFAP1', 'Gene', (0, 5))	('AFAP1', 'Gene', '60312', (181, 186))	('AFAP1', 'Gene', '60312', (0, 5))	('AS1', 'Gene', '5729', (6, 9))	('AS1', 'Gene', (6, 9))	('cell proliferation', 'CPA', (43, 61))	('silencing', 'Var', (10, 19))
578840	28388588	Based on miRNAs profiling data, miR-20b, miR-498 and miR-196 were predicted to be involved in cell apoptosis and autophagy, which are shown to be key regulators of multiple cellular signaling pathways in esophageal cancer.	('miR-20b', 'Gene', '574032', (32, 39))	('miR-498', 'Gene', (41, 48))	('involved', 'Reg', (82, 90))	('miR-20b', 'Gene', (32, 39))	('esophageal cancer', 'Disease', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('autophagy', 'CPA', (113, 122))	('miR-196', 'Var', (53, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (204, 221))	('miR-498', 'Gene', '574460', (41, 48))	('cell apoptosis', 'CPA', (94, 108))
578845	28388588	BDH2 or lncRNA TP73-AS1 knockdown enhanced the chemosensitivity of esophageal cancer cells to and cisplatin.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('enhanced', 'PosReg', (34, 42))	('AS1', 'Gene', '5729', (20, 23))	('TP73', 'Gene', '7161', (15, 19))	('TP73', 'Gene', (15, 19))	('esophageal cancer', 'Disease', (67, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('BDH2', 'Gene', '56898', (0, 4))	('BDH2', 'Gene', (0, 4))	('AS1', 'Gene', (20, 23))	('chemosensitivity', 'CPA', (47, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('knockdown', 'Var', (24, 33))
578847	28388588	LOC285194 expression was significantly down-regulated in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('LOC285194', 'Var', (0, 9))	('expression', 'MPA', (10, 20))	('esophageal cancer', 'Disease', (57, 74))	('down-regulated', 'NegReg', (39, 53))
578849	28388588	Univariate and multivariate analysis demonstrated that LOC285194 down-regulation could predict poor chemotherapy response and survival status, evidenced by the fact that patients with low LOC285194 level had a decreased disease free survival and overall survival.	('patients', 'Species', '9606', (170, 178))	('overall survival', 'CPA', (246, 262))	('LOC285194 level', 'Var', (188, 203))	('decreased disease', 'Disease', 'MESH:D012021', (210, 227))	('LOC285194', 'Gene', (55, 64))	('chemotherapy response', 'CPA', (100, 121))	('down-regulation', 'NegReg', (65, 80))	('decreased disease', 'Disease', (210, 227))
578852	28388588	A microarray analysis has ever identified miR-574-3p, miR-106b, miR-1303, miR-1203, miR-1909, miR-204, miR-371-3p and miR-886-3p, which were differentially expressed between the patients with and without tumor relapse after surgery.	('miR-106b', 'Gene', '406900', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('miR-886-3p', 'Var', (118, 128))	('miR-1203', 'Gene', '100302211', (74, 82))	('miR-371-3p', 'Gene', '100500855', (103, 113))	('miR-204', 'Gene', (94, 101))	('miR-1909', 'Gene', (84, 92))	('miR-106b', 'Gene', (54, 62))	('miR-371-3p', 'Gene', (103, 113))	('miR-1909', 'Gene', '100302210', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('patients', 'Species', '9606', (178, 186))	('miR-1303', 'Gene', (64, 72))	('miR-204', 'Gene', '406987', (94, 101))	('miR-1303', 'Gene', '100302284', (64, 72))	('miR-574-3p', 'Gene', '693159', (42, 52))	('tumor', 'Disease', (204, 209))	('miR-1203', 'Gene', (74, 82))	('miR-574-3p', 'Gene', (42, 52))
578858	28388588	Survival analysis revealed that high lncRNA AFAP1-AS1 level was significantly associated with shorter progression free survival and overall survival and multivariate analysis showed that high AFAP1-AS1 level was found to be an independent risk factor for poor clinical response.	('high', 'Var', (32, 36))	('progression free survival', 'CPA', (102, 127))	('overall survival', 'CPA', (132, 148))	('AFAP1', 'Gene', '60312', (44, 49))	('AS1', 'Gene', '5729', (50, 53))	('AFAP1', 'Gene', (44, 49))	('shorter', 'NegReg', (94, 101))	('AS1', 'Gene', (50, 53))	('AS1', 'Gene', (198, 201))	('lncRNA', 'MPA', (37, 43))	('AS1', 'Gene', '5729', (198, 201))	('AFAP1', 'Gene', '60312', (192, 197))	('AFAP1', 'Gene', (192, 197))
578859	28388588	Hypermethylation of CpG sites in the exon 1 and low expression of LOC100130476 could predict poor survival.	('Hypermethylation', 'Var', (0, 16))	('expression', 'MPA', (52, 62))	('LOC100130476', 'Gene', '100130476', (66, 78))	('poor survival', 'CPA', (93, 106))	('low', 'NegReg', (48, 51))	('LOC100130476', 'Gene', (66, 78))
578862	28388588	Survival analyses revealed that high CCAT2 expression and MYC amplification were significantly associated with poorer overall survival in such patients.	('overall survival', 'MPA', (118, 134))	('MYC amplification', 'Var', (58, 75))	('expression', 'MPA', (43, 53))	('patients', 'Species', '9606', (143, 151))	('poorer', 'NegReg', (111, 117))	('CCAT2', 'Gene', '101805488', (37, 42))	('CCAT2', 'Gene', (37, 42))
578863	28388588	Patients with high CCAT2 expression and MYC amplification had an increased risk of cancer-related death, supporting that CCAT2 is a predictive biomarker and therapeutic target for esophageal cancer.	('death', 'Disease', 'MESH:D003643', (98, 103))	('MYC amplification', 'Var', (40, 57))	('death', 'Disease', (98, 103))	('cancer', 'Disease', (191, 197))	('CCAT2', 'Gene', '101805488', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('expression', 'MPA', (25, 35))	('esophageal cancer', 'Disease', (180, 197))	('CCAT2', 'Gene', '101805488', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CCAT2', 'Gene', (121, 126))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('esophageal cancer', 'Disease', 'MESH:D004938', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('CCAT2', 'Gene', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
578864	28388588	lncRNA PCAT-1 was significantly higher in human esophageal cancer, and high PCAT-1 expression was significantly correlated with advanced clinical stage, lymph node metastasis, and poor prognosis, which is a potential prognostic factor for esophageal cancer.	('esophageal cancer', 'Disease', (48, 65))	('PCAT-1', 'Gene', (7, 13))	('poor prognosis', 'CPA', (180, 194))	('lymph node metastasis', 'CPA', (153, 174))	('high', 'Var', (71, 75))	('higher', 'PosReg', (32, 38))	('PCAT-1', 'Gene', (76, 82))	('human', 'Species', '9606', (42, 47))	('correlated', 'Reg', (112, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('PCAT-1', 'Gene', '100750225', (7, 13))	('esophageal cancer', 'Disease', (239, 256))	('PCAT-1', 'Gene', '100750225', (76, 82))	('expression', 'MPA', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))
578876	28388588	In vitro experiments showed that either FOXCUT or FOXC1 silencing could greatly inhibit cell proliferation, colony formation, migration and invasion in esophageal cancer cells.	('FOXCUT', 'Gene', '101927703', (40, 46))	('silencing', 'Var', (56, 65))	('FOXC1', 'Gene', '2296', (50, 55))	('inhibit', 'NegReg', (80, 87))	('esophageal cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('invasion', 'CPA', (140, 148))	('FOXC1', 'Gene', (50, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('cell proliferation', 'CPA', (88, 106))	('FOXCUT', 'Gene', (40, 46))	('migration', 'CPA', (126, 135))	('colony formation', 'CPA', (108, 124))
578878	28388588	Besides, a recent study identified a three lncRNA signature (including ENST00000435885.1, XLOC_013014 and ENST00000547963.1), which was proved to be able to independently predict the outcome of the patients.	('patients', 'Species', '9606', (198, 206))	('ENST00000435885.1', 'Var', (71, 88))	('XLOC_013014', 'Var', (90, 101))	('ENST00000547963.1', 'Var', (106, 123))	('predict', 'Reg', (171, 178))
578880	28388588	The miR-124/CDK4 axis was an important mechanism in regulating the radiation sensitivity of human esophageal cancer cells, and targeting CDK4 may improve the clinical efficacy of radiotherapy.	('CDK4', 'Gene', (12, 16))	('radiation sensitivity', 'CPA', (67, 88))	('targeting', 'Var', (127, 136))	('CDK4', 'Gene', '1019', (137, 141))	('CDK4', 'Gene', (137, 141))	('CDK4', 'Gene', '1019', (12, 16))	('clinical efficacy', 'CPA', (158, 175))	('esophageal cancer', 'Disease', (98, 115))	('improve', 'PosReg', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('human', 'Species', '9606', (92, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
578887	28388588	HNF1A-AS1 silencing significantly inhibited cell proliferation and anchorage-independent growth, S-phase entry, cell migration and invasion in vitro by preferentially modulating genes that are linked to assembly of chromatin and the nucleosome, which is a key mechanism essential to cell cycle progression.	('invasion', 'CPA', (131, 139))	('HNF1A-AS1', 'Gene', '283460', (0, 9))	('cell proliferation', 'CPA', (44, 62))	('preferentially', 'PosReg', (152, 166))	('inhibited', 'NegReg', (34, 43))	('genes', 'Gene', (178, 183))	('silencing', 'Var', (10, 19))	('HNF1A-AS1', 'Gene', (0, 9))	('cell migration', 'CPA', (112, 126))	('S-phase entry', 'CPA', (97, 110))	('anchorage-independent growth', 'CPA', (67, 95))	('modulating', 'Reg', (167, 177))
578888	28388588	lncRNA HNF1A-AS1 silencing could also inhibit lncRNA H19 expression.	('HNF1A-AS1', 'Gene', (7, 16))	('HNF1A-AS1', 'Gene', '283460', (7, 16))	('inhibit', 'NegReg', (38, 45))	('H19', 'Gene', '283120', (53, 56))	('silencing', 'Var', (17, 26))	('H19', 'Gene', (53, 56))
578892	28388588	However, the current findings mainly focus on the basic research on the functions of non-coding RNAs in esophageal cancer.	('RNAs', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('non-coding', 'Var', (85, 95))
578906	24829692	In 2012, new cases of esophagus, stomach, and colorectal cancers in the world were estimated about 481645, 988602 and 1235108 respectively.	('1235108', 'Var', (118, 125))	('988602', 'Var', (107, 113))	('colorectal cancers', 'Disease', (46, 64))	('colorectal cancers', 'Disease', 'MESH:D015179', (46, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('stomach', 'Disease', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('esophagus', 'Disease', (22, 31))	('rectal cancer', 'Phenotype', 'HP:0100743', (50, 63))
578942	19904251	By inhibiting acid secretion and increasing intragastric pH, PPIs at therapeutic doses can cause a physiological secondary hypergastrinemia in some patients.	('patients', 'Species', '9606', (148, 156))	('secondary hypergastrinemia', 'Disease', 'MESH:D060085', (113, 139))	('cause', 'Reg', (91, 96))	('acid secretion', 'MPA', (14, 28))	('inhibiting', 'NegReg', (3, 13))	('intragastric pH', 'MPA', (44, 59))	('PPIs', 'Var', (61, 65))	('secondary hypergastrinemia', 'Disease', (113, 139))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (123, 139))	('increasing', 'PosReg', (33, 43))
578948	19904251	Most PPIs are metabolized in the liver by the cytochrome p450 2C19 enzyme, and polymorphisms in this gene may be partly responsible for the observed variations in serum gastrin levels among patients taking PPIs.	('gastrin', 'Gene', (169, 176))	('patients', 'Species', '9606', (190, 198))	('polymorphisms', 'Var', (79, 92))	('gastrin', 'Gene', '2520', (169, 176))	('cytochrome p450 2C19 enzyme', 'Enzyme', (46, 73))
579007	19904251	In contrast, studies have failed to find an increased risk of colorectal cancer associated with PPI use, including two nested case-control studies from the United Kingdom and Denmark.	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('PPI', 'Var', (96, 99))	('colorectal cancer', 'Disease', (62, 79))
579009	19904251	on the risk of EAC in GERD patients, treatment with a PPI was associated with an increased risk for developing EAC even after adjusting for severity of symptoms (OR: 2.9).	('EAC', 'Phenotype', 'HP:0011459', (15, 18))	('PPI', 'Var', (54, 57))	('EAC', 'Disease', (111, 114))	('EAC', 'Disease', (15, 18))	('patients', 'Species', '9606', (27, 35))	('EAC', 'Phenotype', 'HP:0011459', (111, 114))
579010	19904251	In contrast, several more recent epidemiological studies suggest that PPI use in patients with BE may be associated with lower rates of neoplastic progression.	('patients', 'Species', '9606', (81, 89))	('BE', 'Phenotype', 'HP:0100580', (95, 97))	('lower', 'NegReg', (121, 126))	('neoplastic progression', 'CPA', (136, 158))	('rat', 'Species', '10116', (127, 130))	('PPI', 'Var', (70, 73))
579011	19904251	of veterans with BE, PPI use (compared with histamine-2 antagonists and no acid suppression) was associated with a lower risk of progression to dysplasia (HR: 0.25, 95% CI: 0.13-0.47).	('dysplasia', 'Disease', 'MESH:D004476', (144, 153))	('lower', 'NegReg', (115, 120))	('PPI', 'Var', (21, 24))	('BE', 'Phenotype', 'HP:0100580', (17, 19))	('dysplasia', 'Disease', (144, 153))
579015	19904251	Thus, future studies investigating the effects of PPI-induced hypergastrinemia will likely need to focus on this subset of patients with significantly elevated gastrin levels.	('gastrin', 'Gene', (67, 74))	('hypergastrinemia', 'Disease', 'None', (62, 78))	('gastrin', 'Gene', (160, 167))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (62, 78))	('elevated gastrin', 'Phenotype', 'HP:0500167', (151, 167))	('patients', 'Species', '9606', (123, 131))	('gastrin', 'Gene', '2520', (67, 74))	('elevated', 'PosReg', (151, 159))	('gastrin', 'Gene', '2520', (160, 167))	('hypergastrinemia', 'Disease', (62, 78))	('PPI-induced', 'Var', (50, 61))
579022	19904251	showed that BE tissue had a 2 orders of magnitude higher expression of CCK2R than did normal esophageal squamous mucosa, and [(125)I]-G17 bound to epithelia within glandular regions of Barrett's mucosa.	('expression', 'MPA', (57, 67))	('CCK2R', 'Gene', (71, 76))	('higher', 'PosReg', (50, 56))	('CCK2R', 'Gene', '887', (71, 76))	('bound', 'Interaction', (138, 143))	('BE', 'Phenotype', 'HP:0100580', (12, 14))	('[(125)I]-G17', 'Var', (125, 137))
579030	19904251	Inhibition of COX-2 in vitro and in vivo decreases the expression of markers of cellular proliferation and induces apoptosis in both BE and EAC, and also results in decreased development of EAC in a rat model.	('cellular proliferation', 'CPA', (80, 102))	('decreased', 'NegReg', (165, 174))	('COX-2', 'Gene', '5743', (14, 19))	('EAC', 'Phenotype', 'HP:0011459', (190, 193))	('decreased development', 'Phenotype', 'HP:0001263', (165, 186))	('decreases', 'NegReg', (41, 50))	('EAC', 'Phenotype', 'HP:0011459', (140, 143))	('development', 'CPA', (175, 186))	('rat', 'Species', '10116', (96, 99))	('BE', 'Phenotype', 'HP:0100580', (133, 135))	('EAC', 'CPA', (190, 193))	('Inhibition', 'Var', (0, 10))	('induces', 'Reg', (107, 114))	('apoptosis', 'CPA', (115, 124))	('expression of', 'MPA', (55, 68))	('rat', 'Species', '10116', (199, 202))	('COX-2', 'Gene', (14, 19))
579047	19904251	Given the widespread use of PPIs for acid suppression in BE patients, it will also be important to determine whether there may be a subset of BE patients with PPI-induced secondary hypergastrinemia who may actually be at increased risk for neoplastic progression.	('patients', 'Species', '9606', (145, 153))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (181, 197))	('secondary hypergastrinemia', 'Disease', 'MESH:D060085', (171, 197))	('BE', 'Phenotype', 'HP:0100580', (142, 144))	('patients', 'Species', '9606', (60, 68))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('secondary hypergastrinemia', 'Disease', (171, 197))	('PPI-induced', 'Var', (159, 170))
579050	19904251	High serum gastrin is associated with a history of advanced neoplasia in Barrett's esophagus.	('neoplasia', 'Disease', 'MESH:D009369', (60, 69))	('High', 'Var', (0, 4))	('gastrin', 'Gene', '2520', (11, 18))	('neoplasia', 'Disease', (60, 69))	('gastrin', 'Gene', (11, 18))	('associated', 'Reg', (22, 32))	('neoplasia', 'Phenotype', 'HP:0002664', (60, 69))	('High serum gastrin', 'Phenotype', 'HP:0500167', (0, 18))	("Barrett's esophagus", 'Disease', (73, 92))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (73, 92))
579060	19456322	Many genes have allele frequency variation that has been associated with risk of developing either alcoholism or complications of alcoholism.	('alcoholism', 'Disease', 'MESH:D000437', (99, 109))	('alcoholism', 'Disease', 'MESH:D000437', (130, 140))	('alcoholism', 'Phenotype', 'HP:0030955', (130, 140))	('alcoholism', 'Phenotype', 'HP:0030955', (99, 109))	('allele frequency variation', 'Var', (16, 42))	('alcoholism', 'Disease', (99, 109))	('alcoholism', 'Disease', (130, 140))	('associated', 'Reg', (57, 67))
579064	19456322	The variants at ADH genes and at ALDH2 that are associated with alcoholism appear to interact by increasing the transient levels of the toxic acetaldehyde.	('ADH', 'Gene', (16, 19))	('ADH', 'Gene', '10327', (16, 19))	('alcoholism', 'Disease', 'MESH:D000437', (64, 74))	('ALDH2', 'Gene', (33, 38))	('variants', 'Var', (4, 12))	('associated', 'Reg', (48, 58))	('alcoholism', 'Phenotype', 'HP:0030955', (64, 74))	('acetaldehyde', 'Chemical', 'MESH:D000079', (142, 154))	('ALDH2', 'Gene', '217', (33, 38))	('transient levels of the toxic acetaldehyde', 'MPA', (112, 154))	('alcoholism', 'Disease', (64, 74))	('increasing', 'PosReg', (97, 107))
579069	19456322	The difference was identified as a substitution of the Glutamic acid at codon position 504 with Lysine (hence the reference to the variant allele as ALDH2*504Lys,).	('ALDH2', 'Gene', (149, 154))	('Glutamic acid', 'Chemical', 'MESH:D018698', (55, 68))	('substitution', 'Var', (35, 47))	('ALDH2', 'Gene', '217', (149, 154))	('Lysine', 'Chemical', 'MESH:D008239', (96, 102))	('Lysine', 'MPA', (96, 102))
579070	19456322	As this atypical form of the enzyme was seen only in East Asians, it was also referred to as the oriental variant, the variant allele acts as a dominant negative with the heterozygote having greatly reduced enzyme activity and the homozygote having no activity; in both cases acetaldehyde accumulates as ethanol is converted to acetaldehyde.	('accumulates', 'PosReg', (289, 300))	('acetaldehyde', 'Chemical', 'MESH:D000079', (276, 288))	('acetaldehyde', 'Chemical', 'MESH:D000079', (328, 340))	('acetaldehyde', 'MPA', (276, 288))	('variant', 'Var', (119, 126))	('activity', 'MPA', (214, 222))	('ethanol', 'Chemical', 'MESH:D000431', (304, 311))	('ethanol', 'MPA', (304, 311))	('reduced', 'NegReg', (199, 206))
579077	19456322	showed that the Glu504Lys polymorphism was associated with efficacy of sublingual nitroglycerin and recently showed that ALDH2 activity is critical for protection from ischemia.	('Glu504Lys', 'Var', (16, 25))	('Glu504Lys', 'SUBSTITUTION', 'None', (16, 25))	('efficacy of sublingual nitroglycerin', 'MPA', (59, 95))	('ALDH2', 'Gene', '217', (121, 126))	('nitroglycerin', 'Chemical', 'MESH:D005996', (82, 95))	('ischemia', 'Disease', (168, 176))	('associated', 'Reg', (43, 53))	('ALDH2', 'Gene', (121, 126))	('ischemia', 'Disease', 'MESH:D007511', (168, 176))
579079	19456322	The 504Lys variant is believed to increase the risk of many disorders, including many cancers.	('The 504Lys', 'Mutation', 'rs671', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('504Lys', 'Var', (4, 10))	('disorders', 'Disease', (60, 69))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('increase', 'PosReg', (34, 42))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancers', 'Disease', (86, 93))
579084	19456322	The hypothesis is supported by associations of variants at two different ADH genes (Hashibi et al., 2008).	('ADH', 'Gene', (73, 76))	('ADH', 'Gene', '10327', (73, 76))	('associations', 'Interaction', (31, 43))	('variants', 'Var', (47, 55))
579126	19456322	As noted above, ALDH2 also has other metabolic functions that could be independently influencing the distribution of ALDH2 variants.	('ALDH2', 'Gene', (16, 21))	('ALDH2', 'Gene', '217', (117, 122))	('ALDH2', 'Gene', '217', (16, 21))	('ALDH2', 'Gene', (117, 122))	('influencing', 'Reg', (85, 96))	('variants', 'Var', (123, 131))
579194	33631646	A 69-year-old female diagnosed with c-T3N0M0 stage II squamous cell carcinoma (SCC) in the lower thoracic esophagus underwent thoracoscopic subtotal esophagectomy with 2-field lymph node dissection after neoadjuvant chemotherapy.	('c-T3N0M0', 'Var', (36, 44))	('SCC', 'Gene', (79, 82))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 77))	('squamous cell carcinoma', 'Disease', (54, 77))
579195	33631646	The pathological diagnosis was advanced esophageal cancer after induction therapy: cT grade 1a, LtAe, 25 x 25 mm, Type 2, SCC, moderately differentiated, ypT3, INFb, ly0, v3, pIM0, pPM0, pDM, ypN0, cM0, ypStage II.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('pDM', 'Var', (187, 190))	('pIM0', 'Var', (175, 179))	('SCC', 'Gene', '6317', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('ly0', 'Var', (166, 169))	('ypT3', 'Var', (154, 158))	('ypN0', 'Var', (192, 196))	('pPM0', 'Var', (181, 185))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
579232	32947897	Several studies have demonstrated the association of non-coding RNAs in regulating various cancer hallmarks, including the radioresistance processes in cells.	('cancer hallmarks', 'Disease', 'MESH:D009369', (91, 107))	('association', 'Interaction', (38, 49))	('non-coding RNAs', 'Var', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer hallmarks', 'Disease', (91, 107))	('radioresistance processes in', 'CPA', (123, 151))
579234	32947897	Furthermore, recent studies have reported the association of long non-coding RNAs (lncRNAs) with altered patients' responses towards radiation therapy due to their active involvement in DNA damage response (DDR), apoptosis, and cell cycle arrest.	('responses towards', 'MPA', (115, 132))	('DNA', 'MPA', (186, 189))	('patients', 'Species', '9606', (105, 113))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (228, 245))	('long non-coding RNAs', 'Var', (61, 81))	('involvement', 'Reg', (171, 182))	('association', 'Interaction', (46, 57))	('apoptosis', 'CPA', (213, 222))	('arrest', 'Disease', 'MESH:D006323', (239, 245))	('arrest', 'Disease', (239, 245))
579239	32947897	Furthermore, dysregulated DNM3OS is implicated in several cancers, including gastric cancer, ovarian cancer, and esophageal squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('DNM3OS', 'Gene', (26, 32))	('implicated', 'Reg', (36, 46))	('ovarian cancer', 'Disease', (93, 107))	('gastric cancer', 'Disease', (77, 91))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('cancers', 'Disease', (58, 65))	('dysregulated', 'Var', (13, 25))
579242	32947897	Additionally, the elevated expression of DNM3OS was also observed in several esophageal cancer cell lines viz.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('expression', 'MPA', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('DNM3OS', 'Var', (41, 47))	('elevated', 'PosReg', (18, 26))
579248	32947897	Moreover, the tumor inhibition rate was higher for the DNM3OS knockout mice group, compared to the control group mice (76.59% vs. 47.03%).	('mice', 'Species', '10090', (71, 75))	('tumor', 'Disease', (14, 19))	('higher', 'PosReg', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mice', 'Species', '10090', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('DNM3OS', 'Var', (55, 61))
579252	32947897	Furthermore, to elucidate the underlying pathways responsible for DNM3OS deregulation, a molecule called "crenolanib" identified with kinase inhibitor signaling.	('crenolanib', 'Chemical', 'MESH:C577197', (106, 116))	('deregulation', 'Var', (73, 85))	('DNM3OS', 'Gene', (66, 72))
579260	32947897	The above findings suggest that the DNM3OS in association with CAFs induced radioresistance via targeting PDGFbeta and FOXO1 genes in ESCC, which indicate the importance of DNM3OS in ESCC as a target molecule.	('FOXO1', 'Gene', '2308', (119, 124))	('induced', 'Reg', (68, 75))	('DNM3OS', 'Var', (36, 42))	('FOXO1', 'Gene', (119, 124))	('radioresistance', 'CPA', (76, 91))	('PDGFbeta', 'Gene', (106, 114))	('PDGFbeta', 'Gene', '5154', (106, 114))
579262	32947897	Several studies have reported the association of dysregulated LINC00473 in head and neck squamous cell carcinoma (HNSCC) and ESCC, enhancing tumor progression inhibiting radiation response.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('ESCC', 'Disease', (125, 129))	('dysregulated', 'Var', (49, 61))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (84, 112))	('LINC00473', 'Gene', '90632', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('enhancing', 'PosReg', (131, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('radiation response', 'CPA', (170, 188))	('LINC00473', 'Gene', (62, 71))	('neck squamous cell carcinoma', 'Disease', (84, 112))
579265	32947897	Similar results were validated in the ESCC cell lines (TE-1, EC9706, Eca109, and KYSE-450), where TE-1 (~6.20-fold) and EC9706 (~6.80-fold) ESCC cell line demonstrated a higher expression level of LINC00473 compared to normal esophageal epithelial cell line Het-1A (Table 1).	('TE', 'Chemical', 'MESH:D013691', (98, 100))	('EC9706', 'CellLine', 'CVCL:E307', (61, 67))	('EC9706', 'CellLine', 'CVCL:E307', (120, 126))	('higher', 'PosReg', (170, 176))	('LINC00473', 'Gene', '90632', (197, 206))	('KYSE', 'Chemical', '-', (81, 85))	('LINC00473', 'Gene', (197, 206))	('TE', 'Chemical', 'MESH:D013691', (55, 57))	('expression level', 'MPA', (177, 193))	('EC9706', 'Var', (120, 126))
579268	32947897	Moreover, the shRNA-mediated knockdown of LINC00473 paired with an accumulated dose of irradiation caused a lower survival fraction in the ESCC cell lines (TE-1 and EC9706) as assessed using the colony survival assay (Table 1).	('knockdown', 'Var', (29, 38))	('EC9706', 'CellLine', 'CVCL:E307', (165, 171))	('lower', 'NegReg', (108, 113))	('LINC00473', 'Gene', '90632', (42, 51))	('TE', 'Chemical', 'MESH:D013691', (156, 158))	('LINC00473', 'Gene', (42, 51))	('survival fraction', 'CPA', (114, 131))
579274	32947897	Validating the role of LINC00473 in association with miR-374a-5p and miR-497-5p in ESCC radioresistance, these researchers observed enhanced cell viability, colony survival, PARP, and CdC25A protein expression levels in miR-374a-5p and miR-497-5p knockdown in ESCC cell.	('PARP', 'Gene', (174, 178))	('miR-374a', 'Gene', '442919', (53, 61))	('ESCC', 'Disease', (83, 87))	('miR-497', 'Gene', (236, 243))	('miR-497', 'Gene', '574456', (236, 243))	('CdC25A', 'Gene', (184, 190))	('radioresistance', 'CPA', (88, 103))	('CdC25A', 'Gene', '993', (184, 190))	('colony survival', 'CPA', (157, 172))	('miR-374a', 'Gene', (220, 228))	('miR-497', 'Gene', (69, 76))	('miR-497', 'Gene', '574456', (69, 76))	('miR-374a', 'Gene', (53, 61))	('cell viability', 'CPA', (141, 155))	('enhanced', 'PosReg', (132, 140))	('knockdown', 'Var', (247, 256))	('LINC00473', 'Gene', '90632', (23, 32))	('LINC00473', 'Gene', (23, 32))	('PARP', 'Gene', '142', (174, 178))	('miR-374a', 'Gene', '442919', (220, 228))
579277	32947897	Additionally, SPIN1 overexpression promoted proliferation and colony formation in vitro, and induced tumor formation and reduced apoptosis in nude mice through PI3K/AKT signaling pathways in ovarian cancer.	('colony formation', 'CPA', (62, 78))	('AKT', 'Gene', (165, 168))	('overexpression', 'Var', (20, 34))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('apoptosis', 'CPA', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('ovarian cancer', 'Disease', (191, 205))	('reduced', 'NegReg', (121, 128))	('tumor', 'Disease', (101, 106))	('induced', 'PosReg', (93, 100))	('SPIN1', 'Gene', (14, 19))	('promoted', 'PosReg', (35, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (191, 205))	('AKT', 'Gene', '11651', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('nude mice', 'Species', '10090', (142, 151))	('ovarian cancer', 'Disease', 'MESH:D010051', (191, 205))	('proliferation', 'CPA', (44, 57))
579282	32947897	Further, its inactivation leads to chromosomal instability in diploid human cell lines.	('leads to', 'Reg', (26, 34))	('inactivation', 'Var', (13, 25))	('chromosomal instability', 'Phenotype', 'HP:0040012', (35, 58))	('human', 'Species', '9606', (70, 75))	('chromosomal instability', 'MPA', (35, 58))
579293	32947897	Moreover, an upregulated expression of POU6F2-AS2 in irradiated ESCC cell lines KYSE-140~5-fold) KYSE-510 (~6.1-fold), KYSE-30 (~2-fold), and KYSE-70 (~1-fold), compared to the control cells (Table 1).	('KYSE-140~5-fold', 'Var', (80, 95))	('POU6F2', 'Gene', '11281', (39, 45))	('KYSE', 'Chemical', '-', (119, 123))	('POU6F2', 'Gene', (39, 45))	('KYSE-510', 'Var', (97, 105))	('expression', 'MPA', (25, 35))	('AS2', 'Chemical', 'MESH:C021591', (46, 49))	('upregulated', 'PosReg', (13, 24))	('KYSE', 'Chemical', '-', (142, 146))	('KYSE', 'Chemical', '-', (80, 84))	('KYSE', 'Chemical', '-', (97, 101))
579297	32947897	Moreover, knockdown of POU6F2-AS2 inhibited the recruitment of Ybx1 to the promoters of cyclin B1 (CCNB1) and p53 gene as well as to the DNA damage sites, thereby, confirming a close relationship between POU6F2-AS2 and DNA repair pathways (Figure 2, Table 1).	('POU6F2', 'Gene', '11281', (204, 210))	('POU6F2', 'Gene', (204, 210))	('p53', 'Gene', (110, 113))	('recruitment', 'MPA', (48, 59))	('Ybx1', 'Gene', '4904', (63, 67))	('p53', 'Gene', '7157', (110, 113))	('inhibited', 'NegReg', (34, 43))	('POU6F2', 'Gene', '11281', (23, 29))	('AS2', 'Chemical', 'MESH:C021591', (211, 214))	('POU6F2', 'Gene', (23, 29))	('CCNB1', 'Gene', (99, 104))	('AS2', 'Chemical', 'MESH:C021591', (30, 33))	('cyclin B1', 'Gene', '891', (88, 97))	('cyclin B1', 'Gene', (88, 97))	('CCNB1', 'Gene', '891', (99, 104))	('knockdown', 'Var', (10, 19))	('Ybx1', 'Gene', (63, 67))
579301	32947897	For instance, several of its single nucleotide polymorphisms (SNPs) associated with both obsessive-compulsive disorders of Tourette's syndrome.	('associated', 'Reg', (68, 78))	('obsessive-compulsive disorders', 'Phenotype', 'HP:0000722', (89, 119))	("obsessive-compulsive disorders of Tourette's syndrome", 'Disease', 'MESH:D009771', (89, 142))	('single nucleotide polymorphisms', 'Var', (29, 60))
579304	32947897	Further analyses suggested that ESCC patients belonging to the FAM-high expression group (n = 13,  Ct = 8.437) exhibited an inadequate short term response to radiotherapy and had a lower survival time, contrary to the FAM-low expression group (n = 22,  Ct = 6.155), whereas, neither of the groups correlated with either T or N stage of tumor stage.	('inadequate', 'NegReg', (124, 134))	('ESCC', 'Disease', (32, 36))	('patients', 'Species', '9606', (37, 45))	('lower', 'NegReg', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('FAM-high expression', 'Var', (63, 82))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (336, 341))	('survival time', 'CPA', (187, 200))
579305	32947897	Furthermore, siRNA-mediated knockdown of FAM201A exhibited decreased proliferation in ESCC cell lines Eca109 and Eca109R.	('FAM201A', 'Gene', (41, 48))	('proliferation', 'CPA', (69, 82))	('FAM201A', 'Gene', '158228', (41, 48))	('decreased', 'NegReg', (59, 68))	('knockdown', 'Var', (28, 37))	('ESCC', 'Disease', (86, 90))
579310	32947897	by luciferase reporter assays, observed that FAM201A mutants suppressed the expression of miR-101 in Eca109 cells, suggesting a negative correlation between FAM201A and miR-101.	('suppressed', 'NegReg', (61, 71))	('FAM201A', 'Gene', (45, 52))	('FAM201A', 'Gene', '158228', (157, 164))	('miR-101', 'Chemical', '-', (90, 97))	('miR-101', 'Chemical', '-', (169, 176))	('FAM201A', 'Gene', '158228', (45, 52))	('negative', 'NegReg', (128, 136))	('mutants', 'Var', (53, 60))	('miR-101', 'Gene', (90, 97))	('expression', 'MPA', (76, 86))	('FAM201A', 'Gene', (157, 164))
579316	32947897	by qRT-PCR observed a downregulated expression of MALAT1 in ESCC cells (EC9706 and KYSE-150) treated with ionizing radiation of 5 Gy for 8 h. Additionally, the overexpression of MALAT1 in irradiated EC9706 and KYSE-150 cells reduced the apoptotic rate leading to enhanced cell viability, suggesting the role of MALAT1 in reducing the radiosensitivity of ESCC cells.	('apoptotic rate', 'CPA', (237, 251))	('overexpression', 'PosReg', (160, 174))	('MALAT1', 'Gene', (178, 184))	('EC9706', 'CellLine', 'CVCL:E307', (199, 205))	('cell viability', 'CPA', (272, 286))	('EC9706', 'CellLine', 'CVCL:E307', (72, 78))	('reduced', 'NegReg', (225, 232))	('KYSE', 'Chemical', '-', (210, 214))	('KYSE', 'Chemical', '-', (83, 87))	('EC9706', 'Var', (199, 205))	('enhanced', 'PosReg', (263, 271))
579326	32947897	by qRT-PCR, examined the expression of LOC285194 in 142 ESCC tissues and observed that the expression of LOC285194 was significantly reduced (~1.10-fold) (Table 1) compared to adjacent healthy tissues.	('expression', 'MPA', (91, 101))	('LOC285194', 'Var', (105, 114))	('LOC285194', 'Chemical', '-', (39, 48))	('LOC285194', 'Chemical', '-', (105, 114))	('reduced', 'NegReg', (133, 140))	('LOC285194', 'Var', (39, 48))
579328	32947897	They observed downregulated levels of LOC285194 in KYSE-30 (~2.0-fold), KYSE-510 (~1.7-fold), KYSE-109 (~2.0-fold) cells lines compared to a standard esophageal epithelial cell line, Het-1A (Table 1).	('LOC285194', 'Var', (38, 47))	('downregulated', 'NegReg', (14, 27))	('KYSE', 'Chemical', '-', (51, 55))	('LOC285194', 'Chemical', '-', (38, 47))	('KYSE', 'Chemical', '-', (94, 98))	('KYSE', 'Chemical', '-', (72, 76))
579332	32947897	The above results indicate that LOC285194 could be used as a biomarker for screening and treating ESCC patients before esophagectomy.	('LOC285194', 'Var', (32, 41))	('LOC285194', 'Chemical', '-', (32, 41))	('patients', 'Species', '9606', (103, 111))	('ESCC', 'Disease', (98, 102))
579333	32947897	Furthermore, to study the prognostic significance of LOC285194 expression, Kaplan-Meier analysis was performed, which revealed that low expression of LOC285194 was associated with wretched disease-free survival (DFS) and overall survival (OS).	('low', 'NegReg', (132, 135))	('LOC285194', 'Var', (150, 159))	('associated', 'Reg', (164, 174))	('LOC285194', 'Chemical', '-', (150, 159))	('overall survival', 'CPA', (221, 237))	('LOC285194', 'Chemical', '-', (53, 62))	('wretched', 'Disease', (180, 188))
579334	32947897	Meanwhile, multivariate analysis revealed that low expression of LOC285194 and distant metastases were independent factors that affected DFS and OS.	('metastases', 'Disease', (87, 97))	('DFS', 'Disease', (137, 140))	('low', 'NegReg', (47, 50))	('LOC285194', 'Var', (65, 74))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('expression', 'MPA', (51, 61))	('LOC285194', 'Chemical', '-', (65, 74))	('affected', 'Reg', (128, 136))
579336	32947897	Therefore, these results suggest that the downregulated expression of LOC285194 signifies a higher risk of disease recurrence and treatment failure.	('LOC285194', 'Chemical', '-', (70, 79))	('downregulated', 'NegReg', (42, 55))	('disease recurrence', 'CPA', (107, 125))	('treatment failure', 'CPA', (130, 147))	('expression', 'MPA', (56, 66))	('LOC285194', 'Var', (70, 79))
579347	32947897	A similar upregulation of about ~2.2-15-fold was found in the cell lines KYSE-30, KYSE-70, KYSE-150, KYSE-450, KYSE-510, and KYSE-10 as compared to the healthy esophageal mucosa cell Het-1A (Table 1).	('KYSE', 'Chemical', '-', (111, 115))	('KYSE-30', 'Var', (73, 80))	('KYSE', 'Chemical', '-', (82, 86))	('KYSE', 'Chemical', '-', (91, 95))	('KYSE-510', 'Var', (111, 119))	('KYSE-150', 'Var', (91, 99))	('KYSE', 'Chemical', '-', (73, 77))	('KYSE-70', 'Var', (82, 89))	('KYSE', 'Chemical', '-', (125, 129))	('KYSE', 'Chemical', '-', (101, 105))	('upregulation', 'PosReg', (10, 22))	('KYSE-450', 'Var', (101, 109))
579356	32947897	Interestingly, reduced tumor volume, tumor growth, and tumor weight observed in response to TUG1 knockdown in the KYSE-30 xenografts compared to the controls after irradiation of 2 Gy.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('knockdown', 'Var', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('reduced', 'NegReg', (15, 22))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('TUG1', 'Gene', (92, 96))	('KYSE', 'Chemical', '-', (114, 118))
579358	32947897	The authors further indicated by Luciferase reporter assays that miR-144-3p was indeed a downstream target of TUG1, where these two transcripts were inversely correlated as established by Pearson's correlation coefficient.	('TUG1', 'Gene', (110, 114))	('miR-144-3p', 'Var', (65, 75))	('miR-144-3p', 'Chemical', '-', (65, 75))
579359	32947897	miR-144-3p acts as a tumor suppressor in ESCC, and depletion of miR-144-3p restored the effects of TUG1 suppression on radiotherapy, consequently validating its role as a regulator of radiation (Figure 3, Table 1).	('effects', 'MPA', (88, 95))	('depletion', 'MPA', (51, 60))	('restored', 'PosReg', (75, 83))	('TUG1', 'Gene', (99, 103))	('suppression', 'NegReg', (104, 115))	('miR-144-3p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (21, 26))	('ESCC', 'Disease', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('miR-144-3p', 'Var', (64, 74))	('miR-144-3p', 'Chemical', '-', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
579364	32947897	Consistent with these findings, knockdown of MET decreased EGFR and phosphorylated-Akt (p-Akt) protein levels, possibly inhibiting cell proliferation.	('Akt', 'Gene', (90, 93))	('inhibiting', 'NegReg', (120, 130))	('EGFR', 'Gene', (59, 63))	('Akt', 'Gene', (83, 86))	('MET', 'Gene', '79811', (45, 48))	('knockdown', 'Var', (32, 41))	('MET', 'Gene', (45, 48))	('decreased', 'NegReg', (49, 58))	('cell proliferation', 'CPA', (131, 149))	('Akt', 'Gene', '207', (83, 86))	('EGFR', 'Gene', '1950', (59, 63))	('Akt', 'Gene', '207', (90, 93))
579369	32947897	The lncRNAs DNM3OS, LINC00473, LINC00657, POU6F2-AS2 found to be involved in radioresistance, while FAM201A, MALAT1, LOC285194, AFAP1-AS1, TUG1 lncRNAs linked to radiosensitivity in ESCC.	('radioresistance', 'CPA', (77, 92))	('AFAP1', 'Gene', (128, 133))	('FAM201A', 'Gene', (100, 107))	('AFAP1', 'Gene', '60312', (128, 133))	('AS2', 'Chemical', 'MESH:C021591', (49, 52))	('FAM201A', 'Gene', '158228', (100, 107))	('LINC00657', 'Gene', '647979', (31, 40))	('LINC00473', 'Gene', '90632', (20, 29))	('involved', 'Reg', (65, 73))	('LOC285194', 'Var', (117, 126))	('AS1', 'Gene', '5729', (134, 137))	('AS1', 'Gene', (134, 137))	('ESCC', 'Disease', (182, 186))	('POU6F2', 'Gene', '11281', (42, 48))	('LOC285194', 'Chemical', '-', (117, 126))	('POU6F2', 'Gene', (42, 48))	('LINC00473', 'Gene', (20, 29))	('LINC00657', 'Gene', (31, 40))
579372	32947897	The reviewed literature data indicate the potential efficacy of DNM3OS and POU6F2-AS2 as targets to improve the outcome of radiotherapy.	('POU6F2', 'Gene', '11281', (75, 81))	('DNM3OS', 'Var', (64, 70))	('POU6F2', 'Gene', (75, 81))	('AS2', 'Chemical', 'MESH:C021591', (82, 85))
579378	32947897	However, several factors, such as familial mutation, epigenetic changes, and other comorbid pathological conditions, increase the resistance in a large cohort of patients, which is alarming and needs more in-depth analysis for improving interventions.	('epigenetic changes', 'Var', (53, 71))	('patients', 'Species', '9606', (162, 170))	('increase', 'PosReg', (117, 125))	('resistance', 'MPA', (130, 140))	('familial mutation', 'Var', (34, 51))
579379	32947897	We have also proposed that modifying the lncRNA signature can influence the sensitivity of refractory patients.	('patients', 'Species', '9606', (102, 110))	('sensitivity', 'MPA', (76, 87))	('modifying', 'Var', (27, 36))	('influence', 'Reg', (62, 71))	('lncRNA signature', 'MPA', (41, 57))
579412	32005248	In the past few years, long non-coding RNAs (lncRNAs), defined as transcripts longer than 200 nt lacking protein-coding capacity, have been reported to have complex biological functions and involved in tumorigenesis and metastasis.	('tumor', 'Disease', (202, 207))	('long non-coding RNAs', 'Var', (23, 43))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('involved', 'Reg', (190, 198))	('metastasis', 'CPA', (220, 230))
579425	32005248	Briefly, 2 mug of total RNAs from the training cohort were reverse transcribed using random primers and Cy5-dUTP or Cy3-dUTP with GoScript  Reverse Transcription system (Promega) in a total reaction volume of 20 mul.	('Cy3-dUTP', 'Chemical', 'MESH:C088941', (116, 124))	('RNAs', 'Protein', (24, 28))	('Cy3-dUTP', 'Var', (116, 124))	('Cy5-dUTP', 'Var', (104, 112))	('Cy5-dUTP', 'Chemical', 'MESH:C088942', (104, 112))
579443	32005248	To validate lncRNA expression levels detected by the microarray analysis, we randomly selected two upregulated lncRNAs (ASLNC11164 and BQ376030) and two downregulated lncRNAs (XLOC_001061 and RP11-473M20.9) in ESCC tissues and detected them by quantitative RT-PCR in 40 pairs of ESCC and noncancerous esophagus tissues randomly chosen from the training cohort.	('RP11', 'Gene', '26121', (192, 196))	('ESCC', 'Disease', 'MESH:C562729', (210, 214))	('XLOC_001061', 'Var', (176, 187))	('upregulated', 'PosReg', (99, 110))	('ESCC', 'Disease', 'MESH:C562729', (279, 283))	('cancer', 'Disease', (291, 297))	('BQ376030', 'Var', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('ESCC', 'Disease', (279, 283))	('RP11', 'Gene', (192, 196))	('ESCC', 'Disease', (210, 214))	('BQ376030', 'Chemical', 'MESH:C025612', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('ASLNC11164', 'Chemical', 'None', (120, 130))	('ASLNC11164', 'Var', (120, 130))
579447	32005248	The formula consists of a linear combination of the expression level of 7 lncRNAs weighted by Cox regression coefficient: Risk score = (0.155 x expression value of BQ376030 + 0.112 x expression value of ASLNC11164 + 0.125 x expression value of BF894811 + 0.155 x expression value of RP11-473M20.9 - 0.182 x expression value of XLOC_007869 - 0.15 x XLOC_006476 - 0.172 x expression value of CK327190).	('CK327190', 'Var', (390, 398))	('BF894811 + 0.155 x', 'Var', (244, 262))	('0.155', 'Var', (136, 141))	('ASLNC11164', 'Chemical', 'None', (203, 213))	('Cox', 'Gene', '1351', (94, 97))	('BQ376030', 'Chemical', 'MESH:C025612', (164, 172))	('BQ376030 + 0.112', 'Var', (164, 180))	('RP11', 'Gene', (283, 287))	('XLOC_007869', 'Chemical', 'None', (327, 338))	('Cox', 'Gene', (94, 97))	('RP11', 'Gene', '26121', (283, 287))	('XLOC_007869 - 0.15', 'Var', (327, 345))	('ASLNC11164 + 0.125 x', 'Var', (203, 223))	('BF894811', 'Chemical', 'MESH:C088437', (244, 252))
579454	32005248	Then we constructed a new risk score formula with the same method used in the training cohort: Risk score = (0.028 x expression value of BQ376030 + 0.053 x expression value of ASLNC11164 + 0.049 x expression value of BF894811 + 0.031 x expression value of RP11-473M20.9 - 0.058 x expression value of XLOC_007869 - 0.116 x XLOC_006476 - 0.061 x expression value of CK327190).	('BF894811', 'Chemical', 'MESH:C088437', (217, 225))	('BF894811 + 0.031 x', 'Var', (217, 235))	('XLOC_007869', 'Chemical', 'None', (300, 311))	('BQ376030 + 0.053', 'Var', (137, 153))	('ASLNC11164', 'Chemical', 'None', (176, 186))	('CK327190', 'Var', (364, 372))	('ASLNC11164 + 0.049 x', 'Var', (176, 196))	('RP11', 'Gene', (256, 260))	('RP11', 'Gene', '26121', (256, 260))	('XLOC_007869 - 0.116 x XLOC_006476 - 0.061', 'Var', (300, 341))	('BQ376030', 'Chemical', 'MESH:C025612', (137, 145))
579492	32005248	Recently, non-coding RNA (including microRNA [miRNA], long non-coding RNA and others) has been found to play critical roles in physiological and pathological processes of organisms, and involved in disease processes including that of cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('non-coding', 'Var', (10, 20))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('play', 'Reg', (104, 108))	('cancer', 'Disease', (234, 240))	('involved', 'Reg', (186, 194))
579507	30578782	We found significantly higher levels of glutathione S-transferase theta 2 (GSTT2) mRNA in squamous mucosa from African Americans compared with European Americans and associated these with variants within the GSTT2 locus in African Americans.	('variants', 'Var', (188, 196))	('GSTT2', 'Gene', (75, 80))	('higher', 'PosReg', (23, 29))	('mRNA', 'MPA', (82, 86))	('glutathione S-transferase theta 2', 'Gene', (40, 73))	('glutathione S-transferase theta 2', 'Gene', '653689', (40, 73))	('GSTT2', 'Gene', (208, 213))
579510	30578782	C-PAC also reduced levels of DNA damage in reflux-exposed rat esophagi, as observed by reduced levels of phospho-H2A histone family member X.	('H2A histone family member X', 'Gene', (113, 140))	('reduced', 'NegReg', (11, 18))	('reduced', 'NegReg', (87, 94))	('C-PAC', 'Var', (0, 5))	('levels', 'MPA', (19, 25))	('H2A histone family member X', 'Gene', '3014', (113, 140))	('C-PAC', 'Chemical', '-', (0, 5))	('rat', 'Species', '10116', (58, 61))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))
579531	30578782	Briefly, cultured Het-1A (immortalized normal esophageal squamous mucosa) and HeLa (squamous cervical cancer) were exposed to mock control (RNAimax; Thermo Fisher), scramble non-target (NT) siRNA or four commercial siRNAs targeting GSTT2 (#LQ-011181-00-0005, Dharmacon, Lafayette, CO) at a concentration of 10nm for 48hrs before harvesting.	('GSTT2', 'Gene', (232, 237))	('squamous cervical cancer', 'Disease', (84, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rat', 'Species', '10116', (297, 300))	('HeLa', 'CellLine', 'CVCL:0030', (78, 82))	('squamous cervical cancer', 'Phenotype', 'HP:0032241', (84, 108))	('#LQ-011181-00-0005', 'Var', (239, 257))	('squamous cervical cancer', 'Disease', 'MESH:D002294', (84, 108))
579533	30578782	Following blocking, membranes were incubated overnight at 4 C with primary GSTT2 (#514667; Santa Cruz, Dallas, TX; 1:500) or gamma-H2AX (#05-636; Millipore, Burlington, MA; 1/1500) antibodies.	('gamma-H2AX', 'Protein', (125, 135))	('GSTT2', 'Gene', (75, 80))	('#05-636;', 'Var', (137, 145))	('#514667;', 'Var', (82, 90))	('gamma-H2AX', 'Chemical', '-', (125, 135))
579541	30578782	Immunoblotting was performed using commercially available antibodies from Cell Signaling Technology (Danvers, MA): GAPDH (#2118; 1:40,000) and Santa Cruz Biotechnology: GSTT2 (#514667; 1:500) and HSP60 (#13115; 1:1000).	('#514667;', 'Var', (176, 184))	('HSP60', 'Gene', '3329', (196, 201))	('#13115;', 'Var', (203, 210))	('GAPDH', 'Gene', '2597', (115, 120))	('GAPDH', 'Gene', (115, 120))	('HSP60', 'Gene', (196, 201))
579555	30578782	The GSTT2 mRNA demonstrated the largest FC difference (FC=5.15) between the two racial groups, while the paralog, GSTT2B, demonstrated the fourth largest FC (Figure 1A; Supplementary Table S2).	('GSTT2B', 'Gene', '653689', (114, 120))	('GSTT2', 'Var', (4, 9))	('rat', 'Species', '10116', (22, 25))	('rat', 'Species', '10116', (129, 132))	('GSTT2B', 'Gene', (114, 120))
579561	30578782	noted differential HLA-DPB1 expression while comparing non-disease AA and EU groups using the Affymetrix ST array platform and were able to show that this was due to differential binding of one ST array probeset as a result of a frequent, population-variable SNP causing difference in response of one probe.	('HLA-DPB1', 'Gene', (19, 27))	('binding', 'Interaction', (179, 186))	('expression', 'MPA', (28, 38))	('HLA-DPB1', 'Gene', '3115', (19, 27))	('SNP', 'Var', (259, 262))	('response', 'MPA', (285, 293))
579568	30578782	characterized a 37kb deletion of GSTT2B (Figure 2A; Supplementary Figure S3A), which they associated with lower levels of GSTT2 expression.	('lower', 'NegReg', (106, 111))	('GSTT2B', 'Gene', '653689', (33, 39))	('GSTT2B', 'Gene', (33, 39))	('deletion', 'Var', (21, 29))	('levels', 'MPA', (112, 118))	('GSTT2 expression', 'MPA', (122, 138))
579570	30578782	and observed a higher frequency (Fisher Exact P=0.018) of the GSTT2B deletion in EA-NE (80.6%) relative to AA-NE (54.8%; Supplementary Figure S3B).	('GSTT2B', 'Gene', (62, 68))	('EA-NE', 'Disease', (81, 86))	('EA-NE', 'Disease', 'None', (81, 86))	('deletion', 'Var', (69, 77))	('GSTT2B', 'Gene', '653689', (62, 68))
579572	30578782	identified a 17bp tandem duplication within the promoter of GSTT2 and GSTT2B (Figure 2A), and using a luciferase-linked assay to assess promoter function, showed the presence of the 17bp tandem duplication associates with lower GSTT2 and GSTT2B promoter activity.	('GSTT2B', 'Gene', (70, 76))	('GSTT2B', 'Gene', '653689', (238, 244))	('presence', 'Var', (166, 174))	('promoter activity', 'MPA', (245, 262))	('GSTT2', 'Gene', (60, 65))	('GSTT2B', 'Gene', (238, 244))	('GSTT2B', 'Gene', '653689', (70, 76))	('lower', 'NegReg', (222, 227))	('GSTT2', 'Gene', (228, 233))
579573	30578782	We observed a significantly higher frequency (EA-NE vs. AA-NE: 97.5% to 67.5%, P=0.000062 by two-sided Fisher Exact Test) of the promoter duplication in EA relative to AA (Figure 2B).	('promoter duplication', 'Var', (129, 149))	('EA-NE', 'Disease', 'None', (46, 51))	('EA-NE', 'Disease', (46, 51))
579574	30578782	The GSTT2B deletion also strongly correlated with GSTT2 expression in the 1000G data (Figure 3C), however, the most important contribution to low GSTT2/2B expression occurs when the 17bp GSTT2/2B promoter duplication is homozygous (Figure 3D) and thus similar to the results seen in the esophagus (Figure 2D).	('GSTT2B', 'Gene', (4, 10))	('deletion', 'Var', (11, 19))	('GSTT2/2B', 'Gene', '2953;653689', (187, 195))	('GSTT2/2B', 'Gene', (187, 195))	('GSTT2/2B', 'Gene', '2953;653689', (146, 154))	('GSTT2/2B', 'Gene', (146, 154))	('expression', 'MPA', (155, 165))	('low', 'NegReg', (142, 145))	('correlated', 'Reg', (34, 44))	('GSTT2B', 'Gene', '653689', (4, 10))
579586	30578782	We transfected Het-1A and HeLa cells using four commercial GSTT2 targeting siRNAs and confirmed successful GSTT2 mRNA and protein knockdown of >50-80% in both cell lines (Supplementary Figure S7A-G).	('mRNA', 'Var', (113, 117))	('GSTT2', 'Gene', (107, 112))	('HeLa', 'CellLine', 'CVCL:0030', (26, 30))	('knockdown', 'Var', (130, 139))
579589	30578782	Cum-OOH treated, GSTT2 knocked-down Het-1A cells showed dramatically more DNA damage compared to controls (control vs. siRNA-05, 06) (P=4.8x10-5, 1.0x10-5, respectively), with more than 50% of the cell population positive for DNA damage response (Figure 4A-B).	('knocked-down', 'Var', (23, 35))	('GSTT2', 'Gene', (17, 22))	('DNA damage', 'MPA', (74, 84))	('OOH', 'Chemical', '-', (4, 7))	('more', 'PosReg', (69, 73))
579596	30578782	In contrast, the C-PAC treated EGDA rats had low esophageal gamma-H2AX levels, similar to the non-surgical controls, yet maintained significantly high GSTT2 levels compared to EGDA positive rats without C-PAC treatment (Figure 4E).	('GSTT2 levels', 'MPA', (151, 163))	('gamma-H2AX', 'Chemical', '-', (60, 70))	('EGDA', 'Phenotype', 'HP:0100628', (176, 180))	('EGDA', 'Chemical', '-', (31, 35))	('EGDA', 'Chemical', '-', (176, 180))	('low', 'NegReg', (45, 48))	('PAC', 'Phenotype', 'HP:0006699', (205, 208))	('PAC', 'Phenotype', 'HP:0006699', (19, 22))	('rats', 'Species', '10116', (190, 194))	('esophageal gamma-H2AX levels', 'MPA', (49, 77))	('C-PAC', 'Var', (17, 22))	('rats', 'Species', '10116', (36, 40))	('C-PAC', 'Chemical', '-', (203, 208))	('C-PAC', 'Chemical', '-', (17, 22))	('EGDA', 'Phenotype', 'HP:0100628', (31, 35))	('high', 'PosReg', (146, 150))
579600	30578782	This promoter variant was a much stronger predictor of GSTT2/2B mRNA level than the whole gene duplication variation that leads to humans inheriting 2, 3 or 4 GSTT2/2B copies (Supplementary Figure S3).	('humans', 'Species', '9606', (131, 137))	('GSTT2/2B', 'Gene', '2953;653689', (55, 63))	('GSTT2/2B', 'Gene', (55, 63))	('GSTT2/2B', 'Gene', '2953;653689', (159, 167))	('GSTT2/2B', 'Gene', (159, 167))	('mRNA level', 'MPA', (64, 74))	('variant', 'Var', (14, 21))
579604	30578782	It is interesting to note that Denisovan sequencing tracks (USCS browser tracks for GSTT2B and GSTT2) show that several individuals from this ancient population had the 17bp duplication variant, while, so far, none of the Neanderthal sequences do (JBrowse regions for GSTT2B and GSTT2).	('GSTT2B', 'Gene', '653689', (268, 274))	('Denisovan', 'Species', '741158', (31, 40))	('GSTT2B', 'Gene', '653689', (84, 90))	('GSTT2B', 'Gene', (268, 274))	('17bp duplication variant', 'Var', (169, 193))	('GSTT2B', 'Gene', (84, 90))	('Neanderthal', 'Species', '63221', (222, 233))
579619	30578782	Although it has been suggested that the effect of NSAIDs in reducing the risk of EAC is through inhibition of inflammation, we propose that NSAIDs could also lower an individual's risk for GERD-related damage through increasing esophageal GSTT2 expression.	('EAC', 'Phenotype', 'HP:0011459', (81, 84))	('esophageal GSTT2', 'Protein', (228, 244))	('inflammation', 'Disease', (110, 122))	('lower', 'NegReg', (158, 163))	('GERD-related', 'Disease', (189, 201))	('EAC', 'Disease', (81, 84))	('increasing', 'PosReg', (217, 227))	('NSAIDs', 'Var', (140, 146))	('expression', 'MPA', (245, 255))	('inflammation', 'Disease', 'MESH:D007249', (110, 122))
579663	29285315	The CXCL8 mRNA expression was significantly up-regulated by TECM (TE-8, TE-9 and TE-15) compared to PBMo-derived macrophages and PBMo-derived macrophages stimulated by Het-1A CM (Figure 1A).	('CXCL8', 'Gene', '3576', (4, 9))	('CXCL8', 'Gene', (4, 9))	('TE-15', 'Var', (81, 86))	('TE-9', 'Var', (72, 76))	('PBMo', 'Chemical', '-', (100, 104))	('TE', 'Chemical', 'MESH:D013691', (66, 68))	('TE', 'Chemical', 'MESH:D013691', (72, 74))	('up-regulated', 'PosReg', (44, 56))	('PBMo', 'Chemical', '-', (129, 133))	('TE', 'Chemical', 'MESH:D013691', (81, 83))	('TE-9', 'CellLine', 'CVCL:1767', (72, 76))	('TE', 'Chemical', 'MESH:D013691', (60, 62))
579666	29285315	The enzyme-linked immunosorbent assay showed that the concentration of secreted CXCL8 was significantly higher in the PBMo-derived macrophages stimulated with TE-8 CM, TE-9 CM and TE-15 CM (19664.8 +- 64.3, 17108.3 +- 601.8, and 15560.9 +- 179.4 pg/ml, respectively) than in the PBMo-derived macrophages (2423.8 +- 78.2 pg/ml) (Figure 1C).	('TE-8 CM', 'Var', (159, 166))	('PBMo', 'Chemical', '-', (279, 283))	('TE', 'Chemical', 'MESH:D013691', (168, 170))	('TE-15 CM', 'Disease', 'MESH:C567193', (180, 188))	('TE', 'Chemical', 'MESH:D013691', (159, 161))	('15560.9', 'Var', (229, 236))	('17108.3 +- 601.8', 'Var', (207, 223))	('CXCL8', 'Gene', '3576', (80, 85))	('CXCL8', 'Gene', (80, 85))	('TE-9', 'CellLine', 'CVCL:1767', (168, 172))	('TE', 'Chemical', 'MESH:D013691', (180, 182))	('TE-9 CM', 'Var', (168, 175))	('concentration', 'MPA', (54, 67))	('PBMo', 'Chemical', '-', (118, 122))	('TE-15 CM', 'Disease', (180, 188))	('higher', 'PosReg', (104, 110))
579668	29285315	The concentration of CXCL8 derived from TE-8 and TE-9 (168.1 +- 13.0 and 596.4 +- 23.3 pg/ml) was lower than that in the PBMo-derived macrophages (Figure 1C).	('concentration', 'MPA', (4, 17))	('CXCL8', 'Gene', '3576', (21, 26))	('CXCL8', 'Gene', (21, 26))	('PBMo', 'Chemical', '-', (121, 125))	('TE', 'Chemical', 'MESH:D013691', (49, 51))	('TE-9', 'CellLine', 'CVCL:1767', (49, 53))	('TE', 'Chemical', 'MESH:D013691', (40, 42))	('lower', 'NegReg', (98, 103))	('TE-9', 'Var', (49, 53))
579671	29285315	We observed the phosphorylation of Akt (Ser473/Thr308) (the PI3K-Akt signal pathway) and Erk1/2 (the MEK-Erk1/2 signal pathway) after 10 min (Figure 2C).	('Thr308', 'Chemical', '-', (47, 53))	('Erk1/2', 'Gene', (105, 111))	('Akt', 'Gene', (65, 68))	('Erk1/2', 'Gene', (89, 95))	('Erk1/2', 'Gene', '5595;5594', (89, 95))	('Ser473', 'Chemical', '-', (40, 46))	('Erk1/2', 'Gene', '5595;5594', (105, 111))	('Akt', 'Gene', '207', (65, 68))	('Akt', 'Gene', '207', (35, 38))	('MEK', 'Gene', (101, 104))	('MEK', 'Gene', '5609', (101, 104))	('phosphorylation', 'MPA', (16, 31))	('Ser473/Thr308', 'Var', (40, 53))	('Akt', 'Gene', (35, 38))
579672	29285315	First, we demonstrated rhCXCL8 did not promote the migration of TE-15 (expressing high level of CXCL8) (Supplementary Figure 2A) and neutralizing antibody against CXCL8 tended to suppress its migration (Supplementary Figure 2B).	('TE', 'Chemical', 'MESH:D013691', (64, 66))	('neutralizing', 'Var', (133, 145))	('CXCL8', 'Gene', '3576', (96, 101))	('CXCL8', 'Gene', '3576', (25, 30))	('CXCL8', 'Gene', (25, 30))	('CXCL8', 'Gene', (96, 101))	('CXCL8', 'Gene', '3576', (163, 168))	('CXCL8', 'Gene', (163, 168))	('suppress', 'NegReg', (179, 187))	('rhCXCL8', 'Chemical', '-', (23, 30))	('migration', 'CPA', (192, 201))
579675	29285315	We found that rhCXCL8 significantly accelerated the migration and invasion of TE-8 and TE-9 cells by performing a transwell migration assay and transwell invasion assay (Figure 3A (i)-(ii), Supplementary Figure 4A (i)-(ii)).	('rhCXCL8', 'Var', (14, 21))	('accelerated', 'PosReg', (36, 47))	('migration', 'CPA', (52, 61))	('transwell migration assay', 'CPA', (114, 139))	('TE', 'Chemical', 'MESH:D013691', (87, 89))	('rhCXCL8', 'Chemical', '-', (14, 21))	('TE-9', 'CellLine', 'CVCL:1767', (87, 91))	('transwell invasion assay', 'CPA', (144, 168))	('invasion', 'CPA', (66, 74))	('TE', 'Chemical', 'MESH:D013691', (78, 80))
579676	29285315	LY294002, a PI3K inhibitor, and PD98059, a MEK1/2 inhibitor, suppressed the migration and invasion of TE-8 and TE-9 cells induced by rhCXCL8 (Figure 3B (i)-(ii), Supplementary Figure 4B (i)-(ii)).	('LY294002', 'Var', (0, 8))	('suppressed', 'NegReg', (61, 71))	('TE', 'Chemical', 'MESH:D013691', (102, 104))	('rhCXCL8', 'Chemical', '-', (133, 140))	('migration', 'CPA', (76, 85))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('TE', 'Chemical', 'MESH:D013691', (111, 113))	('PD98059', 'Var', (32, 39))	('TE-9', 'CellLine', 'CVCL:1767', (111, 115))	('PD98059', 'Chemical', 'MESH:C093973', (32, 39))	('invasion', 'CPA', (90, 98))
579680	29285315	The neutralizing antibodies against CXCR1 or CXCR2 reduced the migration and invasion of TE-8 and TE-9 cells induced by rhCXCL8 (Figure 3E (i)-(ii), Supplementary Figure 4D (i)-(ii)).	('TE', 'Chemical', 'MESH:D013691', (98, 100))	('reduced', 'NegReg', (51, 58))	('rhCXCL8', 'Chemical', '-', (120, 127))	('TE-9', 'CellLine', 'CVCL:1767', (98, 102))	('neutralizing', 'Var', (4, 16))	('migration', 'CPA', (63, 72))	('TE', 'Chemical', 'MESH:D013691', (89, 91))
579683	29285315	LY294002 or PD98059 inhibited the migration and invasion of TE-8 and TE-9 cells induced by TAM-like PBMo-derived macrophages (Figure 4B (i)-(ii), Supplementary Figure 5B (i)-(ii)).	('LY294002', 'Var', (0, 8))	('PD98059', 'Chemical', 'MESH:C093973', (12, 19))	('TAM', 'Chemical', '-', (91, 94))	('PBMo', 'Chemical', '-', (100, 104))	('TE', 'Chemical', 'MESH:D013691', (69, 71))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('inhibited', 'NegReg', (20, 29))	('TE-9', 'CellLine', 'CVCL:1767', (69, 73))	('PD98059', 'Var', (12, 19))	('migration', 'CPA', (34, 43))	('TE', 'Chemical', 'MESH:D013691', (60, 62))
579697	29285315	The overall survival of the patients was not significantly different among the negative-, low- and high-expression CXCL8 groups (p = 0.25) (Figure 5E (ii)).	('CXCL8', 'Gene', '3576', (115, 120))	('high-expression', 'Var', (99, 114))	('CXCL8', 'Gene', (115, 120))	('low-', 'Var', (90, 94))	('patients', 'Species', '9606', (28, 36))
579713	29285315	In the present study, we demonstrated for the first time that rhCXCL8 significantly induced the migration and invasion of human ESCC cell lines.	('human', 'Species', '9606', (122, 127))	('migration', 'CPA', (96, 105))	('rhCXCL8', 'Chemical', '-', (62, 69))	('induced', 'PosReg', (84, 91))	('invasion', 'CPA', (110, 118))	('rhCXCL8', 'Var', (62, 69))
579754	29285315	TE cells were seeded onto coverslips overnight and fixed with 4% paraformaldehyde phosphate buffer solution (Wako) and incubated with rabbit monoclonal antibody against CD11b (1:100, #ab52478, Abcam, Cambridge, UK), mouse monoclonal antibody against CXCL8 (1:20, #ab18672, Abcam), rabbit polyclonal antibody against CXCR1 (1:50, #sc-988, Santa Cruz Biotechnology, Dallas, TX) and CXCR2 (1:50, #sc-682, Santa Cruz) at 4 C overnight.	('mouse', 'Species', '10090', (216, 221))	('TE', 'Chemical', 'MESH:D013691', (0, 2))	('1:50', 'Var', (323, 327))	('CD11b', 'Gene', '3684', (169, 174))	('rabbit', 'Species', '9986', (281, 287))	('CD11b', 'Gene', (169, 174))	('rabbit', 'Species', '9986', (134, 140))	('CXCL8', 'Gene', '3576', (250, 255))	('1:100', 'Var', (176, 181))	('CXCL8', 'Gene', (250, 255))
579762	29285315	The following secondary antibodies were both from GE Healthcare Life Sciences, Little Chalfont, UK: horseradish peroxidase (HRP)-linked sheep anti-mouse IgG (NA931V, NA931) and HRP-linked donkey anti-rabbit IgG (NA934V).	('mouse', 'Species', '10090', (147, 152))	('rabbit', 'Species', '9986', (200, 206))	('NA931V', 'Var', (158, 164))	('NA934V', 'Var', (212, 218))	('NA931', 'Var', (166, 171))	('sheep', 'Species', '9940', (136, 141))	('horseradish', 'Species', '3704', (100, 111))	('donkey', 'Species', '9793', (188, 194))
579768	29285315	The inhibitors against PI3K (LY294002) and MEK1/2 (PD98059) were purchased from Cell SignaIing Technology.	('LY294002', 'Chemical', 'MESH:C085911', (29, 37))	('PD98059', 'Var', (51, 58))	('PD98059', 'Chemical', 'MESH:C093973', (51, 58))	('LY294002', 'Var', (29, 37))
579769	29285315	The neutralizing antibodies were as follows (all from Abcam): normal mouse IgG (#ab188776); mouse antibody against CXCR1 (#ab10400); mouse antibody against CXCR2 (#ab10401); mouse antibody against CXCL8 (#ab18672).	('mouse', 'Species', '10090', (174, 179))	('#ab10401', 'Var', (163, 171))	('mouse', 'Species', '10090', (69, 74))	('CXCL8', 'Gene', '3576', (197, 202))	('mouse', 'Species', '10090', (133, 138))	('mouse', 'Species', '10090', (92, 97))	('CXCL8', 'Gene', (197, 202))
579826	28484712	Moreover, compared with the surgery carried out on Monday, the surgery on Friday increased relapse and death rate (HR (hazard ratio) = 1.415, 95% CI, 1.054-1.901 and HR = 1.559, 95% CI, 1.142-2.128), respectively (Table 5).	('surgery', 'Var', (63, 70))	('relapse', 'CPA', (91, 98))	('death', 'Disease', 'MESH:D003643', (103, 108))	('death', 'Disease', (103, 108))	('increased', 'PosReg', (81, 90))
579845	28484712	Beyond that, we also found that various influential factors are reported to increase the occurrence of complications after surgical resection, including old age, abnormal BMI, large tumor size, low serum albumin, longer duration of operation, and advanced tumor stage which was consistent with what has been reported before.	('low', 'NegReg', (194, 197))	('tumor', 'Disease', (182, 187))	('increase', 'PosReg', (76, 84))	('abnormal BMI', 'Phenotype', 'HP:0045081', (162, 174))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('low serum albumin', 'Phenotype', 'HP:0003073', (194, 211))	('abnormal', 'Var', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('complications', 'Disease', (103, 116))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
579846	28484712	Accordingly, our results also showed that smoking had an obvious influence on the occurrence of complications; we could infer that except the sensitive respiratory system, nicotine addiction can easily induce an inflammatory state, thus impairing the body repairing and healing ability.	('impairing', 'NegReg', (237, 246))	('induce', 'Reg', (202, 208))	('nicotine addiction', 'Var', (172, 190))	('nicotine', 'Chemical', 'MESH:D009538', (172, 180))	('body repairing', 'CPA', (251, 265))
579847	28484712	In contrast to the proposed "obesity paradox" that overweight and obesity promoted better outcomes in patients after gastrectomy, our study revealed that patients with high BMI had an higher morbidity after the gastric surgery; the increased rate was mainly due to the fact that excess fat may increase operation difficulty, operative time, and wound fat liquefaction as well, whose effects were significant in our study.	('obesity', 'Disease', 'MESH:D009765', (29, 36))	('obesity', 'Disease', (29, 36))	('obesity', 'Phenotype', 'HP:0001513', (66, 73))	('patients', 'Species', '9606', (102, 110))	('increase', 'PosReg', (294, 302))	('patients', 'Species', '9606', (154, 162))	('obesity', 'Disease', 'MESH:D009765', (66, 73))	('higher', 'PosReg', (184, 190))	('high', 'Var', (168, 172))	('morbidity', 'MPA', (191, 200))	('obesity', 'Disease', (66, 73))	('overweight', 'Phenotype', 'HP:0025502', (51, 61))	('obesity', 'Phenotype', 'HP:0001513', (29, 36))
579885	28212457	These adaptations favored PVs evolution, conferring specificity in terms of host to all members of Papillomaviridae family, except for BPV, which is able to promote cross-infection.	('cross-infection', 'Disease', (165, 180))	('BP', 'Chemical', '-', (135, 137))	('cross-infection', 'Disease', 'MESH:D003428', (165, 180))	('PVs', 'Disease', (26, 29))	('adaptations', 'Var', (6, 17))
579887	28212457	Along mammals divergence (150 million years ago), this proto-papillomavirus was added with E6 and E7 ORFs.	('proto-papillomavirus', 'Disease', (55, 75))	('proto-papillomavirus', 'Disease', 'MESH:D030361', (55, 75))	('papilloma', 'Phenotype', 'HP:0012740', (61, 70))	('E7 ORFs', 'Var', (98, 105))
579909	28212457	Under normal conditions, PDGFbetaR is activated by PDGF, which promotes receptor dimerization and activation of different kinases, such as: A-cdk2, MAPK, JNK, PI3K and C-Src.	('PDGF', 'Gene', (51, 55))	('activation', 'PosReg', (98, 108))	('C-Src', 'Gene', (168, 173))	('cdk2', 'Gene', '1017', (142, 146))	('C-Src', 'Gene', '6714', (168, 173))	('promotes', 'PosReg', (63, 71))	('JNK', 'Gene', (154, 157))	('receptor dimerization', 'MPA', (72, 93))	('PI3K', 'Var', (159, 163))	('JNK', 'Gene', '5599', (154, 157))	('MAPK', 'Disease', (148, 152))	('PDGFbetaR', 'Gene', (25, 34))	('cdk2', 'Gene', (142, 146))
579913	28212457	The E6 oncoprotein is characterized by the presence of a class I PDZ domain (PSD-95/Dlg/ZO-1), which is located in the C-terminal, and four PVs conserved motifs (Cys-X-X-Cys).	('ZO-1', 'Gene', (88, 92))	('Cys-X-X-Cys', 'Var', (162, 173))	('Cys', 'Chemical', 'MESH:D003545', (162, 165))	('PSD-95', 'Gene', (77, 83))	('Cys', 'Chemical', 'MESH:D003545', (170, 173))	('ZO-1', 'Gene', '7082', (88, 92))	('PSD-95', 'Gene', '1742', (77, 83))
579922	28212457	Thus, p53 deregulation is a characteristic shared by oncogenic viruses.	('deregulation', 'Var', (10, 22))	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))
579957	28212457	Delta and Epsilonpapillomavirus are associated with both papillomas and fibropapillomas, while Xipapillomavirus, only to squamous papillomas .	('papillomas', 'Phenotype', 'HP:0012740', (57, 67))	('papillomas', 'Phenotype', 'HP:0012740', (130, 140))	('papilloma', 'Phenotype', 'HP:0012740', (57, 66))	('papilloma', 'Phenotype', 'HP:0012740', (77, 86))	('squamous papillomas', 'Phenotype', 'HP:0031021', (121, 140))	('Xipapillomavirus', 'Disease', 'None', (95, 111))	('papilloma', 'Phenotype', 'HP:0012740', (130, 139))	('Epsilonpapillomavirus', 'Disease', (10, 31))	('papilloma', 'Phenotype', 'HP:0012740', (97, 106))	('papillomas', 'Phenotype', 'HP:0012740', (77, 87))	('Epsilonpapillomavirus', 'Disease', 'None', (10, 31))	('papilloma', 'Phenotype', 'HP:0012740', (17, 26))	('papillomas and fibropapillomas', 'Disease', 'MESH:D010212', (57, 87))	('squamous papillomas', 'Disease', 'MESH:D010212', (121, 140))	('associated', 'Reg', (36, 46))	('Xipapillomavirus', 'Disease', (95, 111))	('squamous papillomas', 'Disease', (121, 140))	('Delta', 'Var', (0, 5))
579986	28212457	Due to the stimulation of cell proliferation, BPV induces mitotic stress, resulting in cytogenetic aberrations .	('mitotic stress', 'CPA', (58, 72))	('BPV', 'Var', (46, 49))	('stimulation', 'PosReg', (11, 22))	('BP', 'Chemical', '-', (46, 48))	('cell proliferation', 'CPA', (26, 44))	('resulting in', 'Reg', (74, 86))	('cytogenetic aberrations', 'CPA', (87, 110))
580020	28212457	However, a current study showed a lack of correlation between BPV DNA in surgical margins and recurrence of equine sarcoids.	('BP', 'Chemical', '-', (62, 64))	('BPV DNA', 'Var', (62, 69))	('equine sarcoids', 'Disease', (108, 123))	('recurrence of equine', 'Phenotype', 'HP:0001762', (94, 114))	('equine', 'Species', '9796', (108, 114))
580052	28212457	Therefore, BPV-1 and 2 are considered important cofactors for BEH development, once BPV leads to epidermal and dermal hyperproliferation at the same time that it induces DNA damages, contributing to cancer initiation.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('BP', 'Chemical', '-', (11, 13))	('men', 'Species', '9606', (73, 76))	('BPV', 'Var', (84, 87))	('BP', 'Chemical', '-', (84, 86))	('epidermal', 'Disease', (97, 106))	('cancer initiation', 'Disease', 'MESH:D009369', (199, 216))	('BPV-1', 'Species', '337052', (11, 16))	('leads to', 'Reg', (88, 96))	('induces', 'Reg', (162, 169))	('cancer initiation', 'Disease', (199, 216))	('DNA', 'MPA', (170, 173))
580078	28212457	Among these are: (1) the presence of koilocytes in EC biopsies, (2) loss or mutation in p53 as a consequence of the PV E6 oncoprotein, (3) increase in telomerase activity, and detection of DNA sequences of HPV-6, 11, 18, 31 and 33 in EC.	('HPV-6', 'Gene', (206, 211))	('HPV', 'Species', '10566', (206, 209))	('p53', 'Gene', (88, 91))	('increase', 'PosReg', (139, 147))	('p53', 'Gene', '7157', (88, 91))	('loss', 'NegReg', (68, 72))	('mutation', 'Var', (76, 84))	('telomerase activity', 'MPA', (151, 170))
580096	28212457	Studies have demonstrated that BPV early proteins (E6 and E7) show a therapeutic action, while later proteins (L1 and L2) have a prophylactic action.	('BP', 'Chemical', '-', (31, 33))	('E6', 'Var', (51, 53))	('L1 and L2', 'Gene', '28938', (111, 120))	('E7', 'Var', (58, 60))
580101	28212457	Moreover, PVs represent an important problem in the veterinary field, inducing papillomas in dogs, felines and cattle.	('cattle', 'Species', '9913', (111, 117))	('papillomas', 'Phenotype', 'HP:0012740', (79, 89))	('dogs', 'Species', '9615', (93, 97))	('inducing', 'Reg', (70, 78))	('papillomas', 'Disease', 'MESH:D010212', (79, 89))	('papilloma', 'Phenotype', 'HP:0012740', (79, 88))	('PVs', 'Var', (10, 13))	('papillomas', 'Disease', (79, 89))
580115	28210168	For example, acute dysphagia resulting from irradiation of the esophagus was reported in one study on 13% of patients' quality of life questionnaires, 18% of weekly physician ratings, and in 28% of patients' verbal descriptions.	('irradiation', 'Var', (44, 55))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (198, 206))	('dysphagia', 'Disease', (19, 28))	('dysphagia', 'Phenotype', 'HP:0002015', (19, 28))	('dysphagia', 'Disease', 'MESH:D003680', (19, 28))
580145	28210168	Patient characteristics associated with higher rates of severe acute esophagitis include Caucasian race, age >=70 years, female sex, poor initial performance status, low body mass index, gastroesophageal reflux disease, and potentially pretreatment dysphagia.	('gastroesophageal reflux disease', 'Disease', (187, 218))	('dysphagia', 'Disease', 'MESH:D003680', (249, 258))	('low body mass', 'Phenotype', 'HP:0004325', (166, 179))	('low body', 'Var', (166, 174))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (187, 210))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (187, 218))	('esophagitis', 'Phenotype', 'HP:0100633', (69, 80))	('dysphagia', 'Disease', (249, 258))	('low body mass index', 'Phenotype', 'HP:0045082', (166, 185))	('acute esophagitis', 'Disease', (63, 80))	('dysphagia', 'Phenotype', 'HP:0002015', (249, 258))	('Patient', 'Species', '9606', (0, 7))	('acute esophagitis', 'Disease', 'MESH:D004941', (63, 80))
580147	28210168	Higher tumor and nodal stage and the presence of N2 disease are associated with higher rates of esophagitis, likely as surrogates for the volume of esophagus irradiated.	('N2', 'CellLine', 'CVCL:H592', (49, 51))	('tumor', 'Disease', (7, 12))	('esophagitis', 'Phenotype', 'HP:0100633', (96, 107))	('esophagitis', 'Disease', (96, 107))	('esophagitis', 'Disease', 'MESH:D004941', (96, 107))	('N2 disease', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
580149	28210168	Germline polymorphisms may render some patients more susceptible to injury than others.	('patients', 'Species', '9606', (39, 47))	('injury', 'Disease', (68, 74))	('susceptible', 'MPA', (53, 64))	('injury', 'Disease', 'MESH:D058186', (68, 74))	('render', 'Reg', (27, 33))	('more', 'PosReg', (48, 52))	('Germline polymorphisms', 'Var', (0, 22))
580163	28210168	Parameters from the Quantitative Analyses of Normal Tissue Effects in the Clinic report provide estimates of acute esophagitis risk in relation to mean organ dose (eg, mean dose to the entire esophagus <34 Gy results in 5%-20% incidence of grade >3 esophagitis).	('<34', 'Var', (202, 205))	('acute esophagitis', 'Disease', (109, 126))	('esophagitis', 'Disease', 'MESH:D004941', (115, 126))	('acute esophagitis', 'Disease', 'MESH:D004941', (109, 126))	('esophagitis', 'Disease', (249, 260))	('esophagitis', 'Phenotype', 'HP:0100633', (115, 126))	('esophagitis', 'Phenotype', 'HP:0100633', (249, 260))	('esophagitis', 'Disease', (115, 126))	('esophagitis', 'Disease', 'MESH:D004941', (249, 260))
580164	28210168	An individual patient data meta-analysis including 1,082 patients undergoing curative-intent CRT for locally advanced NSCLC found that esophageal volume receiving >=60 Gy (V60) was the best predictor, with a V60 <0.07% associated with <5% risk of grade 3 or higher esophagitis, but V60 >=17% conferring a 59% risk of grade >=2 and 22% of grade >=3 esophagitis.	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('patient', 'Species', '9606', (57, 64))	('esophagitis', 'Phenotype', 'HP:0100633', (265, 276))	('esophagitis', 'Disease', (265, 276))	('patients', 'Species', '9606', (57, 65))	('esophagitis', 'Phenotype', 'HP:0100633', (348, 359))	('esophagitis', 'Disease', 'MESH:D004941', (265, 276))	('esophagitis', 'Disease', (348, 359))	('patient', 'Species', '9606', (14, 21))	('NSCLC', 'Disease', (118, 123))	('V60', 'Var', (282, 285))	('grade', 'Disease', (317, 322))	('esophagitis', 'Disease', 'MESH:D004941', (348, 359))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('V60', 'Var', (208, 211))
580174	28210168	Another potential radioprotective agent, glutamine, has been associated with lower rates of mucositis, weight loss, and TPN use based on a retrospective cohort study in patients with head and neck and thoracic malignancies.	('lower', 'NegReg', (77, 82))	('patients', 'Species', '9606', (169, 177))	('glutamine', 'Var', (41, 50))	('mucositis', 'Disease', (92, 101))	('thoracic malignancies', 'Disease', 'MESH:D009369', (201, 222))	('weight loss', 'Disease', 'MESH:D015431', (103, 114))	('thoracic malignancies', 'Disease', (201, 222))	('mucositis', 'Disease', 'MESH:D052016', (92, 101))	('weight loss', 'Disease', (103, 114))	('weight loss', 'Phenotype', 'HP:0001824', (103, 114))	('glutamine', 'Chemical', 'MESH:D005973', (41, 50))
580197	28210168	An early trial randomizing esophageal cancer patients to sucralfate or a control antacid containing sodium alginate reported significant symptom relief in 80% of patients treated with sucralfate compared to 10% of patients receiving the control and faster ulcer healing with sucralfate.	('sucralfate', 'Chemical', 'MESH:D013392', (57, 67))	('patients', 'Species', '9606', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('esophageal cancer', 'Disease', (27, 44))	('patients', 'Species', '9606', (214, 222))	('sodium alginate', 'Chemical', 'MESH:D000464', (100, 115))	('symptom relief', 'MPA', (137, 151))	('ulcer healing', 'Disease', 'MESH:D014456', (256, 269))	('sucralfate', 'Chemical', 'MESH:D013392', (275, 285))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))	('patients', 'Species', '9606', (45, 53))	('sucralfate', 'Chemical', 'MESH:D013392', (184, 194))	('sucralfate', 'Var', (184, 194))	('ulcer healing', 'Disease', (256, 269))
580216	26683359	In mammals, DNA methylation occurs almost exclusively at the 5'-carbon position of cytosine residues within CpG pairs, and has a profound effect on gene expression.	('carbon', 'Chemical', 'MESH:D002244', (64, 70))	('effect', 'Reg', (138, 144))	('cytosine', 'Chemical', 'MESH:D003596', (83, 91))	('methylation', 'Var', (16, 27))	('gene expression', 'MPA', (148, 163))
580217	26683359	Many tumor suppressor genes (TSGs), such as CDKN2A, FHIT, MGMT, RASSF1A, CDH1 and APC, have been reported to be silenced by promoter hypermethylation in the development of breast cancer, lung cancer, thymic epithelial tumors, colorectal cancer and ESCC.	('thymic epithelial tumors', 'Disease', 'MESH:C536905', (200, 224))	('MGMT', 'Gene', '4255', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('CDKN2A', 'Gene', (44, 50))	('tumor', 'Disease', (218, 223))	('colorectal cancer', 'Phenotype', 'HP:0003003', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CDKN2A', 'Gene', '1029', (44, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('FHIT', 'Gene', (52, 56))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('thymic epithelial tumors', 'Disease', (200, 224))	('ESCC', 'Disease', (248, 252))	('lung cancer', 'Disease', (187, 198))	('promoter hypermethylation', 'Var', (124, 149))	('MGMT', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('RASSF1A', 'Gene', '11186', (64, 71))	('CDH1', 'Gene', '999', (73, 77))	('breast cancer', 'Disease', (172, 185))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('colorectal cancer', 'Disease', 'MESH:D015179', (226, 243))	('RASSF1A', 'Gene', (64, 71))	('FHIT', 'Gene', '2272', (52, 56))	('CDH1', 'Gene', (73, 77))	('colorectal cancer', 'Disease', (226, 243))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('APC', 'Disease', (82, 85))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('silenced', 'NegReg', (112, 120))	('tumor', 'Disease', (5, 10))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))
580218	26683359	On the other hand, some of the oncogenes, such as GADD45A, were abnormally activated by hypomethylated changes, contributing to the occurrence of ESCC.	('oncogenes', 'Gene', (31, 40))	('GADD45A', 'Gene', (50, 57))	('activated', 'PosReg', (75, 84))	('GADD45A', 'Gene', '1647', (50, 57))	('ESCC', 'Disease', (146, 150))	('contributing', 'Reg', (112, 124))	('hypomethylated changes', 'Var', (88, 110))
580223	26683359	Of the18 CpG sites from MLH1 DMR region, 9 continuous clustered CpG loci (-52, -54, -64, -71, -88, -102, -111, -142, -148) were identified to be significantly hypermethylated in ESCC samples than that in NE samples (0.707+-0.133 vs 0.302+-0.09, p<0.001; Fig.	('-52', 'Var', (74, 77))	('hypermethylated', 'PosReg', (159, 174))	('MLH1', 'Gene', '4292', (24, 28))	('MLH1', 'Gene', (24, 28))	('ESCC', 'Disease', (178, 182))
580225	26683359	There were no significant differences in the DNA methylation status of all the 13 CpG sites of the TWIST1 DMR region (-1500bp~-1320), however, 6 continuous clustered CpG loci (-1398, -1418, -1424, -1427, -1430, -1453) showed hypomethylated changes in ESCC samples (0.544+-0.241 vs 0.752+-0.117, p<0.001; Fig.	('hypomethylated', 'MPA', (225, 239))	('-1500bp~-1320', 'Var', (118, 131))	('ESCC', 'Disease', (251, 255))	('-1398', 'Var', (176, 181))	('TWIST1', 'Gene', (99, 105))	('TWIST1', 'Gene', '7291', (99, 105))
580226	26683359	Moreover, significant hypomethylation of CDX1 DMR region were also found in the ESCC group compared to NE group (0.475+-0.194 vs 0.693+-0.102, p<0.001; Fig.	('CDX1', 'Gene', '1044', (41, 45))	('CDX1', 'Gene', (41, 45))	('ESCC', 'Disease', (80, 84))	('0.475+-0.194', 'Var', (113, 125))	('hypomethylation', 'MPA', (22, 37))
580235	26683359	Survival analysis showed that the aberrant methylation of MLH1 significantly related to patients' survival (p=0.001; Fig.	('related', 'Reg', (77, 84))	('patients', 'Species', '9606', (88, 96))	('MLH1', 'Gene', '4292', (58, 62))	('aberrant methylation', 'Var', (34, 54))	('MLH1', 'Gene', (58, 62))
580239	26683359	According to GO analysis and pathway analysis, DMRs were identified in genes associated with cell cycle, adhesion, apoptosis and many biological pathways, which were closely correlated with carcinogenesis.	('carcinogenesis', 'Disease', (190, 204))	('adhesion', 'CPA', (105, 113))	('cell cycle', 'CPA', (93, 103))	('DMRs', 'Var', (47, 51))	('apoptosis', 'CPA', (115, 124))	('correlated', 'Reg', (174, 184))	('carcinogenesis', 'Disease', 'MESH:D063646', (190, 204))	('associated', 'Reg', (77, 87))
580243	26683359	Interestingly, promoter hypermethylation of TWIST1 was also observed in the development of colorectal cancer, vulvar cancer and tonsillar squamous cell carcinoma.	('TWIST1', 'Gene', '7291', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('colorectal cancer', 'Disease', (91, 108))	('vulvar cancer', 'Disease', 'MESH:D014846', (110, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('promoter hypermethylation', 'Var', (15, 40))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tonsillar squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 161))	('tonsillar squamous cell carcinoma', 'Disease', (128, 161))	('observed', 'Reg', (60, 68))	('vulvar cancer', 'Phenotype', 'HP:0030416', (110, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('vulvar cancer', 'Disease', (110, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('TWIST1', 'Gene', (44, 50))
580244	26683359	reported strong inverse correlations between TWIST1 methylation and stromal expression of TWIST1 in colon cancer.	('inverse', 'NegReg', (16, 23))	('TWIST1', 'Gene', (45, 51))	('TWIST1', 'Gene', (90, 96))	('TWIST1', 'Gene', '7291', (45, 51))	('stromal expression', 'MPA', (68, 86))	('TWIST1', 'Gene', '7291', (90, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('colon cancer', 'Disease', 'MESH:D015179', (100, 112))	('methylation', 'Var', (52, 63))	('colon cancer', 'Disease', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
580245	26683359	Wong and colleagues reported promoter-specific hypomethylation of TWIST1 was strongly associated with gene overexpression, indicating the promoter methylation may regulate the TWIST1 expression.	('regulate', 'Reg', (163, 171))	('gene overexpression', 'MPA', (102, 121))	('hypomethylation', 'Var', (47, 62))	('TWIST1', 'Gene', (66, 72))	('TWIST1', 'Gene', '7291', (66, 72))	('associated', 'Reg', (86, 96))	('TWIST1', 'Gene', (176, 182))	('TWIST1', 'Gene', '7291', (176, 182))	('expression', 'MPA', (183, 193))
580246	26683359	Our MeDIP-Seq results, for the first time, identified a DMR (from -1010 to -1715) in upstream 2K of TWIST1.	('from -1010 to -1715', 'Var', (61, 80))	('TWIST1', 'Gene', (100, 106))	('TWIST1', 'Gene', '7291', (100, 106))
580248	26683359	Nevertheless, survival analysis did not found significant correlation between overexpression or methylation of TWIST1 and patients' survival.	('patients', 'Species', '9606', (122, 130))	('TWIST1', 'Gene', '7291', (111, 117))	('TWIST1', 'Gene', (111, 117))	('methylation', 'Var', (96, 107))
580251	26683359	Recent studies showed that CDX1 expression was down-regulated by promoter hypermethylation in colon cancer, whereas a subset of colon cancers may express increased levels of CDX1 mRNA and protein.	('CDX1', 'Gene', '1044', (27, 31))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('down-regulated', 'NegReg', (47, 61))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('colon cancer', 'Disease', (94, 106))	('colon cancers', 'Phenotype', 'HP:0003003', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('expression', 'MPA', (32, 42))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('increased', 'PosReg', (154, 163))	('levels', 'MPA', (164, 170))	('CDX1', 'Gene', (174, 178))	('colon cancers', 'Disease', 'MESH:D015179', (128, 141))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('CDX1', 'Gene', (27, 31))	('colon cancers', 'Disease', (128, 141))	('CDX1', 'Gene', '1044', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('promoter hypermethylation', 'Var', (65, 90))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
580252	26683359	Our results showed that the hypomethylation of CDX1 was related to the gene overexpression in ESCC samples, which indicated that the CDX1 might have oncogenic potential in the development of ESCC.	('CDX1', 'Gene', '1044', (133, 137))	('CDX1', 'Gene', '1044', (47, 51))	('hypomethylation', 'Var', (28, 43))	('oncogenic potential', 'CPA', (149, 168))	('CDX1', 'Gene', (133, 137))	('CDX1', 'Gene', (47, 51))	('ESCC', 'Disease', (191, 195))
580253	26683359	The silencing and promoter hypermethylation of tumor suppressor gene MLH1 and CDH5 have been reported in various cancers.	('tumor', 'Disease', (47, 52))	('promoter', 'MPA', (18, 26))	('CDH5', 'Gene', (78, 82))	('CDH5', 'Gene', '1003', (78, 82))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('reported', 'Reg', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancers', 'Disease', (113, 120))	('MLH1', 'Gene', '4292', (69, 73))	('MLH1', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('silencing', 'Var', (4, 13))
580254	26683359	Deng and colleagues reported that MLH1 silencing by methylation is region specific.	('silencing', 'NegReg', (39, 48))	('MLH1', 'Gene', (34, 38))	('MLH1', 'Gene', '4292', (34, 38))	('methylation', 'Var', (52, 63))
580255	26683359	The loss of expression of MLH1 was correlated with the proximal region (from -322 to +56), but not the distal region (from -796 to -547).	('loss of', 'NegReg', (4, 11))	('MLH1', 'Gene', '4292', (26, 30))	('MLH1', 'Gene', (26, 30))	('expression', 'MPA', (12, 22))	('from -322 to +56', 'Var', (72, 88))
580256	26683359	In our study, the identified MLH1 DMR (from -250 to -10) also located at proximal region.	('MLH1', 'Gene', '4292', (29, 33))	('from -250 to -10', 'Var', (39, 55))	('MLH1', 'Gene', (29, 33))
580257	26683359	Moreover, the survival analysis showed that the methylation of MLH1 significantly correlated with patient survival, indicating the MLH1 might play important role in the carcinogenesis of ESCC.	('ESCC', 'Disease', (187, 191))	('play', 'Reg', (142, 146))	('carcinogenesis', 'Disease', (169, 183))	('patient', 'Species', '9606', (98, 105))	('methylation', 'Var', (48, 59))	('MLH1', 'Gene', '4292', (63, 67))	('correlated', 'Reg', (82, 92))	('MLH1', 'Gene', (63, 67))	('MLH1', 'Gene', '4292', (131, 135))	('carcinogenesis', 'Disease', 'MESH:D063646', (169, 183))	('role', 'Reg', (157, 161))	('MLH1', 'Gene', (131, 135))
580258	26683359	Together, our results show that genome-wide aberrant DNA methylation of cancer-associated genes may be involved in the pathogenesis of ESCC.	('ESCC', 'Disease', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('aberrant DNA methylation', 'Var', (44, 68))	('involved', 'Reg', (103, 111))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
580285	25337558	The evidence that mutation in tumor suppressors such as BRCA1/2 makes cancer cells highly susceptible to inhibitors of a compensatory DNA repair pathway has broadened the range of possible therapeutic targets by extending it to gene products that are in a "synthetic lethality" relationship with oncogenes and tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('BRCA1', 'Gene', '672', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BRCA1', 'Gene', (56, 61))	('tumor', 'Disease', (310, 315))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutation', 'Var', (18, 26))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Disease', (30, 35))
580286	25337558	This approach has led to identify compounds that are highly active in the presence of different types of mutated tumor suppressors and oncogenes.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mutated', 'Var', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
580299	25337558	Therefore, the idea of therapeutic or preventive synthetic lethality rests on the premise that neoplastic cells develop mutations that normal cells do not and that inhibiting first one and then another critical pathway with a drug will be lethal to the cancer cells.	('inhibiting', 'NegReg', (164, 174))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
580301	25337558	In breast or ovary cancer, patients with mutated BRCA1 or 2, essential components of a repair pathway for repairing DNA double-strand breaks have become reliant on another DNA repair component, PARP1, for replication fork progression.	('mutated', 'Var', (41, 48))	('PARP1', 'Gene', '142', (194, 199))	('BRCA1', 'Gene', '672', (49, 54))	('breast or ovary cancer', 'Disease', 'MESH:D001943', (3, 25))	('PARP1', 'Gene', (194, 199))	('patients', 'Species', '9606', (27, 35))	('BRCA1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast or ovary cancer', 'Disease', (3, 25))	('ovary cancer', 'Phenotype', 'HP:0100615', (13, 25))
580303	25337558	In patients with lung cancer, mutations and activation of KRAS occur frequently and are thought to be a primary driver of non-small cell lung cancers (NSCLC), chemotherapy is based on a synthetic lethal interaction among TNF-related apoptosis-inducing ligand (TRAIL), the second mitochondria-derived activator of caspase, Smac/DIABLO, and KRAS, leading to short-term, intermittent treatment with TRAIL and Smac-mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of KRAS- induced lung cancer.	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (122, 149))	('TRAIL', 'Gene', (260, 265))	('second mitochondria-derived activator of caspase', 'Gene', (272, 320))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('lung cancer', 'Disease', 'MESH:D008175', (510, 521))	('DIABLO', 'Gene', '56616', (327, 333))	('second mitochondria-derived activator of caspase', 'Gene', '56616', (272, 320))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (221, 258))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (126, 149))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (510, 521))	('reduced', 'NegReg', (454, 461))	('NSCLC', 'Disease', (151, 156))	('Smac', 'Gene', (322, 326))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('TRAIL', 'Gene', '8743', (396, 401))	('apoptosis', 'CPA', (425, 434))	('lung cancers', 'Phenotype', 'HP:0100526', (137, 149))	('non-small cell lung cancers', 'Disease', (122, 149))	('tumor', 'Disease', (438, 443))	('tumor', 'Disease', (462, 467))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('Smac', 'Gene', '56616', (322, 326))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (122, 149))	('TNF-related apoptosis-inducing ligand', 'Gene', (221, 258))	('tumor', 'Disease', 'MESH:D009369', (438, 443))	('tumor', 'Disease', 'MESH:D009369', (462, 467))	('DIABLO', 'Gene', (327, 333))	('murine', 'Species', '10090', (480, 486))	('cancer', 'Phenotype', 'HP:0002664', (515, 521))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (30, 39))	('TRAIL', 'Gene', (396, 401))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('TRAIL', 'Gene', '8743', (260, 265))	('lung cancer', 'Disease', (510, 521))	('Smac', 'Gene', (406, 410))	('lung cancer', 'Disease', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (462, 467))	('tumor', 'Phenotype', 'HP:0002664', (438, 443))	('Smac', 'Gene', '56616', (406, 410))
580344	25337558	Apart from colitic cancer, colorectal carcinogenesis is also based on a multi-step process characterized by molecular and cellular alterations that result in an identifiable precursor lesion, ie, the adenomatous polyp.	('alterations', 'Var', (131, 142))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (27, 52))	('colitic cancer', 'Disease', (11, 25))	('adenomatous polyp', 'Disease', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('colitic cancer', 'Disease', 'MESH:D009369', (11, 25))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (200, 217))	('adenomatous polyp', 'Disease', 'MESH:D018256', (200, 217))	('colorectal carcinogenesis', 'Disease', (27, 52))
580354	25337558	investigated the effect of sulindac on inhibition of chronic pancreatitis in a cerulein induced chronic pancreatitis mouse model and found that sulindac was a promising reagent for the treatment of chronic pancreatitis via inhibition of inflammatory cell infiltration and stromal fibrosis as well as additional finding that capsaicin also could be a promising agent for the chemoprevention of pancreatic carcinogenesis, possibly via inhibiting pancreatitis and mutant Kras-led ERK activation.	('pancreatitis', 'Disease', 'MESH:D010195', (104, 116))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (53, 73))	('pancreatitis', 'Phenotype', 'HP:0001733', (444, 456))	('pancreatitis', 'Disease', (104, 116))	('inhibiting', 'NegReg', (433, 443))	('pancreatitis', 'Disease', 'MESH:D010195', (206, 218))	('fibrosis', 'Disease', (280, 288))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (393, 418))	('fibrosis', 'Disease', 'MESH:D005355', (280, 288))	('mutant', 'Var', (461, 467))	('pancreatitis', 'Disease', (206, 218))	('mouse', 'Species', '10090', (117, 122))	('pancreatitis', 'Phenotype', 'HP:0001733', (61, 73))	('pancreatitis', 'Disease', 'MESH:D010195', (444, 456))	('Kras', 'Gene', (468, 472))	('pancreatic carcinogenesis', 'Disease', (393, 418))	('sulindac', 'Chemical', 'MESH:D013467', (144, 152))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (96, 116))	('pancreatitis', 'Disease', (444, 456))	('ERK', 'Gene', (477, 480))	('pancreatitis', 'Disease', 'MESH:D010195', (61, 73))	('Kras', 'Gene', '16653', (468, 472))	('pancreatitis', 'Phenotype', 'HP:0001733', (104, 116))	('pancreatitis', 'Disease', (61, 73))	('ERK', 'Gene', '26413', (477, 480))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (198, 218))	('capsaicin', 'Chemical', 'MESH:D002211', (324, 333))	('sulindac', 'Chemical', 'MESH:D013467', (27, 35))	('pancreatitis', 'Phenotype', 'HP:0001733', (206, 218))
580474	24559853	The introduction of 18F-FDG PET/CT has greatly improved preoperative staging of esophageal carcinoma, as it has become possible to assess regional metabolism noninvasively with PET and metabolic tracers.	('improved', 'PosReg', (47, 55))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (80, 100))	('18F-FDG', 'Var', (20, 27))	('esophageal carcinoma', 'Disease', (80, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (80, 100))
580498	24348280	However, dilation can cause esophageal perforation in some patients, and sufficient dilation cannot be achieved for others with refractory stenosis, despite repeated EBDs.	('dilation', 'Var', (9, 17))	('cause', 'Reg', (22, 27))	('patients', 'Species', '9606', (59, 67))	('esophageal perforation', 'Disease', (28, 50))
580598	22086466	With respect to prognosis, immunostaining of ESCC for MMP-1 and PAR-1 was a significant determinant of unfavorable prognosis.	('MMP-1', 'Gene', (54, 59))	('PAR-1', 'Gene', '2149', (64, 69))	('immunostaining', 'Var', (27, 41))	('PAR-1', 'Gene', (64, 69))	('MMP-1', 'Gene', '4312', (54, 59))
580609	22086466	further showed that MMP-9 gene P574R polymorphism may contribute to a genetic risk factor for ESCC in a Chinese population.	('MMP-9', 'Gene', (20, 25))	('P574R polymorphism', 'Var', (31, 49))	('P574R', 'Mutation', 'rs2250889', (31, 36))	('MMP-9', 'Gene', '4318', (20, 25))	('ESCC', 'Disease', (94, 98))
580621	22086466	Among all MMPs, MMP-1 has the unique ability to cleave PAR-1, with subsequent activation of signal transduction pathways and alterations in the expression of downstream genes.	('MMP-1', 'Gene', (16, 21))	('expression of downstream genes', 'MPA', (144, 174))	('alterations', 'Reg', (125, 136))	('MMPs', 'Gene', '4312;4313;4314;4316;4318;4319;4322;4323;118856', (10, 14))	('signal transduction pathways', 'Pathway', (92, 120))	('cleave', 'Var', (48, 54))	('activation', 'PosReg', (78, 88))	('MMPs', 'Gene', (10, 14))	('PAR-1', 'Gene', '2149', (55, 60))	('MMP-1', 'Gene', '4312', (16, 21))	('PAR-1', 'Gene', (55, 60))
580752	11303996	Animal studies have shown that only bilateral cervical vagotomy or dorsal vagal ganglion ablation in the brainstem produces the manometric features of achalasia.	('achalasia', 'Disease', 'MESH:D004931', (151, 160))	('vagal ganglion ablation', 'Phenotype', 'HP:0002886', (74, 97))	('achalasia', 'Phenotype', 'HP:0002571', (151, 160))	('ablation', 'Var', (89, 97))	('achalasia', 'Disease', (151, 160))	('manometric', 'MPA', (128, 138))
580811	33233030	Their median OS was 75.1 months, 34.8 months, and 10.3 months for LNR 0, low, and high, respectively, and a lower survival rate was shown in the group with a large LNR value, as in all patients (p < 0.001).	('survival', 'MPA', (114, 122))	('high', 'Var', (82, 86))	('lower', 'NegReg', (108, 113))	('patients', 'Species', '9606', (185, 193))	('LNR', 'Var', (66, 69))	('low', 'Var', (73, 76))
580831	33233030	In the ypN1 group, low LNR patients showed better outcomes in OS, FFLR, and DFS.	('low LNR', 'Phenotype', 'HP:0012213', (19, 26))	('low', 'Var', (19, 22))	('patients', 'Species', '9606', (27, 35))	('FFLR', 'Disease', (66, 70))	('DFS', 'Disease', (76, 79))
580855	33381388	Patients with high expression of FGF2, FGFBP1, and FGFR3 had poor prognosis.	('FGFBP1', 'Gene', (39, 45))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('FGFR3', 'Gene', (51, 56))	('FGF2', 'Gene', (33, 37))
580860	33381388	In order to start signal, the compound of LMW, FGF2, cell surface heparin sulfate proteoglycans (HSPGs), and fibroblast growth factor receptor (FGFR) activates downstream signaling pathways, including Ras, Raf, MAPK, and ERK.	('FGF2', 'Gene', (47, 51))	('ERK', 'Gene', '5594', (221, 224))	('ERK', 'Gene', (221, 224))	('HSPG', 'Gene', '6383', (97, 101))	('downstream signaling pathways', 'Pathway', (160, 189))	('MAPK', 'Pathway', (211, 215))	('FGFR', 'Gene', (144, 148))	('HSPG', 'Gene', (97, 101))	('activates', 'PosReg', (150, 159))	('heparin', 'Chemical', 'MESH:D006493', (66, 73))	('SP', 'Chemical', 'MESH:C000604007', (98, 100))	('Raf', 'Pathway', (206, 209))	('LMW', 'Var', (42, 45))	('Ras', 'Pathway', (201, 204))
580865	33381388	The increased or mutated expression in FGFR3 leads to malignant progression in bladder cancer, colon cancer, and multiple myeloma.	('malignant progression', 'CPA', (54, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (95, 107))	('colon cancer', 'Disease', 'MESH:D015179', (95, 107))	('leads to', 'Reg', (45, 53))	('expression', 'MPA', (25, 35))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('FGFR3', 'Gene', (39, 44))	('colon cancer', 'Disease', (95, 107))	('multiple myeloma', 'Disease', 'MESH:D009101', (113, 129))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('multiple myeloma', 'Phenotype', 'HP:0006775', (113, 129))	('multiple myeloma', 'Disease', (113, 129))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('bladder cancer', 'Disease', (79, 93))	('mutated', 'Var', (17, 24))
580869	33381388	According to 2020 CSCO esophagus cancer diagnosis and treatment guidelines, the patients of cT1b cT2 N+ or cT3-cT4a, any N needs to be radical surgery and at the same time chemoradiotherapy.	('cT2 N+', 'Var', (97, 103))	('cT3', 'Gene', '285782', (107, 110))	('cT3', 'Gene', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cT1b', 'Gene', (92, 96))
580880	33381388	FGFR3 germ line mutations cause fatal dysplasia, cartilage growth not congruent, and congenital disorders.	('cause', 'Reg', (26, 31))	('FGFR3', 'Gene', (0, 5))	('mutations', 'Var', (16, 25))	('dysplasia', 'Disease', 'MESH:C536170', (38, 47))	('congenital disorders', 'Disease', 'MESH:D009358', (85, 105))	('cartilage growth', 'CPA', (49, 65))	('dysplasia', 'Disease', (38, 47))	('congenital disorders', 'Disease', (85, 105))
580883	33381388	Studies have shown that dysfunction in FGFR3 or mutations of FGFR3 are highly associated with multiple cancers, such as multiple myeloma, bladder cancer, breast cancer, and colorectal cancer.	('bladder cancer', 'Disease', (138, 152))	('multiple cancers', 'Disease', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))	('mutations', 'Var', (48, 57))	('multiple myeloma', 'Disease', (120, 136))	('FGFR3', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('associated', 'Reg', (78, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('multiple cancers', 'Disease', 'MESH:D009369', (94, 110))	('multiple myeloma', 'Phenotype', 'HP:0006775', (120, 136))	('colorectal cancer', 'Disease', (173, 190))	('breast cancer', 'Disease', (154, 167))	('dysfunction', 'Var', (24, 35))	('FGFR3', 'Gene', (39, 44))
580909	31333312	As one of the most common gastrointestinal conditions impacting patients on a day-to-day basis, BES can seriously degrade the quality of life and result in many problems, such as dysphagia, malnutrition, weight loss, aspiration, and respiratory failure.	('BES', 'Var', (96, 99))	('BES', 'Chemical', '-', (96, 99))	('aspiration', 'Disease', (217, 227))	('respiratory failure', 'Disease', 'MESH:D012131', (233, 252))	('malnutrition', 'Disease', 'MESH:D044342', (190, 202))	('result in', 'Reg', (146, 155))	('dysphagia', 'Phenotype', 'HP:0002015', (179, 188))	('aspiration', 'Phenotype', 'HP:0002835', (217, 227))	('respiratory failure', 'Disease', (233, 252))	('weight loss', 'Disease', 'MESH:D015431', (204, 215))	('gastrointestinal conditions', 'Disease', (26, 53))	('quality of life', 'CPA', (126, 141))	('degrade', 'NegReg', (114, 121))	('weight loss', 'Phenotype', 'HP:0001824', (204, 215))	('patients', 'Species', '9606', (64, 72))	('malnutrition', 'Phenotype', 'HP:0004395', (190, 202))	('respiratory failure', 'Phenotype', 'HP:0002878', (233, 252))	('gastrointestinal conditions', 'Disease', 'MESH:D005767', (26, 53))	('dysphagia', 'Disease', 'MESH:D003680', (179, 188))	('weight loss', 'Disease', (204, 215))	('dysphagia', 'Disease', (179, 188))	('malnutrition', 'Disease', (190, 202))	('problems', 'MPA', (161, 169))
580918	31333312	PLLA esophageal BDS manufactured with polydioxanone can reduce stent migration risk, but results in significant hyperblastosis than PLLA-BDS.	('polydioxanone', 'Var', (38, 51))	('hyperblastosis', 'Disease', 'None', (112, 126))	('stent migration', 'CPA', (63, 78))	('results in', 'Reg', (89, 99))	('polydioxanone', 'Chemical', 'MESH:D016687', (38, 51))	('reduce', 'NegReg', (56, 62))	('hyperblastosis', 'Disease', (112, 126))
580973	31333312	As indicated by the distribution of PCNA-positive cells (Figure 6A), the epithelial layer in the stent group was obviously thinner than that in the normal control group (141.2 +- 30.5 mum vs 261.5 +- 17.2 mum; P < 0.05).	('stent', 'Var', (97, 102))	('thinner', 'NegReg', (123, 130))	('PCNA', 'Gene', (36, 40))	('PCNA', 'Gene', '100339381', (36, 40))
581052	29462754	An ERF invades the trachea, bronchus, or lung, and saliva and food flow into the respiratory tract continuously through the fistula, so that severe pneumonia or lung abscess can develop.	('pneumonia', 'Disease', (148, 157))	('pneumonia', 'Disease', 'MESH:D011014', (148, 157))	('abscess', 'Phenotype', 'HP:0025615', (166, 173))	('lung abscess', 'Phenotype', 'HP:0025044', (161, 173))	('fistula', 'Disease', 'MESH:D005402', (124, 131))	('fistula', 'Disease', (124, 131))	('ERF', 'Var', (3, 6))	('lung abscess', 'Disease', (161, 173))	('invades', 'Reg', (7, 14))	('pneumonia', 'Phenotype', 'HP:0002090', (148, 157))
581133	24422746	High-incidence of PTEN mutations in Chinese patients with primary small cell carcinoma of the esophagus Primary small cell carcinoma of the esophagus (PSCCE) is a rare and aggressive tumor with poor prognosis.	('Primary small cell carcinoma of the esophagus', 'Disease', (104, 149))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (112, 132))	('carcinoma', 'Disease', (123, 132))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (123, 149))	('carcinoma', 'Disease', 'MESH:D002277', (77, 86))	('aggressive tumor', 'Disease', 'MESH:D001523', (172, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Primary small cell carcinoma of the esophagus', 'Disease', 'MESH:D018288', (104, 149))	('patients', 'Species', '9606', (44, 52))	('mutations', 'Var', (23, 32))	('aggressive tumor', 'Disease', (172, 188))	('carcinoma', 'Disease', 'MESH:D002277', (123, 132))	('PTEN', 'Gene', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinoma', 'Disease', (77, 86))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (77, 103))	('PTEN', 'Gene', '5728', (18, 22))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (66, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
581136	24422746	Only 1 (2.63%) out of 38 patients had EGFR mutations in L858R missense, and KRAS and PIK3CA were not found in the mutational spot in all patients.	('EGFR', 'Gene', (38, 42))	('mutations', 'Reg', (43, 52))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (25, 33))	('L858R', 'Mutation', 'rs121434568', (56, 61))	('L858R missense', 'Var', (56, 70))
581137	24422746	However, PTEN mutations presented in 14 (36.84%) out of 38 patients, including exon 5 coding for PTEN missense mutation (n =4, 10.53%), exon 6 (n =7, 18.42%), concurrent exon 5 and exon 6 (n =2, 5.26%), and exon 8 (n =1, 2.63%).	('PTEN', 'Disease', (9, 13))	('PTEN', 'Gene', (97, 101))	('patients', 'Species', '9606', (59, 67))	('missense mutation', 'Var', (102, 119))	('mutations', 'Var', (14, 23))
581138	24422746	The incidence of PTEN mutations in Chinese patients with PSCCE was higher than that of previous reports in other histological subtypes of esophageal cancer.	('esophageal cancer', 'Disease', (138, 155))	('higher', 'Reg', (67, 73))	('patients', 'Species', '9606', (43, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('PSCCE', 'Disease', (57, 62))	('mutations', 'Var', (22, 31))	('PTEN', 'Gene', (17, 21))
581146	24422746	Recently studies have indicated that the presence of mutant KRAS is favorable to one of the high-risk factors implicated in esophageal squamous cell carcinoma (ESCC) development .	('favorable', 'Reg', (68, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (124, 158))	('KRAS', 'Gene', (60, 64))	('mutant', 'Var', (53, 59))	('esophageal squamous cell carcinoma', 'Disease', (124, 158))	('presence', 'Var', (41, 49))
581147	24422746	Mutant Phosphatidylinositol 3-kinase CA (PIK3CA) stimulates the AKT pathway and promotes cell growth in several cancers, including ESCC and Non-small cell lung cancer (NSCLC) being associated in these cases with poor prognosis .	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('cell growth', 'CPA', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('ESCC', 'Disease', (131, 135))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('AKT', 'Gene', '207', (64, 67))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('stimulates', 'PosReg', (49, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('PIK3CA', 'Gene', (41, 47))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (140, 166))	('Mutant', 'Var', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('Non-small cell lung cancer', 'Disease', (140, 166))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('AKT', 'Gene', (64, 67))	('promotes', 'PosReg', (80, 88))	('NSCLC', 'Disease', (168, 173))
581148	24422746	Furthermore, PIK3CA mutations were always found in esophageal cancer  and further functional analyses of the mutations are warranted to determine whether or not they may be potentially useful targets of therapy for esophageal cancer .	('PIK3CA', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancer', 'Disease', (51, 68))	('esophageal cancer', 'Disease', (215, 232))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('found', 'Reg', (42, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (215, 232))	('mutations', 'Var', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
581149	24422746	Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) mutation is a frequent event in endometrial cancers.	('endometrial cancers', 'Disease', 'MESH:D016889', (95, 114))	('endometrial cancers', 'Disease', (95, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutation', 'Var', (63, 71))	('PTEN', 'Gene', (57, 61))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
581150	24422746	Recent reports have demonstrateded that the presence of PTEN mutation is highly predictive in glycogenic acanthosis of the esophagus, and there are mutations in the PTEN gene of the ESCC cells and that the wild type PTEN gene has important effects on the ESCC cells in vitro and in vivo .	('effects', 'Reg', (240, 247))	('mutations', 'Var', (148, 157))	('acanthosis', 'Phenotype', 'HP:0025092', (105, 115))	('PTEN', 'Gene', (56, 60))	('mutation', 'Var', (61, 69))	('presence', 'Var', (44, 52))	('glycogenic acanthosis of the esophagus', 'Disease', 'MESH:D004938', (94, 132))	('rat', 'Species', '10116', (27, 30))	('PTEN', 'Gene', (165, 169))	('glycogenic acanthosis of the esophagus', 'Disease', (94, 132))
581163	24422746	PIK3CA mutations in exons 9 and 20 were detected using a validated PIK3CA mutation kit (DxS, Manchester, UK) that identifies three somatic mutations (H1047R, E542 and E545) by Real-Time PCR based on ARMS and Scorpion technology.	('H1047R', 'Mutation', 'rs121913279', (150, 156))	('H1047R', 'Var', (150, 156))	('E542', 'Var', (158, 162))	('E545', 'Var', (167, 171))
581165	24422746	The following primer sets for Exon 5 were used: PTEN-F (forward) 5'ACC TGT TAA GTT TGT ATG CAA C3', PTEN-R (reverse) 3'TCC AGG AAG AGG AAA GGA AA5', Exon 6, PTEN-F 5'CAT AGC AAT TTA GTG AAA TAA CT3'; PTEN-R 3'GAT ATG GTT AAG AAA ACT GTT C5', Exon 8, PTEN-F 5'CTC AGA TTG CCT TAT AAT AGT C3'; PTEN-R 3'TCA TGT TAC TGC TAC GTA AAC5'.	("TAT AAT AGT C3'", 'Disease', (275, 290))	("PTEN-R 3'TCA", 'Var', (292, 304))	("TAT AAT AGT C3'", 'Disease', 'MESH:C565169', (275, 290))
581168	24422746	The presence of EGFR, KRAS, PIK3CA and PTEN mutations in 38 patients were listed in Table  1.	('PIK3CA', 'Gene', (28, 34))	('patients', 'Species', '9606', (60, 68))	('KRAS', 'Gene', (22, 26))	('mutations', 'Var', (44, 53))	('PTEN', 'Gene', (39, 43))	('EGFR', 'Gene', (16, 20))
581170	24422746	An EGFR mutation was identified in 1(2.63%) of the 38 PSCCE patients, resulting in L858R missense mutation in exon 21.	('L858R missense mutation', 'Var', (83, 106))	('PSCCE', 'Disease', (54, 59))	('patients', 'Species', '9606', (60, 68))	('L858R', 'Mutation', 'rs121434568', (83, 88))
581171	24422746	We either did not found KRAS mutations in codons 12, 13 and PIK3CA mutations in exon 9 (E542/E545) and exon 20 (H1047R) in all samples.	('H1047R', 'Var', (112, 118))	('E542/E545', 'Var', (88, 97))	('H1047R', 'Mutation', 'rs121913279', (112, 118))	('PIK3CA', 'Gene', (60, 66))
581172	24422746	PTEN mutations were detected in 14(36.84%) out of 38 patients (Figure  2), including exon 5 coding for PTEN missense mutation (n =4, 10.53%), exon 6 (n =7, 18.42%), concurrent exon 5 and exon 6 (n =2, 5.26%), and exon 8 (n =1, 2.63%).	('PTEN', 'Gene', (103, 107))	('patients', 'Species', '9606', (53, 61))	('mutations', 'Var', (5, 14))	('missense mutation', 'Var', (108, 125))	('PTEN', 'Gene', (0, 4))
581176	24422746	Recently many published reports have demonstrated that EGFR mutations were detected in EC cell lines and patients with EC (Table  3).	('patients', 'Species', '9606', (105, 113))	('EGFR', 'Gene', (55, 59))	('rat', 'Species', '10116', (44, 47))	('detected', 'Reg', (75, 83))	('mutations', 'Var', (60, 69))
581182	24422746	In this study, we found that only 2.63% of 38 patients with PSCCE carring EGFR mutations, consistent with data that reported in the previous studies on other histological types of EC , but significantly different from other reports (Table  3) .	('patients', 'Species', '9606', (46, 54))	('mutations', 'Var', (79, 88))	('EGFR', 'Gene', (74, 78))	('PSCCE', 'Disease', (60, 65))
581187	24422746	In terms of therapeutic implications, this also suggests that PSCCE patients with mutated KRAS should gain little or no benefit from RAS-targeted therapy.	('patients', 'Species', '9606', (68, 76))	('KRAS', 'Gene', (90, 94))	('mutated', 'Var', (82, 89))
581190	24422746	A novel candidate tumor suppressor gene, PTEN gene, known as another effector of PI3K/PTEN/AKT pathway, is always lost by mutations, deletions or promoter methylation silencing at high frequency in many primary and metastatic human cancers, which are important mechanisms for cell cycle progression, survival, metabolism and migration.	('human', 'Species', '9606', (226, 231))	('deletions', 'Var', (133, 142))	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('AKT', 'Gene', '207', (91, 94))	('primary and', 'Disease', (203, 214))	('tumor', 'Disease', (18, 23))	('cancers', 'Disease', (232, 239))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('rat', 'Species', '10116', (328, 331))	('AKT', 'Gene', (91, 94))	('mutations', 'Var', (122, 131))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('promoter methylation silencing', 'Var', (146, 176))	('lost', 'NegReg', (114, 118))	('PTEN gene', 'Gene', (41, 50))
581191	24422746	In this study, PIK3CA mutations in exons 9, 20 did not occur in PSCCE, but 36.84% (14 of 38 patients) of the PSCCE samples were found harboring PTEN mutations.	('mutations', 'Var', (149, 158))	('patients', 'Species', '9606', (92, 100))	('PIK3CA', 'Gene', (15, 21))	('PTEN', 'Gene', (144, 148))	('harboring', 'Reg', (134, 143))
581193	24422746	PTEN mutations have been identified in numerous human malignancies, including brain, ovary and prostate cancers, but they are rarely seen in carcinomas arising from the head and neck region (including esophagus) .	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('malignancies', 'Disease', (54, 66))	('identified', 'Reg', (25, 35))	('prostate cancers', 'Phenotype', 'HP:0012125', (95, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('brain', 'Disease', (78, 83))	('human', 'Species', '9606', (48, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('carcinomas', 'Disease', (141, 151))	('carcinomas', 'Disease', 'MESH:D002277', (141, 151))	('mutations', 'Var', (5, 14))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('ovary and prostate cancers', 'Disease', 'MESH:D011471', (85, 111))	('PTEN', 'Gene', (0, 4))
581195	24422746	Interestingly, 36.84% of the PSCCE samples were found harboring PTEN mutations, much higher than the incidence reported previously in ESCC and other tumors.	('mutations', 'Var', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('PSCCE', 'Disease', (29, 34))	('tumors', 'Disease', (149, 155))	('harboring', 'Reg', (54, 63))	('PTEN', 'Gene', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))
581197	24422746	Next, our work, even though interested in providing evidence for a newly found high incidence of PTEN mutation in PSCCE, is rather preliminary at this stage and a detailed characterization of the molecular mechanisms involved is required further experimental data for better understanding the functional role and significance of PTEN mutation in PSCCE.	('rat', 'Species', '10116', (124, 127))	('mutation', 'Var', (102, 110))	('PSCCE', 'Disease', (114, 119))	('PTEN', 'Gene', (97, 101))
581198	24422746	Our study is the first report of mutational analysis of EGFR, KRAS, PIK3CA and PTEN in a number of patients with PSCCE.	('mutational analysis', 'Var', (33, 52))	('KRAS', 'Gene', (62, 66))	('PIK3CA', 'Gene', (68, 74))	('patients', 'Species', '9606', (99, 107))	('EGFR', 'Gene', (56, 60))	('PSCCE', 'Disease', (113, 118))	('PTEN', 'Gene', (79, 83))
581199	24422746	Furthermore, EGFR mutations in PSCCE are rare but do exist, especially gefitinib associated mutations such as L858R, therefore gefitinib-based gene targeted therapy at EGFR but not KRAS and PIK3CA genes, probably should be included in this carcinoma treatment regimens for patients harboring L858R mutation.	('gefitinib', 'Chemical', 'MESH:D000077156', (71, 80))	('gefitinib', 'Chemical', 'MESH:D000077156', (127, 136))	('patients', 'Species', '9606', (273, 281))	('carcinoma', 'Disease', (240, 249))	('L858R', 'Mutation', 'rs121434568', (292, 297))	('L858R', 'Var', (110, 115))	('carcinoma', 'Disease', 'MESH:D002277', (240, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('L858R', 'Mutation', 'rs121434568', (110, 115))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
581266	21869820	Here we show that some human and murine tumor cell lines are highly resistant to the lytic effect of a type II herpes simplex virus-derived oncolytic virus, FusOn-H2, which was constructed by deleting the N-terminal region of the ICP10 gene.	('lytic effect', 'MPA', (85, 97))	('ICP10', 'Gene', (230, 235))	('murine', 'Species', '10090', (33, 39))	('herpes simplex', 'Phenotype', 'HP:0012302', (111, 125))	('FusOn-H2', 'Chemical', '-', (157, 165))	('deleting', 'Var', (192, 200))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('human', 'Species', '9606', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('resistant', 'NegReg', (68, 77))
581273	21869820	With a few notable exceptions, such as the strong link between a mutated epidermal growth factor (EGFR) gene and clinical responses to its tyrosine kinase inhibitor Iressa , the mechanisms accounting for the heterogeneous responses of tumors to biotherapy remain poorly understood.	('EGFR', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('epidermal growth factor', 'Gene', (73, 96))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('EGFR', 'Gene', '1950', (98, 102))	('epidermal growth factor', 'Gene', '1950', (73, 96))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('tumors', 'Disease', (235, 241))	('mutated', 'Var', (65, 72))
581289	21869820	To the contrary, treatment of implanted tumors with FusOn-H2 virotherapy led to their massive infiltration and destruction by neutrophils, suggesting a need to re-examine current strategies of virotherapy for cancer patients.	('implanted tumors', 'Disease', (30, 46))	('implanted tumors', 'Disease', 'MESH:D057873', (30, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('patients', 'Species', '9606', (216, 224))	('cancer', 'Disease', (209, 215))	('rat', 'Species', '10116', (181, 184))	('FusOn-H2', 'Var', (52, 60))	('FusOn-H2', 'Chemical', '-', (52, 60))	('rat', 'Species', '10116', (100, 103))	('infiltration', 'MPA', (94, 106))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
581346	21869820	Infiltrating neutrophils were much less common in EC9706 tumors treated with PBS (Fig.	('PBS', 'Chemical', 'MESH:D007854', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('EC9706', 'Var', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('rat', 'Species', '10116', (6, 9))	('tumors', 'Disease', (57, 63))	('EC9706', 'CellLine', 'CVCL:E307', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
581375	21869820	Among the five resistant lines, EC9706 (human esophageal carcinoma) and B16 (murine melanoma) showed an extremely high level of ISRE activity.	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('murine', 'Species', '10090', (77, 83))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('ISRE activity', 'MPA', (128, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('esophageal carcinoma', 'Disease', (46, 66))	('EC9706', 'Var', (32, 38))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (46, 66))	('human', 'Species', '9606', (40, 45))	('EC9706', 'CellLine', 'CVCL:E307', (32, 38))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (46, 66))
581380	21869820	When quantified by RT-PCR, ISG56 transcripts were significantly more abundant in EC9706 cells than in the other two lines (Fig.	('more abundant', 'PosReg', (64, 77))	('ISG56', 'Gene', (27, 32))	('EC9706', 'Var', (81, 87))	('EC9706', 'CellLine', 'CVCL:E307', (81, 87))
581401	21869820	For example, it has been reported that TGF-beta blockade increases neutrophil-attracting chemokines, resulting in an influx of CD11b+/Ly6G+ tumor-associated neutrophils that are cytotoxic to tumor cells .	('CD11b', 'Gene', '3684', (127, 132))	('neutrophil-attracting chemokines', 'MPA', (67, 99))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('CD11b', 'Gene', (127, 132))	('TGF-beta', 'Gene', '7040', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('blockade', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('increases', 'PosReg', (57, 66))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TGF-beta', 'Gene', (39, 47))	('tumor', 'Disease', (140, 145))
581441	18382671	It is believed that long-term inflammation due to gastro-esophageal reflux may cause genetic and epigenetic alterations in Barrett's esophagus, and that accumulation of these genetic and epigenetic alterations would lead the acquisition of malignant characteristics in the Barrett's cells, such as dysregulated cell proliferation, impaired apoptosis, and angiogenesis.	('esophageal reflux', 'Phenotype', 'HP:0002020', (57, 74))	('impaired', 'NegReg', (331, 339))	('dysregulated cell proliferation', 'CPA', (298, 329))	('acquisition', 'PosReg', (225, 236))	('epigenetic alterations', 'Var', (187, 209))	('apoptosis', 'CPA', (340, 349))	('lead', 'Reg', (216, 220))	('genetic', 'Var', (175, 182))	('malignant characteristics', 'CPA', (240, 265))	('inflammation', 'Disease', 'MESH:D007249', (30, 42))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (123, 142))	('accumulation', 'PosReg', (153, 165))	('inflammation', 'Disease', (30, 42))	('angiogenesis', 'CPA', (355, 367))
581442	18382671	As genetic alterations, loss of p16 gene expression (by deletion), the loss of p53 expression (by mutation and deletion), the increase in cyclin expression, and the losses of Rb, APC as well as various chromosomal loci in the Barrett's esophagus have been reported.	('p53', 'Gene', (79, 82))	('cyclin', 'Gene', (138, 144))	('p53', 'Gene', '7157', (79, 82))	('cyclin', 'Gene', '5111', (138, 144))	('expression', 'MPA', (41, 51))	('p16', 'Gene', '1029', (32, 35))	('APC', 'Disease', 'MESH:D011125', (179, 182))	('expression', 'MPA', (145, 155))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (226, 245))	('APC', 'Disease', (179, 182))	('expression', 'MPA', (83, 93))	('loss', 'NegReg', (71, 75))	('increase', 'PosReg', (126, 134))	('p16', 'Gene', (32, 35))	('loss', 'NegReg', (24, 28))	('losses', 'NegReg', (165, 171))	('deletion', 'Var', (111, 119))
581451	18382671	We have shown that certain tumor suppressor genes that undergo methylation in BE can function as biomarkers, predicting whether BE patients will or will not develop HGD or EAC.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patients', 'Species', '9606', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('methylation', 'Var', (63, 74))	('HGD', 'Disease', (165, 168))	('EAC', 'Disease', (172, 175))
581461	18382671	A normalized methylation value (NMV) reflecting the percentage of DNA methylated for the gene of interest (GoI) was defined as follows: NMV = 100x(GoI-S/GoI-FM)/(ACTB-S/ACTB-FM), where GoI-S and GoI-FM represent GoI methylation levels in the specimen and fully methylated DNAs, respectively, while ACTB-S and ACTB-FM correspond to beta-actin in the specimen and fully methylated (FM) DNAs, respectively.	('ACTB', 'Gene', '60', (162, 166))	('ACTB', 'Gene', (169, 173))	('NMV', 'Var', (136, 139))	('beta-actin', 'Gene', '728378', (331, 341))	('beta-actin', 'Gene', (331, 341))	('ACTB', 'Gene', '60', (169, 173))	('NMV', 'Chemical', '-', (32, 35))	('ACTB', 'Gene', (298, 302))	('ACTB', 'Gene', '60', (298, 302))	('NMV', 'Chemical', '-', (136, 139))	('ACTB', 'Gene', '60', (309, 313))	('ACTB', 'Gene', (309, 313))	('ACTB', 'Gene', (162, 166))
581466	18382671	Cutoffs of the NMV for the 4-year prediction model were lower than those for the 2-year model, possibly because epigenetic alterations were less widespread in progressor tissues at 4 years than at 2 years prior to progression.	('lower', 'NegReg', (56, 61))	('NMV', 'Chemical', '-', (15, 18))	('epigenetic alterations', 'Var', (112, 134))	('less', 'NegReg', (140, 144))
581493	18382671	However, mechanism(s) by which an "MI-high" epigenetic or methylator phenotype contributes to carcinogenesis remain(s) unclear.	('carcinogenesis', 'Disease', 'MESH:D063646', (94, 108))	('methylator', 'Var', (58, 68))	('carcinogenesis', 'Disease', (94, 108))
581494	18382671	Possible explanations include: 1) methylator phenotype-positive tumors tend to be hypermethylated in promoter regions of other genes, including tumor suppressor genes (such as APC, CDH1, TIMP3, and others); 2) methylator phenotype-positive tumors tend to undergo hMLH1 gene inactivation via promoter hypermethylation.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('TIMP3', 'Gene', (187, 192))	('TIMP3', 'Gene', '7078', (187, 192))	('CDH1', 'Gene', '999', (181, 185))	('tumors', 'Disease', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('CDH1', 'Gene', (181, 185))	('tumors', 'Disease', (64, 70))	('tumor', 'Disease', (240, 245))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', (144, 149))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('promoter hypermethylation', 'Var', (291, 316))	('hMLH1', 'Gene', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('hMLH1', 'Gene', '4292', (263, 268))	('tumor', 'Disease', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('APC', 'Disease', 'MESH:D011125', (176, 179))	('inactivation', 'NegReg', (274, 286))	('APC', 'Disease', (176, 179))
581495	18382671	Although hMLH1 hypermethylation is relatively uncommon in EAC compared to gastric, colorectal, or endometrial cancer, hMLH1 hypermethylation in BE may cause microsatellite instability in the coding regions of the tumor suppressor genes; 3) a methylator phenotype may be associated with chromatin remodeling; and 4) methylated cytosines are hotspots for mutations, as with the p53 gene.	('colorectal', 'Disease', (83, 93))	('p53', 'Gene', (376, 379))	('hMLH1', 'Gene', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('hMLH1', 'Gene', '4292', (118, 123))	('cause', 'Reg', (151, 156))	('cytosines', 'Chemical', 'MESH:D003596', (326, 335))	('microsatellite instability', 'MPA', (157, 183))	('endometrial cancer', 'Phenotype', 'HP:0012114', (98, 116))	('colorectal', 'Disease', 'MESH:D015179', (83, 93))	('hypermethylation', 'Var', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('endometrial cancer', 'Disease', (98, 116))	('hMLH1', 'Gene', (9, 14))	('hMLH1', 'Gene', '4292', (9, 14))	('tumor', 'Disease', (213, 218))	('endometrial cancer', 'Disease', 'MESH:D016889', (98, 116))	('p53', 'Gene', '7157', (376, 379))	('tumor', 'Disease', 'MESH:D009369', (213, 218))
581502	18382671	However, other studies have demonstrated that the risk of developing EAC in patients with short-segment BE is not substantially lower than in patients with long-segment BE.	('EAC', 'Disease', (69, 72))	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (142, 150))	('short-segment BE', 'Var', (90, 106))
581538	32558685	First, previous data show that ablation may alter the tissue DNA methylation profile in comparison with that of pretreatment BE.	('BE', 'Phenotype', 'HP:0100580', (125, 127))	('alter', 'Reg', (44, 49))	('tissue DNA methylation profile', 'MPA', (54, 84))	('ablation', 'Var', (31, 39))	('men', 'Species', '9606', (120, 123))
581647	32558685	Financial support: This work was partially supported by grants from the National Cancer Institute (CA214679 to JBK and CA241164 to PGI and JBK).	('CA214679', 'Var', (99, 107))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Cancer', 'Disease', (81, 87))	('CA241164', 'Var', (119, 127))	('Cancer', 'Disease', 'MESH:D009369', (81, 87))	('PGI', 'Gene', (131, 134))	('PGI', 'Gene', '2821', (131, 134))
581670	31293066	The National Cancer Institute's SEER database was utilized for the present study with information of cancer patients.20 Data for patients with esophageal cancer diagnosed between 2004 and 2015 were extracted from the SEER database with eligibility criteria as follows: (i) age older than 18 years and histologically confirmed cancer arising from the esophagus (ICD-O-3 codes: 8000-8576, 8940-8950, 8980-8981); (ii) primary tumor located in the upper or lower thoracic esophagus;21 (iii) survival time >= 3 months.	('patients', 'Species', '9606', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', (423, 428))	('8940-8950', 'Var', (387, 396))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (326, 332))	('tumor', 'Disease', 'MESH:D009369', (423, 428))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('patients', 'Species', '9606', (129, 137))	('8980-8981)', 'Var', (398, 408))	('esophageal cancer', 'Disease', (143, 160))	('tumor', 'Phenotype', 'HP:0002664', (423, 428))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('cancer', 'Disease', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
581689	31293066	In addition, surgery was also associated with increased OS (surgery vs. nonsurgery: 27.00% vs. 6.10%; P < 0.001; Fig 3c) and CSS (surgery vs. nonsurgery: 42.70% vs. 9.10%; P < 0.11; Fig 3d) for LTEC with supraclavicular node metastasis.	('OS', 'Chemical', '-', (56, 58))	('LTEC', 'Disease', (194, 198))	('CSS', 'Chemical', '-', (125, 128))	('surgery', 'Var', (13, 20))	('CSS', 'MPA', (125, 128))
581693	31293066	Meanwhile, radiotherapy was associated with improved OS (radiotherapy vs. nonradiotherapy: 14.50% vs. 4.20%; P < 0.001; Fig 5a) and CSS (radiotherapy vs. nonradiotherapy: 18.90% vs. 5.50%; P < 0.001; Fig 5b) for LTEC with celiac node metastasis.	('CSS', 'MPA', (132, 135))	('CSS', 'Chemical', '-', (132, 135))	('OS', 'Chemical', '-', (53, 55))	('celiac node metastasis', 'Disease', (222, 244))	('LTEC', 'Disease', (212, 216))	('improved', 'PosReg', (44, 52))	('radiotherapy', 'Var', (11, 23))
581719	30085197	However, the incidences of >=Grade 3 acute esophagitis and pneumonia were significantly lower in the IFI group.	('esophagitis', 'Disease', 'MESH:D004941', (43, 54))	('pneumonia', 'Disease', (59, 68))	('pneumonia', 'Phenotype', 'HP:0002090', (59, 68))	('IFI', 'Var', (101, 104))	('lower', 'NegReg', (88, 93))	('esophagitis', 'Phenotype', 'HP:0100633', (43, 54))	('esophagitis', 'Disease', (43, 54))	('pneumonia', 'Disease', 'MESH:D011014', (59, 68))
581723	30085197	found that ENI can reduce localized regional failure, and improve local control rates and long-term survival in patients with radical radiotherapy.	('ENI', 'Chemical', '-', (11, 14))	('reduce', 'NegReg', (19, 25))	('local control rates', 'CPA', (66, 85))	('improve', 'PosReg', (58, 65))	('ENI', 'Var', (11, 14))	('patients', 'Species', '9606', (112, 120))	('localized regional failure', 'CPA', (26, 52))
581734	30085197	As seen in Figs 7 and 8, the incidences of >=Grade 3 acute radiation-induced esophagitis and >=Grade 3 acute pneumonitis in the IFI group were significantly lower than those in ENI group (OR = 0.467, 95% CI 0.319-0.683, P = 0.000; OR = 0.464 , 95% CI 0.264-0.817, P = 0.008), while there was no significant difference with respect to >=Grade 3 myelosuppression (OR = 0.683, 95% CI 0.410-1.137, P = 0.143), as seen in Fig 9.	('myelosuppression', 'Disease', (344, 360))	('pneumonitis', 'Disease', (109, 120))	('IFI', 'Var', (128, 131))	('ENI', 'Chemical', '-', (177, 180))	('esophagitis', 'Phenotype', 'HP:0100633', (77, 88))	('esophagitis', 'Disease', (77, 88))	('pneumonitis', 'Disease', 'MESH:D011014', (109, 120))	('myelosuppression', 'Disease', 'MESH:D001855', (344, 360))	('esophagitis', 'Disease', 'MESH:D004941', (77, 88))	('lower', 'NegReg', (157, 162))
581735	30085197	The OR value did not differ significantly between the two groups (OR = 1.373, 95% CI 0.766-2.460, P = 0.287), indicating that ENI did not reduce the risk of out-field recurrence or metastasis (Fig 10).	('out-field recurrence', 'CPA', (157, 177))	('metastasis', 'CPA', (181, 191))	('ENI', 'Var', (126, 129))	('ENI', 'Chemical', '-', (126, 129))
581742	30085197	In 2012, a meta-analysis including five studies, involving 405 patients, showed that ENI did not improve the 1-year local control or 1-year survival rates, while it increased the incidence of radiation esophagitis and pneumonia.	('esophagitis', 'Phenotype', 'HP:0100633', (202, 213))	('radiation esophagitis', 'Disease', (192, 213))	('pneumonia', 'Phenotype', 'HP:0002090', (218, 227))	('local control', 'CPA', (116, 129))	('pneumonia', 'Disease', (218, 227))	('radiation esophagitis', 'Disease', 'MESH:D004194', (192, 213))	('pneumonia', 'Disease', 'MESH:D011014', (218, 227))	('ENI', 'Chemical', '-', (85, 88))	('patients', 'Species', '9606', (63, 71))	('increased', 'PosReg', (165, 174))	('ENI', 'Var', (85, 88))
581750	30085197	The incidences of >=Grade 3 acute radiation-induced esophagitis and >=Grade 3 acute pneumonitis in the IFI group were significantly lower due to the decrease in irradiation volume and dose (OR = 0.467, 95% CI 0.319-0.683, P = 0.000; and OR = 0.464, 95% CI 0.264-0.817, P = 0.008, respectively), while there was no significant difference in >=Grade 3 myelosuppression (OR = 0.683, 95% CI 0.410-1.137, P = 0.143).	('myelosuppression', 'Disease', 'MESH:D001855', (350, 366))	('esophagitis', 'Phenotype', 'HP:0100633', (52, 63))	('irradiation volume', 'CPA', (161, 179))	('esophagitis', 'Disease', (52, 63))	('IFI', 'Var', (103, 106))	('pneumonitis', 'Disease', (84, 95))	('esophagitis', 'Disease', 'MESH:D004941', (52, 63))	('myelosuppression', 'Disease', (350, 366))	('lower', 'NegReg', (132, 137))	('pneumonitis', 'Disease', 'MESH:D011014', (84, 95))	('decrease', 'NegReg', (149, 157))
581751	30085197	The side effects of concurrent radiochemotherapy and prophylactic exposure further affect the patient's tolerance, so ENI may lead to more severe radiation esophagitis and pneumonia.	('tolerance', 'MPA', (104, 113))	('pneumonia', 'Disease', (172, 181))	('pneumonia', 'Disease', 'MESH:D011014', (172, 181))	('affect', 'Reg', (83, 89))	('pneumonia', 'Phenotype', 'HP:0002090', (172, 181))	('more', 'PosReg', (134, 138))	('lead to', 'Reg', (126, 133))	('esophagitis', 'Phenotype', 'HP:0100633', (156, 167))	('ENI', 'Chemical', '-', (118, 121))	('patient', 'Species', '9606', (94, 101))	('ENI', 'Var', (118, 121))	('radiation esophagitis', 'Disease', (146, 167))	('radiation esophagitis', 'Disease', 'MESH:D004194', (146, 167))
581761	11473723	These results suggested that the L-myc polymorphism might modify the effects of lifestyle factors on esophageal cancer risk.	('L-myc', 'Gene', '4610', (33, 38))	('esophageal cancer', 'Disease', (101, 118))	('polymorphism', 'Var', (39, 51))	('modify', 'Reg', (58, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('L-myc', 'Gene', (33, 38))
581780	28556988	Another study demonstrated that ligation of the left gastric vessels in a rodent model led to an immediate decrease in gastric perfusion that significantly increased after 28 days and leveled off by 56 days after left gastric vessel ligation.	('gastric perfusion', 'MPA', (119, 136))	('ligation', 'Var', (32, 40))	('increased', 'PosReg', (156, 165))	('rat', 'Species', '10116', (21, 24))	('decrease', 'NegReg', (107, 115))
581795	28556988	Of the 21 patients who underwent laparoscopic ischemic conditioning, ligation of the left gastric and short gastric vessels was performed in 13 patients (complete IC group), whereas eight patients had short gastric vessel ligation only (partial IC group).	('ischemic', 'Disease', 'MESH:D007511', (46, 54))	('short gastric vessel', 'Disease', (201, 221))	('short gastric vessel', 'Disease', 'MESH:D013274', (102, 122))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (144, 152))	('ischemic', 'Disease', (46, 54))	('short gastric vessel', 'Disease', (102, 122))	('short gastric vessel', 'Disease', 'MESH:D013274', (201, 221))	('ligation', 'Var', (69, 77))	('patients', 'Species', '9606', (10, 18))
581820	28556988	ASA class was lower in patients undergoing complete IC than those of the control and partial IC (p=0.01, Table 1).	('patients', 'Species', '9606', (23, 31))	('lower', 'NegReg', (14, 19))	('ASA', 'Chemical', '-', (0, 3))	('complete IC', 'Var', (43, 54))	('ASA', 'Disease', (0, 3))
581824	28556988	CD34 immunostaining showed a 29% increase in microvessel counts in patients undergoing partial IC, as compared to controls (p=0.3, Figure 1).	('patients', 'Species', '9606', (67, 75))	('partial IC', 'Var', (87, 97))	('CD34', 'Gene', '947', (0, 4))	('increase', 'PosReg', (33, 41))	('CD34', 'Gene', (0, 4))	('microvessel counts', 'CPA', (45, 63))
581839	28556988	The basis of ischemic conditioning is that perfusion to conduit tip can be enhanced by ligation of select vessels to the stomach prior to esophagogastrostomy, allowing new microcirculation to develop to the gastric fundus at the site of the anastomosis.	('ischemic', 'Disease', (13, 21))	('perfusion', 'MPA', (43, 52))	('enhanced', 'PosReg', (75, 83))	('ischemic', 'Disease', 'MESH:D007511', (13, 21))	('microcirculation', 'MPA', (172, 188))	('ligation', 'Var', (87, 95))
581934	28470005	Cigarette smoking was not found to be associated with ESP in a previous study, but similar to a high BMI, cigarette smoking is a risk factor for the development of GERD.	('cigarette smoking', 'Var', (106, 123))	('GERD', 'Disease', 'MESH:D005764', (164, 168))	('GERD', 'Disease', (164, 168))	('risk factor', 'Reg', (129, 140))	('ESP', 'Phenotype', 'HP:0031463', (54, 57))
581955	28470005	This study identified certain clinical features to be prevalent in patients with ESP including high body mass index and cigarette smoking, which have not been previously described.	('patients', 'Species', '9606', (67, 75))	('prevalent', 'Reg', (54, 63))	('high body mass index', 'Var', (95, 115))	('ESP', 'Phenotype', 'HP:0031463', (81, 84))	('ESP', 'Disease', (81, 84))	('cigarette smoking', 'Disease', (120, 137))	('high body mass index', 'Phenotype', 'HP:0031418', (95, 115))
581976	27588478	However, dysregulation of Ca2+ signaling is involved in tumorigenesis and tumor progression, such as metastasis, invasion and angiogenesis.	('involved', 'Reg', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('invasion', 'CPA', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Ca2+', 'Chemical', 'MESH:D000069285', (26, 30))	('Ca2+ signaling', 'MPA', (26, 40))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('metastasis', 'CPA', (101, 111))	('angiogenesis', 'CPA', (126, 138))	('tumor', 'Disease', (74, 79))	('dysregulation', 'Var', (9, 22))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
581978	27588478	A number of studies found that [Ca2+]cyt is elevated in a variety of human cancer cells, but a reduction of [Ca2+]cyt via blockade of Ca2+ entry suppress cancer cell growth, suggesting that remodeling of [Ca2+]cyt homeostasis might be valuable in cancer therapy.	('cancer', 'Disease', (247, 253))	('Ca2+', 'Protein', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('suppress', 'NegReg', (145, 153))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('blockade', 'Var', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('[Ca2+]cyt', 'MPA', (108, 117))	('Ca2+', 'Chemical', 'MESH:D000069285', (32, 36))	('human', 'Species', '9606', (69, 74))	('Ca2+', 'Chemical', 'MESH:D000069285', (205, 209))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('Ca2+', 'Chemical', 'MESH:D000069285', (109, 113))	('Ca2+', 'Chemical', 'MESH:D000069285', (134, 138))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', (154, 160))	('reduction', 'NegReg', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
582011	27588478	Figure 4D and 4E summarize the inhibitory effects of KB-R7943 and SN-6 on 0 Na+-induced peaks and rising slopes of Ca2+ entry in the cells.	('KB-R7943', 'Chemical', 'MESH:C101670', (53, 61))	('KB-R7943', 'Var', (53, 61))	('Ca2+', 'Chemical', 'MESH:D000069285', (115, 119))	('0 Na+-induced peaks', 'MPA', (74, 93))	('SN-6', 'Chemical', '-', (66, 70))
582014	27588478	As shown in Figure 5A and 5B, both expression levels of NCX1 transcripts and proteins in three cell lines were significantly upregulated dose-dependently by NNK.	('NCX1', 'Gene', (56, 60))	('NCX1', 'Gene', '6546', (56, 60))	('expression levels', 'MPA', (35, 52))	('NNK', 'Chemical', 'MESH:C016583', (157, 160))	('upregulated', 'PosReg', (125, 136))	('NNK', 'Var', (157, 160))	('proteins', 'MPA', (77, 85))	('transcripts', 'MPA', (61, 72))
582016	27588478	These results suggest that NNK enhances higher NCX1 expression in human ESCC cells than in normal esophageal cells.	('human', 'Species', '9606', (66, 71))	('NCX1', 'Gene', (47, 51))	('NNK', 'Chemical', 'MESH:C016583', (27, 30))	('enhances higher', 'PosReg', (31, 46))	('NCX1', 'Gene', '6546', (47, 51))	('NNK', 'Var', (27, 30))
582019	27588478	Moreover, KB-R7943 and SN-6 significantly prevented NNK-induced Ca2+ influx in these cells (Figure 6B).	('SN-6', 'Chemical', '-', (23, 27))	('prevented', 'NegReg', (42, 51))	('KB-R7943', 'Var', (10, 18))	('KB-R7943', 'Chemical', 'MESH:C101670', (10, 18))	('Ca2+', 'Chemical', 'MESH:D000069285', (64, 68))	('NNK-induced Ca2+ influx', 'MPA', (52, 75))	('NNK', 'Chemical', 'MESH:C016583', (52, 55))
582021	27588478	Interestingly, NNK induced greater NCX1 activity in human ESCC cells (EC-109 and HKESC-1) than in normal esophageal cells (NE-1) (Figure 6E and 6F).	('HKESC-1', 'CellLine', 'CVCL:D568', (81, 88))	('NNK', 'Chemical', 'MESH:C016583', (15, 18))	('NCX1', 'Gene', (35, 39))	('greater', 'PosReg', (27, 34))	('NNK', 'Var', (15, 18))	('EC-109', 'CellLine', 'CVCL:6898', (70, 76))	('NCX1', 'Gene', '6546', (35, 39))	('human', 'Species', '9606', (52, 57))
582022	27588478	Therefore, NNK enhances not only higher NCX1 expression in human ESCC cells but NCX1 activity as well.	('human', 'Species', '9606', (59, 64))	('higher', 'PosReg', (33, 39))	('enhances', 'PosReg', (15, 23))	('NCX1', 'Gene', (80, 84))	('NCX1', 'Gene', (40, 44))	('NCX1', 'Gene', '6546', (80, 84))	('NCX1', 'Gene', '6546', (40, 44))	('NNK', 'Chemical', 'MESH:C016583', (11, 14))	('NNK', 'Var', (11, 14))
582025	27588478	However, NNK-promoted proliferation of human esophageal cells was abolished by KB-R7943 and SN-6 (Figure 7B and 7C).	('NNK', 'Chemical', 'MESH:C016583', (9, 12))	('SN-6', 'Chemical', '-', (92, 96))	('abolished', 'NegReg', (66, 75))	('KB-R7943', 'Chemical', 'MESH:C101670', (79, 87))	('KB-R7943', 'Var', (79, 87))	('proliferation', 'CPA', (22, 35))	('human', 'Species', '9606', (39, 44))
582033	27588478	Specifically, tobacco smoking is the environmental risk factor for ESCC, and it may cause genetic and epigenetic changes to eventually lead to ESCC.	('lead to', 'Reg', (135, 142))	('epigenetic changes', 'Var', (102, 120))	('ESCC', 'Disease', (67, 71))	('ESCC', 'Disease', (143, 147))	('tobacco', 'Species', '4097', (14, 21))	('cause', 'Reg', (84, 89))
582054	27588478	Although further studies are needed to elucidate the detailed mechanisms by how NCX1-mediated Ca2+ entry induces human ESCC, our study has provided a novel perspective that targeting NCX1 may be a potential therapeutic strategy for ESCC.	('induces', 'Reg', (105, 112))	('targeting', 'Var', (173, 182))	('NCX1', 'Gene', (80, 84))	('ESCC', 'Disease', (232, 236))	('NCX1', 'Gene', '6546', (183, 187))	('ESCC', 'Disease', (119, 123))	('NCX1', 'Gene', '6546', (80, 84))	('Ca2+', 'Chemical', 'MESH:D000069285', (94, 98))	('human', 'Species', '9606', (113, 118))	('NCX1', 'Gene', (183, 187))
582205	28152423	Good sample size and significant metabolic differences between the histologically normal tissue samples from controls and EAC patients resulted in a strong PLS-DA model (AUROC = 1.00, CVER = 0.017, P = .007, .005; Figure 6), giving a near-perfect separation of histologically normal tissue from controls and EAC patients.	('EAC', 'Phenotype', 'HP:0011459', (308, 311))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('patients', 'Species', '9606', (312, 320))	('EAC', 'Gene', '1540', (308, 311))	('EAC', 'Gene', (308, 311))	('patients', 'Species', '9606', (126, 134))	('EAC', 'Gene', '1540', (122, 125))	('PLS-DA model', 'MPA', (156, 168))	('EAC', 'Gene', (122, 125))	('differences', 'Var', (43, 54))
582391	24213126	In a study comparing protons with photons using 3D planning in five patients, proton plans spared better all structures (spinal cord, lung, heart and kidneys) and enhanced tumor control probability value by an average of 20%-units (range 2-23% units) using 5% NTCP in any risk organ.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('NTCP', 'Gene', (260, 264))	('NTCP', 'Gene', '6554', (260, 264))	('patients', 'Species', '9606', (68, 76))	('enhanced', 'PosReg', (163, 171))	('spared', 'NegReg', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('proton', 'Var', (78, 84))
582460	19887543	Of note, expression of FcgammaRIIIa enables NK cells to interact with antibody-coated tumor cells and mediate antibody-dependent cellular cytotoxicity and the secretion of IFN-gamma.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('expression', 'Var', (9, 19))	('cytotoxicity', 'Disease', 'MESH:D064420', (138, 150))	('interact', 'Interaction', (56, 64))	('mediate', 'Reg', (102, 109))	('FcgammaRIIIa', 'Gene', '2214', (23, 35))	('FcgammaRIIIa', 'Gene', (23, 35))	('antibody-coated tumor', 'Disease', (70, 91))	('antibody-coated tumor', 'Disease', 'MESH:D058456', (70, 91))	('cytotoxicity', 'Disease', (138, 150))	('secretion', 'MPA', (159, 168))
582510	19887543	Analysis of patient time-to-progression data using the nonparametric Mann-Whitney U test indicated that induction of IFN-gamma was associated with a statistically significant increase in progression-free survival (P = 0.004).	('IFN-gamma', 'Protein', (117, 126))	('progression-free survival', 'CPA', (187, 212))	('induction', 'Var', (104, 113))	('increase', 'PosReg', (175, 183))	('patient', 'Species', '9606', (12, 19))
582558	20927195	To develop such model cell lines, we started with telomerase-immortalized, non-neoplastic Barrett's epithelial (BAR-T) cells, which are spontaneously deficient in p16, and proceeded to knock down p53 using RNAi, to activate Ras by introducing oncogenic H-RasG12V, or both.	('Ras', 'Gene', (224, 227))	('H-RasG12V', 'Chemical', '-', (253, 262))	('H-RasG12V', 'Protein', (253, 262))	('introducing', 'Reg', (231, 242))	('activate', 'PosReg', (215, 223))	('p53', 'Gene', (196, 199))	('knock down', 'Var', (185, 195))
582559	20927195	BAR-T cells infected with either p53 RNAi or oncogenic H-RasG12V alone maintained cell-to-cell contact inhibition and did not exhibit anchorage-independent growth in soft agar.	('p53', 'Var', (33, 36))	('agar', 'Chemical', 'MESH:D000362', (171, 175))	('cell-to-cell contact inhibition', 'CPA', (82, 113))	('H-RasG12V', 'Gene', (55, 64))	('H-RasG12V', 'Chemical', '-', (55, 64))
582572	20927195	By introducing additional, well-defined genetic alterations that target the p53 and Ras pathways, we have induced the malignant transformation of our telomerase-immortalized human Barrett's epithelial cells, and we have developed a number of non-transformed cell lines with well-defined, growth-promoting genetic changes that might recapitulate various stages of neoplastic progression in Barrett's esophagus.	('human', 'Species', '9606', (174, 179))	('alterations', 'Var', (48, 59))	('malignant transformation', 'CPA', (118, 142))	('induced', 'Reg', (106, 113))	('genetic alterations', 'Var', (40, 59))	('growth-promoting', 'PosReg', (288, 304))	('genetic changes', 'Var', (305, 320))	("Barrett's esophagus", 'Disease', (389, 408))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (389, 408))
582575	20927195	As an additional test for in vitro transformation, we cultured our p53 knockdown cells in soft agar to see if they exhibited anchorage-independent growth.	('knockdown', 'Var', (71, 80))	('p53', 'Gene', (67, 70))	('agar', 'Chemical', 'MESH:D000362', (95, 99))
582580	20927195	As shown in Figure 2A, BAR-T cells infected with H-RasG12V showed a marked increase in H-Ras expression associated with an increase in phosphorylation of MEK1/2 and ERK1/2, indicating that the H-Ras G12V was functionally active.	('H-Ras', 'Gene', '3265', (49, 54))	('H-Ras', 'Gene', (49, 54))	('G12V', 'SUBSTITUTION', 'None', (54, 58))	('MEK1/2', 'Gene', '5604;5605', (154, 160))	('G12V', 'Var', (54, 58))	('H-Ras', 'Gene', '3265', (193, 198))	('H-Ras', 'Gene', (193, 198))	('increase', 'PosReg', (123, 131))	('expression', 'MPA', (93, 103))	('G12V', 'SUBSTITUTION', 'None', (199, 203))	('H-RasG12V', 'Chemical', '-', (49, 58))	('increase', 'PosReg', (75, 83))	('G12V', 'Var', (199, 203))	('phosphorylation', 'MPA', (135, 150))	('H-Ras', 'Gene', (87, 92))	('ERK1/2', 'Protein', (165, 171))	('MEK1/2', 'Gene', (154, 160))	('H-Ras', 'Gene', '3265', (87, 92))
582581	20927195	We next determined population doubling time and cell to cell contact inhibition in BAR-T cells expressing H-RasG12V.	('cell to cell contact inhibition', 'CPA', (48, 79))	('H-RasG12V', 'Var', (106, 115))	('H-RasG12V', 'Chemical', '-', (106, 115))
582583	20927195	As expected, the H-RasG12V-expressing cells showed a growth advantage over vector controls when grown in reduced medium (0.5% of the concentration of serum and growth factors found in full media), further supporting that the H-RasG12V was functionally active (data not shown).	('growth advantage', 'CPA', (53, 69))	('H-RasG12V', 'Chemical', '-', (17, 26))	('H-RasG12V', 'Chemical', '-', (225, 234))	('H-RasG12V-expressing', 'Var', (17, 37))
582591	20927195	The clones with combined H-RasG12V expression and p53 knockdown exhibited a significant decrease in population doubling time (Figure 3B), and a loss of cell to cell contact inhibition (Figure 3C).	('decrease', 'NegReg', (88, 96))	('knockdown', 'Var', (54, 63))	('cell to cell contact inhibition', 'CPA', (152, 183))	('p53', 'Gene', (50, 53))	('H-RasG12V expression', 'Var', (25, 45))	('H-RasG12V', 'Chemical', '-', (25, 34))	('loss', 'NegReg', (144, 148))	('population doubling time', 'CPA', (100, 124))
582597	20927195	Therefore, we injected BAR-T p53RNAi H-RasG12V-expressing clones (R1 and R2) subcutaneously into Nu/Nu mice (T cell deficient) and NOD/SCID mice (T, B, and NK cell deficient as well as complement deficient).	('SCID', 'Disease', (135, 139))	('complement deficient', 'Disease', (185, 205))	('T cell deficient', 'Disease', (109, 125))	('complement deficient', 'Disease', 'MESH:D007153', (185, 205))	('NOD', 'Gene', '1822', (131, 134))	('H-RasG12V', 'Chemical', '-', (37, 46))	('mice', 'Species', '10090', (103, 107))	('mice', 'Species', '10090', (140, 144))	('NK cell deficient', 'Disease', 'MESH:D054066', (156, 173))	('T cell deficient', 'Disease', 'MESH:D016399', (109, 125))	('NOD', 'Gene', (131, 134))	('NK cell deficient', 'Disease', (156, 173))	('p53RNAi', 'Var', (29, 36))	('SCID', 'Disease', 'MESH:D053632', (135, 139))
582599	20927195	Unlike the vector-containing control cells (BAR-T p53RNAi cells containing the empty vector p-Babe-zeocin), the cells with p53 knockdown and H-RasG12V expression formed tumors in both the Nu/Nu (Table 1) and the NOD/SCID mice within 10-14 weeks (Table 1 and Figure 6A).	('H-RasG12V expression', 'Var', (141, 161))	('NOD', 'Gene', (212, 215))	('zeocin', 'Chemical', 'MESH:C105427', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('SCID', 'Disease', 'MESH:D053632', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('SCID', 'Disease', (216, 220))	('mice', 'Species', '10090', (221, 225))	('NOD', 'Gene', '1822', (212, 215))	('p53', 'Gene', (123, 126))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))	('H-RasG12V', 'Chemical', '-', (141, 150))
582600	20927195	There were no significant differences between the average volumes of the in vivo tumors formed by the OE33 cancer cells and those formed by BAR-T p53 RNAi cells expressing H-RasG12V clones R1 and R2 (Figure 6B).	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('H-RasG12V', 'Chemical', '-', (172, 181))	('cancer', 'Disease', (107, 113))	('H-RasG12V clones R1', 'Var', (172, 191))
582606	20927195	Following selection with zeocin, we selected a resultant p53RNAi H-RasG12V-expressing clone (R5) for characterization of in vivo tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('zeocin', 'Chemical', 'MESH:C105427', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('H-RasG12V', 'Chemical', '-', (65, 74))	('tumor', 'Disease', (129, 134))	('p53RNAi', 'Var', (57, 64))
582622	20927195	Functional disruption of the Rb pathway can be achieved by inactivation of p16, which is the earliest and most common genetic alteration described in patients with Barrett's esophagus.	('Rb', 'Gene', '5925', (29, 31))	('inactivation', 'Var', (59, 71))	("Barrett's esophagus", 'Disease', (164, 183))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (164, 183))	('patients', 'Species', '9606', (150, 158))	('p16', 'Gene', (75, 78))
582623	20927195	Biopsy specimens of non-neoplastic Barrett's metaplasia demonstrate inactivation of p16 via promoter methylation, loss of heterozygosity (LOH), or mutation in 73% to 87% of patients.	("non-neoplastic Barrett's metaplasia", 'Disease', 'MESH:D001471', (20, 55))	("non-neoplastic Barrett's metaplasia", 'Disease', (20, 55))	('patients', 'Species', '9606', (173, 181))	('mutation', 'Var', (147, 155))	('loss', 'Var', (114, 118))	('promoter', 'MPA', (92, 100))	('inactivation', 'NegReg', (68, 80))	('p16', 'Gene', (84, 87))
582629	20927195	In biopsy specimens of non-dysplastic Barrett's metaplasia, allelic loss of p53 occurs more frequently than p53 mutation and, in the absence of p53 allelic loss, p53 mutations are rare.	('p53', 'Gene', (76, 79))	("non-dysplastic Barrett's metaplasia", 'Disease', (23, 58))	('allelic', 'Var', (60, 67))	("non-dysplastic Barrett's metaplasia", 'Disease', 'MESH:D001471', (23, 58))
582630	20927195	This finding is consistent with reports on other human epithelial cells (including esophageal squamous, embryonic kidney, and mammary cells) in which the introduction of telomerase in combination with the SV40 early region (a viral oncoprotein that knocks down the Rb and p53 pathways) results in immortalized, but not transformed cells.	('embryonic kidney', 'Disease', (104, 120))	('human', 'Species', '9606', (49, 54))	('knocks down', 'NegReg', (249, 260))	('embryonic kidney', 'Disease', 'MESH:D007674', (104, 120))	('introduction', 'Var', (154, 166))	('immortalized', 'CPA', (297, 309))	('Rb', 'Gene', '5925', (265, 267))
582631	20927195	We also activated the mitogenic Ras signaling pathway in our non-neoplastic Barrett's cells by introducing an expression vector containing oncogenic H-RasG12V.	('mitogenic Ras signaling pathway', 'Pathway', (22, 53))	('H-RasG12V', 'Var', (149, 158))	('H-RasG12V', 'Chemical', '-', (149, 158))	('activated', 'PosReg', (8, 17))
582632	20927195	Involvement of the Ras pathway in the early stages of neoplastic progression in Barrett's esophagus has been suggested by studies demonstrating genomic amplification or overexpression of the epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor alpha (TGF-alpha), in biopsy samples of non-dysplastic Barrett's metaplasia.	('Ras pathway', 'Pathway', (19, 30))	('genomic amplification', 'Var', (144, 165))	("non-dysplastic Barrett's metaplasia", 'Disease', (314, 349))	('Involvement', 'Reg', (0, 11))	('transforming growth factor alpha', 'Gene', (247, 279))	('EGFR', 'Gene', '1956', (225, 229))	('transforming growth factor alpha', 'Gene', '7124', (247, 279))	('TGF-alpha', 'Gene', (281, 290))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (80, 99))	('epidermal growth factor receptor', 'Gene', (191, 223))	('EGFR', 'Gene', (225, 229))	("Barrett's esophagus", 'Disease', (80, 99))	("non-dysplastic Barrett's metaplasia", 'Disease', 'MESH:D001471', (314, 349))	('epidermal growth factor receptor', 'Gene', '1956', (191, 223))	('TGF-alpha', 'Gene', '7039', (281, 290))	('overexpression', 'PosReg', (169, 183))
582633	20927195	Although specific K-Ras mutations and expression of oncogenic H-Ras are rarely detected in non-neoplastic Barrett's epithelium, both of these abnormalities are found frequently in dysplastic Barrett's epithelium and in esophageal adenocarcinomas.	('H-Ras', 'Gene', (62, 67))	('found', 'Reg', (160, 165))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (219, 245))	("dysplastic Barrett's epithelium", 'Disease', 'MESH:D001471', (180, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('K-Ras', 'Gene', '3845', (18, 23))	("dysplastic Barrett's epithelium", 'Disease', (180, 211))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (219, 244))	('mutations', 'Var', (24, 33))	('K-Ras', 'Gene', (18, 23))	('esophageal adenocarcinomas', 'Disease', (219, 245))	('H-Ras', 'Gene', '3265', (62, 67))
582634	20927195	In some primary epithelial cells, activation of oncogenic Ras causes oncogene-induced senescence, a form of growth arrest that appears to prevent cancer formation.	('oncogene-induced senescence', 'Disease', (69, 96))	('cancer', 'Disease', (146, 152))	('oncogenic Ras', 'Protein', (48, 61))	('activation', 'Var', (34, 44))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('growth arrest', 'Phenotype', 'HP:0001510', (108, 121))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('growth arrest', 'Disease', 'MESH:D006323', (108, 121))	('growth arrest', 'Disease', (108, 121))
582636	20927195	Thus, it is not surprising that our BAR-T cells, which are p16 deficient, did not exhibit growth arrest after the introduction of H-RasG12V.	('H-RasG12V', 'Var', (130, 139))	('growth arrest', 'Phenotype', 'HP:0001510', (90, 103))	('H-RasG12V', 'Chemical', '-', (130, 139))	('growth arrest', 'Disease', 'MESH:D006323', (90, 103))	('growth arrest', 'Disease', (90, 103))
582644	20927195	It is possible that the chromosomal abnormalities associated with the knockdown of p53 and the insertion of oncogenic H-RasG12V contributed to malignant transformation.	('H-RasG12V', 'Chemical', '-', (118, 127))	('p53', 'Gene', (83, 86))	('knockdown', 'Var', (70, 79))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (24, 49))	('contributed', 'Reg', (128, 139))	('chromosomal abnormalities', 'Disease', (24, 49))	('H-RasG12V', 'Gene', (118, 127))	('malignant transformation', 'CPA', (143, 167))
582645	20927195	In conclusion, without using viral oncoproteins, we have induced the malignant transformation of human hTERT-immortalized Barrett's epithelial cells, which are deficient in p16, through the knockdown of p53 and the forced expression of oncogenic H-Ras G12V.	('knockdown', 'Var', (190, 199))	('malignant transformation', 'CPA', (69, 93))	('G12V', 'Var', (252, 256))	('hTERT', 'Gene', (103, 108))	('induced', 'Reg', (57, 64))	('H-Ras', 'Gene', (246, 251))	('G12V', 'SUBSTITUTION', 'None', (252, 256))	('H-Ras', 'Gene', '3265', (246, 251))	('human', 'Species', '9606', (97, 102))	('hTERT', 'Gene', '7015', (103, 108))	('p53', 'Gene', (203, 206))
582646	20927195	Similar genetic alterations are found frequently in esophageal biopsy specimens from patients with various stages of neoplasia in Barrett's esophagus.	('neoplasia', 'Disease', (117, 126))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (130, 149))	('genetic alterations', 'Var', (8, 27))	('neoplasia', 'Disease', 'MESH:D009369', (117, 126))	('neoplasia', 'Phenotype', 'HP:0002664', (117, 126))	('patients', 'Species', '9606', (85, 93))	('Barrett', 'Disease', (130, 137))
582726	34022894	demonstrated that LINC00261, as a tumor suppressor, can be inactivated by methylation of promoter region, while the demethylation could upregulate LINC00261 and inhibit the progress of pancreatic cancer.	('pancreatic cancer', 'Disease', (185, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('methylation', 'Var', (74, 85))	('progress', 'CPA', (173, 181))	('pancreatic cancer', 'Disease', 'MESH:D010190', (185, 202))	('tumor', 'Disease', (34, 39))	('LINC00261', 'Gene', '140828', (147, 156))	('demethylation', 'Var', (116, 129))	('upregulate', 'PosReg', (136, 146))	('LINC00261', 'Gene', (18, 27))	('LINC00261', 'Gene', '140828', (18, 27))	('LINC00261', 'Gene', (147, 156))	('inhibit', 'NegReg', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (185, 202))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
582748	34022894	In addition, LINC00261 over-expression was found to promote cell apoptosis and to inhibit cell viability, migration, invasiveness, and proliferation.	('invasiveness', 'CPA', (117, 129))	('LINC00261', 'Gene', (13, 22))	('over-expression', 'Var', (23, 38))	('LINC00261', 'Gene', '140828', (13, 22))	('inhibit', 'NegReg', (82, 89))	('cell viability', 'CPA', (90, 104))	('cell apoptosis', 'CPA', (60, 74))	('migration', 'CPA', (106, 115))	('promote', 'PosReg', (52, 59))
582765	34022894	Using HCC-derived cell lines, low LINC00261 expression was reported to significantly promote cell motility.	('expression', 'MPA', (44, 54))	('LINC00261', 'Gene', '140828', (34, 43))	('HCC', 'Gene', (6, 9))	('promote', 'PosReg', (85, 92))	('HCC', 'Phenotype', 'HP:0001402', (6, 9))	('low', 'Var', (30, 33))	('LINC00261', 'Gene', (34, 43))	('cell motility', 'CPA', (93, 106))	('HCC', 'Gene', '619501', (6, 9))
582782	34022894	In addition, LINC00261 inhibition of cell proliferation and promotion of apoptosis were determined to be through sponging of miR-222-3p and reduction of c-myc expression.	('LINC00261', 'Gene', (13, 22))	('LINC00261', 'Gene', '140828', (13, 22))	('inhibition', 'NegReg', (23, 33))	('apoptosis', 'CPA', (73, 82))	('c-myc', 'Gene', '4609', (153, 158))	('reduction', 'NegReg', (140, 149))	('c-myc', 'Gene', (153, 158))	('miR-222-3p', 'Chemical', '-', (125, 135))	('cell proliferation', 'CPA', (37, 55))	('miR-222-3p', 'Var', (125, 135))
582787	34022894	As for Wnt signaling, LINC00261 participates it by promoting SFRP via ceRNA mechanism, and downregulated SFRP is proved to accelerate the tumorigenesis and metathesis of Choriocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('LINC00261', 'Gene', (22, 31))	('tumor', 'Disease', (138, 143))	('accelerate', 'PosReg', (123, 133))	('promoting', 'PosReg', (51, 60))	('downregulated', 'Var', (91, 104))	('Choriocarcinoma', 'Disease', 'MESH:D002822', (170, 185))	('Choriocarcinoma', 'Disease', (170, 185))	('ceRNA', 'CPA', (70, 75))	('Choriocarcinoma', 'Phenotype', 'HP:0100768', (170, 185))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('SFRP', 'CPA', (61, 65))	('LINC00261', 'Gene', '140828', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
582793	34022894	Similarly, in BC, the reintroduction of LINC00261 was shown to arrest cell proliferation by protecting NME1 (a known tumor suppressor) mRNA from degradation.	('LINC00261', 'Gene', (40, 49))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('LINC00261', 'Gene', '140828', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('degradation', 'MPA', (145, 156))	('mRNA', 'MPA', (135, 139))	('tumor', 'Disease', (117, 122))	('cell proliferation', 'CPA', (70, 88))	('arrest', 'Disease', (63, 69))	('reintroduction', 'Var', (22, 36))	('NME1', 'Gene', '4830', (103, 107))	('BC', 'Phenotype', 'HP:0003002', (14, 16))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('NME1', 'Gene', (103, 107))
582797	34022894	In addition, LINC00261 overexpression was also shown to promote apoptosis and decrease cell proliferation in choriocarcinoma.	('decrease', 'NegReg', (78, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('LINC00261', 'Gene', (13, 22))	('apoptosis', 'CPA', (64, 73))	('LINC00261', 'Gene', '140828', (13, 22))	('choriocarcinoma', 'Disease', 'MESH:D002822', (109, 124))	('cell proliferation', 'CPA', (87, 105))	('overexpression', 'Var', (23, 37))	('choriocarcinoma', 'Disease', (109, 124))	('promote', 'PosReg', (56, 63))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (109, 124))
582798	34022894	In contrast to all other studies, one cholangiocarcinoma study reported that low LINC00261 expression actually increased cell apoptosis and inhibited cell proliferation.	('cholangiocarcinoma', 'Disease', (38, 56))	('expression', 'MPA', (91, 101))	('cell proliferation', 'CPA', (150, 168))	('low', 'Var', (77, 80))	('increased', 'PosReg', (111, 120))	('LINC00261', 'Gene', (81, 90))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (38, 56))	('inhibited', 'NegReg', (140, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (38, 56))	('cell apoptosis', 'CPA', (121, 135))	('LINC00261', 'Gene', '140828', (81, 90))
582800	34022894	speculated that low LINC00261 expression did not actually influence signaling pathways or gene expression related to cell proliferation and apoptosis, but that its high expression played a significant role in activating apoptosis and inhibiting cell proliferation.	('activating', 'PosReg', (209, 219))	('low', 'Var', (16, 19))	('LINC00261', 'Gene', '140828', (20, 29))	('LINC00261', 'Gene', (20, 29))	('inhibiting', 'NegReg', (234, 244))	('apoptosis', 'CPA', (220, 229))	('high expression', 'MPA', (164, 179))	('cell proliferation', 'CPA', (245, 263))
582802	34022894	In general, LINC00261 expression may alter tumor-cell motility in many ways.	('alter', 'Reg', (37, 42))	('expression', 'Var', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('LINC00261', 'Gene', '140828', (12, 21))	('tumor', 'Disease', (43, 48))	('LINC00261', 'Gene', (12, 21))
582816	34022894	Similarly, in human esophageal cancer, LINC00261 overexpression was observed to increase 5-FU drug sensitivity in tumor cells by modulating the methylation-dependent suppression of dihydropyrimidine dehydrogenase.	('methylation-dependent', 'MPA', (144, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('increase', 'PosReg', (80, 88))	('LINC00261', 'Gene', (39, 48))	('modulating', 'Reg', (129, 139))	('esophageal cancer', 'Disease', (20, 37))	('tumor', 'Disease', (114, 119))	('suppression', 'NegReg', (166, 177))	('LINC00261', 'Gene', '140828', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('drug sensitivity', 'Phenotype', 'HP:0020174', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('human', 'Species', '9606', (14, 19))	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('overexpression', 'Var', (49, 63))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('5-FU drug sensitivity', 'MPA', (89, 110))	('dihydropyrimidine', 'Chemical', '-', (181, 198))	('dihydropyrimidine dehydrogenase', 'Enzyme', (181, 212))
582827	34022894	Therefore, when Wnt/beta-catenin signaling pathway is dysregulated, cell proliferation will be no longer restrained even if the epithelial sheet is complete.	('cell proliferation', 'CPA', (68, 86))	('beta-catenin', 'Gene', '1499', (20, 32))	('beta-catenin', 'Gene', (20, 32))	('dysregulated', 'Var', (54, 66))
582842	34022894	In view of the fact that LINC00261 can be promoted by the demethylation of promoter region, we summarized the roles of LINC00261, a tumor suppressor gaining increasingly important status, in cancer research.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('LINC00261', 'Gene', '140828', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('LINC00261', 'Gene', (119, 128))	('LINC00261', 'Gene', '140828', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('LINC00261', 'Gene', (25, 34))	('tumor', 'Disease', (132, 137))	('demethylation', 'Var', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
582854	33176589	By comprehensive consideration, POA-VMAT efficiently generate acceptable treatment plans for CTEC without dose escalation to OARs and overall superior to manual planning which is a good option for treating CTEC.	('CTEC', 'Chemical', '-', (206, 210))	('CTEC', 'Chemical', '-', (93, 97))	('CTEC', 'Disease', (93, 97))	('POA-VMAT', 'Var', (32, 40))
582876	33176589	The plan objectives were: For PTV, plans aimed to achieve 57 Gy (-5% to +7%); for spinal cord, maximum dose no more than 45 Gy; for heart, Dmean <= 35 Gy, V30Gy < 40%, V40Gy < 30%.	('V30Gy < 40%', 'Var', (155, 166))	('V40Gy', 'Var', (168, 173))	('Dmean <= 35 Gy', 'Var', (139, 153))	('PTV', 'Chemical', '-', (30, 33))	('Dmean', 'Chemical', '-', (139, 144))
582884	33176589	The HI of the treatment was expressed in terms of D1%-D99% /Dpx100% where Dp is the prescribed dose, the values of D98% and D2% represent the dose received by the 99% and 1% of the volume, respectively.	('D98%', 'Var', (115, 119))	('Dp', 'Chemical', 'MESH:D004176', (74, 76))	('Dp', 'Chemical', 'MESH:D004176', (60, 62))	('D2%', 'Var', (124, 127))
582889	33176589	For healthy tissue, V10 Gy, V15 Gy, and V20 Gy and the integral dose (equal to the mean dose times the volume of healthy tissue), were scored.	('V20 Gy', 'Var', (40, 46))	('V10 Gy', 'Var', (20, 26))	('V15', 'Gene', '28814', (28, 31))	('V15', 'Gene', (28, 31))
582897	33176589	The POA-VMAT results in better PTV coverage than IMRT and VMAT plans.	('POA-VMAT', 'Var', (4, 12))	('PTV coverage', 'CPA', (31, 43))	('PTV', 'Chemical', '-', (31, 34))	('better', 'PosReg', (24, 30))
582898	33176589	The target coverage of PTV for 4 modalities was with a V95 of 95.8 +- 3.2, 95.4 +- 2.3, 99.4 +- 0.3 and 99.8 +- 0.1 for 7f-IMRT, Single-Arc, Double-Arc and POA-VMAT, respectively.	('POA-VMAT', 'Var', (156, 164))	('Single-Arc', 'Var', (129, 139))	('PTV', 'Chemical', '-', (23, 26))	('Double-Arc', 'Var', (141, 151))
582903	33176589	The POA-VMAT plans were significantly improved the dose for spinal cord among all the plans and superior in sparing the heart in terms of Dmean and D35%.	('POA-VMAT', 'Var', (4, 12))	('improved', 'PosReg', (38, 46))	('Dmean', 'Chemical', '-', (138, 143))	('heart', 'MPA', (120, 125))	('dose', 'MPA', (51, 55))
582909	33176589	The results of this study show that the PTV Dmean, D2% and V107% of POA-VMAT was significantly improved compared to 7f-IMRT, Single-Arc, Double-Arc.	('Dmean', 'Chemical', '-', (44, 49))	('improved', 'PosReg', (95, 103))	('V107', 'Var', (59, 63))	('PTV', 'Chemical', '-', (40, 43))	('PTV', 'MPA', (40, 43))
582911	33176589	The results also indicate that Double-Arc and POA-VMAT plans yielded significantly lower lung Dmean, V30 and NTCT than the 7f-IMRT and Single-Arc plans, while the 7f-IMRT could achieve optimal lower lung V10 and similar V5 compared to other 3 methods.	('NTCT', 'MPA', (109, 113))	('POA-VMAT', 'Var', (46, 54))	('lower', 'NegReg', (83, 88))	('lung V10', 'MPA', (199, 207))	('lung Dmean', 'MPA', (89, 99))	('Double-Arc', 'Var', (31, 41))	('V30', 'MPA', (101, 104))	('Dmean', 'Chemical', '-', (94, 99))	('lower', 'NegReg', (193, 198))
582914	33176589	POA-VMAT plans reduced NTCP of lung pneumonitis nearly 1% compared to 7f-IMRT plans.	('lung pneumonitis', 'Disease', 'MESH:D011014', (31, 47))	('NTCP', 'MPA', (23, 27))	('reduced', 'NegReg', (15, 22))	('NTCP', 'Chemical', '-', (23, 27))	('lung pneumonitis', 'Disease', (31, 47))	('POA-VMAT plans', 'Var', (0, 14))
582916	33176589	Similar results for heart Dmean and D35% among the 4 methodologies had been observed in Table 3.	('D35', 'Var', (36, 39))	('heart Dmean', 'CPA', (20, 31))	('Dmean', 'Chemical', '-', (26, 31))
582924	31684197	Results: Patients with positive PD-L1 expression have significantly lower pathological complete response rates (13% versus 32%; p = 0.036) than those with negative PD-L1 expression.	('positive', 'Var', (23, 31))	('pathological complete response rates', 'CPA', (74, 110))	('lower', 'NegReg', (68, 73))	('PD-L1', 'Gene', (32, 37))	('Patients', 'Species', '9606', (9, 17))	('expression', 'Var', (38, 48))
582925	31684197	Conclusions: For patients with ESCC receiving neoadjuvant chemoradiotherapy, positive PD-L1 expression independently predicts the poor chemoradiotherapy response and worse treatment outcome.	('positive', 'Var', (77, 85))	('patients', 'Species', '9606', (17, 25))	('ESCC', 'Disease', (31, 35))	('PD-L1', 'Gene', (86, 91))	('expression', 'MPA', (92, 102))
582962	31684197	Additionally, 22 (21%) patients had N0 status, 36 (34%) patients had N1 status, 35 (33%) patients had N2 status, and 14 (13%) patients had N3 status.	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (23, 31))	('N1 status', 'Var', (69, 78))	('patients', 'Species', '9606', (89, 97))	('N0 status', 'Var', (36, 45))	('patients', 'Species', '9606', (126, 134))
582969	31684197	The three-year OS rates were 47% in patients with negative PD-L1 expression, and 16% in patients with positive PD-L1 expression.	('negative', 'NegReg', (50, 58))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (88, 96))	('PD-L1', 'Gene', (59, 64))	('expression', 'Var', (65, 75))
582970	31684197	The three-year DFS rates were 43% in patients with negative PD-L1 expression, and 6% in patients with positive PD-L1 expression.	('DFS', 'MPA', (15, 18))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (88, 96))	('negative', 'NegReg', (51, 59))	('PD-L1', 'Gene', (60, 65))	('expression', 'Var', (66, 76))
582986	31684197	Taken together, these previous studies and our findings highlight the potential for a combination of anti-PD-1/PD-L1 therapy and chemoradiotherapy in patients with advanced ESCC.	('anti-PD-1/PD-L1', 'Var', (101, 116))	('patients', 'Species', '9606', (150, 158))	('ESCC', 'Disease', (173, 177))
582988	31684197	In conclusion, our study showed that positive PD-L1 expression independently predicts poor response to chemoradiotherapy and worse survival of patients with ESCC receiving neoadjuvant chemoradiotherapy followed by esophagectomy.	('PD-L1', 'Gene', (46, 51))	('positive', 'Var', (37, 45))	('ESCC', 'Disease', (157, 161))	('patients', 'Species', '9606', (143, 151))
583008	31652725	The interactions promote the aggressive phenotypes of certain cancers, such as those of the bladder, endometrium, lung, urinary bladder, and breast cancer through programming the epithelial-mesenchymal transition (EMT).	('programming', 'Reg', (163, 174))	('epithelial-mesenchymal transition', 'CPA', (179, 212))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('interactions', 'Var', (4, 16))	('promote', 'PosReg', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('bladder', 'Disease', (92, 99))	('endometrium', 'Disease', (101, 112))	('breast cancer', 'Disease', (141, 154))	('lung', 'Disease', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('urinary bladder', 'Disease', (120, 135))
583021	31652725	Similar to EMPs, the atypical activity of PMP22 is correlated with metastatic progression in certain cancers.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('metastatic progression', 'CPA', (67, 89))	('atypical', 'Var', (21, 29))	('correlated with', 'Reg', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('PMP22', 'Gene', (42, 47))
583026	31652725	In a retinal epithelial cell line, EMP2 induces intracellular collagen gel contraction through the activation of focal adhesion kinase (FAK) at two phosphorylation sites Tyr576 and Tyr577.	('induces', 'Reg', (40, 47))	('Tyr576', 'Chemical', '-', (170, 176))	('intracellular collagen gel contraction', 'CPA', (48, 86))	('Tyr577', 'Var', (181, 187))	('FAK', 'Gene', (136, 139))	('activation', 'PosReg', (99, 109))	('FAK', 'Gene', '5747', (136, 139))	('focal adhesion kinase', 'Gene', '5747', (113, 134))	('Tyr577', 'Chemical', '-', (181, 187))	('EMP2', 'Gene', (35, 39))	('focal adhesion kinase', 'Gene', (113, 134))	('Tyr576', 'Var', (170, 176))
583031	31652725	In contrast, knockdown of EMP3 expression enhances the induction of CTLs, secretion of interferon-gamma, and the expression of IL-2 receptor alpha by CD8+ T cells.	('CD8', 'Gene', (150, 153))	('expression', 'MPA', (113, 123))	('CD8', 'Gene', '925', (150, 153))	('IL-2 receptor alpha', 'Gene', '3559', (127, 146))	('IL-2 receptor alpha', 'Gene', (127, 146))	('CTLs', 'MPA', (68, 72))	('interferon-gamma', 'Gene', '3458', (87, 103))	('enhances', 'PosReg', (42, 50))	('EMP3', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('induction', 'MPA', (55, 64))	('interferon-gamma', 'Gene', (87, 103))
583043	31652725	Silencing EMP1 expression in glioblastoma cells inhibits their proliferation and invasiveness, as well as the expression of CD44 and matrix metalloprotease (MMP)-2.	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('proliferation', 'CPA', (63, 76))	('inhibits', 'NegReg', (48, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('glioblastoma', 'Disease', (29, 41))	('expression', 'MPA', (110, 120))	('invasiveness', 'CPA', (81, 93))	('EMP1', 'Gene', (10, 14))	('CD44', 'Gene', '960', (124, 128))	('Silencing', 'Var', (0, 9))	('CD44', 'Gene', (124, 128))
583046	31652725	Other consequences of the inhibition of dysregulated CD44 by silencing EMP1 expression include the suppression of the activities of transcription factors such as OCT4, SOX2, and Nanog.	('OCT4', 'Gene', '5460', (162, 166))	('SOX2', 'Gene', '6657', (168, 172))	('OCT4', 'Gene', (162, 166))	('SOX2', 'Gene', (168, 172))	('CD44', 'Gene', '960', (53, 57))	('inhibition', 'NegReg', (26, 36))	('silencing', 'NegReg', (61, 70))	('EMP1', 'Gene', (71, 75))	('dysregulated', 'Var', (40, 52))	('CD44', 'Gene', (53, 57))	('expression', 'MPA', (76, 86))	('transcription', 'MPA', (132, 145))	('activities', 'MPA', (118, 128))	('Nanog', 'Gene', '79923', (178, 183))	('suppression', 'NegReg', (99, 110))	('Nanog', 'Gene', (178, 183))
583058	31652725	Silencing EMP1 expression in prednisolone-resistant leukemic cell lines induces apoptosis, suppresses cell migration and adhesion, decreases the proliferation rate, and sensitizes cells to prednisolone.	('sensitizes', 'Reg', (169, 179))	('suppresses', 'NegReg', (91, 101))	('induces', 'Reg', (72, 79))	('prednisolone', 'Chemical', 'MESH:D011239', (189, 201))	('proliferation rate', 'CPA', (145, 163))	('decreases', 'NegReg', (131, 140))	('prednisolone', 'Chemical', 'MESH:D011239', (29, 41))	('EMP1', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('apoptosis', 'CPA', (80, 89))
583102	31652725	Transcriptional profiling analyses detected the dysregulation of EMP2 mRNA expression in breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (89, 103))	('breast cancers', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EMP2', 'Gene', (65, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('dysregulation', 'Var', (48, 61))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('mRNA expression', 'MPA', (70, 85))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))
583116	31652725	Ectopic expression of EMP2 in nasopharynx cancer cells in vitro impairs cell growth, enhances the efficiency of radiotherapy, induces cell cycle arrest at S phase, and increases apoptosis at both early and late stages.	('cell growth', 'CPA', (72, 83))	('EMP2', 'Gene', (22, 26))	('arrest', 'Disease', 'MESH:D006323', (145, 151))	('induces', 'Reg', (126, 133))	('increases', 'PosReg', (168, 177))	('impairs', 'NegReg', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('arrest', 'Disease', (145, 151))	('Ectopic expression', 'Var', (0, 18))	('apoptosis', 'CPA', (178, 187))	('nasopharynx cancer', 'Phenotype', 'HP:0100630', (30, 48))	('cancer', 'Disease', (42, 48))	('enhances', 'PosReg', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (134, 151))
583120	31652725	EMP2 protein expression inversely correlates with the histologic grades of uroepithelial cancer cells, and overexpression of EMP2 impairs cancer cell proliferation and inhibits tumor development.	('impairs cancer', 'Disease', (130, 144))	('inhibits', 'NegReg', (168, 176))	('overexpression', 'Var', (107, 121))	('EMP2', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('uroepithelial cancer', 'Disease', 'MESH:D009369', (75, 95))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('EMP2', 'Gene', (125, 129))	('impairs cancer', 'Disease', 'MESH:D009369', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('uroepithelial cancer', 'Disease', (75, 95))	('protein', 'Protein', (5, 12))	('tumor', 'Disease', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
583126	31652725	The overall survival rates of GBM patients with high EMP3 levels are reduced compared with those with low EMP3 levels.	('reduced', 'NegReg', (69, 76))	('survival rates', 'CPA', (12, 26))	('patients', 'Species', '9606', (34, 42))	('high', 'Var', (48, 52))	('GBM', 'Disease', (30, 33))
583131	31652725	The expression of EMP3 is likely modulated by miR-765 in oral squamous carcinoma cells, and the depletion of EMP3 markedly stimulates the expression of p66Shc to impair the migratory activity of the cells.	('p66Shc', 'Var', (152, 158))	('stimulates', 'PosReg', (123, 133))	('migratory activity of the cells', 'CPA', (173, 204))	('oral squamous carcinoma', 'Disease', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('miR-765', 'Gene', '768220', (46, 53))	('EMP3', 'Gene', (109, 113))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('depletion', 'Var', (96, 105))	('expression', 'MPA', (138, 148))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (62, 80))	('impair', 'NegReg', (162, 168))	('miR-765', 'Gene', (46, 53))
583136	31652725	The knockdown enhances the expression of cyclin-dependent kinase inhibitors p21 and p27, and reduces the levels of cyclins E and D1.	('cyclin-dependent', 'Protein', (41, 57))	('p27', 'Gene', (84, 87))	('reduces', 'NegReg', (93, 100))	('p21', 'Gene', (76, 79))	('expression', 'MPA', (27, 37))	('enhances', 'PosReg', (14, 22))	('knockdown', 'Var', (4, 13))	('p21', 'Gene', '644914', (76, 79))	('p27', 'Gene', '3429', (84, 87))
583137	31652725	The effects of high EMP3 expression on the malignant phenotype of HCC cells are associated with the increment of cell migration and invasion, as well as the proteolytic activities of MMP-9 and urokinase.	('high', 'Var', (15, 19))	('EMP3', 'Gene', (20, 24))	('malignant phenotype', 'CPA', (43, 62))	('urokinase', 'Protein', (193, 202))	('MMP-9', 'Gene', (183, 188))	('MMP-9', 'Gene', '4318', (183, 188))	('increment', 'PosReg', (100, 109))	('proteolytic activities', 'MPA', (157, 179))	('invasion', 'CPA', (132, 140))
583145	31652725	These findings highlight the importance of the EMP3-ErbB2 association as a potential indicator of progression and metastasis of upper urinary tract urothelial carcinoma.	('association', 'Var', (58, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('upper urinary tract urothelial carcinoma', 'Disease', (128, 168))	('ErbB2', 'Gene', (52, 57))	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014571', (128, 168))	('ErbB2', 'Gene', '2064', (52, 57))
583152	31652725	The inoculation of gallbladder cancer cells overexpressing EMP3 into nude mice induces significantly smaller and lower weight tumors than that of EMP3-depleted cancer cells.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('nude mice', 'Species', '10090', (69, 78))	('lower', 'NegReg', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', (160, 166))	('gallbladder cancer', 'Disease', (19, 37))	('gallbladder cancer', 'Disease', 'MESH:D005706', (19, 37))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('overexpressing', 'Var', (44, 58))	('lower weight', 'Phenotype', 'HP:0004325', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('weight tumors', 'Disease', 'MESH:D015431', (119, 132))	('cancer', 'Disease', (31, 37))	('smaller', 'NegReg', (101, 108))	('EMP3', 'Gene', (59, 63))	('weight tumors', 'Disease', (119, 132))
583153	31652725	The level of miR-663a is augmented in human gallbladder cancer tissues, and knockdown of this miRNA reciprocally increases EMP3 expression.	('human', 'Species', '9606', (38, 43))	('knockdown', 'Var', (76, 85))	('miR-663a', 'Gene', (13, 21))	('miR-663a', 'Gene', '724033', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('gallbladder cancer', 'Disease', 'MESH:D005706', (44, 62))	('gallbladder cancer', 'Disease', (44, 62))	('EMP3', 'Gene', (123, 127))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('increases', 'PosReg', (113, 122))
583159	31652725	Although mutations and loss of functions of PMP22 are related to demyelinating peripheral neuropathies, PMP22 is also reported to increase the aggressiveness of various types of cancers.	('aggressiveness', 'Disease', 'MESH:D001523', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('demyelinating peripheral neuropathies', 'Phenotype', 'HP:0007108', (65, 102))	('mutations', 'Var', (9, 18))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('PMP22', 'Gene', (44, 49))	('aggressiveness', 'Disease', (143, 157))	('loss of functions', 'NegReg', (23, 40))	('cancers', 'Disease', (178, 185))	('demyelinating peripheral neuropathies', 'Disease', (65, 102))	('increase', 'PosReg', (130, 138))	('aggressiveness', 'Phenotype', 'HP:0000718', (143, 157))	('peripheral neuropathies', 'Phenotype', 'HP:0009830', (79, 102))	('demyelinating peripheral neuropathies', 'Disease', 'MESH:D010523', (65, 102))	('PMP22', 'Gene', (104, 109))
583173	31652725	In an animal model using BALB/c mice, anti-EMP2 treatment actually reduces the number of metastatic lesions generated by xenografted mammary gland tumor cells that express high levels of EMP2.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('anti-EMP2', 'Var', (38, 47))	('mice', 'Species', '10090', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('reduces', 'NegReg', (67, 74))
583253	30652377	The 5-year survival of patients with a synchronous SPT in the lung (16.7%) was also worse than those with metachronous lung-SPTs (33.3%, P = 0.003).	('patients', 'Species', '9606', (23, 31))	('SPT', 'Gene', '189', (51, 54))	('SPT', 'Gene', '189', (124, 127))	('survival', 'CPA', (11, 19))	('SPTs', 'Chemical', '-', (124, 128))	('SPT', 'Gene', (51, 54))	('synchronous', 'Var', (39, 50))	('worse', 'NegReg', (84, 89))	('SPT', 'Gene', (124, 127))
583310	30652377	MPTs had a negative effect on the survival, which was most pronounced in patients with MPTs which were synchronous or in the lung or esophagus.	('MPTs', 'Chemical', '-', (0, 4))	('MPTs', 'Chemical', '-', (87, 91))	('patients', 'Species', '9606', (73, 81))	('negative', 'NegReg', (11, 19))	('MPTs', 'Disease', (87, 91))	('MPTs', 'Var', (0, 4))	('survival', 'MPA', (34, 42))
583385	30728854	The role of Tannerella forsythia and Porphyromonas gingivalis in pathogenesis of esophageal cancer Tannerella forsythia and Porphyromonas gingivalis are anaerobic, Gram-negative bacterial species which have been implicated in periodontal diseases as a part of red complex of periodontal pathogens.	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('Porphyromonas gingivalis', 'Species', '837', (37, 61))	('periodontal disease', 'Disease', 'MESH:D010510', (226, 245))	('periodontal disease', 'Disease', (226, 245))	('Tannerella', 'Var', (99, 109))	('periodontal diseases', 'Phenotype', 'HP:0000704', (226, 246))	('periodontal disease', 'Phenotype', 'HP:0000704', (226, 245))	('Tannerella forsythia', 'Species', '28112', (12, 32))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Porphyromonas gingivalis', 'Species', '837', (124, 148))	('esophageal cancer', 'Disease', (81, 98))	('Tannerella forsythia', 'Species', '28112', (99, 119))
583388	30728854	Moreover, the presence of oral P. gingivalis and T. forsythia has been found to be associated with an increased risk of esophageal cancer.	('presence', 'Var', (14, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('P. gingivalis', 'Species', '837', (31, 44))	('associated', 'Reg', (83, 93))	('T. forsythia', 'Species', '28112', (49, 61))	('esophageal cancer', 'Disease', (120, 137))
583429	30728854	In addition, LPS causes the inhibition of alkaline phosphatase, alpha1 collagen and osteocalcin differentiation and mineralization in stem cells of the periodontal ligament, which are involved in the regeneration of periodontal tissues.	('LPS', 'Var', (13, 16))	('osteocalcin differentiation', 'CPA', (84, 111))	('alkaline phosphatase', 'Enzyme', (42, 62))	('alpha1 collagen', 'Protein', (64, 79))	('inhibition', 'NegReg', (28, 38))	('men', 'Species', '9606', (168, 171))	('mineralization', 'CPA', (116, 130))
583440	30728854	Development of T. forsythia along with other periodontal pathogens in the oral cavity may cause gingivitis and lead to periodontal disease.	('periodontal disease', 'Disease', (119, 138))	('T. forsythia', 'Var', (15, 27))	('gingivitis', 'Disease', 'MESH:D005891', (96, 106))	('periodontal disease', 'Disease', 'MESH:D010510', (119, 138))	('T. forsythia', 'Species', '28112', (15, 27))	('gingivitis', 'Disease', (96, 106))	('periodontal disease', 'Phenotype', 'HP:0000704', (119, 138))	('gingivitis', 'Phenotype', 'HP:0000230', (96, 106))	('cause', 'Reg', (90, 95))	('men', 'Species', '9606', (7, 10))	('lead to', 'Reg', (111, 118))
583447	30728854	Fusobacterium nucleatum or P. gingivalis, enhanced the formation of abscesses in rabbits and mice.	('abscesses', 'Phenotype', 'HP:0025615', (68, 77))	('rabbits', 'Species', '9986', (81, 88))	('P. gingivalis', 'Var', (27, 40))	('enhanced', 'PosReg', (42, 50))	('formation of abscesses', 'CPA', (55, 77))	('P. gingivalis', 'Species', '837', (27, 40))	('mice', 'Species', '10090', (93, 97))	('Fusobacterium nucleatum', 'Species', '851', (0, 23))
583466	30728854	T. forsythia has also been shown to increase number of P. gingivalis by its ability to reduce fumarate to succinate (precursor of lipid and phospholipid synthesis).	('lipid', 'Chemical', 'MESH:D008055', (130, 135))	('fumarate to succinate', 'MPA', (94, 115))	('lipid', 'Chemical', 'MESH:D008055', (147, 152))	('reduce', 'NegReg', (87, 93))	('phospholipid', 'Chemical', 'MESH:D010743', (140, 152))	('T. forsythia', 'Species', '28112', (0, 12))	('P. gingivalis', 'Species', '837', (55, 68))	('P. gingivalis', 'Var', (55, 68))	('succinate', 'Chemical', 'MESH:D019802', (106, 115))	('fumarate', 'Chemical', 'MESH:D005650', (94, 102))
583477	30728854	The accumulation of genetic changes initiates the process of carcinogenesis, which causes histological changes in epithelial cells.	('genetic changes', 'Var', (20, 35))	('carcinogenesis', 'Disease', (61, 75))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
583486	30728854	Free radicals cause DNA damage, and the resulting mutations initiate the cancer process.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('initiate', 'Reg', (60, 68))	('DNA damage', 'MPA', (20, 30))
583496	30728854	The results of the study indicate the relationship between T. forsythia and adenocarcinoma, while the presence of more P. gingivalis is associated with a higher risk of esophageal squamous cell carcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('P. gingivalis', 'Species', '837', (119, 132))	('P. gingivalis', 'Var', (119, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (169, 203))	('T. forsythia', 'Species', '28112', (59, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('presence', 'Var', (102, 110))	('adenocarcinoma', 'Disease', (76, 90))	('esophageal squamous cell carcinoma', 'Disease', (169, 203))
583503	30728854	Various forms of periodontal disease caused by P. gingivalis and T. forsythia indicate the systemic inflammatory response in the body.	('P. gingivalis', 'Species', '837', (47, 60))	('P. gingivalis', 'Var', (47, 60))	('periodontal disease', 'Disease', (17, 36))	('periodontal disease', 'Disease', 'MESH:D010510', (17, 36))	('T. forsythia', 'Disease', (65, 77))	('caused', 'Reg', (37, 43))	('T. forsythia', 'Species', '28112', (65, 77))	('periodontal disease', 'Phenotype', 'HP:0000704', (17, 36))
583504	30728854	The long-term presence of P. gingivalis in the mouth can infect epithelial cells in the mouth, disrupt the cell cycle and immune responses of the host, as well as cell apoptosis.	('infect', 'Reg', (57, 63))	('P. gingivalis', 'Species', '837', (26, 39))	('immune responses', 'CPA', (122, 138))	('cell cycle', 'CPA', (107, 117))	('cell apoptosis', 'CPA', (163, 177))	('P. gingivalis', 'Var', (26, 39))	('disrupt', 'NegReg', (95, 102))
583506	30728854	Due to the high probability of infection of the esophagus from the oral niche, it is possible that infection with P. gingivalis may be associated with the development of esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (170, 204))	('men', 'Species', '9606', (162, 165))	('infection', 'Var', (99, 108))	('P. gingivalis', 'Gene', (114, 127))	('associated with', 'Reg', (135, 150))	('esophageal squamous cell carcinoma', 'Disease', (170, 204))	('P. gingivalis', 'Species', '837', (114, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))
583524	30728854	Inflammatory cytokines produced by the inflammation induced by P. gingivalis and T. forsythia may affect the regulation of the Notch pathway.	('T. forsythia', 'Species', '28112', (81, 93))	('P. gingivalis', 'Species', '837', (63, 76))	('P. gingivalis', 'Var', (63, 76))	('inflammation', 'Disease', 'MESH:D007249', (39, 51))	('inflammation', 'Disease', (39, 51))	('regulation', 'MPA', (109, 119))	('affect', 'Reg', (98, 104))	('Notch pathway', 'Pathway', (127, 140))
583535	30728854	MMP9 inactivating chemokines produced by cancer cells inhibits the inflow of neutrophils to the place of inflammation and, consequently, the development of esophageal cancer.	('MMP9', 'Gene', (0, 4))	('inflammation', 'Disease', 'MESH:D007249', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('inflammation', 'Disease', (105, 117))	('cancer', 'Disease', (167, 173))	('inactivating', 'Var', (5, 17))	('esophageal cancer', 'Disease', (156, 173))	('men', 'Species', '9606', (148, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('inhibits', 'NegReg', (54, 62))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
583554	30728854	Overexpression of GLUT-1 and GLUT-4 transporters has been observed in many types of tumors and correlates with the increase in tumor invasiveness.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('GLUT-4 transporters', 'Protein', (29, 48))	('tumor invasiveness', 'Disease', 'MESH:D009369', (127, 145))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('GLUT-1', 'Protein', (18, 24))	('increase', 'PosReg', (115, 123))	('Overexpression', 'Var', (0, 14))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumor invasiveness', 'Disease', (127, 145))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('observed', 'Reg', (58, 66))
583555	30728854	It has been suggested that inhibition of these proteins reduces the rate of glucose uptake, induces cell cycle arrest, and consequently, the arrest of tumor cell proliferation in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('induces', 'Reg', (92, 99))	('cell cycle arrest', 'CPA', (100, 117))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('reduces', 'NegReg', (56, 63))	('inhibition', 'Var', (27, 37))	('arrest of tumor', 'Disease', (141, 156))	('arrest of tumor', 'Disease', 'MESH:D006323', (141, 156))	('rate', 'MPA', (68, 72))
583569	30728854	Detection of P. gingivalis and T. forsythia in pre-cancer lesions may become an important element of cancer diagnostics and become a prognostic indicator of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer lesions', 'Disease', 'MESH:D009062', (51, 65))	('P. gingivalis', 'Var', (13, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('cancer lesions', 'Disease', (51, 65))	('cancer', 'Disease', (101, 107))	('men', 'Species', '9606', (93, 96))	('P. gingivalis', 'Species', '837', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('T. forsythia', 'Species', '28112', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('esophageal cancer', 'Disease', (157, 174))
583601	29350339	PPIs are theorized to alter the esophageal and gastric microbiome both through increasing pH of gastric secretions and also possibly by directly targeting the bacterial proton pumps of certain bacteria that contain P-type ATPase enzymes, such as Streptococcus pneumoniae and H. pylori.	('alter', 'Reg', (22, 27))	('bacterial proton pumps', 'MPA', (159, 181))	('Streptococcus pneumoniae', 'Disease', (246, 270))	('Streptococcus', 'Species', '1313', (246, 259))	('increasing', 'PosReg', (79, 89))	('H. pylori', 'Species', '210', (275, 284))	('H. pylori', 'Disease', (275, 284))	('PPIs', 'Var', (0, 4))	('gastric secretions', 'Disease', 'MESH:D013274', (96, 114))	('targeting', 'Reg', (145, 154))	('gastric secretions', 'Disease', (96, 114))
583603	29350339	The authors found that the microbial communities of esophageal biopsy samples were significantly altered after PPI treatment, with decreased Comamonadaceae and increased Clostridiaceae and Micrococcaceae.	('PPI', 'Var', (111, 114))	('increased', 'PosReg', (160, 169))	('Micrococcaceae', 'CPA', (189, 203))	('decreased', 'NegReg', (131, 140))	('altered', 'Reg', (97, 104))	('microbial communities', 'CPA', (27, 48))	('Comamonadaceae', 'CPA', (141, 155))	('Clostridiaceae', 'CPA', (170, 184))	('men', 'Species', '9606', (120, 123))
583605	29350339	The authors speculated that PPI therapy may result in decreased availability of potentially toxic one-carbon compounds, a preferred carbon and energy source for Methylobacteriaceae.	('carbon', 'Chemical', 'MESH:D002244', (132, 138))	('carbon', 'Chemical', 'MESH:D002244', (102, 108))	('PPI', 'Var', (28, 31))	('decreased', 'NegReg', (54, 63))
583606	29350339	cultured gastric aspirates from 109 patients taking PPIs and 75 patients with untreated GERD and found that the prevalence of oropharyngeal bacteria, including Neisseria, Streptococcus and Corynebacterium, was significantly increased in patients on PPIs when compared with untreated patients.	('oropharyngeal bacteria', 'Disease', (126, 148))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (64, 72))	('PPIs', 'Var', (249, 253))	('patients', 'Species', '9606', (283, 291))	('Streptococcus', 'Disease', (171, 184))	('Streptococcus', 'Species', '1313', (171, 184))	('Corynebacterium', 'Disease', (189, 204))	('rat', 'Species', '10116', (21, 24))	('Neisseria', 'Disease', (160, 169))	('increased', 'PosReg', (224, 233))	('patients', 'Species', '9606', (237, 245))
583610	29350339	High-fiber diets are generally associated with decreased colonic and systemic inflammation, whereas high-fat diets have the opposite effects.	('fat', 'Gene', (105, 108))	('fiber', 'Chemical', 'MESH:D004043', (5, 10))	('fat', 'Gene', '2195', (105, 108))	('High-fiber', 'Var', (0, 10))	('decreased colonic and systemic inflammation', 'Disease', 'MESH:D007249', (47, 90))
583687	29350339	In a study of saliva samples from 87 incident and histopathologically diagnosed ESCC subjects, 63 subjects with squamous dysplasia, and 85 healthy controls, saliva in patients with ESCC had decreased microbial diversity and decreased relative abundance of several genera including Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus and Cardiobacterium.	('microbial diversity', 'CPA', (200, 219))	('squamous dysplasia', 'Disease', (112, 130))	('Lautropia, Bulleidia', 'Disease', 'None', (281, 301))	('ESCC', 'Var', (181, 185))	('Catonella', 'Disease', (303, 312))	('decreased', 'NegReg', (224, 233))	('squamous dysplasia', 'Disease', 'MESH:D002294', (112, 130))	('patients', 'Species', '9606', (167, 175))	('Peptococcus', 'Disease', (341, 352))	('decreased', 'NegReg', (190, 199))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (112, 130))	('Corynebacterium', 'Disease', (314, 329))	('relative abundance', 'MPA', (234, 252))	('Cardiobacterium', 'Disease', (357, 372))
583690	29350339	In a surgical rat model for EAC, rats given penicillin G and streptomycin had a non-significant reduction in EAC development.	('EAC development', 'CPA', (109, 124))	('EAC', 'Phenotype', 'HP:0011459', (109, 112))	('rats', 'Species', '10116', (33, 37))	('rat', 'Species', '10116', (14, 17))	('rat', 'Species', '10116', (33, 36))	('streptomycin', 'Chemical', 'MESH:D013307', (61, 73))	('streptomycin', 'Var', (61, 73))	('EAC', 'Phenotype', 'HP:0011459', (28, 31))	('penicillin G', 'Chemical', 'MESH:D010400', (44, 56))	('reduction', 'NegReg', (96, 105))	('penicillin G', 'Var', (44, 56))	('men', 'Species', '9606', (120, 123))
583695	29350339	If these changes in the microbiome are found to cause increased risk of esophageal disease, an important area of research will be to identify specific microbes that carry responsibility for conferring increased or decreased risk of diseases.	('esophageal disease', 'Disease', (72, 90))	('changes', 'Var', (9, 16))	('esophageal disease', 'Disease', 'MESH:D004935', (72, 90))
583699	28821565	Selected EC9706 and KYSE30 cell lines were both divided into four groups: the blank control group, the negative control (NC) group (transfected with pBSHH1), the siRNA-enhanced group (transfected with pBSHH1-XIAP1-siRNA), and the siRNA-decreased group (transfected with pBSHH1-XIAP2-siRNA).	('pBSHH1', 'Var', (149, 155))	('pBSHH1-XIAP1-siRNA', 'Var', (201, 219))	('EC9706', 'CellLine', 'CVCL:E307', (9, 15))
583710	28821565	Gene silencing for tumor-suppressor genes is a vital event in the development of cancer and can be functioned by inhibiting mutation or by shutting down the promoter region and sites where gene transcription begins.	('tumor-suppressor', 'Gene', '7248', (19, 35))	('inhibiting', 'NegReg', (113, 123))	('shutting down', 'NegReg', (139, 152))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor-suppressor', 'Gene', (19, 35))	('Gene', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('promoter region', 'MPA', (157, 172))	('mutation', 'MPA', (124, 132))
583713	28821565	EC9706, TE10, KYSE70, KYSE510, and KYSE30 cells were conventionally cultured in a 5% CO2 incubator containing the Roswell Park Memorial Institute 1640 medium (RPMI 1640; Gibco BRL Co. Ltd, Gaithersburg, Maryland, U.S.A.) at 37 C. E. coli strain JM109 was incubated in the LB medium at 37 C under shaking conditions at 200 rpm.	('KYSE510', 'Var', (22, 29))	('EC9706', 'Var', (0, 6))	('CO2', 'Chemical', '-', (85, 88))	('RPMI 1640', 'Chemical', '-', (159, 168))	('E. coli', 'Species', '562', (230, 237))
583805	28656264	Additionally, TP53 3'UTR mutant (pcDNA3-Egfp-P53-3'UTR mut) and wild-type (pcDNA3-Egfp-P53-3'UTR; 0.3 microg) plasmids were also included to test whether the mutation at the binding site affects miR-612 binding and subsequent TP53 activity.	('P53', 'Gene', '7157', (227, 230))	('P53', 'Gene', (15, 18))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('P53', 'Gene', '7157', (15, 18))	('affects', 'Reg', (187, 194))	('binding', 'Interaction', (203, 210))	('P53', 'Gene', '7157', (87, 90))	('mutation', 'Var', (158, 166))	('activity', 'MPA', (231, 239))	('P53', 'Gene', (45, 48))	('miR-612', 'Gene', '693197', (195, 202))	('miR-612', 'Gene', (195, 202))	('P53', 'Gene', (227, 230))	('P53', 'Gene', '7157', (45, 48))	('P53', 'Gene', (87, 90))	('TP53', 'Gene', '7157', (226, 230))	('TP53', 'Gene', (226, 230))
583818	28656264	EC109 cells were lysed 48 h after the transfection with miR-612, centrifuged for supernatant at 13,684 x g for 10 min, electrophoresed on a 10% SDS-PAGE gel, transferred to nitrocellulose membrane, blocked with 5% skim milk at 4 C overnight.	('miR-612', 'Gene', '693197', (56, 63))	('transfection', 'Var', (38, 50))	('EC109', 'CellLine', 'CVCL:6898', (0, 5))	('SDS', 'Chemical', 'MESH:D012967', (144, 147))	('miR-612', 'Gene', (56, 63))
583832	28656264	The invasive and migratory abilities for EC109 cells were measured through the Transwell experiment following transfecting the cells with the miR-612 inhibitor along with scrambled siRNA as negative control and blank control.	('inhibitor', 'Var', (150, 159))	('miR-612', 'Gene', '693197', (142, 149))	('miR-612', 'Gene', (142, 149))	('EC109', 'CellLine', 'CVCL:6898', (41, 46))	('rat', 'Species', '10116', (20, 23))
583833	28656264	The cells transfected with the miR-612 inhibitor had significantly reduced invasive ability, as demonstrated by the fewer number of cells migrated out of wells, when compared with the cells without specific inhibition, either by scrambled miRNA or blank media (both P<0.01; Fig.	('miR', 'Gene', (239, 242))	('rat', 'Species', '10116', (103, 106))	('miR', 'Gene', '220972', (239, 242))	('miR-612', 'Gene', '693197', (31, 38))	('miR', 'Gene', '220972', (31, 34))	('reduced', 'NegReg', (67, 74))	('miR', 'Gene', (31, 34))	('invasive ability', 'CPA', (75, 91))	('miR-612', 'Gene', (31, 38))	('fewer', 'NegReg', (116, 121))	('rat', 'Species', '10116', (141, 144))	('inhibitor', 'Var', (39, 48))
583840	28656264	However, the pSilencer/miR-612 or control plasmid pSilencer/NC transfected with mutant TP53 (3'UTR pcDNA3-Esfp-P53-3'UTRmut) had no inhibitory effect on miR-612 (P>0.05; Fig.	('miR-612', 'Gene', '693197', (153, 160))	('miR-612', 'Gene', (153, 160))	('P53', 'Gene', (88, 91))	('TP53', 'Gene', '7157', (87, 91))	('P53', 'Gene', '7157', (111, 114))	('inhibitory', 'MPA', (132, 142))	('mutant', 'Var', (80, 86))	('pSilencer', 'Disease', (50, 59))	('miR-612', 'Gene', '693197', (23, 30))	('miR-612', 'Gene', (23, 30))	('P53', 'Gene', '7157', (88, 91))	('TP53', 'Gene', (87, 91))	('pSilencer/miR-612', 'Gene', '693197', (13, 30))	('pSilencer', 'Disease', 'None', (13, 22))	('pSilencer/miR-612', 'Gene', (13, 30))	('pSilencer', 'Disease', (13, 22))	('pSilencer', 'Disease', 'None', (50, 59))	('P53', 'Gene', (111, 114))
583871	28656264	The present data demonstrated that the inhibition of miR-612 significantly reduced EC109 cell invasion and migration abilities and further demonstrated the promoting role of miR-612 in ESCC progression and metastasis.	('rat', 'Species', '10116', (110, 113))	('inhibition', 'Var', (39, 49))	('miR-612', 'Gene', (53, 60))	('progression', 'CPA', (190, 201))	('EC109', 'CellLine', 'CVCL:6898', (83, 88))	('SCC', 'Gene', '6317', (186, 189))	('rat', 'Species', '10116', (146, 149))	('miR-612', 'Gene', '693197', (53, 60))	('miR-612', 'Gene', (174, 181))	('promoting', 'PosReg', (156, 165))	('reduced', 'NegReg', (75, 82))	('miR-612', 'Gene', '693197', (174, 181))	('EC109 cell invasion', 'CPA', (83, 102))	('SCC', 'Gene', (186, 189))	('rat', 'Species', '10116', (24, 27))	('migration abilities', 'CPA', (107, 126))	('metastasis', 'CPA', (206, 216))
583880	28656264	The mutant P53 may lead to unchecked cell proliferation and tumor development.	('unchecked cell proliferation', 'CPA', (27, 55))	('lead to', 'Reg', (19, 26))	('mutant', 'Var', (4, 10))	('rat', 'Species', '10116', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('P53', 'Gene', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('P53', 'Gene', '7157', (11, 14))	('tumor', 'Disease', (60, 65))
583881	28656264	~50% tumors harbor P53 point mutations, gene loss or loss of function.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('P53', 'Gene', (19, 22))	('point mutations', 'Var', (23, 38))	('P53', 'Gene', '7157', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('gene', 'Var', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('loss of function', 'NegReg', (53, 69))
583896	28651556	Multivariate analysis revealed N2-3 as an independent prognostic factor in both CSS (hazard ratio [HR] = 25.51, P = 0.008) and OS (HR = 4.90, P = 0.022), which indirectly reflected higher risk of delayed distant metastasis.	('N2-3', 'Var', (31, 35))	('OS', 'Chemical', '-', (127, 129))	('CSS', 'Chemical', '-', (80, 83))	('CSS', 'Disease', (80, 83))
583920	28651556	2c) (12067 V, 24 cm in length of the upper spatula, Karl Storz), or FK-WO retractor system (Fig.	('upper spatula', 'Disease', (37, 50))	('12067 V', 'Var', (5, 12))	('upper spatula', 'Disease', 'MESH:D012141', (37, 50))
583922	28651556	A rigid endoscope (videolaryngoscope) 4 mm in diameter (8575AV, 17 cm in length, 15 degree; or 12067VA, 24 cm in length, 0 degree; Karl Storz) connected to an HD camera (OTV-S7ProH-HD-L08E, OTV-S7ProH-HD-12E, or CH-S190-XZ-E; Olympus) is inserted, either by being attached to the distending scope or manually by a surgical assistant, to display an optimal surgical field on a monitor (Fig.	('HD', 'Disease', 'MESH:D006816', (159, 161))	('CH-S190-XZ-E', 'Disease', 'MESH:D016751', (212, 224))	('HD', 'Disease', 'MESH:D006816', (201, 203))	('12067VA', 'Var', (95, 102))	('L08E', 'Mutation', 'p.L08E', (184, 188))	('HD', 'Disease', 'MESH:D006816', (181, 183))	('CH-S190-XZ-E', 'Disease', (212, 224))
583935	28651556	Concerning pathologically positive lymph node metastasis, if pathological N (pN)-stage was pN0, pN1, or pN2a, we held to a strict observation policy.	('pN1', 'Gene', (96, 99))	('pN2a', 'Var', (104, 108))	('pN1', 'Gene', '5270', (96, 99))	('pN0', 'Var', (91, 94))
583936	28651556	In patients with pN2b or more, if the number of positive nodes was more than three, positive nodes were distributed in more than one level, or extracapsular spread was revealed, adjuvant cis-platinum (CDDP)-based CCRT was administered.	('cis-platinum', 'Chemical', 'MESH:D002945', (187, 199))	('pN2b', 'Var', (17, 21))	('extracapsular', 'CPA', (143, 156))	('CDDP', 'Chemical', 'MESH:D002945', (201, 205))	('patients', 'Species', '9606', (3, 11))
583938	28651556	Among them, patients who subsequently underwent open PPL due to positive vertical margin (n = 4), those whose tumor was residual or recurrent after an initial treatment elsewhere (n = 3), those treated without a curative intent (n = 2), those with simultaneous distant metastasis (n = 2), and those with non-SCC malignancy (n = 2) were excluded from the study.	('patients', 'Species', '9606', (12, 20))	('positive', 'Var', (64, 72))	('non-SCC malignancy', 'Disease', 'MESH:D009369', (304, 322))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('non-SCC malignancy', 'Disease', (304, 322))	('SCC', 'Phenotype', 'HP:0002860', (308, 311))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
583961	28651556	Furthermore, another four patients who belonged to N2a (n = 1) or N2b (n = 3) and repeatedly developed multiple second primary cancers in the pharyngolaryngeal region ultimately underwent CCRT (n = 1), RT plus weekly cetuximab (n = 1), or RT alone (n = 2).	('primary cancers', 'Disease', 'MESH:D009369', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tip', 'Gene', '261726', (106, 109))	('patients', 'Species', '9606', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('N2b', 'Var', (66, 69))	('N2a', 'Var', (51, 54))	('tip', 'Gene', (106, 109))	('primary cancers', 'Disease', (119, 134))	('cetuximab', 'Chemical', 'MESH:D000068818', (217, 226))
583976	28651556	Fifty-six patients (78%), including all who had Tis or T1 tumors, resumed oral intake on the first or second postoperative day without obvious dysphasia.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('dysphasia', 'Disease', 'MESH:D001037', (143, 152))	('dysphasia', 'Disease', (143, 152))	('resumed oral intake', 'MPA', (66, 85))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('Tis', 'Var', (48, 51))	('patients', 'Species', '9606', (10, 18))	('dysphasia', 'Phenotype', 'HP:0002357', (143, 152))
583978	28651556	The indication depended on the extent of estimated risk of postoperative dysphasia owing to various factors, including structural changes in the supraglottis leading to aspiration, narrowed esophageal entrance associated with transient mucosal edema, hypersecretion of mucus discharge, history of previous RT on the neck, and wound pain.	('postoperative dysphasia', 'Disease', (59, 82))	('dysphasia', 'Phenotype', 'HP:0002357', (73, 82))	('narrowed', 'Var', (181, 189))	('aspiration', 'Phenotype', 'HP:0002835', (169, 179))	('narrowed esophageal entrance', 'Phenotype', 'HP:0010450', (181, 209))	('aspiration', 'Disease', (169, 179))	('hypersecretion', 'Disease', (251, 265))	('leading to', 'Reg', (158, 168))	('mucosal edema', 'Disease', (236, 249))	('mucosal edema', 'Disease', 'MESH:D004487', (236, 249))	('postoperative dysphasia', 'Disease', 'MESH:D010149', (59, 82))	('pain', 'Phenotype', 'HP:0012531', (332, 336))	('pain', 'Disease', 'MESH:D010146', (332, 336))	('pain', 'Disease', (332, 336))	('edema', 'Phenotype', 'HP:0000969', (244, 249))
583979	28651556	Among them, two patients, who had T3N2b SGC and underwent adjuvant CCRT, developed aspiration pneumonia during or after CCRT, although they recovered after conservative treatment in association with swallowing rehabilitation.	('T3N2b SGC', 'Var', (34, 43))	('aspiration pneumonia', 'Disease', (83, 103))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (83, 103))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (83, 103))	('aspiration', 'Phenotype', 'HP:0002835', (83, 93))	('developed', 'Reg', (73, 82))	('patients', 'Species', '9606', (16, 24))	('pneumonia', 'Phenotype', 'HP:0002090', (94, 103))
583994	28651556	In univariate analysis, patients with N2-3 showed significantly worse CSS (P = 0.010) and OS (P = 0.032) than those with N0-1, whereas no other factor was significantly associated with CSS or OS.	('worse', 'NegReg', (64, 69))	('OS', 'Chemical', '-', (90, 92))	('CSS', 'Chemical', '-', (70, 73))	('patients', 'Species', '9606', (24, 32))	('OS', 'Chemical', '-', (192, 194))	('CSS', 'Disease', (70, 73))	('CSS', 'Chemical', '-', (185, 188))	('N2-3', 'Var', (38, 42))
583997	28651556	Multivariate analysis using the Cox proportional hazards model revealed independent significance of N2-3 as an unfavorable prognostic factor in both CSS (HR = 25.51 [95% CI: 2.29-284.17] vs. N0-1, P = 0.008) and OS (HR = 4.90 [95% CI: 1.26-19.08] vs. N0-1, P = 0.022) (Table 5).	('N2-3', 'Var', (100, 104))	('Cox', 'Gene', '1351', (32, 35))	('CSS', 'Chemical', '-', (149, 152))	('CSS', 'Disease', (149, 152))	('Cox', 'Gene', (32, 35))	('OS', 'Chemical', '-', (212, 214))
584026	28651556	The remaining nine patients developed distant metastasis without locoregional failure, seven of whom died as a consequence, suggesting that N2-3 is a strong predictor of death due to delayed distant metastasis.	('N2-3', 'Var', (140, 144))	('patients', 'Species', '9606', (19, 27))	('failure', 'Disease', 'MESH:D017093', (78, 85))	('distant metastasis', 'CPA', (38, 56))	('death', 'Disease', 'MESH:D003643', (170, 175))	('death', 'Disease', (170, 175))	('failure', 'Disease', (78, 85))
584060	27852047	One study reported and validated a prognostic 4-gene signature (and showed that underexpression of DCK, PAPSS2 and SIRT2 in combination with overexpression of TRIM44 decreased 5-year survival from 58% to 14%.	('TRIM44', 'Gene', '54765', (159, 165))	('TRIM44', 'Gene', (159, 165))	('PAPSS2', 'Gene', '9060', (104, 110))	('PAPSS2', 'Gene', (104, 110))	('SIRT2', 'Gene', '22933', (115, 120))	('DCK', 'Gene', '1633', (99, 102))	('decreased', 'NegReg', (166, 175))	('DCK', 'Gene', (99, 102))	('underexpression', 'Var', (80, 95))	('SIRT2', 'Gene', (115, 120))	('5-year survival', 'CPA', (176, 191))
584116	28194033	ESCC patients with high lncRNA625 expression had significantly shorter survival time than those with low expression.	('patients', 'Species', '9606', (5, 13))	('lncRNA625', 'Var', (24, 33))	('shorter', 'NegReg', (63, 70))	('high lncRNA625', 'Var', (19, 33))	('survival time', 'CPA', (71, 84))
584123	28194033	Examples include the increased expression of HOTAIR in metastatic breast cancer, oncogenicity and tumor-suppressive properties of H19 in different cancers, ANRIL-induced epigenetic silencing of p15 in leukemia, and the ability of MALAT1 to confer high metastatic potential in non-small cell lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('oncogenicity', 'CPA', (81, 93))	('tumor', 'Disease', (98, 103))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (276, 302))	('H19', 'Gene', '283120', (130, 133))	('increased', 'PosReg', (21, 30))	('p15', 'Gene', '1030', (194, 197))	('MALAT1', 'Gene', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (280, 302))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('ANRIL', 'Gene', '100048912', (156, 161))	('high metastatic potential', 'CPA', (247, 272))	('MALAT1', 'Gene', '378938', (230, 236))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (276, 302))	('epigenetic silencing', 'Var', (170, 190))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('expression', 'MPA', (31, 41))	('leukemia', 'Phenotype', 'HP:0001909', (201, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (291, 302))	('HOTAIR', 'Gene', '100124700', (45, 51))	('non-small cell lung cancer', 'Disease', (276, 302))	('ANRIL', 'Gene', (156, 161))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('leukemia', 'Disease', (201, 209))	('breast cancer', 'Disease', (66, 79))	('leukemia', 'Disease', 'MESH:D007938', (201, 209))	('cancers', 'Disease', (147, 154))	('HOTAIR', 'Gene', (45, 51))	('p15', 'Gene', (194, 197))	('H19', 'Gene', (130, 133))
584124	28194033	For example, ESCCAL-1 was found to be an onco-lncRNA in esophageal cancer development, and high expression of BC200 or MALAT1 has been shown to be a novel predictive marker for ESCC patients who received radical resection.	('BC200', 'Gene', '618', (110, 115))	('MALAT1', 'Gene', (119, 125))	('high expression', 'Var', (91, 106))	('esophageal cancer', 'Disease', (56, 73))	('BC200', 'Gene', (110, 115))	('ESCC', 'Disease', (177, 181))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (182, 190))	('ESCCAL-1', 'Gene', (13, 21))	('MALAT1', 'Gene', '378938', (119, 125))	('ESCCAL-1', 'Gene', '101805492', (13, 21))
584160	28194033	PCGs in the network were significantly associated with cancer-related functions (Figure 2c).	('PCGs', 'Chemical', '-', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('associated', 'Reg', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('PCGs', 'Var', (0, 4))	('cancer', 'Disease', (55, 61))
584172	28194033	In addition, DLX6-AS1, AC130710.1.1, and WT1-AS have established functions in development, lung cancer, gastric cancer and acute myeloid leukemia (Table 1).	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('leukemia', 'Phenotype', 'HP:0001909', (137, 145))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (129, 145))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('DLX6-AS1', 'Gene', (13, 21))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (123, 145))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('acute myeloid leukemia', 'Disease', (123, 145))	('AC130710.1.1', 'Var', (23, 35))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('DLX6-AS1', 'Gene', '285987;1750;5729', (13, 21))	('development', 'Disease', (78, 89))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (123, 145))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancer', 'Disease', (91, 102))	('gastric cancer', 'Disease', (104, 118))
584175	28194033	From the statistically significant lncRNAs in URW-LPE (FDR-corrected P-values <0.05), three novel candidate upregulated lncRNAs (lncRNA625, LINC00460 and AC093850.2) with high URWScores and differential expression levels were selected for testing.	('lncRNA625', 'Var', (129, 138))	('upregulated', 'PosReg', (108, 119))	('LINC00460', 'Gene', '728192', (140, 149))	('LINC00460', 'Gene', (140, 149))
584176	28194033	LncRNA625 expression was measured in various human esophageal cancer cell lines and was found to be highly expressed in KYSE150 and KYSE510 ESCC cells (Figure 3b).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancer', 'Disease', (51, 68))	('LncRNA625', 'Gene', (0, 9))	('human', 'Species', '9606', (45, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('KYSE150', 'Var', (120, 127))	('KYSE510', 'Var', (132, 139))
584183	28194033	Similarly, known tumor suppressors, such as SAA1, S100A9, ADI1 and CLDN7, were consistently upregulated after lncRNA625 knockdown (Figure 4b).	('SAA1', 'Gene', '6288', (44, 48))	('lncRNA625', 'Gene', (110, 119))	('upregulated', 'PosReg', (92, 103))	('ADI1', 'Gene', '55256', (58, 62))	('tumor', 'Disease', (17, 22))	('CLDN7', 'Gene', '1366', (67, 72))	('knockdown', 'Var', (120, 129))	('SAA1', 'Gene', (44, 48))	('ADI1', 'Gene', (58, 62))	('CLDN7', 'Gene', (67, 72))	('S100A9', 'Gene', '6280', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('S100A9', 'Gene', (50, 56))
584184	28194033	That is, those upregulated (downregulated) PCGs, following lncRNA625 knockdown, were significantly downregulated (upregulated) in the RNA-seq sample (P-value=1.24e-06 and 0.041, respectively, hypergeometric test).	('PCGs', 'Chemical', '-', (43, 47))	('upregulated', 'PosReg', (15, 26))	('downregulated', 'NegReg', (99, 112))	('lncRNA625', 'Gene', (59, 68))	('knockdown', 'Var', (69, 78))
584186	28194033	To determine the mechanism by which lncRNA625 regulates the transcription of downstream target PCGs, we initially localized lncRNA625 in ESCC tissue and showed that lncRNA625 was located in both nucleus and cytoplasm of tumor cells (Figure 5a).	('lncRNA625', 'Gene', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('PCGs', 'Chemical', '-', (95, 99))	('lncRNA625', 'Var', (165, 174))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
584189	28194033	Searching the UCSC genome browser, showed that EP300 occupancy frequently appeared in the promoter regions of multiple lncRNA625-regulated PCGs including NEK6, TNC, NCOA4 and CROT (Supplementary Figure 5).	('NCOA4', 'Gene', (165, 170))	('CROT', 'Gene', (175, 179))	('NCOA4', 'Gene', '8031', (165, 170))	('lncRNA625-regulated', 'Gene', (119, 138))	('NEK6', 'Gene', (154, 158))	('CROT', 'Gene', '54677', (175, 179))	('TNC', 'Gene', '3371', (160, 163))	('EP300 occupancy', 'Var', (47, 62))	('PCGs', 'Chemical', '-', (139, 143))	('NEK6', 'Gene', '10783', (154, 158))	('TNC', 'Gene', (160, 163))
584190	28194033	In several cancer cell lines, such as HeLa, HepG and SkNSHRA, genes downregulated by lncRNA625 knockdown were enriched for the endogenous EP300 occupancy pattern, but not enriched in hESC (Figure 5d).	('HepG', 'CellLine', 'CVCL:Y479', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('downregulated', 'NegReg', (68, 81))	('lncRNA625', 'Gene', (85, 94))	('knockdown', 'Var', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('HeLa', 'CellLine', 'CVCL:0030', (38, 42))	('cancer', 'Disease', (11, 17))
584193	28194033	Moreover, Gene Set Enrichment Analysis (GSEA) showed that genes regulated by lncRNA625 were enriched in the expression profile after knocking down EP300 (Figure 5g).	('lncRNA625', 'Gene', (77, 86))	('GSEA', 'Chemical', '-', (40, 44))	('EP300', 'Gene', (147, 152))	('expression', 'MPA', (108, 118))	('knocking down', 'Var', (133, 146))
584195	28194033	Use of qRT-PCR confirmed that lncRNA625 induced multiple PCGs, such as NEK6, TNC, KCTD12, NCOA4, CROT, HIST1H2BM, ASUN and CCNG1 after silencing of either EP300 or lncRNA625 (Figure 5h), consistent with the cDNA microarray results.	('ASUN', 'Gene', '55726', (114, 118))	('NCOA4', 'Gene', (90, 95))	('NEK6', 'Gene', '10783', (71, 75))	('NCOA4', 'Gene', '8031', (90, 95))	('KCTD12', 'Gene', '115207', (82, 88))	('TNC', 'Gene', (77, 80))	('CROT', 'Gene', '54677', (97, 101))	('PCGs', 'Chemical', '-', (57, 61))	('induced', 'Reg', (40, 47))	('CROT', 'Gene', (97, 101))	('TNC', 'Gene', '3371', (77, 80))	('CCNG1', 'Gene', (123, 128))	('NEK6', 'Gene', (71, 75))	('KCTD12', 'Gene', (82, 88))	('HIST1H2BM', 'Gene', '8342', (103, 112))	('HIST1H2BM', 'Gene', (103, 112))	('CCNG1', 'Gene', '900', (123, 128))	('lncRNA625', 'Var', (30, 39))	('silencing', 'NegReg', (135, 144))	('lncRNA625', 'Var', (164, 173))	('ASUN', 'Gene', (114, 118))
584196	28194033	Indeed, most of lncRNA625- and EP300-induced downstream PCGs evaluated by qRT-PCR are known positive regulators of cancer, including NEK6, TNC, CCNG1, HIST1H2BM, NCOA4 and KCTD12.	('cancer', 'Disease', (115, 121))	('EP300-induced', 'Var', (31, 44))	('NEK6', 'Gene', (133, 137))	('CCNG1', 'Gene', '900', (144, 149))	('lncRNA625-', 'Gene', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('PCGs', 'Chemical', '-', (56, 60))	('NCOA4', 'Gene', (162, 167))	('CCNG1', 'Gene', (144, 149))	('KCTD12', 'Gene', (172, 178))	('HIST1H2BM', 'Gene', (151, 160))	('NCOA4', 'Gene', '8031', (162, 167))	('NEK6', 'Gene', '10783', (133, 137))	('HIST1H2BM', 'Gene', '8342', (151, 160))	('TNC', 'Gene', '3371', (139, 142))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('KCTD12', 'Gene', '115207', (172, 178))	('TNC', 'Gene', (139, 142))
584201	28194033	Patients with high lncRNA625 expression did not have significantly shorter overall survival (OS) than those with the low expression.	('lncRNA625', 'Gene', (19, 28))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (67, 74))	('overall survival', 'MPA', (75, 91))	('expression', 'MPA', (29, 39))
584202	28194033	For disease-free survival (DFS), patients with high lncRNA625 expression had significantly shorter survival time than those with low expression (median survival 23.2 months vs >80 months, P<0.028; Figure 6a).	('patients', 'Species', '9606', (33, 41))	('survival time', 'CPA', (99, 112))	('high', 'Var', (47, 51))	('shorter', 'NegReg', (91, 98))	('lncRNA625', 'Gene', (52, 61))
584204	28194033	A log-rank test showed that lncRNA625 could classify patients with stage III into high- and low-risk groups (Figure 6a).	('lncRNA625', 'Var', (28, 37))	('stage III', 'Disease', (67, 76))	('patients', 'Species', '9606', (53, 61))
584206	28194033	Stratified analysis for patients with invasive depth 1/2 (T1/T2) and non-lymph node metastasis showed that high lncRNA625 expression did not confer shorter OS and DFS (Supplementary Figure 7).	('high', 'Var', (107, 111))	('lncRNA625', 'Gene', (112, 121))	('patients', 'Species', '9606', (24, 32))
584207	28194033	However, a stratified analysis for patients with either invasive depth 3/4 (T3/T4) or lymph node metastasis showed that lncRNA625 could be a significant predictor of subsequent metastasis and death.	('death', 'Disease', 'MESH:D003643', (192, 197))	('lncRNA625', 'Var', (120, 129))	('death', 'Disease', (192, 197))	('patients', 'Species', '9606', (35, 43))
584211	28194033	The results showed that survival prediction by lncRNA625 levels is independent of clinical and pathological factors for DFS of patients with ESCC (Supplementary Table 7).	('lncRNA625 levels', 'Var', (47, 63))	('patients', 'Species', '9606', (127, 135))	('ESCC', 'Disease', (141, 145))
584216	28194033	These suggested that lncRNA625 has the better prognostic ability in ESCC than other cancers.	('ESCC', 'Disease', (68, 72))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('lncRNA625', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
584220	28194033	Our analysis determined that ESCC patients with high TMPRSS4 expression had significantly shorter survival time than those with low expression (P<0.021).	('ESCC', 'Disease', (29, 33))	('survival time', 'CPA', (98, 111))	('TMPRSS4', 'Gene', '56649', (53, 60))	('shorter', 'NegReg', (90, 97))	('patients', 'Species', '9606', (34, 42))	('high', 'Var', (48, 52))	('TMPRSS4', 'Gene', (53, 60))
584231	28194033	Patients with high lncRNA625 expression had a significantly shorter DFS than those with low expression.	('lncRNA625', 'Gene', (19, 28))	('DFS', 'MPA', (68, 71))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (60, 67))	('expression', 'MPA', (29, 39))
584235	28194033	This suggests that genes upregulated by lncRNA625 and EP300, such as TNC, NEK6, CCNG1, HIST1H2BM, NCOA4, NCOA4 and KCTD12, are highly likely to be induced by lncRNA625 via recruitment of EP300 to target gene promoters.	('NEK6', 'Gene', (74, 78))	('lncRNA625', 'Var', (40, 49))	('CCNG1', 'Gene', (80, 85))	('EP300', 'Gene', (54, 59))	('NCOA4', 'Gene', '8031', (105, 110))	('NCOA4', 'Gene', '8031', (98, 103))	('TNC', 'Gene', '3371', (69, 72))	('KCTD12', 'Gene', '115207', (115, 121))	('lncRNA625', 'Var', (158, 167))	('CCNG1', 'Gene', '900', (80, 85))	('upregulated', 'PosReg', (25, 36))	('TNC', 'Gene', (69, 72))	('HIST1H2BM', 'Gene', (87, 96))	('HIST1H2BM', 'Gene', '8342', (87, 96))	('NEK6', 'Gene', '10783', (74, 78))	('NCOA4', 'Gene', (105, 110))	('KCTD12', 'Gene', (115, 121))	('NCOA4', 'Gene', (98, 103))
584236	28194033	Studies showed that motifs for transcription factors, such as ETS, FOX, AP1 and STAT, are enriched in EP300-bound regions, suggesting that complex regulatory mechanism of lncRNA625 and EP300 might be dependent on other transcription factors.	('AP1', 'Gene', '3726', (72, 75))	('AP1', 'Gene', (72, 75))	('lncRNA625', 'Var', (171, 180))
584237	28194033	We modulated the related EP300 network and showed that the downstream target gene network of lncRNA625 and EP300 likely very complex, causing numerous changes in global gene expression in ESCC patients (Supplementary Figure 8).	('lncRNA625', 'Gene', (93, 102))	('patients', 'Species', '9606', (193, 201))	('EP300', 'Var', (107, 112))	('ESCC', 'Disease', (188, 192))	('changes', 'Reg', (151, 158))	('causing', 'Reg', (134, 141))	('global gene expression', 'MPA', (162, 184))
584267	28194033	The KYSE150, KYSE450, KYSE510 human esophageal cancer cell lines were kindly provided by Dr. Ming-Zhou Guo (Chinese PLA General Hospital, Beijing, China) and cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum.	('KYSE510', 'Var', (22, 29))	('human', 'Species', '9606', (30, 35))	('esophageal cancer', 'Disease', 'MESH:D004938', (36, 53))	('RPMI-1640 medium', 'Chemical', '-', (170, 186))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancer', 'Disease', (36, 53))	('bovine', 'Species', '9913', (215, 221))
584268	28194033	KYSE150, KYSE450 and KYSE510 cells were derived from human esophageal cancer cells.	('esophageal cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('KYSE510', 'Var', (21, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('human', 'Species', '9606', (53, 58))
584304	26610476	Epigenetic Repression of miR-218 Promotes Esophageal Carcinogenesis by Targeting ROBO1 miR-218, consisting of miR-218-1 at 4p15.31 and miR-218-2 at 5q35.1, was significantly decreased in esophageal squamous cell carcinoma (ESCC) in our previous study.	('ROBO1', 'Gene', (81, 86))	('miR-218', 'Var', (87, 94))	('miR-218', 'Chemical', '-', (110, 117))	('miR-218', 'Chemical', '-', (87, 94))	('miR-218-2', 'Gene', '407001', (135, 144))	('miR-218', 'Chemical', '-', (135, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (198, 221))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (187, 221))	('Targeting', 'Reg', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('miR-218-1', 'Gene', '407000', (110, 119))	('Epigenetic', 'MPA', (0, 10))	('decreased', 'NegReg', (174, 183))	('Esophageal Carcinogenesis', 'Disease', (42, 67))	('miR-218', 'Gene', (25, 32))	('miR-218-2', 'Gene', (135, 144))	('Promotes', 'PosReg', (33, 41))	('miR-218', 'Chemical', '-', (25, 32))	('miR-218-1', 'Gene', (110, 119))	('esophageal squamous cell carcinoma', 'Disease', (187, 221))
584305	26610476	The aim of this study was to determine whether aberrant methylation is associated with miR-218 repression.	('miR-218', 'Chemical', '-', (87, 94))	('aberrant methylation', 'Var', (47, 67))	('associated', 'Reg', (71, 81))	('miR-218 repression', 'Gene', (87, 105))
584311	26610476	After demethylation treatment by 5-aza-2'-deoxycytidine, there was a 2.53- and 2.40-fold increase of miR-218 expression in EC109 and EC9706, respectively.	('EC109', 'CellLine', 'CVCL:6898', (123, 128))	('miR-218', 'Gene', (101, 108))	('expression', 'MPA', (109, 119))	('EC9706', 'CellLine', 'CVCL:E307', (133, 139))	('miR-218', 'Chemical', '-', (101, 108))	('EC109', 'Var', (123, 128))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (33, 55))	('EC9706', 'Var', (133, 139))	('increase', 'PosReg', (89, 97))
584314	26610476	In conclusion, our results support that aberrant CpG hypermethylation at least partly accounts for miR-218 silencing in ESCC, which impairs its tumor-suppressive function.	('tumor', 'Disease', (144, 149))	('miR-218', 'Gene', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('ESCC', 'Disease', (120, 124))	('miR-218', 'Chemical', '-', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('hypermethylation', 'Var', (53, 69))	('CpG', 'Protein', (49, 52))	('impairs', 'NegReg', (132, 139))	('aberrant', 'Var', (40, 48))	('silencing', 'NegReg', (107, 116))
584317	26610476	DNA methylation, one of the extensively-studied epigenetic modifications, represses transcription of the promoter regions in tumor suppressor genes and, therefore, inactivates these genes' expressions.	('transcription of the promoter regions', 'MPA', (84, 121))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', (125, 130))	('expressions', 'MPA', (189, 200))	('represses', 'NegReg', (74, 83))	('inactivates', 'NegReg', (164, 175))
584318	26610476	Several tumor-suppressive miRNAs have been reported to be silenced by CpG hypermethylation in esophageal squamous cell carcinoma (ESCC), including miR-375, miR-34a, and miR-129-2.	('miR-129-2', 'Gene', (169, 178))	('miR-34a', 'Gene', '407040', (156, 163))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('miR-129-2', 'Gene', '100302138', (169, 178))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (94, 128))	('miR-34a', 'Gene', (156, 163))	('miR-375', 'Gene', '494324', (147, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('hypermethylation', 'Var', (74, 90))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('miR-375', 'Gene', (147, 154))	('silenced', 'NegReg', (58, 66))	('CpG', 'Protein', (70, 73))
584324	26610476	As an intronic miRNA, miR-218 is supposed to be excised from the same primary transcript and co-regulated with its host genes, SLIT2 and SLIT3.	('SLIT3', 'Gene', '6586', (137, 142))	('SLIT2', 'Gene', (127, 132))	('SLIT3', 'Gene', (137, 142))	('SLIT2', 'Gene', '9353', (127, 132))	('miR-218', 'Chemical', '-', (22, 29))	('miR-218', 'Var', (22, 29))
584325	26610476	SLIT2 and SLIT3 are commonly found to be silenced by aberrant DNA hypermethylation in promoter regions in cancers.	('SLIT3', 'Gene', '6586', (10, 15))	('SLIT2', 'Gene', '9353', (0, 5))	('aberrant DNA hypermethylation', 'Var', (53, 82))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('SLIT3', 'Gene', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('SLIT2', 'Gene', (0, 5))
584326	26610476	Thus, miR-218 is supposed to be transcriptionally silenced by aberrant DNA methylation under the same regulatory mechanism.	('aberrant', 'Var', (62, 70))	('miR-218', 'Chemical', '-', (6, 13))	('miR-218', 'Gene', (6, 13))
584327	26610476	We speculate that the loss of miR-218 in ESCC is a result of CpG islands' hypermethylation in promoter regions.	('hypermethylation', 'Var', (74, 90))	('loss', 'NegReg', (22, 26))	('miR-218', 'Gene', (30, 37))	('miR-218', 'Chemical', '-', (30, 37))
584328	26610476	In this study, we assessed the methylation status of miR-218 CpG islands in cells and clinical samples using bisulphite sequencing, methylation specific PCR, and 5-aza-2'-deoxycytidine treatment assay, and determined that miR-218 were CpG hypermethylated in ESCC.	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (162, 184))	('miR-218', 'Var', (222, 229))	('miR-218', 'Gene', (53, 60))	('miR-218', 'Chemical', '-', (53, 60))	('bisulphite', 'Chemical', 'MESH:C042345', (109, 119))	('miR-218', 'Chemical', '-', (222, 229))	('ESCC', 'Disease', (258, 262))	('clinical samples', 'Species', '191496', (86, 102))
584332	26610476	Dense CpG islands are present at the position (-760 to -212) upstream to the transcription start site (TSS) in miR-218-1, and at the position (-407 to +117) to the TSS in miR-218-2 (Figure 1).	('miR-218-2', 'Gene', (171, 180))	('-760 to -212', 'Var', (47, 59))	('miR-218-2', 'Gene', '407001', (171, 180))	('-407', 'Var', (143, 147))	('miR-218-1', 'Gene', (111, 120))	('miR-218-1', 'Gene', '407000', (111, 120))
584334	26610476	Results showed that both of miR-218-1 and miR-218-2 were CpG-methylated in EC109 and EC9706 (Figure 2).	('EC109', 'Var', (75, 80))	('miR-218-1', 'Gene', '407000', (28, 37))	('EC109', 'CellLine', 'CVCL:6898', (75, 80))	('EC9706', 'Var', (85, 91))	('miR-218-1', 'Gene', (28, 37))	('miR-218-2', 'Gene', '407001', (42, 51))	('miR-218-2', 'Gene', (42, 51))	('EC9706', 'CellLine', 'CVCL:E307', (85, 91))
584336	26610476	The expression level of miR-218 in EC109 and EC9706 were recovered accordingly by 2.53- and 2.40-fold respectively after 5-aza-CdR treatment (Figure 3).	('expression level', 'MPA', (4, 20))	('EC109', 'CellLine', 'CVCL:6898', (35, 40))	('EC9706', 'CellLine', 'CVCL:E307', (45, 51))	('miR-218', 'Gene', (24, 31))	('EC109', 'Var', (35, 40))	('EC9706', 'Var', (45, 51))	('miR-218', 'Chemical', '-', (24, 31))
584338	26610476	miR-218-1 was found fully CpG-methylated in both EC9706 and EC109, while unmethylated in Het-1A (Figure 4A).	('EC9706', 'Var', (49, 55))	('miR-218-1', 'Gene', '407000', (0, 9))	('EC109', 'Var', (60, 65))	('miR-218-1', 'Gene', (0, 9))	('EC9706', 'CellLine', 'CVCL:E307', (49, 55))	('EC109', 'CellLine', 'CVCL:6898', (60, 65))
584342	26610476	The results strongly indicated the hypermethylation of miR-218 was associated with ESCC.	('hypermethylation', 'Var', (35, 51))	('miR-218', 'Gene', (55, 62))	('associated', 'Reg', (67, 77))	('ESCC', 'Disease', (83, 87))	('miR-218', 'Chemical', '-', (55, 62))
584344	26610476	In accordance with the reduced expression of miR-218 in cancer tissues, a significant downregulation of miR-218 in miR-218-1 methylation group (including full methylation and semi-methylation) than that in unmethylation group was detected (p < 0.01) (Figure 5A).	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('miR-218', 'Gene', (104, 111))	('miR-218', 'Chemical', '-', (104, 111))	('miR-218', 'Chemical', '-', (45, 52))	('miR-218', 'Chemical', '-', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('miR-218-1', 'Gene', '407000', (115, 124))	('downregulation', 'NegReg', (86, 100))	('cancer', 'Disease', (56, 62))	('miR-218-1', 'Gene', (115, 124))	('methylation', 'Var', (125, 136))
584356	26610476	To demonstrate that whether miR-218 directly regulates ROBO1, we employed a dual-luciferase reporter assay (Figure 8A).	('miR-218', 'Var', (28, 35))	('regulates', 'Reg', (45, 54))	('ROBO1', 'Gene', (55, 60))	('miR-218', 'Chemical', '-', (28, 35))	('ROBO1', 'Gene', '6091', (55, 60))
584357	26610476	Results showed that miR-218 significantly inhibited nearly 45% expression of constructs of 3'UTR wild-type but not the mutant type, indicating that miR-218 directly regulates ROBO1 by binding to 3'UTR of ROBO1 (p < 0.001) (Figure 8B).	('miR-218', 'Chemical', '-', (20, 27))	('binding', 'Interaction', (184, 191))	('miR-218', 'Chemical', '-', (148, 155))	('regulates', 'Reg', (165, 174))	('ROBO1', 'Gene', (175, 180))	('ROBO1', 'Gene', '6091', (175, 180))	('inhibited', 'NegReg', (42, 51))	('miR-218', 'Var', (148, 155))	('ROBO1', 'Gene', (204, 209))	('ROBO1', 'Gene', '6091', (204, 209))
584358	26610476	Expression of ROBO1 mRNA in cells treated with miR-218 mimic were decreased (fold change = 3.41) compared with negative control.	('miR-218 mimic', 'Var', (47, 60))	('Expression', 'MPA', (0, 10))	('decreased', 'NegReg', (66, 75))	('ROBO1', 'Gene', '6091', (14, 19))	('miR-218', 'Chemical', '-', (47, 54))	('ROBO1', 'Gene', (14, 19))	('mRNA', 'MPA', (20, 24))
584359	26610476	Expression level of ROBO1 protein in miR-218 treated cells was accordingly decreased (fold change = 2.17) compared with negative control (Figure 8C,D).	('miR-218', 'Var', (37, 44))	('ROBO1', 'Gene', '6091', (20, 25))	('Expression level', 'MPA', (0, 16))	('ROBO1', 'Gene', (20, 25))	('miR-218', 'Chemical', '-', (37, 44))	('protein', 'Protein', (26, 33))	('decreased', 'NegReg', (75, 84))
584362	26610476	Taken together, ROBO1 is a downstream gene of miR-218 in ESCC.	('ROBO1', 'Gene', '6091', (16, 21))	('miR-218', 'Var', (46, 53))	('ROBO1', 'Gene', (16, 21))	('miR-218', 'Chemical', '-', (46, 53))
584363	26610476	Aberrant DNA methylation, including hypermethylation of tumor suppressor genes and hypomethylation of oncogenes occurs frequently in cancers, and growing evidences indicate that methylation status may serve as biomarkers that are more sensitive than genetic alterations.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('hypermethylation', 'MPA', (36, 52))	('tumor', 'Disease', (56, 61))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('hypomethylation', 'Var', (83, 98))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
584367	26610476	These studies suggest that the aberrant CpG methylation in miRNA promoter regions may contribute to their dysregulation in tumors.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('dysregulation', 'MPA', (106, 119))	('aberrant CpG methylation', 'Var', (31, 55))	('contribute', 'Reg', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
584370	26610476	Intronic miR-335 is reported to be co-regulated with host gene MEST by promoter hypermethylation in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('hepatocellular carcinoma', 'Disease', (100, 124))	('MEST', 'Gene', (63, 67))	('MEST', 'Gene', '4232', (63, 67))	('promoter hypermethylation', 'Var', (71, 96))	('miR-335', 'Gene', (9, 16))	('miR-335', 'Gene', '442904', (9, 16))
584371	26610476	miR-342 was epigenetic silenced with host gene EVL in colorectal cancer.	('epigenetic silenced', 'Var', (12, 31))	('miR-342', 'Gene', (0, 7))	('EVL', 'Gene', '51466', (47, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('colorectal cancer', 'Disease', (54, 71))	('miR-342', 'Gene', '442909', (0, 7))	('EVL', 'Gene', (47, 50))
584373	26610476	Thus, we speculated miR-218 may be silenced by aberrant CpG methylation together with host genes.	('aberrant', 'Var', (47, 55))	('silenced', 'NegReg', (35, 43))	('miR-218', 'Chemical', '-', (20, 27))	('methylation', 'Var', (60, 71))	('miR-218', 'Gene', (20, 27))
584375	26610476	BSP analysis showed that CpG islands of both miR-218-1 and miR-218-2 were hypermethylated in ESCC cells, while unmethylated and semi-methylated, respectively, in normal esophageal epithelial cell Het-1A.	('hypermethylated', 'Var', (74, 89))	('miR-218-2', 'Gene', (59, 68))	('miR-218-1', 'Gene', (45, 54))	('miR-218-1', 'Gene', '407000', (45, 54))	('miR-218-2', 'Gene', '407001', (59, 68))
584379	26610476	Apart from DNA methylation, other mechanisms may underline miR-218 dysregulation in ESCC.	('dysregulation', 'Var', (67, 80))	('miR-218', 'Gene', (59, 66))	('miR-218', 'Chemical', '-', (59, 66))	('ESCC', 'Disease', (84, 88))
584386	26610476	Uesugi demonstrated that loss of miR-218 activated mTOR-Akt signaling pathway through direct targeting RICTOR in oral cancer.	('mTOR', 'Gene', (51, 55))	('oral cancer', 'Disease', 'MESH:D009062', (113, 124))	('loss', 'Var', (25, 29))	('RICTOR', 'Gene', (103, 109))	('RICTOR', 'Gene', '253260', (103, 109))	('oral cancer', 'Disease', (113, 124))	('miR-218', 'Gene', (33, 40))	('miR-218', 'Chemical', '-', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('activated', 'PosReg', (41, 50))	('targeting', 'Reg', (93, 102))	('mTOR', 'Gene', '2475', (51, 55))
584387	26610476	In cervical cancer, miR-218 involves in focal adhesion pathway by directly targeting LAMB3.	('involves', 'Reg', (28, 36))	('LAMB3', 'Gene', (85, 90))	('targeting', 'Reg', (75, 84))	('LAMB3', 'Gene', '3914', (85, 90))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('miR-218', 'Var', (20, 27))	('cervical cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('miR-218', 'Chemical', '-', (20, 27))	('focal adhesion pathway', 'Pathway', (40, 62))
584390	26610476	He demonstrated miR-218 induces cell cycle arrest in the G2 phase of colon cancer cells.	('cell cycle arrest in the G2 phase', 'CPA', (32, 65))	('colon cancer', 'Disease', (69, 81))	('miR-218', 'Chemical', '-', (16, 23))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (32, 49))	('induces', 'Reg', (24, 31))	('miR-218', 'Var', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colon cancer', 'Disease', 'MESH:D015179', (69, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (69, 81))
584391	26610476	In breast cancer, miR-218 is found to prolong the G1 phase.	('miR-218', 'Chemical', '-', (18, 25))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('miR-218', 'Var', (18, 25))	('prolong', 'PosReg', (38, 45))	('G1 phase', 'CPA', (50, 58))
584392	26610476	However, Tie found miR-218 did not affect cell cycle in gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('miR-218', 'Chemical', '-', (19, 26))	('gastric cancer', 'Disease', (56, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('miR-218', 'Var', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
584410	26610476	In summary, this study describes that the loss of miR-218 in ESCC is partly due to epigenetic hypermethylation at the promoter regions.	('miR-218', 'Gene', (50, 57))	('ESCC', 'Disease', (61, 65))	('miR-218', 'Chemical', '-', (50, 57))	('epigenetic hypermethylation', 'Var', (83, 110))	('loss', 'NegReg', (42, 46))
584413	26610476	The results support that the hypermethylation of CpG islands in miR-218 promoter regions was associated with ESCC tumorigenesis.	('ESCC tumor', 'Disease', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('miR-218', 'Gene', (64, 71))	('ESCC tumor', 'Disease', 'MESH:D004938', (109, 119))	('associated', 'Reg', (93, 103))	('hypermethylation', 'Var', (29, 45))	('miR-218', 'Chemical', '-', (64, 71))	('CpG islands', 'Var', (49, 60))
584649	23286735	However, in patients achieving R0 resection (compared to R1 resection), there were statistically significant improvements at 3 years in OS (54% vs. 0%, p = .045) and DFS (42% vs. 0%, p = 0.002).	('patients', 'Species', '9606', (12, 20))	('improvements', 'PosReg', (109, 121))	('OS', 'Chemical', '-', (136, 138))	('R0 resection', 'Var', (31, 43))	('DFS', 'MPA', (166, 169))
584682	23286735	Similarly, another recent report showed lower recurrence rates and greater OS, DFS and relapse-free survival in the pCR group versus the non-pCR group .	('DFS', 'CPA', (79, 82))	('pCR', 'Var', (116, 119))	('OS', 'Chemical', '-', (75, 77))	('greater', 'PosReg', (67, 74))	('recurrence rates', 'CPA', (46, 62))	('lower', 'NegReg', (40, 45))	('relapse-free survival', 'CPA', (87, 108))
584712	23078998	This technique requires the following two adjustments: (A) blocking a part of the PTV by multi-leaf collimator(s) (MLCs); and (B) fine-tuning the isocenter distance by the half-width of the MLC leaf (2.5 mm in our facility).	('PTV', 'Chemical', '-', (82, 85))	('fine-tuning', 'Var', (130, 141))	('blocking', 'NegReg', (59, 67))
584810	30899002	Here we demonstrate that Rb and mTORC1 contribute to Gln-addiction upon the dysregulation of the Fbxo4-cyclin D1 axis, which leads to the reprogramming of cellular metabolism.	('contribute', 'Reg', (39, 49))	('mTORC1', 'Gene', (32, 38))	('cellular metabolism', 'MPA', (155, 174))	('Gln', 'Chemical', 'MESH:D005973', (53, 56))	('leads to', 'Reg', (125, 133))	('reprogramming', 'MPA', (138, 151))	('dysregulation', 'Var', (76, 89))	('mTORC1', 'Gene', '382056', (32, 38))	('Gln-addiction', 'Disease', (53, 66))
584813	30899002	Our findings reveal a molecular basis for cancer therapy through targeting glutaminolysis and mitochondrial respiration in ESCC with dysregulated Fbxo4-cyclin D1 axis as well as cancers resistant to CDK4/6 inhibitors.	('SCC', 'Gene', '6317', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('SCC', 'Gene', (124, 127))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('targeting', 'Reg', (65, 74))	('cancer', 'Disease', (42, 48))	('glutaminolysis', 'MPA', (75, 89))	('cancer', 'Disease', (178, 184))	('dysregulated', 'Var', (133, 145))	('mitochondrial respiration', 'MPA', (94, 119))	('Fbxo4-cyclin D1 axis', 'MPA', (146, 166))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (178, 184))
584815	30899002	Here, the authors show that the dysregulation of Fbxo4-cyclin D1 leads to mitochondrial dysfunction and glutamine addiction rendering these tumors susceptible to metabolic inhibitors even when resistant to CDK4/6 inhibitors.	('glutamine', 'Chemical', 'MESH:D005973', (104, 113))	('tumors', 'Disease', (140, 146))	('dysregulation', 'Var', (32, 45))	('glutamine addiction', 'MPA', (104, 123))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('leads to', 'Reg', (65, 73))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (74, 99))	('Fbxo4-cyclin D1', 'Gene', (49, 64))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (74, 99))	('mitochondrial dysfunction', 'Disease', (74, 99))
584818	30899002	Genome-wide screening has revealed numerous genetic alterations in ESCC, including inactivating mutations of TP53, Retinoblastoma protein (Rb) and CDKN2A, or activating mutations of NFE2L2, NOTCH1/2, MLL2, and EP300, or amplification of cyclin D1.	('EP300', 'Gene', '328572', (210, 215))	('inactivating mutations', 'Var', (83, 105))	('MLL2', 'Gene', (200, 204))	('SCC', 'Gene', '6317', (68, 71))	('TP53', 'Gene', '22059', (109, 113))	('NFE2L2', 'Gene', (182, 188))	('CDKN2A', 'Gene', '12578', (147, 153))	('CDKN2A', 'Gene', (147, 153))	('SCC', 'Gene', (68, 71))	('Rb', 'Gene', (139, 141))	('activating', 'PosReg', (158, 168))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (115, 129))	('cyclin', 'Gene', (237, 243))	('Retinoblastoma protein', 'Disease', 'MESH:D012175', (115, 137))	('EP300', 'Gene', (210, 215))	('NFE2L2', 'Gene', '18024', (182, 188))	('NOTCH1/2', 'Gene', '18128;18129', (190, 198))	('NOTCH1/2', 'Gene', (190, 198))	('Retinoblastoma protein', 'Disease', (115, 137))	('MLL2', 'Gene', '75410', (200, 204))	('amplification', 'Var', (220, 233))	('TP53', 'Gene', (109, 113))
584819	30899002	Cyclin D1-CDK4/6 promotes G1 cell cycle progression through phosphorylation-dependent inactivation of Rb, the master gatekeeper of cell division.	('phosphorylation-dependent', 'Var', (60, 85))	('promotes', 'PosReg', (17, 25))	('G1 cell cycle progression', 'CPA', (26, 51))	('inactivation', 'Var', (86, 98))	('gatekeeper', 'Species', '111938', (117, 127))
584821	30899002	Overexpression of cyclin D1, due to gene amplification and inactivation of its degradation machinery, (for example, loss of the Fbxo4 E3 ubiquitin ligase or mutations in the cyclin D1 degron), directly contributes to the development and progression of ESCC, supporting a model wherein targeting cyclin D1-CDK4/6 could be effective for ESCC patients.	('SCC', 'Gene', '6317', (253, 256))	('SCC', 'Gene', (336, 339))	('degradation', 'MPA', (79, 90))	('inactivation', 'NegReg', (59, 71))	('SCC', 'Gene', '6317', (336, 339))	('Fbxo4', 'Gene', (128, 133))	('mutations', 'Var', (157, 166))	('patients', 'Species', '9606', (340, 348))	('cyclin D1 degron', 'Gene', (174, 190))	('SCC', 'Gene', (253, 256))	('loss', 'NegReg', (116, 120))	('contributes to', 'Reg', (202, 216))
584827	30899002	Knockdown or chemical suppression of GLS1 typically induces apoptosis, suppresses cell proliferation and tumor growth.	('GLS1', 'Gene', (37, 41))	('suppresses', 'NegReg', (71, 81))	('cell proliferation', 'CPA', (82, 100))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('apoptosis', 'CPA', (60, 69))	('GLS1', 'Gene', '2744', (37, 41))	('suppression', 'NegReg', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('induces', 'Reg', (52, 59))	('tumor', 'Disease', (105, 110))	('chemical', 'Var', (13, 21))
584832	30899002	We demonstrate that cyclin D1 overexpression, either as a consequence of direct mutation, or loss of its regulatory E3 ubiquitin ligase Fbxo4, results in Gln-addiction.	('cyclin D1', 'Protein', (20, 29))	('loss', 'NegReg', (93, 97))	('mutation', 'Var', (80, 88))	('overexpression', 'PosReg', (30, 44))	('Gln-addiction', 'MPA', (154, 167))	('Gln', 'Chemical', 'MESH:D005973', (154, 157))	('results in', 'Reg', (143, 153))	('Fbxo4', 'Gene', (136, 141))
584833	30899002	The dysregulation of Fbxo4-cyclin D1 axis leads to mitochondrial dysfunction and Gln-addiction.	('Gln-addiction', 'Disease', (81, 94))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (51, 76))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (51, 76))	('leads to', 'Reg', (42, 50))	('mitochondrial dysfunction', 'Disease', (51, 76))	('dysregulation', 'Var', (4, 17))	('Gln', 'Chemical', 'MESH:D005973', (81, 84))
584835	30899002	Gln-addiction has been associated with overexpression of c-Myc; however, its role has not been evaluated in cells harboring Fbxo4 mutation or cyclin D1 overexpression, which frequently occurs in human ESCC.	('SCC', 'Gene', (202, 205))	('human', 'Species', '9606', (195, 200))	('overexpression', 'MPA', (39, 53))	('Gln-addiction', 'Disease', (0, 13))	('mutation', 'Var', (130, 138))	('SCC', 'Gene', '6317', (202, 205))	('Fbxo4', 'Gene', (124, 129))	('c-Myc', 'Gene', '4609', (57, 62))	('c-Myc', 'Gene', (57, 62))	('Gln', 'Chemical', 'MESH:D005973', (0, 3))
584838	30899002	Gln-depletion triggered increased cleavage of both PARP and caspase-3, suggesting increased apoptosis of Fbxo4-/- versus +/+ MEFs (Fig.	('Gln', 'Chemical', 'MESH:D005973', (0, 3))	('caspase-3', 'Gene', '12367', (60, 69))	('apoptosis', 'CPA', (92, 101))	('MEFs', 'CellLine', 'CVCL:9115', (125, 129))	('Gln-depletion', 'Var', (0, 13))	('PARP', 'Gene', (51, 55))	('cleavage', 'MPA', (34, 42))	('PARP', 'Gene', '11545', (51, 55))	('caspase-3', 'Gene', (60, 69))	('increased', 'PosReg', (82, 91))	('Fbxo4-/-', 'Var', (105, 113))	('increased', 'PosReg', (24, 33))
584839	30899002	Elevated Gln uptake was apparent in Fbxo4-/- MEFs (Supplementary Fig.	('Gln uptake', 'MPA', (9, 19))	('Gln', 'Chemical', 'MESH:D005973', (9, 12))	('MEFs', 'CellLine', 'CVCL:9115', (45, 49))	('Elevated', 'PosReg', (0, 8))	('Fbxo4-/- MEFs', 'Var', (36, 49))
584843	30899002	To determine whether the sensitivity to Gln-depletion reflected Fbxo4 E3 ligase function, WT Fbxo4 or Fbxo4 DeltaN, DeltaF, DeltaC2, and DeltaC3 were transduced into Fbxo4-/- MEFs.	('DeltaC2', 'Var', (124, 131))	('DeltaF', 'Var', (116, 122))	('DeltaC2', 'DELETION', 'None', (124, 131))	('MEFs', 'CellLine', 'CVCL:9115', (175, 179))	('DeltaC3', 'Var', (137, 144))	('DeltaC3', 'DELETION', 'None', (137, 144))	('DeltaN', 'Var', (108, 114))	('Gln', 'Chemical', 'MESH:D005973', (40, 43))	('Fbxo4', 'Gene', (102, 107))
584852	30899002	Fbxo4 and cyclin D1 double knockout MEFs exhibited lower apoptosis triggered by Gln-depletion relative to Fbxo4 single knockout MEFs (Fig.	('apoptosis triggered by Gln-depletion', 'MPA', (57, 93))	('Gln', 'Chemical', 'MESH:D005973', (80, 83))	('lower', 'NegReg', (51, 56))	('cyclin D1', 'Gene', (10, 19))	('MEFs', 'CellLine', 'CVCL:9115', (128, 132))	('double knockout', 'Var', (20, 35))	('Fbxo4', 'Gene', (0, 5))	('MEFs', 'CellLine', 'CVCL:9115', (36, 40))
584853	30899002	In addition, ectopic expression of WT cyclin D1, or a stabilized Fbxo4-resistant cyclin D1 mutant, D1T286A, greatly sensitized cells to Gln restriction (Fig.	('sensitized', 'Reg', (116, 126))	('D1T286A', 'Var', (99, 106))	('T286A', 'Mutation', 'c.286T>A', (101, 106))	('Gln restriction', 'MPA', (136, 151))	('Gln', 'Chemical', 'MESH:D005973', (136, 139))
584855	30899002	Furthermore, Gln uptake was also increased by ectopic cyclin D1 (Supplementary Fig.	('ectopic', 'Var', (46, 53))	('cyclin D1', 'Protein', (54, 63))	('increased', 'PosReg', (33, 42))	('Gln', 'Chemical', 'MESH:D005973', (13, 16))	('Gln uptake', 'MPA', (13, 23))
584858	30899002	Loss of function mutation of Fbxo4 leads to cyclin D1 accumulation, contributing to the development of human ESCC; moreover, Fbxo4 loss results in susceptibility to upper gastrointestinal tumors in transgenic mice.	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('human', 'Species', '9606', (103, 108))	('Fbxo4', 'Gene', (125, 130))	('mutation', 'Var', (17, 25))	('loss', 'NegReg', (131, 135))	('cyclin D1 accumulation', 'MPA', (44, 66))	('SCC', 'Gene', (110, 113))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (171, 194))	('Loss of function', 'NegReg', (0, 16))	('transgenic mice', 'Species', '10090', (198, 213))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Fbxo4', 'Gene', (29, 34))	('upper gastrointestinal tumors', 'Disease', (165, 194))	('SCC', 'Gene', '6317', (110, 113))	('upper gastrointestinal tumors', 'Disease', 'MESH:D004067', (165, 194))
584863	30899002	Furthermore, SurvExpress survival analysis indicated the dysregulation of Gln metabolism genes correlates with poor prognosis of human esophageal cancer as well as Head and Neck SCC (Fig.	('dysregulation', 'Var', (57, 70))	('SCC', 'Gene', '6317', (178, 181))	('Gln metabolism genes', 'Gene', (74, 94))	('esophageal cancer', 'Disease', (135, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('Gln', 'Chemical', 'MESH:D005973', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('human', 'Species', '9606', (129, 134))	('SCC', 'Gene', (178, 181))
584864	30899002	To corroborate the above genome-wide findings, five representative ESCC cells were chosen to investigate Gln-dependency: TE7 (WT Fbxo4, cyclin D1P287A), TE8 (WT Fbxo4, WT cyclin D1, Akt hyperactivation), TE10 (Fbxo4 S8R, WT cyclin D1), TE15 (WT Fbxo4, WT cyclin D1), and TE1 (Rb deficient).	('TE1', 'Gene', (236, 239))	('TE1', 'Gene', '57816', (271, 274))	('TE1', 'Gene', (204, 207))	('SCC', 'Gene', '6317', (68, 71))	('WT Fbxo4', 'Var', (242, 250))	('Gln', 'Chemical', 'MESH:D005973', (105, 108))	('Akt', 'Gene', '11651', (182, 185))	('TE1', 'Gene', (271, 274))	('TE1', 'Gene', '57816', (236, 239))	('TE1', 'Gene', '57816', (204, 207))	('Akt', 'Gene', (182, 185))	('SCC', 'Gene', (68, 71))
584865	30899002	Gln restriction triggered more PARP cleavage and apoptosis in TE7 and TE10 than in TE15 cells (Fig.	('Gln', 'Chemical', 'MESH:D005973', (0, 3))	('TE1', 'Gene', '57816', (83, 86))	('TE1', 'Gene', '57816', (70, 73))	('PARP', 'Gene', (31, 35))	('PARP', 'Gene', '11545', (31, 35))	('Gln restriction', 'Var', (0, 15))	('TE1', 'Gene', (83, 86))	('TE1', 'Gene', (70, 73))	('apoptosis', 'CPA', (49, 58))
584866	30899002	2d, h), consistent with the notion that dysregulation of Fbxo4-cyclin D1 promotes Gln-dependency.	('promotes', 'PosReg', (73, 81))	('Gln-dependency', 'MPA', (82, 96))	('Gln', 'Chemical', 'MESH:D005973', (82, 85))	('dysregulation', 'Var', (40, 53))
584867	30899002	Importantly, c-Myc knockdown did not reduce Gln-addiction in TE7 or TE10 cells (Supplementary Fig.	('c-Myc', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('Gln-addiction', 'MPA', (44, 57))	('TE1', 'Gene', (68, 71))	('Gln', 'Chemical', 'MESH:D005973', (44, 47))	('c-Myc', 'Gene', '4609', (13, 18))	('TE1', 'Gene', '57816', (68, 71))
584870	30899002	Furthermore, WT Fbxo4 not only reduced cyclin D1 levels but also compromised apoptosis triggered by Gln restriction in TE10 cells (Fig.	('cyclin D1 levels', 'MPA', (39, 55))	('Gln', 'Chemical', 'MESH:D005973', (100, 103))	('reduced', 'NegReg', (31, 38))	('apoptosis', 'CPA', (77, 86))	('TE1', 'Gene', (119, 122))	('compromised', 'NegReg', (65, 76))	('Gln restriction', 'Var', (100, 115))	('TE1', 'Gene', '57816', (119, 122))
584871	30899002	To test whether cyclin D1 is sufficient to drive cellular Gln-dependency, cyclin D1 or D1T286A (a stable oncogenic D1 mutant analogous to D1P287A), were ectopically expressed in TE15 cells.	('TE1', 'Gene', '57816', (178, 181))	('cyclin D1', 'Gene', (74, 83))	('TE1', 'Gene', (178, 181))	('D1T286A', 'Var', (87, 94))	('Gln', 'Chemical', 'MESH:D005973', (58, 61))	('T286A', 'Mutation', 'c.286T>A', (89, 94))
584872	30899002	D1T286A expression drove apoptosis of TE15 cells cultured in Gln-free medium (Fig.	('D1T286A expression', 'Var', (0, 18))	('TE1', 'Gene', '57816', (38, 41))	('T286A', 'Mutation', 'c.286T>A', (2, 7))	('Gln', 'Chemical', 'MESH:D005973', (61, 64))	('apoptosis', 'CPA', (25, 34))	('TE1', 'Gene', (38, 41))
584874	30899002	Likewise, Rb knockdown promoted Gln-addiction in TE15 cells that mimics the findings in TE1 cells (Supplementary Fig.	('TE1', 'Gene', (88, 91))	('promoted', 'PosReg', (23, 31))	('Gln-addiction', 'MPA', (32, 45))	('TE1', 'Gene', '57816', (49, 52))	('Gln', 'Chemical', 'MESH:D005973', (32, 35))	('TE1', 'Gene', '57816', (88, 91))	('TE1', 'Gene', (49, 52))	('knockdown', 'Var', (13, 22))
584882	30899002	In addition, dysregulation of Fbxo4-cyclin D1 also promoted more mTORC1 activation in TE7 and TE10 cells compared to TE15 cells; furthermore, increased basal mTORC1 activation was also detected in TE7 and TE10 cells (Fig.	('TE1', 'Gene', (205, 208))	('mTORC1', 'Gene', '382056', (158, 164))	('TE1', 'Gene', (94, 97))	('dysregulation', 'Var', (13, 26))	('activation', 'MPA', (72, 82))	('Fbxo4-cyclin', 'Var', (30, 42))	('TE1', 'Gene', '57816', (94, 97))	('TE1', 'Gene', '57816', (117, 120))	('mTORC1', 'Gene', (158, 164))	('TE1', 'Gene', '57816', (205, 208))	('promoted', 'PosReg', (51, 59))	('mTORC1', 'Gene', '382056', (65, 71))	('mTORC1', 'Gene', (65, 71))	('TE1', 'Gene', (117, 120))
584886	30899002	Consistent with mTORC1 inhibition, both rapamycin and Rad001, partially suppressed cell apoptosis as determined by reduced cleavage of both PARP and caspases-3 (Fig.	('cleavage', 'MPA', (123, 131))	('caspases-3', 'Protein', (149, 159))	('PARP', 'Gene', (140, 144))	('mTORC1', 'Gene', (16, 22))	('reduced', 'NegReg', (115, 122))	('inhibition', 'NegReg', (23, 33))	('Rad001', 'Var', (54, 60))	('PARP', 'Gene', '11545', (140, 144))	('suppressed', 'NegReg', (72, 82))	('cell apoptosis', 'CPA', (83, 97))	('mTORC1', 'Gene', '382056', (16, 22))
584887	30899002	In addition, Raptor knockdown also compromised cell apoptosis (Fig.	('cell apoptosis', 'CPA', (47, 61))	('Raptor', 'Gene', (13, 19))	('compromised', 'NegReg', (35, 46))	('Raptor', 'Gene', '74370', (13, 19))	('knockdown', 'Var', (20, 29))
584892	30899002	Likewise, overexpression of cyclin D1 or D1T286A, either of which increases CDK4/6 catalytic activity, reduced the ATP/ADP ratio with oncogenic D1T286A having a more profound effect (Fig.	('CDK4/6', 'Protein', (76, 82))	('T286A', 'Mutation', 'c.286T>A', (146, 151))	('reduced', 'NegReg', (103, 110))	('increases', 'PosReg', (66, 75))	('ATP/ADP ratio', 'MPA', (115, 128))	('catalytic activity', 'MPA', (83, 101))	('ADP', 'Chemical', 'MESH:D000244', (119, 122))	('D1T286A', 'Var', (144, 151))	('T286A', 'Mutation', 'c.286T>A', (43, 48))	('ATP', 'Chemical', 'MESH:D000255', (115, 118))
584893	30899002	In addition, TE10 cells with mutant Fbxo4 exhibited a decreased ATP/ADP ratio, as did TE7 cells harboring D1P287A, a mutant refractory to Fbxo4-mediated degradation (Fig.	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('mutant', 'Var', (29, 35))	('TE1', 'Gene', (13, 16))	('ATP/ADP ratio', 'MPA', (64, 77))	('decreased', 'NegReg', (54, 63))	('Fbxo4', 'Gene', (36, 41))	('ADP', 'Chemical', 'MESH:D000244', (68, 71))	('TE1', 'Gene', '57816', (13, 16))
584894	30899002	Moreover, activation of the AMPK pathway was also observed upon Gln-depletion (Fig.	('Gln-depletion', 'Var', (64, 77))	('AMPK pathway', 'Pathway', (28, 40))	('activation', 'PosReg', (10, 20))	('Gln', 'Chemical', 'MESH:D005973', (64, 67))
584895	30899002	4d), supporting reduced ATP/ADP ratio in Fbxo4-/- MEFs.	('ADP', 'Chemical', 'MESH:D000244', (28, 31))	('reduced', 'NegReg', (16, 23))	('ATP', 'Chemical', 'MESH:D000255', (24, 27))	('Fbxo4-/- MEFs', 'Var', (41, 54))	('ATP/ADP ratio', 'MPA', (24, 37))	('MEFs', 'CellLine', 'CVCL:9115', (50, 54))
584900	30899002	Fbxo4-/- MEFs exhibited a lower mitochondrial potential than +/+ counterparts (Fig.	('MEFs', 'CellLine', 'CVCL:9115', (9, 13))	('lower mitochondrial potential', 'Phenotype', 'HP:0040013', (26, 55))	('mitochondrial potential', 'MPA', (32, 55))	('Fbxo4-/- MEFs', 'Var', (0, 13))	('lower', 'NegReg', (26, 31))
584902	30899002	Moreover, ectopic cyclin D1 also compromised mitochondrial membrane potential in NIH3T3 cells (Supplementary Fig.	('cyclin D1', 'Protein', (18, 27))	('mitochondrial membrane potential', 'MPA', (45, 77))	('ectopic', 'Var', (10, 17))	('compromised', 'NegReg', (33, 44))	('NIH3T3', 'CellLine', 'CVCL:0594', (81, 87))
584903	30899002	Gln-addiction and defective mitochondrial respiration suggests the therapeutic potential of targeting both glutaminolysis and mitochondrial respiration in tumors with dysregulated Fbxo4-cyclin D1 axis.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mitochondrial respiration', 'MPA', (28, 53))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('defective', 'Var', (18, 27))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('mitochondrial', 'MPA', (126, 139))	('Gln', 'Chemical', 'MESH:D005973', (0, 3))
584905	30899002	Phenformin induced more apoptosis in Fbxo4-/- MEFs challenged by Gln-depletion or GLS1 inhibition (Fig.	('Gln-depletion', 'MPA', (65, 78))	('GLS1', 'Gene', (82, 86))	('Phenformin', 'Chemical', 'MESH:D010629', (0, 10))	('apoptosis', 'CPA', (24, 33))	('GLS1', 'Gene', '2744', (82, 86))	('Fbxo4-/-', 'Var', (37, 45))	('MEFs', 'CellLine', 'CVCL:9115', (46, 50))	('Gln', 'Chemical', 'MESH:D005973', (65, 68))
584907	30899002	Consistently, combined treatment induced more cell apoptosis in NIH3T3 and TE15 cells with ectopic cyclin D1 expression and in TE7 or TE10 cells harboring dysregulated Fbxo4-cyclin D1 (Fig.	('TE1', 'Gene', '57816', (134, 137))	('TE1', 'Gene', (75, 78))	('dysregulated', 'Var', (155, 167))	('ectopic', 'Var', (91, 98))	('cell apoptosis', 'CPA', (46, 60))	('TE1', 'Gene', (134, 137))	('TE1', 'Gene', '57816', (75, 78))	('cyclin D1', 'Gene', (99, 108))	('NIH3T3', 'CellLine', 'CVCL:0594', (64, 70))
584908	30899002	Taken together, these data provide a molecular basis for treating tumors with dysregulated Fbxo4-cyclin D1.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('treating tumors', 'Disease', (57, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('treating tumors', 'Disease', 'MESH:D019553', (57, 72))	('dysregulated', 'Var', (78, 90))	('Fbxo4-cyclin D1', 'Gene', (91, 106))
584910	30899002	For single treatment, the EC50 for either CB-839 or metformin was uniformly lower in TE7 and TE10 cells relative to TE15 cells (Table 1 and Supplementary Fig.	('EC50', 'MPA', (26, 30))	('CB-839', 'Chemical', 'MESH:C000593334', (42, 48))	('TE7', 'Var', (85, 88))	('TE1', 'Gene', (116, 119))	('TE1', 'Gene', '57816', (93, 96))	('lower', 'NegReg', (76, 81))	('metformin', 'Chemical', 'MESH:D008687', (52, 61))	('metformin', 'Gene', (52, 61))	('CB-839', 'Gene', (42, 48))	('TE1', 'Gene', '57816', (116, 119))	('TE1', 'Gene', (93, 96))
584912	30899002	The combined treatment exhibited synergism at low concentration, with a stronger impact on TE7 and TE10 cells; the EC50s of CB-839 were 0.75 and 0.92 muM, respectively, compared to 1.77 muM for TE15 cells.	('TE1', 'Gene', (194, 197))	('50s', 'Species', '1214577', (117, 120))	('CB-839', 'Var', (124, 130))	('TE1', 'Gene', (99, 102))	('CB-839', 'Chemical', 'MESH:C000593334', (124, 130))	('TE1', 'Gene', '57816', (194, 197))	('TE1', 'Gene', '57816', (99, 102))
584914	30899002	The analyses demonstrated that cells with elevated cyclin D1 were more sensitive to combined treatment, 5 muM CB-839 and 0.5 mM metformin exhibited better suppressing effects in TE7 and TE10 than that in TE15 cells, while similar effects were also revealed in NIH3T3 cells (Supplementary Fig.	('NIH3T3', 'CellLine', 'CVCL:0594', (260, 266))	('TE1', 'Gene', (186, 189))	('cyclin', 'Gene', (51, 57))	('metformin', 'Chemical', 'MESH:D008687', (128, 137))	('TE1', 'Gene', (204, 207))	('CB-839', 'Var', (110, 116))	('TE1', 'Gene', '57816', (186, 189))	('suppressing', 'NegReg', (155, 166))	('CB-839', 'Chemical', 'MESH:C000593334', (110, 116))	('TE7', 'Var', (178, 181))	('TE1', 'Gene', '57816', (204, 207))	('elevated', 'PosReg', (42, 50))
584915	30899002	In addition, combined treatment also effectively suppressed colony formation of NIH3T3 cells with ectopic cyclin D1 expression (Supplementary Fig.	('colony formation', 'CPA', (60, 76))	('suppressed', 'NegReg', (49, 59))	('NIH3T3', 'CellLine', 'CVCL:0594', (80, 86))	('ectopic', 'Var', (98, 105))
584916	30899002	To assess the efficacy of combined treatment in vivo, two cell lines: TE7 (mutant cyclin D1P287A) and TE15 (WT cyclin D1) were chosen.	('TE1', 'Gene', '57816', (102, 105))	('TE1', 'Gene', (102, 105))	('mutant', 'Var', (75, 81))	('cyclin', 'Gene', (82, 88))
584924	30899002	In addition, pathological analyses revealed stronger impacts on cell proliferation (Ki-67 index) and apoptosis (cleaved caspase-3 staining) in TE7 xenografts than that in TE15 tumors (Fig.	('TE1', 'Gene', '57816', (171, 174))	('Ki-67', 'Gene', '17345', (84, 89))	('impacts', 'Reg', (53, 60))	('cell proliferation', 'CPA', (64, 82))	('caspase-3', 'Gene', '12367', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', (176, 182))	('TE7', 'Var', (143, 146))	('TE1', 'Gene', (171, 174))	('caspase-3', 'Gene', (120, 129))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('Ki-67', 'Gene', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('apoptosis', 'CPA', (101, 110))
584927	30899002	Moreover, investigation of genome-wide datasets revealed the reprogramming of Gln metabolism genes upon either palbociclib treatment or CDK4/6 knockdown (Fig.	('Gln metabolism genes', 'Gene', (78, 98))	('knockdown', 'Var', (143, 152))	('palbociclib', 'Chemical', 'MESH:C500026', (111, 122))	('Gln', 'Chemical', 'MESH:D005973', (78, 81))
584930	30899002	Phenotypically, both TE7PDR and TE10PDR cells demonstrated loss of Rb, and upregulation of GLS1 that was independent of c-Myc expression (Fig.	('c-Myc', 'Gene', (120, 125))	('GLS1', 'Gene', (91, 95))	('TE7PDR', 'Var', (21, 27))	('upregulation', 'PosReg', (75, 87))	('TE1', 'Gene', '57816', (32, 35))	('GLS1', 'Gene', '2744', (91, 95))	('c-Myc', 'Gene', '4609', (120, 125))	('loss', 'NegReg', (59, 63))	('TE1', 'Gene', (32, 35))
584931	30899002	PDR cells also exhibited increased Gln uptake relative to parental counterparts (Fig.	('Gln', 'Chemical', 'MESH:D005973', (35, 38))	('Gln uptake', 'MPA', (35, 45))	('PDR', 'Var', (0, 3))	('increased', 'PosReg', (25, 34))
584932	30899002	In accordance with these characteristics, both TE7PDR and TE10PDR cells were more sensitive to Gln-depletion (Supplementary Fig.	('more', 'PosReg', (77, 81))	('TE1', 'Gene', (58, 61))	('Gln', 'Chemical', 'MESH:D005973', (95, 98))	('sensitive to Gln-depletion', 'MPA', (82, 108))	('TE7PDR', 'Var', (47, 53))	('TE1', 'Gene', '57816', (58, 61))
584933	30899002	19a), or GLS1 knockdown (Fig.	('GLS1', 'Gene', '2744', (9, 13))	('GLS1', 'Gene', (9, 13))	('knockdown', 'Var', (14, 23))
584936	30899002	In addition, both TE7PDR and TE10PDR cells showed lower EC50s comparing to their parental counterparts (Table 1 and Supplementary Fig.	('50s', 'Species', '1214577', (58, 61))	('lower', 'NegReg', (50, 55))	('TE1', 'Gene', (29, 32))	('TE7PDR', 'Var', (18, 24))	('TE1', 'Gene', '57816', (29, 32))	('EC50s', 'MPA', (56, 61))
584940	30899002	TE7PDR cells formed squamous cell carcinoma xenografts that responded better to combined treatment than their parental counterparts (Figs.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('squamous cell carcinoma', 'Disease', (20, 43))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('TE7PDR cells', 'Var', (0, 12))
584945	30899002	The current investigation reveals the importance of dysregulation of the Fbxo4-cyclin D1 axis, a frequent occurrence in numerous cancers, in regulating Gln-addiction independent of the known signaling pathways (Fig.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('numerous cancers', 'Disease', 'MESH:D009369', (120, 136))	('Gln', 'Chemical', 'MESH:D005973', (152, 155))	('dysregulation', 'Var', (52, 65))	('numerous cancers', 'Disease', (120, 136))	('Gln-addiction', 'MPA', (152, 165))
584949	30899002	Indeed, we find that cells with dysregulated Fbxo4-cyclin D1 exhibit increased Gln uptake.	('increased', 'PosReg', (69, 78))	('Fbxo4-cyclin D1', 'Gene', (45, 60))	('dysregulated', 'Var', (32, 44))	('Gln uptake', 'MPA', (79, 89))	('Gln', 'Chemical', 'MESH:D005973', (79, 82))
584956	30899002	Loss of Fbxo4 triggers radio-resistant DNA synthesis, and sensitizes cells to chemotherapeutic intervention; moreover, ectopic phospho-dead cyclin D1 (T286A) expression causes DNA re-replication, Cdt1 stabilization, DNA damage, and finally cell apoptosis.	('DNA re-replication', 'CPA', (176, 194))	('Cdt1', 'Gene', (196, 200))	('T286A', 'Mutation', 'c.286T>A', (151, 156))	('DNA damage', 'CPA', (216, 226))	('ectopic', 'Var', (119, 126))	('stabilization', 'PosReg', (201, 214))	('Fbxo4', 'Gene', (8, 13))	('T286A', 'Var', (151, 156))	('cell apoptosis', 'CPA', (240, 254))	('Loss', 'Var', (0, 4))	('Cdt1', 'Gene', '67177', (196, 200))
584958	30899002	Importantly, taking advantage of this genetic predisposition, targeting both GLS1 and OXPHOS effectively induces apoptosis, suppresses cell proliferation in cell culture, and inhibits the growth of tumor xenografts, demonstrating promising therapeutic efficacy.	('suppresses', 'NegReg', (124, 134))	('GLS1', 'Gene', (77, 81))	('induces', 'Reg', (105, 112))	('apoptosis', 'CPA', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('GLS1', 'Gene', '2744', (77, 81))	('OXPHOS', 'Gene', (86, 92))	('cell proliferation in cell culture', 'CPA', (135, 169))	('targeting', 'Var', (62, 71))	('tumor', 'Disease', (198, 203))	('inhibits', 'NegReg', (175, 183))
584962	30899002	Indeed, several CDK4/6 specific inhibitors have been developed, including PD-0332991 (palbociclib), LY2835219 (abemaciclib), and LEE011 (ribociclib), which are being intensively investigated in human tumors in pre-clinical studies and clinical trials.	('CDK4/6', 'Gene', (16, 22))	('palbociclib', 'Chemical', 'MESH:C500026', (86, 97))	('PD-0332991', 'Chemical', 'MESH:C500026', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('LY2835219', 'Var', (100, 109))	('human', 'Species', '9606', (194, 199))	('tumors', 'Disease', (200, 206))	('LY2835219', 'Chemical', 'MESH:C000590451', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('PD-0332991', 'Var', (74, 84))	('LEE011', 'Var', (129, 135))
584964	30899002	We noted that loss of Rb engenders resistance to CDK4/6 inhibitors, but it enhances the sensitivity of tumor cells to combined treatment with CB-839 and metformin.	('metformin', 'Chemical', 'MESH:D008687', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('loss', 'Var', (14, 18))	('resistance to CDK4/6 inhibitors', 'MPA', (35, 66))	('tumor', 'Disease', (103, 108))	('enhances', 'PosReg', (75, 83))	('combined treatment', 'Interaction', (118, 136))	('CB-839', 'Chemical', 'MESH:C000593334', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('sensitivity', 'MPA', (88, 99))
584965	30899002	It is worth noting that one recent study highlighted CDK4/6 knockdown reprograms metabolism in tumor cells, leading to Gln-addiction, which relies on c-Myc upregulation.	('Gln-addiction', 'Disease', (119, 132))	('CDK4/6', 'Gene', (53, 59))	('reprograms', 'Reg', (70, 80))	('c-Myc', 'Gene', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('c-Myc', 'Gene', '4609', (150, 155))	('knockdown', 'Var', (60, 69))	('Gln', 'Chemical', 'MESH:D005973', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('leading to', 'Reg', (108, 118))
584972	30899002	Under glucose-depleted conditions, hyperactivation of mTORC1 drives AMPK activation, promotes energy consumption and reduces ATP/ADP ratio, leading to apoptosis.	('hyperactivation', 'Var', (35, 50))	('ADP', 'Chemical', 'MESH:D000244', (129, 132))	('energy consumption', 'MPA', (94, 112))	('ATP/ADP ratio', 'MPA', (125, 138))	('promotes', 'PosReg', (85, 93))	('leading to', 'Reg', (140, 150))	('mTORC1', 'Gene', (54, 60))	('reduces', 'NegReg', (117, 124))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('AMPK', 'MPA', (68, 72))	('apoptosis', 'CPA', (151, 160))	('glucose', 'Chemical', 'MESH:D005947', (6, 13))	('mTORC1', 'Gene', '382056', (54, 60))
584973	30899002	Consistently, our data suggest activation of mTORC1, resulting from cyclin D1 dysregulation, might drive Gln-addiction through enhancing energy consumption.	('dysregulation', 'Var', (78, 91))	('drive', 'PosReg', (99, 104))	('enhancing', 'PosReg', (127, 136))	('mTORC1', 'Gene', '382056', (45, 51))	('Gln', 'Chemical', 'MESH:D005973', (105, 108))	('energy consumption', 'MPA', (137, 155))	('Gln-addiction', 'Disease', (105, 118))	('mTORC1', 'Gene', (45, 51))	('activation', 'PosReg', (31, 41))	('cyclin D1', 'Protein', (68, 77))
584974	30899002	Recent work revealed that the mTORC1 inhibitor, MLN128, suppresses glucose metabolism, and shifts the metabolism of tumor cells to glutaminolysis in a c-Jun-dependent manner, with an elusive role of c-Myc in this process.	('c-Jun', 'Gene', (151, 156))	('c-Myc', 'Gene', (199, 204))	('MLN128', 'Var', (48, 54))	('mTORC1', 'Gene', '382056', (30, 36))	('c-Myc', 'Gene', '4609', (199, 204))	('MLN128', 'Chemical', '-', (48, 54))	('glucose', 'Chemical', 'MESH:D005947', (67, 74))	('mTORC1', 'Gene', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('c-Jun', 'Gene', '16476', (151, 156))	('glucose metabolism', 'MPA', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('shifts', 'Reg', (91, 97))	('metabolism', 'MPA', (102, 112))	('suppresses', 'NegReg', (56, 66))	('tumor', 'Disease', (116, 121))
584975	30899002	Consistently, combined MLN128 plus CB-839 successfully overcame the metabolic reprogramming and reduced tumor burden in vivo.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('overcame', 'NegReg', (55, 63))	('CB-839', 'Gene', (35, 41))	('metabolic reprogramming', 'CPA', (68, 91))	('tumor', 'Disease', (104, 109))	('MLN128', 'Chemical', '-', (23, 29))	('CB-839', 'Chemical', 'MESH:C000593334', (35, 41))	('MLN128', 'Var', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('reduced', 'NegReg', (96, 103))
584976	30899002	Instead of using MLN128, metformin was combined with CB-839 and administrated in our study.	('CB-839', 'Gene', (53, 59))	('MLN128', 'Chemical', '-', (17, 23))	('MLN128', 'Var', (17, 23))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('CB-839', 'Chemical', 'MESH:C000593334', (53, 59))
584978	30899002	In addition, metformin can activate AMPK and suppress mTORC1; taking these biological functions into account, the observed therapeutic effects in our study are totally consistent with those observed with MLN128 and CB-839.	('suppress', 'NegReg', (45, 53))	('MLN128', 'Chemical', '-', (204, 210))	('MLN128', 'Var', (204, 210))	('activate', 'PosReg', (27, 35))	('AMPK', 'MPA', (36, 40))	('mTORC1', 'Gene', (54, 60))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('CB-839', 'Chemical', 'MESH:C000593334', (215, 221))	('mTORC1', 'Gene', '382056', (54, 60))
584983	30899002	Importantly, the disruption of both glutaminolysis and mitochondrial respiration provides a promising way to treat human ESCC and to overcome palbociclib resistance.	('SCC', 'Gene', (122, 125))	('glutaminolysis', 'Protein', (36, 50))	('palbociclib', 'Chemical', 'MESH:C500026', (142, 153))	('mitochondrial respiration', 'MPA', (55, 80))	('SCC', 'Gene', '6317', (122, 125))	('human', 'Species', '9606', (115, 120))	('disruption', 'Var', (17, 27))
584990	30899002	All cells were authenticated by short tandem repeat analysis for highly polymorphic microsatellites FES/FPS, vWA31, D22S417, D10S526, and D5S592 as performed by the Cell Culture Core to validate the identity of cells by comparing the earliest stocks with those grown more than 8-12 passages.	('D10S526', 'Var', (125, 132))	('D22S417', 'Var', (116, 123))	('FES/FPS', 'Gene', (100, 107))	('stocks', 'Species', '3724', (243, 249))	('D5S592', 'Var', (138, 144))
584998	30899002	For retrovirus production, pMX-puro empty vector, and vectors with Flag-tagged Fbxo4 WT, DeltaN, DeltaF, DeltaC2, and DeltaC3, and pBabe control as well as cyclin D1 WT and T286A were co-transfected with either QPsi or Psi2 vectors; for lentivirus production, lentiviral vectors were co-transfected with pMDLg/pRRE, CMV-VSVG, and RSV-Rev vectors.	('DeltaC3', 'DELETION', 'None', (118, 125))	('T286A', 'Mutation', 'c.286T>A', (173, 178))	('DeltaC2', 'Var', (105, 112))	('DeltaC2', 'DELETION', 'None', (105, 112))	('DeltaC3', 'Var', (118, 125))
584999	30899002	The pLKO.1 shRNA constructs were purchased from Addgene: Rb shRNA#19 (25640), Rb shRNA#63 (25641), Raptor shRNA (1857) and Rictor shRNA (1853), and Dharmacon (GE Healthcare Life Sciences): TRC GLS1 and c-Myc shRNAs.	('Raptor', 'Gene', (99, 105))	('GLS1', 'Gene', '2744', (193, 197))	('Raptor', 'Gene', '74370', (99, 105))	('c-Myc', 'Gene', (202, 207))	('c-Myc', 'Gene', '4609', (202, 207))	('25640', 'Var', (70, 75))	('25641', 'Var', (91, 96))	('GLS1', 'Gene', (193, 197))	('Rictor shRNA', 'Phenotype', 'HP:0040212', (123, 135))
585023	30899002	TE7 (5 x 106), TE15 (5 x 106) and TE7PDR (5 x 106) cells were subcutaneously injected into the flank regions.	('TE1', 'Gene', (15, 18))	('TE1', 'Gene', '57816', (15, 18))	('TE7PDR', 'Var', (34, 40))
585070	27846916	PTV V95% was reduced compared to the planning CT and ranged between 50 and 95 % in patients 2, 3 and 4 and 80-98% in patient 1.	('PTV', 'Chemical', '-', (0, 3))	('patient', 'Species', '9606', (83, 90))	('patient', 'Species', '9606', (117, 124))	('patients', 'Species', '9606', (83, 91))	('reduced', 'NegReg', (13, 20))	('V95', 'Var', (4, 7))
585089	27846916	Severe range deviations may lead to critical dose peaks in OAR as demonstrated for patient 2 (Fig.	('critical dose peaks', 'MPA', (36, 55))	('OAR', 'Disease', (59, 62))	('deviations', 'Var', (13, 23))	('patient', 'Species', '9606', (83, 90))	('lead to', 'Reg', (28, 35))
585279	25312799	In the case of xenografted HT29 tumors, the main contribution to the total fluorescent intensity or the tumor uptake of 99mTc-3P-RGD2 is actually from the integrin alphavbeta3 on new blood vessels.	('tumor uptake', 'CPA', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('fluorescent intensity', 'MPA', (75, 96))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('HT29 tumors', 'CellLine', 'CVCL:0320', (27, 38))	('99mTc-3P-RGD2', 'Var', (120, 133))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
585389	22537917	In addition, STC-1 mRNA expression either in PB or BM was correlated with lymph metastasis, advanced stage and adverse 2-year progression free survival (PFS).	('STC-1', 'Gene', '6781', (13, 18))	('lymph', 'Disease', (74, 79))	('mRNA', 'Var', (19, 23))	('STC-1', 'Gene', (13, 18))	('advanced stage', 'CPA', (92, 106))	('correlated', 'Reg', (58, 68))
585431	22537917	Also in combination, patients with STC-1 mRNA expression in PB and/or BM showed a shortened PFS, as compared to that with STC-1 negative expression (mean 16.7 months (95%CI: 14.461-18.905) vs 20.6 months (95%CI: 19.014-22.167), P = 0.005).	('PFS', 'MPA', (92, 95))	('STC-1', 'Gene', (122, 127))	('STC-1', 'Gene', '6781', (35, 40))	('patients', 'Species', '9606', (21, 29))	('STC-1', 'Gene', (35, 40))	('shortened', 'NegReg', (82, 91))	('mRNA expression', 'Var', (41, 56))	('STC-1', 'Gene', '6781', (122, 127))
585438	22537917	Studies of BM samples by various methods have indicated that the presence or absence of BMM is associated with the clinical outcome of patients with esophageal carcinoma.	('absence', 'NegReg', (77, 84))	('patients', 'Species', '9606', (135, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('absence of BMM', 'Phenotype', 'HP:0005365', (77, 91))	('BMM', 'Gene', (88, 91))	('esophageal carcinoma', 'Disease', (149, 169))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (149, 169))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (149, 169))	('associated', 'Reg', (95, 105))	('presence', 'Var', (65, 73))
585454	22537917	We also found that DTCs detected in PB/BM had no correlations with each other, and together increased the sensitivity to 48.2%, which was much higher than that in controls with benign esophageal disease, and DTCs detected in PB and BM of ESCC patients were both associated with lymph metastasis, clinical stage and adverse prognosis.	('sensitivity', 'MPA', (106, 117))	('lymph metastasis', 'CPA', (278, 294))	('ESCC', 'Gene', (238, 242))	('associated', 'Reg', (262, 272))	('DTC', 'Chemical', '-', (19, 22))	('DTC', 'Chemical', '-', (208, 211))	('patients', 'Species', '9606', (243, 251))	('DTCs', 'Var', (208, 212))	('benign esophageal disease', 'Disease', (177, 202))	('benign esophageal disease', 'Disease', 'MESH:D004935', (177, 202))
585481	33938378	Current studies suggest that eradication of H. pylori can effectively reduce gastric cancer incidence and treatment should be considered for all H. pylori-infected persons to reduce the risk of peptic ulcers and gastric cancers.	('gastric cancer', 'Phenotype', 'HP:0012126', (212, 226))	('ulcers', 'Disease', 'MESH:D014456', (201, 207))	('peptic ulcer', 'Phenotype', 'HP:0004398', (194, 206))	('reduce', 'NegReg', (70, 76))	('gastric cancer', 'Disease', (77, 91))	('persons', 'Species', '9606', (164, 171))	('men', 'Species', '9606', (111, 114))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('reduce gastric cancer', 'Phenotype', 'HP:0006753', (70, 91))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('eradication', 'Var', (29, 40))	('peptic ulcers', 'Phenotype', 'HP:0004398', (194, 207))	('gastric cancer', 'Disease', 'MESH:D013274', (212, 226))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('H. pylori', 'Species', '210', (44, 53))	('gastric cancers', 'Disease', 'MESH:D013274', (212, 227))	('ulcers', 'Disease', (201, 207))	('reduce', 'NegReg', (175, 181))	('pylori-infected', 'Disease', (148, 163))	('gastric cancers', 'Disease', (212, 227))	('gastric cancers', 'Phenotype', 'HP:0012126', (212, 227))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('H. pylori', 'Species', '210', (145, 154))	('pylori-infected', 'Disease', 'MESH:D016481', (148, 163))
585518	33938378	Studying the impact of H. pylori status on beta diversity, we observed that if H. pylori is present in the gastric mucosa it gains a clear predominance, which alters the gastric microbial composition in H. pylori-infected individuals.	('gastric microbial composition', 'MPA', (170, 199))	('H. pylori', 'Species', '210', (23, 32))	('H. pylori', 'Species', '210', (203, 212))	('H. pylori', 'Species', '210', (79, 88))	('alters', 'Reg', (159, 165))	('pylori-infected', 'Disease', 'MESH:D016481', (206, 221))	('H. pylori', 'Var', (79, 88))	('pylori-infected', 'Disease', (206, 221))
585520	33938378	H. pylori-positive individuals have a higher abundance of Proteobacteria, probably resulting from the contribution of H. pylori, while there is a lower abundance of Actinobacteria, Bacteroidetes, and Firmicutes.	('H. pylori', 'Var', (118, 127))	('H. pylori', 'Species', '210', (0, 9))	('Proteobacteria', 'Protein', (58, 72))	('higher', 'PosReg', (38, 44))	('H. pylori-positive', 'Disease', (0, 18))	('H. pylori', 'Species', '210', (118, 127))
585528	33938378	Eradication of H. pylori infection may increase the diversity of gastric microbiota.	('pylori infection', 'Disease', (18, 34))	('diversity of gastric microbiota', 'MPA', (52, 83))	('increase', 'PosReg', (39, 47))	('Eradication', 'Var', (0, 11))	('pylori infection', 'Disease', 'MESH:D016481', (18, 34))	('H. pylori infection', 'Phenotype', 'HP:0005202', (15, 34))	('H. pylori', 'Species', '210', (15, 24))
585551	33938378	Studies using the insulin-gastrin (INS-GAS) transgenic mouse model demonstrated that mice infected with H. pylori together with the colonization of commensal flora developed more severe gastric lesions and had earlier development of GI intraepithelial neoplasia compared with H. pylori-infected germ-free INS-GAS mice, highlighting the idea that the gastric microbiota may participate in the cascade of events leading to gastric cancer following H. pylori infection.	('pylori infection', 'Disease', 'MESH:D016481', (449, 465))	('gastric cancer', 'Disease', (421, 435))	('gastric lesions', 'Disease', 'MESH:D013272', (186, 201))	('men', 'Species', '9606', (225, 228))	('H. pylori', 'Species', '210', (104, 113))	('H. pylori', 'Species', '210', (276, 285))	('cancer', 'Phenotype', 'HP:0002664', (429, 435))	('pylori-infected', 'Disease', (279, 294))	('mice', 'Species', '10090', (85, 89))	('insulin', 'Gene', '3630', (18, 25))	('H. pylori', 'Var', (104, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (421, 435))	('mice', 'Species', '10090', (313, 317))	('pylori infection', 'Disease', (449, 465))	('mouse', 'Species', '10090', (55, 60))	('gastric lesions', 'Disease', (186, 201))	('participate', 'Reg', (373, 384))	('pylori-infected', 'Disease', 'MESH:D016481', (279, 294))	('neoplasia', 'Disease', 'MESH:D009369', (252, 261))	('men', 'Species', '9606', (151, 154))	('H. pylori infection', 'Phenotype', 'HP:0005202', (446, 465))	('neoplasia', 'Disease', (252, 261))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (236, 261))	('infected', 'Disease', 'MESH:D007239', (90, 98))	('earlier', 'PosReg', (210, 217))	('gastric cancer', 'Phenotype', 'HP:0012126', (421, 435))	('infected', 'Disease', (90, 98))	('insulin', 'Gene', (18, 25))	('GI', 'Gene', '2770', (233, 235))	('H. pylori', 'Species', '210', (446, 455))	('infected', 'Disease', 'MESH:D007239', (286, 294))	('infected', 'Disease', (286, 294))	('neoplasia', 'Phenotype', 'HP:0002664', (252, 261))
585606	33938378	revealed that a short-term antibiotic treatment for H. pylori eradication delivered a profound insult to the GI flora and resulted in a perturbed oral and colonic microbiome observed one week after treatment and persisting up to four years later.	('men', 'Species', '9606', (203, 206))	('H. pylori', 'Gene', (52, 61))	('colonic', 'Disease', 'MESH:D003110', (155, 162))	('eradication', 'Var', (62, 73))	('colonic', 'Disease', (155, 162))	('perturbed', 'Reg', (136, 145))	('H. pylori', 'Species', '210', (52, 61))	('men', 'Species', '9606', (43, 46))	('oral and', 'CPA', (146, 154))	('GI', 'Gene', '2770', (109, 111))	('insult', 'MPA', (95, 101))
585607	33938378	Several articles have reported short-term and long-term changes in gut microbiota after H. pylori eradication and are reviewed and summarized in Table 4 and Figure 2.	('H. pylori', 'Species', '210', (88, 97))	('eradication', 'Var', (98, 109))	('changes', 'Reg', (56, 63))
585621	33938378	A large-scale cross-sectional study in Japan demonstrated significantly higher low-density lipoprotein levels and significantly lower high-density lipoprotein levels in men who were H. pylori seropositive, compared with H. pylori seronegative men.	('high-density lipoprotein levels', 'MPA', (134, 165))	('H. pylori', 'Species', '210', (220, 229))	('men', 'Species', '9606', (169, 172))	('seropositive', 'Var', (192, 204))	('low-density lipoprotein levels', 'MPA', (79, 109))	('H. pylori', 'Species', '210', (182, 191))	('men', 'Species', '9606', (243, 246))	('lower', 'NegReg', (128, 133))	('higher', 'PosReg', (72, 78))
585622	33938378	Studies have shown a significant increase in body mass index and body weight after eradication of H. pylori, which may be partially explained by the restoration of ghrelin secretion, the relief of dyspepsia, or a reduced Bacteroidetes-to-Firmicutes ratio.	('reduced', 'NegReg', (213, 220))	('H. pylori', 'Species', '210', (98, 107))	('dyspepsia', 'Phenotype', 'HP:0410281', (197, 206))	('ghrelin', 'Chemical', 'MESH:D054439', (164, 171))	('restoration', 'PosReg', (149, 160))	('Bacteroidetes-to-Firmicutes ratio', 'MPA', (221, 254))	('dyspepsia', 'Disease', (197, 206))	('eradication', 'Var', (83, 94))	('increase', 'PosReg', (33, 41))	('body weight', 'CPA', (65, 76))	('body mass index', 'CPA', (45, 60))	('H. pylori', 'Gene', (98, 107))	('ghrelin secretion', 'MPA', (164, 181))	('dyspepsia', 'Disease', 'MESH:D004415', (197, 206))
585629	33938378	An animal study showed that gut microbes belonging to the families Turicibacteraceae, Erysipelotrichaceae, and Desulfobirionaceae, which have been linked to changes in the host immune response, are influenced by the presence of H. pylori in mice.	('H. pylori', 'Species', '210', (228, 237))	('Erysipelotrichaceae', 'Disease', 'None', (86, 105))	('Erysipelotrichaceae', 'Disease', (86, 105))	('influenced', 'Reg', (198, 208))	('mice', 'Species', '10090', (241, 245))	('H. pylori', 'Gene', (228, 237))	('presence', 'Var', (216, 224))
585661	33938378	The immunoregulatory effect induced by H. pylori strengthens the host's resilience against microbiome perturbations and may result in increased colonic microbiota diversity.	('H. pylori', 'Species', '210', (39, 48))	('colonic', 'Disease', 'MESH:D003110', (144, 151))	('resilience', 'CPA', (72, 82))	('colonic', 'Disease', (144, 151))	('H. pylori', 'Var', (39, 48))	('increased', 'PosReg', (134, 143))	('immunoregulatory effect', 'CPA', (4, 27))	('strengthens', 'PosReg', (49, 60))
585719	30585284	Errors in this cycle lead to mutations in the DNA of the daughter cell and, if unchecked, can lead to the transformation that underlies a variety of diseases, from heritable diseases to neoplasia.	('diseases to neoplasia', 'Disease', 'MESH:D009369', (174, 195))	('transformation', 'MPA', (106, 120))	('mutations', 'Var', (29, 38))	('lead to', 'Reg', (21, 28))	('Errors', 'Var', (0, 6))	('neoplasia', 'Phenotype', 'HP:0002664', (186, 195))	('lead to', 'Reg', (94, 101))	('diseases to neoplasia', 'Disease', (174, 195))
585725	30585284	These risk factors include Caucasian race, male gender, age greater than 60 years, alcohol and smoking, obesity, history of GERD or heartburn, non-acid reflux disease, and genetic heterogeneity favoring familial BE.	('heartburn', 'Phenotype', 'HP:0002020', (132, 141))	('-acid reflux', 'Phenotype', 'HP:0002020', (146, 158))	('familial BE', 'Disease', (203, 214))	('obesity', 'Phenotype', 'HP:0001513', (104, 111))	('reflux disease', 'Disease', (152, 166))	('reflux disease', 'Disease', 'MESH:D005764', (152, 166))	('reflux disease', 'Phenotype', 'HP:0002020', (152, 166))	('obesity', 'Disease', 'MESH:D009765', (104, 111))	('genetic heterogeneity', 'Var', (172, 193))	('alcohol', 'Chemical', 'MESH:D000438', (83, 90))	('obesity', 'Disease', (104, 111))	('BE', 'Phenotype', 'HP:0100580', (212, 214))
585731	30585284	Non-dysplastic BE has predictably lower mutations than esophageal cancer; strikingly, it has a higher burden of mutations than some malignancies such as breast cancer and multiple myeloma.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('multiple myeloma', 'Disease', (171, 187))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (55, 72))	('multiple myeloma', 'Phenotype', 'HP:0006775', (171, 187))	('mutations', 'Var', (112, 121))	('malignancies', 'Disease', 'MESH:D009369', (132, 144))	('BE', 'Phenotype', 'HP:0100580', (15, 17))	('Non-dysplastic', 'Disease', 'MESH:D004416', (0, 14))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('Non-dysplastic', 'Disease', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('multiple myeloma', 'Disease', 'MESH:D009101', (171, 187))	('malignancies', 'Disease', (132, 144))	('breast cancer', 'Disease', (153, 166))
585732	30585284	These areas of probable anomalies in BE include tumor suppressor genes, epigenetics, and oncogenes.	('anomalies', 'Disease', (24, 33))	('tumor', 'Disease', (48, 53))	('BE', 'Phenotype', 'HP:0100580', (37, 39))	('epigenetics', 'Var', (72, 83))	('anomalies', 'Disease', 'MESH:D000014', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
585734	30585284	The loss of function of tumor suppressor genes can be due to a mutation leading to a non-functional protein or to a lack of the encoded protein (reduced amount to no production) culminating in the loss of control of the cell cycle and loss of apoptosis stimulus from the genes.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('lack', 'NegReg', (116, 120))	('apoptosis', 'CPA', (243, 252))	('protein', 'Protein', (100, 107))	('loss of function', 'NegReg', (4, 20))	('tumor', 'Disease', (24, 29))	('loss', 'NegReg', (235, 239))	('mutation', 'Var', (63, 71))	('loss', 'NegReg', (197, 201))	('control', 'MPA', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('non-functional', 'NegReg', (85, 99))
585736	30585284	Eighty percent of BE is associated with p16 anomalies, and these can arise from the hypermethylation of the promoter sequence of p16, loss of heterozygosity, and mutation of the p16 gene.	('p16', 'Gene', (40, 43))	('loss of heterozygosity', 'Var', (134, 156))	('associated', 'Reg', (24, 34))	('p16', 'Gene', (129, 132))	('BE', 'Phenotype', 'HP:0100580', (18, 20))	('p16', 'Gene', (178, 181))	('anomalies', 'Disease', 'MESH:D000014', (44, 53))	('p16', 'Gene', '1029', (40, 43))	('p16', 'Gene', '1029', (129, 132))	('hypermethylation', 'Var', (84, 100))	('mutation', 'Var', (162, 170))	('anomalies', 'Disease', (44, 53))	('p16', 'Gene', '1029', (178, 181))
585737	30585284	Inactivation of CDKN2A leads to genomic instability and the resultant uncontrolled cell multiplication.	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('uncontrolled cell multiplication', 'CPA', (70, 102))	('genomic instability', 'CPA', (32, 51))	('Inactivation', 'Var', (0, 12))	('leads to', 'Reg', (23, 31))
585738	30585284	Whereas the alteration of p53 is found in dysplastic BE and esophageal cancer, its abnormal function points to grave prognosis.	('alteration', 'Var', (12, 22))	('BE', 'Phenotype', 'HP:0100580', (53, 55))	('p53', 'Gene', (26, 29))	('dysplastic BE and esophageal cancer', 'Disease', 'MESH:D004938', (42, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('p53', 'Gene', '7157', (26, 29))
585739	30585284	The presence of a mutated p53 tumor suppressor gene is not a feature of early stage non-dysplastic BE.	('mutated', 'Var', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('p53', 'Gene', (26, 29))	('BE', 'Phenotype', 'HP:0100580', (99, 101))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('p53', 'Gene', '7157', (26, 29))	('tumor', 'Disease', (30, 35))
585742	30585284	Modification in epigenetic governors can disrupt normal gene expression and consequently lead to malignancy.	('disrupt', 'NegReg', (41, 48))	('malignancy', 'Disease', (97, 107))	('Modification', 'Var', (0, 12))	('lead to', 'Reg', (89, 96))	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('epigenetic governors', 'Protein', (16, 36))	('normal gene expression', 'MPA', (49, 71))
585744	30585284	This heralds the development of metaplasia in the esophagus, and this function is achieved via the hypermethylation of promoter sequences on tumor suppressor genes, leading to the inactivation of the latter.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('metaplasia', 'Disease', 'MESH:D008679', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('inactivation', 'MPA', (180, 192))	('metaplasia', 'Disease', (32, 42))	('tumor', 'Disease', (141, 146))	('heralds', 'Reg', (5, 12))	('hypermethylation', 'Var', (99, 115))
585747	30585284	BE is part of the continuum related to the metaplasia-dysplasia-adenocarcinoma sequence; this progression is associated with progressive genetic and epigenetic events that result in multiple aberrations in the cell cycle control and subsequently clonal selection to cause the emergence of esophageal cancer.	('cause', 'Reg', (266, 271))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('aberrations', 'Var', (191, 202))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', 'MESH:D008679', (43, 78))	('cell cycle control', 'CPA', (210, 228))	('esophageal cancer', 'Disease', (289, 306))	('esophageal cancer', 'Disease', 'MESH:D004938', (289, 306))	('BE', 'Phenotype', 'HP:0100580', (0, 2))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', (43, 78))
585758	30585284	This includes the reflux of biliary salts, and deoxycholic acid is the most potent of these bile salts in inducing cell changes related to BE.	('reflux', 'MPA', (18, 24))	('inducing', 'Reg', (106, 114))	('BE', 'Phenotype', 'HP:0100580', (139, 141))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (47, 63))	('reflux of biliary salts', 'Phenotype', 'HP:0000076', (18, 41))	('deoxycholic acid', 'Var', (47, 63))	('biliary salts', 'MPA', (28, 41))	('bile salts', 'Chemical', 'MESH:D001647', (92, 102))	('cell', 'MPA', (115, 119))
585779	30585284	Helicobacter pylori Helicobacter (H.) pylori causes an atrophic effect on the gastric acid-producing cells, leading to a reduction in the production of gastric acid.	('H.) pylori', 'Species', '210', (34, 44))	('atrophic', 'Disease', (55, 63))	('Helicobacter', 'Species', '210', (0, 12))	('Helicobacter', 'Species', '210', (20, 32))	('atrophic', 'Disease', 'MESH:D020966', (55, 63))	('production of gastric acid', 'MPA', (138, 164))	('reduction', 'NegReg', (121, 130))	('Helicobacter', 'Var', (20, 32))
585784	30585284	Metaplasia of the distal esophagus into columnar cells with a potential to progress into malignancy starts with molecular changes where there is a modification of genetic and epigenetic expression to cause dysfunction of tumor suppressor genes or proto-oncogenes such as the p16, p53, and Hox genes.	('malignancy', 'Disease', (89, 99))	('dysfunction of tumor', 'Disease', 'MESH:D009369', (206, 226))	('epigenetic expression', 'Var', (175, 196))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('modification', 'Var', (147, 159))	('p16', 'Gene', (275, 278))	('Metaplasia', 'Disease', (0, 10))	('p53', 'Gene', (280, 283))	('p53', 'Gene', '7157', (280, 283))	('Hox genes', 'Gene', (289, 298))	('Metaplasia', 'Disease', 'MESH:D008679', (0, 10))	('cause', 'Reg', (200, 205))	('dysfunction of tumor', 'Disease', (206, 226))	('malignancy', 'Disease', 'MESH:D009369', (89, 99))	('p16', 'Gene', '1029', (275, 278))
585796	30355278	Patients with high PODXL expression in their pre-neoadjuvant biopsies had a superior histopathologic response (notably 36% with no residual cancer cells) compared to those with negative or low PODXL expression, and were all recurrence-free at last follow-up.	('PODXL', 'Gene', (193, 198))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('histopathologic response', 'CPA', (85, 109))	('PODXL', 'Gene', '5420', (19, 24))	('PODXL', 'Gene', '5420', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PODXL', 'Gene', (19, 24))
585799	30355278	Patients with resectable gastric or esophageal adenocarcinoma with high PODXL expression in their diagnostic biopsies have an excellent prognosis when treated with neoadjuvant +- adjuvant fluoropyrimidine- and oxaliplatin-based chemotherapy.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (210, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (36, 61))	('high', 'Var', (67, 71))	('esophageal adenocarcinoma', 'Disease', (36, 61))	('gastric', 'Disease', (25, 32))	('PODXL', 'Gene', '5420', (72, 77))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (36, 61))	('PODXL', 'Gene', (72, 77))	('Patients', 'Species', '9606', (0, 8))	('fluoropyrimidine', 'Chemical', '-', (188, 204))
585810	30355278	High expression of PODXL has been linked to poor prognosis in a wide range of malignancies including gastrointestinal adenocarcinomas such as colorectal cancer, pancreatic and periampullary cancer and gastric cancer.	('cancer', 'Disease', (153, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('PODXL', 'Gene', '5420', (19, 24))	('cancer', 'Disease', (190, 196))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('High', 'Var', (0, 4))	('gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (101, 133))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('colorectal cancer', 'Disease', (142, 159))	('pancreatic', 'Disease', 'MESH:D010195', (161, 171))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('gastric cancer', 'Phenotype', 'HP:0012126', (201, 215))	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	('PODXL', 'Gene', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('malignancies', 'Disease', (78, 90))	('pancreatic', 'Disease', (161, 171))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('gastric cancer', 'Disease', (201, 215))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('cancer', 'Disease', (209, 215))	('gastrointestinal adenocarcinomas', 'Disease', (101, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('linked', 'Reg', (34, 40))
585853	30355278	3, patients with high PODXL expression in their pre-neoadjuvant biopsies had a superior histopathologic response (notably 36% with no residual cancer cells) compared to those with negative (p = 0.010) or low (p = 0.013) PODXL expression.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('histopathologic response', 'CPA', (88, 112))	('PODXL', 'Gene', '5420', (220, 225))	('high', 'Var', (17, 21))	('PODXL', 'Gene', (220, 225))	('patients', 'Species', '9606', (3, 11))	('expression', 'Var', (28, 38))	('cancer', 'Disease', (143, 149))	('PODXL', 'Gene', '5420', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('PODXL', 'Gene', (22, 27))
585855	30355278	4) demonstrate that patients with high PODXL expression in their pre-neoadjuvant biopsies were all recurrence-free at last follow-up, and had a superior TTR compared to PODXL negative cases (p = 0.026).	('PODXL', 'Gene', '5420', (169, 174))	('high', 'Var', (34, 38))	('patients', 'Species', '9606', (20, 28))	('superior', 'PosReg', (144, 152))	('PODXL', 'Gene', '5420', (39, 44))	('TTR', 'CPA', (153, 156))	('PODXL', 'Gene', (169, 174))	('PODXL', 'Gene', (39, 44))
585887	30355278	In summary, patients with resectable gastric or esophageal adenocarcinoma with high PODXL expression in their diagnostic biopsies have an excellent prognosis when treated with neoadjuvant +- adjuvant fluoropyrimidine- and oxaliplatin-based chemotherapy.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (48, 73))	('patients', 'Species', '9606', (12, 20))	('fluoropyrimidine', 'Chemical', '-', (200, 216))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (48, 73))	('PODXL', 'Gene', '5420', (84, 89))	('high', 'Var', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('PODXL', 'Gene', (84, 89))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (222, 233))	('esophageal adenocarcinoma', 'Disease', (48, 73))	('gastric', 'Disease', (37, 44))
585888	30355278	Furthermore, and importantly, it is suggested that PODXL expression is predictive for benefit of chemotherapy in this setting.	('expression', 'Var', (57, 67))	('PODXL', 'Gene', (51, 56))	('PODXL', 'Gene', '5420', (51, 56))
585891	29129699	Deguelin, an Aurora B Kinase Inhibitor, Exhibits Potent Anti-Tumor Effect in Human Esophageal Squamous Cell Carcinoma Aurora B kinase has emerged as a key regulator of mitosis and deregulation of Aurora B activity is closely related to the development and progression of human cancers.	('Aurora B', 'Gene', (196, 204))	('Aurora B', 'Gene', (13, 21))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('Aurora B', 'Gene', '9212', (118, 126))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (83, 117))	('Aurora B', 'Gene', '9212', (13, 21))	('Aurora B', 'Gene', '9212', (196, 204))	('human', 'Species', '9606', (271, 276))	('deregulation', 'Var', (180, 192))	('activity', 'MPA', (205, 213))	('Esophageal Squamous Cell Carcinoma', 'Disease', (83, 117))	('Carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('Human', 'Species', '9606', (77, 82))	('related', 'Reg', (225, 232))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancers', 'Disease', (277, 284))	('mitosis', 'Disease', (168, 175))	('Aurora B', 'Gene', (118, 126))	('mitosis', 'Disease', 'None', (168, 175))
585892	29129699	In the present study, we found that Aurora B is overexpressed in human esophageal squamous cell carcinoma (ESCC), high levels of Aurora B protein were associated with a worse overall survival rate in ESCC patients.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Aurora', 'Gene', (129, 135))	('patients', 'Species', '9606', (205, 213))	('human', 'Species', '9606', (65, 70))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('protein', 'Protein', (138, 145))	('high levels', 'Var', (114, 125))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('overall survival', 'MPA', (175, 191))	('ESCC', 'Disease', (200, 204))
585896	29129699	Knocking down of Aurora B decreased the sensitivity of ESCC cells to deguelin.	('deguelin', 'Chemical', 'MESH:C107676', (69, 77))	('Knocking down', 'Var', (0, 13))	('Aurora B', 'Gene', (17, 25))	('decreased', 'NegReg', (26, 35))	('sensitivity', 'MPA', (40, 51))
585899	29129699	Aurora B is overexpressed in human esophageal squamous cell carcinoma (ESCC), high levels of Aurora B protein are associated with a worse overall survival rate in ESCC patients.	('ESCC', 'Disease', (163, 167))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('Aurora B', 'Gene', (93, 101))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('patients', 'Species', '9606', (168, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('human', 'Species', '9606', (29, 34))	('worse', 'NegReg', (132, 137))	('high levels', 'Var', (78, 89))	('protein', 'Protein', (102, 109))
585906	29129699	In malignancy, alterations of Aurora kinase have been linked with genetic instability, including mitotic errors, chromosomal aneuploidy, deregulation of cell proliferation and apoptosis, which are highly associated with tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('deregulation', 'CPA', (137, 149))	('Aurora kinase', 'Gene', (30, 43))	('tumor', 'Disease', (220, 225))	('malignancy', 'Disease', (3, 13))	('chromosomal aneuploidy', 'Disease', (113, 135))	('chromosomal aneuploidy', 'Disease', 'MESH:D000782', (113, 135))	('mitotic errors', 'CPA', (97, 111))	('alterations', 'Var', (15, 26))	('cell proliferation', 'CPA', (153, 171))	('Aurora kinase', 'Gene', '41446', (30, 43))	('associated', 'Reg', (204, 214))	('apoptosis', 'CPA', (176, 185))	('linked', 'Reg', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('malignancy', 'Disease', 'MESH:D009369', (3, 13))	('genetic instability', 'CPA', (66, 85))
585908	29129699	Recently, several Aurora B inhibitors have been developed, including AZD1152, BI 811283, ZM447439, and VX-680, etc., the clinical trial data demonstrated that inhibition of Aurora B kinase displayed a generally manageable safety profile and disease stabilization in some patients.	('BI 811283', 'Chemical', '-', (78, 87))	('ZM447439', 'Var', (89, 97))	('Aurora', 'Enzyme', (173, 179))	('patients', 'Species', '9606', (271, 279))	('AZD1152', 'Chemical', 'MESH:C520647', (69, 76))	('disease stabilization', 'CPA', (241, 262))	('inhibition', 'Var', (159, 169))	('ZM447439', 'Chemical', 'MESH:C474722', (89, 97))
585958	29129699	S2b) in athymic nude mice were also attenuated after Aurora B knockdown.	('Aurora', 'Gene', (53, 59))	('knockdown', 'Var', (62, 71))	('nude mice', 'Species', '10090', (16, 25))	('attenuated', 'NegReg', (36, 46))
585959	29129699	These results suggest that Aurora B possesses an important biological function in ESCC and blocking Aurora B expression significantly reduces the tumorigenic properties of ESCC cells.	('expression', 'MPA', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ESCC', 'Disease', (82, 86))	('tumor', 'Disease', (146, 151))	('Aurora B', 'Gene', (100, 108))	('reduces', 'NegReg', (134, 141))	('ESCC', 'Disease', (172, 176))	('blocking', 'Var', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
585982	29129699	Aurora kinase B inhibition leads to failure in cytokinesis and abnormal exit from mitosis, which could result in polyploidy cells, G2/M cell-cycle arrest, and ultimately, apoptosis or cell death.	('G2/M cell-cycle arrest', 'CPA', (131, 153))	('failure', 'NegReg', (36, 43))	('cell death', 'CPA', (184, 194))	('Aurora kinase B', 'Gene', (0, 15))	('polyploidy cell', 'Disease', 'MESH:D011123', (113, 128))	('apoptosis', 'CPA', (171, 180))	('mitosis', 'Disease', (82, 89))	('mitosis', 'Disease', 'None', (82, 89))	('Aurora kinase B', 'Gene', '9212', (0, 15))	('cytokinesis', 'CPA', (47, 58))	('polyploidy cell', 'Disease', (113, 128))	('result in', 'Reg', (103, 112))	('inhibition', 'Var', (16, 26))
585986	29129699	The docked pose suggested that the flat scaffold of this compound fit well with the pocket by forming hydrophobic interactions with Phe172, Leu223, Leu154, etc.	('Leu223', 'Var', (140, 146))	('Phe172', 'Chemical', '-', (132, 138))	('Phe172', 'Var', (132, 138))	('forming', 'Reg', (94, 101))	('Leu154', 'Var', (148, 154))	('Leu223', 'Chemical', '-', (140, 146))	('hydrophobic interactions', 'MPA', (102, 126))	('Leu154', 'Chemical', '-', (148, 154))
585992	29129699	Phosphorylation of a highly conserved serine residue (Ser10) in histone H3 is thought to be crucial for entry into mitosis.	('mitosis', 'Disease', (115, 122))	('serine', 'Chemical', 'MESH:D012694', (38, 44))	('Ser10', 'Chemical', '-', (54, 59))	('mitosis', 'Disease', 'None', (115, 122))	('Ser10', 'Var', (54, 59))	('Phosphorylation', 'MPA', (0, 15))	('H3', 'Chemical', 'MESH:C012616', (72, 74))
586011	29129699	Cumulative evidence indicated that the amplification/overexpression and/or hyperactivation of Aurora B kinase is a frequent finding in a panel of human malignancies, such as breast, liver, lung, prostate cancer and leukemia.	('amplification/overexpression', 'Var', (39, 67))	('prostate cancer', 'Disease', 'MESH:D011471', (195, 210))	('prostate cancer', 'Phenotype', 'HP:0012125', (195, 210))	('lung', 'Disease', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('human', 'Species', '9606', (146, 151))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('Aurora', 'Gene', (94, 100))	('hyperactivation', 'PosReg', (75, 90))	('leukemia', 'Phenotype', 'HP:0001909', (215, 223))	('leukemia', 'Disease', 'MESH:D007938', (215, 223))	('liver', 'Disease', (182, 187))	('prostate cancer', 'Disease', (195, 210))	('leukemia', 'Disease', (215, 223))	('malignancies', 'Disease', (152, 164))	('breast', 'Disease', (174, 180))
586014	29129699	The docking study indicated that deguelin was docked into the ATP-binding pocket of Aurora B and formed hydrophobic interactions with Phe172, Leu223, Leu154, etc.	('formed', 'Reg', (97, 103))	('Leu154', 'Chemical', '-', (150, 156))	('Leu223', 'Chemical', '-', (142, 148))	('ATP', 'Chemical', 'MESH:D000255', (62, 65))	('deguelin', 'Chemical', 'MESH:C107676', (33, 41))	('hydrophobic', 'MPA', (104, 115))	('Phe172', 'Chemical', '-', (134, 140))	('Phe172', 'Var', (134, 140))	('Leu223', 'Var', (142, 148))	('Leu154', 'Var', (150, 156))
586019	29129699	In addition, knockdown of Aurora B decreases the sensitivity of ESCC cells to deguelin, which agrees with our observations that Aurora B plays an important role in the anticancer activity of deguelin.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Aurora B', 'Gene', (26, 34))	('sensitivity', 'MPA', (49, 60))	('decreases', 'NegReg', (35, 44))	('deguelin', 'Chemical', 'MESH:C107676', (191, 199))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('deguelin', 'Chemical', 'MESH:C107676', (78, 86))	('knockdown', 'Var', (13, 22))
586027	29129699	Moreover, knockdown Aurora B in human ESCC cells reduced tumorigenic properties, including in vitro cell growth and in vivo xenografted tumor formation.	('Aurora', 'Gene', (20, 26))	('reduced', 'NegReg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('human', 'Species', '9606', (32, 37))	('tumor', 'Disease', (57, 62))	('knockdown', 'Var', (10, 19))	('tumor', 'Disease', (136, 141))
586030	29129699	Previous studies have demonstrated that the Aurora B specific inhibitor, AZD1152, significantly suppressed human solid tumors, including prostate, lung, breast cancer and nasopharyngeal carcinoma.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('suppressed', 'NegReg', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (171, 195))	('human', 'CPA', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('AZD1152', 'Chemical', 'MESH:C520647', (73, 80))	('solid tumors', 'Disease', (113, 125))	('nasopharyngeal carcinoma', 'Disease', (171, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('lung', 'Disease', (147, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('human', 'Species', '9606', (107, 112))	('prostate', 'Disease', (137, 145))	('solid tumors', 'Disease', 'MESH:D009369', (113, 125))	('AZD1152', 'Var', (73, 80))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (171, 195))	('breast cancer', 'Disease', (153, 166))
586035	29129699	found that AZD1152-HQPA enhanced oxaliplatin and gemcitabine effectiveness in the colon and pancreatic cancer, respectively.	('AZD1152-HQPA', 'Chemical', 'MESH:C531556', (11, 23))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('AZD1152-HQPA', 'Var', (11, 23))	('gemcitabine', 'Chemical', 'MESH:C056507', (49, 60))	('enhanced', 'PosReg', (24, 32))	('oxaliplatin', 'MPA', (33, 44))	('colon', 'Disease', 'MESH:D015179', (82, 87))	('gemcitabine effectiveness', 'MPA', (49, 74))	('pancreatic cancer', 'Disease', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('colon', 'Disease', (82, 87))
586037	29129699	suggested that the potential mechanism for AZD1152-HQPA enhanced chemotherapy effectiveness is due to the DNA fragmentation associated with apoptosis occur in a cell population that has undergone endoreduplication to become > 4 N. Additionally, the M phase and G2 phase are the most sensitive stage to radiotherapy or DNA damage agents.	('chemotherapy effectiveness', 'CPA', (65, 91))	('AZD1152-HQPA', 'Chemical', 'MESH:C531556', (43, 55))	('AZD1152-HQPA', 'Var', (43, 55))	('enhanced', 'PosReg', (56, 64))
586124	20696658	The prophylactic HPV vaccine has high vaccine efficacy against HPV16- and 18-related cervical disease, vulvar and vaginal precancers, and HPV6- and 11-related condyloma acuminata (i.e., genital warts) in men and women.	('genital warts', 'Phenotype', 'HP:0032301', (186, 199))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('HPV', 'Species', '10566', (138, 141))	('condyloma acuminata', 'Disease', 'MESH:D003218', (159, 178))	('women', 'Species', '9606', (212, 217))	('HPV', 'Species', '10566', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('HPV16', 'Species', '333760', (63, 68))	('condyloma acuminata', 'Disease', (159, 178))	('men', 'Species', '9606', (214, 217))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('vulvar', 'Disease', (103, 109))	('cancers', 'Disease', (125, 132))	('HPV6- and', 'Var', (138, 147))	('warts', 'Phenotype', 'HP:0200043', (194, 199))	('HPV', 'Species', '10566', (63, 66))	('men', 'Species', '9606', (204, 207))	('HPV16-', 'Gene', (63, 69))	('cervical disease', 'Disease', (85, 101))
586147	20696658	For example, p16INK4a is sometimes underexpressed in ESCC due to hypermethylation or mutation.	('p16INK4a', 'Gene', (13, 21))	('p16INK4a', 'Gene', '1029', (13, 21))	('hypermethylation', 'Var', (65, 81))	('mutation', 'Var', (85, 93))
586155	20696658	Another evidence of HPV activity is E6/E7 seropositivity, which indicates the presence of an HPV-associated tumor somewhere in the body, but it is only about 50% sensitive for invasive cervical cancer and does not always occur in oral cancer patients either.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('invasive cervical cancer', 'Disease', (176, 200))	('HPV', 'Species', '10566', (20, 23))	('oral cancer', 'Disease', 'MESH:D009062', (230, 241))	('invasive cervical cancer', 'Disease', 'MESH:D002583', (176, 200))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('HPV', 'Species', '10566', (93, 96))	('oral cancer', 'Disease', (230, 241))	('tumor', 'Disease', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('E6/E7', 'Var', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('patients', 'Species', '9606', (242, 250))
586161	20696658	We still have much to learn about HPV-related carcinogenesis, even in the cervix, and it is possible that HPV may cause cancer at additional anatomical sites.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('HPV', 'Var', (106, 109))	('carcinogenesis', 'Disease', (46, 60))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('HPV', 'Species', '10566', (34, 37))	('cause', 'Reg', (114, 119))	('HPV', 'Species', '10566', (106, 109))
586242	33888160	Moreover, the detection of certain bacteria or viruses is associated with profound differences in patient and tumor phenotypes, such as patient age, tumor stage, survival, and somatic mutations in cancer genes or gene expression profiles.	('patient', 'Species', '9606', (136, 143))	('patient', 'Species', '9606', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('mutations', 'Var', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (149, 154))	('differences', 'Reg', (83, 94))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
586285	33888160	Third, one group (n = 22) of bone cancer patients with detection of Pseudomonas poae, Pseudomonas fluorescens, and Pseudomonas sp.	('Pseudomonas fluorescens', 'Species', '294', (86, 109))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('bone cancer', 'Disease', 'MESH:D001859', (29, 40))	('Pseudomonas', 'Var', (115, 126))	('bone cancer', 'Disease', (29, 40))	('Pseudomonas poae', 'Species', '200451', (68, 84))	('patients', 'Species', '9606', (41, 49))
586294	33888160	Furthermore, each cluster was linked with age, survival, gender, number of somatic mutations in known cancer genes, or specific somatic mutations in one of those cancer genes.	('mutations', 'Var', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cluster', 'Species', '100569', (18, 25))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('linked', 'Reg', (30, 36))
586306	33888160	These patients were also more likely to have TP53 mutations (p(cluster 3 vs. other) = 0.0335) (Fig.	('TP53', 'Gene', (45, 49))	('cluster', 'Species', '100569', (63, 70))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (6, 14))	('TP53', 'Gene', '7157', (45, 49))
586320	33888160	In a similar pattern, these patients had a higher frequency of mutations in RNF21 (p = 0.0121) (Fig.	('mutations', 'Var', (63, 72))	('patients', 'Species', '9606', (28, 36))	('RNF21', 'Gene', (76, 81))	('RNF21', 'Gene', '445372', (76, 81))
586325	33888160	Differences in the frequency of mutations between patients in different clusters were observed in KMT2C, CDKN2A, and RNF21.	('cluster', 'Species', '100569', (72, 79))	('patients', 'Species', '9606', (50, 58))	('CDKN2A', 'Gene', (105, 111))	('KMT2C', 'Gene', '58508', (98, 103))	('KMT2C', 'Gene', (98, 103))	('CDKN2A', 'Gene', '1029', (105, 111))	('mutations', 'Var', (32, 41))	('RNF21', 'Gene', (117, 122))	('RNF21', 'Gene', '445372', (117, 122))
586326	33888160	Patients in cluster 2 (Cupriavidus metallidurans), 4 (Methylobacterium populi), or 5 (Pseudomonas protegens) had a higher frequency of mutations in these genes compared to the majority of patients not in any taxon-linked cluster (n = 187) (p (KMT2C) = 0.0308, p (CDKN2A) = 0.0124, p (RNF21) = 0.0107) (Fig.	('CDKN2A', 'Gene', (263, 269))	('CDKN2A', 'Gene', '1029', (263, 269))	('cluster', 'Species', '100569', (221, 228))	('mutations', 'Var', (135, 144))	('cluster', 'Species', '100569', (12, 19))	('RNF21', 'Gene', (284, 289))	('patients', 'Species', '9606', (188, 196))	('Patients', 'Species', '9606', (0, 8))	('KMT2C', 'Gene', (243, 248))	('KMT2C', 'Gene', '58508', (243, 248))	('Methylobacterium populi', 'Species', '223967', (54, 77))	('RNF21', 'Gene', '445372', (284, 289))	('Pseudomonas protegens', 'Species', '380021', (86, 107))	('Cupriavidus metallidurans', 'Species', '119219', (23, 48))
586336	33888160	There was a tendency towards a lower frequency of PBRM1 mutations in patients in cluster 2 (Serratia marcescens) (p = 0.0723) (Fig.	('Serratia marcescens', 'Species', '615', (92, 111))	('mutations', 'Var', (56, 65))	('PBRM1', 'Gene', (50, 55))	('Serratia marcescens', 'Phenotype', 'HP:0002741', (92, 111))	('PBRM1', 'Gene', '55193', (50, 55))	('lower', 'NegReg', (31, 36))	('cluster', 'Species', '100569', (81, 88))	('patients', 'Species', '9606', (69, 77))
586338	33888160	In addition to linking the above identified clusters with patient or cancer phenotypes, an unbiased analysis of links between the detection of a species-level taxa and patient or cancer phenotypes, such as age, survival, gender, number of somatic mutations in known cancer genes, and specific somatic mutations in one of those cancer genes, was performed utilizing both a pan-cancer approach and by analyzing each cancer type separately.	('cancer', 'Disease', (414, 420))	('cancer', 'Disease', (376, 382))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('patient', 'Species', '9606', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('cluster', 'Species', '100569', (44, 51))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutations', 'Var', (247, 256))	('cancer', 'Disease', (327, 333))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (414, 420))	('cancer', 'Disease', 'MESH:D009369', (376, 382))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('cancer', 'Disease', (266, 272))	('patient', 'Species', '9606', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', (179, 185))
586342	33888160	In the cancer-specific analysis, detection of Ralstonia pickettii was linked to improved survival in renal cancer, in fact no patients died (padj = 0.035) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('detection', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('died', 'Disease', (135, 139))	('renal cancer', 'Phenotype', 'HP:0009726', (101, 113))	('died', 'Disease', 'MESH:D003643', (135, 139))	('renal cancer', 'Disease', (101, 113))	('improved', 'PosReg', (80, 88))	('Ralstonia pickettii', 'Var', (46, 65))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('survival', 'MPA', (89, 97))	('cancer', 'Disease', (107, 113))	('renal cancer', 'Disease', 'MESH:D007680', (101, 113))	('Ralstonia pickettii', 'Species', '329', (46, 65))
586343	33888160	In prostate cancer, detection of and increasing Propionibacterium acne RPPB were linked to a decreasing number of cancer gene mutations (padj = 0.0041) (Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('acne', 'Disease', 'MESH:D000152', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('RPPB', 'Gene', (71, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('cancer', 'Disease', (12, 18))	('Propionibacterium', 'Species', '1977903', (48, 65))	('RPPB', 'Chemical', '-', (71, 75))	('prostate cancer', 'Disease', (3, 18))	('acne', 'Phenotype', 'HP:0001061', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (126, 135))	('acne', 'Disease', (66, 70))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('cancer', 'Disease', (114, 120))
586344	33888160	The integration of viral nucleic acids into the human host genome is well recognized as a carcinogenic process.	('human', 'Species', '9606', (48, 53))	('integration', 'Var', (4, 15))	('carcinogenic', 'Disease', (90, 102))	('carcinogenic', 'Disease', 'MESH:D063646', (90, 102))
586351	33888160	Across all analyzed taxa, putative integrations were more common in matched normal samples than in tumor tissue samples (p = 0.0009, Wilcoxon paired signed rank test) (Supplementary Figure 8B, Supplementary Data 13-14) and for viral taxa compared to bacterial taxa (p = 0.0001, Mann-Whitney U test) (Supplementary Figure 8C, Supplementary Data 13-14).	('common', 'Reg', (58, 64))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('integrations', 'Var', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
586360	33888160	Overall, patients with detection of Gordonia polyisoprenivorans exhibited a gene expression pattern indicative of a decreased level of mitotic cell cycling, an increased DNA damage response, reduced blood coagulation, and reduced macrophage activation (Fig.	('patients', 'Species', '9606', (9, 17))	('DNA damage response', 'MPA', (170, 189))	('polyisoprenivorans', 'Var', (45, 63))	('blood coagulation', 'Disease', (199, 216))	('increased', 'PosReg', (160, 169))	('blood coagulation', 'Disease', 'MESH:D001778', (199, 216))	('Gordonia polyisoprenivorans', 'Species', '84595', (36, 63))	('reduced', 'NegReg', (191, 198))	('level of mitotic cell cycling', 'MPA', (126, 155))	('macrophage', 'CPA', (230, 240))	('reduced', 'NegReg', (222, 229))	('decreased', 'NegReg', (116, 125))
586393	33888160	This was despite the higher likelihood of patients linked to Gordonia polyisoprenivorans having Binet C stage and patients linked to Gordonia polyisoprenivorans having a higher likelihood of having TP53 mutations, which are prognostically disadvantageous in CLL.	('CLL', 'Phenotype', 'HP:0005550', (258, 261))	('Gordonia polyisoprenivorans', 'Species', '84595', (61, 88))	('Gordonia polyisoprenivorans', 'Species', '84595', (133, 160))	('TP53', 'Gene', '7157', (198, 202))	('Binet C stage', 'CPA', (96, 109))	('TP53', 'Gene', (198, 202))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (42, 50))	('mutations', 'Var', (203, 212))
586424	33888160	Interestingly, survival of patients with detection of Ralstonia pickettii in their tumor tissue was markedly improved.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Ralstonia pickettii', 'Species', '329', (54, 73))	('Ralstonia pickettii', 'Gene', (54, 73))	('tumor', 'Disease', (83, 88))	('patients', 'Species', '9606', (27, 35))	('improved', 'PosReg', (109, 117))	('detection', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('survival', 'CPA', (15, 23))
586426	33888160	It could be speculated that, while not causing any overt infection, low-level presence of Ralstonia pickettii in the human host is common and improves immunogenicity of renal cancer, thus, improving outcome.	('Ralstonia pickettii', 'Species', '329', (90, 109))	('human', 'Species', '9606', (117, 122))	('immunogenicity', 'MPA', (151, 165))	('renal cancer', 'Disease', (169, 181))	('infection', 'Disease', (57, 66))	('presence', 'Var', (78, 86))	('improving', 'PosReg', (189, 198))	('renal cancer', 'Phenotype', 'HP:0009726', (169, 181))	('Ralstonia pickettii', 'Gene', (90, 109))	('improves', 'PosReg', (142, 150))	('infection', 'Disease', 'MESH:D007239', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('renal cancer', 'Disease', 'MESH:D007680', (169, 181))
586512	33888160	Links between the detection of a taxon and non-synonymous somatic mutations in one of the cancer consensus genes of a patient were analyzed by Fisher exact test for each cancer-taxon pair that was detected in at least 10 patients.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('non-synonymous somatic mutations', 'Var', (43, 75))	('patients', 'Species', '9606', (221, 229))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('patient', 'Species', '9606', (221, 228))	('patient', 'Species', '9606', (118, 125))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
586528	33032547	In the unmatched population, the patients with MDT were more likely to received chemotherapy than the non-MDT patients (84.7% vs. 69.1%; x 2 = 6.373; P = 0.012).MDT-patients had significantly improved overall survival compared with non-MDT patients (p = 0.025).	('improved', 'PosReg', (192, 200))	('overall survival', 'MPA', (201, 217))	('patients', 'Species', '9606', (33, 41))	('MDT', 'Chemical', '-', (161, 164))	('MDT', 'Chemical', '-', (47, 50))	('MDT', 'Chemical', '-', (106, 109))	('patients', 'Species', '9606', (240, 248))	('patients', 'Species', '9606', (165, 173))	('.MDT-patients', 'Var', (160, 173))	('MDT', 'Chemical', '-', (236, 239))	('patients', 'Species', '9606', (110, 118))
586555	33032547	Significantly more patients in the MDT group received chemotherapy than in the non-MDT group (84.7% vs. 69.1%, P = 0.01) (see Table 1).	('patients', 'Species', '9606', (19, 27))	('chemotherapy', 'CPA', (54, 66))	('MDT', 'Chemical', '-', (35, 38))	('MDT', 'Var', (35, 38))	('MDT', 'Chemical', '-', (83, 86))
586557	33032547	The median OS for patients in the MDT group (27 months, 95% CI, 17.5-36.5 months) was significantly longer than that for patients in the non-MDT group (17 months, 95% CI, 12.7-21.3 months, P = 0.025).	('MDT', 'Chemical', '-', (34, 37))	('MDT', 'Var', (34, 37))	('longer', 'PosReg', (100, 106))	('MDT', 'Chemical', '-', (141, 144))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (121, 129))
586560	33032547	In multivariate analysis, MDT (P = 0.019, HR 0.59, 95% CI 0.38-0.92), as well as a PS 1-2 and early tumor stage, was associated with an improved OS (see Table 2).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('MDT', 'Var', (26, 29))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('MDT', 'Chemical', '-', (26, 29))	('improved', 'PosReg', (136, 144))
586562	33032547	MDT (P = 0.01, OR 3.03, 95% CI 1.29-7.08), as well as the male sex (P = 0.02, OR 3.16), a low PS (P = 0.006, OR 6.99), stage III tumors (P = 0.04, OR 2.75), and differentiation III-IV (P = 0.03, OR 3.86), was an independent predictor of receiving chemotherapy (see Table 3).	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('MDT', 'Chemical', '-', (0, 3))	('MDT', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))
586569	33032547	Here, we found that with similar patient characteristics and tumor conditions, MDT was associated with a significantly better OS than non-MDT for EC patients undergoing RT.	('patients', 'Species', '9606', (149, 157))	('patient', 'Species', '9606', (33, 40))	('better', 'PosReg', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('MDT', 'Var', (79, 82))	('MDT', 'Chemical', '-', (79, 82))	('MDT', 'Chemical', '-', (138, 141))	('patient', 'Species', '9606', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
586585	33032547	MDT can improve the overall survival for patients with esophageal cancer receiving radiotherapy.	('MDT', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (55, 72))	('MDT', 'Var', (0, 3))	('patients', 'Species', '9606', (41, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('improve', 'PosReg', (8, 15))	('overall survival', 'MPA', (20, 36))
586811	27731547	Survival for pTis-1N0M0 adenocarcinomas was much better than for squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('squamous cell carcinoma', 'Disease', (65, 88))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 88))	('adenocarcinomas', 'Disease', 'MESH:D000230', (24, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('adenocarcinomas', 'Disease', (24, 39))	('better', 'PosReg', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('pTis-1N0M0', 'Var', (13, 23))
586838	28402280	However, PRKCA and cytokines were significantly downregulated in PLCE1-deficient mouse esophageal epithelia, and knockdown of PLCE1 in human esophageal cancer cells led to reduction of PRKCA and cytokines.	('PRKCA', 'CPA', (185, 190))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (87, 107))	('cytokines', 'MPA', (19, 28))	('esophageal cancer', 'Disease', (141, 158))	('downregulated', 'NegReg', (48, 61))	('PRKCA', 'CPA', (9, 14))	('PLCE1', 'Gene', (126, 131))	('human', 'Species', '9606', (135, 140))	('PLCE1-deficient mouse esophageal epithelia', 'Disease', 'MESH:D004482', (65, 107))	('PLCE1-deficient mouse esophageal epithelia', 'Disease', (65, 107))	('knockdown', 'Var', (113, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cytokines', 'MPA', (195, 204))	('reduction', 'NegReg', (172, 181))
586839	28402280	Finally, high expression of both PLCE1 and PRKCA is significantly associated with poor outcomes of the patients with esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('high expression', 'Var', (9, 24))	('PLCE1', 'Gene', (33, 38))	('associated', 'Reg', (66, 76))	('esophageal cancers', 'Disease', (117, 135))	('esophageal cancers', 'Disease', 'MESH:D004938', (117, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PRKCA', 'Gene', (43, 48))	('patients', 'Species', '9606', (103, 111))
586855	28402280	We have previously reported that PLCE1 single nucleotide polymorphism (SNP rs2274223: A5780G:His1927Arg) was linked to esophagitis, but it was not clear whether PLCE1 expression levels are associated with esophagitis.	('A5780G:His1927Arg', 'Var', (86, 103))	('esophagitis', 'Disease', (119, 130))	('His1927Arg', 'Mutation', 'rs2274223', (93, 103))	('esophagitis', 'Disease', 'MESH:D004941', (119, 130))	('A5780G', 'Mutation', 'rs1048173873', (86, 92))	('PLCE1', 'Gene', (33, 38))	('rs2274223', 'Mutation', 'rs2274223', (75, 84))	('esophagitis', 'Phenotype', 'HP:0100633', (205, 216))	('esophagitis', 'Disease', (205, 216))	('single nucleotide', 'Var', (39, 56))	('esophagitis', 'Disease', 'MESH:D004941', (205, 216))	('linked to', 'Reg', (109, 118))	('esophagitis', 'Phenotype', 'HP:0100633', (119, 130))
586894	28402280	These findings suggest crucial clinical significance of their correlation, and the co-expression of PLCE1 and PRKCA might also be a indicator for esophageal cancer patient survival.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PRKCA', 'Gene', (110, 115))	('correlation', 'Interaction', (62, 73))	('esophageal cancer', 'Disease', (146, 163))	('patient', 'Species', '9606', (164, 171))	('co-expression', 'Var', (83, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('PLCE1', 'Gene', (100, 105))
586896	28402280	It has been well known that Barrett's esophagus is the major cause of esophageal adenocarcinoma, during the progression, cytokines play critical role, for instance, increased expression of IL-1beta in mouse leads to esophageal inflammation and esophageal adenocarcinoma in IL-1beta transgenic mouse model.	('esophageal adenocarcinoma', 'Disease', (70, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (244, 269))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (70, 95))	('expression', 'Var', (175, 185))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (244, 269))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (216, 239))	('IL-1beta', 'Gene', (189, 197))	('mouse', 'Species', '10090', (293, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('esophageal inflammation', 'Disease', 'MESH:D007249', (216, 239))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (28, 47))	('esophageal adenocarcinoma', 'Disease', (244, 269))	('mouse', 'Species', '10090', (201, 206))	('increased', 'PosReg', (165, 174))	('esophageal inflammation', 'Disease', (216, 239))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (70, 95))
586897	28402280	This study provided further evidence that phospholipase C epsilon 1 might also be an important element that was significantly increased in Barrett's esophagus and in EAC, and genetic deletion of PLCE1 resulted in significant downregulation of the expression of some key cytokines, such as NF- kappaB, IL-1beta, IL-6, TNFalpha, IFN-gamma.	('phospholipase C epsilon 1', 'Gene', (42, 67))	('downregulation', 'NegReg', (225, 239))	('genetic deletion', 'Var', (175, 191))	('TNFalpha', 'MPA', (317, 325))	('EAC', 'Disease', (166, 169))	('expression', 'MPA', (247, 257))	('phospholipase C epsilon 1', 'Gene', '51196', (42, 67))	('EAC', 'Phenotype', 'HP:0011459', (166, 169))	('PLCE1', 'Gene', (195, 200))	('increased', 'PosReg', (126, 135))	("Barrett's esophagus", 'Disease', (139, 158))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (139, 158))
586898	28402280	Interestingly, PRKCA was also altered with the changes of PLCE1, suggesting the important significance of their correlation in the development of esophagitis and Barrett's esophagus and their malignant transformation.	('changes', 'Var', (47, 54))	('esophagitis', 'Phenotype', 'HP:0100633', (146, 157))	('esophagitis', 'Disease', (146, 157))	('esophagitis', 'Disease', 'MESH:D004941', (146, 157))	('altered', 'Reg', (30, 37))	('PLCE1', 'Gene', (58, 63))	("Barrett's esophagus", 'Disease', (162, 181))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (162, 181))
586911	28402280	Previous studies have revealed the risk susceptibility of PLCE1 polymorphism (rs2274223) in esophageal carcinoma, we have also shown that the 5780G allele in PLCE1 is associated with esophagitis and esophageal cancer in high-risk areas of ESCC.	('esophageal cancer', 'Disease', (199, 216))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (92, 112))	('associated with', 'Reg', (167, 182))	('esophageal cancer', 'Disease', 'MESH:D004938', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (92, 112))	('rs2274223', 'Mutation', 'rs2274223', (78, 87))	('rs2274223', 'Var', (78, 87))	('esophagitis', 'Phenotype', 'HP:0100633', (183, 194))	('PLCE1', 'Gene', (158, 163))	('esophagitis', 'Disease', (183, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('esophagitis', 'Disease', 'MESH:D004941', (183, 194))	('esophageal carcinoma', 'Disease', (92, 112))	('PLCE1', 'Gene', (58, 63))
586921	28402280	Our recent work has reported that the stromal inflammation in esophageal squamous cell carcinoma occurs at the late stage and the inflammation is a immune response that protects the body from cancer cells, thus, ESCC stromal inflammation is associated with better outcomes.	('inflammation', 'Disease', 'MESH:D007249', (46, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (62, 96))	('ESCC', 'Var', (212, 216))	('inflammation', 'Disease', (46, 58))	('inflammation', 'Disease', (225, 237))	('inflammation', 'Disease', 'MESH:D007249', (130, 142))	('esophageal squamous cell carcinoma', 'Disease', (62, 96))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('inflammation', 'Disease', (130, 142))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
586942	28402280	For PLCE1 deficient mouse esophageal mucosa collection, it was briefed as following: PLCE1-/- and +/+ mice were sacrificed at 3 months, and the esophagus tissues were fixed in 70% ethanol, and then the esophageal mucosa was scraped under dissecting microscope using a scalpel.	('mice', 'Species', '10090', (102, 106))	('ethanol', 'Chemical', 'MESH:D000431', (180, 187))	('PLCE1', 'Gene', (4, 9))	('deficient', 'Var', (10, 19))	('mouse', 'Species', '10090', (20, 25))
586946	28402280	The cells were cultured and transfected with small interfering RNA targeting human PLCE1 (si-PLCE1) or scramble siRNA (NC, negative control), respectively.	('PLCE1', 'Gene', (83, 88))	('small interfering RNA', 'Var', (45, 66))	('human', 'Species', '9606', (77, 82))
586950	28402280	This study has also strongly suggested that the co-expression of PLCE1 and PRKCA could be an indicator for predicting of esophageal cancer patient outcomes, and the partnership of PLCE1 and PRKCA could be a therapeutic target instead of a single target for personalized therapy or prevention.	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('co-expression', 'Var', (48, 61))	('PRKCA', 'Gene', (75, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('PLCE1', 'Gene', (65, 70))	('patient', 'Species', '9606', (139, 146))
586958	28270118	Genetic examination demonstrated a pathogenic MEN1 mutation.	('MEN1', 'Gene', '4221', (46, 50))	('pathogenic', 'Reg', (35, 45))	('mutation', 'Var', (51, 59))	('MEN1', 'Gene', (46, 50))
586965	28270118	Germline mutation of the MEN1 gene is recognized in 80-90% of familial cases and in about 65% of sporadic cases.	('MEN1', 'Gene', '4221', (25, 29))	('Germline mutation', 'Var', (0, 17))	('familial', 'Disease', (62, 70))	('MEN1', 'Gene', (25, 29))
586991	28270118	Germline pathogenic mutation of the MEN1 gene was detected by whole exon analysis using next generation sequencer (Ion ProtonTM system, Thermo Fisher Scientific, Waltham, MA, U.S.A.), which was employed in the on-going institutional project, and was confirmed by the commercial base analysis (Falco biosystems, Kyoto, Japan).	('MEN1', 'Gene', (36, 40))	('mutation', 'Var', (20, 28))	('MEN1', 'Gene', '4221', (36, 40))
587007	28270118	Even for PNET >2 cm in MEN1/ZES, surgical enucleation is generally recommended, while pancreatoduodenectomy is reserved for specific selected cases.	('MEN1', 'Gene', (23, 27))	('PNET', 'Var', (9, 13))	('MEN1', 'Gene', '4221', (23, 27))
587022	28270118	Confirmation of a germline MEN1 mutation confirmed this genetic syndrome.	('MEN1', 'Gene', '4221', (27, 31))	('genetic syndrome', 'Disease', (56, 72))	('MEN1', 'Gene', (27, 31))	('genetic syndrome', 'Disease', 'MESH:D030342', (56, 72))	('mutation', 'Var', (32, 40))
587032	27816685	Herein, we found that HOTAIR was aberrantly upregulated in ESCC cells and that HOTAIR depletion inhibited proliferation and led to G1 cell cycle arrest in ESCC cells.	('led', 'Gene', '399668', (124, 127))	('HOTAIR', 'Gene', (79, 85))	('proliferation', 'CPA', (106, 119))	('HOTAIR', 'Gene', '100124700', (79, 85))	('upregulated', 'PosReg', (44, 55))	('HOTAIR', 'Gene', (22, 28))	('led', 'Gene', (124, 127))	('inhibited', 'NegReg', (96, 105))	('HOTAIR', 'Gene', '100124700', (22, 28))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (134, 151))	('G1 cell cycle arrest', 'CPA', (131, 151))	('depletion', 'Var', (86, 95))
587043	27816685	Recent studies have demonstrated that several lncRNAs, such as HOTAIR, POU3F3, PlncRNA-1, etc., are aberrant in ESCC, opening up a potential avenue for understanding the occurrence and development of ESCC.	('POU3F3', 'Gene', (71, 77))	('HOTAIR', 'Gene', '100124700', (63, 69))	('aberrant', 'Var', (100, 108))	('HOTAIR', 'Gene', (63, 69))	('POU3F3', 'Gene', '5455', (71, 77))	('ESCC', 'Disease', (112, 116))	('PlncRNA-1', 'Gene', '100506428', (79, 88))	('opening', 'Disease', 'MESH:D005597', (118, 125))	('PlncRNA-1', 'Gene', (79, 88))	('opening', 'Disease', (118, 125))
587059	27816685	Six ESCC cell lines (KYSE30, KYSE140, KYSE150, KYSE180, KYSE410, and KYSE510) were purchased from the German Culture Collection (DSMZ, Braunschweig, Germany).	('KYSE510', 'CellLine', 'CVCL:1354', (69, 76))	('KYSE180', 'Var', (47, 54))	('KYSE30', 'Var', (21, 27))	('KYSE510', 'Var', (69, 76))	('KYSE140', 'Var', (29, 36))	('KYSE410', 'Var', (56, 63))	('KYSE150', 'Var', (38, 45))
587064	27816685	For the function study of CCND1, KYSE30 and KYSE510 cells were transfected with either si-CCND1 or si-NC.	('CCND1', 'Gene', (90, 95))	('si-NC', 'Var', (99, 104))	('KYSE510', 'CellLine', 'CVCL:1354', (44, 51))	('CCND1', 'Gene', '595', (90, 95))	('CCND1', 'Gene', (26, 31))	('CCND1', 'Gene', '595', (26, 31))
587075	27816685	Cells were cotransfected with either empty vector or miR-1 and pMIR-Report Luciferase vector comprising 3'UTR of CCND1, wild-type, or mutant HOTAIR fragment.	('HOTAIR', 'Gene', '100124700', (141, 147))	('miR-1', 'Gene', (53, 58))	('CCND1', 'Gene', (113, 118))	('CCND1', 'Gene', '595', (113, 118))	('HOTAIR', 'Gene', (141, 147))	('mutant', 'Var', (134, 140))	('miR-1', 'Gene', '79187', (53, 58))
587090	27816685	We next examined the expression level of HOTAIR in six ESCC cell lines (KYSE30, KYSE140, KYSE150, KYSE180, KYSE410, and KYSE510) and human normal esophageal epithelium cell line HEEpiC by qRT-PCR.	('KYSE510', 'Var', (120, 127))	('KYSE180', 'Var', (98, 105))	('HOTAIR', 'Gene', '100124700', (41, 47))	('KYSE150', 'Var', (89, 96))	('KYSE140', 'Var', (80, 87))	('KYSE510', 'CellLine', 'CVCL:1354', (120, 127))	('human', 'Species', '9606', (133, 138))	('HOTAIR', 'Gene', (41, 47))	('KYSE410', 'Var', (107, 114))
587092	27816685	To understand the significance of HOTAIR upregulation in ESCC cells, we transfected KYSE30 and KYSE510 cells with si-HOTAIR or si-NC.	('HOTAIR', 'Gene', '100124700', (117, 123))	('si-NC', 'Var', (127, 132))	('KYSE510', 'CellLine', 'CVCL:1354', (95, 102))	('HOTAIR', 'Gene', (34, 40))	('HOTAIR', 'Gene', '100124700', (34, 40))	('HOTAIR', 'Gene', (117, 123))
587093	27816685	The data obtained from CCK8 assay showed that the knockdown of HOTAIR significantly inhibited ESCC cell proliferation (Figure 1, C and D).	('HOTAIR', 'Gene', '100124700', (63, 69))	('knockdown', 'Var', (50, 59))	('ESCC cell proliferation', 'CPA', (94, 117))	('HOTAIR', 'Gene', (63, 69))	('inhibited', 'NegReg', (84, 93))
587094	27816685	Flow cytometry analysis showed that the percentage of G1 phase cells increased in the KYSE30 and KYSE510 cells when they were introduced with si-HOTAIR (Figure 1, E and F).	('increased', 'PosReg', (69, 78))	('KYSE510', 'CellLine', 'CVCL:1354', (97, 104))	('HOTAIR', 'Gene', '100124700', (145, 151))	('KYSE30', 'Var', (86, 92))	('KYSE510', 'Var', (97, 104))	('G1 phase cells', 'CPA', (54, 68))	('HOTAIR', 'Gene', (145, 151))
587131	27816685	In addition, we detected the expression of CCND1 mRNA and protein in KYSE30 cells transfected with miR-NC, miR-1 mimics, miR-1 + pcDNA-HOTAIR, miR-1 + pcDNA-NC, si-HOTAR, or si-NC using qRT-PCR and Western blot.	('miR', 'Gene', '220972', (99, 102))	('CCND1', 'Gene', (43, 48))	('miR', 'Gene', '220972', (107, 110))	('miR-1', 'Gene', '79187', (121, 126))	('miR-1', 'Gene', (143, 148))	('miR', 'Gene', (99, 102))	('HOTAIR', 'Gene', '100124700', (135, 141))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (107, 110))	('HOTAIR', 'Gene', (135, 141))	('miR-1', 'Gene', (107, 112))	('miR', 'Gene', '220972', (143, 146))	('miR-1', 'Gene', '79187', (143, 148))	('miR', 'Gene', (121, 124))	('expression', 'MPA', (29, 39))	('miR-1', 'Gene', (121, 126))	('si-NC', 'Var', (174, 179))	('miR', 'Gene', (143, 146))	('si-HOTAR', 'Var', (161, 169))	('miR-1', 'Gene', '79187', (107, 112))	('detected', 'Reg', (16, 24))	('CCND1', 'Gene', '595', (43, 48))
587136	27816685	The results showed that the knockdown of CCND1 inhibited cell proliferation and induced G1 cell cycle arrest in YSE30 and KYSE510 cells (Figure 5, A-D).	('induced', 'Reg', (80, 87))	('inhibited', 'NegReg', (47, 56))	('CCND1', 'Gene', '595', (41, 46))	('KYSE510', 'CellLine', 'CVCL:1354', (122, 129))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('knockdown', 'Var', (28, 37))	('cell proliferation', 'CPA', (57, 75))	('G1 cell cycle arrest', 'CPA', (88, 108))	('CCND1', 'Gene', (41, 46))
587141	27816685	Furthermore, HOTAIR depletion suppressed cell proliferation and induced cell cycle arrest in KYSE30 and KYSE510 cells in vitro.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('suppressed', 'NegReg', (30, 40))	('cell proliferation', 'CPA', (41, 59))	('cell cycle arrest', 'CPA', (72, 89))	('depletion', 'Var', (20, 29))	('HOTAIR', 'Gene', (13, 19))	('KYSE510', 'CellLine', 'CVCL:1354', (104, 111))	('HOTAIR', 'Gene', '100124700', (13, 19))
587146	27816685	Moreover, lncRNA PTEN-P1 could sponge miR-19b and miR-20a, thereby modulating derepression of PTEN tumor suppressor in various malignancies including prostate cancer, glioblastoma, and melanoma, and the deregulation in this network induces tumorigenesis.	('miR-19b', 'Gene', '406980', (38, 45))	('miR-20a', 'Gene', (50, 57))	('tumor', 'Disease', (99, 104))	('miR-20a', 'Gene', '406982', (50, 57))	('tumor', 'Disease', (240, 245))	('PTEN-P1', 'Gene', (17, 24))	('malignancies', 'Disease', 'MESH:D009369', (127, 139))	('malignancies', 'Disease', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('derepression of PTEN tumor', 'Disease', 'MESH:D006223', (78, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('derepression of PTEN tumor', 'Disease', (78, 104))	('prostate cancer', 'Disease', 'MESH:D011471', (150, 165))	('PTEN-P1', 'Gene', '11191', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('prostate cancer', 'Phenotype', 'HP:0012125', (150, 165))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('prostate cancer', 'Disease', (150, 165))	('deregulation', 'Var', (203, 215))	('glioblastoma', 'Disease', 'MESH:D005909', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('induces', 'Reg', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('miR-19b', 'Gene', (38, 45))	('glioblastoma', 'Disease', (167, 179))	('glioblastoma', 'Phenotype', 'HP:0012174', (167, 179))	('modulating', 'Reg', (67, 77))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))
587158	27816685	Moreover, CCND1 deletion could inhibit cell proliferation and G1-S transition in vitro.	('CCND1', 'Gene', '595', (10, 15))	('G1-S transition', 'CPA', (62, 77))	('deletion', 'Var', (16, 24))	('inhibit', 'NegReg', (31, 38))	('CCND1', 'Gene', (10, 15))	('cell proliferation', 'CPA', (39, 57))
587173	27517841	Heterogeneous texture features on CT images were associated with better survival in patients with HER2-positive advanced gastric cancer who received trastuzumab-based treatment.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Heterogeneous', 'Var', (0, 13))	('survival', 'MPA', (72, 80))	('patients', 'Species', '9606', (84, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))	('HER2', 'Gene', (98, 102))	('trastuzumab', 'Chemical', 'MESH:D000068878', (149, 160))	('better', 'PosReg', (65, 71))	('HER2', 'Gene', '2064', (98, 102))	('gastric cancer', 'Disease', (121, 135))	('men', 'Species', '9606', (172, 175))
587178	27517841	In primary esophageal cancer, low entropy and high uniformity values measured on contrast-enhanced CT images after chemoradiation therapy were associated with improved survival.	('primary esophageal cancer', 'Disease', 'MESH:D004938', (3, 28))	('high uniformity values', 'MPA', (46, 68))	('improved', 'PosReg', (159, 167))	('low', 'Var', (30, 33))	('primary esophageal cancer', 'Disease', (3, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('survival', 'MPA', (168, 176))
587207	27517841	In this study, tumor contrast greater than 265.8480, variance greater than 488.3150, correlation less than or equal to 0.1319x10-3, and an ASM less than or equal to 0.0412x10-2 were associated with good overall survival.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('greater than 265.8480', 'Var', (30, 51))	('tumor', 'Disease', (15, 20))	('correlation', 'MPA', (85, 96))	('less', 'NegReg', (97, 101))
587211	27517841	Subsequent studies focused on the histopathological HER2 status to select optimal patients for trastuzumab treatment and revealed that the HER IHC status, HER2/CEP17 ratio, and HER2 gene copy number were associated with good clinical outcomes in trastuzumab treatment.	('trastuzumab', 'Chemical', 'MESH:D000068878', (95, 106))	('gene copy number', 'Var', (182, 198))	('HER2', 'Gene', '2064', (155, 159))	('HER2', 'Gene', '2064', (52, 56))	('patients', 'Species', '9606', (82, 90))	('HER2', 'Gene', (177, 181))	('HER2', 'Gene', '2064', (177, 181))	('men', 'Species', '9606', (263, 266))	('associated', 'Reg', (204, 214))	('men', 'Species', '9606', (112, 115))	('trastuzumab', 'Chemical', 'MESH:D000068878', (246, 257))	('HER2', 'Gene', (155, 159))	('HER2', 'Gene', (52, 56))
587212	27517841	A previous study reported that a high incidence of intratumoral HER2 heterogeneity may result in an inaccurate assessment of the HER2 status and suboptimal patient selection.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('HER2', 'Gene', (129, 133))	('tumor', 'Disease', (56, 61))	('men', 'Species', '9606', (117, 120))	('HER2', 'Gene', (64, 68))	('heterogeneity', 'Var', (69, 82))	('HER2', 'Gene', '2064', (129, 133))	('HER2', 'Gene', '2064', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('patient', 'Species', '9606', (156, 163))
587214	27517841	The present study included only patients with HER2 IHC 3+ or IHC 2+/FISH+ who had shown a good response to trastuzumab treatment.	('patients', 'Species', '9606', (32, 40))	('HER2', 'Gene', (46, 50))	('men', 'Species', '9606', (124, 127))	('HER2', 'Gene', '2064', (46, 50))	('IHC 2+/FISH+', 'Var', (61, 73))	('trastuzumab', 'Chemical', 'MESH:D000068878', (107, 118))	('IHC 3+', 'Var', (51, 57))
587240	27517841	In conclusion, heterogeneous texture features on CT images were associated with better survival in patients with HER2-positive advanced gastric cancer who received trastuzumab-based treatment.	('survival', 'MPA', (87, 95))	('trastuzumab', 'Chemical', 'MESH:D000068878', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('HER2', 'Gene', (113, 117))	('men', 'Species', '9606', (187, 190))	('gastric cancer', 'Disease', (136, 150))	('HER2', 'Gene', '2064', (113, 117))	('patients', 'Species', '9606', (99, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('better', 'PosReg', (80, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('heterogeneous', 'Var', (15, 28))
587249	25789284	Moreover, in patients with these abnormalities, obstructive jaundice is rarely observed.	('obstructive jaundice', 'Disease', (48, 68))	('patients', 'Species', '9606', (13, 21))	('jaundice', 'Phenotype', 'HP:0000952', (60, 68))	('abnormalities', 'Var', (33, 46))	('obstructive jaundice', 'Disease', 'MESH:D041781', (48, 68))
587302	25789284	Increased blood flow in paracholedochal veins of Petren (which exist as a hepatofugal route from the gastric and pancreaticoduodenal veins to the portal vein) caused by portal obstruction may promote formation of paracholedochal varices.	('choledochal varices', 'Phenotype', 'HP:0100890', (217, 236))	('portal obstruction', 'Var', (169, 187))	('blood flow', 'MPA', (10, 20))	('promote', 'PosReg', (192, 199))	('paracholedochal varices', 'Disease', (213, 236))	('Increased', 'PosReg', (0, 9))	('hepatofugal', 'Disease', 'None', (74, 85))	('hepatofugal', 'Disease', (74, 85))
587342	24692500	The FHCRC model is a biological model based on the paradigm of initiation, promotion, and progression where carcinogenesis arises from the accumulation of mutations and clonal expansion of partially altered cells on the pathway to malignancy (Appendix Figure A1).	('mutations', 'Var', (155, 164))	('malignancy', 'Disease', 'MESH:D009369', (231, 241))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('malignancy', 'Disease', (231, 241))	('carcinogenesis', 'Disease', (108, 122))
587351	24692500	Following the method in one of our previous analyses, the cancer incidence rates are comprised of cancers defined/identified by the International Classification of Diseases for Oncology, third edition (ICD-O-3) histology codes 8140- 8141, 8143- 8145, 8190- 8231, 8260-8263, 8310, 8401, 8480-8490, 8550-8551, 8570-8574, and 8576.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Oncology', 'Phenotype', 'HP:0002664', (177, 185))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('8260-8263', 'Var', (263, 272))	('cancers', 'Disease', (98, 105))	('cancer', 'Disease', (98, 104))	('8401', 'Var', (280, 284))	('8190- 8231', 'Var', (251, 261))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('8310', 'Var', (274, 278))	('8140- 8141', 'Var', (227, 237))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('8480-8490', 'Var', (286, 295))	('8570-8574', 'Var', (308, 317))	('8143- 8145', 'Var', (239, 249))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('8550-8551', 'Var', (297, 306))	('8576', 'Var', (323, 327))	('cancer', 'Disease', (58, 64))
587507	20737041	The new median OS of 28.5 months for negative margins patients is comparable to the reported literature in adjuvant gastric cancer taking into account the higher risk profile with our patients as outlined in table 1.	('negative margins', 'Var', (37, 53))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (54, 62))	('gastric cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (116, 130))	('gastric cancer', 'Phenotype', 'HP:0012126', (116, 130))
587511	16026601	Understanding how the millions of SNPs in the human genome are involved in conferring susceptibility or resistance to disease, or in rendering a drug efficacious or toxic in the individual is a major goal of the relatively new fields of pharmacogenomics.	('SNPs', 'Var', (34, 38))	('resistance', 'MPA', (104, 114))	('human', 'Species', '9606', (46, 51))	('involved', 'Reg', (63, 71))
587515	16026601	For example, we found that the different genotypes of SNP GADD45B E1122 are all associated with cancer risk.	('GADD45B', 'Gene', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('E1122', 'Var', (66, 71))	('associated', 'Reg', (80, 90))	('GADD45B', 'Gene', '4616', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
587556	16026601	We also evaluated the odds ratio and its 95% confidence interval for SNP type, which gives an estimate of how much more likely it is that an individual with the SNP type is to be a cancer case than a control case.	('cancer', 'Disease', (181, 187))	('SNP type', 'Var', (161, 169))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))
587563	16026601	Using DF-SNPs, we identified a list of SNPs, SNP types and SNP patterns that might be associated with esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('SNPs', 'Var', (39, 43))	('associated', 'Reg', (86, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
587572	16026601	We further found that two GADD45B E1122 genotypes (numbers 1 and 4 in Table 2) are suggested to modify cancer risk differently, with the homozygous common genotype possibly increasing esophageal cancer risk and the heterozygous genotype possibly decreasing cancer risk.	('increasing', 'PosReg', (173, 183))	('modify', 'Reg', (96, 102))	('decreasing', 'NegReg', (246, 256))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('GADD45B', 'Gene', '4616', (26, 33))	('E1122', 'Var', (34, 39))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('esophageal cancer', 'Disease', (184, 201))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('GADD45B', 'Gene', (26, 33))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
587573	16026601	These data suggest a potentially important role for polymorphisms of GADD45B E1122 as a biomarker of esophageal cancer risk.	('GADD45B', 'Gene', '4616', (69, 76))	('E1122', 'Var', (77, 82))	('GADD45B', 'Gene', (69, 76))	('polymorphisms', 'Var', (52, 65))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
587575	16026601	Also notable is that odds ratios are substantially larger for the patterns of two SNPs than for individual SNPs (compare Table 2 with Table 4), possibly indicating that patterns of SNPs are more predictive of cancer risk than individual SNPs.	('SNPs', 'Var', (181, 185))	('cancer', 'Disease', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
587581	32545762	In addition, the high expression of HDGF was reported to be closely associated with unfavorable clinical outcomes in several malignant diseases.	('HDGF', 'Gene', (36, 40))	('associated', 'Reg', (68, 78))	('high', 'Var', (17, 21))	('malignant diseases', 'Disease', 'MESH:D009369', (125, 143))	('malignant diseases', 'Disease', (125, 143))
587602	32545762	The transfection of the HDGF gene in NIH3T3 fibroblasts increased the expression of VEGF, and the transplanted HDGF-overexpressing NIH3T3 cells formed highly vascularized tumors in a xenograft model.	('HDGF gene', 'Gene', (24, 33))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('increased', 'PosReg', (56, 65))	('transfection', 'Var', (4, 16))	('VEGF', 'Gene', (84, 88))	('NIH3T3', 'CellLine', 'CVCL:0594', (131, 137))	('expression', 'MPA', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('NIH3T3', 'CellLine', 'CVCL:0594', (37, 43))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
587607	32545762	In hepatoma cell lines, experimental studies demonstrated that the blocking of HDGF activated both extrinsic and intrinsic apoptotic pathways.	('rat', 'Species', '10116', (52, 55))	('hepatoma', 'Disease', 'MESH:D006528', (3, 11))	('activated', 'PosReg', (84, 93))	('extrinsic', 'Pathway', (99, 108))	('intrinsic apoptotic pathways', 'Pathway', (113, 141))	('HDGF', 'Gene', (79, 83))	('hepatoma', 'Disease', (3, 11))	('blocking', 'Var', (67, 75))
587619	32545762	With regard to the proliferation of the gut system, the expression of HDGF is suggested to have a suppressive role in the maturation of fetal intestinal cells, and to be associated with the proliferation of these cells.	('rat', 'Species', '10116', (197, 200))	('rat', 'Species', '10116', (26, 29))	('suppressive', 'NegReg', (98, 109))	('maturation of fetal intestinal cells', 'CPA', (122, 158))	('proliferation', 'CPA', (190, 203))	('associated', 'Reg', (170, 180))	('rat', 'Species', '10116', (126, 129))	('expression', 'Var', (56, 66))	('HDGF', 'Gene', (70, 74))
587632	32545762	In fact, various independent groups have demonstrated that HCC patients with higher HDGF expression levels showed an unfavorable clinical outcome in comparison to those with lower HDGF expression levels, and the expression of HDGF was found to be independently associated with disease-free and overall survival after curative surgery in HCC patients.	('patients', 'Species', '9606', (341, 349))	('HCC', 'Phenotype', 'HP:0001402', (337, 340))	('associated with', 'Reg', (261, 276))	('rat', 'Species', '10116', (319, 322))	('patients', 'Species', '9606', (63, 71))	('expression', 'Var', (212, 222))	('HCC', 'Disease', (59, 62))	('overall survival', 'CPA', (294, 310))	('HDGF', 'Protein', (84, 88))	('HCC', 'Phenotype', 'HP:0001402', (59, 62))	('rat', 'Species', '10116', (48, 51))
587640	32545762	investigated the expression levels of HDGF and VEGF in patients with hilar cholangiocarcinoma, and showed that the high expression of HDGF was significantly associated with a poorer clinical outcome.	('high', 'Var', (115, 119))	('associated', 'Reg', (157, 167))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 93))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('HDGF', 'Gene', (134, 138))	('patients', 'Species', '9606', (55, 63))	('cholangiocarcinoma', 'Disease', (75, 93))
587643	32545762	In addition, the expression of HDGF is associated with the clinical biological behavior and prognosis of gallbladder adenocarcinoma.	('gallbladder adenocarcinoma', 'Disease', 'MESH:D000230', (105, 131))	('associated', 'Reg', (39, 49))	('expression', 'Var', (17, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('gallbladder adenocarcinoma', 'Disease', (105, 131))	('HDGF', 'Gene', (31, 35))
587645	32545762	In a previous study, a possible association between the expression of HDGF and the radiosensitivity of esophageal cancer cells was reported.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('radiosensitivity of', 'CPA', (83, 102))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('expression', 'Var', (56, 66))	('HDGF', 'Gene', (70, 74))	('cancer', 'Disease', (114, 120))
587648	32545762	One possible explanation was that esophageal cancer cells with high HDGF expression levels have high proliferative activity, and thus finally cause an unfavorable outcome, regardless of the transiently observed high treatment efficacy.	('rat', 'Species', '10116', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('HDGF', 'Gene', (68, 72))	('cause', 'Reg', (142, 147))	('high', 'Var', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('proliferative activity', 'CPA', (101, 123))
587659	32545762	The knockdown of HDGF was reported to activate the mitochondrial apoptotic pathway, and a recent study revealed the involvement of HDGF in the proliferation and invasion of colorectal cancer cells.	('colorectal cancer', 'Disease', (173, 190))	('HDGF', 'Gene', (131, 135))	('mitochondrial apoptotic pathway', 'Pathway', (51, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('invasion', 'CPA', (161, 169))	('HDGF', 'Gene', (17, 21))	('involvement', 'Reg', (116, 127))	('activate', 'PosReg', (38, 46))	('rat', 'Species', '10116', (150, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))	('knockdown', 'Var', (4, 13))	('proliferation', 'CPA', (143, 156))
587678	32545762	For instance, lncRNA HLA complex P5 (lnc HCP5) was reported to cause gemcitabine resistance in pancreatic cancer cells, through the upregulation of miR-214-3p and its target gene, HDGF.	('upregulation', 'PosReg', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cause', 'Reg', (63, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('gemcitabine', 'Chemical', 'MESH:C056507', (69, 80))	('miR-214-3p', 'Var', (148, 158))	('HCP5', 'Gene', '10866', (41, 45))	('gemcitabine resistance', 'MPA', (69, 91))	('HCP5', 'Gene', (41, 45))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('pancreatic cancer', 'Disease', (95, 112))	('HDGF', 'Gene', (180, 184))
587706	32310341	Evaluation of data for total length of in-hospital stay from 21 studies14, 15, 17, 18, 20, 22, 24, 25, 26, 27, 28, 29, 32, 34, 35, 36, 38, 40, 42, 46 with 3265 patients showed that patients who underwent MIE got to experience less in-hospital duration compared with those who underwent OE (SMD = -0.51; 95% CI = -0.78, -0.24; P = <0.001) (Fig.	('patients', 'Species', '9606', (160, 168))	('MIE', 'Var', (204, 207))	('patients', 'Species', '9606', (181, 189))	('less', 'NegReg', (226, 230))	('in-hospital duration', 'MPA', (231, 251))
587707	32310341	A total of 23 studies15, 16, 17, 18, 20, 22, 24, 25, 26, 27, 28, 29, 31, 32, 34, 35, 36, 38, 40, 41, 42, 46 with 2796 patients included in analyzing the data for total operation time showed that the patients who underwent MIE experienced longer operation time compared to those who underwent OE (SMD = 0.52; 95% CI = 0.16, 0.89; P = 0.005) (Fig.	('longer', 'PosReg', (238, 244))	('patients', 'Species', '9606', (118, 126))	('MIE', 'Var', (222, 225))	('patients', 'Species', '9606', (199, 207))
587708	32310341	Data for total blood loss gathered from 17 studies16, 17, 18, 24, 25, 27, 28, 29, 32, 34, 36, 38, 40, 41, 42, 46 with 2160 patients revealed that MIE resulted in less blood loss in comparison with OE (SMD = -1.44; 95% CI = -1.95, -0.93; P = <0.001) (Fig.	('less', 'NegReg', (162, 166))	('blood loss', 'Disease', 'MESH:D006473', (15, 25))	('blood loss', 'Disease', (15, 25))	('MIE', 'Var', (146, 149))	('patients', 'Species', '9606', (123, 131))	('blood loss', 'Disease', 'MESH:D006473', (167, 177))	('blood loss', 'Disease', (167, 177))
587712	32310341	Postoperative RCs are of great importance and could impact the prognosis of patients, which are also the most frequent morbidity events after esophagectomy.	('RCs', 'Var', (14, 17))	('patients', 'Species', '9606', (76, 84))	('RCs', 'Phenotype', 'HP:0011947', (14, 17))	('impact', 'Reg', (52, 58))	('prognosis', 'CPA', (63, 72))
587713	32310341	Two retrospective studies showed no significant differences regarding RCs between two groups.13, 50 On the other hand, two RCTs showed a significantly lower incidence of respiratory complications after MIE than OE.36, 51 Pooled data from our study also showed that patients who underwent MIE experienced fewer postoperative RCs compared to those who underwent OE (Fig.	('RCs', 'Phenotype', 'HP:0011947', (324, 327))	('respiratory complications', 'Disease', (170, 195))	('RCs', 'Phenotype', 'HP:0011947', (70, 73))	('MIE', 'Var', (288, 291))	('patients', 'Species', '9606', (265, 273))	('fewer', 'NegReg', (304, 309))	('RCs', 'Disease', (324, 327))	('respiratory complications', 'Disease', 'MESH:D012131', (170, 195))	('respiratory complications', 'Phenotype', 'HP:0011947', (170, 195))
587715	32310341	These results were consistent with other recently published studies and could be attributed to the technical difficulty in MIE and a limited operating space for surgeons to perform the delicate procedure.16, 18, 42 Data analyses also demonstrated that patients who underwent MIE experienced shorter postoperative in-hospital stay and had less in-operative blood loss, as compared to those who underwent OE.	('MIE', 'Var', (275, 278))	('patients', 'Species', '9606', (252, 260))	('blood loss', 'Disease', 'MESH:D006473', (356, 366))	('postoperative in-hospital', 'MPA', (299, 324))	('blood loss', 'Disease', (356, 366))	('shorter', 'NegReg', (291, 298))
587719	32310341	In conclusion, while OE was associated with shorter operation time and a slightly better surgical clearance of the tumor (R0 resection rates) compared with MIE, MIE was associated with fewer RCs, lesser blood loss, shorter postoperative in-hospital stay and better overall postoperative outcomes.	('fewer', 'NegReg', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('better', 'PosReg', (82, 88))	('lesser blood loss', 'Disease', (196, 213))	('tumor', 'Disease', (115, 120))	('RCs', 'Phenotype', 'HP:0011947', (191, 194))	('lesser blood loss', 'Disease', 'MESH:D006473', (196, 213))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('MIE', 'Var', (161, 164))	('RCs', 'Disease', (191, 194))
587791	32296589	It has been reported that positive family history and genetic changes may increase the susceptibility to esophageal cancer, and esophageal cancer survival.	('esophageal cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('increase', 'PosReg', (74, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('esophageal cancer', 'Disease', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('genetic changes', 'Var', (54, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))
587850	30403012	Histologic criteria referred to the International Classification of Disease for Oncology codes of 8041-8045 or 8073 (representing small cell or oat cell carcinoma).	('oat cell carcinoma', 'Disease', (144, 162))	('Oncology', 'Phenotype', 'HP:0002664', (80, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('8073', 'Var', (111, 115))	('oat cell carcinoma', 'Disease', 'MESH:D018288', (144, 162))	('small cell', 'Disease', (130, 140))	('oat cell carcinoma', 'Phenotype', 'HP:0030357', (144, 162))
587916	30271084	The T4a (invasion of pleura, pericardium and diaphragm) and T4b (invasion of other structures, e.g., aorta, vertebral body and trachea) stages were defined as a tumor wall thickness greater than 10 mm and invaded adjacent structures.	('T4b', 'Var', (60, 63))	('T4a', 'Var', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
587993	27069317	Mutations of p53 are clearly involved in the pathogenesis of BEA, and the fact that the mutations were detected in premalignant Barrett's epithelium supports the hypothesis that p53 mutations may be a useful marker for patients at increased risk for development of invasive cancer.	('patients', 'Species', '9606', (219, 227))	('BEA', 'Disease', (61, 64))	('BEA', 'Chemical', '-', (61, 64))	('BEA', 'Phenotype', 'HP:0100580', (61, 64))	('BE', 'Phenotype', 'HP:0100580', (61, 63))	('involved', 'Reg', (29, 37))	('Mutations', 'Var', (0, 9))	('invasive cancer', 'Disease', (265, 280))	('p53', 'Gene', (13, 16))	('p53', 'Gene', (178, 181))	('invasive cancer', 'Disease', 'MESH:D009362', (265, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('p53', 'Gene', '7157', (178, 181))	('p53', 'Gene', '7157', (13, 16))	('mutations', 'Var', (182, 191))
588000	27069317	Recently, oxidative DNA damage was also found to be associated with genetic instability via telomeric dysfunction, leading to p53 mutation and BEA tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('leading to', 'Reg', (115, 125))	('p53', 'Gene', '7157', (126, 129))	('telomeric dysfunction', 'Disease', (92, 113))	('mutation', 'Var', (130, 138))	('BEA', 'Disease', (143, 146))	('BEA', 'Chemical', '-', (143, 146))	('BEA', 'Phenotype', 'HP:0100580', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('BE', 'Phenotype', 'HP:0100580', (143, 145))	('p53', 'Gene', (126, 129))	('telomeric dysfunction', 'Disease', 'MESH:C536801', (92, 113))
588050	27069317	This process could be explained by the accumulation of mutation in progenitor cells, leading to the acquisition of the property of cancer stem cells.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('acquisition', 'PosReg', (100, 111))	('mutation', 'Var', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
588061	27069317	also reported that cytoplasmic expression of CD133 was a significant risk factor for the overall survival and tumor stages III and IVA of hepatocellular carcinoma patients.	('patients', 'Species', '9606', (163, 171))	('CD133', 'Gene', (45, 50))	('cytoplasmic expression', 'Var', (19, 41))	('CD133', 'Gene', '8842', (45, 50))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (138, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('IVA of hepatocellular carcinoma', 'Disease', 'MESH:C538167', (131, 162))	('risk', 'Reg', (69, 73))	('IVA of hepatocellular carcinoma', 'Disease', (131, 162))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
588067	27069317	GERD induces inflammatory responses and tissue injury, which mediate intestinal dysplasia and CD133 expression in apical surface of columnar epithelial cells.	('tissue injury', 'CPA', (40, 53))	('inflammatory responses', 'CPA', (13, 35))	('intestinal dysplasia', 'Disease', 'MESH:D007410', (69, 89))	('CD133', 'Gene', (94, 99))	('CD133', 'Gene', '8842', (94, 99))	('expression', 'MPA', (100, 110))	('GERD', 'Var', (0, 4))	('induces', 'Reg', (5, 12))	('intestinal dysplasia', 'Disease', (69, 89))
588077	24795040	Chemoprevention with PPIs in patients with Barrett's esophagus without reflux is cost-effective if PPIs reduce EAC by a minimum of 19 %.	('patients', 'Species', '9606', (29, 37))	('EAC', 'Disease', (111, 114))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (43, 62))	('reduce', 'NegReg', (104, 110))	('PPIs', 'Var', (99, 103))	('EAC', 'Phenotype', 'HP:0011459', (111, 114))
588086	24795040	A recent meta-analysis of these studies reported that PPI use in BE patients was associated with a 71 % reduced risk of progression to high-grade dysplasia (HGD) or EAC.	('dysplasia', 'Disease', (146, 155))	('PPI', 'Var', (54, 57))	('reduced', 'NegReg', (104, 111))	('dysplasia', 'Disease', 'MESH:D004476', (146, 155))	('EAC', 'Phenotype', 'HP:0011459', (165, 168))	('patients', 'Species', '9606', (68, 76))	('BE', 'Phenotype', 'HP:0100580', (65, 67))	('EAC', 'Disease', (165, 168))
588101	24795040	While a recent meta-analysis reported that PPI use is associated with a 71 % reduction in the risk of HGD or EAC in BE patients, we chose a more conservative 50 % risk reduction for EAC and varied this estimate widely (0-100 %) in the sensitivity analysis.	('EAC', 'Phenotype', 'HP:0011459', (109, 112))	('EAC', 'Phenotype', 'HP:0011459', (182, 185))	('PPI', 'Var', (43, 46))	('patients', 'Species', '9606', (119, 127))	('reduction', 'NegReg', (77, 86))	('BE', 'Phenotype', 'HP:0100580', (116, 118))	('HGD', 'Disease', (102, 105))	('EAC', 'Disease', (109, 112))
588110	24795040	In our base case, a 50 % reduction in the risk of EAC was assumed for patients who received PPIs.	('patients', 'Species', '9606', (70, 78))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))	('PPIs', 'Var', (92, 96))	('EAC', 'Disease', (50, 53))
588126	24795040	Our Markov model's base case assumed a 50 % reduction in EAC risk for patients who received PPIs.	('patients', 'Species', '9606', (70, 78))	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('PPIs', 'Var', (92, 96))	('EAC', 'Disease', (57, 60))	('reduction', 'NegReg', (44, 53))
588135	24795040	of veterans with BE, PPI use (compared to histamine-2 antagonists and no acid suppression) had a lower risk of progression to dysplasia (HR 0.25, 95 %CI 0.13-0.47).	('PPI use', 'Var', (21, 28))	('dysplasia', 'Disease', (126, 135))	('BE', 'Phenotype', 'HP:0100580', (17, 19))	('dysplasia', 'Disease', 'MESH:D004476', (126, 135))
588153	24795040	Our model included the two primary major adverse effects of PPIs: increased risks of bone fractures and of C. difficile infection.	('infection', 'Disease', 'MESH:D007239', (120, 129))	('bone fractures', 'Disease', 'MESH:D050723', (85, 99))	('bone fractures', 'Phenotype', 'HP:0020110', (85, 99))	('bone fracture', 'Phenotype', 'HP:0020110', (85, 98))	('C. difficile', 'Species', '1496', (107, 119))	('PPIs', 'Var', (60, 64))	('bone fractures', 'Disease', (85, 99))	('C. difficile infection', 'Phenotype', 'HP:0032167', (107, 129))	('infection', 'Disease', (120, 129))
588188	24167725	In a small randomized crossover study, Rohof and collaborators found that azithromycin, a macrolide antibiotic with prokinetic properties, reduced the size of the hiatus hernia and lowered the position of the acid pocket, resulting in a significant reduction in the post-prandial esophageal acid exposure.	('esophageal acid', 'Chemical', '-', (280, 295))	('rat', 'Species', '10116', (56, 59))	('post-prandial esophageal acid exposure', 'MPA', (266, 304))	('reduction', 'NegReg', (249, 258))	('hiatus hernia', 'Phenotype', 'HP:0002036', (163, 176))	('lowered', 'NegReg', (181, 188))	('position of the acid pocket', 'MPA', (193, 220))	('azithromycin', 'Var', (74, 86))	('hiatus hernia', 'Disease', (163, 176))	('azithromycin', 'Chemical', 'MESH:D017963', (74, 86))	('macrolide', 'Chemical', 'MESH:D018942', (90, 99))	('hiatus hernia', 'Disease', 'MESH:D006551', (163, 176))	('reduced', 'NegReg', (139, 146))	('size', 'MPA', (151, 155))	('hernia', 'Phenotype', 'HP:0100790', (170, 176))
588207	24167725	Furthermore, SOX9 expression correlated with enhanced tumor formation in a xenograft model and poor survival in patients with EAC.	('SOX9', 'Gene', '6662', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('poor', 'NegReg', (95, 99))	('enhanced', 'PosReg', (45, 53))	('survival', 'CPA', (100, 108))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('EAC', 'Disease', (126, 129))	('tumor', 'Disease', (54, 59))	('expression', 'Var', (18, 28))	('SOX9', 'Gene', (13, 17))
588209	24167725	Dulak and colleagues published the first exome (coding regions) sequencing data on 149 EACs and normal tissue pairs and identified novel genes with recurrent mutations, including four chromatin-modifying factors (SPG20, TLR4, DOCK2, and ELMO1, the latter of which has been shown to be involved in cell invasion).	('ELMO1', 'Gene', (237, 242))	('TLR4', 'Gene', (220, 224))	('DOCK2', 'Gene', '1794', (226, 231))	('SPG20', 'Gene', (213, 218))	('ELMO1', 'Gene', '9844', (237, 242))	('DOCK2', 'Gene', (226, 231))	('mutations', 'Var', (158, 167))	('TLR4', 'Gene', '7099', (220, 224))	('SPG20', 'Gene', '23111', (213, 218))
588221	24167725	A Dutch case-control study on a prospective cohort of 720 patients with BE found that aberrant p53 expression detected by immunohistochemistry confers a relative risk for neoplastic progression of 5.6 (95% confidence interval [CI] 3.1-10.3).	('expression', 'MPA', (99, 109))	('neoplastic progression', 'CPA', (171, 193))	('p53', 'Gene', (95, 98))	('aberrant', 'Var', (86, 94))	('p53', 'Gene', '7157', (95, 98))	('patients', 'Species', '9606', (58, 66))
588240	24167725	A GWAS found that a single-nucleotide polymorphism in a gene coding for a zinc transporter (SLC39A6) is associated with worse survival with a hazard ratio for death of 1.3 (95% CI 1.19-1.43).	('rat', 'Species', '10116', (149, 152))	('worse', 'NegReg', (120, 125))	('SLC39A6', 'Gene', '25800', (92, 99))	('death', 'Disease', 'MESH:D003643', (159, 164))	('SLC39A6', 'Gene', (92, 99))	('death', 'Disease', (159, 164))	('single-nucleotide polymorphism', 'Var', (20, 50))
588260	24167725	Although PPI treatment correlated with a better symptomatic response (dysphagia score) compared with topical steroid among patients who had normal pH monitoring, there was no statistical difference in the histologic response, and a resolution of eosinophilia was seen in 33% and 19% of patients, respectively.	('steroid', 'Chemical', 'MESH:D013256', (109, 116))	('PPI', 'Var', (9, 12))	('men', 'Species', '9606', (18, 21))	('dysphagia', 'Disease', (70, 79))	('eosinophilia', 'Disease', 'MESH:D004802', (246, 258))	('better', 'PosReg', (41, 47))	('patients', 'Species', '9606', (123, 131))	('dysphagia', 'Phenotype', 'HP:0002015', (70, 79))	('symptomatic response', 'MPA', (48, 68))	('eosinophilia', 'Disease', (246, 258))	('dysphagia', 'Disease', 'MESH:D003680', (70, 79))	('eosinophilia', 'Phenotype', 'HP:0001880', (246, 258))	('patients', 'Species', '9606', (286, 294))
588314	23244779	Reflux may precipitate asthma either via a vagal reflex initiated by gastric fluid in the esophagus or by micro-aspiration of gastric content into the trachea.	('asthma', 'Phenotype', 'HP:0002099', (23, 29))	('vagal reflex', 'Phenotype', 'HP:0002886', (43, 55))	('precipitate', 'Reg', (11, 22))	('aspiration', 'Phenotype', 'HP:0002835', (112, 122))	('fluid in the esophagus', 'Phenotype', 'HP:0100633', (77, 99))	('vagal reflex', 'MPA', (43, 55))	('asthma', 'Disease', (23, 29))	('Reflux', 'MPA', (0, 6))	('micro-aspiration', 'Var', (106, 122))	('asthma', 'Disease', 'MESH:D001249', (23, 29))
588382	23244779	GERD can cause permanent histopathological changes in asthma, progression to fibrosis, and decrease in the response rate to treatment through direct irritation, hypersensitivity of the airway , and a neural reflex.	('irritation', 'Disease', 'MESH:D001523', (149, 159))	('asthma', 'Disease', 'MESH:D001249', (54, 60))	('asthma', 'Phenotype', 'HP:0002099', (54, 60))	('fibrosis', 'Disease', 'MESH:D005355', (77, 85))	('fibrosis', 'Disease', (77, 85))	('hypersensitivity of', 'Disease', 'MESH:D004342', (161, 180))	('hypersensitivity of', 'Disease', (161, 180))	('GERD', 'Var', (0, 4))	('irritation', 'Disease', (149, 159))	('asthma', 'Disease', (54, 60))	('decrease', 'NegReg', (91, 99))	('response rate to treatment', 'MPA', (107, 133))
588418	23244779	GERD can cause episodes of chest pain that resemble ischemic cardiac pain without accompanying heartburn or regurgitation according to the Montreal definition and classification.	('chest pain', 'Phenotype', 'HP:0100749', (27, 37))	('ischemic', 'Disease', 'MESH:D007511', (52, 60))	('pain', 'Phenotype', 'HP:0012531', (33, 37))	('heartburn', 'Phenotype', 'HP:0002020', (95, 104))	('ischemic', 'Disease', (52, 60))	('GERD', 'Var', (0, 4))	('cardiac pain', 'Disease', (61, 73))	('cardiac pain', 'Disease', 'MESH:D010146', (61, 73))	('chest pain', 'Disease', 'MESH:D002637', (27, 37))	('chest pain', 'Disease', (27, 37))	('cause', 'Reg', (9, 14))	('pain', 'Phenotype', 'HP:0012531', (69, 73))
588428	23244779	However, the presence of acid regurgitation was significantly correlated with nocturnal awakening with dyspnea in this study.	('dyspnea', 'Disease', 'MESH:D004417', (103, 110))	('nocturnal awakening', 'Disease', (78, 97))	('presence', 'Var', (13, 21))	('dyspnea', 'Phenotype', 'HP:0002094', (103, 110))	('acid regurgitation', 'Disease', (25, 43))	('dyspnea', 'Disease', (103, 110))	('correlated', 'Reg', (62, 72))
588591	19250510	Helicobacter Pylori and Gastroesophageal Reflux Disease Gastric colonization with Helicobacter pylori is a proposed protective factor against gastroesophageal reflux disease (GERD), but little population-based data exist and other data conflict.	('gastroesophageal reflux disease', 'Disease', (142, 173))	('Helicobacter pylori', 'Species', '210', (82, 101))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (142, 165))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (142, 173))	('Helicobacter pylori', 'Var', (82, 101))	('Helicobacter Pylori', 'Species', '210', (0, 19))	('Gastroesophageal Reflux Disease', 'Disease', (24, 55))	('Gastroesophageal Reflux Disease', 'Disease', 'MESH:D005764', (24, 55))	('Gastroesophageal Reflux', 'Phenotype', 'HP:0002020', (24, 47))
588652	19250510	We found that the presence of antibodies against H. pylori had a strong inverse association with GERD symptom frequency and severity.	('GERD symptom', 'Disease', (97, 109))	('presence', 'Var', (18, 26))	('antibodies', 'Var', (30, 40))	('inverse', 'NegReg', (72, 79))	('H. pylori', 'Species', '210', (49, 58))
588660	19250510	The main finding of the current study, that the absence of H. pylori was associated with GERD symptoms, also differs from most randomized treatment trials of H. pylori, which indicate there is no increase in GERD symptoms after H. pylori eradication.	('H. pylori', 'Species', '210', (228, 237))	('H. pylori', 'Species', '210', (59, 68))	('H. pylori', 'Species', '210', (158, 167))	('associated', 'Reg', (73, 83))	('GERD symptoms', 'Disease', (89, 102))	('men', 'Species', '9606', (143, 146))	('absence', 'Var', (48, 55))
588673	19250510	Second, the absence of H. pylori may also be associated with increased appetite and a higher BMI, which is a separate risk factor for GERD, although adjustment for BMI did not influence the associations seen in the current study.	('H. pylori', 'Protein', (23, 32))	('men', 'Species', '9606', (155, 158))	('H. pylori', 'Species', '210', (23, 32))	('absence', 'Var', (12, 19))	('BMI', 'MPA', (93, 96))	('increased', 'PosReg', (61, 70))	('appetite', 'MPA', (71, 79))	('increased appetite', 'Phenotype', 'HP:0002591', (61, 79))
588687	19250510	These data are consistent with the hypothesis that the absence of Helicobacter pylori infection may be associated with GERD symptoms and GERD complications (such as esophagitis).	('esophagitis', 'Phenotype', 'HP:0100633', (165, 176))	('esophagitis', 'Disease', (165, 176))	('absence of Helicobacter pylori', 'Phenotype', 'HP:0005202', (55, 85))	('Helicobacter pylori infection', 'Disease', (66, 95))	('associated', 'Reg', (103, 113))	('esophagitis', 'Disease', 'MESH:D004941', (165, 176))	('Helicobacter pylori infection', 'Disease', 'MESH:D016481', (66, 95))	('GERD symptoms', 'Disease', (119, 132))	('absence', 'Var', (55, 62))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (66, 95))
588688	19250510	Future studies are needed to evaluate whether eradication of H. pylori infection in childhood or early adulthood is associated with an increase in the risk of subsequent GERD, and longer term studies of eradication in adults.	('H. pylori', 'Species', '210', (61, 70))	('H. pylori infection', 'Phenotype', 'HP:0005202', (61, 80))	('eradication', 'Var', (46, 57))	('infection', 'Disease', (71, 80))	('GERD', 'Disease', (170, 174))	('H. pylori', 'Gene', (61, 70))	('infection', 'Disease', 'MESH:D007239', (71, 80))
588700	32911639	The carcinogenesis of GI cancers is linked to several molecular abnormalities, which include and are not limited to epigenetic modifications such as DNA methylation, and inactivation of tumor suppressor genes, i.e., TP53, which results in irregular cell cycle replication processes, and activation of oncogenes and various telomerases.	('TP53', 'Gene', (216, 220))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('activation', 'PosReg', (287, 297))	('tumor', 'Disease', (186, 191))	('oncogenes', 'Protein', (301, 310))	('cell cycle replication processes', 'CPA', (249, 281))	('inactivation', 'Var', (170, 182))	('carcinogenesis of GI cancers', 'Disease', (4, 32))	('GI cancer', 'Phenotype', 'HP:0007378', (22, 31))	('linked', 'Reg', (36, 42))	('TP53', 'Gene', '7157', (216, 220))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('telomerases', 'Enzyme', (323, 334))	('carcinogenesis of GI cancers', 'Disease', 'MESH:D063646', (4, 32))
588717	32911639	The process of initiation and formation of neoplastic cells in the GI tract can be classified into four main mechanisms: (i) inherited transmission of mutations; (ii) exposure to different carcinogens; (iii) chronic inflammatory conditions/microbial dysbiosis; and (iv) sporadic mutations and epigenetic changes.	('neoplastic cells in the GI tract', 'Phenotype', 'HP:0007378', (43, 75))	('mutations', 'Var', (151, 160))	('GI', 'Gene', '2770', (67, 69))	('epigenetic changes', 'Var', (293, 311))	('dysbiosis', 'Disease', 'MESH:D064806', (250, 259))	('dysbiosis', 'Disease', (250, 259))
588726	32911639	Cancer-causing mutations can be initiated in three main classes of predisposition genes, oncogenes, tumor suppressor genes, and DNA repair genes, which are involved in establishing genetic stability.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('mutations', 'Var', (15, 24))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
588729	32911639	Exposure to carcinogens can initiate cancer development via somatic mutations that include point mutations, deletions, additions, and modified methylation of DNA.	('point mutations', 'Var', (91, 106))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('additions', 'Var', (119, 128))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('deletions', 'Var', (108, 117))	('modified methylation', 'Var', (134, 154))
588730	32911639	There are several cellular mechanisms to protect DNA from carcinogen-induced mutations and to identify and correct these mutations before they give rise to malignancy.	('malignancy', 'Disease', 'MESH:D009369', (156, 166))	('mutations', 'Var', (77, 86))	('mutations', 'Var', (121, 130))	('malignancy', 'Disease', (156, 166))
588737	32911639	Aflatoxin B1, upon its metabolism by cytochrome P450 in the liver, induces irreversible mutations in the p53 gene of hepatocytes.	('Aflatoxin B1', 'Chemical', 'MESH:D016604', (0, 12))	('mutations', 'Var', (88, 97))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('induces', 'Reg', (67, 74))
588746	32911639	The macrophages that dominate the chronic inflammatory microenvironment produce increased levels of ROS and RNI, which in turn interact with the DNA of proliferating epithelial cells and generate permanent genetic mutations leading to the malignant transformation.	('rat', 'Species', '10116', (191, 194))	('increased', 'PosReg', (80, 89))	('interact', 'Reg', (127, 135))	('rat', 'Species', '10116', (159, 162))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('ROS', 'Protein', (100, 103))	('increased levels of ROS', 'Phenotype', 'HP:0025464', (80, 103))	('malignant transformation', 'CPA', (239, 263))	('RNI', 'Chemical', '-', (108, 111))	('RNI', 'Protein', (108, 111))	('leading to', 'Reg', (224, 234))	('genetic mutations', 'Var', (206, 223))
588794	32911639	A recent study demonstrates that anthocyanins reduce carcinogen-induced DNA damage in cultured human lung epithelial cells, pepsin-induced DNA damage in human airway epithelial cells, and benzo-[a,1]-pyrene dihydrodiol (DBP-diol)-induced DNA adducts and DBP-diol and DBP-diolepoxide (DBPDE)-induced mutagenesis in lacI rat oral fibroblast cells and human oral leukoplakia cells.	('DBP', 'Gene', (254, 257))	('human', 'Species', '9606', (153, 158))	('DBP', 'Gene', (284, 287))	('anthocyanins', 'Chemical', 'MESH:D000872', (33, 45))	('mutagenesis', 'Var', (299, 310))	('rat', 'Species', '10116', (22, 25))	('DBP', 'Gene', (220, 223))	('DBP', 'Gene', '1628', (254, 257))	('DBP', 'Gene', '1628', (284, 287))	('human', 'Species', '9606', (95, 100))	('human', 'Species', '9606', (349, 354))	('DBP', 'Gene', (267, 270))	('benzo-[a,1]-pyrene dihydrodiol', 'Chemical', '-', (188, 218))	('DBP', 'Gene', '1628', (220, 223))	('oral leukoplakia', 'Phenotype', 'HP:0002745', (355, 371))	('DBP', 'Gene', '1628', (267, 270))	('DBPDE', 'Chemical', '-', (284, 289))	('leukoplakia', 'Disease', 'MESH:D007971', (360, 371))	('rat', 'Species', '10116', (319, 322))	('leukoplakia', 'Disease', (360, 371))
588812	32911639	Modulation of intracellular oxidative stress by scavenging the ROS/RNI is, therefore, beneficial in preventing cancer initiation and progression.	('Modulation', 'Var', (0, 10))	('cancer initiation', 'Disease', (111, 128))	('RNI', 'Chemical', '-', (67, 70))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('scavenging', 'Var', (48, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (28, 44))	('ROS/RNI', 'Protein', (63, 70))	('cancer initiation', 'Disease', 'MESH:D009369', (111, 128))
588828	32911639	Upon the segregation of DNA mutations, CDK inhibitors (CDKIs) such as p21 (cip1/waf1/cap20/sdi1/pic1), p27 (kip1), p57 (kip2) specific for CDK2 and CDK4 cyclin complexes and p16INK4, p15INK4B, p18INK4C and, p19INK4D specific for CDK4 and CDK6 cyclin complexes bind to and inactivate their respective CDK-cyclin complexes, thereby blocking cell cycle progression.	('cyclin', 'Gene', '891', (153, 159))	('cyclin', 'Gene', (153, 159))	('pic1', 'Gene', (96, 100))	('p21', 'Gene', '1026', (70, 73))	('CDK4', 'Gene', '1019', (229, 233))	('CDK2', 'Gene', '1017', (139, 143))	('waf1', 'Gene', '1026', (80, 84))	('cyclin', 'Gene', '891', (304, 310))	('cyclin', 'Gene', (304, 310))	('kip1', 'Gene', '1027', (108, 112))	('sdi1', 'Gene', '1026', (91, 95))	('p19INK4D', 'Gene', (207, 215))	('cip1', 'Gene', '1026', (75, 79))	('p27', 'Gene', '3429', (103, 106))	('p27', 'Gene', (103, 106))	('CDK2', 'Gene', (139, 143))	('cap20', 'Gene', '1026', (85, 90))	('kip1', 'Gene', (108, 112))	('cell cycle progression', 'CPA', (339, 361))	('p16INK4', 'Gene', (174, 181))	('cip1', 'Gene', (75, 79))	('CDK4', 'Gene', '1019', (148, 152))	('CDK6', 'Gene', '1021', (238, 242))	('p18INK4C', 'Gene', '1031', (193, 201))	('inactivate', 'NegReg', (272, 282))	('p57', 'Gene', '1028', (115, 118))	('p16INK4', 'Gene', '1029', (174, 181))	('p18INK4C', 'Gene', (193, 201))	('sdi1', 'Gene', (91, 95))	('CDK6', 'Gene', (238, 242))	('p15INK4B', 'Gene', (183, 191))	('p21', 'Gene', (70, 73))	('pic1', 'Gene', '7341', (96, 100))	('p19INK4D', 'Gene', '1032', (207, 215))	('kip2', 'Gene', '1028', (120, 124))	('mutations', 'Var', (28, 37))	('kip2', 'Gene', (120, 124))	('blocking', 'NegReg', (330, 338))	('CDK4', 'Gene', (229, 233))	('cyclin', 'Gene', '891', (243, 249))	('cyclin', 'Gene', (243, 249))	('p15INK4B', 'Gene', '1030', (183, 191))	('cap20', 'Gene', (85, 90))	('p57', 'Gene', (115, 118))	('CDK4', 'Gene', (148, 152))	('waf1', 'Gene', (80, 84))
588829	32911639	Hence, dysregulation of the cell cycle often leads to aberrant cell proliferation, which results in malignant cell growth during which loss of control of cell cycle checkpoints results in genetic instability.	('aberrant cell proliferation', 'CPA', (54, 81))	('genetic instability', 'MPA', (188, 207))	('leads to', 'Reg', (45, 53))	('malignant cell growth', 'CPA', (100, 121))	('loss', 'NegReg', (135, 139))	('rat', 'Species', '10116', (75, 78))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (54, 81))	('results in', 'Reg', (89, 99))	('dysregulation', 'Var', (7, 20))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (7, 38))
588840	32911639	Both peonidin-3-glucoside and C3G interfere with CDK-1,2 and cyclin B1 expression in AGS-gastric adenocarcinoma and SKHep-1, Huh-7 hepatocellular carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('expression', 'MPA', (71, 81))	('C3G', 'Var', (30, 33))	('peonidin-3-glucoside', 'Chemical', 'MESH:C480521', (5, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (131, 155))	('interfere', 'NegReg', (34, 43))	('CDK-1,2', 'Gene', '51755;983;1017', (49, 56))	('AGS-gastric adenocarcinoma and SKHep-1, Huh-7 hepatocellular carcinoma', 'Disease', 'MESH:D013274', (85, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cyclin B1', 'Gene', '891', (61, 70))	('cyclin B1', 'Gene', (61, 70))
588864	32911639	In contrast, C3G-rich blackberry extract suppressed camptothecin (CPT)- or doxorubicin (DOX)-induced stabilization of the covalent DNA-topoisomerase intermediate in HT-29 colon carcinoma cells.	('stabilization', 'MPA', (101, 114))	('C3G-rich', 'Var', (13, 21))	('CPT', 'Chemical', 'MESH:D002166', (66, 69))	('doxorubicin', 'Chemical', 'MESH:D004317', (75, 86))	('HT-29 colon carcinoma', 'Disease', 'MESH:D003110', (165, 186))	('DOX', 'Chemical', 'MESH:D004317', (88, 91))	('camptothecin', 'Chemical', 'MESH:D002166', (52, 64))	('suppressed', 'NegReg', (41, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('camptothecin', 'MPA', (52, 64))	('HT-29 colon carcinoma', 'Disease', (165, 186))	('extract', 'Chemical', '-', (33, 40))
588925	32911639	For example, cyanidin-3-rutinoside showed a prominent inhibitory effect on the growth of HepG2 cells that was not equaled by delphinidin and cyanidin.	('cyanidin', 'Chemical', 'MESH:C017154', (13, 21))	('delphinidin', 'Chemical', 'MESH:C017185', (125, 136))	('HepG2', 'CellLine', 'CVCL:0027', (89, 94))	('cyanidin-3-rutinoside', 'Var', (13, 34))	('growth', 'MPA', (79, 85))	('cyanidin-3-rutinoside', 'Chemical', 'MESH:C428983', (13, 34))	('inhibitory effect', 'NegReg', (54, 71))	('cyanidin', 'Chemical', 'MESH:C017154', (141, 149))
588941	32911639	However, a colon-available extract of raspberry anthocyanin, characterized by increasing amounts of polyphenols and polyphenol breakdown products but less anthocyanin than in the original, was potent in reducing H2O2-induced DNA damage in HT-29 cells and the proliferation of HT-115 CRC cells but did not affect the membrane integrity of Caco-2 cells.	('HT-115 CRC', 'CellLine', 'CVCL:2520', (276, 286))	('HT-29', 'CellLine', 'CVCL:0320', (239, 244))	('polyphenol', 'Chemical', 'MESH:D059808', (100, 110))	('Caco-2', 'CellLine', 'CVCL:0025', (338, 344))	('extract', 'Chemical', '-', (27, 34))	('reducing', 'NegReg', (203, 211))	('rat', 'Species', '10116', (266, 269))	('polyphenols', 'Chemical', 'MESH:D059808', (100, 111))	('H2O2-induced', 'Var', (212, 224))	('proliferation', 'CPA', (259, 272))	('H2O2', 'Chemical', 'MESH:D006861', (212, 216))	('anthocyanin', 'Gene', '10238', (155, 166))	('anthocyanin', 'Gene', '10238', (48, 59))	('polyphenol', 'Chemical', 'MESH:D059808', (116, 126))	('anthocyanin', 'Gene', (155, 166))	('CRC', 'Phenotype', 'HP:0003003', (283, 286))	('anthocyanin', 'Gene', (48, 59))
588954	32911639	Compared to delphinidin-3-O-glucoside, C3G is better able to activate the immune response in the tumor microenvironment by inhibiting the action of immune cell checkpoints.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('inhibiting', 'NegReg', (123, 133))	('C3G', 'Var', (39, 42))	('activate', 'PosReg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('immune response', 'CPA', (74, 89))	('tumor', 'Disease', (97, 102))	('delphinidin-3-O-glucoside', 'Chemical', '-', (12, 37))	('action of immune cell checkpoints', 'MPA', (138, 171))
588955	32911639	However, orally administered C3G did not protect against DNA damage in a vitamin E-deficient rat model, although C3G did protect against DNA damage in human colonocytes, decreasing DNA strand breakage by 39%.	('C3G', 'Var', (113, 116))	('DNA strand breakage', 'MPA', (181, 200))	('decreasing', 'NegReg', (170, 180))	('human', 'Species', '9606', (151, 156))	('vitamin E-deficient', 'Phenotype', 'HP:0100513', (73, 92))	('vitamin E', 'Chemical', 'MESH:D014810', (73, 82))	('rat', 'Species', '10116', (93, 96))
588981	32911639	Methylation of tumor suppressor genes causes their silencing and can induce mutational events, which plays a fundamental role in precipitating the development of a large and diverse number of human GI cancers.	('GI cancers', 'Disease', (198, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('human', 'Species', '9606', (192, 197))	('Methylation', 'Var', (0, 11))	('GI cancers', 'Disease', 'MESH:D009369', (198, 208))	('silencing', 'MPA', (51, 60))	('induce', 'Reg', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('GI cancer', 'Phenotype', 'HP:0007378', (198, 207))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutational events', 'MPA', (76, 93))
588987	32911639	However, on the other hand, DNA methylation, methyltransferase I protein expression and p16 promoter methylation were significantly reduced in 14 FAP patients who received black raspberry powder for nine months by oral administration (1787 mg/individual/day) and rectal insertion (595 mg/individual/day) of two suppositories.	('rat', 'Species', '10116', (227, 230))	('p16', 'Gene', (88, 91))	('rectal insertion', 'Phenotype', 'HP:0002035', (263, 279))	('FAP', 'Disease', (146, 149))	('reduced', 'NegReg', (132, 139))	('1787 mg/individual/day', 'Var', (235, 257))	('p16', 'Gene', '1029', (88, 91))	('expression', 'MPA', (73, 83))	('patients', 'Species', '9606', (150, 158))	('DNA methylation', 'MPA', (28, 43))	('FAP', 'Disease', 'MESH:C567782', (146, 149))	('black raspberry', 'Species', '75079', (172, 187))	('methyltransferase I', 'Enzyme', (45, 64))
589018	31504061	Loss-of-function mutations in the genes encoding SWI/SNF subunits have been reported in more than 20% of human cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('Loss-of-function', 'NegReg', (0, 16))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('SWI/SNF', 'Gene', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('human', 'Species', '9606', (105, 110))	('mutations', 'Var', (17, 26))
589029	31504061	Loss-of-function mutations in the genes encoding SWI/SNF subunits are reported in more than 20% of human cancers, and the critical tumor suppressive role of the SWI/SNF complex has been widely acknowledged.	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('SWI/SNF', 'Gene', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('tumor', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutations', 'Var', (17, 26))	('human', 'Species', '9606', (99, 104))
589032	31504061	These results suggested that not all of the genes encoding the subunits of the SWI/SNF complex have loss-of-function mutations in cancer.	('mutations', 'Var', (117, 126))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('loss-of-function', 'NegReg', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
589044	31504061	Moreover, to make the result more convincing, three additional gene expression datasets (GSE120235, GSE129437 and GSE79284) for BRD9 KD based on 4 different tumor cell lines (G401, MV4-11, HL-60, RN2) were also download, and the following analysis were also performed next.	('tumor', 'Disease', (157, 162))	('SE', 'Disease', 'None', (90, 92))	('KD', 'Disease', 'MESH:C537017', (133, 135))	('SE', 'Disease', 'None', (115, 117))	('SE', 'Disease', 'None', (101, 103))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('RN2', 'CellLine', 'CVCL:4293', (196, 199))	('HL-60', 'CellLine', 'CVCL:0002', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('BRD9', 'Var', (128, 132))	('G401', 'CellLine', 'CVCL:0270', (175, 179))
589051	31504061	The relationship between the mRNA expression level and copy number variation of ACTL6A or BRD9 was described by boxplots using TIMER (http://cistrome.dfci.harvard.edu/TIMER/).	('BRD9', 'Gene', (90, 94))	('ACTL6A', 'Gene', '86', (80, 86))	('copy number variation', 'Var', (55, 76))	('mRNA expression level', 'MPA', (29, 50))	('ACTL6A', 'Gene', (80, 86))
589058	31504061	As shown in Fig 2, SWI/SNF complex genes tended to have point mutations in some cancers, such as melanoma (26.97%), clear cell renal cell carcinoma (ccRCC) (26.77%) and stomach cancer (24.06%).	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (116, 147))	('stomach cancer', 'Disease', (169, 183))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('cancers', 'Disease', (80, 87))	('clear cell renal cell carcinoma', 'Disease', (116, 147))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (127, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('SWI/SNF complex genes', 'Gene', (19, 40))	('stomach cancer', 'Disease', 'MESH:D013274', (169, 183))	('stomach cancer', 'Phenotype', 'HP:0012126', (169, 183))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (116, 147))	('point mutations', 'Var', (56, 71))
589059	31504061	However, there are a variety of cancer types in which the genetic alterations of the SWI/SNF complex tended to have copy number variations, particularly amplifications, such as in lung squamous cell carcinoma (61.06%), ovarian cancer (58.71%), sarcoma (47.89%), esophageal cancer (40.32%), cervical cancer (35.48%), head and neck cancer (32.45%), breast cancer (32.13%), bladder cancer (33.41%), lung adenocarcinoma (31.39%), stomach cancer (29.70%), uterine cancer (26.28%), glioma (23.87%), liver cancer (23.08%) and prostate cancer (22.58%) (Fig 2A).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('stomach cancer', 'Disease', (426, 440))	('carcinoma', 'Phenotype', 'HP:0030731', (406, 415))	('copy number variations', 'Var', (116, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (519, 534))	('breast cancer', 'Phenotype', 'HP:0003002', (347, 360))	('prostate cancer', 'Phenotype', 'HP:0012125', (519, 534))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (396, 415))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('ovarian cancer', 'Disease', (219, 233))	('cancer', 'Disease', 'MESH:D009369', (354, 360))	('cancer', 'Disease', 'MESH:D009369', (434, 440))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('sarcoma', 'Disease', 'MESH:D012509', (244, 251))	('alterations', 'Var', (66, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('prostate cancer', 'Disease', (519, 534))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (396, 415))	('sarcoma', 'Disease', (244, 251))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('cancer', 'Disease', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (476, 482))	('ovarian cancer', 'Phenotype', 'HP:0100615', (219, 233))	('breast cancer', 'Disease', 'MESH:D001943', (347, 360))	('cancer', 'Disease', 'MESH:D009369', (528, 534))	('variations', 'Var', (128, 138))	('breast cancer', 'Disease', (347, 360))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('liver cancer', 'Disease', 'MESH:D006528', (493, 505))	('stomach cancer', 'Disease', 'MESH:D013274', (426, 440))	('stomach cancer', 'Phenotype', 'HP:0012126', (426, 440))	('cancer', 'Disease', (379, 385))	('cancer', 'Disease', (499, 505))	('cancer', 'Disease', (434, 440))	('cervical cancer', 'Disease', 'MESH:D002583', (290, 305))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('cervical cancer', 'Disease', (290, 305))	('cancer', 'Disease', (459, 465))	('glioma', 'Disease', (476, 482))	('uterine cancer', 'Phenotype', 'HP:0010784', (451, 465))	('esophageal cancer', 'Disease', 'MESH:D004938', (262, 279))	('bladder cancer', 'Disease', 'MESH:D001749', (371, 385))	('liver cancer', 'Phenotype', 'HP:0002896', (493, 505))	('cancer', 'Disease', (227, 233))	('glioma', 'Disease', 'MESH:D005910', (476, 482))	('bladder cancer', 'Disease', (371, 385))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', (330, 336))	('cancer', 'Disease', (354, 360))	('liver cancer', 'Disease', (493, 505))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (273, 279))	('head and neck cancer', 'Phenotype', 'HP:0012288', (316, 336))	('esophageal cancer', 'Disease', (262, 279))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('lung adenocarcinoma', 'Disease', (396, 415))	('ovarian cancer', 'Disease', 'MESH:D010051', (219, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (371, 385))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('cancer', 'Disease', (528, 534))	('neck cancer', 'Disease', 'MESH:D006258', (325, 336))	('neck cancer', 'Disease', (325, 336))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (180, 208))	('SWI/SNF', 'Gene', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('cancer', 'Disease', 'MESH:D009369', (499, 505))	('lung squamous cell carcinoma', 'Disease', (180, 208))
589060	31504061	These results suggested that the amplification of distinct genes was the main alteration type in most cancers, and the subunits of SWI/SNF complexes may play an essential oncogenic role in cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('play', 'Reg', (153, 157))	('amplification', 'Var', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('cancers', 'Disease', (189, 196))
589061	31504061	Different types of genetic alterations occurred more frequently in some subunits within the SWI/SNF complex in some cancers.	('occurred', 'Reg', (39, 47))	('genetic alterations', 'Var', (19, 38))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('SWI/SNF', 'Gene', (92, 99))
589068	31504061	These results demonstrated that the different mutations of each subunit played distinct roles in different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (107, 113))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (107, 113))
589069	31504061	In addition, the amplification of ACTL6A and BRD9 commonly occurred in multiple cancers and may play crucial roles in tumor formation.	('play', 'Reg', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('ACTL6A', 'Gene', '86', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('multiple cancers', 'Disease', 'MESH:D009369', (71, 87))	('roles', 'Reg', (109, 114))	('multiple cancers', 'Disease', (71, 87))	('tumor', 'Disease', (118, 123))	('ACTL6A', 'Gene', (34, 40))	('amplification', 'Var', (17, 30))	('occurred', 'Reg', (59, 67))	('BRD9', 'Gene', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
589070	31504061	To determine whether the increased copy number of ACTL6A and BRD9 led to an increase in their expression levels, we acquired two pan-cancer boxplots (Fig 3) regarding the difference of these two genes expression between normal and tumor tissues from Tumor IMmune Estimation Resource (Timer).	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('increase', 'PosReg', (76, 84))	('increased', 'PosReg', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('ACTL6A', 'Gene', (50, 56))	('expression levels', 'MPA', (94, 111))	('tumor', 'Disease', (231, 236))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Tumor', 'Phenotype', 'HP:0002664', (250, 255))	('BRD9', 'Gene', (61, 65))	('copy number', 'Var', (35, 46))	('ACTL6A', 'Gene', '86', (50, 56))
589074	31504061	However, according to the chi-square test, we still can not make a conclusion that the protein levels are increased with the amplification of the copy number of ACTL6A or BRD9 due to the limited sample size and qualitative data (p value > 0.05).	('amplification', 'Var', (125, 138))	('ACTL6A', 'Gene', '86', (161, 167))	('copy number', 'Var', (146, 157))	('ACTL6A', 'Gene', (161, 167))	('increased', 'PosReg', (106, 115))	('protein levels', 'MPA', (87, 101))	('BRD9', 'Gene', (171, 175))
589077	31504061	Regarding ACTL6A, we found that ACTL6A expression might significantly affect the survival time of patients with pancreatic cancer (HR, 1.88; 95% CI, 1.21 to 2.94), brain lower grade glioma (HR, 1.85; 95% CI, 1.13 to 3.01), lung adenocarcinoma (HR, 1.59; 95% CI, 1.04 to 2.43), and sarcoma (HR, 1.61; 95% CI, 1.06 to 2.46) (Fig 4A).	('affect', 'Reg', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('ACTL6A', 'Gene', (10, 16))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('ACTL6A', 'Gene', (32, 38))	('ACTL6A', 'Gene', '86', (10, 16))	('ACTL6A', 'Gene', '86', (32, 38))	('lung adenocarcinoma', 'Disease', (223, 242))	('patients', 'Species', '9606', (98, 106))	('sarcoma', 'Disease', 'MESH:D012509', (281, 288))	('glioma', 'Disease', (182, 188))	('sarcoma', 'Disease', (281, 288))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (223, 242))	('survival time', 'CPA', (81, 94))	('expression', 'Var', (39, 49))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (223, 242))	('pancreatic cancer', 'Disease', (112, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))
589079	31504061	To study how the cancer cells were affected by the genetic alteration of BRD9 or ACTL6A, we performed KEGG analysis and GSEA analysis.	('BRD9', 'Gene', (73, 77))	('ACTL6A', 'Gene', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('GSEA', 'Chemical', '-', (120, 124))	('genetic alteration', 'Var', (51, 69))	('ACTL6A', 'Gene', '86', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
589082	31504061	These results indicated that the amplification of both BRD9 and ACTL6A affect these essential biological pathways in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ACTL6A', 'Gene', '86', (64, 70))	('BRD9', 'Gene', (55, 59))	('human', 'Species', '9606', (117, 122))	('amplification', 'Var', (33, 46))	('essential biological pathways', 'Pathway', (84, 113))	('affect', 'Reg', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('ACTL6A', 'Gene', (64, 70))	('cancers', 'Disease', (123, 130))
589089	31504061	Moreover, the results of KEGG analyses for additional 3 datasets for BRD9 knockdown were associated to oxidoreductase activity in hl60 cell line, ribosome biogenesis in RN2 cell line, and also related to the translation in G401 cell line.	('BRD9', 'Gene', (69, 73))	('associated', 'Reg', (89, 99))	('RN2', 'CellLine', 'CVCL:4293', (169, 172))	('ribosome biogenesis', 'MPA', (146, 165))	('oxidoreductase activity', 'MPA', (103, 126))	('knockdown', 'Var', (74, 83))	('G401', 'CellLine', 'CVCL:0270', (223, 227))
589090	31504061	Within the 3 cancer types (ovarian cancer, esophageal cancer and lung adenocarcinoma) that were commonly mutated in BRD9 and ACTL6A, a significant comutation relationship (p<0.001, log odds ratio = 1.051) was also shown in BRD9 and ACTL6A (Fig 7), which suggested that they may drive the oncogenic process together by affecting the same pathways.	('ACTL6A', 'Gene', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('oncogenic process', 'CPA', (288, 305))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('ovarian cancer', 'Disease', 'MESH:D010051', (27, 41))	('ACTL6A', 'Gene', '86', (232, 238))	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('drive', 'Reg', (278, 283))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('esophageal cancer', 'Disease', (43, 60))	('ACTL6A', 'Gene', (125, 131))	('ovarian cancer', 'Disease', (27, 41))	('lung adenocarcinoma', 'Disease', (65, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (27, 41))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', (13, 19))	('ACTL6A', 'Gene', '86', (125, 131))	('mutated', 'Var', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('affecting', 'Reg', (318, 327))	('BRD9', 'Gene', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('cancer', 'Disease', (35, 41))
589092	31504061	This result suggests that the amplification of ACTL6A and TP63 could be a common oncogenic mechanism across human cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('ACTL6A', 'Gene', (47, 53))	('amplification', 'Var', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (108, 113))	('TP63', 'Gene', '8626', (58, 62))	('ACTL6A', 'Gene', '86', (47, 53))	('TP63', 'Gene', (58, 62))
589105	31504061	These results suggest that the amplification of BRD9 and ACTL6A could be a universal mechanism in human cancer and may play critical roles in tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('BRD9', 'Gene', (48, 52))	('roles', 'Reg', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ACTL6A', 'Gene', (57, 63))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('play', 'Reg', (119, 123))	('human', 'Species', '9606', (98, 103))	('ACTL6A', 'Gene', '86', (57, 63))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('amplification', 'Var', (31, 44))
589111	31504061	Some studies have illustrated that overexpressed ACTL6A promotes epithelial-mesenchymal transition (EMT) and invasion in multiple cancers, such as osteosarcoma, hepatocellular carcinoma, and glioma.	('hepatocellular carcinoma', 'Disease', (161, 185))	('overexpressed', 'Var', (35, 48))	('multiple cancers', 'Disease', 'MESH:D009369', (121, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('ACTL6A', 'Gene', (49, 55))	('osteosarcoma', 'Disease', (147, 159))	('epithelial-mesenchymal transition', 'CPA', (65, 98))	('osteosarcoma', 'Disease', 'MESH:D012516', (147, 159))	('ACTL6A', 'Gene', '86', (49, 55))	('promotes', 'PosReg', (56, 64))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (161, 185))	('multiple cancers', 'Disease', (121, 137))	('glioma', 'Disease', (191, 197))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (161, 185))	('invasion', 'CPA', (109, 117))	('osteosarcoma', 'Phenotype', 'HP:0002669', (147, 159))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
589116	31504061	Thus, we hypothesized that the aberrant overexpression of ACTL6A might reactivate some signaling pathways that occur during embryonic development and drive the oncogenic process.	('aberrant', 'Var', (31, 39))	('drive', 'PosReg', (150, 155))	('overexpression', 'PosReg', (40, 54))	('reactivate', 'Reg', (71, 81))	('oncogenic process', 'CPA', (160, 177))	('ACTL6A', 'Gene', '86', (58, 64))	('signaling pathways', 'Pathway', (87, 105))	('ACTL6A', 'Gene', (58, 64))
589122	31504061	The amplification of BRD9 may play a significant role in cancer.	('role', 'Reg', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('play', 'Reg', (30, 34))	('amplification', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BRD9', 'Gene', (21, 25))
589135	31504061	Increasing small-molecule inhibitors of bromodomain-containing protein, such as GSK2801 and BI9564, have been discovered in the past decade.	('BI9564', 'Var', (92, 98))	('BI9564', 'Chemical', 'MESH:C000619421', (92, 98))	('GSK2801', 'Gene', (80, 87))	('bromodomain-containing protein', 'Protein', (40, 70))
589138	31504061	Another study demonstrated that the inhibition of BRD9 acted in a synthetic lethal manner in cBAF-deficient cancer, and the inhibitor of BRD9 effectively decreased the proliferation of cancer cells in synovial sarcoma and malignant rhabdoid tumors.	('decreased', 'NegReg', (154, 163))	('proliferation', 'CPA', (168, 181))	('synovial sarcoma', 'Disease', 'MESH:D013584', (201, 217))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (201, 217))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('BRD9', 'Gene', (50, 54))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (222, 247))	('BRD9', 'Gene', (137, 141))	('cBAF-deficient cancer', 'Disease', (93, 114))	('inhibition', 'NegReg', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('inhibitor', 'Var', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (108, 114))	('malignant rhabdoid tumors', 'Disease', (222, 247))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('cBAF-deficient cancer', 'Disease', 'MESH:D009369', (93, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('synovial sarcoma', 'Disease', (201, 217))
589144	30764514	We previously reported that moscatilin can induce apoptosis and mitotic catastrophe in esophageal cancer cells, accompanied by upregulation of polo-like kinase 1 (Plk1) expression.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('polo-like kinase 1', 'Gene', '5347', (143, 161))	('esophageal cancer', 'Disease', (87, 104))	('Plk1', 'Gene', (163, 167))	('mitotic catastrophe', 'CPA', (64, 83))	('moscatilin', 'Chemical', 'MESH:C071845', (28, 38))	('polo-like kinase 1', 'Gene', (143, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('upregulation', 'PosReg', (127, 139))	('expression', 'MPA', (169, 179))	('induce', 'PosReg', (43, 49))	('moscatilin', 'Var', (28, 38))	('Plk1', 'Gene', '5347', (163, 167))	('apoptosis', 'CPA', (50, 59))
589208	30764514	Phospho-Plk1 expression in CE81T/VGH xenografts was demonstrated immunohistochemically staining by positive distribution on both nuclear and cytoplasm (Figure 4).	('CE81T/VGH', 'Var', (27, 36))	('Plk1', 'Gene', (8, 12))	('Plk1', 'Gene', '5347', (8, 12))
589222	30764514	In our previous study, moscatilin increased the percentage of phospho-histone H3-positive cells; we concluded that moscatilin induced mitotic arrest.	('mitotic arrest', 'Disease', (134, 148))	('mitotic arrest', 'Disease', 'MESH:D006323', (134, 148))	('moscatilin', 'Chemical', 'MESH:C071845', (23, 33))	('moscatilin', 'Var', (115, 125))	('moscatilin', 'Chemical', 'MESH:C071845', (115, 125))
589226	30764514	Mitotic arrest stemming from perturbation of the mitotic apparatus results in mitotic catastrophe.	('Mitotic arrest', 'Disease', (0, 14))	('results in', 'Reg', (67, 77))	('mitotic catastrophe', 'CPA', (78, 97))	('perturbation', 'Var', (29, 41))	('Mitotic arrest', 'Disease', 'MESH:D006323', (0, 14))
589236	29475139	Nab-paclitaxel significantly inhibited in-vitro cell proliferation with higher in-vivo antitumour efficacy and survival benefit compared to paclitaxel or carboplatin treatments both in mono- and combination therapies.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('inhibited', 'NegReg', (29, 38))	('carboplatin', 'Chemical', 'MESH:D016190', (154, 165))	('in-vitro cell proliferation', 'CPA', (39, 66))	('Nab-paclitaxel', 'Var', (0, 14))	('survival benefit', 'CPA', (111, 127))	('antitumour efficacy', 'CPA', (87, 106))	('higher', 'PosReg', (72, 78))	('paclitaxel', 'Chemical', 'MESH:D017239', (140, 150))	('Nab', 'Chemical', '-', (0, 3))
589238	29475139	This study demonstrates that nab-paclitaxel had stronger antiproliferative and antitumor activity in experimental EAC than the current standard chemotherapeutic agents which supports the rationale for its clinical use in EAC.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('EAC', 'Disease', (114, 117))	('nab-paclitaxel', 'Var', (29, 43))	('tumor', 'Disease', (83, 88))	('nab', 'Chemical', '-', (29, 32))	('stronger', 'PosReg', (48, 56))	('paclitaxel', 'Chemical', 'MESH:D017239', (33, 43))	('EAC', 'Phenotype', 'HP:0011459', (221, 224))	('antiproliferative', 'CPA', (57, 74))	('EAC', 'Phenotype', 'HP:0011459', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
589276	29475139	Cleaved caspase-3 staining was performed with an anti-cleaved caspase-3 primary antibody (1:1,000 dilution; catalog 9661; Cell Signaling Technology) that specifically recognizes the large fragment (17 kDa) of the active protein but not full-length caspase-3.	('17 kDa', 'Var', (198, 204))	('caspase-3', 'Gene', '836', (248, 257))	('caspase-3', 'Gene', '836', (62, 71))	('caspase-3', 'Gene', (8, 17))	('caspase-3', 'Gene', '836', (8, 17))	('caspase-3', 'Gene', (248, 257))	('caspase-3', 'Gene', (62, 71))
589297	29475139	Both in OE33 (Figure 2A) and OE19 (Figure 2B) EAC cell lines microtubule destabilizing protein stathmin was strongly expressed, whereas phosphorylation of stathmin at Ser68, which is essential for function of the stathmin, was weakly expressed.	('stathmin', 'Gene', '3925', (155, 163))	('microtubule destabilizing protein', 'MPA', (61, 94))	('stathmin', 'Gene', (155, 163))	('Ser68', 'Chemical', '-', (167, 172))	('stathmin', 'Gene', (95, 103))	('stathmin', 'Gene', '3925', (95, 103))	('OE19', 'Var', (29, 33))	('stathmin', 'Gene', (213, 221))	('EAC', 'Phenotype', 'HP:0011459', (46, 49))	('stathmin', 'Gene', '3925', (213, 221))
589298	29475139	In addition, phosphorylation of stathmin (p-Stathmin) was significantly enhanced after nab-paclitaxel (NPT) and paclitaxel treatments.	('phosphorylation', 'MPA', (13, 28))	('stathmin', 'Gene', (32, 40))	('stathmin', 'Gene', '3925', (32, 40))	('Stathmin', 'Gene', '3925', (44, 52))	('enhanced', 'PosReg', (72, 80))	('paclitaxel', 'Chemical', 'MESH:D017239', (112, 122))	('Stathmin', 'Gene', (44, 52))	('paclitaxel', 'Chemical', 'MESH:D017239', (91, 101))	('PT', 'Chemical', 'MESH:D017239', (104, 106))	('nab-paclitaxel', 'Var', (87, 101))	('nab', 'Chemical', '-', (87, 90))
589299	29475139	Interestingly, we observed higher expression of p-Stathmin in nab-paclitaxel treatment compared to that of paclitaxel treatment in both cell lines.	('paclitaxel', 'Chemical', 'MESH:D017239', (107, 117))	('paclitaxel', 'Chemical', 'MESH:D017239', (66, 76))	('expression', 'MPA', (34, 44))	('Stathmin', 'Gene', '3925', (50, 58))	('nab', 'Chemical', '-', (62, 65))	('Stathmin', 'Gene', (50, 58))	('higher', 'PosReg', (27, 33))	('nab-paclitaxel treatment', 'Var', (62, 86))
589309	29475139	Mean tumor weight was significantly decreased by NPT treatment compared to control (0.25598 g vs. 0.51198 g, P = 0.0054) (Figure 3D).	('PT', 'Chemical', 'MESH:D017239', (50, 52))	('treatment', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('NPT', 'Gene', (49, 52))	('tumor', 'Disease', (5, 10))	('decreased', 'NegReg', (36, 45))
589310	29475139	In addition, mean tumor weight was significantly lower by nab-paclitaxel compared to paclitaxel both in monotherapy (NPT vs. PT, 0.25598 g vs. 0.37894 g, P = 0.003) and in combination therapy (NPT+CP vs. PT+CP, 0.217 vs. 0.3444, P = 0.0025) (Figure 3D).	('PT', 'Chemical', 'MESH:D017239', (194, 196))	('tumor', 'Disease', (18, 23))	('lower', 'NegReg', (49, 54))	('nab', 'Chemical', '-', (58, 61))	('PT', 'Chemical', 'MESH:D017239', (125, 127))	('PT', 'Chemical', 'MESH:D017239', (204, 206))	('nab-paclitaxel', 'Var', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (85, 95))	('PT', 'Chemical', 'MESH:D017239', (118, 120))	('paclitaxel', 'Chemical', 'MESH:D017239', (62, 72))
589312	29475139	Expression of phospho stathmin (P-Stathmin) with cleaved caspase-3 and PARP in OE19 xenograft tumor lysates were significantly increased after in vivo treatment with nab-paclitaxel (NPT) both in mono- and combination therapies as determined by western blot analysis (Figure 4).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Stathmin', 'Gene', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Expression', 'MPA', (0, 10))	('caspase-3', 'Gene', (57, 66))	('tumor', 'Disease', (94, 99))	('stathmin', 'Gene', (22, 30))	('phospho', 'Var', (14, 21))	('paclitaxel', 'Chemical', 'MESH:D017239', (170, 180))	('PARP', 'Gene', '142', (71, 75))	('stathmin', 'Gene', '3925', (22, 30))	('caspase-3', 'Gene', '836', (57, 66))	('PT', 'Chemical', 'MESH:D017239', (183, 185))	('Stathmin', 'Gene', '3925', (34, 42))	('increased', 'PosReg', (127, 136))	('PARP', 'Gene', (71, 75))	('nab', 'Chemical', '-', (166, 169))
589319	29475139	These results indicated that nab-paclitaxel had stronger in vivo antiproliferative and apoptotic effects compared to paclitaxel both as single agent and in combination with carboplatin.	('antiproliferative', 'CPA', (65, 82))	('paclitaxel', 'Chemical', 'MESH:D017239', (117, 127))	('nab-paclitaxel', 'Var', (29, 43))	('nab', 'Chemical', '-', (29, 32))	('apoptotic effects', 'CPA', (87, 104))	('stronger', 'PosReg', (48, 56))	('paclitaxel', 'Chemical', 'MESH:D017239', (33, 43))	('carboplatin', 'Chemical', 'MESH:D016190', (173, 184))
589320	29475139	We evaluated the impact of drug treatments on the survival of mice harboring OE19 and OE33 peritoneal disseminated xenograft tumors as described earlier by us.	('OE19', 'Var', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('xenograft tumors', 'Disease', 'MESH:D009369', (115, 131))	('mice', 'Species', '10090', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('xenograft tumors', 'Disease', (115, 131))	('OE33', 'Var', (86, 90))
589334	29475139	This present study clearly demonstrates for the first time that nab-paclitaxel had stronger antiproliferative and antitumor activity in experimental EAC both in vitro and in vivo as measured by antiproliferative effects, apoptosis, localized antitumor responses and animal survival benefits than the current standard chemotherapeutic agents paclitaxel and carboplatin.	('animal survival benefits', 'CPA', (266, 290))	('antiproliferative effects', 'CPA', (194, 219))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('paclitaxel', 'Chemical', 'MESH:D017239', (341, 351))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', (246, 251))	('carboplatin', 'Chemical', 'MESH:D016190', (356, 367))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('nab', 'Chemical', '-', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('nab-paclitaxel', 'Var', (64, 78))	('tumor', 'Disease', (118, 123))	('stronger', 'PosReg', (83, 91))	('antiproliferative', 'CPA', (92, 109))	('EAC', 'Phenotype', 'HP:0011459', (149, 152))	('apoptosis', 'CPA', (221, 230))	('paclitaxel', 'Chemical', 'MESH:D017239', (68, 78))	('EAC', 'Disease', (149, 152))
589335	29475139	WST-1 in vitro colorimetric cell proliferation assay revealed that single agent treatment of nab-paclitaxel is more effective in inhibiting both OE19 and OE33 human EAC cancer cell proliferation than PT.	('nab-paclitaxel', 'Var', (93, 107))	('cancer', 'Disease', (169, 175))	('inhibiting', 'NegReg', (129, 139))	('human', 'Species', '9606', (159, 164))	('nab', 'Chemical', '-', (93, 96))	('paclitaxel', 'Chemical', 'MESH:D017239', (97, 107))	('OE33', 'Var', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('EAC', 'Phenotype', 'HP:0011459', (165, 168))	('OE19', 'Var', (145, 149))	('PT', 'Chemical', 'MESH:D017239', (200, 202))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
589337	29475139	In addition, nab paclitaxel combination with CP showed stronger inhibition of cell proliferation compared to that of PT combination with CP.	('nab', 'Var', (13, 16))	('nab', 'Chemical', '-', (13, 16))	('PT', 'Chemical', 'MESH:D017239', (117, 119))	('inhibition', 'NegReg', (64, 74))	('paclitaxel', 'Chemical', 'MESH:D017239', (17, 27))	('combination', 'Interaction', (28, 39))	('cell proliferation', 'CPA', (78, 96))
589338	29475139	High stathmin expression has been associated with human malignancies such as human breast cancer, non-small cell lung cancer, human hepatoma and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (145, 159))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('non-small cell lung cancer', 'Disease', (98, 124))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('human', 'Species', '9606', (50, 55))	('High', 'Var', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('hepatoma', 'Disease', (132, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (145, 159))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('malignancies', 'Disease', (56, 68))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (98, 124))	('human', 'Species', '9606', (126, 131))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', (83, 96))	('gastric cancer', 'Disease', (145, 159))	('human', 'Species', '9606', (77, 82))	('associated', 'Reg', (34, 44))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (98, 124))	('hepatoma', 'Disease', 'MESH:D006528', (132, 140))	('stathmin', 'Gene', '3925', (5, 13))	('stathmin', 'Gene', (5, 13))	('expression', 'MPA', (14, 24))
589339	29475139	Stathmin contributes to poor prognosis, cancer progression and resistance to taxanes in patients and phosphorylation of Stathmin inactivates the protein function.	('Stathmin', 'Gene', (0, 8))	('phosphorylation', 'Var', (101, 116))	('protein', 'Protein', (145, 152))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('resistance', 'CPA', (63, 73))	('cancer', 'Disease', (40, 46))	('taxanes', 'Chemical', 'MESH:D043823', (77, 84))	('Stathmin', 'Gene', '3925', (120, 128))	('inactivates', 'NegReg', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Stathmin', 'Gene', '3925', (0, 8))	('Stathmin', 'Gene', (120, 128))	('poor prognosis', 'CPA', (24, 38))
589343	29475139	Our results showed that nab-paclitaxel as a single agent significantly reduced primary tumor burden compared to that of control, PT and CP.	('PT', 'Chemical', 'MESH:D017239', (129, 131))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('reduced', 'NegReg', (71, 78))	('nab-paclitaxel', 'Var', (24, 38))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('nab', 'Chemical', '-', (24, 27))	('paclitaxel', 'Chemical', 'MESH:D017239', (28, 38))
589346	29475139	NPT compared to PT monotherapy significantly reduced the number of proliferating carcinoma cells as evidenced by reduced numbers of carcinoma cells expressing Ki-67, a nuclear protein expressed in proliferating cells; and also significantly enhanced apoptosis of carcinoma cells as evidenced by an increase in the number of cleaved caspase 3, an apoptotic marker, expressing carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (375, 384))	('enhanced', 'PosReg', (241, 249))	('carcinoma', 'Disease', (375, 384))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinoma', 'Disease', (263, 272))	('reduced', 'NegReg', (113, 120))	('cleaved', 'MPA', (324, 331))	('carcinoma', 'Disease', (81, 90))	('PT', 'Chemical', 'MESH:D017239', (16, 18))	('PT', 'Chemical', 'MESH:D017239', (1, 3))	('carcinoma', 'Disease', 'MESH:D002277', (132, 141))	('Ki-67', 'Gene', (159, 164))	('caspase 3', 'Gene', (332, 341))	('caspase 3', 'Gene', '836', (332, 341))	('increase', 'PosReg', (298, 306))	('carcinoma', 'Disease', 'MESH:D002277', (263, 272))	('carcinoma', 'Disease', 'MESH:D002277', (375, 384))	('apoptosis', 'CPA', (250, 259))	('NPT', 'Var', (0, 3))	('carcinoma', 'Disease', 'MESH:D002277', (81, 90))	('reduced', 'NegReg', (45, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('carcinoma', 'Disease', (132, 141))	('Ki-67', 'Gene', '17345', (159, 164))
589354	29475139	Thus a simple, least invasive, patient-like EAC survival model with similar metastatic behavior has been used and our results showed that nab-paclitaxel significantly enhanced mouse survival compared to that of PT, CP or control.	('PT', 'Chemical', 'MESH:D017239', (211, 213))	('nab-paclitaxel', 'Var', (138, 152))	('enhanced', 'PosReg', (167, 175))	('EAC', 'Phenotype', 'HP:0011459', (44, 47))	('mouse survival', 'CPA', (176, 190))	('paclitaxel', 'Chemical', 'MESH:D017239', (142, 152))	('mouse', 'Species', '10090', (176, 181))	('patient', 'Species', '9606', (31, 38))	('nab', 'Chemical', '-', (138, 141))
589357	29475139	In conclusion, our results convincingly demonstrated that nab-paclitaxel both as mono- and combination therapies had stronger antitumor activity resulting in enhanced animal survival in experimental EAC than the current standard chemotherapeutic agents PT and CP, and appeared to be the superior taxane compared to PT.	('PT', 'Chemical', 'MESH:D017239', (253, 255))	('PT', 'Chemical', 'MESH:D017239', (315, 317))	('enhanced', 'PosReg', (158, 166))	('taxane', 'Chemical', 'MESH:C080625', (296, 302))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('EAC', 'Phenotype', 'HP:0011459', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('nab', 'Chemical', '-', (58, 61))	('stronger', 'PosReg', (117, 125))	('nab-paclitaxel', 'Var', (58, 72))	('tumor', 'Disease', (130, 135))	('animal survival', 'CPA', (167, 182))	('paclitaxel', 'Chemical', 'MESH:D017239', (62, 72))
589359	29046751	Case series of multiple primary cancers in single individuals: diagnostic and therapeutic dilemmas Background and Objectives: Cancer recurrence represents treatment failure; the development of new primary tumors is suggestive of persistent exposure to etiological risk factors or genetic predisposition due to mutations in multiple cell lines.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('mutations', 'Var', (310, 319))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('cancer', 'Disease', (32, 38))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', (205, 211))
589361	29046751	The second case is a 72-years-old Caucasian male presenting a rare dilemma of genetic mutation leading to multiple primary gastrointestinal cancers in a single individual.	('genetic mutation', 'Var', (78, 94))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (123, 147))	('leading to', 'Reg', (95, 105))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('gastrointestinal cancers', 'Disease', (123, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
589365	29046751	Cancer recurrence represents treatment failure; the development of new primary tumors is suggestive of persistent exposure to etiological risk factors or genetic predisposition due to mutations in multiple cell lines.	('tumor', 'Disease', (79, 84))	('mutations', 'Var', (184, 193))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
589377	29046751	Molecular analysis was negative for EGFR, RAS, BRAF, ALK, MET, RET or ERBB2 mutations.	('MET', 'Disease', (58, 61))	('mutations', 'Var', (76, 85))	('ALK', 'Gene', (53, 56))	('RET', 'Gene', '5979', (63, 66))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('EGFR', 'Gene', '1956', (36, 40))	('ALK', 'Gene', '238', (53, 56))	('RET', 'Gene', (63, 66))	('ERBB2', 'Gene', '2064', (70, 75))	('EGFR', 'Gene', (36, 40))	('ERBB2', 'Gene', (70, 75))	('RAS', 'Disease', (42, 45))
589382	29046751	He underwent genetic mutation testing and profiling which was negative for the common known mutations except for CDKN1B missense mutation that could explain multiple small bowel neuroendocrine tumors.	('missense mutation', 'Var', (120, 137))	('bowel neuroendocrine tumors', 'Disease', 'MESH:D018358', (172, 199))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (178, 199))	('bowel neuroendocrine tumors', 'Disease', (172, 199))	('explain', 'Reg', (149, 156))	('CDKN1B', 'Gene', '1027', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('CDKN1B', 'Gene', (113, 119))	('multiple small bowel neuroendocrine tumors', 'Phenotype', 'HP:0004797', (157, 199))
589391	29046751	Familial Adenomatous Polyposis is another inherited disorder with 100% penetrance that happens due to a mutation in the Adenomatous Polyposis Coli (APC) gene.	('Adenomatous Polyposis Coli', 'Disease', 'MESH:D011125', (120, 146))	('APC', 'Disease', (148, 151))	('due to', 'Reg', (95, 101))	('Adenomatous Polyposis', 'Phenotype', 'HP:0005227', (9, 30))	('Adenomatous Polyposis', 'Phenotype', 'HP:0005227', (120, 141))	('Adenomatous Polyposis Coli', 'Phenotype', 'HP:0005227', (120, 146))	('Familial Adenomatous Polyposis', 'Disease', (0, 30))	('mutation', 'Var', (104, 112))	('APC', 'Phenotype', 'HP:0005227', (148, 151))	('APC', 'Disease', 'MESH:D011125', (148, 151))	('Familial Adenomatous Polyposis', 'Disease', 'MESH:D011125', (0, 30))	('Adenomatous Polyposis Coli', 'Disease', (120, 146))
589392	29046751	Peutz-Jeghers syndrome is a syndrome due to a mutation of the STK-11 gene that leads to colorectal, gastric, pancreatic, small intestinal, breast and ovarian cancers.	('a syndrome', 'Disease', (26, 36))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('ovarian cancers', 'Phenotype', 'HP:0100615', (150, 165))	('colorectal', 'Disease', (88, 98))	('leads to', 'Reg', (79, 87))	('small intestinal', 'Disease', (121, 137))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('gastric', 'Disease', (100, 107))	('pancreatic', 'Disease', 'MESH:D010195', (109, 119))	('STK-11', 'Gene', (62, 68))	('a syndrome', 'Disease', 'MESH:D013577', (26, 36))	('STK-11', 'Gene', '6794', (62, 68))	('pancreatic', 'Disease', (109, 119))	('Peutz-Jeghers syndrome', 'Disease', (0, 22))	('mutation', 'Var', (46, 54))	('due to', 'Reg', (37, 43))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (139, 165))
589393	29046751	Hereditary diffuse gastric cancer syndrome is an uncommon disorder that occurs due to CDH-1 mutation and leads to invasive gastric and lobular breast cancer.	('lobular breast cancer', 'Disease', 'MESH:D013274', (135, 156))	('gastric cancer', 'Disease', (19, 33))	('CDH-1', 'Gene', '999', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutation', 'Var', (92, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (19, 33))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (135, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('CDH-1', 'Gene', (86, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('invasive gastric', 'Disease', (114, 130))	('due', 'Reg', (79, 82))	('leads to', 'Reg', (105, 113))	('lobular breast cancer', 'Disease', (135, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
589405	27974706	TM4SF1 could stimulate the self-renewal ability and carcinogenicity of esophageal cancer stem-like cells, and promote cell invasion and migration.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('carcinogenicity of esophageal cancer', 'Disease', (52, 88))	('carcinogenicity of esophageal cancer', 'Disease', 'MESH:D004938', (52, 88))	('stimulate', 'PosReg', (13, 22))	('cell invasion', 'CPA', (118, 131))	('promote', 'PosReg', (110, 117))	('TM4SF1', 'Var', (0, 6))	('self-renewal ability', 'CPA', (27, 47))
589419	27974706	Besides, TM4SF1 was suggested as a possible marker of stem-like cells in thyroid cancer cells and serve as a surface protein marker which singly identifies mesenchymal stem cells from diverse cell sources, in particular, fibroblast-rich connective tissues.	('thyroid cancer', 'Phenotype', 'HP:0002890', (73, 87))	('thyroid cancer', 'Disease', (73, 87))	('thyroid cancer', 'Disease', 'MESH:D013964', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TM4SF1', 'Var', (9, 15))
589432	27974706	To explore the function of TM4SF1, we over expressed TM4SF1 by transfecting pENTER-TM4SF1 vector and silenced TM4SF1 with three specific small interference RNAs (siRNAs) in KYSE150 and KYSE180 cells.	('SE', 'Disease', 'None', (187, 189))	('TM4SF1', 'Gene', (110, 116))	('TM4SF1', 'Gene', (53, 59))	('KYSE180', 'CellLine', 'CVCL:1349', (185, 192))	('silenced', 'Var', (101, 109))	('over expressed', 'PosReg', (38, 52))	('SE', 'Disease', 'None', (175, 177))
589442	27974706	Given the fact that we previously showed cancer stem-like cells of ESCC cells were more resistant to anticancer drugs, our results indicated that TM4SF1 could increase the resistant ability of esophageal cancer stem-like cells.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('resistant ability', 'CPA', (172, 189))	('TM4SF1', 'Var', (146, 152))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('esophageal cancer', 'Disease', (193, 210))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('increase', 'PosReg', (159, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))
589445	27974706	We found that the expression of MMP-2, MMP-9 and VEGF was altered with the expression of TM4SF1 (Figure 2B).	('VEGF', 'Gene', (49, 53))	('MMP-2', 'Gene', '4313', (32, 37))	('expression', 'Var', (75, 85))	('VEGF', 'Gene', '7422', (49, 53))	('MMP-9', 'Gene', '4318', (39, 44))	('expression', 'MPA', (18, 28))	('MMP-9', 'Gene', (39, 44))	('MMP-2', 'Gene', (32, 37))	('TM4SF1', 'Gene', (89, 95))	('altered', 'Reg', (58, 65))
589448	27974706	Four weeks after injection, weight measurement showed that tumor xenografts from lenti-TM4SF1 cells were much heavier than those from KYSE150 and lenti-NC cells.	('tumor', 'Disease', (59, 64))	('heavier', 'PosReg', (110, 117))	('lenti-TM4SF1', 'Var', (81, 93))	('SE', 'Disease', 'None', (136, 138))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
589449	27974706	Similarly, tumor xenografts from lenti-shRNA1, lenti-shRNA2 cells were much lighter than those from KYSE150 and lenti-shNC cells (Figure 3C and 3D).	('lenti-shRNA1', 'Var', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('lenti-shRNA2', 'Var', (47, 59))	('SE', 'Disease', 'None', (102, 104))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('lighter', 'NegReg', (76, 83))
589462	27974706	As these cells did not differ in their growth rate (Supplementary Figure 3), lenti-miR-141 cells were less resistant to cisplatin suggested that overexpression of miR-141 in ESCC cells affected their chemotherapeutic drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (217, 232))	('chemotherapeutic drug resistance', 'MPA', (200, 232))	('affected', 'Reg', (185, 193))	('miR-141', 'Var', (163, 170))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
589464	27974706	To determine specifically whether miR-141 represses proliferative potential of ESCC cells, we tested the tumorigenic ability of these cells both in vitro and in vivo.	('tested', 'Reg', (94, 100))	('represses', 'NegReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('miR-141', 'Var', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('proliferative potential', 'CPA', (52, 75))	('tumor', 'Disease', (105, 110))
589470	27974706	These results indicated that TM4SF1 functioned as a stem renewal factor to be a key regulator factor in the maintenance of cancer stem-like cells and miR-141 regulated the esophageal cancer stem-like cells by suppressing TM4SF1.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('miR-141', 'Var', (150, 157))	('cancer', 'Disease', (183, 189))	('esophageal cancer', 'Disease', (172, 189))	('suppressing', 'NegReg', (209, 220))	('TM4SF1', 'Gene', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (172, 189))	('regulated', 'Reg', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
589483	27974706	TM4SF1 has been reported to be associated with many tumors invasion and metastasis, but has not been reported in esophageal cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TM4SF1', 'Var', (0, 6))	('esophageal cancer', 'Disease', (113, 130))
589484	27974706	The results presented in this study showed that TM4SF1 overexpression significantly enhanced KYSE150 and KYSE180 cells invasion and migration.	('KYSE180', 'CellLine', 'CVCL:1349', (105, 112))	('overexpression', 'Var', (55, 69))	('SE', 'Disease', 'None', (95, 97))	('enhanced', 'PosReg', (84, 92))	('SE', 'Disease', 'None', (107, 109))	('TM4SF1', 'Gene', (48, 54))
589485	27974706	Also, TM4SF1 increased the resistance to cisplatin of KYSE150 cells.	('resistance to cisplatin', 'MPA', (27, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('TM4SF1', 'Var', (6, 12))	('SE', 'Disease', 'None', (56, 58))	('increased', 'PosReg', (13, 22))
589486	27974706	Taken together, we can come to the conclusion that TM4SF1 could be a candidate surface protein marker that could discriminate cancer stem-like cells from ESCC cells, and could promote the ability to self-renew by increasing the number of cancer stem-like cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', (126, 132))	('increasing', 'PosReg', (213, 223))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('promote', 'PosReg', (176, 183))	('TM4SF1', 'Var', (51, 57))
589488	27974706	As miR-141 and TM4SF1 were inversely expressed in SP cells, we explored TM4SF1 is a direct target gene of miR-141 and miR-141 could contribute to the self-renewal of esophageal cancer stem-like cells by suppressing TM4SF1.	('contribute', 'Reg', (132, 142))	('self-renewal', 'CPA', (150, 162))	('TM4SF1', 'MPA', (215, 221))	('miR-141', 'Var', (106, 113))	('esophageal cancer', 'Disease', (166, 183))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('suppressing', 'NegReg', (203, 214))	('SP', 'Chemical', '-', (50, 52))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('miR-141', 'Var', (118, 125))
589494	27974706	It is indicated that miR-141 may play a more important role than miR-200a in SP cells of ESCC.	('miR-200a', 'Gene', (65, 73))	('SP', 'Chemical', '-', (77, 79))	('miR-200a', 'Gene', '406983', (65, 73))	('miR-141', 'Var', (21, 28))
589511	27974706	Mutant construct of TM4SF1 3'UTR, named TM4SF1 3'UTR-mut, which carried a substitution of seven nucleotides within the core binding site of TM4SF13'-UTR, was carried out using MutanBEST Kit (Takara, Dalian, China).	('TM4SF13', 'Gene', (140, 147))	('TM4SF13', 'Gene', '27075', (140, 147))	('substitution', 'Var', (74, 86))
589542	23606979	It is therefore possible that bile acid is also involved in the onset of BE and that bile acid not only damages the esophageal mucosa but also directly induces intestinal metaplasia.	('intestinal', 'Disease', (160, 170))	('BE', 'Phenotype', 'HP:0100580', (73, 75))	('damages', 'NegReg', (104, 111))	('bile acid', 'Var', (85, 94))	('induces', 'Reg', (152, 159))	('bile acid', 'Chemical', 'MESH:D001647', (30, 39))	('bile acid', 'Chemical', 'MESH:D001647', (85, 94))
589578	23606979	Although the risk of BE transforming into BEA is about 0.5%, one study showed that adenocarcinoma developed within 5 years in approximately 20% and 50% of BE patients with low- and high-grade dysplasia, respectively.	('dysplasia', 'Disease', 'MESH:D004476', (192, 201))	('adenocarcinoma', 'Disease', (83, 97))	('low-', 'Var', (172, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('BE', 'Phenotype', 'HP:0100580', (21, 23))	('BEA', 'Disease', (42, 45))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('patients', 'Species', '9606', (158, 166))	('high-grade', 'Var', (181, 191))	('BEA', 'Chemical', '-', (42, 45))	('BEA', 'Phenotype', 'HP:0100580', (42, 45))	('BE', 'Phenotype', 'HP:0100580', (42, 44))	('dysplasia', 'Disease', (192, 201))	('BE', 'Phenotype', 'HP:0100580', (155, 157))
589592	23606979	Moreover, long-term administration of PPI increases the secretion of gastrin and facilitates oncogenesis via activation of cell proliferation and induction of cyclooxygenase 2 (COX2).	('COX2', 'Gene', (177, 181))	('increases', 'PosReg', (42, 51))	('cell proliferation', 'CPA', (123, 141))	('COX2', 'Gene', '5743', (177, 181))	('induction', 'Reg', (146, 155))	('activation', 'PosReg', (109, 119))	('gastrin', 'Gene', '2520', (69, 76))	('cyclooxygenase 2', 'Gene', '5743', (159, 175))	('PPI', 'Var', (38, 41))	('cyclooxygenase 2', 'Gene', (159, 175))	('gastrin', 'Gene', (69, 76))	('oncogenesis', 'CPA', (93, 104))	('facilitates', 'PosReg', (81, 92))
589597	23606979	However, because of their potential to damage tissue in the gastrointestinal tract, NSAIDs may cause peptic ulcers in the stomach and the duodenum in addition to the esophagus.	('ulcers in the stomach', 'Phenotype', 'HP:0002592', (108, 129))	('cause', 'Reg', (95, 100))	('NSAIDs', 'Var', (84, 90))	('gastrointestinal tract', 'Disease', (60, 82))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (60, 82))	('peptic ulcers', 'Disease', (101, 114))	('peptic ulcers', 'Phenotype', 'HP:0004398', (101, 114))	('damage tissue in the gastrointestinal tract', 'Phenotype', 'HP:0007378', (39, 82))	('peptic ulcers', 'Disease', 'MESH:D010437', (101, 114))
589648	32937009	6 ,  7 ,  8  Many studies showed that endoscopic screening might be associated with reduced mortality on UGC in some areas of Asia with high incidence.	('mortality', 'Disease', (92, 101))	('reduced', 'NegReg', (84, 91))	('UGC', 'Chemical', '-', (105, 108))	('endoscopic screening', 'Var', (38, 58))	('mortality', 'Disease', 'MESH:D003643', (92, 101))
589771	33180871	LAPG with DFT was superior to LATG in postoperative nutritional maintenance, and can be the first option for early proximal gastric cancer.	('gastric cancer', 'Disease', (124, 138))	('LATG', 'Chemical', '-', (30, 34))	('DFT', 'Var', (10, 13))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('LAPG', 'Chemical', '-', (0, 4))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('DFT', 'Chemical', '-', (10, 13))
589815	33180871	BW and PNI were actually better maintained after LAPG with DFT than after LATG until 1-year follow up, which was consistent with many previous reports.	('DFT', 'Var', (59, 62))	('better', 'PosReg', (25, 31))	('LAPG', 'Chemical', '-', (49, 53))	('DFT', 'Chemical', '-', (59, 62))	('LATG', 'Chemical', '-', (74, 78))
589849	31547581	The inhibition of VEGF-A with bevacizumab was the first angiogenesis-related tumor treatment, which nowadays is used for several different tumor entities.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('VEGF-A', 'Gene', '7422', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('inhibition', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('VEGF-A', 'Gene', (18, 24))	('tumor', 'Disease', (77, 82))	('angiogenesis-related', 'Disease', (56, 76))
589876	31547581	So far, there were no differences in colorectal cancers with high VEGF expression compared to tumors with low expression in regard to microvessel density.	('VEGF', 'Gene', (66, 70))	('colorectal cancers', 'Disease', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('high', 'Var', (61, 65))	('VEGF', 'Gene', '7422', (66, 70))	('rectal cancer', 'Phenotype', 'HP:0100743', (41, 54))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('colorectal cancers', 'Disease', 'MESH:D015179', (37, 55))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
589903	31435514	EAC is a heterogeneous cancer dominated by copy number alterations, high mutational burden and co-amplification of the receptor tyrosine kinases.	('copy number alterations', 'Var', (43, 66))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('EAC', 'Disease', (0, 3))
589904	31435514	Genes regulating cell cycle (CDKN2A), receptors to growth factors (SMAD4), chromatin remodeling (ARID1A) and Racl pathway (ELMO1 and DOCK2) are significantly mutated in EAC, while ESCC is characterized by alterations in the mechanisms controlling terminal differentiation (KMT2D) and proliferation (FAT1 and FAT2).	('FAT2', 'Gene', (308, 312))	('ELMO1', 'Gene', (123, 128))	('EAC', 'Disease', (169, 172))	('CDKN2A', 'Gene', '1029', (29, 35))	('DOCK2', 'Gene', (133, 138))	('KMT2D', 'Gene', '8085', (273, 278))	('ARID1A', 'Gene', (97, 103))	('FAT1', 'Gene', '2195', (299, 303))	('cell', 'CPA', (17, 21))	('SMAD4', 'Gene', (67, 72))	('ARID1A', 'Gene', '8289', (97, 103))	('EAC', 'Phenotype', 'HP:0011459', (169, 172))	('FAT2', 'Gene', '2196', (308, 312))	('Racl pathway', 'Pathway', (109, 121))	('DOCK2', 'Gene', '1794', (133, 138))	('CDKN2A', 'Gene', (29, 35))	('KMT2D', 'Gene', (273, 278))	('mutated', 'Var', (158, 165))	('SMAD4', 'Gene', '4089', (67, 72))	('ELMO1', 'Gene', '9844', (123, 128))	('FAT1', 'Gene', (299, 303))
589905	31435514	Meanwhile, defected TP53 and PIK3CA genes are the common feature for both EC types.	('TP53', 'Gene', (20, 24))	('defected', 'Var', (11, 19))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('TP53', 'Gene', '7157', (20, 24))
589913	31435514	The major risk factors for ESCC are represented by tobacco smoking, alcohol consumption, genetic variations of low-activity ethanol-metabolizing enzymes (ALDH1/2), human papillomavirus infection, but other environmental factors also play a role in the development of this cancer, such as the consumption of hot beverages, nutritional deficiencies and limited intake of fruits and vegetables.	('ethanol', 'Chemical', 'MESH:D000431', (124, 131))	('papillomavirus infection', 'Disease', (170, 194))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('human', 'Species', '9606', (164, 169))	('nutritional deficiencies', 'Disease', 'MESH:D044342', (322, 346))	('alcohol', 'Chemical', 'MESH:D000438', (68, 75))	('ALDH1/2', 'Gene', (154, 161))	('ESCC', 'Disease', (27, 31))	('men', 'Species', '9606', (259, 262))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('tobacco', 'Species', '4097', (51, 58))	('nutritional deficiencies', 'Disease', (322, 346))	('papillomavirus infection', 'Disease', 'MESH:D030361', (170, 194))	('genetic variations', 'Var', (89, 107))	('cancer', 'Disease', (272, 278))	('play', 'Reg', (233, 237))	('men', 'Species', '9606', (213, 216))	('papillomavirus infection', 'Phenotype', 'HP:0012740', (170, 194))
589922	31435514	In addition to the classic risk factors for the gastroesophageal reflux, male gender and a number of genetic alterations were found associated with oncogenic activity.	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (48, 71))	('gastroesophageal reflux', 'Disease', (48, 71))	('oncogenic activity', 'CPA', (148, 166))	('genetic alterations', 'Var', (101, 120))	('associated', 'Reg', (132, 142))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (48, 71))
589923	31435514	Examples include 19p13 in CRTC1, leading to the aberrant activation, as well as 9q22 in BARX1 which encodes a transcription factor which is important in esophageal specification.	('BARX1', 'Gene', '56033', (88, 93))	('p13', 'Gene', '440926', (19, 22))	('CRTC1', 'Gene', (26, 31))	('9q22', 'Var', (80, 84))	('CRTC1', 'Gene', '23373', (26, 31))	('activation', 'PosReg', (57, 67))	('BARX1', 'Gene', (88, 93))	('p13', 'Gene', (19, 22))
589924	31435514	Furthermore, polymorphisms near TBX5 and GDF7, which encode for a bone morphogenetic protein and a transcription factor that regulates esophageal development are associated with an increased risk of BE.	('GDF7', 'Gene', '151449', (41, 45))	('TBX5', 'Gene', '6910', (32, 36))	('TBX5', 'Gene', (32, 36))	('associated', 'Reg', (162, 172))	('polymorphisms', 'Var', (13, 26))	('men', 'Species', '9606', (153, 156))	('BE', 'Phenotype', 'HP:0100580', (199, 201))	('GDF7', 'Gene', (41, 45))
18128	31435514	The most frequent mutational events occurred at the level of TP53 (81%), ARID1A (17%), SMAD4 (16%), CDKN2A (15%), KCNQ3 (12%), CCDC 102B (9%) and CYP7B1 (7%).	('CDKN2A', 'Gene', '1029', (100, 106))	('mutational', 'Var', (18, 28))	('CYP7B1', 'Gene', '9420', (146, 152))	('TP53', 'Gene', '7157', (61, 65))	('CCDC 102B', 'Gene', (127, 136))	('SMAD4', 'Gene', '4089', (87, 92))	('CCDC 102B', 'Gene', '79839', (127, 136))	('CDKN2A', 'Gene', (100, 106))	('ARID1A', 'Gene', '8289', (73, 79))	('KCNQ3', 'Gene', (114, 119))	('ARID1A', 'Gene', (73, 79))	('CYP7B1', 'Gene', (146, 152))	('SMAD4', 'Gene', (87, 92))	('TP53', 'Gene', (61, 65))	('KCNQ3', 'Gene', '3786', (114, 119))
589930	31435514	Specifically, Arg72Pro substitution in p53 gene disrupts apoptosis and is associated with elevated risk of EAC development and reduced response to chemotherapy.	('EAC', 'Disease', (107, 110))	('apoptosis', 'CPA', (57, 66))	('men', 'Species', '9606', (118, 121))	('disrupts', 'NegReg', (48, 56))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('EAC', 'Phenotype', 'HP:0011459', (107, 110))	('Arg72Pro', 'Mutation', 'rs1042522', (14, 22))	('reduced', 'NegReg', (127, 134))	('Arg72Pro', 'Var', (14, 22))
589931	31435514	T309G substitution in the promoter region of MDM2 gene, regulating the p53 destruction, results in the enhanced MDM2 transcription, which causing the reduced apoptosis in response to the DNA damage.	('T309G', 'Var', (0, 5))	('MDM2', 'Gene', '4193', (112, 116))	('MDM2', 'Gene', (112, 116))	('T309G', 'Mutation', 'rs2279744', (0, 5))	('MDM2', 'Gene', '4193', (45, 49))	('MDM2', 'Gene', (45, 49))	('p53', 'Gene', (71, 74))	('transcription', 'MPA', (117, 130))	('enhanced', 'PosReg', (103, 111))	('apoptosis', 'CPA', (158, 167))	('p53', 'Gene', '7157', (71, 74))	('reduced', 'NegReg', (150, 157))	('response to the DNA damage', 'MPA', (171, 197))
589932	31435514	Additionally, mutations in several Fanconi anemia-predisposing genes, such as heterozygous indels in FANCD2 (p.Val1233-del), FANCE (p.Val311SerfsX2) and FANCL (p.Thr367AsnfsX13) were shown to correlate with enhanced ESCC risk.	('Fanconi anemia-', 'Phenotype', 'HP:0001994', (35, 50))	('FANCE', 'Gene', (125, 130))	('anemia', 'Disease', (43, 49))	('FANCE', 'Gene', '2178', (125, 130))	('FANCD2', 'Gene', '2177', (101, 107))	('p.Val1233-del', 'Mutation', 'p.1233del', (109, 122))	('anemia', 'Disease', 'MESH:D000740', (43, 49))	('ESCC', 'Disease', (216, 220))	('FANCL', 'Gene', (153, 158))	('p.Val1233-del', 'Var', (109, 122))	('FANCD2', 'Gene', (101, 107))	('p.Thr367AsnfsX13', 'Mutation', 'rs759217526', (160, 176))	('enhanced', 'PosReg', (207, 215))	('anemia', 'Phenotype', 'HP:0001903', (43, 49))	('FANCL', 'Gene', '55120', (153, 158))	('p.Thr367AsnfsX13', 'Var', (160, 176))	('p.Val311SerfsX2', 'FRAMESHIFT', 'None', (132, 147))	('p.Val311SerfsX2', 'Var', (132, 147))
589933	31435514	In tobacco smokers, special genomic variants of xenobiotic metabolizing enzymes:cytochrome P450 (CYP3A5) and sulfotransferase (SULT1A1*2/*2), specifically relate to increased ESCC risk, emphasizing the importance of combinatorial influence of genetic predisposition and environmental factors for cancer development.	('men', 'Species', '9606', (277, 280))	('increased ESCC', 'Phenotype', 'HP:0003565', (165, 179))	('SULT1A1', 'Gene', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('CYP3A5', 'Gene', (97, 103))	('tobacco', 'Species', '4097', (3, 10))	('SULT1A1', 'Gene', '6817', (127, 134))	('men', 'Species', '9606', (310, 313))	('ESCC', 'Disease', (175, 179))	('cytochrome P450', 'Enzyme', (80, 95))	('CYP3A5', 'Gene', '1577', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('variants', 'Var', (36, 44))	('cancer', 'Disease', (296, 302))	('relate to', 'Reg', (155, 164))
589934	31435514	The same way bile acid exerts its dismal effect, so reflux present in patients with BE may cause cell transformation by activating PIPLCgamma2, MAPK kinase, and NADPH oxidase NOX5-S, thus causing DNA damage and gene mutation contributing to the development of EAC.	('patients', 'Species', '9606', (70, 78))	('EAC', 'Phenotype', 'HP:0011459', (260, 263))	('gene mutation', 'Var', (211, 224))	('cause', 'Reg', (91, 96))	('MAPK', 'Gene', (144, 148))	('PIPLCgamma2', 'Gene', (131, 142))	('NOX5', 'Gene', '79400', (175, 179))	('MAPK', 'Gene', '5595;5594;5595', (144, 148))	('EAC', 'Disease', (260, 263))	('BE', 'Phenotype', 'HP:0100580', (84, 86))	('men', 'Species', '9606', (252, 255))	('cell transformation', 'CPA', (97, 116))	('contributing', 'Reg', (225, 237))	('NOX5', 'Gene', (175, 179))	('causing', 'Reg', (188, 195))	('DNA damage', 'MPA', (196, 206))	('bile acid', 'Chemical', 'MESH:D001647', (13, 22))	('activating', 'PosReg', (120, 130))
589943	31435514	For instance, it was established that extracellular vesicles (EV)-delivered miRNAs can promote tumor progression and metastasis.	('miRNAs', 'Var', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('promote', 'PosReg', (87, 94))	('tumor', 'Disease', (95, 100))	('metastasis', 'CPA', (117, 127))
589947	31435514	Studies in animal models of gastrointestinal cancer have demonstrated that CCK2R signaling can accelerate tumorigenesis in vivo, such as in gastrin-overexpressing INS-GAS mice that develop proximal gastric cancers.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (28, 51))	('accelerate', 'PosReg', (95, 105))	('gastric cancers', 'Disease', 'MESH:D013274', (198, 213))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('mice', 'Species', '10090', (171, 175))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('gastric cancers', 'Disease', (198, 213))	('gastric cancers', 'Phenotype', 'HP:0012126', (198, 213))	('CCK2R signaling', 'Var', (75, 90))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (28, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('gastrointestinal cancer', 'Disease', (28, 51))	('tumor', 'Disease', (106, 111))
248674	31435514	Inflammatory processes also lead to generation of reactive oxygen species (ROS) which may cause inactivating mutations in tumor suppressor genes or post-translational modifications in DNA repair proteins, thus promoting carcinogenesis.	('inactivating', 'MPA', (96, 108))	('promoting', 'PosReg', (210, 219))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (50, 73))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('carcinogenesis', 'Disease', 'MESH:D063646', (220, 234))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('DNA repair proteins', 'Protein', (184, 203))	('mutations', 'Var', (109, 118))	('lead to', 'Reg', (28, 35))	('ROS', 'Chemical', 'MESH:D017382', (75, 78))	('carcinogenesis', 'Disease', (220, 234))	('tumor', 'Disease', (122, 127))
590209	27698919	Cellular functions in response to TKT modulation were examined, including cell growth, migration and invasion.	('migration', 'CPA', (87, 96))	('modulation', 'Var', (38, 48))	('TKT', 'Gene', (34, 37))	('TKT', 'Gene', '7086', (34, 37))	('invasion', 'CPA', (101, 109))
590212	27698919	Results: TKT silencing inhibited cell migration and invasion but had a minimal effect on cell growth.	('TKT', 'Gene', '7086', (9, 12))	('TKT', 'Gene', (9, 12))	('silencing', 'Var', (13, 22))	('inhibited', 'NegReg', (23, 32))
590216	27698919	In the multivariate analysis, a high TKT level was also shown to be an independent unfavorable prognostic factor (Odds ratio: 1.827, 95% confidence interval: 1.045-3.196, P = 0.035).	('high', 'Var', (32, 36))	('TKT', 'Gene', (37, 40))	('TKT', 'Gene', '7086', (37, 40))
590219	27698919	TKT inhibition may be a useful strategy to intervene in cancer cell invasion and metastasis, which may lead to better prognosis for ESCC patients.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('TKT', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (137, 145))	('inhibition', 'Var', (4, 14))	('SCC', 'CellLine', 'CVCL:1R13', (133, 136))	('TKT', 'Gene', '7086', (0, 3))	('cancer', 'Disease', (56, 62))	('ESCC', 'Disease', (132, 136))
590230	27698919	Furthermore, gene silencing of TKTL1 by siRNA was found to significantly reduce cell proliferation in gastric, colon, and uterine cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('TKTL1', 'Gene', '8277', (31, 36))	('cancer', 'Disease', (130, 136))	('TKTL1', 'Gene', (31, 36))	('gene silencing', 'Var', (13, 27))	('uterine cancer', 'Phenotype', 'HP:0010784', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('reduce', 'NegReg', (73, 79))	('cell proliferation in gastric', 'CPA', (80, 109))
590280	27698919	Apparently, TKT silencing inhibits the migration ability of esophageal cancer cells.	('inhibits', 'NegReg', (26, 34))	('TKT', 'Gene', '7086', (12, 15))	('esophageal cancer', 'Disease', (60, 77))	('silencing', 'Var', (16, 25))	('TKT', 'Gene', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('migration ability of', 'CPA', (39, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
590286	27698919	As shown in the Figure 2A, TKT silencing decreased the levels of mesenchymal markers (fibronectin, N-cadherin, and IQGAP1 scaffold protein) and increased the expression of epithelial marker (gamma-catenin).	('silencing', 'Var', (31, 40))	('N-cadherin', 'Gene', (99, 109))	('IQGAP1', 'Gene', '8826', (115, 121))	('TKT', 'Gene', (27, 30))	('fibronectin', 'Gene', (86, 97))	('expression of', 'MPA', (158, 171))	('IQGAP1', 'Gene', (115, 121))	('N-cadherin', 'Gene', '1000', (99, 109))	('decreased', 'NegReg', (41, 50))	('TKT', 'Gene', '7086', (27, 30))	('fibronectin', 'Gene', '2335', (86, 97))	('increased', 'PosReg', (144, 153))
590287	27698919	As shown in Figure 2B, TKTi displayed a mesenchymal-like nature of the contractile morphology, indicating the cell-extracellular matrix contacts were broke down up TKT silencing.	('silencing', 'Var', (168, 177))	('cell-extracellular matrix contacts', 'CPA', (110, 144))	('broke down', 'NegReg', (150, 160))	('TKT', 'Gene', '7086', (23, 26))	('broke down', 'Phenotype', 'HP:0001061', (150, 160))	('mesenchymal-like nature', 'CPA', (40, 63))	('TKT', 'Gene', '7086', (164, 167))	('TKT', 'Gene', (23, 26))	('TKT', 'Gene', (164, 167))
590291	27698919	As shown in Figure 3A, TKT silencing inhibited Slug and Snail expressions, with a lighter effect on sh2- and strong effect on sh1-transfectants.	('silencing', 'Var', (27, 36))	('Slug', 'Gene', (47, 51))	('inhibited', 'NegReg', (37, 46))	('sh2', 'Gene', '100125854', (100, 103))	('sh2', 'Gene', (100, 103))	('TKT', 'Gene', '7086', (23, 26))	('Snail', 'Gene', '6615', (56, 61))	('Snail', 'Gene', (56, 61))	('TKT', 'Gene', (23, 26))	('Slug', 'Gene', '6591', (47, 51))
590307	27698919	Patients with high TKT expression had shorter DSS than those with low expression (5-yr DSS: 46% versus 17%, P = 0.042).	('DSS', 'Chemical', '-', (87, 90))	('high', 'Var', (14, 18))	('TKT', 'Gene', '7086', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('DSS', 'Chemical', '-', (46, 49))	('TKT', 'Gene', (19, 22))	('DSS', 'MPA', (46, 49))
590313	27698919	TKT inhibition may thus be a useful strategy to intervene in cancer cell invasion and metastases.	('metastases', 'Disease', (86, 96))	('TKT', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('metastases', 'Disease', 'MESH:D009362', (86, 96))	('cancer', 'Disease', (61, 67))	('inhibition', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TKT', 'Gene', '7086', (0, 3))
590321	27698919	Here, we showed that TKT silencing reduced the expression of the transcriptional regulators Slug and Snail in human ESCC cells (Figure 3A).	('Slug', 'Gene', (92, 96))	('silencing', 'Var', (25, 34))	('TKT', 'Gene', (21, 24))	('SCC', 'CellLine', 'CVCL:1R13', (117, 120))	('reduced', 'NegReg', (35, 42))	('human', 'Species', '9606', (110, 115))	('TKT', 'Gene', '7086', (21, 24))	('Snail', 'Gene', (101, 106))	('Slug', 'Gene', '6591', (92, 96))	('Snail', 'Gene', '6615', (101, 106))	('expression', 'MPA', (47, 57))
590341	25766659	Meanwhile, ethanol may also disturb fatty-acid metabolism in these cells.	('fatty-acid metabolism', 'MPA', (36, 57))	('ethanol', 'Var', (11, 18))	('fatty-acid', 'Chemical', 'MESH:D005227', (36, 46))	('disturb fatty-acid metabolism', 'Phenotype', 'HP:0004359', (28, 57))	('disturb', 'Reg', (28, 35))	('ethanol', 'Chemical', 'MESH:D000431', (11, 18))
590342	25766659	(3) Disturbance of signaling pathways in squamous epithelial cells: due to its physico-chemical properties, ethanol changes cell membrane fluidity and shape, and may thus impact multiple signaling pathways.	('ethanol', 'Chemical', 'MESH:D000431', (108, 115))	('impact', 'Reg', (171, 177))	('cell membrane fluidity', 'MPA', (124, 146))	('changes', 'Reg', (116, 123))	('ethanol', 'Var', (108, 115))
590385	25766659	While zinc supplementation prevents alcoholic liver injury through attenuation of oxidative stress, zinc depletion is known to enhance oro-esophageal carcinogenesis in rats and mice.	('attenuation', 'NegReg', (67, 78))	('alcoholic liver injury', 'Disease', 'MESH:D056486', (36, 58))	('alcoholic liver injury', 'Disease', (36, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (82, 98))	('enhance', 'PosReg', (127, 134))	('mice', 'Species', '10090', (177, 181))	('zinc depletion', 'Var', (100, 114))	('rats', 'Species', '10116', (168, 172))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (139, 164))	('oxidative stress', 'MPA', (82, 98))	('esophageal carcinogenesis', 'Disease', (139, 164))
590392	25766659	Mechanistically, iron overload may initiate and promote carcinogenesis through oxidative damage and modification of the immune reaction.	('iron overload', 'Var', (17, 30))	('immune reaction', 'CPA', (120, 135))	('modification', 'Reg', (100, 112))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('iron', 'Chemical', 'MESH:D007501', (17, 21))	('oxidative damage', 'CPA', (79, 95))	('promote', 'PosReg', (48, 55))	('carcinogenesis', 'Disease', (56, 70))
590395	25766659	Inhibition of methyl group transfer regulates expression of genes involved in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('regulates', 'Reg', (36, 45))	('carcinogenesis', 'Disease', (78, 92))	('Inhibition', 'Var', (0, 10))	('expression of genes', 'MPA', (46, 65))
590396	25766659	DNA hypomethylation of oncogenes (e.g., c-Ha-ras, c-Ki-ras and c-fos) is associated with an increased incidence of liver cancer in rats.	('c-Ki-ras', 'Gene', '24525', (50, 58))	('hypomethylation', 'Var', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('c-fos', 'Gene', (63, 68))	('liver cancer', 'Phenotype', 'HP:0002896', (115, 127))	('liver cancer', 'Disease', 'MESH:D006528', (115, 127))	('liver cancer', 'Disease', (115, 127))	('rats', 'Species', '10116', (131, 135))	('c-fos', 'Gene', '314322', (63, 68))	('c-Ha-ras', 'Var', (40, 48))	('c-Ki-ras', 'Gene', (50, 58))
590397	25766659	These data suggest that ethanol may contribute to OESCC through aberrant gene methylation.	('ethanol', 'Chemical', 'MESH:D000431', (24, 31))	('SCC', 'Gene', (52, 55))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('SCC', 'Gene', '6317', (52, 55))	('aberrant gene methylation', 'Var', (64, 89))
590398	25766659	In addition, aberrant gene methylation may impact signaling pathways through critical pathway genes, such as Notch4 of the Notch signaling pathway, PTEN of the phospoinositide 3-kinase (PI3K)/Akt pathway, and Wnt inhibitory factor 1 (WIF1) of the Wnt signaling pathway.	('signaling pathways', 'Pathway', (50, 68))	('PTEN', 'Gene', (148, 152))	('WIF1', 'Gene', '24117', (234, 238))	('WIF1', 'Gene', (234, 238))	('impact', 'Reg', (43, 49))	('Wnt inhibitory factor 1', 'Gene', '24117', (209, 232))	('Notch4', 'Gene', (109, 115))	('Wnt inhibitory factor 1', 'Gene', (209, 232))	('PTEN', 'Gene', '19211', (148, 152))	('Notch signaling pathway', 'Pathway', (123, 146))	('PI3', 'Gene', (186, 189))	('methylation', 'Var', (27, 38))	('phospoinositide 3-kinase', 'Gene', (160, 184))	('phospoinositide 3-kinase', 'Gene', '18708', (160, 184))	('gene', 'Protein', (22, 26))	('Notch4', 'Gene', '18132', (109, 115))	('PI3', 'Gene', '20702', (186, 189))	('aberrant', 'Var', (13, 21))
590401	25766659	Oral epithelium expresses chi and sigma type ADH with high Km values (ADH3 and ADH4), and a negligible amount of ALDH.	('sigma type ADH', 'Disease', 'MESH:D007177', (34, 48))	('ADH3', 'Gene', (70, 74))	('ALDH', 'Gene', (113, 117))	('ADH3', 'Gene', '11529', (70, 74))	('ADH4', 'Gene', (79, 83))	('ADH4', 'Gene', '26876', (79, 83))	('chi', 'Var', (26, 29))	('sigma type ADH', 'Disease', (34, 48))	('ALDH', 'Gene', '11670', (113, 117))
590410	25766659	As the most abundant DNA adduct, N2-ethylidene-2'-deoxyguanosine (N2-EtidG), impairs the DNA repair system and apoptosis.	('impairs', 'NegReg', (77, 84))	("N2-ethylidene-2'-deoxyguanosine", 'Chemical', 'MESH:C525837', (33, 64))	('DNA', 'MPA', (89, 92))	('N2-EtidG', 'Chemical', 'MESH:C525837', (66, 74))	("N2-ethylidene-2'-deoxyguanosine", 'Var', (33, 64))	('apoptosis', 'CPA', (111, 120))
590413	25766659	In animals, lack of ALDH2 leads to an increased level of N2-EtidG in the mouse upper aerodigestive tract after ethanol treatment.	('level of N2-EtidG', 'MPA', (48, 65))	('lack', 'Var', (12, 16))	('ethanol', 'Chemical', 'MESH:D000431', (111, 118))	('ALDH2', 'Gene', (20, 25))	('mouse', 'Species', '10090', (73, 78))	('N2-EtidG', 'Chemical', 'MESH:C525837', (57, 65))	('increased', 'PosReg', (38, 47))
590427	25766659	Activation of Nrf2 prevents ethanol-induced oxidative stress, lipid accumulation and accelerated acetaldehyde metabolism.	('acetaldehyde metabolism', 'Phenotype', 'HP:0003533', (97, 120))	('oxidative stress', 'Phenotype', 'HP:0025464', (44, 60))	('lipid accumulation', 'MPA', (62, 80))	('Nrf2', 'Gene', '18024', (14, 18))	('rat', 'Species', '10116', (91, 94))	('accelerated', 'PosReg', (85, 96))	('prevents', 'NegReg', (19, 27))	('lipid', 'Chemical', 'MESH:D008055', (62, 67))	('Nrf2', 'Gene', (14, 18))	('oxidative stress', 'MPA', (44, 60))	('Activation', 'Var', (0, 10))	('acetaldehyde', 'Chemical', 'MESH:D000079', (97, 109))	('acetaldehyde metabolism', 'MPA', (97, 120))	('ethanol', 'Chemical', 'MESH:D000431', (28, 35))
590433	25766659	Elovl6 deficient mice became obese and developed hepatosteatosis when fed a high-fat diet.	('obese', 'Disease', 'MESH:D009765', (29, 34))	('mice', 'Species', '10090', (17, 21))	('obese', 'Disease', (29, 34))	('Elovl6', 'Gene', (0, 6))	('hepatosteatosis', 'Disease', (49, 64))	('deficient', 'Var', (7, 16))	('hepatosteatosis', 'Disease', 'None', (49, 64))	('developed', 'Reg', (39, 48))
590454	25766659	In the oral cavity, Notch1 is highly activated in oral epithelium differentiation, and disrupted Notch1 interferes with normal palate development.	('Notch1', 'Gene', '18128', (20, 26))	('normal palate development', 'CPA', (120, 145))	('interferes', 'NegReg', (104, 114))	('Notch1', 'Gene', (97, 103))	('Notch1', 'Gene', '18128', (97, 103))	('Notch1', 'Gene', (20, 26))	('disrupted', 'Var', (87, 96))
590455	25766659	Exome sequencing has shown in multiple studies that loss-of-function Notch mutations are frequently seen in OESCC.	('SCC', 'Gene', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('Notch', 'Gene', (69, 74))	('loss-of-function', 'NegReg', (52, 68))	('mutations', 'Var', (75, 84))	('SCC', 'Gene', '6317', (110, 113))
590487	25766659	In head and neck SCC, loss of type 2 TGFbeta receptor or Smad4 not only abrogates TGFbeta-mediated tumor suppression, but also causes a compensatory increase in TGFbeta ligand expression that promotes inflammation and angiogenesis.	('abrogates', 'NegReg', (72, 81))	('tumor', 'Disease', (99, 104))	('inflammation', 'Disease', 'MESH:D007249', (201, 213))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('increase', 'PosReg', (149, 157))	('inflammation', 'Disease', (201, 213))	('promotes', 'PosReg', (192, 200))	('SCC', 'Gene', '6317', (17, 20))	('angiogenesis', 'CPA', (218, 230))	('TGFbeta', 'Protein', (161, 168))	('Smad4', 'Gene', '17128', (57, 62))	('expression', 'MPA', (176, 186))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Smad4', 'Gene', (57, 62))	('TGFbeta-mediated', 'Gene', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('loss', 'Var', (22, 26))	('SCC', 'Gene', (17, 20))
590491	25766659	In the oro-esophagus, NFkappaB alleles are associated with oral carcinogenesis.	('associated with', 'Reg', (43, 58))	('NFkappaB', 'Gene', (22, 30))	('alleles', 'Var', (31, 38))	('NFkappaB', 'Gene', '18033', (22, 30))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (59, 78))	('oral carcinogenesis', 'Disease', (59, 78))
590519	25766659	Knockdown of Notch1 enhances the activation of Wnt target genes, whereas chemical inhibition of gamma-secretase or expression of a Notch1 mutant inhibits Wnt signaling.	('Wnt signaling', 'MPA', (154, 167))	('Notch1', 'Gene', '18128', (13, 19))	('mutant', 'Var', (138, 144))	('Notch1', 'Gene', (131, 137))	('Notch1', 'Gene', '18128', (131, 137))	('enhances', 'PosReg', (20, 28))	('inhibits', 'NegReg', (145, 153))	('activation', 'MPA', (33, 43))	('Wnt target', 'Gene', (47, 57))	('Notch1', 'Gene', (13, 19))
590522	25766659	Nrf2 disruption impedes liver regeneration which can be rescued by reestablishment of Notch1 signaling.	('liver regeneration', 'CPA', (24, 42))	('Nrf2', 'Gene', '18024', (0, 4))	('Notch1', 'Gene', (86, 92))	('rat', 'Species', '10116', (36, 39))	('disruption', 'Var', (5, 15))	('Notch1', 'Gene', '18128', (86, 92))	('Nrf2', 'Gene', (0, 4))	('impedes', 'NegReg', (16, 23))
590539	25766659	Genomics techniques such as NextGen sequencing, CGH array and SNP array are used for detection of DNA alterations, RNA-Seq and microarray for detection of mRNA differential expression, and methylation array for detection of alterations in gene methylation.	('alterations', 'Var', (102, 113))	('rat', 'Species', '10116', (228, 231))	('DNA', 'MPA', (98, 101))	('rat', 'Species', '10116', (106, 109))	('mRNA differential expression', 'MPA', (155, 183))
590546	20920330	Association between the Cytotoxic T-Lymphocyte Antigen 4 +49G > A polymorphism and cancer risk: a meta-analysis As a key gene in the immunosurveillance of cell malignancy, Cytotoxic T-lymphocyte antigen 4 (CTLA-4 is an important negative regulator of T cell activation and proliferation.	('CTLA-4', 'Gene', '1493', (206, 212))	('CTLA-4', 'Gene', (206, 212))	('Cytotoxic T-lymphocyte antigen 4', 'Gene', (172, 204))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('4 +49G > A', 'SUBSTITUTION', 'None', (55, 65))	('4 +49G > A', 'Var', (55, 65))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Association', 'Interaction', (0, 11))	('Cytotoxic T-lymphocyte antigen 4', 'Gene', '1493', (172, 204))	('cancer', 'Disease', (83, 89))
590551	20920330	In four breast cancer studies, patients with the variant genotypes had a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48, P < 0.00001).	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('patients', 'Species', '9606', (31, 39))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('variant', 'Var', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Disease', (8, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
590553	20920330	In 26 solid tumor studies, subjects with the variant genotypes had a significantly higher risk of developing solid tumors (OR = 1.25, 95% CI = 1.18-1.33, P < 0.00001) compared with the 6 non-solid tumor studies (OR = 1.08, 95% CI = 0.79-1.48, P = 0.62).	('solid tumors', 'Disease', (109, 121))	('solid tumor', 'Disease', (191, 202))	('solid tumor', 'Disease', 'MESH:D009369', (191, 202))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('solid tumor', 'Disease', 'MESH:D009369', (109, 120))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('solid tumor', 'Disease', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('variant', 'Var', (45, 52))	('solid tumor', 'Disease', 'MESH:D009369', (6, 17))
590554	20920330	Patients with variant genotypes had significantly increased risk of non-epithelial tumors and epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32, P < 0.00001) and 1.29 (95% CI = 1.17-1.41, P < 0.00001), respectively.	('epithelial tumors', 'Disease', (94, 111))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('epithelial tumors', 'Disease', 'MESH:D002277', (94, 111))	('epithelial tumors', 'Disease', 'MESH:D002277', (72, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('epithelial tumors', 'Disease', (72, 89))	('variant', 'Var', (14, 21))	('epithelial tumor', 'Phenotype', 'HP:0031492', (94, 110))	('epithelial tumor', 'Phenotype', 'HP:0031492', (72, 88))
590566	20920330	An A G dimorphism at position 49 in CTLA-4 exon 1 (rs231775) has been reported by Nistico, which causes an amino acid change (threonine to alanine) in the peptide leader sequence of the CTLA-4 protein.	('amino acid', 'MPA', (107, 117))	('CTLA-4', 'Gene', '1493', (36, 42))	('rs231775', 'Mutation', 'rs231775', (51, 59))	('CTLA-4', 'Gene', (186, 192))	('CTLA-4', 'Gene', '1493', (186, 192))	('CTLA-4', 'Gene', (36, 42))	('alanine', 'Chemical', 'MESH:D000409', (139, 146))	('change', 'Reg', (118, 124))	('causes', 'Reg', (97, 103))	('rs231775', 'Var', (51, 59))	('threonine', 'Chemical', 'MESH:D013912', (126, 135))
590567	20920330	Recent studies found that this polymorphism may influence the ability of CTLA-4 to bind with B7.1 and subsequently, may affect T-cell activation.	('bind', 'Interaction', (83, 87))	('CTLA-4', 'Gene', '1493', (73, 79))	('polymorphism', 'Var', (31, 43))	('B7.1', 'Gene', '941', (93, 97))	('CTLA-4', 'Gene', (73, 79))	('ability', 'MPA', (62, 69))	('affect', 'Reg', (120, 126))	('influence', 'Reg', (48, 57))	('T-cell activation', 'CPA', (127, 144))	('B7.1', 'Gene', (93, 97))
590569	20920330	However, the results of studies on the association between the +49 A > G polymorphism and the risk of cancers have been conflicting.	('+49 A > G', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('+49 A > G', 'Mutation', 'rs231775', (63, 72))
590589	20920330	Compared with the wild-type +49G > A GG genotype, the carriers of variant genotypes (GA/AA) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32, P <0.05) as estimated by a fixed effect model for dominant genetic effects (Figure 6).	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('+49G > A', 'Mutation', 'rs231775', (28, 36))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('variant', 'Var', (66, 73))
590590	20920330	In the six colorectal cancer studies, which included 699 cases and 1,411 controls, subjects with variant genotypes (597 cases and 1,144 controls) had a non-significant increased risk of colorectal cancer (OR = 1.03, 95% CI = 0.78-1.35, P = 0.86) as estimated using a fixed effect model (Figure 1).	('variant', 'Var', (97, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (11, 28))	('colorectal cancer', 'Disease', 'MESH:D015179', (186, 203))	('colorectal cancer', 'Phenotype', 'HP:0003003', (11, 28))	('colorectal cancer', 'Disease', (11, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('colorectal cancer', 'Disease', (186, 203))
590592	20920330	However, in the four breast cancer studies, consisting of 2,411 cases and 2,439 controls, the variant genotypes (1,436 cases and 1,292 controls) were associated with a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48, P < 0.00001) (Figure 1).	('variant', 'Var', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancer', 'Disease', (200, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))
590594	20920330	We also found that patients with the variant genotypes had significantly increased risks for developing either non-epithelial tumors or epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32, P < 0.00001) and 1.29 (95% CI = 1.17-1.41, P < 0.00001), respectively (Figure 5).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (19, 27))	('epithelial tumors', 'Disease', 'MESH:D002277', (115, 132))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('epithelial tumor', 'Phenotype', 'HP:0031492', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('epithelial tumors', 'Disease', (136, 153))	('variant', 'Var', (37, 44))	('epithelial tumors', 'Disease', 'MESH:D002277', (136, 153))	('epithelial tumor', 'Phenotype', 'HP:0031492', (115, 131))	('epithelial tumors', 'Disease', (115, 132))
590595	20920330	In the stratification analyses for ethnicity, we found that the increased risk of cancer associated with +49G > A variant genotypes was more pronounced in Caucasians (OR = 1.29, 95% CI = 1.13-1.47, P = 0.0002), Asians (OR = 1.23, 95% CI = 1.16-1.32, P < 0.00001), and Chinese (OR = 1.23, 95% CI = 1.15-1.31, P < 0.00001) (Figure 2 and 4).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('+49G > A', 'Mutation', 'rs231775', (105, 113))	('+49G > A', 'Var', (105, 113))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
590598	20920330	In this meta-analysis, which includes 22 independent case-control studies with 32 data sets, we found that the carriers of the CTLA-4 +49 (GA+AA) variant genotypes had a 1.24-fold increased risk of cancer in the dominant genetic model.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('variant', 'Var', (146, 153))	('cancer', 'Disease', (198, 204))	('CTLA-4', 'Gene', '1493', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('CTLA-4', 'Gene', (127, 133))
590599	20920330	These results support the hypothesis that polymorphisms of CTLA-4 play an important role in the development of cancer.	('CTLA-4', 'Gene', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('role', 'Reg', (84, 88))	('polymorphisms', 'Var', (42, 55))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('CTLA-4', 'Gene', '1493', (59, 65))	('play', 'Reg', (66, 70))
590612	20920330	Nistico and his colleagues reported a functional polymorphism in CTLA4 exon 1 which causes a threonine to alanine amino acid exchange in this protein's leader sequence.	('alanine amino acid', 'Chemical', '-', (106, 124))	('CTLA4', 'Gene', '1493', (65, 70))	('polymorphism', 'Var', (49, 61))	('CTLA4', 'Gene', (65, 70))	('threonine', 'Chemical', 'MESH:D013912', (93, 102))	('threonine to alanine amino acid exchange', 'MPA', (93, 133))	('causes', 'Reg', (84, 90))
590613	20920330	We noted the impact of the CTLA4 exon 1 + 49 A/G dimorphism on immune regulation after T-cell stimulation.	('CTLA4', 'Gene', '1493', (27, 32))	('CTLA4', 'Gene', (27, 32))	('1 + 49 A/G', 'SUBSTITUTION', 'None', (38, 48))	('1 + 49 A/G', 'Var', (38, 48))	('immune regulation', 'MPA', (63, 80))
590616	20920330	This study evaluated the associations of CTLA-4 +49A/G polymorphisms with different cancers.	('+49A/G', 'Mutation', 'rs231775', (48, 54))	('associations', 'Interaction', (25, 37))	('CTLA-4', 'Gene', (41, 47))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('polymorphisms', 'Var', (55, 68))	('CTLA-4', 'Gene', '1493', (41, 47))
590617	20920330	We found that this polymorphism was associated with an increased risk of developing solid tumors (including lung caner, breast cancer, colorectal cancer, gastric cancer, skin cancer, thymoma, nasopharyngeal carcinoma, cervical squamous cell carcinoma, esophageal cancer, oral squamous cell carcinoma, HBV-related hepatocellular carcinoma, and renal cell cancer), but not non-solid tumors, suggesting that the CTLA-4 gene plays different roles in the carcinogenesis of these two types of tumors.	('esophageal cancer', 'Disease', 'MESH:D004938', (252, 269))	('tumors', 'Disease', (487, 493))	('renal cell cancer', 'Phenotype', 'HP:0005584', (343, 360))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('solid tumors', 'Disease', 'MESH:D009369', (375, 387))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (271, 299))	('squamous cell carcinoma', 'Disease', (227, 250))	('tumors', 'Phenotype', 'HP:0002664', (381, 387))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('oral squamous cell carcinoma', 'Disease', (271, 299))	('thymoma', 'Disease', 'MESH:D013945', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('esophageal cancer', 'Disease', (252, 269))	('CTLA-4', 'Gene', '1493', (409, 415))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (192, 216))	('solid tumors', 'Disease', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('lung caner', 'Disease', (108, 118))	('carcinogenesis', 'Disease', (450, 464))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('skin cancer', 'Disease', (170, 181))	('tumors', 'Disease', 'MESH:D009369', (487, 493))	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('CTLA-4', 'Gene', (409, 415))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (313, 337))	('tumors', 'Disease', (381, 387))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (276, 299))	('carcinogenesis', 'Disease', 'MESH:D063646', (450, 464))	('polymorphism', 'Var', (19, 31))	('skin cancer', 'Phenotype', 'HP:0008069', (170, 181))	('colorectal cancer', 'Disease', (135, 152))	('thymoma', 'Disease', (183, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (227, 250))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (192, 216))	('thymoma', 'Phenotype', 'HP:0100522', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('solid tumors', 'Disease', 'MESH:D009369', (84, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (313, 337))	('tumors', 'Disease', 'MESH:D009369', (381, 387))	('non-solid tumors', 'Disease', 'MESH:D009369', (371, 387))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('gastric cancer', 'Disease', (154, 168))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (276, 299))	('tumor', 'Phenotype', 'HP:0002664', (487, 492))	('tumors', 'Phenotype', 'HP:0002664', (487, 493))	('skin cancer', 'Disease', 'MESH:D012878', (170, 181))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (227, 250))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('hepatocellular carcinoma', 'Disease', (313, 337))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('non-solid tumors', 'Disease', (371, 387))	('renal cell cancer', 'Disease', (343, 360))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('tumors', 'Disease', (90, 96))	('renal cell cancer', 'Disease', 'MESH:C538614', (343, 360))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('gastric cancer', 'Disease', 'MESH:D013274', (154, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('nasopharyngeal carcinoma', 'Disease', (192, 216))
590618	20920330	In our stratified analysis for ethnicity, the CTLA-4 +49G > A variant genotypes (GA + AA) were associated with an increased risk of cancer in Caucasians (OR = 1.29, 95% CI = 1.13-1.47, P = 0.0002), Chinese (OR = 1.23, 95% CI = 1.15-1.31, P < 0.00001), and Asians (OR = 1.23, 95% CI = 1.16-1.32, P < 0.00001), suggesting that the different genetic backgrounds of the different populations may to some extent explain the different risk estimates associated with the variant CTLA-4 genotypes.	('cancer', 'Disease', (132, 138))	('CTLA-4', 'Gene', '1493', (472, 478))	('CTLA-4', 'Gene', '1493', (46, 52))	('+49G > A', 'Mutation', 'rs231775', (53, 61))	('CTLA-4', 'Gene', (46, 52))	('CTLA-4', 'Gene', (472, 478))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('variant', 'Var', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
590620	20920330	In conclusion, our meta-analysis found evidence for an association between CTLA-4 +49A/G polymorphisms and multiple cancers in the general population, particularly for solid tumors.	('multiple cancers', 'Disease', (107, 123))	('CTLA-4', 'Gene', '1493', (75, 81))	('polymorphisms', 'Var', (89, 102))	('multiple cancers', 'Disease', 'MESH:D009369', (107, 123))	('solid tumors', 'Disease', (168, 180))	('CTLA-4', 'Gene', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('solid tumors', 'Disease', 'MESH:D009369', (168, 180))	('+49A/G', 'Mutation', 'rs231775', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
590672	31369200	The calculated Youden Index or J score (defines a test's performance in relation to its optimal cutoff value) for predicting clinical outcomes was 0.59 for DSI >19, vs 0.37 for Ishak Fibrosis score >F4, suggesting increased accuracy of DSI over liver biopsy in predicting clinical outcomes in these patient populations.	('Fibrosis', 'Disease', 'MESH:D005355', (183, 191))	('Fibrosis', 'Disease', (183, 191))	('DSI >19', 'Var', (156, 163))	('patient', 'Species', '9606', (299, 306))
590722	31369200	An increased SHUNT results from increased spillover of the orally administered d4-cholate into the systemic circulation, implying intrinsic hepatic disease, development of portal-systemic collaterals, or both.	('hepatic disease', 'Phenotype', 'HP:0001392', (140, 155))	('hepatic disease', 'Disease', (140, 155))	('d4-cholate', 'Var', (79, 89))	('portal-systemic collaterals', 'Phenotype', 'HP:0025154', (172, 199))	('increased', 'PosReg', (32, 41))	('d4-cholate', 'Chemical', '-', (79, 89))	('SHUNT', 'MPA', (13, 18))	('spillover', 'MPA', (42, 51))	('hepatic disease', 'Disease', 'MESH:D056486', (140, 155))
590839	32185206	The production of ROS causes cellular damage, and it has been reported to play a role in the pathogenesis of various gastrointestinal diseases.	('cellular damage', 'CPA', (29, 44))	('gastrointestinal disease', 'Phenotype', 'HP:0011024', (117, 141))	('gastrointestinal diseases', 'Phenotype', 'HP:0011024', (117, 142))	('play', 'Reg', (74, 78))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('gastrointestinal diseases', 'Disease', (117, 142))	('ROS', 'Protein', (18, 21))	('gastrointestinal diseases', 'Disease', 'MESH:D005767', (117, 142))	('production', 'Var', (4, 14))	('causes', 'Reg', (22, 28))
590853	32185206	MAPK (p38, ERK, and JNK) makes a role in making inflammation through the interaction of three pathway factors.	('inflammation', 'Disease', 'MESH:D007249', (48, 60))	('inflammation', 'Disease', (48, 60))	('JNK', 'Gene', '116554', (20, 23))	('MAPK', 'Gene', (0, 4))	('interaction', 'Interaction', (73, 84))	('ERK', 'Gene', '24338', (11, 14))	('MAPK', 'Gene', '26413;26417', (0, 4))	('p38', 'Var', (6, 9))	('ERK', 'Gene', (11, 14))	('JNK', 'Gene', (20, 23))
590856	32185206	In particular, the phosphorylation of p38 and ERK induces activation of NF-kappaB with many direct and indirect interactions.	('interactions', 'Interaction', (112, 124))	('NF-kappaB', 'Protein', (72, 81))	('p38', 'Protein', (38, 41))	('ERK', 'Gene', (46, 49))	('ERK', 'Gene', '24338', (46, 49))	('phosphorylation', 'Var', (19, 34))	('activation', 'PosReg', (58, 68))
590910	30544419	Of these variables, only MTV0.42 (13.6 mL) and MTV0.50 (7.4 mL) were associated with a pathological response to treatment on ROC curve analysis, with an area under the curve of 0.690 (confidence interval 0.557-0.823; P = .02) and 0.664 (confidence interval 0.527-0.802; P = .048), respectively (Fig.	('MTV0.50', 'Var', (47, 54))	('MTV0.42', 'Var', (25, 32))	('MTV', 'Chemical', '-', (47, 50))	('MTV', 'Chemical', '-', (25, 28))
590942	30555465	In most cancer types [e.g., acute myeloid leukemia (AML), adrenocortical carcinoma (ACC), breast cancer, Ewing sarcoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer (NSCLC), prostate cancer, and squamous cell carcinoma of the skin] chemerin is downregulated, likely via hypermethylation of RARRES2 (Table 1).	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (58, 82))	('RARRES2', 'Gene', (308, 315))	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('cancer', 'Disease', (201, 207))	('AML', 'Disease', (52, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('non-small cell lung cancer', 'Disease', (156, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('RARRES2', 'Gene', '5919', (308, 315))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('Ewing sarcoma', 'Disease', (105, 118))	('prostate cancer', 'Disease', 'MESH:D011471', (192, 207))	('prostate cancer', 'Phenotype', 'HP:0012125', (192, 207))	('hepatocellular carcinoma', 'Disease', (120, 144))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (58, 82))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', (97, 103))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('downregulated', 'NegReg', (262, 275))	('adrenocortical carcinoma', 'Disease', (58, 82))	('prostate cancer', 'Disease', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('acute myeloid leukemia', 'Disease', (28, 50))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (156, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('squamous cell carcinoma of the skin', 'Phenotype', 'HP:0006739', (213, 248))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (160, 182))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (120, 144))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (28, 50))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (156, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('squamous cell carcinoma of the skin', 'Disease', (213, 248))	('NSCLC', 'Disease', (184, 189))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (28, 50))	('hypermethylation', 'Var', (288, 304))	('breast cancer', 'Disease', (90, 103))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (34, 50))	('squamous cell carcinoma of the skin', 'Disease', 'MESH:D002294', (213, 248))	('cancer', 'Disease', (176, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (120, 144))	('AML', 'Disease', 'MESH:D015470', (52, 55))
590951	30555465	Moreover, multivariate analysis on parameters such as age, various gene mutations, chemerin expression, karyotypic classifications, and white blood cell count verified that chemerin was independently able to prognosticate AML patients, while univariate analysis of chemerin expression levels showed that high chemerin expression was associated with positive prognosis.	('mutations', 'Var', (72, 81))	('AML', 'Disease', 'MESH:D015470', (222, 225))	('AML', 'Phenotype', 'HP:0004808', (222, 225))	('patients', 'Species', '9606', (226, 234))	('AML', 'Disease', (222, 225))
590958	30555465	Chemerin's role as a chemoattractant, in recruiting immune cells to sites of inflammation, has already been well documented; for instance, chemerin has been shown to suppress neoplasia by eliciting natural killer cells to the tumor site in melanoma.	('eliciting', 'PosReg', (188, 197))	('neoplasia', 'Phenotype', 'HP:0002664', (175, 184))	('chemerin', 'Var', (139, 147))	('suppress', 'NegReg', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (240, 248))	('Chemerin', 'Gene', (0, 8))	('inflammation', 'Disease', 'MESH:D007249', (77, 89))	('neoplasia', 'Disease', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('inflammation', 'Disease', (77, 89))	('melanoma', 'Disease', (240, 248))	('Chemerin', 'Gene', '5919', (0, 8))	('neoplasia', 'Disease', 'MESH:D009369', (175, 184))	('tumor', 'Disease', (226, 231))
590964	30555465	Specifically, the silenced RARRES2 gene in ACC tumors was characterized by hypermethylation at five CpG sites.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('hypermethylation', 'Var', (75, 91))	('RARRES2', 'Gene', (27, 34))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('RARRES2', 'Gene', '5919', (27, 34))
590967	30555465	Thus, hypermethylation of RARRES2 is likely a common method of gene silencing in tumors where chemerin is downregulated].	('RARRES2', 'Gene', (26, 33))	('tumors', 'Disease', (81, 87))	('hypermethylation', 'Var', (6, 22))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('RARRES2', 'Gene', '5919', (26, 33))	('silencing', 'NegReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
590970	30555465	The phosphorylated sites were identified as Ser33, Ser37, and Thr41.	('Thr41', 'Var', (62, 67))	('Ser33', 'Chemical', '-', (44, 49))	('Ser33', 'Var', (44, 49))	('Ser37', 'Chemical', '-', (51, 56))	('Ser37', 'Var', (51, 56))	('Thr41', 'Chemical', '-', (62, 67))
590977	30555465	beta-catenin (CTNNB1), a proto-oncogene, is frequently mutated in ACC, resulting in constitutive activation of the Wnt/beta-catenin pathway.	('Wnt/beta-catenin pathway', 'Pathway', (115, 139))	('activation', 'PosReg', (97, 107))	('CTNNB1', 'Gene', '1499', (14, 20))	('mutated', 'Var', (55, 62))	('CTNNB1', 'Gene', (14, 20))	('ACC', 'Phenotype', 'HP:0006744', (66, 69))
590980	30555465	Aberrant activation of the Wnt/beta-catenin pathway is common in many other cancer types, such as breast cancer, lung cancer, hepatocellular carcinoma, and squamous cell carcinoma.	('cancer', 'Disease', (105, 111))	('squamous cell carcinoma', 'Disease', (156, 179))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (126, 150))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cancer', 'Disease', (118, 124))	('hepatocellular carcinoma', 'Disease', (126, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (76, 82))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('lung cancer', 'Disease', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('Wnt/beta-catenin pathway', 'Pathway', (27, 51))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (126, 150))
591018	30555465	VEGF, IL-6, and MMP-7 have all been associated with enhanced tumor invasiveness in gastric cancer, while high expression of VEGF and IL-6 have been shown to stimulate metastasis of malignant cells and indicate poor clinical outcomes in gastric cancer patients, suggesting a potential impact of chemerin in this setting.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('IL-6', 'Gene', (133, 137))	('IL-6', 'Gene', (6, 10))	('patients', 'Species', '9606', (251, 259))	('high expression', 'Var', (105, 120))	('tumor invasiveness', 'Disease', 'MESH:D009369', (61, 79))	('metastasis of malignant cells', 'CPA', (167, 196))	('gastric cancer', 'Disease', (236, 250))	('stimulate', 'PosReg', (157, 166))	('gastric cancer', 'Disease', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MMP-7', 'Gene', (16, 21))	('VEGF', 'Gene', '7422', (0, 4))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('tumor invasiveness', 'Disease', (61, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('VEGF', 'Gene', (0, 4))	('MMP-7', 'Gene', '4316', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('enhanced', 'PosReg', (52, 60))	('VEGF', 'Gene', '7422', (124, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('VEGF', 'Gene', (124, 128))
591029	30555465	First, one study found that chem158 K, a bioactive isoform of chemerin, was elevated in the cerebrospinal fluid of patients with malignant glioblastoma.	('patients', 'Species', '9606', (115, 123))	('elevated', 'PosReg', (76, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('malignant glioblastoma', 'Disease', 'MESH:D005909', (129, 151))	('malignant glioblastoma', 'Disease', (129, 151))	('chem158 K', 'Var', (28, 37))
591032	30555465	Experimental results determined that the addition of chem157S, another bioactive isoform of chemerin, to U-87 MG cells resulted in a transient, dose-dependent increase of intracellular calcium, indicating that chemerin could instigate intracellular signaling in U-87 MG cells.	('intracellular calcium', 'MPA', (171, 192))	('U-87 MG', 'CellLine', 'CVCL:0022', (105, 112))	('instigate', 'Reg', (225, 234))	('chem157S', 'Var', (53, 61))	('increase of intracellular calcium', 'Phenotype', 'HP:0003575', (159, 192))	('U-87 MG', 'CellLine', 'CVCL:0022', (262, 269))	('calcium', 'Chemical', 'MESH:D002118', (185, 192))	('increase', 'PosReg', (159, 167))
591053	30555465	Chemerin knockdown, in turn, resulted in increased migratory ability and invasiveness.	('invasiveness', 'CPA', (73, 85))	('increased', 'PosReg', (41, 50))	('knockdown', 'Var', (9, 18))	('Chemerin', 'Gene', (0, 8))	('migratory ability', 'CPA', (51, 68))	('Chemerin', 'Gene', '5919', (0, 8))
591076	30555465	Additionally, high expression of chemerin was shown to be associated with better outcomes for patients in two clinical studies, demonstrating chemerin's potential for therapeutic intervention in melanoma.	('patients', 'Species', '9606', (94, 102))	('high expression', 'Var', (14, 29))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))
591100	30555465	Thus, the results of both in vitro and in vivo experiments indicated that targeting chemerin/CMKLR1 could potentially elicit antitumor effects in clinical settings.	('chemerin/CMKLR1', 'Gene', (84, 99))	('tumor', 'Disease', (129, 134))	('targeting', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('elicit', 'Reg', (118, 124))
591123	30555465	In syngeneic C57BL6 mice implanted with prochemerin-expressing LLC grafts, tumor formation was impeded by prochemerin expression.	('prochemerin', 'Var', (106, 117))	('impeded', 'NegReg', (95, 102))	('mice', 'Species', '10090', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
591158	30555465	In some cases, cancers may silence RARRES2 via hypermethylation to evade immune surveillance.	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('RARRES2', 'Gene', (35, 42))	('silence', 'NegReg', (27, 34))	('cancers', 'Disease', (15, 22))	('RARRES2', 'Gene', '5919', (35, 42))	('hypermethylation', 'Var', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
591161	30555465	Importantly, for cases in which silencing of RARRES2 has been reported, the restoration and/or forced overexpression of chemerin in the microtumor environment may incite compelling antitumor effects, indicating new avenues of research for chemerin in cancer.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('incite', 'NegReg', (163, 169))	('RARRES2', 'Gene', (45, 52))	('overexpression', 'PosReg', (102, 116))	('tumor', 'Disease', (141, 146))	('silencing', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Disease', (251, 257))	('RARRES2', 'Gene', '5919', (45, 52))
591216	27028857	Collectively, these findings provide evidence linking chronic inflammation-associated genomic instability with esophageal carcinogenesis and suggest possibilities for early detection and intervention of esophageal carcinogenesis.	('chronic inflammation', 'Disease', (54, 74))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (203, 228))	('chronic inflammation', 'Disease', 'MESH:D007249', (54, 74))	('esophageal carcinogenesis', 'Disease', (203, 228))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (111, 136))	('genomic instability', 'Var', (86, 105))	('esophageal carcinogenesis', 'Disease', (111, 136))
591240	27028857	As a result, this process can lead to mutations in tumor-related genes, which increases cancer risk.	('lead to', 'Reg', (30, 37))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('increases', 'PosReg', (78, 87))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
591243	27028857	Intriguingly, the immunostaining intensity of 8-OHdG was prominently stronger in tissues with higher degree of chronic inflammation, whereas only a small fraction of non-inflammation tissues showed positive immunostaining (Figure 2A-2E).	('8-OHdG', 'Chemical', 'MESH:C067134', (46, 52))	('inflammation', 'Disease', 'MESH:D007249', (170, 182))	('inflammation', 'Disease', 'MESH:D007249', (119, 131))	('8-OHdG', 'Var', (46, 52))	('inflammation', 'Disease', (170, 182))	('inflammation', 'Disease', (119, 131))	('stronger', 'PosReg', (69, 77))	('immunostaining intensity', 'MPA', (18, 42))	('chronic inflammation', 'Disease', (111, 131))	('chronic inflammation', 'Disease', 'MESH:D007249', (111, 131))
591257	27028857	Immunohistochemical analysis revealed that immunostaining of 8-OHdG and gammaH2AX reached significantly higher positive rates than that in normal tissues (P < 0.05) (Figure 3M-3N).	('8-OHdG', 'Chemical', 'MESH:C067134', (61, 67))	('gammaH2AX', 'Gene', (72, 81))	('gammaH2AX', 'Gene', '15270', (72, 81))	('8-OHdG', 'Var', (61, 67))	('higher', 'PosReg', (104, 110))	('positive rates', 'MPA', (111, 125))
591261	27028857	These findings suggest that chronic inflammation-related genomic instability may trigger the malignant transformation of esophageal epithelial cells.	('genomic instability', 'Var', (57, 76))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (121, 141))	('malignant transformation', 'CPA', (93, 117))	('trigger', 'Reg', (81, 88))	('chronic inflammation', 'Disease', (28, 48))	('chronic inflammation', 'Disease', 'MESH:D007249', (28, 48))
591269	27028857	Oxidative damage to DNA by ROS is frequently postulated to give rise to mutations in tumor-related genes involved in essential cellular processes including proliferation, cell cycle checkpoints, apoptosis, and DNA repair.	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (72, 81))	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('apoptosis', 'CPA', (195, 204))	('ROS', 'Gene', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cell cycle', 'CPA', (171, 181))
591272	27028857	Of the many classes of DNA damage, DNA double-strand breaks (DSBs) is a serious lesion that can cause genomic instability, which may lead to cancer development.	('DNA double-strand breaks', 'Var', (35, 59))	('lead to', 'Reg', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('genomic instability', 'MPA', (102, 121))	('cause', 'Reg', (96, 101))	('DSBs', 'Chemical', '-', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
591276	27028857	Collectively, these results provide evidence linking chronic inflammation-associated genomic instability with esophageal carcinogenesis and suggest possibilities for early detection and intervention of esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (202, 227))	('chronic inflammation', 'Disease', 'MESH:D007249', (53, 73))	('genomic instability', 'Var', (85, 104))	('chronic inflammation', 'Disease', (53, 73))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (110, 135))	('esophageal carcinogenesis', 'Disease', (110, 135))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (202, 227))
591314	26543377	Clinical trials had also revealed that substituting PTX for 5-FU and combining with CDDP had achieved better efficacy in a neoadjuvant and definitive setting for advanced esophageal cancer, and the effective rate was approximately 50%-60% with a more favorable toxicity profile, which was also validated in our cancer center.	('PTX', 'Chemical', 'MESH:D017239', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('substituting', 'Var', (39, 51))	('CDDP', 'Chemical', '-', (84, 88))	('toxicity', 'Disease', 'MESH:D064420', (261, 269))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('toxicity', 'Disease', (261, 269))	('cancer', 'Disease', (182, 188))	('5-FU', 'Chemical', 'MESH:D005472', (60, 64))	('esophageal cancer', 'Disease', (171, 188))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
591395	25216514	Responders had a significantly better disease-free survival than non-responders only if EGFR expression level (p=0.0152) or copy number (p=0.0050) was low.	('expression level', 'MPA', (93, 109))	('disease-free survival', 'CPA', (38, 59))	('better', 'PosReg', (31, 37))	('low', 'NegReg', (151, 154))	('EGFR', 'Gene', '1956', (88, 92))	('copy number', 'Var', (124, 135))	('EGFR', 'Gene', (88, 92))
591397	25216514	EGFR overexpression and gene copy number are independent adverse prognostic factors for neoadjuvant chemotherapy-treated EAC patients, particularly for responders.	('EGFR', 'Gene', (0, 4))	('EAC', 'Disease', (121, 124))	('gene copy number', 'Var', (24, 40))	('overexpression', 'PosReg', (5, 19))	('EAC', 'Phenotype', 'HP:0011459', (121, 124))	('EGFR', 'Gene', '1956', (0, 4))	('patients', 'Species', '9606', (125, 133))
591415	25216514	EGFR expression and copy number changes were significantly positively correlated in neoadjuvant chemotherapy-treated patients (p<0.0001) and primary resection patients (p=0.0057).	('positively', 'PosReg', (59, 69))	('expression', 'MPA', (5, 15))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (117, 125))	('copy number changes', 'Var', (20, 39))	('patients', 'Species', '9606', (159, 167))	('EGFR', 'Gene', '1956', (0, 4))
591441	25216514	In contrast, the frequency of EGFR overexpression, was significantly higher in non-responders than in primary resection patients (p=0.0107; Figure 3B).	('EGFR', 'Gene', (30, 34))	('patients', 'Species', '9606', (120, 128))	('overexpression', 'PosReg', (35, 49))	('non-responders', 'Var', (79, 93))	('EGFR', 'Gene', '1956', (30, 34))	('higher', 'PosReg', (69, 75))
591447	25216514	The oncogenic resistance is associated with highly aggressive cancer phenotype and, therefore no survival benefit.	('oncogenic resistance', 'Var', (4, 24))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
591464	25216514	Our data, however, demonstrated that EGFR expression or copy number changes are strong and independent molecular prognostic factors for disease-free and overall survival in patients with EAC who responded to neoadjuvant chemotherapy but had an unfavorable diagnosis.	('EAC', 'Disease', (187, 190))	('copy number changes', 'Var', (56, 75))	('patients', 'Species', '9606', (173, 181))	('EAC', 'Phenotype', 'HP:0011459', (187, 190))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))
591468	25216514	In addition, inhibition of EGFR activation enhances cisplatin-induced cell death.	('EGFR', 'Gene', '1956', (27, 31))	('activation enhances', 'PosReg', (32, 51))	('EGFR', 'Gene', (27, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('inhibition', 'Var', (13, 23))	('cisplatin-induced cell death', 'CPA', (52, 80))
591482	25216514	In conclusion, our data demonstrate that EGFR overexpression and gene copy number changes are independent adverse prognostic factors in EAC patients and may be useful molecular markers for outcome prediction in patients who receive neoadjuvant platin-based chemotherapy.	('EGFR', 'Gene', (41, 45))	('overexpression', 'PosReg', (46, 60))	('patients', 'Species', '9606', (211, 219))	('gene copy number changes', 'Var', (65, 89))	('EAC', 'Phenotype', 'HP:0011459', (136, 139))	('platin', 'Chemical', 'MESH:D010984', (244, 250))	('EAC', 'Disease', (136, 139))	('patients', 'Species', '9606', (140, 148))	('EGFR', 'Gene', '1956', (41, 45))
591577	22258871	Survival rates were estimated by using the Kaplan-Meier function (log rank test) to compare the OS and CSS among patients with high versus low COX-2 and VEGF expression.	('COX-2', 'Gene', '5743', (143, 148))	('low', 'NegReg', (139, 142))	('CSS', 'Chemical', '-', (103, 106))	('VEGF', 'Gene', (153, 157))	('high', 'Var', (127, 131))	('patients', 'Species', '9606', (113, 121))	('VEGF', 'Gene', '7422', (153, 157))	('COX-2', 'Gene', (143, 148))	('CSS', 'Disease', (103, 106))	('OS', 'Chemical', '-', (96, 98))
591579	22258871	The following parameters were evaluated in univariate analysis: T-stage (T1 or T2 vs. T3), lymph node metastases (no vs. yes), differentiation grade (good and moderate vs. poor), COX-2 (low vs. high), lymph node ratio (<=25% vs. >25%), vasoinvasion (no vs. yes), perineural growth (no vs. yes), VEGF (low vs. high), median age (<64 vs. >=64 years), gender, and perinodal extension (no vs. yes).	('<=25', 'Var', (219, 223))	('VEGF', 'Gene', '7422', (295, 299))	('lymph node metastases', 'Disease', 'MESH:D009362', (91, 112))	('lymph node metastases', 'Disease', (91, 112))	('VEGF', 'Gene', (295, 299))	('perineural growth', 'CPA', (263, 280))	('COX-2', 'Gene', (179, 184))	('COX-2', 'Gene', '5743', (179, 184))	('perinodal extension', 'CPA', (361, 380))
591591	22258871	COX-2 staining was positively associated with lymph node metastases (p = .015, Table 2).	('staining', 'Var', (6, 14))	('associated', 'Reg', (30, 40))	('lymph node metastases', 'Disease', 'MESH:D009362', (46, 67))	('lymph node metastases', 'Disease', (46, 67))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))
591599	22258871	Patients with high VEGF expression more frequently developed recurrence of disease (p = .004, Table 3).	('developed', 'PosReg', (51, 60))	('VEGF', 'Gene', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('recurrence', 'Disease', (61, 71))	('VEGF', 'Gene', '7422', (19, 23))
591605	22258871	For OS, high COX-2 expression was an independent prognostic factor (HR 1.65; 95% CI 1.04-2.61; p = .034, Table 5).	('expression', 'MPA', (19, 29))	('high', 'Var', (8, 12))	('OS', 'Chemical', '-', (4, 6))	('COX-2', 'Gene', (13, 18))	('COX-2', 'Gene', '5743', (13, 18))
591629	22258871	In another study of 40 patients with ESCC, a significant correlation between high COX-2 (65.4%) and VEGF (50%) expression (p < .005) was reported using immunohistochemistry (IHC).	('ESCC', 'Disease', (37, 41))	('high', 'Var', (77, 81))	('VEGF', 'Gene', '7422', (100, 104))	('patients', 'Species', '9606', (23, 31))	('COX-2', 'Gene', (82, 87))	('expression', 'MPA', (111, 121))	('COX-2', 'Gene', '5743', (82, 87))	('VEGF', 'Gene', (100, 104))
591635	22258871	Analysis of (linear) relationships between COX-2 expression and prognostic parameters showed a significant correlation between high COX-2 expression and the presence of lymph node metastases.	('lymph node metastases', 'Disease', 'MESH:D009362', (169, 190))	('COX-2', 'Gene', (132, 137))	('high', 'Var', (127, 131))	('lymph node metastases', 'Disease', (169, 190))	('COX-2', 'Gene', (43, 48))	('COX-2', 'Gene', '5743', (132, 137))	('expression', 'MPA', (138, 148))	('COX-2', 'Gene', '5743', (43, 48))
591798	32117597	Alpha gal epitopes in these grafts were reported to be significantly higher compared with the gal knockout heart valves.	('epitopes', 'Var', (10, 18))	('gal', 'Gene', (6, 9))	('gal', 'Gene', '51083', (6, 9))	('gal', 'Gene', '51083', (94, 97))	('gal', 'Gene', (94, 97))	('higher', 'PosReg', (69, 75))
591837	32117597	Positive or negative effects of perfusion-rotation bioreactor on the recellularization process is not fully understood, for example, reduced expression of GAGs in the acellular scaffold, which might be a plausible cause for the reduced cellular attachment of the whole organ and epithelial lining in the tissue as observed in our study.	('GAGs', 'Chemical', 'MESH:D006025', (155, 159))	('cellular attachment', 'CPA', (236, 255))	('reduced', 'NegReg', (228, 235))	('GAGs', 'Var', (155, 159))	('expression', 'MPA', (141, 151))	('reduced', 'NegReg', (133, 140))
591847	31164139	We searched MEDLINE, Embase, and Cochrane library up to March 31, 2019 for randomized controlled trials (RCTs) comparing T-ESD and conventional endoscopic submucosal dissection (C-ESD) for superficial gastrointestinal neoplasms.	('gastrointestinal neoplasms', 'Disease', (201, 227))	('neoplasms', 'Phenotype', 'HP:0002664', (218, 227))	('T-ESD', 'Var', (121, 126))	('gastrointestinal neoplasms', 'Disease', 'MESH:D004067', (201, 227))	('gastrointestinal neoplasms', 'Phenotype', 'HP:0007378', (201, 227))
591862	31164139	We, therefore, conducted this meta-analysis of randomized trials to assess the efficacy of T-ESD vs conventional ESD (C-ESD) for the treatment of superficial gastrointestinal neoplasms.	('T-ESD', 'Var', (91, 96))	('gastrointestinal neoplasms', 'Disease', 'MESH:D004067', (158, 184))	('gastrointestinal neoplasms', 'Phenotype', 'HP:0007378', (158, 184))	('gastrointestinal neoplasms', 'Disease', (158, 184))	('neoplasms', 'Phenotype', 'HP:0002664', (175, 184))
591882	31164139	The pooled estimate of procedure time demonstrated that there was no significant difference between the T-ESD and C-ESD groups in the gastric neoplasms group (MD = - 0.25, 95% CI - 5.5, 5.01, I2 = 0%, P = 0.93), while in colorectal neoplasms, the procedure time was significantly shorter in the T-ESD group than in the C-ESD group (MD = - 37.94, 95% CI - 54.82, - 21.05, I2 = 60%, P < 0.0001).	('gastric neoplasms', 'Disease', (134, 151))	('neoplasms', 'Phenotype', 'HP:0002664', (232, 241))	('T-ESD', 'Var', (295, 300))	('colorectal neoplasms', 'Disease', 'MESH:D015179', (221, 241))	('gastric neoplasms', 'Disease', 'MESH:D013274', (134, 151))	('gastric neoplasms', 'Phenotype', 'HP:0006753', (134, 151))	('neoplasms', 'Phenotype', 'HP:0002664', (142, 151))	('shorter', 'NegReg', (280, 287))	('colorectal neoplasms', 'Disease', (221, 241))
591909	26460825	The K14-Cdx2::L2-IL-1beta double transgenic mice had half as many metaplastic nodules as control L2-IL-1beta mice.	('metaplastic nodules', 'CPA', (66, 85))	('transgenic mice', 'Species', '10090', (33, 48))	('mice', 'Species', '10090', (109, 113))	(':L2-IL-1beta', 'Var', (13, 25))	('mice', 'Species', '10090', (44, 48))
591912	26460825	Fluorescence activated cell sorting of immune cells infiltrating the metaplasia identified a population of CD11b+Gr-1+ cells that are significantly reduced in K14-Cdx2::L2-IL-1beta mice.	('Gr-1', 'Gene', '546644', (113, 117))	('mice', 'Species', '10090', (181, 185))	('reduced', 'NegReg', (148, 155))	('Gr-1', 'Gene', (113, 117))	('rat', 'Species', '10116', (58, 61))	('K14-Cdx2', 'Var', (159, 167))
591926	26460825	These L2-IL-1beta mice develop a chronic inflammatory esophagitis by 3 months (Figure 1A) that is followed subsequently by the development of a columnar metaplasia with intestinal features that later progresses to dysplasia and cancer.	('columnar metaplasia', 'Disease', (144, 163))	('inflammatory esophagitis', 'Disease', 'MESH:D004941', (41, 65))	('columnar metaplasia', 'Disease', 'MESH:D008679', (144, 163))	('mice', 'Species', '10090', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('inflammatory esophagitis', 'Disease', (41, 65))	('dysplasia and cancer', 'Disease', 'MESH:D009369', (214, 234))	('esophagitis', 'Phenotype', 'HP:0100633', (54, 65))	('L2-IL-1beta', 'Var', (6, 17))
591933	26460825	Given that Cdx2 is expressed in BE, is required for the intestinal phenotype, and that ectopic expression of Cdx2 in the esophagus induces a barrier dysfunction, we hypothesized that the K14-Cdx2 transgene would synergize with the L2-IL-1beta transgene and promote a more rapid progression to metaplasia and cancer.	('K14-Cdx2', 'Var', (187, 195))	('metaplasia and cancer', 'Disease', 'MESH:D008679', (293, 314))	('Cdx2', 'Gene', (109, 113))	('promote', 'PosReg', (257, 264))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('induces', 'Reg', (131, 138))	('ectopic expression', 'Var', (87, 105))
591934	26460825	Unexpectedly, the double transgenic mice had fewer metaplastic nodules at the SCJ compared to the L2-IL-1beta control mice.	('metaplastic nodules at the SCJ', 'CPA', (51, 81))	('fewer', 'NegReg', (45, 50))	('mice', 'Species', '10090', (36, 40))	('transgenic mice', 'Species', '10090', (25, 40))	('mice', 'Species', '10090', (118, 122))	('double transgenic', 'Var', (18, 35))
591942	26460825	Histologic analysis of the esophagus confirmed Cdx2 protein expression in the basal epithelial cell population of only the K14-Cdx2 and K14-Cdx2::L2-IL-1beta transgenic lines but not in wild-type littermates or L2-IL-1beta transgenic mice (Figure 1C).	('K14-Cdx2', 'Var', (123, 131))	('transgenic', 'Species', '10090', (158, 168))	('Cdx2', 'Gene', (47, 51))	('transgenic mice', 'Species', '10090', (223, 238))	('transgenic', 'Species', '10090', (223, 233))
591945	26460825	The L2-IL-1beta transgene induces a brisk inflammatory infiltrate in the esophagus, oral cavity, and tongue of both L2-IL-1beta possessing transgenic lines (Figure 2A and data not shown).	('transgene', 'Var', (16, 25))	('induces', 'Reg', (26, 33))	('transgenic', 'Species', '10090', (139, 149))	('rat', 'Species', '10116', (61, 64))	('L2-IL-1beta', 'Gene', (4, 15))
591948	26460825	Lastly, systemic inflammation induced by IL-1beta expression is similarly unaffected by the K14-Cdx2 transgene.	('IL-1beta', 'Gene', (41, 49))	('K14-Cdx2 transgene', 'Var', (92, 110))	('systemic inflammation', 'Disease', 'MESH:D007249', (8, 29))	('systemic inflammation', 'Disease', (8, 29))
591953	26460825	A prominent, nodular metaplasia was found at the SCJ in nearly 75% of the L2-IL-1beta mice (n = 19), in keeping with previously reported observations ( and Figure 3A and 3B).	('nodular metaplasia', 'Disease', 'MESH:D020518', (13, 31))	('L2-IL-1beta', 'Var', (74, 85))	('nodular metaplasia', 'Disease', (13, 31))	('mice', 'Species', '10090', (86, 90))
591957	26460825	Despite their similar disease frequencies, K14-Cdx2::L2-IL-1beta mice appeared to have a reduced burden of nodular metaplasia compared to the L2-IL-1beta mice (Figure 3A).	('mice', 'Species', '10090', (154, 158))	(':L2-IL-1beta', 'Var', (52, 64))	('nodular metaplasia', 'Disease', (107, 125))	('nodular metaplasia', 'Disease', 'MESH:D020518', (107, 125))	('mice', 'Species', '10090', (65, 69))	('reduced', 'NegReg', (89, 96))
591959	26460825	Most significantly, the K14-Cdx2::L2-IL-1beta mice (2.2 nodules/mouse +- 2.0; n = 17) had half as many metaplastic nodules as the L2-IL-1beta littermates (4.6 nodules/mouse +- 2.4; n = 19) (Figure 3C).	('metaplastic nodules', 'CPA', (103, 122))	('mouse', 'Species', '10090', (64, 69))	('mice', 'Species', '10090', (46, 50))	(':L2-IL-1beta', 'Var', (33, 45))	('mouse', 'Species', '10090', (167, 172))
591963	26460825	In summary, Cdx2 co-expression with IL-1beta reduced the number of nodules of Barrett's-like metaplasia observed in the L2-IL-1beta mice treated with DCA for 12 months.	('reduced', 'NegReg', (45, 52))	('DCA', 'Chemical', '-', (150, 153))	('co-expression', 'Var', (17, 30))	('Cdx2', 'Gene', (12, 16))	('mice', 'Species', '10090', (132, 136))
591965	26460825	The metaplasia which arises in L2-IL-1beta mice has been previously-described as Barrett's-like based on several criteria, the most importantly being 1) the induction of intestinal mucin-producing cells (but not classic goblet cells), 2) the disease arising in the setting of chronic inflammation at the SCJ (as occurs in the human disease), and 3) a gene expression pattern which significantly overlaps with the human BE disease.	('mice', 'Species', '10090', (43, 47))	('inflammation', 'Disease', 'MESH:D007249', (284, 296))	('inflammation', 'Disease', (284, 296))	("Barrett's-like", 'Disease', (81, 95))	('human', 'Species', '9606', (413, 418))	('human', 'Species', '9606', (326, 331))	('L2-IL-1beta', 'Var', (31, 42))	('metaplasia', 'Disease', (4, 14))
591968	26460825	In both L2-IL-1beta and K14-Cdx2::L2-IL-1beta mice, the metaplastic cells express intestinal mucins, as evidenced by positive staining with Alcian blue and Muc2 (Figures 5A and 5B).	('Muc2', 'Gene', (156, 160))	('intestinal mucins', 'Protein', (82, 99))	('Muc2', 'Gene', '17831', (156, 160))	('mice', 'Species', '10090', (46, 50))	(':L2-IL-1beta', 'Var', (33, 45))	('Alcian blue', 'Chemical', 'MESH:D000423', (140, 151))
591971	26460825	We next considered other mechanisms by which Cdx2 co-expression in the squamous epithelium reduced the development of the nodular metaplasia at the SCJ.	('nodular metaplasia', 'Disease', (122, 140))	('nodular metaplasia', 'Disease', 'MESH:D020518', (122, 140))	('reduced', 'NegReg', (91, 98))	('co-expression', 'Var', (50, 63))	('Cdx2', 'Gene', (45, 49))
591979	26460825	In summary, the K14-Cdx2 transgene limits the formation of the BE like metaplasia in L2-IL-1beta transgenic mice by increasing apoptosis in the developing SCJ metaplasia.	('transgenic mice', 'Species', '10090', (97, 112))	('limits', 'NegReg', (35, 41))	('increasing', 'PosReg', (116, 126))	('K14-Cdx2', 'Var', (16, 24))	('apoptosis', 'CPA', (127, 136))
591986	26460825	In particular, there were several genes reduced whose products are associated with immature myeloid cells, including IL-17a, IL-17c, IL-23a, S100A8, S100A9, and Csf3r (Colony stimulating factor 3 receptor-granulocytes), as well as reductions in Granzyme B and a number of serine proteases suggestive of cytotoxic T cells (Table 1).	('IL-23a', 'Gene', '83430', (133, 139))	('Granzyme B', 'Gene', (245, 255))	('IL-17c', 'Gene', (125, 131))	('S100A9', 'Var', (149, 155))	('reductions', 'NegReg', (231, 241))	('Csf3r', 'Gene', (161, 166))	('IL-17a', 'Gene', '16171', (117, 123))	('IL-17c', 'Gene', '234836', (125, 131))	('Granzyme B', 'Gene', '14939', (245, 255))	('Csf3r', 'Gene', '12986', (161, 166))	('S100A8', 'Gene', (141, 147))	('serine proteases', 'Enzyme', (272, 288))	('IL-23a', 'Gene', (133, 139))	('S100A8', 'Gene', '20201', (141, 147))	('IL-17a', 'Gene', (117, 123))
591988	26460825	To explore whether the inflammatory infiltrate at the SCJ was diminished in K14-Cdx2::L2-IL-1beta mice, we stained for CD45+ infiltrating inflammatory cells.	('rat', 'Species', '10116', (131, 134))	('diminished', 'NegReg', (62, 72))	('K14-Cdx2', 'Var', (76, 84))	('rat', 'Species', '10116', (42, 45))	('mice', 'Species', '10090', (98, 102))
591989	26460825	We found that both L2-IL-1beta and K14-Cdx2::L2-IL-1beta mice maintained a brisk CD45+ immune cell infiltration at the SCJ junction as compared to normal WT littermates (Figure 7C, 7D, and 7E).	('CD45+ immune cell', 'MPA', (81, 98))	(':L2-IL-1beta', 'Var', (44, 56))	('mice', 'Species', '10090', (57, 61))	('rat', 'Species', '10116', (105, 108))
591991	26460825	To gain a clearer understanding of how the K14-Cdx2 transgene is altering the nature of the inflammatory response in the L2-IL-1beta mice, we carefully characterized immune cell populations infiltrating the esophagus and SCJ metaplasia by flow cytometry.	('rat', 'Species', '10116', (196, 199))	('mice', 'Species', '10090', (133, 137))	('K14-Cdx2', 'Var', (43, 51))	('altering', 'Reg', (65, 73))
591992	26460825	Levels of T-cells (CD4, CD8), B-cells (B220), dendritic cells (CD11c), natural killer (NK) cells (CD49b) were not altered by the K14-Cdx2 transgene in either the SCJ metaplasia or esophagus (Figure 8A and 8B; n = 5 mice for each genotype, p > 0.05).	('B-cells', 'CellLine', 'CVCL:C764', (30, 37))	('K14-Cdx2 transgene', 'Var', (129, 147))	('CD8', 'Gene', (24, 27))	('CD8', 'Gene', '925', (24, 27))	('mice', 'Species', '10090', (215, 219))
591993	26460825	Cell surface markers for granulocytes (Gr-1) and monocytes (CD11b) appeared to be significantly diminished in the K14-Cdx2::L2-IL-1beta mice, by 4 to 8-fold in both the esophagus (p = 0.049 and p = 0.053, respectively n = 5 mice each genotype) and the SCJ metaplasia (p = 0.003 and p = 0.002, respectively, n = 5 mice each genotype) (Figure 8C), suggesting this effect was systemic and not confined to the SCJ.	('mice', 'Species', '10090', (136, 140))	('mice', 'Species', '10090', (224, 228))	('Gr-1', 'Gene', '546644', (39, 43))	('mice', 'Species', '10090', (313, 317))	('Gr-1', 'Gene', (39, 43))	('diminished', 'NegReg', (96, 106))	('K14-Cdx2::L2-IL-1beta', 'Var', (114, 135))
592003	26460825	We found the CD45+CD11b+ cells from esophagus and SCJ metaplasia of the L2-IL-1beta mice were Ly-6G+ and Ly-6C+ (Figure 10A, 10B), which is consistent with a granulocytic lineage as previously described.	('Ly-6C', 'Gene', (105, 110))	('CD45+CD11b+', 'Gene', (13, 24))	('Ly-6C', 'Gene', '17067', (105, 110))	('Ly-6G', 'Gene', '546644', (94, 99))	('Ly-6G', 'Gene', (94, 99))	('CD45+CD11b+', 'Var', (13, 24))	('mice', 'Species', '10090', (84, 88))
592029	26460825	Moreover, three of them, IL-17c, S100A8 and S100A9, are known to be expressed by squamous epithelium including the esophagus.	('S100A8', 'Gene', (33, 39))	('IL-17c', 'Gene', '234836', (25, 31))	('S100A9', 'Var', (44, 50))	('S100A8', 'Gene', '20201', (33, 39))	('IL-17c', 'Gene', (25, 31))
592030	26460825	Quantitative PCR analysis of the expression of these genes in L2-IL-1beta and K14-Cdx2::L2-IL-1beta mice confirms a strong reduction of their mRNA levels in both the esophagus and SCJ nodular metaplasia in K14-Cdx2::L2-IL-1beta mice (Figure 14A).	(':L2-IL-1beta', 'Var', (87, 99))	('mRNA levels', 'MPA', (142, 153))	('mice', 'Species', '10090', (100, 104))	('SCJ nodular metaplasia', 'Disease', 'MESH:D020518', (180, 202))	('reduction', 'NegReg', (123, 132))	('mice', 'Species', '10090', (228, 232))	('SCJ nodular metaplasia', 'Disease', (180, 202))
592033	26460825	S100A9 protein is detected more abundantly in the squamous epithelium of L2-IL-1beta when compared to K14-Cdx2::L2-IL-1beta mice (Figure 14B).	('L2-IL-1beta', 'Var', (73, 84))	('S100A9', 'Gene', (0, 6))	('mice', 'Species', '10090', (124, 128))	('protein', 'Protein', (7, 14))
592034	26460825	Additionally, S100A9 expressing cells were also much more abundant in the inflammatory cells infiltrating the submucosa of the L2-IL-1beta mice than the K14-Cdx2::L2-IL-1beta transgenic mice.	('rat', 'Species', '10116', (99, 102))	('S100A9', 'Gene', (14, 20))	('L2-IL-1beta', 'Var', (127, 138))	('mice', 'Species', '10090', (186, 190))	('mice', 'Species', '10090', (139, 143))	('transgenic mice', 'Species', '10090', (175, 190))	('more abundant', 'PosReg', (53, 66))
592050	26460825	In our exploration of the mechanism for this protection, we eliminated trivial possibilities, such as Cdx2 expression reducing esophageal IL-1beta levels and systemic inflammation, or that Cdx2 expression reduced cell proliferation, thereby limiting metaplasia formation.	('Cdx2', 'Gene', (189, 193))	('esophageal IL-1beta levels', 'MPA', (127, 153))	('limiting', 'NegReg', (241, 249))	('rat', 'Species', '10116', (12, 15))	('systemic inflammation', 'Disease', 'MESH:D007249', (158, 179))	('rat', 'Species', '10116', (225, 228))	('cell proliferation', 'CPA', (213, 231))	('reduced', 'NegReg', (205, 212))	('reducing', 'NegReg', (118, 126))	('systemic inflammation', 'Disease', (158, 179))	('expression', 'Var', (107, 117))	('Cdx2', 'Gene', (102, 106))	('metaplasia formation', 'CPA', (250, 270))
592051	26460825	In contrast, we clearly demonstrate a very novel mechanism, that Cdx2 expression is associated with an increase in CD8+ cell-dependent apoptosis in the developing metaplasia.	('CD8', 'Gene', '925', (115, 118))	('Cdx2', 'Gene', (65, 69))	('increase', 'PosReg', (103, 111))	('CD8', 'Gene', (115, 118))	('expression', 'Var', (70, 80))	('rat', 'Species', '10116', (31, 34))
592053	26460825	Based on the literature regarding these immature myeloid cells, their loss or disruption in vivo typically leads to enhanced immune-mediated disruption of tumor growth, often via the actions of cytotoxic T-cells, consistent with our findings.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('enhanced', 'PosReg', (116, 124))	('loss', 'NegReg', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('disruption', 'Var', (78, 88))	('tumor', 'Disease', (155, 160))	('rat', 'Species', '10116', (17, 20))
592057	26460825	We clearly demonstrate that Cdx2 expression reduces levels of proinflammatory S100A8/A9 proteins and also IL-17 in the esophagus, but transgenic IL-1beta is entirely unaffected.	('rat', 'Species', '10116', (18, 21))	('Cdx2', 'Gene', (28, 32))	('IL-17', 'MPA', (106, 111))	('S100A8', 'Gene', '20201', (78, 84))	('expression', 'Var', (33, 43))	('S100A8', 'Gene', (78, 84))	('transgenic', 'Species', '10090', (134, 144))	('reduces', 'NegReg', (44, 51))
592060	26460825	Together these findings suggest a Cdx2 expression in the esophagus reduces the production of the proinflammatory S100A8/a9 proteins and IL-17c (Figure 14).	('S100A8', 'Gene', (113, 119))	('expression', 'Var', (39, 49))	('S100A8', 'Gene', '20201', (113, 119))	('IL-17c', 'Gene', '234836', (136, 142))	('reduces', 'NegReg', (67, 74))	('IL-17c', 'Gene', (136, 142))	('Cdx2', 'Gene', (34, 38))
592063	26460825	In contrast, other studies have suggested Cdx2 may inhibit the NF-kappaB signaling pathway, possibly by binding the p65 subunit and inhibiting DNA binding of the NF-kappaB complex.	('DNA binding', 'Interaction', (143, 154))	('Cdx2', 'Var', (42, 46))	('p65', 'Gene', (116, 119))	('inhibit', 'NegReg', (51, 58))	('binding', 'Interaction', (104, 111))	('p65', 'Gene', '19697', (116, 119))	('inhibiting', 'NegReg', (132, 142))	('NF-kappaB signaling pathway', 'Pathway', (63, 90))
592112	26460825	After 72 h, cells were collected and stained with 7AAD, anti-CD45, CD3, CD4, Gr-1 and CD11b mAbs cocktail.	('anti-CD45', 'Var', (56, 65))	('Gr-1', 'Gene', '546644', (77, 81))	('Gr-1', 'Gene', (77, 81))	('CD3', 'Gene', (67, 70))	('CD3', 'Gene', '12501', (67, 70))
592129	24074251	Phase 1 trials are investigating the inhibitory potential of CXCR4 antagonists in vivo in several other entities (for example high-grade glioma; NCT01339039 or multiple myeloma; NCT00903968).	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('multiple myeloma', 'Disease', 'MESH:D009101', (160, 176))	('multiple myeloma', 'Phenotype', 'HP:0006775', (160, 176))	('glioma', 'Disease', (137, 143))	('multiple myeloma', 'Disease', (160, 176))	('NCT01339039', 'Var', (145, 156))
592208	32430661	No significant difference was seen between LCT/EUS (median 6 cm) and LPET (median 6 cm, p = 0.846) 18F-FDG-PET can help to identify subclinical lymph node metastases which are located outside of recommended radiation fields.	('FDG', 'Gene', (103, 106))	('subclinical', 'Var', (132, 143))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('LCT', 'Gene', (43, 46))	('FDG', 'Gene', '23583', (103, 106))	('LCT', 'Gene', '3938', (43, 46))	('metastases', 'Disease', (155, 165))
592216	32430661	Because FDG-PET/CT has also demonstrated promising sensitivity, specificity, and accuracy regarding the detection of lymph node metastases as well as the detection of the primary tumor, implementation of PET into the radiation planning process might change the resulting target volumes, as it has already been demonstrated for other tumor entities like prostate cancer or squamous cell cancer of the tongue.	('prostate cancer', 'Phenotype', 'HP:0012125', (353, 368))	('FDG', 'Gene', (8, 11))	('squamous cell cancer of the tongue', 'Phenotype', 'HP:0030413', (372, 406))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer of the tongue', 'Phenotype', 'HP:0100648', (386, 406))	('PET', 'Var', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('tumor entities like prostate cancer', 'Disease', (333, 368))	('squamous cell cancer', 'Disease', (372, 392))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (372, 392))	('target', 'MPA', (271, 277))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('squamous cell cancer', 'Disease', 'MESH:D002294', (372, 392))	('change', 'Reg', (250, 256))	('metastases', 'Disease', (128, 138))	('FDG', 'Gene', '23583', (8, 11))	('tumor', 'Disease', (333, 338))	('tumor entities like prostate cancer', 'Disease', 'MESH:D011471', (333, 368))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('tumor', 'Disease', (179, 184))
592242	32430661	Less than 5% of these patients had LNM right supraclavicular, gastric, diaphragmatic, celiac, hilar, and retrosternal.	('celiac', 'Disease', (86, 92))	('hilar', 'Disease', (94, 99))	('gastric', 'Disease', (62, 69))	('patients', 'Species', '9606', (22, 30))	('retrosternal', 'Disease', (105, 117))	('LNM', 'Var', (35, 38))	('diaphragmatic', 'Disease', (71, 84))
592246	32430661	The median distance of LNM to the primary tumor was 4.2 and 2.4 cm (p = 0.067) for LNM above the primary tumor and LNM below the primary tumor, respectively.	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('LNM', 'Var', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('LNM', 'Var', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
592284	32430661	In addition, IFI can reduce the dose distribution to the lungs and the rate of pulmonary toxicities, while a concurrent reduction of the doses to the heart can decrease the rate of symptomatic or asymptomatic pericardial effusion.	('decrease', 'NegReg', (160, 168))	('reduce', 'NegReg', (21, 27))	('pulmonary toxicities', 'Disease', (79, 99))	('pulmonary toxicities', 'Disease', 'MESH:D008171', (79, 99))	('pericardial effusion', 'Disease', 'MESH:D010490', (209, 229))	('pericardial effusion', 'Phenotype', 'HP:0001698', (209, 229))	('dose distribution', 'MPA', (32, 49))	('pericardial effusion', 'Disease', (209, 229))	('IFI', 'Var', (13, 16))
592303	31611993	Overexpression of Gli1 in the parental cell line led to decreased levels of radiosensitivity and radiosensitivity of the radioresistant cell line was restored through knockdown of Gli1.	('Gli1', 'Gene', (18, 22))	('Gli1', 'Gene', (180, 184))	('Gli1', 'Gene', '2735', (18, 22))	('decreased', 'NegReg', (56, 65))	('radiosensitivity', 'MPA', (76, 92))	('knockdown', 'Var', (167, 176))	('radiosensitivity', 'MPA', (97, 113))	('Gli1', 'Gene', '2735', (180, 184))	('decreased levels of radiosensitivity', 'Phenotype', 'HP:0010997', (56, 92))
592317	31611993	A previous study established the inhibitory effect of P162, which is a new peptide with anti-cancer mechanism, on glioma-associated oncogene family zinc finger 1 (Gli1), which resulted in noticeable improvements in the level of radiosensitivity in EC cells.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('EC', 'Disease', 'MESH:D004938', (248, 250))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Gli1', 'Gene', (163, 167))	('Gli1', 'Gene', '2735', (163, 167))	('glioma-associated oncogene family zinc finger 1', 'Gene', (114, 161))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('glioma-associated oncogene family zinc finger 1', 'Gene', '2735', (114, 161))	('radiosensitivity', 'MPA', (228, 244))	('improvements', 'PosReg', (199, 211))	('P162', 'Var', (54, 58))
592343	31611993	Radiological measurements of Dq, D0 and N values were higher in Eca109R cells compared with those in Eca109 cells (Table I).	('N', 'Chemical', 'MESH:D009584', (40, 41))	('Eca109R', 'Var', (64, 71))	('higher', 'PosReg', (54, 60))	('N values', 'MPA', (40, 48))
592347	31611993	The expression levels of Gli1, patched 1 (Ptch), smoothened frizzled class receptor (Smo) and Shh were detected by western blotting, and the results revealed that the expression levels of these proteins were significantly higher in Eca109R, compared with Eca109 cells (P<0.05; Fig.	('Ptch', 'Gene', (42, 46))	('higher', 'PosReg', (222, 228))	('Gli1', 'Gene', '2735', (25, 29))	('Ptch', 'Gene', '5727', (42, 46))	('patched 1', 'Gene', '5727', (31, 40))	('Smo', 'Gene', (85, 88))	('Shh', 'Gene', '6469', (94, 97))	('patched 1', 'Gene', (31, 40))	('Eca109R', 'Var', (232, 239))	('Smo', 'Gene', '6608', (85, 88))	('Shh', 'Gene', (94, 97))	('expression levels', 'MPA', (167, 184))	('Gli1', 'Gene', (25, 29))
592355	31611993	The SF2 in pGli1-IRES-EGFP-transfected Eca109 cells was 0.760+-0.033, whereas those in the NC and control groups were 0.532+-0.062 and 0.350+-0.029, respectively (Table II).	('SF2', 'Gene', '6426', (4, 7))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('SF2', 'Gene', (4, 7))	('Gli1', 'Gene', (12, 16))	('Gli1', 'Gene', '2735', (12, 16))	('0.760+-0.033', 'Var', (56, 68))
592357	31611993	Therefore, the transfection of Eca109 cells with the pGli1-IRES-EGFP established an association between overexpression of Gli1 and the radiosensitivity of the cells.	('Gli1', 'Gene', '2735', (122, 126))	('Gli1', 'Gene', (54, 58))	('Gli1', 'Gene', (122, 126))	('Gli1', 'Gene', '2735', (54, 58))	('radiosensitivity of the cells', 'CPA', (135, 164))	('overexpression', 'PosReg', (104, 118))	('transfection', 'Var', (15, 27))
592367	31611993	These results indicated that the radiosensitivity of Eca109R Gli1-silenced cell line was significantly enhanced and that the radioresistance was weakened.	('Gli1', 'Gene', '2735', (61, 65))	('Eca109R', 'Var', (53, 60))	('enhanced', 'PosReg', (103, 111))	('radioresistance', 'CPA', (125, 140))	('radiosensitivity', 'CPA', (33, 49))	('Gli1', 'Gene', (61, 65))	('weakened', 'NegReg', (145, 153))
592372	31611993	Various studies have been performed on the mechanisms of radioresistance, including DNA damage and repair, cell proliferation and apoptosis, abnormal expression of microRNA and lncRNA and disruption of the cell cycle and altered expression of Shh signaling pathway.	('expression', 'MPA', (150, 160))	('apoptosis', 'CPA', (130, 139))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('Shh', 'Gene', (243, 246))	('cell cycle', 'CPA', (206, 216))	('abnormal', 'Var', (141, 149))	('N', 'Chemical', 'MESH:D009584', (181, 182))	('altered', 'Reg', (221, 228))	('cell proliferation', 'CPA', (107, 125))	('N', 'Chemical', 'MESH:D009584', (170, 171))	('Shh', 'Gene', '6469', (243, 246))	('disruption', 'Reg', (188, 198))	('lncRNA', 'Protein', (177, 183))
592383	31611993	In addition, silencing of Gli1 expression was achieved through specific inhibitors of Smo, which led to the inhibition of fission, recurrence and metastasis in ESCC.	('ESCC', 'Disease', (160, 164))	('inhibition', 'NegReg', (108, 118))	('metastasis', 'CPA', (146, 156))	('Smo', 'Gene', '6608', (86, 89))	('fission', 'CPA', (122, 129))	('expression', 'MPA', (31, 41))	('Gli1', 'Gene', (26, 30))	('ESCC', 'Disease', 'MESH:D018307', (160, 164))	('inhibitors', 'Var', (72, 82))	('silencing', 'NegReg', (13, 22))	('Smo', 'Gene', (86, 89))	('Gli1', 'Gene', '2735', (26, 30))	('recurrence', 'CPA', (131, 141))
592385	31611993	The results of the current study revealed higher Gli1 protein expression levels in Eca109R cells, compared with Eca109 cells.	('higher', 'PosReg', (42, 48))	('Gli1', 'Gene', (49, 53))	('Gli1', 'Gene', '2735', (49, 53))	('Eca109R', 'Var', (83, 90))
592390	31611993	Furthermore, the expression of Gli1, Ptch, Shh and Smo was confirmed by western blotting in Eca109 and Eca109R cells; all of the tested proteins exhibited significantly higher expression levels in Eca109R cells compared with Eca109 cells, and immunofluorescence displayed Gli1 protein aggregation around the nucleus.	('higher', 'PosReg', (169, 175))	('Gli1', 'Gene', (272, 276))	('aggregation', 'PosReg', (285, 296))	('Gli1', 'Gene', (31, 35))	('expression levels', 'MPA', (176, 193))	('Eca109R', 'Var', (197, 204))	('Shh', 'Gene', (43, 46))	('Smo', 'Gene', '6608', (51, 54))	('Gli1', 'Gene', '2735', (272, 276))	('Gli1', 'Gene', '2735', (31, 35))	('Ptch', 'Gene', '5727', (37, 41))	('Smo', 'Gene', (51, 54))	('Shh', 'Gene', '6469', (43, 46))	('Ptch', 'Gene', (37, 41))
592397	31611993	A previous study reported that Hh signaling pathway can influence the radiation response in some patient-derived murine xenograft (PDX) model of esophageal adenocarcinoma, and that inhibition of this pathway could increase the radiation efficacy.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (145, 170))	('esophageal adenocarcinoma', 'Disease', (145, 170))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (145, 170))	('inhibition', 'Var', (181, 191))	('increase', 'PosReg', (214, 222))	('radiation efficacy', 'CPA', (227, 245))	('murine', 'Species', '10090', (113, 119))	('patient', 'Species', '9606', (97, 104))	('influence', 'Reg', (56, 65))	('radiation response', 'CPA', (70, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('Hh signaling pathway', 'Pathway', (31, 51))
592496	31362772	In the negative pressure environment of the thoracic cavity, the dilated stomach can easily affect other organs and compress the expansion of the lung on the operative side, thereby seriously impairing respiratory function of patient.	('impairing', 'NegReg', (192, 201))	('dilated', 'Var', (65, 72))	('respiratory function', 'CPA', (202, 222))	('compress', 'NegReg', (116, 124))	('patient', 'Species', '9606', (226, 233))	('affect', 'Reg', (92, 98))	('dilated stomach', 'Phenotype', 'HP:0005207', (65, 80))	('expansion of the lung', 'CPA', (129, 150))	('impairing respiratory function', 'Phenotype', 'HP:0002093', (192, 222))
592500	31362772	Collectively, modified tubular gastric surgery reduces the use of cutting and closing device, the incidence of postoperative complications, and the financial and psychological burden of patients.	('reduces', 'NegReg', (47, 54))	('use', 'MPA', (59, 62))	('modified', 'Var', (14, 22))	('financial', 'CPA', (148, 157))	('patients', 'Species', '9606', (186, 194))
592502	31362772	Our data showed that modified tubular stomach did not increase postoperative lung function damage, shortened the operation time, reduced the influence of anesthetic drugs on respiratory function, and decreased the time of collapse of the lung on the operative side.	('increase postoperative lung function damage', 'Disease', 'MESH:D010149', (54, 97))	('shortened', 'NegReg', (99, 108))	('collapse of the lung', 'Phenotype', 'HP:0002107', (222, 242))	('increase postoperative lung function damage', 'Disease', (54, 97))	('modified', 'Var', (21, 29))	('operation', 'MPA', (113, 122))	('decreased', 'NegReg', (200, 209))	('time of collapse', 'MPA', (214, 230))	('reduced', 'NegReg', (129, 136))
592511	29290069	In non-elderly patients, TNM pStage III (CSS; HR 3.488, p < 0.0001, OS; HR 2.615, p = 0.0007) and PNI < 49.2 (CSS; HR 3.849, p < 0.0001, OS; HR 2.275, p = 0.001) were confirmed as independent poor predictive factors for CSS, and OS when multivariate logistic regression analysis was applied.	('patients', 'Species', '9606', (15, 23))	('TNM', 'Gene', '10178', (25, 28))	('CSS', 'Gene', (110, 113))	('PNI < 49.2', 'Var', (98, 108))	('TNM', 'Gene', (25, 28))	('OS', 'Chemical', '-', (229, 231))	('CSS', 'Gene', '55907', (41, 44))	('CSS', 'Gene', '55907', (220, 223))	('OS', 'Chemical', '-', (137, 139))	('OS', 'Chemical', '-', (68, 70))	('CSS', 'Gene', (220, 223))	('CSS', 'Gene', '55907', (110, 113))	('CSS', 'Gene', (41, 44))
592560	29290069	Kaplan-Meier analysis and the log-rank test demonstrated that patients with a low PNI had a significantly worse prognosis in terms of CSS and OS than those with a high PNI (p < 0.0001, and p = 0.0003, respectively).	('OS', 'Chemical', '-', (142, 144))	('low', 'Var', (78, 81))	('CSS', 'Gene', '55907', (134, 137))	('PNI', 'Gene', (82, 85))	('patients', 'Species', '9606', (62, 70))	('CSS', 'Gene', (134, 137))
592579	29290069	Patients with a low PNI (less than 49.2) showed a significantly shorter CSS and decreased OS in comparison with patients who had a high PNI (49.2 or greater).	('CSS', 'Gene', '55907', (72, 75))	('OS', 'Chemical', '-', (90, 92))	('CSS', 'Gene', (72, 75))	('patients', 'Species', '9606', (112, 120))	('decreased', 'NegReg', (80, 89))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (64, 71))	('PNI (less than 49.2', 'Var', (20, 39))
592582	29290069	Patients with a low PNI are, therefore, more likely to develop postoperative complications, including a systemic inflammatory response, which can also contribute to the decreased CSS and OS.	('systemic inflammatory response', 'CPA', (104, 134))	('low', 'Var', (16, 19))	('develop', 'PosReg', (55, 62))	('OS', 'Chemical', '-', (187, 189))	('Patients', 'Species', '9606', (0, 8))	('CSS', 'Gene', '55907', (179, 182))	('decreased', 'NegReg', (169, 178))	('PNI', 'Gene', (20, 23))	('CSS', 'Gene', (179, 182))
592591	29290069	The possible reason may be that most ESCC patients have some degree of swallowing difficulty due to obstruction or stricture of the esophagus, which results in the eating disorder, malnutrition, and subsequent poor nutritional status.	('obstruction', 'Disease', (100, 111))	('swallowing difficulty', 'Disease', (71, 92))	('SCC', 'Gene', (38, 41))	('eating disorder', 'Disease', (164, 179))	('stricture', 'Var', (115, 124))	('malnutrition', 'Disease', (181, 193))	('malnutrition', 'Disease', 'MESH:D044342', (181, 193))	('SCC', 'Gene', '6317', (38, 41))	('eating disorder', 'Disease', 'MESH:D001068', (164, 179))	('eating disorder', 'Phenotype', 'HP:0100738', (164, 179))	('obstruction', 'Disease', 'MESH:D000402', (100, 111))	('swallowing difficulty', 'Phenotype', 'HP:0002015', (71, 92))	('patients', 'Species', '9606', (42, 50))	('malnutrition', 'Phenotype', 'HP:0004395', (181, 193))	('results in', 'Reg', (149, 159))
592665	25826681	In addition, analysis was performed on 21 later passage xenografts (P3 through P12), of which nine were from small (early in the growth curve) tumors and 12 were from large tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('P12', 'Gene', (79, 82))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('P12', 'Gene', '56655', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('P3', 'Var', (68, 70))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
592673	25826681	A comparison between engrafted and all other specimens (non-engrafted and non-implanted) showed that tumors from older patients (OR:1.09, p = 0.01), Her-2/neu positivity (OR = 2.38, p = 0.03), and poor differentiation (OR = 6.48, p = 0.01) were each associated with a higher chance of engraftment.	('Her-2/neu', 'Gene', '2064', (149, 158))	('Her-2/neu', 'Gene', (149, 158))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('patients', 'Species', '9606', (119, 127))	('poor differentiation', 'CPA', (197, 217))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('positivity', 'Var', (159, 169))	('engraftment', 'CPA', (285, 296))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
592888	24416395	High MT expression was associated with poorer survival (OR = 3.42; 1.06 to 11.04) in melanoma patients, while an inverse effect was identified in patients with colon and rectum tumors.	('High MT expression', 'Var', (0, 18))	('patients', 'Species', '9606', (94, 102))	('survival', 'MPA', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('poorer', 'NegReg', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('colon and rectum tumors', 'Disease', 'MESH:D012004', (160, 183))	('patients', 'Species', '9606', (146, 154))
592904	24416395	Such differences between isoforms may cause between-study discrepancies, which was evident in several tumor types, including colorectal, kidney, and prostate cancers.	('differences', 'Var', (5, 16))	('colorectal', 'Disease', (125, 135))	('prostate cancers', 'Phenotype', 'HP:0012125', (149, 165))	('prostate cancers', 'Disease', (149, 165))	('kidney', 'Disease', (137, 143))	('cause', 'Reg', (38, 43))	('prostate cancer', 'Phenotype', 'HP:0012125', (149, 164))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('prostate cancers', 'Disease', 'MESH:D011471', (149, 165))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
592917	24296693	In the group of patients after pneumatic dilatations, frequency of interventions was higher (1, 2) than in the myotomy group (0, 2) at 2-year follow-up.	('higher', 'PosReg', (85, 91))	('dilatation', 'Phenotype', 'HP:0002617', (41, 51))	('patients', 'Species', '9606', (16, 24))	('pneumatic dilatations', 'Var', (31, 52))	('dilatations', 'Phenotype', 'HP:0002617', (41, 52))
592930	24296693	Barium esophagogram - apart from revealing an enlarging esophageal diameter indirectly suggesting difficulty in its clearance, abnormalities of its wall, and a deteriorated antireflux barrier of LES - may also suggest coexisting upper digestive tract disorders such as impaired gastric empting.	('Barium', 'Chemical', 'MESH:D001464', (0, 6))	('impaired gastric', 'Disease', 'MESH:D005767', (269, 285))	('suggest', 'Reg', (210, 217))	('digestive tract disorders', 'Phenotype', 'HP:0011024', (235, 260))	('impaired gastric', 'Disease', (269, 285))	('antireflux barrier', 'MPA', (173, 191))	('enlarging', 'PosReg', (46, 55))	('coexisting upper digestive tract disorders', 'Phenotype', 'HP:0002788', (218, 260))	('abnormalities', 'Var', (127, 140))
592970	24296693	Outcomes in the patients treated with myotomy were statistically significantly better than in the patients treated with dilation shortly after the procedure and during the 2-year follow-up (Figure 2).	('patients', 'Species', '9606', (98, 106))	('better', 'PosReg', (79, 85))	('patients', 'Species', '9606', (16, 24))	('myotomy', 'Var', (38, 45))
593003	24296693	The average time for presentation of recurrent dysphagia was 10 months for both groups, although percentage of patients who developed dysphagia was higher in the dilation group (Figure 2, Table 2).	('dysphagia', 'Disease', 'MESH:D003680', (47, 56))	('dysphagia', 'Disease', 'MESH:D003680', (134, 143))	('dysphagia', 'Disease', (47, 56))	('dysphagia', 'Disease', (134, 143))	('dilation', 'Var', (162, 170))	('dysphagia', 'Phenotype', 'HP:0002015', (47, 56))	('dysphagia', 'Phenotype', 'HP:0002015', (134, 143))	('patients', 'Species', '9606', (111, 119))
593004	24296693	Our observation, similar to data from the literature, confirms the thesis that incomplete myotomy leads to dysphagia within 2 years after the surgery.	('dysphagia', 'Disease', (107, 116))	('incomplete myotomy', 'Var', (79, 97))	('dysphagia', 'Phenotype', 'HP:0002015', (107, 116))	('dysphagia', 'Disease', 'MESH:D003680', (107, 116))	('leads to', 'Reg', (98, 106))
593019	23833659	In addition, the proteins caspase-3 and Bax in cells treated with flavopiridol were upregulated, while cyclin D1 and Bcl-2 were downregulated.	('Bcl-2', 'Gene', '596', (117, 122))	('upregulated', 'PosReg', (84, 95))	('cyclin D1', 'Gene', '595', (103, 112))	('flavopiridol', 'Var', (66, 78))	('Bax', 'Gene', (40, 43))	('flavopiridol', 'Chemical', 'MESH:C077990', (66, 78))	('caspase-3', 'Gene', (26, 35))	('downregulated', 'NegReg', (128, 141))	('Bax', 'Gene', '581', (40, 43))	('caspase-3', 'Gene', '836', (26, 35))	('cyclin D1', 'Gene', (103, 112))	('Bcl-2', 'Gene', (117, 122))
593020	23833659	In conclusion, flavopiridol may enhance the radiosensitivity of Eca109 cells and the radiosensitizing effect of flavopiridol may be mediated by decreasing the levels of the cyclin D1 protein, thus increasing the percentage of cells at G2/M phase.	('increasing', 'PosReg', (197, 207))	('cyclin D1', 'Gene', '595', (173, 182))	('flavopiridol', 'Var', (112, 124))	('cyclin D1', 'Gene', (173, 182))	('flavopiridol', 'Chemical', 'MESH:C077990', (15, 27))	('decreasing', 'NegReg', (144, 154))	('cells at G2/M phase', 'CPA', (226, 245))	('levels of', 'MPA', (159, 168))	('radiosensitivity', 'CPA', (44, 60))	('enhance', 'PosReg', (32, 39))	('flavopiridol', 'Chemical', 'MESH:C077990', (112, 124))
593028	23833659	Recently, several studies have confirmed that flavopiridol induces cell cycle arrest in a number of types of cancer.	('arrest', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (67, 84))	('flavopiridol', 'Var', (46, 58))	('cancer', 'Disease', (109, 115))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('flavopiridol', 'Chemical', 'MESH:C077990', (46, 58))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
593078	23833659	Caspase-3 and Bax protein was increased significantly in cells treated with flavopiridol and radiation and Bcl-2 protein was significantly decreased.	('Caspase-3', 'Gene', (0, 9))	('Bcl-2', 'Gene', (107, 112))	('Bcl-2', 'Gene', '596', (107, 112))	('flavopiridol', 'Var', (76, 88))	('Bax', 'Gene', '581', (14, 17))	('flavopiridol', 'Chemical', 'MESH:C077990', (76, 88))	('decreased', 'NegReg', (139, 148))	('increased', 'PosReg', (30, 39))	('Bax', 'Gene', (14, 17))	('Caspase-3', 'Gene', '836', (0, 9))
593086	32048521	Cox regression analysis revealed that McKeown approach was a positive prognostic factor compared to the Sweet approach for patients younger than 70 years in univariable analysis (HR = 0.790; 95% CI, 0.625-0.997; P = .047), whereas the surgical approach was not significantly related to the prognosis in the elderly patients.	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (315, 323))	('McKeown', 'Var', (38, 45))
526102	29766388	Candidate gene and array-based approaches have demonstrated that numerous tumor-suppressor genes exhibit aberrant promoter methylation, and some of these altered genes are associated with the neoplastic progression of BE.	('promoter methylation', 'MPA', (114, 134))	('associated with', 'Reg', (172, 187))	('numerous tumor', 'Disease', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('neoplastic progression', 'CPA', (192, 214))	('numerous tumor', 'Disease', 'MESH:D009369', (65, 79))	('aberrant', 'Var', (105, 113))
593192	29766388	missense mutations), and epigenetic modifications, primarily in the form of DNA hypermethylation and hypomethylation of CpG dinucleotides, and are widely believed to be a principal mechanism that drives the initiation and progression of BE and EAC.	('hyper', 'Disease', 'MESH:D053307', (80, 85))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (120, 137))	('epigenetic modifications', 'Var', (25, 49))	('missense mutations', 'Var', (0, 18))	('hyper', 'Disease', (80, 85))	('hypomethylation', 'Var', (101, 116))
593193	29766388	Since the initial discovery of genetic alterations in BE and EAC, our understanding of the molecular evolution of EAC has progressed from one that only accounted for sequence alterations in the pathogenesis and was uniform between all cases of BE and EAC to one that recognizes the role of epigenetic alterations and the tumor microenvironment as well as inter- and intra-lesional heterogeneity.	('tumor', 'Disease', (321, 326))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('alterations', 'Var', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))
593196	29766388	Inflammation appears to create a permissive state for cancer formation by promoting mutations and creating a microenvironment that cooperates with certain DNA alterations to drive tumor progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', (180, 185))	('cancer', 'Disease', (54, 60))	('mutations', 'Var', (84, 93))	('promoting', 'PosReg', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
593198	29766388	also may affect the molecular evolution of BE and EAC by providing factors that promote the clonal selection of tumor stem-like cells that have acquired favorable DNA alterations, such as TP53 mutations, which are highly correlated with progressed BE and EAC.	('TP53', 'Gene', '7157', (188, 192))	('affect', 'Reg', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('correlated', 'Reg', (221, 231))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (193, 202))	('tumor', 'Disease', (112, 117))	('EAC', 'Disease', (255, 258))	('TP53', 'Gene', (188, 192))	('promote', 'PosReg', (80, 87))
593200	29766388	Another consideration that is important to recognize is that as with all cancers studied to date using modern methods, there is substantial intra-lesional and inter-lesional heterogeneity in genetic and epigenetic alterations.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('epigenetic alterations', 'Var', (203, 225))	('genetic', 'Var', (191, 198))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
593203	29766388	The discovery of gene mutations in the DNA of cancer cells opened up the field of cancer molecular genetics and led to a prevailing model of tumorigenesis, which entails the gradual accumulation of gene mutations and epigenetic alterations that drive processes important for tumor initiation and progression.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('drive', 'Reg', (245, 250))	('cancer', 'Disease', (46, 52))	('mutations', 'Var', (203, 212))	('tumor', 'Disease', (141, 146))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('epigenetic alterations', 'Var', (217, 239))
593204	29766388	These DNA alterations perturb signaling pathways and generate mutant proteins that induce oncogenic behavior in the evolving cancer cell.	('proteins', 'Protein', (69, 77))	('mutant', 'Var', (62, 68))	('alterations', 'Var', (10, 21))	('signaling pathways', 'Pathway', (30, 48))	('oncogenic behavior', 'MPA', (90, 108))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('induce', 'PosReg', (83, 89))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('perturb', 'Reg', (22, 29))
593206	29766388	Thus, the serial accumulation of genetic and epigenetic alterations has been believed to mediate the histologic steps of cancers, including EAC.	('genetic', 'Var', (33, 40))	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('EAC', 'Disease', (140, 143))	('epigenetic alterations', 'Var', (45, 67))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
593207	29766388	This has revealed substantial intra-tumor and inter-tumor heterogeneity as well as the presence of gene mutations and epigenetic alterations in pre-cancerous lesions.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('intra-tumor', 'Disease', 'MESH:D009369', (30, 41))	('epigenetic alterations', 'Var', (118, 140))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancerous lesions', 'Disease', 'MESH:D009062', (148, 165))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancerous lesions', 'Disease', (148, 165))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('gene mutations', 'Var', (99, 113))	('intra-tumor', 'Disease', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (36, 41))
593209	29766388	According to this model, cancers in the esophagus are believed to arise via the gradual stepwise accumulation of mutations .	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (113, 122))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('arise', 'Reg', (66, 71))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
593210	29766388	The progression from normal tissue to specialized intestinal metaplasia, followed by low-grade and high-grade dysplasia, finally locally invasive cancer, and then metastatic cancer is thought to be driven by the accumulation of mutations that perturb specific genetic pathways at each step in the tumorigenic process.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('perturb', 'Reg', (243, 250))	('dysplasia', 'Disease', (110, 119))	('dysplasia', 'Disease', 'MESH:D004476', (110, 119))	('invasive cancer', 'Disease', (137, 152))	('mutations', 'Var', (228, 237))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('low-grade', 'Disease', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('invasive cancer', 'Disease', 'MESH:D009362', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', (297, 302))	('specialized intestinal metaplasia', 'Disease', (38, 71))
593213	29766388	This high rate of mutations early in the tumorigenesis process generates many passenger mutations and copy number alterations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('copy number alterations', 'Var', (102, 125))	('mutations', 'Var', (18, 27))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('passenger', 'MPA', (78, 87))
593214	29766388	This initial spurt of mutations and resulting increased evolutionary tempo may be an intrinsic aspect of neoplastic transformation or may be a consequence of a critical genetic or epigenetic event that leads to genomic instability and increased rates of DNA alterations (e.g.	('DNA alterations', 'MPA', (254, 269))	('genomic instability', 'MPA', (211, 230))	('neoplastic transformation', 'Disease', (105, 130))	('increased', 'PosReg', (235, 244))	('mutations', 'Var', (22, 31))	('rates', 'MPA', (245, 250))	('neoplastic transformation', 'Disease', 'MESH:D002471', (105, 130))
593215	29766388	Once all the necessary driver mutations are acquired, cancers grow from a single expansion of a diverse population of tumor cells, characterized by neutral evolution instead of Darwinian survival .	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
593231	29766388	Subsequent epi/genomic alterations lead to oncogenic behaviors, such as proliferation advantage and inhibition of apoptosis in the metaplastic clones, which enables clonal expansion and development of malignancy as described earlier.	('malignancy', 'Disease', 'MESH:D009369', (201, 211))	('epi/genomic alterations', 'Var', (11, 34))	('lead to', 'Reg', (35, 42))	('malignancy', 'Disease', (201, 211))	('inhibition', 'NegReg', (100, 110))	('apoptosis', 'CPA', (114, 123))	('proliferation advantage', 'CPA', (72, 95))
593233	29766388	Genomic studies of BE have revealed that it is not simply a metaplastic tissue but that many BE lesions also harbor somatic genetic alterations and nearly all BE lesions have substantial epigenetic alterations when compared to the normal squamous esophagus or cardia.	('genetic alterations', 'Var', (124, 143))	('epigenetic alterations', 'MPA', (187, 209))	('harbor', 'Reg', (109, 115))	('cardia', 'Disease', 'MESH:D004938', (260, 266))	('cardia', 'Disease', (260, 266))
593234	29766388	The analysis of the molecular events involved in the process of BE progression has been greatly enhanced by dramatic improvements in genomic technologies, including tools to examine somatic nucleotide variants (SNVs; aka gene mutations), larger structural alterations, and epigenetic alterations (DNA methylation, microRNA expression) in cancer and pre-cancer genomes.	('cancer', 'Disease', (338, 344))	('epigenetic alterations', 'Var', (273, 295))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Disease', (353, 359))	('aka', 'Gene', (217, 220))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('aka', 'Gene', '4762', (217, 220))
593235	29766388	Early studies that used PCR-based targeted sequencing identified TP53 mutations in exon 5-8 present in EAC and BE adjacent to EAC compared to corresponding normal squamous tissue from the resection margin.	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))
593236	29766388	Further, specimens of Barrett's epithelium from separate sites had identical p53 mutations, suggesting a clonal origin.	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('mutations', 'Var', (81, 90))
526116	29766388	17p and 9p harbor the tumor suppressors TP53 and CDKN2A, respectively, and studies have revealed frequent LOH through mutation (TP53 and CKN2A) or promoter methylation (CDKN2A).	('CDKN2A', 'Gene', (169, 175))	('CDKN2A', 'Gene', '1029', (49, 55))	('TP53', 'Gene', '7157', (128, 132))	('CDKN2A', 'Gene', '1029', (169, 175))	('TP53', 'Gene', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('mutation', 'Var', (118, 126))	('tumor', 'Disease', (22, 27))	('promoter', 'MPA', (147, 155))	('CDKN2A', 'Gene', (49, 55))
593237	29766388	17p LOH is associated with genomic doubling to a 4N state, consistent with the impact of p53 loss upon genomic instability.	('loss', 'NegReg', (93, 97))	('genomic', 'MPA', (27, 34))	('17p LOH', 'Var', (0, 7))	('p53', 'Gene', (89, 92))	('p53', 'Gene', '7157', (89, 92))
593238	29766388	These findings have led to a model where CDKN2A loss is thought to be an initiating event in BE progression, while TP53 alterations are later events, associated with neoplastic progression and aneuploidy.	('associated', 'Reg', (150, 160))	('loss', 'NegReg', (48, 52))	('aneuploidy', 'Disease', 'MESH:D000782', (193, 203))	('TP53', 'Gene', '7157', (115, 119))	('aneuploidy', 'Disease', (193, 203))	('TP53', 'Gene', (115, 119))	('CDKN2A', 'Gene', (41, 47))	('alterations', 'Var', (120, 131))	('CDKN2A', 'Gene', '1029', (41, 47))	('neoplastic progression', 'CPA', (166, 188))
593242	29766388	For TP53, only 2.5% of non-dysplastic BE contained a mutation but 70% of cases of HGD and EAC were TP53 mutant.	('TP53', 'Gene', (99, 103))	('mutation', 'Var', (53, 61))	('TP53', 'Gene', (4, 8))	('non-dysplastic', 'Disease', (23, 37))	('non-dysplastic', 'Disease', 'MESH:D004416', (23, 37))	('HGD', 'Gene', '3081', (82, 85))	('TP53', 'Gene', '7157', (99, 103))	('HGD', 'Gene', (82, 85))	('TP53', 'Gene', '7157', (4, 8))
593243	29766388	SMAD4 mutations were only found in EAC (13%).	('EAC', 'Disease', (35, 38))	('SMAD4', 'Gene', '4089', (0, 5))	('SMAD4', 'Gene', (0, 5))	('found', 'Reg', (26, 31))	('mutations', 'Var', (6, 15))
593245	29766388	Further insight into the role of genomic alterations was provided by Stachler and colleagues who observed that genome doubling appears to precede progression of EAC to BE in the majority of cases (62.5%) and that tumors with genomic doubling have more frequent oncogene amplification events and less frequent tumor suppressor gene inactivation compared to those without .	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', (309, 314))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('amplification', 'Var', (270, 283))	('less', 'NegReg', (295, 299))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('EAC', 'Disease', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('oncogene', 'Protein', (261, 269))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
593246	29766388	These findings are consistent with other studies, which suggested that the BE-EAC progression sequence is not one characterized by the gradual, linear serial accumulation of mutations in oncogenes and tumor suppressor genes, but rather a non-linear process that leads to BE transformation after the sudden occurrence of genomic doubling and genomic alterations, possibly secondary to TP53 mutations.	('TP53', 'Gene', (384, 388))	('BE transformation', 'CPA', (271, 288))	('mutations', 'Var', (389, 398))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (201, 206))	('leads to', 'Reg', (262, 270))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutations', 'Var', (174, 183))	('TP53', 'Gene', '7157', (384, 388))
593248	29766388	Somatic mutations in 26 genes were identified to be implicated in EAC, affecting the Wnt/b-catenin, RTK-RAS-PI3K, TGF-b/SMAD4, chromatin-remodeling enzyme, G1-S cell cycle control and p53 pathways.	('affecting', 'Reg', (71, 80))	('TGF-b', 'Gene', '7040', (114, 119))	('chromatin-remodeling enzyme', 'Pathway', (127, 154))	('p53', 'Gene', (184, 187))	('SMAD4', 'Gene', (120, 125))	('mutations', 'Var', (8, 17))	('p53', 'Gene', '7157', (184, 187))	('Wnt/b-catenin', 'Pathway', (85, 98))	('TGF-b', 'Gene', (114, 119))	('SMAD4', 'Gene', '4089', (120, 125))
526153	29766388	The etiology of these mutations is unknown, but it has been hypothesized to be linked to bile acid exposure and the induction of oxidative DNA damage.	('bile acid', 'Chemical', 'MESH:D001647', (89, 98))	('oxidative', 'MPA', (129, 138))	('mutations', 'Var', (22, 31))	('linked', 'Reg', (79, 85))
593253	29766388	Since the discovery of DNA hypomethylation in colorectal cancer in 1982, epigenetic research has revealed an epigenetic landscape consisting of a complex array of epigenetic regulatory mechanisms that control gene expression in both cancer  and normal tissue.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('colorectal cancer', 'Disease', 'MESH:D015179', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('control', 'Reg', (201, 208))	('hypomethylation', 'Var', (27, 42))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('colorectal cancer', 'Disease', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
593255	29766388	Aberrant DNA methylation is the best studied epigenetic alteration in cancer and will be the focus of the following discussion.	('Aberrant DNA methylation', 'Var', (0, 24))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))
593257	29766388	Aberrant DNA methylation of promoter CpG islands, which can induce transcriptional repression of tumor suppressor genes, has been found frequently throughout the BE->dysplastic BE->EAC progression sequence.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('transcriptional repression', 'MPA', (67, 93))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))
593259	29766388	Similar patterns consistent with clonal expansion in BE have been reported in studies that focused on LOH or mutations of APC, TP53, and CDKN2A .	('APC', 'Disease', 'MESH:D011125', (122, 125))	('CDKN2A', 'Gene', '1029', (137, 143))	('APC', 'Disease', (122, 125))	('CDKN2A', 'Gene', (137, 143))	('mutations', 'Var', (109, 118))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
593262	29766388	A number of candidate mechanisms have some suggested from published studies and include age-related DNA hyper and hypo-methylation, mutations or changes in expression of genes regulating DNA methylation or chromatin states, and environmental factors .	('hyper', 'Disease', 'MESH:D053307', (104, 109))	('expression', 'MPA', (156, 166))	('hyper', 'Disease', (104, 109))	('mutations', 'Var', (132, 141))	('changes', 'Reg', (145, 152))
593274	29766388	Revilla-Nuin et al found 23 miRNAs involved in BE progression using miRNA sequencing analysis, finding four miRNAs (miR-192, miR-194, miR-196a, and miR-196b) had higher expression in BE patients who progressed to cancer compared to those who did not progress .	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('higher', 'PosReg', (162, 168))	('miR-192', 'Gene', '406967', (116, 123))	('miR-192', 'Gene', (116, 123))	('progressed', 'PosReg', (199, 209))	('miR-196b', 'Gene', (148, 156))	('miR-196a', 'Var', (134, 142))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('miR-196b', 'Gene', '442920', (148, 156))	('expression', 'MPA', (169, 179))	('miR-194', 'Var', (125, 132))	('cancer', 'Disease', (213, 219))	('patients', 'Species', '9606', (186, 194))
526182	29766388	When AFAP1 was silenced using siRNA technologies, esophageal cells exhibited increased apoptosis and reduced proliferation and colon-forming abilities, suggesting a cancer-promoting role for this noncoding RNA in BE and EAC.	('AFAP1', 'Gene', '60312', (5, 10))	('AFAP1', 'Gene', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('esophageal cells', 'CPA', (50, 66))	('colon-forming abilities', 'CPA', (127, 150))	('reduced', 'NegReg', (101, 108))	('apoptosis', 'CPA', (87, 96))	('silenced', 'Var', (15, 23))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('increased', 'PosReg', (77, 86))	('proliferation', 'CPA', (109, 122))
593280	29766388	Nuclear expression of p53 is a surrogate for TP53 mutations that stabilize the p53 protein and complete loss p53 can also indicate a TP53 mutation that leads to failed translation of the protein.	('loss', 'NegReg', (104, 108))	('p53', 'Gene', (79, 82))	('stabilize', 'MPA', (65, 74))	('p53', 'Gene', '7157', (79, 82))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (45, 49))	('mutations', 'Var', (50, 59))	('p53', 'Gene', (22, 25))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', (109, 112))	('translation', 'MPA', (168, 179))	('failed', 'NegReg', (161, 167))	('p53', 'Gene', '7157', (109, 112))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))
593285	29766388	One prospective study of 268 BE patients evaluated whether clonal expansions during the progression of BE lead to homogenous cell populations or result in clonal diversity .	('result in', 'Reg', (145, 154))	('patients', 'Species', '9606', (32, 40))	('clonal', 'MPA', (155, 161))	('clonal expansions', 'Var', (59, 76))	('lead to', 'Reg', (106, 113))	('homogenous', 'MPA', (114, 124))
526212	29766388	Genomic studies of BE have revealed that it is not simply a metaplastic tissue, but characterized by frequent somatic alterations, including mutations in TP53 and other genes.	('TP53', 'Gene', '7157', (154, 158))	('mutations', 'Var', (141, 150))	('TP53', 'Gene', (154, 158))
526214	29766388	In general, both genetic and epigenetic abnormalities are seen in BE before the development of dysplasia or EAC.	('EAC', 'Disease', (108, 111))	('epigenetic abnormalities', 'Var', (29, 53))	('dysplasia', 'Disease', (95, 104))	('dysplasia', 'Disease', 'MESH:D004476', (95, 104))
526215	29766388	This has important implications if these molecular alterations are to be used as assays to predict the risk of BE progression, since while it may be true that certain tumor suppressor genes are inactivated in many cases of BE, most individuals with BE will not progress to dysplasia or cancer.	('alterations', 'Var', (51, 62))	('dysplasia or cancer', 'Disease', 'MESH:D009369', (273, 292))	('dysplasia or cancer', 'Disease', (273, 292))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('inactivated', 'NegReg', (194, 205))	('tumor', 'Disease', (167, 172))
526216	29766388	Specific gene mutations, chromosomal instability, and genetic diversity are associated with neoplastic progression, and it is foreseeable that assays to detect these features could be used to support the pathological assessment of disease and to select patients for more intensive surveillance.	('patients', 'Species', '9606', (253, 261))	('chromosomal', 'MPA', (25, 36))	('neoplastic progression', 'CPA', (92, 114))	('associated', 'Reg', (76, 86))	('genetic diversity', 'Var', (54, 71))
526217	29766388	Genetic and epigenetic alterations play a central role in the formation of Barretts esophagus and esophageal adenocarcinoma.	('Barretts esophagus', 'Disease', (75, 93))	('epigenetic alterations', 'Var', (12, 34))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (98, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('Genetic', 'Var', (0, 7))	('esophageal adenocarcinoma', 'Disease', (98, 123))
526218	29766388	Global epigenetic alterations occur early in the Barretts esophagus to esophageal adenocarcinoma sequence.	('epigenetic alterations', 'Var', (7, 29))	('esophageal adenocarcinoma', 'Disease', (71, 96))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (71, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
593286	29766388	There is considerable inter and intra-lesional genetic and epigenetic heterogeneity in Barretts esophagus and esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (110, 135))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (110, 135))	('Barretts esophagus', 'Disease', (87, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('epigenetic', 'Var', (59, 69))
593295	31226958	In addition, DNMT1 knockdown or inhibition of DNMT1 function contributes to downregulation of miR-124-3p and BCAT1 expression.	('DNMT1', 'Gene', (46, 51))	('DNMT1', 'Gene', '1786', (46, 51))	('miR-124-3p', 'Gene', '406909', (94, 104))	('inhibition', 'NegReg', (32, 42))	('BCAT1', 'Gene', (109, 114))	('knockdown', 'Var', (19, 28))	('DNMT1', 'Gene', '1786', (13, 18))	('miR-124-3p', 'Gene', (94, 104))	('DNMT1', 'Gene', (13, 18))	('expression', 'MPA', (115, 125))	('downregulation', 'NegReg', (76, 90))	('BCAT1', 'Gene', '586', (109, 114))
593300	31226958	In recent years, cancers have been widely regarded to be associated with epigenetic modifications that is defined as a stable change in gene expression without modifications in DNA sequence.	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('epigenetic modifications', 'Var', (73, 97))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('associated', 'Reg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
593307	31226958	For instance, miR-124 might have effects on decreasing risks of ESCC in subgroups of Chinese elderly persons.	('ESCC', 'Disease', (64, 68))	('persons', 'Species', '9606', (101, 108))	('decreasing', 'NegReg', (44, 54))	('miR-124', 'Var', (14, 21))
593313	31226958	These findings suggest that inhibitors against the activity of DNMT1 and/or BCAT1 might be a novel strategy to inhibit development and progression of ESCC.	('activity', 'MPA', (51, 59))	('inhibitors against', 'Var', (28, 46))	('inhibit', 'NegReg', (111, 118))	('development', 'CPA', (119, 130))	('BCAT1', 'Gene', '586', (76, 81))	('ESCC', 'Disease', (150, 154))	('DNMT1', 'Gene', (63, 68))	('DNMT1', 'Gene', '1786', (63, 68))	('BCAT1', 'Gene', (76, 81))
593333	31226958	The human BCAT1 3'-UTR DNA sequence that was predicted to interact with miR-124-3p and the mutant BCAT1 3'-UTR DNA sequence were amplified and inserted into psi-CHECK2 renilla/firefly dual-luciferase expression vector (Promega, Mullion, WI, USA), with the following primers: BCAT1-WT-1: 5'-CCGCTCGAGTTTGAAGGTCCTCCAAGTCCGTGT-3' (forward) and 5'-ATTTGCGGCCGCCTAATGCTGCCACTGAGCTGACAAG-3' (reverse).	('BCAT1', 'Gene', (98, 103))	('human', 'Species', '9606', (4, 9))	('BCAT1', 'Gene', '586', (275, 280))	('miR-124-3p', 'Gene', '406909', (72, 82))	('miR-124-3p', 'Gene', (72, 82))	('BCAT1', 'Gene', (275, 280))	('BCAT1', 'Gene', (10, 15))	('BCAT1', 'Gene', '586', (98, 103))	('mutant', 'Var', (91, 97))	('BCAT1', 'Gene', '586', (10, 15))
593356	31226958	Along the lines of reduced hsa-miR-124-3p mRNA expression, we also observed that the incidence of hsa-miR-124-3p hypermethylation in ESCC tissues was significantly higher than in normal tissues (Fig.	('hsa-miR-124-3p', 'Gene', '406909', (27, 41))	('ESCC', 'Disease', (133, 137))	('hsa-miR-124-3p', 'Gene', (27, 41))	('hsa-miR-124-3p', 'Gene', '406909', (98, 112))	('higher', 'PosReg', (164, 170))	('hypermethylation', 'Var', (113, 129))	('hsa-miR-124-3p', 'Gene', (98, 112))
593358	31226958	In addition, the clinical data indicated that low-level expression of hsa-miR-124-3p was associated with tumor node metastasis (TNM) stage III-IV and poor differentiation grade (Fig.	('associated', 'Reg', (89, 99))	('tumor node metastasis', 'Disease', (105, 126))	('poor differentiation grade', 'CPA', (150, 176))	('hsa-miR-124-3p', 'Gene', '406909', (70, 84))	('hsa-miR-124-3p', 'Gene', (70, 84))	('low-level', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor node metastasis', 'Disease', 'MESH:D009362', (105, 126))
593362	31226958	The data showed that 5'-UTR region of hsa-miR-124-3p could bind to 3'-UTR region of BCAT1 gene with two potential target sites of 671-677 and 7685-7691 (Fig.	('hsa-miR-124-3p', 'Gene', (38, 52))	('7685-7691', 'Var', (142, 151))	('BCAT1', 'Gene', '586', (84, 89))	('hsa-miR-124-3p', 'Gene', '406909', (38, 52))	('BCAT1', 'Gene', (84, 89))	('bind', 'Interaction', (59, 63))
593365	31226958	In contrast, the luciferase activity of BCAT1-MUT1 3'UTR reporter with the mutant binding site was unaffected by co-transfection of miR-124-3p mimics compared with NC mimics co-transfected.	('BCAT1', 'Gene', (40, 45))	('activity', 'MPA', (28, 36))	('miR-124-3p', 'Gene', '406909', (132, 142))	('luciferase', 'Enzyme', (17, 27))	('miR-124-3p', 'Gene', (132, 142))	('mutant', 'Var', (75, 81))	('BCAT1', 'Gene', '586', (40, 45))
593371	31226958	In addition, the clinical data indicated that the expression of BCAT1 was significantly associated with tumor size, pathologic stage, T classification and differentiation grade of ESCC patients.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('differentiation grade', 'CPA', (155, 176))	('tumor', 'Disease', (104, 109))	('expression', 'Var', (50, 60))	('BCAT1', 'Gene', (64, 69))	('patients', 'Species', '9606', (185, 193))	('associated', 'Reg', (88, 98))	('BCAT1', 'Gene', '586', (64, 69))	('ESCC', 'Disease', (180, 184))	('T classification', 'CPA', (134, 150))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
593380	31226958	In addition, the cell migration of two ESCC cells indicated by transwell assay were significantly inhibited by miR-124-3p mimics transfection compared with NC mimics transfection (Fig.	('cell migration of two', 'CPA', (17, 38))	('transfection', 'Var', (129, 141))	('inhibited', 'NegReg', (98, 107))	('miR-124-3p', 'Gene', '406909', (111, 121))	('miR-124-3p', 'Gene', (111, 121))	('transwell assay', 'CPA', (63, 78))
593385	31226958	Similar to the effect of miR-124-3p mimics transfection, knockdown of BCAT1 significantly inhibited cell viability (Fig.	('miR-124-3p', 'Gene', (25, 35))	('BCAT1', 'Gene', '586', (70, 75))	('cell viability', 'CPA', (100, 114))	('knockdown', 'Var', (57, 66))	('BCAT1', 'Gene', (70, 75))	('miR-124-3p', 'Gene', '406909', (25, 35))	('inhibited', 'NegReg', (90, 99))
593398	31226958	Collectively, these findings indicate that DNMT1 is essential for the methylation of hsa-miR-124-3p and subsequently induce the expression of BCAT1, which involves in the cell proliferation and migration of ESCC cells.	('cell proliferation', 'CPA', (171, 189))	('BCAT1', 'Gene', '586', (142, 147))	('DNMT1', 'Gene', (43, 48))	('induce', 'PosReg', (117, 123))	('migration', 'CPA', (194, 203))	('methylation', 'Var', (70, 81))	('DNMT1', 'Gene', '1786', (43, 48))	('BCAT1', 'Gene', (142, 147))	('hsa-miR-124-3p', 'Gene', '406909', (85, 99))	('expression', 'MPA', (128, 138))	('hsa-miR-124-3p', 'Gene', (85, 99))
593410	31226958	Consistent with this, our results indicated that BCAT1 knockdown significantly inhibited cell proliferation and migration of ESCC cell lines KYSE-150 and Eca109.	('knockdown', 'Var', (55, 64))	('BCAT1', 'Gene', '586', (49, 54))	('cell proliferation', 'CPA', (89, 107))	('inhibited', 'NegReg', (79, 88))	('migration of', 'CPA', (112, 124))	('BCAT1', 'Gene', (49, 54))
593412	31226958	The aberrant DNA methylation in BCAT1 promotor region was associated with in colorectal cancer, ovarian cancer and gliomas.	('colorectal cancer', 'Disease', (77, 94))	('BCAT1', 'Gene', (32, 37))	('gliomas', 'Disease', (115, 122))	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (96, 110))	('BCAT1', 'Gene', '586', (32, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('aberrant DNA methylation', 'Var', (4, 28))	('ovarian cancer', 'Disease', (96, 110))
593416	31226958	It should be also noted that BCAT1 expression might be also regulated by DNA methylation in BCAT1 promotor region in KYSE-150 and Eca109 cells although we did not provide the direct evidence.	('BCAT1', 'Gene', (92, 97))	('DNA methylation', 'Var', (73, 88))	('expression', 'MPA', (35, 45))	('regulated', 'Reg', (60, 69))	('BCAT1', 'Gene', '586', (29, 34))	('BCAT1', 'Gene', '586', (92, 97))	('BCAT1', 'Gene', (29, 34))
593418	31226958	Methylation-associated silencing of tumor-suppressive miRNAs might play a crucial role in the tumorigenesis through activating oncogenic pathways.	('Methylation-associated', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('activating', 'PosReg', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('oncogenic pathways', 'Pathway', (127, 145))	('silencing', 'NegReg', (23, 32))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
593419	31226958	MiR-124, as a typical tumor-suppressive miRNA, has also been found epigenetically silenced in cholangiocarcinoma, cervical cancer and pancreatic cancer.	('cancer', 'Disease', (145, 151))	('epigenetically', 'Var', (67, 81))	('pancreatic cancer', 'Disease', 'MESH:D010190', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('MiR-124', 'Gene', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (134, 151))	('cholangiocarcinoma', 'Disease', (94, 112))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cancer', 'Disease', (123, 129))	('tumor', 'Disease', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (94, 112))	('pancreatic cancer', 'Disease', (134, 151))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
593420	31226958	However, in the previous study it is unclear that hypermethylation in miR-124 gene was linked to overexpression of DNMT in ESCC.	('DNMT', 'Gene', '1786', (115, 119))	('DNMT', 'Gene', (115, 119))	('linked', 'Reg', (87, 93))	('hypermethylation', 'Var', (50, 66))	('miR-124', 'Gene', (70, 77))
593421	31226958	In the present study, we provide the direct evidence suggesting that hypermethylation in miR-124 gene was strongly mediated by DNMT1 through DNMT1 knockdown and 5-AZ treatment.	('miR-124', 'Gene', (89, 96))	('DNMT1', 'Gene', '1786', (127, 132))	('5-AZ', 'Chemical', '-', (161, 165))	('DNMT1', 'Gene', '1786', (141, 146))	('mediated', 'Reg', (115, 123))	('hypermethylation', 'MPA', (69, 85))	('DNMT1', 'Gene', (127, 132))	('knockdown', 'Var', (147, 156))	('DNMT1', 'Gene', (141, 146))
593425	31226958	These findings suggest that inhibitors against the activity of DNMT1 and/or BCAT1 might be a novel targeted therapeutic choice against ESCC.	('activity', 'MPA', (51, 59))	('ESCC', 'Disease', (135, 139))	('inhibitors against', 'Var', (28, 46))	('BCAT1', 'Gene', '586', (76, 81))	('DNMT1', 'Gene', (63, 68))	('DNMT1', 'Gene', '1786', (63, 68))	('BCAT1', 'Gene', (76, 81))
593431	31001468	Here, we found that the expression of CACNA2D3 was significantly associated with poor platinum response in ESCC patients from the Gene Expression Omnibus database.	('platinum', 'Chemical', 'MESH:D010984', (86, 94))	('platinum response', 'CPA', (86, 103))	('poor', 'NegReg', (81, 85))	('patients', 'Species', '9606', (112, 120))	('associated with', 'Reg', (65, 80))	('expression', 'Var', (24, 34))	('CACNA2D3', 'Gene', (38, 46))	('ESCC', 'Disease', (107, 111))
593436	31001468	Treatment with the PI3K/Akt inhibitor LY294002 restored the chemosensitivity of CACAN2D3-knockdown cells to cisplatin.	('CACAN2D3-knockdown', 'Gene', (80, 98))	('chemosensitivity', 'MPA', (60, 76))	('LY294002', 'Var', (38, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('Akt', 'Gene', '207', (24, 27))	('LY294002', 'Chemical', 'MESH:C085911', (38, 46))	('Akt', 'Gene', (24, 27))
593437	31001468	In conclusion, the results of the current study indicate that CACAN2D3 enhances the chemosensitivity of ESCC to cisplatin via inducing Ca2+-mediated apoptosis and suppressing PI3K/Akt pathways.	('chemosensitivity', 'MPA', (84, 100))	('Akt', 'Gene', (180, 183))	('CACAN2D3', 'Var', (62, 70))	('enhances', 'PosReg', (71, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('suppressing', 'NegReg', (163, 174))	('inducing', 'PosReg', (126, 134))	('Akt', 'Gene', '207', (180, 183))	('Ca2+-mediated apoptosis', 'MPA', (135, 158))
593448	31001468	The promoter of CACNA2D3 was shown to be highly methylated in gastric cancer, and this was associated with a low survival rate.	('low', 'NegReg', (109, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('methylated', 'Var', (48, 58))	('CACNA2D3', 'Gene', (16, 24))	('associated', 'Reg', (91, 101))	('gastric cancer', 'Disease', (62, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('survival rate', 'CPA', (113, 126))
593449	31001468	Similarly, suppression of CACNA2D3 by methylation was found to promote the metastatic phenotype of breast cancer.	('suppression', 'NegReg', (11, 22))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('methylation', 'Var', (38, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('metastatic phenotype', 'CPA', (75, 95))	('CACNA2D3', 'Gene', (26, 34))	('promote', 'PosReg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
593450	31001468	Another study showed that CACNA2D3 could increase intracellular Ca2+ levels and promote apoptosis in nasopharyngeal cancer and glioma, causing changes in the network of tumor-suppressive properties and inducing upregulation of Nemo-like kinase (NLK) through the non-canonical Wnt/Ca2+ signaling pathway.	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (101, 122))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('changes', 'Reg', (143, 150))	('tumor', 'Disease', (169, 174))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (101, 122))	('network', 'MPA', (158, 165))	('promote', 'PosReg', (80, 87))	('intracellular Ca2+ levels', 'MPA', (50, 75))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('Nemo-like kinase', 'Gene', '51701', (227, 243))	('increase intracellular Ca2+ levels', 'Phenotype', 'HP:0003575', (41, 75))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('glioma', 'Disease', (127, 133))	('increase', 'PosReg', (41, 49))	('Nemo-like kinase', 'Gene', (227, 243))	('inducing upregulation', 'PosReg', (202, 223))	('apoptosis', 'CPA', (88, 97))	('nasopharyngeal cancer', 'Disease', (101, 122))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('CACNA2D3', 'Var', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('NLK', 'Gene', '51701', (245, 248))	('NLK', 'Gene', (245, 248))
593452	31001468	Our previous study also identified CACNA2D3 as a tumor suppressor gene, and methylation of its promoter and allele deletion could inhibit its expression in ESCC.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('inhibit', 'NegReg', (130, 137))	('tumor', 'Disease', (49, 54))	('methylation', 'Var', (76, 87))	('expression', 'MPA', (142, 152))	('CACNA2D3', 'Gene', (35, 43))	('ESCC', 'Disease', (156, 160))
593455	31001468	We found that the expression of CACNA2D3 was significantly associated with poor platinum response in ESCC patients.	('CACNA2D3', 'Gene', (32, 40))	('platinum', 'Chemical', 'MESH:D010984', (80, 88))	('poor', 'NegReg', (75, 79))	('platinum response', 'CPA', (80, 97))	('associated', 'Reg', (59, 69))	('patients', 'Species', '9606', (106, 114))	('ESCC', 'Disease', (101, 105))	('expression', 'Var', (18, 28))
593459	31001468	LY294002 is a commonly used PI3K/AKT pathway inhibitor, and treatment with LY294002 could restore the chemosensitivity of CACAN2D3-knockdown cells to cisplatin.	('LY294002', 'Var', (0, 8))	('AKT', 'Gene', (33, 36))	('chemosensitivity', 'MPA', (102, 118))	('AKT', 'Gene', '207', (33, 36))	('LY294002', 'Chemical', 'MESH:C085911', (75, 83))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('restore', 'PosReg', (90, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('LY294002', 'Var', (75, 83))
593460	31001468	Six ESCC cell lines (KYSE30, KYSE140, KYSE180, KYSE410, KYSE510, and KYSE520) were purchased from DSMZ, the German Resource Centre for Biological Material.	('KYSE30', 'CellLine', 'CVCL:1351', (21, 27))	('KYSE410', 'Var', (47, 54))	('KYSE30', 'Var', (21, 27))	('KYSE180', 'CellLine', 'CVCL:1349', (38, 45))	('KYSE520', 'Var', (69, 76))	('KYSE510', 'Var', (56, 63))	('KYSE140', 'Var', (29, 36))	('KYSE180', 'Var', (38, 45))
593474	31001468	Cells were washed twice with phosphate-buffered saline (PBS) and then loaded with Fluo-3 AM (1 muM) for 30 min in the dark at 37 C. When Fluo-3 AM penetrates the cellular membrane, it is hydrolyzed by cellular esterases to Fluo-3.	('PBS', 'Chemical', '-', (56, 59))	('Fluo-3', 'Chemical', 'MESH:C059715', (137, 143))	('Fluo-3 AM', 'Var', (137, 146))	('Fluo-3', 'Chemical', 'MESH:C059715', (82, 88))	('muM', 'Gene', '56925', (95, 98))	('phosphate-buffered saline', 'Chemical', '-', (29, 54))	('Fluo-3', 'Chemical', 'MESH:C059715', (223, 229))	('Fluo-3 AM', 'Chemical', 'MESH:C059715', (137, 146))	('Fluo-3 AM', 'Chemical', 'MESH:C059715', (82, 91))	('muM', 'Gene', (95, 98))
593505	31001468	We next examined whether knocking down CACNA2D3 would contribute to cisplatin resistance in ESCC.	('cisplatin resistance', 'MPA', (68, 88))	('knocking down', 'Var', (25, 38))	('ESCC', 'Disease', (92, 96))	('contribute', 'Reg', (54, 64))	('CACNA2D3', 'Gene', (39, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
593508	31001468	CACNA2D3 knockdown resulted in significantly higher colony formation efficiency in 180-siCAC cells than in control cells in the presence of cisplatin (Figure 2H).	('knockdown', 'Var', (9, 18))	('colony formation efficiency', 'CPA', (52, 79))	('CACNA2D3', 'Gene', (0, 8))	('higher', 'PosReg', (45, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))
593509	31001468	Taken together, the data showed that CACNA2D3 sensitized ESCC cells to cisplatin.	('ESCC', 'Disease', (57, 61))	('sensitized', 'Reg', (46, 56))	('CACNA2D3', 'Var', (37, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))
593511	31001468	CACNA2D3-overexpressing KYSE30 cells (30-CAC) showed significantly increased intracellular Ca2+ compared with the control cells (30-Vec), whereas knockdown of CACNA2D3 in KYSE180 cells (180-siCAC) caused a decrease in intracellular Ca2+ levels compared with control cells (180-scr) (Figure 3A).	('knockdown', 'Var', (146, 155))	('intracellular Ca2+', 'MPA', (77, 95))	('KYSE30', 'CellLine', 'CVCL:1351', (24, 30))	('intracellular Ca2+ levels', 'MPA', (218, 243))	('KYSE180', 'CellLine', 'CVCL:1349', (171, 178))	('decrease', 'NegReg', (206, 214))	('decrease in intracellular Ca2+ levels', 'Phenotype', 'HP:0003575', (206, 243))	('increased', 'PosReg', (67, 76))	('CACNA2D3', 'Gene', (159, 167))	('increased intracellular Ca2+', 'Phenotype', 'HP:0003575', (67, 95))
593514	31001468	In KYSE180 cells, cisplatin increased apoptosis by 14.2 +- 2.3% in 180-siCAC cells and by 32.3 +- 3.2% in 180-scr cells (Figures 3B,C).	('cisplatin', 'Chemical', 'MESH:D002945', (18, 27))	('KYSE180', 'CellLine', 'CVCL:1349', (3, 10))	('cisplatin', 'Var', (18, 27))	('apoptosis', 'CPA', (38, 47))
593516	31001468	As shown in Figures 3D,E, with cisplatin treatment, the membrane potential of 30-Vec cells decreased by 14.3 +- 2.5%, while that of 30-CAC cells decreased by 25.5 +- 1.6%.	('membrane potential', 'MPA', (56, 74))	('cisplatin', 'Var', (31, 40))	('decreased', 'NegReg', (91, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))
593519	31001468	Conversely, these ratios decreased in 180-siCAC cells treated with cisplatin compared with 180-scr cells (Figure 3F).	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('decreased', 'NegReg', (25, 34))	('cisplatin', 'Var', (67, 76))
593520	31001468	Taken together, these results suggested that CACNA2D3 sensitized ESCC cells to cisplatin through enhancing mitochondria-mediated apoptosis.	('CACNA2D3', 'Var', (45, 53))	('enhancing', 'PosReg', (97, 106))	('mitochondria-mediated apoptosis', 'MPA', (107, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))
593527	31001468	TUNEL analysis also revealed that the apoptosis rate of CACNA2D3 overexpression cells was significantly higher than that of the control cells after cisplatin treatment (Figure 4E).	('CACNA2D3', 'Gene', (56, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('overexpression', 'Var', (65, 79))	('apoptosis rate', 'CPA', (38, 52))	('higher', 'PosReg', (104, 110))
593528	31001468	These results together indicated that CACNA2D3 increased cisplatin sensitivity in vivo.	('increased', 'PosReg', (47, 56))	('CACNA2D3', 'Var', (38, 46))	('cisplatin sensitivity', 'MPA', (57, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))
593533	31001468	Western blotting showed that CACNA2D3 dramatically suppressed the phosphorylation of PI3K and Akt, and the suppression persisted in the presence of cisplatin (Figure 5E).	('Akt', 'Gene', (94, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('phosphorylation', 'MPA', (66, 81))	('PI3K', 'Pathway', (85, 89))	('suppressed', 'NegReg', (51, 61))	('Akt', 'Gene', '207', (94, 97))	('CACNA2D3', 'Var', (29, 37))
593535	31001468	For the rescue experiments, we treated CACNA2D3-knockdown cells with Akt inhibitor LY294002.	('Akt', 'Gene', (69, 72))	('LY294002', 'Chemical', 'MESH:C085911', (83, 91))	('LY294002', 'Var', (83, 91))	('Akt', 'Gene', '207', (69, 72))
593536	31001468	Western blotting showed that LY294002 inhibited Akt activation in 180-siCAC cells and 180-scr cells (Figure 6A).	('Akt', 'Gene', (48, 51))	('LY294002', 'Chemical', 'MESH:C085911', (29, 37))	('inhibited', 'NegReg', (38, 47))	('LY294002', 'Var', (29, 37))	('Akt', 'Gene', '207', (48, 51))	('activation', 'PosReg', (52, 62))
593537	31001468	The CACNA2D3-knockdown cells showed significantly higher sensitivity to cisplatin after treatment with LY294002 (Figure 6B).	('higher', 'PosReg', (50, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('LY294002', 'Var', (103, 111))	('LY294002', 'Chemical', 'MESH:C085911', (103, 111))	('sensitivity to cisplatin', 'MPA', (57, 81))
593538	31001468	The effect of LY294002 on the IC50 reduction caused by cisplatin was significantly stronger in 180-siCAC cells than in 180-scr cells (Figure 6C).	('LY294002', 'Var', (14, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('stronger', 'PosReg', (83, 91))	('LY294002', 'Chemical', 'MESH:C085911', (14, 22))	('IC50', 'MPA', (30, 34))
593539	31001468	The colony formation assays also demonstrated that the combination of cisplatin and LY294002 suppressed colony formation more significantly in 180-siCAC cells than in control cells (Figure 6D).	('LY294002', 'Chemical', 'MESH:C085911', (84, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('LY294002', 'Var', (84, 92))	('suppressed', 'NegReg', (93, 103))	('colony formation', 'CPA', (104, 120))
593540	31001468	These results suggest that inhibition of the Akt signaling pathway can restore the chemosensitivity of CACNA2D3-knockdown cells to cisplatin.	('Akt', 'Gene', (45, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('inhibition', 'Var', (27, 37))	('Akt', 'Gene', '207', (45, 48))	('chemosensitivity', 'MPA', (83, 99))	('restore', 'PosReg', (71, 78))
593559	31001468	CACNA2D3 and cisplatin synergistically induce apoptosis by increasing Ca2+-dependent collapse of mitochondrial membrane potential, indicating that CACNA2D3 enhances cisplatin-induced apoptosis by activating the mitochondrial pathway.	('apoptosis', 'CPA', (46, 55))	('enhances', 'PosReg', (156, 164))	('CACNA2D3', 'Var', (147, 155))	('activating', 'PosReg', (196, 206))	('mitochondrial pathway', 'Pathway', (211, 232))	('increasing', 'PosReg', (59, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
593561	31001468	By pathway enrichment analyses, we found that CACNA2D3 could inhibit DNA replication and block ESCC cells in the G2/M phase by inhibiting the expression of p53, as shown in our previous study.	('block', 'NegReg', (89, 94))	('ESCC', 'Disease', (95, 99))	('DNA replication', 'CPA', (69, 84))	('p53', 'Gene', (156, 159))	('inhibiting', 'NegReg', (127, 137))	('inhibit', 'NegReg', (61, 68))	('p53', 'Gene', '7157', (156, 159))	('expression', 'MPA', (142, 152))	('CACNA2D3', 'Var', (46, 54))
593566	31001468	Consistently, when CACNA2D3 was knocked down in KYSE180 cells, the phosphorylation level of Akt showed a significant increase.	('increase', 'PosReg', (117, 125))	('phosphorylation level', 'MPA', (67, 88))	('Akt', 'Gene', '207', (92, 95))	('CACNA2D3', 'Gene', (19, 27))	('Akt', 'Gene', (92, 95))	('KYSE180', 'CellLine', 'CVCL:1349', (48, 55))	('knocked down', 'Var', (32, 44))
593567	31001468	Interestingly, our data also showed that blockade of the PI3K/Akt pathway by LY294002 in CACNA2D3-knockdown cells could restore chemosensitivity to cisplatin.	('chemosensitivity to cisplatin', 'MPA', (128, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('restore', 'PosReg', (120, 127))	('Akt', 'Gene', '207', (62, 65))	('LY294002', 'Chemical', 'MESH:C085911', (77, 85))	('Akt', 'Gene', (62, 65))	('LY294002', 'Var', (77, 85))
593568	31001468	In summary, in this work we first proved that the expression of CACNA2D3 was associated with chemosensitivity in ESCC patients treated with cisplatin-based therapy.	('ESCC', 'Disease', (113, 117))	('CACNA2D3', 'Gene', (64, 72))	('expression', 'Var', (50, 60))	('chemosensitivity', 'Disease', (93, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('patients', 'Species', '9606', (118, 126))	('associated', 'Reg', (77, 87))
593579	29959381	In conclusion, anti-CD25b IgG may be a promising biomarker in terms of screening individuals at high risk of lung cancer.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('anti-CD25b', 'Var', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))
593591	29959381	Depletion of Treg cells before tumor challenge resulted in tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
593598	29959381	The present study was thus undertaken to detect circulating levels of natural autoantibodies against peptide antigens derived from CD25 and FOXP3 with an enzyme-linked immunosorbent assay (ELISA) developed in-house and to confirm if circulating anti-CD25 and anti-FOXP3 autoantibodies have diagnostic values for early detection of NSCLC.	('FOXP3', 'Gene', (264, 269))	('anti-CD25', 'Var', (245, 254))	('FOXP3', 'Gene', '50943', (140, 145))	('NSCLC', 'Disease', (331, 336))	('FOXP3', 'Gene', '50943', (264, 269))	('NSCLC', 'Disease', 'MESH:D002289', (331, 336))	('NSCLC', 'Phenotype', 'HP:0030358', (331, 336))	('CD25', 'Gene', (131, 135))	('FOXP3', 'Gene', (140, 145))
593599	29959381	The in-house ELISA showed a good reproducibility with coefficients of variation (CV) of 11.9% from anti-CD25a IgG assay, 13.9% from anti-CD25b IgG assay, 13.9% from anti-CD25c IgG assay, and 12.3% from anti-FOXP3 IgG assay (Supplementary Table S1).	('anti-CD25a', 'Var', (99, 109))	('FOXP3', 'Gene', (207, 212))	('FOXP3', 'Gene', '50943', (207, 212))
593617	29959381	In the present study, we found that plasma levels of anti-CD25a and anti-FOXP3 IgG were significantly higher in patients with NSCLC than control subjects, and were gradually increased with NSCLC stages.	('NSCLC', 'Disease', (189, 194))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('plasma levels', 'MPA', (36, 49))	('higher', 'PosReg', (102, 108))	('anti-CD25a', 'Var', (53, 63))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('FOXP3', 'Gene', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('NSCLC', 'Disease', (126, 131))	('FOXP3', 'Gene', '50943', (73, 78))
593624	29959381	A recent report indicated that anti-CD25 antibody could efficiently deplete intra-tumoral Treg cells through Fcgammareceptor (FcgammaR) mediated mechanism in a murine model.	('intra-tumoral', 'Disease', 'MESH:D009369', (76, 89))	('murine', 'Species', '10090', (160, 166))	('anti-CD25', 'Gene', (31, 40))	('intra-tumoral', 'Disease', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('deplete', 'NegReg', (68, 75))	('anti-CD25', 'Var', (31, 40))
593647	27852044	In further stratified analyses, the prognosis of PRR for ESCC mortality was reinforced in men with tumor-node-metastasis stage III (HR, 95% CI, P: 1.18, 1.09-1.28, 0.001), invasion depth T3-T4 (1.17, 1.08-1.26, <0.001) or positive lymph node metastasis (1.37, 1.18-1.59, <0.001).	('invasion', 'Var', (172, 180))	('men', 'Species', '9606', (90, 93))	('ESCC', 'Disease', (57, 61))	('tumor-node-metastasis', 'Disease', (99, 120))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (99, 120))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PRR', 'Gene', (49, 52))	('PRR', 'Gene', '8856', (49, 52))
593697	27852044	increments in neutrophil and platelet count were significantly associated with poor survival of ESCC patients, while per s.d.	('patients', 'Species', '9606', (101, 109))	('associated', 'Reg', (63, 73))	('increments', 'Var', (0, 10))	('ESCC', 'Disease', (96, 100))	('men', 'Species', '9606', (5, 8))	('neutrophil', 'MPA', (14, 24))	('poor', 'NegReg', (79, 83))
593698	27852044	increments in lymphocyte and RDW improved overall survival, even after adjustment, and significance was strikingly significant for RDW and platelet count (adjusted HR = 0.84 and 1.25, 95% CI: 0.75-0.93 and 1.08-1.22, P = 0.001 and < 0.001, respectively).	('overall survival', 'MPA', (42, 58))	('men', 'Species', '9606', (77, 80))	('increments', 'Var', (0, 10))	('men', 'Species', '9606', (5, 8))	('improved', 'PosReg', (33, 41))
593716	27852044	However, in this study, we surprisingly found that elevated RDW was associated with significant better prognosis of ESCC in men, opposing to the findings of most existing studies in cancer field.	('elevated', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('RDW', 'MPA', (60, 63))	('men', 'Species', '9606', (124, 127))	('ESCC', 'Disease', (116, 120))	('better', 'PosReg', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))
593717	27852044	Before going into this seeming contradiction, it is worth mentioning the conclusion of the Malmo Diet and Cancer cohort involving 26709 non-diabetic adults over 14 years of follow-up, that is, low RDW was significantly associated with increased incidence of diabetes mellitus, and this association was independent of traditional risk factors.	('diabetic', 'Disease', 'MESH:D003920', (140, 148))	('Cancer', 'Disease', (106, 112))	('diabetes mellitus', 'Disease', 'MESH:D003920', (258, 275))	('diabetic', 'Disease', (140, 148))	('Cancer', 'Disease', 'MESH:D009369', (106, 112))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('low RDW', 'Var', (193, 200))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (258, 275))	('men', 'Species', '9606', (58, 61))	('diabetes mellitus', 'Disease', (258, 275))
593730	27852044	Although to unravel the precise mechanisms underlying this finding transcends the limits of this study, we postulate that altered PRR might be a strong indicator of chronic inflammation or hyperglycemia, which participates in providing conditions that trigger carcinogenesis and metastasis.	('metastasis', 'CPA', (279, 289))	('carcinogenesis', 'Disease', 'MESH:D063646', (260, 274))	('hyperglycemia', 'Phenotype', 'HP:0003074', (189, 202))	('inflammation', 'Disease', 'MESH:D007249', (173, 185))	('carcinogenesis', 'Disease', (260, 274))	('hyperglycemia', 'Disease', 'MESH:D006943', (189, 202))	('inflammation', 'Disease', (173, 185))	('PRR', 'Gene', '8856', (130, 133))	('hyperglycemia', 'Disease', (189, 202))	('PRR', 'Gene', (130, 133))	('altered', 'Var', (122, 129))
593735	27852044	Moreover, elevated PRR was associated with worse prognosis in male patients especially at an advanced stage and with distant metastasis.	('elevated', 'Var', (10, 18))	('PRR', 'Gene', (19, 22))	('PRR', 'Gene', '8856', (19, 22))	('patients', 'Species', '9606', (67, 75))
593784	25593196	The molecular analysis of cancer cells has uncovered key genetic and epigenetic alterations underlying the development and progression of tumors.	('epigenetic alterations', 'Var', (69, 91))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
593804	25593196	Functional analysis indicated that mutations in ELMO1, found in EAC, significantly enhanced cellular invasion; this suggests the potential contribution of RAC1 signaling to Barrett's tumorigenesis.	('cellular invasion', 'CPA', (92, 109))	('ELMO1', 'Gene', (48, 53))	('RAC1', 'Gene', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('enhanced', 'PosReg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('ELMO1', 'Gene', '9844', (48, 53))	('RAC1', 'Gene', '5879', (155, 159))	('mutations', 'Var', (35, 44))
593810	25593196	A large body of evidence indicating that the normally tightly controlled and regulated RTKs in normal cells are overexpressed, amplified, and mutated, leading to constitutive activation of RTK signaling, resulting in deregulated cell growth and tumorigenesis (reviewed by).	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('mutated', 'Var', (142, 149))	('activation', 'PosReg', (175, 185))	('RTK signaling', 'MPA', (189, 202))	('cell growth', 'CPA', (229, 240))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('deregulated', 'MPA', (217, 228))	('tumor', 'Disease', (245, 250))
593811	25593196	Similarly, gain-of-function mutations of RTK downstream effectors such as RAS, RAF, and PI3K can promote cancer (reviewed by).	('RAF', 'Gene', '22882', (79, 82))	('RAF', 'Gene', (79, 82))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('RTK', 'Gene', (41, 44))	('gain-of-function', 'PosReg', (11, 27))	('PI3K', 'Var', (88, 92))	('RAS', 'Gene', (74, 77))	('mutations', 'Var', (28, 37))	('promote', 'PosReg', (97, 104))
593817	25593196	EGFR mutations (5-10%), amplification (20-30%), and overexpression (30-80%) in human esophageal SCC and AC have provided the rationale for targeting EGFR in esophageal cancer.	('esophageal SCC', 'Disease', 'MESH:D004941', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('human', 'Species', '9606', (79, 84))	('EGFR', 'Gene', (0, 4))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('amplification', 'MPA', (24, 37))	('mutations', 'Var', (5, 14))	('esophageal SCC', 'Disease', (85, 99))	('overexpression', 'PosReg', (52, 66))	('esophageal cancer', 'Disease', (157, 174))
593818	25593196	This suggests that EGFR amplification and overexpression rather than mutations drive esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('esophageal cancers', 'Disease', 'MESH:D004938', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('drive', 'Reg', (79, 84))	('amplification', 'Var', (24, 37))	('overexpression', 'PosReg', (42, 56))	('EGFR', 'Gene', (19, 23))	('esophageal cancers', 'Disease', (85, 103))
593832	25593196	HER-2 is activated through its dimerization with other members of the HER family including EGFR and HER-3, leading to the subsequent activation of downstream signaling.	('downstream signaling', 'MPA', (147, 167))	('HER-2', 'Gene', (0, 5))	('activation', 'PosReg', (133, 143))	('HER-3', 'Gene', '2065', (100, 105))	('dimerization', 'Var', (31, 43))	('HER-3', 'Gene', (100, 105))
593833	25593196	The fact that HER-2 overexpression and amplification have been associated with poor prognosis in ovarian and breast cancers, led to the development and approval of trastuzumab mAb to target HER-2 in breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('trastuzumab', 'Chemical', 'MESH:D000068878', (164, 175))	('breast tumors', 'Disease', 'MESH:D001943', (199, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('amplification', 'Var', (39, 52))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('breast tumors', 'Phenotype', 'HP:0100013', (199, 212))	('overexpression', 'PosReg', (20, 34))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('HER-2', 'Protein', (14, 19))	('ovarian and breast cancers', 'Disease', 'MESH:D010051', (97, 123))	('breast tumors', 'Disease', (199, 212))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancers', 'Phenotype', 'HP:0003002', (109, 123))
593835	25593196	Overexpression of HER-2 in esophageal SCC (23%) and GEJ (22%) adenocarcinomas have been associated with poor response to neoadjuvant chemotherapy and overall poor survival, respectively.	('esophageal SCC', 'Disease', (27, 41))	('adenocarcinomas', 'Disease', 'MESH:D000230', (62, 77))	('esophageal SCC', 'Disease', 'MESH:D004941', (27, 41))	('adenocarcinomas', 'Disease', (62, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('Overexpression', 'Var', (0, 14))	('HER-2', 'Protein', (18, 23))	('GEJ', 'Disease', (52, 55))
593844	25593196	The MET pathway has been chosen as a promising drug target because dysregulation of this pathway occurs in various types of human cancers, including human gastric and esophageal AC.	('dysregulation', 'Var', (67, 80))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('human', 'Species', '9606', (149, 154))	('human', 'Species', '9606', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal AC', 'Disease', (167, 180))
593846	25593196	Notably, gene amplification of c-MET has been associated with poor prognosis in gastric and esophageal cancers.	('c-MET', 'Gene', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('gastric and esophageal cancers', 'Disease', 'MESH:D013274', (80, 110))	('gene amplification', 'Var', (9, 27))	('c-MET', 'Gene', '4233', (31, 36))	('associated', 'Reg', (46, 56))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
593852	25593196	Previous studies showed that acquired resistance to EGFR inhibitors was associated with gene amplification of c-MET in NSCLC, suggesting that combined targeting of EGFR and c-MET could be beneficial to overcome the onset of drug resistance.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('acquired resistance', 'MPA', (29, 48))	('c-MET', 'Gene', (110, 115))	('c-MET', 'Gene', (173, 178))	('drug resistance', 'Phenotype', 'HP:0020174', (224, 239))	('gene amplification', 'Var', (88, 106))	('c-MET', 'Gene', '4233', (110, 115))	('c-MET', 'Gene', '4233', (173, 178))	('NSCLC', 'Disease', (119, 124))
593881	25593196	Another study showed that knockdown of AXL significantly improved in vitro response to standard chemotherapy by promoting apoptosis in NSCLC.	('apoptosis', 'CPA', (122, 131))	('NSCLC', 'Disease', (135, 140))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('knockdown', 'Var', (26, 35))	('AXL', 'Gene', (39, 42))	('improved', 'PosReg', (57, 65))	('promoting', 'PosReg', (112, 121))
593886	25593196	AURKA kinase activity is dependent on the phosphorylation of a threonine residue (T288) located on the activation loop of the kinase.	('AURKA', 'Gene', (0, 5))	('T288', 'Chemical', '-', (82, 86))	('dependent', 'Reg', (25, 34))	('activity', 'MPA', (13, 21))	('AURKA', 'Gene', '6790', (0, 5))	('T288', 'Var', (82, 86))	('threonine', 'Chemical', 'MESH:D013912', (63, 72))
593887	25593196	We, and others, have previously reported the amplification of the region band 13, which harbors the AURKA gene, on the long arm of chromosome 20 (20q13) in upper gastrointestinal cancers.	('AURKA', 'Gene', '6790', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (156, 186))	('AURKA', 'Gene', (100, 105))	('upper gastrointestinal cancers', 'Disease', (156, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('amplification', 'Var', (45, 58))
593890	25593196	Pre-clinical studies showed that activation of AURKA leads to transformation of rodent fibroblast cells and the formation of multipolar mitotic spindles that induce genomic instability, establishing AURKA as a bona fide oncogene.	('AURKA', 'Gene', (199, 204))	('AURKA', 'Gene', '6790', (199, 204))	('genomic', 'MPA', (165, 172))	('AURKA', 'Gene', '6790', (47, 52))	('activation', 'Var', (33, 43))	('AURKA', 'Gene', (47, 52))	('induce', 'Reg', (158, 164))
593891	25593196	AURKA blocks p53 tumor suppressor function through direct phosphorylation of p53 at Ser315, inducing MDM-2 mediated degradation of p53 protein; and Ser215 to suppress its transcriptional activity in cancer cells.	('p53', 'Gene', (131, 134))	('blocks', 'NegReg', (6, 12))	('cancer', 'Disease', (199, 205))	('Ser315', 'Chemical', '-', (84, 90))	('transcriptional activity', 'MPA', (171, 195))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('MDM-2', 'Gene', '4193', (101, 106))	('Ser215', 'Chemical', '-', (148, 154))	('p53', 'Gene', '7157', (77, 80))	('AURKA', 'Gene', '6790', (0, 5))	('degradation', 'MPA', (116, 127))	('p53', 'Gene', '7157', (13, 16))	('AURKA', 'Gene', (0, 5))	('MDM-2', 'Gene', (101, 106))	('Ser215', 'Var', (148, 154))	('tumor', 'Disease', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('p53', 'Gene', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('p53', 'Gene', (13, 16))	('inducing', 'Reg', (92, 100))	('suppress', 'NegReg', (158, 166))	('p53', 'Gene', '7157', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
593895	25593196	A second-generation investigational AURKA inhibitor (MLN8237/alisertib, Millennium), which has 200-fold selectivity for AURKA over AURKB (aurora kinase B) in cell assays, has been recently investigated as monotherapy in phase I clinical trials in patients with advanced solid tumors or lymphomas (NCT01898078, NCT00962091).	('solid tumors or lymphomas', 'Disease', (270, 295))	('MLN8237/alisertib', 'Var', (53, 70))	('aurora kinase B', 'Gene', (138, 153))	('AURKA', 'Gene', (120, 125))	('aurora kinase B', 'Gene', '9212', (138, 153))	('AURKA', 'Gene', '6790', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('solid tumors or lymphomas', 'Disease', 'MESH:D009369', (270, 295))	('lymphomas', 'Phenotype', 'HP:0002665', (286, 295))	('AURKA', 'Gene', '6790', (36, 41))	('AURKB', 'Gene', '9212', (131, 136))	('patients', 'Species', '9606', (247, 255))	('alisertib', 'Chemical', 'MESH:C550258', (61, 70))	('AURKB', 'Gene', (131, 136))	('AURKA', 'Gene', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))
593896	25593196	Notably, a phase I/II study on MLN8237 in patients with solid tumors including esophageal and gastric cancers has just been completed, yet the results have not been reported to date (NCT01045421).	('gastric cancers', 'Phenotype', 'HP:0012126', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('solid tumors', 'Disease', 'MESH:D009369', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('esophageal', 'Disease', (79, 89))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('MLN8237', 'Chemical', 'MESH:C550258', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('MLN8237', 'Var', (31, 38))	('solid tumors', 'Disease', (56, 68))	('gastric cancers', 'Disease', 'MESH:D013274', (94, 109))	('gastric cancers', 'Disease', (94, 109))	('patients', 'Species', '9606', (42, 50))
593897	25593196	In preclinical studies, we investigated whether the combination of MLN8237 with standard chemotherapeutic agents could have a better therapeutic outcome in upper gastrointestinal cancers.	('MLN8237', 'Var', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (156, 186))	('upper gastrointestinal cancers', 'Disease', (156, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('MLN8237', 'Chemical', 'MESH:C550258', (67, 74))
593898	25593196	Indeed, we found that MLN8237 in combination with cisplatin or docetaxel significantly enhanced cell death in esophageal AC xenograft mouse models.	('docetaxel', 'Chemical', 'MESH:D000077143', (63, 72))	('MLN8237', 'Var', (22, 29))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('enhanced', 'PosReg', (87, 95))	('death', 'Disease', 'MESH:D003643', (101, 106))	('esophageal AC', 'Disease', (110, 123))	('death', 'Disease', (101, 106))	('MLN8237', 'Chemical', 'MESH:C550258', (22, 29))	('mouse', 'Species', '10090', (134, 139))
593899	25593196	Mechanistic investigations indicated that AURKA promotes resistance to DNA damaging agents through activation of HDM2, a negative regulator of p53, thereby confirming that inhibition of AURKA in combination with chemotherapy is a good therapeutic approach in upper gastrointestinal cancers.	('HDM2', 'Gene', '4193', (113, 117))	('p53', 'Gene', '7157', (143, 146))	('AURKA', 'Gene', (42, 47))	('AURKA', 'Gene', '6790', (186, 191))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (259, 289))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('resistance to DNA damaging agents', 'MPA', (57, 90))	('activation', 'PosReg', (99, 109))	('upper gastrointestinal cancers', 'Disease', (259, 289))	('AURKA', 'Gene', (186, 191))	('inhibition', 'Var', (172, 182))	('promotes', 'PosReg', (48, 56))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('HDM2', 'Gene', (113, 117))	('p53', 'Gene', (143, 146))	('AURKA', 'Gene', '6790', (42, 47))
593900	25593196	These results strongly support the initiation of clinical studies on MLN8237 in combination with standard chemotherapeutic agents in patients with upper gastrointestinal cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (147, 177))	('upper gastrointestinal cancers', 'Disease', (147, 177))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('MLN8237', 'Chemical', 'MESH:C550258', (69, 76))	('MLN8237', 'Var', (69, 76))
593901	25593196	Additional preclinical studies on combinations of MLN8237 with targeted drugs (listed above) are required prior to designing clinical trials in patients with upper gastrointestinal cancers, especially those who have developed acquired resistance to first-line chemotherapy.	('upper gastrointestinal cancers', 'Disease', (158, 188))	('MLN8237', 'Var', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('patients', 'Species', '9606', (144, 152))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (158, 188))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))
593908	24742823	MET aberrations and c-MET inhibitors in patients with gastric and esophageal cancers in a phase I unit We sought to investigate the demographics and tumor-associated features in patients with gastroesophageal (GE) malignancies referred to our Phase I Program who had formalin-fixed, paraffin-embedded tissue from archival or new biopsies tested for MET mutation and/or amplification.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('esophageal cancers', 'Disease', (66, 84))	('paraffin', 'Chemical', 'MESH:D010232', (283, 291))	('gastroesophageal', 'Disease', 'MESH:D005764', (192, 208))	('gastroesophageal', 'Disease', (192, 208))	('amplification', 'Var', (369, 382))	('patients', 'Species', '9606', (178, 186))	('esophageal cancers', 'Disease', 'MESH:D004938', (66, 84))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('malignancies', 'Disease', 'MESH:D009369', (214, 226))	('malignancies', 'Disease', (214, 226))	('c-MET', 'Gene', '4233', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('c-MET', 'Gene', (20, 25))	('formalin', 'Chemical', 'MESH:D005557', (267, 275))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Disease', (149, 154))	('MET mutation', 'Var', (349, 361))
593909	24742823	MET amplification was found in 5 of 76 (6.6%) patients (3/34 [8.8%] esophageal, 2/26 [7.7%] gastric and none in 22 gastroesophageal junction cancers).	('patients', 'Species', '9606', (46, 54))	('esophageal', 'Disease', (68, 78))	('MET amplification', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('found', 'Reg', (22, 27))	('gastroesophageal junction cancers', 'Disease', 'MESH:D008309', (115, 148))	('gastroesophageal junction cancers', 'Disease', (115, 148))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('gastric', 'Disease', (92, 99))
593915	24742823	In conclusion, MET abnormalities can be found in a small group of patients with GE adenocarcinoma and further studies are necessary to better characterize the prognostic and predictive impact of MET alterations.	('adenocarcinoma', 'Disease', (83, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('MET abnormalities', 'Var', (15, 32))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('patients', 'Species', '9606', (66, 74))
593919	24742823	Genomic sequencing of these tumors suggests that exploring molecular aberrations in selected patients may offer new avenues for targeted therapeutic opportunities.. MET-positive GE cancer is a promising molecular subtype, particularly as a potential target for c-MET inhibitors.	('MET-positive', 'Var', (165, 177))	('c-MET', 'Gene', (261, 266))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('c-MET', 'Gene', '4233', (261, 266))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('patients', 'Species', '9606', (93, 101))
593923	24742823	Moreover, MET gene amplification is one of the well-recognized mechanisms of c-MET overexpression and constitutive activation of MET/HGF pathway, and has been reported in 2% to 10% of GE adenocarcinomas.	('HGF', 'Gene', (133, 136))	('c-MET', 'Gene', '4233', (77, 82))	('activation', 'PosReg', (115, 125))	('HGF', 'Gene', '3082', (133, 136))	('MET gene amplification', 'Var', (10, 32))	('reported', 'Reg', (159, 167))	('c-MET', 'Gene', (77, 82))	('adenocarcinomas', 'Disease', 'MESH:D000230', (187, 202))	('overexpression', 'PosReg', (83, 97))	('adenocarcinomas', 'Disease', (187, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
593926	24742823	Although far less frequent, MET mutations have also been described as a mechanism for c-MET pathway activation in gastric cancer and in other malignancies.	('activation', 'PosReg', (100, 110))	('gastric cancer', 'Disease', (114, 128))	('c-MET', 'Gene', (86, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('MET mutations', 'Var', (28, 41))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('c-MET', 'Gene', '4233', (86, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('malignancies', 'Disease', (142, 154))
593929	24742823	In a recent case series, two out of four patients with MET-amplified GEJ cancers had some tumor shrinkage with crizotinib, a c-MET inhibitor.	('cancers', 'Disease', (73, 80))	('MET-amplified', 'Var', (55, 68))	('c-MET', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('patients', 'Species', '9606', (41, 49))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('c-MET', 'Gene', '4233', (125, 130))	('crizotinib', 'Chemical', 'MESH:D000077547', (111, 121))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
593931	24742823	Early results with this drug in GE cancer showed prolonged survival for patients with high c-MET expression leading to a phase III trial, which is currently accruing patients (NCT01697072).	('c-MET', 'Gene', '4233', (91, 96))	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('c-MET', 'Gene', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('prolonged', 'PosReg', (49, 58))	('high', 'Var', (86, 90))	('patients', 'Species', '9606', (166, 174))	('patients', 'Species', '9606', (72, 80))
593936	24742823	A total of 81 patients with advanced esophageal (n=36), GEJ (n=17) or gastric (n=28) cancers were evaluated for MET mutation/variant (41 patients) or amplification (76 patients).	('MET mutation/variant', 'Var', (112, 132))	('gastric', 'Disease', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('patients', 'Species', '9606', (137, 145))	('cancers', 'Disease', (85, 92))	('patients', 'Species', '9606', (168, 176))	('amplification', 'Var', (150, 163))	('patients', 'Species', '9606', (14, 22))	('GEJ', 'Disease', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
593940	24742823	Five out of 76 (6.6%) patients had a MET gene amplification in FISH analysis (3 esophageal and 2 gastric cancers, all adenocarcinomas).	('MET gene amplification', 'Var', (37, 59))	('FISH analysis', 'Gene', (63, 76))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('patients', 'Species', '9606', (22, 30))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('adenocarcinomas', 'Disease', 'MESH:D000230', (118, 133))	('esophageal', 'Disease', (80, 90))	('gastric cancers', 'Phenotype', 'HP:0012126', (97, 112))	('adenocarcinomas', 'Disease', (118, 133))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('gastric cancers', 'Disease', (97, 112))	('gastric cancers', 'Disease', 'MESH:D013274', (97, 112))
593947	24742823	The proportion of poorly differentiated tumors was similar in MET positive patients compared to wild-type as well (1 out of 3 for MET mutated versus 22 out of 38 for nonmutated and 3 out of 5 for MET amplified versus 37 out of 71 for patients with non-amplified MET).	('MET mutated', 'Var', (130, 141))	('MET', 'Var', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (234, 242))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
593948	24742823	Few concomitant mutations were observed in the MET positive population: one patient with a MET variant and one with MET amplification had a concomitant TP53 mutation, while MET and HER-2 amplification were simultaneously detected in one patient (Table 2).	('variant', 'Var', (95, 102))	('patient', 'Species', '9606', (237, 244))	('TP53', 'Gene', '7157', (152, 156))	('mutation', 'Var', (157, 165))	('patient', 'Species', '9606', (76, 83))	('HER-2', 'Gene', '2064', (181, 186))	('TP53', 'Gene', (152, 156))	('HER-2', 'Gene', (181, 186))
593949	24742823	Patients positive for either MET mutation/variant or MET amplification (MET positive group, n=8) were compared with patients wild-type for both abnormalities (MET negative group, n=30).	('MET amplification', 'Var', (53, 70))	('patients', 'Species', '9606', (116, 124))	('MET mutation/variant', 'Var', (29, 49))	('Patients', 'Species', '9606', (0, 8))
593961	24742823	Our data are in line with previous series' reporting MET amplification in 2-7% of GE adenocarcinomas.	('adenocarcinomas', 'Disease', 'MESH:D000230', (85, 100))	('adenocarcinomas', 'Disease', (85, 100))	('amplification', 'Var', (57, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))
593963	24742823	The prevalence of MET amplification in GE cancer increased up to 5% with higher grade and more advanced disease in a previous report.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('increased', 'PosReg', (49, 58))	('MET amplification', 'Var', (18, 35))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
593971	24742823	In agreement with our results, patients with esophageal cancer and high c-MET expression had significantly reduced OS and disease-free survival in another series.	('esophageal cancer', 'Disease', (45, 62))	('disease-free survival', 'CPA', (122, 143))	('high', 'Var', (67, 71))	('c-MET', 'Gene', (72, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('reduced', 'NegReg', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('c-MET', 'Gene', '4233', (72, 77))	('patients', 'Species', '9606', (31, 39))
593977	24742823	Notably, of 10 patients with MET-amplified GE cancers, none were included in a crizotinib trial.	('patients', 'Species', '9606', (15, 23))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('MET-amplified', 'Var', (29, 42))	('cancers', 'Disease', (46, 53))	('crizotinib', 'Chemical', 'MESH:D000077547', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
593978	24742823	Preclinical data suggest that MET amplified gastric tumors may be sensitive to c-MET inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('MET amplified', 'Var', (30, 43))	('gastric tumors', 'Disease', (44, 58))	('gastric tumors', 'Disease', 'MESH:D013274', (44, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('c-MET', 'Gene', '4233', (79, 84))	('gastric tumors', 'Phenotype', 'HP:0006753', (44, 58))	('c-MET', 'Gene', (79, 84))
593979	24742823	We report disappointing results for the three patients with MET abnormalities included in trials with these agents (1 patient with a MET variant and 2 with MET amplification).	('patient', 'Species', '9606', (46, 53))	('MET variant', 'Var', (133, 144))	('patients', 'Species', '9606', (46, 54))	('variant', 'Var', (137, 144))	('patient', 'Species', '9606', (118, 125))
593982	24742823	reported that two out of four patients with MET-amplified GE tumors had rapid disease progression when treated with crizotinib.	('GE tumors', 'Disease', (58, 67))	('crizotinib', 'Chemical', 'MESH:D000077547', (116, 126))	('MET-amplified', 'Var', (44, 57))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('GE tumors', 'Disease', 'MESH:D009369', (58, 67))
593987	24742823	Additionally, one of the patients receiving a c-MET inhibitor in our series had a N375S MET variant.	('N375S', 'CellLine', 'CVCL:Y439', (82, 87))	('c-MET', 'Gene', (46, 51))	('patients', 'Species', '9606', (25, 33))	('c-MET', 'Gene', '4233', (46, 51))	('N375S MET', 'Var', (82, 91))
593989	24742823	Clinical data suggested that this variant might decrease the risk of gastric cancer, probably through reduced affinity of HGF to the c-MET receptor.	('gastric cancer', 'Disease', (69, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('HGF', 'Gene', (122, 125))	('HGF', 'Gene', '3082', (122, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('c-MET', 'Gene', (133, 138))	('decrease', 'NegReg', (48, 56))	('variant', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('reduced', 'NegReg', (102, 109))	('c-MET', 'Gene', '4233', (133, 138))	('affinity', 'Interaction', (110, 118))
593990	24742823	Although similar prognostic implication was not confirmed in lung cancer, decreased cell death upon treatment with a c-MET inhibitor was showed in the presence of N375S variant.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('N375S', 'Var', (163, 168))	('death', 'Disease', 'MESH:D003643', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('N375S variant', 'CellLine', 'CVCL:Y439', (163, 176))	('death', 'Disease', (89, 94))	('c-MET', 'Gene', '4233', (117, 122))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('decreased', 'NegReg', (74, 83))	('c-MET', 'Gene', (117, 122))
593998	24742823	Nonetheless, our results add to the current body of knowledge correlating the presence of MET genetic abnormalities with aggressive behavior and a worse prognosis in GE cancers.	('genetic abnormalities', 'Disease', (94, 115))	('cancers', 'Disease', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('aggressive behavior', 'Disease', 'MESH:D001523', (121, 140))	('presence', 'Var', (78, 86))	('genetic abnormalities', 'Disease', 'MESH:D030342', (94, 115))	('aggressive behavior', 'Disease', (121, 140))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('aggressive behavior', 'Phenotype', 'HP:0000718', (121, 140))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
594008	24742823	Patient characteristics including demographics, tumor type, MET mutation and/or amplification status and associated genetic abnormalities were summarized using frequency distributions and percentages.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('amplification status', 'Var', (80, 100))	('genetic abnormalities', 'Disease', 'MESH:D030342', (116, 137))	('tumor', 'Disease', (48, 53))	('genetic abnormalities', 'Disease', (116, 137))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('MET mutation', 'Var', (60, 72))	('Patient', 'Species', '9606', (0, 7))
594063	24118313	In the Women's Health Initiative trial, postmenopausal hormone use was associated with a 40% decrease in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('Women', 'Species', '9606', (7, 12))	('postmenopausal hormone use', 'Var', (40, 66))	('men', 'Species', '9606', (9, 12))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('decrease', 'NegReg', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('men', 'Species', '9606', (44, 47))	('postmenopausal hormone use', 'Phenotype', 'HP:0008209', (40, 66))	('colorectal cancer', 'Disease', (105, 122))
594118	23544449	There are two possible reasons for limited study of radiofrequency ablation in patients with superficial distant lymph node metastasis: (1) the technique of small lymph node ablation is difficult to handle and (2) radiofrequency ablation may cause collateral damage to adjacent structures.	('cause', 'Reg', (242, 247))	('radiofrequency ablation', 'Var', (214, 237))	('patients', 'Species', '9606', (79, 87))	('collateral damage', 'CPA', (248, 265))	('small lymph node', 'Phenotype', 'HP:0002732', (157, 173))
594143	23544449	Second, radiofrequency ablation may cause collateral damage to adjacent structures and pain.	('pain', 'Disease', 'MESH:D010146', (87, 91))	('radiofrequency ablation', 'Var', (8, 31))	('cause', 'Reg', (36, 41))	('pain', 'Disease', (87, 91))	('collateral damage', 'CPA', (42, 59))	('pain', 'Phenotype', 'HP:0012531', (87, 91))
594164	23544449	Furthermore, radiofrequency ablation induces thermal destruction of tissues by heating cells to a temperature higher than 60 C, causing irreversible cellular modification called coagulative necrosis.	('causing', 'Reg', (128, 135))	('radiofrequency', 'Var', (13, 27))	('necrosis', 'Disease', (190, 198))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (178, 198))	('necrosis', 'Disease', 'MESH:D009336', (190, 198))
594207	22481235	Patients with primary esophageal tumors expressing low levels of ERCC-1 and high levels of EGFR will exhibit an encouraging PFS and clinical complete response rate, following definitive treatment with cetuximab, cisplatin, irinotecan and external beam radiation.	('esophageal tumors', 'Disease', 'MESH:D004938', (22, 39))	('EGFR', 'Gene', (91, 95))	('esophageal tumors', 'Disease', (22, 39))	('esophageal tumors', 'Phenotype', 'HP:0100751', (22, 39))	('ERCC-1', 'Gene', (65, 71))	('high levels', 'Var', (76, 87))	('cetuximab', 'Chemical', 'MESH:D000068818', (201, 210))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('men', 'Species', '9606', (191, 194))	('ERCC-1', 'Gene', '2067', (65, 71))	('irinotecan', 'Chemical', 'MESH:D000077146', (223, 233))	('low levels', 'Var', (51, 61))	('PFS', 'MPA', (124, 127))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('EGFR', 'Gene', '1956', (91, 95))
594355	33757566	Furthermore, the high expression of SPRY4-IT1 was significantly correlated with tumor differentiation (P = 0.029), T classification (P = 0.013), lymph node metastasis(P = 0.022) and pathological stage (P = 0.001).	('lymph node metastasis', 'CPA', (145, 166))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('SPRY4-IT1', 'Gene', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (36, 45))	('T classification', 'CPA', (115, 131))	('high', 'Var', (17, 21))	('tumor', 'Disease', (80, 85))	('correlated', 'Reg', (64, 74))
594370	33757566	With the deepening research of lncRNA function, the study revealed that there are a large number of abnormal expression of lncRNAs in esophageal cancer, which play an important role in the development and progression of esophageal carcinoma.	('cancer', 'Disease', (145, 151))	('abnormal', 'Var', (100, 108))	('expression', 'MPA', (109, 119))	('esophageal carcinoma', 'Disease', (220, 240))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (220, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (220, 240))	('lncRNAs', 'Gene', (123, 130))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
594392	33757566	The abdominal and cervical surgery: 1) Place the patients in the supine position and separate legs, expose the small bend in the stomach; cut off the left gastric artery, and lymph nodes along the left gastric artery hepatic artery and the celiac axis were dissected.	('gastric artery hepatic artery', 'Disease', 'MESH:D007022', (202, 231))	('gastric artery hepatic artery', 'Disease', (202, 231))	('patients', 'Species', '9606', (49, 57))	('cut', 'Var', (138, 141))
594393	33757566	2) The stomach was mobilized with reserve of the right gastroepiploic artery, meanwhile, dissect the perigastric LNs, separate the esophageal hiatus and mobilize the abdominal esophagus.	('dissect', 'Var', (89, 96))	('gastroepiploic artery', 'Disease', (55, 76))	('gastroepiploic artery', 'Disease', 'MESH:D007022', (55, 76))
594394	33757566	3) Make an 5 cm incision in the anterior border of the sternocleidomastoid muscle of the left cervix, separate the sternocleidomastoid, dissect the LNs in the left lower cervical esophagus [included left cervical paraesophageal (101) and supraclavicular (104)] and cut off the cervical esophagus at the level of thoracic inlet.	('dissect', 'Var', (136, 143))	('sternocleidomastoid muscle', 'Disease', (55, 81))	('sternocleidomastoid muscle', 'Disease', 'MESH:C535977', (55, 81))	('sternocleidomastoid', 'Disease', 'MESH:C535977', (55, 74))	('sternocleidomastoid', 'Disease', 'MESH:C535977', (115, 134))	('sternocleidomastoid muscle', 'Phenotype', 'HP:0012036', (55, 81))	('sternocleidomastoid', 'Disease', (55, 74))	('sternocleidomastoid', 'Disease', (115, 134))
594413	33757566	Among 32 patients with high expression of SPRY4-IT1 harboring lymph-node metastasis, 19 patients (59.4%) had cervical and superior mediastinal lymph-node metastasis and 13 patients (40.6%) only had others' site lymph-node metastasis that didn't include cervical and superior mediastinum.	('patients', 'Species', '9606', (9, 17))	('high expression', 'Var', (23, 38))	('mediastinal lymph-node metastasis', 'Phenotype', 'HP:0100721', (131, 164))	('patients', 'Species', '9606', (88, 96))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (42, 51))	('SPRY4-IT1', 'Gene', (42, 51))	('patients', 'Species', '9606', (172, 180))
594414	33757566	Among 20 patients with low expression of SPRY4-IT1 existing lymph-node metastasis,6 patients (30%) had cervical and superior mediastinal lymph-node metastasis and 14 patients (70%) only had others' site lymph-node metastasis excluded cervical and superior mediastinum.	('patients', 'Species', '9606', (9, 17))	('mediastinal lymph-node metastasis', 'Phenotype', 'HP:0100721', (125, 158))	('patients', 'Species', '9606', (84, 92))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (41, 50))	('SPRY4-IT1', 'Gene', (41, 50))	('low expression', 'Var', (23, 37))	('patients', 'Species', '9606', (166, 174))
594419	33757566	Among 47 patients with the high expression of SPRY4-IT1, 38 patients (80.9%) had lymph-node recurrence.	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (46, 55))	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (60, 68))	('lymph-node recurrence', 'CPA', (81, 102))	('high expression', 'Var', (27, 42))	('SPRY4-IT1', 'Gene', (46, 55))
594449	33757566	This reflected that the high expression of SPRY4-IT1 is associated with a higher risk of cervical and superior mediastinal lymph-node metastasis and that this could be mitigated by radical three-field lymph node dissection surgery.	('SPRY4-IT1', 'Gene', (43, 52))	('mediastinal lymph-node metastasis', 'Phenotype', 'HP:0100721', (111, 144))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (43, 52))	('cervical', 'Disease', (89, 97))	('high', 'Var', (24, 28))
594451	33757566	But no significant differences were observed in the ESCC patients with 3FLND.Thus, patients with high SPRY4-IT1 expression might benefit from 3FLND esophagectomy.	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (102, 111))	('SPRY4-IT1', 'Gene', (102, 111))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (83, 91))	('benefit', 'PosReg', (129, 136))	('high', 'Var', (97, 101))	('esophagectomy', 'Disease', (148, 161))	('expression', 'MPA', (112, 122))
594502	32694918	And the high expression in TC introduced a 52% increased risk of relapse (HR=1.52, 95% CI: 0.88, 2.60) and a 48% increased risk of death (HR=1.48, 95% CI: 0.82, 2.69) (Table 3).	('relapse', 'CPA', (65, 72))	('high expression', 'Var', (8, 23))	('TC', 'Chemical', '-', (27, 29))
594515	32694918	Radiation was reported to elicit an adaptive immune response and the PD-L1 expression in tumor microenvironment could undermine the immunogenic effect of radiation.	('immunogenic effect', 'CPA', (132, 150))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('expression', 'Var', (75, 85))	('adaptive immune response', 'CPA', (36, 60))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PD-L1', 'Gene', (69, 74))	('undermine', 'NegReg', (118, 127))	('elicit', 'Reg', (26, 32))
594525	32694918	The dendritic cells expressing PD-L1 were unable to activate the proliferation of CD8+ T cells, and the antibody against PD-L1 could restore the activation.	('CD8', 'Gene', '925', (82, 85))	('proliferation', 'CPA', (65, 78))	('CD8', 'Gene', (82, 85))	('PD-L1', 'Var', (31, 36))
594537	32694918	Our study demonstrated if the expression of PD-L1 on IC was low, the effector immune cells were less dysfunctional and the expression of PD-L1 on TC affected the immunity and had a significant effect on the prognosis of ESCC.	('expression', 'MPA', (30, 40))	('dysfunctional', 'Disease', 'MESH:D009461', (101, 114))	('expression', 'Var', (123, 133))	('effect', 'Reg', (193, 199))	('dysfunctional', 'Disease', (101, 114))	('PD-L1', 'Gene', (137, 142))	('ESCC', 'Disease', (220, 224))	('TC', 'Chemical', '-', (146, 148))	('affected', 'Reg', (149, 157))	('immunity', 'MPA', (162, 170))	('IC', 'Chemical', '-', (53, 55))
594559	31861019	Most studies have demonstrate that the survival benefits of dissection of paracardial LNs and lesser curvature LNs for AEG.	('AEG', 'Disease', (119, 122))	('dissection', 'Var', (60, 70))	('AEG', 'Disease', 'MESH:D000230', (119, 122))
594563	31861019	Inclusion criteria were as follows: histologically proven AEG; tumor center located below the EGJ; pathological T2-T4a tumors; and R0 resection.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (119, 124))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('AEG', 'Disease', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('AEG', 'Disease', 'MESH:D000230', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('T2-T4a', 'Var', (112, 118))
594698	31681593	Univariate analysis of image texture showed that the IHIST_energy, m_contrast_1, m_Cluster shade_2, Diff_Clusetr Tendency_2, Diff_homogeneity_2, m_lnversevariance_2, Small gradient emphasis_1, GLGCM_small gradient emphasis, high-intensity small zone emphasis (HISE) and low-intensity large zone emphasis (LILE) demonstrated a statistically significant difference in association with the OS rates.	('SE', 'Disease', 'None', (262, 264))	('Small gradient emphasis_1', 'Var', (166, 191))	('association', 'Interaction', (366, 377))	('OS rates', 'Disease', (387, 395))	('low-intensity', 'Var', (270, 283))
594715	31681593	Our analysis showed that IHIST_energy, m_contrast_1, Diff_homogeneity_2, m_Inversevariance_2, HISE, and LILE have strong and independent associations with the OS rates.	('associations', 'Interaction', (137, 149))	('OS rates', 'Disease', (159, 167))	('m_contrast_1', 'Var', (39, 51))	('SE', 'Disease', 'None', (96, 98))	('m_Inversevariance_2', 'Var', (73, 92))
594722	31681593	The high tumor heterogeneity was shown to have a poorer prognosis and treatment resistance.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('high', 'Var', (4, 8))	('treatment resistance', 'CPA', (70, 90))
594752	31043861	Moreover, the abnormal expression of Nectin-4 in cancer cells could also regulate the cellular functions and angiogenesis.	('cellular functions', 'CPA', (86, 104))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('angiogenesis', 'CPA', (109, 121))	('abnormal', 'Var', (14, 22))	('Nectin-4', 'Protein', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('regulate', 'Reg', (73, 81))	('cancer', 'Disease', (49, 55))	('expression', 'MPA', (23, 33))
594756	31043861	The intervention of Nectin-4 expression in EC cell lines could regulate the cell viability as well as the abilities of migration, invasion and tumor formation.	('intervention', 'Var', (4, 16))	('tumor', 'Disease', (143, 148))	('cell viability', 'CPA', (76, 90))	('Nectin-4', 'Gene', (20, 28))	('regulate', 'Reg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
594769	31043861	The cells were maintained in RPMI-1640 or DMEM supplemented with 10% FBS in the presence of benzylpenicillin (100 U/mL), streptomycin (100 mug/mL) and 2 mM l-glutamine, and were cultured under standard culture conditions (5% CO2, 37  C).	('RPMI-1640', 'Chemical', '-', (29, 38))	('CO2', 'Chemical', '-', (225, 228))	('streptomycin', 'Chemical', 'MESH:D013307', (121, 133))	('DMEM', 'Chemical', '-', (42, 46))	('FBS', 'Gene', (69, 72))	('100 U/mL', 'Var', (110, 118))	('FBS', 'Gene', '64319', (69, 72))	('benzylpenicillin', 'Chemical', 'MESH:D010400', (92, 108))	('l-glutamine', 'Chemical', 'MESH:D005973', (156, 167))
594802	31043861	Moreover, the survival analysis showed that the overall survival rate of the patients with higher Nectin-4 expression was significantly poorer compared with those showing lower Nectin-4 expression (HR = 1.704, 95% CI 1.027-2.825, P = 0.039) (Fig.	('poorer', 'NegReg', (136, 142))	('higher', 'PosReg', (91, 97))	('Nectin-4', 'Gene', (98, 106))	('patients', 'Species', '9606', (77, 85))	('expression', 'Var', (107, 117))
594805	31043861	According to the COX model analysis, the Nectin-4 expression level could serve as an independent prognostic predictor for EC patients (Table 2, HR = 1.795, 95% CI 1.042-3.092, P = 0.035), suggesting that abnormal expression of Nectin-4 was involved in the progression of EC.	('abnormal', 'Var', (204, 212))	('Nectin-4', 'Gene', (227, 235))	('involved', 'Reg', (240, 248))	('patients', 'Species', '9606', (125, 133))
594806	31043861	In order to further investigate whether the intervention of Nectin-4 expression in human EC cells had effects on cellular functions, we also carried out the cellular study on the knock-down expression or over-expression of Nectin-4 in EC cells.	('over-expression', 'PosReg', (204, 219))	('knock-down', 'Var', (179, 189))	('human', 'Species', '9606', (83, 88))	('effects', 'Reg', (102, 109))
594809	31043861	5a, in Eca-109 cells, at 48 as well as 72 h after seeding, the proliferation rate of LV-Nectin-4-shRNA group cells was significantly lower than that of LV-NC group cells (both P < 0.01).	('lower', 'NegReg', (133, 138))	('proliferation rate', 'CPA', (63, 81))	('LV-NC', 'Chemical', '-', (152, 157))	('LV-Nectin-4-shRNA', 'Var', (85, 102))
594810	31043861	5c, in TE-1 cells, at 24, 48 as well as 72 h after seeding, the proliferation rate of LV-Nectin-4-shRNA group cells was significantly lower than that of LV-NC group cells (P < 0.01 respectively).	('proliferation rate', 'CPA', (64, 82))	('LV-Nectin-4-shRNA', 'Var', (86, 103))	('LV-NC', 'Chemical', '-', (153, 158))	('lower', 'NegReg', (134, 139))
594812	31043861	Knockdown of Nectin-4 expression significantly decreased the cell migration ability of Eca-109 and TE-1 cells, showing that the cell-free area of the LV-Nectin-4-shRNA group was significantly wider than that of the LV-NC group at 24 h (Fig.	('LV-NC', 'Chemical', '-', (215, 220))	('Knockdown', 'Var', (0, 9))	('Nectin-4', 'Gene', (13, 21))	('cell migration ability', 'CPA', (61, 83))	('decreased', 'NegReg', (47, 56))
594818	31043861	In the tumor model established using Eca-109 cells, the tumor growth curves showed that knockdown expression of Nectin-4 significantly inhibited the tumor growth (Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', (56, 61))	('Nectin-4', 'Gene', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('knockdown expression', 'Var', (88, 108))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('inhibited', 'NegReg', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
594820	31043861	After 28 days, the tumor weight of the LV-Nectin-4-shRNA group was lighter compared with the LV-NC group (Fig.	('lighter', 'NegReg', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('LV-Nectin-4-shRNA', 'Var', (39, 56))	('LV-NC', 'Chemical', '-', (93, 98))
594821	31043861	8c, P < 0.05), and the tumor weight of the LV-Nectin-4-OE group trended to be heavier compared with the LV-Vector-Ctrl group (Fig.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('LV-Nectin-4-OE', 'Var', (43, 57))	('tumor', 'Disease', (23, 28))	('heavier', 'PosReg', (78, 85))
594822	31043861	In the tumor model established using TE-1 cells, the tumor growth curves showed that knockdown expression of Nectin-4 significantly inhibited the tumor growth (Fig.	('inhibited', 'NegReg', (132, 141))	('Nectin-4', 'Gene', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('knockdown expression', 'Var', (85, 105))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
594824	31043861	8f, P < 0.0001), and the tumor weight of the LV-Nectin-4-OE group trended to be heavier compared with the LV-Vector-Ctrl group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('LV-Nectin-4-OE', 'Var', (45, 59))	('tumor', 'Disease', (25, 30))	('heavier', 'PosReg', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
594836	31043861	The underlying molecular mechanism of abnormal Nectin-4 expression in cancer progression still remains to be further investigated.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('abnormal', 'Var', (38, 46))	('Nectin-4', 'Gene', (47, 55))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
594854	30546458	However, the overexpression of RBBP7 significantly enhanced the invasion and migration of ESCC cells, whereas the knockdown of RBBP7 resulted in significantly decreased invasion and migration.	('RBBP7', 'Gene', (31, 36))	('invasion', 'CPA', (64, 72))	('knockdown', 'Var', (114, 123))	('enhanced', 'PosReg', (51, 59))	('RBBP7', 'Gene', '5931', (127, 132))	('overexpression', 'PosReg', (13, 27))	('decreased', 'NegReg', (159, 168))	('RBBP7', 'Gene', '5931', (31, 36))	('RBBP7', 'Gene', (127, 132))
594925	30546458	As shown in Table I, a high expression of RBBP7 was positively correlated with poor differentiation (chi2=5.936, P=0.023, Chi-squared test), regional lymph node involvement (chi2=6.544, P=0.016, Chi-squared test), and advanced pTNM staging (chi2=11.686, P=0.001, Chi-squared test).	('correlated', 'Reg', (63, 73))	('high expression', 'Var', (23, 38))	('regional lymph node involvement', 'CPA', (141, 172))	('advanced pTNM staging', 'CPA', (218, 239))	('RBBP7', 'Gene', '5931', (42, 47))	('men', 'Species', '9606', (168, 171))	('poor differentiation', 'CPA', (79, 99))	('RBBP7', 'Gene', (42, 47))
594932	30546458	In concordance with the immunohistochemical analysis, the median OS and DFS of patients with a higher mRNA expression of RBBP7 were significantly poorer than those of patients with a lower mRNA expression of RBBP7 (19.71 vs. 32.42 months and 13.01 vs. 24.05 months, respectively; log-rank test) (Fig.	('RBBP7', 'Gene', (121, 126))	('RBBP7', 'Gene', '5931', (208, 213))	('higher', 'Var', (95, 101))	('patients', 'Species', '9606', (167, 175))	('DFS', 'CPA', (72, 75))	('mRNA expression', 'MPA', (102, 117))	('RBBP7', 'Gene', (208, 213))	('patients', 'Species', '9606', (79, 87))	('poorer', 'NegReg', (146, 152))	('RBBP7', 'Gene', '5931', (121, 126))
594933	30546458	To explore the roles of RBBP7 in tumor progression, we established stable cell lines in which RBBP7 was overexpressed or knocked down.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('RBBP7', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('RBBP7', 'Gene', '5931', (24, 29))	('tumor', 'Disease', (33, 38))	('RBBP7', 'Gene', (24, 29))	('RBBP7', 'Gene', '5931', (94, 99))	('knocked', 'Var', (121, 128))
594934	30546458	RBBP7 was knocked down in two ESCC cell lines (TE1 and Eca109) (Fig.	('RBBP7', 'Gene', (0, 5))	('knocked', 'Var', (10, 17))	('RBBP7', 'Gene', '5931', (0, 5))
594936	30546458	The results of CCK-8 assays showed that RBBP7 knockdown had no effect on tumor viability (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('knockdown', 'Var', (46, 55))	('RBBP7', 'Gene', '5931', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('RBBP7', 'Gene', (40, 45))
594938	30546458	RBBP7 knockdown did not change the rate of apoptosis under normal culture conditions (TE1: 5.4+-0.4 vs. 5.3+-0.2; P=0.231; Eca109: 4.1+-0.2 vs. 5.2+-0.3; P=0.352; unpaired t-tests) (Fig.	('RBBP7', 'Gene', (0, 5))	('RBBP7', 'Gene', '5931', (0, 5))	('knockdown', 'Var', (6, 15))
594941	30546458	5B and C, RBBP7 knockdown significantly inhibited the migration and invasion of TE1 and Eca109 cells.	('RBBP7', 'Gene', '5931', (10, 15))	('inhibited', 'NegReg', (40, 49))	('RBBP7', 'Gene', (10, 15))	('knockdown', 'Var', (16, 25))
594953	30546458	In a recent study, RBBP7 overexpression was found to facilitate the epithelial-mesenchymal transition and promote migration and invasion.	('epithelial-mesenchymal transition', 'CPA', (68, 101))	('RBBP7', 'Gene', '5931', (19, 24))	('overexpression', 'Var', (25, 39))	('RBBP7', 'Gene', (19, 24))	('promote', 'PosReg', (106, 113))	('facilitate', 'PosReg', (53, 63))
594962	30546458	Our findings suggested that a high expression of RBBP7 could be used as a prognosticator for poor survival.	('high', 'Var', (30, 34))	('RBBP7', 'Gene', (49, 54))	('RBBP7', 'Gene', '5931', (49, 54))
594980	28818096	They identified mutations in neurogenic locus notch homolog protein 1 (NOTCH1) as well as CNVs in MYB proto-oncogene like 2 (MYBL2) and microRNA-4707-5p, and subsequently validated the prognostic values of these genes based on the expression profiles of an independent retrospective ESCC cohort.	('neurogenic locus notch homolog protein 1', 'Gene', (29, 69))	('NOTCH1', 'Gene', (71, 77))	('CNVs', 'Var', (90, 94))	('MYBL2', 'Gene', '4605', (125, 130))	('MYBL2', 'Gene', (125, 130))	('neurogenic locus notch homolog protein 1', 'Gene', '4851', (29, 69))	('mutations', 'Var', (16, 25))	('MYB proto-oncogene like 2', 'Gene', (98, 123))	('MYB proto-oncogene like 2', 'Gene', '4605', (98, 123))	('NOTCH1', 'Gene', '4851', (71, 77))
595006	28818096	All the 4 original studies indicated that a high level of p-mTOR was associated with unfavorable prognosis.	('mTOR', 'Gene', '2475', (60, 64))	('high', 'Var', (44, 48))	('mTOR', 'Gene', (60, 64))
595038	28818096	Four additional original studies also reported unfavorable prognosis for ESCC patients with VEGF overexpression, with the prognostic significance confirmed by multivariate analysis in 2 original studies.	('patients', 'Species', '9606', (78, 86))	('VEGF', 'Gene', (92, 96))	('overexpression', 'Var', (97, 111))	('ESCC', 'Disease', (73, 77))	('VEGF', 'Gene', '7422', (92, 96))
595052	28818096	In one other study, high podoplanin expression was significantly associated unfavorite prognosis only in univariate analysis.	('podoplanin', 'Gene', '10630', (25, 35))	('high', 'Var', (20, 24))	('podoplanin', 'Gene', (25, 35))
595058	28818096	Four original studies consistently elucidated the prognostic value of PKM2 expression for poor clinical outcome, with the prognostic significance confirmed by multivariate analysis in 3 original studies.	('PKM2', 'Gene', (70, 74))	('poor clinical outcome', 'MPA', (90, 111))	('PKM2', 'Gene', '5315', (70, 74))	('expression', 'Var', (75, 85))
595069	28818096	Ten of 14 original studies enrolled in these meta-analyses revealed that high expression of COX-2 was associated with short survival.	('associated', 'Reg', (102, 112))	('short survival', 'CPA', (118, 132))	('COX-2', 'Gene', (92, 97))	('COX-2', 'Gene', '5743', (92, 97))	('high expression', 'Var', (73, 88))
595083	28818096	Several studies demonstrated that ESCC patients with high EGFR expression showed a higher response rate to EGFR inhibitors and monoclonal antibodies against EGFR as well as longer PFS and/or OS than those with low to moderate EGFR expression, although controversial results have also been reported.	('EGFR', 'Gene', (157, 161))	('response', 'MPA', (90, 98))	('EGFR', 'Gene', '1956', (58, 62))	('high', 'Var', (53, 57))	('EGFR', 'Gene', '1956', (107, 111))	('patients', 'Species', '9606', (39, 47))	('EGFR', 'Gene', (58, 62))	('OS', 'Chemical', '-', (191, 193))	('EGFR', 'Gene', (107, 111))	('ESCC', 'Disease', (34, 38))	('EGFR', 'Gene', '1956', (226, 230))	('EGFR', 'Gene', '1956', (157, 161))	('higher', 'PosReg', (83, 89))	('EGFR', 'Gene', (226, 230))
595133	28245822	The mechanism of chylous leakage cessation after lipiodol lymphangiography was suspected to involve the accumulation of lipiodol at the leakage point, inducing an inflammatory reaction and acting as an embolic agent.	('inducing', 'Reg', (151, 159))	('embolic', 'Disease', (202, 209))	('chylous leakage', 'Disease', (17, 32))	('lipiodol', 'Chemical', 'MESH:D004998', (120, 128))	('embolic agent', 'Phenotype', 'HP:0001907', (202, 215))	('lipiodol', 'Chemical', 'MESH:D004998', (49, 57))	('embolic', 'Disease', 'MESH:D004617', (202, 209))	('inflammatory reaction', 'CPA', (163, 184))	('lipiodol', 'Var', (120, 128))
595147	28352763	The effects of miR-218 transfection on ECa9706 and ECa9706-CisR cell viability, including cell viability and apoptosis rate were confirmed using MTT assay, or flow cytometry, respectively.	('ECa9706', 'CellLine', 'CVCL:E307', (39, 46))	('ECa9706-CisR', 'Var', (51, 63))	('MTT', 'Chemical', 'MESH:C070243', (145, 148))	('ECa9706', 'CellLine', 'CVCL:E307', (51, 58))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
595149	28352763	We found that miR-218 was significantly decreased in ECa9706-CisR cells compared with parent Eca9706 cells.	('ECa9706', 'CellLine', 'CVCL:E307', (53, 60))	('Eca9706', 'CellLine', 'CVCL:E307', (93, 100))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('decreased', 'NegReg', (40, 49))	('ECa9706-CisR', 'Var', (53, 65))
595157	28352763	Low sensitivity or even chemoresistance give poor prognosis and also increase economic burden to patients.	('chemoresistance', 'CPA', (24, 39))	('patients', 'Species', '9606', (97, 105))	('increase', 'PosReg', (69, 77))	('Low sensitivity', 'Var', (0, 15))
595178	28352763	For apoptosis analysis, ECa9706 and ECa9706-CisR cells were collected and Annexin V-FITC assay kit was used according to the manufacturer's protocol after treated with 5mM cisplatin for 24h.	('cisplatin', 'Chemical', 'MESH:D002945', (172, 181))	('ECa9706', 'CellLine', 'CVCL:E307', (36, 43))	('4h', 'Chemical', '-', (187, 189))	('ECa9706', 'CellLine', 'CVCL:E307', (24, 31))	('Annexin V', 'Gene', '308', (74, 83))	('Annexin V', 'Gene', (74, 83))	('ECa9706-CisR', 'Var', (36, 48))
595185	28352763	As expected, following transfection of miR-218 mimics, the sensitivity of both ECa9706 and ECa9706-CisR cells to cisplatin was increased compared with negative control cells or miR-C cells, as demonstrated by MTT assay (Figure 2A).	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('transfection', 'Var', (23, 35))	('ECa9706', 'CellLine', 'CVCL:E307', (91, 98))	('MTT', 'Chemical', 'MESH:C070243', (209, 212))	('sensitivity', 'MPA', (59, 70))	('ECa9706-CisR', 'Var', (91, 103))	('miR', 'Gene', '220972', (177, 180))	('ECa9706', 'CellLine', 'CVCL:E307', (79, 86))	('ECa9706', 'Var', (79, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('miR', 'Gene', (177, 180))	('increased', 'PosReg', (127, 136))
595190	28352763	Besides, a study from breast cancer cells had pointed out that survivin, encoded by BIRC5, was significantly reduced after miR-218 transfection and this targeting regulated resistance to chemotherapeutics in breast cancer cells.	('regulated', 'Reg', (163, 172))	('survivin', 'Protein', (63, 71))	('breast cancer', 'Disease', (22, 35))	('BIRC5', 'Gene', '332', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('BIRC5', 'Gene', (84, 89))	('miR', 'Gene', '220972', (123, 126))	('resistance to chemotherapeutics', 'MPA', (173, 204))	('miR', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('reduced', 'NegReg', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', (208, 221))	('transfection', 'Var', (131, 143))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))
595193	28352763	Notably, we found that in the miR-C transfected cells, survivin expression was a bit increased in ECa9706-CisR than the parent ECa9706 cells.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('expression', 'MPA', (64, 74))	('survivin', 'Protein', (55, 63))	('ECa9706', 'CellLine', 'CVCL:E307', (98, 105))	('ECa9706', 'CellLine', 'CVCL:E307', (127, 134))	('increased', 'PosReg', (85, 94))	('ECa9706-CisR', 'Var', (98, 110))
595197	28352763	Specifically, we demonstrated that miR-218 transfection by its mimics could increase chemosensitivity of both ECa9706 cells and ECa9706-CisR cells to cisplatin in vitro, probably via targeting survivin expression.	('transfection', 'Var', (43, 55))	('increase', 'PosReg', (76, 84))	('survivin', 'Protein', (193, 201))	('chemosensitivity', 'MPA', (85, 101))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('ECa9706', 'CellLine', 'CVCL:E307', (110, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('ECa9706', 'CellLine', 'CVCL:E307', (128, 135))	('targeting', 'Reg', (183, 192))
595216	28260931	The results of our meta-analysis suggest that a high NLR value might represent a poor prognosis and worse clinicopathologic characteristics for patients with ESCC.	('ESCC', 'Disease', (158, 162))	('high', 'Var', (48, 52))	('NLR value', 'MPA', (53, 62))	('patients', 'Species', '9606', (144, 152))
595222	28260931	Various prognostic factors including tumor stage and genetic polymorphism have been reported, and more recently, certain serum biomarkers, such as inflammation factors, were also suggested to have predictive potential.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('genetic polymorphism', 'Var', (53, 73))	('inflammation', 'Disease', 'MESH:D007249', (147, 159))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('inflammation', 'Disease', (147, 159))
595241	28260931	We found that high NLR was positively associated with poor OS (pooled HR =1.314; 95% CI, 1.164-1.484; P<0.001; Figure 2), and there was no significant heterogeneity (I =0%, Ph=0.593; Table 2).	('high', 'Var', (14, 18))	('poor OS', 'Disease', (54, 61))	('OS', 'Chemical', '-', (59, 61))	('NLR', 'Gene', (19, 22))
595272	27431358	The effects of CASC9 knockdown on migration and invasion were evaluated by wound healing assay, cell migration and invasion assays in vitro.	('cell migration', 'CPA', (96, 110))	('CASC9', 'Gene', (15, 20))	('CASC9', 'Gene', '101805492', (15, 20))	('knockdown', 'Var', (21, 30))	('migration', 'CPA', (34, 43))
595274	27431358	Furthermore, knockdown of CASC9 significantly suppressed cell migration and invasion in vitro.	('CASC9', 'Gene', '101805492', (26, 31))	('knockdown', 'Var', (13, 22))	('CASC9', 'Gene', (26, 31))	('suppressed', 'NegReg', (46, 56))
595281	27431358	Accumulating data have also indicated that the dysregulation of lncRNAs may play an important functional role in diverse human cancers, including esophageal cancer 8.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('play', 'Reg', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('dysregulation', 'Var', (47, 60))	('esophageal cancer', 'Disease', (146, 163))	('lncRNAs', 'Protein', (64, 71))	('human', 'Species', '9606', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
595285	27431358	These results indicated that the dysregulation of lncRNAs could participate in tumor progression 11, 12.	('dysregulation', 'Var', (33, 46))	('tumor', 'Disease', (79, 84))	('lncRNAs', 'Gene', (50, 57))	('participate', 'Reg', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
595288	27431358	Furthermore, the knockdown of CASC9 expression increases apoptosis and decreased invasive capacity significantly in vitro 14.	('apoptosis', 'CPA', (57, 66))	('knockdown', 'Var', (17, 26))	('CASC9', 'Gene', '101805492', (30, 35))	('invasive capacity', 'CPA', (81, 98))	('increases', 'PosReg', (47, 56))	('CASC9', 'Gene', (30, 35))	('decreased', 'NegReg', (71, 80))
595292	27431358	We further discovered that siRNA-mediated knockdown of CASC9 results in diminished cell migration and invasion in ESCC cells.	('ESCC', 'Disease', (114, 118))	('CASC9', 'Gene', (55, 60))	('CASC9', 'Gene', '101805492', (55, 60))	('cell migration', 'CPA', (83, 97))	('diminished', 'NegReg', (72, 82))	('invasion in', 'CPA', (102, 113))	('knockdown', 'Var', (42, 51))
595319	27431358	At 48 h post-transfection, CASC9 expression was knocked down by approximately 80% in Kyse150 and 75% in TE1 cells by siCASC9-3 transfection when compared with the scrambled siRNA (Fig.	('CASC9', 'Gene', (27, 32))	('CASC9', 'Gene', '101805492', (119, 124))	('transfection', 'Var', (127, 139))	('CASC9', 'Gene', '101805492', (27, 32))	('expression', 'MPA', (33, 43))	('CASC9', 'Gene', (119, 124))	('knocked down', 'NegReg', (48, 60))
595332	27431358	One study reported that dysregulation of CASC9 was associated with apoptosis and invasion, but none provided data of clinical tissues.	('clinical', 'Species', '191496', (117, 125))	('apoptosis', 'CPA', (67, 76))	('CASC9', 'Gene', (41, 46))	('CASC9', 'Gene', '101805492', (41, 46))	('invasion', 'CPA', (81, 89))	('dysregulation', 'Var', (24, 37))	('associated', 'Reg', (51, 61))
595336	27431358	Furthermore, CASC9 knockdown significantly inhibited esophageal cancer cell migration and invasion in vitro.	('inhibited', 'NegReg', (43, 52))	('knockdown', 'Var', (19, 28))	('CASC9', 'Gene', '101805492', (13, 18))	('esophageal cancer', 'Disease', (53, 70))	('invasion in vitro', 'CPA', (90, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('CASC9', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
595377	25408239	Leptin serum levels were measured, as well as those of soluble leptin receptor (SLR), adiponectin, and resistin, using commercial ELISA kits of BioVendor, Brno, Czech Republic (Leptin: RD191001100 HUMAN LEPTIN ELISA, CLINICAL RANGE, SANDWICH IMMUNOASSAY; soluble leptin receptor (SLR): RD194002100 HUMAN LEPTIN RECEPTOR ELISA, SANDWICH IMMUNOASSAY; insulin-like growth factor 1 (IGF 1): RMEE20 Human IGF-1 ELISA, SANDWICH IMMUNOASSAY; adiponectin: RD195023100 HUMAN ADIPONECTIN ELISA, COMPETITIVE IMMUNOASSAY; and resistin: RD191016100 HUMAN RESISTIN ELISA, SANDWICH IMMUNOASSAY).	('insulin-like growth factor 1', 'Gene', (349, 377))	('LEPTIN', 'Gene', '3952', (304, 310))	('ADIPONECTIN', 'Gene', '9370', (466, 477))	('adiponectin', 'Gene', '9370', (435, 446))	('Leptin', 'Gene', (0, 6))	('RESISTIN', 'Gene', (542, 550))	('IGF 1', 'Gene', '3479', (379, 384))	('resistin', 'Gene', (103, 111))	('HUMAN', 'Species', '9606', (298, 303))	('resistin', 'Gene', (514, 522))	('IGF-1', 'Gene', (400, 405))	('LEPTIN', 'Gene', (304, 310))	('IGF 1', 'Gene', (379, 384))	('Leptin', 'Gene', '3952', (0, 6))	('HUMAN', 'Species', '9606', (460, 465))	('leptin', 'Gene', '3952', (263, 269))	('IGF-1', 'Gene', '3479', (400, 405))	('insulin-like growth factor 1', 'Gene', '3479', (349, 377))	('leptin', 'Gene', (263, 269))	('adiponectin', 'Gene', (86, 97))	('LEPTIN', 'Gene', '3952', (203, 209))	('Human', 'Species', '9606', (394, 399))	('ADIPONECTIN', 'Gene', (466, 477))	('adiponectin', 'Gene', (435, 446))	('Leptin', 'Gene', (177, 183))	('resistin', 'Gene', '56729', (103, 111))	('resistin', 'Gene', '56729', (514, 522))	('LEPTIN', 'Gene', (203, 209))	('HUMAN', 'Species', '9606', (197, 202))	('leptin', 'Gene', '3952', (63, 69))	('RESISTIN', 'Gene', '56729', (542, 550))	('leptin', 'Gene', (63, 69))	('Leptin', 'Gene', '3952', (177, 183))	('adiponectin', 'Gene', '9370', (86, 97))	('RD194002100', 'Var', (286, 297))	('HUMAN', 'Species', '9606', (536, 541))
595416	25408239	Moreover, dysregulated adiponectin was found in pancreatic cancer.	('dysregulated', 'Var', (10, 22))	('pancreatic cancer', 'Disease', (48, 65))	('found', 'Reg', (39, 44))	('pancreatic cancer', 'Disease', 'MESH:D010190', (48, 65))	('adiponectin', 'Gene', '9370', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (48, 65))	('adiponectin', 'Gene', (23, 34))
595419	25408239	The worse prognosis of those patients could be connected with the inflammatory process and dysregulation of adiponectin, as well as nutritional status.	('patients', 'Species', '9606', (29, 37))	('adiponectin', 'Gene', '9370', (108, 119))	('adiponectin', 'Gene', (108, 119))	('dysregulation', 'Var', (91, 104))
595430	24888564	Similar to the adenoma-carcinoma sequence of EAC, ESCC develops through progression from normal esophageal epithelium (NEE) to low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), early stage esophageal carcinoma (EEC) and then advanced stage esophageal carcinoma (AEC) with an accumulation of genetic and epigenetic abnormalities (Fig.	('high-grade', 'Disease', (171, 181))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (137, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (279, 299))	('ESCC', 'Disease', (50, 54))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (228, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('genetic', 'Var', (330, 337))	('neoplasia', 'Phenotype', 'HP:0002664', (153, 162))	('intraepithelial neoplasia', 'Disease', (137, 162))	('esophageal carcinoma', 'Disease', (228, 248))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (182, 207))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (279, 299))	('neoplasia', 'Phenotype', 'HP:0002664', (198, 207))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (182, 207))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (228, 248))	('esophageal carcinoma', 'Disease', (279, 299))	('epigenetic abnormalities', 'Var', (342, 366))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (15, 32))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (137, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('intraepithelial neoplasia', 'Disease', (182, 207))	('adenoma-carcinoma', 'Disease', (15, 32))
595446	24888564	MiR-92a, miR-103/107, miR-21, miR143, miR145, miR-205 and miR-296, among others, have been confirmed to be involved in the development of ESCC.	('miR-296', 'Gene', (58, 65))	('miR143', 'Gene', '406935', (30, 36))	('miR-103/107', 'Var', (9, 20))	('miR-205', 'Gene', (46, 53))	('MiR-92a', 'Var', (0, 7))	('miR145', 'Gene', '406937', (38, 44))	('miR-205', 'Gene', '406988', (46, 53))	('miR-21', 'Gene', '406991', (22, 28))	('miR-296', 'Gene', '407022', (58, 65))	('involved', 'Reg', (107, 115))	('miR143', 'Gene', (30, 36))	('miR-21', 'Gene', (22, 28))	('miR145', 'Gene', (38, 44))	('ESCC', 'Disease', (138, 142))
595483	24888564	For example, the GO term 0008219 is correlated with cell death, and nine mRNAs (NM_171982, NM_022470, NM_145725, NM_000332, NM_001098517, NM_001004426, NM_152240, NM_002598 and NM_004394) that were downregulated in the disease and may be regulated by miR-361-3p were enriched in this GO term, while almost eight lncRNAs that neighbored the mRNAs were also enriched in the same GO term (Table 12, Supplementary Material).	('NM_145725', 'Var', (102, 111))	('0008219', 'Var', (25, 32))	('NM_001004426', 'Var', (138, 150))	('NM_022470', 'Var', (91, 100))	('NM_004394', 'Var', (177, 186))	('miR-361-3p', 'Gene', (251, 261))	('NM_152240', 'Var', (152, 161))	('NM_171982', 'Var', (80, 89))	('NM_002598', 'Var', (163, 172))	('NM_000332', 'Var', (113, 122))	('NM_001098517', 'Var', (124, 136))	('miR-361-3p', 'Gene', '100500908', (251, 261))	('downregulated', 'NegReg', (198, 211))
595506	24888564	Braconi et al highlighted the inter-association between two classes of ncRNA, miRNA and lncRNA, and revealed miRNA-dependent regulation of lncRNA MEG3 expression by evaluating the involvement of miR-29, which can modulate DNMT 1 and 3.	('MEG3', 'Gene', '55384', (146, 150))	('miR-29', 'Var', (195, 201))	('expression', 'MPA', (151, 161))	('DNMT 1 and 3', 'Gene', '1786', (222, 234))	('MEG3', 'Gene', (146, 150))
595509	24888564	Wang et al also demonstrated that the lncRNA HULC may act as an endogenous 'sponge', which downregulates miR-372 activity, and inhibition of miR-372 leads to reducing translational repression of its target gene, PRKACB, which in turn induces phosphorylation of CREB and HULC expression.	('HULC', 'Gene', '728655', (45, 49))	('miR-372', 'Gene', '442917', (105, 112))	('miR-372', 'Gene', (141, 148))	('translational repression', 'MPA', (167, 191))	('downregulates', 'NegReg', (91, 104))	('HULC', 'Gene', (270, 274))	('PRKACB', 'Gene', (212, 218))	('CREB', 'Gene', (261, 265))	('miR-372', 'Gene', '442917', (141, 148))	('induces', 'Reg', (234, 241))	('reducing', 'NegReg', (158, 166))	('inhibition', 'Var', (127, 137))	('HULC', 'Gene', '728655', (270, 274))	('HULC', 'Gene', (45, 49))	('phosphorylation', 'MPA', (242, 257))	('CREB', 'Gene', '1385', (261, 265))	('miR-372', 'Gene', (105, 112))	('PRKACB', 'Gene', '5567', (212, 218))	('activity', 'MPA', (113, 121))
595537	24888564	The combination of clinical parameters and genetic/epigenetic alterations increases the quality of the risk assessment of ESCC in IN patients.	('ESCC in', 'Disease', (122, 129))	('genetic/epigenetic alterations', 'Var', (43, 73))	('patients', 'Species', '9606', (133, 141))	('increases', 'PosReg', (74, 83))
595558	23552052	In fact, Keshan disease, a congestive cardiomyopathy, first observed in Keshan County of Heilongjiang province, Northeast China, was found to be caused by a combination of dietary deficiency of selenium and the presence of a mutated strain of Coxsackievirus.	('selenium', 'MPA', (194, 202))	('caused by', 'Reg', (145, 154))	('Keshan disease', 'Disease', (9, 23))	('Keshan disease', 'Disease', 'MESH:C536166', (9, 23))	('Coxsackievirus', 'Species', '12066', (243, 257))	('congestive cardiomyopathy', 'Disease', (27, 52))	('mutated', 'Var', (225, 232))	('congestive cardiomyopathy', 'Disease', 'MESH:D002311', (27, 52))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (38, 52))	('congestive cardiomyopathy', 'Phenotype', 'HP:0001644', (27, 52))	('deficiency', 'NegReg', (180, 190))
595568	23552052	Hydrogen selenide can also be mono-, di-, or tri-methylated for excretion.	('Hydrogen selenide', 'Chemical', 'MESH:C026372', (0, 17))	('tri-methylated', 'Var', (45, 59))	('Hydrogen selenide', 'MPA', (0, 17))	('excretion', 'MPA', (64, 73))
595576	23552052	Symptoms of selenium toxicity, or selenosis, including hair and nail brittleness/loss, gastrointestinal disturbances, skin rash, garlic breath odor, fatigue, or irritability, appeared with 800 mug/day of selenium intake.	('garlic breath odor', 'Disease', 'MESH:C536561', (129, 147))	('fatigue', 'Disease', (149, 156))	('fatigue', 'Phenotype', 'HP:0012378', (149, 156))	('skin rash', 'Disease', 'MESH:D005076', (118, 127))	('irritability', 'Phenotype', 'HP:0000737', (161, 173))	('skin rash', 'Phenotype', 'HP:0000988', (118, 127))	('toxicity', 'Disease', 'MESH:D064420', (21, 29))	('fatigue', 'Disease', 'MESH:D005221', (149, 156))	('toxicity', 'Disease', (21, 29))	('selenosis', 'Disease', (34, 43))	('800 mug/day', 'Var', (189, 200))	('gastrointestinal disturbances', 'Disease', (87, 116))	('brittleness/loss', 'Disease', 'MESH:D010013', (69, 85))	('hair', 'Disease', (55, 59))	('nail brittleness', 'Phenotype', 'HP:0001808', (64, 80))	('skin rash', 'Disease', (118, 127))	('brittleness/loss', 'Disease', (69, 85))	('gastrointestinal disturbances', 'Disease', 'MESH:D005767', (87, 116))	('irritability', 'Disease', (161, 173))	('garlic breath odor', 'Disease', (129, 147))	('irritability', 'Disease', 'MESH:D001523', (161, 173))	('selenosis', 'Chemical', '-', (34, 43))
595578	23552052	Two studies with designs relevant to SELECT tested the efficacy of l-selenomethionine or dl-alpha-tocopherol on prostate cancer incidence and multiplicity and reported null findings.	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (92, 108))	('dl-alpha-tocopherol', 'Chemical', '-', (89, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('l-selenomethionine', 'Var', (67, 85))	('prostate cancer', 'Disease', (112, 127))	('tested', 'Reg', (44, 50))	('dl-alpha-tocopherol', 'Var', (89, 108))
595586	23552052	After 6 years of follow-up, total cancer mortality decreased by 4%, gastric/esophageal cancer mortality decreased by 8%, and esophageal cancer mortality decreased by 16% in the supplement group compared to the placebo group; however, none of these decreases was statistically significant and cancer incidence rates were similar between the two groups.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('esophageal cancer', 'Disease', (76, 93))	('esophageal cancer', 'Disease', (125, 142))	('decreased', 'NegReg', (104, 113))	('decreased', 'NegReg', (51, 60))	('supplement', 'Var', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('decreased', 'NegReg', (153, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
595604	23552052	reported that among men with the AA genotype of codon 16 (rs4880) of SOD2, a gene that encodes the mitochondrial antioxidant enzyme manganese superoxide dismutase, men with higher selenium levels had lower risk of total prostate cancer (RR: 0.3, 95% CI: 0.2-0.7) and of clinically aggressive prostate cancer (RR: 0.2, 95% CI: 0.1-0.5) compared to those with lower selenium levels.	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('SOD2', 'Gene', '6648', (69, 73))	('SOD2', 'Gene', (69, 73))	('manganese superoxide dismutase', 'Gene', '6648', (132, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (292, 307))	('prostate cancer', 'Phenotype', 'HP:0012125', (220, 235))	('total prostate cancer', 'Disease', 'MESH:D011471', (214, 235))	('lower', 'NegReg', (200, 205))	('manganese superoxide dismutase', 'Gene', (132, 162))	('total prostate cancer', 'Disease', (214, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('rs4880', 'Var', (58, 64))	('rs4880', 'Mutation', 'rs4880', (58, 64))
595605	23552052	In an analysis of prostate cancer mortality from the Physicians' Health Study, three different polymorphisms in the selenoprotein gene SEP15 (rs479341, rs1407131, and rs561104) significantly affected survival time in men with prostate cancer, either increasing or decreasing survival depending on the polymorphism and the genotype.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('survival time', 'MPA', (200, 213))	('increasing', 'PosReg', (250, 260))	('SEP15', 'Gene', (135, 140))	('rs561104', 'Var', (167, 175))	('prostate cancer', 'Phenotype', 'HP:0012125', (226, 241))	('prostate cancer', 'Phenotype', 'HP:0012125', (18, 33))	('rs479341', 'Var', (142, 150))	('rs1407131', 'Mutation', 'rs1407131', (152, 161))	('rs1407131', 'Var', (152, 161))	('prostate cancer', 'Disease', (226, 241))	('decreasing', 'NegReg', (264, 274))	('rs479341', 'Mutation', 'rs479341', (142, 150))	('rs561104', 'Mutation', 'rs561104', (167, 175))	('SEP15', 'Gene', '9403', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('affected', 'Reg', (191, 199))	('survival', 'MPA', (275, 283))
595606	23552052	Further, an interaction exists between selenium and genotype of rs561104.	('interaction', 'Interaction', (12, 23))	('rs561104', 'Var', (64, 72))	('rs561104', 'DBSNP_MENTION', 'None', (64, 72))
595607	23552052	High levels of selenium were associated with decreased prostate cancer mortality only in those with the increased risk homozygous variant genotype and not in those with the wild-type genotype (Pinteraction = 0.02).	('selenium', 'MPA', (15, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (55, 70))	('variant', 'Var', (130, 137))	('decreased prostate', 'Phenotype', 'HP:0008687', (45, 63))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('decreased prostate cancer', 'Disease', 'MESH:D011471', (45, 70))	('decreased prostate cancer', 'Disease', (45, 70))
595609	23552052	In a study of 161 men and women, those with the GPX1 679 (rs1050450) T/T genotype had significantly lower plasma selenium levels than those with the C/C genotype.	('plasma selenium levels', 'MPA', (106, 128))	('rs1050450) T/T', 'Var', (58, 72))	('GPX1 679', 'Gene', (48, 56))	('lower', 'NegReg', (100, 105))	('rs1050450', 'Mutation', 'rs1050450', (58, 67))
595704	31623639	In RTOG 94-05 and previous retrospective studies, RT was delivered by 2DRT or Co60 radiation which was now-outdated technique and may bring about risk of radiation toxicity in lung and heart.	('bring about', 'Reg', (134, 145))	('toxicity', 'Disease', 'MESH:D064420', (164, 172))	('toxicity', 'Disease', (164, 172))	('Co60', 'Chemical', 'MESH:C069837', (78, 82))	('Co60 radiation', 'Var', (78, 92))
595727	31173474	Biliary tumorigenic effect on hypopharyngeal cells is significantly enhanced by pH reduction Biliary reflux has been considered a potential risk factor in upper aerodigestive tract malignancies.	('Biliary reflux', 'Disease', (93, 107))	('enhanced', 'PosReg', (68, 76))	('pH reduction', 'Var', (80, 92))	('tract malignancies', 'Disease', 'MESH:D009369', (175, 193))	('tract malignancies', 'Disease', (175, 193))
595748	31173474	HHPCs underwent repetitive exposures for 7 minutes to primary bile acids bile with DCA at pH 4.0, 5.5 or 7.0 respectively and in parallel to corresponding controls at pH 4.0.	('DCA', 'Var', (83, 86))	('bile acids', 'Chemical', 'MESH:D001647', (62, 72))	('HHPC', 'Chemical', '-', (0, 4))	('DCA', 'Chemical', 'MESH:D003840', (83, 86))	('primary bile acids bile', 'MPA', (54, 77))
595749	31173474	Western blot analysis was used to determine the protein expression levels of p-NF-kappaB (p65 S536) in nuclear and cytoplasmic extracts, as well as of p-IKB-alpha (S32/S36) and bcl-2 in cytoplasmic extracts, of experimental and control groups, as has been previously described17, 19, 21, 22, 23 and in supplementary methods.	('bcl-2', 'Gene', (177, 182))	('p65', 'Gene', '5970', (90, 93))	('bcl-2', 'Gene', '596', (177, 182))	('IKB-alpha', 'Gene', (153, 162))	('IKB-alpha', 'Gene', '4792', (153, 162))	('p-NF-kappaB', 'Var', (77, 88))	('p65', 'Gene', (90, 93))
595779	31173474	On the other hand, weakly acidic pH (5.5) contributed to a significant bcl-2 overexpression in cells treated with primary bile acids with DCA relative to primary bile acids without DCA and corresponding weakly acidic control pH (5.5).	('overexpression', 'PosReg', (77, 91))	('bcl-2', 'Gene', '596', (71, 76))	('DCA', 'Var', (138, 141))	('DCA', 'Chemical', 'MESH:D003840', (181, 184))	('bile acids', 'Chemical', 'MESH:D001647', (162, 172))	('DCA', 'Chemical', 'MESH:D003840', (138, 141))	('bile acids', 'Chemical', 'MESH:D001647', (122, 132))	('bcl-2', 'Gene', (71, 76))
595792	31173474	We also observed significant positive correlations between transcriptional factor STAT3 and (a) EGFR, TNF-alpha, bcl-2 (r > 0.86, P < 0.05); (b) DeltaNp63, c-REL (r > 0.97, P < 0.0002), (c) WNT5Alpha (r > 0.88, P < 0.01).	('TNF-alpha', 'Gene', (102, 111))	('EGFR', 'Gene', '1956', (96, 100))	('DeltaNp63', 'Var', (145, 154))	('bcl-2', 'Gene', (113, 118))	('EGFR', 'Gene', (96, 100))	('WNT5A', 'Gene', (190, 195))	('STAT3', 'Gene', '6774', (82, 87))	('bcl-2', 'Gene', '596', (113, 118))	('c-REL', 'Gene', (156, 161))	('WNT5A', 'Gene', '7474', (190, 195))	('STAT3', 'Gene', (82, 87))	('TNF-alpha', 'Gene', '7124', (102, 111))	('c-REL', 'Gene', '5966', (156, 161))
595793	31173474	Significant positive correlations were identified between growth factor EGFR and (a) TNF-alpha, bcl-2 (r > 0.1, P < 0.0001); (b) DeltaNp63, c-REL (r > 0.97, P < 0.0002); (c) WNT5Alpha (r > 0.88, P < 0.01).	('c-REL', 'Gene', '5966', (140, 145))	('TNF-alpha', 'Gene', (85, 94))	('EGFR', 'Gene', '1956', (72, 76))	('WNT5A', 'Gene', '7474', (174, 179))	('DeltaNp63', 'Var', (129, 138))	('EGFR', 'Gene', (72, 76))	('bcl-2', 'Gene', (96, 101))	('TNF-alpha', 'Gene', '7124', (85, 94))	('bcl-2', 'Gene', '596', (96, 101))	('c-REL', 'Gene', (140, 145))	('WNT5A', 'Gene', (174, 179))
595794	31173474	We also found significant positive correlations between cancer-related cytokine TNF-alpha and (a) bcl-2 (r > 0.1, P < 0.0001); (b) DeltaNp63, c-REL (r > 0.97, P < 0.0003); (c) WNT5A (r > 0.88, P < 0.01).	('DeltaNp63', 'Var', (131, 140))	('TNF-alpha', 'Gene', '7124', (80, 89))	('c-REL', 'Gene', (142, 147))	('WNT5A', 'Gene', (176, 181))	('c-REL', 'Gene', '5966', (142, 147))	('bcl-2', 'Gene', '596', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('TNF-alpha', 'Gene', (80, 89))	('WNT5A', 'Gene', '7474', (176, 181))	('correlations', 'Interaction', (35, 47))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('bcl-2', 'Gene', (98, 103))
595803	31173474	Bile with DCA at pH 4.0 also induced the upregulation of the transcriptional levels of receptors and ligands of the innate immune system, such as TLR3 (>4-fold), TLR4 (2.5-fold) TLR6 (>12-fold), IL1A (>3-fold) and others.	('transcriptional levels of receptors', 'MPA', (61, 96))	('TLR4', 'Gene', '7099', (162, 166))	('IL1A', 'Gene', (195, 199))	('TLR6', 'Gene', (178, 182))	('DCA', 'Var', (10, 13))	('DCA', 'Chemical', 'MESH:D003840', (10, 13))	('pH 4.0', 'Var', (17, 23))	('TLR4', 'Gene', (162, 166))	('TLR3', 'Gene', (146, 150))	('TLR6', 'Gene', '10333', (178, 182))	('TLR3', 'Gene', '7098', (146, 150))	('IL1A', 'Gene', '3552', (195, 199))	('upregulation', 'PosReg', (41, 53))
595828	31191005	Methods: qRT-PCR was used to detect the levels of FEZF1-AS1 and mRNA CTNNB1 (beta-catenin) in ESCC tissues and cells.	('FEZF1-AS1', 'Gene', (50, 59))	('CTNNB1', 'Gene', '1499', (69, 75))	('mRNA', 'Var', (64, 68))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (50, 59))	('CTNNB1', 'Gene', (69, 75))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', '1499', (77, 89))
595832	31191005	Silencing of FEZF1-AS1 significantly inhibited the migration and invasion of ESCC cells, while overexpression of FEZF1-AS1 notably accelerated ESCC migration and invasion.	('FEZF1-AS1', 'Gene', '154860;389549;5729', (13, 22))	('accelerated', 'PosReg', (131, 142))	('inhibited', 'NegReg', (37, 46))	('ESCC migration', 'CPA', (143, 157))	('FEZF1-AS1', 'Gene', (113, 122))	('FEZF1-AS1', 'Gene', (13, 22))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (113, 122))	('Silencing', 'Var', (0, 9))	('invasion', 'CPA', (162, 170))	('invasion of ESCC cells', 'CPA', (65, 87))
595835	31191005	Silencing of FEZF1-AS1 could decrease the mRNA and protein level of beta-catenin, while overexpression FEZF1-AS1 could lead to the contrary.	('FEZF1-AS1', 'Gene', '154860;389549;5729', (13, 22))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (103, 112))	('FEZF1-AS1', 'Gene', (13, 22))	('FEZF1-AS1', 'Gene', (103, 112))	('beta-catenin', 'Gene', (68, 80))	('Silencing', 'Var', (0, 9))	('decrease', 'NegReg', (29, 37))	('beta-catenin', 'Gene', '1499', (68, 80))
595844	31191005	Genome-wide associated studies in cancer revealed that >80% of cancer-associated single nucleotide polymorphisms (SNPs) happen in noncoding regions of the genome.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('single nucleotide polymorphisms', 'Var', (81, 112))	('cancer', 'Disease', (63, 69))
595845	31191005	Accumulating research has demonstrated that lncRNAs could interact with key signaling mediators, such as DNA, RNA, and protein molecules, and their misexpression confers the cancer cell capacities for tumor initiation, growth, and metastasis.	('interact', 'Interaction', (58, 66))	('tumor initiation', 'Disease', 'MESH:D009369', (201, 217))	('misexpression', 'Var', (148, 161))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor initiation', 'Disease', (201, 217))	('metastasis', 'CPA', (231, 241))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('growth', 'CPA', (219, 225))
595889	31191005	As shown in Figure 3, there were no significant changes in the cell cycle of FEZF1-AS1 knockdown group and overexpression group.	('FEZF1-AS1', 'Gene', '154860;389549;5729', (77, 86))	('knockdown', 'Var', (87, 96))	('FEZF1-AS1', 'Gene', (77, 86))
595891	31191005	As shown in Figure 4A and B, knockdown of FEZF1-AS1 could obviously suppress the migration and invasion ability of two cell lines.	('FEZF1-AS1', 'Gene', (42, 51))	('suppress', 'NegReg', (68, 76))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (42, 51))	('knockdown', 'Var', (29, 38))
595893	31191005	In summary, our results confirmed that silencing of FEZF1-AS1 caused the negative effect of FEZF1-AS1 on ESCC cell metastatic capacity (Figure 4C, D, F).	('ESCC', 'Disease', (105, 109))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (52, 61))	('FEZF1-AS1', 'Gene', (92, 101))	('negative', 'NegReg', (73, 81))	('silencing', 'Var', (39, 48))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (92, 101))	('FEZF1-AS1', 'Gene', (52, 61))
595906	31191005	There are some papers reported that antisense RNA could affect the expression of its host gene, for example, FOXF1-AS1 regulates cell proliferation, migration, and invasion by affecting its host gene FOXF1 expression in osteosarcoma.	('affect', 'Reg', (56, 62))	('cell proliferation', 'CPA', (129, 147))	('FOXF1', 'Gene', (200, 205))	('FOXF1', 'Gene', '2294', (109, 114))	('osteosarcoma', 'Phenotype', 'HP:0002669', (220, 232))	('osteosarcoma', 'Disease', (220, 232))	('migration', 'CPA', (149, 158))	('AS1', 'Gene', (115, 118))	('expression', 'MPA', (206, 216))	('regulates', 'Reg', (119, 128))	('osteosarcoma', 'Disease', 'MESH:D012516', (220, 232))	('AS1', 'Gene', '5729', (115, 118))	('antisense', 'Var', (36, 45))	('affecting', 'Reg', (176, 185))	('FOXF1', 'Gene', (109, 114))	('invasion', 'CPA', (164, 172))	('FOXF1', 'Gene', '2294', (200, 205))	('expression', 'MPA', (67, 77))
595914	31191005	Our results demonstrated that knockdown FEZF1-AS1 contributed to significantly inhibit cell migration and invasion in vitro and upregulated FEZF1-AS1 contributed to significantly accelerate cell migration and invasion in vitro.	('inhibit', 'NegReg', (79, 86))	('accelerate', 'PosReg', (179, 189))	('FEZF1-AS1', 'Gene', (40, 49))	('FEZF1-AS1', 'Gene', (140, 149))	('knockdown', 'Var', (30, 39))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (40, 49))	('upregulated', 'PosReg', (128, 139))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (140, 149))
595915	31191005	Silencing of FEZF1-AS1 remarkably decreased the expression level of beta-catenin in EC1 and EC9706 cells and overexpression of FEZF1-AS1 resulted in the contrary.	('FEZF1-AS1', 'Gene', '154860;389549;5729', (13, 22))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (127, 136))	('EC1', 'Gene', '4819', (84, 87))	('decreased', 'NegReg', (34, 43))	('FEZF1-AS1', 'Gene', (127, 136))	('FEZF1-AS1', 'Gene', (13, 22))	('beta-catenin', 'Gene', (68, 80))	('Silencing', 'Var', (0, 9))	('EC9706', 'CellLine', 'CVCL:E307', (92, 98))	('EC1', 'Gene', (84, 87))	('beta-catenin', 'Gene', '1499', (68, 80))
595937	31131355	The 5-year OS in the NAC group was significantly superior to that of the postoperative chemotherapy group (55% vs 42%, respectively) (hazard ratio [HR] 0.73, P = 0.04).	('NAC', 'Chemical', '-', (21, 24))	('superior', 'PosReg', (49, 57))	('NAC', 'Var', (21, 24))
595952	31131355	This trial reported that perioperative treatment, that is, three preoperative and three postoperative cycles of chemotherapy using a triplet of epirubicin, cisplatin and 5-FU (ECF) as compared with surgery alone significantly improved survival (5-year OS: 36% vs 23%).13 Regarding perioperative chemotherapy, in the French ACCORD-07, the use of a perioperative combination of cisplatin and FU significantly improved OS in patients with esophageal, EGJ or gastric AC as compared to surgery alone (5-year OS 38% vs 24%).14  Furthermore, the FLOT4 trial, which compared EGJ and gastric AC with docetaxel-based triplet chemotherapy (including four preoperative and four postoperative 2-week cycles of docetaxel, oxaliplatin, leucovorin and FU; FLOT) versus an anthracycline-based triplet chemotherapy (including preoperative and postoperative 3-week cycles of epirubicin, cisplatin, and FU or capecitabine), conducted in Germany, and the phase II part of this trial showed higher proportions of patients achieving pathological complete regression and fewer adverse events in the FLOT group.15 In the phase III part, 3-year OS in the FLOT group was significantly superior to that in the anthracycline-based triplet chemotherapy group (57% vs 48%, respectively; HR 0.75, P = 0.004).	('superior', 'PosReg', (1158, 1166))	('docetaxel', 'Chemical', 'MESH:D000077143', (697, 706))	('FLOT', 'Var', (1129, 1133))	('cisplatin', 'Chemical', 'MESH:D002945', (376, 385))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (708, 719))	('cisplatin', 'Chemical', 'MESH:D002945', (868, 877))	('esophageal', 'Disease', (436, 446))	('docetaxel', 'Chemical', 'MESH:D000077143', (591, 600))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('patients', 'Species', '9606', (422, 430))	('patients', 'Species', '9606', (991, 999))	('5-FU', 'Chemical', 'MESH:D005472', (170, 174))	('esophageal', 'Disease', 'MESH:D004941', (436, 446))
595983	31044027	A comprehensive overview of mitochondrial DNA 4977-bp deletion in cancer studies Mitochondria are cellular machines essential for energy production.	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('4977-bp deletion', 'Var', (46, 62))	('cancer', 'Disease', (66, 72))
595985	31044027	Mitochondrial DNA (mtDNA) mutations and deletions are suspected to be associated with carcinogenesis.	('carcinogenesis', 'Disease', (86, 100))	('deletions', 'Var', (40, 49))	('mtDNA', 'Gene', (19, 24))	('associated', 'Reg', (70, 80))	('mutations', 'Var', (26, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))
595998	31044027	Warburg's view suggested that mitochondrial alterations in function may enhance tumor growth or promote cancer progression.	('mitochondrial alteration', 'Phenotype', 'HP:0012103', (30, 54))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('enhance', 'PosReg', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('promote', 'PosReg', (96, 103))	('tumor', 'Disease', (80, 85))	('alterations', 'Var', (44, 55))	('mitochondrial alterations', 'Var', (30, 55))	('mitochondrial alterations', 'Phenotype', 'HP:0012103', (30, 55))	('mito', 'Species', '262676', (30, 34))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
595999	31044027	Since then, diverse molecular aberrations in mtDNA include point mutations, deletions, insertions, microsatellite instability, polymorphisms, and changes in mtDNA content have been identified and characterized in human cancers.	('changes', 'Reg', (146, 153))	('microsatellite instability', 'MPA', (99, 125))	('human', 'Species', '9606', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('polymorphisms', 'Var', (127, 140))	('point mutations', 'Var', (59, 74))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('insertions', 'Var', (87, 97))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancers', 'Disease', (219, 226))	('deletions', 'Var', (76, 85))
596000	31044027	Indeed, large scale deletions in mtDNA were among the first mtDNA alterations detected to cause human diseases.	('human', 'Species', '9606', (96, 101))	('mtDNA', 'Gene', (33, 38))	('deletions', 'Var', (20, 29))
596001	31044027	So far, as stated by Mitomap (http://www.mitomap.org), a mitochondrial genome database, over 150 deletions in mtDNA associated with various diseases have been reported.	('mtDNA', 'Gene', (110, 115))	('mito', 'Species', '262676', (57, 61))	('deletions', 'Var', (97, 106))	('mito', 'Species', '262676', (41, 45))	('associated', 'Reg', (116, 126))
596002	31044027	Among mtDNA deletions, one of the most vital that causes a huge destruction of almost onethird length of the mitochondrial genome is the 4977-bp mtDNA deletion (mDNA4977).	('deletion', 'Var', (151, 159))	('mito', 'Species', '262676', (109, 113))	('mtDNA', 'Gene', (145, 150))	('destruction', 'NegReg', (64, 75))
596003	31044027	The mDNA4977 is previously reported to be involved in myopathies, Alzheimer disease, Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO) and photoaging of the skin.	('myopathies', 'Disease', 'MESH:D009135', (54, 64))	('myopathies', 'Phenotype', 'HP:0003198', (54, 64))	('mDNA4977', 'Var', (4, 12))	('progressive external ophthalmoplegia', 'Disease', (122, 158))	('myopathies', 'Disease', (54, 64))	('KSS', 'Disease', (108, 111))	('chronic progressive external ophthalmoplegia', 'Phenotype', 'HP:0000544', (114, 158))	('involved', 'Reg', (42, 50))	('external ophthalmoplegia', 'Phenotype', 'HP:0000544', (134, 158))	('Alzheimer disease', 'Disease', 'MESH:D000544', (66, 83))	('Alzheimer disease', 'Disease', (66, 83))	('ophthalmoplegia', 'Phenotype', 'HP:0000602', (143, 158))	('Kearns-Sayre syndrome', 'Disease', (85, 106))	('Kearns-Sayre syndrome', 'Disease', 'MESH:D007625', (85, 106))	('progressive external ophthalmoplegia', 'Phenotype', 'HP:0000590', (122, 158))	('KSS', 'Disease', 'MESH:D007625', (108, 111))	('Alzheimer disease', 'Phenotype', 'HP:0002511', (66, 83))	('progressive external ophthalmoplegia', 'Disease', 'MESH:D017246', (122, 158))
596005	31044027	In this review, we summarize the current progress in understanding the cellular and molecular mechanisms underlying the formation of mDNA4977 and discuss its potential role in tumorigenesis.	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('mDNA4977', 'Var', (133, 141))
596014	31044027	Defects in mitochondria are believed to be partly responsible for cancer progression and development.	('mito', 'Species', '262676', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Defects', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
596016	31044027	Alterations in the mitochondrial genome have been implicated as playing a role in diverse forms of human disease and aging.	('playing', 'Reg', (64, 71))	('Alterations', 'Var', (0, 11))	('mito', 'Species', '262676', (19, 23))	('implicated', 'Reg', (50, 60))	('mitochondrial genome', 'Gene', (19, 39))	('human', 'Species', '9606', (99, 104))
596017	31044027	It is believed that various mtDNA alterations increase with advancing age in human tissues, such as point mutations and deletions in mtDNA have been identified to accumulate in the aged human brain, skeletal muscles, heart and colon tissues.	('deletions', 'Var', (120, 129))	('point mutations', 'Var', (100, 115))	('mtDNA', 'Gene', (133, 138))	('human', 'Species', '9606', (186, 191))	('human', 'Species', '9606', (77, 82))
596018	31044027	Also, mtDNA alterations have been reported as a frequent event in many human cancer studies in the types of point mutations, multiple insertions and deletions and microsatellite instability (MSI).	('MSI', 'Disease', (191, 194))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('deletions', 'Var', (149, 158))	('MSI', 'Disease', 'None', (191, 194))	('microsatellite', 'MPA', (163, 177))	('point mutations', 'Var', (108, 123))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('multiple insertions', 'Var', (125, 144))	('human', 'Species', '9606', (71, 76))
596019	31044027	Among the mtDNA alterations, large scale deletions in mtDNA are one of the essential mtDNA mutations that related to human diseases.	('mtDNA', 'Gene', (54, 59))	('deletions', 'Var', (41, 50))	('human', 'Species', '9606', (117, 122))
596020	31044027	One of the best-described large scale mtDNA deletion is the specific 4977-bp deletion in mitochondrial genome, which has been accumulated in various disorders, including mitochondrial diseases and many different types of cancer.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('mito', 'Species', '262676', (170, 174))	('cancer', 'Disease', (221, 227))	('4977-bp deletion', 'Var', (69, 85))	('mitochondrial diseases', 'Disease', 'MESH:D028361', (170, 192))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('mitochondrial diseases', 'Disease', (170, 192))	('mito', 'Species', '262676', (89, 93))	('mitochondrial genome', 'Gene', (89, 109))
596023	31044027	mtDNA4977 was initially spotted in the muscle of a patient with neuromuscular diseases - Kearns-Sayre/progressive external ophthalmoplegia plus syndrome in 1989, and later frequently discovered to accumulate in various human tissues with aging.	('mtDNA4977', 'Var', (0, 9))	('human', 'Species', '9606', (219, 224))	('ophthalmoplegia', 'Phenotype', 'HP:0000602', (123, 138))	('progressive external ophthalmoplegia', 'Phenotype', 'HP:0000590', (102, 138))	('patient', 'Species', '9606', (51, 58))	('ophthalmoplegia plus syndrome', 'Disease', (123, 152))	('progressive external ophthalmoplegia', 'Disease', 'MESH:D017246', (102, 138))	('ophthalmoplegia plus syndrome', 'Disease', 'MESH:D007625', (123, 152))	('progressive external ophthalmoplegia', 'Disease', (102, 138))	('external ophthalmoplegia', 'Phenotype', 'HP:0000544', (114, 138))
596025	31044027	mtDNA4977 removes all 5 tRNA genes (tRNAGly, tRNAArg, tRNAHis, tRNASer and tRNALeu) and 7 genes encoding 4 Complex I subunits (ND3, ND4, ND4L, partial ND5), 1 Complex IV subunit (COX III), 2 Complex V subunits (ATP6 and partial ATP8), that are crucial for supporting normal mitochondrial OXPHOS function (Figure 1).	('mtDNA4977', 'Var', (0, 9))	('ND5', 'Gene', '4540', (151, 154))	('ATP8', 'Gene', (228, 232))	('ND5', 'Gene', (151, 154))	('ATP6', 'Gene', (211, 215))	('ND4', 'Gene', (132, 135))	('ND3', 'Gene', '4537', (127, 130))	('ND4L', 'Gene', (137, 141))	('ND4', 'Gene', '4538', (132, 135))	('mito', 'Species', '262676', (274, 278))	('ATP6', 'Gene', '4508', (211, 215))	('ND4', 'Gene', (137, 140))	('ND4', 'Gene', '4538', (137, 140))	('ND3', 'Gene', (127, 130))	('ND4L', 'Gene', '4539', (137, 141))	('ATP8', 'Gene', '4509', (228, 232))
596026	31044027	mtDNA4977 has been categorized in class I deletions as these deletions almost take place within two 13-bp perfect direct repeats (ACCTCCCTCACCA) flanking the 5'- and 3'-end breakpoints, located at nucleotide positions 8470-8482 (within the ATPase 8 gene) and 13447-13459 (within the ND5 gene).	('ATPase 8', 'Gene', (240, 248))	('ND5', 'Gene', (283, 286))	('13447-13459', 'Var', (259, 270))	('8470-8482', 'Var', (218, 227))	('ND5', 'Gene', '4540', (283, 286))	('ATPase 8', 'Gene', '4509', (240, 248))
596029	31044027	The major effect of this large deletion could cause a complete failure of ATP production and subsequently impair mitochondrial functions.	('failure', 'NegReg', (63, 70))	('ATP', 'Chemical', 'MESH:D000255', (74, 77))	('impair', 'NegReg', (106, 112))	('mito', 'Species', '262676', (113, 117))	('deletion', 'Var', (31, 39))	('ATP production', 'MPA', (74, 88))	('mitochondrial functions', 'MPA', (113, 136))
596030	31044027	For a long time, the sources on how deletions are generated within mtDNA genome are not well established, despite the prevalence of mtDNA deletions in human patients with mitochondrial disease and the precise molecular mechanisms underlying the formation are still under debate.	('human', 'Species', '9606', (151, 156))	('mtDNA', 'Gene', (132, 137))	('mitochondrial disease', 'Disease', (171, 192))	('patients', 'Species', '9606', (157, 165))	('deletions', 'Var', (138, 147))	('mitochondrial disease', 'Disease', 'MESH:D028361', (171, 192))
596035	31044027	The human skin may either be affected directly from prolonged exposure to ultraviolet radiation by promoting base substitutions or indirectly by introducing free radicals which consequently increasing the chances of common deletion occurrences.	('human', 'Species', '9606', (4, 9))	('base', 'MPA', (109, 113))	('free radicals', 'Chemical', 'MESH:D005609', (157, 170))	('deletion', 'Var', (223, 231))	('increasing', 'PosReg', (190, 200))	('promoting', 'PosReg', (99, 108))
596037	31044027	According to their observations, mito-TALEN induces the breaks adjacent to the 5' repeat and hence triggers formation of the common deletion.	('breaks', 'MPA', (56, 62))	('mito', 'Species', '262676', (33, 37))	('mito-TALEN', 'Var', (33, 43))	('common deletion', 'MPA', (125, 140))	('triggers', 'Reg', (99, 107))	('induces', 'Reg', (44, 51))
596038	31044027	Finally, they clarified that mtDNA4977 was generated as a consequence of frequent fork stalling, a process which was mediated by the mitochondrial replisome, but independent of canonical DSB repair.	('mito', 'Species', '262676', (133, 137))	('fork stalling', 'CPA', (82, 95))	('mtDNA4977', 'Var', (29, 38))
596039	31044027	DNA can be easily damage by endogenous (cellular metabolic pathways, ROS and errors in DNA replication) or exogenous sources (environmental factors including ionizing radiations and ultraviolet (UV) radiations from the sun).	('radiations', 'Disease', 'MESH:D004194', (167, 177))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('radiations', 'Disease', (167, 177))	('radiations', 'Disease', 'MESH:D004194', (199, 209))	('radiations', 'Disease', (199, 209))	('ROS', 'Gene', (69, 72))	('DNA replication', 'Gene', (87, 102))	('errors', 'Var', (77, 83))
596042	31044027	Interruption of ANT1 (adenine nucleotide translocator isoform 1) function is associated with increased ROS production, which leads to accumulation of mtDNA deletions.	('adenine nucleotide translocator isoform 1', 'Gene', '291', (22, 63))	('adenine nucleotide translocator isoform 1', 'Gene', (22, 63))	('accumulation', 'PosReg', (134, 146))	('increased', 'PosReg', (93, 102))	('increased ROS production', 'Phenotype', 'HP:0025464', (93, 117))	('deletions', 'Var', (156, 165))	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('ANT1', 'Gene', (16, 20))	('ROS production', 'MPA', (103, 117))	('Interruption', 'NegReg', (0, 12))	('mtDNA', 'Gene', (150, 155))	('ANT1', 'Gene', '291', (16, 20))
596043	31044027	In the same manner, a partial loss of SOD2 (manganese superoxide dismutase) results in raised ROS levels and mitochondrial oxidative stress, which link to elevated mtDNA deletions.	('SOD2', 'Gene', (38, 42))	('oxidative stress', 'Phenotype', 'HP:0025464', (123, 139))	('raised', 'PosReg', (87, 93))	('ROS levels', 'MPA', (94, 104))	('loss', 'NegReg', (30, 34))	('deletions', 'Var', (170, 179))	('ROS', 'Chemical', 'MESH:D017382', (94, 97))	('mito', 'Species', '262676', (109, 113))	('mitochondrial oxidative stress', 'MPA', (109, 139))	('mtDNA', 'Gene', (164, 169))	('raised ROS levels', 'Phenotype', 'HP:0025464', (87, 104))	('SOD2', 'Gene', '6648', (38, 42))	('elevated', 'PosReg', (155, 163))
596044	31044027	But, when the proportion of mtDNA4977 exceeded this threshold, resulting in decreased mitochondrial membrane potential, ATP synthesis rate and cellular ATP/ADP ratio.A similar approach using a series of cybrids containing different proportions of mtDNA4977 associated with a chronic progressive external ophthalmoplegia (CPEO) patient has been conducted by Wei and colleagues.	('chronic progressive external ophthalmoplegia', 'Phenotype', 'HP:0000544', (275, 319))	('mito', 'Species', '262676', (86, 90))	('ADP', 'Chemical', 'MESH:D000244', (156, 159))	('associated', 'Reg', (257, 267))	('progressive external ophthalmoplegia', 'Phenotype', 'HP:0000590', (283, 319))	('mtDNA4977', 'Var', (247, 256))	('ATP', 'Chemical', 'MESH:D000255', (120, 123))	('ophthalmoplegia', 'Phenotype', 'HP:0000602', (304, 319))	('progressive external ophthalmoplegia', 'Disease', (283, 319))	('progressive external ophthalmoplegia', 'Disease', 'MESH:D017246', (283, 319))	('external ophthalmoplegia', 'Phenotype', 'HP:0000544', (295, 319))	('decreased mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (76, 118))	('patient', 'Species', '9606', (327, 334))	('ATP', 'Chemical', 'MESH:D000255', (152, 155))
596045	31044027	In this case, they determined that mitochondrial oxidative stress and increased mitochondrial mass and mtDNA in response to mtDNA4977 correlate with impaired respiratory function.	('increased', 'PosReg', (70, 79))	('mtDNA', 'CPA', (103, 108))	('mitochondrial oxidative stress', 'MPA', (35, 65))	('mito', 'Species', '262676', (35, 39))	('mito', 'Species', '262676', (80, 84))	('impaired respiratory function', 'Disease', (149, 178))	('mtDNA4977', 'Var', (124, 133))	('impaired respiratory function', 'Disease', 'MESH:D012131', (149, 178))	('oxidative stress', 'Phenotype', 'HP:0025464', (49, 65))	('increased mitochondrial mass', 'Phenotype', 'HP:0040014', (70, 98))	('impaired respiratory function', 'Phenotype', 'HP:0002093', (149, 178))	('mitochondrial mass', 'CPA', (80, 98))
596046	31044027	In a subsequent paper from the same group, Wei's team observed that a feed-forward, self-accelerating vicious cycle of mitochondrial ROS production could be triggered following brief, intense oxidative stress treatment in cybrids harboring mtDNA4977.	('mtDNA4977', 'Var', (240, 249))	('oxidative stress', 'Phenotype', 'HP:0025464', (192, 208))	('mito', 'Species', '262676', (119, 123))	('mitochondrial ROS production', 'MPA', (119, 147))	('ROS', 'Chemical', 'MESH:D017382', (133, 136))
596048	31044027	Accumulation of mtDNA4977 is intimately associated with ROS in the dermis of both naturally and photoaged human skin in vivo.	('human', 'Species', '9606', (106, 111))	('ROS', 'Disease', (56, 59))	('ROS', 'Chemical', 'MESH:D017382', (56, 59))	('mtDNA4977', 'Var', (16, 25))
596052	31044027	on human keratinocytes, the level of the mtDNA4977 had a significant increased following 2 weeks of UVA irradiation.	('human', 'Species', '9606', (3, 8))	('mtDNA4977', 'Var', (41, 50))	('increased', 'PosReg', (69, 78))
596053	31044027	This situation could be either the replication is reduced or blocked in deleted mtDNA genomes to permit degradation of mitochondria carrying the mtDNA4977.	('mitochondria', 'MPA', (119, 131))	('degradation', 'MPA', (104, 115))	('mtDNA4977', 'Var', (145, 154))	('mito', 'Species', '262676', (119, 123))
596054	31044027	Birch-Machin's group study suggests that mtDNA deletions may be useful as a biomarker of cumulative UV radiation exposure in human skin with the major species have been the mtDNA4977, and a 3895-bp deletion.	('mtDNA', 'Gene', (41, 46))	('deletions', 'Var', (47, 56))	('human', 'Species', '9606', (125, 130))
596059	31044027	revealed that acrolein promotes mitochondrial ROS over-production, resulting in the formation of the mtDNA4977 and also depletion of mtDNA content in human lung cells.	('human', 'Species', '9606', (150, 155))	('acrolein', 'Var', (14, 22))	('mtDNA4977', 'MPA', (101, 110))	('mitochondrial ROS over-production', 'MPA', (32, 65))	('mito', 'Species', '262676', (32, 36))	('depletion of mtDNA content', 'MPA', (120, 146))	('ROS', 'Chemical', 'MESH:D017382', (46, 49))	('acrolein', 'Chemical', 'MESH:D000171', (14, 22))	('formation', 'MPA', (84, 93))
596060	31044027	detected the mtDNA4977 in oral tumors.	('oral tumors', 'Disease', 'MESH:D020820', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('mtDNA4977', 'Var', (13, 22))	('oral tumors', 'Disease', (26, 37))	('oral tumors', 'Phenotype', 'HP:0100649', (26, 37))
596061	31044027	They also observed a positive correlation between this large-scale deletion and human non-tumor oral tissues with betel quid chewing history.	('tumor oral tissues', 'Phenotype', 'HP:0100649', (90, 108))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('deletion', 'Var', (67, 75))	('tumor', 'Disease', (90, 95))	('human', 'Species', '9606', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
596065	31044027	It was found that the mtDNA4977 was found to accumulate in non-tumorous tissues (28/60, 47%) rather than in tumor tissues (3/60, 5%).	('mtDNA4977', 'Var', (22, 31))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('accumulate', 'PosReg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('non-tumorous', 'Disease', 'MESH:D009369', (59, 71))	('tumor', 'Disease', (108, 113))	('non-tumorous', 'Disease', (59, 71))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
596066	31044027	In addition, the author demonstrated that the mtDNA4977 was associated with NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme deficiency in carcinogenesis of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('carcinogenesis of breast cancer', 'Disease', 'MESH:D063646', (137, 168))	('oxidoreductase 1 (NQO1) enzyme deficiency', 'Disease', 'MESH:C537475', (92, 133))	('mtDNA4977', 'Var', (46, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('carcinogenesis of breast cancer', 'Disease', (137, 168))	('associated', 'Reg', (60, 70))
596067	31044027	In another study that involved a quantitative real-time PCR assay to examine the level of the mtDNA4977 in 55 primary breast cancer patients and 21 patients with benign breast disease, all of the cases were detected to be deleted in mtDNA4977.	('benign breast disease', 'Disease', 'MESH:D001941', (162, 183))	('patients', 'Species', '9606', (148, 156))	('deleted', 'Var', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mtDNA4977', 'Gene', (233, 242))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('patients', 'Species', '9606', (132, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('benign breast disease', 'Disease', (162, 183))
596070	31044027	analyzed this large-scale deletion of mtDNA in 106 Vietnamese breast cancer patients by sequencing PCR products.	('patients', 'Species', '9606', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('deletion', 'Var', (26, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('mtDNA', 'Gene', (38, 43))
596071	31044027	They noticed that the mtDNA4977 was significantly more frequent in normal tissue in comparison with paired cancer tissue.	('mtDNA4977', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))
596072	31044027	which demonstrated the lower proportion deletion in tumors than in adjacent non-tumoral tissues.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('deletion', 'Var', (40, 48))	('tumor', 'Disease', (52, 57))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
596073	31044027	In almost all of the previous studies of the mtDNA4977 in breast cancer have reported a lower frequency in cancerous tissues as compared with corresponding non-cancerous paired tissues.	('cancerous', 'Disease', (107, 116))	('cancerous', 'Disease', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancerous', 'Disease', 'MESH:D009369', (107, 116))	('mtDNA4977', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('cancerous', 'Disease', 'MESH:D009369', (160, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
596074	31044027	The lower incidence of the mtDNA4977 in cancerous tissue than in noncancerous tissue has been also reported in other different cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancerous', 'Disease', 'MESH:D009369', (68, 77))	('mtDNA4977', 'Var', (27, 36))	('cancerous', 'Disease', (68, 77))	('cancerous', 'Disease', (40, 49))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancerous', 'Disease', 'MESH:D009369', (40, 49))
596075	31044027	The clarification of the lower incidence of the mtDNA4977 in tumors could be either the consequence of a dilution effect because of mitotic clonal expansion throughout cancer progression or an active selection mechanism that eliminates cancer cells harboring the deleted mtDNA.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('mito', 'Species', '262676', (132, 136))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('mtDNA4977', 'Var', (48, 57))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('eliminates', 'NegReg', (225, 235))
596076	31044027	An increased accumulation of mtDNA4977 has also been reported in cancerous breast tissues.	('accumulation', 'PosReg', (13, 25))	('cancerous', 'Disease', 'MESH:D009369', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mtDNA4977', 'Var', (29, 38))	('cancerous', 'Disease', (65, 74))
596077	31044027	found a high mtDNA large scale deletion rate in the breast cancer tissue samples than that inthe matched normal tissues nearby to the tumor.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('deletion', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
596078	31044027	carried out a comprehensive experiment to detect the mtDNA4977 as well as mtDNA copy number alteration in breast carcinoma and benign breast disease patients.	('patients', 'Species', '9606', (149, 157))	('mtDNA', 'Gene', (74, 79))	('copy number alteration', 'Var', (80, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('breast carcinoma', 'Phenotype', 'HP:0003002', (106, 122))	('mtDNA4977', 'Var', (53, 62))	('breast carcinoma and benign breast disease', 'Disease', 'MESH:D001943', (106, 148))
596079	31044027	The authors revealed that the mtDNA4977 in the blood of breast carcinoma patients was significantly higher (51/107, 48%) than that of benign breast disease patients and healthy controls.	('patients', 'Species', '9606', (156, 164))	('breast carcinoma', 'Phenotype', 'HP:0003002', (56, 72))	('mtDNA4977', 'Var', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('benign breast disease', 'Disease', 'MESH:D001941', (134, 155))	('benign breast disease', 'Disease', (134, 155))	('breast carcinoma', 'Disease', (56, 72))	('higher', 'PosReg', (100, 106))	('patients', 'Species', '9606', (73, 81))	('breast carcinoma', 'Disease', 'MESH:D001943', (56, 72))
596081	31044027	These outcomes conclude that the occurrence of mtDNA4977 in blood may potentially serve as a biomarker for breast cancer.	('mtDNA4977', 'Var', (47, 56))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
596083	31044027	published the results of a study in which mtDNA4977 was not detected in any of tumor tissues of breast cancer as well as in adjacent non-tumor tissues.	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mtDNA4977', 'Var', (42, 51))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer', 'Disease', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
596085	31044027	The mtDNA large scale deletions have been first described in gastric carcinomas by Maximo et al.	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('deletions', 'Var', (22, 31))	('gastric carcinomas', 'Disease', 'MESH:D013274', (61, 79))	('gastric carcinomas', 'Disease', (61, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
596086	31044027	They reported a high frequency of 4977-bp mtDNA deletion (53.1%) in 17/32 primary sporadic gastric carcinomas.	('mtDNA', 'Gene', (42, 47))	('4977-bp', 'Var', (34, 41))	('gastric carcinomas', 'Disease', 'MESH:D013274', (91, 109))	('gastric carcinomas', 'Disease', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))
596087	31044027	Consistent with these data, Wang and Lu also detected a higher mtDNA4977 rate in gastric cancer tissues (86/108, 79.6%) than in the adjacent normal tissues (73/108, 67.6%).	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('mtDNA4977', 'Var', (63, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('higher', 'PosReg', (56, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
596089	31044027	also found a low frequency (6/107, 5.6%) of 4977-bp deletion in tumoral tissues of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('tumor', 'Disease', (64, 69))	('gastric cancer', 'Disease', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('4977-bp deletion', 'Var', (44, 60))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('deletion', 'Var', (52, 60))
596091	31044027	A decreased proportion of mtDNA4977 that found in tumor tissue as compared to adjacent non-tumor tissue also has been reported in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('mtDNA4977', 'Var', (26, 35))	('colorectal cancer', 'Disease', (130, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('decreased', 'NegReg', (2, 11))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (50, 55))
596093	31044027	They found that the level of the mtDNA4977 in tumor tissues of colorectal cancer (52%) was significantly less than that in adjacent non-tumor tissues (83%).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('less', 'NegReg', (105, 109))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('colorectal cancer', 'Disease', (63, 80))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('mtDNA4977', 'Var', (33, 42))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
596095	31044027	The authors revealed that the level of deletion in cancerous tissues appeared lower than those in noncancerous areas.	('cancerous', 'Disease', (101, 110))	('deletion', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancerous', 'Disease', 'MESH:D009369', (101, 110))	('cancerous', 'Disease', 'MESH:D009369', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lower', 'NegReg', (78, 83))	('cancerous', 'Disease', (51, 60))
596097	31044027	also demonstrated that the mtDNA4977 was found at a significantly higher frequency in normal tissues compared to paired cancer tissues in colorectal cancer cases of Swedish and Vietnamese patients.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (149, 155))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('colorectal cancer', 'Disease', (138, 155))	('patients', 'Species', '9606', (188, 196))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mtDNA4977', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))
596099	31044027	reported that the mtDNA4977 was significantly increased in cancer-associated mesenteric arteries than healthy controls.	('increased', 'PosReg', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mtDNA4977', 'Var', (18, 27))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
596100	31044027	The authors suggested that the presence of this large-scale deletion in blood vessels nearby cancer cells may be related to oxidative stress in the tumor microenvironment which may contribute to more mtDNA damage.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('related', 'Reg', (113, 120))	('deletion', 'Var', (60, 68))	('tumor', 'Disease', (148, 153))	('more', 'PosReg', (195, 199))	('contribute', 'Reg', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('oxidative stress', 'Phenotype', 'HP:0025464', (124, 140))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mtDNA', 'Disease', (200, 205))
596101	31044027	Overall, 6 published studies and findings that have examined the mtDNA4977 in patients with hepatocellular carcinoma (HCC).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mtDNA4977', 'Var', (65, 74))	('patients', 'Species', '9606', (78, 86))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('hepatocellular carcinoma', 'Disease', (92, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))
596102	31044027	The large-scale deletion has been first described in human hepatic cancer samples by Fukushima et al.	('hepatic cancer', 'Phenotype', 'HP:0002896', (59, 73))	('deletion', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('human', 'Species', '9606', (53, 58))	('hepatic cancer', 'Disease', (59, 73))	('hepatic cancer', 'Disease', 'MESH:D008113', (59, 73))
596107	31044027	The incidence of the mtDNA4977 in HCC was much lower than that in non-cancerous hepatic tissues and this had also been reported in two previous studies by Wheelhouse et al.	('cancerous hepatic', 'Disease', (70, 87))	('lower', 'NegReg', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mtDNA4977', 'Var', (21, 30))	('HCC', 'Disease', (34, 37))	('cancerous hepatic', 'Disease', 'MESH:D008113', (70, 87))
596108	31044027	used nested PCR assay to screen a common deletion of the mtDNA4977 in blood and tissues of 105 HCC patients and 69 unrelated healthy subjects.	('deletion', 'Var', (41, 49))	('mtDNA4977', 'Gene', (57, 66))	('patients', 'Species', '9606', (99, 107))
596109	31044027	They detected 9.52% of HCC patients contained this deletion, while it was absent in nearby normal tissues and healthy subjects.	('HCC', 'Disease', (23, 26))	('contained', 'Reg', (36, 45))	('deletion', 'Var', (51, 59))	('patients', 'Species', '9606', (27, 35))
596111	31044027	conducted an analysis among a high-risk population of esophageal squamous cell carcinoma in China and discovered that 89% of tumors and 95% of the adjacent normal tissues carried the mtDNA4977.	('esophageal squamous cell carcinoma', 'Disease', (54, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))	('mtDNA4977', 'Var', (183, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
596114	31044027	They claimed that the frequency of specimens with the mtDNA4977 increased in association with the degree of dysplasia, thus the mtDNA4977 may be a potential biomarker to predict the severity of dysplasia.	('dysplasia', 'Disease', (108, 117))	('dysplasia', 'Disease', 'MESH:D004476', (108, 117))	('dysplasia', 'Disease', (194, 203))	('degree', 'Disease', (98, 104))	('dysplasia', 'Disease', 'MESH:D004476', (194, 203))	('mtDNA4977', 'Var', (54, 63))	('increased', 'PosReg', (64, 73))	('mtDNA4977', 'Var', (128, 137))
596116	31044027	that reported very impressive data on the accumulation of large-scale deletions of mtDNA in human oral tissues, similar results were also reported by Tan et al.	('deletions', 'Var', (70, 79))	('human', 'Species', '9606', (92, 97))	('mtDNA', 'Gene', (83, 88))
596119	31044027	on paired oral cancer and precancerous lesions using the combination techniques of laser microdissection and qPCR, revealed a higher level of the mtDNA4977 in stromal non-tumor tissue compared with tumor tissue.	('precancerous lesions', 'Disease', 'MESH:D011230', (26, 46))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('precancerous lesions', 'Disease', (26, 46))	('higher', 'PosReg', (126, 132))	('oral cancer', 'Disease', (10, 21))	('oral cancer', 'Disease', 'MESH:D009062', (10, 21))	('mtDNA4977', 'Var', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
596120	31044027	reported an interesting finding on the correlation between mtDNA4977 and polymorphism in cytochrome P450 2E1 (CYP2E1) gene in oral cancer in the North Indian population.	('correlation', 'Interaction', (39, 50))	('oral cancer', 'Disease', 'MESH:D009062', (126, 137))	('CYP2E1', 'Gene', '1571', (110, 116))	('polymorphism', 'Var', (73, 85))	('oral cancer', 'Disease', (126, 137))	('CYP2E1', 'Gene', (110, 116))	('cytochrome P450 2E1', 'Gene', (89, 108))	('mtDNA4977', 'Gene', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cytochrome P450 2E1', 'Gene', '1571', (89, 108))
596121	31044027	Their outcomes suggested that CYP2E1gene polymorphisms coexist with mtDNA4977 can contribute to a high risk factor for oral cancer.	('oral cancer', 'Disease', 'MESH:D009062', (119, 130))	('polymorphisms', 'Var', (41, 54))	('oral cancer', 'Disease', (119, 130))	('CYP2E1', 'Gene', '1571', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CYP2E1', 'Gene', (30, 36))
596122	31044027	The mtDNA4977 has also previously been investigated in several other cancers including skin cancer, thyroid cancer,  lung cancer, endometrial cancer, cervix cancer, as well as prostate cancer.	('thyroid cancer', 'Disease', (100, 114))	('cervix cancer', 'Phenotype', 'HP:0030079', (150, 163))	('lung cancer', 'Disease', (117, 128))	('cervix cancer', 'Disease', 'MESH:D002583', (150, 163))	('investigated', 'Reg', (39, 51))	('skin cancer', 'Disease', 'MESH:D012878', (87, 98))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('mtDNA4977', 'Var', (4, 13))	('prostate cancer', 'Disease', 'MESH:D011471', (176, 191))	('thyroid cancer', 'Disease', 'MESH:D013964', (100, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (176, 191))	('endometrial cancer', 'Phenotype', 'HP:0012114', (130, 148))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('prostate cancer', 'Disease', (176, 191))	('thyroid cancer', 'Phenotype', 'HP:0002890', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('endometrial cancer', 'Disease', (130, 148))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('skin cancer', 'Disease', (87, 98))	('cervix cancer', 'Disease', (150, 163))	('cancers', 'Disease', (69, 76))	('endometrial cancer', 'Disease', 'MESH:D016889', (130, 148))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('skin cancer', 'Phenotype', 'HP:0008069', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
596126	31044027	Given such a higher frequency of mtDNA4977, the author concluded that their finding is likely to be a useful biomarker for assessing the degree of malignancy in prostate cancer patients.	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('malignancy in prostate cancer', 'Disease', 'MESH:D011471', (147, 176))	('patients', 'Species', '9606', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('malignancy in prostate cancer', 'Disease', (147, 176))	('mtDNA4977', 'Var', (33, 42))
596127	31044027	examined the relationship between the levels of mtDNA4977 in blood samples from 206 melanoma patients and 219 healthy controls.	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('mtDNA4977', 'Var', (48, 57))	('patients', 'Species', '9606', (93, 101))
596129	31044027	Furthermore, they reported elevated levels of mtDNA4977 were associated with increased risk of melanoma and suggested that mtDNA deletions may mediate the connection between sun exposure and melanoma risk.	('deletions', 'Var', (129, 138))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('melanoma', 'Disease', (191, 199))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('elevated', 'PosReg', (27, 35))	('mtDNA4977', 'Var', (46, 55))	('mtDNA', 'Gene', (123, 128))
596136	31044027	The most well-studied of all mtDNA cancer alterations are in the displacement loop (D-loop) region of mtDNA non-coding part.	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('alterations', 'Var', (42, 53))
596137	31044027	Previous studies have reported that D-loop mutations were associated with poor prognosis in some types of cancer.	('D-loop mutations', 'Var', (36, 52))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
596140	31044027	detected numerous mtDNA deletions from photoaged, tumor-free skin of multiple individuals which include the mtDNA4977.	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('deletions', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mtDNA', 'Gene', (18, 23))	('tumor', 'Disease', (50, 55))	('numerous mtDNA deletions', 'Phenotype', 'HP:0003689', (9, 33))
596144	31044027	suggested that mtDNA4977 could be one of the markers for radiation-induced damage due to the occurrences of this common deletion in all the tumor cells after gamma-ray irradiation at any doses.	('occurrences', 'Reg', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mtDNA4977', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
596148	31044027	In previous studies, mtDNA4977 has been predominantly reported to be detected in normal tissues adjacent to cancerous tissues.	('cancerous', 'Disease', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mtDNA4977', 'Var', (21, 30))	('cancerous', 'Disease', 'MESH:D009369', (108, 117))
596149	31044027	also noticed a significantly decreased proportions of mtDNA4977 in cancerous tissue compared to adjacent non-cancerous tissue.	('cancerous', 'Disease', (67, 76))	('cancerous', 'Disease', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancerous', 'Disease', 'MESH:D009369', (109, 118))	('decreased', 'NegReg', (29, 38))	('mtDNA4977', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancerous', 'Disease', 'MESH:D009369', (67, 76))
596151	31044027	Through clonal expansion, the cells with mutations resume proliferation which will result in a larger frequency of alterations in adjacent normal tissue than cancerous tissue.	('mutations', 'Var', (41, 50))	('cancerous', 'Disease', 'MESH:D009369', (158, 167))	('cancerous', 'Disease', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('alterations', 'MPA', (115, 126))
596152	31044027	believed that minor frequency of mtDNA4977 might have some role in tumor progression and prediction of survival outcome in esophageal cancer.	('esophageal cancer', 'Disease', (123, 140))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('mtDNA4977', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
596156	31044027	However, they concluded that undetectable mtDNA4977 might be a marker or risk factor for ischemic stroke.	('stroke', 'Phenotype', 'HP:0001297', (98, 104))	('ischemic stroke', 'Disease', 'MESH:D002544', (89, 104))	('ischemic stroke', 'Phenotype', 'HP:0002140', (89, 104))	('ischemic stroke', 'Disease', (89, 104))	('mtDNA4977', 'Gene', (42, 51))	('undetectable', 'Var', (29, 41))
596157	31044027	In contrast, in more recent an Italian cohort study, about 515 patients with stable coronary artery disease, the authors demonstrated that the mtDNA4977 were highly observed and had prognostic implications in patients with major adverse cardiac events.	('coronary artery disease', 'Disease', 'MESH:D003324', (84, 107))	('mtDNA4977', 'Var', (143, 152))	('implications', 'Reg', (193, 205))	('coronary artery disease', 'Disease', (84, 107))	('major', 'Disease', (223, 228))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (63, 71))
596158	31044027	It is widely accepted that deletion of mtDNA4977 participates in the pathogenesis of cancer, but there still remains some issue as to whether a mtDNA4977 contributes to cancer initiation and progression, and this remains an active area of investigation.	('contributes', 'Reg', (154, 165))	('cancer initiation', 'Disease', 'MESH:D009369', (169, 186))	('cancer', 'Disease', (169, 175))	('mtDNA4977', 'Gene', (39, 48))	('cancer initiation', 'Disease', (169, 186))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('deletion', 'Var', (27, 35))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('participates', 'Reg', (49, 61))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
596159	31044027	Results in the previous studies have been inconsistent and many factors may influence the proportion of the deletion in cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('deletion', 'Var', (108, 116))	('influence', 'Reg', (76, 85))
596160	31044027	Although it is an encouraging finding across many studies, active investigations are needed to discover whether the deletion can potentially be applied as an effective biomarker for cancer.	('deletion', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (182, 188))
596164	31044027	The existence of different proportion of the mtDNA4977 in tumor tissue as compared with corresponding non-tumorous tissue could be classified as alterations in connection with the presence of various environmental and genetic factors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('non-tumorous', 'Disease', (102, 114))	('non-tumorous', 'Disease', 'MESH:D009369', (102, 114))	('mtDNA4977', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
596165	31044027	More studies and attention should be given before a clear conclusion could be achieved regarding the effect and role of this large mtDNA deletion in carcinogenesis.	('carcinogenesis', 'Disease', (149, 163))	('deletion', 'Var', (137, 145))	('mtDNA', 'Gene', (131, 136))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))
596174	29285292	CA19-9 was associated with subcarinal and paracardial LNM (P=0.000, P=0.038).	('associated', 'Reg', (11, 21))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('CA19-9', 'Var', (0, 6))
596187	29285292	CA199 and CA724 are elevated in a variety of cancers, especially gastrointestinal cancer.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (65, 88))	('CA724', 'Var', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('especially gastrointestinal cancer', 'Disease', 'MESH:D004067', (54, 88))	('especially gastrointestinal cancer', 'Disease', (54, 88))	('CA199', 'Var', (0, 5))	('elevated', 'PosReg', (20, 28))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('CA199', 'Chemical', 'MESH:C086528', (0, 5))
596188	29285292	(2) SCC-Ag, Cyrfra21-1, CEA and CA19-9, which showed a significant correlation with LNM, were selected to evaluate the relationship with lymph node metastatic number and stations.	('CEA', 'Gene', (24, 27))	('SCC', 'Gene', (4, 7))	('CEA', 'Gene', '1084', (24, 27))	('Cyrfra21-1', 'Var', (12, 22))	('SCC', 'Gene', '6317', (4, 7))	('CA19-9', 'Chemical', 'MESH:C086528', (32, 38))
596191	29285292	The median and interquartile range of SCC-Ag, Cyfra21-1, CEA, CA19-9 and CA72-4 were 0.7 ug/L (0.4-1.3 ug/L), 2.36 ug/L(1.69-3.26 ug/L), 2.19 ug/L(1.49- 3.11 ug/L), 8.66 U/ml (5.06-15.92 U/ml) and 1.30 U/ml (0.92-2.44 U/ml).	('Cyfra21-1', 'Var', (46, 55))	('SCC', 'Gene', (38, 41))	('CEA', 'Gene', (57, 60))	('SCC', 'Gene', '6317', (38, 41))	('CEA', 'Gene', '1084', (57, 60))	('CA19-9', 'Chemical', 'MESH:C086528', (62, 68))
596193	29285292	The positive rate of serum SCC-Ag, Cyfra21-1, CEA and CA19-9 were associated with LNM in the Chi-square test (Table 2; all P<0.05).	('SCC', 'Gene', (27, 30))	('CA19-9', 'Var', (54, 60))	('associated', 'Reg', (66, 76))	('CEA', 'Gene', (46, 49))	('SCC', 'Gene', '6317', (27, 30))	('CEA', 'Gene', '1084', (46, 49))	('CA19-9', 'Chemical', 'MESH:C086528', (54, 60))	('LNM', 'Disease', (82, 85))	('Cyfra21-1', 'Var', (35, 44))
596194	29285292	Same statistically significant results were found when assessing the relation between the biomarkers level and LNM using the Mann-Whitney-U test (SCC-Ag, P=0.000; Cyfra21-1, P=0.049; CEA, P=0.032; CA19-9, P= 0.024; CA72-2, P=0.361).	('Cyfra21-1', 'Var', (163, 172))	('CEA', 'Gene', (183, 186))	('CEA', 'Gene', '1084', (183, 186))	('SCC', 'Gene', (146, 149))	('CA19-9', 'Chemical', 'MESH:C086528', (197, 203))	('SCC', 'Gene', '6317', (146, 149))
596195	29285292	On the multivariate analysis, SCC-Ag and CA19-9 were independent risk factors for LNM (Table 2; P<0.05).	('SCC', 'Gene', '6317', (30, 33))	('CA19-9', 'Chemical', 'MESH:C086528', (41, 47))	('CA19-9', 'Var', (41, 47))	('SCC', 'Gene', (30, 33))	('LNM', 'Disease', (82, 85))
596201	29285292	Patients with pN0-1stage were considered earlier and less extensive LNM, while patients with pN2-3 stage were considered more extensive LNM.	('pN2', 'Gene', (93, 96))	('Patients', 'Species', '9606', (0, 8))	('pN2', 'Gene', '351', (93, 96))	('patients', 'Species', '9606', (79, 87))	('pN0-1stage', 'Var', (14, 24))
596202	29285292	High positive rate of preoperative serum CEA and CA199 were associated with more extensive LNM (P=0.039, P=0.000, respectively).	('CA199', 'Chemical', 'MESH:C086528', (49, 54))	('serum', 'Protein', (35, 40))	('CA199', 'Var', (49, 54))	('CEA', 'Gene', (41, 44))	('extensive', 'Disease', (81, 90))	('CEA', 'Gene', '1084', (41, 44))
596210	29285292	The positive rate of serum CA19-9 was associated with subcarinal and paracardial LNM (P=0.000, P=0.038) (Table 6).	('CA19-9', 'Chemical', 'MESH:C086528', (27, 33))	('associated', 'Reg', (38, 48))	('CA19-9', 'Protein', (27, 33))	('serum', 'Var', (21, 26))
596223	29285292	In our study, the positive rate of SCC-Ag and Cyfra21-1 were 18.1% and 24.3%.	('SCC', 'Gene', (35, 38))	('Cyfra21-1', 'Var', (46, 55))	('SCC', 'Gene', '6317', (35, 38))
596230	29285292	Although Cyfra21-1, CEA and CA19-9 were associated with LNM in ESCC, they do not serve as precise predictors for early stage LNM.	('Cyfra21-1', 'Var', (9, 18))	('CEA', 'Gene', '1084', (20, 23))	('LNM', 'Disease', (56, 59))	('SCC', 'Gene', '6317', (64, 67))	('CA19-9', 'Chemical', 'MESH:C086528', (28, 34))	('CA19-9', 'Var', (28, 34))	('associated with', 'Reg', (40, 55))	('CEA', 'Gene', (20, 23))	('SCC', 'Gene', (64, 67))
596241	29285292	In abdominal lymph node stations, CA19-9 was correlated with paracardial LNM.	('CA19-9', 'Chemical', 'MESH:C086528', (34, 40))	('paracardial LNM', 'Disease', (61, 76))	('correlated', 'Reg', (45, 55))	('CA19-9', 'Var', (34, 40))
596249	29285292	CA19-9 is also called sialylated Lewis Antigen which is speculated to play roles in the extravasation of cancer cells from blood and the promotion of metastatic spread to distant organs.	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('metastatic spread to distant organs', 'CPA', (150, 185))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CA19-9', 'Var', (0, 6))	('promotion', 'PosReg', (137, 146))	('extravasation', 'MPA', (88, 101))
596253	29285292	first reported CA19-9 with a new cutoff value was associated with LNM and hematogenic metastasis.	('CA19-9', 'Var', (15, 21))	('hematogenic metastasis', 'Disease', (74, 96))	('hematogenic metastasis', 'Disease', 'MESH:D009362', (74, 96))	('CA19-9', 'Chemical', 'MESH:C086528', (15, 21))	('associated', 'Reg', (50, 60))	('LNM', 'Disease', (66, 69))
596256	29285292	In conclusion, this study demonstrates the correlation between LNM and the positive rate of preoperative serum SCC-Ag, Cyfra21-1, CEA and CA19-9.	('CA19-9', 'Chemical', 'MESH:C086528', (138, 144))	('Cyfra21-1', 'Var', (119, 128))	('SCC', 'Gene', (111, 114))	('CA19-9', 'Var', (138, 144))	('CEA', 'Gene', (130, 133))	('SCC', 'Gene', '6317', (111, 114))	('CEA', 'Gene', '1084', (130, 133))
596264	29285292	The normal upper limit was 1.5 ug/L, 3.3 ug/L, 5 ug/L, 39 U/ml and 6 U/ml for SCC-Ag, Cyfra21-1, CEA, CA19-9 and CA72-4 respectively.	('CEA', 'Gene', (97, 100))	('SCC', 'Gene', '6317', (78, 81))	('CEA', 'Gene', '1084', (97, 100))	('SCC', 'Gene', (78, 81))	('CA19-9', 'Chemical', 'MESH:C086528', (102, 108))	('Cyfra21-1', 'Var', (86, 95))
596385	22135048	For example, Limburg and colleagues found that neither selenomethionine nor celecoxib for 10 months inhibited esophageal SCC.	('esophageal SCC', 'Disease', (110, 124))	('esophageal SCC', 'Disease', 'MESH:D004941', (110, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('celecoxib', 'Chemical', 'MESH:D000068579', (76, 85))	('selenomethionine', 'Chemical', 'MESH:D012645', (55, 71))	('inhibited', 'NegReg', (100, 109))	('selenomethionine', 'Var', (55, 71))
596386	22135048	Selenomethionine had a protective effect in the subgroup with mild dysplasia, but the correlation was not significant (P = 0.08).	('Selenomethionine', 'Var', (0, 16))	('Selenomethionine', 'Chemical', 'MESH:D012645', (0, 16))	('dysplasia', 'Disease', (67, 76))	('dysplasia', 'Disease', 'MESH:D004476', (67, 76))
596403	22135048	One of the downstream targets of mTOR is p70S6Kinase, whose subtract is pS6, a component of the S40 ribosome subunit.	('mTOR', 'Gene', (33, 37))	('mTOR', 'Gene', '2475', (33, 37))	('p70S6Kinase', 'Var', (41, 52))
596413	26185530	The proper formation of apicobasal polarity is essential for normal epithelium physiology and tissue homeostasis, while loss of polarity is a hallmark of cancer development including esophageal oncogenesis.	('hallmark of cancer', 'Disease', (142, 160))	('esophageal oncogenesis', 'Disease', (183, 205))	('hallmark of cancer', 'Disease', 'MESH:D009369', (142, 160))	('esophageal oncogenesis', 'Disease', 'MESH:D063646', (183, 205))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('loss', 'Var', (120, 124))
596414	26185530	In this review, we summarized the stages of esophageal cancer development associated with the loss or deregulation of epithelial cell apicobasal polarity.	('esophageal cancer', 'Disease', (44, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('deregulation', 'Var', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))
596424	26185530	In this review, following an overview of epithelial cell polarity changes in cancer development, we highlight the latest advancements in our understanding of how the misexpression of polarity genes contributes to the progress of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('misexpression', 'Var', (166, 179))	('progress', 'PosReg', (217, 225))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('esophageal cancer', 'Disease', (229, 246))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (229, 246))	('cancer', 'Disease', (240, 246))	('polarity genes', 'Gene', (183, 197))
596434	26185530	Inactivation of LKB1 has been linked to tumorigenesis in various types of cancer.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Disease', (74, 80))	('linked to', 'Reg', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('LKB1', 'Gene', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Inactivation', 'Var', (0, 12))
596435	26185530	For example, loss of LKB1 induces a progrowth metabolic program in proliferating A549 cells, which were derived from non-small cell lung cancer tissue, and cells lacking LKB1 display increased uptake and utilization of glucose and glutamine.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('induces', 'Reg', (26, 33))	('uptake', 'MPA', (193, 199))	('LKB1', 'Gene', (21, 25))	('glutamine', 'Chemical', 'MESH:D005973', (231, 240))	('increased', 'PosReg', (183, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('progrowth metabolic program', 'MPA', (36, 63))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (117, 143))	('cancer', 'Disease', (137, 143))	('LKB1', 'Gene', (170, 174))	('lacking', 'NegReg', (162, 169))	('loss', 'Var', (13, 17))	('glucose', 'Chemical', 'MESH:D005947', (219, 226))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (121, 143))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
596437	26185530	In addition, mouse germline of LKB1 mutation displays an impaired spindle orientation in the upper gastrointestinal tract.	('mouse', 'Species', '10090', (13, 18))	('upper gastrointestinal tract', 'Disease', (93, 121))	('impaired', 'NegReg', (57, 65))	('LKB1', 'Gene', (31, 35))	('upper gastrointestinal tract', 'Disease', 'MESH:D004067', (93, 121))	('mutation', 'Var', (36, 44))
596438	26185530	This observation is validated by spindle misorientation in three-dimensional MDCK cell cysts caused by RNAi for LKB1 (PMID:22815934).	('caused by', 'Reg', (93, 102))	('RNAi', 'Var', (103, 107))	('MDCK', 'CellLine', 'CVCL:0422', (77, 81))	('LKB1', 'Gene', (112, 116))
596450	26185530	Conclusively, dysregulation of LKB1 is a crucial step in the progression of esophageal cancer, including proliferation, migration, and invasion (Figure 2).	('esophageal cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('dysregulation', 'Var', (14, 27))	('LKB1', 'Gene', (31, 35))	('proliferation', 'CPA', (105, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('migration', 'CPA', (120, 129))	('invasion', 'CPA', (135, 143))
596455	26185530	Mislocalized claudin-7, therefore, apparently promotes transformation and regulates E-cadherin expression during oncogenesis of esophageal keratinocytes.	('E-cadherin', 'Gene', (84, 94))	('regulates', 'MPA', (74, 83))	('claudin-7', 'Gene', (13, 22))	('E-cadherin', 'Gene', '999', (84, 94))	('Mislocalized', 'Var', (0, 12))	('transformation', 'CPA', (55, 69))	('promotes', 'PosReg', (46, 54))	('claudin-7', 'Gene', '1366', (13, 22))	('expression', 'MPA', (95, 105))
596465	26185530	Aberrant DNA copy number in human ESCC cells was investigated using a high-density oligonucleotide microarray, and a homozygous deletion of PARD3 gene, encoding the PAR-3 protein, was detected.	('human', 'Species', '9606', (28, 33))	('PAR-3', 'Gene', (165, 170))	('PARD3', 'Gene', '56288', (140, 145))	('PAR-3', 'Gene', '56288', (165, 170))	('PARD3', 'Gene', (140, 145))	('deletion', 'Var', (128, 136))
596467	26185530	Conversely, knockdown of PARD3 caused a disrupted localization of ZO-1 protein at cell-cell borders.	('ZO-1', 'Gene', '7082', (66, 70))	('disrupted', 'NegReg', (40, 49))	('PARD3', 'Gene', (25, 30))	('PARD3', 'Gene', '56288', (25, 30))	('knockdown', 'Var', (12, 21))	('localization', 'MPA', (50, 62))	('ZO-1', 'Gene', (66, 70))
596473	26185530	Therefore, these observations raise the intriguing possibility that abnormality in PARD3 could be a novel mechanism for the progression of ESCC (Figure 2).	('PARD3', 'Gene', (83, 88))	('PARD3', 'Gene', '56288', (83, 88))	('abnormality', 'Var', (68, 79))	('ESCC', 'Disease', (139, 143))
596480	26185530	The growth arrest and apoptosis induction were confirmed in vivo in a xenograft model with hyperactivated LGL1.	('LGL1', 'Gene', (106, 110))	('growth arrest', 'Disease', 'MESH:D006323', (4, 17))	('hyperactivated', 'Var', (91, 105))	('growth arrest', 'Disease', (4, 17))	('growth arrest', 'Phenotype', 'HP:0001510', (4, 17))
596487	26185530	Metastasis to lymph nodes and the TNM stage of ESCC were associated with miR-92a significantly, and this may result from the direct targeting of the 3'-UTR of E-cadherin by miR-92a and the repression in E-cadherin expression.	('E-cadherin', 'Gene', '999', (159, 169))	('TNM', 'Gene', '10178', (34, 37))	('miR-92a', 'Var', (173, 180))	('Metastasis to lymph nodes', 'CPA', (0, 25))	('ESCC', 'Disease', (47, 51))	('miR-92a', 'Gene', (73, 80))	('TNM', 'Gene', (34, 37))	('E-cadherin', 'Gene', (159, 169))	('E-cadherin', 'Gene', (203, 213))	('E-cadherin', 'Gene', '999', (203, 213))	('repression', 'NegReg', (189, 199))	('associated', 'Reg', (57, 67))
596504	26185530	In addition to disrupted epithelium organization, alterations in genes regulating epithelial polarization have been implicated in the development of esophageal cancer, including enhanced cell proliferation, abnormal metabolism, and reduced apoptosis.	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('enhanced', 'PosReg', (178, 186))	('abnormal metabolism', 'Phenotype', 'HP:0032245', (207, 226))	('alterations', 'Var', (50, 61))	('implicated', 'Reg', (116, 126))	('reduced', 'NegReg', (232, 239))	('esophageal cancer', 'Disease', (149, 166))	('apoptosis', 'CPA', (240, 249))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('abnormal metabolism', 'CPA', (207, 226))	('cell proliferation', 'CPA', (187, 205))
596599	23412468	In some studies, myocardial perfusion scintigraphy, using 99m technetium (Tc-99m) sestamibi, Tc-99m tetrofosmin or thallium-201, demonstrated myocardial perfusion defects in the RT fields of some patients who had been treated for left breast cancer or esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (252, 269))	('Tc-99m', 'Var', (93, 99))	('tetrofosmin', 'Chemical', '-', (100, 111))	('left breast cancer', 'Disease', 'MESH:D001943', (230, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('thallium-201', 'Chemical', 'MESH:C000615114', (115, 127))	('technetium', 'Chemical', 'MESH:D013667', (62, 72))	('sestamibi', 'Chemical', '-', (82, 91))	('myocardial perfusion defects', 'Disease', 'MESH:D009202', (142, 170))	('patients', 'Species', '9606', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('esophageal cancer', 'Disease', (252, 269))	('myocardial perfusion defects', 'Disease', (142, 170))	('left breast cancer', 'Disease', (230, 248))	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))
596671	23412468	Although comparison with results of previous studies might not be appropriate, I-123 BMIPP demonstrated higher sensitivity of abnormal uptake than myocardial perfusion scintigraphy and FDG-PET in patients with esophageal cancer (Table 5).	('I-123 BMIPP', 'Chemical', '-', (79, 90))	('FDG', 'Chemical', 'MESH:D019788', (185, 188))	('esophageal cancer', 'Disease', (210, 227))	('patients', 'Species', '9606', (196, 204))	('sensitivity', 'MPA', (111, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (210, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('I-123', 'Var', (79, 84))	('abnormal uptake', 'MPA', (126, 141))
596676	23412468	also reported that the cumulative mortality from ischemic heart disease was significantly higher in patients with a high dose per volume of heart than in those without RT.	('high dose per volume', 'Var', (116, 136))	('ischemic heart disease', 'Disease', 'MESH:D003324', (49, 71))	('patients', 'Species', '9606', (100, 108))	('ischemic heart disease', 'Disease', (49, 71))	('higher', 'PosReg', (90, 96))
596681	23412468	Some studies have also shown that abnormal I-123 BMIPP uptake in acute coronary syndrome and idiopathic dilated cardiomyopathy was significantly associated with cardiac events.	('abnormal', 'Var', (34, 42))	('cardiac events', 'Disease', (161, 175))	('I-123 BMIPP uptake', 'MPA', (43, 61))	('idiopathic dilated cardiomyopathy', 'Disease', 'MESH:C536277', (93, 126))	('associated', 'Reg', (145, 155))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (112, 126))	('idiopathic dilated cardiomyopathy', 'Disease', (93, 126))	('I-123 BMIPP', 'Chemical', '-', (43, 54))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (104, 126))	('coronary syndrome', 'Disease', (71, 88))	('coronary syndrome', 'Phenotype', 'HP:0001677', (71, 88))	('coronary syndrome', 'Disease', 'MESH:D003324', (71, 88))
596712	33118416	The most prominent types of conjugated polymers are polyaniline, polypyrrole, polyacetylene and its derivatives which have been intensively studied due to their intrinsic conductivity, polythiophenes, polyphenylenes, polyfluorenes, poly(arylenevinylene), and poly(phenyleneethynylene).	('polythiophenes', 'Var', (185, 199))	('poly(phenyleneethynylene', 'Chemical', 'MESH:C473966', (259, 283))	('polyaniline', 'Chemical', 'MESH:C416807', (52, 63))	('poly(arylenevinylene', 'Chemical', '-', (232, 252))	('polyfluorenes', 'Chemical', '-', (217, 230))	('polyacetylene', 'Chemical', 'MESH:D000078789', (78, 91))	('polymers', 'Chemical', 'MESH:D011108', (39, 47))	('polypyrrole', 'Chemical', 'MESH:C067635', (65, 76))	('intrinsic conductivity', 'MPA', (161, 183))	('polyphenylenes', 'Chemical', 'MESH:C041325', (201, 215))	('polythiophenes', 'Chemical', 'MESH:C066730', (185, 199))
596731	33118416	However, the release of 131I and 131I-tyrosine in the blood represents a potential health risk (Schuster et al.,).	('131I-tyrosine', 'Var', (33, 46))	('tyrosine', 'Chemical', 'MESH:D014443', (38, 46))	('131I', 'Chemical', 'MESH:C000614965', (24, 28))	('131I', 'Var', (24, 28))	('release', 'MPA', (13, 20))	('131I', 'Chemical', 'MESH:C000614965', (33, 37))
596779	33118416	They observed that NPs with folate presented the same biodistribution results than NPs without folate.	('folate', 'Chemical', 'MESH:D005492', (95, 101))	('folate', 'Chemical', 'MESH:D005492', (28, 34))	('biodistribution', 'MPA', (54, 69))	('folate', 'Var', (28, 34))
596789	33118416	Also, NPs produced by PLGA-MPEG presented the highest level in the blood up to 24 h. In biodistribution studies, it was detected that NPs were less uptake by spleen and liver in comparison with free etoposide.	('uptake', 'MPA', (148, 154))	('less', 'NegReg', (143, 147))	('NPs', 'Var', (134, 137))	('MPEG', 'Chemical', 'MESH:C028210', (27, 31))	('etoposide', 'Chemical', 'MESH:D005047', (199, 208))
596807	33118416	According to the in vivo studies, they observed that 177Lu-BN-PLGA-PTX NPs showed the lowest tumor proliferation, followed by PLGA-PTX NPs and 177Lu-BN-PLGA NPs.	('PTX', 'Chemical', 'MESH:D017239', (67, 70))	('PTX', 'Chemical', 'MESH:D017239', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('177Lu', 'Chemical', 'MESH:C000615061', (53, 58))	('177Lu-BN-PLGA-PTX', 'Var', (53, 70))	('lowest', 'NegReg', (86, 92))	('177Lu', 'Chemical', 'MESH:C000615061', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
596808	33118416	Also, 177Lu-BN-PLGA-PTX NPs presented the lowest metabolic tumoral activity, indicating that the combination of drug, polymer and radioactive agent increase the therapeutical response (Gibbens-Bandala et al.,).	('177Lu-BN-PLGA-PTX', 'Var', (6, 23))	('increase', 'PosReg', (148, 156))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('therapeutical response', 'CPA', (161, 183))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('lowest', 'NegReg', (42, 48))	('PTX', 'Chemical', 'MESH:D017239', (20, 23))	('polymer', 'Chemical', 'MESH:D011108', (118, 125))	('177Lu', 'Chemical', 'MESH:C000615061', (6, 11))
596810	33118416	They observed that 177Lu-DOTA-PLGA-MTX NPs showed a passive nonspecific uptake, while 177Lu-DOTA-HA-PLGA NPs with or without MTX had an increase of uptake due to HA presence.	('177Lu', 'Chemical', 'MESH:C000615061', (86, 91))	('177Lu-DOTA-HA-PLGA', 'Var', (86, 104))	('MTX', 'Chemical', 'MESH:D008727', (125, 128))	('uptake', 'MPA', (148, 154))	('177Lu', 'Chemical', 'MESH:C000615061', (19, 24))	('HA', 'Chemical', 'MESH:D017886', (162, 164))	('increase', 'PosReg', (136, 144))	('HA', 'Chemical', 'MESH:D017886', (97, 99))	('MTX', 'Chemical', 'MESH:D008727', (35, 38))	('passive nonspecific uptake', 'MPA', (52, 78))
596813	33118416	According to these results, 177Lu-DOTA-HA-PLGA-MTX NPs are a promising agent to treat rheumatic arthritis (Trujillo-Nolasco et al.,).	('arthritis', 'Phenotype', 'HP:0001369', (96, 105))	('177Lu-DOTA-HA-PLGA-MTX', 'Var', (28, 50))	('MTX', 'Chemical', 'MESH:D008727', (47, 50))	('rheumatic arthritis', 'Phenotype', 'HP:0001370', (86, 105))	('HA', 'Chemical', 'MESH:D017886', (39, 41))	('rheumatic arthritis', 'Disease', 'MESH:D012213', (86, 105))	('177Lu', 'Chemical', 'MESH:C000615061', (28, 33))	('rheumatic arthritis', 'Disease', (86, 105))
596847	33118416	The results showed that the 89Zr-chitosan NPs showed a lower efflux than the 64Cu-chitosan NPs.	('64Cu', 'Chemical', 'MESH:C000615411', (77, 81))	('lower', 'NegReg', (55, 60))	('efflux', 'MPA', (61, 67))	('89Zr-chitosan', 'Var', (28, 41))
596850	33118416	Thereby, it was verified that the nanosystems using silver for therapeutic applications labeled with 111Ag can be used as theranostics due to the presence of 111Ag which evaluates the pharmacokinetics and biodistribution of silver nanosystems (Aweda et al.,).	('silver', 'Chemical', 'MESH:D012834', (52, 58))	('silver', 'Chemical', 'MESH:D012834', (224, 230))	('presence', 'Var', (146, 154))	('111Ag', 'Chemical', 'MESH:C000617013', (158, 163))	('111Ag', 'Var', (158, 163))	('111Ag', 'Chemical', 'MESH:C000617013', (101, 106))
596874	33118416	Furthermore, the authors suggested that an alteration of the 99mTc radionuclide by a beta (177-Luthetium) or alpha emitter (223 Radium) could promote a therapeutic effect on the tumor (Carmo et al.,).	('tumor', 'Disease', (178, 183))	('223 Radium', 'Var', (124, 134))	('alteration', 'Var', (43, 53))	('99mTc radionuclide', 'MPA', (61, 79))	('therapeutic effect', 'CPA', (152, 170))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('promote', 'PosReg', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
596910	33118416	The combined therapeutic effects (chemo- and radiotherapy) of 131I-HSA-PTX were found to be highly effective in the 4T1 cancer xenograft model compared to radiotherapy- and chemotherapy-alone groups (Tian et al.,).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PTX', 'Chemical', 'MESH:D017239', (71, 74))	('131I', 'Chemical', 'MESH:C000614965', (62, 66))	('cancer', 'Disease', (120, 126))	('131I-HSA-PTX', 'Var', (62, 74))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
596936	31578148	Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation, we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PDHK1', 'Gene', '5163', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('S203', 'Var', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('PGK1', 'Gene', (34, 38))	('PDHK1', 'Gene', (48, 53))	('PGK1', 'Gene', '5230', (34, 38))
596937	31578148	The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types, respectively.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('TNM', 'Gene', '10178', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mRNA level', 'MPA', (9, 19))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('hypomethylation', 'Var', (52, 67))	('elevated', 'PosReg', (38, 46))	('PGK1', 'Gene', '5230', (4, 8))	('associated', 'Reg', (92, 102))	('PGK1', 'Gene', (4, 8))	('TNM', 'Gene', (117, 120))	('cancer', 'Disease', (142, 148))
596939	31578148	Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival (OS) in cancers of the breast, liver, lung, stomach, and esophagus and with advanced TNM stage in breast and esophageal cancers.	('short', 'NegReg', (105, 110))	('associated', 'Reg', (89, 99))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('PDHK1', 'Gene', (36, 41))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('cancers of the breast', 'Phenotype', 'HP:0100013', (136, 157))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('lung', 'Disease', (166, 170))	('S203', 'Var', (27, 31))	('PDHK1', 'Gene', '5163', (36, 41))	('cancers of the breast', 'Disease', 'MESH:D001943', (136, 157))	('PGK1', 'Gene', '5230', (22, 26))	('breast and esophageal cancers', 'Disease', 'MESH:D001943', (226, 255))	('TNM', 'Gene', '10178', (213, 216))	('phosphorylation levels', 'MPA', (47, 69))	('TNM', 'Gene', (213, 216))	('PGK1', 'Gene', (22, 26))	('stomach', 'Disease', (172, 179))	('T338', 'Var', (42, 46))	('liver', 'Disease', (159, 164))	('esophagus', 'Disease', (185, 194))	('cancers of the breast', 'Disease', (136, 157))
596940	31578148	PGK1 pS203 and PDHK1 pT338 were also independent predictors of short OS in liver, lung, and stomach cancer.	('lung', 'Disease', (82, 86))	('pS203', 'Var', (5, 10))	('liver', 'Disease', (75, 80))	('short OS', 'Disease', (63, 71))	('stomach cancer', 'Disease', 'MESH:D013274', (92, 106))	('PDHK1', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PDHK1', 'Gene', '5163', (15, 20))	('stomach cancer', 'Phenotype', 'HP:0012126', (92, 106))	('stomach cancer', 'Disease', (92, 106))	('PGK1', 'Gene', (0, 4))	('PGK1', 'Gene', '5230', (0, 4))
596950	31578148	In response to receptor tyrosine kinase activation, the expression of K-Ras G12V and B-Raf V600E, hypoxia, pyruvate metabolism in mitochondria is suppressed.	('G12V', 'Mutation', 'p.G12V', (76, 80))	('hypoxia', 'Disease', (98, 105))	('V600E', 'Mutation', 'p.V600E', (91, 96))	('B-Raf V600E', 'Var', (85, 96))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('activation', 'PosReg', (40, 50))	('pyruvate', 'Chemical', 'MESH:D011773', (107, 115))	('pyruvate metabolism in mitochondria', 'MPA', (107, 142))	('V600E', 'Var', (91, 96))	('K-Ras G12V', 'Var', (70, 80))	('tyrosine', 'Chemical', 'None', (24, 32))	('suppressed', 'NegReg', (146, 156))
596954	31578148	In addition, PGK1 S203 and PDHK1 T338 phosphorylation levels were found to be positively correlated with each other, and both were correlated with PDH S293 inactivating phosphorylation levels and poor prognosis in patients with glioblastoma (GBM).	('correlated', 'Interaction', (89, 99))	('correlated', 'Reg', (131, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (228, 240))	('PDHK1', 'Gene', '5163', (27, 32))	('patients', 'Species', '9606', (214, 222))	('PDH', 'Gene', '54704', (27, 30))	('PDH', 'Gene', '54704', (147, 150))	('GBM', 'Phenotype', 'HP:0012174', (242, 245))	('PDHK1', 'Gene', (27, 32))	('glioblastoma', 'Disease', (228, 240))	('glioblastoma', 'Phenotype', 'HP:0012174', (228, 240))	('PGK1', 'Gene', '5230', (13, 17))	('inactivating', 'NegReg', (156, 168))	('PDH', 'Gene', (27, 30))	('PDH', 'Gene', (147, 150))	('PGK1', 'Gene', (13, 17))	('S203', 'Var', (18, 22))	('GBM', 'Disease', (242, 245))	('phosphorylation levels', 'MPA', (38, 60))	('GBM', 'Disease', 'MESH:D005909', (242, 245))
596957	31578148	We also analyzed the clinical relevance of PGK1 S203 and PDHK1 T338 phosphorylation levels by conducting immunohistochemical experiments in an additional 818 independent cancer cases (including 619 with paired normal tissues).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('PGK1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('PDHK1', 'Gene', (57, 62))	('PGK1', 'Gene', '5230', (43, 47))	('PDHK1', 'Gene', '5163', (57, 62))	('clinical', 'Species', '191496', (21, 29))	('S203', 'Var', (48, 52))
596968	31578148	Rabbit polyclonal antibodies recognizing phospho-PGK1 S203 and phospho-PDHK1 T338 were obtained from Signalway Antibody (College Park, MD, USA).	('PGK1', 'Gene', '5230', (49, 53))	('S203', 'Var', (54, 58))	('PDHK1', 'Gene', (71, 76))	('PDHK1', 'Gene', '5163', (71, 76))	('PGK1', 'Gene', (49, 53))	('Rabbit', 'Species', '9986', (0, 6))
596996	31578148	DNA methylation regulates gene expression and is implicated in tumor progression and therapeutic response.	('tumor', 'Disease', (63, 68))	('gene expression', 'MPA', (26, 41))	('regulates', 'Reg', (16, 25))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('implicated', 'Reg', (49, 59))
597004	31578148	3b; Additional file 1: Table S4), suggesting promoter hypomethylation as a mechanism promoting PGK1 expression.	('promoter hypomethylation', 'Var', (45, 69))	('expression', 'MPA', (100, 110))	('PGK1', 'Gene', (95, 99))	('PGK1', 'Gene', '5230', (95, 99))	('promoting', 'PosReg', (85, 94))
597006	31578148	We next analyzed the association between PGK1 promoter hypomethylation and the survival of patients with STAD, BLCA, ESCA, LIHC, and BRCA, and found that only in BRCA, hypomethylation of cg13203541 was associated with short OS (HR = 0.551, 95% CI 0.361-0.841, P = 0.005; Additional file 1: Table S5; Fig.	('BRCA', 'Phenotype', 'HP:0003002', (162, 166))	('BRCA', 'Disease', (133, 137))	('ESCA', 'Phenotype', 'HP:0011459', (117, 121))	('BLCA', 'Disease', 'MESH:D001749', (111, 115))	('LIHC', 'Disease', 'MESH:D006528', (123, 127))	('BRCA', 'Disease', 'MESH:D001943', (133, 137))	('PGK1', 'Gene', (41, 45))	('STAD', 'Disease', (105, 109))	('cg13203541', 'Var', (187, 197))	('patients', 'Species', '9606', (91, 99))	('BRCA', 'Disease', (162, 166))	('short OS', 'Disease', (218, 226))	('BRCA', 'Disease', 'MESH:D001943', (162, 166))	('hypomethylation', 'Var', (168, 183))	('ESCA', 'Disease', (117, 121))	('BRCA', 'Phenotype', 'HP:0003002', (133, 137))	('STAD', 'Disease', 'MESH:D013274', (105, 109))	('ESCA', 'Disease', 'MESH:D004938', (117, 121))	('associated', 'Reg', (202, 212))	('LIHC', 'Disease', (123, 127))	('BLCA', 'Disease', (111, 115))	('PGK1', 'Gene', '5230', (41, 45))
597007	31578148	A multivariate Cox regression model showed that cg13203541 methylation was an independent predictor of prolonged OS in BRCA (HR = 0.599, 95% CI 0.382-0.939, P = 0.026; Additional file 1: Table S5).	('cg13203541 methylation', 'Var', (48, 70))	('BRCA', 'Disease', (119, 123))	('BRCA', 'Phenotype', 'HP:0003002', (119, 123))	('BRCA', 'Disease', 'MESH:D001943', (119, 123))
597015	31578148	Kaplan-Meier analysis showed that higher levels of both PGK1 pS203 and PDHK1 pT338 were associated with shorter OS in patients with these five cancer types (all P < 0.05) (Fig.	('shorter OS', 'Disease', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('PGK1', 'Gene', '5230', (56, 60))	('PGK1', 'Gene', (56, 60))	('higher', 'PosReg', (34, 40))	('pS203', 'Var', (61, 66))	('PDHK1', 'Gene', (71, 76))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('PDHK1', 'Gene', '5163', (71, 76))	('patients', 'Species', '9606', (118, 126))
597016	31578148	An independent variable t test showed that both PGK1 pS203 and PDHK1 pT338 were associated with advanced TNM stage in patients with BRCA and ESCA (all P < 0.05) (Table 1).	('PGK1', 'Gene', (48, 52))	('TNM', 'Gene', (105, 108))	('PDHK1', 'Gene', '5163', (63, 68))	('PGK1', 'Gene', '5230', (48, 52))	('pS203', 'Var', (53, 58))	('BRCA', 'Disease', 'MESH:D001943', (132, 136))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('patients', 'Species', '9606', (118, 126))	('ESCA', 'Phenotype', 'HP:0011459', (141, 145))	('ESCA', 'Disease', (141, 145))	('associated', 'Reg', (80, 90))	('TNM', 'Gene', '10178', (105, 108))	('PDHK1', 'Gene', (63, 68))	('BRCA', 'Disease', (132, 136))	('ESCA', 'Disease', 'MESH:D004938', (141, 145))
597019	31578148	Additional analyses of a cohort of 818 cases revealed that the phosphorylation levels of PGK1 S203 and PDHK1 T338 were independent prognostic biomarkers for LIHC, LUAD, and STAD.	('PDHK1', 'Gene', (103, 108))	('T338', 'Var', (109, 113))	('PDHK1', 'Gene', '5163', (103, 108))	('phosphorylation levels', 'MPA', (63, 85))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('LIHC', 'Disease', (157, 161))	('LUAD', 'Disease', (163, 167))	('STAD', 'Disease', 'MESH:D013274', (173, 177))	('LUAD', 'Disease', 'MESH:C538231', (163, 167))	('PGK1', 'Gene', (89, 93))	('STAD', 'Disease', (173, 177))	('LIHC', 'Disease', 'MESH:D006528', (157, 161))	('PGK1', 'Gene', '5230', (89, 93))	('S203', 'Var', (94, 98))
597020	31578148	All these findings suggest that PGK1 gene modification and PGK1-mitochondrial function were significantly associated with clinical behaviors of cancer patients.	('clinical behaviors', 'Disease', (122, 140))	('associated', 'Reg', (106, 116))	('PGK1', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PGK1', 'Gene', '5230', (32, 36))	('patients', 'Species', '9606', (151, 159))	('gene modification', 'Var', (37, 54))	('cancer', 'Disease', (144, 150))	('PGK1', 'Gene', (59, 63))	('clinical', 'Species', '191496', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PGK1', 'Gene', '5230', (59, 63))
597030	31578148	Therefore, in the present study, we analyzed the DNA methylation data for 14 cancer types from TCGA datasets and identified hypomethylation of the PGK1 promoter (cg13203541) as an independent prognostic biomarker in BRCA patients (Additional file 1: Table S5).	('patients', 'Species', '9606', (221, 229))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hypomethylation', 'Var', (124, 139))	('BRCA', 'Disease', (216, 220))	('cg13203541', 'Var', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('PGK1', 'Gene', (147, 151))	('BRCA', 'Phenotype', 'HP:0003002', (216, 220))	('BRCA', 'Disease', 'MESH:D001943', (216, 220))	('PGK1', 'Gene', '5230', (147, 151))
597031	31578148	We also detected mitochondrial PGK1-dependent PDHK1 T338 phosphorylation in additional cases of five cancer types and demonstrated that mitochondrial function of PGK1 significantly affected the clinical behaviors of patients with these cancers.	('PGK1', 'Gene', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mitochondrial function', 'MPA', (136, 158))	('PDHK1', 'Gene', '5163', (46, 51))	('affected', 'Reg', (181, 189))	('PGK1', 'Gene', '5230', (31, 35))	('PDHK1', 'Gene', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('cancer', 'Disease', (236, 242))	('cancers', 'Disease', (236, 243))	('patients', 'Species', '9606', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('T338', 'Var', (52, 56))	('PGK1', 'Gene', (31, 35))	('PGK1', 'Gene', '5230', (162, 166))	('cancer', 'Disease', (101, 107))	('clinical behaviors', 'CPA', (194, 212))	('clinical', 'Species', '191496', (194, 202))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('phosphorylation', 'MPA', (57, 72))
597033	31578148	One important example is isocitrate dehydrogenase 1 (IDH1) mutation, which has important clinical significance and was found in GBM and myeloid malignancies, such as acute myelocytic leukaemia (AML) and myelodysplastic syndromes (MDS).	('AML', 'Disease', 'MESH:D015470', (194, 197))	('myeloid malignancies', 'Disease', (136, 156))	('acute myelocytic leukaemia', 'Disease', 'MESH:D015470', (166, 192))	('isocitrate', 'Chemical', 'MESH:D007523', (25, 35))	('AML', 'Disease', (194, 197))	('mutation', 'Var', (59, 67))	('AML', 'Phenotype', 'HP:0004808', (194, 197))	('acute myelocytic leukaemia', 'Phenotype', 'HP:0004808', (166, 192))	('MDS', 'Phenotype', 'HP:0002863', (230, 233))	('clinical', 'Species', '191496', (89, 97))	('GBM', 'Disease', (128, 131))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (203, 228))	('myeloid malignancies', 'Disease', 'OMIM:601308', (136, 156))	('GBM', 'Disease', 'MESH:D005909', (128, 131))	('myelodysplastic syndromes', 'Disease', (203, 228))	('MDS', 'Disease', 'MESH:D009190', (230, 233))	('IDH1', 'Gene', (53, 57))	('acute myelocytic leukaemia', 'Disease', (166, 192))	('found', 'Reg', (119, 124))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (203, 228))	('MDS', 'Disease', (230, 233))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('IDH1', 'Gene', '3417', (53, 57))	('myelocytic leukaemia', 'Phenotype', 'HP:0012324', (172, 192))
597034	31578148	A clinical study suggested that IDH1 mutation was an independent, favorable prognostic marker in grade 2-4 glioma.	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('IDH1', 'Gene', '3417', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('clinical', 'Species', '191496', (2, 10))	('glioma', 'Disease', (107, 113))
597047	31578148	This study was funded by The National Key R&D Program of China (2017YFC1308702, 2017YFC1311000, 2018YFC1312100), the Beijing Municipal Science & Technology Commission (Z181100006218032, Z181100001918002), the CAMS Initiative for Innovative Medicine (2017-I2M-1-005, 2017-I2M-2-003, 2019-I2M-2-002), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2017PT32001, 2017PT32017).	('Z181100006218032', 'Chemical', 'MESH:C017788', (168, 184))	('Technology Commission', 'Var', (145, 166))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('N', 'Chemical', 'MESH:D009584', (299, 300))	('Innovative', 'Var', (229, 239))
597058	31579417	The present study highlighted the potential value of ILK in predicting the efficacy of chemoradiotherapeutic treatment in patients with ESCC, and that ILK gene-silencing inhibits the progression of ESCC.	('ESCC', 'Disease', (198, 202))	('ILK', 'Gene', (53, 56))	('ESCC', 'Disease', (136, 140))	('gene-silencing', 'Var', (155, 169))	('ILK', 'Gene', '3611', (151, 154))	('ILK', 'Gene', '3611', (53, 56))	('patients', 'Species', '9606', (122, 130))	('inhibits', 'NegReg', (170, 178))	('ESCC', 'Disease', 'MESH:C562729', (198, 202))	('ILK', 'Gene', (151, 154))	('ESCC', 'Disease', 'MESH:C562729', (136, 140))
597115	31579417	ILK gene-silencing was shown to inhibit the proliferation of TE-1 cells.	('inhibit', 'NegReg', (32, 39))	('gene-silencing', 'Var', (4, 18))	('proliferation of TE-1 cells', 'CPA', (44, 71))	('ILK', 'Gene', '3611', (0, 3))	('ILK', 'Gene', (0, 3))
597117	31579417	The degree of apoptosis in TE-1 cells of the shILK group increased significantly (P<0.01), indicating that the ILK gene is significantly associated with apoptosis in these cells (Fig.	('ILK', 'Gene', (111, 114))	('associated with', 'Reg', (137, 152))	('ILK', 'Gene', '3611', (111, 114))	('ILK', 'Gene', (47, 50))	('gene', 'Var', (115, 119))	('ILK', 'Gene', '3611', (47, 50))	('apoptosis', 'CPA', (153, 162))
597121	31579417	The migration and invasion abilities of TE-1 cells in the shILK group were significantly inhibited compared with those of the shCtrl group (P<0.01), suggesting that ILK gene-silencing inhibits the migration and invasion abilities of TE-1 cells (Figs.	('inhibited', 'NegReg', (89, 98))	('ILK', 'Gene', (60, 63))	('ILK', 'Gene', '3611', (60, 63))	('invasion abilities', 'CPA', (18, 36))	('inhibits', 'NegReg', (184, 192))	('gene-silencing', 'Var', (169, 183))	('ILK', 'Gene', (165, 168))	('migration', 'CPA', (4, 13))	('ILK', 'Gene', '3611', (165, 168))
597122	31579417	The effect of ILK gene-silencing on TE-1 cell migration was also detected using a wound-healing assay three days post-transfection with shRNA lentivirus.	('gene-silencing', 'Var', (18, 32))	('ILK', 'Gene', (14, 17))	('ILK', 'Gene', '3611', (14, 17))
597129	31579417	These findings indicated that the abnormal expression of ILK may be associated with the occurrence and development of ESCC, and that ILK may be involved in the regulation of chemoradiotherapy sensitivity, and thus closely associated with sensitivity to chemoradiotherapy in patients with esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (288, 305))	('ESCC', 'Disease', (118, 122))	('associated', 'Reg', (68, 78))	('abnormal', 'Var', (34, 42))	('patients', 'Species', '9606', (274, 282))	('ILK', 'Gene', (133, 136))	('involved', 'Reg', (144, 152))	('ILK', 'Gene', '3611', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('ILK', 'Gene', (57, 60))	('ILK', 'Gene', '3611', (57, 60))	('ESCC', 'Disease', 'MESH:C562729', (118, 122))	('esophageal cancer', 'Disease', (288, 305))	('associated', 'Reg', (222, 232))	('expression', 'MPA', (43, 53))
597131	31579417	To the best of our knowledge, the present study shows for the first time that ILK gene-silencing significantly inhibits the proliferation, invasion and migration, and promotes apoptosis in ESCC TE-1 cells.	('ESCC', 'Disease', 'MESH:C562729', (189, 193))	('promotes', 'PosReg', (167, 175))	('proliferation', 'CPA', (124, 137))	('inhibits', 'NegReg', (111, 119))	('ILK', 'Gene', (78, 81))	('ILK', 'Gene', '3611', (78, 81))	('ESCC', 'Disease', (189, 193))	('apoptosis', 'CPA', (176, 185))	('gene-silencing', 'Var', (82, 96))
597139	31579417	Abnormal expression of the ILK gene may be an important factor to increase the malignancy of ESCC.	('malignancy', 'Disease', 'MESH:D009369', (79, 89))	('increase', 'PosReg', (66, 74))	('malignancy', 'Disease', (79, 89))	('ESCC', 'Disease', 'MESH:C562729', (93, 97))	('ILK', 'Gene', (27, 30))	('Abnormal', 'Var', (0, 8))	('ILK', 'Gene', '3611', (27, 30))	('ESCC', 'Disease', (93, 97))
597142	31579417	The apoptotic rate of TE-1 cells was increased relative to the control group following ILK knockdown.	('ILK', 'Gene', '3611', (87, 90))	('apoptotic rate', 'CPA', (4, 18))	('ILK', 'Gene', (87, 90))	('knockdown', 'Var', (91, 100))
597147	31579417	The results showed that ILK silencing inhibited the invasive properties of TE-1 cells, and therefore, ILK may promote the invasion of ESCC cells.	('ESCC', 'Disease', 'MESH:C562729', (134, 138))	('invasive properties of TE-1 cells', 'CPA', (52, 85))	('ESCC', 'Disease', (134, 138))	('invasion', 'CPA', (122, 130))	('inhibited', 'NegReg', (38, 47))	('ILK', 'Gene', (102, 105))	('ILK', 'Gene', '3611', (102, 105))	('promote', 'PosReg', (110, 117))	('ILK', 'Gene', '3611', (24, 27))	('ILK', 'Gene', (24, 27))	('silencing', 'Var', (28, 37))
597148	31579417	In addition, studies have reported that abnormal expression of ILK affects the chemoradiotherapeutic sensitivity of tumor cells.	('affects', 'Reg', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('ILK', 'Gene', (63, 66))	('tumor', 'Disease', (116, 121))	('ILK', 'Gene', '3611', (63, 66))	('abnormal expression', 'Var', (40, 59))
597149	31579417	Duxbury et al found that overexpression of ILK increased the chemotherapeutic resistance of pancreatic cancer cells to gemcitabine, and that ILK knockout increased the sensitivity of caspase-3-mediated apoptosis to gemcitabine.	('ILK', 'Gene', '3611', (141, 144))	('gemcitabine', 'Chemical', 'MESH:C056507', (119, 130))	('knockout', 'Var', (145, 153))	('sensitivity', 'MPA', (168, 179))	('gemcitabine', 'Chemical', 'MESH:C056507', (215, 226))	('chemotherapeutic resistance', 'MPA', (61, 88))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('caspase-3', 'Gene', (183, 192))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('ILK', 'Gene', (43, 46))	('ILK', 'Gene', '3611', (43, 46))	('increased', 'PosReg', (47, 56))	('caspase-3', 'Gene', '836', (183, 192))	('increased', 'PosReg', (154, 163))	('pancreatic cancer', 'Disease', (92, 109))	('ILK', 'Gene', (141, 144))	('overexpression', 'PosReg', (25, 39))
597154	31579417	It was revealed for the first time that the inhibition of ILK expression promoted the biological characteristics of ESCC, and increased the degree of tumor malignancy.	('inhibition', 'Var', (44, 54))	('ESCC', 'Disease', (116, 120))	('tumor malignancy', 'Disease', (150, 166))	('biological characteristics of', 'CPA', (86, 115))	('ILK', 'Gene', (58, 61))	('ILK', 'Gene', '3611', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('promoted', 'PosReg', (73, 81))	('increased', 'PosReg', (126, 135))	('tumor malignancy', 'Disease', 'MESH:D009369', (150, 166))	('ESCC', 'Disease', 'MESH:C562729', (116, 120))
597204	30519852	A high-throughput human circRNA microarray was conducted using plasma samples from 10 ESCC patients, including 5 patients with T3N0M0 (case 1) and another 5 patients with T3N1-3M0 (case 2), as well as 5 normal plasma samples (control), to assess differences in the circRNA expression profile in ESCC.	('patients', 'Species', '9606', (91, 99))	('T3N0M0', 'Var', (127, 133))	('patients', 'Species', '9606', (113, 121))	('human', 'Species', '9606', (18, 23))	('patients', 'Species', '9606', (157, 165))	('ESCC', 'Disease', (86, 90))
597227	30519852	The colony formation experiment and CCK-8 assay showed that, after knockdown of circ-TTC17, the proliferation ability of KYSE30 and KYSE450 cells was significantly decreased (Fig.	('TTC17', 'Gene', (85, 90))	('proliferation ability', 'CPA', (96, 117))	('decreased', 'NegReg', (164, 173))	('TTC17', 'Gene', '55761', (85, 90))	('knockdown', 'Var', (67, 76))
597233	30519852	A total of 20 miRNAs (e.g., miR-153, miR-217, miR-224, and miR-370) and corresponding target mRNAs were predicted to have an interaction with circ-TTC17 in this study (Supplementary Fig.	('TTC17', 'Gene', (147, 152))	('miR-153', 'Var', (28, 35))	('miR-224', 'Gene', '407009', (46, 53))	('miR-224', 'Gene', (46, 53))	('miR-370', 'Gene', (59, 66))	('interaction', 'Interaction', (125, 136))	('TTC17', 'Gene', '55761', (147, 152))	('miR-370', 'Gene', '442915', (59, 66))	('miR-217', 'Gene', '406999', (37, 44))	('miR-217', 'Gene', (37, 44))
597238	30519852	characterized a novel circRNA termed hsa_circ_0067934 in ESCC tumor tissues and cell lines, finding that high expression level of hsa_circ_0067934 was associated with poor differentiation and TNM stage I-II.	('expression level', 'MPA', (110, 126))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('associated', 'Reg', (151, 161))	('hsa_circ_0067934', 'Var', (130, 146))	('ESCC tumor', 'Disease', 'MESH:D004938', (57, 67))	('poor differentiation', 'CPA', (167, 187))	('TNM', 'Disease', (192, 195))	('ESCC tumor', 'Disease', (57, 67))
597253	30166523	However, acquisition of radioresistance ultimately results in esophageal cancer relapse.	('acquisition', 'Var', (9, 20))	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('radioresistance', 'CPA', (24, 39))	('results in', 'Reg', (51, 61))
597258	30166523	Genetic alteration of CD59 expression modulated the radiosensitivity of esophageal cancer cells to ionizing radiation.	('Genetic alteration', 'Var', (0, 18))	('radiosensitivity', 'CPA', (52, 68))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('CD59', 'Gene', (22, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('modulated', 'Reg', (38, 47))
597281	30166523	Cross-linking of CD59 with other raft components leads to the formation of stabilized membrane patches enriched with Src kinase family proteins, which are thereby centers of signal transduction.	('Src', 'Gene', '6714', (117, 120))	('Cross-linking', 'Var', (0, 13))	('Src', 'Gene', (117, 120))	('CD59', 'Gene', (17, 21))
597305	30166523	At 12 h after irradiation, the number of gammaH2AX foci-positive cells significantly decreased in CD59-sufficient cells compared with that in CD59-deficient cells (Fig.	('gammaH2AX', 'Chemical', '-', (41, 50))	('decreased', 'NegReg', (85, 94))	('CD59-sufficient', 'Var', (98, 113))	('gammaH2AX', 'Protein', (41, 50))
597309	30166523	ATM phosphorylates Chk2 and rapidly inactivates the cyclin B-cdc2 complex, preventing cells with genomic DNA damage from entering mitosis (M phase) via G2/M checkpoint arrest, thus allowing time for DNA damage repair.	('Chk2', 'Gene', '11200', (19, 23))	('genomic DNA', 'Var', (97, 108))	('Chk2', 'Gene', (19, 23))	('cdc2', 'Gene', (61, 65))	('mitosis', 'Disease', (130, 137))	('inactivates', 'NegReg', (36, 47))	('mitosis', 'Disease', 'None', (130, 137))	('ATM', 'Gene', (0, 3))	('preventing', 'NegReg', (75, 85))	('cdc2', 'Gene', '983', (61, 65))	('ATM', 'Gene', '472', (0, 3))
597311	30166523	Furthermore, CD59-deficient cells exhibited higher Chk2 phosphorylation levels at 0.5 and 12 h than CD59-sufficient cells, resulting in downregulated levels of cdc2 at 0.5 h and cyclin B1 at 12 h (Fig.	('cdc2', 'Gene', '983', (160, 164))	('downregulated', 'NegReg', (136, 149))	('CD59-deficient', 'Var', (13, 27))	('cyclin B1', 'Gene', '891', (178, 187))	('higher', 'PosReg', (44, 50))	('Chk2', 'Gene', '11200', (51, 55))	('Chk2', 'Gene', (51, 55))	('levels', 'MPA', (150, 156))	('cdc2', 'Gene', (160, 164))	('phosphorylation levels', 'MPA', (56, 78))	('cyclin B1', 'Gene', (178, 187))
597321	30166523	Notably, Src phosphorylation (Y416) in CD59-deficient cells was unresponsive to irradiation, with Src remaining inactivated both without irradiation and with irradiation after 0.5 and 12 h (Fig.	('Src', 'Gene', '6714', (9, 12))	('Src', 'Gene', (98, 101))	('Src', 'Gene', '6714', (98, 101))	('Y416', 'Chemical', '-', (30, 34))	('Y416', 'Var', (30, 34))	('Src', 'Gene', (9, 12))
597324	30166523	We further detected whether chemical inhibition of Src may enhance the susceptibility of ESCC cells to irradiation.	('chemical inhibition', 'Var', (28, 47))	('enhance', 'PosReg', (59, 66))	('Src', 'Gene', (51, 54))	('Src', 'Gene', '6714', (51, 54))	('susceptibility', 'MPA', (71, 85))	('ESCC', 'Disease', (89, 93))
597327	30166523	Notably, although saracatinib significantly suppressed the growth of colonies represented by their smaller size compared with the control treatment, it failed to inhibit the colony formation ability of Eca109 cells without irradiation (Fig.	('suppressed', 'NegReg', (44, 54))	('saracatinib', 'Chemical', 'MESH:C515233', (18, 29))	('colony formation', 'CPA', (174, 190))	('growth', 'MPA', (59, 65))	('saracatinib', 'Var', (18, 29))
597328	30166523	Moreover, saracatinib significantly induced Eca109 cell into senescence.	('Eca109 cell into senescence', 'CPA', (44, 71))	('induced', 'PosReg', (36, 43))	('saracatinib', 'Var', (10, 21))	('saracatinib', 'Chemical', 'MESH:C515233', (10, 21))
597329	30166523	The percentage of senescent cells was significantly increased by saracatinib treatment (30.4%) compared with that in control treatment (3.1%) at 6 days after irradiation (Figs.	('saracatinib', 'Var', (65, 76))	('increased', 'PosReg', (52, 61))	('saracatinib', 'Chemical', 'MESH:C515233', (65, 76))
597333	30166523	However, patients with a high CD59 level displayed shorter OS and disease-free survival (DFS) after radiotherapy than those with a low CD59 level (Figs.	('high CD59 level', 'Var', (25, 40))	('patients', 'Species', '9606', (9, 17))	('shorter', 'NegReg', (51, 58))	('disease-free survival', 'CPA', (66, 87))
597344	30166523	Consistent with this, the phosphorylation levels of ATM (S1981) and Chk2 (T68) were upregulated, thus leading to reduced levels of cdc2 and cyclin B1 in CD59-deficient ESCC cells after ionizing radiation.	('cyclin B1', 'Gene', '891', (140, 149))	('cyclin B1', 'Gene', (140, 149))	('levels', 'MPA', (121, 127))	('upregulated', 'PosReg', (84, 95))	('S1981', 'Var', (57, 62))	('Chk2', 'Gene', '11200', (68, 72))	('cdc2', 'Gene', '983', (131, 135))	('ATM', 'Gene', '472', (52, 55))	('Chk2', 'Gene', (68, 72))	('phosphorylation levels', 'MPA', (26, 48))	('reduced', 'NegReg', (113, 120))	('ATM', 'Gene', (52, 55))	('cdc2', 'Gene', (131, 135))
597355	30166523	We found that saracatinib increased the susceptibility of ESCC cells to ionizing radiation by elevating DNA damage, reducing colony formation, and inducing cellular senescence.	('DNA damage', 'MPA', (104, 114))	('inducing', 'Reg', (147, 155))	('saracatinib', 'Chemical', 'MESH:C515233', (14, 25))	('colony formation', 'CPA', (125, 141))	('reducing', 'NegReg', (116, 124))	('elevating', 'PosReg', (94, 103))	('saracatinib', 'Var', (14, 25))	('susceptibility', 'MPA', (40, 54))	('cellular senescence', 'CPA', (156, 175))
597414	25416315	Cryotherapy is reported to cause chest pain, dysphagia, and perforation in rare cases.	('Cryotherapy', 'Var', (0, 11))	('dysphagia', 'Disease', (45, 54))	('chest pain', 'Disease', 'MESH:D002637', (33, 43))	('perforation', 'Disease', (60, 71))	('chest pain', 'Disease', (33, 43))	('dysphagia', 'Phenotype', 'HP:0002015', (45, 54))	('pain', 'Phenotype', 'HP:0012531', (39, 43))	('cause', 'Reg', (27, 32))	('chest pain', 'Phenotype', 'HP:0100749', (33, 43))	('dysphagia', 'Disease', 'MESH:D003680', (45, 54))
597431	25416315	Risk factors associated with recurrence include piecemeal resection, multifocal or large lesions, long-segment Barrett's esophagus, lack of adjuvant mucosal ablative therapies (such as APC) of Barrett's esophagus after complete remission, and greater than 10 months' time to achieve complete remission.	('piecemeal resection', 'Disease', (48, 67))	("Barrett's esophagus", 'Disease', (111, 130))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (111, 130))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (193, 212))	('APC', 'Disease', 'MESH:D011125', (185, 188))	('multifocal', 'Var', (69, 79))	('APC', 'Disease', (185, 188))
597449	29152113	The prognostic significance of MCL1 copy number gain in esophageal squamous cell carcinoma MCL1 copy number variations have been reported to be associated with cancer prognosis in several cancers.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('MCL1', 'Gene', '4170', (31, 35))	('associated with', 'Reg', (144, 159))	('MCL1', 'Gene', (91, 95))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('esophageal squamous cell carcinoma', 'Disease', (56, 90))	('gain', 'PosReg', (48, 52))	('MCL1', 'Gene', '4170', (91, 95))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('cancers', 'Disease', (188, 195))	('cancer', 'Disease', (188, 194))	('copy number variations', 'Var', (96, 118))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('copy number', 'Var', (36, 47))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (56, 90))	('MCL1', 'Gene', (31, 35))
597466	29152113	Studies using targeted gene deletion, RNA interference or inducible expression have shown that Mcl1 is essential for the growth of diverse tumors, including acute myeloid leukaemia, lymphomas, papillary thyroid carcinoma, breast cancers, oral squamous cell carcinomas, and non-small-cell lung carcinoma.	('carcinomas', 'Phenotype', 'HP:0030731', (257, 267))	('lymphomas', 'Disease', 'MESH:D008223', (182, 191))	('papillary thyroid carcinoma', 'Disease', (193, 220))	('myeloid leukaemia', 'Disease', 'MESH:D007938', (163, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('lymphomas', 'Phenotype', 'HP:0002665', (182, 191))	('lung carcinoma', 'Disease', 'MESH:D008175', (288, 302))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (193, 220))	('Mcl1', 'Gene', '4170', (95, 99))	('RNA', 'MPA', (38, 41))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (243, 267))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('lymphomas', 'Disease', (182, 191))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (203, 220))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (238, 267))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (163, 180))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (277, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (182, 190))	('tumors', 'Disease', (139, 145))	('lung carcinoma', 'Disease', (288, 302))	('myeloid leukaemia', 'Disease', (163, 180))	('gene deletion', 'Var', (23, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('breast cancers', 'Disease', 'MESH:D001943', (222, 236))	('breast cancers', 'Disease', (222, 236))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (157, 180))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (273, 302))	('oral squamous cell carcinomas', 'Disease', (238, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (193, 220))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('breast cancers', 'Phenotype', 'HP:0003002', (222, 236))	('Mcl1', 'Gene', (95, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
597469	29152113	Gene copy number gain or amplification of MCL1 is frequently found in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (70, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('found', 'Reg', (61, 66))	('Gene copy number gain', 'Var', (0, 21))	('MCL1', 'Gene', '4170', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('solid tumors', 'Disease', (70, 82))	('MCL1', 'Gene', (42, 46))	('amplification', 'Var', (25, 38))
597470	29152113	What is more, MCL1 copy number variations have been reported to be associated with cancer prognosis in papillary thyroid carcinoma and non-small-cell lung carcinoma.	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (103, 130))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (139, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('copy number variations', 'Var', (19, 41))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung carcinoma', 'Disease', 'MESH:D008175', (150, 164))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (103, 130))	('MCL1', 'Gene', (14, 18))	('MCL1', 'Gene', '4170', (14, 18))	('lung carcinoma', 'Disease', (150, 164))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (113, 130))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (135, 164))	('papillary thyroid carcinoma', 'Disease', (103, 130))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('associated with', 'Reg', (67, 82))	('cancer', 'Disease', (83, 89))
597471	29152113	Nevertheless, there have been rare studies addressing the roles of MCL1 copy number variations in ESCC outcomes.	('copy number variations', 'Var', (72, 94))	('MCL1', 'Gene', (67, 71))	('MCL1', 'Gene', '4170', (67, 71))	('ESCC', 'Disease', (98, 102))
597472	29152113	In this study, we detected MCL1 copy number variation in 262 ESCC using tissue microarrays, and searched for correlations between MCL1 copy number gain and prognosis in ESCC; additionally, we compared it in patients with different lymph node status and clinical stage.	('patients', 'Species', '9606', (207, 215))	('MCL1', 'Gene', (130, 134))	('MCL1', 'Gene', '4170', (130, 134))	('ESCC', 'Disease', (61, 65))	('MCL1', 'Gene', (27, 31))	('MCL1', 'Gene', '4170', (27, 31))	('copy number variation', 'Var', (32, 53))
597481	29152113	Sex, age, grade, invasive depth, vessel involvement, nerve involvement, lymph node metastasis, tumor site, smoking and clinical stage were not statistically correlated with high MCL1 gain (P>0.05).	('men', 'Species', '9606', (66, 69))	('high', 'Var', (173, 177))	('gain', 'PosReg', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('MCL1', 'Gene', '4170', (178, 182))	('MCL1', 'Gene', (178, 182))	('men', 'Species', '9606', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
597486	29152113	In patients with lymph node metastasis (n=127), high MCL1 gain tended to associate with poorer DFS (P=0.098) and OS (P=0.133) (Figure 2).	('DFS', 'MPA', (95, 98))	('MCL1', 'Gene', (53, 57))	('MCL1', 'Gene', '4170', (53, 57))	('gain', 'PosReg', (58, 62))	('patients', 'Species', '9606', (3, 11))	('poorer', 'NegReg', (88, 94))	('high', 'Var', (48, 52))
597487	29152113	Among 37 patients with high MCL1 gain, a poorer prognosis was observed, with a median DFS and OS of 18.0 and 23.0 months compared to 20.0 and 26.0 months for 90 patients without high MCL1 gain.	('patients', 'Species', '9606', (9, 17))	('high', 'Var', (23, 27))	('MCL1', 'Gene', '4170', (28, 32))	('patients', 'Species', '9606', (161, 169))	('MCL1', 'Gene', (183, 187))	('MCL1', 'Gene', '4170', (183, 187))	('MCL1', 'Gene', (28, 32))
597488	29152113	However, in patients without lymph node metastasis (n=135), high MCL1 gain tended to associate with better DFS (P=0.090) and OS (P=0.081) (Figure 2).	('patients', 'Species', '9606', (12, 20))	('high', 'Var', (60, 64))	('gain', 'PosReg', (70, 74))	('better', 'PosReg', (100, 106))	('MCL1', 'Gene', (65, 69))	('MCL1', 'Gene', '4170', (65, 69))	('DFS', 'MPA', (107, 110))
597489	29152113	Based on the primary survival curves, we made further analysis, and found significant time point for the bidirectional prognostic value of high MCL1 gain.	('high', 'Var', (139, 143))	('MCL1', 'Gene', (144, 148))	('MCL1', 'Gene', '4170', (144, 148))
597490	29152113	In patients without lymph node metastasis and with disease free survival time greater than or equal to 12 months (n=120), high MCL1 gain was associated with better DFS (P=0.009) and OS (P=0.014) (Figure 2).	('MCL1', 'Gene', (127, 131))	('MCL1', 'Gene', '4170', (127, 131))	('high', 'Var', (122, 126))	('DFS', 'MPA', (164, 167))	('better', 'PosReg', (157, 163))	('gain', 'PosReg', (132, 136))	('patients', 'Species', '9606', (3, 11))
597491	29152113	In patients with lymph node metastasis and with disease free survival time greater than or equal to 29 months (n=36), high MCL1 gain tended to associate with poorer DFS (P=0.007) and OS (P=0.029) (Figure 2 and 3) (Table 3).	('high', 'Var', (118, 122))	('poorer', 'NegReg', (158, 164))	('MCL1', 'Gene', '4170', (123, 127))	('gain', 'PosReg', (128, 132))	('MCL1', 'Gene', (123, 127))	('DFS', 'MPA', (165, 168))	('patients', 'Species', '9606', (3, 11))
597492	29152113	Among 9 patients with high MCL1 gain, a significantly poorer prognosis was observed, with a median DFS and OS of 40.0 and 48.0 months compared to non-reached median survival for 27 patients without high MCL1 gain.	('high', 'Var', (22, 26))	('MCL1', 'Gene', (27, 31))	('MCL1', 'Gene', '4170', (27, 31))	('MCL1', 'Gene', '4170', (203, 207))	('patients', 'Species', '9606', (181, 189))	('MCL1', 'Gene', (203, 207))	('patients', 'Species', '9606', (8, 16))
597494	29152113	Among 33 patients with high MCL1 gain, a poorer prognosis was observed, with a median DFS and OS of 17.0 and 22.0 months compared to 18.0 and 24.0 months for 73 patients without high MCL1 gain.	('patients', 'Species', '9606', (9, 17))	('high', 'Var', (23, 27))	('MCL1', 'Gene', '4170', (28, 32))	('patients', 'Species', '9606', (161, 169))	('MCL1', 'Gene', (183, 187))	('MCL1', 'Gene', '4170', (183, 187))	('MCL1', 'Gene', (28, 32))
597495	29152113	However, in stage I-II patients (n=156), high MCL1 gain tended to associate with better DFS (P=0.142) and OS (P=0.135) (Figure 2).	('MCL1', 'Gene', (46, 50))	('DFS', 'MPA', (88, 91))	('better', 'PosReg', (81, 87))	('gain', 'PosReg', (51, 55))	('patients', 'Species', '9606', (23, 31))	('high', 'Var', (41, 45))	('MCL1', 'Gene', '4170', (46, 50))
597498	29152113	In stage III-IVa patients with disease free survival time greater than or equal to 29 months (n=25), high MCL1 gain tended to associate with poorer DFS (P=0.021) and OS (P=0.068) (Figure 2 and 3) (Table 3).	('MCL1', 'Gene', '4170', (106, 110))	('MCL1', 'Gene', (106, 110))	('gain', 'PosReg', (111, 115))	('poorer', 'NegReg', (141, 147))	('patients', 'Species', '9606', (17, 25))	('stage III-IVa', 'Disease', (3, 16))	('high', 'Var', (101, 105))	('DFS', 'MPA', (148, 151))
597499	29152113	Among 7 patients with high MCL1 gain, a significantly poorer prognosis was observed, with a median DFS and OS of 37.0 and 48.0 months compared to non-reached median survival for 18 patients without high MCL1 gain.	('high', 'Var', (22, 26))	('MCL1', 'Gene', (27, 31))	('MCL1', 'Gene', '4170', (27, 31))	('MCL1', 'Gene', '4170', (203, 207))	('patients', 'Species', '9606', (181, 189))	('MCL1', 'Gene', (203, 207))	('patients', 'Species', '9606', (8, 16))
597500	29152113	In the present retrospective study with FISH method, we investigated the clinicopathologic significance of MCL1 copy number gain in ESCC.	('MCL1', 'Gene', (107, 111))	('MCL1', 'Gene', '4170', (107, 111))	('ESCC', 'Disease', (132, 136))	('copy number gain', 'Var', (112, 128))
597501	29152113	Herein, we firstly observed high MCL1 copy number gain was bidirectional correlated with DFS and OS in ESCC patients with different lymph node status and clinical stage.	('MCL1', 'Gene', (33, 37))	('patients', 'Species', '9606', (108, 116))	('DFS', 'Disease', (89, 92))	('copy number', 'Var', (38, 49))	('gain', 'PosReg', (50, 54))	('ESCC', 'Disease', (103, 107))	('MCL1', 'Gene', '4170', (33, 37))
597510	29152113	In this study, we detected MCL1 copy number variation in TMA from ESCC tumor tissues in a Chinese population, additionally, conducted survival analyses to analyze prognostic values of MCL1 copy number gain on survival.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('MCL1', 'Gene', (27, 31))	('MCL1', 'Gene', '4170', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ESCC', 'Disease', (66, 70))	('MCL1', 'Gene', '4170', (184, 188))	('tumor', 'Disease', (71, 76))	('copy number variation', 'Var', (32, 53))	('MCL1', 'Gene', (184, 188))
597514	29152113	The copy number analysis of 1q21.2 or MCL1 locus inevitably raises important issues about how to define the 'MCL1 gain/amplification' and whether to include the 'low-level gain' in the MCL1 gain or not.	('MCL1', 'Gene', (109, 113))	('copy', 'Var', (4, 8))	('MCL1', 'Gene', '4170', (185, 189))	('MCL1', 'Gene', '4170', (38, 42))	('raises', 'Reg', (60, 66))	('MCL1', 'Gene', (185, 189))	('MCL1', 'Gene', (38, 42))	('MCL1', 'Gene', '4170', (109, 113))
597517	29152113	We found a poorer prognosis was observed in patients with high MCL1 copy number gain, not low copy number gain.	('patients', 'Species', '9606', (44, 52))	('MCL1', 'Gene', '4170', (63, 67))	('copy number gain', 'Var', (68, 84))	('MCL1', 'Gene', (63, 67))	('high', 'Var', (58, 62))
597519	29152113	However, the clinical meaning of MCL1 high copy number gain or low copy number gain needs to be validated in prospective and larger scale study.	('MCL1', 'Gene', (33, 37))	('low', 'NegReg', (63, 66))	('high copy number', 'Var', (38, 54))	('MCL1', 'Gene', '4170', (33, 37))
597523	29152113	Our study categorized the lymph node status with the combined analysis of MCL1 copy number variation, and to examine this classification method in predicting the prognosis of ESCC patients.	('MCL1', 'Gene', '4170', (74, 78))	('MCL1', 'Gene', (74, 78))	('ESCC', 'Disease', (175, 179))	('copy number variation', 'Var', (79, 100))	('patients', 'Species', '9606', (180, 188))
597524	29152113	High MCL1 copy number gain was found in 29.1% of 127 ESCC patients with lymph node metastasis and 29.6% of 135 ESCC patients without lymph node metastasis.	('MCL1', 'Gene', (5, 9))	('ESCC', 'Disease', (53, 57))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (58, 66))	('MCL1', 'Gene', '4170', (5, 9))
597539	29152113	To evaluate the copy number of MCL1, FISH assay was performed on the TMA sections of 5 mm thickness by using MCL1 probe (Abbott Molecular, Abbott Park, IL, USA) that hybridize to 1q21.2 (MCL1) with spectrum gold signal, and Hybridization instrument (Abbott Molecular), according to manufacturer's instruction as previously described.	('hybridize', 'Var', (166, 175))	('men', 'Species', '9606', (244, 247))	('MCL1', 'Gene', (109, 113))	('MCL1', 'Gene', '4170', (109, 113))	('MCL1', 'Gene', (31, 35))	('MCL1', 'Gene', '4170', (187, 191))	('MCL1', 'Gene', '4170', (31, 35))	('MCL1', 'Gene', (187, 191))
597540	29152113	Tumor tissue was scanned to detect hot spots for MCL1 copy numbers by using x400 magnification.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('copy numbers', 'Var', (54, 66))	('MCL1', 'Gene', (49, 53))	('MCL1', 'Gene', '4170', (49, 53))
597543	29152113	An identical protocol is used at our institution for the evaluation of MYC copy number variation, with respect to the number of counted nuclei: (1) high MCL1 gain (>5.0 average MCL1 gene copies/nucleus); (2) low MCL1 gain (2.5 to 5 average MCL1 copies/nucleus); and (3) normal or loss of MCL1 (<2.5 average MCL1 copies/nucleus).	('MCL1', 'Gene', '4170', (288, 292))	('MCL1', 'Gene', '4170', (177, 181))	('gain', 'PosReg', (158, 162))	('gain', 'PosReg', (217, 221))	('low', 'Var', (208, 211))	('MCL1', 'Gene', (288, 292))	('MCL1', 'Gene', (177, 181))	('loss', 'NegReg', (280, 284))	('MYC', 'Gene', '4609', (71, 74))	('MCL1', 'Gene', (212, 216))	('MCL1', 'Gene', '4170', (240, 244))	('MCL1', 'Gene', '4170', (212, 216))	('MCL1', 'Gene', (240, 244))	('MYC', 'Gene', (71, 74))	('MCL1', 'Gene', (307, 311))	('MCL1', 'Gene', '4170', (307, 311))	('MCL1', 'Gene', (153, 157))	('MCL1', 'Gene', '4170', (153, 157))
597552	28042960	As observed in other settings, the presence of SCCA expression clustered in the group of tumors characterized by a lower responsiveness to neoadjuvant treatments.	('presence', 'Var', (35, 43))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('SCCA', 'Gene', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
597589	28042960	Furthermore, subjects with high levels of SCCA-1 in the epidermis were more susceptible to barrier disruption by external stimuli, and this was accompanied with a further subsequent increase of SCCA-1.	('increase', 'PosReg', (182, 190))	('SCCA-1', 'Gene', (194, 200))	('SCCA-1', 'Gene', '6317', (42, 48))	('high', 'Var', (27, 31))	('SCCA-1', 'Gene', (42, 48))	('susceptible', 'Reg', (76, 87))	('SCCA-1', 'Gene', '6317', (194, 200))
597635	28491877	NRH is postulated to be the most common cause of portal hypertension associated with hematologic disorders.	('portal hypertension', 'Phenotype', 'HP:0001409', (49, 68))	('hypertension', 'Disease', 'MESH:D006973', (56, 68))	('hematologic disorders', 'Phenotype', 'HP:0001871', (85, 106))	('NRH', 'Var', (0, 3))	('hematologic disorders', 'Disease', 'MESH:D006402', (85, 106))	('hematologic disorders', 'Disease', (85, 106))	('hypertension', 'Disease', (56, 68))	('hypertension', 'Phenotype', 'HP:0000822', (56, 68))
597682	28491877	One study showed that cumulative exposure to didanosine, stavudine, tenofovir, combinations of didanosine with stavudine, and didanosine with tenofovir was longer in HIV seropositive patients with NRH compared to HIV seropositive patients without NRH.	('didanosine', 'Chemical', 'MESH:D016049', (95, 105))	('HIV seropositive', 'Disease', (166, 182))	('stavudine', 'Chemical', 'MESH:D018119', (111, 120))	('didanosine', 'Chemical', 'MESH:D016049', (45, 55))	('tenofovir', 'Chemical', 'MESH:D000068698', (142, 151))	('combinations', 'Var', (79, 91))	('stavudine', 'Chemical', 'MESH:D018119', (57, 66))	('HIV seropositive', 'Disease', 'MESH:D006679', (166, 182))	('patients', 'Species', '9606', (230, 238))	('HIV seropositive', 'Disease', (213, 229))	('patients', 'Species', '9606', (183, 191))	('NRH', 'Disease', (197, 200))	('didanosine', 'Chemical', 'MESH:D016049', (126, 136))	('HIV seropositive', 'Disease', 'MESH:D006679', (213, 229))	('longer', 'PosReg', (156, 162))	('tenofovir', 'Chemical', 'MESH:D000068698', (68, 77))
597727	26742493	The present meta-analysis found evidence of an association between tooth loss and the risk of developing EC, with the loss of tooth significantly increasing the risk by 30%.	('tooth loss', 'Disease', (67, 77))	('loss', 'Var', (118, 122))	('tooth loss', 'Phenotype', 'HP:0006480', (67, 77))	('tooth loss', 'Disease', 'MESH:D016388', (67, 77))
597758	24758892	This study provides evidence that grand multiparity may confer a protective effect on the risk of death from pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('death', 'Disease', 'MESH:D003643', (98, 103))	('death', 'Disease', (98, 103))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('pancreatic cancer', 'Disease', (109, 126))	('grand multiparity', 'Var', (34, 51))
597793	24758892	Our study results support the hypothesis that multiparity reduces the risk of death from cancer of the pancreas.	('death', 'Disease', 'MESH:D003643', (78, 83))	('reduces', 'NegReg', (58, 65))	('death', 'Disease', (78, 83))	('cancer of the pancreas', 'Disease', (89, 111))	('cancer of the pancreas', 'Phenotype', 'HP:0002894', (89, 111))	('cancer of the pancreas', 'Disease', 'MESH:D010190', (89, 111))	('multiparity', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
597852	23844321	reported in their case-control study among consecutive patients undergoing a standard upper endoscopy that hiatal hernia was the only risk factor to be strongly associated with the development of GERD, and for GERD patients, male gender, age, an increased body mass index (BMI), duration of reflux symptoms, and presence of hiatal hernia were all associated with the development of BE, and finally, the development EAC/high grade dysplasia among patients with BE was associated with male gender, smoking, decreased fruit and vegetable intake, and a long segment of BE, but not with age, BMI, or a hiatal hernia.	('hiatal hernia', 'Disease', 'MESH:D006551', (107, 120))	('GERD', 'Disease', (196, 200))	('associated', 'Reg', (161, 171))	('hiatal hernia', 'Disease', (107, 120))	('hernia', 'Phenotype', 'HP:0100790', (114, 120))	('hiatal hernia', 'Disease', 'MESH:D006551', (597, 610))	('hiatal hernia', 'Phenotype', 'HP:0002036', (324, 337))	('fruit', 'Var', (515, 520))	('hiatal hernia', 'Disease', (597, 610))	('increased body mass index', 'Phenotype', 'HP:0031418', (246, 271))	('GERD', 'Disease', 'MESH:D005764', (196, 200))	('hernia', 'Phenotype', 'HP:0100790', (604, 610))	('hernia', 'Phenotype', 'HP:0100790', (331, 337))	('GERD', 'Disease', (210, 214))	('men', 'Species', '9606', (557, 560))	('hiatal hernia', 'Phenotype', 'HP:0002036', (107, 120))	('dysplasia', 'Disease', (430, 439))	('men', 'Species', '9606', (374, 377))	('hiatal hernia', 'Phenotype', 'HP:0002036', (597, 610))	('dysplasia', 'Disease', 'MESH:D004476', (430, 439))	('BE', 'Phenotype', 'HP:0100580', (382, 384))	('GERD', 'Disease', 'MESH:D005764', (210, 214))	('BE', 'Phenotype', 'HP:0100580', (565, 567))	('patients', 'Species', '9606', (446, 454))	('men', 'Species', '9606', (188, 191))	('BE', 'Phenotype', 'HP:0100580', (460, 462))	('reflux symptoms', 'Phenotype', 'HP:0002020', (291, 306))	('patients', 'Species', '9606', (215, 223))	('hiatal hernia', 'Disease', 'MESH:D006551', (324, 337))	('decreased', 'NegReg', (505, 514))	('hiatal hernia', 'Disease', (324, 337))	('men', 'Species', '9606', (410, 413))	('EAC', 'Phenotype', 'HP:0011459', (415, 418))	('patients', 'Species', '9606', (55, 63))	('increased body mass', 'Phenotype', 'HP:0004324', (246, 265))
597864	23844321	Possible explanations for this inverse correlation between HP infection and EAC development is hypochlorhydria which was induced by chronic atrophic gastritis, having resulted from the infection, thereby reducing acid reflux from the stomach.	('acid reflux', 'Phenotype', 'HP:0002020', (213, 224))	('atrophic gastritis', 'Disease', (140, 158))	('men', 'Species', '9606', (87, 90))	('chronic atrophic gastritis', 'Phenotype', 'HP:0002582', (132, 158))	('hypochlorhydria', 'Disease', 'MESH:D000126', (95, 110))	('acid reflux from the stomach', 'MPA', (213, 241))	('infection', 'Var', (185, 194))	('HP infection', 'Disease', 'MESH:C537262', (59, 71))	('reducing', 'NegReg', (204, 212))	('gastritis', 'Phenotype', 'HP:0005263', (149, 158))	('hypochlorhydria', 'Disease', (95, 110))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))	('HP infection', 'Disease', (59, 71))	('atrophic gastritis', 'Disease', 'MESH:D005757', (140, 158))
597882	23844321	Moreover, the vast majority of duodenal reflux occurs at a pH range of 4 to 7, at which bile acids, the major component of duodenal juice, are capable of damaging the esophageal mucosa.	('bile', 'Var', (88, 92))	('duodenal reflux', 'Disease', (31, 46))	('duodenal reflux', 'Phenotype', 'HP:0002020', (31, 46))	('to 7', 'Species', '1214577', (73, 77))	('damaging', 'NegReg', (154, 162))	('bile acids', 'Chemical', 'MESH:D001647', (88, 98))	('esophageal mucosa', 'MPA', (167, 184))
597890	23844321	These findings together may suggest that bile acids are more harmful to the esophageal squamous epithelial cell than gastric acid and cause more severe mucosal damage, ultimately Barrett's metaplasia, especially when it is combined with weakly acidic environment than gastric acid does.	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (179, 199))	('men', 'Species', '9606', (258, 261))	("Barrett's metaplasia", 'Disease', (179, 199))	('cause', 'Reg', (134, 139))	('mucosal damage', 'Disease', 'MESH:D009059', (152, 166))	('bile acids', 'Chemical', 'MESH:D001647', (41, 51))	('esophageal squamous', 'Disease', 'MESH:D000077277', (76, 95))	('esophageal squamous', 'Disease', (76, 95))	('bile acids', 'Var', (41, 51))	('mucosal damage', 'Disease', (152, 166))
597920	33026449	Patients aged 70 years or older with clinical stage T2 to T4, N0/1, M0/1a unresectable (because of comorbidities, T4 disease, unresectable lymph node, or refused surgery) ESCC were randomized 1:1 to receive RT plus icotinib or RT alone.	('M0/1a', 'Var', (68, 73))	('icotinib', 'Chemical', 'MESH:C531470', (215, 223))	('age', 'Gene', '5973', (9, 12))	('age', 'Gene', (48, 51))	('Patients', 'Species', '9606', (0, 8))	('age', 'Gene', (9, 12))	('age', 'Gene', '5973', (48, 51))
598044	33026449	The response rate was higher (17.6% vs 0%, P = .34) for patients with high EGFR-expressing tumors.	('tumors', 'Disease', (91, 97))	('patients', 'Species', '9606', (56, 64))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('higher', 'PosReg', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('EGFR', 'Gene', '1956', (75, 79))	('response', 'MPA', (4, 12))	('high', 'Var', (70, 74))	('EGFR', 'Gene', (75, 79))
598046	33026449	Another study suggested that EGFR amplification appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (82, 90))	('esophageal cancer', 'Disease', (96, 113))	('gefitinib', 'Chemical', 'MESH:D000077156', (135, 144))	('EGFR', 'Gene', '1956', (29, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('EGFR', 'Gene', (29, 33))	('amplification', 'Var', (34, 47))
598058	31649800	Materials and Methods: The PLCE1 rs2274223 polymorphism was genotyped in 60 patients with gastric cancer and 69 control subjects using polymerase chain reaction and restriction fragment length polymorphisms (PCR-RFLP) methods.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', (90, 104))	('rs2274223', 'Var', (33, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('PLCE1', 'Gene', (27, 32))	('men', 'Species', '9606', (181, 184))	('rs2274223', 'DBSNP_MENTION', 'None', (33, 42))
598060	31649800	Conclusion: The PLCE1 rs2274223 polymorphism was not correlated with gastric cancer in Iranian population.	('gastric cancer', 'Disease', (69, 83))	('rs2274223', 'DBSNP_MENTION', 'None', (22, 31))	('correlated', 'Reg', (53, 63))	('PLCE1', 'Gene', (16, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('rs2274223', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
598063	31649800	Recent evidence has shown that genetic variants, especially single nucleotide polymorphisms (SNPs), can mediate the effect of environmental risk factors through modifying functions of various signaling pathways involved in gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (223, 245))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (223, 245))	('signaling pathways', 'Pathway', (192, 210))	('modifying', 'Reg', (161, 170))	('functions', 'MPA', (171, 180))	('single nucleotide polymorphisms', 'Var', (60, 91))
598064	31649800	Different SNPs in PLCE1 gene are shown to have correlation with the risk of different type of cancers including esophageal and gastric - .	('type of cancers', 'Disease', 'MESH:D009369', (86, 101))	('correlation with', 'Reg', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('type of cancers', 'Disease', (86, 101))	('SNPs', 'Var', (10, 14))	('PLCE1', 'Gene', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('esophageal', 'Disease', (112, 122))	('gastric -', 'Disease', (127, 136))
598067	31649800	Recent studies have identified a new susceptibility for single nucleotide polymorphism (SNP) (rs2274223: A5780G), located in exon 26 of PLCE1, which may correlate with the risk of esophageal and gastric cancers,  .For instance, Wang et al.	('rs2274223', 'Var', (94, 103))	('gastric cancers', 'Disease', 'MESH:D013274', (195, 210))	('single nucleotide polymorphism', 'Var', (56, 86))	('gastric cancers', 'Disease', (195, 210))	('gastric cancers', 'Phenotype', 'HP:0012126', (195, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('rs2274223', 'DBSNP_MENTION', 'None', (94, 103))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('A5780G', 'Mutation', 'rs2274223', (105, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (195, 209))
598068	31649800	reported a relatively high correlation between esophageal squamous cell carcinoma and rs2274223 A>G polymorphism in Chinese population .	('esophageal squamous cell carcinoma', 'Disease', (47, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('rs2274223', 'Var', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (47, 81))	('rs2274223', 'DBSNP_MENTION', 'None', (86, 95))
598069	31649800	demonstrated a close relationship between rs2274223 polymorphism and increased risk of gastric adenocarcinoma and esophageal squamous cell carcinoma in Chinese population.	('rs2274223', 'Var', (42, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('polymorphism', 'Var', (52, 64))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (87, 109))	('rs2274223', 'DBSNP_MENTION', 'None', (42, 51))	('gastric adenocarcinoma', 'Disease', (87, 109))	('esophageal squamous cell carcinoma', 'Disease', (114, 148))
598070	31649800	In this study, we attempted to evaluate the correlation between the PLCE1 (rs2274223 A>G) polymorphism and the risk of gastric adenocarcinoma in northern Iran.	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('rs2274223', 'DBSNP_MENTION', 'None', (75, 84))	('gastric adenocarcinoma', 'Disease', (119, 141))	('rs2274223', 'Var', (75, 84))	('PLCE1', 'Gene', (68, 73))
598076	31649800	SNP Selection  The functional rs2274223 SNP was selected in PLCE1 gene for genotyping based on previous published data and the NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/build 131).	('rs2274223', 'Var', (30, 39))	('PLCE1', 'Gene', (60, 65))	('rs2274223', 'DBSNP_MENTION', 'None', (30, 39))
598077	31649800	PCR primers and amplification conditions   Exon 26 of PLCE1 gene was amplified using polymerase chain reaction followed by restriction fragment length polymorphisms (PCR-RFLP) methods to identify genotypes of rs2274223 A>G polymorphism.	('PLCE1', 'Gene', (54, 59))	('rs2274223', 'Var', (209, 218))	('rs2274223', 'DBSNP_MENTION', 'None', (209, 218))
598084	31649800	As indicated in Table 3, the variant rs2274223 was no significantly associated with gastric cancer [OR=2.04; CI 0.667-6.251; p=0.221 (for the GG genotypes vs. the AA genotypes) and OR=1.45; CI 0.626-3.398; p=0.382 (for the GA genotypes vs. the AA genotypes)].	('rs2274223', 'DBSNP_MENTION', 'None', (37, 46))	('gastric cancer', 'Disease', (84, 98))	('rs2274223', 'Var', (37, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
598085	31649800	In this case-control study, we considered the correlation between a potentially functional SNP of PLCE1 (rs2274223) and the risk of gastric adenocarcinoma in Iranian population.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('rs2274223', 'DBSNP_MENTION', 'None', (105, 114))	('PLCE1', 'Gene', (98, 103))	('rs2274223', 'Var', (105, 114))	('gastric adenocarcinoma', 'Disease', (132, 154))
598087	31649800	Numerous studies have investigated several potentially functional SNPs of PLCE1 in various cancers such as gastric, esophagus and colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('PLCE1', 'Gene', (74, 79))	('colorectal cancers', 'Disease', (130, 148))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('gastric', 'Disease', (107, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('esophagus', 'Disease', (116, 125))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('colorectal cancers', 'Disease', 'MESH:D015179', (130, 148))	('SNPs', 'Var', (66, 70))
598088	31649800	investigated the correlation between the rs2274223 A>G and the risk of esophagus cancer in 2,240 patients with gastric cancer.	('rs2274223', 'Var', (41, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('esophagus cancer', 'Disease', (71, 87))	('rs2274223', 'DBSNP_MENTION', 'None', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('esophagus cancer', 'Disease', 'MESH:D004938', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
598089	31649800	considered the correlation between the PLCE1 rs2274223 and the risk of gastric cancer in 1059 patients with pathologically confirmed gastric adenocarcinoma and 1240 frequency-matched healthy controls.	('rs2274223', 'Var', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PLCE1', 'Gene', (39, 44))	('gastric adenocarcinoma', 'Disease', (133, 155))	('rs2274223', 'DBSNP_MENTION', 'None', (45, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))
598090	31649800	investigated the relationship between the rs2274223 with esophagus cancer and its tumorigenesis in 2,031 Chinese patients with gastric cancer and 2,044 controls.	('rs2274223', 'Var', (42, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('tumorigenesis', 'CPA', (82, 95))	('esophagus cancer', 'Disease', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('rs2274223', 'DBSNP_MENTION', 'None', (42, 51))
598091	31649800	also reported a significant correlation between rs2274223 and the risk of colorectal cancer in Turkish population (OR = 2.018).	('rs2274223', 'Var', (48, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('rs2274223', 'DBSNP_MENTION', 'None', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colorectal cancer', 'Disease', (74, 91))
598092	31649800	In a meta-analysis study on 13676 patients with gastric cancer, it has been concluded that there is a significant relationship between PLCE1 rs2274223 polymorphisms and the incidence and increased risk of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('rs2274223', 'Var', (141, 150))	('PLCE1', 'Gene', (135, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('gastric cancer', 'Disease', (205, 219))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('polymorphisms', 'Var', (151, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (205, 219))	('rs2274223', 'DBSNP_MENTION', 'None', (141, 150))
598093	31649800	investigated the relationship between four functional SNPs in PLCE1 gene (including rs12263737, rs2274223, rs11187842 and rs753724) and the risk of esophagus cancer in 222 Chinese cases and 326 controls.	('rs2274223', 'Var', (96, 105))	('esophagus cancer', 'Disease', (148, 164))	('rs753724', 'Mutation', 'rs753724', (122, 130))	('rs11187842', 'Var', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('rs11187842', 'Mutation', 'rs11187842', (107, 117))	('rs12263737', 'Var', (84, 94))	('rs2274223', 'DBSNP_MENTION', 'None', (96, 105))	('rs12263737', 'Mutation', 'rs12263737', (84, 94))	('rs753724', 'Var', (122, 130))	('PLCE1', 'Gene', (62, 67))
598094	31649800	The results demonstrated that these polymorphisms are closely associated with higher risk of esophageal cancer.	('polymorphisms', 'Var', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('associated', 'Reg', (62, 72))	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))
598095	31649800	In other research, genetic variation in PLCE1 and the risk of upper gastrointestinal cancers and esophageal adenocarcinoma was evaluated in Caucasian populations.	('esophageal adenocarcinoma', 'Disease', (97, 122))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (97, 122))	('upper gastrointestinal cancers', 'Disease', (62, 92))	('upper gastrointestinal cancer', 'Disease', 'MESH:D005770', (62, 91))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('genetic variation', 'Var', (19, 36))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (68, 91))	('PLCE1', 'Gene', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('upper gastrointestinal cancers', 'Disease', 'MESH:D005770', (62, 92))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (97, 122))
598096	31649800	The results showed that rs4072037 SNP in PLCE1 is associated with higher risk of upper gastrointestinal cancer, while rs2274223 and rs4072037 were correlated with increased risk of esophageal adenocarcinoma.	('PLCE1', 'Gene', (41, 46))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (87, 110))	('rs4072037', 'Mutation', 'rs4072037', (24, 33))	('rs2274223', 'DBSNP_MENTION', 'None', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs2274223', 'Var', (118, 127))	('rs4072037', 'Var', (132, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('rs4072037', 'Mutation', 'rs4072037', (132, 141))	('rs4072037', 'DBSNP_MENTION', 'None', (132, 141))	('esophageal adenocarcinoma', 'Disease', (181, 206))	('upper gastrointestinal cancer', 'Disease', (81, 110))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (181, 206))	('rs4072037', 'Var', (24, 33))	('rs4072037', 'DBSNP_MENTION', 'None', (24, 33))
598097	31649800	A significant correlation was observed between three functional SNPs in PLCE1 gene (rs2274223 A>G, rs3765524 C>T and rs7922612 C>T) and gastric cancer.	('PLCE1', 'Gene', (72, 77))	('rs2274223', 'DBSNP_MENTION', 'None', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('rs2274223', 'Var', (84, 93))	('rs3765524 C>T', 'Var', (99, 112))	('gastric cancer', 'Disease', (136, 150))	('rs3765524', 'Mutation', 'rs3765524', (99, 108))	('rs7922612 C>T', 'Var', (117, 130))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('rs7922612', 'Mutation', 'rs7922612', (117, 126))
598098	31649800	The effect of three different SNPs in PLCE1 gene (rs2274223A> G, rs3765524C>T and rs7922612C>T) and gastric cancer was also evaluated in 135 cases and 195 healthy controls in Kashmir Valley population.	('rs2274223A> G', 'DBSNP_MENTION', 'None', (50, 63))	('rs3765524C>T', 'Var', (65, 77))	('rs2274223A> G', 'Var', (50, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('rs7922612C>T', 'DBSNP_MENTION', 'None', (82, 94))	('rs3765524C>T', 'DBSNP_MENTION', 'None', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('PLCE1', 'Gene', (38, 43))	('rs7922612C>T', 'Var', (82, 94))	('gastric cancer', 'Disease', (100, 114))
598099	31649800	Although G2274223, T3765524, and T7922612 haplotypes were significantly correlated with higher risk of gastric cancer, these polymorphisms were not independently correlated with gastric cancer and several associated factors such as smoking and family history may be involved.	('T7922612', 'Var', (33, 41))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('T3765524', 'Var', (19, 27))	('T3765524', 'Chemical', 'MESH:D014221', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric cancer', 'Disease', (178, 192))	('G2274223', 'Var', (9, 17))	('gastric cancer', 'Disease', (103, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (178, 192))
598100	31649800	They demonstrated that there is a relationship between rs2274223 A>G polymorphism (all genotypes of AA, AG and GG) and disease stage, which was most popular among Asian populations.	('rs2274223', 'DBSNP_MENTION', 'None', (55, 64))	('relationship', 'Reg', (34, 46))	('rs2274223', 'Var', (55, 64))	('disease', 'Disease', (119, 126))
598101	31649800	In another investigation, the correlation between rs2274223 polymorphism was considered in 380 esophageal cancer patients and 380 healthy controls.	('rs2274223', 'DBSNP_MENTION', 'None', (50, 59))	('esophageal cancer', 'Disease', (95, 112))	('rs2274223', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
598102	31649800	The results revealed that the rs2274223 is significantly associated with increased risk of the cancer.	('rs2274223', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('rs2274223', 'DBSNP_MENTION', 'None', (30, 39))	('cancer', 'Disease', (95, 101))
598104	31649800	For these reasons, some studies considered rs2274223 SNP as a sensitive biomarker for gastric cancer.	('rs2274223', 'DBSNP_MENTION', 'None', (43, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('rs2274223', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (86, 100))
598105	31649800	investigated the relation between rs2274223G, rs3203713G and rs11599672T polymorphisms in patients with head and neck cancers, but did not find any significant correlation.	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('rs2274223G', 'Var', (34, 44))	('rs3203713G', 'Var', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('head and neck cancers', 'Disease', 'MESH:D006258', (104, 125))	('rs11599672', 'Mutation', 'rs11599672', (61, 71))	('head and neck cancers', 'Phenotype', 'HP:0012288', (104, 125))	('rs11599672T', 'Var', (61, 72))	('rs3203713', 'Mutation', 'rs3203713', (46, 55))
598106	31649800	In summary, in this case-control study, we investigated the correlation between the functional rs2274223 SNP in PLCE1 gene and increased risk of gastric cancer for the first time in Iranian population.	('rs2274223', 'DBSNP_MENTION', 'None', (95, 104))	('PLCE1', 'Gene', (112, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (145, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('rs2274223', 'Var', (95, 104))	('gastric cancer', 'Disease', (145, 159))
598107	31649800	Although previous studies reported a close relationship between this SNP and enhanced risk of different cancers, we could not find a significant correlation between rs2274223 SNP in PLCE1 gene and the risk of gastric cancer, tumor characteristics, and disease stage.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs2274223', 'DBSNP_MENTION', 'None', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('gastric cancer', 'Disease', (209, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (209, 223))	('rs2274223', 'Var', (165, 174))	('PLCE1', 'Gene', (182, 187))
598146	31331297	For the T2 N2, T3 N1-2 and T4aN0-1 ESCC, the patients were classified as stage IIIb.	('patients', 'Species', '9606', (45, 53))	('T3 N1-2', 'Var', (15, 22))	('T4aN0-1', 'Var', (27, 34))	('T2 N2', 'Var', (8, 13))
598147	31331297	For the T4bN0-3 and T1-4 N3 ESCC, the patients were classified as Iva.	('T1-4 N3', 'Var', (20, 27))	('T4bN0-3', 'Var', (8, 15))	('patients', 'Species', '9606', (38, 46))
598205	31331297	Hu et.al, studied 218 ESCC patients and found that the patients with LMR > 2.57 had a better 5-year OS and disease-free survival than the patients with LMR < 2.57.	('LMR > 2.57', 'Var', (69, 79))	('OS', 'Chemical', '-', (100, 102))	('LMR', 'Chemical', '-', (69, 72))	('ESCC', 'Disease', (22, 26))	('better', 'PosReg', (86, 92))	('LMR', 'Chemical', '-', (152, 155))	('patients', 'Species', '9606', (27, 35))	('disease-free survival', 'CPA', (107, 128))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (138, 146))
598331	31057700	The results revealed that the group who received supercharged colon had a significantly lower rate of conduit necrosis and anastomotic leak.	('anastomotic leak', 'Disease', 'MESH:D057868', (123, 139))	('necrosis', 'Disease', (110, 118))	('conduit necrosis', 'Phenotype', 'HP:0010885', (102, 118))	('anastomotic leak', 'Disease', (123, 139))	('necrosis', 'Disease', 'MESH:D009336', (110, 118))	('lower', 'NegReg', (88, 93))	('supercharged', 'Var', (49, 61))
598387	27770376	Both T1a and T1b ESCC are designated as superficial esophageal neoplasms (SENs) regardless of lymph node or distant organ metastasis.	('superficial esophageal neoplasms', 'Disease', (40, 72))	('superficial esophageal neoplasms', 'Disease', 'MESH:D004938', (40, 72))	('T1b', 'Var', (13, 16))	('ESCC', 'Disease', (17, 21))	('T1a', 'Var', (5, 8))	('neoplasms', 'Phenotype', 'HP:0002664', (63, 72))	('esophageal neoplasms', 'Phenotype', 'HP:0100751', (52, 72))
598412	27770376	Therefore, the shape and size of the EVs at ESD were F-1 in five procedures (SEN 1, 2, 3, 5, and 7) and F-2 in one procedure (SEN 6).	('F-2', 'Gene', (104, 107))	('SEN 6', 'Gene', (126, 131))	('F-2', 'Gene', '2147', (104, 107))	('F-1', 'Var', (53, 56))	('SEN 6', 'Gene', '6411', (126, 131))	('EVs', 'Phenotype', 'HP:0002040', (37, 40))	('SEN 1, 2, 3', 'Gene', '10934;6409;6410', (77, 88))
598559	25701246	In species-specific analyses, after Bonferroni correction, two species on the HOMIM array were significantly associated with current smoking status D. invisus and M. micronuciformis.	('associated', 'Reg', (109, 119))	('M. micronuciformis', 'Species', '187326', (163, 181))	('M. micronuciformis', 'Var', (163, 181))	('D. invisus', 'Species', '218538', (148, 158))
598584	25701246	Specific individual bacterial species, D. invisus and M. micronuciformis, were also highly associated with current smoking.	('M. micronuciformis', 'Species', '187326', (54, 72))	('M. micronuciformis', 'Var', (54, 72))	('associated', 'Reg', (91, 101))	('D. invisus', 'Species', '218538', (39, 49))	('current smoking', 'Disease', (107, 122))
598613	27066445	The studies were performed in the Sleep Laboratory at Nationwide Children's Hospital with simultaneous EPM-MII (with no sedation or sleep deprivation) for 7 to 10 hours.	('sleep deprivation', 'Disease', (132, 149))	('Children', 'Species', '9606', (65, 73))	('sleep deprivation', 'Disease', 'MESH:D012892', (132, 149))	('EPM-MII', 'Var', (103, 110))
598672	27066445	Poor sleep quality may also enhance esophageal sensitivity, making arousals due to pain more frequent with GER episodes because of hyperalgesia.	('esophageal sensitivity', 'MPA', (36, 58))	('pain', 'Disease', 'MESH:D010146', (83, 87))	('pain', 'Disease', (83, 87))	('hyperalgesia', 'Phenotype', 'HP:0031005', (131, 143))	('GER', 'Gene', '59330', (107, 110))	('Poor sleep', 'Phenotype', 'HP:0002360', (0, 10))	('pain', 'Phenotype', 'HP:0012531', (83, 87))	('Poor', 'Var', (0, 4))	('GER', 'Gene', (107, 110))	('arousals', 'Disease', (67, 75))	('enhance', 'PosReg', (28, 35))	('GER', 'Phenotype', 'HP:0002020', (107, 110))	('hyperalgesia', 'Disease', 'MESH:D006930', (131, 143))	('hyperalgesia', 'Disease', (131, 143))
598783	21128279	By using FF-PE tissues, aberrant miRNA expression patterns have been described in a variety of hematological and solid malignancies.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('described', 'Reg', (69, 78))	('malignancies', 'Disease', (119, 131))	('aberrant', 'Var', (24, 32))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))
598884	33552118	We used seven data sets, including six GeneChips (GPL570, GPL571, GSE23400, GSE32424, GSE45168, and GSE70409), and RNA-seq data (2,307 cases in total, with 620 cases of ESCC and 1,687 non-cancer cases) to investigate the expression of PTTG1 in ESCC.	('PTTG1', 'Gene', (235, 240))	('GPL570', 'Var', (50, 56))	('ESCC', 'Disease', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('GSE45168', 'Var', (86, 94))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('GSE70409', 'Var', (100, 108))	('ESCC', 'Disease', (244, 248))	('cancer', 'Disease', (188, 194))	('GSE32424', 'Var', (76, 84))	('GSE23400', 'Var', (66, 74))
598885	33552118	After research, it was found that the expression of PTTG1 in four high-throughput platforms (GPL570, GSE23400, GSE70409, and TCGA-GTEx) was significantly higher than in the non-cancer control group (Figures 4A-F,M).	('GSE23400', 'Var', (101, 109))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('expression', 'MPA', (38, 48))	('higher', 'PosReg', (154, 160))	('PTTG1', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('GSE70409', 'Var', (111, 119))
598886	33552118	Further analysis of public RNA-seq data showed that the average expression of PTTG1 in ESCC was 11.5794 +- 0.7270, which was significantly higher than that of the non-cancer control group (7.5575 +- 2.5127, P < 0.001).	('expression', 'MPA', (64, 74))	('PTTG1', 'Gene', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('ESCC', 'Disease', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('higher', 'PosReg', (139, 145))	('11.5794 +- 0.7270', 'Var', (96, 113))
598889	33552118	The survival condition of patients with high PTTG1 expression was worse than that of patients with low PTTG1 expression (HR = 1.29), but no significant statistical difference was found (Figure 4O).	('high', 'Var', (40, 44))	('worse', 'NegReg', (66, 71))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (85, 93))	('survival condition', 'CPA', (4, 22))	('PTTG1', 'Gene', (45, 50))	('expression', 'Var', (51, 61))
598909	33552118	In vitro, knocking down PTTG1 in EC-1 and Eca-109 cell lines could inhibit EMT, migration, and metastasis.	('knocking down', 'Var', (10, 23))	('rat', 'Species', '10116', (83, 86))	('inhibit', 'NegReg', (67, 74))	('EC-1', 'CellLine', 'CVCL:5V05', (33, 37))	('PTTG1', 'Gene', (24, 29))
598910	33552118	In our study, we have confirmed that PTTG1 was significantly overexpressed in ESCC tissues, and in the prognosis analysis, the survival condition of patients with high PTTG1 expression was worse than that of patients with low PTTG1 expression (HR = 1.29), but no significant statistical difference was found.	('high', 'Var', (163, 167))	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (208, 216))	('survival', 'CPA', (127, 135))	('expression', 'MPA', (174, 184))	('PTTG1', 'Gene', (168, 173))	('overexpressed', 'PosReg', (61, 74))
598922	33552118	However, only one relevant study reported its role in tumors, showing that genetic changes in SLC25A17 (CNV deletion) were closely associated with the overall survival rate and relapse-free survival rate of neuroblastoma patients.	('SLC25A17', 'Gene', (94, 102))	('patients', 'Species', '9606', (221, 229))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('neuroblastoma', 'Disease', (207, 220))	('associated', 'Reg', (131, 141))	('relapse-free survival', 'CPA', (177, 198))	('SLC25A17', 'Gene', '10478', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('rat', 'Species', '10116', (168, 171))	('neuroblastoma', 'Phenotype', 'HP:0003006', (207, 220))	('genetic changes', 'Var', (75, 90))	('rat', 'Species', '10116', (199, 202))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))	('neuroblastoma', 'Disease', 'MESH:D009447', (207, 220))
598926	33552118	This results in cells in a pre-tumor state, and the lack of p53 or p16 tumor suppressor proteins and the loss of p19 would cause odontogenic tumors and metastases to local lymph nodes and lungs.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('p16', 'Gene', '1029', (67, 70))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('lack', 'NegReg', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('odontogenic tumors', 'Disease', (129, 147))	('odontogenic tumors', 'Phenotype', 'HP:0100612', (129, 147))	('p19', 'Gene', '1029', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('odontogenic tumors', 'Disease', 'MESH:D009808', (129, 147))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('metastases', 'Disease', (152, 162))	('loss', 'Var', (105, 109))	('p53', 'Gene', '7157', (60, 63))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (141, 146))	('cause', 'Reg', (123, 128))	('p53', 'Gene', (60, 63))	('p19', 'Gene', (113, 116))	('p16', 'Gene', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
598931	33552118	The research team also proved that ERH knockdown could inhibit the transfer of BUC T24 cells in vitro and in vivo through nude mice tail vein metastasis experiments.	('knockdown', 'Var', (39, 48))	('ERH', 'Gene', (35, 38))	('nude mice', 'Species', '10090', (122, 131))	('ERH', 'Gene', '2079', (35, 38))	('transfer of BUC T24 cells', 'CPA', (67, 92))	('inhibit', 'NegReg', (55, 62))
598932	33552118	They found that ERH gene knockdown suppressed MYC-mediated migration and invasion in bladder cancer T24 cells.	('ERH', 'Gene', '2079', (16, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('bladder cancer', 'Disease', 'MESH:D001749', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MYC', 'Gene', (46, 49))	('suppressed', 'NegReg', (35, 45))	('ERH', 'Gene', (16, 19))	('bladder cancer', 'Disease', (85, 99))	('invasion', 'CPA', (73, 81))	('rat', 'Species', '10116', (62, 65))	('knockdown', 'Var', (25, 34))	('MYC', 'Gene', '4609', (46, 49))
598944	29926523	Long noncoding RNAs (lncRNAs) dysregulation have been reported to involve in various human cancers, which highlights the potential of lncRNAs used as novel biomarkers for cancer diagnosis.	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('dysregulation', 'Var', (30, 43))	('ncRNA', 'Gene', (22, 27))	('ncRNA', 'Gene', '54719', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (91, 97))	('cancers', 'Disease', (91, 98))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Disease', (171, 177))	('ncRNA', 'Gene', '54719', (22, 27))	('involve', 'Reg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('ncRNA', 'Gene', (135, 140))	('human', 'Species', '9606', (85, 90))
598948	29926523	Moreover, copy number variation analyses revealed that genomic loci copy number amplification or deletion might contribute to these lncRNAs dysregulation.	('ncRNA', 'Gene', (133, 138))	('contribute', 'Reg', (112, 122))	('ncRNA', 'Gene', '54719', (133, 138))	('copy number amplification', 'Var', (68, 93))	('deletion', 'Var', (97, 105))
598950	29926523	Further experimental validation revealed that knockdown of DUXAP8 could impair esophageal cancer cells proliferation and invasion in vitro.	('esophageal cancer', 'Disease', (79, 96))	('knockdown', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('DUXAP8', 'Gene', (59, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('DUXAP8', 'Gene', '503637', (59, 65))	('invasion in vitro', 'CPA', (121, 138))	('impair', 'NegReg', (72, 78))
598959	29926523	Four public esophageal cancer microarray profiling datasets (GSE45670,23 GSE53622,12 GSE89102, GSE92396) were downloaded from the Gene Expression Omnibus (GEO).	('public esophageal cancer', 'Disease', 'MESH:D004938', (5, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('GSE45670,23', 'Var', (61, 72))	('public esophageal cancer', 'Disease', (5, 29))
598963	29926523	Then, all of lncRNAs genomic regions were mapped to the GISTIC peaks, and GISTIC 2.0 was used to annotate and determine the significant recurrent of each lncRNAs genomic loci copy number amplifications or deletions.	('deletions', 'Var', (205, 214))	('ncRNA', 'Gene', '54719', (155, 160))	('copy number amplifications', 'Var', (175, 201))	('ncRNA', 'Gene', (14, 19))	('ncRNA', 'Gene', (155, 160))	('ncRNA', 'Gene', '54719', (14, 19))
598977	29926523	To identify the differentially expressed lncRNAs in esophageal cancer tissues, we firstly downloaded the TCGA esophageal cancer and normal tissue samples RNA sequencing data and four microarray datasets (GSE45670, GSE53622, GSE89102, and GSE92396) from GEO.	('GSE92396', 'Var', (238, 246))	('GSE45670', 'Var', (204, 212))	('GSE89102', 'Var', (224, 232))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (52, 69))	('GSE53622', 'Var', (214, 222))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('esophageal cancer', 'Disease', (110, 127))	('ncRNA', 'Gene', (42, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('ncRNA', 'Gene', '54719', (42, 47))
598978	29926523	The TCGA data consist of 369 esophageal cancer samples and 24 normal tissue samples, while the GSE45670 dataset consists of 28 tumor and 10 normal samples; GSE53622 consists of 60 paired esophageal cancer samples; GSE89102 consists of five paired esophageal cancer samples; GSE92396 consists of 12 tumor and nine normal samples.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (298, 303))	('esophageal cancer', 'Disease', (247, 264))	('tumor', 'Disease', (127, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (247, 264))	('esophageal cancer', 'Disease', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('esophageal cancer', 'Disease', (187, 204))	('GSE89102', 'Var', (214, 222))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
598986	29926523	To date, a growing number of studies reveal that genetic alterations, epigenetic modifications, and even transcription factors are involved in regulation of lncRNAs expression in diverse cancer cells.	('ncRNA', 'Gene', '54719', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('ncRNA', 'Gene', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('epigenetic modifications', 'Var', (70, 94))	('involved', 'Reg', (131, 139))
598990	29926523	These results indicate that genomic copy number variations are related to part of those lncRNAs dysregulation in human esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('ncRNA', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ncRNA', 'Gene', '54719', (89, 94))	('related', 'Reg', (63, 70))	('genomic copy number variations', 'Var', (28, 58))	('human', 'Species', '9606', (113, 118))	('esophageal cancer', 'Disease', (119, 136))
599005	29926523	The results of qRT-PCR showed that both two siRNAs could significantly decrease DUXAP8 expression in KYSE510 and KYSE330 cells (Figure 5C).	('DUXAP8', 'Gene', (80, 86))	('decrease', 'NegReg', (71, 79))	('DUXAP8', 'Gene', '503637', (80, 86))	('expression', 'MPA', (87, 97))	('KYSE330', 'Var', (113, 120))
599006	29926523	Furthermore, CCK8 assays showed that knockdown of DUXAP8 expression could impair KYSE510 and KYSE330 cells proliferation (Figure 5D) and transwell assays showed that downregulation of DUXAP8 inhibited KYSE510 cells migration and invasion ability, which is consistent with our go analyses results.	('impair', 'NegReg', (74, 80))	('inhibited', 'NegReg', (191, 200))	('DUXAP8', 'Gene', (184, 190))	('knockdown', 'Var', (37, 46))	('DUXAP8', 'Gene', '503637', (50, 56))	('DUXAP8', 'Gene', '503637', (184, 190))	('KYSE510 cells migration', 'CPA', (201, 224))	('DUXAP8', 'Gene', (50, 56))	('invasion ability', 'CPA', (229, 245))	('downregulation', 'NegReg', (166, 180))
599015	29926523	Further somatic copy number variation analyses revealed that lncRNAs genome loci copy number amplifications or deletions are involved in part of lncRNAs dysregulation in esophageal cancer tissues, such as PVT1, LINC00887, LINC00964, LINC01415, and WEE2-AS1.	('WEE2-AS1', 'Gene', (248, 256))	('ncRNA', 'Gene', '54719', (62, 67))	('ncRNA', 'Gene', (146, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))	('PVT1', 'Gene', (205, 209))	('PVT1', 'Gene', '5820', (205, 209))	('ncRNA', 'Gene', '54719', (146, 151))	('esophageal cancer', 'Disease', (170, 187))	('LINC01415', 'Gene', (233, 242))	('LINC00964', 'Gene', (222, 231))	('LINC00887', 'Gene', '100131551', (211, 220))	('LINC01415', 'Gene', '100132501', (233, 242))	('deletions', 'Var', (111, 120))	('involved', 'Reg', (125, 133))	('LINC00964', 'Gene', '157381', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('WEE2-AS1', 'Gene', '285962;494551;5729', (248, 256))	('copy number amplifications', 'Var', (81, 107))	('ncRNA', 'Gene', (62, 67))	('LINC00887', 'Gene', (211, 220))
599021	29926523	As well as our findings, Sun et al24 reported that DUXAP8 promotes cell proliferation and invasion through repressing EGR1 and RHOB expression in human non small cell lung cancer; Ma et al25 found that DUXAP8 promotes cell proliferation through epigenetically silencing PLEKHO1 expression in gastric cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (156, 178))	('gastric cancer', 'Disease', (292, 306))	('EGR1', 'Gene', (118, 122))	('PLEKHO1', 'Gene', '51177', (270, 277))	('RHOB', 'Gene', '388', (127, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (292, 306))	('EGR1', 'Gene', '1958', (118, 122))	('PLEKHO1', 'Gene', (270, 277))	('DUXAP8', 'Gene', (202, 208))	('RHOB', 'Gene', (127, 131))	('small cell lung cancer', 'Disease', 'MESH:D055752', (156, 178))	('DUXAP8', 'Gene', '503637', (202, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('DUXAP8', 'Gene', (51, 57))	('DUXAP8', 'Gene', '503637', (51, 57))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (152, 178))	('promotes', 'PosReg', (209, 217))	('small cell lung cancer', 'Disease', (156, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (292, 306))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('human', 'Species', '9606', (146, 151))	('cell proliferation', 'CPA', (218, 236))	('epigenetically silencing', 'Var', (245, 269))
599023	29926523	Similarly, we also found that knockdown of DUXAP8 could impair esophageal cancer cells proliferation and invasion, and DUXAP8 expression is positively related to oncogenes MAGEA4 and GABRA3 expression, but negatively related to tumor suppressors INPP5A and TIMP4.	('DUXAP8', 'Gene', '503637', (119, 125))	('INPP5A', 'Gene', '3632', (246, 252))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('GABRA3', 'Gene', '2556', (183, 189))	('MAGEA4', 'Gene', '4103', (172, 178))	('knockdown', 'Var', (30, 39))	('INPP5A', 'Gene', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('invasion', 'CPA', (105, 113))	('GABRA3', 'Gene', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('DUXAP8', 'Gene', (43, 49))	('TIMP4', 'Gene', (257, 262))	('TIMP4', 'Gene', '7079', (257, 262))	('DUXAP8', 'Gene', '503637', (43, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('MAGEA4', 'Gene', (172, 178))	('esophageal cancer', 'Disease', (63, 80))	('negatively', 'NegReg', (206, 216))	('impair', 'NegReg', (56, 62))	('tumor', 'Disease', (228, 233))	('DUXAP8', 'Gene', (119, 125))
599032	26986156	Immunohistochemical staining confirmed the cyst was positive for carbohydrate antigen 199 (CA199) and carbohydrate antigen 125 (CA125).	('carbohydrate antigen 125', 'Gene', (102, 126))	('CA199', 'Var', (91, 96))	('CA125', 'Gene', (128, 133))	('CA199', 'Chemical', '-', (91, 96))	('CA125', 'Gene', '94025', (128, 133))	('carbohydrate antigen 125', 'Gene', '94025', (102, 126))
599040	26986156	To our knowledge, this is the first report to share our experience with a very rarely clinical entity of both periesophageal and intramural esophageal bronchogenic cysts with positive expressions of CA199 and CA125 by immunohistochemical study and also review of the literature with an emphasis on endoscopic ultrasonography image characteristics to guide correct examination scheme.	('CA125', 'Gene', '94025', (209, 214))	('bronchogenic cysts', 'Phenotype', 'HP:0100730', (151, 169))	('esophageal bronchogenic cysts', 'Disease', 'MESH:D001994', (140, 169))	('CA199', 'Var', (199, 204))	('CA199', 'Chemical', '-', (199, 204))	('CA125', 'Gene', (209, 214))	('periesophageal', 'Disease', (110, 124))	('esophageal bronchogenic cysts', 'Disease', (140, 169))	('bronchogenic cyst', 'Phenotype', 'HP:0100730', (151, 168))
599052	26986156	We also found that positive expression of CA199 and CA125 in cyst sections by immunohistochemical staining (Figure 3E and F).	('CA125', 'Gene', '94025', (52, 57))	('CA199', 'Chemical', '-', (42, 47))	('CA125', 'Gene', (52, 57))	('CA199', 'Var', (42, 47))
599066	26986156	Both of serum and intracystic fluid levels of CA125 and CA199 were found to be remarkably elevated.	('CA125', 'Gene', (46, 51))	('CA199', 'Chemical', '-', (56, 61))	('elevated', 'PosReg', (90, 98))	('intracystic fluid', 'Phenotype', 'HP:0031527', (18, 35))	('CA199', 'Var', (56, 61))	('CA125', 'Gene', '94025', (46, 51))
599068	26986156	We also first confirm CA199 and CA125 are positive expression in cyst sections by immunohistochemical staining.	('CA199', 'Var', (22, 27))	('CA125', 'Gene', '94025', (32, 37))	('CA199', 'Chemical', '-', (22, 27))	('CA125', 'Gene', (32, 37))
599079	26157703	Despite higher mean prescribed radiation doses in the normal tissue-sparing IMRT cohort (64.5 vs. 60.8 Gy, p = 0.04), patients treated with normal tissue-sparing IMRT had significantly lower lung V20, V10, V5, mean lung, esophageal V60, and mean esophagus doses compared to patients treated with standard RT (p <= 0.001).	('lower', 'NegReg', (185, 190))	('lung V20', 'MPA', (191, 199))	('patients', 'Species', '9606', (274, 282))	('esophagus doses', 'MPA', (246, 261))	('V10', 'MPA', (201, 204))	('esophageal V60', 'MPA', (221, 235))	('patients', 'Species', '9606', (118, 126))	('normal tissue-sparing', 'Var', (140, 161))
599081	26157703	These data provide proof of principle that suboptimal radiation dose distributions are associated with significant acute and late lung and esophageal toxicity that may result in hospitalization or even premature mortality.	('suboptimal', 'Var', (43, 53))	('esophageal toxicity', 'Disease', (139, 158))	('result in', 'Reg', (168, 177))	('lung', 'Disease', (130, 134))	('esophageal toxicity', 'Disease', 'MESH:D004935', (139, 158))
599093	26157703	We investigated whether IMRT designed to limit lung V20, V10, V5, mean lung dose, and esophageal dose could reduce the risk of treatment toxicity compared to historical controls treated with usual care.	('toxicity', 'Disease', (137, 145))	('V10', 'Var', (57, 60))	('treatment', 'CPA', (127, 136))	('reduce', 'NegReg', (108, 114))	('toxicity', 'Disease', 'MESH:D064420', (137, 145))
599173	26157703	In conclusion, these hypothesis-generating data suggest that suboptimal radiation dose distributions associated with standard technique may result in significant acute and late lung and esophageal toxicity that result in hospitalization or even premature mortality.	('esophageal toxicity', 'Disease', 'MESH:D004935', (186, 205))	('result in', 'Reg', (211, 220))	('result', 'Reg', (140, 146))	('suboptimal', 'Var', (61, 71))	('hospitalization', 'Disease', (221, 236))	('esophageal toxicity', 'Disease', (186, 205))
599193	25714027	Acetaldehyde, a genotoxic compound, acts as a carcinogen in humans by inducing mutations, promoting sister chromatid exchange, and interfering with DNA synthesis and repair.	('repair', 'MPA', (166, 172))	('promoting', 'PosReg', (90, 99))	('humans', 'Species', '9606', (60, 66))	('inducing', 'Reg', (70, 78))	('interfering', 'NegReg', (131, 142))	('DNA synthesis', 'MPA', (148, 161))	('sister', 'MPA', (100, 106))	('mutations', 'Var', (79, 88))	('Acetaldehyde', 'Chemical', 'MESH:D000079', (0, 12))
599194	25714027	The formation of acetaldehyde-derived DNA adducts, such as N2-(3-hydroxybutyl)-dG, alpha-methyl-Upsilon-OH-propano-dG, and N2-(4-hydroxybutyl)-dG, induces DNA polymerase errors, thus initiating mutations that silence tumor suppressors and/or activate oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('N2-(3-hydroxybutyl)-dG', 'Chemical', '-', (59, 81))	('silence', 'NegReg', (209, 216))	('acetaldehyde', 'Chemical', 'MESH:D000079', (17, 29))	('induces', 'Reg', (147, 154))	('errors', 'MPA', (170, 176))	('mutations', 'Var', (194, 203))	('alpha-methyl-Upsilon-OH-propano-dG', 'Chemical', '-', (83, 117))	('N2-(4-hydroxybutyl)-dG', 'Chemical', '-', (123, 145))	('DNA', 'MPA', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('activate', 'PosReg', (242, 250))	('initiating', 'Reg', (183, 193))	('oncogenes', 'Gene', (251, 260))
599198	25714027	These G-to-T transversions often are preferred sites for the formation of CpG islands, which have been linked to the silencing of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('transversions', 'Var', (13, 26))
599221	25714027	Also, there were more EGFR(+) cells in the suprabasal layers of the esophagus in the 4-NQO/Untr.	('4-NQO', 'Chemical', 'MESH:D015112', (85, 90))	('4-NQO/Untr', 'Var', (85, 95))	('more', 'PosReg', (17, 21))
599231	25714027	Next, we determined the changes in the localization of E-cadherin in the epithelia of the esophagi in the V.C./EtOH, 4-NQO/Untr., and 4-NQO/EtOH experimental groups compared to the V.C./Untr.	('E-cadherin', 'Protein', (55, 65))	('EtOH', 'Chemical', 'MESH:D000431', (111, 115))	('V.C./EtOH', 'Var', (106, 115))	('4-NQO/EtOH', 'Var', (134, 144))	('4-NQO', 'Chemical', 'MESH:D015112', (117, 122))	('changes', 'Reg', (24, 31))	('localization', 'MPA', (39, 51))	('EtOH', 'Chemical', 'MESH:D000431', (140, 144))	('4-NQO', 'Chemical', 'MESH:D015112', (134, 139))
599242	25714027	group, the average percentages of beta-catenin(+) cells in the epithelial layer as fold changes were as follows: V.C./EtOH (~1.1), 4-NQO/Untr.	('V.C./EtOH', 'Var', (113, 122))	('4-NQO', 'Chemical', 'MESH:D015112', (131, 136))	('EtOH', 'Chemical', 'MESH:D000431', (118, 122))	('beta-catenin(+', 'Gene', (34, 48))	('beta-catenin(+)', 'Gene', '1499', (34, 49))
599253	25714027	group (set at 1.0), the percentages of FoxM1(+) cells in the epithelia (as fold changes) were as follows: V.C./EtOH (~1.2), 4-NQO/Untr.	('EtOH', 'Chemical', 'MESH:D000431', (111, 115))	('4-NQO', 'Chemical', 'MESH:D015112', (124, 129))	('FoxM1', 'Gene', (39, 44))	('V.C./EtOH', 'Var', (106, 115))
599260	25714027	As expected, we detected increases in Wnt3a transcript levels in mice treated with 4-NQO (4-NQO/Untr.)	('4-NQO', 'Var', (83, 88))	('Wnt3a', 'Gene', '22416', (38, 43))	('4-NQO', 'Chemical', 'MESH:D015112', (83, 88))	('increases', 'PosReg', (25, 34))	('4-NQO', 'Chemical', 'MESH:D015112', (90, 95))	('mice', 'Species', '10090', (65, 69))	('Wnt3a', 'Gene', (38, 43))
599279	25714027	The development and progression of the early stages of tumorigenesis can be influenced by the phosphorylation activities in the mitogen activated protein kinase (MAPK) pathways.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('phosphorylation', 'Var', (94, 109))	('influenced', 'Reg', (76, 86))
599283	25714027	In addition, we showed that the phosphorylation of p38 may be a target of tumorigenesis induced by 4-NQO and potentially by ethanol.	('4-NQO', 'Chemical', 'MESH:D015112', (99, 104))	('ethanol', 'Chemical', 'MESH:D000431', (124, 131))	('p38', 'Gene', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('4-NQO', 'Var', (99, 104))	('phosphorylation', 'MPA', (32, 47))
599301	25714027	In normal tissues E-cadherin mediates cell-cell adhesion and functions as a tumor suppressor; however, its deregulation can initiate epithelial-to-mesenchymal transition (EMT) and tumor metastasis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('E-cadherin', 'Protein', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (180, 185))	('deregulation', 'Var', (107, 119))	('epithelial-to-mesenchymal transition', 'CPA', (133, 169))	('tumor metastasis', 'Disease', 'MESH:D009362', (180, 196))	('initiate', 'PosReg', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor metastasis', 'Disease', (180, 196))
599311	25714027	Modifications in the proliferative nature of stem/progenitor cells have been implicated in the initiation and recurrence of several cancers, including HNSCC and OSCC.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('HNSCC', 'Disease', (151, 156))	('implicated', 'Reg', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('OSCC', 'Disease', (161, 165))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))	('proliferative nature', 'CPA', (21, 41))	('Modifications', 'Var', (0, 13))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('rat', 'Species', '10116', (28, 31))
599330	25714027	We detected increased percentages of SLC2A1(+) cells in the esophagi of mice after the administration of ethanol, 4-NQO, and 4-NQO followed by ethanol (Fig.	('4-NQO', 'Var', (125, 130))	('4-NQO', 'Chemical', 'MESH:D015112', (125, 130))	('rat', 'Species', '10116', (95, 98))	('increased', 'PosReg', (12, 21))	('4-NQO', 'Chemical', 'MESH:D015112', (114, 119))	('ethanol', 'Chemical', 'MESH:D000431', (105, 112))	('SLC2A1', 'Gene', (37, 43))	('mice', 'Species', '10090', (72, 76))	('ethanol', 'Chemical', 'MESH:D000431', (143, 150))
599334	25714027	Finally, a similar increase in SLC2A1 protein levels in the esophagi of 4-NQO/Untr.	('increase', 'PosReg', (19, 27))	('4-NQO/Untr', 'Var', (72, 82))	('4-NQO', 'Chemical', 'MESH:D015112', (72, 77))	('SLC2A1 protein levels', 'MPA', (31, 52))
599339	25714027	Aberrant regulation of MAPK signaling is seen in many cancer types, including ESCC.	('regulation', 'MPA', (9, 19))	('ESCC', 'Disease', (78, 82))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('MAPK signaling', 'Pathway', (23, 37))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('seen', 'Reg', (41, 45))
599341	25714027	Here, we detected higher levels of phosphorylated ERK 1/2 after the administration of 4-NQO and 4-NQO/EtOH (Fig.	('rat', 'Species', '10116', (76, 79))	('4-NQO', 'Chemical', 'MESH:D015112', (96, 101))	('4-NQO', 'Chemical', 'MESH:D015112', (86, 91))	('phosphorylated', 'MPA', (35, 49))	('ERK 1/2', 'Gene', (50, 57))	('4-NQO/EtOH', 'Var', (96, 106))	('ERK 1/2', 'Gene', '26417;26413', (50, 57))	('EtOH', 'Chemical', 'MESH:D000431', (102, 106))	('higher', 'PosReg', (18, 24))
599342	25714027	We measured increased levels of phosphorylated p38 in the V.C./EtOH group compared to the V.C./Untr.	('V.C./EtOH', 'Var', (58, 67))	('levels of phosphorylated p38', 'MPA', (22, 50))	('EtOH', 'Chemical', 'MESH:D000431', (63, 67))	('increased', 'PosReg', (12, 21))
599344	25714027	The activation of p38 through phosphorylation on Thr180 and Tyr182 residues has been associated with the angiogenic, invasive, and migratory properties of ESCC.	('migratory properties', 'CPA', (131, 151))	('phosphorylation', 'MPA', (30, 45))	('Thr180', 'Chemical', '-', (49, 55))	('angiogenic', 'CPA', (105, 115))	('p38', 'Protein', (18, 21))	('Tyr182 residues', 'Var', (60, 75))	('SCC', 'Phenotype', 'HP:0002860', (156, 159))	('Tyr182', 'Chemical', '-', (60, 66))	('rat', 'Species', '10116', (134, 137))	('Thr180', 'Var', (49, 55))	('ESCC', 'Disease', (155, 159))	('activation', 'PosReg', (4, 14))	('associated', 'Reg', (85, 95))	('invasive', 'CPA', (117, 125))
599345	25714027	p38 contributes to immune and inflammatory responses by causing the release of tumor-related cytokines and chemokines such as interleukin-6 (IL-6), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) in ESCC.	('ESCC', 'Disease', (236, 240))	('causing', 'Reg', (56, 63))	('immune', 'CPA', (19, 25))	('IL-6', 'Gene', (141, 145))	('interleukin-6', 'Gene', '16193', (126, 139))	('VEGF', 'Gene', (227, 231))	('vascular endothelial growth factor', 'Gene', (191, 225))	('SCC', 'Phenotype', 'HP:0002860', (237, 240))	('release', 'MPA', (68, 75))	('platelet-derived', 'MPA', (148, 164))	('VEGF', 'Gene', '22339', (227, 231))	('inflammatory responses', 'CPA', (30, 52))	('IL-6', 'Gene', '16193', (141, 145))	('vascular endothelial growth factor', 'Gene', '22339', (191, 225))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('interleukin-6', 'Gene', (126, 139))	('p38', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
599346	25714027	More specifically, p38 inhibits the phosphorylating capacity of GSK-3beta, which participates in the degradation of beta-catenin by phosphorylating the Ser33/37 and Thr42 residues of beta-catenin.	('GSK-3beta', 'Gene', '56637', (64, 73))	('p38', 'Var', (19, 22))	('Ser33/37', 'Var', (152, 160))	('degradation', 'MPA', (101, 112))	('Thr42', 'Chemical', '-', (165, 170))	('phosphorylating', 'MPA', (132, 147))	('phosphorylating capacity', 'MPA', (36, 60))	('Thr42', 'Var', (165, 170))	('Ser33', 'Chemical', '-', (152, 157))	('GSK-3beta', 'Gene', (64, 73))	('inhibits', 'NegReg', (23, 31))
599425	22075705	When both cultured cell lines were treated with an ETA selective antagonist (BQ123) or an ETB selective antagonist (BQ788), inhibition of cell growth was observed.	('ETA', 'Gene', '1909', (51, 54))	('inhibition', 'NegReg', (124, 134))	('cell growth', 'CPA', (138, 149))	('BQ788', 'Chemical', 'MESH:C086539', (116, 121))	('ETB', 'Gene', (90, 93))	('ETB', 'Gene', '1910', (90, 93))	('BQ123', 'Var', (77, 82))	('ETA', 'Gene', (51, 54))	('BQ123', 'Chemical', 'MESH:C072247', (77, 82))
599442	22075705	ET receptor specific antagonists, BQ123 for ETA and BQ788 for ETB were purchased from Sigma-Aldrich Japan (Tokyo, Japan).	('BQ788', 'Var', (52, 57))	('BQ123', 'Var', (34, 39))	('BQ123', 'Chemical', 'MESH:C072247', (34, 39))	('ETB', 'Gene', (62, 65))	('ETA', 'Gene', (44, 47))	('ETB', 'Gene', '1910', (62, 65))	('ETA', 'Gene', '1909', (44, 47))	('BQ788', 'Chemical', 'MESH:C086539', (52, 57))
599449	22075705	The intensity of the immunohistochemical staining with anti-ETA or ETB antibody was evaluated by scoring the staining reaction in four groups: (-), none/weak; (+), weak/moderate; (++), moderate/strong, and (+++), very strong cytoplasmic staining intensity, respectively.	('++', 'Var', (180, 182))	('ETA', 'Gene', '1909', (60, 63))	('ETA', 'Gene', (60, 63))	('ETB', 'Gene', (67, 70))	('+', 'Var', (160, 161))	('+++', 'Var', (207, 210))	('ETB', 'Gene', '1910', (67, 70))
599455	22075705	SCC cells were treated with ET receptor antagonists, BQ123 for ETA and BQ788 for ETB for 24 and 48 h in culture medium.	('ETA', 'Gene', '1909', (63, 66))	('SCC', 'Gene', (0, 3))	('ETB', 'Gene', '1910', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (0, 3))	('BQ788', 'Chemical', 'MESH:C086539', (71, 76))	('SCC', 'Gene', '6317', (0, 3))	('BQ788', 'Var', (71, 76))	('BQ123', 'Var', (53, 58))	('BQ123', 'Chemical', 'MESH:C072247', (53, 58))	('ETA', 'Gene', (63, 66))	('ETB', 'Gene', (81, 84))
599476	22075705	To investigate the hypothesis, we used ET receptor antagonists, BQ123 for ETA and BQ788 for ETB.	('BQ123', 'Var', (64, 69))	('BQ123', 'Chemical', 'MESH:C072247', (64, 69))	('BQ788', 'Chemical', 'MESH:C086539', (82, 87))	('ETB', 'Gene', '1910', (92, 95))	('ETA', 'Gene', '1909', (74, 77))	('ETA', 'Gene', (74, 77))	('BQ788', 'Var', (82, 87))	('ETB', 'Gene', (92, 95))
599477	22075705	2A and B, ET receptor antagonists, BQ123 and BQ788 suppressed the cell growth of lingual SCC cell line, SAS.	('BQ788', 'Var', (45, 50))	('SCC', 'Gene', '6317', (89, 92))	('BQ123', 'Var', (35, 40))	('BQ123', 'Chemical', 'MESH:C072247', (35, 40))	('suppressed', 'NegReg', (51, 61))	('BQ788', 'Chemical', 'MESH:C086539', (45, 50))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
599483	22075705	Similar suppression of cell growth by the knockdown of ETA or ETB was also observed when esophageal SCC cell line, KYSE70 was treated with siRNA for ETA or ETB (Fig.	('ETA', 'Gene', '1909', (149, 152))	('ETA', 'Gene', (149, 152))	('SCC', 'Gene', (100, 103))	('ETA', 'Gene', '1909', (55, 58))	('ETB', 'Gene', (62, 65))	('ETB', 'Gene', '1910', (156, 159))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('suppression', 'NegReg', (8, 19))	('SCC', 'Gene', '6317', (100, 103))	('ETB', 'Gene', '1910', (62, 65))	('cell growth', 'CPA', (23, 34))	('ETB', 'Gene', (156, 159))	('ETA', 'Gene', (55, 58))	('knockdown', 'Var', (42, 51))
599487	22075705	In addition, similar suppression of MAPK pathway by knockdown of ET receptors was observed when SAS and KYSE70 were treated with ETA or ETB-siRNA (Fig.	('ETB-', 'Gene', '1910', (136, 140))	('ET receptors', 'Protein', (65, 77))	('ETA', 'Gene', (129, 132))	('MAPK pathway', 'Pathway', (36, 48))	('ETA', 'Gene', '1909', (129, 132))	('ETB-', 'Gene', (136, 140))	('knockdown', 'Var', (52, 61))	('suppression', 'NegReg', (21, 32))
599489	22075705	These results suggest that the cell growth suppression of SCCs by the knockdown or blockade of ET receptors is mediated through the direct inhibition of MAPK signalling pathway.	('MAPK signalling pathway', 'Pathway', (153, 176))	('cell growth suppression', 'CPA', (31, 54))	('SCC', 'Gene', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('inhibition', 'NegReg', (139, 149))	('knockdown', 'Var', (70, 79))	('SCC', 'Gene', '6317', (58, 61))	('blockade', 'Var', (83, 91))	('ET receptors', 'Protein', (95, 107))
599505	22075705	It is reported that phosphorylation of FAK is involved in the inhibition of apoptosis and promote cell growth in SCC cell lines.	('SCC', 'Gene', '6317', (113, 116))	('FAK', 'Gene', (39, 42))	('phosphorylation', 'Var', (20, 35))	('promote', 'PosReg', (90, 97))	('cell growth', 'CPA', (98, 109))	('apoptosis', 'CPA', (76, 85))	('inhibition', 'NegReg', (62, 72))	('SCC', 'Gene', (113, 116))	('SCC', 'Phenotype', 'HP:0002860', (113, 116))
599506	22075705	The intracellular messages link p-FAK at Tyr925 to signalling pathways that activate MAPK cascades.	('MAPK cascades', 'Pathway', (85, 98))	('signalling pathways', 'Pathway', (51, 70))	('p-FAK at Tyr925', 'Var', (32, 47))	('Tyr925', 'Chemical', '-', (41, 47))
599540	23250491	Stenosis of the esophagus seriously affects the patients' quality of life and causes certain complications, including poor nutrition.	('poor nutrition', 'Disease', (118, 132))	('Stenosis', 'Var', (0, 8))	('affects', 'Reg', (36, 43))	('causes', 'Reg', (78, 84))	('quality of life', 'CPA', (58, 73))	('patients', 'Species', '9606', (48, 56))
599541	23250491	Dilatation at an early stage may alleviate the severity of the stenosis and, to some extent, avoid the formation of permanent cicatricial stenosis at later stages which may result in esophageal reconstruction due to dysphagia.	('Dilatation', 'Phenotype', 'HP:0002617', (0, 10))	('Dilatation', 'Var', (0, 10))	('alleviate', 'NegReg', (33, 42))	('severity', 'MPA', (47, 55))	('dysphagia', 'Disease', 'MESH:D003680', (216, 225))	('result in', 'Reg', (173, 182))	('esophageal reconstruction', 'Disease', (183, 208))	('dysphagia', 'Disease', (216, 225))	('dysphagia', 'Phenotype', 'HP:0002015', (216, 225))
599591	22915782	The following parameters were analysed for correlation of acute esophagitis: the mean doses delivered to the esophagus, the volume of the esophagus irradiated (total esophageal volume that was contoured in PTV), the mean doses irradiated to the lung, the percentage of esophagus volume receiving >=10 Gy (V10), >=20Gy V20), >=30 Gy(V30), >= 35Gy (V35), >=40Gy (V40), >=45Gy (V45), >=50Gy (V50), >=55Gy (V55), >=60Gy (V60), and the duration of >= Grade 2 acute esophagitis.	('>=50Gy (V50', 'Var', (381, 392))	('>=40Gy (V40', 'Var', (353, 364))	('>=20Gy V20', 'Var', (311, 321))	('esophagitis', 'Phenotype', 'HP:0100633', (460, 471))	('>=30 Gy', 'Var', (324, 331))	('esophagitis', 'Phenotype', 'HP:0100633', (64, 75))	('acute esophagitis', 'Disease', (58, 75))	('>= 35Gy', 'Var', (338, 345))	('acute esophagitis', 'Disease', (454, 471))	('>=10 Gy', 'Var', (296, 303))	('>=55Gy (V55', 'Var', (395, 406))	('V35', 'Gene', '28474', (347, 350))	('acute esophagitis', 'Disease', 'MESH:D004941', (454, 471))	('V35', 'Gene', (347, 350))	('acute esophagitis', 'Disease', 'MESH:D004941', (58, 75))
599607	22915782	V10, V20, V30, V35, V40, V45) were all significantly associated with acute esophagitis (Figure 3).	('V30', 'Var', (10, 13))	('V35', 'Gene', (15, 18))	('V20', 'Var', (5, 8))	('V45', 'Var', (25, 28))	('V40', 'Var', (20, 23))	('associated', 'Reg', (53, 63))	('acute esophagitis', 'Disease', (69, 86))	('esophagitis', 'Phenotype', 'HP:0100633', (75, 86))	('V35', 'Gene', '28474', (15, 18))	('V10', 'Var', (0, 3))	('acute esophagitis', 'Disease', 'MESH:D004941', (69, 86))
599623	22915782	For example, some reports mentioned esophageal volumes >35 Gy associated with acute esophagitis; others mentioned no association between the risk of acute esophagitis and volumes of esophagus.	('acute esophagitis', 'Disease', (78, 95))	('associated', 'Reg', (62, 72))	('acute esophagitis', 'Disease', 'MESH:D004941', (149, 166))	('esophagitis', 'Phenotype', 'HP:0100633', (155, 166))	('>35 Gy', 'Var', (55, 61))	('acute esophagitis', 'Disease', 'MESH:D004941', (78, 95))	('esophagitis', 'Phenotype', 'HP:0100633', (84, 95))	('acute esophagitis', 'Disease', (149, 166))
599670	27629392	In addition, dysregulation of USP14 has been reported in the development and progression of several tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('reported', 'Reg', (45, 53))	('dysregulation', 'Var', (13, 26))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('USP14', 'Gene', (30, 35))
599679	27629392	After blocking with 5% fat-free milk in TBS [20 mmol/L Tris, 0.15 mol/L NaCl (pH 7.0), 0.1% Tween 20], the membranes were incubated with primary antibodies (anti-USP14, anti-E-cadherin, anti-N-cadherin, anti-beta-catenin, anti-cyclin D1, anti-c-Myc, and anti-GAPDH) (Santa Cruz Biotechnology, Santa Cruz, CA, USA) at 4 C overnight.	('c-Myc', 'Gene', (243, 248))	('cyclin D1', 'Gene', (227, 236))	('N-cadherin', 'Gene', '1000', (191, 201))	('Tris', 'Chemical', '-', (55, 59))	('Tween 20', 'Chemical', 'MESH:D011136', (92, 100))	('GAPDH', 'Gene', '2597', (259, 264))	('E-cadherin', 'Gene', (174, 184))	('GAPDH', 'Gene', (259, 264))	('TBS', 'Chemical', 'MESH:D013725', (40, 43))	('beta-catenin', 'Gene', (208, 220))	('cyclin D1', 'Gene', '595', (227, 236))	('c-Myc', 'Gene', '4609', (243, 248))	('E-cadherin', 'Gene', '999', (174, 184))	('beta-catenin', 'Gene', '1499', (208, 220))	('NaCl', 'Chemical', 'MESH:D012965', (72, 76))	('N-cadherin', 'Gene', (191, 201))	('anti-USP14', 'Var', (157, 167))
599697	27629392	After transfection of sh-USP14, both the protein and mRNA levels of USP14 were dramatically decreased in EC109 (Fig.	('transfection', 'Var', (6, 18))	('mRNA levels', 'MPA', (53, 64))	('protein', 'MPA', (41, 48))	('EC109', 'CellLine', 'CVCL:6898', (105, 110))	('decreased', 'NegReg', (92, 101))	('sh-USP14', 'Var', (22, 30))
599704	27629392	4B) of the tumors were dramatically reduced in the USP14-knockdown group mice compared with the control group (p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('USP14-knockdown', 'Var', (51, 66))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('mice', 'Species', '10090', (73, 77))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('reduced', 'NegReg', (36, 43))
599706	27629392	The results of the Western blot analysis demonstrated that the protein expression levels of beta-catenin, cyclin D1, and c-Myc were dramatically decreased in EC109 cells transfected with sh-USP14, compared with the sh-NC group (Fig.	('c-Myc', 'Gene', '4609', (121, 126))	('cyclin D1', 'Gene', '595', (106, 115))	('c-Myc', 'Gene', (121, 126))	('sh-USP14', 'Var', (187, 195))	('cyclin D1', 'Gene', (106, 115))	('decreased', 'NegReg', (145, 154))	('beta-catenin', 'Gene', (92, 104))	('protein expression levels', 'MPA', (63, 88))	('beta-catenin', 'Gene', '1499', (92, 104))	('EC109', 'CellLine', 'CVCL:6898', (158, 163))
599708	27629392	It has been reported that USP14 expression was specifically upregulated in both lung adenocarcinoma cell lines and tumor tissues, and knockdown of USP14 expression significantly inhibited cell growth and cell cycle arrest in NSCLC cells.	('lung adenocarcinoma cell', 'Disease', (80, 104))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('upregulated', 'PosReg', (60, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (204, 221))	('tumor', 'Disease', (115, 120))	('NSCLC', 'Disease', (225, 230))	('inhibited', 'NegReg', (178, 187))	('knockdown', 'Var', (134, 143))	('arrest', 'Disease', 'MESH:D006323', (215, 221))	('NSCLC', 'Disease', 'MESH:D002289', (225, 230))	('USP14', 'Gene', (26, 31))	('lung adenocarcinoma cell', 'Disease', 'MESH:D000077192', (80, 104))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('expression', 'MPA', (32, 42))	('arrest', 'Disease', (215, 221))	('USP14', 'Gene', (147, 152))
599709	27629392	found that USP14 is highly expressed in colorectal cancer and human primary hepatocellular carcinoma (HCC) tissues, and knockdown of USP14 with the lentiviral vector delivery of shRNA in human HCC cells suppressed cell proliferation, altered the cell cycle, and induced cell apoptosis.	('HCC', 'CellLine', 'CVCL:0C54', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('HCC', 'CellLine', 'CVCL:0C54', (193, 196))	('cell cycle', 'CPA', (246, 256))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('cell proliferation', 'CPA', (214, 232))	('induced', 'Reg', (262, 269))	('primary hepatocellular carcinoma', 'Disease', 'MESH:D006528', (68, 100))	('cell apoptosis', 'CPA', (270, 284))	('colorectal cancer', 'Disease', (40, 57))	('human', 'Species', '9606', (62, 67))	('suppressed', 'NegReg', (203, 213))	('primary hepatocellular carcinoma', 'Disease', (68, 100))	('USP14', 'Gene', (133, 138))	('knockdown', 'Var', (120, 129))	('altered', 'Reg', (234, 241))	('HCC', 'Phenotype', 'HP:0001402', (193, 196))	('human', 'Species', '9606', (187, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))
599718	27629392	It was reported that aberrant beta-catenin expression was found in 54.3% (144 of 265) of ESCCs, and aberrant beta-catenin expression was closely associated with tumor size, tumor location, degree of differentiation, and lymph node status in GSK3beta- ESCC.	('beta-catenin', 'Gene', '1499', (30, 42))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('aberrant', 'Var', (21, 29))	('aberrant', 'Var', (100, 108))	('ESCCs', 'Disease', (89, 94))	('associated', 'Reg', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('beta-catenin', 'Gene', (109, 121))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('beta-catenin', 'Gene', '1499', (109, 121))	('found', 'Reg', (58, 63))	('beta-catenin', 'Gene', (30, 42))	('tumor', 'Disease', (161, 166))	('GSK3beta', 'Gene', (241, 249))	('GSK3beta', 'Gene', '2931', (241, 249))
599719	27629392	found that inhibition of sal-like protein 4 (SALL4) reduces tumorigenicity via the Wnt/beta-catenin signaling pathway in ESCC.	('beta-catenin', 'Gene', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('reduces', 'NegReg', (52, 59))	('beta-catenin', 'Gene', '1499', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('inhibition', 'Var', (11, 21))	('SALL4', 'Gene', '57167', (45, 50))	('sal-like protein 4', 'Gene', '57167', (25, 43))	('tumor', 'Disease', (60, 65))	('ESCC', 'Disease', (121, 125))	('sal-like protein 4', 'Gene', (25, 43))	('SALL4', 'Gene', (45, 50))
599722	27629392	These data suggest that knockdown of USP14 inhibits the proliferation and tumorigenesis in ESCC cells by suppressing and inhibiting the Wnt/beta-catenin signaling pathway.	('suppressing', 'NegReg', (105, 116))	('beta-catenin', 'Gene', '1499', (140, 152))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('USP14', 'Gene', (37, 42))	('proliferation', 'CPA', (56, 69))	('inhibiting', 'NegReg', (121, 131))	('tumor', 'Disease', (74, 79))	('knockdown', 'Var', (24, 33))	('inhibits', 'NegReg', (43, 51))	('beta-catenin', 'Gene', (140, 152))
599744	29776344	We retrospectively analyzed the data of consecutive T4b thoracic ESCC patients who were treated with dCRT (cisplatin and fluorouracil) at Shizuoka Cancer Center between April 2004 and September 2015.	('patients', 'Species', '9606', (70, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('dCRT', 'Chemical', '-', (101, 105))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('fluorouracil', 'Chemical', 'MESH:D005472', (121, 133))	('Shizuoka Cancer', 'Disease', (138, 153))	('T4b', 'Var', (52, 55))	('Shizuoka Cancer', 'Disease', 'MESH:D009369', (138, 153))
599749	29776344	This study demonstrated that total circumferential lesion and CRP >=1.00 mg/dL are risk factors for esophageal fistula in T4b thoracic ESCC treated with dCRT.	('T4b', 'Var', (122, 125))	('esophageal fistula', 'Disease', 'MESH:D004937', (100, 118))	('dCRT', 'Chemical', '-', (153, 157))	('CRP', 'Gene', (62, 65))	('esophageal fistula', 'Disease', (100, 118))	('CRP', 'Gene', '1401', (62, 65))
599763	29776344	Inclusion criteria were as follows: (1) age over 20 years; (2) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1; (3) depth T4b in accordance with the UICC-TNM classification 7th edition; (4) primary lesion located in the thoracic esophagus; (5) no distant organ metastasis other than supraclavicular lymph node metastasis; (6) no esophageal fistula before dCRT; (7) creatinine clearance >=50 mL/min; and (8) other organ functions preserved.	('dCRT', 'Chemical', '-', (377, 381))	('depth T4b', 'Var', (138, 147))	('creatinine clearance', 'MPA', (387, 407))	('supraclavicular lymph node metastasis', 'Disease', 'MESH:D009362', (305, 342))	('esophageal fistula', 'Disease', 'MESH:D004937', (351, 369))	('Oncology', 'Phenotype', 'HP:0002664', (83, 91))	('supraclavicular lymph node metastasis', 'Disease', (305, 342))	('esophageal fistula', 'Disease', (351, 369))
599802	29776344	In the current study, the risk factors of esophageal fistula for T4b ESCC were total circumferential lesion and CRP >=1.00 mg/dL.	('esophageal fistula', 'Disease', 'MESH:D004937', (42, 60))	('CRP', 'Gene', '1401', (112, 115))	('esophageal fistula', 'Disease', (42, 60))	('T4b', 'Var', (65, 68))	('CRP', 'Gene', (112, 115))
599805	29776344	First, regarding the backgrounds of the subjects, better selection was performed in this study than in JCOG0303: JCOG0303 included patients with non-T4b ESCC, while those included in this study were limited to T4b ESCC.	('patients', 'Species', '9606', (131, 139))	('non-T4b', 'Var', (145, 152))	('JCOG0303', 'Var', (113, 121))
599806	29776344	Therefore, we specifically investigated risk factors of esophageal fistula in T4b ESCC in this study, which is clinically relevant.	('esophageal fistula', 'Disease', (56, 74))	('esophageal fistula', 'Disease', 'MESH:D004937', (56, 74))	('T4b', 'Var', (78, 81))
599807	29776344	A second difference between the studies was that, in JCOG0303, the definition of esophageal stenosis was not described, so it might have differed depending on the clinical investigator.	('JCOG0303', 'Var', (53, 61))	('esophageal stenosis', 'Disease', 'MESH:D004940', (81, 100))	('esophageal stenosis', 'Disease', (81, 100))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (81, 100))
599809	29776344	This enabled us to perform a more precise evaluation of risk factors of esophageal fistula only in T4b ESCC patients.	('patients', 'Species', '9606', (108, 116))	('T4b', 'Var', (99, 102))	('esophageal fistula', 'Disease', 'MESH:D004937', (72, 90))	('esophageal fistula', 'Disease', (72, 90))
599813	29776344	A possible explanation for this is that T4b ESCC patients generally do not eat well and are often dehydrated.	('T4b ESCC', 'Var', (40, 48))	('eat', 'CPA', (75, 78))	('patients', 'Species', '9606', (49, 57))
599820	29776344	Therefore, induction chemotherapy followed by CRT may be a feasible treatment strategy for T4b thoracic ESCC with such risk factors.	('T4b', 'Var', (91, 94))	('CRT', 'Gene', (46, 49))	('CRT', 'Gene', '799', (46, 49))
599824	29776344	Considering these limitations, we particularly focused on T4b disease and used a precise definition of esophageal stenosis, so that we could reveal reliable risk factors for esophageal fistula formation in T4b ESCC in the current study.	('esophageal stenosis', 'Disease', 'MESH:D004940', (103, 122))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (103, 122))	('esophageal fistula', 'Disease', 'MESH:D004937', (174, 192))	('esophageal fistula', 'Disease', (174, 192))	('T4b', 'Var', (206, 209))	('esophageal stenosis', 'Disease', (103, 122))
599825	29776344	This study suggested that total circumferential lesion and elevated CRP level are risk factors for esophageal fistula in T4b thoracic ESCC treated with dCRT.	('esophageal fistula', 'Disease', 'MESH:D004937', (99, 117))	('esophageal fistula', 'Disease', (99, 117))	('CRP', 'Gene', (68, 71))	('dCRT', 'Chemical', '-', (152, 156))	('T4b', 'Var', (121, 124))	('CRP', 'Gene', '1401', (68, 71))	('elevated CRP', 'Phenotype', 'HP:0011227', (59, 71))
599897	26087059	Similar effects of butyrate and propionate on body weight and food intake were seen in FFAR3 deficient mice, which indicated that there may be additional mediators necessary for these desired effects.	('mice', 'Species', '10090', (103, 107))	('food intake', 'CPA', (62, 73))	('butyrate', 'Chemical', 'MESH:D002087', (19, 27))	('deficient', 'Var', (93, 102))	('propionate', 'Chemical', 'MESH:D011422', (32, 42))	('body weight', 'CPA', (46, 57))	('FFAR3', 'Gene', (87, 92))
599924	26087059	As previously described propionate and butyrate have an affinity for FFAR3, whereas acetate appears to have more of an affinity for FFAR2.	('acetate', 'Chemical', 'MESH:D000085', (84, 91))	('propionate', 'Chemical', 'MESH:D011422', (24, 34))	('FFAR3', 'Var', (69, 74))	('butyrate', 'Chemical', 'MESH:D002087', (39, 47))	('butyrate', 'MPA', (39, 47))	('propionate', 'MPA', (24, 34))
599932	26087059	In mice models, antibiotic-induced depletion of Firmicutes and Bacteroidetes resulted in increased GLP-1 secretion, which ultimately in improved systemic glucose intolerance, hyperinsulinemia, and insulin resistance independent of obesity as compared with untreated controls when exposed to diet-induced obesity.	('insulin', 'Gene', (197, 204))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (175, 191))	('insulin resistance', 'Phenotype', 'HP:0000855', (197, 215))	('obesity', 'Phenotype', 'HP:0001513', (231, 238))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (175, 191))	('improved', 'PosReg', (136, 144))	('glucose intolerance', 'Phenotype', 'HP:0001952', (154, 173))	('insulin', 'Gene', (180, 187))	('obesity', 'Disease', (304, 311))	('glucose', 'Chemical', 'MESH:D005947', (154, 161))	('diet-induced obesity', 'Phenotype', 'HP:0012743', (291, 311))	('depletion', 'Var', (35, 44))	('GLP-1 secretion', 'MPA', (99, 114))	('obesity', 'Disease', 'MESH:D009765', (304, 311))	('hyperinsulinemia', 'Disease', (175, 191))	('mice', 'Species', '10090', (3, 7))	('insulin', 'Gene', '3630', (197, 204))	('obesity', 'Disease', (231, 238))	('increased', 'PosReg', (89, 98))	('systemic glucose intolerance', 'MPA', (145, 173))	('obesity', 'Disease', 'MESH:D009765', (231, 238))	('insulin', 'Gene', '3630', (180, 187))	('obesity', 'Phenotype', 'HP:0001513', (304, 311))
599949	26087059	Patients with a diagnosis of Crohn's disease known to carry the NOD2 mutation have an increased population of mucosa-adherent bacteria, in particular Escherichia coli.	('Escherichia coli', 'Disease', (150, 166))	('Escherichia coli', 'Species', '562', (150, 166))	('increased', 'PosReg', (86, 95))	("Crohn's disease", 'Phenotype', 'HP:0100280', (29, 44))	('mutation', 'Var', (69, 77))	('NOD2', 'Gene', '64127', (64, 68))	('Patients', 'Species', '9606', (0, 8))	("Crohn's disease", 'Disease', 'MESH:D003424', (29, 44))	("Crohn's disease", 'Disease', (29, 44))	('population of mucosa-adherent bacteria', 'MPA', (96, 134))	('NOD2', 'Gene', (64, 68))
599954	26087059	Recent studies have demonstrated a higher abundance of Fusobacterium varium in patients with ulcerative colitis,which may in part be responsible for colonic mucosal erosion as seen in mice models due to compromised mucosal integrity.	('mucosal erosion', 'Phenotype', 'HP:0031446', (157, 172))	('ulcerative colitis', 'Disease', 'MESH:D003093', (93, 111))	('colonic mucosal erosion', 'Disease', (149, 172))	('colonic mucosal erosion', 'Disease', 'MESH:D052016', (149, 172))	('responsible', 'Reg', (133, 144))	('Fusobacterium varium', 'Species', '856', (55, 75))	('Fusobacterium varium', 'Var', (55, 75))	('patients', 'Species', '9606', (79, 87))	('mice', 'Species', '10090', (184, 188))	('colitis', 'Phenotype', 'HP:0002583', (104, 111))	('ulcerative colitis', 'Disease', (93, 111))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (93, 111))	('higher', 'PosReg', (35, 41))
599964	26087059	To date no prebiotic or probiotic regimen has been consistently beneficial in Crohn's disease, with the exception of Faealibacerium prausinitzii which has been demonstrated to have anti-inflammatory effects in vitro and in vivo in mice models.	('men', 'Species', '9606', (38, 41))	('Faealibacerium', 'Var', (117, 131))	('anti-inflammatory', 'MPA', (181, 198))	('mice', 'Species', '10090', (231, 235))	("Crohn's disease", 'Phenotype', 'HP:0100280', (78, 93))	("Crohn's disease", 'Disease', 'MESH:D003424', (78, 93))	("Crohn's disease", 'Disease', (78, 93))
600004	26087059	The investigators found that eradication of SIBO eliminated IBS in 48% of subjects, which let them to conclude that there is an association between IBS and SIBO.	('SIBO', 'Disease', (156, 160))	('SIBO', 'Disease', 'None', (156, 160))	('SIBO', 'Disease', (44, 48))	('association', 'Interaction', (128, 139))	('SIBO', 'Disease', 'None', (44, 48))	('IBS', 'Disease', 'MESH:D043183', (148, 151))	('IBS', 'Disease', (148, 151))	('eradication', 'Var', (29, 40))	('IBS', 'Disease', 'MESH:D043183', (60, 63))	('IBS', 'Disease', (60, 63))
600017	26087059	In this study, 84 patients with IBS-D (diarrhea predominant) according to Rome III criteria were randomly allocated to receive once daily I.31 at a high dose (n=28), I.31 at a low dose (n=27), and placebo (n=29).	('diarrhea', 'Disease', (39, 47))	('I.31', 'Var', (138, 142))	('diarrhea', 'Disease', 'MESH:D003967', (39, 47))	('I.31', 'Var', (166, 170))	('patients', 'Species', '9606', (18, 26))	('IBS', 'Disease', 'MESH:D043183', (32, 35))	('IBS', 'Disease', (32, 35))	('diarrhea', 'Phenotype', 'HP:0002014', (39, 47))
600029	26087059	Rifixamin when compared with placebo was more efficacious for global IBS symptom improvement (OR 1.57) and significantly more likely to be associated with decreased bloating (OR 1.55).	('OR 1.57', 'Gene', '127064', (94, 101))	('IBS', 'Disease', 'MESH:D043183', (69, 72))	('IBS', 'Disease', (69, 72))	('decreased', 'NegReg', (155, 164))	('bloating', 'Disease', (165, 173))	('bloating', 'Phenotype', 'HP:0003270', (165, 173))	('Rifixamin', 'Var', (0, 9))	('Rifixamin', 'Chemical', '-', (0, 9))	('men', 'Species', '9606', (88, 91))	('OR 1.57', 'Gene', (94, 101))	('OR 1.55', 'Gene', '283694', (175, 182))	('OR 1.55', 'Gene', (175, 182))
600056	26087059	There was noted improvement in liver fibrosis with VSL#3 supplementation, which was consistent with results from previous studies likely secondary to its effect on collagen expression and modulation of apoptosis.	('men', 'Species', '9606', (63, 66))	('supplementation', 'Var', (57, 72))	('liver fibrosis', 'Disease', 'MESH:D008103', (31, 45))	('liver fibrosis', 'Phenotype', 'HP:0001395', (31, 45))	('improvement', 'PosReg', (16, 27))	('collagen expression', 'MPA', (164, 183))	('men', 'Species', '9606', (23, 26))	('VSL#3', 'Gene', (51, 56))	('liver fibrosis', 'Disease', (31, 45))
600061	26087059	who randomized 44 obese children with biopsy-proven NAFLD to VSL#3 (n=22) or placebo (n=22).	('VSL#3', 'Gene', (61, 66))	('obese', 'Disease', 'MESH:D009765', (18, 23))	('obese', 'Disease', (18, 23))	('NAFLD', 'Var', (52, 57))	('children', 'Species', '9606', (24, 32))
600081	26087059	There have been several mechanisms proposed to explain the paradox as to why H. pylori is carcinogenic in the stomach yet chemoprotective in the esophagus.	('carcinogenic', 'Disease', (90, 102))	('H. pylori', 'Species', '210', (77, 86))	('H. pylori', 'Var', (77, 86))	('carcinogenic', 'Disease', 'MESH:D063646', (90, 102))
600082	26087059	One possible mechanism is that by inhibiting parietal cell function and/or inducing the development of atrophic gastritis, H. pylori blunts the acid secretion required to develop gastroesophageal reflux disease and its resultant sequelae, i.e., Barrett's esophagus and ultimately esophageal adenocarcinoma.	("Barrett's esophagus", 'Disease', 'MESH:D001471', (245, 264))	('blunts', 'NegReg', (133, 139))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (245, 264))	('gastroesophageal reflux disease', 'Disease', (179, 210))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (179, 210))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (179, 202))	('gastritis', 'Phenotype', 'HP:0005263', (112, 121))	('inhibiting', 'NegReg', (34, 44))	('acid secretion required', 'MPA', (144, 167))	('men', 'Species', '9606', (95, 98))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (280, 305))	('atrophic gastritis', 'Disease', 'MESH:D005757', (103, 121))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (280, 305))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (103, 121))	('esophageal adenocarcinoma', 'Disease', (280, 305))	('H. pylori', 'Species', '210', (123, 132))	("Barrett's esophagus", 'Disease', (245, 264))	('atrophic gastritis', 'Disease', (103, 121))	('H. pylori', 'Var', (123, 132))	('inducing', 'Reg', (75, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
600083	26087059	A second possibility is that loss of H. plyori contributes to alterations in the gastric microflora, which ultimately results in reflux-mediated esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (145, 170))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (145, 170))	('results in', 'Reg', (118, 128))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (145, 170))	('loss', 'Var', (29, 33))	('gastric microflora', 'MPA', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('H. plyori', 'Protein', (37, 46))	('alterations', 'Reg', (62, 73))
600132	25525311	Evaluation parameters The comparison of all VMAT plans was evaluated using the following terms: Homogeneity Index (HI): (D2% - D98%)/D50%, a ratio evaluating the dose homogeneity in GTV where D2%, D98% and D50% are the minimum dose delivered to 2%, 98% and 50% volume of the GTV respectively.	('GTV', 'Chemical', '-', (182, 185))	('GTV', 'Chemical', '-', (275, 278))	('D98%', 'Var', (197, 201))	('D50%', 'Var', (206, 210))	('HI', 'Disease', 'MESH:C538424', (115, 117))	('D2%', 'Var', (192, 195))
600135	25525311	Target volumes: D98%, D95%, D50% and Dmax for GTV were analyzed, where D98%, D95%, D50% is minimum dose delivered to 98%, 95% and 50% Volume of GTV respectively and Dmax is the maximum dose.	('D95%', 'Var', (77, 81))	('D98%', 'Var', (71, 75))	('GTV', 'Chemical', '-', (144, 147))	('GTV', 'Chemical', '-', (46, 49))	('D50%', 'Var', (83, 87))
600140	25525311	There was no statistical significance differences were observed between VMAT15, VMAT20, VMAT30 and VMAT40 plans in dosimetric parameter of GTV such as D98%, D95% and D50%.	('GTV', 'Chemical', '-', (139, 142))	('D95%', 'Var', (157, 161))	('D50%', 'Var', (166, 170))	('VMAT15', 'Var', (72, 78))	('VMAT20', 'Var', (80, 86))	('VMAT40', 'Var', (99, 105))	('VMAT30', 'Var', (88, 94))	('D98%', 'Var', (151, 155))
600210	33619875	ESpCC was established by pathological examination, and confirmed by IHC staining (Figure 1) which indicated p63 (+), CK5 / 6 (+), p53 (+), PCK (+), SMA (-), S-100 (-), desmin (-), and Ki-67 (80%).	('desmin', 'Gene', (168, 174))	('PCK (+', 'Var', (139, 145))	('p63', 'Gene', (108, 111))	('desmin', 'Gene', '1674', (168, 174))	('p53', 'Gene', (130, 133))	('p63', 'Gene', '8626', (108, 111))	('p53', 'Gene', '7157', (130, 133))
600269	33586344	Nitrosamines, lack of nutrients, and unhealthy lifestyles have been identified as major risk factors for esophageal cancer.	('Nitrosamines', 'Chemical', 'MESH:D009602', (0, 12))	('lack', 'Var', (14, 18))	('esophageal cancer', 'Disease', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))
600374	32202699	22 ,  24   An estimated 80% of esophageal cancer patients report some weight loss in the 6 months prior to diagnosis, 25 ,  26  but since high BMI is a strong risk factor for EA, most patients are nevertheless overweight or obese at the time of diagnosis despite the weight loss.	('obese', 'Disease', (224, 229))	('high BMI', 'Var', (138, 146))	('weight loss', 'Disease', 'MESH:D015431', (70, 81))	('weight loss', 'Disease', (267, 278))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('patients', 'Species', '9606', (184, 192))	('weight loss', 'Phenotype', 'HP:0001824', (267, 278))	('weight loss', 'Phenotype', 'HP:0001824', (70, 81))	('EA', 'Phenotype', 'HP:0011459', (175, 177))	('weight loss', 'Disease', (70, 81))	('overweight', 'Phenotype', 'HP:0025502', (210, 220))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('patients', 'Species', '9606', (49, 57))	('weight loss', 'Disease', 'MESH:D015431', (267, 278))	('obese', 'Disease', 'MESH:D009765', (224, 229))
600382	32202699	Finally, we hypothesized that a-BMI changes may have different associations with survival depending on patients' starting BMI, so we tested whether the association with DeltaBMI and overall survival in EA was modified by average a-BMI.	('EA', 'Phenotype', 'HP:0011459', (202, 204))	('changes', 'Var', (36, 43))	('tested', 'Reg', (133, 139))	('patients', 'Species', '9606', (103, 111))
600420	32202699	In the adjusted model, d-BMI was associated with overall survival (global Wald P-value = .01, Table 2; Table S6), with lowest hazard of death among patients with d-BMI >= 25 and <35 kg/m2.	('overall survival', 'MPA', (49, 65))	('patients', 'Species', '9606', (148, 156))	('death', 'Disease', 'MESH:D003643', (136, 141))	('death', 'Disease', (136, 141))	('d-BMI >= 25', 'Var', (162, 173))	('d-BMI', 'Var', (23, 28))
600427	32202699	Moreover, both d-BMI and percent loss of weight in 6 months prior to diagnosis remain significantly associated with all-cause hazard of death in the fully adjusted model (Table 3, Model 3; Table S8).	('loss of weight', 'Phenotype', 'HP:0001824', (33, 47))	('death', 'Disease', 'MESH:D003643', (136, 141))	('death', 'Disease', (136, 141))	('loss', 'NegReg', (33, 37))	('associated', 'Reg', (100, 110))	('d-BMI', 'Var', (15, 20))
600439	32202699	Consistent with previous studies that examined only d-BMI and weight loss leading up to diagnosis, we found that patients with BMI >= 25.0 and <35 kg/m2 at the time of diagnosis (d-BMI) had an decreased hazard of all-cause mortality compared to patients with d-BMI 18.5-25 kg/m2  15 ,  16 ,  17 ,  18 ,  19  and weight loss in the 6 months before diagnosis 11 ,  22 ,  24 ,  29  was also associated with an increased hazard of all-cause mortality.	('weight loss', 'Disease', 'MESH:D015431', (62, 73))	('BMI 1', 'Gene', (261, 266))	('weight loss', 'Disease', (312, 323))	('all-cause', 'CPA', (213, 222))	('patients', 'Species', '9606', (245, 253))	('weight loss', 'Phenotype', 'HP:0001824', (312, 323))	('patients', 'Species', '9606', (113, 121))	('mortality', 'Disease', (437, 446))	('mortality', 'Disease', 'MESH:D003643', (223, 232))	('weight loss', 'Disease', (62, 73))	('<35 kg/m2', 'Var', (143, 152))	('>= 25.0', 'Var', (131, 138))	('weight loss', 'Phenotype', 'HP:0001824', (62, 73))	('BMI 1', 'Gene', '648', (261, 266))	('mortality', 'Disease', (223, 232))	('weight loss', 'Disease', 'MESH:D015431', (312, 323))	('decreased', 'NegReg', (193, 202))	('mortality', 'Disease', 'MESH:D003643', (437, 446))
600440	32202699	Yet, because weight loss only in the 6 months prior to diagnosis, but not previous weight loss, was associated with poorer survival, the remaining observed association between d-BMI < 25 kg/m2 and overall survival is likely capturing overall poor health status and complex unaccounted clinical factors (reverse causation and residual confounding).	('weight loss', 'Disease', 'MESH:D015431', (83, 94))	('weight loss', 'Disease', (13, 24))	('weight loss', 'Phenotype', 'HP:0001824', (13, 24))	('weight loss', 'Disease', (83, 94))	('< 25 kg/m2', 'Var', (182, 192))	('survival', 'MPA', (123, 131))	('weight loss', 'Phenotype', 'HP:0001824', (83, 94))	('d-BMI', 'Gene', (176, 181))	('poorer', 'NegReg', (116, 122))	('weight loss', 'Disease', 'MESH:D015431', (13, 24))
600479	21112493	More recent studies, however, include a substantial proportion of short-segment Barrett's patients, whose GERD severity and esophageal cancer risk may differ considerably from those for patients with long-segment disease.	('GERD', 'Disease', 'MESH:D005764', (106, 110))	('esophageal cancer', 'Disease', (124, 141))	('GERD', 'Disease', (106, 110))	('short-segment', 'Var', (66, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('patients', 'Species', '9606', (90, 98))	('patients', 'Species', '9606', (186, 194))
600508	21112493	Patients with longer segments of metaplasia have more cells at risk for mutation and, therefore, should be more likely to acquire the critical combination of DNA alterations that results in malignancy.	('malignancy', 'Disease', 'MESH:D009369', (190, 200))	('results in', 'Reg', (179, 189))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (72, 80))	('malignancy', 'Disease', (190, 200))
600519	21112493	A recent randomized, sham-controlled trial of radiofrequency ablation (RFA) for patients with high-grade dysplasia in Barrett's esophagus has demonstrated that RFA, which has few serious side effects, decreases the progression from high-grade dysplasia to cancer at one year.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (118, 137))	('patients', 'Species', '9606', (80, 88))	('dysplasia to cancer', 'Disease', 'MESH:D009369', (243, 262))	('dysplasia', 'Disease', 'MESH:D015792', (243, 252))	('decreases', 'NegReg', (201, 210))	('dysplasia', 'Disease', 'MESH:D015792', (105, 114))	('dysplasia to cancer', 'Disease', (243, 262))	('RFA', 'Var', (160, 163))	('dysplasia', 'Disease', (243, 252))	('dysplasia', 'Disease', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))
600538	31423229	Furthermore, ALND was associated with improved survival in local diseases (T1-3/N0-1; HR=0.50, 95% CI=0.30-0.84) and locally advanced diseases (T4/Nany or T1-3/N2-3; HR=0.32, 95% CI=0.15-0.68).	('improved', 'PosReg', (38, 46))	('T1-3', 'Gene', '29123;9173;292', (75, 79))	('T1-3', 'Gene', (75, 79))	('T1-3', 'Gene', '29123;9173;292', (155, 159))	('ALND', 'Chemical', '-', (13, 17))	('local diseases', 'Disease', (59, 73))	('T1-3', 'Gene', (155, 159))	('ALND', 'Var', (13, 17))
600581	31423229	2D and E) also yielded non-significant results (P=0.743, P=0.534, P=0.396 and P=0.818 for T1-2, T3-4, N0 and N+ cases, respectively).	('T1-2', 'Gene', '923;9173;292', (90, 94))	('T3-4', 'Var', (96, 100))	('T1-2', 'Gene', (90, 94))
600608	31423229	Additionally, ALND was associated with improved survival in local diseases (T1-3/N0-1; HR=0.50, 95% CI=0.30-0.84, P<0.001; Fig.	('ALND', 'Chemical', '-', (14, 18))	('ALND', 'Var', (14, 18))	('T1-3', 'Gene', '29123;9173;292', (76, 80))	('local diseases', 'Disease', (60, 74))	('improved', 'PosReg', (39, 47))	('T1-3', 'Gene', (76, 80))
600609	31423229	7E) and locally advanced diseases (T4/Nany or T1-3/N2-3; HR=0.32, 95% CI=0.15-0.68, P=0.022; Fig.	('T1-3', 'Gene', (46, 50))	('T1-3', 'Gene', '29123;9173;292', (46, 50))	('T4/Nany', 'Var', (35, 42))
600660	30923783	In studies comparing MIE with OE, mediastinoscopic surgery and robotic surgery are usually not included; these studies show that MIE has a longer operative time and less blood loss than OE.	('blood loss', 'Disease', 'MESH:D006473', (170, 180))	('MIE', 'Var', (129, 132))	('OE', 'Chemical', '-', (186, 188))	('MIE', 'Chemical', '-', (129, 132))	('blood loss', 'Disease', (170, 180))	('OE', 'Chemical', '-', (30, 32))	('MIE', 'Chemical', '-', (21, 24))
600687	30923783	Glatz also reported the usefulness of laparoscopic surgery in esophagectomy.26 They compared hybrid minimally invasive laparoscopic-thoracotomic esophagectomy (HMIE) with OE.26 Their analysis showed that HMIE is associated with a reduction in postoperative pulmonary morbidity, less perioperative blood loss, and shorter duration of hospital stay.	('OE', 'Chemical', '-', (171, 173))	('blood loss', 'Disease', 'MESH:D006473', (297, 307))	('HMIE', 'Var', (204, 208))	('MIE', 'Chemical', '-', (205, 208))	('reduction', 'NegReg', (230, 239))	('blood loss', 'Disease', (297, 307))	('MIE', 'Chemical', '-', (161, 164))
600702	30923783	The study found that TEP is associated with longer operative time, less blood loss, and a lower rate of pneumonia and RLN palsy than previously reported for OE.13 Long-term oncological outcomes of the TIME trial were reported by Straatman et al.35 There were no differences in long-term survival between the two groups.	('blood loss', 'Disease', 'MESH:D006473', (72, 82))	('pneumonia', 'Disease', (104, 113))	('TEP', 'Var', (21, 24))	('OE', 'Chemical', '-', (157, 159))	('pneumonia', 'Disease', 'MESH:D011014', (104, 113))	('blood loss', 'Disease', (72, 82))	('pneumonia', 'Phenotype', 'HP:0002090', (104, 113))	('lower', 'NegReg', (90, 95))	('RLN palsy', 'Disease', (118, 127))	('TEP', 'Chemical', '-', (21, 24))	('RLN palsy', 'Disease', 'MESH:D010243', (118, 127))
600707	30923783	Even though there was no significant difference in postoperative complications between the two groups, serum C-reactive protein (CRP) levels during the first 3 and 5 postoperative days and peak CRP levels were significantly lower after MIE versus OE (MIE vs OE, median, 15.21 vs 19.50 mg/dL; P < 0.001).	('OE', 'Chemical', '-', (247, 249))	('CRP', 'Gene', (194, 197))	('CRP', 'Gene', (129, 132))	('C-reactive protein', 'Gene', '1401', (109, 127))	('MIE', 'Chemical', '-', (236, 239))	('MIE', 'Var', (236, 239))	('CRP', 'Gene', '1401', (194, 197))	('C-reactive protein', 'Gene', (109, 127))	('lower', 'NegReg', (224, 229))	('CRP', 'Gene', '1401', (129, 132))	('OE', 'Chemical', '-', (258, 260))	('MIE', 'Chemical', '-', (251, 254))
600708	30923783	DFS and OS rates were significantly better in the MIE group than in the OE group (3-year DFS rate, 81.7% vs 69.3%; log-rank P = 0.021; 3-year OS rate, 89.9% vs 79.2%; log-rank P = 0.007) (Table 1).	('DFS', 'CPA', (0, 3))	('OS rates', 'CPA', (8, 16))	('OE', 'Chemical', '-', (72, 74))	('MIE', 'Var', (50, 53))	('MIE', 'Chemical', '-', (50, 53))	('better', 'PosReg', (36, 42))
600710	30923783	Results of operative time and blood loss were similar to the report by Biere et al.13 Concerning respiratory complications, the rate of atelectasis and the proportion of patients who required more than 48 hours of postoperative respiratory ventilation were significantly lower in the MIE group than in the OE group (3.6% vs 5.1%, P = 0.002, and 8.9% vs 10.9%, P = 0.006, respectively).	('patients', 'Species', '9606', (170, 178))	('respiratory complications', 'CPA', (97, 122))	('blood loss', 'Disease', 'MESH:D006473', (30, 40))	('OE', 'Chemical', '-', (306, 308))	('MIE', 'Var', (284, 287))	('lower', 'NegReg', (271, 276))	('respiratory complications', 'Phenotype', 'HP:0011947', (97, 122))	('MIE', 'Chemical', '-', (284, 287))	('atelectasis', 'CPA', (136, 147))	('blood loss', 'Disease', (30, 40))	('atelectasis', 'Phenotype', 'HP:0100750', (136, 147))
600712	30923783	In addition, the 30-day reoperation rate was significantly higher in the MIE group than in the OE group (7.0% vs 5.3%, P = 0.004) (Table 1).37 Nozaki et al evaluated the safety profile of MIE, including both TELD and TEP, for T1bN0M0 esophageal cancer using data from JCOG Study 0502.	('esophageal cancer', 'Disease', (234, 251))	('TEP', 'Chemical', '-', (217, 220))	('MIE', 'Chemical', '-', (73, 76))	('T1bN0M0', 'Var', (226, 233))	('esophageal cancer', 'Disease', 'MESH:D004938', (234, 251))	('MIE', 'Chemical', '-', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('OE', 'Chemical', '-', (95, 97))
600716	30923783	In addition, mean constipation scores were significantly better for the MIE group at 3 months after surgery (P = 0.037).	('constipation', 'Disease', 'MESH:D003248', (18, 30))	('MIE', 'Var', (72, 75))	('constipation', 'Disease', (18, 30))	('MIE', 'Chemical', '-', (72, 75))	('better', 'PosReg', (57, 63))	('constipation', 'Phenotype', 'HP:0002019', (18, 30))
600726	30923783	Concerning respiratory complications, MIE is particularly beneficial in reducing postoperative respiratory complications such as atelectasis, even though it is controversial as to whether MIE contributes dramatically to decreasing the incidence of pneumonia.	('MIE', 'Var', (38, 41))	('atelectasis', 'Phenotype', 'HP:0100750', (129, 140))	('respiratory complications', 'Phenotype', 'HP:0011947', (95, 120))	('pneumonia', 'Disease', (248, 257))	('MIE', 'Chemical', '-', (38, 41))	('pneumonia', 'Disease', 'MESH:D011014', (248, 257))	('respiratory complications', 'Phenotype', 'HP:0011947', (11, 36))	('reducing', 'NegReg', (72, 80))	('MIE', 'Chemical', '-', (188, 191))	('pneumonia', 'Phenotype', 'HP:0002090', (248, 257))	('atelectasis', 'Disease', (129, 140))
600731	30923783	The dispersion of empirical value of each hospital for MIE may be an important reason for MIE not contributing markedly to decreasing the incidence of pneumonia and is, rather, associated with a higher reoperation rate.	('MIE', 'Chemical', '-', (90, 93))	('pneumonia', 'Disease', (151, 160))	('pneumonia', 'Disease', 'MESH:D011014', (151, 160))	('MIE', 'Chemical', '-', (55, 58))	('MIE', 'Var', (90, 93))	('pneumonia', 'Phenotype', 'HP:0002090', (151, 160))	('associated with', 'Reg', (177, 192))
600762	30333480	Interestingly, miR-6775-3p and its host gene SLC7A5 were directly transcriptionally induced by p53.	('miR-6775', 'Gene', '102465464', (15, 23))	('miR-6775', 'Gene', (15, 23))	('p53', 'Var', (95, 98))
600850	30333480	In addition, ESCC patients who had low miR-6775-3p expression and high expression of MAGE-A family showed worse clinical outcomes, and the patients who had high miR-6775-3p expression and low expression of MAGE-A family showed better clinical outcomes, as compared with other patients (Fig 4g).	('patients', 'Species', '9606', (276, 284))	('miR-6775', 'Gene', '102465464', (39, 47))	('miR-6775', 'Gene', (161, 169))	('patients', 'Species', '9606', (139, 147))	('miR-6775', 'Gene', '102465464', (161, 169))	('ESCC', 'Disease', (13, 17))	('low', 'NegReg', (35, 38))	('high', 'Var', (66, 70))	('patients', 'Species', '9606', (18, 26))	('miR-6775', 'Gene', (39, 47))
600866	30333480	When cells treated with Oxaliplatin, the specific binding of p53 to SLC7A5 promoter was markedly increased as compared with the untreated cells (Fig.	('binding', 'Interaction', (50, 57))	('p53', 'Var', (61, 64))	('increased', 'PosReg', (97, 106))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (24, 35))
600868	30333480	In addition, the luciferase reporter assay results demonstrated that p53 increased the luciferase reporter activity of p21WAF1 and SLC7A5/miR-6775 promoters in a dose dependent manner (Fig 6f).	('p21', 'Gene', '644914', (119, 122))	('increased', 'PosReg', (73, 82))	('p53', 'Var', (69, 72))	('miR-6775', 'Gene', (138, 146))	('miR-6775', 'Gene', '102465464', (138, 146))	('luciferase reporter', 'Enzyme', (87, 106))	('p21', 'Gene', (119, 122))
600890	30333480	In our present study, we found that p53 directly transcriptionally induce the expression of miR-6775-3p and its host gene SLC7A5.	('miR-6775', 'Gene', (92, 100))	('miR-6775', 'Gene', '102465464', (92, 100))	('expression', 'MPA', (78, 88))	('p53', 'Var', (36, 39))	('induce', 'PosReg', (67, 73))
600902	30333480	Interestingly, miR-6775-3p and SLC7A5 were directly transcriptionally induced by p53.	('SLC7A5', 'Gene', (31, 37))	('miR-6775', 'Gene', '102465464', (15, 23))	('miR-6775', 'Gene', (15, 23))	('p53', 'Var', (81, 84))
600929	29893036	Patients with locally advanced resectable ESCC (cT1-4aN+M0 or cT3-4aN0M0) who could not undergo direct surgery were administered two cycles of neoadjuvant chemotherapy consisting of intravenous (IV) drips of 70 mg/m2 paclitaxel on days 1 and 8, and an IV drip of 30 mg/m2 nedaplatin on days 1-3.	('cT3-4aN0M0', 'Gene', '158809', (62, 72))	('nedaplatin', 'Chemical', 'MESH:C053989', (272, 282))	('Patients', 'Species', '9606', (0, 8))	('cT3-4aN0M0', 'Gene', (62, 72))	('cT1-4aN+M0', 'Var', (48, 58))	('ESCC', 'Disease', (42, 46))	('paclitaxel', 'Chemical', 'MESH:D017239', (217, 227))
600991	29904747	The late toxicity of fistula formation has been shown to be related to D1cc exceeding 50 Gy, with patients receiving adjuvant anti-angiogenic therapies being at particularly high risk.	('D1cc', 'Var', (71, 75))	('toxicity of fistula', 'Disease', (9, 28))	('toxicity of fistula', 'Disease', 'MESH:D005402', (9, 28))	('patients', 'Species', '9606', (98, 106))
601049	29581622	TRT had been suggested to be the most significant risk factor for bevacizumab-related TEF.	('TRT', 'Chemical', '-', (0, 3))	('TEF', 'Disease', (86, 89))	('TRT', 'Var', (0, 3))	('bevacizumab', 'Chemical', 'MESH:D000068258', (66, 77))
601160	28593183	The presence of PDX-1 is reported to indicate the existence of distinct pathways to metaplasia development, as suggested by Leys et al.	('PDX-1', 'Gene', (16, 21))	('presence', 'Var', (4, 12))	('metaplasia', 'Disease', (84, 94))	('metaplasia', 'Disease', 'MESH:D008679', (84, 94))
601210	22919374	In a separate study, we studied the effect of neoadjuvant chemoradiation on outcomes after MIE and noted that there were no significant differences in operative blood loss, median operative time, total or individual complication rates, pneumonia, atrial fibrillation, recurrent laryngeal nerve injury, or anastomotic leaks between patients who received neoadjuvant chemoradiation and patients who did not.	('blood loss', 'Disease', (161, 171))	('laryngeal nerve injury', 'Disease', 'MESH:D061224', (278, 300))	('pneumonia', 'Phenotype', 'HP:0002090', (236, 245))	('anastomotic leaks', 'Disease', 'MESH:D057868', (305, 322))	('neoadjuvant', 'Var', (353, 364))	('atrial fibrillation', 'Disease', (247, 266))	('anastomotic leaks', 'Disease', (305, 322))	('blood loss', 'Disease', 'MESH:D006473', (161, 171))	('patients', 'Species', '9606', (384, 392))	('pneumonia', 'Disease', (236, 245))	('pneumonia', 'Disease', 'MESH:D011014', (236, 245))	('atrial fibrillation', 'Disease', 'MESH:D001281', (247, 266))	('MIE', 'Chemical', '-', (91, 94))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (247, 266))	('laryngeal nerve injury', 'Disease', (278, 300))	('patients', 'Species', '9606', (331, 339))
601216	22919374	For MIE or hybrid MIE, 30-day mortality was 2.3%, combined major and minor morbidity was 46.2%, anastomotic leak rate was 7.7%, and respiratory tract infection rate was 13.2%.	('MIE', 'Var', (4, 7))	('respiratory tract infection', 'Disease', 'MESH:D012141', (132, 159))	('MIE', 'Chemical', '-', (18, 21))	('anastomotic leak', 'Disease', 'MESH:D057868', (96, 112))	('respiratory tract infection', 'Phenotype', 'HP:0011947', (132, 159))	('anastomotic leak', 'Disease', (96, 112))	('respiratory tract infection', 'Disease', (132, 159))	('MIE', 'Chemical', '-', (4, 7))
601220	22919374	Blood loss for MIE (compared to open esophagectomy) was uniformly lower in all studies, whereas hospital and ICU length of stay, total complication rate, and pulmonary complications were significantly lower with MIE in most studies.	('Blood', 'MPA', (0, 5))	('pulmonary complications', 'Disease', (158, 181))	('lower', 'NegReg', (66, 71))	('MIE', 'Chemical', '-', (212, 215))	('MIE', 'Chemical', '-', (15, 18))	('pulmonary complications', 'Phenotype', 'HP:0006532', (158, 181))	('hospital and', 'CPA', (96, 108))	('pulmonary complications', 'Disease', 'MESH:D008171', (158, 181))	('lower', 'NegReg', (201, 206))	('MIE', 'Var', (212, 215))
601224	22919374	Blood loss, ICU length of stay, overall hospital stay, and total morbidity were significantly lower in the MIE group.	('Blood loss', 'CPA', (0, 10))	('MIE', 'Var', (107, 110))	('MIE', 'Chemical', '-', (107, 110))	('lower', 'NegReg', (94, 99))	('ICU length of stay', 'CPA', (12, 30))
601226	22919374	Median number of lymph nodes retrieved was significantly higher with MIE versus open esophagectomy (16 versus 10) attributed to better visualization with MIE.	('MIE', 'Var', (69, 72))	('MIE', 'Chemical', '-', (69, 72))	('MIE', 'Chemical', '-', (154, 157))	('higher', 'PosReg', (57, 63))
601228	22919374	It was found that total complications were lower with MIE (odds ratio or OR 1.93, 95% confidence interval or CI 1.08-3.43 for open versus MIE).	('MIE', 'Chemical', '-', (54, 57))	('MIE', 'Var', (54, 57))	('MIE', 'Chemical', '-', (138, 141))	('lower', 'NegReg', (43, 48))
601233	22919374	Reintervention rate was higher with MIE compared to open (21% versus 17.6%, P = 0.006).	('Reintervention', 'MPA', (0, 14))	('MIE', 'Var', (36, 39))	('MIE', 'Chemical', '-', (36, 39))
601264	22919374	At 3 months, postoperative fatigue, general pain, and gastrointestinal pain were all less with MIE.	('fatigue', 'Phenotype', 'HP:0012378', (27, 34))	('gastrointestinal pain', 'Disease', (54, 75))	('pain', 'Phenotype', 'HP:0012531', (71, 75))	('MIE', 'Chemical', '-', (95, 98))	('less', 'NegReg', (85, 89))	('postoperative fatigue', 'Phenotype', 'HP:0030973', (13, 34))	('MIE', 'Var', (95, 98))	('pain', 'Phenotype', 'HP:0012531', (44, 48))	('pain', 'Disease', 'MESH:D010146', (71, 75))	('postoperative fatigue', 'Disease', 'MESH:D005221', (13, 34))	('pain', 'Disease', (71, 75))	('postoperative fatigue', 'Disease', (13, 34))	('pain', 'Disease', 'MESH:D010146', (44, 48))	('pain', 'Disease', (44, 48))	('gastrointestinal pain', 'Disease', 'MESH:D010146', (54, 75))	('gastrointestinal pain', 'Phenotype', 'HP:0002027', (54, 75))
601271	22919374	The reflux score was slightly worse in the MIE group (P = 0.02), and there was no significant difference in the dumping symptoms between open and MIE.	('worse', 'NegReg', (30, 35))	('MIE', 'Chemical', '-', (146, 149))	('reflux score', 'MPA', (4, 16))	('MIE', 'Var', (43, 46))	('MIE', 'Chemical', '-', (43, 46))
601285	22919374	The data suggest that operative mortality is not significantly different between open and MIE, and operative morbidity in a few studies is improved after MIE.	('MIE', 'Chemical', '-', (90, 93))	('operative morbidity', 'CPA', (99, 118))	('MIE', 'Var', (154, 157))	('improved', 'PosReg', (139, 147))	('MIE', 'Chemical', '-', (154, 157))
601301	18553366	In this initial study, histologic downgrading of dysplasia after PDT was associated with the loss of biomarkers that have been associated with progression of neoplasia in Barrett esophagus.	('biomarkers', 'MPA', (101, 111))	('neoplasia', 'Disease', 'MESH:D009369', (158, 167))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (171, 188))	('loss', 'NegReg', (93, 97))	('dysplasia', 'Disease', (49, 58))	('PDT', 'Var', (65, 68))	('downgrading', 'NegReg', (34, 45))	('dysplasia', 'Disease', 'MESH:D004476', (49, 58))	('neoplasia', 'Disease', (158, 167))	('neoplasia', 'Phenotype', 'HP:0002664', (158, 167))
601302	18553366	Patients with persistently positive biomarkers appeared to be at a higher risk of recurrent HGD.	('recurrent HGD', 'Phenotype', 'HP:0410246', (82, 95))	('Patients', 'Species', '9606', (0, 8))	('HGD', 'Disease', (92, 95))	('biomarkers', 'Var', (36, 46))
601306	18553366	Interruption of the metaplasia-dysplasia-carcinoma sequence by ablating or resecting this at-risk mucosa has been proposed as a strategy to reduce the incidence of esophageal adenocarcinoma and has served as the rationale for the recommendation of esophagectomy for patients with HGD.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('patients', 'Species', '9606', (266, 274))	('reduce', 'NegReg', (140, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (20, 50))	('ablating', 'Var', (63, 71))	('metaplasia-dysplasia-carcinoma', 'Disease', (20, 50))	('men', 'Species', '9606', (235, 238))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (164, 189))	('esophageal adenocarcinoma', 'Disease', (164, 189))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (164, 189))
601310	18553366	Thirteen percent of patients who received PDT plus omeprazole progressed to cancer compared with 28% of patients in the omeprazole group.	('omeprazole', 'Chemical', 'MESH:D009853', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('patients', 'Species', '9606', (104, 112))	('PDT', 'Var', (42, 45))	('progressed', 'PosReg', (62, 72))	('patients', 'Species', '9606', (20, 28))	('omeprazole', 'Chemical', 'MESH:D009853', (120, 130))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
601314	18553366	Loss of these genes by allelic loss (deletions or loss of heterozygosity [LOH]), point mutations, or promoter hypermethylation (for p16) have been observed in a substantial number of patients with BE.	('deletions', 'Var', (37, 46))	('point mutations', 'Var', (81, 96))	('loss', 'NegReg', (31, 35))	('promoter hypermethylation', 'Var', (101, 126))	('p16', 'Gene', '1029', (132, 135))	('Loss', 'NegReg', (0, 4))	('loss of', 'NegReg', (50, 57))	('p16', 'Gene', (132, 135))	('patients', 'Species', '9606', (183, 191))
601319	18553366	We hypothesized that patients who remain positive for genetic alterations despite achieving a histologic response to PDT would be at risk for recurrence of dysplasia.	('dysplasia', 'Disease', (156, 165))	('positive', 'Reg', (41, 49))	('patients', 'Species', '9606', (21, 29))	('dysplasia', 'Disease', 'MESH:D004476', (156, 165))	('genetic alterations', 'Var', (54, 73))
601363	18553366	Despite the elimination of dysplasia, a substantial minority of patients (5%-19%) remained positive by FISH, particularly for gains at oncogene loci (8q24, 17q31.1).	('dysplasia', 'Disease', (27, 36))	('patients', 'Species', '9606', (64, 72))	('dysplasia', 'Disease', 'MESH:D004476', (27, 36))	('oncogene', 'Gene', (135, 143))	('8q24', 'Var', (150, 154))	('gains', 'PosReg', (126, 131))
601415	33374564	Regarding diffusion parameters, there were several statistically significant correlations for the gross tumor volume (GTV) volume as well as Dmean and V5Gy-V30Gy of the lung that are shown in Table 1.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('significant', 'Reg', (65, 76))	('tumor', 'Disease', (104, 109))	('V5Gy-V30Gy', 'Var', (151, 161))	('Dmean', 'Chemical', '-', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
601416	33374564	For the blood gas analysis (partial pressure of carbon dioxide (pCO2) and partial pressure of oxygen (pO2)), there were statistically significant correlations with V60Gy (%) 12 weeks after treatment (pCO2: R = 0.294, p = 0.0031; pO2: R = 0.282, p = 0.0039), as well as the Dmean 6 months after treatment (pO2: R = -0.351, p = 0.0018).	('correlations', 'Interaction', (146, 158))	('Dmean', 'Chemical', '-', (273, 278))	('pCO2', 'Chemical', '-', (200, 204))	('pO2', 'Chemical', 'MESH:C093415', (229, 232))	('partial pressure of oxygen', 'MPA', (74, 100))	('pO2', 'Chemical', 'MESH:C093415', (305, 308))	('oxygen', 'Chemical', 'MESH:D010100', (94, 100))	('pCO2', 'Chemical', '-', (64, 68))	('pO2', 'Chemical', 'MESH:C093415', (102, 105))	('V60Gy', 'Var', (164, 169))	('carbon dioxide', 'Chemical', 'MESH:D002245', (48, 62))
601424	33374564	For Delta DLCO at 6 weeks after treatment, V15Gy, V25Gy, and V30Gy (%) and Dmean (Gy) of the lung as well as Dmean (Gy) of the heart, and for Delta DLCO at 12 weeks after RT, Dmean and D50% (Gy) of the heart remained significant.	('Dmean', 'Chemical', '-', (75, 80))	('Dmean', 'Var', (75, 80))	('V15Gy', 'Var', (43, 48))	('Dmean', 'Chemical', '-', (109, 114))	('V25Gy', 'Var', (50, 55))	('V30Gy', 'Var', (61, 66))	('Dmean', 'Chemical', '-', (175, 180))
601455	33374564	The dose constraints used for the heart were: Dmean < 35 Gy, D33% < 60 Gy, and D50% < 45 Gy.	('Dmean < 35 Gy', 'Var', (46, 59))	('D33% < 60 Gy', 'Var', (61, 73))	('D50% <', 'Var', (79, 85))	('Dmean', 'Chemical', '-', (46, 51))
601456	33374564	For our analyses, the following dose-volume parameters were analyzed: lung Dmean, V5Gy-V60Gy in 5 Gy steps, as well as heart Dmean, D33%, and D50%.	('D50%', 'Var', (142, 146))	('Dmean', 'Chemical', '-', (75, 80))	('V5Gy-V60Gy', 'Var', (82, 92))	('D33%', 'Var', (132, 136))	('Dmean', 'Chemical', '-', (125, 130))
601464	33374564	Within known dose constraints, an individual weighing of the risk radiation-induced side effects on the lung for different dose levels (e.g., V20Gy, Dmean for pneumonitis, V10Gy-V30Gy for DLCO decline, higher doses for fibrosis) should be done according to each patient's specifics on an individual basis.	('pneumonitis', 'Disease', (159, 170))	('Dmean', 'Chemical', '-', (149, 154))	('V10Gy-V30Gy', 'Var', (172, 183))	('fibrosis', 'Disease', 'MESH:D005355', (219, 227))	('fibrosis', 'Disease', (219, 227))	('pneumonitis', 'Disease', 'MESH:D011014', (159, 170))	('DLCO decline', 'MPA', (188, 200))	('V20Gy', 'Var', (142, 147))	('patient', 'Species', '9606', (262, 269))
601469	30171414	Mucosal resection covering 3/4 of the entire circumference is likely to be associated with postoperative cicatricial stenosis.	('stenosis', 'Disease', 'MESH:D003251', (117, 125))	('Mucosal', 'Var', (0, 7))	('stenosis', 'Disease', (117, 125))
601567	30171414	Although there have been a few reports on molecular-targeted drugs, epidermal growth factor receptor (EGFR) inhibitors have been reported to be associated with response rates in the range of 10-20%.	('epidermal growth factor receptor', 'Gene', (68, 100))	('epidermal growth factor receptor', 'Gene', '1956', (68, 100))	('inhibitors', 'Var', (108, 118))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
601609	30171414	In the JCOG0508 Study, cT1bN0 esophageal cancer with a limited depth of invasion (up to SM2), which was estimated to be treatable endoscopically, was treated endoscopically, and patients with pathologically confirmed complete resection who had pT1a with positive vascular invasion or pT1b received prophylactic chemoradiotherapy.	('cT1bN0', 'Var', (23, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('T1a', 'Gene', '10630', (245, 248))	('T1a', 'Gene', (245, 248))	('pT1', 'Gene', '58492', (284, 287))	('patients', 'Species', '9606', (178, 186))	('pT1', 'Gene', (244, 247))	('SM2', 'Gene', '53366', (88, 91))	('pT1', 'Gene', '58492', (244, 247))	('esophageal cancer', 'Disease', (30, 47))	('SM2', 'Gene', (88, 91))	('pT1', 'Gene', (284, 287))
601678	30171414	However, it should be kept in mind that stenting may also cause complications, causing pain and further decreasing the QOL, and the treatment(s) should be undertaken after providing adequate explanation to the patient and obtaining informed consent.	('pain', 'Disease', 'MESH:D010146', (87, 91))	('QOL', 'MPA', (119, 122))	('pain', 'Disease', (87, 91))	('causing', 'Reg', (79, 86))	('stenting', 'Var', (40, 48))	('patient', 'Species', '9606', (210, 217))	('decreasing', 'NegReg', (104, 114))	('pain', 'Phenotype', 'HP:0012531', (87, 91))
601694	10761707	L-myc Restriction Fragment Length Polymorphism in Japanese Patients with Esophageal Cancer L-myc polymorphism is a representative genetic trait related to an individual's susceptibility to several cancers.	('L-myc', 'Gene', (91, 96))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('L-myc', 'Gene', '4610', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancers', 'Disease', (197, 204))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (73, 90))	('L-myc', 'Gene', (0, 5))	('polymorphism', 'Var', (97, 109))	('L-myc', 'Gene', '4610', (0, 5))	('Esophageal Cancer', 'Disease', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Patients', 'Species', '9606', (59, 67))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))
601695	10761707	However, there have been no reports concerning the association between esophageal cancer and L-myc polymorphism.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('L-myc', 'Gene', '4610', (93, 98))	('L-myc', 'Gene', (93, 98))	('esophageal cancer', 'Disease', (71, 88))	('polymorphism', 'Var', (99, 111))
601701	10761707	These results suggest that L-myc polymorphism may be implicated as a genetic trait affecting an individual's susceptibility to esophageal cancer, at least among Japanese patients.	('patients', 'Species', '9606', (170, 178))	('esophageal cancer', 'Disease', (127, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('affecting', 'Reg', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('L-myc', 'Gene', (27, 32))	('polymorphism', 'Var', (33, 45))	('L-myc', 'Gene', '4610', (27, 32))
601715	28652754	A 48-year-old male underwent an uneventful transthoracic esophagectomy for pT3N1M0 squamous cell carcinoma in the esophagus 3 months prior.	('carcinoma in the esophagus', 'Phenotype', 'HP:0011459', (97, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('squamous cell carcinoma', 'Disease', (83, 106))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 106))	('pT3N1M0', 'Var', (75, 82))
601742	28652754	In addition, Ganeshan et al analyzed 440 postoperative patients with esophageal cancer and found that the type of approach to resection affects the incidence of PDH; transhiatal esophagectomy was associated with the highest incidence of PDH compared to other types of esophagectomy.	('DH', 'Phenotype', 'HP:0000776', (162, 164))	('DH', 'Phenotype', 'HP:0000776', (238, 240))	('DH', 'Disease', 'MESH:D065630', (162, 164))	('esophageal cancer', 'Disease', (69, 86))	('DH', 'Disease', 'MESH:D065630', (238, 240))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('transhiatal', 'Var', (166, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('patients', 'Species', '9606', (55, 63))
601747	28652754	Herniation of the intestinal tract adjacent to the gastric conduit may result in bowel obstruction, pain, or colonic and small bowel ischemia.	('bowel obstruction', 'Disease', 'MESH:D015212', (81, 98))	('pain', 'Disease', 'MESH:D010146', (100, 104))	('Herniation', 'Var', (0, 10))	('pain', 'Disease', (100, 104))	('bowel obstruction', 'Phenotype', 'HP:0005214', (81, 98))	('bowel obstruction', 'Disease', (81, 98))	('colonic and small bowel ischemia', 'Disease', 'MESH:D007511', (109, 141))	('result in', 'Reg', (71, 80))	('pain', 'Phenotype', 'HP:0012531', (100, 104))
601836	24100804	performed a meta-analysis of 33 large clinical studies and found a strong positive effect of CD3+ tumor-infiltrating lymphocytes on patients' survival.	('positive', 'PosReg', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('patients', 'Species', '9606', (132, 140))	('CD3+', 'Var', (93, 97))
601849	24100804	Specifically, neutrophil-derived hepatocyte growth factor has been correlated with increased tumor growth in lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('hepatocyte growth factor', 'Gene', '3082', (33, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('increased', 'PosReg', (83, 92))	('lung cancers', 'Disease', 'MESH:D008175', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('lung cancers', 'Phenotype', 'HP:0100526', (109, 121))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('neutrophil-derived', 'Var', (14, 32))	('lung cancers', 'Disease', (109, 121))	('hepatocyte growth factor', 'Gene', (33, 57))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
601854	24100804	For example, the presence of intratumoral neutrophils decreased the 5-year recurrence-free survival rate from 87 to just 53 %.	('recurrence-free survival', 'CPA', (75, 99))	('tumor', 'Disease', (34, 39))	('presence', 'Var', (17, 25))	('decreased', 'NegReg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
601884	24100804	It is also important to consider that Tregs could reduce the efficacy of immunotherapeutic protocols and thus, depletion of these cells could enhance vaccine-mediated anti-tumor immune responses and the efficacy of chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('reduce', 'NegReg', (50, 56))	('tumor', 'Disease', (172, 177))	('chemotherapy', 'CPA', (215, 227))	('enhance', 'PosReg', (142, 149))	('Tregs', 'Chemical', '-', (38, 43))	('efficacy of immunotherapeutic protocols', 'CPA', (61, 100))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('depletion', 'Var', (111, 120))
601934	24100804	Statistical analysis showed a remarkable correlation of the immune score with clinical outcome; patients with Im4 had a 5-year disease-free survival of 85.4 %, whereas patients with Im0 had a 5-year disease-free survival of 31.6 %.	('Im4', 'Var', (110, 113))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (96, 104))	('disease-free survival', 'CPA', (127, 148))
601977	23591277	In these studies, pathways involving insulin and insulin growth factor (IGF) as mitogens, and/or aberrations in the IGF proproliferative anti-apoptotic pathways, have been implicated in pathogenesis.	('insulin and insulin growth', 'Disease', 'MESH:C565529', (37, 63))	('aberrations', 'Var', (97, 108))	('proproliferative anti-apoptotic pathways', 'Pathway', (120, 160))
601989	23591277	Cases were patients with a diagnosis of BE, diagnosed at least 1 year after the start of the up-to-standard follow-up period in GPRD (to exclude potentially prevalent BE cases) and identified by the appropriate diagnostic codes in the GPRD database (Medcode, 4614; read code, J101611 for BE; Medcode, 5596; read code, J102500 for Barrett's ulcer of the esophagus).	('ulcer of the esophagus', 'Phenotype', 'HP:0004791', (340, 362))	('BE', 'Phenotype', 'HP:0100580', (167, 169))	('BE', 'Phenotype', 'HP:0100580', (40, 42))	('BE', 'Phenotype', 'HP:0100580', (288, 290))	('J102500', 'Var', (318, 325))	('patients', 'Species', '9606', (11, 19))	('ulcer', 'Disease', 'MESH:D014456', (340, 345))	('ulcer', 'Disease', (340, 345))
601997	23591277	GERD was defined using standard codes for reflux esophagitis and gastroesophageal reflux from the GPRD database (Medcodes 2535, 15054, 7104, 16605, 15579, 16450; read codes, J101100, J101111, J101112, J101113, J101114).	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (65, 88))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (65, 88))	('gastroesophageal reflux', 'Disease', (65, 88))	('J101111', 'Var', (183, 190))	('esophagitis', 'Phenotype', 'HP:0100633', (49, 60))	('J101114', 'Var', (210, 217))	('reflux esophagitis', 'Disease', (42, 60))	('reflux esophagitis', 'Disease', 'MESH:D005764', (42, 60))	('J101113', 'Var', (201, 208))	('J101112', 'Var', (192, 199))	('J101100', 'Var', (174, 181))
602006	23591277	However, in the presence of the interaction terms in the logistic model, this OR may not reflect the true effect of DM2.	('DM2', 'Gene', (116, 119))	('interaction', 'Var', (32, 43))	('DM2', 'Gene', '28508', (116, 119))
602015	23591277	Several investigators have assessed the potential nonme-chanical pathways by which abdominal visceral fat can increase esophageal injury, BE, and EAC risk.	('increase', 'PosReg', (110, 118))	('EAC', 'Disease', (146, 149))	('BE', 'Phenotype', 'HP:0100580', (138, 140))	('abdominal visceral fat', 'Var', (83, 105))	('esophageal injury', 'Disease', (119, 136))	('esophageal injury', 'Disease', 'MESH:D004941', (119, 136))	('EAC', 'Phenotype', 'HP:0011459', (146, 149))
602197	33921660	Kaplan-Meier survival analysis showed that the overall survival was significantly shorter in patients with high expression of the CREB1 gene than those in patients with low expression of the CREB1 gene, and the prognosis of patients with low expression of the CREB1 gene was better.	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (224, 232))	('high expression', 'Var', (107, 122))	('CREB1', 'Gene', (130, 135))	('shorter', 'NegReg', (82, 89))
602203	33921660	Current studies have found that epigenetic modifications play an important role in the occurrence and development of ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (117, 131))	('epigenetic modifications', 'Var', (32, 56))	('ovarian cancer', 'Disease', (117, 131))
602230	33921660	To identify a molecular signature-based classification, we conducted an integrated tumor map and cluster identify analysis of 9,759 tumor samples from PanCancer-33 cancers (Figure 1b) for which Gyn disease (Figure 1c), mutation (Figure 1d), and methylation (Figure 1e), and a smaller set of protein expression profiles were available.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Cancer', 'Disease', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', (83, 88))	('Gyn disease', 'Disease', (194, 205))	('Cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutation', 'Var', (219, 227))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancers', 'Disease', (164, 171))	('tumor', 'Disease', (132, 137))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
602232	33921660	The OV-like tumors are further characterized by mutations and methylation in CREB1.	('methylation', 'Var', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('OV', 'Phenotype', 'HP:0100615', (4, 6))	('CREB1', 'Gene', (77, 82))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
602233	33921660	Indeed, we mined "TCGA, PanCancer Atlas" data via the cBioPortal website for the genetic alterations of CREB1 gene.	('CGA', 'Gene', '1113', (19, 22))	('CREB1', 'Gene', (104, 109))	('Cancer', 'Disease', (27, 33))	('genetic alterations', 'Var', (81, 100))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CGA', 'Gene', (19, 22))
602235	33921660	This pan-cancer analysis also indicated that CREB1 gene alterations occurred most frequently in OV, compared with other cancer types (Figure 2a).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (9, 15))	('alterations', 'Var', (56, 67))	('OV', 'Phenotype', 'HP:0100615', (96, 98))	('CREB1', 'Gene', (45, 50))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
602236	33921660	From the diagram of CREB1 gene and the encoded protein, mutations occurred more frequently in the kinase inducible domain (KID) that is responsible for heteromerization and transactivation (Figure 2c).	('mutations', 'Var', (56, 65))	('KID', 'Disease', 'MESH:C536168', (123, 126))	('KID', 'Disease', (123, 126))
602240	33921660	Meanwhile, sub-localization of CREB1 in human cell line A-431 and U-251 MG demonstrated that CREB1 protein existed at the nucleus of A-431 and U-251 MG cells41 (Figure 3b).	('A-431', 'CellLine', 'CVCL:0037', (56, 61))	('U-251 MG', 'CellLine', 'CVCL:0021', (66, 74))	('CREB1', 'Gene', (93, 98))	('A-431', 'CellLine', 'CVCL:0037', (133, 138))	('U-251 MG', 'CellLine', 'CVCL:0021', (143, 151))	('protein', 'Protein', (99, 106))	('human', 'Species', '9606', (40, 45))	('U-251 MG', 'Var', (143, 151))
602244	33921660	Subsequently, OV patients with high levels of CREB1mRNA expression had low overall survival (Figure 3e).	('low', 'NegReg', (71, 74))	('OV', 'Phenotype', 'HP:0100615', (14, 16))	('CREB1mRNA', 'Var', (46, 55))	('patients', 'Species', '9606', (17, 25))	('overall survival', 'MPA', (75, 91))
602245	33921660	High CREB1 expression was defined as TPM in the 1st quartile, and low FBXW4 expression was defined as TPM in the 4th quartile.	('FBXW4', 'Gene', (70, 75))	('High', 'Var', (0, 4))	('FBXW4', 'Gene', '6468', (70, 75))	('expression', 'MPA', (11, 21))	('CREB1', 'Gene', (5, 10))	('expression', 'MPA', (76, 86))	('low', 'NegReg', (66, 69))
602246	33921660	The results showed that in the patients with high CREB1 expression, the gene sets were significantly enriched in OXPHOS (normalized enrichment score (NES) = 1.862, p = 0.002) (Figure 3f).	('expression', 'MPA', (56, 66))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('CREB1', 'Gene', (50, 55))	('OXPHOS', 'Disease', (113, 119))
602249	33921660	Similar to the above-mentioned TCGA data, the overall survival rate of OV patients with high CREB1 mRNA expression levels was lower than that of OV patients with low CREB1 mRNA expression levels (Figure 4c).	('OV', 'Phenotype', 'HP:0100615', (71, 73))	('high', 'Var', (88, 92))	('patients', 'Species', '9606', (148, 156))	('lower', 'NegReg', (126, 131))	('patients', 'Species', '9606', (74, 82))	('CGA', 'Gene', (32, 35))	('OV', 'Phenotype', 'HP:0100615', (145, 147))	('CGA', 'Gene', '1113', (32, 35))
602256	33921660	The cancer genomics (mutations, copy number variations, and mRNA levels) and patients' survival data in these cancer types were analyzed for the role of CREB1.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('copy number variations', 'Var', (32, 54))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('patients', 'Species', '9606', (77, 85))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
602270	33921660	Current studies have shown that the abnormal expression of several genes may be closely associated with the survival of ovarian cancer patients through the screening of gene expression profiles, and that these genes are involved in the development and progression of ovarian cancer by promoting or suppressing apoptosis, generating or reversing chemotherapy resistance.	('patients', 'Species', '9606', (135, 143))	('promoting', 'PosReg', (285, 294))	('ovarian cancer', 'Disease', (267, 281))	('ovarian cancer', 'Phenotype', 'HP:0100615', (267, 281))	('ovarian cancer', 'Disease', 'MESH:D010051', (120, 134))	('suppressing', 'NegReg', (298, 309))	('abnormal', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('chemotherapy resistance', 'CPA', (345, 368))	('genes', 'Var', (210, 215))	('involved', 'Reg', (220, 228))	('reversing', 'NegReg', (335, 344))	('ovarian cancer', 'Disease', (120, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (267, 281))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('expression', 'MPA', (45, 55))	('associated', 'Reg', (88, 98))	('apoptosis', 'CPA', (310, 319))
602273	33921660	found that the mutation of Ser l33 to Ala l33 in the CREB1 sequence, which results in an inability to be activated by phosphorylation, significantly inhibits murine ovarian granulosa cell survival.	('ovarian granulosa', 'Disease', (165, 182))	('mutation', 'Var', (15, 23))	('ovarian granulosa', 'Disease', 'MESH:D010049', (165, 182))	('Ser', 'Chemical', 'MESH:D012694', (27, 30))	('inhibits', 'NegReg', (149, 157))	('CREB1', 'Gene', (53, 58))	('murine', 'Species', '10090', (158, 164))	('Ser', 'Gene', (27, 30))	('Ala', 'Chemical', 'MESH:D000409', (38, 41))
602275	33921660	Tumor development is not only about the activation of oncogenes and inactivation of oncogenes but also about abnormal expression of apoptosis-related genes and overexpression of growth factors and uncontrolled cell cycle.	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('oncogenes', 'Gene', (84, 93))	('Tumor', 'Disease', (0, 5))	('oncogenes', 'Protein', (54, 63))	('activation', 'PosReg', (40, 50))	('apoptosis-related genes', 'Gene', (132, 155))	('expression', 'MPA', (118, 128))	('inactivation', 'Var', (68, 80))
602282	33921660	However, there is still evidence that CREB1 inhibits the proliferative effects of the stress-induced acetylcholinesterase variant AChE-R in glioblastoma, suggesting a controversial or tissue-specific role for CREB1 in human cancers.	('CREB1', 'Gene', (38, 43))	('proliferative effects', 'MPA', (57, 78))	('AChE-R', 'Gene', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('glioblastoma', 'Disease', (140, 152))	('glioblastoma', 'Disease', 'MESH:D005909', (140, 152))	('variant', 'Var', (122, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('human', 'Species', '9606', (218, 223))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('inhibits', 'NegReg', (44, 52))	('cancers', 'Disease', (224, 231))
602355	29309563	In theory, lower neoadjuvant radiation dose reduces acute toxicity, shortens time before surgery, may decrease postoperative complications, and reduce late radiation toxicity.	('postoperative complications', 'CPA', (111, 138))	('decrease', 'NegReg', (102, 110))	('reduce', 'NegReg', (144, 150))	('toxicity', 'Disease', 'MESH:D064420', (58, 66))	('toxicity', 'Disease', (58, 66))	('lower', 'Var', (11, 16))	('toxicity', 'Disease', 'MESH:D064420', (166, 174))	('toxicity', 'Disease', (166, 174))	('late radiation toxicity', 'Disease', 'MESH:D004194', (151, 174))	('shortens', 'NegReg', (68, 76))	('reduces', 'NegReg', (44, 51))	('late radiation toxicity', 'Disease', (151, 174))
602372	29309563	The primary objective of this study is to compare overall survival (OS), defined as the months from diagnosis to last contact or death, among four radiation dose groups (40-41.4, 45, 50.4, and 54 Gy).	('OS', 'Chemical', '-', (68, 70))	('death', 'Disease', 'MESH:D003643', (129, 134))	('40-41.4', 'Var', (170, 177))	('death', 'Disease', (129, 134))
602422	29713660	The dysfunction of these adhesion molecules has been implicated in esophageal disease conditions.	('esophageal disease', 'Disease', 'MESH:D004935', (67, 85))	('esophageal disease', 'Disease', (67, 85))	('dysfunction', 'Var', (4, 15))	('implicated', 'Reg', (53, 63))
602451	29713660	As summarized in Table 1, sphere formation assays have been used to characterize EADC and ESCC CSCs expressing a variety of markers, including CD54 (intercellular adhesion molecule 1), CD49f, CD44, CD271, CD90, and aldehyde dehydrogenase, either alone or in combination.	('CD271', 'Gene', (198, 203))	('CD54', 'Gene', (143, 147))	('CD90', 'Gene', '7070', (205, 209))	('CD44', 'Var', (192, 196))	('CD49f', 'Gene', '3655', (185, 190))	('CD90', 'Gene', (205, 209))	('EADC', 'Chemical', '-', (81, 85))	('CD49f', 'Gene', (185, 190))	('intercellular adhesion molecule 1', 'Gene', (149, 182))	('intercellular adhesion molecule 1', 'Gene', '3383', (149, 182))	('CD271', 'Gene', '4804', (198, 203))	('CD54', 'Gene', '3383', (143, 147))
602467	29713660	For example, Wnt3A is essential for stem cell maintenance in colonic, but not small intestinal, 3D organoids, in mice in which withdrawal of Wnt3A facilitates differentiation in murine colonic organoids.	('colonic', 'Disease', (61, 68))	('colonic', 'Disease', 'MESH:D015179', (185, 192))	('differentiation', 'CPA', (159, 174))	('facilitates', 'PosReg', (147, 158))	('withdrawal', 'Var', (127, 137))	('colonic', 'Disease', (185, 192))	('murine', 'Species', '10090', (178, 184))	('Wnt3A', 'Gene', (141, 146))	('colonic', 'Disease', 'MESH:D015179', (61, 68))	('mice', 'Species', '10090', (113, 117))
602476	29713660	DeWard et al have shown that esophageal basal keratinocytes defined by Sox2 expression comprise stem cells and transit-amplifying cells defined by distinct levels of cell surface CD73, alpha6 integrin (CD49f), and beta4 integrin expression with differential 3D organoid formation capabilities.	('beta4 integrin', 'Protein', (214, 228))	('CD49f', 'Gene', '3655', (202, 207))	('alpha6 integrin', 'Protein', (185, 200))	('CD73', 'Gene', (179, 183))	('Sox2', 'Gene', '6657', (71, 75))	('Sox2', 'Gene', (71, 75))	('CD49f', 'Gene', (202, 207))	('expression', 'Var', (76, 86))	('CD73', 'Gene', '4907', (179, 183))
602489	29713660	In studies using OTC coupled with RNA interference, genetic or pharmacologic pan-Notch inhibition showed that activated Notch signaling drives terminal differentiation by transcriptionally activating early differentiation markers such as involucrin and cytokeratin K13 in a Notch3-dependent manner.	('K13', 'Gene', (265, 268))	('activating', 'PosReg', (189, 199))	('K13', 'Gene', '3860', (265, 268))	('terminal differentiation', 'CPA', (143, 167))	('Notch', 'Var', (120, 125))
602498	29713660	In these studies, genetic modulations of these molecules resulted in impaired epithelial stratification as corroborated by altered transepithelial resistance or dextran flux, however, the absence of fibroblasts in the OTC-like system may have potentially exaggerated the observed barrier defects because the reconstituted epithelia contained much fewer regular basal cells than the typical OTC with fibroblasts.	('barrier', 'MPA', (280, 287))	('exaggerated', 'PosReg', (255, 266))	('transepithelial resistance', 'MPA', (131, 157))	('dextran flux', 'MPA', (161, 173))	('modulations', 'Var', (26, 37))	('dextran', 'Chemical', 'MESH:D003911', (161, 168))	('genetic modulations', 'Var', (18, 37))	('altered', 'Reg', (123, 130))	('impaired', 'NegReg', (69, 77))	('epithelial', 'MPA', (78, 88))
602522	29713660	Common genetic lesions in ESCC include inactivation of the p53, p120 catenin, and p16INK4A tumor-suppressor genes, as well as overexpression of the cyclin D1 and EGFR oncogenes.	('cyclin', 'Gene', (148, 154))	('p53', 'Gene', (59, 62))	('ESCC', 'Disease', (26, 30))	('genetic lesions', 'Disease', 'MESH:D020022', (7, 22))	('overexpression', 'PosReg', (126, 140))	('p16INK4A', 'Gene', (82, 90))	('EGFR', 'Gene', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('p120 catenin', 'Gene', '1500', (64, 76))	('p16INK4A', 'Gene', '1029', (82, 90))	('p120 catenin', 'Gene', (64, 76))	('genetic lesions', 'Disease', (7, 22))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('inactivation', 'Var', (39, 51))	('tumor', 'Disease', (91, 96))
602523	29713660	Our genetically engineered mouse models of ESCC, which include targeting of EGFR and cyclin D1 to esophageal epithelium coupled with or without chemically induced carcinogenesis, show esophageal epithelial hyperplasia and dysplasia, respectively.	('carcinogenesis', 'Disease', (163, 177))	('esophageal epithelial hyperplasia and dysplasia', 'Disease', 'MESH:D017573', (184, 231))	('ESCC', 'Disease', (43, 47))	('mouse', 'Species', '10090', (27, 32))	('EGFR', 'Gene', (76, 80))	('targeting', 'Var', (63, 72))	('carcinogenesis', 'Disease', 'MESH:D063646', (163, 177))	('esophageal epithelial hyperplasia', 'Phenotype', 'HP:0012859', (184, 217))
602526	29713660	In particular, concurrent EGFR overexpression and p53 mutation appeared to be necessary for malignant transformation and invasive growth of human esophageal keratinocytes.	('EGFR', 'Gene', (26, 30))	('mutation', 'Var', (54, 62))	('human', 'Species', '9606', (140, 145))	('invasive growth', 'CPA', (121, 136))	('p53', 'Gene', (50, 53))	('malignant transformation', 'CPA', (92, 116))	('overexpression', 'PosReg', (31, 45))
602535	29713660	Sato et al generated human BE tissue-derived organoids under conditions including pharmacologic Notch inhibition to promote secretory cell lineage differentiation whereas addition of fibroblast growth factor-10 permitted long-term passage of BE-derived organoids.	('secretory cell lineage differentiation', 'CPA', (124, 162))	('human', 'Species', '9606', (21, 26))	('Notch inhibition', 'Var', (96, 112))	('promote', 'PosReg', (116, 123))	('fibroblast growth factor-10', 'Gene', (183, 210))	('derived organoids', 'Chemical', '-', (245, 262))	('derived organoids', 'Chemical', '-', (37, 54))	('fibroblast growth factor-10', 'Gene', '2255', (183, 210))
602537	29713660	Jiang et al identified unique p63-positive transitional basal cells expressing cytokeratins K5 and K7 as a putative BE cell of origin along with functional validation in 3D organoid assays.	('p63', 'Gene', '8626', (30, 33))	('p63', 'Gene', (30, 33))	('cytokeratins', 'Var', (79, 91))
602543	29713660	Moreover, genetic or pharmacologic inhibition of Notch appeared to facilitate transdifferentiation of esophageal keratinocytes toward columnar-like cell phenotypes in OTC with concurrent expression of Cdx1 and c-Myc.	('c-Myc', 'Gene', '4609', (210, 215))	('Cdx1', 'Gene', '1044', (201, 205))	('Notch', 'Gene', (49, 54))	('c-Myc', 'Gene', (210, 215))	('facilitate', 'PosReg', (67, 77))	('OTC', 'Disease', (167, 170))	('inhibition', 'Var', (35, 45))	('Cdx1', 'Gene', (201, 205))	('transdifferentiation', 'CPA', (78, 98))
602547	29713660	OTC served as a testing platform for molecularly targeted therapeutics including EGFR, mutant p53, and PIK3CA.	('mutant', 'Var', (87, 93))	('PIK3CA', 'Gene', '5290', (103, 109))	('p53', 'Gene', (94, 97))	('PIK3CA', 'Gene', (103, 109))
602556	28700599	High CD147 expression reduced the 3-year survival rate (OR = 3.26, 95% CI = (1.53, 6.93), p = 0.02) and 5-year survival rate(OR = 4.35, 95% CI = (2.13, 8.90), p < 0.0001).	('High', 'Var', (0, 4))	('CD147', 'Gene', (5, 10))	('reduced', 'NegReg', (22, 29))	('3-year survival rate', 'CPA', (34, 54))	('5-year survival rate', 'CPA', (104, 124))	('CD147', 'Gene', '682', (5, 10))
602557	28700599	High CD147 expression reduced overall survival in esophageal cancer (HR = 1.60, 95% CI = (1.19, 2.15), p = 0.02).	('High', 'Var', (0, 4))	('CD147', 'Gene', (5, 10))	('esophageal cancer', 'Disease', (50, 67))	('reduced', 'NegReg', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('overall survival', 'MPA', (30, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))	('CD147', 'Gene', '682', (5, 10))
602561	28700599	High CD147 expression in patients with esophageal cancer was associated with worse survival outcomes and common clinicopathological indicators of poor prognosis.	('High', 'Var', (0, 4))	('CD147', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('survival', 'CPA', (83, 91))	('patients', 'Species', '9606', (25, 33))	('esophageal cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))	('CD147', 'Gene', '682', (5, 10))
602581	28700599	In both studies, high CD147 expression was related to poor OS.	('CD147', 'Gene', (22, 27))	('expression', 'MPA', (28, 38))	('high', 'Var', (17, 21))	('related', 'Reg', (43, 50))	('poor OS', 'Disease', (54, 61))	('CD147', 'Gene', '682', (22, 27))
602584	28700599	Without heterogeneity (p = 0.61, I2 = 0%), a fixed-effects model showed that high CD147 expression (57.95%) was statistically significantly associated with a lower 3-year survival rate than that of low expression (81.82%) (OR = 3.26, 95% CI = (1.53, 6.93), p = 0.02) (Fig 2B).	('CD147', 'Gene', '682', (82, 87))	('lower', 'NegReg', (158, 163))	('high', 'Var', (77, 81))	('CD147', 'Gene', (82, 87))	('3-year survival rate', 'CPA', (164, 184))
602586	28700599	(OR = 4.0, 95% CI = (1.46, 10.95)) and Wan and Wu (OR = 4.75, 95% CI = (1.72, 13.13)) showed that high CD147 expression is statistically significantly associated with a lower 5-year survival rate.	('expression', 'MPA', (109, 119))	('high', 'Var', (98, 102))	('5-year survival rate', 'CPA', (175, 195))	('CD147', 'Gene', '682', (103, 108))	('lower', 'NegReg', (169, 174))	('CD147', 'Gene', (103, 108))
602587	28700599	Without heterogeneity (p = 0.81, I2 = 0%), a significant difference in the 5-year survival rate was detected between groups with high CD147 expression (29.55%) and low CD147 expression (62.12%) assuming a fixed-effects model (OR = 4.35, 95% CI = (2.13, 8.90), p < 0.0001) (Fig 2C).	('expression', 'MPA', (140, 150))	('CD147', 'Gene', '682', (134, 139))	('high', 'Var', (129, 133))	('CD147', 'Gene', '682', (168, 173))	('CD147', 'Gene', (134, 139))	('CD147', 'Gene', (168, 173))
602598	28700599	A random-effects model showed a difference in the rate of high CD147 expression between the two groups (OR = 3.27, 95% CI = (1.47, 7.29), p = 0.004) with heterogeneity (I2 = 59%, p = 0.09) (Fig 3D).	('CD147', 'Gene', '682', (63, 68))	('CD147', 'Gene', (63, 68))	('high', 'Var', (58, 62))	('expression', 'MPA', (69, 79))
602617	28700599	Based on our results, we concluded that high CD147 expression was significantly associated with malignant tissues.	('high', 'Var', (40, 44))	('malignant tissues', 'CPA', (96, 113))	('associated', 'Reg', (80, 90))	('expression', 'MPA', (51, 61))	('CD147', 'Gene', '682', (45, 50))	('CD147', 'Gene', (45, 50))
602626	28700599	Last,16 studies reported an association between high CD147 expression and ESCC; therefore, our results were particularly representative of ESCC.	('CD147', 'Gene', (53, 58))	('ESCC', 'Disease', (74, 78))	('expression', 'MPA', (59, 69))	('high', 'Var', (48, 52))	('CD147', 'Gene', '682', (53, 58))
602628	28700599	also showed that high CD147 expression in Type II/III AEGs was significantly associated with cancer tissue types (esophageal cancer versus noncancerous tissues (OR = 11.81, 95%CI = (2.55, 54.64)), poor 3-year survival (OR = 4.05, 95% CI = (1.30, 12.58)), poor 5-year survival (OR = 4.00, 95% CI = (1.46, 10.95)), TNM stage (OR = 4.11, 95% CI = (1.52, 11.14)), lymph node metastasis (OR = 4.40, 95% CI = (1.64, 11.78)), and histological differentiation (OR = 3.30, 95% CI = (1.21, 9.00)).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('CD147', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TNM', 'Gene', '10178', (313, 316))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('cancer', 'Disease', (125, 131))	('TNM', 'Gene', (313, 316))	('poor 3-year survival', 'CPA', (197, 217))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('CD147', 'Gene', '682', (22, 27))	('cancer', 'Disease', (93, 99))	('histological differentiation', 'CPA', (423, 451))	('high', 'Var', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lymph node metastasis', 'CPA', (360, 381))	('poor 5-year survival', 'CPA', (255, 275))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
602630	28700599	Our results indicated that high CD147 was significantly associated with EC tissues, supporting the notion that CD147 could potentially be applied as a clinical marker for the early diagnosis of EC.	('CD147', 'Gene', '682', (32, 37))	('CD147', 'Gene', (32, 37))	('high', 'Var', (27, 31))	('associated', 'Reg', (56, 66))	('CD147', 'Gene', '682', (111, 116))	('CD147', 'Gene', (111, 116))
602631	28700599	We demonstrated that high CD147 expression strongly predicted a poorer TNM stage, invasion depth, lymph node metastasis, and a worse survival rate in patients with EC.	('TNM', 'Gene', (71, 74))	('CD147', 'Gene', '682', (26, 31))	('worse', 'NegReg', (127, 132))	('CD147', 'Gene', (26, 31))	('lymph node metastasis', 'CPA', (98, 119))	('high', 'Var', (21, 25))	('patients', 'Species', '9606', (150, 158))	('TNM', 'Gene', '10178', (71, 74))	('invasion depth', 'CPA', (82, 96))	('expression', 'MPA', (32, 42))	('poorer', 'NegReg', (64, 70))
602641	28275311	Our meta-analysis provides strong evidence that detection of CTCs in peripheral blood at baseline is an independent prognosticator of poor survival outcomes in esophageal cancer patients.	('patients', 'Species', '9606', (178, 186))	('CTCs', 'Var', (61, 65))	('esophageal cancer', 'Disease', (160, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
602652	28275311	At present, many studies on the correlations between CTC positivity and the prognoses of breast cancer, colorectal cancer, gastric cancer, and lung cancer have shown that CTCs-positivity can indicate poor prognosis.	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('CTCs-positivity', 'Var', (171, 186))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', (143, 154))	('breast cancer', 'Disease', (89, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('gastric cancer', 'Disease', (123, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('man', 'Species', '9606', (12, 15))	('colorectal cancer', 'Disease', (104, 121))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))
602825	23893879	ENG hypermethylation showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (N) (p<0.01).	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (168, 193))	('ENG', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('esophageal squamous cell carcinoma', 'Disease', (122, 156))	('N', 'Chemical', 'MESH:D009584', (223, 224))	('esophageal adenocarcinoma', 'Disease', (168, 193))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (122, 156))	('ENG', 'Gene', '2022', (0, 3))	('hypermethylation', 'Var', (4, 20))
602827	23893879	ENG hypermethylation frequency was 46.2% in ESCC and 11.9% in N, but increased early and sequentially during EAC-associated neoplastic progression, to 13.3% in Barrett's metaplasia (BE), 25% in dysplastic BE (D), and 26.9% in frank EAC.	('BE', 'Chemical', '-', (205, 207))	('D', 'Chemical', 'MESH:D003903', (209, 210))	('ENG', 'Gene', (0, 3))	('increased', 'PosReg', (69, 78))	('dysplastic', 'Disease', (194, 204))	('BE', 'Chemical', '-', (182, 184))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('dysplastic', 'Disease', 'MESH:D004416', (194, 204))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (160, 180))	('N', 'Chemical', 'MESH:D009584', (1, 2))	("Barrett's metaplasia", 'Disease', (160, 180))	('ENG', 'Gene', '2022', (0, 3))	('hypermethylation', 'Var', (4, 20))
602830	23893879	We conclude that promoter hypermethylation of ENG is a frequent, tissue-specific event in human ESCC and exhibits a field defect with promising biomarker potential for the early detection of ESCC.	('ENG', 'Gene', '2022', (46, 49))	('human', 'Species', '9606', (90, 95))	('promoter hypermethylation', 'Var', (17, 42))	('ENG', 'Gene', (46, 49))	('ESCC', 'Disease', (96, 100))
602831	23893879	In addition, ENG hypermethylation occurs in a subset of human EAC, and early during BE-associated esophageal neoplastic progression.	('occurs', 'Reg', (34, 40))	('human', 'Species', '9606', (56, 61))	('ENG', 'Gene', '2022', (13, 16))	('EAC', 'Disease', (62, 65))	('ENG', 'Gene', (13, 16))	('hypermethylation', 'Var', (17, 33))	('BE', 'Chemical', '-', (84, 86))
602837	23893879	Germline mutations in the ENG gene can lead to an autosomal dominant vascular dysplasia, hereditary hemorrhagic telangiectasia type 1 syndrome .	('Germline mutations', 'Var', (0, 18))	('autosomal dominant vascular dysplasia', 'Disease', (50, 87))	('lead to', 'Reg', (39, 46))	('telangiectasia', 'Phenotype', 'HP:0001009', (112, 126))	('ENG', 'Gene', '2022', (26, 29))	('hereditary hemorrhagic telangiectasia type 1 syndrome', 'Disease', 'MESH:D013683', (89, 142))	('ENG', 'Gene', (26, 29))	('autosomal dominant vascular dysplasia', 'Disease', 'MESH:D000783', (50, 87))
602840	23893879	Although ENG hypermethylation has been reported in human lung, colonrectal and breast cancers , there has been only one study that evaluated ENG hypermethylation in 2 ESCC patients and 16 ESCC cell lines .	('ENG', 'Gene', '2022', (141, 144))	('breast cancers', 'Phenotype', 'HP:0003002', (79, 93))	('ENG', 'Gene', (141, 144))	('colonrectal', 'Disease', (63, 74))	('breast cancers', 'Disease', 'MESH:D001943', (79, 93))	('ENG', 'Gene', '2022', (9, 12))	('breast cancers', 'Disease', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('human', 'Species', '9606', (51, 56))	('ENG', 'Gene', (9, 12))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('patients', 'Species', '9606', (172, 180))	('lung', 'Disease', (57, 61))	('hypermethylation', 'Var', (13, 29))
602842	23893879	We also evaluated the effect of the demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-dC), on reactivation of epigenetically silenced ENG in esophageal cancer cells.	('epigenetically silenced', 'Var', (111, 134))	('esophageal cancer', 'Disease', (142, 159))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (81, 89))	('ENG', 'Gene', '2022', (135, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (142, 159))	('reactivation', 'MPA', (95, 107))	('ENG', 'Gene', (135, 138))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (57, 79))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))
602867	23893879	Mean NMV and frequency of ENG hypermethylation for each tissue type are shown in Table 1.	('ENG', 'Gene', (26, 29))	('hypermethylation', 'Var', (30, 46))	('NMV', 'Chemical', '-', (5, 8))	('ENG', 'Gene', '2022', (26, 29))
602870	23893879	Similarly, the frequency of ENG hypermethylation was significantly higher in ESCC than in N (46.2% vs. 11.9%, p < 0.001), and was sequentially increased in BE (13.3%), D (25%), and EAC (26.9%) vs. N (11.9%; p > 0.05, p > 0.05 and p < 0.05, respectively, Chi-square for independence test).	('increased', 'PosReg', (143, 152))	('D', 'Chemical', 'MESH:D003903', (168, 169))	('higher', 'PosReg', (67, 73))	('N', 'Chemical', 'MESH:D009584', (197, 198))	('BE', 'Chemical', '-', (156, 158))	('ESCC', 'Disease', (77, 81))	('ENG', 'Gene', (28, 31))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('hypermethylation', 'Var', (32, 48))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('ENG', 'Gene', '2022', (28, 31))
602876	23893879	After 5-Aza-dC treatment, the NMV of ENG was diminished and ENG mRNA levels were increased (Figure 2).	('N', 'Chemical', 'MESH:D009584', (61, 62))	('increased', 'PosReg', (81, 90))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('ENG', 'Gene', '2022', (60, 63))	('NMV', 'Chemical', '-', (30, 33))	('5-Aza-dC', 'Var', (6, 14))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (6, 14))	('ENG', 'Gene', '2022', (37, 40))	('diminished', 'NegReg', (45, 55))	('ENG', 'Gene', (37, 40))	('ENG', 'Gene', (60, 63))
602878	23893879	Our results demonstrate that ENG promoter hypermethylation occurs frequently in human ESCC (46.2%), but only in a smaller subset of EAC (26.9%).	('hypermethylation', 'Var', (42, 58))	('ENG', 'Gene', '2022', (29, 32))	('human', 'Species', '9606', (80, 85))	('ENG', 'Gene', (29, 32))	('ESCC', 'Disease', (86, 90))
602881	23893879	In addition, ENG was hypermethylated more frequently in ESCC than in EAC.	('ESCC', 'Disease', (56, 60))	('ENG', 'Gene', '2022', (13, 16))	('hypermethylated', 'Var', (21, 36))	('ENG', 'Gene', (13, 16))
602882	23893879	Taken together, these findings imply that hypermethylation of ENG is a common event in ESCC, occurs early in some subjects during the development of EAC, increases in frequency during Barrett's-associated esophageal adenocarcinogenesis, and is a cell type-specific event (i.e., more common in ESCC than in EAC).	('increases', 'PosReg', (154, 163))	('hypermethylation', 'Var', (42, 58))	('esophageal adenocarcinogenesis', 'Disease', (205, 235))	('esophageal adenocarcinogenesis', 'Disease', 'MESH:D004941', (205, 235))	('ESCC', 'Disease', (87, 91))	('ENG', 'Gene', '2022', (62, 65))	('ESCC', 'Disease', (293, 297))	('ENG', 'Gene', (62, 65))	('EAC', 'Disease', (149, 152))
602884	23893879	Thus, ENG hypermethylation appears to constitute a critical field-defect event in human ESCC.	('hypermethylation', 'Var', (10, 26))	('ESCC', 'Disease', (88, 92))	('ENG', 'Gene', (6, 9))	('human', 'Species', '9606', (82, 87))	('ENG', 'Gene', '2022', (6, 9))
602886	23893879	ENG was significantly downregulated in non-small cell lung cancer based on Affymetrix GeneChip assay, and its promoter was aberrantly methylated in 5 (71%) of 7 lung cancer cell lines, in 11 (69%) of 16 primary lung tumors, and in 4 (80%) of 5 normal lung tissues based on combined bisulfite restriction analysis .	('lung tumors', 'Disease', (211, 222))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (43, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bisulfite', 'Chemical', 'MESH:C042345', (282, 291))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (39, 65))	('ENG', 'Gene', (0, 3))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('non-small cell lung cancer', 'Disease', (39, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('aberrantly methylated', 'Var', (123, 144))	('lung tumors', 'Disease', 'MESH:D008175', (211, 222))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('downregulated', 'NegReg', (22, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('lung tumors', 'Phenotype', 'HP:0100526', (211, 222))	('lung cancer', 'Disease', (161, 172))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (39, 65))	('ENG', 'Gene', '2022', (0, 3))
602887	23893879	Based on qMSP assays, ENG was methylated in 3 of 34 colon cancers, but not in normal colonic mucosae.	('methylated', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colonic mucosae', 'Disease', 'MESH:D015179', (85, 100))	('colonic mucosae', 'Disease', (85, 100))	('colon cancers', 'Disease', 'MESH:D015179', (52, 65))	('ENG', 'Gene', '2022', (22, 25))	('colon cancers', 'Phenotype', 'HP:0003003', (52, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('ENG', 'Gene', (22, 25))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('colon cancers', 'Disease', (52, 65))
602888	23893879	In a large cohort of invasive breast cancers, lack of ENG expression in the tumor cell compartment correlated with ENG gene methylation and poor clinical outcome, and its expression in breast tumor cells suppressed invasion and metastasis .	('invasive breast cancers', 'Disease', 'MESH:D001943', (21, 44))	('tumor', 'Disease', (76, 81))	('ENG', 'Gene', '2022', (54, 57))	('breast tumor', 'Phenotype', 'HP:0100013', (185, 197))	('breast cancers', 'Phenotype', 'HP:0003002', (30, 44))	('invasive breast cancers', 'Disease', (21, 44))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('breast tumor', 'Disease', (185, 197))	('suppressed', 'NegReg', (204, 214))	('ENG', 'Gene', (54, 57))	('methylation', 'Var', (124, 135))	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ENG', 'Gene', '2022', (115, 118))	('lack', 'NegReg', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('ENG', 'Gene', (115, 118))	('breast tumor', 'Disease', 'MESH:D001943', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
602891	23893879	It has been reported that hypermethylation of gene promoters in histologically normal tissue can be related to the initiation of carcinomas .	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('hypermethylation', 'Var', (26, 42))	('initiation of carcinomas', 'Disease', (115, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('related', 'Reg', (100, 107))	('initiation of carcinomas', 'Disease', 'MESH:D007319', (115, 139))
602892	23893879	For example, methylation of the MLH1 promoter was observed in small foci of normal colonic epithelial cells from patients with colon cancer and was associated with silencing of this gene, but was not observed in sections of normal colon from healthy volunteers, suggesting that tumors with gene silencing due to epigenetic alteration may evolve from rare clones of methylated cells in normal epithelia.	('MLH1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('gene silencing', 'NegReg', (290, 304))	('tumors', 'Disease', (278, 284))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('methylation', 'Var', (13, 24))	('patients', 'Species', '9606', (113, 121))	('colon cancer', 'Disease', 'MESH:D015179', (127, 139))	('colon cancer', 'Phenotype', 'HP:0003003', (127, 139))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('epigenetic alteration', 'Var', (312, 333))	('colon cancer', 'Disease', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('MLH1', 'Gene', '4292', (32, 36))
602897	23893879	It can therefore be hypothesized that increased ENG methylation in normal esophageal cells extends their lifespan enough to put them at higher risk for future malignant evolution.	('ENG', 'Gene', (48, 51))	('lifespan', 'CPA', (105, 113))	('extends', 'PosReg', (91, 98))	('methylation', 'Var', (52, 63))	('increased', 'PosReg', (38, 47))	('ENG', 'Gene', '2022', (48, 51))
602899	23893879	These results also further imply that hypermethylation of ENG is an early and unique event, constituting a potentially powerful biomarker for early ESCC detection.	('hypermethylation', 'Var', (38, 54))	('ENG', 'Gene', (58, 61))	('ENG', 'Gene', '2022', (58, 61))
602901	23893879	In agreement with previous findings , the current study found that methylation of ENG in ESCC cancer cell lines was associated with silenced or reduced expression of ENG mRNA.	('ENG', 'Gene', (82, 85))	('reduced', 'NegReg', (144, 151))	('N', 'Chemical', 'MESH:D009584', (167, 168))	('ENG', 'Gene', '2022', (166, 169))	('ENG', 'Gene', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('N', 'Chemical', 'MESH:D009584', (172, 173))	('ENG', 'Gene', '2022', (82, 85))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('expression', 'MPA', (152, 162))	('cancer', 'Disease', (94, 100))	('methylation', 'Var', (67, 78))
602905	23893879	In addition, the known involvement of ENG in angiogenesis suggests the possibility that anti-angiogenesis therapy may be directed toward a subset of these patients, such as those whose tumors lack ENG methylation.	('ENG', 'Gene', '2022', (38, 41))	('ENG', 'Gene', (38, 41))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('involvement', 'Reg', (23, 34))	('ENG', 'Gene', '2022', (197, 200))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('ENG', 'Gene', (197, 200))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('methylation', 'Var', (201, 212))
602906	23893879	The current findings establish that hypermethylation of the ENG promoter, leading to gene silencing, is a common event in human ESCC.	('human', 'Species', '9606', (122, 127))	('ENG', 'Gene', '2022', (60, 63))	('hypermethylation', 'Var', (36, 52))	('gene', 'MPA', (85, 89))	('ESCC', 'Disease', (128, 132))	('ENG', 'Gene', (60, 63))
602907	23893879	In addition, these results show that ENG hypermethylation occurs early during a subset of Barrett's-associated esophageal adenocarcinogenesis.	('hypermethylation', 'Var', (41, 57))	('esophageal adenocarcinogenesis', 'Disease', 'MESH:D004941', (111, 141))	('ENG', 'Gene', '2022', (37, 40))	('ENG', 'Gene', (37, 40))	('esophageal adenocarcinogenesis', 'Disease', (111, 141))
602913	22593728	The patient was treated with CDDP (80 mg/m2) on day 1 and VP-16 (100 mg/m2) on days 1, 3, and 5, every 4 weeks.	('VP-16', 'Gene', '3054', (58, 63))	('patient', 'Species', '9606', (4, 11))	('CDDP', 'Chemical', '-', (29, 33))	('VP-16', 'Gene', (58, 63))	('100', 'Var', (65, 68))
602953	22593728	The t-CDDP concentration decreased abruptly immediately after administration of CDDP (alphaphase); afterward it decreased more slowly (betaphase) (Fig.	('CDDP', 'Chemical', '-', (80, 84))	('decreased', 'NegReg', (25, 34))	('t-CDDP concentration', 'MPA', (4, 24))	('t-CDDP', 'Chemical', '-', (4, 10))	('CDDP', 'Var', (80, 84))	('CDDP', 'Chemical', '-', (6, 10))
603024	20197389	In view of these results, we determined whether 2-ME2 reduces BEAC tumor growth.	('BEAC', 'Disease', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('BE', 'Chemical', 'MESH:D001608', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('2-ME2', 'Chemical', 'MESH:D000077584', (48, 53))	('tumor', 'Disease', (67, 72))	('reduces', 'NegReg', (54, 61))	('2-ME2', 'Var', (48, 53))
603026	20197389	The evidence presented points out that the impact of 2-ME2 on beta-catenin-orchestrated signal transduction plausibly plays a multi-faceted functional role to inhibit the proliferation and cell migration of 2-ME2 treated malignant cells and it could be a potential candidate in novel treatment strategies for Barrett's esophageal adenocarcinoma.	('2-ME2', 'Chemical', 'MESH:D000077584', (53, 58))	('cell migration', 'CPA', (189, 203))	('beta-catenin', 'Gene', (62, 74))	('2-ME2', 'Var', (53, 58))	("Barrett's esophageal adenocarcinoma", 'Disease', 'MESH:D001471', (309, 344))	('2-ME2', 'Chemical', 'MESH:D000077584', (207, 212))	('proliferation', 'CPA', (171, 184))	('beta-catenin', 'Gene', '1499', (62, 74))	("Barrett's esophageal adenocarcinoma", 'Phenotype', 'HP:0100580', (309, 344))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	("Barrett's esophageal adenocarcinoma", 'Disease', (309, 344))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (319, 344))	('inhibit', 'NegReg', (159, 166))
603039	20197389	Notable among many cancers causing pathways is the deregulation of beta-catenin activity that has been shown to augment tumor proliferation and survival and propagate cancer metastases.	('augment', 'PosReg', (112, 119))	('cancer metastases', 'Disease', (167, 184))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('deregulation', 'Var', (51, 63))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('activity', 'MPA', (80, 88))	('cancer metastases', 'Disease', 'MESH:D009362', (167, 184))	('beta-catenin', 'Gene', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('beta-catenin', 'Gene', '1499', (67, 79))	('tumor', 'Disease', (120, 125))
603040	20197389	Expectably, anticancer therapies that correct the aberrant beta-catenin functions are emerging as novel chemotherapeutics against a subset of tumors.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('beta-catenin', 'Gene', '1499', (59, 71))	('cancer', 'Disease', (16, 22))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('aberrant', 'Var', (50, 58))	('beta-catenin', 'Gene', (59, 71))
603048	20197389	We have established that the cytotoxic effects of 2-ME2 occur in parallel with increased expression of membranous beta-catenin and enhanced beta-catenin-E-cadherin association at the plasma membrane of 2-ME2 treated cells.	('E-cadherin', 'Gene', (153, 163))	('beta-catenin', 'Gene', (114, 126))	('increased', 'PosReg', (79, 88))	('expression', 'MPA', (89, 99))	('association', 'Interaction', (164, 175))	('E-cadherin', 'Gene', '999', (153, 163))	('beta-catenin', 'Gene', '1499', (140, 152))	('2-ME2', 'Chemical', 'MESH:D000077584', (50, 55))	('expression', 'Species', '29278', (89, 99))	('2-ME2', 'Var', (50, 55))	('beta-catenin', 'Gene', '1499', (114, 126))	('2-ME2', 'Chemical', 'MESH:D000077584', (202, 207))	('enhanced', 'PosReg', (131, 139))	('beta-catenin', 'Gene', (140, 152))
603049	20197389	We also describe that by selecting the beta-catenin-E-cadherin membranous complex as a specific drug target 2-ME2 efficiently inhibits cell motility of BEAC cells.	('inhibits', 'NegReg', (126, 134))	('beta-catenin', 'Gene', (39, 51))	('cell motility of BEAC cells', 'CPA', (135, 162))	('BE', 'Chemical', 'MESH:D001608', (152, 154))	('E-cadherin', 'Gene', (52, 62))	('2-ME2', 'Chemical', 'MESH:D000077584', (108, 113))	('beta-catenin', 'Gene', '1499', (39, 51))	('2-ME2', 'Var', (108, 113))	('E-cadherin', 'Gene', '999', (52, 62))
603077	20197389	The objective of this study was to evaluate if 2-ME2 is able to exhibit an anti-proliferative effect on Bic-1 and OE33 cells.	('2-ME2', 'Chemical', 'MESH:D000077584', (47, 52))	('2-ME2', 'Var', (47, 52))	('Bic-1', 'Chemical', '-', (104, 109))	('anti-proliferative effect', 'CPA', (75, 100))
603088	20197389	These findings suggest that the common denominator in 2-ME2-triggerred programmed cell death is elevating of the Bax/Bcl-2 protein ratio.	('elevating', 'PosReg', (96, 105))	('Bcl-2', 'Gene', '596', (117, 122))	('2-ME2-triggerred', 'Var', (54, 70))	('Bax', 'Gene', (113, 116))	('2-ME2', 'Chemical', 'MESH:D000077584', (54, 59))	('programmed', 'Disease', (71, 81))	('Bax', 'Gene', '581', (113, 116))	('Bcl-2', 'Gene', (117, 122))
603090	20197389	Our goal was to evaluate whether beta-catenin could be a target molecule of 2-ME2 to exert its catastrophic effect on Barrett's adenocarcinoma cells.	('2-ME2', 'Var', (76, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('beta-catenin', 'Gene', (33, 45))	('adenocarcinoma', 'Disease', (128, 142))	('beta-catenin', 'Gene', '1499', (33, 45))	('2-ME2', 'Chemical', 'MESH:D000077584', (76, 81))
603096	20197389	These reports led us to investigate whether 2-ME2 would alter the cellular levels of beta-catenin in Bic-1 cell lysates to achieve its antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Bic-1', 'Chemical', '-', (101, 106))	('beta-catenin', 'Gene', '1499', (85, 97))	('2-ME2', 'Chemical', 'MESH:D000077584', (44, 49))	('2-ME2', 'Var', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('alter', 'Reg', (56, 61))	('beta-catenin', 'Gene', (85, 97))
603099	20197389	As a result of our unforeseen observations showing that 2-ME2 effectively induces rather than reduce the total intracellular beta-catenin protein expression in Bic-1 cell lysates (Fig.	('induces', 'Reg', (74, 81))	('beta-catenin', 'Gene', (125, 137))	('Bic-1', 'Chemical', '-', (160, 165))	('beta-catenin', 'Gene', '1499', (125, 137))	('expression', 'Species', '29278', (146, 156))	('2-ME2', 'Chemical', 'MESH:D000077584', (56, 61))	('reduce', 'NegReg', (94, 100))	('2-ME2', 'Var', (56, 61))
603100	20197389	3A), we hypothesized that 2-ME2 treatments may change the beta-catenin distribution intercellularly to mediate its antiproliferative actions.	('beta-catenin', 'Gene', (58, 70))	('change', 'Reg', (47, 53))	('2-ME2', 'Chemical', 'MESH:D000077584', (26, 31))	('beta-catenin', 'Gene', '1499', (58, 70))	('2-ME2', 'Var', (26, 31))	('antiproliferative actions', 'CPA', (115, 140))
603105	20197389	Taken together, these data indicate that 2-ME2 exclusively upregulates beta-catenin expression in Bic-1 cells at the plasma membrane fractions, and that event could be responsible for the growth inhibitory properties of 2-ME2 on malignant cells.	('upregulates', 'PosReg', (59, 70))	('Bic-1', 'Chemical', '-', (98, 103))	('expression', 'Species', '29278', (84, 94))	('2-ME2', 'Chemical', 'MESH:D000077584', (220, 225))	('expression', 'MPA', (84, 94))	('beta-catenin', 'Gene', (71, 83))	('2-ME2', 'Chemical', 'MESH:D000077584', (41, 46))	('2-ME2', 'Var', (41, 46))	('beta-catenin', 'Gene', '1499', (71, 83))
603109	20197389	Anti-cancer strategies that modulate the subcellular distribution of beta-catenin-E-cadherin to promote cell-to-cell adhesion are increasingly being viewed as novel, especially in the setting of invasive cancers with deregulated beta-catenin signaling.	('cancer', 'Disease', (204, 210))	('modulate', 'Var', (28, 36))	('cell-to-cell adhesion', 'CPA', (104, 125))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('invasive cancers', 'Disease', 'MESH:D009362', (195, 211))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('beta-catenin', 'Gene', (69, 81))	('cancer', 'Disease', (5, 11))	('beta-catenin', 'Gene', '1499', (69, 81))	('promote', 'PosReg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('E-cadherin', 'Gene', (82, 92))	('invasive cancers', 'Disease', (195, 211))	('beta-catenin', 'Gene', (229, 241))	('E-cadherin', 'Gene', '999', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('beta-catenin', 'Gene', '1499', (229, 241))
603110	20197389	Within that context and to further expand on our findings that 2-ME2 induces preferential expression of membranous beta-catenin in Bic-1 cells, we explored the hypothesis whether 2-ME2 treatments could promote beta-catenin-E-cadherin binding in Bic-1 cells.	('Bic-1', 'Chemical', '-', (131, 136))	('Bic-1', 'Chemical', '-', (245, 250))	('beta-catenin', 'Gene', (115, 127))	('beta-catenin', 'Gene', '1499', (210, 222))	('binding', 'Interaction', (234, 241))	('expression', 'Species', '29278', (90, 100))	('promote', 'PosReg', (202, 209))	('2-ME2', 'Chemical', 'MESH:D000077584', (179, 184))	('expression', 'MPA', (90, 100))	('2-ME2', 'Chemical', 'MESH:D000077584', (63, 68))	('E-cadherin', 'Gene', (223, 233))	('2-ME2', 'Var', (63, 68))	('E-cadherin', 'Gene', '999', (223, 233))	('beta-catenin', 'Gene', '1499', (115, 127))	('beta-catenin', 'Gene', (210, 222))
603112	20197389	As noted earlier, the augmentation of beta-catenin-E-cadherin binding and/or correction of E-cadherin deficiency in tumor cells lead to inhibition of tumor cell migration, a hallmark of invasive phenotype.	('correction', 'Var', (77, 87))	('augmentation', 'PosReg', (22, 34))	('beta-catenin', 'Gene', (38, 50))	('binding', 'Interaction', (62, 69))	('deficiency', 'Var', (102, 112))	('E-cadherin', 'Gene', (91, 101))	('beta-catenin', 'Gene', '1499', (38, 50))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('E-cadherin', 'Gene', '999', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('inhibition', 'NegReg', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (150, 155))	('E-cadherin', 'Gene', (51, 61))	('E-cadherin', 'Gene', '999', (51, 61))
603128	20197389	We found silencing of beta-catenin gene in Bic-1 cells promoted their cell migration as compared to the corresponding controls (Fig.	('beta-catenin', 'Gene', '1499', (22, 34))	('silencing', 'Var', (9, 18))	('cell migration', 'CPA', (70, 84))	('Bic-1', 'Chemical', '-', (43, 48))	('beta-catenin', 'Gene', (22, 34))	('promoted', 'PosReg', (55, 63))
603132	20197389	As shown in Figure 4B, beta-catenin protein levels enhanced significantly in 2-ME2-exposed beta-catenin-shRNA transfected Bic-1 cells at 24h.	('2-ME2', 'Chemical', 'MESH:D000077584', (77, 82))	('beta-catenin', 'Gene', (91, 103))	('transfected', 'Var', (110, 121))	('enhanced', 'PosReg', (51, 59))	('beta-catenin', 'Gene', (23, 35))	('Bic-1', 'Chemical', '-', (122, 127))	('beta-catenin', 'Gene', '1499', (91, 103))	('beta-catenin', 'Gene', '1499', (23, 35))
603134	20197389	Altogether, these results support the claim that the repressions of E-cadherin and beta-catenin protein by shRNAs are restored by 2-ME2.	('beta-catenin', 'Gene', (83, 95))	('shRNAs', 'Gene', (107, 113))	('2-ME2', 'Chemical', 'MESH:D000077584', (130, 135))	('beta-catenin', 'Gene', '1499', (83, 95))	('repressions', 'MPA', (53, 64))	('2-ME2', 'Var', (130, 135))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))
603140	20197389	To illustrate that point, measurable xenografts were noted within a week of Bic-1 inoculation into the hind leg of nude mice, whereas OE33 cells produced comparable xenografts at 3-4 weeks after implantation (Supl.	('Bic-1', 'Chemical', '-', (76, 81))	('inoculation', 'Var', (82, 93))	('nude mice', 'Species', '10090', (115, 124))	('Bic-1', 'Gene', (76, 81))
603148	20197389	Previous studies suggest that both Bic-1 and OE33 cells have mutated p53 gene.	('p53', 'Gene', '7157', (69, 72))	('p53', 'Gene', (69, 72))	('mutated', 'Var', (61, 68))	('Bic-1', 'Chemical', '-', (35, 40))
603158	20197389	2-ME2 is being increasingly recognized as a novel chemotherapy drug due to its propensity to activate a wide array of anti-cancer targets with a relative sparing of the normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('2-ME2', 'Chemical', 'MESH:D000077584', (0, 5))	('2-ME2', 'Var', (0, 5))	('cancer', 'Disease', (123, 129))	('activate', 'PosReg', (93, 101))
603159	20197389	We have carried out studies to determine the therapeutic efficacy of 2-ME2 against EAC and to identify surrogate biomarkers which would be useful in predicting its anti-cancer responses.	('EAC', 'Disease', (83, 86))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('2-ME2', 'Chemical', 'MESH:D000077584', (69, 74))	('2-ME2', 'Var', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
603160	20197389	Our studies clearly establish 2-ME2, at a concentration of 5 muM, attenuated the in vitro proliferation of BEAC-derived Bic-1 and OE33 cells through the induction of apoptosis.	('in vitro proliferation', 'CPA', (81, 103))	('2-ME2', 'Chemical', 'MESH:D000077584', (30, 35))	('attenuated', 'NegReg', (66, 76))	('muM', 'Gene', (61, 64))	('BE', 'Chemical', 'MESH:D001608', (107, 109))	('2-ME2', 'Var', (30, 35))	('Bic-1', 'Chemical', '-', (120, 125))	('apoptosis', 'CPA', (166, 175))	('muM', 'Gene', '56925', (61, 64))
603162	20197389	The growth of Bic-1 xenografts was significantly slower in the 2-ME2 group than in animals treated with vehicle (control) (Fig.	('growth', 'CPA', (4, 10))	('Bic-1', 'Gene', (14, 19))	('2-ME2', 'Chemical', 'MESH:D000077584', (63, 68))	('2-ME2', 'Var', (63, 68))	('slower', 'NegReg', (49, 55))	('Bic-1', 'Chemical', '-', (14, 19))
603163	20197389	Therefore, 2-ME2 may prove to be a therapeutic agent for patients with BEAC if its poor bioavailability in humans as well in animals is addressed.	('patients', 'Species', '9606', (57, 65))	('BEAC', 'Disease', (71, 75))	('2-ME2', 'Chemical', 'MESH:D000077584', (11, 16))	('2-ME2', 'Var', (11, 16))	('BE', 'Chemical', 'MESH:D001608', (71, 73))	('humans', 'Species', '9606', (107, 113))
603166	20197389	It is now customary knowledge that the pro-inflammatory cytokines produced by inflamed cells of BE augment the nuclear translocation of beta-catenin that eventually culminates in neoplastic transformation by transactivation of oncogenes Anderson, 2006 4931 /id;Tselepis, 2003 4883 /id}.	('beta-catenin', 'Gene', '1499', (136, 148))	('culminates in', 'Reg', (165, 178))	('BE', 'Chemical', 'MESH:D001608', (96, 98))	('nuclear translocation of', 'MPA', (111, 135))	('transactivation', 'Var', (208, 223))	('neoplastic transformation', 'CPA', (179, 204))	('beta-catenin', 'Gene', (136, 148))	('oncogenes', 'Gene', (227, 236))	('augment', 'PosReg', (99, 106))
603174	20197389	These studies strengthen our above hypothesis and suggest that 2-ME2 may be able to restore the cell adhesion property of the BEAC cells.	('cell adhesion property', 'CPA', (96, 118))	('2-ME2', 'Chemical', 'MESH:D000077584', (63, 68))	('2-ME2', 'Var', (63, 68))	('restore', 'PosReg', (84, 91))	('BE', 'Chemical', 'MESH:D001608', (126, 128))
603176	20197389	The picture evolving from our transwell motility assays is that contrary to the motile and invasive phenotype of the 2-ME2-unexposed cells, the 2-ME2-treated cells exhibit a drastic inhibition of cellular migration in E-cadherin and beta-catenin deficient Bic-1 cells.	('cellular migration', 'CPA', (196, 214))	('beta-catenin', 'Gene', (233, 245))	('2-ME2-treated', 'Var', (144, 157))	('E-cadherin', 'Gene', (218, 228))	('E-cadherin', 'Gene', '999', (218, 228))	('beta-catenin', 'Gene', '1499', (233, 245))	('2-ME2', 'Chemical', 'MESH:D000077584', (144, 149))	('Bic-1', 'Chemical', '-', (256, 261))	('inhibition', 'NegReg', (182, 192))	('2-ME2', 'Chemical', 'MESH:D000077584', (117, 122))
603177	20197389	Loss of E-cadherin expression promotes cancer dissemination through local proteolysis and via enhanced motility and migration of cancer cells across the matrigel basement membrane.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('motility', 'CPA', (103, 111))	('cancer', 'Disease', (39, 45))	('promotes', 'PosReg', (30, 38))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('enhanced', 'PosReg', (94, 102))	('Loss', 'Var', (0, 4))	('local proteolysis', 'MPA', (68, 85))	('expression', 'Species', '29278', (19, 29))
603181	20197389	Since we found that 2-ME2 enhances membrane beta-catenin and E-cadherin levels in these cells even after silencing of the expressions of these two molecules, we sought to determine how does 2-ME2 nullifies the effect of shRNA mediated down regulation of beta-catenin and E-cadherin expression?	('beta-catenin', 'Gene', (254, 266))	('expression', 'Species', '29278', (282, 292))	('E-cadherin', 'Gene', (61, 71))	('down', 'MPA', (235, 239))	('beta-catenin', 'Gene', '1499', (254, 266))	('expression', 'MPA', (282, 292))	('beta-catenin', 'Gene', (44, 56))	('E-cadherin', 'Gene', '999', (61, 71))	('2-ME2', 'Chemical', 'MESH:D000077584', (20, 25))	('2-ME2', 'Var', (20, 25))	('enhances', 'PosReg', (26, 34))	('expression', 'Species', '29278', (122, 132))	('E-cadherin', 'Gene', (271, 281))	('E-cadherin', 'Gene', '999', (271, 281))	('beta-catenin', 'Gene', '1499', (44, 56))	('2-ME2', 'Chemical', 'MESH:D000077584', (190, 195))
603182	20197389	We provide evidence to suggest that the induction of membranous beta-catenin protein and E-cadherin by 2-ME2 is accomplished by protein stabilization (Fig.	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('2-ME2', 'Chemical', 'MESH:D000077584', (103, 108))	('beta-catenin', 'Gene', (64, 76))	('2-ME2', 'Var', (103, 108))	('beta-catenin', 'Gene', '1499', (64, 76))
603184	20197389	In conclusion, after reviewing the current body of evidence, our results are the first to describe the in vitro and in vivo antitumor effects of 2-ME2 on BEAC-derived cell lines and xenografts, respectively.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('BE', 'Chemical', 'MESH:D001608', (154, 156))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('2-ME2', 'Chemical', 'MESH:D000077584', (145, 150))	('2-ME2', 'Var', (145, 150))
603188	19801978	SOX2 Is an Amplified Lineage Survival Oncogene in Lung and Esophageal Squamous Cell Carcinomas Lineage survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development.	('alterations', 'Var', (151, 162))	('cancers', 'Disease', (166, 173))	('Esophageal Squamous Cell Carcinomas', 'Disease', 'MESH:D000077277', (59, 94))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('Carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('Squamous Cell Carcinomas', 'Phenotype', 'HP:0002860', (70, 94))	('activated', 'PosReg', (126, 135))	('Esophageal Squamous Cell Carcinomas', 'Disease', (59, 94))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Lung', 'Disease', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
603190	19801978	Furthermore, ectopic expression of SOX2 cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells.	('FGFR2', 'Gene', (65, 70))	('FGFR2', 'Gene', '2263', (65, 70))	('transform', 'Reg', (74, 83))	('SOX2', 'Gene', (35, 39))	('FOXE1', 'Gene', (56, 61))	('FOXE1', 'Gene', '2304', (56, 61))	('ectopic expression', 'Var', (13, 31))
603197	19801978	Significant focal deletions including deletions of CDKN2A/B on 9p21.3 were also identified (Supplemental Table 1; Supplemental Figure 1a).	('Supplemental Figure 1a', 'Disease', 'MESH:C536041', (114, 136))	('Supplemental Figure 1a', 'Disease', (114, 136))	('CDKN2A/B', 'Gene', (51, 59))	('deletions', 'Var', (38, 47))	('CDKN2A/B', 'Gene', '1029;1030', (51, 59))
603204	19801978	Indeed, one lung SCC sample did harbor higher amplification at DCUN1D1/ATP11B than at SOX2 (Supplemental Figure 1b), and also one lung SCC sample showed amplification at 183.03-183.27 Mb on chromosome 3, syntenic to the region containing lincRNA-Sox2, a non-coding RNA identified as a target of Sox2 in mouse ES cells.	('SCC', 'Gene', '6317', (135, 138))	('lincRNA-Sox2', 'Gene', (238, 250))	('higher', 'PosReg', (39, 45))	('SCC', 'Gene', '6317', (17, 20))	('mouse', 'Species', '10090', (303, 308))	('SCC', 'Gene', (135, 138))	('amplification', 'MPA', (46, 59))	('SCC', 'Gene', (17, 20))	('DCUN1D1/ATP11B', 'Var', (63, 77))
603209	19801978	Three to ten independent shRNAs were tested and analyzed after introduction into four SCC cell lines (esophageal lines TE10 and TT and lung lines NCI-H520 and HCC95) that harbor 3q26.33 amplification and two control lung adenocarcinoma cell lines that lack 3q26.33 amplification, NCI-H1437 and NCI-H1355.	('HCC95', 'CellLine', 'CVCL:5137', (159, 164))	('lung adenocarcinoma', 'Disease', (216, 235))	('lung lines NCI-H520', 'Disease', 'MESH:D008171', (135, 154))	('SCC', 'Gene', (86, 89))	('lung lines NCI-H520', 'Disease', (135, 154))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (216, 235))	('NCI-H1355', 'CellLine', 'CVCL:1464', (294, 303))	('3q26.33 amplification', 'Var', (178, 199))	('SCC', 'Gene', '6317', (86, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (216, 235))	('NCI-H1437', 'CellLine', 'CVCL:1472', (280, 289))
603216	19801978	Further results suggest that the reduction in anchorage-independence upon SOX2 knockdown exceeds the reduction in proliferation and that SOX2 is essential for some tumor cells with lower-level copy-gain at 3q26.33 (Supplemental Note; Supplemental Figure 3c-d).	('tumor', 'Disease', (164, 169))	('reduction', 'NegReg', (33, 42))	('proliferation', 'CPA', (114, 127))	('SOX2', 'Gene', (74, 78))	('anchorage-independence', 'MPA', (46, 68))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('knockdown', 'Var', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
603217	19801978	To confirm that the effects of SOX2 shRNA are attributable to SOX2 suppression, we tested whether we could rescue the effects of suppression of SOX2 with ectopic wild-type SOX2 or SOX2 R74P, a loss-of-function DNA-binding domain mutant identified in a patient with congenital tracheoesophageal fistula.	('patient', 'Species', '9606', (252, 259))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (276, 301))	('R74P', 'Mutation', 'p.R74P', (185, 189))	('SOX2', 'Gene', (180, 184))	('congenital tracheoesophageal fistula', 'Disease', (265, 301))	('loss-of-function', 'NegReg', (193, 209))	('R74P', 'Var', (185, 189))	('tested', 'Reg', (83, 89))	('SOX2', 'Gene', (144, 148))	('congenital tracheoesophageal fistula', 'Disease', 'MESH:D014138', (265, 301))
603218	19801978	We introduced wild-type and mutant SOX2 into HCC95 cells and subsequently introduced shSOX2b, which targets the SOX2 3' UTR.	('shSOX2b', 'Gene', (85, 92))	('HCC95', 'CellLine', 'CVCL:5137', (45, 50))	('mutant', 'Var', (28, 34))
603219	19801978	Expression of wild-type SOX2 restored anchorage-independent growth, whereas SOX2 R74P or GFP control failed to do so (Figure 2e).	('restored', 'PosReg', (29, 37))	('R74P', 'Mutation', 'p.R74P', (81, 85))	('R74P', 'Var', (81, 85))	('anchorage-independent growth', 'MPA', (38, 66))
603223	19801978	FOXE1 is expressed in the epithelium of the developing esophagus, and congenital mutations cause cleft palate and hypothyroidism.	('cause', 'Reg', (91, 96))	('hypothyroidism', 'Disease', 'MESH:D007037', (114, 128))	('FOXE1', 'Gene', '2304', (0, 5))	('hypothyroidism', 'Phenotype', 'HP:0000821', (114, 128))	('FOXE1', 'Gene', (0, 5))	('cleft palate', 'Disease', (97, 109))	('cleft palate', 'Disease', 'MESH:D002972', (97, 109))	('hypothyroidism', 'Disease', (114, 128))	('mutations', 'Var', (81, 90))	('cleft palate', 'Phenotype', 'HP:0000175', (97, 109))
603224	19801978	Another highly correlated gene, the receptor tyrosine kinase gene FGFR2, was of particular interest given that activating mutations are observed in lung SCC.	('SCC', 'Gene', '6317', (153, 156))	('FGFR2', 'Gene', (66, 71))	('FGFR2', 'Gene', '2263', (66, 71))	('activating', 'PosReg', (111, 121))	('mutations', 'Var', (122, 131))	('SCC', 'Gene', (153, 156))
603228	19801978	Neither SOX2 nor FGFR2 expression alone could transform AALE cells, but the combination of SOX2 with the FGFR2 IIIb isoform found in epithelial cancers promoted anchorage-independent growth (Figure 3b).	('FGFR2', 'Gene', (17, 22))	('FGFR2', 'Gene', '2263', (17, 22))	('epithelial cancers', 'Disease', 'MESH:D000077216', (133, 151))	('combination', 'Var', (76, 87))	('anchorage-independent growth', 'CPA', (161, 189))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('epithelial cancers', 'Disease', (133, 151))	('FGFR2', 'Gene', (105, 110))	('promoted', 'PosReg', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('FGFR2', 'Gene', '2263', (105, 110))
603231	19801978	Experimentally, Nkx2.1-/- mice form hypoplastic lungs that stem from an undivided foregut with Sox2+/p63+ squamous epithelium.	('Nkx2.1-/-', 'Var', (16, 25))	('hypoplastic', 'Disease', 'MESH:D000741', (36, 47))	('hypoplastic', 'Disease', (36, 47))	('mice', 'Species', '10090', (26, 30))	('hypoplastic lungs', 'Phenotype', 'HP:0002089', (36, 53))
603234	19801978	We found SOX2 amplifications to be enriched in the lung SCC tumor population, while NKX2-1 amplification was enriched in lung adenocarcinoma (Supplemental Figure 4a-b), consistent with a previous study of NKX2-1 and with a report that the copy-number of lung adenocarcinoma and SCC are distinguished by SCC-specific amplification chromosome 3q at 180-200 Mb.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (254, 273))	('amplification chromosome', 'Var', (316, 340))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (254, 273))	('lung adenocarcinoma', 'Disease', (121, 140))	('SOX2', 'Gene', (9, 13))	('SCC', 'Gene', '6317', (303, 306))	('lung SCC tumor', 'Disease', 'MESH:D008175', (51, 65))	('SCC', 'Gene', (303, 306))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (121, 140))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('SCC', 'Gene', '6317', (278, 281))	('SCC', 'Gene', '6317', (56, 59))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (121, 140))	('NKX2-1', 'Gene', '7080', (84, 90))	('NKX2-1', 'Gene', '7080', (205, 211))	('lung adenocarcinoma', 'Disease', (254, 273))	('SCC', 'Gene', (278, 281))	('SCC', 'Gene', (56, 59))	('NKX2-1', 'Gene', (84, 90))	('NKX2-1', 'Gene', (205, 211))	('lung SCC tumor', 'Disease', (51, 65))
603239	19801978	Although the lineage-restricted nature of SOX2 amplifications in lung and esophageal SCC argues for a role as a lineage survival oncogene, we sought to determine how SOX2's role as a pluripotency factor could contribute to its oncogenic activity.	('SOX2', 'Gene', (42, 46))	('SCC', 'Gene', '6317', (85, 88))	('pluripotency', 'Disease', (183, 195))	('pluripotency', 'Disease', 'None', (183, 195))	('contribute', 'Reg', (209, 219))	('SCC', 'Gene', (85, 88))	('amplifications', 'Var', (47, 61))	('oncogenic activity', 'CPA', (227, 245))
603290	32527212	IL-1B rs2853550 polymorphism contributes to esophageal cancer susceptibility in Chinese Han population of Northwest China Esophageal cancer (EC) is one of the most common human cancers, with a particularly aggressive behavior and increased incidence worldwide.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('IL-1B', 'Gene', (0, 5))	('cancer', 'Disease', (133, 139))	('rs2853550', 'Mutation', 'rs2853550', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('aggressive behavior', 'Phenotype', 'HP:0000718', (206, 225))	('rs2853550 polymorphism', 'Var', (6, 28))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('human', 'Species', '9606', (171, 176))	('cancer', 'Disease', (55, 61))	('IL-1B', 'Gene', '3553', (0, 5))
603291	32527212	The aim of this study was to assess the associations of single-nucleotide polymorphisms (SNPs) in IL-1B with the risk of EC in a northwest Chinese Han population.	('associations', 'Interaction', (40, 52))	('IL-1B', 'Gene', '3553', (98, 103))	('IL-1B', 'Gene', (98, 103))	('single-nucleotide polymorphisms', 'Var', (56, 87))
603292	32527212	In order to evaluate the correlations between IL-1B polymorphisms and EC risk, an Agena MassARRAY platform was used to determine the genotype of the candidate SNPs among 384 EC patients and 499 controls.	('IL-1B', 'Gene', (46, 51))	('patients', 'Species', '9606', (177, 185))	('IL-1B', 'Gene', '3553', (46, 51))	('polymorphisms', 'Var', (52, 65))
603293	32527212	The associations between IL-1B variants and EC risk were examined using logistic regression analysis with adjustment for gender and age.	('IL-1B', 'Gene', '3553', (25, 30))	('variants', 'Var', (31, 39))	('IL-1B', 'Gene', (25, 30))	('associations', 'Interaction', (4, 16))
603294	32527212	Haplotype construction and analysis were performed to detect the potential associations between haplotypes within IL-1B and EC susceptibility.	('IL-1B', 'Gene', '3553', (114, 119))	('IL-1B', 'Gene', (114, 119))	('haplotypes', 'Var', (96, 106))
603295	32527212	A significant relationship was found between IL-1B rs2853550 and an increased risk of EC in the allele model [odds ratio (OR) = 1.38, 95% confidence interval (95% CI): 1.01-1.89, p = 0.041), the codominant model (A/G, OR = 1.63, 95% CI: 1.10-2.42, p = 0.011), and the dominant model (OR = 1.49, 95% CI: 1.02-2.18, p = 0.041).	('rs2853550', 'Mutation', 'rs2853550', (51, 60))	('rs2853550', 'Var', (51, 60))	('IL-1B', 'Gene', '3553', (45, 50))	('IL-1B', 'Gene', (45, 50))
603298	32527212	This study demonstrated that rs2853550 in IL-1B might increase EC susceptibility in the Chinese Han population of Northwest China.	('IL-1B', 'Gene', '3553', (42, 47))	('rs2853550', 'Var', (29, 38))	('increase', 'PosReg', (54, 62))	('IL-1B', 'Gene', (42, 47))	('rs2853550', 'Mutation', 'rs2853550', (29, 38))
603306	32527212	Previous studies have uncovered several significant IL-1B polymorphisms associated with diverse diseases in different cohorts worldwide.	('IL-1B', 'Gene', '3553', (52, 57))	('associated', 'Reg', (72, 82))	('polymorphisms', 'Var', (58, 71))	('diverse diseases', 'Disease', (88, 104))	('IL-1B', 'Gene', (52, 57))
603308	32527212	IL-1B rs16944 has been demonstrated to affect IL-1B expression and was found to be associated with increased EC risk in an Irish population (Azim et al.).	('IL-1B', 'Gene', (46, 51))	('rs16944', 'Mutation', 'rs16944', (6, 13))	('affect', 'Reg', (39, 45))	('expression', 'MPA', (52, 62))	('IL-1B', 'Gene', (0, 5))	('IL-1B', 'Gene', '3553', (46, 51))	('associated', 'Reg', (83, 93))	('rs16944', 'Var', (6, 13))	('IL-1B', 'Gene', '3553', (0, 5))
603311	32527212	Additionally, IL-1B variants have been proved to be associated with gastric cancer susceptibility (He et al.)	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('variants', 'Var', (20, 28))	('IL-1B', 'Gene', '3553', (14, 19))	('associated', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gastric cancer', 'Disease', (68, 82))	('IL-1B', 'Gene', (14, 19))
603313	32527212	Although the significant evidence has be detected between IL-1B polymorphisms and multiple diseases in numerous populations.	('IL-1B', 'Gene', '3553', (58, 63))	('multiple diseases', 'Disease', (82, 99))	('IL-1B', 'Gene', (58, 63))	('polymorphisms', 'Var', (64, 77))
603314	32527212	The relationships between IL-1B polymorphisms and EC susceptibility are seldom reported in the Han population from northwest China.	('polymorphisms', 'Var', (32, 45))	('IL-1B', 'Gene', (26, 31))	('IL-1B', 'Gene', '3553', (26, 31))
603315	32527212	Therefore, we performed the research that aimed to discover the potential roles of IL-1B variants in EC susceptibility.	('variants', 'Var', (89, 97))	('IL-1B', 'Gene', (83, 88))	('IL-1B', 'Gene', '3553', (83, 88))
603316	32527212	After reading the previous publications of IL-1B polymorphisms, we selected several SNPs as the candidate variations (Sasayama et al.	('variations', 'Var', (106, 116))	('IL-1B', 'Gene', '3553', (43, 48))	('IL-1B', 'Gene', (43, 48))
603317	32527212	In this study, we aimed to investigate the relationships between seven SNPs within IL-1B, namely rs2853550, rs1143643, rs3136558, rs1143630, rs1143627, rs16944, and rs1143623, and the risk of EC in a Han population from northwest China.	('rs1143627', 'Mutation', 'rs1143627', (141, 150))	('rs1143627', 'Var', (141, 150))	('rs16944', 'Var', (152, 159))	('rs1143630', 'Var', (130, 139))	('rs3136558', 'Var', (119, 128))	('IL-1B', 'Gene', '3553', (83, 88))	('rs1143643', 'Var', (108, 117))	('rs1143643', 'Chemical', '-', (108, 117))	('rs1143630', 'Mutation', 'rs1143630', (130, 139))	('rs16944', 'Mutation', 'rs16944', (152, 159))	('rs3136558', 'Mutation', 'rs3136558', (119, 128))	('rs2853550', 'Mutation', 'rs2853550', (97, 106))	('rs1143623', 'Mutation', 'rs1143623', (165, 174))	('rs1143623', 'Var', (165, 174))	('IL-1B', 'Gene', (83, 88))	('rs2853550', 'Var', (97, 106))
603318	32527212	Our results are supposed to provide significant evidence for the innate role of IL-1B and its polymorphisms in EC pathogenesis.	('IL-1B', 'Gene', '3553', (80, 85))	('IL-1B', 'Gene', (80, 85))	('polymorphisms', 'Var', (94, 107))
603328	32527212	According to the previous publications, several polymorphisms in IL-1B were selected as the candidates (Sasayama et al.	('IL-1B', 'Gene', '3553', (65, 70))	('IL-1B', 'Gene', (65, 70))	('polymorphisms', 'Var', (48, 61))
603331	32527212	IL-1B polymorphisms rs2853550, rs1143643, rs3136558, rs1143630, rs1143627, rs16944, and rs1143623, of which the MAFs were greater than 5% in the global population, were eventually eligible and genotyped in EC patients and healthy controls.	('MAF', 'Gene', (112, 115))	('rs1143643', 'Var', (31, 40))	('rs1143630', 'Mutation', 'rs1143630', (53, 62))	('rs2853550', 'Var', (20, 29))	('MAF', 'Gene', '4094', (112, 115))	('rs2853550', 'Mutation', 'rs2853550', (20, 29))	('rs3136558', 'Var', (42, 51))	('rs3136558', 'Mutation', 'rs3136558', (42, 51))	('rs16944', 'Var', (75, 82))	('rs1143627', 'Mutation', 'rs1143627', (64, 73))	('IL-1B', 'Gene', (0, 5))	('patients', 'Species', '9606', (209, 217))	('IL-1B', 'Gene', '3553', (0, 5))	('rs1143623', 'Mutation', 'rs1143623', (88, 97))	('rs1143630', 'Var', (53, 62))	('rs1143643', 'Chemical', '-', (31, 40))	('rs1143623', 'Var', (88, 97))	('rs16944', 'Mutation', 'rs16944', (75, 82))	('rs1143627', 'Var', (64, 73))
603338	32527212	Basic characteristics and allele frequencies of IL-1B polymorphisms are presented in Table 2.	('IL-1B', 'Gene', (48, 53))	('polymorphisms', 'Var', (54, 67))	('IL-1B', 'Gene', '3553', (48, 53))
603340	32527212	We evaluated the correlation between the IL-1B SNPs and EC susceptibility using four genetic models, hypothesizing that the minor allele of each variant was a risk factor.	('IL-1B', 'Gene', '3553', (41, 46))	('IL-1B', 'Gene', (41, 46))	('variant', 'Var', (145, 152))	('minor', 'Var', (124, 129))
603344	32527212	Furthermore, compared with the "G/G" genotype in rs2853550, the "A/G" genotype contributed to an increased risk of EC after adjusting for age and gender (OR = 1.63, 95% CI: 1.10-2.42, p = 0.011).	('rs2853550', 'Mutation', 'rs2853550', (49, 58))	('A/G', 'Var', (65, 68))	('rs2853550', 'Var', (49, 58))
603345	32527212	Additionally, after correction for age and gender, IL-1B rs2853550 was showed to be linked to an increased risk of EC based on the results of the dominant model (adjusted OR = 1.49, 95% CI:1.02-2.18, p = 0.041).	('rs2853550', 'Mutation', 'rs2853550', (57, 66))	('IL-1B', 'Gene', (51, 56))	('IL-1B', 'Gene', '3553', (51, 56))	('rs2853550', 'Var', (57, 66))
603346	32527212	However, IL-1B variants rs1143643, rs3136558, rs1143630, rs1143627, rs16944, and rs1143623 did not show evidence of a correlation with EC susceptibility in this cohort.	('rs1143643', 'Var', (24, 33))	('rs3136558', 'Mutation', 'rs3136558', (35, 44))	('rs1143630', 'Var', (46, 55))	('rs1143643', 'Chemical', '-', (24, 33))	('rs16944', 'Mutation', 'rs16944', (68, 75))	('IL-1B', 'Gene', (9, 14))	('rs1143630', 'Mutation', 'rs1143630', (46, 55))	('rs1143627', 'Mutation', 'rs1143627', (57, 66))	('variants rs1143643', 'Var', (15, 33))	('rs1143627', 'Var', (57, 66))	('rs16944', 'Var', (68, 75))	('rs1143623', 'Mutation', 'rs1143623', (81, 90))	('IL-1B', 'Gene', '3553', (9, 14))	('rs3136558', 'Var', (35, 44))	('rs1143623', 'Var', (81, 90))
603347	32527212	Finally, four IL-1B polymorphisms (rs1143630, rs1143627, rs16944, and rs1143623) mapped to a 4-kb LD block, forming four haplotypes with frequencies greater than 0.05 among our subjects (Table 4).	('rs1143623', 'Mutation', 'rs1143623', (70, 79))	('rs16944', 'Mutation', 'rs16944', (57, 64))	('rs1143630', 'Mutation', 'rs1143630', (35, 44))	('rs1143623', 'Var', (70, 79))	('rs1143627', 'Mutation', 'rs1143627', (46, 55))	('IL-1B', 'Gene', '3553', (14, 19))	('rs1143627', 'Var', (46, 55))	('rs16944', 'Var', (57, 64))	('IL-1B', 'Gene', (14, 19))	('rs1143630', 'Var', (35, 44))
603349	32527212	Unfortunately, there were no statistically significant correlations between any IL-1B haplotype and EC risk in our cohort (Table 4).	('correlations', 'Interaction', (55, 67))	('IL-1B', 'Gene', (80, 85))	('haplotype', 'Var', (86, 95))	('IL-1B', 'Gene', '3553', (80, 85))
603350	32527212	Their functional importance, particularly those of rs2853550, rs1143627, and rs16944, was evident from the low RegulomeDB score and the prediction of multiple functions in HaploReg.	('RegulomeDB score', 'MPA', (111, 127))	('rs1143627', 'Var', (62, 71))	('rs16944', 'Mutation', 'rs16944', (77, 84))	('rs2853550', 'Var', (51, 60))	('rs16944', 'Var', (77, 84))	('rs1143627', 'Mutation', 'rs1143627', (62, 71))	('rs2853550', 'Mutation', 'rs2853550', (51, 60))	('low', 'NegReg', (107, 110))
603353	32527212	In the present study, we genotyped seven polymorphisms in IL-1B and systematically evaluated their correlations with EC risk in a Chinese Han population of Northwest China.	('polymorphisms', 'Var', (41, 54))	('correlations', 'Interaction', (99, 111))	('IL-1B', 'Gene', '3553', (58, 63))	('IL-1B', 'Gene', (58, 63))
603355	32527212	Furthermore, functional analysis showed the potential effect of rs2853550 polymorphism, which strengthens the prospect that rs2853550 contributes to EC susceptibility.	('contributes', 'Reg', (134, 145))	('rs2853550', 'Var', (124, 133))	('rs2853550', 'Mutation', 'rs2853550', (64, 73))	('rs2853550', 'Var', (64, 73))	('rs2853550', 'Mutation', 'rs2853550', (124, 133))
603364	32527212	Moreover, it is biologically reasonable that functional IL-1B polymorphisms play potential roles in the development of EC.	('polymorphisms', 'Var', (62, 75))	('roles', 'Reg', (91, 96))	('IL-1B', 'Gene', '3553', (56, 61))	('IL-1B', 'Gene', (56, 61))
603365	32527212	Polymorphisms within the inflammatory and immune factor-encoding IL-1B gene can result in aberrant IL-1beta levels, and their effects on oncogenic processes have been validated in diverse diseases (Ozbabacan et al.).	('result in', 'Reg', (80, 89))	('IL-1B', 'Gene', '3553', (65, 70))	('IL-1beta', 'Gene', '3552', (99, 107))	('Polymorphisms', 'Var', (0, 13))	('IL-1beta', 'Gene', (99, 107))	('IL-1B', 'Gene', (65, 70))	('effects', 'Reg', (126, 133))
603366	32527212	The association of IL-1B rs2853550 with cancer risk has been discussed in several studies.	('IL-1B', 'Gene', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('rs2853550', 'Mutation', 'rs2853550', (25, 34))	('rs2853550', 'Var', (25, 34))	('IL-1B', 'Gene', '3553', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
603367	32527212	have reported that IL-1B rs2853550 heterozygotes (OR = 0.34, 95% CI: 0.2-0.7, p = 0.0028) and the "A" allele are associated with a significantly reduced risk of colorectal cancer (OR = 0.43, 95% CI: 0.2-0.9, p = 0.0015) (He et al.).	('reduced', 'NegReg', (145, 152))	('colorectal cancer', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('IL-1B', 'Gene', (19, 24))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('rs2853550', 'Mutation', 'rs2853550', (25, 34))	('rs2853550', 'Var', (25, 34))	('IL-1B', 'Gene', '3553', (19, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))
603368	32527212	Two other independent studies have revealed that the "A" allele of IL-1B rs2853550 might reduce the risk of bowel disease and gastric cancer when was compared with the "G" allele (Nemetz et al.	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('bowel disease', 'Disease', 'MESH:D015212', (108, 121))	('IL-1B', 'Gene', '3553', (67, 72))	('IL-1B', 'Gene', (67, 72))	('gastric cancer', 'Disease', (126, 140))	('reduce', 'NegReg', (89, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('rs2853550', 'Mutation', 'rs2853550', (73, 82))	('bowel disease', 'Disease', (108, 121))	('rs2853550', 'Var', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
603371	32527212	In accordance with database analyses, we hypothesize that the rs2853550 polymorphism might influence the expression of IL-1B and thereby affect individual susceptibility to EC.	('IL-1B', 'Gene', '3553', (119, 124))	('influence', 'Reg', (91, 100))	('rs2853550', 'Mutation', 'rs2853550', (62, 71))	('IL-1B', 'Gene', (119, 124))	('rs2853550', 'Var', (62, 71))	('affect', 'Reg', (137, 143))	('expression', 'MPA', (105, 115))
603372	32527212	However, Ito and colleagues did not find any association of the IL-1B rs2853550 polymorphism with EC risk in Japanese people, which might be attributable to the limited sample size of the Japanese population in that study (75 EC patients and 136 controls) (Ito et al.).	('patients', 'Species', '9606', (229, 237))	('rs2853550', 'Mutation', 'rs2853550', (70, 79))	('rs2853550', 'Var', (70, 79))	('people', 'Species', '9606', (118, 124))	('IL-1B', 'Gene', (64, 69))	('IL-1B', 'Gene', '3553', (64, 69))
603373	32527212	have showed evidence of an association between the IL-1B rs16944 G > A polymorphism and EC risk in a southern Chinese Han population using SNP association analyses (Zheng et al.).	('rs16944', 'Mutation', 'rs16944', (57, 64))	('rs16944 G > A', 'Var', (57, 70))	('association', 'Interaction', (27, 38))	('IL-1B', 'Gene', '3553', (51, 56))	('IL-1B', 'Gene', (51, 56))
603375	32527212	Additionally, we did not find any associations of rs1143643, rs3136558, rs1143630, rs1143627, and rs1143623 with esophageal cancer susceptibility in this work.	('rs1143627', 'Var', (83, 92))	('cancer', 'Disease', (124, 130))	('rs1143630', 'Mutation', 'rs1143630', (72, 81))	('rs1143623', 'Mutation', 'rs1143623', (98, 107))	('rs1143643', 'Var', (50, 59))	('rs3136558', 'Mutation', 'rs3136558', (61, 70))	('rs1143643', 'Chemical', '-', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rs1143623', 'Var', (98, 107))	('rs1143627', 'Mutation', 'rs1143627', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('rs1143630', 'Var', (72, 81))	('rs3136558', 'Var', (61, 70))
603376	32527212	First, our study found the significant evidence of rs2853550 in correlation to EC development in Chinese Han population of Northwest China.	('rs2853550', 'Mutation', 'rs2853550', (51, 60))	('rs2853550', 'Var', (51, 60))	('EC development', 'CPA', (79, 93))
603378	32527212	Second, we performed a function prediction of rs2853550 with database, however, the biological function exerted by rs2853550 need to be further elucidated with well-designed studies.	('rs2853550', 'Var', (115, 124))	('rs2853550', 'Var', (46, 55))	('rs2853550', 'Mutation', 'rs2853550', (115, 124))	('rs2853550', 'Mutation', 'rs2853550', (46, 55))
603379	32527212	Therefore, further confirmation is necessary to better understand the role of IL-1B rs2853550 in EC risk.	('IL-1B', 'Gene', '3553', (78, 83))	('IL-1B', 'Gene', (78, 83))	('rs2853550', 'Var', (84, 93))	('rs2853550', 'Mutation', 'rs2853550', (84, 93))
603380	32527212	In summary, our study provides strong evidence that the IL-1B rs2853550 polymorphism could contribute to the risk of EC in the northwest Chinese Han population.	('IL-1B', 'Gene', '3553', (56, 61))	('rs2853550', 'Mutation', 'rs2853550', (62, 71))	('rs2853550', 'Var', (62, 71))	('IL-1B', 'Gene', (56, 61))	('risk', 'Reg', (109, 113))
603385	31706287	Copy number variation is highly correlated with differential gene expression: a pan-cancer study Cancer is a heterogeneous disease with many genetic variations.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('Copy number variation', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))
603386	31706287	Lines of evidence have shown copy number variations (CNVs) of certain genes are involved in development and progression of many cancers through the alterations of their gene expression levels on individual or several cancer types.	('gene expression levels', 'MPA', (169, 191))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('copy number variations', 'Var', (29, 51))	('cancers', 'Disease', (128, 135))	('alterations', 'Reg', (148, 159))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('involved', 'Reg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Disease', (128, 134))
603391	31706287	Genetic structural variation in the human genome can be present in many forms, ranging from single nucleotide polymorphisms (SNPs) to large chromosome aberrance.	('human', 'Species', '9606', (36, 41))	('single nucleotide polymorphisms', 'Var', (92, 123))	('large', 'Disease', (134, 139))
603394	31706287	It is generally accepted that somatic CNV is highly associated with the development and progression of numerous cancers by impacting gene expression level.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('associated', 'Reg', (52, 62))	('impacting', 'Reg', (123, 132))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('CNV', 'Var', (38, 41))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gene expression level', 'MPA', (133, 154))
603406	31706287	copy number amplification and expression level upregulation ratio against copy number deletion and expression level downregulation, copy number deletion and expression level downregulation ratio against copy number amplification and expression level upregulation more than 50 % on each gene across 9159 tumor samples were applied to identify AUGs and DDGs with a higher rho (> 0.4) and a higher number (> 146.5) of copy number amplification and expression level upregulation than the median level of 30 most popular oncogenes (Additional file 2: Table S4) or a higher rho (> 0.41) and a higher number (> 18.5) of copy number deletion and expression level downregulation than the median level of 10 tumor suppressor genes (Additional file 2: Table S5).	('tumor', 'Phenotype', 'HP:0002664', (698, 703))	('tumor', 'Disease', (698, 703))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('downregulation', 'NegReg', (655, 669))	('tumor', 'Disease', (303, 308))	('expression level', 'MPA', (445, 461))	('upregulation', 'PosReg', (462, 474))	('tumor', 'Disease', 'MESH:D009369', (698, 703))	('expression level', 'MPA', (638, 654))	('AU', 'Disease', 'MESH:C566303', (342, 344))	('copy number deletion', 'Var', (613, 633))
603407	31706287	AUGs and DDGs were sorted by the amount of copy number amplification and expression level upregulation, copy number deletion and expression level downregulation respectively and 31 representative AUGs and 29 representative DDGs matched with KEGG genes were identified from top 100 highly concordant genes.	('downregulation', 'NegReg', (146, 160))	('AU', 'Disease', 'MESH:C566303', (0, 2))	('AU', 'Disease', 'MESH:C566303', (196, 198))	('upregulation', 'PosReg', (90, 102))	('expression', 'MPA', (129, 139))	('copy number deletion', 'Var', (104, 124))
603413	31706287	For all cancer types under study, median Z scores of gene expression with copy number amplified were strikingly higher than those with copy number deleted (Fig.	('higher', 'PosReg', (112, 118))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('copy number amplified', 'Var', (74, 95))	('Z scores', 'MPA', (41, 49))	('gene expression', 'MPA', (53, 68))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
603415	31706287	In addition, the spearman's correlation coefficient (rho) test and linear regression analysis among cell lines and tumors were implemented to uncover the close association between differential gene expression and CNV with rho ranging from 0.075 to 0.53 (mean r = 0.97; Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('differential gene', 'Var', (180, 197))	('CNV', 'Disease', (213, 216))
603416	31706287	Remarkably, for substantial number of genes, their copy numbers exert a positive correlation with the corresponding gene expression level among 1025 cell lines dataset (88.11%; Additional file 1: Figure S3A; Figure S3B) and 9159 tumor samples (94.15%; Fig.	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('positive', 'PosReg', (72, 80))	('copy numbers', 'Var', (51, 63))	('gene expression level', 'MPA', (116, 137))
603419	31706287	Concordantly, a recent study by GTEx consortium also associated genetic variants with gene expression levels across 44 human healthy tissues and gene expression levels were found to be affected by local genetic variation for most genes based on eQTL analysis.	('genetic variants', 'Var', (64, 80))	('affected', 'Reg', (185, 193))	('variants', 'Var', (72, 80))	('associated', 'Reg', (53, 63))	('gene expression levels', 'MPA', (86, 108))	('human', 'Species', '9606', (119, 124))
603424	31706287	Intriguingly, the amount of copy number amplification and expression level upregulation, copy number deletion and expression level downregulation, representing our so-called highly concordant genes on CNV and differential gene expression, occupied 15 and 20% of the total variant copy number count on average for cell lines and tumor samples, respectively.	('copy number', 'Var', (28, 39))	('deletion', 'Var', (101, 109))	('expression', 'MPA', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('upregulation', 'PosReg', (75, 87))	('copy number deletion', 'Var', (89, 109))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('expression', 'MPA', (114, 124))	('downregulation', 'NegReg', (131, 145))	('tumor', 'Disease', (328, 333))
603425	31706287	Nevertheless, the mean proportion of copy number amplification and expression level downregulation, copy number deletion and expression level upregulation count only took up 0.7 and 0.5% for both cell lines and tumor samples (Additional file 1: Figure S4A and S4B), which indicated that the copy number amplification barely causes gene expression downregulation and the copy number deletion hardly promotes gene expression upregulation.	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('copy number deletion', 'Var', (370, 390))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('downregulation', 'NegReg', (347, 361))	('S4B', 'Chemical', 'MESH:D013455', (260, 263))	('copy number amplification', 'Var', (291, 316))	('gene expression', 'MPA', (331, 346))	('upregulation', 'PosReg', (423, 435))	('gene expression', 'MPA', (407, 422))
603426	31706287	It is obvious that the frequency of copy number amplification and expression level upregulation totally exceeded copy number deletion and expression level downregulation for both cell lines and tumor samples (Fig.	('expression level', 'MPA', (66, 82))	('upregulation', 'PosReg', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('copy number amplification', 'Var', (36, 61))	('expression', 'MPA', (138, 148))	('tumor', 'Disease', (194, 199))	('downregulation', 'NegReg', (155, 169))
603427	31706287	In order to identify highly concordant genes on CNV and differential gene expression, the sum of copy number amplification and expression level upregulation, copy number deletion and expression level downregulation for all genes across 9159 tumor samples in TCGA were counted (Fig.	('tumor', 'Disease', (241, 246))	('copy number deletion', 'Var', (158, 178))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('upregulation', 'PosReg', (144, 156))	('downregulation', 'NegReg', (200, 214))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
603431	31706287	Nine AUGs obtained preponderant count of copy number amplification and expression level upregulation compared to copy number deletion and expression level downregulation across 9159 tumor samples, while the only DDG (STK11) showed an overwhelming degree of copy number deletion and expression level downregulation (73%) against copy number amplification and expression level upregulation, in accordance with previous reports in literature (Table 2).	('expression', 'MPA', (71, 81))	('tumor', 'Disease', (182, 187))	('STK11', 'Gene', (217, 222))	('expression', 'MPA', (282, 292))	('copy number deletion', 'Var', (257, 277))	('upregulation', 'PosReg', (88, 100))	('copy', 'Var', (41, 45))	('expression', 'MPA', (358, 368))	('downregulation', 'NegReg', (155, 169))	('STK11', 'Gene', '6794', (217, 222))	('AU', 'Disease', 'MESH:C566303', (5, 7))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('downregulation', 'NegReg', (299, 313))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
603432	31706287	A&U represents the frequency of a gene with copy number amplified and expression level upregulated across 31 cancer types in TCGA, while D&D represents the frequency of a gene with copy number deleted and expression level downregulated.	('level', 'PosReg', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('and expression', 'MPA', (66, 80))	('cancer', 'Disease', (109, 115))	('expression', 'NegReg', (205, 215))	('with copy number', 'Var', (39, 55))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
603433	31706287	means the gene with copy number amplification and expression level upregulation in tumor, AUG;   means the gene with copy number deletion and expression level downregulation in tumor, DDG.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('expression', 'MPA', (142, 152))	('AU', 'Disease', 'MESH:C566303', (90, 92))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('upregulation', 'PosReg', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('copy number deletion', 'Var', (117, 137))	('downregulation', 'NegReg', (159, 173))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('copy number amplification', 'Var', (20, 45))
603434	31706287	Thus, to identify AUGs and DDGs, the criteria applied in this work is the copy number amplification and expression level upregulation ratio against copy number deletion and expression level downregulation, copy number deletion and expression level downregulation ratio against copy number amplification and expression level upregulation with the cutoff value of 50 %.	('upregulation', 'PosReg', (324, 336))	('upregulation', 'PosReg', (121, 133))	('AU', 'Disease', 'MESH:C566303', (18, 20))	('copy', 'Var', (148, 152))	('copy number deletion', 'Var', (206, 226))	('expression level', 'MPA', (104, 120))	('expression', 'MPA', (173, 183))	('downregulation', 'NegReg', (190, 204))	('downregulation', 'NegReg', (248, 262))
603435	31706287	Further by filtering parameter included a higher rho and a higher number of copy number amplification and expression level upregulation than the median level of 30 most popular oncogenes (Additional file 2: Table S4) or a higher number of copy number deletion and expression level downregulation than the median level of 10 tumor suppressor genes (Additional file 2:Table S5), which ultimately led to 560 AUGs such as DERL1, DVL3, FADD and 365 DDGs (e.g.	('FADD', 'Gene', (431, 435))	('copy number deletion', 'Var', (239, 259))	('AU', 'Disease', 'MESH:C566303', (405, 407))	('FADD', 'Gene', '8772', (431, 435))	('expression', 'MPA', (264, 274))	('expression', 'MPA', (106, 116))	('downregulation', 'NegReg', (281, 295))	('tumor', 'Disease', (324, 329))	('DVL3', 'Gene', (425, 429))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('rho', 'MPA', (49, 52))	('higher', 'PosReg', (42, 48))	('upregulation', 'PosReg', (123, 135))	('DERL1', 'Gene', '79139', (418, 423))	('copy number', 'Var', (76, 87))	('DVL3', 'Gene', '1857', (425, 429))	('DERL1', 'Gene', (418, 423))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
603437	31706287	For representative AUGs and DDGs matched with KEGG pathway-related genes, their aberrant rate of copy number amplification and expression level upregulation, copy number deletion and expression level downregulation in corresponding tumor samples across 31 cancer types were analyzed and shown in Fig.	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('expression', 'MPA', (127, 137))	('copy number deletion', 'Var', (158, 178))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('cancer', 'Disease', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('KEGG', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Disease', (232, 237))	('AU', 'Disease', 'MESH:C566303', (19, 21))	('upregulation', 'PosReg', (144, 156))	('downregulation', 'NegReg', (200, 214))
603440	31706287	Figure 4b shows the distribution of copy number deletion and expression level downregulation rate across 31 cancers of 38 representative DDGs involving in many known tumor suppressor genes such as MTAP, KLHL9, PTEN, SMAD4, RB1, etc.	('SMAD4', 'Gene', '4089', (216, 221))	('RB1', 'Gene', (223, 226))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('KLHL9', 'Gene', '55958', (203, 208))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('PTEN', 'Gene', (210, 214))	('downregulation', 'NegReg', (78, 92))	('RB1', 'Gene', '5925', (223, 226))	('PTEN', 'Gene', '5728', (210, 214))	('tumor', 'Disease', (166, 171))	('SMAD4', 'Gene', (216, 221))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancers', 'Disease', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('KLHL9', 'Gene', (203, 208))	('MTAP', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('MTAP', 'Gene', '4507', (197, 201))	('copy number deletion', 'Var', (36, 56))
603449	31706287	For examples, the copy number amplification and expression level upregulation of FYTTD1 and CTTN would remarkably cause a poor prognosis in tumor patients of ESCA and head and neck squamous cell carcinoma (HNSC) respectively (Fig.	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('expression level', 'MPA', (48, 64))	('FYTTD1', 'Gene', '84248', (81, 87))	('CTTN', 'Gene', '2017', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('patients', 'Species', '9606', (146, 154))	('FYTTD1', 'Gene', (81, 87))	('HNSC', 'Disease', (206, 210))	('ESCA', 'Disease', (158, 162))	('copy number amplification', 'Var', (18, 43))	('ESCA', 'Disease', 'MESH:D004938', (158, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (167, 204))	('HNSC', 'Disease', 'MESH:C535575', (206, 210))	('CTTN', 'Gene', (92, 96))	('upregulation', 'PosReg', (65, 77))	('cause', 'Reg', (114, 119))	('tumor', 'Disease', (140, 145))
603450	31706287	5b), while the copy number deletion and expression level downregulation of MTAP was significantly associated with a worse prognosis (Fig.	('copy number deletion', 'Var', (15, 35))	('downregulation', 'NegReg', (57, 71))	('MTAP', 'Gene', (75, 79))	('MTAP', 'Gene', '4507', (75, 79))
603454	31706287	In addition, we overlapped the AUGs and DDGs identified by the ratio of copy number amplification and expression level upregulation versus copy number deletion and expression level downregulation between CCLP and TCGA respectively.	('expression', 'MPA', (102, 112))	('AU', 'Disease', 'MESH:C566303', (31, 33))	('downregulation', 'NegReg', (181, 195))	('upregulation', 'PosReg', (119, 131))	('copy number deletion', 'Var', (139, 159))
603458	31706287	This finding reveals the qualitative relationship between genetic variation and its downstream effect, especially for oncogenes and tumor suppressor genes, which is of a critical importance for prevention, diagnosis and treatment of cancer.	('genetic variation', 'Var', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('oncogenes', 'Gene', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Disease', (132, 137))
603459	31706287	Besides, not only in cell lines but in patients copy number amplification strikingly harbored a higher expressed level compared to copy number deletion.	('copy number amplification', 'Var', (48, 73))	('patients', 'Species', '9606', (39, 47))	('higher', 'PosReg', (96, 102))	('expressed level', 'MPA', (103, 118))
603462	31706287	A recent study by GTEx consortium associated genetic variants with gene expression levels across 44 human healthy tissues and gene expression levels are found to be affected by local genetic variation for most genes based on eQTL analysis.	('gene expression levels', 'MPA', (67, 89))	('affected', 'Reg', (165, 173))	('variants', 'Var', (53, 61))	('human', 'Species', '9606', (100, 105))
603464	31706287	Moreover, it has been widely reported that copy number is remarkably correlated with expression of protein in literature such as FGFR1, HER2, MET, FADD, EGFR.	('correlated', 'Reg', (69, 79))	('FGFR1', 'Gene', (129, 134))	('FADD', 'Gene', (147, 151))	('FADD', 'Gene', '8772', (147, 151))	('FGFR1', 'Gene', '2260', (129, 134))	('copy number', 'Var', (43, 54))	('EGFR', 'Gene', '1956', (153, 157))	('MET', 'Disease', (142, 145))	('HER2', 'Gene', '2064', (136, 140))	('HER2', 'Gene', (136, 140))	('expression of protein', 'MPA', (85, 106))	('EGFR', 'Gene', (153, 157))
603465	31706287	Notably, FGFR1, known as fibroblast growth factor receptor 1, has been discovered that its copy number amplification is strikingly correlated with FGFR1 gene upregulation and FGFR1 protein upregulation in tumor samples.	('protein', 'Protein', (181, 188))	('upregulation', 'PosReg', (158, 170))	('FGFR1', 'Gene', '2260', (9, 14))	('fibroblast growth factor receptor 1', 'Gene', '2260', (25, 60))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('fibroblast growth factor receptor 1', 'Gene', (25, 60))	('FGFR1', 'Gene', (175, 180))	('FGFR1', 'Gene', (147, 152))	('FGFR1', 'Gene', '2260', (147, 152))	('tumor', 'Disease', (205, 210))	('FGFR1', 'Gene', '2260', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('FGFR1', 'Gene', (9, 14))	('copy number amplification', 'Var', (91, 116))	('upregulation', 'PosReg', (189, 201))
603470	31706287	For examples, numerous studies reported that DERL1 overexpression was significantly related to cancer cell proliferation, invasion and poor prognosis, which might be driven by copy number amplification for DERL1 obtained the majority of copy number amplification and expression level upregulation in many cancers (Fig.	('DERL1', 'Gene', (206, 211))	('copy number amplification', 'Var', (237, 262))	('DERL1', 'Gene', '79139', (206, 211))	('related', 'Reg', (84, 91))	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('upregulation', 'PosReg', (284, 296))	('DERL1', 'Gene', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('cancer', 'Disease', (95, 101))	('invasion', 'CPA', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('DERL1', 'Gene', '79139', (45, 50))	('overexpression', 'PosReg', (51, 65))	('expression level', 'MPA', (267, 283))	('copy', 'Var', (176, 180))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancers', 'Disease', (305, 312))	('cancer', 'Disease', (305, 311))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
603475	31706287	With respect to wnt signaling, lost function of DDGs such as inhibitory SMAD4 and APC would definitely enhance the function of wnt signaling leading to tumorigenesis, while attenuated function of ubiquitin mediated proteolysis facilitate proliferation.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('ubiquitin mediated proteolysis', 'MPA', (196, 226))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('facilitate', 'PosReg', (227, 237))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('APC', 'Disease', (82, 85))	('inhibitory', 'Var', (61, 71))	('tumor', 'Disease', (152, 157))	('proliferation', 'CPA', (238, 251))	('enhance', 'PosReg', (103, 110))	('wnt signaling', 'MPA', (127, 140))	('attenuated', 'NegReg', (173, 183))	('SMAD4', 'Gene', '4089', (72, 77))	('SMAD4', 'Gene', (72, 77))	('function', 'MPA', (115, 123))
603477	31706287	By further integrated analysis of CNV and differential gene expression of FYTTD1 in ESCA patients, we observed that 24.73% patients showed a high level of copy number amplification with a median Z score of 4.15 which means FYTTD1 was strikingly overexpressed (Additional file 1: Figure S6).	('FYTTD1', 'Gene', (74, 80))	('ESCA', 'Disease', 'MESH:D004938', (84, 88))	('FYTTD1', 'Gene', '84248', (74, 80))	('FYTTD1', 'Gene', (223, 229))	('patients', 'Species', '9606', (123, 131))	('overexpressed', 'PosReg', (245, 258))	('FYTTD1', 'Gene', '84248', (223, 229))	('patients', 'Species', '9606', (89, 97))	('copy number', 'Var', (155, 166))	('ESCA', 'Disease', (84, 88))
603482	31706287	In addition, we identified amplification and overexpression of FYTTD1 is highly related with poor prognosis in ESCA, which may be a potential prognostic marker in ESCA.	('ESCA', 'Disease', 'MESH:D004938', (163, 167))	('ESCA', 'Disease', (111, 115))	('FYTTD1', 'Gene', (63, 69))	('ESCA', 'Disease', (163, 167))	('FYTTD1', 'Gene', '84248', (63, 69))	('amplification', 'Var', (27, 40))	('overexpression', 'PosReg', (45, 59))	('ESCA', 'Disease', 'MESH:D004938', (111, 115))
603503	30227865	Furthermore, changes in heart volume may influence the dose distribution of radiation to the tumor target and organs at risk.	('heart', 'MPA', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('changes', 'Var', (13, 20))	('dose distribution', 'MPA', (55, 72))	('influence', 'Reg', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
603527	30227865	On 3DCT, EE and MIP images, respectively, the heart volume was reduced by 3.27%, 4.45% and 4.52% (p = 0.027, p < 0.001 and p < 0.001), and the MHD was reduced by 0.98%, 1.40% and 1.29% (p = 0.035, p = 0.001 and p < 0.001).	('MIP', 'Var', (16, 19))	('reduced', 'NegReg', (151, 158))	('reduced', 'NegReg', (63, 70))	('heart volume', 'CPA', (46, 58))	('MHD', 'Disease', 'None', (143, 146))	('MHD', 'Disease', (143, 146))
603542	30227865	These results are also supported by the relative dose data: the V20, V30, V40, V45 and V50 values and the mean heart dose were greater when the esophageal tumor was in the middle region than in an upper or lower location.	('V20', 'MPA', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('V45', 'MPA', (79, 82))	('V30', 'Var', (69, 72))	('esophageal tumor', 'Disease', 'MESH:D004938', (144, 160))	('esophageal tumor', 'Disease', (144, 160))	('esophageal tumor', 'Phenotype', 'HP:0100751', (144, 160))	('V50 values', 'MPA', (87, 97))	('V40', 'Var', (74, 77))
603544	30227865	They also discovered that the heart dose of patients with new myocardial perfusion defects were significantly larger than those of patients without new defects.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (44, 52))	('larger', 'PosReg', (110, 116))	('defects', 'Var', (83, 90))	('heart dose', 'MPA', (30, 40))	('myocardial', 'Var', (62, 72))
603566	30227865	The coefficients of variation for the gross tumor volumes delineated on CE-4DCT images are smaller than those delineated on plain scan images, indicating that CE-4DCT can reduce the error of organ delineation.	('error of organ delineation', 'Disease', (182, 208))	('error of organ delineation', 'Disease', 'MESH:D019965', (182, 208))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CE-4DCT', 'Var', (72, 79))	('tumor', 'Disease', (44, 49))	('CE-4DCT', 'Var', (159, 166))
603567	30227865	Morphological changes resulting from heart volume variation could result in inaccurate dose delivery to the tumor and organs at risk.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('dose delivery', 'MPA', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('heart', 'MPA', (37, 42))	('tumor', 'Disease', (108, 113))	('result', 'Reg', (66, 72))	('variation', 'Var', (50, 59))
603577	29855157	As a result, the inhibition of GSK-3beta induces EMT phenotype with upregulated vimentin and downregulated E-cadherin as well as increased Snail and Zinc finger E box-binding homeobox (ZEB)-1 gene expression.	('upregulated', 'PosReg', (68, 79))	('GSK-3beta', 'Gene', '2932', (31, 40))	('GSK-3beta', 'Gene', (31, 40))	('Zinc finger E box-binding homeobox (ZEB)-1', 'Gene', '6935', (149, 191))	('EMT phenotype', 'CPA', (49, 62))	('vimentin', 'Gene', '7431', (80, 88))	('increased', 'PosReg', (129, 138))	('inhibition', 'Var', (17, 27))	('vimentin', 'Gene', (80, 88))	('Snail', 'Gene', '6615', (139, 144))	('downregulated', 'NegReg', (93, 106))	('E-cadherin', 'Gene', (107, 117))	('Snail', 'Gene', (139, 144))	('expression', 'MPA', (197, 207))	('E-cadherin', 'Gene', '999', (107, 117))
603602	29855157	Detecting how GSK-3 inhibitor, SB-415286, downregulates GSK-3beta subunit, the same method of electrophoresis and membrane transfer was carried out with the protein lysate of KYSE 30 or KYSE110 cell line.	('SB-415286', 'Chemical', 'MESH:C417520', (31, 40))	('SB-415286', 'Var', (31, 40))	('GSK-3beta', 'Gene', '2932', (56, 65))	('GSK-3beta', 'Gene', (56, 65))	('downregulates', 'NegReg', (42, 55))
603613	29855157	The following probes were used for PCR: GAPDH (hs99999905_m1), CDH1(E-cadherin) (hs01023894_m1), SNAI1(Snail) (hs00195591_m1), CD274(PDL1) (hs01125301_m1), and ZEB1 (hs00232783) (all from Applied Biosystems).	('CDH1', 'Gene', (63, 67))	('PDL1', 'Gene', (133, 137))	('Snail', 'Gene', '6615', (103, 108))	('CD274', 'Gene', (127, 132))	('SNAI1', 'Gene', '6615', (97, 102))	('PDL1', 'Gene', '29126', (133, 137))	('SNAI1', 'Gene', (97, 102))	('hs01023894_m1', 'Var', (81, 94))	('ZEB1', 'Gene', '6935', (160, 164))	('hs00195591_m1', 'Var', (111, 124))	('E-cadherin', 'Gene', (68, 78))	('hs01125301_m1', 'Var', (140, 153))	('E-cadherin', 'Gene', '999', (68, 78))	('hs00232783', 'Var', (166, 176))	('GAPDH', 'Gene', '2597', (40, 45))	('Snail', 'Gene', (103, 108))	('hs99999905_m1', 'Var', (47, 60))	('GAPDH', 'Gene', (40, 45))	('ZEB1', 'Gene', (160, 164))	('CD274', 'Gene', '29126', (127, 132))	('CDH1', 'Gene', '999', (63, 67))
603633	29855157	At first, we proved that SB-415286 reduced the expression of the GSK-3beta protein in a dose-dependent manner in KYSE30 cell line.	('GSK-3beta', 'Gene', '2932', (65, 74))	('SB-415286', 'Var', (25, 34))	('GSK-3beta', 'Gene', (65, 74))	('reduced', 'NegReg', (35, 42))	('SB-415286', 'Chemical', 'MESH:C417520', (25, 34))	('expression', 'MPA', (47, 57))
603635	29855157	After EMT conversion using SB-415286, we examined the PD-L1 expression in KYSE30, KYSE110, HCT116, and SW480.	('HCT116', 'CellLine', 'CVCL:0291', (91, 97))	('PD-L1', 'Gene', (54, 59))	('KYSE110', 'Var', (82, 89))	('SW480', 'CellLine', 'CVCL:0546', (103, 108))	('PD-L1', 'Gene', '29126', (54, 59))	('SB-415286', 'Chemical', 'MESH:C417520', (27, 36))
603641	29855157	As the EMT conversion using SB-415286 upregulated the surface expression of PD-L1 on tumor cells, we next performed coculture experiment using EMT-converted tumor cells and IL-2-activated T cells expressing PD-1 to examine whether an increment of surface PD-L1 expression on tumor cells functionally induces T-cell apoptosis.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (275, 280))	('induces', 'Reg', (300, 307))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('surface expression', 'MPA', (54, 72))	('increment', 'Var', (234, 243))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('PD-L1', 'Gene', (255, 260))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('PD-L1', 'Gene', '29126', (255, 260))	('T-cell apoptosis', 'CPA', (308, 324))	('PD-1', 'Gene', (207, 211))	('men', 'Species', '9606', (239, 242))	('PD-1', 'Gene', '5133', (207, 211))	('IL-2', 'Gene', '3558', (173, 177))	('SB-415286', 'Chemical', 'MESH:C417520', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('SB-415286', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('PD-L1', 'Gene', (76, 81))	('tumor', 'Disease', (157, 162))	('PD-L1', 'Gene', '29126', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('upregulated', 'PosReg', (38, 49))	('men', 'Species', '9606', (132, 135))	('IL-2', 'Gene', (173, 177))
603644	29855157	The results from 3 independent experiments showed the significant difference between GSK-3 inhibitor-treated and nontreated groups in both KYSE30 cell line and SW480 cell line with P = .028 and P = .041, respectively (Figure 3B).	('men', 'Species', '9606', (37, 40))	('SW480', 'CellLine', 'CVCL:0546', (160, 165))	('GSK-3', 'Gene', (85, 90))	('inhibitor-treated', 'Var', (91, 108))
603651	29855157	The treatment against metastatic ESCC is still challenging, and immunotherapy with anti-PD-1 mAb is becoming a promising novel strategy,3, 34, 35, 36, 37 in which inhibition of PD-L1 and PD-1 interaction with the anti-PD-1 mAb resulted in the significant clinical response in the early phase clinical trial for advanced ESCC.	('interaction', 'Interaction', (192, 203))	('PD-1', 'Gene', '5133', (88, 92))	('clinical', 'Species', '191496', (292, 300))	('PD-1', 'Gene', '5133', (187, 191))	('PD-L1', 'Gene', (177, 182))	('men', 'Species', '9606', (9, 12))	('PD-L1', 'Gene', '29126', (177, 182))	('PD-1', 'Gene', (187, 191))	('PD-1', 'Gene', (88, 92))	('clinical', 'Species', '191496', (255, 263))	('PD-1', 'Gene', (218, 222))	('inhibition', 'Var', (163, 173))	('PD-1', 'Gene', '5133', (218, 222))
603666	29855157	As described above, inhibition of GSK-3 also induced upregulation of ZEB-1, which was an EMT-inducing transcriptional factor.	('GSK-3', 'Gene', (34, 39))	('inhibition', 'Var', (20, 30))	('ZEB-1', 'Gene', (69, 74))	('upregulation', 'PosReg', (53, 65))	('ZEB-1', 'Gene', '6935', (69, 74))
603757	26439687	Inhibiting VEGF-C/VEGFR-3 signaling suppresses tumor lymphangiogenesis and lymphatic metastasis in pre-clinical models and may be a promising strategy for treating ESCC and other cancers.	('clinical', 'Species', '191496', (103, 111))	('Inhibiting', 'Var', (0, 10))	('VEGFR-3', 'Gene', '2324', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('suppresses', 'NegReg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('ESCC', 'Disease', (164, 168))	('lymphatic metastasis', 'CPA', (75, 95))	('VEGFR-3', 'Gene', (18, 25))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))	('tumor', 'Disease', (47, 52))
603762	26439687	In lung cancer, downregulated RASSF8 increases cell migration and growth, functioning as a tumor suppressor.	('growth', 'CPA', (66, 72))	('lung cancer', 'Disease', (3, 14))	('downregulated', 'Var', (16, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('RASSF8', 'Gene', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('increases', 'PosReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cell migration', 'CPA', (47, 61))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('tumor', 'Disease', (91, 96))
603766	26439687	More importantly, downregulated RASSF8 increased VEGF-C expression by promoting the nuclear-cytoplasmic translocation of nuclear factor-kappaB (NF-kappaB) p65, leading to lymphangiogenesis and lymphatic metastasis.	('VEGF-C', 'Gene', (49, 55))	('NF-kappaB', 'Gene', '4790', (144, 153))	('RASSF8', 'Gene', (32, 38))	('leading to', 'Reg', (160, 170))	('increased VEGF-', 'Phenotype', 'HP:0030269', (39, 54))	('promoting', 'PosReg', (70, 79))	('NF-kappaB', 'Gene', (144, 153))	('lymphatic metastasis', 'CPA', (193, 213))	('expression', 'MPA', (56, 66))	('downregulated', 'Var', (18, 31))	('nuclear factor-kappaB', 'Gene', (121, 142))	('increased', 'PosReg', (39, 48))	('nuclear factor-kappaB', 'Gene', '4790', (121, 142))	('lymphangiogenesis', 'CPA', (171, 188))	('p65', 'Gene', (155, 158))	('nuclear-cytoplasmic translocation', 'MPA', (84, 117))	('p65', 'Gene', '5970', (155, 158))
603781	26439687	EC109 cells stably expressing RASSF8 or RASSF8-RNAi, and control EC109 cells were implanted in the footpads of BALB/c-nu mice.	('RASSF8', 'Var', (30, 36))	('RASSF8-RNAi', 'Var', (40, 51))	('mice', 'Species', '10090', (121, 125))
603782	26439687	The lymphatic vessel density in the tumors that developed from RASSF8-overexpressing cells was lower than that of tumors from the control cells.	('lower', 'NegReg', (95, 100))	('RASSF8-overexpressing', 'Gene', (63, 84))	('RASSF8-overexpressing', 'Var', (63, 84))	('lymphatic vessel density', 'CPA', (4, 28))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
603783	26439687	Conversely, lymphatic vessel density was significantly increased in tumors formed by RASSF8 knockdown cells (Fig.	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('knockdown', 'Var', (92, 101))	('increased', 'PosReg', (55, 64))	('RASSF8', 'Gene', (85, 91))	('lymphatic vessel density', 'CPA', (12, 36))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
603785	26439687	Accordingly, VEGF-C expression in the mice footpad tumors was significantly increased in RASSF8 knockdown tissues and was decreased in RASSF8 overexpression tissues (Fig.	('knockdown', 'Var', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('expression', 'MPA', (20, 30))	('mice', 'Species', '10090', (38, 42))	('increased', 'PosReg', (76, 85))	('decreased', 'NegReg', (122, 131))	('RASSF8', 'Gene', (89, 95))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('VEGF-C', 'Gene', (13, 19))
603787	26439687	Phosphorylated (phospho)-AKT (Ser 473) and phospho-ERK (T202/Y204) were dramatically upregulated in HLECs stimulated by TSNs from RASSF8-RNAi-transduced EC109 or KYSE410 cells (Fig.	('AKT', 'Gene', (25, 28))	('ERK', 'Gene', (51, 54))	('upregulated', 'PosReg', (85, 96))	('AKT', 'Gene', '207', (25, 28))	('T202/Y204', 'Var', (56, 65))	('ERK', 'Gene', '5594', (51, 54))	('Ser', 'Chemical', 'MESH:D012694', (30, 33))
603788	26439687	Importantly, we found that treatment with a PI3K/AKT signaling inhibitor LY294002 or MEK/ERK signaling inhibitor U0126 could reduce the ability of RASSF8 knockdown cells to induce migration and tube formation in HLECs (Fig.	('MEK', 'Gene', '5609', (85, 88))	('AKT', 'Gene', (49, 52))	('LY294002', 'Var', (73, 81))	('migration', 'CPA', (180, 189))	('ERK', 'Gene', '5594', (89, 92))	('HLECs', 'Disease', (212, 217))	('tube formation', 'CPA', (194, 208))	('reduce', 'NegReg', (125, 131))	('ERK', 'Gene', (89, 92))	('RASSF8', 'Gene', (147, 153))	('induce', 'PosReg', (173, 179))	('AKT', 'Gene', '207', (49, 52))	('LY294002', 'Chemical', 'MESH:C085911', (73, 81))	('U0126', 'Chemical', 'MESH:C113580', (113, 118))	('MEK', 'Gene', (85, 88))
603793	26439687	As expected, nuclear NF-kappaB p65 expression was significantly decreased in RASSF8 overexpression cells and was increased in RASSF8 knockdown cells (Fig.	('p65', 'Gene', '5970', (31, 34))	('NF-kappaB', 'Gene', '4790', (21, 30))	('expression', 'MPA', (35, 45))	('RASSF8', 'Gene', (77, 83))	('overexpression', 'Var', (84, 98))	('NF-kappaB', 'Gene', (21, 30))	('p65', 'Gene', (31, 34))	('increased', 'PosReg', (113, 122))	('decreased', 'NegReg', (64, 73))
603800	26439687	Furthermore, loss of RASSF8 in ESCC cells may promote lymphatic endothelium migration and capillary-like tube formation, and in vivo tumor lymphangiogenesis and lymphatic metastasis, via VEGF-C upregulation under NF-kappaB transcriptional control.	('lymphatic metastasis', 'CPA', (161, 181))	('promote', 'PosReg', (46, 53))	('lymphatic endothelium migration', 'CPA', (54, 85))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('upregulation', 'PosReg', (194, 206))	('NF-kappaB', 'Gene', '4790', (213, 222))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('VEGF-C', 'Gene', (187, 193))	('NF-kappaB', 'Gene', (213, 222))	('tumor', 'Disease', (133, 138))	('loss', 'Var', (13, 17))	('RASSF8', 'Gene', (21, 27))
603805	26439687	The clinical results and in vitro/in vivo observations demonstrate higher VEGF-C expression and lymphatic vessel density in ESCC tumor tissues with loss of RASSF8.	('clinical', 'Species', '191496', (4, 12))	('higher', 'PosReg', (67, 73))	('lymphatic vessel density', 'CPA', (96, 120))	('loss', 'Var', (148, 152))	('RASSF8', 'Gene', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('VEGF-C', 'Gene', (74, 80))	('tumor', 'Disease', (129, 134))	('ESCC', 'Disease', (124, 128))	('expression', 'MPA', (81, 91))
603808	26439687	RASSF8 is a negative regulator of NF-kappaB transcriptional activity in lung cancer, where the regulatory protein IkappaB-alpha is degraded and p65 dimers enter the nucleus following RASSF8 knockdown in A549 and H1792 cell lines.	('A549', 'CellLine', 'CVCL:0023', (203, 207))	('knockdown', 'Var', (190, 199))	('NF-kappaB', 'Gene', '4790', (34, 43))	('RASSF8', 'Gene', (183, 189))	('enter', 'Reg', (155, 160))	('IkappaB-alpha', 'Gene', (114, 127))	('lung cancer', 'Disease', (72, 83))	('p65', 'Gene', (144, 147))	('degraded', 'NegReg', (131, 139))	('NF-kappaB', 'Gene', (34, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('IkappaB-alpha', 'Gene', '4792', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('H1792', 'CellLine', 'CVCL:1495', (212, 217))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('p65', 'Gene', '5970', (144, 147))
603809	26439687	Our results are consistent with that report: in our study, p65 was upregulated in the nuclei of RASSF8 knockdown ESCC cells and downregulated in RASSF8 overexpression ESCC cells.	('p65', 'Gene', '5970', (59, 62))	('p65', 'Gene', (59, 62))	('downregulated', 'NegReg', (128, 141))	('RASSF8', 'Gene', (96, 102))	('upregulated', 'PosReg', (67, 78))	('knockdown', 'Var', (103, 112))
603810	26439687	Luciferase assay suggested that downregulated RASSF8 increases NF-kappaB activation.	('downregulated', 'Var', (32, 45))	('RASSF8', 'Gene', (46, 52))	('NF-kappaB', 'Gene', '4790', (63, 72))	('activation', 'MPA', (73, 83))	('NF-kappaB', 'Gene', (63, 72))	('increases', 'PosReg', (53, 62))
603811	26439687	The observed NF-kappaB activation following RASSF8 depletion is the likely cause of the VEGF-C increase in ESCC cells.	('NF-kappaB', 'Gene', '4790', (13, 22))	('increase', 'PosReg', (95, 103))	('activation', 'PosReg', (23, 33))	('RASSF8', 'Gene', (44, 50))	('NF-kappaB', 'Gene', (13, 22))	('depletion', 'Var', (51, 60))
603816	26439687	RASSF8 methylation has been reported in a small subset of leukemia.	('reported', 'Reg', (28, 36))	('leukemia', 'Disease', (58, 66))	('leukemia', 'Disease', 'MESH:D007938', (58, 66))	('leukemia', 'Phenotype', 'HP:0001909', (58, 66))	('methylation', 'Var', (7, 18))	('RASSF8', 'Gene', (0, 6))
603831	26439687	The ESCC cell lines KYSE30, KYSE140, KYSE180, KYSE410, KYSE510, KYSE520 were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), the German Resource Center for Biological Material.	('KYSE520', 'Var', (64, 71))	('KYSE410', 'Var', (46, 53))	('KYSE140', 'Var', (28, 35))	('KYSE510', 'Var', (55, 62))	('KYSE180', 'Var', (37, 44))	('von', 'Disease', 'MESH:D014842', (109, 112))	('von', 'Disease', (109, 112))
603838	26439687	The primary antibodies used were anti-RASSF8 (Sigma, HPA038163), anti-VEGF-C (R&D, AF752), anti-phospho-AKT (Cell Signaling, Danvers, MA, USA, 4691S), anti-AKT (Cell Signaling, 4060S), anti-phospho-ERK1/2 (Cell Signaling, 4370P), anti-ERK (Cell Signaling, 9102S), anti-p65 (Cell Signaling, 6956S), anti-beta-tubulin (Cell Signaling, 2128S), and anti-GAPDH (Abgent, San Diego, CA, USA).	('AKT', 'Gene', '207', (156, 159))	('AKT', 'Gene', (104, 107))	('ERK', 'Gene', '5594', (198, 201))	('AKT', 'Gene', (156, 159))	('ERK1/2', 'Gene', (198, 204))	('ERK', 'Gene', (235, 238))	('ERK', 'Gene', '5594', (235, 238))	('AKT', 'Gene', '207', (104, 107))	('ERK', 'Gene', (198, 201))	('ERK1/2', 'Gene', '5595;5594', (198, 204))	('p65', 'Gene', (269, 272))	('and', 'Var', (341, 344))	('GAPDH', 'Gene', (350, 355))	('p65', 'Gene', '5970', (269, 272))	('GAPDH', 'Gene', '2597', (350, 355))
603852	26439687	The inhibitors of PI3K/AKT signaling LY294002 (Selleck Chemicals, Houston, TX, USA) and of MEK/ERK signaling U0126 (Selleck Chemicals) were dissolved in DMSO respectively at a stock concentration of 10mM and added to cell cultures at a concentration of 10uM.	('DMSO', 'Chemical', 'MESH:D004121', (153, 157))	('ERK', 'Gene', '5594', (95, 98))	('AKT', 'Gene', '207', (23, 26))	('LY294002', 'Chemical', 'MESH:C085911', (37, 45))	('ERK', 'Gene', (95, 98))	('MEK', 'Gene', '5609', (91, 94))	('AKT', 'Gene', (23, 26))	('LY294002', 'Var', (37, 45))	('MEK', 'Gene', (91, 94))	('U0126', 'Chemical', 'MESH:C113580', (109, 114))
603859	25595897	Here we report that VEGFR1 or VEGFR2 blockade can significantly attenuate VEGF-induced Src and Erk signaling, as well as the proliferation and migration of VEGFR1+ and VEGFR2+ bone marrow cells and their pro-invasive effect on cancer cells.	('attenuate', 'NegReg', (64, 73))	('VEGFR1', 'Gene', (20, 26))	('VEGFR2', 'Gene', (30, 36))	('blockade', 'Var', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('proliferation', 'CPA', (125, 138))	('Erk', 'Gene', (95, 98))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('Src', 'Gene', (87, 90))	('cancer', 'Disease', (227, 233))	('Src', 'Gene', '6714', (87, 90))	('migration', 'CPA', (143, 152))	('Erk', 'Gene', '2048', (95, 98))
603860	25595897	Importantly, our in vivo data show for the first time that systemic blockade of VEGFR1+ or VEGFR2+ non-tumor cells with neutralizing antibodies is sufficient to significantly suppress esophageal tumor growth, angiogenesis and metastasis in mice.	('metastasis', 'CPA', (226, 236))	('VEGFR2+', 'Gene', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('esophageal tumor', 'Phenotype', 'HP:0100751', (184, 200))	('blockade', 'Var', (68, 76))	('tumor', 'Disease', (103, 108))	('mice', 'Species', '10090', (240, 244))	('angiogenesis', 'CPA', (209, 221))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('suppress', 'NegReg', (175, 183))	('VEGFR1+', 'Gene', (80, 87))	('esophageal tumor', 'Disease', 'MESH:D004938', (184, 200))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('esophageal tumor', 'Disease', (184, 200))
603861	25595897	Moreover, our tissue microarray study of human EC clinical specimens showed the clinicopathological significance of VEGFR1 and VEGFR2 in EC, which suggest that anti-VEGFR1/VEGFR2 therapies may be particularly beneficial for patients with aggressive EC.	('anti-VEGFR1/VEGFR2', 'Var', (160, 178))	('aggressive EC', 'Disease', (238, 251))	('human', 'Species', '9606', (41, 46))	('patients', 'Species', '9606', (224, 232))
603872	25595897	The outcome of this study enhances our understanding of the functional significance of VEGFR1+/VEGFR2+ non-tumor and tumor cells, which may serve as therapeutic targets in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('VEGFR1+/VEGFR2+', 'Var', (87, 102))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (117, 122))	('ESCC', 'Disease', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
603873	25595897	To study the roles of VEGFR1- and VEGFR2-expressing non-tumor cells in the development of esophageal cancer, we made use of mouse-specific antibodies to determine if blockade of host VEGFR1 and VEGFR2 had any effects on growth of xenografted human ESCC tumors in mouse models.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('VEGFR1', 'Gene', (183, 189))	('growth', 'MPA', (220, 226))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('tumors', 'Disease', (253, 259))	('tumor', 'Disease', (56, 61))	('mouse', 'Species', '10090', (124, 129))	('esophageal cancer', 'Disease', (90, 107))	('tumor', 'Disease', (253, 258))	('blockade', 'Var', (166, 174))	('effects', 'Reg', (209, 216))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('mouse', 'Species', '10090', (263, 268))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('human', 'Species', '9606', (242, 247))	('VEGFR2', 'Gene', (194, 200))
603875	25595897	The results showed that the antibodies MF-1 or DC101 significantly suppressed tumor growth in human ESCC tumour xenografts in a dose-dependent manner.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumour', 'Disease', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('DC101', 'Gene', (47, 52))	('MF-1', 'Gene', (39, 43))	('antibodies', 'Var', (28, 38))	('human', 'Species', '9606', (94, 99))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (78, 83))	('suppressed', 'NegReg', (67, 77))
603877	25595897	We also found that MF-1 and DC101, alone or in combination, could significantly reduce Ki-67-positive tumor cells in the KYSE30 and KYSE270 xenografts, suggesting that blockade of host VEGFR1/VEGFR2 could inhibit tumor cell proliferation (Figure 1B and Supplementary Figure S1A).	('tumor', 'Disease', (213, 218))	('DC101', 'Gene', (28, 33))	('inhibit', 'NegReg', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('blockade', 'Var', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('reduce', 'NegReg', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('VEGFR1/VEGFR2', 'Gene', (185, 198))	('Ki-67-positive', 'Protein', (87, 101))
603878	25595897	Since the mouse-specific MF-1 and DC101 antibodies exerted no significant inhibitory effect on proliferation of human ESCC cells in vitro (Supplementary Figure S2), the observed anti-tumor activity was unlikely to be a direct effect on human cancer cells but could be mediated by mouse non-tumor cells that expressed VEGFR1 or VEGFR2.	('inhibitory', 'NegReg', (74, 84))	('human', 'Species', '9606', (236, 241))	('mouse', 'Species', '10090', (10, 15))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('antibodies', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumor', 'Disease', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('DC101', 'Gene', (34, 39))	('proliferation', 'CPA', (95, 108))	('mouse', 'Species', '10090', (280, 285))	('human', 'Species', '9606', (112, 117))	('tumor', 'Disease', (290, 295))	('MF-1', 'Gene', (25, 29))
603880	25595897	The results showed no significant difference in the expression of p-EGFR and EGFR between the treated and control groups (Supplementary Figure S3), thus confirming that the suppressive effects of MF-1 and DC101 antibodies on tumor growth were not due to blockade of EGFR on cancer cells.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('p-EGFR', 'Gene', '1956', (66, 72))	('antibodies', 'Var', (211, 221))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('EGFR', 'Gene', (68, 72))	('DC101', 'Gene', (205, 210))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('EGFR', 'Gene', '1956', (266, 270))	('tumor', 'Disease', (225, 230))	('cancer', 'Disease', (274, 280))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (266, 270))	('p-EGFR', 'Gene', (66, 72))	('MF-1', 'Gene', (196, 200))	('EGFR', 'Gene', (77, 81))
603882	25595897	With the exception of the group treated with high dosage DC101, which showed a slight but statistically insignificant weight loss after two weeks, there was no obvious difference in body weight among the other groups (Supplementary Figure S4A).	('weight loss', 'Phenotype', 'HP:0001824', (118, 129))	('weight loss', 'Disease', 'MESH:D015431', (118, 129))	('weight loss', 'Disease', (118, 129))	('DC101', 'Var', (57, 62))
603886	25595897	Western blot analysis showed that VEGF upregulated the expression of p-VEGFR1, p-VEGFR2, p-Src and p-ERK in HUVECs, and that VEGFR1 and VEGFR2 antibodies attenuated these effects (Figure 2D).	('upregulated', 'PosReg', (39, 50))	('expression', 'MPA', (55, 65))	('Src', 'Gene', '6714', (91, 94))	('p-ERK', 'Gene', '9451', (99, 104))	('p-VEGFR1', 'Var', (69, 77))	('p-VEGFR2', 'Var', (79, 87))	('p-ERK', 'Gene', (99, 104))	('Src', 'Gene', (91, 94))
603894	25595897	It was reported that VEGFR1+ and VEGFR2+ BMDCs contribute to tumor angiogenesis and progression.	('VEGFR2+', 'Var', (33, 40))	('contribute', 'Reg', (47, 57))	('progression', 'CPA', (84, 95))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('VEGFR1+', 'Var', (21, 28))
603898	25595897	In addition, our results showed that VEGF increased the expressions of p-Src and p-Erk in these cells, and that the effects were abrogated by blockade of VEGFR1 and VEGFR2 (Figure 4E), which were consistent with the effects on HUVECs (Figure 2D).	('increased', 'PosReg', (42, 51))	('VEGFR1', 'Gene', (154, 160))	('Erk', 'Gene', (83, 86))	('VEGFR2', 'Gene', (165, 171))	('abrogated', 'NegReg', (129, 138))	('Erk', 'Gene', '2048', (83, 86))	('Src', 'Gene', (73, 76))	('blockade', 'Var', (142, 150))	('expressions', 'MPA', (56, 67))	('Src', 'Gene', '6714', (73, 76))
603902	25595897	The results showed enhanced invasion of human ESCC cells within 24 h, and that blocking VEGFR1 on bone marrow cells with MF-1, or VEGFR2 with DC101, partially abolished this effect (Figure 5D).	('blocking', 'Var', (79, 87))	('abolished', 'NegReg', (159, 168))	('invasion', 'CPA', (28, 36))	('VEGFR1', 'Gene', (88, 94))	('human', 'Species', '9606', (40, 45))	('enhanced', 'PosReg', (19, 27))
603903	25595897	These data collectively indicate that VEGFR1+/VEGFR2+ endothelial and BMDCs play a vital role in the chemo-attraction of circulating cancer cells, and that blockade of VEGFR1/VEGFR2 could significantly prohibit this process.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('VEGFR1/VEGFR2', 'Gene', (168, 181))	('prohibit', 'NegReg', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('blockade', 'Var', (156, 164))
603904	25595897	In light of the pro-invasive effect of HUVECs and BMDCs on cancer cells, we next determined whether blockade of host VEGFR1 and VEGFR2 could inhibit cancer metastasis.	('cancer', 'Disease', (149, 155))	('VEGFR1', 'Gene', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer metastasis', 'Disease', 'MESH:D009362', (149, 166))	('cancer metastasis', 'Disease', (149, 166))	('blockade', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('VEGFR2', 'Gene', (128, 134))	('cancer', 'Disease', (59, 65))	('inhibit', 'NegReg', (141, 148))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
603906	25595897	Furthermore, treatment with the antibodies was found to improve the survival rates of the mice (Figure 6E).	('antibodies', 'Var', (32, 42))	('survival rates', 'CPA', (68, 82))	('mice', 'Species', '10090', (90, 94))	('improve', 'PosReg', (56, 63))
603923	25595897	The results suggest that activation of the Src and Erk pathways may contribute to the functions of VEGFR1+ and VEGFR2+ BMDCs in promoting cancer progression.	('cancer', 'Disease', (138, 144))	('Src', 'Gene', (43, 46))	('Erk', 'Gene', (51, 54))	('Src', 'Gene', '6714', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('promoting', 'PosReg', (128, 137))	('Erk', 'Gene', '2048', (51, 54))	('VEGFR1+', 'Var', (99, 106))	('activation', 'PosReg', (25, 35))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('VEGFR2+', 'Var', (111, 118))
603932	25595897	In this study, we showed that blockade of host VEGFR1 or VEGFR2 by using the species-specific neutralizing antibodies could suppress ESCC tumor growth, angiogenesis and metastasis in preclinical models, thus providing strong evidence of the importance of tumor micro- and systemic environments in cancer progression.	('VEGFR2', 'Gene', (57, 63))	('cancer', 'Disease', (297, 303))	('suppress', 'NegReg', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', (255, 260))	('tumor', 'Disease', (138, 143))	('blockade', 'Var', (30, 38))	('metastasis', 'CPA', (169, 179))	('ESCC', 'Disease', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('VEGFR1', 'Gene', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
603933	25595897	Our results showed that simultaneous blockade VEGFR1 and VEGFR2 had co-adjuvant inhibitory effect on tumor growth and metastasis.	('VEGFR2', 'Gene', (57, 63))	('blockade', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('inhibitory', 'NegReg', (80, 90))	('VEGFR1', 'Gene', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
603938	25595897	IMC-1121B (also known as Ramucirumab) was recently approved by FDA in April 2014 as second-line therapy for patients with gastric cancer.	('IMC-1121B', 'Var', (0, 9))	('Ramucirumab', 'Chemical', 'MESH:C543333', (25, 36))	('gastric cancer', 'Disease', (122, 136))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('patients', 'Species', '9606', (108, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
603942	25595897	Human ESCC cell lines KYSE30, KYSE150, KYSE270, KYSE410, KYSE510, KYSE520 (DSMZ, Braunschweig, Germany), as well as HKESC-1 and HKESC-2, were maintained in RPMI 1640 (Sigma, St Louis, MO) supplemented with 10% fetal bovine serum (Invitrogen, Gaithersburg, MD).	('Human', 'Species', '9606', (0, 5))	('KYSE510', 'Var', (57, 64))	('HKESC-1', 'CellLine', 'CVCL:D568', (116, 123))	('HKESC-2', 'CellLine', 'CVCL:D571', (128, 135))	('KYSE150', 'Var', (30, 37))	('KYSE520', 'Var', (66, 73))	('bovine', 'Species', '9913', (216, 222))	('KYSE270', 'Var', (39, 46))	('KYSE410', 'Var', (48, 55))
603966	21977915	PXR polymorphisms 25385C/T, 7635A/G, and 8055C/T were genotyped in 249 BE patients, 233 RE patients, and 201 controls matched for age and gender.	('7635A/G', 'Mutation', 'rs6785049', (28, 35))	('patients', 'Species', '9606', (91, 99))	('25385C/T', 'Mutation', 'g.25385C>T', (18, 26))	('7635A/G', 'Var', (28, 35))	('patients', 'Species', '9606', (74, 82))	('BE', 'Phenotype', 'HP:0100580', (71, 73))	('8055C/T', 'Var', (41, 48))	('8055C/T', 'Mutation', 'rs2276707', (41, 48))	('25385C/T', 'Var', (18, 26))
603983	21977915	Variability at the PXR genetic locus is therefore thought to be associated with pathophysiological changes in steroid, cholesterol or bile acid levels.	('associated', 'Reg', (64, 74))	('cholesterol', 'MPA', (119, 130))	('Variability', 'Var', (0, 11))	('cholesterol', 'Chemical', 'MESH:D002784', (119, 130))	('bile acid levels', 'MPA', (134, 150))	('steroid', 'Chemical', 'MESH:D013256', (110, 117))	('steroid', 'MPA', (110, 117))	('bile acid', 'Chemical', 'MESH:D001647', (134, 143))
603984	21977915	Polymorphisms in the PXR gene are associated with diseases such as inflammatory bowel disease and primary sclerosing cholangitis.	('associated', 'Reg', (34, 44))	('inflammatory bowel disease', 'Disease', (67, 93))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (106, 128))	('PXR', 'Gene', (21, 24))	('Polymorphisms', 'Var', (0, 13))	('cholangitis', 'Disease', (117, 128))	('cholangitis', 'Phenotype', 'HP:0030151', (117, 128))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (67, 93))	('cholangitis', 'Disease', 'MESH:D002761', (117, 128))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (67, 93))
603985	21977915	As these chronic inflammatory diseases are associated with aberrant bile acid metabolism, there may also be a link between PXR and BE.	('chronic inflammatory diseases', 'Disease', (9, 38))	('BE', 'Phenotype', 'HP:0100580', (131, 133))	('aberrant', 'Var', (59, 67))	('aberrant bile acid metabolism', 'Phenotype', 'HP:0030984', (59, 88))	('associated', 'Reg', (43, 53))	('bile acid metabolism', 'MPA', (68, 88))	('bile acid', 'Chemical', 'MESH:D001647', (68, 77))
603988	21977915	In addition, a link between PXR polymorphisms and esophageal disease was found.	('esophageal disease', 'Disease', (50, 68))	('polymorphisms', 'Var', (32, 45))	('esophageal disease', 'Disease', 'MESH:D004935', (50, 68))	('link', 'Reg', (15, 19))
604016	21977915	We analyzed polymorphisms -25385C/T, 7635A/G, and 8055C/T as these should be informative for eight PXR polymorphisms and were observed by Zhang et al  to have an effect on PXR function in humans.	('polymorphisms', 'Var', (12, 25))	('8055C/T', 'Mutation', 'rs2276707', (50, 57))	('effect', 'Reg', (162, 168))	('PXR function', 'MPA', (172, 184))	('7635A/G', 'Mutation', 'rs6785049', (37, 44))	('humans', 'Species', '9606', (188, 194))	('-25385C/T', 'Mutation', 'rs3814055', (26, 35))	('7635A/G', 'Var', (37, 44))
604031	21977915	Allele frequencies of SNP 7635A/G and 8055C/T for patient and healthy control populations are listed in Table 3.	('7635A/G', 'Mutation', 'rs6785049', (26, 33))	('8055C/T', 'Var', (38, 45))	('8055C/T', 'Mutation', 'rs2276707', (38, 45))	('SNP 7635A/G', 'Var', (22, 33))	('patient', 'Species', '9606', (50, 57))
604032	21977915	In comparing genotype distributions, an increase was demonstrated in the minor allele frequency among BE patients as compared with RE patients and healthy controls for both 7635A/G and 8055C/T.	('patients', 'Species', '9606', (105, 113))	('7635A/G', 'Mutation', 'rs6785049', (173, 180))	('8055C/T', 'Var', (185, 192))	('increase', 'PosReg', (40, 48))	('8055C/T', 'Mutation', 'rs2276707', (185, 192))	('patients', 'Species', '9606', (134, 142))	('7635A/G', 'Var', (173, 180))	('BE', 'Phenotype', 'HP:0100580', (102, 104))
604035	21977915	At low pH, bile acids are thought to cause esophageal mucosal injury, which has been substantiated both in vitro and in animal model systems.	('esophageal mucosal injury', 'Disease', (43, 68))	('bile acids', 'Chemical', 'MESH:D001647', (11, 21))	('esophageal mucosal injury', 'Disease', 'MESH:D052016', (43, 68))	('bile acids', 'Var', (11, 21))	('cause', 'Reg', (37, 42))
604050	21977915	Recent studies associate PXR polymorphisms with other pathogenic conditions of the gastrointestinal tract, such as inflammatory bowel disease and primary sclerosing cholangitis.	('gastrointestinal tract', 'Disease', 'MESH:D004067', (83, 105))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (154, 176))	('cholangitis', 'Disease', (165, 176))	('PXR', 'Gene', (25, 28))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (115, 141))	('cholangitis', 'Phenotype', 'HP:0030151', (165, 176))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (115, 141))	('conditions of the gastrointestinal tract', 'Phenotype', 'HP:0011024', (65, 105))	('gastrointestinal tract', 'Disease', (83, 105))	('cholangitis', 'Disease', 'MESH:D002761', (165, 176))	('inflammatory bowel disease', 'Disease', (115, 141))	('polymorphisms', 'Var', (29, 42))
604161	30532557	It was reported that the combination of E2F8 and E2F7 is essential for embryonic development in mice, angiogenesis, and lymphangiogenesis in zebrafish.	('E2F8', 'Var', (40, 44))	('mice', 'Species', '10090', (96, 100))	('E2F7', 'Gene', (49, 53))	('zebrafish', 'Species', '7955', (141, 150))	('angiogenesis', 'CPA', (102, 114))	('lymphangiogenesis', 'CPA', (120, 137))	('E2F7', 'Gene', '52679', (49, 53))
604163	30532557	Sun et al discovered that E2F8 influenced the cell cycle and further promoted papillary thyroid cancer development.	('papillary thyroid cancer', 'Disease', (78, 102))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (78, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('E2F8', 'Var', (26, 30))	('thyroid cancer', 'Phenotype', 'HP:0002890', (88, 102))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (78, 102))	('cell cycle', 'CPA', (46, 56))	('promoted', 'PosReg', (69, 77))	('influenced', 'Reg', (31, 41))
604165	30532557	All these studies indicated that E2F8 could act as a potential oncogene in several cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('E2F8', 'Var', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
604186	30532557	The following primary antibodies were used: anti-E2F8, anti-CCND1, and anti-p21; anti-GAPDH was used as an internal control.	('GAPDH', 'Gene', '14433', (86, 91))	('GAPDH', 'Gene', (86, 91))	('anti-p21', 'Var', (71, 79))	('anti-CCND1', 'Var', (55, 65))	('anti-E2F8', 'Var', (44, 53))
604201	30532557	The results of EdU assays showed that the rate at which TE-10 cells incorporated EdU in the downregulated E2F8 group distinctly decreased compared to the rate in the control group; however, the opposite results were detected in the EC-1 cell lines when comparing the rate at which cells incorporated EdU in the upregulated E2F8 group to that of the NC group (Figure 2D).	('EdU', 'Chemical', 'MESH:C031086', (15, 18))	('TE-1', 'Gene', '57816', (56, 60))	('EC-1', 'Gene', (232, 236))	('upregulated', 'PosReg', (311, 322))	('EdU', 'Chemical', 'MESH:C031086', (81, 84))	('TE-1', 'Gene', (56, 60))	('decreased', 'NegReg', (128, 137))	('E2F8', 'Var', (323, 327))	('EdU', 'Chemical', 'MESH:C031086', (300, 303))	('EC-1', 'Gene', '4819', (232, 236))
604219	30532557	Sun et al found that E2F8 can promote papillary thyroid cancer progression by regulating the cell cycle.	('promote', 'PosReg', (30, 37))	('regulating', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('papillary thyroid cancer', 'Disease', (38, 62))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (38, 62))	('E2F8', 'Var', (21, 25))	('cell cycle', 'CPA', (93, 103))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (38, 62))	('thyroid cancer', 'Phenotype', 'HP:0002890', (48, 62))
604224	30532557	Through Western blotting, E2F8 was revealed to have the ability to influence p21, which can be a universal inhibitor of cyclin kinases and CCND1, which was identified as a key factor in regulating the cell cycle.	('influence', 'Reg', (67, 76))	('E2F8', 'Var', (26, 30))	('cyclin', 'Gene', '18538', (120, 126))	('cyclin', 'Gene', (120, 126))	('p21', 'Gene', (77, 80))
604243	29190930	Recent studies have indicated that the dysregulation of miRNAs is involved in a variety of human cancers and mediate in initiation, promotion, progression, and resistance to cancer chemotherapy.	('mediate', 'Reg', (109, 116))	('dysregulation', 'Var', (39, 52))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('involved', 'Reg', (66, 74))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('human', 'Species', '9606', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
604252	29190930	Our previous study proved that the heterozygote of PLCE1 rs2274223 is associated with the susceptibility to HPV infection in Kazakh patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('esophageal cancer', 'Disease', (146, 163))	('rs2274223', 'Mutation', 'rs2274223', (57, 66))	('HPV infection', 'Disease', 'MESH:D030361', (108, 121))	('rs2274223', 'Var', (57, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('PLCE1', 'Gene', (51, 56))	('susceptibility', 'Reg', (90, 104))	('patients', 'Species', '9606', (132, 140))	('HPV infection', 'Disease', (108, 121))
604286	29190930	Our previous study proved that hyper-methylation-mediated silencing of miR-34a contributes to esophageal carcinoma in the Kazakh population.	('miR-34a', 'Gene', '407040', (71, 78))	('esophageal carcinoma', 'Disease', (94, 114))	('miR-34a', 'Gene', (71, 78))	('hyper-methylation-mediated', 'Var', (31, 57))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (94, 114))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (94, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('silencing', 'NegReg', (58, 67))
604306	29190930	Notably, the knockdown of endogenous PLCE1 expression by siRNA significantly suppressed cell growth (Figure 3D, P =0.006) and colony formation (Figure 3G, P <0.001), but enhanced apoptosis (Figure 3J, P =0.0003) and migration (Figure 3L, P =0.004) in Eca109 cells; this phenotype was similar to that induced by the overexpression of the miR-34a mimic.	('suppressed', 'NegReg', (77, 87))	('miR-34a', 'Gene', '407040', (337, 344))	('miR-34a', 'Gene', (337, 344))	('PLCE1', 'Gene', (37, 42))	('apoptosis', 'CPA', (179, 188))	('cell growth', 'CPA', (88, 99))	('enhanced', 'PosReg', (170, 178))	('migration', 'CPA', (216, 225))	('colony formation', 'CPA', (126, 142))	('knockdown', 'Var', (13, 22))
604307	29190930	We found that miR-34a overexpression or PLCE1 knockdown resulted in the same down-regulation of Bcl-2 and up-regulation of cleaved PARP and Bax (Figure 3M).	('Bax', 'Gene', '581', (140, 143))	('miR-34a', 'Gene', '407040', (14, 21))	('Bcl-2', 'Gene', (96, 101))	('miR-34a', 'Gene', (14, 21))	('Bcl-2', 'Gene', '596', (96, 101))	('knockdown', 'Var', (46, 55))	('overexpression', 'PosReg', (22, 36))	('down-regulation', 'NegReg', (77, 92))	('cleaved', 'CPA', (123, 130))	('PLCE1', 'Gene', (40, 45))	('PARP', 'Gene', '1302', (131, 135))	('Bax', 'Gene', (140, 143))	('up-regulation', 'PosReg', (106, 119))	('PARP', 'Gene', (131, 135))
604314	29190930	The Eca109 cells treated with miR-34a mimic and si-PLCE1 showed decreased colony masses than the controls (P =0.0009, P =0.0001), and the co-transfected group showed less masses than the two groups (P =0.0005, P =0.00012).	('si-PLCE1', 'Var', (48, 56))	('less', 'NegReg', (166, 170))	('miR-34a', 'Gene', '407040', (30, 37))	('colony masses', 'CPA', (74, 87))	('miR-34a', 'Gene', (30, 37))	('masses', 'CPA', (171, 177))	('decreased', 'NegReg', (64, 73))
604315	29190930	The knockdown of endogenous PLCE1 expression by siRNA significantly increased cell apoptosis and suppressed migration in Eca109 cells more than the controls (Figure 4D-4E, P =0.0024; Figure 4F-4G, P =0.00128); this phenomenon was similar to that induced by the overexpression of the miR-34a mimic (Figure 4D-4E, P =0.0017; Figure 4F-4G, P =0.0179).	('migration', 'CPA', (108, 117))	('miR-34a', 'Gene', '407040', (283, 290))	('cell apoptosis', 'CPA', (78, 92))	('miR-34a', 'Gene', (283, 290))	('PLCE1', 'Gene', (28, 33))	('knockdown', 'Var', (4, 13))	('suppressed', 'NegReg', (97, 107))	('increased', 'PosReg', (68, 77))
604317	29190930	These results suggested that the knockdown of PLCE1 can strengthen the antitumor effects of miR-34a.	('PLCE1', 'Gene', (46, 51))	('knockdown', 'Var', (33, 42))	('miR-34a', 'Gene', '407040', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('strengthen', 'PosReg', (56, 66))	('miR-34a', 'Gene', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
604332	29190930	Carcinogenic factors can trigger related gene mutations, resulting in abnormal gene expressions that ultimately affect the body tumor, as well as induce tumor growth, invasion, metastasis, and a series of complex processes.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('body tumor', 'Disease', (123, 133))	('gene expressions', 'MPA', (79, 95))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('invasion', 'CPA', (167, 175))	('metastasis', 'CPA', (177, 187))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('affect', 'Reg', (112, 118))	('induce', 'Reg', (146, 152))	('tumor', 'Disease', (128, 133))	('body tumor', 'Disease', 'MESH:D002345', (123, 133))
604333	29190930	The current study confirmed that the aberrant expression of miR-34a is associated with lymph node metastasis and advanced stage in ESCC.	('aberrant expression', 'Var', (37, 56))	('miR-34a', 'Gene', '407040', (60, 67))	('miR-34a', 'Gene', (60, 67))	('advanced stage', 'CPA', (113, 127))	('lymph node metastasis', 'CPA', (87, 108))	('associated', 'Reg', (71, 81))	('ESCC', 'Disease', (131, 135))
604335	29190930	Thus far, dysregulated miRNA expression has been implicated in affecting the malignant biological functions of esophageal cancer.	('dysregulated', 'Var', (10, 22))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('esophageal cancer', 'Disease', (111, 128))	('affecting', 'Reg', (63, 72))	('malignant biological functions', 'CPA', (77, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('implicated', 'Reg', (49, 59))
604339	29190930	Dysregulation of miRNAs can be caused by aberrant DNA methylation, which has been observed to benefit tumorigenesis.	('aberrant', 'Var', (41, 49))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('benefit', 'PosReg', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('DNA', 'Protein', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
604340	29190930	Our previous findings revealed that methylation causes a decrease in the expression of miR-34a, and hypermethylation of certain miR-34a sites is related to esophageal advanced cancer stage and lymph node metastasis.	('miR-34a', 'Gene', '407040', (87, 94))	('decrease', 'NegReg', (57, 65))	('hypermethylation', 'Var', (100, 116))	('miR-34a', 'Gene', '407040', (128, 135))	('miR-34a', 'Gene', (128, 135))	('miR-34a', 'Gene', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lymph node metastasis', 'CPA', (193, 214))	('esophageal advanced cancer', 'Disease', 'MESH:D004938', (156, 182))	('expression', 'MPA', (73, 83))	('related', 'Reg', (145, 152))	('esophageal advanced cancer', 'Disease', (156, 182))	('methylation', 'Var', (36, 47))
604379	29190930	Although PLCE1 expression has been found to promote tumor formation in a mouse model of skin cancer, PLCE1-/- mice have exhibited decreased susceptibility to tumor development.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (158, 163))	('PLCE1', 'Gene', (9, 14))	('expression', 'Var', (15, 25))	('skin cancer', 'Disease', (88, 99))	('promote', 'PosReg', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (52, 57))	('skin cancer', 'Disease', 'MESH:D012878', (88, 99))	('mice', 'Species', '10090', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mouse', 'Species', '10090', (73, 78))	('PLCE1-/-', 'Gene', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('skin cancer', 'Phenotype', 'HP:0008069', (88, 99))	('decreased', 'NegReg', (130, 139))
604380	29190930	In a study by Oka, PLCE-/- mice showed reduced cell death secondary to UVB irradiation compared with PLCE+/- and "PLCE+/- mice.	('mice', 'Species', '10090', (122, 126))	('cell death', 'CPA', (47, 57))	('PLCE', 'Gene', (101, 105))	('mice', 'Species', '10090', (27, 31))	('PLCE', 'Gene', '74055', (101, 105))	('PLCE', 'Gene', (19, 23))	('PLCE', 'Gene', (114, 118))	('PLCE', 'Gene', '74055', (19, 23))	('PLCE', 'Gene', '74055', (114, 118))	('reduced', 'NegReg', (39, 46))	('irradiation', 'Var', (75, 86))	('UVB', 'Gene', (71, 74))
604384	29190930	More recently, many studies have suggested that genetic variants in PLCE1 may serve as candidate markers for cancers and influence cancer risk.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', (109, 115))	('cancers', 'Disease', (109, 116))	('genetic variants', 'Var', (48, 64))	('PLCE1', 'Gene', (68, 73))	('influence', 'Reg', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
604385	29190930	Moreover, the heterozygote of PLCE1 rs2274223 enhanced susceptibility to HPV infection in Kazakh ESCC patients.	('HPV infection', 'Disease', 'MESH:D030361', (73, 86))	('patients', 'Species', '9606', (102, 110))	('PLCE1', 'Gene', (30, 35))	('susceptibility', 'MPA', (55, 69))	('rs2274223', 'Mutation', 'rs2274223', (36, 45))	('rs2274223', 'Var', (36, 45))	('HPV infection', 'Disease', (73, 86))	('enhanced', 'PosReg', (46, 54))
604386	29190930	applied the shRNA-silencing PLCE1 gene in bladder cancer cell line T24 in, expressions of MMP and BCL2 decreased and invasion ability of bladder cancer cells was inhibited, which eventually prevented tumor development.	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('shRNA-silencing', 'Var', (12, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('prevented', 'NegReg', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('bladder cancer', 'Disease', (137, 151))	('inhibited', 'NegReg', (162, 171))	('BCL2', 'Gene', '596', (98, 102))	('PLCE1 gene', 'Gene', (28, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('decreased', 'NegReg', (103, 112))	('MMP', 'Gene', (90, 93))	('tumor', 'Disease', (200, 205))	('expressions', 'MPA', (75, 86))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('BCL2', 'Gene', (98, 102))	('invasion ability', 'CPA', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))
604387	29190930	In esophageal carcinoma cells, PLCE1 knockdown increased p53 expression and apoptosis via regulating p53 promoter methylation.	('esophageal carcinoma', 'Disease', (3, 23))	('p53', 'Gene', '7157', (57, 60))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (3, 23))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (3, 23))	('knockdown', 'Var', (37, 46))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('increased', 'PosReg', (47, 56))	('p53', 'Gene', (57, 60))	('regulating', 'Reg', (90, 100))	('apoptosis', 'CPA', (76, 85))	('PLCE1', 'Gene', (31, 36))	('expression', 'MPA', (61, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
604424	29190930	The resulting blots were immersed in the first antibodies diluted with 5% non-fat milk overnight at 4 C, including PLCE1 (sc-28404, 1:200), Bax (ab32503, 1:1000), cleaved-PARP (ab32064, 1:5000), Snail (13099-1-AP, 1:250), Slug (12129-1-AP, 1:250), caspase-3 (19677-1-AP, 1:250), caspase-7 (BA0688-1, 1:125), Bcl-2 (AB112, 1:1000), and beta-actin (Zhongshanjinqiao 140411, 1:1000); and then treated with a secondary antibody for 2 h at room temperature.	('Bax', 'Gene', '581', (140, 143))	('PARP', 'Gene', '1302', (171, 175))	('Snail', 'Gene', (195, 200))	('13099-1-AP', 'Var', (202, 212))	('ab32064', 'Var', (177, 184))	('beta-actin', 'Gene', '728378', (335, 345))	('Bcl-2', 'Gene', '596', (308, 313))	('caspase-7', 'Gene', (279, 288))	('Slug', 'Gene', (222, 226))	('PARP', 'Gene', (171, 175))	('Snail', 'Gene', '6615', (195, 200))	('beta-actin', 'Gene', (335, 345))	('12129-1-AP', 'Var', (228, 238))	('19677-1-AP', 'Var', (259, 269))	('caspase-7', 'Gene', '840', (279, 288))	('Slug', 'Gene', '6591', (222, 226))	('caspase-3', 'Gene', '836', (248, 257))	('Bcl-2', 'Gene', (308, 313))	('Bax', 'Gene', (140, 143))	('caspase-3', 'Gene', (248, 257))
604486	28537901	Higher levels of CXCL10 in the serum were found in patients with R0 resection status (p = 0.041).	('CXCL10', 'Gene', '3627', (17, 23))	('CXCL10', 'Gene', (17, 23))	('Higher', 'PosReg', (0, 6))	('patients', 'Species', '9606', (51, 59))	('R0 resection', 'Var', (65, 77))
604493	28537901	No factors were found to have prognostic relevance in the patients' serum, though high IL-6 levels showed a trend to be associated with worse prognosis (p = 0.124) (Figure 1A).	('high', 'Var', (82, 86))	('patients', 'Species', '9606', (58, 66))	('high IL-6 levels', 'Phenotype', 'HP:0030783', (82, 98))	('IL-6', 'Gene', (87, 91))	('IL-6', 'Gene', '3569', (87, 91))
604557	28537901	In SCC tumors low levels of CCL11 were associated with better prognosis compared to patients expressing higher levels of CCL11.	('SCC tumors', 'Disease', (3, 13))	('CCL11', 'Gene', '6356', (121, 126))	('patients', 'Species', '9606', (84, 92))	('CCL11', 'Gene', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('low levels', 'Var', (14, 24))	('CCL11', 'Gene', (121, 126))	('CCL11', 'Gene', '6356', (28, 33))	('SCC tumors', 'Disease', 'MESH:D009369', (3, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
604625	28168163	On univariate analysis, variables associated with worse survival included: clinical stage IIIB (p = 0.037), planning target volume (PTV) over 450 cc (p < 0.001), heart V30 over 40% (p = -0.048), and esophageal mean dose over 20% (p = 0.024), V5 (p = -0.015), and V60 (p = -0.011).	('V60', 'Var', (263, 266))	('PTV', 'Chemical', '-', (132, 135))	('heart', 'CPA', (162, 167))
604629	28168163	Grade 2 or higher acute esophagitis was reduced if V60 <= 20% (62 vs. 81.3%, p = 0.018).	('V60 <= 20%', 'Var', (51, 61))	('esophagitis', 'Phenotype', 'HP:0100633', (24, 35))	('reduced', 'NegReg', (40, 47))	('acute esophagitis', 'Disease', (18, 35))	('acute esophagitis', 'Disease', 'MESH:D004941', (18, 35))
604661	28168163	On univariate analysis decreased survival was detected in the subset of patients with: (1) stage IIIB (p = 0.037), (2) PTV > 450 cc (p < 0.001), (3) heart V30 > 40% (p = 0.048), (4) esophageal mean dose of >20% (p = 0.024), (5) esophageal V5 > 60% (p = 0.015), and (6) esophageal V60 > 20% (p = 0.011).	('decreased', 'NegReg', (23, 32))	('heart V30 > 40%', 'Var', (149, 164))	('PTV > 450 cc', 'Var', (119, 131))	('PTV', 'Chemical', '-', (119, 122))	('patients', 'Species', '9606', (72, 80))
604663	28168163	On univariate analysis, large PTV was associated with a reduced LRC [<=450 vs. >450 cc, HR = 1.86; 95% confidence interval (CI) (1.03-3.36), p = 0.039].	('LRC [', 'MPA', (64, 69))	('reduced', 'NegReg', (56, 63))	('PTV', 'Gene', (30, 33))	('large', 'Var', (24, 29))	('PTV', 'Chemical', '-', (30, 33))
604667	28168163	On univariate analysis, the use of 3D-CRT (p = 0.036) and V5 <= 65 (p = 0.036) were associated with a lower rate of pneumonitis.	('lower', 'NegReg', (102, 107))	('V5 <= 65', 'Var', (58, 66))	('CRT', 'Gene', '799', (38, 41))	('pneumonitis', 'Disease', 'MESH:D011014', (116, 127))	('CRT', 'Gene', (38, 41))	('pneumonitis', 'Disease', (116, 127))
604668	28168163	On multivariate analysis, lung V5 <= 65 was associated with a decreased acute grade 2 or higher lung toxicity (7.4 vs. 23.8%, p = 0.027).	('lung toxicity', 'Disease', 'MESH:D008171', (96, 109))	('lung toxicity', 'Disease', (96, 109))	('lung V5 <= 65', 'Var', (26, 39))	('decreased', 'NegReg', (62, 71))
604672	28168163	On univariate analysis, a lower radiation therapy dose as a continuous variable (p = -0.041) and esophageal V60 <= 20% (p = -0.027) were associated with lower rates of acute grade 2 or higher esophagitis.	('esophagitis', 'Disease', (192, 203))	('esophagitis', 'Disease', 'MESH:D004941', (192, 203))	('lower', 'NegReg', (153, 158))	('esophageal', 'Var', (97, 107))	('esophagitis', 'Phenotype', 'HP:0100633', (192, 203))
604694	28168163	The data correlate well with a prior study showing that V20 values between 22 and 31 Gy led to an 8% pneumonitis rate.	('pneumonitis', 'Disease', (101, 112))	('V20 values', 'Var', (56, 66))	('pneumonitis', 'Disease', 'MESH:D011014', (101, 112))
604698	28168163	A prior study, showed that V5 <= 42% did indeed correlate with a lower rate of acute pneumonitis for NSCLC patients treated with concurrent chemoradiation.	('acute pneumonitis', 'Disease', 'MESH:D011014', (79, 96))	('NSCLC', 'Disease', (101, 106))	('lower', 'NegReg', (65, 70))	('acute pneumonitis', 'Disease', (79, 96))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('V5 <= 42%', 'Var', (27, 36))	('patients', 'Species', '9606', (107, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
604699	28168163	A review of 220 esophageal cancer patients also treated with radiation alone showed that V5 <= 60% correlated with lower rates of acute pneumonitis.	('V5 <= 60%', 'Var', (89, 98))	('acute pneumonitis', 'Disease', 'MESH:D011014', (130, 147))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('acute pneumonitis', 'Disease', (130, 147))	('lower', 'NegReg', (115, 120))	('patients', 'Species', '9606', (34, 42))	('esophageal cancer', 'Disease', (16, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (16, 33))
604705	28168163	A retrospective analysis of another series of 109 NSCLC patients treated with concurrent chemoradiation showed the esophageal V60 correlated with higher rates of acute esophagitis.	('patients', 'Species', '9606', (56, 64))	('esophagitis', 'Phenotype', 'HP:0100633', (168, 179))	('acute esophagitis', 'Disease', 'MESH:D004941', (162, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('esophageal', 'Var', (115, 125))	('NSCLC', 'Disease', (50, 55))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('acute esophagitis', 'Disease', (162, 179))
604725	28168163	Acute grade 2 or higher lung toxicity was lower in the V5 <= 65% group and acute grade 2 plus esophagitis was lower in the V60 <= 20% group.	('lung toxicity', 'Disease', 'MESH:D008171', (24, 37))	('lower', 'NegReg', (42, 47))	('V5 <= 65%', 'Var', (55, 64))	('esophagitis', 'Phenotype', 'HP:0100633', (94, 105))	('esophagitis', 'Disease', (94, 105))	('esophagitis', 'Disease', 'MESH:D004941', (94, 105))	('lower', 'NegReg', (110, 115))	('lung toxicity', 'Disease', (24, 37))	('V60 <= 20%', 'Var', (123, 133))
604731	26934647	The knockdown of endogenous APE1 in EAC FLO-1 cells significantly increased oxidative DNA damage (P < 0.01) and DNA single- and double-strand breaks (P < 0.01), whereas overexpression of APE1 in EAC OE33 cells reversed these effects.	('APE1', 'Gene', (28, 32))	('increased', 'PosReg', (66, 75))	('APE1', 'Gene', '328', (28, 32))	('APE1', 'Gene', (187, 191))	('oxidative DNA damage', 'MPA', (76, 96))	('EAC', 'Phenotype', 'HP:0011459', (195, 198))	('APE1', 'Gene', '328', (187, 191))	('knockdown', 'Var', (4, 13))	('EAC', 'Phenotype', 'HP:0011459', (36, 39))
604733	26934647	In contrast, knockdown of endogenous APE1 in FLO-1 cells increased apoptosis under the same conditions.	('apoptosis', 'CPA', (67, 76))	('endogenous', 'Var', (26, 36))	('APE1', 'Gene', (37, 41))	('APE1', 'Gene', '328', (37, 41))	('increased', 'PosReg', (57, 66))	('knockdown', 'Var', (13, 22))
604742	26934647	Previous studies have shown that short exposure to bile salts and low pH induces oxidative stress and DNA damage in esophageal tissues and cells.	('bile salts', 'Chemical', 'MESH:D001647', (51, 61))	('oxidative stress', 'Phenotype', 'HP:0025464', (81, 97))	('induces', 'Reg', (73, 80))	('DNA damage', 'MPA', (102, 112))	('low', 'Var', (66, 69))	('oxidative stress', 'MPA', (81, 97))
604750	26934647	Apurinic/apyrimidinic (AP) sites are one of the major types of oxidative DNA damage generated by ROS and are repaired primarily by BER pathways.	('ROS', 'Gene', (97, 100))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('Apurinic/apyrimidinic', 'Var', (0, 21))	('BE', 'Phenotype', 'HP:0100580', (131, 133))
604769	26934647	We investigated whether modulations of APE1 expression level affect apurinic/apyrimidinic (AP) sites accumulation in response to acidic bile salts.	('modulations', 'Var', (24, 35))	('affect', 'Reg', (61, 67))	('APE1', 'Gene', (39, 43))	('APE1', 'Gene', '328', (39, 43))	('bile salts', 'Chemical', 'MESH:D001647', (136, 146))	('response to acidic bile salts', 'MPA', (117, 146))
604770	26934647	We treated OE33 cells, following overexpression of APE1, and FLO-1 cells, after APE1 knockdown, with acidic bile salts for 30 min followed by incubation in regular complete media for 3 h post-treatment, and then measured AP sites.	('APE1', 'Gene', '328', (51, 55))	('APE1', 'Gene', (80, 84))	('APE1', 'Gene', '328', (80, 84))	('bile salts', 'Chemical', 'MESH:D001647', (108, 118))	('knockdown', 'Var', (85, 94))	('APE1', 'Gene', (51, 55))
604771	26934647	We found that the expression of APE1 significantly attenuated AP sites accumulation in response to acidic bile salts in OE33 cells (P = 0.02, Figure 2A).	('bile salts', 'Chemical', 'MESH:D001647', (106, 116))	('APE1', 'Gene', (32, 36))	('AP sites accumulation', 'MPA', (62, 83))	('attenuated', 'NegReg', (51, 61))	('APE1', 'Gene', '328', (32, 36))	('response to acidic bile salts', 'MPA', (87, 116))	('expression', 'Var', (18, 28))
604772	26934647	The knockdown of endogenous APE1 in FLO-1 cells significantly increased acidic bile salts-induced accumulation of AP sites (P < 0.01, Figure 2B).	('APE1', 'Gene', (28, 32))	('increased', 'PosReg', (62, 71))	('APE1', 'Gene', '328', (28, 32))	('knockdown', 'Var', (4, 13))	('acidic bile salts-induced accumulation of AP sites', 'MPA', (72, 122))	('bile salts', 'Chemical', 'MESH:D001647', (79, 89))
604773	26934647	We next examined levels of oxidative DNA damage induced by acidic bile salts following modulations of APE1 expression.	('bile salts', 'Chemical', 'MESH:D001647', (66, 76))	('modulations', 'Var', (87, 98))	('APE1', 'Gene', '328', (102, 106))	('APE1', 'Gene', (102, 106))	('oxidative DNA damage', 'MPA', (27, 47))
604774	26934647	The data indicated that the expression of APE1 in OE33 cells significantly reduced oxidative DNA damage, as indicated by a decreased 8-OH-dG level, in response to acidic bile salts as compared to control cells (P < 0.01, Figure 2C).	('APE1', 'Gene', (42, 46))	('oxidative DNA damage', 'MPA', (83, 103))	('decreased', 'NegReg', (123, 132))	('APE1', 'Gene', '328', (42, 46))	('8-OH-dG', 'Chemical', 'MESH:C067134', (133, 140))	('8-OH-dG level', 'MPA', (133, 146))	('reduced', 'NegReg', (75, 82))	('response to acidic bile salts', 'MPA', (151, 180))	('bile salts', 'Chemical', 'MESH:D001647', (170, 180))	('expression', 'Var', (28, 38))
604775	26934647	In contrast, knockdown of endogenous APE1 in FLO-1 cells significantly enhanced acidic bile salts-induced oxidative DNA damage as depicted by an increased 8-OH-dG level relative to control cells (P < 0.01, Figure 2D).	('enhanced', 'PosReg', (71, 79))	('8-OH-dG level', 'MPA', (155, 168))	('acidic bile salts-induced oxidative DNA damage', 'MPA', (80, 126))	('increased', 'PosReg', (145, 154))	('APE1', 'Gene', (37, 41))	('bile salts', 'Chemical', 'MESH:D001647', (87, 97))	('APE1', 'Gene', '328', (37, 41))	('8-OH-dG', 'Chemical', 'MESH:C067134', (155, 162))	('knockdown', 'Var', (13, 22))
604779	26934647	Conversely, knockdown of endogenous APE1 in FLO-1 cells significantly enhanced acidic bile salts-induced double-strand DNA damage relative to control cells as shown by an increased p-H2AX (S139) level (P < 0.01, Figure 3B).	('acidic bile salts-induced double-strand DNA damage', 'MPA', (79, 129))	('bile salts', 'Chemical', 'MESH:D001647', (86, 96))	('H2AX', 'Gene', (183, 187))	('knockdown', 'Var', (12, 21))	('APE1', 'Gene', (36, 40))	('APE1', 'Gene', '328', (36, 40))	('enhanced', 'PosReg', (70, 78))	('increased', 'PosReg', (171, 180))	('H2AX', 'Gene', '3014', (183, 187))
604781	26934647	Our data indicated that the expression of APE1 in OE33 cells significantly reduced acidic bile salts-induced DNA damage relative to control cells (P < 0.01, Figure 3C).	('APE1', 'Gene', (42, 46))	('APE1', 'Gene', '328', (42, 46))	('bile salts', 'Chemical', 'MESH:D001647', (90, 100))	('reduced', 'NegReg', (75, 82))	('expression', 'Var', (28, 38))	('acidic bile salts-induced DNA damage', 'MPA', (83, 119))
604782	26934647	However, knockdown of endogenous APE1 in FLO-1 cells significantly increased acidic bile salts-induced DNA damage as compared to control cells (P = 0.035, Figure 3D).	('knockdown', 'Var', (9, 18))	('acidic bile salts-induced DNA damage', 'MPA', (77, 113))	('APE1', 'Gene', (33, 37))	('bile salts', 'Chemical', 'MESH:D001647', (84, 94))	('APE1', 'Gene', '328', (33, 37))	('increased', 'PosReg', (67, 76))
604785	26934647	We evaluated apoptosis following APE1 expression and knockdown using Annexin-V/PI staining following treatment with acidic bile salts.	('knockdown', 'Var', (53, 62))	('APE1', 'Gene', (33, 37))	('apoptosis', 'CPA', (13, 22))	('bile salts', 'Chemical', 'MESH:D001647', (123, 133))	('expression', 'Var', (38, 48))	('APE1', 'Gene', '328', (33, 37))	('Annexin-V', 'Gene', '308', (69, 78))	('Annexin-V', 'Gene', (69, 78))
604787	26934647	Treatment with acidic bile salts induced 30.4% apoptotic cell death in APE1 knockdown FLO-1 cells as opposed to 13.8% apoptotic cell death in control FLO-1 cells (P < 0.05, Figure 4B).	('knockdown', 'Var', (76, 85))	('apoptotic cell death', 'CPA', (47, 67))	('APE1', 'Gene', (71, 75))	('bile salts', 'Chemical', 'MESH:D001647', (22, 32))	('APE1', 'Gene', '328', (71, 75))
604792	26934647	Western blot analysis data indicated that the expression of APE1 significantly decreased acidic bile salts-induced p-H2AX (S139) protein levels and cleavage of caspase-3 and PARP in OE33 cells (Figure 5A).	('bile salts', 'Chemical', 'MESH:D001647', (96, 106))	('expression', 'Var', (46, 56))	('caspase-3', 'Gene', (160, 169))	('decreased', 'NegReg', (79, 88))	('decreased acidic bile', 'Phenotype', 'HP:0030985', (79, 100))	('H2AX', 'Gene', (117, 121))	('PARP', 'Gene', (174, 178))	('APE1', 'Gene', (60, 64))	('caspase-3', 'Gene', '836', (160, 169))	('APE1', 'Gene', '328', (60, 64))	('PARP', 'Gene', '142', (174, 178))	('cleavage', 'MPA', (148, 156))	('H2AX', 'Gene', '3014', (117, 121))
604794	26934647	In contrast, knocking down endogenous APE1 substantially increased acidic bile salts-induced p-H2AX (S139) protein level and cleavage of caspase-3 and PARP in FLO-1 cells (Figure 5B).	('knocking down', 'Var', (13, 26))	('APE1', 'Gene', '328', (38, 42))	('PARP', 'Gene', (151, 155))	('caspase-3', 'Gene', (137, 146))	('H2AX', 'Gene', '3014', (95, 99))	('increased', 'PosReg', (57, 66))	('H2AX', 'Gene', (95, 99))	('bile salts', 'Chemical', 'MESH:D001647', (74, 84))	('cleavage', 'MPA', (125, 133))	('caspase-3', 'Gene', '836', (137, 146))	('APE1', 'Gene', (38, 42))	('PARP', 'Gene', '142', (151, 155))
604795	26934647	Previous studies have shown that DNA damage induces cell death through activation of stress response JNK and p38 MAPK pathways.	('JNK', 'Gene', (101, 104))	('p38', 'Gene', '1432', (109, 112))	('activation', 'PosReg', (71, 81))	('cell death', 'CPA', (52, 62))	('MAPK', 'Gene', '5594', (113, 117))	('JNK', 'Gene', '5599', (101, 104))	('DNA', 'Var', (33, 36))	('p38', 'Gene', (109, 112))	('MAPK', 'Gene', (113, 117))
604800	26934647	We found that the expression of APE1 in OE33 cells decreased acidic bile salts-induced JNK, p-JNK (T183/Y185), p38, and p-p38 (T180/Y182) protein levels as compared to control cells (Figure 6A).	('JNK', 'Gene', (87, 90))	('decreased acidic bile', 'Phenotype', 'HP:0030985', (51, 72))	('p38', 'Gene', '1432', (111, 114))	('JNK', 'Gene', '5599', (94, 97))	('APE1', 'Gene', (32, 36))	('JNK', 'Gene', '5599', (87, 90))	('p38', 'Gene', '1432', (122, 125))	('p38', 'Gene', (111, 114))	('decreased', 'NegReg', (51, 60))	('APE1', 'Gene', '328', (32, 36))	('p38', 'Gene', (122, 125))	('bile salts', 'Chemical', 'MESH:D001647', (68, 78))	('expression', 'Var', (18, 28))	('JNK', 'Gene', (94, 97))
604802	26934647	Conversely, knockdown of endogenous APE1 in FLO-1 cells substantially increased acidic bile salts-induced p-JNK (T183/Y185) and p-p38 (T180/Y182) protein levels as compared to control cells (Figure 6B).	('increased', 'PosReg', (70, 79))	('JNK', 'Gene', '5599', (108, 111))	('p38', 'Gene', '1432', (130, 133))	('APE1', 'Gene', (36, 40))	('knockdown', 'Var', (12, 21))	('T183/Y185', 'Var', (113, 122))	('bile salts', 'Chemical', 'MESH:D001647', (87, 97))	('APE1', 'Gene', '328', (36, 40))	('p38', 'Gene', (130, 133))	('JNK', 'Gene', (108, 111))
604806	26934647	Accordingly, the CellTiter-Glo assay data indicated that inhibition of APE1 with CRT sensitized FLO-1 cells to acidic bile salts as indicated by significantly decreased cell survival (P < 0.05, Figure 7B).	('inhibition', 'Var', (57, 67))	('APE1', 'Gene', (71, 75))	('bile salts', 'Chemical', 'MESH:D001647', (118, 128))	('cell survival', 'CPA', (169, 182))	('decreased', 'NegReg', (159, 168))	('CRT', 'Gene', '799', (81, 84))	('APE1', 'Gene', '328', (71, 75))	('CRT', 'Gene', (81, 84))
604820	26934647	In support of this hypothesis, a report by Wang and colleagues indicated that APE1 protein expression was elevated in osteosarcoma tissues, and there was a significant direct association between high APE1 expression levels and reduced overall survival of patients.	('expression', 'MPA', (91, 101))	('APE1', 'Gene', (200, 204))	('reduced', 'NegReg', (227, 234))	('APE1', 'Gene', '328', (200, 204))	('APE1', 'Gene', (78, 82))	('protein', 'Protein', (83, 90))	('expression levels', 'MPA', (205, 222))	('osteosarcoma', 'Phenotype', 'HP:0002669', (118, 130))	('patients', 'Species', '9606', (255, 263))	('high', 'Var', (195, 199))	('APE1', 'Gene', '328', (78, 82))	('overall survival', 'CPA', (235, 251))	('elevated', 'PosReg', (106, 114))	('osteosarcoma tissues', 'Disease', 'MESH:D012516', (118, 138))	('osteosarcoma tissues', 'Disease', (118, 138))
604822	26934647	We found that modulation of APE1 expression affects oxidative DNA damage, as indicated by AP sites accumulation or 8-OH-dG staining, in response to acidic bile salts in EAC cells.	('APE1', 'Gene', (28, 32))	('oxidative DNA damage', 'MPA', (52, 72))	('APE1', 'Gene', '328', (28, 32))	('affects', 'Reg', (44, 51))	('modulation', 'Var', (14, 24))	('bile salts', 'Chemical', 'MESH:D001647', (155, 165))	('response', 'MPA', (136, 144))	('AP sites', 'MPA', (90, 98))	('EAC', 'Phenotype', 'HP:0011459', (169, 172))	('8-OH-dG', 'Chemical', 'MESH:C067134', (115, 122))	('accumulation', 'PosReg', (99, 111))
604823	26934647	Our data showed that the expression of APE1 significantly attenuated oxidative DNA damage.	('attenuated', 'NegReg', (58, 68))	('oxidative DNA damage', 'MPA', (69, 89))	('APE1', 'Gene', '328', (39, 43))	('APE1', 'Gene', (39, 43))	('expression', 'Var', (25, 35))
604824	26934647	Conversely, knocking down of APE1 expression significantly increased oxidative DNA damage.	('oxidative DNA damage', 'MPA', (69, 89))	('APE1', 'Gene', (29, 33))	('APE1', 'Gene', '328', (29, 33))	('knocking down', 'Var', (12, 25))	('increased', 'PosReg', (59, 68))
604826	26934647	In response to acidic bile salts treatment, we found that DNA double-strand breaks levels were significantly reduced after expression of APE1, and increased after knocking down of APE1 in EAC cells.	('APE1', 'Gene', (180, 184))	('increased', 'PosReg', (147, 156))	('APE1', 'Gene', '328', (180, 184))	('EAC', 'Phenotype', 'HP:0011459', (188, 191))	('knocking down', 'Var', (163, 176))	('expression', 'Var', (123, 133))	('bile salts', 'Chemical', 'MESH:D001647', (22, 32))	('APE1', 'Gene', (137, 141))	('DNA double-strand breaks levels', 'MPA', (58, 89))	('reduced', 'NegReg', (109, 116))	('APE1', 'Gene', '328', (137, 141))
604831	26934647	Indeed, our results indicated that expression of APE1 substantially decreased apoptosis and knocking down of APE1 markedly increased apoptosis in response to acidic bile salts.	('response to acidic bile salts', 'MPA', (146, 175))	('increased', 'PosReg', (123, 132))	('decreased', 'NegReg', (68, 77))	('bile salts', 'Chemical', 'MESH:D001647', (165, 175))	('apoptosis', 'CPA', (78, 87))	('APE1', 'Gene', '328', (49, 53))	('apoptosis', 'CPA', (133, 142))	('APE1', 'Gene', (109, 113))	('APE1', 'Gene', '328', (109, 113))	('knocking down', 'Var', (92, 105))	('APE1', 'Gene', (49, 53))
604834	26934647	This is particularly relevant to our EAC cell models which express mutant p53 but still undergo apoptotic cell death in response to DNA damaging agents.	('undergo', 'Reg', (88, 95))	('EAC', 'Phenotype', 'HP:0011459', (37, 40))	('response to DNA damaging agents', 'MPA', (120, 151))	('p53', 'Gene', (74, 77))	('apoptotic cell death', 'CPA', (96, 116))	('mutant', 'Var', (67, 73))	('p53', 'Gene', '7157', (74, 77))
604841	26934647	One study showed that inhibition of APE1 with CRT at acidic environment induces an increase in p-H2AX level and cleavage of PARP-1 in HCT116 cells.	('inhibition', 'Var', (22, 32))	('cleavage', 'MPA', (112, 120))	('increase', 'PosReg', (83, 91))	('HCT116', 'CellLine', 'CVCL:0291', (134, 140))	('H2AX', 'Gene', '3014', (97, 101))	('PARP-1', 'Gene', (124, 130))	('H2AX', 'Gene', (97, 101))	('PARP-1', 'Gene', '142', (124, 130))	('APE1', 'Gene', (36, 40))	('CRT', 'Gene', '799', (46, 49))	('APE1', 'Gene', '328', (36, 40))	('CRT', 'Gene', (46, 49))
604855	26934647	p-JNK (T183/Y185), JNK, p-p38 (T180/Y182), and p38 antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).	('p38', 'Gene', '1432', (26, 29))	('JNK', 'Gene', (2, 5))	('p38', 'Gene', '1432', (47, 50))	('JNK', 'Gene', (19, 22))	('JNK', 'Gene', '5599', (2, 5))	('T180/Y182', 'Var', (31, 40))	('p38', 'Gene', (26, 29))	('T183/Y185', 'Var', (7, 16))	('JNK', 'Gene', '5599', (19, 22))	('p38', 'Gene', (47, 50))
605025	26923747	ICD-8: 291.00-291.99, 303.00-303.99, 571.09, 571.10, 577.10, ICD-10: E24.4, E52.9A, F10.1, F10.2-10.9, G31.2, G62.1, G72.1, I42.6, K29.2, K.70, K85.2, K86.0, T50.0A, Z50.2, Z71.4, Z72.1.	('E24.4', 'Var', (69, 74))	('K86.0', 'Var', (151, 156))	('Z72.1', 'Var', (180, 185))	('I42.6', 'Var', (124, 129))	('Z71.4', 'Var', (173, 178))	('T50.0A', 'Var', (158, 164))	('G72.1', 'Var', (117, 122))	('E52.9A', 'Var', (76, 82))	('Z50.2', 'Var', (166, 171))	('G62.1', 'Var', (110, 115))	('F10.1', 'Var', (84, 89))	('G31.2', 'Var', (103, 108))	('K.70', 'Var', (138, 142))	('F10.2-10.9', 'CellLine', 'CVCL:0H94', (91, 101))	('K85.2', 'Var', (144, 149))	('K29.2', 'Var', (131, 136))	('F10.2-10.9', 'Var', (91, 101))
605026	26923747	ICD-8: 070.00, 070.02, 070.04, 070.06, 070.08, 573.00, 456.00-456.09, ICD-10: B15.0, B16.0, B16.2, B19.0, K70.4, K72, K76.6, I85.	('B16.2', 'CellLine', 'CVCL:N540', (92, 97))	('K70.4', 'Var', (106, 111))	('B15.0', 'Var', (78, 83))	('K72', 'Gene', (113, 116))	('K76.6', 'Var', (118, 123))	('K72', 'Gene', '140807', (113, 116))	('B19.0', 'Var', (99, 104))	('B16.0', 'Var', (85, 90))	('B16.2', 'Var', (92, 97))
605027	26923747	ICD-8: 249.00-249.09, 250.00-250.09, ICD-10: E10, E11, E14.	('E14', 'Gene', '4863', (55, 58))	('E14', 'Gene', (55, 58))	('E10', 'Var', (45, 48))	('E11', 'Var', (50, 53))
605028	26923747	Low- and high-dose aspirin (B01AC06, N02BA01, N02BA51); Selective cyclooxygenase-2 inhibitors: M01AH01, M01AH02, M01AH03, M01AH05, M01AC05, M01AB05, M01AC06; other NSAIDs: All other codes within group M01A.	('cyclooxygenase-2', 'Gene', '5743', (66, 82))	('cyclooxygenase-2', 'Gene', (66, 82))	('M01A', 'Mutation', 'p.M01A', (140, 144))	('M01A', 'Mutation', 'p.M01A', (104, 108))	('M01A', 'Mutation', 'p.M01A', (122, 126))	('M01AH01', 'Var', (95, 102))	('M01A', 'Mutation', 'p.M01A', (201, 205))	('M01A', 'Mutation', 'p.M01A', (131, 135))	('M01A', 'Mutation', 'p.M01A', (149, 153))	('M01AH02', 'Var', (104, 111))	('M01AH03', 'Var', (113, 120))	('M01AH05', 'Var', (122, 129))	('M01A', 'Mutation', 'p.M01A', (113, 117))	('M01AC06', 'Var', (149, 156))	('M01AB05', 'Var', (140, 147))	('M01A', 'Mutation', 'p.M01A', (95, 99))	('M01AC05', 'Var', (131, 138))	('aspirin', 'Chemical', 'MESH:D001241', (19, 26))
605029	26923747	H. pylori eradication (amoxicillin, clarithromycin, and metronidazole): J01CA04, J01FA09, and P01AB01.	('J01FA09', 'Var', (81, 88))	('J01CA04', 'Var', (72, 79))	('H. pylori', 'Species', '210', (0, 9))	('J01', 'CellLine', 'CVCL:2530', (72, 75))	('H. pylori', 'Disease', (0, 9))	('J01', 'CellLine', 'CVCL:2530', (81, 84))	('amoxicillin', 'Chemical', 'MESH:D000658', (23, 34))	('J01FA09', 'CellLine', 'CVCL:W356', (81, 88))	('metronidazole', 'Chemical', 'MESH:D008795', (56, 69))	('P01AB01', 'Var', (94, 101))	('clarithromycin', 'Chemical', 'MESH:D017291', (36, 50))
605030	24709955	 XPF-673C>T Polymorphism Effect on the Susceptibility to Esophageal Cancer in Chinese Population Xeroderma pigmentsum group F (XPF) plays a pivotal role in DNA nucleotide excision repair and has been linked to the development of various cancers.	('XPF', 'Gene', (1, 4))	('Esophageal Cancer', 'Disease', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('linked to', 'Reg', (200, 209))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (57, 74))	('Xeroderma pigmentsum group F', 'Gene', '2072', (97, 125))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('XPF', 'Gene', (127, 130))	('Polymorphism', 'Var', (12, 24))	('cancers', 'Disease', (237, 244))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('XPF', 'Gene', '2072', (1, 4))	('Xeroderma pigmentsum group F', 'Gene', (97, 125))	('-673C>T', 'Mutation', 'rs3136038', (4, 11))	('XPF', 'Gene', '2072', (127, 130))
605031	24709955	This study aims to assess the association of XPF genetic variants with the susceptibility to esophageal squamous cell carcinoma (ESCC) in Chinese population.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('XPF', 'Gene', '2072', (45, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal squamous cell carcinoma', 'Disease', (93, 127))	('XPF', 'Gene', (45, 48))	('variants', 'Var', (57, 65))	('association', 'Interaction', (30, 41))
605033	24709955	Genotype of XPF -673C>T and 11985A>G variants were determined by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP).	('XPF', 'Gene', (12, 15))	('-673C>T', 'Mutation', 'rs3136038', (16, 23))	('11985A>G', 'Var', (28, 36))	('11985A>G', 'Mutation', 'rs254942', (28, 36))	('XPF', 'Gene', '2072', (12, 15))
605037	24709955	These findings indicated that genetic variants in XPF might contribute to the susceptibility to ESCC.	('XPF', 'Gene', (50, 53))	('susceptibility', 'Reg', (78, 92))	('contribute', 'Reg', (60, 70))	('genetic variants', 'Var', (30, 46))	('ESCC', 'Disease', (96, 100))	('XPF', 'Gene', '2072', (50, 53))
605041	24709955	Deficiencies in the DNA repair capacity have been linked to increased risk of multiple cancers.	('Deficiencies', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('linked', 'Reg', (50, 56))	('DNA', 'MPA', (20, 23))	('multiple cancers', 'Disease', (78, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (78, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))
605043	24709955	Epidemiological studies also showed that XPF genetic variants contributed to the susceptibility to various cancers, such as bladder, breast, lung and gastric cancer.	('bladder', 'Disease', (124, 131))	('contributed', 'Reg', (62, 73))	('cancers', 'Disease', (107, 114))	('breast', 'Disease', (133, 139))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('XPF', 'Gene', '2072', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('susceptibility', 'Reg', (81, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('genetic variants', 'Var', (45, 61))	('lung', 'Disease', (141, 145))	('gastric cancer', 'Disease', (150, 164))	('XPF', 'Gene', (41, 44))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('variants', 'Var', (53, 61))
605044	24709955	Considering the pivotal role of XPF in NER, we supposed that XPF polymorphisms contributed to the risk of developing ESCC.	('XPF', 'Gene', (32, 35))	('XPF', 'Gene', (61, 64))	('polymorphisms', 'Var', (65, 78))	('XPF', 'Gene', '2072', (32, 35))	('ESCC', 'Disease', (117, 121))	('XPF', 'Gene', '2072', (61, 64))
605053	24709955	The genotypes of XPF-673C>T (rs3136038) and 11985A>G (rs254942) polymorphisms were determined by polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP).	('rs254942', 'Mutation', 'rs254942', (54, 62))	('rs3136038', 'Mutation', 'rs3136038', (29, 38))	('rs254942', 'Var', (54, 62))	('rs3136038', 'Var', (29, 38))	('XPF-673C', 'Gene', (17, 25))	('11985A>G', 'Mutation', 'rs254942', (44, 52))
605061	24709955	Odds ratios (OR) and 95% confidence intervals (CI) were used to evaluate the association of XPF variants with the risk of ESCC by unconditional logistic regression model adjusted by age, sex and smoking status.	('variants', 'Var', (96, 104))	('ESCC', 'Disease', (122, 126))	('XPF', 'Gene', (92, 95))	('XPF', 'Gene', '2072', (92, 95))	('association', 'Interaction', (77, 88))
605064	24709955	The genotype distributions of XPF-673C>T and 11985A>G polymorphisms in the cases and controls were summarized in Table 2.	('11985A>G', 'Var', (45, 53))	('XPF-673C', 'Gene', (30, 38))	('11985A>G', 'Mutation', 'rs254942', (45, 53))
605065	24709955	The observed genotype frequencies of XPF polymorphism (-673C>T and 11985A>G) in both controls were consistent with Hardy-Weinberg equilibrium in both sets (Tangshan set: P = 0.06 and P = 0.50; Beijing set: P = 0.40 and P = 0.97).	('-673C>T', 'Mutation', 'rs3136038', (55, 62))	('XPF', 'Gene', (37, 40))	('-673C>T', 'Var', (55, 62))	('XPF', 'Gene', '2072', (37, 40))	('11985A>G', 'Var', (67, 75))	('11985A>G', 'Mutation', 'rs254942', (67, 75))
605066	24709955	Multivariate logistic regression analysis were used to calculate the association of XPF -673C>T or 11985A>G genotypes with ESCC risk (Table 2).	('XPF', 'Gene', (84, 87))	('11985A>G', 'Var', (99, 107))	('11985A>G', 'Mutation', 'rs254942', (99, 107))	('ESCC', 'Disease', (123, 127))	('-673C>T', 'Mutation', 'rs3136038', (88, 95))	('XPF', 'Gene', '2072', (84, 87))
605068	24709955	For 11985 A>G polymorphism, our study didn't show any association of genotypes of 11985A>G polymorphism with the risk of ESCC.	('11985A>G', 'Var', (82, 90))	('11985A>G', 'Mutation', 'rs254942', (82, 90))	('11985 A>G', 'Mutation', 'rs254942', (4, 13))	('ESCC', 'Disease', (121, 125))	('11985 A>G', 'Var', (4, 13))
605069	24709955	The risk of ESCC associated with the -673C>T polymorphism was further evaluated by stratifying for age, sex and smoking status using the combined data of two case-control sets (Table 3).	('the -673C>T', 'Var', (33, 44))	('-673C>T', 'Mutation', 'rs3136038', (37, 44))	('ESCC', 'Disease', (12, 16))
605070	24709955	Because tobacco smoking is predisposing factor for ESCC, we then investigated whether a gene-smoking interaction existed between the -673C>T polymorphism and smoking (Table 3).	('tobacco', 'Species', '4097', (8, 15))	('ESCC', 'Disease', (51, 55))	('the -673C>T', 'Var', (129, 140))	('-673C>T', 'Mutation', 'rs3136038', (133, 140))
605071	24709955	In this study, we investigated the associations of XPF -673C>T and 11985A>G genetic variants with the risk of ESCC in Chinese population.	('-673C>T', 'Mutation', 'rs3136038', (55, 62))	('XPF', 'Gene', '2072', (51, 54))	('XPF', 'Gene', (51, 54))	('ESCC', 'Disease', (110, 114))	('11985A>G', 'Var', (67, 75))	('11985A>G', 'Mutation', 'rs254942', (67, 75))
605073	24709955	The ethnic difference in the XPF polymorphisms might have significant effect on disease phenotype.	('XPF', 'Gene', (29, 32))	('XPF', 'Gene', '2072', (29, 32))	('polymorphisms', 'Var', (33, 46))	('effect', 'Reg', (70, 76))
605074	24709955	Researchers found a significant association of XPF rs1799801 in exon 11 with a reduced risk of bladder cancer in Caucasian population, but not in Chinese population.	('reduced', 'NegReg', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rs1799801', 'Mutation', 'rs1799801', (51, 60))	('XPF', 'Gene', (47, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))	('rs1799801', 'Var', (51, 60))	('XPF', 'Gene', '2072', (47, 50))
605085	24709955	Genetic variant in the promoter of XPF may influence the activation of substrates in cigarette smoke and then contribute to the different susceptibility to cancers.	('contribute to', 'Reg', (110, 123))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('influence', 'Reg', (43, 52))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('XPF', 'Gene', '2072', (35, 38))	('substrates in cigarette smoke', 'MPA', (71, 100))	('Genetic variant', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('XPF', 'Gene', (35, 38))	('activation', 'MPA', (57, 67))
605090	24709955	As a key DNA damage repair protein, the low expression of XPF can delay DNA repair, and further increase genome instability and promote tumorigenesis.	('low expression', 'Var', (40, 54))	('tumorigenesis', 'CPA', (136, 149))	('XPF', 'Gene', (58, 61))	('DNA repair', 'MPA', (72, 82))	('delay', 'NegReg', (66, 71))	('promote', 'PosReg', (128, 135))	('genome instability', 'MPA', (105, 123))	('increase', 'PosReg', (96, 104))	('XPF', 'Gene', '2072', (58, 61))
605093	24709955	In addition, there were several of XPF polymorphisms were discovered and have been demonstrated to be associated with various cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('associated', 'Reg', (102, 112))	('polymorphisms', 'Var', (39, 52))	('XPF', 'Gene', '2072', (35, 38))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('XPF', 'Gene', (35, 38))	('cancers', 'Disease', 'MESH:D009369', (126, 133))
605094	24709955	More potential functional XPF polymorphisms still need to be validated by larger studies with diverse populations.	('XPF', 'Gene', (26, 29))	('polymorphisms', 'Var', (30, 43))	('XPF', 'Gene', '2072', (26, 29))
605135	32045872	In 2013, BMI was divided into different groups according to the 'Criteria of Weight for Adults' released by the NHFPC of China, which defined four groups according to the following BMI cut-offs: underweight (BMI<18.5 kg/m2), normal (BMI >= 18.5 to <24 kg/m2), overweight (BMI >= 24 to <28 kg/m2), and obese (BMI <= 28 kg/m2).	('obese', 'Disease', 'MESH:D009765', (301, 306))	('BMI <= 28 kg/m2', 'Var', (308, 323))	('BMI >= 18.5 to <24 kg/m2', 'Var', (233, 257))	('overweight', 'Phenotype', 'HP:0025502', (260, 270))	('obese', 'Disease', (301, 306))	('BMI >= 24 to <28 kg/m2', 'Var', (272, 294))
605157	32045872	Overweight or obesity was associated with a significantly reduced risk of ESCC (HR 0.66, 95 %CI 0.47-0.93) compared with the normal BMI group.	('ESCC', 'Disease', (74, 78))	('obesity', 'Phenotype', 'HP:0001513', (14, 21))	('Overweight', 'Var', (0, 10))	('obesity', 'Disease', 'MESH:D009765', (14, 21))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('obesity', 'Disease', (14, 21))	('reduced', 'NegReg', (58, 65))
605176	32045872	A high BMI was associated positively with the risk of gastroesophageal reflux disease (GERD) and EAC, but inversely with the risk of ESCC.	('EAC', 'Disease', (97, 100))	('high', 'Var', (2, 6))	('gastroesophageal reflux disease', 'Disease', (54, 85))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (54, 77))	('GERD', 'Disease', (87, 91))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (54, 85))	('GERD', 'Disease', 'MESH:D005764', (87, 91))	('EAC', 'Phenotype', 'HP:0011459', (97, 100))
605202	32045872	In summary, we confirmed that overweight or obesity in individuals was associated with a reduced risk of ESCC in the Linxian dysplasia-based NIT cohort, particularly in women and persons with a family history of cancer.	('Linxian dysplasia', 'Disease', (117, 134))	('ESCC', 'Disease', (105, 109))	('Linxian dysplasia', 'Disease', 'MESH:C536170', (117, 134))	('obesity', 'Disease', 'MESH:D009765', (44, 51))	('women', 'Species', '9606', (169, 174))	('overweight', 'Phenotype', 'HP:0025502', (30, 40))	('obesity', 'Disease', (44, 51))	('persons', 'Species', '9606', (179, 186))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('reduced', 'NegReg', (89, 96))	('obesity', 'Phenotype', 'HP:0001513', (44, 51))	('overweight', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
605210	32117645	The ShRNA-mediated method was used to knock down the expression of SPARC.	('expression', 'Species', '29278', (53, 63))	('knock', 'Var', (38, 43))	('SPARC', 'Gene', (67, 72))	('SPARC', 'Gene', '6678', (67, 72))
605212	32117645	The malignant phenotype of the ESCC cell line was amplified by an overexpression of EN2 but was attenuated by a disruption of EN2.	('disruption', 'Var', (112, 122))	('overexpression', 'PosReg', (66, 80))	('attenuated', 'NegReg', (96, 106))	('expression', 'Species', '29278', (70, 80))	('EN2', 'Gene', (126, 129))	('amplified', 'PosReg', (50, 59))	('malignant phenotype of', 'CPA', (4, 26))	('EN2', 'Gene', '2020', (84, 87))	('ESCC', 'Disease', 'MESH:C562729', (31, 35))	('ESCC', 'Disease', (31, 35))	('EN2', 'Gene', '2020', (126, 129))	('EN2', 'Gene', (84, 87))
605213	32117645	RNA profiling analysis revealed that distinct sets of genes were modulated by the expression of EN2 in various ESCC cell lines and oncogenes were among these.	('expression', 'Species', '29278', (82, 92))	('EN2', 'Gene', '2020', (96, 99))	('ESCC', 'Disease', 'MESH:C562729', (111, 115))	('EN2', 'Gene', (96, 99))	('expression', 'Var', (82, 92))	('modulated', 'Reg', (65, 74))	('ESCC', 'Disease', (111, 115))
605216	32117645	ShRNA-mediated knockdown of SPARC attenuated the malignant phenotype of EN2-infected cells.	('SPARC', 'Gene', '6678', (28, 33))	('knockdown', 'Var', (15, 24))	('EN2', 'Gene', '2020', (72, 75))	('SPARC', 'Gene', (28, 33))	('malignant phenotype of', 'CPA', (49, 71))	('EN2', 'Gene', (72, 75))	('attenuated', 'NegReg', (34, 44))
605224	32117645	The aberrant expression of homeobox genes has been observed in a variety of cancers.	('expression', 'Species', '29278', (13, 23))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('homeobox genes', 'Gene', (27, 41))	('cancers', 'Disease', (76, 83))	('expression', 'MPA', (13, 23))	('aberrant', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('observed', 'Reg', (51, 59))
605238	32117645	Human EN2 cDNA (G136030; YouBio, Hunan, China) was amplified and cloned into pVAX1 for pVAX-EN2 (VT1048; YouBio, Hunan, China) using the HindIII and XhoI sites.	('Human', 'Species', '9606', (0, 5))	('EN2', 'Gene', '2020', (6, 9))	('EN2', 'Gene', (92, 95))	('EN2', 'Gene', (6, 9))	('EN2', 'Gene', '2020', (92, 95))	('pVAX-EN2', 'Chemical', '-', (87, 95))	('G136030;', 'Var', (16, 24))
605245	32117645	The positive cell clones were selected using G418 (500 mug/mL; Thermo Fisher Scientific, Waltham, MA USA) and were named EN2-Eca109, NEO-Eca109, EN2-Kyse150 and NEO-Kyse150.	('EN2', 'Gene', '2020', (145, 148))	('EN2', 'Gene', '2020', (121, 124))	('EN2', 'Gene', (145, 148))	('EN2', 'Gene', (121, 124))	('NEO-Kyse150', 'Var', (161, 172))	('NEO-Eca109', 'Var', (133, 143))
605254	32117645	Mutants of the human EN2 gene were generated using our own previously established protocol.	('EN2', 'Gene', (21, 24))	('EN2', 'Gene', '2020', (21, 24))	('Mutants', 'Var', (0, 7))	('human', 'Species', '9606', (15, 20))
605256	32117645	The mutated EN2 sequences were then cloned into pCDH-NEO.	('mutated', 'Var', (4, 11))	('EN2', 'Gene', (12, 15))	('EN2', 'Gene', '2020', (12, 15))	('pCDH-NEO', 'Chemical', '-', (48, 56))
605282	32117645	The mRNA expression levels of EN2 were examined in three ESCC cell lines, namely Eca109, Kyse150 and TE-1, as well as the SHEE cell line, which is an immortalized epithelial cell line derived from the fetal esophageal epithelium induced by HPV 18 E6E7 AAV.	('EN2', 'Gene', (30, 33))	('ESCC', 'Disease', (57, 61))	('expression', 'Species', '29278', (9, 19))	('E6E7 AAV', 'Var', (247, 255))	('EN2', 'Gene', '2020', (30, 33))	('TE-1', 'CellLine', 'CVCL:1759', (101, 105))	('ESCC', 'Disease', 'MESH:C562729', (57, 61))
605284	32117645	The mRNA expression of EN2 in Eca109 and Kyse150 was lower than TE-1 (Fig.	('EN2', 'Gene', (23, 26))	('TE-1', 'CellLine', 'CVCL:1759', (64, 68))	('Kyse150', 'Var', (41, 48))	('expression', 'Species', '29278', (9, 19))	('mRNA expression', 'MPA', (4, 19))	('EN2', 'Gene', '2020', (23, 26))	('lower', 'NegReg', (53, 58))
605302	32117645	We subsequently assessed whether the disruption of EN2 affects the malignant phenotype of TE-1 cells.	('malignant phenotype of TE-1 cells', 'CPA', (67, 100))	('disruption', 'Var', (37, 47))	('EN2', 'Gene', '2020', (51, 54))	('EN2', 'Gene', (51, 54))	('TE-1', 'CellLine', 'CVCL:1759', (90, 94))	('affects', 'Reg', (55, 62))
605303	32117645	TE-1 cells with the disrupted EN2 locus exhibited a reduced growth rate (Fig.	('EN2', 'Gene', (30, 33))	('TE-1', 'CellLine', 'CVCL:1759', (0, 4))	('reduced', 'NegReg', (52, 59))	('EN2', 'Gene', '2020', (30, 33))	('disrupted', 'Var', (20, 29))	('reduced growth rate', 'Phenotype', 'HP:0001510', (52, 71))	('growth rate', 'CPA', (60, 71))
605304	32117645	The disruption of EN2 hindered the migration (Figs.	('migration', 'CPA', (35, 44))	('EN2', 'Gene', '2020', (18, 21))	('EN2', 'Gene', (18, 21))	('disruption', 'Var', (4, 14))	('hindered', 'NegReg', (22, 30))
605306	32117645	These results demonstrate that the disruption of EN2 negatively affects the malignant phenotype of TE-1 cells and further supports its oncogenic role in ESCC.	('TE-1', 'CellLine', 'CVCL:1759', (99, 103))	('EN2', 'Gene', '2020', (49, 52))	('affects', 'Reg', (64, 71))	('EN2', 'Gene', (49, 52))	('negatively', 'NegReg', (53, 63))	('ESCC', 'Disease', 'MESH:C562729', (153, 157))	('malignant phenotype of TE-1 cells', 'CPA', (76, 109))	('disruption', 'Var', (35, 45))	('ESCC', 'Disease', (153, 157))
605317	32117645	There are many well-documented pro-oncogenic genes that are upregulated upon the expression of EN2, implying that EN2 could modulate the expression of the downstream targets genes in a cellular, context-dependent manner.	('pro-oncogenic genes', 'Gene', (31, 50))	('expression', 'MPA', (137, 147))	('upregulated', 'PosReg', (60, 71))	('EN2', 'Gene', '2020', (114, 117))	('expression', 'Species', '29278', (137, 147))	('expression', 'Var', (81, 91))	('EN2', 'Gene', '2020', (95, 98))	('expression', 'Species', '29278', (81, 91))	('EN2', 'Gene', (114, 117))	('modulate', 'Reg', (124, 132))	('EN2', 'Gene', (95, 98))
605329	32117645	The expression vectors, each containing a mutated EN2, were introduced respectively into Eca109 using the lentivirus system and generating the Mut.1-Eca109 and Mut.2-Eca109 cell lines.	('mutated', 'Var', (42, 49))	('expression vectors', 'Species', '29278', (4, 22))	('EN2', 'Gene', (50, 53))	('EN2', 'Gene', '2020', (50, 53))
605331	32117645	Both mutants were shown to hinder the promoting effects of EN2 on the proliferation of Eca109 (Fig.	('EN2', 'Gene', '2020', (59, 62))	('EN2', 'Gene', (59, 62))	('hinder', 'NegReg', (27, 33))	('mutants', 'Var', (5, 12))	('Eca109', 'Gene', (87, 93))
605332	32117645	The mutants largely eliminated the enhancing effects of EN2 on the cell's migratory abilities (Figs.	('mutants', 'Var', (4, 11))	('eliminated', 'NegReg', (20, 30))	('EN2', 'Gene', '2020', (56, 59))	('migratory abilities', 'CPA', (74, 93))	('EN2', 'Gene', (56, 59))
605333	32117645	The expression status of SPARC in the Mut1-Eca109 and Mut2-Eca109 cell lines was investigated and the results revealed that the mutations in the homeodomain also abrogate the function of EN2 in inducing the expression of SPARC (Figs.	('abrogate', 'NegReg', (162, 170))	('function', 'MPA', (175, 183))	('expression', 'Species', '29278', (4, 14))	('mutations', 'Var', (128, 137))	('EN2', 'Gene', '2020', (187, 190))	('SPARC', 'Gene', '6678', (25, 30))	('inducing', 'PosReg', (194, 202))	('expression', 'Species', '29278', (207, 217))	('SPARC', 'Gene', '6678', (221, 226))	('EN2', 'Gene', (187, 190))	('SPARC', 'Gene', (25, 30))	('expression', 'MPA', (207, 217))	('SPARC', 'Gene', (221, 226))
605351	32117645	For instance, the expression of SPARC is significantly upregulated upon the expression of EN2 in two of three ESCC cell lines.	('SPARC', 'Gene', (32, 37))	('EN2', 'Gene', '2020', (90, 93))	('ESCC', 'Disease', 'MESH:C562729', (110, 114))	('expression', 'Species', '29278', (76, 86))	('expression', 'Species', '29278', (18, 28))	('expression', 'MPA', (18, 28))	('upregulated', 'PosReg', (55, 66))	('EN2', 'Gene', (90, 93))	('ESCC', 'Disease', (110, 114))	('SPARC', 'Gene', '6678', (32, 37))	('expression', 'Var', (76, 86))
605367	31572541	In addition, YAP was knocked-down in ESCC cell lines and the effects on cell migration and invasion were examined.	('ESCC', 'Disease', (37, 41))	('cell migration', 'CPA', (72, 86))	('knocked-down', 'Var', (21, 33))	('YAP', 'Gene', (13, 16))	('ESCC', 'Disease', 'MESH:D018307', (37, 41))
605371	31572541	Western blot analysis showed that when YAP was knocked down, expression levels of vimentin and N-cadherin were reduced, whereas that of E-cadherin was increased.	('increased', 'PosReg', (151, 160))	('knocked down', 'Var', (47, 59))	('N-cadherin', 'Gene', '1000', (95, 105))	('E-cadherin', 'Gene', (136, 146))	('E-cadherin', 'Gene', '999', (136, 146))	('reduced', 'NegReg', (111, 118))	('vimentin', 'Gene', '7431', (82, 90))	('vimentin', 'Gene', (82, 90))	('YAP', 'Gene', (39, 42))	('expression levels', 'MPA', (61, 78))	('N-cadherin', 'Gene', (95, 105))
605404	31572541	The percentage of positive tumor cells was assessed according to the following patterns: i) No staining, 0; ii) <=10%, 1; iii) 10-50%, 2; iv) and >50% 3.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('<=10%', 'Var', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', (27, 32))	('10-50%', 'Var', (127, 133))
605438	31572541	Compared with the control group, cell migration and invasion were both significantly decreased by the downregulation of YAP after siYAP#1 and siYAP#2 transfection (P<0.001), in both cell lines.	('YAP#1', 'Gene', (132, 137))	('decreased', 'NegReg', (85, 94))	('transfection', 'Var', (150, 162))	('downregulation', 'NegReg', (102, 116))	('YAP#1', 'Gene', '10413', (132, 137))	('cell migration', 'CPA', (33, 47))	('YAP#2', 'Gene', (144, 149))	('invasion', 'CPA', (52, 60))	('YAP', 'Gene', (120, 123))	('YAP#2', 'Gene', '10413', (144, 149))
605449	31572541	In papillary thyroid cancer B-CPAP and KI cell lines, knockdown of YAP was found to inhibit the proliferation, migration, and invasion, and cause cell cycle arrest and induce autophagy of tumor cells.	('tumor', 'Disease', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('knockdown', 'Var', (54, 63))	('cause', 'Reg', (140, 145))	('arrest', 'Disease', (157, 163))	('inhibit', 'NegReg', (84, 91))	('papillary thyroid cancer', 'Disease', (3, 27))	('induce', 'PosReg', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('YAP', 'Gene', (67, 70))	('invasion', 'CPA', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('thyroid cancer', 'Phenotype', 'HP:0002890', (13, 27))	('arrest', 'Disease', 'MESH:D006323', (157, 163))	('papillary thyroid cancer', 'Disease', 'MESH:C536915', (3, 27))
605626	29967326	Patients with risk score greater than 0.5, who were more likely to experience local progression, were classified into high-risk group, and those with risk score less than 0.5 were classified into low-risk group.	('risk score greater than 0.5', 'Var', (14, 41))	('local progression', 'CPA', (78, 95))	('Patients', 'Species', '9606', (0, 8))
605652	29967326	4, a higher specificity was achieved by the RF model with mid-CRT radiomic features compared to that with pre-CRT radiomic features, which was further improved by combining both pre- and mid-CRT radiomic features; This result indicates that radiomic features extracted from the images during treatment rather than the baseline images may efficiently discriminate local tumor control from other confounding circumstances such as inflammation after treatment or inactivating residual tumor bulk, and such multiple-time point observations would provide more accurate overall judgment for the tumor characteristics associated with treatment.	('CRT', 'Gene', '799', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (482, 487))	('inflammation', 'Disease', (428, 440))	('tumor', 'Disease', (369, 374))	('CRT', 'Gene', (191, 194))	('CRT', 'Gene', '799', (62, 65))	('CRT', 'Gene', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (369, 374))	('CRT', 'Gene', '799', (110, 113))	('tumor', 'Disease', (589, 594))	('CRT', 'Gene', (110, 113))	('inactivating', 'Var', (460, 472))	('tumor', 'Phenotype', 'HP:0002664', (482, 487))	('tumor', 'Disease', 'MESH:D009369', (589, 594))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('discriminate', 'Reg', (350, 362))	('tumor', 'Phenotype', 'HP:0002664', (589, 594))	('inflammation', 'Disease', 'MESH:D007249', (428, 440))	('tumor', 'Disease', (482, 487))
605699	29114598	The pathologic response after CCRT was graded into 4 categories, as done on the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) study: grade 1 (no evidence of residual tumor cells), grade 2 (<10% residual tumor cells), grade 3 (10%-50% residual tumor cells), and grade 4 (>50% residual tumor cells).	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('<10', 'Var', (218, 221))	('Oesophageal cancer', 'Disease', 'MESH:D009369', (102, 120))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (313, 318))	('tumor', 'Disease', (272, 277))	('Oesophageal cancer', 'Disease', (102, 120))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('CCRT', 'Chemical', '-', (30, 34))	('10%-50', 'Var', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('tumor', 'Disease', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))
605762	29114598	Lin et al compared the long-term outcomes with 3-dimensional CRT and IMRT and reported that OS, locoregional control, and cardiac death were significantly better after IMRT than after 3-dimensional CRT.	('CRT', 'Gene', (61, 64))	('locoregional control', 'CPA', (96, 116))	('cardiac death', 'Disease', (122, 135))	('better', 'PosReg', (155, 161))	('IMRT', 'Var', (168, 172))	('CRT', 'Gene', '799', (198, 201))	('CRT', 'Gene', '799', (61, 64))	('cardiac death', 'Phenotype', 'HP:0001645', (122, 135))	('cardiac death', 'Disease', 'MESH:D003643', (122, 135))	('CRT', 'Gene', (198, 201))
605763	29114598	This appears to be in part due to the increased cardiac mortality seen in the patients who received 3-dimensional CRT, which was seen at both the single institutional and population levels.	('cardiac', 'MPA', (48, 55))	('CRT', 'Gene', '799', (114, 117))	('patients', 'Species', '9606', (78, 86))	('CRT', 'Gene', (114, 117))	('3-dimensional', 'Var', (100, 113))	('increased', 'PosReg', (38, 47))
605787	27900538	While Tobacco, alcohol, mate, nitrogenous compounds, chewing betel nut and deficits of minerals and vitamins have been associated with SCC, tobacco, gastro-esophageal reflux, Barrett's esophagus, obesity and low-fiber diet have been linked with ADC.	('obesity', 'Disease', 'MESH:D009765', (196, 203))	('esophageal reflux', 'Phenotype', 'HP:0002020', (156, 173))	('associated', 'Reg', (119, 129))	('alcohol', 'Chemical', 'MESH:D000438', (15, 22))	('tobacco', 'Species', '4097', (140, 147))	('ADC', 'Disease', (245, 248))	('SCC', 'Phenotype', 'HP:0002860', (135, 138))	('Tobacco', 'Species', '4097', (6, 13))	('gastro-esophageal reflux', 'Disease', (149, 173))	('obesity', 'Phenotype', 'HP:0001513', (196, 203))	('gastro-esophageal reflux', 'Disease', 'MESH:D005764', (149, 173))	("Barrett's esophagus", 'Disease', (175, 194))	('SCC', 'Gene', '6317', (135, 138))	('tobacco', 'Disease', (140, 147))	('SCC', 'Gene', (135, 138))	('obesity', 'Disease', (196, 203))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (175, 194))	('deficits', 'Var', (75, 83))	('linked', 'Reg', (233, 239))
605814	27900538	Moreover, surgery remains the first treatment of choice in all T1b-T2N0M0 tumors (E: moderate; R: strong).	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('T1b-T2N0M0', 'Var', (63, 73))	('men', 'Species', '9606', (41, 44))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
605974	34008702	The prevalence of p16 positivity in this sample was 46.55% (n=27), 29.31% in men and 17.24% in women.	('p16', 'Gene', '1029', (18, 21))	('men', 'Species', '9606', (97, 100))	('men', 'Species', '9606', (77, 80))	('women', 'Species', '9606', (95, 100))	('p16', 'Gene', (18, 21))	('positivity', 'Var', (22, 32))
605978	34008702	The main reason for it to be studied, allowing the analysis of viral infection in these tumor types, is the fact that, although uncertain, HPV positive patients have shown better prognosis, as well as better response to treatment with neoadjuvant chemotherapy  .	('viral infection', 'Disease', 'MESH:D001102', (63, 78))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('better', 'PosReg', (172, 178))	('positive', 'Var', (143, 151))	('men', 'Species', '9606', (225, 228))	('viral infection', 'Disease', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('HPV', 'Species', '10566', (139, 142))	('HPV', 'Gene', (139, 142))	('tumor', 'Disease', (88, 93))	('patients', 'Species', '9606', (152, 160))
606027	30922862	Therefore, we performed the current study which is the first large, open, prospective study to assess the safety and efficacy of CbFAS for eradication of flat type MGIN and HGIN.	('MGIN', 'Protein', (164, 168))	('eradication', 'MPA', (139, 150))	('CbFAS', 'Chemical', '-', (129, 134))	('HGIN', 'Disease', (173, 177))	('flat type', 'Var', (154, 163))
606104	30922862	Since accurate assessment of the presence of this submucosally located intraepithelial neoplasia based on endoscopic findings or biopsy samples is as yet not feasible, it is important that ablation penetrates deeply into the submucosa, but this also increases the risk of post-treatment stricture.	('neoplasia', 'Disease', 'MESH:D009369', (87, 96))	('neoplasia', 'Phenotype', 'HP:0002664', (87, 96))	('stricture', 'Disease', (287, 296))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (71, 96))	('ablation', 'Var', (189, 197))	('neoplasia', 'Disease', (87, 96))
606105	30922862	How deeply cryoablation reaches is not yet known, and careful evaluation of this depth and its relation to submucosally located intraepithelial neoplasia is needed.	('neoplasia', 'Disease', 'MESH:D009369', (144, 153))	('neoplasia', 'Disease', (144, 153))	('neoplasia', 'Phenotype', 'HP:0002664', (144, 153))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (128, 153))	('cryoablation', 'Var', (11, 23))
606154	32022306	These three cancers were 1) esophagus, divided into esophageal adenocarcinoma (i.e., all histology coded as 8140-8141, 8143-8145, 8190, 8200-8202, 8210-8215, 8220-8221, 8230-8231, 8260-8263, 8310, 8401, 8480-8482, 8490, 8550-8551, 8570-8574, or 8576) and esophageal squamous cell carcinoma (SSC; i.e., all histology coded as 8050-8052, 8070-8076, or 8082-8084), respectively; 2) oral cavity and pharynx, divided into subsites related to human papilloma virus (HPV) infection (i.e., all primary sites coded as C019, C024, C090, C091, C98, C99, C100-C104, C108, C109, or C142) and those related to smoking (i.e., all primary sites coded as C020-C023, C028-C031, C039-C041, C048-C052, C058-C062, C068, or C069), respectively; and 3) stomach, divided into cardia (i.e., primary site coded as C160) and non-cardia (i.e., all primary sites coded as C161-C166), respectively.	('cardia', 'Disease', (802, 808))	('C028-C031', 'Var', (649, 658))	('C048-C052', 'Var', (671, 680))	('age', 'Gene', '5973', (57, 60))	('papilloma', 'Phenotype', 'HP:0012740', (443, 452))	('adenocarcinoma', 'Disease', (63, 77))	('cardia', 'Disease', (752, 758))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('age', 'Gene', '5973', (260, 263))	('esophageal squamous cell carcinoma', 'Disease', (255, 289))	('C039-C041', 'Var', (660, 669))	('adenocarcinoma', 'Disease', 'MESH:D000230', (63, 77))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (52, 77))	('cardia', 'Disease', 'MESH:D004938', (802, 808))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('cardia', 'Disease', 'MESH:D004938', (752, 758))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (255, 289))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('age', 'Gene', (57, 60))	('papilloma virus (HPV) infection', 'Disease', 'MESH:D030361', (443, 474))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('cancers', 'Disease', (12, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('C020-C023', 'Var', (638, 647))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('age', 'Gene', (260, 263))
606246	31817790	HCPT significantly decreased the proliferation and anchorage-independent growth of ESCC cells (KYSE410, KYSE510, KYSE30, and KYSE450).	('ESCC', 'Disease', 'MESH:C562729', (83, 87))	('KYSE410', 'Var', (95, 102))	('KYSE30', 'Var', (113, 119))	('CPT', 'Chemical', 'MESH:D002166', (1, 4))	('KYSE510', 'Var', (104, 111))	('proliferation', 'CPA', (33, 46))	('anchorage-independent growth', 'CPA', (51, 79))	('KYSE450', 'Var', (125, 132))	('ESCC', 'Disease', (83, 87))	('decreased', 'NegReg', (19, 28))
606248	31817790	In addition, HCPT stimulated ESCC cells apoptosis, which was associated with elevated expression of cleaved PARP, cleaved caspase-3, cleaved caspase-7, Bax, Bim, and inhibition of Bcl-2 expression.	('ESCC', 'Disease', (29, 33))	('Bcl-2', 'Gene', (180, 185))	('apoptosis', 'CPA', (40, 49))	('Bim', 'Gene', '10018', (157, 160))	('elevated', 'PosReg', (77, 85))	('PARP', 'Gene', (108, 112))	('Bax', 'Gene', (152, 155))	('CPT', 'Chemical', 'MESH:D002166', (14, 17))	('Bcl-2', 'Gene', '596', (180, 185))	('inhibition', 'NegReg', (166, 176))	('Bim', 'Gene', (157, 160))	('cleaved', 'MPA', (133, 140))	('Bax', 'Gene', '581', (152, 155))	('caspase-7', 'Gene', (141, 150))	('expression', 'MPA', (86, 96))	('ESCC', 'Disease', 'MESH:C562729', (29, 33))	('caspase-3', 'Gene', '836', (122, 131))	('cleaved', 'MPA', (114, 121))	('cleaved', 'Var', (100, 107))	('PARP', 'Gene', '1302', (108, 112))	('caspase-3', 'Gene', (122, 131))	('caspase-7', 'Gene', '840', (141, 150))
606261	31817790	The lack of TOP I or functional inactivation of the enzyme leads to DNA double-strand break (DSB) formation.	('lack', 'NegReg', (4, 8))	('TOP I', 'Gene', (12, 17))	('DNA double-strand break', 'MPA', (68, 91))	('inactivation', 'Var', (32, 44))	('TOP I', 'Gene', '7150', (12, 17))
606276	31817790	Moreover, patients with a high expression of TOP I had a relatively shorter overall survival time than those with low expression of the gene (p = 0.014) (Figure 1D) (Data obtained from ).	('overall survival', 'MPA', (76, 92))	('high', 'Var', (26, 30))	('TOP I', 'Gene', (45, 50))	('TOP I', 'Gene', '7150', (45, 50))	('patients', 'Species', '9606', (10, 18))	('shorter', 'NegReg', (68, 75))
606278	31817790	The TOP I was highly expressed in most of the ESCC cell lines, especially in KYSE410, KYSE510, KYSE30, and KYSE450 cells, however its level was relatively low in normal esophageal epithelial cell SHEE (Figure 1E, Figure S5A).	('KYSE30', 'Var', (95, 101))	('TOP I', 'Gene', '7150', (4, 9))	('ESCC', 'Disease', (46, 50))	('KYSE410', 'Var', (77, 84))	('KYSE510', 'Var', (86, 93))	('ESCC', 'Disease', 'MESH:C562729', (46, 50))	('TOP I', 'Gene', (4, 9))	('KYSE450', 'Var', (107, 114))
606279	31817790	In order to examine the effects of HCPT on ESCC cells, we selected four kinds of ESCC cell lines (KYSE410, KYSE510, KYSE30, and KYSE450), which contained higher levels of TOP I protein for cell proliferation assay (Figure 1E).	('ESCC', 'Disease', 'MESH:C562729', (81, 85))	('TOP I', 'Gene', '7150', (171, 176))	('KYSE30', 'Var', (116, 122))	('ESCC', 'Disease', (43, 47))	('KYSE410', 'Var', (98, 105))	('ESCC', 'Disease', (81, 85))	('higher', 'PosReg', (154, 160))	('TOP I', 'Gene', (171, 176))	('CPT', 'Chemical', 'MESH:D002166', (36, 39))	('KYSE450', 'Var', (128, 135))	('KYSE510', 'Var', (107, 114))	('ESCC', 'Disease', 'MESH:C562729', (43, 47))
606285	31817790	The incubation of KYSE410, KYSE510, KYSE30, and KYSE450 cells with HCPT led to cell cycle arrest at the G2/M phase (Figure 3A), inhibition of cyclin B1 expression, and elevation of p21 expression (Figure 3B, Figure S5B).	('KYSE410', 'Var', (18, 25))	('p21', 'Gene', (181, 184))	('inhibition', 'NegReg', (128, 138))	('cyclin B1', 'Gene', '891', (142, 151))	('expression', 'MPA', (185, 195))	('p21', 'Gene', '644914', (181, 184))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (79, 96))	('KYSE510', 'Var', (27, 34))	('cyclin B1', 'Gene', (142, 151))	('KYSE450', 'Var', (48, 55))	('elevation', 'PosReg', (168, 177))	('S5B', 'Chemical', 'MESH:D013455', (215, 218))	('cell cycle arrest at the G2/M phase', 'CPA', (79, 114))	('CPT', 'Chemical', 'MESH:D002166', (68, 71))	('expression', 'MPA', (152, 162))	('KYSE30', 'Var', (36, 42))
606289	31817790	The expression of cleaved PARP, cleaved caspase-3, cleaved caspase-7, Bax, and Bim, which are markers of apoptosis, was significantly increased after HCPT treatment for 72 h, while that of the anti-apoptotic protein Bcl-2 was markedly decreased (Figure 3D, Figure S6).	('Bax', 'Gene', (70, 73))	('PARP', 'Gene', '1302', (26, 30))	('PARP', 'Gene', (26, 30))	('cleaved', 'Var', (51, 58))	('caspase-7', 'Gene', (59, 68))	('caspase-3', 'Gene', (40, 49))	('expression', 'MPA', (4, 14))	('cleaved', 'Var', (32, 39))	('Bim', 'Gene', (79, 82))	('Bax', 'Gene', '581', (70, 73))	('caspase-7', 'Gene', '840', (59, 68))	('Bim', 'Gene', '10018', (79, 82))	('Bcl-2', 'Gene', (216, 221))	('Bcl-2', 'Gene', '596', (216, 221))	('increased', 'PosReg', (134, 143))	('caspase-3', 'Gene', '836', (40, 49))	('CPT', 'Chemical', 'MESH:D002166', (151, 154))
606329	31817790	Since human TOP I is essential for topological stress releasing and topology modulation, the damage of TOP I function will lead to supercoiled DNA because the DNA strands cannot release superhelix during transcription and replication.	('human', 'Species', '9606', (6, 11))	('TOP I', 'Gene', (12, 17))	('supercoiled DNA', 'Disease', (131, 146))	('lead to', 'Reg', (123, 130))	('TOP I', 'Gene', '7150', (103, 108))	('damage', 'Var', (93, 99))	('TOP I', 'Gene', '7150', (12, 17))	('TOP I', 'Gene', (103, 108))
606349	31817790	Moreover, HCPT suppresses ESCC PDX tumor growth in vivo, which is associated with reduced expression of TOP I and other cell proliferation markers and elevated expression of apoptosis markers.	('TOP I', 'Gene', (104, 109))	('expression', 'MPA', (160, 170))	('suppresses', 'NegReg', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ESCC', 'Disease', (26, 30))	('HCPT', 'Var', (10, 14))	('tumor', 'Disease', (35, 40))	('expression', 'MPA', (90, 100))	('TOP I', 'Gene', '7150', (104, 109))	('elevated', 'PosReg', (151, 159))	('reduced', 'NegReg', (82, 89))	('ESCC', 'Disease', 'MESH:C562729', (26, 30))	('CPT', 'Chemical', 'MESH:D002166', (11, 14))
606353	31817790	TOP I antibody was purchased from Abcam and antibodies to detect apoptosis such as: cleaved PARP (Cat: 9664), cleaved caspase-3 (Cat: 5625), cleaved caspase-7 (Cat: 8438), Bim (Cat: 2933), Bax (Cat: 5023), and Bcl-2 (Cat: 15071) as well as p21 (Cat: 2947) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('p21', 'Gene', (240, 243))	('Bim', 'Gene', '10018', (172, 175))	('p21', 'Gene', '644914', (240, 243))	('TOP I', 'Gene', (0, 5))	('Cat: 9664', 'Var', (98, 107))	('PARP', 'Gene', (92, 96))	('Bim', 'Gene', (172, 175))	('caspase-3', 'Gene', '836', (118, 127))	('caspase-7', 'Gene', (149, 158))	('TOP I', 'Gene', '7150', (0, 5))	('caspase-3', 'Gene', (118, 127))	('Bcl-2', 'Gene', (210, 215))	('Bax', 'Gene', (189, 192))	('Bax', 'Gene', '581', (189, 192))	('Bcl-2', 'Gene', '596', (210, 215))	('Cat: 5625', 'Var', (129, 138))	('TOP I antibody', 'Phenotype', 'HP:0030859', (0, 14))	('PARP', 'Gene', '1302', (92, 96))	('caspase-7', 'Gene', '840', (149, 158))
606354	31817790	KYSE410, KYSE510, KYSE30, and KYSE450 human esophageal cancer cell lines were purchased from the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China).	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('human', 'Species', '9606', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('KYSE30', 'Var', (18, 24))	('esophageal cancer', 'Disease', (44, 61))	('KYSE510', 'Var', (9, 16))
606356	31817790	The cells were cultured in RPMI-1640 contained with streptomycin (100 mug/mL), penicillin (100 units/mL), and 10% FBS (BI, Kibbutz, Israel) in an incubator with 5% CO2 and 37  C atmosphere.	('streptomycin', 'Chemical', 'MESH:D013307', (52, 64))	('100 units/mL', 'Var', (91, 103))	('100 mug/mL', 'Var', (66, 76))	('CO2', 'Chemical', 'MESH:D002245', (164, 167))	('penicillin', 'Chemical', 'MESH:D010406', (79, 89))
606398	31291201	LncRNA MIR22HG abrogation inhibits proliferation and induces apoptosis in esophageal adenocarcinoma cells via activation of the STAT3/c-Myc/FAK signaling Long non-coding RNAs (lncRNAs) have involved in human malignancies and played an important role in gene regulations.	('inhibits', 'NegReg', (26, 34))	('MIR22HG', 'Gene', (7, 14))	('MIR22HG', 'Gene', '84981', (7, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('human', 'Species', '9606', (202, 207))	('STAT3', 'Gene', (128, 133))	('FAK', 'Gene', (140, 143))	('malignancies', 'Disease', 'MESH:D009369', (208, 220))	('induces', 'Reg', (53, 60))	('apoptosis', 'CPA', (61, 70))	('malignancies', 'Disease', (208, 220))	('STAT3', 'Gene', '6774', (128, 133))	('FAK', 'Gene', '5747', (140, 143))	('c-Myc', 'Gene', (134, 139))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (74, 99))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (74, 99))	('c-Myc', 'Gene', '4609', (134, 139))	('abrogation', 'Var', (15, 25))	('activation', 'PosReg', (110, 120))	('proliferation', 'CPA', (35, 48))	('esophageal adenocarcinoma', 'Disease', (74, 99))
606399	31291201	The dysregulation of lncRNA MIR22HG has been reported in several cancers.	('reported', 'Reg', (45, 53))	('dysregulation', 'Var', (4, 17))	('MIR22HG', 'Gene', (28, 35))	('MIR22HG', 'Gene', '84981', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))
606404	31291201	In this study, abrogation of MIR22HG inhibited cell proliferation, colony formation, invasion and migration in EAC 3 cell lines (OE33, OE19 and FLO-1).	('EAC', 'Phenotype', 'HP:0011459', (111, 114))	('abrogation', 'Var', (15, 25))	('colony formation', 'CPA', (67, 83))	('inhibited', 'NegReg', (37, 46))	('invasion', 'CPA', (85, 93))	('migration', 'CPA', (98, 107))	('MIR22HG', 'Gene', (29, 36))	('MIR22HG', 'Gene', '84981', (29, 36))	('cell proliferation', 'CPA', (47, 65))
606405	31291201	Mechanistically, MIR22HG silencing decreased the expression of STAT3/c-Myc/p-FAK proteins and induced apoptosis in EAC cell lines.	('silencing', 'Var', (25, 34))	('FAK', 'Gene', '5747', (77, 80))	('MIR22HG', 'Gene', '84981', (17, 24))	('apoptosis', 'CPA', (102, 111))	('FAK', 'Gene', (77, 80))	('c-Myc', 'Gene', (69, 74))	('expression', 'MPA', (49, 59))	('decreased', 'NegReg', (35, 44))	('STAT3', 'Gene', '6774', (63, 68))	('EAC', 'Phenotype', 'HP:0011459', (115, 118))	('induced', 'Reg', (94, 101))	('c-Myc', 'Gene', '4609', (69, 74))	('STAT3', 'Gene', (63, 68))	('MIR22HG', 'Gene', (17, 24))
606408	31291201	Much progress has been made in the molecular understanding of EAC, including tumor suppressor gene mutations, aberrant protein expression and cancer stem cell identification.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('EAC', 'Phenotype', 'HP:0011459', (62, 65))	('mutations', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('EAC', 'Disease', (62, 65))	('tumor', 'Disease', (77, 82))	('cancer', 'Disease', (142, 148))
606411	31291201	A number of studies have shown that ncRNAs are capable of influencing various cellular processes such as cell proliferation, cell cycle progression, cell growth, and apoptosis, and their misexpression confers tumor initiation, cancer cells growth and metastasis.	('cellular processes', 'CPA', (78, 96))	('tumor', 'Disease', (209, 214))	('influencing', 'Reg', (58, 69))	('cell growth', 'CPA', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cell cycle progression', 'CPA', (125, 147))	('confers', 'PosReg', (201, 208))	('misexpression', 'Var', (187, 200))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('metastasis', 'CPA', (251, 261))	('apoptosis', 'CPA', (166, 175))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('cell proliferation', 'CPA', (105, 123))
606419	31291201	We found that the proliferation, colony formation, migration and invasion were decreased after Knockdown of MIR22HG on EAC cell lines.	('Knockdown', 'Var', (95, 104))	('EAC', 'Phenotype', 'HP:0011459', (119, 122))	('decreased', 'NegReg', (79, 88))	('migration', 'CPA', (51, 60))	('colony formation', 'CPA', (33, 49))	('MIR22HG', 'Gene', (108, 115))	('proliferation', 'CPA', (18, 31))	('MIR22HG', 'Gene', '84981', (108, 115))	('invasion', 'CPA', (65, 73))
606425	31291201	Functionally, we found that the cell proliferation measured by WST-1 assays was significantly decreased upon knockdown of MIR22HG in OE33, FLO-1 and OE19 cells (Figure 1C).	('MIR22HG', 'Gene', (122, 129))	('MIR22HG', 'Gene', '84981', (122, 129))	('decreased', 'NegReg', (94, 103))	('knockdown', 'Var', (109, 118))	('cell proliferation', 'CPA', (32, 50))
606426	31291201	In consistent with WST -1 assay results, knockdown of MIR22HG significantly inhibited the colony formation ability of the EAC cells compared with the non-target control (Figure 1D and 1E).	('colony formation ability of the EAC cells', 'CPA', (90, 131))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('MIR22HG', 'Gene', (54, 61))	('inhibited', 'NegReg', (76, 85))	('knockdown', 'Var', (41, 50))	('MIR22HG', 'Gene', '84981', (54, 61))
606429	31291201	We observed that knockdown of MIR22HG significantly decreased the migration and invasion potential in OE33 and FLO-1 cells (Figure 2A and 2B), indicating that MIR22HG may have a role in EAC metastasis or tumor progression.	('migration', 'CPA', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('decreased', 'NegReg', (52, 61))	('knockdown', 'Var', (17, 26))	('MIR22HG', 'Gene', (159, 166))	('MIR22HG', 'Gene', '84981', (159, 166))	('EAC', 'Disease', (186, 189))	('invasion potential', 'CPA', (80, 98))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('MIR22HG', 'Gene', (30, 37))	('MIR22HG', 'Gene', '84981', (30, 37))	('role', 'Reg', (178, 182))	('EAC', 'Phenotype', 'HP:0011459', (186, 189))
606430	31291201	To understand the mechanisms of MIR22HG roles in regulating EAC cell proliferation in OE33 and FLO-1 cells, we performed western blot and found that knockdown of MIR22HG resulted in reduced total and phosphor STAT3 (t-STAT3 and p-STAT3) as well as phosphor FAK (p-FAK) proteins expression in OE33 and FLO-1 cell lines, while c-Myc protein was decreased in FLO-1 cells but unchanged in OE33 cells (Figure 3A).	('knockdown', 'Var', (149, 158))	('p-STAT3', 'Gene', (228, 235))	('STAT3', 'Gene', '6774', (230, 235))	('FAK', 'Gene', (257, 260))	('p-STAT3', 'Gene', '6774', (228, 235))	('decreased', 'NegReg', (343, 352))	('expression', 'MPA', (278, 288))	('FAK', 'Gene', '5747', (257, 260))	('FAK', 'Gene', (264, 267))	('c-Myc', 'Gene', (325, 330))	('reduced', 'NegReg', (182, 189))	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('STAT3', 'Gene', (218, 223))	('MIR22HG', 'Gene', (162, 169))	('MIR22HG', 'Gene', '84981', (162, 169))	('c-Myc', 'Gene', '4609', (325, 330))	('FAK', 'Gene', '5747', (264, 267))	('STAT3', 'Gene', (209, 214))	('STAT3', 'Gene', '6774', (218, 223))	('STAT3', 'Gene', '6774', (209, 214))	('MIR22HG', 'Gene', (32, 39))	('STAT3', 'Gene', (230, 235))	('MIR22HG', 'Gene', '84981', (32, 39))
606435	31291201	To further make clear the relationship among MIR22HG, STAT3, c-Myc and p-FAK proteins and roles in EAC proliferation and apoptosis, we performed knockdown of STAT3 with siRNA in OE33 and FLO-1 cells (Figure 4A).	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('knockdown', 'Var', (145, 154))	('MIR22HG', 'Gene', (45, 52))	('MIR22HG', 'Gene', '84981', (45, 52))	('STAT3', 'Gene', '6774', (54, 59))	('c-Myc', 'Gene', '4609', (61, 66))	('STAT3', 'Gene', (54, 59))	('STAT3', 'Gene', '6774', (158, 163))	('c-Myc', 'Gene', (61, 66))	('FAK', 'Gene', (73, 76))	('FAK', 'Gene', '5747', (73, 76))	('STAT3', 'Gene', (158, 163))
606436	31291201	The cell proliferation was decreased by 40% upon STAT3 knockdown in OE33 and FLO-1 cells at 120 h (Figure 4B) and apoptosis was induced in OE33 (Figure 4C).	('knockdown', 'Var', (55, 64))	('STAT3', 'Gene', (49, 54))	('cell proliferation', 'CPA', (4, 22))	('decreased', 'NegReg', (27, 36))	('STAT3', 'Gene', '6774', (49, 54))	('induced', 'Reg', (128, 135))	('apoptosis', 'CPA', (114, 123))
606437	31291201	We found that p-FAK protein was decreased in OE33 and FLO1 cells, while c-Myc was decreased in FLO-1 cells and unchanged in OE33 cells (Figure 4C), which was similar as MIR22HG knockdown in EAC cell lines (Figure 3A).	('EAC', 'Phenotype', 'HP:0011459', (190, 193))	('FAK', 'Gene', (16, 19))	('FLO1', 'Var', (54, 58))	('c-Myc', 'Gene', '4609', (72, 77))	('FAK', 'Gene', '5747', (16, 19))	('c-Myc', 'Gene', (72, 77))	('decreased', 'NegReg', (32, 41))	('MIR22HG', 'Gene', (169, 176))	('MIR22HG', 'Gene', '84981', (169, 176))	('decreased', 'NegReg', (82, 91))
606447	31291201	Recent studies showed oncogenes were usually activated by genetic or epigenetic alterations in cancer cells.	('epigenetic alterations', 'Var', (69, 91))	('genetic', 'Var', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('oncogenes', 'Gene', (22, 31))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('activated', 'PosReg', (45, 54))
606451	31291201	We identified which genes were differentially expressed upon knockdown of MIR22HG, in comparison with untreated cells.	('knockdown', 'Var', (61, 70))	('MIR22HG', 'Gene', (74, 81))	('MIR22HG', 'Gene', '84981', (74, 81))
606457	31291201	Hyper activated STAT3 promotes the expression of genes involved in cell proliferation, self-renewal, angiogenesis, inflammation-phenotypes and survival, which collectively contribute to malignant transformation and progression.	('promotes', 'PosReg', (22, 30))	('angiogenesis', 'CPA', (101, 113))	('inflammation-phenotypes', 'Disease', 'MESH:D007249', (115, 138))	('STAT3', 'Gene', '6774', (16, 21))	('expression', 'MPA', (35, 45))	('inflammation-phenotypes', 'Disease', (115, 138))	('STAT3', 'Gene', (16, 21))	('malignant transformation', 'CPA', (186, 210))	('Hyper', 'Var', (0, 5))	('contribute', 'Reg', (172, 182))	('cell', 'CPA', (67, 71))
606458	31291201	A recent study showed that overexpression of FAK has been shown to block the caspase-3-mediated apoptosis; conversely, inhibition of FAK leads to apoptosis in cancer cells.	('cancer', 'Disease', (159, 165))	('FAK', 'Gene', (133, 136))	('FAK', 'Gene', '5747', (133, 136))	('inhibition', 'Var', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('caspase-3', 'Gene', (77, 86))	('FAK', 'Gene', '5747', (45, 48))	('block', 'NegReg', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('caspase-3', 'Gene', '836', (77, 86))	('FAK', 'Gene', (45, 48))	('apoptosis', 'CPA', (146, 155))
606463	31291201	During the occurrence of EMT, degradation of E-cadherin can promotes cancer invasion by allows the release of cell-cell restriction, which is in accordance with the disruption of adherent junctions.	('promotes', 'PosReg', (60, 68))	('degradation', 'Var', (30, 41))	('EMT', 'Gene', (25, 28))	('release', 'MPA', (99, 106))	('EMT', 'Gene', '3702', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cell-cell restriction', 'MPA', (110, 131))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))	('cancer', 'Disease', (69, 75))
606465	31291201	In summary, we found that knockdown of MIR22HG has the effect of suppressing EAC proliferation, cell migration and invasion in vitro by inhibiting STAT3/c-Myc/p-FAK proteins (Figure 5).	('inhibiting', 'NegReg', (136, 146))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('cell migration', 'CPA', (96, 110))	('c-Myc', 'Gene', '4609', (153, 158))	('invasion', 'CPA', (115, 123))	('FAK', 'Gene', (161, 164))	('FAK', 'Gene', '5747', (161, 164))	('c-Myc', 'Gene', (153, 158))	('knockdown', 'Var', (26, 35))	('STAT3', 'Gene', '6774', (147, 152))	('MIR22HG', 'Gene', (39, 46))	('MIR22HG', 'Gene', '84981', (39, 46))	('suppressing', 'NegReg', (65, 76))	('EAC proliferation', 'CPA', (77, 94))	('STAT3', 'Gene', (147, 152))
606577	30387840	For IL1B, it was only reported that the rs16944 G>A polymorphism may contribute to ESCC susceptibility.	('contribute', 'Reg', (69, 79))	('IL1B', 'Gene', '3553', (4, 8))	('rs16944 G>A', 'Var', (40, 51))	('ESCC', 'Disease', (83, 87))	('rs16944', 'Mutation', 'rs16944', (40, 47))	('IL1B', 'Gene', (4, 8))
606664	27184872	Kaplan-Meier analysis showed that patients positive for CTCs had significantly shorter survival time than patients negative for CTCs.	('shorter', 'NegReg', (79, 86))	('survival time', 'CPA', (87, 100))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (34, 42))	('CTCs', 'Var', (56, 60))
606666	27184872	CTCs positivity is an independent prognostic biomarker that indicates a worse prognosis for patients with ESCC.	('positivity', 'Var', (5, 15))	('ESCC', 'Disease', (106, 110))	('patients', 'Species', '9606', (92, 100))
606709	27184872	Kaplan-Meier analysis showed that CTCs-positive patients had significantly shorter survival time (DFS and OS) than CTCs-negative patients (Figure 2).	('CTCs-positive', 'Var', (34, 47))	('patients', 'Species', '9606', (129, 137))	('survival time', 'CPA', (83, 96))	('shorter', 'NegReg', (75, 82))	('patients', 'Species', '9606', (48, 56))
606738	27184872	In the present study, we observed that CTCs positivity was associated with advanced tumor stage in ESCC patients.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CTCs', 'MPA', (39, 43))	('ESCC', 'Disease', (99, 103))	('associated', 'Reg', (59, 69))	('tumor', 'Disease', (84, 89))	('positivity', 'Var', (44, 54))	('patients', 'Species', '9606', (104, 112))
606756	25620088	In the ESCC microenvironment, not only cancer cells but also TAMs expressed Cyr61.	('men', 'Species', '9606', (24, 27))	('TAMs', 'Chemical', '-', (61, 65))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Cyr61', 'Var', (76, 81))
606757	25620088	Interestingly, the expression levels of Cyr61 showed a significant positive correlation with the number of CD204-positive macrophages in ESCCs by immunohistochemistry.	('positive', 'PosReg', (67, 75))	('Cyr61', 'Var', (40, 45))	('ESCCs', 'Disease', (137, 142))	('CD204', 'Gene', '4481', (107, 112))	('expression levels', 'MPA', (19, 36))	('CD204', 'Gene', (107, 112))
606760	25620088	These results suggest that Cyr61 may contribute to the expression of CD204 and the promotion of cell migration via the MEK/ERK pathway in TAMs in the ESCC microenvironment.	('promotion', 'PosReg', (83, 92))	('cell migration', 'CPA', (96, 110))	('TAMs', 'Chemical', '-', (138, 142))	('Cyr61', 'Var', (27, 32))	('MEK/ERK pathway', 'Pathway', (119, 134))	('CD204', 'Gene', '4481', (69, 74))	('CD204', 'Gene', (69, 74))	('men', 'Species', '9606', (167, 170))
606771	25620088	We also demonstrated that conditioned media of five ESCC cell lines (TE-8, TE-9, TE-10, TE-11, and TE-15) induced the mRNA and protein expressions of CD204 along with the mRNA upregulation of vascular endothelial growth factor A (VEGFA) in THP-1 human monocytic leukemia cells in vitro.	('induced', 'PosReg', (106, 113))	('upregulation', 'PosReg', (176, 188))	('TE-15', 'Var', (99, 104))	('CD204', 'Gene', (150, 155))	('CD204', 'Gene', '4481', (150, 155))	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('VEGFA', 'Gene', (230, 235))	('vascular endothelial growth factor A', 'Gene', (192, 228))	('leukemia', 'Disease', (262, 270))	('leukemia', 'Disease', 'MESH:D007938', (262, 270))	('TE-11', 'Var', (88, 93))	('TE-10', 'Var', (81, 86))	('human', 'Species', '9606', (246, 251))	('VEGFA', 'Gene', '7422', (230, 235))	('THP-1', 'Gene', '2736', (240, 245))	('THP-1', 'Gene', (240, 245))	('mRNA', 'MPA', (171, 175))	('TE-9', 'Var', (75, 79))	('vascular endothelial growth factor A', 'Gene', '7422', (192, 228))
314914	25620088	The individuality of the TE series ESCC cell lines was confirmed by a short tandem repeat analysis at RIKEN and at the Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University (Sendai, Japan).	('men', 'Species', '9606', (185, 188))	('Cancer', 'Disease', 'MESH:D009369', (201, 207))	('short tandem repeat analysis', 'Var', (70, 98))	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Cancer', 'Disease', (201, 207))
606793	25620088	For the immunofluorescence examination, formalin-fixed and paraffin-embedded tissue sections were stained with antibodies against Cyr61 (Santa Cruz Biotechnology) and CD204 (Trans Genic).	('paraffin', 'Chemical', 'MESH:D010232', (59, 67))	('formalin', 'Chemical', 'MESH:D005557', (40, 48))	('Cyr61', 'Var', (130, 135))	('CD204', 'Gene', '4481', (167, 172))	('CD204', 'Gene', (167, 172))
606796	25620088	Cyr61- and CD204+ cells were observed under a laser-scanning microscope (LSM700; Carl Zeiss, Oberkochen, Germany) and analyzed using the LSM software ZEN 2009 (Carl Zeiss).	('CD204', 'Gene', (11, 16))	('Cyr61-', 'Var', (0, 6))	('CD204', 'Gene', '4481', (11, 16))
606807	25620088	Among the microarray data containing probes for 42405 human genes, 366 genes were > 22.5-fold upregulated in TE-8CM-treated THP-1 cells (Table S1).	('THP-1', 'Gene', '2736', (124, 129))	('THP-1', 'Gene', (124, 129))	('upregulated', 'PosReg', (94, 105))	('TE-8CM-treated', 'Var', (109, 123))	('human', 'Species', '9606', (54, 59))
606808	25620088	Among these genes, we decided to focus on CYR61, known to promote not only macrophage polarization but also cell proliferation, invasion, survival, and metastasis of various cancers.	('promote', 'PosReg', (58, 65))	('metastasis of various cancers', 'Disease', (152, 181))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('invasion', 'CPA', (128, 136))	('survival', 'CPA', (138, 146))	('cell proliferation', 'CPA', (108, 126))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('CYR61', 'Var', (42, 47))	('metastasis of various cancers', 'Disease', 'MESH:D009362', (152, 181))
606809	25620088	The significant induction of CYR61 mRNA by TE-8CM as well as by the other four TECMs exposure was validated in MPhi-like THP-1 cells (Fig.1D).	('THP-1', 'Gene', (121, 126))	('TE-8CM', 'Var', (43, 49))	('CYR61', 'Protein', (29, 34))	('THP-1', 'Gene', '2736', (121, 126))
606815	25620088	Moreover, CD204+ macrophages with Cyr61 expression were evidently present within the cancer nests (Fig.2A, arrows).	('Cyr61 expression', 'Var', (34, 50))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('CD204', 'Gene', '4481', (10, 15))	('CD204', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
606818	25620088	The expression levels of Cyr61 in the ESCCs showed a significant positive correlation with the number of infiltrating CD204+ macrophages in the cancer nests and lymph node metastasis (Table3).	('expression levels', 'MPA', (4, 21))	('CD204', 'Gene', (118, 123))	('CD204', 'Gene', '4481', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('Cyr61', 'Var', (25, 30))	('cancer', 'Disease', (144, 150))	('lymph node metastasis', 'CPA', (161, 182))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
606821	25620088	Moreover, in the transwell assay, rhCyr61 (100 ng/mL) facilitated the migration of MPhi-like THP-1 cells (Fig.3C).	('migration', 'CPA', (70, 79))	('THP-1', 'Gene', '2736', (93, 98))	('facilitated', 'PosReg', (54, 65))	('THP-1', 'Gene', (93, 98))	('rhCyr61', 'Var', (34, 41))
606823	25620088	Not only the significant induction of CD204 by TE-10CM exposure (Fig.3D) but also the TECM-induced migration of MPhi-like THP-1 cells was blocked by the addition of anti-Cyr61 antibody into the culture media (Fig.3E).	('THP-1', 'Gene', (122, 127))	('CD204', 'Gene', '4481', (38, 43))	('TE-10CM', 'Var', (47, 54))	('migration', 'CPA', (99, 108))	('CD204', 'Gene', (38, 43))	('THP-1', 'Gene', '2736', (122, 127))
606824	25620088	As MEK/ERK pathways are known to be involved in the Cyr61-mediated recruitment of macrophages, we hypothesized that the MEK/ERK pathway may be activated by Cyr61 in MPhi-like THP-1 cells.	('THP-1', 'Gene', (175, 180))	('Cyr61', 'Var', (156, 161))	('men', 'Species', '9606', (74, 77))	('MEK/ERK pathway', 'Pathway', (120, 135))	('THP-1', 'Gene', '2736', (175, 180))
606826	25620088	Pretreatment with a MEK1/2 inhibitor U0126 at 10 mumol/L for 0.5 or 2 h significantly inhibited both ERK1/2 phosphorylation and the Cyr61-mediated migration (Fig.4B and C).	('U0126', 'Var', (37, 42))	('men', 'Species', '9606', (8, 11))	('Cyr61-mediated migration', 'CPA', (132, 156))	('U0126', 'Chemical', 'MESH:C113580', (37, 42))	('ERK1/2', 'Gene', (101, 107))	('phosphorylation', 'MPA', (108, 123))	('inhibited', 'NegReg', (86, 95))	('MEK1/2', 'Gene', '5604;5605', (20, 26))	('ERK1/2', 'Gene', '5595;5594', (101, 107))	('MEK1/2', 'Gene', (20, 26))
606827	25620088	Interestingly, CD204 expression was also inhibited by U0126 treatment at 10 mumol/L for 0.5 h (Fig.4D).	('CD204', 'Gene', '4481', (15, 20))	('CD204', 'Gene', (15, 20))	('men', 'Species', '9606', (65, 68))	('U0126', 'Var', (54, 59))	('expression', 'MPA', (21, 31))	('inhibited', 'NegReg', (41, 50))	('U0126', 'Chemical', 'MESH:C113580', (54, 59))
606830	25620088	Cyr61 (also called CCN1) is a component of the extracellular matrix which belongs to the CCN protein family.	('Cyr61', 'Var', (0, 5))	('CCN1', 'Gene', (19, 23))	('CCN1', 'Gene', '3491', (19, 23))
606831	25620088	CYR61-null mice suffer developmental failure and embryonic death due to vascular defects in the placenta.	('embryonic death', 'Disease', (49, 64))	('developmental failure', 'Phenotype', 'HP:0001263', (23, 44))	('CYR61-null', 'Var', (0, 10))	('vascular defects in the placenta', 'Phenotype', 'HP:0100767', (72, 104))	('mice', 'Species', '10090', (11, 15))	('embryonic death', 'Disease', 'MESH:D003643', (49, 64))	('vascular defects', 'Disease', 'MESH:D000783', (72, 88))	('vascular defects', 'Disease', (72, 88))	('developmental failure', 'Disease', (23, 44))	('developmental failure', 'Disease', 'MESH:D017093', (23, 44))
606833	25620088	In terms of cancer, the overexpression of Cyr61 has been linked to the growth and progression of various cancers.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Disease', (12, 18))	('Cyr61', 'Var', (42, 47))	('cancers', 'Disease', (105, 112))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('overexpression', 'PosReg', (24, 38))	('linked', 'Reg', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
606834	25620088	Cyr61 has also been reported to support the chemotaxis of various cell types including murine macrophages, and to induce a proinflammatory genetic program of murine macrophages.	('murine', 'Species', '10090', (87, 93))	('support', 'PosReg', (32, 39))	('chemotaxis of', 'CPA', (44, 57))	('Cyr61', 'Var', (0, 5))	('proinflammatory genetic', 'MPA', (123, 146))	('murine', 'Species', '10090', (158, 164))	('induce', 'PosReg', (114, 120))
606835	25620088	From these reports, we speculate that Cyr61 might also be involved in the recruitment or differentiation of macrophages in the ESCC microenvironment.	('men', 'Species', '9606', (144, 147))	('involved', 'Reg', (58, 66))	('Cyr61', 'Var', (38, 43))	('men', 'Species', '9606', (81, 84))	('differentiation', 'CPA', (89, 104))
606836	25620088	In this study, Cyr61 expression and secretion were significantly induced by TECMs in MPhi-like THP-1 cells.	('THP-1', 'Gene', '2736', (95, 100))	('THP-1', 'Gene', (95, 100))	('secretion', 'MPA', (36, 45))	('Cyr61', 'Gene', (15, 20))	('induced', 'PosReg', (65, 72))	('expression', 'MPA', (21, 31))	('TECMs', 'Var', (76, 81))
606838	25620088	In our immunofluorescence examination, Cyr61 was detected in cancer cells as well as stromal cells of ESCC tissues.	('detected', 'Reg', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cyr61', 'Var', (39, 44))
606840	25620088	These findings suggested that not only cancer cells but also TAMs expressed Cyr61 in the ESCC microenvironment.	('TAMs', 'Chemical', '-', (61, 65))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Cyr61', 'Var', (76, 81))	('men', 'Species', '9606', (106, 109))
606841	25620088	To our knowledge, there are only a few reports describing Cyr61 expression in the cancer stroma of ESCC.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer stroma', 'Disease', (82, 95))	('cancer stroma', 'Disease', 'MESH:D009369', (82, 95))	('Cyr61', 'Var', (58, 63))
606843	25620088	Our present findings may provide new knowledge with regard to Cyr61 expression in the ESCC microenvironment.	('Cyr61', 'Var', (62, 67))	('men', 'Species', '9606', (103, 106))	('ESCC', 'Disease', (86, 90))
606844	25620088	The overexpression of Cyr61 in ESCC tissues has been reported to be associated with poor survival of ESCC patients, although there was no association between Cyr61 expression and clinicopathological variables including histological grade, clinical stage, and lymph node metastasis.	('Cyr61', 'Var', (22, 27))	('poor', 'NegReg', (84, 88))	('patients', 'Species', '9606', (106, 114))	('overexpression', 'PosReg', (4, 18))	('ESCC', 'Disease', (101, 105))
606845	25620088	Interestingly, the number of infiltrating CD204+ macrophages but not those of other macrophage markers including CD68 and CD163 showed a significant positive correlation with the overall expression levels of Cyr61 in ESCC.	('CD163', 'Gene', (122, 127))	('expression levels', 'MPA', (187, 204))	('CD204', 'Gene', (42, 47))	('CD68', 'Gene', (113, 117))	('ESCC', 'Gene', (217, 221))	('CD204', 'Gene', '4481', (42, 47))	('CD68', 'Gene', '968', (113, 117))	('Cyr61', 'Var', (208, 213))	('CD163', 'Gene', '9332', (122, 127))
606846	25620088	As we already reported that CD204 was a useful marker for TAMs contributing to the angiogenesis, progression, and prognosis of ESCC, We speculated that Cyr61 might associated with the aggressiveness of ESCC by the induction of cell migration and CD204 expression in macrophages.	('aggressiveness', 'Phenotype', 'HP:0000718', (184, 198))	('CD204', 'Gene', '4481', (246, 251))	('cell migration', 'CPA', (227, 241))	('aggressiveness', 'Disease', (184, 198))	('CD204', 'Gene', (246, 251))	('associated', 'Reg', (164, 174))	('aggressiveness', 'Disease', 'MESH:D001523', (184, 198))	('ESCC', 'Disease', (202, 206))	('TAMs', 'Chemical', '-', (58, 62))	('CD204', 'Gene', '4481', (28, 33))	('CD204', 'Gene', (28, 33))	('Cyr61', 'Var', (152, 157))	('expression', 'MPA', (252, 262))	('induction', 'PosReg', (214, 223))
606847	25620088	In accordance with previous reports, we observed here that rhCyr61 protein promoted the migration of MPhi-like THP-1 cells.	('THP-1', 'Gene', '2736', (111, 116))	('promoted', 'PosReg', (75, 83))	('THP-1', 'Gene', (111, 116))	('rhCyr61', 'Var', (59, 66))
606848	25620088	We found that the expression of CD204, an M2-marker, was also induced by rhCyr61.	('CD204', 'Gene', '4481', (32, 37))	('induced', 'PosReg', (62, 69))	('CD204', 'Gene', (32, 37))	('expression', 'MPA', (18, 28))	('rhCyr61', 'Var', (73, 80))
606850	25620088	Conversely, M1 factors, including IL-6, IFN-gamma, and TNF-alpha showed tendency to be downregulated by rhCyr61 not reaching the statistical significance (data not shown).	('TNF-alpha', 'Gene', '7124', (55, 64))	('rhCyr61', 'Var', (104, 111))	('IL-6', 'Gene', (34, 38))	('downregulated', 'NegReg', (87, 100))	('TNF-alpha', 'Gene', (55, 64))	('IFN-gamma', 'Gene', '3458', (40, 49))	('IFN-gamma', 'Gene', (40, 49))	('IL-6', 'Gene', '3569', (34, 38))
606852	25620088	The effect of Cyr61 on CD204 expression in macrophages has not yet been reported.	('CD204', 'Gene', '4481', (23, 28))	('Cyr61', 'Var', (14, 19))	('CD204', 'Gene', (23, 28))
606855	25620088	Cyr61 might thus be one of the important inducers of CD204 in macrophages.	('Cyr61', 'Var', (0, 5))	('CD204', 'Gene', '4481', (53, 58))	('CD204', 'Gene', (53, 58))
606856	25620088	Cyr61 has been shown to recruit macrophages through the activation of the MEK/ERK signaling pathway in myeloid-derived macrophage and mouse macrophage cell lines in vitro.	('Cyr61', 'Var', (0, 5))	('MEK/ERK signaling pathway', 'Pathway', (74, 99))	('mouse', 'Species', '10090', (134, 139))
606857	25620088	Indeed, we detected the activation of the MEK/ERK pathway in MPhi-like THP-1 cells by rhCyr61 treatment.	('rhCyr61', 'Var', (86, 93))	('men', 'Species', '9606', (99, 102))	('MEK/ERK pathway', 'Pathway', (42, 57))	('activation', 'PosReg', (24, 34))	('THP-1', 'Gene', '2736', (71, 76))	('THP-1', 'Gene', (71, 76))
606858	25620088	In addition, pretreatment with U0126, a MEK1/2 inhibitor, significantly inhibited not only the Cyr61-mediated migration but also the CD204 expression.	('CD204', 'Gene', '4481', (133, 138))	('CD204', 'Gene', (133, 138))	('expression', 'MPA', (139, 149))	('U0126', 'Chemical', 'MESH:C113580', (31, 36))	('MEK1/2', 'Gene', '5604;5605', (40, 46))	('Cyr61-mediated', 'MPA', (95, 109))	('MEK1/2', 'Gene', (40, 46))	('inhibited', 'NegReg', (72, 81))	('men', 'Species', '9606', (21, 24))	('U0126', 'Var', (31, 36))
606866	25620088	In conclusion, it cannot be overlooked that not only cancer cells but also TAMs express Cyr61 in the ESCC microenvironment.	('Cyr61', 'Var', (88, 93))	('TAMs', 'Chemical', '-', (75, 79))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('men', 'Species', '9606', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
606868	25620088	In this study, our overall results overall indicate that Cyr61 contributes to the expression of CD204 and the promotion of cell migration via MEK/ERK pathway in TAMs of ESCCs within their specific tumor microenvironment.	('Cyr61', 'Var', (57, 62))	('MEK/ERK pathway', 'Pathway', (142, 157))	('TAMs', 'Chemical', '-', (161, 165))	('cell migration', 'CPA', (123, 137))	('promotion', 'PosReg', (110, 119))	('expression', 'MPA', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('men', 'Species', '9606', (215, 218))	('CD204', 'Gene', '4481', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('CD204', 'Gene', (96, 101))	('tumor', 'Disease', (197, 202))
606871	25505717	However, ESD can result in a large artificial ulcer, which may lead to a considerable deformity.	('ESD', 'Var', (9, 12))	('deformity', 'Disease', (86, 95))	('ulcer', 'Disease', 'MESH:D014456', (46, 51))	('ulcer', 'Disease', (46, 51))	('lead', 'Reg', (63, 67))	('result in', 'Reg', (17, 26))	('deformity', 'Disease', 'MESH:D009140', (86, 95))
606878	25505717	The occurrence of post-ESD stricture in the esophagus and stomach can result in dysphagia or gastric outlet obstruction-which substantially decreases patient quality of life, requiring multiple sessions of endoscopic balloon dilation (EBD)-or even aspiration pneumonia.	('pneumonia', 'Phenotype', 'HP:0002090', (259, 268))	('aspiration', 'Phenotype', 'HP:0002835', (248, 258))	('patient', 'Species', '9606', (150, 157))	('stricture', 'Var', (27, 36))	('dysphagia', 'Disease', (80, 89))	('pneumonia', 'Disease', (259, 268))	('gastric outlet obstruction-which', 'Disease', (93, 125))	('pneumonia', 'Disease', 'MESH:D011014', (259, 268))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (248, 268))	('dysphagia', 'Phenotype', 'HP:0002015', (80, 89))	('dysphagia', 'Disease', 'MESH:D003680', (80, 89))	('result in', 'Reg', (70, 79))	('decreases', 'NegReg', (140, 149))
606932	25505717	In this study, ESD of more than three-fourths the circumference in the prepylorus, antrum, and cardia was considered a risk factor for stricture formation.	('cardia', 'Disease', 'MESH:D004938', (95, 101))	('stricture formation', 'Disease', (135, 154))	('cardia', 'Disease', (95, 101))	('ESD', 'Var', (15, 18))
607071	25247579	For colorectal cancer, resection of lung and liver metastases has been shown to prolong survival and has become standard therapy.	('survival', 'CPA', (88, 96))	('liver metastases', 'Disease', (45, 61))	('colorectal cancer', 'Disease', (4, 21))	('prolong', 'PosReg', (80, 87))	('liver metastases', 'Disease', 'MESH:D009362', (45, 61))	('resection', 'Var', (23, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (4, 21))
607194	21470402	Occurrence of multipolar mitoses and association with Aurora-A/-B kinases and p53 mutations in aneuploid esophageal carcinoma cells Aurora kinases and loss of p53 function are implicated in the carcinogenesis of aneuploid esophageal cancers.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (105, 125))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Aurora-A/-B', 'Gene', '9212', (54, 65))	('p53', 'Gene', '7157', (159, 162))	('carcinogenesis of aneuploid esophageal cancers', 'Disease', (194, 240))	('aneuploid esophageal carcinoma', 'Disease', (95, 125))	('implicated', 'Reg', (176, 186))	('p53', 'Gene', (159, 162))	('aneuploid esophageal carcinoma', 'Disease', 'MESH:D000782', (95, 125))	('p53', 'Gene', '7157', (78, 81))	('association', 'Interaction', (37, 48))	('carcinogenesis of aneuploid esophageal cancers', 'Disease', 'MESH:D000782', (194, 240))	('Aurora-A/-B', 'Gene', (54, 65))	('p53', 'Gene', (78, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('loss', 'NegReg', (151, 155))	('mutations', 'Var', (82, 91))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('function', 'MPA', (163, 171))
607196	21470402	Here, we investigated the occurrence of multipolar mitoses, Aurora-A/-B gene copy numbers and expression/activation as well as p53 alterations in aneuploid ESCC and BAC cancer cell lines.	('cancer', 'Disease', (169, 175))	('aneuploid', 'Var', (146, 155))	('Aurora-A/-B', 'Gene', (60, 71))	('Aurora-A/-B', 'Gene', '6790;9212', (60, 71))	('alterations', 'Var', (131, 142))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
607198	21470402	In contrast, both ESCC (OE21, Kyse-410) and BAC (OE33, OE19) cell lines were aneuploid and displayed elevated gene copy numbers of Aurora-A (chromosome 20 polysomy: OE21, OE33, OE19; gene amplification: Kyse-410) and Aurora-B (chromosome 17 polysomy: OE21, Kyse-410).	('elevated', 'PosReg', (101, 109))	('Kyse-410', 'Var', (257, 265))	('gene copy numbers', 'MPA', (110, 127))	('Aurora-A', 'Gene', (131, 139))	('Aurora-A', 'Gene', '6790', (131, 139))	('Aurora-B', 'Gene', (217, 225))	('Aurora-B', 'Gene', '9212', (217, 225))
607199	21470402	Aurora-B gene copy numbers were not elevated in OE19 and OE33 cells despite chromosome 17 polysomy.	('Aurora-B', 'Gene', (0, 8))	('Aurora-B', 'Gene', '9212', (0, 8))	('polysomy', 'Var', (90, 98))
607201	21470402	Aurora-B expression and activity (Aurora-B/phosphoT232) was higher in OE21 and Kyse-410 than in OE33 and OE19 cells.	('activity', 'MPA', (24, 32))	('higher', 'PosReg', (60, 66))	('Aurora-B', 'Gene', (34, 42))	('expression', 'MPA', (9, 19))	('Kyse-410', 'Var', (79, 87))	('Aurora-B', 'Gene', (0, 8))	('Aurora-B', 'Gene', '9212', (0, 8))	('Aurora-B', 'Gene', '9212', (34, 42))
607202	21470402	The mitotic index was highest in OE21, followed by OE33 > OE19 > Kyse-410 and EPC-hTERT cells.	('highest', 'Reg', (22, 29))	('mitotic index', 'CPA', (4, 17))	('OE33', 'Var', (51, 55))	('OE21', 'Var', (33, 37))	('EPC-hTERT', 'CellLine', 'CVCL:4361', (78, 87))
607203	21470402	Distinct p53 mutations and p53 protein expression patterns were found in all esophageal cancer cell lines, but complete functional p53 inactivation occurred in OE21 and OE33 only.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('p53', 'Gene', '7157', (27, 30))	('p53', 'Gene', (131, 134))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', '7157', (131, 134))	('inactivation', 'NegReg', (135, 147))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('expression', 'MPA', (39, 49))	('esophageal cancer', 'Disease', (77, 94))	('mutations', 'Var', (13, 22))	('p53', 'Gene', (27, 30))
607204	21470402	High Aurora-A expression alone is not associated with overt multipolar mitoses in aneuploid ESCC and BAC cancer cells, as specifically shown here for OE21 and OE33 cells, respectively.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('aneuploid', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Aurora-A', 'Gene', '6790', (5, 13))	('Aurora-A', 'Gene', (5, 13))
607205	21470402	Additional p53 loss of function mutations are necessary for this to occur, at least for invasive esophageal cancer cells.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (32, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('loss of function', 'NegReg', (15, 31))
607209	21470402	Several specific molecular alterations play crucial roles in the carcinogenesis of ESCC or BAC, with tumor cell aneuploidy and p53 mutations being major hallmarks of both ESCC and BAC.	('mutations', 'Var', (131, 140))	('tumor cell aneuploidy', 'Disease', 'MESH:D000782', (101, 122))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor cell aneuploidy', 'Disease', (101, 122))	('ESCC', 'Disease', (171, 175))	('BAC', 'Disease', (91, 94))	('ESCC', 'Disease', (83, 87))	('roles', 'Reg', (52, 57))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
607212	21470402	Moreover, p53 is mutated in 35% to 80% of ESCC and in about 50% to 90% of BAC.	('ESCC', 'Disease', (42, 46))	('p53', 'Gene', '7157', (10, 13))	('p53', 'Gene', (10, 13))	('mutated', 'Var', (17, 24))
607217	21470402	Amplification of the Aurora-A locus (AURKA, 20q13.2) and subsequent overexpression of Aurora-A was observed for example in colorectal and pancreatic cancer, as well as in ESCCs and BACs.	('Amplification', 'Var', (0, 13))	('BACs', 'Gene', '10998', (181, 185))	('ESCCs', 'Disease', (171, 176))	('Aurora-A', 'Gene', (21, 29))	('AURKA', 'Gene', '6790', (37, 42))	('Aurora-A', 'Gene', '6790', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('overexpression', 'PosReg', (68, 82))	('AURKA', 'Gene', (37, 42))	('Aurora-A', 'Gene', '6790', (86, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('Aurora-A', 'Gene', (86, 94))	('BACs', 'Gene', (181, 185))	('colorectal and pancreatic cancer', 'Disease', 'MESH:D010190', (123, 155))
607218	21470402	Overexpression of Aurora-A has been functionally associated with supernumerary centrosomes and aneuploidy.	('aneuploidy', 'Disease', 'MESH:D000782', (95, 105))	('associated', 'Reg', (49, 59))	('aneuploidy', 'Disease', (95, 105))	('supernumerary centrosomes', 'CPA', (65, 90))	('Overexpression', 'Var', (0, 14))	('Aurora-A', 'Gene', '6790', (18, 26))	('Aurora-A', 'Gene', (18, 26))
607219	21470402	In esophageal cancers, a polymorphism of Aurora-A was associated with increased esophageal cancer risk.	('polymorphism', 'Var', (25, 37))	('esophageal cancers', 'Disease', (3, 21))	('esophageal cancers', 'Disease', 'MESH:D004938', (3, 21))	('Aurora-A', 'Gene', (41, 49))	('esophageal cancer', 'Disease', (80, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('Aurora-A', 'Gene', '6790', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('associated', 'Reg', (54, 64))
607220	21470402	This Aurora-A polymorphism showed reduced Aurora-A kinase activity, lack of phosphorylation of its substrate Lats2 and associated genetic instability, at least by ectopic expression of the Aurora-A isoforms in immortalized fibroblasts.	('associated', 'Reg', (119, 129))	('reduced', 'NegReg', (34, 41))	('activity', 'MPA', (58, 66))	('Aurora-A', 'Gene', (5, 13))	('polymorphism', 'Var', (14, 26))	('Aurora-A', 'Gene', '6790', (189, 197))	('Aurora-A', 'Gene', '6790', (42, 50))	('phosphorylation', 'MPA', (76, 91))	('Aurora-A', 'Gene', (189, 197))	('Aurora-A', 'Gene', (42, 50))	('Lats2', 'Gene', '26524', (109, 114))	('genetic instability', 'Disease', 'MESH:D030342', (130, 149))	('lack', 'NegReg', (68, 72))	('Aurora-A', 'Gene', '6790', (5, 13))	('genetic instability', 'Disease', (130, 149))	('Lats2', 'Gene', (109, 114))
607227	21470402	In view of the crucial role of the tumor suppressor p53 for maintenance of genetic stability and its frequent mutation in esophageal cancer, it is of interest that also a centrosomal localization and functional involvement in centrosome duplication has been described for p53.	('esophageal cancer', 'Disease', (122, 139))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('p53', 'Gene', (272, 275))	('p53', 'Gene', '7157', (272, 275))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('tumor', 'Disease', (35, 40))	('mutation', 'Var', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
607229	21470402	Together, (Aurora-A dependent or independent) disruption of p53 function may result in escape of the p53 dependent G1 post-mitotic checkpoint and potentially also centrosomal dysfunction.	('G1 post-mitotic checkpoint', 'CPA', (115, 141))	('disruption', 'Var', (46, 56))	('p53', 'Gene', (101, 104))	('p53', 'Gene', (60, 63))	('p53', 'Gene', '7157', (101, 104))	('Aurora-A', 'Gene', (11, 19))	('escape', 'PosReg', (87, 93))	('Aurora-A', 'Gene', '6790', (11, 19))	('centrosomal dysfunction', 'CPA', (163, 186))	('p53', 'Gene', '7157', (60, 63))
607230	21470402	The aim of the present study was to investigate the occurrence of multipolar mitoses and association with Aurora kinases and p53 mutations in previously established esophageal carcinoma cell lines and control esophageal epithelial cells.	('esophageal carcinoma cell lines', 'Disease', 'MESH:D000077277', (165, 196))	('mutations', 'Var', (129, 138))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (165, 185))	('p53', 'Gene', '7157', (125, 128))	('p53', 'Gene', (125, 128))	('esophageal carcinoma cell lines', 'Disease', (165, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('association', 'Interaction', (89, 100))
607231	21470402	For the present study, a control diploid cell line derived from normal esophageal epithelial cells as well as four aneuploid esophageal cancer cell lines with squamous cell (OE21, Kyse-410, hereafter referred to as ESCC) and adenocarcinoma (OE33, OE19, hereafter referred to as "BAC") differentiation and growth patterns, i.e.	('adenocarcinoma', 'Disease', 'MESH:D000230', (225, 239))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('aneuploid esophageal cancer', 'Disease', 'MESH:D004938', (115, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('aneuploid esophageal cancer', 'Disease', (115, 142))	('OE33', 'Var', (241, 245))	('adenocarcinoma', 'Disease', (225, 239))
607235	21470402	In contrast, OE33 (~30%) and markedly OE19 (~50%) and EPC-hTERT (~70%) cells had a high G0/G1-phase population, with reduced S- and G2/M-phase populations.	('OE33', 'Var', (13, 17))	('OE19', 'Var', (38, 42))	('reduced', 'NegReg', (117, 124))	('EPC-hTERT', 'CellLine', 'CVCL:4361', (54, 63))	('G0/G1-phase population', 'CPA', (88, 110))
607236	21470402	For Aurora-A (Table 1, Figure 2), fluorescence in situ hybridization (FISH) revealed chromosome 20 polysomy with concomitantly elevated Aurora-A gene copy numbers in OE21, OE33 and OE19 cells and an Aurora-A gene amplification with up to nine Aurora-A gene copies in Kyse-410 cells.	('Aurora-A', 'Gene', (243, 251))	('Aurora-A', 'Gene', '6790', (243, 251))	('Aurora-A', 'Gene', '6790', (136, 144))	('Aurora-A', 'Gene', (136, 144))	('Aurora-A', 'Gene', '6790', (199, 207))	('Aurora-A', 'Gene', '6790', (4, 12))	('Aurora-A', 'Gene', (4, 12))	('Aurora-A', 'Gene', (199, 207))	('elevated', 'PosReg', (127, 135))	('polysomy', 'Var', (99, 107))
607238	21470402	In contrast, OE21, OE33 and OE19 cells exhibited lower Aurora-A mRNA expression, despite chromosome 20 polysomy.	('OE33', 'Var', (19, 23))	('Aurora-A', 'Gene', '6790', (55, 63))	('OE19', 'Var', (28, 32))	('Aurora-A', 'Gene', (55, 63))	('lower', 'NegReg', (49, 54))	('OE21', 'Var', (13, 17))
607239	21470402	Still, high Aurora-A protein expression was seen in OE33, but not OE21 and OE19 cells.	('OE33', 'Var', (52, 56))	('Aurora-A', 'Gene', '6790', (12, 20))	('high', 'PosReg', (7, 11))	('expression', 'MPA', (29, 39))	('Aurora-A', 'Gene', (12, 20))
607242	21470402	For Aurora-B (Table 1, Figure 3), chromosome 17 polysomy and concomitantly elevated Aurora-B gene copy numbers were observed by FISH in the ESCC cell lines OE21 and Kyse-410.	('polysomy', 'Var', (48, 56))	('Aurora-B', 'Gene', (84, 92))	('elevated', 'PosReg', (75, 83))	('Aurora-B', 'Gene', '9212', (84, 92))	('chromosome 17 polysomy', 'Var', (34, 56))	('Aurora-B', 'Gene', (4, 12))	('Aurora-B', 'Gene', '9212', (4, 12))
607243	21470402	Interestingly, in the BAC cell lines OE33 and OE19 elevated chromosome 17 specific signals with lower Aurora-B gene specific signals, resulting in Aurora-B to chromosome 17 ratios below 1, were observed.	('lower', 'NegReg', (96, 101))	('chromosome 17 specific signals', 'MPA', (60, 90))	('Aurora-B', 'Gene', (147, 155))	('Aurora-B', 'Gene', (102, 110))	('elevated', 'PosReg', (51, 59))	('Aurora-B', 'Gene', '9212', (102, 110))	('Aurora-B', 'Gene', '9212', (147, 155))	('OE19', 'Var', (46, 50))
607250	21470402	Aurora-A gene amplification and protein overexpression have been linked to the occurrence of supernumerary centrosomes, formation of multipolar mitoses and aneuploidy.	('linked', 'Reg', (65, 71))	('Aurora-A', 'Gene', '6790', (0, 8))	('overexpression', 'PosReg', (40, 54))	('aneuploidy', 'Disease', (156, 166))	('Aurora-A', 'Gene', (0, 8))	('protein', 'Protein', (32, 39))	('gene amplification', 'Var', (9, 27))	('supernumerary centrosomes', 'CPA', (93, 118))	('aneuploidy', 'Disease', 'MESH:D000782', (156, 166))
607257	21470402	Aurora-A positive multipolar mitoses were most frequent in OE33 (13.8 +- 4.2%) followed by OE21 (7.7 +- 5.0%) and Kyse-410 (6.3 +- 2.0%) cells.	('multipolar mitoses', 'CPA', (18, 36))	('Aurora-A', 'Gene', '6790', (0, 8))	('Aurora-A', 'Gene', (0, 8))	('OE33', 'Var', (59, 63))	('OE21', 'Var', (91, 95))
607262	21470402	In view of the role of p53 in post-mitotic cell cycle control, centrosome duplication and Aurora-A interaction as well as its frequent mutation in esophageal carcinogenesis, we next determined p53 mutation status, p53 protein expression and intracellular localization in the control EPC-hTERT cell line and in the four esophageal cancer cell lines (Figure 5).	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (147, 172))	('esophageal carcinogenesis', 'Disease', (147, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (319, 336))	('p53', 'Gene', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('expression', 'MPA', (226, 236))	('p53', 'Gene', '7157', (193, 196))	('mutation', 'Var', (197, 205))	('p53', 'Gene', (214, 217))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('Aurora-A', 'Gene', '6790', (90, 98))	('p53', 'Gene', '7157', (214, 217))	('EPC-hTERT', 'CellLine', 'CVCL:4361', (283, 292))	('Aurora-A', 'Gene', (90, 98))	('protein', 'Protein', (218, 225))	('esophageal cancer', 'Disease', (319, 336))
607265	21470402	In contrast, all ESCC and BAC cell lines displayed p53 mutations (Figure 5A): OE21 cells exhibited p53 mutations in exon 4 (c.269C>T, c.270delC, p.S90fs31X), which introduce a stop codon at the N-terminus of the p53 core domain.	('p53', 'Gene', '7157', (212, 215))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('p.S90fs', 'Var', (145, 152))	('c.270delC', 'Mutation', 'c.270delC', (134, 143))	('c.269C>T', 'Var', (124, 132))	('c.270delC', 'Var', (134, 143))	('p.S90fs', 'FRAMESHIFT', 'None', (145, 152))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('p53', 'Gene', (212, 215))	('c.269C>T', 'Mutation', 'rs146340390', (124, 132))
607269	21470402	Kyse-410 cells displayed a point mutation in exon 10 (c.1009C>T, p.R337C) of the tetramerization domain (Figure 5A).	('p.R337C', 'Mutation', 'rs587782529', (65, 72))	('p.R337C', 'Var', (65, 72))	('c.1009C>T', 'Mutation', 'rs587782529', (54, 63))	('c.1009C>T', 'Var', (54, 63))
607271	21470402	There are conflicting reports about whether this mutated p53 protein forms tetramers, binds DNA, induces apoptosis and transactivates target genes or not.	('mutated', 'Var', (49, 56))	('binds', 'Interaction', (86, 91))	('apoptosis', 'CPA', (105, 114))	('tetramers', 'MPA', (75, 84))	('transactivates', 'Reg', (119, 133))	('p53', 'Gene', (57, 60))	('induces', 'Reg', (97, 104))	('protein', 'Protein', (61, 68))	('DNA', 'Protein', (92, 95))	('p53', 'Gene', '7157', (57, 60))
607272	21470402	It seems that p53 with this mutation is partially functional depending on the experimental conditions.	('mutation', 'Var', (28, 36))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))
607273	21470402	In our case, this mutated p53 protein was clearly detectable in immunoblot analysis (Figure 5B) and displayed a strong nuclear staining in most, but not all Kyse-410 cells by indirect immunofluorescence (Figure 5C).	('p53', 'Gene', (26, 29))	('protein', 'Protein', (30, 37))	('p53', 'Gene', '7157', (26, 29))	('mutated', 'Var', (18, 25))
607274	21470402	OE33 cells had a point mutation in exon 5 (c.404G>A, p.C135Y), which is consistent with previous reports (Figure 5A).	('p.C135Y', 'Var', (53, 60))	('p.C135Y', 'Mutation', 'rs587781991', (53, 60))	('c.404G>A', 'Var', (43, 51))	('c.404G>A', 'Mutation', 'rs587780075', (43, 51))
607275	21470402	This mutation abolishes the p53 transactivation activity as well as growth suppressive activity of the mutated protein and has a dominant negative effect on wild type p53.	('p53', 'Gene', (28, 31))	('growth suppressive activity', 'CPA', (68, 95))	('p53', 'Gene', '7157', (28, 31))	('transactivation activity', 'MPA', (32, 56))	('p53', 'Gene', '7157', (167, 170))	('abolishes', 'NegReg', (14, 23))	('p53', 'Gene', (167, 170))	('mutation', 'Var', (5, 13))
607276	21470402	Accordingly, this mutated p53 protein was still expressed and accumulated in OE33 cell nuclei, although in some cells to a weaker extent (Figure 5B, C).	('accumulated', 'PosReg', (62, 73))	('mutated', 'Var', (18, 25))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('protein', 'Protein', (30, 37))
607277	21470402	OE19 cells exhibited a mutation in exon 9 (c.928_930insA, p.N310fs26X), which is in accordance with mutation databases.	('p.N310fs', 'Var', (58, 66))	('c.928_930insA', 'Mutation', 'c.928_930insA', (43, 56))	('c.928_930insA', 'Var', (43, 56))	('p.N310fs', 'FRAMESHIFT', 'None', (58, 66))
607278	21470402	This mutation is within the flexible linker, which connects the p53 core domain with the tetramerization domain, causes a stop codon within the tetramerization domain (protein mass of truncated protein is about 40 kDa) and most likely inactivates p53 oligomerization (Figure 5A).	('causes', 'Reg', (113, 119))	('inactivates', 'NegReg', (235, 246))	('p53', 'Gene', '7157', (247, 250))	('p53', 'Gene', (64, 67))	('mutation', 'Var', (5, 13))	('p53', 'Gene', (247, 250))	('p53', 'Gene', '7157', (64, 67))
607279	21470402	However, the latter is insufficient to fully abolish p53 tumor suppressive function and p53 monomer mutants with retention of transcriptional activity have been described.	('mutants', 'Var', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('tumor', 'Disease', (57, 62))	('monomer', 'Var', (92, 99))
607280	21470402	In OE19 cells, this potentially still functional mutated p53 protein was strongly expressed as truncated protein at 40 kDa in immunoblot analysis (Figure 5B, asterisks) and clearly accumulated in OE19 cell nuclei (Figure 5C).	('mutated', 'Var', (49, 56))	('protein', 'Protein', (61, 68))	('p53', 'Gene', '7157', (57, 60))	('p53', 'Gene', (57, 60))
607281	21470402	Thus, loss of function p53 mutations may result in escape of post-mitotic G1 cell cycle control and possibly also centrosomal dysfunction in some (OE21, OE33), but not all (Kyse-410, OE19) esophageal cancer cells.	('esophageal cancer', 'Disease', (189, 206))	('mutations', 'Var', (27, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (189, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('loss of function', 'NegReg', (6, 22))	('centrosomal dysfunction', 'MPA', (114, 137))	('escape', 'PosReg', (51, 57))	('p53', 'Gene', (23, 26))	('post-mitotic G1 cell cycle control', 'CPA', (61, 95))	('p53', 'Gene', '7157', (23, 26))
607282	21470402	This study addressed Aurora kinases A and B, p53 mutations and occurrence of multipolar mitoses in aneuploid esophageal squamous cell carcinoma (ESCC) and Barrett's adenocarcinoma (BAC) cell lines (for data summary refer to Table 3).	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('mutations', 'Var', (49, 58))	("Barrett's adenocarcinoma", 'Disease', 'MESH:D001471', (155, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('aneuploid esophageal squamous cell carcinoma', 'Disease', (99, 143))	('Aurora kinases A and B', 'Gene', '6790;9212', (21, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('aneuploid esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (99, 143))	("Barrett's adenocarcinoma", 'Disease', (155, 179))
607283	21470402	Amplification of 20q13 and/or Aurora-A has been reported to occur frequently in human esophageal carcinomas by extract-based methods, such as (array-based) comparative genomic hybridization.	('Amplification', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('Aurora-A', 'Gene', '6790', (30, 38))	('Aurora-A', 'Gene', (30, 38))	('esophageal carcinomas', 'Disease', (86, 107))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (86, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('human', 'Species', '9606', (80, 85))	('20q13', 'Gene', (17, 22))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (86, 107))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (86, 107))
607285	21470402	A clear-cut Aurora-A gene amplification was only seen in Kyse-410 cells, as described before, whilst all other investigated cell lines had increased Aurora-A gene copy numbers due to chromosome 20 polysomy.	('increased', 'PosReg', (139, 148))	('polysomy', 'Var', (197, 205))	('Aurora-A', 'Gene', '6790', (12, 20))	('Aurora-A', 'Gene', '6790', (149, 157))	('Aurora-A', 'Gene', (12, 20))	('Aurora-A', 'Gene', (149, 157))
607290	21470402	In contrast to Aurora-A, there was a more close association between Aurora-B gene copy numbers and Aurora-B mRNA and protein expression in the ESCC and BAC cell lines.	('copy numbers', 'Var', (82, 94))	('Aurora-B', 'Gene', (68, 76))	('Aurora-B', 'Gene', (99, 107))	('Aurora-B', 'Gene', '9212', (68, 76))	('Aurora-A', 'Gene', (15, 23))	('Aurora-B', 'Gene', '9212', (99, 107))	('Aurora-A', 'Gene', '6790', (15, 23))
607291	21470402	Both ESCC cell lines (OE21, Kyse-410) had elevated Aurora-B gene copy numbers due to chromosome 17 polysomy and concomitant high Aurora-B expression, but not activation (phosphorylation at T232).	('Aurora-B', 'Gene', '9212', (51, 59))	('chromosome 17 polysomy', 'Var', (85, 107))	('Aurora-B', 'Gene', (129, 137))	('expression', 'MPA', (138, 148))	('Aurora-B', 'Gene', '9212', (129, 137))	('high', 'PosReg', (124, 128))	('Aurora-B', 'Gene', (51, 59))	('elevated', 'PosReg', (42, 50))	('polysomy', 'Var', (99, 107))
607296	21470402	The apparently "reduced" Aurora-B gene copy numbers in BAC cells may be due to a partial deletion, loss of the short arm of chromosome 17 or even duplication of centromere 17 alone.	('Aurora-B', 'Gene', '9212', (25, 33))	('copy numbers', 'MPA', (39, 51))	('Aurora-B', 'Gene', (25, 33))	('short arm of chromosome 17', 'Protein', (111, 137))	('loss', 'NegReg', (99, 103))	('duplication', 'Var', (146, 157))	('short arm', 'Phenotype', 'HP:0009824', (111, 120))
607297	21470402	It will be of interest for future studies to investigate potentially deregulated chromosome integrity, for example by telomere alterations or breakage-fusion-bridge cycles, during mitosis of BAC cells.	('deregulated', 'NegReg', (69, 80))	('mitosis', 'Disease', (180, 187))	('telomere alterations', 'CPA', (118, 138))	('breakage-fusion-bridge', 'Var', (142, 164))	('mitosis', 'Disease', 'None', (180, 187))	('chromosome integrity', 'CPA', (81, 101))
607298	21470402	Irrespective of this, the present results allow further insights into the direct association of high Aurora-A expression with supernumerary centrosomes and the associated occurrence of multipolar mitoses and aneuploidy described in other model systems now also for aneuploid esophageal cancer cells.	('aneuploid esophageal cancer', 'Disease', 'MESH:D004938', (265, 292))	('aneuploidy', 'Disease', (208, 218))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('aneuploid esophageal cancer', 'Disease', (265, 292))	('high', 'Var', (96, 100))	('expression', 'MPA', (110, 120))	('multipolar mitoses', 'CPA', (185, 203))	('Aurora-A', 'Gene', '6790', (101, 109))	('aneuploidy', 'Disease', 'MESH:D000782', (208, 218))	('Aurora-A', 'Gene', (101, 109))
607301	21470402	Thus, other factors are required to sustain cycling of multipolar mitotic esophageal cancer cells in order to allow development and maintenance of individual aneuploid ESCC and BAC cell clones.	('multipolar mitotic esophageal cancer', 'Disease', 'MESH:D004938', (55, 91))	('ESCC', 'Gene', (168, 172))	('aneuploid', 'Var', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('multipolar mitotic esophageal cancer', 'Disease', (55, 91))
607302	21470402	Since up to 80% of ESCC and 90% of BAC display mutations of p53, this tumor suppressor protein is a very likely contributing factor, particularly in view of its role in G1 cell cycle and DNA damage control, its centrosomal function as well as its inactivation and/or degradation upon interaction with Aurora-A.	('Aurora-A', 'Gene', '6790', (301, 309))	('ESCC', 'Disease', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Aurora-A', 'Gene', (301, 309))	('tumor', 'Disease', (70, 75))	('centrosomal', 'MPA', (211, 222))	('mutations', 'Var', (47, 56))	('p53', 'Gene', (60, 63))	('degradation', 'MPA', (267, 278))	('inactivation', 'MPA', (247, 259))	('p53', 'Gene', '7157', (60, 63))	('interaction', 'Interaction', (284, 295))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
607304	21470402	In the present study, p53 mutations were found in the four representative esophageal cancer cell lines, but in different domains and therefore with different consequences for protein expression and/or function.	('p53', 'Gene', (22, 25))	('mutations', 'Var', (26, 35))	('function', 'MPA', (201, 209))	('p53', 'Gene', '7157', (22, 25))	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
607305	21470402	None of the p53 mutations detected corresponded to known p53 gain of function mutations.	('gain of function', 'PosReg', (61, 77))	('mutations', 'Var', (16, 25))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (57, 60))	('p53', 'Gene', '7157', (57, 60))
607306	21470402	Instead, OE21 cells had p53 mutations (exon 4; c.269C>T, c.270delC, p.S90fs31X), which caused weak expression of a presumably non-functional, largely truncated (about 14 kDa) p53 protein.	('expression', 'MPA', (99, 109))	('protein', 'Protein', (179, 186))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('c.270delC', 'Mutation', 'c.270delC', (57, 66))	('p.S90fs', 'FRAMESHIFT', 'None', (68, 75))	('c.270delC', 'Var', (57, 66))	('c.269C>T', 'Mutation', 'rs146340390', (47, 55))	('non-functional', 'MPA', (126, 140))	('p53', 'Gene', (175, 178))	('mutations', 'Var', (28, 37))	('p.S90fs', 'Var', (68, 75))	('p53', 'Gene', '7157', (175, 178))
607307	21470402	Also OE33 cells had a p53 mutation (exon 5; c.404G>A, p.C135Y) resulting in a non-functional, nuclear accumulated p53 protein, lacking transactivation and growth suppressive activity.	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('c.404G>A', 'Var', (44, 52))	('lacking', 'NegReg', (127, 134))	('p.C135Y', 'Mutation', 'rs587781991', (54, 61))	('p53', 'Gene', (22, 25))	('transactivation', 'MPA', (135, 150))	('c.404G>A', 'Mutation', 'rs587780075', (44, 52))	('p53', 'Gene', '7157', (22, 25))	('non-functional', 'MPA', (78, 92))	('nuclear accumulated', 'MPA', (94, 113))
607308	21470402	In contrast, Kyse-410 cells had a cell culture acquired p53 mutation (exon 10; c.1009C>T, p.R337C), resulting in expression and nuclear accumulation of an at least partially functional p53 protein.	('expression', 'MPA', (113, 123))	('p53', 'Gene', (185, 188))	('p53', 'Gene', '7157', (185, 188))	('nuclear accumulation', 'MPA', (128, 148))	('protein', 'Protein', (189, 196))	('p53', 'Gene', (56, 59))	('c.1009C>T', 'Mutation', 'rs587782529', (79, 88))	('p.R337C', 'Mutation', 'rs587782529', (90, 97))	('p53', 'Gene', '7157', (56, 59))	('p.R337C', 'Var', (90, 97))	('c.1009C>T', 'Var', (79, 88))
607309	21470402	Similarly, the p53 mutation confirmed in OE19 cells (exon 9; c.928_930insA, p.N310fs26X), may cause expression of a truncated (about 40 kDa), but still partially functional p53 protein with lost oligomerization activity.	('about', 'Var', (127, 132))	('oligomerization activity', 'MPA', (195, 219))	('p53', 'Gene', (173, 176))	('truncated', 'MPA', (116, 125))	('functional', 'MPA', (162, 172))	('p53', 'Gene', '7157', (173, 176))	('p53', 'Gene', (15, 18))	('expression', 'MPA', (100, 110))	('p53', 'Gene', '7157', (15, 18))	('protein', 'Protein', (177, 184))	('p.N310fs', 'Var', (76, 84))	('c.928_930insA', 'Mutation', 'c.928_930insA', (61, 74))	('cause', 'Reg', (94, 99))	('p.N310fs', 'FRAMESHIFT', 'None', (76, 84))
607310	21470402	Thus, esophageal cancer cells with both high Aurora-A expression and p53 loss of function mutations have a high occurrence of multipolar mitoses (e.g.	('esophageal cancer', 'Disease', (6, 23))	('mutations', 'Var', (90, 99))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (6, 23))	('loss of function', 'NegReg', (73, 89))	('Aurora-A', 'Gene', '6790', (45, 53))	('Aurora-A', 'Gene', (45, 53))	('multipolar mitoses', 'MPA', (126, 144))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
607315	21470402	In summary, high Aurora-A expression together with p53 mutations may contribute to aneuploid esophageal cancer cells via supernumerary centrosomes and associated occurrence of multipolar mitoses.	('expression', 'MPA', (26, 36))	('multipolar mitoses', 'CPA', (176, 194))	('p53', 'Gene', (51, 54))	('high', 'PosReg', (12, 16))	('p53', 'Gene', '7157', (51, 54))	('aneuploid esophageal cancer', 'Disease', 'MESH:D004938', (83, 110))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Aurora-A', 'Gene', '6790', (17, 25))	('aneuploid esophageal cancer', 'Disease', (83, 110))	('Aurora-A', 'Gene', (17, 25))	('occurrence', 'Reg', (162, 172))	('supernumerary centrosomes', 'CPA', (121, 146))	('contribute', 'Reg', (69, 79))
607318	21470402	The study included as control a normal esophageal epithelial cell line (EPC-hTERT cells) as well as four esophageal cancer cell lines (OE21, Kyse-410, OE33, OE19).	('EPC-hTERT', 'CellLine', 'CVCL:4361', (72, 81))	('OE33', 'Var', (151, 155))	('esophageal cancer', 'Disease', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))
607342	21470402	Note that the p53 antibody used was raised against the N-terminal domain (amino acids 1-45), recognizing also mutated and expressed (also truncated) p53 proteins.	('p53', 'Gene', (149, 152))	('p53', 'Gene', (14, 17))	('mutated', 'Var', (110, 117))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', '7157', (149, 152))	('proteins', 'Protein', (153, 161))
607354	21470402	The p53 sequence of the GenBank database with accession number NC_000017.9 NC_000017:c7531642-7512445 was used as reference.	('p53', 'Gene', '7157', (4, 7))	('p53', 'Gene', (4, 7))	('c7531642-7512445', 'Var', (85, 101))
607372	33714262	The rate of lymph node metastasis in the N110 group was 9 +- 12.45%, and the average intraoperative blood loss was 170 +- 57.47 mL.	('lymph node metastasis', 'CPA', (12, 33))	('intraoperative blood loss', 'Disease', (85, 110))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (85, 110))	('N110', 'Chemical', '-', (41, 45))	('N110', 'Var', (41, 45))
607399	33714262	The lymph node metastasis rate of the N110 group was 9 +- 12.45%.	('N110', 'Var', (38, 42))	('lymph node metastasis rate', 'CPA', (4, 30))	('N110', 'Chemical', '-', (38, 42))
607412	33714262	In the Japanese multicenter prospective study, mediastinal lymph node metastasis of Siewert II AEG was mainly below the mediastinum; N110 lymph node metastasis was a common occurrence, with a metastasis rate of 9.0%.	('mediastinal lymph', 'Disease', (47, 64))	('N110', 'Var', (133, 137))	('AEG', 'Chemical', '-', (95, 98))	('N110', 'Chemical', '-', (133, 137))
607471	33167521	Moreover, polymorphisms in the leptin receptor (ObR) gene have been reported to be related to NAFLD.	('leptin receptor', 'Gene', (31, 46))	('leptin receptor', 'Gene', '3953', (31, 46))	('ObR', 'Gene', (48, 51))	('polymorphisms', 'Var', (10, 23))	('NAFLD', 'Disease', (94, 99))	('related', 'Reg', (83, 90))
607474	33167521	Adiponectin levels are reduced in individuals with NAFLD and are inversely related to the severity of steatosis, necroinflammation, and fibrosis.	('NAFLD', 'Var', (51, 56))	('inflammation', 'Disease', 'MESH:D007249', (118, 130))	('steatosis', 'Disease', 'MESH:D005234', (102, 111))	('fibrosis', 'Disease', 'MESH:D005355', (136, 144))	('fibrosis', 'Disease', (136, 144))	('inflammation', 'Disease', (118, 130))	('reduced', 'NegReg', (23, 30))	('Adiponectin levels', 'MPA', (0, 18))	('steatosis', 'Phenotype', 'HP:0001397', (102, 111))	('steatosis', 'Disease', (102, 111))
607478	33167521	Comprehensive crosstalk between adiponectin and its cognate receptors, specifically AdipoR2, in the liver attenuates hepatic lipoinflammation by interacting with hepatic PPARs.	('hepatic', 'MPA', (162, 169))	('AdipoR2', 'Gene', (84, 91))	('liver attenuates hepatic lipoinflammation', 'Disease', (100, 141))	('AdipoR2', 'Gene', '79602', (84, 91))	('liver attenuates hepatic lipoinflammation', 'Disease', 'MESH:D017093', (100, 141))	('crosstalk', 'Var', (14, 23))	('interacting', 'Interaction', (145, 156))
607479	33167521	In addition, adiponectin protects hepatocytes from tumor necrosis factor-alpha (TNF-alpha)-induced death; specifically, adiponectin is a potent TNF-alpha-neutralizing adipokine.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('tumor necrosis factor-alpha', 'Gene', '7124', (51, 78))	('tumor necrosis factor-alpha', 'Gene', (51, 78))	('adiponectin', 'Var', (120, 131))
607481	33167521	Furthermore, the single-nucleotide polymorphism (SNP) rs1501299 in the adiponectin gene might be related to increased NAFLD susceptibility.	('rs1501299', 'Mutation', 'rs1501299', (54, 63))	('increased', 'PosReg', (108, 117))	('adiponectin', 'Gene', (71, 82))	('rs1501299', 'Var', (54, 63))	('NAFLD', 'Disease', (118, 123))	('single-nucleotide polymorphism', 'Var', (17, 47))
607488	33167521	While viral suppression can be achieved in the majority of patients with the high-barrier-to-resistance new-generation of Nuc, HBsAg loss is achieved by PegIFN-alpha and/or Nuc in only 10% of patients after a 5-year follow-up.	('patients', 'Species', '9606', (192, 200))	('HBsAg loss', 'Disease', (127, 137))	('rat', 'Species', '10116', (112, 115))	('HBsAg loss', 'Disease', 'MESH:D014786', (127, 137))	('PegIFN-alpha', 'Chemical', '-', (153, 165))	('patients', 'Species', '9606', (59, 67))	('high-barrier-to-resistance', 'Var', (77, 103))
607493	33167521	In HepG2-HBV-stable cells, HBV replication was found to be upregulated by adiponectin and downregulated by adiponectin-targeting small interfering RNAs.	('HBV', 'Gene', (27, 30))	('HBV', 'Species', '10407', (27, 30))	('adiponectin', 'MPA', (74, 85))	('upregulated', 'PosReg', (59, 70))	('HepG2-HBV', 'CellLine', 'CVCL:0027', (3, 12))	('downregulated', 'NegReg', (90, 103))	('small interfering RNAs', 'Var', (129, 151))	('HBV', 'Species', '10407', (9, 12))
607495	33167521	Particularly in overweight and obese HBV-infected patients, a high HBV load was found to be positively associated with serum adiponectin levels.	('overweight', 'Phenotype', 'HP:0025502', (16, 26))	('obese HBV-infected', 'Disease', (31, 49))	('HBV', 'Species', '10407', (37, 40))	('patients', 'Species', '9606', (50, 58))	('obese HBV-infected', 'Disease', 'MESH:D009765', (31, 49))	('serum adiponectin levels', 'MPA', (119, 143))	('HBV', 'Gene', (67, 70))	('high', 'Var', (62, 66))	('HBV', 'Species', '10407', (67, 70))
607507	33167521	Hepatitis C virus (HCV), a human pathogen responsible for acute and chronic liver disease, has variants classified into eight genotypes and chronically infects an estimated 71.1 million individuals worldwide.	('Hepatitis C virus', 'Disease', (0, 17))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('Hepatitis C virus', 'Species', '11103', (0, 17))	('infects', 'Reg', (152, 159))	('liver disease', 'Phenotype', 'HP:0001392', (76, 89))	('liver disease', 'Disease', (76, 89))	('human', 'Species', '9606', (27, 32))	('liver disease', 'Disease', 'MESH:D008107', (76, 89))	('HCV', 'Species', '11103', (19, 22))	('variants', 'Var', (95, 103))
607515	33167521	Regarding genotype-specific characteristics, the connection between steatosis and leptin in patients infected with genotype (G) 1 or G2 HCV has been reported.	('HCV', 'Species', '11103', (136, 139))	('genotype', 'Var', (115, 123))	('steatosis', 'Disease', (68, 77))	('leptin', 'MPA', (82, 88))	('steatosis', 'Disease', 'MESH:D005234', (68, 77))	('patients', 'Species', '9606', (92, 100))	('infected', 'Disease', 'MESH:D007239', (101, 109))	('steatosis', 'Phenotype', 'HP:0001397', (68, 77))	('connection', 'Reg', (49, 59))	('infected', 'Disease', (101, 109))
607538	33167521	However, high serum levels of adiponectin were associated with higher all-cause, liver-unrelated, and liver-related mortality.	('serum levels', 'MPA', (14, 26))	('adiponectin', 'Protein', (30, 41))	('mortality', 'Disease', 'MESH:D003643', (116, 125))	('liver-related', 'Disease', (102, 115))	('mortality', 'Disease', (116, 125))	('all-cause', 'CPA', (70, 79))	('high serum levels of adiponectin', 'Phenotype', 'HP:0030686', (9, 41))	('liver-unrelated', 'Disease', (81, 96))	('higher', 'PosReg', (63, 69))	('high', 'Var', (9, 13))
607584	33167521	In addition, a study of cirrhosis and control patients showed that transplant-free survival was significantly lower among patients with alcoholic liver disease and adiponectin >=17 mug/mL.	('adiponectin', 'Protein', (164, 175))	('patients', 'Species', '9606', (46, 54))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (136, 159))	('liver disease', 'Phenotype', 'HP:0001392', (146, 159))	('alcoholic liver disease', 'Disease', (136, 159))	('cirrhosis', 'Phenotype', 'HP:0001394', (24, 33))	('transplant-free survival', 'CPA', (67, 91))	('lower', 'NegReg', (110, 115))	('cirrhosis', 'Disease', 'MESH:D005355', (24, 33))	('>=17 mug/mL', 'Var', (176, 187))	('patients', 'Species', '9606', (122, 130))	('cirrhosis', 'Disease', (24, 33))
607586	33167521	Emerging evidence has revealed that dysregulated adiponectin-fibroblast growth factor (FGF) 15 (human homolog, FGF19) axis and impaired hepatic adiponectin-FGF15/19 signaling are associated with alcoholic liver damage in rodents and humans.	('associated', 'Reg', (179, 189))	('human', 'Species', '9606', (233, 238))	('hepatic adiponectin-FGF15/19 signaling', 'MPA', (136, 174))	('human', 'Species', '9606', (96, 101))	('FGF19', 'Gene', '9965', (111, 116))	('ob', 'Gene', '16846', (65, 67))	('dysregulated', 'Var', (36, 48))	('alcoholic liver damage', 'Disease', (195, 217))	('FGF19', 'Gene', (111, 116))	('impaired', 'NegReg', (127, 135))	('humans', 'Species', '9606', (233, 239))	('alcoholic liver damage', 'Disease', 'MESH:D008108', (195, 217))
607606	33167521	By stimulating adipogenesis, opposing inflammation, and influencing rates of lipid oxidation and lipolysis, adiponectin critically governs lipid spillover into nonadipose tissues.	('lipolysis', 'MPA', (97, 106))	('adipose', 'Gene', '230796', (163, 170))	('adipose', 'Gene', (163, 170))	('stimulating', 'Reg', (3, 14))	('governs', 'Reg', (131, 138))	('adipogenesis', 'MPA', (15, 27))	('influencing', 'Reg', (56, 67))	('rat', 'Species', '10116', (68, 71))	('inflammation', 'Disease', 'MESH:D007249', (38, 50))	('lipid oxidation', 'MPA', (77, 92))	('lipid', 'Chemical', 'MESH:D008055', (139, 144))	('lipid', 'Chemical', 'MESH:D008055', (77, 82))	('inflammation', 'Disease', (38, 50))	('adiponectin', 'Var', (108, 119))
607622	33167521	High levels of LMW adiponectin are associated with a decreased risk of Barrett's esophagus among patients with GERD.	('LMW', 'Var', (15, 18))	("Barrett's esophagus", 'Disease', (71, 90))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (71, 90))	('GERD', 'Disease', (111, 115))	('GERD', 'Disease', 'MESH:D005764', (111, 115))	('decreased', 'NegReg', (53, 62))	('adiponectin', 'Protein', (19, 30))	('patients', 'Species', '9606', (97, 105))
607652	33167521	Adiponectin expression was significantly suppressed by induction of colitis, and intracolonic silencing of adipoR1 in mice exacerbated TNBS-induced colitis.	('silencing', 'Var', (94, 103))	('Adiponectin expression', 'MPA', (0, 22))	('colitis', 'Phenotype', 'HP:0002583', (68, 75))	('adipoR1', 'Gene', (107, 114))	('colitis', 'Disease', 'MESH:D003092', (148, 155))	('colonic', 'Disease', 'MESH:D003110', (86, 93))	('suppressed', 'NegReg', (41, 51))	('colonic', 'Disease', (86, 93))	('colitis', 'Disease', (148, 155))	('TNBS', 'Chemical', '-', (135, 139))	('colitis', 'Disease', 'MESH:D003092', (68, 75))	('exacerbated', 'PosReg', (123, 134))	('mice', 'Species', '10090', (118, 122))	('colitis', 'Phenotype', 'HP:0002583', (148, 155))	('adipoR1', 'Gene', '72674', (107, 114))	('colitis', 'Disease', (68, 75))
607665	33167521	Intriguingly, high leptin expression was an indicator of favorable tumor features and better survival in CRC patients.	('expression', 'MPA', (26, 36))	('leptin', 'Protein', (19, 25))	('patients', 'Species', '9606', (109, 117))	('CRC', 'Disease', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('high leptin', 'Phenotype', 'HP:0031793', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('high', 'Var', (14, 18))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('tumor', 'Disease', (67, 72))
607694	33167521	The rs12733285C/T genotype and the A allele of rs1342387 (A/G or A/A) of ADIPOR1 are protective factors for CRC, while the rs266729G/C genotype and the G allele of ADIPOQ are risk factors for colon cancer.	('rs266729', 'Mutation', 'rs266729', (123, 131))	('ADIPOQ', 'Gene', '9370', (164, 170))	('colon cancer', 'Phenotype', 'HP:0003003', (192, 204))	('ADIPOQ', 'Gene', (164, 170))	('rs266729G/C', 'Var', (123, 134))	('rs12733285', 'Mutation', 'rs12733285', (4, 14))	('ADIPOR1', 'Gene', '51094', (73, 80))	('rs12733285C/T', 'Var', (4, 17))	('colon cancer', 'Disease', 'MESH:D015179', (192, 204))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('ADIPOR1', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colon cancer', 'Disease', (192, 204))	('CRC', 'Disease', (108, 111))	('rs1342387', 'Mutation', 'rs1342387', (47, 56))
607702	33167521	In addition, the resistin C-420G and G+299A polymorphisms have potential roles in the genetic predisposition to colon cancer.	('roles', 'Reg', (73, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('resistin', 'Gene', (17, 25))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('resistin', 'Gene', '56729', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('G+299A', 'Mutation', 'rs3745367', (37, 43))	('G+299A', 'Var', (37, 43))	('colon cancer', 'Disease', (112, 124))	('C-420G', 'Var', (26, 32))	('C-420G', 'Mutation', 'rs1862513', (26, 32))
607711	33167521	High levels of adiponectin were found in BDL rats, reflecting the antifibrotic role of adiponectin, as adiponectin overexpression in activated HSCs was found to reduce the proliferation but augment the apoptosis of HSCs.	('adiponectin', 'Var', (103, 114))	('proliferation', 'CPA', (172, 185))	('rats', 'Species', '10116', (45, 49))	('High levels of adiponectin', 'Phenotype', 'HP:0030686', (0, 26))	('men', 'Species', '9606', (193, 196))	('reduce', 'NegReg', (161, 167))	('apoptosis', 'CPA', (202, 211))	('rat', 'Species', '10116', (179, 182))	('augment', 'NegReg', (190, 197))	('rat', 'Species', '10116', (45, 48))
607714	33167521	Obesity, diabetes, and hyperlipidemia are known risk factors for the development of gallstones, and there is convincing evidence that excess body weight is associated with an increased risk for gallbladder cancer.	('gallstones', 'Disease', 'MESH:D042882', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('gallstone', 'Phenotype', 'HP:0001081', (84, 93))	('hyperlipidemia', 'Phenotype', 'HP:0003077', (23, 37))	('men', 'Species', '9606', (76, 79))	('diabetes', 'Disease', (9, 17))	('gallbladder cancer', 'Disease', (194, 212))	('hyperlipidemia', 'Disease', 'MESH:D006949', (23, 37))	('excess body', 'Var', (134, 145))	('gallbladder cancer', 'Disease', 'MESH:D005706', (194, 212))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('associated', 'Reg', (156, 166))	('excess body weight', 'Phenotype', 'HP:0004324', (134, 152))	('diabetes', 'Disease', 'MESH:D003920', (9, 17))	('hyperlipidemia', 'Disease', (23, 37))	('gallstones', 'Disease', (84, 94))	('gallstones', 'Phenotype', 'HP:0001081', (84, 94))
607723	33167521	A large body of evidence demonstrates that high BMI, as an approximation for general adiposity, is a risk factor for the development of gallbladder cancers.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('rat', 'Species', '10116', (32, 35))	('men', 'Species', '9606', (128, 131))	('high BMI', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gallbladder cancers', 'Disease', (136, 155))	('gallbladder cancers', 'Disease', 'MESH:D005706', (136, 155))
607754	31646714	The incidence of >=grade 3 neutropenia and febrile neutropenia (FN) reached 66.6% and 22.9%, respectively.9 Thus, although DCF has a highly promising antitumor activity, it has a very high risk of severe neutropenia or FN, which is a safety concern as preoperative treatment.	('neutropenia', 'Disease', (51, 62))	('neutropenia', 'Disease', (204, 215))	('neutropenia', 'Disease', 'MESH:D009503', (27, 38))	('neutropenia and febrile neutropenia', 'Disease', 'MESH:D009503', (27, 62))	('neutropenia', 'Disease', 'MESH:D009503', (51, 62))	('neutropenia', 'Phenotype', 'HP:0001875', (27, 38))	('neutropenia', 'Disease', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('neutropenia', 'Phenotype', 'HP:0001875', (51, 62))	('neutropenia', 'Disease', 'MESH:D009503', (204, 215))	('DCF', 'Var', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('neutropenia', 'Phenotype', 'HP:0001875', (204, 215))	('DCF', 'Chemical', '-', (123, 126))	('tumor', 'Disease', (154, 159))
607828	31646714	However, it should be taken into account that giving pegfilgrastim may have attenuated the antitumor effects of DCF therapy.	('attenuated', 'NegReg', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('pegfilgrastim', 'Var', (53, 66))	('DCF', 'Chemical', '-', (112, 115))	('tumor', 'Disease', (95, 100))
607888	23185410	OCT4 was found to be an independent predictive factor for median survival time, and the patients from the subgroup with both high expression of OCT4 and Survivin had the worst prognosis investigated by log-rank test.	('Survivin', 'Protein', (153, 161))	('OCT4', 'Gene', (144, 148))	('high expression', 'Var', (125, 140))	('patients', 'Species', '9606', (88, 96))
607889	23185410	By Western blotting and RT-PCR, we found that OCT4 could up-regulate Survivin expression in the esophageal cancer cell lines Eca109 and TE1.	('expression', 'MPA', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('OCT4', 'Var', (46, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('Survivin', 'Protein', (69, 77))	('up-regulate', 'PosReg', (57, 68))
607890	23185410	Simultaneously knockdown of OCT4 and Survivin expression induced cell apoptosis and G2-phase decrease of cell cycle by flow cytometry, and finally exerted an enhanced anti-proliferation potency in Eca109 and TE1 cell lines by MTT assay.	('OCT4', 'Gene', (28, 32))	('knockdown', 'Var', (15, 24))	('G2-phase decrease of cell cycle', 'Phenotype', 'HP:0003214', (84, 115))	('enhanced', 'PosReg', (158, 166))	('G2-phase decrease', 'CPA', (84, 101))	('anti-proliferation potency', 'CPA', (167, 193))	('Survivin expression', 'Gene', (37, 56))	('cell apoptosis', 'CPA', (65, 79))	('MTT', 'Chemical', 'MESH:C022616', (226, 229))	('cell cycle', 'CPA', (105, 115))
607903	23185410	Previous study demonstrated that knockdown of Survivin expression in a number of human cancer cell lines, such as A549, HeLa and MCF-7 cells, resulted in a significant reduction of cell viability, and combination of Survivin-directed silencing strategy with chemotherapeutic agents constituted a valuable approach for cancer treatment with an enhanced antitumor efficacy.	('enhanced', 'PosReg', (343, 351))	('cancer', 'Disease', (318, 324))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('silencing', 'NegReg', (234, 243))	('Survivin', 'Gene', (46, 54))	('human', 'Species', '9606', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('HeLa', 'CellLine', 'CVCL:0030', (120, 124))	('cell viability', 'CPA', (181, 195))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('knockdown', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MCF-7', 'CellLine', 'CVCL:0031', (129, 134))	('tumor', 'Disease', (356, 361))	('reduction', 'NegReg', (168, 177))	('men', 'Species', '9606', (330, 333))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
607907	23185410	Recently, it was reported that Survivin expression was dramatically decreased in OCT4 knockdown murine embryonic stem cells, suggesting that there is a relationship between OCT4 and Survivin.	('expression', 'MPA', (40, 50))	('decreased', 'NegReg', (68, 77))	('knockdown', 'Var', (86, 95))	('Survivin', 'Protein', (31, 39))	('OCT4', 'Gene', (81, 85))	('murine', 'Species', '10090', (96, 102))
607913	23185410	The median survival of ESCC patients with OCT4 positive expression was significantly less than that of patients with OCT4 negative expression (p<0.001).	('ESCC', 'Disease', (23, 27))	('less', 'NegReg', (85, 89))	('OCT4 positive expression', 'Var', (42, 66))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (28, 36))
607914	23185410	Among the three subgroups (OCT4-positive/Survivin-positive, OCT4-negative/Survivin-positive, OCT4-negative/Survivin-negative), patients with OCT4-positive/Survivin-positive ESCC had a significantly poorest prognosis (p<0.001), and the longest OS was documented in OCT4-negative/Survivin-negative subgroup (Fig.	('men', 'Species', '9606', (254, 257))	('ESCC', 'Disease', (173, 177))	('OCT4-positive/Survivin-positive', 'Var', (141, 172))	('patients', 'Species', '9606', (127, 135))	('poorest', 'NegReg', (198, 205))
607918	23185410	To indentify whether the specific small hairpin RNA (shRNA) targeting OCT4 (OCT4-shRNA), Survivin (Sur-shRNA), or double shRNAs (Dual-shRNA) targeting both OCT4 and Survivin, influenced esophageal cancer cell proliferation, MTT assay was performed to detect cell viability.	('Sur', 'Gene', '6833', (165, 168))	('Sur', 'Gene', (99, 102))	('double shRNAs', 'Var', (114, 127))	('OCT4', 'Gene', (70, 74))	('Sur', 'Gene', (165, 168))	('influenced', 'Reg', (175, 185))	('esophageal cancer', 'Disease', (186, 203))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('Sur', 'Gene', '6833', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Sur', 'Gene', '6833', (89, 92))	('MTT', 'Chemical', 'MESH:C022616', (224, 227))	('Sur', 'Gene', (89, 92))
607919	23185410	Cell viability was obviously decreased in the Eca109 and TE1 cells transfected with OCT4-shRNA and Sur-shRNA when compared with the parental or Ctr-shRNA transfected cells.	('Ctr', 'Gene', (144, 147))	('OCT4-shRNA', 'Var', (84, 94))	('Sur', 'Gene', (99, 102))	('Cell viability', 'CPA', (0, 14))	('decreased', 'NegReg', (29, 38))	('Sur', 'Gene', '6833', (99, 102))	('Ctr', 'Gene', '799', (144, 147))
607923	23185410	Compared with the parental and Ctr-shRNA groups, the percentages of G2-phase cells were significantly reduced in the OCT4-shRNA, Sur-shRNA and Dual-shRNA transfected groups, but there were no significantly differences for the G1 and S phase cells (Fig.	('Sur', 'Gene', (129, 132))	('Ctr', 'Gene', '799', (31, 34))	('Ctr', 'Gene', (31, 34))	('G2-phase cells', 'CPA', (68, 82))	('OCT4-shRNA', 'Var', (117, 127))	('Sur', 'Gene', '6833', (129, 132))	('reduced', 'NegReg', (102, 109))	('transfected', 'Var', (154, 165))
607932	23185410	The function of OCT4 could modulate a series of signal pathways, such as the Wnt/beta-catenin, TGF-beta, JAK/STAT3 signal pathways, to activate or restrain the downstream target genes.	('beta-catenin', 'Gene', '1499', (81, 93))	('TGF-beta', 'Gene', '7040', (95, 103))	('JAK/STAT3 signal pathways', 'Pathway', (105, 130))	('TGF-beta', 'Gene', (95, 103))	('activate', 'PosReg', (135, 143))	('OCT4', 'Gene', (16, 20))	('function', 'Var', (4, 12))	('signal pathways', 'Pathway', (48, 63))	('beta-catenin', 'Gene', (81, 93))	('modulate', 'Reg', (27, 35))	('restrain', 'NegReg', (147, 155))
607936	23185410	Drugs of LY2183108 and YM155 targeting Survivin were put into use in clinical trials in different stages and the effect was promising.	('LY2183108', 'Var', (9, 18))	('YM155', 'Chemical', 'MESH:C523798', (23, 28))	('YM155', 'Var', (23, 28))	('Survivin', 'Protein', (39, 47))	('LY2183108', 'Chemical', '-', (9, 18))
607937	23185410	Although tumor growth speed was slowed down on the strength of silencing Survivin, tumors still possess the ability of development and expansion and deprive of patients' life, suggesting that Survivin was not a single factor for prognosis.	('men', 'Species', '9606', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('patients', 'Species', '9606', (160, 168))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('deprive', 'NegReg', (149, 156))	('development', 'CPA', (119, 130))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('expansion', 'CPA', (135, 144))	('tumors', 'Disease', (83, 89))	('silencing', 'Var', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Survivin', 'Gene', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('slowed down', 'NegReg', (32, 43))
607939	23185410	Patients with OCT4-positive or Survivin-positive tumors presented much poorer prognosis than those with OCT4-negative or Survivin-negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (139, 145))	('Survivin-positive', 'Protein', (31, 48))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('poorer', 'NegReg', (71, 77))	('OCT4-positive', 'Var', (14, 27))
607987	22026449	Clear documented examples of clonal expansion demonstrate that there is interaction and competition between heterogeneous clones within a neoplasm and those clones may displace normal cells in a tissue.	('neoplasm', 'Disease', (138, 146))	('interaction', 'Interaction', (72, 83))	('neoplasm', 'Disease', 'MESH:D009369', (138, 146))	('neoplasm', 'Phenotype', 'HP:0002664', (138, 146))	('rat', 'Species', '10116', (53, 56))	('displace', 'NegReg', (168, 176))	('clones', 'Var', (157, 163))
607990	22026449	More recent studies of cell competition in cancer have found that cells containing a mutant tumor suppressor lgl or a mutant lgl-binding protein, mahj, can be competitively eliminated.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', (92, 97))	('mutant', 'Var', (85, 91))	('lgl', 'Gene', (109, 112))
607991	22026449	Indirect measures from human neoplasms suggest that oncogenic mutations may only increase clone relative fitness by 0.5% in clonal competition.	('neoplasms', 'Phenotype', 'HP:0002664', (29, 38))	('neoplasms', 'Disease', (29, 38))	('neoplasm', 'Phenotype', 'HP:0002664', (29, 37))	('neoplasms', 'Disease', 'MESH:D009369', (29, 38))	('human', 'Species', '9606', (23, 28))	('increase', 'PosReg', (81, 89))	('clone relative fitness', 'CPA', (90, 112))	('clonal competition', 'CPA', (124, 142))	('mutations', 'Var', (62, 71))
607992	22026449	In Drosophila, cells containing extra copies of the myc proto-oncogene can outcompete wild-type cells.	('myc', 'Gene', (52, 55))	('Drosophila', 'Species', '7227', (3, 13))	('extra copies', 'Var', (32, 44))	('myc', 'Gene', '31310', (52, 55))
608036	22026449	There is a statistically significant reduction in BE cells at 500 muM ascorbic acid relative to the 0 mum treatment for CP-B and CP-C cell lines (Figure 2B, C), demonstrating that the presence of Vitamin C gives the EPC2 squamous cells a relative competitive advantage.	('CP-C', 'Chemical', 'MESH:C015101', (129, 133))	('CP-B', 'Gene', '1360', (120, 124))	('CP-B', 'Gene', (120, 124))	('muM', 'Gene', '56925', (66, 69))	('Vitamin C', 'Chemical', 'MESH:D001205', (196, 205))	('presence', 'Var', (184, 192))	('mum', 'Gene', '56925', (102, 105))	('muM', 'Gene', (66, 69))	('rat', 'Species', '10116', (168, 171))	('mum', 'Gene', (102, 105))	('EPC2', 'Gene', '26122', (216, 220))	('ascorbic acid', 'Chemical', 'MESH:D001205', (70, 83))	('EPC2', 'Gene', (216, 220))
608065	22026449	The utility of our assay is demonstrated in proof of principle experiments with ascorbic acid, where we find that vitamin C increases the fitness of esophageal squamous cells relative to Barrett's esophagus cells.	('vitamin', 'Var', (114, 121))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (187, 206))	('fitness of esophageal squamous', 'Disease', 'MESH:D000077277', (138, 168))	('increases', 'PosReg', (124, 133))	('vitamin C', 'Chemical', 'MESH:D001205', (114, 123))	('fitness of esophageal squamous', 'Disease', (138, 168))	('ascorbic acid', 'Chemical', 'MESH:D001205', (80, 93))	('rat', 'Species', '10116', (35, 38))
608071	22026449	A meta-analysis and other recent studies have reported that intake of antioxidants such as vitamin C, E, and beta-carotene are inversely associated with risk of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (161, 186))	('beta-carotene', 'Chemical', 'MESH:D019207', (109, 122))	('esophageal adenocarcinoma', 'Disease', (161, 186))	('inversely', 'NegReg', (127, 136))	('beta-carotene', 'Var', (109, 122))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (161, 186))	('vitamin C', 'Chemical', 'MESH:D001205', (91, 100))
608087	22026449	This work was funded by a Landon AACR Innovator Award for Cancer Prevention, NIH grants R01CA140657, R01 CA119224, P01CA091955, R03CA137811, Wistar Cancer Center P30 CA010815, Research Scholar Grant #117209-RSG-09-163-01-CNE from the American Cancer Society, the Pew Charitable Trust and NIH postdoctoral fellowship F32 CA132450.	('P30', 'Gene', '201161', (162, 165))	('Cancer', 'Disease', (243, 249))	('P30', 'Gene', (162, 165))	('Cancer', 'Disease', 'MESH:D009369', (243, 249))	('Cancer', 'Phenotype', 'HP:0002664', (243, 249))	('Cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Cancer', 'Disease', (58, 64))	('P01CA091955', 'Var', (115, 126))	('R03CA137811', 'Var', (128, 139))	('Cancer', 'Disease', 'MESH:D009369', (58, 64))	('Cancer', 'Disease', (148, 154))	('09-163-01-CNE', 'CellLine', 'CVCL:6888', (211, 224))	('Cancer', 'Disease', 'MESH:D009369', (148, 154))
608107	33121270	reported that the incidence of delayed perforation was significantly associated with a tumor location at the anal side of the ampulla, where the ESD ulcer has a greater risk of being exposed to bile and pancreatic juice; consequent perforation forces the patient to undergo emergency surgery and suffer a life-threatening condition due to severe peritonitis and retroperitonitis.	('peritonitis', 'Phenotype', 'HP:0002586', (367, 378))	('peritonitis', 'Disease', 'MESH:D010534', (346, 357))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('retroperitonitis', 'Disease', (362, 378))	('peritonitis', 'Disease', (346, 357))	('perforation', 'Var', (232, 243))	('associated', 'Reg', (69, 79))	('peritonitis', 'Disease', (367, 378))	('tumor', 'Disease', (87, 92))	('patient', 'Species', '9606', (255, 262))	('rat', 'Species', '10116', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ulcer', 'Disease', (149, 154))	('ulcer', 'Disease', 'MESH:D014456', (149, 154))	('rat', 'Species', '10116', (237, 240))	('retroperitonitis', 'Disease', 'MESH:D012186', (362, 378))	('peritonitis', 'Phenotype', 'HP:0002586', (346, 357))	('peritonitis', 'Disease', 'MESH:D010534', (367, 378))
608117	33121270	The primers employed are as follows:DES: Ss03378045_u1, MyoD: Ss03378464_u1, PAX7: Ss03376692_u1, FGF2: Ss03375809_u1, TGFbeta1: Ss03382325_u1, IGF2: Ss03388131_u1, EGF: Ss03391285_m1, and VEGF: Ss03393993_m1.	('IGF2', 'Gene', (144, 148))	('IGF2', 'Gene', '396916', (144, 148))	('PAX7', 'Gene', (77, 81))	('FGF2', 'Gene', (98, 102))	('MyoD', 'Gene', '407604', (56, 60))	('Ss03378045_u1', 'Var', (41, 54))	('Ss03393993_m1', 'Var', (195, 208))	('TGFbeta1', 'Gene', (119, 127))	('PAX7', 'Gene', '494466', (77, 81))	('FGF2', 'Gene', '397643', (98, 102))	('Ss03391285_m1', 'Var', (170, 183))	('Ss03376692_u1', 'Var', (83, 96))	('VEGF', 'Gene', '397157', (189, 193))	('TGFbeta1', 'Gene', '397078', (119, 127))	('VEGF', 'Gene', (189, 193))	('MyoD', 'Gene', (56, 60))	('Ss03378464_u1', 'Var', (62, 75))
608167	33121270	In addition, there is a risk of stenosis or involvement of the ampulla of Vater with hand-sewing, along with a risk of dissemination of the tumor itself and the duodenal contents into the abdominal cavity.	('hand-sewing', 'Var', (85, 96))	('stenosis', 'Disease', (32, 40))	('stenosis', 'Disease', 'MESH:D003251', (32, 40))	('dissemination', 'CPA', (119, 132))	('involvement', 'Reg', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
608196	32351616	Further investigation showed that DHA evidently induced cell cycle arrest at the G2/M phase in Eca109 cells.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('DHA', 'Var', (34, 37))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('DHA', 'Chemical', 'MESH:C039060', (34, 37))	('arrest', 'Disease', (67, 73))
608215	32351616	Allelic loss of the essential autophagy gene beclin1 is frequent in human breast, ovarian, and prostate cancers.	('beclin1', 'Gene', '8678', (45, 52))	('human', 'Species', '9606', (68, 73))	('prostate cancers', 'Phenotype', 'HP:0012125', (95, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('prostate cancers', 'Disease', (95, 111))	('Allelic loss', 'Var', (0, 12))	('beclin1', 'Gene', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('prostate cancers', 'Disease', 'MESH:D011471', (95, 111))	('breast', 'Disease', (74, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (95, 110))	('ovarian', 'Disease', (82, 89))
608264	32351616	To study the toxic effect of DHA on esophageal cancer cells in vitro, crystal violet assay was performed to evaluate the viability of Eca109 cells after treated with different concentrations of DHA (0, 50, 100, 150 and 200 muM) for 48 h. The results showed that DHA inhibited the viability of Eca109 cells in a dose-dependent manner (Fig.	('crystal violet', 'Chemical', 'MESH:D005840', (70, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (36, 53))	('inhibited', 'NegReg', (266, 275))	('DHA', 'Chemical', 'MESH:C039060', (194, 197))	('DHA', 'Var', (262, 265))	('DHA', 'Chemical', 'MESH:C039060', (29, 32))	('viability', 'CPA', (280, 289))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancer', 'Disease', (36, 53))	('DHA', 'Chemical', 'MESH:C039060', (262, 265))
608272	32351616	2a, the colony spheres of Eca109 cells were less or smaller after treated with 100 muM DHA compared with that treated with DMSO.	('less', 'NegReg', (44, 48))	('DMSO', 'Chemical', 'MESH:D004121', (123, 127))	('colony spheres of Eca109 cells', 'CPA', (8, 38))	('smaller', 'NegReg', (52, 59))	('100 muM DHA', 'Var', (79, 90))	('DHA', 'Chemical', 'MESH:C039060', (87, 90))
608276	32351616	2c, d, the cell cycle distribution of the G2/M phase markedly increased in Eca109 cells treated with DHA.	('increased', 'PosReg', (62, 71))	('DHA', 'Var', (101, 104))	('cell cycle distribution of the G2/M phase', 'CPA', (11, 52))	('DHA', 'Chemical', 'MESH:C039060', (101, 104))
608281	32351616	It was shown that the MFI in Eca109 cells treated with DHA was higher than that with DMSO (Fig.	('DHA', 'Var', (55, 58))	('MFI', 'MPA', (22, 25))	('DMSO', 'Chemical', 'MESH:D004121', (85, 89))	('higher', 'PosReg', (63, 69))	('DHA', 'Chemical', 'MESH:C039060', (55, 58))
608298	32351616	5i-m, NAC, an antioxidant, could inhibit the upregulation or puncta formation of LC3 induced by DHA.	('DHA', 'Var', (96, 99))	('inhibit', 'NegReg', (33, 40))	('NAC', 'Gene', '6622', (6, 9))	('NAC', 'Gene', (6, 9))	('LC3', 'Gene', '84557', (81, 84))	('upregulation', 'PosReg', (45, 57))	('DHA', 'Chemical', 'MESH:C039060', (96, 99))	('LC3', 'Gene', (81, 84))	('puncta', 'MPA', (61, 67))
608301	32351616	Furthermore, we found that DHA could upregulate the expression of gamma-H2AX and inhibit by NAC, which indicated that DHA could trigger the DNA damage response (DDR) in Eca109 cells (Fig.	('DHA', 'Chemical', 'MESH:C039060', (118, 121))	('gamma-H2AX', 'Protein', (66, 76))	('NAC', 'Gene', (92, 95))	('upregulate', 'PosReg', (37, 47))	('DDR', 'Chemical', '-', (161, 164))	('DNA', 'MPA', (140, 143))	('expression', 'MPA', (52, 62))	('DHA', 'Var', (118, 121))	('DHA', 'Chemical', 'MESH:C039060', (27, 30))	('NAC', 'Gene', '6622', (92, 95))
608304	32351616	6a, b, compared with Eca109 cells treated with DHA only, the percentage of cells in the G2/M phase decreased significantly in cells treated with DHA combined with CQ, which indicated that autophagy played a key role in DHA treated Eca109 cells.	('decreased', 'NegReg', (99, 108))	('DHA', 'Var', (145, 148))	('DHA', 'Chemical', 'MESH:C039060', (47, 50))	('DHA', 'Chemical', 'MESH:C039060', (219, 222))	('DHA', 'Chemical', 'MESH:C039060', (145, 148))
608315	32351616	In the present study, we found that DHA significantly inhibited Eca109 cell proliferation in vitro and in vivo, which was consistent with previous studies.	('inhibited', 'NegReg', (54, 63))	('Eca109 cell proliferation', 'CPA', (64, 89))	('DHA', 'Var', (36, 39))	('DHA', 'Chemical', 'MESH:C039060', (36, 39))
608317	32351616	This phenotype of esophageal cancer cells treated with DHA was similar to other cancer cells treated with DHA.	('cancer', 'Disease', (29, 35))	('esophageal cancer', 'Disease', (18, 35))	('DHA', 'Var', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('DHA', 'Chemical', 'MESH:C039060', (106, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('DHA', 'Chemical', 'MESH:C039060', (55, 58))	('cancer', 'Disease', (80, 86))
608318	32351616	Moreover, we found that DHA could inhibit the tumorigenicity of Eca109 cells in vitro evaluated by plate colony formation assay and soft agar assay.	('agar', 'Chemical', 'MESH:D000362', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('DHA', 'Var', (24, 27))	('inhibit', 'NegReg', (34, 41))	('DHA', 'Chemical', 'MESH:C039060', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
608319	32351616	Furthermore, DHA could also induce cell cycle arrest at the G2/M phase in Eca109 cells by upregulating the expression of cyclinB1 and CDK1.	('DHA', 'Var', (13, 16))	('cyclinB1', 'Gene', (121, 129))	('cyclinB1', 'Gene', '891', (121, 129))	('expression', 'MPA', (107, 117))	('CDK1', 'Gene', '983', (134, 138))	('DHA', 'Chemical', 'MESH:C039060', (13, 16))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('CDK1', 'Gene', (134, 138))	('upregulating', 'PosReg', (90, 102))	('arrest', 'Disease', (46, 52))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (35, 52))
608322	32351616	It was shown that DHA significantly increased the intracellular ROS level of Eca109 cells, especially in those who became smoother and smaller after treated with DHA.	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('DHA', 'Chemical', 'MESH:C039060', (162, 165))	('DHA', 'Var', (18, 21))	('intracellular ROS level', 'MPA', (50, 73))	('increased', 'PosReg', (36, 45))	('DHA', 'Chemical', 'MESH:C039060', (18, 21))	('smaller', 'NegReg', (135, 142))
608339	32351616	We measured the DDR marker gamma-H2AX in DHA treated Eca109 cells and found that DHA significantly upregulated the expression of gamma-H2AX.	('upregulated', 'PosReg', (99, 110))	('DHA', 'Chemical', 'MESH:C039060', (81, 84))	('DDR', 'Chemical', '-', (16, 19))	('expression', 'MPA', (115, 125))	('DHA', 'Chemical', 'MESH:C039060', (41, 44))	('DHA', 'Var', (81, 84))	('gamma-H2AX', 'Protein', (129, 139))
608341	32351616	A previous study showed that ROS induced by polyhexamethylene guanidine phosphate caused DDR in lung epithelial cells.	('DDR', 'Chemical', '-', (89, 92))	('polyhexamethylene guanidine', 'Var', (44, 71))	('polyhexamethylene guanidine phosphate', 'Chemical', 'MESH:C060540', (44, 81))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))	('DDR', 'MPA', (89, 92))	('ROS', 'Protein', (29, 32))
608349	32351616	We then inhibited autophagy in Eca109 cells by CQ and ATG5 knockdown before DHA treatment and found that the percentage of G2/M phase in cells treated with CQ plus DHA or shATG5 plus DHA was significantly decreased compared with that treated with DHA only, respectively.	('DHA', 'Chemical', 'MESH:C039060', (183, 186))	('autophagy', 'CPA', (18, 27))	('inhibited', 'NegReg', (8, 17))	('CQ plus DHA', 'Disease', 'MESH:C538228', (156, 167))	('CQ plus DHA', 'Disease', (156, 167))	('ATG5', 'Gene', '9474', (173, 177))	('ATG5', 'Gene', '9474', (54, 58))	('DHA', 'Chemical', 'MESH:C039060', (164, 167))	('knockdown', 'Var', (59, 68))	('decreased', 'NegReg', (205, 214))	('DHA', 'Chemical', 'MESH:C039060', (247, 250))	('ATG5', 'Gene', (54, 58))	('G2/M phase', 'CPA', (123, 133))	('ATG5', 'Gene', (173, 177))	('DHA', 'Chemical', 'MESH:C039060', (76, 79))
608351	32351616	In the present study, we demonstrated that DHA induces Eca109 cells G2/M phase arrest via the ROS-autophagy-TRF2-DDR pathway and clarified a new anticancer mechanism for DHA.	('DHA', 'Var', (43, 46))	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('cancer', 'Disease', (149, 155))	('DHA', 'Chemical', 'MESH:C039060', (170, 173))	('TRF2', 'Gene', '7014', (108, 112))	('ROS', 'Chemical', 'MESH:D017382', (94, 97))	('DHA', 'Chemical', 'MESH:C039060', (43, 46))	('TRF2', 'Gene', (108, 112))	('arrest', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DDR', 'Chemical', '-', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
608354	32351616	The results from the present study suggest that DHA has potent anti-tumor effects on esophageal cancer, which might be due to the induction of ROS-mediated autophagy and TRF2 degradation, and cell cycle arrest at the G2/M phase.	('tumor', 'Disease', (68, 73))	('arrest', 'Disease', 'MESH:D006323', (203, 209))	('ROS', 'Chemical', 'MESH:D017382', (143, 146))	('ROS-mediated', 'Protein', (143, 155))	('arrest', 'Disease', (203, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DHA', 'Var', (48, 51))	('TRF2', 'Gene', '7014', (170, 174))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (192, 209))	('TRF2', 'Gene', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('DHA', 'Chemical', 'MESH:C039060', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('esophageal cancer', 'Disease', (85, 102))	('degradation', 'MPA', (175, 186))
608366	31632486	Moreover, we found that EP300 knockdown led to inhibition of cell proliferation, colony formation, migration and invasion.	('invasion', 'CPA', (113, 121))	('EP300', 'Gene', (24, 29))	('inhibition', 'NegReg', (47, 57))	('EP300', 'Gene', '2033', (24, 29))	('colony formation', 'CPA', (81, 97))	('knockdown', 'Var', (30, 39))	('migration', 'CPA', (99, 108))	('cell proliferation', 'CPA', (61, 79))
608367	31632486	RNA-sequencing showed EP300 knockdown led to a significant change of genes expression associated with angiogenesis, hypoxia and epithelial-to-mesenchymal transition (EMT).	('EP300', 'Gene', (22, 27))	('epithelial-to-mesenchymal transition', 'CPA', (128, 164))	('hypoxia', 'Disease', (116, 123))	('hypoxia', 'Disease', 'MESH:D000860', (116, 123))	('change', 'Reg', (59, 65))	('angiogenesis', 'CPA', (102, 114))	('knockdown', 'Var', (28, 37))	('EP300', 'Gene', '2033', (22, 27))	('genes expression', 'MPA', (69, 85))
608374	31632486	These studies not only validated mutations of known cancer-related genes including TP53, CDKN2A, FAT1, NOTCH1, PIK3CA, EGFR, KMT2D, NFE2L2, but also identified several new recurrent alterations including ZNF750, AJUBA, FAM135B, TET2, XPO1 in ESCC.	('ZNF750', 'Gene', '79755', (204, 210))	('XPO1', 'Gene', '7514', (234, 238))	('mutations', 'Var', (33, 42))	('TET2', 'Gene', (228, 232))	('ZNF750', 'Gene', (204, 210))	('FAM135B', 'Gene', '51059', (219, 226))	('NFE2L2', 'Gene', '4780', (132, 138))	('NOTCH1', 'Gene', '4851', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('PIK3CA', 'Gene', '5290', (111, 117))	('ESCC', 'Disease', (242, 246))	('TP53', 'Gene', (83, 87))	('CDKN2A', 'Gene', (89, 95))	('EGFR', 'Gene', (119, 123))	('KMT2D', 'Gene', (125, 130))	('NFE2L2', 'Gene', (132, 138))	('TET2', 'Gene', '54790', (228, 232))	('FAM135B', 'Gene', (219, 226))	('FAT1', 'Gene', (97, 101))	('AJUBA', 'Gene', '84962', (212, 217))	('PIK3CA', 'Gene', (111, 117))	('XPO1', 'Gene', (234, 238))	('AJUBA', 'Gene', (212, 217))	('cancer', 'Disease', (52, 58))	('CDKN2A', 'Gene', '1029', (89, 95))	('TP53', 'Gene', '7157', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('EGFR', 'Gene', '1956', (119, 123))	('NOTCH1', 'Gene', (103, 109))	('ESCC', 'Disease', 'MESH:C562729', (242, 246))	('FAT1', 'Gene', '2195', (97, 101))	('KMT2D', 'Gene', '8085', (125, 130))
608380	31632486	A range of mutations involving these genes affected 61% of the 325 next generation- sequenced ESCC cases (Figure 1A).	('ESCC', 'Disease', 'MESH:C562729', (94, 98))	('affected', 'Reg', (43, 51))	('mutations', 'Var', (11, 20))	('ESCC', 'Disease', (94, 98))
608381	31632486	Interestingly, most of mutations identified in chromatin-remodeling regulators are uncommon in esophageal adenocarcinoma (EAC) but are enriched in ESCC.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (95, 120))	('esophageal adenocarcinoma', 'Disease', (95, 120))	('mutations', 'Var', (23, 32))	('ESCC', 'Disease', (147, 151))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (95, 120))	('EAC', 'Disease', 'MESH:D004941', (122, 125))	('EAC', 'Disease', (122, 125))	('ESCC', 'Disease', 'MESH:C562729', (147, 151))
608384	31632486	Moreover, nearly 50% of the missense mutations in EP300 are at the three identical amino acid, c.G4195: p.D1399 (7/26, 26.9%) followed by c.4241A: p.Y1414 (3/26, 8.6%) and c.4540G: p.E1514 (2/35, 5.7%) (Figure 1B).	('EP300', 'Gene', (50, 55))	('EP300', 'Gene', '2033', (50, 55))	('c.4241A: p.Y1414', 'Var', (138, 154))	('c.G4195: p.D1399', 'Var', (95, 111))	('missense mutations', 'Var', (28, 46))	('c.4540G: p.E1514', 'Var', (172, 188))
608387	31632486	Most intriguingly, we observed a significant phosphorylated site at Y1414C on EP300 (p < 0.0001, FDR < 0.047), for that was also identified as a harmful mutation.	('EP300', 'Gene', (78, 83))	('phosphorylated', 'MPA', (45, 59))	('Y1414C', 'Var', (68, 74))	('EP300', 'Gene', '2033', (78, 83))	('Y1414C', 'SUBSTITUTION', 'None', (68, 74))
608388	31632486	Y1414C located in KAT11 domain which is required for H3K56 acetylation (Figure 1B), suggesting that phosphorylated modification may be a possible mechanism for EP300 dysregulation.	('Y1414C', 'Var', (0, 6))	('Y1414C', 'SUBSTITUTION', 'None', (0, 6))	('EP300', 'Gene', (160, 165))	('EP300', 'Gene', '2033', (160, 165))
608390	31632486	Collectively, the variation of EP300 may be involved in the tumorigenesis and development of esophageal cancer.	('involved', 'Reg', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('variation', 'Var', (18, 27))	('EP300', 'Gene', '2033', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('EP300', 'Gene', (31, 36))	('tumor', 'Disease', (60, 65))
608391	31632486	The other most common target of alterations was MLL2 with 12.9% cases harboring mutations.	('alterations', 'Var', (32, 43))	('MLL2', 'Gene', (48, 52))	('MLL2', 'Gene', '8085', (48, 52))
608394	31632486	Interestingly, in ESCC, the mutations of MLL2 were clearly inactivating events represented by nonsense mutations (n = 18, 42.9%), frameshift insertions/deletions (n = 9, 21.4%).	('MLL2', 'Gene', '8085', (41, 45))	('frameshift insertions/deletions', 'Var', (130, 161))	('ESCC', 'Disease', 'MESH:C562729', (18, 22))	('ESCC', 'Disease', (18, 22))	('MLL2', 'Gene', (41, 45))	('mutations', 'Var', (28, 37))
608395	31632486	MLL3 also involved five nonsense and ten missense mutations in eighteen samples with mutation frequency of 5.5% (Figure 1A and 1B).	('nonsense', 'Var', (24, 32))	('involved', 'Reg', (10, 18))	('MLL3', 'Gene', (0, 4))	('missense mutations', 'Var', (41, 59))	('MLL3', 'Gene', '58508', (0, 4))
608396	31632486	In particular, the corresponding mutations are predicted to generate truncated proteins lacking the entire C-terminal cluster of conserved domains (including the SET domain) or significant portions of protein, thus disrupt their function and consequently deregulate the control of chromatin-based processes, ultimately leading to oncogenic transformation and the development of cancer.	('control', 'MPA', (270, 277))	('lacking', 'NegReg', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('mutations', 'Var', (33, 42))	('chromatin-based processes', 'MPA', (281, 306))	('deregulate', 'Reg', (255, 265))	('oncogenic transformation', 'CPA', (330, 354))	('leading to', 'Reg', (319, 329))	('protein', 'Protein', (201, 208))	('cancer', 'Disease', (378, 384))	('disrupt', 'NegReg', (215, 222))	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('function', 'MPA', (229, 237))
608397	31632486	Recent cancer genetics studies have uncovered frequent somatic loss-of-function mutations in the genes encoding MLL2/3 complex subunits in a variety of cancer types.	('MLL2', 'Gene', '8085', (112, 116))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('mutations', 'Var', (80, 89))	('loss-of-function', 'NegReg', (63, 79))	('MLL2', 'Gene', (112, 116))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
608398	31632486	KDM6A, a member of demethyltransferases interacts with MLL2, was also identified to be mutated in 6.2% of ESCC.	('ESCC', 'Disease', 'MESH:C562729', (106, 110))	('mutated', 'Var', (87, 94))	('ESCC', 'Disease', (106, 110))	('MLL2', 'Gene', '8085', (55, 59))	('KDM6A', 'Gene', '7403', (0, 5))	('MLL2', 'Gene', (55, 59))	('KDM6A', 'Gene', (0, 5))
608403	31632486	To be specific, the patients of pathological grade 2 with mutant EP300 (EP300mutant) had a shorter OS time than those with wild type EP300 (p = 0.021, Figure 2A).	('EP300', 'Gene', '2033', (133, 138))	('mutant', 'Var', (58, 64))	('EP300', 'Gene', (65, 70))	('EP300', 'Gene', '2033', (65, 70))	('EP300', 'Gene', (72, 77))	('patients', 'Species', '9606', (20, 28))	('EP300', 'Gene', '2033', (72, 77))	('OS time', 'MPA', (99, 106))	('shorter', 'NegReg', (91, 98))	('EP300', 'Gene', (133, 138))
608425	31632486	We observed that EP300 knockdown significantly inhibited proliferation of KYSE140 and KYSE180 cells as monitored by MTT and colony formation assay (p < 0.05, Figure 4C- 4D).	('inhibited', 'NegReg', (47, 56))	('EP300', 'Gene', '2033', (17, 22))	('knockdown', 'Var', (23, 32))	('EP300', 'Gene', (17, 22))	('proliferation', 'CPA', (57, 70))	('MTT', 'Chemical', 'MESH:C022616', (116, 119))	('colony formation assay', 'CPA', (124, 146))
608426	31632486	Similarly, migration and invasion of KYSE140 and KYSE180 cells were also inhibited by EP300 knockdown as monitored by wound healing and transwell assay (p < 0.05, Figure 4E-4F).	('4E-4F', 'Chemical', 'MESH:C006011', (170, 175))	('migration', 'CPA', (11, 20))	('knockdown', 'Var', (92, 101))	('EP300', 'Gene', '2033', (86, 91))	('inhibited', 'NegReg', (73, 82))	('EP300', 'Gene', (86, 91))
608428	31632486	In order to explore the biologic mechanism of EP300 in ESCC tumorigenesis, RNA-Sequencing method was performed in EP300 knockdown KYSE140 and control cells to distinguish the differentially expressed genes.	('EP300', 'Gene', (114, 119))	('ESCC', 'Disease', (55, 59))	('ESCC', 'Disease', 'MESH:C562729', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('knockdown', 'Var', (120, 129))	('EP300', 'Gene', '2033', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('EP300', 'Gene', '2033', (114, 119))	('EP300', 'Gene', (46, 51))	('tumor', 'Disease', (60, 65))
608429	31632486	The pathway enrichment analysis showed that these differentially expressed genes were enriched in the signaling pathways including PI3K-Akt signaling pathway, NF-kappa B signaling pathway, two-component system, pathways in cancer, transcriptional dysregulation in cancer, microRNAs in cancer and EMT indicating that EP300 may contribute to ESCC tumorigenesis via these pathways (Figure 5A).	('ESCC', 'Disease', 'MESH:C562729', (340, 344))	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('contribute', 'Reg', (326, 336))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('EP300', 'Gene', (316, 321))	('tumor', 'Disease', (345, 350))	('dysregulation', 'Var', (247, 260))	('ESCC', 'Disease', (340, 344))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('EP300', 'Gene', '2033', (316, 321))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
608436	31632486	Our results demonstrated that angiogenesis was inhibited after EP300 knockdown in ESCC cells, directly indicating the promotion effect of EP300 on angiogenesis (Figure 6A).	('inhibited', 'NegReg', (47, 56))	('ESCC', 'Disease', (82, 86))	('EP300', 'Gene', (138, 143))	('EP300', 'Gene', (63, 68))	('promotion', 'PosReg', (118, 127))	('EP300', 'Gene', '2033', (138, 143))	('angiogenesis', 'CPA', (30, 42))	('angiogenesis', 'CPA', (147, 159))	('EP300', 'Gene', '2033', (63, 68))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))	('knockdown', 'Var', (69, 78))
608437	31632486	The results showed that a set of angiogenesis, hypoxia, and EMT related molecular markers were affected after knockdown of EP300 in ESCC.	('knockdown', 'Var', (110, 119))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('EP300', 'Gene', (123, 128))	('angiogenesis', 'CPA', (33, 45))	('EP300', 'Gene', '2033', (123, 128))	('hypoxia', 'Disease', (47, 54))	('ESCC', 'Disease', 'MESH:C562729', (132, 136))	('EMT', 'CPA', (60, 63))	('ESCC', 'Disease', (132, 136))	('affected', 'Reg', (95, 103))
608438	31632486	In details, the decrease of FGF2, FLT1, CCL2 mRNA, along with increase of SERPINF1 mRNA were observed in EP300 knockdown ESCC cells, predicting that EP300 may promote tumor initiation via angiogenesis in ESCC (Figure 6B).	('ESCC', 'Disease', (204, 208))	('decrease', 'NegReg', (16, 24))	('CCL2', 'Gene', '6347', (40, 44))	('FLT1', 'Gene', '2321', (34, 38))	('SERPINF1', 'Gene', '5176', (74, 82))	('ESCC', 'Disease', 'MESH:C562729', (121, 125))	('EP300', 'Gene', (149, 154))	('promote', 'PosReg', (159, 166))	('increase', 'PosReg', (62, 70))	('ESCC', 'Disease', (121, 125))	('tumor', 'Disease', (167, 172))	('EP300', 'Gene', '2033', (105, 110))	('FGF2', 'Gene', '2247', (28, 32))	('angiogenesis', 'CPA', (188, 200))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('ESCC', 'Disease', 'MESH:C562729', (204, 208))	('CCL2', 'Gene', (40, 44))	('EP300', 'Gene', (105, 110))	('SERPINF1', 'Gene', (74, 82))	('knockdown', 'Var', (111, 120))	('FGF2', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('EP300', 'Gene', '2033', (149, 154))	('FLT1', 'Gene', (34, 38))	('mRNA', 'MPA', (83, 87))
608443	31632486	And we found that both mutation of EP300 and high expression of EP300 predicted a shorter survival time.	('EP300', 'Gene', (64, 69))	('mutation', 'Var', (23, 31))	('EP300', 'Gene', '2033', (64, 69))	('EP300', 'Gene', (35, 40))	('EP300', 'Gene', '2033', (35, 40))	('survival time', 'CPA', (90, 103))	('shorter', 'NegReg', (82, 89))
608448	31632486	It is well acknowledged that the patterns of mutations in known oncogenes and tumor suppressor genes are remarkably characteristic and nonrandom.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', (78, 83))
608449	31632486	Whereas tumor suppressor genes are mutated through protein-truncating alterations throughout their length, meaning that > 20% of the mutations are inactivating.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutations', 'Var', (133, 142))	('tumor', 'Disease', (8, 13))	('protein-truncating', 'MPA', (51, 69))
608450	31632486	Thus, the mutation pattern of MLL2 and MLL3 may indicate the tumor-suppressor role in ESCC, which is supported by a large number of researches.	('MLL2', 'Gene', '8085', (30, 34))	('MLL3', 'Gene', (39, 43))	('ESCC', 'Disease', 'MESH:C562729', (86, 90))	('mutation', 'Var', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MLL3', 'Gene', '58508', (39, 43))	('MLL2', 'Gene', (30, 34))	('tumor', 'Disease', (61, 66))	('ESCC', 'Disease', (86, 90))
608451	31632486	In terms of EP300, 19% of the mutations were at the identical amino acid, codon 4195 and 32% the mutations were concentrated in three sites (codon 4195, 4241, 4540).	('4241', 'Var', (153, 157))	('mutations', 'Var', (30, 39))	('codon 4195', 'Var', (141, 151))	('EP300', 'Gene', (12, 17))	('EP300', 'Gene', '2033', (12, 17))
608452	31632486	Meanwhile, 19% of the mutations of EP300 were inactivating.	('EP300', 'Gene', (35, 40))	('EP300', 'Gene', '2033', (35, 40))	('mutations', 'Var', (22, 31))
608460	31632486	And we also found that both mutation of EP300 and high expression of EP300 are associated with poor prognosis in ESCC, which was highly in accordance to Gao' results that EP300-mutated and overexpressed tumors had a dismal overall survival and Li's results showing that high expression EP300 was correlated with aggressive features and poor prognosis.	('ESCC', 'Disease', (113, 117))	('EP300', 'Gene', (171, 176))	('EP300', 'Gene', (40, 45))	('EP300', 'Gene', '2033', (40, 45))	('EP300', 'Gene', '2033', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('EP300', 'Gene', (69, 74))	('EP300', 'Gene', '2033', (69, 74))	('mutation', 'Var', (28, 36))	('EP300', 'Gene', (286, 291))	('EP300', 'Gene', '2033', (286, 291))	('ESCC', 'Disease', 'MESH:C562729', (113, 117))
608480	31632486	In summary, we used genomics data to show the link between histone modifier gene mutations and ESCC.	('ESCC', 'Disease', 'MESH:C562729', (95, 99))	('ESCC', 'Disease', (95, 99))	('link', 'Interaction', (46, 50))	('mutations', 'Var', (81, 90))
608481	31632486	Our functional and clinical analyses show that deletion of EP300 inhibits angiogenesis, hypoxia and EMT process, and high expression and mutation of EP300 correlates with poor prognosis, thus it may act as an oncogene in ESCC.	('expression', 'MPA', (122, 132))	('hypoxia', 'Disease', 'MESH:D000860', (88, 95))	('mutation', 'Var', (137, 145))	('EP300', 'Gene', (59, 64))	('inhibits', 'NegReg', (65, 73))	('EP300', 'Gene', '2033', (59, 64))	('hypoxia', 'Disease', (88, 95))	('angiogenesis', 'CPA', (74, 86))	('ESCC', 'Disease', 'MESH:C562729', (221, 225))	('deletion', 'Var', (47, 55))	('EP300', 'Gene', (149, 154))	('EP300', 'Gene', '2033', (149, 154))	('ESCC', 'Disease', (221, 225))
608487	31632486	All esophageal cancer cell lines including KYSE140, KYSE180, ECA109, KYSE410, KYSE510, KYSE150, TE1 were preserved in Translational Medicine Research Center of Shanxi Medical University (Taiyuan, China).	('KYSE510', 'Var', (78, 85))	('KYSE140', 'Var', (43, 50))	('KYSE180', 'Var', (52, 59))	('KYSE150', 'Var', (87, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('KYSE410', 'Var', (69, 76))	('esophageal cancer', 'Disease', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
608507	31632486	5 x 105 cells KYSE140NC, KYSE180NC, KYSE140-EP300sh and KYSE180sh cells were seeded into the gel in 50mul complete DMEM medium (Lonza, Walkersville, USA) incubated at 37 C for 12hr.	('EP300', 'Gene', '2033', (44, 49))	('EP300', 'Gene', (44, 49))	('KYSE140NC', 'Var', (14, 23))	('KYSE180NC', 'Var', (25, 34))	('KYSE180sh', 'Var', (56, 65))
608565	31380007	A recent study has shown that patients who underwent transthoracic esophagectomy had significantly more lymph nodes removed than those who underwent transhiatal esophagectomy.	('more', 'PosReg', (99, 103))	('patients', 'Species', '9606', (30, 38))	('transthoracic', 'Var', (53, 66))	('lymph nodes removed', 'CPA', (104, 123))
608585	30746368	The results were similar for HSP70, with a poorer survival of 17 mo in cases with high HSP70 expression, in contrast to 40 mo (P = 0.006) in cases with a low expression.	('HSP70', 'Gene', (87, 92))	('HSP70', 'Gene', '3308', (29, 34))	('high', 'Var', (82, 86))	('HSP70', 'Gene', (29, 34))	('expression', 'MPA', (93, 103))	('HSP70', 'Gene', '3308', (87, 92))
608591	30746368	Overexpression of HSPs is associated with several malignancies and contributes to the development, progression, and metastasis of cancer, in addition to the inhibition of cellular death.	('HSP', 'Gene', (18, 21))	('progression', 'CPA', (99, 110))	('malignancies', 'Disease', (50, 62))	('cellular death', 'CPA', (171, 185))	('malignancies', 'Disease', 'MESH:D009369', (50, 62))	('metastasis of cancer', 'Disease', (116, 136))	('HSP', 'Gene', '7190', (18, 21))	('Overexpression', 'Var', (0, 14))	('development', 'CPA', (86, 97))	('metastasis of cancer', 'Disease', 'MESH:D009362', (116, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('contributes', 'Reg', (67, 78))	('associated', 'Reg', (26, 36))
608648	30746368	Conservatively treated patients presented significantly more often with high HSP27 and HSP70 expressions, compared to those whom underwent radical surgery.	('HSP70', 'Gene', (87, 92))	('patients', 'Species', '9606', (23, 31))	('HSP27', 'Gene', (77, 82))	('HSP70', 'Gene', '3308', (87, 92))	('HSP27', 'Gene', '3315', (77, 82))	('high', 'Var', (72, 76))
608649	30746368	About 67.9% of all patients with high HSP27, and 75% of those with high HSP70, were inoperable at time of diagnosis (P < 0.01 and P = 0.01).	('HSP27', 'Gene', '3315', (38, 43))	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (19, 27))	('HSP70', 'Gene', (72, 77))	('HSP70', 'Gene', '3308', (72, 77))	('HSP27', 'Gene', (38, 43))
608651	30746368	The results were similar for HSP70 immunostaining - cases with a high expression had an inferior survival rate of 17 mo in comparison to the rate of 40 mo for those with negative or low expression (P = 0.006).	('inferior', 'NegReg', (88, 96))	('HSP70', 'Gene', '3308', (29, 34))	('survival rate', 'CPA', (97, 110))	('HSP70', 'Gene', (29, 34))	('high expression', 'Var', (65, 80))
608656	30746368	44 patients with stage II cancer had available survival data, and survival among patients with high HSP27 expression (27 cases) was 23.9 mo compared to 53.2 mo for low expression (17 cases).	('HSP27', 'Gene', (100, 105))	('cancer', 'Disease', (26, 32))	('HSP27', 'Gene', '3315', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('high', 'Var', (95, 99))	('expression', 'MPA', (106, 116))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
608660	30746368	About 47 patients had stage II disease and there was a statistically significant difference in survival between the 16 cases with high HSP70 expression (17.8 mo) compared to the 31 cases with low expression (43.0 mo) (P = 0.018).	('patients', 'Species', '9606', (9, 17))	('high', 'Var', (130, 134))	('HSP70', 'Gene', (135, 140))	('expression', 'MPA', (141, 151))	('stage II disease', 'Disease', 'MESH:D058625', (22, 38))	('stage II disease', 'Disease', (22, 38))	('HSP70', 'Gene', '3308', (135, 140))
608669	30746368	This is consistent with the finding that overexpression is associated with higher grade, i.e., more aggressive disease, and therefore more likely to be inoperable at time of diagnosis.	('more', 'PosReg', (95, 99))	('aggressive disease', 'Disease', 'MESH:D001523', (100, 118))	('overexpression', 'Var', (41, 55))	('aggressive disease', 'Disease', (100, 118))
608670	30746368	We found that patients with stage II EAC and high HSP27/70 expressions had significantly poorer prognosis, making them a high risk subgroup.	('EAC', 'Phenotype', 'HP:0011459', (37, 40))	('poorer', 'NegReg', (89, 95))	('EAC', 'Gene', '1540', (37, 40))	('high', 'Var', (45, 49))	('EAC', 'Gene', (37, 40))	('HSP27', 'Gene', '3315', (50, 55))	('HSP27', 'Gene', (50, 55))	('patients', 'Species', '9606', (14, 22))
608672	30746368	Giaginis et al found no effect on survival, but high HSP27 expression was significantly associated with higher T, N, and M stages, signaling more aggressive disease.	('aggressive disease', 'Disease', 'MESH:D001523', (146, 164))	('aggressive disease', 'Disease', (146, 164))	('higher', 'PosReg', (104, 110))	('HSP27', 'Gene', '3315', (53, 58))	('HSP27', 'Gene', (53, 58))	('expression', 'MPA', (59, 69))	('high', 'Var', (48, 52))
608673	30746368	Lee et al employed study methods similar to those used in the present study, and while HSP70 was not associated with survival when analyzing the entire patient population, there was a significant correlation between high expression and poor survival in adenocarcinomas of the cardia and those of the intestinal type.	('adenocarcinomas of the cardia', 'Disease', (253, 282))	('HSP70', 'Gene', (87, 92))	('poor', 'NegReg', (236, 240))	('high', 'Var', (216, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('adenocarcinomas of the cardia', 'Disease', 'MESH:D004938', (253, 282))	('HSP70', 'Gene', '3308', (87, 92))	('patient', 'Species', '9606', (152, 159))
608682	30746368	One of the studies with RPPAs did find that a combination of low HSP27 and high HER2 correlated with better overall survival in EAC, but no IHC was performed, therefore yielding results that are not comparable to ours.	('HSP27', 'Gene', (65, 70))	('overall survival', 'MPA', (108, 124))	('HSP27', 'Gene', '3315', (65, 70))	('EAC', 'Gene', (128, 131))	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('low', 'NegReg', (61, 64))	('high', 'Var', (75, 79))	('EAC', 'Gene', '1540', (128, 131))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('better', 'PosReg', (101, 107))
608688	30746368	We found that patients with stage II EAC and high HSP27/70 expressions had significantly poorer prognosis, making them a possible target group for HSP inhibitors.	('EAC', 'Phenotype', 'HP:0011459', (37, 40))	('poorer', 'NegReg', (89, 95))	('HSP', 'Gene', '7190', (147, 150))	('expressions', 'MPA', (59, 70))	('EAC', 'Gene', '1540', (37, 40))	('HSP', 'Gene', (50, 53))	('EAC', 'Gene', (37, 40))	('high', 'Var', (45, 49))	('HSP27', 'Gene', '3315', (50, 55))	('HSP', 'Gene', (147, 150))	('patients', 'Species', '9606', (14, 22))	('HSP', 'Gene', '7190', (50, 53))	('HSP27', 'Gene', (50, 55))
608697	30746368	The results were similar for HSP70, with a poorer survival of 17 mo in cases with high HSP70 expression, in contrast to 40 mo in cases with a low expression.	('HSP70', 'Gene', (87, 92))	('HSP70', 'Gene', '3308', (29, 34))	('high', 'Var', (82, 86))	('HSP70', 'Gene', (29, 34))	('expression', 'MPA', (93, 103))	('HSP70', 'Gene', '3308', (87, 92))
608705	30629674	DIULs >=5 mm, multiple DILUs, and both characteristics were observed in 35 (7.4%), 31 (6.6%), and 16 (3.4%) patients, respectively.	('multiple DILUs', 'Disease', (14, 28))	('DIULs', 'Disease', (0, 5))	('DIULs', 'Chemical', '-', (0, 5))	('patients', 'Species', '9606', (108, 116))	('>=5', 'Var', (6, 9))
608711	30629674	Multiple logistic regression analyses showed that the slow-metabolizing ADH1B*1/*1 genotype (odds ratio [95% confidence interval], 12.5 [4.82-32.4] and 9.89 [3.50-27.9]), the inactive heterozygous ALDH2*1/*2 genotype (2.94 [1.18-7.38] and 3.79 [1.40-10.3]), a lower body mass index per -1 kg/m2 (1.17 [1.02-1.35] and 1.38 [1.14-1.67]), and a mean corpuscular volume >=106 fl (3.70 [1.56-8.81] and 3.27 [1.24-8.64]) increased the risk of DIULs >=5 mm and multiple DIULs, respectively.	('>=106', 'Var', (366, 371))	('ADH1B', 'Gene', '125', (72, 77))	('ALDH2', 'Gene', '217', (197, 202))	('ALDH2', 'Gene', (197, 202))	('DIULs', 'Disease', (437, 442))	('DIULs', 'Chemical', '-', (437, 442))	('lower body mass', 'Phenotype', 'HP:0004325', (260, 275))	('lower body mass index', 'Phenotype', 'HP:0045082', (260, 281))	('multiple', 'Disease', (454, 462))	('DIULs', 'Chemical', '-', (463, 468))	('ADH1B', 'Gene', (72, 77))	('lower', 'NegReg', (260, 265))
608712	30629674	The combination of ADH1B*1/*1 and ALDH2*1/*2 markedly increased the risk of esophageal DIULs >=5 mm (39.3 [10.6-146]).	('ADH1B', 'Gene', (19, 24))	('esophageal DIULs >=5 mm', 'Disease', (76, 99))	('DIULs', 'Chemical', '-', (87, 92))	('ALDH2', 'Gene', '217', (34, 39))	('ADH1B', 'Gene', '125', (19, 24))	('combination', 'Var', (4, 15))	('increased', 'PosReg', (54, 63))	('ALDH2', 'Gene', (34, 39))
608716	30629674	These genetic polymorphisms have been investigated mainly in relation to alcohol metabolism and alcohol drinking behaviors, but a recent phenome-wide association study has highlighted that ADH1B rs1229984 is associated with a wide range of phenotype traits including psychological traits and socioeconomic status, some of which do not appear to be mediated by alcohol.	('rs1229984', 'Var', (195, 204))	('rs1229984', 'Mutation', 'rs1229984', (195, 204))	('ADH1B', 'Gene', (189, 194))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))	('alcohol drinking', 'Phenotype', 'HP:0030955', (96, 112))	('associated', 'Reg', (208, 218))	('ADH1B', 'Gene', '125', (189, 194))	('alcohol', 'Chemical', 'MESH:D000438', (360, 367))	('psychological traits', 'Disease', (267, 287))	('alcohol', 'Chemical', 'MESH:D000438', (73, 80))
608733	30629674	The endoscopy examinations were performed with an Olympus XQ230, Q240, Q240Z, Q260, or Q260Z panendoscope (Olympus Optical Co. Ltd., Tokyo, Japan) as described in detail previously.	('Q240Z', 'SUBSTITUTION', 'None', (71, 76))	('Q260Z', 'SUBSTITUTION', 'None', (87, 92))	('Q240Z', 'Var', (71, 76))	('Q260Z', 'Var', (87, 92))
608738	30629674	We dichotomized the results into an MCV <106 fl group and an MCV >=106 fl group, since macrocytosis with an MCV value >=106 fl was found to be associated with an increased risk of SCC in the upper aerodigestive tract in our previous studies in alcohol-dependent men.	('associated', 'Reg', (143, 153))	('men', 'Species', '9606', (262, 265))	('SCC', 'Gene', (180, 183))	('SCC', 'Phenotype', 'HP:0002860', (180, 183))	('alcohol', 'Chemical', 'MESH:D000438', (244, 251))	('SCC', 'Gene', '6317', (180, 183))	('MCV', 'Var', (108, 111))
608764	30629674	The presence of the ALDH2*1/*2 genotype increased the OR for DIULs >=5 mm (2.94 [1.18-7.38]) and SCC (18.2 [3.11-106]), compared with the presence of the ALDH2*1/*1 genotype.	('ALDH2', 'Gene', '217', (20, 25))	('ALDH2', 'Gene', '217', (154, 159))	('OR for DIULs >=5 mm', 'MPA', (54, 73))	('ALDH2', 'Gene', (20, 25))	('ALDH2', 'Gene', (154, 159))	('SCC', 'Gene', (97, 100))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('DIULs', 'Chemical', '-', (61, 66))	('increased', 'PosReg', (40, 49))	('presence', 'Var', (4, 12))	('SCC', 'Gene', '6317', (97, 100))
608768	30629674	The presence of the ADH1B*1/*1 genotype increased the risk of multiple DIULs (9.89 [3.50-27.9]), compared with the presence of the ADH1B*2 allele.	('ADH1B', 'Gene', '125', (131, 136))	('DIULs', 'Chemical', '-', (71, 76))	('ADH1B', 'Gene', (20, 25))	('multiple DIULs', 'Disease', (62, 76))	('ADH1B', 'Gene', '125', (20, 25))	('presence', 'Var', (4, 12))	('ADH1B', 'Gene', (131, 136))
608769	30629674	The presence of the ALDH2*1/*2 genotype increased the OR (18.2 [3.11-106]), compared with the presence of the ALDH2*1/*1 genotype.	('ALDH2', 'Gene', '217', (20, 25))	('ALDH2', 'Gene', (20, 25))	('ALDH2', 'Gene', '217', (110, 115))	('increased', 'PosReg', (40, 49))	('presence', 'Var', (4, 12))	('ALDH2', 'Gene', (110, 115))
608791	30629674	Recent studies have reported that ADH1B rs1229984 affects alcohol-independent functions, such as educational attainment and vascular /metabolic conditions, which may also modify the present associations.	('affects', 'Reg', (50, 57))	('alcohol', 'Chemical', 'MESH:D000438', (58, 65))	('educational attainment', 'CPA', (97, 119))	('men', 'Species', '9606', (115, 118))	('ADH1B', 'Gene', (34, 39))	('vascular /metabolic conditions', 'CPA', (124, 154))	('ADH1B', 'Gene', '125', (34, 39))	('alcohol-independent functions', 'MPA', (58, 87))	('rs1229984', 'Var', (40, 49))	('rs1229984', 'Mutation', 'rs1229984', (40, 49))
608796	30629674	Among homozygotes and heterozygotes for the inactive ALDH2*2 allele, the blood acetaldehyde levels were approximately 19 and 6 times higher than that among homozygotes for the active ALDH2*1 allele, respectively, in an alcohol challenge test.	('blood acetaldehyde', 'Phenotype', 'HP:0003533', (73, 91))	('ALDH2', 'Gene', (183, 188))	('inactive', 'Var', (44, 52))	('ALDH2', 'Gene', (53, 58))	('alcohol challenge', 'Phenotype', 'HP:0030955', (219, 236))	('blood acetaldehyde levels', 'Phenotype', 'HP:0003533', (73, 98))	('blood acetaldehyde levels', 'MPA', (73, 98))	('higher', 'PosReg', (133, 139))	('acetaldehyde', 'Chemical', 'MESH:D000079', (79, 91))	('alcohol', 'Chemical', 'MESH:D000438', (219, 226))	('ALDH2', 'Gene', '217', (183, 188))	('ALDH2', 'Gene', '217', (53, 58))
608815	30629674	These findings were consistent with the results that both an MCV >=106 fl and a low BMI were associated with a risk of esophageal SCC in a case-control study and a follow-up study in alcohol-dependent men performed at the same treatment center.	('esophageal SCC', 'Disease', 'MESH:D004941', (119, 133))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('MCV >=106 fl', 'Var', (61, 73))	('low BMI', 'Phenotype', 'HP:0045082', (80, 87))	('men', 'Species', '9606', (201, 204))	('men', 'Species', '9606', (232, 235))	('BMI', 'MPA', (84, 87))	('esophageal SCC', 'Disease', (119, 133))	('alcohol', 'Chemical', 'MESH:D000438', (183, 190))
608816	30629674	A low BMI increased the risk of newly diagnosed high-grade dysplasia or SCC in the esophagus in a Japanese cohort study.	('low BMI', 'Phenotype', 'HP:0045082', (2, 9))	('low', 'Var', (2, 5))	('BMI increased', 'Phenotype', 'HP:0031418', (6, 19))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('dysplasia', 'Disease', (59, 68))	('SCC', 'Gene', '6317', (72, 75))	('BMI', 'MPA', (6, 9))	('dysplasia', 'Disease', 'MESH:D004476', (59, 68))
608820	30629674	The presence of LGIN in DIULs >=5 mm was correlated with the presence of the ALDH2*1/*2 genotype and the ADH1B*1/*1 genotype in alcohol-dependent men treated at our treatment center and was associated with a very high risk of the future development of SCC in the upper autodigestive tract.	('men', 'Species', '9606', (244, 247))	('ADH1B', 'Gene', (105, 110))	('ALDH2', 'Gene', (77, 82))	('ADH1B', 'Gene', '125', (105, 110))	('men', 'Species', '9606', (146, 149))	('LGIN', 'Chemical', '-', (16, 20))	('men', 'Species', '9606', (170, 173))	('SCC', 'Gene', (252, 255))	('SCC', 'Phenotype', 'HP:0002860', (252, 255))	('presence', 'Var', (61, 69))	('ALDH2', 'Gene', '217', (77, 82))	('alcohol', 'Chemical', 'MESH:D000438', (128, 135))	('associated with', 'Reg', (190, 205))	('DIULs', 'Chemical', '-', (24, 29))	('SCC', 'Gene', '6317', (252, 255))
608821	30629674	The 5-year cumulative rate of SCC detection in the upper aerodigestive tract was more than 30% in those with dyaplastic DIULs >=5 mm, as opposed to 4% in those without DIULs >=5 mm, and its hazard ratio was 5.88.	('SCC', 'Gene', '6317', (30, 33))	('DIULs', 'Chemical', '-', (120, 125))	('SCC', 'Gene', (30, 33))	('dyaplastic DIULs >=5 mm', 'Var', (109, 132))	('DIULs', 'Chemical', '-', (168, 173))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))
608824	30629674	In the present study, 45.7% of the DIULs >=5 mm were accompanied by the presence of multiple DIULs, and both types of DIULs were positively associated with the ALDH2*1/*2 genotype, the ADH1B*1/*1 genotype, a low BMI, and an MCV >=106 fl.	('low', 'NegReg', (208, 211))	('DIULs', 'Chemical', '-', (93, 98))	('associated', 'Reg', (140, 150))	('DIULs', 'Chemical', '-', (35, 40))	('DIULs', 'Chemical', '-', (118, 123))	('ALDH2', 'Gene', (160, 165))	('low BMI', 'Phenotype', 'HP:0045082', (208, 215))	('MCV >=106 fl', 'Var', (224, 236))	('ADH1B', 'Gene', (185, 190))	('ADH1B', 'Gene', '125', (185, 190))	('ALDH2', 'Gene', '217', (160, 165))
608828	30629674	Ethanol and acetaldehyde measurements of blood and saliva obtained while the patients were intoxicated might have clarified whether any gender differences in exposure levels to ethanol and acetaldehyde exist according to the ADH1B and ALDH2 genotypes.	('ADH1B', 'Gene', '125', (225, 230))	('ALDH2', 'Gene', (235, 240))	('genotypes', 'Var', (241, 250))	('men', 'Species', '9606', (32, 35))	('ethanol', 'Chemical', 'MESH:D000431', (177, 184))	('patients', 'Species', '9606', (77, 85))	('acetaldehyde', 'Chemical', 'MESH:D000079', (189, 201))	('ALDH2', 'Gene', '217', (235, 240))	('Ethanol', 'Chemical', 'MESH:D000431', (0, 7))	('ADH1B', 'Gene', (225, 230))	('acetaldehyde', 'Chemical', 'MESH:D000079', (12, 24))
608854	30003188	After propensity score matching, operative time was significantly longer in the MIE group (n = 3515) than in the OE group (n = 3515) (526 +- 149 vs 461 +- 156 minutes, P < .001), whereas blood loss was markedly less in the MIE group than in the OE group (442 +- 612 mL vs 608 +- 591 mL, P < .001).	('OE', 'Chemical', '-', (113, 115))	('less', 'NegReg', (211, 215))	('MIE', 'Chemical', '-', (223, 226))	('blood loss', 'Disease', 'MESH:D006473', (187, 197))	('MIE', 'Chemical', '-', (80, 83))	('MIE', 'Var', (80, 83))	('blood loss', 'Disease', (187, 197))	('longer', 'PosReg', (66, 72))	('OE', 'Chemical', '-', (245, 247))
608855	30003188	The population of patients who required more than 48 hours of postoperative respiratory ventilation was also significantly less in the MIE group than in the OE group (8.9% vs 10.9%, P = .006); however, the reoperation rate within 30 days was significantly higher in the MIE group than in the OE group (7.0% vs 5.3%, P = .004).	('higher', 'PosReg', (256, 262))	('OE', 'Chemical', '-', (157, 159))	('OE', 'Chemical', '-', (292, 294))	('MIE', 'Chemical', '-', (135, 138))	('MIE', 'Var', (270, 273))	('MIE', 'Chemical', '-', (270, 273))	('patients', 'Species', '9606', (18, 26))	('reoperation', 'CPA', (206, 217))
608893	30003188	OS was better in the NAC-S group than in the CRT group (adjusted HR 1.72; 95% CI 1.19-2.50).	('NAC-S', 'Var', (21, 26))	('NAC-S', 'Chemical', '-', (21, 26))	('better', 'PosReg', (7, 13))	('OS', 'Chemical', '-', (0, 2))
608922	30003188	The combination of gemcitabine plus vinorelbine was well tolerated as a second-line treatment for platinum-based chemotherapy-refractory EC patients and appeared to provide enhanced clinical activity especially in patients with low expression of miRNA-21439 (Table 2).	('miRNA-21439', 'Var', (246, 257))	('patients', 'Species', '9606', (214, 222))	('vinorelbine', 'Chemical', 'MESH:D000077235', (36, 47))	('EC', 'Phenotype', 'HP:0011459', (137, 139))	('platinum', 'Chemical', 'MESH:D010984', (98, 106))	('clinical activity', 'MPA', (182, 199))	('patients', 'Species', '9606', (140, 148))	('enhanced', 'PosReg', (173, 181))	('expression', 'MPA', (232, 242))	('gemcitabine', 'Chemical', 'MESH:C056507', (19, 30))	('low', 'NegReg', (228, 231))
608989	30003188	Raskob et al randomly assigned patients with cancer who had acute symptomatic or incidental VTE to receive either low molecular weight heparin for at least 5 days followed by oral edoxaban or subcutaneous dalteparin.	('low', 'Var', (114, 117))	('VTE', 'Disease', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('edoxaban', 'Chemical', 'MESH:C552171', (180, 188))	('heparin', 'Chemical', 'MESH:D006493', (135, 142))	('dalteparin', 'Chemical', 'MESH:D017985', (205, 215))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('patients', 'Species', '9606', (31, 39))	('cancer', 'Disease', (45, 51))	('VTE', 'Disease', 'MESH:D054556', (92, 95))
609006	28587272	Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases.	('Cancers', 'Disease', 'MESH:D009369', (91, 98))	('Cancers', 'Phenotype', 'HP:0002664', (91, 98))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rat', 'Species', '10116', (80, 83))	('epigenetic changes', 'Var', (213, 231))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('cancers', 'Disease', (263, 270))	('elicit', 'Reg', (206, 212))	('alcohol', 'Chemical', 'MESH:D000438', (144, 151))	('Alcohol', 'Chemical', 'MESH:D000438', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('Association', 'Interaction', (0, 11))	('Alcohol Use', 'Phenotype', 'HP:0030955', (24, 35))	('alcohol use', 'Phenotype', 'HP:0030955', (144, 155))	('rat', 'Species', '10116', (254, 257))	('Cancers', 'Disease', (91, 98))
609012	28587272	Epigenetic modification is defined as chromosomal modifications that result in changes to gene expression without alteration of the DNA sequence.	('rat', 'Species', '10116', (118, 121))	('changes', 'Reg', (79, 86))	('gene expression', 'MPA', (90, 105))	('Epigenetic modification', 'Var', (0, 23))
609013	28587272	Classical epigenetic regulation involves DNA methylation and histone modification, in which modification of DNA or histones, respectively, alters chromatin structure, thereby affecting gene expression.	('histone', 'Gene', (61, 68))	('histone', 'Gene', '24829', (115, 122))	('modification', 'Var', (92, 104))	('affecting', 'Reg', (175, 184))	('DNA', 'Gene', (108, 111))	('gene expression', 'MPA', (185, 200))	('chromatin structure', 'MPA', (146, 165))	('histone', 'Gene', '24829', (61, 68))	('histone', 'Gene', (115, 122))	('alters', 'Reg', (139, 145))
609029	28587272	Most histone modifications occur at their unstructured alkaline N-terminal tails, via acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation.	('ubiquitination', 'MPA', (129, 143))	('histone', 'Gene', (5, 12))	('phosphorylation', 'MPA', (112, 127))	('SUMOylation', 'MPA', (149, 160))	('histone', 'Gene', '24829', (5, 12))	('methylation', 'MPA', (99, 110))	('acetylation', 'MPA', (86, 97))	('modifications', 'Var', (13, 26))
609030	28587272	Histone acetylation, which most commonly occurs at basic amino acids lysine and arginine, is the most widely studied epigenetic protein modification.	('Histone', 'Gene', (0, 7))	('lysine', 'Chemical', 'MESH:D008239', (69, 75))	('lysine', 'Var', (69, 75))	('arginine', 'Var', (80, 88))	('basic amino acids', 'Chemical', 'MESH:D024361', (51, 68))	('arginine', 'Chemical', 'MESH:D001120', (80, 88))	('Histone', 'Gene', '24829', (0, 7))
609036	28587272	The most extensively studied histone methylation sites include histone H3 lysine 4 (H3K4), H3K9, H3K27, H3K36, H3K79, and H4K20.	('histone', 'Gene', (29, 36))	('H3K79', 'Var', (111, 116))	('histone', 'Gene', '24829', (63, 70))	('H3K9', 'Var', (91, 95))	('H3', 'Chemical', 'MESH:C012616', (111, 113))	('H4K20', 'Var', (122, 127))	('H3', 'Chemical', 'MESH:C012616', (97, 99))	('H3', 'Chemical', 'MESH:C012616', (84, 86))	('H3', 'Chemical', 'MESH:C012616', (71, 73))	('H3', 'Chemical', 'MESH:C012616', (91, 93))	('histone', 'Gene', '24829', (29, 36))	('H3K36', 'Var', (104, 109))	('histone', 'Gene', (63, 70))	('lysine', 'Chemical', 'MESH:D008239', (74, 80))	('H3', 'Chemical', 'MESH:C012616', (104, 106))	('H3K27', 'Var', (97, 102))
609041	28587272	For instance, H3K9 methylation within the coding region of a gene has been found to correlate with transcription activation, whereas the same modification is associated with inactive transcription when found in the promoter region.	('methylation', 'Var', (19, 30))	('transcription activation', 'MPA', (99, 123))	('H3K9', 'Protein', (14, 18))	('H3', 'Chemical', 'MESH:C012616', (14, 16))
609053	28587272	Both tobacco-induced DNA changes and tobacco-induced epigenetic changes affect molecular regulatory mechanisms, including (1) receptors, (2) cell cycle regulators, (3) signaling pathways, (4) apoptosis mediators, (5) angiogenic factors, and (6) invasive and metastasis mediators, to induce carcinogenesis.	('epigenetic changes', 'Var', (53, 71))	('tobacco', 'Species', '4097', (5, 12))	('affect', 'Reg', (72, 78))	('tobacco', 'Species', '4097', (37, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (290, 304))	('signaling pathways', 'Pathway', (168, 186))	('molecular regulatory mechanisms', 'MPA', (79, 110))	('carcinogenesis', 'Disease', (290, 304))	('cell cycle', 'CPA', (141, 151))	('induce', 'Reg', (283, 289))	('apoptosis', 'MPA', (192, 201))	('angiogenic', 'CPA', (217, 227))
609058	28587272	Inhalation and metabolic activation of these carcinogens during exposure to tobacco smoke often causes changes in DNA sequences, such as formation of DNA adducts, induction of double-stranded DNA (dsDNA) breaks, and development of point mutations.	('tobacco', 'Species', '4097', (76, 83))	('point mutations', 'Var', (231, 246))	('DNA', 'Gene', (114, 117))	('causes changes', 'Reg', (96, 110))
609063	28587272	Tobacco smoke may play a potential role in RAR-beta gene methylation during early pathogenesis of lung cancer.	('methylation', 'Var', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('RAR-beta', 'Gene', (43, 51))	('Tobacco', 'Species', '4097', (0, 7))	('RAR-beta', 'Gene', '5915', (43, 51))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))
609065	28587272	Methylation at cg05575921, a CpG residue in the aryl hydrocarbon receptor repressor (AHRR), is the most sensitive indicator of smoking status at all levels of smoking.	('Methylation', 'Var', (0, 11))	('AHRR', 'Gene', '57491', (85, 89))	('cg05575921', 'Var', (15, 25))	('aryl hydrocarbon receptor repressor', 'Gene', '57491', (48, 83))	('AHRR', 'Gene', (85, 89))	('aryl hydrocarbon receptor repressor', 'Gene', (48, 83))	('indicator', 'Reg', (114, 123))
609067	28587272	In bladder cancer, there is a relationship between epigenetic silencing of the tumor-suppressor genes p16 (INK4A), RASSF1A, PRSS3, and the four SFRP genes and exposure to both tobacco and arsenic.	('PRSS3', 'Gene', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('RASSF1A', 'Gene', '11186', (115, 122))	('INK4A', 'Gene', (107, 112))	('PRSS3', 'Gene', '5646', (124, 129))	('bladder cancer', 'Disease', (3, 17))	('RASSF1A', 'Gene', (115, 122))	('SFRP genes', 'Gene', (144, 154))	('tumor', 'Disease', (79, 84))	('epigenetic silencing', 'Var', (51, 71))	('tobacco', 'Species', '4097', (176, 183))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('arsenic', 'Chemical', 'MESH:D001151', (188, 195))	('p16', 'Gene', (102, 105))	('p16', 'Gene', '1029', (102, 105))	('INK4A', 'Gene', '1029', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
609069	28587272	Epigenetic silencing of RASSF1A, PRSS3, or any of the SFRP genes is significantly associated with advanced tumor stage (P < 0.001, P < 0.04, and P < 0.005, respectively).	('associated', 'Reg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('PRSS3', 'Gene', (33, 38))	('PRSS3', 'Gene', '5646', (33, 38))	('SFRP genes', 'Gene', (54, 64))	('RASSF1A', 'Gene', (24, 31))	('Epigenetic silencing', 'Var', (0, 20))	('RASSF1A', 'Gene', '11186', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
609075	28587272	CSE has been shown to cause hypermethylation and inactivation of the WW domain-containing oxidoreductase (WWOX) gene in T-24 human bladder cancer cells.	('WW domain-containing oxidoreductase', 'Gene', (69, 104))	('bladder cancer', 'Disease', (131, 145))	('inactivation', 'NegReg', (49, 61))	('WW domain-containing oxidoreductase', 'Gene', '51741', (69, 104))	('WWOX', 'Gene', '51741', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('human', 'Species', '9606', (125, 130))	('CSE', 'Var', (0, 3))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('WWOX', 'Gene', (106, 110))	('hypermethylation', 'MPA', (28, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (131, 145))
609078	28587272	The DAP-kinase gene methylation rates of NNK-induced hyperplasias and adenocarcinomas were 46% and 52%, respectively.	('rat', 'Species', '10116', (32, 35))	('adenocarcinomas', 'Disease', 'MESH:D000230', (70, 85))	('adenocarcinomas', 'Disease', (70, 85))	('NNK', 'Chemical', 'MESH:C016583', (41, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('hyperplasias', 'Disease', (53, 65))	('methylation', 'Var', (20, 31))	('NNK-induced', 'Gene', (41, 52))	('hyperplasias', 'Disease', 'MESH:D006965', (53, 65))	('DAP-kinase gene', 'Gene', (4, 19))
609086	28587272	MicroRNA-487b (miR-487b) is a tumor suppressor microRNA that is silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis.	('miR-487b', 'Gene', '664616', (15, 23))	('tobacco', 'Species', '4097', (105, 112))	('pulmonary carcinogenesis', 'Disease', (121, 145))	('MicroRNA-487b', 'Var', (0, 13))	('miR-487b', 'Gene', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('pulmonary carcinogenesis', 'Disease', 'MESH:D063646', (121, 145))	('tumor', 'Disease', (30, 35))
609087	28587272	Cigarette smoke mediates the epigenetic repression of miR-217 and miR-218 during esophageal adenocarcinogenesis and transformation of human bronchial epithelial (HBE) cells, respectively.	('human', 'Species', '9606', (134, 139))	('epigenetic repression', 'Var', (29, 50))	('HBE', 'CellLine', 'CVCL:0287', (162, 165))	('miR-217', 'Gene', '406999', (54, 61))	('esophageal adenocarcinogenesis', 'Disease', (81, 111))	('miR-217', 'Gene', (54, 61))	('miR-218', 'Gene', (66, 73))	('esophageal adenocarcinogenesis', 'Disease', 'MESH:D004941', (81, 111))
609109	28587272	Therefore, alcohol plays an important role in DNA methylation events and histone modifications that promote carcinogenesis.	('histone', 'Gene', '24829', (73, 80))	('histone', 'Gene', (73, 80))	('alcohol', 'Chemical', 'MESH:D000438', (11, 18))	('promote', 'PosReg', (100, 107))	('modifications', 'Var', (81, 94))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('methylation', 'Var', (50, 61))	('carcinogenesis', 'Disease', (108, 122))
609124	28587272	In animal models, treatment with a combination of 4-nitroquinoline-1-oxide (4-NQO) and arecoline has been shown to induce hypermethylation of PARbeta, whose expression is lost during carcinogenesis.	('carcinogenesis', 'Disease', (183, 197))	('4-NQO', 'Chemical', 'MESH:D015112', (76, 81))	('arecoline', 'Chemical', 'MESH:D001115', (87, 96))	('hypermethylation', 'MPA', (122, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (183, 197))	('4-nitroquinoline-1-oxide', 'Var', (50, 74))	('PARbeta', 'Protein', (142, 149))	('4-nitroquinoline-1-oxide', 'Chemical', 'MESH:D015112', (50, 74))
609125	28587272	An increasing number of studies have described the association between specific lifestyle choices (smoking, betel quid chewing, and alcohol consumption) and epigenetic modulation of carcinogenesis.	('association', 'Interaction', (51, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (182, 196))	('epigenetic modulation', 'Var', (157, 178))	('carcinogenesis', 'Disease', (182, 196))	('betel quid chewing', 'Disease', (108, 126))	('alcohol', 'Chemical', 'MESH:D000438', (132, 139))
609144	28587272	Most developed epigenetic drugs are in pre-clinical, phase 1, or phase 2 testing for lung cancer, breast cancer, prostate cancer, and leukemia.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('leukemia', 'Disease', 'MESH:D007938', (134, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('lung cancer', 'Disease', (85, 96))	('breast cancer', 'Disease', (98, 111))	('leukemia', 'Disease', (134, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('epigenetic drugs', 'Var', (15, 31))	('prostate cancer', 'Disease', (113, 128))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
609151	27507047	UHRF1 regulates global DNA hypomethylation and is associated with poor prognosis in esophageal squamous cell carcinoma Global DNA hypomethylation contributes to oncogenesis through various mechanisms.	('global DNA hypomethylation', 'MPA', (16, 42))	('oncogenesis', 'CPA', (161, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('Global', 'MPA', (119, 125))	('UHRF1', 'Gene', (0, 5))	('UHRF1', 'Gene', '29128', (0, 5))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (84, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('contributes', 'Reg', (146, 157))	('associated', 'Reg', (50, 60))	('hypomethylation', 'Var', (130, 145))	('esophageal squamous cell carcinoma', 'Disease', (84, 118))
609163	27507047	In particular, including alterations of DNA methylation, epigenetic changes are reversible and could be potential targets for cancer treatment and chemoprevention.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('epigenetic changes', 'Var', (57, 75))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('DNA', 'Protein', (40, 43))	('alterations', 'Reg', (25, 36))
609164	27507047	Alterations in DNA methylation correlated with human cancers include site-specific CpG island promoter hypermethylation and global DNA hypomethylation.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('C', 'Chemical', 'MESH:D003596', (83, 84))	('cancers', 'Disease', (53, 60))	('global DNA', 'MPA', (124, 134))	('hypermethylation', 'Var', (103, 119))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('DNA', 'Gene', (15, 18))	('human', 'Species', '9606', (47, 52))	('CpG', 'Protein', (83, 86))
609166	27507047	We have previously described that LINE-1 hypomethylation robustly correlates with poorer outcome in some cancers, including esophageal, gastric, and liver cancers, implying that LINE- 1 hypomethylation might be an attracting biomarker of predicting patient outcome.	('patient', 'Species', '9606', (249, 256))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('hypomethylation', 'Var', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('poorer', 'Disease', (82, 88))	('LINE-1', 'Gene', (34, 40))	('liver cancers', 'Phenotype', 'HP:0002896', (149, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('liver cancers', 'Disease', (149, 162))	('liver cancers', 'Disease', 'MESH:D006528', (149, 162))	('esophageal', 'Disease', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('gastric', 'Disease', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', (155, 162))
609167	27507047	In addition, we found that LINE-1 hypomethylation in ESCC might contribute to the acquirement of malignant tumor behavior through genomic gains of oncogenes such as CDK6.	('gains', 'PosReg', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('ESCC', 'Gene', (53, 57))	('malignant tumor', 'Disease', (97, 112))	('contribute', 'Reg', (64, 74))	('CDK6', 'Gene', (165, 169))	('CDK6', 'Gene', '1021', (165, 169))	('malignant tumor', 'Disease', 'MESH:D018198', (97, 112))	('hypomethylation', 'Var', (34, 49))
609168	27507047	Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) plays a crucial role in DNA methylation by recognizing hemimethylated DNA during DNA replication and recruiting DNA methyltransferase 1 (DNMT1) to preserve DNA methylation pattern in daughter cells.	('hemimethylated', 'Var', (112, 126))	('DNMT1', 'Gene', (194, 199))	('UHRF1', 'Gene', (50, 55))	('DNA methyltransferase 1', 'Gene', (169, 192))	('PHD', 'Disease', 'MESH:D011547', (20, 23))	('recruiting', 'PosReg', (158, 168))	('DNMT1', 'Gene', '1786', (194, 199))	('DNA methyltransferase 1', 'Gene', '1786', (169, 192))	('PHD', 'Disease', (20, 23))	('DNA methylation pattern', 'MPA', (213, 236))
609184	27507047	Conversely, to investigate whether UHRF1 knockdown increased global DNA methylation level we transfected TE-11 cells, which exhibited high expression of UHRF1 and LINE-1 hypomethylation, with siRNA specific for UHRF1 (Figure 3A).	('UHRF1', 'Gene', (153, 158))	('increased', 'PosReg', (51, 60))	('global DNA methylation level', 'MPA', (61, 89))	('knockdown', 'Var', (41, 50))	('C', 'Chemical', 'MESH:D003596', (0, 1))
609192	27507047	In Kaplan-Meier analysis, the LINE-1 hypomethylation group (n = 43) exhibited significantly poorer OS and CSS than the LINE-1 hypermethylation group (n = 117) (3-year OS rate 56.1% vs. 78.8%, log-rank P = 0.0162; 3-year CSS rate 63.7% vs. 84.7%, log-rank P = 0.0351; Figure 4B).	('CSS', 'Chemical', '-', (220, 223))	('OS', 'Chemical', '-', (167, 169))	('OS', 'Chemical', '-', (99, 101))	('CSS', 'Chemical', '-', (106, 109))	('poorer', 'NegReg', (92, 98))	('LINE-1 hypomethylation', 'Var', (30, 52))
609195	27507047	This result shows a proportional reduction in the regression coefficient for UHRF1 expression due to the inclusion of LINE-1 hypomethylation in the Cox regression model (Figure 4C).	('C', 'Chemical', 'MESH:D003596', (178, 179))	('reduction', 'NegReg', (33, 42))	('UHRF1', 'Gene', (77, 82))	('hypomethylation', 'Var', (125, 140))	('C', 'Chemical', 'MESH:D003596', (148, 149))	('expression', 'MPA', (83, 93))	('regression', 'MPA', (50, 60))
609197	27507047	We have previously reported that LINE-1 hypomethylation (global DNA hypomethylation) is strongly associated with poorer patient outcome in some cancers, including esophageal, gastric, and liver cancers, implying that LINE-1 hypomethylation may be a useful prognostic biomarker in gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (280, 304))	('liver cancers', 'Disease', (188, 201))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancers', 'Disease', (194, 201))	('associated', 'Reg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancers', 'Disease', 'MESH:D009369', (297, 304))	('gastrointestinal cancers', 'Disease', (280, 304))	('patient', 'Species', '9606', (120, 127))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('esophageal', 'Disease', (163, 173))	('poorer', 'NegReg', (113, 119))	('liver cancers', 'Disease', 'MESH:D006528', (188, 201))	('gastric', 'Disease', (175, 182))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('hypomethylation', 'Var', (40, 55))	('liver cancers', 'Phenotype', 'HP:0002896', (188, 201))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('cancers', 'Disease', (297, 304))	('LINE-1', 'Gene', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('cancers', 'Disease', 'MESH:D009369', (144, 151))
609199	27507047	Collectively, our data indicate that UHRF1 may regulate global DNA methylation, and that UHRF1 overexpression contributes to an unfavorable prognosis in patients with ESCC via global DNA hypomethylation (Figure 4C).	('C', 'Chemical', 'MESH:D003596', (212, 213))	('patients', 'Species', '9606', (153, 161))	('regulate', 'Reg', (47, 55))	('global DNA hypomethylation', 'Var', (176, 202))	('ESCC', 'Disease', (167, 171))	('contributes to', 'Reg', (110, 124))	('C', 'Chemical', 'MESH:D003596', (170, 171))	('UHRF1', 'Gene', (89, 94))	('overexpression', 'PosReg', (95, 109))	('global DNA methylation', 'MPA', (56, 78))	('C', 'Chemical', 'MESH:D003596', (169, 170))	('C', 'Chemical', 'MESH:D003596', (0, 1))
609201	27507047	Moreover, cancer cells with UHRF1 overexpression present enhanced rates of growth and migration and morphologic features resembling epithelial mesenchymal transition (EMT).	('overexpression', 'Var', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('epithelial mesenchymal transition', 'Disease', (132, 165))	('UHRF1', 'Gene', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('enhanced', 'PosReg', (57, 65))	('cancer', 'Disease', (10, 16))
609204	27507047	Our study also supports an epigenetic role of UHRF1 in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (55, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('UHRF1', 'Gene', (46, 51))	('epigenetic', 'Var', (27, 37))
609209	27507047	As MBD1 specifically binds methylated CpG sequences in the DNA, GFP localization should also be specific for methylated CpG sequences.	('C', 'Chemical', 'MESH:D003596', (38, 39))	('MBD1', 'Gene', (3, 7))	('binds', 'Interaction', (21, 26))	('MBD1', 'Gene', '4152', (3, 7))	('methylated', 'Var', (27, 37))	('CpG', 'Protein', (38, 41))	('C', 'Chemical', 'MESH:D003596', (120, 121))
609213	27507047	Inhibition of UHRF1 using siRNA decreased cellular proliferation and migration in colorectal cancer cell lines.	('colorectal cancer', 'Disease', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('UHRF1', 'Gene', (14, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('Inhibition', 'Var', (0, 10))	('cellular proliferation', 'CPA', (42, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('decreased', 'NegReg', (32, 41))	('migration', 'CPA', (69, 78))
609214	27507047	Another mechanism is through inactivation of various tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inactivation', 'Var', (29, 41))	('tumor', 'Disease', (53, 58))
609218	27507047	Further studies are needed to validate our findings and clarify the mechanism how LINE-1 hypomethylation affects tumor behavior.	('tumor', 'Disease', (113, 118))	('affects', 'Reg', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('LINE-1', 'Gene', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('hypomethylation', 'Var', (89, 104))
609245	27507047	The primers for real-time PCR were as follows: UHRF1, Hs00273589_m1 (Taqman probe, Applied Biosystems, Foster City, CA), and 18S, Hs99999901_S1 (Taqman probe, Applied Biosystems).	('Hs00273589_m1', 'Var', (54, 67))	('C', 'Chemical', 'MESH:D003596', (27, 28))	('Hs99999901_S1', 'Var', (130, 143))	('C', 'Chemical', 'MESH:D003596', (110, 111))	('C', 'Chemical', 'MESH:D003596', (116, 117))
609247	27507047	These cell lines were cultured in RPMI 1640 or DMEM added with 10% FBS in a 5% CO2 atmosphere at 37 C. We used two chemically synthesized UHRF1-specific small-interfering RNAs (siRNAs) (s26553 and s26554, Life Technologies).	('RPMI 1640', 'Chemical', '-', (34, 43))	('C', 'Chemical', 'MESH:D003596', (79, 80))	('C', 'Chemical', 'MESH:D003596', (100, 101))	('FBS', 'Disease', (67, 70))	('s26554', 'Var', (197, 203))	('s26553', 'Var', (186, 192))	('DMEM', 'Chemical', '-', (47, 51))	('FBS', 'Disease', 'MESH:D005198', (67, 70))	('CO2', 'Chemical', '-', (79, 82))
609299	25250506	One reason for this significant difference might be that U.S. surgeons prefer a limited D0/1 lymphadenectomy, although the D2-lymphadenectomy is associated with a lower loco-regional recurrence and cancer-related death than those associated with D0/1.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('death', 'Disease', 'MESH:D003643', (213, 218))	('D2-lymphadenectomy', 'Var', (123, 141))	('death', 'Disease', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('lower', 'NegReg', (163, 168))	('loco-regional recurrence', 'CPA', (169, 193))
609338	25250506	Wells and Melton reviewed several Hoxb genes that are expressed by the anterior gut tube, as well as the deletion of the shh-responsive transcription factors Gli2 and Gli3, which produced embryos lacking esophagus, trachea, or lungs.	('Hoxb genes', 'Gene', (34, 44))	('deletion', 'Var', (105, 113))	('lacking', 'NegReg', (196, 203))	('Gli2', 'Gene', '2736', (158, 162))	('esophagus', 'CPA', (204, 213))	('Gli3', 'Gene', '2737', (167, 171))	('Gli2', 'Gene', (158, 162))	('trachea', 'CPA', (215, 222))	('Gli3', 'Gene', (167, 171))
609366	25250506	However, an earlier paper reported an investigation of 1,346 patients with adenocarcinoma of the EGJ, in which the survival rates for AEG Type I were markedly better than those for the AEG Type II and III.	('AEG', 'Chemical', '-', (134, 137))	('AEG', 'Chemical', '-', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('AEG Type I', 'Var', (134, 144))	('survival', 'MPA', (115, 123))	('adenocarcinoma', 'Disease', 'MESH:D000230', (75, 89))	('patients', 'Species', '9606', (61, 69))	('better', 'PosReg', (159, 165))	('AEG Type II', 'Disease', (185, 196))	('AEG Type II', 'Disease', 'MESH:C565948', (185, 196))	('adenocarcinoma', 'Disease', (75, 89))
609381	25250506	However, in addition to the differences between AC and ESCC, the differences in the embryological development of their primary and metastatic sites:such as the heterogeneity of the tumor itself, of mutations, of mitochondrial DNA mutations, and of genetic variations:also contribute importantly to the picture.	('tumor', 'Disease', (181, 186))	('men', 'Species', '9606', (105, 108))	('mutations', 'Var', (198, 207))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mitochondrial DNA', 'Gene', (212, 229))
609382	25250506	However, the actual understanding that mutations are the prime cause of the majority of cancers has recently been questioned, with an alternate proposal that describes a sequence of six consecutive events that could reasonably explain the origin of cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancer', 'Disease', (249, 255))	('cancers', 'Disease', (88, 95))	('mutations', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
609396	20978481	Red meat intake was positively associated with esophageal squamous cell carcinoma (HR for the top versus bottom quintile = 1.79, 95% CI: 1.07-3.01, P for trend = 0.019).	('esophageal squamous cell carcinoma', 'Disease', (47, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('Red meat', 'Var', (0, 8))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (47, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))
609427	20978481	The cancer endpoints were defined by anatomic site and histologic code of the International Classification of Diseases for Oncology (ICD-O-3); esophageal cancer included topography codes: C15.0-C15.9, gastric cardia cancer included code: C16.0, and gastric non-cardia cancer included codes: C16.1-C16.7, as well as C16.8 (overlapping tumors) and C16.9 (not otherwise specified).	('C15.0-C15.9', 'Var', (188, 199))	('gastric non-cardia cancer', 'Disease', (249, 274))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('tumors', 'Disease', (334, 340))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (201, 222))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('gastric cardia cancer', 'Disease', (201, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (334, 340))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('Oncology', 'Phenotype', 'HP:0002664', (123, 131))	('gastric non-cardia cancer', 'Disease', 'MESH:D013274', (249, 274))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('esophageal cancer', 'Disease', (143, 160))	('cancer', 'Disease', (268, 274))	('C16.8', 'Var', (315, 320))	('C16.9', 'Var', (346, 351))	('C16.9', 'CellLine', 'CVCL:2322', (346, 351))	('C16.0', 'Var', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Disease', (154, 160))	('C16.1-C16.7', 'CellLine', 'CVCL:2322', (291, 302))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('C16.1-C16.7', 'Var', (291, 302))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (4, 10))
609428	20978481	Esophageal cancers were categorized as squamous cell carcinomas, which included histology codes: 8050-8076; and adenocarcinomas, which included: 8140, 8141, 8190-8231, 8260-8263, 8310, 8430, 8480-8490, 8560, 8570-8572.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (39, 63))	('Esophageal cancers', 'Disease', (0, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (39, 63))	('8140', 'Var', (145, 149))	('8260-8263', 'Var', (168, 177))	('8310', 'Var', (179, 183))	('8430', 'Var', (185, 189))	('8480-8490', 'Var', (191, 200))	('squamous cell carcinomas', 'Disease', (39, 63))	('8141', 'Var', (151, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('8190-8231', 'Var', (157, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('8570-8572', 'Var', (208, 217))	('Esophageal cancers', 'Disease', 'MESH:D004938', (0, 18))	('adenocarcinomas', 'Disease', 'MESH:D000230', (112, 127))	('8560', 'Var', (202, 206))	('adenocarcinomas', 'Disease', (112, 127))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))
609438	20978481	Red meat intake was positively associated with esophageal squamous cell carcinoma (HR for the top versus bottom quintile = 1.79, 95% CI: 1.07-3.01, P for trend = 0.019; HR = 1.06, 95% CI: 1.00-1.13 for each 10g/1000kcal increase), but not with adenocarcinoma of the esophagus or gastric (cardia or non-cardia) cancer (Table 2).	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (249, 275))	('esophageal squamous cell carcinoma', 'Disease', (47, 81))	('adenocarcinoma of the esophagus or gastric (cardia or non-cardia) cancer', 'Disease', 'MESH:D004938', (244, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('Red meat', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (47, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('associated', 'Interaction', (31, 41))
609443	20978481	In addition to HCAs, we found a suggestive positive association for heme iron intake and esophageal adenocarcinoma (HR for the top versus bottom quintile = 1.47, 95% CI: 0.99-2.20, P for trend = 0.063), but no associations between other meat-related variables, including B[a]P, nitrate, or nitrite, and esophageal or gastric cancers.	('gastric cancer', 'Phenotype', 'HP:0012126', (317, 331))	('cancers', 'Phenotype', 'HP:0002664', (325, 332))	('iron', 'Chemical', 'MESH:D007501', (73, 77))	('heme', 'Chemical', 'MESH:D006418', (68, 72))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (89, 114))	('HCAs', 'Chemical', '-', (15, 19))	('esophageal or gastric cancers', 'Disease', (303, 332))	('esophageal adenocarcinoma', 'Disease', (89, 114))	('esophageal or gastric cancers', 'Disease', 'MESH:D013274', (303, 332))	('nitrate', 'Chemical', 'MESH:D009566', (278, 285))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (89, 114))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('nitrite', 'Chemical', 'MESH:D009573', (290, 297))	('gastric cancers', 'Phenotype', 'HP:0012126', (317, 332))	('heme', 'Var', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))
609453	20978481	There are more case-control studies than cohort studies even though this is not an ideal study design for dietary analyses or for digestive tract cancers; in these studies, red meat intake has been positively associated with both adenocarcinoma and squamous cell cancer of the esophagus.	('associated', 'Reg', (209, 219))	('red meat', 'Var', (173, 181))	('adenocarcinoma and squamous cell cancer', 'Disease', 'MESH:D002294', (230, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('cancer of the esophagus', 'Phenotype', 'HP:0100751', (263, 286))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (249, 269))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tract cancers', 'Disease', (140, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('tract cancers', 'Disease', 'MESH:D014571', (140, 153))
609459	20978481	Only one other study investigated HCA intake and esophageal cancer by subtype and this was a case-control study that reported an increased risk of squamous cell carcinoma for those in the highest quartile of MeIQx and DiMeIQx, but no association for adenocarcinoma of the esophagus.	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('HCA', 'Gene', (34, 37))	('DiMeIQx', 'Var', (218, 225))	('squamous cell carcinoma', 'Disease', (147, 170))	('esophageal cancer', 'Disease', (49, 66))	('adenocarcinoma of the esophagus', 'Disease', (250, 281))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 170))	('MeIQx', 'Chemical', 'MESH:C036990', (220, 225))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('MeIQx', 'Var', (208, 213))	('MeIQx', 'Chemical', 'MESH:C036990', (208, 213))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (255, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('HCA', 'Gene', '266790', (34, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (250, 281))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
609462	20978481	Our observation that DiMeIQx was positively associated with gastric cardia cancer is supported by animal studies showing a diet high in HCAs results in increased stomach tumors.	('increased stomach', 'Phenotype', 'HP:0005207', (152, 169))	('stomach tumors', 'Disease', 'MESH:D013274', (162, 176))	('gastric cardia cancer', 'Disease', (60, 81))	('increased', 'PosReg', (152, 161))	('DiMeIQx', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('MeIQx', 'Chemical', 'MESH:C036990', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (60, 81))	('HCAs', 'Chemical', '-', (136, 140))	('stomach tumors', 'Disease', (162, 176))	('stomach tumors', 'Phenotype', 'HP:0006753', (162, 176))
609487	32705225	Further study revealed how N-acetyl cysteine (NAC), a ROS inhibitor, attenuated these effects, demonstrating that ROS and JNK inhibitors mediated a marked reversal of neferine-triggered cell cycle arrest and apoptosis in ESCC cells.	('NAC', 'Chemical', 'MESH:D000111', (46, 49))	('apoptosis', 'CPA', (208, 217))	('JNK', 'Gene', '5599', (122, 125))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (186, 203))	('inhibitors', 'Var', (126, 136))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (27, 44))	('ROS', 'Chemical', 'MESH:D017382', (114, 117))	('neferine', 'Chemical', 'MESH:C057222', (167, 175))	('arrest', 'Disease', 'MESH:D006323', (197, 203))	('ROS', 'Gene', (114, 117))	('JNK', 'Gene', (122, 125))	('ROS', 'Chemical', 'MESH:D017382', (54, 57))	('arrest', 'Disease', (197, 203))
609507	32705225	Previous studies have demonstrated that dysregulation of apoptosis can result in a variety of human diseases, including development and regression of tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('human diseases', 'Disease', (94, 108))	('development', 'CPA', (120, 131))	('dysregulation', 'Var', (40, 53))	('result in', 'Reg', (71, 80))	('human', 'Species', '9606', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('apoptosis', 'Protein', (57, 66))	('regression', 'CPA', (136, 146))
609508	32705225	In fact, dysregulation-related resistance to apoptosis is one of the causes for tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('dysregulation-related', 'Var', (9, 30))	('resistance to apoptosis', 'CPA', (31, 54))
609510	32705225	Particularly, a moderate ROS level is required for cell proliferation but excessive production of ROS induces apoptosis causing cell death.	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('ROS', 'Protein', (98, 101))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('induces', 'Reg', (102, 109))	('excessive production', 'Var', (74, 94))	('excessive production of ROS', 'Phenotype', 'HP:0025464', (74, 101))	('apoptosis', 'CPA', (110, 119))
609544	32705225	1D) revealed suppression of clonogenicity in KYSE30 and KYSE150 relative to the control group (Fig.	('KYSE150', 'Var', (56, 63))	('KYSE150', 'CellLine', 'CVCL:1348', (56, 63))	('KYSE30', 'Var', (45, 51))	('clonogenicity', 'CPA', (28, 41))	('suppression', 'NegReg', (13, 24))
609547	32705225	A higher G2/M-phase distribution in neferine-treated KYSE30 and KYSE150 cells relative to the control group (Fig.	('higher', 'PosReg', (2, 8))	('neferine', 'Chemical', 'MESH:C057222', (36, 44))	('G2/M-phase distribution', 'MPA', (9, 32))	('neferine-treated', 'Var', (36, 52))	('KYSE150', 'CellLine', 'CVCL:1348', (64, 71))
609553	32705225	The results revealed significantly higher apoptosis in neferine-treated KYSE30 and KYSE150 cells, relative to the control group (Fig.	('neferine', 'Chemical', 'MESH:C057222', (55, 63))	('KYSE150', 'CellLine', 'CVCL:1348', (83, 90))	('apoptosis', 'CPA', (42, 51))	('neferine-treated', 'Var', (55, 71))	('higher', 'PosReg', (35, 41))
609558	32705225	Neferine has been demonstrated to cause excessive ROS production leading to apoptosis.	('ROS', 'Chemical', 'MESH:D017382', (50, 53))	('Neferine', 'Chemical', 'MESH:C057222', (0, 8))	('Neferine', 'Var', (0, 8))	('apoptosis', 'CPA', (76, 85))	('ROS production', 'MPA', (50, 64))
609560	32705225	The results revealed significantly higher intracellular ROS levels at 6, 12 and 24 h, in neferine-treated cells relative to the control group.	('neferine-treated', 'Var', (89, 105))	('ROS', 'Chemical', 'MESH:D017382', (56, 59))	('neferine', 'Chemical', 'MESH:C057222', (89, 97))	('higher', 'PosReg', (35, 41))	('intracellular ROS levels', 'MPA', (42, 66))
609568	32705225	5A and B), downregulate the expression of apoptotic-related proteins, cleaved caspase-3, cleaved caspase-9 and cleaved PARP (Fig.	('caspase-9', 'Gene', (97, 106))	('PARP', 'Gene', (119, 123))	('apoptotic-related', 'Gene', (42, 59))	('expression', 'MPA', (28, 38))	('caspase-3', 'Gene', (78, 87))	('cleaved', 'Var', (111, 118))	('caspase-9', 'Gene', '842', (97, 106))	('downregulate', 'NegReg', (11, 23))	('cleaved', 'Var', (89, 96))	('caspase-3', 'Gene', '836', (78, 87))	('PARP', 'Gene', '1302', (119, 123))	('cleaved', 'Var', (70, 77))
609570	32705225	These results indicated that neferine may affect apoptosis and the cell cycle of ESCC cells by inducing ROS accumulation.	('affect', 'Reg', (42, 48))	('neferine', 'Chemical', 'MESH:C057222', (29, 37))	('ROS accumulation', 'MPA', (104, 120))	('ROS', 'Chemical', 'MESH:D017382', (104, 107))	('neferine', 'Var', (29, 37))	('inducing', 'Reg', (95, 103))	('cell cycle', 'CPA', (67, 77))	('apoptosis', 'CPA', (49, 58))
609574	32705225	6A and B) and downregulate the expression of apoptotic-related proteins; cleaved caspase-3, cleaved caspase-9 and cleaved PARP (Fig.	('caspase-3', 'Gene', '836', (81, 90))	('caspase-9', 'Gene', (100, 109))	('cleaved', 'Var', (73, 80))	('PARP', 'Gene', (122, 126))	('cleaved', 'Var', (114, 121))	('caspase-3', 'Gene', (81, 90))	('expression', 'MPA', (31, 41))	('caspase-9', 'Gene', '842', (100, 109))	('downregulate', 'NegReg', (14, 26))	('cleaved', 'Var', (92, 99))	('PARP', 'Gene', '1302', (122, 126))	('apoptotic-related', 'Protein', (45, 62))
609596	32705225	Previous studies have revealed that neferine inhibits progression of multiple malignancies, through cell cycle arrest, although this effect varies.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (100, 117))	('neferine', 'Chemical', 'MESH:C057222', (36, 44))	('arrest', 'Disease', 'MESH:D006323', (111, 117))	('malignancies', 'Disease', (78, 90))	('inhibits', 'NegReg', (45, 53))	('arrest', 'Disease', (111, 117))	('neferine', 'Var', (36, 44))	('malignancies', 'Disease', 'MESH:D009369', (78, 90))
609609	32705225	Recent studies have shown that ROS accelerates the death of tumor cells, thereby effectively treating cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ROS', 'Var', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ROS', 'Chemical', 'MESH:D017382', (31, 34))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('accelerates', 'PosReg', (35, 46))	('tumor', 'Disease', (60, 65))
609612	32705225	In addition to apoptosis, neferine-triggered ROS production resulted in cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('neferine-triggered', 'Var', (26, 44))	('arrest', 'Disease', (83, 89))	('neferine', 'Chemical', 'MESH:C057222', (26, 34))
609614	32705225	In addition, studies have revealed that ROS activates the JNK signaling pathway and promotes tumor cell apoptosis.	('JNK', 'Gene', '5599', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('activates', 'PosReg', (44, 53))	('ROS', 'Var', (40, 43))	('JNK', 'Gene', (58, 61))	('ROS', 'Chemical', 'MESH:D017382', (40, 43))	('promotes', 'PosReg', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
609632	31601234	PVT1 antisense oligonucleotides (ASOs) were tested for their antitumor activity in vitro and in vivo.	('tumor', 'Disease', (65, 70))	('antisense', 'Var', (5, 14))	('PVT1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
609634	31601234	High expression of PVT1 was associated with poor differentiation, lymph node metastases, and shorter survival.	('PVT1', 'Gene', (19, 23))	('High', 'Var', (0, 4))	('metastases', 'Disease', (77, 87))	('poor differentiation', 'CPA', (44, 64))	('shorter', 'NegReg', (93, 100))	('metastases', 'Disease', 'MESH:D009362', (77, 87))
609635	31601234	Effective knockdown of PVT1 in EAC cells using PVT1 ASOs resulted in decreased cell proliferation, invasion, colony formation, tumor sphere formation, and reduced proportion of ALDH1A1+ cells.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('PVT1', 'Var', (47, 51))	('EAC', 'Disease', 'MESH:D004941', (31, 34))	('reduced', 'NegReg', (155, 162))	('tumor', 'Disease', (127, 132))	('cell proliferation', 'CPA', (79, 97))	('decreased', 'NegReg', (69, 78))	('colony formation', 'CPA', (109, 125))	('ALDH1A1', 'Gene', (177, 184))	('invasion', 'CPA', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('ALDH1A1', 'Gene', '216', (177, 184))	('EAC', 'Disease', (31, 34))
609637	31601234	Inhibition of PVT1 by PVT1 ASOs suppressed YAP1 expression through increased phosphor-LATS1and phosphor-YAP1 while knockout of YAP1 in EAC cells significantly suppressed PVT1 levels indicating a positive regulation of PVT1 by YAP1.	('knockout', 'Var', (115, 123))	('EAC', 'Disease', 'MESH:D004941', (135, 138))	('EAC', 'Disease', (135, 138))	('expression', 'MPA', (48, 58))	('increased', 'PosReg', (67, 76))	('suppressed', 'NegReg', (159, 169))	('LATS1', 'Gene', (86, 91))	('LATS1', 'Gene', '9113', (86, 91))	('PVT1 levels', 'MPA', (170, 181))	('YAP1', 'Gene', (43, 47))	('suppressed', 'NegReg', (32, 42))
609646	31601234	Amplification of 8q24 is one of the most frequent events in many cancers including EAC.	('EAC', 'Disease', (83, 86))	('Amplification', 'Var', (0, 13))	('EAC', 'Disease', 'MESH:D004941', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('frequent', 'Reg', (41, 49))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))
609647	31601234	In recent years, increasing evidence suggests that the plasmacytoma variant translocation 1 (PVT1) gene, which maps to 8q24, plays an oncogenic role through either amplification or overexpression.	('plasmacytoma variant translocation 1', 'Gene', (55, 91))	('plasmacytoma variant translocation 1', 'Gene', '5820', (55, 91))	('plasmacytoma', 'Phenotype', 'HP:0011857', (55, 67))	('overexpression', 'PosReg', (181, 195))	('amplification', 'Var', (164, 177))	('PVT1', 'Gene', (93, 97))
609654	31601234	Inhibition of LncRNA has been reported as a potential therapeutic strategy in some human diseases including cancer.	('human', 'Species', '9606', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Inhibition', 'Var', (0, 10))	('LncRNA', 'Protein', (14, 20))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
609659	31601234	The anticancer effect of silencing PVT1 with ASOs was examined in vitro and in vivo.	('silencing', 'Var', (25, 34))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('PVT1', 'Gene', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
609690	31601234	First, genomic alteration of PVT1 was analyzed using the TCGA dataset across multiple cancer types; we found that ESCA was the second-ranking cancer type with high PVT1 alterations with 20% PVT1 amplification and around 75% of ESCA cases contained both amplification and duplications (> 3 N) (Fig.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('alterations', 'Var', (169, 180))	('cancer', 'Disease', (142, 148))	('ESCA', 'Disease', 'MESH:D004938', (227, 231))	('ESCA', 'Disease', 'MESH:D004938', (114, 118))	('amplification', 'PosReg', (195, 208))	('contained', 'Reg', (238, 247))	('ESCA', 'Disease', (227, 231))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PVT1', 'Gene', (164, 168))	('duplications', 'Var', (271, 283))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('ESCA', 'Disease', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('PVT1', 'Gene', (190, 194))	('cancer', 'Disease', (86, 92))
609692	31601234	When integrated with TCGA RNA Seq data in ESCA, genetic alterations of PVT1 either duplication or amplification were significantly associated with PVT1 expression level (Fig.	('PVT1', 'Gene', (71, 75))	('ESCA', 'Disease', (42, 46))	('associated', 'Reg', (131, 141))	('amplification', 'Var', (98, 111))	('duplication', 'Var', (83, 94))	('ESCA', 'Disease', 'MESH:D004938', (42, 46))	('PVT1 expression level', 'MPA', (147, 168))	('genetic alterations', 'Var', (48, 67))
609707	31601234	The results showed that both PVT1 ASOs could significantly suppress colony formation in a dose-dependent manner in both EAC cells compared with untreated or control ASO-treated cells (Fig.	('colony formation', 'CPA', (68, 84))	('PVT1 ASOs', 'Var', (29, 38))	('EAC', 'Disease', (120, 123))	('suppress', 'NegReg', (59, 67))	('EAC', 'Disease', 'MESH:D004941', (120, 123))
609713	31601234	In addition, the expression of PVT1 as measured by qPCR in tumor tissues showed significant reduction when treated with PVT1 ASO compared with the control ASO group (Fig.	('tumor', 'Disease', (59, 64))	('PVT1 ASO', 'Var', (120, 128))	('expression', 'MPA', (17, 27))	('reduction', 'NegReg', (92, 101))	('PVT1', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
609716	31601234	Figures 4a & b show that tumor sphere formation in both JHESO and OE19 cells were significantly reduced upon treatment with PVT1 ASOs compared with that in EAC cells treated with control ASO.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('with PVT1', 'Var', (119, 128))	('EAC', 'Disease', 'MESH:D004941', (156, 159))	('EAC', 'Disease', (156, 159))	('tumor', 'Disease', (25, 30))	('significantly', 'NegReg', (82, 95))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
609720	31601234	While PVT1 knockdown by ASOs greatly decreased the population of ALDH1A1+ cells (Fig.	('ALDH1A1', 'Gene', (65, 72))	('PVT1', 'Gene', (6, 10))	('ALDH1A1', 'Gene', '216', (65, 72))	('decreased', 'NegReg', (37, 46))	('knockdown', 'Var', (11, 20))
609738	31601234	These data suggested that blocking both PVT1 and YAP1 resulted in a synergistical inhibition of EAC cell growth in vitro.	('blocking', 'Var', (26, 34))	('YAP1', 'Gene', (49, 53))	('EAC', 'Disease', 'MESH:D004941', (96, 99))	('inhibition', 'NegReg', (82, 92))	('EAC', 'Disease', (96, 99))	('PVT1', 'Gene', (40, 44))
609747	31601234	In the present study, we verified that amplification of PVT1 gene is a common event in EAC.	('amplification', 'Var', (39, 52))	('EAC', 'Disease', 'MESH:D004941', (87, 90))	('EAC', 'Disease', (87, 90))	('PVT1', 'Gene', (56, 60))
609751	31601234	Furthermore, we demonstrated, for the first time, that there is mutual regulation of PVT1 and YAP1 in EAC cells and that co-suppression of PVT1 and YAP1 by their specific ASO led to more effective suppression of EAC tumor growth in vitro and in vivo.	('tumor', 'Disease', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('PVT1', 'Gene', (85, 89))	('YAP1', 'Gene', (148, 152))	('YAP1', 'Gene', (94, 98))	('suppression', 'NegReg', (197, 208))	('EAC', 'Disease', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('EAC', 'Disease', (212, 215))	('co-suppression', 'Var', (121, 135))	('EAC', 'Disease', 'MESH:D004941', (102, 105))	('PVT1', 'Gene', (139, 143))	('EAC', 'Disease', 'MESH:D004941', (212, 215))
609752	31601234	Chromosome translocation was the first identified abnormality of PVT1 in tumors (Burkitt lymphoma).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (81, 97))	('Burkitt lymphoma', 'Disease', (81, 97))	('Chromosome translocation', 'Var', (0, 24))	('PVT1', 'Gene', (65, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (89, 97))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (81, 97))	('tumors', 'Disease', (73, 79))
609753	31601234	However, in many solid tumors, amplification and gain in copy number are the most frequent genetic alterations of PVT1.	('solid tumors', 'Disease', (17, 29))	('copy number', 'MPA', (57, 68))	('gain', 'PosReg', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('PVT1', 'Gene', (114, 118))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('amplification', 'Var', (31, 44))
609761	31601234	Mechanistically, PVT1 lncRNA knockdown increased phosphorylated LATS1 and phosphorylation of YAP1 which led to inactivated YAP1 leading to tumor growth inhibition.	('phosphorylation', 'MPA', (74, 89))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('phosphorylated', 'MPA', (49, 63))	('knockdown', 'Var', (29, 38))	('PVT1', 'Gene', (17, 21))	('LATS1', 'Gene', (64, 69))	('YAP1', 'Gene', (93, 97))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('increased', 'PosReg', (39, 48))	('inactivated', 'NegReg', (111, 122))	('LATS1', 'Gene', '9113', (64, 69))	('YAP1', 'Gene', (123, 127))
609762	31601234	On the other hand, the PVT1 levels were significantly repressed in YAP1 knockout cells but enhanced in EAC cells with inducible YAP1 overexpression indicating a positive feedback regulation of PVT1 by YAP1.	('knockout', 'Var', (72, 80))	('EAC', 'Disease', (103, 106))	('EAC', 'Disease', 'MESH:D004941', (103, 106))	('PVT1 levels', 'MPA', (23, 34))	('YAP1', 'Gene', (128, 132))	('YAP1', 'Gene', (67, 71))	('enhanced', 'PosReg', (91, 99))
609768	31601234	In this study, we investigated the cooperative antitumor effect through knockdown of PVT1 and YAP1 using their specific ASOs.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PVT1', 'Gene', (85, 89))	('investigated', 'Reg', (18, 30))	('tumor', 'Disease', (51, 56))	('YAP1', 'Gene', (94, 98))	('knockdown', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
609773	31601234	ASOs antisense oligonucleotides ceRNA competing endogenous RNA CIN chromosomal instability CNVs copy number variations CSC cancer stem cell EAC Esophageal adenocarcinoma EC Esophageal cancer ESCA Esophageal carcinoma ESCC esophageal squamous cell carcinoma LncRNA Long non-coding RNA PVT1 plasmacytoma variant translocation 1 qPCR quantitative real-time PCR TCGA The Cancer Genome Atlas Conception and design: SS, JAA; Development of methodology: SS, YX; Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ESCC', 'Disease', 'MESH:C562729', (217, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (222, 256))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ESCA', 'Disease', (191, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('Esophageal carcinoma', 'Disease', (196, 216))	('ESCA', 'Disease', 'MESH:D004938', (191, 195))	('Cancer', 'Phenotype', 'HP:0002664', (367, 373))	('plasmacytoma variant translocation 1', 'Gene', (289, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('ESCC', 'Disease', (217, 221))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('esophageal squamous cell carcinoma', 'Disease', (222, 256))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (144, 169))	('Esophageal cancer', 'Disease', (173, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('chromosomal instability', 'Phenotype', 'HP:0040012', (67, 90))	('Esophageal adenocarcinoma', 'Disease', (144, 169))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (196, 216))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (196, 216))	('plasmacytoma variant translocation 1', 'Gene', '5820', (289, 325))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (144, 169))	('cancer', 'Disease', (123, 129))	('variations', 'Var', (108, 118))	('Esophageal cancer', 'Disease', 'MESH:D004938', (173, 190))	('EAC', 'Disease', (140, 143))	('plasmacytoma', 'Phenotype', 'HP:0011857', (289, 301))	('patients', 'Species', '9606', (515, 523))	('EAC', 'Disease', 'MESH:D004941', (140, 143))
609792	31528223	Using data from the FIESTA cohort, a total of 6865 eligible patients who underwent radical surgery for esophageal cancer (n=2535), gastric cancer (n=3012) and colorectal cancer (n=1318) at Fujian Provincial Cancer Hospital (the current Fujian Cancer Hospital & Fujian Medical University Cancer Hospital) and survived hospitalization between January 2000 and December 2010 were analyzed in the current study, and they were followed up as of December 2015.	('Cancer', 'Disease', 'MESH:D009369', (207, 213))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('Cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('Cancer', 'Phenotype', 'HP:0002664', (287, 293))	('Cancer', 'Disease', (243, 249))	('n=1318', 'Var', (178, 184))	('patients', 'Species', '9606', (60, 68))	('colorectal cancer', 'Disease', (159, 176))	('n=3012', 'Var', (147, 153))	('Cancer', 'Disease', (287, 293))	('gastric cancer', 'Disease', (131, 145))	('Cancer', 'Phenotype', 'HP:0002664', (207, 213))	('Cancer', 'Disease', 'MESH:D009369', (243, 249))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('Cancer', 'Disease', (207, 213))	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('Cancer', 'Disease', 'MESH:D009369', (287, 293))	('esophageal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))
609811	31528223	Accordingly, 6865 patients were classified into five groups according to above glucose thresholds in mmol/L: fasting glucose concentrations <=4.36 (group I: n=891), (4.36, 6.09] (group II: n=3469), (6.09, 8.95] (group III: n=1440), (8.95, 11.5] (group IV: n=430) and >11.5 (group V: n=635).	('glucose', 'Chemical', 'MESH:D005947', (117, 124))	('8.95', 'Var', (233, 237))	('patients', 'Species', '9606', (18, 26))	('4.36', 'Var', (166, 170))	('6.09', 'Var', (199, 203))	('glucose', 'Chemical', 'MESH:D005947', (79, 86))
609819	31528223	Compared with patients with preoperative fasting glucose concentrations ranging 4.36-6.09 mmol/L, the cancer-specific mortality risk was significantly increased for both lower (than 4.36 mml/L) and higher (than 6.09 mmol/L) fasting glucose.	('than', 'Var', (206, 210))	('increased', 'PosReg', (151, 160))	('than 4.36 mml/L', 'Var', (177, 192))	('glucose', 'Chemical', 'MESH:D005947', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('glucose', 'Chemical', 'MESH:D005947', (232, 239))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('patients', 'Species', '9606', (14, 22))	('higher', 'PosReg', (198, 204))
609825	31528223	Additionally, low glucose can enhance the cytotoxicity of metformin to cancer cells both in vitro and in vivo.	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('glucose', 'Chemical', 'MESH:D005947', (18, 25))	('cancer', 'Disease', (71, 77))	('low glucose', 'Var', (14, 25))	('cytotoxicity', 'Disease', (42, 54))	('metformin', 'Chemical', 'MESH:D008687', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('enhance', 'PosReg', (30, 37))
609826	31528223	We in the FIESTA cohort study show that preoperative fasting glucose concentration less than 4.36 mmol/L was independently associated with a 35% increased mortality risk of common digestive tract cancer, especially for early stages (58% increase) and gastric cancer (47% increase).	('less than 4.36', 'Var', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('gastric cancer', 'Phenotype', 'HP:0012126', (251, 265))	('tract cancer', 'Disease', 'MESH:D014571', (190, 202))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tract cancer', 'Disease', (190, 202))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (180, 202))	('glucose', 'Chemical', 'MESH:D005947', (61, 68))	('gastric cancer', 'Disease', (251, 265))	('gastric cancer', 'Disease', 'MESH:D013274', (251, 265))
609969	31013858	For example, HER-2 positive advanced esophagogastric cancer patients benefit from anti HER-2 targeted therapy (trastuzumab), while HER-2 negative patients experience no benefit.	('HER-2', 'Gene', (87, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('HER-2', 'Gene', (131, 136))	('targeted therapy', 'Var', (93, 109))	('patients', 'Species', '9606', (60, 68))	('benefit', 'PosReg', (69, 76))	('HER-2', 'Gene', '2064', (13, 18))	('trastuzumab', 'Chemical', 'MESH:D000068878', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('HER-2', 'Gene', (13, 18))	('gastric cancer', 'Disease', (45, 59))	('HER-2', 'Gene', '2064', (87, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (45, 59))	('patients', 'Species', '9606', (146, 154))	('HER-2', 'Gene', '2064', (131, 136))
610007	31013858	The overaccumulation of mutations in CIN tumors may thus be exploited by inducing additional DNA damage.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('DNA damage', 'MPA', (93, 103))	('CIN tumors', 'Disease', (37, 47))	('mutations', 'Var', (24, 33))	('CIN tumors', 'Disease', 'MESH:D009369', (37, 47))
610021	31013858	Patients treated with neoadjuvant vinorelbine, cisplatin, and radiotherapy had a median OS of 100.1 months compared to 66.5 months in the surgery alone arm, HR = 0.71 (0.53-0.96).	('cisplatin', 'Var', (47, 56))	('Patients', 'Species', '9606', (0, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('vinorelbine', 'Var', (34, 45))	('vinorelbine', 'Chemical', 'MESH:D000077235', (34, 45))	('OS', 'Chemical', '-', (88, 90))
610032	31013858	Two nomograms predicting survival benefit in patient subgroups after neoadjuvant chemoradiotherapy found T4 disease, N+, higher grade, and higher T or N status related to survival benefit.	('patient', 'Species', '9606', (45, 52))	('T or', 'MPA', (146, 150))	('higher', 'Var', (121, 127))
610034	31013858	For the N0 vs. N+ subgroups in two large RCTs comparing neoadjuvant chemoradiation to surgery alone there was no superior benefit from nCRT in N+ tumors compared to N0 tumors.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('nCRT', 'Var', (135, 139))	('N0 tumors', 'Disease', 'MESH:D009369', (165, 174))	('tumors', 'Disease', (146, 152))	('N0 tumors', 'Disease', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
610077	31031844	Tylosis with ESCC has been linked to the autosomal dominant mutations in RHBDF2 gene and a high risk of ESCC is found in the ESCC patients with Tylosis, with a young age at onset and penetrance estimated to be as high as 90%.	('Tylosis', 'Disease', 'MESH:D053546', (0, 7))	('linked', 'Reg', (27, 33))	('Tylosis', 'Disease', (144, 151))	('Tylosis', 'Disease', (0, 7))	('ESCC', 'Disease', (13, 17))	('RHBDF2', 'Gene', '79651', (73, 79))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (60, 69))	('RHBDF2', 'Gene', (73, 79))	('Tylosis', 'Disease', 'MESH:D053546', (144, 151))
610154	31031844	Loss of heterozygosity (LOH) is more common in patients with a family history of upper gastrointestinal cancer than in those without such history.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (87, 110))	('Loss of heterozygosity', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('patients', 'Species', '9606', (47, 55))	('upper gastrointestinal cancer', 'Disease', 'MESH:D004067', (81, 110))	('upper gastrointestinal cancer', 'Disease', (81, 110))
610155	31031844	Two markers (D6S1027 on 6q and D9S910 on 9q) had significantly more LOH in patients with metastasis, and one marker (D4S2361 on 4p) showed significantly higher LOH in patients with a lower pathological tumor grade.	('D6S1027 on', 'Var', (13, 23))	('tumor', 'Disease', (202, 207))	('D9S910', 'Var', (31, 37))	('patients', 'Species', '9606', (167, 175))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('more', 'PosReg', (63, 67))	('metastasis', 'CPA', (89, 99))	('LOH', 'MPA', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
610157	31031844	LOH is significantly associated with poorer prognosis of glioma patients and colorectal cancers.	('colorectal cancers', 'Disease', 'MESH:D015179', (77, 95))	('patients', 'Species', '9606', (64, 72))	('colorectal cancers', 'Disease', (77, 95))	('LOH', 'Var', (0, 3))	('glioma', 'Disease', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))
610221	29392577	Significantly, defervescence by day 5 was more common in the B-CAP group (94%) than in the PO-CAP group (60%), and 30-day mortality was higher in the PO-CAP group (40%) than in the B-CAP group (12%).	('PO-CAP', 'Chemical', '-', (150, 156))	('B-CAP', 'Chemical', '-', (181, 186))	('higher', 'PosReg', (136, 142))	('B-CAP', 'Var', (61, 66))	('defervescence', 'Disease', (15, 28))	('B-CAP', 'Chemical', '-', (61, 66))	('PO-CAP', 'Chemical', '-', (91, 97))
610307	29234487	Normal processing of endogenous as well as environmental factors and agents such as alcohol, is central to cellular homeostasis, and the deregulation of these pathways leads to liver and gastrointestinal inflammation and injury- often caused by a complex interplay between genetic and environmental factors.	('deregulation', 'Var', (137, 149))	('alcohol', 'Chemical', 'MESH:D000438', (84, 91))	('liver and gastrointestinal inflammation and injury- often', 'Disease', 'MESH:D056486', (177, 234))	('men', 'Species', '9606', (292, 295))	('gastrointestinal inflammation', 'Phenotype', 'HP:0004386', (187, 216))	('leads to', 'Reg', (168, 176))	('men', 'Species', '9606', (50, 53))
610316	29234487	Nevertheless, the risk of cancer is proportional to the dosage of used alcohol as many studies showed that compared to nondrinkers and occasional drinkers, the pooled relative risk (RR) was 1.03 for any, 0.97 for light, 1.04 for moderate, and 1.21 for heavy drinkers.	('alcohol', 'Chemical', 'MESH:D000438', (71, 78))	('moderate', 'Var', (229, 237))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
610324	29234487	One of the most formidable of post replication DNA lesions, is the replication fork lesion, a barrier to chromosome duplication, which leads to mitotic catastrophe, complex chromosome rearrangements, and cell death.	('mitotic catastrophe', 'MPA', (144, 163))	('men', 'Species', '9606', (193, 196))	('replication fork', 'Disease', (67, 83))	('leads to', 'Reg', (135, 143))	('lesion', 'Var', (84, 90))
610328	29234487	FA is caused by bi-allelic mutations of fifteen members of FANC pathway with inability to respond to cellular stress and ensuing DNA damage during S phase and loss of genome integrity.	('FANC', 'Gene', (59, 63))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('FA', 'Phenotype', 'HP:0001994', (59, 61))	('inability', 'Disease', (77, 86))	('loss', 'NegReg', (159, 163))	('bi-allelic mutations', 'Var', (16, 36))	('caused by', 'Reg', (6, 15))	('inability', 'Disease', 'MESH:D016388', (77, 86))
610334	29234487	Fanc mutant intercrosses with ALDH2 mutant mice are susceptible to ethanol teratogenicity and defective DNA inter-strand cross link repair.	('mice', 'Species', '10090', (43, 47))	('defective DNA inter-strand cross link repair', 'Phenotype', 'HP:0410166', (94, 138))	('ALDH2', 'Gene', (30, 35))	('ethanol', 'Chemical', 'MESH:D000431', (67, 74))	('DNA inter-strand cross link repair', 'MPA', (104, 138))	('mutant', 'Var', (36, 42))	('susceptible', 'Reg', (52, 63))	('defective', 'NegReg', (94, 103))	('ethanol teratogenicity', 'MPA', (67, 89))
610338	29234487	Defective TGF-beta signaling is implicated in liver injury, inflammation and multiple cancers owing to the frequent somatic mutations in, or deregulation of, its components, such as Smad3, Smad4, and TGF-beta receptors 1 and 2 (TBR1 and TBR2) (Figure 1).	('Smad4', 'Gene', (189, 194))	('liver injury', 'Disease', (46, 58))	('deregulation', 'MPA', (141, 153))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('multiple cancers', 'Disease', (77, 93))	('Smad3', 'Gene', '17127', (182, 187))	('liver injury', 'Disease', 'MESH:D056486', (46, 58))	('TBR1', 'Gene', '21375', (228, 232))	('TBR2', 'Gene', '13813', (237, 241))	('inflammation', 'Disease', (60, 72))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('Defective', 'Var', (0, 9))	('Smad3', 'Gene', (182, 187))	('TGF-beta', 'Gene', (10, 18))	('Smad4', 'Gene', '17128', (189, 194))	('TBR2', 'Gene', (237, 241))	('implicated', 'Reg', (32, 42))	('TBR1', 'Gene', (228, 232))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('multiple cancers', 'Disease', 'MESH:D009369', (77, 93))	('mutations', 'Var', (124, 133))
610342	29234487	The major role of beta2SP in maintaining genomic stability following alcohol-induced DNA damage is supported by the fact that beta2SP defective mouse embryos display some symptom of human fetal alcohol syndrome (Figure 2).	('defective', 'Var', (134, 143))	('fetal alcohol syndrome', 'Disease', 'MESH:D063647', (188, 210))	('mouse', 'Species', '10090', (144, 149))	('alcohol', 'Chemical', 'MESH:D000438', (194, 201))	('beta2', 'Gene', (126, 131))	('human', 'Species', '9606', (182, 187))	('fetal alcohol syndrome', 'Disease', (188, 210))	('beta2', 'Gene', (18, 23))	('beta2', 'Gene', '15130', (126, 131))	('alcohol', 'Chemical', 'MESH:D000438', (69, 76))	('alcohol syndrome', 'Phenotype', 'HP:0030955', (194, 210))	('beta2', 'Gene', '15130', (18, 23))
610343	29234487	Furthermore, the development of hepatocellular cancers (HCCs) in beta2SP heterozygote mutants establishes beta2SP as a functional tumor suppressor.	('hepatocellular cancers', 'Disease', (32, 54))	('mutants', 'Var', (86, 93))	('men', 'Species', '9606', (24, 27))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('hepatocellular cancers', 'Disease', 'MESH:D006528', (32, 54))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('beta2', 'Gene', (106, 111))	('beta2', 'Gene', (65, 70))	('beta2', 'Gene', '15130', (65, 70))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('beta2', 'Gene', '15130', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (130, 135))
610346	29234487	Indeed, loss of beta2SP leads to decreased Fancd2 levels and sensitizes beta2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both ALDH2 and Fancd2 and resemble human fetal alcohol syndrome.	('fetal alcohol syndrome', 'Disease', 'MESH:D063647', (243, 265))	('alcohol syndrome', 'Phenotype', 'HP:0030955', (249, 265))	('beta2', 'Gene', (16, 21))	('human', 'Species', '9606', (237, 242))	('beta2', 'Gene', '15130', (16, 21))	('sensitizes', 'Reg', (61, 71))	('fetal alcohol syndrome', 'Disease', (243, 265))	('mutants', 'Var', (80, 87))	('ethanol', 'Chemical', 'MESH:D000431', (105, 112))	('men', 'Species', '9606', (118, 121))	('loss', 'NegReg', (8, 12))	('Fancd2 levels', 'MPA', (43, 56))	('decreased', 'NegReg', (33, 42))	('beta2', 'Gene', (72, 77))	('beta2', 'Gene', '15130', (72, 77))
610351	29234487	Alcohol feeding to mice expressing the HCV Ns5a in a hepatocyte specific manner aggravates liver inflammation via activation of overexpressed TLR4 in the parenchymal cells.	('activation', 'PosReg', (114, 124))	('HCV Ns5a', 'Var', (39, 47))	('liver inflammation', 'Disease', 'MESH:D007249', (91, 109))	('aggravates', 'PosReg', (80, 90))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('TLR4', 'Gene', (142, 146))	('liver inflammation', 'Phenotype', 'HP:0012115', (91, 109))	('liver inflammation', 'Disease', (91, 109))	('TLR4', 'Gene', '21898', (142, 146))	('Alcohol feeding', 'Phenotype', 'HP:0030955', (0, 15))	('overexpressed', 'MPA', (128, 141))	('aggravates liver', 'Phenotype', 'HP:0002240', (80, 96))	('mice', 'Species', '10090', (19, 23))	('Ns5a', 'Var', (43, 47))
610358	29234487	Whilst the phenotypes in the TGF-beta deficient mutant mice are dramatic and restricted to specific compartments, it is clear that multiple tiers of control are present in the human disease- LOI at chromosome 11 leading to raised levels of TERT, IGF2, etc.	('mutant', 'Var', (48, 54))	('men', 'Species', '9606', (107, 110))	('IGF2', 'Gene', '3481', (246, 250))	('TGF-beta', 'Gene', (29, 37))	('human', 'Species', '9606', (176, 181))	('TERT', 'Gene', (240, 244))	('mice', 'Species', '10090', (55, 59))	('TERT', 'Gene', '7015', (240, 244))	('IGF2', 'Gene', (246, 250))	('raised', 'PosReg', (223, 229))	('deficient mutant', 'Var', (38, 54))	('levels', 'MPA', (230, 236))
610359	29234487	The heterozygous TGF-beta deficient mutants develop cancers spontaneously on a C57BL/6 background and in this regard the heterozygotes resemble sporadic cancer formation in humans.	('TGF-beta', 'Gene', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('deficient', 'NegReg', (26, 35))	('cancer', 'Disease', (153, 159))	('humans', 'Species', '9606', (173, 179))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutants', 'Var', (36, 43))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('develop', 'Reg', (44, 51))
610443	27382308	In our data, strong correlations were found between the tumor movement and the bilateral lung centroid motion and also showed a good correlation between the GTV motion and the lung volume variation, so even during free breathing, the chest expansion bears the risk for increasing the tumor motion and deformation.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('chest expansion', 'Var', (234, 249))	('tumor movement', 'Disease', (56, 70))	('deformation', 'CPA', (301, 312))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('GTV', 'Chemical', '-', (157, 160))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('tumor movement', 'Disease', 'MESH:D009069', (56, 70))	('increasing', 'PosReg', (269, 279))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumor', 'Disease', (284, 289))
610485	26818094	Patients with high expression of TRPV6 exhibits a worse survival when compared to those with low or intermediate TRPV6 expression in breast cancer.	('breast cancer', 'Disease', (133, 146))	('TRPV6', 'Gene', '55503', (113, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('TRPV6', 'Gene', (113, 118))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('TRPV6', 'Gene', '55503', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('TRPV6', 'Gene', (33, 38))
610499	26818094	The ESCC cell lines, including KYSE30, KYSE140, KYSE180, KYSE 410, KYSE510, KYSE520, HKESC1, CE81T, EC109 and EC9706were all kindly provided by Prof. Xinyuan Guan from Hong Kong University, and maintained in Dulbecco's Modified Eagle Medium supplemented with 10 % fetal bovine serum and 10 % penicillin-streptomycin at 37  C in a humidified incubator containing 5 % CO2.	('EC9706were', 'Var', (110, 120))	('EC109', 'CellLine', 'CVCL:6898', (100, 105))	('CE81T', 'Var', (93, 98))	('CO2', 'Gene', '717', (366, 369))	('KYSE30', 'Var', (31, 37))	('HKESC1', 'CellLine', 'CVCL:D568', (85, 91))	('bovine', 'Species', '9913', (270, 276))	('EC9706', 'CellLine', 'CVCL:E307', (110, 116))	('KYSE520', 'Var', (76, 83))	('CO2', 'Gene', (366, 369))	('KYSE510', 'Var', (67, 74))	('KYSE 410', 'Var', (57, 65))	('KYSE140', 'Var', (39, 46))	('KYSE180', 'Var', (48, 55))
610523	26818094	The staining index of TRPV6 in each informative nontumor tissue was equal or greater than 5; therefore, staining index 5-7 was counted as normal expression of TRPV6 whereas 0-4 was counted as downregulation of TRPV6.	('staining', 'Var', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TRPV6', 'Gene', (22, 27))	('tumor', 'Disease', (51, 56))	('TRPV6', 'Gene', '55503', (159, 164))	('TRPV6', 'Gene', '55503', (210, 215))	('downregulation', 'NegReg', (192, 206))	('TRPV6', 'Gene', (210, 215))	('TRPV6', 'Gene', '55503', (22, 27))	('TRPV6', 'Gene', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
610527	26818094	In mRNA cohort, the optimal cutoff value of TRPV6 with the best discriminatory power was determined to be 0.207 based on the ROC curve.	('0.207', 'Var', (106, 111))	('TRPV6', 'Gene', (44, 49))	('TRPV6', 'Gene', '55503', (44, 49))
610529	26818094	Then, TRPV6 mRNA expression in mRNA cohort was divided into two groups: downregulation (<=0.207, n = 66) and normal expression (>0.207, n = 108) group.	('<=0.207', 'Var', (88, 95))	('TRPV6', 'Gene', '55503', (6, 11))	('TRPV6', 'Gene', (6, 11))	('downregulation', 'NegReg', (72, 86))
610564	26818094	Additionally, breast cancer patients with high expression of TRPV6 have a worse survival when compared to those with low or intermediate TRPV6 expression.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('TRPV6', 'Gene', (61, 66))	('TRPV6', 'Gene', '55503', (137, 142))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('TRPV6', 'Gene', (137, 142))	('high expression', 'Var', (42, 57))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('TRPV6', 'Gene', '55503', (61, 66))	('patients', 'Species', '9606', (28, 36))
610667	22720064	In the adjusted models, older age, history of weight loss, history of GI bleeding, persistent vomiting, being current cigarette smoker, family history of UGI cancer, and H. pylori positivity were all positively associated with risk of UGI cancers.	('GI bleeding', 'Disease', 'MESH:D006470', (70, 81))	('GI bleeding', 'Disease', (70, 81))	('positivity', 'Var', (180, 190))	('UGI cancers', 'Disease', (235, 246))	('vomiting', 'Disease', 'MESH:D014839', (94, 102))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('UGI cancers', 'Disease', 'MESH:D009369', (235, 246))	('pylori positivity', 'Phenotype', 'HP:0005202', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('vomiting', 'Disease', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('vomiting', 'Phenotype', 'HP:0002013', (94, 102))	('GI bleeding', 'Phenotype', 'HP:0002239', (70, 81))	('persistent vomiting', 'Phenotype', 'HP:0002572', (83, 102))	('H. pylori', 'Gene', (170, 179))	('weight loss', 'Disease', 'MESH:D015431', (46, 57))	('H. pylori', 'Species', '210', (170, 179))	('associated', 'Reg', (211, 221))	('weight loss', 'Phenotype', 'HP:0001824', (46, 57))	('UGI cancer', 'Disease', 'MESH:D009369', (154, 164))	('UGI cancer', 'Disease', 'MESH:D009369', (235, 245))	('UGI cancer', 'Disease', (154, 164))	('weight loss', 'Disease', (46, 57))
610871	33744728	Obviously, the late recurrent patients have the best post-recurrent five-year survival under CCRT (33.3%), which conferred a significant survival benefit compared with SCRT (25%) or RT alone (11.6%).	('CCRT', 'Var', (93, 97))	('patients', 'Species', '9606', (30, 38))	('post', 'Gene', '159371', (53, 57))	('post', 'Gene', (53, 57))
610876	33744728	2C), which indicated that overall prognosis of patients after radical resection was mainly impacted by RFS.	('patients', 'Species', '9606', (47, 55))	('impacted', 'Reg', (91, 99))	('RFS', 'Var', (103, 106))
610902	32824814	Moreover, the expression of PTTG3P, PTTG1 and PTTG2 depends on the type of mutation in TP53 gene, and they correlate with genes from p53 pathway.	('depends', 'Reg', (52, 59))	('PTTG1', 'Gene', (36, 41))	('PTTG3P', 'Gene', '26255', (28, 34))	('PTTG1', 'Gene', '9232', (36, 41))	('TP53', 'Gene', '7157', (87, 91))	('PTTG2', 'Gene', '10744', (46, 51))	('PTTG3P', 'Gene', (28, 34))	('mutation', 'Var', (75, 83))	('TP53', 'Gene', (87, 91))	('p53', 'Gene', '7157', (133, 136))	('p53', 'Gene', (133, 136))	('correlate', 'Reg', (107, 116))	('PTTG2', 'Gene', (46, 51))
610910	32824814	Moreover, patients with high expressions of PTTG3P, PTTG1 or PTTG2 have worse outcomes due to upregulation of oncogenic pathways and more aggressive phenotypes.	('PTTG3P', 'Gene', (44, 50))	('PTTG2', 'Gene', (61, 66))	('upregulation', 'PosReg', (94, 106))	('aggressive phenotypes', 'CPA', (138, 159))	('PTTG3P', 'Gene', '26255', (44, 50))	('PTTG1', 'Gene', (52, 57))	('patients', 'Species', '9606', (10, 18))	('PTTG1', 'Gene', '9232', (52, 57))	('PTTG2', 'Gene', '10744', (61, 66))	('high expressions', 'Var', (24, 40))	('oncogenic pathways', 'Pathway', (110, 128))
610921	32824814	The aforementioned functions include the capability to synthesize proteins due to events such as insertions, premature stop codons, frameshift-causing deletions and splicing errors.	('frameshift-causing', 'Reg', (132, 150))	('men', 'Species', '9606', (9, 12))	('premature stop codons', 'Var', (109, 130))	('splicing errors', 'Var', (165, 180))	('insertions', 'Var', (97, 107))
610925	32824814	It has also shown examples of ectopic expression of PTENP1 inhibited proliferation, colony formation and migration of HNSCC cells, which proves that PTENP1 may serve as a prognostic factor in patients with HNSCC.	('rat', 'Species', '10116', (108, 111))	('HNSCC', 'Disease', (206, 211))	('proliferation', 'CPA', (69, 82))	('rat', 'Species', '10116', (76, 79))	('PTENP1', 'Gene', '11191', (149, 155))	('inhibited', 'NegReg', (59, 68))	('colony formation', 'CPA', (84, 100))	('migration of HNSCC cells', 'CPA', (105, 129))	('patients', 'Species', '9606', (192, 200))	('ectopic expression', 'Var', (30, 48))	('PTENP1', 'Gene', (52, 58))	('PTENP1', 'Gene', '11191', (52, 58))	('PTENP1', 'Gene', (149, 155))
610940	32824814	indicated that PTTG2 silencing results in increased levels of p53 protein.	('increased', 'PosReg', (42, 51))	('PTTG2', 'Gene', (15, 20))	('silencing', 'Var', (21, 30))	('PTTG2', 'Gene', '10744', (15, 20))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('levels', 'MPA', (52, 58))
610942	32824814	Mutations in TP53 gene are prevalent in many cancers, including HNSCC.	('TP53', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('HNSCC', 'Disease', (64, 69))	('TP53', 'Gene', '7157', (13, 17))	('cancers', 'Disease', (45, 52))	('prevalent', 'Reg', (27, 36))
610944	32824814	Mutations in p53 can be divided into two main groups: DNA contact mutations (such as R273H and R280K) and conformational mutations (such as R175H and V143A).	('R280K', 'Var', (95, 100))	('V143A', 'Var', (150, 155))	('V143A', 'Mutation', 'p.V143A', (150, 155))	('R280K', 'Mutation', 'rs121912660', (95, 100))	('R273H', 'Mutation', 'rs28934576', (85, 90))	('R175H', 'Mutation', 'rs28934578', (140, 145))	('p53', 'Gene', (13, 16))	('R273H', 'Var', (85, 90))	('p53', 'Gene', '7157', (13, 16))	('R175H', 'Var', (140, 145))
610945	32824814	Missense mutations in the DNA-binding domain are the most common ones among TP53 mutations.	('common', 'Reg', (58, 64))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('Missense mutations in', 'Var', (0, 21))
610946	32824814	It should be noted that besides loss-of-function of wild type p53 and dominant-negative forms of p53, some mutations cause gain-of-function and lead to tumor progression, metastatic potential as well as may influence drug resistance.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('drug resistance', 'CPA', (217, 232))	('influence', 'Reg', (207, 216))	('p53', 'Gene', (97, 100))	('mutations', 'Var', (107, 116))	('gain-of-function', 'PosReg', (123, 139))	('drug resistance', 'Phenotype', 'HP:0020174', (217, 232))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('p53', 'Gene', '7157', (62, 65))	('p53', 'Gene', '7157', (97, 100))	('tumor', 'Disease', (152, 157))	('lead to', 'Reg', (144, 151))	('metastatic potential', 'CPA', (171, 191))	('p53', 'Gene', (62, 65))	('loss-of-function', 'NegReg', (32, 48))
610948	32824814	Moreover, specific TP53 mutations are associated with different anatomical sites of HNSCC and modulate its cellular activity in different ways.	('associated', 'Reg', (38, 48))	('modulate', 'Reg', (94, 102))	('HNSCC', 'Disease', (84, 89))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('cellular activity', 'MPA', (107, 124))	('mutations', 'Var', (24, 33))
610952	32824814	The expression levels of PTTG3P, PTTG1 and PTTG2 genes were analyzed and correlated with clinicopathological parameters such as: age (<=60 vs. >60), gender (women vs. men), smoking category (1, 2 vs. 3, 4, 5), alcohol history (negative vs. positive), T-stage (T1 + T2 vs. T3 + T4), N-stage (N0 + N1 vs. N2 + N3), cancer grade (G1 + G2 vs. G3 + G4), cancer stage (I + II vs. III + IV), HPV p16 marker (negative vs. positive), perineural invasion (negative vs. positive), lymphovascular invasion (negative vs. positive), and lymphoid neck dissection status (negative vs. positive) in all localizations of the HNSCC samples.	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('N0 + N1', 'Var', (291, 298))	('men', 'Species', '9606', (159, 162))	('HPV', 'Species', '10566', (385, 388))	('PTTG3P', 'Gene', (25, 31))	('PTTG2', 'Gene', (43, 48))	('women', 'Species', '9606', (157, 162))	('cancer', 'Disease', (349, 355))	('p16', 'Gene', (389, 392))	('PTTG3P', 'Gene', '26255', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('men', 'Species', '9606', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('PTTG1', 'Gene', (33, 38))	('p16', 'Gene', '1029', (389, 392))	('G1 + G2 vs. G3 + G4', 'Var', (327, 346))	('perineural invasion', 'CPA', (425, 444))	('alcohol', 'Chemical', 'MESH:D000438', (210, 217))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('PTTG2', 'Gene', '10744', (43, 48))	('cancer', 'Disease', (313, 319))	('PTTG1', 'Gene', '9232', (33, 38))
610956	32824814	Next, specific mutations in TP53, described previously by Caponio et al.	('TP53', 'Gene', (28, 32))	('TP53', 'Gene', '7157', (28, 32))	('mutations', 'Var', (15, 24))
610958	32824814	The mutant p53-interacting partners and genes transcriptionally activated by mutant p53 protein, described by Freed-Pastor and Prives, and their correlations with PTTG3P, PTTG1 or PTTG2 were evaluated using StarBase v3.0 database.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('PTTG3P', 'Gene', '26255', (163, 169))	('PTTG1', 'Gene', (171, 176))	('PTTG1', 'Gene', '9232', (171, 176))	('PTTG2', 'Gene', '10744', (180, 185))	('PTTG3P', 'Gene', (163, 169))	('activated', 'PosReg', (64, 73))	('p53', 'Gene', (84, 87))	('PTTG2', 'Gene', (180, 185))	('p53', 'Gene', '7157', (84, 87))	('protein', 'Protein', (88, 95))	('mutant', 'Var', (77, 83))
610984	32824814	In all analyzed genes, a significantly higher (p < 0.05) expression of mutant and wild type TP53 cases (compared to normal samples) was observed.	('expression', 'MPA', (57, 67))	('higher', 'PosReg', (39, 45))	('mutant', 'Var', (71, 77))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))
610987	32824814	In all examined cases, the highest expressions of PTTG3P, PTTG1 and PTTG2 were observed in wild type TP53 versus DNA contact mutations (p = 0.0127; p = 0.0072; p = 0.0323, respectively), Figure 4B.	('mutations', 'Var', (125, 134))	('PTTG2', 'Gene', '10744', (68, 73))	('TP53', 'Gene', '7157', (101, 105))	('expressions', 'MPA', (35, 46))	('PTTG1', 'Gene', (58, 63))	('PTTG2', 'Gene', (68, 73))	('PTTG3P', 'Gene', '26255', (50, 56))	('PTTG1', 'Gene', '9232', (58, 63))	('TP53', 'Gene', (101, 105))	('PTTG3P', 'Gene', (50, 56))
610988	32824814	Analysis of different division of TP53 mutation types showed significant differences between missense mutations versus wild type and truncating mutations versus wild type for PTTG3P and PTTG1 (p = 0.0011; p = 0.0025, respectively).	('PTTG3P', 'Gene', (175, 181))	('TP53', 'Gene', (34, 38))	('truncating mutations', 'Var', (133, 153))	('missense mutations', 'Var', (93, 111))	('PTTG3P', 'Gene', '26255', (175, 181))	('differences', 'Reg', (73, 84))	('PTTG1', 'Gene', (186, 191))	('TP53', 'Gene', '7157', (34, 38))	('PTTG1', 'Gene', '9232', (186, 191))
610989	32824814	Finally, for PTTG2, significant difference was observed only between missense mutations versus wild type TP53 (p = 0.0099), Figure 4B.	('difference', 'Reg', (32, 42))	('PTTG2', 'Gene', (13, 18))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('missense mutations', 'Var', (69, 87))	('PTTG2', 'Gene', '10744', (13, 18))
610990	32824814	Next, selected mutant p53-interacting partners and genes transcriptionally activated by mutant p53 protein were analyzed.	('p53', 'Gene', (22, 25))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', (95, 98))	('mutant', 'Var', (88, 94))	('p53', 'Gene', '7157', (95, 98))	('protein', 'Protein', (99, 106))
610991	32824814	In the case of mutant p53-interacting partners and PTTG3P statistically significant positive correlation (p < 0.05) of NF-YB, NF-YC, Pin1 and p73 expression, and negative of Ets-1, VDR and p63 was indicated.	('NF-YB', 'Gene', (119, 124))	('VDR', 'Gene', '7421', (181, 184))	('PTTG3P', 'Gene', (51, 57))	('NF-YB', 'Gene', '4801', (119, 124))	('expression', 'MPA', (146, 156))	('Pin1', 'Gene', (133, 137))	('PTTG3P', 'Gene', '26255', (51, 57))	('NF-YC', 'Gene', (126, 131))	('p53', 'Gene', '7157', (22, 25))	('Ets-1', 'Gene', '2113', (174, 179))	('p63', 'Gene', (189, 192))	('NF-YC', 'Gene', '4802', (126, 131))	('p53', 'Gene', (22, 25))	('Pin1', 'Gene', '5300', (133, 137))	('p63', 'Gene', '8626', (189, 192))	('VDR', 'Gene', (181, 184))	('mutant', 'Var', (15, 21))	('Ets-1', 'Gene', (174, 179))	('p73', 'Gene', '7161', (142, 145))	('p73', 'Gene', (142, 145))	('positive', 'PosReg', (84, 92))
610995	32824814	The group of genes transcriptionally activated by mutant p53 protein and positively correlated (R > 0.2, p < 0.05) with PTTG3P comprised CCNA2, KIF20A, MCM6, TIMM50, TERT, CENPA, CCNB2, CDK1, CCNB1, DUT, MIS18A, STMN1 and CDC25C, whereas in the group of negatively correlated (R < -0.17, p < 0.05) were IGF2, MMP3, CYP51A1 and MMP13.	('STMN1', 'Gene', (212, 217))	('MMP13', 'Gene', '4322', (327, 332))	('activated', 'PosReg', (37, 46))	('CDC25C', 'Gene', '995', (222, 228))	('DUT', 'Gene', '1854', (199, 202))	('mutant', 'Var', (50, 56))	('CCNB2', 'Gene', '9133', (179, 184))	('p53', 'Gene', '7157', (57, 60))	('CYP51A1', 'Gene', (315, 322))	('CDK1', 'Gene', '983', (186, 190))	('CCNB1', 'Gene', '891', (192, 197))	('CDK1', 'Gene', (186, 190))	('PTTG3P', 'Gene', (120, 126))	('CCNA2', 'Gene', '890', (137, 142))	('p53', 'Gene', (57, 60))	('PTTG3P', 'Gene', '26255', (120, 126))	('CYP51A1', 'Gene', '1595', (315, 322))	('TIMM50', 'Gene', '92609', (158, 164))	('IGF2', 'Gene', (303, 307))	('MIS18A', 'Gene', (204, 210))	('CENPA', 'Gene', (172, 177))	('MMP3', 'Gene', '4314', (309, 313))	('CCNB2', 'Gene', (179, 184))	('MCM6', 'Gene', '4175', (152, 156))	('CENPA', 'Gene', '1058', (172, 177))	('DUT', 'Gene', (199, 202))	('MIS18A', 'Gene', '54069', (204, 210))	('MMP3', 'Gene', (309, 313))	('CCNB1', 'Gene', (192, 197))	('KIF20A', 'Gene', (144, 150))	('protein', 'Protein', (61, 68))	('MCM6', 'Gene', (152, 156))	('STMN1', 'Gene', '3925', (212, 217))	('MMP13', 'Gene', (327, 332))	('TIMM50', 'Gene', (158, 164))	('IGF2', 'Gene', '3481', (303, 307))	('TERT', 'Gene', (166, 170))	('TERT', 'Gene', '7015', (166, 170))	('CDC25C', 'Gene', (222, 228))	('KIF20A', 'Gene', '10112', (144, 150))	('CCNA2', 'Gene', (137, 142))
611032	32824814	Our results indicated that expression levels of PTTG3P, PTTG1 and PTTG2 depend on TP53 mutation type.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('PTTG2', 'Gene', '10744', (66, 71))	('expression levels', 'MPA', (27, 44))	('PTTG3P', 'Gene', (48, 54))	('depend', 'Reg', (72, 78))	('PTTG2', 'Gene', (66, 71))	('PTTG1', 'Gene', (56, 61))	('mutation', 'Var', (87, 95))	('PTTG1', 'Gene', '9232', (56, 61))	('PTTG3P', 'Gene', '26255', (48, 54))
611035	32824814	The aforementioned genes interact with mutated and non-mutated p53.	('p53', 'Gene', '7157', (63, 66))	('p53', 'Gene', (63, 66))	('men', 'Species', '9606', (9, 12))	('interact', 'Reg', (25, 33))	('mutated', 'Var', (39, 46))
611036	32824814	NF-Y influences the cell cycle progression, Pin1 promotes mutant p53 gain-of-function, and PML enhances transcriptional activity of mutant p53.	('cell cycle progression', 'CPA', (20, 42))	('mutant', 'Var', (58, 64))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('enhances', 'PosReg', (95, 103))	('PML', 'Gene', (91, 94))	('transcriptional activity', 'MPA', (104, 128))	('mutant', 'Var', (132, 138))	('Pin1', 'Gene', '5300', (44, 48))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('Pin1', 'Gene', (44, 48))	('gain-of-function', 'PosReg', (69, 85))	('PML', 'Gene', '5371', (91, 94))	('influences', 'Reg', (5, 15))
611037	32824814	Only p73 interacts with specific mutated variants of p53 and is responsible for regulation of the cell cycle and induction of apoptosis.	('variants', 'Var', (41, 49))	('regulation', 'MPA', (80, 90))	('interacts', 'Interaction', (9, 18))	('responsible', 'Reg', (64, 75))	('apoptosis', 'CPA', (126, 135))	('p73', 'Gene', '7161', (5, 8))	('p53', 'Gene', (53, 56))	('p73', 'Gene', (5, 8))	('p53', 'Gene', '7157', (53, 56))	('cell cycle', 'CPA', (98, 108))
611040	32824814	To further investigate the connection between the PTTG gene family and p53, we analyzed genes transcriptionally activated by mutant p53.	('mutant', 'Var', (125, 131))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))
611044	32824814	These findings indicate that higher expression of PTTG3P, PTTG1 and PTTG2 is connected with activation of prosurvival and protumorigenic downstream genes by mutant p53 protein.	('higher', 'PosReg', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('protein', 'Protein', (168, 175))	('mutant', 'Var', (157, 163))	('PTTG2', 'Gene', '10744', (68, 73))	('activation', 'PosReg', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('PTTG3P', 'Gene', '26255', (50, 56))	('PTTG1', 'Gene', (58, 63))	('tumor', 'Disease', (125, 130))	('PTTG2', 'Gene', (68, 73))	('PTTG1', 'Gene', '9232', (58, 63))	('p53', 'Gene', (164, 167))	('PTTG3P', 'Gene', (50, 56))	('expression', 'MPA', (36, 46))	('p53', 'Gene', '7157', (164, 167))
611054	32824814	High expression of PTTG1 was found to be associated with advanced cancers and short disease-free survival.	('PTTG1', 'Gene', (19, 24))	('associated', 'Reg', (41, 51))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('short disease-free', 'Disease', 'MESH:D008569', (78, 96))	('short disease-free', 'Disease', (78, 96))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('PTTG1', 'Gene', '9232', (19, 24))
611055	32824814	Moreover Read et al., postulated that PTTG1IP does not reduce the stability of mutated p53 as it is observed in the case of mutant p53 protein in colorectal tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal tumors', 'Disease', 'MESH:D015179', (146, 163))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('mutant', 'Var', (124, 130))	('PTTG1IP', 'Gene', (38, 45))	('p53', 'Gene', (131, 134))	('colorectal tumors', 'Disease', (146, 163))	('PTTG1IP', 'Gene', '754', (38, 45))	('p53', 'Gene', '7157', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('protein', 'Protein', (135, 142))
611058	32824814	As mentioned above, a higher expression of PTTG3P was observed in pharyngeal tumors with HPV status.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('higher', 'PosReg', (22, 28))	('PTTG3P', 'Gene', '26255', (43, 49))	('pharyngeal tumors', 'Phenotype', 'HP:0100638', (66, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('HPV', 'Species', '10566', (89, 92))	('HPV status', 'Var', (89, 99))	('PTTG3P', 'Gene', (43, 49))	('expression', 'MPA', (29, 39))	('men', 'Species', '9606', (3, 6))
611080	32824814	demonstrated similar results in gastric cancer:high expressions of PTTG3P were correlated with significantly shorter DFS.	('gastric cancer', 'Disease', (32, 46))	('PTTG3P', 'Gene', '26255', (67, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('high expressions', 'Var', (47, 63))	('rat', 'Species', '10116', (7, 10))	('DFS', 'Disease', (117, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('PTTG3P', 'Gene', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('shorter', 'NegReg', (109, 116))
611085	32824814	GSEA analysis indicated that patients with low expressions of pseudogene PTTG3P, as well as PTTG1 and PTTG2 genes have significantly negatively enriched genes involved in some pathways, such as DNA repair, E2F targets, Myc targets and peroxisome.	('patients', 'Species', '9606', (29, 37))	('PTTG3P', 'Gene', '26255', (73, 79))	('PTTG1', 'Gene', (92, 97))	('low', 'NegReg', (43, 46))	('PTTG1', 'Gene', '9232', (92, 97))	('pseudogene', 'Var', (62, 72))	('PTTG2', 'Gene', (102, 107))	('Myc', 'Gene', '4609', (219, 222))	('Myc', 'Gene', (219, 222))	('involved', 'Reg', (159, 167))	('PTTG3P', 'Gene', (73, 79))	('PTTG2', 'Gene', '10744', (102, 107))	('pathways', 'Pathway', (176, 184))	('GSEA', 'Chemical', '-', (0, 4))	('negatively', 'NegReg', (133, 143))
611089	32824814	The result of DNA repair defects may be the accumulation of mutations that contribute to genomic instability and then to carcinogenesis.	('defects', 'Var', (25, 32))	('contribute', 'Reg', (75, 85))	('DNA repair', 'Gene', (14, 24))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('genomic instability', 'CPA', (89, 108))	('mutations', 'Var', (60, 69))	('carcinogenesis', 'Disease', (121, 135))
611100	32824814	This could potentially explain the observed worse patients' disease-free survival and more advanced cancers (higher grade) in the group of patients with high levels in comparison to patients with low levels of PTTG1.	('worse', 'NegReg', (44, 49))	('disease-free survival', 'CPA', (60, 81))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('high levels', 'Var', (153, 164))	('patients', 'Species', '9606', (182, 190))	('PTTG1', 'Gene', (210, 215))	('PTTG1', 'Gene', '9232', (210, 215))	('cancers', 'Disease', (100, 107))
611111	32824814	Patients with low expressions of PTTG3P and PTTG2 displayed significantly longer disease-free survival.	('disease-free survival', 'CPA', (81, 102))	('low expressions', 'Var', (14, 29))	('longer', 'PosReg', (74, 80))	('PTTG3P', 'Gene', '26255', (33, 39))	('PTTG2', 'Gene', (44, 49))	('Patients', 'Species', '9606', (0, 8))	('PTTG3P', 'Gene', (33, 39))	('PTTG2', 'Gene', '10744', (44, 49))
611112	32824814	Analysis of gene correlations and GSEA indicated that patients with high expressions of PTTG3P, PTTG1 and PTTG2 have different expression patterns of genes associated with carcinogenesis pathways in comparison to patients with low expressions of these three transcripts.	('PTTG2', 'Gene', '10744', (106, 111))	('expression', 'MPA', (127, 137))	('patients', 'Species', '9606', (54, 62))	('PTTG3P', 'Gene', '26255', (88, 94))	('PTTG2', 'Gene', (106, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (172, 186))	('PTTG1', 'Gene', (96, 101))	('high expressions', 'Var', (68, 84))	('PTTG1', 'Gene', '9232', (96, 101))	('patients', 'Species', '9606', (213, 221))	('carcinogenesis', 'Disease', (172, 186))	('PTTG3P', 'Gene', (88, 94))	('GSEA', 'Chemical', '-', (34, 38))
611185	29511340	Furthermore, we found that CASC9 knockdown significantly repressed ESCC migration and invasion in vitro and metastasis in nude mice in vivo.	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('metastasis', 'CPA', (108, 118))	('CASC9', 'Gene', (27, 32))	('CASC9', 'Gene', '101805492', (27, 32))	('knockdown', 'Var', (33, 42))	('nude mice', 'Species', '10090', (122, 131))	('repressed', 'NegReg', (57, 66))	('invasion', 'CPA', (86, 94))	('ESCC migration', 'CPA', (67, 81))
611188	29511340	LAMC2 overexpression partially compromised the decrease of cell migration and invasion capacity in CASC9 knockdowns.	('invasion capacity', 'CPA', (78, 95))	('knockdowns', 'Var', (105, 115))	('cell migration', 'CPA', (59, 73))	('decrease', 'NegReg', (47, 55))	('CASC9', 'Gene', '101805492', (99, 104))	('overexpression', 'PosReg', (6, 20))	('CASC9', 'Gene', (99, 104))	('LAMC2', 'Gene', (0, 5))	('LAMC2', 'Gene', '3918', (0, 5))
611189	29511340	In addition, we found that both CASC9 and LAMC2 depletion reduced the phosphorylation of FAK, PI3K, and Akt, which are downstream effectors of the integrin pathway.	('LAMC2', 'Gene', '3918', (42, 47))	('Akt', 'Gene', (104, 107))	('FAK', 'Gene', (89, 92))	('FAK', 'Gene', '5747', (89, 92))	('CASC9', 'Gene', (32, 37))	('phosphorylation', 'MPA', (70, 85))	('CASC9', 'Gene', '101805492', (32, 37))	('depletion', 'Var', (48, 57))	('Akt', 'Gene', '207', (104, 107))	('reduced', 'NegReg', (58, 65))	('PI3K', 'Pathway', (94, 98))	('LAMC2', 'Gene', (42, 47))
611199	29511340	Recently, many studies have revealed that alterations in gene expression, cytokine secretion, epithelial-to-mesenchymal transition (EMT), and the tumor microenvironment were associated with metastasis, which could only partially elucidate this complex process in a specific cancer type.	('gene expression', 'MPA', (57, 72))	('associated', 'Reg', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('alterations', 'Var', (42, 53))	('cytokine secretion', 'MPA', (74, 92))	('epithelial-to-mesenchymal transition', 'CPA', (94, 130))	('metastasis', 'CPA', (190, 200))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumor', 'Disease', (146, 151))	('cancer', 'Disease', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
611202	29511340	Upon ligation, the integrin pathway is activated through phosphorylation of focal adhesion kinase (FAK), inducing downstream signaling pathways.	('downstream signaling pathways', 'Pathway', (114, 143))	('activated', 'PosReg', (39, 48))	('integrin pathway', 'Pathway', (19, 35))	('FAK', 'Gene', (99, 102))	('phosphorylation', 'Var', (57, 72))	('FAK', 'Gene', '5747', (99, 102))	('focal adhesion kinase', 'Gene', '5747', (76, 97))	('focal adhesion kinase', 'Gene', (76, 97))	('inducing', 'Reg', (105, 113))
611203	29511340	Indeed, FAK, PI3K, and Akt hyperactivation are commonly found in human malignancies, such as breast cancer, lung cancer, and ESCC, and are associated with tumor metastasis.	('human', 'Species', '9606', (65, 70))	('Akt', 'Gene', (23, 26))	('tumor metastasis', 'Disease', (155, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('hyperactivation', 'PosReg', (27, 42))	('Akt', 'Gene', '207', (23, 26))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('lung cancer', 'Disease', (108, 119))	('breast cancer', 'Disease', (93, 106))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))	('FAK', 'Gene', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('malignancies', 'Disease', (71, 83))	('associated', 'Reg', (139, 149))	('FAK', 'Gene', '5747', (8, 11))	('PI3K', 'Var', (13, 17))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('tumor metastasis', 'Disease', 'MESH:D009362', (155, 171))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('ESCC', 'Disease', (125, 129))
611204	29511340	Notably, lncRNA signatures reveal their involvement in tumorigenesis when aberrantly expressed, which is correlated with tumor behavior and prognosis.	('lncRNA signatures', 'Gene', (9, 26))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('involvement', 'Reg', (40, 51))	('aberrantly expressed', 'Var', (74, 94))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
611205	29511340	In esophageal cancer, lncRNAs MALAT1, HOTAIR, AFAP1-AS1, HNF1A-AS1, and CCAT1 are upregulated and promote cancer metastasis through multiple mechanisms, including miRNA sponging, epigenetic modification, and transcription regulation.	('AS1', 'Gene', '5729', (52, 55))	('promote', 'PosReg', (98, 105))	('epigenetic modification', 'Var', (179, 202))	('CCAT1', 'Gene', '100507056', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer metastasis', 'Disease', (106, 123))	('CCAT1', 'Gene', (72, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('AS1', 'Gene', '5729', (63, 66))	('MALAT1', 'Gene', (30, 36))	('HOTAIR', 'Gene', '100124700', (38, 44))	('cancer metastasis', 'Disease', 'MESH:D009362', (106, 123))	('AS1', 'Gene', (52, 55))	('esophageal cancer', 'Disease', (3, 20))	('upregulated', 'PosReg', (82, 93))	('HNF1A-AS1', 'Gene', (57, 66))	('MALAT1', 'Gene', '378938', (30, 36))	('HOTAIR', 'Gene', (38, 44))	('AFAP1', 'Gene', '60312', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('AS1', 'Gene', (63, 66))	('HNF1A-AS1', 'Gene', '283460', (57, 66))	('AFAP1', 'Gene', (46, 51))
611218	29511340	A prognostic analysis using 69 ESCC tissues with complete follow-up information revealed that both high CASC9 expression in ESCC tissues and high T:N ratio were associated with reduced overall survival (Fig.	('CASC9', 'Gene', (104, 109))	('CASC9', 'Gene', '101805492', (104, 109))	('reduced', 'NegReg', (177, 184))	('high', 'Var', (99, 103))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('expression', 'MPA', (110, 120))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('overall survival', 'MPA', (185, 201))	('high', 'Var', (141, 145))
611226	29511340	Transwell assay demonstrated that CASC9 depletion almost completely inhibited the migration and invasion ability of KYSE150 and KYSE450 using two different siRNAs (Fig.	('depletion', 'Var', (40, 49))	('invasion ability', 'CPA', (96, 112))	('KYSE450', 'Enzyme', (128, 135))	('KYSE150', 'Enzyme', (116, 123))	('inhibited', 'NegReg', (68, 77))	('migration', 'CPA', (82, 91))	('CASC9', 'Gene', '101805492', (34, 39))	('CASC9', 'Gene', (34, 39))
611228	29511340	A wound healing assay consistently confirmed that CASC9 depletion inhibited cell motility (Fig.	('CASC9', 'Gene', (50, 55))	('cell motility', 'CPA', (76, 89))	('CASC9', 'Gene', '101805492', (50, 55))	('inhibited', 'NegReg', (66, 75))	('depletion', 'Var', (56, 65))
611231	29511340	We found that knockdown of CASC9 resulted in significantly decreased metastasis to the lungs, bone, and other sites.	('CASC9', 'Gene', '101805492', (27, 32))	('CASC9', 'Gene', (27, 32))	('decreased', 'NegReg', (59, 68))	('metastasis to the lungs', 'CPA', (69, 92))	('knockdown', 'Var', (14, 23))
611232	29511340	Notably, three mice from the LV-NC group presented bone and other remote metastasis, while no mice from the LV-CASC9 group exhibited metastasis in other places (Fig.	('NC', 'Phenotype', 'HP:0100630', (32, 34))	('CASC9', 'Gene', '101805492', (111, 116))	('CASC9', 'Gene', (111, 116))	('LV-NC', 'Var', (29, 34))	('mice', 'Species', '10090', (94, 98))	('bone and', 'CPA', (51, 59))	('mice', 'Species', '10090', (15, 19))
611233	29511340	In addition, metastatic nodules at the lung surface in the LV-NC group were significantly more frequent than in the LV-CASC9 group (Fig.	('CASC9', 'Gene', '101805492', (119, 124))	('more frequent', 'PosReg', (90, 103))	('NC', 'Phenotype', 'HP:0100630', (62, 64))	('CASC9', 'Gene', (119, 124))	('LV-NC', 'Var', (59, 64))	('metastatic nodules at the lung surface', 'CPA', (13, 51))
611234	29511340	Metastatic nodules from LV-NC group were also much larger than that in the LV-CASC9 group (Fig.	('larger', 'PosReg', (51, 57))	('NC', 'Phenotype', 'HP:0100630', (27, 29))	('CASC9', 'Gene', '101805492', (78, 83))	('CASC9', 'Gene', (78, 83))	('Metastatic nodules', 'CPA', (0, 18))	('LV-NC', 'Var', (24, 29))
611239	29511340	A pathway analysis demonstrated that CASC9 knockdown had major consequences on genes that were primarily connected with metabolic pathways, ECM-receptor interactions and focal adhesions (Fig.	('genes', 'Gene', (79, 84))	('knockdown', 'Var', (43, 52))	('CASC9', 'Gene', (37, 42))	('CASC9', 'Gene', '101805492', (37, 42))	('consequences', 'Reg', (63, 75))	('metabolic pathways', 'Pathway', (120, 138))
611241	29511340	Then, using CASC9 loss- and gain-of-function experiments, we confirmed that the genes identified by microarray decreased in CASC9 knockdown cells and increased in CASC9 overexpressing cells (Fig.	('CASC9', 'Gene', (124, 129))	('decreased', 'NegReg', (111, 120))	('CASC9', 'Gene', (163, 168))	('CASC9', 'Gene', '101805492', (163, 168))	('knockdown', 'Var', (130, 139))	('CASC9', 'Gene', (12, 17))	('CASC9', 'Gene', '101805492', (12, 17))	('CASC9', 'Gene', '101805492', (124, 129))	('increased', 'PosReg', (150, 159))	('loss-', 'NegReg', (18, 23))
611246	29511340	Next, using western blot and immunofluorescence, we validated the protein levels alteration of LAMC2 and ITGB4 in response to CASC9 knockdown (Fig.	('knockdown', 'Var', (132, 141))	('alteration', 'Reg', (81, 91))	('LAMC2', 'Gene', '3918', (95, 100))	('ITGB4', 'Gene', (105, 110))	('ITGB4', 'Gene', '3691', (105, 110))	('LAMC2', 'Gene', (95, 100))	('CASC9', 'Gene', (126, 131))	('CASC9', 'Gene', '101805492', (126, 131))	('protein levels', 'MPA', (66, 80))
611252	29511340	4c), and high LAMC2 expression was associated with primary tumor invasion depth, lymph node metastasis, and advanced TNM stage (Fig.	('LAMC2', 'Gene', '3918', (14, 19))	('tumor', 'Disease', (59, 64))	('expression', 'MPA', (20, 30))	('LAMC2', 'Gene', (14, 19))	('TNM', 'Gene', '10178', (117, 120))	('associated', 'Reg', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('lymph node metastasis', 'CPA', (81, 102))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('TNM', 'Gene', (117, 120))	('high', 'Var', (9, 13))
611253	29511340	More importantly, high LAMC2 expression predicted poor prognosis (Fig.	('poor', 'CPA', (50, 54))	('LAMC2', 'Gene', (23, 28))	('high', 'Var', (18, 22))	('LAMC2', 'Gene', '3918', (23, 28))	('expression', 'MPA', (29, 39))
611259	29511340	The silencing of LAMC2 significantly attenuated the number of motile cells in KYSE150 and KYSE450 cells (Fig.	('LAMC2', 'Gene', '3918', (17, 22))	('number of motile cells in KYSE150', 'CPA', (52, 85))	('attenuated', 'NegReg', (37, 47))	('silencing', 'Var', (4, 13))	('LAMC2', 'Gene', (17, 22))
611263	29511340	We ectopically overexpressed LAMC2 with simultaneous knockdown of CASC9 expression (Supplementary Figure 2H, I) and discovered that overexpression of LAMC2 partially attenuated the decreased cell migration and invasion capacity caused by CASC9 knockdown (Fig.	('CASC9', 'Gene', (66, 71))	('CASC9', 'Gene', '101805492', (66, 71))	('LAMC2', 'Gene', (29, 34))	('invasion capacity', 'CPA', (210, 227))	('CASC9', 'Gene', (238, 243))	('CASC9', 'Gene', '101805492', (238, 243))	('LAMC2', 'Gene', '3918', (29, 34))	('LAMC2', 'Gene', '3918', (150, 155))	('cell migration', 'CPA', (191, 205))	('attenuated', 'NegReg', (166, 176))	('LAMC2', 'Gene', (150, 155))	('knockdown', 'Var', (244, 253))	('decreased', 'NegReg', (181, 190))
611266	29511340	As a result, we found that both CASC9 and LAMC2 depletion decreased pFAK, pPI3K, and pAkt levels, but they had no influence on total protein levels (Fig.	('Akt', 'Gene', (86, 89))	('pPI3K', 'MPA', (74, 79))	('LAMC2', 'Gene', '3918', (42, 47))	('decreased', 'NegReg', (58, 67))	('CASC9', 'Gene', (32, 37))	('CASC9', 'Gene', '101805492', (32, 37))	('Akt', 'Gene', '207', (86, 89))	('FAK', 'Gene', (69, 72))	('FAK', 'Gene', '5747', (69, 72))	('depletion', 'Var', (48, 57))	('LAMC2', 'Gene', (42, 47))
611270	29511340	6c) and CASC9 depletion reduced MMP10 and MMP13 expression (Fig.	('reduced', 'NegReg', (24, 31))	('MMP10', 'Gene', '4319', (32, 37))	('depletion', 'Var', (14, 23))	('CASC9', 'Gene', (8, 13))	('CASC9', 'Gene', '101805492', (8, 13))	('MMP13', 'Gene', (42, 47))	('MMP13', 'Gene', '4322', (42, 47))	('MMP10', 'Gene', (32, 37))
611276	29511340	We next treated ESCC cells with C646, a histone acetyltransferase (HAT) inhibitor, and found that LAMC2 expression was significantly decreased in response (Supplementary Figure 3B).	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('C646', 'Chemical', '-', (32, 36))	('expression', 'MPA', (104, 114))	('LAMC2', 'Gene', (98, 103))	('LAMC2', 'Gene', '3918', (98, 103))	('C646', 'Var', (32, 36))	('decreased', 'NegReg', (133, 142))
611287	29511340	Furthermore, ChIP assays indicated that CASC9 depletion decreased the enrichment of CBP and H3K27ac acetylation at the promoter region of LAMC2, but not the negative control, MyoD gene (Fig.	('depletion', 'Var', (46, 55))	('LAMC2', 'Gene', (138, 143))	('LAMC2', 'Gene', '3918', (138, 143))	('decreased', 'NegReg', (56, 65))	('MyoD', 'Gene', (175, 179))	('CBP', 'Gene', (84, 87))	('H3K27ac', 'Protein', (92, 99))	('enrichment', 'MPA', (70, 80))	('MyoD', 'Gene', '4654', (175, 179))	('CASC9', 'Gene', (40, 45))	('CASC9', 'Gene', '101805492', (40, 45))	('CBP', 'Gene', '1387', (84, 87))	('acetylation', 'MPA', (100, 111))
611300	29511340	Researches demonstrate that imbalance of laminins such as expression disorder or genomic variation is thought to be correlated with tumorigenesis.	('imbalance', 'Phenotype', 'HP:0002172', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('laminins', 'Protein', (41, 49))	('expression', 'MPA', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('genomic variation', 'Var', (81, 98))	('tumor', 'Disease', (132, 137))	('correlated', 'Reg', (116, 126))
611305	29511340	Then, we described an intensive correlation between CASC9 and LAMC2 expression in ESCC tissues, plus that LAMC2 overexpression could partially attenuate the decrease of cell migration and invasion capacity caused by CASC9 knockdown, providing sufficient evidence that LAMC2 was a target gene of CASC9.	('attenuate', 'NegReg', (143, 152))	('CASC9', 'Gene', (52, 57))	('CASC9', 'Gene', '101805492', (52, 57))	('LAMC2', 'Gene', (268, 273))	('LAMC2', 'Gene', (62, 67))	('decrease', 'NegReg', (157, 165))	('LAMC2', 'Gene', '3918', (268, 273))	('LAMC2', 'Gene', '3918', (62, 67))	('CASC9', 'Gene', '101805492', (295, 300))	('knockdown', 'Var', (222, 231))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('CASC9', 'Gene', '101805492', (216, 221))	('LAMC2', 'Gene', (106, 111))	('CASC9', 'Gene', (295, 300))	('LAMC2', 'Gene', '3918', (106, 111))	('CASC9', 'Gene', (216, 221))
611309	29511340	Our data indicated that both CASC9 and LAMC2 depletion attenuated the activation of FAK, PI3K, and Akt.	('FAK', 'Gene', (84, 87))	('FAK', 'Gene', '5747', (84, 87))	('Akt', 'Gene', '207', (99, 102))	('attenuated', 'NegReg', (55, 65))	('CASC9', 'Gene', (29, 34))	('CASC9', 'Gene', '101805492', (29, 34))	('Akt', 'Gene', (99, 102))	('PI3K', 'Pathway', (89, 93))	('LAMC2', 'Gene', (39, 44))	('LAMC2', 'Gene', '3918', (39, 44))	('depletion', 'Var', (45, 54))	('activation', 'PosReg', (70, 80))
611355	29511340	Sections were then subjected to incubation with either the Ki67 (ab15580, Abcam) or CK5 (ab52635, Abcam) antibody followed by secondary antibody incubation.	('CK5', 'Gene', '3852', (84, 87))	('CK5', 'Gene', (84, 87))	('ab15580', 'Var', (65, 72))
611384	30233782	Meanwhile, a genome-wide association study of 2,515 EAC cases and 3,207 controls provided data to suggest that germline variations at the cyclin-dependent kinase inhibitor 2A locus may influence susceptibility to EAC.	('variations', 'Var', (120, 130))	('EAC', 'Phenotype', 'HP:0011459', (213, 216))	('EAC', 'Disease', (213, 216))	('EAC', 'Phenotype', 'HP:0011459', (52, 55))	('influence susceptibility', 'Reg', (185, 209))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (138, 174))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (138, 174))
611387	30233782	Osteopontin (OPN) isoforms have also been investigated in EAC, where results indicated that all OPN isoforms were frequently co-overexpressed in primary EACs, and that isoforms OPNb and OPNc enhanced invasion and dissemination through collective yet distinct mechanisms.	('Osteopontin', 'Gene', (0, 11))	('Osteopontin', 'Gene', '6696', (0, 11))	('OPN', 'Gene', (96, 99))	('OPN', 'Gene', '6696', (13, 16))	('isoforms', 'Var', (168, 176))	('OPN', 'Gene', '6696', (177, 180))	('OPN', 'Gene', '6696', (186, 189))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('OPN', 'Gene', (177, 180))	('OPN', 'Gene', '6696', (96, 99))	('EAC', 'Disease', (58, 61))	('enhanced', 'PosReg', (191, 199))	('OPN', 'Gene', (186, 189))	('OPN', 'Gene', (13, 16))	('EAC', 'Phenotype', 'HP:0011459', (153, 156))
611391	30233782	The DEGs of GSE92396 between the normal tissues and the tumor samples were analyzed with limma package (version 3.34.8) in R language.	('GSE92396', 'Var', (12, 20))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))
611405	30233782	IL8 stimulation on endothelial cells has been reported to begin angiogenic processes characterized by secretion of matrix metalloproteinases (MMPs), which can break down the extracellular matrix and stimulate the formation of new vessels.	('stimulation', 'Var', (4, 15))	('angiogenic processes', 'CPA', (64, 84))	('secretion', 'MPA', (102, 111))	('break down', 'Phenotype', 'HP:0001061', (159, 169))	('stimulate', 'PosReg', (199, 208))	('break down', 'NegReg', (159, 169))	('formation of new vessels', 'CPA', (213, 237))	('MMPs', 'Gene', (142, 146))	('IL8', 'Gene', (0, 3))	('IL8', 'Gene', '3576', (0, 3))	('MMPs', 'Gene', '4313', (142, 146))
611418	30233782	CFTR encodes an ATP-binding cassette membrane protein that functions as a chloride channel, and is mutated in cystic fibrosis.	('CFTR', 'Gene', (0, 4))	('cystic fibrosis', 'Disease', 'MESH:D003550', (110, 125))	('mutated', 'Var', (99, 106))	('cystic fibrosis', 'Disease', (110, 125))	('CFTR', 'Gene', '1080', (0, 4))
611419	30233782	A previous large-scale meta-analysis suggested that the novel single nucleotide polymorphism (SNP) rs17451754, which is located within intron 21 of the CFTR gene, markedly associates with the risk of Barrett's esophagus and EAC.	('rs17451754', 'Var', (99, 109))	('CFTR', 'Gene', '1080', (152, 156))	('associates with', 'Reg', (172, 187))	('single nucleotide polymorphism', 'Var', (62, 92))	('rs17451754', 'Mutation', 'rs17451754', (99, 109))	('CFTR', 'Gene', (152, 156))	('EAC', 'Phenotype', 'HP:0011459', (224, 227))	("Barrett's esophagus", 'Disease', (200, 219))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (200, 219))	('EAC', 'Disease', (224, 227))
611439	29627387	The aim of this study was to identify factors that predict pathologic nodal involvement in patients with endoscopic ultrasound (EUS)-proven T2N0 esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (145, 170))	('nodal', 'Gene', (70, 75))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (145, 170))	('patients', 'Species', '9606', (91, 99))	('nodal', 'Gene', '4838', (70, 75))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (145, 170))	('T2N0', 'Var', (140, 144))
611444	29627387	We identified 80 patients with uT2N0 esophageal adenocarcinoma treated with surgery alone.	('uT2N0', 'Var', (31, 36))	('esophageal adenocarcinoma', 'Disease', (37, 62))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (37, 62))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (37, 62))	('patients', 'Species', '9606', (17, 25))
611453	29627387	The current consensus is that patients with early-stage, T1N0 esophageal adenocarcinoma should undergo resection (either endoscopic or surgical) without induction therapy.	('T1N0', 'Var', (57, 61))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (62, 87))	('patients', 'Species', '9606', (30, 38))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (62, 87))	('esophageal adenocarcinoma', 'Disease', (62, 87))
611457	29627387	It has been reported that approximately 50% of patients with cT2N0 esophageal cancer are upstaged at resection.	('patients', 'Species', '9606', (47, 55))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cT2N0', 'Var', (61, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))
611465	29627387	Patients with uT2N0 esophageal adenocarcinoma were identified from a prospectively maintained database and retrospectively reviewed.	('Patients', 'Species', '9606', (0, 8))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (20, 45))	('esophageal adenocarcinoma', 'Disease', (20, 45))	('uT2N0', 'Var', (14, 19))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (20, 45))
611499	29627387	Nodal disease was identified at resection in 35% of patients with uT2N0 disease, and these patients, who were treated with surgery alone or with surgery and adjuvant chemotherapy, had disappointing survival outcomes.	('patients', 'Species', '9606', (91, 99))	('Nodal', 'Gene', (0, 5))	('Nodal', 'Gene', '4838', (0, 5))	('uT2N0 disease', 'Var', (66, 79))	('patients', 'Species', '9606', (52, 60))
611500	29627387	Vascular invasion was identified as an independent risk factor for nodal involvement, and this finding may help guide treatment for patients with cT2N0 esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (152, 177))	('esophageal adenocarcinoma', 'Disease', (152, 177))	('cT2N0', 'Var', (146, 151))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (152, 177))	('nodal', 'Gene', '4838', (67, 72))	('nodal', 'Gene', (67, 72))	('patients', 'Species', '9606', (132, 140))
611522	29627387	The finding that our patients with uT2N0 disease with nodal metastases at resection had poor survival outcomes (5-year OS, 41%; 5-year RFS, 32%) establishes a rationale for further investigating whether these patients would benefit from induction therapy.	('survival', 'MPA', (93, 101))	('patients', 'Species', '9606', (21, 29))	('nodal metastases', 'Disease', (54, 70))	('patients', 'Species', '9606', (209, 217))	('nodal metastases', 'Disease', 'MESH:D009362', (54, 70))	('OS', 'Chemical', '-', (119, 121))	('uT2N0', 'Var', (35, 40))
611529	29627387	Although the small cohort size is a major limitation, owing to the uncommon presentation of cT2N0 esophageal adenocarcinoma, this study still represents one of the largest series of patients with cT2N0 esophageal adenocarcinoma treated by surgery with or without adjuvant chemotherapy at a single institution.	('cT2N0', 'Var', (196, 201))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (98, 123))	('esophageal adenocarcinoma', 'Disease', (98, 123))	('esophageal adenocarcinoma', 'Disease', (202, 227))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (202, 227))	('patients', 'Species', '9606', (182, 190))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (202, 227))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (98, 123))
611532	29627387	Clinical staging was inaccurate for 91% of patients with uT2N0 esophageal adenocarcinoma in our series, and the presence of nodal involvement was undetected in 35% of patients.	('nodal', 'Gene', (124, 129))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (167, 175))	('nodal', 'Gene', '4838', (124, 129))	('uT2N0', 'Var', (57, 62))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (63, 88))	('esophageal adenocarcinoma', 'Disease', (63, 88))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (63, 88))
611537	29627387	Finally, patients with uT2N0 disease with vascular invasion on preoperative biopsy may benefit from preoperative chemoradiation, as they have an increased risk of harboring occult nodal metastasis.	('patients', 'Species', '9606', (9, 17))	('nodal', 'Gene', '4838', (180, 185))	('nodal', 'Gene', (180, 185))	('uT2N0', 'Var', (23, 28))
611592	29905908	In patients with confirmed low-grade dysplasia, the subsequent incidence of high-grade dysplasia and EAC combined was 5.18 (3.63-7.19), and the incidence of EAC alone 2.51 (1.49-3.99) per 100 patient-years.	('patient', 'Species', '9606', (192, 199))	('dysplasia', 'Disease', 'MESH:D004476', (87, 96))	('low-grade', 'Var', (27, 36))	('EAC', 'Phenotype', 'HP:0011459', (157, 160))	('EAC', 'Disease', (101, 104))	('dysplasia', 'Disease', (37, 46))	('patient', 'Species', '9606', (3, 10))	('patients', 'Species', '9606', (3, 11))	('dysplasia', 'Disease', 'MESH:D004476', (37, 46))	('EAC', 'Phenotype', 'HP:0011459', (101, 104))	('dysplasia', 'Disease', (87, 96))
611652	29966526	Outcomes of esophagectomy after chemotherapy with biweekly docetaxel plus cisplatin and fluorouracil for advanced esophageal cancer: a retrospective cohort analysis Docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy can cause severe adverse events, including neutropenia and febrile neutropenia.	('Docetaxel', 'Var', (165, 174))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (191, 205))	('fluorouracil', 'Chemical', 'MESH:D005472', (193, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('neutropenia', 'Phenotype', 'HP:0001875', (263, 274))	('neutropenia', 'Phenotype', 'HP:0001875', (287, 298))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophagectomy', 'Disease', (12, 25))	('esophageal cancer', 'Disease', (114, 131))	('fluorouracil', 'Chemical', 'MESH:D005472', (88, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('Docetaxel', 'Chemical', 'MESH:D000077143', (165, 174))	('neutropenia and febrile neutropenia', 'Disease', 'MESH:D009503', (263, 298))	('DCF', 'Chemical', '-', (207, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('docetaxel', 'Chemical', 'MESH:D000077143', (59, 68))
611660	29966526	Grade 3 or 4 neutropenia was less frequent in the bDCF than in the DCF group (40.9 vs. 81.1%, p = 0.002).	('bDCF', 'Var', (50, 54))	('neutropenia', 'Disease', 'MESH:D009503', (13, 24))	('less', 'NegReg', (29, 33))	('DCF', 'Chemical', '-', (51, 54))	('neutropenia', 'Phenotype', 'HP:0001875', (13, 24))	('bDCF', 'Chemical', '-', (50, 54))	('DCF', 'Chemical', '-', (67, 70))	('neutropenia', 'Disease', (13, 24))
611661	29966526	Anorexia was more frequent in the DCF group than in the bDCF group (18.9 vs. 0%, p = 0.030).	('DCF', 'Chemical', '-', (34, 37))	('Anorexia', 'Disease', (0, 8))	('bDCF', 'Chemical', '-', (56, 60))	('DCF', 'Var', (34, 37))	('Anorexia', 'Phenotype', 'HP:0002039', (0, 8))	('DCF', 'Chemical', '-', (57, 60))	('Anorexia', 'Disease', 'MESH:D000855', (0, 8))
611662	29966526	The clinical response rate of the bDCF group was significantly higher than that of the DCF group (86.4 vs. 62.2%, p = 0.047).	('DCF', 'Chemical', '-', (35, 38))	('DCF', 'Chemical', '-', (87, 90))	('bDCF', 'Var', (34, 38))	('bDCF', 'Chemical', '-', (34, 38))	('clinical response', 'CPA', (4, 21))	('higher', 'PosReg', (63, 69))
611669	29966526	However, DCF therapy can cause severe adverse events, such as grade 3 or 4 neutropenia (range 66.6-78.2%) and febrile neutropenia (FN) (range 14.5-22.9%).	('grade 3', 'Disease', (62, 69))	('neutropenia', 'Phenotype', 'HP:0001875', (75, 86))	('DCF', 'Var', (9, 12))	('neutropenia', 'Disease', (118, 129))	('febrile neutropenia', 'Disease', (110, 129))	('febrile neutropenia', 'Disease', 'MESH:D009503', (110, 129))	('neutropenia', 'Disease', (75, 86))	('neutropenia', 'Disease', 'MESH:D009503', (118, 129))	('DCF', 'Chemical', '-', (9, 12))	('neutropenia', 'Phenotype', 'HP:0001875', (118, 129))	('neutropenia', 'Disease', 'MESH:D009503', (75, 86))
611678	29966526	Therefore, myelosuppression and gastrointestinal side effects caused by preoperative DCF therapy may worsen postoperative infections leading to life-threatening diseases in high-risk patients with esophageal cancer and may reduce long-term survival benefits by increasing the incidence of postoperative infections.	('postoperative infections', 'Disease', (108, 132))	('worsen', 'PosReg', (101, 107))	('postoperative infections', 'Disease', (289, 313))	('gastrointestinal side effects', 'Disease', 'MESH:D005767', (32, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('gastrointestinal side effects', 'Disease', (32, 61))	('myelosuppression', 'Disease', 'MESH:D001855', (11, 27))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('therapy', 'Var', (89, 96))	('postoperative infections', 'Disease', 'MESH:D010149', (108, 132))	('reduce', 'NegReg', (223, 229))	('increasing', 'PosReg', (261, 271))	('esophageal cancer', 'Disease', (197, 214))	('postoperative infections', 'Disease', 'MESH:D010149', (289, 313))	('myelosuppression', 'Disease', (11, 27))	('DCF', 'Chemical', '-', (85, 88))	('patients', 'Species', '9606', (183, 191))	('DCF', 'Gene', (85, 88))
611711	29966526	Although a significant difference was not observed in the American Society of Anesthesiologists performance status between the two groups, it was generally higher in the bDCF group than in the DCF group.	('bDCF', 'Var', (170, 174))	('higher', 'PosReg', (156, 162))	('bDCF', 'Chemical', '-', (170, 174))	('DCF', 'Chemical', '-', (193, 196))	('DCF', 'Chemical', '-', (171, 174))
611712	29966526	Although grade 3 or 4 neutropenia was less frequently observed in the bDCF group compared with that in the DCF group (40.9 vs. 81.1%, p = 0.002), there was no significant difference in FN frequency (9.1 vs. 13.5%, Table 2).	('bDCF', 'Chemical', '-', (70, 74))	('neutropenia', 'Disease', (22, 33))	('DCF', 'Chemical', '-', (107, 110))	('DCF', 'Chemical', '-', (71, 74))	('less', 'NegReg', (38, 42))	('bDCF', 'Var', (70, 74))	('neutropenia', 'Phenotype', 'HP:0001875', (22, 33))	('neutropenia', 'Disease', 'MESH:D009503', (22, 33))
611713	29966526	G-CSF was administered significantly more frequently in the DCF group (60/87 courses, 69%) as compared with the bDCF group (13/59 courses, 22%, p < 0.001, Table 3).	('G-CSF', 'Gene', '1440', (0, 5))	('G-CSF', 'Gene', (0, 5))	('DCF', 'Var', (60, 63))	('bDCF', 'Chemical', '-', (112, 116))	('DCF', 'Chemical', '-', (113, 116))	('DCF', 'Chemical', '-', (60, 63))
611716	29966526	However, the period between day 1 of the last course of chemotherapy and the day of operation tended to be shorter in the bDCF group (bDCF 45.1 days vs. DCF 52.3 days; Table 2).	('bDCF', 'Var', (122, 126))	('DCF', 'Chemical', '-', (135, 138))	('DCF', 'Chemical', '-', (153, 156))	('shorter', 'NegReg', (107, 114))	('bDCF', 'Chemical', '-', (122, 126))	('bDCF', 'Chemical', '-', (134, 138))	('DCF', 'Chemical', '-', (123, 126))
611723	29966526	The postoperative hospital stay was significantly shorter for the bDCF group (19.4 days; range 10-33 days) as compared with that for the DCF group (28.4 days; range 12-106 days; p = 0.008, Table 5).	('DCF', 'Chemical', '-', (137, 140))	('bDCF', 'Chemical', '-', (66, 70))	('DCF', 'Chemical', '-', (67, 70))	('shorter', 'NegReg', (50, 57))	('bDCF', 'Var', (66, 70))
611826	26539332	Overexpression of IFITM3 predicts the high risk of lymphatic metastatic recurrence in pN0 esophageal squamous cell carcinoma after Ivor-Lewis esophagectomy Background.	('pN0', 'Var', (86, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (90, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('IFITM3', 'Gene', (18, 24))	('IFITM3', 'Gene', '10410', (18, 24))	('Overexpression', 'Var', (0, 14))	('lymphatic metastatic recurrence', 'CPA', (51, 82))	('esophageal squamous cell carcinoma', 'Disease', (90, 124))
611827	26539332	Recent studies have shown that the aberrant expression of IFITM3 is implicated in the lymph node metastasis of many malignancies.	('IFITM3', 'Gene', '10410', (58, 64))	('lymph node metastasis', 'CPA', (86, 107))	('malignancies', 'Disease', 'MESH:D009369', (116, 128))	('IFITM3', 'Gene', (58, 64))	('malignancies', 'Disease', (116, 128))	('aberrant expression', 'Var', (35, 54))	('implicated', 'Reg', (68, 78))
611835	26539332	Even pN0 ESCC patients will still experience lymphatic metastatic recurrence.	('ESCC', 'Disease', (9, 13))	('experience', 'Reg', (34, 44))	('lymphatic metastatic recurrence', 'CPA', (45, 76))	('pN0', 'Var', (5, 8))	('patients', 'Species', '9606', (14, 22))
611878	26539332	In the low IFITM3 expression group, the 3-year lymphatic recurrence rate was only 26.7%.	('low', 'Var', (7, 10))	('IFITM3', 'Gene', (11, 17))	('IFITM3', 'Gene', '10410', (11, 17))
611882	26539332	Patients with early T status and low expression of IFITM3 may have a lower recurrence risk of lymphatic metastasis (Fig.	('lymphatic metastasis', 'CPA', (94, 114))	('IFITM3', 'Gene', (51, 57))	('low', 'Var', (33, 36))	('IFITM3', 'Gene', '10410', (51, 57))	('Patients', 'Species', '9606', (0, 8))	('expression', 'MPA', (37, 47))
611884	26539332	Figure 4 demonstrated that the long survival of patients was associated with moderate-high differentiation, early T status of tumor and low IFITM3 expression.	('IFITM3', 'Gene', '10410', (140, 146))	('expression', 'MPA', (147, 157))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('low', 'Var', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('moderate-high', 'Var', (77, 90))	('IFITM3', 'Gene', (140, 146))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Disease', (126, 131))
611912	15230979	Control region mutations and the 'common deletion' are frequent in the mitochondrial DNA of patients with esophageal squamous cell carcinoma North central China has some of the highest rates of esophageal squamous cell carcinoma in the world with cumulative mortality surpassing 20%.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('mutations', 'Var', (15, 24))	('esophageal squamous cell carcinoma', 'Disease', (106, 140))	('patients', 'Species', '9606', (92, 100))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (194, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (205, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('esophageal squamous cell carcinoma', 'Disease', (194, 228))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (106, 140))
611913	15230979	Mitochondrial DNA (mtDNA) accumulates more mutations than nuclear DNA and because of its high abundance has been proposed as a early detection device for subjects with cancer at various sites.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
611916	15230979	Direct DNA sequencing revealed that 7/21 (33%, 95% CI = 17-55%) tumor samples had mutations in the control region, with clustering evident in the hyper-variable segment 1 (HSV1) and the homopolymeric stretch surrounding position 309.	('tumor', 'Disease', (64, 69))	('HSV1', 'Species', '10298', (172, 176))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('HSV1', 'Gene', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('men', 'Species', '9606', (164, 167))
611917	15230979	We detected the 4977 bp 'common deletion' in 92% of the tumor and adjacent normal esophageal tissue samples examined, whereas no evidence of the common deletion was found in corresponding peripheral blood samples.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('4977 bp', 'Var', (16, 23))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
611926	15230979	Somatic mtDNA mutations have been found in colorectal, head and neck, esophageal, gastric, bladder, ovarian, and breast cancers among others.	('breast cancers', 'Disease', 'MESH:D001943', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancers', 'Disease', (113, 127))	('ovarian', 'Disease', (100, 107))	('bladder', 'Disease', (91, 98))	('mtDNA', 'Gene', (8, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('colorectal', 'Disease', (43, 53))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('esophageal', 'Disease', (70, 80))	('breast cancers', 'Phenotype', 'HP:0003002', (113, 127))	('found', 'Reg', (34, 39))	('mutations', 'Var', (14, 23))	('gastric', 'Disease', (82, 89))	('bladder', 'Disease', 'MESH:D001745', (91, 98))
611928	15230979	A study of ovarian cancer found that 60% of tumors had at least one mtDNA mutation, with 33% of the mutations in the CR.	('tumors', 'Disease', (44, 50))	('mutation', 'Var', (74, 82))	('CR', 'Chemical', '-', (117, 119))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (11, 25))	('ovarian cancer', 'Disease', 'MESH:D010051', (11, 25))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('ovarian cancer', 'Disease', (11, 25))	('mtDNA', 'Gene', (68, 73))
611929	15230979	In one recent breast cancer study, 74% of tumor samples had at least one acquired mutation and 81% of the mutations identified were within the CR, demonstrating that this region of the mitochondrial genome is much more susceptible to mutation than the coding region.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Disease', (42, 47))	('mutation', 'Var', (82, 90))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('CR', 'Chemical', '-', (143, 145))
611930	15230979	In addition to alterations in the CR, several studies have examined the 4977 bp 'common deletion' of the mitochondrial genome in cancer and in degenerative diseases.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('degenerative diseases', 'Disease', (143, 164))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('4977 bp', 'Var', (72, 79))	('degenerative diseases', 'Disease', 'MESH:D019636', (143, 164))	('CR', 'Chemical', '-', (34, 36))
611933	15230979	The authors reported that only 2/37 (5%) of ESCC tumors harbored CR mutations.	('CR', 'Chemical', '-', (65, 67))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('ESCC tumors', 'Disease', 'MESH:D004938', (44, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('harbored', 'Reg', (56, 64))	('mutations', 'Var', (68, 77))	('ESCC tumors', 'Disease', (44, 55))
611934	15230979	In contrast, a recent analysis restricted to the two hypervariable regions of the D-loop found that 13/38 (34%) of ESCC tumors in a Japanese series had acquired mutations.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('ESCC tumors', 'Disease', (115, 126))	('ESCC tumors', 'Disease', 'MESH:D004938', (115, 126))
611935	15230979	A study of esophageal adenocarcinoma in Germany found 8/20 (40%) had CR alterations in the tumor or tumor-associated Barrett's epithelium.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('alterations', 'Var', (72, 83))	('CR', 'Chemical', '-', (69, 71))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('esophageal adenocarcinoma', 'Disease', (11, 36))	('tumor', 'Disease', (91, 96))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (11, 36))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (11, 36))
611945	15230979	To identify point mutations, insertions, and deletions in the CR of the tumor tissues, we compared each of the case subjects CR sequence from tumor DNA to their sequence from blood DNA.	('CR', 'Chemical', '-', (125, 127))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (142, 147))	('deletions', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('CR', 'Chemical', '-', (62, 64))
611947	15230979	Two pairs of forward and reverse PCR primers were designed such that one (Mitin2) produced a 271 bp amplicon from intact mitochondrial DNA in the region of cytochrome oxidase subunit III (Mitin2F 9500-9520; Mitin2R 9761-9742) and the other (Mitout2) produced a 5,190 bp amplicon spanning the region between ATPase 8 and NADH Dehydrogenase Subunit 5 in wild type mtDNA (Mitout2F 8370-8392; Mitout2R 13560-13539).	('ATPase 8', 'Gene', (307, 315))	('NADH Dehydrogenase Subunit 5', 'Gene', '4540', (320, 348))	('Mitin2F 9500-9520; Mitin2R 9761-9742', 'Var', (188, 224))	('CR', 'Chemical', '-', (34, 36))	('Mitout2F 8370-8392; Mitout2R 13560-13539', 'Var', (369, 409))	('NADH Dehydrogenase Subunit 5', 'Gene', (320, 348))	('ATPase 8', 'Gene', '4509', (307, 315))
611956	15230979	The 33% rate of mutation that we found is comparable to some of the findings for other solid tumors, but is higher than a previous report for gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('gastric cancer', 'Disease', (142, 156))	('mutation', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('solid tumors', 'Disease', (87, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))
611957	15230979	In contrast, a recent analysis restricted to the two hypervariable regions of the D-loop found that 13/38 (34%) ESCC tumors in a Japanese series had acquired mutations.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('ESCC tumors', 'Disease', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('ESCC tumors', 'Disease', 'MESH:D004938', (112, 123))	('mutations', 'Var', (158, 167))
611959	15230979	First, 4 of the 7 subjects with alterations in their tumors had a change in the homopolymeric stretch of Cs that are assigned to position 309.	('Cs', 'Chemical', 'MESH:D002586', (105, 107))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('change', 'Reg', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('alterations', 'Var', (32, 43))	('homopolymeric stretch of', 'MPA', (80, 104))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))
611960	15230979	This region accounts for 22% of detected mutations across a broad spectrum of tumors.	('mutations', 'Var', (41, 50))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
611963	15230979	Of the seven subjects with CR alterations in their tumors, 3 had an adjacent normal tissue CR sequence identical to blood and 4 shared some of the mtDNA changes seen in the adjacent tumor.	('CR', 'Chemical', '-', (27, 29))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (51, 56))	('tumors', 'Disease', (51, 57))	('alterations', 'Var', (30, 41))	('CR', 'Chemical', '-', (91, 93))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
611964	15230979	In total, 11/31 (36%) of the CR alterations found in the tumor samples were also present in the adjacent normal tissue.	('CR', 'Chemical', '-', (29, 31))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('alterations', 'Var', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
611974	15230979	Certain diseases of aging, such as ocular myopathy, are commonly associated with an increase in mtDNA mutations and these mutations are often found to be clustered to regions such as the common deletion.	('mtDNA', 'Gene', (96, 101))	('ocular myopathy', 'Disease', 'MESH:D009135', (35, 50))	('myopathy', 'Phenotype', 'HP:0003198', (42, 50))	('increase', 'PosReg', (84, 92))	('mutations', 'Var', (102, 111))	('ocular myopathy', 'Disease', (35, 50))
611976	15230979	In our study we found that 89% of tumors and 95% of the adjacent normal tissue carried the deletion.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('deletion', 'Var', (91, 99))	('tumors', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
611980	15230979	These investigators used a quantitative assay to show that people who chew betel quid, which contains multiple genotoxic substances, had an increased percentage of mtDNA carrying the common deletion in both tumor and histologically normal oral tissue.	('deletion', 'Var', (190, 198))	('people', 'Species', '9606', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('mtDNA', 'Gene', (164, 169))	('tumor', 'Disease', (207, 212))
611981	15230979	In summary, CR mutations were present in 33% of the tumors we examined.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('CR', 'Chemical', '-', (12, 14))	('mutations', 'Var', (15, 24))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))
612019	23762579	When diffuse megaesophagus is found, contrast imaging is typically not indicated since a cause for esophageal dysphagia has been defined and contrast administration may result in aspiration.	('aspiration', 'Phenotype', 'HP:0002835', (179, 189))	('result in', 'Reg', (169, 178))	('esophageal dysphagia', 'Disease', (99, 119))	('dysphagia', 'Phenotype', 'HP:0002015', (110, 119))	('esophageal dysphagia', 'Phenotype', 'HP:0200136', (99, 119))	('esophageal dysphagia', 'Disease', 'MESH:D003680', (99, 119))	('contrast', 'Var', (141, 149))	('aspiration', 'Disease', (179, 189))
612025	23762579	In cases where the cause for dysphagia is not clear on survey radiographs, barium contrast studies should be postponed if severe aspiration pneumonia is present, as aspiration of barium during the imaging procedure will further compromise lung function.	('dysphagia', 'Disease', 'MESH:D003680', (29, 38))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (129, 149))	('compromise lung function', 'Phenotype', 'HP:0005952', (228, 252))	('lung', 'MPA', (239, 243))	('dysphagia', 'Disease', (29, 38))	('aspiration', 'Var', (165, 175))	('barium', 'Chemical', 'MESH:D001464', (75, 81))	('aspiration', 'Phenotype', 'HP:0002835', (129, 139))	('dysphagia', 'Phenotype', 'HP:0002015', (29, 38))	('pneumonia', 'Phenotype', 'HP:0002090', (140, 149))	('aspiration pneumonia', 'Disease', (129, 149))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (129, 149))	('severe aspiration pneumonia', 'Phenotype', 'HP:0011952', (122, 149))	('aspiration', 'Phenotype', 'HP:0002835', (165, 175))	('barium', 'Chemical', 'MESH:D001464', (179, 185))	('compromise', 'NegReg', (228, 238))
612038	23762579	Approximately 95% of vascular ring anomalies resulting in megaesophagus and esophageal dysphagia originate from persistence of the right aortic arch.	('vascular ring anomalies', 'Disease', 'MESH:D000073872', (21, 44))	('esophageal dysphagia', 'Phenotype', 'HP:0200136', (76, 96))	('esophageal dysphagia', 'Disease', (76, 96))	('persistence', 'Var', (112, 123))	('esophageal dysphagia', 'Disease', 'MESH:D003680', (76, 96))	('resulting in', 'Reg', (45, 57))	('vascular ring', 'Phenotype', 'HP:0010775', (21, 34))	('dysphagia', 'Phenotype', 'HP:0002015', (87, 96))	('megaesophagus', 'Disease', (58, 71))	('right aortic arch', 'Phenotype', 'HP:0012020', (131, 148))	('vascular ring anomalies', 'Disease', (21, 44))	('originate from', 'Reg', (97, 111))
612160	32095316	Five prognosis-related hub RNAs (CDCA2, MTBP, CENPE, PBK, AL033384.1) were identified.	('CENPE', 'Gene', '1062', (46, 51))	('CDCA2', 'Gene', (33, 38))	('AL033384.1', 'Var', (58, 68))	('CDCA2', 'Gene', '157313', (33, 38))	('MTBP', 'Gene', '27085', (40, 44))	('PBK', 'Gene', (53, 56))	('MTBP', 'Gene', (40, 44))	('CENPE', 'Gene', (46, 51))	('PBK', 'Gene', '55872', (53, 56))
612161	32095316	Additionally, we constructed a prognostic scoring system for ESCC using ten signature RNAs (MLIP, TNFSF10, SIK2, LINC01068, LINC00601, TTTY14, AC084262.1, LINC01415, miR-5699-3p, miR-552-5p).	('TTTY14', 'Gene', (135, 141))	('MLIP', 'Gene', (92, 96))	('ESCC', 'Disease', (61, 65))	('LINC01415', 'Gene', (155, 164))	('LINC00601', 'Gene', (124, 133))	('TNFSF10', 'Gene', '8743', (98, 105))	('TTTY14', 'Gene', '83869', (135, 141))	('miR-552-5p', 'Var', (179, 189))	('LINC01415', 'Gene', '100132501', (155, 164))	('miR-5699-3p', 'Var', (166, 177))	('LINC01068', 'Gene', (113, 122))	('SIK2', 'Gene', (107, 111))	('SIK2', 'Gene', '23235', (107, 111))	('LINC00601', 'Gene', '101101772', (124, 133))	('ESCC', 'Disease', 'MESH:C562729', (61, 65))	('AC084262.1', 'Var', (143, 153))	('LINC01068', 'Gene', '103724388', (113, 122))	('TNFSF10', 'Gene', (98, 105))	('MLIP', 'Gene', '90523', (92, 96))
612175	32095316	For ESCC, researchers have identified multiple driving genes, including TP53, NOTCH1, FAM135B, EP300, and TET2, and the mutation status of FAM135B, EP300 and TET2 are associated with the prognosis of patients.	('EP300', 'Gene', (95, 100))	('EP300', 'Gene', (148, 153))	('ESCC', 'Disease', (4, 8))	('FAM135B', 'Gene', '51059', (86, 93))	('TP53', 'Gene', '7157', (72, 76))	('NOTCH1', 'Gene', (78, 84))	('FAM135B', 'Gene', (86, 93))	('TET2', 'Gene', '54790', (158, 162))	('TET2', 'Gene', (106, 110))	('FAM135B', 'Gene', '51059', (139, 146))	('NOTCH1', 'Gene', '4851', (78, 84))	('mutation', 'Var', (120, 128))	('ESCC', 'Disease', 'MESH:C562729', (4, 8))	('EP300', 'Gene', '2033', (95, 100))	('patients', 'Species', '9606', (200, 208))	('TET2', 'Gene', '54790', (106, 110))	('EP300', 'Gene', '2033', (148, 153))	('TP53', 'Gene', (72, 76))	('FAM135B', 'Gene', (139, 146))	('associated', 'Reg', (167, 177))	('TET2', 'Gene', (158, 162))
612202	32095316	The formulas for the three prognostic models were as follows: lncRNA-based prognostic score = (0.447 x expression level of LINC01068) + (0.3677 x expression level of LINC00601) + (0.3075 x expression level of TTTY14) + (-0.8750 x expression level of AC084262.1) + (-0.4744 x expression level of LINC01415); miRNA-based prognostic score = (1.2932 x expression level of miR-5699-3p) + (0.7202 x expression level of miR-552-5p); mRNA-based prognostic score = (0.5139 x expression level of MLIP) + (0.5746 x expression level of TNFSF10) + (-1.0069 x expression level of SIK2).	('LINC01068', 'Gene', (123, 132))	('LINC01415', 'Gene', (295, 304))	('LINC01415', 'Gene', '100132501', (295, 304))	('LINC01068', 'Gene', '103724388', (123, 132))	('MLIP', 'Gene', (486, 490))	('0.5139', 'Var', (457, 463))	('TTTY14', 'Gene', '83869', (209, 215))	('SIK2', 'Gene', (566, 570))	('TTTY14', 'Gene', (209, 215))	('LINC00601', 'Gene', (166, 175))	('TNFSF10', 'Gene', (524, 531))	('SIK2', 'Gene', '23235', (566, 570))	('LINC00601', 'Gene', '101101772', (166, 175))	('MLIP', 'Gene', '90523', (486, 490))	('TNFSF10', 'Gene', '8743', (524, 531))
612203	32095316	Of three prognostic models, seven RNAs were shown to be risky RNAs (LINC01068, LINC00601, TTTY14, miR-5699-3p, miR-552-5p, MLIP, TNFSF10, HR >1) and three RNAs were the protective RNAs (AC084262.1, LINC01415, SIK2, HR <1) (Figs.	('TTTY14', 'Gene', '83869', (90, 96))	('SIK2', 'Gene', '23235', (209, 213))	('miR-5699-3p', 'Var', (98, 109))	('miR-552-5p', 'Var', (111, 121))	('LINC01415', 'Gene', '100132501', (198, 207))	('MLIP', 'Gene', (123, 127))	('TTTY14', 'Gene', (90, 96))	('LINC01068', 'Gene', '103724388', (68, 77))	('LINC00601', 'Gene', (79, 88))	('TNFSF10', 'Gene', (129, 136))	('LINC00601', 'Gene', '101101772', (79, 88))	('MLIP', 'Gene', '90523', (123, 127))	('SIK2', 'Gene', (209, 213))	('LINC01068', 'Gene', (68, 77))	('TNFSF10', 'Gene', '8743', (129, 136))	('LINC01415', 'Gene', (198, 207))
612211	32095316	The formula was as follows: RNA-based prognostic score = (0.42895 x expression level of LINC01068) + (0.34829 x expression level of LINC00601) + (0.2185 x expression level of TTTY14) + (-1.393 x expression level of AC084262.1) + (-0.33364 x expression level of LINC01415) + (1.06024 x expression level of miR-5699-3p) + (0.34784 x expression level of miR-552-5p) + (0.3418 x expression level of MLIP) + (0.05437 x expression level of TNFSF10) + (-1.38365 x expression level of SIK2).	('SIK2', 'Gene', (477, 481))	('LINC01068', 'Gene', '103724388', (88, 97))	('SIK2', 'Gene', '23235', (477, 481))	('0.34784', 'Var', (321, 328))	('MLIP', 'Gene', (395, 399))	('TTTY14', 'Gene', (175, 181))	('TNFSF10', 'Gene', (434, 441))	('LINC01068', 'Gene', (88, 97))	('TTTY14', 'Gene', '83869', (175, 181))	('TNFSF10', 'Gene', '8743', (434, 441))	('LINC01415', 'Gene', (261, 270))	('LINC00601', 'Gene', '101101772', (132, 141))	('LINC01415', 'Gene', '100132501', (261, 270))	('LINC00601', 'Gene', (132, 141))	('MLIP', 'Gene', '90523', (395, 399))
612225	32095316	Of prognostic models, seven RNAs were shown to be risky RNAs (LINC01068, LINC00601, TTTY14, miR-5699-3p, miR-552-5p, MLIP, TNFSF10, HR >1) and three RNAs were the protective RNAs (AC084262.1, LINC01415, SIK2, HR <1).	('LINC01068', 'Gene', (62, 71))	('miR-552-5p', 'Var', (105, 115))	('miR-5699-3p', 'Var', (92, 103))	('TTTY14', 'Gene', (84, 90))	('SIK2', 'Gene', '23235', (203, 207))	('TTTY14', 'Gene', '83869', (84, 90))	('MLIP', 'Gene', '90523', (117, 121))	('LINC00601', 'Gene', (73, 82))	('LINC01415', 'Gene', (192, 201))	('LINC00601', 'Gene', '101101772', (73, 82))	('LINC01068', 'Gene', '103724388', (62, 71))	('LINC01415', 'Gene', '100132501', (192, 201))	('SIK2', 'Gene', (203, 207))	('TNFSF10', 'Gene', (123, 130))	('MLIP', 'Gene', (117, 121))	('TNFSF10', 'Gene', '8743', (123, 130))
612228	32095316	miR-552-5p facilitates osteosarcoma cell proliferation and metastasis by targeting WIF1, which means miR-552-5p may become a new target for the treatment of osteosarcoma.	('metastasis', 'CPA', (59, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (157, 169))	('osteosarcoma', 'Disease', (157, 169))	('osteosarcoma', 'Disease', 'MESH:D012516', (157, 169))	('WIF1', 'Gene', (83, 87))	('facilitates', 'PosReg', (11, 22))	('miR-552-5p', 'Var', (0, 10))	('WIF1', 'Gene', '11197', (83, 87))	('targeting', 'Reg', (73, 82))	('osteosarcoma', 'Phenotype', 'HP:0002669', (23, 35))	('osteosarcoma', 'Disease', (23, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (23, 35))
612230	32095316	Frequent amplification of TNFSF10 was associated with the development and progression of esophageal cancer.	('esophageal cancer', 'Disease', (89, 106))	('associated with', 'Reg', (38, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Frequent amplification', 'Var', (0, 22))	('TNFSF10', 'Gene', (26, 33))	('TNFSF10', 'Gene', '8743', (26, 33))
612232	32095316	However, functional studies of the other RNAs (LINC01068, LINC00601, AC084262.1, LINC01415, miR-5699-3p, MLIP) have not been reported in cancer research.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('LINC01068', 'Gene', '103724388', (47, 56))	('miR-5699-3p', 'Var', (92, 103))	('LINC01415', 'Gene', (81, 90))	('MLIP', 'Gene', (105, 109))	('LINC01415', 'Gene', '100132501', (81, 90))	('LINC00601', 'Gene', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('LINC00601', 'Gene', '101101772', (58, 67))	('MLIP', 'Gene', '90523', (105, 109))	('cancer', 'Disease', (137, 143))	('LINC01068', 'Gene', (47, 56))
612240	31851619	Results: Higher expression and potency of endothelial to mesenchymal transformation (EMT) was found in radioresistant ESCC cells (KYSE-150R) than in ESCC cells (KYSE-150).	('ESCC', 'Disease', (118, 122))	('ESCC', 'Disease', (149, 153))	('radioresistant', 'Disease', (103, 117))	('Higher', 'PosReg', (9, 15))	('KYSE-150R', 'Var', (130, 139))	('endothelial to mesenchymal transformation', 'CPA', (42, 83))	('ESCC', 'Disease', 'MESH:C562729', (149, 153))	('ESCC', 'Disease', 'MESH:C562729', (118, 122))	('expression', 'MPA', (16, 26))
612241	31851619	Silencing circRNA_100367 inhibited the proliferation and migration of KYSE-150R cells, and decreased the expression of beta-catenin (an important molecule in Wnt pathway) in KYSE-150R cells.	('beta-catenin', 'Gene', '1499', (119, 131))	('circRNA_100367', 'Gene', (10, 24))	('migration of KYSE-150R cells', 'CPA', (57, 85))	('proliferation', 'CPA', (39, 52))	('beta-catenin', 'Gene', (119, 131))	('inhibited', 'NegReg', (25, 34))	('Silencing', 'Var', (0, 9))	('expression', 'MPA', (105, 115))	('decreased', 'NegReg', (91, 100))
612243	31851619	Low Wnt3 expression was associated with the short survival time in patients with ESCC and Wnt3 knockdown inhibited the proliferation and migration of KYSE-150R cells.	('ESCC', 'Disease', 'MESH:C562729', (81, 85))	('patients', 'Species', '9606', (67, 75))	('Wnt3', 'Gene', (90, 94))	('inhibited', 'NegReg', (105, 114))	('ESCC', 'Disease', (81, 85))	('knockdown', 'Var', (95, 104))	('expression', 'MPA', (9, 19))	('Wnt3', 'Gene', '7473', (4, 8))	('Low', 'NegReg', (0, 3))	('Wnt3', 'Gene', (4, 8))	('Wnt3', 'Gene', '7473', (90, 94))
612244	31851619	CircRNA_100367 enhanced the radioresistance of KYSE-150R cells through miR-217/Wnt3 pathway.	('Wnt3', 'Gene', (79, 83))	('CircRNA_100367', 'Var', (0, 14))	('miR-217', 'Gene', '406999', (71, 78))	('miR-217', 'Gene', (71, 78))	('radioresistance', 'CPA', (28, 43))	('Wnt3', 'Gene', '7473', (79, 83))	('enhanced', 'PosReg', (15, 23))
612245	31851619	Conclusion: Our results revealed that circRNA_100367 attenuated radioresistance of ESCC through miR-217/Wnt3 pathway.	('miR-217', 'Gene', (96, 103))	('Wnt3', 'Gene', (104, 108))	('radioresistance', 'CPA', (64, 79))	('circRNA_100367', 'Var', (38, 52))	('ESCC', 'Disease', 'MESH:C562729', (83, 87))	('attenuated', 'NegReg', (53, 63))	('Wnt3', 'Gene', '7473', (104, 108))	('ESCC', 'Disease', (83, 87))	('miR-217', 'Gene', '406999', (96, 103))
612251	31851619	Studies have shown that the occurrence of radioresistance of ESCC cells is related with the abnormal expression of genes.	('genes', 'Protein', (115, 120))	('ESCC', 'Disease', (61, 65))	('radioresistance', 'CPA', (42, 57))	('expression of', 'MPA', (101, 114))	('abnormal', 'Var', (92, 100))	('ESCC', 'Disease', 'MESH:C562729', (61, 65))
612261	31851619	So, finding the downstream miRNAs/proteins that regulated by circRNA_100367 is important to reveal the underlying mechanism of circRNA_100367 mediated radiation sensitivity of ESCC.	('ESCC', 'Disease', (176, 180))	('circRNA_100367', 'Var', (127, 141))	('miR', 'Gene', '220972', (27, 30))	('ESCC', 'Disease', 'MESH:C562729', (176, 180))	('miR', 'Gene', (27, 30))
612268	31851619	The expression of Wnt3 can activate Wnt-beta-catenin signaling pathway in liver cancer, gastric cancer, lung cancer, and ESCC, etc.	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('ESCC', 'Disease', 'MESH:C562729', (121, 125))	('beta-catenin', 'Gene', (40, 52))	('beta-catenin', 'Gene', '1499', (40, 52))	('liver cancer', 'Disease', 'MESH:D006528', (74, 86))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('Wnt3', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('activate', 'PosReg', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('expression', 'Var', (4, 14))	('liver cancer', 'Phenotype', 'HP:0002896', (74, 86))	('ESCC', 'Disease', (121, 125))	('liver cancer', 'Disease', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('gastric cancer', 'Disease', (88, 102))	('lung cancer', 'Disease', (104, 115))	('Wnt3', 'Gene', '7473', (18, 22))
612269	31851619	Studies have shown that Wnt3 is up-regulated in cancer tissues, such as gastric cancer and lung cancer, and knockdown of Wnt3 can suppress the progression of cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('Wnt3', 'Gene', '7473', (24, 28))	('cancer', 'Disease', (48, 54))	('suppress', 'NegReg', (130, 138))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (80, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('knockdown', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Wnt3', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('cancer', 'Disease', (158, 164))	('Wnt3', 'Gene', (24, 28))	('lung cancer', 'Disease', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('up-regulated', 'PosReg', (32, 44))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('gastric cancer', 'Disease', (72, 86))	('Wnt3', 'Gene', '7473', (121, 125))
612276	31851619	As shown in Figure 2A, EMT-related molecule E-cadherin was decreased and vimentin and snail expressions were increased in KYSE-150R cells than that of KYSE-150 cells, indicating stronger molecular characteristics of EMT in KYSE-150R cells.	('snail', 'Gene', (86, 91))	('vimentin', 'Gene', '7431', (73, 81))	('decreased', 'NegReg', (59, 68))	('vimentin', 'Gene', (73, 81))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('snail', 'Gene', '6615', (86, 91))	('increased', 'PosReg', (109, 118))	('KYSE-150R cells', 'Var', (122, 137))
612277	31851619	The number of CD133+ cells in KYSE-150R cells was greater than that in KYSE-150 cells (Figure 2C).	('CD133', 'Gene', '8842', (14, 19))	('KYSE-150R', 'Var', (30, 39))	('CD133', 'Gene', (14, 19))
612279	31851619	However, the degradation degree of circRNA_100367 was much lower than DCAF8 mRNA, indicating circRNA_100367 exists in esophageal squamous cell carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('DCAF8', 'Gene', '50717', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (129, 153))	('lower', 'NegReg', (59, 64))	('circRNA_100367', 'Var', (93, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:C562729', (118, 153))	('esophageal squamous cell carcinomas', 'Disease', (118, 153))	('degradation', 'MPA', (13, 24))	('DCAF8', 'Gene', (70, 75))
612285	31851619	The luciferase activity of miR-217 was significantly increased in circRNA_100367 mut (Figure 4D), indicating miR-217 could bind to the binding sites of circRNA_100367.	('miR-217', 'Gene', (27, 34))	('activity', 'MPA', (15, 23))	('miR-217', 'Gene', (109, 116))	('increased', 'PosReg', (53, 62))	('circRNA_100367 mut', 'Var', (66, 84))	('miR-217', 'Gene', '406999', (109, 116))	('bind', 'Interaction', (123, 127))	('luciferase', 'Enzyme', (4, 14))	('miR-217', 'Gene', '406999', (27, 34))
612286	31851619	Moreover, the enrichment of circRNA_100367 in biotin-labeled miR-217 further proved the interaction between circRNA_100367 and miR-217 (Figure 4E).	('circRNA_100367', 'Var', (28, 42))	('circRNA_100367', 'Var', (108, 122))	('miR-217', 'Gene', '406999', (61, 68))	('miR-217', 'Gene', (61, 68))	('miR-217', 'Gene', '406999', (127, 134))	('interaction', 'Interaction', (88, 99))	('biotin', 'Chemical', 'MESH:D001710', (46, 52))	('miR-217', 'Gene', (127, 134))
612291	31851619	As shown in Figure 5D, overexpression of Wnt3 promoted the migration of KYSE-150 cells, while knockdown of Wnt3 inhibited the migration of KYSE-150R cells.	('promoted', 'PosReg', (46, 54))	('knockdown', 'Var', (94, 103))	('inhibited', 'NegReg', (112, 121))	('Wnt3', 'Gene', (107, 111))	('migration of KYSE-150 cells', 'CPA', (59, 86))	('Wnt3', 'Gene', '7473', (107, 111))	('Wnt3', 'Gene', '7473', (41, 45))	('migration', 'CPA', (126, 135))	('Wnt3', 'Gene', (41, 45))
612301	31851619	Since silencing circRNA_100367 inhibited the proliferation and migration of KYSE-150R cells in vitro, we determined the role of circRNA_100367 in vivo using a xenograft nude mouse model.	('inhibited', 'NegReg', (31, 40))	('silencing', 'Var', (6, 15))	('circRNA_100367', 'Gene', (16, 30))	('mouse', 'Species', '10090', (174, 179))
612302	31851619	Tumor volume was significantly larger in KYSE-150R+Gy group than that of KYSE-150+Gy group.	('Tumor volume', 'CPA', (0, 12))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('KYSE-150+Gy', 'Chemical', 'MESH:C045845', (73, 84))	('KYSE-150R+Gy', 'Var', (41, 53))	('larger', 'PosReg', (31, 37))
612303	31851619	CircRNA_100367 overexpression significantly increased the tumor volume of KYSE-150+circRNA_100367+Gy group, and silencing circRNA_100367 significantly reduced the tumor volume of KYSE-150R+sh-circRNA_100367+Gy group (Figure 7B).	('silencing circRNA_100367', 'Var', (112, 136))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('reduced', 'NegReg', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('100367+Gy', 'Chemical', 'None', (200, 209))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('100367+Gy', 'Chemical', 'None', (91, 100))	('increased', 'PosReg', (44, 53))	('circRNA_100367', 'Var', (122, 136))
612304	31851619	The protein level of E-cadherin was decreased and the protein levels of vimentin, snail, Wnt3, andbeta-catenin were increased in the KYSE-150+sh-circRNA_100367+Gy group compared with KYSE-150+ Gy group.	('Wnt3', 'Gene', (89, 93))	('protein level', 'MPA', (4, 17))	('vimentin', 'Gene', '7431', (72, 80))	('100367+Gy', 'Chemical', 'None', (153, 162))	('beta-catenin', 'Gene', (98, 110))	('vimentin', 'Gene', (72, 80))	('protein levels', 'MPA', (54, 68))	('snail', 'Gene', (82, 87))	('KYSE-150+sh-circRNA_100367+Gy', 'Var', (133, 162))	('Wnt3', 'Gene', '7473', (89, 93))	('increased', 'PosReg', (116, 125))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('beta-catenin', 'Gene', '1499', (98, 110))	('snail', 'Gene', '6615', (82, 87))	('decreased', 'NegReg', (36, 45))
612305	31851619	Also, the protein level of E-cadherin was elevated and the protein levels of vimentin, snail, Wnt3, andbeta-catenin were reduced in the KYSE-150R+sh-circRNA_100367+Gy group compared with KYSE-150R+ Gy group (Figure 7C).	('Wnt3', 'Gene', '7473', (94, 98))	('protein level of', 'MPA', (10, 26))	('beta-catenin', 'Gene', (103, 115))	('Wnt3', 'Gene', (94, 98))	('reduced', 'NegReg', (121, 128))	('beta-catenin', 'Gene', '1499', (103, 115))	('snail', 'Gene', '6615', (87, 92))	('vimentin', 'Gene', '7431', (77, 85))	('100367+Gy', 'Chemical', 'None', (157, 166))	('KYSE-150R+sh-circRNA_100367+Gy', 'Var', (136, 166))	('vimentin', 'Gene', (77, 85))	('E-cadherin', 'Gene', (27, 37))	('E-cadherin', 'Gene', '999', (27, 37))	('elevated', 'PosReg', (42, 50))	('snail', 'Gene', (87, 92))
612308	31851619	In this study, the upregulation of circRNA_100367 was observed in KYSE-150/KYSE-150R cells with a most extent than the other two ESCC cell lines and their radioresistant cells.	('upregulation', 'PosReg', (19, 31))	('ESCC', 'Disease', 'MESH:C562729', (129, 133))	('circRNA_100367', 'Var', (35, 49))	('ESCC', 'Disease', (129, 133))
612309	31851619	Also, previous studies showed abnormally expressed circRNAs are related with the phenotypic change of cancer cells.	('circRNAs', 'Gene', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('related', 'Reg', (64, 71))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('abnormally', 'Var', (30, 40))
612310	31851619	So we further transfected sh-circRNA_100367 into KYSE-150R cells to determine whether circRNA_100367 changed the phenotype of ESCC radioresistant cells.	('ESCC', 'Disease', 'MESH:C562729', (126, 130))	('circRNA_100367', 'Var', (86, 100))	('changed', 'Reg', (101, 108))	('ESCC', 'Disease', (126, 130))
612311	31851619	These results indicated that upregulation of circRNA_100367 suppressed the radiation sensitivity of radioresistant ESCC KYSE-150R.	('ESCC', 'Disease', (115, 119))	('circRNA_100367', 'Var', (45, 59))	('suppressed', 'NegReg', (60, 70))	('upregulation', 'PosReg', (29, 41))	('ESCC', 'Disease', 'MESH:C562729', (115, 119))	('radiation', 'CPA', (75, 84))
612314	31851619	For example, abnormally expressed miR-217 enhanced the chemosensitivity of acute myeloid leukemia and cervical carcinoma.	('miR-217', 'Gene', '406999', (34, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('cervical carcinoma', 'Disease', (102, 120))	('acute myeloid leukemia', 'Disease', (75, 97))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (81, 97))	('abnormally expressed', 'Var', (13, 33))	('enhanced', 'PosReg', (42, 50))	('cervical carcinoma', 'Disease', 'MESH:D002583', (102, 120))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (75, 97))	('chemosensitivity', 'MPA', (55, 71))	('miR-217', 'Gene', (34, 41))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (75, 97))
612321	31851619	In this study, we found silencing Wnt3 down-regulated the expression of nucleus beta-catenin, which was consistent with previous report.	('Wnt3', 'Gene', (34, 38))	('expression', 'MPA', (58, 68))	('beta-catenin', 'Gene', (80, 92))	('beta-catenin', 'Gene', '1499', (80, 92))	('Wnt3', 'Gene', '7473', (34, 38))	('down-regulated', 'NegReg', (39, 53))	('silencing', 'Var', (24, 33))
612323	31851619	In this study, results showed that silencing Wnt3 enhanced the radiation sensitivity of KYSE-150R cells.	('Wnt3', 'Gene', (45, 49))	('silencing', 'Var', (35, 44))	('Wnt3', 'Gene', '7473', (45, 49))	('enhanced', 'PosReg', (50, 58))	('radiation sensitivity of KYSE-150R cells', 'CPA', (63, 103))
612324	31851619	In addition, silencing Wnt3 changed the phenotype of KYSE-150R cells, which suppressed the colony formation and the migration of KYSE-150R cells.	('colony formation', 'CPA', (91, 107))	('Wnt3', 'Gene', '7473', (23, 27))	('suppressed', 'NegReg', (76, 86))	('Wnt3', 'Gene', (23, 27))	('migration', 'CPA', (116, 125))	('silencing', 'Var', (13, 22))
612331	31851619	In conclusion, highly expressed circRNA_100367 is related with the radiation sensitivity of ESCC, and silencing circRNA_100367 decreased the proliferation and migration of KYSE-150R cells in vitro, and inhibited tumor growth in vivo.	('decreased', 'NegReg', (127, 136))	('ESCC', 'Disease', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('proliferation', 'CPA', (141, 154))	('circRNA_100367', 'Gene', (112, 126))	('inhibited', 'NegReg', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('silencing', 'Var', (102, 111))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))	('tumor', 'Disease', (212, 217))
612341	31851619	The 2-DeltaDeltaCT method was used to calculate the relative expressions of circRNA_100385, circRNA_104983, circRNA_001059, circRNA_100984, circRNA_100367, circRNA_103783, circRNA_100312 and Wnt3.	('circRNA_104983', 'Var', (92, 106))	('Wnt3', 'Gene', (191, 195))	('Wnt3', 'Gene', '7473', (191, 195))
612349	31851619	1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) assay kit (Sigma-Aldrich, Billerica, MA, USA) was used to detect the proliferation of KYSE-150 cells and KYSE-150R cells with different treatments under the radiation dose of 0Gy, 3Gy and 6Gy.	('1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan', 'Chemical', 'MESH:C408384', (0, 49))	('0Gy', 'Var', (231, 234))	('3Gy', 'Var', (236, 239))	('MTT', 'Chemical', 'MESH:C022616', (51, 54))
612353	31851619	Wnt3 wild-type (Wnt3 WT) and Wnt3 mutant (Wnt3 mut) reporter vectors were also constructed and inserted into the psiCHECK-2 (Promega).	('Wnt3', 'Gene', (42, 46))	('Wnt3', 'Gene', (0, 4))	('Wnt3', 'Gene', '7473', (29, 33))	('Wnt3', 'Gene', '7473', (16, 20))	('Wnt3', 'Gene', (29, 33))	('Wnt3', 'Gene', '7473', (0, 4))	('Wnt3', 'Gene', (16, 20))	('Wnt3', 'Gene', '7473', (42, 46))	('mutant', 'Var', (34, 40))
612354	31851619	100 nmol reporter plasmids (circRNA_100367, circRNA_100367 mut) together with miR-217 or negative control were transfected into KYSE-150R cells.	('miR-217', 'Gene', '406999', (78, 85))	('circRNA_100367', 'Var', (44, 58))	('miR-217', 'Gene', (78, 85))
612360	31851619	So, the nude mice were divided into four groups, namely KYSE-150+Gy group (n=5), KYSE-150R+Gy group (n=5), KYSE-150+circRNA_100367+Gy group (n=5) and KYSE-150R+sh-circRNA_100367+Gy group (n=5).	('100367+Gy', 'Chemical', 'None', (124, 133))	('nude mice', 'Species', '10090', (8, 17))	('KYSE-150R+Gy', 'Var', (81, 93))	('KYSE-150+circRNA_100367+Gy', 'Var', (107, 133))	('KYSE-150+Gy', 'Chemical', 'MESH:C045845', (56, 67))	('100367+Gy', 'Chemical', 'None', (171, 180))
612473	29993360	The percentage of patients achieving complete tumor regression at the primary site (pT0) was significantly higher in the NACRT group.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('NACRT', 'Var', (121, 126))	('NACRT', 'Chemical', '-', (121, 126))	('tumor', 'Disease', (46, 51))	('patients', 'Species', '9606', (18, 26))	('pT0', 'Chemical', 'MESH:D010984', (84, 87))	('higher', 'PosReg', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
612475	29993360	Patients receiving NACRT had better resectability rates and pathological response rates, but similar postoperative morbidity compared to the NACT group.	('resectability rates', 'CPA', (36, 55))	('NACT', 'Chemical', '-', (141, 145))	('Patients', 'Species', '9606', (0, 8))	('NACRT', 'Var', (19, 24))	('pathological response rates', 'CPA', (60, 87))	('NACRT', 'Chemical', '-', (19, 24))	('better', 'PosReg', (29, 35))
612531	29993360	The percentage of patients with resectable disease was statistically greater in the NACRT group as compared to the NACT group (P=0.0027).	('greater', 'PosReg', (69, 76))	('NACRT', 'Var', (84, 89))	('NACT', 'Chemical', '-', (115, 119))	('NACRT', 'Chemical', '-', (84, 89))	('patients', 'Species', '9606', (18, 26))	('resectable disease', 'CPA', (32, 50))
612540	29993360	Median blood loss during surgery was statistically less in the NACRT group compared with the NACT group (200 mL versus 250 mL; P=0.0168).	('NACRT', 'Chemical', '-', (63, 68))	('blood loss', 'Disease', (7, 17))	('NACT', 'Chemical', '-', (93, 97))	('less', 'NegReg', (51, 55))	('blood loss during surgery', 'Phenotype', 'HP:0004846', (7, 32))	('blood loss', 'Disease', 'MESH:D006473', (7, 17))	('NACRT', 'Var', (63, 68))
612554	29993360	There was a tendency to achieve higher complete pathological regression in the NACRT group as compared to the NACT group (P=0.0675).	('complete pathological regression', 'CPA', (39, 71))	('NACT', 'Chemical', '-', (110, 114))	('NACRT', 'Var', (79, 84))	('NACRT', 'Chemical', '-', (79, 84))
612577	29993360	The CROSS trial, which included esophageal and gastroesophageal tumors, has clearly shown that NACRT improves overall survival and disease-free survival over surgery alone.	('overall survival', 'CPA', (110, 126))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('esophageal tumors', 'Phenotype', 'HP:0100751', (53, 70))	('gastroesophageal tumors', 'Disease', (47, 70))	('esophageal', 'Disease', 'MESH:D004941', (53, 63))	('NACRT', 'Var', (95, 100))	('esophageal', 'Disease', 'MESH:D004941', (32, 42))	('gastroesophageal tumors', 'Phenotype', 'HP:0100751', (47, 70))	('NACRT', 'Chemical', '-', (95, 100))	('gastroesophageal tumors', 'Disease', 'MESH:D005764', (47, 70))	('disease-free survival', 'CPA', (131, 152))	('esophageal', 'Disease', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('improves', 'PosReg', (101, 109))	('esophageal', 'Disease', (32, 42))
612586	28943918	Following transfection of PAR-2 shRNA-1, PAR-2 expression was significantly downregulated in mRNA level and protein level in EC109 cells (P<0.05).	('EC109', 'CellLine', 'CVCL:6898', (125, 130))	('transfection', 'Var', (10, 22))	('downregulated', 'NegReg', (76, 89))	('PAR-2', 'Gene', (41, 46))	('expression', 'MPA', (47, 57))
612587	28943918	The proliferation of EC109 cells transfected with PAR-2 shRNA was significantly lower than the negative control group (P<0.05).	('PAR-2 shRNA', 'Var', (50, 61))	('EC109', 'CellLine', 'CVCL:6898', (21, 26))	('proliferation', 'CPA', (4, 17))	('lower', 'NegReg', (80, 85))
612591	28943918	Subsequent to silencing of PAR-2, the proliferation of EC109 cells was inhibited and the capabilities of invasion and migration were reduced.	('silencing', 'Var', (14, 23))	('inhibited', 'NegReg', (71, 80))	('EC109', 'CellLine', 'CVCL:6898', (55, 60))	('reduced', 'NegReg', (133, 140))	('PAR-2', 'Gene', (27, 32))
612639	28943918	2A, the band intensities were 0.35+-0.03, 0.43+-0.04, 0.44+-0.04 and 0.45+-0.41 in PAR-2 shRNA-1 group, PAR-2 shRNA-2 group, non-specific sequence group and blank control group, respectively.	('0.44+-0.04', 'Var', (54, 64))	('PAR-2 shRNA-1 group', 'Gene', (83, 102))	('0.45+-0.41', 'Var', (69, 79))	('0.43+-0.04', 'Var', (42, 52))	('PAR-2 shRNA-1 group', 'Gene', '2150', (83, 102))
612643	28943918	3, EC109 cell proliferation in the PAR-2 shRNA group was significantly lower than the negative control group (P<0.05), and the growth inhibition ratios were 5.92, 24.89 and 32.28% at 24, 48 and 72 h post-transfection, respectively.	('EC109 cell proliferation', 'CPA', (3, 27))	('growth', 'CPA', (127, 133))	('PAR-2 shRNA', 'Var', (35, 46))	('lower', 'NegReg', (71, 76))	('EC109', 'CellLine', 'CVCL:6898', (3, 8))
612644	28943918	The results indicated that silenced PAR-2 can repress cellular proliferation in EC109 cell lines, while the transfection reagent and negative plasmid have no significant inhibition roles in EC109 cell viability.	('silenced', 'Var', (27, 35))	('PAR-2', 'Gene', (36, 41))	('EC109', 'CellLine', 'CVCL:6898', (80, 85))	('EC109', 'CellLine', 'CVCL:6898', (190, 195))	('cellular proliferation', 'CPA', (54, 76))	('repress', 'NegReg', (46, 53))
612645	28943918	To investigate the effect of silenced PAR-2 on cell cycles of EC109 cells, flow cytometry was used to detect the changes of cell cycle.	('silenced', 'Var', (29, 37))	('PAR-2', 'Gene', (38, 43))	('EC109', 'CellLine', 'CVCL:6898', (62, 67))
612647	28943918	The ratio of S phase cells was significantly lower in EC109 cells transfected with PAR-2 shRNA than in EC109 cells (P<0.05), which indicated that silenced PAR-2 inhibited cell cycle of EC109 cells.	('PAR-2', 'Gene', (155, 160))	('EC109', 'CellLine', 'CVCL:6898', (103, 108))	('inhibited', 'NegReg', (161, 170))	('EC109', 'CellLine', 'CVCL:6898', (185, 190))	('silenced', 'Var', (146, 154))	('lower', 'NegReg', (45, 50))	('EC109', 'CellLine', 'CVCL:6898', (54, 59))	('cell cycle', 'CPA', (171, 181))	('PAR-2', 'Gene', (83, 88))
612651	28943918	5B, under the microscope (magnification, x200), the number of EC109 cells that moved through the artificial basement membrane by deformation was significantly lower in the PAR-2 shRNA group (24.2+-2.82) compared with the control group (43.8+-2.14; Table I, P<0.01).	('deformation', 'Var', (129, 140))	('EC109', 'CellLine', 'CVCL:6898', (62, 67))	('PAR-2 shRNA', 'Var', (172, 183))	('lower', 'NegReg', (159, 164))
612657	28943918	Among tumors in the digestive system, activated PAR-2 can promote invasion and metastasis of tumor cells, regulate tumor cell proliferation, adhesion and angiogenesis.	('activated', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('promote', 'PosReg', (58, 65))	('adhesion', 'CPA', (141, 149))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (115, 120))	('tumors', 'Disease', (6, 12))	('regulate', 'Reg', (106, 114))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('angiogenesis', 'CPA', (154, 166))	('PAR-2', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
612661	28943918	MTT assay was applied to detect the proliferation of EC109 cells subsequent to silencing PAR-2.	('PAR-2', 'Gene', (89, 94))	('EC109', 'CellLine', 'CVCL:6898', (53, 58))	('silencing', 'Var', (79, 88))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))
612670	28943918	In the present study, Matrigel and Transwell assays were applied to detect the changes of cell invasion and metastasis of EC109 cells following PAR-2 silencing.	('metastasis', 'CPA', (108, 118))	('cell invasion', 'CPA', (90, 103))	('silencing', 'Var', (150, 159))	('PAR-2', 'Gene', (144, 149))	('EC109', 'CellLine', 'CVCL:6898', (122, 127))
612672	28943918	Although it remains unclear whether PAR-2 is involved in repressing the capabilities of cell proliferation, invasion and metastasis in EC109 cells subsequent to gene silencing, PAR-2 target silence by RNAi technology may become a new candidate for treatment in esophageal cancers.	('metastasis', 'CPA', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('PAR-2', 'Gene', (177, 182))	('EC109', 'CellLine', 'CVCL:6898', (135, 140))	('esophageal cancers', 'Disease', (261, 279))	('esophageal cancers', 'Disease', 'MESH:D004938', (261, 279))	('gene silencing', 'Var', (161, 175))	('cell proliferation', 'CPA', (88, 106))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('invasion', 'CPA', (108, 116))
612673	26675332	Variations in telomere maintenance and the role of telomerase inhibition in gastrointestinal cancer Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance.	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (76, 99))	('telomere maintenance', 'Protein', (14, 34))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('human', 'Species', '9606', (176, 181))	('Variations', 'Var', (0, 10))	('inhibition', 'NegReg', (62, 72))	('gastrointestinal cancer', 'Disease', (76, 99))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (76, 99))
612687	26675332	These terminal DNA sequences were named telomeres, and later experiments in yeast showed that artificial chromosomes could be stabilized by the addition of these telomere repeats, indicating their crucial role in the maintenance of chromosomal stability.	('telomere repeats', 'Var', (162, 178))	('artificial chromosomes', 'CPA', (94, 116))	('addition', 'Var', (144, 152))	('yeast', 'Species', '4932', (76, 81))
612704	26675332	While several groups have demonstrated that promoter methylation is associated with lower hTERT expression reflecting the well-described mechanism of gene silencing through hypermethylation of promoter regions, others have shown that hypermethylation of the hTERT promoter region leads to increased hTERT expression, whereas demethylation of this region inhibits hTERT transcription.	('hTERT', 'Gene', '7015', (299, 304))	('hypermethylation', 'Var', (234, 250))	('hTERT', 'Gene', '7015', (90, 95))	('hTERT', 'Gene', (258, 263))	('increased', 'PosReg', (289, 298))	('hTERT', 'Gene', '7015', (363, 368))	('inhibits', 'NegReg', (354, 362))	('demethylation', 'Var', (325, 338))	('promoter methylation', 'Var', (44, 64))	('hTERT', 'Gene', (299, 304))	('hTERT', 'Gene', (90, 95))	('lower', 'NegReg', (84, 89))	('hTERT', 'Gene', (363, 368))	('hTERT', 'Gene', '7015', (258, 263))
612712	26675332	While phosphorylation of hTERT by AKT and protein kinase C is associated with increased telomerase activity, phosphorylation by the c-ABL kinase at specific tyrosine residues has been reported to decrease telomerase activity and telomere length.	('AKT', 'Gene', (34, 37))	('hTERT', 'Gene', '7015', (25, 30))	('c-ABL', 'Gene', '25', (132, 137))	('decrease', 'NegReg', (196, 204))	('hTERT', 'Gene', (25, 30))	('telomerase', 'CPA', (205, 215))	('phosphorylation', 'Var', (109, 124))	('protein kinase C', 'Enzyme', (42, 58))	('phosphorylation', 'MPA', (6, 21))	('increased', 'PosReg', (78, 87))	('telomerase activity', 'MPA', (88, 107))	('c-ABL', 'Gene', (132, 137))	('AKT', 'Gene', '207', (34, 37))	('telomere length', 'CPA', (229, 244))	('tyrosine', 'Chemical', 'MESH:D014443', (157, 165))
612717	26675332	Consequently, removal of TRF1 from telomeres allows telomerase to access and results in telomerase activity and elongation of telomeres.	('TRF1', 'Gene', (25, 29))	('TRF1', 'Gene', '7013', (25, 29))	('telomerase', 'CPA', (88, 98))	('removal', 'Var', (14, 21))	('results in', 'Reg', (77, 87))	('elongation of telomeres', 'CPA', (112, 135))	('activity', 'MPA', (99, 107))	('telomerase', 'Enzyme', (52, 62))
612721	26675332	However, mutations in genes that physiologically repress DNA recombination such as p53, ATRX, DAXX, and H3F3A seem to facilitate recombination-based telomere maintenance.	('p53', 'Gene', (83, 86))	('recombination-based', 'MPA', (129, 148))	('p53', 'Gene', '7157', (83, 86))	('mutations', 'Var', (9, 18))	('DAXX', 'Gene', '1616', (94, 98))	('ATRX', 'Gene', '546', (88, 92))	('DAXX', 'Gene', (94, 98))	('facilitate', 'PosReg', (118, 128))	('H3F3A', 'Gene', '3020', (104, 109))	('H3F3A', 'Gene', (104, 109))	('ATRX', 'Gene', (88, 92))
612728	26675332	Quante et al have demonstrated that genetic alterations frequently found in early esophageal carcinogenesis such as overexpression of cyclin D1 or inactivation of p53 can independently induce transcriptional activation of hTERT through transcriptional activators that are specific for the respective genetic alteration.	('esophageal carcinogenesis', 'Disease', (82, 107))	('activation', 'PosReg', (208, 218))	('inactivation', 'Var', (147, 159))	('p53', 'Gene', (163, 166))	('p53', 'Gene', '7157', (163, 166))	('overexpression', 'PosReg', (116, 130))	('cyclin D1', 'Gene', '595', (134, 143))	('hTERT', 'Gene', '7015', (222, 227))	('cyclin D1', 'Gene', (134, 143))	('transcriptional', 'MPA', (192, 207))	('hTERT', 'Gene', (222, 227))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (82, 107))
612730	26675332	Activating mutations within the hTERT promoter have been described in different types of cancer, but their frequency in both types of esophageal cancer is extremely low.	('cancer', 'Disease', (145, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('Activating mutations', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('hTERT', 'Gene', '7015', (32, 37))	('esophageal cancer', 'Disease', (134, 151))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('hTERT', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
612736	26675332	The risk for the development of gastric cancer is increased in people with shorter telomeres in peripheral blood lymphocytes.	('people', 'Species', '9606', (63, 69))	('gastric cancer', 'Disease', (32, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('shorter telomeres', 'Var', (75, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('shorter telomeres in peripheral blood', 'Phenotype', 'HP:0031413', (75, 112))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
612745	26675332	Like in other tumors, telomere shortening in colorectal cancer (CRC) occurs with cell proliferation in preneoplastic lesions and leads to chromosomal instability.	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('telomere shortening', 'Phenotype', 'HP:0031413', (22, 41))	('colorectal cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('chromosomal instability', 'Phenotype', 'HP:0040012', (138, 161))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('telomere shortening', 'Var', (22, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (45, 62))	('leads to', 'Reg', (129, 137))	('chromosomal instability', 'MPA', (138, 161))
612753	26675332	Bertorelle et al were able to show that patients with high levels of hTERT messenger RNA (mRNA) in their tumor cells had a significantly higher risk of death during the observation period of 70 months.	('hTERT', 'Gene', '7015', (69, 74))	('patients', 'Species', '9606', (40, 48))	('hTERT', 'Gene', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('high levels', 'Var', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('death', 'Disease', 'MESH:D003643', (152, 157))	('death', 'Disease', (152, 157))	('tumor', 'Disease', (105, 110))
612759	26675332	Activating mutations within the hTERT promoter are among the most frequent genetic alterations in HCC and can be found in approximately 60% of these tumors.	('Activating mutations', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('hTERT', 'Gene', '7015', (32, 37))	('HCC', 'Disease', (98, 101))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('HCC', 'Phenotype', 'HP:0001402', (98, 101))	('hTERT', 'Gene', (32, 37))
612760	26675332	Moreover, recent data indicate that somatic hTERT promoter mutations might serve as a biomarker to predict transformation of premalignant lesions into HCC.	('HCC', 'Disease', (151, 154))	('hTERT', 'Gene', '7015', (44, 49))	('mutations', 'Var', (59, 68))	('HCC', 'Phenotype', 'HP:0001402', (151, 154))	('premalignant lesions', 'Disease', (125, 145))	('hTERT', 'Gene', (44, 49))
612769	26675332	Activating KRAS mutations are the main driver of tumor progression in more than 90% of PDAC.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('KRAS', 'Gene', (11, 15))	('Activating', 'PosReg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PDAC', 'Chemical', '-', (87, 91))	('KRAS', 'Gene', '3845', (11, 15))	('mutations', 'Var', (16, 25))	('tumor', 'Disease', (49, 54))	('PDAC', 'Disease', (87, 91))	('PDAC', 'Phenotype', 'HP:0006725', (87, 91))
612777	26675332	In EAC cells that were microdissected from human tumor samples, GRN163L successfully inhibited telomerase, induced apoptosis, and resulted in a reduction of tumor size in mouse xenografts.	('tumor', 'Disease', (157, 162))	('telomerase', 'Protein', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('inhibited', 'NegReg', (85, 94))	('reduction', 'NegReg', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('GRN163L', 'Var', (64, 71))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('tumor', 'Disease', (49, 54))	('induced', 'PosReg', (107, 114))	('GRN163L', 'Chemical', 'MESH:C519562', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('apoptosis', 'CPA', (115, 124))	('mouse', 'Species', '10090', (171, 176))	('human', 'Species', '9606', (43, 48))
612779	26675332	Interestingly, in PDAC, GRN163L successfully reduced the number of putative cancer stem cells, a cellular subpopulation that is thought to be involved in both resistance to chemotherapy and in metastatic progression, and significantly impaired the engraftment of PANC1 cells in nude mice.	('reduced', 'NegReg', (45, 52))	('GRN163L', 'Chemical', 'MESH:C519562', (24, 31))	('nude mice', 'Species', '10090', (278, 287))	('PDAC', 'Chemical', '-', (18, 22))	('impaired', 'NegReg', (235, 243))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('engraftment of PANC1 cells in', 'CPA', (248, 277))	('GRN163L', 'Var', (24, 31))	('PANC1', 'CellLine', 'CVCL:0480', (263, 268))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('PDAC', 'Phenotype', 'HP:0006725', (18, 22))
612785	26675332	As outlined, telomerase is present in the majority of cancers and its peptides are capable of producing strong immune responses through the induction of CD8+ cytotoxic T lymphocytes via major histocompatibility complex presentation resulting in cell lysis.	('CD8', 'Gene', (153, 156))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('CD8', 'Gene', '925', (153, 156))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cell lysis', 'CPA', (245, 255))	('immune responses', 'MPA', (111, 127))	('peptides', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
612787	26675332	GV1001 is a 16 amino acid major histocompatibility complex class II-restricted hTERT peptide vaccine and is used in combination with an adjuvant to enhance immune responses.	('hTERT', 'Gene', (79, 84))	('immune responses', 'CPA', (156, 172))	('GV1001', 'Chemical', '-', (0, 6))	('enhance', 'PosReg', (148, 155))	('GV1001', 'Var', (0, 6))	('hTERT', 'Gene', '7015', (79, 84))
612789	26675332	While GV1001 did not induce a significant immune response and antitumor effect in patients with HCC, early trials in pancreatic cancer have reported promising results.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('tumor', 'Disease', (66, 71))	('patients', 'Species', '9606', (82, 90))	('pancreatic cancer', 'Disease', (117, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('GV1001', 'Chemical', '-', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HCC', 'Disease', (96, 99))	('GV1001', 'Var', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('HCC', 'Phenotype', 'HP:0001402', (96, 99))
612803	26675332	These variations add another layer of complexity to the sophisticated machinery of telomere maintenance in cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('variations', 'Var', (6, 16))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))
612834	25164985	The quantification was performed by multiple reaction monitoring (MRM) at positive mode to detect the specific precursor to product ion transitions m/z 116   m/z 70 for proline, and m/z 122   m/z 75 for IS.	('proline', 'Chemical', 'MESH:D011392', (169, 176))	('m/z 116   m/z 70', 'Var', (148, 164))	('m/z 122   m/z 75', 'Var', (182, 198))
612898	23549398	One study of 56 ESCC cases from north central China found at least one genetic alteration in TP53 in 96% of the tumors studied, including mutations (77%), allelic loss within the gene (73%), and/or loss of heterozygosity (LOH) at the TP53 microsatellite marker (80%); and three-quarters of the cases had two or more such alterations.	('TP53', 'Gene', '7157', (234, 238))	('TP53', 'Gene', (234, 238))	('TP53', 'Gene', '7157', (93, 97))	('loss', 'NegReg', (198, 202))	('TP53', 'Gene', (93, 97))	('allelic loss', 'Var', (155, 167))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))	('mutations', 'Var', (138, 147))
612899	23549398	In a study conducted in northeastern Iran, 90% of the 119 ESCC cases evaluated had a TP53 mutation, including 11 with two or three mutations.	('TP53', 'Gene', '7157', (85, 89))	('TP53', 'Gene', (85, 89))	('mutation', 'Var', (90, 98))	('ESCC', 'Disease', (58, 62))
612902	23549398	Another study of 60 ESCCs from north central China observed at least one alteration in p16INK4a in 68% of cases (50% aberrant methylation, 17% microsatellite LOH) and at least one alteration in p15INK4b in 50% (35% homozygous deletion, 47% microsatellite LOH, 18% aberrant methylation).	('p16INK4a', 'Gene', '1029', (87, 95))	('p15INK4b', 'Gene', (194, 202))	('microsatellite LOH', 'Var', (240, 258))	('deletion', 'Var', (226, 234))	('p16INK4a', 'Gene', (87, 95))	('p15INK4b', 'Gene', '1030', (194, 202))	('alteration', 'Var', (73, 83))
612903	23549398	Recently whole exome sequencing found that ESCCs had an average of 83 mutations per tumor, and that the most frequent mutations in ESCC occurred in TP53 (92% of the 12 cases sequenced), NOTCH1 (33%), NOTCH3 (25%), and FBXW7 (17%).	('ESCC', 'Gene', (131, 135))	('FBXW7', 'Gene', (218, 223))	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('TP53', 'Gene', '7157', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutations', 'Var', (118, 127))	('TP53', 'Gene', (148, 152))	('tumor', 'Disease', (84, 89))	('NOTCH3', 'Gene', (200, 206))	('FBXW7', 'Gene', '55294', (218, 223))	('NOTCH1', 'Gene', '4851', (186, 192))	('NOTCH1', 'Gene', (186, 192))	('NOTCH3', 'Gene', '4854', (200, 206))
612909	23549398	Nucleic acid-based studies of precursors have shown increased allelic loss (pointing to potential tumor suppressor gene inactivation sites) with increasing grade of dysplasia at a wide variety of microsatellite loci (i.e., 3p, 4p, 5q, 8p, 9p, 9q, 10p, 11p, 13q, and 17p).	('loss', 'NegReg', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('allelic', 'Var', (62, 69))	('tumor', 'Disease', (98, 103))	('dysplasia', 'Disease', (165, 174))	('dysplasia', 'Disease', 'MESH:D004476', (165, 174))
612910	23549398	Mutation studies in esophageal squamous precursors have been limited to TP53, where missense mutations were evident early in esophageal carcinogenesis (four of 11 samples with dysplasia vs one of three normal epithelia).	('esophageal squamous', 'Disease', 'MESH:D000077277', (20, 39))	('esophageal squamous', 'Disease', (20, 39))	('TP53', 'Gene', '7157', (72, 76))	('dysplasia', 'Disease', 'MESH:D004476', (176, 185))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (125, 150))	('TP53', 'Gene', (72, 76))	('esophageal carcinogenesis', 'Disease', (125, 150))	('dysplasia', 'Disease', (176, 185))	('missense mutations', 'Var', (84, 102))
612913	23549398	More recently, high throughput genome-wide methods in the analysis of patterns of RNA expression, differential methylation, and gene copy number have shown promise in distinguishing patients with and without high-grade squamous dysplasia.	('squamous dysplasia', 'Disease', (219, 237))	('RNA', 'Gene', (82, 85))	('gene copy number', 'Var', (128, 144))	('squamous dysplasia', 'Disease', 'MESH:D002294', (219, 237))	('patients', 'Species', '9606', (182, 190))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (219, 237))
612972	23549398	Trial endpoints were typically histologic or cytologic regression or progression, or prevalence of dysplasia, with a few reports of other intermediate endpoint markers (e.g., prevalence of micronuclei or proliferation markers).	('progression', 'CPA', (69, 80))	('dysplasia', 'Disease', 'MESH:D004476', (99, 108))	('proliferation markers', 'CPA', (204, 225))	('dysplasia', 'Disease', (99, 108))	('histologic', 'CPA', (31, 41))	('micronuclei', 'Var', (189, 200))
612973	23549398	Evidence for a beneficial effect on premalignancy was observed in four of these studies: the combination of retinol+riboflavin+zinc reduced micronuclei; multivitamins improved cytology; selenomethionine improved histology; and strawberries improved histology and reduced proliferation and expression of several cancer-related proteins.	('improved', 'PosReg', (167, 175))	('improved', 'PosReg', (240, 248))	('proliferation', 'CPA', (271, 284))	('riboflavin', 'Chemical', 'MESH:D012256', (116, 126))	('selenomethionine', 'Var', (186, 202))	('micronuclei', 'CPA', (140, 151))	('improved', 'PosReg', (203, 211))	('cytology', 'CPA', (176, 184))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('reduced', 'NegReg', (132, 139))	('reduced', 'NegReg', (263, 270))	('histology', 'CPA', (249, 258))	('expression', 'MPA', (289, 299))	('retinol', 'Chemical', 'MESH:D014801', (108, 115))	('selenomethionine', 'Chemical', 'MESH:D012645', (186, 202))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('histology', 'CPA', (212, 221))
612992	22292433	In addition, we found that overexpression of NF-kappaB p65 could not successfully induce miR-34a expression in esophageal cancer cell lines with mutant p53 or decreased p53.	('mutant', 'Var', (145, 151))	('p53', 'Gene', (152, 155))	('p53', 'Gene', (169, 172))	('NF-kappaB p65', 'Gene', (45, 58))	('esophageal cancer', 'Disease', (111, 128))	('expression', 'Species', '29278', (31, 41))	('p53', 'Gene', '7157', (152, 155))	('p53', 'Gene', '7157', (169, 172))	('expression', 'Species', '29278', (97, 107))	('miR-34a', 'Gene', '407040', (89, 96))	('decreased', 'NegReg', (159, 168))	('NF-kappaB p65', 'Gene', '5970', (45, 58))	('miR-34a', 'Gene', (89, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('expression', 'MPA', (97, 107))
612993	22292433	Reporter assay further showed that NF-kappaB-induced miR-34a transcriptional activity was reduced by p53 impairment.	('transcriptional activity', 'MPA', (61, 85))	('reduced', 'NegReg', (90, 97))	('miR-34a', 'Gene', '407040', (53, 60))	('p53', 'Gene', (101, 104))	('miR-34a', 'Gene', (53, 60))	('NF-kappaB', 'Gene', '4790', (35, 44))	('p53', 'Gene', '7157', (101, 104))	('impairment', 'Var', (105, 115))	('NF-kappaB', 'Gene', (35, 44))
612994	22292433	Nevertheless, CHIP analysis suggested binding of NF-kappaB to miR-34a promoter was not affected in cells with mutant p53.	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('mutant', 'Var', (110, 116))	('NF-kappaB', 'Gene', '4790', (49, 58))	('miR-34a', 'Gene', '407040', (62, 69))	('NF-kappaB', 'Gene', (49, 58))	('miR-34a', 'Gene', (62, 69))
612999	22292433	Emerging evidence has demonstrated that these small RNAs are involved in almost every aspects of tumor biology and could function as oncogenes or tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('involved', 'Reg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (97, 102))	('small RNAs', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
613003	22292433	Recent data suggest that dysregulation of miR-34a exists in many types of human cancers and is correlated with clinic treatment.	('miR-34a', 'Gene', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('dysregulation', 'Var', (25, 38))	('human', 'Species', '9606', (74, 79))	('miR-34a', 'Gene', '407040', (42, 49))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
613005	22292433	In chronic lymphocytic leukemia, deletion or mutation of p53 is associated with miR-34a downregulation.	('downregulation', 'NegReg', (88, 102))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (3, 31))	('miR-34a', 'Gene', '407040', (80, 87))	('deletion', 'Var', (33, 41))	('chronic lymphocytic leukemia', 'Disease', (3, 31))	('miR-34a', 'Gene', (80, 87))	('mutation', 'Var', (45, 53))	('p53', 'Gene', (57, 60))	('leukemia', 'Phenotype', 'HP:0001909', (23, 31))	('p53', 'Gene', '7157', (57, 60))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (3, 31))
613006	22292433	While in neuroblastoma and non-small-cell lung cancer, no significant correlation between p53 mutation and miR-34a dysregulation is observed.	('p53', 'Gene', (90, 93))	('miR-34a', 'Gene', '407040', (107, 114))	('neuroblastoma', 'Disease', (9, 22))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (27, 53))	('p53', 'Gene', '7157', (90, 93))	('miR-34a', 'Gene', (107, 114))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (31, 53))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutation', 'Var', (94, 102))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
613007	22292433	Though researchers have reported other mechanisms for miR-34a abnormality, like deletion of 1p36.3, aberrant CpG methylation or CEBPalpha mutation, more detailed study on regulation of miR-34a transcription is of great importance.	('deletion', 'Var', (80, 88))	('aberrant', 'Var', (100, 108))	('miR-34a', 'Gene', '407040', (54, 61))	('1p36.3', 'Gene', (92, 98))	('miR-34a', 'Gene', (54, 61))	('mutation', 'Var', (138, 146))	('CEBPalpha', 'Gene', (128, 137))	('miR-34a', 'Gene', '407040', (185, 192))	('CEBPalpha', 'Gene', '1050', (128, 137))	('miR-34a', 'Gene', (185, 192))
613012	22292433	Different research groups have independently reported that blockade of NF-kappaB signal pathway caused a significant increase in spontaneous epithelial squamous cell carcinoma or diethylnitrosamine induced hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', (206, 230))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (206, 230))	('increase', 'PosReg', (117, 125))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (179, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (206, 230))	('NF-kappaB', 'Gene', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('epithelial squamous cell carcinoma', 'Disease', (141, 175))	('diethylnitrosamine induced', 'MPA', (179, 205))	('blockade', 'Var', (59, 67))	('epithelial squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 175))	('NF-kappaB', 'Gene', '4790', (71, 80))
613021	22292433	Transfection of this mutant IkappaBalpha indeed leaded a significant reduction of nuclear NF-kappaB p65 translocation.	('mutant', 'Var', (21, 27))	('IkappaBalpha', 'Gene', (28, 40))	('NF-kappaB p65', 'Gene', (90, 103))	('NF-kappaB p65', 'Gene', '5970', (90, 103))	('reduction', 'NegReg', (69, 78))	('IkappaBalpha', 'Gene', '4792', (28, 40))
613028	22292433	Mutation of the first NF-kappaB binding site had no impact on the transcriptional activity enhancement caused by p65 overexpression, while mutation of the other two greatly weakened the transactivity ability (Figure 2b).	('weakened', 'NegReg', (173, 181))	('p65', 'Gene', (113, 116))	('mutation', 'Var', (139, 147))	('expression', 'Species', '29278', (121, 131))	('NF-kappaB', 'Gene', (22, 31))	('Mutation', 'Var', (0, 8))	('transcriptional activity', 'MPA', (66, 90))	('enhancement', 'PosReg', (91, 102))	('transactivity ability', 'MPA', (186, 207))	('p65', 'Gene', '5970', (113, 116))	('overexpression', 'PosReg', (117, 131))	('NF-kappaB', 'Gene', '4790', (22, 31))
613030	22292433	Furthermore, we also found that mutation of the p53 binding site in miR-34a promoter region impaired the transcriptional enhancement mediated by p65, suggesting p53 may involve in NF-kappaB mediate induction of miR-34a.	('p53', 'Gene', (48, 51))	('p65', 'Gene', '5970', (145, 148))	('miR-34a', 'Gene', '407040', (211, 218))	('p53', 'Gene', '7157', (48, 51))	('transcriptional enhancement', 'MPA', (105, 132))	('miR-34a', 'Gene', (211, 218))	('miR-34a', 'Gene', '407040', (68, 75))	('impaired', 'NegReg', (92, 100))	('p65', 'Gene', (145, 148))	('NF-kappaB', 'Gene', '4790', (180, 189))	('p53', 'Gene', (161, 164))	('miR-34a', 'Gene', (68, 75))	('mutation', 'Var', (32, 40))	('NF-kappaB', 'Gene', (180, 189))	('p53', 'Gene', '7157', (161, 164))
613042	22292433	For mutation of the known p53 binding site could attenuate the effect of p65 on miR-34a transcriptional activity, we speculated that p53 may coordinate with NF-kappaB to regulate miR-34a transcription.	('NF-kappaB', 'Gene', '4790', (157, 166))	('p65', 'Gene', '5970', (73, 76))	('miR-34a', 'Gene', '407040', (80, 87))	('p53', 'Gene', '7157', (133, 136))	('mutation', 'Var', (4, 12))	('NF-kappaB', 'Gene', (157, 166))	('miR-34a', 'Gene', (80, 87))	('p53', 'Gene', (26, 29))	('attenuate', 'NegReg', (49, 58))	('p53', 'Gene', '7157', (26, 29))	('p53', 'Gene', (133, 136))	('effect', 'MPA', (63, 69))	('miR-34a', 'Gene', '407040', (179, 186))	('p65', 'Gene', (73, 76))	('miR-34a', 'Gene', (179, 186))
613050	22292433	And knock-down of p53 level dramatically impaired the transactivity enhancement caused by p65 (Figure 5b).	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('p65', 'Gene', '5970', (90, 93))	('transactivity enhancement', 'MPA', (54, 79))	('knock-down', 'Var', (4, 14))	('impaired', 'NegReg', (41, 49))	('p65', 'Gene', (90, 93))
613058	22292433	EC109 cells were cotransfected with DNIkappaB and wildtype p53, however, miR-34a levels were still increased by p53 overexpression in cells with decreased NF-kappaB activity (Figure 6).	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('miR-34a', 'Gene', '407040', (73, 80))	('miR-34a', 'Gene', (73, 80))	('NF-kappaB', 'Gene', '4790', (155, 164))	('p53', 'Gene', (112, 115))	('increased', 'PosReg', (99, 108))	('EC109', 'CellLine', 'CVCL:6898', (0, 5))	('overexpression', 'Var', (116, 130))	('p53', 'Gene', '7157', (112, 115))	('NF-kappaB', 'Gene', (155, 164))	('expression', 'Species', '29278', (120, 130))
613062	22292433	In this study, we identified that:1) overexpression of NF-kappaB p65 subunit could increase miR-34a levels and ectopic expression of DN IkappaB leaded a significant reduction of miR-34a expression; 2) mutation of either the kappaB sites or the p53 binding site of miR-34a gene could impair p65-induced transcriptional activity; 3) NF-kappaB could specifically bind to the kappaB site located at -149 of miR-34a gene; 4) Expression of miR-34a could not be induced by NF-kappaB in the absence of wildtype p53 function, probably owing to the downregulated transcriptional activity; 5) NF-kappaB could bind with miR-34a promoter even in cells with mutant p53; 6) NF-kappaB might not be necessary for p53-mediated miR-34a upregulation.	('p65', 'Gene', (290, 293))	('miR-34a', 'Gene', '407040', (403, 410))	('NF-kappaB', 'Gene', (582, 591))	('bind', 'Interaction', (598, 602))	('miR-34a', 'Gene', (434, 441))	('p53', 'Gene', '7157', (651, 654))	('miR-34a', 'Gene', (92, 99))	('p53', 'Gene', (503, 506))	('NF-kappaB', 'Gene', (659, 668))	('mutation', 'Var', (201, 209))	('increase miR-34a levels', 'Phenotype', 'HP:0032428', (83, 106))	('miR-34a', 'Gene', (178, 185))	('impair', 'NegReg', (283, 289))	('NF-kappaB', 'Gene', '4790', (582, 591))	('miR-34a', 'Gene', (608, 615))	('NF-kappaB', 'Gene', '4790', (659, 668))	('p53', 'Gene', (651, 654))	('miR-34a', 'Gene', '407040', (434, 441))	('miR-34a', 'Gene', '407040', (92, 99))	('p65', 'Gene', '5970', (290, 293))	('expression', 'Species', '29278', (186, 196))	('miR-34a', 'Gene', '407040', (178, 185))	('miR-34a', 'Gene', (709, 716))	('p53', 'Gene', '7157', (696, 699))	('mutant', 'Var', (644, 650))	('p65', 'Gene', (65, 68))	('miR-34a', 'Gene', '407040', (608, 615))	('NF-kappaB', 'Gene', (55, 64))	('NF-kappaB', 'Gene', (331, 340))	('p53', 'Gene', '7157', (244, 247))	('NF-kappaB', 'Gene', (466, 475))	('miR-34a', 'Gene', (264, 271))	('miR-34a', 'Gene', '407040', (709, 716))	('NF-kappaB', 'Gene', '4790', (331, 340))	('p53', 'Gene', (696, 699))	('NF-kappaB', 'Gene', '4790', (55, 64))	('miR-34a', 'Gene', '407040', (264, 271))	('NF-kappaB', 'Gene', '4790', (466, 475))	('p65', 'Gene', '5970', (65, 68))	('p53', 'Gene', (244, 247))	('expression', 'Species', '29278', (41, 51))	('NF-kappaB p65', 'Gene', (55, 68))	('miR-34a', 'Gene', (403, 410))	('NF-kappaB p65', 'Gene', '5970', (55, 68))	('p53', 'Gene', '7157', (503, 506))	('expression', 'Species', '29278', (119, 129))	('Expression', 'Species', '29278', (420, 430))
613104	22292433	In brief, biotin labelled DNA probes containing candidate NF-kappaB binding sites from miR-34a promoter (34aKappaB2 TCGCGATGGCCGGGGAGTCCGGGACCTCGGCT, 34aKappaB3 CCGTCGGTCTGGGGACAGCCCAGCTCCCCGGA, only one stand shown) were mixed with 10 ug of nuclear extract in a 20 ul reaction volume containing 1X binding buffer, 5 mM MgCl2, 5% glycerol, 0.05% NP40 and 50 ng/ul poly(dI:dC).	('miR-34a', 'Gene', '407040', (87, 94))	('34aKappaB3 CCGTCGGTCTGGGGACAGCCCAGCTCCCCGGA', 'Var', (150, 193))	('NF-kappaB', 'Gene', '4790', (58, 67))	('miR-34a', 'Gene', (87, 94))	('34aKappaB2', 'Var', (105, 115))	('biotin', 'Chemical', 'MESH:D001710', (10, 16))	('MgCl2', 'Chemical', 'MESH:D015636', (320, 325))	('glycerol', 'Chemical', 'MESH:D005990', (330, 338))	('NF-kappaB', 'Gene', (58, 67))
613112	22216294	Extremely High Tp53 Mutation Load in Esophageal Squamous Cell Carcinoma in Golestan Province, Iran Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes.	('Tp53', 'Gene', '7157', (15, 19))	('Esophageal Squamous Cell Carcinoma', 'Disease', (37, 71))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (37, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('esophageal squamous cell carcinoma', 'Disease', (175, 209))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('Tp53', 'Gene', (15, 19))	('Carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('Golestan', 'Chemical', '-', (75, 83))	('Mutation Load', 'Var', (20, 33))	('Golestan', 'Chemical', '-', (99, 107))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (175, 209))	('person', 'Species', '9606', (261, 267))
613116	22216294	A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations.	('detected', 'Reg', (35, 43))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('patients', 'Species', '9606', (83, 91))	('mutations', 'Var', (20, 29))
613117	22216294	The mutation pattern was heterogeneous with infrequent mutations at common TP53 "hotspots" but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs).	('mutations', 'Var', (55, 64))	('men', 'Species', '9606', (153, 156))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (254, 286))	('TP53', 'Gene', '7157', (75, 79))	('PAHs', 'Chemical', 'MESH:D011084', (288, 292))	('TP53', 'Gene', (75, 79))
613119	22216294	ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('TP53', 'Gene', '7157', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('TP53', 'Gene', (70, 74))	('cancer', 'Disease', (106, 112))	('mutations', 'Var', (75, 84))	('people', 'Species', '9606', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('Golestan', 'Chemical', '-', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
613132	22216294	In 2001, two studies reported a description of TP53 mutation patterns in retrospective series of ESCC from referral hospitals in Tehran, Iran, an area with medium risk of ESCC.	('ESCC', 'Disease', (97, 101))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))	('mutation', 'Var', (52, 60))
613133	22216294	Compared to ESCC from elsewhere, tumors from Tehran had significantly higher rate of G:C to A:T transitions at CpG dinucleotides, a mutation type commonly detected in cancers associated with inflammatory conditions.	('G:C to A:T transitions', 'Var', (85, 107))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancers', 'Disease', (167, 174))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (111, 128))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (33, 39))
613136	22216294	We report the highest rate of somatic TP53 mutations ever reported for any cancer, further supporting the notion that ESCC in this area develops as the consequence of heavy exposure to environmental mutagens, and providing molecular clues for potentially preventable risk factors.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('TP53', 'Gene', (38, 42))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (43, 52))	('men', 'Species', '9606', (192, 195))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', '7157', (38, 42))
613148	22216294	Somatic TP53 mutations were confirmed in 107 patients (89.9%) including nine patients with two different mutations and two patients with three mutations (total: 120 mutations; see detailed mutation description in Table S2).	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (45, 53))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))
613150	22216294	There was no association between mutations and tumor grade or stage.	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
613151	22216294	Only 9 (7.5%) of the mutations occurred at "hotspot" TP53 codons (codons 175, 245, 273 and 282 where 20% of known TP53 mutations occur in all cancers).	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TP53', 'Gene', '7157', (114, 118))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (114, 118))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('TP53', 'Gene', (53, 57))	('mutations', 'Var', (21, 30))
613152	22216294	Among the G:C to T:A mutations, 8/20 (40%) occurred at codons previously described as sites of PAH adduct formation which are commonly mutated in lung cancer of smokers.	('PAH', 'Gene', (95, 98))	('PAH', 'Gene', '5053', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('occurred', 'Reg', (43, 51))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('mutations', 'Var', (21, 30))
613153	22216294	Table 2 compares the patterns of mutations of ESCC from Golestan with previously published mutation patterns from Tehran.	('ESCC', 'Gene', (46, 50))	('mutations', 'Var', (33, 42))	('Golestan', 'Chemical', '-', (56, 64))
613154	22216294	Since the previous studies examined only exons 5-8 of TP53, for comparability, this part of analysis was done only on mutations in these exons (101 of the total 120 mutations, Figure 1).	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))	('mutations', 'Var', (165, 174))
613157	22216294	Figure 2B further illustrates the pattern of mutations in exons 5-8 in Tehran, in Golestan, and in the Henan Province of China, another area of high incidence.	('mutations in exons', 'Var', (45, 63))	('Golestan', 'Chemical', '-', (82, 90))	('Tehran', 'Gene', (71, 77))
613159	22216294	Furthermore, the overall pattern of mutations in ESCC from Golestan was not statistically different from the one of ESCC from Henan.	('ESCC', 'Gene', (49, 53))	('Golestan', 'Chemical', '-', (59, 67))	('mutations', 'Var', (36, 45))
613161	22216294	Mutation types also showed differences according to the temperature of tea consumption, with G:C to A:T mutations at CpG sites being significantly more common among hot tea drinkers (within 0-1 min of pouring) than among subjects who drank tea at lower temperature (>=4 minutes after pouring; adjusted OR: 6.40, 95% CI, 1.16-35.16) Wild-type TP53 was more common in hot tea drinkers (OR: 6.27, 95% CI, 1.04-37.69).	('CpG', 'Gene', (117, 120))	('mutations', 'Var', (104, 113))	('common', 'Reg', (152, 158))	('TP53', 'Gene', '7157', (342, 346))	('TP53', 'Gene', (342, 346))
613162	22216294	In contrast, G:C to T:A, G:C to C:G, A:T to G:C and A:T to C:G mutations were found only in subjects who reported drinking tea >=2 minutes after pouring (Figure 3).	('A:T to C:G', 'Var', (52, 62))	('drinking tea', 'Chemical', '-', (114, 126))	('A:T to G:C', 'Var', (37, 47))
613163	22216294	Overall, these observations suggest that there is an association between the temperature of tea consumption and the presence and types of TP53 mutation.	('TP53', 'Gene', (138, 142))	('TP53', 'Gene', '7157', (138, 142))	('mutation', 'Var', (143, 151))
613166	22216294	Of the 50 evaluable cases with missense mutation, 41 (82%) were positive for p53 (strong or moderate staining) and 9 were negative (negative or weak staining).	('positive', 'Reg', (64, 72))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('missense mutation', 'Var', (31, 48))
613167	22216294	In contrast, among cases with mutations predicting absence of p53 protein (nonsense, splice, or frameshift mutations), 28 (77.8%) of 36 evaluable cases were negative (no or weak staining), whereas only 8 (22.2%) were positive (strong or moderate staining) (Table S3).	('frameshift mutations', 'Var', (96, 116))	('negative', 'NegReg', (157, 165))	('protein', 'Protein', (66, 73))	('splice', 'Var', (85, 91))	('absence', 'NegReg', (51, 58))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
613168	22216294	Thus, overall, there was a highly significant association between the presence of missense mutation and p53 expression scores (p<0.001), and there was a strong association between nonsense/splice/frameshift mutations and lack of p53 expression (p = 0.013/p = 0.005/p = 0.018 respectively).	('p53', 'Gene', (104, 107))	('expression', 'MPA', (233, 243))	('p53', 'Gene', '7157', (104, 107))	('expression scores', 'MPA', (108, 125))	('p53', 'Gene', (229, 232))	('p53', 'Gene', '7157', (229, 232))	('lack', 'NegReg', (221, 225))	('missense mutation', 'Var', (82, 99))	('nonsense/splice/frameshift mutations', 'Var', (180, 216))
613171	22216294	As an approach to identify new clues for the mechanisms of mutagenesis leading to ESCC in that part of the world, we have analyzed for the first time the patterns of mutations in the tumor suppressor gene TP53.	('mutations', 'Var', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('ESCC', 'Disease', (82, 86))	('TP53', 'Gene', '7157', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('TP53', 'Gene', (205, 209))	('tumor', 'Disease', (183, 188))
613176	22216294	Moreover, in Golestan, 10% of patients with mutations showed more than one mutation in TP53.	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('patients', 'Species', '9606', (30, 38))	('mutations', 'Var', (44, 53))	('Golestan', 'Chemical', '-', (13, 21))	('Golestan', 'Disease', (13, 21))
613179	22216294	Overall, mutations attributable to endogenous mutagenic processes were infrequent; for example, G:C to A:T mutations at CpG sites, a type of mutation which often occurs as the result of spontaneous deamination of 5'methylcytosine, represented only 13.3% of all mutations, in contrast to 25% of mutations in all cancers compiled in the TP53 mutation database (n = 26597) and 33% of the mutations in ESCC cases from Tehran (n = 85).	('mutations', 'Var', (107, 116))	('TP53', 'Gene', (335, 339))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('TP53', 'Gene', '7157', (335, 339))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
613180	22216294	This type of mutation is frequent in tumor types where PAHs play an important role, such as lung cancer in smokers.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutation', 'Var', (13, 21))	('PAHs', 'Chemical', 'MESH:D011084', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (37, 42))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))
613181	22216294	In the present series, although G:C to T:A transversions are less frequent than in lung cancers of smokers, 40% of them occurred at codons described as sites of adduction of PAH.	('transversions', 'Var', (43, 56))	('PAH', 'Gene', '5053', (174, 177))	('lung cancers', 'Disease', (83, 95))	('PAH', 'Gene', (174, 177))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('occurred', 'Reg', (120, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lung cancers', 'Disease', 'MESH:D008175', (83, 95))	('lung cancers', 'Phenotype', 'HP:0100526', (83, 95))
613186	22216294	Our mutation data are consistent with a role for PAH in mutagenesis in ESCC in Golestan.	('ESCC', 'Gene', (71, 75))	('mutagenesis', 'Var', (56, 67))	('PAH', 'Gene', (49, 52))	('PAH', 'Gene', '5053', (49, 52))	('Golestan', 'Chemical', '-', (79, 87))
613196	22216294	Of the 15 patients who used only opium, all had a mutation in TP53, although the types of mutations were not significantly different than in patients who did not report opium use.	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (141, 149))	('mutation', 'Var', (50, 58))
613198	22216294	Wild-type TP53 and G:C to A:T transitions (in particular at CpG sites) were most often seen in subjects who reported drinking tea within 1 minute of pouring.	('seen', 'Reg', (87, 91))	('TP53', 'Gene', (10, 14))	('drinking tea', 'Chemical', '-', (117, 129))	('G:C to A:T', 'Var', (19, 29))	('TP53', 'Gene', '7157', (10, 14))
613199	22216294	Conversely, transversion mutations (including G:C to T:A mutations) were observed only in subjects who reported a preference for drinking tea with a longer delay (at least 2 minutes after pouring).	('mutations', 'Var', (57, 66))	('drinking tea', 'Chemical', '-', (129, 141))	('G:C to T', 'Var', (46, 54))
613203	22216294	A comparison between mutation patterns in Golestan and other areas of the world is only possible for mutations in exons 5-8, which are the only exons that have been analyzed in the majority of previously published studies (see Figure 2B).	('exons 5-8', 'Gene', (114, 123))	('mutations', 'Var', (101, 110))	('Golestan', 'Chemical', '-', (42, 50))
613204	22216294	This comparison shows that the mutations in ESCC from Golestan are different from the ESCC mutations seen in Tehran, strengthening the hypothesis of specific risk factors in Golestan.	('Golestan', 'Chemical', '-', (174, 182))	('mutations', 'Var', (31, 40))	('Golestan', 'Chemical', '-', (54, 62))	('ESCC', 'Gene', (44, 48))
613205	22216294	The differences were less marked between the patterns of mutations in ESCC from Golestan and from Henan Province, China, another high incidence area.	('Golestan', 'Chemical', '-', (80, 88))	('mutations', 'Var', (57, 66))	('ESCC', 'Gene', (70, 74))
613208	22216294	In conclusion, this study shows an extremely high prevalence of diverse types of TP53 mutations in ESCC tumors from Golestan.	('mutations', 'Var', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('Golestan', 'Chemical', '-', (116, 124))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
613209	22216294	Most of these mutations are missense, leading to the accumulation of mutant p53 protein.	('mutant', 'Var', (69, 75))	('p53', 'Gene', (76, 79))	('missense', 'Var', (28, 36))	('p53', 'Gene', '7157', (76, 79))	('protein', 'Protein', (80, 87))	('accumulation', 'PosReg', (53, 65))
613210	22216294	Thus, ESCC from Golestan might be responsive to treatment by drugs that rescue p53 protein function, such as PRIMA-MET, a drug that has been shown to induce massive apoptosis in cells that express mutant p53 proteins.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', (204, 207))	('proteins', 'Protein', (208, 216))	('p53', 'Gene', '7157', (204, 207))	('Golestan', 'Chemical', '-', (16, 24))	('mutant', 'Var', (197, 203))	('men', 'Species', '9606', (53, 56))	('function', 'MPA', (91, 99))
613213	22216294	Further studies are needed to analyze in detail the mechanisms causing the extremely high load of TP53 mutation observed in ESCC cases from Golestan and to assess whether similar mechanisms may characterize ESCC carcinogenesis throughout the so-called "Central Asian Esophageal Cancer Belt", an area encompassing several populations and extending from the Caspian Sea to the Sea of China in which ESCC is the most frequent type of cancer.	('Golestan', 'Chemical', '-', (140, 148))	('ESCC', 'Disease', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (431, 437))	('cancer', 'Disease', (431, 437))	('carcinogenesis', 'Disease', 'MESH:D063646', (212, 226))	('Cancer', 'Phenotype', 'HP:0002664', (278, 284))	('carcinogenesis', 'Disease', (212, 226))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('TP53', 'Gene', '7157', (98, 102))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (267, 284))	('mutation', 'Var', (103, 111))	('ESCC', 'Disease', (124, 128))	('Esophageal Cancer', 'Disease', (267, 284))	('TP53', 'Gene', (98, 102))
613225	22216294	TP53 mutation analysis of exons 2 through 11 was performed by direct sequencing of PCR products encompassing the entire coding sequence and splice junctions.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
613249	31885302	However, stricture following >=3/4 circumferential ESD markedly reduces the quality of life of patients, who often require long-term repeated, periodic endoscopic balloon dilatation (EBD).	('patients', 'Species', '9606', (95, 103))	('stricture', 'Var', (9, 18))	('quality of life', 'CPA', (76, 91))	('dilatation', 'Phenotype', 'HP:0002617', (171, 181))	('reduces', 'NegReg', (64, 71))
613291	31885302	Furthermore, the number of balloon dilatation in patients with stenosis was markedly lower in the OHA group compared with the IT+ST group (P < 0.05; Table 2).	('OHA', 'Chemical', 'MESH:D010136', (98, 101))	('lower', 'NegReg', (85, 90))	('dilatation', 'Phenotype', 'HP:0002617', (35, 45))	('OHA', 'Var', (98, 101))	('stenosis', 'Disease', (63, 71))	('patients', 'Species', '9606', (49, 57))	('stenosis', 'Disease', 'MESH:D003251', (63, 71))
613320	31885302	In the present study, we found that the stricture rate was markedly lower in the OHA group in comparison with the IT+ST group (P < 0.05).	('OHA', 'Chemical', 'MESH:D010136', (81, 84))	('OHA', 'Var', (81, 84))	('stricture rate', 'CPA', (40, 54))	('lower', 'NegReg', (68, 73))
613321	31885302	At the same time, the rate of balloon dilatation procedures in the OHA group was significantly lower than that in the IT+ST group (P < 0.05).	('dilatation', 'Phenotype', 'HP:0002617', (38, 48))	('OHA', 'Var', (67, 70))	('lower', 'NegReg', (95, 100))	('balloon', 'CPA', (30, 37))	('OHA', 'Chemical', 'MESH:D010136', (67, 70))
613332	31371781	Knockdown of p300 could inhibit cell metastasis, but CBP knockdown did not affect the cell mobility.	('p300', 'Var', (13, 17))	('cell metastasis', 'CPA', (32, 47))	('CBP', 'Gene', (53, 56))	('inhibit', 'NegReg', (24, 31))	('CBP', 'Gene', '1387', (53, 56))
613335	31371781	In a tail vein injection pulmonary metastasis mouse model, intraperitoneal administration of garcinol (20 mg/kg) or 5-FU (20 mg/kg) significantly decreased the number of lung tumor nodules and the expression levels of Ki-67, p300, and p-Smad2/3 in lung tissues.	('5-FU', 'Chemical', 'MESH:D005472', (116, 120))	('pulmonary metastasis', 'Disease', (25, 45))	('lung tumor', 'Disease', (170, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('Ki-67', 'Gene', '17345', (218, 223))	('mouse', 'Species', '10090', (46, 51))	('decreased', 'NegReg', (146, 155))	('Smad2', 'Gene', '4087', (237, 242))	('lung tumor', 'Disease', 'MESH:D008175', (170, 180))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (25, 45))	('Ki-67', 'Gene', (218, 223))	('Smad2', 'Gene', (237, 242))	('lung tumor', 'Phenotype', 'HP:0100526', (170, 180))	('p300', 'Var', (225, 229))	('expression levels', 'MPA', (197, 214))	('garcinol', 'Chemical', 'MESH:C054597', (93, 101))
613346	31371781	The high expression of p300 is associated with poor prognosis and an unfavorable impact on survival in non-small cell  lung cancer (NSCLC) and ESCC patients.	('patients', 'Species', '9606', (148, 156))	('small cell  lung cancer', 'Phenotype', 'HP:0030357', (107, 130))	('lung cancer', 'Disease', (119, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('ESCC', 'Disease', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('non-small cell  lung cancer', 'Phenotype', 'HP:0030358', (103, 130))	('NSCLC', 'Disease', (132, 137))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('p300', 'Var', (23, 27))
613347	31371781	Linc00460, which is upregulated by CBP/p300 through histone acetylation, promotes carcinogenesis in ESCC.	('Linc00460', 'Gene', '728192', (0, 9))	('Linc00460', 'Gene', (0, 9))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('upregulated', 'PosReg', (20, 31))	('ESCC', 'Disease', (100, 104))	('carcinogenesis', 'Disease', (82, 96))	('promotes', 'PosReg', (73, 81))	('CBP/p300', 'Var', (35, 43))
613348	31371781	p300 and CBP may be new targets for the treatment of cancer and metastasis.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('p300', 'Var', (0, 4))	('CBP', 'Gene', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CBP', 'Gene', '1387', (9, 12))
613351	31371781	The protein level and acetylation ability of p300 are also increased after TGF-beta1 stimulation.	('protein level', 'MPA', (4, 17))	('p300', 'Var', (45, 49))	('acetylation ability', 'MPA', (22, 41))	('increased', 'PosReg', (59, 68))	('TGF-beta1', 'Gene', '7040', (75, 84))	('TGF-beta1', 'Gene', (75, 84))
613354	31371781	Recent studies have indicated that some of the natural compounds that target HATs, especially p300, exhibit anticancer activity.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('p300', 'Var', (94, 98))	('cancer', 'Disease', (112, 118))
613356	31371781	Garcinol, which is extracted from Garcinia yunnanensis Hu, is regarded as a potent inhibits or HATs, especially p300.	('p300', 'Var', (112, 116))	('inhibits', 'NegReg', (83, 91))	('Garcinia yunnanensis Hu', 'Disease', (34, 57))	('Garcinol', 'Chemical', 'MESH:C054597', (0, 8))	('Garcinia yunnanensis Hu', 'Disease', 'MESH:D065766', (34, 57))
613360	31371781	However, the mechanism by which Garcinol inhibits cell metastasis requires further research, and the process by which p300 mediates downstream signaling and influences cell metastasis has not been reported.	('inhibits', 'NegReg', (41, 49))	('Garcinol', 'Chemical', 'MESH:C054597', (32, 40))	('influences', 'Reg', (157, 167))	('cell metastasis', 'CPA', (50, 65))	('p300', 'Var', (118, 122))	('cell metastasis', 'CPA', (168, 183))
613361	31371781	In the present study, we provided evidence that Garcinol inhibits cell migration and invasion by suppressing p300, but not its paralog CBP, and the silencing of p300 can decrease EMT marker protein levels.	('EMT marker protein levels', 'MPA', (179, 204))	('Garcinol', 'Chemical', 'MESH:C054597', (48, 56))	('p300', 'Gene', (161, 165))	('cell migration', 'CPA', (66, 80))	('silencing', 'Var', (148, 157))	('CBP', 'Gene', (135, 138))	('decrease EMT', 'Phenotype', 'HP:0032198', (170, 182))	('CBP', 'Gene', '1387', (135, 138))	('invasion', 'CPA', (85, 93))	('decrease', 'NegReg', (170, 178))	('suppressing', 'NegReg', (97, 108))	('inhibits', 'NegReg', (57, 65))	('p300', 'Protein', (109, 113))
613381	31371781	The human gene primers used in the qPCR reactions were as follows: p300, 5'-AGGGGCAACAAGAAGAAACC-3' and 5'-AACAATGGGCAGGGA-3'; CBP, 5'-CATCTTCCCAACACCTGA-3' and 5'-GTCCCCTTCCACTTTCTT-3'; and 18S, 5'-GTAACCCGTTGAACCCCATT-3' and 5'-CCATCCAATCGGTAGTAGCG-3'.	('CBP', 'Gene', '1387', (127, 130))	('human', 'Species', '9606', (4, 9))	('CBP', 'Gene', (127, 130))	('p300', 'Var', (67, 71))
613398	31371781	1g, Garcinol decreased the protein levels of p300 and CBP in a dose dependent manner.	('decreased', 'NegReg', (13, 22))	('p300', 'Var', (45, 49))	('CBP', 'Gene', (54, 57))	('Garcinol', 'Chemical', 'MESH:C054597', (4, 12))	('CBP', 'Gene', '1387', (54, 57))	('protein levels', 'MPA', (27, 41))
613403	31371781	siRNAs targeting p300 and CBP were transfected into KYSE150 cells, and the protein levels and mRNA levels of p300 and CBP were decreased (Fig.	('p300', 'Var', (17, 21))	('decreased', 'NegReg', (127, 136))	('mRNA levels', 'MPA', (94, 105))	('CBP', 'Gene', (118, 121))	('protein levels', 'MPA', (75, 89))	('KYSE150', 'CellLine', 'CVCL:1348', (52, 59))	('CBP', 'Gene', (26, 29))	('CBP', 'Gene', '1387', (118, 121))	('CBP', 'Gene', '1387', (26, 29))	('p300', 'Var', (109, 113))
613404	31371781	p300-1 siRNA, p300-2 siRNA, and CBP-2209 siRNA were selected for subsequent experiments.	('p300-1', 'Var', (0, 6))	('CBP', 'Gene', '1387', (32, 35))	('CBP', 'Gene', (32, 35))	('p300-2', 'Var', (14, 20))
613405	31371781	The wound healing assay showed that the knockdown of p300 inhibited the migration of KYSE150 cells, but the knockdown of CBP did not (Fig.	('CBP', 'Gene', '1387', (121, 124))	('CBP', 'Gene', (121, 124))	('migration of KYSE150 cells', 'CPA', (72, 98))	('inhibited', 'NegReg', (58, 67))	('KYSE150', 'CellLine', 'CVCL:1348', (85, 92))	('p300', 'Var', (53, 57))
613406	31371781	The Transwell and Matrigel assays showed similar effects of p300 and CBP siRNA as the wound healing assay.	('p300', 'Var', (60, 64))	('wound healing assay', 'CPA', (86, 105))	('CBP', 'Gene', (69, 72))	('CBP', 'Gene', '1387', (69, 72))
613408	31371781	2f, g. Thus, the expression of p300 is related to the mobility of KYSE150 cells, and the antimetastatic effect of Garcinol may depend on the downregulation of p300.	('Garcinol', 'Chemical', 'MESH:C054597', (114, 122))	('antimetastatic effect', 'CPA', (89, 110))	('KYSE150', 'CellLine', 'CVCL:1348', (66, 73))	('related', 'Reg', (39, 46))	('p300', 'Var', (31, 35))	('downregulation', 'NegReg', (141, 155))	('p300', 'Var', (159, 163))
613409	31371781	The protein levels of p300 and CBP were decreased after transfection with p300 and CBP siRNAs for 24 h and 48 h, and the cell numbers were counted (Fig.	('p300', 'Var', (74, 78))	('protein levels', 'MPA', (4, 18))	('CBP', 'Gene', (31, 34))	('CBP', 'Gene', (83, 86))	('CBP', 'Gene', '1387', (31, 34))	('CBP', 'Gene', '1387', (83, 86))	('decreased', 'NegReg', (40, 49))
613410	31371781	The results indicated that the knockdown of p300 suppressed cell growth at 48 h. The expression of the EMT marker was also regulated by p300 and CBP siRNAs.	('expression', 'MPA', (85, 95))	('EMT marker', 'Gene', (103, 113))	('p300', 'Var', (136, 140))	('CBP', 'Gene', (145, 148))	('CBP', 'Gene', '1387', (145, 148))	('regulated', 'Reg', (123, 132))
613411	31371781	The knockdown of p300 increased the protein level of E-cadherin and decreased the protein level of snail, while the knockdown of CBP did not influence the expression of E-cadherin but decreased the protein level of snail (Fig.	('decreased', 'NegReg', (68, 77))	('p300', 'Var', (17, 21))	('snail', 'Gene', '6615', (99, 104))	('E-cadherin', 'Gene', (169, 179))	('E-cadherin', 'Gene', '999', (169, 179))	('E-cadherin', 'Gene', (53, 63))	('E-cadherin', 'Gene', '999', (53, 63))	('snail', 'Gene', (215, 220))	('increased', 'PosReg', (22, 31))	('decreased', 'NegReg', (184, 193))	('snail', 'Gene', (99, 104))	('protein level', 'MPA', (198, 211))	('CBP', 'Gene', (129, 132))	('snail', 'Gene', '6615', (215, 220))	('CBP', 'Gene', '1387', (129, 132))
613412	31371781	The expression of the EMT marker decreased after p300 knockdown or Garcinol treatment (Fig.	('decreased', 'NegReg', (33, 42))	('p300 knockdown', 'Var', (49, 63))	('expression', 'MPA', (4, 14))	('Garcinol', 'Chemical', 'MESH:C054597', (67, 75))
613413	31371781	Taken together, our results indicate that p300 is essential for the mediation of KYSE150 cell metastasis and that Garcinol inhibits metastasis by downregulating the expression of p300.	('Garcinol', 'Chemical', 'MESH:C054597', (114, 122))	('p300', 'Var', (179, 183))	('metastasis', 'CPA', (132, 142))	('expression', 'MPA', (165, 175))	('downregulating', 'NegReg', (146, 160))	('KYSE150', 'CellLine', 'CVCL:1348', (81, 88))	('inhibits', 'NegReg', (123, 131))
613415	31371781	The expression of p300 mRNA was lower after Garcinol treatment than after vehicle treatment in p300 or CBP knockdown cells (Fig.	('CBP', 'Gene', (103, 106))	('expression', 'MPA', (4, 14))	('Garcinol', 'Chemical', 'MESH:C054597', (44, 52))	('p300 mRNA', 'Var', (18, 27))	('CBP', 'Gene', '1387', (103, 106))	('lower', 'NegReg', (32, 37))
613417	31371781	Garcinol further decreased the expression of p300 mRNA after the knockdown of p300.	('expression', 'MPA', (31, 41))	('Garcinol', 'Chemical', 'MESH:C054597', (0, 8))	('p300', 'Var', (45, 49))	('decreased', 'NegReg', (17, 26))
613418	31371781	These data indicate that the metastatic inhibition by Garcinol may be related to the expression of p300 but not CBP.	('p300', 'Var', (99, 103))	('Garcinol', 'Chemical', 'MESH:C054597', (54, 62))	('metastatic inhibition', 'CPA', (29, 50))	('CBP', 'Gene', (112, 115))	('CBP', 'Gene', '1387', (112, 115))
613419	31371781	p300 and p-Smad2/3 can form a complex in the nucleus and activate downstream metastasis signaling.	('p300', 'Var', (0, 4))	('downstream metastasis signaling', 'Pathway', (66, 97))	('Smad2', 'Gene', '4087', (11, 16))	('Smad2', 'Gene', (11, 16))	('activate', 'PosReg', (57, 65))
613420	31371781	4a, b, the activation of some protein kinases, including p-Stat3, p-AKT, p-Src, p-Smad2/3, p-MEK, and p-S6, was decreased upon Garcinol treatment in both KYSE150 and KYSE450 cells.	('Src', 'Gene', (75, 78))	('Src', 'Gene', '6714', (75, 78))	('KYSE150', 'CellLine', 'CVCL:1348', (154, 161))	('Smad2', 'Gene', '4087', (82, 87))	('Stat3', 'Gene', '6774', (59, 64))	('protein kinases', 'Enzyme', (30, 45))	('Smad2', 'Gene', (82, 87))	('MEK', 'Gene', (93, 96))	('AKT', 'Gene', '207', (68, 71))	('MEK', 'Gene', '5609', (93, 96))	('Garcinol', 'Chemical', 'MESH:C054597', (127, 135))	('decreased', 'NegReg', (112, 121))	('Stat3', 'Gene', (59, 64))	('activation', 'PosReg', (11, 21))	('p-S6', 'Var', (102, 106))	('AKT', 'Gene', (68, 71))	('KYSE450', 'CellLine', 'CVCL:1353', (166, 173))
613421	31371781	The knockdown of p300 increased the protein level of p-Stat3 and decrease the protein level of p-MEK at the same time, but 15 muM Garcinol reversed the expression of p-Stat3 (Fig.	('Stat3', 'Gene', '6774', (55, 60))	('p300', 'Var', (17, 21))	('Stat3', 'Gene', (55, 60))	('increased', 'PosReg', (22, 31))	('Garcinol', 'Chemical', 'MESH:C054597', (130, 138))	('MEK', 'Gene', (97, 100))	('decrease', 'NegReg', (65, 73))	('MEK', 'Gene', '5609', (97, 100))	('protein level', 'MPA', (36, 49))	('Stat3', 'Gene', '6774', (168, 173))	('Stat3', 'Gene', (168, 173))
613425	31371781	After TGF-beta1 simulation for 24 h, Garcinol decreased the protein levels of vimentin, snail, p-Smad2/3, p-Stat3, p-Src, p-AKT, p-MEK, and p-S6 in KYSE150 and KYSE450 cells (Fig.	('Stat3', 'Gene', '6774', (108, 113))	('Smad2', 'Gene', (97, 102))	('KYSE450', 'CellLine', 'CVCL:1353', (160, 167))	('AKT', 'Gene', (124, 127))	('KYSE150', 'CellLine', 'CVCL:1348', (148, 155))	('Src', 'Gene', (117, 120))	('decreased', 'NegReg', (46, 55))	('MEK', 'Gene', '5609', (131, 134))	('snail', 'Gene', '6615', (88, 93))	('p-S6', 'Var', (140, 144))	('TGF-beta1', 'Gene', (6, 15))	('Garcinol', 'Chemical', 'MESH:C054597', (37, 45))	('vimentin', 'Gene', '7431', (78, 86))	('MEK', 'Gene', (131, 134))	('Src', 'Gene', '6714', (117, 120))	('protein levels', 'MPA', (60, 74))	('vimentin', 'Gene', (78, 86))	('TGF-beta1', 'Gene', '7040', (6, 15))	('AKT', 'Gene', '207', (124, 127))	('Stat3', 'Gene', (108, 113))	('snail', 'Gene', (88, 93))	('Smad2', 'Gene', '4087', (97, 102))
613435	31371781	The weight of the lungs in the Garcinol and 5-FU treated groups was decreased compared to that in the vehicle group (Fig.	('decreased', 'NegReg', (68, 77))	('5-FU', 'Var', (44, 48))	('Garcinol', 'Chemical', 'MESH:C054597', (31, 39))	('weight of the lungs', 'CPA', (4, 23))	('5-FU', 'Chemical', 'MESH:D005472', (44, 48))
613439	31371781	After Garcinol or 5-FU injection, the levels of p300 and p-Smad2/3 were also decreased in the lung tissues (Fig.	('5-FU', 'Chemical', 'MESH:D005472', (18, 22))	('p300', 'Var', (48, 52))	('levels', 'MPA', (38, 44))	('Smad2', 'Gene', '4087', (59, 64))	('Garcinol', 'Chemical', 'MESH:C054597', (6, 14))	('Smad2', 'Gene', (59, 64))	('decreased', 'NegReg', (77, 86))
613441	31371781	p300 and CBP function as transcriptional cofactors and HATs.	('CBP', 'Gene', (9, 12))	('p300', 'Var', (0, 4))	('CBP', 'Gene', '1387', (9, 12))
613442	31371781	The high expression of p300 is associated with poor survival in esophageal cancer patients, and p300 has been an important drug target in cancer research.	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Disease', (75, 81))	('poor', 'NegReg', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('p300', 'Var', (23, 27))
613445	31371781	Our data also suggested that Garcinol inhibits p300 and CBP without downregulating their mRNA levels (Fig.	('p300', 'Var', (47, 51))	('inhibits', 'NegReg', (38, 46))	('CBP', 'Gene', (56, 59))	('Garcinol', 'Chemical', 'MESH:C054597', (29, 37))	('CBP', 'Gene', '1387', (56, 59))	('mRNA levels', 'MPA', (89, 100))
613448	31371781	Garcinol treatment leads to a decrease in p-Smad2/3 and p300 in the nucleus, which causes the downregulation of EMT markers.	('EMT markers', 'CPA', (112, 123))	('Smad2', 'Gene', '4087', (44, 49))	('decrease', 'NegReg', (30, 38))	('Smad2', 'Gene', (44, 49))	('Garcinol', 'Chemical', 'MESH:C054597', (0, 8))	('p300', 'Var', (56, 60))	('downregulation', 'NegReg', (94, 108))
613449	31371781	p300 and CBP have multiple functional domains that accommodate diverse protein-protein interactions to enable a large number of disparate transcription factors.	('CBP', 'Gene', (9, 12))	('p300', 'Var', (0, 4))	('protein-protein', 'Protein', (71, 86))	('CBP', 'Gene', '1387', (9, 12))
613451	31371781	Research has shown that p300 promotes proliferation, migration, and invasion in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('proliferation', 'CPA', (38, 51))	('invasion', 'CPA', (68, 76))	('p300', 'Var', (24, 28))	('NSCLC', 'Disease', (80, 85))	('migration', 'CPA', (53, 62))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('promotes', 'PosReg', (29, 37))
613452	31371781	The overexpression of p300 is a poor prognostic factor in breast cancer, prostate cancer, hepatocellular carcinoma, and esophageal squamous cell carcinoma.	('prostate cancer', 'Disease', (73, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('p300', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('hepatocellular carcinoma', 'Disease', (90, 114))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('breast cancer', 'Disease', (58, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('overexpression', 'PosReg', (4, 18))
613453	31371781	In our previous studies, we found that Garcinol has a potential effect on p300 and CBP, leads to p-Stat3, p-Src and p-AKT downregulation, and inhibits EMT functions and characteristics.	('p300', 'Var', (74, 78))	('AKT', 'Gene', '207', (118, 121))	('CBP', 'Gene', (83, 86))	('downregulation', 'NegReg', (122, 136))	('inhibits', 'NegReg', (142, 150))	('Garcinol', 'Chemical', 'MESH:C054597', (39, 47))	('CBP', 'Gene', '1387', (83, 86))	('AKT', 'Gene', (118, 121))	('Src', 'Gene', (108, 111))	('Stat3', 'Gene', '6774', (99, 104))	('Src', 'Gene', '6714', (108, 111))	('Stat3', 'Gene', (99, 104))
613454	31371781	Then, we investigated the role of p300/CBP in inhibiting ESCC metastasis, and the results indicated that p300, but not CBP, has an antimetastatic effect.	('inhibiting', 'NegReg', (46, 56))	('ESCC', 'Disease', (57, 61))	('CBP', 'Gene', '1387', (119, 122))	('antimetastatic effect', 'CPA', (131, 152))	('CBP', 'Gene', (39, 42))	('p300', 'Var', (105, 109))	('CBP', 'Gene', (119, 122))	('CBP', 'Gene', '1387', (39, 42))
613463	31371781	In conclusion, we demonstrated that Garcinol can inhibit p300 and p-Smad2/3 in the nucleus to block the transcription of metastasis-related genes.	('Garcinol', 'Chemical', 'MESH:C054597', (36, 44))	('Smad2', 'Gene', '4087', (68, 73))	('block', 'NegReg', (94, 99))	('metastasis-related genes', 'Gene', (121, 145))	('transcription', 'MPA', (104, 117))	('Smad2', 'Gene', (68, 73))	('inhibit', 'NegReg', (49, 56))	('p300', 'Var', (57, 61))
613464	31371781	We also found that the knockdown of p300 can downregulate p-MEK and p-S6, which are related to EMT.	('MEK', 'Gene', '5609', (60, 63))	('knockdown', 'Var', (23, 32))	('p-S6', 'Protein', (68, 72))	('downregulate', 'NegReg', (45, 57))	('p300', 'Var', (36, 40))	('MEK', 'Gene', (60, 63))
613469	31956298	EphA5 knockdown enhances the invasion and migration ability of esophageal squamous cell carcinoma via epithelial-mesenchymal transition through activating Wnt/beta-catenin pathway The erythropoietin-producing hepatocellular (Eph) receptor A5 (EphA5) has been found to be overexpressed in some malignant tumors and is associated with disease prognosis.	('beta-catenin', 'Gene', (159, 171))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('beta-catenin', 'Gene', '1499', (159, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('EphA5', 'Gene', '2044', (0, 5))	('epithelial-mesenchymal', 'CPA', (102, 124))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('EphA5', 'Gene', (243, 248))	('associated', 'Reg', (317, 327))	('erythropoietin-producing hepatocellular (Eph) receptor A5', 'Gene', '2044', (184, 241))	('enhances', 'PosReg', (16, 24))	('EphA5', 'Gene', (0, 5))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('EphA5', 'Gene', '2044', (243, 248))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (63, 97))	('malignant tumors', 'Disease', (293, 309))	('knockdown', 'Var', (6, 15))	('malignant tumors', 'Disease', 'MESH:D009369', (293, 309))
613477	31956298	The cell viability assay and colony formation assay revealed that EphA5 knockdown enhanced the proliferation of KYSE150 and KYSE450 cells in vitro.	('enhanced', 'PosReg', (82, 90))	('knockdown', 'Var', (72, 81))	('EphA5', 'Gene', (66, 71))	('proliferation', 'CPA', (95, 108))	('EphA5', 'Gene', '2044', (66, 71))
613478	31956298	The invasion and migration of ESCC cells were accelerated after EphA5 knockdown.	('knockdown', 'Var', (70, 79))	('accelerated', 'PosReg', (46, 57))	('EphA5', 'Gene', (64, 69))	('ESCC', 'Disease', (30, 34))	('EphA5', 'Gene', '2044', (64, 69))	('ESCC', 'Disease', 'MESH:C562729', (30, 34))
613479	31956298	The expression of EMT biomarkers was altered in ESCC cells transfected with siRNA targeting EphA5.	('ESCC', 'Disease', 'MESH:C562729', (48, 52))	('EphA5', 'Gene', (92, 97))	('EphA5', 'Gene', '2044', (92, 97))	('expression', 'MPA', (4, 14))	('ESCC', 'Disease', (48, 52))	('siRNA', 'Var', (76, 81))	('altered', 'Reg', (37, 44))
613481	31956298	EphA5 knockdown promotes the proliferation of esophageal squamous cell carcinoma,enhances invasion and migration ability via epithelial-mesenchymal transition through activating Wnt/beta-catenin pathway.	('promotes', 'PosReg', (16, 24))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (46, 80))	('beta-catenin', 'Gene', '1499', (182, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('EphA5', 'Gene', (0, 5))	('proliferation', 'CPA', (29, 42))	('enhances', 'PosReg', (81, 89))	('epithelial-mesenchymal transition', 'CPA', (125, 158))	('EphA5', 'Gene', '2044', (0, 5))	('knockdown', 'Var', (6, 15))	('esophageal squamous cell carcinoma', 'Disease', (46, 80))	('activating', 'PosReg', (167, 177))	('beta-catenin', 'Gene', (182, 194))
613500	31956298	Human esophageal carcinoma cell lines (KYSE30, KYSE 70, KYSE 140, KYSE150, KYSE 180, KYSE 410, KYSE450, KYSE510) and human normal esophageal epithelial cells (HEEC) were provided by the Chinese Academy of Cell Resource Center (Shanghai, China).	('KYSE150', 'Var', (66, 73))	('KYSE', 'Var', (56, 60))	('KYSE30', 'Var', (39, 45))	('KYSE 410', 'Var', (85, 93))	('Human', 'Species', '9606', (0, 5))	('human', 'Species', '9606', (117, 122))	('esophageal carcinoma', 'Disease', (6, 26))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (6, 26))	('HEEC', 'CellLine', 'CVCL:3285', (159, 163))	('KYSE510', 'Var', (104, 111))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (6, 26))	('KYSE 180', 'Var', (75, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('KYSE450', 'Var', (95, 102))
613532	31956298	The SI >= 3 was considered as EphA5-high expression tumors, those with 0 < SI < 3 were regarded as EphA5-low expression while others with SI = 0 regarded as EphA5-negative expression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('EphA5', 'Gene', (157, 162))	('SI >= 3', 'Var', (4, 11))	('tumors', 'Disease', (52, 58))	('EphA5', 'Gene', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('EphA5', 'Gene', '2044', (30, 35))	('EphA5', 'Gene', '2044', (157, 162))	('EphA5', 'Gene', (99, 104))	('EphA5', 'Gene', '2044', (99, 104))
613534	31956298	EphA5 was rarely expressed in HEEC cells, but was highly expressed in KYSE150, KYSE450 and KYSE410 cells.	('KYSE410', 'Var', (91, 98))	('EphA5', 'Gene', (0, 5))	('EphA5', 'Gene', '2044', (0, 5))	('KYSE410', 'CellLine', 'CVCL:1352', (91, 98))	('HEEC', 'CellLine', 'CVCL:3285', (30, 34))
613545	31956298	Among 10 ESCC patients with high expression of EphA5, there were 7 patients with advanced tumor stage (T3 and T4), 8 patients with positive lymph nodes, and 9 patients with moderately differentiated squamous cell carcinoma.	('ESCC', 'Disease', (9, 13))	('squamous cell carcinoma', 'Disease', (199, 222))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('EphA5', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('EphA5', 'Gene', '2044', (47, 52))	('ESCC', 'Disease', 'MESH:C562729', (9, 13))	('high expression', 'Var', (28, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (159, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 222))	('patients', 'Species', '9606', (14, 22))
613552	31956298	The cell viability assay showed that EphA5 knockdown accelerated the proliferation of KYSE150 cells and KYSE450 cells (Fig.	('EphA5', 'Gene', (37, 42))	('proliferation', 'CPA', (69, 82))	('EphA5', 'Gene', '2044', (37, 42))	('accelerated', 'PosReg', (53, 64))	('knockdown', 'Var', (43, 52))
613553	31956298	We observed that the number of colonies formed by cells with EphA5 knockdown was more than that of negative controls (Fig.	('EphA5', 'Gene', '2044', (61, 66))	('knockdown', 'Var', (67, 76))	('EphA5', 'Gene', (61, 66))
613554	31956298	Having shown that EphA5 knockdown enhanced the cell proliferation, we then analyzed the cell apoptosis and cell cycle by flow cytometry.	('enhanced', 'PosReg', (34, 42))	('EphA5', 'Gene', '2044', (18, 23))	('EphA5', 'Gene', (18, 23))	('knockdown', 'Var', (24, 33))	('cell proliferation', 'CPA', (47, 65))
613557	31956298	In the wound-healing assay, the cells with EphA5 knockdown displayed significantly accelerated wound healing compared to the respective controls (Fig.	('knockdown', 'Var', (49, 58))	('accelerated', 'PosReg', (83, 94))	('EphA5', 'Gene', (43, 48))	('EphA5', 'Gene', '2044', (43, 48))	('accelerated wound healing', 'Phenotype', 'HP:0001058', (83, 108))	('wound healing', 'CPA', (95, 108))
613558	31956298	Transwell invasion assay revealed that EphA5 knockdown significantly increased the invaded number of cells and promoted the invasion ability (Fig.	('increased', 'PosReg', (69, 78))	('EphA5', 'Gene', (39, 44))	('EphA5', 'Gene', '2044', (39, 44))	('invaded number of cells', 'CPA', (83, 106))	('invasion ability', 'CPA', (124, 140))	('promoted', 'PosReg', (111, 119))	('knockdown', 'Var', (45, 54))
613561	31956298	As expected, E-cadherin was decreased, while N-cadherin and the relevant transcription factor Snail were remarkably increased in KYSE150 and KYSE450 cells with EphA5 knockdown compared with the controls cells (Fig.	('knockdown', 'Var', (166, 175))	('decreased', 'NegReg', (28, 37))	('Snail', 'Gene', '6615', (94, 99))	('EphA5', 'Gene', (160, 165))	('N-cadherin', 'Gene', (45, 55))	('EphA5', 'Gene', '2044', (160, 165))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('increased', 'PosReg', (116, 125))	('Snail', 'Gene', (94, 99))	('N-cadherin', 'Gene', '1000', (45, 55))
613563	31956298	Consistently, silencing of EphA5 promoted EMT in KYSE150 and KYSE450 ESCC cells.	('silencing', 'Var', (14, 23))	('promoted', 'PosReg', (33, 41))	('EMT', 'CPA', (42, 45))	('ESCC', 'Disease', 'MESH:C562729', (69, 73))	('ESCC', 'Disease', (69, 73))	('EphA5', 'Gene', (27, 32))	('EphA5', 'Gene', '2044', (27, 32))
613564	31956298	To evaluate whether the effect of EphA5 knockdown on the EMT process was associated with Wnt/beta-catenin signaling pathway, the expression of total beta-catenin, GSK-3beta and phosphorylated GSK-3beta (p-GSK-3betaSer9) were investigated.	('GSK-3beta', 'Gene', (192, 201))	('beta-catenin', 'Gene', (93, 105))	('GSK-3beta', 'Gene', '2932', (163, 172))	('GSK-3beta', 'Gene', (163, 172))	('knockdown', 'Var', (40, 49))	('beta-catenin', 'Gene', (149, 161))	('associated', 'Reg', (73, 83))	('GSK-3beta', 'Gene', '2932', (205, 214))	('GSK-3beta', 'Gene', (205, 214))	('beta-catenin', 'Gene', '1499', (93, 105))	('EphA5', 'Gene', (34, 39))	('beta-catenin', 'Gene', '1499', (149, 161))	('EphA5', 'Gene', '2044', (34, 39))	('GSK-3beta', 'Gene', '2932', (192, 201))
613567	31956298	Moreover, beta-catenin expression could been observed in the cytoplasm and nucleus of cells with EphA5 knockdown, but it was only expressed on the cell membrane in the control groups (Fig.	('beta-catenin', 'Gene', (10, 22))	('EphA5', 'Gene', (97, 102))	('EphA5', 'Gene', '2044', (97, 102))	('beta-catenin', 'Gene', '1499', (10, 22))	('knockdown', 'Var', (103, 112))
613569	31956298	4a, b, EphA5 knockdown increased the expression of c-Myc and CyclinD1 compared with the negative controls.	('c-Myc', 'Gene', '4609', (51, 56))	('EphA5', 'Gene', '2044', (7, 12))	('c-Myc', 'Gene', (51, 56))	('CyclinD1', 'Gene', (61, 69))	('increased', 'PosReg', (23, 32))	('EphA5', 'Gene', (7, 12))	('expression', 'MPA', (37, 47))	('knockdown', 'Var', (13, 22))	('CyclinD1', 'Gene', '595', (61, 69))
613573	31956298	Thus, Wnt/beta-catenin signaling pathway was essential to the development of EMT triggered by EphA5 knockdown.	('EphA5', 'Gene', (94, 99))	('beta-catenin', 'Gene', (10, 22))	('EphA5', 'Gene', '2044', (94, 99))	('knockdown', 'Var', (100, 109))	('beta-catenin', 'Gene', '1499', (10, 22))
613577	31956298	The study revealed that high EphA5 expression in lung cancer indicated higher locoregional recurrence and lower cumulative overall patient survival.	('higher', 'PosReg', (71, 77))	('lower', 'NegReg', (106, 111))	('EphA5', 'Gene', (29, 34))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('locoregional recurrence', 'CPA', (78, 101))	('EphA5', 'Gene', '2044', (29, 34))	('expression', 'MPA', (35, 45))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('high', 'Var', (24, 28))	('patient', 'Species', '9606', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
613587	31956298	KYSE150, KYSE450 and KYSE410 cells exhibited higher EphA5 expression than other ESCC cells.	('KYSE410', 'CellLine', 'CVCL:1352', (21, 28))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('KYSE410', 'Var', (21, 28))	('KYSE450', 'Var', (9, 16))	('higher', 'PosReg', (45, 51))	('EphA5', 'Gene', (52, 57))	('KYSE150', 'Var', (0, 7))	('EphA5', 'Gene', '2044', (52, 57))	('ESCC', 'Disease', (80, 84))
613590	31956298	Our finds showed that EphA5 knockdown enhanced malignant characteristics of KYSE150 and KYSE450 cells in vitro,such as the ability of cell proliferation, migration and invasion.	('cell proliferation', 'CPA', (134, 152))	('EphA5', 'Gene', (22, 27))	('enhanced', 'PosReg', (38, 46))	('malignant characteristics', 'CPA', (47, 72))	('EphA5', 'Gene', '2044', (22, 27))	('knockdown', 'Var', (28, 37))	('invasion', 'CPA', (168, 176))	('migration', 'CPA', (154, 163))
613591	31956298	It seems to be contradictory with the results that high EphA5 expression is related to lymph node metastasis in ESCC patients.	('expression', 'MPA', (62, 72))	('ESCC', 'Disease', (112, 116))	('EphA5', 'Gene', '2044', (56, 61))	('high', 'Var', (51, 55))	('patients', 'Species', '9606', (117, 125))	('ESCC', 'Disease', 'MESH:C562729', (112, 116))	('lymph node metastasis', 'CPA', (87, 108))	('EphA5', 'Gene', (56, 61))	('related', 'Reg', (76, 83))
613592	31956298	To explain the contradictory data, an EphA5 overexpression plasmids was transfected into the EphA5 knockdown KYSE150 cells.	('EphA5', 'Gene', (38, 43))	('knockdown', 'Var', (99, 108))	('EphA5', 'Gene', '2044', (38, 43))	('EphA5', 'Gene', (93, 98))	('EphA5', 'Gene', '2044', (93, 98))
613593	31956298	We found that EphA5 overexpression could reverse the cancer-related characteristics in the KYSE150 cells with EphA5 knockdown.	('EphA5', 'Gene', '2044', (110, 115))	('reverse', 'NegReg', (41, 48))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('knockdown', 'Var', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('EphA5', 'Gene', (14, 19))	('EphA5', 'Gene', '2044', (14, 19))	('EphA5', 'Gene', (110, 115))
613599	31956298	However, the current study did not find cell cycle and apoptosis changes in the ESCC cells with EphA5 knockdown.	('knockdown', 'Var', (102, 111))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('EphA5', 'Gene', (96, 101))	('EphA5', 'Gene', '2044', (96, 101))	('ESCC', 'Disease', (80, 84))
613603	31956298	Thus, the expression of E-cadherin, N-cadherin, and Snail was measured in ESCC cells following EphA5 knocked down.	('N-cadherin', 'Gene', '1000', (36, 46))	('ESCC', 'Disease', (74, 78))	('E-cadherin', 'Gene', '999', (24, 34))	('expression', 'MPA', (10, 20))	('EphA5', 'Gene', (95, 100))	('Snail', 'Gene', (52, 57))	('E-cadherin', 'Gene', (24, 34))	('EphA5', 'Gene', '2044', (95, 100))	('ESCC', 'Disease', 'MESH:C562729', (74, 78))	('Snail', 'Gene', '6615', (52, 57))	('knocked down', 'Var', (101, 113))	('N-cadherin', 'Gene', (36, 46))
613607	31956298	Furthermore, the report found that loss of EphA5 resulted in higher expression of cancer stem cell (CSC) markers in HER2-positive breast cancer cells, including CD44+/CD24-/low, NANOG, CD133+.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('HER2-positive breast cancer', 'Disease', (116, 143))	('expression', 'MPA', (68, 78))	('NANOG', 'Gene', '79923', (178, 183))	('higher', 'PosReg', (61, 67))	('EphA5', 'Gene', (43, 48))	('NANOG', 'Gene', (178, 183))	('loss', 'Var', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CD133+', 'Var', (185, 191))	('EphA5', 'Gene', '2044', (43, 48))	('cancer', 'Disease', (137, 143))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (116, 143))	('CD44+/CD24-/low', 'Var', (161, 176))
613613	31956298	And then to further confirm that the Wnt/beta-catenin pathway linked EphA5 and EMT, beta-catenin was depleted in the EphA5 knockdown cells by siRNA duplexes transfection.	('beta-catenin', 'Gene', (41, 53))	('beta-catenin', 'Gene', '1499', (41, 53))	('beta-catenin', 'Gene', '1499', (84, 96))	('beta-catenin', 'Gene', (84, 96))	('knockdown', 'Var', (123, 132))	('EphA5', 'Gene', (69, 74))	('EphA5', 'Gene', (117, 122))	('depleted', 'NegReg', (101, 109))	('EphA5', 'Gene', '2044', (69, 74))	('EphA5', 'Gene', '2044', (117, 122))
613614	31956298	Western blot analysis showed that beta-catenin depletion eliminated the effects of EphA5 knockdown on EMT, indicating a reversal of the EMT markers altered in the ESCC cells with EphA5 knockdown.	('EphA5', 'Gene', '2044', (83, 88))	('ESCC', 'Disease', (163, 167))	('eliminated', 'NegReg', (57, 67))	('beta-catenin', 'Gene', '1499', (34, 46))	('ESCC', 'Disease', 'MESH:C562729', (163, 167))	('EphA5', 'Gene', (179, 184))	('EphA5', 'Gene', '2044', (179, 184))	('knockdown', 'Var', (89, 98))	('EphA5', 'Gene', (83, 88))	('beta-catenin', 'Gene', (34, 46))
613618	31956298	The present study indicated that EphA5 knockdown increased the levels of N-cadherin and Snail, and yet decreased the E-cadherin expression.	('Snail', 'Gene', '6615', (88, 93))	('EphA5', 'Gene', (33, 38))	('increased', 'PosReg', (49, 58))	('knockdown', 'Var', (39, 48))	('decreased', 'NegReg', (103, 112))	('levels of', 'MPA', (63, 72))	('EphA5', 'Gene', '2044', (33, 38))	('N-cadherin', 'Gene', (73, 83))	('N-cadherin', 'Gene', '1000', (73, 83))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))	('Snail', 'Gene', (88, 93))
613620	31956298	Together, these findings demonstrate that EphA5 knockdown can trigger EMT by activating Wnt/beta-catenin signaling in ESCC.	('ESCC', 'Disease', (118, 122))	('trigger', 'PosReg', (62, 69))	('EMT', 'CPA', (70, 73))	('beta-catenin', 'Gene', '1499', (92, 104))	('EphA5', 'Gene', (42, 47))	('beta-catenin', 'Gene', (92, 104))	('ESCC', 'Disease', 'MESH:C562729', (118, 122))	('EphA5', 'Gene', '2044', (42, 47))	('activating', 'PosReg', (77, 87))	('knockdown', 'Var', (48, 57))
613623	31956298	High EphA5 expression may promote lymph node metastasis, although this seems to be inconsistent with the in vitro results.	('promote', 'PosReg', (26, 33))	('High', 'Var', (0, 4))	('EphA5', 'Gene', (5, 10))	('EphA5', 'Gene', '2044', (5, 10))	('lymph node metastasis', 'CPA', (34, 55))
613670	30516569	), as follows: high (IHC3+), strong intensity in 10% or more of cancer cells; medium (IHC2+), weak-moderate intensity in 10% or more; low (IHC1+), faint intensity in 10% or more; absent (IHC0).	('rat', 'Species', '10116', (103, 106))	('IHC2+', 'Var', (86, 91))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('IHC2+', 'Chemical', 'MESH:C053584', (86, 91))	('IHC1+', 'Chemical', 'MESH:C053584', (139, 144))	('IHC3+', 'Chemical', 'MESH:C053584', (21, 26))	('IHC1+', 'Var', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('intensity', 'MPA', (36, 45))
613684	30516569	Invasive depth of the adenocarcinoma component was likewise T3 in most ASC tumors (9 of 13 tumors with evaluable subpopulation depth), T4 in one tumor, T2 in one tumor, and T1b in two tumors.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('ASC', 'Disease', 'MESH:D018196', (71, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('tumor', 'Disease', (162, 167))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (91, 96))	('T1b', 'Var', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Invasive depth of the adenocarcinoma component', 'Disease', 'MESH:D007222', (0, 46))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', (91, 97))	('Invasive depth of the adenocarcinoma component', 'Disease', (0, 46))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (184, 190))	('ASC', 'Disease', (71, 74))
613715	30516569	Preliminary data indicate that EAC and ESCC components of esophageal ASC tumors share patterns of allelic loss at multiple chromosomal locations, TP53 mutation, and/or aberrant expression of p53, p16, and RB in some tumors, while other esophageal ASC tumors exhibit significantly divergent alterations in microsatellites and beta-catenin and EGFR expression.	('esophageal ASC', 'Disease', (236, 250))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (216, 222))	('rat', 'Species', '10116', (294, 297))	('microsatellites', 'Var', (305, 320))	('p53', 'Gene', '7157', (191, 194))	('allelic', 'MPA', (98, 105))	('beta-catenin', 'Gene', (325, 337))	('tumors', 'Disease', (73, 79))	('beta-catenin', 'Gene', '1499', (325, 337))	('expression', 'MPA', (177, 187))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('aberrant', 'Var', (168, 176))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('TP53', 'Gene', (146, 150))	('p53', 'Gene', (191, 194))	('esophageal ASC', 'Disease', (58, 72))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('loss', 'NegReg', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('EGFR', 'Gene', (342, 346))	('SCC', 'Gene', '6317', (40, 43))	('tumors', 'Disease', (251, 257))	('esophageal ASC', 'Disease', 'MESH:D018196', (236, 250))	('mutation', 'Var', (151, 159))	('expression', 'MPA', (347, 357))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('SCC', 'Gene', (40, 43))	('TP53', 'Gene', '7157', (146, 150))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('p16', 'Gene', (196, 199))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('EGFR', 'Gene', '1956', (342, 346))	('esophageal ASC', 'Disease', 'MESH:D018196', (58, 72))	('p16', 'Gene', '1029', (196, 199))
613719	30516569	Novel clinicopathologic annotations include BMI, adjacent Barrett's, smoking history, and HER2 expression and amplification using modern disease-specific methods.	('HER2', 'Gene', (90, 94))	('amplification', 'Var', (110, 123))	('HER2', 'Gene', '2064', (90, 94))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('BMI', 'Disease', (44, 47))
613726	30099693	Folic acid supplementation and higher serum levels are associated with increased risk of prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('prostate cancer', 'Disease', (89, 104))	('supplementation', 'Var', (11, 26))	('prostate cancer', 'Disease', 'MESH:D011471', (89, 104))	('Folic acid', 'Chemical', 'MESH:D005492', (0, 10))	('serum levels', 'MPA', (38, 50))	('men', 'Species', '9606', (17, 20))
613749	30099693	Furthermore, folate deficiency can impair conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), the nucleic acid necessary for DNA synthesis and repair.	('folate', 'Chemical', 'MESH:D005492', (13, 19))	('deoxythymidine monophosphate', 'MPA', (93, 121))	('deoxythymidine monophosphate', 'Chemical', 'MESH:D013938', (93, 121))	('deficiency', 'Var', (20, 30))	('impair', 'NegReg', (35, 41))	('folate', 'Protein', (13, 19))	('dUMP', 'Chemical', 'MESH:C007267', (84, 88))	('deoxyuridine monophosphate', 'Chemical', 'MESH:C007267', (56, 82))	('conversion', 'MPA', (42, 52))	('folate deficiency', 'Phenotype', 'HP:0100507', (13, 30))	('dTMP', 'Chemical', 'MESH:D013938', (123, 127))
613750	30099693	The misincorporation of uracil for thymidine can eventually lead to unstable DNA, DNA strand breaks, and faulty DNA repair.	('misincorporation', 'Var', (4, 20))	('uracil', 'Chemical', 'MESH:D014498', (24, 30))	('unstable DNA', 'Disease', (68, 80))	('lead to', 'Reg', (60, 67))	('thymidine', 'Chemical', 'MESH:D013936', (35, 44))
613758	30099693	Just as overt folate deficiency and excess intake may interfere with cell replication and survival, reduced enzyme efficiency can also interfere with nutrient metabolism and influence disease risk.	('folate deficiency', 'Phenotype', 'HP:0100507', (14, 31))	('interfere', 'NegReg', (54, 63))	('efficiency', 'MPA', (115, 125))	('reduced', 'NegReg', (100, 107))	('influence', 'Reg', (174, 183))	('nutrient metabolism', 'MPA', (150, 169))	('cell replication', 'CPA', (69, 85))	('deficiency', 'Var', (21, 31))	('folate', 'Chemical', 'MESH:D005492', (14, 20))	('disease risk', 'MPA', (184, 196))	('interfere', 'Reg', (135, 144))	('survival', 'CPA', (90, 98))	('enzyme', 'Enzyme', (108, 114))
613761	30099693	There are two well-described MTHFR gene polymorphisms: C677T and A1298C.	('A1298C', 'Mutation', 'rs1801131', (65, 71))	('A1298C', 'Var', (65, 71))	('MTHFR', 'Gene', (29, 34))	('MTHFR', 'Gene', '4524', (29, 34))	('C677T', 'Mutation', 'rs1801133', (55, 60))	('C677T', 'Var', (55, 60))
613767	30099693	The combination of folate deficiency and polymorphisms may result in DNA hypo- or hypermethylation.	('deficiency', 'Var', (26, 36))	('polymorphisms', 'Var', (41, 54))	('folate deficiency', 'Phenotype', 'HP:0100507', (19, 36))	('DNA hypo-', 'MPA', (69, 78))	('hypermethylation', 'MPA', (82, 98))	('result', 'Reg', (59, 65))	('folate', 'Chemical', 'MESH:D005492', (19, 25))
613792	30099693	Increased risk of cervical cancer was observed with deficiency per serum folate in Asian, but not American studies.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('serum', 'Protein', (67, 72))	('deficiency', 'Var', (52, 62))	('folate', 'Chemical', 'MESH:D005492', (73, 79))	('cervical cancer', 'Disease', (18, 33))	('cervical cancer', 'Disease', 'MESH:D002583', (18, 33))
613821	30099693	They also suggested that type II or non-estrogen-dependent cancers are more likely to be related to p53 mutations, DNA damage, and changes to cell proliferation, yet the type of endometrial cancer not distinguished in most studies.	('endometrial cancer', 'Disease', (178, 196))	('mutations', 'Var', (104, 113))	('endometrial cancer', 'Phenotype', 'HP:0012114', (178, 196))	('type II', 'Disease', (25, 32))	('related', 'Reg', (89, 96))	('endometrial cancer', 'Disease', 'MESH:D016889', (178, 196))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('p53', 'Gene', '7157', (100, 103))	('cell proliferation', 'CPA', (142, 160))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('changes', 'Reg', (131, 138))	('p53', 'Gene', (100, 103))
613822	30099693	Gene variants associated with the folate metabolic pathway disturb nutrient bioavailability and contribute to a range of diseases.	('folate', 'Enzyme', (34, 40))	('folate', 'Chemical', 'MESH:D005492', (34, 40))	('nutrient bioavailability', 'MPA', (67, 91))	('contribute', 'Reg', (96, 106))	('variants', 'Var', (5, 13))	('disturb', 'NegReg', (59, 66))	('diseases', 'Disease', (121, 129))
613824	30099693	In a meta-analysis of 134 case-control studies, the MTHFR C677T polymorphism was significantly associated with increased tumor risk.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('associated', 'Reg', (95, 105))	('C677T', 'Mutation', 'rs1801133', (58, 63))	('tumor', 'Disease', (121, 126))	('MTHFR', 'Gene', '4524', (52, 57))	('C677T', 'Var', (58, 63))	('MTHFR', 'Gene', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
613826	30099693	Mutation of the 677 gene has also been associated with increased risk of lung, hepatocellular, breast, brain, and ovarian cancer in Asian populations and breast cancer in Turkish population.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('ovarian cancer', 'Disease', (114, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('hepatocellular', 'Disease', (79, 93))	('Mutation', 'Var', (0, 8))	('lung', 'Disease', (73, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))	('brain', 'Disease', (103, 108))	('breast', 'Disease', (95, 101))
613828	30099693	Two meta-analyses showed no association between MTHFR C677T allele and glioma, while an increased risk of brain tumor and meningioma was associated with the heterozygous genotype.	('MTHFR', 'Gene', '4524', (48, 53))	('C677T', 'Mutation', 'rs1801133', (54, 59))	('C677T', 'Var', (54, 59))	('meningioma', 'Disease', (122, 132))	('brain tumor', 'Disease', 'MESH:D001932', (106, 117))	('glioma', 'Disease', (71, 77))	('brain tumor', 'Disease', (106, 117))	('meningioma', 'Phenotype', 'HP:0002858', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('brain tumor', 'Phenotype', 'HP:0030692', (106, 117))	('MTHFR', 'Gene', (48, 53))	('meningioma', 'Disease', 'MESH:D008577', (122, 132))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
613832	30099693	High total and dietary folate intake was inversely associated with colorectal cancer for the wild-type allele, whereas MTHFRTT showed a protective effect for colorectal with high total folate intake compared to low total folate intake.	('MTHFR', 'Gene', '4524', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal', 'Disease', (67, 77))	('high total folate intake', 'Phenotype', 'HP:0032164', (174, 198))	('folate', 'Chemical', 'MESH:D005492', (185, 191))	('high', 'Var', (174, 178))	('MTHFR', 'Gene', (119, 124))	('colorectal', 'Disease', 'MESH:D015179', (158, 168))	('associated', 'Reg', (51, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('low total folate intake', 'Phenotype', 'HP:0100507', (211, 234))	('inversely', 'NegReg', (41, 50))	('colorectal', 'Disease', (158, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('folate', 'Chemical', 'MESH:D005492', (221, 227))	('colorectal', 'Disease', 'MESH:D015179', (67, 77))	('folate', 'Chemical', 'MESH:D005492', (23, 29))	('colorectal cancer', 'Disease', (67, 84))
613833	30099693	The presence of the MTHFR A1298C variant has been significantly associated with increased risk for cervical cancer, globally and among Asians.	('associated', 'Reg', (64, 74))	('MTHFR', 'Gene', '4524', (20, 25))	('cervical cancer', 'Disease', 'MESH:D002583', (99, 114))	('cervical cancer', 'Disease', (99, 114))	('A1298C', 'Mutation', 'rs1801131', (26, 32))	('MTHFR', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('presence', 'Var', (4, 12))
613834	30099693	Homozygosity for A1298C in Asians has been associated with an increased risk of myeloid leukemia and non-Hodgkin lymphoma.	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (105, 121))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (101, 121))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('non-Hodgkin lymphoma', 'Disease', (101, 121))	('myeloid leukemia', 'Disease', (80, 96))	('A1298C', 'Mutation', 'rs1801131', (17, 23))	('A1298C', 'Var', (17, 23))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (101, 121))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (80, 96))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))	('myeloid leukemia', 'Disease', 'MESH:D007951', (80, 96))
613836	30099693	Homozygosity for SHMT C1420T has been associated with a protective effect against colorectal cancer and overall cancer risk for Asian ethnicity.	('cancer', 'Disease', (93, 99))	('C1420T', 'Var', (22, 28))	('colorectal cancer', 'Disease', (82, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('SHMT', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('C1420T', 'Mutation', 'rs1979277', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SHMT', 'Gene', '6470', (17, 21))
613837	30099693	Another study found no association between colorectal cancer and SHMT; however, subgroup analysis showed a significant decreased cancer risk with low folate intake in the presence of SHMT1 variation.	('low', 'NegReg', (146, 149))	('colorectal cancer', 'Disease', (43, 60))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('variation', 'Var', (189, 198))	('SHMT1', 'Gene', '6470', (183, 188))	('cancer', 'Disease', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('SHMT', 'Gene', (65, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('SHMT', 'Gene', (183, 187))	('decreased', 'NegReg', (119, 128))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('folate', 'Chemical', 'MESH:D005492', (150, 156))	('SHMT1', 'Gene', (183, 188))	('SHMT', 'Gene', '6470', (65, 69))	('SHMT', 'Gene', '6470', (183, 187))	('colorectal cancer', 'Disease', 'MESH:D015179', (43, 60))	('low folate intake', 'Phenotype', 'HP:0100507', (146, 163))
613842	30099693	Inadequate folate intake or deficiency, as measured by serum levels, may increase risk for cancer, including cancers of the head and neck, oral cavity and pharynx, esophagus, pancreatic, bladder, and cervix.	('Inadequate', 'NegReg', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('oral cavity', 'Disease', (139, 150))	('bladder', 'Disease', (187, 194))	('cervix', 'Disease', (200, 206))	('folate', 'Chemical', 'MESH:D005492', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('pancreatic', 'Disease', 'MESH:D010195', (175, 185))	('deficiency', 'Var', (28, 38))	('Inadequate folate intake', 'Phenotype', 'HP:0100507', (0, 24))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('cancer', 'Disease', (109, 115))	('pancreatic', 'Disease', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophagus', 'Disease', (164, 173))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
613851	30099693	Finally, it is important to note that dozens of enzymes affect the efficiency of folate-related metabolic pathways, and polymorphisms in these enzymes may alter substrate availability of folate and/or other nutrients as well as gene expression.	('affect', 'Reg', (56, 62))	('gene', 'MPA', (228, 232))	('polymorphisms', 'Var', (120, 133))	('folate-related metabolic pathways', 'Pathway', (81, 114))	('efficiency', 'MPA', (67, 77))	('folate', 'Chemical', 'MESH:D005492', (187, 193))	('substrate availability of folate', 'MPA', (161, 193))	('alter', 'Reg', (155, 160))	('folate', 'Chemical', 'MESH:D005492', (81, 87))
613926	29915168	Our results indicated that high dose CCRT was significantly associated with higher OS (P=0.026) and PFS (P=0.037) compared with low-dose CCRT.	('OS', 'Chemical', '-', (83, 85))	('CR', 'Chemical', '-', (138, 140))	('high dose', 'Var', (27, 36))	('PFS', 'CPA', (100, 103))	('CR', 'Chemical', '-', (38, 40))	('higher', 'PosReg', (76, 82))
613927	29915168	Compared with the excessive-dose group, high-dose CCRT tended to prolong the OS (P=0.033), as shown in Figure 4.	('CR', 'Chemical', '-', (51, 53))	('prolong', 'PosReg', (65, 72))	('OS', 'Chemical', '-', (77, 79))	('high-dose CCRT', 'Var', (40, 54))
613969	29915168	In recent years, due to the application of 3DRT and IMRT, higher doses can be administered, and greater biological effects can be achieved at the tumor area.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('3DRT', 'Var', (43, 47))	('tumor', 'Disease', (146, 151))	('biological', 'MPA', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
613988	29915168	In addition, compared with a standard or excessive CCRT dose, high-dose CCRT generates more favorable survival outcomes.	('CR', 'Chemical', '-', (52, 54))	('CR', 'Chemical', '-', (73, 75))	('high-dose', 'Var', (62, 71))	('survival', 'CPA', (102, 110))
613991	29568917	In specific, the functional and clinical significance of EPB41L3 in esophageal squamous cell carcinoma (ESCC) has not been explored to date.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('EPB41L3', 'Var', (57, 64))	('esophageal squamous cell carcinoma', 'Disease', (68, 102))	('si', 'Chemical', '-', (41, 43))	('SCC', 'Gene', (105, 108))	('SCC', 'Gene', '6317', (105, 108))
613995	29568917	Notably, patients with higher EPB41L3 expression had markedly higher overall survival rates compared with patients with lower EPB41L3 expression.	('EPB41L3', 'Var', (30, 37))	('patients', 'Species', '9606', (9, 17))	('si', 'Chemical', '-', (44, 46))	('si', 'Chemical', '-', (140, 142))	('higher', 'PosReg', (62, 68))	('patients', 'Species', '9606', (106, 114))	('overall', 'CPA', (69, 76))
613996	29568917	In summary, the present results suggest that EPB41L3 may be a tumor suppressor gene in ESCC development, representing a potential therapeutic target and a prognostic indicator for ESCC.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('SCC', 'Gene', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('SCC', 'Gene', '6317', (181, 184))	('EPB41L3', 'Var', (45, 52))	('SCC', 'Gene', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
614002	29568917	TSGs can be inactivated by both genetic and epigenetic mechanisms.	('epigenetic', 'Var', (44, 54))	('TSG', 'Gene', '57045', (0, 3))	('TSG', 'Gene', (0, 3))
614003	29568917	Genetic deletions and point mutations disrupt TSG functions, and epigenetic mechanisms, including CpG island promoter methylation and histone modifications, frequently lead to the loss of TSG functions and are involved in tumor development and progression.	('TSG', 'Gene', '57045', (188, 191))	('point mutations', 'Var', (22, 37))	('disrupt', 'NegReg', (38, 45))	('histone', 'Protein', (134, 141))	('TSG', 'Gene', (46, 49))	('loss', 'NegReg', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('involved', 'Reg', (210, 218))	('CpG island promoter methylation', 'Protein', (98, 129))	('TSG', 'Gene', '57045', (46, 49))	('TSG', 'Gene', (188, 191))	('tumor', 'Disease', (222, 227))	('si', 'Chemical', '-', (251, 253))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))
614004	29568917	The aberrant methylation of CpG islands leads to gene silencing, resulting in TSG inactivation, which can increase the rate of tumor formation by disabling multiple normal cellular processes, such as apoptosis and cell cycle progression.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('si', 'Chemical', '-', (54, 56))	('disabling', 'NegReg', (146, 155))	('tumor', 'Disease', (127, 132))	('methylation', 'Var', (13, 24))	('cell cycle progression', 'CPA', (214, 236))	('TSG', 'Gene', (78, 81))	('si', 'Chemical', '-', (206, 208))	('TSG', 'Gene', '57045', (78, 81))	('aberrant methylation', 'Var', (4, 24))	('increase', 'PosReg', (106, 114))	('inactivation', 'NegReg', (82, 94))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('si', 'Chemical', '-', (232, 234))	('apoptosis', 'CPA', (200, 209))	('gene', 'MPA', (49, 53))
614005	29568917	In breast cancer and renal clear cell carcinoma, methylation of erythrocyte membrane protein band 4.1 like 3 (EPB41L3) disables its tumor suppressive functions, suggesting that this gene is a potential example of TSG inactivation in human cancers.	('human', 'Species', '9606', (233, 238))	('tumor', 'Disease', (132, 137))	('si', 'Chemical', '-', (145, 147))	('erythrocyte membrane protein band 4.1 like 3', 'Gene', (64, 108))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancers', 'Disease', (239, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('TSG', 'Gene', '57045', (213, 216))	('erythrocyte membrane protein band 4.1 like 3', 'Gene', '23136', (64, 108))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('EPB41L3', 'Gene', (110, 117))	('TSG', 'Gene', (213, 216))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (21, 47))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('renal clear cell carcinoma', 'Disease', (21, 47))	('breast cancer', 'Disease', (3, 16))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('disables', 'NegReg', (119, 127))	('methylation', 'Var', (49, 60))
614010	29568917	Our subsequent study revealed that EPB41L3 suppressed tumor cell invasion and inhibited matrix metallopeptidase (MMP)2 and MMP9 expression in ESCC cells.	('SCC', 'Gene', (143, 146))	('matrix metallopeptidase (MMP)2', 'Gene', '4313', (88, 118))	('inhibited', 'NegReg', (78, 87))	('si', 'Chemical', '-', (134, 136))	('SCC', 'Gene', '6317', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('EPB41L3', 'Var', (35, 42))	('matrix metallopeptidase (MMP)2', 'Gene', (88, 118))	('expression', 'MPA', (128, 138))	('si', 'Chemical', '-', (69, 71))	('tumor', 'Disease', (54, 59))	('MMP9', 'Gene', '4318', (123, 127))	('MMP9', 'Gene', (123, 127))	('suppressed', 'NegReg', (43, 53))
614011	29568917	However, the underlying mechanism by which EPB41L3 displays a tumor suppressive role has not been fully elucidated.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('EPB41L3', 'Var', (43, 50))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('si', 'Chemical', '-', (75, 77))
614018	29568917	The results suggested that EPB41L3 may be a potential tumor suppressor and prognostic indicator in ESCC.	('SCC', 'Gene', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('SCC', 'Gene', '6317', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('EPB41L3', 'Var', (27, 34))	('tumor', 'Disease', (54, 59))
614025	29568917	For further analysis, '-' and '+' were considered as low expression, while '++' and '+++' as high expression.	('si', 'Chemical', '-', (42, 44))	('si', 'Chemical', '-', (17, 19))	("'+'", 'Var', (30, 33))	('si', 'Chemical', '-', (104, 106))	('si', 'Chemical', '-', (63, 65))	("'++'", 'Var', (75, 79))
614065	29568917	The siRNA with the highest knockdown efficiency was selected for subsequent experiments (sense, GCUGCGAAUAAACAGAUUUTT and antisense, AAAUCUGUUUAUUCGCAGCTT).	('knockdown', 'Var', (27, 36))	('antisense', 'Var', (122, 131))	('si', 'Chemical', '-', (4, 6))
614068	29568917	KYSE-519 cells transfected with siRNA-EPB41L3 or the negative control siRNA were termed si-510-epb and si-510-nc respectively.	('si-510-nc', 'Var', (103, 112))	('si', 'Chemical', '-', (32, 34))	('si', 'Chemical', '-', (88, 90))	('KYSE-519', 'CellLine', 'CVCL:V775', (0, 8))	('si', 'Chemical', '-', (103, 105))	('si', 'Chemical', '-', (70, 72))	('siRNA-EPB41L3', 'Var', (32, 45))	('si-510-epb', 'Var', (88, 98))
614103	29568917	If the downregulation of EPB41L3 was due to methylation, treatment with 5-aza-2-deoxycytidine would be expected to increase EPB41L3 expression.	('methylation', 'Var', (44, 55))	('si', 'Chemical', '-', (138, 140))	('increase', 'PosReg', (115, 123))	('EPB41L3', 'Gene', (25, 32))	('downregulation', 'NegReg', (7, 21))	('EPB41L3', 'Gene', (124, 131))	('expression', 'MPA', (132, 142))	('5-aza-2-deoxycytidine', 'Chemical', 'MESH:D000077209', (72, 93))
614105	29568917	Furthermore, western blotting confirmed restoration of EPB41L3 protein expression in KYSE-150 and KYSE-510 (Fig.	('expression', 'MPA', (71, 81))	('si', 'Chemical', '-', (77, 79))	('protein', 'Protein', (63, 70))	('KYSE-510', 'CellLine', 'CVCL:1354', (98, 106))	('EPB41L3', 'Gene', (55, 62))	('KYSE-510', 'Var', (98, 106))
614113	29568917	By contrast, the transfection of EPB41L3 siRNA in KYSE-510 cells resulted in increased cell proliferation compared with control cells (P<0.05; Fig.	('EPB41L3', 'Var', (33, 40))	('KYSE-510', 'CellLine', 'CVCL:1354', (50, 58))	('cell proliferation', 'CPA', (87, 105))	('si', 'Chemical', '-', (41, 43))	('increased', 'PosReg', (77, 86))
614116	29568917	Collectively, these results indicated that EPB41L3 inhibited the growth of ESCC cells in vitro.	('growth of', 'CPA', (65, 74))	('EPB41L3', 'Var', (43, 50))	('SCC', 'Gene', (76, 79))	('SCC', 'Gene', '6317', (76, 79))	('inhibited', 'NegReg', (51, 60))
614118	29568917	KYSE-510 cells transfected with siRNA-EPB41L3 or control siRNA were termed si-510-epb or si-510-nc, respectively.	('si', 'Chemical', '-', (57, 59))	('si', 'Chemical', '-', (32, 34))	('si', 'Chemical', '-', (89, 91))	('KYSE-510', 'CellLine', 'CVCL:1354', (0, 8))	('si-510-nc', 'Var', (89, 98))	('siRNA-EPB41L3', 'Var', (32, 45))	('si', 'Chemical', '-', (75, 77))
614119	29568917	To further examine the role of EPB41L3 in tumor growth in vivo, tumor xenografts were generated in mice by injecting vec-510-epb, vec-510-nc, si-510-epb and si-510-nc cells (four nude mice per group).	('mice', 'Species', '10090', (99, 103))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (42, 47))	('vec-510-epb', 'Var', (117, 128))	('si', 'Chemical', '-', (157, 159))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('si-510-nc', 'Var', (157, 166))	('nude mice', 'Species', '10090', (179, 188))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('mice', 'Species', '10090', (184, 188))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('si', 'Chemical', '-', (142, 144))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('si-510-epb', 'Var', (142, 152))	('vec-510-nc', 'Var', (130, 140))
614124	29568917	The group injected with vec-510-epb cells formed significantly smaller tumors compared with the group injected with the control vec-510-nc cells (Fig.	('smaller', 'NegReg', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('vec-510-epb cells', 'Var', (24, 41))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('si', 'Chemical', '-', (49, 51))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
614125	29568917	The group injected with si-510-EPB cells formed significantly larger tumors compared with the group injected with the control si-510-NC cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('si', 'Chemical', '-', (126, 128))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('si', 'Chemical', '-', (48, 50))	('si-510-EPB cells', 'Var', (24, 40))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('si', 'Chemical', '-', (24, 26))	('larger', 'PosReg', (62, 68))
614128	29568917	Compared with the control group, KYSE-150 and KYSE-510 cells overexpressing EPB41L3 had significantly higher apoptotic rates compared with cells transfected with control plasmid (20.3 vs. 2.9%, and 19.9 vs. 5.2%, respectively) (Fig.	('KYSE-510', 'CellLine', 'CVCL:1354', (46, 54))	('si', 'Chemical', '-', (71, 73))	('si', 'Chemical', '-', (88, 90))	('higher', 'PosReg', (102, 108))	('apoptotic rates', 'CPA', (109, 124))	('EPB41L3', 'Var', (76, 83))
614131	29568917	Then, the expression levels of caspase-8, caspase-9 and caspase-3 were detected in KYSE-510 cells following EPB41L3 knockdown by siRNA.	('si', 'Chemical', '-', (16, 18))	('expression levels', 'MPA', (10, 27))	('si', 'Chemical', '-', (129, 131))	('caspase-3', 'Gene', '836', (56, 65))	('caspase-8', 'Gene', (31, 40))	('knockdown', 'Var', (116, 125))	('caspase-9', 'Gene', '842', (42, 51))	('caspase-8', 'Gene', '841', (31, 40))	('EPB41L3', 'Gene', (108, 115))	('KYSE-510', 'CellLine', 'CVCL:1354', (83, 91))	('caspase-3', 'Gene', (56, 65))	('caspase-9', 'Gene', (42, 51))
614132	29568917	The results demonstrated that expression of caspase-8, caspase-9 and caspase-3 was markedly decreased following EPB41L3 knockdown compared with control cells (Fig.	('EPB41L3', 'Gene', (112, 119))	('caspase-9', 'Gene', (55, 64))	('expression', 'MPA', (30, 40))	('caspase-3', 'Gene', '836', (69, 78))	('caspase-8', 'Gene', '841', (44, 53))	('knockdown', 'Var', (120, 129))	('caspase-8', 'Gene', (44, 53))	('decreased', 'NegReg', (92, 101))	('caspase-3', 'Gene', (69, 78))	('caspase-9', 'Gene', '842', (55, 64))	('si', 'Chemical', '-', (36, 38))
614137	29568917	The results demonstrated that overexpression of EPB41L3 decreased the protein expression levels of CDK1 and CyclinB1 in vec-150-epb and vec-510-epb cells, compared with their respective controls (Fig.	('si', 'Chemical', '-', (84, 86))	('si', 'Chemical', '-', (40, 42))	('CyclinB1', 'Gene', '891', (108, 116))	('CDK1', 'Gene', (99, 103))	('decreased', 'NegReg', (56, 65))	('CDK1', 'Gene', '983', (99, 103))	('EPB41L3', 'Var', (48, 55))	('CyclinB1', 'Gene', (108, 116))	('protein expression levels', 'MPA', (70, 95))
614139	29568917	The expression levels of CDK1 and CyclinB1 were significantly increased in the knockdown cells compared with control cells (Fig.	('expression levels', 'MPA', (4, 21))	('increased', 'PosReg', (62, 71))	('CyclinB1', 'Gene', '891', (34, 42))	('si', 'Chemical', '-', (48, 50))	('CDK1', 'Gene', (25, 29))	('CDK1', 'Gene', '983', (25, 29))	('CyclinB1', 'Gene', (34, 42))	('si', 'Chemical', '-', (10, 12))	('knockdown', 'Var', (79, 88))
614140	29568917	Together with the flow cytometry results, these data suggested that inhibition of CDK1/CyclinB1 might be the main mechanism of the G2/M arrest induced by EPB41L3.	('EPB41L3', 'Var', (154, 161))	('CDK1', 'Gene', '983', (82, 86))	('CDK1', 'Gene', (82, 86))	('G2/M arrest', 'CPA', (131, 142))	('CyclinB1', 'Gene', '891', (87, 95))	('inhibition', 'NegReg', (68, 78))	('CyclinB1', 'Gene', (87, 95))
614150	29568917	These findings revealed that EPB41L3 may have the potential to serve as a prognosis predictor in ESCC.	('si', 'Chemical', '-', (80, 82))	('SCC', 'Gene', '6317', (98, 101))	('EPB41L3', 'Var', (29, 36))	('SCC', 'Gene', (98, 101))
614159	29568917	EPB41L3 has been demonstrated to be partly silenced due to hypermethylation.	('si', 'Chemical', '-', (43, 45))	('hypermethylation', 'Var', (59, 75))	('EPB41L3', 'Gene', (0, 7))
614162	29568917	Aberrant DNA methylation is one of the best-characterized epigenetic modifications, contributing to tumor initiation and progression.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Aberrant DNA methylation', 'Var', (0, 24))	('tumor initiation', 'Disease', (100, 116))	('contributing', 'Reg', (84, 96))	('si', 'Chemical', '-', (128, 130))	('tumor initiation', 'Disease', 'MESH:D009369', (100, 116))
614164	29568917	The present data provided evidence that EPB41L3 expression was downregulated in ESCC cells due to promoter methylation.	('si', 'Chemical', '-', (54, 56))	('promoter methylation', 'Var', (98, 118))	('SCC', 'Gene', '6317', (81, 84))	('expression', 'MPA', (48, 58))	('downregulated', 'NegReg', (63, 76))	('SCC', 'Gene', (81, 84))	('EPB41L3', 'Gene', (40, 47))
614169	29568917	DNA methylation provides an alternative way for tumor suppressor gene function loss.	('loss', 'NegReg', (79, 83))	('tumor', 'Disease', (48, 53))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
614170	29568917	Having detected EPB41L3 methylation in ESCC cells, the present study aimed to explore the mechanisms underlying the role of EPB41L3 as a tumor suppressor.	('detected', 'Reg', (7, 15))	('SCC', 'Gene', '6317', (40, 43))	('tumor', 'Disease', (137, 142))	('methylation', 'Var', (24, 35))	('EPB41L3', 'Var', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('EPB41L3', 'Gene', (16, 23))	('SCC', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
614175	29568917	Previous study has revealed that apoptosis in MCF-7 cells was primarily associated with the activation of Caspase-8, and inhibition of this activation blocked the ability of EPB41L3 to induce cell death in MCF-7.	('si', 'Chemical', '-', (39, 41))	('apoptosis', 'CPA', (33, 42))	('blocked', 'NegReg', (151, 158))	('activation', 'PosReg', (92, 102))	('cell death', 'CPA', (192, 202))	('MCF-7', 'CellLine', 'CVCL:0031', (206, 211))	('MCF-7', 'CellLine', 'CVCL:0031', (46, 51))	('inhibition', 'Var', (121, 131))	('Caspase-8', 'Gene', '841', (106, 115))	('Caspase-8', 'Gene', (106, 115))
614179	29568917	By contrast, EPB41L3 knockdown by siRNA resulted in the opposite effects.	('knockdown', 'Var', (21, 30))	('EPB41L3', 'Gene', (13, 20))	('si', 'Chemical', '-', (34, 36))	('si', 'Chemical', '-', (60, 62))
614180	29568917	Kuns et al reported that, during pregnancy, the overexpression of EPB41L3 results in reduced CyclinA expression and Rb phosphorylation, which is accompanied by decreased tyrosine kinase receptor ErbB2 phosphorylation, causing the mammary epithelial cells to be arrested in the G1 phase.	('Rb', 'Chemical', 'MESH:D012413', (116, 118))	('CyclinA', 'Gene', (93, 100))	('decreased tyrosine', 'Phenotype', 'HP:0500133', (160, 178))	('si', 'Chemical', '-', (174, 176))	('Rb phosphorylation', 'MPA', (116, 134))	('ErbB2', 'Gene', (195, 200))	('EPB41L3', 'Var', (66, 73))	('phosphorylation', 'MPA', (201, 216))	('CyclinA', 'Gene', '890', (93, 100))	('si', 'Chemical', '-', (58, 60))	('overexpression', 'PosReg', (48, 62))	('decreased', 'NegReg', (160, 169))	('ErbB2', 'Gene', '2064', (195, 200))	('si', 'Chemical', '-', (107, 109))	('reduced', 'NegReg', (85, 92))	('si', 'Chemical', '-', (221, 223))
614187	29568917	The present findings indicate that ectopic expression of EPB41L3 may inhibit cell proliferation by upregulating apoptosis and causing G2/M phase arrest.	('causing', 'Reg', (126, 133))	('EPB41L3', 'Gene', (57, 64))	('G2/M phase arrest', 'CPA', (134, 151))	('apoptosis', 'CPA', (112, 121))	('si', 'Chemical', '-', (129, 131))	('inhibit', 'NegReg', (69, 76))	('si', 'Chemical', '-', (118, 120))	('si', 'Chemical', '-', (49, 51))	('upregulating', 'PosReg', (99, 111))	('cell proliferation', 'CPA', (77, 95))	('ectopic expression', 'Var', (35, 53))
614188	29568917	To date, several genes have been reported to be hypermethylated in ESCC, including cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16INK4a.	('cyclin-dependent kinase inhibitor 2A', 'Gene', (83, 119))	('CDKN2A', 'Gene', '1029', (121, 127))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (83, 119))	('SCC', 'Gene', '6317', (68, 71))	('p16INK4a', 'Gene', (129, 137))	('CDKN2A', 'Gene', (121, 127))	('p16INK4a', 'Gene', '1029', (129, 137))	('SCC', 'Gene', (68, 71))	('hypermethylated', 'Var', (48, 63))
614190	29568917	Recent study has focused on the correlation of epigenetic changes and ESCC patient survival.	('SCC', 'Gene', (71, 74))	('patient', 'Species', '9606', (75, 82))	('SCC', 'Gene', '6317', (71, 74))	('epigenetic changes', 'Var', (47, 65))
614195	29568917	Survival analysis revealed that patients with higher expression of EPB41L3 had improved prognosis.	('patients', 'Species', '9606', (32, 40))	('prognosis', 'CPA', (88, 97))	('improved', 'PosReg', (79, 87))	('si', 'Chemical', '-', (14, 16))	('si', 'Chemical', '-', (59, 61))	('si', 'Chemical', '-', (94, 96))	('EPB41L3', 'Var', (67, 74))
614198	29568917	These results indicate that EPB41L3 has a significant correlation with tumor progression.	('si', 'Chemical', '-', (84, 86))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('si', 'Chemical', '-', (42, 44))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('EPB41L3', 'Var', (28, 35))	('tumor', 'Disease', (71, 76))
614199	29568917	Through a tissue microarray, the current study revealed the clinical importance of EPB41L3 in ESCC patients, which may have the potential to be prognostic indicator.	('SCC', 'Gene', (95, 98))	('SCC', 'Gene', '6317', (95, 98))	('EPB41L3', 'Var', (83, 90))	('patients', 'Species', '9606', (99, 107))
614203	29568917	Furthermore, because chemotherapy and radiation remain important in ESCC treatment, predictive indicators may be critical for identifying patients who may benefit from molecular targeted agents or are more sensitive to radiotherapy.	('molecular targeted', 'Var', (168, 186))	('si', 'Chemical', '-', (209, 211))	('SCC', 'Gene', (69, 72))	('SCC', 'Gene', '6317', (69, 72))	('patients', 'Species', '9606', (138, 146))
614204	29568917	Further studies are warranted to probe the clinical significance of EPB41L3 in ESCC.	('SCC', 'Gene', '6317', (80, 83))	('si', 'Chemical', '-', (52, 54))	('EPB41L3', 'Var', (68, 75))	('SCC', 'Gene', (80, 83))
614205	29568917	In summary, low levels of EPB41L3 may be an unfavorable indicator of ESCC prognosis.	('si', 'Chemical', '-', (80, 82))	('SCC', 'Gene', (70, 73))	('EPB41L3', 'Var', (26, 33))	('SCC', 'Gene', '6317', (70, 73))
614207	29568917	Detection of the tumor EPB41L3 methylation status may aid in predicting prognosis in patients with ESCC.	('EPB41L3', 'Gene', (23, 30))	('SCC', 'Gene', (100, 103))	('tumor', 'Disease', (17, 22))	('si', 'Chemical', '-', (78, 80))	('SCC', 'Gene', '6317', (100, 103))	('patients', 'Species', '9606', (85, 93))	('methylation', 'Var', (31, 42))	('aid', 'Reg', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
614213	28418888	Inactivation of the PI3K/AKT pathway with specific inhibitors, or with PTEN overexpression, resulted in reversed cadherin switching and inhibited cancer cell motility.	('AKT', 'Gene', (25, 28))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('inhibited', 'NegReg', (136, 145))	('PTEN', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (71, 75))	('AKT', 'Gene', '207', (25, 28))	('reversed', 'Reg', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cadherin', 'Protein', (113, 121))	('Inactivation', 'Var', (0, 12))
614218	28418888	Each of these events is attributed, at least in part, to the acquisition of genetic alterations in the tumor cells.	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('genetic alterations', 'Var', (76, 95))
614223	28418888	LY294002 and wortmannin are potent PI3K inhibitors that are commonly used in laboratory and preclinical studies but have been precluded from clinical use due to instability, poor solubility and/or high toxicity.	('LY294002', 'Var', (0, 8))	('toxicity', 'Disease', 'MESH:D064420', (202, 210))	('clinical', 'Species', '191496', (141, 149))	('toxicity', 'Disease', (202, 210))	('PI3K', 'Enzyme', (35, 39))	('wortmannin', 'Chemical', 'MESH:D000077191', (13, 23))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('clinical', 'Species', '191496', (95, 103))
614225	28418888	Moreover, because increased invasiveness may be conferred by EMT during which epithelial markers are usually downregulated while mesenchymal markers are upregulated, we also examined the expression levels of EMT markers including E-cadherin and N-cadherin in ESCC cells (including the I3 cells), and determined whether PI3K/AKT inhibition by LY294002 and wortmannin could reverse the EMT program.	('E-cadherin', 'Gene', (230, 240))	('invasiveness', 'CPA', (28, 40))	('wortmannin', 'Chemical', 'MESH:D000077191', (355, 365))	('downregulated', 'NegReg', (109, 122))	('AKT', 'Gene', (324, 327))	('LY294002', 'Var', (342, 350))	('LY294002', 'Chemical', 'MESH:C085911', (342, 350))	('upregulated', 'PosReg', (153, 164))	('N-cadherin', 'Gene', (245, 255))	('E-cadherin', 'Gene', '999', (230, 240))	('AKT', 'Gene', '207', (324, 327))	('N-cadherin', 'Gene', '1000', (245, 255))
614226	28418888	The KYSE410-I3 and KYSE510-I3 sublines showed significantly higher invasive potential (Figure 1A), and enhanced EMT as indicated by marked decrease in E-cadherin and increase in N-cadherin expression (Figure 1B), compared with their respective parental ESCC cell lines, although no significant difference in morphology was observed (Figure 1C).	('KYSE510-I3', 'Var', (19, 29))	('N-cadherin', 'Gene', (178, 188))	('higher', 'PosReg', (60, 66))	('increase', 'PosReg', (166, 174))	('KYSE410-I3', 'Var', (4, 14))	('expression', 'MPA', (189, 199))	('enhanced', 'PosReg', (103, 111))	('N-cadherin', 'Gene', '1000', (178, 188))	('E-cadherin', 'Gene', (151, 161))	('invasive potential', 'CPA', (67, 85))	('EMT', 'CPA', (112, 115))	('E-cadherin', 'Gene', '999', (151, 161))	('decrease', 'NegReg', (139, 147))
614234	28418888	Treatment with a low concentration (5 muM) of LY294002 or wortmannin, which had no significant inhibitory effects on cell proliferation of these cells within 24 hours, also markedly inhibited ESCC cell invasion (Figure 3B).	('wortmannin', 'Chemical', 'MESH:D000077191', (58, 68))	('LY294002', 'Var', (46, 54))	('ESCC cell invasion', 'CPA', (192, 210))	('inhibited', 'NegReg', (182, 191))	('LY294002', 'Chemical', 'MESH:C085911', (46, 54))
614239	28418888	Since our results showed that PI3K/AKT inhibition reduced the migration and invasive potential of esophageal cancer cells in vitro (Figure 3), we evaluated the efficacy of PI3K/AKT blockade in inhibiting metastasis of esophageal cancer cells in vivo.	('inhibition', 'Var', (39, 49))	('migration', 'CPA', (62, 71))	('AKT', 'Gene', (35, 38))	('AKT', 'Gene', '207', (177, 180))	('metastasis', 'CPA', (204, 214))	('AKT', 'Gene', (177, 180))	('esophageal cancer', 'Disease', (98, 115))	('reduced', 'NegReg', (50, 57))	('esophageal cancer', 'Disease', (218, 235))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('AKT', 'Gene', '207', (35, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))	('inhibiting', 'NegReg', (193, 203))
614263	28418888	Our immunohistochemical evaluation of primary ESCC showed no significant correlation between p-AKT nuclear expression and pathological stage, which was consistent with what was described in two recent studies reporting that low p-AKT alone or concurrent high EGFR and low p-AKT expression is associated with better outcome in esophageal cancer patients who received chemotherapy, but p-AKT alone may not be an ideal predictor of survival for patients without chemotherapy.	('better', 'PosReg', (308, 314))	('AKT', 'Gene', (230, 233))	('high', 'Var', (254, 258))	('low', 'NegReg', (224, 227))	('AKT', 'Gene', '207', (95, 98))	('expression', 'MPA', (278, 288))	('patients', 'Species', '9606', (442, 450))	('EGFR', 'Gene', '1956', (259, 263))	('AKT', 'Gene', (386, 389))	('AKT', 'Gene', (274, 277))	('AKT', 'Gene', '207', (230, 233))	('esophageal cancer', 'Disease', 'MESH:D004938', (326, 343))	('patients', 'Species', '9606', (344, 352))	('low', 'NegReg', (268, 271))	('esophageal cancer', 'Disease', (326, 343))	('AKT', 'Gene', '207', (386, 389))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('AKT', 'Gene', '207', (274, 277))	('AKT', 'Gene', (95, 98))	('EGFR', 'Gene', (259, 263))
614394	27081034	PRSS8 methylation and its significance in esophageal squamous cell carcinoma Esophageal cancer is one of the most common cancers worldwide, and the incidence and mortality is increasing rapidly in recent years in China, but the underlying mechanisms are largely unclear.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (42, 76))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('carcinoma Esophageal cancer', 'Phenotype', 'HP:0011459', (67, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('esophageal squamous cell carcinoma', 'Disease', (42, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('methylation', 'Var', (6, 17))	('Esophageal cancer', 'Disease', (77, 94))	('PRSS8', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('PRSS8', 'Gene', '5652', (0, 5))
614398	27081034	Methylation specific PCR showed that PRSS8 was hypermethylated in ESCC tissues and ESCC cell lines, which was linked to the downregulation of PRSS8 expression and decreased activities of PRSS8 promoter.	('PRSS8', 'Gene', (142, 147))	('PRSS8', 'Gene', (187, 192))	('PRSS8', 'Gene', (37, 42))	('PRSS8', 'Gene', '5652', (142, 147))	('hypermethylated', 'Var', (47, 62))	('activities', 'MPA', (173, 183))	('PRSS8', 'Gene', '5652', (187, 192))	('PRSS8', 'Gene', '5652', (37, 42))	('decreased', 'NegReg', (163, 172))	('expression', 'MPA', (148, 158))	('downregulation', 'NegReg', (124, 138))
614400	27081034	However, the restored PRSS8 and its tumor inhibition could be reversed by small interfering RNA targeting PRSS8.	('small interfering', 'Var', (74, 91))	('PRSS8', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('PRSS8', 'Gene', (106, 111))	('PRSS8', 'Gene', '5652', (22, 27))	('PRSS8', 'Gene', '5652', (106, 111))	('tumor', 'Disease', (36, 41))
614402	27081034	In conclusion, our finding showed that PRSS8 methylation and its stromal expression had important clinical significance in ESCC.	('PRSS8', 'Gene', (39, 44))	('PRSS8', 'Gene', '5652', (39, 44))	('methylation', 'Var', (45, 56))	('ESCC', 'Disease', (123, 127))
614405	27081034	Numerous studies have shown that the silence or decreased expression of tumor suppressor genes could be one of the major causes of esophageal carcinogenesis, in particular, promoter hypermethylation of tumor suppressor genes leads to silence and downregulation of gene expression, which is linked to tumor formation and progression.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('silence', 'MPA', (234, 241))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (300, 305))	('tumor', 'Disease', (72, 77))	('downregulation', 'NegReg', (246, 260))	('expression', 'MPA', (58, 68))	('promoter hypermethylation', 'Var', (173, 198))	('decreased', 'NegReg', (48, 57))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (131, 156))	('esophageal carcinogenesis', 'Disease', (131, 156))	('gene expression', 'MPA', (264, 279))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
614406	27081034	In the present study, we found that PRSS8 (protease serine 8), a trypsin-like serine peptidase, is hypermethylated in ESCC tissues and ESCC cell lines.	('ESCC', 'Disease', (118, 122))	('hypermethylated', 'Var', (99, 114))	('protease serine 8', 'Gene', '5652', (43, 60))	('PRSS8', 'Gene', (36, 41))	('PRSS8', 'Gene', '5652', (36, 41))	('protease serine 8', 'Gene', (43, 60))
614412	27081034	In prostate cancer, reduced PRSS8 was associated with hypermethylation of PRSS8.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('reduced', 'NegReg', (20, 27))	('PRSS8', 'Gene', '5652', (28, 33))	('PRSS8', 'Gene', (74, 79))	('PRSS8', 'Gene', '5652', (74, 79))	('hypermethylation', 'Var', (54, 70))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('PRSS8', 'Gene', (28, 33))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
614414	27081034	More importantly, the PRSS8 methylation likely played a crucial roles in ESCC, evidenced by restoration of PRSS8 by de-methylation agent and knockdown the restoration of PRSS8 in ESCC cells exhibiting inverse functions.	('knockdown', 'Var', (141, 150))	('played', 'Reg', (47, 53))	('PRSS8', 'Gene', '5652', (107, 112))	('PRSS8', 'Gene', (170, 175))	('PRSS8', 'Gene', '5652', (170, 175))	('de-methylation', 'NegReg', (116, 130))	('PRSS8', 'Gene', (22, 27))	('PRSS8', 'Gene', '5652', (22, 27))	('ESCC', 'Disease', (73, 77))	('PRSS8', 'Gene', (107, 112))
614433	27081034	To determine whether the reduction of PRSS8 in ESCC tissues and cell lines was caused by hypermethylation in PRSS8 promoter region, we used the methylation CpG island prediction software and identified one CpG island in PRSS8 promoter region (-4238 to -4116) (Figure 3A).	('reduction', 'NegReg', (25, 34))	('PRSS8', 'Gene', (220, 225))	('PRSS8', 'Gene', '5652', (38, 43))	('PRSS8', 'Gene', '5652', (220, 225))	('-4238 to -4116', 'Var', (243, 257))	('PRSS8', 'Gene', (109, 114))	('PRSS8', 'Gene', '5652', (109, 114))	('PRSS8', 'Gene', (38, 43))
614434	27081034	Figure 3B showed the examples of PRSS8 promoter region hypermethylation in ESCC tissues (4 clones) and in 2 ESCC cell lines (KYSE450 and EC9706) that showed undetectable PRSS8 level, but another 2 cell lines (TE1 and TE8) exhibited expression of PRSS8 and showed no methylation in PRSS 8 promoter region.	('EC9706', 'CellLine', 'CVCL:E307', (137, 143))	('hypermethylation', 'Var', (55, 71))	('TE1', 'Gene', (209, 212))	('PRSS8', 'Gene', (170, 175))	('PRSS8', 'Gene', (246, 251))	('PRSS8', 'Gene', '5652', (170, 175))	('PRSS 8', 'Gene', '5652', (281, 287))	('PRSS8', 'Gene', (33, 38))	('PRSS8', 'Gene', '5652', (33, 38))	('PRSS8', 'Gene', '5652', (246, 251))	('TE1', 'Gene', '57816', (209, 212))	('PRSS 8', 'Gene', (281, 287))
614435	27081034	To determine whether this CpG island at the PRSS8 promoter region has biological function, we then constructed reporters with truncated PRSS8 promoter region into pGL4 vector (Promega, Madison, WI).	('truncated', 'Var', (126, 135))	('pGL4', 'Gene', '6390', (163, 167))	('PRSS8', 'Gene', (136, 141))	('pGL4', 'Gene', (163, 167))	('PRSS8', 'Gene', (44, 49))	('PRSS8', 'Gene', '5652', (44, 49))	('PRSS8', 'Gene', '5652', (136, 141))
614439	27081034	These findings indicated that PRSS8 promoter methylation in KYSE450 cells significantly impacted promoter reporter activity, compared to TE1 cells that have no methylation, suggested that the CpG island in PRSS8 promoter region indeed has biological functions, and this region hypermethylation might lead to repression of PRSS8 expression.	('TE1', 'Gene', '57816', (137, 140))	('PRSS8', 'Gene', (206, 211))	('PRSS8', 'Gene', '5652', (206, 211))	('promoter reporter activity', 'MPA', (97, 123))	('repression', 'NegReg', (308, 318))	('PRSS8', 'Gene', (322, 327))	('TE1', 'Gene', (137, 140))	('methylation', 'Var', (45, 56))	('PRSS8', 'Gene', (30, 35))	('PRSS8', 'Gene', '5652', (322, 327))	('hypermethylation', 'Var', (277, 293))	('impacted', 'Reg', (88, 96))	('expression', 'MPA', (328, 338))	('PRSS8', 'Gene', '5652', (30, 35))
614450	27081034	In addition, restoration of PRSS8 led to cell cycle arrest at G1 phase in both KYSE450 and EC9706 cell lines, but this G1 phase arrest was attenuated by small interfering RNA, in comparison to the control groups (Table 2).	('cell cycle arrest', 'CPA', (41, 58))	('PRSS8', 'Gene', '5652', (28, 33))	('attenuated', 'NegReg', (139, 149))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (41, 58))	('small interfering RNA', 'Var', (153, 174))	('restoration', 'Var', (13, 24))	('PRSS8', 'Gene', (28, 33))	('EC9706', 'CellLine', 'CVCL:E307', (91, 97))
614458	27081034	Numerous studies have revealed that epigenetic alterations play a pathological role in cancer initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('epigenetic alterations', 'Var', (36, 58))	('pathological role', 'Reg', (66, 83))	('cancer initiation', 'Disease', 'MESH:D009369', (87, 104))	('cancer initiation', 'Disease', (87, 104))
614459	27081034	Indeed, promoter hypermethylation-induced inactivation of tumor suppressor genes has been observed at the multistep process of carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('inactivation', 'NegReg', (42, 54))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('carcinogenesis', 'Disease', (127, 141))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('promoter hypermethylation-induced', 'Var', (8, 41))
614461	27081034	In this study, we have found that PRSS8 promoter was hypermethylated in esophageal squamous cell carcinoma tissues and cancer cell lines, resulting in downregulation of PRSS8 at mRNA and protein levels, which was supported by the GEO Profiles (http://www.ncbi.nlm.nih.gov/geoprofiles/) and Oncomine (http://www.oncomine.com) online data (Supplemental Figure 1) showing that PRSS8 was significantly reduced in esophageal squamous cell carcinoma and adenocarcinoma in comparison with the adjacent non-tumor esophagus.	('PRSS8', 'Gene', '5652', (34, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (499, 504))	('PRSS8', 'Gene', '5652', (169, 174))	('Oncomine', 'Chemical', '-', (290, 298))	('downregulation', 'NegReg', (151, 165))	('oncomine', 'Chemical', '-', (311, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (453, 462))	('PRSS8', 'Gene', (34, 39))	('PRSS8', 'Gene', '5652', (374, 379))	('reduced', 'NegReg', (398, 405))	('tumor', 'Phenotype', 'HP:0002664', (499, 504))	('PRSS8', 'Gene', (169, 174))	('cancer', 'Disease', (119, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (420, 443))	('PRSS8', 'Gene', (374, 379))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('esophageal squamous cell carcinoma tissues', 'Disease', (72, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (434, 443))	('tumor esophagus', 'Phenotype', 'HP:0100751', (499, 514))	('hypermethylated', 'Var', (53, 68))	('esophageal squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D000077277', (409, 462))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', (499, 504))	('esophageal squamous cell carcinoma tissues', 'Disease', 'MESH:D000077277', (72, 114))
614465	27081034	Previous studies have reported that the inactivation of tumor suppressor genes was one of the major causes of esophageal carcinogenesis, and hypermethylation-induced silence of tumor suppressors, such as P16, E-cadherin and selenium-binding protein 1, etc, are frequently observed in esophageal cancers.	('selenium-binding protein 1', 'Gene', (224, 250))	('esophageal cancers', 'Disease', 'MESH:D004938', (284, 302))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('esophageal carcinogenesis', 'Disease', (110, 135))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('selenium-binding protein 1', 'Gene', '8991', (224, 250))	('E-cadherin', 'Gene', (209, 219))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (110, 135))	('cancers', 'Phenotype', 'HP:0002664', (295, 302))	('silence', 'NegReg', (166, 173))	('E-cadherin', 'Gene', '999', (209, 219))	('tumor', 'Disease', (177, 182))	('P16', 'Gene', '1029', (204, 207))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('causes', 'Reg', (100, 106))	('P16', 'Gene', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('inactivation', 'Var', (40, 52))	('esophageal cancers', 'Disease', (284, 302))	('hypermethylation-induced', 'Var', (141, 165))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('observed', 'Reg', (272, 280))
614467	27081034	We used the approaches of restoration by demethylation, truncated promoter reporters, and knockdown by small interfering RNA, to provide direct evidence identifying the critical role of PRSS8 in esophageal cancer.	('esophageal cancer', 'Disease', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('PRSS8', 'Gene', (186, 191))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('demethylation', 'Var', (41, 54))	('PRSS8', 'Gene', '5652', (186, 191))
614468	27081034	More interestingly, the alterations of PRSS8 expression were well correlated with esophageal cancer differentiation and outcomes of the ESCC patients, indicating that PRSS8 might be a useful biomarker for the evaluation of ESCC differentiation and for the prediction of ESCC outcomes.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('correlated', 'Reg', (66, 76))	('alterations', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PRSS8', 'Gene', (39, 44))	('expression', 'MPA', (45, 55))	('PRSS8', 'Gene', '5652', (39, 44))	('PRSS8', 'Gene', (167, 172))	('esophageal cancer', 'Disease', (82, 99))	('PRSS8', 'Gene', '5652', (167, 172))	('patients', 'Species', '9606', (141, 149))
614474	27081034	In conclusion, we have identified that PRSS8 acts as a tumor suppressor gene in ESCC, the hypermethylation of the promoter region leads to repression of expression, and reduced expression is significantly associated with cancer differentiation and survival.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('repression', 'NegReg', (139, 149))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('hypermethylation', 'Var', (90, 106))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Disease', (221, 227))	('reduced', 'NegReg', (169, 176))	('tumor', 'Disease', (55, 60))	('survival', 'CPA', (248, 256))	('PRSS8', 'Gene', (39, 44))	('PRSS8', 'Gene', '5652', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('expression', 'MPA', (153, 163))	('associated', 'Reg', (205, 215))	('expression', 'MPA', (177, 187))	('ESCC', 'Disease', (80, 84))
614476	27081034	Taken together, our findings have demonstrated that PRSS8 methylation and its stromal expression has important clinical significance in esophageal squamous cell carcinoma.	('PRSS8', 'Gene', (52, 57))	('esophageal squamous cell carcinoma', 'Disease', (136, 170))	('PRSS8', 'Gene', '5652', (52, 57))	('methylation', 'Var', (58, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (136, 170))
614488	27081034	The genomic DNA for PRSS8 promoter reporter construction were extracted from the KYSE450 cells having hypermethylation in PRSS8 promoter, or from the TE1 having unmethylation in PRSS8 promoter region, respectively.	('PRSS8', 'Gene', '5652', (20, 25))	('TE1', 'Gene', (150, 153))	('PRSS8', 'Gene', '5652', (122, 127))	('PRSS8', 'Gene', (122, 127))	('PRSS8', 'Gene', (20, 25))	('TE1', 'Gene', '57816', (150, 153))	('hypermethylation', 'Var', (102, 118))	('PRSS8', 'Gene', (178, 183))	('PRSS8', 'Gene', '5652', (178, 183))
614496	27081034	The cells were collected for immunoblotting analysis using the following primary antibodies: anti-PRSS8, anti-P21, anti-Cyclin D1, anti-E-cadherin, anti-snail and anti-Twist (from Cell Signaling Technologies Inc., CA).	('P21', 'Gene', (110, 113))	('snail', 'Gene', (153, 158))	('Cyclin D1', 'Gene', '595', (120, 129))	('E-cadherin', 'Gene', (136, 146))	('E-cadherin', 'Gene', '999', (136, 146))	('PRSS8', 'Gene', (98, 103))	('Cyclin D1', 'Gene', (120, 129))	('P21', 'Gene', '1026', (110, 113))	('PRSS8', 'Gene', '5652', (98, 103))	('snail', 'Gene', '6615', (153, 158))	('anti-Twist', 'Var', (163, 173))
614501	27081034	As reported previously, the KYSE450 and EC9706 cells were seeded in a 100-mm Petri dish, then were treated with DAC or with treatment of DAC and transfection of siR-PRSS8.	('siR-PRSS8', 'Gene', (161, 170))	('DAC', 'Chemical', '-', (137, 140))	('DAC', 'Chemical', '-', (112, 115))	('EC9706', 'CellLine', 'CVCL:E307', (40, 46))	('siR-PRSS8', 'Gene', '5652', (161, 170))	('transfection', 'Var', (145, 157))
614503	27081034	The cells were treated with 30muM of DAC or with the treatment of DAC and transfection of siR-PRSS8.	('transfection', 'Var', (74, 86))	('DAC', 'Chemical', '-', (37, 40))	('DAC', 'Chemical', '-', (66, 69))	('siR-PRSS8', 'Gene', (90, 99))	('siR-PRSS8', 'Gene', '5652', (90, 99))
614521	26933477	Selenium is associated with a reduced risk of esophageal cancer in some studies.	('Selenium', 'Chemical', 'MESH:D012643', (0, 8))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('reduced', 'NegReg', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Selenium', 'Var', (0, 8))
614536	26933477	The Al activity cannot be reported as a concentration because it is produced by neutron reactions with three isotopes; 28Al, 28silicon (Si), and 31Phosphorous (P).	('28silicon', 'Var', (125, 134))	('Al', 'Chemical', 'MESH:D000535', (121, 123))	('31Phosphorous', 'Chemical', '-', (145, 158))	('Si', 'Chemical', 'MESH:D012825', (136, 138))	('31Phosphorous', 'Var', (145, 158))	('Al', 'Chemical', 'MESH:D000535', (4, 6))
614814	28977901	demonstrated that the 5-year survival was significantly lower in ESCC patients with high stathmin than in those with low stathmin, which indicated that stathmin could be used as a marker for ESCC prognosis.	('lower', 'NegReg', (56, 61))	('patients', 'Species', '9606', (70, 78))	('high stathmin', 'Var', (84, 97))	('ESCC', 'Disease', (65, 69))
614833	28977901	After treatment with 2% FBS medium for 6 h, the intermediate filaments of the cells with stathmin overexpression maintained their shape, bearing tension and retaining rigidity; however, most of those of the control cells shrank and disintegrated (Supplementary Figure 3A and 3B).	('FBS', 'Disease', (24, 27))	('shrank', 'CPA', (221, 227))	('shape', 'MPA', (130, 135))	('rigidity', 'Disease', 'MESH:D009127', (167, 175))	('disintegrated', 'CPA', (232, 245))	('FBS', 'Disease', 'MESH:D005198', (24, 27))	('overexpression', 'Var', (98, 112))	('rigidity', 'Phenotype', 'HP:0002063', (167, 175))	('rigidity', 'Disease', (167, 175))	('stathmin', 'Gene', (89, 97))
614834	28977901	In addition, knockdown of KRT17 decreased cell mobility in KYSE 170-STMN1 cells (Supplementary Figure 4A-4C).	('decreased', 'NegReg', (32, 41))	('cell mobility', 'CPA', (42, 55))	('KRT17', 'Gene', '3872', (26, 31))	('knockdown', 'Var', (13, 22))	('KRT17', 'Gene', (26, 31))
614835	28977901	The transcriptome data showed that fibronectin (FN) and adhesion-related molecules were significantly increased in the STMN1 group.	('increased', 'PosReg', (102, 111))	('fibronectin', 'Gene', (35, 46))	('FN', 'Gene', '2335', (48, 50))	('fibronectin', 'Gene', '2335', (35, 46))	('adhesion-related molecules', 'MPA', (56, 82))	('STMN1', 'Var', (119, 124))
614840	28977901	However, the integrinbeta3, 4, and 5 and vinculin and p-vinculin levels did not significantly differ between the STMN1 group and the control group (Supplementary Figure 6A).	('vinculin', 'Gene', '7414', (41, 49))	('vinculin', 'Gene', (41, 49))	('vinculin', 'Gene', '7414', (56, 64))	('vinculin', 'Gene', (56, 64))	('integrinbeta3, 4, and 5', 'Gene', '3690;3691;3693', (13, 36))	('STMN1', 'Var', (113, 118))
614841	28977901	Following knockdown of stathmin by siRNA, the protein levels of integrinalpha5beta1 and FAK were greatly reduced in the KYSE 510 and KYSE 170-STMN1 cells (Figure 8E and 8F).	('FAK', 'Gene', (88, 91))	('FAK', 'Gene', '5747', (88, 91))	('protein levels', 'MPA', (46, 60))	('reduced', 'NegReg', (105, 112))	('stathmin', 'Gene', (23, 31))	('knockdown', 'Var', (10, 19))
614850	28977901	After 49 days, all three mice in the STMN1 group had developed lung metastatic nodules, and two of the three mice injected with control cells had also developed metastatic nodules (Figure 6B).	('lung metastatic nodules', 'CPA', (63, 86))	('mice', 'Species', '10090', (25, 29))	('STMN1', 'Var', (37, 42))	('mice', 'Species', '10090', (109, 113))
614851	28977901	HE staining of the mouse lung tissue revealed that the size of the nodules in the STMN1 group was much larger than that of the control group (Figure 6C and 6D).	('larger', 'PosReg', (103, 109))	('HE', 'Chemical', 'MESH:D006371', (0, 2))	('STMN1 group', 'Var', (82, 93))	('mouse', 'Species', '10090', (19, 24))
614852	28977901	Furthermore, mouse body weight was reduced in the KYSE170-STMN1 metastasis model relative to the control group (P<0.001) (Figure 6A).	('mouse', 'Species', '10090', (13, 18))	('KYSE170-STMN1', 'Var', (50, 63))	('mouse body weight', 'CPA', (13, 30))	('reduced', 'NegReg', (35, 42))
614857	28977901	As shown in Figure 7D, significant increases in stathmin, Ki67 and keratin17 in tumor tissues were observed in the STMN1 group.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('increases', 'PosReg', (35, 44))	('stathmin', 'Protein', (48, 56))	('Ki67', 'Gene', '17345', (58, 62))	('tumor', 'Disease', (80, 85))	('STMN1', 'Var', (115, 120))	('keratin17', 'Protein', (67, 76))	('Ki67', 'Gene', (58, 62))
614861	28977901	The protein and phosphorylation levels of AKT, JNK and mTOR did not significantly differ between the STMN1 group and the control group (Supplementary Figure 5A-5C).	('mTOR', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (55, 59))	('AKT', 'Gene', (42, 45))	('phosphorylation levels', 'MPA', (16, 38))	('STMN1', 'Var', (101, 106))	('JNK', 'Gene', (47, 50))	('AKT', 'Gene', '207', (42, 45))	('JNK', 'Gene', '5599', (47, 50))
614862	28977901	In contrast, the P-ERK level was significantly increased in the STMN1 group compared to that in the control group.	('P-ERK', 'Gene', (17, 22))	('increased', 'PosReg', (47, 56))	('P-ERK', 'Gene', '9451', (17, 22))	('STMN1', 'Var', (64, 69))
614864	28977901	Real-time PCR analysis confirmed that the mRNA level of ERK downstream transcription factors, including FOS, EGR1 and JUN, were increased in the STMN1-group cells (Figure 8B).	('mRNA level', 'MPA', (42, 52))	('ERK', 'Gene', (56, 59))	('increased', 'PosReg', (128, 137))	('FOS', 'Gene', (104, 107))	('EGR1', 'Gene', (109, 113))	('FOS', 'Gene', '2353', (104, 107))	('EGR1', 'Gene', '1958', (109, 113))	('STMN1-group', 'Var', (145, 156))	('JUN', 'MPA', (118, 121))	('ERK', 'Gene', '5594', (56, 59))
614867	28977901	The P-ERK levels were decreased after treatment with AZD8330 for 3 h. The in vitro wound-healing assay showed that the motility of the KYSE 170-STMN1 cells treated with AZD8330 was inhibited compared with that of the DMSO group (Figure 8C and 8D).	('AZD8330', 'Chemical', 'MESH:C581956', (169, 176))	('inhibited', 'NegReg', (181, 190))	('AZD8330', 'Chemical', 'MESH:C581956', (53, 60))	('P-ERK', 'Gene', '9451', (4, 9))	('DMSO', 'Chemical', 'MESH:D004121', (217, 221))	('motility', 'CPA', (119, 127))	('AZD8330', 'Var', (169, 176))	('P-ERK', 'Gene', (4, 9))
614868	28977901	Following knockdown of stathmin by siRNA, the protein levels of integrinalpha5beta1, FAK and P-ERK were greatly reduced in the KYSE 510 and KYSE 170-STMN1 cells (Figure 8E and 8F).	('FAK', 'Gene', (85, 88))	('FAK', 'Gene', '5747', (85, 88))	('P-ERK', 'Gene', (93, 98))	('protein levels', 'MPA', (46, 60))	('stathmin', 'Gene', (23, 31))	('reduced', 'NegReg', (112, 119))	('P-ERK', 'Gene', '9451', (93, 98))	('knockdown', 'Var', (10, 19))
614883	28977901	In neuroblastoma cells, changes in the level of stathmin expression regulate the level of activation of the RhoA/ROCK pathway and consequently modulate changes in microfilaments.	('stathmin', 'Gene', (48, 56))	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('changes', 'Var', (24, 31))	('changes', 'MPA', (152, 159))	('RhoA/ROCK pathway', 'Pathway', (108, 125))	('activation', 'MPA', (90, 100))	('neuroblastoma', 'Disease', 'MESH:D009447', (3, 16))	('modulate', 'Reg', (143, 151))	('neuroblastoma', 'Disease', (3, 16))	('microfilaments', 'MPA', (163, 177))
614886	28977901	We found that the mRNA levels of adhesion-related molecules and FN were significantly increased in the STMN1 group, which suggest that stathmin may exert a strong impact on cell-extracellular matrix adhesion.	('cell-extracellular matrix adhesion', 'CPA', (173, 207))	('increased', 'PosReg', (86, 95))	('STMN1', 'Var', (103, 108))	('FN', 'Gene', '2335', (64, 66))	('mRNA levels of adhesion-related molecules', 'MPA', (18, 59))	('impact', 'Reg', (163, 169))
614895	28977901	In this study, we found that stathmin promotes invasion, metastasis and adhesion of ESCC cells, and we found that integrinalpha5beta1/FAK protein levels were increased in STMN1 group.	('adhesion', 'CPA', (72, 80))	('FAK', 'Gene', '5747', (134, 137))	('promotes', 'PosReg', (38, 46))	('stathmin', 'Gene', (29, 37))	('invasion', 'CPA', (47, 55))	('metastasis', 'CPA', (57, 67))	('FAK', 'Gene', (134, 137))	('STMN1', 'Var', (171, 176))	('increased', 'PosReg', (158, 167))
614896	28977901	Silencing of FAK by specific siRNA significantly suppressed the adhesion, invasion and migration of KYSE 170-STMN1 cells.	('invasion', 'CPA', (74, 82))	('FAK', 'Gene', '5747', (13, 16))	('migration of KYSE', 'CPA', (87, 104))	('FAK', 'Gene', (13, 16))	('suppressed', 'NegReg', (49, 59))	('adhesion', 'CPA', (64, 72))	('Silencing', 'Var', (0, 9))
614901	28977901	The levels of the ERK downstream transcription factors FOS, JUN, EGR1 were significantly increased in the STMN1 group, which indicated that the overexpression of stathmin increased activation of the ERK pathway.	('JUN', 'MPA', (60, 63))	('ERK', 'Gene', (18, 21))	('STMN1', 'Var', (106, 111))	('FOS', 'Gene', (55, 58))	('levels of', 'MPA', (4, 13))	('EGR1', 'Gene', '1958', (65, 69))	('ERK', 'Gene', '5594', (199, 202))	('activation', 'PosReg', (181, 191))	('FOS', 'Gene', '2353', (55, 58))	('increased', 'PosReg', (89, 98))	('ERK', 'Gene', '5594', (18, 21))	('ERK', 'Gene', (199, 202))	('EGR1', 'Gene', (65, 69))
614947	24595008	Variations in the MHC Region Confer Risk to Esophageal Squamous Cell Carcinoma on the Subjects from High-Incidence Area in Northern China The human major histocompatibility complex (MHC) is the most important region in vertebrate genome, and is crucial in innate immunity.	('Esophageal Squamous Cell Carcinoma', 'Disease', (44, 78))	('Risk', 'Reg', (36, 40))	('human', 'Species', '9606', (142, 147))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (44, 78))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('Carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Variations', 'Var', (0, 10))
614948	24595008	Recent studies have demonstrated the possible role of polymorphisms in the MHC region to high risk for esophageal squamous cell carcinoma (ESCC).	('polymorphisms', 'Var', (54, 67))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (103, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal squamous cell carcinoma', 'Disease', (103, 137))	('MHC region', 'Gene', (75, 85))
614949	24595008	Of the 24 promising SNPs analyzed, we identified three independent SNPs in the MHC region associated with ESCC: rs35399661 (P = 6.07E-06, OR = 1.71, 95%CI = 1.36-2.17), rs3763338 (P = 1.62E-05, OR = 0.63, 95%CI = 0.50-0.78) and rs2844695 (P = 7.60E-05, OR = 0.74, 95%CI = 0.64-0.86).	('rs35399661', 'Var', (112, 122))	('ESCC', 'Disease', (106, 110))	('rs3763338', 'Mutation', 'rs3763338', (169, 178))	('rs2844695', 'Mutation', 'rs2844695', (228, 237))	('rs2844695', 'Var', (228, 237))	('rs35399661', 'Mutation', 'rs35399661', (112, 122))	('rs3763338', 'Var', (169, 178))
614951	24595008	Further analyses showed that rs2844695 was preferentially associated with younger ESCC cases (P = 0.009).	('ESCC', 'Disease', (82, 86))	('rs2844695', 'Mutation', 'rs2844695', (29, 38))	('rs2844695', 'Var', (29, 38))
614978	24595008	In brief, after dewaxing, inactivating, endogenous peroxidase activity and blocking cross-reactivity with pre-immune serum, the sections were incubated over night at 4 C with the primary antibodies (antibody for TRIM27 was diluted at 1:150 and the one for HLA-DQA1 was 1:100).	('HLA-DQA1', 'Gene', (256, 264))	('activity', 'MPA', (62, 70))	('TRIM27', 'Gene', (212, 218))	('inactivating', 'Var', (26, 38))	('HLA-DQA1', 'Gene', '3117', (256, 264))	('TRIM27', 'Gene', '5987', (212, 218))
614981	24595008	Since SNP rs17533090 was highly correlated with SNP rs35399661 and could be completely represented by the latter (D' = 1/r2 = 1 in HapMap CHB data), only the rs35399661 locus was kept for further statistical analysis.	('SNP', 'Var', (6, 9))	('rs35399661', 'Mutation', 'rs35399661', (52, 62))	('HapMap CHB', 'Disease', (131, 141))	('SNP', 'Var', (48, 51))	('HapMap CHB', 'Disease', 'None', (131, 141))	('correlated', 'Interaction', (32, 42))	('rs35399661', 'Mutation', 'rs35399661', (158, 168))	('rs17533090', 'Mutation', 'rs17533090', (10, 20))
614982	24595008	Of the 24 promising SNPs analyzed, we identified three independent SNPs in the MHC region that associated with ESCC through CLRA: rs35399661 (P = 6.07E-06, OR = 1.71, 95%CI = 1.35-2.17), rs3763338 (P = 1.62E-05, OR = 0.63, 95%CI = 0.50-0.78) and rs2844695 (P = 7.60E-05, OR = 0.74, 95%CI = 0.64-0.86) (Table 1).	('rs35399661', 'Var', (130, 140))	('ESCC through', 'Disease', (111, 123))	('rs2844695', 'Mutation', 'rs2844695', (246, 255))	('rs2844695', 'Var', (246, 255))	('rs35399661', 'Mutation', 'rs35399661', (130, 140))	('rs3763338', 'Mutation', 'rs3763338', (187, 196))	('rs3763338', 'Var', (187, 196))	('associated', 'Reg', (95, 105))
614983	24595008	The Bonferroni corrected P values for rs35399661, rs3763338 and rs2844695 were 0.021, 0.057 and 0.267, respectively (Table 1).	('rs35399661', 'Var', (38, 48))	('rs3763338', 'Mutation', 'rs3763338', (50, 59))	('rs2844695', 'Mutation', 'rs2844695', (64, 73))	('rs3763338', 'Var', (50, 59))	('rs2844695', 'Var', (64, 73))	('rs35399661', 'Mutation', 'rs35399661', (38, 48))
614985	24595008	Signal I surrounding rs35399661 covers two (HLA-DQA1 and HLA-DRB1) genes (Figure 1); Signal II surrounding rs3763338 covers four (TRIM27, ZNF311, OR2W1 and OR2B3) genes (Figure 2); Signal III surrounding rs2844695 covers two (DPCR1 and C6 or f205) genes (Figure 3).	('rs35399661', 'Var', (21, 31))	('HLA-DRB1', 'Gene', '3123', (57, 65))	('rs2844695', 'Mutation', 'rs2844695', (204, 213))	('rs3763338', 'Mutation', 'rs3763338', (107, 116))	('HLA-DQA1', 'Gene', '3117', (44, 52))	('ZNF311', 'Gene', (138, 144))	('HLA-DRB1', 'Gene', (57, 65))	('rs3763338', 'Var', (107, 116))	('rs2844695', 'Var', (204, 213))	('OR2B3', 'Gene', '442184', (156, 161))	('OR2W1', 'Gene', '26692', (146, 151))	('ZNF311', 'Gene', '282890', (138, 144))	('DPCR1', 'Gene', (226, 231))	('HLA-DQA1', 'Gene', (44, 52))	('OR2W1', 'Gene', (146, 151))	('TRIM27', 'Gene', '5987', (130, 136))	('OR2B3', 'Gene', (156, 161))	('DPCR1', 'Gene', '135656', (226, 231))	('TRIM27', 'Gene', (130, 136))	('rs35399661', 'Mutation', 'rs35399661', (21, 31))
614986	24595008	To further correlate the three promising SNPs identified above with clinicopathological characteristics of ESCC, we performed stratified analyses of rs35399661, rs3763338 and rs2844695 by gender, age, family history, alcohol consumption, smoking status, tumor location, gross type, cancer cell differentiation, regional lymph node metastasis and pathological staging (Tables 2-3).	('rs3763338', 'Var', (161, 170))	('tumor', 'Disease', (254, 259))	('rs35399661', 'Mutation', 'rs35399661', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('alcohol', 'Chemical', 'MESH:D000438', (217, 224))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('cancer', 'Disease', (282, 288))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('rs2844695', 'Mutation', 'rs2844695', (175, 184))	('rs35399661', 'Var', (149, 159))	('rs2844695', 'Var', (175, 184))	('ESCC', 'Disease', (107, 111))	('rs3763338', 'Mutation', 'rs3763338', (161, 170))
614987	24595008	The chi2 test of each subgroup showed the rs2844695 was preferentially associated with younger ESCC cases (P = 0.009, OR = 1.32, 95%CI = 1.07-1.62) (Table 2).	('rs2844695', 'Var', (42, 51))	('ESCC', 'Disease', (95, 99))	('rs2844695', 'Mutation', 'rs2844695', (42, 51))
614988	24595008	To further demonstrated the clinical relevance of the two SNPs showing the association with ESCC, expression of TRIM27 (for rs3763338) and HLA-DQA1 (for rs35399661) proteins in ESCC and the neighboring normal tissues was determined using immunohistochemical analysis (Figure 4).	('ESCC', 'Disease', (92, 96))	('rs35399661', 'Mutation', 'rs35399661', (153, 163))	('for rs3763338', 'Var', (120, 133))	('rs3763338', 'Mutation', 'rs3763338', (124, 133))	('HLA-DQA1', 'Gene', '3117', (139, 147))	('TRIM27', 'Gene', '5987', (112, 118))	('HLA-DQA1', 'Gene', (139, 147))	('TRIM27', 'Gene', (112, 118))
615000	24595008	Compared to many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions _ENREF_21.	('lesions _ENREF_21', 'Var', (134, 151))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
615006	24595008	The presence of HLA-DQ expression in premalignant lesions and on some tumor cells appears to confer an advantage to the host in terms of restricted tumor growth _ENREF_24 and survival _ENREF_24through their role as initiators of CD4+ T helper cell responses against the tumor.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('HLA', 'Gene', (16, 19))	('survival', 'CPA', (175, 183))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('advantage', 'PosReg', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('restricted', 'NegReg', (137, 147))	('presence', 'Var', (4, 12))	('tumor', 'Disease', (270, 275))	('HLA', 'Gene', '3117', (16, 19))
615011	24595008	However, to our knowledge, the association between DPCR1 variations and risk of ESCC has not yet been investigated.	('DPCR1', 'Gene', '135656', (51, 56))	('ESCC', 'Disease', (80, 84))	('DPCR1', 'Gene', (51, 56))	('variations', 'Var', (57, 67))
615015	24595008	Our results demonstrated that rs2844695 was preferentially associated with younger ESCC cases.	('rs2844695', 'Var', (30, 39))	('associated', 'Reg', (59, 69))	('rs2844695', 'Mutation', 'rs2844695', (30, 39))	('ESCC', 'Disease', (83, 87))
615016	24595008	The other factors (gender, age, family history, alcohol consumption, smoking, tumor location, gross type, degree of differentiation, the regional lymph node metastasis and pathological stage) did not significantly alter the effects ofrs35399661 and rs3763338 on the risk to ESCC, indicating that the three SNPs identified as most promising from our study could provide orthologous information to existing clinicophthological covariates.	('ESCC', 'Disease', (274, 278))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('alcohol', 'Chemical', 'MESH:D000438', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ofrs35399661', 'Var', (232, 244))	('rs3763338', 'Mutation', 'rs3763338', (249, 258))	('tumor', 'Disease', (78, 83))	('rs3763338', 'Var', (249, 258))	('rs35399661', 'Mutation', 'rs35399661', (234, 244))
615021	24595008	Furthermore, the percentage of patients expressing HLA-DQA1 is higher for negative family history than positive family history.	('HLA-DQA1', 'Gene', '3117', (51, 59))	('HLA-DQA1', 'Gene', (51, 59))	('patients', 'Species', '9606', (31, 39))	('negative family history', 'Var', (74, 97))	('higher', 'Reg', (63, 69))
615023	24595008	The limitation of the present study is the absence of replication in another independent samples for rs35399661 (HLA-DQA1 genes), rs3763338 (TRIM27 genes) and rs2844695 (DPCR1 genes).	('TRIM27', 'Gene', '5987', (141, 147))	('rs3763338', 'Mutation', 'rs3763338', (130, 139))	('DPCR1', 'Gene', '135656', (170, 175))	('rs2844695', 'Mutation', 'rs2844695', (159, 168))	('TRIM27', 'Gene', (141, 147))	('rs2844695', 'Var', (159, 168))	('rs35399661', 'Mutation', 'rs35399661', (101, 111))	('rs3763338', 'Var', (130, 139))	('HLA-DQA1', 'Gene', '3117', (113, 121))	('DPCR1', 'Gene', (170, 175))	('HLA-DQA1', 'Gene', (113, 121))	('rs35399661', 'Var', (101, 111))
615024	24595008	Interestingly, recent studies have demonstrated that polymorphisms occurred in HLA-DQA1 increase the risk and prognosis to lung squamous cell carcinoma and gastric cancer.	('HLA-DQA1', 'Gene', '3117', (79, 87))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 151))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (123, 151))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('lung squamous cell carcinoma', 'Disease', (123, 151))	('gastric cancer', 'Disease', (156, 170))	('HLA-DQA1', 'Gene', (79, 87))	('increase', 'PosReg', (88, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (156, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (156, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('polymorphisms', 'Var', (53, 66))
615071	20947516	The tumor:nontumor ratios were then calculated using the comparative method (2-DeltaDeltaCt), where Ct = threshold cycle and DeltaDeltaCt = (Ct gene tumor - Ct 18S rRNA tumor) - (Ct gene nontumor - Ct 18S rRNA nontumor), as previously described.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('DeltaDeltaCt', 'Var', (125, 137))
615129	20947516	Patients with high IRS/low miR-375 had the worst prognosis.	('miR-375', 'Gene', (27, 34))	('Patients', 'Species', '9606', (0, 8))	('high IRS/low', 'Var', (14, 26))	('miR-375', 'Gene', '494324', (27, 34))
615130	20947516	Patients with either high IRS/high miR-375 or low IRS/low miR-375 had an intermediate prognosis.	('miR-375', 'Gene', (35, 42))	('low IRS/low', 'Var', (46, 57))	('miR-375', 'Gene', '494324', (58, 65))	('Patients', 'Species', '9606', (0, 8))	('miR-375', 'Gene', '494324', (35, 42))	('miR-375', 'Gene', (58, 65))
615131	20947516	Patients with low IRS/high miR-375 had the best prognosis (Fig.	('miR-375', 'Gene', (27, 34))	('low IRS/high', 'Var', (14, 26))	('miR-375', 'Gene', '494324', (27, 34))	('Patients', 'Species', '9606', (0, 8))
615132	20947516	From the survival curve shown in Figure 3C, we found that the survival curve for the low IRS/low miR-375 superimposed the curve for the high IRS/high miR-375.	('miR-375', 'Gene', '494324', (150, 157))	('low IRS/low', 'Var', (85, 96))	('miR-375', 'Gene', (97, 104))	('miR-375', 'Gene', (150, 157))	('miR-375', 'Gene', '494324', (97, 104))
615139	20947516	In this study, both IRS and miR-375 were significantly associated with cancer-specific mortality only in patients who did not receive any neoadjuvant therapy (NAT -naive) (Figure 4).	('miR-375', 'Gene', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('patients', 'Species', '9606', (105, 113))	('IRS', 'Var', (20, 23))	('cancer', 'Disease', (71, 77))	('associated with', 'Reg', (55, 70))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-375', 'Gene', '494324', (28, 35))
615142	20947516	Similar to what was seen before, either high IRS or low miR-375 was associated with poor survival (P=0.0021 and P=0.032, Kaplan-Meier log rank; Figure 4A-B; respectively).	('poor', 'NegReg', (84, 88))	('miR-375', 'Gene', (56, 63))	('high IRS', 'Var', (40, 48))	('miR-375', 'Gene', '494324', (56, 63))	('low', 'Var', (52, 55))
615214	33395075	Endoscopic images were captured by endoscopes from different vendors in multiple centers, including GIF-H260Z, GIF-HQ290, GIF-XQ260, GIF-Q260, GIF-H260, CF-H290, CF-HQ290, CF-H260, CF-HQ260, CF-Q260, PCF-Q260, PCF-PQ260, Olympus, Japan; EG-2990i, EG29-i10, EG27-i10, EC38-i10, EC-3490, EC-3870, EC-3890, Pentax, Japan; and EG-580RD, EC-L590, Fujifilm, Japan.	('GI', 'Gene', '2770', (133, 135))	('EC38-i10', 'Var', (267, 275))	('EC-3490', 'CellLine', 'CVCL:N412', (277, 284))	('EG-2990i', 'Var', (237, 245))	('GI', 'Gene', '2770', (100, 102))	('EC-3870', 'CellLine', 'CVCL:1X03', (286, 293))	('EG27-i10', 'Var', (257, 265))	('EC-3890', 'CellLine', 'CVCL:5V07', (295, 302))	('GI', 'Gene', '2770', (111, 113))	('CF-H290', 'CellLine', 'CVCL:A555', (153, 160))	('EC-3870', 'Var', (286, 293))	('EC-3490', 'Var', (277, 284))	('CF-HQ260', 'CellLine', 'CVCL:L934', (181, 189))	('CF-HQ290', 'CellLine', 'CVCL:V762', (162, 170))	('H260Z', 'Var', (104, 109))	('H260Z', 'SUBSTITUTION', 'None', (104, 109))	('GI', 'Gene', '2770', (122, 124))	('GI', 'Gene', '2770', (143, 145))
615238	33395075	Table 2 displays the excellent performance of ISRGS in detecting 10 major GI diseases in the multicenter test set, with accuracies ranging from 0.9765 (95% CI, 0.9732-0.9794) to 0.9960 (95% CI, 0.9945-0.9971).	('GI diseases', 'Disease', (74, 85))	('GI diseases', 'Disease', 'MESH:D005767', (74, 85))	('GI disease', 'Phenotype', 'HP:0011024', (74, 84))	('GI diseases', 'Phenotype', 'HP:0011024', (74, 85))	('0.9960', 'Var', (178, 184))
615265	32878338	DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer.	('regulates', 'Reg', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('aberrant', 'Var', (88, 96))	('gene expression', 'MPA', (67, 82))
615277	32878338	In addition, the consumption of agricultural foods that are contaminated with mycotoxin-producing fungi can alter cellular functions, leading to genetic mutations and the onset of cancer.	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('leading to', 'Reg', (134, 144))	('cellular functions', 'CPA', (114, 132))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('alter', 'Reg', (108, 113))	('cancer', 'Disease', (180, 186))	('genetic mutations', 'Var', (145, 162))
615284	32878338	The initiation and progression of cancer is a multi-stage process that occurs from aberrant signaling pathways and is the result of an accumulation in both genetic and epigenetic modifications.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('epigenetic modifications', 'Var', (168, 192))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('accumulation', 'PosReg', (135, 147))	('occurs', 'Reg', (71, 77))
615285	32878338	Among these, DNA methylation is the most dysregulated epigenetic mechanism in cancer and hence, it will be the focus of this review.	('methylation', 'Var', (17, 28))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('DNA methylation', 'Var', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
615292	32878338	Numerous data indicate that aberrant DNA methylation is a hallmark of cancer.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('aberrant', 'Var', (28, 36))	('DNA', 'Protein', (37, 40))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
615293	32878338	Global DNA hypomethylation, due to its association with a loss in genome stability and an increase in genetic mutations, has been recognized as a frequent early event in various cancers.	('genome stability', 'CPA', (66, 82))	('Global DNA', 'Var', (0, 10))	('loss', 'NegReg', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('increase', 'PosReg', (90, 98))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('genetic mutations', 'CPA', (102, 119))	('cancers', 'Disease', (178, 185))
615294	32878338	Similarly, the hypermethylation of CpG dinucleotides, mainly those located within the promoter regions of genes, has been observed in tumor tissues compared to surrounding healthy tissues, and it was implicated as a common mechanism by which cancer cells inactivate tumor suppressor genes, as well as escape cell cycle regulatory checkpoints and apoptotic cell death.	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('apoptotic cell death', 'CPA', (346, 366))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('cell cycle regulatory checkpoints', 'CPA', (308, 341))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (35, 52))	('hypermethylation', 'Var', (15, 31))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('observed', 'Reg', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('inactivate', 'NegReg', (255, 265))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Disease', (266, 271))	('escape', 'PosReg', (301, 307))	('tumor', 'Disease', (134, 139))
615295	32878338	Recent evidence also suggests that promoter DNA hypomethylation can lead to cancer by activating genes, including oncogenes, that have been implicated in cellular transformation, invasion, and metastasis.	('promoter DNA hypomethylation', 'Var', (35, 63))	('lead to', 'Reg', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('activating', 'PosReg', (86, 96))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
615309	32878338	During methyl transfer, SAM is converted to S-adenosylhomocysteine (SAH), which is subsequently hydrolyzed back to Hcy by adenosylhomocysteinase hydrolase (Ahcy).	('Hcy', 'Chemical', 'MESH:D006710', (115, 118))	('adenosylhomocysteinase hydrolase', 'Gene', (122, 154))	('SAM', 'Chemical', 'MESH:D012436', (24, 27))	('Ahcy', 'Gene', (156, 160))	('methyl', 'Var', (7, 13))	('Ahcy', 'Gene', '191', (156, 160))	('S-adenosylhomocysteine', 'Chemical', 'MESH:D012435', (44, 66))	('adenosylhomocysteinase hydrolase', 'Gene', '191', (122, 154))
615312	32878338	1C metabolism demonstrates the essential role of micronutrients in cellular pathways, and fluctuations in these nutrients can influence SAM/SAH ratios, thus impacting the epigenome through DNA methylation processes.	('impacting', 'Reg', (157, 166))	('epigenome', 'MPA', (171, 180))	('SAM/SAH ratios', 'MPA', (136, 150))	('SAM', 'Chemical', 'MESH:D012436', (136, 139))	('DNA methylation processes', 'MPA', (189, 214))	('influence', 'Reg', (126, 135))	('rat', 'Species', '10116', (21, 24))	('fluctuations', 'Var', (90, 102))	('cellular', 'Pathway', (67, 75))	('rat', 'Species', '10116', (144, 147))
615324	32878338	Folate deficiency (0 mg/kg diet for 4-6 weeks) in weanling Sprague-Dawley rats were shown to selectively induce hepatic p53 promoter hypomethylation and aberrancies in the p53 gene that may lead to carcinogenesis in later life.	('induce', 'PosReg', (105, 111))	('promoter hypomethylation', 'MPA', (124, 148))	('Sprague-Dawley rats', 'Species', '10116', (59, 78))	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('Folate deficiency', 'Phenotype', 'HP:0100507', (0, 17))	('carcinogenesis', 'Disease', (198, 212))	('deficiency', 'Var', (7, 17))	('p53', 'Protein', (120, 123))	('hepatic', 'MPA', (112, 119))	('aberrancies', 'Disease', (153, 164))	('carcinogenesis', 'Disease', 'MESH:D063646', (198, 212))	('aberrancies', 'Disease', 'MESH:D002869', (153, 164))	('lead to', 'Reg', (190, 197))	('p53', 'Gene', (172, 175))
615330	32878338	Furthermore, in a long-term follow-up trial, folic acid (400 microg/day) in combination with vitamin B12 (500 microg/day) for 2-3 years increased the risk of developing colorectal carcinomas in Caucasians aged 65 years and over.	('B12', 'Gene', (101, 104))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (169, 190))	('400 microg/day', 'Var', (57, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('B12', 'Gene', '7126', (101, 104))	('folic acid', 'Chemical', 'MESH:D005492', (45, 55))	('increased', 'PosReg', (136, 145))	('colorectal carcinomas', 'Disease', (169, 190))
615331	32878338	The daily use of folic acid (800 microg) and vitamin B12 (400 microg) was also shown to increase the risk of developing lung cancer in Norwegians with a mean age of 62.3 years.	('B12', 'Gene', (53, 56))	('lung cancer', 'Disease', (120, 131))	('folic acid', 'Chemical', 'MESH:D005492', (17, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('400 microg', 'Var', (58, 68))	('800 microg', 'Var', (29, 39))	('B12', 'Gene', '7126', (53, 56))
615333	32878338	showed that folate (10 mg/day) supplementation for 6 months was associated with lower DNA methylation levels in the rectal mucosa of patients (aged 49-82 years) with colorectal carcinomas versus those with adenomas.	('DNA methylation levels', 'MPA', (86, 108))	('patients', 'Species', '9606', (133, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (166, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('men', 'Species', '9606', (37, 40))	('lower', 'NegReg', (80, 85))	('adenomas', 'Disease', 'MESH:D000236', (206, 214))	('folate', 'Chemical', 'MESH:D005492', (12, 18))	('adenomas', 'Disease', (206, 214))	('supplementation', 'Var', (31, 46))	('colorectal carcinomas', 'Disease', (166, 187))
615339	32878338	Differential CpG methylation was also found in lung cancer patients.	('CpG methylation', 'Var', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('patients', 'Species', '9606', (59, 67))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('found', 'Reg', (38, 43))
615348	32878338	Changes in the levels of these vitamins can alter DNA methylation and gene expression and ultimately promote carcinogenesis.	('promote', 'PosReg', (101, 108))	('DNA methylation', 'MPA', (50, 65))	('carcinogenesis', 'Disease', 'MESH:D063646', (109, 123))	('alter', 'Reg', (44, 49))	('carcinogenesis', 'Disease', (109, 123))	('gene expression', 'MPA', (70, 85))	('Changes', 'Var', (0, 7))
615351	32878338	Changes in vitamin B2 intake can affect the methyl supply and alter DNA methylation patterns.	('methyl supply', 'MPA', (44, 57))	('affect', 'Reg', (33, 39))	('Changes', 'Var', (0, 7))	('alter', 'Reg', (62, 67))	('vitamin B2', 'Chemical', 'MESH:D012256', (11, 21))	('DNA methylation patterns', 'MPA', (68, 92))
615358	32878338	The methylation score for several tumor suppressor genes in tumors from individuals with head and neck cancer were calculated and compared to dietary intake of vitamin B12.	('head and neck cancer', 'Phenotype', 'HP:0012288', (89, 109))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('B12', 'Gene', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('methylation', 'Var', (4, 15))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('head and neck cancer', 'Disease', 'MESH:D006258', (89, 109))	('tumor', 'Disease', (60, 65))	('B12', 'Gene', '7126', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumors', 'Disease', (60, 66))
615374	32878338	Maternal choline deficiency altered methylation patterns in fetal gene promoter regions.	('methylation patterns', 'MPA', (36, 56))	('altered', 'Reg', (28, 35))	('deficiency', 'Var', (17, 27))	('choline deficiency', 'Phenotype', 'HP:0025048', (9, 27))	('choline', 'Chemical', 'MESH:D002794', (9, 16))
615378	32878338	The hypermethylation of IGF2 promoter regions was attributed to the concomitant hypomethylation of the DNMT1 promoter and its increased expression.	('expression', 'MPA', (136, 146))	('DNMT1', 'Gene', '1786', (103, 108))	('hypomethylation', 'Var', (80, 95))	('IGF2', 'Gene', '3481', (24, 28))	('hypermethylation', 'MPA', (4, 20))	('IGF2', 'Gene', (24, 28))	('increased', 'PosReg', (126, 135))	('DNMT1', 'Gene', (103, 108))
615381	32878338	Hypomethylation in the promoter region of the oncogene c-myc was found in hepatocellular carcinoma tissue of choline-deficient rats, whereas the promoters of some tumor suppressor genes (p53, p16INK4a, PtprO, Cdh1, and Cx26) were hypermethylated.	('Cdh1', 'Gene', '83502', (209, 213))	('PtprO', 'Gene', '50677', (202, 207))	('Cx26', 'Gene', (219, 223))	('tumor', 'Disease', (163, 168))	('found', 'Reg', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('choline', 'Chemical', 'MESH:D002794', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('Hypomethylation', 'Var', (0, 15))	('c-myc', 'Gene', (55, 60))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('Cx26', 'Gene', '394266', (219, 223))	('rats', 'Species', '10116', (127, 131))	('Cdh1', 'Gene', (209, 213))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (74, 98))	('p16INK4a', 'Var', (192, 200))	('PtprO', 'Gene', (202, 207))	('c-myc', 'Gene', '24577', (55, 60))	('p53', 'Gene', (187, 190))	('hepatocellular carcinoma', 'Disease', (74, 98))
615382	32878338	Furthermore, deletion of the BHMT gene resulted in the spontaneous development of pre-neoplastic foci in the liver, supporting the protective role of choline and betaine against cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('resulted in', 'Reg', (39, 50))	('BHMT', 'Gene', '635', (29, 33))	('deletion', 'Var', (13, 21))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('BHMT', 'Gene', (29, 33))	('men', 'Species', '9606', (74, 77))	('betaine', 'Chemical', 'MESH:D001622', (162, 169))	('choline', 'Chemical', 'MESH:D002794', (150, 157))
615385	32878338	Being a precursor to SAM, methionine is a major driver of DNA methylation, and fluctuations in methionine can significantly alter the methylation status of DNA.	('SAM', 'Chemical', 'MESH:D012436', (21, 24))	('methionine', 'Chemical', 'MESH:D008715', (95, 105))	('fluctuations', 'Var', (79, 91))	('methionine', 'Chemical', 'MESH:D008715', (26, 36))	('alter', 'Reg', (124, 129))	('methylation status', 'MPA', (134, 152))
615388	32878338	Methionine was associated exclusively with decreasing methylation levels of p16INK4a, RASSF1A, and MTHFR in former smokers and RASSF1A and GSTP1 in current smokers.	('RASSF1A', 'Gene', (127, 134))	('MTHFR', 'Gene', '4524', (99, 104))	('decreasing', 'NegReg', (43, 53))	('methylation levels', 'MPA', (54, 72))	('GSTP1', 'Gene', '2950', (139, 144))	('RASSF1A', 'Gene', (86, 93))	('MTHFR', 'Gene', (99, 104))	('RASSF1A', 'Gene', '11186', (127, 134))	('RASSF1A', 'Gene', '11186', (86, 93))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('p16INK4a', 'Var', (76, 84))	('GSTP1', 'Gene', (139, 144))	('Methionine', 'Var', (0, 10))
615389	32878338	RASSF1A and p16INK4a are well-known tumor suppressors that are frequently hypermethylated in lung cancer; thus, methionine supplementation may have a protective role in lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('methionine', 'Chemical', 'MESH:D008715', (112, 122))	('RASSF1A', 'Gene', (0, 7))	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('RASSF1A', 'Gene', '11186', (0, 7))	('men', 'Species', '9606', (129, 132))	('p16INK4a', 'Var', (12, 20))	('patients', 'Species', '9606', (181, 189))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('lung cancer', 'Disease', (169, 180))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Disease', (36, 41))
615395	32878338	Methionine deficiency is associated with increased risk, whereas high intake reduces the risk of colorectal cancer and colorectal adenomas greater than 1 cm.	('colorectal adenomas', 'Disease', 'MESH:D015179', (119, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('Methionine deficiency', 'Var', (0, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colorectal cancer', 'Disease', (97, 114))	('Methionine deficiency', 'Phenotype', 'HP:0003658', (0, 21))	('reduces', 'NegReg', (77, 84))	('colorectal adenomas', 'Disease', (119, 138))
615397	32878338	Interestingly, methionine restriction is being investigated as an anti-cancer strategy (thoroughly reviewed by Chaturvedi et al.).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('methionine restriction', 'Var', (15, 37))	('cancer', 'Disease', (71, 77))	('rat', 'Species', '10116', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('methionine', 'Chemical', 'MESH:D008715', (15, 25))
615399	32878338	Preclinical studies in rodent models have revealed that methionine restriction is effective against carcinomas and inhibits the development of colonic tumors and prostatic intraepithelial neoplasia.	('methionine restriction', 'Var', (56, 78))	('neoplasia', 'Phenotype', 'HP:0002664', (188, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('carcinomas', 'Disease', (100, 110))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('prostatic intraepithelial neoplasia', 'Disease', (162, 197))	('men', 'Species', '9606', (135, 138))	('methionine', 'Chemical', 'MESH:D008715', (56, 66))	('inhibits', 'NegReg', (115, 123))	('development', 'CPA', (128, 139))	('colonic tumors', 'Disease', 'MESH:D003110', (143, 157))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (162, 197))	('colonic tumors', 'Disease', (143, 157))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (172, 197))	('carcinomas', 'Disease', 'MESH:D009369', (100, 110))
615412	32878338	Another study revealed that through global DNA hypermethylation, curcumin (0.01-100 microM; 24 h) decreased the expression of the argyrophilic nucleolar protein (AgNOR), which is a protein that is highly expressed in malignant cells compared to normal cells and reflects the rapidity of cancer cell proliferation.	('rat', 'Species', '10116', (306, 309))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('curcumin', 'Chemical', 'MESH:D003474', (65, 73))	('decreased', 'NegReg', (98, 107))	('hypermethylation', 'Var', (47, 63))	('expression', 'MPA', (112, 122))
615427	32878338	Resveratrol also exhibits effective anti-cancer activity through epigenetic mechanisms.	('epigenetic', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Resveratrol', 'Chemical', 'MESH:D000077185', (0, 11))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
615442	32878338	Studies on the mechanisms underlying the anti-cancer activities of SFN indicate that its regulatory effects on the tumor cell cycle, apoptosis, and angiogenesis are mediated by an epigenetic modulation of essential cell signaling pathways and genes.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cancer', 'Disease', (46, 52))	('apoptosis', 'CPA', (133, 142))	('epigenetic modulation', 'Var', (180, 201))	('tumor', 'Disease', (115, 120))	('SFN', 'Chemical', 'MESH:C016766', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('essential cell signaling pathways', 'Pathway', (205, 238))	('SFN', 'Gene', (67, 70))	('mediated by', 'Reg', (165, 176))	('angiogenesis', 'CPA', (148, 160))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
615447	32878338	This NRF2 promoter hypomethylation occurred as a result of reduced DNMT expression and was associated with an increase in NRF2 expression as well as an increase in the mRNA and protein expression of its downstream target NAD(P)H quinone dehydrogenase 1 (NQO1).	('promoter', 'MPA', (10, 18))	('increase', 'PosReg', (110, 118))	('NAD(P)H quinone dehydrogenase 1', 'Gene', '1728', (221, 252))	('reduced', 'NegReg', (59, 66))	('increase', 'PosReg', (152, 160))	('expression', 'MPA', (127, 137))	('DNMT', 'Gene', '1786', (67, 71))	('DNMT', 'Gene', (67, 71))	('expression', 'MPA', (72, 82))	('NQO1', 'Gene', (254, 258))	('NRF2', 'Gene', (5, 9))	('NRF2', 'Gene', (122, 126))	('hypomethylation', 'Var', (19, 34))	('NQO1', 'Gene', '1728', (254, 258))
615456	32878338	In contrast, SFN (2.0-32.0 microM) treatment in human hepatocellular carcinoma (HepG2) cells induced cell cycle arrest and apoptosis through the hypermethylation of genes such as E2F3, THAP1, and ANKHD1, which are involved in cell cycle progression and cell proliferation.	('hypermethylation', 'Var', (145, 161))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 78))	('arrest', 'Disease', 'MESH:D006323', (112, 118))	('E2F3', 'Gene', '1871', (179, 183))	('HepG2', 'CellLine', 'CVCL:0027', (80, 85))	('THAP1', 'Gene', (185, 190))	('human', 'Species', '9606', (48, 53))	('ANKHD1', 'Gene', '54882', (196, 202))	('men', 'Species', '9606', (40, 43))	('hepatocellular carcinoma', 'Disease', (54, 78))	('SFN', 'Chemical', 'MESH:C016766', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('ANKHD1', 'Gene', (196, 202))	('apoptosis', 'CPA', (123, 132))	('arrest', 'Disease', (112, 118))	('rat', 'Species', '10116', (265, 268))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (101, 118))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (54, 78))	('THAP1', 'Gene', '55145', (185, 190))	('E2F3', 'Gene', (179, 183))
615465	32878338	Genistein also induced promoter hypomethylation and reactivated the expression of tumor suppressor genes GSTP1, EPHB2, p21, RARbeta, p16INK4a, and MGMT in breast cancer, kidney cancer, esophageal squamous cell carcinoma, and prostate cancer cell lines, leading to cell cycle arrest and cell death.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('reactivated', 'PosReg', (52, 63))	('EPHB2', 'Gene', '2048', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('EPHB2', 'Gene', (112, 117))	('expression', 'MPA', (68, 78))	('esophageal squamous cell carcinoma', 'Disease', (185, 219))	('prostate cancer', 'Disease', 'MESH:D011471', (225, 240))	('kidney cancer', 'Phenotype', 'HP:0009726', (170, 183))	('promoter hypomethylation', 'MPA', (23, 47))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('kidney cancer', 'Disease', (170, 183))	('tumor', 'Disease', (82, 87))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (264, 281))	('p21', 'Gene', (119, 122))	('p16INK4a', 'Var', (133, 141))	('prostate cancer', 'Phenotype', 'HP:0012125', (225, 240))	('p21', 'Gene', '644914', (119, 122))	('prostate cancer', 'Disease', (225, 240))	('arrest', 'Disease', (275, 281))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('GSTP1', 'Gene', '2950', (105, 110))	('cell death', 'CPA', (286, 296))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (196, 219))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (185, 219))	('GSTP1', 'Gene', (105, 110))	('induced', 'Reg', (15, 22))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast cancer', 'Disease', (155, 168))	('Genistein', 'Chemical', 'MESH:D019833', (0, 9))	('arrest', 'Disease', 'MESH:D006323', (275, 281))	('kidney cancer', 'Disease', 'MESH:D007680', (170, 183))
615472	32878338	Genistein (2-20 micromol/L) inhibited the proliferation of human esophageal squamous cell carcinoma (KYSE 510) cell line by reversing DNA hypermethylation and reactivating the expression of RARbeta, p16INK4a, and MGMT.	('human', 'Species', '9606', (59, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('proliferation', 'CPA', (42, 55))	('p16INK4a', 'Var', (199, 207))	('DNA hypermethylation', 'MPA', (134, 154))	('esophageal squamous cell carcinoma', 'Disease', (65, 99))	('inhibited', 'NegReg', (28, 37))	('expression', 'MPA', (176, 186))	('reversing', 'NegReg', (124, 133))	('rat', 'Species', '10116', (49, 52))	('Genistein', 'Chemical', 'MESH:D019833', (0, 9))	('reactivating', 'PosReg', (159, 171))	('RARbeta', 'Gene', (190, 197))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (65, 99))
615473	32878338	This reversal of RARbeta promoter hypermethylation and increase in its expression was also observed by genistein in KYSE 150 cell line and prostate cancer (LNCaP and PC3) cell lines.	('expression', 'MPA', (71, 81))	('increase', 'PosReg', (55, 63))	('hypermethylation', 'Var', (34, 50))	('RARbeta', 'Gene', (17, 24))	('prostate cancer', 'Disease', (139, 154))	('LNCaP', 'CellLine', 'CVCL:0395', (156, 161))	('genistein', 'Chemical', 'MESH:D019833', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('prostate cancer', 'Disease', 'MESH:D011471', (139, 154))	('PC3', 'CellLine', 'CVCL:0035', (166, 169))	('prostate cancer', 'Phenotype', 'HP:0012125', (139, 154))
615477	32878338	EGCG (5-50 microM) was found to induce global DNA hypomethylation by inhibiting DNMT activity; and the inhibition in DNMT activity is a result of direct blockage of the active site of DNMTs as well as a reduction in the levels of SAM and SAH.	('DNMT', 'Gene', (117, 121))	('DNMT', 'Gene', '1786', (80, 84))	('DNMT', 'Gene', '1786', (117, 121))	('global DNA hypomethylation', 'MPA', (39, 65))	('DNMT', 'Gene', '1786', (184, 188))	('DNMT', 'Gene', (80, 84))	('SAM', 'Chemical', 'MESH:D012436', (230, 233))	('DNMT', 'Gene', (184, 188))	('levels of SAM', 'MPA', (220, 233))	('blockage', 'NegReg', (153, 161))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('inhibiting', 'NegReg', (69, 79))	('EGCG', 'Var', (0, 4))	('induce', 'PosReg', (32, 38))	('reduction', 'NegReg', (203, 212))	('activity', 'MPA', (122, 130))	('inhibition', 'NegReg', (103, 113))
615478	32878338	EGCG (50 microM) also disrupts global DNA methylation by altering folic acid metabolism.	('disrupts', 'NegReg', (22, 30))	('global DNA methylation', 'MPA', (31, 53))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('folic acid metabolism', 'MPA', (66, 87))	('folic acid', 'Chemical', 'MESH:D005492', (66, 76))	('EGCG', 'Var', (0, 4))	('altering', 'Reg', (57, 65))
615479	32878338	EGCG-mediated inhibition of DNMTs has been linked with promoter demethylation and the re-expression of several tumor suppressor genes such as p21, p16INK4a, RARbeta, MGMT, and human mutL homologue 1 (hMLH1) in various cancer cell lines.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('DNMT', 'Gene', (28, 32))	('p16INK4a', 'Var', (147, 155))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('p21', 'Gene', (142, 145))	('p21', 'Gene', '644914', (142, 145))	('promoter demethylation', 'MPA', (55, 77))	('tumor', 'Disease', (111, 116))	('human', 'Species', '9606', (176, 181))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('hMLH1', 'Gene', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('re-expression', 'MPA', (86, 99))	('hMLH1', 'Gene', '4292', (200, 205))	('DNMT', 'Gene', '1786', (28, 32))
615483	32878338	EGCG inhibited DNA methylation as well as the catalytic activities of the cytochrome P450 enzymes, CYP1A, CYP2B1, and CYP2E1 preventing lung tumorigenesis in A/J mice (an inbred albino strain of mice commonly used in cancer studies).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('CYP2B1', 'Var', (106, 112))	('inhibited', 'NegReg', (5, 14))	('cytochrome P450', 'Gene', '4051', (74, 89))	('mice', 'Species', '10090', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('cytochrome P450', 'Gene', (74, 89))	('catalytic activities', 'MPA', (46, 66))	('mice', 'Species', '10090', (162, 166))	('cancer', 'Disease', (217, 223))	('CYP2E1', 'Gene', (118, 124))	('CYP1A', 'Var', (99, 104))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('CYP2E1', 'Gene', '13106', (118, 124))	('DNA methylation', 'MPA', (15, 30))
615484	32878338	In human lung cancer (A549 and H460) cell lines, EGCG (0-50 muM; 72 h)-induced promoter demethylation and the restoration of WIF1 expression downregulated the Wnt signaling pathway but did not inhibit cell proliferation.	('expression', 'MPA', (130, 140))	('rat', 'Species', '10116', (115, 118))	('promoter demethylation', 'MPA', (79, 101))	('restoration', 'Var', (110, 121))	('WIF1', 'Gene', (125, 129))	('Wnt', 'Gene', '7474;64566', (159, 162))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('WIF1', 'Gene', '11197', (125, 129))	('H460', 'CellLine', 'CVCL:0459', (31, 35))	('rat', 'Species', '10116', (213, 216))	('EGCG', 'Chemical', 'MESH:C045651', (49, 53))	('downregulated', 'NegReg', (141, 154))	('Wnt', 'Gene', (159, 162))	('lung cancer', 'Disease', (9, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('A549', 'CellLine', 'CVCL:0023', (22, 26))
615487	32878338	EGCG (25-200 mg/L; 96 h) was also found to inhibit cell growth and induce apoptosis in esophageal cancer (ECa109) cell line through demethylation and reactivation of the p16INK4a gene.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('apoptosis', 'CPA', (74, 83))	('cell growth', 'CPA', (51, 62))	('inhibit', 'NegReg', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('reactivation', 'Var', (150, 162))	('cancer', 'Disease', (98, 104))	('EGCG', 'Var', (0, 4))	('ECa109', 'CellLine', 'CVCL:6898', (106, 112))	('induce', 'PosReg', (67, 73))	('demethylation', 'Var', (132, 145))	('p16INK4a', 'Gene', (170, 178))
615488	32878338	In breast cancer (MCF7 and MDA-MB-231) cell lines, EGCG (20 muM; 48 h) reduced DNMT expression and activity, which in turn decreased the methylation status of SCUBE2 (signal peptide-CUB (complement protein C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 2).	('Bmp1', 'Gene', '649', (225, 229))	('decreased', 'NegReg', (123, 132))	('men', 'Species', '9606', (193, 196))	('Bmp1', 'Gene', (225, 229))	('C1r', 'Gene', (206, 209))	('SCUBE2', 'Gene', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (27, 37))	('C1r', 'Gene', '715', (206, 209))	('reduced', 'NegReg', (71, 78))	('EGCG', 'Var', (51, 55))	('methylation status', 'MPA', (137, 155))	('C1', 'CellLine', 'CVCL:4T75', (206, 208))	('MCF7', 'CellLine', 'CVCL:0031', (18, 22))	('SCUBE2', 'Gene', '57758', (159, 165))	('EGF', 'Gene', '1950', (231, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('EGCG', 'Chemical', 'MESH:C045651', (51, 55))	('expression', 'MPA', (84, 94))	('DNMT', 'Gene', '1786', (79, 83))	('DNMT', 'Gene', (79, 83))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('activity', 'MPA', (99, 107))	('EGF', 'Gene', (231, 234))	('C1', 'CellLine', 'CVCL:4T75', (210, 212))
615490	32878338	Similarly, in HSC3 and SCC9 oral carcinoma cell lines, EGCG (5-50 microM; 6 days)-induced inhibition of tumor invasion, angiogenesis, and metastasis was correlated with partial demethylation and upregulation of the tumor suppressor, RECK.	('SCC9 oral carcinoma', 'Disease', 'MESH:D009062', (23, 42))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('EGCG', 'Chemical', 'MESH:C045651', (55, 59))	('RECK', 'Gene', (233, 237))	('angiogenesis', 'CPA', (120, 132))	('HSC3', 'Gene', (14, 18))	('SCC9 oral carcinoma', 'Disease', (23, 42))	('tumor', 'Disease', (104, 109))	('upregulation', 'PosReg', (195, 207))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('RECK', 'Gene', '8434', (233, 237))	('inhibition', 'NegReg', (90, 100))	('EGCG', 'Gene', (55, 59))	('metastasis', 'CPA', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('HSC3', 'Gene', '150353', (14, 18))	('partial demethylation', 'Var', (169, 190))
615513	32878338	Similarly, the FA-induced increase in MBD2 expression was shown to occur due to MBD2 promoter hypomethylation.	('MBD2', 'Gene', '8932', (38, 42))	('increase', 'PosReg', (26, 34))	('MBD2', 'Gene', (80, 84))	('hypomethylation', 'Var', (94, 109))	('MBD2', 'Gene', '8932', (80, 84))	('MBD2', 'Gene', (38, 42))	('expression', 'MPA', (43, 53))
615520	32878338	FB1 contamination in corn (223.6 mug/g) and rice (21.6 mug/g) was associated with an increased risk of esophageal cancer in the Golestan Province of Northeastern Iran.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('223.6', 'Var', (27, 32))	('rice', 'Species', '4530', (44, 48))	('associated', 'Reg', (66, 76))	('FB1', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
615526	32878338	They documented that FB1 (200 microM) induces global DNA hypomethylation in the HepG2 cell line via a mechanism that alters the DNA methyltransferase/demethylase balance, thereby disrupting the structural integrity of DNA.	('HepG2', 'CellLine', 'CVCL:0027', (80, 85))	('demethylase', 'Gene', (150, 161))	('200', 'Var', (26, 29))	('disrupting', 'NegReg', (179, 189))	('men', 'Species', '9606', (9, 12))	('demethylase', 'Gene', '8932', (150, 161))	('FB1', 'Gene', (21, 24))	('structural integrity', 'MPA', (194, 214))	('alters', 'Reg', (117, 123))
615555	32878338	Since global DNA hypomethylation and promoter hypermethylation are hallmarks of cancer, OTA-induced changes in DNA methylation may provide a mechanism for controlling the expression of genes involved in carcinogenesis.	('expression', 'MPA', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (203, 217))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('OTA', 'Chemical', 'MESH:C025589', (88, 91))	('carcinogenesis', 'Disease', (203, 217))	('promoter', 'MPA', (37, 45))	('changes', 'Var', (100, 107))	('cancer', 'Disease', (80, 86))
615560	32878338	Since the transversion mutation (G T) on codon 249 of the p53 tumor suppressor gene has been associated with AFB1 intake, extensive research has been conducted on the relationship between AFB1 concentration and the incidence of hepatocellular carcinoma.	('AFB1', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('rat', 'Species', '10116', (200, 203))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (228, 252))	('tumor', 'Disease', (62, 67))	('hepatocellular carcinoma', 'Disease', (228, 252))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (228, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('associated', 'Reg', (93, 103))	('transversion mutation', 'Var', (10, 31))	('AFB1', 'Chemical', 'MESH:D016604', (109, 113))	('AFB1', 'Chemical', 'MESH:D016604', (188, 192))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
615562	32878338	They found a correlation between the RASSF1A and p16INK4a methylation statuses and the AFB1-DNA adduct levels.	('RASSF1A', 'Gene', '11186', (37, 44))	('p16INK4a', 'Var', (49, 57))	('AFB1', 'Chemical', 'MESH:D016604', (87, 91))	('RASSF1A', 'Gene', (37, 44))	('AFB1-DNA adduct levels', 'MPA', (87, 109))
615563	32878338	This study concluded that exposure to AFB1 may induce carcinogenesis by altering the DNA methylation status and the expression of genes associated with cancer development.	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('cancer', 'Disease', (152, 158))	('induce', 'PosReg', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('DNA methylation status', 'MPA', (85, 107))	('carcinogenesis', 'Disease', (54, 68))	('AFB1', 'Chemical', 'MESH:D016604', (38, 42))	('exposure', 'Var', (26, 34))	('altering', 'Reg', (72, 80))	('men', 'Species', '9606', (166, 169))	('AFB1', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('expression of genes', 'MPA', (116, 135))
615564	32878338	reported that a regular intake of AFB1 decreased Sat2 and LINE-1 promoter methylation in white blood cells from 1140 cancer-free patients of the Cancer Screening Program cohort in Taiwan, suggesting that AFB1 plays a major role in hepatocellular carcinoma by inducing global DNA hypomethylation.	('hepatocellular carcinoma', 'Disease', (231, 255))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('AFB1', 'Chemical', 'MESH:D016604', (204, 208))	('global DNA hypomethylation', 'MPA', (268, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('Cancer', 'Disease', (145, 151))	('decreased', 'NegReg', (39, 48))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('AFB1', 'Var', (204, 208))	('AFB1', 'Chemical', 'MESH:D016604', (34, 38))	('patients', 'Species', '9606', (129, 137))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (231, 255))	('Sat2', 'Gene', (49, 53))	('Sat2', 'Gene', '112483', (49, 53))	('inducing', 'Reg', (259, 267))	('Cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (231, 255))
615565	32878338	In another study, primary human hepatocytes were treated with 0.3 microM AFB1 for 5 days, followed by 3 days of withdrawal from the carcinogenic exposure.	('AFB1', 'Chemical', 'MESH:D016604', (73, 77))	('0.3 microM', 'Var', (62, 72))	('carcinogenic', 'Disease', 'MESH:D063646', (132, 144))	('AFB1', 'Gene', (73, 77))	('carcinogenic', 'Disease', (132, 144))	('human', 'Species', '9606', (26, 31))
615567	32878338	In addition, the persistent hypomethylation and upregulation of 6 hepatocellular carcinoma related genes (TXNRD1, PCNA, CCNK, DIAPH3, RAB27A, and HIST1H2BF) were identified to have an influence at the transcriptome level.	('TXNRD1', 'Gene', (106, 112))	('DIAPH3', 'Gene', (126, 132))	('TXNRD1', 'Gene', '7296', (106, 112))	('CCNK', 'Gene', '8812', (120, 124))	('PCNA', 'Gene', '5111', (114, 118))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('RAB27A', 'Gene', '5873', (134, 140))	('hypomethylation', 'Var', (28, 43))	('HIST1H2BF', 'Gene', (146, 155))	('hepatocellular carcinoma', 'Disease', (66, 90))	('RAB27A', 'Gene', (134, 140))	('CCNK', 'Gene', (120, 124))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('DIAPH3', 'Gene', '81624', (126, 132))	('HIST1H2BF', 'Gene', '8343', (146, 155))	('PCNA', 'Gene', (114, 118))	('upregulation', 'PosReg', (48, 60))
615568	32878338	These genes are known to induce and promote carcinogenesis by elevating cell growth, invasion, and metastasis.	('cell growth', 'CPA', (72, 83))	('elevating', 'PosReg', (62, 71))	('promote', 'PosReg', (36, 43))	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('induce', 'PosReg', (25, 31))	('carcinogenesis', 'Disease', (44, 58))	('genes', 'Var', (6, 11))	('invasion', 'CPA', (85, 93))	('metastasis', 'CPA', (99, 109))
615593	32878338	Depending on the gene, DNA hypermethylation is associated with transcriptional repression, leading to tumor suppressor gene silencing.	('hypermethylation', 'Var', (27, 43))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('silencing', 'NegReg', (124, 133))
615595	32878338	The DON-induced DNA hypermethylation in porcine oocytes may provide a mechanism for ovarian cancer.	('ovarian cancer', 'Disease', (84, 98))	('hypermethylation', 'Var', (20, 36))	('DON', 'Chemical', 'MESH:C007262', (4, 7))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('DNA hypermethylation', 'Var', (16, 36))
615599	32878338	In chickens, the liver is also a target of T-2 toxin, and its toxicity has been attributed to oxidative stress, DNA damage, lipid peroxidation, apoptosis, and autophagy.	('chickens', 'Species', '9031', (3, 11))	('oxidative stress', 'MPA', (94, 110))	('lipid peroxidation', 'MPA', (124, 142))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('DNA damage', 'MPA', (112, 122))	('autophagy', 'CPA', (159, 168))	('apoptosis', 'CPA', (144, 153))	('toxicity', 'Disease', (62, 70))	('T-2', 'Var', (43, 46))	('lipid', 'Chemical', 'MESH:D008055', (124, 129))	('oxidative stress', 'Phenotype', 'HP:0025464', (94, 110))
615608	32878338	Ras association domain family 4 (RASSF4) is a tumor suppressor protein that is widely expressed in normal tissues; however, loss of expression due to DNA hypermethylation is related to nasopharyngeal carcinoma, non-small cell lung cancer, colorectal cancer, and head and neck cancers.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('colorectal cancer', 'Disease', 'MESH:D015179', (239, 256))	('carcinoma', 'Disease', (200, 209))	('Ras association domain family 4', 'Gene', '83937', (0, 31))	('colorectal cancer', 'Disease', (239, 256))	('RASSF4', 'Gene', (33, 39))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (211, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('DNA', 'Gene', (150, 153))	('head and neck cancers', 'Phenotype', 'HP:0012288', (262, 283))	('carcinoma', 'Disease', 'MESH:D009369', (200, 209))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('lung cancer', 'Disease', (226, 237))	('loss of', 'NegReg', (124, 131))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (185, 209))	('tumor', 'Disease', (46, 51))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (215, 237))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('head and neck cancers', 'Disease', 'MESH:D006258', (262, 283))	('colorectal cancer', 'Phenotype', 'HP:0003003', (239, 256))	('Ras association domain family 4', 'Gene', (0, 31))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('head and neck cancer', 'Phenotype', 'HP:0012288', (262, 282))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('expression', 'MPA', (132, 142))	('hypermethylation', 'Var', (154, 170))
615614	32878338	Cancer development is a continuous, progressive event, involving the activation of oncogenes and the inhibition of tumor suppressor genes by alterations of the epigenome.	('oncogenes', 'Protein', (83, 92))	('epigenome', 'Protein', (160, 169))	('alterations', 'Var', (141, 152))	('men', 'Species', '9606', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('inhibition', 'NegReg', (101, 111))	('tumor', 'Disease', (115, 120))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('rat', 'Species', '10116', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('activation', 'PosReg', (69, 79))
615617	32878338	As discussed in this review, DNA methylation is a common epigenetic mechanism by which micronutrients, bioactive dietary compounds, and mycotoxins affect cancer cell growth, invasive capacities, and metastasis.	('invasive capacities', 'CPA', (174, 193))	('methylation', 'Var', (33, 44))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('metastasis', 'CPA', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('affect', 'Reg', (147, 153))
615621	32878338	Other challenges include the bioavailability of the exact concentration required to reverse the epigenetic modification and the effect of these micronutrients and bioactive compounds in combination with existing anti-cancer drugs.	('epigenetic modification', 'Var', (96, 119))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('rat', 'Species', '10116', (65, 68))
615681	32621256	However, over 80% traditional AdCCs have a definite activation of MYB/MYB1 caused by gene fusion or other mechanisms.	('gene fusion', 'Var', (85, 96))	('MYB', 'Gene', (66, 69))	('MYB', 'Gene', '4602', (70, 73))	('MYB', 'Gene', (70, 73))	('MYB', 'Gene', '4602', (66, 69))	('activation', 'PosReg', (52, 62))
615697	32621256	However, no reported esophageal MEC has been demonstrated harboring the t (11;19) (q21;p13) translocation and CRTC1-MAML2 gene fusion or the t(11;15) (q21;q26) translocation and CRTC3-MAML2 gene fusion.	('MAML2', 'Gene', '84441', (116, 121))	('p13', 'Gene', (87, 90))	('t(11;15) (q21;q26', 'Var', (141, 158))	('CRTC3', 'Gene', '64784', (178, 183))	('CRTC1', 'Gene', (110, 115))	('CRTC3', 'Gene', (178, 183))	('MAML2', 'Gene', (184, 189))	('MAML2', 'Gene', '84441', (184, 189))	('p13', 'Gene', '440926', (87, 90))	('CRTC1', 'Gene', '23373', (110, 115))	('MAML2', 'Gene', (116, 121))
615712	32298379	In addition, circulating IL-10 might help to identify patients with advanced disease and high IL-17A might indicate a limited prognosis.	('IL-17A', 'Gene', (94, 100))	('patients', 'Species', '9606', (54, 62))	('IL-10', 'Gene', '3586', (25, 30))	('high', 'Var', (89, 93))	('IL-17A', 'Gene', '3605', (94, 100))	('IL-10', 'Gene', (25, 30))
615800	32298379	Nevertheless, we suggest that manipulating regulatory T cells to produce less IL-10 might be a potential treatment option, which has already been tested in other malignancies with promising results.	('IL-10', 'Gene', (78, 83))	('malignancies', 'Disease', 'MESH:D009369', (162, 174))	('manipulating', 'Var', (30, 42))	('IL-10', 'Gene', '3586', (78, 83))	('malignancies', 'Disease', (162, 174))
615850	32298379	In the field of cancer therapy, pegylated IL-10 is used to induce cancer immunity that is opposite to antagonizing IL-10.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('IL-10', 'Gene', '3586', (42, 47))	('pegylated', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (16, 22))	('IL-10', 'Gene', '3586', (115, 120))	('induce', 'PosReg', (59, 65))	('IL-10', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('IL-10', 'Gene', (115, 120))	('cancer', 'Disease', (66, 72))
615898	30641964	Increased efficacy was found for OxF-prolonged compared to an anthracycline-based triplet (ATr) in terms of both OS, HR = 0.56 (95% CrI = 0.33 to 0.95) and DFS, HR = 0.49 (95% CrI = 0.30 to 0.80).	('DFS', 'MPA', (156, 159))	('anthracycline', 'Chemical', 'MESH:D018943', (62, 75))	('OxF', 'Chemical', '-', (33, 36))	('OxF-prolonged', 'Var', (33, 46))	('OS', 'Chemical', '-', (113, 115))	('ATr', 'Chemical', '-', (91, 94))
615947	30641964	The ARTIST II trial (Clinical-Trials.gov identifier: NCT01761461) with node positive stage II and III gastric cancer patients (with an R0 and D2 lymph node dissection) is a three arm study comparing S-1 vs. Oxaliplatin + S-1 vs. Oxaliplatin+S-1 with radiotherapy and will confirm or reproach the results of our NMA.	('S-1', 'Chemical', '-', (199, 202))	('S-1', 'Chemical', '-', (241, 244))	('gastric cancer', 'Disease', (102, 116))	('S-1', 'Chemical', '-', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (207, 218))	('S-1', 'Var', (199, 202))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (229, 240))	('patients', 'Species', '9606', (117, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))
616117	29190931	Cancers of the lung & bronchus, colon & rectum, prostate, and stomach in men and cancers of the lung & bronchus, breast, colon & rectum, and pancreas in women will be the top leading causes of cancer death in 2029, and the predicted top leading causes of cancer death in 2029 in Yangpu are similar to those in developed countries in 2008.	('women', 'Species', '9606', (153, 158))	('cancer death', 'Disease', 'MESH:D003643', (193, 205))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('pancreas', 'Disease', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer death', 'Disease', 'MESH:D003643', (255, 267))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer death', 'Disease', (193, 205))	('men', 'Species', '9606', (73, 76))	('cancers of the lung', 'Disease', 'MESH:D008175', (81, 100))	('men', 'Var', (73, 76))	('cancer death', 'Disease', (255, 267))	('pancreas', 'Disease', 'MESH:D010190', (141, 149))	('Cancers of the lung', 'Disease', (0, 19))	('Cancers of the lung', 'Disease', 'MESH:D008175', (0, 19))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('men', 'Species', '9606', (155, 158))	('cancers of the lung', 'Disease', (81, 100))
616126	29190931	Cancers of the lung & bronchus, colon & rectum, prostate, and stomach in men and cancers of the lung & bronchus, breast, colon & rectum, and pancreas in women will be the leading causes of cancer death in 2029, and these malignancies requires public heath interventions in advance.	('women', 'Species', '9606', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('pancreas', 'Disease', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('men', 'Species', '9606', (73, 76))	('cancers of the lung', 'Disease', 'MESH:D008175', (81, 100))	('men', 'Var', (73, 76))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))	('malignancies', 'Disease', (221, 233))	('pancreas', 'Disease', 'MESH:D010190', (141, 149))	('Cancers of the lung', 'Disease', (0, 19))	('Cancers of the lung', 'Disease', 'MESH:D008175', (0, 19))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer death', 'Disease', 'MESH:D003643', (189, 201))	('men', 'Species', '9606', (155, 158))	('rectum', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer death', 'Disease', (189, 201))	('cancers of the lung', 'Disease', (81, 100))
616138	28652779	However, the altered radiotherapy increased the risk of acute radiation esophagitis (OR =1.70, 95% CI: 1.27-2.28, P<0.001) and acute radiation tracheitis (OR =1.47, 95% CI: 1.09-1.99, P=0.01).	('acute radiation tracheitis', 'Disease', (127, 153))	('acute radiation tracheitis', 'Disease', 'MESH:D004194', (127, 153))	('esophagitis', 'Phenotype', 'HP:0100633', (72, 83))	('acute radiation esophagitis', 'Disease', 'MESH:D004194', (56, 83))	('acute radiation esophagitis', 'Disease', (56, 83))	('altered', 'Var', (13, 20))
616140	28652779	Chinese patients with squamous cell esophagus carcinomas gained a significant benefit in terms of the response rate, survival and local control rates from the modified fractionation radiotherapy, but also had an increased risk of acute radiation reactions.	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('esophagus carcinoma', 'Phenotype', 'HP:0011459', (36, 55))	('response', 'CPA', (102, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('local control', 'CPA', (130, 143))	('squamous cell esophagus carcinomas', 'Disease', 'MESH:D002294', (22, 56))	('survival', 'CPA', (117, 125))	('modified', 'Var', (159, 167))	('squamous cell esophagus carcinomas', 'Disease', (22, 56))	('benefit', 'PosReg', (78, 85))	('patients', 'Species', '9606', (8, 16))
616159	28652779	For the 5-year survival, there was strong evidence, based on 11 studies, indicating that patients benefited from the modified RT (OR =2.36, 95% CI: 1.74-3.21, P<0.001).	('patients', 'Species', '9606', (89, 97))	('modified RT', 'Var', (117, 128))	('benefited', 'PosReg', (98, 107))
616161	28652779	The occurrences of acute radiation esophagitis and tracheitis were higher in the modified RT group than in the conventional RT group, with an OR value of 1.70 (95% CI: 1.27-2.28, P<0.001) and 1.47 (95% CI: 1.09-1.99, P=0.01), respectively.	('modified RT', 'Var', (81, 92))	('higher', 'PosReg', (67, 73))	('acute radiation esophagitis', 'Disease', 'MESH:D004194', (19, 46))	('acute radiation esophagitis', 'Disease', (19, 46))	('esophagitis', 'Phenotype', 'HP:0100633', (35, 46))	('esophagitis and tracheitis', 'Disease', 'MESH:D014136', (35, 61))
616177	28652779	In regard to head and neck cancer, a meta-analysis suggested that there was a significant benefit with OS and locoregional control (LRC) at 5 years for hyperfractionated and/or accelerated RT.	('head and neck cancer', 'Phenotype', 'HP:0012288', (13, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('hyperfractionated', 'Var', (152, 169))	('benefit', 'PosReg', (90, 97))	('accelerated RT', 'CPA', (177, 191))	('locoregional control', 'CPA', (110, 130))	('neck cancer', 'Disease', (22, 33))	('neck cancer', 'Disease', 'MESH:D006258', (22, 33))
616185	28652779	In contrast to the results of this study, some of the included studies suggested that the differences in the survival rates and acute toxicity between the modified and the conventional RT groups in patients with esophageal cancer were not statistically significant.	('toxicity', 'Disease', 'MESH:D064420', (134, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (212, 229))	('toxicity', 'Disease', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('patients', 'Species', '9606', (198, 206))	('modified', 'Var', (155, 163))	('esophageal cancer', 'Disease', (212, 229))
616192	28652779	The overall OR indicated that altered RT increased the incidence of acute radiation reactions, such as radiation esophagitis and tracheitis, which were the primary acute side effects occurring during RT for esophageal cancer.	('acute', 'Disease', (68, 73))	('esophagitis and tracheitis', 'Disease', 'MESH:D014136', (113, 139))	('esophageal cancer', 'Disease', (207, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('radiation esophagitis', 'Disease', (103, 124))	('altered', 'Var', (30, 37))	('radiation esophagitis', 'Disease', 'MESH:D004194', (103, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (207, 224))	('esophagitis', 'Phenotype', 'HP:0100633', (113, 124))
616193	28652779	Possible explanations for these results are that the altered RT may increase the total dose of RT and shorten the total treatment time, which is related to the occurrence of acute radiation esophagitis and tracheitis, whereas the RT time and dose in conventional RT are more in line with the biologic characteristics of RT, allowing sufficient time for the repair for related organs and tissues.	('esophagitis and tracheitis', 'Disease', 'MESH:D014136', (190, 216))	('dose', 'MPA', (87, 91))	('shorten', 'NegReg', (102, 109))	('acute radiation esophagitis', 'Disease', 'MESH:D004194', (174, 201))	('acute radiation esophagitis', 'Disease', (174, 201))	('altered', 'Var', (53, 60))	('increase', 'PosReg', (68, 76))	('esophagitis', 'Phenotype', 'HP:0100633', (190, 201))
616201	28652779	In Chinese patients with squamous cell esophagus carcinoma, a significant benefit was obtained with modified fractionation RT, suggesting that the appropriateness of its use be reinforced in clinical practice.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('esophagus carcinoma', 'Phenotype', 'HP:0011459', (39, 58))	('modified fractionation', 'Var', (100, 122))	('patients', 'Species', '9606', (11, 19))	('squamous cell esophagus carcinoma', 'Disease', (25, 58))	('squamous cell esophagus carcinoma', 'Disease', 'MESH:D002294', (25, 58))	('benefit', 'PosReg', (74, 81))
616226	27977606	The criteria of enrollment were treatment-naive patients with histologically proven thoracic esophageal squamous cell carcinoma (ESCC); aged >=70 years; KPS >=70; clinical stage T1-3; complete resection (R0); without any other site of carcinoma or with metastatic disease.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('carcinoma', 'Disease', 'MESH:D002277', (235, 244))	('KPS >=70', 'Var', (153, 161))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('carcinoma', 'Disease', 'MESH:D002277', (118, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('T1-3', 'Gene', '29123;9173;292', (178, 182))	('thoracic', 'Disease', (84, 92))	('esophageal squamous cell carcinoma', 'Disease', (93, 127))	('carcinoma', 'Disease', (118, 127))	('carcinoma', 'Disease', (235, 244))	('T1-3', 'Gene', (178, 182))	('patients', 'Species', '9606', (48, 56))
616284	27977606	Relatively low survival may attribute to microscopic residual/macroscopic residual disease resection and clinical stage IV in patients' cohort.	('low', 'NegReg', (11, 14))	('microscopic', 'Var', (41, 52))	('patients', 'Species', '9606', (126, 134))
616357	27388201	Moreover, GPX2 expression has statistically significant difference in the tumour histological grade of ESCC (P < 0.001), while there was no statistically significant difference in age, sex, tumour size, tumour location, gross morphology and clinical TNM stages (P > 0.05).	('TNM', 'Gene', (250, 253))	('expression', 'Var', (15, 25))	('tumour', 'Disease', (190, 196))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('significant difference', 'Reg', (44, 66))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', (203, 209))	('TNM', 'Gene', '10178', (250, 253))	('GPX2', 'Gene', '2877', (10, 14))	('ESCC', 'Disease', (103, 107))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (190, 196))	('GPX2', 'Gene', (10, 14))
616500	23179937	investigated 228 cases of esophageal carcinoma patients and found that cases with COX-2 overexpression had deeper tumor invasion, more advanced clinical staging, poorer histological differentiation and poorer prognoses than those with low or no expression of COX-2.	('COX-2', 'Gene', '4513', (259, 264))	('COX-2', 'Gene', '4513', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('COX-2', 'Gene', (259, 264))	('deeper tumor', 'Disease', (107, 119))	('patients', 'Species', '9606', (47, 55))	('COX-2', 'Gene', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('overexpression', 'Var', (88, 102))	('esophageal carcinoma', 'Disease', (26, 46))	('deeper tumor', 'Disease', 'MESH:D009369', (107, 119))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (26, 46))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (26, 46))
616520	23179937	investigated 82 cases of oropharyngeal squamous cell carcinoma and detected that cases with COX-2 expression had a worse prognosis than those with negative COX-2 expression.	('expression', 'Var', (98, 108))	('COX-2', 'Gene', '4513', (156, 161))	('COX-2', 'Gene', (92, 97))	('COX-2', 'Gene', '4513', (92, 97))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (25, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinoma', 'Disease', (39, 62))	('COX-2', 'Gene', (156, 161))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 62))
616527	23179937	Some scholars have proposed that the inhibition of P300 can prevent tumorigenesis.	('tumor', 'Disease', (68, 73))	('prevent', 'NegReg', (60, 67))	('inhibition', 'Var', (37, 47))	('P300', 'Gene', '2033', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('P300', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
616539	22139084	The human cadherin 11 is a pro-apoptotic tumor suppressor modulating cell stemness through Wnt/beta-catenin signaling and silenced in common carcinomas Genetic alterations of 16q21-q22, the locus of a 6-cadherin cluster, are frequently involved in multiple tumors, suggesting the presence of critical tumor suppressor genes (TSGs).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('carcinomas', 'Disease', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('beta-catenin', 'Gene', (95, 107))	('beta-catenin', 'Gene', '1499', (95, 107))	('tumor', 'Disease', (257, 262))	('multiple tumors', 'Disease', (248, 263))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('TSG', 'Gene', '57045', (325, 328))	('cadherin 11', 'Gene', (10, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('tumor', 'Disease', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('carcinomas', 'Disease', 'MESH:D002277', (141, 151))	('cadherin 11', 'Gene', '1009', (10, 21))	('alterations', 'Var', (160, 171))	('TSG', 'Gene', (325, 328))	('tumor', 'Disease', (301, 306))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('involved', 'Reg', (236, 244))	('human', 'Species', '9606', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('multiple tumors', 'Disease', 'MESH:D009369', (248, 263))
616542	22139084	Aberrant methylation was also frequently detected in multiple primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('primary tumors', 'Disease', (62, 76))	('primary tumors', 'Disease', 'MESH:D009369', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Aberrant methylation', 'Var', (0, 20))	('detected', 'Reg', (41, 49))
616545	22139084	Thus, our work identifies CDH11 as a functional tumor suppressor and an important antagonist of Wnt/beta-catenin and AKT/Rho A signaling, with frequent epigenetic inactivation in common carcinomas.	('AKT', 'Gene', '207', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('AKT', 'Gene', (117, 120))	('Rho A', 'Gene', '387', (121, 126))	('carcinomas', 'Disease', 'MESH:D002277', (186, 196))	('Rho A', 'Gene', (121, 126))	('carcinomas', 'Disease', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('epigenetic inactivation', 'Var', (152, 175))	('CDH11', 'Gene', (26, 31))
616553	22139084	Epigenetic alterations of TSGs, including promoter CpG methylation and histone modifications, are frequently involved in tumor development and progression.	('Epigenetic alterations', 'Var', (0, 22))	('promoter', 'MPA', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('TSG', 'Gene', (26, 29))	('histone modifications', 'MPA', (71, 92))	('TSG', 'Gene', '57045', (26, 29))	('involved', 'Reg', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
616554	22139084	Remarkably, epigenetic silencing of CDH1 and CDH13 in tumors has been reported in multiple epithelial tumors and hematopoietic malignancies, indicating that promoter CpG methylation-mediated silencing is an important regulatory mechanism for disrupting cadherin members in tumorigenesis.	('CDH1', 'Gene', '999', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CDH1', 'Gene', '999', (36, 40))	('tumor', 'Disease', (273, 278))	('hematopoietic malignancies', 'Disease', (113, 139))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('CDH1', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('epigenetic silencing', 'Var', (12, 32))	('CDH1', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Disease', (102, 108))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (113, 139))	('CDH13', 'Gene', '1012', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (102, 107))	('disrupting', 'NegReg', (242, 252))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('reported', 'Reg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (54, 59))	('CDH13', 'Gene', (45, 50))
616557	22139084	Our present epigenetic and functional studies demonstrated that CDH11 was frequently inactivated by promoter methylation in multiple carcinomas and functioned as a tumor suppressor, by inducing tumor cell apoptosis and inhibiting cell motility and invasion, as well as cell stemness through Wnt/beta-catenin and AKT/Rho A signaling.	('CDH11', 'Gene', (64, 69))	('tumor', 'Disease', (164, 169))	('cell stemness', 'CPA', (269, 282))	('multiple carcinomas', 'Disease', 'MESH:C537656', (124, 143))	('inhibiting', 'NegReg', (219, 229))	('AKT', 'Gene', '207', (312, 315))	('Rho A', 'Gene', (316, 321))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('promoter methylation', 'Var', (100, 120))	('inducing', 'PosReg', (185, 193))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('Wnt/beta-catenin', 'Pathway', (291, 307))	('invasion', 'CPA', (248, 256))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('multiple carcinomas', 'Disease', (124, 143))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('AKT', 'Gene', (312, 315))	('inactivated', 'NegReg', (85, 96))	('Rho A', 'Gene', '387', (316, 321))
616558	22139084	Genome-wide identification of gene deletions using aCGH identifies candidate TSG loci in tumors.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('aCGH', 'Gene', (51, 55))	('TSG', 'Gene', (77, 80))	('deletions', 'Var', (35, 44))	('TSG', 'Gene', '57045', (77, 80))
616565	22139084	Further analysis of CDH11 promoter showed that it contains a typical CpG island (http://ccnt.hsc.usc.edu/cpgislands2; Figure 2a), suggesting that CDH11 is likely subject to methylation-mediated silencing.	('hsc', 'Gene', '2523', (93, 96))	('CDH11', 'Gene', (20, 25))	('hsc', 'Gene', (93, 96))	('CDH11', 'Var', (146, 151))
616567	22139084	MSP analysis showed that CDH11 was frequently methylated in cell lines of nasopharyngeal, esophageal, gastric, hepatocellular, colorectal, breast and cervix carcinomas, well correlated with the expression levels (Figure 2b; Supplementary Figure S1).	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('gastric', 'Disease', (102, 109))	('colorectal', 'Disease', 'MESH:D015179', (127, 137))	('hepatocellular', 'Disease', (111, 125))	('CDH11', 'Gene', (25, 30))	('breast and cervix carcinomas', 'Disease', 'MESH:D002583', (139, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('nasopharyngeal', 'Disease', (74, 88))	('esophageal', 'Disease', (90, 100))	('correlated', 'Reg', (174, 184))	('colorectal', 'Disease', (127, 137))	('methylated', 'Var', (46, 56))
616572	22139084	CDH11 could also be activated in colon cell line HCT116 by genetic disruption of both DNMT1 and DNMT3B, accompanied by CDH11 promoter demethylation, but not in single knockout (KO) of either DNA methyltransferase 1 (DNMT1) or DNMT3B (Figure 2d), similarly to other known and novel TSGs we previously studied, indicating that the maintenance of CDH11 promoter methylation is mediated by DNMT1 and DNMT3B.	('CDH11', 'Gene', (119, 124))	('DNA methyltransferase 1', 'Gene', (191, 214))	('activated', 'PosReg', (20, 29))	('DNMT1', 'Gene', '1786', (386, 391))	('DNA methyltransferase 1', 'Gene', '1786', (191, 214))	('DNMT1', 'Gene', '1786', (216, 221))	('DNMT3B', 'Gene', (96, 102))	('DNMT3B', 'Gene', '1789', (96, 102))	('DNMT1', 'Gene', (86, 91))	('TSG', 'Gene', '57045', (281, 284))	('promoter', 'MPA', (125, 133))	('HCT116', 'CellLine', 'CVCL:0291', (49, 55))	('TSG', 'Gene', (281, 284))	('disruption', 'Var', (67, 77))	('DNMT3B', 'Gene', (396, 402))	('DNMT3B', 'Gene', '1789', (396, 402))	('DNMT1', 'Gene', (386, 391))	('DNMT1', 'Gene', (216, 221))	('CDH11', 'Gene', (344, 349))	('genetic disruption', 'Var', (59, 77))	('demethylation', 'NegReg', (134, 147))	('CDH11', 'Gene', (0, 5))	('DNMT1', 'Gene', '1786', (86, 91))	('DNMT3B', 'Gene', '1789', (226, 232))	('DNMT3B', 'Gene', (226, 232))
616573	22139084	CDH11 methylation was further detected in multiple primary carcinomas with variable frequencies, as summarized in Supplementary Table S2.	('CDH11', 'Gene', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('carcinomas', 'Disease', (59, 69))	('carcinomas', 'Disease', 'MESH:D002277', (59, 69))	('methylation', 'Var', (6, 17))	('detected', 'Reg', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
616574	22139084	CDH11 methylation was frequently detected in 94% (17 of 18) of NPC, 93% (13 of 14) of esophageal, 100% (13 of 13) of gastric, 66% (28 of 42) of HCC, 90% (10 of 11) of colonal and 91% (11 of 12) of breast carcinomas (Figure 4; Supplementary Table S2), while only seldom detected in normal tissues (nine normal nasopharyx, nine normal breast tissues, paired normal tissues of esophageal carcinoma and HCC; Figure 4).	('esophageal carcinoma', 'Disease', (374, 394))	('colonal', 'Disease', (167, 174))	('breast carcinomas', 'Phenotype', 'HP:0003002', (197, 214))	('esophageal', 'Disease', (86, 96))	('HCC', 'Gene', '619501', (144, 147))	('HCC', 'Phenotype', 'HP:0001402', (144, 147))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (374, 394))	('HCC', 'Gene', (144, 147))	('methylation', 'Var', (6, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('detected', 'Reg', (33, 41))	('breast carcinomas', 'Disease', 'MESH:D001943', (197, 214))	('NPC', 'Phenotype', 'HP:0100630', (63, 66))	('HCC', 'Gene', '619501', (399, 402))	('CDH11', 'Gene', (0, 5))	('breast carcinomas', 'Disease', (197, 214))	('HCC', 'Phenotype', 'HP:0001402', (399, 402))	('NPC', 'Disease', (63, 66))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (374, 394))	('gastric', 'Disease', (117, 124))	('HCC', 'Gene', (399, 402))	('carcinoma', 'Phenotype', 'HP:0030731', (385, 394))
616575	22139084	These results suggest that hypermethylation of the CDH11 promoter is a common event in multiple tumorigenesis.	('multiple', 'Disease', (87, 95))	('hypermethylation', 'Var', (27, 43))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('CDH11', 'Gene', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
616579	22139084	The frequent downregulation and methylation of CDH11 in common tumors indicated that it is likely a tumor suppressor.	('tumor', 'Disease', (63, 68))	('methylation', 'Var', (32, 43))	('CDH11', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('downregulation', 'NegReg', (13, 27))	('tumors', 'Disease', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
616582	22139084	Results of colony formation assays showed that ectopic expression of CDH11 significantly suppressed the numbers of tumor cell colonies to <50% of the control cells (Figures 5c; Supplementary Figure S3B), indicating that CDH11 indeed suppresses the tumorigenecity of tumor cells.	('CDH11', 'Var', (220, 225))	('tumor', 'Disease', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('suppressed', 'NegReg', (89, 99))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('CDH11', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('suppresses', 'NegReg', (233, 243))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
616585	22139084	Results showed that CDH11 expression significantly increased the number of apoptotic HONE1 and KYSE150 cells when compared with controls (from ~1.5 to ~10% *P<0.05; Figure 5d).	('CDH11', 'Gene', (20, 25))	('HONE1', 'CellLine', 'CVCL:8706', (85, 90))	('increased', 'PosReg', (51, 60))	('expression', 'Var', (26, 36))	('KYSE150', 'CellLine', 'CVCL:1348', (95, 102))
616588	22139084	By TOPflash reporter assay measuring endogenous beta-catenin/TcF activity, it was found that CDH11-expressing tumor cells showed 2-3-fold reduced TOPflash activities when compared with controls (Figure 6a), suggesting that CDH11 led to decreased beta-catenin/TcF activities.	('TcF', 'Gene', (259, 262))	('CDH11', 'Var', (223, 228))	('TcF', 'Gene', '3172', (259, 262))	('reduced', 'NegReg', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('TcF', 'Gene', (61, 64))	('TcF', 'Gene', '3172', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('TOPflash activities', 'MPA', (146, 165))	('activities', 'MPA', (263, 273))	('decreased', 'NegReg', (236, 245))	('CDH11-expressing', 'Gene', (93, 109))
616596	22139084	Collectively, these results indicate that CDH11 expression could inhibit tumor cell metastasis and migration via disrupting stress filament integrity mediated by multiple signaling pathways.	('stress filament integrity', 'MPA', (124, 149))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('disrupting', 'NegReg', (113, 123))	('CDH11', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('expression', 'Var', (48, 58))	('migration', 'CPA', (99, 108))	('inhibit', 'NegReg', (65, 72))
616599	22139084	Dramatic morphological changes were observed in CDH11-expressing tumor cells, in which spindle-like, fibroblastic morphology was replaced by the typical cobblestone-like appearance of normal epithelial cells (Figure 8a), indicating that CDH11 most likely reverses tumor cell EMT.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('CDH11', 'Var', (237, 242))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (264, 269))	('CDH11-expressing', 'Gene', (48, 64))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
616608	22139084	Recently, increasing evidence indicate that CDH11 might be a candidate tumor suppressor for locus 16q, a frequent loss of heterozygosity region in multiple cancers.	('CDH11', 'Gene', (44, 49))	('locus 16q', 'Var', (92, 101))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('multiple cancers', 'Disease', 'MESH:D009369', (147, 163))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('multiple cancers', 'Disease', (147, 163))	('tumor', 'Disease', (71, 76))
616614	22139084	TSGs are more frequently inactivated through epigenetic mechanisms such as promoter CpG methylation, or a combination of genetic and epigenetic inactivation, than biallelic genetic inactivation alone.	('inactivated', 'NegReg', (25, 36))	('TSG', 'Gene', '57045', (0, 3))	('promoter CpG methylation', 'Var', (75, 99))	('TSG', 'Gene', (0, 3))
616615	22139084	Three cadherin members (CDH1 and CDH13 at 16q, CDH4) as TSGs being inactivated genetically and/or epigenetically in various tumors and involved in tumor cell invasion and metastasis have been previously reported.	('CDH1', 'Gene', (24, 28))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Disease', (147, 152))	('CDH13', 'Gene', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('involved', 'Reg', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Disease', (124, 130))	('TSG', 'Gene', '57045', (56, 59))	('CDH4', 'Gene', (47, 51))	('CDH1', 'Gene', '999', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('epigenetically', 'Var', (98, 112))	('TSG', 'Gene', (56, 59))	('CDH1', 'Gene', '999', (24, 28))	('CDH4', 'Gene', '1002', (47, 51))	('CDH1', 'Gene', (33, 37))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('CDH13', 'Gene', '1012', (33, 38))	('inactivated', 'NegReg', (67, 78))
616627	22139084	In summary, our study identifies CDH11 as a functional tumor suppressor and an important regulator of Wnt/beta-catenin and AKT/Rho A signaling, with frequent epigenetic inactivation in common carcinomas.	('carcinomas', 'Disease', (192, 202))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('carcinomas', 'Disease', 'MESH:D002277', (192, 202))	('epigenetic inactivation', 'Var', (158, 181))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Rho A', 'Gene', '387', (127, 132))	('Rho A', 'Gene', (127, 132))	('tumor', 'Disease', (55, 60))	('AKT', 'Gene', '207', (123, 126))	('AKT', 'Gene', (123, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('CDH11', 'Gene', (33, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))
616667	32351288	Early detection of susceptible populations by detecting nucleic acid or protein molecular markers in the blood has become an area of intense investigation in current tumor diagnosis research.	('nucleic acid', 'Var', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('protein', 'Protein', (72, 79))	('tumor', 'Disease', (166, 171))
616684	32351288	However, a large body of epidemiological studies in recent years have shown that patients with autoimmune diseases have a significantly increased or decreased risk for certain cancers, suggesting that autoantibodies may promote or inhibit cancer progression.	('cancers', 'Disease', (176, 183))	('autoimmune diseases', 'Disease', (95, 114))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (95, 114))	('inhibit', 'NegReg', (231, 238))	('autoantibodies', 'Var', (201, 215))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('promote', 'PosReg', (220, 227))	('cancer', 'Disease', (239, 245))	('decreased', 'NegReg', (149, 158))	('autoimmune diseases', 'Disease', 'MESH:D001327', (95, 114))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
616685	32351288	Antigen changes in cancer cells, which have been shown to be closely related to tumor proliferation and grade, induce the production of autoantibodies by the immune system.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('changes', 'Var', (8, 15))	('production', 'MPA', (122, 132))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('Antigen', 'MPA', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Disease', (19, 25))	('induce', 'Reg', (111, 117))	('tumor', 'Disease', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('autoantibodies', 'MPA', (136, 150))
616698	32351288	A growing number of studies have shown that different miRNAs play different roles in promoting cancer or tumor suppression, and these abnormally expressed miRNAs can unbalance the expression of oncogenic or suppressor genes in the body, eventually leading to tumor production.	('leading to', 'Reg', (248, 258))	('tumor suppression', 'Disease', 'MESH:D009369', (105, 122))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('cancer', 'Disease', (95, 101))	('expression', 'MPA', (180, 190))	('tumor suppression', 'Disease', (105, 122))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (259, 264))	('abnormally', 'Var', (134, 144))	('tumor', 'Disease', (105, 110))
616707	32351288	Zhang et al measured the serum miRNA concentration by RT-qPCR and identified seven serum miRNAs (miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a, and miR-127-3p) that were significantly up-regulated in the serum of ESCC patients compared to the control group.	('miR-10a', 'Gene', (97, 104))	('miR-22', 'Gene', (133, 139))	('miR-127-3p', 'Gene', (156, 166))	('miR-100', 'Gene', (114, 121))	('patients', 'Species', '9606', (226, 234))	('miR-22', 'Gene', '407004', (106, 112))	('miR-100', 'Gene', '406892', (114, 121))	('miR-223', 'Gene', (133, 140))	('miR-22', 'Gene', (106, 112))	('miR-10a', 'Gene', '406902', (97, 104))	('miR-148b', 'Gene', '442892', (123, 131))	('miR-148b', 'Gene', (123, 131))	('ESCC', 'Disease', (221, 225))	('up-regulated', 'PosReg', (192, 204))	('miR-133a', 'Var', (142, 150))	('serum miRNA concentration', 'MPA', (25, 50))	('miR-223', 'Gene', '407008', (133, 140))	('miR-127-3p', 'Gene', '100302165', (156, 166))	('miR-22', 'Gene', '407004', (133, 139))
616730	32351288	Researchers first detected KRAS oncogenic mutations in the blood cf-DNA of patients with pancreatic cancer in 1994 by using PCR, which was consistent with that detected in tumor tissues.	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('KRAS', 'Gene', '3845', (27, 31))	('tumor', 'Disease', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('patients', 'Species', '9606', (75, 83))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('KRAS', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('mutations', 'Var', (42, 51))	('pancreatic cancer', 'Disease', (89, 106))
616731	32351288	In other words, the small part of cf-DNA carrying tumor-specific mutations is indeed released by tumor cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('mutations', 'Var', (65, 74))
616732	32351288	Thus, tumor-associated mutations in cf-DNA can serve as tumor-specific markers, and these tumor-derived cf-DNA fragments carrying tumor characteristics are referred to as ctDNA.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (90, 95))	('cf-DNA', 'Gene', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (6, 11))
616743	32351288	Increasing studies have confirmed that detection of ctDNA in the blood of tumor patients can also identify all driver gene mutations in the tumor tissue.	('patients', 'Species', '9606', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutations', 'Var', (123, 132))	('tumor', 'Disease', (140, 145))
616744	32351288	Lebofsky et al performed in-depth sequencing analysis of plasma ctDNA and metastatic tumor tissue from 34 tumor patients (including 18 different tumor types), covering 6800 COSMIC tumor hotspot mutations in 46 genes.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutations', 'Var', (194, 203))	('tumor', 'Disease', (180, 185))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (106, 111))
616745	32351288	The results showed that in 27 patients, 28 (97%) of 29 mutant genes in metastatic tumor tissue were detected in paired plasma ctDNA.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mutant genes', 'Var', (55, 67))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('detected', 'Reg', (100, 108))
616746	32351288	These results indicate that plasma ctDNA has the potential to replace tumor metastatic lesion tissue for the detection of mutant genes.	('mutant genes', 'Var', (122, 134))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
616840	32258977	Van Workum et al performed propensity score-matched analysis to compare minimally invasive Ivor Lewis versus minimally invasive McKeown esophagectomy.36 They concluded that Ivor Lewis MIE was associated with a lower incidence of anastomotic leakage, 90-day mortality and other postoperative morbidities as compared to McKeown MIE in patients in whom both procedures were oncologically feasible.	('mortality', 'Disease', (257, 266))	('anastomotic leakage', 'Disease', (229, 248))	('MIE', 'Chemical', '-', (184, 187))	('anastomotic leakage', 'Disease', 'MESH:D057868', (229, 248))	('patients', 'Species', '9606', (333, 341))	('lower', 'NegReg', (210, 215))	('mortality', 'Disease', 'MESH:D003643', (257, 266))	('MIE', 'Chemical', '-', (326, 329))	('Ivor Lewis MIE', 'Var', (173, 187))
616866	30887517	In a patient-derived xenograft mouse model, xanthohumol reduced tumor volume specifically in high AKT-expressing tumors, with little effect on low AKT tumors.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('reduced', 'NegReg', (56, 63))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('mouse', 'Species', '10090', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor volume', 'MPA', (64, 76))	('high AKT-expressing', 'Var', (93, 112))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
616878	30887517	Antibodies to detect cytochrome c, p-mTOR (Ser2448), or beta-actin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA) or Zhongshan Jinqiao Biological Technology Co., Ltd (Beijing, China).	('Ser2448', 'Chemical', '-', (43, 50))	('beta-actin', 'Gene', '728378', (56, 66))	('Ser2448', 'Var', (43, 50))	('beta-actin', 'Gene', (56, 66))
616879	30887517	Cells were cultured in RPMI-1640 containing penicillin (100 units/ml), streptomycin (100 mug/ml) and 10% fetal bovine serum (FBS, Biological Industries, Kibbutz Beit-Haemek, Israel).	('FBS', 'Disease', (125, 128))	('RPMI-1640', 'Chemical', '-', (23, 32))	('penicillin', 'Chemical', 'MESH:D010406', (44, 54))	('bovine', 'Species', '9913', (111, 117))	('100', 'Var', (85, 88))	('streptomycin', 'Chemical', 'MESH:D013307', (71, 83))	('FBS', 'Disease', 'MESH:D005198', (125, 128))
616895	30887517	For knocking down the expression of AKT1/2 in ESCC cells, the pLKO.1-mock, shRNA-Akt1 or shRNA-Akt2 plasmids together with packaging vectors, pMD2.0G and psPAX (Addgene Inc., Cambridge, MA) were transfected into 293T cells using the Simple-Fect transfection reagent (Signaling Dawn Biotech, Wuhan, Hubei, China) following the manufacturer's protocols.	('knocking', 'Var', (4, 12))	('Akt1', 'Gene', (81, 85))	('Akt1', 'Gene', '207', (81, 85))	('Akt2', 'Gene', (95, 99))	('Akt2', 'Gene', '208', (95, 99))	('293T', 'CellLine', 'CVCL:0063', (212, 216))
616904	30887517	From the docking results, we found that xanthohumol formed hydrogen bonds at Ala230, Glu228, Glu234 and Lys158 in the backbone of AKT1 (Fig.	('Lys158', 'Var', (104, 110))	('Glu228', 'Var', (85, 91))	('Glu234', 'Chemical', '-', (93, 99))	('hydrogen', 'Interaction', (59, 67))	('Glu234', 'Var', (93, 99))	('Glu228', 'Chemical', '-', (85, 91))	('Ala230', 'Chemical', '-', (77, 83))	('hydrogen', 'Chemical', 'MESH:D006859', (59, 67))	('Lys158', 'Chemical', '-', (104, 110))
616905	30887517	2 f, upper panel) and at Glu236, Thr213 and Lys181 of AKT2, respectively (Fig.	('Lys181', 'Var', (44, 50))	('AKT2', 'Gene', (54, 58))	('Lys181', 'Chemical', '-', (44, 50))	('Thr213', 'Chemical', '-', (33, 39))	('Glu236', 'Chemical', '-', (25, 31))	('Thr213', 'Var', (33, 39))
616908	30887517	Based on the human phosphokinase array results, p-p27, p-p38alpha and p-ERK1/2 decreased more in the HEG18 case compared to the HEG5 case (Fig.	('ERK1/2', 'Gene', (72, 78))	('decreased', 'NegReg', (79, 88))	('ERK1/2', 'Gene', '5595;5594', (72, 78))	('p-p27', 'Var', (48, 53))	('p38alpha', 'Gene', '1432', (57, 65))	('p38alpha', 'Gene', (57, 65))	('HEG18', 'Var', (101, 106))
616909	30887517	Some cancer types, such as colon cancer, lung cancer and esophageal cancer, showed decreased expression of p27.36 The p27 protein is reported as a downstream target of AKT that can be phosphorylated by AKT at Thr198.37, 38 According to the kinase array results, we hypothesized that p27 plays a role in the enhanced therapeutic effects of xanthohumol.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (27, 39))	('decreased', 'NegReg', (83, 92))	('lung cancer', 'Disease', (41, 52))	('Thr198', 'Chemical', '-', (209, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colon cancer', 'Disease', 'MESH:D015179', (27, 39))	('enhanced', 'PosReg', (307, 315))	('p27.36', 'Var', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('esophageal cancer', 'Disease', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('colon cancer', 'Disease', (27, 39))
616910	30887517	Several selective AKT inhibitors, including MK2206, GSK2141795 and GSK690693, are undergoing clinical trials against different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('GSK2141795', 'Var', (52, 62))	('MK2206', 'Var', (44, 50))	('GSK690693', 'Var', (67, 76))	('GSK2141795', 'Chemical', 'MESH:C000595149', (52, 62))	('GSK690693', 'Chemical', 'MESH:C528328', (67, 76))	('AKT', 'Pathway', (18, 21))	('MK2206', 'Chemical', 'MESH:C548887', (44, 50))
616944	31245159	In a phase II trial, in a subset of patients who were recruited between 2010 and 2012 (n=300), it was demonstrated that the histopathological findings (pathological remission) were significantly better with FLOT and the rate of curative resections was higher than that with the MAGIC regimen (85% vs. 74%, respectively).	('better', 'PosReg', (195, 201))	('curative resections', 'CPA', (228, 247))	('patients', 'Species', '9606', (36, 44))	('higher', 'PosReg', (252, 258))	('FLOT', 'Var', (207, 211))
617032	30197671	When the DNA in cells or cells tend to be cancerous, the P53 gene can remove them in time, thus playing an anticancer effect; but if the P53 gene mutation occurs, it will lose such a regulatory effect and mutate from the cancer cell-removing gene into the oncogene, thus being transformed from normal cells into cancer cells.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('P53', 'Gene', (57, 60))	('cancerous', 'Disease', 'MESH:D009369', (42, 51))	('P53', 'Gene', '7157', (137, 140))	('cancer', 'Disease', (312, 318))	('cancer', 'Disease', (111, 117))	('mutation', 'Var', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('mutate', 'Var', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('P53', 'Gene', '7157', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('regulatory effect', 'MPA', (183, 200))	('cancerous', 'Disease', (42, 51))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('P53', 'Gene', (137, 140))	('cancer', 'Disease', (42, 48))	('lose', 'NegReg', (171, 175))
617034	30197671	On the contrary, after the P53 protein mutation, its half-life is extended, and its stability is also increased significantly, so that the immunological detection can detect the mutant P53 protein.	('mutation', 'Var', (39, 47))	('protein', 'Protein', (189, 196))	('protein', 'Protein', (31, 38))	('P53', 'Gene', (185, 188))	('P53', 'Gene', '7157', (185, 188))	('P53', 'Gene', (27, 30))	('half-life', 'MPA', (53, 62))	('P53', 'Gene', '7157', (27, 30))	('increased', 'PosReg', (102, 111))	('stability', 'MPA', (84, 93))
617096	29328465	After 48 h of incubation, the IC50 value of diphyllin was 0.2792 microM in ECA-109 cells and 0.2058 microM in TE-1 cells (Fig.	('0.2792 microM', 'Var', (58, 71))	('0.2058 microM', 'Var', (93, 106))	('diphyllin', 'Chemical', 'MESH:C010130', (44, 53))
617100	29328465	The results revealed that the diphyllin group exhibited significant S arrest compared with the normal group both in TE-1 and ECA-109 cells (Fig.	('S arrest', 'Disease', (68, 76))	('S arrest', 'Disease', 'MESH:D006323', (68, 76))	('diphyllin', 'Chemical', 'MESH:C010130', (30, 39))	('diphyllin', 'Var', (30, 39))
617141	29190937	Although some studies have reported the use of 18FDG PET-CT for the detection of SPCs, the accuracy of PET-CT remains to be controversial.	('SPC', 'Gene', '5541', (81, 84))	('SPC', 'Gene', (81, 84))	('18FDG', 'Chemical', 'MESH:D019788', (47, 52))	('18FDG', 'Var', (47, 52))
617149	29190937	Figure 2 shows the forest plot of sensitivity and specificity for 18FDG PET-CT in the detection of SPCs.	('18FDG', 'Var', (66, 71))	('18FDG', 'Chemical', 'MESH:D019788', (66, 71))	('SPC', 'Gene', '5541', (99, 102))	('SPC', 'Gene', (99, 102))
617161	29190937	In the previous study, 18FDG PET-CT showed a high sensitivity of 88.5% (23 of 26 patients) in detecting SPCs, which was significantly higher than the 61.5% (16 of 26) from a conventional staging work-up.	('SPC', 'Gene', (104, 107))	('18FDG', 'Var', (23, 28))	('18FDG', 'Chemical', 'MESH:D019788', (23, 28))	('higher', 'PosReg', (134, 140))	('patients', 'Species', '9606', (81, 89))	('SPC', 'Gene', '5541', (104, 107))
617167	29190937	This meta-analysis showed that the negative predictive values for 18FDG PET-CT were 0.99, 0.98, and 0.97 when the prevalences of SPCs in cancer patients were assumed to be 5%, 10%, and 15%.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('SPC', 'Gene', '5541', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('patients', 'Species', '9606', (144, 152))	('18FDG', 'Chemical', 'MESH:D019788', (66, 71))	('SPC', 'Gene', (129, 132))	('cancer', 'Disease', (137, 143))	('18FDG', 'Var', (66, 71))
617168	29190937	When the prevalence of SPCs in cancer patients were assumed to be 5-15%, 18FDG PET-CT is very informative lowering the probability of disease to as low as 1-3% when the results of PET-CT are negative.	('18FDG', 'Chemical', 'MESH:D019788', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('18FDG PET-CT', 'Var', (73, 85))	('SPC', 'Gene', '5541', (23, 26))	('lowering', 'NegReg', (106, 114))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('SPC', 'Gene', (23, 26))	('patients', 'Species', '9606', (38, 46))	('cancer', 'Disease', (31, 37))
617221	28247864	Patients with microscopic specialized metaplasia at the cardia have been seen to progress to macroscopically evident Barrett's esophagus.	('microscopic specialized metaplasia', 'Var', (14, 48))	('cardia', 'Disease', 'MESH:D004938', (56, 62))	('progress', 'PosReg', (81, 89))	('cardia', 'Disease', (56, 62))	('Patients', 'Species', '9606', (0, 8))	("Barrett's esophagus", 'Disease', (117, 136))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (117, 136))
617227	28247864	Direct visualization of clonal mutations in the mitochondrial DNA-encoded gene cytochrome c oxidase (CCO) shows that specialized Barrett's glands are clonal; similarly, the metaplastic crypts of gastric intestinal metaplasia are also clonal.	('gastric intestinal metaplasia', 'Disease', 'MESH:D013274', (195, 224))	("Barrett's glands", 'Phenotype', 'HP:0100580', (129, 145))	('mutations', 'Var', (31, 40))	('CCO', 'Gene', (101, 104))	("Barrett's gland", 'Phenotype', 'HP:0100580', (129, 144))	('gastric intestinal metaplasia', 'Disease', (195, 224))
617228	28247864	Such CCO mutations are thought not to confer a fitness advantage, so this can be interpreted in terms of a CCO-mutant stem cell drifting to fixation within the stem cell niche.	('fitness advantage', 'Disease', (47, 64))	('mutations', 'Var', (9, 18))	('CCO-mutant', 'Gene', (107, 117))	('fitness advantage', 'Disease', 'MESH:D012640', (47, 64))
617243	28247864	For example, we reported a patch of entirely CCO-mutated gastric glands (or gastric units) where direct sequencing showed all glands to contained a clonal mutation (G A transition at position 2593 in the 16S rRNA [MTRNR2] gene) showing that a single, wholly mutated gastric gland has expanded by multiple fission events to form this clonal patch.	('contained', 'Reg', (136, 145))	('MTRNR2', 'Gene', '4550', (214, 220))	('transition', 'Var', (169, 179))	('MTRNR2', 'Gene', (214, 220))
617252	28247864	Finally, mutations occur within Barrett's glands, leading to the selection of the dysplastic phenotype, which if low-grade may remain stable for many years.	('dysplastic', 'Disease', 'MESH:D004416', (82, 92))	("Barrett's gland", 'Phenotype', 'HP:0100580', (32, 47))	('dysplastic', 'Disease', (82, 92))	("Barrett's glands", 'Phenotype', 'HP:0100580', (32, 48))	('mutations', 'Var', (9, 18))	('leading to', 'Reg', (50, 60))
617350	26846932	If the tumor is sensitive to radiation, to some extent, IFRT could also significantly reduce nodal and distant micrometastases.	('nodal', 'Gene', '4838', (93, 98))	('IFRT', 'Var', (56, 60))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('metastases', 'Disease', (116, 126))	('metastases', 'Disease', 'MESH:D009362', (116, 126))	('reduce', 'NegReg', (86, 92))	('nodal', 'Gene', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
617354	26846932	showed that that the incidental irradiation dose to high-risk nodal regions is considerable for T1-3N0M0 esophageal SCC using three-dimensional CRT.	('SCC', 'Gene', (116, 119))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('nodal', 'Gene', '4838', (62, 67))	('SCC', 'Gene', '6317', (116, 119))	('T1-3N0M0', 'Var', (96, 104))	('CR', 'Chemical', '-', (144, 146))	('nodal', 'Gene', (62, 67))
617418	26846932	Although ENI might delay cervical node progression in the elective field, it does not decrease the incidence of these failures.	('delay', 'NegReg', (19, 24))	('ENI', 'Chemical', '-', (9, 12))	('ENI', 'Var', (9, 12))	('cervical node progression', 'CPA', (25, 50))
617566	23925817	In addition, miRNAs have been associated with unique patterns of expressions in cancers and identified with several different cancer types as both oncogenes and tumor suppressors.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('expressions', 'MPA', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('miRNAs', 'Var', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', (161, 166))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
617623	23925817	When a miRNA had been reported in the BE and EAC literature multiple times, it was more likely to be associated with BE/EAC in our training set.	('BE/EAC', 'Gene', '1540', (117, 123))	('BE/EAC', 'Gene', (117, 123))	('miRNA', 'Var', (7, 12))	('EAC', 'Phenotype', 'HP:0011459', (120, 123))	('EAC', 'Gene', '1540', (120, 123))	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('associated', 'Reg', (101, 111))	('EAC', 'Gene', (120, 123))	('BE', 'Phenotype', 'HP:0100580', (38, 40))	('EAC', 'Gene', '1540', (45, 48))	('BE', 'Phenotype', 'HP:0100580', (117, 119))	('EAC', 'Gene', (45, 48))
617639	23925817	Previous studies have described miR-203 and miR-205 as highly expressed in squamous epithelium compared to BE or EAC, while miR-21 and miR-194 have demonstrated increased expression in BE, gastric epithelium, and EAC compared to squamous esophageal epithelium,.	('miR-21', 'Gene', '406991', (124, 130))	('EAC', 'Phenotype', 'HP:0011459', (213, 216))	('EAC', 'Gene', '1540', (113, 116))	('EAC', 'Gene', (113, 116))	('miR-21', 'Gene', (124, 130))	('miR-205', 'Gene', '406988', (44, 51))	('EAC', 'Gene', '1540', (213, 216))	('EAC', 'Gene', (213, 216))	('increased', 'PosReg', (161, 170))	('BE', 'Phenotype', 'HP:0100580', (185, 187))	('miR-203', 'Gene', (32, 39))	('squamous esophageal', 'Disease', (229, 248))	('expression', 'MPA', (171, 181))	('squamous esophageal', 'Disease', 'MESH:D000077277', (229, 248))	('EAC', 'Phenotype', 'HP:0011459', (113, 116))	('miR-205', 'Gene', (44, 51))	('miR-203', 'Gene', '406986', (32, 39))	('miR-194', 'Var', (135, 142))	('BE', 'Phenotype', 'HP:0100580', (107, 109))
617642	23925817	In our analysis, miR143, miR145, miR-21, miR-192, miR-194, miR-215 were all increased in BE and EAC while miR-203, miR-205, miR-27b, miR-99c, miR-149, miR-210, miR-221, and miR-617 were all decreased in BE/EAC.	('miR-21', 'Gene', (151, 157))	('miR-617', 'Gene', '693202', (173, 180))	('miR-99c', 'Var', (133, 140))	('EAC', 'Phenotype', 'HP:0011459', (206, 209))	('miR-221', 'Gene', (160, 167))	('miR143', 'Gene', (17, 23))	('miR-21', 'Gene', '406991', (59, 65))	('EAC', 'Gene', '1540', (96, 99))	('miR-27b', 'Gene', (124, 131))	('EAC', 'Gene', (96, 99))	('miR-221', 'Gene', '407006', (160, 167))	('miR-21', 'Gene', '406991', (33, 39))	('increased', 'PosReg', (76, 85))	('miR-192', 'Gene', (41, 48))	('miR145', 'Gene', '406937', (25, 31))	('miR-27b', 'Gene', '407019', (124, 131))	('decreased', 'NegReg', (190, 199))	('miR-203', 'Gene', (106, 113))	('BE', 'Phenotype', 'HP:0100580', (89, 91))	('EAC', 'Gene', '1540', (206, 209))	('miR-149', 'Gene', (142, 149))	('BE/EAC', 'Gene', '1540', (203, 209))	('miR-194', 'Var', (50, 57))	('EAC', 'Gene', (206, 209))	('miR-617', 'Gene', (173, 180))	('BE/EAC', 'Gene', (203, 209))	('miR-205', 'Gene', '406988', (115, 122))	('miR143', 'Gene', '406935', (17, 23))	('miR-21', 'Gene', (59, 65))	('miR-21', 'Gene', (33, 39))	('miR-203', 'Gene', '406986', (106, 113))	('miR-210', 'Gene', '406992', (151, 158))	('miR-21', 'Gene', '406991', (151, 157))	('miR-149', 'Gene', '406941', (142, 149))	('miR-215', 'Gene', '406997', (59, 66))	('miR145', 'Gene', (25, 31))	('miR-192', 'Gene', '406967', (41, 48))	('miR-215', 'Gene', (59, 66))	('EAC', 'Phenotype', 'HP:0011459', (96, 99))	('miR-210', 'Gene', (151, 158))	('BE', 'Phenotype', 'HP:0100580', (203, 205))	('miR-205', 'Gene', (115, 122))
617728	22754488	Surveillance biopsies following HALO-360 RFA demonstrated a focus of LGD in a residual region of Barrett's metaplasia at the distal esophagus.	("Barrett's metaplasia", 'Disease', (97, 117))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (97, 117))	('HALO-360 RFA', 'Var', (32, 44))
617762	33403008	The combination of mSEPT9 with CEA, CA724, SNCG, or AFP significantly enhanced the sensitivity for CRC, GC, EC, and HCC to 86.4% (AUC = 0.99, specificity = 92.8%), 63.6% (AUC = 0.86, specificity = 91.1%), 71.3% (AUC = 0.81, specificity = 82.1%), and 83.3% (AUC = 0.93, specificity = 85.1%), respectively.	('mSEPT9', 'Gene', (19, 25))	('AFP', 'Gene', '174', (52, 55))	('SNCG', 'Gene', (43, 47))	('CEA', 'Gene', '5670', (31, 34))	('EC', 'Disease', 'MESH:D005955', (108, 110))	('CA724', 'Chemical', '-', (36, 41))	('enhanced', 'PosReg', (70, 78))	('mSEPT9', 'Gene', '53860', (19, 25))	('CA724', 'Var', (36, 41))	('combination', 'Interaction', (4, 15))	('AFP', 'Gene', (52, 55))	('CEA', 'Gene', (31, 34))	('SNCG', 'Gene', '6623', (43, 47))
617793	33403008	If the p value is 0.7, 0.5, 0.4, and 0.759 for CRC, GC, EC, and HCC, respectively, an estimated 81 CRC cases, 96 GC cases, 92 EC cases, and 72 HCC cases were required, making a total of at least 341 cancer cases.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('0.759', 'Var', (37, 42))	('EC', 'Disease', 'MESH:D005955', (56, 58))	('CRC', 'Disease', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('CRC', 'Disease', (47, 50))	('cancer', 'Disease', (199, 205))	('EC', 'Disease', 'MESH:D005955', (126, 128))
617845	33403008	For GC, the combination of the mSEPT9 assay and CA724 increased the sensitivity to 63.6% (AUC = 0.86) at a specificity of 91.1%; this was significantly higher than the mSEPT9 assay alone (sensitivity = 47.7%, AUC = 0.76) or CA724 alone (sensitivity = 45.5%, AUC = 0.72).	('higher', 'PosReg', (152, 158))	('mSEPT9', 'Gene', '53860', (31, 37))	('CA724', 'Var', (48, 53))	('mSEPT9', 'Gene', (168, 174))	('increased', 'PosReg', (54, 63))	('mSEPT9', 'Gene', (31, 37))	('CA724', 'Chemical', '-', (48, 53))	('CA724', 'Chemical', '-', (224, 229))	('sensitivity', 'MPA', (68, 79))	('mSEPT9', 'Gene', '53860', (168, 174))
617872	33403008	Furthermore, mSEPT9 detected HC with a sensitivity of 34.1%, thus suggesting that alterations in the methylation status of SEPT9 already happen before HC transforms into HCC.	('mSEPT9', 'Gene', '53860', (13, 19))	('mSEPT9', 'Gene', (13, 19))	('HCC', 'Disease', (170, 173))	('SEPT9', 'Gene', '10801', (14, 19))	('SEPT9', 'Gene', '10801', (123, 128))	('methylation status', 'MPA', (101, 119))	('SEPT9', 'Gene', (14, 19))	('SEPT9', 'Gene', (123, 128))	('alterations', 'Var', (82, 93))
618024	32429571	contributed to patient management and acquisition of data of PDT; M.Y., M.I., and Y.H.	('M.I.', 'Var', (72, 76))	('PDT', 'Gene', (61, 64))	('patient', 'Species', '9606', (15, 22))	('men', 'Species', '9606', (29, 32))
618077	30803360	Irregular microsurface pattern in a moderately differentiated adenocarcinoma might be frequently visualized using M-BLI and M-BLI-bright compared with using M-NBI.	('M-NBI', 'Chemical', '-', (157, 162))	('M-BLI', 'Var', (114, 119))	('BLI', 'Chemical', '-', (116, 119))	('adenocarcinoma', 'Disease', (62, 76))	('BLI', 'Chemical', '-', (126, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('M-BLI-bright', 'Var', (124, 136))
618092	30803360	It is suggested that BLI amplification can predict the pathologic diagnosis and infiltration depth of early colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('BLI', 'Chemical', '-', (21, 24))	('amplification', 'Var', (25, 38))	('colorectal cancer', 'Disease', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
618112	30228315	MiRNAs are involved in the regulation of multiple biological and pathological processes, and their aberrant expression contributes to the initiation and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('contributes', 'Reg', (119, 130))	('aberrant', 'Var', (99, 107))	('MiRNAs', 'Protein', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('expression', 'MPA', (108, 118))
618127	30228315	A survival analysis using a Cox regression model demonstrated that four of these nine miRNAs (miR-25-3p, miR-152-3p, miR-331-3p, and miR-30c-5p) were significantly associated with recurrence-free survival (Table 2).	('miR-25', 'Gene', (94, 100))	('miR-331', 'Gene', '442903', (117, 124))	('associated with', 'Reg', (164, 179))	('miR-331', 'Gene', (117, 124))	('miR-152-3p', 'Var', (105, 115))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('miR-25', 'Gene', '407014', (94, 100))	('miR-30c-5p', 'Var', (133, 143))	('recurrence-free survival', 'CPA', (180, 204))
618130	30228315	We confirmed that two of the four, miR-152-3p and miR-331-3p, were significantly down-regulated in patients with recurrence compared with those without (Fig.	('miR-152-3p', 'Var', (35, 45))	('down-regulated', 'NegReg', (81, 95))	('miR-331', 'Gene', '442903', (50, 57))	('patients', 'Species', '9606', (99, 107))	('miR-331', 'Gene', (50, 57))
618134	30228315	A Kaplan-Meier curve analysis showed that patients with a high expression of miR-331-3p had a significantly longer median recurrence-free survival time than those with a low expression (>237.2 months versus 31.5 months, log rank P < 0.001), which was consistent with the results for the discovery cohort (Fig.	('recurrence-free survival time', 'CPA', (122, 151))	('high expression', 'Var', (58, 73))	('miR-331', 'Gene', '442903', (77, 84))	('longer', 'PosReg', (108, 114))	('miR-331', 'Gene', (77, 84))	('patients', 'Species', '9606', (42, 50))
618157	30228315	A recent study in 67 patients with hepatocellular carcinoma indicated that high levels of miR-331-3p was associated with a poor prognosis.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (35, 59))	('miR-331', 'Gene', '442903', (90, 97))	('hepatocellular carcinoma', 'Disease', (35, 59))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (35, 59))	('miR-331', 'Gene', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('patients', 'Species', '9606', (21, 29))	('high levels', 'Var', (75, 86))
618185	26462025	Gene set enrichment analysis revealed that ERBB signaling pathway is significantly enriched in patients with PFS >=4 months (n = 12) than PFS < 4 months (n = 21) (p < 0.001).	('patients', 'Species', '9606', (95, 103))	('ERBB', 'Gene', (43, 47))	('enriched', 'Reg', (83, 91))	('ERBB', 'Gene', '1956', (43, 47))	('PFS >=4 months', 'Var', (109, 123))
618199	26462025	Over the past decade, molecularly targeted therapies, which block important oncogenic pathways, have made remarkable progress, especially in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (199, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('EGFR', 'Gene', (175, 179))	('cell lung cancer', 'Disease', (209, 225))	('NSCLC', 'Disease', (227, 232))	('epidermal growth factor receptor', 'Gene', (141, 173))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('cell lung cancer', 'Disease', 'MESH:D008175', (209, 225))	('mutation-positive', 'Var', (181, 198))	('epidermal growth factor receptor', 'Gene', '1956', (141, 173))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))
618205	26462025	EGFR overexpression and amplification was frequently observed in ESCC and was correlated with advanced tumor stage and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('EGFR', 'Gene', (0, 4))	('tumor', 'Disease', (103, 108))	('overexpression', 'PosReg', (5, 19))	('amplification', 'Var', (24, 37))	('ESCC', 'Disease', (65, 69))	('correlated', 'Reg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
618209	26462025	Of note, a higher rate of disease control with gefitinib was observed in female patients with ESCC and high EGFR expression.	('patients', 'Species', '9606', (80, 88))	('EGFR', 'Gene', (108, 112))	('high', 'Var', (103, 107))	('gefitinib', 'Chemical', 'MESH:D000077156', (47, 56))	('ESCC', 'Disease', (94, 98))
618210	26462025	Erlotinib also exhibited higher ORR (15% vs. 0%) and longer time to progression (3.3 vs. 1.6 months) in ESCC, compared with adenocarcinoma.	('Erlotinib', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('ESCC', 'Disease', (104, 108))	('ORR', 'MPA', (32, 35))	('adenocarcinoma', 'Disease', (124, 138))	('higher', 'PosReg', (25, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (124, 138))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))
618250	26462025	EGFR mutations were found in 3 patients (1 CB, 2 non-CB).	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (31, 39))	('EGFR', 'Gene', (0, 4))	('found', 'Reg', (20, 25))
618251	26462025	Interestingly, all these EGFR mutations were not classic drug-sensitive exon 19 and 21 mutations frequently identified in NSCLC, but atypical exon 20 mutations (V765M, C775Y, and G810D).	('V765M', 'Var', (161, 166))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('EGFR', 'Gene', (25, 29))	('C775Y', 'Mutation', 'p.C775Y', (168, 173))	('G810D', 'Var', (179, 184))	('G810D', 'Mutation', 'rs121913431', (179, 184))	('C775Y', 'Var', (168, 173))	('V765M', 'Mutation', 'rs374873413', (161, 166))	('NSCLC', 'Disease', (122, 127))
618255	26462025	Significant inhibition of tumor cell growth by dacomitinib was found in cells with high-EGFR expression (TE2 and TE3) in comparison to that against low-EGFR expressing HCE4 (Figure 5A-5C).	('TE2', 'Gene', '8260', (105, 108))	('dacomitinib', 'Chemical', 'MESH:C525726', (47, 58))	('TE2', 'Gene', (105, 108))	('inhibition', 'NegReg', (12, 22))	('high-EGFR expression', 'Var', (83, 103))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('HCE4', 'Chemical', '-', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
618259	26462025	Taken together, high EGFR expression was associated with sensitivity to dacomitinib in ESCC cell lines.	('expression', 'MPA', (26, 36))	('EGFR', 'Gene', (21, 25))	('associated', 'Reg', (41, 51))	('high', 'Var', (16, 20))	('sensitivity to dacomitinib', 'MPA', (57, 83))	('dacomitinib', 'Chemical', 'MESH:C525726', (72, 83))
618285	26462025	Recently, whole exome sequencing studies in ESCC have been reported, uncovering recurrent somatic mutations in TP53 (60-93%), CDKN2A (3-8%), RB1 (8-9%), PIK3CA (7-9%) and PTEN (5%).	('PIK3CA', 'Gene', '5290', (153, 159))	('RB1', 'Gene', (141, 144))	('TP53', 'Gene', '7157', (111, 115))	('RB1', 'Gene', '5925', (141, 144))	('CDKN2A', 'Gene', (126, 132))	('mutations', 'Var', (98, 107))	('TP53', 'Gene', (111, 115))	('CDKN2A', 'Gene', '1029', (126, 132))	('PTEN', 'Gene', (171, 175))	('PTEN', 'Gene', '5728', (171, 175))	('PIK3CA', 'Gene', (153, 159))
618286	26462025	In our study, genes involved in cell cycle and apoptosis regulation were mutated in 69% of cases by somatic alterations of TP53 (61%), CDKN2A (8%) and MLH1 (8%), which was comparable to the previous reports.	('CDKN2A', 'Gene', (135, 141))	('CDKN2A', 'Gene', '1029', (135, 141))	('alterations', 'Var', (108, 119))	('apoptosis', 'CPA', (47, 56))	('MLH1', 'Gene', '4292', (151, 155))	('MLH1', 'Gene', (151, 155))	('mutated', 'Reg', (73, 80))	('cell cycle', 'CPA', (32, 42))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
618287	26462025	Consistent with previous reports, we also found mutations in PI3K/mTOR pathway including PIK3CA (3%), PTEN (3%) and STK11 (3%).	('mTOR', 'Gene', (66, 70))	('STK11', 'Gene', (116, 121))	('mTOR', 'Gene', '2475', (66, 70))	('PIK3CA', 'Gene', (89, 95))	('STK11', 'Gene', '6794', (116, 121))	('PIK3CA', 'Gene', '5290', (89, 95))	('PTEN', 'Gene', (102, 106))	('PTEN', 'Gene', '5728', (102, 106))	('mutations', 'Var', (48, 57))
618288	26462025	Although somatic mutations in the EGFR tyrosine kinase domain have been associated with dramatic response to EGFR-TKIs in NSCLC, these drug-sensitive EGFR mutations are rare in ESCC.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('EGFR', 'Gene', (34, 38))	('ESCC', 'Disease', (177, 181))	('associated', 'Reg', (72, 82))	('NSCLC', 'Disease', (122, 127))	('mutations', 'Var', (17, 26))
618289	26462025	In our study, three patients harbored EGFR exon 20 mutations (V765M, G810D, C775Y).	('EGFR', 'Gene', (38, 42))	('C775Y', 'Mutation', 'p.C775Y', (76, 81))	('V765M', 'Var', (62, 67))	('G810D', 'Var', (69, 74))	('patients', 'Species', '9606', (20, 28))	('G810D', 'Mutation', 'rs121913431', (69, 74))	('V765M', 'Mutation', 'rs374873413', (62, 67))	('C775Y', 'Var', (76, 81))
618290	26462025	Interestingly, a NSCLC patient with V765M EGFR mutations had a partial response to gefitinib.	('V765M', 'Var', (36, 41))	('NSCLC', 'Disease', (17, 22))	('gefitinib', 'Chemical', 'MESH:D000077156', (83, 92))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('EGFR', 'Gene', (42, 46))	('V765M', 'Mutation', 'rs374873413', (36, 41))	('patient', 'Species', '9606', (23, 30))
618291	26462025	Consistent with this report, a case with V765M EGFR mutation in our study showed PFS of 4.1 months with 10% of tumor shrinkage.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('V765M', 'Var', (41, 46))	('EGFR', 'Gene', (47, 51))	('V765M', 'Mutation', 'rs374873413', (41, 46))
618292	26462025	The activating mutation (D820E) in exon 17 of KIT tyrosine kinase in a patient showing rapid progression within 28 days has been previously reported in imatinib-resistant gastrointestinal stromal tumors.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('imatinib', 'Chemical', 'MESH:D000068877', (152, 160))	('activating', 'PosReg', (4, 14))	('gastrointestinal stromal tumors', 'Disease', (171, 202))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (171, 202))	('D820E', 'Var', (25, 30))	('patient', 'Species', '9606', (71, 78))	('D820E', 'Mutation', 'rs1057519711', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (171, 202))
618310	26462025	Fresh or archival formalin-fixed paraffin embedded (FFPE) tumor tissues were collected at baseline for biomarker analysis, which included characterization of gene expression by Nanostring nCounter  Cancer Human Cancer Reference Kit, which is a sensitive assay quantifying mRNA transcripts of 230 genes using multiplexed, color-coded probes, and somatic mutations by Ion Torrent AmpliSeq Cancer Hotspot Panel v2 (CHPv2), which is a next generation sequencing assay detecting 2,800 Catalogue Of Somatic Mutations In Cancer (COSMIC) mutations from 50 genes.	('Cancer', 'Disease', (514, 520))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('mutations', 'Var', (530, 539))	('Cancer', 'Phenotype', 'HP:0002664', (514, 520))	('Cancer Human Cancer', 'Disease', (198, 217))	('OS', 'Chemical', '-', (523, 525))	('Cancer', 'Phenotype', 'HP:0002664', (387, 393))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('paraffin', 'Chemical', 'MESH:D010232', (33, 41))	('Mutations', 'Var', (501, 510))	('formalin', 'Chemical', 'MESH:D005557', (18, 26))	('Cancer Human Cancer', 'Disease', 'MESH:D009369', (198, 217))	('Cancer', 'Phenotype', 'HP:0002664', (198, 204))
618317	26462025	For the predictive biomarker analysis, we defined clinical benefit (CB) as PFS >= 4 months on dacomitinib based on the previous results that second-line therapies with either cytotoxic agent or EGFR inhibitors in R/M-ESCC have shown PFS of less than 4 months.	('inhibitors', 'Var', (199, 209))	('clinical', 'Species', '191496', (50, 58))	('dacomitinib', 'Chemical', 'MESH:C525726', (94, 105))	('EGFR', 'Gene', (194, 198))
618326	26462025	p-EGFR (Y1068), EGFR, p-AKT(S473), AKT, p-ERK (T202/Y204), and ERK secondary antibodies were purchased from Cell Signaling Technology (Beverly, MA, USA) and beta-actin from Santa Cruz biotechnology (Santa Cruz, CA, USA).	('Y1068', 'Var', (8, 13))	('beta-actin', 'Gene', '728378', (157, 167))	('beta-actin', 'Gene', (157, 167))	('p-ERK', 'Gene', '9451', (40, 45))	('p-ERK', 'Gene', (40, 45))
618447	23350746	Low body mass has been associated with increased chemotherapy-related toxicity and more rapidly progressing disease in small cohorts of patients with colorectal or breast carcinoma.	('rapidly progressing disease', 'CPA', (88, 115))	('Low body mass', 'Var', (0, 13))	('toxicity', 'Disease', 'MESH:D064420', (70, 78))	('toxicity', 'Disease', (70, 78))	('increased', 'PosReg', (39, 48))	('patients', 'Species', '9606', (136, 144))	('colorectal or breast carcinoma', 'Disease', 'MESH:D015179', (150, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('breast carcinoma', 'Phenotype', 'HP:0003002', (164, 180))	('Low body mass', 'Phenotype', 'HP:0004325', (0, 13))	('colorectal or breast carcinoma', 'Disease', (150, 180))
618465	24312652	DNA methylation, a stable epigenetic modification, is cell type-dependent, and different between cancer and normal cells.	('cancer', 'Disease', (97, 103))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('DNA methylation', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
618468	24312652	Second, using eight pairs of cancer and non-cancer cell samples prepared by laser capture microdissection, we confirmed that at least one of the three regions was almost completely methylated in ESCC cells, and all the three regions were almost completely unmethylated in non-cancer cells.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('methylated', 'Var', (181, 191))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('ESCC', 'Disease', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
618471	24312652	Finally, we observed that, by correction of the cancer cell content, CpG islands in promoter regions of tumor-suppressor genes were almost completely methylated.	('methylated', 'Var', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', (104, 109))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
618478	24312652	With SNP microarray, the fraction of cancer cells can be calculated by detecting genomic regions with copy number alterations and measuring the degree of allelic imbalance using SNPs in the genomic regions.	('imbalance', 'Phenotype', 'HP:0002172', (162, 171))	('copy number alterations', 'Var', (102, 125))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
618496	24312652	Significant copy number alterations (gain or loss) were defined as more than a 1.5-fold increase or less than a 0.67-fold decrease.	('gain or loss', 'Disease', 'MESH:D015430', (37, 49))	('gain or loss', 'Disease', (37, 49))	('copy number alterations', 'Var', (12, 35))	('increase', 'PosReg', (88, 96))
618502	24312652	Genome-wide methylation analysis was performed using DNA of i) 28 ESCCs obtained by endoscopic biopsy, ii) four ESCC cell lines (KYSE30, KYSE50, KYSE220, and KYSE270), iii) peripheral leukocytes of one healthy volunteer, iv) a pool of normal esophageal mucosae of four healthy volunteers, and v) a pool of non-cancerous esophageal mucosae of eight ESCC patients.	('non-cancerous esophageal mucosae', 'Disease', 'MESH:D004938', (306, 338))	('patients', 'Species', '9606', (353, 361))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('KYSE50', 'Var', (137, 143))	('non-cancerous esophageal mucosae', 'Disease', (306, 338))	('KYSE220', 'Var', (145, 152))	('KYSE270', 'Var', (158, 165))
618514	24312652	Assuming that 2-fold or 0.5-fold copy number alterations were present in cancer cells, a deviation of the measured methylation level from the true fraction of cancer cells was calculated to be less than 17.2% (Figure S1).	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('methylation level', 'MPA', (115, 132))	('copy number alterations', 'Var', (33, 56))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
618516	24312652	Therefore, the effect of the copy number alterations of TFAP2B, and RAPGEFL1 was considered to be minimal in the estimation of a fraction of cancer cells.	('RAPGEFL1', 'Gene', '51195', (68, 76))	('TFAP2B', 'Gene', '7021', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('copy number alterations', 'Var', (29, 52))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('RAPGEFL1', 'Gene', (68, 76))	('TFAP2B', 'Gene', (56, 62))	('cancer', 'Disease', (141, 147))
618528	24312652	For this purpose, we selected CpG sites within 200 bp from transcription start sites (TSS200) for two tumor-suppressor genes (cg22879515 (MIR34B), and cg23180938 (CDO1)), and assessed distributions of their beta values obtained in the initial genome-wide methylation analysis.	('cg23180938', 'Var', (151, 161))	('MIR34B', 'Gene', '407041', (138, 144))	('MIR34B', 'Gene', (138, 144))	('cg22879515', 'Var', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('CDO1', 'Gene', '1036', (163, 167))	('CDO1', 'Gene', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
618537	24312652	Therefore, we can expect to identify specific genomic regions highly and frequently methylated in in the other types of cancer cells, but not in normal cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('methylated', 'Var', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
618543	24312652	Since cancer cells are theoretically clonal, the heterogeneity was considered to be due to methylation or demethylation during cancer progression.	('methylation', 'Var', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', (6, 12))
618546	24312652	To exclude the effects of copy number alterations on the estimation, we also investigated copy number alterations of the three regions in 15 ESCCs, and confirmed that copy number alterations that could cause a large deviation of the estimation of the fraction of cancer cells were not observed in the three regions.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Disease', (263, 269))	('copy', 'Var', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('alterations', 'Var', (179, 190))
618555	23596512	Here, we studied the interaction of various habits related factors and polymorphism of GSTM1/GSTT1 genes towards inducing promoter hypermethylation of multiple tumour suppressor genes.	('tumour', 'Disease', (160, 166))	('promoter hypermethylation', 'MPA', (122, 147))	('inducing', 'PosReg', (113, 121))	('polymorphism', 'Var', (71, 83))	('GSTM1/GSTT1', 'Gene', (87, 98))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
618567	23596512	Moreover, polymorphism in various carcinogen metabolizing genes modulates the effect of these environmental carcinogens and further increases the risk of ESCC.	('modulates', 'Reg', (64, 73))	('polymorphism', 'Var', (10, 22))	('ESCC', 'Disease', (154, 158))	('men', 'Species', '9606', (101, 104))	('increases', 'PosReg', (132, 141))	('effect of these', 'MPA', (78, 93))
618569	23596512	Epigenetic events like aberrant DNA methylation of tumours suppressor genes (TSGs) are considered as important factors in development and progression of ESCC.	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('aberrant DNA methylation', 'Var', (23, 47))	('ESCC', 'Disease', (153, 157))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('men', 'Species', '9606', (129, 132))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('tumours', 'Disease', (51, 58))
618573	23596512	Furthermore, null genotype of GSTM1 gene was associated with an increased susceptibility of CpG island hypermethylation in gastric-mucosa.	('gastric-mucosa', 'Disease', 'MESH:D013274', (123, 137))	('CpG island hypermethylation', 'Disease', (92, 119))	('gastric-mucosa', 'Disease', (123, 137))	('GSTM1', 'Gene', (30, 35))	('null', 'Var', (13, 17))
618581	23596512	Multifactor dimensionality reduction (MDR) and false-positive report frequencies (FPRP) were used to predict high order interactions involving those factors of Epigenetic, Genetic and Environmental in ESCC from NE Indian population.	('Epigenetic', 'Var', (160, 170))	('men', 'Species', '9606', (14, 17))	('interactions', 'Interaction', (120, 132))	('men', 'Species', '9606', (191, 194))	('ESCC', 'Disease', (201, 205))
618610	23596512	The frequency of promoter methylation was significantly higher in tobacco chewers as compared to non-chewers for all the genes under study (p<0.001, Figure 2A) whereas, smokers had higher frequency of p16, DAPK and GSTP1 methylation than non-smokers (Figure 2B).	('GSTP1', 'Gene', (215, 220))	('p16', 'Var', (201, 204))	('DAPK', 'Gene', (206, 210))	('higher', 'PosReg', (181, 187))	('GSTP1', 'Gene', '2950', (215, 220))	('tobacco', 'Species', '4097', (66, 73))	('DAPK', 'Gene', '1612', (206, 210))	('promoter methylation', 'MPA', (17, 37))	('higher', 'PosReg', (56, 62))	('methylation', 'Var', (221, 232))
618614	23596512	Null variants of GSTM1 and GSTT1 had a moderately increased risk of ESCC; however, the risk was significantly higher for GSTT1 null variants only (Table 1).	('Null variants', 'Var', (0, 13))	('ESCC', 'Disease', (68, 72))	('rat', 'Species', '10116', (43, 46))	('GSTT1', 'Gene', (27, 32))	('GSTM1', 'Gene', (17, 22))
618617	23596512	Tobacco chewing had 4.84, 5.69, 5.28 and 6.27 folds increased risk, and smoking had 5.14, 2.67, 2.63 and 2.84 folds risk of ESCC with promoter hypermethylation of p16, DAPK, GSTP1 and BRCA1 genes respectively.	('GSTP1', 'Gene', (174, 179))	('BRCA1', 'Gene', '672', (184, 189))	('DAPK', 'Gene', (168, 172))	('promoter hypermethylation', 'Var', (134, 159))	('DAPK', 'Gene', '1612', (168, 172))	('p16', 'Gene', (163, 166))	('Tobacco', 'Species', '4097', (0, 7))	('BRCA1', 'Gene', (184, 189))	('ESCC', 'Disease', (124, 128))	('GSTP1', 'Gene', '2950', (174, 179))
618631	23596512	Betel quid chewing, alcohol consumption and null GSTT1 interaction was the best model predicted with a maximum TBA (0.75), TrBA (0.75), CVC (10/10) and an odds ratio of 9.88 [95% CI = 3.67-26.54].	('interaction', 'Var', (55, 66))	('rat', 'Species', '10116', (160, 163))	('TrBA', 'Chemical', '-', (123, 127))	('alcohol', 'Chemical', 'MESH:D000438', (20, 27))	('GSTT1', 'Gene', (49, 54))	('TBA', 'Chemical', '-', (111, 114))
618633	23596512	The best predicted model for ESCC with methylation index of 0.25-0.50 comprised of tobacco and betel quid chewing, smoking and null GSTT1 gene (OR = 25.14 [95% CI = 9.76-64.78]; TBA = 0.77, TrBA = 0.83, CVC = 9/10).	('ESCC', 'Disease', (29, 33))	('GSTT1', 'Gene', (132, 137))	('TrBA', 'Chemical', '-', (190, 194))	('TBA', 'Chemical', '-', (178, 181))	('tobacco', 'Species', '4097', (83, 90))	('null', 'Var', (127, 131))
618637	23596512	Moreover, alcohol consumption showed strong synergy with betel quid chewing (1.71%) and GSTT1 null genotype (1.49%).	('GSTT1', 'Gene', (88, 93))	('synergy', 'Interaction', (44, 51))	('genotype', 'Var', (99, 107))	('alcohol', 'Chemical', 'MESH:D000438', (10, 17))	('null genotype', 'Var', (94, 107))
618638	23596512	The model considering ESCC cases with promoter hypermethylation and controls had sizeable entropy removed from the case control group by tobacco chewing (8.48%) and smoking (3.85%) individually, their interaction among themselves (3.85%) as well as with GSTT1 null genotypes (0.66%); in addition, only a minuscule proportion of the entropy could be explained by betel quid chewing (0.13%) and GSTT1 null (0.66%) on their own, but a large percentage of the entropy was removed by interaction of these two factors (1.45%).	('GSTT1', 'Gene', (393, 398))	('ESCC', 'Disease', (22, 26))	('tobacco', 'Species', '4097', (137, 144))	('promoter hypermethylation', 'Var', (38, 63))	('entropy', 'MPA', (90, 97))	('interaction', 'Interaction', (479, 490))
618655	23596512	The role of promoter hypermethylation of tumour suppressor genes is recognized as one of the key events in instigation and progression of cancer by repressing the expression of the corresponding genes.	('cancer', 'Disease', (138, 144))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('repressing', 'NegReg', (148, 158))	('promoter hypermethylation', 'Var', (12, 37))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('expression', 'MPA', (163, 173))	('tumour', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
618658	23596512	In our study group, 37.5%, 61.60%, 58.92% and 20.53% of the ESCC tumours had p16, DAPK, GSTP1 and BRCA1 promoter methylation respectively, which was significantly higher than adjacent normal tissues.	('ESCC tumours', 'Disease', (60, 72))	('DAPK', 'Gene', (82, 86))	('DAPK', 'Gene', '1612', (82, 86))	('GSTP1', 'Gene', '2950', (88, 93))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('BRCA1', 'Gene', '672', (98, 103))	('p16', 'Var', (77, 80))	('ESCC tumours', 'Disease', 'MESH:D004938', (60, 72))	('higher', 'PosReg', (163, 169))	('GSTP1', 'Gene', (88, 93))	('BRCA1', 'Gene', (98, 103))
618659	23596512	found a comparatively higher proportion of p16 (52%) and a lower percentage of DAPK (24%) promoter hypermethylation in ESCC tumours, which might be due to ethnic variations; however, they reported a similar proportion of BRCA1 promoter methylation (28%).	('higher', 'PosReg', (22, 28))	('BRCA1', 'Gene', '672', (221, 226))	('ESCC tumours', 'Disease', (119, 131))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('DAPK', 'Gene', (79, 83))	('DAPK', 'Gene', '1612', (79, 83))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('rat', 'Species', '10116', (13, 16))	('promoter hypermethylation', 'MPA', (90, 115))	('BRCA1', 'Gene', (221, 226))	('p16', 'Var', (43, 46))	('ESCC tumours', 'Disease', 'MESH:D004938', (119, 131))
618669	23596512	A recent study combining cell, animal and clinical lung cancer tissues as a modelfound that, NNK attenuates DNMT1 degradation and also induces its nuclear accumulation resulting in subsequent hypermethylation of promoters of tumour suppressor genes.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('NNK', 'Var', (93, 96))	('tumour', 'Disease', (225, 231))	('NNK', 'Chemical', 'MESH:C016583', (93, 96))	('promoters', 'MPA', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('hypermethylation', 'MPA', (192, 208))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('nuclear accumulation', 'MPA', (147, 167))	('attenuates', 'NegReg', (97, 107))	('DNMT1 degradation', 'MPA', (108, 125))	('induces', 'Reg', (135, 142))
618670	23596512	Benzo[a]pyrene present in tobacco is converted to its carcinogenic form BPDE (benzo[a]pyrenediolepoxide) by the phase I enzymes CYP1A1, CYP1B1, etc., which are further metabolized by the GSTs.	('tobacco', 'Species', '4097', (26, 33))	('carcinogenic', 'Disease', (54, 66))	('benzo[a]pyrenediolepoxide', 'Chemical', 'MESH:D015123', (78, 103))	('Benzo[a]pyrene', 'Chemical', 'MESH:D001564', (0, 14))	('GSTs', 'Gene', (187, 191))	('BPDE', 'Chemical', 'MESH:D015123', (72, 76))	('carcinogenic', 'Disease', 'MESH:D063646', (54, 66))	('CYP1B1', 'Var', (136, 142))	('CYP1A1', 'Var', (128, 134))	('GSTs', 'Gene', '2950', (187, 191))
618673	23596512	In a case-control study on lung cancer, null genotype of GSTM1 has been found to increase the risk of promoter hypermethylation of DAPK and Rarbeta.	('Rarbeta', 'Gene', '24706', (140, 147))	('promoter hypermethylation', 'MPA', (102, 127))	('DAPK', 'Gene', '1612', (131, 135))	('null genotype', 'Var', (40, 53))	('lung cancer', 'Disease', (27, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('GSTM1', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('Rarbeta', 'Gene', (140, 147))	('DAPK', 'Gene', (131, 135))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))
618675	23596512	In our study, the interaction of tobacco and betel quid chewing, smoking and null GSTT1 genotype was the best model for both ESCC with promoter hypermethylation and MI = 0.25-0.50 in MDR.	('tobacco', 'Species', '4097', (33, 40))	('GSTT1', 'Gene', (82, 87))	('promoter', 'MPA', (135, 143))	('MDR', 'Gene', (183, 186))	('ESCC', 'Disease', (125, 129))	('MI = 0.25-0.50', 'Var', (165, 179))
618677	23596512	This further supports the hypothesis that a complex interaction is likely to interplay between tobacco-related habits and carcinogen metabolizing gene polymorphisms towards promoting aberrant DNA methylation in ESCC.	('tobacco', 'Species', '4097', (95, 102))	('ESCC', 'Gene', (211, 215))	('aberrant', 'Var', (183, 191))	('promoting', 'PosReg', (173, 182))	('DNA', 'Protein', (192, 195))
618687	20424117	EGFR and mutant p53 expand esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors Transforming growth factor (TGF)-beta is a potent inducer of epithelial to mesenchymal transition (EMT).	('epithelial to mesenchymal transition', 'CPA', (204, 240))	('ZEB', 'Gene', '9839', (117, 120))	('EGFR', 'Gene', (0, 4))	('mutant', 'Var', (9, 15))	('p53', 'Gene', (16, 19))	('ZEB', 'Gene', (117, 120))	('p53', 'Gene', '7157', (16, 19))	('Transforming growth factor (TGF)-beta', 'Gene', '7040', (143, 180))	('EGFR', 'Gene', '1956', (0, 4))
618689	20424117	We have found that both epidermal growth factor receptor (EGFR) overexpression and mutant p53 tumor suppressor genes contribute to enrichment of an EMT-competent cellular subpopulation amongst telomerase-immortalized human esophageal epithelial cells during malignant transformation.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('human', 'Species', '9606', (217, 222))	('mutant', 'Var', (83, 89))	('epidermal growth factor receptor', 'Gene', (24, 56))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('epidermal growth factor receptor', 'Gene', '1956', (24, 56))
618690	20424117	EGFR overexpression triggers oncogene-induced senescence, accompanied by induction of cyclin dependent kinase inhibitors p15INK4B, p16INK4A and p21.	('cyclin dependent kinase inhibitors', 'MPA', (86, 120))	('EGFR', 'Gene', (0, 4))	('p16INK4A', 'Gene', '1029', (131, 139))	('oncogene-induced', 'Protein', (29, 45))	('p15INK4B', 'Var', (121, 129))	('overexpression', 'Var', (5, 19))	('p16INK4A', 'Gene', (131, 139))	('p21', 'Var', (144, 147))
618692	20424117	RNA interference directed against ZEB resulted in induction of p15INK4B and p16INK4A, reactivating the EGFR-dependent senescence program.	('reactivating', 'PosReg', (86, 98))	('p16INK4A', 'Gene', '1029', (76, 84))	('p15INK4B', 'Var', (63, 71))	('p16INK4A', 'Gene', (76, 84))	('EGFR-dependent senescence program', 'MPA', (103, 136))	('RNA', 'MPA', (0, 3))
618693	20424117	Importantly, TGF-beta-mediated EMT did not take place when cellular senescence programs were activated by either ZEB knockdown or activation of wild-type p53 function.	('TGF-beta', 'Gene', '7040', (13, 21))	('knockdown', 'Var', (117, 126))	('TGF-beta', 'Gene', (13, 21))
618697	20424117	Genetic lesions associated frequently with ESCC include inactivation of tumor suppressors p53 and p16INK4A and overexpression of cyclin D1 and epidermal growth factor receptor (EGFR) in addition to telomerase activation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cyclin D1', 'Gene', '595', (129, 138))	('epidermal growth factor receptor', 'Gene', (143, 175))	('p16INK4A', 'Gene', (98, 106))	('tumor', 'Disease', (72, 77))	('ESCC', 'Disease', (43, 47))	('cyclin D1', 'Gene', (129, 138))	('inactivation', 'Var', (56, 68))	('epidermal growth factor receptor', 'Gene', '1956', (143, 175))	('p16INK4A', 'Gene', '1029', (98, 106))	('overexpression', 'PosReg', (111, 125))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('p53', 'Protein', (90, 93))
618707	20424117	Zeb1 deficient mouse embryonic fibroblasts undergo premature replicative senescence and ectopic E-cadherin expression.	('E-cadherin', 'Protein', (96, 106))	('Zeb1', 'Gene', '21417', (0, 4))	('premature replicative senescence', 'CPA', (51, 83))	('Zeb1', 'Gene', (0, 4))	('undergo', 'Reg', (43, 50))	('expression', 'MPA', (107, 117))	('ectopic', 'CPA', (88, 95))	('mouse', 'Species', '10090', (15, 20))	('deficient', 'Var', (5, 14))
618708	20424117	Cellular senescence is induced by eroded telomeres, oncogene-induced DNA damage and epigenetic derepression of the INK4A/ARF locus.	('INK4A/ARF', 'Gene', (115, 124))	('induced', 'Reg', (23, 30))	('INK4A/ARF', 'Gene', '1029', (115, 124))	('Cellular senescence', 'CPA', (0, 19))	('epigenetic derepression', 'Var', (84, 107))
618709	20424117	Senescent cells exhibit flat and enlarged cell morphology as well as proliferative arrest accompanied by increased senescence-associated beta-galactosidase (SABG) activity and upregulation of cell cycle inhibitors such as p15INK4B, p16INK4A and p21 (CDKN1A).	('CDKN1A', 'Gene', (250, 256))	('p16INK4A', 'Gene', (232, 240))	('cell cycle', 'CPA', (192, 202))	('upregulation', 'PosReg', (176, 188))	('flat', 'CPA', (24, 28))	('p15INK4B', 'Var', (222, 230))	('CDKN1A', 'Gene', '1026', (250, 256))	('beta-galactosidase', 'Gene', '2720', (137, 155))	('activity', 'MPA', (163, 171))	('p16INK4A', 'Gene', '1029', (232, 240))	('SABG', 'Chemical', '-', (157, 161))	('increased', 'PosReg', (105, 114))	('beta-galactosidase', 'Gene', (137, 155))	('proliferative arrest', 'CPA', (69, 89))
618713	20424117	We have demonstrated recently that EGFR overexpression and p53 mutations (p53R175H and p53V143A) are necessary and sufficient to transform EPC2-hTERT cells, leading to increased cell motility, anchorage independent growth and tumor formation in nude mice.	('p53', 'Gene', (59, 62))	('increased', 'PosReg', (168, 177))	('p53R175H', 'Var', (74, 82))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (139, 149))	('nude mice', 'Species', '10090', (245, 254))	('cell motility', 'CPA', (178, 191))	('anchorage independent growth', 'CPA', (193, 221))	('EGFR', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('p53V143A', 'Var', (87, 95))	('tumor', 'Disease', (226, 231))
618715	20424117	We find that EGFR and mutant p53 cooperate to enrich an EMT-competent subpopulation of human esophageal cells expressing ZEB1 and ZEB2, which suppress p15INK4B and p16INK4A to overcome EGFR-mediated senescence.	('ZEB1', 'Gene', '6935', (121, 125))	('p16INK4A', 'Gene', '1029', (164, 172))	('ZEB2', 'Gene', '9839', (130, 134))	('human', 'Species', '9606', (87, 92))	('ZEB2', 'Gene', (130, 134))	('p53', 'Gene', (29, 32))	('p15INK4B', 'Var', (151, 159))	('p16INK4A', 'Gene', (164, 172))	('mutant', 'Var', (22, 28))	('ZEB1', 'Gene', (121, 125))	('suppress', 'NegReg', (142, 150))
618720	20424117	Retroviral vectors expressing EGFR in pFB-Neo and/or either p53R175H or p53V143A in pBABE-puro were stably transduced into EPC1-hTERT and EPC2-hTERT cells as described previously.	('EPC1', 'Gene', '80314', (123, 127))	('EGFR', 'Gene', (30, 34))	('EPC1', 'Gene', (123, 127))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (138, 148))	('p53R175H', 'Var', (60, 68))	('hTERT', 'Gene', (143, 148))	('hTERT', 'Gene', '7015', (128, 133))	('pFB-Neo', 'Chemical', '-', (38, 45))	('p53V143A', 'Var', (72, 80))	('hTERT', 'Gene', '7015', (143, 148))	('hTERT', 'Gene', (128, 133))
618725	20424117	Real-time RT-PCR was done with TaqMan  Gene Expression Assays (Applied Biosystems) for CDH1 (Hs00170423_m1), CDH2 (Hs00983062_m1), ZEB1 (Hs00232783_m1), ZEB2 (Hs00207691_m1), SNAI1 (Hs00195591_m1), SNAI2 (Hs00161804_m1), TWIST1 (Hs00361186_m1) and CDKN1A (Hs00355782_m1) using the ABI PRISM  7000 Sequence Detection System (Applied Biosystems).	('ZEB1', 'Gene', '6935', (131, 135))	('Hs00232783_m1', 'Var', (137, 150))	('CDH1', 'Gene', (87, 91))	('SNAI2', 'Gene', (198, 203))	('Hs00170423_m1', 'Var', (93, 106))	('SNAI1', 'Gene', '6615', (175, 180))	('SNAI1', 'Gene', (175, 180))	('TWIST1', 'Gene', (221, 227))	('CDKN1A', 'Gene', (248, 254))	('SNAI2', 'Gene', '6591', (198, 203))	('CDKN1A', 'Gene', '1026', (248, 254))	('CDH2', 'Gene', (109, 113))	('Hs00983062_m1', 'Var', (115, 128))	('Hs00361186_m1', 'Var', (229, 242))	('ZEB1', 'Gene', (131, 135))	('Hs00161804_m1', 'Var', (205, 218))	('Hs00355782_m1', 'Var', (256, 269))	('TWIST1', 'Gene', '7291', (221, 227))	('Hs00207691_m1', 'Var', (159, 172))	('Hs00195591_m1', 'Var', (182, 195))	('ZEB2', 'Gene', (153, 157))	('CDH1', 'Gene', '999', (87, 91))	('CDH2', 'Gene', '1000', (109, 113))	('ZEB2', 'Gene', '9839', (153, 157))
618734	20424117	EGFR overexpression and concurrent expression of mutant p53 transform EPC2-hTERT cells, conferring invasive characteristics as described previously.	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (70, 80))	('invasive characteristics', 'CPA', (99, 123))	('mutant', 'Var', (49, 55))	('p53', 'Gene', (56, 59))
618736	20424117	When cells were treated with TGF-beta in monolayer culture, more than 90% of EPC2-hTERT-EGFR-p53R175H cells exhibited of spindle-shaped cell morphology within 3 weeks (Fig.	('exhibited', 'Reg', (108, 117))	('TGF-beta', 'Gene', '7040', (29, 37))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (77, 87))	('TGF-beta', 'Gene', (29, 37))	('EPC2-hTERT-EGFR-p53R175H', 'Var', (77, 101))	('spindle-shaped cell morphology', 'CPA', (121, 151))
618745	20424117	S1B), elimination of EMT-competent cells during TGF-beta treatment was an unlikely mechanism for minimal EMT observed in EPC2-hTERT-neo-p53R175H and EPC2-hTERT-neo-puro cells (Fig.	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (149, 159))	('EPC2-hTERT-neo-p53R175H', 'Var', (121, 144))	('TGF-beta', 'Gene', (48, 56))	('TGF-beta', 'Gene', '7040', (48, 56))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (121, 131))
618750	20424117	Consistent with such a notion, spontaneous EMT was observed without TGF-beta treatment in the cells with EGFR overexpression, but not without EGFR overexpression (Fig.	('TGF-beta', 'Gene', '7040', (68, 76))	('overexpression', 'Var', (110, 124))	('TGF-beta', 'Gene', (68, 76))	('EGFR', 'Gene', (105, 109))
618762	20424117	In addition, Western blotting detected upregulation of cyclin-dependent kinase inhibitors (CDKI) p15INK4B, p16INK4A and p21 in EPC2-hTERT-EGFR-puro cells (Fig.	('p16INK4A', 'Gene', '1029', (107, 115))	('CDKI', 'Gene', (91, 95))	('upregulation', 'PosReg', (39, 51))	('CDKI', 'Gene', '12575', (91, 95))	('p16INK4A', 'Gene', (107, 115))	('p21', 'Var', (120, 123))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (127, 137))	('p15INK4B', 'Var', (97, 105))
618764	20424117	Interestingly, ZEB 1 and ZEB2 were found to be upregulated as p15INK4B and p16INK4A were downregulated reciprocally in such a cell population (Fig.	('ZEB2', 'Gene', '9839', (25, 29))	('p16INK4A', 'Gene', (75, 83))	('upregulated', 'PosReg', (47, 58))	('downregulated', 'NegReg', (89, 102))	('ZEB 1', 'Gene', '6935', (15, 20))	('p16INK4A', 'Gene', '1029', (75, 83))	('ZEB2', 'Gene', (25, 29))	('ZEB 1', 'Gene', (15, 20))	('p15INK4B', 'Var', (62, 70))
618765	20424117	Moreover, induction of ZEB1 and ZEB2 was accelerated when EGFR was transduced in EPC2-hTERT cells along with p53R175H, alleviating EGFR-mediated senescence and CDKI upregulation (data not shown, and Fig.	('p53R175H', 'Var', (109, 117))	('CDKI', 'Gene', '12575', (160, 164))	('ZEB2', 'Gene', (32, 36))	('EGFR', 'Gene', (58, 62))	('ZEB1', 'Gene', (23, 27))	('ZEB1', 'Gene', '6935', (23, 27))	('induction', 'MPA', (10, 19))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (81, 91))	('alleviating', 'NegReg', (119, 130))	('accelerated', 'PosReg', (41, 52))	('EGFR-mediated senescence', 'CPA', (131, 155))	('ZEB2', 'Gene', '9839', (32, 36))	('upregulation', 'PosReg', (165, 177))	('transduced', 'Var', (67, 77))	('CDKI', 'Gene', (160, 164))
618766	20424117	ZEB was also induced following EGFR transduction in EPC1-hTERT, an independently established immortalized human esophageal cell line (Fig.	('human', 'Species', '9606', (106, 111))	('EGFR', 'Gene', (31, 35))	('induced', 'Reg', (13, 20))	('EPC1', 'Gene', '80314', (52, 56))	('hTERT', 'Gene', '7015', (57, 62))	('EPC1', 'Gene', (52, 56))	('hTERT', 'Gene', (57, 62))	('transduction', 'Var', (36, 48))
618768	20424117	To address the role of ZEB1 and ZEB2 in TGF-beta-mediated EMT, we targeted ZEB in EPC2-hTERT-EGFR-p53R175H cells by RNA interference.	('RNA', 'Var', (116, 119))	('ZEB2', 'Gene', (32, 36))	('targeted', 'Reg', (66, 74))	('ZEB1', 'Gene', (23, 27))	('TGF-beta', 'Gene', '7040', (40, 48))	('ZEB1', 'Gene', '6935', (23, 27))	('TGF-beta', 'Gene', (40, 48))	('ZEB2', 'Gene', '9839', (32, 36))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (82, 92))	('ZEB', 'Gene', (75, 78))
618769	20424117	Stable knockdown of either ZEB1 or ZEB2 resulted in upregulation of p15INK4B and p16INK4A, accompanied by transcriptional activation of the respective promoters (Fig.	('ZEB2', 'Gene', (35, 39))	('upregulation', 'PosReg', (52, 64))	('p16INK4A', 'Gene', (81, 89))	('p15INK4B', 'Var', (68, 76))	('activation', 'PosReg', (122, 132))	('p16INK4A', 'Gene', '1029', (81, 89))	('ZEB1', 'Gene', '6935', (27, 31))	('ZEB2', 'Gene', '9839', (35, 39))	('ZEB1', 'Gene', (27, 31))	('transcriptional', 'MPA', (106, 121))
618772	20424117	Interestingly, ZEB1 knockdown resulted in partial inhibition of ZEB2, despite the lack of homology between the ZEB1 shRNAs and ZEB2 mRNA (Fig.	('ZEB2', 'Gene', '9839', (64, 68))	('ZEB1', 'Gene', (111, 115))	('ZEB2', 'Gene', '9839', (127, 131))	('ZEB1', 'Gene', '6935', (111, 115))	('ZEB1', 'Gene', '6935', (15, 19))	('ZEB2', 'Gene', (64, 68))	('inhibition', 'NegReg', (50, 60))	('ZEB1', 'Gene', (15, 19))	('ZEB2', 'Gene', (127, 131))	('knockdown', 'Var', (20, 29))
618774	20424117	Therefore, ZEB1 and/or ZEB2 is/are required for EPC2-hTERT-EGFR-p53R175H cells to undergo EMT in response to TGF-beta, and that ZEB may prevent EGFR from activating cellular senescence checkpoint functions through suppression of p15INK4B and p16INK4A.	('p16INK4A', 'Gene', (242, 250))	('ZEB1', 'Gene', (11, 15))	('ZEB2', 'Gene', '9839', (23, 27))	('p15INK4B', 'Var', (229, 237))	('p16INK4A', 'Gene', '1029', (242, 250))	('TGF-beta', 'Gene', '7040', (109, 117))	('ZEB2', 'Gene', (23, 27))	('suppression', 'NegReg', (214, 225))	('cellular senescence checkpoint functions', 'MPA', (165, 205))	('TGF-beta', 'Gene', (109, 117))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (48, 58))	('ZEB1', 'Gene', '6935', (11, 15))
618775	20424117	Cellular senescence upon ZEB knockdown was associated with reactivation of CDKI (Fig.	('knockdown', 'Var', (29, 38))	('CDKI', 'Gene', '12575', (75, 79))	('CDKI', 'Gene', (75, 79))	('Cellular senescence', 'CPA', (0, 19))	('reactivation', 'MPA', (59, 71))
618778	20424117	To determine whether senescence can block EMT, we established EPC2-hTERT-EGFR-p53V143A cells, where temperature sensitive mutant p53V143A gains a tertiary conformation similar to wild-type p53 and DNA binding as well as transcriptional activities at 32.5 C. When EPC2-hTERT-EGFR-p53V143A cells were exposed to 32 C, massive senescence was induced as determined by SABG assays (Fig.	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (62, 72))	('senescence', 'CPA', (324, 334))	('p53V143A', 'Gene', (129, 137))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (263, 273))	('tertiary', 'MPA', (146, 154))	('SABG', 'Chemical', '-', (364, 368))	('mutant', 'Var', (122, 128))	('transcriptional', 'MPA', (220, 235))
618779	20424117	This supported the notion that mutant p53 may alleviate EGFR-induced senescence by suppressing p21 as observed in EPC2-hTERT-EGFR-p53R175H cells (Fig.	('alleviate', 'NegReg', (46, 55))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (114, 124))	('p21', 'MPA', (95, 98))	('mutant', 'Var', (31, 37))	('p53', 'Gene', (38, 41))	('suppressing', 'NegReg', (83, 94))	('EGFR-induced senescence', 'Disease', (56, 79))
618789	20424117	In aggregate, our data indicate that EGFR overexpression and p53 mutation in non-transformed human esophageal cells may lead to enrichment of EMT competent subpopulation of cells with ZEB upregulation.	('EMT competent subpopulation of', 'CPA', (142, 172))	('lead to', 'Reg', (120, 127))	('human', 'Species', '9606', (93, 98))	('mutation', 'Var', (65, 73))	('upregulation', 'PosReg', (188, 200))	('overexpression', 'PosReg', (42, 56))	('enrichment', 'MPA', (128, 138))	('p53', 'Gene', (61, 64))	('EGFR', 'Gene', (37, 41))
618796	20424117	We now demonstrate that EGFR and mutant p53, essential for malignant transformation of human esophageal cells may promote selective expansion of an EMT-competent subpopulation of cells expressing ZEB1 and ZEB2 (Fig.	('ZEB2', 'Gene', (205, 209))	('human', 'Species', '9606', (87, 92))	('p53', 'Gene', (40, 43))	('ZEB1', 'Gene', (196, 200))	('ZEB1', 'Gene', '6935', (196, 200))	('mutant', 'Var', (33, 39))	('ZEB2', 'Gene', '9839', (205, 209))	('promote', 'PosReg', (114, 121))
618803	20424117	ZEB1 knockdown resulted in mesenchymal to epithelial transition and increased sensitivity to Erlotinib, an EGFR inhibitor in head and neck squamous cell carcinoma cell lines.	('sensitivity', 'MPA', (78, 89))	('neck squamous cell carcinoma', 'Disease', (134, 162))	('mesenchymal to epithelial transition', 'CPA', (27, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (134, 162))	('knockdown', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('Erlotinib', 'Chemical', 'MESH:D000069347', (93, 102))	('ZEB1', 'Gene', (0, 4))	('ZEB1', 'Gene', '6935', (0, 4))	('increased', 'PosReg', (68, 77))
618808	20424117	Given downregulation of p15INK4B and p16INK4A following EGFR-induced senescence (Fig.	('p16INK4A', 'Gene', '1029', (37, 45))	('downregulation', 'NegReg', (6, 20))	('p16INK4A', 'Gene', (37, 45))	('p15INK4B', 'Var', (24, 32))
618814	20424117	EGFR overexpression led to upregulation of p15INK4B, p16INK4A and p21 in EPC2-hTERT cells (Fig.	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (73, 83))	('p15INK4B', 'Var', (43, 51))	('p16INK4A', 'Gene', (53, 61))	('p16INK4A', 'Gene', '1029', (53, 61))	('upregulation', 'PosReg', (27, 39))	('p21', 'Var', (66, 69))
618816	20424117	4B) is reinforced by premature replicative senescence associated with upregulation of p15INK4B and p21 in Zeb1 knockout mouse embryonic fibroblasts, although ZEB knockdown did not result in derepression of p21 in our cell systems (data not shown).	('Zeb1', 'Gene', (106, 110))	('upregulation', 'PosReg', (70, 82))	('Zeb1', 'Gene', '21417', (106, 110))	('p21', 'Gene', (99, 102))	('p15INK4B', 'Var', (86, 94))	('mouse', 'Species', '10090', (120, 125))
618820	20424117	Mutant p53 may stabilize Slug protein by preventing MDM2-mediated proteasomal degradation of Slug.	('Slug', 'Gene', '6591', (25, 29))	('Slug', 'Gene', '6591', (93, 97))	('Slug', 'Gene', (25, 29))	('stabilize', 'MPA', (15, 24))	('preventing', 'NegReg', (41, 51))	('Slug', 'Gene', (93, 97))	('MDM2', 'Gene', '4193', (52, 56))	('Mutant', 'Var', (0, 6))	('MDM2', 'Gene', (52, 56))	('p53', 'Gene', (7, 10))
618823	20424117	demonstrated that TGF-beta induces formation of a ternary complex comprising of mutant p53, Smad2 and DeltaNp63alpha in a Ras-MAPK-dependent fashion and facilitates cell invasion by suppressing DeltaNp63alpha-mediated inhibition of the TGF-beta-induced promigratory responses.	('cell invasion', 'CPA', (165, 178))	('Smad2', 'Gene', '4087', (92, 97))	('mutant', 'Var', (80, 86))	('p53', 'Gene', (87, 90))	('TGF-beta', 'Gene', (18, 26))	('Smad2', 'Gene', (92, 97))	('suppressing', 'NegReg', (182, 193))	('ternary complex', 'MPA', (50, 65))	('TGF-beta', 'Gene', '7040', (236, 244))	('induces', 'Reg', (27, 34))	('DeltaNp63alpha-mediated inhibition', 'MPA', (194, 228))	('facilitates', 'PosReg', (153, 164))	('TGF-beta', 'Gene', (236, 244))	('DeltaNp63alpha', 'Gene', (102, 116))	('promigratory responses', 'CPA', (253, 275))	('TGF-beta', 'Gene', '7040', (18, 26))
618824	20424117	Since ZEB1 has been implicated in transcriptional repression of p53 family members, DeltaNp63, TAp73 and DeltaNp73, it is tempting to speculate that DeltaNp63 may be a target for ZEB1 upon TGF-beta-induced EMT.	('DeltaNp73', 'Var', (105, 114))	('TGF-beta', 'Gene', (189, 197))	('ZEB1', 'Gene', '6935', (179, 183))	('ZEB1', 'Gene', (6, 10))	('ZEB1', 'Gene', (179, 183))	('DeltaNp63', 'Gene', (84, 93))	('ZEB1', 'Gene', '6935', (6, 10))	('TGF-beta', 'Gene', '7040', (189, 197))
618833	20424117	In conclusion, our novel data underscore the role of EGFR overexpression and p53 mutations in enrichment of a subset of esophageal cells that is capable of undergoing EMT in response to TGF-beta through ZEB transcription factors, shedding new insights upon invasive cell growth and inactivation of senescence checkpoint functions during malignant transformation.	('TGF-beta', 'Gene', '7040', (186, 194))	('TGF-beta', 'Gene', (186, 194))	('p53', 'Gene', (77, 80))	('mutations', 'Var', (81, 90))	('EGFR', 'Gene', (53, 57))
618837	33446653	Particularly, HRASG12S mutation was found in KYSE180C cells.	('HRASG12S', 'Chemical', '-', (14, 22))	('found', 'Reg', (36, 41))	('HRASG12S', 'Var', (14, 22))
618839	33446653	By contrast, down-regulation of HRASG12S restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts.	('MEK162', 'Gene', (124, 130))	('combination', 'Interaction', (99, 110))	('restored', 'PosReg', (41, 49))	('MEK162', 'Chemical', 'MESH:C581313', (124, 130))	('CYH33', 'Var', (114, 119))	('KYSE180C1', 'CellLine', 'CVCL:1349', (168, 177))	('down-regulation', 'NegReg', (13, 28))	('KYSE180C1', 'CellLine', 'CVCL:1349', (69, 78))	('sensitivity', 'MPA', (54, 65))	('HRASG12S', 'Gene', (32, 40))	('HRASG12S', 'Chemical', '-', (32, 40))
618840	33446653	Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively.	('RAD001', 'Var', (177, 183))	('extracellular signal-regulated kinase 1', 'Gene', (291, 330))	('overcame', 'PosReg', (203, 211))	('enhanced', 'PosReg', (264, 272))	('c-Myc', 'Gene', '4609', (75, 80))	('CYH33', 'Var', (167, 172))	('CYH33', 'Var', (230, 235))	('mitogen-activated', 'MPA', (30, 47))	('MEK162', 'Chemical', 'MESH:C581313', (185, 191))	('c-Myc', 'Gene', (341, 346))	('extracellular signal-regulated kinase 1', 'Gene', '5594', (291, 330))	('c-Myc', 'Gene', '4609', (341, 346))	('ERK', 'Gene', '5594', (332, 335))	('inhibition', 'NegReg', (273, 283))	('resistance', 'MPA', (216, 226))	('elevated', 'PosReg', (13, 21))	('mTORC1', 'Gene', (22, 28))	('ERK', 'Gene', (332, 335))	('c-Myc', 'Gene', (75, 80))	('mTORC1', 'Gene', '382056', (22, 28))
618848	33446653	Somatic copy number variations (CNV) involving 11q13.2-11q13.3 (47.2%), 3q26.32-3q26.33 (12.0%), and 9q21.3 (26.5%), as well as somatic mutations in tumor protein p53 (TP53, 80.5%), lysine methyltransferase 2D (KMT2D, 15.2%), notch receptor 1 (NOTCH1, 13.2%), nuclear factor erythroid 2 like 2 (NFE2L2, 9.3%), zinc finger protein 750 (ZNF750, 9.0%), FAT atypical cadherin 1 (FAT1, 8.8%), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, 8.2%) genes have been frequently found in ESCC.	('FAT1', 'Gene', '2195', (375, 379))	('lysine methyltransferase 2D', 'Gene', '8085', (182, 209))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (392, 462))	('mutations', 'Var', (136, 145))	('notch receptor 1', 'Gene', (226, 242))	('zinc finger protein 750', 'Gene', '79755', (310, 333))	('TP53', 'Gene', '7157', (168, 172))	('KMT2D', 'Gene', '8085', (211, 216))	('PIK3CA', 'Gene', (464, 470))	('nuclear factor erythroid 2 like 2', 'Gene', '4780', (260, 293))	('notch receptor 1', 'Gene', '4851', (226, 242))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('zinc finger protein 750', 'Gene', (310, 333))	('NOTCH1', 'Gene', (244, 250))	('nuclear factor erythroid 2 like 2', 'Gene', (260, 293))	('NFE2L2', 'Gene', '4780', (295, 301))	('FAT1', 'Gene', (375, 379))	('p53', 'Gene', '7157', (163, 166))	('FAT atypical cadherin 1', 'Gene', (350, 373))	('ZNF750', 'Gene', '79755', (335, 341))	('NOTCH1', 'Gene', '4851', (244, 250))	('lysine methyltransferase 2D', 'Gene', (182, 209))	('ESCC', 'Disease', (514, 518))	('TP53', 'Gene', (168, 172))	('ZNF750', 'Gene', (335, 341))	('NFE2L2', 'Gene', (295, 301))	('p53', 'Gene', (163, 166))	('KMT2D', 'Gene', (211, 216))	('tumor', 'Disease', (149, 154))	('PIK3CA', 'Gene', '5290', (464, 470))	('FAT atypical cadherin 1', 'Gene', '2195', (350, 373))
618849	33446653	Notably, mutation of PIK3CA leads to hyper-activation of PI3Kalpha, which plays a key role in the regulation of multiple cellular events, including cell growth and proliferation.	('mutation', 'Var', (9, 17))	('PIK3CA', 'Gene', (21, 27))	('hyper-activation', 'PosReg', (37, 53))	('PIK3CA', 'Gene', '5290', (21, 27))	('PI3Kalpha', 'Gene', '5290', (57, 66))	('PI3Kalpha', 'Gene', (57, 66))
618850	33446653	Aberrant activation of PI3K also occurs frequently in ESCC via amplification of PIK3CA, hyper-activation of upstream receptor tyrosine kinases (RTKs), alteration in downstream effector AKT, as well as functional loss of phosphatase and tensin homolog (PTEN).	('activation', 'PosReg', (9, 19))	('AKT', 'Gene', (185, 188))	('phosphatase and tensin homolog', 'Gene', '5728', (220, 250))	('PI3K', 'Pathway', (23, 27))	('ESCC', 'Disease', (54, 58))	('PTEN', 'Gene', (252, 256))	('PTEN', 'Gene', '5728', (252, 256))	('PIK3CA', 'Gene', (80, 86))	('alteration', 'Var', (151, 161))	('AKT', 'Gene', '207', (185, 188))	('PIK3CA', 'Gene', '5290', (80, 86))	('loss', 'NegReg', (212, 216))	('amplification', 'Var', (63, 76))
618852	33446653	Alpelisib, a PI3Kalpha-specific inhibitor, is currently in clinical trials to treat ESCC patients (NCT03292250 and NCT01822613).	('PI3Kalpha', 'Gene', '5290', (13, 22))	('PI3Kalpha', 'Gene', (13, 22))	('ESCC', 'Disease', (84, 88))	('NCT03292250', 'Var', (99, 110))	('patients', 'Species', '9606', (89, 97))
618857	33446653	CYH33 is a novel PI3Kalpha-selective inhibitor with a distinctive structure, which is discovered by our group and is currently in clinical trials for the treatment of solid tumors including advanced ESCC (NCT03544905).	('PI3Kalpha', 'Gene', '5290', (17, 26))	('NCT03544905', 'Var', (205, 216))	('PI3Kalpha', 'Gene', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('ESCC', 'Disease', (199, 203))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('CYH33', 'Var', (0, 5))
618858	33446653	Our previous study has reported that CYH33 displayed significant activity against the proliferation of ESCC cells and the growth of xenografts derived from ESCC cells or ESCC patients.	('activity', 'MPA', (65, 73))	('proliferation', 'CPA', (86, 99))	('CYH33', 'Var', (37, 42))	('patients', 'Species', '9606', (175, 183))	('growth', 'CPA', (122, 128))
618859	33446653	CYH33 also sensitized ESCC to radiation by abrogating survival signals in tumor cells and tumor microenvironment, indicating its potential in ESCC treatment.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('abrogating', 'NegReg', (43, 53))	('sensitized', 'Reg', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('CYH33', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
618860	33446653	Mutation and gain of copy number were frequently found in CYH33-resistant cells, which were accompanied with activation of pathways involving mammalian target of Rapamycin complex1 (mTORC1), c-Myc, or mitogen-activated protein kinase (MAPK).	('mTORC1', 'Gene', '382056', (182, 188))	('Mutation', 'Var', (0, 8))	('activation', 'PosReg', (109, 119))	('c-Myc', 'Gene', '4609', (191, 196))	('Rapamycin', 'Chemical', 'MESH:D020123', (162, 171))	('mTORC1', 'Gene', (182, 188))	('copy number', 'Var', (21, 32))	('CYH33-resistant', 'Var', (58, 73))	('c-Myc', 'Gene', (191, 196))	('gain', 'PosReg', (13, 17))
618861	33446653	Thus, inhibiting these pathways by RAD001, OTX015, or MEK162 sensitized the resistant ESCC cells to CYH33.	('RAD001', 'Var', (35, 41))	('OTX015', 'Var', (43, 49))	('MEK162', 'Gene', (54, 60))	('inhibiting', 'NegReg', (6, 16))	('MEK162', 'Chemical', 'MESH:C581313', (54, 60))	('sensitized', 'Reg', (61, 71))
618862	33446653	CYH33 was provided by Shanghai HaiHe Pharmaceutical Co. Ltd. Alpelisib, GSK21118436, MEK162, GDC0994, BI-D1870, RAD001, and OTX015 were purchased from Selleck Chemicals (Houston, TX, USA).	('GSK21118436', 'Var', (72, 83))	('BI-D1870', 'Chemical', 'MESH:C516541', (102, 110))	('GDC0994', 'Chemical', '-', (93, 100))	('BI-D1870', 'Var', (102, 110))	('GSK21118436', 'Chemical', '-', (72, 83))	('MEK162', 'Chemical', 'MESH:C581313', (85, 91))
618865	33446653	The esophageal squamous cell carcinoma COLO680N, KYSE30, KYSE180, KYSE70, KYSE140, KYSE150, KYSE410, KYSE450, and KYSE510 cells were kindly provided by Dr. Hideaki Shimada (Department of Surgery, Toho University School of Medicine).	('KYSE150', 'Var', (83, 90))	('KYSE140', 'Var', (74, 81))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (4, 38))	('KYSE510', 'CellLine', 'CVCL:1354', (114, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('KYSE410', 'Var', (92, 99))	('esophageal squamous cell carcinoma', 'Disease', (4, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('KYSE180', 'Var', (57, 64))	('KYSE30', 'Var', (49, 55))	('KYSE70', 'Var', (66, 72))
618866	33446653	Cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum in a humidified atmosphere of 95% air and 5% CO2 at 37  C. We established CYH33-resistant cells by exposing ESCC KYSE70, KYSE180, KYSE410, and KYSE510 cells to increasing concentrations of CYH33 as described previously.	('KYSE510', 'CellLine', 'CVCL:1354', (219, 226))	('KYSE510', 'Var', (219, 226))	('CO2', 'Chemical', 'MESH:D002245', (121, 124))	('KYSE410', 'Var', (206, 213))
618872	33446653	Cell lysates were prepared and standard western blotting was performed with antibodies against HRAS (Abcam, Cambridge, UK), Akt, phospho-Akt (Ser473), phospho-Akt (Thr308), S6K, phospho-S6K (Thr389), 4EBP1, phospho-4EBP1 (Thr37/46), MEK, phospho-MEK (Ser217/221), extracellular signal-regulated kinase 1 (ERK), phospho-ERK (Thr202/Tyr204), p90RSK, phospho-p90RSK (Thr359/Ser363), c-Myc, S6, phospho-S6 (Ser235/236), phospho-S6 (Ser240/244) (Cell Signaling Technology, Danvers, MA, USA), and GAPDH, beta-Actin (Sigma, St. Louis, MO, USA).	('4EBP1', 'Gene', '1978', (200, 205))	('HRAS', 'Gene', (95, 99))	('ERK', 'Gene', '5594', (319, 322))	('ERK', 'Gene', (305, 308))	('S6K', 'Mutation', 'p.S6K', (173, 176))	('p90RSK', 'Gene', (340, 346))	('Akt', 'Gene', (124, 127))	('4EBP1', 'Gene', '1978', (215, 220))	('p90RSK', 'Gene', '6195', (356, 362))	('ERK', 'Gene', (319, 322))	('c-Myc', 'Gene', (380, 385))	('extracellular signal-regulated kinase 1', 'Gene', (264, 303))	('Akt', 'Gene', '207', (124, 127))	('Thr359/Ser363', 'Var', (364, 377))	('4EBP1', 'Gene', (200, 205))	('c-Myc', 'Gene', '4609', (380, 385))	('Akt', 'Gene', (137, 140))	('p90RSK', 'Gene', '6195', (340, 346))	('S6K', 'Mutation', 'p.S6K', (186, 189))	('beta-Actin', 'Gene', (498, 508))	('Akt', 'Gene', (159, 162))	('extracellular signal-regulated kinase 1', 'Gene', '5594', (264, 303))	('ERK', 'Gene', '5594', (305, 308))	('beta-Actin', 'Gene', '728378', (498, 508))	('Akt', 'Gene', '207', (137, 140))	('p90RSK', 'Gene', (356, 362))	('4EBP1', 'Gene', (215, 220))	('HRAS', 'Gene', '3265', (95, 99))	('Akt', 'Gene', '207', (159, 162))
618875	33446653	HEK293T cells seeded in 6-well plates were transfected with PGMLV-6395, PGMLV-HRAS, or PGMLV-HRASG12S along with pCMV-VSV-G (#8454, Addgene) and pCMV-dR8.2 dvpr (#8455, Addgene) using Lipofectamine 2000 (Invitrogen, Carisbad, CA, USA) following the manufacturer's instructions.	('HRAS', 'Gene', '3265', (93, 97))	('HRAS', 'Gene', '3265', (78, 82))	('HRAS', 'Gene', (93, 97))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('HRASG12S', 'Chemical', '-', (93, 101))	('HRAS', 'Gene', (78, 82))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (184, 202))	('PGMLV-6395', 'Var', (60, 70))
618877	33446653	ESCC cells were infected with viruses in the presence of 6 mug/mL polybrene (Sigma, St. Louis, MO, USA).	('polybrene', 'Var', (66, 75))	('infected', 'Disease', 'MESH:D007239', (16, 24))	('infected', 'Disease', (16, 24))	('polybrene', 'Chemical', 'MESH:D006583', (66, 75))
618887	33446653	We have reported that CYH33 is a novel PI3Kalpha-selective inhibitor and sensitize ESCC to radiation.	('PI3Kalpha', 'Gene', (39, 48))	('CYH33', 'Var', (22, 27))	('sensitize', 'Reg', (73, 82))	('PI3Kalpha', 'Gene', '5290', (39, 48))
618891	33446653	To monitor the occurrence of resistance to PI3Kalpha inhibitors in ESCC and develop strategies to overcome the acquired resistance, we exposed 4 types of ESCC cell lines (KYSE70, KYSE180, KYSE410, and KYSE510) that are sensitive to PI3Kalpha inhibitors to increasing concentrations of CYH33 for about 6 months.	('KYSE510', 'CellLine', 'CVCL:1354', (201, 208))	('KYSE410', 'Var', (188, 195))	('PI3Kalpha', 'Gene', '5290', (43, 52))	('PI3Kalpha', 'Gene', '5290', (232, 241))	('PI3Kalpha', 'Gene', (232, 241))	('PI3Kalpha', 'Gene', (43, 52))
618892	33446653	These cells developed resistance to CYH33 and were named KYSE70C, KYSE180C, KYSE410C, and KYSE510C, respectively.	('KYSE510C', 'CellLine', 'CVCL:1354', (90, 98))	('KYSE410C', 'Var', (76, 84))	('resistance', 'MPA', (22, 32))	('KYSE70C', 'Var', (57, 64))	('KYSE180C', 'Var', (66, 74))	('developed', 'Reg', (12, 21))	('KYSE510C', 'Var', (90, 98))
618893	33446653	1B, the growth inhibitory curves of CYH33 in KYSE70C, KYSE180C, KYSE410C, and KYSE510C cells indicated that these cells were resistant to CYH33 compared with their parental cells.	('CYH33', 'Gene', (36, 41))	('growth inhibitory', 'MPA', (8, 25))	('KYSE510C', 'Var', (78, 86))	('KYSE510C', 'CellLine', 'CVCL:1354', (78, 86))	('KYSE410C', 'Var', (64, 72))	('KYSE70C', 'Var', (45, 52))	('KYSE180C', 'Var', (54, 62))
618897	33446653	CYH33 and alpelisib significantly arrested cells at G1 phase in parental cells, while they displayed little effect on cell cycle distribution in resistant cells (Fig.	('arrest', 'Disease', (34, 40))	('alpelisib', 'Chemical', 'MESH:C585539', (10, 19))	('arrest', 'Disease', 'MESH:D006323', (34, 40))	('CYH33', 'Var', (0, 5))	('cells at G1 phase', 'CPA', (43, 60))	('alpelisib', 'Gene', (10, 19))
618898	33446653	Thus, KYSE70C, KYSE180C, KYSE410C, and KYSE510C cells with adaptive resistance to CYH33 were successfully established.	('KYSE180C', 'Var', (15, 23))	('KYSE510C', 'CellLine', 'CVCL:1354', (39, 47))	('KYSE410C', 'Var', (25, 33))
618899	33446653	Using stringent criteria for the analysis of these data, we identified 51, 29, 52, and 173 high-confidence non-synonymous somatic mutations in KYSE70C, KYSE180C, KYSE410C, and KYSE510C cells, respectively (Supplemental Tables S1-S4).	('KYSE510C', 'CellLine', 'CVCL:1354', (176, 184))	('KYSE410C', 'Var', (162, 170))	('KYSE70C', 'Var', (143, 150))	('KYSE180C', 'Var', (152, 160))	('KYSE510C', 'Var', (176, 184))
618901	33446653	2A including PDE3AK330N in KYSE70C cells, HRASG12S in KYSE180C cells, AKT3Q78K in KYSE410C cells, and STK11P221L and PTPRTD905N in KYSE510C cells.	('KYSE510C', 'CellLine', 'CVCL:1354', (131, 139))	('STK11', 'Gene', (102, 107))	('AKT3', 'Gene', (70, 74))	('AKT3', 'Gene', '10000', (70, 74))	('STK11', 'Gene', '6794', (102, 107))	('HRASG12S', 'Chemical', '-', (42, 50))	('PTPRTD905N', 'Var', (117, 127))	('HRASG12S', 'Var', (42, 50))	('PDE3AK330N', 'Var', (13, 23))
618902	33446653	In addition to gained mutations, we also detected amplification of multiple chromosome segments in the CYH33-resistant cells, such as amplification of chr8q24 in KYSE180C cells, chr22q11 in KYSE410C cells, and chr2q31 in KYSE510C cells (Fig.	('KYSE510C', 'CellLine', 'CVCL:1354', (221, 229))	('chr2q31', 'Var', (210, 217))	('amplification', 'Var', (134, 147))	('chr22q11', 'Var', (178, 186))	('chr8q24', 'Gene', (151, 158))
618904	33446653	3A, CYH33 suppressed the phosphorylation level of Akt, which is the intermediate downstream effector of PI3K, in resistant and parental cells in a dose-dependent manner, suggesting that the acquired resistance was not due to the lack of inhibition on its cellular target.	('Akt', 'Gene', '207', (50, 53))	('Akt', 'Gene', (50, 53))	('suppressed', 'NegReg', (10, 20))	('phosphorylation level', 'MPA', (25, 46))	('CYH33', 'Var', (4, 9))
618906	33446653	CYH33 slightly suppressed the level of phosphorylated ribosomal protein S6 (S6), a downstream effector of mTORC1, in KTSE70C, KYSE410C, and KYSE510C cells, while the phosphorylation of S6 was almost completely blocked by CYH33 in parental counterparts.	('mTORC1', 'Gene', '382056', (106, 112))	('ribosomal protein S6', 'Gene', (54, 74))	('KYSE510C', 'Var', (140, 148))	('ribosomal protein S6', 'Gene', '6194', (54, 74))	('mTORC1', 'Gene', (106, 112))	('KYSE510C', 'CellLine', 'CVCL:1354', (140, 148))	('KYSE410C', 'Var', (126, 134))	('suppressed', 'NegReg', (15, 25))	('level of phosphorylated', 'MPA', (30, 53))	('CYH33', 'Var', (0, 5))
618908	33446653	Gene enrichment analysis revealed that RAS signaling pathway, PI3K-Akt signaling pathway, and MAPK signaling pathway were highly activated in most CYH33-resistant cells (Supplemental Fig.	('activated', 'PosReg', (129, 138))	('Akt', 'Gene', (67, 70))	('MAPK signaling pathway', 'Pathway', (94, 116))	('CYH33-resistant', 'Var', (147, 162))	('RAS signaling pathway', 'Pathway', (39, 60))	('Akt', 'Gene', '207', (67, 70))
618909	33446653	CYH33 significantly inhibited mTORC1 signaling pathway in all 4 types of parental cells, while CYH33 displayed little effect on this set of genes in KYSE70C, KYSE180C, and KYSE410C cells.	('KYSE70C', 'Var', (149, 156))	('KYSE410C', 'Var', (172, 180))	('mTORC1', 'Gene', '382056', (30, 36))	('mTORC1', 'Gene', (30, 36))	('KYSE180C', 'Var', (158, 166))	('inhibited', 'NegReg', (20, 29))	('CYH33', 'Var', (0, 5))
618910	33446653	mTORC1 signaling pathway even elevated in KYSE510C cells after CYH33 treatment (Fig.	('mTORC1', 'Gene', '382056', (0, 6))	('elevated', 'PosReg', (30, 38))	('mTORC1', 'Gene', (0, 6))	('KYSE510C', 'CellLine', 'CVCL:1354', (42, 50))	('CYH33', 'Var', (63, 68))
618912	33446653	Similarly, "MYC_targets" gene set was down-regulated in CYH33-treated group in all 4 types of parental cells, while this effect was mild in KYSE70C, KYSE180C, and KYSE410C cells.	('down-regulated', 'NegReg', (38, 52))	('MYC', 'Gene', (12, 15))	('CYH33-treated', 'Var', (56, 69))	('KYSE70C', 'Var', (140, 147))	('KYSE180C', 'Var', (149, 157))	('MYC', 'Gene', '4609', (12, 15))
618913	33446653	"MYC targets" gene set was even up-regulated in KYSE510C cells treated with CYH33 (Fig.	('MYC', 'Gene', '4609', (1, 4))	('CYH33', 'Var', (76, 81))	('up-regulated', 'PosReg', (32, 44))	('MYC', 'Gene', (1, 4))	('KYSE510C', 'CellLine', 'CVCL:1354', (48, 56))
618915	33446653	ERK was hyper-activated in KYSE180C and KYSE510C cells compared to their parental cells, which was not attenuated by CYH33.	('KYSE510C', 'Var', (40, 48))	('hyper-activated', 'PosReg', (8, 23))	('KYSE180C', 'Var', (27, 35))	('KYSE510C', 'CellLine', 'CVCL:1354', (40, 48))	('ERK', 'Gene', '5594', (0, 3))	('ERK', 'Gene', (0, 3))
618916	33446653	Higher expression level of c-Myc was detected in KYSE180C cells than that in their parental cells.	('c-Myc', 'Gene', (27, 32))	('KYSE180C', 'Var', (49, 57))	('Higher', 'PosReg', (0, 6))	('expression level', 'MPA', (7, 23))	('c-Myc', 'Gene', '4609', (27, 32))
618917	33446653	Although the level of c-Myc was similar in CYH33-resistant and parental cells, CYH33 markedly down-regulated c-Myc in KYSE410 and KYSE510 cells but not in KYSE410C and KYSE510C cells (Fig.	('c-Myc', 'Gene', (109, 114))	('CYH33', 'Var', (79, 84))	('KYSE510', 'CellLine', 'CVCL:1354', (130, 137))	('c-Myc', 'Gene', '4609', (22, 27))	('c-Myc', 'Gene', '4609', (109, 114))	('down-regulated', 'NegReg', (94, 108))	('KYSE510', 'CellLine', 'CVCL:1354', (168, 175))	('KYSE510C', 'CellLine', 'CVCL:1354', (168, 176))	('c-Myc', 'Gene', (22, 27))	('KYSE510', 'Var', (130, 137))	('KYSE410', 'Var', (118, 125))
618919	33446653	As mTOR and c-Myc have been reported to confer resistance to PI3K inhibitors in multiple cancers and we detected HRASG12S mutant in KYSE180C cells, we further investigated whether HRASG12S mutant was associated with resistance to CYH33.	('mTOR', 'Gene', '2475', (3, 7))	('HRASG12S', 'Var', (113, 121))	('HRASG12S', 'Chemical', '-', (113, 121))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('c-Myc', 'Gene', '4609', (12, 17))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('c-Myc', 'Gene', (12, 17))	('associated', 'Reg', (200, 210))	('HRASG12S', 'Chemical', '-', (180, 188))	('mTOR', 'Gene', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
618920	33446653	To verify mutation of HRASG12S in KYSE180C cells, we generated 3 lines of monoclonal cells from KYSE180C cells, namely KYSE180C1, KYSE180C2 and KYSE180C3.	('KYSE180C3', 'CellLine', 'CVCL:1349', (144, 153))	('KYSE180C3', 'Var', (144, 153))	('HRASG12S', 'Gene', (22, 30))	('HRASG12S', 'Chemical', '-', (22, 30))	('KYSE180C1', 'CellLine', 'CVCL:1349', (119, 128))	('KYSE180C2', 'Var', (130, 139))
618923	33446653	4B), demonstrating a heterozygous G to A mutation in all KYSE180C monoclonal cells, which resulted in a heterozygous G12S mutation in HRAS.	('HRAS', 'Gene', (134, 138))	('G12S', 'Mutation', 'rs104894229', (117, 121))	('mutation', 'Var', (41, 49))	('resulted in', 'Reg', (90, 101))	('G12S', 'Var', (117, 121))	('HRAS', 'Gene', '3265', (134, 138))
618924	33446653	Accordingly, both Akt and ERK were hyper-phosphorylated in KYSE180C monoclonal cells compared to parental cells (Fig.	('Akt', 'Gene', (18, 21))	('hyper-phosphorylated', 'PosReg', (35, 55))	('ERK', 'Gene', '5594', (26, 29))	('ERK', 'Gene', (26, 29))	('Akt', 'Gene', '207', (18, 21))	('KYSE180C monoclonal', 'Var', (59, 78))
618925	33446653	Though CYH33 was able to inhibit the phosphorylation of Akt in KYSE180C monoclonal cells, phosphorylation of ERK remained unchanged upon CYH33 treatment (Fig.	('CYH33', 'Var', (137, 142))	('phosphorylation', 'MPA', (37, 52))	('Akt', 'Gene', (56, 59))	('ERK', 'Gene', '5594', (109, 112))	('phosphorylation', 'MPA', (90, 105))	('ERK', 'Gene', (109, 112))	('inhibit', 'NegReg', (25, 32))	('Akt', 'Gene', '207', (56, 59))
618926	33446653	To determine whether ectopic expression of HRASG12S in ESCC cells is able to induce resistance to CYH33, we established KYSE180 cells stably overexpressing HRASG12S (KYSE180-H).	('resistance to CYH33', 'MPA', (84, 103))	('induce', 'PosReg', (77, 83))	('HRASG12S', 'Var', (43, 51))	('HRASG12S', 'Chemical', '-', (43, 51))	('HRASG12S', 'Var', (156, 164))	('KYSE180-H', 'CellLine', 'CVCL:1349', (166, 175))	('HRASG12S', 'Chemical', '-', (156, 164))
618927	33446653	Introduction of HRASG12S significantly activated PI3K pathway and MAPK pathway with enhanced level of phosphorylated Akt, ERK and S6 compared to those in KYSE180 cells transfected with a vehicle plasmid (KYSE180-V, Fig.	('PI3K pathway', 'Pathway', (49, 61))	('HRASG12S', 'Chemical', '-', (16, 24))	('MAPK pathway', 'Pathway', (66, 78))	('activated', 'PosReg', (39, 48))	('HRASG12S', 'Var', (16, 24))	('Akt', 'Gene', (117, 120))	('level', 'MPA', (93, 98))	('ERK', 'Gene', '5594', (122, 125))	('Akt', 'Gene', '207', (117, 120))	('ERK', 'Gene', (122, 125))	('enhanced', 'PosReg', (84, 92))
618930	33446653	3A), which was accompanied with reduction in cell population arrested at G1 phase after CYH33 treatment (Fig.	('arrest', 'Disease', (61, 67))	('CYH33', 'Var', (88, 93))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('reduction', 'NegReg', (32, 41))
618933	33446653	To investigate whether HRASG12S mutation was able to mediate resistance to CYH33 in other ESCC cells, we generated KYSE70, KYSE410, and KYSE510 cells expressing HRASG12S, and found that these cells displayed reduced sensitivity to CYH33 (Supplemental Fig.	('HRASG12S', 'Chemical', '-', (23, 31))	('sensitivity', 'MPA', (216, 227))	('HRASG12S', 'Chemical', '-', (161, 169))	('KYSE510', 'CellLine', 'CVCL:1354', (136, 143))	('HRASG12S', 'Var', (161, 169))	('reduced', 'NegReg', (208, 215))	('mutation', 'Var', (32, 40))
618935	33446653	4H, knockdown of HRASG12S by siRNA sensitized KYSE180C1 cells to CYH33 demonstrated as reduced IC50 values of CYH33 against cell proliferation.	('IC50 values', 'MPA', (95, 106))	('HRASG12S', 'Chemical', '-', (17, 25))	('CYH33', 'Var', (110, 115))	('reduced', 'NegReg', (87, 94))	('KYSE180C1', 'CellLine', 'CVCL:1349', (46, 55))
618936	33446653	Collectively, activation of HRAS by G12S mutation rendered resistance to CYH33 in ESCC cells.	('activation', 'PosReg', (14, 24))	('HRAS', 'Gene', '3265', (28, 32))	('resistance to', 'MPA', (59, 72))	('HRAS', 'Gene', (28, 32))	('G12S', 'Mutation', 'rs104894229', (36, 40))	('G12S', 'Var', (36, 40))
618938	33446653	5A, GSK2118436, MEK162, GDC0994, and BI-D1870 at the concentration of 1 muM inhibited their respective target demonstrated as phosphorylated MAPK (MEK), ERK, ribosomal protein S6 kinase A (RSK) or S6.	('GDC0994', 'Chemical', '-', (24, 31))	('GSK2118436', 'Var', (4, 14))	('RSK', 'Gene', '6195', (189, 192))	('RSK', 'Gene', (189, 192))	('ERK', 'Gene', '5594', (153, 156))	('BI-D1870', 'Var', (37, 45))	('ERK', 'Gene', (153, 156))	('ribosomal protein S6 kinase A', 'Gene', '6195', (158, 187))	('MEK162', 'Chemical', 'MESH:C581313', (16, 22))	('BI-D1870', 'Chemical', 'MESH:C516541', (37, 45))	('GSK2118436', 'Chemical', 'MESH:C561627', (4, 14))	('inhibited', 'NegReg', (76, 85))	('MEK162', 'Var', (16, 22))	('phosphorylated', 'MPA', (126, 140))	('ribosomal protein S6 kinase A', 'Gene', (158, 187))
618939	33446653	GSK2118436 and MEK162 sensitized KYSE180C1 cells to CYH33 to a greater degree than GDC0994 and BI-D1870, indicating that inhibition of MEK would abrogate HRASG12S-mediated resistance to CYH33 (Fig.	('HRASG12S-mediated resistance', 'CPA', (154, 182))	('abrogate', 'NegReg', (145, 153))	('GDC0994', 'Chemical', '-', (83, 90))	('HRASG12S', 'Chemical', '-', (154, 162))	('MEK162', 'Chemical', 'MESH:C581313', (15, 21))	('inhibition', 'Var', (121, 131))	('GSK2118436', 'Chemical', 'MESH:C561627', (0, 10))	('MEK', 'Gene', (135, 138))	('BI-D1870', 'Chemical', 'MESH:C516541', (95, 103))	('KYSE180C1', 'CellLine', 'CVCL:1349', (33, 42))
618940	33446653	MEK162 at the concentration of 1 muM also sensitized KYSE180C2 and KYSE180C3 cells to CYH33 (Supplemental Fig.	('MEK162', 'Var', (0, 6))	('sensitized', 'Reg', (42, 52))	('MEK162', 'Chemical', 'MESH:C581313', (0, 6))	('KYSE180C3', 'CellLine', 'CVCL:1349', (67, 76))
618941	33446653	Consistently, combination of CYH33 and MEK162 enhanced G1 phase arrest in KYSE180C1 cells (Fig.	('arrest', 'Disease', (64, 70))	('KYSE180C1', 'CellLine', 'CVCL:1349', (74, 83))	('MEK162', 'Gene', (39, 45))	('MEK162', 'Chemical', 'MESH:C581313', (39, 45))	('CYH33', 'Var', (29, 34))	('enhanced', 'PosReg', (46, 54))	('arrest', 'Disease', 'MESH:D006323', (64, 70))
618943	33446653	CYH33 alone slightly inhibited the growth of KYSE180C1 xenografts, while co-administration of CYH33 and MEK162 potently inhibited tumor growth and resulted in significant reduction in tumor weight compared to the control group (Fig.	('MEK162', 'Chemical', 'MESH:C581313', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('growth', 'CPA', (35, 41))	('CYH33', 'Var', (94, 99))	('inhibited', 'NegReg', (120, 129))	('tumor weight', 'Disease', 'MESH:D015431', (184, 196))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('reduction', 'NegReg', (171, 180))	('tumor', 'Disease', (184, 189))	('KYSE180C1', 'CellLine', 'CVCL:1349', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('inhibited', 'NegReg', (21, 30))	('MEK162', 'Gene', (104, 110))	('tumor', 'Disease', (130, 135))	('tumor weight', 'Disease', (184, 196))
618944	33446653	Accordingly, co-administration of CYH33 and MEK162 simultaneously blocked phosphorylation of Akt and ERK, resulting in enhanced inhibition on phosphorylation of S6 (Supplemental Fig.	('phosphorylation', 'MPA', (74, 89))	('CYH33', 'Var', (34, 39))	('MEK162', 'Var', (44, 50))	('Akt', 'Gene', (93, 96))	('inhibition', 'NegReg', (128, 138))	('ERK', 'Gene', '5594', (101, 104))	('ERK', 'Gene', (101, 104))	('blocked', 'NegReg', (66, 73))	('phosphorylation', 'MPA', (142, 157))	('MEK162', 'Chemical', 'MESH:C581313', (44, 50))	('Akt', 'Gene', '207', (93, 96))	('enhanced', 'PosReg', (119, 127))
618948	33446653	Co-administration of CYH33 and MEK162 significantly inhibited the growth of KYSE180-H xenografts (Fig.	('MEK162', 'Chemical', 'MESH:C581313', (31, 37))	('CYH33', 'Var', (21, 26))	('MEK162', 'Var', (31, 37))	('KYSE180-H', 'CellLine', 'CVCL:1349', (76, 85))	('growth of KYSE180-H xenografts', 'CPA', (66, 96))	('inhibited', 'NegReg', (52, 61))
618950	33446653	Collectively, inhibition of MEK restored the sensitivity of KYSE180C1 and KYSE180-H cells to CYH33 in vitro and in vivo.	('sensitivity', 'MPA', (45, 56))	('KYSE180C1', 'CellLine', 'CVCL:1349', (60, 69))	('MEK', 'Gene', (28, 31))	('KYSE180-H', 'CellLine', 'CVCL:1349', (74, 83))	('restored', 'PosReg', (32, 40))	('inhibition', 'Var', (14, 24))
618951	33446653	We found that activation of MAPK pathway, mTORC1, and c-Myc was frequently occurred in CYH33-resistant ESCC cells (Fig.	('MAPK pathway', 'Pathway', (28, 40))	('activation', 'PosReg', (14, 24))	('CYH33-resistant', 'Var', (87, 102))	('mTORC1', 'Gene', '382056', (42, 48))	('mTORC1', 'Gene', (42, 48))	('c-Myc', 'Gene', '4609', (54, 59))	('c-Myc', 'Gene', (54, 59))
618953	33446653	6B, CYH33 and MEK162 at the concentration of 1 muM suppressed phosphorylation of Akt or ERK, respectively.	('Akt', 'Gene', '207', (81, 84))	('MEK162', 'Chemical', 'MESH:C581313', (14, 20))	('MEK162', 'Gene', (14, 20))	('ERK', 'Gene', '5594', (88, 91))	('phosphorylation', 'MPA', (62, 77))	('Akt', 'Gene', (81, 84))	('ERK', 'Gene', (88, 91))	('suppressed', 'NegReg', (51, 61))	('CYH33', 'Var', (4, 9))
618954	33446653	However, combined CYH33 and MEK162 simultaneously blocked activity of both PI3K pathway and MAPK pathway in CYH33-resistant cells.	('MEK162', 'Chemical', 'MESH:C581313', (28, 34))	('CYH33', 'Var', (18, 23))	('activity', 'MPA', (58, 66))	('blocked', 'NegReg', (50, 57))	('MAPK pathway', 'Pathway', (92, 104))	('PI3K pathway', 'Pathway', (75, 87))	('MEK162', 'Gene', (28, 34))
618955	33446653	CYH33 partially suppressed phosphorylation of eukaryotic translation initiation facter 4E binding protein 1 (4EBP1), S6K1, and S6, and co-treatment of CYH33 and RAD001 resulted in enhanced inhibition on phosphorylation of 4EBP1 and S6K (Fig.	('suppressed', 'NegReg', (16, 26))	('4E binding protein 1', 'Gene', (87, 107))	('S6K', 'Mutation', 'p.S6K', (232, 235))	('CYH33', 'Var', (151, 156))	('phosphorylation', 'MPA', (27, 42))	('phosphorylation', 'MPA', (203, 218))	('S6K1', 'Gene', '6198', (117, 121))	('4EBP1', 'Gene', '1978', (109, 114))	('4EBP1', 'Gene', (222, 227))	('S6K1', 'Gene', (117, 121))	('S6K', 'Gene', (232, 235))	('S6K', 'Mutation', 'p.S6K', (117, 120))	('enhanced', 'PosReg', (180, 188))	('4E binding protein 1', 'Gene', '1978', (87, 107))	('4EBP1', 'Gene', '1978', (222, 227))	('4EBP1', 'Gene', (109, 114))	('inhibition', 'NegReg', (189, 199))
618957	33446653	CYH33 at 1 muM reduced the level of c-Myc protein in KYSE180C and KYSE410C cells.	('KYSE410C', 'Var', (66, 74))	('c-Myc', 'Gene', '4609', (36, 41))	('reduced', 'NegReg', (15, 22))	('CYH33', 'Var', (0, 5))	('c-Myc', 'Gene', (36, 41))
618958	33446653	Pretreatment with OTX015 for 23 h enhanced the ability of CYH33 to reduce the level of c-Myc protein in KYSE70C, KYSE180C, and KYSE410C cells (Fig.	('reduce', 'NegReg', (67, 73))	('KYSE180C', 'Var', (113, 121))	('c-Myc', 'Gene', '4609', (87, 92))	('enhanced', 'PosReg', (34, 42))	('c-Myc', 'Gene', (87, 92))	('KYSE410C', 'Var', (127, 135))	('KYSE70C', 'Var', (104, 111))
618960	33446653	CYH33 is a novel PI3Kalpha-selective inhibitor in clinical trials for the advanced solid tumors including ESCC based on its promising efficacy in preclinical settings (Fig.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('PI3Kalpha', 'Gene', '5290', (17, 26))	('PI3Kalpha', 'Gene', (17, 26))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('ESCC', 'Disease', (106, 110))	('CYH33', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
618962	33446653	In this study, we found gained mutations and amplification of chromosome segments in established CYH33-resistant ESCC cells, which is associated with PI3Kalpha-independent activation of mTORC1, MAPK, and c-Myc signaling.	('mutations', 'Var', (31, 40))	('c-Myc', 'Gene', '4609', (204, 209))	('amplification', 'Var', (45, 58))	('mTORC1', 'Gene', '382056', (186, 192))	('c-Myc', 'Gene', (204, 209))	('PI3Kalpha', 'Gene', '5290', (150, 159))	('PI3Kalpha', 'Gene', (150, 159))	('mTORC1', 'Gene', (186, 192))
618963	33446653	Especially, gain-of-function HRASG12S mutant was able to confer resistance to CYH33 in ESCC cells, which could be abrogated by co-current inhibition of MAPK and PI3Kalpha.	('HRASG12S', 'Var', (29, 37))	('PI3Kalpha', 'Gene', (161, 170))	('resistance', 'MPA', (64, 74))	('PI3Kalpha', 'Gene', '5290', (161, 170))	('gain-of-function', 'PosReg', (12, 28))	('HRASG12S', 'Chemical', '-', (29, 37))
618966	33446653	For example, EGFRT790M mutant mediates resistance to the first- and second-generation of EGFR inhibitors, while C797S mutant mediates resistance to inhibitors targeting T790M mutant.	('EGFRT790M', 'Mutation', 'rs121434569', (13, 22))	('T790M', 'Var', (169, 174))	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', '1956', (89, 93))	('C797S', 'Mutation', 'rs1057519861', (112, 117))	('resistance', 'MPA', (39, 49))	('C797S', 'Var', (112, 117))	('T790M', 'Mutation', 'rs121434569', (17, 22))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mediates', 'Reg', (30, 38))	('T790M', 'Mutation', 'rs121434569', (169, 174))
618970	33446653	We found that HRASG12S mutant was associated with resistance to PI3Kalpha inhibitors in ESCC cells by the three lines of evidences: firstly, ectopic expression of HRASG12S in ESCC cells significantly enhanced MAPK signaling and rendered resistance to CYH33; secondly, knockdown of HRASG12S or inhibition of signaling downstream of HRAS sensitized resistant cells to CYH33; thirdly, combination of CYH33 and MEK inhibitor synergistically inhibited the growth of xenografts that have originated from resistant cells harboring HRASG12S.	('HRAS', 'Gene', '3265', (331, 335))	('HRASG12S', 'Chemical', '-', (281, 289))	('HRAS', 'Gene', (14, 18))	('resistance to CYH33', 'MPA', (237, 256))	('HRAS', 'Gene', (331, 335))	('enhanced', 'PosReg', (200, 208))	('PI3Kalpha', 'Gene', (64, 73))	('HRASG12S', 'Chemical', '-', (524, 532))	('HRAS', 'Gene', '3265', (163, 167))	('HRAS', 'Gene', (163, 167))	('HRAS', 'Gene', '3265', (281, 285))	('HRAS', 'Gene', (281, 285))	('growth of xenografts', 'CPA', (451, 471))	('HRAS', 'Gene', '3265', (524, 528))	('HRASG12S', 'Chemical', '-', (14, 22))	('PI3Kalpha', 'Gene', '5290', (64, 73))	('mutant', 'Var', (23, 29))	('HRAS', 'Gene', (524, 528))	('inhibited', 'NegReg', (437, 446))	('MAPK signaling', 'MPA', (209, 223))	('HRASG12S', 'Chemical', '-', (163, 171))	('HRAS', 'Gene', '3265', (14, 18))
618972	33446653	Our study also suggested that concurrent inhibition of PI3Kalpha and RAS/MEK is worthwhile to be considered in the treatment of ESCC harboring mutation in KRAS or HRAS.	('KRAS', 'Gene', (155, 159))	('KRAS', 'Gene', '3845', (155, 159))	('HRAS', 'Gene', '3265', (163, 167))	('mutation', 'Var', (143, 151))	('PI3Kalpha', 'Gene', '5290', (55, 64))	('PI3Kalpha', 'Gene', (55, 64))	('HRAS', 'Gene', (163, 167))
618976	33446653	Persistent mTORC1 activation was found to compromise alpelisib efficacy in breast cancer, while inhibition of mTORC1 with RAD001 enhanced the efficacy of PI3Kalpha inhibitors and delayed onset of resistance.	('PI3Kalpha', 'Gene', (154, 163))	('enhanced', 'PosReg', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mTORC1', 'Gene', (110, 116))	('breast cancer', 'Disease', (75, 88))	('alpelisib', 'Chemical', 'MESH:C585539', (53, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('mTORC1', 'Gene', '382056', (11, 17))	('alpelisib efficacy', 'MPA', (53, 71))	('compromise', 'NegReg', (42, 52))	('mTORC1', 'Gene', '382056', (110, 116))	('RAD001', 'Gene', (122, 128))	('inhibition', 'Var', (96, 106))	('mTORC1', 'Gene', (11, 17))	('efficacy', 'MPA', (142, 150))	('activation', 'PosReg', (18, 28))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('PI3Kalpha', 'Gene', '5290', (154, 163))
618979	33446653	We also previously reported that decrease in phosphorylated ERK indicated the therapeutic efficacy of CYH33 in breast cancer.	('decrease', 'NegReg', (33, 41))	('ERK', 'Gene', '5594', (60, 63))	('phosphorylated', 'MPA', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ERK', 'Gene', (60, 63))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('CYH33', 'Var', (102, 107))
618983	33446653	However, TP53 mutation was frequently detected in ESCC.	('detected', 'Reg', (38, 46))	('TP53', 'Gene', '7157', (9, 13))	('mutation', 'Var', (14, 22))	('TP53', 'Gene', (9, 13))	('ESCC', 'Disease', (50, 54))
618985	33446653	In summary, genomic and transcriptomic profiling revealed that activation of mTORC1, MAPK, and c-Myc signaling was associated with adaptive resistance to CYH33 in ESCC cells, and combination of CYH33 and RAD001, MEK162, or OTX015 demonstrated synergistic activity against these resistant cells.	('c-Myc', 'Gene', (95, 100))	('mTORC1', 'Gene', '382056', (77, 83))	('MAPK', 'Gene', (85, 89))	('mTORC1', 'Gene', (77, 83))	('CYH33', 'Var', (194, 199))	('MEK162', 'Gene', (212, 218))	('c-Myc', 'Gene', '4609', (95, 100))	('OTX015', 'Gene', (223, 229))	('adaptive resistance to CYH33', 'MPA', (131, 159))	('MEK162', 'Chemical', 'MESH:C581313', (212, 218))	('activation', 'PosReg', (63, 73))
618988	33069225	The Cancer Genome Atlas (TCGA) was used to investigate the frequency of gene expressions, mutations, and amplification of these 14 antigens and also the possible effects of antibody induction.	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('mutations', 'Var', (90, 99))
619001	33069225	The appearance of neoantigens and cancer antigens specific to cancer cells is believed to result from genetic mutations and gene expression abnormalities due to genetic instability.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (62, 68))	('result', 'Reg', (90, 96))	('abnormalities', 'Var', (140, 153))
619008	33069225	Esophageal squamous cell carcinoma (ESCC) has a mutated p53, a tumor suppressor, at a frequency of around 80%.	('tumor', 'Disease', (63, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('SCC', 'Gene', '6317', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutated', 'Var', (48, 55))	('squamous cell carcinoma', 'Disease', (11, 34))	('p53', 'Gene', (56, 59))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (11, 34))	('p53', 'Gene', '7157', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('SCC', 'Gene', (37, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
619022	33069225	The signal of all antibodies was evaluated by calculating the difference in absorbency between plante wells containing antibodies and wells containing phosphate-buffered saline.	('antibodies', 'Var', (119, 129))	('absorbency', 'MPA', (76, 86))	('phosphate-buffered saline', 'Chemical', '-', (151, 176))
619047	33069225	TCGA data confirmed that 156 (68.7%) of 227 patients with ESCC have p53 gene mutations.	('patients', 'Species', '9606', (44, 52))	('SCC', 'Gene', (59, 62))	('SCC', 'Gene', '6317', (59, 62))	('mutations', 'Var', (77, 86))	('p53', 'Gene', '7157', (68, 71))	('p53', 'Gene', (68, 71))
619051	33069225	It is known that when gene mutation occurs in p53, there is an increase in the expression of abnormal genes and abnormal proteins.	('expression of abnormal genes', 'MPA', (79, 107))	('increase', 'PosReg', (63, 71))	('proteins', 'Protein', (121, 129))	('p53', 'Gene', (46, 49))	('gene mutation', 'Var', (22, 35))	('p53', 'Gene', '7157', (46, 49))
619054	33069225	However, according to TCGA data, the frequencies of gene mutation of each cancer type were 0, 0.24, 0.27, 0.9, 0.09, 0.32, and 0.09% and the gene amplification rates were 0, 1.5, 1.9, 2.7, 0.3, 0.65, and 0.8%, respectively.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gene mutation', 'Var', (52, 65))
619059	33069225	Studies conducted using ovarian cancer cell lines have reported that the expression level of NY-ESO-1 was increased using DNA methylation inhibitors, indicating that epigenetic mechanisms such as acetylation and methylation may be involved in NY-ESO-1 expression.	('ovarian cancer', 'Phenotype', 'HP:0100615', (24, 38))	('expression level', 'MPA', (73, 89))	('NY-ESO-1', 'Gene', '246100', (93, 101))	('ovarian cancer', 'Disease', 'MESH:D010051', (24, 38))	('methylation', 'Var', (212, 223))	('NY-ESO-1', 'Gene', (93, 101))	('acetylation', 'MPA', (196, 207))	('DNA', 'MPA', (122, 125))	('NY-ESO-1', 'Gene', '246100', (243, 251))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('NY-ESO-1', 'Gene', (243, 251))	('ovarian cancer', 'Disease', (24, 38))	('increased', 'PosReg', (106, 115))
619062	33069225	Moreover, it was confirmed that the combination of CEA and SCC, conventional tumor markers, significantly increased the sensitivity compared with the use of the panel alone or the combination of tumor markers.	('sensitivity', 'MPA', (120, 131))	('tumor', 'Disease', (195, 200))	('SCC', 'Gene', (59, 62))	('CEA', 'Gene', '1048', (51, 54))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('SCC', 'Gene', '6317', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('increased', 'PosReg', (106, 115))	('combination', 'Var', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('CEA', 'Gene', (51, 54))
619116	32308681	No substantial survival advantages were detected from the use of 3D-CRT/IMRT in a retrospective analysis based on four prospective clinical trials, which assessed the toxicity as well as long-term survival of ESCC patients treated with 3D-CRT or IMRT in comparison with that of 2D-RT.	('toxicity', 'Disease', 'MESH:D064420', (167, 175))	('toxicity', 'Disease', (167, 175))	('patients', 'Species', '9606', (214, 222))	('ESCC', 'Disease', (209, 213))	('3D-CRT', 'Var', (236, 242))
619119	32308681	In conclusion, we found that overall survival significantly improved with IMRT-treated, compared with that of 3D-CRT-treated esophageal cancer patients, but we should also pay special attention to the effect of chemotherapy, as well as change of lifestyle, such as quit drinking.	('quit drinking', 'Disease', (265, 278))	('overall survival', 'MPA', (29, 45))	('esophageal cancer', 'Disease', (125, 142))	('patients', 'Species', '9606', (143, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('improved', 'PosReg', (60, 68))	('IMRT-treated', 'Var', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
619125	31535225	A recent phase II trial revealed that combined ER and chemoradiotherapy (CRT) is efficacious as an esophagus-preserving treatment for cT1bN0 squamous cell carcinoma (SCC).	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('squamous cell carcinoma', 'Disease', (141, 164))	('men', 'Species', '9606', (125, 128))	('SCC', 'Disease', 'MESH:D002294', (166, 169))	('SCC', 'Phenotype', 'HP:0002860', (166, 169))	('SCC', 'Disease', (166, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('cT1bN0', 'Var', (134, 140))
619152	31535225	The study enrolled patients with cT1bN0M0 SCCs with tumor size <= 5 cm and <= 3/4 circumference.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('SCC', 'Disease', 'MESH:D002294', (42, 45))	('patients', 'Species', '9606', (19, 27))	('tumor', 'Disease', (52, 57))	('cT1bN0M0', 'Var', (33, 41))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('SCC', 'Disease', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
619155	31535225	The 3-year overall survival rate of the Group B patients, the primary endpoint, was 90.7% [90% confidence interval (CI) 84.0-94.7], suggesting that the combined ER and CRT strategy is efficacious as esophagus-preserving treatment for cT1bN0M0 SCC.	('SCC', 'Phenotype', 'HP:0002860', (243, 246))	('SCC', 'Disease', (243, 246))	('SCC', 'Disease', 'MESH:D002294', (243, 246))	('men', 'Species', '9606', (225, 228))	('cT1bN0M0', 'Var', (234, 242))	('patients', 'Species', '9606', (48, 56))
619160	31535225	In Japan, efforts are being made to establish an esophagus-sparing treatment for T1bN0 SCC using definitive CRT, even for patients who are fit for surgery.	('SCC', 'Disease', 'MESH:D002294', (87, 90))	('T1bN0', 'Var', (81, 86))	('men', 'Species', '9606', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('patients', 'Species', '9606', (122, 130))	('SCC', 'Disease', (87, 90))
619198	31535225	Both the incidence of atelectasis and the population of patients who required more than 48 h of postoperative mechanical ventilation were significantly lower in the MIE group than in the OE group, whereas the incidence of pneumonia was similar in the two groups.	('patients', 'Species', '9606', (56, 64))	('postoperative mechanical ventilation', 'Phenotype', 'HP:0004887', (96, 132))	('pneumonia', 'Phenotype', 'HP:0002090', (222, 231))	('lower', 'NegReg', (152, 157))	('atelectasis', 'Disease', (22, 33))	('atelectasis', 'Disease', 'MESH:D001261', (22, 33))	('pneumonia', 'Disease', (222, 231))	('pneumonia', 'Disease', 'MESH:D011014', (222, 231))	('atelectasis', 'Phenotype', 'HP:0100750', (22, 33))	('MIE', 'Var', (165, 168))
619210	31535225	The overall complication rate was significantly lower in the RAMIE group than in the OTE group (59% vs. 80%, P = 0.02).	('complication', 'CPA', (12, 24))	('RAMIE', 'Species', '83906', (61, 66))	('lower', 'NegReg', (48, 53))	('RAMIE', 'Var', (61, 66))
619211	31535225	Notably, both pulmonary complications (32% vs. 58%, P = 0.005) and cardiac complications (22% vs. 47%, P = 0.006) were significantly lower in the RAMIE group than in the OTE group.	('pulmonary complications', 'Disease', 'MESH:D008171', (14, 37))	('cardiac complications', 'Disease', (67, 88))	('RAMIE', 'Species', '83906', (146, 151))	('pulmonary complications', 'Phenotype', 'HP:0006532', (14, 37))	('cardiac complications', 'Disease', 'MESH:D005117', (67, 88))	('lower', 'NegReg', (133, 138))	('pulmonary complications', 'Disease', (14, 37))	('RAMIE', 'Var', (146, 151))
619269	11910703	Conversely, heavy drinking has been associated with liver disease; cardiovascular disease; disorders of the digestive tract; and illness or death from alcohol-related injuries, motor vehicle crashes, and violence.	('liver disease', 'Phenotype', 'HP:0001392', (52, 65))	('cardiovascular disease', 'Disease', 'MESH:D002318', (67, 89))	('liver disease', 'Disease', (52, 65))	('heavy drinking', 'Var', (12, 26))	('liver disease', 'Disease', 'MESH:D008107', (52, 65))	('disorders of the digestive tract', 'Phenotype', 'HP:0011024', (91, 123))	('disorders of the digestive tract', 'Disease', (91, 123))	('cardiovascular disease', 'Disease', (67, 89))	('alcohol', 'Chemical', 'MESH:D000438', (151, 158))	('illness or death', 'Disease', 'MESH:D003643', (129, 145))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (67, 89))	('associated', 'Reg', (36, 46))	('illness or death', 'Disease', (129, 145))
619272	11910703	Alcohol consumption also is associated with primary liver cancer.	('primary liver cancer', 'Disease', (44, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('associated', 'Reg', (28, 38))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('liver cancer', 'Phenotype', 'HP:0002896', (52, 64))	('Alcohol consumption', 'Var', (0, 19))	('primary liver cancer', 'Disease', 'MESH:D006528', (44, 64))
619372	11910703	In addition, genetic factors also may influence a person's risk-benefit balance as suggested by the previously mentioned findings that the association between alcohol consumption and female breast cancer may be limited to women with a family history of breast cancer (i.e., with predisposing genetic factors).	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('men', 'Species', '9606', (224, 227))	('genetic', 'Var', (13, 20))	('women', 'Species', '9606', (222, 227))	('men', 'Species', '9606', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('influence', 'Reg', (38, 47))	('alcohol', 'Chemical', 'MESH:D000438', (159, 166))	('person', 'Species', '9606', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('breast cancer', 'Disease', (253, 266))
619471	31367085	Ingestion of lye and other corrosives can cause severe esophagitis with formation of stricture at later stages.	('esophagitis', 'Phenotype', 'HP:0100633', (55, 66))	('esophagitis', 'Disease', (55, 66))	('cause', 'Reg', (42, 47))	('esophagitis', 'Disease', 'MESH:D004941', (55, 66))	('Ingestion', 'Var', (0, 9))
619515	31367085	Rupture of necrotic mediastinal lymph nodes may lead to formation of sinus or fistula.	('necrotic', 'Disease', (11, 19))	('sinus', 'Disease', (69, 74))	('necrotic', 'Disease', 'MESH:D009336', (11, 19))	('Rupture', 'Var', (0, 7))	('lead to', 'Reg', (48, 55))	('fistula', 'Disease', 'MESH:D005402', (78, 85))	('fistula', 'Disease', (78, 85))
619595	28122632	A 65-year-old male who had received definitive chemoradiation therapy for cuT3N0 esophageal squamous cell carcinoma (SCC), with an initially complete clinical response, was found to have recurrent cancer 2 years later located at 30 cm from the incisors on surveillance endoscopy.	('esophageal squamous cell carcinoma', 'Disease', (81, 115))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('cuT3N0', 'Var', (74, 80))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (81, 115))
619607	28122632	A 71-year-old male with cuT2N2 distal esophageal adenocarcinoma in the presence of Barrett's esophagus extending up to the thoracic inlet underwent 3HMIE after neoadjuvant chemoradiation.	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (38, 63))	('esophageal adenocarcinoma', 'Disease', (38, 63))	('cuT2N2', 'Var', (24, 30))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (83, 102))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (38, 63))
619629	26910910	Obatoclax also substantially reduced the expression of lysosomal cathepsins B, D and L. Moreover, cathepsin knockdown was sufficient to induce cytotoxicity, connecting lysosomal function to cell viability.	('knockdown', 'Var', (108, 117))	('cytotoxicity', 'Disease', (143, 155))	('cathepsin', 'Gene', (98, 107))	('cytotoxicity', 'Disease', 'MESH:D064420', (143, 155))	('induce', 'Reg', (136, 142))
619637	26910910	Overexpression of Bcl-2 and related anti-apoptotic family members may lead to an increase in the apoptotic threshold of cancer cells and has been linked to chemoresistance and poor clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Bcl-2', 'Gene', (18, 23))	('chemoresistance', 'CPA', (156, 171))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('Overexpression', 'Var', (0, 14))	('increase', 'PosReg', (81, 89))	('Bcl-2', 'Gene', '596', (18, 23))	('linked to', 'Reg', (146, 155))
619651	26910910	At the time of investigation, EC109/CDDP was about 11-fold resistant to cisplatin than the parental cell line EC109, as evidenced by an IC50 (48 h) of 32.4 +- 3.1 muM versus 3.0 +- 0.1 muM, respectively.	('muM', 'Gene', '56925', (185, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('muM', 'Gene', '56925', (163, 166))	('CDDP', 'Chemical', '-', (36, 40))	('muM', 'Gene', (185, 188))	('muM', 'Gene', (163, 166))	('EC109/CDDP', 'Var', (30, 40))	('resistant', 'NegReg', (59, 68))
619657	26910910	The IC50 values for EC109 and EC109/CDDP were 0.064 +- 0.006 muM and 0.056 +- 0.004 muM, respectively.	('muM', 'Gene', (61, 64))	('CDDP', 'Chemical', '-', (36, 40))	('EC109', 'Var', (20, 25))	('muM', 'Gene', '56925', (84, 87))	('EC109/CDDP', 'Var', (30, 40))	('muM', 'Gene', (84, 87))	('muM', 'Gene', '56925', (61, 64))
619658	26910910	Also, obatoclax similarly decreased colony-forming ability of HKESC-1 and HKESC-1/cis cells with IC50 values of 0.024 +- 0.001 muM and 0.027 +- 0.002 muM, respectively (Figure 1C).	('muM', 'Gene', (150, 153))	('HKESC-1', 'CellLine', 'CVCL:D568', (74, 81))	('HKESC-1', 'CellLine', 'CVCL:D568', (62, 69))	('muM', 'Gene', (127, 130))	('obatoclax', 'Chemical', 'MESH:C520962', (6, 15))	('0.027', 'Var', (135, 140))	('muM', 'Gene', '56925', (127, 130))	('muM', 'Gene', '56925', (150, 153))	('decreased', 'NegReg', (26, 35))	('colony-forming ability', 'CPA', (36, 58))
619661	26910910	Bcl-2 expression was elevated in EC109/CDDP cells compared to EC109 cells, whereas it was decreased in HKESC-1/cis cells compared with HKESC-1 cells.	('expression', 'MPA', (6, 16))	('decreased', 'NegReg', (90, 99))	('elevated', 'PosReg', (21, 29))	('EC109/CDDP', 'Var', (33, 43))	('CDDP', 'Chemical', '-', (39, 43))	('HKESC-1', 'CellLine', 'CVCL:D568', (103, 110))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))	('HKESC-1', 'CellLine', 'CVCL:D568', (135, 142))
619664	26910910	Nonetheless, Bax level was increased in EC109/CDDP cells compared to EC109 cells, while it was decreased in HKESC-1/cis cells compared with HKESC-1 cells (Figure 1D).	('decreased', 'NegReg', (95, 104))	('EC109/CDDP', 'Var', (40, 50))	('increased', 'PosReg', (27, 36))	('HKESC-1', 'CellLine', 'CVCL:D568', (140, 147))	('CDDP', 'Chemical', '-', (46, 50))	('Bax', 'Gene', (13, 16))	('HKESC-1', 'CellLine', 'CVCL:D568', (108, 115))	('Bax', 'Gene', '581', (13, 16))
619682	26910910	Both EC109 and EC109/CDDP cells displayed extensive cytoplasmic vacuolization, with numerous vesicles engulfing cytoplasmic materials and components, which are typical structures of autophagosomes and autolysosomes.	('EC109/CDDP', 'Var', (15, 25))	('cytoplasmic vacuolization', 'CPA', (52, 77))	('CDDP', 'Chemical', '-', (21, 25))	('EC109', 'Var', (5, 10))
619690	26910910	Indeed, similar blunting effects of ATG5 and ATG7 knockdown were observed in CQ-treated cells (Figure S2).	('knockdown', 'Var', (50, 59))	('ATG7', 'Gene', '10533', (45, 49))	('ATG5', 'Gene', '9474', (36, 40))	('CQ', 'Chemical', 'MESH:D002738', (77, 79))	('ATG5', 'Gene', (36, 40))	('ATG7', 'Gene', (45, 49))
619691	26910910	Also, knockdown of ATG5 or ATG7 decreased basal LC3- II expression (Figure S3).	('LC3', 'Gene', '84557', (48, 51))	('ATG7', 'Gene', '10533', (27, 31))	('LC3', 'Gene', (48, 51))	('ATG5', 'Gene', '9474', (19, 23))	('knockdown', 'Var', (6, 15))	('ATG5', 'Gene', (19, 23))	('decreased', 'NegReg', (32, 41))	('ATG7', 'Gene', (27, 31))
619708	26910910	Importantly, knockdown of CTSD or CTSL significantly suppressed cell viability in EC109 and EC109/CDDP cells.	('CTSL', 'Gene', '1514', (34, 38))	('CTSD', 'Gene', '1509', (26, 30))	('CTSD', 'Gene', (26, 30))	('CDDP', 'Chemical', '-', (98, 102))	('knockdown', 'Var', (13, 22))	('suppressed', 'NegReg', (53, 63))	('cell viability', 'CPA', (64, 78))	('CTSL', 'Gene', (34, 38))
619710	26910910	In HKESC-1 and HKESC-1/cis cells, knockdown of CTSB or CTSD significantly induced the loss of cell viability, whereas CTSL downregulation exerted no effect (Figure 7C).	('loss', 'NegReg', (86, 90))	('HKESC-1', 'CellLine', 'CVCL:D568', (3, 10))	('CTSL', 'Gene', '1514', (118, 122))	('CTSB', 'Gene', '1508', (47, 51))	('CTSL', 'Gene', (118, 122))	('cell viability', 'CPA', (94, 108))	('HKESC-1', 'CellLine', 'CVCL:D568', (15, 22))	('knockdown', 'Var', (34, 43))	('CTSB', 'Gene', (47, 51))	('CTSD', 'Gene', '1509', (55, 59))	('CTSD', 'Gene', (55, 59))
619721	26910910	Dysregulation of Bcl-2 family members have been associated with multiple instances of cisplatin resistance.	('Bcl-2', 'Gene', (17, 22))	('Bcl-2', 'Gene', '596', (17, 22))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (48, 58))	('cisplatin resistance', 'MPA', (86, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))
619740	26910910	Loss of cell viability induced by cathepsin knockdown further connects the impaired lysosome function with the cytotoxicity of obatoclax.	('impaired lysosome function', 'MPA', (75, 101))	('cytotoxicity', 'Disease', 'MESH:D064420', (111, 123))	('obatoclax', 'Chemical', 'MESH:C520962', (127, 136))	('Loss', 'NegReg', (0, 4))	('knockdown', 'Var', (44, 53))	('cell viability', 'CPA', (8, 22))	('cytotoxicity', 'Disease', (111, 123))	('cathepsin', 'Gene', (34, 43))
619741	26910910	In this respect, both EC109 and EC109/CDDP cells were vulnerable to downregulation of CTSD or CTSL, whereas HKESC-1 and HKESC-1/cis cells were sensitive to CTSB or CTSD knockdown.	('CTSL', 'Gene', '1514', (94, 98))	('CTSD', 'Gene', '1509', (86, 90))	('CTSD', 'Gene', (86, 90))	('HKESC-1', 'CellLine', 'CVCL:D568', (120, 127))	('CTSB', 'Gene', '1508', (156, 160))	('CTSL', 'Gene', (94, 98))	('CTSB', 'Gene', (156, 160))	('downregulation', 'NegReg', (68, 82))	('HKESC-1', 'CellLine', 'CVCL:D568', (108, 115))	('CTSD', 'Gene', '1509', (164, 168))	('EC109/CDDP', 'Var', (32, 42))	('CTSD', 'Gene', (164, 168))	('CDDP', 'Chemical', '-', (38, 42))
619758	26910910	All primary antibodies were incubated overnight at 4 C: anti-Bcl-2 (2870), anti-Bcl-xL (2764), anti-Mcl-1 (5453), anti-Bad (9239), anti-Bid (2002), anti-Bim (2933), anti-Puma (12450), anti-Bak (12105), anti-Bax (5023), anti-ATG5 (8540), anti-ATG7 (2631), anti-Beclin-1 (3738), anti-beta-actin (4970), anti-cathepsin D (2284), anti-LC3B (2775), anti-p62 (8025), anti-ubiquitin (3936) (Cell signaling, Beverly, MA), anti-cathepsin B (C6243) (Sigma-Aldrich), and anti-cathepsin L (BMS1032) (eBioscience, San Diego, CA).	('Bim', 'Gene', (153, 156))	('p62', 'Gene', (349, 352))	('cathepsin B', 'Gene', (419, 430))	('ATG7', 'Gene', (242, 246))	('Beclin-1', 'Gene', '8678', (260, 268))	('Bcl-2', 'Gene', (61, 66))	('Bid', 'Gene', '637', (136, 139))	('cathepsin B', 'Gene', '1508', (419, 430))	('beta-actin', 'Gene', (282, 292))	('Beclin-1', 'Gene', (260, 268))	('ATG5', 'Gene', (224, 228))	('Mcl-1', 'Gene', '4170', (100, 105))	('Bax', 'Gene', (207, 210))	('cathepsin L', 'Gene', (465, 476))	('ATG5', 'Gene', '9474', (224, 228))	('anti-ubiquitin', 'Protein', (361, 375))	('Bax', 'Gene', '581', (207, 210))	('Bcl-2', 'Gene', '596', (61, 66))	('Bcl-xL', 'Gene', (80, 86))	('Bak', 'Gene', (189, 192))	('Bak', 'Gene', '578', (189, 192))	('Bid', 'Gene', (136, 139))	('Bcl-xL', 'Gene', '598', (80, 86))	('cathepsin L', 'Gene', '1514', (465, 476))	('Mcl-1', 'Gene', (100, 105))	('beta-actin', 'Gene', '728378', (282, 292))	('ATG7', 'Gene', '10533', (242, 246))	('Bim', 'Gene', '10018', (153, 156))	('cathepsin D', 'Gene', (306, 317))	('LC3B', 'Gene', (331, 335))	('Puma', 'Gene', '27113', (170, 174))	('Puma', 'Gene', (170, 174))	('p62', 'Gene', '8878', (349, 352))	('2775', 'Var', (337, 341))	('cathepsin D', 'Gene', '1509', (306, 317))	('LC3B', 'Gene', '81631', (331, 335))
619765	26910910	The expression of ATG5 and ATG7 was lowered using predesigned target-specific siRNA oligonucleotides (ATG5-Hs_ATG5L_6, SI02655310, Hs_ATG5L_2, SI00069251; ATG7-Hs_ATG7_5, SI04952339, Hs_ATG7L_5, SI02655373) purchased from Qiagen (Hilden, Germany).	('lowered', 'NegReg', (36, 43))	('ATG7', 'Gene', (155, 159))	('SI02655310', 'Var', (119, 129))	('ATG5', 'Gene', '9474', (18, 22))	('SI02655373', 'Var', (195, 205))	('oligonucleotides', 'Chemical', 'MESH:D009841', (84, 100))	('ATG7', 'Gene', (163, 167))	('ATG7', 'Gene', (186, 190))	('SI04952339', 'Var', (171, 181))	('expression', 'MPA', (4, 14))	('ATG5', 'Gene', '9474', (110, 114))	('ATG5', 'Gene', (18, 22))	('ATG5', 'Gene', '9474', (102, 106))	('ATG5', 'Gene', '9474', (134, 138))	('ATG7', 'Gene', '10533', (27, 31))	('ATG5', 'Gene', (110, 114))	('ATG7', 'Gene', '10533', (155, 159))	('ATG7', 'Gene', '10533', (186, 190))	('ATG7', 'Gene', '10533', (163, 167))	('SI00069251', 'Var', (143, 153))	('ATG5', 'Gene', (102, 106))	('ATG5', 'Gene', (134, 138))	('ATG7', 'Gene', (27, 31))
619766	26910910	The expression of Beclin-1, CTSB, D and L was downregulated by predesigned target-specific siRNA oligonucleotides (Beclin-1-SASI_Hs02_00336256, SASI_Hs01_00090914; CTSB-SASI_Hs01_00108033, SASI_Hs01_00108034, SASI_Hs01_00108035; CTSD- SASI_Hs02_00332783, SASI_Hs01_00141231, SASI_Hs01_00141234; CTSL- SASI_Hs01_00079399, SASI_Hs01_00079400, SASI_Hs02_00332791) from Sigma-Aldrich.	('CTSL', 'Gene', (295, 299))	('CTSB', 'Gene', (28, 32))	('CTSD', 'Gene', '1509', (229, 233))	('expression', 'MPA', (4, 14))	('CTSD', 'Gene', (229, 233))	('oligonucleotides', 'Chemical', 'MESH:D009841', (97, 113))	('CTSL', 'Gene', '1514', (295, 299))	('Beclin-1', 'Gene', (18, 26))	('downregulated', 'NegReg', (46, 59))	('Beclin-1', 'Gene', '8678', (18, 26))	('Beclin-1', 'Gene', (115, 123))	('CTSB', 'Gene', '1508', (164, 168))	('CTSB', 'Gene', '1508', (28, 32))	('SASI_Hs01_00079400', 'Var', (321, 339))	('Beclin-1', 'Gene', '8678', (115, 123))	('CTSB', 'Gene', (164, 168))
619864	26610479	Unambiguous evidence indicates that dysregulation of ncRNAs is deeply implicated in carcinogenesis, cancer progression and metastases of various cancers, including ESCC.	('dysregulation', 'Var', (36, 49))	('cancer', 'Disease', (145, 151))	('ncRNA', 'Gene', (53, 58))	('carcinogenesis', 'Disease', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('metastases of various cancers', 'Disease', 'MESH:D009362', (123, 152))	('ESCC', 'Disease', (164, 168))	('ncRNA', 'Gene', '54719', (53, 58))	('metastases of various cancers', 'Disease', (123, 152))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('implicated', 'Reg', (70, 80))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
619877	26610479	A number of miRNAs target particular oncogenes or tumor suppressors and function in the pathogenesis of many cancers.	('target', 'Reg', (19, 25))	('miRNAs', 'Var', (12, 18))	('function', 'Reg', (72, 80))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('oncogenes', 'Protein', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (50, 55))
619881	26610479	Dysregulation of miRNAs has been shown to have an effect on tumor growth in ESCC (Figure 1).	('Dysregulation', 'Var', (0, 13))	('miRNAs', 'Protein', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('effect', 'Reg', (50, 56))	('ESCC', 'Disease', (76, 80))	('tumor', 'Disease', (60, 65))
619882	26610479	The development of ESCC is closely related to lifestyle habits, such as tobacco smoking and/or alcohol drinking, and chronic stimuli induce genetic and epigenetic alterations in normal esophageal mucosa.	('alcohol drinking', 'Phenotype', 'HP:0030955', (95, 111))	('ESCC', 'Disease', (19, 23))	('esophageal mucosa', 'Disease', 'MESH:D004941', (185, 202))	('alcohol', 'Chemical', 'MESH:D000438', (95, 102))	('genetic', 'Var', (140, 147))	('epigenetic alterations', 'Var', (152, 174))	('tobacco', 'Species', '4097', (72, 79))	('rat', 'Species', '10116', (167, 170))	('esophageal mucosa', 'Disease', (185, 202))
619883	26610479	showed that smoke exposure increased the risk for ESCC to induce single nucleotide polymorphisms in miR-423.	('single nucleotide polymorphisms', 'Var', (65, 96))	('miR-423', 'Gene', (100, 107))	('ESCC', 'Disease', (50, 54))	('miR-423', 'Gene', '494335', (100, 107))
619911	26610479	The expressions of miR-9, miR-25 and miR-92a, which regulate CDH1 expression, were shown to be upregulated in ESCC tissues and to promote cell migration and invasion.	('miR-92a', 'Gene', (37, 44))	('miR-9', 'Var', (19, 24))	('upregulated', 'PosReg', (95, 106))	('promote', 'PosReg', (130, 137))	('CDH1', 'Gene', '999', (61, 65))	('rat', 'Species', '10116', (146, 149))	('miR-25', 'Gene', (26, 32))	('invasion', 'CPA', (157, 165))	('cell migration', 'CPA', (138, 152))	('ESCC', 'Disease', (110, 114))	('CDH1', 'Gene', (61, 65))	('miR-25', 'Gene', '407014', (26, 32))
619914	26610479	miR-21 and miR-183 promote ESCC cell growth and invasion through targeting PDCD4.	('PDCD4', 'Gene', (75, 80))	('promote', 'PosReg', (19, 26))	('PDCD4', 'Gene', '27250', (75, 80))	('miR-21', 'Var', (0, 6))	('ESCC', 'Disease', (27, 31))	('miR-183', 'Gene', '406959', (11, 18))	('invasion', 'CPA', (48, 56))	('miR-183', 'Gene', (11, 18))
619916	26610479	Furthermore, knockdown of miR-21 significantly increased the expression of PTEN protein and consequently reduced cell proliferation, invasion and migration.	('rat', 'Species', '10116', (149, 152))	('rat', 'Species', '10116', (125, 128))	('cell proliferation', 'CPA', (113, 131))	('increased', 'PosReg', (47, 56))	('PTEN', 'Gene', (75, 79))	('reduced', 'NegReg', (105, 112))	('knockdown', 'Var', (13, 22))	('PTEN', 'Gene', '5728', (75, 79))	('miR-21', 'Gene', (26, 32))	('expression', 'MPA', (61, 71))
619923	26610479	showed that the overexpression of miR-200b or knockdown of Kindlin-2 in ESCC cells suppressed cell protrusion and focal adhesion (FA) formation and decreased cell spreading and invasiveness/migration.	('invasiveness', 'Disease', (177, 189))	('overexpression', 'PosReg', (16, 30))	('knockdown', 'Var', (46, 55))	('rat', 'Species', '10116', (193, 196))	('miR-200b', 'Gene', '406984', (34, 42))	('decreased', 'NegReg', (148, 157))	('miR-200b', 'Gene', (34, 42))	('Kindlin-2', 'Gene', (59, 68))	('focal adhesion', 'CPA', (114, 128))	('cell spreading', 'CPA', (158, 172))	('suppressed', 'NegReg', (83, 93))	('Kindlin-2', 'Gene', '10979', (59, 68))	('invasiveness', 'Disease', 'MESH:D009362', (177, 189))	('cell protrusion', 'CPA', (94, 109))
619936	26610479	Plasma concentrations of miR-18a, miR-21 and miR-375 were significantly higher in ESCC patients compared to healthy volunteers, and plasma levels of miR-18a were significantly lower in postoperative samples compared to preoperative samples.	('miR-21', 'Var', (34, 40))	('miR-375', 'Gene', (45, 52))	('miR-18a', 'Gene', (25, 32))	('ESCC', 'Disease', (82, 86))	('miR-18a', 'Gene', (149, 156))	('plasma levels', 'MPA', (132, 145))	('rat', 'Species', '10116', (225, 228))	('rat', 'Species', '10116', (192, 195))	('lower', 'NegReg', (176, 181))	('miR-375', 'Gene', '494324', (45, 52))	('miR-18a', 'Gene', '406953', (25, 32))	('higher', 'PosReg', (72, 78))	('Plasma concentrations', 'MPA', (0, 21))	('patients', 'Species', '9606', (87, 95))	('miR-18a', 'Gene', '406953', (149, 156))	('rat', 'Species', '10116', (14, 17))
619938	26610479	reported that the levels of miR-21 in exosomes were higher in patients with ESCC than those in the control group, and exosomal miR-21 expression was associated with advanced tumor stage, positive lymph node status and the presence of metastasis.	('tumor', 'Disease', (174, 179))	('miR-21', 'Gene', (127, 133))	('levels of miR-21 in exosomes', 'MPA', (18, 46))	('exosomal', 'Var', (118, 126))	('associated', 'Reg', (149, 159))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('higher', 'PosReg', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('ESCC', 'Disease', (76, 80))	('patients', 'Species', '9606', (62, 70))	('positive lymph node status', 'CPA', (187, 213))	('metastasis', 'CPA', (234, 244))
619941	26610479	Tumor-suppressive miRNAs (TS-miRs), miR-101 and miR-217, could suppress MALAT1 expression through posttranscriptional regulation.	('miR-217', 'Gene', '406999', (48, 55))	('MALAT1', 'Gene', '378938', (72, 78))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-217', 'Gene', (48, 55))	('posttranscriptional regulation', 'MPA', (98, 128))	('MALAT1', 'Gene', (72, 78))	('miR-101', 'Var', (36, 43))	('suppress', 'NegReg', (63, 71))
619949	26610479	A recent study further identified a novel intronic HOTAIR enhancer and a functional ESCC susceptibility SNP rs920778 in Chinese populations.	('HOTAIR', 'Gene', (51, 57))	('intronic', 'MPA', (42, 50))	('ESCC', 'Disease', (84, 88))	('enhancer', 'PosReg', (58, 66))	('HOTAIR', 'Gene', '100124700', (51, 57))	('rs920778', 'Mutation', 'rs920778', (108, 116))	('rs920778', 'Var', (108, 116))
619968	25159167	Several therapeutic challenges remain to be overcome before the use of CXCR4 inhibitors can be translated into clinical practice, but promising preclinical data demonstrate that CXCR4 antagonists can mobilize tumor cells from their protective microenvironments, interfere with their metastatic and tumorigenic potentials, and/or make tumor cells more susceptible to chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('tumor', 'Disease', (298, 303))	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('antagonists', 'Var', (184, 195))	('tumor', 'Disease', (334, 339))	('mobilize', 'MPA', (200, 208))	('make', 'Reg', (329, 333))	('interfere', 'NegReg', (262, 271))	('CXCR4', 'Gene', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
619982	25159167	Therefore, the evaluation of CXCR4/SDF-1alpha expression level may have a significant prognostic value in various types of malignancies, because the high expression of CXCR4 or SDF-1alpha has been shown to predict poor survival outcomes in colon, pancreatic, prostate, breast, ovarian, and lung cancer patients.	('lung cancer', 'Disease', (290, 301))	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('prostate', 'Disease', (259, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (290, 301))	('SDF-1alpha', 'Gene', (177, 187))	('CXCR4', 'Var', (168, 173))	('colon', 'Disease', (240, 245))	('patients', 'Species', '9606', (302, 310))	('breast', 'Disease', (269, 275))	('malignancies', 'Disease', (123, 135))	('pancreatic', 'Disease', 'MESH:D010195', (247, 257))	('lung cancer', 'Disease', 'MESH:D008175', (290, 301))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('pancreatic', 'Disease', (247, 257))	('ovarian', 'Disease', (277, 284))
619996	25159167	The feasibility of a CXCR4-based therapeutic approach for inhibiting HIV-1 infection is supported by the fact that CCR5 mutations confer individuals with resistance to HIV-1 infection.	('HIV-1 infection', 'Disease', (168, 183))	('HIV-1 infection', 'Disease', 'MESH:D015658', (168, 183))	('HIV-1 infection', 'Disease', (69, 84))	('CCR5', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('HIV-1 infection', 'Disease', 'MESH:D015658', (69, 84))
619998	25159167	Both AMD3100 and ALX40-4C inhibit HIV-1 infection by directly blocking the interaction between CXCR4 and HIV-1.	('AMD3100', 'Var', (5, 12))	('blocking', 'NegReg', (62, 70))	('HIV-1 infection', 'Disease', (34, 49))	('inhibit', 'NegReg', (26, 33))	('HIV-1', 'Species', '11676', (105, 110))	('HIV-1 infection', 'Disease', 'MESH:D015658', (34, 49))	('AMD3100', 'Chemical', 'MESH:C088327', (5, 12))	('HIV-1', 'Species', '11676', (34, 39))	('interaction', 'Interaction', (75, 86))	('ALX40-4C', 'Var', (17, 25))
620001	25159167	Similarly, T22, T140, TC14012, and FC131 can inhibit HIV-1 entry via CXCR4 (Table 1), and smaller, yet more potent, anti-HIV peptide or nonpeptide compounds have been developed more recently, based on the structure of T140.	('HIV-1 entry', 'MPA', (53, 64))	('HIV', 'Species', '12721', (121, 124))	('FC131', 'Chemical', 'MESH:C496951', (35, 40))	('T140', 'Chemical', 'MESH:C116977', (218, 222))	('HIV-1', 'Species', '11676', (53, 58))	('TC14012', 'Var', (22, 29))	('HIV', 'Species', '12721', (53, 56))	('TC14012', 'Chemical', 'MESH:C504129', (22, 29))	('inhibit', 'NegReg', (45, 52))	('T140', 'Var', (16, 20))	('T140', 'Chemical', 'MESH:C116977', (16, 20))
620002	25159167	Furthermore, CGP64222, R3G, and NeoR were reported as potent CXCR4 antagonistic inhibitors (Table 1).	('CXCR4 antagonistic inhibitors', 'MPA', (61, 90))	('CGP64222', 'Chemical', 'MESH:C402842', (13, 21))	('CGP64222', 'Var', (13, 21))	('R3G', 'Var', (23, 26))
620004	25159167	Interestingly, the antiviral and binding activities were more potent for an all-D-amino acid analog of V1 peptide (also known as DV1) than for V1 peptide (Table 1).	('DV1', 'Gene', (129, 132))	('DV1', 'Gene', '28981', (129, 132))	('antiviral', 'MPA', (19, 28))	('all-D-amino acid', 'Var', (76, 92))	('binding', 'Interaction', (33, 40))	('potent', 'PosReg', (62, 68))
620005	25159167	For instance, RCP168 can selectively inhibit CXCR4.	('RCP168', 'Var', (14, 20))	('inhibit', 'NegReg', (37, 44))	('RCP168', 'Chemical', '-', (14, 20))	('CXCR4', 'MPA', (45, 50))
620007	25159167	Despite its strong binding and antiviral activities, RCP168 does not significantly interfere with SDF-1alpha signaling, which is important for maintaining the normal physiological functions of CXCR4.	('SDF-1alpha signaling', 'MPA', (98, 118))	('interfere', 'Reg', (83, 92))	('RCP168', 'Chemical', '-', (53, 59))	('RCP168', 'Var', (53, 59))	('binding', 'Interaction', (19, 26))
620012	25159167	For instance, pyrazole GPR109 receptor agonists recently provided the proof of concept; analogs of acifran selectively activate the Gi pathway that mediates the beneficial lipolytic effect, but not the beta-arrestin pathway involved in the adverse side effect of cutaneous flushing.	('flushing', 'Phenotype', 'HP:0031284', (273, 281))	('lipolytic effect', 'MPA', (172, 188))	('analogs', 'Var', (88, 95))	('cutaneous flushing', 'Disease', 'MESH:D005483', (263, 281))	('cutaneous flushing', 'Disease', (263, 281))	('pyrazole', 'Chemical', 'MESH:C031280', (14, 22))	('acifran', 'Gene', (99, 106))	('Gi pathway', 'Pathway', (132, 142))	('activate', 'PosReg', (119, 127))	('acifran', 'Chemical', 'MESH:C036804', (99, 106))
620019	25159167	This finding was further supported by a report that downregulation of CXCR4 expression by small interfering RNA (siRNA) can increase apoptosis and inhibit esophageal tumor growth.	('increase', 'PosReg', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('apoptosis', 'CPA', (133, 142))	('esophageal tumor', 'Disease', 'MESH:D004938', (155, 171))	('CXCR4 expression', 'MPA', (70, 86))	('esophageal tumor', 'Disease', (155, 171))	('inhibit', 'NegReg', (147, 154))	('downregulation', 'NegReg', (52, 66))	('small interfering', 'Var', (90, 107))	('esophageal tumor', 'Phenotype', 'HP:0100751', (155, 171))
620026	25159167	In this regard, several pre-clinical studies demonstrated that anti-CXCR4 monoclonal antibodies and AMD3100 have anti-tumor activity by significantly suppressing tumor cell migration, proliferation, and survival.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('suppressing', 'NegReg', (150, 161))	('tumor', 'Disease', (162, 167))	('AMD3100', 'Gene', (100, 107))	('proliferation', 'CPA', (184, 197))	('anti-CXCR4', 'Var', (63, 73))	('survival', 'CPA', (203, 211))	('AMD3100', 'Chemical', 'MESH:C088327', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
620027	25159167	Furthermore, AMD3100 can reduce ascitic fluid formation and enhance in vitro docetaxel cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('AMD3100', 'Var', (13, 20))	('ascitic', 'Disease', 'MESH:D001201', (32, 39))	('ascitic', 'Disease', (32, 39))	('reduce', 'NegReg', (25, 31))	('cytotoxicity', 'Disease', (87, 99))	('docetaxel', 'Chemical', 'MESH:D000077143', (77, 86))	('enhance', 'PosReg', (60, 67))	('AMD3100', 'Chemical', 'MESH:C088327', (13, 20))
620033	25159167	As such, these findings indicate that the modulation of the CXCR4-SDF-1alpha pathway may have an important role in inhibiting aggressive pancreatic tumors.	('aggressive pancreatic tumors', 'Disease', 'MESH:D010190', (126, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('aggressive pancreatic tumors', 'Disease', (126, 154))	('modulation', 'Var', (42, 52))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (137, 154))	('inhibiting', 'NegReg', (115, 125))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
620051	25159167	AMD3100 can inhibit the spontaneous and SDF-1alpha-induced proliferation of melanoma cell lines.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('inhibit', 'NegReg', (12, 19))	('AMD3100', 'Var', (0, 7))	('spontaneous', 'CPA', (24, 35))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('AMD3100', 'Chemical', 'MESH:C088327', (0, 7))
620055	25159167	demonstrated that BCC with higher CXCR4 expression has concomitantly higher microvessel density, and that SDF-1alpha induces angiogenic activity by upregulating several genes associated with angiogenesis, including interleukin (IL)-6, bone morphogenetic protein (BMP)-6, and cyclooxygenase 2 (COX)-2.	('CXCR4 expression', 'MPA', (34, 50))	('COX', 'Gene', '5743', (293, 296))	('bone morphogenetic protein (BMP)-6', 'Gene', '654', (235, 269))	('angiogenic activity', 'CPA', (125, 144))	('microvessel density', 'CPA', (76, 95))	('induces', 'PosReg', (117, 124))	('cyclooxygenase 2', 'Gene', '5743', (275, 291))	('COX', 'Gene', (293, 296))	('cyclooxygenase 2', 'Gene', (275, 291))	('upregulating', 'PosReg', (148, 160))	('higher', 'PosReg', (27, 33))	('BCC', 'Phenotype', 'HP:0002671', (18, 21))	('interleukin (IL)-6', 'Gene', '3569', (215, 233))	('SDF-1alpha', 'Var', (106, 116))	('higher', 'PosReg', (69, 75))	('interleukin (IL)-6', 'Gene', (215, 233))
620063	25159167	AMD3100 significantly inhibited the lung metastasis, ameliorated body weight loss, and improved the survival rate of mice.	('ameliorated', 'PosReg', (53, 64))	('weight loss', 'Disease', 'MESH:D015431', (70, 81))	('inhibited', 'NegReg', (22, 31))	('AMD3100', 'Var', (0, 7))	('improved', 'PosReg', (87, 95))	('lung metastasis', 'CPA', (36, 51))	('weight loss', 'Disease', (70, 81))	('survival rate', 'CPA', (100, 113))	('mice', 'Species', '10090', (117, 121))	('weight loss', 'Phenotype', 'HP:0001824', (70, 81))	('AMD3100', 'Chemical', 'MESH:C088327', (0, 7))
620065	25159167	Furthermore, TN14003, a small synthetic peptide antagonist of CXCR4, can reduce tumor growth, microvessel density, and lung metastasis in tumor-bearing nude mice (Table 1).	('nude mice', 'Species', '10090', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('TN14003', 'Var', (13, 20))	('microvessel density', 'CPA', (94, 113))	('tumor', 'Disease', (80, 85))	('lung metastasis', 'CPA', (119, 134))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('reduce', 'NegReg', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
620071	25159167	Stage IV NSCLC patients with high expression of CXCR4 also have an extremely poor median survival time of only 2.7 months (compared to 5.6 months for low CXCR4-expressing patients).	('patients', 'Species', '9606', (15, 23))	('high expression', 'Var', (29, 44))	('NSCLC', 'Disease', (9, 14))	('patients', 'Species', '9606', (171, 179))	('NSCLC', 'Disease', 'MESH:D002289', (9, 14))	('CXCR4', 'Gene', (48, 53))
620072	25159167	Furthermore, recent reports indicate that CXCR4 is expressed by CSCs in NSCLC, and that inhibition and/or siRNA targeting of CXCR4 and of the downstream action of signal transducer and activator of transcription 3 (STAT3) significantly suppress the self-renewal and chemoresistant capacity of various NSCLC cell lines.	('self-renewal', 'CPA', (249, 261))	('chemoresistant capacity', 'CPA', (266, 289))	('signal transducer and activator of transcription 3', 'Gene', '6774', (163, 213))	('NSCLC', 'Disease', (72, 77))	('STAT3', 'Gene', '6774', (215, 220))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('suppress', 'NegReg', (236, 244))	('STAT3', 'Gene', (215, 220))	('NSCLC', 'Disease', (301, 306))	('NSCLC', 'Disease', 'MESH:D002289', (301, 306))	('inhibition', 'Var', (88, 98))
620076	25159167	Inoculation of nude mice with lung cancer cells with low CXCR4 expression also resulted in a 0- to 2-fold decrease in lung metastatic foci compared to inoculation with cells with high expression of CXCR4.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('nude mice', 'Species', '10090', (15, 24))	('lung cancer', 'Disease', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CXCR4', 'Gene', (57, 62))	('lung metastatic foci', 'CPA', (118, 138))	('decrease', 'NegReg', (106, 114))	('low', 'Var', (53, 56))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))
620084	25159167	divided cancer patients into low-level and high-level CXCR4 expression groups using immunohistochemical staining, and demonstrated that the high-level CXCR4 expression group had a higher incidence of distant metastasis, especially bone metastasis, during the first year (10.3 % versus 1.1 %) and shorter event-free survival (17.43 months versus 27.5 months).	('bone metastasis', 'CPA', (231, 246))	('patients', 'Species', '9606', (15, 23))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('high-level CXCR4 expression', 'Var', (140, 167))	('higher', 'PosReg', (180, 186))	('distant metastasis', 'CPA', (200, 218))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
620087	25159167	Given the importance of CXCR4 in breast carcinogenesis, the observation that a neutralizing antibody against CXCR4 prevents breast cancer metastasis to lungs and lymph nodes is not surprising.	('prevents', 'NegReg', (115, 123))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (33, 54))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('neutralizing', 'Var', (79, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('breast carcinogenesis', 'Disease', (33, 54))
620089	25159167	The specific CXCR4 inhibitor AMD3465 was recently shown to trigger a reduction in breast cancer cell invasiveness and metastases to the lungs and liver through the modulation of oncogenic signaling that includes the STAT3 pathway.	('breast cancer cell invasiveness', 'Disease', 'MESH:D001943', (82, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('breast cancer cell invasiveness', 'Disease', (82, 113))	('metastases', 'Disease', (118, 128))	('STAT3', 'Gene', '6774', (216, 221))	('modulation', 'Reg', (164, 174))	('oncogenic', 'MPA', (178, 187))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('reduction', 'NegReg', (69, 78))	('AMD3465', 'Var', (29, 36))	('STAT3', 'Gene', (216, 221))	('AMD3465', 'Chemical', 'MESH:C503590', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
620091	25159167	Similarly, the expression of CXCR4 is an independent prognostic marker of ovarian carcinoma, a common gynecological malignancy.	('malignancy', 'Disease', (116, 126))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (74, 91))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (74, 91))	('ovarian carcinoma', 'Disease', (74, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('expression', 'MPA', (15, 25))	('malignancy', 'Disease', 'MESH:D009369', (116, 126))	('CXCR4', 'Var', (29, 34))
620093	25159167	CXCR4 expression was predictive of significantly reduced overall survival after a median follow-up of 37 months, and the intensity of SDF-1alpha staining correlated with ascites.	('ascites', 'Phenotype', 'HP:0001541', (170, 177))	('reduced', 'NegReg', (49, 56))	('overall survival', 'MPA', (57, 73))	('CXCR4 expression', 'Var', (0, 16))	('ascites', 'Disease', (170, 177))	('ascites', 'Disease', 'MESH:D001201', (170, 177))
620096	25159167	Significantly lower cisplatin-based chemosensitivity, a poorer progression-free survival, and a lower overall survival were recently found to be associated with high CXCR4 expression.	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('lower', 'NegReg', (14, 19))	('progression-free survival', 'CPA', (63, 88))	('poorer', 'NegReg', (56, 62))	('lower', 'NegReg', (96, 101))	('cisplatin-based chemosensitivity', 'MPA', (20, 52))	('high', 'Var', (161, 165))	('overall survival', 'MPA', (102, 118))
620098	25159167	In fact, knockdown of CXCR4 by siRNA suppresses in vitro cell proliferation, results in G1/S arrest, and increases apoptosis and chemosensitivity in both cisplatin-sensitive and cisplatin-resistant cells.	('knockdown', 'Var', (9, 18))	('suppresses', 'NegReg', (37, 47))	('G1/S arrest', 'CPA', (88, 99))	('results in', 'Reg', (77, 87))	('cell proliferation', 'CPA', (57, 75))	('chemosensitivity', 'CPA', (129, 145))	('apoptosis', 'CPA', (115, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('increases', 'PosReg', (105, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))
620100	25159167	Strong CXCR4 expression in RCC is significantly associated with advanced T-status, tumor dedifferentiation, and poor overall and recurrence-free survival.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('associated', 'Reg', (48, 58))	('CXCR4', 'Var', (7, 12))	('advanced', 'Disease', (64, 72))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
620102	25159167	The neutralization of SDF-1alpha in SCID mice abrogates RCC metastasis to SDF-1alpha-expressing distant organs.	('SDF-1alpha', 'Gene', (22, 32))	('RCC', 'Disease', (56, 59))	('abrogates', 'NegReg', (46, 55))	('SCID', 'Gene', '19090', (36, 40))	('SCID', 'Phenotype', 'HP:0004430', (36, 40))	('mice', 'Species', '10090', (41, 45))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('SCID', 'Gene', (36, 40))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('neutralization', 'Var', (4, 18))
620105	25159167	In fact, AMD3100 or siRNA can downregulate CXCR4 expression and increase the sensitivity of CSCs to tyrosine kinase inhibitors, thereby reducing the capability of CSCs to modulate tumor growth.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('reducing', 'NegReg', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('modulate', 'MPA', (171, 179))	('tumor', 'Disease', (180, 185))	('downregulate', 'NegReg', (30, 42))	('increase', 'PosReg', (64, 72))	('AMD3100', 'Chemical', 'MESH:C088327', (9, 16))	('AMD3100', 'Var', (9, 16))	('CXCR4 expression', 'MPA', (43, 59))	('sensitivity', 'MPA', (77, 88))
620109	25159167	In this study, AKT inhibition was shown to reverse CXCR4 expression and cellular invasion in prostate cancers.	('CXCR4 expression', 'MPA', (51, 67))	('AKT', 'Gene', '207', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibition', 'Var', (19, 29))	('prostate cancers', 'Disease', 'MESH:D011471', (93, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cellular invasion', 'CPA', (72, 89))	('AKT', 'Gene', (15, 18))	('prostate cancers', 'Phenotype', 'HP:0012125', (93, 109))	('reverse', 'NegReg', (43, 50))	('prostate cancers', 'Disease', (93, 109))
620110	25159167	Furthermore, in the human prostate cancer PC-3 tumor xenograft model, AMD3100 significantly inhibited SDF-1alpha-induced CXCR4/AKT signal transduction and tumor growth, while AMD3100-treated PC-3 tumors showed lower in vivo levels of microvessel formation, proliferative index (as demonstrated by Ki-67), and anti-apoptotic protein Bcl-2 (B-cell lymphoma 2) compared to control tumors.	('tumor', 'Disease', (378, 383))	('levels', 'MPA', (224, 230))	('inhibited', 'NegReg', (92, 101))	('tumor', 'Disease', (196, 201))	('AMD3100', 'Chemical', 'MESH:C088327', (175, 182))	('AMD3100', 'Chemical', 'MESH:C088327', (70, 77))	('B-cell lymphoma 2', 'Gene', '596', (339, 356))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (378, 383))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Bcl-2', 'Gene', '596', (332, 337))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (339, 354))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))	('PC-3', 'CellLine', 'CVCL:0035', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('PC-3', 'CellLine', 'CVCL:0035', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('prostate cancer', 'Disease', (26, 41))	('tumors', 'Phenotype', 'HP:0002664', (378, 384))	('AMD3100', 'Var', (70, 77))	('lower', 'NegReg', (210, 215))	('AKT', 'Gene', '207', (127, 130))	('B-cell lymphoma 2', 'Gene', (339, 356))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('microvessel formation', 'MPA', (234, 255))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Disease', (378, 384))	('proliferative index', 'MPA', (257, 276))	('tumors', 'Disease', (196, 202))	('tumor', 'Disease', (47, 52))	('human', 'Species', '9606', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (378, 384))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('lymphoma', 'Phenotype', 'HP:0002665', (346, 354))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Bcl-2', 'Gene', (332, 337))	('AKT', 'Gene', (127, 130))
620111	25159167	In addition, AMD3100 can chemosensitize prostate cancer cells to docetaxel.	('chemosensitize', 'CPA', (25, 39))	('AMD3100', 'Var', (13, 20))	('docetaxel', 'Chemical', 'MESH:D000077143', (65, 74))	('prostate cancer', 'Disease', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('prostate cancer', 'Disease', 'MESH:D011471', (40, 55))	('AMD3100', 'Chemical', 'MESH:C088327', (13, 20))	('prostate cancer', 'Phenotype', 'HP:0012125', (40, 55))
620123	25159167	GBM recurrence can also be prevented by AMD3100 and neutralizing antibodies through inhibition of the development of functional tumor vasculogenesis.	('inhibition', 'NegReg', (84, 94))	('GBM recurrence', 'Disease', (0, 14))	('functional tumor', 'Disease', 'MESH:D009369', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('prevented', 'NegReg', (27, 36))	('AMD3100', 'Chemical', 'MESH:C088327', (40, 47))	('functional tumor', 'Disease', (117, 133))	('AMD3100', 'Var', (40, 47))
620124	25159167	reported that AMD3100 can increase the apoptosis of GBM, thereby decreasing its growth potential.	('apoptosis', 'CPA', (39, 48))	('AMD3100', 'Chemical', 'MESH:C088327', (14, 21))	('AMD3100', 'Var', (14, 21))	('growth potential', 'CPA', (80, 96))	('decreasing', 'NegReg', (65, 75))	('increase', 'PosReg', (26, 34))
620131	25159167	In addition, AMD3100 and AMD3465 achieved similar outcomes, further indicating that the CXCR4-SDF-1alpha pathway may indeed represent an effective drug target for increasing the number of leukemic cells available in peripheral blood that can be targeted by chemotherapy.	('AMD3100', 'Var', (13, 20))	('leukemic', 'Disease', (188, 196))	('AMD3465', 'Var', (25, 32))	('AMD3465', 'Chemical', 'MESH:C503590', (25, 32))	('leukemic', 'Disease', 'MESH:D007938', (188, 196))	('AMD3100', 'Chemical', 'MESH:C088327', (13, 20))
620136	25159167	Indeed, AMD3100 or T140 can mobilize HSCs by blocking CXCR4, and for this reason, AMD3100 (Plerixafor) was approved in 2008 for the treatment of patients with lymphoma and multiple myeloma to increase the number of HSCs available for transplantation.	('patients', 'Species', '9606', (145, 153))	('multiple myeloma', 'Disease', 'MESH:D009101', (172, 188))	('AMD3100', 'Var', (82, 89))	('CXCR4', 'MPA', (54, 59))	('mobilize', 'MPA', (28, 36))	('multiple myeloma', 'Phenotype', 'HP:0006775', (172, 188))	('multiple myeloma', 'Disease', (172, 188))	('lymphoma', 'Disease', (159, 167))	('AMD3100', 'Chemical', 'MESH:C088327', (8, 15))	('lymphoma', 'Disease', 'MESH:D008223', (159, 167))	('T140', 'Chemical', 'MESH:C116977', (19, 23))	('lymphoma', 'Phenotype', 'HP:0002665', (159, 167))	('AMD3100', 'Var', (8, 15))	('AMD3100', 'Chemical', 'MESH:C088327', (82, 89))	('blocking', 'NegReg', (45, 53))
620137	25159167	Similarly, a lipopeptide pepducin, ATI-2341, can inhibit the function of CXCR4 and increase the mobilization of HSCs and HPCs (Table 1).	('increase', 'PosReg', (83, 91))	('ATI-2341', 'Chemical', 'MESH:C586629', (35, 43))	('function of CXCR4', 'MPA', (61, 78))	('HPC', 'Disease', 'MESH:C537262', (121, 124))	('mobilization of HSCs', 'MPA', (96, 116))	('ATI-2341', 'Var', (35, 43))	('HPC', 'Disease', (121, 124))	('inhibit', 'NegReg', (49, 56))
620138	25159167	HSC mobilization can also be effectively induced by inhibitory CXCR4 nanobodies and AMD3100.	('HSC mobilization', 'CPA', (0, 16))	('AMD3100', 'Chemical', 'MESH:C088327', (84, 91))	('inhibitory CXCR4 nanobodies', 'Var', (52, 79))	('AMD3100', 'Var', (84, 91))
620315	33762693	Lymph node recurrences involved a left recurrent nerve lymph node (106recL: Lymph node number according to the Japanese Classification of Esophageal Cancer, 11th edition), a left tracheobronchial lymph node (106tbL), a left main bronchus lymph node (109L), and a thoracic paraaortic lymph node (112ao), which were difficult to approach for lymph node dissection (Fig.	('106tbL', 'Var', (208, 214))	('Cancer', 'Disease', (149, 155))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('involved', 'Reg', (23, 31))
620327	33762693	Unfortunately, patients with esophageal cancer often have comorbidities and are in poor clinical condition as a result of advanced age, body weight loss, habitual alcohol use, smoking, poor respiratory function (chronic obstructive pulmonary disease), hypertension, and/or a history of prior cancer.	('hypertension', 'Disease', 'MESH:D006973', (252, 264))	('patients', 'Species', '9606', (15, 23))	('hypertension', 'Disease', (252, 264))	('poor respiratory function', 'Phenotype', 'HP:0002093', (185, 210))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (212, 249))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (212, 249))	('hypertension', 'Phenotype', 'HP:0000822', (252, 264))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('alcohol', 'Chemical', 'MESH:D000438', (163, 170))	('chronic obstructive pulmonary disease', 'Disease', (212, 249))	('weight loss', 'Disease', 'MESH:D015431', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('alcohol use', 'Phenotype', 'HP:0030955', (163, 174))	('weight loss', 'Phenotype', 'HP:0001824', (141, 152))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (220, 249))	('weight loss', 'Disease', (141, 152))	('poor', 'Var', (185, 189))	('cancer', 'Disease', 'MESH:D009369', (292, 298))
620397	33718392	In this article, we summarize the current existing literature on PIWIL1 in human tumors, including its expression, biological functions and regulatory mechanisms, providing new insights into how the dysregulation of PIWIL1 contributes to tumor initiation, development and chemoresistance through diverse signaling pathways.	('tumors', 'Disease', (81, 87))	('development', 'CPA', (256, 267))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('contributes', 'Reg', (223, 234))	('tumor initiation', 'Disease', 'MESH:D009369', (238, 254))	('dysregulation', 'Var', (199, 212))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor initiation', 'Disease', (238, 254))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('human', 'Species', '9606', (75, 80))	('chemoresistance', 'CPA', (272, 287))	('PIWIL1', 'Gene', (216, 222))
620406	33718392	The aberrant expression of piRNAs has been demonstrated in various cancer types.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('aberrant', 'Var', (4, 12))	('piRNAs', 'Protein', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('demonstrated', 'Reg', (43, 55))
620407	33718392	Numerous studies have found that dysregulated piRNAs affect cancer hallmarks for tumor initiation and progression.	('tumor initiation', 'Disease', (81, 97))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('progression', 'CPA', (102, 113))	('affect', 'Reg', (53, 59))	('cancer', 'Disease', (60, 66))	('dysregulated', 'Var', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor initiation', 'Disease', 'MESH:D009369', (81, 97))	('piRNAs', 'Protein', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
620427	33718392	Amplifications are more frequent in diffuse glioma, sarcoma, pheochromocytoma, ovarian cancer, bladder cancer, cervical cancer, esophageal squamous cell carcinoma, and renal non-clear cell carcinoma (Figure 1B).	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('renal non-clear cell carcinoma', 'Disease', 'MESH:C538614', (168, 198))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cervical cancer', 'Disease', (111, 126))	('cervical cancer', 'Disease', 'MESH:D002583', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('Amplifications', 'Var', (0, 14))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (61, 77))	('frequent', 'Reg', (24, 32))	('esophageal squamous cell carcinoma', 'Disease', (128, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('renal non-clear cell carcinoma', 'Phenotype', 'HP:0006770', (168, 198))	('sarcoma', 'Disease', (52, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pheochromocytoma, ovarian cancer', 'Disease', 'MESH:D010673', (61, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (128, 162))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('renal non-clear cell carcinoma', 'Disease', (168, 198))
620428	33718392	These results suggest that PIWIL1 dysregulation is frequently occurring in human tumor tissues and PIWIL1 might serve as a novel biomarker in several malignancies.	('PIWIL1', 'Var', (99, 105))	('dysregulation', 'Var', (34, 47))	('malignancies', 'Disease', (150, 162))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('PIWIL1', 'Gene', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('human', 'Species', '9606', (75, 80))	('tumor', 'Disease', (81, 86))	('malignancies', 'Disease', 'MESH:D009369', (150, 162))
620429	33718392	In melanoma, endometrial cancer, mature B-cell neoplasms, non-small cell lung cancer, colon cancer, bladder cancer, invasive breast cancer, esophagogastric adenocarcinoma and head and neck cancer, PIWIL1 is often mutated (Figure 1B).	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (140, 170))	('head and neck cancer', 'Disease', 'MESH:D006258', (175, 195))	('melanoma', 'Disease', (3, 11))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('invasive breast cancer', 'Disease', (116, 138))	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('endometrial cancer', 'Phenotype', 'HP:0012114', (13, 31))	('colon cancer', 'Disease', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('invasive breast cancer', 'Disease', 'MESH:D001943', (116, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('B-cell neoplasms', 'Disease', 'MESH:D016393', (40, 56))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('endometrial cancer', 'Disease', (13, 31))	('adenocarcinoma', 'Disease', (156, 170))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (58, 84))	('endometrial cancer', 'Disease', 'MESH:D016889', (13, 31))	('B-cell neoplasms', 'Disease', (40, 56))	('B-cell neoplasms', 'Phenotype', 'HP:0012191', (40, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (100, 114))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (62, 84))	('head and neck cancer', 'Phenotype', 'HP:0012288', (175, 195))	('bladder cancer', 'Disease', (100, 114))	('adenocarcinoma', 'Disease', 'MESH:D000230', (156, 170))	('neoplasms', 'Phenotype', 'HP:0002664', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('lung cancer', 'Disease', (73, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))	('mutated', 'Var', (213, 220))
620430	33718392	Consistently, data from the IntOGen database3 revealed that 362 PIWIL1 mutations were found in 28,076 samples of various cancers, including a range of mutation types (such as missense and truncating mutations).	('found', 'Reg', (86, 91))	('cancers', 'Disease', (121, 128))	('missense', 'Var', (175, 183))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PIWIL1', 'Gene', (64, 70))	('mutations', 'Var', (71, 80))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
620431	33718392	Dysregulation of PIWIL1 occurs in a broad range of human cancers and is often associated with adverse clinicopathological features and shorter survival of cancer patients.	('associated', 'Reg', (78, 88))	('patients', 'Species', '9606', (162, 170))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancers', 'Disease', (57, 64))	('human', 'Species', '9606', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('PIWIL1', 'Gene', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
620443	33718392	Furthermore, PIWIL1 was found to be a poor prognostic factor in several tumors, including gastric cancer, soft-tissue sarcoma, esophageal squamous cell carcinoma, colon cancer, glioma, hepatocellular carcinoma, breast cancer, bladder cancer, and renal cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (127, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('hepatocellular carcinoma', 'Disease', (185, 209))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('sarcoma', 'Disease', (118, 125))	('tumors', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (246, 266))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colon cancer', 'Disease', (163, 175))	('PIWIL1', 'Var', (13, 19))	('glioma', 'Disease', (177, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('breast cancer', 'Disease', (211, 224))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (185, 209))	('renal cell carcinoma', 'Disease', (246, 266))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (106, 125))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (246, 266))	('esophageal squamous cell carcinoma', 'Disease', (127, 161))	('bladder cancer', 'Disease', 'MESH:D001749', (226, 240))	('bladder cancer', 'Disease', (226, 240))	('colon cancer', 'Phenotype', 'HP:0003003', (163, 175))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('gastric cancer', 'Disease', (90, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (226, 240))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (185, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('colon cancer', 'Disease', 'MESH:D015179', (163, 175))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
620444	33718392	However, a study in patients with renal cell carcinoma showed that high PIWIL1 expression is correlated with better prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('high', 'Var', (67, 71))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (34, 54))	('expression', 'MPA', (79, 89))	('renal cell carcinoma', 'Disease', (34, 54))	('patients', 'Species', '9606', (20, 28))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (34, 54))	('PIWIL1', 'Gene', (72, 78))
620447	33718392	Thus, the identification of aberrant PIWIL1 expression in tumor tissues might be useful in cancer diagnosis as well as in prognostic evaluation.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('PIWIL1', 'Gene', (37, 43))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('aberrant', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
620450	33718392	In addition, aberrant promoter DNA hypomethylation is one of the major mechanisms for PIWIL1 overexpression in lung cancer and endometrial cancer.	('endometrial cancer', 'Phenotype', 'HP:0012114', (127, 145))	('PIWIL1', 'Gene', (86, 92))	('endometrial cancer', 'Disease', 'MESH:D016889', (127, 145))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('promoter', 'MPA', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('overexpression', 'PosReg', (93, 107))	('endometrial cancer', 'Disease', (127, 145))	('aberrant', 'Var', (13, 21))
620453	33718392	Owing to their functions in the regulation of gene expression, non-coding RNAs regulate multiple biological processes, such as cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('regulate', 'Reg', (79, 87))	('cancer', 'Disease', (127, 133))	('non-coding RNAs', 'Var', (63, 78))
620457	33718392	Furthermore, lncRNA FALEC induces PIWIL1 expression by serving as a molecular sponge for miR-2116-3p, which directly binds to the 3'-UTR of PIWIL1 mRNA.	('induces', 'Reg', (26, 33))	('FALEC', 'Gene', '100874054', (20, 25))	('FALEC', 'Gene', (20, 25))	('miR-2116', 'Chemical', '-', (89, 97))	('miR-2116-3p', 'Var', (89, 100))	('PIWIL1 expression', 'Gene', (34, 51))	('3p', 'Chemical', '-', (98, 100))
620470	33718392	Their results suggested that PIWIL1 can significantly boost cell proliferation, migration, tumorigenesis and metastasis by forming a complex with UPF1, UPF2, SMG1 and other components to degrade mRNAs and lncRNAs with tumor suppressor potential.	('SMG1', 'Gene', '23049', (158, 162))	('cell proliferation', 'CPA', (60, 78))	('UPF2', 'Gene', (152, 156))	('migration', 'CPA', (80, 89))	('PIWIL1', 'Var', (29, 35))	('tumor', 'Disease', (218, 223))	('tumor', 'Disease', (91, 96))	('SMG1', 'Gene', (158, 162))	('complex', 'Interaction', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('UPF1', 'Gene', (146, 150))	('metastasis', 'CPA', (109, 119))	('degrade', 'NegReg', (187, 194))	('UPF2', 'Gene', '26019', (152, 156))	('boost', 'PosReg', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('UPF1', 'Gene', '5976', (146, 150))
620472	33718392	PIWIL1 causes epigenetic silencing of PTEN gene via the upregulation of DNA methyltransferase DNMT1 in endometrial cancer cells.	('endometrial cancer', 'Disease', (103, 121))	('PTEN', 'Gene', '5728', (38, 42))	('epigenetic', 'Var', (14, 24))	('upregulation', 'PosReg', (56, 68))	('PIWIL1', 'Var', (0, 6))	('endometrial cancer', 'Phenotype', 'HP:0012114', (103, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('endometrial cancer', 'Disease', 'MESH:D016889', (103, 121))	('PTEN', 'Gene', (38, 42))
620475	33718392	In cervical cancer, PIWIL1 has been associated with enhanced sphere formation and tumorigenesis, increased resistance to cisplatin, and elevated expression of several stem cell self-renewal-genes (OCT4, NANOG and BMI1).	('NANOG', 'Gene', '79923', (203, 208))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('resistance to cisplatin', 'MPA', (107, 130))	('sphere formation', 'CPA', (61, 77))	('expression', 'MPA', (145, 155))	('NANOG', 'Gene', (203, 208))	('tumor', 'Disease', (82, 87))	('PIWIL1', 'Var', (20, 26))	('OCT4', 'Gene', '5460', (197, 201))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('BMI1', 'Gene', (213, 217))	('increased', 'PosReg', (97, 106))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('cervical cancer', 'Disease', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('elevated', 'PosReg', (136, 144))	('OCT4', 'Gene', (197, 201))	('BMI1', 'Gene', '648', (213, 217))	('enhanced', 'PosReg', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
620476	33718392	PIWIL1 can drive EMT in endometrial cancer cells by upregulating the expression of Vimentin and N-cadherin and by decreasing E-cadherin expression.	('decreasing', 'NegReg', (114, 124))	('E-cadherin', 'Gene', '999', (125, 135))	('expression', 'MPA', (136, 146))	('Vimentin', 'Gene', (83, 91))	('endometrial cancer', 'Phenotype', 'HP:0012114', (24, 42))	('Vimentin', 'Gene', '7431', (83, 91))	('endometrial cancer', 'Disease', 'MESH:D016889', (24, 42))	('PIWIL1', 'Var', (0, 6))	('N-cadherin', 'Gene', (96, 106))	('expression', 'MPA', (69, 79))	('upregulating', 'PosReg', (52, 64))	('N-cadherin', 'Gene', '1000', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('E-cadherin', 'Gene', (125, 135))	('EMT', 'CPA', (17, 20))	('endometrial cancer', 'Disease', (24, 42))
620478	33718392	Recently, it was shown that PIWIL1 is enriched in glioma stem-like cells (GSCs) and silencing PIWIL1 in GSCs impaired their self-renewal and triggered senescence or apoptosis.	('PIWIL1', 'Gene', (94, 100))	('triggered', 'Reg', (141, 150))	('impaired', 'NegReg', (109, 117))	('apoptosis', 'CPA', (165, 174))	('glioma', 'Disease', (50, 56))	('silencing', 'Var', (84, 93))	('self-renewal', 'CPA', (124, 136))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('senescence', 'CPA', (151, 161))
620479	33718392	PIWIL1 knockdown strongly increased the expression of BTG2 and FBXW7, but reduced the levels of c-MYC, Olig2 and Nestin in GSCs.	('expression', 'MPA', (40, 50))	('c-MYC', 'Gene', (96, 101))	('FBXW7', 'Gene', '55294', (63, 68))	('BTG2', 'Gene', (54, 58))	('BTG2', 'Gene', '7832', (54, 58))	('Olig2', 'Gene', (103, 108))	('Nestin', 'Gene', '10763', (113, 119))	('Olig2', 'Gene', '10215', (103, 108))	('FBXW7', 'Gene', (63, 68))	('increased', 'PosReg', (26, 35))	('c-MYC', 'Gene', '4609', (96, 101))	('Nestin', 'Gene', (113, 119))	('PIWIL1', 'Gene', (0, 6))	('reduced', 'NegReg', (74, 81))	('knockdown', 'Var', (7, 16))
620484	33718392	Inactivation of PIWIL1 in mouse models of pancreatic cancer leads to significant tumor shrinkage and a dramatic reduction in metastatic growth.	('pancreatic cancer', 'Disease', (42, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('metastatic growth', 'CPA', (125, 142))	('PIWIL1', 'Gene', (16, 22))	('reduction', 'NegReg', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mouse', 'Species', '10090', (26, 31))	('Inactivation', 'Var', (0, 12))	('tumor', 'Disease', (81, 86))
620485	33718392	Knockout of PIWIL1 using the CRISPR/Cas9 system markedly attenuates the tumor growth of gastric cancer in vivo.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor growth of gastric cancer', 'Phenotype', 'HP:0006753', (72, 102))	('gastric cancer', 'Disease', (88, 102))	('PIWIL1', 'Gene', (12, 18))	('tumor', 'Disease', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('Knockout', 'Var', (0, 8))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('attenuates', 'NegReg', (57, 67))
620489	33718392	For example, PLX4720 is a selective B-RAF inhibitor, and treatment with this drug strongly downregulates the expression of PIWIL1 in colon cancer cells.	('B-RAF', 'Gene', '673', (36, 41))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('expression', 'MPA', (109, 119))	('downregulates', 'NegReg', (91, 104))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('B-RAF', 'Gene', (36, 41))	('PLX4720', 'Var', (13, 20))	('colon cancer', 'Disease', (133, 145))	('PIWIL1', 'Gene', (123, 129))
620491	33718392	Other targets that have been explored in PIWIL1-expressing tumors include miR-154-5p and miR-2116-3p.	('miR-154', 'Gene', (74, 81))	('miR-154', 'Gene', '406946', (74, 81))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('miR-2116', 'Chemical', '-', (89, 97))	('miR-2116-3p', 'Var', (89, 100))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('3p', 'Chemical', '-', (98, 100))
620494	33718392	After knocking down PIWIL1 in cervical cancer cells by shRNA, increased sensitivity to cisplatin was observed.	('increased', 'PosReg', (62, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('cervical cancer', 'Disease', (30, 45))	('cervical cancer', 'Disease', 'MESH:D002583', (30, 45))	('sensitivity to cisplatin', 'MPA', (72, 96))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('PIWIL1', 'Gene', (20, 26))	('knocking down', 'Var', (6, 19))
620498	33718392	Whether genomic mutations in PIWIL1 gene are associated with induced PIWIL1 expression remains unclear, and the functional consequences of such mutations in tumor cells are not well understood.	('tumor', 'Disease', (157, 162))	('PIWIL1', 'Gene', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('associated', 'Reg', (45, 55))	('expression', 'MPA', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('PIWIL1', 'Gene', (69, 75))	('genomic mutations', 'Var', (8, 25))
620506	32546690	Pathway analysis indicated that aberrantly methylated DEGs mainly associated with the P13K-AKT signaling, cAMP signaling and cell cycle process.	('aberrantly methylated', 'Var', (32, 53))	('P13K', 'Mutation', 'p.P13K', (86, 90))	('AKT', 'Gene', '207', (91, 94))	('cAMP', 'Gene', (106, 110))	('cAMP', 'Gene', '820', (106, 110))	('associated', 'Reg', (66, 76))	('cell cycle process', 'CPA', (125, 143))	('DEGs', 'Protein', (54, 58))	('AKT', 'Gene', (91, 94))
620508	32546690	Patients with high expression of AURKA were associated with shorter overall survival.	('AURKA', 'Gene', '6790', (33, 38))	('Patients', 'Species', '9606', (0, 8))	('AURKA', 'Gene', (33, 38))	('overall survival', 'MPA', (68, 84))	('high expression', 'Var', (14, 29))	('shorter', 'NegReg', (60, 67))
620512	32546690	DNA methylation is the most common epigenetic change, and it is closely related to gene expression regulation, embryonic development, X chromosome inactivation, genomic stability and genomic imprinting, and plays a significant role in cancer progression.	('role', 'Reg', (227, 231))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('methylation', 'Var', (4, 15))	('plays', 'Reg', (207, 212))	('related', 'Reg', (72, 79))	('DNA', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
620513	32546690	DNA methylation of gene promoters is associated with silencing of key genes, especially oncogenes and tumor suppressors and is considered to be a hallmark in many carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('oncogenes', 'Gene', (88, 97))	('carcinomas', 'Disease', 'MESH:D009369', (163, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('carcinomas', 'Disease', (163, 173))	('silencing', 'MPA', (53, 62))	('DNA methylation', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
620514	32546690	In the present research, we used publicly available datasets of gene expression (GSE20347, GSE38129) and gene methylation (GSE52826) to identify genes and pathways that were both abnormally methylated and differentially expressed between tumor tissues and normal esophagus from patients with ESCC.	('GSE20347', 'Var', (81, 89))	('differentially', 'Reg', (205, 219))	('GSE38129', 'Var', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (238, 243))	('ESCC', 'Disease', (292, 296))	('patients', 'Species', '9606', (278, 286))
620521	32546690	4G), while hypermethylated/low-expression genes were significantly enriched in Pancreatic secretion, Renin secretion, Amphetamine addiction, Salivary secretion, cAMP signaling pathway, Histidine metabolism, Long-term potentiation, Gastric acid secretion, Dopaminergic synapse and Circadian entrainment (Fig.	('Renin', 'Gene', (101, 106))	('Gastric acid secretion', 'Disease', (231, 253))	('cAMP', 'Gene', (161, 165))	('cAMP', 'Gene', '820', (161, 165))	('Amphetamine addiction', 'Disease', (118, 139))	('Circadian entrainment', 'Disease', (280, 301))	('Amphetamine', 'Chemical', 'MESH:D000661', (118, 129))	('Long-term potentiation', 'Disease', (207, 229))	('Histidine', 'MPA', (185, 194))	('Renin', 'Gene', '5972', (101, 106))	('Pancreatic secretion', 'Disease', 'MESH:D010195', (79, 99))	('Salivary secretion', 'Disease', (141, 159))	('hypermethylated/low-expression genes', 'Var', (11, 47))	('Pancreatic secretion', 'Disease', (79, 99))
620529	32546690	Hypermethylated/low-expression hub genes and hypomethylated/high-expression hub genes were then validated in another database TCGA to confirm the outcomes.	('hub', 'Gene', (76, 79))	('hub', 'Gene', '1993', (31, 34))	('hub', 'Gene', '1993', (76, 79))	('Hypermethylated/low-expression', 'Var', (0, 30))	('hub', 'Gene', (31, 34))	('Hypermethylated/low-expression', 'NegReg', (0, 30))
620540	32546690	Patients with high expression of AURKA were associated with shorter overall survival (Fig.	('AURKA', 'Gene', '6790', (33, 38))	('Patients', 'Species', '9606', (0, 8))	('AURKA', 'Gene', (33, 38))	('overall survival', 'MPA', (68, 84))	('high expression', 'Var', (14, 29))	('shorter', 'NegReg', (60, 67))
620542	32546690	Enrichment of these genes demonstrated that aberrant methylation indeed affects certain pathways and hub genes.	('pathways', 'Pathway', (88, 96))	('hub', 'Gene', (101, 104))	('aberrant methylation', 'Var', (44, 64))	('affects', 'Reg', (72, 79))	('hub', 'Gene', '1993', (101, 104))
620543	32546690	The GO enrichment analysis revealed that the primary biological processes of the hypomethylated/high-expression genes were involved in the regulation of extracellular matrix organization, extracellular structure organization, mitotic cell cycle process, cell cycle process, collagen catabolic process and nuclear division, while the hypermethylated/low-expression genes were primarily linked to response to cAMP, purine-containing compound, oxygen-containing compound, muscle system process, inorganic substance.	('cAMP', 'Gene', (407, 411))	('cAMP', 'Gene', '820', (407, 411))	('involved', 'Reg', (123, 131))	('collagen', 'CPA', (274, 282))	('hypomethylated/high-expression', 'Var', (81, 111))	('purine', 'Chemical', 'MESH:C030985', (413, 419))	('regulation', 'MPA', (139, 149))	('cell cycle process', 'CPA', (254, 272))	('mitotic cell cycle process', 'CPA', (226, 252))	('hypomethylated/high-expression', 'PosReg', (81, 111))	('nuclear division', 'CPA', (305, 321))	('extracellular matrix organization', 'CPA', (153, 186))	('extracellular structure organization', 'CPA', (188, 224))	('oxygen', 'Chemical', 'MESH:D010100', (441, 447))
620549	32546690	Furthermore, the enriched KEGG pathways of hypomethylated highly expressed genes were mainly linked to ECM-receptor interaction, Focal adhesion, Amoebiasis, PI3K-Akt signaling pathway and Cell cycle.	('Cell cycle', 'Disease', (188, 198))	('Amoebiasis', 'Disease', (145, 155))	('Akt', 'Gene', (162, 165))	('Focal adhesion', 'Disease', (129, 143))	('linked', 'Reg', (93, 99))	('hypomethylated', 'Var', (43, 57))	('Amoebiasis', 'Disease', 'MESH:D000562', (145, 155))	('KEGG pathways', 'Pathway', (26, 39))	('ECM-receptor interaction', 'Disease', (103, 127))	('Akt', 'Gene', '207', (162, 165))
620554	32546690	In contrast, hypermethylated/low-expression genes were related to Pancreatic secretion, Renin secretion, Amphetamine addiction, Salivary secretion and cAMP signaling pathway.	('Pancreatic secretion', 'Disease', (66, 86))	('Renin', 'Gene', '5972', (88, 93))	('Pancreatic secretion', 'Disease', 'MESH:D010195', (66, 86))	('Salivary secretion', 'Disease', (128, 146))	('Amphetamine', 'Chemical', 'MESH:D000661', (105, 116))	('Amphetamine addiction', 'Disease', (105, 126))	('Renin', 'Gene', (88, 93))	('cAMP', 'Gene', (151, 155))	('cAMP', 'Gene', '820', (151, 155))	('hypermethylated/low-expression genes', 'Var', (13, 49))	('related', 'Reg', (55, 62))
620568	32546690	The dysregulation of KIF14 has been confirmed in many human malignancies.	('malignancies', 'Disease', (60, 72))	('dysregulation', 'Var', (4, 17))	('KIF14', 'Gene', (21, 26))	('KIF14', 'Gene', '9928', (21, 26))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('human', 'Species', '9606', (54, 59))
620576	32546690	Errors in the regulation mechanism of CDK1 directly lead to cell differentiation disorders, cell cycle disorders, malignant cell proliferation and abnormal transformation, and ultimately malignant tumor formation.	('abnormal transformation', 'CPA', (147, 170))	('malignant tumor', 'Disease', (187, 202))	('Errors', 'Var', (0, 6))	('CDK1', 'Gene', '983', (38, 42))	('malignant tumor', 'Disease', 'MESH:D009369', (187, 202))	('CDK1', 'Gene', (38, 42))	('cell differentiation disorders', 'CPA', (60, 90))	('cell cycle disorders', 'CPA', (92, 112))	('malignant cell proliferation', 'CPA', (114, 142))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('lead to', 'Reg', (52, 59))
620581	32546690	The mutation or overexpression of AURKA may also cause carcinogenesis.	('AURKA', 'Gene', (34, 39))	('overexpression', 'PosReg', (16, 30))	('mutation', 'Var', (4, 12))	('AURKA', 'Gene', '6790', (34, 39))	('cause', 'Reg', (49, 54))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('carcinogenesis', 'Disease', (55, 69))
620599	32546690	Current studies have shown that the mutation of the TGM1 gene is closely related to lamella stratified ichthyosis and may also affect the proliferation and differentiation of breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('ichthyosis', 'Disease', 'MESH:D007057', (103, 113))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('proliferation', 'CPA', (138, 151))	('differentiation', 'CPA', (156, 171))	('ichthyosis', 'Phenotype', 'HP:0008064', (103, 113))	('TGM1', 'Gene', '7051', (52, 56))	('ichthyosis', 'Disease', (103, 113))	('TGM1', 'Gene', (52, 56))	('affect', 'Reg', (127, 133))	('mutation', 'Var', (36, 44))	('related', 'Reg', (73, 80))
620628	32546690	To confirm the results, we used the MEXPRESS to validate hypermethylated/low-expression hub genes and hypomethylated/ high-expression hub genes in the TCGA database.	('hub', 'Gene', '1993', (88, 91))	('hub', 'Gene', '1993', (134, 137))	('hypermethylated/low-expression', 'Var', (57, 87))	('hypermethylated/low-expression', 'NegReg', (57, 87))	('hub', 'Gene', (88, 91))	('hub', 'Gene', (134, 137))
620638	32454908	Besides, correlation analyses between proportions of TIICs and clinicopathological characters, including age, gender, histologic grade, tumor location, histologic type, LRP1B mutation, TP53 mutation, tumor stage, lymph node stage, and TNM stage, were conducted.	('mutation', 'Var', (190, 198))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('TNM', 'Gene', (235, 238))	('TP53', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('mutation', 'Var', (175, 183))	('LRP1B', 'Gene', '53353', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('TNM', 'Gene', '10178', (235, 238))	('tumor', 'Disease', (136, 141))	('TP53', 'Gene', '7157', (185, 189))	('LRP1B', 'Gene', (169, 174))
620676	32454908	As for mutation in EC, the percentages of naive B cell and regulatory T cells (Tregs) were higher, and T cell follicular helper and activated dendritic cells were lower for LRP1B mutation (Figure 2(f)).	('higher', 'PosReg', (91, 97))	('LRP1B', 'Gene', '53353', (173, 178))	('mutation', 'Var', (179, 187))	('Tregs', 'Chemical', '-', (79, 84))	('lower', 'NegReg', (163, 168))	('LRP1B', 'Gene', (173, 178))
620677	32454908	The proportion of monocytes increased, and neutrophils were cut for TP53 mutation (Figure 2(g)).	('increased', 'PosReg', (28, 37))	('TP53', 'Gene', (68, 72))	('monocytes increased', 'Phenotype', 'HP:0012311', (18, 37))	('TP53', 'Gene', '7157', (68, 72))	('mutation', 'Var', (73, 81))
620704	32454908	In this study, by analyzing the correlations between clinicopathological characters and TIICs, we found that Treg density infiltration in EC patients had a close association with age, histologic grade, tumor location, histologic type, LRP1B mutation, tumor stage, lymph node stage, and TNM stage.	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', (202, 207))	('Treg', 'Chemical', '-', (109, 113))	('patients', 'Species', '9606', (141, 149))	('LRP1B', 'Gene', '53353', (235, 240))	('TNM', 'Gene', '10178', (286, 289))	('mutation', 'Var', (241, 249))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('TNM', 'Gene', (286, 289))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('LRP1B', 'Gene', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
620715	32454908	In EC, a research once has pointed that LRP1B possessed the recurrent copy-number variant character, significantly promoting cancer cell proliferation, migration, and invasion.	('migration', 'CPA', (152, 161))	('LRP1B', 'Gene', (40, 45))	('promoting', 'PosReg', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('invasion', 'CPA', (167, 175))	('LRP1B', 'Gene', '53353', (40, 45))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('copy-number variant', 'Var', (70, 89))
620727	32454908	Similarly, there is just a report in breast cancer that the high expression of PABPC1 would promote cancer tumorigenesis and resistance and in lung adenocarcinoma, it might be involved in tumor development.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (143, 162))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('involved', 'Reg', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('PABPC1', 'Gene', '26986', (79, 85))	('breast cancer', 'Disease', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('high', 'Var', (60, 64))	('resistance', 'CPA', (125, 135))	('cancer', 'Disease', (100, 106))	('lung adenocarcinoma', 'Disease', (143, 162))	('PABPC1', 'Gene', (79, 85))	('promote', 'PosReg', (92, 99))	('cancer', 'Disease', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (143, 162))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
620796	23652249	(10)  To put this into perspective, if we examine a case where the deformable registration incorrectly expands 25% of the outer edge of the esophagus by 1 mm, this would appear (for a 2 cm diameter esophagus) as an apparent esophageal expansion of 5%, which falls within the ranges of values found for each grade of esophagitis.	('deformable', 'Var', (67, 77))	('esophagitis', 'Phenotype', 'HP:0100633', (316, 327))	('esophagitis', 'Disease', (316, 327))	('falls', 'Phenotype', 'HP:0002527', (258, 263))	('esophagitis', 'Disease', 'MESH:D004941', (316, 327))	('esophageal', 'Disease', (224, 234))
620849	26035313	High levels of HtrA1 mRNA were associated with longer overall survival (OS) and disease-free survival (DFS) (Table II).	('OS', 'Chemical', '-', (72, 74))	('longer', 'PosReg', (47, 53))	('High levels', 'Var', (0, 11))	('overall survival', 'CPA', (54, 70))	('disease-free survival', 'CPA', (80, 101))	('HtrA1', 'Gene', '5654', (15, 20))	('HtrA1', 'Gene', (15, 20))
621002	26076489	Genomic instability has emerged as an important predictor of subsequent cancer development in the context of Barrett's esophagus.	("Barrett's esophagus", 'Disease', (109, 128))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (109, 128))	('Genomic instability', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
621006	26076489	Here, we found that infection with Helicobacter pylori in a Barrett's esophagus cohort was associated with decreased incidence of aneuploidy, a measure of genomic instability that predicts progression to esophageal adenocarcinoma.	('aneuploidy', 'Disease', 'MESH:D000782', (130, 140))	('infection', 'Disease', (20, 29))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (204, 229))	('Helicobacter pylori', 'Species', '210', (35, 54))	('infection', 'Disease', 'MESH:D007239', (20, 29))	('esophageal adenocarcinoma', 'Disease', (204, 229))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (60, 79))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (204, 229))	('decreased', 'NegReg', (107, 116))	('aneuploidy', 'Disease', (130, 140))	('Helicobacter pylori', 'Var', (35, 54))
621014	26076489	Mutations in SHP2 and aberrant activation of this protein have been implicated in squamous head and neck cancer, but not esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (121, 146))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (121, 146))	('Mutations', 'Var', (0, 9))	('squamous head and neck cancer', 'Disease', 'MESH:D006258', (82, 111))	('head and neck cancer', 'Phenotype', 'HP:0012288', (91, 111))	('implicated', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('SHP2', 'Gene', (13, 17))	('activation', 'PosReg', (31, 41))	('esophageal adenocarcinoma', 'Disease', (121, 146))	('SHP2', 'Gene', '5781', (13, 17))
621024	26076489	Indeed, changes in pH have been shown to modify microbial communities in the stomach and esophagus of a Barrett's esophagus and esophagitis cohort.	('changes', 'Var', (8, 15))	('esophagitis', 'Phenotype', 'HP:0100633', (128, 139))	('microbial communities', 'CPA', (48, 69))	('esophagitis cohort', 'Disease', 'MESH:D004941', (128, 146))	('modify', 'Reg', (41, 47))	('esophagitis cohort', 'Disease', (128, 146))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (104, 123))
621085	25301735	Here we further analyzed its epigenetic inactivation, biological functions and related cell signaling in digestive cancers (colorectal, gastric and esophageal cancers) in detail.	('colorectal', 'Disease', (124, 134))	('cancers', 'Disease', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('epigenetic inactivation', 'Var', (29, 52))	('gastric and esophageal cancers', 'Disease', 'MESH:D013274', (136, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
621089	25301735	Mechanistically, SOX10 competes with TCF4 to bind beta-catenin and transrepresses its downstream target genes via its own DNA-binding property.	('beta-catenin', 'Gene', '1499', (50, 62))	('beta-catenin', 'Gene', (50, 62))	('TCF4', 'Gene', '6925', (37, 41))	('transrepresses', 'PosReg', (67, 81))	('DNA-binding', 'Interaction', (122, 133))	('TCF4', 'Gene', (37, 41))	('SOX10', 'Var', (17, 22))	('bind', 'Interaction', (45, 49))
621090	25301735	SOX10 mutations that disrupt the SOX10-beta-catenin interaction partially prevented tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('interaction', 'Interaction', (52, 63))	('tumor', 'Disease', (84, 89))	('SOX10', 'Gene', (0, 5))	('beta-catenin', 'Gene', (39, 51))	('beta-catenin', 'Gene', '1499', (39, 51))	('prevented', 'NegReg', (74, 83))	('mutations', 'Var', (6, 15))
621100	25301735	Abnormalities (over- or under- expression, or genetic mutations) of SOX factors have been shown to play critical roles in human disease pathogenesis including cancer formation and development.	('cancer', 'Disease', (159, 165))	('genetic mutations', 'Var', (46, 63))	('human', 'Species', '9606', (122, 127))	('roles', 'Reg', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('play', 'Reg', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('under-', 'NegReg', (24, 30))
621116	25301735	We also found that SOX10 could be activated in the colorectal cancer cell line HCT116 which is completely methylated for this gene, by genetic demethylation through only double knockout (KO) of both DNMT1 and DNMT3B (DKO cell line), but not single KO of DNMT1 or DNMT3B alone (1KO or 3BKO cell line) (Figure 1E).	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('SOX10', 'Gene', (19, 24))	('DNMT3B', 'Gene', (263, 269))	('DNMT3B', 'Gene', '1789', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('demethylation', 'Var', (143, 156))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('HCT116', 'CellLine', 'CVCL:0291', (79, 85))	('DNMT3B', 'Gene', (209, 215))	('DNMT3B', 'Gene', '1789', (209, 215))	('activated', 'PosReg', (34, 43))	('colorectal cancer', 'Disease', (51, 68))	('DNMT1', 'Gene', (254, 259))	('DNMT1', 'Gene', (199, 204))	('DNMT1', 'Gene', '1786', (199, 204))	('DNMT1', 'Gene', '1786', (254, 259))
621129	25301735	Methylation was detected in multiple tumors, including 64% (7/11) of CRC, 77% (40/52) of gastric and 76% (13/17) of ESCC samples (Supplementary Figure S2B).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('Methylation', 'Var', (0, 11))	('ESCC', 'Disease', (116, 120))	('multiple tumors', 'Disease', (28, 43))	('multiple tumors', 'Disease', 'MESH:D009369', (28, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('detected', 'Reg', (16, 24))	('gastric', 'Disease', (89, 96))	('CRC', 'Disease', (69, 72))
621132	25301735	We thus explored whether tumor cells are functionally dependent on SOX10 inactivation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('SOX10', 'Gene', (67, 72))	('tumor', 'Disease', (25, 30))	('inactivation', 'Var', (73, 85))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
621134	25301735	To further confirmed the inhibitory effects of SOX10 on tumor growth in vivo, HCT116 and KYSE150 cells infected with LV-SOX10 or LV-GFP were implanted subcutaneously into the flank of nude mice.	('HCT116', 'CellLine', 'CVCL:0291', (78, 84))	('nude mice', 'Species', '10090', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('LV-SOX10', 'Var', (117, 125))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
621135	25301735	Compared to LV-GFP control group, expression of SOX10 significantly inhibited tumor growth in nude mice (Figure 3E).	('nude mice', 'Species', '10090', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('expression', 'Var', (34, 44))	('inhibited', 'NegReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SOX10', 'Gene', (48, 53))	('tumor', 'Disease', (78, 83))
621139	25301735	HCT116, KYSE150 and AGS cells infected with LV-SOX10 filled the wound much slower than LV-GFP infected cells (Figure 4A).	('slower', 'NegReg', (75, 81))	('HCT116', 'CellLine', 'CVCL:0291', (0, 6))	('AGS', 'Disease', (20, 23))	('LV-SOX10', 'Var', (44, 52))	('AGS', 'Disease', 'MESH:C535607', (20, 23))
621141	25301735	As shown in Figure 4D, lung metastatic clusters presented in mice subcutaneously injected with KYSE150-SOX10 cells (16.6+-4.8 clusters per mice) were significantly fewer than those in the LV-GFP group (38.8+-6.8 clusters per mice), as examined by HE staining.	('mice', 'Species', '10090', (61, 65))	('lung metastatic clusters', 'CPA', (23, 47))	('mice', 'Species', '10090', (225, 229))	('mice', 'Species', '10090', (139, 143))	('KYSE150-SOX10 cells', 'Var', (95, 114))	('HE', 'Chemical', 'MESH:D006371', (247, 249))	('fewer', 'NegReg', (164, 169))
621146	25301735	SW620 cells infected with LV-GFP showed a prominent mesenchymal-like phenotype, including a fibroblast-like morphology, loss of cell-cell contacts, expression of the mesenchymal marker vimentin as described previously.	('vimentin', 'Gene', (185, 193))	('mesenchymal-like phenotype', 'CPA', (52, 78))	('SW620', 'CellLine', 'CVCL:0547', (0, 5))	('expression', 'MPA', (148, 158))	('loss', 'NegReg', (120, 124))	('LV-GFP', 'Var', (26, 32))	('vimentin', 'Gene', '7431', (185, 193))	('fibroblast-like morphology', 'CPA', (92, 118))
621147	25301735	However, ectopic expression of SOX10 in SW620 cells led to cobblestone morphology in monolayer cultures, with tight cell-cell contacts characteristics of normal epithelial cells (Figure 4F), indicating that SOX10 most likely reversed tumor cell EMT.	('led to', 'Reg', (52, 58))	('ectopic expression', 'Var', (9, 27))	('cobblestone', 'Chemical', '-', (59, 70))	('tumor', 'Disease', (234, 239))	('cobblestone morphology', 'CPA', (59, 81))	('SW620', 'CellLine', 'CVCL:0547', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('SOX10', 'Gene', (31, 36))
621149	25301735	Furthermore, SOX10 expression downregulated 3 stem cell markers: NANOG, ABCG2 and Oct4, at the transcriptional level (Figure 4H).	('Oct4', 'Gene', (82, 86))	('downregulated', 'NegReg', (30, 43))	('ABCG2', 'Gene', (72, 77))	('expression', 'Var', (19, 29))	('NANOG', 'Gene', '79923', (65, 70))	('Oct4', 'Gene', '5460', (82, 86))	('NANOG', 'Gene', (65, 70))	('ABCG2', 'Gene', '9429', (72, 77))	('SOX10', 'Gene', (13, 18))
621153	25301735	The impact of SOX10 overexpression on beta-catenin/TCF activity was further examined in HCT116 colon cancer cells which contain a heterozygous activating mutation in beta-catenin.	('beta-catenin', 'Gene', (38, 50))	('TCF', 'Gene', (51, 54))	('TCF', 'Gene', '3172', (51, 54))	('beta-catenin', 'Gene', (166, 178))	('activating', 'PosReg', (143, 153))	('colon cancer', 'Disease', 'MESH:D015179', (95, 107))	('colon cancer', 'Phenotype', 'HP:0003003', (95, 107))	('beta-catenin', 'Gene', '1499', (38, 50))	('mutation', 'Var', (154, 162))	('beta-catenin', 'Gene', '1499', (166, 178))	('colon cancer', 'Disease', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('HCT116', 'CellLine', 'CVCL:0291', (88, 94))
621154	25301735	SOX10 inhibits beta-catenin promoter activities in a dose-dependent manner (Figure 5A).	('beta-catenin', 'Gene', '1499', (15, 27))	('beta-catenin', 'Gene', (15, 27))	('SOX10', 'Var', (0, 5))	('inhibits', 'NegReg', (6, 14))
621156	25301735	Collectively, these data suggest that SOX10 can antagonize the canonical Wnt/beta-catenin signaling cascade in digestive cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (121, 127))	('SOX10', 'Var', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('beta-catenin', 'Gene', (77, 89))	('antagonize', 'NegReg', (48, 58))	('beta-catenin', 'Gene', '1499', (77, 89))
621159	25301735	Consistent with the findings from in vitro binding assays, V5-tagged SOX10 was able to pull down GST-tagged beta-catenin (GST-beta-catenin) but not GST alone, suggesting that SOX10 directly interact with beta-catenin (Figure 5F).	('GST', 'Gene', (122, 125))	('beta-catenin', 'Gene', (108, 120))	('GST', 'Gene', '373156', (122, 125))	('beta-catenin', 'Gene', '1499', (126, 138))	('GST', 'Gene', (97, 100))	('GST', 'Gene', (148, 151))	('V5-tagged', 'Var', (59, 68))	('beta-catenin', 'Gene', '1499', (108, 120))	('GST', 'Gene', '373156', (97, 100))	('interact', 'Interaction', (190, 198))	('beta-catenin', 'Gene', (204, 216))	('GST', 'Gene', '373156', (148, 151))	('beta-catenin', 'Gene', '1499', (204, 216))	('pull down', 'NegReg', (87, 96))	('SOX10', 'Gene', (69, 74))	('beta-catenin', 'Gene', (126, 138))
621167	25301735	We generated the SOX10-482ins6 mutant, which carries an insertion of 6 nucleotides between positions 482 and 483, resulting in the addition of a leucine and an arginine residue into the HMG box and disruption of the structure of SOX10 DNA-binding domain (Figure 6A).	('arginine', 'Chemical', 'MESH:D001120', (160, 168))	('structure', 'MPA', (216, 225))	('disruption', 'Reg', (198, 208))	('addition', 'Reg', (131, 139))	('leucine', 'Chemical', 'MESH:D007930', (145, 152))	('482ins6', 'Mutation', 'c.482ins6', (23, 30))	('leucine', 'Var', (145, 152))	('SOX10-482ins6', 'Var', (17, 30))
621173	25301735	We first examined whether SOX10 DB or 3G mutants lose their ability to suppress Wnt/beta-catenin signaling.	('mutants', 'Var', (41, 48))	('beta-catenin', 'Gene', (84, 96))	('SOX10', 'Gene', (26, 31))	('suppress', 'NegReg', (71, 79))	('beta-catenin', 'Gene', '1499', (84, 96))	('lose', 'NegReg', (49, 53))
621174	25301735	Indeed, while ectopic SOX10 expression in HCT116 cells significantly inhibited the TOPFlash reporter as compared to control cells, transfection with SOX10-DB or SOX10-3G mutants largely reversed the suppressive effect on the reporter (Figure 6C).	('HCT116', 'CellLine', 'CVCL:0291', (42, 48))	('SOX10', 'Gene', (22, 27))	('mutants', 'Var', (170, 177))	('ectopic', 'Var', (14, 21))	('inhibited', 'NegReg', (69, 78))	('TOPFlash reporter', 'MPA', (83, 100))
621175	25301735	qRT-PCR and western blot analysis confirmed that mutations or deletion of the conserved DVAELDQYL motif as well as HMG domain mutation impaired the ability of SOX10 to attenuate Wnt signaling (Figure 6D).	('Wnt signaling', 'MPA', (178, 191))	('mutations', 'Var', (49, 58))	('HMG', 'Gene', (115, 118))	('impaired', 'NegReg', (135, 143))	('attenuate', 'NegReg', (168, 177))	('DVAELDQYL', 'Chemical', '-', (88, 97))	('DVAELDQYL', 'Gene', (88, 97))	('deletion', 'Var', (62, 70))	('ability', 'MPA', (148, 155))
621176	25301735	Furthermore, tumor cells with ectopic SOX10 expression migrated significantly slower than control cells, whereas introduction of SOX10-DB, -3G or -482ins6 mutants only partially suppressed tumor cell migration as by transwell assays (Figure 6F).	('tumor', 'Disease', (13, 18))	('-482ins6', 'INSERTION', 'None', (146, 154))	('tumor', 'Disease', (189, 194))	('ectopic', 'Var', (30, 37))	('migrated', 'CPA', (55, 63))	('slower', 'NegReg', (78, 84))	('suppressed', 'NegReg', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('-482ins6', 'Var', (146, 154))	('SOX10', 'Gene', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
621178	25301735	In this study, we found that while SOX10 is ubiquitously expressed in human normal adult and fetal tissues, it is frequently silenced or downregulated due to promoter methylation in digestive (colon, gastric and esophageal) cancer cell lines and primary tumors.	('downregulated', 'NegReg', (137, 150))	('primary tumors', 'Disease', 'MESH:D009369', (246, 260))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('silenced', 'NegReg', (125, 133))	('digestive', 'Disease', (182, 191))	('esophageal', 'Disease', (212, 222))	('human', 'Species', '9606', (70, 75))	('promoter methylation', 'Var', (158, 178))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('esophageal', 'Disease', 'MESH:D004941', (212, 222))	('primary tumors', 'Disease', (246, 260))	('cancer', 'Disease', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('SOX10', 'Gene', (35, 40))
621183	25301735	Mutations in Wnt pathway components such as APC or stabilizing mutations in beta-catenin itself that lead to constitutive signaling are frequently found in digestive cancers.	('mutations', 'Var', (63, 72))	('cancers', 'Disease', (166, 173))	('APC', 'Disease', 'MESH:D011125', (44, 47))	('APC', 'Disease', (44, 47))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('Wnt', 'Gene', (13, 16))	('beta-catenin', 'Gene', (76, 88))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('beta-catenin', 'Gene', '1499', (76, 88))	('found', 'Reg', (147, 152))	('constitutive signaling', 'MPA', (109, 131))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('lead to', 'Reg', (101, 108))
621184	25301735	Epigenetic downregulation of tumor suppressor genes, especially in the setting of key signaling pathways, have been proven to be a complementary mechanism to genetic mutation during carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Epigenetic', 'Var', (0, 10))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))
621186	25301735	We reported here that SOX10, another SOX family member, functions as a TSG but is silenced by promoter CpG methylation in multiple digestive cancers.	('TSG', 'Gene', '57045', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('SOX10', 'Gene', (22, 27))	('TSG', 'Gene', (71, 74))	('silenced', 'NegReg', (82, 90))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('methylation', 'Var', (107, 118))	('cancers', 'Disease', (141, 148))	('multiple digestive cancer', 'Phenotype', 'HP:0200008', (122, 147))
621191	25301735	We used digestive cancer cell lines with mutant (HCT116 and AGS ) or wild-type beta-catenin (KYSE150), all of which have complete silenced expression of SOX10.	('AGS', 'Disease', (60, 63))	('mutant', 'Var', (41, 47))	('beta-catenin', 'Gene', '1499', (79, 91))	('AGS', 'Disease', 'MESH:C535607', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('HCT116', 'CellLine', 'CVCL:0291', (49, 55))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('beta-catenin', 'Gene', (79, 91))
621192	25301735	Ectopic expression of SOX10 could effectively suppress tumor proliferation and metastasis in cell lines harboring wild-type as well as mutant beta-catenin.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('suppress', 'NegReg', (46, 54))	('beta-catenin', 'Gene', (142, 154))	('mutant', 'Var', (135, 141))	('SOX10', 'Gene', (22, 27))	('tumor', 'Disease', (55, 60))	('beta-catenin', 'Gene', '1499', (142, 154))
621193	25301735	Consistent with this, SOX10 could interact with mutant beta-catenin and repress target gene transcription.	('beta-catenin', 'Gene', (55, 67))	('mutant', 'Var', (48, 54))	('repress', 'NegReg', (72, 79))	('beta-catenin', 'Gene', '1499', (55, 67))	('SOX10', 'Gene', (22, 27))	('interact', 'Interaction', (34, 42))
621197	25301735	This transrepresson ability is dependent on the DNA-binding activity of SOX10's HMG domain, because a SOX10 mutant that is incapable of DNA binding can still interact with beta-catenin, but fails to suppress the TOPFlash reporter as well as Wnt-target gene expression.	('interact', 'Interaction', (158, 166))	('beta-catenin', 'Gene', (172, 184))	('beta-catenin', 'Gene', '1499', (172, 184))	('mutant', 'Var', (108, 114))	('TOPFlash reporter', 'MPA', (212, 229))	('SOX10', 'Gene', (102, 107))
621199	25301735	Since disrupting SOX10-beta-catenin interaction could only partially abolished tumor suppressor functions of SOX10, there may be other signaling pathways participated in the complex mechanisms of tumor suppression by SOX10.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (79, 84))	('disrupting', 'Var', (6, 16))	('abolished', 'NegReg', (69, 78))	('beta-catenin', 'Gene', (23, 35))	('interaction', 'Interaction', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('beta-catenin', 'Gene', '1499', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
621206	25301735	In summary, our study identifies SOX10 as a functional tumor suppressor and an important regulator of the Wnt/beta-catenin signaling pathway, with frequent epigenetic inactivation in certain digestive tumor.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('beta-catenin', 'Gene', (110, 122))	('SOX10', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('beta-catenin', 'Gene', '1499', (110, 122))	('tumor', 'Disease', (55, 60))	('digestive tumor', 'Phenotype', 'HP:0007378', (191, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('epigenetic inactivation', 'Var', (156, 179))
621214	25301735	Whole-cell extracts of HCT116 or 293T cells expressing V5-SOX10 or its mutants were immunoprecipitated with anti-V5 or anti-beta-catenin, followed by western blot analysis using anti-V5, anti-beta-catenin, or anti-TCF4 antibodies.	('beta-catenin', 'Gene', '1499', (192, 204))	('HCT116', 'CellLine', 'CVCL:0291', (23, 29))	('beta-catenin', 'Gene', (124, 136))	('V5-SOX10', 'Gene', (55, 63))	('beta-catenin', 'Gene', '1499', (124, 136))	('mutants', 'Var', (71, 78))	('beta-catenin', 'Gene', (192, 204))	('293T', 'CellLine', 'CVCL:0063', (33, 37))	('TCF4', 'Gene', (214, 218))	('TCF4', 'Gene', '6925', (214, 218))
621225	22565611	In multivariate analysis, GTV failure was associated with tumor status (T3/T4 vs. T1/T2: OR=6.35, p value =0.002), change in standardized uptake value on PET before and after treatment (decrease >52%: OR=0.368, p value = 0.003) and tumor length (>8 cm: 4.08, p value = 0.009).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('T3/T4', 'Var', (72, 77))	('T1/T2', 'Gene', '9173;292', (82, 87))	('GTV failure', 'Disease', (26, 37))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('T1/T2', 'Gene', (82, 87))	('men', 'Species', '9606', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('GTV failure', 'Disease', 'MESH:D017093', (26, 37))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('change', 'Reg', (115, 121))	('standardized uptake value on PET', 'MPA', (125, 157))	('tumor', 'Disease', (232, 237))
621306	22565611	Proton-beam therapy has also been shown to effectively increase the dose to the primary tumor while reducing toxicity to proximal critical structures compared with 3-D conformal and IMRT techniques.	('Proton-beam therapy', 'Var', (0, 19))	('increase', 'PosReg', (55, 63))	('primary tumor', 'Disease', (80, 93))	('reducing', 'NegReg', (100, 108))	('dose', 'MPA', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('primary tumor', 'Disease', 'MESH:D009369', (80, 93))	('toxicity', 'Disease', 'MESH:D064420', (109, 117))	('toxicity', 'Disease', (109, 117))
621308	22565611	Inhibition of key kinases in oncologic signaling pathways such as PI3K/AKT can lead to effective radiosensitization, which may translate into improved local control.	('local control', 'CPA', (151, 164))	('AKT', 'Gene', '207', (71, 74))	('radiosensitization', 'CPA', (97, 115))	('improved', 'PosReg', (142, 150))	('Inhibition', 'Var', (0, 10))	('AKT', 'Gene', (71, 74))
621311	22565611	Other biologic targets being investigated for this purpose include inhibitors of Hedgehog, BCL-2, VEGF, mTOR, and HSP-90.	('inhibitors', 'Var', (67, 77))	('mTOR', 'Gene', (104, 108))	('mTOR', 'Gene', '2475', (104, 108))	('VEGF', 'Gene', '7422', (98, 102))	('BCL-2', 'Gene', (91, 96))	('Hedgehog', 'Gene', (81, 89))	('HSP-90', 'Gene', (114, 120))	('HSP-90', 'Gene', '3320', (114, 120))	('VEGF', 'Gene', (98, 102))	('BCL-2', 'Gene', '596', (91, 96))
621323	22500191	Helicobacter pylori: Eradication or Preservation Helicobacter pylori infects about 50% of the world's population and inevitably results in the development of gastritis.	('results in', 'Reg', (128, 138))	('Helicobacter pylori', 'Species', '210', (0, 19))	('gastritis', 'Phenotype', 'HP:0005263', (158, 167))	('Helicobacter pylori', 'Species', '210', (49, 68))	('Preservation', 'Var', (36, 48))	('gastritis', 'Disease', 'MESH:D005756', (158, 167))	('Eradication', 'Var', (21, 32))	('gastritis', 'Disease', (158, 167))	('Helicobacter pylori', 'Gene', (49, 68))
621332	22500191	"Treaters" would suggest that eradication of the organism would likely reduce the development of gastric inflammation, development of peptic ulcer disease (especially in those patients who are also taking nonsteroidal anti-inflammatory drugs [NSAIDs]), and the theoretical benefit of reducing the progression to frank gastric malignancy.	('gastric inflammation', 'Disease', 'MESH:D007249', (97, 117))	('patients', 'Species', '9606', (176, 184))	('eradication', 'Var', (30, 41))	('reduce', 'NegReg', (71, 77))	('gastric malignancy', 'Phenotype', 'HP:0006753', (318, 336))	('gastric malignancy', 'Disease', (318, 336))	('gastric malignancy', 'Disease', 'MESH:D013274', (318, 336))	('gastric inflammation', 'Disease', (97, 117))	('gastric inflammation', 'Phenotype', 'HP:0005263', (97, 117))	('peptic ulcer', 'Phenotype', 'HP:0004398', (134, 146))	('peptic ulcer disease', 'Disease', (134, 154))	('peptic ulcer disease', 'Disease', 'MESH:D010437', (134, 154))
621333	22500191	"Commensalists" suggest that H. pylori, rather than being a pathogen, is in fact a commensal, and eradication worsens gastro-esophageal reflux disease or even induces asthma.	('asthma', 'Phenotype', 'HP:0002099', (167, 173))	('gastro-esophageal reflux disease', 'Phenotype', 'HP:0002020', (118, 150))	('eradication', 'Var', (98, 109))	('induces', 'Reg', (159, 166))	('gastro-esophageal reflux disease', 'Disease', (118, 150))	('reflux disease', 'Phenotype', 'HP:0002020', (136, 150))	('asthma', 'Disease', 'MESH:D001249', (167, 173))	('worsens', 'NegReg', (110, 117))	('H. pylori', 'Species', '210', (29, 38))	('asthma', 'Disease', (167, 173))	('gastro-esophageal reflux disease', 'Disease', 'MESH:D005764', (118, 150))	('H. pylori', 'Disease', (29, 38))
621337	22500191	A recent review evaluated the results of 11 studies and concluded that H. pylori eradication did not result in a significant difference in the frequency of symptomatic or endoscopically proven erosive gastro-esophageal reflux disease, when compared with persistent infection, regardless of follow-up period, location, or the baseline disease.	('reflux disease', 'Phenotype', 'HP:0002020', (219, 233))	('gastro-esophageal reflux disease', 'Disease', 'MESH:D005764', (201, 233))	('infection', 'Disease', (265, 274))	('persistent infection', 'Phenotype', 'HP:0031035', (254, 274))	('gastro-esophageal reflux disease', 'Disease', (201, 233))	('infection', 'Disease', 'MESH:D007239', (265, 274))	('H. pylori', 'Species', '210', (71, 80))	('eradication', 'Var', (81, 92))	('gastro-esophageal reflux disease', 'Phenotype', 'HP:0002020', (201, 233))
621357	22500191	It is now well accepted that habitation of the body of the stomach by H. pylori results in a large increase in the incidence of gastric adenocarcinoma.	('H. pylori', 'Var', (70, 79))	('H. pylori', 'Species', '210', (70, 79))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (128, 150))	('gastric adenocarcinoma', 'Disease', (128, 150))	('increase', 'PosReg', (99, 107))
621407	33275808	Mutations in guanine nucleotide-binding protein G(s) subunit alpha isoforms short (GNAS) possibly play a pivotal role in the development of IPMNs, 2 ,  3  a concept that has been confirmed by numerous molecular studies of human tissues and genetically engineered mouse models.	('guanine nucleotide', 'Chemical', 'MESH:D006150', (13, 31))	('play', 'Reg', (98, 102))	('Mutations', 'Var', (0, 9))	('GNAS', 'Gene', (83, 87))	('mouse', 'Species', '10090', (263, 268))	('IPMN', 'Chemical', '-', (140, 144))	('human', 'Species', '9606', (222, 227))	('IPMNs', 'Disease', (140, 145))
621414	33275808	7  The initial belief was that GNAS mutation is associated with intestinal-type IPMN or mucinous (colloid-type) carcinoma.	('mucin', 'Gene', (88, 93))	('IPMN', 'Chemical', '-', (80, 84))	('carcinoma', 'Disease', 'MESH:D009369', (112, 121))	('associated', 'Reg', (48, 58))	('intestinal-type IPMN', 'Disease', (64, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('GNAS', 'Gene', (31, 35))	('mucin', 'Gene', '100508689', (88, 93))	('carcinoma', 'Disease', (112, 121))	('mutation', 'Var', (36, 44))
621443	33275808	Panc1 cells expressing mCherry or CDX2 or mCherry-Atoh1 were injected into 6-wk-old BALB/cAJcl-nu/nu mice (Clea Japan, Inc) using a fine needle after placing the mouse under general anesthesia.	('mouse', 'Species', '10090', (162, 167))	('hes', 'Gene', (187, 190))	('mice', 'Species', '10090', (101, 105))	('Panc1', 'CellLine', 'CVCL:0480', (0, 5))	('mCherry-Atoh1', 'Var', (42, 55))	('hes', 'Gene', '3280', (187, 190))
621462	33275808	We also evaluated a series of intestinal phenotypic genes and found that MUC2 and trefoil factor 3 (TFF3), both of which are phenotypic genes for goblet cells, were slightly induced by Atoh1, but not by CDX2.	('Atoh1', 'Var', (185, 190))	('trefoil factor 3', 'Gene', (82, 98))	('MUC2', 'Gene', (73, 77))	('TFF3', 'Gene', (100, 104))	('MUC2', 'Gene', '4583', (73, 77))	('TFF3', 'Gene', '7033', (100, 104))	('trefoil factor 3', 'Gene', '7033', (82, 98))	('induced', 'PosReg', (174, 181))
621477	33275808	The results of ELDA also revealed a significant tumorigenicity of Atoh1-expressing cells, but not CDX2-expressing cells (Figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Atoh1-expressing', 'Var', (66, 82))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
621563	32676460	Previous studies have reported that an imbalance of the microbiome may promote esophageal cancer development and progression.	('promote', 'PosReg', (71, 78))	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('imbalance', 'Var', (39, 48))	('progression', 'CPA', (113, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('imbalance', 'Phenotype', 'HP:0002172', (39, 48))
621645	31694907	The specific mechanisms through which these age-associated molecular changes contribute to the increased risk of aging-related disease, such as cancer, are incompletely understood.	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('changes', 'Var', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
621648	31694907	Recent studies in various types of cancer point to the significance of epigenetic aging in tumorigenesis, and its potential use for cancer risk prediction.	('cancer', 'Disease', (132, 138))	('epigenetic aging', 'Var', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (35, 41))
621652	31694907	The molecular, cellular and physiologic changes associated with aging are myriad and include, among others, cellular senescence, the accumulation of genetic alterations, onset of low-grade inflammation ('inflammaging'), protein misfolding, epigenetic alterations, and cumulative oxidative stress damage.	('inflammation', 'Disease', (189, 201))	('genetic alterations', 'Var', (149, 168))	('protein', 'Protein', (220, 227))	('epigenetic alterations', 'CPA', (240, 262))	('oxidative stress', 'Phenotype', 'HP:0025464', (279, 295))	('cellular senescence', 'CPA', (108, 127))	('inflammation', 'Disease', 'MESH:D007249', (189, 201))
621654	31694907	Epigenetic age, as estimated by drift/clock CpG dinucleotides, is receiving increased attention because it appears to be a robust marker of tissue age and to hold promise for improving the risk prediction of age-related diseases.	('improving', 'PosReg', (175, 184))	('Epigenetic', 'Var', (0, 10))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (44, 61))
621662	31694907	Conversely, a pronounced and consistent pattern of DNA methylation loss is observed at lamina-associated, partially-methylated domains in primary cancer samples, as well as in aged tissue.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('DNA', 'Gene', (51, 54))	('loss', 'NegReg', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('methylation', 'Var', (55, 66))
621665	31694907	In the next sections, we will review our current understanding of DNA methylation changes as part of an 'epigenetic aging' process, and discuss their implications in cancer etiology.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('methylation changes', 'Var', (70, 89))	('changes', 'Var', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
621668	31694907	As individuals age, DNAm patterns undergo characteristic age-related changes presumably secondary to effects caused by the human microbiome, lifestyle and environmental factors, and more directly through epigenetic drift associated with errors in maintaining DNA methylation patterns.	('human microbiome', 'Species', '646099', (123, 139))	('changes', 'Reg', (69, 76))	('DNAm', 'MPA', (20, 24))	('errors', 'Var', (237, 243))
621673	31694907	Such alterations may therefore play a functional role in the aging process and in cancer development beyond their role as autonomous clocks.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('alterations', 'Var', (5, 16))	('play', 'Reg', (31, 35))
621686	31694907	In a recent study, our team sought to better understand the dynamics and role of epigenetic drift in the colon and rectum as an indicator of tissue aging and as a way to more accurately estimate the sojourn time of the adenoma-carcinoma sequence.	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (219, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('adenoma-carcinoma', 'Disease', (219, 236))	('epigenetic drift', 'Var', (81, 97))
621687	31694907	This analysis showed that age-related epigenetic drift is a genome-wide phenomenon that occurs in normal colorectal tissues and that also appears to progress at an accelerated pace in colorectal neoplasia.	('epigenetic drift', 'Var', (38, 54))	('colorectal neoplasia', 'Disease', (184, 204))	('colorectal neoplasia', 'Disease', 'MESH:D015179', (184, 204))	('progress', 'PosReg', (149, 157))	('neoplasia', 'Phenotype', 'HP:0002664', (195, 204))
621688	31694907	We also found that epigenetic drift has increased variance (a second order drift process) in colorectal cancer compared to normal colon tissue.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('variance', 'MPA', (50, 58))	('epigenetic drift', 'Var', (19, 35))	('increased', 'PosReg', (40, 49))	('colorectal cancer', 'Disease', (93, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))
621693	31694907	Similar results were obtained in a parallel study of differential methylomic drift in Barrett's esophagus (BE), the only known precursor lesion for esophageal adenocarcinoma (discussed in more detail below).	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (148, 173))	("Barrett's esophagus", 'Disease', (86, 105))	('adenocarcinoma', 'Disease', (159, 173))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (86, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('methylomic', 'Var', (66, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (159, 173))
621699	31694907	Based on the recognition that increased cell proliferation in association with clonal growth is a hallmark feature of many cancers, a biological clock such as the epiTOC, or epigenetic drift that is linked to the overall number of stem cell divisions, may be informative in at least two ways: 1) to provide an estimate of cumulative stem cell divisions and therefore accumulation of DNA sequence mutations, and 2) to determine changes in gene expression associated with age-related monotonic increases or decreases in DNA methylation at gene regulatory sites, e.g., gene promoters, enhancers, silencers and transposable elements.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutations', 'Var', (396, 405))	('decreases', 'NegReg', (505, 514))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('silencers', 'Disease', (593, 602))	('silencers', 'Disease', 'None', (593, 602))	('changes', 'Reg', (427, 434))
621701	31694907	Consistent with this mechanism as a cause of cancer related to DNA methylation alterations, hypomethylated CpG dinucleotide rich regions (i.e., CpG-islands) have been shown to undergo epigenetic drift because of sporadic de novo methylation errors that occur when tissue stem cells replicate their genome hundreds to thousands of times during an individual's lifetime.	('methylation', 'Var', (229, 240))	('alterations', 'Var', (79, 90))	('epigenetic drift', 'MPA', (184, 200))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('undergo', 'Reg', (176, 183))	('cancer', 'Disease', (45, 51))
621703	31694907	The relative contributions of passive and active processes on epigenetic aging are not known but both mechanisms likely lead to the aberrant DNA methylation of candidate tumor suppressor genes and oncogenes.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('lead to', 'Reg', (120, 127))	('aberrant', 'Var', (132, 140))	('tumor', 'Disease', (170, 175))	('DNA methylation', 'MPA', (141, 156))
621707	31694907	Determining the mechanisms behind epigenetic clocks is of more than academic importance because it could inform us how they relate to other age-related cellular processes such as senescence, mutation accumulation, loss of mitochondrial function, and epigenetic silencing and cancer.	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('mutation accumulation', 'Var', (191, 212))	('mitochondrial', 'MPA', (222, 235))	('loss', 'NegReg', (214, 218))	('epigenetic silencing', 'Var', (250, 270))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (275, 281))
621709	31694907	The importance of distinguishing the roles of cell cycle frequency vs. methylation error rates may be appreciated when one considers that the aberrant DNA methylation resulting from low fidelity DNMT activity can globally contribute to increased genomic alterations and epigenetic alterations, while in contrast, an increased rate of de novo methylation errors likely would mainly contribute to cancer formation via altering specific cancer driver genes, like MLH1, since these would require clonal expansion events to be detectable.	('methylation', 'Var', (342, 353))	('MLH1', 'Gene', '4292', (460, 464))	('DNMT', 'Gene', '1786', (195, 199))	('cancer', 'Disease', 'MESH:D009369', (395, 401))	('increased', 'PosReg', (236, 245))	('DNMT', 'Gene', (195, 199))	('aberrant', 'Var', (142, 150))	('epigenetic alterations', 'MPA', (270, 292))	('cancer', 'Disease', (434, 440))	('altering', 'Reg', (416, 424))	('low', 'Var', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (434, 440))	('cancer', 'Disease', (395, 401))	('cancer', 'Phenotype', 'HP:0002664', (395, 401))	('errors', 'Var', (354, 360))	('MLH1', 'Gene', (460, 464))	('contribute', 'Reg', (381, 391))	('genomic', 'MPA', (246, 253))	('cancer', 'Disease', 'MESH:D009369', (434, 440))
621713	31694907	There has been considerable interest and excitement in the use of epigenetic age as a measure of biological age to predict the risk for aging-related diseases such as cancer.	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (167, 173))	('epigenetic age', 'Var', (66, 80))	('cancer', 'Disease', 'MESH:D009369', (167, 173))
621714	31694907	It is plausible that the stochastic process inherent in epigenetic drift can induce aberrant methylation events that accumulate in normal cells and eventually induce cancer formation, as suggested by a common set of changes in DNA methylation pattern during aging and in cancer.	('cancer', 'Disease', (166, 172))	('accumulate', 'PosReg', (117, 127))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('induce', 'Reg', (159, 165))	('epigenetic drift', 'Var', (56, 72))	('methylation', 'MPA', (93, 104))	('changes', 'Reg', (216, 223))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', (271, 277))	('induce', 'Reg', (77, 83))
621716	31694907	For those clones that acquire a cancer promoting epigenetic alteration secondary to epigenetic drift or clock phenomenon, they outcompete other clones and contribute to the clonal evolution of the cancer.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('epigenetic alteration', 'Var', (49, 70))
621718	31694907	Furthermore, Klutstein et al., demonstrated that tissue-specific cancer risk is highly correlated with the degree of aberrant age-dependent methylation in normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('aberrant', 'Var', (117, 125))
621719	31694907	Altogether, considerable evidence suggests that age-associated epigenetic drift or epigenetic aging may predispose normal cells to transforming into cancer cells.	('cancer', 'Disease', (149, 155))	('transforming', 'CPA', (131, 143))	('predispose', 'Reg', (104, 114))	('epigenetic drift', 'Var', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('epigenetic aging', 'Var', (83, 99))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
621720	31694907	Recently, studies have found epigenetic age acceleration in the blood samples collected from patients who developed cancer at follow up, compared to cancer-free participants.	('epigenetic age', 'Var', (29, 43))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('participants', 'Species', '9606', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('acceleration', 'PosReg', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
621721	31694907	It's noteworthy that the association of epigenetic age acceleration in the blood samples with cancer risk likely reflects a systemic effect of DNA methylation changes on cancer predisposition, such as through immune system alterations captured in the leukocyte DNA methylation alterations, which is in distinct contrast with epigenetic drift in the tissue samples, which may predispose to cancer via altering tumor suppressor genes and/or oncogenes that drive the expansion of cancer-initiating clones.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tumor', 'Disease', (409, 414))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (477, 483))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (477, 483))	('alterations', 'Var', (277, 288))	('tumor', 'Disease', 'MESH:D009369', (409, 414))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('cancer', 'Disease', (477, 483))	('cancer', 'Disease', (389, 395))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
621722	31694907	It's well accepted that the majority of human cancers develop via the accumulation of genetic and epigenetic alterations over time.	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('genetic', 'Var', (86, 93))	('epigenetic alterations', 'Var', (98, 120))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('human', 'Species', '9606', (40, 45))
621727	31694907	One concrete example demonstrating how age-related DNA methylation could promote cancer formation is HAND2, a gene encoding a member of the basic helix-loop-helix family of transcription factors highly expressed in the endometrial stroma.	('HAND2', 'Gene', '9464', (101, 106))	('DNA methylation', 'Var', (51, 66))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('methylation', 'Var', (55, 66))	('cancer', 'Disease', (81, 87))	('endometrial stroma', 'Disease', 'MESH:D014591', (219, 237))	('endometrial stroma', 'Disease', (219, 237))	('HAND2', 'Gene', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('promote', 'PosReg', (73, 80))
621733	31694907	In colorectal cancers, we similarly found that advanced epigenetic drift was frequently (in over 50% of drift-related CpG island (CGI) in the right colon) associated with significant reductions in gene expression.	('reductions', 'NegReg', (183, 193))	('gene expression', 'MPA', (197, 212))	('colorectal cancers', 'Disease', 'MESH:D015179', (3, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancers', 'Disease', (3, 21))	('epigenetic drift', 'Var', (56, 72))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
621734	31694907	Although our analysis does not demonstrate causality, the fact that epigenetic drift at CGIs in normal colon is more prominently associated with transcriptional changes in colorectal neoplasia than CGI that undergo little or no drift in normal colorectum suggests a potential role of epigenetic drift in the molecular pathogenesis of cancer.	('associated', 'Reg', (129, 139))	('colorectal neoplasia', 'Disease', 'MESH:D015179', (172, 192))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('neoplasia', 'Phenotype', 'HP:0002664', (183, 192))	('epigenetic drift', 'Var', (68, 84))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('transcriptional changes', 'MPA', (145, 168))	('colorectal neoplasia', 'Disease', (172, 192))	('cancer', 'Disease', (334, 340))
621735	31694907	Of particular interest, epigenetic aging may target and silence specific transcription factors that function as tumor suppressors.	('epigenetic aging', 'Var', (24, 40))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('transcription factors', 'Protein', (73, 94))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('silence', 'NegReg', (56, 63))	('target', 'Reg', (45, 51))	('tumor', 'Disease', (112, 117))
621736	31694907	Indeed, a comprehensive analysis of transcription factor landscapes revealed that bivalently and PRC2 marked transcription factors highly expressed in normal tissue are prone to be inactivated in cancer, predominantly via promoter hypermethylation.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bivalently', 'Var', (82, 92))	('inactivated', 'NegReg', (181, 192))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('promoter hypermethylation', 'Var', (222, 247))	('cancer', 'Disease', (196, 202))	('PRC2 marked transcription factors', 'Gene', (97, 130))
621739	31694907	Given the recent demonstration of the age-related accumulation in normal tissue of pathogenic gene mutations that clearly inactivate tumor suppressor genes and activate oncogenes, the potential role of concurrent epigenetic alterations playing a key and perhaps cooperating role in inducing the tumor-promoting events becomes more compelling.	('oncogenes', 'Gene', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('inactivate', 'NegReg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('mutations', 'Var', (99, 108))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('activate', 'PosReg', (160, 168))	('tumor', 'Disease', (295, 300))
621745	31694907	While much has been uncovered in linking epigenetic aging and cancer risk, several knowledge gaps need to be closed in the near future, particularly with regard to understanding the biological and clinical significance of the epigenetic drift phenomena.	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('epigenetic', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
621755	31694907	Undoubtedly, epigenetic aging is not simply a 'molecular clock' when it comes to cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('epigenetic aging', 'Var', (13, 29))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
621795	31814675	CA72-4, CEA and CA199 are routinely recommended, which can be combined with AFP and CA125 in some patients.	('CA125', 'Gene', (84, 89))	('AFP', 'Gene', '174', (76, 79))	('CA199', 'Var', (16, 21))	('CEA', 'Gene', (8, 11))	('CEA', 'Gene', '5670', (8, 11))	('patients', 'Species', '9606', (98, 106))	('CA125', 'Gene', '94025', (84, 89))	('AFP', 'Gene', (76, 79))
621917	31814675	For the radical resection specimens with submucosal invasion, distinction between SM1 (upper 1/3 of the submucosa), SM2 (middle 1/3 of the submucosa) and SM3 (lower 1/3 of the submucosa), the section margin, and the capillary and nerve invasion is recommended to make.	('SM1', 'Gene', '7911', (82, 85))	('SM2', 'Gene', (116, 119))	('SM1', 'Gene', (82, 85))	('SM3', 'Var', (154, 157))	('SM2', 'Gene', '53366', (116, 119))
621987	31814675	Note: There are still debates about whether to perform additional surgery and the operation timing of additional surgery after eCura C resection, which mainly focuses on the following: (1) More than 80% of patients with eCura C will not have a local recurrence or lymph node metastasis.	('patients', 'Species', '9606', (206, 214))	('local recurrence', 'CPA', (244, 260))	('eCura C', 'Var', (220, 227))	('lymph node metastasis', 'CPA', (264, 285))
622041	31814675	Timing of supplementary parenteral nutrition (SPN): For patients with low nutritional risk of NRS-2002 <=3 or NUTRIC Score <=5, only when EN fails to meet 60% of patient's target energy and protein requirements for more than 7 d, may the SPN support therapy be considered.	('NRS', 'Gene', (94, 97))	('patients', 'Species', '9606', (56, 64))	('supplementary parenteral nutrition', 'Phenotype', 'HP:0025156', (10, 44))	('<=5', 'Var', (123, 126))	('patient', 'Species', '9606', (56, 63))	('NRS', 'Gene', '83985', (94, 97))	('patient', 'Species', '9606', (162, 169))
622042	31814675	On the contrary, the SPN is recommended earlier for patients with high nutritional risk of NRS-2002 >=5 or NUTRIC Score >=6, when they are unable to obtain the 60% target energy and protein requirements within 48-72 h through EN.	('NRS', 'Gene', '83985', (91, 94))	('>=5', 'Var', (100, 103))	('NRS', 'Gene', (91, 94))	('patients', 'Species', '9606', (52, 60))
622143	31814675	(1) Indications For patients with advanced gastric or EGJ adenocarcinoma who have overexpression of epidermal growth factor receptor 2 (EGFR2/HER2) (+++ by immunohistochemical staining, or ++ by immunohistochemical staining and positive FISH test).	('HER2', 'Gene', (142, 146))	('HER2', 'Gene', '2064', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('epidermal growth factor receptor 2', 'Gene', (100, 134))	('epidermal growth factor receptor 2', 'Gene', '2064', (100, 134))	('overexpression', 'PosReg', (82, 96))	('+++', 'Var', (149, 152))	('gastric or EGJ adenocarcinoma', 'Disease', 'MESH:D013274', (43, 72))	('patients', 'Species', '9606', (20, 28))	('gastric or EGJ adenocarcinoma', 'Disease', (43, 72))
622318	28280356	Patients with high ARHI expression had significantly higher 5-year survival rates than those with low levels of ARHI expression (log-rank test, P<0.01; Figure 2A).	('ARHI', 'Gene', (19, 23))	('higher', 'PosReg', (53, 59))	('5-year survival rates', 'CPA', (60, 81))	('ARHI', 'Gene', (112, 116))	('ARHI', 'Gene', '9077', (19, 23))	('high', 'Var', (14, 18))	('ARHI', 'Gene', '9077', (112, 116))	('Patients', 'Species', '9606', (0, 8))
622319	28280356	A univariate analysis demonstrated that N stage (P<0.001), TNM stage (P=0.001), and high ARHI expression (P=0.005) were significant prognostic factors (Table 2).	('TNM', 'Gene', '10178', (59, 62))	('high', 'Var', (84, 88))	('ARHI', 'Gene', (89, 93))	('TNM', 'Gene', (59, 62))	('ARHI', 'Gene', '9077', (89, 93))
622324	28280356	The proliferation of ECA109 cells following PCMV-ARHI-AC-GFP transfection was significantly inhibited compared with the control group and the blank group.	('ARHI', 'Gene', '9077', (49, 53))	('proliferation', 'CPA', (4, 17))	('inhibited', 'NegReg', (92, 101))	('transfection', 'Var', (61, 73))	('ARHI', 'Gene', (49, 53))
622333	28280356	The results of cell proliferation assays and cell invasion assays showed that inhibition of ARHI can promote the proliferation and invasion of ECA109 cells (Figure S1).	('ARHI', 'Gene', (92, 96))	('promote', 'PosReg', (101, 108))	('invasion', 'CPA', (131, 139))	('inhibition', 'Var', (78, 88))	('ARHI', 'Gene', '9077', (92, 96))	('proliferation', 'CPA', (113, 126))
622368	28280356	Based on Annexin V and light staining, it was found that apoptosis was significantly higher in the transfected group than the control group.	('apoptosis', 'CPA', (57, 66))	('higher', 'PosReg', (85, 91))	('Annexin V', 'Gene', '308', (9, 18))	('Annexin V', 'Gene', (9, 18))	('transfected', 'Var', (99, 110))
622445	27057845	Canalejo Castrillero et al demonstrated that the average healing time in patients receiving antiviral therapy was shorter than that for patients receiving symptomatic therapy alone (7.2 +- 4.8 and 8.8 +- 5.9 days, respectively).	('antiviral therapy', 'Var', (92, 109))	('shorter', 'NegReg', (114, 121))	('healing time', 'CPA', (57, 69))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (73, 81))
622625	26350593	Anti-Tumor Effects of Peptide Therapeutic and Peptide Vaccine Antibody Co-targeting HER-1 and HER-2 in Esophageal Cancer (EC) and HER-1 and IGF-1R in Triple-Negative Breast Cancer (TNBC) Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC).	('HER-1', 'Gene', (84, 89))	('Esophageal Cancer', 'Disease', (103, 120))	('HER-1', 'Gene', '1956', (130, 135))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('HER-2', 'Gene', '2064', (94, 99))	('Co-targeting', 'Var', (71, 83))	('HER-2', 'Gene', (94, 99))	('HER-1', 'Gene', (130, 135))	('Tumor', 'Phenotype', 'HP:0002664', (5, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (330, 343))	('Breast Cancer', 'Disease', 'MESH:D001943', (166, 179))	('esophageal cancer', 'Disease', 'MESH:D004938', (287, 304))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (103, 120))	('breast cancer', 'Disease', 'MESH:D001943', (330, 343))	('IGF-1R', 'Gene', (140, 146))	('IGF-1R', 'Gene', '3480', (140, 146))	('breast cancer', 'Disease', (330, 343))	('Breast Cancer', 'Disease', (166, 179))	('esophageal cancer', 'Disease', (287, 304))	('Cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('HER-1', 'Gene', '1956', (84, 89))	('Breast Cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
622656	26350593	HER-1 and HER-2 targeted inhibitors are widely considered a potential therapeutic strategy in the treatment of EC.	('HER-2', 'Protein', (10, 15))	('inhibitors', 'Var', (25, 35))	('HER-1', 'Gene', '1956', (0, 5))	('HER-1', 'Gene', (0, 5))
622666	26350593	Indeed, a preclinical study showed that co-inhibition of HER-1 and IGF-IR sensitized HER-1/IGF-1R expressing human breast cancer cells to radiation.	('human', 'Species', '9606', (109, 114))	('IGF-IR', 'Gene', '3480', (67, 73))	('co-inhibition', 'Var', (40, 53))	('HER-1', 'Gene', (57, 62))	('HER-1', 'Gene', (85, 90))	('HER-1', 'Gene', '1956', (57, 62))	('HER-1', 'Gene', '1956', (85, 90))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('sensitized', 'Reg', (74, 84))	('breast cancer', 'Disease', (115, 128))	('IGF-IR', 'Gene', (67, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
622671	26350593	Taken together, these studies provide strong rationale for investigating novel combination strategies using inhibitors against HER-1, HER-2 and IGF-IR to treat patients with EC or TNBC.	('patients', 'Species', '9606', (160, 168))	('IGF-IR', 'Gene', (144, 150))	('TNBC', 'Disease', (180, 184))	('IGF-IR', 'Gene', '3480', (144, 150))	('HER-2', 'Protein', (134, 139))	('HER-1', 'Gene', (127, 132))	('inhibitors', 'Var', (108, 118))	('HER-1', 'Gene', '1956', (127, 132))
622679	26350593	Previously, we designed two novel HER-2 B-cell epitope peptide vaccines (HER-2-266-296, pertuzumab-like, and HER-2-597-629, trastuzumab-like) and demonstrated antitumor effects in several in vitro and in vivo models of human breast cancers.	('HER-2-597-629', 'CellLine', 'CVCL:G017', (109, 122))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('human', 'Species', '9606', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('HER-2-266-296', 'CellLine', 'CVCL:J924', (73, 86))	('pertuzumab', 'Chemical', 'MESH:C485206', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('HER-2-266-296', 'Var', (73, 86))	('HER-2-597-629', 'Var', (109, 122))	('trastuzumab', 'Chemical', 'MESH:D000068878', (124, 135))	('tumor', 'Disease', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('breast cancers', 'Phenotype', 'HP:0003002', (225, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancers', 'Disease', 'MESH:D001943', (225, 239))	('breast cancers', 'Disease', (225, 239))
622715	26350593	The following antibodies were purchased from Cell Signaling: Rabbit anti-phospho-IGF-1 receptor beta (Tyr1131) (#3021, 1:200); rabbit anti-IGF-1 receptor beta (#3018, 1:250); rabbit anti-phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (#9101, 1:1000); rabbit anti-p44/42 MAPK (Erk1/2) (#9102, 1:1000); rabbit anti-phospho-Akt XP (Ser473) (#9018, 1:1000); rabbit anti-AKT (#9272, 1:1000); rabbit anti-phospho-EGFR (Tyr1148) (#4404, 1:200); and mouse anti-EGFR (#2239, 1:200).	('rabbit', 'Species', '9986', (299, 305))	('Tyr1131', 'Chemical', '-', (102, 109))	('EGFR', 'Gene', '1956', (451, 455))	('p44', 'Gene', (195, 198))	('Erk1/2', 'Gene', '5595;5594', (274, 280))	('p44', 'Gene', '10561', (195, 198))	('rabbit', 'Species', '9986', (385, 391))	('IGF-1', 'Gene', (139, 144))	('AKT', 'Gene', (364, 367))	('rabbit', 'Species', '9986', (352, 358))	('Erk1/2', 'Gene', '5595;5594', (208, 214))	('rabbit', 'Species', '9986', (249, 255))	('rabbit', 'Species', '9986', (175, 181))	('EGFR', 'Gene', (405, 409))	('IGF-1', 'Gene', '3479', (139, 144))	('#9272', 'Var', (369, 374))	('EGFR', 'Gene', (451, 455))	('Akt', 'Gene', (319, 322))	('IGF-1', 'Gene', (81, 86))	('Rabbit', 'Species', '9986', (61, 67))	('rabbit', 'Species', '9986', (127, 133))	('AKT', 'Gene', '207', (364, 367))	('p44', 'Gene', (261, 264))	('Erk1/2', 'Gene', (274, 280))	('p44', 'Gene', '10561', (261, 264))	('IGF-1', 'Gene', '3479', (81, 86))	('Akt', 'Gene', '207', (319, 322))	('mouse', 'Species', '10090', (440, 445))	('Erk1/2', 'Gene', (208, 214))	('EGFR', 'Gene', '1956', (405, 409))
622721	26350593	These include one HER-1 epitope (HER-1-418-435), two HER-2 epitopes (HER-2-266-296 and HER-2-597-626) and two IGF-1R epitope (IGF-1R-56-81 and IGF-1R-233-251).	('HER-1', 'Gene', '1956', (18, 23))	('HER-2-266-296', 'CellLine', 'CVCL:J924', (69, 82))	('HER-1', 'Gene', (33, 38))	('HER-1', 'Gene', '1956', (33, 38))	('HER-2-266-296', 'Var', (69, 82))	('HER-2-597-626', 'CellLine', 'CVCL:G017', (87, 100))	('HER-1', 'Gene', (18, 23))
622727	26350593	The 266-296 peptide vaccine significantly reduced tumor onset in both transplantable tumor models (FVB/n and BALB/c) and significantly reduced in tumor development in two transgenic mouse tumor models (BALB-neuT and VEGF(+/-)Neu2-5(+/-)).	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', (85, 90))	('reduced', 'NegReg', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mouse', 'Species', '10090', (182, 187))	('neu', 'Gene', '2064', (207, 210))	('neu', 'Gene', (207, 210))	('266-296', 'Var', (4, 11))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('reduced', 'NegReg', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
622728	26350593	The 597-626 epitope significantly reduced tumor burden in transgenic BALB-neuT mice.	('reduced', 'NegReg', (34, 41))	('tumor', 'Disease', (42, 47))	('neu', 'Gene', '2064', (74, 77))	('mice', 'Species', '10090', (79, 83))	('neu', 'Gene', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('597-626', 'Var', (4, 11))
622738	26350593	Notably, combination treatment with both anti-HER-1-418 and anti-HER-2-597 significantly inhibited proliferation over single treatment alone (* p < 0.05).	('HER-1', 'Gene', '1956', (46, 51))	('inhibited', 'NegReg', (89, 98))	('anti-HER-2-597', 'Var', (60, 74))	('proliferation', 'CPA', (99, 112))	('HER-1', 'Gene', (46, 51))
622740	26350593	Combination treatments of HER-1-418 or HER-2-266 and HER-1-418 and HER-2-597 inhibited proliferation more than single treatment alone (* p < 0.05).	('HER-2-597', 'Var', (67, 76))	('proliferation', 'CPA', (87, 100))	('HER-2-266', 'Var', (39, 48))	('HER-1', 'Gene', (53, 58))	('HER-1', 'Gene', (26, 31))	('inhibited', 'NegReg', (77, 86))	('HER-1', 'Gene', '1956', (53, 58))	('HER-1', 'Gene', '1956', (26, 31))
622743	26350593	Combination treatment in TNBC cells with anti-HER-1-418 and anti-IGF-1R-56 showed greater inhibition of proliferation over single treatment alone (# p < 0.005) as compared to the anti-HER-1-418 and anti-IGF-1R-233 or anti-IGF-1R-56 and anti-IGF-1R-233 combinations, which significantly inhibited cell proliferation over negative control (** p < 0.001), but did not show an increased advantage over single treatment alone (Figure 1C).	('inhibition', 'NegReg', (90, 100))	('HER-1', 'Gene', (184, 189))	('anti-IGF-1R-56', 'Var', (60, 74))	('HER-1', 'Gene', '1956', (46, 51))	('proliferation', 'CPA', (104, 117))	('HER-1', 'Gene', '1956', (184, 189))	('cell proliferation', 'CPA', (296, 314))	('inhibited', 'NegReg', (286, 295))	('HER-1', 'Gene', (46, 51))
622747	26350593	Active immunization with the MVF-HER-1, MVF-HER-2 and MVF-IGF-1R chimeric peptides elicited the production of high-affinity antibodies that induced ADCC.	('elicited', 'Reg', (83, 91))	('MVF-IGF-1R', 'Gene', (54, 64))	('HER-1', 'Gene', (33, 38))	('high-affinity', 'Protein', (110, 123))	('ADCC', 'Disease', (148, 152))	('chimeric peptides', 'Var', (65, 82))	('HER-1', 'Gene', '1956', (33, 38))	('induced', 'Reg', (140, 147))	('MVF-HER-2', 'Gene', (40, 49))
622751	26350593	At an effector: Target cell ratio of 1:100, both combinations of HER-1-418 and HER-2-597 or HER-1-418 and HER-2-266 induced significantly higher levels of ADCC than single treatment alone (# p <= 0.05).	('HER-2-266', 'Var', (106, 115))	('HER-1', 'Gene', (92, 97))	('ADCC', 'MPA', (155, 159))	('combinations', 'Interaction', (49, 61))	('HER-1', 'Gene', '1956', (92, 97))	('HER-2-597', 'Var', (79, 88))	('HER-1', 'Gene', (65, 70))	('HER-1', 'Gene', '1956', (65, 70))	('higher', 'PosReg', (138, 144))
622754	26350593	Anti-HER-1-418 and anti-IGF-1R-56 peptide vaccine antibodies, in combination and alone, induced significantly higher levels of ADCC as compared to negative control (* p < 0.05, ** p < 0.005) (Figure 2B).	('HER-1', 'Gene', (5, 10))	('HER-1', 'Gene', '1956', (5, 10))	('anti-IGF-1R-56', 'Var', (19, 33))	('higher', 'PosReg', (110, 116))	('ADCC', 'MPA', (127, 131))
622755	26350593	Notably, the combination of anti-HER-1-418 and anti-IGF-1R-56 uniquely induced significantly higher levels of ADCC compared to single treatment alone (* p < 0.05).	('higher', 'PosReg', (93, 99))	('anti-IGF-1R-56', 'Var', (47, 61))	('HER-1', 'Gene', (33, 38))	('HER-1', 'Gene', '1956', (33, 38))	('ADCC', 'MPA', (110, 114))
622762	26350593	Combination treatment with anti-HER-2-266 and anti-HER-1-418 showed significant downregulation of receptor phosphorylation over single treatment alone (* p < 0.005).	('HER-1', 'Gene', '1956', (51, 56))	('receptor phosphorylation', 'MPA', (98, 122))	('downregulation', 'NegReg', (80, 94))	('HER-1', 'Gene', (51, 56))	('anti-HER-2-266', 'Var', (27, 41))
622763	26350593	In this assay, the combination of anti-HER-2-266 with anti-HER-1-418 appears to confer advantage over the anti-HER-2-597 combination.	('advantage', 'PosReg', (87, 96))	('HER-1', 'Gene', '1956', (59, 64))	('anti-HER-2-266', 'Var', (34, 48))	('HER-1', 'Gene', (59, 64))
622768	26350593	Treatment with peptide vaccine antibodies in TNBC cells (MDA-MB-231) showed increased inhibition of receptor phosphorylation with the combination treatment of anti-HER-1-418 and anti-IGF-1R-56.	('receptor phosphorylation', 'MPA', (100, 124))	('anti-IGF-1R-56', 'Var', (178, 192))	('HER-1', 'Gene', (164, 169))	('HER-1', 'Gene', '1956', (164, 169))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (57, 67))	('inhibition', 'NegReg', (86, 96))
622769	26350593	Results were determined by western blot analysis of total protein lysates performed for p-Tyr1131, IGF-IR, total IGF-IR, and beta-actin.	('IGF-IR', 'Gene', (99, 105))	('IGF-IR', 'Gene', (113, 119))	('IGF-IR', 'Gene', '3480', (113, 119))	('IGF-IR', 'Gene', '3480', (99, 105))	('p-Tyr1131', 'Var', (88, 97))	('Tyr1131', 'Chemical', '-', (90, 97))	('beta-actin', 'Gene', '728378', (125, 135))	('beta-actin', 'Gene', (125, 135))
622775	26350593	The combinations of anti-HER-1-418 with HER-2-266 and anti-HER-1-418 with HER-2-597 showed significantly higher levels of apoptosis than single treatment alone (* p < 0.005), in addition to higher levels than negative control (**p < 0.001) (Figure 4A).	('combinations', 'Interaction', (4, 16))	('HER-1', 'Gene', '1956', (25, 30))	('HER-1', 'Gene', '1956', (59, 64))	('HER-2-597', 'Var', (74, 83))	('higher', 'PosReg', (105, 111))	('apoptosis', 'CPA', (122, 131))	('HER-2-266', 'Var', (40, 49))	('HER-1', 'Gene', (59, 64))	('HER-1', 'Gene', (25, 30))	('higher', 'PosReg', (190, 196))
622777	26350593	In TNBC cells, while single peptide vaccine antibody treatment significantly increased apoptosis over negative control (* p < 0.005), the combinations of anti-HER-1-418 with anti-IGF-1R-56 showed significantly higher levels of apoptosis over single treatment alone (** p < 0.001), in addition to higher levels than negative control (** p < 0.001) (Figure 4B).	('HER-1', 'Gene', '1956', (159, 164))	('combinations', 'Interaction', (138, 150))	('anti-IGF-1R-56', 'Var', (174, 188))	('apoptosis', 'CPA', (87, 96))	('apoptosis', 'MPA', (227, 236))	('increased', 'PosReg', (77, 86))	('higher', 'PosReg', (210, 216))	('HER-1', 'Gene', (159, 164))
622795	26350593	Furthermore, anti-HER-1-418 in combination with anti-HER-2-266 or anti-HER-2-597 vaccine antibodies also induced greater levels of ADCC and apoptosis than single treatment, exhibiting indirect methods of tumor suppression as well.	('HER-1', 'Gene', '1956', (18, 23))	('anti-HER-2-597', 'Var', (66, 80))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('induced', 'Reg', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('apoptosis', 'CPA', (140, 149))	('HER-1', 'Gene', (18, 23))	('tumor', 'Disease', (204, 209))	('ADCC', 'MPA', (131, 135))	('greater', 'PosReg', (113, 120))
622796	26350593	Interestingly, depending on the mechanisms being measured, the HER-2-597 or HER-2-266 epitope had greater effects in combination with HER-1-418 treatments.	('HER-1', 'Gene', (134, 139))	('HER-1', 'Gene', '1956', (134, 139))	('HER-2-597', 'Var', (63, 72))	('HER-2-266', 'Gene', (76, 85))
622804	26350593	Crosstalk between IGF-1R and HER-1 has also been extensively described in TNBC.	('IGF-1R', 'Gene', (18, 24))	('HER-1', 'Gene', (29, 34))	('HER-1', 'Gene', '1956', (29, 34))	('Crosstalk', 'Var', (0, 9))	('described', 'Reg', (61, 70))	('TNBC', 'Disease', (74, 78))
622806	26350593	Furthermore, anti-HER-1-418 and anti-IGF-1R-56 vaccine antibodies induced greater levels of ADCC and apoptosis than single treatment.	('HER-1', 'Gene', '1956', (18, 23))	('HER-1', 'Gene', (18, 23))	('apoptosis', 'CPA', (101, 110))	('ADCC', 'MPA', (92, 96))	('anti-IGF-1R-56', 'Var', (32, 46))
622819	26230607	High GC parameters were inversely associated with DNA content flow cytometric abnormalities, such as aneuploidy, ploidy >2.7N, and an elevated 4N fraction > 6%, and with risk of adenocarcinoma.	('associated', 'Reg', (34, 44))	('DNA content', 'MPA', (50, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('adenocarcinoma', 'Disease', (178, 192))	('aneuploidy', 'Disease', (101, 111))	('4N fraction', 'MPA', (143, 154))	('adenocarcinoma', 'Disease', 'MESH:D000230', (178, 192))	('ploidy >2.7N', 'Var', (113, 125))	('aneuploidy', 'Disease', 'MESH:D000782', (101, 111))
622820	26230607	The results of this study show, for the first time, an inverse relationship between high GC counts and flow cytometric abnormalities and risk of adenocarcinoma in BE.	('high', 'Var', (84, 88))	('BE', 'Phenotype', 'HP:0100580', (163, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('adenocarcinoma', 'Disease', (145, 159))	('inverse', 'NegReg', (55, 62))	('adenocarcinoma', 'Disease', 'MESH:D000230', (145, 159))
622878	26230607	GC parameter values were significantly lower in patients who were aneuploid compared to those who were diploid regardless of whether the was analysis was performed using dysplastic (p values = 0.022, 0.0006, 0.022, and 0.0009 for total #GC, total # crypt with >=1 GC, mean # GC/crypt, and proportion of crypts with >=1 GC, respectively) or non-dysplastic crypts (p = 0.0041, 0.0042, 0.0094 and 0.0197, respectively, for similar comparisons).	('aneuploid', 'Var', (66, 75))	('patients', 'Species', '9606', (48, 56))	('lower', 'NegReg', (39, 44))
622883	26230607	All four GC parameters also showed an inverse association with flow cytometric DNA content abnormalities, such as aneuploidy, ploidy >2.7N, and an elevated 4N fraction > 6%.	('4N fraction', 'MPA', (156, 167))	('aneuploidy', 'Disease', 'MESH:D000782', (114, 124))	('aneuploidy', 'Disease', (114, 124))	('ploidy >2.7N', 'Var', (126, 138))
622885	26230607	Some retrospective cross-sectional studies of BE patients have shown that cancer occurs significantly more frequently in areas of low GC density (the latter measured on a semi quantitative scale) while others have shown that areas of mucosa with high GC density do not correlate with foci of high-grade dysplasia/cancer.	('dysplasia/cancer', 'Disease', (303, 319))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('BE', 'Phenotype', 'HP:0100580', (46, 48))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('cancer', 'Disease', (74, 80))	('low', 'Var', (130, 133))	('dysplasia/cancer', 'Disease', 'MESH:D009369', (303, 319))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Disease', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (313, 319))
622886	26230607	A prior cross- sectional study, by Liu et al, suggested that DNA content abnormalities occur with equal frequency in non-dysplastic columnar epithelium either with, or without, GC and that these alterations are independent of the extent of GC in the esophagus.	('abnormalities', 'Var', (73, 86))	('non-dysplastic columnar', 'Disease', (117, 140))	('non-dysplastic columnar', 'Disease', 'MESH:D004416', (117, 140))	('DNA content', 'MPA', (61, 72))
622890	26230607	MUC2 deficient mice develop adenocarcinomas and when crossed with APC deficient mice, the result is accelerated tumor development and metastasis.	('MUC2', 'Gene', '17831', (0, 4))	('MUC2', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('APC', 'Disease', 'MESH:D011125', (66, 69))	('adenocarcinomas', 'Disease', 'MESH:D000230', (28, 43))	('APC', 'Disease', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('adenocarcinomas', 'Disease', (28, 43))	('mice', 'Species', '10090', (80, 84))	('accelerated', 'PosReg', (100, 111))	('tumor', 'Disease', (112, 117))	('mice', 'Species', '10090', (15, 19))	('deficient', 'Var', (5, 14))
622909	26230607	Loss of GC may represent a biological mechanism that enhances development of adenocarcinoma, or may be a secondary phenomenon due to other factors such as genetic abnormalities that also are responsible for neoplastic progression.	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('enhances', 'PosReg', (53, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('genetic abnormalities', 'Disease', 'MESH:D030342', (155, 176))	('genetic abnormalities', 'Disease', (155, 176))	('Loss', 'Var', (0, 4))	('adenocarcinoma', 'Disease', (77, 91))
623048	22935172	After an overnight incubation, the recombinant pcDNA3.1-HtrA1 plasmid and the sense or antisense HtrA1 siRNAs were transfected into Eca-109 cells using Lipofectamine 2000.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (152, 170))	('HtrA1', 'Gene', '5654', (97, 102))	('HtrA1', 'Gene', '5654', (56, 61))	('HtrA1', 'Gene', (56, 61))	('antisense', 'Var', (87, 96))	('HtrA1', 'Gene', (97, 102))
623081	22935172	A single nucleotide polymorphism (SNP), rsll200638, was identified in the HtrA1 gene promoter and found to be significantly correlated with age-related macular degeneration (AMD) with a population-attributable risk of 49.3%.	('rsll200638', 'Var', (40, 50))	('AMD', 'Disease', 'MESH:D006009', (174, 177))	('AMD', 'Disease', (174, 177))	('correlated with', 'Reg', (124, 139))	('age-related macular degeneration', 'Disease', (140, 172))	('macular degeneration', 'Phenotype', 'HP:0000608', (152, 172))	('HtrA1', 'Gene', '5654', (74, 79))	('HtrA1', 'Gene', (74, 79))
623082	22935172	Individuals with the HtrA1 polymorphism have a ten-fold greater risk of developing AMD.	('polymorphism', 'Var', (27, 39))	('AMD', 'Disease', (83, 86))	('HtrA1', 'Gene', '5654', (21, 26))	('HtrA1', 'Gene', (21, 26))	('AMD', 'Disease', 'MESH:D006009', (83, 86))
623102	22935172	also confirmed that downregulating HtrA1 can promote cell invasion, that stimulating HtrA1 can reduce cell invasiveness and that HtrA1 is a microtubule-associated protein that regulates cell motility by regulating the stability of microtubules.	('HtrA1', 'Gene', '5654', (85, 90))	('stability of microtubules', 'MPA', (218, 243))	('cell invasiveness', 'CPA', (102, 119))	('HtrA1', 'Gene', (129, 134))	('microtubule-associated protein', 'Gene', '51115', (140, 170))	('reduce', 'NegReg', (95, 101))	('HtrA1', 'Gene', (85, 90))	('regulating', 'Reg', (203, 213))	('HtrA1', 'Gene', '5654', (35, 40))	('stimulating', 'Var', (73, 84))	('microtubule-associated protein', 'Gene', (140, 170))	('promote', 'PosReg', (45, 52))	('cell', 'CPA', (186, 190))	('cell invasion', 'CPA', (53, 66))	('HtrA1', 'Gene', (35, 40))	('HtrA1', 'Gene', '5654', (129, 134))	('downregulating', 'Var', (20, 34))
623119	32615943	However, subgroup analysis showed a significant association between high expressed PODXL and poor OS in the colorectal cancer, pancreatic cancer, urothelial bladder cancer, renal cell carcinoma and glioblastoma multiforme.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('PODXL', 'Gene', '5420', (83, 88))	('poor OS', 'Disease', (93, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (198, 210))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Disease', (127, 144))	('glioblastoma multiforme', 'Disease', (198, 221))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('PODXL', 'Gene', (83, 88))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (173, 193))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (198, 221))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('high expressed', 'Var', (68, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('renal cell carcinoma', 'Disease', (173, 193))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (146, 171))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (173, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('colorectal cancer', 'Disease', (108, 125))	('urothelial bladder cancer', 'Disease', (146, 171))
623121	32615943	The result of meta-analysis showed that high expressed PODXL was significantly linked with poor OS in pancreatic cancer and glioblastoma multiforme, but not in gastric cancer, esophageal cancer or lung adenocarcinoma.	('high expressed', 'Var', (40, 54))	('gastric cancer', 'Disease', (160, 174))	('cancer', 'Disease', (113, 119))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (197, 216))	('poor OS', 'Disease', (91, 98))	('PODXL', 'Gene', (55, 60))	('cancer', 'Disease', (168, 174))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (197, 216))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('gastric cancer', 'Disease', 'MESH:D013274', (160, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('glioblastoma multiforme', 'Disease', (124, 147))	('linked', 'Reg', (79, 85))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (124, 147))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (160, 174))	('cancer', 'Disease', (187, 193))	('PODXL', 'Gene', '5420', (55, 60))	('lung adenocarcinoma', 'Disease', (197, 216))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
623151	32615943	The pooled HR and 95% CI indicated that high-expressed PODXL was significantly related to poor OS in patients with various cancers (HR = 2.33, 95% CI = 1.76-3.09, P < 0.0001) with a significant heterogeneity across these studies (I2 = 63.4%, P = 0.001) (Fig.2a).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('patients', 'Species', '9606', (101, 109))	('PODXL', 'Gene', '5420', (55, 60))	('poor OS', 'Disease', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('PODXL', 'Gene', (55, 60))	('high-expressed', 'Var', (40, 54))	('related', 'Reg', (79, 86))
623158	32615943	Subgroup analysis showed that, high expressed PODXL were linked with poor OS in colorectal cancer (HR = 1.79, 95% CI = 1.35-2.37, P < 0.0001), pancreatic cancer (HR = 2.98, 95% CI = 1.95-4.55, P < 0.0001), urothelial bladder cancer (HR = 2.14, 95% CI = 1.48-3.10) and other cancers (HR = 2.60, 95% CI = 1.45-4.66, P = 0.001), but not in patients with the gastric cancer (HR = 2.76, 95% CI = 0.45-15.84, P = 0.256).	('bladder cancer', 'Phenotype', 'HP:0009725', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (206, 231))	('gastric cancer', 'Disease', (355, 369))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('cancers', 'Disease', 'MESH:D009369', (274, 281))	('urothelial bladder cancer', 'Disease', (206, 231))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('colorectal cancer', 'Disease', (80, 97))	('high', 'Var', (31, 35))	('patients', 'Species', '9606', (337, 345))	('gastric cancer', 'Disease', 'MESH:D013274', (355, 369))	('PODXL', 'Gene', '5420', (46, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('gastric cancer', 'Phenotype', 'HP:0012126', (355, 369))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('cancers', 'Disease', (274, 281))	('PODXL', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
623159	32615943	In conclusion, high expressed level of PODXL was associated with poor OS in 6 types of cancers.	('high', 'Var', (15, 19))	('cancers', 'Disease', (87, 94))	('poor OS', 'Disease', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('PODXL', 'Gene', '5420', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('PODXL', 'Gene', (39, 44))
623160	32615943	And regarding the analysis type, we also found that the high expression of PODXL was significantly associated with the much shorter OS, when the studies were assessed with K-M curve.	('PODXL', 'Gene', '5420', (75, 80))	('PODXL', 'Gene', (75, 80))	('associated', 'Reg', (99, 109))	('high expression', 'Var', (56, 71))
623165	32615943	As a result, these correlations indicated that the high expressed PODXL was associated with the advanced biological behavior in various cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('PODXL', 'Gene', '5420', (66, 71))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('PODXL', 'Gene', (66, 71))	('associated', 'Reg', (76, 86))	('advanced biological behavior', 'CPA', (96, 124))	('high expressed', 'Var', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
623173	32615943	And among the 31 types of cancers, 9040 patients, the significant association between high expressed PODXL and poor OS was found in 3 types of cancers, including the glioblastoma multiforme, kidney renal papillary cell carcinoma and pancreatic adenocarcinoma (Table 5).	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('PODXL', 'Gene', (101, 106))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (198, 228))	('glioblastoma multiforme', 'Disease', (166, 189))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (166, 189))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('high', 'Var', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (233, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('patients', 'Species', '9606', (40, 48))	('PODXL', 'Gene', '5420', (101, 106))	('kidney renal papillary cell carcinoma and pancreatic adenocarcinoma', 'Disease', 'MESH:C538614', (191, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('cancers', 'Disease', 'MESH:D009369', (143, 150))
623185	32615943	Our meta-analysis not only indicated that high expressed PODXL was associated with poor OS, DFS or CSS in patients with cancers, but also showed that membrane expression was correlated with poor OS as well.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PODXL', 'Gene', (57, 62))	('DFS', 'Disease', (92, 95))	('CSS', 'Disease', (99, 102))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('poor OS', 'Disease', (83, 90))	('high expressed', 'Var', (42, 56))	('CSS', 'Chemical', '-', (99, 102))	('membrane expression', 'MPA', (150, 169))	('associated', 'Reg', (67, 77))	('cancers', 'Disease', (120, 127))	('patients', 'Species', '9606', (106, 114))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('PODXL', 'Gene', '5420', (57, 62))
623202	32615943	According to these reports, it could be deduced that high expressed PODXL promoted tumor progression by enhancing a series of cell changes such as EMT, cell migration and invasion.	('PODXL', 'Gene', '5420', (68, 73))	('promoted', 'PosReg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('high expressed', 'Var', (53, 67))	('PODXL', 'Gene', (68, 73))	('tumor', 'Disease', (83, 88))	('invasion', 'CPA', (171, 179))	('cell changes', 'CPA', (126, 138))	('cell migration', 'CPA', (152, 166))	('enhancing', 'PosReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('EMT', 'CPA', (147, 150))
623206	32615943	Overexpressed PODXL could be detected in peripheral blood and used as a non-invasive diagnostic biomarker for the detection of pancreatic cancer.	('pancreatic cancer', 'Disease', (127, 144))	('Overexpressed', 'Var', (0, 13))	('PODXL', 'Gene', '5420', (14, 19))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('PODXL', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))
623208	32615943	High expression of miR-509-3-5p and miR-5100 inhibited the invasion and metastasis of gastric cancers and pancreatic cancers by directly targeting PODXL, functioning as a tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (106, 123))	('inhibited', 'NegReg', (45, 54))	('PODXL', 'Gene', '5420', (147, 152))	('targeting', 'Reg', (137, 146))	('miR-509-3-5p', 'Var', (19, 31))	('miR-5100', 'Gene', '100847014', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (106, 124))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancers', 'Disease', 'MESH:D013274', (86, 101))	('pancreatic cancers', 'Disease', (106, 124))	('PODXL', 'Gene', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancers', 'Disease', (86, 101))	('gastric cancers', 'Phenotype', 'HP:0012126', (86, 101))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('pancreatic cancers', 'Disease', 'MESH:D010190', (106, 124))	('miR-5100', 'Gene', (36, 44))	('tumor', 'Disease', (171, 176))
623214	32615943	Our meta-analysis showed that PODXL plays a significant role in cancer progression, and high-expressed PODXL could be linked to aggressive biological phenotype and poor prognosis.	('PODXL', 'Gene', (30, 35))	('PODXL', 'Gene', '5420', (103, 108))	('cancer', 'Disease', (64, 70))	('linked', 'Reg', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('high-expressed', 'Var', (88, 102))	('PODXL', 'Gene', (103, 108))	('PODXL', 'Gene', '5420', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
623215	32615943	Specifically, the high expressed PODXL was correlated with poor prognosis significantly in the glioblastoma multiforme and pancreatic cancer, but not in the esophageal adenocarcinoma, gastric cancer and lung adenocarcinoma.	('high expressed', 'Var', (18, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('adenocarcinoma', 'Disease', 'MESH:D000230', (208, 222))	('glioblastoma multiforme', 'Disease', (95, 118))	('adenocarcinoma', 'Disease', 'MESH:D000230', (168, 182))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (95, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (157, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('lung adenocarcinoma', 'Disease', (203, 222))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('PODXL', 'Gene', '5420', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (203, 222))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (203, 222))	('gastric cancer', 'Disease', (184, 198))	('PODXL', 'Gene', (33, 38))	('adenocarcinoma', 'Disease', (208, 222))	('pancreatic cancer', 'Disease', (123, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('adenocarcinoma', 'Disease', (168, 182))
623220	27412386	Preclinical evidence suggests that inhibition of cyclooxygenase 2 (COX2) increases the effectiveness of chemoradiation, and observational studies in humans suggest that COX-2 inhibition may reduce esophageal cancer risk.	('COX-2', 'Gene', '4513', (169, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('humans', 'Species', '9606', (149, 155))	('COX2', 'Gene', (67, 71))	('increases', 'PosReg', (73, 82))	('inhibition', 'Var', (175, 185))	('COX-2', 'Gene', (169, 174))	('COX2', 'Gene', '5743', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cyclooxygenase 2', 'Gene', '5743', (49, 65))	('cyclooxygenase 2', 'Gene', (49, 65))	('inhibition', 'Var', (35, 45))	('esophageal cancer', 'Disease', (197, 214))	('reduce', 'NegReg', (190, 196))	('effectiveness of chemoradiation', 'CPA', (87, 118))
623239	27412386	Several lines of study suggest that non-steroidal anti-inflammatory (NSAID) medications modify the natural history of selected gastrointestinal malignancies and that inhibition of cyclooxygenase 2 (COX2) plays an important role in this effect.	('modify', 'Reg', (88, 94))	('cyclooxygenase 2', 'Gene', (180, 196))	('COX2', 'Gene', '5743', (198, 202))	('COX2', 'Gene', (198, 202))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (127, 156))	('gastrointestinal malignancies', 'Disease', (127, 156))	('natural history', 'MPA', (99, 114))	('cyclooxygenase 2', 'Gene', '5743', (180, 196))	('inhibition', 'Var', (166, 176))
623242	27412386	Several preclinical studies have shown that the selective COX2 inhibitor celecoxib works synergistically with radiation to increase cancer cell death and high expression of COX2 correlates with decreased response to radiation.	('cancer cell death', 'Disease', (132, 149))	('COX2', 'Gene', (173, 177))	('COX2', 'Gene', '5743', (173, 177))	('response', 'MPA', (204, 212))	('celecoxib', 'Chemical', 'MESH:D000068579', (73, 82))	('high', 'Var', (154, 158))	('COX2', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer cell death', 'Disease', 'MESH:D003643', (132, 149))	('expression', 'MPA', (159, 169))	('increase', 'PosReg', (123, 131))	('COX2', 'Gene', '5743', (58, 62))	('decreased', 'NegReg', (194, 203))	('decreased response to radiation', 'Phenotype', 'HP:0011133', (194, 225))	('celecoxib', 'Gene', (73, 82))
623290	27412386	In addition, one patient could not complete his chemoradiation following the development of a paraneoplastic neurologic syndrome associated with anti-Yo antibodies and was taken to surgery early.	('neurologic syndrome', 'Phenotype', 'HP:0000707', (109, 128))	('paraneoplastic neurologic syndrome', 'Disease', (94, 128))	('associated', 'Reg', (129, 139))	('patient', 'Species', '9606', (17, 24))	('paraneoplastic neurologic syndrome', 'Disease', 'MESH:D020361', (94, 128))	('anti-Yo', 'Var', (145, 152))
623313	27412386	In an exploratory analysis, we used pathological staging defined after surgical resection to segregate patients into four groups: patients with (1) pathological complete response, (2) microscopic residual disease or stage I, (3) stage II, or (4) stage III/IV cancers.	('stage II', 'Disease', (229, 237))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('microscopic residual disease', 'Var', (184, 212))	('patients', 'Species', '9606', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('patients', 'Species', '9606', (103, 111))	('IV cancers', 'Disease', (256, 266))	('IV cancers', 'Disease', 'MESH:D009369', (256, 266))
623460	24454001	In addition, laboratory findings at the time of chemotherapy were included as categorical variables based on the normal ranges and consisted of the following: hemoglobin (>11.2 g/dL vs. <=11.2 g/dL), white blood cell count (>8,630/microL vs. <=8,630/microL), platelet count (> 138x103/microL vs. <=138x103/microL), serum albumin (>3.5 g/dL vs. <=3.5 g/dL), total bilirubin (>1.5 mg/dL vs. <=1.5 mg/dL), aspartate aminotransferase (>40 U/L vs. <=40 U/L), alanine aminotransferase (>40 U/L vs. <=40 U/L), alkaline phosphatase (>128 U/L vs. <=128 U/L), and serum creatinine (>1.1 mg/dL vs. <=1.1 mg/dL).	('> 138x103/microL', 'Var', (275, 291))	('serum creatinine', 'MPA', (554, 570))	('aspartate aminotransferase', 'MPA', (403, 429))	('alanine aminotransferase', 'Gene', (454, 478))	('>128 U/L', 'Var', (525, 533))	('serum albumin', 'MPA', (315, 328))	('alanine aminotransferase', 'Gene', '2875', (454, 478))	('alkaline phosphatase', 'MPA', (503, 523))	('>40 U/L', 'Var', (480, 487))
623481	24454001	For other variables, the scoring system was as follows: weight loss (+) vs. (-) (35 points vs. 0 points), low albumin vs. normal albumin (61 points vs. 0 points), and esophagectomy (+) vs. (-) (27 points vs. 0 points).	('low albumin', 'Phenotype', 'HP:0003073', (106, 117))	('weight loss', 'Disease', 'MESH:D015431', (56, 67))	('esophagectomy', 'Disease', (167, 180))	('low', 'Var', (106, 109))	('weight loss', 'Disease', (56, 67))	('weight loss', 'Phenotype', 'HP:0001824', (56, 67))
623517	33665481	T-cells with genetically engineered chimeric antigen receptors can treat hematologic and solid malignancies by directing their antigen specificity.	('chimeric', 'Var', (36, 44))	('malignancies', 'Disease', 'MESH:D009369', (95, 107))	('antigen', 'MPA', (127, 134))	('malignancies', 'Disease', (95, 107))
623536	33665481	ALC loss during the initial phase (fractions 0-15) of partial-body RT is well described by pure exponential decay, permitting calculation of patient-specific ALC loss kinetics.	('partial-body', 'Var', (54, 66))	('patient', 'Species', '9606', (141, 148))	('loss', 'NegReg', (4, 8))	('ALC', 'MPA', (0, 3))
623547	33665481	Spleen doses (MSD, V10, V15, V20, and V25) were also significantly higher in patients with GE cancer.	('higher', 'PosReg', (67, 73))	('Spleen doses', 'MPA', (0, 12))	('V10', 'Var', (19, 22))	('V15', 'Gene', '28814', (24, 27))	('V20', 'Var', (29, 32))	('patients', 'Species', '9606', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('GE', 'Chemical', '-', (91, 93))	('V15', 'Gene', (24, 27))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
623551	33665481	Although there was some variation in the level of significance and the resulting odds ratio (OR), depending on which spleen dose parameter was used as a covariate, baseline ALC < 1500 was significantly associated with increased odds of developing both >=grade 3 and grade 4 lymphopenia.	('ALC < 1500', 'Var', (173, 183))	('lymphopenia', 'Phenotype', 'HP:0001888', (274, 285))	('lymphopenia', 'Disease', (274, 285))	('lymphopenia', 'Disease', 'MESH:D008231', (274, 285))
623575	33665481	They found that individuals who had higher MSD or higher V5-V20 relative to spleen size (dichotomized at the mean) had increased odds of developing >=grade 3 lymphopenia, with MSD being the strongest predictor of lymphopenia risk.	('lymphopenia', 'Disease', 'MESH:D008231', (158, 169))	('higher', 'PosReg', (50, 56))	('MSD', 'Var', (43, 46))	('lymphopenia', 'Phenotype', 'HP:0001888', (213, 224))	('lymphopenia', 'Disease', (213, 224))	('lymphopenia', 'Disease', (158, 169))	('V5-V20', 'Var', (57, 63))	('lymphopenia', 'Phenotype', 'HP:0001888', (158, 169))	('lymphopenia', 'Disease', 'MESH:D008231', (213, 224))
623576	33665481	Similarly, Saito et al reported that MSD and V5-V30 were linearly correlated with log-transformed nadir ALC during RT for esophageal cancer and noted that higher MSD was the only significant dosimetric predictor of grade 4 lymphopenia.	('lymphopenia', 'Disease', 'MESH:D008231', (223, 234))	('V5-V30', 'Var', (45, 51))	('lymphopenia', 'Phenotype', 'HP:0001888', (223, 234))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('lymphopenia', 'Disease', (223, 234))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
623601	33596916	Dual luciferase reporter gene assay and RNA pull down assay were used to investigate the potential crosstalk between miR-186-5p and SNHG3; and miR-186-5p and METTL3.	('METTL3', 'Gene', '56339', (158, 164))	('miR-186-5p', 'Var', (143, 153))	('METTL3', 'Gene', (158, 164))	('miR-186-5p', 'Var', (117, 127))	('SNHG3', 'Gene', (132, 137))	('miR-186-5p', 'Chemical', '-', (143, 153))	('miR-186-5p', 'Chemical', '-', (117, 127))
623604	33596916	Furthermore, SNHG3 could promote the m6A level, however miR-186-5p inhibited the m6A level through targeting METTL3.	('inhibited', 'NegReg', (67, 76))	('miR-186-5p', 'Var', (56, 66))	('targeting', 'Reg', (99, 108))	('m6A', 'Gene', (81, 84))	('m6A', 'Gene', (37, 40))	('promote', 'PosReg', (25, 32))	('miR-186-5p', 'Chemical', '-', (56, 66))	('m6A', 'Gene', '56339', (81, 84))	('m6A', 'Gene', '56339', (37, 40))	('METTL3', 'Gene', '56339', (109, 115))	('METTL3', 'Gene', (109, 115))
623605	33596916	SNHG3 interacts with miR-186-5p to negatively regulate the expression of miR-186-5p; and miR-186-5p might bind to the 3'UTR of METTL3 to regulate its expression.	('expression', 'MPA', (150, 160))	('METTL3', 'Gene', '56339', (127, 133))	('METTL3', 'Gene', (127, 133))	('negatively', 'NegReg', (35, 45))	('regulate', 'Reg', (137, 145))	('miR-186-5p', 'Gene', (73, 83))	('miR-186-5p', 'Chemical', '-', (89, 99))	('miR-186-5p', 'Chemical', '-', (21, 31))	('expression', 'MPA', (59, 69))	('bind', 'Interaction', (106, 110))	('miR-186-5p', 'Chemical', '-', (73, 83))	('miR-186-5p', 'Var', (89, 99))
623621	33596916	reported that cells with hypomethylation of mRNA m6A were more resistant to tyrosine kinase inhibitor (TKI) therapy.	('m6A', 'Gene', (49, 52))	('m6A', 'Gene', '56339', (49, 52))	('hypomethylation', 'Var', (25, 40))	('resistant', 'MPA', (63, 72))
623624	33596916	Here, we found that CDDP, CPB and L-OHP could enhance the m6A level in ESCC cells.	('CPB', 'Gene', (26, 29))	('m6A', 'Gene', '56339', (58, 61))	('L-OHP', 'Var', (34, 39))	('CPB', 'Gene', '1360', (26, 29))	('enhance', 'PosReg', (46, 53))	('CDDP', 'Chemical', '-', (20, 24))	('m6A', 'Gene', (58, 61))	('L-OHP', 'Chemical', 'MESH:D000077150', (34, 39))
623627	33596916	SNHG3 was previously found to exert oncogenic roles in a plethora of cancers: Based on current studies, SNHG3 was involved in TGF-beta, NOTCH, JAK2/STAT3 and HGF pathway to promote cancer cell proliferation, invasion and inhibit apoptosis rate.	('TGF-beta', 'Gene', (126, 134))	('JAK2', 'Gene', '3717', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('inhibit', 'NegReg', (221, 228))	('STAT3', 'Gene', (148, 153))	('SNHG3', 'Var', (104, 109))	('HGF', 'Gene', '3082', (158, 161))	('plethora of cancers', 'Disease', (57, 76))	('JAK2', 'Gene', (143, 147))	('promote', 'PosReg', (173, 180))	('STAT3', 'Gene', '6774', (148, 153))	('invasion', 'CPA', (208, 216))	('HGF', 'Gene', (158, 161))	('plethora', 'Phenotype', 'HP:0001050', (57, 65))	('plethora of cancers', 'Disease', 'MESH:D009369', (57, 76))	('cancer', 'Disease', (181, 187))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('TGF-beta', 'Gene', '7039', (126, 134))	('apoptosis rate', 'CPA', (229, 243))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('involved', 'Reg', (114, 122))
623636	33596916	The culture condition is 5% CO2 and 37  C. Cells were transfected with SNHG3 down regulated lentivirus, METTL3 and miR-186-5p up and down regulated lentivirus, which were purchased from Genechem (Shanghai, China) according to the manufacturer's instructions.	('down regulated', 'NegReg', (133, 147))	('lentivirus', 'MPA', (148, 158))	('METTL3', 'Gene', '56339', (104, 110))	('miR-186-5p', 'Var', (115, 125))	('METTL3', 'Gene', (104, 110))	('SNHG3', 'Gene', (71, 76))	('miR-186-5p', 'Chemical', '-', (115, 125))	('CO2', 'Chemical', 'MESH:D002245', (28, 31))	('lentivirus', 'Protein', (92, 102))	('down regulated', 'NegReg', (77, 91))
623648	33596916	The wild-type (WT) and mutant (Mut) binding sites of SNHG3 or METTL3 sequence was cloned into pmirGLO luciferase vector (Promega) to construct SNHG3 or METTL3-Wt and SNHG3 or METTL3-Mut, which were then co-transfected respectively with miR-186-5p mimics or NC mimics into KY-SE150 cell line.	('METTL3', 'Gene', (175, 181))	('METTL3', 'Gene', '56339', (62, 68))	('KY-SE150', 'Chemical', '-', (272, 280))	('miR-186-5p', 'Chemical', '-', (236, 246))	('METTL3', 'Gene', (62, 68))	('METTL3', 'Gene', '56339', (152, 158))	('miR-186-5p', 'Var', (236, 246))	('METTL3', 'Gene', '56339', (175, 181))	('METTL3', 'Gene', (152, 158))	('mutant', 'Var', (23, 29))
623661	33596916	Then we treated KY-SE150 with IC50 for CDDP, CPB and L-OHP respectively for 24 h. After that, we found that CDDP, CPB and L-OHP could enhance the m6A level in KYSE-150 and Eca-9706 (Fig.	('m6A', 'Gene', (146, 149))	('CDDP', 'Chemical', '-', (108, 112))	('CPB', 'Gene', '1360', (45, 48))	('L-OHP', 'Var', (122, 127))	('KY-SE150', 'Chemical', '-', (16, 24))	('CPB', 'Gene', '1360', (114, 117))	('m6A', 'Gene', '56339', (146, 149))	('L-OHP', 'Chemical', 'MESH:D000077150', (53, 58))	('L-OHP', 'Chemical', 'MESH:D000077150', (122, 127))	('CDDP', 'Var', (108, 112))	('CDDP', 'Chemical', '-', (39, 43))	('CPB', 'Gene', (45, 48))	('Eca-9706', 'CellLine', 'CVCL:E307', (172, 180))	('CPB', 'Gene', (114, 117))	('enhance', 'PosReg', (134, 141))
623666	33596916	Moreover, miR-186-5p overexpression resulted in suppressed m6A level and down-regulated METTL3 as well (Fig.	('m6A', 'Gene', '56339', (59, 62))	('miR-186-5p', 'Var', (10, 20))	('overexpression', 'PosReg', (21, 35))	('suppressed', 'NegReg', (48, 58))	('METTL3', 'Gene', '56339', (88, 94))	('miR-186-5p', 'Chemical', '-', (10, 20))	('down-regulated', 'NegReg', (73, 87))	('METTL3', 'Gene', (88, 94))	('m6A', 'Gene', (59, 62))
623668	33596916	Besides, increase in m6A level caused by platinum could be rescued by miR-186-5p overexpression and METTL3 knock down.	('m6A', 'Gene', '56339', (21, 24))	('knock down', 'Var', (107, 117))	('miR-186-5p', 'Var', (70, 80))	('METTL3', 'Gene', '56339', (100, 106))	('increase', 'PosReg', (9, 17))	('METTL3', 'Gene', (100, 106))	('miR-186-5p', 'Chemical', '-', (70, 80))	('platinum', 'Chemical', 'MESH:D010984', (41, 49))	('m6A', 'Gene', (21, 24))
623669	33596916	Therefore, we hypothesized that SNHG3 and miR-186-5p could regulate m6A level by targeting METTL3.	('METTL3', 'Gene', (91, 97))	('targeting', 'Reg', (81, 90))	('miR-186-5p', 'Chemical', '-', (42, 52))	('regulate', 'Reg', (59, 67))	('m6A', 'Gene', (68, 71))	('METTL3', 'Gene', '56339', (91, 97))	('m6A', 'Gene', '56339', (68, 71))	('miR-186-5p', 'Var', (42, 52))
623671	33596916	Besides, miR-186-5p overexpression led to decreased proliferation rate and increased apoptosis rate as well (Fig.	('proliferation rate', 'CPA', (52, 70))	('decreased', 'NegReg', (42, 51))	('apoptosis rate', 'CPA', (85, 99))	('miR-186-5p', 'Var', (9, 19))	('overexpression', 'PosReg', (20, 34))	('increased', 'PosReg', (75, 84))	('miR-186-5p', 'Chemical', '-', (9, 19))
623673	33596916	Previously, we have shown that SNHG3 knock down could lead to overexpression of miR-186-5p (Fig.	('SNHG3', 'Gene', (31, 36))	('lead to', 'Reg', (54, 61))	('miR-186-5p', 'Var', (80, 90))	('knock down', 'Var', (37, 47))	('miR-186-5p', 'Chemical', '-', (80, 90))	('overexpression', 'MPA', (62, 76))
623674	33596916	We then transfected SNHG3-WT and SNHG3-Mut in KYSE-150 respectively and found that miR-186-5p was significantly suppressed in SNHG3-WT group but not significantly influenced in SNHG3-Mut group (Fig.	('miR-186-5p', 'Chemical', '-', (83, 93))	('miR-186-5p', 'MPA', (83, 93))	('suppressed', 'NegReg', (112, 122))	('SNHG3-WT', 'Var', (126, 134))
623677	33596916	We found that miR-186-5p overexpression resulted in inhibited expression of METTL3, however, miR-186-5p knock down led to overexpression of METTL3 (Fig.	('miR-186-5p knock down', 'Var', (93, 114))	('METTL3', 'Gene', (140, 146))	('METTL3', 'Gene', '56339', (76, 82))	('expression', 'MPA', (62, 72))	('overexpression', 'PosReg', (122, 136))	('METTL3', 'Gene', (76, 82))	('inhibited', 'NegReg', (52, 61))	('miR-186-5p', 'Chemical', '-', (14, 24))	('miR-186-5p', 'Chemical', '-', (93, 103))	('METTL3', 'Gene', '56339', (140, 146))
623679	33596916	Then we have knocked miR-186-5p and METTL3 in the meantime, and found that METTL3 expression was not significantly different from that in control group (Fig.	('miR-186-5p', 'Var', (21, 31))	('METTL3', 'Gene', (75, 81))	('miR-186-5p', 'Chemical', '-', (21, 31))	('METTL3', 'Gene', '56339', (36, 42))	('METTL3', 'Gene', '56339', (75, 81))	('METTL3', 'Gene', (36, 42))
623681	33596916	Then we harvested the xenografts and found aberrant high expression of miR-186-5p and low expression of METTL3 in SNHG3 knocked down xenografts (Fig.	('expression', 'MPA', (57, 67))	('miR-186-5p', 'Chemical', '-', (71, 81))	('knocked down', 'Var', (120, 132))	('SNHG3', 'Gene', (114, 119))	('METTL3', 'Gene', '56339', (104, 110))	('expression', 'MPA', (90, 100))	('miR-186-5p', 'Gene', (71, 81))	('METTL3', 'Gene', (104, 110))	('high', 'PosReg', (52, 56))
623682	33596916	It was reported that m6A methylation took part in various biological functions, including chemotherapy resistance, by modifying target RNAs.	('target RNAs', 'MPA', (128, 139))	('m6A', 'Gene', '56339', (21, 24))	('modifying', 'Reg', (118, 127))	('chemotherapy resistance', 'CPA', (90, 113))	('methylation', 'Var', (25, 36))	('m6A', 'Gene', (21, 24))
623684	33596916	Previous studies have demonstrated that m6A methylation affects the physiological processes, including DNA damage repair, embryogenesis, heat shock responses, metastasis and proliferation.	('shock', 'Disease', (142, 147))	('methylation', 'Var', (44, 55))	('shock', 'Phenotype', 'HP:0031273', (142, 147))	('metastasis', 'CPA', (159, 169))	('physiological', 'CPA', (68, 81))	('m6A', 'Gene', (40, 43))	('embryogenesis', 'CPA', (122, 135))	('DNA damage repair', 'MPA', (103, 120))	('shock', 'Disease', 'MESH:D012769', (142, 147))	('m6A', 'Gene', '56339', (40, 43))	('proliferation', 'CPA', (174, 187))	('affects', 'Reg', (56, 63))
623689	33596916	In previous study, Taketo et.al showed that METTL3 knockdown sensitized pancreatic cancer to multiple anti-cancer reagents, including gemcitabine, 5-fluorouracil, cisplatin and irradiation as well.	('METTL3', 'Gene', (44, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pancreatic cancer', 'Disease', (72, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('sensitized', 'Reg', (61, 71))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (147, 161))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('METTL3', 'Gene', '56339', (44, 50))	('cancer', 'Disease', (107, 113))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))	('cancer', 'Disease', (83, 89))	('knockdown', 'Var', (51, 60))
623691	33596916	It was shown that ALKBH5 knockdown could suppress proliferation and migration of ESCC cells.	('ALKBH5', 'Gene', (18, 24))	('knockdown', 'Var', (25, 34))	('ALKBH5', 'Gene', '54890', (18, 24))	('suppress', 'NegReg', (41, 49))
623692	33596916	found that knockdown of FTO could sensitize tumors to anti-PD-1 treatment.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('FTO', 'Gene', '79068', (24, 27))	('sensitize', 'Reg', (34, 43))	('FTO', 'Gene', (24, 27))	('knockdown', 'Var', (11, 20))
623695	33596916	We assumed that SNHG3/miR-186-5p played important role in regulating esophageal cancer progression.	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('SNHG3/miR-186-5p', 'Var', (16, 32))	('miR-186-5p', 'Chemical', '-', (22, 32))
623696	33596916	More importantly, we found that SNHG3/miR-186-5p expression was associated with m6A level in esophageal cancer.	('associated', 'Reg', (64, 74))	('SNHG3/miR-186-5p expression', 'Var', (32, 59))	('m6A', 'Gene', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('miR-186-5p', 'Chemical', '-', (38, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('m6A', 'Gene', '56339', (80, 83))
623699	33596916	stated that SNHG3 expression was higher in highly metastatic HCC cells (HCCLM3) than lowly metastatic HCC cells, such as Hep3B and PLC/PRF/5.Besides, SNHG3 also plays important roles in regulating drug resistance: high SNHG3 expression leads to poor survival and sorafenib resistance in hepatocellular carcinoma.	('SNHG3', 'Gene', (219, 224))	('HCC', 'CellLine', 'CVCL:0C54', (102, 105))	('high', 'Var', (214, 218))	('drug resistance', 'Phenotype', 'HP:0020174', (197, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (287, 311))	('Hep3B', 'CellLine', 'CVCL:0326', (121, 126))	('sorafenib', 'Chemical', 'MESH:D000077157', (263, 272))	('resistance', 'MPA', (273, 283))	('HCC', 'CellLine', 'CVCL:0C54', (72, 75))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (287, 311))	('PLC', 'Gene', '3339', (131, 134))	('poor survival', 'CPA', (245, 258))	('PLC', 'Gene', (131, 134))	('hepatocellular carcinoma', 'Disease', (287, 311))	('HCC', 'CellLine', 'CVCL:0C54', (61, 64))
623764	32110101	However, inaccurate LN dissection and pathological evaluation may result in inappropriate pathologic nodal staging and treatment, a phenomenon called stage migration.	('men', 'Species', '9606', (124, 127))	('inaccurate', 'Var', (9, 19))	('inappropriate pathologic nodal staging', 'CPA', (76, 114))	('treatment', 'CPA', (119, 128))	('men', 'Species', '9606', (137, 140))	('result in', 'Reg', (66, 75))
623832	32110101	Patients who were classified as pN0 with micro involvement in an LN had a poor prognosis which nearly equaled to the patients with histologically detected nodal involvement (pN1).	('pN1', 'Gene', '5270', (174, 177))	('micro involvement', 'Var', (41, 58))	('Patients', 'Species', '9606', (0, 8))	('pN1', 'Gene', (174, 177))	('men', 'Species', '9606', (54, 57))	('patients', 'Species', '9606', (117, 125))	('men', 'Species', '9606', (168, 171))
623924	31118771	Kaplan-Meier survival analysis has shown that patients with RRBP1 high-expression presented poorer prognosis.	('patients', 'Species', '9606', (46, 54))	('RRBP1', 'Gene', '6238', (60, 65))	('high-expression', 'Var', (66, 81))	('RRBP1', 'Gene', (60, 65))
623925	31118771	The mean survival time of patients with RRBP1 high-expression was 56 months, which was significantly reduced than those with RRBP1 low-expression (73 months) (Table 3, Figure 3, P<0.001).	('RRBP1', 'Gene', '6238', (125, 130))	('high-expression', 'Var', (46, 61))	('RRBP1', 'Gene', '6238', (40, 45))	('RRBP1', 'Gene', (40, 45))	('patients', 'Species', '9606', (26, 34))	('reduced', 'NegReg', (101, 108))	('survival time', 'CPA', (9, 22))	('RRBP1', 'Gene', (125, 130))
623947	30733679	Overexpressions of both DDX5 and TCF12 were associated with clinicopathological features and poor prognosis of OS patients.	('associated', 'Reg', (44, 54))	('TCF12', 'Gene', (33, 38))	('DDX5', 'Gene', '1655', (24, 28))	('OS', 'Phenotype', 'HP:0002669', (111, 113))	('Overexpressions', 'Var', (0, 15))	('TCF12', 'Gene', '6938', (33, 38))	('patients', 'Species', '9606', (114, 122))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('DDX5', 'Gene', (24, 28))
623948	30733679	siRNA based knockdown of DDX5 inhibited the proliferation of MG63 cells as demonstrated by an in vitro MTS assay and 5-ethynyl-2-deoxyuridine DNA proliferation detection, and promoted apoptosis of MG63 cells measured by flow cytometry.	('si', 'Chemical', 'MESH:D012825', (190, 192))	('DDX5', 'Gene', '1655', (25, 29))	('inhibited', 'NegReg', (30, 39))	('MG63', 'CellLine', 'CVCL:0426', (197, 201))	('knockdown', 'Var', (12, 21))	('promoted', 'PosReg', (175, 183))	('si', 'Chemical', 'MESH:D012825', (0, 2))	('DDX5', 'Gene', (25, 29))	('5-ethynyl-2-deoxyuridine', 'Chemical', 'MESH:C031086', (117, 141))	('MG63', 'CellLine', 'CVCL:0426', (61, 65))	('apoptosis', 'CPA', (184, 193))	('proliferation', 'CPA', (44, 57))
623949	30733679	In addition, DDX5 knockdown inhibited the MG63 cell migration and invasion on transwell assays.	('knockdown', 'Var', (18, 27))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('MG63', 'CellLine', 'CVCL:0426', (42, 46))	('inhibited', 'NegReg', (28, 37))	('invasion on transwell assays', 'CPA', (66, 94))	('DDX5', 'Gene', (13, 17))	('DDX5', 'Gene', '1655', (13, 17))	('MG63 cell migration', 'CPA', (42, 61))
623950	30733679	Further experiments showed that DDX5 knockdown not only inhibited the expression of TCF12 but also decreased the mRNA and protein levels of Cyclin E1, an important regulator of G1-S phase progression, suggesting that DDX5 was required for the entry of cells into S phase.	('DDX5', 'Gene', (217, 221))	('TCF12', 'Gene', (84, 89))	('decreased', 'NegReg', (99, 108))	('DDX5', 'Gene', '1655', (217, 221))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('Cyclin E1', 'Gene', '898', (140, 149))	('DDX5', 'Gene', (32, 36))	('knockdown', 'Var', (37, 46))	('TCF12', 'Gene', '6938', (84, 89))	('expression', 'MPA', (70, 80))	('si', 'Chemical', 'MESH:D012825', (195, 197))	('DDX5', 'Gene', '1655', (32, 36))	('Cyclin E1', 'Gene', (140, 149))	('inhibited', 'NegReg', (56, 65))
623951	30733679	Overexpression of TCF12 reversed the cell proliferation, migration and invasion in MG63 cells induced by DDX5 knockdown accompanied by the upregulation of Cyclin E1.	('knockdown', 'Var', (110, 119))	('TCF12', 'Gene', '6938', (18, 23))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('MG63', 'CellLine', 'CVCL:0426', (83, 87))	('upregulation', 'PosReg', (139, 151))	('DDX5', 'Gene', (105, 109))	('invasion', 'CPA', (71, 79))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('migration', 'CPA', (57, 66))	('Cyclin E1', 'Gene', '898', (155, 164))	('DDX5', 'Gene', '1655', (105, 109))	('TCF12', 'Gene', (18, 23))	('cell proliferation', 'CPA', (37, 55))	('Cyclin E1', 'Gene', (155, 164))
623995	30733679	MG63 cells transfected with DDX5 small interfering RNA (siRNA) or negative control were seeded on coverslips, incubated and immunostained according to our previous protocol.	('DDX5', 'Gene', (28, 32))	('MG63', 'CellLine', 'CVCL:0426', (0, 4))	('DDX5', 'Gene', '1655', (28, 32))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('small interfering', 'Var', (33, 50))
624015	30733679	Results showed that the rates of both high DDX5 and TCF12 expression had no difference in terms of sex, age, and disease site.	('TCF12', 'Gene', '6938', (52, 57))	('high', 'Var', (38, 42))	('DDX5', 'Gene', (43, 47))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('TCF12', 'Gene', (52, 57))	('DDX5', 'Gene', '1655', (43, 47))	('si', 'Chemical', 'MESH:D012825', (121, 123))
624018	30733679	Kaplan-Meier survival analyses of the 72 OS patients with a well-documented clinical follow-up indicated that high expression of DDX5 and TCF12 were associated with shorter survival (P < 0.05, P < 0.01) (Figures 1D,E).	('shorter', 'NegReg', (165, 172))	('patients', 'Species', '9606', (44, 52))	('TCF12', 'Gene', '6938', (138, 143))	('survival', 'MPA', (173, 181))	('DDX5', 'Gene', (129, 133))	('DDX5', 'Gene', '1655', (129, 133))	('high expression', 'Var', (110, 125))	('OS', 'Phenotype', 'HP:0002669', (41, 43))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('TCF12', 'Gene', (138, 143))
624022	30733679	To further investigate the biological role of DDX5 in OS, MG63 cells were transfected with DDX5 siRNA to knock down DDX5.	('DDX5', 'Gene', '1655', (116, 120))	('MG63', 'CellLine', 'CVCL:0426', (58, 62))	('DDX5', 'Gene', (91, 95))	('DDX5', 'Gene', (46, 50))	('OS', 'Phenotype', 'HP:0002669', (54, 56))	('DDX5', 'Gene', '1655', (46, 50))	('knock down', 'Var', (105, 115))	('DDX5', 'Gene', (116, 120))	('DDX5', 'Gene', '1655', (91, 95))	('si', 'Chemical', 'MESH:D012825', (96, 98))
624026	30733679	As shown in Figure 2, DDX5 knockdown significantly inhibited the progression of OS.	('knockdown', 'Var', (27, 36))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('progression of OS', 'CPA', (65, 82))	('DDX5', 'Gene', (22, 26))	('DDX5', 'Gene', '1655', (22, 26))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('inhibited', 'NegReg', (51, 60))	('OS', 'Phenotype', 'HP:0002669', (80, 82))
624031	30733679	The results of flow cytometry indicated that DDX5 knockdown promoted the early and late apoptosis of MG63 cells.	('promoted', 'PosReg', (60, 68))	('knockdown', 'Var', (50, 59))	('MG63', 'CellLine', 'CVCL:0426', (101, 105))	('DDX5', 'Gene', (45, 49))	('si', 'Chemical', 'MESH:D012825', (94, 96))	('DDX5', 'Gene', '1655', (45, 49))
624035	30733679	siRNA based knockdown of endogenous DDX5 in MG63 cells significantly inhibited their DNA synthesis.	('knockdown', 'Var', (12, 21))	('DDX5', 'Gene', (36, 40))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('DNA synthesis', 'MPA', (85, 98))	('DDX5', 'Gene', '1655', (36, 40))	('inhibited', 'NegReg', (69, 78))	('si', 'Chemical', 'MESH:D012825', (0, 2))	('MG63', 'CellLine', 'CVCL:0426', (44, 48))	('si', 'Chemical', 'MESH:D012825', (55, 57))
624037	30733679	We detected the expression of Cyclin E1 after DDX5 knockdown in MG63 cells by qRT-PCR and Western blot.	('Cyclin E1', 'Gene', '898', (30, 39))	('DDX5', 'Gene', (46, 50))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('DDX5', 'Gene', '1655', (46, 50))	('Cyclin E1', 'Gene', (30, 39))	('MG63', 'CellLine', 'CVCL:0426', (64, 68))	('knockdown', 'Var', (51, 60))
624038	30733679	As shown in Figures 4C-E, DDX5 knockdown downregulated the expression of Cyclin E1, indicating an essential role of DDX5 in promoting the proliferation of OS cells.	('DDX5', 'Gene', '1655', (116, 120))	('promoting', 'PosReg', (124, 133))	('downregulated', 'NegReg', (41, 54))	('proliferation', 'CPA', (138, 151))	('Cyclin E1', 'Gene', '898', (73, 82))	('OS', 'Phenotype', 'HP:0002669', (155, 157))	('expression', 'MPA', (59, 69))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('DDX5', 'Gene', (26, 30))	('DDX5', 'Gene', (116, 120))	('DDX5', 'Gene', '1655', (26, 30))	('Cyclin E1', 'Gene', (73, 82))	('knockdown', 'Var', (31, 40))
624045	30733679	To determine whether TCF12 responds for the oncogenic effects of DDX5 in OS cells, MG63 cells were co-transfected with si-Con and pENTER-Con, si-DDX5 and pENTER-Con, si-DDX5 and pENTER-TCF12.	('OS', 'Phenotype', 'HP:0002669', (73, 75))	('DDX5', 'Gene', (65, 69))	('TCF12', 'Gene', '6938', (21, 26))	('DDX5', 'Gene', '1655', (65, 69))	('DDX5', 'Gene', (145, 149))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('MG63', 'CellLine', 'CVCL:0426', (83, 87))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('DDX5', 'Gene', (169, 173))	('si-Con', 'Var', (119, 125))	('DDX5', 'Gene', '1655', (169, 173))	('si-Con', 'Chemical', '-', (119, 125))	('TCF12', 'Gene', (185, 190))	('DDX5', 'Gene', '1655', (145, 149))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('TCF12', 'Gene', (21, 26))	('TCF12', 'Gene', '6938', (185, 190))
624048	30733679	Furthermore, cell proliferation, migration and invasion induced by DDX5 knockdown were reversed by TCF12 overexpression (Figures 6C-H).	('si', 'Chemical', 'MESH:D012825', (115, 117))	('cell proliferation', 'CPA', (13, 31))	('TCF12', 'Gene', (99, 104))	('migration', 'CPA', (33, 42))	('DDX5', 'Gene', (67, 71))	('overexpression', 'PosReg', (105, 119))	('invasion', 'CPA', (47, 55))	('DDX5', 'Gene', '1655', (67, 71))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('knockdown', 'Var', (72, 81))	('TCF12', 'Gene', '6938', (99, 104))
624049	30733679	Collectively, these data further demonstrated that overexpression of TCF12 reversed the cell proliferation, migration and invasion in MG63 cells induced by DDX5 knockdown accompanied by the upregulation of Cyclin E1.	('Cyclin E1', 'Gene', (206, 215))	('migration', 'CPA', (108, 117))	('MG63', 'CellLine', 'CVCL:0426', (134, 138))	('TCF12', 'Gene', '6938', (69, 74))	('DDX5', 'Gene', (156, 160))	('upregulation', 'PosReg', (190, 202))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('invasion', 'CPA', (122, 130))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('DDX5', 'Gene', '1655', (156, 160))	('Cyclin E1', 'Gene', '898', (206, 215))	('knockdown', 'Var', (161, 170))	('cell proliferation', 'CPA', (88, 106))	('TCF12', 'Gene', (69, 74))	('overexpression', 'PosReg', (51, 65))
624052	30733679	In this study, we found that the expression of DDX5 was significantly increased in OS, and the high expression of DDX5 was associated with clinicopathological features and poor prognosis of OS patients, suggesting that DDX5 might be an important prognostic biomarker of OS.	('DDX5', 'Gene', '1655', (219, 223))	('associated', 'Reg', (123, 133))	('patients', 'Species', '9606', (193, 201))	('si', 'Chemical', 'MESH:D012825', (183, 185))	('OS', 'Phenotype', 'HP:0002669', (190, 192))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('increased', 'PosReg', (70, 79))	('OS', 'Phenotype', 'HP:0002669', (270, 272))	('high', 'Var', (95, 99))	('DDX5', 'Gene', (114, 118))	('DDX5', 'Gene', '1655', (114, 118))	('DDX5', 'Gene', (47, 51))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('expression', 'MPA', (33, 43))	('DDX5', 'Gene', '1655', (47, 51))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('DDX5', 'Gene', (219, 223))	('OS', 'Phenotype', 'HP:0002669', (83, 85))
624054	30733679	Furthermore, we found that knockdown of DDX5 not only inhibited the proliferation, invasion and metastasis, but also induced the apoptosis of MG63 cells.	('inhibited', 'NegReg', (54, 63))	('knockdown', 'Var', (27, 36))	('si', 'Chemical', 'MESH:D012825', (87, 89))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('apoptosis', 'CPA', (129, 138))	('DDX5', 'Gene', (40, 44))	('MG63', 'CellLine', 'CVCL:0426', (142, 146))	('DDX5', 'Gene', '1655', (40, 44))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('induced', 'Reg', (117, 124))
624059	30733679	DDX5 overexpression promotes the proliferation and progression of non-small cell lung cancer cells by increasing beta-catenin, which is a signaling molecule of Wnt signaling pathway, and activating the downstream gene c-Myc.	('si', 'Chemical', 'MESH:D012825', (138, 140))	('c-Myc', 'Gene', '4609', (218, 223))	('overexpression', 'Var', (5, 19))	('non-small cell lung cancer', 'Disease', (66, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('DDX5', 'Gene', '1655', (0, 4))	('promotes', 'PosReg', (20, 28))	('increasing', 'PosReg', (102, 112))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('DDX5', 'Gene', (0, 4))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (66, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('activating', 'PosReg', (187, 197))	('si', 'Chemical', 'MESH:D012825', (108, 110))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('proliferation', 'CPA', (33, 46))	('beta-catenin', 'Gene', (113, 125))	('progression', 'CPA', (51, 62))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (66, 92))	('c-Myc', 'Gene', (218, 223))	('beta-catenin', 'Gene', '1499', (113, 125))
624070	30733679	The results showed that DDX5 binds to TCF12 and DDX5 knockdown reduced TCF12 expression, decreasing Cyclin E1 and ultimately stimulating cell cycle progression.	('knockdown', 'Var', (53, 62))	('DDX5', 'Gene', '1655', (24, 28))	('stimulating', 'Reg', (125, 136))	('DDX5', 'Gene', '1655', (48, 52))	('TCF12', 'Gene', (71, 76))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('TCF12', 'Gene', (38, 43))	('TCF12', 'Gene', '6938', (71, 76))	('TCF12', 'Gene', '6938', (38, 43))	('DDX5', 'Gene', (24, 28))	('DDX5', 'Gene', (48, 52))	('reduced', 'NegReg', (63, 70))	('decreasing', 'NegReg', (89, 99))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('Cyclin E1', 'Gene', (100, 109))	('cell cycle progression', 'CPA', (137, 159))	('expression', 'MPA', (77, 87))	('Cyclin E1', 'Gene', '898', (100, 109))	('si', 'Chemical', 'MESH:D012825', (83, 85))
624077	30733679	The disruption of the cell cycle checkpoint leads to the malignant transformation of human cells.	('cell', 'CPA', (22, 26))	('disruption', 'Var', (4, 14))	('leads to', 'Reg', (44, 52))	('malignant transformation of human cells', 'CPA', (57, 96))	('human', 'Species', '9606', (85, 90))
624080	30733679	Moreover, the result of EdU DNA proliferation in vitro detection showed that DDX5 knockdown decreased the number of cells entering the S phase, which indicated that DDX5 is required for G1-S phase progression.	('si', 'Chemical', 'MESH:D012825', (204, 206))	('knockdown', 'Var', (82, 91))	('DDX5', 'Gene', (77, 81))	('EdU', 'Chemical', 'MESH:C031086', (24, 27))	('decreased', 'NegReg', (92, 101))	('DDX5', 'Gene', '1655', (77, 81))	('DDX5', 'Gene', (165, 169))	('DDX5', 'Gene', '1655', (165, 169))
624126	28670162	To maintain the ratio of the scanning segments of the normal esophagi in the reference group to the anatomic distribution of the ESCCs, 3 healthy participants randomly underwent T2*WI of the upper thoracic portion of the esophagus, 16 healthy participants randomly received T2*WI of the mid-thoracic portion, and the remaining 1 healthy participant underwent T2*WI of lower thoracic portion.	('participant', 'Species', '9606', (146, 157))	('participant', 'Species', '9606', (337, 348))	('participants', 'Species', '9606', (243, 255))	('T2*WI', 'Var', (274, 279))	('T2*WI', 'Var', (178, 183))	('participants', 'Species', '9606', (146, 158))	('participant', 'Species', '9606', (243, 254))
624165	26609239	Over the past decades, a large number of studies focused on aberrant expression of protein-coding RNAs in cancers, which provided many promising approaches for cancer diagnosis and treatment.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('RNAs', 'Gene', (98, 102))	('aberrant', 'Var', (60, 68))
624166	26609239	In recent years, however, along with the advance of high-resolution microarray and genome-wide sequencing technology, increasing evidence obtained from the studies of genomics and transcriptomics suggest that non-coding RNAs can also be applied as new biomarkers for cancer detection and molecular targets for cancer therapy.	('cancer', 'Disease', (310, 316))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('non-coding RNAs', 'Var', (209, 224))	('cancer', 'Disease', 'MESH:D009369', (310, 316))
624169	26609239	A number of studies demonstrated the deregulation of lncR-NAs in cancers, suggesting that the aberrant expression of lncRNAs is associated with tumorigenesis, metastasis, and prognosis of cancer.	('tumor', 'Disease', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancers', 'Disease', (65, 72))	('metastasis', 'CPA', (159, 169))	('expression', 'MPA', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('associated', 'Reg', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cancer', 'Disease', (188, 194))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('aberrant', 'Var', (94, 102))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('lncRNAs', 'Gene', (117, 124))
624172	26609239	MALAT1 silencing decreased renal cell carcinoma cell proliferation and invasion and increased apoptosis.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (27, 47))	('MALAT1', 'Gene', '378938', (0, 6))	('decreased renal cell carcinoma', 'Disease', 'MESH:C538614', (17, 47))	('MALAT1', 'Gene', (0, 6))	('invasion', 'CPA', (71, 79))	('increased', 'PosReg', (84, 93))	('decreased renal cell carcinoma', 'Disease', (17, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('apoptosis', 'CPA', (94, 103))	('silencing', 'Var', (7, 16))
624177	26609239	In order to determine whether aberrant expression of lncR-NAs is a cause for cancer or only a consequence of cancerous phenotype, numerous studies have investigated the biological functions of lncRNAs during the progression of cancer as well as mechanistic associations involved.	('aberrant', 'Var', (30, 38))	('lncR-NAs', 'Gene', (53, 61))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('investigated', 'Reg', (152, 164))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
624187	26609239	In vitro study, inhibition of HOTAIR expression was shown to decrease the invasiveness and migration of ESCC cells and significantly increase the response of ESCC cells to apoptosis induction.	('response', 'MPA', (146, 154))	('decrease', 'NegReg', (61, 69))	('HOTAIR', 'Gene', (30, 36))	('invasiveness', 'CPA', (74, 86))	('increase', 'PosReg', (133, 141))	('HOTAIR', 'Gene', '100124700', (30, 36))	('inhibition', 'Var', (16, 26))
624194	26609239	CpG islands in POU3F3 were densely methylated when lnc-POU3F3 was overexpressed in the cells.	('POU3F3', 'Gene', (55, 61))	('POU3F3', 'Gene', '5455', (55, 61))	('densely', 'PosReg', (27, 34))	('POU3F3', 'Gene', (15, 21))	('POU3F3', 'Gene', '5455', (15, 21))	('methylated', 'Var', (35, 45))
624195	26609239	Consistently, the methylation at these sites was reduced by silencing lnc-POU3F3.	('reduced', 'NegReg', (49, 56))	('POU3F3', 'Gene', (74, 80))	('methylation', 'MPA', (18, 29))	('POU3F3', 'Gene', '5455', (74, 80))	('silencing', 'Var', (60, 69))
624202	26609239	FOXC1 and FOXCUT expression levels were significantly elevated in tumor samples from patients with the presence of metastasis and poor differentiation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FOXCUT', 'Gene', (10, 16))	('poor', 'Var', (130, 134))	('metastasis', 'CPA', (115, 125))	('tumor', 'Disease', (66, 71))	('elevated', 'PosReg', (54, 62))	('FOXC1', 'Gene', '2296', (0, 5))	('FOXCUT', 'Gene', '101927703', (10, 16))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('FOXC1', 'Gene', (0, 5))
624204	26609239	And, patients with high expression of FOXCUT or FOXC1 had a significantly poor prognosis.	('FOXCUT', 'Gene', (38, 44))	('FOXC1', 'Gene', (48, 53))	('patients', 'Species', '9606', (5, 13))	('high expression', 'Var', (19, 34))	('FOXCUT', 'Gene', '101927703', (38, 44))	('FOXC1', 'Gene', '2296', (48, 53))
624205	26609239	These data suggest that high expression of FOXCUT or FOXC1 might play an important role in the tumorigenesis, development, progression of ESCC, and both of them may serve as prognostic biomarkers for ESCC patients.	('patients', 'Species', '9606', (205, 213))	('FOXCUT', 'Gene', '101927703', (43, 49))	('play', 'Reg', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('FOXCUT', 'Gene', (43, 49))	('development', 'CPA', (110, 121))	('FOXC1', 'Gene', (53, 58))	('high', 'Var', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('FOXC1', 'Gene', '2296', (53, 58))	('expression', 'MPA', (29, 39))	('ESCC', 'Disease', (138, 142))	('ESCC', 'Disease', (200, 204))	('tumor', 'Disease', (95, 100))
624208	26609239	Its silence can significantly inhibit the growth of prostate cancer cells by inactivation of androgen receptor.	('androgen receptor', 'Gene', (93, 110))	('growth', 'CPA', (42, 48))	('silence', 'Var', (4, 11))	('inhibit', 'NegReg', (30, 37))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('androgen receptor', 'Gene', '367', (93, 110))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('inactivation', 'NegReg', (77, 89))	('prostate cancer', 'Disease', (52, 67))
624211	26609239	Furthermore, knockdown of PlncRNA-1 reduced cell proliferation and increased the apoptosis in vitro.	('PlncRNA-1', 'Gene', '100506428', (26, 35))	('cell proliferation', 'CPA', (44, 62))	('PlncRNA-1', 'Gene', (26, 35))	('apoptosis in vitro', 'CPA', (81, 99))	('increased', 'PosReg', (67, 76))	('reduced', 'NegReg', (36, 43))	('knockdown', 'Var', (13, 22))
624213	26609239	Overexpression of PlncRNA-1 is correlated with advanced tumor stage and lymph node metastasis, and may serve as a potential prognostic marker and therapeutic target for ESCC.	('ESCC', 'Disease', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('PlncRNA-1', 'Gene', '100506428', (18, 27))	('Overexpression', 'Var', (0, 14))	('PlncRNA-1', 'Gene', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('lymph node metastasis', 'CPA', (72, 93))
624216	26609239	Inhibition of MALAT1 suppressed tumor growth in vitro and in vivo, as well as cell migratory and invasive capacity, confirming its oncogenic roles in ESCC.	('suppressed', 'NegReg', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('ESCC', 'Disease', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('MALAT1', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (32, 37))
624218	26609239	Silencing of MALAT significantly suppressed the proliferation of ESCC cells by arresting cell cycle at G2/M, which may be due to MALAT1-mediated upregulation of p21 and p27 expression and/or the inhibition of B-MYB expression.	('arresting', 'NegReg', (79, 88))	('MALAT1', 'Gene', (129, 135))	('p21', 'Gene', (161, 164))	('upregulation', 'PosReg', (145, 157))	('p21', 'Gene', '644914', (161, 164))	('cell cycle at G2/M', 'CPA', (89, 107))	('proliferation', 'CPA', (48, 61))	('B-MYB', 'Gene', '4605', (209, 214))	('MALAT', 'Gene', (13, 18))	('p27', 'Gene', '3429', (169, 172))	('inhibition', 'NegReg', (195, 205))	('B-MYB', 'Gene', (209, 214))	('expression', 'MPA', (173, 183))	('p27', 'Gene', (169, 172))	('Silencing', 'Var', (0, 9))	('suppressed', 'NegReg', (33, 43))	('MALAT1', 'Gene', '378938', (129, 135))	('expression', 'MPA', (215, 225))
624219	26609239	Consistently, the capacities of invasion and migration of ESCC cells were inhibited after overexpression of miR-101, miR-217, or MALAT1 siRNA, which may be attributed to the deregulation of downstream target genes of MALAT1, such as MIA2, HNF4G, ROBO1, CCT4, and CTHRC1.	('MALAT1', 'Gene', (129, 135))	('miR-217', 'Gene', (117, 124))	('CTHRC1', 'Gene', '115908', (263, 269))	('miR', 'Gene', (108, 111))	('miR', 'Gene', (117, 120))	('MALAT1', 'Gene', '378938', (129, 135))	('ROBO1', 'Gene', (246, 251))	('inhibited', 'NegReg', (74, 83))	('HNF4G', 'Gene', '3174', (239, 244))	('CTHRC1', 'Gene', (263, 269))	('CCT4', 'Gene', (253, 257))	('overexpression', 'PosReg', (90, 104))	('MIA2', 'Gene', (233, 237))	('ROBO1', 'Gene', '6091', (246, 251))	('CCT4', 'Gene', '10575', (253, 257))	('MALAT1', 'Gene', (217, 223))	('miR-217', 'Gene', '406999', (117, 124))	('MIA2', 'Gene', '4253', (233, 237))	('HNF4G', 'Gene', (239, 244))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', '220972', (117, 120))	('deregulation', 'Var', (174, 186))	('MALAT1', 'Gene', '378938', (217, 223))
624225	26609239	In addition, SPRY4-IT1 high expression was correlated with lower overall survival rates and could be an independent prognostic factor in patients with ESCC.	('high', 'Var', (23, 27))	('lower', 'NegReg', (59, 64))	('ESCC', 'Disease', (151, 155))	('patients', 'Species', '9606', (137, 145))	('SPRY4-IT1', 'Gene', (13, 22))	('overall', 'CPA', (65, 72))
624226	26609239	Knockdown of SPRY4-IT1 also significantly reduced tumor weight and volume in nude mice compared with control, suggesting that knockdown of SPRY4-IT1 can suppress the development of ESCC in vivo.	('reduced', 'NegReg', (42, 49))	('development of ESCC', 'CPA', (166, 185))	('suppress', 'NegReg', (153, 161))	('nude mice', 'Species', '10090', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('knockdown', 'Var', (126, 135))	('tumor', 'Disease', (50, 55))	('SPRY4-IT1', 'Var', (139, 148))
624229	26609239	Patients with LOI of IGF2 in their tumor had deeper degree of lymph node involvement and were more likely to occur metastasis than those with MOI of IGF2.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('IGF2', 'Gene', '3481', (149, 153))	('LOI', 'Var', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IGF2', 'Gene', (149, 153))	('tumor', 'Disease', (35, 40))	('IGF2', 'Gene', '3481', (21, 25))	('Patients', 'Species', '9606', (0, 8))	('occur metastasis', 'CPA', (109, 125))	('IGF2', 'Gene', (21, 25))
624230	26609239	In addition, they found that H19 CBS6 hypermethylation is related to LOI of IGF2 in human ESCC and IGF2 LOI usually leads to an overexpression of IGF2, which was correlated with lymph node involvement, neoplastic grade, and tumor metastasis.	('overexpression', 'PosReg', (128, 142))	('LOI', 'Var', (69, 72))	('IGF2', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('LOI', 'Var', (104, 107))	('tumor metastasis', 'Disease', 'MESH:D009362', (224, 240))	('IGF2', 'Gene', (76, 80))	('IGF2', 'Gene', '3481', (99, 103))	('tumor metastasis', 'Disease', (224, 240))	('H19', 'Gene', '283120', (29, 32))	('human', 'Species', '9606', (84, 89))	('H19', 'Gene', (29, 32))	('IGF2', 'Gene', (99, 103))	('IGF2', 'Gene', '3481', (76, 80))	('IGF2', 'Gene', '3481', (146, 150))	('leads to', 'Reg', (116, 124))
624231	26609239	Therefore, H19 CBS6 methylation potentially represents a novel clinically relevant epigenetic marker to identify individuals at increased risk for the occurrence, progression, and prognosis of ESCC.	('H19', 'Gene', (11, 14))	('methylation', 'Var', (20, 31))	('H19', 'Gene', '283120', (11, 14))	('ESCC', 'Disease', (193, 197))
624236	26609239	SiRNA-mediated knockdown of UCA1 significantly decreased proliferation, migration, and invasion capability of EC cells compared with the control group, which indicated that downregulation of UCA1 can suppress the development of EC.	('invasion capability', 'CPA', (87, 106))	('migration', 'CPA', (72, 81))	('knockdown', 'Var', (15, 24))	('decreased', 'NegReg', (47, 56))	('UCA1', 'Gene', '652995', (191, 195))	('UCA1', 'Gene', (191, 195))	('suppress', 'NegReg', (200, 208))	('development of', 'CPA', (213, 227))	('downregulation', 'Var', (173, 187))	('proliferation', 'CPA', (57, 70))	('UCA1', 'Gene', '652995', (28, 32))	('UCA1', 'Gene', (28, 32))
624247	26609239	Alterations in methylation of protein-coding genes are associated with Barrett's esophagus and EAC.	('EAC', 'Phenotype', 'HP:0011459', (95, 98))	("Barrett's esophagus", 'Disease', (71, 90))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (71, 90))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (55, 65))	('EAC', 'Disease', (95, 98))	('methylation', 'MPA', (15, 26))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (71, 90))
624249	26609239	This elevated expression of AFAP1-AS1, its role in cell proliferation and apoptosis, and its effect on cell migration and invasion suggest that dysregulated expression of AFAP1-AS1 is involved in development or progression of EAC.	('AS1', 'Gene', '5729', (177, 180))	('AS1', 'Gene', (177, 180))	('elevated', 'PosReg', (5, 13))	('AFAP1', 'Gene', (171, 176))	('AFAP1', 'Gene', '60312', (171, 176))	('EAC', 'Phenotype', 'HP:0011459', (226, 229))	('expression', 'MPA', (14, 24))	('AFAP1', 'Gene', '60312', (28, 33))	('AFAP1', 'Gene', (28, 33))	('EAC', 'Disease', (226, 229))	('AS1', 'Gene', '5729', (34, 37))	('AS1', 'Gene', (34, 37))	('involved', 'Reg', (184, 192))	('dysregulated', 'Var', (144, 156))
624254	26609239	Further mechanistic studies revealed that HNF1A-AS1 knockdown preferentially affect gene expression due to assembly of chromatin and the nucleosome, which is essential for cell-cycle progression.	('preferentially', 'PosReg', (62, 76))	('gene expression', 'MPA', (84, 99))	('HNF1A-AS1', 'Gene', '283460', (42, 51))	('assembly', 'MPA', (107, 115))	('affect', 'Reg', (77, 83))	('knockdown', 'Var', (52, 61))	('HNF1A-AS1', 'Gene', (42, 51))
624255	26609239	As discussed earlier, H19, as a well-known cancer-related lncRNA, is inhibited by HNF1A-AS1 knockdown, indicating a functional correlation between HNF1A-AS1 and H19 in primary EACs.	('H19', 'Gene', (161, 164))	('HNF1A-AS1', 'Gene', (147, 156))	('HNF1A-AS1', 'Gene', '283460', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('knockdown', 'Var', (92, 101))	('H19', 'Gene', '283120', (22, 25))	('HNF1A-AS1', 'Gene', (82, 91))	('primary EACs', 'Disease', (168, 180))	('H19', 'Gene', (22, 25))	('inhibited', 'NegReg', (69, 78))	('HNF1A-AS1', 'Gene', '283460', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('EAC', 'Phenotype', 'HP:0011459', (176, 179))	('H19', 'Gene', '283120', (161, 164))
624257	26609239	It was first reported to be a tumor suppressor unit in osteosarcoma and depletion of this lncRNA promoted proliferation of normal osteoblasts through regulation of apoptotic and cell-cycle transcripts as well as VEGF receptor 1.	('promoted', 'PosReg', (97, 105))	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('osteosarcoma', 'Disease', (55, 67))	('cell-cycle', 'CPA', (178, 188))	('osteosarcoma', 'Disease', 'MESH:D012516', (55, 67))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('depletion', 'Var', (72, 81))	('apoptotic', 'MPA', (164, 173))	('proliferation', 'CPA', (106, 119))	('tumor', 'Disease', (30, 35))	('regulation', 'Reg', (150, 160))
624258	26609239	Decreased LOC285194 expression has been reported in several cancers, and was strongly associated with malignant potential and poor patient prognosis.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('expression', 'MPA', (20, 30))	('LOC285194', 'Var', (10, 19))	('cancers', 'Disease', (60, 67))	('malignant potential', 'CPA', (102, 121))	('Decreased', 'NegReg', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('associated', 'Reg', (86, 96))	('patient', 'Species', '9606', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
624259	26609239	Our previous studies demonstrated that LOC285194 expression was significantly downregulated in ESCC tumor tissues when compared with the adjacent normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('expression', 'MPA', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('LOC285194', 'Var', (39, 48))	('downregulated', 'NegReg', (78, 91))
624260	26609239	Low expression of LOC285194 was associated with larger tumor size, advanced TNM stage, more lymph node metastases, and distant metastases.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Low', 'NegReg', (0, 3))	('metastases', 'Disease', 'MESH:D009362', (127, 137))	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('expression', 'MPA', (4, 14))	('LOC285194', 'Var', (18, 27))	('tumor', 'Disease', (55, 60))	('TNM', 'Gene', '10178', (76, 79))	('more', 'PosReg', (87, 91))	('metastases', 'Disease', (127, 137))	('metastases', 'Disease', (103, 113))	('TNM', 'Gene', (76, 79))
624261	26609239	Furthermore, decreased expression of LOC285194 could potentially serve as a molecular marker to predict the clinical outcomes of ESCC patients after surgery, and select patients who will benefit from the preoperative chemoradiotherapy.	('LOC285194', 'Var', (37, 46))	('decreased', 'NegReg', (13, 22))	('patients', 'Species', '9606', (169, 177))	('ESCC', 'Disease', (129, 133))	('patients', 'Species', '9606', (134, 142))	('expression', 'MPA', (23, 33))
624301	24143297	Because blind dissection can cause severe bleeding by cutting large perforating vessels during procedure, direct visualization of submucosal layer is very important to prevent bleeding.	('bleeding', 'Disease', (176, 184))	('bleeding', 'Disease', 'MESH:D006470', (42, 50))	('bleeding', 'Disease', (42, 50))	('cause', 'Reg', (29, 34))	('blind dissection', 'Var', (8, 24))	('bleeding', 'Disease', 'MESH:D006470', (176, 184))
624390	24143297	The quality of bowel preparation can be enhanced by split-dose regimens, which are superior to single-dose regimens.	('men', 'Species', '9606', (67, 70))	('men', 'Species', '9606', (111, 114))	('enhanced', 'PosReg', (40, 48))	('split-dose regimens', 'Var', (52, 71))
624429	24143297	conducted a meta-analysis including a total of 588 patients and found that ESWL was effective in relieving main pancreatic duct obstruction and in alleviating pain in CP, most often in combination with endoscopic therapy.	('pancreatic duct obstruction', 'Disease', 'MESH:D021441', (112, 139))	('pain', 'Phenotype', 'HP:0012531', (159, 163))	('ESWL', 'Var', (75, 79))	('pain', 'Disease', 'MESH:D010146', (159, 163))	('pain', 'Disease', (159, 163))	('patients', 'Species', '9606', (51, 59))	('duct obstruction', 'Phenotype', 'HP:0000579', (123, 139))	('alleviating', 'NegReg', (147, 158))	('pancreatic duct obstruction', 'Disease', (112, 139))
624475	19062237	Physical activity was associated with reduced risk of esophageal and gastric adenocarcinomas but was unrelated to esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('reduced', 'NegReg', (38, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (114, 148))	('Physical activity', 'Var', (0, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('esophageal squamous cell carcinoma', 'Disease', (114, 148))	('esophageal and gastric adenocarcinomas', 'Disease', 'MESH:D013274', (54, 92))
624485	19062237	For example, BMI is associated with increased risk of esophageal adenocarcinoma but may be related to decreased risk of esophageal squamous cell carcinoma.	('BMI', 'Var', (13, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (54, 79))	('esophageal adenocarcinoma', 'Disease', (54, 79))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (54, 79))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))
624511	19062237	Esophageal carcinoma was further classified by histologic codes as squamous cell carcinoma (8050-8076) or adenocarcinoma (8140-8141, 8190-8231, 8260-8263, 8310, 8430, 8480-8490, 8560, 8570-8572).	('Esophageal carcinoma', 'Disease', (0, 20))	('8480-8490', 'Var', (167, 176))	('8050-8076', 'Var', (92, 101))	('8140-8141', 'Var', (122, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adenocarcinoma', 'Disease', (106, 120))	('8190-8231', 'Var', (133, 142))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (0, 20))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (0, 20))	('adenocarcinoma', 'Disease', 'MESH:D000230', (106, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('squamous cell carcinoma', 'Disease', (67, 90))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 90))	('8430', 'Var', (161, 165))	('8260-8263', 'Var', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('8310', 'Var', (155, 159))
624545	19062237	In this large prospective study of U.S. men and women, increased physical activity was associated with decreased risk of adenocarcinomas of the upper gastrointestinal tract.	('physical', 'Var', (65, 73))	('decreased', 'NegReg', (103, 112))	('adenocarcinomas of the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (121, 172))	('men', 'Species', '9606', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('men', 'Species', '9606', (40, 43))	('women', 'Species', '9606', (48, 53))	('increased physical activity', 'Phenotype', 'HP:0003546', (55, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))
624582	19062237	Physical activity improves insulin sensitivity and lowers circulating insulin, thereby enhancing insulin-like growth factor (IGF) binding protein-1, which reduces bioavailable IGF-1.	('reduces bioavailable IGF-1', 'Phenotype', 'HP:0030269', (155, 181))	('insulin', 'Gene', '3630', (97, 104))	('reduces', 'NegReg', (155, 162))	('bioavailable', 'MPA', (163, 175))	('Physical', 'Var', (0, 8))	('lowers', 'NegReg', (51, 57))	('insulin-like growth factor (IGF) binding protein-1', 'Gene', '3484', (97, 147))	('enhancing', 'PosReg', (87, 96))	('insulin', 'Gene', (27, 34))	('insulin', 'Gene', (70, 77))	('insulin', 'Gene', '3630', (27, 34))	('improves', 'PosReg', (18, 26))	('insulin', 'Gene', '3630', (70, 77))	('IGF-1', 'Gene', '3479', (176, 181))	('IGF-1', 'Gene', (176, 181))	('insulin', 'Gene', (97, 104))
624591	32370538	Encouraging results in animal models have been obtained with SG1002 in heart failure, atherosclerosis, ischemic damage, and Duchenne muscular dystrophy; with TC-2153 in Alzheimer's disease, schizophrenia, age-related memory decline, fragile X syndrome, and cocaine addiction; and with DATS in brain, colon, gastric, and breast cancer.	('schizophrenia', 'Disease', 'MESH:D012559', (190, 203))	('ischemic damage', 'Disease', 'MESH:D003324', (103, 118))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (133, 151))	('as', 'Gene', '112935892', (323, 325))	('fragile X syndrome', 'Disease', 'MESH:D005600', (233, 251))	('schizophrenia', 'Phenotype', 'HP:0100753', (190, 203))	('SG1002', 'Chemical', '-', (61, 67))	('memory decline', 'Phenotype', 'HP:0002354', (217, 231))	('DATS', 'Chemical', 'MESH:C042577', (285, 289))	('heart failure', 'Disease', (71, 84))	('ischemic damage', 'Disease', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('as', 'Gene', '112935892', (185, 187))	('brain', 'Disease', (293, 298))	('fragile X syndrome', 'Disease', (233, 251))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (169, 188))	("Alzheimer's disease", 'Disease', (169, 188))	('SG1002', 'Var', (61, 67))	('atherosclerosis', 'Disease', 'MESH:D050197', (86, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (320, 333))	('TC-2153', 'CellLine', 'CVCL:K915', (158, 165))	('atherosclerosis', 'Disease', (86, 101))	('di', 'Disease', 'MESH:D003643', (267, 269))	('schizophrenia', 'Disease', (190, 203))	('Duchenne muscular dystrophy', 'Disease', (124, 151))	('heart failure', 'Phenotype', 'HP:0001635', (71, 84))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (169, 188))	('TC-2153', 'Var', (158, 165))	('Duchenne muscular dystrophy', 'Disease', 'MESH:D020388', (124, 151))	('heart failure', 'Disease', 'MESH:D006333', (71, 84))	('di', 'Disease', 'MESH:D003643', (181, 183))	('breast cancer', 'Disease', 'MESH:D001943', (320, 333))	('colon', 'Disease', (300, 305))	('atherosclerosis', 'Phenotype', 'HP:0002621', (86, 101))	('breast cancer', 'Disease', (320, 333))	('as', 'Gene', '112935892', (308, 310))
624603	32370538	H2S, through SS and transcription factor Nrf2, is capable of transactivating more than 200 cytoprotective genes, thereby upregulating transcription of multiple antioxidant enzymes, phase II detoxifying enzymes, enzymes that catalyze the synthesis and regeneration of GSH, and enzymes in charge of regulating NADPH regeneration, mitochondrial bioenergetics, and lipid metabolism.	('of', 'Gene', '6688', (58, 60))	('et', 'Gene', '79157', (368, 370))	('lipid', 'Chemical', 'MESH:D008055', (361, 366))	('the', 'Gene', '25085', (113, 116))	('et', 'Gene', '79157', (350, 352))	('H2S', 'Var', (0, 3))	('the', 'Gene', '25085', (240, 243))	('transcription', 'MPA', (134, 147))	('Nrf2', 'Gene', (41, 45))	('H2S', 'Chemical', 'MESH:D003903', (0, 3))	('et', 'Gene', '79157', (191, 193))	('of', 'Gene', '6688', (264, 266))	('upregulating', 'PosReg', (121, 133))	('GSH', 'Chemical', '-', (267, 270))	('NADPH', 'Chemical', 'MESH:D009249', (308, 313))	('of', 'Gene', '6688', (294, 296))	('mitochondrial', 'CPA', (328, 341))	('transactivating', 'PosReg', (61, 76))	('SS', 'Chemical', '-', (13, 15))	('as', 'Gene', '112935892', (183, 185))	('the', 'Gene', (233, 236))	('cytoprotective genes', 'Gene', (91, 111))	('rat', 'Species', '10116', (257, 260))	('rat', 'Species', '10116', (320, 323))	('the', 'Gene', (113, 116))	('antioxidant', 'Enzyme', (160, 171))	('of', 'Gene', '6688', (148, 150))	('the', 'Gene', '25085', (233, 236))	('the', 'Gene', (240, 243))
624605	32370538	Moreover, it has been shown that H2S activation of signal transducer and activator of transcription 3 (STAT3) induces the transcription of additional cytoprotective proteins, including heat shock proteins such as Hsp90, and that H2S inhibits Nf-kappa-beta, which is upregulated in many diseases related to inflammation:including cancer.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('as', 'Gene', '112935892', (14, 16))	('H2S', 'Var', (33, 36))	('of', 'Gene', '6688', (83, 85))	('as', 'Gene', '112935892', (290, 292))	('Hsp90', 'Protein', (213, 218))	('upregulated', 'PosReg', (266, 277))	('of', 'Gene', '6688', (136, 138))	('heat', 'MPA', (185, 189))	('H2S', 'Chemical', 'MESH:D003903', (33, 36))	('inflammation', 'Disease', 'MESH:D007249', (306, 318))	('the', 'Gene', (118, 121))	('as', 'Gene', '112935892', (210, 212))	('of', 'Gene', '6688', (48, 50))	('shock', 'Phenotype', 'HP:0031273', (190, 195))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('di', 'Disease', 'MESH:D003643', (286, 288))	('shock proteins', 'Disease', 'MESH:D012769', (190, 204))	('H2S', 'Chemical', 'MESH:D003903', (229, 232))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('S', 'Chemical', 'MESH:D013455', (231, 232))	('the', 'Gene', '25085', (118, 121))	('inflammation', 'Disease', (306, 318))	('et', 'Gene', '79157', (252, 254))	('di', 'Disease', 'MESH:D003643', (141, 143))	('di', 'Disease', 'MESH:D003643', (324, 326))	('di', 'Disease', 'MESH:D003643', (180, 182))	('inhibits', 'NegReg', (233, 241))	('transcription', 'MPA', (122, 135))	('S', 'Chemical', 'MESH:D013455', (103, 104))	('cancer', 'Disease', (329, 335))	('shock proteins', 'Disease', (190, 204))
624621	32370538	Both directly and indirectly:through the H2S-cysteine-glutathione connection (see The H2S-cysteine-glutathione connection section):H2S regulates the homeostasis of the cellular immune system.	('the', 'Gene', '25085', (145, 148))	('di', 'Disease', 'MESH:D003643', (5, 7))	('as', 'Gene', '112935892', (156, 158))	('H2S', 'Chemical', 'MESH:D003903', (41, 44))	('The', 'Gene', '25085', (82, 85))	('H2S-cysteine', 'Chemical', '-', (86, 98))	('of', 'Gene', '6688', (161, 163))	('H2S', 'Chemical', 'MESH:D003903', (86, 89))	('the', 'Gene', (164, 167))	('the', 'Gene', (37, 40))	('H2S-cysteine', 'Chemical', '-', (41, 53))	('the', 'Gene', '25085', (164, 167))	('glutathione', 'Chemical', 'MESH:D005978', (54, 65))	('the', 'Gene', (145, 148))	('regulates', 'Reg', (135, 144))	('H2S', 'Var', (131, 134))	('di', 'Disease', 'MESH:D003643', (20, 22))	('The', 'Gene', (82, 85))	('the', 'Gene', '25085', (37, 40))	('glutathione', 'Chemical', 'MESH:D005978', (99, 110))	('H2S', 'Chemical', 'MESH:D003903', (131, 134))
624622	32370538	In addition, H2S is also able to improve progenitor-cell proliferation, viability, and therapeutic potential.	('improve', 'PosReg', (33, 40))	('the', 'Gene', '25085', (87, 90))	('H2S', 'Chemical', 'MESH:D003903', (13, 16))	('di', 'Disease', 'MESH:D003643', (5, 7))	('viability', 'CPA', (72, 81))	('rat', 'Species', '10116', (64, 67))	('H2S', 'Var', (13, 16))	('progenitor-cell proliferation', 'CPA', (41, 70))	('the', 'Gene', (87, 90))
624668	32370538	Direct interference of H2S on pathways related to aging was identified in all but one of the hallmarks of aging, and it is likely that H2S exerts antiaging effects by inhibiting formation of advanced glycation end-products as well as by blocking activation of their receptors.	('advanced glycation end-products', 'MPA', (191, 222))	('of', 'Gene', '6688', (257, 259))	('the', 'Gene', '25085', (89, 92))	('antiaging', 'CPA', (146, 155))	('of', 'Gene', '6688', (103, 105))	('H2S', 'Var', (135, 138))	('receptors', 'Interaction', (266, 275))	('the', 'Gene', (260, 263))	('as', 'Gene', '112935892', (57, 59))	('H2S', 'Chemical', 'MESH:D003903', (135, 138))	('as', 'Gene', '112935892', (223, 225))	('inhibiting', 'NegReg', (167, 177))	('H2S', 'Chemical', 'MESH:D003903', (23, 26))	('of', 'Gene', '6688', (86, 88))	('the', 'Gene', '25085', (260, 263))	('as', 'Gene', '112935892', (231, 233))	('of', 'Gene', '6688', (20, 22))	('of', 'Gene', '6688', (188, 190))	('blocking', 'NegReg', (237, 245))	('the', 'Gene', (89, 92))	('activation', 'MPA', (246, 256))
624671	32370538	A deficit of sulfur in the diet is known to compromise GSH synthesis to a much greater extent than protein synthesis, with potentially devastating consequences for the immune system, the antioxidant defense system, and the detoxification system.	('the', 'Gene', (183, 186))	('GSH', 'Chemical', '-', (55, 58))	('sulfur', 'MPA', (13, 19))	('the', 'Gene', (62, 65))	('the', 'Gene', (110, 113))	('et', 'Gene', '79157', (224, 226))	('the', 'Gene', '25085', (183, 186))	('of', 'Gene', '6688', (10, 12))	('the', 'Gene', (23, 26))	('as', 'Gene', '112935892', (138, 140))	('the', 'Gene', (164, 167))	('the', 'Gene', '25085', (62, 65))	('the', 'Gene', '25085', (110, 113))	('et', 'Gene', '79157', (29, 31))	('the', 'Gene', '25085', (23, 26))	('sulfur', 'Chemical', 'MESH:D013455', (13, 19))	('the', 'Gene', '25085', (164, 167))	('the', 'Gene', (219, 222))	('compromise', 'NegReg', (44, 54))	('deficit', 'Var', (2, 9))	('consequences', 'Reg', (147, 159))	('the', 'Gene', '25085', (219, 222))
624697	32370538	comparatively studied the antiproliferative effects of ajoene (allyl-(S = O)-CH2-CH = CH-S-S-allyl) and 12 ajoene analogues on WHCO1 esophageal cancer cells, they found that the analogues obtained on substituting either or both allyl groups by benzyl moieties were considerably more active: This observation is in line with the well-known fact that nucleophilic substitution reactions on benzylic carbon atoms are usually faster than on allylic positions.	('nucleophilic', 'MPA', (349, 361))	('CO', 'Chemical', 'MESH:D002248', (129, 131))	('S', 'Chemical', 'MESH:D013455', (70, 71))	('the', 'Gene', (215, 218))	('cancer', 'Disease', (144, 150))	('the', 'Gene', (174, 177))	('the', 'Gene', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('the', 'Gene', (324, 327))	('benzyl', 'Chemical', '-', (244, 250))	('ajoene', 'Chemical', 'MESH:C048980', (55, 61))	('the', 'Gene', (22, 25))	('the', 'Gene', '25085', (215, 218))	('di', 'Disease', 'MESH:D003643', (17, 19))	('S', 'Chemical', 'MESH:D013455', (91, 92))	('the', 'Gene', '25085', (174, 177))	('the', 'Gene', '25085', (158, 161))	('ajoene', 'Chemical', 'MESH:C048980', (107, 113))	('et', 'Gene', '79157', (254, 256))	('the', 'Gene', '25085', (324, 327))	('substituting', 'Var', (200, 212))	('as', 'Gene', '112935892', (423, 425))	('rat', 'Species', '10116', (37, 40))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('the', 'Gene', '25085', (22, 25))	('rat', 'Species', '10116', (5, 8))	('S', 'Chemical', 'MESH:D013455', (89, 90))	('of', 'Gene', '6688', (52, 54))	('carbon', 'Chemical', 'MESH:D002244', (397, 403))	('benzyl', 'Chemical', '-', (388, 394))
624701	32370538	These authors found that the half maximal inhibitory concentration (IC50) values (muM) for bis(4-cyanobenzyl)disulfide, DADS, and DBDS were 3.66, 16.76, and 43.60, respectively; whereas toward the normal kidney epithelial cell line (NKE) the respective values were 65.71, 45.43, and 70.11.	('bis(4-cyanobenzyl)disulfide', 'Chemical', '-', (91, 118))	('the', 'Gene', '25085', (238, 241))	('bis', 'Var', (91, 94))	('the', 'Gene', (193, 196))	('DBDS', 'Chemical', 'MESH:C492349', (130, 134))	('the', 'Gene', '25085', (193, 196))	('as', 'Gene', '112935892', (183, 185))	('rat', 'Species', '10116', (60, 63))	('the', 'Gene', (214, 217))	('The', 'Gene', (0, 3))	('DADS', 'Chemical', 'MESH:C028009', (120, 124))	('the', 'Gene', '25085', (214, 217))	('The', 'Gene', '25085', (0, 3))	('the', 'Gene', (25, 28))	('the', 'Gene', '25085', (25, 28))	('the', 'Gene', (238, 241))
624714	32370538	Regarding possible drug-drug interactions, it has been found that DBTS potently inhibits the activity of the cytochrome P450 enzymes.	('DBTS', 'Chemical', 'MESH:C495415', (66, 70))	('DBTS', 'Var', (66, 70))	('of', 'Gene', '6688', (102, 104))	('the', 'Gene', (105, 108))	('activity', 'MPA', (93, 101))	('di', 'Disease', 'MESH:D003643', (5, 7))	('the', 'Gene', '25085', (105, 108))	('the', 'Gene', (89, 92))	('inhibits', 'NegReg', (80, 88))	('the', 'Gene', '25085', (89, 92))	('cytochrome P450 enzymes', 'Enzyme', (109, 132))	('as', 'Gene', '112935892', (47, 49))
624716	32370538	At ambient temperature in the presence of cysteine (500 muM, 20 equivalents), the H2S-releasing efficiency of DBTS after 90 min was 34%, and that of DBTTS 35%; under comparable conditions in the presence of GSH, the respective H2S-releasing efficiencies were 17% and 32%.	('DBTS', 'Chemical', 'MESH:C495415', (110, 114))	('cysteine', 'Chemical', 'MESH:D003545', (42, 50))	('the', 'Gene', (191, 194))	('rat', 'Species', '10116', (16, 19))	('the', 'Gene', '25085', (26, 29))	('as', 'Gene', '112935892', (235, 237))	('of', 'Gene', '6688', (146, 148))	('as', 'Gene', '112935892', (90, 92))	('H2S-', 'Chemical', 'MESH:D003903', (227, 231))	('the', 'Gene', '25085', (191, 194))	('the', 'Gene', (78, 81))	('of', 'Gene', '6688', (39, 41))	('as', 'Gene', '112935892', (129, 131))	('the', 'Gene', (212, 215))	('H2S-', 'Chemical', 'MESH:D003903', (82, 86))	('DBTTS', 'Chemical', '-', (149, 154))	('of', 'Gene', '6688', (204, 206))	('the', 'Gene', '25085', (78, 81))	('the', 'Gene', '25085', (212, 215))	('di', 'Disease', 'MESH:D003643', (180, 182))	('500 muM', 'Var', (52, 59))	('of', 'Gene', '6688', (107, 109))	('the', 'Gene', (26, 29))	('GSH', 'Chemical', '-', (207, 210))
624724	32370538	In addition, ajoene S-thiolates vimentin at Cys328, disrupting the vimentin network, and hence exerts antimetastatic activity in human HeLa and MDA-MB-231 cancer cells.	('ajoene S-thiolates', 'Chemical', '-', (13, 31))	('men', 'Species', '9606', (69, 72))	('the', 'Gene', '25085', (63, 66))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (144, 154))	('et', 'Gene', '79157', (107, 109))	('HeLa', 'CellLine', 'CVCL:0030', (135, 139))	('di', 'Disease', 'MESH:D003643', (5, 7))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('et', 'Gene', '79157', (77, 79))	('Cys328', 'Var', (44, 50))	('di', 'Disease', 'MESH:D003643', (52, 54))	('human', 'Species', '9606', (129, 134))	('the', 'Gene', (63, 66))	('Cys328', 'Chemical', '-', (44, 50))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('men', 'Species', '9606', (34, 37))
624727	32370538	The same authors have provided additional evidence:stemming from experiments involving microscopic observation of purified tubulin:that DBTS disrupts the microtubule network.	('vide', 'Chemical', '-', (25, 29))	('men', 'Species', '9606', (71, 74))	('the', 'Gene', (150, 153))	('The', 'Gene', (0, 3))	('of', 'Gene', '6688', (111, 113))	('the', 'Gene', '25085', (150, 153))	('et', 'Gene', '79157', (167, 169))	('DBTS', 'Chemical', 'MESH:C495415', (136, 140))	('di', 'Disease', 'MESH:D003643', (141, 143))	('DBTS', 'Var', (136, 140))	('The', 'Gene', '25085', (0, 3))	('di', 'Disease', 'MESH:D003643', (33, 35))	('vide', 'Chemical', '-', (43, 47))
624732	32370538	In this instance, to a first approximation the following steps may be considered: (i) transport of a molecule of the active compound to a cell, (ii) transport across the cell membrane and into the cytoplasm, (iii) transport through the cytoplasm from the endofacial side of the cell membrane to an intracellular protein, (iv) S-thiolation of a protein's free cysteine residue, and (v) apoptosis induction by the S-thiolated proteins.	('the', 'Gene', '25085', (193, 196))	('the', 'Gene', '25085', (232, 235))	('cysteine', 'Chemical', 'MESH:D003545', (359, 367))	('of', 'Gene', '6688', (258, 260))	('as', 'Gene', '112935892', (242, 244))	('the', 'Gene', '25085', (43, 46))	('the', 'Gene', '25085', (113, 116))	('the', 'Gene', (166, 169))	('apoptosis induction', 'CPA', (385, 404))	('of', 'Gene', '6688', (271, 273))	('of', 'Gene', '6688', (96, 98))	('proteins', 'Protein', (424, 432))	('the', 'Gene', (251, 254))	('S-thiolated', 'Var', (412, 423))	('transport', 'MPA', (214, 223))	('free cysteine residue', 'MPA', (354, 375))	('the', 'Gene', '25085', (166, 169))	('the', 'Gene', (274, 277))	('thiolation', 'Chemical', '-', (328, 338))	('of', 'Gene', '6688', (110, 112))	('S', 'Chemical', 'MESH:D013455', (326, 327))	('the', 'Gene', (408, 411))	('thiolate', 'Chemical', '-', (414, 422))	('the', 'Gene', '25085', (251, 254))	('mole', 'Phenotype', 'HP:0003764', (101, 105))	('S-thiolation', 'MPA', (326, 338))	('the', 'Gene', (193, 196))	('the', 'Gene', (232, 235))	('of', 'Gene', '6688', (339, 341))	('the', 'Gene', (43, 46))	('the', 'Gene', (113, 116))	('the', 'Gene', '25085', (274, 277))	('the', 'Gene', '25085', (408, 411))	('as', 'Gene', '112935892', (203, 205))	('S', 'Chemical', 'MESH:D013455', (412, 413))
624737	32370538	studied the cytotoxicities (toward human MCF-7 breast cancer cells) of DBDS and of four symmetric para-substituted derivatives bearing fluoro, methoxy, cyano, and nitro substituent groups in both para positions; they found that the difluoro derivative and DBDS exhibited very similar cytotoxicities, that a decrease in potency accompanied the incorporation of nitro and methoxy groups, and that replacement of the para-H atoms by cyano groups led to a dramatic enhancement of cytotoxic activity.	('the', 'Gene', (8, 11))	('of', 'Gene', '6688', (68, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('human', 'Species', '9606', (35, 40))	('cytotoxicities', 'Disease', 'MESH:D064420', (12, 26))	('di', 'Disease', 'MESH:D003643', (3, 5))	('of', 'Gene', '6688', (407, 409))	('nitro', 'Chemical', '-', (163, 168))	('rat', 'Species', '10116', (350, 353))	('et', 'Gene', '79157', (144, 146))	('di', 'Disease', 'MESH:D003643', (232, 234))	('the', 'Gene', '25085', (8, 11))	('nitro', 'Chemical', '-', (360, 365))	('enhancement', 'PosReg', (461, 472))	('the', 'Gene', (228, 231))	('the', 'Gene', (339, 342))	('of', 'Gene', '6688', (80, 82))	('para-H atoms', 'Disease', (414, 426))	('as', 'Gene', '112935892', (50, 52))	('the', 'Gene', (212, 215))	('as', 'Gene', '112935892', (312, 314))	('of', 'Gene', '6688', (357, 359))	('nitro', 'MPA', (360, 365))	('men', 'Species', '9606', (468, 471))	('DBDS', 'Chemical', 'MESH:C492349', (256, 260))	('cytotoxic activity', 'CPA', (476, 494))	('cytotoxicities', 'Disease', (284, 298))	('the', 'Gene', (410, 413))	('the', 'Gene', '25085', (228, 231))	('the', 'Gene', '25085', (339, 342))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (41, 60))	('MCF-7 breast cancer', 'Disease', (41, 60))	('cyano', 'Chemical', '-', (152, 157))	('the', 'Gene', '25085', (212, 215))	('et', 'Gene', '79157', (371, 373))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('incorporation', 'Var', (343, 356))	('men', 'Species', '9606', (402, 405))	('DBDS', 'Chemical', 'MESH:C492349', (71, 75))	('cytotoxicities', 'Disease', (12, 26))	('potency', 'MPA', (319, 326))	('para-H atoms', 'Disease', 'MESH:D000848', (414, 426))	('the', 'Gene', '25085', (410, 413))	('cyano', 'Chemical', '-', (430, 435))	('cytotoxicities', 'Disease', 'MESH:D064420', (284, 298))	('et', 'Gene', '79157', (92, 94))	('of', 'Gene', '6688', (473, 475))
624791	32370538	found that the cytotoxicity of a series of benzyl thiosulfonates (R-S-SO2-p-tolyl) was essentially the same for R = benzyl, R = p-fluorobenzyl, and R = p-methoxybenzyl, a result that may also be explained by invoking a reactivity-leveling effect related to high leaving group (p-tolylsulfinate) ability and poor transmission of electronic effects through six atoms.	('of', 'Gene', '6688', (28, 30))	('R = p-methoxybenzyl', 'Var', (148, 167))	('benzyl', 'Chemical', '-', (116, 122))	('p-fluorobenzyl', 'Chemical', '-', (128, 142))	('benzyl', 'Chemical', '-', (43, 49))	('of', 'Gene', '6688', (40, 42))	('of', 'Gene', '6688', (325, 327))	('cytotoxicity', 'Disease', (15, 27))	('benzyl thiosulfonates', 'Chemical', '-', (43, 64))	('the', 'Gene', (99, 102))	('cytotoxicity', 'Disease', 'MESH:D064420', (15, 27))	('R-S-SO2-p-tolyl', 'Chemical', '-', (66, 81))	('benzyl', 'Chemical', '-', (136, 142))	('the', 'Gene', (11, 14))	('benzyl', 'Chemical', '-', (161, 167))	('p-methoxybenzyl', 'Chemical', '-', (152, 167))	('as', 'Gene', '112935892', (84, 86))	('the', 'Gene', '25085', (99, 102))	('R = benzyl', 'Var', (112, 122))	('the', 'Gene', '25085', (11, 14))
624796	32370538	In spite of the fact that the substituent's electronic effects differed widely, it was found that most of the observed initial rates differed only by factors of less than 7, and that para-substitution consistently led to substantially diminished rates.	('the', 'Gene', (12, 15))	('para-substitution', 'Var', (183, 200))	('of', 'Gene', '6688', (103, 105))	('rat', 'Species', '10116', (246, 249))	('the', 'Gene', '25085', (12, 15))	('di', 'Disease', 'MESH:D003643', (235, 237))	('the', 'Gene', (26, 29))	('as', 'Gene', '112935892', (84, 86))	('the', 'Gene', '25085', (26, 29))	('di', 'Disease', 'MESH:D003643', (133, 135))	('rat', 'Species', '10116', (127, 130))	('the', 'Gene', (106, 109))	('the', 'Gene', '25085', (106, 109))	('of', 'Gene', '6688', (9, 11))	('di', 'Disease', 'MESH:D003643', (63, 65))	('of', 'Gene', '6688', (158, 160))
624797	32370538	It is noteworthy that the rate of reaction of the parent compound (diphenyltetrasulfide) was found to be 25 times greater than that of DATS, that this is expected on substitution of the electron-withdrawing phenyl group for the electron-donating allyl group and that this observation also fits well with the fact that 7-methyl-1,2,3,4,5-benzopentathiepin is about 30 times more reactive than DBTS toward GSH.	('substitution', 'Var', (166, 178))	('reaction', 'MPA', (34, 42))	('of', 'Gene', '6688', (179, 181))	('the', 'Gene', '25085', (304, 307))	('GSH', 'Chemical', '-', (404, 407))	('the', 'Gene', (182, 185))	('the', 'Gene', '25085', (224, 227))	('as', 'Gene', '112935892', (90, 92))	('the', 'Gene', (46, 49))	('the', 'Gene', (22, 25))	('DATS', 'Chemical', 'MESH:C042577', (135, 139))	('fits', 'Disease', 'MESH:D012640', (289, 293))	('diphenyltetrasulfide', 'Chemical', '-', (67, 87))	('the', 'Gene', '25085', (182, 185))	('DBTS', 'Chemical', 'MESH:C495415', (392, 396))	('the', 'Gene', '25085', (46, 49))	('the', 'Gene', '25085', (22, 25))	('of', 'Gene', '6688', (31, 33))	('fits', 'Disease', (289, 293))	('as', 'Gene', '112935892', (79, 81))	('the', 'Gene', (304, 307))	('rat', 'Species', '10116', (26, 29))	('reactive', 'MPA', (378, 386))	('of', 'Gene', '6688', (132, 134))	('the', 'Gene', (224, 227))	('7-methyl-1,2,3,4,5-benzopentathiepin', 'Chemical', '-', (318, 354))	('of', 'Gene', '6688', (43, 45))
624800	32370538	Moreover, the molecular weight of DBTTS already exceeds the limit imposed by the "rule of three" (RO3) (see Druglikeness, RO5, RO3, Ghose filter, Veber's rule section), and its lipophilicity is too high from the perspective of Lipinski's rule of five (RO5).	('of', 'Gene', '6688', (243, 245))	('the', 'Gene', (56, 59))	('molecular weight', 'MPA', (14, 30))	('the', 'Gene', (208, 211))	('the', 'Gene', (77, 80))	('of', 'Gene', '6688', (224, 226))	('the', 'Gene', '25085', (56, 59))	('lipophilicity', 'MPA', (177, 190))	('DBTTS', 'Var', (34, 39))	('the', 'Gene', '25085', (208, 211))	('of', 'Gene', '6688', (31, 33))	('of', 'Gene', '6688', (87, 89))	('mole', 'Phenotype', 'HP:0003764', (14, 18))	('the', 'Gene', '25085', (77, 80))	('DBTTS', 'Chemical', '-', (34, 39))	('exceeds', 'PosReg', (48, 55))	('the', 'Gene', (10, 13))	('the', 'Gene', '25085', (10, 13))
624817	32370538	Lipophilicity affects receptor binding, plasma protein binding, metabolic drug stability, and drug distribution/excretion, and it is therefore a crucial physicochemical property of a drug molecule.	('as', 'Gene', '112935892', (42, 44))	('et', 'Gene', '79157', (65, 67))	('mole', 'Phenotype', 'HP:0003764', (188, 192))	('di', 'Disease', 'MESH:D003643', (99, 101))	('di', 'Disease', 'MESH:D003643', (34, 36))	('the', 'Gene', (133, 136))	('Lipophilicity', 'Var', (0, 13))	('di', 'Disease', 'MESH:D003643', (58, 60))	('the', 'Gene', '25085', (133, 136))	('affects', 'Reg', (14, 21))	('et', 'Gene', '79157', (116, 118))	('of', 'Gene', '6688', (178, 180))
624826	32370538	The half-life of I (6.25 muM) in the presence of GSH (188 muM) in buffered water-acetonitrile solution at 25 C is less than 1 min, which corresponds to an apparent second-order rate constant of about 60 M-1s-1.	('GSH', 'Chemical', '-', (49, 52))	('rat', 'Species', '10116', (177, 180))	('water', 'Chemical', 'MESH:D014867', (75, 80))	('of', 'Gene', '6688', (14, 16))	('the', 'Gene', (33, 36))	('The', 'Gene', (0, 3))	('the', 'Gene', '25085', (33, 36))	('acetonitrile', 'Chemical', 'MESH:C032159', (81, 93))	('The', 'Gene', '25085', (0, 3))	('188 muM', 'Var', (54, 61))	('of', 'Gene', '6688', (191, 193))	('GSH', 'Gene', (49, 52))	('of', 'Gene', '6688', (46, 48))
624831	32370538	It is highly likely that the first step in the mechanism of these processes is the nucleophilic attack of RS- on a sulfur atom attached to the aromatic nucleus (i.e., S1 or S5) or on a sulfur atom adjacent to it (i.e., S2 or S4), with concomitant cleavage of the weaker S1-S2 or S4-S5 bonds and formation of either a thiolate (ArS-) or a hydropolysulfide (Ar-S-S-S-S-) relatively stable anion.	('Ar-S-S-S-S', 'Chemical', 'MESH:D001128', (356, 366))	('S4-S5', 'Var', (279, 284))	('the', 'Gene', '25085', (139, 142))	('the', 'Gene', '25085', (43, 46))	('S', 'Chemical', 'MESH:D013455', (173, 174))	('of', 'Gene', '6688', (57, 59))	('the', 'Gene', (79, 82))	('S', 'Chemical', 'MESH:D013455', (363, 364))	('the', 'Gene', '25085', (25, 28))	('S', 'Chemical', 'MESH:D013455', (219, 220))	('of', 'Gene', '6688', (256, 258))	('sulfur', 'Chemical', 'MESH:D013455', (185, 191))	('polysulfide', 'Chemical', 'MESH:C032915', (343, 354))	('the', 'Gene', (310, 313))	('S', 'Chemical', 'MESH:D013455', (282, 283))	('S', 'Chemical', 'MESH:D013455', (107, 108))	('S', 'Chemical', 'MESH:D013455', (361, 362))	('of', 'Gene', '6688', (103, 105))	('S', 'Chemical', 'MESH:D013455', (225, 226))	('cleavage', 'MPA', (247, 255))	('S', 'Chemical', 'MESH:D013455', (273, 274))	('ArS-', 'Chemical', 'MESH:D001128', (327, 331))	('S', 'Chemical', 'MESH:D013455', (329, 330))	('the', 'Gene', '25085', (79, 82))	('the', 'Gene', (259, 262))	('S', 'Chemical', 'MESH:D013455', (359, 360))	('the', 'Gene', '25085', (310, 313))	('the', 'Gene', (60, 63))	('S', 'Chemical', 'MESH:D013455', (167, 168))	('thiolate', 'MPA', (317, 325))	('sulfur', 'Chemical', 'MESH:D013455', (115, 121))	('S1-S2', 'Protein', (270, 275))	('S', 'Chemical', 'MESH:D013455', (279, 280))	('the', 'Gene', (139, 142))	('S', 'Chemical', 'MESH:D013455', (365, 366))	('the', 'Gene', (43, 46))	('the', 'Gene', '25085', (259, 262))	('thiolate', 'Chemical', '-', (317, 325))	('the', 'Gene', '25085', (60, 63))	('the', 'Gene', (25, 28))	('S', 'Chemical', 'MESH:D013455', (270, 271))	('hydropolysulfide', 'MPA', (338, 354))	('of', 'Gene', '6688', (305, 307))
624839	32370538	2, 3, and 4) and/or by thiolation of cellular proteins.	('of', 'Gene', '6688', (34, 36))	('thiolation', 'Chemical', '-', (23, 33))	('cellular proteins', 'Protein', (37, 54))	('thiolation', 'Var', (23, 33))
624855	32370538	Eventually, they found that benzopentathiepin derivative TC-2153 had "reasonable aqueous solubility," low acute toxicity (>1000 mg/kg), was able:on parenteral administration:to cross the blood-brain barrier of mice, and inhibited STEP almost as potently as S8.	('the', 'Gene', (183, 186))	('as', 'Gene', '112935892', (242, 244))	('rat', 'Species', '10116', (167, 170))	('the', 'Gene', '25085', (183, 186))	('mice', 'Species', '10090', (210, 214))	('low acute toxicity', 'Disease', 'MESH:D012120', (102, 120))	('of', 'Gene', '6688', (207, 209))	('S8', 'Chemical', 'MESH:C039415', (257, 259))	('as', 'Gene', '112935892', (137, 139))	('S', 'Chemical', 'MESH:D013455', (257, 258))	('as', 'Gene', '112935892', (72, 74))	('the', 'Gene', (12, 15))	('TC-2153', 'CellLine', 'CVCL:K915', (57, 64))	('S', 'Chemical', 'MESH:D013455', (230, 231))	('as', 'Gene', '112935892', (254, 256))	('benzopentathiepin', 'Chemical', '-', (28, 45))	('the', 'Gene', '25085', (12, 15))	('TC-2153', 'Var', (57, 64))	('inhibited', 'NegReg', (220, 229))	('low acute toxicity', 'Disease', (102, 120))
624861	32370538	Rather, we believe that an enzyme trisulfide may be formed at an early stage, probably after the loss of a molecule of H2S from intramolecular disproportionation involving the initially formed Cys465-S-SH and Cys472-S-SH bishydropersulfide.	('the', 'Gene', '25085', (2, 5))	('bishydropersulfide', 'Chemical', '-', (221, 239))	('Cys465', 'Chemical', '-', (193, 199))	('H2S', 'Chemical', 'MESH:D003903', (119, 122))	('S', 'Chemical', 'MESH:D013455', (218, 219))	('the', 'Gene', (172, 175))	('the', 'Gene', (93, 96))	('S', 'Chemical', 'MESH:D013455', (202, 203))	('S', 'Chemical', 'MESH:D013455', (121, 122))	('S', 'Chemical', 'MESH:D013455', (200, 201))	('mole', 'Phenotype', 'HP:0003764', (133, 137))	('di', 'Disease', 'MESH:D003643', (143, 145))	('Cys472', 'Chemical', '-', (209, 215))	('of', 'Gene', '6688', (116, 118))	('Cys465-S-SH', 'Var', (193, 204))	('the', 'Gene', '25085', (172, 175))	('S', 'Chemical', 'MESH:D013455', (216, 217))	('the', 'Gene', '25085', (93, 96))	('of', 'Gene', '6688', (102, 104))	('the', 'Gene', (2, 5))	('trisulfide', 'Chemical', '-', (34, 44))	('mole', 'Phenotype', 'HP:0003764', (107, 111))	('Cys472-S-SH', 'Var', (209, 220))
624879	32370538	Kondo et al., in a study of a murine model of HF, were able to increase levels of circulating H2S, circulating SS, cardiac H2S, and cardiac SS by about two- to three-fold by orally administering mice 20 mg SG1002/kg/day.	('SG1002', 'Chemical', '-', (206, 212))	('levels', 'MPA', (72, 78))	('as', 'Gene', '112935892', (68, 70))	('mice', 'Species', '10090', (195, 199))	('murine', 'Species', '10090', (30, 36))	('of', 'Gene', '6688', (25, 27))	('circulating SS', 'MPA', (99, 113))	('H2S', 'Chemical', 'MESH:D003903', (94, 97))	('SS', 'Chemical', '-', (111, 113))	('di', 'Disease', 'MESH:D003643', (135, 137))	('SG1002/kg/day', 'Var', (206, 219))	('SS', 'Chemical', '-', (140, 142))	('of', 'Gene', '6688', (79, 81))	('cardiac SS', 'Disease', (132, 142))	('di', 'Disease', 'MESH:D003643', (118, 120))	('et', 'Gene', '79157', (6, 8))	('H2S', 'Chemical', 'MESH:D003903', (123, 126))	('of', 'Gene', '6688', (43, 45))	('cardiac SS', 'Disease', 'MESH:D006331', (132, 142))
624884	32370538	We hypothesize: (i) that the reduction of S8 to H2S is carried out mostly by intestinal epithelial cells, (ii) that this step involves interaction of a cell's outer membrane with a sulfur species (S8, GS-S7-S-, or HS-S7-S-) located on the surface of an alpha-sulfur particle, (iii) that the high bioavailability of SG1002 is mainly due to the presence of ionic species on the crystal surface (Na2SO4, Na2S2O3) that render it hydrophilic and/or susceptible to catalysis by GS- or HS-, and (iv) that the rate of H2S generation is tightly controlled by the cells of the intestinal epithelium (Fig.	('the', 'Gene', '25085', (550, 553))	('of', 'Gene', '6688', (147, 149))	('rat', 'Species', '10116', (502, 505))	('the', 'Gene', (581, 584))	('S8', 'Chemical', 'MESH:C039415', (197, 199))	('S', 'Chemical', 'MESH:D013455', (204, 205))	('the', 'Gene', (287, 290))	('the', 'Gene', (563, 566))	('the', 'Gene', (7, 10))	('SG1002', 'Chemical', '-', (315, 321))	('S', 'Chemical', 'MESH:D013455', (197, 198))	('of', 'Gene', '6688', (352, 354))	('S', 'Chemical', 'MESH:D013455', (315, 316))	('the', 'Gene', '25085', (25, 28))	('the', 'Gene', (372, 375))	('S', 'Chemical', 'MESH:D013455', (512, 513))	('S', 'Chemical', 'MESH:D013455', (220, 221))	('of', 'Gene', '6688', (247, 249))	('of', 'Gene', '6688', (312, 314))	('HS-', 'Chemical', 'MESH:D006859', (214, 217))	('the', 'Gene', '25085', (581, 584))	('the', 'Gene', (339, 342))	('Na2S2O3', 'Var', (401, 408))	('H2S', 'Chemical', 'MESH:D003903', (48, 51))	('of', 'Gene', '6688', (39, 41))	('alpha-sulfur', 'Chemical', 'MESH:D013455', (253, 265))	('S', 'Chemical', 'MESH:D013455', (473, 474))	('S8', 'Chemical', 'MESH:C039415', (42, 44))	('the', 'Gene', '25085', (563, 566))	('the', 'Gene', '25085', (287, 290))	('S', 'Chemical', 'MESH:D013455', (480, 481))	('SG1002', 'Gene', (315, 321))	('S', 'Chemical', 'MESH:D013455', (217, 218))	('sulfur', 'Chemical', 'MESH:D013455', (259, 265))	('the', 'Gene', '25085', (7, 10))	('S', 'Chemical', 'MESH:D013455', (42, 43))	('S', 'Chemical', 'MESH:D013455', (202, 203))	('the', 'Gene', (498, 501))	('the', 'Gene', '25085', (372, 375))	('Na2SO4', 'Chemical', '-', (393, 399))	('the', 'Gene', (91, 94))	('the', 'Gene', (235, 238))	('S', 'Chemical', 'MESH:D013455', (50, 51))	('sulfur', 'Chemical', 'MESH:D013455', (181, 187))	('the', 'Gene', '25085', (339, 342))	('bioavailability', 'MPA', (296, 311))	('the', 'Gene', (550, 553))	('of', 'Gene', '6688', (507, 509))	('S', 'Chemical', 'MESH:D013455', (396, 397))	('the', 'Gene', '25085', (498, 501))	('rat', 'Species', '10116', (518, 521))	('the', 'Gene', '25085', (91, 94))	('HS-', 'Chemical', 'MESH:D006859', (479, 482))	('S', 'Chemical', 'MESH:D013455', (404, 405))	('S', 'Chemical', 'MESH:D013455', (207, 208))	('of', 'Gene', '6688', (560, 562))	('the', 'Gene', '25085', (235, 238))	('S', 'Chemical', 'MESH:D013455', (215, 216))	('the', 'Gene', (25, 28))	('H2S', 'Chemical', 'MESH:D003903', (510, 513))
624915	32370538	The RO5 states that oral drugs match at least three of the four following criteria: (i) molecular weight <500 Daltons, (ii) cLogP) <5, (iii) <5 hydrogen-bond donors, and (iv) <10 hydrogen-bond acceptors.	('<500', 'Var', (105, 109))	('as', 'Gene', '112935892', (42, 44))	('mole', 'Phenotype', 'HP:0003764', (88, 92))	('hydrogen-bond acceptors', 'MPA', (179, 202))	('hydrogen', 'Chemical', 'MESH:D006859', (144, 152))	('of', 'Gene', '6688', (52, 54))	('hydrogen', 'Chemical', 'MESH:D006859', (179, 187))	('The', 'Gene', (0, 3))	('hydrogen-bond donors', 'MPA', (144, 164))	('The', 'Gene', '25085', (0, 3))	('the', 'Gene', (55, 58))	('molecular weight', 'MPA', (88, 104))	('the', 'Gene', '25085', (55, 58))
624933	32370538	One of the disadvantages of inorganic sulfide salts, such as IK-1001, is that they rapidly generate H2S when in aqueous solution in a pH-dependent manner and volatilization of H2S results in lowering of concentration of sulfur species, ultimately impacting their handling and biological usefulness.	('inorganic sulfide salts', 'Chemical', '-', (28, 51))	('of', 'Gene', '6688', (217, 219))	('of', 'Gene', '6688', (4, 6))	('rat', 'Species', '10116', (95, 98))	('impacting', 'Reg', (247, 256))	('the', 'Gene', (7, 10))	('of', 'Gene', '6688', (200, 202))	('H2S', 'MPA', (100, 103))	('di', 'Disease', 'MESH:D003643', (11, 13))	('H2S', 'Chemical', 'MESH:D003903', (176, 179))	('as', 'Gene', '112935892', (58, 60))	('volatilization', 'Var', (158, 172))	('of', 'Gene', '6688', (25, 27))	('the', 'Gene', (78, 81))	('IK-1001', 'Chemical', '-', (61, 68))	('the', 'Gene', '25085', (7, 10))	('handling', 'MPA', (263, 271))	('H2S', 'Chemical', 'MESH:D003903', (100, 103))	('the', 'Gene', '25085', (78, 81))	('of', 'Gene', '6688', (173, 175))	('biological usefulness', 'CPA', (276, 297))	('the', 'Gene', (257, 260))	('rat', 'Species', '10116', (210, 213))	('sulfur', 'Chemical', 'MESH:D013455', (220, 226))	('the', 'Gene', '25085', (257, 260))	('lowering', 'NegReg', (191, 199))
624950	32370538	Among the known H2S prodrugs, SG1002 stands out because it lacks a carbon-based scaffold, its properties cannot be tuned or adjusted by conventional lead optimization, it is not a therapeutic targeted-based agent, it is not water soluble, it violates the druglikeness rules (RO5, RO3, Veber's rules), it has a 100% prodrug-to-H2S conversion efficiency, and it is bioactivated.	('the', 'Gene', '25085', (6, 9))	('the', 'Gene', (251, 254))	('H2S', 'Chemical', 'MESH:D003903', (326, 329))	('the', 'Gene', (180, 183))	('prodrug-to-H2S', 'Enzyme', (315, 329))	('the', 'Gene', '25085', (180, 183))	('as', 'Gene', '112935892', (75, 77))	('as', 'Gene', '112935892', (305, 307))	('SG1002', 'Var', (30, 36))	('carbon', 'Chemical', 'MESH:D002244', (67, 73))	('SG1002', 'Chemical', '-', (30, 36))	('the', 'Gene', (6, 9))	('water', 'Chemical', 'MESH:D014867', (224, 229))	('the', 'Gene', '25085', (251, 254))	('et', 'Gene', '79157', (196, 198))	('H2S', 'Chemical', 'MESH:D003903', (16, 19))	('as', 'Gene', '112935892', (202, 204))
624953	32370538	Moreover, the fact that SG1002 is orally active presents a huge advantage, because its administration may involve capsules or pills (generally the most accepted and convenient form of administration to patients), which increases patient compliance, avoids painful and intrusive forms of administration such as injections and/or infusions that typically require patients showing up at hospitals/health centers, and a prescheduled time for infusion (i.e., 45 min or longer) all resulting in patients' inconvenience and high rates of noncompliance.	('rat', 'Species', '10116', (95, 98))	('as', 'Gene', '112935892', (307, 309))	('rat', 'Species', '10116', (295, 298))	('the', 'Gene', (143, 146))	('SG1002', 'Var', (24, 30))	('pain', 'Disease', (256, 260))	('rat', 'Species', '10116', (522, 525))	('the', 'Gene', '25085', (10, 13))	('patients', 'Species', '9606', (489, 497))	('patients', 'Species', '9606', (202, 210))	('pain', 'Phenotype', 'HP:0012531', (256, 260))	('the', 'Gene', '25085', (143, 146))	('patient compliance', 'CPA', (229, 247))	('patient', 'Species', '9606', (229, 236))	('patients', 'Species', '9606', (361, 369))	('as', 'Gene', '112935892', (224, 226))	('pain', 'Disease', 'MESH:D010146', (256, 260))	('of', 'Gene', '6688', (284, 286))	('SG1002', 'Chemical', '-', (24, 30))	('patient', 'Species', '9606', (489, 496))	('of', 'Gene', '6688', (181, 183))	('patient', 'Species', '9606', (202, 209))	('rat', 'Species', '10116', (192, 195))	('the', 'Gene', (10, 13))	('patient', 'Species', '9606', (361, 368))	('of', 'Gene', '6688', (528, 530))
624956	32370538	Cystathionine gamma-lyase (CSE) is an enzyme that converts L-cysteine into H2S, and in vivo studies have shown that H2S protects against acute myocardial ischemia/reperfusion injury.	('H2S', 'Chemical', 'MESH:D003903', (116, 119))	('di', 'Disease', 'MESH:D003643', (95, 97))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('H2S', 'Chemical', 'MESH:D003903', (75, 78))	('myocardial ischemia', 'Phenotype', 'HP:0002637', (143, 162))	('as', 'Gene', '112935892', (22, 24))	('S', 'Chemical', 'MESH:D013455', (77, 78))	('myocardial ischemia', 'Disease', 'MESH:D003324', (143, 162))	('myocardial ischemia', 'Disease', (143, 162))	('Cys', 'Chemical', 'MESH:D003545', (0, 3))	('di', 'Disease', 'MESH:D003643', (149, 151))	('H2S', 'Var', (116, 119))	('S', 'Chemical', 'MESH:D013455', (28, 29))	('L-cysteine', 'Chemical', 'MESH:D003545', (59, 69))
624965	32370538	The results show that H2S and SS levels were lower in CSE KO mice versus WT mice, that CSE KO mice had a much-enlarged heart as well as pulmonary edema versus WT mice, and that CSE KO mice exhibited significant left ventricular cavity dilatation.	('much-enlarged', 'PosReg', (105, 118))	('S', 'Chemical', 'MESH:D013455', (31, 32))	('pulmonary edema versus WT', 'Disease', 'MESH:D011654', (136, 161))	('di', 'Disease', 'MESH:D003643', (235, 237))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('The', 'Gene', (0, 3))	('lower', 'NegReg', (45, 50))	('pulmonary edema', 'Phenotype', 'HP:0100598', (136, 151))	('mice', 'Species', '10090', (94, 98))	('S', 'Chemical', 'MESH:D013455', (30, 31))	('heart', 'MPA', (119, 124))	('mice', 'Species', '10090', (61, 65))	('edema', 'Phenotype', 'HP:0000969', (146, 151))	('mice', 'Species', '10090', (162, 166))	('mice', 'Species', '10090', (76, 80))	('The', 'Gene', '25085', (0, 3))	('S', 'Chemical', 'MESH:D013455', (178, 179))	('H2S', 'Chemical', 'MESH:D003903', (22, 25))	('CSE KO', 'Var', (87, 93))	('enlarged heart', 'Phenotype', 'HP:0001640', (110, 124))	('SS', 'Chemical', '-', (30, 32))	('S', 'Chemical', 'MESH:D013455', (88, 89))	('ventricular cavity dilatation', 'Phenotype', 'HP:0006698', (216, 245))	('mice', 'Species', '10090', (184, 188))	('S', 'Chemical', 'MESH:D013455', (24, 25))	('as', 'Gene', '112935892', (125, 127))	('dilatation', 'Phenotype', 'HP:0002617', (235, 245))	('pulmonary edema versus WT', 'Disease', (136, 161))	('as', 'Gene', '112935892', (133, 135))
624967	32370538	The results of administration of SG1002 to WT C57BL/6J mice (20 mg/kg/day) post-TAC demonstrate that SG1002 partially restored free H2S and significantly restored SS levels in the blood and heart, and that the hearts of SG1002-treated mice showed both significantly less size increase and significantly less pulmonary edema compared with vehicle mice.	('restored', 'PosReg', (154, 162))	('the', 'Gene', (176, 179))	('of', 'Gene', '6688', (217, 219))	('The', 'Gene', (0, 3))	('the', 'Gene', (206, 209))	('mice', 'Species', '10090', (235, 239))	('less', 'NegReg', (303, 307))	('mice', 'Species', '10090', (346, 350))	('SG1002', 'Chemical', '-', (220, 226))	('SS levels in', 'MPA', (163, 175))	('the', 'Gene', '25085', (176, 179))	('rat', 'Species', '10116', (23, 26))	('SG1002', 'Chemical', '-', (101, 107))	('restored', 'PosReg', (118, 126))	('TAC', 'Chemical', '-', (80, 83))	('The', 'Gene', '25085', (0, 3))	('the', 'Gene', '25085', (206, 209))	('as', 'Gene', '112935892', (281, 283))	('rat', 'Species', '10116', (91, 94))	('pulmonary edema', 'Disease', 'MESH:D011654', (308, 323))	('SG1002', 'Chemical', '-', (33, 39))	('edema', 'Phenotype', 'HP:0000969', (318, 323))	('pulmonary edema', 'Phenotype', 'HP:0100598', (308, 323))	('SS', 'Chemical', '-', (163, 165))	('H2S', 'Chemical', 'MESH:D003903', (132, 135))	('of', 'Gene', '6688', (30, 32))	('free H2S', 'MPA', (127, 135))	('pulmonary edema', 'Disease', (308, 323))	('mice', 'Species', '10090', (55, 59))	('SG1002', 'Var', (101, 107))	('of', 'Gene', '6688', (12, 14))	('size', 'MPA', (271, 275))
624982	32370538	The CBS+/- mice developed cardiac remodeling, and SG1002 was found to prevent this unwanted heart condition (Fig.	('di', 'Disease', 'MESH:D003643', (101, 103))	('di', 'Disease', 'MESH:D003643', (29, 31))	('as', 'Gene', '112935892', (58, 60))	('SG1002', 'Var', (50, 56))	('SG1002', 'Chemical', '-', (50, 56))	('The', 'Gene', (0, 3))	('mice', 'Species', '10090', (11, 15))	('S', 'Chemical', 'MESH:D013455', (50, 51))	('The', 'Gene', '25085', (0, 3))	('S', 'Chemical', 'MESH:D013455', (6, 7))
624986	32370538	The study revealed that pigs that received SG1002 had 2.7 times higher H2S circulating levels and 4 times higher level of SS than pigs that received placebo.	('H2S', 'Chemical', 'MESH:D003903', (71, 74))	('of', 'Gene', '6688', (119, 121))	('SS', 'Chemical', '-', (122, 124))	('higher', 'PosReg', (64, 70))	('SG1002', 'Chemical', '-', (43, 49))	('pigs', 'Species', '9823', (130, 134))	('H2S', 'Protein', (71, 74))	('The', 'Gene', (0, 3))	('higher', 'PosReg', (106, 112))	('SG1002', 'Var', (43, 49))	('pigs', 'Species', '9823', (24, 28))	('The', 'Gene', '25085', (0, 3))
624987	32370538	Moreover, SG1002 also preserved existing capillaries in ischemic limbs to a 1.6 times greater extent than in pigs that received placebo.	('ischemic', 'Disease', 'MESH:D007511', (56, 64))	('pigs', 'Species', '9823', (109, 113))	('ischemic', 'Disease', (56, 64))	('SG1002', 'Var', (10, 16))	('SG1002', 'Chemical', '-', (10, 16))
624992	32370538	Mice that received SG1002 showed that plaque formation was significantly reduced, indicating the beneficial antiatherosclerotic effect of SG1002 and its potential therapeutic use for atherosclerosis.	('SG1002', 'Var', (138, 144))	('the', 'Gene', (184, 187))	('the', 'Gene', '25085', (113, 116))	('SG1002', 'Var', (19, 25))	('Mice', 'Species', '10090', (0, 4))	('plaque formation', 'CPA', (38, 54))	('reduced', 'NegReg', (73, 80))	('the', 'Gene', '25085', (184, 187))	('beneficial', 'PosReg', (97, 107))	('of', 'Gene', '6688', (135, 137))	('the', 'Gene', (93, 96))	('the', 'Gene', (163, 166))	('atherosclerosis', 'Disease', 'MESH:D050197', (183, 198))	('as', 'Gene', '112935892', (56, 58))	('SG1002', 'Chemical', '-', (138, 144))	('atherosclerosis', 'Disease', (183, 198))	('SG1002', 'Chemical', '-', (19, 25))	('atherosclerosis', 'Phenotype', 'HP:0002621', (183, 198))	('di', 'Disease', 'MESH:D003643', (84, 86))	('the', 'Gene', '25085', (93, 96))	('the', 'Gene', '25085', (163, 166))	('the', 'Gene', (113, 116))
624997	32370538	The trial comprised seven healthy subjects (male) and eight HF patients (male, female); enrolled subjects were randomized into two groups (group = one subject placebo: three subjects SG1002) and received placebo or SG1002 orally in escalating dosages (200, 400, 800 mg, BID, each day) for 7 days.	('SG1002', 'Chemical', '-', (183, 189))	('SG1002', 'Var', (215, 221))	('The', 'Gene', (0, 3))	('SG1002', 'Chemical', '-', (215, 221))	('The', 'Gene', '25085', (0, 3))	('patients', 'Species', '9606', (63, 71))
625007	32370538	Further, oxidative stress affects the integrity of the sperm nuclear and mitochondrial genomes, leading to DNA strand breaks, aberrant recombination and/or defective packing, as well as chromatin cross-linking.	('as', 'Gene', '112935892', (175, 177))	('defective', 'NegReg', (156, 165))	('aberrant', 'Var', (126, 134))	('the', 'Gene', '25085', (51, 54))	('affects', 'Reg', (26, 33))	('of', 'Gene', '6688', (48, 50))	('di', 'Disease', 'MESH:D003643', (99, 101))	('the', 'Gene', (34, 37))	('as', 'Gene', '112935892', (183, 185))	('packing', 'MPA', (166, 173))	('the', 'Gene', '25085', (3, 6))	('DNA strand breaks', 'CPA', (107, 124))	('the', 'Gene', (3, 6))	('the', 'Gene', '25085', (34, 37))	('oxidative stress', 'Phenotype', 'HP:0025464', (9, 25))	('the', 'Gene', (51, 54))
625012	32370538	Sulfur-deficient diets, however, are common and may lead to cysteine deficiency, especially in males, and, consequently, to deficits in the biosynthesis of important cysteine-rich proteins such as so-called CRISPs.	('Sulfur', 'Chemical', 'MESH:D013455', (0, 6))	('the', 'Gene', (146, 149))	('S', 'Chemical', 'MESH:D013455', (210, 211))	('cysteine', 'Chemical', 'MESH:D003545', (166, 174))	('the', 'Gene', '25085', (146, 149))	('cysteine deficiency', 'Disease', 'MESH:C565659', (60, 79))	('cysteine deficiency', 'Disease', (60, 79))	('as', 'Gene', '112935892', (194, 196))	('Sulfur-deficient', 'Var', (0, 16))	('the', 'Gene', (136, 139))	('cysteine', 'Chemical', 'MESH:D003545', (60, 68))	('of', 'Gene', '6688', (153, 155))	('the', 'Gene', '25085', (136, 139))	('lead to', 'Reg', (52, 59))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('deficits', 'NegReg', (124, 132))
625025	32370538	The outcomes for the group receiving SG1002 were as follows: The percentage of morphologically abnormal spermatozoa decreased from 60% to 36% (p = 0.017).	('as', 'Gene', '112935892', (121, 123))	('as', 'Gene', '112935892', (49, 51))	('The', 'Gene', (61, 64))	('SG1002', 'Chemical', '-', (37, 43))	('abnormal spermatozoa', 'Phenotype', 'HP:0012864', (95, 115))	('The', 'Gene', '25085', (61, 64))	('of', 'Gene', '6688', (76, 78))	('The', 'Gene', (0, 3))	('SG1002', 'Var', (37, 43))	('The', 'Gene', '25085', (0, 3))	('the', 'Gene', (17, 20))	('the', 'Gene', '25085', (17, 20))
625034	32370538	One final consideration is warranted: Semen quality is a marker not only of fecundity but also of general health; impaired semen quality has been associated with shorter life expectancy and enhanced long-term morbidity.	('of', 'Gene', '6688', (95, 97))	('semen', 'MPA', (123, 128))	('S', 'Chemical', 'MESH:D013455', (38, 39))	('di', 'Disease', 'MESH:D003643', (214, 216))	('men', 'Species', '9606', (125, 128))	('as', 'Gene', '112935892', (146, 148))	('di', 'Disease', 'MESH:D003643', (81, 83))	('as', 'Gene', '112935892', (138, 140))	('of', 'Gene', '6688', (73, 75))	('shorter', 'NegReg', (162, 169))	('men', 'Species', '9606', (40, 43))	('rat', 'Species', '10116', (17, 20))	('enhanced', 'PosReg', (190, 198))	('impaired', 'Var', (114, 122))
625037	32370538	This potential is, in the case of SG1002, exclusively based on the fact that it is an H2S prodrug, whereas the other donors elicit pharmacologic effects that are only partially mediated by H2S.	('as', 'Gene', '112935892', (27, 29))	('the', 'Gene', '25085', (107, 110))	('as', 'Gene', '112935892', (104, 106))	('as', 'Gene', '112935892', (55, 57))	('the', 'Gene', (22, 25))	('the', 'Gene', '25085', (22, 25))	('of', 'Gene', '6688', (31, 33))	('the', 'Gene', (112, 115))	('H2S', 'Chemical', 'MESH:D003903', (86, 89))	('the', 'Gene', (63, 66))	('di', 'Disease', 'MESH:D003643', (179, 181))	('SG1002', 'Var', (34, 40))	('the', 'Gene', '25085', (112, 115))	('H2S', 'Chemical', 'MESH:D003903', (189, 192))	('SG1002', 'Chemical', '-', (34, 40))	('elicit', 'Reg', (124, 130))	('the', 'Gene', '25085', (63, 66))	('the', 'Gene', (107, 110))
625043	32370538	These features position SG1002 as the H2S donor of choice when studying biological systems in vivo, whereas its almost nil water solubility makes it the least attractive one to choose for in vitro experiments.	('the', 'Gene', (149, 152))	('as', 'Gene', '112935892', (31, 33))	('men', 'Species', '9606', (203, 206))	('the', 'Gene', '25085', (149, 152))	('as', 'Gene', '112935892', (155, 157))	('of', 'Gene', '6688', (48, 50))	('The', 'Gene', (0, 3))	('water', 'Chemical', 'MESH:D014867', (123, 128))	('as', 'Gene', '112935892', (105, 107))	('The', 'Gene', '25085', (0, 3))	('H2S', 'Chemical', 'MESH:D003903', (38, 41))	('the', 'Gene', (34, 37))	('SG1002', 'Var', (24, 30))	('SG1002', 'Chemical', '-', (24, 30))	('the', 'Gene', '25085', (34, 37))
625097	32088803	Also, familial adenomatous polyposis (FAP) caused by germline mutations in the adenomatous polyposis coli (APC) gene, has been associated with an increased risk of developing BE.	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (79, 105))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (79, 100))	('adenomatous polyposis coli', 'Disease', (79, 105))	('familial adenomatous polyposis', 'Disease', (6, 36))	('FAP', 'Disease', 'MESH:C567782', (38, 41))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (6, 36))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (79, 105))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (15, 36))	('APC', 'Phenotype', 'HP:0005227', (107, 110))	('APC', 'Disease', 'MESH:D011125', (107, 110))	('BE', 'Phenotype', 'HP:0100580', (175, 177))	('APC', 'Disease', (107, 110))	('mutations', 'Var', (62, 71))	('FAP', 'Disease', (38, 41))
625098	32088803	It is not known whether adenomatous polyposis caused by bi-allelic germline mutations in the MUTYH gene (MUTYH-associated polyposis (MAP)) is also associated with BE.	('MUTYH', 'Gene', (105, 110))	('polyposis', 'Disease', (122, 131))	('polyposis', 'Disease', (36, 45))	('mutations', 'Var', (76, 85))	('MUTYH', 'Gene', '4595', (105, 110))	('associated', 'Reg', (147, 157))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (24, 45))	('BE', 'Phenotype', 'HP:0100580', (163, 165))	('polyposis', 'Disease', 'MESH:D011125', (122, 131))	('caused', 'Reg', (46, 52))	('polyposis', 'Disease', 'MESH:D011125', (36, 45))	('MUTYH', 'Gene', (93, 98))	('MUTYH', 'Gene', '4595', (93, 98))	('adenomatous polyposis', 'Disease', (24, 45))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (24, 45))
625158	31151431	The results of Cox multivariate analysis indicated that among these tumor biomarkers, CA19-9 (>= 37 vs. < 37) [hazard ratio (HR) = 2.130, 95% confidence interval (CI) = 1.138-3.986, p = 0.018] and CEA (>= 5 vs. < 5) (HR = 1.827, 95% CI = 1.089-3.064, p = 0.022) were the independent prognostic factors of poor OS.	('tumor', 'Disease', (68, 73))	('CA19-9', 'Chemical', 'MESH:C086528', (86, 92))	('OS', 'Chemical', '-', (310, 312))	('CEA', 'Gene', '1048', (197, 200))	('CEA', 'Gene', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('poor OS', 'Disease', (305, 312))	('CA19-9', 'Var', (86, 92))	('Cox', 'Gene', '1351', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Cox', 'Gene', (15, 18))
625159	31151431	For the ESCC patients with CA19-9 < 37, CEA < 5 or SCC-Ag < 1.5, the surgery plus postoperative chemotherapy group had a significantly longer OS than the surgery group alone (p < 0.05), but this significant difference of OS between these two groups cannot be found in patients with CA19-9 >= 37, CEA >= 5 or SCC-Ag >= 1.5 (p > 0.05).	('patients', 'Species', '9606', (268, 276))	('CA19-9', 'Chemical', 'MESH:C086528', (27, 33))	('SCC', 'Gene', '6317', (308, 311))	('SCC', 'Gene', (51, 54))	('OS', 'Chemical', '-', (142, 144))	('patients', 'Species', '9606', (13, 21))	('CEA', 'Gene', '1048', (40, 43))	('SCC', 'Gene', '6317', (51, 54))	('CEA', 'Gene', (40, 43))	('SCC', 'Gene', (9, 12))	('OS', 'Chemical', '-', (221, 223))	('CEA', 'Gene', '1048', (296, 299))	('SCC', 'Gene', (308, 311))	('SCC', 'Gene', '6317', (9, 12))	('CA19-9 < 37', 'Var', (27, 38))	('CEA', 'Gene', (296, 299))	('CA19-9', 'Chemical', 'MESH:C086528', (282, 288))
625181	31151431	According to the manufacturer's protocols and previous study, the normal upper limits were used as the optimal cut-off values of CA19-9, CA72-4, CEA, Cyfra21-1 and SCC-Ag: 37 U/ml, 6 U/ml, 5 mug/L, 3.4 ng/ml and 1.5 ng/ml, respectively.	('CA72', 'Chemical', '-', (137, 141))	('CEA', 'Gene', (145, 148))	('CA72-4', 'Var', (137, 143))	('SCC', 'Gene', '6317', (164, 167))	('Cyfra21-1', 'Var', (150, 159))	('CA19-9', 'Var', (129, 135))	('CA19-9', 'Chemical', 'MESH:C086528', (129, 135))	('CEA', 'Gene', '1048', (145, 148))	('SCC', 'Gene', (164, 167))
625192	31151431	Our results showed that the high CEA and Cyfra21-1 were both significantly associated with older age and more advanced pN stage (p < 0.05), elevated SCC-Ag was significantly related to larger tumor size, more advanced pN stage and TNM stage, and CA72-4 was significantly associated with tumor size (p < 0.05).	('CEA', 'Gene', '1048', (33, 36))	('elevated', 'PosReg', (140, 148))	('pN stage', 'CPA', (218, 226))	('Cyfra21-1', 'Var', (41, 50))	('CA72', 'Chemical', '-', (246, 250))	('tumor', 'Disease', (287, 292))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('CEA', 'Gene', (33, 36))	('SCC', 'Gene', '6317', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('TNM', 'Gene', '10178', (231, 234))	('associated', 'Reg', (75, 85))	('TNM', 'Gene', (231, 234))	('SCC', 'Gene', (149, 152))	('related', 'Reg', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('larger', 'PosReg', (185, 191))
625195	31151431	In univariate analysis, our result indicated that male patients, larger tumor size, advanced pT stage, advanced pN stage, advanced TNM stage, patients who did not receive postoperative chemotherapy and elevated CA19-9, CEA, Cyfra21-1 and SCC-Ag were significantly related to poor OS (p < 0.05, Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('larger', 'PosReg', (65, 71))	('poor OS', 'Disease', (275, 282))	('OS', 'Chemical', '-', (280, 282))	('elevated', 'PosReg', (202, 210))	('CEA', 'Gene', (219, 222))	('TNM', 'Gene', '10178', (131, 134))	('SCC', 'Gene', '6317', (238, 241))	('advanced pT', 'Disease', (84, 95))	('TNM', 'Gene', (131, 134))	('CA19-9', 'Var', (211, 217))	('tumor', 'Disease', (72, 77))	('SCC', 'Gene', (238, 241))	('CA19-9', 'Chemical', 'MESH:C086528', (211, 217))	('CEA', 'Gene', '1048', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('related', 'Reg', (264, 271))	('Cyfra21-1', 'Var', (224, 233))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (142, 150))
625197	31151431	Among these tumor biomarkers, CA19-9 (>= 37 vs. < 37) [hazard ratio (HR) = 2.130, 95% confidence interval (CI) = 1.138-3.986, p = 0.018] and CEA (>= 5 vs. < 5) (HR = 1.827, 95% CI = 1.089-3.064, p = 0.022) were the independent prognostic factors of poor OS (Table 2).	('CEA', 'Gene', (141, 144))	('CEA', 'Gene', '1048', (141, 144))	('OS', 'Chemical', '-', (254, 256))	('CA19-9', 'Var', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CA19-9', 'Chemical', 'MESH:C086528', (30, 36))	('tumor', 'Disease', (12, 17))	('poor OS', 'Disease', (249, 256))
625202	31151431	Our result indicated that for the ESCC patients with CA19-9 < 37 U/ml, CEA < 5 mug/L or SCC-Ag < 1.5 ng/ml, the surgery plus postoperative chemotherapy group had a significantly longer OS than the surgery group alone (p < 0.05, Fig.	('patients', 'Species', '9606', (39, 47))	('SCC', 'Gene', (35, 38))	('longer', 'PosReg', (178, 184))	('CEA', 'Gene', (71, 74))	('CEA', 'Gene', '1048', (71, 74))	('CA19-9 < 37 U/ml', 'Var', (53, 69))	('CA19-9', 'Chemical', 'MESH:C086528', (53, 59))	('SCC', 'Gene', '6317', (35, 38))	('SCC', 'Gene', (88, 91))	('SCC', 'Gene', '6317', (88, 91))	('OS', 'Chemical', '-', (185, 187))
625204	31151431	On the other hand, regardless of patients with CA72-4 < 6 U/ml or CA72-4 >= 6 U/ml, or in patients with Cyfra21-1 < 3.4 ng/ml or Cyfra21-1 >= 3.4 ng/ml, our results showed that the surgery plus chemotherapy group had significantly longer or a tendency of longer OS than the surgery group alone (Additional file 1: Figure S1).	('patients', 'Species', '9606', (33, 41))	('CA72', 'Chemical', '-', (66, 70))	('OS', 'Chemical', '-', (262, 264))	('CA72-4', 'Var', (66, 72))	('longer', 'PosReg', (255, 261))	('Cyfra21-1 >=', 'Var', (129, 141))	('CA72', 'Chemical', '-', (47, 51))	('patients', 'Species', '9606', (90, 98))	('CA72-4 <', 'Var', (47, 55))
625213	31151431	found that Cyfra21-1 and SCC-Ag were both independently significant poor predictors of prognosis in patients with stage II ESCC.	('SCC', 'Gene', '6317', (124, 127))	('SCC', 'Gene', (25, 28))	('SCC', 'Gene', (124, 127))	('SCC', 'Gene', '6317', (25, 28))	('patients', 'Species', '9606', (100, 108))	('Cyfra21-1', 'Var', (11, 20))
625216	31151431	In this study, our results showed that CA19-9 and CEA were the only two independent prognostic indicators for poor OS among these five tumor biomarkers.	('CA19-9', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('CEA', 'Gene', '1048', (50, 53))	('OS', 'Chemical', '-', (115, 117))	('tumor', 'Disease', (135, 140))	('poor OS', 'Disease', (110, 117))	('CEA', 'Gene', (50, 53))	('CA19-9', 'Chemical', 'MESH:C086528', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
625217	31151431	These aforementioned results showed that CA19-9 and CEA maybe were potentially superior to other tumor biomarkers as indicators for predicting prognosis in ESCC patients.	('SCC', 'Gene', (157, 160))	('CEA', 'Gene', '1048', (52, 55))	('CA19-9', 'Chemical', 'MESH:C086528', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CEA', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('SCC', 'Gene', '6317', (157, 160))	('tumor', 'Disease', (97, 102))	('patients', 'Species', '9606', (161, 169))	('CA19-9', 'Var', (41, 47))
625225	31151431	Our result indicated that ESCC patients with low CA19-9, CEA, SCC-Ag may be more likely to benefit from the postoperative chemotherapy.	('SCC', 'Gene', (27, 30))	('CA19-9', 'Chemical', 'MESH:C086528', (49, 55))	('SCC', 'Gene', '6317', (62, 65))	('low CA19-9', 'Var', (45, 55))	('SCC', 'Gene', '6317', (27, 30))	('CEA', 'Gene', (57, 60))	('CEA', 'Gene', '1048', (57, 60))	('patients', 'Species', '9606', (31, 39))	('benefit', 'PosReg', (91, 98))	('CA19-9', 'Var', (49, 55))	('SCC', 'Gene', (62, 65))
625232	31151431	81772629, 81702431, 81602158 and 81602156), Individualized Medical Platform of National Clinical Research Center for Cancer (13ZCZCSY20300), Demonstrative research platform of clinical evaluation technology for new anticancer drugs (No.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('81602158', 'Var', (20, 28))	('81602156', 'Var', (33, 41))	('Cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (219, 225))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))
625261	29609018	The treatment plan included neoadjuvant chemotherapy (5-FU 800 mg/m2 on days 1-5 and CDDP 80 mg g/m2 on day 1; two courses), followed by a thoracoscopic esophagectomy.	('5-FU', 'Chemical', 'MESH:D005472', (54, 58))	('5-FU 800 mg/m2', 'Var', (54, 68))	('CDDP', 'Var', (85, 89))	('CDDP', 'Chemical', '-', (85, 89))
625304	26603452	Changes in this balance could lead to esophageal diseases including GERD, Barrett's esophagus, and carcinogenesis (Katz and Kaestner; Marchetti et al.	('lead to', 'Reg', (30, 37))	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('GERD', 'Disease', (68, 72))	('esophageal diseases', 'Disease', 'MESH:D004935', (38, 57))	("Barrett's esophagus", 'Disease', (74, 93))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (74, 93))	('carcinogenesis', 'Disease', (99, 113))	('Changes', 'Var', (0, 7))	('esophageal diseases', 'Disease', (38, 57))
625306	26603452	Alterations in adherens junction proteins are associated with esophageal diseases like eosinophilic esophagitis and cancer.	('esophagitis', 'Phenotype', 'HP:0100633', (100, 111))	('eosinophilic esophagitis', 'Phenotype', 'HP:0410151', (87, 111))	('eosinophilic esophagitis', 'Disease', (87, 111))	('cancer', 'Disease', (116, 122))	('Alterations', 'Var', (0, 11))	('esophageal diseases', 'Disease', 'MESH:D004935', (62, 81))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('adherens junction proteins', 'Protein', (15, 41))	('eosinophilic esophagitis', 'Disease', 'MESH:D004802', (87, 111))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('associated', 'Reg', (46, 56))	('esophageal diseases', 'Disease', (62, 81))
625317	26603452	In the large intestine, where it has been studied more extensively, activation of CaSR modulates colonic fluid movement and inhibits cAMP-activated fluid secretion (Geibel et al.).	('activation', 'Var', (68, 78))	('cAMP-activated fluid secretion', 'MPA', (133, 163))	('cAMP', 'Chemical', '-', (133, 137))	('inhibits', 'NegReg', (124, 132))	('modulates', 'Reg', (87, 96))	('colonic fluid movement', 'Disease', (97, 119))	('CaSR', 'Gene', (82, 86))	('colonic fluid movement', 'Disease', 'MESH:D009069', (97, 119))
625399	26603452	High Ca+2 and Gd3+, both reduced proliferation significantly (by 22% and 14%, respectively, P < 0.04) compared to control (Fig.5B).	('reduced', 'NegReg', (25, 32))	('Gd3+', 'Chemical', 'MESH:C026226', (14, 18))	('High Ca+2', 'Var', (0, 9))	('proliferation', 'CPA', (33, 46))	('Ca+2', 'Chemical', 'MESH:D000069285', (5, 9))	('Gd3+', 'Var', (14, 18))
625409	26603452	The presence of multiple bands at MW <108 kD was also reported by other studies on wild-type and mutant isoforms of CaSR expressed in HEK cells, (White et al.)	('mutant', 'Var', (97, 103))	('HEK', 'CellLine', 'CVCL:M624', (134, 137))	('CaSR', 'Gene', (116, 120))
625410	26603452	The significant morphological changes induced by CCT suggested an effect on junctional proteins.	('effect', 'Reg', (66, 72))	('morphological changes', 'CPA', (16, 37))	('junctional proteins', 'Protein', (76, 95))	('CCT', 'Var', (49, 52))	('CCT', 'Chemical', 'MESH:D000069449', (49, 52))
625434	26603452	Because CCT induced a significant change in the morphology of the cells, we examined the effect of CCT on Rho.	('change', 'Reg', (34, 40))	('CCT', 'Chemical', 'MESH:D000069449', (99, 102))	('morphology of the cells', 'CPA', (48, 71))	('CCT', 'Var', (8, 11))	('CCT', 'Chemical', 'MESH:D000069449', (8, 11))
625438	26603452	In an esophageal cell line HET1A, stimulating CaSR by spermine or Mg2+ resulted in intracellular calcium mobilization, activation of ERK1 and 2, and the secretion of cytokine IL-8 (Justinich et al.	('Mg2+', 'Chemical', '-', (66, 70))	('ERK1 and 2', 'Gene', '5595;5594', (133, 143))	('calcium', 'Chemical', 'MESH:D002118', (97, 104))	('IL-8', 'Gene', '3576', (175, 179))	('activation', 'PosReg', (119, 129))	('IL-8', 'Gene', (175, 179))	('spermine', 'Chemical', 'MESH:D013096', (54, 62))	('Mg2+', 'Var', (66, 70))	('secretion', 'MPA', (153, 162))	('intracellular calcium mobilization', 'MPA', (83, 117))
625577	19909531	Spearman's rho analysis identified statistical correlations (p < 0.05) between prolonged GT dependence or high grade dysphagia with IPC V65, IPC V60, IPC Dmean, and CPI Dmax.	('dysphagia', 'Disease', (117, 126))	('CPI', 'Chemical', '-', (165, 168))	('IPC V65', 'Var', (132, 139))	('dysphagia', 'Phenotype', 'HP:0002015', (117, 126))	('IPC Dmean', 'Var', (150, 159))	('IPC V60', 'Var', (141, 148))	('prolonged GT', 'Phenotype', 'HP:0008151', (79, 91))	('dysphagia', 'Disease', 'MESH:D003680', (117, 126))	('GT', 'Chemical', '-', (89, 91))
625579	19909531	Our analysis suggests that adhering to the following parameters may decrease the risk of prolonged GT dependence and dysphagia: IPC V65 < 15%, IPC V60 < 40%, IPC Dmean < 55 Gy, and CPI Dmax < 60 Gy.	('GT', 'Chemical', '-', (99, 101))	('dysphagia', 'Disease', (117, 126))	('CPI', 'Chemical', '-', (181, 184))	('decrease', 'NegReg', (68, 76))	('CPI Dmax < 60 Gy', 'Var', (181, 197))	('dysphagia', 'Phenotype', 'HP:0002015', (117, 126))	('IPC V60 < 40%', 'Var', (143, 156))	('prolonged GT', 'Phenotype', 'HP:0008151', (89, 101))	('prolonged GT dependence', 'Disease', (89, 112))	('dysphagia', 'Disease', 'MESH:D003680', (117, 126))	('IPC V65 < 15%', 'Var', (128, 141))	('IPC Dmean < 55 Gy', 'Var', (158, 175))
625670	19909531	Further analysis of dose-response relationships and volume-response relationships revealed that IPC V65 more than 65%, CPI V60 more than 78%, CPI Dmax more than 70 Gy were associated with more than 50% probability of developing high grade dysphagia.	('CPI V60 more than 78%', 'Var', (119, 140))	('CPI', 'Chemical', '-', (142, 145))	('CPI', 'Chemical', '-', (119, 122))	('dysphagia', 'Disease', (239, 248))	('dysphagia', 'Phenotype', 'HP:0002015', (239, 248))	('IPC V65', 'Var', (96, 103))	('dysphagia', 'Disease', 'MESH:D003680', (239, 248))
625675	19909531	Notably, we were able to identify DVH parameters which were significantly associated with prolonged GT dependence, including V65 of the IPC, V60 of the IPC, mean dose to the IPC, and maximum dose to the CPI.	('CPI', 'Chemical', '-', (203, 206))	('GT dependence', 'Disease', (100, 113))	('GT', 'Chemical', '-', (100, 102))	('V60', 'Var', (141, 144))	('prolonged GT', 'Phenotype', 'HP:0008151', (90, 102))	('V65', 'Var', (125, 128))	('associated', 'Reg', (74, 84))
625676	19909531	Based on these dose/volume-response relationships, we currently recommend IPC V65 less than 15%, IPC V60 less than 40%, IPC Dmean less than 55 Gy, and CPI Dmax less than 60 Gy as potentially important DVH constraints to guide IMRT planning in an attempt to significantly reduce the risk of swallowing dysfunction and prolonged GT dependence.	('swallowing dysfunction', 'Disease', 'MESH:D003680', (290, 312))	('less than', 'Var', (160, 169))	('swallowing dysfunction', 'Phenotype', 'HP:0002015', (290, 312))	('less than 15%', 'Var', (82, 95))	('GT', 'Chemical', '-', (327, 329))	('swallowing dysfunction', 'Disease', (290, 312))	('reduce', 'NegReg', (271, 277))	('prolonged GT', 'Phenotype', 'HP:0008151', (317, 329))	('CPI', 'Chemical', '-', (151, 154))
625713	19909531	This is based on the rationale that high dose radiation to a large volume of the constrictor muscles (resulting in high values of V60 and V65) also results in high dose to large volumes of mucosal surface which is believed to lead to more severe mucositis.	('mucositis', 'Disease', (246, 255))	('lead to', 'Reg', (226, 233))	('V60', 'MPA', (130, 133))	('V65', 'Var', (138, 141))	('high dose', 'MPA', (159, 168))	('mucositis', 'Disease', 'MESH:D052016', (246, 255))
625723	19909531	To minimize the risk of prolonged GT dependence, we currently strive to keep IPC V65 less than 15%, IPC V60 less than 40%, and maintain IPC Dmean less than 55 Gy, and CPI Dmax less than 60 Gy during IMRT planning in an attempt to decrease the risk of prolonged GT dependence.	('GT', 'Chemical', '-', (34, 36))	('GT', 'Chemical', '-', (261, 263))	('prolonged GT', 'Phenotype', 'HP:0008151', (251, 263))	('IPC V60', 'Var', (100, 107))	('prolonged GT', 'Phenotype', 'HP:0008151', (24, 36))	('CPI', 'Chemical', '-', (167, 170))	('less', 'Var', (176, 180))
625818	16026610	Preliminary data obtained from 2 esophageal biopsies indicated an increase of TS levels following 5-FU treatment.	('increase', 'PosReg', (66, 74))	('5-FU', 'Var', (98, 102))	('TS', 'Gene', '7298', (78, 80))	('5-FU', 'Chemical', 'MESH:D005472', (98, 102))
625820	16026610	The results indicated a general trend towards DPD down-regulation in the cells that had been exposed to 5-FU in vitro, though this effect was modest in most cases and we observed a greater than 2-fold decrease in only 7/13 breast samples and 2/10 colorectal samples.	('DPD', 'Gene', (46, 49))	('breast', 'Disease', (223, 229))	('5-FU', 'Var', (104, 108))	('down-regulation', 'NegReg', (50, 65))	('colorectal', 'Disease', 'MESH:D015179', (247, 257))	('5-FU', 'Chemical', 'MESH:D005472', (104, 108))	('DPD', 'Gene', '1806', (46, 49))	('decrease', 'NegReg', (201, 209))	('colorectal', 'Disease', (247, 257))
625841	16026610	While mutation-mediated resistance can be much more profound than that observed here, our data suggest that the functional effects may still be sufficient to render the patient's tumor resistant to treatment within one cycle of chemotherapy.	('mutation-mediated', 'Var', (6, 23))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('patient', 'Species', '9606', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
625848	16026610	Resistance to anthracyclines is thought to be mediated by a number of different mechanisms, which include mutation or alteration of its target enzyme, TOPO IIalpha, and up-regulation of drug efflux proteins, such as BCRP, MRP1, MVP and MDR-1.	('drug efflux proteins', 'MPA', (186, 206))	('MRP1', 'Gene', (222, 226))	('TOPO', 'Enzyme', (151, 155))	('MVP', 'Gene', '9961', (228, 231))	('MDR-1', 'Gene', (236, 241))	('BCRP', 'Gene', (216, 220))	('mutation', 'Var', (106, 114))	('alteration', 'Reg', (118, 128))	('up-regulation', 'PosReg', (169, 182))	('BCRP', 'Gene', '9429', (216, 220))	('MRP1', 'Gene', '5243', (222, 226))	('MVP', 'Gene', (228, 231))	('MDR-1', 'Gene', '5243', (236, 241))	('anthracyclines', 'Chemical', 'MESH:D018943', (14, 28))
625854	16026610	Treatment with 5-FU has been shown to acutely induce TS expression in cell lines, animal models and human tumors.	('TS', 'Gene', '7298', (53, 55))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('human', 'Species', '9606', (100, 105))	('5-FU', 'Var', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('induce', 'PosReg', (46, 52))	('5-FU', 'Chemical', 'MESH:D005472', (15, 19))
625932	33375499	The results of a subgroup analysis in the JCOG9907 study showed that preoperative chemotherapy was more effective in clinical stage II or T1-2 esophageal cancer patients than in stage III or T3 patients, i.e., in patients with relatively early-stage disease.	('patients', 'Species', '9606', (194, 202))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (213, 221))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('T1-2', 'Var', (138, 142))	('esophageal cancer', 'Disease', (143, 160))
625969	33375499	In 1999, a phase III trial conducted in the US in patients with T1-3N0-1M0 ESCC showed that CRT with CF concurrently with 50.4 Gy radiation yielded a significantly improved 5-year OS of 26%, as compared to 0% for radiation alone.	('improved', 'PosReg', (164, 172))	('patients', 'Species', '9606', (50, 58))	('T1-3N0-1M0', 'Var', (64, 74))	('CF', 'Chemical', '-', (101, 103))	('CRT', 'Gene', '799', (92, 95))	('CRT', 'Gene', (92, 95))
626060	31798770	In a meta-analysis of studies involving EUS-based staging of pre-operative ESCC compared with pathological staging, the pooled sensitivity for T1a was 84%, T1b was 83% and T4 84%.	('T1b', 'Var', (156, 159))	('ESCC', 'Disease', (75, 79))	('T1a', 'Gene', '10630', (143, 146))	('T1a', 'Gene', (143, 146))
626068	31798770	However, recent studies show that in well differentiated T1b tumors with submucosal invasion <= 500 mum and lack of lymphovascular invasion, the risk of lymph node metastasis is 0% to 2% and hence, EET can be safely employed.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('T1b', 'Gene', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('<= 500', 'Var', (93, 99))
626085	31798770	RFA also lowered the risk of progression to EAC (1.2% vs 9.3%, P = 0.045).	('RFA', 'Var', (0, 3))	('EAC', 'Gene', (44, 47))	('EAC', 'Gene', '1540', (44, 47))	('lowered', 'NegReg', (9, 16))
626105	31798770	Perioperative mortality following ESD in T1a and T1b ESCC tumors was lower (0.3%) when compared with esophagectomy (1.5%, P = 0.186) and morbidity was also lower (15.2% vs 27.7%, P = 0.001).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('ESCC', 'Disease', (53, 57))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('lower', 'NegReg', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('T1b', 'Var', (49, 52))	('T1a', 'Gene', '10630', (41, 44))	('T1a', 'Gene', (41, 44))	('lower', 'NegReg', (156, 161))
626133	31798770	Cryotherapy has been shown to improve mean dysphagia score from 2.4 to 1.7 with lower scores indicating better swallowing function.	('improve', 'PosReg', (30, 37))	('Cryotherapy', 'Var', (0, 11))	('swallowing', 'MPA', (111, 121))	('dysphagia', 'Disease', 'MESH:D003680', (43, 52))	('better swallowing function', 'Phenotype', 'HP:0002015', (104, 130))	('dysphagia', 'Disease', (43, 52))	('dysphagia', 'Phenotype', 'HP:0002015', (43, 52))
626277	29601131	ALN axillary-lymph node CECT contrast-enhanced computed tomography CER chemotherapy-effective rate CF cisplatin plus 5-fluorouracil DCF docetaxel, cisplatin, plus 5-fluorouracil ESCC esophageal squamous cell carcinoma HCER high CER LCER low CER LN lymph node LNM lymph node metastasis nCRT neoadjuvant chemoradiotherapy nCT neoadjuvant chemotherapy non-MLN non-metastatic LN OS overall survival pp-MLN plausible positive metastatic LN RFS recurrence-free survival TRG-LN TRG of the lymph node TRG-PT TRG of the primary tumor TRG tumor regression grade Neoadjuvant chemoradiotherapy followed by surgery has been one of the standard treatments for locally advanced thoracic ESCC, and nCT followed by surgery is the standard in Japan, based on the results of many clinical trials.1, 2, 3 These studies have shown that nCT or nCRT improves the prognosis of patients with ESCC.	('5-fluorouracil', 'Chemical', 'MESH:D005472', (163, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('OS', 'Chemical', '-', (375, 377))	('LCER', 'Chemical', '-', (232, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('prognosis', 'MPA', (840, 849))	('TRG', 'Gene', '6965', (500, 503))	('TRG', 'Gene', '6965', (493, 496))	('TRG', 'Gene', '6965', (525, 528))	('docetaxel', 'Chemical', 'MESH:D000077143', (136, 145))	('CECT', 'Chemical', '-', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (529, 534))	('TRG', 'Gene', (500, 503))	('TRG', 'Gene', (493, 496))	('TRG', 'Gene', (525, 528))	('nCRT', 'Var', (822, 826))	('tumor', 'Disease', (519, 524))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('esophageal squamous cell carcinoma', 'Disease', (183, 217))	('tumor', 'Disease', 'MESH:D009369', (519, 524))	('ESCC', 'Disease', (867, 871))	('patients', 'Species', '9606', (853, 861))	('improves', 'PosReg', (827, 835))	('MLN', 'Gene', (353, 356))	('MLN', 'Gene', '4295', (353, 356))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (117, 131))	('TRG', 'Gene', '6965', (471, 474))	('ALN', 'Chemical', 'MESH:D000535', (0, 3))	('TRG', 'Gene', '6965', (464, 467))	('tumor', 'Disease', (529, 534))	('tumor', 'Phenotype', 'HP:0002664', (519, 524))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (183, 217))	('MLN', 'Gene', (398, 401))	('TRG', 'Gene', (471, 474))	('DCF', 'Chemical', 'MESH:D015649', (132, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('TRG', 'Gene', (464, 467))	('MLN', 'Gene', '4295', (398, 401))	('tumor', 'Disease', 'MESH:D009369', (529, 534))
626323	29601131	This showed that ypT3-4 (vs ypT0-2, HR; 2.551, P = .023), positive venous infiltration (vs negative, HR; 3.526, P = .006), and LCER (vs HCER, HR; 1.922, P = .033) were predictors of shorter RFS.	('positive venous infiltration', 'MPA', (58, 86))	('shorter', 'NegReg', (182, 189))	('LCER', 'Chemical', '-', (127, 131))	('RFS', 'MPA', (190, 193))	('LCER', 'Disease', (127, 131))	('ypT3-4', 'Var', (17, 23))
626330	29601131	Multivariate analysis showed that ypT3-4 (vs ypT0-2, HR; 3.397, P = .033) and LCER (vs HCER, HR; 3.543, P = .008) were predictors of a shorter RFS.	('LCER', 'Chemical', '-', (78, 82))	('LCER', 'Disease', (78, 82))	('ypT3-4', 'Var', (34, 40))	('shorter', 'NegReg', (135, 142))	('RFS', 'MPA', (143, 146))
626350	26154995	Esophageal Squamous Cell Carcinoma and Gastric Cardia Adenocarcinoma Shared Susceptibility Locus in C20orf54: Evidence from Published Studies This study aimed to determine whether C20orf54 rs13042395 polymorphism modify the risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinomas (GCA) in common population.	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('gastric cardia adenocarcinomas', 'Disease', (278, 308))	('rs13042395', 'Var', (189, 199))	('Gastric Cardia Adenocarcinoma', 'Disease', 'MESH:D004938', (39, 68))	('esophageal squamous cell carcinoma', 'Disease', (232, 266))	('rs13042395', 'Mutation', 'rs13042395', (189, 199))	('C20orf54', 'Gene', '113278', (100, 108))	('C20orf54', 'Gene', '113278', (180, 188))	('C20orf54', 'Gene', (100, 108))	('C20orf54', 'Gene', (180, 188))	('gastric cardia adenocarcinomas', 'Disease', 'MESH:D004938', (278, 308))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (232, 266))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (0, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('Gastric Cardia Adenocarcinoma', 'Disease', (39, 68))	('Esophageal Squamous Cell Carcinoma', 'Disease', (0, 34))	('Carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
626353	26154995	Overall, the results indicated that the C20orf54 rs13042395 genotype was subtly decrease the risk of ESCC (T vs. C: OR = 0.95; 95%CI = 0.90-0.99; P = 0.02) and the rs13042395 polymorphism was associated with a decreased risk of GCA (T vs. C: OR = 0.95; 95%CI = 0.91-0.98; P < 0.01).	('rs13042395', 'Var', (164, 174))	('rs13042395', 'Mutation', 'rs13042395', (49, 59))	('GCA', 'Disease', (228, 231))	('decreased', 'NegReg', (210, 219))	('C20orf54', 'Gene', (40, 48))	('rs13042395', 'Var', (49, 59))	('C20orf54', 'Gene', '113278', (40, 48))	('ESCC', 'Disease', (101, 105))	('rs13042395', 'Mutation', 'rs13042395', (164, 174))	('decrease', 'NegReg', (80, 88))
626354	26154995	Subgroup analysis was also stratified by body mass index (BMI), rs13042395 polymorphism was significantly associated with a subtly decreased cancer risk in under-weight group and normal group, but no association was observed in over-weight group.	('rs13042395', 'Var', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('decreased', 'NegReg', (131, 140))	('rat', 'Species', '10116', (29, 32))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('rs13042395', 'Mutation', 'rs13042395', (64, 74))
626355	26154995	In conclusion, C20orf54 rs13042395 polymorphism was significantly associated with decreased ESCC and GCA risk especially for the subjects with under-weight or normal.	('rs13042395', 'Mutation', 'rs13042395', (24, 34))	('ESCC', 'Disease', (92, 96))	('rs13042395', 'Var', (24, 34))	('GCA', 'Disease', (101, 104))	('C20orf54', 'Gene', (15, 23))	('C20orf54', 'Gene', '113278', (15, 23))	('decreased ESCC', 'Phenotype', 'HP:0025022', (82, 96))	('decreased', 'NegReg', (82, 91))
626362	26154995	In 2010, a large-scale genome-wide association study (GWAS) reported that a new and notable susceptibility locus (rs13042395) located in 5' flanking region of chromosome 20 open reading frame 54 (C20orf54), it encodes riboflavin transporter 2 protein (RFT2) that was newly identified to play an important role in esophageal and carcinogenesis by modulating riboflavin uptake.	('modulating', 'Reg', (346, 356))	('C20orf54', 'Gene', '113278', (196, 204))	('riboflavin', 'Chemical', 'MESH:D012256', (357, 367))	('carcinogenesis', 'Disease', (328, 342))	('RFT2', 'Gene', '113278', (252, 256))	('rs13042395', 'Mutation', 'rs13042395', (114, 124))	('riboflavin', 'Chemical', 'MESH:D012256', (218, 228))	('rs13042395', 'Var', (114, 124))	('riboflavin transporter 2', 'Gene', '113278', (218, 242))	('esophageal', 'Disease', (313, 323))	('C20orf54', 'Gene', (196, 204))	('riboflavin transporter 2', 'Gene', (218, 242))	('RFT2', 'Gene', (252, 256))	('riboflavin uptake', 'MPA', (357, 374))	('carcinogenesis', 'Disease', 'MESH:D063646', (328, 342))
626366	26154995	For C20orf54 rs13042395 genotype and risk of ESCC and GCA, the results were inconsistent.	('C20orf54', 'Gene', (4, 12))	('C20orf54', 'Gene', '113278', (4, 12))	('rs13042395', 'Var', (13, 23))	('GCA', 'Disease', (54, 57))	('ESCC', 'Disease', (45, 49))	('rs13042395', 'Mutation', 'rs13042395', (13, 23))
626368	26154995	The objective of the present study was to quantitatively assess the association between C20orf54 rs13042395 polymorphism and risk of ESCC and/or GCA.	('ESCC', 'Disease', (133, 137))	('rs13042395', 'Mutation', 'rs13042395', (97, 107))	('rs13042395 polymorphism', 'Var', (97, 120))	('C20orf54', 'Gene', (88, 96))	('C20orf54', 'Gene', '113278', (88, 96))	('GCA', 'Disease', (145, 148))
626371	26154995	The evaluation of the association between the C20orf54 rs13042395 polymorphism and the susceptibility to ESCC and GCA is presented in Table 3.	('ESCC', 'Disease', (105, 109))	('GCA', 'Disease', (114, 117))	('rs13042395', 'Mutation', 'rs13042395', (55, 65))	('C20orf54', 'Gene', (46, 54))	('rs13042395', 'Var', (55, 65))	('C20orf54', 'Gene', '113278', (46, 54))
626372	26154995	Overall analysis indicated that the variant T allele of rs13042395 could significantly decrease the risk of ESCC and/or GCA in all genetic models (T vs. C: OR = 0.95, 95% CI = 0.92-0.97, P < 0.01; CT vs. CC: OR = 0.94, 95% CI = 0.88-0.99, P = 0.04; TT vs. CC: OR = 0.91, 95% CI = 0.83-0.99, P = 0.04; CT + TT vs. CC: OR = 0.94, 95% CI = 0.89-0.99, P = 0.01) except recessive model (TT vs. CT + CC: OR = 0.93, 95% CI = 0.86-1.02, P = 0.12) (Fig.	('rs13042395', 'Mutation', 'rs13042395', (56, 66))	('variant', 'Var', (36, 43))	('rs13042395', 'Var', (56, 66))	('decrease', 'NegReg', (87, 95))	('ESCC', 'Disease', (108, 112))	('GCA', 'Disease', (120, 123))
626373	26154995	The association between C20orf54 rs13042395 polymorphism and ESCC risk was explored in eight studies.	('C20orf54', 'Gene', (24, 32))	('C20orf54', 'Gene', '113278', (24, 32))	('ESCC', 'Disease', (61, 65))	('rs13042395', 'Mutation', 'rs13042395', (33, 43))	('rs13042395 polymorphism', 'Var', (33, 56))
626374	26154995	The results indicated that the C20orf54 rs13042395 genotype subtly decreased the risk of ESCC, as revealed by the allele genetic model (T vs. C: OR = 0.95, 95% CI = 0.90-0.99, P = 0.02) (Table 3).	('C20orf54', 'Gene', '113278', (31, 39))	('ESCC', 'Disease', (89, 93))	('C20orf54', 'Gene', (31, 39))	('decreased', 'NegReg', (67, 76))	('rs13042395', 'Mutation', 'rs13042395', (40, 50))	('rs13042395', 'Var', (40, 50))
626376	26154995	The C20orf54 rs13042395 polymorphism was associated with a decreased risk of GCA (T vs. C: OR = 0.95, 95% CI = 0.91-0.98, P < 0.01) (Table 3).	('C20orf54', 'Gene', (4, 12))	('C20orf54', 'Gene', '113278', (4, 12))	('rs13042395', 'Var', (13, 23))	('decreased', 'NegReg', (59, 68))	('GCA', 'Disease', (77, 80))	('rs13042395', 'Mutation', 'rs13042395', (13, 23))
626378	26154995	Furthermore, the subgroup analysis was stratified by BMI, C20orf54 rs13042395 polymorphism was significantly associated with a subtly decreased cancer risk in under-weight group (T vs. C: OR = 0.87, 95% CI = 0.77-0.98, P = 0.02; TT vs. CC: OR = 0.70, 95% CI = 0.52-0.93, P = 0.02; TT vs. CT + CC: OR = 0.74, 95% CI = 0.56-0.98, P = 0.04) and normal weight group (T vs. C: OR = 0.85, 95% CI = 0.80-0.91, P < 0.01; TC vs. CC: OR = 0.82, 95% CI = 0.75-0.89, P < 0.01; CT + TT vs. CC: OR = 0.81, 95% CI = 0.75-0.88, P < 0.01), but no association was observed in over weight group (Table 4).	('decreased', 'NegReg', (134, 143))	('C20orf54', 'Gene', (58, 66))	('C20orf54', 'Gene', '113278', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('rs13042395 polymorphism', 'Var', (67, 90))	('rs13042395', 'Mutation', 'rs13042395', (67, 77))	('rat', 'Species', '10116', (41, 44))	('polymorphism', 'Var', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
626380	26154995	Results from previous individual published studies investigating the associations between C20orf54 rs13042395 polymorphism and cancer risk (ESCC and/or GCA) were inconclusive.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs13042395', 'Var', (99, 109))	('associations', 'Interaction', (69, 81))	('C20orf54', 'Gene', (90, 98))	('C20orf54', 'Gene', '113278', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('rs13042395', 'Mutation', 'rs13042395', (99, 109))
626381	26154995	The present study is considered to be the first quantitative meta-analysis concerning the effect of C20orf54 rs13042395 polymorphism on risks of ESCC and GCA and specific stratified analysis (smoking status, drinking status and BMI).	('rs13042395', 'Var', (109, 119))	('C20orf54', 'Gene', (100, 108))	('C20orf54', 'Gene', '113278', (100, 108))	('rat', 'Species', '10116', (173, 176))	('GCA', 'Disease', (154, 157))	('rs13042395', 'Mutation', 'rs13042395', (109, 119))	('ESCC', 'Disease', (145, 149))
626382	26154995	By analyzing the data that extracted from 10 published studies, we revealed that C20orf54 rs13042395 polymorphism might be associated with decreased ESCC and GCA risk especially for under-weight and normal weight groups.	('C20orf54', 'Gene', '113278', (81, 89))	('ESCC', 'Disease', (149, 153))	('decreased ESCC', 'Phenotype', 'HP:0025022', (139, 153))	('rs13042395', 'Mutation', 'rs13042395', (90, 100))	('rs13042395', 'Var', (90, 100))	('decreased', 'NegReg', (139, 148))	('C20orf54', 'Gene', (81, 89))	('GCA', 'Disease', (158, 161))
626383	26154995	The genetic basis of ESCC and GCA between a large number of SNPs and disease predisposition has been explored, and the rs13042395 in C20orf54 was significantly associated with ESCC and GCA risk in the GWAS among Chinese population.	('ESCC', 'Disease', (176, 180))	('rs13042395', 'Var', (119, 129))	('C20orf54', 'Gene', (133, 141))	('GCA', 'Disease', (185, 188))	('rs13042395', 'Mutation', 'rs13042395', (119, 129))	('associated with', 'Reg', (160, 175))	('C20orf54', 'Gene', '113278', (133, 141))
626384	26154995	However, other two Chinese population-based GWASs both failed to expore a significant association of rs13042395 with the risk of ESCC and GCA.	('GCA', 'Disease', (138, 141))	('rs13042395', 'Mutation', 'rs13042395', (101, 111))	('rs13042395', 'Var', (101, 111))	('ESCC', 'Disease', (129, 133))
626385	26154995	In the present study, we identified a significant association of rs13042395 with the risk of ESCC and GCA.	('rs13042395', 'Mutation', 'rs13042395', (65, 75))	('association', 'Reg', (50, 61))	('rs13042395', 'Var', (65, 75))	('GCA', 'Disease', (102, 105))	('ESCC', 'Disease', (93, 97))
626390	26154995	Interestingly, our results indicated that smoking and drinking did not significantly alter the effects of C20orf54 rs13042395 polymorphism on the risk of ESCC and/or GCA.	('C20orf54', 'Gene', '113278', (106, 114))	('rs13042395', 'Mutation', 'rs13042395', (115, 125))	('GCA', 'Disease', (166, 169))	('ESCC', 'Disease', (154, 158))	('rs13042395', 'Var', (115, 125))	('C20orf54', 'Gene', (106, 114))
626391	26154995	In the present study, the C20orf54 rs13042395 T allele significantly decreased the risk of ESCC and/or GCA in the subjects with BMI less than 24 especially between 18.5 to 24.	('C20orf54', 'Gene', '113278', (26, 34))	('GCA', 'Disease', (103, 106))	('rs13042395 T', 'Var', (35, 47))	('ESCC', 'Disease', (91, 95))	('rs13042395', 'Mutation', 'rs13042395', (35, 45))	('decreased', 'NegReg', (69, 78))	('C20orf54', 'Gene', (26, 34))
626396	26154995	In summary, current data suggest that C20orf54 rs13042395may be associated with a significantly decreased risk of ESCC and GCA, especially for the subjects with BMI less than 24 particularly between 18.5 to 24.	('C20orf54', 'Gene', (38, 46))	('ESCC', 'Disease', (114, 118))	('rs13042395may', 'Var', (47, 60))	('decreased', 'NegReg', (96, 105))	('C20orf54', 'Gene', '113278', (38, 46))	('GCA', 'Disease', (123, 126))	('rs13042395', 'Mutation', 'rs13042395', (47, 57))
626397	26154995	We comprehensively identified studies through searching PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Wanfang database using terms "C20orf54", "RFT2" and "rs13042395" for both case-control and cohort studies, which evaluated the association between C20orf54 rs13042395 polymorphism and the risk of ESCC and/or GCA (last search update: March 24, 2015).	('C20orf54', 'Gene', '113278', (171, 179))	('C20orf54', 'Gene', (171, 179))	('RFT2', 'Gene', (183, 187))	('rs13042395', 'Mutation', 'rs13042395', (297, 307))	('rs13042395 polymorphism', 'Var', (297, 320))	('rs13042395', 'Mutation', 'rs13042395', (194, 204))	('C20orf54', 'Gene', (288, 296))	('GCA', 'Disease', (349, 352))	('C20orf54', 'Gene', '113278', (288, 296))	('RFT2', 'Gene', '113278', (183, 187))	('ESCC', 'Disease', (337, 341))	('polymorphism', 'Var', (308, 320))
626398	26154995	Studies were included in the analysis if following criteria were met: (i) based on case-control studies (including cohort studies and GWASs) examined the associations between the C20orf54 rs13042395 and ESCC or GCA; (ii) sufficient allele or genotype data for estimating an odds ratio (OR) with corresponding 95% confidence intervals (95%CIs); (iii) genotype distribution of control groups must be in accordance with the assumptions of Hardy-Weinberg equilibrium (HWE).	('Hardy-Weinberg equilibrium', 'Disease', (436, 462))	('associations', 'Interaction', (154, 166))	('rs13042395', 'Var', (188, 198))	('C20orf54', 'Gene', '113278', (179, 187))	('GCA', 'Disease', (211, 214))	('ESCC', 'Disease', (203, 207))	('rs13042395', 'Mutation', 'rs13042395', (188, 198))	('rat', 'Species', '10116', (279, 282))	('C20orf54', 'Gene', (179, 187))
626400	26154995	Data for analyses, including first author, publication year, study design, ethnicity, cancer type, source of control, detection methods of C20orf54 rs13042395 polymorphism and quality control or not, characteristics of cases and controls.	('polymorphism', 'Var', (159, 171))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs13042395 polymorphism', 'Var', (148, 171))	('C20orf54', 'Gene', (139, 147))	('rs13042395', 'Mutation', 'rs13042395', (148, 158))	('C20orf54', 'Gene', '113278', (139, 147))	('cancer', 'Disease', (86, 92))
626403	26154995	RevMan 5.0 was used to estimate the association between C20orf54 rs13042395 polymorphism and cancer risk by the pooled ORs with corresponding to 95%CIs.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('rs13042395', 'Mutation', 'rs13042395', (65, 75))	('C20orf54', 'Gene', (56, 64))	('C20orf54', 'Gene', '113278', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rs13042395', 'Var', (65, 75))
626431	25023649	The ESCC cell lines, including Kyse140, Kyse30, Kyse510, Kyse520, Eca109, TE-1, Kyse410, Kyse180, EC18, HKESC1 and 108CA, were grown in the Dulbecco's modified Eagle's medium (DMEM, Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (FBS) (HyClone, Logan, UT, USA), 100 units of penicillin and 100 units of streptomycin at 37 C in a 5% CO2 atmosphere in a humidified incubator.	('HKESC1', 'CellLine', 'CVCL:D568', (104, 110))	('Kyse410', 'Chemical', '-', (80, 87))	('Kyse180', 'Var', (89, 96))	('Kyse30', 'Var', (40, 46))	('Kyse140', 'Var', (31, 38))	('FBS', 'Disease', 'MESH:D005198', (255, 258))	('CO2', 'Gene', '717', (357, 360))	('bovine', 'Species', '9913', (241, 247))	('Kyse520', 'Var', (57, 64))	('Kyse510', 'Var', (48, 55))	('CO2', 'Gene', (357, 360))	('FBS', 'Disease', (255, 258))	('Kyse410', 'Var', (80, 87))
626459	25023649	Real-time PCR analysis revealed that miR-208 expression was markedly increased in all eleven ESCC cell lines, including Kyse140, Kyse30, Kyse510, Kyse520, Eca109, TE-1, Kyse410, Kyse180, EC18, HKESC1 and 108CA, compared with that in NEEC (Figure 1A).	('Kyse140', 'Var', (120, 127))	('Kyse520', 'Var', (146, 153))	('Kyse410', 'Chemical', '-', (169, 176))	('increased', 'PosReg', (69, 78))	('Kyse510', 'Var', (137, 144))	('Kyse30', 'Var', (129, 135))	('Kyse180', 'Var', (178, 185))	('HKESC1', 'CellLine', 'CVCL:D568', (193, 199))	('expression', 'MPA', (45, 55))	('miR-208', 'Gene', (37, 44))	('miR-208', 'Gene', '406990', (37, 44))	('Kyse410', 'Var', (169, 176))
626482	25023649	The MTT assay and the colony formation assay both showed that silencing SOX6 in miR-208 inhibitor transfected cells increased the growth rate of the cells (Figure 5B and C).	('silencing', 'Var', (62, 71))	('SOX6', 'Gene', (72, 76))	('miR-208', 'Gene', (80, 87))	('SOX6', 'Gene', '55553', (72, 76))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('miR-208', 'Gene', '406990', (80, 87))	('growth rate of the cells', 'CPA', (130, 154))	('increased', 'PosReg', (116, 125))
626493	25023649	Inhibition of miR-208 improved cardiac function and patient survival during heart failure.	('miR-208', 'Gene', (14, 21))	('cardiac function', 'CPA', (31, 47))	('miR-208', 'Gene', '406990', (14, 21))	('improved cardiac function', 'Phenotype', 'HP:0001635', (22, 47))	('heart failure', 'Phenotype', 'HP:0001635', (76, 89))	('heart failure', 'Disease', 'MESH:D006333', (76, 89))	('patient survival', 'CPA', (52, 68))	('Inhibition', 'Var', (0, 10))	('heart failure', 'Disease', (76, 89))	('patient', 'Species', '9606', (52, 59))	('improved', 'PosReg', (22, 30))
626498	25023649	Systematic reporter studies have shown that functional regulation by miRNAs is highly sensitive to base pair mismatches within nucleotides 2-8 of the miRNA, which have been defined as the seed region.	('miR', 'Gene', (150, 153))	('base pair mismatches', 'Var', (99, 119))	('miR', 'Gene', '29116', (150, 153))	('sensitive', 'Reg', (86, 95))	('miR', 'Gene', (69, 72))	('functional regulation', 'MPA', (44, 65))	('miR', 'Gene', '29116', (69, 72))
626499	25023649	The functional importance of seed region complementarity as the major determinant of miRNA targeting has well established, which the microRNAs with mutation in the seed sequences could not genetically match with target genes and fail to inhibit the target genes expression.	('mutation', 'Var', (148, 156))	('miR', 'Gene', '29116', (85, 88))	('miR', 'Gene', (85, 88))
626501	25023649	Consistently, miR-208 with mutated seed sequence failed to show an inhibitory effect on the luciferase activity of SOX6.	('mutated', 'Var', (27, 34))	('miR-208', 'Gene', (14, 21))	('luciferase', 'Enzyme', (92, 102))	('activity', 'MPA', (103, 111))	('miR-208', 'Gene', '406990', (14, 21))	('SOX6', 'Gene', (115, 119))	('SOX6', 'Gene', '55553', (115, 119))
626572	22533738	High expression of Skp2 was associated with poor overall survival in resectable ESCC (p = 0.01).	('overall survival', 'MPA', (49, 65))	('High', 'Var', (0, 4))	('poor', 'NegReg', (44, 48))	('Skp2', 'Gene', '6502', (19, 23))	('Skp2', 'Gene', (19, 23))	('ESCC', 'Disease', (80, 84))
626625	22533738	In patients with negative Skp2 expression, the 2-year, 3-year, and 5-year survival rates were 78.5%, 68.3%, and 49.9%, respectively, with a median survival of 60.0 months.	('negative', 'Var', (17, 25))	('patients', 'Species', '9606', (3, 11))	('Skp2', 'Gene', '6502', (26, 30))	('Skp2', 'Gene', (26, 30))
626626	22533738	In patients with positive Skp2 expression, the 2-year, 3-year, and 5-year survival rates were 61.5%, 43.0%, and 30.4%, respectively, with a median survival of 32.6 months.	('positive', 'Var', (17, 25))	('patients', 'Species', '9606', (3, 11))	('Skp2', 'Gene', '6502', (26, 30))	('expression', 'Var', (31, 41))	('Skp2', 'Gene', (26, 30))
626627	22533738	Patients with positive Skp2 expression exhibited decreased survival time compared with those with negative expression (p = 0.001, Figure 2).	('survival time', 'CPA', (59, 72))	('Skp2', 'Gene', '6502', (23, 27))	('decreased', 'NegReg', (49, 58))	('Patients', 'Species', '9606', (0, 8))	('positive', 'Var', (14, 22))	('expression', 'Var', (28, 38))	('Skp2', 'Gene', (23, 27))
626630	22533738	Hence, we performed a MTT assay to assess the effect of Skp2 on cell proliferation in ESCC cell lines, including KYSE30, KYSE140 and KYSE180.	('MTT', 'Chemical', 'MESH:C070243', (22, 25))	('Skp2', 'Gene', '6502', (56, 60))	('KYSE30', 'Var', (113, 119))	('KYSE180', 'CellLine', 'CVCL:1349', (133, 140))	('Skp2', 'Gene', (56, 60))	('KYSE140', 'Var', (121, 128))	('KYSE180', 'Var', (133, 140))	('KYSE140', 'CellLine', 'CVCL:1347', (121, 128))
626633	22533738	In contrast, we utilized siRNA specifically targeting Skp2 to knockdown the protein level of Skp2 (Figure 3) and found that decreased expression of Skp2 attenuated the proliferation of ESCC cells (the right panels of Figure 4A-C).	('Skp2', 'Gene', '6502', (148, 152))	('proliferation', 'CPA', (168, 181))	('Skp2', 'Gene', '6502', (93, 97))	('expression', 'MPA', (134, 144))	('Skp2', 'Gene', (148, 152))	('Skp2', 'Gene', (93, 97))	('protein level', 'MPA', (76, 89))	('decreased', 'NegReg', (124, 133))	('Skp2', 'Gene', '6502', (54, 58))	('attenuated', 'NegReg', (153, 163))	('ESCC', 'Disease', (185, 189))	('Skp2', 'Gene', (54, 58))	('knockdown', 'Var', (62, 71))
626636	22533738	Except that KYSE140 cells seldom or never formed colonies in plates (data not shown), in both KYSE30 and KYSE180 cell lines, overexpression of Skp2 could dramatically enhance the potential of colony formation (the upper panels of Figure 5A and 5C, see also the left panels of Figure 5B and 5D).	('enhance', 'PosReg', (167, 174))	('KYSE180', 'CellLine', 'CVCL:1349', (105, 112))	('KYSE180', 'Var', (105, 112))	('colony formation', 'CPA', (192, 208))	('Skp2', 'Gene', '6502', (143, 147))	('overexpression', 'PosReg', (125, 139))	('KYSE140', 'CellLine', 'CVCL:1347', (12, 19))	('Skp2', 'Gene', (143, 147))
626637	22533738	Conversely, knockdown of Skp2 led to a significant decrease in colony-forming efficiency (the lower panels of Figure 5A and 5C, see also the right panels of Figure 5B-5D).	('colony-forming efficiency', 'CPA', (63, 88))	('Skp2', 'Gene', (25, 29))	('knockdown', 'Var', (12, 21))	('decrease', 'NegReg', (51, 59))	('Skp2', 'Gene', '6502', (25, 29))
626641	22533738	With the constant treatment of MG132 at the concentration of 10 muM, the proliferation of all the three cell lines was significantly aborted.	('proliferation', 'CPA', (73, 86))	('MG132', 'Chemical', 'MESH:C072553', (31, 36))	('aborted', 'NegReg', (133, 140))	('MG132', 'Var', (31, 36))
626642	22533738	However, KYSE30 cells could be highly eliminated with the treatment of 1 muM MG132 as well, showing much higher sensitivity to the inhibition of MG132 than KYSE140 and KYSE180 cells (Figure 6A-6C).	('sensitivity', 'MPA', (112, 123))	('KYSE140', 'CellLine', 'CVCL:1347', (156, 163))	('higher', 'PosReg', (105, 111))	('MG132', 'Var', (145, 150))	('MG132', 'Chemical', 'MESH:C072553', (145, 150))	('KYSE180', 'CellLine', 'CVCL:1349', (168, 175))	('MG132', 'Chemical', 'MESH:C072553', (77, 82))
626644	22533738	Taken together, our data indicated that inhibition of protein ubiqutination could depress the cell proliferation and colony formation in ESCC cells, suggesting the potential application of proteasome inhibitor in the therapy for human ESCC.	('inhibition', 'Var', (40, 50))	('depress', 'NegReg', (82, 89))	('human', 'Species', '9606', (229, 234))	('protein', 'Protein', (54, 61))	('cell proliferation', 'CPA', (94, 112))	('colony formation', 'CPA', (117, 133))
626655	22533738	In the present study, we initially showed that high expression of Skp2 in tumor cell nuclei was associated with advanced local invasion of primary carcinoma.	('primary carcinoma', 'Disease', (139, 156))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('associated', 'Reg', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Skp2', 'Gene', (66, 70))	('high expression', 'Var', (47, 62))	('primary carcinoma', 'Disease', 'MESH:D002277', (139, 156))	('tumor', 'Disease', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('Skp2', 'Gene', '6502', (66, 70))
626657	22533738	Multivariate Cox proportional hazards analysis further confirmed that high Skp2 expression was an unfavorable prognostic factor independent of conventional prognostic factors, such as T categories and N categories.	('Cox', 'Gene', (13, 16))	('Skp2', 'Gene', '6502', (75, 79))	('T categories', 'Disease', (184, 196))	('expression', 'MPA', (80, 90))	('high', 'Var', (70, 74))	('Skp2', 'Gene', (75, 79))	('Cox', 'Gene', '1351', (13, 16))
626683	22533738	As a consequence, the presence of a Skp2 inhibitor might advance ESCC therapeutic strategy.	('advance', 'PosReg', (57, 64))	('Skp2', 'Gene', '6502', (36, 40))	('ESCC', 'Disease', (65, 69))	('Skp2', 'Gene', (36, 40))	('presence', 'Var', (22, 30))
626687	29440913	However, the association between MLH1 methylation and esophageal cancer (EC), as well as its clinical significance, remains unclear.	('MLH1', 'Gene', (33, 37))	('methylation', 'Var', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('MLH1', 'Gene', '4292', (33, 37))
626689	29440913	In addition, we observed that MLH1 promoter methylation was associated with age (odds ratio [OR]=1.79; 95% CI =1.20-2.66), advanced tumor grade (OR=3.7; 95% CI =2.37-5.77), lymph node metastasis (OR=2.65; 95% CI =1.81-3.88), distant metastasis (OR=7.60; 95% CI =1.23-47.19), advanced clinical stage (OR=4.46; 95% CI =2.88-6.91), and poor prognosis in EC patients (hazard ratio =1.64, 95% CI =1.00-2.69).	('methylation', 'Var', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('distant metastasis', 'CPA', (225, 243))	('MLH1', 'Gene', '4292', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('lymph node metastasis', 'CPA', (173, 194))	('MLH1', 'Gene', (30, 34))	('tumor', 'Disease', (132, 137))	('patients', 'Species', '9606', (354, 362))	('associated', 'Reg', (60, 70))
626690	29440913	The pooled sensitivity, specificity, and area under the curve of MLH1 methylation in EC patients versus healthy individuals were 0.15, 0.99, and 0.77, respectively.	('MLH1', 'Gene', (65, 69))	('methylation', 'Var', (70, 81))	('patients', 'Species', '9606', (88, 96))	('MLH1', 'Gene', '4292', (65, 69))
626691	29440913	Our findings indicate that MLH1 methylation is involved in the carcinogenesis, progression, and metastasis of EC.	('methylation', 'Var', (32, 43))	('metastasis', 'CPA', (96, 106))	('involved', 'Reg', (47, 55))	('MLH1', 'Gene', '4292', (27, 31))	('MLH1', 'Gene', (27, 31))	('carcinogenesis', 'Disease', 'MESH:D063646', (63, 77))	('carcinogenesis', 'Disease', (63, 77))
626692	29440913	Moreover, methylated MLH1 could be a potential diagnostic and prognostic biomarker for EC.	('methylated', 'Var', (10, 20))	('MLH1', 'Gene', '4292', (21, 25))	('MLH1', 'Gene', (21, 25))
626701	29440913	Encompassing complicated aspects of cancer development, epigenetic modification is considered to have a crucial role in the carcinogenesis of EC.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('epigenetic modification', 'Var', (56, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('carcinogenesis', 'Disease', (124, 138))
626702	29440913	As one of the most important epigenetic alterations, abnormal DNA methylation in the promoter region induces transcriptional silencing of tumor suppressor genes (TSGs) and plays an important role in the progression of several cancers, such as cervical cancer, hepatocellular carcinoma, and head and neck squamous cell carcinoma.	('silencing', 'NegReg', (125, 134))	('tumor', 'Disease', (138, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (290, 327))	('TSG', 'Gene', '57045', (162, 165))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (260, 284))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('TSG', 'Gene', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('transcriptional', 'MPA', (109, 124))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('hepatocellular carcinoma', 'Disease', (260, 284))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('neck squamous cell carcinoma', 'Disease', (299, 327))	('cervical cancer', 'Disease', (243, 258))	('cervical cancer', 'Disease', 'MESH:D002583', (243, 258))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (299, 327))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('role', 'Reg', (191, 195))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (260, 284))	('cancers', 'Disease', (226, 233))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (304, 327))	('abnormal DNA methylation', 'Var', (53, 77))
626703	29440913	In addition, aberrant methylation has been shown to occur early in the progression of precancerous lesions to EC.	('methylation', 'MPA', (22, 33))	('precancerous lesions', 'Disease', 'MESH:D011230', (86, 106))	('precancerous lesions', 'Disease', (86, 106))	('aberrant', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
626704	29440913	Moreover, due to precise and convenient methods of detection, DNA methylation has become a noninvasive biomarker for the early detection and diagnosis of cancer.	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DNA', 'Var', (62, 65))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))
626705	29440913	The mutL homolog-1 (MLH1) gene on chromosome 3p22.3 is a key component of the DNA mismatch repair (MMR) pathway, which is a system for recognizing and repairing erroneous insertion, deletion, and misincorporation of bases during DNA replication and is critical for maintaining genomic stability.	('mutL homolog-1', 'Gene', (4, 18))	('erroneous insertion', 'Var', (161, 180))	('MLH1', 'Gene', '4292', (20, 24))	('MLH1', 'Gene', (20, 24))	('deletion', 'Var', (182, 190))	('mutL homolog-1', 'Gene', '4292', (4, 18))	('misincorporation', 'Var', (196, 212))
626706	29440913	Inactivation of MLH1 was reported to be a contributing factor in the initiation and development of gastrointestinal cancer exhibiting high-frequency microsatellite instability.	('MLH1', 'Gene', '4292', (16, 20))	('MLH1', 'Gene', (16, 20))	('gastrointestinal cancer', 'Disease', (99, 122))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (99, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (99, 122))	('Inactivation', 'Var', (0, 12))
626707	29440913	Moreover, hypermethylation of the MLH1 gene promoter was shown to be responsible for the loss of MLH1 expression in a wide variety of cancers, including lung cancer, colorectal cancer, gastric carcinoma, ovarian cancer, and ECs.	('hypermethylation', 'Var', (10, 26))	('ovarian cancer', 'Disease', (204, 218))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('ovarian cancer', 'Phenotype', 'HP:0100615', (204, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('colorectal cancer', 'Disease', 'MESH:D015179', (166, 183))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('colorectal cancer', 'Disease', (166, 183))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('MLH1', 'Gene', (34, 38))	('lung cancer', 'Disease', (153, 164))	('ovarian cancer', 'Disease', 'MESH:D010051', (204, 218))	('MLH1', 'Gene', (97, 101))	('loss', 'NegReg', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('gastric carcinoma', 'Disease', 'MESH:D013274', (185, 202))	('expression', 'MPA', (102, 112))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (166, 183))	('MLH1', 'Gene', '4292', (34, 38))	('gastric carcinoma', 'Disease', (185, 202))	('MLH1', 'Gene', '4292', (97, 101))	('ECs', 'Disease', (224, 227))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (185, 202))
626712	29440913	In addition, we assessed the diagnostic value of MLH1 methylation for EC.	('methylation', 'Var', (54, 65))	('MLH1', 'Gene', '4292', (49, 53))	('MLH1', 'Gene', (49, 53))
626713	29440913	We used the following key words and search terms, individually as well as in various combinations: "MLH1," "hMLH1," "MutL homolog-1," "methylation," "DNA methylation," "promoter methylation," "esophageal carcinoma," "esophagus cancer," "esophageal tumor," and "esophageal malignancy."	('MLH1', 'Gene', (109, 113))	('esophageal tumor', 'Disease', (237, 253))	('esophageal tumor', 'Phenotype', 'HP:0100751', (237, 253))	('MLH1', 'Gene', (100, 104))	('MutL homolog-1', 'Gene', '4292', (117, 131))	('esophageal malignancy', 'Disease', (261, 282))	('esophagus cancer', 'Disease', (217, 233))	('MLH1', 'Gene', '4292', (109, 113))	('methylation', 'Var', (135, 146))	('hMLH1', 'Gene', (108, 113))	('MLH1', 'Gene', '4292', (100, 104))	('MutL homolog-1', 'Gene', (117, 131))	('hMLH1', 'Gene', '4292', (108, 113))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (193, 213))	('esophagus cancer', 'Disease', 'MESH:D004938', (217, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('esophageal tumor', 'Disease', 'MESH:D004938', (237, 253))	('promoter methylation', 'Var', (169, 189))	('esophageal malignancy', 'Disease', 'MESH:D004938', (261, 282))	('esophageal carcinoma', 'Disease', (193, 213))	('DNA', 'Var', (150, 153))	('esophageal malignancy', 'Phenotype', 'HP:0100751', (261, 282))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (193, 213))
626716	29440913	The following information was extracted: first author, publication year, countries, the ethnicity of subjects, the number of samples, control source, methods to detect MLH1 methylation, frequency of MLH1 methylation, HR and the corresponding 95% CI for EC patients with methylated MLH1, and clinicopathological characteristics (including age, gender, smoking history, alcohol consumption, tumor location, differentiation grade, tumor stage, lymph node metastasis, distant metastasis, and clinical stage).	('tumor', 'Phenotype', 'HP:0002664', (389, 394))	('tumor', 'Phenotype', 'HP:0002664', (428, 433))	('MLH1', 'Gene', '4292', (168, 172))	('MLH1', 'Gene', '4292', (199, 203))	('differentiation grade', 'CPA', (405, 426))	('methylation', 'Var', (204, 215))	('methylation', 'Var', (173, 184))	('methylated', 'Var', (270, 280))	('lymph node metastasis', 'CPA', (441, 462))	('MLH1', 'Gene', (281, 285))	('tumor', 'Disease', (389, 394))	('distant metastasis', 'CPA', (464, 482))	('tumor', 'Disease', (428, 433))	('alcohol', 'Chemical', 'MESH:D000438', (368, 375))	('tumor', 'Disease', 'MESH:D009369', (389, 394))	('tumor', 'Disease', 'MESH:D009369', (428, 433))	('patients', 'Species', '9606', (256, 264))	('MLH1', 'Gene', '4292', (281, 285))	('MLH1', 'Gene', (168, 172))	('MLH1', 'Gene', (199, 203))
626717	29440913	The pooled ORs and corresponding 95% CIs were used to evaluate the strengths of the associations between MLH1 methylation and the development of EC carcinogenesis, along with clinicopathological features of EC patients.	('MLH1', 'Gene', (105, 109))	('EC carcinogenesis', 'Disease', (145, 162))	('associations', 'Interaction', (84, 96))	('methylation', 'Var', (110, 121))	('patients', 'Species', '9606', (210, 218))	('EC carcinogenesis', 'Disease', 'MESH:D063646', (145, 162))	('MLH1', 'Gene', '4292', (105, 109))
626718	29440913	HRs with 95% CIs were calculated to evaluate the association between MLH1 methylation and the prognosis of EC patients.	('methylation', 'Var', (74, 85))	('association', 'Interaction', (49, 60))	('MLH1', 'Gene', '4292', (69, 73))	('MLH1', 'Gene', (69, 73))	('patients', 'Species', '9606', (110, 118))
626719	29440913	Pooled sensitivity and specificity were used to assess the diagnostic power of MLH1 methylation test for EC.	('MLH1', 'Gene', (79, 83))	('methylation', 'Var', (84, 95))	('MLH1', 'Gene', '4292', (79, 83))
626720	29440913	Fagan plot analysis was performed with 25%, 50%, and 75% pretest probability to assess the diagnostic power of MLH1 methylation in clinical practice for EC diagnosis.	('methylation', 'Var', (116, 127))	('MLH1', 'Gene', '4292', (111, 115))	('MLH1', 'Gene', (111, 115))
626724	29440913	The results of this subgroup analysis showed that MLH1 hypermethylation was significantly associated with EC in all subgroups (Table 2).	('hypermethylation', 'Var', (55, 71))	('MLH1', 'Gene', (50, 54))	('MLH1', 'Gene', '4292', (50, 54))	('associated', 'Reg', (90, 100))
626725	29440913	Furthermore, a total of six studies involving 191 ECs and 262 precancerous lesions were included to evaluate the association between the methylation of MLH1 in ECs and precancerous lesions.	('MLH1', 'Gene', (152, 156))	('association', 'Interaction', (113, 124))	('methylation', 'Var', (137, 148))	('ECs', 'Disease', (160, 163))	('MLH1', 'Gene', '4292', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('precancerous lesions', 'Disease', 'MESH:D011230', (168, 188))	('precancerous lesions', 'Disease', 'MESH:D011230', (62, 82))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('precancerous lesions', 'Disease', (62, 82))	('precancerous lesions', 'Disease', (168, 188))
626727	29440913	The analysis of the association between MLH1 methylation and esophageal precancerous lesions included 196 precancerous samples and 192 normal controls from five studies.	('esophageal precancerous lesions', 'Disease', (61, 92))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (75, 81))	('association', 'Interaction', (20, 31))	('cancer', 'Disease', (109, 115))	('methylation', 'Var', (45, 56))	('esophageal precancerous lesions', 'Disease', 'MESH:D011230', (61, 92))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MLH1', 'Gene', '4292', (40, 44))	('MLH1', 'Gene', (40, 44))
626730	29440913	Our analyses demonstrated that MLH1 methylation was significantly associated with age (OR=1.79; 95% CI =1.20-2.66; P<0.01), T grade (OR=3.7; 95% CI =2.37-5.77; P<0.01), lymph node metastasis (OR=2.65; 95% CI =1.81-3.88; P<0.01), distant metastasis (OR=7.60; 95% CI =1.23-47.19; P=0.03), and clinical stage (OR=4.46; 95% CI =2.88-6.91; P<0.01).	('T grade', 'CPA', (124, 131))	('lymph node metastasis', 'CPA', (169, 190))	('associated', 'Reg', (66, 76))	('distant metastasis', 'CPA', (229, 247))	('MLH1', 'Gene', '4292', (31, 35))	('MLH1', 'Gene', (31, 35))	('clinical stage', 'CPA', (291, 305))	('methylation', 'Var', (36, 47))
626733	29440913	The results revealed that MLH1 methylation was significantly associated with poor OS of EC patients (HR =1.64; 95% CI =1.00-2.69; P<0.05; Figure 5).	('patients', 'Species', '9606', (91, 99))	('MLH1', 'Gene', '4292', (26, 30))	('MLH1', 'Gene', (26, 30))	('methylation', 'Var', (31, 42))	('poor OS', 'Disease', (77, 84))	('associated', 'Reg', (61, 71))
626735	29440913	We further calculated the pooled sensitivity, specificity, and AUC and performed Fagan plot analysis from 15 case-control studies to evaluate the diagnostic value of MLH1 promoter methylation for EC patients.	('MLH1', 'Gene', (166, 170))	('MLH1', 'Gene', '4292', (166, 170))	('methylation', 'Var', (180, 191))	('patients', 'Species', '9606', (199, 207))
626736	29440913	The analysis demonstrated that the probabilities of a patient being diagnosed with EC were 89%, 96%, and 99%, respectively, if the MLH1 promoter methylation detection result was positive.	('patient', 'Species', '9606', (54, 61))	('methylation', 'Var', (145, 156))	('MLH1', 'Gene', '4292', (131, 135))	('MLH1', 'Gene', (131, 135))
626739	29440913	Aberrant DNA methylation in the TSG promoter has been identified as an important mechanism of tumorigenesis and progression of several cancers, including cervical cancer, oral cancer, and colorectal cancer.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('oral cancer', 'Disease', 'MESH:D009062', (171, 182))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Aberrant DNA methylation', 'Var', (0, 24))	('oral cancer', 'Disease', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('TSG', 'Gene', '57045', (32, 35))	('mechanism', 'Reg', (81, 90))	('colorectal cancer', 'Disease', (188, 205))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('TSG', 'Gene', (32, 35))	('cancers', 'Disease', (135, 142))	('cervical cancer', 'Disease', (154, 169))	('cervical cancer', 'Disease', 'MESH:D002583', (154, 169))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))
626740	29440913	In addition, as a relatively early molecular change, aberrant methylation was reported to be a potential biomarker for early cancer diagnosis.	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('aberrant methylation', 'Var', (53, 73))
626742	29440913	Several previous studies evaluated whether MLH1 promoter methylation is associated with EC risk, but the results of these studies were inconsistent because of the use of different histotypes, control types, population ethnicities, and detection methods.	('methylation', 'Var', (57, 68))	('MLH1', 'Gene', '4292', (43, 47))	('associated', 'Reg', (72, 82))	('MLH1', 'Gene', (43, 47))
626745	29440913	Moreover, the subgroup analysis based on ethnicity revealed that the OR of the association between MLH1 methylation and EC was higher for Caucasian populations than for Asian populations, indicating that the Caucasian population may be more susceptible to MLH1 promoter methylation.	('MLH1', 'Gene', '4292', (256, 260))	('MLH1', 'Gene', (256, 260))	('MLH1', 'Gene', '4292', (99, 103))	('MLH1', 'Gene', (99, 103))	('association', 'Interaction', (79, 90))	('methylation', 'Var', (104, 115))
626751	29440913	Moreover, the frequency of MLH1 methylation was markedly higher in premalignant lesions than in healthy controls.	('methylation', 'Var', (32, 43))	('higher', 'PosReg', (57, 63))	('MLH1', 'Gene', '4292', (27, 31))	('MLH1', 'Gene', (27, 31))	('premalignant lesions', 'Disease', (67, 87))
626752	29440913	These results collectively indicate that hypermethylation of the MLH1 promoter is involved in the onset and carcinogenesis of EC.	('hypermethylation', 'Var', (41, 57))	('involved', 'Reg', (82, 90))	('MLH1', 'Gene', '4292', (65, 69))	('MLH1', 'Gene', (65, 69))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))
626755	29440913	Our findings revealed that MLH1 promoter methylation was more likely to occur in elderly patients, which may account for the finding that patients aged >60 years showed a rapid increase in EC.	('MLH1', 'Gene', '4292', (27, 31))	('occur', 'Reg', (72, 77))	('MLH1', 'Gene', (27, 31))	('methylation', 'Var', (41, 52))	('increase', 'PosReg', (177, 185))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (138, 146))
626759	29440913	The results revealed that compared with EC patients with MLH1 promoter hypomethylation, those with MLH1 promoter hypermethylation had a 1.64-fold higher risk of poor OS, indicating that hypermethylation of the MLH1 promoter is a potential prognosis biomarker for EC patients.	('poor OS', 'Disease', (161, 168))	('patients', 'Species', '9606', (266, 274))	('MLH1', 'Gene', '4292', (57, 61))	('MLH1', 'Gene', (57, 61))	('patients', 'Species', '9606', (43, 51))	('MLH1', 'Gene', '4292', (99, 103))	('MLH1', 'Gene', (99, 103))	('hypermethylation', 'Var', (186, 202))	('MLH1', 'Gene', '4292', (210, 214))	('MLH1', 'Gene', (210, 214))
626763	29440913	The MLH1 methylation test exhibited a pooled sensitivity of 0.15, a specificity of 0.99, and an AUC of 0.77, indicating that MLH1 promoter methylation has a moderate diagnostic accuracy for EC.	('MLH1', 'Gene', '4292', (4, 8))	('MLH1', 'Gene', (4, 8))	('MLH1', 'Gene', '4292', (125, 129))	('MLH1', 'Gene', (125, 129))	('methylation', 'Var', (139, 150))
626766	29440913	The Fagan plot analysis demonstrated that if the pretest probabilities were assumed to be 25%, 50%, and 75%, then 89%, 96%, and 99% of patients would be correctly diagnosed with EC following positive MLH1 methylation tests, suggesting that methylated MLH1 has effective diagnostic power to distinguish EC patients from healthy individuals.	('patients', 'Species', '9606', (135, 143))	('MLH1', 'Gene', '4292', (251, 255))	('methylated', 'Var', (240, 250))	('patients', 'Species', '9606', (305, 313))	('MLH1', 'Gene', (251, 255))	('MLH1', 'Gene', '4292', (200, 204))	('diagnosed', 'Reg', (163, 172))	('methylation', 'Var', (205, 216))	('MLH1', 'Gene', (200, 204))
626768	29440913	This integrated analysis provided a strong evidence that MLH1 methylation is significantly associated with the carcinogenesis, progression, and metastasis of EC.	('carcinogenesis', 'Disease', (111, 125))	('MLH1', 'Gene', '4292', (57, 61))	('MLH1', 'Gene', (57, 61))	('progression', 'CPA', (127, 138))	('methylation', 'Var', (62, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('metastasis', 'CPA', (144, 154))	('associated with', 'Reg', (91, 106))
626769	29440913	In addition, methylated MLH1 is a promising biomarker for the diagnosis and prognosis of EC.	('MLH1', 'Gene', '4292', (24, 28))	('MLH1', 'Gene', (24, 28))	('methylated', 'Var', (13, 23))
626796	28321167	All cases that underwent esophageal ESD performed using FlushKnife-BTS or FlushKnife-BT at Kobe University Hospital and Kishiwada Tokushukai Hospital between October 2015 and January 2016 were retrospectively reviewed.	('FlushKnife-BTS', 'Gene', '1201', (56, 70))	('FlushKnife-BT', 'Chemical', '-', (74, 87))	('FlushKnife-BT', 'Chemical', '-', (56, 69))	('FlushKnife-BTS', 'Gene', (56, 70))	('FlushKnife-BT', 'Var', (74, 87))
626919	23301842	Overexpression of Cks1 and Cks2 has been reported to be associated with high aggressiveness and poor prognosis in a few malignancies, including prostate and hepatocellular carcinomas.	('Cks2', 'Gene', (27, 31))	('malignancies', 'Disease', 'MESH:D009369', (120, 132))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (157, 182))	('hepatocellular carcinomas', 'Disease', (157, 182))	('aggressiveness', 'Disease', (77, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (157, 182))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (157, 181))	('Cks1', 'Gene', '137529', (18, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (77, 91))	('malignancies', 'Disease', (120, 132))	('associated', 'Reg', (56, 66))	('Overexpression', 'Var', (0, 14))	('prostate', 'Disease', (144, 152))	('aggressiveness', 'Disease', 'MESH:D001523', (77, 91))	('Cks2', 'Gene', '1164', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('Cks1', 'Gene', (18, 22))
626976	23301842	Together, the results suggest that expressions of Cks1 and Cks2 have potential value for esophageal carcinoma diagnosis.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('Cks1', 'Gene', (50, 54))	('esophageal carcinoma', 'Disease', (89, 109))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (89, 109))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (89, 109))	('Cks1', 'Gene', '137529', (50, 54))	('Cks2', 'Gene', '1164', (59, 63))	('Cks2', 'Gene', (59, 63))	('expressions', 'Var', (35, 46))
626986	23301842	The percent of Cks1 high experssion at mRNA and protein levels is 53% (14 out of 26 cases).	('Cks1', 'Gene', (15, 19))	('high', 'Var', (20, 24))	('Cks1', 'Gene', '137529', (15, 19))
627014	23301842	The results suggest that abnormal expression of Cks1 and Cks2 may contribute to esophageal carcinoma's initiation and progression.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (80, 100))	('abnormal', 'Var', (25, 33))	('Cks1', 'Gene', '137529', (48, 52))	('Cks2', 'Gene', (57, 61))	("esophageal carcinoma's initiation", 'Disease', (80, 113))	('Cks2', 'Gene', '1164', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('contribute', 'Reg', (66, 76))	('Cks1', 'Gene', (48, 52))	("esophageal carcinoma's initiation", 'Disease', 'MESH:D004938', (80, 113))
627015	23301842	Alterations in gene expression in esophageal carcinoma may yield clues to their pathogenesis.	('esophageal carcinoma', 'Disease', (34, 54))	('Alterations', 'Var', (0, 11))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (34, 54))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (34, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
627381	33510558	The diagnoses of hypertension, dyslipidemia and DM were defined using anthropometric measurements or laboratory data (SBP = 140 mmHg or DBP = 90 mmHg; total cholesterol level >= 240 mg/dL; fasting glucose level >= 126 mg/dL) or ICD codes (ICD I10 to I13 or I15; E78; E11 to E14) and medication use, including antihypertensive medication, dyslipidemia medication or insulin or oral hypoglycemic agents.	('insulin', 'Gene', (365, 372))	('age', 'Gene', (394, 397))	('I15; E78; E11 to E14', 'Var', (257, 277))	('glucose', 'Chemical', 'MESH:D005947', (197, 204))	('DM', 'Disease', 'MESH:D009223', (48, 50))	('dyslipidemia', 'Disease', 'MESH:D050171', (338, 350))	('dyslipidemia', 'Phenotype', 'HP:0003119', (31, 43))	('dyslipidemia', 'Disease', (31, 43))	('hypertension', 'Disease', 'MESH:D006973', (17, 29))	('hypertension', 'Disease', (17, 29))	('age', 'Gene', '5973', (394, 397))	('dyslipidemia', 'Phenotype', 'HP:0003119', (338, 350))	('I10', 'Var', (243, 246))	('dyslipidemia', 'Disease', (338, 350))	('insulin', 'Gene', '3630', (365, 372))	('cholesterol', 'Chemical', 'MESH:D002784', (157, 168))	('hypertension', 'Phenotype', 'HP:0000822', (17, 29))	('hypoglycemic agents', 'Phenotype', 'HP:0001988', (381, 400))	('antihypertensive medication', 'Phenotype', 'HP:0000822', (309, 336))	('DM', 'Phenotype', 'HP:0000819', (48, 50))	('dyslipidemia', 'Disease', 'MESH:D050171', (31, 43))	('men', 'Species', '9606', (92, 95))
627382	33510558	In the subgroup analysis, the definition of chronic liver disease or liver cirrhosis was based on ICD codes (B15-B19, K70.3, K74.6).	('liver disease', 'Phenotype', 'HP:0001392', (52, 65))	('K74.6', 'Var', (125, 130))	('B15-B19', 'Var', (109, 116))	('K70.3', 'Var', (118, 123))	('liver cirrhosis', 'Disease', 'MESH:D008103', (69, 84))	('liver cirrhosis', 'Disease', (69, 84))	('chronic liver disease', 'Disease', (44, 65))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (69, 84))	('chronic liver disease', 'Disease', 'MESH:D058625', (44, 65))
627388	33510558	Cancer was defined based on both the registration codes for serious diseases and the following ICD-10 codes: C15 (esophageal); C16 (stomach); C18-20 (colorectal); C22.0, 22.2, 22.3, 22.4, 22.7, and 22.9 (liver); C22.1, C23, and C24 (gallbladder and biliary tract); and C25 (pancreatic).	('C23', 'Gene', '4691', (219, 222))	('C16', 'Var', (127, 130))	('age', 'Gene', (119, 122))	('C15', 'Gene', '51316', (109, 112))	('C22.0', 'Var', (163, 168))	('age', 'Gene', '5973', (119, 122))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('C22.1', 'Var', (212, 217))	('C15', 'Gene', (109, 112))	('C18-20', 'Var', (142, 148))	('C25', 'Var', (269, 272))	('C23', 'Gene', (219, 222))	('C24', 'Var', (228, 231))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
627401	33510558	Older age, current smoking, heavy drinking, hypertension, dyslipidemia, diabetes, high BMI, high waist circumference, elevated levels of fasting glucose, total cholesterol, triglycerides, AST, ALT and low physical activity were associated with increased GGT points in both men and women (P for trend < 0.001 for all; Table 1).	('hypertension', 'Disease', (44, 56))	('age', 'Gene', (6, 9))	('GGT', 'Gene', (254, 257))	('men', 'Species', '9606', (273, 276))	('levels', 'MPA', (127, 133))	('cholesterol', 'Chemical', 'MESH:D002784', (160, 171))	('AST', 'Gene', '26503', (188, 191))	('hypertension', 'Phenotype', 'HP:0000822', (44, 56))	('diabetes', 'Disease', (72, 80))	('triglycerides', 'Chemical', 'MESH:D014280', (173, 186))	('age', 'Gene', '5973', (6, 9))	('dyslipidemia', 'Disease', (58, 70))	('high', 'Var', (92, 96))	('hypertension', 'Disease', 'MESH:D006973', (44, 56))	('glucose', 'Chemical', 'MESH:D005947', (145, 152))	('dyslipidemia', 'Disease', 'MESH:D050171', (58, 70))	('GGT', 'Gene', '728226', (254, 257))	('elevated', 'PosReg', (118, 126))	('AST', 'Gene', (188, 191))	('total cholesterol', 'MPA', (154, 171))	('triglycerides', 'MPA', (173, 186))	('high', 'Var', (82, 86))	('women', 'Species', '9606', (281, 286))	('ALT', 'MPA', (193, 196))	('diabetes', 'Disease', 'MESH:D003920', (72, 80))	('men', 'Species', '9606', (283, 286))	('dyslipidemia', 'Phenotype', 'HP:0003119', (58, 70))	('high waist circumference', 'Phenotype', 'HP:0031819', (92, 116))	('increased', 'PosReg', (244, 253))	('low', 'NegReg', (201, 204))
627461	33510558	Among 3559109 participants, 43574 digestive cancers developed during a median of 6.8 years of follow-up.	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('developed', 'Reg', (52, 61))	('43574', 'Var', (28, 33))	('participants', 'Species', '9606', (14, 26))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
627468	32330901	Depletion of PDGFB significantly suppressed the proliferation, invasion and migration of cancer cells.	('proliferation', 'CPA', (48, 61))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Depletion', 'Var', (0, 9))	('PDGFB', 'Gene', '5155', (13, 18))	('cancer', 'Disease', (89, 95))	('suppressed', 'NegReg', (33, 43))	('PDGFB', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
627469	32330901	Inhibiting PDGFB induced cellular apoptosis and promoted the sensitivity to ionizing radiation (IR).	('PDGFB', 'Gene', (11, 16))	('Inhibiting', 'Var', (0, 10))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (61, 94))	('PDGFB', 'Gene', '5155', (11, 16))	('promoted', 'PosReg', (48, 56))	('sensitivity to ionizing radiation', 'MPA', (61, 94))
627492	32330901	According to the Chi-square test, change rates of PDGF-BB were probably associated with response to radiotherapy (p = 0.042).	('change', 'Var', (34, 40))	('PDGF-B', 'Gene', '5155', (50, 56))	('associated', 'Reg', (72, 82))	('PDGF-B', 'Gene', (50, 56))
627503	32330901	Moreover, the transwell assay was applied to show that PDGFB depletion also reduced cell invasion in both ESCC cell-lines (Figure 3D).	('PDGFB', 'Gene', '5155', (55, 60))	('depletion', 'Var', (61, 70))	('PDGFB', 'Gene', (55, 60))	('reduced', 'NegReg', (76, 83))	('cell invasion', 'CPA', (84, 97))
627504	32330901	Next, we conducted studies with the Annexin V-APC/PI apoptosis assay and observed that PDGFB gene silencing promoted the apoptosis of both cell-lines (Figure 3E).	('PDGFB', 'Gene', (87, 92))	('APC', 'Gene', '324', (46, 49))	('promoted', 'PosReg', (108, 116))	('APC', 'Gene', (46, 49))	('PDGFB', 'Gene', '5155', (87, 92))	('apoptosis', 'CPA', (121, 130))	('Annexin V', 'Gene', '308', (36, 45))	('Annexin V', 'Gene', (36, 45))	('gene silencing', 'Var', (93, 107))
627505	32330901	Put together, these results suggest that depletion of PDGFB inhibits ESCC cell growth and induces apoptosis.	('ESCC', 'Disease', (69, 73))	('apoptosis', 'CPA', (98, 107))	('PDGFB', 'Gene', '5155', (54, 59))	('induces', 'Reg', (90, 97))	('depletion', 'Var', (41, 50))	('inhibits', 'NegReg', (60, 68))	('PDGFB', 'Gene', (54, 59))
627508	32330901	This result suggests that inhibition of PDGFB increases radio-sensitivity in ESCC cells.	('inhibition', 'Var', (26, 36))	('PDGFB', 'Gene', '5155', (40, 45))	('increases', 'PosReg', (46, 55))	('radio-sensitivity', 'MPA', (56, 73))	('PDGFB', 'Gene', (40, 45))
627516	32330901	It showed that the PI3K/AKT pathway was significantly activated by the addition of PDGF-BB in both the KYSE30 and KYSE150 cell-lines, and pretreatment with IR suppressed PDGF-BB-induced phosphorylation of PI3K and AKT in both cell-lines.	('PDGF-B', 'Gene', (83, 89))	('activated', 'PosReg', (54, 63))	('AKT', 'Gene', (24, 27))	('PI3K', 'Pathway', (205, 209))	('PDGF-B', 'Gene', '5155', (83, 89))	('PDGF-B', 'Gene', (170, 176))	('AKT', 'Gene', '207', (214, 217))	('KYSE150', 'CellLine', 'CVCL:1348', (114, 121))	('PDGF-B', 'Gene', '5155', (170, 176))	('suppressed', 'NegReg', (159, 169))	('addition', 'Var', (71, 79))	('AKT', 'Gene', '207', (24, 27))	('AKT', 'Gene', (214, 217))	('phosphorylation', 'MPA', (186, 201))
627542	32330901	Inhibiting PDGFB promoted the sensitivity of ESCC cells to IR.	('PDGFB', 'Gene', (11, 16))	('sensitivity', 'MPA', (30, 41))	('Inhibiting', 'Var', (0, 10))	('promoted', 'PosReg', (17, 25))	('PDGFB', 'Gene', '5155', (11, 16))
627700	30519093	Tissue microarrays were conducted on 209 surgically resected T3N1-3M0 ESCC tumors, including 163 pairs of primary tumors (PTs) and their corresponding metastatic lymph nodes (MLNs).	('primary tumors', 'Disease', (106, 120))	('primary tumors', 'Disease', 'MESH:D009369', (106, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('T3N1-3M0', 'Var', (61, 69))	('ESCC tumors', 'Disease', (70, 81))	('MLN', 'Gene', (175, 178))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ESCC tumors', 'Disease', 'MESH:D004938', (70, 81))	('MLN', 'Gene', '4295', (175, 178))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
627705	30519093	High expression of HDAC6 in MLNs but not in PTs suggests a poor prognosis for patients with resected T3N1-3M0 ESCC.	('T3N1-3M0', 'Var', (101, 109))	('MLN', 'Gene', '4295', (28, 31))	('expression', 'MPA', (5, 15))	('patients', 'Species', '9606', (78, 86))	('MLN', 'Gene', (28, 31))	('HDAC6', 'Gene', (19, 24))
627721	30519093	Its dysregulation relates to many kinds of cancers, with variable effects; high expression of HDAC6 has been shown to be associated with tumor development in hepatocellular cancer, pancreatic cancer, and glioblastoma, while decreased expression has been found to be associated with the suppression of proliferation, migration, or invasion in breast cancer, lung cancer, and gastric cancer.	('glioblastoma', 'Disease', 'MESH:D005909', (204, 216))	('high expression', 'Var', (75, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (181, 198))	('breast cancer', 'Disease', (342, 355))	('lung cancer', 'Disease', (357, 368))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (374, 388))	('proliferation', 'CPA', (301, 314))	('glioblastoma', 'Disease', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('pancreatic cancer', 'Disease', (181, 198))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('migration', 'CPA', (316, 325))	('suppression', 'NegReg', (286, 297))	('hepatocellular cancer', 'Disease', (158, 179))	('HDAC6', 'Gene', (94, 99))	('lung cancer', 'Disease', 'MESH:D008175', (357, 368))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (158, 179))	('gastric cancer', 'Phenotype', 'HP:0012126', (374, 388))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('tumor', 'Disease', (137, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (357, 368))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (158, 179))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (181, 198))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (342, 355))	('associated', 'Reg', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('gastric cancer', 'Disease', (374, 388))	('invasion', 'CPA', (330, 338))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (342, 355))
627727	30519093	Additional selection criteria included 1) pathological proof of thoracic T3N1-3M0 ESCC according to the eighth edition American Joint Committee on Cancer TNM staging system, 2) the absence of neoadjuvant or adjuvant therapy, 3) complete surgical resection, 4) and sufficient formalin-fixed and paraffin-embedded PT and MLN samples for tissue micro-arrays (TMAs).	('TNM', 'Gene', (154, 157))	('TMAs', 'Chemical', '-', (356, 360))	('MLN', 'Gene', (319, 322))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('MLN', 'Gene', '4295', (319, 322))	('paraffin', 'Chemical', 'MESH:D010232', (294, 302))	('formalin', 'Chemical', 'MESH:D005557', (275, 283))	('TNM', 'Gene', '10178', (154, 157))	('T3N1-3M0', 'Var', (73, 81))
627763	30519093	The 5-year OS rates for high and low HDAC6 expression in MLNs were 12.1% and 21.4%, respectively (Figure 3A and B).	('low', 'NegReg', (33, 36))	('OS', 'Chemical', '-', (11, 13))	('MLN', 'Gene', (57, 60))	('high', 'Var', (24, 28))	('MLN', 'Gene', '4295', (57, 60))	('HDAC6', 'Gene', (37, 42))
627765	30519093	The 5-year OS rates for high and low HDAC6 expression in PTs were 17.4% and 18.0%, respectively (Figure 3C and D).	('HDAC6', 'Gene', (37, 42))	('OS', 'Chemical', '-', (11, 13))	('low', 'Var', (33, 36))
627770	30519093	In patients with pN2 and pN3, there was no significant difference in OS or DFS between high and low HDAC6 expression in MLNs (Figure 4C-F).	('pN3', 'Gene', (25, 28))	('pN3', 'Gene', '6336', (25, 28))	('pN2', 'Gene', (17, 20))	('OS', 'Chemical', '-', (69, 71))	('pN2', 'Gene', '351', (17, 20))	('MLN', 'Gene', (120, 123))	('HDAC6', 'Gene', (100, 105))	('high', 'Var', (87, 91))	('patients', 'Species', '9606', (3, 11))	('low', 'Var', (96, 99))	('MLN', 'Gene', '4295', (120, 123))	('DFS', 'MPA', (75, 78))
627783	30519093	Our previous study also revealed that high expression of C-terminal Hsp-interacting protein (CHIP) in MLNs suggests a poor prognosis for patients with resected T3N1-3M0 ESCC.	('C-terminal Hsp-interacting protein', 'Protein', (57, 91))	('MLN', 'Gene', (102, 105))	('patients', 'Species', '9606', (137, 145))	('MLN', 'Gene', '4295', (102, 105))	('T3N1-3M0 ESCC', 'Var', (160, 173))	('expression', 'MPA', (43, 53))
627786	30519093	In an ESCC in vitro model, Li et al confirmed its role in tumor progression by showing that cell proliferation and migration could both be significantly reduced after HDAC6 inhibition.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('HDAC6', 'Gene', (167, 172))	('migration', 'CPA', (115, 124))	('reduced', 'NegReg', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cell proliferation', 'CPA', (92, 110))	('inhibition', 'Var', (173, 183))
627796	30519093	HDAC6 expression was decreased in MLNs compared to their paired PTs and may serve as an independent predictor for prognosis of complete surgically resected T3N1-3M0 ESCC patients.	('patients', 'Species', '9606', (170, 178))	('HDAC6', 'Gene', (0, 5))	('decreased', 'NegReg', (21, 30))	('expression', 'MPA', (6, 16))	('T3N1-3M0 ESCC', 'Var', (156, 169))	('MLN', 'Gene', (34, 37))	('MLN', 'Gene', '4295', (34, 37))
627805	30233226	Multiple mechanisms are related to the development of ESCC in achalasia, and they include bacterial overgrowth, food stasis, genetic alterations, and chronic inflammation.	('genetic alterations', 'Var', (125, 144))	('ESCC', 'Disease', (54, 58))	('men', 'Species', '9606', (46, 49))	('overgrowth', 'Phenotype', 'HP:0001548', (100, 110))	('achalasia', 'Phenotype', 'HP:0002571', (62, 71))	('inflammation', 'Disease', 'MESH:D007249', (158, 170))	('achalasia', 'Disease', (62, 71))	('achalasia', 'Disease', 'MESH:D004931', (62, 71))	('food stasis', 'Disease', (112, 123))	('inflammation', 'Disease', (158, 170))
627843	30233226	The cyclin D1 (CCND1) G870A polymorphism has also been associated with ESCC.	('G870A', 'Var', (22, 27))	('ESCC', 'Disease', (71, 75))	('CCND1', 'Gene', (15, 20))	('associated', 'Reg', (55, 65))	('CCND1', 'Gene', '595', (15, 20))	('cyclin D1', 'Gene', '595', (4, 13))	('G870A', 'Mutation', 'rs9344', (22, 27))	('cyclin D1', 'Gene', (4, 13))
627885	30233226	Regarding p53, in addition to overexpression in ESCC with achalasia, there are also mutational changes of that tumor suppressor.	('achalasia', 'Disease', 'MESH:D004931', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('p53', 'Gene', '7157', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('p53', 'Gene', (10, 13))	('achalasia', 'Phenotype', 'HP:0002571', (58, 67))	('mutational changes', 'Var', (84, 102))	('tumor', 'Disease', (111, 116))	('ESCC', 'Disease', (48, 52))	('achalasia', 'Disease', (58, 67))
627887	30233226	Other genetic abnormalities described in ESCC associated with achalasia include mutations that could be associated with advanced megaesophagus due to Chagas disease.	('Chagas disease', 'Disease', (150, 164))	('mutations', 'Var', (80, 89))	('advanced megaesophagus', 'Disease', (120, 142))	('genetic abnormalities', 'Disease', 'MESH:D030342', (6, 27))	('associated', 'Reg', (104, 114))	('ESCC', 'Disease', (41, 45))	('genetic abnormalities', 'Disease', (6, 27))	('achalasia', 'Phenotype', 'HP:0002571', (62, 71))	('Chagas disease', 'Disease', 'MESH:D014355', (150, 164))	('associated', 'Reg', (46, 56))	('achalasia', 'Disease', (62, 71))	('achalasia', 'Disease', 'MESH:D004931', (62, 71))
627888	30233226	A silent mutation at codon 88 of exon 7 of the FHIT gene and a mutation involving exon 6 of the TP53 gene, as well as mutations in exons 5 and 7 of that gene, have been reported.	('FHIT', 'Gene', (47, 51))	('TP53', 'Gene', (96, 100))	('mutations', 'Var', (118, 127))	('FHIT', 'Gene', '2272', (47, 51))	('TP53', 'Gene', '7157', (96, 100))
627920	30233226	Finally, several preventive strategies are under investigation to prevent ESCC (achalasia related or nonrelated) using agents such as nonsteroidal antiinflammatory drugs, selenium, alpha-difluoromethylornithine, and retinoids.	('achalasia', 'Disease', (80, 89))	('alpha-difluoromethylornithine', 'Var', (181, 210))	('retinoids', 'Chemical', 'MESH:D012176', (216, 225))	('achalasia', 'Disease', 'MESH:D004931', (80, 89))	('ESCC', 'Disease', (74, 78))	('alpha-difluoromethylornithine', 'Chemical', 'MESH:D000518', (181, 210))	('selenium', 'Chemical', 'MESH:D012643', (171, 179))	('achalasia', 'Phenotype', 'HP:0002571', (80, 89))
627928	30002691	The expression levels of UCA1 and MALAT1 lncRNAs in ESCC tissues were significantly higher than those in adjacent carcinoma tissues, and there were statistically significant differences in TNM staging between the patients with high lncRNA expression and low lncRNA expression.	('MALAT1', 'Gene', (34, 40))	('expression levels', 'MPA', (4, 21))	('carcinoma tissues', 'Disease', 'MESH:D009380', (114, 131))	('significant differences', 'Reg', (162, 185))	('TNM', 'Gene', '10178', (189, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinoma tissues', 'Disease', (114, 131))	('high lncRNA expression', 'Var', (227, 249))	('MALAT1', 'Gene', '378938', (34, 40))	('UCA1', 'Gene', '652995', (25, 29))	('ESCC', 'Disease', (52, 56))	('TNM', 'Gene', (189, 192))	('UCA1', 'Gene', (25, 29))	('patients', 'Species', '9606', (213, 221))	('higher', 'PosReg', (84, 90))
627929	30002691	The OS and DFS of patients with high UCA1 and MALAT1 lncRNA expression levels were significantly shorter than those with low expression levels.	('high', 'Var', (32, 36))	('DFS', 'CPA', (11, 14))	('UCA1', 'Gene', '652995', (37, 41))	('MALAT1', 'Gene', '378938', (46, 52))	('UCA1', 'Gene', (37, 41))	('shorter', 'NegReg', (97, 104))	('patients', 'Species', '9606', (18, 26))	('MALAT1', 'Gene', (46, 52))
627945	30002691	The enhanced MALAT1 expression levels were positively correlated with clinical stages, primary tumor size, and lymph node metastasis, and inhibition of MALAT1 suppressed tumor proliferation in vitro and in vivo, as well as the migratory and invasive capacity.	('MALAT1', 'Gene', (13, 19))	('inhibition', 'Var', (138, 148))	('expression levels', 'MPA', (20, 37))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('enhanced', 'PosReg', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('MALAT1', 'Gene', '378938', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (170, 175))	('lymph node metastasis', 'Disease', (111, 132))	('lymph node metastasis', 'Disease', 'MESH:D009362', (111, 132))	('suppressed', 'NegReg', (159, 169))	('MALAT1', 'Gene', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('MALAT1', 'Gene', '378938', (13, 19))	('tumor', 'Disease', (95, 100))
627946	30002691	Furthermore, silencing of MALAT1 could significantly suppress the proliferation of ESCC cells through the arrest of the G2/M cell cycle, which may be due to MALAT1-mediated up-regulation of p21 and p27 expression and the inhibition of B-MYB expression.	('p27', 'Gene', (198, 201))	('inhibition', 'NegReg', (221, 231))	('MALAT1', 'Gene', (157, 163))	('B-MYB', 'Gene', (235, 240))	('proliferation', 'CPA', (66, 79))	('expression', 'MPA', (202, 212))	('expression', 'MPA', (241, 251))	('up-regulation', 'PosReg', (173, 186))	('p21', 'Gene', (190, 193))	('suppress', 'NegReg', (53, 61))	('arrest', 'CPA', (106, 112))	('MALAT1', 'Gene', '378938', (26, 32))	('B-MYB', 'Gene', '4605', (235, 240))	('p27', 'Gene', '10671', (198, 201))	('MALAT1', 'Gene', (26, 32))	('p21', 'Gene', '644914', (190, 193))	('silencing', 'Var', (13, 22))	('MALAT1', 'Gene', '378938', (157, 163))
627947	30002691	Recently, animal experiments showed that knockdown of MALAT1 decreased tumor formation and improved survival.	('improved', 'PosReg', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('survival', 'CPA', (100, 108))	('MALAT1', 'Gene', '378938', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('MALAT1', 'Gene', (54, 60))	('decreased', 'NegReg', (61, 70))	('tumor', 'Disease', (71, 76))	('knockdown', 'Var', (41, 50))
627959	30002691	The relative expression levels of UCA1 were 0.485 +-0.248 in ESCC tissues and 0.199 +-0.122 in adjacent carcinoma tissues, with a significant difference (t = 10.348, p < 0.05).	('0.199 +-0.122', 'Var', (78, 91))	('carcinoma tissues', 'Disease', 'MESH:D009380', (104, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('expression', 'MPA', (13, 23))	('ESCC', 'Disease', (61, 65))	('carcinoma tissues', 'Disease', (104, 121))	('UCA1', 'Gene', '652995', (34, 38))	('UCA1', 'Gene', (34, 38))
627962	30002691	Clinical characteristics were compared between groups and the difference in TNM staging between the high UCA1 expression group and the low UCA1 expression group as well as between the high MALAT1 expression group and the low MALAT1 expression group was statistically significant (chi2 = 12.257, 26.839, p < 0.05).	('MALAT1', 'Gene', '378938', (189, 195))	('UCA1', 'Gene', '652995', (105, 109))	('UCA1', 'Gene', '652995', (139, 143))	('UCA1', 'Gene', (105, 109))	('UCA1', 'Gene', (139, 143))	('MALAT1', 'Gene', (189, 195))	('MALAT1', 'Gene', '378938', (225, 231))	('high', 'Var', (100, 104))	('TNM', 'Gene', '10178', (76, 79))	('MALAT1', 'Gene', (225, 231))	('TNM', 'Gene', (76, 79))
627963	30002691	The OS and DFS of patients with high UCA1 and MALAT1 lncRNA expression in ESCC tissues were significantly lower than those of patients with low expression levels (chi2 = 4.880, 5.894, 8.635, 8.906, p < 0.05).	('high', 'Var', (32, 36))	('lower', 'NegReg', (106, 111))	('UCA1', 'Gene', '652995', (37, 41))	('MALAT1', 'Gene', '378938', (46, 52))	('UCA1', 'Gene', (37, 41))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (18, 26))	('MALAT1', 'Gene', (46, 52))
627967	30002691	The OS and DFS of patients with high expression of UCA1 and MALAT1 lncRNAs in ESCC tissues were found to be significantly lower than those of patients with low expression levels, suggesting that the high expression of these two types of lncRNA played a role in determining OS and DFS.	('lower', 'NegReg', (122, 127))	('DFS', 'CPA', (11, 14))	('MALAT1', 'Gene', '378938', (60, 66))	('patients', 'Species', '9606', (18, 26))	('UCA1', 'Gene', '652995', (51, 55))	('patients', 'Species', '9606', (142, 150))	('UCA1', 'Gene', (51, 55))	('MALAT1', 'Gene', (60, 66))	('high expression', 'Var', (32, 47))
627973	30002691	Previous studies have found that the inhibition of MALAT1 can up-regulate the expression of caspase-8, caspase-3 and Bax, and down-regulate the expression of Bcl-2 and Bcl-xL, all of which were related to the development ESCC.	('Bcl-2', 'Gene', '596', (158, 163))	('inhibition', 'Var', (37, 47))	('expression', 'MPA', (78, 88))	('MALAT1', 'Gene', '378938', (51, 57))	('Bcl-xL', 'Gene', '598', (168, 174))	('caspase-3', 'Gene', '836', (103, 112))	('up-regulate', 'PosReg', (62, 73))	('down-regulate', 'NegReg', (126, 139))	('expression', 'MPA', (144, 154))	('Bax', 'Gene', '581', (117, 120))	('MALAT1', 'Gene', (51, 57))	('Bcl-xL', 'Gene', (168, 174))	('caspase-8', 'Gene', (92, 101))	('caspase-8', 'Gene', '841', (92, 101))	('caspase-3', 'Gene', (103, 112))	('Bcl-2', 'Gene', (158, 163))	('Bax', 'Gene', (117, 120))
627974	30002691	The expression of MALAT1 in ESCC tissues at the middle-advanced stage has been found to be higher than that at the early stage, and the amplitude of the up-regulation is associated with the progression of tumor TNM staging and lymph node metastasis, suggesting that the inhibition of MALAT1 could stagnate the proliferation of ESCC tumor cells.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('expression', 'MPA', (4, 14))	('MALAT1', 'Gene', (18, 24))	('proliferation', 'CPA', (310, 323))	('lymph node metastasis', 'Disease', (227, 248))	('TNM', 'Gene', '10178', (211, 214))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('TNM', 'Gene', (211, 214))	('MALAT1', 'Gene', '378938', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('ESCC', 'Disease', (327, 331))	('MALAT1', 'Gene', (284, 290))	('inhibition', 'Var', (270, 280))	('higher', 'PosReg', (91, 97))	('stagnate', 'NegReg', (297, 305))	('MALAT1', 'Gene', '378938', (284, 290))	('tumor', 'Disease', (332, 337))	('lymph node metastasis', 'Disease', 'MESH:D009362', (227, 248))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('tumor', 'Disease', (205, 210))
627996	28638583	Magnesium deficiency may increase or decrease the risk of carcinogenesis paradoxically, too.	('decrease', 'NegReg', (37, 45))	('Magnesium', 'Chemical', 'MESH:D008274', (0, 9))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('Magnesium deficiency', 'Phenotype', 'HP:0002917', (0, 20))	('carcinogenesis', 'Disease', (58, 72))	('deficiency', 'Var', (10, 20))	('Magnesium', 'Protein', (0, 9))
628006	28638583	In a case-control study from a high-risk area of esophageal cancer in India (Kashmir Valley), no association was found between copper concentration and TP53 mutation status but lower zinc levels were seen in patients with TP53 mutant tumor compared with those with no mutation.	('lower', 'NegReg', (177, 182))	('lower zinc levels', 'Phenotype', 'HP:0031831', (177, 194))	('copper', 'Chemical', 'MESH:D003300', (127, 133))	('tumor', 'Disease', (234, 239))	('esophageal cancer', 'Disease', (49, 66))	('mutant', 'Var', (227, 233))	('patients', 'Species', '9606', (208, 216))	('TP53', 'Gene', '7157', (152, 156))	('zinc levels', 'MPA', (183, 194))	('mutation', 'Var', (157, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('TP53', 'Gene', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('TP53', 'Gene', '7157', (222, 226))	('TP53', 'Gene', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
628010	28638583	In their study, a strong association was found between high tissue zinc concentration and reduced risk of developing esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (117, 151))	('reduced', 'NegReg', (90, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('esophageal squamous cell carcinoma', 'Disease', (117, 151))	('high', 'Var', (55, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
628135	27818599	However, the presence of HGD is associated with a greater relative risk for developing adenocarcinoma.	('adenocarcinoma', 'Disease', (87, 101))	('HGD', 'Gene', '3081', (25, 28))	('presence', 'Var', (13, 21))	('adenocarcinoma', 'Disease', 'MESH:D000230', (87, 101))	('HGD', 'Gene', (25, 28))
628158	19930673	Association between the methylenetetrahydrofolate reductase C677T polymorphism and hepatocellular carcinoma risk: a meta-analysis Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (83, 107))	('C677T', 'Mutation', 'rs1801133', (60, 65))	('methylenetetrahydrofolate reductase', 'Gene', (24, 59))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (83, 107))	('C677T', 'Var', (60, 65))	('MTHFR', 'Gene', (167, 172))	('Methylenetetrahydrofolate reductase', 'Gene', (130, 165))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (24, 59))	('hepatocellular carcinoma', 'Disease', (83, 107))	('folate', 'Chemical', 'MESH:D005492', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('Methylenetetrahydrofolate reductase', 'Gene', '4524', (130, 165))	('folate', 'Chemical', 'MESH:D005492', (149, 155))	('Association', 'Interaction', (0, 11))	('folate', 'Chemical', 'MESH:D005492', (211, 217))	('MTHFR', 'Gene', '4524', (167, 172))
628161	19930673	To shed light on the influence of MTHFR C677T polymorphism on HCC, a meta-analysis was conducted.	('C677T', 'Mutation', 'rs1801133', (40, 45))	('MTHFR', 'Gene', '4524', (34, 39))	('C677T', 'Var', (40, 45))	('HCC', 'Gene', (62, 65))	('MTHFR', 'Gene', (34, 39))	('HCC', 'Gene', '619501', (62, 65))	('HCC', 'Phenotype', 'HP:0001402', (62, 65))
628163	19930673	Using genetic model analysis, C677T polymorphism was found to increase the risk of HCC in a complete overdominant model, which indicates that heterozygotes CT are at a lesser risk of HCC than either homozygotes CC or TT.	('HCC', 'Gene', '619501', (183, 186))	('HCC', 'Phenotype', 'HP:0001402', (183, 186))	('HCC', 'Phenotype', 'HP:0001402', (83, 86))	('C677T', 'Mutation', 'rs1801133', (30, 35))	('C677T', 'Var', (30, 35))	('HCC', 'Gene', (183, 186))	('HCC', 'Gene', (83, 86))	('HCC', 'Gene', '619501', (83, 86))
628166	19930673	Meanwhile, the C677T polymorphism also increased HCC risk in a recessive model when cases were compared to CLD patients of four studies: RE OR reached 1.85 (95%CI: 1.00-3.42, p for heterogeneity = 0.06).	('CLD', 'Disease', (107, 110))	('C677T', 'Var', (15, 20))	('increased HCC', 'Phenotype', 'HP:0001899', (39, 52))	('HCC', 'Gene', (49, 52))	('CLD', 'Disease', 'None', (107, 110))	('HCC', 'Phenotype', 'HP:0001402', (49, 52))	('increased', 'PosReg', (39, 48))	('HCC', 'Gene', '619501', (49, 52))	('C677T', 'Mutation', 'rs1801133', (15, 20))	('patients', 'Species', '9606', (111, 119))
628167	19930673	MTHFR C677T polymorphism increased the risk of HCC in an overdominant model, and might be a risk factor for HCC occurrence, especially in CLD patients.	('CLD', 'Disease', (138, 141))	('MTHFR', 'Gene', '4524', (0, 5))	('HCC', 'Phenotype', 'HP:0001402', (108, 111))	('risk', 'Reg', (92, 96))	('increased', 'PosReg', (25, 34))	('HCC', 'Gene', (47, 50))	('CLD', 'Disease', 'None', (138, 141))	('C677T', 'Mutation', 'rs1801133', (6, 11))	('C677T', 'Var', (6, 11))	('MTHFR', 'Gene', (0, 5))	('HCC', 'Gene', '619501', (47, 50))	('HCC', 'Phenotype', 'HP:0001402', (47, 50))	('HCC', 'Gene', (108, 111))	('patients', 'Species', '9606', (142, 150))	('HCC', 'Gene', '619501', (108, 111))
628169	19930673	Genetic variation has been postulated to influence the variable risk for HCC observed both within and across populations.	('HCC', 'Gene', '619501', (73, 76))	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('Genetic variation', 'Var', (0, 17))	('HCC', 'Gene', (73, 76))
628178	19930673	The three software programs simultaneously predicted that C677T (rs1801133), which changes the amino acid Ala to Val, damages the protein function.	('C677T (rs1801133', 'Var', (58, 74))	('damages', 'NegReg', (118, 125))	('amino acid Ala', 'MPA', (95, 109))	('C677T', 'Mutation', 'rs1801133', (58, 63))	('Ala', 'Chemical', 'MESH:D000409', (106, 109))	('rs1801133', 'Var', (65, 74))	('Val', 'Chemical', 'MESH:D014633', (113, 116))	('protein', 'Protein', (130, 137))	('rs1801133', 'Mutation', 'rs1801133', (65, 74))
628179	19930673	The relationship of C677T and cancers has been widely studied.	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('C677T', 'Mutation', 'rs1801133', (20, 25))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('C677T', 'Var', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
628180	19930673	C677T was reported to be associated with prostate cancer, breast cancer, colorectal cancer, stomach cancer, bladder cancer, esophageal cancer, and leukemia, among others.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('esophageal cancer', 'Disease', (124, 141))	('associated', 'Reg', (25, 35))	('C677T', 'Mutation', 'rs1801133', (0, 5))	('colorectal cancer', 'Disease', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (41, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('stomach cancer', 'Disease', 'MESH:D013274', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('stomach cancer', 'Phenotype', 'HP:0012126', (92, 106))	('prostate cancer', 'Disease', (41, 56))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('C677T', 'Var', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('leukemia', 'Disease', (147, 155))	('leukemia', 'Disease', 'MESH:D007938', (147, 155))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('breast cancer', 'Disease', (58, 71))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('stomach cancer', 'Disease', (92, 106))
628181	19930673	A number of studies have explored the correlation of MTHFR C677T polymorphism and HCC, but the results are controversial.	('MTHFR', 'Gene', (53, 58))	('HCC', 'Gene', (82, 85))	('correlation', 'Interaction', (38, 49))	('C677T', 'Mutation', 'rs1801133', (59, 64))	('C677T', 'Var', (59, 64))	('HCC', 'Gene', '619501', (82, 85))	('HCC', 'Phenotype', 'HP:0001402', (82, 85))	('MTHFR', 'Gene', '4524', (53, 58))
628182	19930673	To shed light on the influence of MTHFR C677T polymorphism on HCC, a meta-analysis was carried out.	('C677T', 'Mutation', 'rs1801133', (40, 45))	('MTHFR', 'Gene', '4524', (34, 39))	('C677T', 'Var', (40, 45))	('HCC', 'Gene', (62, 65))	('MTHFR', 'Gene', (34, 39))	('HCC', 'Gene', '619501', (62, 65))	('HCC', 'Phenotype', 'HP:0001402', (62, 65))
628184	19930673	The reports and dissection database published in the Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), and Wan Fang (Chinese) database were also searched to collect articles of case-control studies or cohort studies on associations between MTHFR polymorphisms and susceptibility to HCC before May 2009.	('HCC', 'Gene', (315, 318))	('MTHFR', 'Gene', (273, 278))	('HCC', 'Gene', '619501', (315, 318))	('HCC', 'Phenotype', 'HP:0001402', (315, 318))	('associations', 'Interaction', (252, 264))	('polymorphisms', 'Var', (279, 292))	('MTHFR', 'Gene', '4524', (273, 278))
628185	19930673	Studies were selected if there were available data for MTHFR C677T polymorphism with the risk of HCC using a case-control or cohort design.	('C677T', 'Mutation', 'rs1801133', (61, 66))	('HCC', 'Phenotype', 'HP:0001402', (97, 100))	('C677T', 'Var', (61, 66))	('MTHFR', 'Gene', '4524', (55, 60))	('HCC', 'Gene', (97, 100))	('MTHFR', 'Gene', (55, 60))	('HCC', 'Gene', '619501', (97, 100))
628186	19930673	Studies that determined the distribution of the C677T genotype in cases with HCC diagnosed by histopathological biopsy or by elevated alpha-fetoprotein (AFP) and distinct iconography changes (CT, MRI, and B ultrasonography), and in controls free of cancer were eligible for inclusion in the meta-analysis.	('elevated', 'PosReg', (125, 133))	('AFP', 'Gene', (153, 156))	('HCC', 'Gene', '619501', (77, 80))	('alpha-fetoprotein', 'Gene', (134, 151))	('AFP', 'Gene', '174', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('HCC', 'Phenotype', 'HP:0001402', (77, 80))	('cancer', 'Disease', (249, 255))	('C677T', 'Mutation', 'rs1801133', (48, 53))	('C677T', 'Var', (48, 53))	('alpha-fetoprotein', 'Gene', '174', (134, 151))	('elevated alpha-fetoprotein', 'Phenotype', 'HP:0006254', (125, 151))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('HCC', 'Gene', (77, 80))
628189	19930673	If OR1>R2>1 and OR1>OR3>1 (or OR1<OR2<1 and OR1<OR3<1), then a codominant model is suggested.	('OR1<OR2<1', 'Gene', (30, 39))	('OR1>R2>1', 'Var', (3, 11))	('OR1<OR3', 'Var', (44, 51))	('OR1<OR2<1', 'Gene', '389090', (30, 39))	('OR1>OR3>1', 'Var', (16, 25))
628201	19930673	The meta-analysis of four studies (including 329 HCC cases and 625 CLD patients) showed a positive association of 677TT with HCC in CLD patients: pooled FE OR3 (TT/CT) reached 1.81 (95%CI: 1.22-2.71, p for heterogeneity = 0.25) (Figure 2), indicating that a complete overdominant model was still applicable.	('HCC', 'Gene', '619501', (125, 128))	('CLD', 'Disease', (67, 70))	('HCC', 'Phenotype', 'HP:0001402', (125, 128))	('CLD', 'Disease', (132, 135))	('patients', 'Species', '9606', (71, 79))	('HCC', 'Gene', (49, 52))	('CLD', 'Disease', 'None', (132, 135))	('CLD', 'Disease', 'None', (67, 70))	('HCC', 'Phenotype', 'HP:0001402', (49, 52))	('patients', 'Species', '9606', (136, 144))	('HCC', 'Gene', (125, 128))	('HCC', 'Gene', '619501', (49, 52))	('677TT', 'Var', (114, 119))
628205	19930673	Subgroup meta-analysis of (1) the comparison between the healthy controls and HCC cases of 10 studies; (2) five studies of European populations and (3) five studies of Asian populations all showed that 677T allele had a non-significantly increased risk of HCC and had a non-significant trend of overdominant model to HCC occurrence (detailed data not shown).	('HCC', 'Gene', (256, 259))	('HCC', 'Gene', (78, 81))	('HCC', 'Phenotype', 'HP:0001402', (317, 320))	('677T', 'Var', (202, 206))	('HCC', 'Gene', '619501', (256, 259))	('HCC', 'Gene', '619501', (78, 81))	('HCC', 'Phenotype', 'HP:0001402', (256, 259))	('HCC', 'Phenotype', 'HP:0001402', (78, 81))	('HCC', 'Gene', (317, 320))	('HCC', 'Gene', '619501', (317, 320))
628207	19930673	However, the sensitivity analysis showed that the association between C677T and HCC (TT vs. CT) of 10 studies (including all cases and controls) was vulnerable: when someone studies was omitted at a time, the 95%CI of the OR3 (TT/CT) model would include 1.0 (Figure 3).	('HCC', 'Gene', '619501', (80, 83))	('HCC', 'Phenotype', 'HP:0001402', (80, 83))	('C677T', 'Var', (70, 75))	('C677T', 'Mutation', 'rs1801133', (70, 75))	('HCC', 'Gene', (80, 83))
628208	19930673	Further, the sensitivity analysis showed that the association between C677T and HCC (TT vs. CT) was also vulnerable when CLD patients were used as controls (Figure 4).	('CLD', 'Disease', (121, 124))	('HCC', 'Gene', '619501', (80, 83))	('HCC', 'Phenotype', 'HP:0001402', (80, 83))	('CLD', 'Disease', 'None', (121, 124))	('C677T', 'Var', (70, 75))	('C677T', 'Mutation', 'rs1801133', (70, 75))	('HCC', 'Gene', (80, 83))	('patients', 'Species', '9606', (125, 133))
628209	19930673	When meta-analysis was performed in four studies using CLD patients as controls, the cumulative meta-analysis of the recessive model and the OR3 (TT/CT) of C677T showed a stable increased risk trend of HCC occurrence as evidences accumulated (figure not shown).	('C677T', 'Mutation', 'rs1801133', (156, 161))	('C677T', 'Var', (156, 161))	('CLD', 'Disease', 'None', (55, 58))	('HCC', 'Gene', (202, 205))	('patients', 'Species', '9606', (59, 67))	('HCC', 'Gene', '619501', (202, 205))	('HCC', 'Phenotype', 'HP:0001402', (202, 205))	('CLD', 'Disease', (55, 58))
628210	19930673	Because most HCC occurred in LC patients, MTHFR C677T polymorphism may have important clinical values.	('MTHFR', 'Gene', '4524', (42, 47))	('patients', 'Species', '9606', (32, 40))	('HCC', 'Gene', (13, 16))	('HCC', 'Gene', '619501', (13, 16))	('C677T', 'Mutation', 'rs1801133', (48, 53))	('occurred', 'Reg', (17, 25))	('C677T', 'Var', (48, 53))	('HCC', 'Phenotype', 'HP:0001402', (13, 16))	('MTHFR', 'Gene', (42, 47))	('LC', 'Phenotype', 'HP:0001394', (29, 31))
628218	19930673	Individuals who are heterozygous (CT) or homozygous (TT) for MTHFR C677T polymorphism have an in vitro enzyme activity that is 65% or 30% of that of wild-type homozygous (CC) individuals, respectively.	('C677T', 'Mutation', 'rs1801133', (67, 72))	('MTHFR', 'Gene', (61, 66))	('polymorphism', 'Var', (73, 85))	('activity', 'MPA', (110, 118))	('C677T polymorphism', 'Var', (67, 85))	('MTHFR', 'Gene', '4524', (61, 66))
628223	19930673	Impaired MTHFR activity, on the other hand, might influence cancer risk by the level of S-adenosyl-L-methionine, the common donor of the methyl group that is necessary for maintaining the methylation patterns in DNA.	('donor', 'Species', '9606', (124, 129))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('Impaired', 'Var', (0, 8))	('activity', 'MPA', (15, 23))	('S-adenosyl-L-methionine', 'Chemical', 'MESH:D012436', (88, 111))	('cancer', 'Disease', (60, 66))	('MTHFR', 'Gene', '4524', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('influence', 'Reg', (50, 59))	('MTHFR', 'Gene', (9, 14))
628226	19930673	This meta-analysis of 10 studies (1814 cases/2862 controls) showed that the CT heterozygotes of C677T polymorphism had the least risk of HCC, especially among CLD controls, supporting this hypothesis.	('HCC', 'Gene', (137, 140))	('CLD', 'Disease', 'None', (159, 162))	('C677T', 'Mutation', 'rs1801133', (96, 101))	('HCC', 'Gene', '619501', (137, 140))	('HCC', 'Phenotype', 'HP:0001402', (137, 140))	('C677T', 'Var', (96, 101))	('CLD', 'Disease', (159, 162))
628228	19930673	The meta-analysis in the current work was the first time which used genetic analysis to explore the genetic model underlying hepatocarcinogenesis and found that MTHFR C677T polymorphism increased the risk of HCC in a complete overdominant model, suggesting it might be a risk factor for HCC, especially in CLD patients.	('HCC', 'Gene', (287, 290))	('patients', 'Species', '9606', (310, 318))	('CLD', 'Disease', (306, 309))	('C677T', 'Var', (167, 172))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (125, 145))	('C677T', 'Mutation', 'rs1801133', (167, 172))	('HCC', 'Gene', '619501', (208, 211))	('HCC', 'Phenotype', 'HP:0001402', (208, 211))	('increased', 'PosReg', (186, 195))	('CLD', 'Disease', 'None', (306, 309))	('MTHFR', 'Gene', (161, 166))	('HCC', 'Gene', '619501', (287, 290))	('HCC', 'Phenotype', 'HP:0001402', (287, 290))	('hepatocarcinogenesis', 'Disease', (125, 145))	('HCC', 'Gene', (208, 211))	('MTHFR', 'Gene', '4524', (161, 166))
628229	19930673	However, sensitivity analysis showed that the association of C677T with HCC was not robust.	('C677T', 'Mutation', 'rs1801133', (61, 66))	('HCC', 'Phenotype', 'HP:0001402', (72, 75))	('C677T', 'Var', (61, 66))	('HCC', 'Gene', (72, 75))	('HCC', 'Gene', '619501', (72, 75))
628231	19930673	PAR (14.88%, 95%CI: 1.22-28.54) among the CLD patients indicated that the role of C677T polymorphism in HCC occurrence was modest.	('HCC', 'Phenotype', 'HP:0001402', (104, 107))	('C677T', 'Var', (82, 87))	('patients', 'Species', '9606', (46, 54))	('CLD', 'Disease', 'None', (42, 45))	('C677T', 'Mutation', 'rs1801133', (82, 87))	('HCC', 'Gene', (104, 107))	('HCC', 'Gene', '619501', (104, 107))	('CLD', 'Disease', (42, 45))
628234	19930673	Several studies have reported the association between MTHFR C677T polymorphism and various kinds of cancers, and a number of meta-analysis articles have summarized the effects.	('C677T polymorphism', 'Var', (60, 78))	('association', 'Interaction', (34, 45))	('C677T', 'Mutation', 'rs1801133', (60, 65))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('MTHFR', 'Gene', (54, 59))	('polymorphism', 'Var', (66, 78))	('MTHFR', 'Gene', '4524', (54, 59))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
628235	19930673	According to the results, the 677T allele increased the risk of breast cancer in premenopausal women, gastric cancer, bladder cancer, esophageal cancer, multiple myeloma, and non-Hodgkin lymphoma.	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastric cancer', 'Disease', (102, 116))	('multiple myeloma', 'Disease', (153, 169))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (175, 195))	('677T', 'Var', (30, 34))	('esophageal cancer', 'Disease', (134, 151))	('women', 'Species', '9606', (95, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (118, 132))	('bladder cancer', 'Disease', (118, 132))	('cancer in premenopausal women', 'Phenotype', 'HP:0008209', (71, 100))	('multiple myeloma', 'Phenotype', 'HP:0006775', (153, 169))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('bladder cancer', 'Phenotype', 'HP:0009725', (118, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('lymphoma', 'Phenotype', 'HP:0002665', (187, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (179, 195))	('multiple myeloma', 'Disease', 'MESH:D009101', (153, 169))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (175, 195))	('non-Hodgkin lymphoma', 'Disease', (175, 195))	('breast cancer', 'Disease', (64, 77))
628237	19930673	The discrepancy of the role of C677T on different cancers has yet to be elucidated.	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Disease', (50, 57))	('C677T', 'Mutation', 'rs1801133', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('C677T', 'Var', (31, 36))
628238	19930673	We postulate that it is the interaction between MTHFR polymorphism and folate and the balance of 5,10-methylene-THF and 5-methylene-THF determine the susceptibility of different kinds of cancers.	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('MTHFR', 'Gene', '4524', (48, 53))	('cancers', 'Disease', (187, 194))	('5,10-methylene-THF', 'Chemical', 'MESH:C013123', (97, 115))	('interaction', 'Interaction', (28, 39))	('polymorphism', 'Var', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('5-methylene-THF', 'Chemical', '-', (120, 135))	('MTHFR', 'Gene', (48, 53))	('folate', 'Chemical', 'MESH:D005492', (71, 77))	('determine', 'Reg', (136, 145))
628239	19930673	The carcinogenesis of breast cancer in premenopausal women, gastric cancer, bladder cancer, esophageal cancer, multiple myeloma, and non-Hodgkin lymphoma may be more related to genome hypomethylation, while the carcinogenesis of prostate cancer, colorectal cancer, and acute lymphoblastic leukemia may be more related to DNA synthesis.	('related', 'Reg', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (137, 153))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (269, 297))	('multiple myeloma', 'Disease', 'MESH:D009101', (111, 127))	('non-Hodgkin lymphoma', 'Disease', (133, 153))	('esophageal cancer', 'Disease', (92, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (133, 153))	('lymphoma', 'Phenotype', 'HP:0002665', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('genome hypomethylation', 'Var', (177, 199))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (133, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (246, 263))	('multiple myeloma', 'Disease', (111, 127))	('carcinogenesis of prostate cancer', 'Disease', 'MESH:D011471', (211, 244))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (275, 297))	('colorectal cancer', 'Disease', (246, 263))	('women', 'Species', '9606', (53, 58))	('gastric cancer', 'Disease', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('leukemia', 'Phenotype', 'HP:0001909', (289, 297))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('carcinogenesis of breast cancer', 'Disease', 'MESH:D063646', (4, 35))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('carcinogenesis of prostate cancer', 'Disease', (211, 244))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))	('bladder cancer', 'Disease', (76, 90))	('carcinogenesis of breast cancer', 'Disease', (4, 35))	('cancer in premenopausal women', 'Phenotype', 'HP:0008209', (29, 58))	('acute lymphoblastic leukemia', 'Disease', (269, 297))	('multiple myeloma', 'Phenotype', 'HP:0006775', (111, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (246, 263))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (269, 297))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
628244	19930673	The association between MTHFR C677T polymorphism and HCC warrants further examination, especially in other ethnicities.	('HCC', 'Gene', (53, 56))	('C677T', 'Mutation', 'rs1801133', (30, 35))	('MTHFR', 'Gene', '4524', (24, 29))	('HCC', 'Gene', '619501', (53, 56))	('HCC', 'Phenotype', 'HP:0001402', (53, 56))	('MTHFR', 'Gene', (24, 29))	('C677T polymorphism', 'Var', (30, 48))
628246	19930673	(MTHFR): methylenetetrahydrofolate reductase; (HCC): hepatocellular carcinoma; (SNP): single nucleotide polymorphism; (OR): odds ratio; (CI): confidence interval.	('HCC', 'Gene', (47, 50))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (53, 77))	('HCC', 'Gene', '619501', (47, 50))	('MTHFR', 'Gene', '4524', (1, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('hepatocellular carcinoma', 'Disease', (53, 77))	('single nucleotide polymorphism', 'Var', (86, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (53, 77))	('methylenetetrahydrofolate reductase', 'Gene', (9, 44))	('HCC', 'Phenotype', 'HP:0001402', (47, 50))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (9, 44))	('MTHFR', 'Gene', (1, 6))
628257	34039257	lncRNAs participate in embryogenesis, angiogenesis, and cancer progression by exerting epigenetic changes in many processes, including inactivation of X chromatin, regulation of the function of key metabolic genes, cell cycle control, and cell differentiation (Yao et al.	('X chromatin', 'Protein', (151, 162))	('cell cycle control', 'CPA', (215, 233))	('regulation', 'Reg', (164, 174))	('participate', 'Reg', (8, 19))	('function', 'MPA', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cell differentiation', 'CPA', (239, 259))	('inactivation', 'Var', (135, 147))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
628289	34039257	The effect of p53-regulated lncRNA TUG1 on the proliferation of non-small cell lung cancer cells was partly exerted through epigenetic regulation of homeobox B7 (HOXB7).	('homeobox B7', 'Gene', (149, 160))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('effect', 'Reg', (4, 10))	('HOXB7', 'Gene', '3217', (162, 167))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('HOXB7', 'Gene', (162, 167))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('exerted', 'Reg', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (64, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (68, 90))	('proliferation', 'CPA', (47, 60))	('homeobox B7', 'Gene', '3217', (149, 160))	('epigenetic regulation', 'Var', (124, 145))
628293	34039257	3. lncRNA TUG1 affected proliferation by regulating wnt/beta-catenin signal pathway, miR-384, miR-498, miR-29c, miR-299-3p, or microRNA-9, in oral squamous cell carcinoma, nasopharyngeal carcinoma,esophageal squamous cell carcinoma, pancreatic cancer, breast cancer, respectively.	('miR-498', 'Gene', '574460', (94, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (233, 250))	('miR-29c', 'Gene', (103, 110))	('affected', 'Reg', (15, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('beta-catenin', 'Gene', (56, 68))	('miR-498', 'Gene', (94, 101))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (172, 196))	('miR-299-3p', 'Var', (112, 122))	('beta-catenin', 'Gene', '1499', (56, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 170))	('microRNA-9', 'Var', (127, 137))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('oral squamous cell carcinoma', 'Disease', (142, 170))	('breast cancer', 'Disease', (252, 265))	('pancreatic cancer', 'Disease', 'MESH:D010190', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('carcinoma,esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (187, 231))	('miR-384', 'Gene', (85, 92))	('pancreatic cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('regulating', 'Reg', (41, 51))	('miR-384', 'Gene', '494333', (85, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('miR-29c', 'Gene', '407026', (103, 110))
628326	34039257	lncRNA TUG1 promoted the proliferation, migration, and invasion of osteosarcoma through competitively sponging of miR-219a-5p, resulting in the up-regulation of phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and the activation of the protein kinase B (AKT) signal pathway (Yang et al.).	('promoted', 'PosReg', (12, 20))	('protein kinase B', 'Gene', (268, 284))	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('proliferation', 'CPA', (25, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))	('up-regulation', 'PosReg', (144, 157))	('AKT', 'Gene', (286, 289))	('activation', 'PosReg', (250, 260))	('phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (161, 232))	('miR-219a-5p', 'Var', (114, 125))	('PIK3CA', 'Gene', (234, 240))	('protein kinase B', 'Gene', '2185', (268, 284))	('PIK3CA', 'Gene', '5290', (234, 240))	('invasion', 'CPA', (55, 63))	('migration', 'CPA', (40, 49))	('osteosarcoma', 'Disease', (67, 79))	('AKT', 'Gene', '207', (286, 289))
628328	34039257	To sum up, lncRNA TUG1 promoted invasion and metastasis by some molecule, including miR-143p, miR-9-5p, miR-212-3p, miR-219a-5p, miR-140-5p, miR-212-3p, miR-335-5p, miR-132-3p, SOX4, RUNX2, PFN2, ROCK1,FOXA1, or POU2F1 in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (222, 234))	('PFN2', 'Gene', (190, 194))	('SOX4', 'Gene', (177, 181))	('miR-212', 'Gene', '406994', (141, 148))	('ROCK1', 'Gene', (196, 201))	('miR-140', 'Gene', (129, 136))	('miR-143p', 'Gene', '406935', (84, 92))	('miR-335', 'Gene', (153, 160))	('promoted', 'PosReg', (23, 31))	('PFN2', 'Gene', '5217', (190, 194))	('miR-140', 'Gene', '406932', (129, 136))	('SOX4', 'Gene', '6659', (177, 181))	('miR-143p', 'Gene', (84, 92))	('miR-132-3p', 'Gene', (165, 175))	('miR-212', 'Gene', (104, 111))	('RUNX2', 'Gene', (183, 188))	('miR-9-5p', 'Gene', '407052', (94, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (222, 234))	('invasion', 'CPA', (32, 40))	('POU2F1', 'Gene', '5451', (212, 218))	('RUNX2', 'Gene', '860', (183, 188))	('ROCK1', 'Gene', '6093', (196, 201))	('FOXA1', 'Gene', '3169', (202, 207))	('miR-212', 'Gene', (141, 148))	('miR-9-5p', 'Gene', (94, 102))	('POU2F1', 'Gene', (212, 218))	('FOXA1', 'Gene', (202, 207))	('miR-212', 'Gene', '406994', (104, 111))	('miR-335', 'Gene', '442904', (153, 160))	('osteosarcoma', 'Disease', (222, 234))	('miR-132-3p', 'Gene', '100302255', (165, 175))	('miR-219a-5p', 'Var', (116, 127))
628336	34039257	lncRNA TUG1 knockout promoted cell growth by promoting cell cycle progression and regulating the expression of cyclinD1 and CDK4 (Fan et al.).	('lncRNA TUG1', 'Gene', (0, 11))	('cyclinD1', 'Gene', (111, 119))	('knockout', 'Var', (12, 20))	('CDK4', 'Gene', '1019', (124, 128))	('promoting', 'PosReg', (45, 54))	('regulating', 'Reg', (82, 92))	('cell cycle progression', 'CPA', (55, 77))	('cyclinD1', 'Gene', '595', (111, 119))	('promoted', 'PosReg', (21, 29))	('cell growth', 'CPA', (30, 41))	('expression', 'MPA', (97, 107))	('CDK4', 'Gene', (124, 128))
628353	34039257	In tongue squamous cell carcinoma, down-regulation of lncRNA TUG1 inhibited cell proliferation, and silencing of lncRNA TUG1 regulated the progression of the cell cycle (Li et al.).	('tongue squamous cell carcinoma', 'Disease', (3, 33))	('silencing', 'Var', (100, 109))	('progression of the cell cycle', 'CPA', (139, 168))	('cell proliferation', 'CPA', (76, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('inhibited', 'NegReg', (66, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))	('lncRNA TUG1', 'Gene', (54, 65))	('lncRNA TUG1', 'Gene', (113, 124))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 33))	('down-regulation', 'NegReg', (35, 50))	('regulated', 'Reg', (125, 134))
628354	34039257	TUG1 knockout blocked cell cycle, accelerated apoptosis and inhibitted the proliferation of pancreatic cancer cells (Hui Bingqing and Yetao).	('proliferation', 'CPA', (75, 88))	('apoptosis', 'CPA', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TUG1', 'Gene', (0, 4))	('knockout', 'Var', (5, 13))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('pancreatic cancer', 'Disease', (92, 109))	('accelerated', 'PosReg', (34, 45))	('blocked', 'NegReg', (14, 21))	('cell cycle', 'CPA', (22, 32))	('inhibitted', 'NegReg', (60, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))
628355	34039257	Knocking out the TUG1 reduced that enhancer of zeste homolog 2 (EZH2) binded to the promoter regions of Rho family GTPase 3 (RND3) and metallothionein 2A (MT2A) (Hui Bingqing and Yetao).	('TUG1', 'Gene', (17, 21))	('enhancer of zeste homolog 2', 'Gene', '2146', (35, 62))	('MT2A', 'Gene', '4502', (155, 159))	('metallothionein 2A', 'Gene', (135, 153))	('enhancer of zeste homolog 2', 'Gene', (35, 62))	('MT2A', 'Gene', (155, 159))	('binded', 'Interaction', (70, 76))	('EZH2', 'Gene', '2146', (64, 68))	('RND3', 'Gene', (125, 129))	('metallothionein 2A', 'Gene', '4502', (135, 153))	('EZH2', 'Gene', (64, 68))	('Knocking', 'Var', (0, 8))	('RND3', 'Gene', '390', (125, 129))
628360	34039257	lncRNA TUG1 knockout inhibited glucose consumption, lactic acid production, and reduced the cell viability of osteosarcoma cells.	('lactic acid production', 'MPA', (52, 74))	('lncRNA TUG1', 'Gene', (0, 11))	('knockout', 'Var', (12, 20))	('glucose consumption', 'MPA', (31, 50))	('osteosarcoma', 'Disease', (110, 122))	('reduced', 'NegReg', (80, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (110, 122))	('osteosarcoma', 'Disease', 'MESH:D012516', (110, 122))	('inhibited', 'NegReg', (21, 30))	('lactic acid', 'Chemical', 'MESH:D019344', (52, 63))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))
628362	34039257	The abnormal expression of lncRNA TUG1 significantly affected the expression of hexokinase-2 (HK2), which might be an important molecule through which lncRNA TUG1 affects glycolysis (Xiufu et al.).	('lncRNA TUG1', 'Gene', (27, 38))	('affected', 'Reg', (53, 61))	('abnormal', 'Var', (4, 12))	('glycolysis', 'MPA', (171, 181))	('expression', 'MPA', (66, 76))	('HK2', 'Gene', '3099', (94, 97))	('affects', 'Reg', (163, 170))	('hexokinase-2', 'Gene', (80, 92))	('HK2', 'Gene', (94, 97))	('hexokinase-2', 'Gene', '3099', (80, 92))
628363	34039257	HK2 gene knockout weakened the effect of lncRNA TUG1 overexpression on glycolysis in osteosarcoma cells (Xiufu et al.).	('HK2', 'Gene', '3099', (0, 3))	('knockout', 'Var', (9, 17))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('glycolysis', 'MPA', (71, 81))	('HK2', 'Gene', (0, 3))	('weakened', 'NegReg', (18, 26))
628364	34039257	lncRNA TUG1 was up-regulated in AML patients and cells, and its knockout inhibited glycolysis in AML cells by targeting miR-185 (Weide et al.).	('glycolysis', 'MPA', (83, 93))	('lncRNA TUG1', 'Gene', (0, 11))	('AML', 'Disease', 'MESH:D015470', (32, 35))	('miR-185', 'Gene', (120, 127))	('patients', 'Species', '9606', (36, 44))	('knockout', 'Var', (64, 72))	('AML', 'Phenotype', 'HP:0004808', (97, 100))	('AML', 'Disease', (97, 100))	('AML', 'Phenotype', 'HP:0004808', (32, 35))	('up-regulated', 'PosReg', (16, 28))	('AML', 'Disease', (32, 35))	('inhibited', 'NegReg', (73, 82))	('AML', 'Disease', 'MESH:D015470', (97, 100))	('targeting', 'Reg', (110, 119))	('miR-185', 'Gene', '406961', (120, 127))
628368	34039257	Knockout of lncRNA TUG1 inhibited angiogenesis in ovarian cancer by regulating LRG1 (Mingjun et al.).	('ovarian cancer', 'Disease', 'MESH:D010051', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('LRG1', 'Gene', (79, 83))	('ovarian cancer', 'Disease', (50, 64))	('inhibited', 'NegReg', (24, 33))	('lncRNA TUG1', 'Gene', (12, 23))	('Knockout', 'Var', (0, 8))	('angiogenesis', 'CPA', (34, 46))	('LRG1', 'Gene', '116844', (79, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (50, 64))
628373	34039257	lncRNA TUG1 regulated CCND2, through EZH2-related miR-194-5p silencing, to promote the growth of bladder cancer cells and confer cisplatin resistance (Gan et al.).	('growth', 'MPA', (87, 93))	('cisplatin resistance', 'MPA', (129, 149))	('promote', 'PosReg', (75, 82))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('CCND2', 'Gene', (22, 27))	('bladder cancer', 'Disease', (97, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('CCND2', 'Gene', '894', (22, 27))	('silencing', 'Var', (61, 70))	('confer', 'Reg', (122, 128))	('miR-194-5p silencing', 'Var', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('EZH2', 'Gene', '2146', (37, 41))	('EZH2', 'Gene', (37, 41))
628376	34039257	lncRNA TUG1 knockout can induce apoptosis by inhibiting MET/Akt signalling, thus reducing the resistance of osteosarcoma cells to cisplatin (Zhou Qiang and Yuan).	('resistance', 'MPA', (94, 104))	('reducing', 'NegReg', (81, 89))	('lncRNA TUG1', 'Gene', (0, 11))	('knockout', 'Var', (12, 20))	('Akt', 'Gene', '207', (60, 63))	('induce', 'PosReg', (25, 31))	('osteosarcoma', 'Phenotype', 'HP:0002669', (108, 120))	('osteosarcoma', 'Disease', (108, 120))	('osteosarcoma', 'Disease', 'MESH:D012516', (108, 120))	('MET', 'Gene', '79811', (56, 59))	('inhibiting', 'NegReg', (45, 55))	('Akt', 'Gene', (60, 63))	('MET', 'Gene', (56, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))
628380	34039257	lncRNA TUG1 enhanced adriamycin resistance in AML by inhibiting the expression of miR-34a through EZH2 epigenetically (Li et al.).	('EZH2', 'Gene', (98, 102))	('expression', 'MPA', (68, 78))	('AML', 'Phenotype', 'HP:0004808', (46, 49))	('epigenetically', 'Var', (103, 117))	('AML', 'Disease', (46, 49))	('miR-34a', 'Gene', '407040', (82, 89))	('adriamycin', 'Chemical', 'MESH:D004317', (21, 31))	('enhanced', 'PosReg', (12, 20))	('adriamycin resistance', 'MPA', (21, 42))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('miR-34a', 'Gene', (82, 89))	('inhibiting', 'NegReg', (53, 63))	('EZH2', 'Gene', '2146', (98, 102))
628387	34039257	Knockout of lncRNA TUG1 enhanced the radiosensitivity of prostate cancer through the lncRNA TUG1/miR-139-5p/structural maintenance of chromosomes protein 1A (SMC1A) axis (Dianhui et al.).	('prostate cancer', 'Disease', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('enhanced', 'PosReg', (24, 32))	('lncRNA TUG1', 'Gene', (12, 23))	('Knockout', 'Var', (0, 8))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('radiosensitivity', 'CPA', (37, 53))
628389	34039257	The high expression of lncRNA TUG1 was associated with chemotherapy resistance and poor prognosis in oesophageal squamous cell carcinoma (Lin et al.).	('chemotherapy resistance', 'CPA', (55, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('oesophageal squamous cell carcinoma', 'Disease', (101, 136))	('associated', 'Reg', (39, 49))	('high', 'Var', (4, 8))	('lncRNA TUG1', 'Gene', (23, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 136))
628404	34039257	At present, there are relatively fewer clinical studies on lncRNA TUG1, but existing studies suggest that lncRNA TUG1 may be an effective diagnostic or prognostic cancer biomarker.	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('lncRNA TUG1', 'Var', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
628417	34039257	Although lncRNA TUG1 could reduce the radiosensitivity of bladder cancer, it could also enhance the radiosensitivity of esophageal cancer.	('cancer', 'Disease', (131, 137))	('radiosensitivity', 'MPA', (38, 54))	('radiosensitivity', 'MPA', (100, 116))	('lncRNA', 'Var', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('reduce', 'NegReg', (27, 33))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', (66, 72))	('enhance', 'PosReg', (88, 95))
628422	34039257	If any of the key proteins in this signalling pathway are mutated, resulting in abnormal signal activation, it may induce the development of cancer (Shuang et al.).	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('induce', 'Reg', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('mutated', 'Var', (58, 65))	('cancer', 'Disease', (141, 147))	('signal activation', 'MPA', (89, 106))
628423	34039257	For example, activating the Wnt/beta-catenin signalling pathway regulated the invasion and proliferation of oesophageal squamous cell carcinoma, cervical cancer, bladder cancer, and colorectal cancer, and induced their epithelial cell transformation (Fu-Bing et al.).	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (193, 199))	('beta-catenin', 'Gene', (32, 44))	('beta-catenin', 'Gene', '1499', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('activating', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('epithelial cell transformation', 'CPA', (219, 249))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))	('induced', 'Reg', (205, 212))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('colorectal cancer', 'Disease', (182, 199))	('proliferation', 'CPA', (91, 104))	('bladder cancer', 'Disease', 'MESH:D001749', (162, 176))	('bladder cancer', 'Disease', (162, 176))	('invasion', 'CPA', (78, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (162, 176))	('cancer', 'Disease', (154, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('oesophageal squamous cell carcinoma', 'Disease', (108, 143))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 143))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
628429	34039257	lncRNA TUG1 promoted the proliferation, migration, and invasion of hepatoma cells by activating the JAK2/STAT3 pathway, upregulating the expression of AURKA, interacting with miR-216B-5p and inhibiting apoptosis by activating DLX2, or by down-regulating miR-142-3p to regulate the miR-29c-3p/COL1A1 axis.	('proliferation', 'CPA', (25, 38))	('STAT3', 'Gene', '6774', (105, 110))	('migration', 'CPA', (40, 49))	('miR-142-3p', 'Pathway', (254, 264))	('hepatoma', 'Disease', 'MESH:D006528', (67, 75))	('COL1A1', 'Gene', (292, 298))	('activating', 'PosReg', (215, 225))	('expression', 'MPA', (137, 147))	('interacting', 'Interaction', (158, 169))	('JAK2', 'Gene', '3717', (100, 104))	('miR-142-3p', 'Chemical', '-', (254, 264))	('promoted', 'PosReg', (12, 20))	('activating', 'PosReg', (85, 95))	('upregulating', 'PosReg', (120, 132))	('down-regulating', 'NegReg', (238, 253))	('hepatoma', 'Disease', (67, 75))	('miR-29c', 'Gene', '407026', (281, 288))	('miR-216B-5p', 'Var', (175, 186))	('DLX2', 'Gene', (226, 230))	('apoptosis', 'CPA', (202, 211))	('invasion', 'CPA', (55, 63))	('DLX2', 'Gene', '1746', (226, 230))	('JAK2', 'Gene', (100, 104))	('AURKA', 'Gene', '6790', (151, 156))	('inhibiting', 'NegReg', (191, 201))	('AURKA', 'Gene', (151, 156))	('miR-29c', 'Gene', (281, 288))	('STAT3', 'Gene', (105, 110))	('COL1A1', 'Gene', '1277', (292, 298))
628430	34039257	lncRNA TUG1 regulated downstream genes, including miR-143p, miR-9-5p, miR-212-3p, miR-140-5p, microRNA-212-3p, miR-335-5p and miR-219a-5p, to participate in the proliferation and invasion of osteosarcoma cells.	('miR-212', 'Gene', '406994', (70, 77))	('invasion', 'CPA', (179, 187))	('osteosarcoma', 'Phenotype', 'HP:0002669', (191, 203))	('miR-140', 'Gene', (82, 89))	('lncRNA TUG1', 'Gene', (0, 11))	('miR-140', 'Gene', '406932', (82, 89))	('miR-335', 'Gene', '442904', (111, 118))	('miR-143p', 'Gene', '406935', (50, 58))	('miR-9-5p', 'Gene', '407052', (60, 68))	('participate', 'Reg', (142, 153))	('miR-143p', 'Gene', (50, 58))	('osteosarcoma', 'Disease', (191, 203))	('miR-212', 'Gene', (70, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (191, 203))	('miR-9-5p', 'Gene', (60, 68))	('proliferation', 'CPA', (161, 174))	('miR-219a-5p', 'Var', (126, 137))	('miR-335', 'Gene', (111, 118))	('microRNA-212-3p', 'Var', (94, 109))
628450	32510183	The CI of GTVMRI to GTVPET2.5 was significantly lower than that of GTVMRI to GTV50%, GTVMRI to GTVCT, GTVPET2.5 to GTV50%, and GTVPET2.5 to GTVCT (P = .000-0.021).	('GTVPET2.5', 'Var', (20, 29))	('GTV', 'Chemical', '-', (95, 98))	('GTV', 'Chemical', '-', (85, 88))	('lower', 'NegReg', (48, 53))	('GTV', 'Chemical', '-', (102, 105))	('GTV', 'Chemical', '-', (127, 130))	('GTV', 'Chemical', '-', (20, 23))	('GTV', 'Chemical', '-', (140, 143))	('GTV', 'Chemical', '-', (10, 13))	('GTV', 'Chemical', '-', (67, 70))	('GTV', 'Chemical', '-', (115, 118))	('GTV', 'Chemical', '-', (77, 80))
628504	32510183	Similarly, the DI of GTVMRI in GTVPET2.5 was significantly smaller than that of GTV50% or GTVCT in GTVPET2.5 (P = .034 and .014, respectively).	('GTV', 'Chemical', '-', (80, 83))	('GTV', 'Chemical', '-', (99, 102))	('GTV', 'Chemical', '-', (21, 24))	('smaller', 'NegReg', (59, 66))	('GTVMRI', 'Var', (21, 27))	('GTV', 'Chemical', '-', (31, 34))	('GTV', 'Chemical', '-', (90, 93))
628509	32510183	The longitudinal length of GTV50% was significantly larger than GTVPET2.5 and GTVDWI (t = 8.625, 9.268, P = .000, .000, respectively).	('longitudinal length', 'CPA', (4, 23))	('GTV', 'Chemical', '-', (78, 81))	('GTV', 'Chemical', '-', (64, 67))	('GTV', 'Chemical', '-', (27, 30))	('GTV50%', 'Var', (27, 33))	('larger', 'PosReg', (52, 58))
628516	32510183	Furthermore, Karki et al 9  reported that the size of GTVs on MRI were significantly smaller than those on 3DCT for lung cancer.	('smaller', 'NegReg', (85, 92))	('lung cancer', 'Disease', (116, 127))	('GTVs', 'Chemical', '-', (54, 58))	('MRI', 'Var', (62, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))
628536	32510183	Finally, it should be noted that, the inconsistency of breathing pattern during the acquisition of T2W-MRI and PET-CT might affect the position and shape of the tumor to some extent.	('affect', 'Reg', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('PET-CT', 'Gene', (111, 117))	('tumor', 'Disease', (161, 166))	('inconsistency', 'Var', (38, 51))	('T2W-MRI', 'Gene', (99, 106))
628546	32510183	The GTV size of primary esophageal carcinoma derived from T2W-MRI is similar to that from EE phase of 4DCT, but the similarity and inclusion relation between the GTVs form the two images were unsatisfied.	('T2W-MRI', 'Var', (58, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('esophageal carcinoma', 'Disease', (24, 44))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (24, 44))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (24, 44))	('GTV', 'Chemical', '-', (4, 7))	('GTV', 'Chemical', '-', (162, 165))	('GTVs', 'Chemical', '-', (162, 166))
628557	31315622	The pegfilgrastim group had a significantly lower incidence of neutropenia than the control group (9.1% vs 61.0%; p < 0.001).	('pegfilgrastim', 'Var', (4, 17))	('lower', 'NegReg', (44, 49))	('neutropenia', 'Disease', (63, 74))	('neutropenia', 'Disease', 'MESH:D009503', (63, 74))	('neutropenia', 'Phenotype', 'HP:0001875', (63, 74))
628558	31315622	The incidence of febrile neutropenia was 3.0% in the pegfilgrastim group and 32.2% in the control group (p = 0.001).	('febrile neutropenia', 'Disease', 'MESH:D009503', (17, 36))	('neutropenia', 'Phenotype', 'HP:0001875', (25, 36))	('pegfilgrastim', 'Var', (53, 66))	('febrile neutropenia', 'Disease', (17, 36))
628569	31315622	The DCF regimen, which is more potent than the conventional CF regimen, is associated with high rates of febrile neutropenia, which is viewed as problematic.	('DCF', 'Chemical', '-', (4, 7))	('DCF', 'Var', (4, 7))	('neutropenia', 'Phenotype', 'HP:0001875', (113, 124))	('febrile neutropenia', 'Disease', 'MESH:D009503', (105, 124))	('febrile neutropenia', 'Disease', (105, 124))
628599	31315622	The incidence of neutropenia was 9.1% in the pegfilgrastim group and 61.0% in the control group, respectively (p < 0.001).	('neutropenia', 'Disease', (17, 28))	('pegfilgrastim', 'Var', (45, 58))	('neutropenia', 'Disease', 'MESH:D009503', (17, 28))	('neutropenia', 'Phenotype', 'HP:0001875', (17, 28))
628600	31315622	The incidence of febrile neutropenia was 3.0% in the pegfilgrastim group and 32.2% in the control group, respectively (p = 0.001).	('febrile neutropenia', 'Disease', 'MESH:D009503', (17, 36))	('neutropenia', 'Phenotype', 'HP:0001875', (25, 36))	('pegfilgrastim', 'Var', (53, 66))	('febrile neutropenia', 'Disease', (17, 36))
628607	31315622	Although several background risk factors were suspected among the risk factors for febrile neutropenia in univariate analysis, only the absence of pegfilgrastim administration remained as an independent risk factor for febrile neutropenia through multivariate analysis.	('neutropenia', 'Phenotype', 'HP:0001875', (91, 102))	('febrile neutropenia', 'Disease', (219, 238))	('febrile neutropenia', 'Disease', 'MESH:D009503', (219, 238))	('absence', 'Var', (136, 143))	('neutropenia', 'Phenotype', 'HP:0001875', (227, 238))	('febrile neutropenia', 'Disease', (83, 102))	('febrile neutropenia', 'Disease', 'MESH:D009503', (83, 102))
628609	31315622	In study 2, the pegfilgrastim group had a significantly lower incidence of both neutropenia and febrile neutropenia than the control group.	('neutropenia and febrile neutropenia', 'Disease', 'MESH:D009503', (80, 115))	('lower', 'NegReg', (56, 61))	('neutropenia', 'Phenotype', 'HP:0001875', (104, 115))	('pegfilgrastim', 'Var', (16, 29))	('neutropenia', 'Phenotype', 'HP:0001875', (80, 91))
628618	31315622	The DCF regimen, which is more potent than the conventional CF regimen, causes high rates of febrile neutropenia, which is viewed as problematic.	('DCF', 'Chemical', '-', (4, 7))	('febrile neutropenia', 'Disease', 'MESH:D009503', (93, 112))	('febrile neutropenia', 'Disease', (93, 112))	('neutropenia', 'Phenotype', 'HP:0001875', (101, 112))	('DCF', 'Var', (4, 7))
628684	29487725	Collectively, these studies suggest bile reflux elevates HH signaling which induces an intestinal phenotype through BMP4, SOX9 and FOXA2 in the esophageal squamous epithelium.	('FOXA2', 'Gene', '3170', (131, 136))	('BMP4', 'Gene', (116, 120))	('intestinal phenotype', 'MPA', (87, 107))	('SOX9', 'Gene', '6662', (122, 126))	('FOXA2', 'Gene', (131, 136))	('reflux elevates', 'Phenotype', 'HP:0002020', (41, 56))	('elevates HH', 'Phenotype', 'HP:0001900', (48, 59))	('elevates', 'PosReg', (48, 56))	('BMP4', 'Gene', '652', (116, 120))	('HH signaling', 'MPA', (57, 69))	('induces', 'Reg', (76, 83))	('bile', 'Var', (36, 40))	('SOX9', 'Gene', (122, 126))
628685	29487725	The elevated BMP signaling observed in BE is potentially mediated by miR-200c, miR-130 and let-7c (Figure 1B).	('BE', 'Phenotype', 'HP:0100580', (39, 41))	('miR-130', 'Var', (79, 86))	('BMP', 'Gene', '649', (13, 16))	('let-7c', 'Gene', (91, 97))	('let-7c', 'Gene', '406885', (91, 97))	('elevated', 'PosReg', (4, 12))	('BMP', 'Gene', (13, 16))	('miR-200c', 'Gene', (69, 77))	('miR-200c', 'Gene', '406985', (69, 77))
628700	29487725	ERK inactivation in BE is thought to promote the observed increase in CDX2 transcriptional activity and promote the terminal differentiation of intestinal epithelial cells.	('CDX2', 'Gene', (70, 74))	('inactivation', 'Var', (4, 16))	('increase', 'PosReg', (58, 66))	('CDX2', 'Gene', '1045', (70, 74))	('promote', 'PosReg', (37, 44))	('promote', 'PosReg', (104, 111))	('transcriptional activity', 'MPA', (75, 99))	('BE', 'Phenotype', 'HP:0100580', (20, 22))	('ERK', 'Gene', '5594', (0, 3))	('terminal differentiation', 'CPA', (116, 140))	('ERK', 'Gene', (0, 3))
628728	29487725	Additionally, loss of miR-200a in meningiomas was shown to promote tumor growth by directly targeting beta-catenin (CTNNB1), but its role in BE remains unclear due to conflicting reports on the dysregulation of miR-200a.	('miR-200a', 'Gene', (22, 30))	('loss', 'Var', (14, 18))	('targeting', 'Reg', (92, 101))	('miR-200a', 'Gene', '406983', (22, 30))	('beta-catenin', 'Gene', '1499', (102, 114))	('meningiomas', 'Phenotype', 'HP:0002858', (34, 45))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CTNNB1', 'Gene', '1499', (116, 122))	('promote', 'PosReg', (59, 66))	('meningiomas', 'Disease', (34, 45))	('tumor', 'Disease', (67, 72))	('meningiomas', 'Disease', 'MESH:D008577', (34, 45))	('miR-200a', 'Gene', (211, 219))	('beta-catenin', 'Gene', (102, 114))	('BE', 'Phenotype', 'HP:0100580', (141, 143))	('miR-200a', 'Gene', '406983', (211, 219))	('CTNNB1', 'Gene', (116, 122))
628733	29487725	miR-21, miR-130b and miR-181b are upregulated in BE and are known to positively regulate NF-kappaB signaling (Figure 4A).	('regulate', 'Reg', (80, 88))	('miR-130b', 'Gene', '406920', (8, 16))	('NF-kappaB', 'Gene', '4790', (89, 98))	('miR-181b', 'Var', (21, 29))	('upregulated', 'PosReg', (34, 45))	('NF-kappaB', 'Gene', (89, 98))	('miR-130b', 'Gene', (8, 16))	('miR-21', 'Gene', (0, 6))	('miR-21', 'Gene', '406991', (0, 6))	('BE', 'Phenotype', 'HP:0100580', (49, 51))
628735	29487725	miR-130b, miR-181b and miR-501-5p are known to drive inflammation through NF-kappaB by targeting the Ubiquitin-Specific-Processing Protease (CYLD), a known NF-kappaB suppressor.	('drive', 'PosReg', (47, 52))	('NF-kappaB', 'Gene', (74, 83))	('inflammation', 'Disease', 'MESH:D007249', (53, 65))	('miR-130b', 'Gene', (0, 8))	('Ubiquitin-Specific-Processing Protease', 'Gene', '57663', (101, 139))	('miR-181b', 'Var', (10, 18))	('miR-501', 'Gene', (23, 30))	('CYLD', 'Gene', (141, 145))	('targeting', 'Reg', (87, 96))	('inflammation', 'Disease', (53, 65))	('Ubiquitin-Specific-Processing Protease', 'Gene', (101, 139))	('NF-kappaB', 'Gene', '4790', (156, 165))	('CYLD', 'Gene', '1540', (141, 145))	('miR-130b', 'Gene', '406920', (0, 8))	('miR-501', 'Gene', '574503', (23, 30))	('NF-kappaB', 'Gene', '4790', (74, 83))	('NF-kappaB', 'Gene', (156, 165))
628744	29487725	Using IPA, we were able to correlate miRNAs dysregulated in BE to the intestinalization of esophageal tissue through upregulation of Hedgehog signaling, and in the maintenance of epithelial stemness in BE through upregulation of BMP4 signaling.	('BMP4', 'Gene', (229, 233))	('Hedgehog', 'MPA', (133, 141))	('epithelial stemness', 'Disease', (179, 198))	('epithelial stemness', 'Disease', 'MESH:D002277', (179, 198))	('BMP4', 'Gene', '652', (229, 233))	('dysregulated', 'Var', (44, 56))	('BE', 'Phenotype', 'HP:0100580', (60, 62))	('BE', 'Phenotype', 'HP:0100580', (202, 204))	('upregulation', 'PosReg', (213, 225))	('upregulation', 'PosReg', (117, 129))
628745	29487725	We further elaborated on the potential mechanisms by which dysregulated miRNAs downregulate NOTCH and ERK signaling while upregulating JNK and p38 signaling to induce mucin expression and maintain intestinal identity.	('dysregulated', 'Var', (59, 71))	('upregulating', 'PosReg', (122, 134))	('NOTCH', 'MPA', (92, 97))	('mucin expression', 'MPA', (167, 183))	('JNK', 'Gene', (135, 138))	('p38', 'Gene', '5594', (143, 146))	('p38', 'Gene', (143, 146))	('maintain', 'Reg', (188, 196))	('ERK', 'Gene', '5594', (102, 105))	('downregulate', 'NegReg', (79, 91))	('JNK', 'Gene', '5599', (135, 138))	('ERK', 'Gene', (102, 105))	('induce', 'PosReg', (160, 166))	('intestinal identity', 'CPA', (197, 216))	('miRNAs', 'Gene', (72, 78))
628746	29487725	We identified miRNAs which potentially play a role in regulating proliferation and tumorigenicity by suppressing WNT signaling in BE and enhancing WNT signaling during the dysplastic progression to EAC.	('enhancing', 'PosReg', (137, 146))	('WNT signaling', 'MPA', (147, 160))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('dysplastic', 'Disease', (172, 182))	('WNT signaling', 'MPA', (113, 126))	('EAC', 'Phenotype', 'HP:0011459', (198, 201))	('tumor', 'Disease', (83, 88))	('dysplastic', 'Disease', 'MESH:D004416', (172, 182))	('BE', 'Phenotype', 'HP:0100580', (130, 132))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('suppressing', 'NegReg', (101, 112))	('miRNAs', 'Var', (14, 20))
628749	29487725	utilized muscle biopsies from BE patients with or without dysplasia to identify dysregulation of miR-15b, miR-21, miR-203, miR-485-5p and let-7a as collectively predictive for dysplasia in BE.	('miR-203', 'Gene', (114, 121))	('BE', 'Phenotype', 'HP:0100580', (189, 191))	('patients', 'Species', '9606', (33, 41))	('miR-21', 'Gene', (106, 112))	('miR-203', 'Gene', '406986', (114, 121))	('dysplasia', 'Disease', 'MESH:D004476', (58, 67))	('dysplasia', 'Disease', 'MESH:D004476', (176, 185))	('miR-15b', 'Gene', (97, 104))	('predictive', 'Reg', (161, 171))	('BE', 'Phenotype', 'HP:0100580', (30, 32))	('let-7a', 'Gene', (138, 144))	('miR-21', 'Gene', '406991', (106, 112))	('miR-15b', 'Gene', '406949', (97, 104))	('dysregulation', 'Var', (80, 93))	('dysplasia', 'Disease', (58, 67))	('dysplasia', 'Disease', (176, 185))	('miR-485-5p', 'Var', (123, 133))
628750	29487725	Transduction of human cancer cells with lentiviral vectors encoding for antisense oligos to selected miRNAs has been shown to reduce pancreatic tumor burden in SCID mice.	('SCID', 'Disease', (160, 164))	('mice', 'Species', '10090', (165, 169))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (133, 149))	('reduce', 'NegReg', (126, 132))	('cancer', 'Disease', (22, 28))	('pancreatic tumor', 'Disease', (133, 149))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('human', 'Species', '9606', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('antisense oligos', 'Var', (72, 88))	('pancreatic tumor', 'Disease', 'MESH:D010190', (133, 149))	('SCID', 'Disease', 'MESH:D053632', (160, 164))
628751	29487725	In particular, knockdown of miR-122-5p, miR-21, miR-200c, miR-7, miR-143, miR-503, mir-424 and miR-181b are of particular interest due to their functional ties to key regulators of BE progression in the NOTCH, MAPK, EMT, Wnt, NFkappaB and EMT pathways (Figures 1-4).	('miR-7', 'Gene', '10859', (58, 63))	('mir-424', 'Gene', '494336', (83, 90))	('mir-424', 'Gene', (83, 90))	('NOTCH', 'Pathway', (203, 208))	('NFkappaB', 'Gene', '4790', (226, 234))	('miR-181b', 'Var', (95, 103))	('NFkappaB', 'Gene', (226, 234))	('miR-143', 'Gene', '406935', (65, 72))	('miR-143', 'Gene', (65, 72))	('BE', 'Phenotype', 'HP:0100580', (181, 183))	('miR-21', 'Gene', '406991', (40, 46))	('Wnt', 'Pathway', (221, 224))	('EMT', 'CPA', (216, 219))	('MAPK', 'Pathway', (210, 214))	('miR-200c', 'Gene', '406985', (48, 56))	('miR-7', 'Gene', (58, 63))	('miR-122-5p', 'Gene', (28, 38))	('knockdown', 'Var', (15, 24))	('miR-503', 'Gene', (74, 81))	('miR-503', 'Gene', '574506', (74, 81))	('miR-122-5p', 'Gene', '100188847', (28, 38))	('EMT', 'CPA', (239, 242))	('miR-21', 'Gene', (40, 46))	('miR-200c', 'Gene', (48, 56))
628804	27274285	PIM1 polymorphism and PIM1 expression as predisposing factors of esophageal squamous cell carcinoma in the Asian population Our study aimed to identify the association between a PIM1 polymorphism and PIM1 expression levels with clinicopathological features of esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('esophageal squamous cell carcinoma', 'Disease', (65, 99))	('expression levels', 'MPA', (205, 222))	('PIM1', 'Gene', '5292', (178, 182))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (260, 294))	('PIM1', 'Gene', (178, 182))	('PIM1', 'Gene', (200, 204))	('PIM1', 'Gene', '5292', (200, 204))	('PIM1', 'Gene', '5292', (0, 4))	('PIM1', 'Gene', (0, 4))	('association', 'Interaction', (156, 167))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (65, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('polymorphism', 'Var', (183, 195))	('esophageal squamous cell carcinoma', 'Disease', (260, 294))	('PIM1', 'Gene', (22, 26))	('PIM1', 'Gene', '5292', (22, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (271, 294))
628806	27274285	Polymerase chain reaction-direct sequencing was employed to analyze all genotypes containing the PIM1 -1 882 A>T mutation.	('882 A>T', 'Var', (105, 112))	('PIM1 -1', 'Gene', (97, 104))	('882 A>T', 'Mutation', 'c.882A>T', (105, 112))
628809	27274285	PIM1 -1 882 A>T and the overexpression of PIM1 were associated with the clinicopathological features of ESCC, and PIM1 -1 882 A>T may help to reduce the risk of ESCC in the Asian population.	('PIM1 -1 882 A>T', 'Var', (114, 129))	('882 A>T', 'Mutation', 'c.882A>T', (8, 15))	('associated', 'Reg', (52, 62))	('ESCC', 'Disease', (161, 165))	('overexpression', 'PosReg', (24, 38))	('ESCC', 'Disease', (104, 108))	('PIM1 -1 882 A>T', 'Var', (0, 15))	('reduce', 'NegReg', (142, 148))	('PIM1', 'Gene', (42, 46))	('882 A>T', 'Mutation', 'c.882A>T', (122, 129))
628817	27274285	The postoperative recurrence, invasion, and metastasis of ESCC are influenced by relevant factors such as proto-oncogene activation, tumor-suppressor gene inactivation, and abnormal protein expression.	('protein', 'Protein', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('inactivation', 'Var', (155, 167))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('invasion', 'CPA', (30, 38))	('metastasis', 'CPA', (44, 54))	('influenced by', 'Reg', (67, 80))	('tumor', 'Disease', (133, 138))	('ESCC', 'Disease', (58, 62))
628821	27274285	Overexpression of the PIM1 protein has been implicated in the tumorigenesis of ESCC, gastric cancer, and colon cancer.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('colon cancer', 'Disease', 'MESH:D015179', (105, 117))	('protein', 'Protein', (27, 34))	('colon cancer', 'Disease', (105, 117))	('PIM1', 'Gene', (22, 26))	('tumor', 'Disease', (62, 67))	('implicated', 'Reg', (44, 54))	('gastric cancer', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('ESCC', 'Disease', (79, 83))	('Overexpression', 'Var', (0, 14))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
628822	27274285	This study aims to investigate the association between PIM1 polymorphisms and clinical pathological features of ESCC through detecting the PIM1 -1 882 A>T mutation and evaluating PIM1 protein expression in ESCC.	('882 A>T', 'Mutation', 'c.882A>T', (147, 154))	('882 A>T', 'Var', (147, 154))	('PIM1 -1', 'Gene', (139, 146))	('ESCC', 'Disease', (112, 116))
628832	27274285	Direct DNA sequencing (SinoGenoMax Co., Ltd., Beijing, People's Republic of China) was used to screen the single nucleotide polymorphism.	("People's Republic", 'Disease', 'MESH:D006212', (55, 72))	("People's Republic", 'Disease', (55, 72))	('single nucleotide polymorphism', 'Var', (106, 136))
628844	27274285	However, there was no significant difference in the frequency of the PIM1 polymorphism with regard to sex, age, clinical stage, or tumor size according to the rank test (all P>0.05) (Table 2).	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('polymorphism', 'Var', (74, 86))	('PIM1', 'Gene', (69, 73))
628850	27274285	In our study, we found that PIM1 polymorphism and alteration of PIM1 expression participated in the development of ESCC and were closely related to the clinicopathological features of ESCC, revealing that PIM1 could be useful for predicting biological behavior in patients with ESCC.	('ESCC', 'Disease', (115, 119))	('related', 'Reg', (137, 144))	('PIM1', 'Gene', (64, 68))	('alteration', 'Reg', (50, 60))	('polymorphism', 'Var', (33, 45))	('patients', 'Species', '9606', (264, 272))	('PIM1', 'Gene', (28, 32))	('participated', 'Reg', (80, 92))	('ESCC', 'Disease', (184, 188))
628851	27274285	Kim et al found that the T-C-T-C haplotypes of PIM1 (-1,196 T>C, IVS4 +55 T>C, IVS4 +1,416 T>A, and +3,684 C>A) were associated with an increased risk of lung cancer.	('lung cancer', 'Disease', (154, 165))	('+55 T>C', 'Var', (70, 77))	('416 T>A', 'SUBSTITUTION', 'None', (87, 94))	('IVS4 +55 T>C', 'Mutation', 'c.IVS4+55T>C', (65, 77))	('associated', 'Reg', (117, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('PIM1', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('-1,196 T>C', 'Var', (53, 63))	('684 C>A', 'Mutation', 'c.684C>A', (103, 110))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('+55 T>C', 'SUBSTITUTION', 'None', (70, 77))	('416 T>A', 'Var', (87, 94))	('196 T>C', 'Mutation', 'c.196T>C', (56, 63))
628852	27274285	Akagi et al found that the E135K mutation of PIM1 may be associated with acute myeloid leukemia.	('E135K', 'Var', (27, 32))	('acute myeloid leukemia', 'Disease', (73, 95))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (73, 95))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('E135K', 'Mutation', 'rs200523275', (27, 32))	('PIM1', 'Gene', (45, 49))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (73, 95))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (79, 95))	('associated', 'Reg', (57, 67))
628854	27274285	However, we found that individuals with the AA genotype exhibited the highest positive protein expression, and there was just one patient carrying the TT genotype among the 168 patients with ESCC, suggesting that the PIM1 polymorphism was associated with PIM1 protein expression.	('associated', 'Reg', (239, 249))	('patient', 'Species', '9606', (130, 137))	('patients', 'Species', '9606', (177, 185))	('PIM1 protein', 'Protein', (255, 267))	('PIM1', 'Gene', (217, 221))	('positive protein expression', 'MPA', (78, 105))	('polymorphism', 'Var', (222, 234))	('patient', 'Species', '9606', (177, 184))
628855	27274285	Our study first explored the PIM1 -1 882 A>T polymorphism and found that the AA genotype and A allele might contribute to the development and progression of ESCC, while the -1 882 A>T mutation (TT genotype and T allele) might decrease the risk of ESCC.	('ESCC', 'Disease', (247, 251))	('the -1 882 A>T', 'Var', (169, 183))	('882 A>T', 'Mutation', 'c.882A>T', (176, 183))	('decrease', 'NegReg', (226, 234))	('ESCC', 'Disease', (157, 161))	('PIM1 -1', 'Gene', (29, 36))	('882 A>T', 'Mutation', 'c.882A>T', (37, 44))	('contribute', 'Reg', (108, 118))
628861	27274285	It is possible that the PIM1 -1 882 A>T polymorphism affects the combination of the promoter region and signal factor, leading to an increase in PIMI expression and further inhibiting the malignant transformation of cells.	('malignant transformation of cells', 'CPA', (188, 221))	('affects', 'Reg', (53, 60))	('PIM', 'Gene', '5292', (24, 27))	('882 A>T', 'Mutation', 'c.882A>T', (32, 39))	('PIM', 'Gene', (145, 148))	('polymorphism', 'Var', (40, 52))	('PIM', 'Gene', '5292', (145, 148))	('PIM', 'Gene', (24, 27))	('increase', 'PosReg', (133, 141))	('inhibiting', 'NegReg', (173, 183))
628862	27274285	Our research explored the PIM1 polymorphism and PIM1 expression in the progression of ESCC and was the first to study the possible effect of the novel -1 882 A>T single nucleotide polymorphism on the development of ESCC.	('ESCC', 'Disease', (215, 219))	('882 A>T', 'Var', (154, 161))	('882 A>T', 'Mutation', 'c.882A>T', (154, 161))	('PIM1', 'Gene', (48, 52))	('ESCC', 'Disease', (86, 90))
628863	27274285	Collectively, our study demonstrated that the PIM1 -1 882 A>T polymorphism may help to reduce the risk of ESCC, and PIM1 expression may also serve as an index to detect biological behavior in the Asian population.	('polymorphism', 'Var', (62, 74))	('ESCC', 'Disease', (106, 110))	('882 A>T', 'Mutation', 'c.882A>T', (54, 61))	('PIM1 -1', 'Gene', (46, 53))	('reduce', 'NegReg', (87, 93))	('882 A>T polymorphism', 'Var', (54, 74))
628864	25220908	A three-gene signature and clinical outcome in esophageal squamous cell carcinoma It is increasingly apparent that cancer development depends not only on genetic alterations, but also on epigenetic changes involving histone modifications.	('cancer', 'Disease', (115, 121))	('esophageal squamous cell carcinoma', 'Disease', (47, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('epigenetic', 'Var', (187, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('histone', 'Protein', (216, 223))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (47, 81))	('genetic alterations', 'Var', (154, 173))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
628867	25220908	The presence of a high-risk three-gene signature in the ESCC tumors was significantly associated with decreased overall survival (OS) of the patients.	('decreased', 'NegReg', (102, 111))	('ESCC tumors', 'Disease', (56, 67))	('OS', 'Chemical', '-', (130, 132))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('overall survival', 'MPA', (112, 128))	('presence', 'Var', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (141, 149))	('ESCC tumors', 'Disease', 'MESH:D004938', (56, 67))
628872	25220908	Epigenetic alterations that involve modifications to histones are thought to play critical roles in cancer, with effects on processes ranging from tumor development to metastasis.	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('effects', 'Reg', (113, 120))	('histones', 'Protein', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('modifications', 'Var', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('metastasis', 'CPA', (168, 178))
628880	25220908	It is increasingly apparent that cancer development depends not only on genetic alterations, but also on epigenetic changes involving histone modifications.	('genetic alterations', 'Var', (72, 91))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('histone modifications', 'MPA', (134, 155))
628882	25220908	Specifically, the histone demethylase GASC1 (the gene amplified in squamous cell carcinoma 1), a member of the JmjC-domain-containing proteins, has been shown to be overexpressed, amplified, and/or mutated in such human cancers as breast cancer, prostate cancer, metastatic lung sarcomatoid carcinoma, and leukemia.	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (279, 300))	('mutated', 'Var', (198, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('GASC1', 'Gene', (38, 43))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('prostate cancer', 'Disease', 'MESH:D011471', (246, 261))	('prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('human', 'Species', '9606', (214, 219))	('prostate cancer', 'Disease', (246, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('metastatic lung sarcomatoid carcinoma', 'Disease', (263, 300))	('leukemia', 'Phenotype', 'HP:0001909', (306, 314))	('gene amplified in squamous cell carcinoma 1', 'Gene', (49, 92))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('metastatic lung sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (263, 300))	('cancers', 'Disease', (220, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('overexpressed', 'PosReg', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('leukemia', 'Disease', (306, 314))	('leukemia', 'Disease', 'MESH:D007938', (306, 314))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('gene amplified in squamous cell carcinoma 1', 'Gene', '23081', (49, 92))	('breast cancer', 'Disease', (231, 244))
628909	25220908	PPARG, MDM2, and NANOG were also independent factors for OS according to multivariable Cox proportional hazard regression analyses (Table 2).	('NANOG', 'Var', (17, 22))	('Cox', 'Gene', '1351', (87, 90))	('OS', 'Chemical', '-', (57, 59))	('PPARG', 'Var', (0, 5))	('Cox', 'Gene', (87, 90))
628921	25220908	Patients with a high-risk gene signature had a shorter OS than those with a low-risk gene signature (p < 0.001, Fig.	('OS', 'Chemical', '-', (55, 57))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (47, 54))	('high-risk gene signature', 'Var', (16, 40))
628927	25220908	These studies suggest that the genes modulated by histone demethylases may serve as predictors for the poor prognosis of cancer patients.	('histone demethylases', 'Var', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Disease', (121, 127))
628929	25220908	The presence of a high-risk three-gene signature in the ESCC tumors was significantly associated with decreased OS.	('OS', 'Chemical', '-', (112, 114))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('presence', 'Var', (4, 12))	('ESCC tumors', 'Disease', (56, 67))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('decreased', 'NegReg', (102, 111))	('ESCC tumors', 'Disease', 'MESH:D004938', (56, 67))
628934	25220908	Similarly, our analysis of a subgroup of patients with G2 disease showed that patients with a high-risk gene signature had a lower OS than patients with a low-risk gene signature.	('patients', 'Species', '9606', (139, 147))	('OS', 'Chemical', '-', (131, 133))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (41, 49))	('lower', 'NegReg', (125, 130))	('high-risk gene signature', 'Var', (94, 118))
628936	25220908	In addition, as we can see in Supporting Information Tables 2 and 3, the number of ESCC patients with T1/T2 or G1/G3 is small in cohort 1 and cohort 2, which is the reason that they are not included in analysis.	('T1/T2', 'Var', (102, 107))	('patients', 'Species', '9606', (88, 96))	('G1/G3', 'Var', (111, 116))	('ESCC', 'Disease', (83, 87))
628943	25220908	Alternatively, NANOG may enhance proliferation of cancer cells.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('enhance', 'PosReg', (25, 32))	('NANOG', 'Var', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
628944	25220908	This concept was supported by reports of exogenous overexpression of NANOG in mesenchymal stem cells and NIH3T3 cells that promoted cell proliferation and enhanced colony formation.	('NANOG', 'Var', (69, 74))	('promoted', 'PosReg', (123, 131))	('enhanced', 'PosReg', (155, 163))	('cell proliferation', 'CPA', (132, 150))	('colony formation', 'CPA', (164, 180))	('NIH3T3', 'CellLine', 'CVCL:0594', (105, 111))	('overexpression', 'PosReg', (51, 65))
628945	25220908	In addition, NANOG upregulated the expression of ezrin, which is involved in tumor progression and regulates cellular activities including survival, adhesion, and migration/invasion by organizing membrane-cytoskeleton-associated complexes.	('upregulated', 'PosReg', (19, 30))	('migration/invasion', 'CPA', (163, 181))	('NANOG', 'Var', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('expression', 'MPA', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ezrin', 'Gene', (49, 54))	('tumor', 'Disease', (77, 82))
628947	25220908	Despite the sometimes conflicting results from studies, the overall trend is that MDM2 expression is associated with decreased OS, increased recurrence, increased metastasis, and decreased response to therapeutic intervention in a wide variety of tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('decreased', 'NegReg', (179, 188))	('expression', 'Var', (87, 97))	('increased', 'PosReg', (131, 140))	('tumors', 'Disease', (247, 253))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('metastasis', 'CPA', (163, 173))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('MDM2', 'Gene', (82, 86))	('increased', 'PosReg', (153, 162))	('decreased', 'NegReg', (117, 126))	('response to therapeutic intervention', 'MPA', (189, 225))	('OS', 'Chemical', '-', (127, 129))	('recurrence', 'CPA', (141, 151))
629000	33858379	Epidemiological studies have found that risk factors for ESCC, including smoking, alcohol drinking, high-temperature foods, diet, and polycyclic aromatic hydrocarbons from a variety of sources.	('a', 'Gene', '351', (13, 14))	('a', 'Gene', '351', (172, 173))	('a', 'Gene', '351', (25, 26))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (134, 166))	('ESCC', 'Disease', (57, 61))	('alcohol', 'Chemical', 'MESH:D000438', (82, 89))	('alcohol drinking', 'Phenotype', 'HP:0030955', (82, 98))	('a', 'Gene', '351', (111, 112))	('a', 'Gene', '351', (145, 146))	('a', 'Gene', '351', (149, 150))	('polycyclic', 'Var', (134, 144))	('a', 'Gene', '351', (37, 38))	('a', 'Gene', '351', (82, 83))	('a', 'Gene', '351', (130, 131))	('a', 'Gene', '351', (46, 47))	('a', 'Gene', '351', (160, 161))	('a', 'Gene', '351', (175, 176))
629177	33607840	To be specific, codes C15.0 and C15.3 were used to identify upper esophageal tumors, while C15.4 was for middle esophageal tumors and C15.2 and C15.5 were for lower esophageal tumors.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('esophageal tumors', 'Disease', 'MESH:D004938', (112, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('esophageal tumors', 'Phenotype', 'HP:0100751', (112, 129))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('C15.4', 'Var', (91, 96))	('esophageal tumors', 'Disease', 'MESH:D004938', (165, 182))	('middle esophageal tumors', 'Disease', 'MESH:D004938', (105, 129))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('esophageal tumors', 'Disease', (165, 182))	('esophageal tumors', 'Disease', 'MESH:D004938', (66, 83))	('esophageal tumors', 'Phenotype', 'HP:0100751', (165, 182))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('esophageal tumors', 'Disease', (66, 83))	('esophageal tumors', 'Phenotype', 'HP:0100751', (66, 83))	('middle esophageal tumors', 'Disease', (105, 129))
629178	33607840	Moreover, histologic recode broad groupings were applied for the classification of histological subtypes (codes 8140-8389 were for adenomas and adenocarcinomas (AC), codes 8050-8089 were for squamous cell carcinomas (SCC) and all other remaining codes as other histology.	('codes 8050-8089', 'Var', (166, 181))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (191, 215))	('carcinoma', 'Disease', 'MESH:D009369', (205, 214))	('adenomas', 'Disease', (131, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('codes 8140-8389', 'Var', (106, 121))	('carcinoma', 'Disease', (205, 214))	('carcinoma', 'Disease', (149, 158))	('carcinoma', 'Disease', 'MESH:D009369', (149, 158))
629252	33607840	Dinh et al found that treatment for patients with high stage and high-grade prostate cancer was related to a decreased risk of prostate cancer-specific mortality.	('decreased', 'NegReg', (109, 118))	('prostate cancer', 'Disease', 'MESH:D011471', (127, 142))	('mortality', 'Disease', (152, 161))	('age', 'Gene', (57, 60))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('patients', 'Species', '9606', (36, 44))	('high-grade', 'Var', (65, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('prostate cancer', 'Disease', (127, 142))	('age', 'Gene', '5973', (57, 60))	('mortality', 'Disease', 'MESH:D003643', (152, 161))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
629343	32457839	Indeed, high values of these parameters are associated with worse outcome, confirming that more heterogeneous tumors have a poor prognosis.	('high', 'Var', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))
629402	32000719	Several single-arm longitudinal studies have reported improvement in dysphagia scores with both FCSEMS and PCSEMS.	('dysphagia', 'Disease', (69, 78))	('PCSEMS', 'Var', (107, 113))	('dysphagia', 'Phenotype', 'HP:0002015', (69, 78))	('dysphagia', 'Disease', 'MESH:D003680', (69, 78))	('improvement', 'PosReg', (54, 65))
629410	32000719	in a retrospective study of 252 patients with benign and malignant esophageal lesions have reported a higher incidence of tissue ingrowth or outgrowth with PCSEMS as compared to FCSEMS (53.4 vs. 29.1%, p = 0.004).	('patients', 'Species', '9606', (32, 40))	('tissue ingrowth', 'CPA', (122, 137))	('malignant esophageal lesions', 'Disease', (57, 85))	('malignant esophageal lesions', 'Disease', 'MESH:D004941', (57, 85))	('PCSEMS', 'Var', (156, 162))
629441	30901891	In addition, multivariate analysis identified the presence of CTC as a strong, independent prognostic marker of tumor recurrence and overall survival.	('CTC', 'Gene', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('presence', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('overall survival', 'CPA', (133, 149))	('tumor', 'Disease', (112, 117))
629637	28629367	Multiple chromosomal gains, amplifications and losses that represent regions potentially involved in etiology defined the pattern of abnormalities in the tumor genome.	('amplifications', 'Var', (28, 42))	('Multiple chromosomal gains', 'Phenotype', 'HP:0040012', (0, 26))	('losses', 'NegReg', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
629638	28629367	The preponderance of chromosomal aberrations in African-American ESCC predicts concomitant changes in gene activity during carcinogenesis.	('changes', 'Reg', (91, 98))	('preponderance of chromosomal aberrations', 'Phenotype', 'HP:0040012', (4, 44))	('gene activity', 'MPA', (102, 115))	('chromosomal aberrations', 'Var', (21, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (123, 137))	('carcinogenesis', 'Disease', (123, 137))
629640	28629367	Particularly noteworthy is the dysregulation of NRF2 mediated oxidative stress genes and genes that encode drug-metabolizing enzymes and xenobiotics that may, in part, contribute to the aggressive nature of ESCC among blacks.	('NRF2', 'Gene', '4780', (48, 52))	('ESCC', 'Disease', (207, 211))	('NRF2', 'Gene', (48, 52))	('genes', 'Gene', (89, 94))	('oxidative stress', 'Phenotype', 'HP:0025464', (62, 78))	('contribute', 'Reg', (168, 178))	('dysregulation', 'Var', (31, 44))
629689	28629367	Our findings in African-American ESCC reveal dysregulation of genes involved in detox networks, including NRF2 pathway, which is a primary mediator of detoxification and metabolism responses (Additional file 5).	('NRF2', 'Gene', '4780', (106, 110))	('genes', 'Gene', (62, 67))	('dysregulation', 'Var', (45, 58))	('NRF2', 'Gene', (106, 110))	('detox', 'Pathway', (80, 85))
629696	28629367	Mutations in NFE2L2 confer malignant potential and resistance to therapy in advanced ESCC.	('NFE2L2', 'Gene', '4780', (13, 19))	('malignant potential', 'CPA', (27, 46))	('NFE2L2', 'Gene', (13, 19))	('ESCC', 'Disease', (85, 89))	('Mutations', 'Var', (0, 9))
629697	28629367	However, only 10% of Asian ESCC carry mutations in the NFE2L2 gene or its negative regulator KEAP1.	('KEAP1', 'Gene', '9817', (93, 98))	('KEAP1', 'Gene', (93, 98))	('NFE2L2', 'Gene', '4780', (55, 61))	('Asian ESCC', 'Disease', (21, 31))	('mutations', 'Var', (38, 47))	('NFE2L2', 'Gene', (55, 61))
629708	28629367	Therefore, the effect of the dysregulated NRF2 pathway may amplify the impairment of the dynamics of these pathways.	('NRF2', 'Gene', (42, 46))	('dysregulated', 'Var', (29, 41))	('NRF2', 'Gene', '4780', (42, 46))
629712	28629367	Recent studies that outlined the genomic and molecular characterization of esophageal carcinoma in the Asian population suggested the dysregulation of the receptor tyrosine kinase (RTK)-MAPK-PI3K, NOTCH, Hippo, cell cycle, and epigenetic pathways as the primary molecular mechanism of ESCC.	('Hippo', 'CPA', (204, 209))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (75, 95))	('epigenetic pathways', 'Pathway', (227, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('PI3', 'Gene', (191, 194))	('dysregulation', 'Var', (134, 147))	('RTK', 'Gene', '5979', (181, 184))	('receptor tyrosine kinase', 'Gene', (155, 179))	('PI3', 'Gene', '5266', (191, 194))	('receptor tyrosine kinase', 'Gene', '5979', (155, 179))	('ESCC', 'Disease', (285, 289))	('cell cycle', 'CPA', (211, 221))	('esophageal carcinoma', 'Disease', (75, 95))	('RTK', 'Gene', (181, 184))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (75, 95))	('NOTCH', 'Pathway', (197, 202))
629713	28629367	The amplification or over-expression of FGFR1, MET, EGFR, ERBB2, ERBB4, and IL7R was observed in the majority of the patients and has been suggested as main drivers for the ESCC tumorigenesis.	('tumor', 'Disease', (178, 183))	('ERBB4', 'Gene', '2066', (65, 70))	('MET', 'Gene', (47, 50))	('ESCC', 'Disease', (173, 177))	('over-expression', 'PosReg', (21, 36))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('ERBB2', 'Gene', '2064', (58, 63))	('ERBB4', 'Gene', (65, 70))	('IL7R', 'Gene', '3575', (76, 80))	('ERBB2', 'Gene', (58, 63))	('amplification', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('IL7R', 'Gene', (76, 80))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
629718	28629367	Overexpression of this gene may play a role in breast, and pancreatic cancer tumorigenesis.	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('play', 'Reg', (32, 36))	('pancreatic cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (77, 82))	('breast', 'Disease', (47, 53))
629723	28629367	We previously identified a single nucleotide mutation of SCEL gene in both normal and squamous cell carcinoma of esophagus in African-Americans.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 109))	('squamous cell carcinoma', 'Disease', (86, 109))	('single nucleotide mutation', 'Var', (27, 53))	('SCEL', 'Gene', (57, 61))	('SCEL', 'Gene', '8796', (57, 61))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (100, 122))
629731	27556695	Both genotyping methods demonstrated significant associations between the tag SNPs rs1635566 and rs882537 in the PADI4 locus with gastric carcinoma in two independent cohorts.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('gastric carcinoma', 'Disease', 'MESH:D013274', (130, 147))	('rs882537', 'Var', (97, 105))	('gastric carcinoma', 'Disease', (130, 147))	('rs882537', 'Mutation', 'rs882537', (97, 105))	('rs1635566', 'Var', (83, 92))	('PADI4', 'Gene', '23569', (113, 118))	('PADI4', 'Gene', (113, 118))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (130, 147))	('rs1635566', 'Mutation', 'rs1635566', (83, 92))
629747	27556695	To gain further insight into its tumorigenic mechanism, we investigated whether common polymorphisms in the PADI4 region are associated with various cancer risks using a SNP microarray.	('cancer', 'Disease', (149, 155))	('PADI4', 'Gene', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('PADI4', 'Gene', '23569', (108, 113))	('associated', 'Reg', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('polymorphisms', 'Var', (87, 100))	('tumor', 'Disease', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
629752	27556695	The genotypic frequency of the SNPs at rs882537, rs1748034, rs1748032, rs1635566 and rs1635584 were significantly different between the gastric carcinoma cohort and the healthy control cohort.	('rs1635566', 'Var', (71, 80))	('gastric carcinoma cohort', 'Disease', 'MESH:D013274', (136, 160))	('rs1635584', 'Mutation', 'rs1635584', (85, 94))	('rs1635584', 'Var', (85, 94))	('rs882537', 'Mutation', 'rs882537', (39, 47))	('rs882537', 'Var', (39, 47))	('rs1635566', 'Mutation', 'rs1635566', (71, 80))	('rs1748034', 'Var', (49, 58))	('gastric carcinoma cohort', 'Disease', (136, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('rs1748034', 'Mutation', 'rs1748034', (49, 58))	('different', 'Reg', (114, 123))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (136, 153))	('rs1748032', 'Var', (60, 69))	('rs1748032', 'Mutation', 'rs1748032', (60, 69))
629754	27556695	The allelic frequency of the SNP at rs1635564 was significantly different between the rectal carcinoma cohorts and the control cohort.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('rs1635564', 'Var', (36, 45))	('rs1635564', 'Mutation', 'rs1635564', (36, 45))	('different', 'Reg', (64, 73))	('rectal carcinoma', 'Disease', 'MESH:D012004', (86, 102))	('rectal carcinoma', 'Disease', (86, 102))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (86, 102))
629757	27556695	All 5 SNPs (rs41265997, rs1635566, rs882537, rs1635586 and rs1748034) yielded genotypic data, and the study sample success rate was 99%.	('rs41265997', 'Mutation', 'rs41265997', (12, 22))	('rs1748034', 'Mutation', 'rs1748034', (59, 68))	('rs1748034', 'Var', (59, 68))	('rs1635566', 'Var', (24, 33))	('rs41265997', 'Var', (12, 22))	('rs882537', 'Mutation', 'rs882537', (35, 43))	('rs1635586', 'Var', (45, 54))	('rs1635586', 'Mutation', 'rs1635586', (45, 54))	('rs882537', 'Var', (35, 43))	('rs1635566', 'Mutation', 'rs1635566', (24, 33))
629760	27556695	The allele frequency (odds ratio=3.827392, 95% CI=[1.262104-11.606753], p=0.010243) and gene frequency (p=0.028771) for rs1635566 demonstrated a statistically significant association with gastric carcinoma.	('gastric carcinoma', 'Disease', 'MESH:D013274', (188, 205))	('rs1635566', 'Var', (120, 129))	('gastric carcinoma', 'Disease', (188, 205))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (188, 205))	('rs1635566', 'Mutation', 'rs1635566', (120, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('significant association', 'Reg', (159, 182))
629761	27556695	The SNP at rs882537 also showed significant differences with regard to the allele frequency (odds ratio=1.337557, 95%CI= [1.019987~1.754002], p=0.035307) in the gastric carcinoma cohort.	('gastric carcinoma cohort', 'Disease', 'MESH:D013274', (161, 185))	('differences', 'Reg', (44, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('rs882537', 'Mutation', 'rs882537', (11, 19))	('gastric carcinoma cohort', 'Disease', (161, 185))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (161, 178))	('rs882537', 'Var', (11, 19))
629762	27556695	The genotyping assay did not detect a significant difference in either the allelic or genotypic frequencies of rs1635586 and rs1748034 (p>0.05) between patients with gastric cancer and healthy control subjects.	('gastric cancer', 'Disease', (166, 180))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('rs1748034', 'Mutation', 'rs1748034', (125, 134))	('rs1748034', 'Var', (125, 134))	('rs1635586', 'Var', (111, 120))	('patients', 'Species', '9606', (152, 160))	('rs1635586', 'Mutation', 'rs1635586', (111, 120))
629763	27556695	Following multiple-test corrections, the SNPs at rs882537 and rs1635566 still showed a significant difference with regard to the allelic frequency and genotypic frequency.	('rs882537', 'Mutation', 'rs882537', (49, 57))	('rs1635566', 'Mutation', 'rs1635566', (62, 71))	('rs882537', 'Var', (49, 57))	('rs1635566', 'Var', (62, 71))
629764	27556695	Both the Illumina microarray assay and TaqMan assay demonstrated that the nucleotide variants at rs882537 and rs1635566 are significantly associated with gastric cancer risk.	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('rs1635566', 'Mutation', 'rs1635566', (110, 119))	('associated with', 'Reg', (138, 153))	('rs882537', 'Mutation', 'rs882537', (97, 105))	('gastric cancer', 'Disease', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (154, 168))	('rs1635566', 'Var', (110, 119))
629799	27556695	Western blot analysis detected an approximately 3-fold increase in the protein expression levels of CXCR2, KRT14 and TNF-alpha in the extracts of SGC 7901 cells overexpressing PADI4 relative to cells transfected with mock plasmid (Figure 5C-5F).	('PADI4', 'Gene', (176, 181))	('increase', 'PosReg', (55, 63))	('KRT14', 'Gene', (107, 112))	('SGC', 'Gene', (146, 149))	('PADI4', 'Gene', '23569', (176, 181))	('CXCR2', 'Gene', '3579', (100, 105))	('protein expression levels', 'MPA', (71, 96))	('TNF-alpha', 'Gene', (117, 126))	('SGC', 'Gene', '6443', (146, 149))	('CXCR2', 'Gene', (100, 105))	('KRT14', 'Gene', '3861', (107, 112))	('overexpressing', 'Var', (161, 175))
629800	27556695	In the present study, we used an Illumina custom-designed SNP microarray to genotype 59 tag SNPs in the PADI4 locus to determine the association of these SNPs to various tumor types.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('association', 'Interaction', (133, 144))	('PADI4', 'Gene', '23569', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PADI4', 'Gene', (104, 109))	('SNPs', 'Var', (92, 96))	('tumor', 'Disease', (170, 175))
629801	27556695	Several SNPs, including rs882537, rs1748034, rs1748032, rs1635566 and rs1635584, showed significant differences with regard to allelic frequency, genotypic frequency or both between the gastric carcinoma samples and the control samples.	('gastric carcinoma', 'Disease', (186, 203))	('rs1635566', 'Mutation', 'rs1635566', (56, 65))	('rs1748034', 'Mutation', 'rs1748034', (34, 43))	('rs1748032', 'Var', (45, 54))	('rs1748034', 'Var', (34, 43))	('rs1748032', 'Mutation', 'rs1748032', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (186, 203))	('rs882537', 'Mutation', 'rs882537', (24, 32))	('differences', 'Reg', (100, 111))	('rs1635584', 'Var', (70, 79))	('rs1635566', 'Var', (56, 65))	('gastric carcinoma', 'Disease', 'MESH:D013274', (186, 203))	('rs1635584', 'Mutation', 'rs1635584', (70, 79))	('rs882537', 'Var', (24, 32))
629803	27556695	The analysis showed a significant difference in the allele frequency and the genotype frequency for rs1635566 between the gastric carcinoma samples and the controls.	('difference', 'Reg', (34, 44))	('gastric carcinoma', 'Disease', 'MESH:D013274', (122, 139))	('rs1635566', 'Mutation', 'rs1635566', (100, 109))	('gastric carcinoma', 'Disease', (122, 139))	('rs1635566', 'Var', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (122, 139))
629804	27556695	The analysis also detected a significant association of rs882537 and this cancer with regard to the allele frequency.	('rs882537', 'Var', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('association', 'Interaction', (41, 52))	('cancer', 'Disease', (74, 80))	('rs882537', 'Mutation', 'rs882537', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
629807	27556695	In addition, our Illumina SNP microarray assay showed a significant association of rs1635586 with breast cancer and esophageal carcinoma as well as a significant association of rs1635564 with rectal carcinoma.	('rs1635564', 'Var', (177, 186))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('association', 'Interaction', (68, 79))	('rs1635564', 'Mutation', 'rs1635564', (177, 186))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (116, 136))	('rectal carcinoma', 'Disease', 'MESH:D012004', (192, 208))	('breast cancer', 'Disease', (98, 111))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (116, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('rectal carcinoma', 'Disease', (192, 208))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (192, 208))	('rs1635586', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rs1635586', 'Mutation', 'rs1635586', (83, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('esophageal carcinoma', 'Disease', (116, 136))
629808	27556695	We previously reported that the haplotype GC, which contains rs2501796 and rs2477134 in the PADI4 locus, was significantly associated with an increased risk of esophageal carcinoma.	('associated', 'Reg', (123, 133))	('rs2501796', 'Var', (61, 70))	('rs2501796', 'Mutation', 'rs2501796', (61, 70))	('rs2477134', 'Var', (75, 84))	('rs2477134', 'Mutation', 'rs2477134', (75, 84))	('PADI4', 'Gene', '23569', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('PADI4', 'Gene', (92, 97))	('esophageal carcinoma', 'Disease', (160, 180))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (160, 180))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (160, 180))
629809	27556695	Many studies have also reported that genetic variants in the PADI4 locus are related to rheumatoid arthritis.	('arthritis', 'Phenotype', 'HP:0001369', (99, 108))	('genetic variants', 'Var', (37, 53))	('related', 'Reg', (77, 84))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (88, 108))	('PADI4', 'Gene', '23569', (61, 66))	('rheumatoid arthritis', 'Disease', (88, 108))	('PADI4', 'Gene', (61, 66))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (88, 108))
629811	27556695	The tag SNP rs1635566/rs59611518 is on the fourteenth intron of the PADI4 gene and 203 bp upstream of the fifteenth exon, and rs882537/rs3829723 is on the second intron and 589 bp upstream of the third exon.	('rs1635566/rs59611518', 'Var', (12, 32))	('rs882537', 'Mutation', 'rs882537', (126, 134))	('rs1635566', 'Mutation', 'rs1635566', (12, 21))	('rs59611518', 'Mutation', 'rs59611518', (22, 32))	('rs3829723', 'Mutation', 'rs3829723', (135, 144))	('rs882537/rs3829723', 'Var', (126, 144))	('PADI4', 'Gene', '23569', (68, 73))	('PADI4', 'Gene', (68, 73))
629814	27556695	identified four exonic SNPs, three of which are involved in amino acid substitutions: padi4-89, padi4-90, padi4-92 and padi4-104, resulting in Ser55 to Gly, Ala82 to Val and Ala112 to Gly, respectively.	('padi4', 'Gene', '23569', (119, 124))	('padi4', 'Gene', '23569', (106, 111))	('Ser55 to Gly', 'Mutation', 'rs11203366', (143, 155))	('padi4', 'Gene', (96, 101))	('padi4', 'Gene', '23569', (86, 91))	('Ala112 to Gly', 'Mutation', 'rs874881', (174, 187))	('padi4', 'Gene', (86, 91))	('Ala112 to Gly', 'Var', (174, 187))	('padi4', 'Gene', '23569', (96, 101))	('Ala82 to Val', 'Mutation', 'rs11203367', (157, 169))	('Ser55 to Gly', 'Var', (143, 155))	('Ala82 to Val', 'Var', (157, 169))	('padi4', 'Gene', (119, 124))	('padi4', 'Gene', (106, 111))
629815	27556695	The authors found that the mRNA of the susceptible haplotype was more stable than that of the non-susceptible haplotype, suggesting that SNPs in the PADI4-coding region contribute to mRNA stability.	('mRNA stability', 'MPA', (183, 197))	('PADI4', 'Gene', '23569', (149, 154))	('PADI4', 'Gene', (149, 154))	('SNPs', 'Var', (137, 141))
629819	27556695	To date, we do not know whether the SNPs rs1635566 and rs882537 play a role in enhancing mRNA stability.	('mRNA stability', 'MPA', (89, 103))	('rs1635566', 'Mutation', 'rs1635566', (41, 50))	('enhancing', 'PosReg', (79, 88))	('rs1635566', 'Var', (41, 50))	('rs882537', 'Mutation', 'rs882537', (55, 63))	('rs882537', 'Var', (55, 63))
629820	27556695	We will genotype more SNPs in this region, particularly in the exon region, to identify functional SNPs that may affect the expression level or enzymatic activity of PADI4 as well as the related signaling pathway in a future study.	('expression level', 'MPA', (124, 140))	('PADI4', 'Gene', '23569', (166, 171))	('PADI4', 'Gene', (166, 171))	('SNPs', 'Var', (99, 103))	('affect', 'Reg', (113, 119))	('signaling pathway', 'Pathway', (195, 212))	('enzymatic activity', 'MPA', (144, 162))
629823	27556695	The increased expression of PADI4 in gastric tumor tissues corresponds to the present finding regarding the significant association of PADI4-encoding DNA variants with gastric carcinoma.	('PADI4', 'Gene', '23569', (28, 33))	('PADI4', 'Gene', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('variants', 'Var', (154, 162))	('association', 'Interaction', (120, 131))	('gastric tumor', 'Disease', (37, 50))	('gastric carcinoma', 'Disease', 'MESH:D013274', (168, 185))	('PADI4', 'Gene', '23569', (135, 140))	('PADI4', 'Gene', (135, 140))	('gastric carcinoma', 'Disease', (168, 185))	('expression', 'MPA', (14, 24))	('gastric tumor', 'Disease', 'MESH:D013274', (37, 50))	('gastric tumor', 'Phenotype', 'HP:0006753', (37, 50))	('increased', 'PosReg', (4, 13))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (168, 185))
629824	27556695	To date, citrullination of histones, cytokeratin, antithrombin and fibronectin has been detected and found to be involved in abnormal apoptosis, increased coagulation, and disordered cell proliferation and differentiation, all of which are main features of malignant tumors.	('antithrombin', 'Gene', (50, 62))	('apoptosis', 'CPA', (134, 143))	('antithrombin', 'Gene', '462', (50, 62))	('histones', 'Protein', (27, 35))	('malignant tumors', 'Disease', 'MESH:D018198', (257, 273))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('coagulation', 'CPA', (155, 166))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('increased coagulation', 'Phenotype', 'HP:0001928', (145, 166))	('malignant tumors', 'Disease', (257, 273))	('disordered cell proliferation', 'Phenotype', 'HP:0031377', (172, 201))	('increased', 'PosReg', (145, 154))	('fibronectin', 'Gene', (67, 78))	('differentiation', 'CPA', (206, 221))	('disordered cell proliferation', 'Disease', (172, 201))	('disordered cell proliferation', 'Disease', 'MESH:D065703', (172, 201))	('involved', 'Reg', (113, 121))	('citrullination', 'Var', (9, 23))	('fibronectin', 'Gene', '2335', (67, 78))
629831	27556695	These results demonstrate that altered PADI4 expression significantly affects CXCR2, KRT14 and TNF-alpha expression and suggests that PADI4 plays a role in gastric tumorigenesis through the CXCR2, KRT14 and TNF-alpha pathways.	('altered', 'Var', (31, 38))	('KRT14', 'Gene', '3861', (197, 202))	('KRT14', 'Gene', '3861', (85, 90))	('KRT14', 'Gene', (197, 202))	('KRT14', 'Gene', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('gastric tumor', 'Disease', (156, 169))	('gastric tumor', 'Disease', 'MESH:D013274', (156, 169))	('TNF-alpha expression', 'MPA', (95, 115))	('gastric tumor', 'Phenotype', 'HP:0006753', (156, 169))	('PADI4', 'Gene', (39, 44))	('PADI4', 'Gene', (134, 139))	('CXCR2', 'Gene', (190, 195))	('CXCR2', 'Gene', (78, 83))	('PADI4', 'Gene', '23569', (39, 44))	('affects', 'Reg', (70, 77))	('CXCR2', 'Gene', '3579', (190, 195))	('PADI4', 'Gene', '23569', (134, 139))	('CXCR2', 'Gene', '3579', (78, 83))
629843	27556695	TNF-alpha polymorphisms have been found to be associated with gastric carcinogenesis.	('TNF-alpha', 'Gene', (0, 9))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (62, 84))	('polymorphisms', 'Var', (10, 23))	('associated', 'Reg', (46, 56))	('gastric carcinogenesis', 'Disease', (62, 84))
629855	27556695	found that upregulation of CXCR2 is dependent on the dysfunction of p53; Cai et al.	('CXCR2', 'Gene', '3579', (27, 32))	('CXCR2', 'Gene', (27, 32))	('p53', 'Gene', (68, 71))	('dysfunction', 'Var', (53, 64))	('p53', 'Gene', '7157', (68, 71))	('upregulation', 'PosReg', (11, 23))
629874	27556695	Peripheral blood samples were collected from patients with breast cancer (n=281, 281 females, aged 26-80 years, mean age 49.3 years), cervical carcinoma (n=202, 202 females, aged 29-61 years, mean age 54.4 years), esophageal carcinoma (n=157, 30 females, aged 39-86 years, mean age 60.8 years), gastric carcinoma (n=221, 64 females, aged 31-80 years, mean age 58.2 years), liver cancer (n=202, 30 females, aged 30-79 years, mean age 55.9 years), ovarian cancer (n=197, 197 females, aged 19-76 years, mean age 52.9 years) or rectal carcinoma (n=101, 36 females, aged 30-75 years, mean age 55.6 years).	('gastric carcinoma', 'Disease', (295, 312))	('cervical carcinoma', 'Disease', 'MESH:D002575', (134, 152))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (524, 540))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (45, 53))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (295, 312))	('esophageal carcinoma', 'Disease', (214, 234))	('rectal carcinoma', 'Disease', (524, 540))	('cancer', 'Phenotype', 'HP:0002664', (454, 460))	('ovarian cancer', 'Disease', 'MESH:D010051', (446, 460))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (531, 540))	('rectal carcinoma', 'Disease', 'MESH:D012004', (524, 540))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (214, 234))	('liver cancer', 'Disease', 'MESH:D006528', (373, 385))	('n=197', 'Var', (462, 467))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('breast cancer', 'Disease', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('ovarian cancer', 'Disease', (446, 460))	('liver cancer', 'Phenotype', 'HP:0002896', (373, 385))	('ovarian cancer', 'Phenotype', 'HP:0100615', (446, 460))	('liver cancer', 'Disease', (373, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('cervical carcinoma', 'Disease', (134, 152))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (214, 234))	('gastric carcinoma', 'Disease', 'MESH:D013274', (295, 312))
629875	27556695	To verify the Illumina genotyping results, tag SNPs of rs41265997, rs1635566, rs882537, rs1635586 and rs1748034 were selected for the genotyping of cohorts of patients with gastric cancer (n=190, 64 women, mean age=57.7) and healthy controls (n=288, 72 women, mean age=40).	('rs1635566', 'Var', (67, 76))	('rs1748034', 'Mutation', 'rs1748034', (102, 111))	('gastric cancer', 'Disease', (173, 187))	('rs1748034', 'Var', (102, 111))	('rs1635586', 'Var', (88, 97))	('rs41265997', 'Var', (55, 65))	('women', 'Species', '9606', (253, 258))	('rs1635586', 'Mutation', 'rs1635586', (88, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('rs1635566', 'Mutation', 'rs1635566', (67, 76))	('women', 'Species', '9606', (199, 204))	('rs882537', 'Var', (78, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (173, 187))	('patients', 'Species', '9606', (159, 167))	('rs41265997', 'Mutation', 'rs41265997', (55, 65))	('rs882537', 'Mutation', 'rs882537', (78, 86))
629941	26319974	Pulmonary morbidity (37 vs. 30%), cardiac arrhythmias (22 vs. 19%), and anastomotic leak rates (22 vs. 15%) were increased in the higher IOF rate cohort, but the increases were not statistically significant.	('cardiac arrhythmias', 'Disease', 'MESH:D001145', (34, 53))	('cardiac arrhythmias', 'Disease', (34, 53))	('higher', 'Var', (130, 136))	('anastomotic leak', 'Disease', (72, 88))	('arrhythmias', 'Phenotype', 'HP:0011675', (42, 53))	('IOF', 'Phenotype', 'HP:0031527', (137, 140))	('Pulmonary', 'Disease', (0, 9))	('cardiac arrhythmias', 'Phenotype', 'HP:0011675', (34, 53))	('increased', 'PosReg', (113, 122))	('anastomotic leak', 'Disease', 'MESH:D057868', (72, 88))	('IOF', 'MPA', (137, 140))
630008	26516367	testified that ERCC1 mRNA expression and ERCC1 (rs11615) gene polymorphisms correlated with treatment response to CDDP-based chemotherapy.	('ERCC1', 'Gene', '2067', (41, 46))	('ERCC1', 'Gene', (41, 46))	('rs11615', 'Var', (48, 55))	('CDDP', 'Chemical', 'MESH:D002945', (114, 118))	('ERCC1', 'Gene', '2067', (15, 20))	('ERCC1', 'Gene', (15, 20))	('correlated', 'Reg', (76, 86))	('rs11615', 'Mutation', 'rs11615', (48, 55))
630011	26516367	The results showed that miR-192 and miR-194 in pre-therapeutic biopsies are considered indicators of major histopathologic regression.	('miR-192', 'Gene', (24, 31))	('miR-192', 'Gene', '406967', (24, 31))	('miR-194', 'Var', (36, 43))
630059	24790704	Inhibition of antioxidant enzymes that remove ROS was found to accelerate cancer growth.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('accelerate', 'PosReg', (63, 73))	('Inhibition', 'Var', (0, 10))	('ROS', 'Chemical', 'MESH:D017382', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
630066	24790704	Promoter hypermethylation of GPX3 gene was detected in carcinoma tissues not normal breast tissues.	('carcinoma', 'Disease', 'MESH:D002277', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinoma', 'Disease', (55, 64))	('detected', 'Reg', (43, 51))	('GPX3', 'Gene', (29, 33))	('Promoter hypermethylation', 'Var', (0, 25))
630076	24790704	Promoter hypermethylation mechanism which is a "frequent event in human cancers" may result in GPX3 gene silencing and inhibition of GPX3 expression.	('GPX3', 'Gene', (133, 137))	('GPX3 gene', 'Gene', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('silencing', 'NegReg', (105, 114))	('inhibition', 'NegReg', (119, 129))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('expression', 'MPA', (138, 148))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('Promoter hypermethylation', 'Var', (0, 25))
630077	24790704	GPX3 promoter hypermethylation and downregulation were detected in prostate cancer; endometrial adenocarcinoma; cervical, thyroid, and lung cancer; head and neck carcinoma; gastric cancer; and multiple myeloma.	('promoter', 'PosReg', (5, 13))	('thyroid', 'Disease', (122, 129))	('endometrial adenocarcinoma', 'Disease', (84, 110))	('prostate cancer', 'Disease', (67, 82))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (84, 110))	('lung cancer', 'Disease', (135, 146))	('gastric cancer', 'Disease', (173, 187))	('neck carcinoma', 'Disease', 'MESH:D006258', (157, 171))	('multiple myeloma', 'Phenotype', 'HP:0006775', (193, 209))	('neck carcinoma', 'Disease', (157, 171))	('cervical', 'Disease', (112, 120))	('hypermethylation', 'Var', (14, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (173, 187))	('multiple myeloma', 'Disease', 'MESH:D009101', (193, 209))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('downregulation', 'NegReg', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (148, 171))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('GPX3', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (84, 110))	('prostate cancer', 'Disease', 'MESH:D011471', (67, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (173, 187))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('multiple myeloma', 'Disease', (193, 209))
630078	24790704	GPX3 hypermethylation correlates with disease poor prognosis and resistance to chemotherapy in head and neck cancer patients and multiple myeloma.	('neck cancer', 'Disease', 'MESH:D006258', (104, 115))	('neck cancer', 'Disease', (104, 115))	('multiple myeloma', 'Phenotype', 'HP:0006775', (129, 145))	('GPX3', 'Gene', (0, 4))	('patients', 'Species', '9606', (116, 124))	('multiple myeloma', 'Disease', 'MESH:D009101', (129, 145))	('hypermethylation', 'Var', (5, 21))	('head and neck cancer', 'Phenotype', 'HP:0012288', (95, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('multiple myeloma', 'Disease', (129, 145))
630079	24790704	Recently, we found that inactivation of the GPX3 gene by promoter hypermethylation in gastric cancer is associated with high incidence of lymph node metastasis.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('GPX3', 'Gene', (44, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('inactivation', 'Var', (24, 36))	('promoter hypermethylation', 'Var', (57, 82))	('associated', 'Reg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (86, 100))	('lymph node metastasis', 'CPA', (138, 159))
630084	24790704	ROS was found to stimulate cancer cell motility and invasion by activating protein kinase-C (PKC) and the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERKs) signaling pathways, thus increasing the risk of metastasis.	('increasing', 'PosReg', (221, 231))	('ROS', 'Var', (0, 3))	('metastasis', 'CPA', (244, 254))	('activating', 'PosReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('ERKs', 'Gene', (190, 194))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('stimulate', 'PosReg', (17, 26))	('ERKs', 'Gene', '5595;5594;5595', (190, 194))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('invasion', 'CPA', (52, 60))
630086	24790704	Since almost all IBC patients presented with positive axillary lymph node metastasis, herein, we investigated whether expression and epigenetic regulation of GPX3 may contribute to the aggressive phenotype IBC versus non-IBC.	('GPX3', 'Gene', (158, 162))	('contribute', 'Reg', (167, 177))	('epigenetic regulation', 'Var', (133, 154))	('IBC', 'Disease', (206, 209))	('IBC', 'Disease', (17, 20))	('patients', 'Species', '9606', (21, 29))
630130	24790704	On the contrary, agarose gel electrophoresis of all GPX3-MSP products breast carcinoma tissue samples showed bands of 200 bp corresponding to both unmethylated (Figure 3(a)) and methylated GPX3-MSP products (Figure 3(b)).	('breast carcinoma', 'Phenotype', 'HP:0003002', (70, 86))	('methylated', 'Var', (178, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('agarose', 'Chemical', 'MESH:D012685', (17, 24))	('breast carcinoma', 'Disease', (70, 86))	('breast carcinoma', 'Disease', 'MESH:D001943', (70, 86))	('GPX3-MSP products', 'Gene', (52, 69))
630131	24790704	The present results showed that GPX3 methylation was detected in breast carcinoma tissues and not in normal breast tissues.	('breast carcinoma tissues', 'Disease', 'MESH:D001943', (65, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('methylation', 'Var', (37, 48))	('breast carcinoma tissues', 'Disease', (65, 89))	('detected', 'Reg', (53, 61))	('GPX3', 'Gene', (32, 36))	('breast carcinoma', 'Phenotype', 'HP:0003002', (65, 81))
630132	24790704	Thus, GPX3 promoter methylation is responsible for the downregulation of GPX3 mRNA in breast carcinoma tissues since it was not detected in normal breast tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('breast carcinoma tissues', 'Disease', 'MESH:D001943', (86, 110))	('mRNA', 'MPA', (78, 82))	('breast carcinoma tissues', 'Disease', (86, 110))	('GPX3', 'Gene', (73, 77))	('methylation', 'Var', (20, 31))	('breast carcinoma', 'Phenotype', 'HP:0003002', (86, 102))	('downregulation', 'NegReg', (55, 69))
630140	24790704	In addition, ROS augment carcinoma cell motility and invasion by activating protein kinase-C (PKC) and the ERK/MAPK signaling pathways, thus increasing the risk of metastasis.	('ROS', 'Var', (13, 16))	('ERK', 'Gene', '5594', (107, 110))	('ERK', 'Gene', (107, 110))	('carcinoma cell motility', 'Disease', 'MESH:D015835', (25, 48))	('augment', 'PosReg', (17, 24))	('invasion', 'CPA', (53, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('activating', 'PosReg', (65, 75))	('carcinoma cell motility', 'Disease', (25, 48))	('increasing', 'PosReg', (141, 151))	('metastasis', 'CPA', (164, 174))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))
630144	24790704	Downregulation and genetic imbalance among GPXs were found to play a key role in breast cancer.	('breast cancer', 'Disease', (81, 94))	('imbalance', 'Phenotype', 'HP:0002172', (27, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('Downregulation', 'NegReg', (0, 14))	('genetic imbalance', 'Var', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
630150	24790704	The impaired function of GPX3 would result in the accumulation of an increased amount of hydrogen peroxide and other ROS which may induce breast carcinogenesis via induction of oxidative DNA damage, genetic instability, neoplastic transformation, and mutation of the p53 tumor suppressor gene.	('function', 'MPA', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('increased', 'PosReg', (69, 78))	('GPX3', 'Gene', (25, 29))	('oxidative DNA damage', 'MPA', (177, 197))	('mutation', 'Var', (251, 259))	('tumor', 'Disease', (271, 276))	('genetic instability', 'CPA', (199, 218))	('ROS', 'Chemical', 'MESH:D017382', (117, 120))	('p53', 'Gene', (267, 270))	('p53', 'Gene', '7157', (267, 270))	('breast carcinogenesis', 'Disease', (138, 159))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (138, 159))	('induce', 'PosReg', (131, 137))	('accumulation', 'PosReg', (50, 62))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (89, 106))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('neoplastic transformation', 'CPA', (220, 245))
630153	24790704	In fact, GPX3 promoter hypermethylation is linked to downregulation of GPX3 expression in different types of cancer cells and treatment with 5-Aza to human esophageal adenocarcinoma cancer cells SKGT4 and human myeloma cells KMS11 restores GPX3 gene expression.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('esophageal adenocarcinoma cancer', 'Disease', (156, 188))	('myeloma', 'Disease', (211, 218))	('downregulation', 'NegReg', (53, 67))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (156, 181))	('5-Aza', 'Chemical', 'MESH:D001374', (141, 146))	('SKGT4', 'CellLine', 'CVCL:2195', (195, 200))	('GPX3 gene', 'Gene', (240, 249))	('cancer', 'Disease', (182, 188))	('hypermethylation', 'Var', (23, 39))	('human', 'Species', '9606', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('restores', 'PosReg', (231, 239))	('cancer', 'Disease', (109, 115))	('GPX3', 'Gene', (9, 13))	('human', 'Species', '9606', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('esophageal adenocarcinoma cancer', 'Disease', 'MESH:D004938', (156, 188))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('expression', 'MPA', (76, 86))	('myeloma', 'Disease', 'MESH:D009101', (211, 218))	('expression', 'MPA', (250, 260))	('GPX3', 'Gene', (71, 75))
630154	24790704	Our previous studies demonstrated that GPX3 was downregulated in Barrett's carcinoma due to hypermethylation of the promoter region.	('GPX3', 'Gene', (39, 43))	("Barrett's carcinoma", 'Disease', (65, 84))	('downregulated', 'NegReg', (48, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	("Barrett's carcinoma", 'Disease', 'MESH:D001471', (65, 84))	('hypermethylation', 'Var', (92, 108))
630155	24790704	In addition, we found that loss in DNA copy number, hypermethylation of the promoter region, and downregulation of mRNA expression of GPX3 are associated with lymph node metastasis in gastric carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('gastric carcinomas', 'Disease', (184, 202))	('lymph node metastasis', 'CPA', (159, 180))	('hypermethylation', 'Var', (52, 68))	('GPX3', 'Gene', (134, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))	('DNA', 'MPA', (35, 38))	('loss', 'NegReg', (27, 31))	('downregulation', 'NegReg', (97, 111))	('gastric carcinomas', 'Disease', 'MESH:D013274', (184, 202))	('mRNA expression', 'MPA', (115, 130))
630156	24790704	Reactivation of GPX3 in gastric adenocarcinoma cell line AGS inhibits cell motility as assessed by wound healing assay.	('GPX3', 'Gene', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (24, 46))	('Reactivation', 'Var', (0, 12))	('gastric adenocarcinoma', 'Disease', (24, 46))	('cell motility', 'CPA', (70, 83))	('inhibits', 'NegReg', (61, 69))
630165	24790704	Interestingly, loss of GPX3 contributes to high infiltration of tumor associated macrophages that support tumor survival in GPX3 knockout mice model.	('GPX3', 'Gene', (23, 27))	('tumor', 'Disease', (64, 69))	('mice', 'Species', '10090', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('loss', 'Var', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (106, 111))
630169	24790704	In addition, methylation silencing of GPX3 in IBC may contribute to invasion of IBC carcinoma cells into lymphatic vessels, formation of tumor emboli, and IBC chemoresistance as suggested in other cancers.	('carcinoma cells', 'Disease', (84, 99))	('tumor', 'Disease', (137, 142))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('contribute', 'Reg', (54, 64))	('IBC chemoresistance', 'CPA', (155, 174))	('methylation silencing', 'Var', (13, 34))	('cancers', 'Disease', (197, 204))	('invasion', 'CPA', (68, 76))	('GPX3', 'Gene', (38, 42))	('IBC carcinoma', 'Disease', 'MESH:D058922', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('IBC carcinoma', 'Disease', (80, 93))	('carcinoma cells', 'Disease', 'MESH:C538614', (84, 99))
630172	23705663	Polymorphism of A133S and promoter hypermethylation in Ras association domain family 1A gene (RASSF1A) is associated with risk of esophageal and gastric cardia cancers in Chinese population from high incidence area in northern China The role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive.	('Polymorphism', 'Var', (0, 12))	('esophageal and gastric cardia carcinogenesis', 'Disease', 'MESH:D004938', (282, 326))	('esophageal and gastric cardia cancers', 'Disease', 'MESH:D013274', (130, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('associated', 'Reg', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('RASSF1A', 'Gene', '11186', (267, 274))	('A133S', 'SUBSTITUTION', 'None', (16, 21))	('promoter hypermethylation', 'Var', (26, 51))	('RASSF1A', 'Gene', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('A133S', 'Var', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('RASSF1A', 'Gene', '11186', (94, 101))	('tumor', 'Disease', (245, 250))	('RASSF1A', 'Gene', (267, 274))
630174	23705663	We firstly analyzed the prevalence of RASSF1A A133S in a total of 228 cancer patients with ESCC (n=112) and GCA (n=116) and 235 normal controls by polymerase chain reaction (PCR) and restriction enzyme-digestion assay.	('RASSF1A', 'Gene', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('A133S', 'Var', (46, 51))	('ESCC', 'Disease', (91, 95))	('GCA', 'Gene', '25801', (108, 111))	('GCA', 'Gene', (108, 111))	('patients', 'Species', '9606', (77, 85))	('A133S', 'SUBSTITUTION', 'None', (46, 51))	('RASSF1A', 'Gene', '11186', (38, 45))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
630177	23705663	The frequency of 133Ala/Se and Ser/Ser genotype was significantly higher in GCA patients than in normal controls (19.0% vs. 10.2%, P=0.02).	('patients', 'Species', '9606', (80, 88))	('Ser', 'Chemical', 'MESH:D012694', (35, 38))	('133Ala/Se', 'Var', (17, 26))	('Ser', 'Chemical', 'MESH:D012694', (31, 34))	('Se', 'Chemical', 'MESH:D012643', (31, 33))	('Se', 'Chemical', 'MESH:D012643', (35, 37))	('Se', 'Chemical', 'MESH:D012643', (24, 26))	('GCA', 'Gene', '25801', (76, 79))	('Ser/Ser', 'Var', (31, 38))	('GCA', 'Gene', (76, 79))	('higher', 'PosReg', (66, 72))	('Ala', 'Chemical', 'MESH:D000409', (20, 23))
630180	23705663	Promoter methylation of RASSF1A gene in ESCC was also associated with age and cancer cell differentiation (for age: OR=3.11, 95% CI=1.10-8.73; for differentiation: OR=0.29, 95% CI=0.12-0.69).	('cancer', 'Disease', (78, 84))	('RASSF1A', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('Promoter methylation', 'Var', (0, 20))	('RASSF1A', 'Gene', '11186', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('associated', 'Reg', (54, 64))	('age', 'CPA', (70, 73))
630181	23705663	RASSF1A positive expression was significantly decreased the risk of GCA (OR=0.16, 95% CI=0.03-0.83).	('GCA', 'Gene', (68, 71))	('positive expression', 'Var', (8, 27))	('RASSF1A', 'Gene', (0, 7))	('RASSF1A', 'Gene', '11186', (0, 7))	('decreased', 'NegReg', (46, 55))	('GCA', 'Gene', '25801', (68, 71))
630184	23705663	The present findings suggest that alterations of RASSF1A may play an important role in gastric cardia carcinogenesis in terms of polymorphism, promoter hypermethylation and protein expression.	('role', 'Reg', (79, 83))	('gastric cardia carcinogenesis', 'Disease', (87, 116))	('RASSF1A', 'Gene', (49, 56))	('promoter hypermethylation', 'MPA', (143, 168))	('polymorphism', 'MPA', (129, 141))	('gastric cardia carcinogenesis', 'Disease', 'MESH:D004938', (87, 116))	('protein expression', 'MPA', (173, 191))	('play', 'Reg', (61, 65))	('RASSF1A', 'Gene', '11186', (49, 56))	('rat', 'Species', '10116', (38, 41))	('alterations', 'Var', (34, 45))
630185	23705663	Whereas, RASSF1A hypermethylation may probably also be involved in esophageal squamous cell carcinogenesis.	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (67, 106))	('involved', 'Reg', (55, 63))	('esophageal squamous cell carcinogenesis', 'Disease', (67, 106))	('RASSF1A', 'Gene', (9, 16))	('hypermethylation', 'Var', (17, 33))	('RASSF1A', 'Gene', '11186', (9, 16))
630193	23705663	The single nucleotide polymorphism (SNP) Ala133Ser (A133S) in RASSF1A has been reported to be involved in the lung and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('A133S', 'Var', (52, 57))	('RASSF1A', 'Gene', (62, 69))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('lung', 'Disease', (110, 114))	('breast cancer', 'Disease', (119, 132))	('single nucleotide polymorphism', 'Var', (4, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('A133S', 'SUBSTITUTION', 'None', (52, 57))	('RASSF1A', 'Gene', '11186', (62, 69))	('Ala133Ser', 'SUBSTITUTION', 'None', (41, 50))	('Ala133Ser', 'Var', (41, 50))	('involved', 'Reg', (94, 102))
630212	23705663	A total of 143 ESCC tissue specimens and 92 GCA tissue specimens were used for methylation detection, including 62 matched esophageal cancer and normal tissues, and 30 matched gastric cardia cancer and normal tissues.	('gastric cardia cancer', 'Disease', (176, 197))	('esophageal cancer', 'Disease', (123, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (176, 197))	('methylation', 'Var', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('GCA', 'Gene', '25801', (44, 47))	('GCA', 'Gene', (44, 47))
630242	23705663	All the 235 control, 112 ESCC and 116 GCA samples were analyzed for the presence of A133S (Table 1).	('GCA', 'Gene', (38, 41))	('A133S', 'Var', (84, 89))	('GCA', 'Gene', '25801', (38, 41))	('A133S', 'SUBSTITUTION', 'None', (84, 89))
630244	23705663	The homozygous or heterozygous for A133S were accounted for 11.6% (13/112) in the ESCC and 10.2% (24/235) in control subjects.	('ESCC', 'Disease', (82, 86))	('A133S', 'Var', (35, 40))	('A133S', 'SUBSTITUTION', 'None', (35, 40))
630245	23705663	Though the frequencies of A133S in ESCC was a little higher than in controls, Ala/Se and Ser/Ser genotype did not increase the risk of ESCC compared with Ala/Ala genotype (11.2% vs. 10.2%, P=0.69; OR=1.15; 95% CI=0.51-2.44).	('Se', 'Chemical', 'MESH:D012643', (82, 84))	('ESCC', 'Disease', (135, 139))	('Se', 'Chemical', 'MESH:D012643', (89, 91))	('Ser', 'Chemical', 'MESH:D012694', (93, 96))	('Ser', 'Chemical', 'MESH:D012694', (89, 92))	('Ala', 'Chemical', 'MESH:D000409', (154, 157))	('A133S', 'Var', (26, 31))	('Ala', 'Chemical', 'MESH:D000409', (78, 81))	('Ala', 'Chemical', 'MESH:D000409', (158, 161))	('Se', 'Chemical', 'MESH:D012643', (93, 95))	('ESCC', 'Disease', (35, 39))	('A133S', 'SUBSTITUTION', 'None', (26, 31))
630246	23705663	Intriguingly, in GCA, there was a significant difference of the frequency of the RASSF1A A133S T allele compared with the controls (19.0% vs. 10.2%).	('A133S', 'SUBSTITUTION', 'None', (89, 94))	('GCA', 'Gene', '25801', (17, 20))	('GCA', 'Gene', (17, 20))	('RASSF1A', 'Gene', '11186', (81, 88))	('A133S', 'Var', (89, 94))	('RASSF1A', 'Gene', (81, 88))
630247	23705663	The individuals carrying A133S (Ser/Ser) genotype had a much higher susceptibility to GCA compared with people carrying Ala/Ala genotype (P=0.04, OR=9.01, 95% CI= 0.99-83.31).	('people', 'Species', '9606', (104, 110))	('A133S', 'Var', (25, 30))	('Ala', 'Chemical', 'MESH:D000409', (124, 127))	('GCA', 'Gene', '25801', (86, 89))	('susceptibility', 'Reg', (68, 82))	('GCA', 'Gene', (86, 89))	('A133S', 'SUBSTITUTION', 'None', (25, 30))	('Ser', 'Chemical', 'MESH:D012694', (32, 35))	('Ser', 'Chemical', 'MESH:D012694', (36, 39))	('Ala', 'Chemical', 'MESH:D000409', (120, 123))
630251	23705663	Interestingly, the similar results were observed in GCA, the promoter hypermethylation of RASSF1A gene significantly increased almost 7.5-fold higher the risk to GCA development (65% in GCA vs. 20% in adjacent normal mucosa, OR=7.50, 95% CI=2.78-20.23) (Table 2 and Figure 2).	('increased', 'PosReg', (117, 126))	('RASSF1A', 'Gene', (90, 97))	('GCA', 'Gene', '25801', (52, 55))	('GCA', 'Gene', (52, 55))	('GCA', 'Gene', '25801', (162, 165))	('promoter hypermethylation', 'Var', (61, 86))	('GCA', 'Gene', (162, 165))	('higher', 'PosReg', (143, 149))	('GCA', 'Gene', '25801', (186, 189))	('GCA', 'Gene', (186, 189))	('RASSF1A', 'Gene', '11186', (90, 97))
630260	23705663	There was a significant correlation between RASSF1A promoter hypermethylation and loss of RASSF1A protein expression in GCA (P=0.001, Fisher's exact test).	('GCA', 'Gene', '25801', (120, 123))	('RASSF1A', 'Gene', '11186', (44, 51))	('GCA', 'Gene', (120, 123))	('RASSF1A', 'Gene', (90, 97))	('expression', 'MPA', (106, 116))	('hypermethylation', 'Var', (61, 77))	('loss', 'NegReg', (82, 86))	('RASSF1A', 'Gene', '11186', (90, 97))	('RASSF1A', 'Gene', (44, 51))	('protein', 'Protein', (98, 105))
630267	23705663	In the present study, we firstly investigated the RASSF1A A133S polymorphism and the risk to ESCC and GCA development on the patients from Linzhou, the high incidence area for both ESCC and GCA.	('GCA', 'Gene', '25801', (102, 105))	('GCA', 'Gene', (102, 105))	('RASSF1A', 'Gene', '11186', (50, 57))	('A133S', 'SUBSTITUTION', 'None', (58, 63))	('RASSF1A', 'Gene', (50, 57))	('GCA', 'Gene', '25801', (190, 193))	('GCA', 'Gene', (190, 193))	('ESCC', 'Disease', (93, 97))	('A133S', 'Var', (58, 63))	('patients', 'Species', '9606', (125, 133))
630268	23705663	Our results demonstrated that the existence of polymorphic allele of RASSF1A might participate in gastric cardia carcinogenesis.	('participate', 'Reg', (83, 94))	('polymorphic allele', 'Var', (47, 65))	('gastric cardia carcinogenesis', 'Disease', 'MESH:D004938', (98, 127))	('RASSF1A', 'Gene', (69, 76))	('rat', 'Species', '10116', (19, 22))	('gastric cardia carcinogenesis', 'Disease', (98, 127))	('RASSF1A', 'Gene', '11186', (69, 76))
630269	23705663	The carriers with Ser/Ser genotype (the homozygote for codon RASSF1A A133S) and with mutated T allele genotype (Ala/Ser+Ser/Ser genotype) could have 9-fold (OR=9.01, 95% CI=0.99-83.31) and 2-fold (OR=2.06, 95% CI=1.09-3.97) higher risk to GCA, respectively.	('RASSF1A', 'Gene', (61, 68))	('Ser', 'Chemical', 'MESH:D012694', (120, 123))	('A133S', 'Var', (69, 74))	('RASSF1A', 'Gene', '11186', (61, 68))	('Ser', 'Chemical', 'MESH:D012694', (124, 127))	('Ser', 'Chemical', 'MESH:D012694', (18, 21))	('A133S', 'SUBSTITUTION', 'None', (69, 74))	('Ser', 'Chemical', 'MESH:D012694', (22, 25))	('Ala', 'Chemical', 'MESH:D000409', (112, 115))	('higher', 'PosReg', (224, 230))	('GCA', 'Gene', '25801', (239, 242))	('Ser/Ser', 'Var', (18, 25))	('GCA', 'Gene', (239, 242))	('Ser', 'Chemical', 'MESH:D012694', (116, 119))
630270	23705663	In contrast, the presence of SNP A133S in RASSF1A seems to be not involved in esophageal squamous cell carcinogenesis (P=0.69).	('RASSF1A', 'Gene', (42, 49))	('A133S', 'Var', (33, 38))	('esophageal squamous cell carcinogenesis', 'Disease', 'MESH:D000077277', (78, 117))	('RASSF1A', 'Gene', '11186', (42, 49))	('involved', 'Reg', (66, 74))	('esophageal squamous cell carcinogenesis', 'Disease', (78, 117))	('A133S', 'SUBSTITUTION', 'None', (33, 38))
630272	23705663	It has been reported that single nucleotide polymorphism at codon 133 of the RASSF1 gene is preferentially associated with human lung adenocarcinoma risk, but not for human lung squamous cell carcinoma.	('single nucleotide polymorphism at', 'Var', (26, 59))	('RASSF1', 'Gene', '11186', (77, 83))	('human', 'Species', '9606', (123, 128))	('associated', 'Reg', (107, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (129, 148))	('RASSF1', 'Gene', (77, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('lung adenocarcinoma', 'Disease', (129, 148))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (173, 201))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (173, 201))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (129, 148))	('human', 'Species', '9606', (167, 172))	('lung squamous cell carcinoma', 'Disease', (173, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
630274	23705663	Aberrant RASSF1A promoter methylation was found in 53% (76/143) of Chinese ESCC, significantly increased 5.9-fold higher the risk to ESCC (OR=5.90, 95% CI=2.78-12.52).	('Aberrant', 'Var', (0, 8))	('ESCC', 'Disease', (133, 137))	('RASSF1A', 'Gene', (9, 16))	('increased', 'PosReg', (95, 104))	('higher', 'PosReg', (114, 120))	('RASSF1A', 'Gene', '11186', (9, 16))
630275	23705663	Interestingly, another two reports also show higher frequency of RASSF1A promoter methylation in Chinese ESCC from Hong Kong (34%, 22/64) and Hangzhou (48.5%, 32/66), the high incidence area for ESCC in China.	('methylation', 'Var', (82, 93))	('RASSF1A', 'Gene', (65, 72))	('promoter', 'MPA', (73, 81))	('RASSF1A', 'Gene', '11186', (65, 72))
630276	23705663	It is noteworthy that Chinese ESCC from low incidence area seems to have low frequency of RASSF1A promoter methylation (14.9% 22/64).	('RASSF1A', 'Gene', '11186', (90, 97))	('methylation', 'Var', (107, 118))	('RASSF1A', 'Gene', (90, 97))
630283	23705663	Furthermore, our results is close to the findings of RASSF1A gene methylation in GCA patients from Hebei province (58.7%, 54/92), another high incidence area for ESCC and GCA in TaiHang Mountain.	('GCA', 'Gene', (171, 174))	('methylation', 'Var', (66, 77))	('patients', 'Species', '9606', (85, 93))	('RASSF1A', 'Gene', (53, 60))	('GCA', 'Gene', '25801', (81, 84))	('GCA', 'Gene', (81, 84))	('GCA', 'Gene', '25801', (171, 174))	('RASSF1A', 'Gene', '11186', (53, 60))
630284	23705663	It is noteworthy that, in the present study, we also observed the RASSF1A promoter methylation in the normal esophageal and gastric cardia epithelial tissue adjacent to corresponding ESCC and GCA (in ESCC: 13%, 23/143; in GCA: 20%, 19/92).	('GCA', 'Gene', '25801', (192, 195))	('gastric cardia epithelial', 'Disease', 'MESH:D004938', (124, 149))	('RASSF1A', 'Gene', (66, 73))	('gastric cardia epithelial', 'Disease', (124, 149))	('RASSF1A', 'Gene', '11186', (66, 73))	('methylation', 'Var', (83, 94))	('GCA', 'Gene', '25801', (222, 225))	('GCA', 'Gene', (222, 225))	('GCA', 'Gene', (192, 195))
630286	23705663	The present results indicate that RASSF1A promoter methylation may be a promising early indicator for esophageal and gastric cardia carcinogenesis.	('esophageal and gastric cardia carcinogenesis', 'Disease', 'MESH:D004938', (102, 146))	('RASSF1A', 'Gene', (34, 41))	('methylation', 'Var', (51, 62))	('RASSF1A', 'Gene', '11186', (34, 41))
630288	23705663	Another interesting finding in this study is that RASSF1A promoter hypermethylation could significantly downregulated RASSF1A protein expression both in ESCC and GCA, further indicating the possible crucial role of RASSF1A promoter hypermethylation and protein expression in esophageal and gastric cardia carcinogenesis.	('protein', 'Protein', (126, 133))	('RASSF1A', 'Gene', '11186', (50, 57))	('expression', 'MPA', (134, 144))	('RASSF1A', 'Gene', '11186', (215, 222))	('esophageal and gastric cardia carcinogenesis', 'Disease', 'MESH:D004938', (275, 319))	('GCA', 'Gene', '25801', (162, 165))	('RASSF1A', 'Gene', (118, 125))	('GCA', 'Gene', (162, 165))	('downregulated', 'NegReg', (104, 117))	('RASSF1A', 'Gene', (50, 57))	('RASSF1A', 'Gene', (215, 222))	('RASSF1A', 'Gene', '11186', (118, 125))	('promoter hypermethylation', 'Var', (58, 83))	('ESCC', 'Disease', (153, 157))
630290	23705663	In conclusion, this is the first study to reveal the interactions of RASSF1A polymorphism, promoter methylation and protein expression on the risk of esophageal and gastric cardia carcinogenesis.	('RASSF1A', 'Gene', (69, 76))	('RASSF1A', 'Gene', '11186', (69, 76))	('polymorphism', 'Var', (77, 89))	('esophageal and gastric cardia carcinogenesis', 'Disease', 'MESH:D004938', (150, 194))	('interactions', 'Interaction', (53, 65))
630291	23705663	RASSF1A promoter hypermethylation could significantly increase 6-fold and 8-fold higher risk to ESCC and GCA development, respectively, and induce the inactivation of RASSF1A protein expression both in ESCC and GCA, which indicate that RASSF1A promoter hypermethylation may play an important role both in esophageal and gastric cardia carcinogenesis.	('protein', 'Protein', (175, 182))	('RASSF1A', 'Gene', (167, 174))	('RASSF1A', 'Gene', (0, 7))	('RASSF1A', 'Gene', '11186', (236, 243))	('inactivation', 'NegReg', (151, 163))	('promoter hypermethylation', 'Var', (8, 33))	('RASSF1A', 'Gene', '11186', (167, 174))	('increase', 'PosReg', (54, 62))	('ESCC', 'Disease', (202, 206))	('RASSF1A', 'Gene', '11186', (0, 7))	('GCA', 'Gene', '25801', (211, 214))	('GCA', 'Gene', (105, 108))	('expression', 'MPA', (183, 193))	('GCA', 'Gene', (211, 214))	('ESCC', 'Disease', (96, 100))	('esophageal and gastric cardia carcinogenesis', 'Disease', 'MESH:D004938', (305, 349))	('GCA', 'Gene', '25801', (105, 108))	('RASSF1A', 'Gene', (236, 243))
630292	23705663	The T allele (Ala/Ser + Ser/Ser genotype) of RASSF1A A133S could increase the risk to GCA development, but not to ESCC.	('increase', 'PosReg', (65, 73))	('Ala', 'Chemical', 'MESH:D000409', (14, 17))	('Ser', 'Chemical', 'MESH:D012694', (24, 27))	('Ser', 'Chemical', 'MESH:D012694', (28, 31))	('GCA', 'Gene', '25801', (86, 89))	('GCA', 'Gene', (86, 89))	('RASSF1A', 'Gene', (45, 52))	('A133S', 'Var', (53, 58))	('Ser', 'Chemical', 'MESH:D012694', (18, 21))	('RASSF1A', 'Gene', '11186', (45, 52))	('A133S', 'SUBSTITUTION', 'None', (53, 58))
630294	23705663	RASSF1A: Ras association domain family 1A gene; ESCC: Esophageal squamous cell carcinoma; SNP: Single nucleotide polymorphism; GCA: Gastric cardia adenocarcinoma; PCR: Polymerase chain reaction.	('Single nucleotide polymorphism', 'Var', (95, 125))	('GCA', 'Gene', '25801', (127, 130))	('RASSF1A', 'Gene', (0, 7))	('GCA', 'Gene', (127, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('RASSF1A', 'Gene', '11186', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))	('cardia adenocarcinoma', 'Disease', 'MESH:D004938', (140, 161))	('cardia adenocarcinoma', 'Disease', (140, 161))	('Esophageal squamous cell carcinoma', 'Disease', (54, 88))
630295	19086848	Fhit tumor suppressor: guardian of the preneoplastic genome Environmental agents induce intragenic alterations in the FRA3B/FHIT chromosome fragile site, resulting in fragile FHIT allele loss early in cancer development.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('FHIT chromosome fragile', 'Disease', (124, 147))	('FHIT chromosome fragile', 'Disease', 'MESH:D002873', (124, 147))	('fragile FHIT', 'Disease', (167, 179))	('loss', 'NegReg', (187, 191))	('cancer', 'Disease', (201, 207))	('Fhit', 'Gene', '14198', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('fragile FHIT', 'Disease', 'MESH:D005600', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('alterations', 'Var', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Fhit', 'Gene', (0, 4))	('tumor', 'Disease', (5, 10))	('chromosome fragile site', 'Phenotype', 'HP:0040012', (129, 152))
630300	19086848	Malignant transformation is a multistep process involving numerous genetic changes, which include loss of tumor-suppressor gene function, oncogene activation and alterations of modifier genes.	('oncogene', 'CPA', (138, 146))	('alterations', 'Var', (162, 173))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('loss', 'NegReg', (98, 102))	('Malignant transformation', 'CPA', (0, 24))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('activation', 'PosReg', (147, 157))	('tumor', 'Disease', (106, 111))
630301	19086848	Precancerous cells experience selective pressure to escape from the cell cycle block induced by checkpoint responses to DNA damage, and DNA damage checkpoint genes are frequently mutated to overcome the block and allow neoplastic progression.	('cell', 'CPA', (68, 72))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('allow', 'Reg', (213, 218))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('escape', 'MPA', (52, 58))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('neoplastic progression', 'CPA', (219, 241))	('mutated', 'Var', (179, 186))
630303	19086848	In four major regions of 3p (3p25, 3p21.3, 3p14.2 and 3p12), allelic losses have been reported in cancers of the kidney, lung and breast, among others.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('lung', 'Disease', (121, 125))	('cancers of the kidney', 'Phenotype', 'HP:0009726', (98, 119))	('cancers of the kidney', 'Disease', 'MESH:D007680', (98, 119))	('p14', 'Gene', '20202', (44, 47))	('breast', 'Disease', (130, 136))	('p14', 'Gene', (44, 47))	('cancers of the kidney', 'Disease', (98, 119))	('allelic losses', 'Var', (61, 75))
630308	19086848	Loss of Fhit expression is observed in premalignant lesions of lung, esophagus, cervix and other organs, suggesting that loss of Fhit expression, due to the susceptibility of FHIT/FRA3B to carcinogen damage, plays a role in initial stages of multistep carcinogenesis (Figure 1).	('carcinogen damage', 'Disease', (189, 206))	('Fhit', 'Gene', (129, 133))	('loss', 'Var', (121, 125))	('carcinogen damage', 'Disease', 'MESH:D004194', (189, 206))	('plays', 'Reg', (208, 213))	('multistep carcinogenesis', 'Disease', (242, 266))	('multistep carcinogenesis', 'Disease', 'MESH:D063646', (242, 266))
630309	19086848	Since the FHIT gene is prone to breakage and deletion in precancer or early carcinogenesis, and precancerous lesions and cancers show clonal expansion of cells with specific FHIT gene alterations, it was proposed that FHIT gene alteration and loss of Fhit function provides a selective advantage for this clonal growth.	('alteration', 'Var', (228, 238))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('FHIT', 'Gene', (174, 178))	('loss', 'NegReg', (243, 247))	('carcinogenesis', 'Disease', (76, 90))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('deletion', 'Var', (45, 53))	('FHIT', 'Gene', (218, 222))	('precancerous lesions and cancers', 'Disease', 'MESH:D011230', (96, 128))	('alterations', 'Var', (184, 195))	('FHIT', 'Gene', (10, 14))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
630312	19086848	In this review we summarize new studies describing FHIT alterations in human cancers, from analysis of Fhitdeficient mice to identification of important Fhit biological functions.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('alterations', 'Var', (56, 67))	('cancers', 'Disease', (77, 84))	('mice', 'Species', '10090', (117, 121))	('FHIT', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (71, 76))
630315	19086848	Many cancer cell lines and primary cancers exhibiting hemi- or homo-zygous deletions with end points within the FHIT gene and reduced or absent Fhit expression have been reported.	('primary cancers', 'Disease', (27, 42))	('deletions', 'Var', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('FHIT', 'Gene', (112, 116))	('primary cancers', 'Disease', 'MESH:D009369', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', (5, 11))	('Fhit', 'Protein', (144, 148))	('expression', 'MPA', (149, 159))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('absent', 'NegReg', (137, 143))	('cancer', 'Disease', (35, 41))	('reduced', 'NegReg', (126, 133))
630325	19086848	Several studies have shown that FHIT alterations are common in environmental carcinogen-related cancers, such as those of lung and esophagus.	('FHIT', 'Gene', (32, 36))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('esophagus', 'Disease', (131, 140))	('common', 'Reg', (53, 59))	('alterations', 'Var', (37, 48))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('lung', 'Disease', (122, 126))	('cancers', 'Disease', (96, 103))
630326	19086848	An association between smoking and loss of Fhit expression or FHIT deletion was shown in lung and esophageal cancers.	('esophageal cancers', 'Disease', 'MESH:D004938', (98, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('loss', 'NegReg', (35, 39))	('deletion', 'Var', (67, 75))	('FHIT', 'Gene', (62, 66))	('Fhit expression', 'Protein', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancers', 'Disease', (98, 116))
630327	19086848	In fact, alterations in Fhit expression in lung carcinomas were more frequent and occurred earlier than p53 mutations or deregulation of the epidermal growth factor receptor (EGFR).	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('p53', 'Gene', (104, 107))	('EGFR', 'Gene', (175, 179))	('epidermal growth factor receptor', 'Gene', (141, 173))	('epidermal growth factor receptor', 'Gene', '13649', (141, 173))	('lung carcinomas', 'Disease', 'MESH:D008175', (43, 58))	('alterations', 'Var', (9, 20))	('deregulation', 'Var', (121, 133))	('p53', 'Gene', '22060', (104, 107))	('Fhit', 'Gene', (24, 28))	('lung carcinomas', 'Disease', (43, 58))	('expression', 'MPA', (29, 39))	('EGFR', 'Gene', '13649', (175, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
630329	19086848	These studies suggested that loss of Fhit is an early event in the development of lung cancer, and that predisposing genetic changes have occurred even in normal-appearing epithelium in cases heavily exposed to environmental carcinogens.	('Fhit', 'Protein', (37, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('loss', 'Var', (29, 33))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))
630330	19086848	Recent studies point to detection of FHIT deletions in purified bronchial epithelial cells from sputum as a way to improve early detection of lung cancer with 58% sensitivity.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('FHIT', 'Gene', (37, 41))	('deletions', 'Var', (42, 51))	('lung cancer', 'Disease', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('improve', 'PosReg', (115, 122))
630333	19086848	In support of this idea, loss of FHIT function is observed more frequently in cancers developing in individuals with constitutional alterations to genes involved in DNA repair, such as the BRCA1 and 2 and mismatch repair genes.	('loss of FHIT function', 'Disease', (25, 46))	('alterations', 'Var', (132, 143))	('BRCA1 and 2', 'Gene', '12189;12190', (189, 200))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('loss of FHIT function', 'Disease', 'MESH:D060825', (25, 46))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mismatch repair genes', 'Gene', (205, 226))
630334	19086848	The mouse Fhit ortholog also encompasses a common fragile site, Fra14A2 on murine chromosome 14, and sustains homozygous deletions in murine cancer cell lines; therefore, Fhit-knockout mice have served as models for the study of Fhit function.	('mouse', 'Species', '10090', (4, 9))	('Fra14A2', 'Gene', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('murine', 'Species', '10090', (75, 81))	('murine', 'Species', '10090', (134, 140))	('mice', 'Species', '10090', (185, 189))	('deletions', 'Var', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('Fra14A2', 'Gene', '14198', (64, 71))
630336	19086848	Fhit+/- and Fhit-/- mice, although healthy and fertile, showed increased susceptibility to spontaneous and carcinogen-induced tumors.	('Fhit-/-', 'Var', (12, 19))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('Fhit+/-', 'Var', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('mice', 'Species', '10090', (20, 24))	('susceptibility', 'Reg', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
630338	19086848	All Fhit+/- mice developed several fore stomach tumors, and some developed sebaceous gland tumors after six doses of intragastric NMBA, while only 25% of wild-type mice developed tumors.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('sebaceous gland', 'Phenotype', 'HP:0032227', (75, 90))	('mice', 'Species', '10090', (164, 168))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mice', 'Species', '10090', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('NMBA', 'Chemical', 'MESH:C014707', (130, 134))	('Fhit+/-', 'Var', (4, 11))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('stomach tumors', 'Disease', 'MESH:D013274', (40, 54))	('tumors', 'Disease', (91, 97))	('developed', 'PosReg', (65, 74))	('tumors', 'Disease', (179, 185))	('stomach tumors', 'Disease', (40, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('stomach tumors', 'Phenotype', 'HP:0006753', (40, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
630340	19086848	The NMBA-induced tumor spectrum in Fhit+/- mice was similar to a human syndrome called Muir-Torre syndrome, a variant of the hereditary nonpolyposis colorectal cancer (HNPCC or Lynch) syndrome, which is caused by inactivation of a mismatch repair gene, usually MSH2.	('mice', 'Species', '10090', (43, 47))	('human', 'Species', '9606', (65, 70))	('tumor', 'Disease', (17, 22))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (125, 166))	('inactivation', 'Var', (213, 225))	('Muir-Torre syndrome', 'Disease', (87, 106))	('hereditary nonpolyposis colorectal cancer (HNPCC or Lynch) syndrome', 'Disease', 'MESH:D003123', (125, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('MSH2', 'Gene', (261, 265))	('NMBA', 'Chemical', 'MESH:C014707', (4, 8))	('Muir-Torre syndrome', 'Disease', 'MESH:D055653', (87, 106))	('MSH2', 'Gene', '4436', (261, 265))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
630341	19086848	Homozygous deletions of FHIT were observed in half of the cancer cell lines with a mutant mismatch repair gene; among nine Msh2-negative human colon cancer cells, eight were negative for Fhit, and Fhit loss was reported in 90% of BRCA1- and BRCA2-associated cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutant', 'Var', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('loss', 'NegReg', (202, 206))	('Msh2', 'Gene', (123, 127))	('BRCA2', 'Gene', '675', (241, 246))	('human', 'Species', '9606', (137, 142))	('BRCA2', 'Gene', (241, 246))	('Msh2', 'Gene', '4436', (123, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (143, 155))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (258, 265))	('BRCA1', 'Gene', '672', (230, 235))	('cancer', 'Disease', (149, 155))	('BRCA1', 'Gene', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colon cancer', 'Disease', 'MESH:D015179', (143, 155))	('cancer', 'Disease', (258, 264))	('cancers', 'Disease', (258, 265))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('FHIT', 'Gene', (24, 28))	('colon cancer', 'Disease', (143, 155))	('cancer', 'Disease', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
630346	19086848	Another possible role of Fhit in response to carcinogen was demonstrated in the study of Balansky et al., who found that after treatment with benzo[a]pyrene (B[a]P), a prototypic genotoxic, carcinogenic polycyclic aromatic hydrocarbon (PAH), preneoplastic lesions of the uterus were more frequent in Fhit+/- mice.	('Fhit+/-', 'Var', (300, 307))	('P', 'Chemical', 'MESH:D010758', (236, 237))	('PAH', 'Chemical', 'MESH:D011084', (236, 239))	('P', 'Chemical', 'MESH:D010758', (162, 163))	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (142, 156))	('polycyclic aromatic hydrocarbon', 'Chemical', 'MESH:D011084', (203, 234))	('mice', 'Species', '10090', (308, 312))	('carcinogenic', 'CPA', (190, 202))	('preneoplastic lesions of the uterus', 'CPA', (242, 277))
630347	19086848	They also found that B6/129 F1 mice underwent spontaneous alopecia areata and hair bulb cell apoptosis, which was greatly accelerated either by Fhit heterozygosity or by B[a]P treatment, suggesting that Fhit plays a role in the pathogenesis of alopecia areata.	('alopecia areata', 'Disease', 'MESH:D000506', (58, 73))	('alopecia areata', 'Disease', (244, 259))	('P', 'Chemical', 'MESH:D010758', (174, 175))	('hair bulb cell apoptosis', 'CPA', (78, 102))	('alopecia areata', 'Phenotype', 'HP:0002229', (58, 73))	('alopecia areata', 'Disease', 'MESH:D000506', (244, 259))	('alopecia', 'Phenotype', 'HP:0001596', (244, 252))	('alopecia', 'Phenotype', 'HP:0001596', (58, 66))	('accelerated', 'PosReg', (122, 133))	('mice', 'Species', '10090', (31, 35))	('alopecia areata', 'Phenotype', 'HP:0002229', (244, 259))	('heterozygosity', 'Var', (149, 163))	('alopecia areata', 'Disease', (58, 73))	('Fhit heterozygosity', 'Var', (144, 163))
630353	19086848	reported that 4-methylnitrosamino-1-3-pyridyl-1-butanone induced lung tumors (adenomas and carcinomas) in 100% of Fhit-/-Vhl+/- mice and adenomas in 40% of Fhit-/- mice by 20 months of age.	('lung tumors', 'Disease', 'MESH:D008175', (65, 76))	('adenomas', 'Disease', 'MESH:D000236', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('4-methylnitrosamino-1-3-pyridyl-1-butanone', 'Var', (14, 56))	('adenomas', 'Disease', (78, 86))	('Vhl', 'Gene', '22346', (121, 124))	('lung tumors', 'Phenotype', 'HP:0100526', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mice', 'Species', '10090', (164, 168))	('induced', 'Reg', (57, 64))	('adenomas and carcinomas', 'Disease', 'MESH:D000236', (78, 101))	('lung tumors', 'Disease', (65, 76))	('adenomas', 'Disease', 'MESH:D000236', (137, 145))	('mice', 'Species', '10090', (128, 132))	('adenomas', 'Disease', (137, 145))	('Vhl', 'Gene', (121, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('4-methylnitrosamino-1-3-pyridyl-1-butanone', 'Chemical', 'MESH:C016583', (14, 56))
630360	19086848	Furthermore, a recent study from our laboratory has shown that p53-negative lung cancer cells expressing Fhit are more sensitive to H2O2 treatment compared with Fhit-negative cells undergoing apoptosis or G2/M arrest when Fhit was present (Figure 2).	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('p53', 'Gene', (63, 66))	('H2O2', 'Chemical', 'MESH:D006861', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('sensitive', 'MPA', (119, 128))	('p53', 'Gene', '22060', (63, 66))	('Fhit', 'Var', (105, 109))
630364	19086848	The results suggested that the DNA-damage-susceptible FRA3B/FHIT chromosome fragile region encodes a protein that is necessary for protecting cells from accumulation of DNA damage through its role in modulation of checkpoint proteins; and the inactivation of Fhit contributes to the accumulation of abnormal checkpoint phenotypes in cancer development.	('inactivation', 'Var', (243, 255))	('Fhit', 'Gene', (259, 263))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('FHIT chromosome fragile', 'Disease', (60, 83))	('cancer', 'Disease', (333, 339))	('FHIT chromosome fragile', 'Disease', 'MESH:D002873', (60, 83))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('checkpoint phenotypes', 'MPA', (308, 329))	('chromosome fragile region', 'Phenotype', 'HP:0040012', (65, 90))	('modulation', 'MPA', (200, 210))	('accumulation', 'PosReg', (283, 295))
630368	19086848	The conserved HIT motif (His-X-His-X-His-X-X, where X is a hydro phobic residue) of Fhit is located near its C-terminal end and the hydrolytic activity of Fhit is lost when histidine 96 (H96) is replaced with asparagine (Fhit-H96N), showing that the H96 central histidine residue of the triad is essential for Ap3A hydrolase activity; however, the FhitH96N protein suppresses tumorigenicity about as well as wild-type Fhit.	('H96N', 'Mutation', 'p.H96N', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('Ap3A hydrolase', 'Gene', (310, 324))	('FhitH96N', 'Var', (348, 356))	('histidine', 'Chemical', 'MESH:D006639', (173, 182))	('tumor', 'Disease', (376, 381))	('HIT', 'Disease', (14, 17))	('HIT', 'Disease', 'MESH:D013921', (14, 17))	('Ap3A hydrolase', 'Gene', '14198', (310, 324))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('histidine', 'Chemical', 'MESH:D006639', (262, 271))	('protein', 'Protein', (357, 364))	('H96N', 'Mutation', 'p.H96N', (352, 356))	('suppresses', 'NegReg', (365, 375))
630371	19086848	Recently, it was observed that the sequence DSIY114EEL of Fhit, which fits the consensus for targets of phosphorylation by Src tyrosine kinase family members, could be phosphorylated in vitro and in vivo.	('Src', 'Gene', (123, 126))	('fits', 'Disease', 'MESH:D012640', (70, 74))	('tyrosine', 'Chemical', 'MESH:D014443', (127, 135))	('DSIY114EEL', 'Var', (44, 54))	('Fhit', 'Gene', (58, 62))	('fits', 'Disease', (70, 74))	('Src', 'Gene', '20779', (123, 126))
630373	19086848	Recent studies have shown that a Fhit mutant that carries a phenylalanine instead of a tyrosine at position 114 (Y114F), and thus unable to be phosphorylated on tyrosine 114 by Src, does not induce apoptosis in cancer cells and prevents Fhit degradation.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('tyrosine', 'Chemical', 'MESH:D014443', (87, 95))	('Y114F', 'Mutation', 'rs141172262', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('prevents', 'NegReg', (228, 236))	('cancer', 'Disease', (211, 217))	('phenylalanine', 'Var', (60, 73))	('Src', 'Gene', '20779', (177, 180))	('Y114F', 'Var', (113, 118))	('tyrosine', 'Chemical', 'MESH:D014443', (161, 169))	('Src', 'Gene', (177, 180))	('phenylalanine instead of a tyrosine at position 114', 'Mutation', 'rs141172262', (60, 111))	('Fhit degradation', 'MPA', (237, 253))
630389	19086848	Papers of special note have been highlighted as:   of interest    of considerable interest   The FHIT gene is a tumor-suppressor gene altered by chromosome translocations and deletions.	('P', 'Chemical', 'MESH:D010758', (0, 1))	('deletions', 'Var', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('FHIT gene', 'Gene', (97, 106))	('altered', 'Reg', (134, 141))	('tumor', 'Disease', (112, 117))
630390	19086848	FHIT alterations are an early event in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (39, 53))	('alterations', 'Var', (5, 16))	('FHIT', 'Gene', (0, 4))	('carcinogenesis', 'Disease', (39, 53))
630391	19086848	FHIT alterations are common in environmental carcinogen-related cancers, such as those of the lung and esophagus.	('esophagus', 'Disease', (103, 112))	('lung', 'Disease', (94, 98))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('alterations', 'Var', (5, 16))	('cancers', 'Disease', (64, 71))	('FHIT', 'Gene', (0, 4))	('common', 'Reg', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
630392	19086848	Loss of FHIT function is observed more frequently in cancers with alterations to genes involved in DNA repair.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('FHIT', 'Protein', (8, 12))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('Loss', 'NegReg', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('alterations', 'Var', (66, 77))
630399	19086848	Overexpression of Fhit results in apoptosis in Fhit-deficient cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Fhit-deficient cancer', 'Disease', (47, 68))	('Fhit-deficient cancer', 'Disease', 'MESH:D009369', (47, 68))	('apoptosis', 'CPA', (34, 43))	('Overexpression', 'Var', (0, 14))	('Fhit', 'Gene', (18, 22))
630401	19086848	Lung cancer cells expressing Fhit are more sensitive to H2O2 treatment.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('H2O2', 'Chemical', 'MESH:D006861', (56, 60))	('sensitive', 'MPA', (43, 52))	('cancer', 'Disease', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('Fhit', 'Var', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
630405	19086848	The Fhit mutant H96N has shown that the H96 residue is essential for Ap3A hydrolase activity, but suppresses the tumorigenicity just as well as wild-type FHIT.	('tumor', 'Disease', (113, 118))	('suppresses', 'NegReg', (98, 108))	('Ap3A hydrolase', 'Gene', (69, 83))	('H96N', 'Mutation', 'p.H96N', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('H96', 'Var', (40, 43))	('H96N', 'Var', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutant H96N', 'Var', (9, 20))	('Ap3A hydrolase', 'Gene', '14198', (69, 83))
630406	19086848	The Fhit mutant Y114F, unable to be phosphorylated on tyrosine 114 by Src, does not induce apoptosis in cancer cells and prevents Fhit degradation.	('Fhit degradation', 'MPA', (130, 146))	('Y114F', 'Mutation', 'rs141172262', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tyrosine', 'Chemical', 'MESH:D014443', (54, 62))	('Y114F', 'Var', (16, 21))	('Src', 'Gene', '20779', (70, 73))	('Src', 'Gene', (70, 73))	('prevents', 'NegReg', (121, 129))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
630409	19086848	The finding that Fhit interacts with Fdxr may be part of specific molecular machinery to protect important proteins from degradation, and also affects the cellular response to the damaging effects of ROS.	('Fhit', 'Var', (17, 21))	('degradation', 'MPA', (121, 132))	('affects', 'Reg', (143, 150))	('cellular response to the damaging effects of ROS', 'MPA', (155, 203))	('ROS', 'Chemical', 'MESH:D017382', (200, 203))
630459	21425140	With the publication of results in non small cell lung cancer indicating the potential impact of EGFR mutation on effectiveness of EGFR TKI's, during the course of the study an attempt was made to retrieve additional tissue to study for EGFR mutation.	('non small cell lung cancer', 'Disease', (35, 61))	('EGFR', 'Gene', '1956', (237, 241))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (35, 61))	('EGFR', 'Gene', '1956', (97, 101))	('mutation', 'Var', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('EGFR', 'Gene', (237, 241))	('non small cell lung cancer', 'Disease', 'MESH:D002289', (35, 61))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', (131, 135))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (39, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('impact', 'Reg', (87, 93))
630501	21425140	In the limited analysis in 5 patients for mutation of the EGFR, no mutations were observed, including one squamous cancer that achieved a partial response.	('EGFR', 'Gene', '1956', (58, 62))	('patients', 'Species', '9606', (29, 37))	('EGFR', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutation', 'Var', (42, 50))	('squamous cancer', 'Phenotype', 'HP:0002860', (106, 121))	('squamous cancer', 'Disease', 'MESH:D002294', (106, 121))	('squamous cancer', 'Disease', (106, 121))
630506	21425140	K-ras mutation, recently identified as a potential marker of EGFr therapy resistance, was tested and found in only 2 of 23 patients (9%), both of whom had early progressive disease on therapy.	('K-ras', 'Gene', '3845', (0, 5))	('found', 'Reg', (101, 106))	('mutation', 'Var', (6, 14))	('patients', 'Species', '9606', (123, 131))	('EGFr', 'Gene', (61, 65))	('K-ras', 'Gene', (0, 5))	('EGFr', 'Gene', '1956', (61, 65))
630507	21425140	No EGFR mutations were found in 26 patients studied.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('mutations', 'Var', (8, 17))	('patients', 'Species', '9606', (35, 43))
630508	21425140	High EGFR copy number was observed in two patients, one responder and one non responder.	('patients', 'Species', '9606', (42, 50))	('copy number', 'Var', (10, 21))	('EGFR', 'Gene', '1956', (5, 9))	('EGFR', 'Gene', (5, 9))
630514	21425140	Potential predictive molecular markers of response were assessed, including EGFR mutation (none found) and amplification of EGFR (none found).	('amplification', 'Var', (107, 120))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'Gene', '1956', (76, 80))	('mutation', 'Var', (81, 89))	('EGFR', 'Gene', (124, 128))	('EGFR', 'Gene', (76, 80))
630519	21425140	In a separate report, these authors reported the evaluation EGFR mutations in a cohort of 17 patients with adenocarcinoma and identified 2 with mutations (12%); both of these patients were treated with gefitinib and failed to respond.	('gefitinib', 'Chemical', 'MESH:D000077156', (202, 211))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (175, 183))	('EGFR', 'Gene', '1956', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('adenocarcinoma', 'Disease', (107, 121))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('EGFR', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
630527	21425140	From the trials of TKI's in esophageal cancer, there also is no clear molecular marker predictive of response to therapy, including K-ras or EGFR mutation, with the possible exception of either amplification of, or increased copy number of, the EGFR gene, which was observed in two responding patients.	('esophageal cancer', 'Disease', (28, 45))	('EGFR', 'Gene', '1956', (141, 145))	('amplification', 'Var', (194, 207))	('patients', 'Species', '9606', (293, 301))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('K-ras', 'Gene', (132, 137))	('EGFR', 'Gene', (141, 145))	('K-ras', 'Gene', '3845', (132, 137))	('EGFR', 'Gene', '1956', (245, 249))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('copy', 'MPA', (225, 229))	('increased', 'PosReg', (215, 224))	('EGFR', 'Gene', (245, 249))	('mutation', 'Var', (146, 154))
630530	21425140	This contrasts with the important role of K-ras mutation in identifying resistance to EGFR targeted agents in colorectal and non small cell lung cancers, and EGFR mutation in determining benefit for treatment with EGFR TKI's in non small cell lung cancer.	('K-ras', 'Gene', '3845', (42, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('EGFR', 'Gene', '1956', (214, 218))	('lung cancers', 'Phenotype', 'HP:0100526', (140, 152))	('non small cell lung cancer', 'Disease', 'MESH:D002289', (125, 151))	('EGFR', 'Gene', '1956', (158, 162))	('mutation', 'Var', (163, 171))	('non small cell lung cancer', 'Disease', 'MESH:D002289', (228, 254))	('EGFR', 'Gene', '1956', (86, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (232, 254))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (129, 151))	('K-ras', 'Gene', (42, 47))	('non small cell lung cancer', 'Disease', (125, 151))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (129, 152))	('non small cell lung cancer', 'Disease', (228, 254))	('EGFR', 'Gene', (214, 218))	('resistance', 'MPA', (72, 82))	('colorectal and non small cell lung cancers', 'Disease', 'MESH:D002289', (110, 152))	('EGFR', 'Gene', (158, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (125, 151))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (228, 254))	('EGFR', 'Gene', (86, 90))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
630653	19111725	Zinc-replenishment but not by a COX-2 inhibitor reduced the overexpression of these 4 proteins.	('Zinc-replenishment', 'Var', (0, 18))	('overexpression of', 'MPA', (60, 77))	('COX-2', 'Gene', '29527', (32, 37))	('COX-2', 'Gene', (32, 37))
630665	19111725	By causing unregulated cell proliferation and extensive genetic changes in the squamous epithelium, dietary ZD creates a protumorigenic microenvironment in the rat esophagus and tongue.	('dietary', 'Var', (100, 107))	('rat', 'Species', '10116', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('genetic changes', 'CPA', (56, 71))	('rat', 'Species', '10116', (35, 38))	('cell proliferation', 'CPA', (23, 41))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
630671	19111725	We hypothesized that global transcriptome profiling using an expanded genome array (Affymetrix) that analyzes >30,000 transcripts and variants from ~28,000 rat genes would identify key biologic differences affected by nutritional ZD during early esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (246, 271))	('rat', 'Species', '10116', (156, 159))	('variants', 'Var', (134, 142))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (246, 271))
630709	19111725	Among the upregulated genes, "response to external stimulus" pathway comprising S100A8 and 6 genes (CDKN1A, GJA1, MX2, PPP2R1A, SECTM1, and SERPINB3) was the only significantly overrepresented pathway (EASE score =.02), a novel result that supports S100A8 as a relevant marker in ZD-induced esophageal hyperplasia.	('esophageal hyperplasia', 'Disease', (291, 313))	('MX2', 'Gene', (114, 117))	('MX2', 'Gene', '286918', (114, 117))	('SECTM1', 'Gene', (128, 134))	('PPP2R1A', 'Gene', '117281', (119, 126))	('GJA1', 'Gene', (108, 112))	('upregulated', 'PosReg', (10, 21))	('S100A8', 'Gene', (80, 86))	('esophageal hyperplasia', 'Disease', 'MESH:D006965', (291, 313))	('SECTM1', 'Gene', '287885', (128, 134))	('overrepresented', 'PosReg', (177, 192))	('PPP2R1A', 'Gene', (119, 126))	('GJA1', 'Gene', '24392', (108, 112))	('S100A8', 'Var', (249, 255))
630730	19111725	These results demonstrate an in vivo link between S100A8-RAGE co-overexpression and downstream NF-kappaB-COX-2 signaling that is modulated by zinc nutrition.	('NF-kappaB', 'Gene', '4790', (95, 104))	('NF-kappaB', 'Gene', (95, 104))	('S100A8-RAGE', 'Var', (50, 61))	('COX-2', 'Gene', '29527', (105, 110))	('COX-2', 'Gene', (105, 110))	('rat', 'Species', '10116', (21, 24))
630736	19111725	Consistent with the array data (Table 1), hyperplastic ZD esophagi had significantly higher S100A8 (P<.001) and S100A9 (P<.01) mRNA levels than ZS esophagi.	('S100A9', 'Gene', (112, 118))	('hyperplastic', 'Var', (42, 54))	('higher', 'PosReg', (85, 91))	('S100A8', 'MPA', (92, 98))	('S100A9', 'Gene', '94195', (112, 118))	('mRNA levels', 'MPA', (127, 138))
630749	19111725	This result suggests that S100A8 is a relevant marker belonging to a causal pathway that drives esophageal cell proliferation rather than simply an epiphenomenon of this process or of nutritional zinc deficit.	('S100A8', 'Var', (26, 32))	('drives', 'PosReg', (89, 95))	('rat', 'Species', '10116', (119, 122))	('rat', 'Species', '10116', (126, 129))	('esophageal cell proliferation', 'CPA', (96, 125))
630762	19111725	Blockade of RAGE suppresses tumor growth and metastasis.	('tumor', 'Disease', (28, 33))	('RAGE', 'Gene', (12, 16))	('Blockade', 'Var', (0, 8))	('suppresses', 'NegReg', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
630779	19111725	Thus, the downregulated gene G0S2 is epigenetically silenced through promoter hypermethylation in primary head and neck SCC development.	('silenced', 'NegReg', (52, 60))	('G0S2', 'Gene', (29, 33))	('G0S2', 'Gene', '289388', (29, 33))	('downregulated', 'NegReg', (10, 23))	('SCC', 'Gene', '6317', (120, 123))	('promoter hypermethylation', 'Var', (69, 94))	('SCC', 'Gene', (120, 123))
630780	19111725	Loss of the structural protein UPK1B expression in bladder carcinoma is attributed to methylation of a CpG island within the UPK1B promoter and hypermethylation of TPM1 gene is a mechanism for TPM1 silencing in breast cancer cell lines.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (51, 68))	('methylation', 'Var', (86, 97))	('UPK1B', 'Gene', '303924', (125, 130))	('bladder carcinoma', 'Disease', 'MESH:D001749', (51, 68))	('UPK1B', 'Gene', '303924', (31, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('hypermethylation', 'Var', (144, 160))	('Loss', 'NegReg', (0, 4))	('bladder carcinoma', 'Disease', (51, 68))	('UPK1B', 'Gene', (31, 36))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('UPK1B', 'Gene', (125, 130))	('breast cancer', 'Disease', (211, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('expression', 'MPA', (37, 47))	('silencing', 'NegReg', (198, 207))	('TPM1', 'Gene', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('TPM1', 'Gene', (193, 197))
630791	32966340	While these cells were able to tolerate 2% EtOH for 8 h in both three-dimensional organoids and monolayer culture conditions, RNA sequencing suggested that EtOH induced mitochondrial dysfunction.	('EtOH', 'Chemical', '-', (156, 160))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (169, 194))	('EtOH', 'Chemical', '-', (43, 47))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (169, 194))	('EtOH', 'Var', (156, 160))	('mitochondrial dysfunction', 'Disease', (169, 194))
630794	32966340	In EPC2, EtOH decreased ATP level while impairing mitochondrial respiration and electron transportation chain functions, as determined by ATP fluorometric assay, respirometry, and liquid chromatography-mass spectrometry.	('ATP level', 'MPA', (24, 33))	('decreased', 'NegReg', (14, 23))	('impairing', 'NegReg', (40, 49))	('EtOH', 'Chemical', '-', (9, 13))	('ATP', 'Chemical', 'MESH:D000255', (24, 27))	('mitochondrial respiration', 'MPA', (50, 75))	('EPC2', 'Var', (3, 7))	('ATP', 'Chemical', 'MESH:D000255', (138, 141))	('EtOH', 'Var', (9, 13))	('electron transportation chain functions', 'MPA', (80, 119))
630857	32966340	Cells were incubated with MitoTracker  Green (1:20,000; M7514; Thermo Fisher Scientific) and MitoTracker  Deep Red (1:50,000; M22426; Thermo Fisher Scientific) in KSFM at 37 C for 30 min to determine mitochondrial mass and mitochondrial membrane potential, respectively.	('MitoTracker', 'Chemical', '-', (26, 37))	('mitochondrial mass', 'MPA', (200, 218))	('KSFM', 'Chemical', '-', (163, 167))	('MitoTracker', 'Chemical', '-', (93, 104))	('mitochondrial membrane potential', 'MPA', (223, 255))	('1:50,000', 'Var', (116, 124))
630861	32966340	The following primary antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA) and used at the indicated dilutions: rabbit anti-LC3B (#2775) (1:1000), mouse anti-p62/SQSTM1 (D-3; sc-28359) (1:1000), rabbit anti-phospho-S6 (Ser235/236; #2211 and #4858) (1:1000 for #2211 or 1:2000 for # 4858), mouse anti-S6 (#2317) (1:1000), rabbit anti-S6 (#2217) (1:1000), rabbit anti-phospho 4EBP1 (Thr37/46; #9459 (1:1000), rabbit anti-4EBP1 (#9452) (1:1000), rabbit anti-phospho-AMPK (#2535) (1:1000), rabbit anti-AMPK (#2603) (1:1000) and mouse anti-beta-Actin (AC-74; A5316; Sigma-Aldrich) (1:10000).	('LC3B', 'Gene', (147, 151))	('#2603', 'Var', (527, 532))	('mouse', 'Species', '10090', (547, 552))	('4EBP1', 'Gene', '13685', (442, 447))	('AMPK', 'Gene', (521, 525))	('4EBP1', 'Gene', (442, 447))	('AMPK', 'Gene', '78975', (521, 525))	('beta-Actin', 'Gene', (558, 568))	('SQSTM1', 'Gene', '18412', (185, 191))	('p62', 'Gene', (181, 184))	('p62', 'Gene', '18412', (181, 184))	('AMPK', 'Gene', (486, 490))	('mouse', 'Species', '10090', (170, 175))	('LC3B', 'Gene', '67443', (147, 151))	('mouse', 'Species', '10090', (312, 317))	('AMPK', 'Gene', '78975', (486, 490))	('4EBP1', 'Gene', '13685', (397, 402))	('4EBP1', 'Gene', (397, 402))	('beta-Actin', 'Gene', '11461', (558, 568))	('SQSTM1', 'Gene', (185, 191))
630862	32966340	SiRNA directed against ADH1B (s1061 and s1062) and CYP2E1 (s3837 and s3838) or a non-target control sequence (SCR Silencer Select Negative Control #1) were purchased from Thermo Fisher Scientific.	('s3838', 'Var', (69, 74))	('s3837', 'Var', (59, 64))	('ADH1B', 'Gene', (23, 28))	('ADH1B', 'Gene', '125', (23, 28))	('s1061', 'Var', (30, 35))
630864	32966340	RNA isolation, cDNA synthesis and qRT-PCR were done using StepOnePlus  Real-Time PCR System (Applied Biosystems) by TaqMan  Gene Expression Assays (Applied Biosystems) for ADH1B (s02511271_s1) and CYP2E1 (Hs00559367_m1), and SYBR  Green PCR for human ACTB (5'-TTGCCGACAGGATGCAGAA-3' and 5'-GCCGATCCACACGGAGTACT-3').	('s02511271_s1', 'Var', (179, 191))	('ACTB', 'Gene', '60', (251, 255))	('ADH1B', 'Gene', (172, 177))	('human', 'Species', '9606', (245, 250))	('ACTB', 'Gene', (251, 255))	('ADH1B', 'Gene', '125', (172, 177))	('Hs00559367_m1', 'Var', (205, 218))
630880	32966340	This result was further corroborated by flow cytometry for DAPI-stained cells, where DAPI-positive dead cells were higher in EPC3 than in EPC1 or EPC2 following 2% EtOH exposure for 8 h (Fig 2B).	('DAPI', 'Chemical', 'MESH:C007293', (59, 63))	('EPC3', 'CellLine', 'CVCL:4361', (125, 129))	('DAPI', 'Chemical', 'MESH:C007293', (85, 89))	('EtOH', 'Chemical', '-', (164, 168))	('higher', 'PosReg', (115, 121))	('EPC3', 'Var', (125, 129))
630910	32966340	Nevertheless, our data suggest that EtOH may induce mitochondrial depolarization at least in a small subset of esophageal keratinocytes.	('EtOH', 'Chemical', '-', (36, 40))	('mitochondrial depolarization', 'MPA', (52, 80))	('EtOH', 'Var', (36, 40))
630914	32966340	We observed a significant decrease in the ATP level upon EtOH exposure (2%, 8 h) (Fig 6A), suggesting that EtOH exposure may induce mitochondrial dysfunction in EPC2 cells.	('EtOH', 'Chemical', '-', (107, 111))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (132, 157))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (132, 157))	('induce', 'Reg', (125, 131))	('EtOH', 'Chemical', '-', (57, 61))	('mitochondrial dysfunction', 'Disease', (132, 157))	('ATP', 'Chemical', 'MESH:D000255', (42, 45))	('EtOH', 'Var', (107, 111))
630917	32966340	The amount of acetyl-CoA and citrate/isocitrate was increased in EtOH-treated cells, suggesting inhibition in the first step of the TCA cycle.	('EtOH', 'Chemical', '-', (65, 69))	('EtOH-treated', 'Var', (65, 77))	('increased', 'PosReg', (52, 61))	('amount', 'MPA', (4, 10))	('citrate', 'Chemical', 'MESH:D019343', (40, 47))	('citrate', 'Chemical', 'MESH:D019343', (29, 36))	('isocitrate', 'Chemical', 'MESH:C034219', (37, 47))	('TCA', 'Chemical', 'MESH:D014233', (132, 135))	('TCA cycle', 'Enzyme', (132, 141))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (14, 24))	('inhibition', 'NegReg', (96, 106))
630920	32966340	While EtOH treatment did not affect the basal oxygen consumption rate, we observed a significant decrease in substrate specific response of the mitochondrial complexes of the ETC (Fig 6C), where EtOH strongly inhibited the activities of complexes I, II, III and IV in the presence of their respective substrates.	('activities', 'MPA', (223, 233))	('III', 'Enzyme', (254, 257))	('complexes I', 'Enzyme', (237, 248))	('EtOH', 'Chemical', '-', (195, 199))	('EtOH', 'Var', (195, 199))	('inhibited', 'NegReg', (209, 218))	('substrate specific response', 'MPA', (109, 136))	('decrease', 'NegReg', (97, 105))	('EtOH', 'Chemical', '-', (6, 10))	('mitochondrial complexes', 'Enzyme', (144, 167))	('oxygen', 'Chemical', 'MESH:D010100', (46, 52))
630922	32966340	The GSH:GSSG ratio (reduced glutathione vs. oxidized glutathione), an indicator of oxidative stress, was found to be decreased in EtOH-treated cells (Fig 6D).	('GSH', 'Chemical', '-', (4, 7))	('GSH', 'MPA', (4, 7))	('decreased', 'NegReg', (117, 126))	('glutathione', 'Chemical', 'MESH:D005978', (28, 39))	('oxidative stress', 'Phenotype', 'HP:0025464', (83, 99))	('EtOH', 'Chemical', '-', (130, 134))	('EtOH-treated', 'Var', (130, 142))	('GSSG', 'Chemical', 'MESH:D019803', (8, 12))	('glutathione', 'Chemical', 'MESH:D005978', (53, 64))
630926	32966340	In EPC2 cells, partial knockdown of CYP2E1 and ADH1B appeared to prevent EtOH from inducing cells with DeltaPsim reduction (S6 Fig), suggesting that EtOH oxidation mediated by these enzymes may contribute to mitochondrial dysfunction in esophageal keratinocytes.	('EtOH', 'Chemical', '-', (73, 77))	('EtOH', 'MPA', (73, 77))	('ADH1B', 'Gene', (47, 52))	('EtOH', 'Chemical', '-', (149, 153))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (208, 233))	('ADH1B', 'Gene', '125', (47, 52))	('CYP2E1', 'Var', (36, 42))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (208, 233))	('prevent', 'NegReg', (65, 72))	('esophageal keratinocytes', 'Disease', (237, 261))	('mitochondrial dysfunction', 'Disease', (208, 233))	('DeltaPsim reduction', 'Disease', 'MESH:D007022', (103, 122))	('DeltaPsim reduction', 'Disease', (103, 122))	('contribute', 'Reg', (194, 204))
630956	32966340	EtOH-induced AMPK phosphorylation was augmented in EPC2, but not in EPC1, when autophagy flux was blocked by CQ, suggesting that inhibition of autophagy may exacerbate the intracellular energy crisis and mitochondrial dysfunction induced by alcohol (i.e.	('AMPK', 'Gene', '78975', (13, 17))	('autophagy', 'CPA', (143, 152))	('augmented', 'PosReg', (38, 47))	('exacerbate', 'PosReg', (157, 167))	('inhibition', 'Var', (129, 139))	('AMPK', 'Gene', (13, 17))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (204, 229))	('intracellular energy crisis', 'CPA', (172, 199))	('alcohol', 'Chemical', 'MESH:D000438', (241, 248))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (204, 229))	('CQ', 'Chemical', 'MESH:D002738', (109, 111))	('mitochondrial dysfunction', 'Disease', (204, 229))	('EtOH', 'Chemical', '-', (0, 4))	('EtOH-induced', 'CPA', (0, 12))
630963	32966340	In this study, we have demonstrated for the first time that EtOH induces mitochondrial dysfunction and oxidative stress in esophageal keratinocytes where autophagy may provide cytoprotection against EtOH-induced cell death as validated in two independent cell lines EPC1 and EPC2.	('EtOH', 'Var', (60, 64))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (73, 98))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (73, 98))	('cytoprotection', 'CPA', (176, 190))	('EtOH', 'Chemical', '-', (199, 203))	('induces', 'Reg', (65, 72))	('mitochondrial dysfunction', 'Disease', (73, 98))	('EtOH', 'Chemical', '-', (60, 64))	('oxidative stress', 'Phenotype', 'HP:0025464', (103, 119))	('autophagy', 'CPA', (154, 163))	('oxidative stress', 'CPA', (103, 119))
630975	32966340	EtOH and acetaldehyde in circulation have been associated with mitochondrial damage in the liver, the brain, the heart and muscle.	('acetaldehyde', 'Var', (9, 21))	('EtOH', 'Var', (0, 4))	('mitochondrial damage', 'Disease', (63, 83))	('mitochondrial damage', 'Disease', 'MESH:D028361', (63, 83))	('EtOH', 'Chemical', '-', (0, 4))	('associated', 'Reg', (47, 57))	('acetaldehyde', 'Chemical', 'MESH:D000079', (9, 21))
630977	32966340	However, we observed variability in EtOH sensitivity amongst the cell lines used in this study, likely reflecting their genetic background, as corroborated by PCA (S4 Fig), where overall gene expression pattern was closer in EPC1 and EPC2, as compared with EPC3.	('EtOH', 'Chemical', '-', (36, 40))	('EPC2', 'Var', (234, 238))	('EPC1', 'Var', (225, 229))	('closer', 'PosReg', (215, 221))	('EPC3', 'CellLine', 'CVCL:4361', (257, 261))
630978	32966340	We have previously demonstrated that acetaldehyde causes oxidative stress and DNA damage in murine esophageal keratinocytes, which was augmented in cells with loss of Aldh2, a mitochondrial enzyme essential for acetaldehyde clearance.	('acetaldehyde', 'Chemical', 'MESH:D000079', (211, 223))	('acetaldehyde', 'Chemical', 'MESH:D000079', (37, 49))	('oxidative stress', 'Phenotype', 'HP:0025464', (57, 73))	('murine', 'Species', '10090', (92, 98))	('oxidative stress', 'MPA', (57, 73))	('loss', 'Var', (159, 163))	('DNA damage', 'MPA', (78, 88))	('augmented', 'PosReg', (135, 144))	('Aldh2', 'Gene', '11669', (167, 172))	('Aldh2', 'Gene', (167, 172))
630979	32966340	Single nucleotide polymorphisms resulting in mutant ALDH2 causes delayed acetaldehyde clearance and enhanced EtOH toxicity.	('mutant', 'Var', (45, 51))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('delayed acetaldehyde clearance', 'Phenotype', 'HP:0003533', (65, 95))	('delayed', 'NegReg', (65, 72))	('enhanced', 'PosReg', (100, 108))	('EtOH', 'Chemical', '-', (109, 113))	('toxicity', 'Disease', 'MESH:D064420', (114, 122))	('toxicity', 'Disease', (114, 122))	('acetaldehyde', 'Chemical', 'MESH:D000079', (73, 85))	('ALDH2', 'Gene', (52, 57))	('acetaldehyde clearance', 'MPA', (73, 95))
630980	32966340	Such ALDH2 mutations are common in East Asians and linked to esophageal cancer susceptibility in alcohol users.	('mutations', 'Var', (11, 20))	('linked to', 'Reg', (51, 60))	('ALDH2', 'Gene', (5, 10))	('alcohol', 'Chemical', 'MESH:D000438', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
630981	32966340	Interestingly, EPC1 and EPC2 cells carry wild-type ALDH2 while EPC3 cells, which were isolated from a Japanese patient, carry the mutant form of ALDH2 (unpublished findings by SO, personal communications).	('EPC3', 'CellLine', 'CVCL:4361', (63, 67))	('patient', 'Species', '9606', (111, 118))	('ALDH2', 'Gene', (145, 150))	('mutant', 'Var', (130, 136))	('ALDH2', 'Gene', (51, 56))
630982	32966340	It is therefore tempting to speculate that this ALDH2 mutation may contribute to increased death of EPC3 cells upon EtOH exposure (Fig 2B).	('mutation', 'Var', (54, 62))	('ALDH2', 'Gene', (48, 53))	('EtOH', 'Chemical', '-', (116, 120))	('EPC3', 'CellLine', 'CVCL:4361', (100, 104))	('contribute', 'Reg', (67, 77))
630988	32966340	Besides ALDH2, our data suggest that the alcohol metabolizing enzymes ADH1B and CYP2E1 may contribute to mitochondrial dysfunction through EtOH oxidation and acetaldehyde production (S5 Fig).	('CYP2E1', 'Var', (80, 86))	('acetaldehyde production', 'MPA', (158, 181))	('contribute', 'Reg', (91, 101))	('EtOH', 'Chemical', '-', (139, 143))	('acetaldehyde', 'Chemical', 'MESH:D000079', (158, 170))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (105, 130))	('EtOH oxidation', 'MPA', (139, 153))	('alcohol', 'Chemical', 'MESH:D000438', (41, 48))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (105, 130))	('ADH1B', 'Gene', (70, 75))	('mitochondrial dysfunction', 'Disease', (105, 130))	('ADH1B', 'Gene', '125', (70, 75))
630989	32966340	Consistent with this, CYP2E1 has been implicated in ROS generation and mitochondrial dysfunction in alcohol-induced hepatic steatosis.	('alcohol', 'Chemical', 'MESH:D000438', (100, 107))	('steatosis', 'Phenotype', 'HP:0001397', (124, 133))	('CYP2E1', 'Var', (22, 28))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (116, 133))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (71, 96))	('ROS generation', 'MPA', (52, 66))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (71, 96))	('implicated', 'Reg', (38, 48))	('hepatic steatosis', 'Disease', (116, 133))	('hepatic steatosis', 'Disease', 'MESH:D005234', (116, 133))	('mitochondrial dysfunction', 'Disease', (71, 96))
630990	32966340	Additionally, our RNAi experiments show for the first time that esophageal keratinocytes can metabolize EtOH via ADH1B and CYP2E1 in vitro without requiring hepatic metabolism.	('ADH1B', 'Gene', (113, 118))	('hepatic metabolism', 'Disease', (157, 175))	('hepatic metabolism', 'Disease', 'MESH:D056486', (157, 175))	('ADH1B', 'Gene', '125', (113, 118))	('CYP2E1', 'Var', (123, 129))	('EtOH', 'Chemical', '-', (104, 108))
630997	32966340	Additionally, EtOH affects the mitochondrial antioxidant mechanism, further exacerbating this damage.	('mitochondrial antioxidant mechanism', 'MPA', (31, 66))	('affects', 'Reg', (19, 26))	('EtOH', 'Var', (14, 18))	('exacerbating', 'PosReg', (76, 88))	('EtOH', 'Chemical', '-', (14, 18))
630999	32966340	Perturbations in mitochondrial respiration result in dramatic increases in cellular ROS levels.	('Perturbations', 'Var', (0, 13))	('mitochondrial respiration', 'MPA', (17, 42))	('increases', 'PosReg', (62, 71))	('cellular ROS levels', 'MPA', (75, 94))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))
631062	32966340	We have determined cellular ATP level and metabolic profiling (Fig 6), EtOH oxidation by ADH1B and CYP2E1 (new data, S5 Fig), and pharmacological modulations of AMPK (Fig 10B and C).	('AMPK', 'Gene', '78975', (161, 165))	('EtOH', 'Chemical', '-', (71, 75))	('ADH1B', 'Gene', (89, 94))	('AMPK', 'Gene', (161, 165))	('ATP', 'Chemical', 'MESH:D000255', (28, 31))	('CYP2E1', 'Var', (99, 105))	('ADH1B', 'Gene', '125', (89, 94))	('EtOH oxidation', 'MPA', (71, 85))
631090	32966340	Additionally, EtOH affects the mitochondrial antioxidant mechanism, further exacerbating the damage (Ref 45, PMID: 11371722) as discussed in revised page 28, lines 701- 704.	('mitochondrial antioxidant mechanism', 'MPA', (31, 66))	('affects', 'Reg', (19, 26))	('EtOH', 'Var', (14, 18))	('exacerbating', 'PosReg', (76, 88))	('damage', 'MPA', (93, 99))	('EtOH', 'Chemical', '-', (14, 18))
631092	32966340	To this end, we first assessed mitochondrial membrane potential ( Psim) by flow cytometry in EtOH-treated EPC1 and EPC2 cells (new Fig 5) where EtOH induced a small subset of cells with decreased  Psim, indicating mitochondrial depolarization.	('EtOH', 'Chemical', '-', (93, 97))	('EtOH', 'Var', (144, 148))	('decreased  Psim', 'Disease', 'MESH:D002303', (186, 201))	('EtOH', 'Chemical', '-', (144, 148))	('decreased  Psim', 'Disease', (186, 201))
631094	32966340	We have observed that knockdown of either molecule prevented EtOH from inducing cells with mitochondrial depolarization, suggesting that EtOH oxidation may be involved in mitochondrial dysfunction.	('mitochondrial dysfunction', 'Disease', (171, 196))	('prevented', 'NegReg', (51, 60))	('involved', 'Reg', (159, 167))	('knockdown', 'Var', (22, 31))	('EtOH', 'Chemical', '-', (61, 65))	('EtOH', 'Chemical', '-', (137, 141))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (171, 196))	('EtOH', 'MPA', (61, 65))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (171, 196))
631096	32966340	We have previously demonstrated that acetaldehyde causes oxidative stress in murine esophageal keratinocytes and that was augmented in cells with loss of Aldh2, a mitochondrial enzyme essential in acetaldehyde clearance (Ref 5, PMID: 27186430).	('acetaldehyde', 'Chemical', 'MESH:D000079', (197, 209))	('Aldh2', 'Gene', (154, 159))	('Aldh2', 'Gene', '11669', (154, 159))	('acetaldehyde', 'Chemical', 'MESH:D000079', (37, 49))	('oxidative stress', 'Phenotype', 'HP:0025464', (57, 73))	('murine', 'Species', '10090', (77, 83))	('loss', 'Var', (146, 150))	('acetaldehyde', 'MPA', (37, 49))	('oxidative stress', 'MPA', (57, 73))	('augmented', 'PosReg', (122, 131))
631098	32966340	EPC1 and EPC2 cells carry wild-type ALDH2 while EPC3 carries a single nucleotide polymorphism for ALDH2.	('EPC3', 'CellLine', 'CVCL:4361', (48, 52))	('ALDH2', 'Gene', (36, 41))	('single nucleotide polymorphism', 'Var', (63, 93))	('ALDH2', 'Gene', (98, 103))
631099	32966340	This mutant ALDH2 enhances EtOH toxicity by delaying acetaldehyde clearance.	('ALDH2', 'Gene', (12, 17))	('acetaldehyde clearance', 'MPA', (53, 75))	('acetaldehyde', 'Chemical', 'MESH:D000079', (53, 65))	('EtOH', 'Chemical', '-', (27, 31))	('mutant', 'Var', (5, 11))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))	('enhances', 'PosReg', (18, 26))	('toxicity', 'Disease', (32, 40))	('delaying', 'NegReg', (44, 52))
631194	31810484	Therefore, patients in PJIRSTR group had fewer patients of Visick grade II and III than PJIRDTR group, PJIRDTR group had fewer patients of Visick grade II and III than TGRY group, and TGRY group had patients of Visick grade IV.	('Visick grade II', 'MPA', (59, 74))	('JI', 'Phenotype', 'HP:0004786', (89, 91))	('DT', 'Chemical', '-', (92, 94))	('fewer', 'NegReg', (41, 46))	('JI', 'Chemical', '-', (89, 91))	('TG', 'Chemical', '-', (184, 186))	('fewer', 'NegReg', (121, 126))	('PJIRDTR', 'Var', (103, 110))	('DT', 'Chemical', '-', (107, 109))	('patients', 'Species', '9606', (47, 55))	('JI', 'Chemical', '-', (24, 26))	('JI', 'Phenotype', 'HP:0004786', (104, 106))	('patients', 'Species', '9606', (127, 135))	('JI', 'Phenotype', 'HP:0004786', (24, 26))	('JI', 'Chemical', '-', (104, 106))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (11, 19))	('TG', 'Chemical', '-', (168, 170))
631207	31810484	The serum vitamin B12 level in the LPG-DT group was significantly higher than in the LTG group.	('serum vitamin B12 level', 'MPA', (4, 27))	('LPG-DT', 'Chemical', '-', (35, 41))	('LPG-DT', 'Var', (35, 41))	('vitamin B12', 'Chemical', 'MESH:D014805', (10, 21))	('LTG', 'Chemical', '-', (85, 88))	('higher', 'PosReg', (66, 72))
631209	31810484	A recent study has shown that body weight and skeletal muscle index reduction rates were lower in the LPG-DT group than in the LTG group.	('lower', 'NegReg', (89, 94))	('LTG', 'Chemical', '-', (127, 130))	('reduction', 'NegReg', (68, 77))	('LPG-DT', 'Chemical', '-', (102, 108))	('LPG-DT', 'Var', (102, 108))
631216	31810484	Therefore, lack of internal factor, B12, or tetrahydrofolate can cause the development of the nucleus to lag behind the development of the cytoplasm and eventually resulting in megaloblastic anemia.	('megaloblastic anemia', 'Disease', 'MESH:D000749', (177, 197))	('resulting in', 'Reg', (164, 176))	('cause', 'Reg', (65, 70))	('development of the nucleus', 'CPA', (75, 101))	('anemia', 'Phenotype', 'HP:0001903', (191, 197))	('megaloblastic anemia', 'Phenotype', 'HP:0001889', (177, 197))	('B12', 'Chemical', 'MESH:C034730', (36, 39))	('lack', 'Var', (11, 15))	('tetrahydrofolate', 'Chemical', 'MESH:C030371', (44, 60))	('megaloblastic anemia', 'Disease', (177, 197))
631217	31810484	Loss of the normal physiological function in TGRY group, due to the excision of the distal residual stomach, can make patients more prone to malnutrition and lose weight postoperatively.	('TG', 'Chemical', '-', (45, 47))	('excision', 'Var', (68, 76))	('malnutrition', 'Phenotype', 'HP:0004395', (141, 153))	('prone', 'Reg', (132, 137))	('malnutrition', 'Disease', (141, 153))	('lose', 'NegReg', (158, 162))	('patients', 'Species', '9606', (118, 126))	('malnutrition', 'Disease', 'MESH:D044342', (141, 153))
631356	30300985	Second, magnified NBI might provide an add-on benefit due to its higher sensitivity and specificity than dNBI.	('higher', 'PosReg', (65, 71))	('magnified', 'Var', (8, 17))	('dNBI', 'Chemical', '-', (105, 109))	('sensitivity', 'MPA', (72, 83))
631357	30300985	recently showed a higher image resolution with magnified NBI than with dNBI.	('higher', 'PosReg', (18, 24))	('image resolution', 'MPA', (25, 41))	('magnified', 'Var', (47, 56))	('dNBI', 'Chemical', '-', (71, 75))
631390	30881043	MYBL2 was found to be positively correlated with Ki67 (gamma=0.286, P=0.003).	('Ki67', 'Var', (49, 53))	('Ki67', 'Chemical', '-', (49, 53))	('correlated', 'Interaction', (33, 43))	('MYBL2', 'Gene', (0, 5))
631391	30881043	Furthermore, Kaplan-Meier curves indicated that MYBL2 expression in ESCC tissue was associated with poor patient outcome (P<0.001), with MYBL2-positive patients who exhibited high Ki67 expression in ESCC tissue showing the worst prognosis for overall survival (P=0.003).	('patient', 'Species', '9606', (105, 112))	('MYBL2', 'Gene', (48, 53))	('Ki67', 'Chemical', '-', (180, 184))	('high Ki67 expression', 'Var', (175, 195))	('patient', 'Species', '9606', (152, 159))	('patients', 'Species', '9606', (152, 160))
631392	30881043	We also found that loss of MYBL2 caused a reduction in levels of cell cycle-related G2/M proteins CDK1 and cyclin B1 in ESCC cells.	('cyclin B1', 'Gene', '891', (107, 116))	('cyclin B1', 'Gene', (107, 116))	('MYBL2', 'Gene', (27, 32))	('CDK1', 'Gene', (98, 102))	('CDK1', 'Gene', '983', (98, 102))	('loss', 'Var', (19, 23))	('reduction', 'NegReg', (42, 51))
631420	30881043	Positive staining of MYBL2 was observed in the nuclei and cytoplasm: Ki67 in the nuclei, CDK1 and cyclin B1 mainly in the cytoplasm.	('MYBL2', 'Gene', (21, 26))	('Ki67', 'Chemical', '-', (69, 73))	('CDK1', 'Gene', (89, 93))	('Ki67', 'Var', (69, 73))	('cyclin B1', 'Gene', '891', (98, 107))	('CDK1', 'Gene', '983', (89, 93))	('cyclin B1', 'Gene', (98, 107))
631439	30881043	The primary antibodies and their dilutions were anti-MYBL2 (1:1,000; Abcam), anti-CDK1, anti-cyclin B1, anti-p21 (1:500; Proteintech), and anti-beta-actin (1:1,000; Proteintech).	('anti-beta-actin', 'Var', (139, 154))	('cyclin B1', 'Gene', '891', (93, 102))	('cyclin B1', 'Gene', (93, 102))	('CDK1', 'Gene', '983', (82, 86))	('CDK1', 'Gene', (82, 86))	('anti-MYBL2', 'Var', (48, 58))	('p21', 'Gene', '1026', (109, 112))	('p21', 'Gene', (109, 112))
631448	30881043	Furthermore, high MYBL2 expression was found to be significantly associated with histological differentiation (P=0.022), tumor invasion (P<0.001), lymph-node metastasis (P=0.01), and clinical stage (P<0.001, Table 2).	('histological differentiation', 'CPA', (81, 109))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('lymph-node metastasis', 'CPA', (147, 168))	('high', 'Var', (13, 17))	('MYBL2', 'Gene', (18, 23))	('expression', 'MPA', (24, 34))	('clinical stage', 'CPA', (183, 197))	('tumor', 'Disease', (121, 126))	('associated', 'Reg', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
631451	30881043	Expression of Ki67 was dramatically higher in ESCC tissue with high MYBL2 expression (57 of 76, 75%) when compared to tissue with low MYBL2 expression (14 of 31, 45.2%; P=0.003; Table 2).	('ESCC', 'Disease', (46, 50))	('MYBL2', 'Gene', (68, 73))	('higher', 'PosReg', (36, 42))	('Expression', 'MPA', (0, 10))	('expression', 'Var', (74, 84))	('Ki67', 'Var', (14, 18))	('Ki67', 'Chemical', '-', (14, 18))	('high', 'Var', (63, 67))
631457	30881043	The MYBL2-positive patient group exhibiting higher expression of Ki67 in ESCC tissue showed the worst prognosis for OS (P=0.003, Figure 1G).	('patient', 'Species', '9606', (19, 26))	('higher', 'PosReg', (44, 50))	('MYBL2-positive', 'Gene', (4, 18))	('Ki67', 'Var', (65, 69))	('Ki67', 'Chemical', '-', (65, 69))	('expression', 'MPA', (51, 61))
631458	30881043	Univariate Cox regression analysis confirmed that histological differentiation (P=0.005), tumor invasion (P=0.02), lymph-node metastasis (P<0.001), clinical stage (P=0.025), and high Ki67 (P=0.046) and MYBL2 expression (P=0.001) were negatively correlated with postoperative survival in ESCC patients.	('negatively', 'NegReg', (234, 244))	('ESCC', 'Disease', (287, 291))	('MYBL2', 'Gene', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('lymph-node metastasis', 'CPA', (115, 136))	('Ki67', 'Chemical', '-', (183, 187))	('expression', 'MPA', (208, 218))	('high Ki67', 'Var', (178, 187))	('patients', 'Species', '9606', (292, 300))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
631460	30881043	Next, we analyzed MYBL2 mRNA and protein levels in TE7, EC9706, EC109, and KYSE510 cell lines (Figure 2A).	('EC9706', 'Var', (56, 62))	('KYSE510', 'CellLine', 'CVCL:1354', (75, 82))	('MYBL2', 'Protein', (18, 23))	('EC9706', 'CellLine', 'CVCL:E307', (56, 62))	('EC109', 'CellLine', 'CVCL:6898', (64, 69))
631467	30881043	We found that the proportion of cells in the G2/M phase was increased in EC9706 cells knocked down for MYBL2.	('EC9706', 'Gene', (73, 79))	('MYBL2', 'Gene', (103, 108))	('EC9706', 'CellLine', 'CVCL:E307', (73, 79))	('knocked down', 'Var', (86, 98))	('increased', 'PosReg', (60, 69))
631469	30881043	Loss of MYBL2 caused a reduction in CDK1 and cyclin B1 levels in ESCC cells, whereas these proteins were upregulated in KYSE510 cells overexpressing MYBL2 (Figure 3B).	('upregulated', 'PosReg', (105, 116))	('CDK1', 'Gene', (36, 40))	('cyclin B1', 'Gene', '891', (45, 54))	('cyclin B1', 'Gene', (45, 54))	('reduction', 'NegReg', (23, 32))	('KYSE510', 'CellLine', 'CVCL:1354', (120, 127))	('MYBL2', 'Gene', (8, 13))	('Loss', 'Var', (0, 4))	('CDK1', 'Gene', '983', (36, 40))
631474	30881043	In order to assess the effect of MYBL2 on ESCC cells in vivo, we established a xenograft mouse model where EC9706 cells transfected with Lv-shNC or Lv-shMYBL2 were injected subcutaneously into the dorsal region of the mice.	('Lv-shNC', 'Var', (137, 144))	('EC9706', 'CellLine', 'CVCL:E307', (107, 113))	('mice', 'Species', '10090', (218, 222))	('Lv-shMYBL2', 'Var', (148, 158))	('mouse', 'Species', '10090', (89, 94))
631476	30881043	In addition, immunohistochemistry analysis indicated that MYBL2-depleted tumor tissue had a marked decrease in Ki67 expression, suggesting that the loss of MYBL2 inhibited tumor proliferation (Figure 4B and C).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Ki67', 'Protein', (111, 115))	('tumor', 'Disease', (172, 177))	('loss', 'Var', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('decrease', 'NegReg', (99, 107))	('tumor', 'Disease', (73, 78))	('Ki67', 'Chemical', '-', (111, 115))	('inhibited', 'NegReg', (162, 171))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('MYBL2', 'Gene', (156, 161))
631499	30656409	In esophageal cancer, although the relationship between expression of MAGE-A, NY-ESO-1, LAGE-1, and TTK and prognosis value is still in a controversial situation, MAGE-A, NY-ESO-1, LAGE-1, and TTK are highly expressed and can induce specific CTL cells to produce particular killing effect on tumor cells, and some clinical trials have demonstrated that immunotherapy for esophageal cancer patients is effective and safe, which provides a new therapeutic strategy for the treatment of esophageal cancer in the future.	('TTK', 'Gene', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (495, 501))	('LAGE-1', 'Gene', '30848', (181, 187))	('LAGE-1', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('NY-ESO-1', 'Gene', '1485', (78, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('TTK', 'Gene', (193, 196))	('MAGE-A', 'Var', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('NY-ESO-1', 'Gene', (78, 86))	('TTK', 'Gene', '7272', (100, 103))	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (484, 501))	('LAGE-1', 'Gene', '30848', (88, 94))	('NY-ESO-1', 'Gene', '1485', (171, 179))	('patients', 'Species', '9606', (389, 397))	('NY-ESO-1', 'Gene', (171, 179))	('esophageal cancer', 'Disease', 'MESH:D004938', (371, 388))	('esophageal cancer', 'Disease', (484, 501))	('tumor', 'Disease', (292, 297))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('LAGE-1', 'Gene', (181, 187))	('TTK', 'Gene', '7272', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('esophageal cancer', 'Disease', (371, 388))
631566	30656409	This study demonstrated that genetically engineered T cells expressing MAGE-A4-specific TCR could prevent the growth of esophageal cancer expressed MAGE-A4 in immunodeficient NOG mice (Shirakura et al.).	('prevent', 'NegReg', (98, 105))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('mice', 'Species', '10090', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('MAGE-A4', 'Var', (148, 155))	('esophageal cancer', 'Disease', (120, 137))	('immunodeficient', 'Disease', 'MESH:D007153', (159, 174))	('immunodeficient', 'Disease', (159, 174))	('growth', 'MPA', (110, 116))
631608	30656409	In three ESCC patients who had not undergone any treatment intervention before surgery, the cytotoxicity of CTLs induced by DCs carrying chimeric mRNA was significantly higher than that of mock DCs (p < 0.05) (Forghanifard et al.).	('higher', 'PosReg', (169, 175))	('cytotoxicity', 'Disease', (92, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (92, 104))	('patients', 'Species', '9606', (14, 22))	('chimeric mRNA', 'Var', (137, 150))
631673	30656409	Inhibition of TTK has emerged as a promising therapeutic strategy for the treatment of aneuploid tumors, with triple-negative breast cancer (TNBC) (Maia et al.	('aneuploid tumors', 'Disease', 'MESH:D000782', (87, 103))	('TTK', 'Gene', (14, 17))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('aneuploid tumors', 'Disease', (87, 103))	('TNBC', 'Disease', (141, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('TTK', 'Gene', '7272', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TNBC', 'Disease', 'None', (141, 145))
631675	30656409	Human cancer cells treated with Mps1 inhibitor exhibit effects consistent with Mps1 kinase inhibition, specifically spindle assembly checkpoint inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death (Mason et al.).	('Human', 'Species', '9606', (0, 5))	('aneuploidy', 'Disease', (196, 206))	('Mps1', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('aneuploidy', 'Disease', 'MESH:D000782', (196, 206))	('inhibition', 'NegReg', (91, 101))	('spindle assembly checkpoint inactivation', 'Disease', (116, 156))	('cell death', 'CPA', (223, 233))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('Mps1', 'Gene', (79, 83))	('Mps1', 'Gene', '7272', (79, 83))	('cancer', 'Disease', (6, 12))	('inhibitor', 'Var', (37, 46))	('chromosome missegregation', 'CPA', (169, 194))	('Mps1', 'Gene', '7272', (32, 36))
631683	30656409	To solve the above problems, future research could take the expression of other members of the cancer-testis antigens family in esophageal cancer into account, considering whether there is a correlation expression among each antigen to cover more esophageal cancer patients; whether epigenetic modifying agents can effectively improve the expression of cancer-testis antigens in esophageal cancer (James et al.	('esophageal cancer', 'Disease', (379, 396))	('cancer-testis', 'Disease', (353, 366))	('cancer-testis', 'Disease', 'MESH:D013736', (95, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('patients', 'Species', '9606', (265, 273))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('esophageal cancer', 'Disease', (128, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (247, 264))	('expression', 'MPA', (339, 349))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('esophageal cancer', 'Disease', (247, 264))	('cancer-testis', 'Disease', (95, 108))	('epigenetic', 'Var', (283, 293))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer-testis', 'Disease', 'MESH:D013736', (353, 366))	('esophageal cancer', 'Disease', 'MESH:D004938', (379, 396))	('improve', 'PosReg', (327, 334))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))
631711	28584720	Previous studies have found that low-risk HPV is associated with recurrent respiratory papillomatosis, while high-risk HPV is associated with laryngeal cancer.	('low-risk', 'Var', (33, 41))	('HPV', 'Species', '10566', (42, 45))	('respiratory papillomatosis', 'Disease', 'MESH:C535297', (75, 101))	('laryngeal cancer', 'Disease', (142, 158))	('associated', 'Reg', (49, 59))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (142, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('HPV', 'Species', '10566', (119, 122))	('respiratory papillomatosis', 'Disease', (75, 101))	('laryngeal cancer', 'Disease', 'MESH:D007822', (142, 158))
631743	28584720	However, the 5-year local/regional control rate was significantly better in HPV- positive tumors than in HPV-negative tumors (100% vs. 75%, p = 0.0494; Fig.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('HPV', 'Species', '10566', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('better', 'PosReg', (66, 72))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('HPV- positive', 'Var', (76, 89))	('HPV', 'Species', '10566', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('local/regional control', 'CPA', (20, 42))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
631795	28138450	Stricture at the site of gastric anastomosis and redundancy of the transposed antethoracic jejunal loop may progressively cause an inability to eat and pulmonary fibrosis.	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (152, 170))	('Stricture', 'Var', (0, 9))	('cause', 'Reg', (122, 127))	('redundancy', 'Var', (49, 59))	('pulmonary fibrosis', 'Disease', (152, 170))	('inability to eat', 'CPA', (131, 147))	('jejunal loop', 'Phenotype', 'HP:0004786', (91, 103))	('gastric anastomosis', 'Disease', 'MESH:D013274', (25, 44))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (152, 170))	('gastric anastomosis', 'Disease', (25, 44))
631802	28042239	Thirty-one patients (27 men) were analyzed: 13 with low-grade dysplasia Barrett's esophagus, 16 with in situ adenocarcinoma, 1 with pT1SM1 adenocarcinoma, and 1 with pT1SM2 adenocarcinoma.	('men', 'Species', '9606', (24, 27))	('adenocarcinoma', 'Disease', 'MESH:D000230', (139, 153))	('low-grade', 'Var', (52, 61))	('adenocarcinoma', 'Disease', (109, 123))	('situ adenocarcinoma', 'Disease', (104, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('adenocarcinoma', 'Disease', 'MESH:D000230', (109, 123))	('situ adenocarcinoma', 'Disease', 'MESH:D065311', (104, 123))	("dysplasia Barrett's esophagus", 'Disease', 'MESH:D001471', (62, 91))	("dysplasia Barrett's esophagus", 'Disease', (62, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (72, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('patients', 'Species', '9606', (11, 19))	('adenocarcinoma', 'Disease', (139, 153))	('adenocarcinoma', 'Disease', (173, 187))	('adenocarcinoma', 'Disease', 'MESH:D000230', (173, 187))
631818	28042239	Barrett's esophagus was examined under high-definition white-light endoscopy (EG29-i10, EG-2990Zi, PENTAX MEDICAL , Tokyo, JAPAN) and, if necessary, by chromoendoscopy with acetic acid.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (0, 19))	('EG-2990Zi', 'Var', (88, 97))	('EG29-i10', 'Var', (78, 86))	('acetic acid', 'Chemical', 'MESH:D019342', (173, 184))
631917	33660414	STAT3 was found to bind to the MIR19B promoter and increased the expression of miR-19b-3p in ESCC cells.	('miR-19b-3p', 'Var', (79, 89))	('increased', 'PosReg', (51, 60))	('MIR19B', 'Gene', '406980', (31, 37))	('expression', 'MPA', (65, 75))	('miR-19b-3p', 'Chemical', '-', (79, 89))	('MIR19B', 'Gene', (31, 37))
631918	33660414	In summary, our results demonstrated that the miR-19b-3p-MAP2K3-STAT3 feedback loop regulates ESCC tumorigenesis and elucidates the potential of therapeutically targeting this pathway in ESCC.	('miR-19b-3p-MAP2K3-STAT3', 'Var', (46, 69))	('tumor', 'Disease', (99, 104))	('regulates', 'Reg', (84, 93))	('miR-19b-3p', 'Chemical', '-', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('ESCC', 'Disease', (94, 98))
631920	33660414	MAP2K3 was found to inhibit cell proliferation and invasion via the EGFR-STAT3 signaling pathway.	('MAP2K3', 'Var', (0, 6))	('inhibit', 'NegReg', (20, 27))	('cell proliferation', 'CPA', (28, 46))	('EGFR', 'Gene', '1956', (68, 72))	('invasion', 'CPA', (51, 59))	('EGFR', 'Gene', (68, 72))
631921	33660414	miR-19b-3p could suppress MAP2K3 expression and could be transcriptional activated by STAT3 in ESCC cells.	('MAP2K3', 'Gene', (26, 32))	('miR-19b-3p', 'Var', (0, 10))	('miR-19b-3p', 'Chemical', '-', (0, 10))	('expression', 'MPA', (33, 43))	('suppress', 'NegReg', (17, 25))
631925	33660414	Mitogen-activated protein kinase 3 (MAP2K3), a dual-specificity kinase in the MAP kinase kinase (MKK) family, is activated by MKK kinase proteins through Ser-189 and Thr-193 phosphorylation.	('Ser-189', 'Var', (154, 161))	('phosphorylation', 'MPA', (174, 189))	('activated', 'PosReg', (113, 122))	('Mitogen-activated protein kinase 3', 'Gene', '5595', (0, 34))	('Ser', 'Chemical', 'MESH:D012694', (154, 157))	('Thr-193', 'Var', (166, 173))	('Thr', 'Chemical', 'MESH:D013912', (166, 169))	('Mitogen-activated protein kinase 3', 'Gene', (0, 34))	('MAP2K3', 'Gene', (36, 42))
631926	33660414	MAP2K3 was identified as an oncogene whose depletion reduces tumor growth and improves biological response to chemotherapy [4, 5].	('depletion', 'Var', (43, 52))	('improves', 'PosReg', (78, 86))	('biological response to chemotherapy', 'CPA', (87, 122))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('MAP2K3', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('reduces', 'NegReg', (53, 60))	('tumor', 'Disease', (61, 66))
631934	33660414	For example, cancer cell-derived exosome transmitted miR-1910-3p promotes breast cancer cell proliferation, metastasis, and autophagy [13].	('breast cancer', 'Disease', (74, 87))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('metastasis', 'CPA', (108, 118))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('autophagy', 'CPA', (124, 133))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('miR-1910-3p', 'Var', (53, 64))	('promotes', 'PosReg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
631938	33660414	Furthermore, we also found that MAP2K3 is suppressed by miR-19b-3p, which is transcriptionally activated by STAT3 in ESCC cells.	('suppressed', 'NegReg', (42, 52))	('miR-19b-3p', 'Var', (56, 66))	('miR-19b-3p', 'Chemical', '-', (56, 66))	('MAP2K3', 'Protein', (32, 38))
631939	33660414	Our study is the first to demonstrate that the miR-19b-3p/MAP2K3/STAT3 feedback loop regulates ESCC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('regulates', 'Reg', (85, 94))	('ESCC', 'Disease', (95, 99))	('miR-19b-3p', 'Chemical', '-', (47, 57))	('miR-19b-3p/MAP2K3/STAT3', 'Var', (47, 70))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
631945	33660414	Antibodies against human beta-actin, MAP2K3, p-MAP2K3, STAT1, p-STAT1, EGFR, p-EGFR, caspase 3, cleaved(cl-) caspase 3, GFP, Ki67, Flag, STAT3, p-STAT3, ubiquitin (Ub), HA, MDM2, cleaved(cl-) PARP, CD9, CD63, and TSG101 were purchased from Cell Signaling Technology (MA, USA).	('EGFR', 'Gene', '1956', (79, 83))	('CD9', 'Gene', (198, 201))	('p-MAP2K3', 'Var', (45, 53))	('EGFR', 'Gene', '1956', (71, 75))	('CD63', 'Gene', '967', (203, 207))	('PARP', 'Gene', '1302', (192, 196))	('Ki67', 'Gene', (125, 129))	('STAT1', 'Gene', (64, 69))	('CD9', 'Gene', '928', (198, 201))	('EGFR', 'Gene', (79, 83))	('PARP', 'Gene', (192, 196))	('STAT1', 'Gene', (55, 60))	('caspase 3', 'Gene', (109, 118))	('caspase 3', 'Gene', (85, 94))	('TSG101', 'Gene', (213, 219))	('caspase 3', 'Gene', '836', (85, 94))	('EGFR', 'Gene', (71, 75))	('caspase 3', 'Gene', '836', (109, 118))	('TSG101', 'Gene', '7251', (213, 219))	('CD63', 'Gene', (203, 207))	('STAT1', 'Gene', '6772', (64, 69))	('Ki67', 'Gene', '17345', (125, 129))	('STAT1', 'Gene', '6772', (55, 60))	('human', 'Species', '9606', (19, 24))
631949	33660414	The Flag-wild-type (WT) MAP2K3 plasmid, dominant-negative MAP2K3 (S-A), constituted activated MAP2K3(S-E) constructed by replacing Ser-189 and Thr-193 with Ala or Glu residues, Flag-MDM2, MDM2C464A, GFP-STAT3 WT, STAT3 (Y705A), STAT3 (S727A), STAT3 DeltaN-terminal domain (NTD), Delta coiled-coil domain (CCD), DeltaDNA-binding domain (DBD), Delta Linker domain (LD), Delta Src Homology 2 (SH2), Delta Transactivation domain (TAD) plasmids, MIR19B transcriptional activity reporter plasmids, and three mutant type plasmids (mt1: -1462/-1452; mt2: -1295/-1285; and mt3: both mutant) were purchased from Vigene (Guangzhou, China).	('MIR19B', 'Gene', '406980', (441, 447))	('Y705A', 'Mutation', 'p.Y705A', (220, 225))	('MIR19B', 'Gene', (441, 447))	('Thr-193 with Ala or Glu', 'Var', (143, 166))	('S727A', 'Mutation', 'p.S727A', (235, 240))	('Thr-193 with Ala or Glu', 'SUBSTITUTION', 'None', (143, 166))	('Thr-193 with Ala', 'SUBSTITUTION', 'None', (143, 159))	('NTD', 'Gene', '80199', (273, 276))	('Ser-189 and Thr-193 with Ala', 'SUBSTITUTION', 'None', (131, 159))	('NTD', 'Gene', (273, 276))
631964	33660414	For reporter assays, HEK-293T or ESCC cells were cotransfected with luciferase reporter, miR-19b-3p mimic or inhibitor and 10 ng Renilla luciferase reporter plasmid using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA).	('miR-19b-3p', 'Var', (89, 99))	('miR-19b-3p', 'Chemical', '-', (89, 99))	('luciferase', 'Enzyme', (68, 78))	('Lipofectamine', 'Chemical', 'MESH:C086724', (171, 184))	('HEK-293T', 'CellLine', 'CVCL:0063', (21, 29))
631982	33660414	1A, MAP2K3 transfection increased the expression of Ser-189 and Thr-193 phosphorylation (p-MAP2K3) in ESCC cell lines, KYSE150 and KYSE520.	('Ser-189', 'MPA', (52, 59))	('expression', 'MPA', (38, 48))	('Thr', 'Chemical', 'MESH:D013912', (64, 67))	('Ser', 'Chemical', 'MESH:D012694', (52, 55))	('MAP2K3', 'Gene', (4, 10))	('Thr-193 phosphorylation', 'MPA', (64, 87))	('transfection', 'Var', (11, 23))	('increased', 'PosReg', (24, 33))
631983	33660414	Both ESCC cells with MAP2K3 transfection showed a significant decrease in cell proliferation and colony formation detected by CCK8 and colony formation assay, respectively (Fig.	('cell proliferation', 'CPA', (74, 92))	('colony formation', 'CPA', (97, 113))	('MAP2K3', 'Gene', (21, 27))	('transfection', 'Var', (28, 40))	('decrease', 'NegReg', (62, 70))	('CCK', 'Gene', (126, 129))	('CCK', 'Gene', '885', (126, 129))	('colony formation assay', 'CPA', (135, 157))
631985	33660414	We constructed the dominant-negative MAP2K3(S-A) plasmid and constitutively activated MAP2K3(S-E) by the replacing of Ser-189 and Thr-193 with Ala-189 and Ala-193 or Glu-189 and Glu-193.	('Thr-193 with Ala', 'SUBSTITUTION', 'None', (130, 146))	('Glu-189', 'Var', (166, 173))	('Glu', 'Chemical', 'MESH:D018698', (166, 169))	('replacing', 'Var', (105, 114))	('Ser-189 and Thr-193 with Ala', 'Mutation', 'p.S,T189,193A', (118, 146))	('MAP2K3', 'Gene', (86, 92))	('Ser-189', 'Var', (118, 125))	('Glu', 'Chemical', 'MESH:D018698', (178, 181))	('Ala', 'Chemical', 'MESH:D000409', (143, 146))	('MAP2K3', 'Gene', (37, 43))	('Thr-193 with Ala', 'Var', (130, 146))	('Ala', 'Chemical', 'MESH:D000409', (155, 158))
631986	33660414	However, MAP2K3(S-A) abolished the antitumor effect, suggesting that Ser-189 and Thr-193 phosphorylation sites affect MAP2K3's function on cell proliferation and invasion in ESCC.	('function', 'MPA', (127, 135))	('Thr', 'Chemical', 'MESH:D013912', (81, 84))	('Thr-193', 'Var', (81, 88))	('affect', 'Reg', (111, 117))	('Ser', 'Chemical', 'MESH:D012694', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('ESCC', 'Disease', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Ser-189', 'Var', (69, 76))	('cell proliferation', 'CPA', (139, 157))	('tumor', 'Disease', (39, 44))	('MAP2K3', 'Gene', (118, 124))	('invasion', 'CPA', (162, 170))
631992	33660414	First, for the GSE20347 (n = 34) and the GSE23400 (n = 106) cohorts in the GEO database, the expression of MAP2K3 was significantly lower in ESCC than in paired nontumor tissues (Fig.	('tumor', 'Disease', (164, 169))	('MAP2K3', 'Gene', (107, 113))	('expression', 'MPA', (93, 103))	('GSE20347', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('lower', 'NegReg', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('ESCC', 'Disease', (141, 145))
631993	33660414	Then, we identified MAP2K3 expression in six esophageal cell lines, including five ESCC cell lines KYSE150, KYSE520, TE1, KYSE410, and KYSE180, and the NE1 immortalized esophageal epithelial cell line.	('NE1', 'CellLine', 'CVCL:E306', (152, 155))	('KYSE520', 'Var', (108, 115))	('MAP2K3', 'Gene', (20, 26))
631994	33660414	Compared to NE1, the expression of p-MAP2K3 and total MAP2K3 was lower in ESCC cells (Fig.	('MAP2K3', 'Gene', (54, 60))	('ESCC', 'Disease', (74, 78))	('NE1', 'CellLine', 'CVCL:E306', (12, 15))	('lower', 'NegReg', (65, 70))	('expression', 'MPA', (21, 31))	('p-MAP2K3', 'Var', (35, 43))
631995	33660414	2D, elevated protein expression of MAP2K3 was observed by IHC in normal epithelial (n = 140) when compared to case-matched carcinoma in situ (CIS) (n = 12) and ESCC tissue(n = 140).	('protein expression', 'MPA', (13, 31))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (123, 140))	('carcinoma', 'Disease', (123, 132))	('IHC', 'Var', (58, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinoma', 'Disease', 'MESH:D009369', (123, 132))	('elevated', 'PosReg', (4, 12))	('MAP2K3', 'Gene', (35, 41))	('CIS', 'Phenotype', 'HP:0030075', (142, 145))
631997	33660414	Survival data were available in 70 cases, and Kaplan-Meier analysis indicated that ESCC patients with high MAP2K3 expression tended to have a better overall survival, which is consistent with the survival data from TCGA (P = 0.11, log-rank test, Fig.	('high', 'Var', (102, 106))	('patients', 'Species', '9606', (88, 96))	('overall survival', 'MPA', (149, 165))	('MAP2K3', 'Gene', (107, 113))	('better', 'PosReg', (142, 148))	('ESCC', 'Disease', (83, 87))
632001	33660414	However, knockdown of MAP2K3 also increased both p38 expression and STAT1 expression in ESCC cells, indicating that EGFR and STAT3 are regulated by MAP2K3 in ESCC (Fig.	('expression', 'MPA', (74, 84))	('STAT1', 'Gene', (68, 73))	('STAT1', 'Gene', '6772', (68, 73))	('EGFR', 'Gene', '1956', (116, 120))	('knockdown', 'Var', (9, 18))	('p38', 'Gene', '1432', (49, 52))	('increased', 'PosReg', (34, 43))	('EGFR', 'Gene', (116, 120))	('p38', 'Gene', (49, 52))	('MAP2K3', 'Gene', (22, 28))
632003	33660414	3D, MAP2K3 decreased STAT3 transcription activity and the mRNA expression of downstream STAT3 genes, such as cyclin D1, survivin and vascular endothelial growth factor (VEGF).	('vascular endothelial growth factor', 'Gene', '7422', (133, 167))	('STAT3 genes', 'Gene', (88, 99))	('MAP2K3', 'Var', (4, 10))	('decreased', 'NegReg', (11, 20))	('VEGF', 'Gene', (169, 173))	('STAT3 transcription activity', 'MPA', (21, 49))	('mRNA expression', 'MPA', (58, 73))	('cyclin D1', 'Gene', '595', (109, 118))	('cyclin D1', 'Gene', (109, 118))	('VEGF', 'Gene', '7422', (169, 173))	('vascular endothelial growth factor', 'Gene', (133, 167))	('survivin', 'Gene', (120, 128))
632005	33660414	The half-life of STAT3 was significantly increased in MAP2K3 knockdown cells as detected by cycloheximide chase assay (Figure 3H).	('MAP2K3', 'Gene', (54, 60))	('half-life', 'MPA', (4, 13))	('increased', 'PosReg', (41, 50))	('knockdown', 'Var', (61, 70))	('cycloheximide', 'Chemical', 'MESH:D003513', (92, 105))
632006	33660414	Tyrosine 705 (Y705) and serine 727 (S727) phosphorylation sites on STAT3 play an important role in STAT3 degradation.	('Y705', 'Var', (14, 18))	('serine', 'Chemical', 'MESH:D012694', (24, 30))	('STAT3 degradation', 'MPA', (99, 116))	('STAT3', 'Gene', (67, 72))	('S727', 'Var', (36, 40))	('Tyrosine', 'Chemical', 'MESH:D014443', (0, 8))
632007	33660414	We found that MAP2K3 binds with both wild-type and mutant STAT3 but did not increase the polyubiquitination of STAT3 S727A (Figure S4D and Figure S3J).	('binds', 'Interaction', (21, 26))	('mutant', 'Var', (51, 57))	('polyubiquitination', 'MPA', (89, 107))	('S727A', 'Mutation', 'p.S727A', (117, 122))	('STAT3', 'Gene', (58, 63))
632010	33660414	Moreover, the tyrosine 705 (Y705) and serine 727 (S727) phosphorylation site mutations of STAT3 abolished the observed interactions with MDM2 (Figure 4B).	('Y705', 'Var', (28, 32))	('abolished', 'NegReg', (96, 105))	('STAT3', 'Gene', (90, 95))	('serine', 'Chemical', 'MESH:D012694', (38, 44))	('S727', 'Var', (50, 54))	('interactions', 'Interaction', (119, 131))	('serine 727 (S727', 'Var', (38, 54))	('tyrosine', 'Chemical', 'MESH:D014443', (14, 22))
632011	33660414	By analyzing the lysine residues within the SH2 domain for possible ubiquitination sites, we mutated a predicted K631 lysine residues to Ala and found that STAT3 ubiquitination was abolished (Figure 4I).	('abolished', 'NegReg', (181, 190))	('lysine', 'Chemical', 'MESH:D008239', (118, 124))	('STAT3 ubiquitination', 'MPA', (156, 176))	('Ala', 'Chemical', 'MESH:D000409', (137, 140))	('lysine', 'Chemical', 'MESH:D008239', (17, 23))	('K631', 'Var', (113, 117))
632016	33660414	Thus, using predictions of TargetScan, DIANA-TarBase and miRTarBase databases, we identified 3 miRNAs (miR-21-5p, miR-19a-3p, and miR-19b-3p) in common that could serve as potential upstream regulators of MAP2K3 (Figure 6A).	('miR-21-5p', 'Gene', '406997', (103, 112))	('miR-19b-3p', 'Chemical', '-', (130, 140))	('miR-19a-3p', 'Var', (114, 124))	('miR-19b-3p', 'Var', (130, 140))	('miR-21-5p', 'Gene', (103, 112))
632017	33660414	PCR analysis revealed that all three miRNAs mimics decreased MAP2K3 mRNA expression, with miR-19b-3p being the most significant (Figure S7B).	('MAP2K3', 'Gene', (61, 67))	('mRNA expression', 'MPA', (68, 83))	('decreased', 'NegReg', (51, 60))	('miR-19b-3p', 'Var', (90, 100))	('miR-19b-3p', 'Chemical', '-', (90, 100))
632024	33660414	Consistent with previous report that the expression of exosomal miR-19b-3p was significantly higher in ESCC patient's plasma than healthy control (Figure 6C).	('higher', 'PosReg', (93, 99))	('miR-19b-3p', 'Var', (64, 74))	('expression', 'MPA', (41, 51))	('miR-19b-3p', 'Chemical', '-', (64, 74))	('patient', 'Species', '9606', (108, 115))	('ESCC', 'Disease', (103, 107))
632026	33660414	Therefore, the data showed that exosomes from ESCC patient plasma could transfer miR-19b-3p into tumor cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('miR-19b-3p', 'Chemical', '-', (81, 91))	('tumor', 'Disease', (97, 102))	('patient', 'Species', '9606', (51, 58))	('miR-19b-3p', 'Var', (81, 91))
632027	33660414	Then, we determined whether miR-19b-3p plays a role in ESCC tumorigenesis.	('miR-19b-3p', 'Var', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('miR-19b-3p', 'Chemical', '-', (28, 38))	('ESCC', 'Disease', (55, 59))	('tumor', 'Disease', (60, 65))
632028	33660414	First, we transfected the miR-19-3p mimic into ESCC cells that exhibit decreased apoptosis and increased cell survival, colony formation, and cell invasion, compared to control cells.	('cell invasion', 'CPA', (142, 155))	('apoptosis', 'CPA', (81, 90))	('miR-19-3p mimic', 'Var', (26, 41))	('cell survival', 'CPA', (105, 118))	('colony formation', 'CPA', (120, 136))	('miR-19-3p', 'Chemical', '-', (26, 35))	('increased', 'PosReg', (95, 104))	('decreased', 'NegReg', (71, 80))
632029	33660414	ESCC cells transfected with the miR-19b-3p inhibitor exhibited the opposite results (Figure 6F-I), indicating that miR-19-3p promotes ESCC tumorigenesis.	('miR-19-3p', 'Var', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('miR-19b-3p', 'Chemical', '-', (32, 42))	('ESCC', 'Disease', (134, 138))	('miR-19-3p', 'Chemical', '-', (115, 124))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('promotes', 'PosReg', (125, 133))
632030	33660414	The rescue experiments result also supported that miR-19b-3p promotes ESCC tumorigenesis by suppressing MAP2K3 (Figure S7F).	('suppressing', 'NegReg', (92, 103))	('promotes', 'PosReg', (61, 69))	('miR-19b-3p', 'Chemical', '-', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('MAP2K3', 'Gene', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ESCC', 'Disease', (70, 74))	('miR-19b-3p', 'Var', (50, 60))	('tumor', 'Disease', (75, 80))
632031	33660414	In our cohort ESCC samples, the expression of miR-19b-3p was higher in ESCC compared with normal esophageal epithelium and inversely correlation with MAP2K3 as detected by qRT-PCR (Figure 6J and Figure S7G).	('ESCC', 'Disease', (71, 75))	('higher', 'PosReg', (61, 67))	('miR-19b-3p', 'Chemical', '-', (46, 56))	('correlation', 'Reg', (133, 144))	('miR-19b-3p', 'Var', (46, 56))	('expression', 'MPA', (32, 42))
632033	33660414	Furthermore, the exosome tracing and functional analysis results demonstrated that exosomes extracted from KYSE150 and KYSE520 cells transfected with miR-19b-3p mimics can transfer into recipient ESCC cells and significantly increase the proliferation, colony formation ability of recipient ESCC cells (Figure S8).	('colony formation ability', 'CPA', (253, 277))	('increase', 'PosReg', (225, 233))	('miR-19b-3p', 'Chemical', '-', (150, 160))	('proliferation', 'CPA', (238, 251))	('miR-19b-3p', 'Var', (150, 160))
632034	33660414	All these results indicated that plasma-derived exosomal miR-19b-3p can promote proliferation and invasion in ESCC cells by suppressing MAP2K3.	('MAP2K3', 'Gene', (136, 142))	('invasion', 'CPA', (98, 106))	('proliferation', 'CPA', (80, 93))	('suppressing', 'NegReg', (124, 135))	('miR-19b-3p', 'Chemical', '-', (57, 67))	('promote', 'PosReg', (72, 79))	('ESCC', 'Disease', (110, 114))	('miR-19b-3p', 'Var', (57, 67))
632036	33660414	Inspection of the MIR19B genomic region revealed a conserved STAT3-binding according to the JASPAR website (http://jaspar.genereg.net/analysis), and two STAT3 binding sites were identified (-1462/-1452 and -1295/-1285 sites).	('STAT3-binding', 'Interaction', (61, 74))	('MIR19B', 'Gene', '406980', (18, 24))	('MIR19B', 'Gene', (18, 24))	('-1462/-1452', 'Var', (190, 201))
632039	33660414	As shown in Figure 7A, STAT3 increased, while si-STAT3 decreased expression of miR-19b-3p in both KYSE150 and KYSE520 cells.	('decreased', 'NegReg', (55, 64))	('miR-19b-3p', 'Gene', (79, 89))	('expression', 'MPA', (65, 75))	('miR-19b-3p', 'Chemical', '-', (79, 89))	('si-STAT3', 'Var', (46, 54))
632042	33660414	After transfection of KYSE150 and KYSE520 cells with STAT3, the STAT3 occupancy at the MIR19B promoter significantly increased (Figure 7C).	('increased', 'PosReg', (117, 126))	('MIR19B', 'Gene', '406980', (87, 93))	('KYSE150', 'Var', (22, 29))	('KYSE520', 'Var', (34, 41))	('STAT3 occupancy', 'MPA', (64, 79))	('MIR19B', 'Gene', (87, 93))
632045	33660414	In contrast, STAT3 knockdown decreased expression and transcriptional activity of miR-19b-3p, and overexpression of MAP2K3 restored it (Figure 7E, F).	('knockdown', 'Var', (19, 28))	('miR-19b-3p', 'Gene', (82, 92))	('miR-19b-3p', 'Chemical', '-', (82, 92))	('decreased', 'NegReg', (29, 38))	('expression', 'MPA', (39, 49))	('transcriptional activity', 'MPA', (54, 78))	('STAT3', 'Gene', (13, 18))
632046	33660414	In this study, we show that the miR-19b-3p/MAP2K3/STAT3 feedback loop regulates ESCC tumorigenesis.	('tumor', 'Disease', (85, 90))	('miR-19b-3p', 'Chemical', '-', (32, 42))	('miR-19b-3p/MAP2K3/STAT3', 'Var', (32, 55))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('regulates', 'Reg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ESCC', 'Disease', (80, 84))
632048	33660414	In addition, exosomal miR-19b-3p from ESCC patient plasma could be transferred to the ESCC cells and suppress MAP2K3 expression to mediate cell proliferation and invasion.	('miR-19b-3p', 'Chemical', '-', (22, 32))	('patient', 'Species', '9606', (43, 50))	('suppress', 'NegReg', (101, 109))	('expression', 'MPA', (117, 127))	('cell proliferation', 'CPA', (139, 157))	('MAP2K3', 'Gene', (110, 116))	('miR-19b-3p', 'Var', (22, 32))	('invasion', 'CPA', (162, 170))
632051	33660414	MAP2K3 has been shown to enhance tumor progression, and the loss of MAP2K3 results in inhibition of cellular proliferation and increased response of tumor cells to chemotherapeutic drugs in vivo [5, 16, 17].	('MAP2K3', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('enhance', 'PosReg', (25, 32))	('MAP2K3', 'Gene', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('response', 'MPA', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('loss', 'Var', (60, 64))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', (33, 38))	('cellular proliferation', 'CPA', (100, 122))	('increased', 'PosReg', (127, 136))	('inhibition', 'NegReg', (86, 96))
632052	33660414	However, recent research has demonstrated that the loss of MAP2K3 copy number occurs in NSCLC and that MAP2K3 inhibits cell proliferation and promotes cellular senescence in hepatocellular carcinoma, breast cancer, and melanoma [7, 18, 19, 20, 21].	('inhibits', 'NegReg', (110, 118))	('MAP2K3', 'Gene', (59, 65))	('loss', 'NegReg', (51, 55))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('hepatocellular carcinoma', 'Disease', (174, 198))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('cell proliferation', 'CPA', (119, 137))	('MAP2K3', 'Var', (103, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (174, 198))	('melanoma', 'Disease', (219, 227))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('cellular senescence', 'CPA', (151, 170))	('NSCLC', 'Disease', (88, 93))	('copy number', 'Var', (66, 77))	('breast cancer', 'Disease', (200, 213))	('promotes', 'PosReg', (142, 150))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (174, 198))
632055	33660414	However, in our study, we found that MAP2K3 inhibits cell proliferation and colony formation, indicating that MAP2K3 plays a tumor suppressor role in ESCC.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('colony formation', 'CPA', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('ESCC', 'Disease', (150, 154))	('MAP2K3', 'Var', (37, 43))	('inhibits', 'NegReg', (44, 52))	('cell proliferation', 'CPA', (53, 71))
632058	33660414	MDM2 is known to induce ubiquitination of several target proteins, such as p53 [23].	('induce', 'Reg', (17, 23))	('ubiquitination', 'MPA', (24, 38))	('MDM2', 'Var', (0, 4))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))
632061	33660414	Then, we identified miR-19b-3p as an upstream regulator of MAP2K3 by luciferase reporter assay.	('miR-19b-3p', 'Var', (20, 30))	('MAP2K3', 'Gene', (59, 65))	('miR-19b-3p', 'Chemical', '-', (20, 30))
632062	33660414	In cancer, miR-19b-3p promotes cell proliferation, invasion, and metastasis in clear cell renal cell carcinoma, lung, colorectal, and breast cancer [26, 27].	('metastasis', 'CPA', (65, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('invasion', 'CPA', (51, 59))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (79, 110))	('lung', 'Disease', (112, 116))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))	('promotes', 'PosReg', (22, 30))	('breast cancer', 'Disease', (134, 147))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('clear cell renal cell carcinoma', 'Disease', (79, 110))	('cancer', 'Disease', (141, 147))	('colorectal', 'Disease', (118, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('miR-19b-3p', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cell proliferation', 'CPA', (31, 49))	('miR-19b-3p', 'Chemical', '-', (11, 21))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (79, 110))	('cancer', 'Disease', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
632063	33660414	High expression of miR-19b-3p was found in colon cancer and associated with poor patient survival [28].	('poor', 'NegReg', (76, 80))	('patient', 'Species', '9606', (81, 88))	('colon cancer', 'Phenotype', 'HP:0003003', (43, 55))	('colon cancer', 'Disease', 'MESH:D015179', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('miR-19b-3p', 'Chemical', '-', (19, 29))	('colon cancer', 'Disease', (43, 55))	('found', 'Reg', (34, 39))	('miR-19b-3p', 'Var', (19, 29))	('associated', 'Reg', (60, 70))
632067	33660414	In this study, we reported that miR-19b-3p can promote cell proliferation and suppress apoptosis in ESCC by targeting MAP2K3.	('targeting', 'Reg', (108, 117))	('miR-19b-3p', 'Chemical', '-', (32, 42))	('promote', 'PosReg', (47, 54))	('cell proliferation', 'CPA', (55, 73))	('apoptosis', 'CPA', (87, 96))	('suppress', 'NegReg', (78, 86))	('ESCC', 'Disease', (100, 104))	('miR-19b-3p', 'Var', (32, 42))	('MAP2K3', 'Gene', (118, 124))
632068	33660414	And the rescue experiments convince us that the function of miR-19b-3p is partly dependent on suppressing MAP2K3.	('MAP2K3', 'Protein', (106, 112))	('miR-19b-3p', 'Chemical', '-', (60, 70))	('suppressing', 'NegReg', (94, 105))	('miR-19b-3p', 'Var', (60, 70))
632071	33660414	Thus, miR-19b-3p, MAP2K3, and STAT3 formed a positively feedback loop to contribute to ESCC progression.	('contribute', 'Reg', (73, 83))	('miR-19b-3p', 'Var', (6, 16))	('ESCC', 'Disease', (87, 91))	('MAP2K3', 'Gene', (18, 24))	('miR-19b-3p', 'Chemical', '-', (6, 16))
632073	33660414	Furthermore, we found that miR-19b-3p suppressed MAP2K3 expression and could be transcriptional activated by STAT3 in ESCC cells.	('miR-19b-3p', 'Var', (27, 37))	('suppressed', 'NegReg', (38, 48))	('expression', 'MPA', (56, 66))	('MAP2K3', 'Gene', (49, 55))	('miR-19b-3p', 'Chemical', '-', (27, 37))
632074	33660414	Our study is the first to demonstrate that miR-19b-3p/MAP2K3/STAT3 feedback loop regulates ESCC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('regulates', 'Reg', (81, 90))	('ESCC', 'Disease', (91, 95))	('miR-19b-3p', 'Chemical', '-', (43, 53))	('tumor', 'Disease', (96, 101))	('miR-19b-3p/MAP2K3/STAT3', 'Var', (43, 66))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
632077	31118675	Moreover, the abnormal expression of Annexin A1 is closely related to the occurrence and development of tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('abnormal', 'Var', (14, 22))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('related', 'Reg', (59, 66))	('Annexin A1', 'Protein', (37, 47))	('expression', 'MPA', (23, 33))
632109	31118675	The N-terminal peptide WKYMVm-NH2 of Annexin A1 promotes viral replication and enhances the inflammatory response by activating FPR2/ALX in influenza A virus.	('ALX', 'Gene', '84941', (133, 136))	('activating', 'PosReg', (117, 127))	('ALX', 'Gene', (133, 136))	('FPR2', 'Gene', '2358', (128, 132))	('FPR2', 'Gene', (128, 132))	('inflammatory response', 'CPA', (92, 113))	('promotes', 'PosReg', (48, 56))	('influenza A virus', 'Species', '11320', (140, 157))	('enhances', 'PosReg', (79, 87))	('WKYMVm-NH2', 'Var', (23, 33))	('viral replication', 'CPA', (57, 74))
632112	31118675	Annexin A1 is highly expressed in colorectal cancer, lung adenocarcinoma, pancreatic cancer, liver cancer, and glioma, down-regulation or deletion in cervical cancer, thyroid cancer, laryngeal cancer, prostate cancer, head and neck cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('cancer', 'Disease', (232, 238))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (175, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (201, 216))	('colorectal cancer', 'Disease', (34, 51))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (53, 72))	('prostate cancer', 'Phenotype', 'HP:0012125', (201, 216))	('liver cancer', 'Phenotype', 'HP:0002896', (93, 105))	('down-regulation', 'NegReg', (119, 134))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('liver cancer', 'Disease', (93, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('prostate cancer', 'Disease', (201, 216))	('cancer', 'Disease', (159, 165))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('thyroid cancer', 'Disease', (167, 181))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('laryngeal cancer', 'Disease', 'MESH:D007822', (183, 199))	('head and neck cancer', 'Phenotype', 'HP:0012288', (218, 238))	('glioma', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('laryngeal cancer', 'Disease', (183, 199))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (183, 199))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Annexin A1', 'Protein', (0, 10))	('cancer', 'Disease', (85, 91))	('pancreatic cancer', 'Disease', (74, 91))	('cancer', 'Disease', (45, 51))	('thyroid cancer', 'Disease', 'MESH:D013964', (167, 181))	('deletion', 'Var', (138, 146))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('lung adenocarcinoma', 'Disease', (53, 72))	('liver cancer', 'Disease', 'MESH:D006528', (93, 105))	('head and neck cancer', 'Disease', 'MESH:D006258', (218, 238))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('thyroid cancer', 'Phenotype', 'HP:0002890', (167, 181))	('cancer', 'Disease', (99, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (34, 51))	('cancer', 'Disease', (210, 216))
632117	31118675	The negative correlation between Annexin A1 and COX-2 (cyclooxygenase-2) indicated that Annexin A1 can regulate COX-2 production to inhibit cell proliferation of gastrointestinal cancer.	('inhibit', 'NegReg', (132, 139))	('cell proliferation', 'CPA', (140, 158))	('cyclooxygenase-2', 'Gene', '5743', (55, 71))	('COX-2', 'Gene', '5743', (48, 53))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (162, 185))	('cyclooxygenase-2', 'Gene', (55, 71))	('Annexin', 'Var', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('COX-2', 'Gene', (112, 117))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (162, 185))	('COX-2', 'Gene', '5743', (112, 117))	('regulate', 'Reg', (103, 111))	('COX-2', 'Gene', (48, 53))	('gastrointestinal cancer', 'Disease', (162, 185))
632118	31118675	However, Cheng et al showed that the high expression of Annexin A1 is significantly associated with stage IV disease, peritoneal metastasis, and serosal invasion of gastric cancer, and the high expression of Annexin A1 is an independent risk factor for poor overall survival of gastric cancer patients, which can promote the migration and invasion of gastric cancer cells.	('gastric cancer', 'Disease', 'MESH:D013274', (351, 365))	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('invasion', 'CPA', (339, 347))	('migration', 'CPA', (325, 334))	('gastric cancer', 'Disease', 'MESH:D013274', (278, 292))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('gastric cancer', 'Phenotype', 'HP:0012126', (351, 365))	('associated', 'Reg', (84, 94))	('gastric cancer', 'Disease', (165, 179))	('peritoneal metastasis', 'CPA', (118, 139))	('high', 'Var', (37, 41))	('gastric cancer', 'Phenotype', 'HP:0012126', (278, 292))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Annexin A1', 'Gene', (56, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (165, 179))	('gastric cancer', 'Disease', (351, 365))	('stage IV disease', 'Disease', (100, 116))	('promote', 'PosReg', (313, 320))	('high expression', 'Var', (189, 204))	('patients', 'Species', '9606', (293, 301))	('gastric cancer', 'Disease', (278, 292))	('serosal invasion', 'CPA', (145, 161))
632144	29599126	This review focusses on current knowledge of the roles of IRF-1 and IRF-2 in human cancer, with particular attention paid to the impact of IRF-1 inactivation.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('IRF-1', 'Gene', (139, 144))	('p', 'Gene', '23436', (117, 118))	('p', 'Gene', '23436', (96, 97))	('inactivation', 'Var', (145, 157))	('p', 'Gene', '23436', (131, 132))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('human', 'Species', '9606', (77, 82))
632146	29599126	In human cancers, the accumulation of genetic aberrations is known to affect the normal functions of several genes that control cell proliferation and survival.	('affect', 'Reg', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('normal functions', 'MPA', (81, 97))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('p', 'Gene', '23436', (133, 134))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('genetic aberrations', 'Var', (38, 57))
632181	29599126	Defects in IRF-6 gene have been observed in patients with cleft lip and/or palate.	('cleft lip', 'Phenotype', 'HP:0410030', (58, 67))	('IRF-6', 'Gene', (11, 16))	('cleft lip and/or palate', 'Disease', 'MESH:D002971', (58, 81))	('patients', 'Species', '9606', (44, 52))	('observed', 'Reg', (32, 40))	('Defects', 'Var', (0, 7))	('cleft lip and/', 'Phenotype', 'HP:0000202', (58, 72))	('cleft lip and/or palate', 'Disease', (58, 81))	('IRF-6', 'Gene', '3664', (11, 16))
632182	29599126	In addition, aberrations in IRF-6 predisposes for squamous cell carcinoma and defective development of mammary gland.	('p', 'Gene', '23436', (40, 41))	('aberrations', 'Var', (13, 24))	('p', 'Gene', '23436', (34, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('defective development of mammary gland', 'Phenotype', 'HP:0100783', (78, 116))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('squamous cell carcinoma', 'Disease', (50, 73))	('IRF-6', 'Gene', '3664', (28, 33))	('IRF-6', 'Gene', (28, 33))	('p', 'Gene', '23436', (94, 95))
632191	29599126	Additionally, macrophages differentiation and activation during inflammatory response is also activated by IRF-1-IRF-8 heterodimer.	('p', 'Gene', '23436', (80, 81))	('activation', 'CPA', (46, 56))	('heterodimer', 'Var', (119, 130))	('IRF-1-IRF-8', 'Gene', '3659;3394', (107, 118))	('p', 'Gene', '23436', (19, 20))	('IRF-1-IRF-8', 'Gene', (107, 118))	('activated', 'PosReg', (94, 103))
632194	29599126	This review discusses the functions of IRF-1 and IRF-2 in human cancers, with a focus on the potential contribution of IRF-1 inactivation to human carcinogenesis and the future of IRF-1 as a therapeutic target.	('human', 'Species', '9606', (58, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (147, 161))	('p', 'Gene', '23436', (196, 197))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('carcinogenesis', 'Disease', (147, 161))	('inactivation', 'Var', (125, 137))	('cancers', 'Disease', (64, 71))	('human', 'Species', '9606', (141, 146))	('IRF-1', 'Gene', (119, 124))	('p', 'Gene', '23436', (93, 94))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
632200	29599126	In contrast with other tumor suppressors, loss of IRF-1 function rarely induces oncogenicity; however, IRF-1 inactivation is a cofactor in increased risk of tumorigenesis mediated by p53 nullizygosity or Ha-ras oncogene overexpression.	('tumor', 'Disease', (157, 162))	('p', 'Gene', '23436', (32, 33))	('loss', 'Var', (42, 46))	('p', 'Gene', '23436', (226, 227))	('Ha-ras', 'Gene', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('nullizygosity', 'Var', (187, 200))	('p', 'Gene', '23436', (31, 32))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Ha-ras', 'Gene', '15461', (204, 210))	('inactivation', 'NegReg', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (23, 28))	('p', 'Gene', '23436', (183, 184))	('IRF-1', 'Gene', (103, 108))
632207	29599126	Cyclin D1 and survivin have also been reported as downstream targets of IRF-1, and in vitro activation of this IRF decreases cyclin D1 expression and CDK 4 (CDK4) activity.	('cyclin D1', 'Gene', (125, 134))	('IRF-1', 'Gene', (72, 77))	('p', 'Gene', '23436', (40, 41))	('decreases', 'NegReg', (115, 124))	('Cyclin D1', 'Gene', '595', (0, 9))	('CDK 4', 'Gene', '1019', (150, 155))	('p', 'Gene', '23436', (137, 138))	('activity', 'MPA', (163, 171))	('CDK4', 'Gene', (157, 161))	('CDK 4', 'Gene', (150, 155))	('CDK4', 'Gene', '1019', (157, 161))	('Cyclin D1', 'Gene', (0, 9))	('activation', 'Var', (92, 102))	('cyclin D1', 'Gene', '595', (125, 134))
632220	29599126	Such changes inhibit the growth of cells with damaged DNA by inducing G1 cell cycle arrest, an effect that is dependent on ataxia telangiectasia mutated (ATM) and mediated by binding of the promoter region of p21WAF1/CIP1, which contains binding sites for both IRF-1 and p53.	('p', 'Gene', '23436', (209, 210))	('ataxia telangiectasia mutated', 'Gene', '472', (123, 152))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (73, 90))	('p', 'Gene', '23436', (112, 113))	('ataxia', 'Phenotype', 'HP:0001251', (123, 129))	('growth', 'CPA', (25, 31))	('changes', 'Var', (5, 12))	('p', 'Gene', '23436', (271, 272))	('ATM', 'Gene', '472', (154, 157))	('inhibit', 'NegReg', (13, 20))	('p', 'Gene', '23436', (190, 191))	('ataxia telangiectasia mutated', 'Gene', (123, 152))	('p21WAF1/CIP1', 'Gene', '1026', (209, 221))	('p21WAF1/CIP1', 'Gene', (209, 221))	('G1 cell cycle arrest', 'CPA', (70, 90))	('inducing', 'Reg', (61, 69))	('binding', 'Interaction', (175, 182))	('ATM', 'Gene', (154, 157))	('telangiectasia', 'Phenotype', 'HP:0001009', (130, 144))
632222	29599126	Deletion or mutation of IRF-1 and exon skipping (a form of RNA splicing to skip faulty exons) in the corresponding mRNA are also associated with the development of various hematopoietic malignancies and syndromes.	('p', 'Gene', '23436', (43, 44))	('associated with', 'Reg', (129, 144))	('p', 'Gene', '23436', (78, 79))	('hematopoietic malignancies', 'Disease', (172, 198))	('p', 'Gene', '23436', (64, 65))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (172, 198))	('p', 'Gene', '23436', (178, 179))	('p', 'Gene', '23436', (42, 43))	('p', 'Gene', '23436', (107, 108))	('p', 'Gene', '23436', (155, 156))	('syndromes', 'Disease', (203, 212))	('mutation', 'Var', (12, 20))	('IRF-1', 'Gene', (24, 29))	('Deletion', 'Var', (0, 8))
632231	29599126	Human leukemia and pre-leukemic myelodysplastic syndrome (MDS) are characterized by a remarkable cytogenetic abnormality, namely, the loss of chromosome 5 or a deletion within its long arm (del(5q) or 5q-).	('Human', 'Species', '9606', (0, 5))	('del(5q', 'Var', (190, 196))	('MDS', 'Phenotype', 'HP:0002863', (58, 61))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (32, 56))	('p', 'Gene', '23436', (40, 41))	('leukemia', 'Disease', (6, 14))	('MDS', 'Disease', 'MESH:D009190', (58, 61))	('deletion', 'Var', (160, 168))	('leukemia', 'Disease', 'MESH:D007938', (6, 14))	('leukemia', 'Phenotype', 'HP:0001909', (6, 14))	('leukemic myelodysplastic syndrome', 'Disease', 'MESH:D009190', (23, 56))	('leukemic myelodysplastic syndrome', 'Disease', (23, 56))	('loss', 'NegReg', (134, 138))	('MDS', 'Disease', (58, 61))	('p', 'Gene', '23436', (19, 20))
632235	29599126	Once the IRF-1 locus had been determined, a full-length IRF-1 cDNA probe was used to perform Southern blotting of DNA from patients with different types of leukemia and MDS associated with del(5q) to confirm IRF-1 inactivation in clinical samples.	('p', 'Gene', '23436', (242, 243))	('MDS', 'Disease', (169, 172))	('MDS', 'Disease', 'MESH:D009190', (169, 172))	('p', 'Gene', '23436', (85, 86))	('MDS', 'Phenotype', 'HP:0002863', (169, 172))	('p', 'Gene', '23436', (123, 124))	('patients', 'Species', '9606', (123, 131))	('p', 'Gene', '23436', (149, 150))	('leukemia', 'Phenotype', 'HP:0001909', (156, 164))	('leukemia', 'Disease', 'MESH:D007938', (156, 164))	('del(5q', 'Var', (189, 195))	('p', 'Gene', '23436', (67, 68))	('leukemia', 'Disease', (156, 164))	('clinical samples', 'Species', '191496', (230, 246))
632236	29599126	The results of the present study indicated an unusual instability in the 5q region, as deletion of one IRF-1 allele was accompanied by rearrangement or deletion of the second allele in some cases.	('rearrangement', 'MPA', (135, 148))	('deletion', 'MPA', (152, 160))	('p', 'Gene', '23436', (125, 126))	('deletion', 'Var', (87, 95))	('p', 'Gene', '23436', (19, 20))	('IRF-1', 'Gene', (103, 108))
632237	29599126	This led to the conclusion that deletions or rearrangements are more frequent than point mutations at this locus in human leukemia and MDS, and loss of IRF-1 may be critical in the development of AML and MDS.	('loss', 'Var', (144, 148))	('leukemia', 'Disease', (122, 130))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('MDS', 'Disease', (204, 207))	('MDS', 'Phenotype', 'HP:0002863', (135, 138))	('MDS', 'Phenotype', 'HP:0002863', (204, 207))	('rearrangements', 'Var', (45, 59))	('MDS', 'Disease', 'MESH:D009190', (135, 138))	('AML', 'Disease', 'MESH:D015470', (196, 199))	('AML', 'Disease', (196, 199))	('AML', 'Phenotype', 'HP:0004808', (196, 199))	('human', 'Species', '9606', (116, 121))	('deletions', 'Var', (32, 41))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('IRF-1', 'Gene', (152, 157))	('MDS', 'Disease', (135, 138))	('p', 'Gene', '23436', (83, 84))	('MDS', 'Disease', 'MESH:D009190', (204, 207))	('p', 'Gene', '23436', (187, 188))
632245	29599126	Their results showed that accelerated exon skipping is common in patients with a 5q deletion and one deleted IRF-1 allele, and occurs in most APL cases (in which IRF-1 protein expression was found to be absent).	('p', 'Gene', '23436', (46, 47))	('p', 'Gene', '23436', (47, 48))	('5q deletion', 'Var', (81, 92))	('accelerated', 'PosReg', (26, 37))	('p', 'Gene', '23436', (168, 169))	('p', 'Gene', '23436', (178, 179))	('patients', 'Species', '9606', (65, 73))	('IRF-1', 'Gene', (109, 114))	('p', 'Gene', '23436', (65, 66))	('APL', 'Phenotype', 'HP:0004836', (142, 145))
632246	29599126	Such exon skipping thus leads to loss of IRF-1 function and increases risk of malignancy.	('malignancy', 'Disease', (78, 88))	('function', 'MPA', (47, 55))	('loss', 'NegReg', (33, 37))	('exon skipping', 'Var', (5, 18))	('IRF-1', 'Protein', (41, 46))	('malignancy', 'Disease', 'MESH:D009369', (78, 88))
632258	29599126	They also demonstrated that IRF-1 expression negatively correlates with tumor size, confirming that loss of IRF-1 is associated with breast carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('breast carcinogenesis', 'Disease', (133, 154))	('loss', 'Var', (100, 104))	('p', 'Gene', '23436', (36, 37))	('negatively', 'NegReg', (45, 55))	('associated', 'Reg', (117, 127))	('tumor', 'Disease', (72, 77))	('IRF-1', 'Gene', (108, 113))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (133, 154))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('IRF-1', 'Gene', (28, 33))
632260	29599126	Moreover, the mechanism by which dysregulation of IRF-1 and IRF-2 affects breast carcinoma cells has been proposed to involve disruption of the IRF-1/IRF-2 ratio, and as this ratio has been reported to change during the cell cycle, monitoring the status of IRF-1 and IRF-2 in such histological studies is highly challenging.	('dysregulation', 'Var', (33, 46))	('p', 'Gene', '23436', (109, 110))	('breast carcinoma', 'Disease', 'MESH:D001943', (74, 90))	('p', 'Gene', '23436', (131, 132))	('p', 'Gene', '23436', (106, 107))	('p', 'Gene', '23436', (192, 193))	('IRF-1', 'Gene', (50, 55))	('breast carcinoma', 'Phenotype', 'HP:0003002', (74, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('IRF-1/IRF-2 ratio', 'MPA', (144, 161))	('IRF-2', 'Gene', (60, 65))	('breast carcinoma', 'Disease', (74, 90))
632263	29599126	At the genetic level, there have been no reports of point mutations that cause IRF-1 inactivation in breast cancer; however, an IRF-1 polymorphism (A4396G) has been identified in breast cancer cell lines, and has been found to be more frequent amongst African Americans.	('inactivation', 'NegReg', (85, 97))	('p', 'Gene', '23436', (43, 44))	('p', 'Gene', '23436', (134, 135))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('A4396G', 'Var', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('IRF-1', 'Gene', (128, 133))	('breast cancer', 'Disease', (179, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('A4396G', 'Mutation', 'rs1388560715', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('p', 'Gene', '23436', (52, 53))	('breast cancer', 'Disease', (101, 114))	('p', 'Gene', '23436', (141, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
632265	29599126	It has been hypothesized that this variant influences the binding of certain critical transcription factors with tumor-suppressing potential, including microphthalmia transcription factor (MITF), which activates INK4A, a tumor suppressor that inhibits cell cycle progression.	('p', 'Gene', '23436', (122, 123))	('microphthalmia', 'Phenotype', 'HP:0000568', (152, 166))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('microphthalmia transcription factor', 'Gene', (152, 187))	('p', 'Gene', '23436', (121, 122))	('p', 'Gene', '23436', (263, 264))	('binding', 'Interaction', (58, 65))	('p', 'Gene', '23436', (230, 231))	('p', 'Gene', '23436', (175, 176))	('MITF', 'Gene', '4286', (189, 193))	('p', 'Gene', '23436', (229, 230))	('inhibits', 'NegReg', (243, 251))	('tumor', 'Disease', (113, 118))	('p', 'Gene', '23436', (157, 158))	('tumor', 'Disease', (221, 226))	('INK4A', 'Gene', '1029', (212, 217))	('p', 'Gene', '23436', (14, 15))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('MITF', 'Gene', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('microphthalmia transcription factor', 'Gene', '4286', (152, 187))	('influences', 'Reg', (43, 53))	('p', 'Gene', '23436', (94, 95))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('activates', 'PosReg', (202, 211))	('p', 'Gene', '23436', (131, 132))	('variant', 'Var', (35, 42))	('INK4A', 'Gene', (212, 217))
632269	29599126	In addition, 5q12-31 deletions were noted in 11% of sporadic breast cancers, and 5q31.1 loss was observed in 50% of BRCA1 mutation-positive breast tumors.	('BRCA1', 'Gene', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('breast tumors', 'Phenotype', 'HP:0100013', (140, 153))	('BRCA1', 'Gene', '672', (116, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('deletions', 'Var', (21, 30))	('loss', 'NegReg', (88, 92))	('breast tumors', 'Disease', 'MESH:D001943', (140, 153))	('breast tumors', 'Disease', (140, 153))	('p', 'Gene', '23436', (131, 132))	('breast cancers', 'Phenotype', 'HP:0003002', (61, 75))	('breast cancers', 'Disease', 'MESH:D001943', (61, 75))	('p', 'Gene', '23436', (53, 54))	('breast cancers', 'Disease', (61, 75))
632270	29599126	Given that somatic loss of IRF-1 may be a critical event in breast oncogenesis, in 2010, Cavalli and colleagues investigated its incidence in 52 patients with invasive breast tumors.	('patients', 'Species', '9606', (145, 153))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('IRF-1', 'Gene', (27, 32))	('invasive breast tumors', 'Disease', 'MESH:D001943', (159, 181))	('breast tumors', 'Phenotype', 'HP:0100013', (168, 181))	('invasive breast tumors', 'Disease', (159, 181))	('loss', 'Var', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('breast oncogenesis', 'Disease', (60, 78))
632273	29599126	One such study revealed that 50% of gastric tumors exhibit LOH at the 5q region implying a critical contribution of IRF-1 to the development of stomach carcinoma.	('p', 'Gene', '23436', (82, 83))	('gastric tumors', 'Disease', 'MESH:D013274', (36, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('LOH', 'Var', (59, 62))	('stomach carcinoma', 'Phenotype', 'HP:0012126', (144, 161))	('stomach carcinoma', 'Disease', (144, 161))	('gastric tumors', 'Phenotype', 'HP:0006753', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('stomach carcinoma', 'Disease', 'MESH:D013274', (144, 161))	('p', 'Gene', '23436', (135, 136))	('gastric tumors', 'Disease', (36, 50))
632277	29599126	Sequencing of the IRF-1 gene in gastric adenocarcinoma tissues confirmed LOH at this locus, and led to the identification of a loss-of-function point mutation resulting in a methionine-to-leucine substitution at codon 8.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (32, 54))	('IRF-1', 'Gene', (18, 23))	('loss-of-function', 'NegReg', (127, 143))	('gastric adenocarcinoma', 'Disease', (32, 54))	('methionine-to-leucine substitution at codon 8', 'Mutation', 'rs121912469', (174, 219))	('p', 'Gene', '23436', (144, 145))	('methionine-to-leucine', 'Var', (174, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
632278	29599126	This mutation attenuates the transcriptional activity of IRF-1 and consequently, its tumor-suppressing capability is lost.	('tumor', 'Disease', (85, 90))	('p', 'Gene', '23436', (105, 106))	('attenuates', 'NegReg', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('p', 'Gene', '23436', (93, 94))	('IRF-1', 'Gene', (57, 62))	('lost', 'NegReg', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p', 'Gene', '23436', (94, 95))	('mutation', 'Var', (5, 13))	('p', 'Gene', '23436', (37, 38))
632279	29599126	Although it is not clear how this mutation brings about this effect, it has been proposed that it may enhance the interaction of IRF-1 with other factors, impairing the function of this protein as a regulator of transcription.	('p', 'Gene', '23436', (81, 82))	('enhance', 'PosReg', (102, 109))	('p', 'Gene', '23436', (157, 158))	('mutation', 'Var', (34, 42))	('IRF-1', 'Gene', (129, 134))	('interaction', 'Interaction', (114, 125))	('p', 'Gene', '23436', (220, 221))	('p', 'Gene', '23436', (186, 187))	('function', 'MPA', (169, 177))	('p', 'Gene', '23436', (84, 85))
632287	29599126	Recently, it has also been reported that high IRF-1 expression in hepatocellular carcinoma (HCC) is associated with better outcome in terms of frequency of recurrence following surgical resection.	('HCC', 'Gene', (92, 95))	('p', 'Gene', '23436', (54, 55))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('IRF-1', 'Gene', (46, 51))	('HCC', 'Gene', '619501', (92, 95))	('hepatocellular carcinoma', 'Disease', (66, 90))	('p', 'Gene', '23436', (68, 69))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('high', 'Var', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('HCC', 'Phenotype', 'HP:0001402', (92, 95))	('p', 'Gene', '23436', (29, 30))
632294	29599126	Kuroboshi and colleagues have expressed doubt concerning the nature of altered IRF-1 expression in uterine endometrial carcinoma compared with pre- and postmenopausal endometrial tissue, suggesting that the modified levels of this protein could be either an outcome or a cause of the development of this malignancy.	('p', 'Gene', '23436', (132, 133))	('p', 'Gene', '23436', (152, 153))	('p', 'Gene', '23436', (32, 33))	('levels', 'MPA', (216, 222))	('p', 'Gene', '23436', (290, 291))	('p', 'Gene', '23436', (160, 161))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (107, 128))	('p', 'Gene', '23436', (143, 144))	('p', 'Gene', '23436', (87, 88))	('endometrial carcinoma', 'Disease', (107, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (107, 128))	('malignancy', 'Disease', 'MESH:D009369', (304, 314))	('IRF-1', 'Gene', (79, 84))	('malignancy', 'Disease', (304, 314))	('p', 'Gene', '23436', (231, 232))	('modified', 'Var', (207, 215))
632299	29599126	Alterations in the IRF-1 gene have been reported in both hematologic malignancies and solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (86, 98))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('hematologic malignancies', 'Disease', 'MESH:D019337', (57, 81))	('IRF-1', 'Gene', (19, 24))	('solid tumors', 'Disease', (86, 98))	('p', 'Gene', '23436', (42, 43))	('hematologic malignancies', 'Disease', (57, 81))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
632300	29599126	For instance, inactivating rearrangements or deletions in IRF-1 have been reported in AML, and LOH of this gene has been observed in gastric and esopharyngeal cancers and renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (171, 191))	('AML', 'Phenotype', 'HP:0004808', (86, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('AML', 'Disease', (86, 89))	('LOH', 'NegReg', (95, 98))	('inactivating rearrangements', 'Var', (14, 41))	('gastric and esopharyngeal cancers', 'Disease', 'MESH:D013274', (133, 166))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('deletions', 'Var', (45, 54))	('AML', 'Disease', 'MESH:D015470', (86, 89))	('renal cell carcinoma', 'Disease', (171, 191))	('p', 'Gene', '23436', (76, 77))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (171, 191))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('IRF-1', 'Gene', (58, 63))	('p', 'Gene', '23436', (148, 149))	('observed', 'Reg', (121, 129))
632301	29599126	In addition, a missense mutation in exon 2 of IRF-1 has been identified in stomach cancer.	('IRF-1', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('stomach cancer', 'Disease', 'MESH:D013274', (75, 89))	('stomach cancer', 'Phenotype', 'HP:0012126', (75, 89))	('identified', 'Reg', (61, 71))	('stomach cancer', 'Disease', (75, 89))	('missense mutation in', 'Var', (15, 35))
632303	29599126	We previously mentioned in this review that genetic alterations in IRF-1 have also been documented in breast cancer.	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('p', 'Gene', '23436', (3, 4))	('documented', 'Reg', (88, 98))	('genetic alterations', 'Var', (44, 63))	('IRF-1', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
632306	29599126	These variants are highly expressed in cervical cancer tissue and associated with attenuated IRF-1 transcriptional activity.	('attenuated', 'NegReg', (82, 92))	('IRF-1', 'Gene', (93, 98))	('variants', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cervical cancer', 'Disease', (39, 54))	('cervical cancer', 'Disease', 'MESH:D002583', (39, 54))	('p', 'Gene', '23436', (28, 29))	('p', 'Gene', '23436', (107, 108))
632309	29599126	Skipping of exon 2 in mutant IRF-1 is associated with an absent DBD and loss of the tumor-suppressing action of the encoded protein.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('loss', 'NegReg', (72, 76))	('p', 'Gene', '23436', (92, 93))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('p', 'Gene', '23436', (3, 4))	('DBD', 'Chemical', '-', (64, 67))	('IRF-1', 'Gene', (29, 34))	('p', 'Gene', '23436', (4, 5))	('tumor', 'Disease', (84, 89))	('DBD', 'CPA', (64, 67))	('p', 'Gene', '23436', (93, 94))	('mutant', 'Var', (22, 28))	('absent', 'NegReg', (57, 63))	('p', 'Gene', '23436', (124, 125))
632310	29599126	Moreover, faulty IRF-1 mRNA can result from accelerated exon skipping, with affected transcripts lacking a translation initiation site.	('faulty', 'Var', (10, 16))	('accelerated', 'PosReg', (44, 55))	('p', 'Gene', '23436', (64, 65))	('mRNA', 'MPA', (23, 27))	('p', 'Gene', '23436', (93, 94))	('p', 'Gene', '23436', (65, 66))	('IRF-1', 'Gene', (17, 22))
632313	29599126	SUMOylation of IRF-1 stabilizes this protein and protects it from degradation, but also leads to loss of its transcriptional activity, inhibiting IRF-1-mediated apoptosis and tumor-suppressing activity; therefore, levels of IRF-1 SUMOylation are increased in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('levels', 'MPA', (214, 220))	('IRF-1', 'Gene', (15, 20))	('p', 'Gene', '23436', (184, 185))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('p', 'Gene', '23436', (49, 50))	('SUMOylation', 'MPA', (230, 241))	('p', 'Gene', '23436', (183, 184))	('degradation', 'MPA', (66, 77))	('tumor', 'Disease', (175, 180))	('loss', 'NegReg', (97, 101))	('p', 'Gene', '23436', (117, 118))	('inhibiting', 'NegReg', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('p', 'Gene', '23436', (37, 38))	('SUMOylation', 'Var', (0, 11))	('p', 'Gene', '23436', (164, 165))	('increased', 'PosReg', (246, 255))	('tumor', 'Disease', (259, 264))	('p', 'Gene', '23436', (162, 163))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
632314	29599126	Indeed, SUMO-IRF-1 induces transformation of NIH 3T3 cells in a dose-dependent manner, implying that following SUMOylation, IRF-1 loses its antioncogenic activity and mimics the oncogenic factor IRF-2.	('p', 'Gene', '23436', (71, 72))	('IRF-1', 'Gene', (124, 129))	('p', 'Gene', '23436', (89, 90))	('SUMOylation', 'Var', (111, 122))	('antioncogenic activity', 'CPA', (140, 162))	('loses', 'NegReg', (130, 135))	('NIH 3T3', 'CellLine', 'CVCL:0594', (45, 52))
632332	29599126	That IRF-1 is a potential target for new therapies has been highlighted by correlations between its inactivation and several types of human cancers.	('p', 'Gene', '23436', (46, 47))	('p', 'Gene', '23436', (16, 17))	('human', 'Species', '9606', (134, 139))	('inactivation', 'Var', (100, 112))	('p', 'Gene', '23436', (127, 128))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('IRF-1', 'Gene', (5, 10))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
632341	29599126	A recent study has implicated the inactivation of type I interferon receptor chain (IFNAR1) in colorectal cancer (CRC) development and patients' overall poor prognosis.	('interferon receptor', 'Gene', (57, 76))	('patients', 'Species', '9606', (135, 143))	('colorectal cancer', 'Disease', (95, 112))	('inactivation', 'Var', (34, 46))	('IFNAR1', 'Gene', (84, 90))	('p', 'Gene', '23436', (21, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('p', 'Gene', '23436', (158, 159))	('interferon receptor', 'Gene', '3455', (57, 76))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('IFNAR1', 'Gene', '3454', (84, 90))	('p', 'Gene', '23436', (52, 53))	('p', 'Gene', '23436', (72, 73))	('p', 'Gene', '23436', (125, 126))	('p', 'Gene', '23436', (135, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('p', 'Gene', '23436', (153, 154))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
632342	29599126	Authors have reported that genetic or pharmacological stabilization of IFNAR1 can improve CRC patients' response to chimeric antigen receptor treatment and inhibition of programmed cell death protein 1 (PD-1), which, in turn increases the efficacy of tumor immunotherapy by augmenting the activity and the number of cytotoxic T cells in the tumor niche.	('tumor', 'Disease', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('IFNAR1', 'Gene', (71, 77))	('PD-1', 'Gene', (203, 207))	('increases', 'PosReg', (225, 234))	('PD-1', 'Gene', '5133', (203, 207))	('IFNAR1', 'Gene', '3454', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('efficacy', 'CPA', (239, 247))	('CRC', 'Disease', (90, 93))	('activity', 'CPA', (289, 297))	('patients', 'Species', '9606', (94, 102))	('p', 'Gene', '23436', (137, 138))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('p', 'Gene', '23436', (192, 193))	('augmenting', 'PosReg', (274, 284))	('p', 'Gene', '23436', (15, 16))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('inhibition', 'NegReg', (156, 166))	('programmed cell death protein 1', 'Gene', (170, 201))	('genetic', 'Var', (27, 34))	('tumor', 'Disease', (341, 346))	('p', 'Gene', '23436', (38, 39))	('p', 'Gene', '23436', (268, 269))	('p', 'Gene', '23436', (94, 95))	('p', 'Gene', '23436', (84, 85))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	('p', 'Gene', '23436', (107, 108))	('p', 'Gene', '23436', (170, 171))	('programmed cell death protein 1', 'Gene', '5133', (170, 201))
632349	29599126	Concerning DNA, LOH along with monosomy and mutation play a major role in limiting the functionality of IRF-1, ultimately resulting in oncogenesis.	('mutation', 'Var', (44, 52))	('resulting in', 'Reg', (122, 134))	('IRF-1', 'Gene', (104, 109))	('oncogenesis', 'CPA', (135, 146))	('limiting', 'NegReg', (74, 82))	('p', 'Gene', '23436', (53, 54))	('functionality', 'MPA', (87, 100))
632416	28417001	The incidence of anastomotic leak, anastomotic stenosis and recurrent laryngeal nerve injury was significantly higher in the McKeown MIE group than that in the Ivor Lewis MIE group.	('anastomotic leak', 'Disease', 'MESH:D057868', (17, 33))	('laryngeal nerve injury', 'Disease', 'MESH:D061224', (70, 92))	('McKeown MIE', 'Var', (125, 136))	('anastomotic leak', 'Disease', (17, 33))	('anastomotic stenosis', 'Disease', (35, 55))	('anastomotic stenosis', 'Disease', 'MESH:D057868', (35, 55))	('higher', 'PosReg', (111, 117))	('MIE', 'Chemical', '-', (133, 136))	('laryngeal nerve injury', 'Disease', (70, 92))	('MIE', 'Chemical', '-', (171, 174))
632418	28417001	Lymph nodes harvested were significantly more in the MIE-McKeown group than in Ivor Lewis MIE group (P < 0.05).	('Lymph nodes harvested', 'CPA', (0, 21))	('MIE', 'Chemical', '-', (90, 93))	('MIE-McKeown', 'Var', (53, 64))	('more', 'PosReg', (41, 45))	('MIE', 'Chemical', '-', (53, 56))
321137	28417001	The potential benefits of McKeown MIE are a more proximal resection margin and improved lymph node dissection.	('improved', 'PosReg', (79, 87))	('MIE', 'Chemical', '-', (34, 37))	('McKeown', 'Var', (26, 33))	('lymph node dissection', 'CPA', (88, 109))
632484	28417001	The mean operative time of McKeown MIE group is significant shorter than the Ivor Lewis MIE group (296.1 +- 35.9s vs. 322.8 +- 50.5s, p = 0.013, respectively).	('shorter', 'NegReg', (60, 67))	('MIE', 'Chemical', '-', (88, 91))	('MIE', 'Chemical', '-', (35, 38))	('McKeown', 'Var', (27, 34))
632485	28417001	However, the occurrence of anastomotic leak, anastomotic stenosis and RLN injury in the McKeown MIE group was significant higher than those in the Ivor Lewis MIE group.	('higher', 'PosReg', (122, 128))	('anastomotic leak', 'Disease', 'MESH:D057868', (27, 43))	('MIE', 'Chemical', '-', (96, 99))	('McKeown MIE', 'Var', (88, 99))	('anastomotic leak', 'Disease', (27, 43))	('MIE', 'Chemical', '-', (158, 161))	('anastomotic stenosis and RLN injury', 'Disease', 'MESH:D057868', (45, 80))
632492	28417001	Lymph nodes harvested were significantly more in the MIE-McKeown group than that of in Ivor Lewis MIE group (P < 0.05).	('Lymph nodes harvested', 'CPA', (0, 21))	('MIE-McKeown', 'Var', (53, 64))	('more', 'PosReg', (41, 45))	('MIE', 'Chemical', '-', (53, 56))	('MIE', 'Chemical', '-', (98, 101))
632500	28417001	In our comparison of short-term and long-term outcomes between the MIE-chest and MIE-neck groups, the mean operative time of McKeown MIE group is significant shorter than the Ivor Lewis MIE group (p = 0.013).	('shorter', 'NegReg', (158, 165))	('McKeown MIE', 'Var', (125, 136))	('MIE', 'Chemical', '-', (67, 70))	('MIE', 'Chemical', '-', (186, 189))	('MIE', 'Chemical', '-', (81, 84))	('MIE', 'Chemical', '-', (133, 136))
632508	28417001	Significantly, more lymph nodes were resected in patients who underwent McKeown MIE in the present study (P < 0.05).	('more', 'PosReg', (15, 19))	('MIE', 'Chemical', '-', (80, 83))	('patients', 'Species', '9606', (49, 57))	('lymph nodes', 'CPA', (20, 31))	('McKeown', 'Var', (72, 79))
632522	28031525	FLNC knockdown in esophageal cancer cell lines decreased cell migration in wound healing and transwell migration assays, and invasion in transwell migration assays.	('esophageal cancer', 'Disease', (18, 35))	('cell migration in wound healing', 'CPA', (57, 88))	('knockdown', 'Var', (5, 14))	('esophageal cancer', 'Disease', 'MESH:D004938', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('FLNC', 'Gene', (0, 4))	('transwell migration assays', 'CPA', (93, 119))	('invasion in transwell migration assays', 'CPA', (125, 163))	('decreased', 'NegReg', (47, 56))
632523	28031525	Furthermore, FLNC knockdown reduced the amount of activated Rac-1 (GTP-Rac1) and activated Cdc42 (GTP-Cdc42).	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (28, 35))	('GTP-Cdc42', 'Gene', (98, 107))	('Rac-1', 'Gene', (60, 65))	('Rac-1', 'Gene', '5879', (60, 65))	('Cdc42', 'Gene', '998', (91, 96))	('activated', 'PosReg', (81, 90))	('Cdc42', 'Gene', '998', (102, 107))	('GTP-Cdc42', 'Gene', '998', (98, 107))	('FLNC', 'Gene', (13, 17))	('Cdc42', 'Gene', (91, 96))	('GTP-Rac1', 'Gene', '5879', (67, 75))	('GTP-Rac1', 'Gene', (67, 75))	('Cdc42', 'Gene', (102, 107))
632546	28031525	Expression levels were measured as ratio of all patients and the percentages of the low and high FLNC expression groups were 30.7% (23/75 patients) and 69.3% (52/75 patients), respectively.	('high', 'Var', (92, 96))	('FLNC', 'Protein', (97, 101))	('patients', 'Species', '9606', (165, 173))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (138, 146))
632548	28031525	However, overall survival of patients in the high FLNC expression group was significantly shorter than the survival of patients in the low FLNC expression group (P = 0.0135) (Figure 2).	('patients', 'Species', '9606', (29, 37))	('patients', 'Species', '9606', (119, 127))	('high FLNC expression', 'Var', (45, 65))	('shorter', 'NegReg', (90, 97))
632549	28031525	These data indicate a correlation between high FLNC expression and poor prognosis in patients with ESCC.	('high', 'Var', (42, 46))	('FLNC', 'Protein', (47, 51))	('patients', 'Species', '9606', (85, 93))	('ESCC', 'Disease', (99, 103))
632552	28031525	FLNA and FLNB expression levels in FLNC shRNA infected cells were almost equivalent to those in SshRNA infected cells, indicating that FLNC shRNA specifically inhibited FLNC expression.	('FLNA', 'Gene', (0, 4))	('FLNC', 'Gene', (169, 173))	('FLNA', 'Gene', '2316', (0, 4))	('FLNC shRNA', 'Var', (135, 145))	('FLNB', 'Gene', '2317', (9, 13))	('FLNB', 'Gene', (9, 13))	('inhibited', 'NegReg', (159, 168))
632553	28031525	The MTT assay showed that the proliferative abilities of TE-1 and TE-8 FLNC knock-down cells were almost same as those of the control cells (Supplementary Figure S2).	('proliferative abilities', 'CPA', (30, 53))	('FLNC', 'Gene', (71, 75))	('knock-down', 'Var', (76, 86))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('men', 'Species', '9606', (147, 150))
632554	28031525	These data indicate that FLNC knockdown decreased the migratory and invasive abilities of cancer cells (Figure 4D).	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (90, 96))	('FLNC', 'Gene', (25, 29))	('knockdown', 'Var', (30, 39))	('decreased', 'NegReg', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
632555	28031525	To investigate how FLNC knockdown inhibits ESCC cell motility, we examined Rho GTPase activation (Figure 5).	('FLNC', 'Gene', (19, 23))	('inhibits', 'NegReg', (34, 42))	('GTP', 'Chemical', 'MESH:D006160', (79, 82))	('ESCC cell motility', 'CPA', (43, 61))	('knockdown', 'Var', (24, 33))
632556	28031525	The levels of activated Rac1 (ENSG00000136238) (GTP-Rac1) and Cdc42 (ENSG00000070831) (GTP-Cdc42) were clearly reduced in FLNC knockdown cells compared with SshRNA infected cells.	('GTP-Cdc42', 'Gene', '998', (87, 96))	('GTP-Rac1', 'Gene', '5879', (48, 56))	('Cdc42', 'Gene', (62, 67))	('GTP-Rac1', 'Gene', (48, 56))	('ENSG00000070831', 'Var', (69, 84))	('Cdc42', 'Gene', '998', (62, 67))	('Cdc42', 'Gene', '998', (91, 96))	('Rac1', 'Gene', (24, 28))	('reduced', 'NegReg', (111, 118))	('Rac1', 'Gene', '5879', (24, 28))	('Rac1', 'Gene', '5879', (52, 56))	('FLNC', 'Gene', (122, 126))	('Cdc42', 'Gene', (91, 96))	('ENSG00000136238', 'Var', (30, 45))	('GTP-Cdc42', 'Gene', (87, 96))	('Rac1', 'Gene', (52, 56))	('knockdown', 'Var', (127, 136))
632562	28031525	Moreover, in prostate, leukemia, and breast cancer, high expression of FLNC mRNA has been associated with better prognosis by 'in silico' analysis.	('breast cancer', 'Disease', (37, 50))	('leukemia', 'Disease', (23, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('FLNC', 'Gene', (71, 75))	('prostate', 'Disease', (13, 21))	('high', 'Var', (52, 56))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('leukemia', 'Phenotype', 'HP:0001909', (23, 31))	('leukemia', 'Disease', 'MESH:D007938', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
632567	28031525	Moreover, ESCC patients with high FLNC expression had poorer prognosis, consistent with the fact that lymphatic metastasis is a serious prognostic factor for ESCC.	('ESCC', 'Disease', (158, 162))	('high FLNC expression', 'Var', (29, 49))	('patients', 'Species', '9606', (15, 23))	('ESCC', 'Disease', (10, 14))
632576	28031525	Rho GTPase activation assays showed that FLNC knockdown reduced GTP-Rac1 and GTP-Cdc42 levels.	('GTP', 'Chemical', 'MESH:D006160', (64, 67))	('GTP', 'Chemical', 'MESH:D006160', (4, 7))	('GTP-Cdc42', 'Gene', (77, 86))	('knockdown', 'Var', (46, 55))	('reduced', 'NegReg', (56, 63))	('GTP-Cdc42', 'Gene', '998', (77, 86))	('FLNC', 'Gene', (41, 45))	('GTP-Rac1', 'Gene', '5879', (64, 72))	('GTP-Rac1', 'Gene', (64, 72))	('GTP', 'Chemical', 'MESH:D006160', (77, 80))
632582	28031525	Several studies indicate that Rho GTPase is associated with lymphatic metastasis.	('associated', 'Reg', (44, 54))	('lymphatic metastasis', 'CPA', (60, 80))	('GTP', 'Chemical', 'MESH:D006160', (34, 37))	('Rho', 'Var', (30, 33))
632591	28031525	Our studies show that high FLNC expression in ESCC patients is correlated with lymphatic invasion, lymphatic metastasis, and an unfavorable prognosis.	('correlated', 'Reg', (63, 73))	('ESCC', 'Disease', (46, 50))	('FLNC', 'Protein', (27, 31))	('high', 'Var', (22, 26))	('patients', 'Species', '9606', (51, 59))	('lymphatic metastasis', 'CPA', (99, 119))	('lymphatic invasion', 'CPA', (79, 97))
632592	28031525	Additionally, we demonstrate that FLNC knockdown inhibited ESCC cell migration and invasion, possibly by regulating Rho GTPase.	('GTP', 'Chemical', 'MESH:D006160', (120, 123))	('knockdown', 'Var', (39, 48))	('ESCC', 'Disease', (59, 63))	('invasion', 'CPA', (83, 91))	('FLNC', 'Gene', (34, 38))	('inhibited', 'NegReg', (49, 58))
632668	25749389	When the oligo-dT primers were used, the relative expression of linear ITCH was significantly higher than that of circular ITCH (5.8-fold in Eca-109 cells and 10-fold in TE-1 cells; Figure 1C).	('cir', 'Gene', '9541', (114, 117))	('linear', 'Var', (64, 70))	('TE-1', 'CellLine', 'CVCL:1759', (170, 174))	('ITCH', 'Phenotype', 'HP:0000989', (71, 75))	('cir', 'Gene', (114, 117))	('ITCH', 'Phenotype', 'HP:0000989', (123, 127))	('higher', 'PosReg', (94, 100))	('expression', 'MPA', (50, 60))
632672	25749389	The results of both showed that miR-216b, miR-17, miR-214, miR-7, and miR-128 could bind to the 3'-UTR of ITCH and cir-ITCH.	('miR-17', 'Gene', (42, 48))	('cir', 'Gene', (115, 118))	('cir', 'Gene', '9541', (115, 118))	('miR-7', 'Gene', '10859', (59, 64))	('miR-17', 'Gene', '406952', (42, 48))	('miR-214', 'Gene', (50, 57))	('ITCH', 'Phenotype', 'HP:0000989', (119, 123))	('-ITCH', 'Phenotype', 'HP:0000989', (118, 123))	('bind', 'Interaction', (84, 88))	('miR-216b', 'Gene', '100126319', (32, 40))	('miR-128', 'Var', (70, 77))	('miR-216b', 'Gene', (32, 40))	('miR-214', 'Gene', '406996', (50, 57))	('ITCH', 'Phenotype', 'HP:0000989', (106, 110))	('miR-7', 'Gene', (59, 64))
632702	25749389	These results illustrate the basic interaction between circular RNA, miRNA, and protein in cells, and alteration of this fine regulation may contribute to cancer initiation and progression.	('cir', 'Gene', '9541', (55, 58))	('cancer initiation', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('alteration', 'Var', (102, 112))	('interaction', 'Interaction', (35, 46))	('cir', 'Gene', (55, 58))	('cancer initiation', 'Disease', 'MESH:D009369', (155, 172))	('contribute', 'Reg', (141, 151))
632722	25749389	According to previous research, ITCH could promote the ubiquitination and degradation of phosphorylated Dvl2, and therefore, inhibit canonical Wnt signaling.	('inhibit', 'NegReg', (125, 132))	('canonical Wnt signaling', 'Pathway', (133, 156))	('promote', 'PosReg', (43, 50))	('Dvl2', 'Gene', '1856', (104, 108))	('ITCH', 'Phenotype', 'HP:0000989', (32, 36))	('degradation', 'MPA', (74, 85))	('ITCH', 'Var', (32, 36))	('ubiquitination', 'MPA', (55, 69))	('Dvl2', 'Gene', (104, 108))
632776	24859412	RPPA array demonstrated that metformin decreased various oncogenes including PI3K/mTORsignaling and survival/cancer stem cell-related genes in cells treated with metformin compared with its control.	('metformin', 'Chemical', 'MESH:D008687', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('oncogenes', 'Gene', (57, 66))	('cancer', 'Disease', (109, 115))	('metformin', 'Var', (162, 171))	('mTOR', 'Gene', (82, 86))	('mTOR', 'Gene', '2475', (82, 86))	('decreased', 'NegReg', (39, 48))	('metformin', 'Chemical', 'MESH:D008687', (162, 171))
632777	24859412	Immunoblots and transcriptional analyses further confirm that metformin downregulated these CSC-related genes and the components of the mTOR pathway in a dose-dependent manner.	('metformin', 'Var', (62, 71))	('CSC-related', 'Disease', (92, 103))	('mTOR', 'Gene', '2475', (136, 140))	('metformin', 'Chemical', 'MESH:D008687', (62, 71))	('mTOR', 'Gene', (136, 140))	('downregulated', 'NegReg', (72, 85))
632790	24859412	Loss of LKB1 is known to confer aggressive phenotype to some esophageal cancer cells.	('LKB1', 'Gene', '6794', (8, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('LKB1', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('esophageal cancer', 'Disease', (61, 78))	('Loss', 'Var', (0, 4))
632821	24859412	However, synergistic inhibition of cell proliferation was noted in all these cell lines when metformin in combination with 5-FU indicating metformin sensitize 5-FU on inhibition of EC cell growth (Fig.	('metformin', 'Chemical', 'MESH:D008687', (139, 148))	('EC cell growth', 'CPA', (181, 195))	('inhibition', 'NegReg', (167, 177))	('cell proliferation', 'CPA', (35, 53))	('metformin', 'Var', (139, 148))	('5-FU', 'Chemical', 'MESH:D005472', (159, 163))	('metformin', 'Chemical', 'MESH:D008687', (93, 102))	('5-FU', 'Chemical', 'MESH:D005472', (123, 127))
632844	24859412	6B, the most reduced ones are proteins in the PI3K/mTOR signaling including phospho-S6-p-235 and phospho-S6p-240 and AKT and genes (beta-catenin and C-MYC) in stem cell signaling.	('mTOR', 'Gene', (51, 55))	('AKT', 'Gene', '207', (117, 120))	('phospho-S6-p-235', 'Var', (76, 92))	('mTOR', 'Gene', '2475', (51, 55))	('phospho-S6p-240', 'Var', (97, 112))	('beta-catenin', 'Gene', (132, 144))	('AKT', 'Gene', (117, 120))	('C-MYC', 'Gene', '4609', (149, 154))	('beta-catenin', 'Gene', '1499', (132, 144))	('reduced', 'NegReg', (13, 20))	('C-MYC', 'Gene', (149, 154))
632846	24859412	6C, metformin alone strongly decreased the expression of stem cell signaling markers (Jagged1, Shh, YAP1) and mTOR pathway components-phospho-AKT, phosphor-S6, phosphor-70S6 in a dose-dependent manner.	('mTOR', 'Gene', (110, 114))	('phosphor-70S6', 'Var', (160, 173))	('mTOR', 'Gene', '2475', (110, 114))	('YAP1', 'Gene', (100, 104))	('YAP1', 'Gene', '10413', (100, 104))	('AKT', 'Gene', '207', (142, 145))	('Shh', 'Gene', (95, 98))	('AKT', 'Gene', (142, 145))	('Jagged1', 'Gene', '182', (86, 93))	('phosphor-S6', 'Var', (147, 158))	('metformin', 'Chemical', 'MESH:D008687', (4, 13))	('decreased', 'NegReg', (29, 38))	('Shh', 'Gene', '6469', (95, 98))	('expression', 'MPA', (43, 53))	('Jagged1', 'Gene', (86, 93))
632851	24859412	It has been implicated that metformin, commonly used as an oral anti-hyperglycemic agent, may reduce cancer risk and have antitumor effects in many types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('metformin', 'Var', (28, 37))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (157, 163))	('metformin', 'Chemical', 'MESH:D008687', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('reduce', 'NegReg', (94, 100))	('tumor', 'Disease', (126, 131))
632854	24859412	In this study, we demonstrated that metformin inhibit cell growth in both ESCC and EAC cells and sensitize 5-FU cytotoxic effects by targeting CSCs and mTOR signal pathways.	('targeting', 'Reg', (133, 142))	('inhibit', 'NegReg', (46, 53))	('mTOR', 'Gene', (152, 156))	('metformin', 'Var', (36, 45))	('metformin', 'Chemical', 'MESH:D008687', (36, 45))	('mTOR', 'Gene', '2475', (152, 156))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('CSCs', 'Pathway', (143, 147))	('cell growth', 'CPA', (54, 65))	('5-FU', 'Chemical', 'MESH:D005472', (107, 111))	('EAC', 'Phenotype', 'HP:0011459', (83, 86))	('5-FU cytotoxic effects', 'MPA', (107, 129))	('sensitize', 'NegReg', (97, 106))
632857	24859412	Most importantly metformin sensitizes the cytotoxic agent (5-FU) on both types of EC cells and inhibits the growth of EC cells in vitro and in a xenograft nude mouse model.	('5-FU', 'Chemical', 'MESH:D005472', (59, 63))	('metformin', 'Var', (17, 26))	('growth', 'CPA', (108, 114))	('metformin', 'Chemical', 'MESH:D008687', (17, 26))	('inhibits', 'NegReg', (95, 103))	('mouse', 'Species', '10090', (160, 165))
632863	24859412	Amplification or mutations in the RTK-PI3K-mTOR pathway have been identified by whole genomic sequencing, whole exome sequencing and high-density genomic profiling arrays in EC tumors.	('Amplification', 'Var', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('EC tumors', 'Disease', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))	('EC tumors', 'Disease', 'MESH:D009369', (174, 183))	('mutations', 'Var', (17, 26))
632864	24859412	Mutations were discovered in 23% of EC tumor, with PIK3CA/mTOR being the most frequently mutated.	('mTOR', 'Gene', (58, 62))	('EC tumor', 'Disease', 'MESH:D009369', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PIK3CA', 'Gene', (51, 57))	('Mutations', 'Var', (0, 9))	('EC tumor', 'Disease', (36, 44))	('PIK3CA', 'Gene', '5290', (51, 57))	('mTOR', 'Gene', '2475', (58, 62))
632868	24859412	Taken together, metformin suppresses EC cell growth in vitro and in vivo due to its ability to reduce the CSCs population as well as causing inhibition of the mTOR pathway in bulk tumor cells.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('metformin', 'Var', (16, 25))	('inhibition', 'NegReg', (141, 151))	('metformin', 'Chemical', 'MESH:D008687', (16, 25))	('reduce', 'NegReg', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mTOR', 'Gene', (159, 163))	('suppresses', 'NegReg', (26, 36))	('tumor', 'Disease', (180, 185))	('mTOR', 'Gene', '2475', (159, 163))	('CSCs population', 'MPA', (106, 121))	('EC cell growth', 'CPA', (37, 51))
632870	24859412	In conclusion, our non-clinical results are supportive of our prior retrospective observations in the clinic that patients who were taking metformin (for diabetes) had better therapy outcome than those who were not taking metformin, and we find metformin inhibited the EAC cell growth and increased the sensitivity to 5-FU cytotoxic effects by targeting the genes of CSCs and mTOR signal pathways.	('metformin', 'Chemical', 'MESH:D008687', (139, 148))	('diabetes', 'Disease', (154, 162))	('metformin', 'Chemical', 'MESH:D008687', (245, 254))	('EAC cell growth', 'CPA', (269, 284))	('metformin', 'Chemical', 'MESH:D008687', (222, 231))	('mTOR', 'Gene', '2475', (376, 380))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('increased', 'PosReg', (289, 298))	('CSCs', 'Pathway', (367, 371))	('mTOR', 'Gene', (376, 380))	('sensitivity', 'MPA', (303, 314))	('EAC', 'Phenotype', 'HP:0011459', (269, 272))	('inhibited', 'NegReg', (255, 264))	('metformin', 'Var', (245, 254))	('patients', 'Species', '9606', (114, 122))	('targeting', 'Reg', (344, 353))	('5-FU', 'Chemical', 'MESH:D005472', (318, 322))
632876	21936950	SPHK1 was overexpressed in the EC9706-P4 subline with high invasive capacity.	('EC9706', 'CellLine', 'CVCL:E307', (31, 37))	('overexpressed', 'PosReg', (10, 23))	('SPHK1', 'Gene', (0, 5))	('EC9706-P4', 'Var', (31, 40))
632881	21936950	SPHK1 overexpression significantly increased the invasiveness of EC9706 cells in vitro and also increased EC9706 cell growth and spontaneous metastasis in vivo, promoting significant increases in tumor growth, tumor burden and spontaneous lung metastasis in nude mice.	('increased', 'PosReg', (96, 105))	('increased', 'PosReg', (35, 44))	('SPHK1', 'Gene', (0, 5))	('tumor', 'Disease', (196, 201))	('spontaneous metastasis', 'CPA', (129, 151))	('EC9706', 'CellLine', 'CVCL:E307', (106, 112))	('overexpression', 'Var', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('increases', 'PosReg', (183, 192))	('EC9706', 'CellLine', 'CVCL:E307', (65, 71))	('spontaneous lung metastasis', 'CPA', (227, 254))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('nude mice', 'Species', '10090', (258, 267))	('EC9706', 'Var', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('invasiveness', 'CPA', (49, 61))
632904	21936950	Overexpression of SPHK1 facilitates anchorage-independent growth in vitro and leads to tumor formation in SCID mice.	('leads to', 'Reg', (78, 86))	('anchorage-independent growth', 'CPA', (36, 64))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('facilitates', 'PosReg', (24, 35))	('SCID', 'Disease', 'MESH:D053632', (106, 110))	('SCID', 'Disease', (106, 110))	('tumor', 'Disease', (87, 92))	('SPHK1', 'Gene', (18, 23))	('mice', 'Species', '10090', (111, 115))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
632914	21936950	Such selection rounds for highly invasive cells were repeated four times, resulting in a subline from each generation designated as EC9706-P1, EC9706-P2, EC9706-P3 and EC9706-P4.	('EC9706', 'CellLine', 'CVCL:E307', (154, 160))	('EC9706-P4', 'Var', (168, 177))	('EC9706', 'CellLine', 'CVCL:E307', (143, 149))	('EC9706', 'CellLine', 'CVCL:E307', (168, 174))	('EC9706-P2', 'Var', (143, 152))	('EC9706-P3', 'Var', (154, 163))	('EC9706', 'CellLine', 'CVCL:E307', (132, 138))	('EC9706-P1', 'Var', (132, 141))
632938	21936950	Blots were blocked and then probed with antibodies against the tag of SPHK1 protein c-myc (9E10 1:3000, Sigma, St. Louis, MO) or directlly against the SPHK1 protein (1 mug/ml, ab16491, Abcam), beta-actin (1:5000, Sigma, St. Louis, MO), phospho-EGFR (Y1068,1:1000, Invitrogen), EGFR(1:1000, Invitrogen).	('EGFR', 'Gene', '1956', (244, 248))	('beta-actin', 'Gene', (193, 203))	('EGFR', 'Gene', (244, 248))	('beta-actin', 'Gene', '728378', (193, 203))	('EGFR', 'Gene', '1956', (277, 281))	('SPHK1', 'Gene', (151, 156))	('c-myc', 'Gene', '4609', (84, 89))	('c-myc', 'Gene', (84, 89))	('EGFR', 'Gene', (277, 281))	('protein', 'Protein', (157, 164))	('Y1068,1:1000', 'Var', (250, 262))
632951	21936950	The gene expression profiles of EC9706 and EC9706-P4 were then analyzed by microarrays.	('EC9706', 'Var', (32, 38))	('EC9706', 'CellLine', 'CVCL:E307', (32, 38))	('EC9706-P4', 'Var', (43, 52))	('EC9706', 'CellLine', 'CVCL:E307', (43, 49))
632952	21936950	Between these cell lines, 124 genes were differentially expressed, including 71 upregulated genes and 53 downregulated genes in EC9706-P4 relative to EC9706 (cutoff, fold >= 2.0, Additional file 1).	('EC9706', 'CellLine', 'CVCL:E307', (150, 156))	('EC9706-P4', 'Var', (128, 137))	('upregulated', 'PosReg', (80, 91))	('EC9706', 'CellLine', 'CVCL:E307', (128, 134))	('downregulated', 'NegReg', (105, 118))
632956	21936950	SPHK1 expression was analyzed by RT-PCR and immunofluorecence in esophageal carcinoma cell lines, including KYSE30, KYSE150, KYSE510, KYSE2, EC9706, and NEC cells (Figure 2A).	('SPHK1', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('KYSE510', 'Var', (125, 132))	('esophageal carcinoma', 'Disease', (65, 85))	('EC9706', 'CellLine', 'CVCL:E307', (141, 147))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (65, 85))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (65, 85))	('KYSE30', 'Var', (108, 114))	('KYSE150', 'Var', (116, 123))
632969	21936950	In the 3D Matrigel culture assays, SPHK1 overexpression significantly increased the diameter and the invasive morphology (Figure 4C) as well as the proliferation (Figure 4D, F) of the EC9706 cell clones, but did not influence their apoptosis levels in an Annexin V assay (Figure 4E, F).	('EC9706', 'Var', (184, 190))	('overexpression', 'Var', (41, 55))	('proliferation', 'CPA', (148, 161))	('increased', 'PosReg', (70, 79))	('Annexin V', 'Gene', '308', (255, 264))	('Annexin V', 'Gene', (255, 264))	('EC9706', 'CellLine', 'CVCL:E307', (184, 190))	('invasive morphology', 'CPA', (101, 120))	('SPHK1', 'Gene', (35, 40))	('diameter', 'CPA', (84, 92))
632970	21936950	We also examined whether SPHK1 could increase EC9706 cell growth and spontaneous metastasis in nude mice.	('EC9706', 'Var', (46, 52))	('nude mice', 'Species', '10090', (95, 104))	('SPHK1', 'Gene', (25, 30))	('increase', 'PosReg', (37, 45))	('spontaneous metastasis', 'CPA', (69, 91))	('EC9706', 'CellLine', 'CVCL:E307', (46, 52))
632976	21936950	Western blot analysis indicated that the expression of SPHK1 significantly correlated with the phosphorylation of EGFR, while knockdown of SPHK1 by RNAi decreased EGFR phosphorylation in EC9706-P4 and KYSE2 cells (Figure 6A, B).	('phosphorylation', 'MPA', (168, 183))	('EGFR', 'Gene', '1956', (163, 167))	('EGFR', 'Gene', '1956', (114, 118))	('correlated', 'Reg', (75, 85))	('decreased', 'NegReg', (153, 162))	('EGFR', 'Gene', (163, 167))	('EC9706', 'CellLine', 'CVCL:E307', (187, 193))	('SPHK1', 'Gene', (55, 60))	('EGFR', 'Gene', (114, 118))	('knockdown', 'Var', (126, 135))	('phosphorylation', 'MPA', (95, 110))	('SPHK1', 'Gene', (139, 144))
632984	21936950	Although EC9706, an esophageal squamous carcinoma cell line, can invade and form spontaneous lung metastasis nodules in nu/nu mice, its metastatic potential is relatively low.	('esophageal squamous carcinoma', 'Disease', (20, 49))	('mice', 'Species', '10090', (126, 130))	('EC9706', 'Var', (9, 15))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (20, 49))	('invade', 'CPA', (65, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('EC9706', 'CellLine', 'CVCL:E307', (9, 15))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (31, 49))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (20, 49))
632985	21936950	The metastatic ability of EC9706 may arise from a few subclones with high metastatic potential among the parental cells.	('metastatic ability', 'CPA', (4, 22))	('EC9706', 'Var', (26, 32))	('EC9706', 'CellLine', 'CVCL:E307', (26, 32))
632991	21936950	Deletion of the SPHK1 gene in these mice resulted in reduction of adenoma size.	('reduction of adenoma', 'Disease', 'MESH:D000236', (53, 73))	('reduction of adenoma', 'Disease', (53, 73))	('mice', 'Species', '10090', (36, 40))	('SPHK1', 'Gene', (16, 21))	('Deletion', 'Var', (0, 8))
632996	21936950	Interestingly, neutralizing S1P, the product of SPHK1 enzymatic activity, with a specific monoclonal antibody was remarkably effective in slowing progression of cancers, such as lung, colon, breast, melanoma and ovarian cancers in murine xenograft and allograft models.	('neutralizing', 'Var', (15, 27))	('murine', 'Species', '10090', (231, 237))	('lung', 'Disease', (178, 182))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('S1P', 'Gene', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('colon', 'Disease', (184, 189))	('slowing', 'NegReg', (138, 145))	('SPHK1', 'Gene', (48, 53))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancers', 'Disease', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('ovarian cancers', 'Phenotype', 'HP:0100615', (212, 227))	('breast', 'Disease', (191, 197))	('S1P', 'Gene', '13609', (28, 31))	('melanoma and ovarian cancers', 'Disease', 'MESH:D010051', (199, 227))
632997	21936950	A critical question raised by these observations is how neutralization of this simple lysophospholipid can have such dramatic effects on tumor progression.	('tumor', 'Disease', (137, 142))	('effects', 'Reg', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('neutralization', 'Var', (56, 70))	('lysophospholipid', 'Chemical', 'MESH:D008246', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
633013	21936950	In breast cancer, Sukocheva, O et al demonstrated that E2-induced EGFR transactivation in human breast cancer cells is driven via a novel signaling system controlled by the lipid kinase sphingosine kinase-1 (SphK1).	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('human', 'Species', '9606', (90, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer', 'Disease', (96, 109))	('E2-induced', 'Var', (55, 65))	('sphingosine kinase-1', 'Gene', (186, 206))	('SphK1', 'Gene', '8877', (208, 213))	('sphingosine kinase-1', 'Gene', '8877', (186, 206))	('SphK1', 'Gene', (208, 213))	('transactivation', 'PosReg', (71, 86))
633021	21936950	Thus, modulating SPHK1 expression or activity is an attractive additional therapeutic strategy for treatment of esophageal cancer and perhaps other cancers as well.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('perhaps other cancers', 'Disease', (134, 155))	('SPHK1', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('activity', 'MPA', (37, 45))	('esophageal cancer', 'Disease', (112, 129))	('perhaps other cancers', 'Disease', 'MESH:D009369', (134, 155))	('modulating', 'Var', (6, 16))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))	('expression', 'MPA', (23, 33))
633027	19936245	A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations Telomerase is an enzyme specialized in maintaining telomere lengths in highly proliferative cells.	('Familial Liver Disorders', 'Disease', 'MESH:D008107', (21, 45))	('Associate', 'Reg', (46, 55))	('Telomerase', 'Gene', (61, 71))	('Familial Liver Disorders', 'Disease', (21, 45))	('Liver Disorders', 'Phenotype', 'HP:0001392', (30, 45))	('Mutations', 'Var', (72, 81))
633028	19936245	Loss-of-function mutations cause critical telomere shortening and are associated with the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia and with idiopathic pulmonary fibrosis.	('Loss-of-function', 'NegReg', (0, 16))	('bone marrow failure syndromes dyskeratosis congenita', 'Disease', 'MESH:D000080983', (90, 142))	('aplastic anemia', 'Disease', 'MESH:D000741', (147, 162))	('marrow failure', 'Phenotype', 'HP:0005528', (95, 109))	('idiopathic pulmonary fibrosis', 'Disease', (172, 201))	('aplastic anemia', 'Phenotype', 'HP:0001915', (147, 162))	('bone marrow failure', 'Phenotype', 'HP:0005528', (90, 109))	('telomere shortening', 'Phenotype', 'HP:0031413', (42, 61))	('critical telomere shortening', 'MPA', (33, 61))	('aplastic anemia', 'Disease', (147, 162))	('anemia', 'Phenotype', 'HP:0001903', (156, 162))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (172, 201))	('mutations', 'Var', (17, 26))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (183, 201))
633029	19936245	Here, we sought to determine the spectrum of clinical manifestations associated with telomerase loss-of-function mutations.	('loss-of-function', 'NegReg', (96, 112))	('man', 'Species', '9606', (54, 57))	('mutations', 'Var', (113, 122))	('telomerase', 'Protein', (85, 95))
633030	19936245	Sixty-nine individuals from five unrelated families with a variety of hematologic, hepatic, and autoimmune disorders were screened for telomerase complex gene mutations; leukocyte telomere length was measured by flow fluorescence in situ hybridization in mutation carriers and some non-carriers; the effects of the identified mutations on telomerase activity were determined; and genetic and clinical data were correlated.	('autoimmune disorders', 'Disease', (96, 116))	('mutations', 'Var', (159, 168))	('autoimmune disorders', 'Disease', 'MESH:D001327', (96, 116))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (96, 116))
633031	19936245	In six generations of a large family, a loss-of-function mutation in the telomerase enzyme gene TERT associated with severe telomere shortening and a range of hematologic manifestations, from macrocytosis to acute myeloid leukemia, with severe liver diseases marked by fibrosis and inflammation, and one case of idiopathic pulmonary fibrosis but not with autoimmune disorders.	('liver disease', 'Phenotype', 'HP:0001392', (244, 257))	('liver diseases', 'Disease', 'MESH:D008107', (244, 258))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (208, 230))	('leukemia', 'Phenotype', 'HP:0001909', (222, 230))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (214, 230))	('inflammation', 'Disease', 'MESH:D007249', (282, 294))	('liver diseases', 'Disease', (244, 258))	('autoimmune disorders', 'Disease', (355, 375))	('telomere shortening', 'Phenotype', 'HP:0031413', (124, 143))	('loss-of-function', 'NegReg', (40, 56))	('mutation', 'Var', (57, 65))	('inflammation', 'Disease', (282, 294))	('macrocytosis to acute myeloid leukemia', 'Disease', (192, 230))	('TERT', 'Gene', (96, 100))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (312, 341))	('TERT', 'Gene', '7015', (96, 100))	('idiopathic pulmonary fibrosis', 'Disease', (312, 341))	('telomere', 'MPA', (124, 132))	('autoimmune disorders', 'Disease', 'MESH:D001327', (355, 375))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (355, 375))	('fibrosis', 'Disease', (333, 341))	('fibrosis', 'Disease', 'MESH:D005355', (333, 341))	('macrocytosis to acute myeloid leukemia', 'Disease', 'MESH:D015470', (192, 230))	('man', 'Species', '9606', (171, 174))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (323, 341))	('fibrosis', 'Disease', (269, 277))	('liver diseases', 'Phenotype', 'HP:0001392', (244, 258))	('fibrosis', 'Disease', 'MESH:D005355', (269, 277))
633032	19936245	Additionally, we identified four unrelated families in which loss-of-function TERC or TERT gene mutations tracked with marrow failure, pulmonary fibrosis, and a spectrum of liver disorders.	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (135, 153))	('liver disorders', 'Phenotype', 'HP:0001392', (173, 188))	('TERC', 'Gene', (78, 82))	('pulmonary fibrosis', 'Disease', (135, 153))	('marrow failure', 'Phenotype', 'HP:0005528', (119, 133))	('marrow failure', 'Disease', 'MESH:D000080983', (119, 133))	('TERC', 'Gene', '7012', (78, 82))	('liver disorders', 'Disease', 'MESH:D008107', (173, 188))	('TERT', 'Gene', (86, 90))	('marrow failure', 'Disease', (119, 133))	('mutations', 'Var', (96, 105))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (135, 153))	('TERT', 'Gene', '7015', (86, 90))	('loss-of-function', 'NegReg', (61, 77))	('liver disorders', 'Disease', (173, 188))
633033	19936245	These results indicate that heterozygous telomerase loss-of-function mutations associate with but are not determinant of a large spectrum of hematologic and liver abnormalities, with the latter sometimes occurring in the absence of marrow failure.	('mutations', 'Var', (69, 78))	('marrow failure', 'Disease', 'MESH:D000080983', (232, 246))	('marrow failure', 'Phenotype', 'HP:0005528', (232, 246))	('telomerase', 'Protein', (41, 51))	('loss-of-function', 'NegReg', (52, 68))	('marrow failure', 'Disease', (232, 246))	('liver abnormalities', 'Phenotype', 'HP:0001392', (157, 176))	('liver abnormalities', 'Disease', (157, 176))	('liver abnormalities', 'Disease', 'MESH:D056486', (157, 176))	('hematologic and liver abnormalities', 'Phenotype', 'HP:0001871', (141, 176))
633034	19936245	Our findings, along with the link between pulmonary fibrosis and telomerase mutations, also suggest a common pathogenic mechanism for fibrotic diseases in which defective telomere repair plays important role.	('pulmonary fibrosis', 'Disease', (42, 60))	('fibrotic diseases', 'Disease', 'MESH:D004194', (134, 151))	('defective', 'Var', (161, 170))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (42, 60))	('fibrotic diseases', 'Disease', (134, 151))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (42, 60))
633035	19936245	Progressive telomere shortening signals proliferation arrest and cellular senescence via p53, p21, and PMS2.	('telomere shortening', 'Phenotype', 'HP:0031413', (12, 31))	('Progressive telomere shortening', 'Phenotype', 'HP:0031413', (0, 31))	('PMS2', 'Gene', (103, 107))	('p21', 'Gene', (94, 97))	('p53', 'Var', (89, 92))	('PMS2', 'Gene', '5395', (103, 107))	('cellular senescence', 'CPA', (65, 84))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('telomere shortening', 'Var', (12, 31))	('p21', 'Gene', '644914', (94, 97))	('arrest', 'Disease', (54, 60))
633036	19936245	In order to maintain proliferative capacity without compromising chromosome stability, embryonic and adult stem cells and certain somatic cells counter telomeric attrition by telomerase-catalyzed addition of TTAGGG repeats to the 3' telomeric overhangs.	('TTAGGG repeats', 'Var', (208, 222))	('embryonic', 'Disease', (87, 96))	('embryonic', 'Disease', 'MESH:D009373', (87, 96))
633037	19936245	Defective telomere repair has been causally associated with several human diseases.	('telomere repair', 'Protein', (10, 25))	('associated', 'Reg', (44, 54))	('human', 'Species', '9606', (68, 73))	('Defective', 'Var', (0, 9))
633038	19936245	Genetic linkage analysis of the constitutional marrow failure syndrome dyskeratosis congenita led to the discovery of mutations in the genes DKC1 (which encodes dyskerin) and telomerase RNA component (TERC) .	('DKC1', 'Gene', '1736', (141, 145))	('marrow failure', 'Phenotype', 'HP:0005528', (47, 61))	('TERC', 'Gene', '7012', (201, 205))	('mutations', 'Var', (118, 127))	('constitutional marrow failure syndrome dyskeratosis congenita', 'Disease', 'MESH:D019871', (32, 93))	('TERC', 'Gene', (201, 205))	('DKC1', 'Gene', (141, 145))
633039	19936245	We reported mutations in TERC  and telomerase reverse transcriptase (TERT) to be risk factors for apparently acquired aplastic anemia, a marrow failure disease occurring in patients who lack the typical physical anomalies and family history of dyskeratosis congenita.	('telomerase reverse transcriptase', 'Gene', (35, 67))	('dyskeratosis congenita', 'Disease', (244, 266))	('aplastic anemia', 'Phenotype', 'HP:0001915', (118, 133))	('marrow failure', 'Phenotype', 'HP:0005528', (137, 151))	('TERT', 'Gene', (69, 73))	('TERT', 'Gene', '7015', (69, 73))	('anomalies', 'Disease', (212, 221))	('anemia', 'Phenotype', 'HP:0001903', (127, 133))	('patients', 'Species', '9606', (173, 181))	('telomerase reverse transcriptase', 'Gene', '7015', (35, 67))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (244, 266))	('risk', 'Reg', (81, 85))	('TERC', 'Gene', '7012', (25, 29))	('marrow failure disease', 'Disease', 'MESH:D000080983', (137, 159))	('mutations', 'Var', (12, 21))	('TERC', 'Gene', (25, 29))	('anomalies', 'Disease', 'MESH:D000014', (212, 221))	('aplastic anemia', 'Disease', 'MESH:D000741', (118, 133))	('marrow failure disease', 'Disease', (137, 159))	('aplastic anemia', 'Disease', (118, 133))
633040	19936245	Mutations in telomerase complex genes also appear in families with idiopathic pulmonary fibrosis, and pulmonary disease, esophageal stricture, malignancy, and liver disease also have been reported in twenty, seventeen, eight, and seven percent of dyskeratosis congenita patients, respectively.	('malignancy', 'Disease', 'MESH:D009369', (143, 153))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (78, 96))	('liver disease', 'Disease', (159, 172))	('telomerase', 'Gene', (13, 23))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (247, 269))	('malignancy', 'Disease', (143, 153))	('Mutations', 'Var', (0, 9))	('esophageal stricture', 'Disease', (121, 141))	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (67, 96))	('pulmonary disease', 'Disease', 'MESH:D008171', (102, 119))	('esophageal stricture', 'Disease', 'MESH:D004940', (121, 141))	('pulmonary disease', 'Disease', (102, 119))	('idiopathic pulmonary fibrosis', 'Disease', (67, 96))	('reported', 'Reg', (188, 196))	('dyskeratosis congenita', 'Disease', (247, 269))	('patients', 'Species', '9606', (270, 278))	('liver disease', 'Phenotype', 'HP:0001392', (159, 172))	('esophageal stricture', 'Phenotype', 'HP:0002043', (121, 141))	('liver disease', 'Disease', 'MESH:D008107', (159, 172))
633042	19936245	Using a different approach, we studied the family members of five unrelated patients with marrow failure and telomerase mutations; we genetically screened relatives who had a variety of hematologic, hepatic, and autoimmune disorders.	('patients', 'Species', '9606', (76, 84))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (212, 232))	('marrow failure', 'Disease', (90, 104))	('autoimmune disorders', 'Disease', 'MESH:D001327', (212, 232))	('marrow failure', 'Phenotype', 'HP:0005528', (90, 104))	('marrow failure', 'Disease', 'MESH:D000080983', (90, 104))	('mutations', 'Var', (120, 129))	('autoimmune disorders', 'Disease', (212, 232))
633043	19936245	We found that mutations were associated with a wide range of hematologic abnormalities, from macrocytosis to acute myeloid leukemia, and with severe liver diseases characterized by fibrosis, inflammation, and regeneration occurring independently of marrow failure or other affected organs.	('liver disease', 'Phenotype', 'HP:0001392', (149, 162))	('hematologic abnormalities', 'Disease', 'MESH:D006402', (61, 86))	('hematologic abnormalities', 'Disease', (61, 86))	('liver diseases', 'Disease', (149, 163))	('macrocytosis to acute myeloid leukemia', 'Disease', 'MESH:D015470', (93, 131))	('marrow failure', 'Disease', 'MESH:D000080983', (249, 263))	('hematologic abnormalities', 'Phenotype', 'HP:0001871', (61, 86))	('associated', 'Reg', (29, 39))	('mutations', 'Var', (14, 23))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('inflammation', 'Disease', 'MESH:D007249', (191, 203))	('marrow failure', 'Disease', (249, 263))	('liver diseases', 'Phenotype', 'HP:0001392', (149, 163))	('marrow failure', 'Phenotype', 'HP:0005528', (249, 263))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (115, 131))	('severe', 'Disease', (142, 148))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (109, 131))	('fibrosis', 'Disease', (181, 189))	('inflammation', 'Disease', (191, 203))	('fibrosis', 'Disease', 'MESH:D005355', (181, 189))	('macrocytosis to acute myeloid leukemia', 'Disease', (93, 131))	('liver diseases', 'Disease', 'MESH:D008107', (149, 163))
633054	19936245	In our first report, only one paternal aunt (Subject A-IV-23) was found to carry the mutation and have liver disease.	('liver disease', 'Phenotype', 'HP:0001392', (103, 116))	('liver disease', 'Disease', 'MESH:D008107', (103, 116))	('liver disease', 'Disease', (103, 116))	('mutation', 'Var', (85, 93))
633059	19936245	The paternal aunt with a twenty-year history of aplastic anemia (Subject A-IV-25) and also heterozygous for the mutation developed dyspnea and cough at the age of forty-six after our first report.	('cough', 'Disease', (143, 148))	('dyspnea', 'Disease', (131, 138))	('mutation', 'Var', (112, 120))	('aplastic anemia', 'Phenotype', 'HP:0001915', (48, 63))	('dyspnea', 'Disease', 'MESH:D004417', (131, 138))	('aplastic anemia', 'Disease', 'MESH:D000741', (48, 63))	('cough', 'Phenotype', 'HP:0012735', (143, 148))	('cough', 'Disease', 'MESH:D003371', (143, 148))	('developed', 'Reg', (121, 130))	('anemia', 'Phenotype', 'HP:0001903', (57, 63))	('aplastic anemia', 'Disease', (48, 63))	('dyspnea', 'Phenotype', 'HP:0002094', (131, 138))
633076	19936245	There was no nail dystrophy, leukoplakia, or skin hyperpigmentation, all physical features characteristic of dyskeratosis congenita, in any of the mutation-carriers.	('dyskeratosis congenita', 'Disease', (109, 131))	('leukoplakia', 'Disease', 'MESH:D007971', (29, 40))	('skin hyperpigmentation', 'Phenotype', 'HP:0000953', (45, 67))	('leukoplakia', 'Disease', (29, 40))	('skin hyperpigmentation', 'Disease', (45, 67))	('mutation-carriers', 'Var', (147, 164))	('dystrophy', 'Disease', (18, 27))	('dystrophy', 'Disease', 'MESH:D009136', (18, 27))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (109, 131))	('nail dystrophy', 'Phenotype', 'HP:0008404', (13, 27))	('skin hyperpigmentation', 'Disease', 'MESH:D017495', (45, 67))
633126	19936245	Here we found by co-transfection experiments that TERC nucleotide 109-123 deletion completely abolished telomerase enzymatic activity, TERC nucleotide 341-360 deletion reduced telomerase activity to approximately one-third of that observed for wild-type TERC, and TERT S368P reduced telomerase activity to approximately 10% of that observed for wild-type TERT ( Fig.	('telomerase enzymatic activity', 'MPA', (104, 133))	('reduced', 'NegReg', (275, 282))	('TERC', 'Gene', (50, 54))	('TERC', 'Gene', '7012', (50, 54))	('deletion', 'Var', (74, 82))	('TERC', 'Gene', '7012', (135, 139))	('TERC', 'Gene', (254, 258))	('S368P', 'Mutation', 'p.S368P', (269, 274))	('abolished', 'NegReg', (94, 103))	('TERT', 'Gene', (264, 268))	('TERC', 'Gene', '7012', (254, 258))	('activity', 'MPA', (294, 302))	('TERT', 'Gene', '7015', (264, 268))	('TERT', 'Gene', (355, 359))	('TERT', 'Gene', '7015', (355, 359))	('TERC', 'Gene', (135, 139))	('telomerase activity', 'MPA', (176, 195))	('reduced', 'NegReg', (168, 175))
633130	19936245	In a recent series of 150 patients with idiopathic interstitial pneumonias, four patients (3%) also had cryptogenic liver cirrhosis diagnosed in the sixth or seventh decades of life; none of these four patients, however, carried a telomerase mutation.	('pneumonias', 'Phenotype', 'HP:0002090', (64, 74))	('idiopathic interstitial pneumonias', 'Disease', (40, 74))	('cirrhosis', 'Phenotype', 'HP:0001394', (122, 131))	('liver cirrhosis', 'Disease', (116, 131))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (202, 210))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (116, 131))	('idiopathic interstitial pneumonias', 'Disease', 'MESH:D054988', (40, 74))	('liver cirrhosis', 'Disease', 'MESH:D008103', (116, 131))	('mutation', 'Var', (242, 250))
633132	19936245	Similar to the spectrum of hematological findings associated with telomerase mutations, ranging from isolated macrocytosis to acute myeloid leukemia, liver disease was heterogeneous in severity and pathology among telomerase-mutation carriers.	('liver disease', 'Disease', 'MESH:D008107', (150, 163))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (126, 148))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('mutations', 'Var', (77, 86))	('liver disease', 'Phenotype', 'HP:0001392', (150, 163))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (132, 148))	('liver disease', 'Disease', (150, 163))	('macrocytosis to acute myeloid leukemia', 'Disease', (110, 148))	('macrocytosis to acute myeloid leukemia', 'Disease', 'MESH:D015470', (110, 148))
633134	19936245	In others, iron accumulation was observed, in the absence of a history of blood transfusion or HFE gene mutation.	('iron', 'Chemical', 'MESH:D007501', (11, 15))	('HFE', 'Gene', (95, 98))	('iron accumulation', 'MPA', (11, 28))	('mutation', 'Var', (104, 112))	('HFE', 'Gene', '3077', (95, 98))
633141	19936245	As was hypothesized for pulmonary fibrosis, shortened telomeres may result from dysfunctional telomere repair, increased cell turn-over, or a combination of factors and contribute to liver fibrosis.	('increased', 'PosReg', (111, 120))	('shortened', 'NegReg', (44, 53))	('liver fibrosis', 'Disease', (183, 197))	('cell turn-over', 'CPA', (121, 135))	('result', 'Reg', (68, 74))	('telomere', 'Protein', (94, 102))	('contribute', 'Reg', (169, 179))	('liver fibrosis', 'Disease', 'MESH:D008103', (183, 197))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (24, 42))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (24, 42))	('shortened telomeres', 'Phenotype', 'HP:0031413', (44, 63))	('liver fibrosis', 'Phenotype', 'HP:0001395', (183, 197))	('dysfunctional', 'Var', (80, 93))	('pulmonary fibrosis', 'Disease', (24, 42))
633142	19936245	In murine models, chronic chemical liver injury is associated with increased regeneration defects and liver cirrhosis in telomerase-deficient mice; restoration of telomerase activity by gene transduction abrogates liver cirrhosis and improves liver function.	('liver injury', 'Disease', 'MESH:D056486', (35, 47))	('abrogates', 'NegReg', (204, 213))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (214, 229))	('restoration', 'Var', (148, 159))	('improves', 'PosReg', (234, 242))	('cirrhosis', 'Phenotype', 'HP:0001394', (220, 229))	('mice', 'Species', '10090', (142, 146))	('liver cirrhosis', 'Disease', (102, 117))	('liver cirrhosis', 'Disease', 'MESH:D008103', (214, 229))	('cirrhosis', 'Phenotype', 'HP:0001394', (108, 117))	('murine', 'Species', '10090', (3, 9))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (102, 117))	('improves liver function', 'Phenotype', 'HP:0001410', (234, 257))	('liver injury', 'Disease', (35, 47))	('liver cirrhosis', 'Disease', 'MESH:D008103', (102, 117))	('liver function', 'CPA', (243, 257))	('liver cirrhosis', 'Disease', (214, 229))
633155	19936245	We recently found an increased rate of constitutional TERT hypomorphic mutations in patients with acute myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (112, 120))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (98, 120))	('constitutional', 'Var', (39, 53))	('TERT', 'Gene', '7015', (54, 58))	('patients', 'Species', '9606', (84, 92))	('acute myeloid leukemia', 'Disease', (98, 120))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (104, 120))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (98, 120))	('TERT', 'Gene', (54, 58))
633158	19936245	Mutations in telomerase and short telomeres must work in concert with other genetic and environmental factors to result in the diverse phenotypes with which these mutations now have been associated.	('short telomeres', 'Phenotype', 'HP:0031413', (28, 43))	('mutations', 'Var', (163, 172))	('Mutations', 'Var', (0, 9))	('result in', 'Reg', (113, 122))	('associated', 'Reg', (187, 197))	('iron', 'Chemical', 'MESH:D007501', (91, 95))
633164	19936245	Complete blood counts were performed at the NIH Clinical Center for clinically healthy subjects found to carry a telomerase mutation, and the diagnosis of macrocytosis or anemia were established based on the standard laboratory parameters.	('macrocytosis or anemia', 'Disease', (155, 177))	('telomerase', 'Gene', (113, 123))	('mutation', 'Var', (124, 132))	('anemia', 'Phenotype', 'HP:0001903', (171, 177))	('macrocytosis or anemia', 'Disease', 'MESH:C564004', (155, 177))
633167	19936245	DNA samples from 188 healthy persons served as controls for TERC and TERT gene mutations: 117 were white (94 from Human Variation Panel HD100CAU, Coriell Cell Repositories [http://locus.umdnj.edu/nigms/cells/humdiv.html], and 23 from SNP500Cancer [http://snp500cancer.nci.nih.gov]), 24 black (from SNP500Cancer), 23 Hispanic (from SNP500Cancer), and 24 Asian (from SNP500Cancer).	('TERC', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('TERC', 'Gene', '7012', (60, 64))	('Human', 'Species', '9606', (114, 119))	('TERT', 'Gene', (69, 73))	('TERT', 'Gene', '7015', (69, 73))	('persons', 'Species', '9606', (29, 36))	('mutations', 'Var', (79, 88))
633197	31686859	Of these, GSE77861, GSE100942, GSE45670, GSE26886, and GSE17351 were based on the platform of the GPL570 (Affymetrix Human Genome U133Plus 2.0 arrays, including 53 patients and 46 normal controls in total; GSE38129, GSE33426, GSE29001, and GSE20347 based on GPL571 (Affymetrix Human Genome U133A 2.0 Array), including 127 patients and 83 normal controls in total; GSE23400 based on GPL96 or GPL97 (Affymetrix Human Genome U133A or U133B 2.0 Array), and included 53 patients and 53 normal controls for GPL96, and 51 patients and 51 normal controls based on GPL97 platform.	('GSE77861', 'Var', (10, 18))	('patients', 'Species', '9606', (465, 473))	('Human', 'Species', '9606', (409, 414))	('patients', 'Species', '9606', (322, 330))	('Human', 'Species', '9606', (117, 122))	('patients', 'Species', '9606', (164, 172))	('GSE23400', 'Var', (364, 372))	('patients', 'Species', '9606', (515, 523))	('Human', 'Species', '9606', (277, 282))
633212	31686859	Nucleotide sequences corresponding to the portion of the wild type or mutant human KLF4 and DSC2 3'-UTR fragments were synthesized by Sangon Biotech (Shanghai, China), and the predicted binding sites (seed sequences) for mir-92b-3p were included.	('mir-92b', 'Gene', '693235', (221, 228))	('mutant', 'Var', (70, 76))	('KLF4', 'Gene', '9314', (83, 87))	('DSC2', 'Gene', (92, 96))	('binding', 'Interaction', (186, 193))	('KLF4', 'Gene', (83, 87))	('mir-92b', 'Gene', (221, 228))	('DSC2', 'Gene', '1824', (92, 96))	('human', 'Species', '9606', (77, 82))
633232	31686859	In the present work, we aimed to explore the key miRNAs and their regulatory mechanism in ESCC, Therefore, four miRNAs included in the turquoise and brown modules were worthy of our attention and selected to further analyze: has-let-7i, has-mir-181c, has-mir-181d, and has-mir-92b.	('has-mir-181d', 'Var', (251, 263))	('mir-92b', 'Gene', (273, 280))	('mir-181c', 'Gene', '406957', (241, 249))	('let-7i', 'Gene', (229, 235))	('ESCC', 'Disease', 'MESH:C562729', (90, 94))	('mir-92b', 'Gene', '693235', (273, 280))	('let-7i', 'Gene', '406891', (229, 235))	('ESCC', 'Disease', (90, 94))	('mir-181c', 'Gene', (241, 249))
633233	31686859	First the correlation analyses between each miRNA and grade were conducted, as shown in Figures 5E-H, the three miRNAs (has-let-7i, has-mir-181c, and has-mir-181d) included in turquoise module positively related to grade which is in accord with the turquoise module.	('has-mir-181d', 'Var', (150, 162))	('grade', 'Disease', (215, 220))	('let-7i', 'Gene', (124, 130))	('related', 'Reg', (204, 211))	('let-7i', 'Gene', '406891', (124, 130))	('mir-181c', 'Gene', (136, 144))	('mir-181c', 'Gene', '406957', (136, 144))
633248	31686859	Meanwhile, mutations of the potential miR-92b-3p binding sites of KLF4 and DSC2 3'-UTRs could not alter luciferase activity, implying that miR-92b-3p target the KLF4 and DSC2 by binding the predicted site (Figure 6I).	('miR-92b-3', 'Gene', (139, 148))	('mutations', 'Var', (11, 20))	('DSC2', 'Gene', '1824', (75, 79))	('KLF4', 'Gene', '9314', (161, 165))	('DSC2', 'Gene', (170, 174))	('miR-92b-3', 'Gene', '407047', (38, 47))	('KLF4', 'Gene', (161, 165))	('activity', 'MPA', (115, 123))	('miR-92b-3', 'Gene', (38, 47))	('KLF4', 'Gene', (66, 70))	('KLF4', 'Gene', '9314', (66, 70))	('DSC2', 'Gene', (75, 79))	('DSC2', 'Gene', '1824', (170, 174))	('miR-92b-3', 'Gene', '407047', (139, 148))
633254	31686859	Abnormal expression of tumor-related genes is one of the key mechanisms involved in the development of ESCC through the accumulation of genetic and epigenetic abnormalities.	('ESCC', 'Disease', 'MESH:C562729', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('epigenetic abnormalities', 'Disease', (148, 172))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Abnormal', 'Var', (0, 8))	('ESCC', 'Disease', (103, 107))	('tumor', 'Disease', (23, 28))	('epigenetic abnormalities', 'Disease', 'MESH:D002869', (148, 172))
633260	31686859	Furthermore, the enriched KEGG pathways of DEGs and DEMs in ESCC showed significantly enriched MicroRNAs in cancer, which imply that miRNAs play a very significant role in carcinogenesis, and the dysregulation of miRNAs is closely associated with ESCC progression.	('KEGG pathways', 'Pathway', (26, 39))	('ESCC', 'Disease', (247, 251))	('ESCC', 'Disease', (60, 64))	('dysregulation', 'Var', (196, 209))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('carcinogenesis', 'Disease', 'MESH:D063646', (172, 186))	('ESCC', 'Disease', 'MESH:C562729', (60, 64))	('carcinogenesis', 'Disease', (172, 186))	('associated', 'Reg', (231, 241))	('ESCC', 'Disease', 'MESH:C562729', (247, 251))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
633275	31686859	Consistent with our results, previous studies have shown that down-regulated KLF4 in ESCC was significantly related with poor differentiation, and inhibition of KLF4 prevented the inhibition of G1-S transition induced by sodium butyrate.	('poor differentiation', 'CPA', (121, 141))	('KLF4', 'Gene', (77, 81))	('sodium butyrate', 'Chemical', 'MESH:D020148', (221, 236))	('ESCC', 'Disease', 'MESH:C562729', (85, 89))	('KLF4', 'Gene', '9314', (161, 165))	('down-regulated', 'NegReg', (62, 76))	('KLF4', 'Gene', (161, 165))	('ESCC', 'Disease', (85, 89))	('inhibition', 'Var', (147, 157))	('prevented', 'NegReg', (166, 175))	('G1-S transition', 'CPA', (194, 209))	('inhibition', 'NegReg', (180, 190))	('KLF4', 'Gene', '9314', (77, 81))
633280	31686859	Finally, in this study, we confirmed that miR-92-3p directly binds to 3'-UTR of the KLF4 and DCS2 transcript and prevented protein expression by Western blot and luciferase reporter assay.	('protein expression', 'MPA', (123, 141))	('KLF4', 'Gene', (84, 88))	('prevented', 'NegReg', (113, 122))	('DCS2', 'Gene', (93, 97))	('miR-92-3p', 'Var', (42, 51))	('binds', 'Interaction', (61, 66))	('KLF4', 'Gene', '9314', (84, 88))
633292	30470267	Further, laparoscopy compromises operative control, as the surgeon must choose between operating with 2 instruments while an assistant positions the camera, or manipulating the camera and using only 1 laparoscopic instrument, which also requires expert assistance.	('manipulating', 'Var', (160, 172))	('laparoscopy', 'Disease', (9, 20))	('operative control', 'MPA', (33, 50))	('men', 'Species', '9606', (110, 113))	('men', 'Species', '9606', (220, 223))
633300	30470267	Robotics has been found to increase the cost of colorectal cancer surgery by approximately $2000 to 5000 per procedure compared to laparoscopy.	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('increase', 'PosReg', (27, 35))	('colorectal cancer', 'Disease', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Robotics', 'Var', (0, 8))	('rectal cancer', 'Phenotype', 'HP:0100743', (52, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))
633310	30470267	In a case-matched comparison of robotic and open surgery for right-sided colon cancers, Luca and colleagues found that robotic surgery was associated with shorter hospital stays (5 vs 8 days; P = 0.001) and resection of at least 15 lymph nodes (100% vs 88.2%; P = 0.038).	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hospital', 'MPA', (163, 171))	('colon cancers', 'Phenotype', 'HP:0003003', (73, 86))	('colon cancers', 'Disease', 'MESH:D015179', (73, 86))	('shorter', 'NegReg', (155, 162))	('resection', 'CPA', (207, 216))	('colon cancer', 'Phenotype', 'HP:0003003', (73, 85))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('colon cancers', 'Disease', (73, 86))	('robotic surgery', 'Var', (119, 134))
633311	30470267	More conclusively, a meta-analysis of 7 studies (including the randomized trial by Park and colleagues), found that in right colectomy, use of robotics was associated with lower estimated blood loss (P = 0.0002), fewer postoperative complications (P = 0.02), and significantly faster recovery of bowel function (P < 0.00001) compared with laparoscopy.	('blood loss', 'Disease', (188, 198))	('bowel function', 'MPA', (296, 310))	('recovery', 'MPA', (284, 292))	('right colectomy', 'Disease', (119, 134))	('robotics', 'Var', (143, 151))	('lower', 'NegReg', (172, 177))	('blood loss', 'Disease', 'MESH:D006473', (188, 198))	('faster', 'PosReg', (277, 283))
633313	30470267	As conversion increases wound infection and complication rates and length of stay, and may impact cancer-specific outcomes, this lower rate represents a key advantage.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('infection', 'Disease', (30, 39))	('increases', 'PosReg', (14, 23))	('infection', 'Disease', 'MESH:D007239', (30, 39))	('conversion', 'Var', (3, 13))	('impact', 'Reg', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('complication', 'CPA', (44, 56))	('cancer', 'Disease', (98, 104))
633316	30470267	Intracorporeal anastomoses are also associated with a lower rate of surgical site infections and incisional hernias than those created extracorporeally.	('incisional hernias', 'Phenotype', 'HP:0004872', (97, 115))	('incisional hernia', 'Phenotype', 'HP:0004872', (97, 114))	('hernias', 'Phenotype', 'HP:0100790', (108, 115))	('hernias', 'Disease', (108, 115))	('hernias', 'Disease', 'MESH:D006547', (108, 115))	('infections', 'Disease', 'MESH:D007239', (82, 92))	('hernia', 'Phenotype', 'HP:0100790', (108, 114))	('infections', 'Disease', (82, 92))	('anastomoses', 'Var', (15, 26))	('lower', 'NegReg', (54, 59))
633360	30470267	Among patients without complications, robotic TME was also associated with faster recovery of bowel function and shorter median length of stay (5 days in the robotic group vs 7 days in the laparoscopic and open groups; P < 0.001).	('bowel function', 'MPA', (94, 108))	('TME', 'Chemical', '-', (46, 49))	('recovery', 'MPA', (82, 90))	('patients', 'Species', '9606', (6, 14))	('faster', 'PosReg', (75, 81))	('shorter', 'NegReg', (113, 120))	('robotic', 'Var', (38, 45))
633362	30470267	A propensity case-matched retrospective study of 556 rectal cancer patients with long-term follow-up averaging 51.8 months found that robotic TME was associated with significantly lower incidence of late voiding dysfunction (as measured by urodynamics or the international prostate symptom score) compared to laparoscopic TME (0.7% vs 4.3%; P = 0.01).	('rectal cancer', 'Disease', (53, 66))	('rectal cancer', 'Phenotype', 'HP:0100743', (53, 66))	('patients', 'Species', '9606', (67, 75))	('TME', 'Chemical', '-', (142, 145))	('late voiding dysfunction', 'Disease', (199, 223))	('robotic', 'Var', (134, 141))	('lower', 'NegReg', (180, 185))	('late voiding dysfunction', 'Disease', 'MESH:C537271', (199, 223))	('TME', 'Chemical', '-', (322, 325))	('rectal cancer', 'Disease', 'MESH:D012004', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
633599	30470267	Patients with a CDH1 mutation are excellent candidates for a robotic approach.	('CDH1', 'Gene', '999', (16, 20))	('Patients', 'Species', '9606', (0, 8))	('CDH1', 'Gene', (16, 20))	('mutation', 'Var', (21, 29))
633600	30470267	CDH1 positive patients have an approximately 70% lifetime risk of developing gastric adenocarcinoma, therefore it is recommended that these patients undergo a prophylactic total gastrectomy.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (77, 99))	('gastric adenocarcinoma', 'Disease', (77, 99))	('CDH1', 'Gene', '999', (0, 4))	('patients', 'Species', '9606', (140, 148))	('CDH1', 'Gene', (0, 4))	('patients', 'Species', '9606', (14, 22))	('men', 'Species', '9606', (122, 125))	('positive', 'Var', (5, 13))
633686	30568505	The number of PD-1+ TILs was significantly positively correlated with CD8+ TILs (P<0.001).	('CD8', 'Gene', '925', (70, 73))	('CD8', 'Gene', (70, 73))	('PD-1+ TILs', 'Var', (14, 24))
633688	30568505	Increased numbers of PD-1+ and TIGIT+ TILs alone or both, as well as PD-L1 and PD-L2 expression alone or both, were significantly and associated with a shorter overall survival among these patients.	('PD-1+', 'Var', (21, 26))	('overall survival', 'MPA', (160, 176))	('TIGIT', 'Chemical', '-', (31, 36))	('shorter', 'NegReg', (152, 159))	('patients', 'Species', '9606', (189, 197))	('PD-L1', 'Gene', (69, 74))
633689	30568505	The combined analysis of the expression of PD-1, TIGIT, PD-L1, and PD-L2 found that a group of patients with PD-1+/TIGIT+ TILs and PD-L1- and/or PD-L2-positive tumor cells had the worst prognosis in primary ESCC.	('primary ESCC', 'Disease', (199, 211))	('patients', 'Species', '9606', (95, 103))	('PD-1+/TIGIT+ TILs', 'Var', (109, 126))	('TIGIT', 'Chemical', '-', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('TIGIT', 'Chemical', '-', (49, 54))	('tumor', 'Disease', (160, 165))
633737	30568505	Representative IHC images of PD-L1, PD-L2, PD-1, TIGIT, and CD8 are presented in Figure 1A-E. PD-L1 and PD-L2 were highly expressed in 45.5 and 59.7% of the ESCC samples, respectively (Table 1 and Figure 1A and B).	('PD-L1', 'Var', (94, 99))	('CD8', 'Gene', '925', (60, 63))	('ESCC', 'Disease', (157, 161))	('TIGIT', 'Chemical', '-', (49, 54))	('PD-L2', 'Var', (104, 109))	('CD8', 'Gene', (60, 63))
633744	30568505	Kaplan-Meier survival analysis revealed that the patients carrying a high number of PD-1+ TILs (n=73/154, 47.4%) or TIGIT+ TILs (n=76/154, 49.4%) tended to exhibit a shorter OS (P=0.044, Figure 3A, and P=0.045, Figure 3B).	('TIGIT', 'Chemical', '-', (116, 121))	('TIGIT+ TILs', 'Var', (116, 127))	('PD-1+ TILs', 'Var', (84, 94))	('patients', 'Species', '9606', (49, 57))
633748	30568505	The results indicated that PD-1+ TILs, TIGIT+ TILs, PD-L1, and PD-L2-positive expressions in cancer were the independent unfavorable prognostic factors in ESCC (Table 3).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('PD-1+ TILs', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ESCC', 'Disease', (155, 159))	('TIGIT', 'Chemical', '-', (39, 44))
633753	30568505	The Kaplan-Meier survival results showed that PD-1+/TIGIT+ TILs in cancer demonstrated significantly lower survival rates than patients with PD-1-/TIGIT- TILs (P=0.005, Figure 3F).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('survival', 'MPA', (107, 115))	('PD-1+/TIGIT+ TILs', 'Var', (46, 63))	('cancer', 'Disease', (67, 73))	('TIGIT', 'Chemical', '-', (147, 152))	('lower', 'NegReg', (101, 106))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TIGIT', 'Chemical', '-', (52, 57))
633759	30568505	According to the above prognosis results, we found that patients with PD-1+/TIGIT+ TILs and PD-L1- and/or PD-L2-positive tumor cells (n=34/154, 22.1%) had a markedly shorter OS than patients with PD-1-/TIGIT- TILs and PD-L1- and PD-L2-negative tumor cells (n=10/154, 6.5%) (P=0.003, Figure 3H).	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('patients', 'Species', '9606', (56, 64))	('PD-1+/TIGIT+ TILs', 'Var', (70, 87))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('TIGIT', 'Chemical', '-', (76, 81))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', (121, 126))	('shorter', 'NegReg', (166, 173))	('patients', 'Species', '9606', (182, 190))	('TIGIT', 'Chemical', '-', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('PD-L1- and/or', 'Var', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
633762	30568505	The results indicated that PD-1+/TIGIT+ TILs, PD-L1-positive/PD-L2-positive and combined PD-1+/TIGIT+ TILs, and PD-L1 positive and/or PD-L2 positive in cancer were the independent unfavorable prognostic factors in ESCC (Table 3).	('cancer', 'Disease', (152, 158))	('ESCC', 'Disease', (214, 218))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('TIGIT', 'Chemical', '-', (95, 100))	('PD-1+/TIGIT+', 'Gene', (89, 101))	('PD-L1', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('PD-1+/TIGIT+', 'Var', (27, 39))	('TIGIT', 'Chemical', '-', (33, 38))
633774	30568505	In our study, we found that PD-L1-positive tumor had more CD8+ T cells than PD-L1-negative tumor.	('more', 'PosReg', (53, 57))	('CD8', 'Gene', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CD8', 'Gene', '925', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('PD-L1-positive', 'Var', (28, 42))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (91, 96))
633780	30568505	Patients with high expression of PD-1 or TIGIT have significantly shorter OS than low expression of PD-1 and TIGIT patients, and they have similar survival rate, suggesting that TIGIT may have similar effect with PD-1 in immune inhibition in ESCC.	('patients', 'Species', '9606', (115, 123))	('ESCC', 'Disease', (242, 246))	('TIGIT', 'Chemical', '-', (109, 114))	('shorter', 'NegReg', (66, 73))	('TIGIT', 'Chemical', '-', (178, 183))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('TIGIT', 'Chemical', '-', (41, 46))	('PD-1', 'Gene', (33, 37))
633781	30568505	Some studies on mouse models have shown a synergistic effect of the inhibition of both pathways in boosting the antitumor immune response.	('inhibition', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('boosting', 'PosReg', (99, 107))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Disease', (116, 121))
633785	30568505	We also found that patients with PD-L1-positive/PD-L2-positive tumor had significantly shorter OS than PD-L1-negative/PD-L2-negative patients, and PD-L1 positive/PD-L2 positive was an independent unfavorable prognostic factor in ESCC.	('ESCC', 'Disease', (229, 233))	('tumor', 'Disease', (63, 68))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (133, 141))	('shorter', 'NegReg', (87, 94))	('PD-L1-positive/PD-L2-positive', 'Var', (33, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
633791	30568505	Multivariate analysis showed that combined PD-1+/TIGIT+ TILs and PD-L1 positive and/or PD-L2 positive in cancer were the independent unfavorable prognostic factors in ESCC.	('cancer', 'Disease', (105, 111))	('ESCC', 'Disease', (167, 171))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('PD-1+/TIGIT+ TILs', 'Var', (43, 60))	('PD-L1', 'Gene', (65, 70))	('TIGIT', 'Chemical', '-', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('PD-L2', 'Gene', (87, 92))
633792	30568505	Our data suggest that patients with PD-1+/TIGIT+ TILs and PD-L1- and/or PD-L2-positive tumor cells may benefit from immune checkpoints blockade therapy but need multiple blockade of these immune molecules or optimize immune checkpoints blockade in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('PD-1+/TIGIT+', 'Var', (36, 48))	('patients', 'Species', '9606', (22, 30))	('TIGIT', 'Chemical', '-', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ESCC', 'Disease', (248, 252))
633810	29145896	Like other malicious tumors, the pathogenesis and progression of ESCC are a long procedure involving activation of oncogenes and/or inactivation of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (21, 26))	('activation', 'PosReg', (101, 111))	('oncogenes', 'Protein', (115, 124))	('tumor', 'Disease', (148, 153))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('inactivation', 'Var', (132, 144))	('ESCC', 'Disease', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
633829	29145896	It was also shown that dysregulation of the Hippo pathway is associated with epithelial-mesenchymal transition and cancer development, mainly driven by TAZ and YAP.	('cancer', 'Disease', (115, 121))	('epithelial-mesenchymal transition', 'CPA', (77, 110))	('dysregulation', 'Var', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Hippo pathway', 'Pathway', (44, 57))	('associated', 'Reg', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
633831	29145896	To date, numerous miRNAs have been verified to target LATS2 and involved in Hippo pathway in diverse types of cancer, like miR-181b, miR-93, and miR-372.	('involved', 'Reg', (64, 72))	('cancer', 'Disease', (110, 116))	('target', 'Reg', (47, 53))	('miR-181b', 'Var', (123, 131))	('miR-93', 'Var', (133, 139))	('miR-93', 'Chemical', '-', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('miR-372', 'Gene', (145, 152))	('Hippo pathway', 'Pathway', (76, 89))	('miR-372', 'Gene', '442917', (145, 152))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('LATS2', 'Protein', (54, 59))
633835	29145896	HEEC, Kyse30, Kyse70, TE1 and Eca109 cells were maintained in RPMI-1640 medium (Gibco, USA) containing 10% fetal bovine serum (FBS, Gibco, USA) and 1% penicillin/ streptomycin (Invitrogen, Shanghai, China).	('bovine', 'Species', '9913', (113, 119))	('RPMI-1640 medium', 'Chemical', '-', (62, 78))	('streptomycin', 'Chemical', 'MESH:D013307', (163, 175))	('FBS', 'Disease', 'MESH:D005198', (127, 130))	('HEEC', 'CellLine', 'None', (0, 4))	('penicillin', 'Chemical', 'MESH:D010406', (151, 161))	('FBS', 'Disease', (127, 130))	('Kyse30', 'Var', (6, 12))	('Kyse70', 'Var', (14, 20))
633836	29145896	Ec9706 cells were expanded in DMEM medium (Gibco, USA) supplemented with 10% FBS and 1% penicillin/streptomycin.	('penicillin', 'Chemical', 'MESH:D010406', (88, 98))	('FBS', 'Disease', 'MESH:D005198', (77, 80))	('FBS', 'Disease', (77, 80))	('streptomycin', 'Chemical', 'MESH:D013307', (99, 111))	('Ec9706', 'CellLine', 'CVCL:E307', (0, 6))	('DMEM medium', 'Chemical', '-', (30, 41))	('Ec9706', 'Var', (0, 6))
633882	29145896	Analogously, cell invasion was reduced in anti-miR-31-transfected cells as determined by the matrigel invasion assay, and enforced expression of miR-31 caused the contrary effect (Fig.	('reduced', 'NegReg', (31, 38))	('cell invasion', 'CPA', (13, 26))	('expression', 'Species', '29278', (131, 141))	('miR-31', 'Gene', (145, 151))	('matrigel invasion assay', 'CPA', (93, 116))	('anti-miR-31-transfected', 'Var', (42, 65))
633883	29145896	In order to clarify the mechanisms by which miR-31 promotes tumorigenesis, the target mRNAs of miR-31 was identified in silico prediction models.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('miR-31', 'Var', (44, 50))	('promotes', 'PosReg', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
633887	29145896	Then, the mRNA and protein levels of LATS2 were analyzed in Eca109 and TE1 cells after mutable expression of miR-31.	('expression', 'Species', '29278', (95, 105))	('mutable', 'Var', (87, 94))	('miR-31', 'Var', (109, 115))
633895	29145896	3b, c), while silencing of LATS2 expression stimulated cell growth compared with the control group.	('silencing', 'Var', (14, 23))	('stimulated', 'PosReg', (44, 54))	('expression', 'Species', '29278', (33, 43))	('LATS2', 'Gene', (27, 32))	('cell growth', 'CPA', (55, 66))
633896	29145896	Obviously, wound healing assay disclosed that overexpression of LATS2 constrained the migratory activity of ESCC cells, yet loss of LATS2 promoted the migratory activity (Fig.	('loss', 'Var', (124, 128))	('promoted', 'PosReg', (138, 146))	('migratory activity', 'CPA', (151, 169))	('expression', 'Species', '29278', (50, 60))	('migratory activity', 'CPA', (86, 104))	('LATS2', 'Gene', (132, 137))
633897	29145896	Meanwhile, Invasion assay demonstrated that enforced expression of LATS2 reduced the invasiveness of ESCC cells, and knockdown of LATS2 caused the contrary effect.	('LATS2', 'Gene', (67, 72))	('LATS2', 'Gene', (130, 135))	('reduced', 'NegReg', (73, 80))	('expression', 'Species', '29278', (53, 63))	('invasiveness of ESCC cells', 'CPA', (85, 111))	('knockdown', 'Var', (117, 126))
633898	29145896	We then determined the mechanism underlying the tumor development effect of miR-31 and decreased whether LATS2 is involved in this process.	('miR-31', 'Var', (76, 82))	('tumor', 'Disease', (48, 53))	('decreased', 'NegReg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
633900	29145896	These findings demonstrate that LATS2 is a functional target of miR-31 and that ectopic expression of LATS2 can reverse the tumor effect of miR-31.	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('LATS2', 'Gene', (102, 107))	('tumor', 'Disease', (124, 129))	('expression', 'Species', '29278', (88, 98))	('reverse', 'NegReg', (112, 119))	('ectopic expression', 'Var', (80, 98))
633904	29145896	By means of qRT-PCR and western blotting assays, it was showed that both silencing of miR-31 and LATS2 overexpression in ESCC cells induced the expression of epithelial markers (E-cadherin and beta-catenin) that was elevated by a concomitant decreased of mesenchymal markers (vimentin and N-cadherin) (Figs.	('silencing', 'Var', (73, 82))	('expression', 'Species', '29278', (144, 154))	('beta-catenin', 'Protein', (193, 205))	('vimentin', 'Protein', (276, 284))	('overexpression', 'Var', (103, 117))	('expression', 'MPA', (144, 154))	('expression', 'Species', '29278', (107, 117))	('miR-31', 'Gene', (86, 92))	('elevated', 'PosReg', (216, 224))	('decreased', 'NegReg', (242, 251))	('N-cadherin', 'Protein', (289, 299))	('LATS2', 'Gene', (97, 102))	('E-cadherin', 'Protein', (178, 188))
633905	29145896	Likewise, immunofluorescence assay also indicated that the expression of epithelial protein markers was significantly increased in anti-miR-31 and LATS2 overexpression transfected ESCC cells, while the expression of mesenchymal protein markers was significantly lessened (Figs.	('expression', 'Species', '29278', (157, 167))	('overexpression', 'PosReg', (153, 167))	('expression', 'Species', '29278', (202, 212))	('expression', 'Species', '29278', (59, 69))	('LATS2', 'Gene', (147, 152))	('increased', 'PosReg', (118, 127))	('expression', 'MPA', (202, 212))	('expression', 'MPA', (59, 69))	('lessened', 'NegReg', (262, 270))	('anti-miR-31', 'Gene', (131, 142))	('transfected', 'Var', (168, 179))
633914	29145896	The median OS and PFS of patients with TAZ high expression were 33 months and 19 months, lower than 85 months and 57 months of patients with low expression (P < 0.001) (Fig.	('TAZ high expression', 'Var', (39, 58))	('OS', 'Chemical', '-', (11, 13))	('expression', 'Species', '29278', (48, 58))	('expression', 'Species', '29278', (145, 155))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (25, 33))	('PFS', 'CPA', (18, 21))
633916	29145896	Furthermore, in the same ESCC patients the inverse association between miR-31 and LATS2 was significant (r = -0.737, p = 0.001) and miR-31 and TAZ has a positive correlation(r = 0.626, p = 0.002) based on Pearson Correlation analysis.	('LATS2', 'Gene', (82, 87))	('miR-31', 'Var', (132, 138))	('inverse', 'NegReg', (43, 50))	('ESCC', 'Disease', (25, 29))	('patients', 'Species', '9606', (30, 38))	('miR-31', 'Gene', (71, 77))
633923	29145896	9a, loss of miR-31 expression significantly reduced the growth volume and rate of Eca109 cells-derived tumors in mice compared with anti-miR-NC cells.	('growth volume', 'CPA', (56, 69))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('miR-31', 'Gene', (12, 18))	('reduced', 'NegReg', (44, 51))	('mice', 'Species', '10090', (113, 117))	('expression', 'Species', '29278', (19, 29))	('loss', 'Var', (4, 8))
633926	29145896	Additionally, restoration of siRNA/LATS2 significantly increased tumor volume (Fig.	('restoration', 'Var', (14, 25))	('tumor', 'Disease', (65, 70))	('increased', 'PosReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('siRNA/LATS2', 'Gene', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
633935	29145896	In this study, we reported that miR-31 acted as an oncogene in the development of ESCC by directly inhibiting LATS2 expression and ulteriorly stimulating TAZ, ultimately triggering EMT in cancer cells.	('triggering', 'Reg', (170, 180))	('EMT', 'CPA', (181, 184))	('expression', 'MPA', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('expression', 'Species', '29278', (116, 126))	('inhibiting', 'NegReg', (99, 109))	('ESCC', 'Disease', (82, 86))	('miR-31', 'Var', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('LATS2', 'Gene', (110, 115))	('TAZ', 'MPA', (154, 157))	('stimulating', 'Reg', (142, 153))
633937	29145896	Moreover, we reported for the first time that miR-31 could directly silence LATS2 expression inhibiting EMT in ESCC cancer cells.	('silence', 'NegReg', (68, 75))	('expression', 'Species', '29278', (82, 92))	('EMT in', 'CPA', (104, 110))	('expression', 'MPA', (82, 92))	('miR-31', 'Var', (46, 52))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('LATS2', 'Gene', (76, 81))	('inhibiting', 'NegReg', (93, 103))
633946	29145896	It was publicized that restoration of LATS2 significantly attenuated the oncogenic effects of miR-25.	('miR-25', 'Gene', (94, 100))	('attenuated', 'NegReg', (58, 68))	('LATS2', 'Gene', (38, 43))	('miR-25', 'Chemical', '-', (94, 100))	('restoration', 'Var', (23, 34))	('oncogenic effects', 'CPA', (73, 90))
633948	29145896	MiR-181b was also reported to promote ovarian cancer cell growth and invasion by targeting LATS2.	('MiR-181b', 'Var', (0, 8))	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('promote', 'PosReg', (30, 37))	('LATS2', 'Gene', (91, 96))	('targeting', 'Reg', (81, 90))	('ovarian cancer', 'Disease', 'MESH:D010051', (38, 52))	('invasion', 'CPA', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('ovarian cancer', 'Disease', (38, 52))
633966	29145896	Thus, we identified miR-31-mediated LATS2 signaling pathways to be involved in cancer EMT process, which is a pivotal step for ESCC metastasis.	('involved', 'Reg', (67, 75))	('miR-31-mediated', 'Var', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('LATS2', 'Gene', (36, 41))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
634126	23735656	miR-21 and miR-223), and modulation of interleukin (IL)-13-driven epithelial responses (e.g.	('miR-223', 'Gene', (11, 18))	('miR-223', 'Gene', '407008', (11, 18))	('miR-21', 'Var', (0, 6))	('modulation', 'Reg', (25, 35))
634157	23735656	Conversely, utilizing a Th1-associated delayed-type hypersensitivity model, miR-21 deficiency significantly enhanced the delayed-type hypersensitivity responses.	('delayed-type hypersensitivity', 'Phenotype', 'HP:0002972', (121, 150))	('hypersensitivity', 'Disease', (52, 68))	('hypersensitivity', 'Disease', 'MESH:D004342', (52, 68))	('miR-21', 'Gene', (76, 82))	('enhanced', 'PosReg', (108, 116))	('delayed-type hypersensitivity', 'Phenotype', 'HP:0002972', (39, 68))	('deficiency', 'Var', (83, 93))	('hypersensitivity', 'Disease', 'MESH:D004342', (134, 150))	('delayed-type hypersensitivity responses', 'Phenotype', 'HP:0002972', (121, 160))	('hypersensitivity', 'Disease', (134, 150))
634164	23735656	These results demonstrate that small perturbations in miRNA levels can have profound effects on adaptive immunity.	('perturbations', 'Var', (37, 50))	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (54, 57))	('adaptive immunity', 'CPA', (96, 113))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('effects', 'Reg', (85, 92))
634168	23735656	Inhibition of miR-126 by antagomiRs abrogated the asthmatic response as demonstrated by reduced inflammation, airway hyperreactivity, Th2 cytokines (e.g.	('asthma', 'Phenotype', 'HP:0002099', (50, 56))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('Th2', 'Gene', '15111', (134, 137))	('miR-126', 'Gene', '406913', (14, 21))	('asthmatic response', 'Phenotype', 'HP:0002099', (50, 68))	('airway hyperreactivity', 'CPA', (110, 132))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('abrogated', 'NegReg', (36, 45))	('Inhibition', 'Var', (0, 10))	('miR', 'Gene', (14, 17))	('miR-126', 'Gene', (14, 21))	('asthma', 'Disease', (50, 56))	('reduced', 'NegReg', (88, 95))	('Th2', 'Gene', (134, 137))	('asthma', 'Disease', 'MESH:D001249', (50, 56))	('inflammation', 'Disease', (96, 108))	('miR', 'Gene', '220972', (14, 17))
634171	23735656	Inhibition of miR-126 by antagomiRs in the chronic asthma model reduced recruitment of intraepithelial eosinophils in the conducting airways but had no effect on mucus cell hyperplasia or subepithelial fibrosis.	('hyperplasia', 'Disease', 'MESH:D006965', (173, 184))	('recruitment of intraepithelial eosinophils in', 'MPA', (72, 117))	('asthma', 'Disease', (51, 57))	('hyperplasia', 'Disease', (173, 184))	('subepithelial fibrosis', 'Disease', 'MESH:D005355', (188, 210))	('subepithelial fibrosis', 'Disease', (188, 210))	('asthma', 'Disease', 'MESH:D001249', (51, 57))	('miR-126', 'Gene', '406913', (14, 21))	('asthma', 'Phenotype', 'HP:0002099', (51, 57))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (64, 71))	('miR', 'Gene', (14, 17))	('miR-126', 'Gene', (14, 21))	('miR', 'Gene', '220972', (14, 17))
634228	23735656	CD8+ T cell development is dependent upon the miRNA-processing enzyme DICER, and CD4+ T cells deficient in DICER preferentially differentiate into Th1 cells.	('miR', 'Gene', (46, 49))	('DICER', 'Gene', '23405', (70, 75))	('CD4+ T cells deficient', 'Phenotype', 'HP:0005407', (81, 103))	('DICER', 'Gene', (107, 112))	('DICER', 'Gene', (70, 75))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('preferentially', 'PosReg', (113, 127))	('deficient', 'Var', (94, 103))	('DICER', 'Gene', '23405', (107, 112))	('miR', 'Gene', '220972', (46, 49))
634230	23735656	For patients with severe asthma, miR-146a and miR-146b were reduced in both CD4+ and CD8+ T cells, while miR-28-5p was downregulated in CD8+ T cells only.	('miR-28', 'Gene', (105, 111))	('asthma', 'Disease', 'MESH:D001249', (25, 31))	('asthma', 'Disease', (25, 31))	('CD8', 'Gene', (136, 139))	('CD8', 'Gene', (85, 88))	('miR-28', 'Gene', '407020', (105, 111))	('CD8', 'Gene', '925', (85, 88))	('severe asthma', 'Phenotype', 'HP:0012653', (18, 31))	('asthma', 'Phenotype', 'HP:0002099', (25, 31))	('miR-146b', 'Gene', (46, 54))	('CD8', 'Gene', '925', (136, 139))	('reduced', 'NegReg', (60, 67))	('miR-146a', 'Var', (33, 41))	('miR-146b', 'Gene', '574447', (46, 54))	('patients', 'Species', '9606', (4, 12))
634233	23735656	Further studies are needed to determine whether miR-146a and miR-146b have pro- or anti-inflammatory effects in asthma and whether their roles are context and timing dependent.	('miR-146a', 'Var', (48, 56))	('pro-', 'MPA', (75, 79))	('asthma', 'Phenotype', 'HP:0002099', (112, 118))	('miR-146b', 'Gene', '574447', (61, 69))	('anti-inflammatory', 'MPA', (83, 100))	('asthma', 'Disease', (112, 118))	('asthma', 'Disease', 'MESH:D001249', (112, 118))	('miR-146b', 'Gene', (61, 69))
634249	23735656	Both miR-146a and miR-146b have been found to be upregulated in patients with eosinophilic esophagitis.	('patients', 'Species', '9606', (64, 72))	('eosinophilic esophagitis', 'Disease', 'MESH:D004802', (78, 102))	('miR-146b', 'Gene', (18, 26))	('miR-146b', 'Gene', '574447', (18, 26))	('upregulated', 'PosReg', (49, 60))	('eosinophilic esophagitis', 'Disease', (78, 102))	('miR-146a', 'Var', (5, 13))	('esophagitis', 'Phenotype', 'HP:0100633', (91, 102))	('eosinophilic esophagitis', 'Phenotype', 'HP:0410151', (78, 102))
634301	23735656	MiR-21 deficiency reduced eosinophil progenitor cell growth, whereas miR-223 deficiency accelerated eosinophil growth (Figure 2) .	('MiR-21', 'Gene', (0, 6))	('deficiency', 'Var', (77, 87))	('eosinophil', 'MPA', (100, 110))	('accelerated', 'PosReg', (88, 99))	('miR-223', 'Gene', (69, 76))	('reduced eosinophil', 'Phenotype', 'HP:0031891', (18, 36))	('deficiency reduced eosinophil', 'Disease', 'MESH:D004802', (7, 36))	('MiR-21', 'Gene', '406991', (0, 6))	('deficiency reduced eosinophil', 'Disease', (7, 36))	('miR-223', 'Gene', '407008', (69, 76))
634304	23735656	While microarray analysis of differentially regulated genes between miR-21+/+ and miR-21-/- eosinophil progenitor cultures identified only one gene (Psrc1) as a predicted target of miR-21, functional enrichment analysis identified an overall functional effect in the pathways associated with the observed phenotype and known role of miR-21 in other systems.	('pathways', 'Pathway', (267, 275))	('Psrc1', 'Gene', (149, 154))	('Psrc1', 'Gene', '84722', (149, 154))	('miR-21+/+', 'Var', (68, 77))	('miR-21-/-', 'Var', (82, 91))
634307	23735656	MiR-223 deficiency resulted in increased eosinophil progenitor proliferation compared to wild-type cells.	('increased', 'PosReg', (31, 40))	('eosinophil progenitor proliferation', 'CPA', (41, 76))	('MiR-223', 'Gene', '407008', (0, 7))	('deficiency', 'Var', (8, 18))	('MiR-223', 'Gene', (0, 7))	('increased eosinophil', 'Phenotype', 'HP:0001880', (31, 51))
634316	23735656	Early studies utilized a global miRNA deletion in T cells by deleting the miRNA processing enzyme DICER.	('miR', 'Gene', (32, 35))	('miR', 'Gene', (74, 77))	('miR', 'Gene', '220972', (74, 77))	('DICER', 'Gene', '23405', (98, 103))	('deleting', 'NegReg', (61, 69))	('deletion', 'Var', (38, 46))	('DICER', 'Gene', (98, 103))	('miR', 'Gene', '220972', (32, 35))
634317	23735656	DICER deficient T helper cells proliferated poorly upon stimulation, and preferentially expressed the Th1 cytokine IFNgamma.	('IFN', 'Gene', (115, 118))	('deficient T helper cells', 'Phenotype', 'HP:0008165', (6, 30))	('preferentially', 'PosReg', (73, 87))	('deficient', 'Var', (6, 15))	('expressed', 'Reg', (88, 97))	('DICER', 'Gene', '23405', (0, 5))	('IFN', 'Gene', '3439', (115, 118))	('T helper cells proliferated', 'CPA', (16, 43))	('DICER', 'Gene', (0, 5))
634320	23735656	Inhibiting miR-181a expression in immature T cells reduces antigen sensitivity significantly impairs T cell selection.	('T cell selection', 'CPA', (101, 117))	('Inhibiting', 'Var', (0, 10))	('expression', 'MPA', (20, 30))	('reduces', 'NegReg', (51, 58))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('impairs', 'NegReg', (93, 100))	('antigen sensitivity', 'MPA', (59, 78))
634325	23735656	MiR-155 deficient T helper cells exhibit a Th2 bias in vitro in part due to up-regulation of the miR-155 target cMaf.	('Th2', 'Gene', '15111', (43, 46))	('up-regulation', 'PosReg', (76, 89))	('miR-155', 'Gene', '406947', (97, 104))	('MiR-155', 'Gene', '406947', (0, 7))	('deficient T helper cells', 'Phenotype', 'HP:0008165', (8, 32))	('cMaf', 'Gene', '4094', (112, 116))	('cMaf', 'Gene', (112, 116))	('MiR-155', 'Gene', (0, 7))	('Th2', 'Gene', (43, 46))	('miR-155', 'Gene', (97, 104))	('deficient', 'Var', (8, 17))
634328	23735656	miR-146a has been found to selectively target Treg mediated suppression of Th1 responses by targeting STAT1.	('miR-146a', 'Var', (0, 8))	('Treg', 'Chemical', '-', (46, 50))	('Th1 responses', 'MPA', (75, 88))	('suppression', 'MPA', (60, 71))	('STAT1', 'Gene', (102, 107))	('STAT1', 'Gene', '6772', (102, 107))
634353	23735656	Since the Th1 and Th2 responses exist in a balanced state, miR-21, miR-146a, and let-7 may work additively or synergistically to initiate and/or maintain an exaggerated Th2 response by targeting different components of the Th-cell polarization pathway.	('Th-cell polarization pathway', 'Pathway', (223, 251))	('Th', 'Chemical', 'MESH:D013910', (18, 20))	('Th', 'Chemical', 'MESH:D013910', (169, 171))	('Th2', 'Gene', (18, 21))	('let-7', 'Gene', '266952', (81, 86))	('let-7', 'Gene', (81, 86))	('Th2', 'Gene', (169, 172))	('targeting', 'Reg', (185, 194))	('miR-21', 'Var', (59, 65))	('Th2', 'Gene', '15111', (18, 21))	('Th2', 'Gene', '15111', (169, 172))	('miR-146a', 'Var', (67, 75))	('Th', 'Chemical', 'MESH:D013910', (223, 225))	('Th', 'Chemical', 'MESH:D013910', (10, 12))
634366	23735656	DNA methylation and histone modifications have been shown to regulate the expression of multiple miRNAs.	('modifications', 'Var', (28, 41))	('expression', 'MPA', (74, 84))	('regulate', 'Reg', (61, 69))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))
634369	23735656	A sixth area worth future investigation is the relationship between miRNAs dysregulated in helminth infections and the allergy related miRNAs.	('miR', 'Gene', (135, 138))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', (68, 71))	('helminth infections', 'Disease', 'MESH:D007239', (91, 110))	('allergy', 'Disease', (119, 126))	('allergy', 'Disease', 'MESH:D004342', (119, 126))	('allergy', 'Phenotype', 'HP:0012393', (119, 126))	('dysregulated', 'Var', (75, 87))	('helminth infections', 'Disease', (91, 110))	('miR', 'Gene', '220972', (135, 138))
634389	23874915	Esophageal Squamous Cell Carcinoma and Gastric Cardia Adenocarcinoma Shared Susceptibility Locus in PLCE1: A Meta-Analysis Two recent genome-wide association studies have identified a shared susceptibility variation PLCE1 rs2274223 for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinomas (GCA).	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('gastric cardia adenocarcinomas', 'Disease', 'MESH:D004938', (282, 312))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (236, 270))	('Gastric Cardia Adenocarcinoma', 'Disease', 'MESH:D004938', (39, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('PLCE1', 'Gene', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('PLCE1', 'Gene', '51196', (100, 105))	('gastric cardia adenocarcinomas', 'Disease', (282, 312))	('rs2274223', 'Mutation', 'rs2274223', (222, 231))	('rs2274223', 'Var', (222, 231))	('PLCE1', 'Gene', (216, 221))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (0, 34))	('PLCE1', 'Gene', '51196', (216, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('susceptibility', 'Reg', (191, 205))	('esophageal squamous cell carcinoma', 'Disease', (236, 270))	('Gastric Cardia Adenocarcinoma', 'Disease', (39, 68))	('Esophageal Squamous Cell Carcinoma', 'Disease', (0, 34))	('Carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (247, 270))
634390	23874915	Our aim is to provide a precise quantification of the association between PLCE1 rs2274223 variation and the risk of ESCC and GCA.	('rs2274223', 'Mutation', 'rs2274223', (80, 89))	('PLCE1', 'Gene', (74, 79))	('PLCE1', 'Gene', '51196', (74, 79))	('ESCC', 'Disease', (116, 120))	('GCA', 'Disease', (125, 128))	('rs2274223 variation', 'Var', (80, 99))
634391	23874915	Overall, PLCE1 rs2274223 G allele (G vs. A: OR=1.26, 95% CI: 1.15-1.39 for ESCC; OR=1.51, 95% CI: 1.35-1.69 for GCA) and its carrier (GG +AG vs. AA: OR = 1.23; 95% CI =1.02-1.49 for ESCC; OR =1.62; 95% CI =1.15-2.29 for GCA) were significantly associated with the risk of ESCC and GCA.	('PLCE1', 'Gene', (9, 14))	('rs2274223', 'Mutation', 'rs2274223', (15, 24))	('PLCE1', 'Gene', '51196', (9, 14))	('associated', 'Reg', (244, 254))	('rs2274223 G', 'Var', (15, 26))	('ESCC', 'Disease', (272, 276))	('GCA', 'Disease', (281, 284))
634392	23874915	In stratified analysis by ethnicity, significant association of PLCE1 rs2274223 G allele and the risk of ESCC (OR=1.33, 95% CI 1.21-1.45) and GCA (OR =1.56, 95% CI: 1.47-1.64) was observed in Chinese population.	('ESCC', 'Disease', (105, 109))	('GCA', 'Disease', (142, 145))	('rs2274223 G', 'Var', (70, 81))	('association', 'Interaction', (49, 60))	('PLCE1', 'Gene', (64, 69))	('PLCE1', 'Gene', '51196', (64, 69))	('rs2274223', 'Mutation', 'rs2274223', (70, 79))
634393	23874915	Our meta-analysis results indicated that PLCE1 rs2274223 G allele significantly contributed to the risk of ESCC and GCA, especially in Chinese population.	('PLCE1', 'Gene', (41, 46))	('PLCE1', 'Gene', '51196', (41, 46))	('rs2274223', 'Mutation', 'rs2274223', (47, 56))	('GCA', 'Disease', (116, 119))	('rs2274223 G', 'Var', (47, 58))	('ESCC', 'Disease', (107, 111))
634401	23874915	Recently, two independent genome-wide association studies (GWAS) in Chinese subjects simultaneously reported that a novel variant (A5780G, rs2274223) in the phospholipase C epsilon gene (PLCE1) gene was strongly associated with ESCC and GCA.	('rs2274223', 'Mutation', 'rs2274223', (139, 148))	('ESCC', 'Disease', (228, 232))	('phospholipase C epsilon', 'Gene', (157, 180))	('associated', 'Reg', (212, 222))	('PLCE1', 'Gene', (187, 192))	('A5780G', 'Mutation', 'rs2274223', (131, 137))	('rs2274223', 'Var', (139, 148))	('PLCE1', 'Gene', '51196', (187, 192))	('A5780G', 'Var', (131, 137))	('GCA', 'Disease', (237, 240))	('phospholipase C epsilon', 'Gene', '5334', (157, 180))
634405	23874915	The variant rs2274223 is a nonsynonymous SNP located in exon 26 of PLCE1, which causes an amino acid change from histidine to arginine (His1927Arg) in the calcium-dependent lipid-binding (C2) domain of PLCE1 protein.	('PLCE1', 'Gene', '51196', (202, 207))	('His1927Arg', 'SUBSTITUTION', 'None', (136, 146))	('His1927Arg', 'Var', (136, 146))	('arginine', 'Chemical', 'MESH:D001120', (126, 134))	('rs2274223', 'Mutation', 'rs2274223', (12, 21))	('rs2274223', 'Var', (12, 21))	('PLCE1', 'Gene', (67, 72))	('PLCE1', 'Gene', '51196', (67, 72))	('histidine', 'Chemical', 'MESH:D006639', (113, 122))	('PLCE1', 'Gene', (202, 207))	('lipid', 'Chemical', 'MESH:D008055', (173, 178))	('calcium', 'Chemical', 'MESH:D002118', (155, 162))
634406	23874915	Several studies characterized and replicated the PLCE1 rs2274223 alteration in South Africa, Caucasian and Asian population for ESCC and GCA after GWAS.	('rs2274223', 'Mutation', 'rs2274223', (55, 64))	('PLCE1', 'Gene', '51196', (49, 54))	('rs2274223', 'Var', (55, 64))	('PLCE1', 'Gene', (49, 54))
634407	23874915	To summarize the effect of PLCE1 rs2274223 in ESCC and GCA risk, we combined risk estimate data from different populations and performed a meta-analysis.	('ESCC', 'Disease', (46, 50))	('GCA', 'Disease', (55, 58))	('rs2274223', 'Mutation', 'rs2274223', (33, 42))	('rs2274223', 'Var', (33, 42))	('PLCE1', 'Gene', (27, 32))	('PLCE1', 'Gene', '51196', (27, 32))
634413	23874915	Specifically, titles and abstracts were included if they indicated that it was a case-control study on PLCE1 polymorphism.	('PLCE1', 'Gene', '51196', (103, 108))	('PLCE1', 'Gene', (103, 108))	('polymorphism', 'Var', (109, 121))
634414	23874915	The list of all titles and abstracts identified provided a pool of PLCE1 polymorphism studies.	('polymorphism', 'Var', (73, 85))	('PLCE1', 'Gene', '51196', (67, 72))	('PLCE1', 'Gene', (67, 72))
634416	23874915	The risk of ESCC and GCA associated with the PLCE1 rs2274223 variant was indicated by pooled OR with 95% CI.	('rs2274223', 'Var', (51, 60))	('ESCC', 'Disease', (12, 16))	('PLCE1', 'Gene', (45, 50))	('GCA', 'Disease', (21, 24))	('PLCE1', 'Gene', '51196', (45, 50))	('rs2274223', 'Mutation', 'rs2274223', (51, 60))
634418	23874915	The association of PLCE1 rs2274223 polymorphism and ESCC risk was observed in eight studies.	('PLCE1', 'Gene', (19, 24))	('PLCE1', 'Gene', '51196', (19, 24))	('rs2274223 polymorphism', 'Var', (25, 47))	('ESCC', 'Disease', (52, 56))	('rs2274223', 'Mutation', 'rs2274223', (25, 34))
634419	23874915	Overall analysis indicated that the G allele of PLCE1 rs2274223 was significantly associated with increased risk of ESCC, with a pooled OR (95% CI) of 1.26 (1.15-1.39) and P < 0.001 for Z test (Figure 1).	('PLCE1', 'Gene', '51196', (48, 53))	('rs2274223', 'Mutation', 'rs2274223', (54, 63))	('rs2274223', 'Var', (54, 63))	('ESCC', 'Disease', (116, 120))	('PLCE1', 'Gene', (48, 53))
634420	23874915	Furthermore, we investigated the association between the PLCE1 rs2274223 genotype and ESCC risk, assuming dominant and recessive models in five studies.	('PLCE1', 'Gene', (57, 62))	('PLCE1', 'Gene', '51196', (57, 62))	('investigated', 'Reg', (16, 28))	('rs2274223', 'Mutation', 'rs2274223', (63, 72))	('rs2274223', 'Var', (63, 72))	('ESCC', 'Disease', (86, 90))
634421	23874915	The PLCE1 rs2274223 genotype was associated with ESCC risk, as revealed by the recessive genetic model (GG vs. AG+ AA: OR = 1.22; 95% CI = 1.03-1.45; P = 0.024, Figure 2) without genetic heterogeneity (Q = 2.976, I2=0, P heterogeneity = 0.562), dominant model (GG +AG vs. AA: OR = 1.23; 95% CI =1.02-1.49; P =0.032 and P heterogeneity = 0.022, Figure 3), homozygous model (GG vs. AA: OR =1.37; 95% CI =1.11-1.69; P =0.003), and heterozygous model (GA vs. AA: OR =1.21; 95% CI =1.01-1.46; P =0.049) with substantial heterogeneity.	('PLCE1', 'Gene', (4, 9))	('PLCE1', 'Gene', '51196', (4, 9))	('ESCC', 'Disease', (49, 53))	('rs2274223', 'Mutation', 'rs2274223', (10, 19))	('rs2274223', 'Var', (10, 19))
634425	23874915	Figure 5 indicated that the summary odds ratios of PLCE1 rs2274223 on the basis of 2968 cases and 9826 controls, a significantly increased GCA risk was observed for G allele in the total population (P < 0.001), compared with the A allele with the pooled OR of 1.51 (95% CI: 1.35-1.70).	('PLCE1', 'Gene', '51196', (51, 56))	('rs2274223', 'Mutation', 'rs2274223', (57, 66))	('increased', 'PosReg', (129, 138))	('rs2274223', 'Var', (57, 66))	('GCA', 'Disease', (139, 142))	('PLCE1', 'Gene', (51, 56))
634426	23874915	In the present study, the results of our meta-analysis indicated that the G allele of PLCE1 rs2274223 variation was significantly associated with increased risk of ESCC and GCA.	('PLCE1', 'Gene', (86, 91))	('PLCE1', 'Gene', '51196', (86, 91))	('GCA', 'Disease', (173, 176))	('rs2274223', 'Mutation', 'rs2274223', (92, 101))	('rs2274223', 'Var', (92, 101))	('ESCC', 'Disease', (164, 168))	('associated', 'Reg', (130, 140))
634428	23874915	Three independent GWAS recently performed in Chinese populations identified PLCE1 rs2274223 variation as a susceptibility locus for both ESCC and GCA.	('PLCE1', 'Gene', (76, 81))	('rs2274223 variation', 'Var', (82, 101))	('PLCE1', 'Gene', '51196', (76, 81))	('GCA', 'Disease', (146, 149))	('ESCC', 'Disease', (137, 141))	('rs2274223', 'Mutation', 'rs2274223', (82, 91))	('susceptibility', 'Reg', (107, 121))
634429	23874915	To our knowledge, this is the first meta-analysis combining GWAS and replication results to comprehensively evaluate the association between PLCE1 rs2274223 and ESCC and GCA risk.	('PLCE1', 'Gene', '51196', (141, 146))	('association', 'Interaction', (121, 132))	('GCA', 'Disease', (170, 173))	('ESCC', 'Disease', (161, 165))	('rs2274223', 'Mutation', 'rs2274223', (147, 156))	('rs2274223', 'Var', (147, 156))	('PLCE1', 'Gene', (141, 146))
634430	23874915	Overall, we found PLCE1 rs2274223 allele G increased both ESCC and GCA risk with pooled OR (95%CI) of 1.26 (1.15-1.39) and 1.51 (95% CI: 1.35-1.69), respectively.	('GCA', 'Disease', (67, 70))	('PLCE1', 'Gene', '51196', (18, 23))	('increased', 'PosReg', (43, 52))	('ESCC', 'Disease', (58, 62))	('PLCE1', 'Gene', (18, 23))	('rs2274223', 'Mutation', 'rs2274223', (24, 33))	('rs2274223', 'Var', (24, 33))
634431	23874915	Our results further supported that PLCE1 rs2274223 allele G was a common susceptibility locus for ESCC and GCA.	('PLCE1', 'Gene', '51196', (35, 40))	('rs2274223', 'Var', (41, 50))	('GCA', 'Disease', (107, 110))	('ESCC', 'Disease', (98, 102))	('susceptibility', 'Reg', (73, 87))	('rs2274223', 'Mutation', 'rs2274223', (41, 50))	('PLCE1', 'Gene', (35, 40))
634432	23874915	Furthermore, the association with PLCE1 rs2274223 allele G was stronger for GCA than for ESCC.	('GCA', 'Disease', (76, 79))	('stronger', 'Reg', (63, 71))	('rs2274223', 'Mutation', 'rs2274223', (40, 49))	('rs2274223', 'Var', (40, 49))	('PLCE1', 'Gene', (34, 39))	('PLCE1', 'Gene', '51196', (34, 39))
634434	23874915	In addition, recent evidence has demonstrated that PLCE1 rs2274223 variant was associated with improved gastric cancer patient survival.	('patient', 'Species', '9606', (119, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('PLCE1', 'Gene', '51196', (51, 56))	('rs2274223', 'Mutation', 'rs2274223', (57, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('rs2274223', 'Var', (57, 66))	('improved', 'PosReg', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PLCE1', 'Gene', (51, 56))	('gastric cancer', 'Disease', (104, 118))
634438	23874915	However, the mechanism of PLCE1 genetic variation on ESCC and GCA susceptibility is unknown; it will therefore be of interest in future studies to investigate the variant and gene functional change and activity, to assess how PLCE1 rs2274223 genotype influences ESCC and GCA risk.	('influences', 'Reg', (251, 261))	('rs2274223', 'Mutation', 'rs2274223', (232, 241))	('rs2274223', 'Var', (232, 241))	('PLCE1', 'Gene', (226, 231))	('PLCE1', 'Gene', (26, 31))	('PLCE1', 'Gene', '51196', (26, 31))	('ESCC', 'Disease', (262, 266))	('GCA', 'Disease', (271, 274))	('PLCE1', 'Gene', '51196', (226, 231))
634439	23874915	We have noted that the overall frequency of the PLCE1 rs2274223 allele was different in Asians, compared with South Africa and Caucasian in ESCC or GCA patients and controls, suggesting a possible role of ethnic divergence.	('PLCE1', 'Gene', '51196', (48, 53))	('GCA', 'Disease', (148, 151))	('rs2274223', 'Mutation', 'rs2274223', (54, 63))	('rs2274223', 'Var', (54, 63))	('ESCC', 'Disease', (140, 144))	('PLCE1', 'Gene', (48, 53))	('patients', 'Species', '9606', (152, 160))	('different', 'Reg', (75, 84))
634440	23874915	Significant association of PLCE1 rs2274223 variation with ESCC (OR=1.33, 95% CI 1.21-1.45) and GCA (OR =1.56, 95% CI: 1.47-1.64) risk was observed in Chinese population.	('rs2274223', 'Mutation', 'rs2274223', (33, 42))	('rs2274223', 'Var', (33, 42))	('GCA', 'Disease', (95, 98))	('ESCC', 'Disease', (58, 62))	('PLCE1', 'Gene', (27, 32))	('PLCE1', 'Gene', '51196', (27, 32))
634441	23874915	The pooled OR values were higher in Chinese population than in mixed populations under both allele and genotype models, suggesting that the PLCE1 rs2274223 variation has a stronger effect in Chinese population.	('PLCE1', 'Gene', (140, 145))	('rs2274223', 'Mutation', 'rs2274223', (146, 155))	('rs2274223', 'Var', (146, 155))	('PLCE1', 'Gene', '51196', (140, 145))
634442	23874915	We expect that as more studies become available, a more accurate estimation of the relationship of PLCE1 rs2274223 variation and ESCC and GCA will be obtained.	('rs2274223 variation', 'Var', (105, 124))	('GCA', 'Disease', (138, 141))	('ESCC', 'Disease', (129, 133))	('rs2274223', 'Mutation', 'rs2274223', (105, 114))	('PLCE1', 'Gene', (99, 104))	('PLCE1', 'Gene', '51196', (99, 104))
634443	23874915	Since ESCC and GCA are complex and multifactorial diseases, the exact effect of PLCE1 rs2274223 variation in the context of gene-gene and gene-environment interaction was lacking examination.	('PLCE1', 'Gene', (80, 85))	('rs2274223', 'Mutation', 'rs2274223', (86, 95))	('rs2274223', 'Var', (86, 95))	('PLCE1', 'Gene', '51196', (80, 85))	('GCA', 'Disease', (15, 18))	('multifactorial diseases', 'Disease', 'MESH:D004194', (35, 58))	('ESCC', 'Disease', (6, 10))	('multifactorial diseases', 'Disease', (35, 58))
634444	23874915	In conclusion, this meta-analysis provides evidence supporting an association between PLCE1 rs2274223 variation and genetic risk of ESCC or GCA.	('PLCE1', 'Gene', (86, 91))	('rs2274223 variation', 'Var', (92, 111))	('PLCE1', 'Gene', '51196', (86, 91))	('association', 'Interaction', (66, 77))	('rs2274223', 'Mutation', 'rs2274223', (92, 101))	('GCA', 'Disease', (140, 143))	('ESCC', 'Disease', (132, 136))
634445	23874915	However, it is necessary to conduct larger studies in different ethnic populations, with strict selection of patients, and well-matched controls to confirm the association, before PLCE1 rs2274223 variation can be used to prevent ESCC and GCA, and to screen high-risk individuals.	('ESCC', 'Disease', (229, 233))	('rs2274223 variation', 'Var', (186, 205))	('rs2274223', 'Mutation', 'rs2274223', (186, 195))	('PLCE1', 'Gene', '51196', (180, 185))	('patients', 'Species', '9606', (109, 117))	('GCA', 'Disease', (238, 241))	('prevent', 'Reg', (221, 228))	('PLCE1', 'Gene', (180, 185))
634446	22448886	Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy P53 mutations are an adverse prognostic factor in esophageal cancer.	('patients', 'Species', '9606', (94, 102))	('esophageal cancer', 'Disease', (76, 93))	('P53', 'Gene', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', (184, 201))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('P53', 'Gene', '7157', (134, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('KRas', 'Gene', (45, 49))	('KRas', 'Gene', '3845', (45, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('mutations', 'Var', (138, 147))
634447	22448886	P53 and KRas mutations are involved in chemo-radioresistance.	('KRas', 'Gene', (8, 12))	('KRas', 'Gene', '3845', (8, 12))	('chemo-radioresistance', 'CPA', (39, 60))	('involved', 'Reg', (27, 35))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('mutations', 'Var', (13, 22))
634468	22448886	Mutations of the p53 gene are responsible for reduced chemo- and radio-induced apoptosis in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Mutations', 'Var', (0, 9))	('reduced', 'NegReg', (46, 53))	('esophageal cancer', 'Disease', (92, 109))	('p53', 'Gene', (17, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))	('p53', 'Gene', '7157', (17, 20))
634469	22448886	These mutations are present in around 50% of esophageal cancers, and associated with advanced-stage disease, poor response to CRT and shorter survival.	('advanced-stage disease', 'Disease', (85, 107))	('esophageal cancers', 'Disease', (45, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('esophageal cancers', 'Disease', 'MESH:D004938', (45, 63))	('associated with', 'Reg', (69, 84))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('mutations', 'Var', (6, 15))
634470	22448886	It has even been suggested that the analysis of p53 polymorphisms performed on endoscopic biopsies could identify patients with Barrett's esophagus who are at risk of neoplastic progression.	('p53', 'Gene', (48, 51))	('p53', 'Gene', '7157', (48, 51))	('polymorphisms', 'Var', (52, 65))	('patients', 'Species', '9606', (114, 122))	("Barrett's esophagus", 'Disease', (128, 147))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (128, 147))
634472	22448886	It is mutated in 30% of solid tumors, and particularly in 95% of pancreatic cancers and 50% of colon cancer, but probably only in less than 10% of esophageal tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('esophageal tumors', 'Disease', 'MESH:D004938', (147, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('solid tumors', 'Disease', 'MESH:D009369', (24, 36))	('pancreatic cancers', 'Disease', 'MESH:D010190', (65, 83))	('mutated', 'Var', (6, 13))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('colon cancer', 'Phenotype', 'HP:0003003', (95, 107))	('esophageal tumors', 'Phenotype', 'HP:0100751', (147, 164))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('colon cancer', 'Disease', 'MESH:D015179', (95, 107))	('solid tumors', 'Disease', (24, 36))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (65, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('esophageal tumors', 'Disease', (147, 164))	('colon cancer', 'Disease', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('pancreatic cancers', 'Disease', (65, 83))
634474	22448886	In colon cancer, Ras mutations have been shown to be predictive of resistance to anti-EGFR therapy.	('mutations', 'Var', (21, 30))	('resistance', 'MPA', (67, 77))	('EGFR', 'Gene', '1956', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('EGFR', 'Gene', (86, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('colon cancer', 'Disease', (3, 15))	('Ras', 'Gene', (17, 20))
634541	22448886	Table 5 shows the prognostic value of p53 mutations for overall survival, event-free survival and response rate in other reports on esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('esophageal cancer', 'Disease', (132, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('mutations', 'Var', (42, 51))
634545	22448886	Many studies previously demonstrated that p53 antibodies were restricted to cancer patients bearing p53 mutations.	('p53', 'Gene', (42, 45))	('mutations', 'Var', (104, 113))	('p53', 'Gene', '7157', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('p53', 'Gene', '7157', (100, 103))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('p53', 'Gene', (100, 103))
634546	22448886	Indeed, they have the same drawbacks as immunohistochemistry, because they are absent in patients in whom p53 mutations result in the absence of p53 protein synthesis and accumulation.	('p53', 'Gene', '7157', (106, 109))	('accumulation', 'MPA', (171, 183))	('mutations', 'Var', (110, 119))	('absence', 'NegReg', (134, 141))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('patients', 'Species', '9606', (89, 97))	('p53', 'Gene', (106, 109))
634551	22448886	Indeed, the perioperative variations in serum p53 antibodies have been shown to predict overall survival.	('p53', 'Gene', (46, 49))	('predict', 'Reg', (80, 87))	('p53', 'Gene', '7157', (46, 49))	('overall survival', 'CPA', (88, 104))	('variations', 'Var', (26, 36))
634553	22448886	As p53 mutated tumors have a worse prognosis and different response to treatment than p53 wild type tumors, monitoring the p53 tumor status and function is central in the context of individualized medicine.	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutated', 'Var', (7, 14))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('p53', 'Gene', '7157', (86, 89))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('type tumors', 'Disease', 'MESH:D009369', (95, 106))	('tumors', 'Disease', (15, 21))	('p53', 'Gene', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (100, 106))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('p53', 'Gene', '7157', (123, 126))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('p53', 'Gene', '7157', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('p53', 'Gene', (123, 126))	('p53', 'Gene', (3, 6))	('type tumors', 'Disease', (95, 106))
634554	22448886	In brief, our study shows that anti-p53 antibodies are an independent prognostic marker in esophageal cancer patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (109, 117))	('antibodies', 'Var', (40, 50))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('esophageal cancer', 'Disease', (91, 108))
634557	22448886	Larger-scale studies are needed to better define the prognostic implications of p53 mutations, their distribution amongst the histological subtypes of esophageal cancer, and whether treatments should be adapted to the tumor p53 status.	('esophageal cancer', 'Disease', (151, 168))	('p53', 'Gene', (224, 227))	('p53', 'Gene', '7157', (224, 227))	('p53', 'Gene', (80, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mutations', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('p53', 'Gene', '7157', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', (218, 223))
634607	17187659	Human ESCC cell lines, EC9706, TE12, COLO-680N, KYSE510, KYSE450, KYSE410, KYSE180, KYSE150, KYSE140, KYSE70, KYSE30 and YES2 were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum at 37 C under 5% CO2 and saturated moisture.	('Human', 'Species', '9606', (0, 5))	('EC9706', 'CellLine', 'CVCL:E307', (23, 29))	('KYSE450', 'Var', (57, 64))	('bovine', 'Species', '9913', (188, 194))	('KYSE180', 'Var', (75, 82))	('COLO', 'Species', '307630', (37, 41))	('KYSE150', 'Var', (84, 91))	('CO2', 'Chemical', '-', (218, 221))	('KYSE70', 'Var', (102, 108))	('KYSE140', 'Var', (93, 100))	('KYSE410', 'Var', (66, 73))	('KYSE510', 'Var', (48, 55))	('KYSE30', 'Var', (110, 116))	('EC9706', 'Var', (23, 29))
634626	17187659	In addition, we had detected the expression patterns of mutant p53 protein in the TMA (see additional file 1).	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('TMA', 'Chemical', '-', (82, 85))	('mutant', 'Var', (56, 62))	('protein', 'Protein', (67, 74))
634630	17187659	Expression of CK14 was seen only in KYSE180.	('CK14', 'Gene', '3861', (14, 18))	('CK14', 'Gene', (14, 18))	('KYSE180', 'Var', (36, 43))
634631	17187659	High expression of laminin-5gamma2 was detected in COLO-680N, KYSE510, KYSE150, KYSE140, moderate in KYSE410, KYSE180, KYSE70 and negative in others (Figure 4).	('KYSE180', 'Var', (110, 117))	('gamma2', 'Gene', '7453', (28, 34))	('expression', 'MPA', (5, 15))	('KYSE70', 'Var', (119, 125))	('KYSE150', 'Var', (71, 78))	('KYSE510', 'Var', (62, 69))	('KYSE140', 'Var', (80, 87))	('COLO', 'Species', '307630', (51, 55))	('gamma2', 'Gene', (28, 34))	('COLO-680N', 'Var', (51, 60))	('KYSE410', 'Var', (101, 108))
634632	17187659	Six cell lines, EC9706, KYSE450, KYSE180, COLO-680N, KYSE410, KYSE510, which were classified as "strong" migration group, had more migrated cells than the other six cell lines, YES2, KYSE150, KYSE140, KYSE30, KYSE70, TE12, classified as "weak" migration group.	('KYSE410', 'Var', (53, 60))	('more', 'PosReg', (126, 130))	('KYSE510', 'Var', (62, 69))	('COLO', 'Species', '307630', (42, 46))	('EC9706', 'CellLine', 'CVCL:E307', (16, 22))	('migrated cells', 'CPA', (131, 145))
634633	17187659	Among them, EC9706 had the most migrated cells and TE12 had the least migrated cells, which were defined as the "strongest" and the "weakest", respectively.	('EC9706', 'Var', (12, 18))	('EC9706', 'CellLine', 'CVCL:E307', (12, 18))	('least', 'NegReg', (64, 69))	('migrated cells', 'CPA', (32, 46))
634647	17187659	Alterations in cell-cycle regulatory genes are commonly found in human cancers.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cell-cycle regulatory genes', 'Gene', (15, 42))	('cancers', 'Disease', (71, 78))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('found', 'Reg', (56, 61))
634664	17187659	demonstrated that CK14 selectively labeled the basal cells of normal esophageal epithelia and also labeled all DYS, all CIS and all ESCC.. We further found that dysregulation of CK14 might be an "intermediate" and "late" event in ESCC progression, uncommon in mild and moderate DYS, but substantially upregulated in severe DYS and CIS and more universal in relatively late stages of invasive cancers.	('CK14', 'Gene', (178, 182))	('invasive cancers', 'Disease', (383, 399))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (69, 89))	('CIS', 'Phenotype', 'HP:0030075', (331, 334))	('CK14', 'Gene', (18, 22))	('esophageal epithelia', 'Disease', 'MESH:D004941', (69, 89))	('dysregulation', 'Var', (161, 174))	('severe DYS', 'Disease', (316, 326))	('esophageal epithelia', 'Disease', (69, 89))	('ESCC', 'Disease', (230, 234))	('CK14', 'Gene', '3861', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('CIS', 'Phenotype', 'HP:0030075', (120, 123))	('CK14', 'Gene', '3861', (18, 22))	('invasive cancers', 'Disease', 'MESH:D009362', (383, 399))	('upregulated', 'PosReg', (301, 312))	('cancers', 'Phenotype', 'HP:0002664', (392, 399))
634680	17187659	This is partly because characteristic distribution and expression of annexin I have been found in different normal tissues, and dysregulation of annexin I expression has been described in a variety of cancerous and precancerous lesions.	('cancerous', 'Disease', (201, 210))	('precancerous lesions', 'Disease', 'MESH:D011230', (215, 235))	('precancerous lesions', 'Disease', (215, 235))	('cancerous', 'Disease', (218, 227))	('expression', 'MPA', (155, 165))	('cancerous', 'Disease', 'MESH:D009369', (201, 210))	('annexin I', 'Gene', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancerous', 'Disease', 'MESH:D009369', (218, 227))	('dysregulation', 'Var', (128, 141))	('annexin', 'Protein', (69, 76))	('described', 'Reg', (175, 184))
634702	17187659	Thus, its dysregulation might be a "late" step of carcinogenesis.	('dysregulation', 'Var', (10, 23))	('carcinogenesis', 'Disease', (50, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (50, 64))
634705	33066132	Aberrant DNA Methylation of ABC Transporters in Cancer ATP-binding cassette (ABC) transporters play a crucial role in multidrug resistance (MDR) of cancers.	('role', 'Reg', (110, 114))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('ABC', 'Gene', '10058', (77, 80))	('DNA', 'MPA', (9, 12))	('drug resistance', 'Phenotype', 'HP:0020174', (123, 138))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('Aberrant', 'Var', (0, 8))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('ABC', 'Gene', (77, 80))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('ABC', 'Gene', '10058', (28, 31))	('Cancer', 'Disease', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('multidrug resistance', 'Disease', (118, 138))	('ABC', 'Gene', (28, 31))	('MDR', 'Gene', '18669', (140, 143))	('cancers', 'Disease', (148, 155))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('MDR', 'Gene', (140, 143))	('ATP', 'Chemical', 'MESH:D000255', (55, 58))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))
634709	33066132	Alterations in the DNA methylation status of ABC transporters have been reported for a variety of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ABC transporter', 'Gene', (45, 60))	('DNA', 'MPA', (19, 22))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('ABC transporter', 'Gene', '9429', (45, 60))	('Alterations', 'Var', (0, 11))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('reported', 'Reg', (72, 80))	('cancer', 'Disease', (98, 104))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('n', 'Chemical', 'MESH:D009584', (9, 10))
634712	33066132	After giving an overview of the applied methodologies and the CpGs analyzed, we summarize and discuss the findings on aberrant DNA methylation of ABC transporters by cancer types.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('ABC transporter', 'Gene', (146, 161))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('n', 'Chemical', 'MESH:D009584', (153, 154))	('DNA methylation', 'MPA', (127, 142))	('ABC transporter', 'Gene', '9429', (146, 161))	('aberrant', 'Var', (118, 126))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('cancer', 'Disease', (166, 172))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('n', 'Chemical', 'MESH:D009584', (108, 109))
634713	33066132	We conclude our review with the discussion of the potential to target aberrant DNA methylation of ABC transporters for cancer therapy.	('n', 'Chemical', 'MESH:D009584', (54, 55))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('aberrant', 'Var', (70, 78))	('cancer', 'Disease', (119, 125))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('ABC transporter', 'Gene', (98, 113))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('ABC transporter', 'Gene', '9429', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
634722	33066132	Overexpression of ABCB1, ABCC1, and/or ABCG2 is a major cause of MDR in cancer.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('ABCC1', 'Gene', '4363', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('MDR', 'Gene', '18669', (65, 68))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('ABCC1', 'Gene', (25, 30))	('ABCG2', 'Gene', (39, 44))	('ABCB1', 'Gene', (18, 23))	('MDR', 'Gene', (65, 68))	('cause', 'Reg', (56, 61))	('Overexpression', 'Var', (0, 14))	('ABCG2', 'Gene', '9429', (39, 44))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
634725	33066132	Since dysregulation of lipid homeostasis is considered an important factor in carcinogenesis, increasing evidence suggests that altered expression of ABC transporters not only contributes to MDR, but also to initiation, progression, and metastasis of cancer.	('n', 'Chemical', 'MESH:D009584', (178, 179))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('n', 'Chemical', 'MESH:D009584', (217, 218))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('MDR', 'Gene', '18669', (191, 194))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('metastasis', 'CPA', (237, 247))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('MDR', 'Gene', (191, 194))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('n', 'Chemical', 'MESH:D009584', (230, 231))	('ABC transporter', 'Gene', (150, 165))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('contributes', 'Reg', (176, 187))	('n', 'Chemical', 'MESH:D009584', (253, 254))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('progression', 'CPA', (220, 231))	('ABC transporter', 'Gene', '9429', (150, 165))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('lipid', 'Chemical', 'MESH:D008055', (23, 28))	('cancer', 'Disease', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('altered', 'Var', (128, 135))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('n', 'Chemical', 'MESH:D009584', (234, 235))	('initiation', 'CPA', (208, 218))	('n', 'Chemical', 'MESH:D009584', (76, 77))
634726	33066132	Carcinogenesis is a multistep process, driven by the accumulation of genetic and epigenetic alterations.	('Carcinogenesis', 'Disease', (0, 14))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('epigenetic alterations', 'Var', (81, 103))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('n', 'Chemical', 'MESH:D009584', (9, 10))
634727	33066132	Changes in DNA methylation, the most widely studied epigenetic modification, occur more frequently than classical transforming events such as gene mutations and even may precede them.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('DNA methylation', 'MPA', (11, 26))	('n', 'Chemical', 'MESH:D009584', (158, 159))	('n', 'Chemical', 'MESH:D009584', (3, 4))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('Changes', 'Var', (0, 7))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('n', 'Chemical', 'MESH:D009584', (9, 10))
634729	33066132	Compared to normal cells, cancer cells frequently show global genomic hypomethylation, largely due to a loss of methylation of CpG dinucleotides (CpGs) in repetitive elements.	('loss', 'NegReg', (104, 108))	('n', 'Chemical', 'MESH:D009584', (12, 13))	('genomic', 'MPA', (62, 69))	('cancer', 'Disease', (26, 32))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('CpG', 'Var', (127, 130))	('n', 'Chemical', 'MESH:D009584', (171, 172))	('men', 'Species', '9606', (169, 172))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (127, 144))	('n', 'Chemical', 'MESH:D009584', (153, 154))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('methylation', 'MPA', (112, 123))	('n', 'Chemical', 'MESH:D009584', (84, 85))
634732	33066132	Hypermethylation of the promoter region commonly leads to transcriptional inactivation of genes.	('n', 'Chemical', 'MESH:D009584', (15, 16))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('Hypermethylation', 'Var', (0, 16))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('leads to', 'Reg', (49, 57))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('transcriptional', 'MPA', (58, 73))
634733	33066132	Aberrant DNA methylation of genes involved in cell cycle, DNA repair, toxic catabolism, cell adherence, apoptosis, and/or angiogenesis, but also of ABC transporters, has been detected in a variety of cancer types.	('n', 'Chemical', 'MESH:D009584', (44, 45))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('ABC transporter', 'Gene', '9429', (148, 163))	('n', 'Chemical', 'MESH:D009584', (185, 186))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('n', 'Chemical', 'MESH:D009584', (202, 203))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('Aberrant', 'Var', (0, 8))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('detected', 'Reg', (175, 183))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('ABC transporter', 'Gene', (148, 163))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (155, 156))	('cancer', 'Disease', (200, 206))
634737	33066132	After giving an overview of the applied methodologies and the CpGs analyzed, we summarize and discuss the findings on aberrant DNA methylation of ABC transporters by cancer types and the potential to target aberrant DNA methylation of ABC transporters for cancer therapy.	('n', 'Chemical', 'MESH:D009584', (242, 243))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('ABC transporter', 'Gene', (146, 161))	('cancer', 'Disease', (256, 262))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('ABC transporter', 'Gene', '9429', (235, 250))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('n', 'Chemical', 'MESH:D009584', (153, 154))	('DNA methylation', 'MPA', (127, 142))	('ABC transporter', 'Gene', '9429', (146, 161))	('n', 'Chemical', 'MESH:D009584', (230, 231))	('aberrant', 'Var', (118, 126))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('n', 'Chemical', 'MESH:D009584', (191, 192))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('n', 'Chemical', 'MESH:D009584', (213, 214))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('n', 'Chemical', 'MESH:D009584', (180, 181))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('ABC transporter', 'Gene', (235, 250))	('n', 'Chemical', 'MESH:D009584', (258, 259))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('n', 'Chemical', 'MESH:D009584', (108, 109))
634761	33066132	Increasing evidence suggests that polymorphisms in the ABCB1 gene may also affect ABCB1 expression and function.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('ABCB1', 'Gene', (82, 87))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('polymorphisms', 'Var', (34, 47))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('function', 'MPA', (103, 111))	('affect', 'Reg', (75, 81))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('ABCB1', 'Gene', (55, 60))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('expression', 'MPA', (88, 98))	('n', 'Chemical', 'MESH:D009584', (8, 9))
634763	33066132	rs1045642 is in strong linkage disequilibrium with the SNPs rs1128503 (1236C > T, exon 12) and rs2032582 (2677G > T/A, exon 21), with the haplotypes 1236C-2677G-3435C and 1236T-2677T-3435T being most abundant.	('1236C > T', 'Mutation', 'rs1128503', (71, 80))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('1236C-2677G-3435C', 'Var', (149, 166))	('rs1128503', 'Mutation', 'rs1128503', (60, 69))	('1236T-2677T-3435', 'CellLine', 'CVCL:X286', (171, 187))	('2677G > T', 'Var', (106, 115))	('n', 'Chemical', 'MESH:D009584', (192, 193))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('2677G > T', 'SUBSTITUTION', 'None', (106, 115))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('rs1045642', 'Var', (0, 9))	('linkage', 'Interaction', (23, 30))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('rs1045642', 'Mutation', 'rs1045642', (0, 9))	('n', 'Chemical', 'MESH:D009584', (206, 207))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('1236T-2677T-3435T', 'Var', (171, 188))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('n', 'Chemical', 'MESH:D009584', (203, 204))	('rs2032582', 'Mutation', 'rs2032582', (95, 104))
634766	33066132	ABCB1 overexpression in MDR cancer cells is frequently associated with altered expression or activity of transcription factors, but also with gene rearrangements and mutations in the ABCB1 promoter.	('n', 'Chemical', 'MESH:D009584', (19, 20))	('altered', 'Reg', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('overexpression', 'PosReg', (6, 20))	('n', 'Chemical', 'MESH:D009584', (153, 154))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('n', 'Chemical', 'MESH:D009584', (177, 178))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('expression', 'MPA', (79, 89))	('mutations', 'Var', (166, 175))	('MDR', 'Gene', '18669', (24, 27))	('ABCB1', 'Gene', (0, 5))	('associated', 'Reg', (55, 65))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('MDR', 'Gene', (24, 27))	('ABCB1', 'Gene', (183, 188))	('activity', 'MPA', (93, 101))	('n', 'Chemical', 'MESH:D009584', (158, 159))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('cancer', 'Disease', (28, 34))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('men', 'Species', '9606', (156, 159))	('n', 'Chemical', 'MESH:D009584', (163, 164))	('n', 'Chemical', 'MESH:D009584', (108, 109))
634767	33066132	Recently, ABCB1 has been found to be upregulated through fusion of ABCB1 with SLC25A40, the gene upstream of ABCB1, in drug resistant high-grade serous ovarian and breast cancer.	('ABCB1', 'Gene', (67, 72))	('n', 'Chemical', 'MESH:D009584', (161, 162))	('ABCB1', 'Gene', (10, 15))	('upregulated', 'PosReg', (37, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('fusion', 'Var', (57, 63))	('serous ovarian and breast cancer', 'Disease', 'MESH:D018284', (145, 177))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (158, 159))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('SLC25A40', 'Gene', (78, 86))	('SLC25A40', 'Gene', '55972', (78, 86))	('n', 'Chemical', 'MESH:D009584', (131, 132))
634768	33066132	Overexpression of ABCB1 is frequently linked to hypomethylation of the ABCB1 promoter (see Section 4).	('linked', 'Reg', (38, 44))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('ABCB1', 'Gene', (71, 76))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('hypomethylation', 'Var', (48, 63))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('ABCB1', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('n', 'Chemical', 'MESH:D009584', (97, 98))
634779	33066132	Numerous SNPs have been identified in the ABCC1 gene, however, to date none of them has been associated with altered ABCC1 expression.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('SNPs', 'Var', (9, 13))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('ABCC1', 'Gene', (42, 47))	('ABCC1', 'Gene', (117, 122))	('ABCC1', 'Gene', '4363', (42, 47))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('ABCC1', 'Gene', '4363', (117, 122))	('n', 'Chemical', 'MESH:D009584', (73, 74))
634801	33066132	ABCG2 gene amplification has been reported for a variety of cancer types, e.g., breast and colorectal cancer, and glioblastoma.	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('reported', 'Reg', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('glioblastoma', 'Disease', (114, 126))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('amplification', 'Var', (11, 24))	('ABCG2', 'Gene', (0, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('ABCG2', 'Gene', '9429', (0, 5))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('cancer', 'Disease', (102, 108))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast', 'Disease', (80, 86))	('cancer', 'Disease', (60, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
634803	33066132	miRNAs (miR-132-3p, miR-212-3p) have been found to be involved in post-transcriptional regulation of ABCG2 in clear cell renal cell carcinoma.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('miR-212-3p', 'Var', (20, 30))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (110, 141))	('n', 'Chemical', 'MESH:D009584', (137, 138))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('involved', 'Reg', (54, 62))	('clear cell renal cell carcinoma', 'Disease', (110, 141))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('miR-132-3p', 'Gene', '100302255', (8, 18))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (121, 141))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (110, 141))	('ABCG2', 'Gene', (101, 106))	('post-transcriptional regulation', 'MPA', (66, 97))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('ABCG2', 'Gene', '9429', (101, 106))	('miR-132-3p', 'Gene', (8, 18))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (108, 109))
634847	33066132	Mutations in ABCD1 cause X-linked adrenoleukodystrophy, a progressive neurodegenerative disease, characterized by the accumulation of very long chain fatty acids in plasma and tissues.	('n', 'Chemical', 'MESH:D009584', (148, 149))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('chain', 'Chemical', '-', (144, 149))	('ABCD1', 'Gene', (13, 18))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('Mutations', 'Var', (0, 9))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('fatty acids', 'Chemical', 'MESH:D005227', (150, 161))	('X-linked adrenoleukodystrophy', 'Disease', 'MESH:D000326', (25, 54))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('progressive neurodegenerative disease', 'Phenotype', 'HP:0002180', (58, 95))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('X-linked adrenoleukodystrophy', 'Disease', (25, 54))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('very long chain fatty acids', 'MPA', (134, 161))	('cause', 'Reg', (19, 24))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('ABCD1', 'Gene', '215', (13, 18))	('neurodegenerative disease', 'Disease', 'MESH:D019636', (70, 95))	('neurodegenerative disease', 'Disease', (70, 95))	('n', 'Chemical', 'MESH:D009584', (163, 164))
634857	33066132	Mutations in ABCG5 and ABCG8 cause sitosterolemia, a rare autosomal recessive disorder, characterized by hyperabsorption of plant sterols such as sitosterol.	('sitosterolemia', 'Disease', 'MESH:C537345', (35, 49))	('ABCG8', 'Gene', (23, 28))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (58, 86))	('sitosterolemia', 'Disease', (35, 49))	('ABCG5', 'Gene', (13, 18))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('Mutations', 'Var', (0, 9))	('sitosterol', 'Chemical', 'MESH:C025473', (35, 45))	('ABCG8', 'Gene', '64241', (23, 28))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('autosomal recessive disorder', 'Disease', (58, 86))	('sitosterol', 'Chemical', 'MESH:C025473', (146, 156))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('ABCG5', 'Gene', '64240', (13, 18))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('cause', 'Reg', (29, 34))
634889	33066132	Aberrant DNA methylation has already been detected in various solid and hematological cancers.	('n', 'Chemical', 'MESH:D009584', (88, 89))	('Aberrant', 'Var', (0, 8))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('hematological cancers', 'Disease', 'MESH:D009369', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('hematological cancers', 'Disease', (72, 93))	('DNA', 'Protein', (9, 12))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('detected', 'Reg', (42, 50))
634901	33066132	The ABCB1 promoter has been found to be unmethylated (DMS 114), lowly methylated (<25%; A549, NCI-H520, GLC-4) or highly methylated (>75%; HCC827, NCI-H1703, SW 1573).	('HCC827', 'Var', (139, 145))	('DMS 114', 'Chemical', '-', (54, 61))	('NCI-H1703', 'CellLine', 'CVCL:1490', (147, 156))	('ABCB1', 'Gene', (4, 9))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('unmethylated', 'Chemical', '-', (40, 52))	('NCI-H1703', 'Var', (147, 156))	('HCC827', 'CellLine', 'CVCL:2063', (139, 145))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (31, 32))
634907	33066132	In SW 1573/2R160, a doxorubicin-resistant subline of SW 1573 overexpressing ABCB1 and ABCC1, the ABCB1 promoter was significantly lower methylated compared to the parental cell line.	('lower', 'NegReg', (130, 135))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('and', 'Var', (82, 85))	('methylated', 'MPA', (136, 146))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('overexpressing', 'PosReg', (61, 75))	('n', 'Chemical', 'MESH:D009584', (179, 180))	('ABCC1', 'Gene', (86, 91))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('doxorubicin', 'Chemical', 'MESH:D004317', (20, 31))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('ABCB1', 'Gene', (76, 81))	('n', 'Chemical', 'MESH:D009584', (73, 74))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('ABCC1', 'Gene', '4363', (86, 91))
634911	33066132	Overexpression of ABCG2 in the MDR cell line model PC-6/SN2-5H, established by continuous exposure of PC-6 cells to SN-38, the active metabolite of the DNA topoisomerase I inhibitor irinotecan, was associated with hypomethylation of the ABCG2 promoter.	('n', 'Chemical', 'MESH:D009584', (185, 186))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('ABCG2', 'Gene', (18, 23))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('ABCG2', 'Gene', '9429', (18, 23))	('MDR', 'Gene', '18669', (31, 34))	('PC-6', 'CellLine', 'CVCL:C002', (102, 106))	('MDR', 'Gene', (31, 34))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (191, 192))	('irinotecan', 'Chemical', 'MESH:D000077146', (182, 192))	('hypomethylation', 'Var', (214, 229))	('PC-6', 'CellLine', 'CVCL:C002', (51, 55))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('n', 'Chemical', 'MESH:D009584', (228, 229))	('ABCG2', 'Gene', (237, 242))	('ABCG2', 'Gene', '9429', (237, 242))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('SN-38', 'Chemical', 'MESH:D000077146', (116, 121))
634912	33066132	Findings for MDR cell line models suggest that changes in ABCB1 and ABCG2 promoter methylation are involved in acquiring MDR in lung cancer.	('n', 'Chemical', 'MESH:D009584', (130, 131))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('involved', 'Reg', (99, 107))	('MDR', 'Gene', '18669', (121, 124))	('ABCB1', 'Gene', (58, 63))	('changes', 'Var', (47, 54))	('ABCG2', 'Gene', (68, 73))	('MDR', 'Gene', (121, 124))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('ABCG2', 'Gene', '9429', (68, 73))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('MDR', 'Gene', '18669', (13, 16))	('MDR', 'Gene', (13, 16))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('n', 'Chemical', 'MESH:D009584', (118, 119))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('acquiring', 'PosReg', (111, 120))	('lung cancer', 'Disease', (128, 139))	('n', 'Chemical', 'MESH:D009584', (100, 101))
634915	33066132	The ABCB1 promoter has been found to be methylated in 26 of the 36 tumors, but also in each of the control samples.	('methylated', 'Var', (40, 50))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('ABCB1', 'Gene', (4, 9))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
634920	33066132	Upregulation of ABCB1 was associated with hypermethylation of the ABCB1 promoter.	('Upregulation', 'PosReg', (0, 12))	('ABCB1', 'Gene', (16, 21))	('hypermethylation', 'Var', (42, 58))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('ABCB1', 'Gene', (66, 71))	('n', 'Chemical', 'MESH:D009584', (11, 12))
634939	33066132	Results obtained by BS suggested allele-specific methylation of the ABCB1 downstream promoter and allele-specific regulation of ABCB1 promoter usage in drug-resistant MCF7 cells.	('n', 'Chemical', 'MESH:D009584', (77, 78))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('ABCB1', 'Gene', (68, 73))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('MCF7', 'CellLine', 'CVCL:0031', (167, 171))	('methylation', 'Var', (49, 60))	('ABCB1', 'Gene', (128, 133))
634940	33066132	However, the lack of both ABCB1 upregulation and ABCB1 promoter hypomethylation in MCF7/DOX-2 contradicts to results obtained for other doxorubicin-resistant sublines of MCF7.	('n', 'Chemical', 'MESH:D009584', (78, 79))	('ABCB1', 'Gene', (26, 31))	('upregulation', 'PosReg', (32, 44))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('MCF7', 'CellLine', 'CVCL:0031', (170, 174))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('DOX', 'Chemical', 'MESH:D004317', (88, 91))	('doxorubicin', 'Chemical', 'MESH:D004317', (136, 147))	('n', 'Chemical', 'MESH:D009584', (163, 164))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('ABCB1', 'Gene', (49, 54))	('n', 'Chemical', 'MESH:D009584', (146, 147))	('n', 'Chemical', 'MESH:D009584', (155, 156))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('hypomethylation', 'Var', (64, 79))	('MCF7', 'CellLine', 'CVCL:0031', (83, 87))
634949	33066132	In the study by Sharma et al., reporting ABCB1 promoter hypomethylation, the average methylation status across six CpGs has been determined by MSP.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('hypomethylation', 'Var', (56, 71))	('ABCB1', 'Gene', (41, 46))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (70, 71))
634952	33066132	The ABCB1 promoter has been found to be hypomethylated in 47% of the tumors and 44% of paired sera of IDC patients, but also in two of 15 paired normal breast tissues and three of 30 sera from healthy women.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('n', 'Chemical', 'MESH:D009584', (205, 206))	('women', 'Species', '9606', (201, 206))	('ABCB1', 'Gene', (4, 9))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('hypomethylated', 'Var', (40, 54))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('tumors', 'Disease', (69, 75))	('patients', 'Species', '9606', (106, 114))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (145, 146))
634953	33066132	Hypomethylation of the ABCB1 promoter in tumor and serum samples was associated with a shorter median overall survival of the patients.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('tumor', 'Disease', (41, 46))	('Hypomethylation', 'Var', (0, 15))	('n', 'Chemical', 'MESH:D009584', (131, 132))	('shorter', 'NegReg', (87, 94))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('overall survival', 'MPA', (102, 118))	('patients', 'Species', '9606', (126, 134))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('ABCB1', 'Gene', (23, 28))
634958	33066132	The ABCB1 promoter methylation status correlated with response to doxorubicin treatment, suggesting that it could be used to predict the response to doxorubicin.	('n', 'Chemical', 'MESH:D009584', (29, 30))	('methylation', 'Var', (19, 30))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('response to doxorubicin', 'MPA', (54, 77))	('men', 'Species', '9606', (83, 86))	('ABCB1', 'Gene', (4, 9))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('doxorubicin', 'Chemical', 'MESH:D004317', (149, 160))	('correlated', 'Reg', (38, 48))	('n', 'Chemical', 'MESH:D009584', (159, 160))
634972	33066132	In summary, only two studies have investigated ABCG2 promoter methylation in breast cancer, with none of them reporting aberrant methylation compared to normal breast cells/tissues.	('n', 'Chemical', 'MESH:D009584', (75, 76))	('methylation', 'Var', (62, 73))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('n', 'Chemical', 'MESH:D009584', (153, 154))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('breast cancer', 'Disease', (77, 90))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('ABCG2', 'Gene', (47, 52))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('ABCG2', 'Gene', '9429', (47, 52))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (139, 140))
634974	33066132	In addition, hypomethylation of the ABCB1 promoter in the MDR phenotype of breast cancer has been reported in four out of six studies.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('hypomethylation', 'Var', (13, 28))	('ABCB1', 'Gene', (36, 41))	('MDR', 'Gene', '18669', (58, 61))	('breast cancer', 'Disease', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('MDR', 'Gene', (58, 61))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('n', 'Chemical', 'MESH:D009584', (108, 109))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('n', 'Chemical', 'MESH:D009584', (84, 85))
634975	33066132	These findings suggest a role of ABCB1 promoter methylation in breast carcinogenesis and in establishing the MDR phenotype.	('MDR', 'Gene', (109, 112))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('breast carcinogenesis', 'Disease', (63, 84))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('methylation', 'Var', (48, 59))	('ABCB1', 'Gene', (33, 38))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('MDR', 'Gene', '18669', (109, 112))	('breast carcinogenesis', 'Disease', 'MESH:D001943', (63, 84))
634986	33066132	SW480/tria cells have been found to overexpress ABCB1, and ABCB1 overexpression was associated with ABCB1 promoter hypomethylation.	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('SW480', 'CellLine', 'CVCL:0546', (0, 5))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('ABCB1', 'Gene', (59, 64))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('overexpress', 'PosReg', (36, 47))	('ABCB1', 'Gene', (48, 53))	('ABCB1', 'Gene', (100, 105))	('associated', 'Reg', (84, 94))	('overexpression', 'PosReg', (65, 79))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('hypomethylation', 'Var', (115, 130))
634991	33066132	However, hypomethylation of region 1 of the ABCB1 promoter was not the only mechanism underlying ABCB1 upregulation.	('n', 'Chemical', 'MESH:D009584', (33, 34))	('upregulation', 'PosReg', (103, 115))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('ABCB1', 'Gene', (44, 49))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('ABCB1', 'Gene', (97, 102))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('hypomethylation', 'Var', (9, 24))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('n', 'Chemical', 'MESH:D009584', (114, 115))
634995	33066132	Twenty-six genes including ABCD1 were aberrantly methylated and their methylation status was correlated with gene expression.	('ABCD1', 'Gene', (27, 32))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('ABCD1', 'Gene', '215', (27, 32))	('n', 'Chemical', 'MESH:D009584', (3, 4))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('aberrantly methylated', 'Var', (38, 59))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('n', 'Chemical', 'MESH:D009584', (80, 81))
635002	33066132	have investigated whether DNA methylation changes are linked to better prognosis and higher chemotherapy sensitivity of Epstein-Barr virus-associated gastric cancer (EBVGC), compared to other molecular subtypes.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('methylation changes', 'Var', (30, 49))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('higher', 'PosReg', (85, 91))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('gastric cancer', 'Disease', (150, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('changes', 'Var', (42, 49))	('chemotherapy sensitivity', 'CPA', (92, 116))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('Epstein-Barr virus', 'Species', '10376', (120, 138))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))
635005	33066132	This finding hints at a contribution of ABCG2 promoter hypermethylation to higher sensitivity to chemotherapy in EBVGC.	('n', 'Chemical', 'MESH:D009584', (15, 16))	('sensitivity to chemotherapy', 'MPA', (82, 109))	('hypermethylation', 'Var', (55, 71))	('higher', 'PosReg', (75, 81))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('EBVGC', 'Disease', (113, 118))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('ABCG2', 'Gene', (40, 45))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('ABCG2', 'Gene', '9429', (40, 45))
635010	33066132	These findings suggest that ABCB6 methylation is a potential predictive biomarker for early intrahepatic recurrence of HCV-related hepatic cancers.	('n', 'Chemical', 'MESH:D009584', (112, 113))	('ABCB6', 'Gene', (28, 33))	('methylation', 'Var', (34, 45))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('HCV', 'Species', '11103', (119, 122))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('ABCB6', 'Gene', '10058', (28, 33))	('hepatic cancers', 'Disease', 'MESH:D008113', (131, 146))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('hepatic cancers', 'Disease', (131, 146))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('n', 'Chemical', 'MESH:D009584', (8, 9))
635013	33066132	ABCB1, ABCC1, and ABCG2 mRNA levels were significantly higher in SW1990/GZ than in the parental cell line.	('n', 'Chemical', 'MESH:D009584', (15, 16))	('ABCG2', 'Gene', (18, 23))	('SW1990/GZ', 'Var', (65, 74))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('ABCB1', 'Gene', (0, 5))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('ABCG2', 'Gene', '9429', (18, 23))	('ABCC1', 'Gene', (7, 12))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('higher', 'PosReg', (55, 61))	('ABCC1', 'Gene', '4363', (7, 12))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('SW1990', 'CellLine', 'CVCL:1723', (65, 71))	('mRNA levels', 'MPA', (24, 35))
635016	33066132	including three human sporadic clear cell renal carcinoma cell lines, CpGs 1-52 in the ABCG2 promoter were highly methylated in the cell lines UOK121 and UOK143, resulting in transcriptional silencing.	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (178, 179))	('UOK143', 'Chemical', '-', (154, 160))	('transcriptional', 'MPA', (175, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('CpGs 1-52', 'Var', (70, 79))	('UOK121', 'CellLine', 'CVCL:B100', (143, 149))	('renal carcinoma', 'Phenotype', 'HP:0005584', (42, 57))	('human', 'Species', '9606', (16, 21))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (198, 199))	('ABCG2', 'Gene', (87, 92))	('ABCG2', 'Gene', '9429', (87, 92))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (151, 152))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (31, 57))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('sporadic clear cell renal carcinoma', 'Disease', 'MESH:C538614', (22, 57))	('sporadic clear cell renal carcinoma', 'Disease', (22, 57))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('n', 'Chemical', 'MESH:D009584', (195, 196))	('n', 'Chemical', 'MESH:D009584', (139, 140))	('n', 'Chemical', 'MESH:D009584', (187, 188))
635018	33066132	Hypermethylation of the ABCG2 promoter in the cell lines UOK121 and UOK143 was associated with the methyl CpG binding domain proteins (MBDs) MBD2 and MeCP2, as well as with histone deacetylation and methylation of lysine at position 9 on histone H3 (H3K9).	('associated', 'Reg', (79, 89))	('n', 'Chemical', 'MESH:D009584', (218, 219))	('MBDs', 'Disease', 'None', (135, 139))	('Hypermethylation', 'Var', (0, 16))	('UOK121', 'CellLine', 'CVCL:B100', (57, 63))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('n', 'Chemical', 'MESH:D009584', (243, 244))	('n', 'Chemical', 'MESH:D009584', (178, 179))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('MBD2', 'Gene', '8932', (141, 145))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('UOK143', 'Chemical', '-', (68, 74))	('UOK143', 'Var', (68, 74))	('n', 'Chemical', 'MESH:D009584', (231, 232))	('n', 'Chemical', 'MESH:D009584', (193, 194))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('MBDs', 'Disease', (135, 139))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (15, 16))	('ABCG2', 'Gene', (24, 29))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('ABCG2', 'Gene', '9429', (24, 29))	('MeCP2', 'Gene', '4204', (150, 155))	('histone deacetylation', 'MPA', (173, 194))	('n', 'Chemical', 'MESH:D009584', (236, 237))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('methylation', 'MPA', (199, 210))	('MBD2', 'Gene', (141, 145))	('lysine', 'Chemical', 'MESH:D008239', (214, 220))	('MeCP2', 'Gene', (150, 155))	('n', 'Chemical', 'MESH:D009584', (196, 197))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('n', 'Chemical', 'MESH:D009584', (131, 132))
635026	33066132	Aberrant ABCG2 expression has been found to be regulated post-transcriptionally.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('Aberrant', 'Var', (0, 8))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('ABCG2', 'Gene', (9, 14))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('ABCG2', 'Gene', '9429', (9, 14))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (65, 66))
635034	33066132	Cancer-specific hypermethylation in urine sediments has been reported for 15 genes, including ABCC6.	('n', 'Chemical', 'MESH:D009584', (2, 3))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('ABCC6', 'Gene', (94, 99))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('hypermethylation', 'Var', (16, 32))	('men', 'Species', '9606', (46, 49))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('n', 'Chemical', 'MESH:D009584', (31, 32))
635042	33066132	The ABCB1 promoter has been found to be hypermethylated in a large percentage of primary prostate cancers, whereas it was almost never methylated in benign tissues.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('hypermethylated', 'Var', (40, 55))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('ABCB1', 'Gene', (4, 9))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('primary prostate cancers', 'Disease', (81, 105))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('prostate cancers', 'Phenotype', 'HP:0012125', (89, 105))	('n', 'Chemical', 'MESH:D009584', (151, 152))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('primary prostate cancers', 'Disease', 'MESH:D011471', (81, 105))
635049	33066132	In a study by Enokida et al., including 177 prostate cancer samples and 69 benign prostate hypertrophy samples, the ABCB1 promoter has been found to be significantly more often methylated in prostate cancer samples than in benign prostate hypertrophy samples.	('n', 'Chemical', 'MESH:D009584', (218, 219))	('n', 'Chemical', 'MESH:D009584', (161, 162))	('prostate cancer', 'Disease', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('benign prostate hypertrophy', 'Disease', 'MESH:D011470', (223, 250))	('n', 'Chemical', 'MESH:D009584', (202, 203))	('benign prostate hypertrophy', 'Disease', (75, 102))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('prostate cancer', 'Disease', 'MESH:D011471', (191, 206))	('prostate cancer', 'Phenotype', 'HP:0012125', (191, 206))	('more', 'PosReg', (166, 170))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('n', 'Chemical', 'MESH:D009584', (221, 222))	('n', 'Chemical', 'MESH:D009584', (15, 16))	('prostate cancer', 'Disease', (191, 206))	('benign prostate hypertrophy', 'Disease', (223, 250))	('n', 'Chemical', 'MESH:D009584', (189, 190))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('benign prostate hypertrophy', 'Phenotype', 'HP:0008711', (75, 102))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('n', 'Chemical', 'MESH:D009584', (228, 229))	('n', 'Chemical', 'MESH:D009584', (225, 226))	('benign prostate hypertrophy', 'Disease', 'MESH:D011470', (75, 102))	('ABCB1', 'Gene', (116, 121))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (44, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))	('n', 'Chemical', 'MESH:D009584', (155, 156))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('benign prostate hypertrophy', 'Phenotype', 'HP:0008711', (223, 250))	('methylated', 'Var', (177, 187))
635053	33066132	Hypermethylation of the ABCB1 promoter has been detected in more than 70% of prostate cancer tissues while it occurred rarely in normal prostate tissues.	('n', 'Chemical', 'MESH:D009584', (15, 16))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('detected', 'Reg', (48, 56))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('prostate cancer', 'Disease', (77, 92))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('ABCB1', 'Gene', (24, 29))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))
635056	33066132	The ABCB1 promoter was hypermethylated in 38.2% of samples from patients without prostate cancer recurrence and in 16.1% of patients with biochemical recurrence after radical prostatectomy.	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('prostate cancer', 'Disease', (81, 96))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('hypermethylated', 'Var', (23, 38))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('ABCB1', 'Gene', (4, 9))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('patients', 'Species', '9606', (124, 132))
635058	33066132	The findings described above indicate that ABCB1 promoter hypermethylation is a frequent event in prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('ABCB1', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (73, 74))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('prostate cancer', 'Disease', (98, 113))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('promoter hypermethylation', 'Var', (49, 74))	('n', 'Chemical', 'MESH:D009584', (9, 10))
635066	33066132	ABCA1 promoter hypermethylation and downregulation of ABCA1 expression has been found to contribute to aberrant accumulation of cholesterol in prostate cancer cell lines.	('expression', 'MPA', (60, 70))	('accumulation', 'MPA', (112, 124))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('cholesterol', 'Chemical', 'MESH:D002784', (128, 139))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('ABCA1', 'Gene', (54, 59))	('hypermethylation', 'Var', (15, 31))	('cholesterol', 'MPA', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('n', 'Chemical', 'MESH:D009584', (166, 167))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('prostate cancer', 'Disease', 'MESH:D011471', (143, 158))	('downregulation', 'NegReg', (36, 50))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (143, 158))	('prostate cancer', 'Disease', (143, 158))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('ABCA1', 'Gene', (0, 5))	('n', 'Chemical', 'MESH:D009584', (69, 70))
635067	33066132	Analyses of prostate cancer and benign prostate tissues have shown that ABCA1 promoter hypermethylation occurs frequently in prostate cancer but not in benign prostatic tissue.	('prostate cancer', 'Disease', (12, 27))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('benign prostate', 'Disease', (32, 47))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('promoter', 'MPA', (78, 86))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('hypermethylation', 'Var', (87, 103))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('benign prostate', 'Disease', 'MESH:D011472', (32, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (125, 140))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (125, 140))	('prostate cancer', 'Disease', (125, 140))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (12, 27))	('ABCA1', 'Gene', (72, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (12, 27))
635068	33066132	Interestingly, aberrant ABCA1 promoter methylation was more prevalent in intermediate- and high-grade cancers than in low-grade cancers, suggesting that downregulation of ABCA1 could play a role in the development and progression of prostate cancer.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (233, 248))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('n', 'Chemical', 'MESH:D009584', (156, 157))	('prostate cancer', 'Phenotype', 'HP:0012125', (233, 248))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('n', 'Chemical', 'MESH:D009584', (211, 212))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('prostate cancer', 'Disease', (233, 248))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('methylation', 'Var', (39, 50))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('ABCA1', 'Gene', (171, 176))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('aberrant', 'Var', (15, 23))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('promoter', 'MPA', (30, 38))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('n', 'Chemical', 'MESH:D009584', (166, 167))	('n', 'Chemical', 'MESH:D009584', (215, 216))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('n', 'Chemical', 'MESH:D009584', (244, 245))	('cancers', 'Disease', (102, 109))	('downregulation', 'NegReg', (153, 167))	('intermediate-', 'Disease', (73, 86))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('n', 'Chemical', 'MESH:D009584', (228, 229))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('n', 'Chemical', 'MESH:D009584', (196, 197))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('ABCA1', 'Gene', (24, 29))	('prevalent', 'Reg', (60, 69))	('men', 'Species', '9606', (209, 212))
635072	33066132	ABCG5 was one of the genes more frequently hypermethylated in samples from African-American than in samples from Caucasian men.	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('ABCG5', 'Gene', (0, 5))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('hypermethylated', 'Var', (43, 58))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('men', 'Species', '9606', (123, 126))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('ABCG5', 'Gene', '64240', (0, 5))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (125, 126))
635074	33066132	By analyzing three ovarian cancer cell lines, HEY C2, SK-OV-3, and A2780, and three MDR sublines of A2780 selected against cisplatin, A2780/CP70, A2780/MCP2, and A2780/MCP3, ABCA1 has been found to be expressed in A2780/MCP2 and A2780/MCP3 cells but downregulated in A2780 and A2780/CP70 cells.	('ovarian cancer', 'Disease', 'MESH:D010051', (19, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('downregulated', 'NegReg', (250, 263))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('ABCA1', 'Gene', (174, 179))	('n', 'Chemical', 'MESH:D009584', (274, 275))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('n', 'Chemical', 'MESH:D009584', (265, 266))	('HEY C2', 'CellLine', 'CVCL:X009', (46, 52))	('n', 'Chemical', 'MESH:D009584', (131, 132))	('ovarian cancer', 'Disease', (19, 33))	('n', 'Chemical', 'MESH:D009584', (192, 193))	('SK-OV-3', 'CellLine', 'CVCL:0532', (54, 61))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('ovarian cancer', 'Phenotype', 'HP:0100615', (19, 33))	('n', 'Chemical', 'MESH:D009584', (159, 160))	('n', 'Chemical', 'MESH:D009584', (253, 254))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('MDR', 'Gene', '18669', (84, 87))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('MDR', 'Gene', (84, 87))	('n', 'Chemical', 'MESH:D009584', (226, 227))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('n', 'Chemical', 'MESH:D009584', (212, 213))	('A2780/MCP2', 'Var', (146, 156))	('n', 'Chemical', 'MESH:D009584', (187, 188))
635075	33066132	Downregulation of ABCA1 in A2780 and A2780/CP70 cells was associated with methylation of the ABCA1 promoter.	('methylation', 'Var', (74, 85))	('Downregulation', 'NegReg', (0, 14))	('A2780', 'Var', (27, 32))	('A2780/CP70', 'Var', (37, 47))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (3, 4))	('ABCA1', 'Gene', (18, 23))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('ABCA1', 'Gene', (93, 98))	('n', 'Chemical', 'MESH:D009584', (84, 85))
635079	33066132	In addition, hypermethylation of the ABCA1 promoter was associated with prognosis in ovarian cancer patients.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('prognosis', 'Disease', (72, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('ovarian cancer', 'Disease', 'MESH:D010051', (85, 99))	('ABCA1', 'Gene', (37, 42))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('associated', 'Reg', (56, 66))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('ovarian cancer', 'Disease', (85, 99))	('patients', 'Species', '9606', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('hypermethylation', 'Var', (13, 29))
635096	33066132	By treating the parental cells with 5-aza-dC and trichostatin A and applying chromatin immunoprecipitation, the authors have shown that ABCB1 promoter methylation was associated with methyl-CpG binding protein 2 (MeCP2) and deacetylated histone.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (242, 243))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (161, 162))	('methylation', 'Var', (151, 162))	('histone', 'Protein', (237, 244))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (208, 209))	('ABCB1', 'Gene', (136, 141))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (199, 200))	('deacetylated', 'MPA', (224, 236))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (221, 222))	('MeCP2', 'Gene', '4204', (213, 218))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (36, 44))	('methyl-CpG binding protein 2', 'Gene', '4204', (183, 211))	('trichostatin A', 'Chemical', 'MESH:C012589', (49, 63))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('methyl-CpG binding protein 2', 'Gene', (183, 211))	('MeCP2', 'Gene', (213, 218))	('n', 'Chemical', 'MESH:D009584', (196, 197))	('associated', 'Reg', (167, 177))
635097	33066132	Demethylation and release of MeCP2 from the ABCB1 promoter resulted in histone acetylation and thus transcriptional activation.	('n', 'Chemical', 'MESH:D009584', (15, 16))	('transcriptional', 'MPA', (100, 115))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('MeCP2', 'Gene', (29, 34))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('n', 'Chemical', 'MESH:D009584', (12, 13))	('ABCB1', 'Gene', (44, 49))	('histone acetylation', 'MPA', (71, 90))	('Demethylation', 'Var', (0, 13))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('activation', 'PosReg', (116, 126))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('MeCP2', 'Gene', '4204', (29, 34))
635110	33066132	In the AML patient cohort, a statistically significant inverse correlation has been found between ABCB1 promoter methylation and ABCB1 gene expression.	('ABCB1', 'Gene', (98, 103))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (137, 138))	('AML', 'Disease', 'MESH:D015470', (7, 10))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('AML', 'Disease', (7, 10))	('n', 'Chemical', 'MESH:D009584', (73, 74))	('AML', 'Phenotype', 'HP:0004808', (7, 10))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('expression', 'MPA', (140, 150))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('methylation', 'Var', (113, 124))	('patient', 'Species', '9606', (11, 18))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('inverse', 'NegReg', (55, 62))	('ABCB1', 'Gene', (129, 134))
635113	33066132	In summary, the findings described above show that alterations in ABCB1 promoter methylation frequently occur in acute leukemia.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('alterations', 'Var', (51, 62))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('promoter', 'MPA', (72, 80))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('acute leukemia', 'Phenotype', 'HP:0002488', (113, 127))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('occur', 'Reg', (104, 109))	('leukemia', 'Phenotype', 'HP:0001909', (119, 127))	('ABCB1', 'Gene', (66, 71))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('acute leukemia', 'Disease', (113, 127))	('acute leukemia', 'Disease', 'MESH:D015470', (113, 127))
635119	33066132	These results suggest a role of ABCB1 promoter hypomethylation in developing MDR in CML.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('hypomethylation', 'Var', (47, 62))	('MDR', 'Gene', (77, 80))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('MDR', 'Gene', '18669', (77, 80))	('CML', 'Phenotype', 'HP:0005506', (84, 87))	('ABCB1', 'Gene', (32, 37))
635137	33066132	However, most ABCB1 inhibitors of the second generation turned out to be substrates of the enzyme cytochrome P4503A4, resulting in unpredictable pharmacokinetic interactions, limiting their application.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('pharmacokinetic interactions', 'MPA', (145, 173))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (181, 182))	('inhibitors', 'Var', (20, 30))	('ABCB1', 'Gene', (14, 19))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('n', 'Chemical', 'MESH:D009584', (171, 172))	('cytochrome P4503A4', 'Gene', '1576', (98, 116))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('n', 'Chemical', 'MESH:D009584', (162, 163))	('cytochrome P4503A4', 'Gene', (98, 116))	('n', 'Chemical', 'MESH:D009584', (155, 156))
635144	33066132	A further strategy to overcome MDR is to target ABC transporters by using epigenetic modulators.	('ABC transporter', 'Gene', (48, 63))	('ABC transporter', 'Gene', '9429', (48, 63))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('MDR', 'Gene', '18669', (31, 34))	('MDR', 'Gene', (31, 34))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('epigenetic modulators', 'Var', (74, 95))	('n', 'Chemical', 'MESH:D009584', (55, 56))
635145	33066132	Epigenetic modulators can trigger effects via altering gene expression by epigenetic mechanisms, in particular by targeting DNA methyl transferases (DNMTs) and/or histone modifying enzymes.	('n', 'Chemical', 'MESH:D009584', (98, 99))	('DNMT', 'Gene', '1786', (149, 153))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('DNMT', 'Gene', (149, 153))	('n', 'Chemical', 'MESH:D009584', (178, 179))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('gene expression', 'MPA', (55, 70))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('targeting', 'Reg', (114, 123))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('n', 'Chemical', 'MESH:D009584', (182, 183))	('Epigenetic modulators', 'Var', (0, 21))	('DNA', 'MPA', (124, 127))	('altering', 'Reg', (46, 54))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (69, 70))
635146	33066132	Increasing evidence suggests that epigenetic modulators have the potential to revert epigenetic aberrations and thus to reprogram neoplastic cells toward a normal state.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('epigenetic aberrations', 'MPA', (85, 107))	('n', 'Chemical', 'MESH:D009584', (156, 157))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('revert', 'NegReg', (78, 84))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('epigenetic modulators', 'Var', (34, 55))
635148	33066132	There are two possibilities how an epigenetic modulator can target DNMTs, either by inhibiting DNMTs or by increasing DNMT activity.	('epigenetic modulator', 'Var', (35, 55))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('DNMT', 'Gene', '1786', (118, 122))	('DNMT', 'Gene', (118, 122))	('DNMT', 'Gene', '1786', (67, 71))	('DNMT', 'Gene', (67, 71))	('DNMT', 'Gene', '1786', (95, 99))	('increasing', 'PosReg', (107, 117))	('DNMT', 'Gene', (95, 99))	('inhibiting', 'NegReg', (84, 94))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('activity', 'MPA', (123, 131))	('n', 'Chemical', 'MESH:D009584', (108, 109))
635149	33066132	Epigenetic modulators inhibiting DNMTs show DNA demethylating activity, whereas those increasing DNMT activity lead to DNA hypermethylation.	('n', 'Chemical', 'MESH:D009584', (94, 95))	('DNMT', 'Gene', '1786', (97, 101))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('DNMT', 'Gene', (97, 101))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('DNMT', 'Gene', '1786', (33, 37))	('hypermethylation', 'MPA', (123, 139))	('DNMT', 'Gene', (33, 37))	('Epigenetic', 'Var', (0, 10))	('DNA demethylating activity', 'MPA', (44, 70))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('inhibiting', 'NegReg', (22, 32))
635158	33066132	Two studies have shown that epigenetic modulators increasing DNMT activity offer the possibility to target cancer stem cells.	('n', 'Chemical', 'MESH:D009584', (33, 34))	('increasing', 'PosReg', (50, 60))	('epigenetic modulators', 'Var', (28, 49))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('activity', 'MPA', (66, 74))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('DNMT', 'Gene', '1786', (61, 65))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('DNMT', 'Gene', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('cancer', 'Disease', (107, 113))
635159	33066132	In a study by Wang et al., afatinib, a tyrosine kinase inhibitor, has been found to increase DNMT activity, resulting in hypermethylation of the ABCG2 promoter and lower ABCG2 mRNA levels in several ABCG2 overexpressing cell lines: MCF7-FLV1000, a flavopiridol-resistant subline of the breast cancer cell line MCF7; S1-M1-80, a mitoxantrone-selected subline of the colon carcinoma cell line S1; CNE-2-s18, a high-metastatic clone of the nasopharyngeal carcinoma cell line CNE2.	('DNMT', 'Gene', '1786', (93, 97))	('n', 'Chemical', 'MESH:D009584', (369, 370))	('DNMT', 'Gene', (93, 97))	('lower', 'NegReg', (164, 169))	('n', 'Chemical', 'MESH:D009584', (161, 162))	('flavopiridol', 'Chemical', 'MESH:C077990', (248, 260))	('ABCG2', 'Gene', (170, 175))	('breast cancer', 'Disease', 'MESH:D001943', (286, 299))	('n', 'Chemical', 'MESH:D009584', (217, 218))	('breast cancer', 'Disease', (286, 299))	('ABCG2', 'Gene', '9429', (170, 175))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (295, 296))	('ABCG2', 'Gene', (145, 150))	('mRNA levels', 'MPA', (176, 187))	('ABCG2', 'Gene', '9429', (145, 150))	('increase', 'PosReg', (84, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (371, 380))	('carcinoma', 'Phenotype', 'HP:0030731', (452, 461))	('colon carcinoma', 'Disease', (365, 380))	('n', 'Chemical', 'MESH:D009584', (446, 447))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('ABCG2', 'Gene', (199, 204))	('carcinoma', 'Disease', (452, 461))	('n', 'Chemical', 'MESH:D009584', (334, 335))	('n', 'Chemical', 'MESH:D009584', (73, 74))	('carcinoma', 'Disease', (371, 380))	('afatinib', 'Var', (27, 35))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (437, 438))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('CNE2', 'Gene', '108353832', (472, 476))	('ABCG2', 'Gene', '9429', (199, 204))	('afatinib', 'Chemical', 'MESH:D000077716', (27, 35))	('CNE', 'CellLine', 'CVCL:6888', (395, 398))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (469, 470))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (189, 190))	('n', 'Chemical', 'MESH:D009584', (268, 269))	('n', 'Chemical', 'MESH:D009584', (388, 389))	('CNE', 'CellLine', 'CVCL:6888', (472, 475))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('S1', 'CellLine', 'CVCL:Z231', (391, 393))	('MCF7', 'CellLine', 'CVCL:0031', (232, 236))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (437, 461))	('breast cancer', 'Phenotype', 'HP:0003002', (286, 299))	('n', 'Chemical', 'MESH:D009584', (355, 356))	('hypermethylation', 'MPA', (121, 137))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('CNE2', 'Gene', (472, 476))	('n', 'Chemical', 'MESH:D009584', (276, 277))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (427, 428))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('carcinoma', 'Disease', 'MESH:D009369', (452, 461))	('MCF7', 'CellLine', 'CVCL:0031', (310, 314))	('colon carcinoma', 'Disease', 'MESH:D003110', (365, 380))	('carcinoma', 'Disease', 'MESH:D009369', (371, 380))	('mitoxantrone', 'Chemical', 'MESH:D008942', (328, 340))	('n', 'Chemical', 'MESH:D009584', (227, 228))	('n', 'Chemical', 'MESH:D009584', (376, 377))	('n', 'Chemical', 'MESH:D009584', (457, 458))	('n', 'Chemical', 'MESH:D009584', (338, 339))	('S1', 'CellLine', 'CVCL:Z231', (316, 318))	('n', 'Chemical', 'MESH:D009584', (307, 308))
635171	33066132	Thus, there is an urgent need for more studies investigating the clinical relevance of aberrant DNA methylation of ABC transporters in these cancer types.	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('ABC transporter', 'Gene', (115, 130))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('ABC transporter', 'Gene', '9429', (115, 130))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('aberrant', 'Var', (87, 95))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('cancer', 'Disease', (141, 147))
635172	33066132	The ABCB1 downstream promoter has been found to be commonly hypermethylated in breast and prostate cancer as well as in acute leukemia.	('n', 'Chemical', 'MESH:D009584', (118, 119))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (79, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('hypermethylated', 'Var', (60, 75))	('ABCB1', 'Gene', (4, 9))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('acute leukemia', 'Phenotype', 'HP:0002488', (120, 134))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('acute leukemia', 'Disease', 'MESH:D015470', (120, 134))	('acute leukemia', 'Disease', (120, 134))
635173	33066132	MDR cell line models and tumors of the MDR phenotype frequently show ABCB1 promoter hypomethylation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('MDR', 'Gene', '18669', (0, 3))	('MDR', 'Gene', (39, 42))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('MDR', 'Gene', (0, 3))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('ABCB1', 'Gene', (69, 74))	('hypomethylation', 'Var', (84, 99))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('promoter', 'MPA', (75, 83))	('MDR', 'Gene', '18669', (39, 42))
635175	33066132	ABCB1 promoter methylation has been found to be inversely correlated with ABCB1 expression at the mRNA and/or protein level in prostate cancer and acute leukemia.	('acute leukemia', 'Disease', (147, 161))	('ABCB1', 'Gene', (74, 79))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('correlated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('methylation', 'Var', (15, 26))	('acute leukemia', 'Disease', 'MESH:D015470', (147, 161))	('ABCB1', 'Gene', (0, 5))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('expression', 'MPA', (80, 90))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('acute leukemia', 'Phenotype', 'HP:0002488', (147, 161))	('prostate cancer', 'Disease', 'MESH:D011471', (127, 142))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('prostate cancer', 'Disease', (127, 142))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('leukemia', 'Phenotype', 'HP:0001909', (153, 161))
635177	33066132	Hypermethylation of the ABCG2 promoter has been reported for colon cancer, multiple myeloma, EBV gastric cancer, and acute leukemia.	('multiple myeloma', 'Disease', (75, 91))	('acute leukemia', 'Phenotype', 'HP:0002488', (117, 131))	('gastric cancer', 'Disease', (97, 111))	('Hypermethylation', 'Var', (0, 16))	('colon cancer', 'Disease', 'MESH:D015179', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('colon cancer', 'Disease', (61, 73))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('multiple myeloma', 'Phenotype', 'HP:0006775', (75, 91))	('n', 'Chemical', 'MESH:D009584', (15, 16))	('acute leukemia', 'Disease', (117, 131))	('ABCG2', 'Gene', (24, 29))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('ABCG2', 'Gene', '9429', (24, 29))	('reported', 'Reg', (48, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('multiple myeloma', 'Disease', 'MESH:D009101', (75, 91))	('colon cancer', 'Phenotype', 'HP:0003003', (61, 73))	('acute leukemia', 'Disease', 'MESH:D015470', (117, 131))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('n', 'Chemical', 'MESH:D009584', (69, 70))
635178	33066132	ABCG2 promoter hypomethylation has been observed in MDR cell line models of ALL leukemia, ovarian carcinoma, and a stem-like cell subpopulation of prostate carcinoma.	('n', 'Chemical', 'MESH:D009584', (161, 162))	('observed', 'Reg', (40, 48))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (90, 107))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('prostate carcinoma', 'Disease', 'MESH:D011471', (147, 165))	('ovarian carcinoma', 'Disease', (90, 107))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('leukemia', 'Disease', (80, 88))	('leukemia', 'Disease', 'MESH:D007938', (80, 88))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('ABCG2', 'Gene', (0, 5))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (147, 165))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (90, 107))	('ABCG2', 'Gene', '9429', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('prostate carcinoma', 'Disease', (147, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('MDR', 'Gene', '18669', (52, 55))	('hypomethylation', 'Var', (15, 30))	('MDR', 'Gene', (52, 55))
635181	33066132	However, findings suggest a potential of targeting cancer stem cells by using epigenetic modulators increasing DNMT activity, resulting in ABCG2 promoter hypermethylation and downregulation of ABCG2.	('n', 'Chemical', 'MESH:D009584', (75, 76))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('n', 'Chemical', 'MESH:D009584', (178, 179))	('ABCG2', 'Gene', (139, 144))	('ABCG2', 'Gene', '9429', (139, 144))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('n', 'Chemical', 'MESH:D009584', (137, 138))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('ABCG2', 'Gene', (193, 198))	('ABCG2', 'Gene', '9429', (193, 198))	('increasing', 'PosReg', (100, 110))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('DNMT', 'Gene', '1786', (111, 115))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('DNMT', 'Gene', (111, 115))	('downregulation', 'NegReg', (175, 189))	('n', 'Chemical', 'MESH:D009584', (188, 189))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('promoter', 'MPA', (145, 153))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('epigenetic modulators', 'Var', (78, 99))	('cancer', 'Disease', (51, 57))	('n', 'Chemical', 'MESH:D009584', (108, 109))	('hypermethylation', 'Var', (154, 170))
635213	32761410	Pathologic analysis showed a well-differentiated adenocarcinoma with short-segment Barrett's esophagus, 0-IIc, 30 x 20 mm, pT1a-SMM ly0 v0 N0 M0, and pStage0 according to the 8th edition of the UICC TNM staging system.	('TNM', 'Gene', '10178', (199, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('adenocarcinoma', 'Disease', (49, 63))	('pT1a-SMM ly0 v0 N0 M0', 'Var', (123, 144))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (83, 102))	('TNM', 'Gene', (199, 202))	('pStage0', 'Var', (150, 157))	("Barrett's esophagus", 'Disease', (83, 102))	('adenocarcinoma', 'Disease', 'MESH:D000230', (49, 63))
635258	31941487	Compared with the corresponding subgroups treated with RT alone, CRT significantly benefited patients with diabetes (P = 0.003), cT4 (P = 0.030) and cN0 (P = 0.049), whereas no benefit was identified between CRT and RT alone in the other subgroups, including cT1-3, cN1, cM, pTLo, pTV, age and gender.	('pTLo', 'Disease', (275, 279))	('diabetes', 'Disease', (107, 115))	('cT4', 'Var', (129, 132))	('diabetes', 'Disease', 'MESH:D003920', (107, 115))	('cN0', 'Var', (149, 152))	('cT1-3', 'Gene', '4102', (259, 264))	('cN1', 'Gene', '84618', (266, 269))	('benefited', 'PosReg', (83, 92))	('cN1', 'Gene', (266, 269))	('patients', 'Species', '9606', (93, 101))	('cT1-3', 'Gene', (259, 264))
635259	31941487	CRT with the current chemotherapy regimens may not improve the survival of elderly ESCC patients compared to RT-alone, except in patients with cT4 stage, cN0 stage or diabetes.	('diabetes', 'Disease', (167, 175))	('cT4 stage', 'Var', (143, 152))	('ESCC', 'Disease', 'MESH:C562729', (83, 87))	('diabetes', 'Disease', 'MESH:D003920', (167, 175))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (88, 96))	('cN0 stage', 'Var', (154, 163))	('ESCC', 'Disease', (83, 87))
635271	31941487	In brief: histologically proven ESCC; > 70 years old and life expectancy >=3 months; pretreatment assessment available to define the clinical stage and to assess the suitability for RT-alone or CRT; Eastern Cooperative Oncology Group scoring (ECOG) <=3; clinical stage of TanyNanyM0 or M1 only with supraclavicular lymph node metastasis (SLNM); no neo- or adjuvant chemotherapy; no post-RT salvage surgery performed; and sufficient follow-up data available for survival assessment.	('ESCC', 'Disease', (32, 36))	('ESCC', 'Disease', 'MESH:C562729', (32, 36))	('Oncology', 'Phenotype', 'HP:0002664', (219, 227))	('TanyNanyM0', 'Var', (272, 282))	('EC', 'Disease', 'MESH:D004938', (243, 245))
635291	31941487	The results indicated that compared with the corresponding subgroups treated with RT-alone, CRT significantly benefited patients with diabetes (P = 0.003), cT4 (P = 0.030) and cN0 (P = 0.049) (Fig.	('diabetes', 'Disease', (134, 142))	('benefited', 'PosReg', (110, 119))	('cT4', 'Var', (156, 159))	('diabetes', 'Disease', 'MESH:D003920', (134, 142))	('patients', 'Species', '9606', (120, 128))	('cN0', 'Var', (176, 179))
635317	31941487	Numerous studies in non-elderly patients have found that for patients with LNM, CRT can achieve a greater survival benefit than RT-alone.	('patients', 'Species', '9606', (32, 40))	('CRT', 'Var', (80, 83))	('patients', 'Species', '9606', (61, 69))	('LNM', 'Disease', (75, 78))	('survival benefit', 'CPA', (106, 122))
635319	31941487	Unfortunately, contrary to the non-elderly patients, the current study found that whether in the entire cohort or in the PSM patients, compared with RT-alone, CRT benefited survival only in N0 patients, and not in N1 patients who were hypothesized to benefit from CC.	('benefited', 'PosReg', (163, 172))	('patients', 'Species', '9606', (193, 201))	('CRT', 'Var', (159, 162))	('patients', 'Species', '9606', (43, 51))	('survival', 'MPA', (173, 181))	('patients', 'Species', '9606', (217, 225))	('patients', 'Species', '9606', (125, 133))
635333	31941487	Our results demonstrated that CRT with the current chemotherapy regimens may not improve the survival of elderly ESCC compared to RT-alone, except in patients with cT4 or cN0 or diabetes.	('diabetes', 'Disease', (178, 186))	('cN0', 'Var', (171, 174))	('ESCC', 'Disease', (113, 117))	('diabetes', 'Disease', 'MESH:D003920', (178, 186))	('cT4', 'Var', (164, 167))	('patients', 'Species', '9606', (150, 158))	('ESCC', 'Disease', 'MESH:C562729', (113, 117))
635342	31769242	The aberrant expression of circRNAs contributes to the initiation and development of various cancers by disrupting the interplay of specific signaling pathways, including the Wnt/beta-catenin pathway, which controls a plethora of cellular processes that drive cancer development.	('contributes', 'Reg', (36, 47))	('interplay', 'MPA', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('disrupting', 'NegReg', (104, 114))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('plethora', 'Phenotype', 'HP:0001050', (218, 226))	('development', 'CPA', (70, 81))	('specific signaling pathways', 'Pathway', (132, 159))	('cancer', 'Disease', (260, 266))	('men', 'Species', '9606', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cir', 'Gene', '9541', (27, 30))	('beta-catenin', 'Gene', (179, 191))	('cancer', 'Disease', (93, 99))	('cancers', 'Disease', (93, 100))	('beta-catenin', 'Gene', '1499', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('aberrant expression', 'Var', (4, 23))	('cir', 'Gene', (27, 30))	('men', 'Species', '9606', (274, 277))
635398	31769242	APC knockdown contributes to the accumulation of beta-catenin in the cytoplasm and transfer to the nucleus.	('beta-catenin', 'Gene', (49, 61))	('APC', 'Phenotype', 'HP:0005227', (0, 3))	('APC', 'Gene', (0, 3))	('beta-catenin', 'Gene', '1499', (49, 61))	('APC', 'Gene', '324', (0, 3))	('transfer', 'MPA', (83, 91))	('knockdown', 'Var', (4, 13))	('accumulation', 'PosReg', (33, 45))
635414	31769242	Moreover, the knockdown of circLgr4 or Lgr4 impaired Wnt/beta-catenin activation and decreased CRC stem cells in tumor, hence circLgr4-peptide-Lgr4 pathway can be used for CRC therapy.	('CRC', 'Phenotype', 'HP:0003003', (172, 175))	('impaired', 'NegReg', (44, 52))	('Lgr4', 'Gene', (143, 147))	('beta-catenin', 'Gene', (57, 69))	('beta-catenin', 'Gene', '1499', (57, 69))	('Lgr4', 'Gene', '55366', (130, 134))	('CRC', 'Disease', 'MESH:D015179', (172, 175))	('Lgr4', 'Gene', (39, 43))	('cir', 'Gene', '9541', (126, 129))	('CRC', 'Disease', (172, 175))	('Lgr4', 'Gene', '55366', (31, 35))	('tumor', 'Disease', (113, 118))	('Lgr4', 'Gene', (31, 35))	('CRC', 'Disease', (95, 98))	('Lgr4', 'Gene', '55366', (143, 147))	('cir', 'Gene', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('CRC', 'Phenotype', 'HP:0003003', (95, 98))	('cir', 'Gene', '9541', (27, 30))	('decreased', 'NegReg', (85, 94))	('Lgr4', 'Gene', '55366', (39, 43))	('cir', 'Gene', (27, 30))	('knockdown', 'Var', (14, 23))	('Lgr4', 'Gene', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CRC', 'Disease', 'MESH:D015179', (95, 98))
635453	31769242	Therefore, modulating the expression levels of some circRNAs can inhibit cancer cell stemness and block liver cancer progression.	('cir', 'Gene', '9541', (52, 55))	('inhibit', 'NegReg', (65, 72))	('liver cancer', 'Phenotype', 'HP:0002896', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer cell stemness and block liver cancer', 'Disease', 'MESH:D009369', (73, 116))	('expression levels', 'MPA', (26, 43))	('modulating', 'Var', (11, 21))	('cir', 'Gene', (52, 55))
635487	31769242	Downregulated circ-ITCH was observed in triple-negative breast cancer, and further studies revealed that circ-ITCH had the ability to inactivate Wnt/beta-catenin signaling pathway by sponging miR-214 and miR-17.	('-ITCH', 'Phenotype', 'HP:0000989', (109, 114))	('cir', 'Gene', (105, 108))	('ITCH', 'Gene', (110, 114))	('ITCH', 'Gene', '83737', (19, 23))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Disease', (56, 69))	('miR-214', 'Gene', '406996', (192, 199))	('-ITCH', 'Phenotype', 'HP:0000989', (18, 23))	('ITCH', 'Phenotype', 'HP:0000989', (19, 23))	('miR-17', 'Gene', '406952', (204, 210))	('cir', 'Gene', '9541', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ITCH', 'Gene', '83737', (110, 114))	('sponging', 'Var', (183, 191))	('beta-catenin', 'Gene', (149, 161))	('miR-214', 'Gene', (192, 199))	('beta-catenin', 'Gene', '1499', (149, 161))	('cir', 'Gene', (14, 17))	('ITCH', 'Gene', (19, 23))	('ITCH', 'Phenotype', 'HP:0000989', (110, 114))	('miR-17', 'Gene', (204, 210))	('inactivate', 'NegReg', (134, 144))	('cir', 'Gene', '9541', (105, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))
635497	31769242	Therefore, cir-ITCH plays an anti-oncogenic role in glioma by sponging miR-214 and increasing ITCH expression.	('sponging', 'Var', (62, 70))	('glioma', 'Disease', (52, 58))	('miR-214', 'Gene', (71, 78))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('-ITCH', 'Phenotype', 'HP:0000989', (14, 19))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('ITCH', 'Phenotype', 'HP:0000989', (94, 98))	('ITCH', 'Gene', '83737', (94, 98))	('cir', 'Gene', (11, 14))	('ITCH', 'Phenotype', 'HP:0000989', (15, 19))	('ITCH', 'Gene', '83737', (15, 19))	('cir', 'Gene', '9541', (11, 14))	('ITCH', 'Gene', (94, 98))	('ITCH', 'Gene', (15, 19))	('increasing', 'PosReg', (83, 93))	('miR-214', 'Gene', '406996', (71, 78))
635500	31769242	noted that cZNF292 silencing can down-regulate the expression of beta-catenin, Cyclin A, and CDK2, which in turn promotes Wnt/beta-catenin signaling pathway while increasing some inhibitors of the pathway, such as APC and Axin.	('beta-catenin', 'Gene', '1499', (65, 77))	('APC', 'Gene', '324', (214, 217))	('inhibitors', 'MPA', (179, 189))	('expression', 'MPA', (51, 61))	('APC', 'Phenotype', 'HP:0005227', (214, 217))	('Axin', 'Gene', '8312', (222, 226))	('Cyclin A', 'Gene', (79, 87))	('increasing', 'PosReg', (163, 173))	('beta-catenin', 'Gene', (126, 138))	('cZNF292', 'Gene', (11, 18))	('promotes', 'PosReg', (113, 121))	('Axin', 'Gene', (222, 226))	('APC', 'Gene', (214, 217))	('beta-catenin', 'Gene', '1499', (126, 138))	('silencing', 'Var', (19, 28))	('CDK2', 'Gene', '1017', (93, 97))	('down-regulate', 'NegReg', (33, 46))	('Cyclin A', 'Gene', '890', (79, 87))	('CDK2', 'Gene', (93, 97))	('beta-catenin', 'Gene', (65, 77))
635501	31769242	Therefore, cZNF292 depletion suppresses glioma progression through the blocking of Wnt/beta-catenin.	('suppresses', 'NegReg', (29, 39))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('depletion', 'Var', (19, 28))	('beta-catenin', 'Gene', (87, 99))	('beta-catenin', 'Gene', '1499', (87, 99))	('glioma', 'Disease', (40, 46))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('cZNF292', 'Gene', (11, 18))
635503	31769242	Hsa_circ_0000177 silencing dramatically suppressed the proliferation and invasion of glioma cells in vitro.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('suppressed', 'NegReg', (40, 50))	('cir', 'Gene', (4, 7))	('glioma', 'Disease', (85, 91))	('silencing', 'Var', (17, 26))	('cir', 'Gene', '9541', (4, 7))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
635504	31769242	In addition, miR-638 knockdown restored the invasion and proliferation of glioma cells transfected with hsa_circ_0000177 small interfering RNA.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('cir', 'Gene', '9541', (108, 111))	('invasion', 'CPA', (44, 52))	('restored', 'PosReg', (31, 39))	('miR-638', 'Gene', '693223', (13, 20))	('glioma', 'Disease', (74, 80))	('small interfering', 'Var', (121, 138))	('proliferation', 'CPA', (57, 70))	('cir', 'Gene', (108, 111))	('miR-638', 'Gene', (13, 20))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
635507	31769242	Therefore, restoring cir-ITCH expression or silencing cZNF292 and hsa_circ_0000177 may provide a potential direction in glioma treatment.	('ITCH', 'Gene', '83737', (25, 29))	('restoring', 'PosReg', (11, 20))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('ITCH', 'Phenotype', 'HP:0000989', (25, 29))	('-ITCH', 'Phenotype', 'HP:0000989', (24, 29))	('cir', 'Gene', '9541', (70, 73))	('ITCH', 'Gene', (25, 29))	('cZNF292', 'Gene', (54, 61))	('men', 'Species', '9606', (132, 135))	('cir', 'Gene', (21, 24))	('glioma', 'Disease', (120, 126))	('silencing', 'Var', (44, 53))	('cir', 'Gene', (70, 73))	('cir', 'Gene', '9541', (21, 24))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
635536	31769242	Therefore, knocking down of circ-CBFB may be a potential target in the treatment of CLL.	('knocking down', 'Var', (11, 24))	('CBFB', 'Gene', '865', (33, 37))	('CLL', 'Disease', 'MESH:D015451', (84, 87))	('men', 'Species', '9606', (76, 79))	('CBFB', 'Gene', (33, 37))	('CLL', 'Phenotype', 'HP:0005550', (84, 87))	('CLL', 'Disease', (84, 87))	('cir', 'Gene', (28, 31))	('cir', 'Gene', '9541', (28, 31))
635541	31769242	Furthermore, suppression of tumor growth by knockdown of has_circ_0002577 was observed in vivo.	('tumor', 'Disease', (28, 33))	('cir', 'Gene', (61, 64))	('knockdown', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('cir', 'Gene', '9541', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('suppression', 'NegReg', (13, 24))
635652	30410609	Although the non-significant difference between the overall GC cases and control subjects, Veillonella was associated with increased risk of cardia cancer, which is a unique part connecting the esophagus and stomach.	('cardia cancer', 'Disease', 'MESH:D004938', (141, 154))	('GC', 'Phenotype', 'HP:0012126', (60, 62))	('Veillonella', 'Var', (91, 102))	('cardia cancer', 'Disease', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Veillonella', 'Species', '39777', (91, 102))
635665	28723101	Over the last several years, peptides have been considered to have fundamental benefits over other affinity agents, such as antibodies, due to their fast blood clearance, low immunogenicity, rapid tissue penetration, and reproducible chemical synthesis.	('peptides', 'Var', (29, 37))	('benefits', 'PosReg', (79, 87))	('peptide', 'Chemical', 'MESH:D010455', (29, 36))
635727	28723101	There are also hybrid AAV libraries created by shuffling the DNA of the capsid genes of several different AAVs.	('AAV', 'Gene', (106, 109))	('AAV', 'Gene', '17', (106, 109))	('AAV', 'Gene', (22, 25))	('AAV', 'Gene', '17', (22, 25))	('shuffling', 'Var', (47, 56))
635768	28723101	These results were then used to create serotype-independent MrkA antibodies, which were shown to reduce biofilm formation of Klebsiella pneumoniae in vitro (by activating an immune response) and confer protection against Klebsiella pneumoniae in multiple murine pneumonia models.	('reduce biofilm formation of Klebsiella', 'Phenotype', 'HP:0002742', (97, 135))	('pneumonia', 'Disease', (262, 271))	('biofilm formation', 'CPA', (104, 121))	('pneumonia', 'Disease', 'MESH:D011014', (262, 271))	('pneumonia', 'Phenotype', 'HP:0002090', (232, 241))	('pneumonia', 'Phenotype', 'HP:0002090', (136, 145))	('Klebsiella pneumoniae', 'Species', '573', (125, 146))	('pneumonia', 'Disease', (232, 241))	('antibodies', 'Var', (65, 75))	('pneumonia', 'Disease', 'MESH:D011014', (232, 241))	('pneumonia', 'Disease', (136, 145))	('pneumonia', 'Disease', 'MESH:D011014', (136, 145))	('murine', 'Species', '10090', (255, 261))	('Klebsiella pneumoniae', 'Species', '573', (221, 242))	('pneumonia', 'Phenotype', 'HP:0002090', (262, 271))	('MrkA', 'Gene', (60, 64))	('reduce', 'NegReg', (97, 103))
635800	28723101	These peptides were also able to invoke an anti-Leprae immune response in Balb/c mice, demonstrating their potential application as a vaccine.	('mice', 'Species', '10090', (81, 85))	('invoke', 'Reg', (33, 39))	('anti-Leprae immune response', 'CPA', (43, 70))	('peptides', 'Var', (6, 14))	('peptide', 'Chemical', 'MESH:D010455', (6, 13))
635869	28723101	Furthermore, mice infected with P. brasiliensis had a highly significant reduction in lung colony-forming units upon treatment with the peptide.	('mice', 'Species', '10090', (13, 17))	('peptide', 'Chemical', 'MESH:D010455', (136, 143))	('P. brasiliensis', 'Species', '121759', (32, 47))	('reduction', 'NegReg', (73, 82))	('lung colony-forming units', 'CPA', (86, 111))	('P. brasiliensis', 'Var', (32, 47))
635885	28723101	have also conjugated two lung cancer cell-targeting peptides, TP H1299.1 and TP H2009.1, which were isolated from a 20-mer peptide library, to the anticancer drug Doxorubicin, which is widely used in clinics.	('Doxorubicin', 'Chemical', 'MESH:D004317', (163, 174))	('TP H2009.1', 'Var', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('lung cancer', 'Disease', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('peptide', 'Chemical', 'MESH:D010455', (123, 130))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('H1299.1', 'CellLine', 'CVCL:0060', (65, 72))	('peptide', 'Chemical', 'MESH:D010455', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
635890	28723101	The results in the A54-doxorubicin group showed a reduction in tumor size and prolongation of long-term survival compared to the control group.	('tumor', 'Disease', (63, 68))	('reduction', 'NegReg', (50, 59))	('prolongation', 'PosReg', (78, 90))	('doxorubicin', 'Chemical', 'MESH:D004317', (23, 34))	('long-term survival', 'CPA', (94, 112))	('A54-doxorubicin', 'Var', (19, 34))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
635924	28723101	Recently, an X7 AAV2 library was utilized for screening peptides that efficiently target and deliver genes to the pulmonary vasculature after intravenous administration.	('AAV2', 'Species', '10804', (16, 20))	('genes', 'Var', (101, 106))	('deliver', 'MPA', (93, 100))	('peptide', 'Chemical', 'MESH:D010455', (56, 63))
635940	28723101	The mutant AAV displaying the targeting peptide was shown to demonstrate efficient, target-specific, long-lasting transgene expression in endothelial cell tissues associated with the blood-brain barrier.	('mutant', 'Var', (4, 10))	('AAV', 'Gene', (11, 14))	('peptide', 'Chemical', 'MESH:D010455', (40, 47))	('expression', 'Species', '29278', (124, 134))	('AAV', 'Gene', '17', (11, 14))
635944	28723101	It is an X-linked (caused by a mutation on the X chromosome) genodermatosis, which usually causes anomalies in the skin, appendages, and other organs.	('causes', 'Reg', (91, 97))	('anomalies in the skin', 'Phenotype', 'HP:0000951', (98, 119))	('mutation', 'Var', (31, 39))	('genodermatosis', 'Disease', 'None', (61, 75))	('genodermatosis', 'Disease', (61, 75))
635945	28723101	The gene therapy was shown to ameliorate the severe cerebrovascular pathology associated with incontinentia pigmenti.	('gene therapy', 'Var', (4, 16))	('ameliorate', 'PosReg', (30, 40))	('incontinentia pigmenti', 'Gene', '8517', (94, 116))	('severe cerebrovascular pathology', 'Disease', (45, 77))	('incontinentia pigmenti', 'Gene', (94, 116))
635953	28723101	discovered three cell-targeting peptides: W10-R2-11, W10-R2-21, and W10-R3-18, for the human embryonic progenitor cell line W10.	('peptide', 'Chemical', 'MESH:D010455', (32, 39))	('W10-R2-21', 'Var', (53, 62))	('W10-R3-18', 'Var', (68, 77))	('human', 'Species', '9606', (87, 92))	('W10-R2-11', 'Var', (42, 51))
635964	28723101	The fluorescence microscopy data demonstrated CP15 peptide was the most effective peptide in targeting the colon cancer cell lines SW480 and HT29.	('colon cancer', 'Disease', (107, 119))	('HT29', 'CellLine', 'CVCL:0320', (141, 145))	('peptide', 'Chemical', 'MESH:D010455', (82, 89))	('SW480', 'CellLine', 'CVCL:0546', (131, 136))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('peptide', 'Chemical', 'MESH:D010455', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colon cancer', 'Disease', 'MESH:D015179', (107, 119))	('CP15 peptide', 'Var', (46, 58))
635977	28723101	It is known that mutations in EGF receptor downstream effectors such as KRAS (an oncogene that when mutated can cause normal cells to become cancerous) can cause a constitutive activation of the signaling pathway.	('cause', 'Reg', (156, 161))	('cancerous', 'Disease', (141, 150))	('KRAS', 'Gene', (72, 76))	('EGF receptor', 'Gene', '1956', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('activation', 'PosReg', (177, 187))	('KRAS', 'Gene', '3845', (72, 76))	('cancerous', 'Disease', 'MESH:D009369', (141, 150))	('EGF receptor', 'Gene', (30, 42))	('mutations', 'Var', (17, 26))	('signaling pathway', 'Pathway', (195, 212))
635984	28723101	The two BCAM-mimetic peptides demonstrated efficacy against the hepatic colonization of human KRAS mutant colorectal cancer cells by inhibiting interactions with BCAM and LAMA5.	('BCAM', 'Gene', '4059', (8, 12))	('BCAM', 'Gene', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('KRAS', 'Gene', (94, 98))	('colorectal cancer', 'Disease', (106, 123))	('inhibiting', 'NegReg', (133, 143))	('interactions', 'Interaction', (144, 156))	('BCAM', 'Gene', (8, 12))	('LAMA5', 'Gene', (171, 176))	('KRAS', 'Gene', '3845', (94, 98))	('peptide', 'Chemical', 'MESH:D010455', (21, 28))	('hepatic colonization', 'CPA', (64, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('human', 'Species', '9606', (88, 93))	('mutant', 'Var', (99, 105))	('BCAM', 'Gene', '4059', (162, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('LAMA5', 'Gene', '3911', (171, 176))
635994	28723101	The peptide was then incorporated into a surface-functionalized fluorescent silver nanoparticle and evaluated by injecting it intravenously into mice bearing a p32-expressing breast tumor.	('breast tumor', 'Phenotype', 'HP:0100013', (175, 187))	('p32-expressing', 'Var', (160, 174))	('breast tumor', 'Disease', 'MESH:D001943', (175, 187))	('mice', 'Species', '10090', (145, 149))	('peptide', 'Chemical', 'MESH:D010455', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('breast tumor', 'Disease', (175, 187))
636031	28723101	The results demonstrated that the peptides ALKRQGRTLYGFGG and KIPKASSVPTELSAISTLYL were the most effective at differentiating induced pluripotent stem cells into osteoblasts.	('KIPKASSVPTELSAISTLYL', 'Var', (62, 82))	('peptide', 'Chemical', 'MESH:D010455', (34, 41))	('induced pluripotent', 'MPA', (126, 145))	('differentiating', 'Reg', (110, 125))
636043	28723101	Inhibition of angiogenesis has been established as a way of treating liver fibrosis.	('liver fibrosis', 'Disease', 'MESH:D008103', (69, 83))	('liver fibrosis', 'Phenotype', 'HP:0001395', (69, 83))	('Inhibition', 'Var', (0, 10))	('angiogenesis', 'CPA', (14, 26))	('liver fibrosis', 'Disease', (69, 83))
636063	28723101	That is to say, displaying peptides on AAV2 needs to move from the preclinical stage to the clinical stage.	('peptides', 'Var', (27, 35))	('peptide', 'Chemical', 'MESH:D010455', (27, 34))	('AAV2', 'Species', '10804', (39, 43))	('AAV2', 'Gene', (39, 43))
636064	28723101	It will be an exciting field to follow as new clinical trials using targeting peptides on AAV2 are used to improve a system that already shows great promise.	('AAV2', 'Species', '10804', (90, 94))	('AAV2', 'Gene', (90, 94))	('peptides', 'Var', (78, 86))	('peptide', 'Chemical', 'MESH:D010455', (78, 85))
636085	29416351	Multiple sequential genetic and epigenetic changes are involved in the process of carcinogenesis.	('carcinogenesis', 'Disease', (82, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('epigenetic changes', 'Var', (32, 50))	('involved', 'Reg', (55, 63))
636093	29416351	Overexpression of Axl is reported to correlate with poor prognosis.	('Axl', 'Gene', '558', (18, 21))	('Overexpression', 'Var', (0, 14))	('Axl', 'Gene', (18, 21))
636139	29416351	In esophageal cancer, it has been shown that genetic silencing of Axl can inhibit proliferation, migration and invasion.	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('Axl', 'Gene', '558', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('inhibit', 'NegReg', (74, 81))	('proliferation', 'CPA', (82, 95))	('Axl', 'Gene', (66, 69))	('genetic silencing', 'Var', (45, 62))
636169	28487205	In African Americans, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('haplotype variants', 'Var', (60, 78))	('linked', 'Reg', (128, 134))	('mtDNA', 'Gene', (82, 87))	('depletion', 'MPA', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
636170	28487205	Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome (nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, which in turn can contribute to cancer disparity and tumor aggressiveness related to racial disparities.	('epithelial-to-mesenchymal transition', 'CPA', (181, 217))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (114, 139))	('resistance to apoptosis', 'CPA', (152, 175))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('mito', 'Species', '262676', (83, 87))	('promote', 'PosReg', (144, 151))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (114, 139))	('mitochondrial dysfunction', 'Disease', (114, 139))	('aggressiveness', 'Phenotype', 'HP:0000718', (302, 316))	('mutations', 'Var', (31, 40))	('depletion', 'MPA', (8, 17))	('mito', 'Species', '262676', (114, 118))	('tumor aggressiveness', 'Disease', (296, 316))	('mtDNA', 'Gene', (44, 49))	('lead to', 'Reg', (106, 113))	('cancer', 'Disease', (275, 281))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('metastatic disease', 'CPA', (223, 241))	('contribute', 'Reg', (261, 271))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (296, 316))
636171	28487205	Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African Americans and other ethnicities.	('genetic variations', 'Var', (49, 67))	('mtDNA', 'Gene', (146, 151))	('nDNA', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('cancers', 'Phenotype', 'HP:0002664', (333, 340))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancers', 'Disease', (333, 340))	('cancers', 'Disease', 'MESH:D009369', (333, 340))	('underlie', 'Reg', (281, 289))	('mito', 'Species', '262676', (123, 127))	('tumor', 'Disease', (245, 250))	('mito', 'Species', '262676', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('variations', 'Var', (57, 67))
636173	28487205	In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities.	('differences', 'Var', (23, 34))	('mito', 'Species', '262676', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mito', 'Species', '262676', (94, 98))	('mitochondrial function', 'MPA', (38, 60))	('alter', 'Reg', (65, 70))	('cross talk', 'MPA', (75, 85))	('contribute', 'Reg', (172, 182))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
636180	28487205	Consistently, in human cancers, the mitochondrial genes that encode the components of the electron transport chain (ETC) of OXPHOS are frequently mutated and/or repressed.	('mutated', 'Var', (146, 153))	('human', 'Species', '9606', (17, 22))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('mito', 'Species', '262676', (36, 40))	('cancers', 'Disease', (23, 30))	('mitochondrial genes', 'Gene', (36, 55))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
636197	28487205	mtDNA mutations affect mitochondrial respiratory enzyme complexes and can promote oncogenesis through a) increased production of ROS, b) further damage to the mtDNA, and c) resistance to apoptosis.	('increased production of ROS', 'Phenotype', 'HP:0025464', (105, 132))	('promote', 'PosReg', (74, 81))	('oncogenesis', 'CPA', (82, 93))	('mitochondrial respiratory enzyme complexes', 'Enzyme', (23, 65))	('rat', 'Species', '10116', (42, 45))	('affect', 'Reg', (16, 22))	('production', 'MPA', (115, 125))	('mito', 'Species', '262676', (23, 27))	('damage', 'MPA', (145, 151))	('increased', 'PosReg', (105, 114))	('mtDNA', 'Gene', (0, 5))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('mutations', 'Var', (6, 15))
636200	28487205	The haplogroup M7b2 was associated with a higher risk of leukemia.	('leukemia', 'Disease', (57, 65))	('haplogroup M7b2', 'Var', (4, 19))	('M7b2', 'Var', (15, 19))	('leukemia', 'Phenotype', 'HP:0001909', (57, 65))	('leukemia', 'Disease', 'MESH:D007938', (57, 65))
636202	28487205	In a cohort study, they demonstrated an association for four germline mutations in cytochrome oxidase subunit I (T6253C, C6340T, G6261A, and A6663G).	('T6253C', 'Mutation', 'g.6253T>C', (113, 119))	('C6340T', 'Var', (121, 127))	('C6340T', 'Mutation', 'g.6340C>T', (121, 127))	('G6261A', 'SUBSTITUTION', 'None', (129, 135))	('association', 'Reg', (40, 51))	('T6253C', 'Var', (113, 119))	('A6663G', 'Var', (141, 147))	('A6663G', 'Mutation', 'rs1489050457', (141, 147))	('G6261A', 'Var', (129, 135))	('rat', 'Species', '10116', (31, 34))
636203	28487205	A variety of studies have associated breast cancer risk with certain mtDNA single nucleotide polymorphisms (SNPs) in various populations.	('breast cancer', 'Disease', (37, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('mtDNA', 'Gene', (69, 74))	('single nucleotide polymorphisms', 'Var', (75, 106))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
636204	28487205	In European-American, Polish, Malay, North Indian and AA populations, the G10398A substitution in the N haplogroup affecting the ND3 locus is linked to a higher susceptibility to breast cancer.	('ND3', 'Gene', '4537', (129, 132))	('G10398A', 'Mutation', 'rs2853826', (74, 81))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('G10398A', 'Var', (74, 81))	('breast cancer', 'Disease', (179, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('ND3', 'Gene', (129, 132))
636205	28487205	For AA women, there is a cumulative increase in risk when the T4216C substitution in the ND1 locus is present along with G10398A.	('T4216C', 'Var', (62, 68))	('ND1', 'Gene', '4535', (89, 92))	('G10398A', 'Mutation', 'rs2853826', (121, 128))	('ND1', 'Gene', (89, 92))	('women', 'Species', '9606', (7, 12))	('T4216C', 'Mutation', 'rs117240203', (62, 68))	('G10398A', 'Var', (121, 128))
636206	28487205	Although the A10398G and T16519C substitutions increase breast cancer risk, the T3197C and G13708A SNPs decrease the risk (Figure 2).	('T16519C', 'Mutation', 'g.16519T>C', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('T3197C', 'Var', (80, 86))	('T16519C', 'Var', (25, 32))	('T3197C', 'Mutation', 'rs1343852348', (80, 86))	('A10398G', 'Mutation', 'rs2853826', (13, 20))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('G13708A', 'Var', (91, 98))	('decrease', 'NegReg', (104, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('increase', 'PosReg', (47, 55))	('A10398G', 'Var', (13, 20))	('breast cancer', 'Disease', (56, 69))	('G13708A', 'Mutation', 'g.13708G>A', (91, 98))
636207	28487205	Other cancers that exhibit a higher prevalence in the presence of germline mtDNA mutations include esophageal and pancreatic cancers.	('pancreatic cancers', 'Disease', (114, 132))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('esophageal', 'Disease', (99, 109))	('cancers', 'Disease', (125, 132))	('pancreatic cancers', 'Disease', 'MESH:D010190', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (114, 132))	('mtDNA', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('mutations', 'Var', (81, 90))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))
636208	28487205	The 10398A polymorphism, for instance, confers a higher risk for esophageal cancer for Indian populations.	('10398A', 'Var', (4, 10))	('esophageal cancer', 'Disease', (65, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
636209	28487205	In Chinese, there is an association between mtDNA haplogroups D4a and D5a and increased risk of esophageal cancer.	('D5a', 'Var', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('Chinese', 'Species', '10029', (3, 10))	('mtDNA', 'Gene', (44, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('D4a', 'Var', (62, 65))
636210	28487205	In European haplotypes, the heritable SNP rs2857285 in the ND4 gene is associated with a more invasive form of ovarian cancer.	('ovarian cancer', 'Disease', (111, 125))	('rs2857285', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('rs2857285', 'DBSNP_MENTION', 'None', (42, 51))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('ND4', 'Gene', '4538', (59, 62))	('associated with', 'Reg', (71, 86))	('ND4', 'Gene', (59, 62))
636211	28487205	For patients with pancreatic cancer, germline mutation 16519T in the displacement loop (D-loop) worsened the prognosis.	('pancreatic cancer', 'Disease', (18, 35))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('men', 'Species', '9606', (77, 80))	('germline mutation 16519T', 'Var', (37, 61))	('worsened', 'NegReg', (96, 104))	('patients', 'Species', '9606', (4, 12))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))
636212	28487205	Also, there is an association between a G5460A SNP (in haplogroup H) encoding an A331T substitution in the ND2 gene with pancreatic cancer.	('G5460A', 'Mutation', 'g.5460G>A', (40, 46))	('pancreatic cancer', 'Disease', (121, 138))	('G5460A', 'Var', (40, 46))	('A331T', 'Var', (81, 86))	('A331T', 'Mutation', 'rs3021088', (81, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ND2', 'Gene', (107, 110))	('ND2', 'Gene', '4536', (107, 110))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))
636213	28487205	and Halfdanarson et al., however, did not find any significant correlation between mtDNA polymorphisms and pancreatic cancer in Caucasian populations.	('pancreatic cancer', 'Disease', (107, 124))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('polymorphisms', 'Var', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))	('mtDNA', 'Gene', (83, 88))
636214	28487205	In a multi-ethnic cohort study, the missense 4917 SNP in the ND2 gene was associated with a risk of colorectal cancer in European-Americans but not Africans, Asians, or Latinos.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('ND2', 'Gene', '4536', (61, 64))	('ND2', 'Gene', (61, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('colorectal cancer', 'Disease', (100, 117))	('missense 4917 SNP', 'Var', (36, 53))	('associated', 'Reg', (74, 84))
636215	28487205	The same study also found that, for the T haplotype, the risk of colorectal cancer was elevated.	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('colorectal cancer', 'Disease', (65, 82))	('T haplotype', 'Var', (40, 51))	('elevated', 'PosReg', (87, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))
636220	28487205	Our results demonstrate that depletion of mtDNA promotes apoptotic resistance and tumor aggressiveness.	('depletion', 'Var', (29, 38))	('apoptotic resistance', 'CPA', (57, 77))	('mtDNA', 'Gene', (42, 47))	('aggressiveness', 'Phenotype', 'HP:0000718', (88, 102))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (82, 102))	('rat', 'Species', '10116', (19, 22))	('promotes', 'PosReg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor aggressiveness', 'Disease', (82, 102))
636224	28487205	A low mtDNA content can be caused by mutations in the p53 gene, the POLG gene, and the gene for the mitochondrial transcription factor, TFAM.	('low', 'NegReg', (2, 5))	('caused', 'Reg', (27, 33))	('mtDNA content', 'MPA', (6, 19))	('TFAM', 'Gene', (136, 140))	('p53', 'Gene', (54, 57))	('POLG gene', 'Gene', (68, 77))	('mutations', 'Var', (37, 46))	('mito', 'Species', '262676', (100, 104))
636225	28487205	In a yeast screen designed to identify nuclear genes involved in the maintenance of mtDNA, Zhang and Singh identified more than 50 human homologs whose inactivation caused depletion of mtDNA.	('yeast', 'Species', '4932', (5, 10))	('human', 'Species', '9606', (131, 136))	('inactivation', 'Var', (152, 164))	('mtDNA', 'MPA', (185, 190))	('depletion', 'MPA', (172, 181))
636226	28487205	It is likely that germline variants or somatic mutations in these genes alter mtDNA content and may promote apoptotic resistance and risk of cancers.	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('mtDNA content', 'MPA', (78, 91))	('germline variants', 'Var', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('alter', 'Reg', (72, 77))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('apoptotic resistance', 'CPA', (108, 128))	('promote', 'PosReg', (100, 107))	('cancers', 'Disease', (141, 148))
636228	28487205	In addition to mtDNA depletion, mtDNA variants associated with different races also lead to mitochondria-to-nucleus cross-talk.	('lead to', 'Reg', (84, 91))	('variants', 'Var', (38, 46))	('mitochondria-to-nucleus cross-talk', 'MPA', (92, 126))	('mtDNA', 'Gene', (32, 37))	('mito', 'Species', '262676', (92, 96))
636230	28487205	Mutations in mtDNA have been reported in many cancers.	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('Mutations', 'Var', (0, 9))	('reported', 'Reg', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mtDNA', 'Gene', (13, 18))
636231	28487205	Although these mutations occur throughout the mitochondrial genome, in human cancers, the displacement loop (or D-loop) region is a mutational "hot spot."	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('mito', 'Species', '262676', (46, 50))	('cancers', 'Disease', (77, 84))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('men', 'Species', '9606', (98, 101))	('human', 'Species', '9606', (71, 76))
636233	28487205	Mutations in this region may affect copy numbers and expression of mitochondrial genes, thus making D-loop instabilities a driver of oncogenesis.	('copy numbers', 'MPA', (36, 48))	('affect', 'Reg', (29, 35))	('mitochondrial genes', 'Gene', (67, 86))	('Mutations', 'Var', (0, 9))	('mito', 'Species', '262676', (67, 71))	('expression', 'MPA', (53, 63))
636234	28487205	Maurya et al., who analyzed the D-loop regions in 14 urothelial cell carcinomas, found 28 somatic mutations, which included nine insertion/deletion changes and two single-base substitutions.	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('urothelial cell carcinomas', 'Disease', (53, 79))	('urothelial cell carcinomas', 'Disease', 'MESH:D002292', (53, 79))	('insertion/deletion changes', 'Var', (129, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
636237	28487205	There are also D-Loop mutations in acute lymphoblastic leukemia (ALL) cases, with 89 G insertions, 95 G insertions, 182 C/T substitutions, 308 C insertions, and 311 C insertions, making a total of 132 mutations at 25 locations.	('D-Loop mutations', 'Var', (15, 31))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (35, 63))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('acute lymphoblastic leukemia', 'Disease', (35, 63))	('C insertions', 'Var', (143, 155))	('insertions', 'Var', (87, 97))	('insertions', 'Var', (104, 114))	('182 C/T', 'Mutation', 'rs557454864', (116, 123))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (35, 63))	('C/T substitutions', 'Var', (120, 137))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (41, 63))
636238	28487205	In a comprehensive study involving 54 hepatocellular carcinomas, 31 gastric cancers, 31 lung cancers, and 25 colorectal cancers, the incidence of somatic D-loop mutations in cancers of later stages was higher than that of early-stage cancers.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (38, 62))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('gastric cancers', 'Disease', 'MESH:D013274', (68, 83))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancers', 'Disease', (76, 83))	('gastric cancers', 'Disease', (68, 83))	('gastric cancers', 'Phenotype', 'HP:0012126', (68, 83))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('colorectal cancers', 'Disease', (109, 127))	('lung cancers', 'Disease', 'MESH:D008175', (88, 100))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', (120, 127))	('lung cancers', 'Disease', (88, 100))	('cancers', 'Disease', 'MESH:D009369', (234, 241))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (38, 63))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('lung cancers', 'Phenotype', 'HP:0100526', (88, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (38, 63))	('D-loop mutations', 'Var', (154, 170))	('colorectal cancers', 'Disease', 'MESH:D015179', (109, 127))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers', 'Disease', (93, 100))	('hepatocellular carcinomas', 'Disease', (38, 63))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('cancers', 'Disease', (234, 241))
636239	28487205	In addition to D-loop disruptions, deletions, point mutations, insertions, and duplications in other parts of the mitochondrial genome are known.	('mito', 'Species', '262676', (114, 118))	('D-loop', 'MPA', (15, 21))	('insertions', 'Var', (63, 73))	('deletions', 'Var', (35, 44))	('point mutations', 'Var', (46, 61))
636240	28487205	Somatic mutations in mtDNA genes have been noted in human ovarian, thyroid, salivary, kidney, liver lung, colon, gastric, brain, bladder, head and neck, prostate, and breast cancers, and in leukemia.	('prostate', 'Disease', (153, 161))	('liver lung', 'Disease', (94, 104))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))	('ovarian', 'Disease', (58, 65))	('gastric', 'Disease', (113, 120))	('colon', 'Disease', (106, 111))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('mutations', 'Var', (8, 17))	('kidney', 'Disease', (86, 92))	('salivary', 'Disease', (76, 84))	('leukemia', 'Disease', (190, 198))	('mtDNA', 'Gene', (21, 26))	('leukemia', 'Disease', 'MESH:D007938', (190, 198))	('breast cancers', 'Disease', (167, 181))	('breast cancers', 'Disease', 'MESH:D001943', (167, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('bladder', 'Disease', (129, 136))	('thyroid', 'Disease', (67, 74))	('liver lung', 'Disease', 'MESH:D017093', (94, 104))	('noted', 'Reg', (43, 48))	('breast cancers', 'Phenotype', 'HP:0003002', (167, 181))	('ovarian', 'Disease', 'MESH:D010049', (58, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('human', 'Species', '9606', (52, 57))	('brain', 'Disease', (122, 127))
636241	28487205	For example, a 40-bp insertion localized in the COX I gene appears to be specific for renal cell oncocytoma, and a deletion mutation is resulting in the loss of mtDNA within NADH dehydrogenase subunit III is associated with renal carcinoma.	('renal carcinoma', 'Phenotype', 'HP:0005584', (224, 239))	('renal cell oncocytoma', 'Disease', (86, 107))	('NADH', 'Chemical', 'MESH:D009243', (174, 178))	('mtDNA', 'MPA', (161, 166))	('loss', 'NegReg', (153, 157))	('associated', 'Reg', (208, 218))	('deletion mutation', 'Var', (115, 132))	('renal cell oncocytoma', 'Disease', 'MESH:C537750', (86, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('renal cell oncocytoma', 'Phenotype', 'HP:0011798', (86, 107))	('renal carcinoma', 'Disease', (224, 239))	('renal carcinoma', 'Disease', 'MESH:D002292', (224, 239))
636242	28487205	In cancers of AA women, two variants of the cytochrome b gene, 13G and I2-992T, are more frequent in breast cancer patients compared to healthy controls.	('patients', 'Species', '9606', (115, 123))	('cytochrome b', 'Gene', '4519', (44, 56))	('13G', 'Var', (63, 66))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', (3, 10))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('women', 'Species', '9606', (17, 22))	('cytochrome b', 'Gene', (44, 56))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('I2-992T', 'Var', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
636243	28487205	As determined in a multi-ethnic study, there is also a positive correlation between the SNP T4216C in the ND1 gene and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('colorectal cancer', 'Disease', (119, 136))	('T4216C', 'Mutation', 'rs117240203', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ND1', 'Gene', '4535', (106, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('SNP T4216C', 'Var', (88, 98))	('ND1', 'Gene', (106, 109))
636244	28487205	In a population-based study involving prostate cancer patients of European and AA descent, the frequency of COX I missense mutations was higher in cancer patients compared to healthy controls, with some of these sequence variants possibly representing germ line mutations.	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('patients', 'Species', '9606', (54, 62))	('higher', 'PosReg', (137, 143))	('cancer', 'Disease', (47, 53))	('patients', 'Species', '9606', (154, 162))	('prostate cancer', 'Disease', (38, 53))	('variants', 'Var', (221, 229))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (147, 153))	('COX I', 'Gene', (108, 113))	('missense mutations', 'Var', (114, 132))
636245	28487205	Specifically, the authors associated two SNPs, T6221C and T7389C, with a higher incidence of prostate cancer.	('prostate cancer', 'Disease', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('T6221C', 'Var', (47, 53))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))	('T6221C', 'Mutation', 'g.6221T>C', (47, 53))	('T7389C', 'Var', (58, 64))	('T7389C', 'Mutation', 'rs1262507444', (58, 64))
636246	28487205	In renal cell carcinomas, the co-occurrence of somatic and germ-line mtDNA mutations has been reported.	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('mtDNA', 'Gene', (69, 74))	('renal cell carcinomas', 'Disease', 'MESH:D002292', (3, 24))	('mutations', 'Var', (75, 84))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (3, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('renal cell carcinomas', 'Disease', (3, 24))
636247	28487205	In contrast, somatic variants of the ATP6 and ND3 genes in the Mexican Mestizo populations could not be linked to a higher risk of prostate cancer.	('variants', 'Var', (21, 29))	('linked', 'Reg', (104, 110))	('ND3', 'Gene', (46, 49))	('ATP6', 'Gene', (37, 41))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('ATP6', 'Gene', '4508', (37, 41))	('ND3', 'Gene', '4537', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('prostate cancer', 'Disease', (131, 146))
636248	28487205	suggested that mtDNA mutations in tumors can be divided into two main groups: (1) severe mutations that inhibit OXPHOS, increase ROS production, and promote tumor cell proliferation and (2) milder mutations that permit tumors to adapt to new environments.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', (219, 224))	('mtDNA', 'Gene', (15, 20))	('men', 'Species', '9606', (249, 252))	('mutations', 'Var', (89, 98))	('rat', 'Species', '10116', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('increase ROS production', 'Phenotype', 'HP:0025464', (120, 143))	('tumor', 'Disease', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('OXPHOS', 'MPA', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('promote', 'PosReg', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (157, 162))	('tumors', 'Disease', (34, 40))	('ROS production', 'MPA', (129, 143))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('increase', 'PosReg', (120, 128))	('inhibit', 'NegReg', (104, 111))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))
636249	28487205	The severely deleterious tumorigenic mutations that inhibit mitochondrial respiration could be advantageous in the initial phases of tumor growth when the tumor requires mitochondrial ROS to drive cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('inhibit', 'NegReg', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mito', 'Species', '262676', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (25, 30))	('rat', 'Species', '10116', (79, 82))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mito', 'Species', '262676', (60, 64))	('mutations', 'Var', (37, 46))	('rat', 'Species', '10116', (209, 212))	('tumor', 'Disease', (133, 138))	('mitochondrial respiration', 'MPA', (60, 85))	('ROS', 'Chemical', 'MESH:D017382', (184, 187))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
636250	28487205	However, the adaptive mtDNA mutations may permit the tumor cells to flourish in new environments as they metastasize.	('permit', 'Reg', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('men', 'Species', '9606', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mtDNA', 'Gene', (22, 27))	('tumor', 'Disease', (53, 58))	('mutations', 'Var', (28, 37))
636251	28487205	Since the migratory tumor cells could be exposed to similar environmental challenges as the humans who migrated out of Africa, the same mtDNA mutations might be adaptive in both tumors and people.	('mutations', 'Var', (142, 151))	('tumor', 'Disease', (178, 183))	('people', 'Species', '9606', (189, 195))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('men', 'Species', '9606', (67, 70))	('humans', 'Species', '9606', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('rat', 'Species', '10116', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('rat', 'Species', '10116', (106, 109))	('mtDNA', 'Gene', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (20, 25))
636252	28487205	Both an increase and a decrease in mtDNA copy number are associated with an increased risk for tumorigenesis.	('decrease', 'NegReg', (23, 31))	('mtDNA', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('copy number', 'Var', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
636255	28487205	Depletion of mtDNA may result in disruption of mitochondrial respiration, and the ensuing dysfunction in mito-nuclear signaling can drive oncogenesis.	('drive', 'PosReg', (132, 137))	('dysfunction', 'Var', (90, 101))	('result in', 'Reg', (23, 32))	('disruption', 'NegReg', (33, 43))	('mito-nuclear signaling', 'MPA', (105, 127))	('Depletion', 'Var', (0, 9))	('mito', 'Species', '262676', (105, 109))	('mito', 'Species', '262676', (47, 51))	('mtDNA', 'Gene', (13, 18))	('oncogenesis', 'CPA', (138, 149))	('mitochondrial respiration', 'MPA', (47, 72))	('rat', 'Species', '10116', (66, 69))
636257	28487205	Mutations in or depletion of mtDNA can have a causative effect in carcinogenesis through disruption of the OXPHOS enzyme complexes and the ensuing oxidative stress and retrograde signaling.	('oxidative stress', 'MPA', (147, 163))	('retrograde signaling', 'MPA', (168, 188))	('oxidative stress', 'Phenotype', 'HP:0025464', (147, 163))	('mtDNA', 'Gene', (29, 34))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('disruption', 'NegReg', (89, 99))	('depletion', 'MPA', (16, 25))	('Mutations in', 'Var', (0, 12))	('causative effect', 'Reg', (46, 62))	('carcinogenesis', 'Disease', (66, 80))	('OXPHOS enzyme complexes', 'MPA', (107, 130))
636258	28487205	Conversely, mtDNA dysfunction may not directly generate the cancer phenotype but influence tumor progression and maintenance by causing a metabolic shift from respiration to aerobic glycolysis.	('influence', 'Reg', (81, 90))	('metabolic shift from respiration', 'MPA', (138, 170))	('maintenance', 'CPA', (113, 124))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('causing', 'Reg', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mtDNA dysfunction', 'Var', (12, 29))	('rat', 'Species', '10116', (164, 167))	('tumor', 'Disease', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('rat', 'Species', '10116', (51, 54))
636260	28487205	Prostate cell (PC3) cybrids harboring the T8993G mtDNA mutation generate tumors that are seven times larger than wild-type cybrids, which barely grew in mice.	('mtDNA', 'Gene', (49, 54))	('PC3', 'Gene', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('T8993G', 'Var', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('rat', 'Species', '10116', (68, 71))	('tumors', 'Disease', (73, 79))	('T8993G', 'Mutation', 'g.8993T>G', (42, 48))	('mice', 'Species', '10090', (153, 157))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('PC3', 'Gene', '30951', (15, 18))
636261	28487205	Additionally, after transplantation into nude mice, cybrids constructed using a common HeLa nucleus and mitochondria containing a point mutation in ATP synthase subunit 6 conferred a growth advantage in early tumor stages, possibly through the prevention of apoptosis.	('growth advantage', 'CPA', (183, 199))	('mito', 'Species', '262676', (104, 108))	('tumor', 'Disease', (209, 214))	('point mutation', 'Var', (130, 144))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('nude mice', 'Species', '10090', (41, 50))	('ATP', 'Chemical', 'MESH:D000255', (148, 151))	('HeLa', 'CellLine', 'CVCL:0030', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
636267	28487205	The most parsimonious mechanism explaining NUMT accumulation involves de novo transposition from the mitochondria to the nucleus; however, NUMTs also accumulate via segmental duplication (sometimes within repetitive elements), and possibly by RNA retro-transposition.	('men', 'Species', '9606', (219, 222))	('transposition', 'MPA', (78, 91))	('mito', 'Species', '262676', (101, 105))	('novo transposition', 'Phenotype', 'HP:0011540', (73, 91))	('accumulate', 'PosReg', (150, 160))	('-transposition', 'Phenotype', 'HP:0011540', (252, 266))	('men', 'Species', '9606', (168, 171))	('segmental duplication', 'Var', (165, 186))
636270	28487205	In human cancers, there are mutations in genes encoding OXPHOS proteins, TCA cycle enzymes, mtDNA regulatory elements, and mitochondrial biogenesis.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mito', 'Species', '262676', (123, 127))	('TCA', 'Enzyme', (73, 76))	('men', 'Species', '9606', (112, 115))	('mutations', 'Var', (28, 37))
636271	28487205	Succinate dehydrogenase (SDH), or complex II of the ETC, serves as a link between the TCA cycle and the ETC, and the gene encoding it is frequently mutated in paraganglioma, breast cancer, gastric cancer, and renal carcinoma.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('paraganglioma', 'Disease', 'MESH:D010235', (159, 172))	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('SDH', 'Gene', (25, 28))	('renal carcinoma', 'Disease', (209, 224))	('mutated', 'Var', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('renal carcinoma', 'Phenotype', 'HP:0005584', (209, 224))	('renal carcinoma', 'Disease', 'MESH:D002292', (209, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('paraganglioma', 'Phenotype', 'HP:0002668', (159, 172))	('gastric cancer', 'Disease', (189, 203))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('paraganglioma', 'Disease', (159, 172))	('gastric cancer', 'Disease', 'MESH:D013274', (189, 203))
636273	28487205	Patients with hereditary paraganglioma carry germline mutations in the SDHD gene, whereas mutations in SDHC cause an autosomal dominant form of paraganglioma.	('mutations', 'Var', (90, 99))	('paraganglioma', 'Disease', 'MESH:D010235', (25, 38))	('SDHD', 'Gene', '6392', (71, 75))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('paraganglioma', 'Phenotype', 'HP:0002668', (144, 157))	('hereditary paraganglioma carry', 'Disease', 'MESH:D009386', (14, 44))	('SDHD', 'Gene', (71, 75))	('SDHC', 'Gene', (103, 107))	('paraganglioma', 'Disease', (144, 157))	('paraganglioma', 'Disease', (25, 38))	('Patients', 'Species', '9606', (0, 8))	('paraganglioma', 'Phenotype', 'HP:0002668', (25, 38))	('SDHC', 'Gene', '6391', (103, 107))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('germline mutations', 'Var', (45, 63))	('cause', 'Reg', (108, 113))	('paraganglioma', 'Disease', 'MESH:D010235', (144, 157))	('hereditary paraganglioma carry', 'Disease', (14, 44))
636274	28487205	The main mechanism of SDH mutation-derived tumorigenesis is disruption of the ETC, leading to increases in the levels of cell-damaging ROS.	('mutation-derived', 'Var', (26, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('levels of cell-damaging ROS', 'MPA', (111, 138))	('increases', 'PosReg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ROS', 'Chemical', 'MESH:D017382', (135, 138))	('tumor', 'Disease', (43, 48))	('SDH', 'Gene', (22, 25))
636275	28487205	Also, murine fibroblasts deficient in SDHA cause succinate accumulation and translocation of HIF-1alpha into the nucleus.	('SDHA', 'Gene', (38, 42))	('succinate', 'Chemical', 'MESH:D019802', (49, 58))	('HIF-1alpha', 'Gene', (93, 103))	('HIF-1alpha', 'Gene', '15251', (93, 103))	('deficient', 'Var', (25, 34))	('translocation', 'MPA', (76, 89))	('succinate accumulation', 'MPA', (49, 71))	('murine', 'Species', '10090', (6, 12))
636276	28487205	Mutations in SDHA are seen in pituitary adenoma, and SDHB mutations are associated with an early onset of familial renal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('mutations', 'Var', (58, 67))	('renal carcinoma', 'Phenotype', 'HP:0005584', (115, 130))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (30, 47))	('familial renal carcinoma', 'Disease', (106, 130))	('associated with', 'Reg', (72, 87))	('SDHB', 'Gene', (53, 57))	('Mutations', 'Var', (0, 9))	('familial renal carcinoma', 'Disease', 'MESH:C536851', (106, 130))	('seen', 'Reg', (22, 26))	('pituitary adenoma', 'Disease', (30, 47))	('pituitary adenoma', 'Disease', 'MESH:D010911', (30, 47))	('SDHA', 'Gene', (13, 17))
636278	28487205	Germline mutations in the gene encoding fumarate dehydrogenase (FDH), the TCA cycle enzyme that reversibly hydrates fumarate to malate, is seen in skin leiomyomata, renal cell cancers, and uterine leiomyomas.	('Germline mutations', 'Var', (0, 18))	('skin leiomyomata', 'Disease', 'MESH:C535516', (147, 163))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('fumarate dehydrogenase', 'Gene', (40, 62))	('fumarate dehydrogenase', 'Gene', '128', (40, 62))	('leiomyomas', 'Disease', (197, 207))	('renal cell cancers', 'Disease', 'MESH:D002292', (165, 183))	('rat', 'Species', '10116', (120, 123))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('rat', 'Species', '10116', (110, 113))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (189, 207))	('leiomyomas', 'Disease', 'MESH:D007889', (197, 207))	('seen', 'Reg', (139, 143))	('fumarate', 'Chemical', 'MESH:D005650', (116, 124))	('rat', 'Species', '10116', (44, 47))	('skin leiomyomata', 'Disease', (147, 163))	('FDH', 'Gene', '128', (64, 67))	('renal cell cancers', 'Disease', (165, 183))	('malate', 'Chemical', 'MESH:C030298', (128, 134))	('skin leiomyomata', 'Phenotype', 'HP:0007620', (147, 163))	('FDH', 'Gene', (64, 67))	('fumarate', 'Chemical', 'MESH:D005650', (40, 48))
636279	28487205	identified, in Danish patients with pheochromocytoma or paraganglioma, eight germline variants in the SDHB, SDHC, and SDHD genes.	('paraganglioma', 'Disease', 'MESH:D010235', (56, 69))	('SDHD', 'Gene', (118, 122))	('pheochromocytoma', 'Disease', (36, 52))	('SDHD', 'Gene', '6392', (118, 122))	('patients', 'Species', '9606', (22, 30))	('pheochromocytoma', 'Disease', 'MESH:D010673', (36, 52))	('SDHC', 'Gene', (108, 112))	('variants', 'Var', (86, 94))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (36, 52))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('paraganglioma', 'Phenotype', 'HP:0002668', (56, 69))	('SDHB', 'Gene', (102, 106))	('SDHC', 'Gene', '6391', (108, 112))	('paraganglioma', 'Disease', (56, 69))
636280	28487205	Heterozygous missense mutations in the isocitrate dehydrogenase (IDH) gene are frequently seen in acute myelocytic leukemia (AML), gliomas, and astrocytomas.	('IDH', 'Gene', (65, 68))	('astrocytomas', 'Disease', (144, 156))	('gliomas', 'Disease', (131, 138))	('acute myelocytic leukemia', 'Disease', 'MESH:D015470', (98, 123))	('isocitrate dehydrogenase', 'Gene', (39, 63))	('IDH', 'Gene', '3417', (65, 68))	('acute myelocytic leukemia', 'Phenotype', 'HP:0004808', (98, 123))	('myelocytic leukemia', 'Phenotype', 'HP:0012324', (104, 123))	('Heterozygous missense mutations', 'Var', (0, 31))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('acute myelocytic leukemia', 'Disease', (98, 123))	('astrocytomas', 'Disease', 'MESH:D001254', (144, 156))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('seen', 'Reg', (90, 94))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('AML', 'Disease', 'MESH:D015470', (125, 128))	('AML', 'Disease', (125, 128))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('isocitrate dehydrogenase', 'Gene', '3417', (39, 63))
636283	28487205	Under physiological conditions, IDH de-carboxylates isocitrate to alpha-ketoglutarate and reduces NADP+ to NADPH.	('isocitrate', 'MPA', (52, 62))	('reduces', 'NegReg', (90, 97))	('NADP+', 'MPA', (98, 103))	('NADPH', 'Chemical', 'MESH:D009249', (107, 112))	('de-carboxylates', 'Var', (36, 51))	('isocitrate', 'Chemical', 'MESH:C034219', (52, 62))	('IDH', 'Gene', (32, 35))	('IDH', 'Gene', '3417', (32, 35))	('NADPH', 'MPA', (107, 112))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (66, 85))	('NADP+', 'Chemical', 'MESH:D009249', (98, 103))
636284	28487205	Mutated forms of IDH convert isocitrate to 2-hydroxyglutarate, an oncometabolite that alters global gene expression patterns through DNA methylation and chromatin remodeling.	('IDH', 'Gene', '3417', (17, 20))	('global gene expression patterns', 'MPA', (93, 124))	('alters', 'Reg', (86, 92))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (43, 61))	('isocitrate', 'Chemical', 'MESH:C034219', (29, 39))	('Mutated', 'Var', (0, 7))	('IDH', 'Gene', (17, 20))
636286	28487205	In a cohort of AML patients, the G-allele of the IDH1105 SNP was associated with shorter survival and a poorer prognosis compared to the T-allele.	('G-allele', 'Var', (33, 41))	('AML', 'Disease', 'MESH:D015470', (15, 18))	('IDH1', 'Gene', '3417', (49, 53))	('patients', 'Species', '9606', (19, 27))	('AML', 'Disease', (15, 18))	('survival', 'MPA', (89, 97))	('IDH1', 'Gene', (49, 53))	('shorter', 'NegReg', (81, 88))
636287	28487205	In another study, the SNPs rs12478635 in the IDH1 gene and rs11632348 in the IDH2 gene exhibited associations with death risk for patients with hepatocellular carcinoma.	('SNPs rs12478635', 'Var', (22, 37))	('IDH1', 'Gene', '3417', (45, 49))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (144, 168))	('rs11632348', 'Mutation', 'rs11632348', (59, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('hepatocellular carcinoma', 'Disease', (144, 168))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (144, 168))	('rs11632348', 'Var', (59, 69))	('IDH2', 'Gene', (77, 81))	('patients', 'Species', '9606', (130, 138))	('associations', 'Reg', (97, 109))	('IDH2', 'Gene', '3418', (77, 81))	('rs12478635', 'Mutation', 'rs12478635', (27, 37))	('IDH1', 'Gene', (45, 49))
636291	28487205	Deregulation/mutations in manganese superoxide dismutase (MnSOD/SOD2), glutathione peroxidase (Gpx), and thioredoxin-2 (Trx2) are seen in several human cancers.	('Deregulation/mutations', 'MPA', (0, 22))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('MnSOD', 'Gene', (58, 63))	('thioredoxin-2', 'Gene', (105, 118))	('Deregulation/mutations', 'Var', (0, 22))	('Trx2', 'Gene', (120, 124))	('manganese superoxide dismutase', 'Gene', '6648', (26, 56))	('SOD2', 'Gene', '6648', (64, 68))	('human', 'Species', '9606', (146, 151))	('SOD2', 'Gene', (64, 68))	('thioredoxin-2', 'Gene', '25828', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('manganese superoxide dismutase', 'Gene', (26, 56))	('MnSOD', 'Gene', '6648', (58, 63))	('Trx2', 'Gene', '25828', (120, 124))
636295	28487205	This activity of SOD2 is aided by Sirt2 deacetylase, and loss of the latter promotes oncogenesis.	('Sirt2', 'Gene', '22933', (34, 39))	('oncogenesis', 'CPA', (85, 96))	('activity', 'MPA', (5, 13))	('acetyl', 'Chemical', 'MESH:D003545', (42, 48))	('Sirt2', 'Gene', (34, 39))	('SOD2', 'Gene', '6648', (17, 21))	('promotes', 'PosReg', (76, 84))	('loss', 'Var', (57, 61))	('SOD2', 'Gene', (17, 21))
636298	28487205	Variants of the SOD2 gene are linked to increased susceptibility to various cancers.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('Variants', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('SOD2', 'Gene', '6648', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('SOD2', 'Gene', (16, 20))
636299	28487205	Five SNPs are currently identified: rs7855, rs5746151, rs5746136, rs2758331, and rs4880.	('rs7855', 'Var', (36, 42))	('rs7855', 'Mutation', 'rs7855', (36, 42))	('rs5746136', 'Mutation', 'rs5746136', (55, 64))	('rs4880', 'Var', (81, 87))	('rs2758331', 'Mutation', 'rs2758331', (66, 75))	('rs4880', 'Mutation', 'rs4880', (81, 87))	('rs5746151', 'Var', (44, 53))	('rs5746136', 'Var', (55, 64))	('rs5746151', 'Mutation', 'rs5746151', (44, 53))	('rs2758331', 'Var', (66, 75))
636300	28487205	The rs4880 SNP in the mitochondrial targeting sequence involves a T47C substitution that results in an Ala to Val change in the mitochondrial targeting sequence.	('rs4880', 'Mutation', 'rs4880', (4, 10))	('mito', 'Species', '262676', (128, 132))	('Ala', 'Chemical', 'MESH:D000409', (103, 106))	('Val', 'Chemical', 'MESH:D014633', (110, 113))	('mitochondrial targeting sequence', 'MPA', (128, 160))	('mito', 'Species', '262676', (22, 26))	('Ala to Val change', 'MPA', (103, 120))	('T47C', 'Var', (66, 70))	('T47C', 'Mutation', 'rs4880', (66, 70))	('rs4880', 'Var', (4, 10))
636302	28487205	In a recent study of pediatric medulloblastoma patients, the T47C SNP was linked to a higher incidence of the disease.	('pediatric medulloblastoma', 'Disease', (21, 46))	('patients', 'Species', '9606', (47, 55))	('T47C', 'Mutation', 'rs4880', (61, 65))	('medulloblastoma', 'Phenotype', 'HP:0002885', (31, 46))	('pediatric medulloblastoma', 'Disease', 'MESH:D008527', (21, 46))	('T47C SNP', 'Var', (61, 69))
636303	28487205	In a Chinese population, T47C is associated with a poorer prognosis for gastric cancer and for squamous cell carcinoma.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('Chinese', 'Species', '10029', (5, 12))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('T47C', 'Var', (25, 29))	('T47C', 'Mutation', 'rs4880', (25, 29))	('squamous cell carcinoma', 'Disease', (95, 118))	('gastric cancer', 'Disease', (72, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 118))
636308	28487205	The Gpx1 Pro198Leu SNP is associated with a higher risk of bladder cancer.	('Gpx1', 'Gene', '2876', (4, 8))	('Pro198Leu', 'Mutation', 'rs1050450', (9, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('Gpx1', 'Gene', (4, 8))	('Pro198Leu SNP', 'Var', (9, 22))	('bladder cancer', 'Disease', (59, 73))
636309	28487205	Gpx4 expression is downregulated in pancreatic and breast cancer cells, and there is a Gpx4 deletion in large B-cell lymphomas and renal cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('expression', 'MPA', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('downregulated', 'NegReg', (19, 32))	('pancreatic and breast cancer', 'Disease', 'MESH:D001943', (36, 64))	('deletion', 'Var', (92, 100))	('Gpx4', 'Gene', '2879', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('lymphomas', 'Phenotype', 'HP:0002665', (117, 126))	('Gpx4', 'Gene', '2879', (87, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('lymphomas and renal cancers', 'Disease', 'MESH:D007680', (117, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (117, 125))	('renal cancer', 'Phenotype', 'HP:0009726', (131, 143))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (110, 126))	('Gpx4', 'Gene', (0, 4))	('Gpx4', 'Gene', (87, 91))
636316	28487205	Mutations in either can lead to depletion of mtDNA, which in turn initiates mitochondrial dysfunction.	('mtDNA', 'Gene', (45, 50))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (76, 101))	('turn initiates mitochondrial dysfunction', 'Disease', (61, 101))	('depletion', 'MPA', (32, 41))	('Mutations', 'Var', (0, 9))	('turn initiates mitochondrial dysfunction', 'Disease', 'MESH:D028361', (61, 101))	('lead to', 'Reg', (24, 31))
636317	28487205	In POLG1, there are numerous somatic and germ-line mutations that are associated with various cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('mutations', 'Var', (51, 60))	('POLG1', 'Gene', (3, 8))	('associated', 'Reg', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('POLG1', 'Gene', '5428', (3, 8))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
636318	28487205	detected POLG1 mutations in 63% of breast tumors.	('breast tumors', 'Disease', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('breast tumors', 'Disease', 'MESH:D061325', (35, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (15, 24))	('breast tumors', 'Phenotype', 'HP:0100013', (35, 48))	('POLG1', 'Gene', (9, 14))	('POLG1', 'Gene', '5428', (9, 14))
636321	28487205	In primary tumors, there is a higher frequency of POLG1 mutations, mostly missense mutations and substitutions.	('POLG1', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('substitutions', 'Var', (97, 110))	('primary tumors', 'Disease', (3, 17))	('POLG1', 'Gene', '5428', (50, 55))	('missense mutations', 'Var', (74, 92))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('primary tumors', 'Disease', 'MESH:D001932', (3, 17))
636322	28487205	At the 1143 amino acid position in the polymerase domain, there is a missense variation that changes glutamic acid to glycine.	('glutamic acid to glycine', 'MPA', (101, 125))	('glutamic acid', 'Chemical', 'MESH:D018698', (101, 114))	('glycine', 'Chemical', 'MESH:D005998', (118, 125))	('changes', 'Reg', (93, 100))	('missense variation', 'Var', (69, 87))
636324	28487205	It remains to be determined if E1143G, along with the POLG1 variants, T251I and P587L, are involved in the predisposition to cancer.	('involved', 'Reg', (91, 99))	('POLG1', 'Gene', (54, 59))	('P587L', 'Var', (80, 85))	('E1143G', 'Mutation', 'rs2307441', (31, 37))	('POLG1', 'Gene', '5428', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('E1143G', 'Var', (31, 37))	('P587L', 'Mutation', 'rs113994096', (80, 85))	('T251I', 'Mutation', 'rs113994094', (70, 75))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('T251I', 'Var', (70, 75))
636325	28487205	As determined with a German cohort of patients, an SNP in the promoter region of POLG (rs2856268, A>G) is associated with higher risk of breast cancer.	('SNP in', 'Var', (51, 57))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('rs2856268', 'Var', (87, 96))	('breast cancer', 'Disease', (137, 150))	('POLG', 'Gene', (81, 85))	('patients', 'Species', '9606', (38, 46))	('rs2856268', 'Mutation', 'rs2856268', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
636326	28487205	In the AA population, variants in the CAG repeat sequence length of the POLG gene are associated with increased risk of breast cancer and testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('testicular cancer', 'Disease', (138, 155))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('variants', 'Var', (22, 30))	('testicular cancer', 'Phenotype', 'HP:0010788', (138, 155))	('POLG', 'Gene', (72, 76))	('testicular cancer', 'Disease', 'MESH:D013736', (138, 155))
636327	28487205	As determined for an Indian population, the SNPs, rs41553913 at POLRMT and rs9905016 at POLG2, increase the risk of oral leukoplakia and cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('oral leukoplakia', 'Phenotype', 'HP:0002745', (116, 132))	('rs41553913', 'Var', (50, 60))	('POLG2', 'Gene', '11232', (88, 93))	('oral leukoplakia', 'Disease', 'MESH:D007972', (116, 132))	('rs41553913', 'Mutation', 'rs41553913', (50, 60))	('increase', 'PosReg', (95, 103))	('rs9905016', 'Var', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('rs9905016', 'Mutation', 'rs9905016', (75, 84))	('oral leukoplakia', 'Disease', (116, 132))	('POLG2', 'Gene', (88, 93))	('POLRMT', 'Gene', '5442', (64, 70))	('POLRMT', 'Gene', (64, 70))
636328	28487205	The authors speculate that, in cancer tissues, these polymorphisms are associated with increased mtDNA replication, although the mechanism remains elusive.	('increased', 'PosReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('mtDNA replication', 'CPA', (97, 114))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('polymorphisms', 'Var', (53, 66))
636329	28487205	In colorectal cancers and breast cancers, truncating mutations in TFAM are associated with mtDNA depletion and oxidative stress.	('breast cancers', 'Disease', (26, 40))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('colorectal cancers', 'Disease', 'MESH:D015179', (3, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('oxidative stress', 'MPA', (111, 127))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('breast cancers', 'Phenotype', 'HP:0003002', (26, 40))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancers', 'Disease', (3, 21))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('truncating mutations', 'Var', (42, 62))	('TFAM', 'Gene', (66, 70))	('mtDNA depletion', 'MPA', (91, 106))	('associated', 'Reg', (75, 85))	('oxidative stress', 'Phenotype', 'HP:0025464', (111, 127))	('breast cancers', 'Disease', 'MESH:D001943', (26, 40))
636334	28487205	5) DNA single- and double-strand breaks that are either induced by carcinogens or occur as a result of inefficient repair of other lesions.	('carcinogens', 'Disease', (67, 78))	('carcinogens', 'Disease', 'MESH:D063646', (67, 78))	('single-', 'Var', (7, 14))
636337	28487205	In human fibroblasts, an H2O2-producing system of glucose and glucose oxidase leads to a greater accumulation of strand breaks, oxidized bases, and abasic sites in mtDNA compared to nDNA.	('oxidized bases', 'MPA', (128, 142))	('strand breaks', 'MPA', (113, 126))	('H2O2', 'Chemical', 'MESH:D006861', (25, 29))	('human', 'Species', '9606', (3, 8))	('glucose', 'Chemical', 'MESH:D005947', (50, 57))	('accumulation', 'PosReg', (97, 109))	('abasic', 'Var', (148, 154))	('glucose', 'Chemical', 'MESH:D005947', (62, 69))
636338	28487205	In fact, strand breaks induced by H2O2 occur at a tenfold higher frequency in mtDNA, with the sugar-phosphate backbone as the primary target.	('strand breaks', 'MPA', (9, 22))	('sugar-phosphate', 'Chemical', 'MESH:D013403', (94, 109))	('H2O2', 'Var', (34, 38))	('H2O2', 'Chemical', 'MESH:D006861', (34, 38))
636340	28487205	Although both oxidized bases block DNA polymerase, 8-oxodG is more mutagenic and is responsible for the characteristic G T substitutions.	('8-oxodG', 'Var', (51, 58))	('mutagenic', 'MPA', (67, 76))	('DNA polymerase', 'Enzyme', (35, 49))	('substitutions', 'Var', (123, 136))	('8-oxodG', 'Chemical', '-', (51, 58))
636355	28487205	Mitochondrial BER starts with a) lesion recognition and strand scission, followed by b) gap tailoring, and converging at the c) DNA ligation step.	('lesion', 'Var', (33, 39))	('ER', 'Gene', '2099', (15, 17))	('strand', 'Var', (56, 62))
636357	28487205	The mitochondrial isoform of APE1 is generated by truncation of the nuclear localization signal.	('APE1', 'Gene', (29, 33))	('nuclear localization signal', 'MPA', (68, 95))	('truncation', 'Var', (50, 60))	('APE1', 'Gene', '328', (29, 33))	('rat', 'Species', '10116', (41, 44))	('mito', 'Species', '262676', (4, 8))
636361	28487205	Variations in OGG1 correlate with various cancers.	('cancers', 'Disease', (42, 49))	('correlate', 'Reg', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('OGG1', 'Gene', '4968', (14, 18))	('Variations', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('OGG1', 'Gene', (14, 18))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
636362	28487205	The C1245G SNP has a Ser326Cys change in the catalytic subunit of OGG1, which has an impaired capacity to excise 8-oxoguanine.	('8-oxoguanine', 'Chemical', 'MESH:C024829', (113, 125))	('capacity', 'MPA', (94, 102))	('excise 8-oxoguanine', 'MPA', (106, 125))	('C1245G', 'Var', (4, 10))	('C1245G', 'Mutation', 'rs1052133', (4, 10))	('Ser326Cys', 'Var', (21, 30))	('Ser326Cys', 'SUBSTITUTION', 'None', (21, 30))	('OGG1', 'Gene', (66, 70))	('OGG1', 'Gene', '4968', (66, 70))
636364	28487205	In a meta-analysis of Asian patients, Ser326Cys was associated higher risk of lung cancer.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('Ser326Cys', 'Var', (38, 47))	('patients', 'Species', '9606', (28, 36))	('Ser326Cys', 'SUBSTITUTION', 'None', (38, 47))
636365	28487205	A higher susceptibility to head and neck cancer was linked to the C1245G SNP.	('head and neck cancer', 'Phenotype', 'HP:0012288', (27, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('neck cancer', 'Disease', 'MESH:D006258', (36, 47))	('neck cancer', 'Disease', (36, 47))	('C1245G', 'Var', (66, 72))	('C1245G', 'Mutation', 'rs1052133', (66, 72))
636367	28487205	In certain North Indian ethnic groups, the SNP C1245G at exon seven was detected in about a quarter of the population, although its relevance in cancer risk remains to be evaluated.	('cancer', 'Disease', (145, 151))	('C1245G', 'Var', (47, 53))	('C1245G', 'Mutation', 'rs1052133', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
636369	28487205	The mitoTFs are broadly classified into two groups: a) the hormone and steroid receptors, such as those for estrogen, progesterone, androgen, and glucocorticoids and b) downstream factors activated upon binding of hormones and cytokines to their respective receptors (e.g., p53 HER1, and HER2).	('progesterone', 'Chemical', 'MESH:D011374', (118, 130))	('HER1', 'Gene', '1956', (278, 282))	('p53', 'Var', (274, 277))	('HER2', 'Gene', (288, 292))	('binding', 'Interaction', (203, 210))	('HER2', 'Gene', '2064', (288, 292))	('HER1', 'Gene', (278, 282))	('mito', 'Species', '262676', (4, 8))
636382	28487205	SNPs in the estrogen receptor gene are involved in breast cancer susceptibility.	('involved', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('SNPs', 'Var', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('estrogen receptor', 'Gene', '2099', (12, 29))	('breast cancer', 'Disease', (51, 64))	('estrogen receptor', 'Gene', (12, 29))
636383	28487205	In a meta-analysis, three SNPs (rs2077647:T>C, rs2228480:G>A, and rs3798577:T>C) correlated with breast cancer risk in various ethnic populations.	('rs2228480:G>A', 'Var', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs2077647:T>C', 'Var', (32, 45))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('rs3798577:T>C', 'DBSNP_MENTION', 'None', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('rs3798577:T>C', 'Var', (66, 79))	('breast cancer', 'Disease', (97, 110))	('rs2228480:G>A', 'DBSNP_MENTION', 'None', (47, 60))	('rs2077647:T>C', 'DBSNP_MENTION', 'None', (32, 45))	('correlated with', 'Reg', (81, 96))
636384	28487205	Amongst Caucasians, the rs2228480 AA genotype was associated with a lower risk compared to the GG genotype, whereas the rs3798577TT genotype correlated with increased risk in an Asian population.	('rs2228480', 'Mutation', 'rs2228480', (24, 33))	('rs3798577TT', 'Var', (120, 131))	('rs3798577', 'Mutation', 'rs3798577', (120, 129))	('rs2228480 AA', 'Var', (24, 36))
636385	28487205	In all the ethnic groups, rs2077647:T>C was associated with a higher risk of breast cancer, albeit non-significantly.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('rs2077647:T>C', 'Var', (26, 39))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('rs2077647:T>C', 'DBSNP_MENTION', 'None', (26, 39))
636386	28487205	In a recent study, the 13950T/C SNP of ERbeta was associated with higher risk of uterine leiomyomas.	('13950T/C', 'SUBSTITUTION', 'None', (23, 31))	('13950T/C', 'Var', (23, 31))	('ERbeta', 'Gene', (39, 45))	('leiomyomas', 'Disease', 'MESH:D007889', (89, 99))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (81, 99))	('ERbeta', 'Gene', '2099', (39, 45))	('leiomyomas', 'Disease', (89, 99))
636400	28487205	Three polymorphisms of the PR (Alu insertion, 331G/Aand, and Val660Leu) have been investigated in the context of cancer susceptibility.	('Alu', 'Chemical', '-', (31, 34))	('331G/Aand', 'Var', (46, 55))	('331G/A', 'Mutation', 'rs10895068', (46, 52))	('Val660Leu', 'Mutation', 'rs1042838', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Val660Leu', 'Var', (61, 70))	('PR', 'Gene', '5241', (27, 29))
636401	28487205	In a Chinese cohort, the Alu insertion and Val660Leu polymorphisms were associated with a risk of ovarian cancer, whereas the 331G/A SNP could not be correlated with any cancer risk.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('ovarian cancer', 'Disease', 'MESH:D010051', (98, 112))	('Chinese', 'Species', '10029', (5, 12))	('cancer', 'Disease', (170, 176))	('ovarian cancer', 'Disease', (98, 112))	('Val660Leu', 'Mutation', 'rs1042838', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('331G/A', 'Mutation', 'rs10895068', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (106, 112))	('Alu insertion', 'Var', (25, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('Val660Leu', 'Var', (43, 52))	('Alu', 'Chemical', '-', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
636402	28487205	In a Caucasian cohort of endometrial cancer patients, the 331G/A SNP could not be correlated with a cancer risk, but, in another study, the Alu insertion variant was associated with a higher breast cancer incidence in Mexican women.	('endometrial cancer', 'Disease', (25, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('endometrial cancer', 'Disease', 'MESH:D016889', (25, 43))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('patients', 'Species', '9606', (44, 52))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Alu', 'Gene', (140, 143))	('cancer', 'Disease', (37, 43))	('women', 'Species', '9606', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('higher', 'PosReg', (184, 190))	('cancer', 'Disease', (100, 106))	('Alu', 'Chemical', '-', (140, 143))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('endometrial cancer', 'Phenotype', 'HP:0012114', (25, 43))	('variant', 'Var', (154, 161))	('331G/A', 'Mutation', 'rs10895068', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
636407	28487205	Mitochondrial fission is initiated upon translocation of the cytoplasmic dynamin-related protein 1 (Drp1) to the mitochondrial outer membrane; impairment of Drp1 results in fragmented mitochondria, which lead to apoptosis.	('Drp1', 'Gene', '10059', (100, 104))	('impairment', 'Var', (143, 153))	('mito', 'Species', '262676', (184, 188))	('men', 'Species', '9606', (149, 152))	('dynamin-related protein 1', 'Gene', (73, 98))	('Drp1', 'Gene', (157, 161))	('apoptosis', 'CPA', (212, 221))	('fragmented mitochondria', 'MPA', (173, 196))	('Drp1', 'Gene', (100, 104))	('men', 'Species', '9606', (177, 180))	('mito', 'Species', '262676', (113, 117))	('Drp1', 'Gene', '10059', (157, 161))	('lead to', 'Reg', (204, 211))	('dynamin-related protein 1', 'Gene', '10059', (73, 98))
636413	28487205	Inherited variations in the AR gene are associated with higher incidences of several types of cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('variations', 'Var', (10, 20))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('AR', 'Gene', '367', (28, 30))	('associated', 'Reg', (40, 50))	('cancers', 'Disease', (94, 101))
636415	28487205	For Mexican men, a lower number of CAG repeats correlates to earlier and more aggressive forms of prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('prostate cancer', 'Disease', (98, 113))	('men', 'Species', '9606', (12, 15))	('CAG repeats', 'Var', (35, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))
636416	28487205	For Asian women, there is a link between shorter CAG repeats and a higher risk of developing epithelial ovarian cancer.	('epithelial ovarian cancer', 'Disease', (93, 118))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (93, 118))	('shorter', 'Var', (41, 48))	('epithelial ovarian cancer', 'Disease', 'MESH:D010051', (93, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('CAG', 'Protein', (49, 52))	('women', 'Species', '9606', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
636418	28487205	Although the CAG repeat length does not affect prostate cancer risk amongst European men, carriers of the SNP rs1204038A allele are more likely to develop this cancer.	('develop', 'PosReg', (147, 154))	('prostate cancer', 'Phenotype', 'HP:0012125', (47, 62))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('rs1204038A', 'Var', (110, 120))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('prostate cancer', 'Disease', (47, 62))	('men', 'Species', '9606', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('prostate cancer', 'Disease', 'MESH:D011471', (47, 62))	('SNP', 'Gene', (106, 109))
636419	28487205	performed a comprehensive analysis of the prevalence of germline and somatic AR mutations in AA men suffering from prostate cancer.	('prostate cancer', 'Disease', (115, 130))	('men', 'Species', '9606', (96, 99))	('mutations', 'Var', (80, 89))	('AR', 'Gene', '367', (77, 79))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))
636421	28487205	Furthermore, the A-allele of the E213 G/A SNP was more frequent amongst the AA men, although this polymorphism could not be correlated to a higher cancer risk.	('men', 'Species', '9606', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('E213 G/A', 'Mutation', 'p.E213G,A', (33, 41))	('E213 G/A', 'Var', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
636430	28487205	For Han Chinese, SNPs in the non-coding region of GR were linked to a higher incidence of pediatric ALL.	('SNPs in', 'Var', (17, 24))	('pediatric ALL', 'Disease', (90, 103))	('Chinese', 'Species', '10029', (8, 15))	('GR', 'Gene', '2908', (50, 52))
636431	28487205	Five SNPs were analyzed, of which the rs41423247 and rs7701443 polymorphisms were significantly associated with a poorer prognosis.	('rs41423247', 'Mutation', 'rs41423247', (38, 48))	('rs7701443', 'Mutation', 'rs7701443', (53, 62))	('rs7701443', 'Var', (53, 62))	('rs41423247', 'Var', (38, 48))
636442	28487205	For HCT116 cells, there is an association between the mitochondrial DNA polymerase gamma (POLG) and p53, with p53 also binding to mtDNA and enhancing the function of POLG.	('function', 'MPA', (154, 162))	('enhancing', 'PosReg', (140, 149))	('mito', 'Species', '262676', (54, 58))	('HCT116', 'CellLine', 'CVCL:0291', (4, 10))	('association', 'Interaction', (30, 41))	('p53', 'Var', (110, 113))	('binding', 'Interaction', (119, 126))	('p53', 'Gene', (100, 103))
636448	28487205	In malignant cells, the tumor suppressive actions of p53 are often directed towards subverting the glycolytic pathway and counteracting the Warburg effect.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('p53', 'Var', (53, 56))	('tumor', 'Disease', (24, 29))	('subverting', 'NegReg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('glycolytic pathway', 'Pathway', (99, 117))
636449	28487205	In leukemia cells, p53 induces the expression of TIGAR (Tp53 induced glycolysis and apoptosis regulator), inhibits glycolysis, and increases the production of ROS, ultimately clearing damaged cells via apoptosis.	('inhibits', 'NegReg', (106, 114))	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('leukemia', 'Disease', 'MESH:D007938', (3, 11))	('increases', 'PosReg', (131, 140))	('TIGAR', 'Gene', (49, 54))	('leukemia', 'Disease', (3, 11))	('p53', 'Var', (19, 22))	('expression', 'MPA', (35, 45))	('ROS', 'Chemical', 'MESH:D017382', (159, 162))	('production', 'MPA', (145, 155))	('Tp53 induced glycolysis and apoptosis regulator', 'Gene', '57103', (56, 103))	('glycolysis', 'MPA', (115, 125))	('TIGAR', 'Gene', '57103', (49, 54))
636450	28487205	p53 also prevents the uptake of glucose, the substrate for glycolysis, by blocking the expression of the glucose transporters, GLUT1 and GLUT4.	('glucose', 'Chemical', 'MESH:D005947', (32, 39))	('glucose transporters', 'MPA', (105, 125))	('rat', 'Species', '10116', (50, 53))	('GLUT1', 'Gene', (127, 132))	('glucose', 'Chemical', 'MESH:D005947', (105, 112))	('expression', 'MPA', (87, 97))	('p53', 'Var', (0, 3))	('GLUT1', 'Gene', '6513', (127, 132))	('blocking', 'NegReg', (74, 82))	('GLUT4', 'Gene', '6517', (137, 142))	('GLUT4', 'Gene', (137, 142))	('uptake of glucose', 'MPA', (22, 39))	('prevents', 'NegReg', (9, 17))
636451	28487205	In cancer cells, p53 hinders glycolysis through the use of alternate substrates.	('glycolysis', 'MPA', (29, 39))	('rat', 'Species', '10116', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('p53', 'Var', (17, 20))	('hinders', 'NegReg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
636452	28487205	identified mitochondrial phosphate-activated glutaminase (GLS2) as a transcriptional target of p53.	('GLS2', 'Gene', '27165', (58, 62))	('GLS2', 'Gene', (58, 62))	('mito', 'Species', '262676', (11, 15))	('p53', 'Var', (95, 98))
636453	28487205	Activation of GLS2 shifts the cellular metabolism from glycolysis to aerobic respiration and glutaminolysis.	('glycolysis', 'MPA', (55, 65))	('GLS2', 'Gene', '27165', (14, 18))	('aerobic respiration', 'MPA', (69, 88))	('shifts', 'Reg', (19, 25))	('rat', 'Species', '10116', (82, 85))	('GLS2', 'Gene', (14, 18))	('Activation', 'Var', (0, 10))	('cellular metabolism', 'MPA', (30, 49))
636454	28487205	Consistent with these findings, a dominant-negative mutant of p53 up-regulates the expression of hexokinase II, which, in AS-30D hepatoma cells, docks at the mitochondrial outer membrane and increases glycolytic activity.	('AS-30D hepatoma', 'Disease', (122, 137))	('hexokinase', 'Enzyme', (97, 107))	('mutant', 'Var', (52, 58))	('AS-30D hepatoma', 'Disease', 'MESH:D006528', (122, 137))	('up-regulates', 'PosReg', (66, 78))	('increases', 'PosReg', (191, 200))	('expression', 'MPA', (83, 93))	('mito', 'Species', '262676', (158, 162))	('p53', 'Gene', (62, 65))	('glycolytic activity', 'MPA', (201, 220))
636455	28487205	Similarly, deletion of p53 in human colon cancer cells leads to decreased expression of cytochrome c oxidase and a disruption in mitochondrial activity and structure.	('human', 'Species', '9606', (30, 35))	('expression', 'MPA', (74, 84))	('disruption', 'NegReg', (115, 125))	('colon cancer', 'Phenotype', 'HP:0003003', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colon cancer', 'Disease', 'MESH:D015179', (36, 48))	('colon cancer', 'Disease', (36, 48))	('mitochondrial activity', 'MPA', (129, 151))	('mito', 'Species', '262676', (129, 133))	('cytochrome c', 'Gene', (88, 100))	('p53', 'Gene', (23, 26))	('deletion', 'Var', (11, 19))	('cytochrome c', 'Gene', '54205', (88, 100))	('decreased', 'NegReg', (64, 73))
636458	28487205	Disruption of the SCO2 gene in p53+/+ cells also directed the cellular metabolism towards glycolysis in the same way as a loss of p53.	('directed', 'Reg', (49, 57))	('SCO2', 'Gene', '9997', (18, 22))	('SCO2', 'Gene', (18, 22))	('cellular metabolism towards glycolysis', 'MPA', (62, 100))	('Disruption', 'Var', (0, 10))
636459	28487205	Conversely, disruption of the mitochondrial ETC increases the accumulation of p53 and leads to activation of apoptotic pathways.	('apoptotic pathways', 'Pathway', (109, 127))	('disruption', 'Var', (12, 22))	('increases', 'PosReg', (48, 57))	('p53', 'Protein', (78, 81))	('activation', 'PosReg', (95, 105))	('accumulation', 'MPA', (62, 74))	('mito', 'Species', '262676', (30, 34))	('mitochondrial ETC', 'Protein', (30, 47))
636461	28487205	Although the somatic loss of p53 usually accompanies the development of most human cancers, there are germline mutations/SNPs in the familial Li-Fraumeni syndrome, encompassing cancers such as premenopausal breast cancer, bone and soft-tissue sarcomas, adrenal cortical carcinomas, and brain tumors.	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (231, 251))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('adrenal cortical carcinomas', 'Phenotype', 'HP:0006744', (253, 280))	('cancers', 'Disease', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Li-Fraumeni syndrome', 'Disease', (142, 162))	('adrenal cortical carcinomas', 'Disease', (253, 280))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (142, 162))	('premenopausal breast cancer', 'Disease', (193, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('sarcomas', 'Disease', 'MESH:D012509', (243, 251))	('men', 'Species', '9606', (64, 67))	('adrenal cortical carcinomas', 'Disease', 'MESH:D018268', (253, 280))	('brain tumors', 'Disease', 'MESH:D001932', (286, 298))	('premenopausal breast cancer', 'Disease', 'MESH:D001943', (193, 220))	('sarcomas', 'Phenotype', 'HP:0100242', (243, 251))	('carcinomas', 'Phenotype', 'HP:0030731', (270, 280))	('sarcomas', 'Disease', (243, 251))	('brain tumors', 'Phenotype', 'HP:0030692', (286, 298))	('mutations/SNPs', 'Var', (111, 125))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (193, 220))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('men', 'Species', '9606', (149, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('human', 'Species', '9606', (77, 82))	('men', 'Species', '9606', (196, 199))	('brain tumors', 'Disease', (286, 298))	('p53', 'Gene', (29, 32))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
636490	28487205	In breast cancer tissues, miR-485-3p and miR-485-5p inhibit PGC-1alpha to regulate mitochondrial respiration and are consequently down-regulated.	('down-regulated', 'NegReg', (130, 144))	('inhibit', 'NegReg', (52, 59))	('PGC-1alpha', 'Gene', (60, 70))	('miR-485-5p', 'Var', (41, 51))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('miR-485-3p', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('mitochondrial respiration', 'MPA', (83, 108))	('PGC-1alpha', 'Gene', '10891', (60, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('rat', 'Species', '10116', (102, 105))	('mito', 'Species', '262676', (83, 87))
636491	28487205	An indirect route for inducing cancer is through ROS generation and subsequent disruption of the ETC.	('ROS', 'Var', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('disruption', 'Var', (79, 89))	('rat', 'Species', '10116', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('inducing', 'Reg', (22, 30))
636494	28487205	After predicting 33 pre-miRNA and 25 miRNA candidates in the mitochondrial genome by in silico analysis, miR-365, pre-miR302a, and pre-let-7b were co-localized in the mitochondria.	('miR302a', 'Gene', '407028', (118, 125))	('miR-365', 'Var', (105, 112))	('miR302a', 'Gene', (118, 125))	('mito', 'Species', '262676', (167, 171))	('let-7b', 'Gene', '406884', (135, 141))	('mito', 'Species', '262676', (61, 65))	('let-7b', 'Gene', (135, 141))
636512	28487205	The authors hypothesize that the Akt-mediated increase in OXPHOS could be part of a metabolic adaptation in response to inactivation of the tumor suppressive PTEN.	('inactivation', 'Var', (120, 132))	('OXPHOS', 'MPA', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
636515	28487205	In contrast, a pro-apoptotic role of Akt was seen in HCT11 cells expressing a mutant k-ras oncogene; Akt rapidly translocated into the mitochondria and increased ROS production, leading to cell death.	('mito', 'Species', '262676', (135, 139))	('Akt', 'Gene', (101, 104))	('increased', 'PosReg', (152, 161))	('increased ROS production', 'Phenotype', 'HP:0025464', (152, 176))	('ROS production', 'MPA', (162, 176))	('cell death', 'CPA', (189, 199))	('leading to', 'Reg', (178, 188))	('translocated into', 'MPA', (113, 130))	('ROS', 'Chemical', 'MESH:D017382', (162, 165))	('mutant', 'Var', (78, 84))	('HCT11', 'CellLine', 'CVCL:5679', (53, 58))
636516	28487205	Recently, Buroker reviewed the genetic variants of Akt and their involvement in various cancers.	('Akt', 'Gene', (51, 54))	('men', 'Species', '9606', (72, 75))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('genetic variants', 'Var', (31, 47))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('involvement', 'Reg', (65, 76))
636517	28487205	Three rSNPS (rs10157763, rs10927067 and rs2125230) in Akt codon one are associated with an aggressive form of prostate cancer.	('rs2125230', 'Mutation', 'rs2125230', (40, 49))	('rs2125230', 'Var', (40, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('associated with', 'Reg', (72, 87))	('Akt', 'Gene', (54, 57))	('rs10927067', 'Var', (25, 35))	('rs10927067', 'Mutation', 'rs10927067', (25, 35))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('rs10157763', 'Mutation', 'rs10157763', (13, 23))	('prostate cancer', 'Disease', (110, 125))	('rs10157763', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
636518	28487205	Other intron one rSNPs (rs4132509, rs12031994, rs2345994) are associated with risk of renal cell carcinoma.	('rs4132509', 'Mutation', 'rs4132509', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('associated', 'Reg', (62, 72))	('rs12031994', 'Mutation', 'rs12031994', (35, 45))	('rs12031994', 'Var', (35, 45))	('rs2345994', 'Var', (47, 56))	('rs2345994', 'Mutation', 'rs2345994', (47, 56))	('rs4132509', 'Var', (24, 33))	('renal cell carcinoma', 'Disease', (86, 106))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (86, 106))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (86, 106))
636539	28487205	A dinucleotide CA repeat polymorphism in intron 1 of HER1, ranging from 14 to 21 repeats, has been implicated in the regulation of EGFR expression.	('regulation', 'MPA', (117, 127))	('dinucleotide CA repeat polymorphism', 'Var', (2, 37))	('expression', 'MPA', (136, 146))	('HER1', 'Gene', (53, 57))	('implicated', 'Reg', (99, 109))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('dinucleotide CA', 'Chemical', '-', (2, 17))	('HER1', 'Gene', '1956', (53, 57))
636541	28487205	In the same study, two SNPs, G216T and C191A, were present at higher frequencies in lung cancer tissues of patients of Northern European and AA descent compared to East Asians.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('G216T', 'Var', (29, 34))	('C191A', 'Mutation', 'rs61737968', (39, 44))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('C191A', 'Var', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('patients', 'Species', '9606', (107, 115))	('G216T', 'Mutation', 'rs757930144', (29, 34))
636542	28487205	Another functional SNP, rs4444903, is associated with a higher risk of hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 95))	('hepatocellular carcinoma', 'Disease', (71, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (71, 95))	('rs4444903', 'Var', (24, 33))	('rs4444903', 'Mutation', 'rs4444903', (24, 33))
636543	28487205	In Austrian women, a polymorphism in the HER2 codon 655, rs1136201, corresponds to a more aggressive form of breast cancer.	('women', 'Species', '9606', (12, 17))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('rs1136201', 'Var', (57, 66))	('HER2', 'Gene', (41, 45))	('rs1136201', 'Mutation', 'rs1136201', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HER2', 'Gene', '2064', (41, 45))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
636544	28487205	Also localized in the mitochondria are the kinases, Abl, ATM, Src, JNK, ERK1/2, P38MAPK, GSK3B, PKA, PKC, and PINK1.	('ERK1/2', 'Gene', (72, 78))	('JNK', 'Gene', (67, 70))	('GSK3B', 'Gene', '2932', (89, 94))	('Src', 'Gene', (62, 65))	('Src', 'Gene', '6714', (62, 65))	('P38MAPK', 'Var', (80, 87))	('ERK1/2', 'Gene', '5595;5594', (72, 78))	('GSK3B', 'Gene', (89, 94))	('ATM', 'Gene', (57, 60))	('PINK1', 'Gene', '65018', (110, 115))	('JNK', 'Gene', '5599', (67, 70))	('Abl', 'Gene', '25', (52, 55))	('mito', 'Species', '262676', (22, 26))	('PINK1', 'Gene', (110, 115))	('ATM', 'Gene', '472', (57, 60))	('Abl', 'Gene', (52, 55))
636555	28487205	Mitochondrial Ras affects metabolism, apoptosis, and mitochondrial biogenesis, which can often be correlated with tumor initiation and/or maintenance.	('tumor initiation', 'Disease', 'MESH:D009369', (114, 130))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('apoptosis', 'CPA', (38, 47))	('metabolism', 'MPA', (26, 36))	('tumor initiation', 'Disease', (114, 130))	('mito', 'Species', '262676', (53, 57))	('affects', 'Reg', (18, 25))	('Mitochondrial', 'Var', (0, 13))	('mitochondrial biogenesis', 'CPA', (53, 77))
636556	28487205	In a murine model of acute myeloid leukemia, NRAS was associated with the anti-apoptotic Bcl-2 protein and protected the leukemic cells from apoptosis.	('Bcl-2 protein', 'Protein', (89, 102))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (21, 43))	('NRAS', 'Var', (45, 49))	('leukemia', 'Phenotype', 'HP:0001909', (35, 43))	('leukemic', 'Disease', 'MESH:D007938', (121, 129))	('murine', 'Species', '10090', (5, 11))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (27, 43))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (21, 43))	('acute myeloid leukemia', 'Disease', (21, 43))	('apoptosis', 'CPA', (141, 150))	('leukemic', 'Disease', (121, 129))	('anti-apoptotic', 'MPA', (74, 88))
636559	28487205	In the mitochondria, mutant KRAS also increase ROS via the PI3K-Akt pathway, leading to cell death.	('PI3K-Akt pathway', 'Pathway', (59, 75))	('KRAS', 'Gene', (28, 32))	('increase', 'PosReg', (38, 46))	('mutant', 'Var', (21, 27))	('ROS', 'MPA', (47, 50))	('mito', 'Species', '262676', (7, 11))	('ROS', 'Chemical', 'MESH:D017382', (47, 50))
636560	28487205	In HEK293 cells, translocation of HRAS and KRAS into the mitochondria leads to a reduction of mitochondrial membrane potential and respiration, thus causing a metabolic shift to glycolysis.	('metabolic shift', 'MPA', (159, 174))	('HRAS', 'Gene', (34, 38))	('mitochondrial membrane potential', 'MPA', (94, 126))	('mito', 'Species', '262676', (94, 98))	('HEK293', 'CellLine', 'CVCL:0045', (3, 9))	('causing', 'Reg', (149, 156))	('respiration', 'MPA', (131, 142))	('mito', 'Species', '262676', (57, 61))	('KRAS', 'Var', (43, 47))	('reduction', 'NegReg', (81, 90))	('rat', 'Species', '10116', (136, 139))	('HRAS', 'Gene', '3265', (34, 38))
636562	28487205	For human hepatocellular carcinoma, KRAS-induced mitophagy (clearance of diseased mitochondria) and the resulting loss of mitochondria has been linked to early tumorigenesis.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (10, 34))	('human', 'Species', '9606', (4, 9))	('hepatocellular carcinoma', 'Disease', (10, 34))	('mito', 'Species', '262676', (122, 126))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (10, 34))	('mitochondria', 'MPA', (122, 134))	('loss', 'NegReg', (114, 118))	('KRAS-induced', 'Var', (36, 48))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mito', 'Species', '262676', (82, 86))	('mitophagy', 'CPA', (49, 58))	('tumor', 'Disease', (160, 165))	('linked', 'Reg', (144, 150))	('mito', 'Species', '262676', (49, 53))
636563	28487205	A germline SNP, rs61764370, located in the 3'UTR of the KRAS oncogene alters the binding capacity of the let-7 miRNA.	('rs61764370', 'Mutation', 'rs61764370', (16, 26))	('KRAS', 'Gene', (56, 60))	('rs61764370', 'Var', (16, 26))	('alters', 'Reg', (70, 76))	('binding', 'Interaction', (81, 88))	('let-7 miRNA', 'Protein', (105, 116))
636565	28487205	In another study, the rs61764370 SNP was associated with a higher risk of chronic myeloid leukemia in Mexican-Mestizo women.	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (74, 98))	('rs61764370', 'Mutation', 'rs61764370', (22, 32))	('chronic myeloid leukemia', 'Disease', (74, 98))	('women', 'Species', '9606', (118, 123))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (82, 98))	('rs61764370', 'Var', (22, 32))	('leukemia', 'Phenotype', 'HP:0001909', (90, 98))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (74, 98))
636566	28487205	An indication of the role of HRAS polymorphisms in cancer susceptibility came from a study of an Italian gastric cancer cohort.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('HRAS', 'Gene', '3265', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('polymorphisms', 'Var', (34, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))	('gastric cancer', 'Disease', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (113, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (105, 119))	('HRAS', 'Gene', (29, 33))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
636567	28487205	Thirteen rare inheritable variants were detected in the tandem-repeat sequence downstream of the structural part of the HRAS gene and were correlated with a higher incidence of cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('HRAS', 'Gene', '3265', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('HRAS', 'Gene', (120, 124))	('correlated with', 'Reg', (139, 154))	('variants', 'Var', (26, 34))
636569	28487205	Regarding NRAS, the only relevant genetic variant discovered is the G138R SNP, which is associated with higher colorectal cancer risk among Taiwanese patients.	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('patients', 'Species', '9606', (150, 158))	('G138R', 'Var', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('higher', 'PosReg', (104, 110))	('G138R', 'Mutation', 'rs751774011', (68, 73))
636582	28487205	Upon mutagenic stress, the nuclear levels of PDC increased, and the mitochondrial levels concomitantly decreased, prompting the authors to postulate that the PDC is translocated from the mitochondria to the nucleus as an intact complex.	('PD', 'Disease', 'MESH:D010300', (158, 160))	('mito', 'Species', '262676', (187, 191))	('increased', 'PosReg', (49, 58))	('nuclear levels', 'MPA', (27, 41))	('decreased', 'NegReg', (103, 112))	('mitochondrial levels', 'MPA', (68, 88))	('PD', 'Disease', 'MESH:D010300', (45, 47))	('mito', 'Species', '262676', (68, 72))	('mutagenic', 'Var', (5, 14))
636589	28487205	Moreover, in human cells, deletion of COQ7 increases the levels of ROS and the ROS-responsive genes, SOD2 and NRF2.	('COQ7', 'Gene', (38, 42))	('SOD2', 'Gene', '6648', (101, 105))	('ROS', 'MPA', (67, 70))	('NRF2', 'Gene', (110, 114))	('ROS', 'Chemical', 'MESH:D017382', (79, 82))	('human', 'Species', '9606', (13, 18))	('SOD2', 'Gene', (101, 105))	('deletion', 'Var', (26, 34))	('levels', 'MPA', (57, 63))	('ROS', 'Chemical', 'MESH:D017382', (67, 70))	('increases', 'PosReg', (43, 52))	('COQ7', 'Gene', '10229', (38, 42))	('NRF2', 'Gene', '4780', (110, 114))
636595	28487205	Deregulated expression of nuclear genes encoding the mitochondrial proteins can result in various pathologies.	('result in', 'Reg', (80, 89))	('nuclear genes', 'Gene', (26, 39))	('Deregulated', 'Var', (0, 11))	('pathologies', 'Disease', (98, 109))	('mito', 'Species', '262676', (53, 57))	('expression', 'MPA', (12, 22))
636599	28487205	The main 'sensors' that trigger a retrograde response include mtDNA mutations and/or loss in copy numbers, disruption of the OXPHOS machinery, an increase in oxidative stress, and loss of mitochondrial membrane potential.	('disruption', 'Reg', (107, 117))	('mtDNA', 'Gene', (62, 67))	('increase', 'PosReg', (146, 154))	('loss', 'NegReg', (180, 184))	('increase in oxidative stress', 'Phenotype', 'HP:0025464', (146, 174))	('oxidative stress', 'Phenotype', 'HP:0025464', (158, 174))	('mito', 'Species', '262676', (188, 192))	('copy', 'MPA', (93, 97))	('loss', 'NegReg', (85, 89))	('oxidative stress', 'MPA', (158, 174))	('mutations', 'Var', (68, 77))	('OXPHOS machinery', 'MPA', (125, 141))	('mitochondrial membrane potential', 'MPA', (188, 220))
636601	28487205	showed that, in the MERRF (myoclonic epilepsy with ragged red fibers) condition, disruption of the ETC and the resulting low production of ATP-triggered retrograde signaling.	('MERRF', 'Disease', (20, 25))	('disruption', 'Var', (81, 91))	('myoclonic epilepsy', 'Disease', (27, 45))	('myoclonic epilepsy', 'Disease', 'MESH:D004831', (27, 45))	('myoclonic epilepsy', 'Phenotype', 'HP:0002123', (27, 45))	('MERRF', 'Disease', 'MESH:D017243', (20, 25))	('epilepsy', 'Phenotype', 'HP:0001250', (37, 45))	('low', 'NegReg', (121, 124))	('ragged red fibers', 'Phenotype', 'HP:0003200', (51, 68))	('ATP', 'Chemical', 'MESH:D000255', (139, 142))
636604	28487205	A knock-in D257A mutation in the exonuclease domain of POLG abolishes its DNA-proofreading capacity and increases the frequency of mtDNA mutations, with the mice displaying signs of premature aging.	('DNA-proofreading capacity', 'MPA', (74, 99))	('mtDNA', 'Gene', (131, 136))	('mice', 'Species', '10090', (157, 161))	('D257A mutation in', 'Var', (11, 28))	('increases', 'PosReg', (104, 113))	('mutations', 'Var', (137, 146))	('abolishes', 'NegReg', (60, 69))	('POLG', 'Gene', (55, 59))	('D257A', 'Mutation', 'p.D257A', (11, 16))
636623	28487205	Silencing of hnRNPA2 leads to apoptosis.	('hnRNPA2', 'Gene', (13, 20))	('apoptosis', 'CPA', (30, 39))	('Silencing', 'Var', (0, 9))	('hnRNPA2', 'Gene', '3181', (13, 20))
636625	28487205	In breast cancer cells, the hnRNPA 1 and two proteins modulate expression of the pyruvate kinase gene by alternative splicing, an action that leads to expression of pyruvate kinase isoform M (PKM).	('hnRNPA 1', 'Gene', '3178', (28, 36))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('pyruvate', 'Chemical', 'MESH:D019289', (81, 89))	('pyruvate', 'Chemical', 'MESH:D019289', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('modulate', 'Reg', (54, 62))	('alternative splicing', 'Var', (105, 125))	('breast cancer', 'Disease', (3, 16))	('expression', 'MPA', (151, 161))	('leads to', 'Reg', (142, 150))	('expression', 'MPA', (63, 73))	('pyruvate kinase gene', 'Gene', (81, 101))	('PKM', 'Gene', (192, 195))	('pyruvate kinase isoform M', 'Gene', '5315', (165, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('pyruvate kinase isoform M', 'Gene', (165, 190))	('hnRNPA 1', 'Gene', (28, 36))	('PKM', 'Gene', '5315', (192, 195))
636627	28487205	In breast and colorectal epithelial cells, alternative splicing of the GTPase Rac1b by hnRNPA1 correlates with cancerous transformation.	('cancerous', 'Disease', (111, 120))	('hnRNPA1', 'Gene', '3178', (87, 94))	('GTPase Rac1b', 'Gene', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancerous', 'Disease', 'MESH:D009369', (111, 120))	('alternative splicing', 'Var', (43, 63))	('GTP', 'Chemical', 'MESH:D006160', (71, 74))	('hnRNPA1', 'Gene', (87, 94))
636632	28487205	Inefficient electron transport through the ETC complexes leads to formation of free radicals or ROS, which, upon exceeding the capacity of the antioxidant enzymes, leads to damage of the ETC and respiratory stress.	('leads to', 'Reg', (164, 172))	('rat', 'Species', '10116', (200, 203))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('Inefficient', 'Var', (0, 11))	('respiratory stress', 'CPA', (195, 213))	('electron transport', 'MPA', (12, 30))	('free radicals', 'Chemical', 'MESH:D005609', (79, 92))	('damage', 'MPA', (173, 179))	('free radicals', 'MPA', (79, 92))
636636	28487205	Apart from inducing retrograde signaling, ROS also acts indirectly by oxidatively damaging mtDNA, as the proximity of mtDNA to the ETC makes it particularly susceptible to mutations.	('mutations', 'Var', (172, 181))	('inducing', 'Reg', (11, 19))	('retrograde signaling', 'MPA', (20, 40))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('susceptible', 'Reg', (157, 168))	('ROS', 'Gene', (42, 45))	('oxidatively', 'MPA', (70, 81))
636642	28487205	showed that ROS-induced mutations in the mtDNA-encoded NADH dehydrogenase subunit 6 (ND6) increased the metastatic potential of tumor cells engrafted in mice.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('increased', 'PosReg', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ROS', 'Chemical', 'MESH:D017382', (12, 15))	('ND6', 'Gene', (85, 88))	('tumor', 'Disease', (128, 133))	('mice', 'Species', '10090', (153, 157))	('mutations', 'Var', (24, 33))	('ND6', 'Gene', '17722', (85, 88))	('NADH dehydrogenase subunit 6', 'Gene', '17722', (55, 83))	('NADH dehydrogenase subunit 6', 'Gene', (55, 83))
636643	28487205	In cancer cells, ROS-mediated deregulation of mitochondrial redox leads to activation of the Akt proliferation and survival pathways.	('mitochondrial redox', 'MPA', (46, 65))	('ROS', 'Chemical', 'MESH:D017382', (17, 20))	('mito', 'Species', '262676', (46, 50))	('activation', 'PosReg', (75, 85))	('Akt', 'Pathway', (93, 96))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('survival', 'CPA', (115, 123))	('deregulation', 'Var', (30, 42))	('rat', 'Species', '10116', (104, 107))
636663	28487205	Disruption of mitochondrial Ca2+ signaling triggers the opening of permeability transition pores (mPTPs) and initiates the apoptotic cascade.	('mito', 'Species', '262676', (14, 18))	('apoptotic cascade', 'CPA', (123, 140))	('permeability transition pores', 'MPA', (67, 96))	('Ca2+', 'Chemical', 'MESH:D000069285', (28, 32))	('initiates', 'Reg', (109, 118))	('opening', 'MPA', (56, 63))	('Disruption', 'Var', (0, 10))
636688	28487205	p53 is a target of AMPK phosphorylation, and this phosphorylation triggers the accumulation of mitochondrial p53 that promotes apoptosis via the Bak-Bcl-xL complex.	('AMPK', 'Gene', '5562', (19, 23))	('accumulation', 'PosReg', (79, 91))	('AMPK', 'Gene', (19, 23))	('Bcl-xL', 'Gene', '598', (149, 155))	('apoptosis', 'CPA', (127, 136))	('promotes', 'PosReg', (118, 126))	('mito', 'Species', '262676', (95, 99))	('Bcl-xL', 'Gene', (149, 155))	('mitochondrial', 'Var', (95, 108))
636702	28487205	Alterations in mtDNMT1 affect transcription from the light and heavy strands of mtDNA, suggesting a correlation between 5hmC- and 5mC-mediated transcriptional regulation of mtDNA by a nuclear-encoded gene.	('transcription', 'MPA', (30, 43))	('Alterations', 'Var', (0, 11))	('5hmC', 'Chemical', 'MESH:C011865', (120, 124))	('affect', 'Reg', (23, 29))	('5mC', 'Chemical', 'MESH:D044503', (130, 133))	('rat', 'Species', '10116', (4, 7))	('DNMT1', 'Gene', (17, 22))	('DNMT1', 'Gene', '1786', (17, 22))
636703	28487205	These findings provide evidence implicating epigenetic regulation of the mitochondrial genome by nuclear-encoded, translocated mtDNMT1 relative to mitochondrial dysfunction.	('mito', 'Species', '262676', (73, 77))	('mitochondrial dysfunction', 'Disease', (147, 172))	('DNMT1', 'Gene', (129, 134))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (147, 172))	('epigenetic', 'Var', (44, 54))	('DNMT1', 'Gene', '1786', (129, 134))	('mito', 'Species', '262676', (147, 151))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (147, 172))
636704	28487205	described epigenetic regulatory mechanisms affecting the transcriptional control of nuclear DNA-encoded mitochondrial proteins.	('affecting', 'Reg', (43, 52))	('mito', 'Species', '262676', (104, 108))	('transcriptional control', 'MPA', (57, 80))	('epigenetic regulatory', 'Var', (10, 31))
636706	28487205	We have demonstrated that mtDNA dysfunction in human cells to leads a reduced rate of repair of oxidative DNA damage and to increased frequencies of mutation within the nuclear genome.	('reduced', 'NegReg', (70, 77))	('rat', 'Species', '10116', (15, 18))	('increased', 'PosReg', (124, 133))	('repair of oxidative DNA damage', 'MPA', (86, 116))	('mtDNA dysfunction', 'Disease', (26, 43))	('rat', 'Species', '10116', (78, 81))	('human', 'Species', '9606', (47, 52))	('mutation', 'Var', (149, 157))	('rate', 'MPA', (78, 82))
636707	28487205	The mitochondria-mediated mutator phenotype is suppressed by inactivating subunits of error-prone DNA repair.	('mitochondria-mediated mutator phenotype', 'MPA', (4, 43))	('suppressed', 'NegReg', (47, 57))	('inactivating', 'Var', (61, 73))	('mito', 'Species', '262676', (4, 8))
636711	28487205	nDNA mutations may activate proto-oncogenes and/or inactivate tumor suppressor genes, leading to genomic instability, which is involved in the development of cancers.	('proto-oncogenes', 'Protein', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('mutations', 'Var', (5, 14))	('nDNA', 'Gene', (0, 4))	('genomic instability', 'MPA', (97, 116))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('men', 'Species', '9606', (150, 153))	('leading to', 'Reg', (86, 96))	('inactivate', 'NegReg', (51, 61))	('activate', 'PosReg', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
636716	28487205	If mitochondrial dysfunction is persistent and defective, mitochondria accumulate in the cell, leading to instability of the nuclear genome.	('defective', 'Var', (47, 56))	('mito', 'Species', '262676', (3, 7))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (3, 28))	('mitochondrial dysfunction', 'Disease', (3, 28))	('leading to', 'Reg', (95, 105))	('accumulate', 'PosReg', (71, 81))	('instability', 'MPA', (106, 117))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (3, 28))	('mito', 'Species', '262676', (58, 62))
636717	28487205	Nuclear genome instability causes cells to acquire new functions, such as resistance to apoptosis and cellular transformation, migration, and invasive characteristics involved in tumorigenesis (Figure 3).	('invasive characteristics', 'CPA', (142, 166))	('cellular transformation', 'CPA', (102, 125))	('Nuclear genome instability', 'Var', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('resistance to apoptosis', 'CPA', (74, 97))	('rat', 'Species', '10116', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('migration', 'CPA', (127, 136))	('tumor', 'Disease', (179, 184))
636719	28487205	Our studies suggest that a mitochondrial defect leads to cellular senescence and that senescence bypass is induced due to the instability of the nuclear genome.	('leads to', 'Reg', (48, 56))	('cellular senescence', 'CPA', (57, 76))	('mito', 'Species', '262676', (27, 31))	('defect', 'Var', (41, 47))
636722	28487205	We suggest that variants or mutations in either mitochondrial or nuclear genome-encoded mitochondrial proteins contribute to mitochondrial dysfunction or to suboptimal mitochondrial function, which contributes to cancer diversity and tumor aggressiveness related to racial disparities.	('mito', 'Species', '262676', (125, 129))	('suboptimal mitochondrial function', 'MPA', (157, 190))	('tumor aggressiveness', 'Disease', (234, 254))	('cancer', 'Disease', (213, 219))	('aggressiveness', 'Phenotype', 'HP:0000718', (240, 254))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (125, 150))	('mito', 'Species', '262676', (88, 92))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (234, 254))	('contribute', 'Reg', (111, 121))	('variants', 'Var', (16, 24))	('mutations', 'Var', (28, 37))	('contributes', 'Reg', (198, 209))	('mito', 'Species', '262676', (48, 52))	('mito', 'Species', '262676', (168, 172))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (125, 150))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('mitochondrial dysfunction', 'Disease', (125, 150))
636723	28487205	Ethnic differences, either at the level of expression or genetic variations in mitochondria-localized transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to cancer and aggressiveness of cancers frequently observed in AAs and other populations.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('aggressiveness of cancers', 'Disease', 'MESH:D009369', (229, 254))	('mito', 'Species', '262676', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', (218, 224))	('aggressiveness', 'Phenotype', 'HP:0000718', (229, 243))	('underlie', 'Reg', (191, 199))	('genetic variations', 'Var', (57, 75))	('tumor', 'Disease', (155, 160))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('aggressiveness of cancers', 'Disease', (229, 254))
636724	28487205	Differences in mitochondrial function may alter the mipigenetic cross talk between mitochondria and the nucleus and contribute to cancer disparities.	('Differences', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('mipigenetic cross talk between mitochondria', 'MPA', (52, 95))	('cancer', 'Disease', (130, 136))	('contribute to', 'Reg', (116, 129))	('alter', 'Reg', (42, 47))	('mito', 'Species', '262676', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mito', 'Species', '262676', (83, 87))
636794	28614248	Vanbiervliet et al have suggested that previous upper variceal digestive bleeding, peptic esophagitis, high AST to platelet ratio index (APRI) score, and low prothrombin time (PT index) are the risk factors for EVL-induced ulcer bleeding.	('peptic esophagitis', 'Disease', 'MESH:D004942', (83, 101))	('bleeding', 'Disease', (73, 81))	('ulcer bleeding', 'Disease', 'MESH:D014456', (223, 237))	('bleeding', 'Disease', 'MESH:D006470', (229, 237))	('esophagitis', 'Phenotype', 'HP:0100633', (90, 101))	('low', 'Var', (154, 157))	('bleeding', 'Disease', (229, 237))	('AST', 'Gene', (108, 111))	('EVL', 'Chemical', '-', (211, 214))	('ulcer bleeding', 'Disease', (223, 237))	('AST', 'Gene', '26503', (108, 111))	('low prothrombin time', 'Phenotype', 'HP:0032198', (154, 174))	('peptic esophagitis', 'Disease', (83, 101))	('high', 'Var', (103, 107))	('bleeding', 'Disease', 'MESH:D006470', (73, 81))	('digestive bleeding', 'Phenotype', 'HP:0002239', (63, 81))	('EV', 'Phenotype', 'HP:0002040', (211, 213))
636964	28456115	Following treatment with OXi4503, the tumor rim showed less vascular endothelial cell and tumor cell apoptosis, and higher cellular proliferation compared to the tumor center up to 24 hours posttreatment.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('OXi4503', 'Var', (25, 32))	('higher', 'PosReg', (116, 122))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cellular proliferation', 'CPA', (123, 145))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('less', 'NegReg', (55, 59))
637038	27889946	Based on the cut-off value of plasma fibrinogen concentration, 63 and 35 patients were classified into two groups at high (>400 mg/dL) and low (<=400 mg/dL) fibrinogen levels, respectively.	('fibrinogen', 'Gene', '2244', (37, 47))	('fibrinogen', 'Gene', (37, 47))	('>400 mg/dL', 'Var', (123, 133))	('fibrinogen', 'Gene', '2244', (157, 167))	('fibrinogen', 'Gene', (157, 167))	('patients', 'Species', '9606', (73, 81))
637040	27889946	Patients with high fibrinogen and NLR levels had a significantly worse prognosis than those with low fibrinogen and NLR levels (P = 0.0242 and P = 0.0019, respectively; Fig.	('fibrinogen', 'Gene', '2244', (101, 111))	('fibrinogen', 'Gene', (101, 111))	('NLR', 'MPA', (34, 37))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('fibrinogen', 'Gene', '2244', (19, 29))	('fibrinogen', 'Gene', (19, 29))	('low fibrinogen', 'Phenotype', 'HP:0011900', (97, 111))	('high fibrinogen', 'Phenotype', 'HP:0011899', (14, 29))
637050	27889946	Prognosis was significantly worse in patients with an F-NLR score of 2, than those with an F-NLR score of 0-1 (P < 0.0001).	('F-NLR', 'Var', (54, 59))	('worse', 'Reg', (28, 33))	('patients', 'Species', '9606', (37, 45))
637052	27889946	Survival rate was significantly lower in patients with a GPS of 2 than those with a GPS of 0-1 (P < 0.0001).	('patients', 'Species', '9606', (41, 49))	('Survival rate', 'CPA', (0, 13))	('GPS of 2', 'Var', (57, 65))	('lower', 'NegReg', (32, 37))
637057	27889946	Furthermore, hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0) significantly correlated with a worse prognosis in this study (P = 0.0242 and P = 0.0019, respectively).	('hyperfibrinogenemia', 'Phenotype', 'HP:0011899', (13, 32))	('hyperfibrinogenemia', 'Disease', 'None', (13, 32))	('>400 mg/dL', 'Var', (34, 44))	('hyperfibrinogenemia', 'Disease', (13, 32))
637075	27889946	In this study, a high GPS was also significantly associated with a worse tumor response and prognosis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('prognosis', 'CPA', (92, 101))	('high', 'Var', (17, 21))	('GPS', 'Protein', (22, 25))	('tumor', 'Disease', (73, 78))
637142	26379361	A Genetic Variant in miRNA-219-1 Is Associated with Risk of Esophageal Squamous Cell Carcinoma in Chinese Kazakhs Background.	('Genetic Variant', 'Var', (2, 17))	('Carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('miRNA-219-1', 'Gene', (21, 32))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (60, 94))	('Esophageal Squamous Cell Carcinoma', 'Disease', (60, 94))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('Associated', 'Reg', (36, 46))
637145	26379361	The aim of the study is to evaluate the association of miR219-1 single-nucleotide polymorphisms (SNPs) with EC.	('miR219-1', 'Gene', '407002', (55, 63))	('single-nucleotide polymorphisms', 'Var', (64, 95))	('association', 'Interaction', (40, 51))	('miR219-1', 'Gene', (55, 63))
637147	26379361	The miR-219-1 rs107822G > A and rs213210T > C genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).	('rs107822G > A', 'Var', (14, 27))	('miR-219', 'Gene', (4, 11))	('rs213210T > C', 'DBSNP_MENTION', 'None', (32, 45))	('rs213210T > C', 'Var', (32, 45))	('rs107822G > A', 'DBSNP_MENTION', 'None', (14, 27))	('miR-219', 'Gene', '407002', (4, 11))
637148	26379361	Linkage disequilibrium (LD) and haplotype analysis were used to detect the degree of association on miR-219-1 rs107822 and rs213210.	('rs213210', 'DBSNP_MENTION', 'None', (123, 131))	('rs213210', 'Var', (123, 131))	('rs107822', 'DBSNP_MENTION', 'None', (110, 118))	('rs107822', 'Var', (110, 118))	('miR-219-1', 'Gene', (100, 109))
637149	26379361	Real-time quantitative polymerase chain reaction (qRT-PCR) was performed to detect miR-219-1 expression with miR-219-1 rs107822 polymorphism.	('rs107822', 'Var', (119, 127))	('miR-219-1', 'Gene', (109, 118))	('rs107822', 'DBSNP_MENTION', 'None', (119, 127))	('miR-219-1', 'Gene', (83, 92))
637150	26379361	The SNP rs107822G > A in the miR-219-1 gene decreased the risk of Kazakh ESCC.	('rs107822G > A', 'DBSNP_MENTION', 'None', (8, 21))	('Kazakh ESCC', 'Disease', (66, 77))	('rs107822G > A', 'Var', (8, 21))	('decreased', 'NegReg', (44, 53))	('miR-219-1', 'Gene', (29, 38))
637151	26379361	Furthermore, two miR-219-1 SNPs, namely, rs107822 and rs213210, may tag each other to decrease the risk of Kazakh ESCC.	('rs213210', 'Var', (54, 62))	('rs107822', 'Var', (41, 49))	('miR-219-1', 'Gene', (17, 26))	('Kazakh ESCC', 'Disease', (107, 118))	('decrease', 'NegReg', (86, 94))	('rs213210', 'DBSNP_MENTION', 'None', (54, 62))	('rs107822', 'DBSNP_MENTION', 'None', (41, 49))
637152	26379361	These findings indicated that functional polymorphisms miR-219-1 rs107822G > A might change individual susceptibility to Kazakh ESCC.	('Kazakh ESCC', 'Disease', (121, 132))	('rs107822G > A', 'DBSNP_MENTION', 'None', (65, 78))	('miR-219-1', 'Gene', (55, 64))	('rs107822G > A', 'Var', (65, 78))	('change', 'Reg', (85, 91))
637156	26379361	miRNAs also function as tumor suppressor or oncogenes participating in diverse biological pathways.	('miRNAs', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))
637157	26379361	Single-nucleotide polymorphisms (SNPs) in pre-miRNA or miRNA sequence affect the susceptibility of numerous cancers.	('affect', 'Reg', (70, 76))	('numerous cancers', 'Disease', 'MESH:D009369', (99, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('numerous cancers', 'Disease', (99, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))
637158	26379361	For example, polymorphism rs11614913T > C in hsa-miR-196a2 was associated with the increased risk of gastric cancer.	('gastric cancer', 'Disease', (101, 115))	('rs11614913T > C', 'Var', (26, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('associated', 'Reg', (63, 73))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('rs11614913T > C', 'DBSNP_MENTION', 'None', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('hsa-miR-196a2', 'Gene', (45, 58))
637159	26379361	Polymorphism rs6505162C > A in miR-423 decreased the risk of Caucasian EC, whereas polymorphism rs2910164G > C in miR-146a precursor contributed to breast cancer and hepatocellular carcinoma susceptibility.	('miR-146a', 'Gene', '406938', (114, 122))	('rs6505162C > A', 'DBSNP_MENTION', 'None', (13, 27))	('miR-423', 'Gene', '494335', (31, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (166, 190))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('decreased', 'NegReg', (39, 48))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (166, 190))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('rs6505162C > A', 'Var', (13, 27))	('hepatocellular carcinoma', 'Disease', (166, 190))	('breast cancer', 'Disease', (148, 161))	('miR-146a', 'Gene', (114, 122))	('Caucasian EC', 'Disease', (61, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('rs2910164G > C', 'Var', (96, 110))	('miR-423', 'Gene', (31, 38))	('rs2910164G > C', 'DBSNP_MENTION', 'None', (96, 110))
637160	26379361	The rs213210 genetic variant in miR-219-1 significantly increased the mortality risk of stage III colorectal adenocarcinoma patients and was associated with the increased risk of Caucasian EC; however, no significant correlation was found between rs213210 in miR-219-1 and bladder cancer and renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (292, 312))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (98, 123))	('rs213210', 'DBSNP_MENTION', 'None', (4, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('renal cell carcinoma', 'Disease', (292, 312))	('rs213210', 'DBSNP_MENTION', 'None', (247, 255))	('associated', 'Reg', (141, 151))	('miR-219-1', 'Gene', (32, 41))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (292, 312))	('rs213210', 'Var', (4, 12))	('Caucasian EC', 'Disease', (179, 191))	('colorectal adenocarcinoma', 'Disease', (98, 123))	('increased', 'PosReg', (56, 65))	('rs213210', 'Var', (247, 255))	('bladder cancer', 'Disease', 'MESH:D001749', (273, 287))	('bladder cancer', 'Disease', (273, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('bladder cancer', 'Phenotype', 'HP:0009725', (273, 287))
637167	26379361	Differences in the distributions of demographic characteristics, genotype of the miR219-1 rs107822G > A, and rs213210T > C variants between the cases and controls were analyzed using Student's t-test and chi 2 test.	('rs107822G > A', 'DBSNP_MENTION', 'None', (90, 103))	('rs107822G > A', 'Var', (90, 103))	('rs213210T > C', 'DBSNP_MENTION', 'None', (109, 122))	('miR219-1', 'Gene', (81, 89))	('rs213210T > C', 'Var', (109, 122))
637168	26379361	The observed genotype frequencies for miR-219-1 rs107822G > A and rs213210T > C were all consistent with the HWE in controls (P = 0.323 and P = 0.954, resp.).	('rs213210T > C', 'DBSNP_MENTION', 'None', (66, 79))	('rs213210T > C', 'Var', (66, 79))	('miR-219-1', 'Gene', (38, 47))	('rs107822G > A', 'DBSNP_MENTION', 'None', (48, 61))	('rs107822G > A', 'Var', (48, 61))
637169	26379361	The genotype distributions of miR219-1 rs107822G > A and rs213210T > C in the cases and controls are listed in Table 3.	('miR219-1', 'Gene', (30, 38))	('rs107822G > A', 'DBSNP_MENTION', 'None', (39, 52))	('rs107822G > A', 'Var', (39, 52))	('rs213210T > C', 'DBSNP_MENTION', 'None', (57, 70))	('rs213210T > C', 'Var', (57, 70))
637170	26379361	In the single-locus analyses, the genotype frequencies of miR-219-1 rs107822G > A were 32.8% (GG), 49.5% (GA), and 17.7% (AA) in the case patients and 24.6% (GG), 38.2% (GA), and 37.2% (AA) in the controls.	('GA', 'Chemical', 'MESH:D005708', (106, 108))	('miR-219-1', 'Gene', (58, 67))	('rs107822G > A', 'DBSNP_MENTION', 'None', (68, 81))	('GA', 'Chemical', 'MESH:D005708', (170, 172))	('rs107822G > A', 'Var', (68, 81))
637171	26379361	When the miR-219-1 rs107822 GG homozygote genotype was used as reference group in the codominant model, the GA genotypes were not associated with the risk for Kazakh ESCC (GA versus GG: adjust OR = 0.976, 95% CI = 0.626-1.522, P = 0.914, Table 3), but the AA genotype showed a statistically decreased risk for Kazakh ESCC (AA versus GG: adjust OR = 0.365, 95% CI = 0.217-0.614, P = 1.429 x 10-4, Table 3).	('rs107822', 'Var', (19, 27))	('rs107822', 'DBSNP_MENTION', 'None', (19, 27))	('Kazakh ESCC', 'Disease', (159, 170))	('Kazakh ESCC', 'Disease', (310, 321))	('decreased', 'NegReg', (291, 300))	('miR-219-1', 'Gene', (9, 18))
637172	26379361	In the recessive model, the miR-219-1 rs107822 AA homozygote genotype was associated with a statistically decreased risk for Kazakh ESCC, compared with the miR-219-1 rs107822 GG + GA genotypes (AA versus GG + GA: adjust OR = 0.371, 95% CI = 0.238-0.577, P = 1.134 x 10-5, Table 3).	('decreased', 'NegReg', (106, 115))	('rs107822', 'DBSNP_MENTION', 'None', (38, 46))	('rs107822', 'DBSNP_MENTION', 'None', (166, 174))	('miR-219-1', 'Gene', (28, 37))	('rs107822', 'Var', (38, 46))	('Kazakh ESCC', 'Disease', (125, 136))	('rs107822', 'Var', (166, 174))
637173	26379361	However, in the dominant model, the miR-219-1 rs107822 GA + AA variants were not associated with the risk for Kazakh ESCC, compared with the miR-219-1 rs107822 GG genotype (GA + AA versus GG: adjust OR = 0.677, 95% CI = 0.449 to 1.020, P = 0.063, Table 3).	('miR-219-1', 'Gene', (36, 45))	('rs107822', 'Var', (151, 159))	('rs107822', 'DBSNP_MENTION', 'None', (46, 54))	('Kazakh ESCC', 'Disease', (110, 121))	('rs107822', 'Var', (46, 54))	('rs107822', 'DBSNP_MENTION', 'None', (151, 159))
637174	26379361	No association was observed between the miR-219-1 rs213210T > C polymorphisms and the risk of Kazakh ESCC (P > 0.05) (Table 3).	('Kazakh ESCC', 'Disease', (94, 105))	('rs213210T > C', 'DBSNP_MENTION', 'None', (50, 63))	('miR-219-1', 'Gene', (40, 49))	('rs213210T > C', 'Var', (50, 63))
637175	26379361	Stratification analyses were performed to further investigate the potential effects of miR-219-1 rs107822G > A genotype on Kazakh ESCC risk in terms of clinicopathological parameters (including gender, age, histologic stage, depth of invasion, lymph node metastasis, and TNM stage).	('rs107822G > A', 'Var', (97, 110))	('ESCC', 'Disease', (130, 134))	('miR-219-1', 'Gene', (87, 96))	('rs107822G > A', 'DBSNP_MENTION', 'None', (97, 110))
637176	26379361	However, no significant association was found between miR-219-1 rs107822G > A and Kazakh ESCC concerning gender, age, histologic stage, depth of invasion, lymph node metastasis, and TNM stage (P > 0.05 for all) (Table 4).	('miR-219-1', 'Gene', (54, 63))	('rs107822G > A', 'DBSNP_MENTION', 'None', (64, 77))	('rs107822G > A', 'Var', (64, 77))
637177	26379361	The LD of rs107822 and rs213210 in miR-219-1 was estimated using r 2 and D' statistic (http://analysis.bio-x.cn/SHEsisMain.htm).	('rs213210', 'Var', (23, 31))	('rs213210', 'DBSNP_MENTION', 'None', (23, 31))	('rs107822', 'DBSNP_MENTION', 'None', (10, 18))	('rs107822', 'Var', (10, 18))	('miR-219-1', 'Gene', (35, 44))
637178	26379361	Two miR219-1 polymorphisms, namely, rs107822 and rs213210, showed strong LD in the cases and complete LD in the controls (cases: D' = 0.8808, r 2 = 0.2503; controls: D' = 1, r 2 = 0.1732; Figure 1), suggesting that the two miR-219-1 SNPs may tag each other for Kazakh ESCC.	('miR219-1', 'Gene', (4, 12))	('rs107822', 'DBSNP_MENTION', 'None', (36, 44))	('rs213210', 'Var', (49, 57))	('rs213210', 'DBSNP_MENTION', 'None', (49, 57))	('rs107822', 'Var', (36, 44))
637179	26379361	Among the haplotypes derived from the observed genotypes, the Grs107822Trs213210 was the most common in both cases and controls (56.6% and 45.4%, resp.)	('Grs107822Trs213210', 'Var', (62, 80))	('Grs107822Trs213210', 'Chemical', '-', (62, 80))	('common', 'Reg', (94, 100))
637180	26379361	To study the effect of the variants of miR-219-1 rs107822 on mature miRNA expression, qRT-PCR was used to measure the miR-219-1-5p expression levels with different rs107822 genotypes in tumor and normal tissue samples (n = 100).	('rs107822', 'DBSNP_MENTION', 'None', (49, 57))	('rs107822', 'DBSNP_MENTION', 'None', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('miR-219-1', 'Gene', (39, 48))	('rs107822', 'Var', (164, 172))	('rs107822', 'Var', (49, 57))
637185	26379361	A subsequent research involving zebrafish discovered that overexpression of miR-219-1 can induce embryonic cell death.	('miR-219-1', 'Var', (76, 85))	('overexpression', 'PosReg', (58, 72))	('embryonic cell death', 'Disease', (97, 117))	('zebrafish', 'Species', '7955', (32, 41))	('embryonic cell death', 'Disease', 'MESH:D003643', (97, 117))
637186	26379361	Interestingly, miR-219-1 rs213210 has significantly increased the mortality risk of confirmed stage III colorectal adenocarcinoma patients and increased the risk of Caucasian EC, indicating that miR-219-1 polymorphisms may contribute to cancer susceptibility.	('increased', 'PosReg', (143, 152))	('increased', 'PosReg', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('rs213210', 'Var', (25, 33))	('rs213210', 'DBSNP_MENTION', 'None', (25, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('contribute', 'Reg', (223, 233))	('Caucasian EC', 'Disease', (165, 177))	('miR-219-1', 'Gene', (15, 24))
637187	26379361	In the codominant and recessive models, miR-219-1 rs107822G > A polymorphism was associated with significantly decreased Kazakh ESCC risk.	('rs107822G > A', 'DBSNP_MENTION', 'None', (50, 63))	('rs107822G > A', 'Var', (50, 63))	('decreased', 'NegReg', (111, 120))	('miR-219-1', 'Gene', (40, 49))	('Kazakh ESCC', 'Disease', (121, 132))
637188	26379361	However, no significant association existed between miR-219-1 rs213210T > C and the risk of Kazakh ESCC in our study.	('rs213210T > C', 'Var', (62, 75))	('miR-219-1', 'Gene', (52, 61))	('Kazakh ESCC', 'Disease', (92, 103))	('rs213210T > C', 'DBSNP_MENTION', 'None', (62, 75))
637189	26379361	These results suggested that the polymorphism rs107822G > A in the miR-219-1 is a protective factor against ESCC in the Kazakh population.	('rs107822G > A', 'DBSNP_MENTION', 'None', (46, 59))	('miR-219-1', 'Gene', (67, 76))	('rs107822G > A', 'Var', (46, 59))	('ESCC', 'Disease', (108, 112))
637190	26379361	Our stratified analyses found no significant association between miR-219-1 rs107822 and Kazakh ESCC with regard to gender, age, histologic stage, depth of invasion, lymph node metastasis, and TNM stage.	('rs107822', 'Var', (75, 83))	('miR-219-1', 'Gene', (65, 74))	('rs107822', 'DBSNP_MENTION', 'None', (75, 83))
637191	26379361	Furthermore, two SNPs, rs107822 and rs213210, in the miR-219-1 gene showed strong LD with the cases and complete LD with the controls.	('miR-219-1', 'Gene', (53, 62))	('rs107822', 'Var', (23, 31))	('rs107822', 'DBSNP_MENTION', 'None', (23, 31))	('rs213210', 'DBSNP_MENTION', 'None', (36, 44))	('rs213210', 'Var', (36, 44))
637193	26379361	found that an SNP within the miR-27a terminal loop significantly influenced the miR-27a genotype-based expression, suggesting that the SNPs located in the miRNA terminal loop may slightly influence the processing of pri-miRNA and affect the miRNA biogenesis.	('SNPs', 'Var', (135, 139))	('affect', 'Reg', (230, 236))	('miR-27a', 'Gene', (80, 87))	('influence', 'Reg', (188, 197))	('miR-27a', 'Gene', (29, 36))	('processing', 'MPA', (202, 212))	('miR-27a', 'Gene', '407018', (80, 87))	('miRNA biogenesis', 'MPA', (241, 257))	('miR-27a', 'Gene', '407018', (29, 36))	('pri-miRNA', 'Protein', (216, 225))	('influenced', 'Reg', (65, 75))
637194	26379361	Second, through interfering with pri-miRNA and pre-miRNA processing and maturation, an SNP located at nucleotide 8 (t8) of mature miR-125a in a normal subject blocks pri-miR-125a processing to pre-miRNA, thereby reducing the miRNA-mediated translational suppression of its target.	('miR-125a', 'Gene', (170, 178))	('reducing', 'NegReg', (212, 220))	('miR-125a', 'Gene', '406910', (130, 138))	('miRNA-mediated translational suppression', 'MPA', (225, 265))	('miR-125a', 'Gene', (130, 138))	('processing', 'MPA', (179, 189))	('miR-125a', 'Gene', '406910', (170, 178))	('SNP located', 'Var', (87, 98))	('interfering', 'Reg', (16, 27))	('blocks', 'NegReg', (159, 165))
637195	26379361	rs11614913 CC in hsa-mir-196a2 was associated with a statistically significant increase in mature hsa-mir-196a expression, suggesting that miRNA-related SNPs may affect pri-miRNA to pre-miRNA processing and maturation.	('increase', 'PosReg', (79, 87))	('rs11614913', 'Var', (0, 10))	('hsa-mir-196a2', 'Gene', (17, 30))	('maturation', 'CPA', (207, 217))	('affect', 'Reg', (162, 168))	('rs11614913', 'DBSNP_MENTION', 'None', (0, 10))	('mature', 'MPA', (91, 97))	('pri-miRNA to pre-miRNA processing', 'CPA', (169, 202))
637196	26379361	Lastly, alteration of the miRNA-mRNA interaction affinity, such as rs11614913 SNP in hsa-mir-196a2, can affect the binding of mature hsa-mir-196a2-3p to its target LSP1Mrna, suggesting that SNPs can affect the miRNA functions by changing the miRNA-mRNA interaction.	('affect', 'Reg', (104, 110))	('changing', 'Reg', (229, 237))	('rs11614913', 'DBSNP_MENTION', 'None', (67, 77))	('alteration', 'Reg', (8, 18))	('miRNA-mRNA interaction', 'MPA', (242, 264))	('rs11614913', 'Var', (67, 77))	('miRNA-mRNA interaction', 'MPA', (26, 48))	('binding', 'Interaction', (115, 122))	('LSP1Mrna', 'Protein', (164, 172))	('affect', 'Reg', (199, 205))	('miRNA functions', 'MPA', (210, 225))
637197	26379361	The rs6505162A > C in pre-miRNA miR-423 increased the EC risk but did not change the levels of mature miR-423.	('rs6505162A > C', 'DBSNP_MENTION', 'None', (4, 18))	('miR-423', 'Gene', (32, 39))	('rs6505162A > C', 'Var', (4, 18))	('increased', 'PosReg', (40, 49))
637198	26379361	To further characterize the functional relevance of the miR219-1 rs107822 SNP, qRT-PCR was used to detect the effects of different SNP rs107822 genotypes on the expression of mature miR-219-1.	('rs107822', 'DBSNP_MENTION', 'None', (65, 73))	('expression', 'MPA', (161, 171))	('rs107822', 'DBSNP_MENTION', 'None', (135, 143))	('rs107822', 'Var', (65, 73))	('miR-219-1', 'Gene', (182, 191))	('rs107822', 'Var', (135, 143))
637199	26379361	The miR-219-1 rs107822 GA and AA genotypes decreased the mature miR-219-1 expression compared with the miR-219-1 rs107822 GG genotypes in both Kazakh ESCC tumor tissues and adjacent normal tissues.	('expression', 'MPA', (74, 84))	('ESCC tumor', 'Disease', (150, 160))	('rs107822', 'Var', (113, 121))	('rs107822', 'DBSNP_MENTION', 'None', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ESCC tumor', 'Disease', 'MESH:D004938', (150, 160))	('miR-219-1', 'Gene', (64, 73))	('rs107822', 'Var', (14, 22))	('miR-219-1', 'Gene', (4, 13))	('rs107822', 'DBSNP_MENTION', 'None', (113, 121))	('decreased', 'NegReg', (43, 52))
637200	26379361	However, the miR-219-1 rs107822G > A polymorphisms decreased the risk of Kazakh ESCC.	('rs107822G > A', 'DBSNP_MENTION', 'None', (23, 36))	('decreased', 'NegReg', (51, 60))	('rs107822G > A', 'Var', (23, 36))	('miR-219-1', 'Gene', (13, 22))	('Kazakh ESCC', 'Disease', (73, 84))
637201	26379361	Thus, we deduced that miR-219-1 rs107822G > A polymorphisms may be ascribed to the binding efficiency between miR-219-1 and its target mRNAs before influencing miR-219-1 to regulate its target mRNAs and decrease the risk of Kazakh ESCC.	('miR-219-1', 'Gene', (110, 119))	('miR-219-1', 'Gene', (22, 31))	('rs107822G > A', 'DBSNP_MENTION', 'None', (32, 45))	('binding', 'Interaction', (83, 90))	('influencing', 'Reg', (148, 159))	('Kazakh ESCC', 'Disease', (224, 235))	('decrease', 'NegReg', (203, 211))	('rs107822G > A', 'Var', (32, 45))	('polymorphisms', 'Var', (46, 59))
637202	26379361	In conclusion, the present study provided evidence that the SNP rs107822G > A in miRNA-219-1 gene decreased the risk of Kazakh ESCC.	('miRNA-219-1', 'Gene', (81, 92))	('Kazakh ESCC', 'Disease', (120, 131))	('rs107822G > A', 'DBSNP_MENTION', 'None', (64, 77))	('rs107822G > A', 'Var', (64, 77))	('decreased', 'NegReg', (98, 107))
637203	26379361	Furthermore, two SNPs (rs107822 and rs213210) in the miR-219-1 gene may tag each other to decrease the risk of Kazakh ESCC.	('miR-219-1', 'Gene', (53, 62))	('rs107822', 'Var', (23, 31))	('rs107822', 'DBSNP_MENTION', 'None', (23, 31))	('Kazakh ESCC', 'Disease', (111, 122))	('rs213210', 'DBSNP_MENTION', 'None', (36, 44))	('decrease', 'NegReg', (90, 98))	('rs213210', 'Var', (36, 44))
637204	26379361	miR-219-1 rs107822G > A influenced the mature miR-219-1 expression with different rs107822 genotypes in both Kazakh ESCC tumor tissues and adjacent normal tissues.	('miR-219-1', 'Gene', (46, 55))	('rs107822', 'DBSNP_MENTION', 'None', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('rs107822', 'Var', (82, 90))	('miR-219-1', 'Gene', (0, 9))	('rs107822', 'Var', (10, 18))	('expression', 'MPA', (56, 66))	('influenced', 'Reg', (24, 34))	('rs107822', 'DBSNP_MENTION', 'None', (82, 90))	('rs107822G > A', 'DBSNP_MENTION', 'None', (10, 23))	('rs107822G > A', 'Var', (10, 23))
637212	24449022	Therefore, the pathological diagnosis of the tumor was T3N1M0 Stage III according to the TNM classification of the International Union for Cancer classification.	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TNM', 'Gene', (89, 92))	('tumor', 'Disease', (45, 50))	('T3N1M0', 'Var', (55, 61))	('Cancer', 'Disease', (139, 145))	('Cancer', 'Disease', 'MESH:D009369', (139, 145))	('TNM', 'Gene', '10178', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
637240	20699457	116 esophageal or gastric cancers (79 esophageal) occurred in the bisphosphonate cohort and 115 (72 esophageal) in the control cohort.	('esophageal', 'Disease', 'MESH:D004941', (100, 110))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('esophageal or gastric cancers', 'Disease', (4, 33))	('esophageal', 'Disease', (4, 14))	('esophageal', 'Disease', (38, 48))	('esophageal', 'Disease', (100, 110))	('occurred', 'Reg', (50, 58))	('esophageal or gastric cancers', 'Disease', 'MESH:D013274', (4, 33))	('bisphosphonate', 'Chemical', 'MESH:D004164', (66, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('bisphosphonate', 'Var', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('gastric cancers', 'Phenotype', 'HP:0012126', (18, 33))	('esophageal', 'Disease', 'MESH:D004941', (38, 48))	('esophageal', 'Disease', 'MESH:D004941', (4, 14))
637302	20699457	Ever use of HRT, NSAIDs, PPIs and H2RAs before the index date was higher in the bisphosphonate cohort than in the control cohort.	('PPIs', 'Var', (25, 29))	('H2RAs', 'Var', (34, 39))	('bisphosphonate', 'Chemical', 'MESH:D004164', (80, 94))	('higher', 'PosReg', (66, 72))
637316	20699457	Specifically, GERD diagnosis was associated with a 49% increase in the incidence of esophageal and gastric cancer (HR =1.49, 95%CI 0.85, 2.61) in the bisphosphonate cohort and a 69% increase in the control cohort (HR=1.69, 95%CI 1.06, 2.71), with similar increases in risk seen for esophageal cancer only.	('bisphosphonate', 'Chemical', 'MESH:D004164', (150, 164))	('increase', 'PosReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (282, 299))	('esophageal and gastric cancer', 'Disease', 'MESH:D013274', (84, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (282, 299))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('GERD diagnosis', 'Var', (14, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))
637346	33490631	Therefore, we attempted to perform ESD with the GIF-H290T (diameter: 9.9 mm; Olympus), which is commonly used for endoscopic treatment after bougienage.	('H290T', 'SUBSTITUTION', 'None', (52, 57))	('GIF', 'Gene', '2694', (48, 51))	('H290T', 'Var', (52, 57))	('GIF', 'Gene', (48, 51))
637349	33490631	We then performed bougienage with the GIF-H290T (diameter: 9.9 mm).	('GIF', 'Gene', (38, 41))	('GIF', 'Gene', '2694', (38, 41))	('H290T', 'SUBSTITUTION', 'None', (42, 47))	('H290T', 'Var', (42, 47))
637350	33490631	Finally, the stricture was extended so that the GIF-H290T, with a handmade distal endoscope attachment with plastic tape, could pass through (Fig.	('H290T', 'SUBSTITUTION', 'None', (52, 57))	('GIF', 'Gene', '2694', (48, 51))	('H290T', 'Var', (52, 57))	('GIF', 'Gene', (48, 51))
637360	33490631	Fortunately, the stricture in this case had a diameter that the GIF-H290 (diameter: 8.9 mm) could barely pass through, so we attempted to perform ESD with the GIF-H290T (diameter: 9.9 mm), which is commonly used in esophageal ESD after stepwise scope bougienage.	('H290T', 'SUBSTITUTION', 'None', (163, 168))	('H290T', 'Var', (163, 168))	('GIF', 'Gene', (64, 67))	('GIF', 'Gene', '2694', (64, 67))	('GIF', 'Gene', '2694', (159, 162))	('GIF', 'Gene', (159, 162))
637379	31830929	Human papillomavirus (HPV), mainly HPV16 followed by HPV18, is now recognized as a cause of a fraction of oropharyngeal cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Human papillomavirus', 'Species', '10566', (0, 20))	('HPV', 'Species', '10566', (35, 38))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('HPV', 'Species', '10566', (22, 25))	('cause', 'Reg', (83, 88))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('HPV', 'Species', '10566', (53, 56))	('Human papillomavirus', 'Disease', (0, 20))	('HPV16', 'Species', '333760', (35, 40))	('HPV16', 'Var', (35, 40))	('HPV18', 'Var', (53, 58))
637388	31830929	In this study, we analyzed the transcript expression profiles and functions of E6 and E7 to delineate the role of HPV18 in esophageal (EC109 and EC9706) and tongue (Tca83) cancers based on cell lines established from Chinese.	('E7', 'Gene', '25479181', (86, 88))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('E6', 'Gene', 'None', (79, 81))	('EC9706', 'Var', (145, 151))	('esophageal', 'Disease', (123, 133))	('HPV', 'Species', '10566', (114, 117))	('Tca83', 'Chemical', '-', (165, 170))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('HPV18', 'Gene', (114, 119))
637392	31830929	The EC109, EC9706 and Tca83 cell lines were generous gifts from Prof. Zeng Yi, the National Institute for Viral Disease Control and Prevention of Chinese Center for Disease Control and Prevention in 2012.	('EC9706', 'Var', (11, 17))	('Viral Disease', 'Disease', (106, 119))	('Viral Disease', 'Disease', 'MESH:D001102', (106, 119))	('Tca83', 'Chemical', '-', (22, 27))
637406	31830929	Viral genome integration resulting in disruption and loss of viral transcripts are remarkable features of HPV-mediated oncogenesis.	('disruption', 'MPA', (38, 48))	('Viral', 'Var', (0, 5))	('viral transcripts', 'MPA', (61, 78))	('loss', 'NegReg', (53, 57))	('HPV', 'Species', '10566', (106, 109))
637407	31830929	Therefore, we examined the HPV transcription profiles in esophageal (EC109 and EC9706), tongue (Tca83) and cervical (HeLa) cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('HPV', 'Species', '10566', (27, 30))	('EC9706', 'Var', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('Tca83', 'Chemical', '-', (96, 101))	('EC109', 'Var', (69, 74))	('cancer', 'Disease', (123, 129))	('HeLa', 'CellLine', 'CVCL:0030', (117, 121))
637414	31830929	Whilst spliced E6 variant I (E6*I) and E7 were markedly higher in EC109, EC9706 and HeLa (E6*I: 412,299 - 491,899; E7: 599,610 - 626,397) compared to Tca83 (E6*I: 293,362; E7: 457,654) (Table 1).	('E6', 'Gene', 'None', (90, 92))	('Tca83', 'Chemical', '-', (150, 155))	('EC9706', 'Var', (73, 79))	('E7', 'Gene', '25479181', (39, 41))	('E6', 'Gene', 'None', (29, 31))	('E7', 'Gene', '25479181', (115, 117))	('HeLa', 'CellLine', 'CVCL:0030', (84, 88))	('E6', 'Gene', 'None', (15, 17))	('variant I', 'Var', (18, 27))	('higher', 'PosReg', (56, 62))	('E7', 'Gene', '25479181', (172, 174))	('E6', 'Gene', 'None', (157, 159))
637415	31830929	Furthermore, the E7 to E6 ratios in EC109 and EC9706 were nearly doubled relative to those in HeLa and Tca83 (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (94, 98))	('EC109', 'Var', (36, 41))	('doubled', 'PosReg', (65, 72))	('EC9706', 'Var', (46, 52))	('Tca83', 'Chemical', '-', (103, 108))	('E7', 'Gene', '25479181', (17, 19))	('E6', 'Gene', 'None', (23, 25))
637418	31830929	Following the differential expression of HPV18 oncoproteins reported above, we next examined whether E6 and E7 oncoproteins in esophageal (EC109 and EC9706) and tongue (Tca83) cancer cells target key cellular proteins in a similar manner to cervical cancer cells, such as HeLa.	('E7', 'Gene', '25479181', (108, 110))	('HPV', 'Species', '10566', (41, 44))	('EC9706', 'Var', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('Tca83', 'Chemical', '-', (169, 174))	('E6', 'Gene', 'None', (101, 103))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('HPV18', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('HeLa', 'CellLine', 'CVCL:0030', (272, 276))
637423	31830929	2a and b (i)], downregulation of HPV18 E6 in all the esophageal (EC109 and EC9706) and tongue (Tca83) SCC cell lines resulted in a significant rescue of p53 as well as its downstream transactivation target, p21 [Fig.	('downregulation', 'NegReg', (15, 29))	('Tca83', 'Chemical', '-', (95, 100))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('E6', 'Gene', 'None', (39, 41))	('p21', 'Gene', (207, 210))	('p53', 'Gene', (153, 156))	('EC9706', 'Var', (75, 81))	('HPV', 'Species', '10566', (33, 36))	('p21', 'Gene', '644914', (207, 210))	('p53', 'Gene', '7157', (153, 156))	('SCC', 'Gene', (102, 105))	('HPV18', 'Gene', (33, 38))	('rescue', 'PosReg', (143, 149))
637429	31830929	2a and b (iii)], and increased p107 was only found in EC9706 [Fig.	('EC9706', 'Var', (54, 60))	('p107', 'Gene', (31, 35))	('p107', 'Gene', '5933', (31, 35))
637433	31830929	We further examined whether these transcripts harbored mutations that could potentially lead to amino acid alterations, and subsequently affect E7-pRB recognition in EC109, EC9706 and Tca83 compared to HeLa.	('lead to', 'Reg', (88, 95))	('EC9706', 'Var', (173, 179))	('pRB', 'Gene', (147, 150))	('E7', 'Gene', '25479181', (144, 146))	('HeLa', 'CellLine', 'CVCL:0030', (202, 206))	('Tca83', 'Chemical', '-', (184, 189))	('pRB', 'Gene', '5925', (147, 150))	('affect', 'Reg', (137, 143))	('amino acid alterations', 'MPA', (96, 118))
637434	31830929	We observed that RB2 harbored same-sense mutations, corresponding to amino acid positions at T694, R679 and T864, while no exonic mutation was detected within RB1 (Additional file 1).	('RB1', 'Gene', (159, 162))	('R679', 'Var', (99, 103))	('RB1', 'Gene', '5925', (159, 162))	('T694', 'Var', (93, 97))	('T864', 'Var', (108, 112))	('RB2', 'Gene', '5934', (17, 20))	('RB2', 'Gene', (17, 20))
637439	31830929	In general, we observed a higher basal level of both total and phosphorylated AKT at position S473 [pAKT(S473)], ERK 1/2 phosphorylated at position T202/Y204 [pERK1/2(T202/Y204)], MMP2 and MMP9 in EC109, EC9706 and Tca83 compared to HeLa cells (Fig.	('MMP9', 'Gene', (189, 193))	('AKT', 'Gene', '207', (101, 104))	('Tca83', 'Chemical', '-', (215, 220))	('higher', 'PosReg', (26, 32))	('MMP9', 'Gene', '4318', (189, 193))	('ERK', 'Gene', '5594', (160, 163))	('EC9706', 'Var', (204, 210))	('AKT', 'Gene', '207', (78, 81))	('AKT', 'Gene', (101, 104))	('ERK', 'Gene', (160, 163))	('ERK', 'Gene', (113, 116))	('ERK', 'Gene', '5594', (113, 116))	('MMP2', 'Gene', (180, 184))	('HeLa', 'CellLine', 'CVCL:0030', (233, 237))	('basal level', 'MPA', (33, 44))	('AKT', 'Gene', (78, 81))	('MMP2', 'Gene', '4313', (180, 184))
637441	31830929	When HPV18 E6 and E7 in Tca83 cells were depleted using siRNA, we observed significant reduction in pERK1/2 (T202/Y204) and MMP2, together with a significant elevation in ERK1/2 in Tca83 [Fig.	('E6', 'Gene', 'None', (11, 13))	('ERK', 'Gene', '5594', (101, 104))	('E7', 'Gene', '25479181', (18, 20))	('T202/Y204', 'Var', (109, 118))	('ERK', 'Gene', (101, 104))	('Tca83', 'Chemical', '-', (181, 186))	('MMP2', 'Gene', (124, 128))	('Tca83', 'Chemical', '-', (24, 29))	('elevation', 'PosReg', (158, 167))	('ERK', 'Gene', '5594', (171, 174))	('ERK', 'Gene', (171, 174))	('HPV', 'Species', '10566', (5, 8))	('reduction', 'NegReg', (87, 96))	('MMP2', 'Gene', '4313', (124, 128))
637445	31830929	Downregulation of E6 and E7 resulted in a dramatic reduced level of AKT in EC109, but not in the other cells [Fig.	('level', 'MPA', (59, 64))	('reduced', 'NegReg', (51, 58))	('EC109', 'Var', (75, 80))	('Downregulation', 'NegReg', (0, 14))	('E6', 'Gene', 'None', (18, 20))	('AKT', 'Gene', '207', (68, 71))	('E7', 'Gene', '25479181', (25, 27))	('AKT', 'Gene', (68, 71))
637446	31830929	In addition, E6 and E7 downregulation had no significant effect on ERK activity, MMP2 and MMP9 levels in EC109 and EC9706.	('downregulation', 'NegReg', (23, 37))	('EC9706', 'Var', (115, 121))	('MMP2', 'Gene', (81, 85))	('ERK', 'Gene', '5594', (67, 70))	('ERK', 'Gene', (67, 70))	('MMP9', 'Gene', (90, 94))	('MMP2', 'Gene', '4313', (81, 85))	('MMP9', 'Gene', '4318', (90, 94))	('E7', 'Gene', '25479181', (20, 22))	('E6', 'Gene', 'None', (13, 15))
637454	31830929	Our results showed that ablation of E6 and E7 in HeLa led to a significant increased levels of full length caspases 8, 9 and 3 [Fig.	('caspases', 'Gene', 'None', (107, 115))	('full length', 'MPA', (95, 106))	('E7', 'Gene', '25479181', (43, 45))	('levels', 'MPA', (85, 91))	('caspases', 'Gene', (107, 115))	('E6', 'Gene', 'None', (36, 38))	('increased', 'PosReg', (75, 84))	('ablation', 'Var', (24, 32))	('HeLa', 'CellLine', 'CVCL:0030', (49, 53))
637457	31830929	However, we did not observe activation of these initiator and effector caspases in EC109 and EC9706 (Fig.	('caspases', 'Gene', 'None', (71, 79))	('EC9706', 'Var', (93, 99))	('EC109', 'Var', (83, 88))	('caspases', 'Gene', (71, 79))
637463	31830929	We observed a significant reduction in Ki67 expression in HeLa, EC9706 and Tca83, but not in EC109 upon ablation of E6 and E7 [Fig.	('Tca83', 'Chemical', '-', (75, 80))	('expression', 'MPA', (44, 54))	('Ki67', 'Gene', (39, 43))	('reduction', 'NegReg', (26, 35))	('EC9706', 'Var', (64, 70))	('E6', 'Gene', 'None', (116, 118))	('E7', 'Gene', '25479181', (123, 125))	('ablation', 'Var', (104, 112))	('HeLa', 'CellLine', 'CVCL:0030', (58, 62))
637465	31830929	Our results indicated that E6 and E7 promote proliferation of EC9706 and Tca83.	('E6', 'Gene', 'None', (27, 29))	('proliferation', 'CPA', (45, 58))	('promote', 'PosReg', (37, 44))	('Tca83', 'Gene', (73, 78))	('Tca83', 'Chemical', '-', (73, 78))	('E7', 'Gene', '25479181', (34, 36))	('EC9706', 'Var', (62, 68))
637466	31830929	Surprisingly, ablation of E6 and E7 was not adequate to initiate activation of caspase pathway in both EC109 and EC9706, as well as did not affect proliferation of EC109.	('caspase pathway', 'Pathway', (79, 94))	('E7', 'Gene', '25479181', (33, 35))	('E6', 'Gene', 'None', (26, 28))	('EC9706', 'Var', (113, 119))	('ablation', 'Var', (14, 22))
637477	31830929	Both EC109 and EC9706 expressed relatively higher levels of E7 and E6*I, while HeLa and Tca83 expressed relatively higher levels of E6.	('Tca83', 'Chemical', '-', (88, 93))	('higher', 'PosReg', (43, 49))	('E6', 'Gene', 'None', (132, 134))	('EC9706', 'Var', (15, 21))	('E6', 'Gene', 'None', (67, 69))	('E7', 'Gene', '25479181', (60, 62))	('HeLa', 'CellLine', 'CVCL:0030', (79, 83))	('EC109', 'Var', (5, 10))
637496	31830929	The role of HPV oncoproteins in EC109 and EC9706 in cellular targeting are indeed distinct from that in HeLa and Tca83.	('EC109', 'Var', (32, 37))	('Tca83', 'Chemical', '-', (113, 118))	('HeLa', 'CellLine', 'CVCL:0030', (104, 108))	('cellular targeting', 'MPA', (52, 70))	('HPV', 'Species', '10566', (12, 15))	('EC9706', 'Var', (42, 48))
637497	31830929	Although these cells share certain degrees of similarity, EC109 and EC9706 can differ from each other in term of HPV18 genome transcripts and subset of cellular proteins targeted by HPV oncoproteins.	('HPV', 'Species', '10566', (182, 185))	('HPV18', 'Gene', (113, 118))	('EC109', 'Var', (58, 63))	('EC9706', 'Var', (68, 74))	('HPV', 'Species', '10566', (113, 116))
637503	31830929	This could occur through perturbation of transforming growth factor-beta1 (TGF-beta1) signaling, which is important for epithelial-mesenchymal transition (EMT) of EC9706, and subsequently leading to inactivation of Fas-mediated apoptosis in a caspase-independent fashion.	('EC9706', 'Var', (163, 169))	('inactivation', 'NegReg', (199, 211))	('transforming growth factor-beta1', 'Gene', '7040', (41, 73))	('Fas-mediated', 'Pathway', (215, 227))	('perturbation', 'Var', (25, 37))	('transforming growth factor-beta1', 'Gene', (41, 73))	('TGF-beta1', 'Gene', '7040', (75, 84))	('TGF-beta1', 'Gene', (75, 84))
637532	31344837	Due to some substitutions in residues critical for GTP hydrolysis, which correspond to Gly14, Ala61, and Gln63 of RHOA, RND proteins are unable to hydrolyze GTP and consequently, are always activated.	('activated', 'PosReg', (190, 199))	('unable', 'NegReg', (137, 143))	('Gly14', 'Chemical', '-', (87, 92))	('GTP', 'Chemical', 'MESH:D006160', (157, 160))	('Gln63', 'Var', (105, 110))	('GTP', 'Chemical', 'MESH:D006160', (51, 54))	('Gln63', 'Chemical', '-', (105, 110))	('Ala61', 'Chemical', '-', (94, 99))	('Gly14', 'Var', (87, 92))	('hydrolyze GTP', 'MPA', (147, 160))
637539	31344837	Concerning post-translational prenylation, unlike the proteins of the RHOA, RAC1, and CDC42 subfamilies (see Figure 1), which are predominantly geranyl-geranylated, RND proteins are farnesylated due to a methionine in the C-terminal CAAX box.	('RAC1', 'Gene', (76, 80))	('methionine', 'Var', (204, 214))	('CDC42', 'Gene', '998', (86, 91))	('CDC42', 'Gene', (86, 91))	('methionine', 'Chemical', 'MESH:D008715', (204, 214))	('RAC1', 'Gene', '5879', (76, 80))
637542	31344837	Dysregulation of classic Rho GTPases activity can lead to dysregulation of processes important for tumorigenesis, such as metastasis or angiogenesis capacity.	('GTP', 'Chemical', 'MESH:D006160', (29, 32))	('tumor', 'Disease', (99, 104))	('lead to', 'Reg', (50, 57))	('Dysregulation', 'Var', (0, 13))	('processes', 'MPA', (75, 84))	('angiogenesis capacity', 'CPA', (136, 157))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('activity', 'MPA', (37, 45))	('metastasis', 'CPA', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('dysregulation', 'MPA', (58, 71))
637568	31344837	When phosphorylation occurs near the CAAX box, it alters the localization and function of Rho GTPases.	('alters', 'Reg', (50, 56))	('phosphorylation', 'Var', (5, 20))	('Rho GTPases', 'Protein', (90, 101))	('GTP', 'Chemical', 'MESH:D006160', (94, 97))	('localization', 'MPA', (61, 73))	('function', 'MPA', (78, 86))
637584	31344837	The effect of RND1 is related to the stimulation of the GTPase activity of plexin A1, which is responsible for a decrease in R-Ras activity.	('R-Ras activity', 'MPA', (125, 139))	('decrease', 'NegReg', (113, 121))	('activity', 'MPA', (63, 71))	('stimulation', 'PosReg', (37, 48))	('plexin A1', 'Gene', '5361', (75, 84))	('GTPase', 'Enzyme', (56, 62))	('GTP', 'Chemical', 'MESH:D006160', (56, 59))	('RND1', 'Var', (14, 18))	('plexin A1', 'Gene', (75, 84))
637586	31344837	In Cos-7 cells, co-expression of RND1 and plexin B1 causes cell contraction after stimulation of plexin B1 by its ligand, semaphorin 4D (Sema4D).	('co-expression', 'Var', (16, 29))	('Sema4D', 'Gene', '10507', (137, 143))	('plexin B1', 'Gene', '5364', (97, 106))	('Cos', 'Chemical', '-', (3, 6))	('stimulation', 'PosReg', (82, 93))	('plexin B1', 'Gene', '5364', (42, 51))	('RND1', 'Gene', (33, 37))	('Sema4D', 'Gene', (137, 143))	('plexin B1', 'Gene', (42, 51))	('semaphorin 4D', 'Gene', (122, 135))	('plexin B1', 'Gene', (97, 106))	('cell contraction', 'CPA', (59, 75))	('semaphorin 4D', 'Gene', '10507', (122, 135))
637592	31344837	In Cos-7 cells, co-expression of RND1 and plexins B2 or B3 also induces cell contraction after Sema4D stimulation.	('co-expression', 'Var', (16, 29))	('Cos', 'Chemical', '-', (3, 6))	('induces', 'Reg', (64, 71))	('cell contraction', 'CPA', (72, 88))	('Sema4D', 'Gene', (95, 101))	('RND1', 'Gene', (33, 37))	('Sema4D', 'Gene', '10507', (95, 101))
637593	31344837	(i) In pheochromocytoma PC-12 cells, depletion of RND1 with siRNA suppresses fibroblast growth factor (FGF)-induced neurite extension.	('depletion', 'Var', (37, 46))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (7, 23))	('RND1', 'Gene', (50, 54))	('pheochromocytoma', 'Disease', (7, 23))	('suppresses', 'NegReg', (66, 76))	('pheochromocytoma', 'Disease', 'MESH:D010673', (7, 23))	('PC-12', 'CellLine', 'CVCL:0481', (24, 29))
637600	31344837	Depletion of RND1 with morpholino antisense oligonucleotide (MO) in four-cell stage Xenopus embryos (into the equatorial zone) induces aberrant gastrulation movements, i.e., the leading endo-mesordermal cells fail to crawl under the ectoderm (Figure 5).	('induces', 'Reg', (127, 134))	('gastrulation movements', 'CPA', (144, 166))	('Xenopus', 'Species', '8355', (84, 91))	('Depletion', 'Var', (0, 9))	('RND1', 'Gene', (13, 17))	('oligonucleotide', 'Chemical', 'MESH:D009841', (44, 59))	('morpholino', 'Chemical', 'MESH:D060172', (23, 33))
637606	31344837	Depletion of RND1 with siRNA in endothelial cells leads to an increase in VEGF-mediated endothelial migration and in the formation of neo-vessels (Figure 6).	('VEGF', 'Gene', '7422', (74, 78))	('formation of neo-vessels', 'CPA', (121, 145))	('rat', 'Species', '10116', (103, 106))	('VEGF', 'Gene', (74, 78))	('Depletion', 'Var', (0, 9))	('RND1', 'Gene', (13, 17))	('increase', 'PosReg', (62, 70))
637614	31344837	In adenoid cystic carcinoma and in breast cancer, the deletion of RND1 gene concerns only one of the two alleles.	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (3, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('RND1', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('deletion', 'Var', (54, 62))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('adenoid cystic carcinoma', 'Disease', (3, 27))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
637615	31344837	In several tumors, it has been reported that methylation of RND1 promoter and histone deacetylation induce the repression of RND1 gene transcription (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('repression', 'MPA', (111, 121))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('RND1 gene', 'Gene', (125, 134))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('RND1', 'Gene', (60, 64))	('methylation', 'Var', (45, 56))
637625	31344837	Analysis of the genomic database in the cbioportal website  reveals that several mutations in the RND1 open reading frame exist in human tumors (Figure 2 and Table 1).	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('human', 'Species', '9606', (131, 136))	('RND1', 'Gene', (98, 102))	('mutations', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
637626	31344837	Unlike RAC1 and RHOA gene mutations, which occur preferentially in the G1 guanosine nucleotide binding site and the switch I and II domains, RND1 mutations spread over almost the entire gene sequence (Figure 2).	('mutations', 'Var', (146, 155))	('RND1', 'Gene', (141, 145))	('guanosine nucleotide', 'Chemical', '-', (74, 94))	('RAC1', 'Gene', '5879', (7, 11))	('RAC1', 'Gene', (7, 11))
637627	31344837	The impact on RND1 function of four missense mutations discovered in breast tumors has been studied.	('missense mutations', 'Var', (36, 54))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('breast tumors', 'Phenotype', 'HP:0100013', (69, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('breast tumors', 'Disease', 'MESH:D001943', (69, 82))	('breast tumors', 'Disease', (69, 82))
637628	31344837	Unlike wild type RND1, G70R, E98D, and F180C mutants are not able to induce a growth inhibitory activity, show an aberrant localization in the cytoplasm, and lose their ability to bind to plexin B1.	('F180C', 'Mutation', 'p.F180C', (39, 44))	('bind', 'Interaction', (180, 184))	('E98D', 'Var', (29, 33))	('G70R', 'Mutation', 'rs587780072', (23, 27))	('G70R', 'Var', (23, 27))	('growth inhibitory activity', 'MPA', (78, 104))	('plexin B1', 'Gene', (188, 197))	('plexin B1', 'Gene', '5364', (188, 197))	('lose', 'NegReg', (158, 162))	('ability', 'MPA', (169, 176))	('F180C', 'Var', (39, 44))	('E98D', 'Mutation', 'rs1298303254', (29, 33))	('localization', 'MPA', (123, 135))
637629	31344837	The M185V RND1 mutant behaves similarly to the wild type in terms of subcellular localization and interaction with plexin B1.	('plexin B1', 'Gene', '5364', (115, 124))	('M185V', 'Var', (4, 9))	('interaction', 'Interaction', (98, 109))	('subcellular localization', 'MPA', (69, 93))	('plexin B1', 'Gene', (115, 124))	('M185V', 'Mutation', 'rs781851745', (4, 9))	('RND1', 'Gene', (10, 14))
637630	31344837	The impact of other RND1 mutations on its function and tumor initiation and progression remains to be determined.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('RND1', 'Gene', (20, 24))
637632	31344837	In breast tissue, the loss of RND1 induces tumorigenesis in mammary epithelial cells.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('induces', 'Reg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('RND1', 'Gene', (30, 34))	('tumor', 'Disease', (43, 48))	('loss', 'Var', (22, 26))
637634	31344837	The loss of RND1 in mammary epithelial cells also contributes to tumor progression via (i) the induction of epithelial to mesenchymal transition (EMT), (ii) the induction of proliferation, and (iii) the ability to migrate and metastasize.	('induction', 'Reg', (161, 170))	('tumor', 'Disease', (65, 70))	('RND1', 'Gene', (12, 16))	('rat', 'Species', '10116', (181, 184))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('contributes', 'Reg', (50, 61))	('rat', 'Species', '10116', (217, 220))	('proliferation', 'CPA', (174, 187))	('epithelial to mesenchymal transition', 'CPA', (108, 144))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('loss', 'Var', (4, 8))
637635	31344837	These tumor progression effects induced by RND1 depletion are mediated through the activation of the Ras and MAPK pathways.	('MAPK pathways', 'Pathway', (109, 122))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('RND1', 'Gene', (43, 47))	('depletion', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('activation', 'PosReg', (83, 93))
637636	31344837	The role of RND1 in EMT has been extended to hepatocellular carcinoma cells, in which the depletion of RND1 also causes EMT, this time via the activation of RHOA.	('RND1', 'Gene', (103, 107))	('hepatocellular carcinoma', 'Disease', (45, 69))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (45, 69))	('RHOA', 'CPA', (157, 161))	('causes', 'Reg', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('activation', 'PosReg', (143, 153))	('depletion', 'Var', (90, 99))	('EMT', 'CPA', (120, 123))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (45, 69))
637637	31344837	In glioblastoma initiating cells, the expression of RND1 is inversely correlated with mesenchymal gene expression, such as TWIST1, SNAI1, and SNAI2, suggesting that RND1 blocks the mesenchymal phenotype.	('TWIST1', 'Gene', (123, 129))	('TWIST1', 'Gene', '7291', (123, 129))	('RND1', 'Gene', (52, 56))	('mesenchymal phenotype', 'CPA', (181, 202))	('expression', 'MPA', (38, 48))	('SNAI2', 'Gene', '6591', (142, 147))	('SNAI2', 'Gene', (142, 147))	('RND1', 'Var', (165, 169))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('SNAI1', 'Gene', (131, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('SNAI1', 'Gene', '6615', (131, 136))	('blocks', 'NegReg', (170, 176))
637639	31344837	The depletion of RND1 induces hepatocellular carcinoma proliferation, whereas it decreases esophageal squamous cell carcinoma proliferation.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('esophageal squamous cell carcinoma proliferation', 'Disease', (91, 139))	('depletion', 'Var', (4, 13))	('rat', 'Species', '10116', (133, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (30, 54))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (30, 54))	('RND1', 'Gene', (17, 21))	('esophageal squamous cell carcinoma proliferation', 'Disease', 'MESH:D000077277', (91, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('rat', 'Species', '10116', (62, 65))	('hepatocellular carcinoma', 'Disease', (30, 54))	('decreases', 'NegReg', (81, 90))	('induces', 'Reg', (22, 29))
637640	31344837	The silencing of RND1 increases the in vitro migration and invasion of glioblastoma initiating cells and hepatocellular carcinoma cells.	('glioblastoma', 'Disease', (71, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (105, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('hepatocellular carcinoma', 'Disease', (105, 129))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (105, 129))	('RND1', 'Gene', (17, 21))	('increases', 'PosReg', (22, 31))	('invasion', 'CPA', (59, 67))	('silencing', 'Var', (4, 13))	('rat', 'Species', '10116', (48, 51))
637641	31344837	In hepatocellular carcinoma cells, the increase of invasion induced by RND1 depletion is mediated by the activation of RHOA.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('activation', 'PosReg', (105, 115))	('RND1', 'Gene', (71, 75))	('increase', 'PosReg', (39, 47))	('RHOA', 'Protein', (119, 123))	('invasion', 'CPA', (51, 59))	('depletion', 'Var', (76, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
637642	31344837	In contrast to these data, the silencing of RND1 in esophageal carcinoma cells decreases their in vitro migration and metastasis capacity.	('silencing', 'Var', (31, 40))	('decreases', 'NegReg', (79, 88))	('esophageal carcinoma', 'Disease', (52, 72))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (52, 72))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (52, 72))	('RND1', 'Gene', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('rat', 'Species', '10116', (107, 110))
637643	31344837	All these proliferation and migration data show that a dysregulation of the amount of RND1 (either overexpression or decreased expression) in cancer cells increases the proliferation and migratory capacity of these cells.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('rat', 'Species', '10116', (176, 179))	('RND1', 'Gene', (86, 90))	('increases', 'PosReg', (155, 164))	('expression', 'MPA', (127, 137))	('overexpression', 'PosReg', (99, 113))	('decreased', 'NegReg', (117, 126))	('rat', 'Species', '10116', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('proliferation', 'CPA', (169, 182))	('rat', 'Species', '10116', (17, 20))	('dysregulation', 'Var', (55, 68))	('rat', 'Species', '10116', (31, 34))	('cancer', 'Disease', (142, 148))
637647	31344837	In glioblastoma, we identified an RND1low signature of six genes (ITGA5, COL3A1, COL5A1, MET, COL1A2, LAMC1), upregulated in glioblastoma patients with low RND1, that predicts the overall survival of glioblastoma patients.	('MET', 'Gene', (89, 92))	('COL3A1', 'Gene', '1281', (73, 79))	('COL1A2', 'Gene', (94, 100))	('glioblastoma', 'Disease', (125, 137))	('patients', 'Species', '9606', (213, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('COL5A1', 'Gene', '1289', (81, 87))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('COL3A1', 'Gene', (73, 79))	('patients', 'Species', '9606', (138, 146))	('glioblastoma', 'Disease', 'MESH:D005909', (200, 212))	('low', 'Var', (152, 155))	('glioblastoma', 'Disease', (3, 15))	('LAMC1', 'Gene', '3915', (102, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('glioblastoma', 'Disease', (200, 212))	('LAMC1', 'Gene', (102, 107))	('COL5A1', 'Gene', (81, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (200, 212))	('ITGA5', 'Gene', (66, 71))	('ITGA5', 'Gene', '3678', (66, 71))	('COL1A2', 'Gene', '1278', (94, 100))	('upregulated', 'PosReg', (110, 121))	('predicts', 'Reg', (167, 175))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))
637658	31344837	In hepatocellular carcinoma, RND1 depletion with siRNA induces the resistance of hepatocellular carcinoma cells to cisplatin, a water-soluble platinum complex, whereas RND1 re-expression induced by cell treatment with an inducer of promoter hypomethylation and an histone deacetylase inhibitor increases the cellular sensitivity to the Raf inhibitor, sorafenib.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('Raf', 'Gene', (336, 339))	('induces', 'Reg', (55, 62))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('resistance', 'MPA', (67, 77))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('depletion', 'Var', (34, 43))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('Raf', 'Gene', '22882', (336, 339))	('water', 'Chemical', 'MESH:D014867', (128, 133))	('RND1', 'Gene', (168, 172))	('sorafenib', 'Chemical', 'MESH:D000077157', (351, 360))	('platinum', 'Chemical', 'MESH:D010984', (142, 150))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))	('increases', 'PosReg', (294, 303))	('cellular sensitivity to', 'MPA', (308, 331))	('hepatocellular carcinoma', 'Disease', (3, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('hepatocellular carcinoma', 'Disease', (81, 105))
637662	31344837	Figure 7 shows that in these hematological and lymphoid tumors, the lower RND1 is expressed, the more sensitive the tumor is to inhibitors of growth factor receptors i.e., IGFR1 (AEW541), EGFR (erlotinib), c-met (PF2341066), multiple receptor tyrosine kinase (TKI258), the MAPK pathway (AZD6244, PD-0325901, RAF265), tyrosine kinases i.e., Abl and Alk (nilotinib, TAE684) and gamma secretase (L-685458).	('lymphoid tumors', 'Disease', 'MESH:D009369', (47, 62))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('erlotinib', 'Chemical', 'MESH:D000069347', (194, 203))	('IGFR1', 'Gene', '100132417', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Abl', 'Gene', (340, 343))	('MAPK pathway', 'Pathway', (273, 285))	('EGFR', 'Gene', '1956', (188, 192))	('lymphoid tumor', 'Phenotype', 'HP:0002665', (47, 61))	('c-met', 'Gene', (206, 211))	('TKI258', 'Var', (260, 266))	('PF2341066', 'Var', (213, 222))	('AZD6244', 'Var', (287, 294))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('lymphoid tumors', 'Disease', (47, 62))	('Alk', 'Gene', (348, 351))	('IGFR1', 'Gene', (172, 177))	('Abl', 'Gene', '25', (340, 343))	('tumor', 'Disease', (56, 61))	('c-met', 'Gene', '4233', (206, 211))	('Alk', 'Gene', '238', (348, 351))	('EGFR', 'Gene', (188, 192))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('PD-0325901', 'Var', (296, 306))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('lymphoid tumors', 'Phenotype', 'HP:0002665', (47, 62))	('tumor', 'Disease', (116, 121))
637664	31344837	In these tumor cells, the only significant correlation observed between RND3 expression and anticancer agent susceptibility is for PD-0332991, a cdk 4/6 inhibitor (Table 3), showing that the response profile to these agents is specific to a particular RND member.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('RND3', 'Gene', '390', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('PD-0332991', 'Var', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('cdk 4/6', 'Gene', '1019;1021', (145, 152))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cdk 4/6', 'Gene', (145, 152))	('RND3', 'Gene', (72, 76))	('cancer', 'Disease', (96, 102))	('PD-0332991', 'Chemical', 'MESH:C500026', (131, 141))
637693	27050148	EGFR is dysregulated in several malignant tumors located in head and neck, esophageal, gastric, lung, colorectal, and other organs, which correlates with increased metastasis, decreased survival, a poor prognosis and radiotherapy (RT) and chemotherapy (CT) resistance.	('EGFR', 'Gene', (0, 4))	('malignant tumors', 'Disease', 'MESH:D018198', (32, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('dysregulated', 'Var', (8, 20))	('decreased', 'NegReg', (176, 185))	('colorectal', 'Disease', 'MESH:D015179', (102, 112))	('colorectal', 'Disease', (102, 112))	('increased', 'PosReg', (154, 163))	('tumors located in head and neck', 'Phenotype', 'HP:0012288', (42, 73))	('metastasis', 'CPA', (164, 174))	('survival', 'CPA', (186, 194))	('EGFR', 'Gene', '1956', (0, 4))	('malignant tumors', 'Disease', (32, 48))
637698	27050148	Further, experimental observations demonstrated that in contrast to other approved anti-EGFR antibodies, the intrinsic properties of nimotuzumab require bivalent binding for stable attachment to the cellular surface, leading nimotuzumab have the maximum clinical benefit and absence of severe dermatological toxicity (high uptake in tumors overexpressing the receptor and low uptake in normal tissues).	('toxicity', 'Disease', 'MESH:D064420', (308, 316))	('overexpressing', 'PosReg', (340, 354))	('toxicity', 'Disease', (308, 316))	('nimotuzumab', 'Chemical', 'MESH:C501466', (225, 236))	('tumors', 'Disease', (333, 339))	('tumors', 'Disease', 'MESH:D009369', (333, 339))	('nimotuzumab', 'Chemical', 'MESH:C501466', (133, 144))	('men', 'Species', '9606', (187, 190))	('men', 'Species', '9606', (15, 18))	('EGFR', 'Gene', '1956', (88, 92))	('nimotuzumab', 'Var', (225, 236))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('EGFR', 'Gene', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (333, 339))
637711	27050148	The majority of patients had stage IV disease (97.6%) when received nimotuzumab and 140 (68.3%) patients were adenocarcinoma (ADC).	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('stage IV disease', 'Disease', 'MESH:D058625', (29, 45))	('patients', 'Species', '9606', (16, 24))	('nimotuzumab', 'Chemical', 'MESH:C501466', (68, 79))	('adenocarcinoma', 'Disease', (110, 124))	('nimotuzumab', 'Var', (68, 79))	('patients', 'Species', '9606', (96, 104))	('stage IV disease', 'Disease', (29, 45))	('adenocarcinoma', 'Disease', 'MESH:D000230', (110, 124))
637736	27050148	Univariate analysis was performed to determinate the association between factors (sex, age, histology, differentiation, surgery history, RT/CRT history, CT history, treatment lines, nimotuzumab >200mg/week and nimotuzumab >6 doses) and overall survival (OS) or progression free survival (PFS).	('>200mg/week', 'Var', (194, 205))	('OS', 'Chemical', '-', (254, 256))	('nimotuzumab', 'Chemical', 'MESH:C501466', (182, 193))	('progression free survival', 'CPA', (261, 286))	('men', 'Species', '9606', (170, 173))	('nimotuzumab', 'Chemical', 'MESH:C501466', (210, 221))	('overall survival', 'CPA', (236, 252))
637751	27050148	In the GC arm, patients who received more than 200 mg/week and six doses had longer OS than the others (p=0.0005, Figure 3i), and males who received nimotuzumab over six doses had obvious increase in PFS than females who only received nimotuzumab in less than six doses (p<0.0001, Figure 3j).	('patients', 'Species', '9606', (15, 23))	('GC', 'Phenotype', 'HP:0012126', (7, 9))	('nimotuzumab', 'Chemical', 'MESH:C501466', (235, 246))	('nimotuzumab', 'Var', (149, 160))	('OS', 'Chemical', '-', (84, 86))	('increase', 'PosReg', (188, 196))	('PFS', 'MPA', (200, 203))	('nimotuzumab', 'Chemical', 'MESH:C501466', (149, 160))
637911	25893524	Our study demonstrates that patients treated by Ivor Lewis esophagectomy exhibited better survival than those treated by the other two approaches (Fig 1).	('survival', 'CPA', (90, 98))	('patients', 'Species', '9606', (28, 36))	('Ivor Lewis', 'Var', (48, 58))	('better', 'PosReg', (83, 89))
637932	22174605	Similar to other solid tumors, chromosome loss is a common molecular defect in esophageal cancer.	('esophageal cancer', 'Disease', (79, 96))	('solid tumors', 'Disease', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('molecular defect', 'Disease', (59, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('molecular defect', 'Disease', 'MESH:C567116', (59, 75))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('chromosome loss', 'Var', (31, 46))
637939	22174605	Eight loci (D3S1597, D3S2452, D3S1285, D4S174, D5S2501, D9S125, D13S153, and D17S786) showed LOH in the informative LGD samples, and another eight loci were found to present LOH in the informative HGD specimens.	('D17S786', 'Var', (77, 84))	('D9S125', 'Var', (56, 62))	('D3S2452', 'Var', (21, 28))	('D13S153', 'Var', (64, 71))	('D3S1285', 'Var', (30, 37))	('D4S174', 'Var', (39, 45))	('D5S2501', 'Var', (47, 54))	('men', 'Species', '9606', (206, 209))	('D3S1597', 'Var', (12, 19))
637941	22174605	Furthermore, by comparing the occurrence of LOH in samples with different pathological statuses from the same patient, we found a regain of heterozygosity at loci D3S2452, D4S174, D9S125 and D17S261, in the SCC samples of four patients, respectively comparing to the HGD specimens which showed LOH at the corresponding loci.	('D17S261', 'Var', (191, 198))	('SCC', 'Gene', '6317', (207, 210))	('D4S174', 'Var', (172, 178))	('regain', 'PosReg', (130, 136))	('D9S125', 'Var', (180, 186))	('men', 'Species', '9606', (276, 279))	('patients', 'Species', '9606', (227, 235))	('S261', 'CellLine', 'CVCL:2490', (194, 198))	('SCC', 'Gene', (207, 210))	('patient', 'Species', '9606', (227, 234))	('patient', 'Species', '9606', (110, 117))	('SCC', 'Phenotype', 'HP:0002860', (207, 210))	('heterozygosity', 'MPA', (140, 154))	('D3S2452', 'Var', (163, 170))
637946	22174605	As the alterations accumulate to a certain degree, the cell morphology and behavior undergoes a radical change, leading to malignancy.	('malignancy', 'Disease', (123, 133))	('leading to', 'Reg', (112, 122))	('behavior', 'CPA', (75, 83))	('cell morphology', 'CPA', (55, 70))	('alterations', 'Var', (7, 18))	('malignancy', 'Disease', 'MESH:D009369', (123, 133))
637949	22174605	Of 16 loci, we found eight loci to show LOH in low-grade dysplasia, indicating that LOH at these eight loci may be involved in the early-stage tumorigenesis of ESCC, and that these specific loci could be used as markers for screening of esophageal cancer.	('SCC', 'Gene', (161, 164))	('SCC', 'Phenotype', 'HP:0002860', (161, 164))	('tumor', 'Disease', (143, 148))	('esophageal cancer', 'Disease', (237, 254))	('esophageal cancer', 'Disease', 'MESH:D004938', (237, 254))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('dysplasia', 'Disease', (57, 66))	('SCC', 'Gene', '6317', (161, 164))	('involved', 'Reg', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('dysplasia', 'Disease', 'MESH:D004476', (57, 66))	('LOH', 'Var', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
637953	22174605	Another candidate gene DEC1 at chromosome 9q has been reported to be down-regulated in esophageal cancer, and transfection of the cDNA of DEC1 could inhibit the proliferation of some cancer cells, suggesting that it may participate in the development of esophageal cancer.	('DEC1', 'Gene', (23, 27))	('DEC1', 'Gene', '50514', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('transfection', 'Var', (110, 122))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inhibit', 'NegReg', (149, 156))	('cancer', 'Disease', (183, 189))	('men', 'Species', '9606', (246, 249))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('DEC1', 'Gene', '50514', (138, 142))	('DEC1', 'Gene', (138, 142))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('esophageal cancer', 'Disease', 'MESH:D004938', (254, 271))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('down-regulated', 'NegReg', (69, 83))	('participate', 'Reg', (220, 231))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('esophageal cancer', 'Disease', (254, 271))	('esophageal cancer', 'Disease', (87, 104))	('cancer', 'Disease', (265, 271))
637957	22174605	Studies of the P53 gene in esophageal cancer have shown that LOH and mutations are the leading causes of its inactivation, which is in accordance with the "two-hit" model of tumorigenesis and indicates that P53 is a major tumor suppressor in esophageal cancer.	('tumor', 'Disease', (174, 179))	('P53', 'Gene', (207, 210))	('P53', 'Gene', (15, 18))	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('esophageal cancer', 'Disease', (27, 44))	('P53', 'Gene', '7157', (207, 210))	('P53', 'Gene', '7157', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))	('inactivation', 'MPA', (109, 121))	('esophageal cancer', 'Disease', (242, 259))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('esophageal cancer', 'Disease', 'MESH:D004938', (242, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
637958	22174605	In addition, eight other loci were found to show LOH in the HGD samples, indicating that LOH at these loci may be involved in the late stages of tumorigenesis (such as invasion and metastasis) in esophageal cancer.	('LOH', 'Var', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('involved', 'Reg', (114, 122))	('invasion', 'CPA', (168, 176))	('esophageal cancer', 'Disease', (196, 213))
637995	32978904	Elevated POU5F1 was associated with poor OS, DFS, RFS, and DSS in various cancers.	('POU5F1', 'Var', (9, 15))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('DFS', 'Disease', (45, 48))	('cancers', 'Disease', (74, 81))	('DSS', 'Gene', (59, 62))	('poor OS', 'Disease', (36, 43))	('DSS', 'Gene', '5376', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RFS', 'Disease', (50, 53))
637996	32978904	POU5F1 was confirmed as an independent risk factor for LIHC and correlated with tumor occurrence, stage, and invasion depth.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('LIHC', 'Disease', (55, 59))	('POU5F1', 'Var', (0, 6))
637997	32978904	GSEA indicated that POU5F1 participated in multiple cancer-related pathways and cell proliferation pathways.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('participated', 'Reg', (27, 39))	('cell proliferation', 'CPA', (80, 98))	('cancer', 'Disease', (52, 58))	('POU5F1', 'Var', (20, 26))	('GSEA', 'Chemical', '-', (0, 4))
638014	32978904	9 ,  10  Published literatures have certified that increased POU5F1 was correlated with clinicopathological features and prognosis not only in LIHC, but also in bladder carcinoma, non-small cell lung carcinoma, and oral squamous cell cancer.	('bladder carcinoma', 'Disease', (161, 178))	('bladder carcinoma', 'Disease', 'MESH:D001749', (161, 178))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (180, 209))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('increased', 'PosReg', (51, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (180, 209))	('POU5F1', 'Var', (61, 67))	('LIHC', 'Disease', (143, 147))	('non-small cell lung carcinoma', 'Disease', (180, 209))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (161, 178))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (184, 209))	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (215, 240))	('oral squamous cell cancer', 'Disease', (215, 240))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (220, 240))
638019	32978904	found that high expression of POU5F1 was connected with longer survival in esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('esophageal squamous cell carcinoma', 'Disease', (75, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('longer', 'PosReg', (56, 62))	('POU5F1', 'Gene', (30, 36))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (75, 109))	('high', 'Var', (11, 15))
638024	32978904	We comprehensively retrieved PubMed, Embase, Web of Science, and Cochrane Library to search studies published from 1 January 2000 to 1 June 2019 with language limitation in English and screened studies reporting prognosis and clinicopathological features in cancer patients with aberrant expression of POU5F1.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('aberrant expression', 'Var', (279, 298))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('patients', 'Species', '9606', (265, 273))	('cancer', 'Disease', (258, 264))	('POU5F1', 'Gene', (302, 308))
638050	32978904	The results showed that increased POU5F1 was correlated with inferior outcomes for OS (HR = 2.45, 95% CI = 2.22-2.71, p < .001), DFS (HR = 2.66, 95% CI = 2.22-3.19, p < .001), DSS (HR = 4.03, 95% CI = 2.70-6.01, p < .001), and RFS (HR = 2.59, 95% CI = 1.85-3.63, p < .001).	('DSS', 'Gene', (176, 179))	('DFS', 'Disease', (129, 132))	('DSS', 'Gene', '5376', (176, 179))	('RFS', 'Disease', (227, 230))	('POU5F1', 'Var', (34, 40))
638056	32978904	To explore why elevated POU5F1 could lead to worse prognosis in various cancers, the correlations between POU5F1 status and neoplastic clinicopathological parameters were evaluated (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('elevated', 'Var', (15, 23))	('POU5F1', 'Gene', (24, 30))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
638071	32978904	As shown in Figure 3A-H, elevated POU5F1 was associated with tumor occurrence (p < .001), advanced histological grade (p = .016), stage (p = .025), tumor invasion depth (p = .019), and distant metastasis (p = .018).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor invasion depth', 'Disease', (148, 168))	('tumor', 'Disease', (148, 153))	('associated', 'Reg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('distant metastasis', 'CPA', (185, 203))	('POU5F1', 'Gene', (34, 40))	('stage', 'CPA', (130, 135))	('tumor invasion depth', 'Disease', 'MESH:D009361', (148, 168))	('tumor', 'Disease', (61, 66))	('elevated', 'Var', (25, 33))
638072	32978904	Increased POU5F1 was significantly correlated with tumor occurrence (OR = 65.63, p < .001), advanced stage (OR = 2.06, p = .007), and tumor invasion depth (OR = 2.00, p = .001).	('tumor invasion depth', 'Disease', (134, 154))	('POU5F1', 'Var', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('tumor invasion depth', 'Disease', 'MESH:D009361', (134, 154))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('advanced stage', 'CPA', (92, 106))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', (134, 139))
638073	32978904	In addition, POU5F1 (HR = 1.64, p = .038) was identified as an independent risk factor for OS of LIHC through multivariate analysis, as were tumor stage (HR =1.51, p < .001), tumor invasion depth (HR = 1.51, p < .001), and distant metastasis (HR = 3.73, p = .026) (Table 4).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (141, 146))	('tumor invasion depth', 'Disease', 'MESH:D009361', (175, 195))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('distant metastasis', 'CPA', (223, 241))	('POU5F1', 'Var', (13, 19))	('tumor invasion depth', 'Disease', (175, 195))
638078	32978904	As exhibited in Figure 4A, T cells CD4 memory resting (p = .019), T cells regulatory (p = .048), macrophage M1 (p = .012), and dendritic cells resting (p = .002) increased in the high POU5F1 group of normal liver tissues, while T cells follicular helper (p = .031) decreased.	('dendritic cells', 'CPA', (127, 142))	('increased', 'PosReg', (162, 171))	('CD4', 'Gene', (35, 38))	('CD4', 'Gene', '920', (35, 38))	('T cells regulatory', 'CPA', (66, 84))	('high POU5F1', 'Var', (179, 190))
638079	32978904	In LIHC tumor tissues, B cells memory (p = .001) and T cells follicular helper (p = 007) were enriched in the high POU5F1 group, and B cells naive (p < .001), monocytes (p = .004), and dendritic cells activated (p = .006) were increased in the low POU5F1 group (Figure 4B).	('increased', 'PosReg', (227, 236))	('dendritic cells activated', 'CPA', (185, 210))	('high POU5F1', 'Var', (110, 121))	('LIHC tumor', 'Disease', 'MESH:D009369', (3, 13))	('LIHC tumor', 'Disease', (3, 13))	('B cells naive', 'CPA', (133, 146))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('T cells follicular helper', 'CPA', (53, 78))	('B cells memory', 'CPA', (23, 37))
638080	32978904	In addition, B cells memory (p < .001), T cells follicular helper (p = .039), and dendritic cells activated (p < .001) were positively related to POU5F1 in LIHC tumor tissues (Figure 4C-E).	('B cells memory', 'CPA', (13, 27))	('POU5F1', 'Var', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('T cells follicular helper', 'CPA', (40, 65))	('LIHC tumor', 'Disease', 'MESH:D009369', (156, 166))	('LIHC tumor', 'Disease', (156, 166))	('dendritic cells activated', 'CPA', (82, 107))
638081	32978904	POU5F1-related signaling pathways were analyzed through GSEA to identify pathways that were differentially activated in LIHC between low and high POU5F1 expression phenotypes.	('GSEA', 'Chemical', '-', (56, 60))	('low', 'Var', (133, 136))	('POU5F1', 'Gene', (146, 152))	('high', 'Var', (141, 145))	('activated', 'PosReg', (107, 116))
638082	32978904	GO terms enriched in the high POU5F1 phenotype mainly contained DNA replication, regulation of cell cycle G2M phase transition, signal transduction by p53 class mediator and so on.	('p53', 'Gene', '7157', (151, 154))	('p53', 'Gene', (151, 154))	('high POU5F1', 'Var', (25, 36))	('DNA replication', 'CPA', (64, 79))
638083	32978904	Multiple cancer-related KEGG pathways were enriched in the high POU5F1 phenotype, such as bladder cancer, colorectal cancer, non-small cell lung cancer, and renal cell carcinoma.	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', (9, 15))	('colorectal cancer', 'Disease', (106, 123))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (125, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', (98, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('KEGG pathways', 'Pathway', (24, 37))	('high POU5F1', 'Var', (59, 70))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (129, 151))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (125, 151))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (157, 177))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('non-small cell lung cancer', 'Disease', (125, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('renal cell carcinoma', 'Disease', (157, 177))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (157, 177))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
638084	32978904	Several well-known cancer-related signaling pathways were also enriched in the high POU5F1 phenotype, including the MTOR signaling pathway, p53 signaling pathway, and WNT signaling pathway.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('high POU5F1', 'Var', (79, 90))	('cancer', 'Disease', (19, 25))	('p53', 'Gene', (140, 143))	('MTOR', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('WNT signaling pathway', 'Pathway', (167, 188))	('MTOR', 'Gene', '2475', (116, 120))	('p53', 'Gene', '7157', (140, 143))
638095	32978904	The amalgamative results indicated that elevated POU5F1 was associated with poor OS, DFS, DSS, and RFS in various cancers.	('DSS', 'Gene', '5376', (90, 93))	('POU5F1', 'Var', (49, 55))	('RFS', 'Disease', (99, 102))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('DFS', 'Disease', (85, 88))	('cancers', 'Disease', (114, 121))	('elevated', 'PosReg', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('poor OS', 'Disease', (76, 83))	('DSS', 'Gene', (90, 93))
638096	32978904	In particular, TSA confirmed that the sample size of current studies has far exceeded the APIS, suggesting it was quite credible to draw a conclusion that elevated POU5F1 was apparently connected with shorter OS in various cancers.	('cancers', 'Disease', (223, 230))	('shorter OS', 'Disease', (201, 211))	('TSA', 'Chemical', '-', (15, 18))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('elevated POU5F1', 'Var', (155, 170))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('POU5F1', 'Var', (164, 170))	('connected', 'Reg', (186, 195))
638098	32978904	These results indicated that POU5F1 might serve as a prognostic pan-cancer biomarker and potential therapeutic target.	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('POU5F1', 'Var', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))
638101	32978904	The GSEA results suggested that POU5F1 might participate in the pathological progression of LIHC and other cancers by promoting cell proliferation.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('POU5F1', 'Var', (32, 38))	('promoting', 'PosReg', (118, 127))	('LIHC', 'Disease', (92, 96))	('cell proliferation', 'CPA', (128, 146))	('participate', 'Reg', (45, 56))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('GSEA', 'Chemical', '-', (4, 8))
638105	32978904	T cells follicular helper decreased in the high POU5F1 group in normal liver tissues, but increased in the high POU5F1 group in LIHC tumor tissues.	('T cells follicular helper', 'CPA', (0, 25))	('increased', 'PosReg', (90, 99))	('high POU5F1', 'Var', (107, 118))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('LIHC tumor', 'Disease', 'MESH:D009369', (128, 138))	('LIHC tumor', 'Disease', (128, 138))	('high POU5F1', 'Var', (43, 54))	('decreased', 'NegReg', (26, 35))
638110	32978904	76  In addition, although the diagnostic value of POU5F1 in LIHC was quite gratifying, the necessity of applying POU5F1 and AFP together in the diagnosis of LIHC to improve the diagnostic specificity needed to be emphasized, in view of POU5F1, was upregulated in a variety of cancers and might reduce the diagnostic specificity.	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('reduce', 'NegReg', (294, 300))	('cancers', 'Disease', (276, 283))	('POU5F1', 'Var', (236, 242))	('LIHC', 'Disease', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('upregulated', 'PosReg', (248, 259))	('diagnostic specificity', 'MPA', (305, 327))
638112	32978904	Based on related studies of hub genes, we visualized the pathways POU5F1 might play a role in LIHC (Figure 8B).	('hub', 'Gene', (28, 31))	('LIHC', 'Disease', (94, 98))	('POU5F1', 'Var', (66, 72))	('hub', 'Gene', '1993', (28, 31))
638124	32978904	POU5F1 may influence the progression of LIHC by regulating the tumor immune microenvironment and participating in cell proliferation-related pathways.	('tumor', 'Disease', (63, 68))	('LIHC', 'Disease', (40, 44))	('regulating', 'Reg', (48, 58))	('participating', 'Reg', (97, 110))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('influence', 'Reg', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('POU5F1', 'Var', (0, 6))	('cell proliferation-related', 'CPA', (114, 140))
638140	32793445	The overall major morbidity rates and pulmonary complication rates were lower in hybrid MIE than in OE, with similar 30-day mortality and oncologic parameters.	('mortality', 'Disease', (124, 133))	('hybrid MIE', 'Var', (81, 91))	('major morbidity rates', 'CPA', (12, 33))	('lower', 'NegReg', (72, 77))	('pulmonary complication rates', 'CPA', (38, 66))	('mortality', 'Disease', 'MESH:D003643', (124, 133))
638141	32793445	They reported superior perioperative outcomes of hybrid MIE when compared with OE in terms of in-hospital mortality, surgery-related mortality, and postoperative morbidity.	('mortality', 'Disease', 'MESH:D003643', (133, 142))	('mortality', 'Disease', 'MESH:D003643', (106, 115))	('mortality', 'Disease', (133, 142))	('hybrid MIE', 'Var', (49, 59))	('mortality', 'Disease', (106, 115))	('superior', 'PosReg', (14, 22))
638180	32793445	Our group compared outcomes between RAMIE and conventional MIE and reported that the total number of harvested LNs was significantly higher in RAMIE than in conventional MIE.	('RAMIE', 'Species', '83906', (36, 41))	('RAMIE', 'Species', '83906', (143, 148))	('RAMIE', 'Var', (143, 148))	('higher', 'PosReg', (133, 139))
638192	32793445	The 3-year and 5-year all-cause mortality rates were lower by 18% and 15%, respectively, after MIE when compared with OE.	('MIE', 'Var', (95, 98))	('lower', 'NegReg', (53, 58))	('mortality', 'Disease', 'MESH:D003643', (32, 41))	('mortality', 'Disease', (32, 41))
638193	32793445	Moreover, the 3-year and the 5-year disease-specific mortality rates were lower by 17% and 16%, respectively, after MIE when compared with OE.	('lower', 'NegReg', (74, 79))	('MIE', 'Var', (116, 119))	('mortality', 'Disease', (53, 62))	('mortality', 'Disease', 'MESH:D003643', (53, 62))
638243	31754312	Cancers were coded according to the the ICD10 (liver cancer C22, esophageal cancer C15, gastric cancer C16, colorectal cancer C18-C20).	('colorectal cancer', 'Disease', (108, 125))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('C18-C20', 'Var', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('C18-C20', 'Chemical', 'MESH:C456584', (126, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('liver cancer C22, esophageal cancer C15, gastric cancer C16', 'Disease', 'MESH:D009369', (47, 106))	('liver cancer', 'Phenotype', 'HP:0002896', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
638499	33807389	Moreover, the dysregulation of miR-125a-5p/125b has been found to be an early event in the esophageal (Barrett) oncogenesis and correlated inversely with HER2 status.	('dysregulation', 'Var', (14, 27))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('HER2', 'Gene', (154, 158))	('HER2', 'Gene', '2064', (154, 158))	('esophageal', 'Disease', (91, 101))
638543	33807389	The expression of MMPs is known to enhance cancer mobility and invasiveness.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('enhance', 'PosReg', (35, 42))	('MMPs', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('expression', 'Var', (4, 14))	('invasiveness', 'CPA', (63, 75))
638590	33807389	A study showed that the down-regulation of miR-148a, via modulation of ACVR1, was associated with enhanced expression of stem cell markers and increased proliferation rate of stem cells.	('enhanced', 'PosReg', (98, 106))	('increased', 'PosReg', (143, 152))	('miR-148a', 'Gene', (43, 51))	('ACVR1', 'Gene', (71, 76))	('stem cell markers', 'CPA', (121, 138))	('ACVR1', 'Gene', '90', (71, 76))	('expression', 'MPA', (107, 117))	('modulation', 'Var', (57, 67))	('proliferation rate of stem cells', 'CPA', (153, 185))	('down-regulation', 'NegReg', (24, 39))	('miR-148a', 'Gene', '406940', (43, 51))
638605	33807389	MiR-199a-5p acts by modulating the expression of MAP3K11, which is a positive regulator of the JNK pathway.	('modulating', 'Reg', (20, 30))	('JNK', 'Gene', (95, 98))	('expression', 'MPA', (35, 45))	('MiR-199a-5p', 'Var', (0, 11))	('MAP3K11', 'Gene', '4296', (49, 56))	('JNK', 'Gene', '5599', (95, 98))	('MAP3K11', 'Gene', (49, 56))
638637	33807389	Although QKI-5 acts as a tumor suppressor in many cancer types, within EC its expression has been found to be up-regulated and it was directly linked to the metastatic potential; furthermore, the silencing of QKI-5 expression can increase apoptotic rate and decrease proliferation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('up-regulated', 'PosReg', (110, 122))	('cancer', 'Disease', (50, 56))	('QKI', 'Gene', (209, 212))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('QKI', 'Gene', '9444', (9, 12))	('decrease', 'NegReg', (258, 266))	('proliferation', 'CPA', (267, 280))	('QKI', 'Gene', (9, 12))	('silencing', 'Var', (196, 205))	('linked', 'Reg', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', (25, 30))	('apoptotic rate', 'CPA', (239, 253))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('expression', 'MPA', (78, 88))	('QKI', 'Gene', '9444', (209, 212))	('metastatic potential', 'CPA', (157, 177))	('increase', 'PosReg', (230, 238))
638644	33807389	MiR-125b also regulates HCLS1 Associated Protein X-1 (HAX-1) expression, which is involved in mitochondria-dependent apoptosis.	('HCLS1 Associated Protein X-1', 'Gene', (24, 52))	('HAX-1', 'Gene', (54, 59))	('MiR-125b', 'Var', (0, 8))	('regulates', 'Reg', (14, 23))	('HCLS1 Associated Protein X-1', 'Gene', '10456', (24, 52))	('HAX-1', 'Gene', '10456', (54, 59))	('expression', 'MPA', (61, 71))
638645	33807389	It was observed that the ectopic expression of HAX-1 in colon cancer has an antiapoptotic effect on cancer cells.	('HAX-1', 'Gene', (47, 52))	('colon cancer', 'Phenotype', 'HP:0003003', (56, 68))	('antiapoptotic effect', 'CPA', (76, 96))	('colon cancer', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('HAX-1', 'Gene', '10456', (47, 52))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('ectopic expression', 'Var', (25, 43))	('colon cancer', 'Disease', 'MESH:D015179', (56, 68))
638661	33807389	Many of the studies that were mentioned in chapter 2 used miRNA mimics or miRNA depletion systems (such as miRNA sponges) to evaluate the consequences of the manipulation of these molecules with the purpose of testing their hypotheses in vitro or in xenograft models, nevertheless.	('miR', 'Gene', (74, 77))	('miR', 'Gene', '220972', (74, 77))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('manipulation', 'Var', (158, 170))	('miR', 'Gene', '220972', (107, 110))	('miR', 'Gene', (107, 110))	('testing', 'Reg', (210, 217))
638664	33807389	MiRNAs are post-transcriptional regulators and have been proved to modulate several oncogenic and tumor-suppressive pathways involved in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('MiRNAs', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('modulate', 'Reg', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Disease', (137, 143))	('tumor', 'Disease', (98, 103))	('oncogenic', 'Pathway', (84, 93))
638678	33538099	 MicroRNA-210 targets FBXO31 to inhibit tumor progression and regulates the Wnt/beta-catenin signaling pathway and EMT in esophageal squamous cell carcinoma MicroRNA-210 targets FBXO31 to inhibit tumor progression and regulates the Wnt/beta-catenin signaling pathway and EMT in esophageal squamous cell carcinoma Evidence from previous studies showed that the dysregulation of microRNA (miR) is frequently associated with tumor progression.	('tumor', 'Disease', (196, 201))	('inhibit', 'NegReg', (32, 39))	('esophageal squamous cell carcinoma', 'Disease', (122, 156))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('associated', 'Reg', (406, 416))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('regulates', 'Reg', (218, 227))	('dysregulation', 'Var', (360, 373))	('MicroRNA-210', 'Gene', '406992', (1, 13))	('inhibit', 'NegReg', (188, 195))	('beta-catenin', 'Gene', (80, 92))	('esophageal squamous cell carcinoma', 'Disease', (278, 312))	('beta-catenin', 'Gene', '1499', (80, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (122, 156))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (422, 427))	('FBXO31', 'Gene', (22, 28))	('microRNA', 'Protein', (377, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('MicroRNA-210', 'Gene', (1, 13))	('tumor', 'Disease', 'MESH:D009369', (422, 427))	('FBXO31', 'Gene', '79791', (22, 28))	('MicroRNA-210', 'Gene', '406992', (157, 169))	('tumor', 'Disease', (40, 45))	('beta-catenin', 'Gene', (236, 248))	('beta-catenin', 'Gene', '1499', (236, 248))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (278, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (289, 312))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('FBXO31', 'Gene', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (422, 427))	('MicroRNA-210', 'Gene', (157, 169))	('FBXO31', 'Gene', '79791', (178, 184))
638679	33538099	The aberrant miR-210 expression has been identified in a variety of tumors.	('identified', 'Reg', (41, 51))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('aberrant', 'Var', (4, 12))	('expression', 'MPA', (21, 31))	('miR-210', 'Gene', (13, 20))	('miR-210', 'Gene', '406992', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
638713	33538099	The medium contained 10% fetal bovine serum (FBS; Gibco) and cells were incubated in a humidified chamber with 5% CO2 at 37 C. MiR-210 mimic, inhibitor, small interfering RNA (siRNA) against FBXO31 (si- FBXO31) and the negative control (NC) were commercially synthesized by GenePharma.	('MiR-210', 'Gene', '406992', (127, 134))	('FBXO31', 'Gene', (203, 209))	('FBXO31', 'Gene', '79791', (191, 197))	('CO2', 'Chemical', 'MESH:D002245', (114, 117))	('small', 'Var', (153, 158))	('MiR-210', 'Gene', (127, 134))	('FBXO31', 'Gene', (191, 197))	('FBXO31', 'Gene', '79791', (203, 209))
638721	33538099	Primary antibodies used in the western blot analysis were antibodies against cyclin D1 (1:1000), c-Myc (1:1000), beta-catenin (1:1000), E-cadherin (1:2000), N-cadherin(1:2000), vimentin (1:1000) and GAPDH (1:1000), which were all obtained from Abcam.	('GAPDH', 'Gene', (199, 204))	('c-Myc', 'Gene', '4609', (97, 102))	('1:1000', 'Var', (206, 212))	('N-cadherin', 'Gene', (157, 167))	('1:1000', 'Var', (104, 110))	('cyclin D1', 'Gene', '595', (77, 86))	('GAPDH', 'Gene', '2597', (199, 204))	('vimentin', 'Gene', '7431', (177, 185))	('E-cadherin', 'Gene', (136, 146))	('N-cadherin', 'Gene', '1000', (157, 167))	('cyclin D1', 'Gene', (77, 86))	('E-cadherin', 'Gene', '999', (136, 146))	('c-Myc', 'Gene', (97, 102))	('beta-catenin', 'Gene', (113, 125))	('1:1000', 'Var', (187, 193))	('vimentin', 'Gene', (177, 185))	('beta-catenin', 'Gene', '1499', (113, 125))
638724	33538099	The FBXO31 3'-UTR fragments with the wild-type (WT) or mutant-type (MUT) putative binding sites of miR-210 were cloned into pGL3 vectors (Promega).	('mutant-type', 'Var', (55, 66))	('FBXO31', 'Gene', '79791', (4, 10))	('miR-210', 'Gene', (99, 106))	('miR-210', 'Gene', '406992', (99, 106))	('FBXO31', 'Gene', (4, 10))
638748	33538099	The results revealed that the luciferase activity of the FBXO31-3'UTR-WT was dramatically reduced by miR-210 mimics whereas the luciferase activity in FBXO31-3'UTR-MUT group was not obviously affected by miR-210 mimics (Figure 4(b)), indicating that FBXO31 was a target of miR-210.	('FBXO31', 'Gene', '79791', (151, 157))	('mimics', 'Var', (109, 115))	('miR-210', 'Gene', (101, 108))	('reduced', 'NegReg', (90, 97))	('FBXO31', 'Gene', (57, 63))	('miR-210', 'Gene', '406992', (101, 108))	('luciferase', 'Enzyme', (30, 40))	('miR-210', 'Gene', (204, 211))	('miR-210', 'Gene', '406992', (204, 211))	('FBXO31', 'Gene', (151, 157))	('miR-210', 'Gene', (273, 280))	('FBXO31', 'Gene', '79791', (250, 256))	('miR-210', 'Gene', '406992', (273, 280))	('FBXO31', 'Gene', '79791', (57, 63))	('activity', 'MPA', (41, 49))	('FBXO31', 'Gene', (250, 256))
638756	33538099	As shown in Figure 5(c), patients with high FBXO31 expressions had a shorter overall survival rate than those with low FBXO31 expressions.	('high', 'Var', (39, 43))	('FBXO31', 'Gene', (44, 50))	('FBXO31', 'Gene', (119, 125))	('shorter', 'NegReg', (69, 76))	('patients', 'Species', '9606', (25, 33))	('overall survival', 'MPA', (77, 93))	('FBXO31', 'Gene', '79791', (44, 50))	('FBXO31', 'Gene', '79791', (119, 125))
638765	33538099	FBXO31 inhibition relieved the miR-210-inhibitor-induced effects on ESCC cells.	('miR-210', 'Gene', '406992', (31, 38))	('effects', 'MPA', (57, 64))	('FBXO31', 'Gene', '79791', (0, 6))	('inhibition', 'Var', (7, 17))	('FBXO31', 'Gene', (0, 6))	('miR-210', 'Gene', (31, 38))
638767	33538099	First, we observed that the promotion of FBXO31 expression induced by miR-210 inhibitor was abated through FBXO31 knockdown (Figure 7(a),(b)).	('miR-210', 'Gene', '406992', (70, 77))	('FBXO31', 'Gene', '79791', (41, 47))	('FBXO31', 'Gene', '79791', (107, 113))	('knockdown', 'Var', (114, 123))	('expression', 'MPA', (48, 58))	('FBXO31', 'Gene', (41, 47))	('miR-210', 'Gene', (70, 77))	('FBXO31', 'Gene', (107, 113))	('promotion', 'PosReg', (28, 37))
638768	33538099	The results of the CCK-8 assay indicated that the intervention of miR-210 evoked ESCC cell viability, which was abolished by the silence of FBXO31 (Figure 7(c)).	('FBXO31', 'Gene', (140, 146))	('evoked', 'Reg', (74, 80))	('ESCC', 'Disease', (81, 85))	('intervention', 'Var', (50, 62))	('miR-210', 'Gene', (66, 73))	('FBXO31', 'Gene', '79791', (140, 146))	('miR-210', 'Gene', '406992', (66, 73))
638774	33538099	32  For instance, miR-455-3p inhibited ESCC cell proliferation and invasion, and served as a prognostic marker.	('inhibited', 'NegReg', (29, 38))	('ESCC', 'Disease', (39, 43))	('invasion', 'CPA', (67, 75))	('miR-455-3p', 'Chemical', '-', (18, 28))	('miR-455-3p', 'Var', (18, 28))
638777	33538099	35   MiR-210 is an important regulator of various tumors, and aberrant miR-210 expression has been identified in a variety of tumors.	('tumors', 'Disease', (126, 132))	('miR-210', 'Gene', (71, 78))	('expression', 'MPA', (79, 89))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('MiR-210', 'Gene', '406992', (5, 12))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('MiR-210', 'Gene', (5, 12))	('aberrant', 'Var', (62, 70))	('miR-210', 'Gene', '406992', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('identified', 'Reg', (99, 109))
638886	30905354	Of the 6 patients with progressive disease, 4 (67%) developed advanced ESCC that exceeded the limits of endoscopic therapy (1 ESCC-T3N1Mx, 1 ESCC-T1smN1M1, 1 ESCC-T2N0Mx and 1 ESCC-T1smNxMx).	('patients', 'Species', '9606', (9, 17))	('ESCC-T1smN1M1', 'Var', (141, 154))	('ESCC', 'Disease', (71, 75))	('ESCC-T2N0Mx', 'Var', (158, 169))	('ESCC-T3N1Mx', 'Var', (126, 137))
638930	30905354	RFA intentionally aims to ablate the epithelium and muscularis mucosa but preserve the submucosa, reasoning that this will reduce the risk for complications like bleeding, fibrosis and stricturing.	('bleeding', 'Disease', (162, 170))	('stricturing', 'Disease', (185, 196))	('fibrosis', 'Disease', 'MESH:D005355', (172, 180))	('reduce', 'NegReg', (123, 129))	('fibrosis', 'Disease', (172, 180))	('ablate', 'Var', (26, 32))	('bleeding', 'Disease', 'MESH:D006470', (162, 170))
638975	31255175	The resection margins were free and the final TNM stage was T3N3aM0 (WHO 2017).	('TNM', 'Gene', (46, 49))	('TNM', 'Gene', '10178', (46, 49))	('T3N3aM0', 'Var', (60, 67))
639021	31255175	Radiological imaging and endoscopy were indicative of a T2N0M0 gastric cancer; hence, the multidisciplinary team decided to proceed to surgery, without administration of neoadjuvant treatment.	('gastric cancer', 'Disease', (63, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('T2N0M0', 'Var', (56, 62))	('men', 'Species', '9606', (187, 190))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
639048	30687318	Moreover, common mechanisms and pathways may be involved both in fibrogenesis and oncogenesis, and recent data have suggested that autoimmunity in SSc may be triggered by antigen mutation in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('autoimmunity', 'Disease', (131, 143))	('SSc', 'Disease', (147, 150))	('autoimmunity', 'Disease', 'MESH:D001327', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('antigen mutation', 'Var', (171, 187))	('autoimmunity', 'Phenotype', 'HP:0002960', (131, 143))
639070	30687318	In contrast, anti-centromere-positive patients had a lower risk of cancer (SIR = 0.59, 0.44-0.76).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (38, 46))	('anti-centromere-positive', 'Var', (13, 37))	('anti-centromere-positive', 'Phenotype', 'HP:0030873', (13, 37))
639112	30687318	Interestingly, cyclophosphamide was reported as a risk factor for cervical intraepithelial neoplasia with a dose-dependent cumulative risk (plus 13% increased risk of cervical dysplasia per each increase of one gram according to a series of patients with systemic lupus erythematosus).	('systemic lupus erythematosus', 'Disease', (255, 283))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (255, 283))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (66, 100))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (255, 283))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (15, 31))	('cervical intraepithelial neoplasia', 'Disease', 'MESH:D018290', (66, 100))	('cervical intraepithelial neoplasia', 'Disease', (66, 100))	('cervical dysplasia', 'Disease', (167, 185))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (75, 100))	('cyclophosphamide', 'Var', (15, 31))	('cervical dysplasia', 'Disease', 'MESH:D002575', (167, 185))	('neoplasia', 'Phenotype', 'HP:0002664', (91, 100))	('patients', 'Species', '9606', (241, 249))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (167, 185))
639129	30687318	For example, free radicals can randomly induce point mutations in tumor suppressor genes and contribute to the progression of cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('contribute', 'Reg', (93, 103))	('tumor', 'Disease', (66, 71))	('point mutations', 'Var', (47, 62))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('progression', 'CPA', (111, 122))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('induce', 'Reg', (40, 46))
639143	30687318	On the one hand, EMT has been clearly observed during the development of lung cancer, when epithelial cells transform into malignant cells under the activation of oncoproteins such as mutant Kras (Kirsten rat sarcoma viral oncogene).	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('men', 'Species', '9606', (65, 68))	('rat', 'Species', '10116', (205, 208))	('mutant', 'Var', (184, 190))	('Kras', 'Gene', '24525', (191, 195))	('sarcoma', 'Disease', 'MESH:D012509', (209, 216))	('sarcoma', 'Disease', (209, 216))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (209, 216))	('Kras', 'Gene', (191, 195))
639147	30687318	As abovementioned, the implication of EMT in both diseases is particularly interesting and may originate from common genetic and epigenetic alterations, involving telomere shortening, chromosomal instability, senescence, increased proliferation rates, immune deregulation, and impaired cell metabolism.	('chromosomal', 'Var', (184, 195))	('originate', 'Reg', (95, 104))	('cell metabolism', 'CPA', (286, 301))	('increased', 'PosReg', (221, 230))	('rat', 'Species', '10116', (245, 248))	('immune deregulation', 'CPA', (252, 271))	('men', 'Species', '9606', (8, 11))	('telomere shortening', 'Var', (163, 182))	('senescence', 'CPA', (209, 219))	('chromosomal instability', 'Phenotype', 'HP:0040012', (184, 207))	('rat', 'Species', '10116', (144, 147))	('telomere shortening', 'Phenotype', 'HP:0031413', (163, 182))	('rat', 'Species', '10116', (238, 241))
639149	30687318	Epigenetic mechanisms could contribute to the pathogenesis of SSc, as a consequence of the exposure to environmental factors such as silica (see below paragraph 2.4.1).	('SSc', 'Disease', (62, 65))	('men', 'Species', '9606', (110, 113))	('contribute', 'Reg', (28, 38))	('silica', 'Chemical', 'MESH:D012822', (133, 139))	('Epigenetic mechanisms', 'Var', (0, 21))
639156	30687318	The demethylation within CD40L gene could result in the reactivation of the inactive X chromosome, maybe contributing to the female susceptibility of the disease.	('CD40L', 'Gene', '959', (25, 30))	('reactivation', 'MPA', (56, 68))	('CD40L', 'Gene', (25, 30))	('demethylation', 'Var', (4, 17))	('contributing', 'Reg', (105, 117))	('result in', 'Reg', (42, 51))
639158	30687318	Endothelial cells are concerned by such epigenetic changes, since CpG hypermethylation of the bone morphogenetic protein receptor factor type 2 (BMPR2) was recently reported.	('hypermethylation', 'Var', (70, 86))	('bone morphogenetic protein receptor factor type 2', 'Gene', '659', (94, 143))	('BMPR2', 'Gene', (145, 150))	('BMPR2', 'Gene', '659', (145, 150))	('bone morphogenetic protein receptor factor type 2', 'Gene', (94, 143))
639159	30687318	Another example is represented by the hypomethylation of TNFSF7, the promoter of CD70, observed in SSc, which results in the overexpression of CD70 by CD4+ T cells.	('hypomethylation', 'Var', (38, 53))	('TNFSF7', 'Gene', '970', (57, 63))	('CD70', 'Gene', (143, 147))	('CD70', 'Gene', '970', (81, 85))	('CD70', 'Gene', '970', (143, 147))	('CD70', 'Gene', (81, 85))	('TNFSF7', 'Gene', (57, 63))	('overexpression', 'PosReg', (125, 139))
639161	30687318	So, CD70 hypomethylation could contribute to autoimmune diseases whereas hypermethylation would be rather associated with the development of malignancies, in particular breast cancers.	('hypermethylation', 'Var', (73, 89))	('associated', 'Reg', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('particular breast cancers', 'Disease', (158, 183))	('autoimmune diseases', 'Disease', 'MESH:D001327', (45, 64))	('particular breast cancers', 'Disease', 'MESH:D001943', (158, 183))	('rat', 'Species', '10116', (99, 102))	('autoimmune diseases', 'Disease', (45, 64))	('breast cancers', 'Phenotype', 'HP:0003002', (169, 183))	('malignancies', 'Disease', 'MESH:D009369', (141, 153))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (45, 64))	('men', 'Species', '9606', (133, 136))	('hypomethylation', 'Var', (9, 24))	('CD70', 'Gene', (4, 8))	('CD70', 'Gene', '970', (4, 8))	('malignancies', 'Disease', (141, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))	('autoimmune disease', 'Phenotype', 'HP:0002960', (45, 63))	('contribute', 'Reg', (31, 41))
639168	30687318	Second, impaired transcription of genes and deregulated gene expression induced by histone modifications may also contribute to the development of both cancer and SSc.	('cancer', 'Disease', (152, 158))	('impaired', 'NegReg', (8, 16))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('histone modifications', 'Var', (83, 104))	('men', 'Species', '9606', (139, 142))	('SSc', 'Disease', (163, 166))	('transcription of', 'MPA', (17, 33))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('deregulated gene expression', 'MPA', (44, 71))	('contribute', 'Reg', (114, 124))
639201	30687318	In the field of cancer, the dysfunction in Wnt pathway could favor cancer emergence and spread, but also resistance to anti-tumor treatments (including immunotherapy such as immune checkpoint inhibitors).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Wnt pathway', 'Pathway', (43, 54))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Disease', (16, 22))	('tumor', 'Disease', (124, 129))	('men', 'Species', '9606', (135, 138))	('dysfunction', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('favor', 'PosReg', (61, 66))	('spread', 'CPA', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('resistance', 'CPA', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
639202	30687318	Aberrant Wnt pathway could in fact induce deficient immunosurveillance toward cancer, leading to immune-evasion.	('deficient immunosurveillance', 'Phenotype', 'HP:0002721', (42, 70))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Aberrant', 'Var', (0, 8))	('immune-evasion', 'MPA', (97, 111))	('deficient immunosurveillance toward cancer', 'Disease', (42, 84))	('deficient immunosurveillance toward cancer', 'Disease', 'MESH:D009369', (42, 84))	('leading to', 'Reg', (86, 96))	('Wnt pathway', 'Pathway', (9, 20))
639204	30687318	Some authors hypothesize that dysfunction of regulation of the TGFbeta / SMAD pathway by caveolin-1 (Cav-1) is involved in both the development of fibrosis and breast cancer.	('TGFbeta', 'Gene', '7040', (63, 70))	('fibrosis', 'Disease', 'MESH:D005355', (147, 155))	('fibrosis', 'Disease', (147, 155))	('breast cancer', 'Disease', (160, 173))	('men', 'Species', '9606', (139, 142))	('involved', 'Reg', (111, 119))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('TGFbeta', 'Gene', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('caveolin-1', 'Gene', (89, 99))	('dysfunction', 'Var', (30, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('caveolin-1', 'Gene', '857', (89, 99))
639234	30687318	The frequency of cancers was significantly increased in patients with anti-RNA-PolIII (14.2%) compared to patients with anti-Scl70 (6.3%) and anti-centromere (6.8%) autoantibodies (p < 0.0001 and p < 0.001).	('patients', 'Species', '9606', (56, 64))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('anti-RNA-PolIII', 'Var', (70, 85))	('cancers', 'Disease', (17, 24))	('patients', 'Species', '9606', (106, 114))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('increased', 'PosReg', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
639236	30687318	In addition, SSc patients with anti-RNA-PolIII had twice as much risk of developing cancer as anti-centromere patients (p < 0.0001).	('SSc', 'Disease', (13, 16))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (17, 25))	('anti-RNA-PolIII', 'Var', (31, 46))	('patients', 'Species', '9606', (110, 118))
639237	30687318	These data were confirmed by a study of EULAR, where anti-RNA-PolIII antibodies were associated with synchronous malignancy (-6 months + 12 months) with an OR estimated at 7.38 (95% CI 1.61-33.8).	('synchronous malignancy', 'Disease', (101, 123))	('anti-RNA-PolIII antibodies', 'Var', (53, 79))	('synchronous malignancy', 'Disease', 'MESH:D009378', (101, 123))	('antibodies', 'Var', (69, 79))	('associated', 'Reg', (85, 95))
639239	30687318	In multivariate analysis anti-RNA-PolIII was also associated with older age, acute renal crisis and diffuse skin involvement.	('acute renal crisis', 'Phenotype', 'HP:0001919', (77, 95))	('diffuse skin involvement', 'Disease', (100, 124))	('anti-RNA-PolIII', 'Var', (25, 40))	('acute renal crisis', 'Disease', 'MESH:D058186', (77, 95))	('associated', 'Reg', (50, 60))	('acute renal crisis', 'Disease', (77, 95))	('men', 'Species', '9606', (120, 123))
639241	30687318	Of note, in an Australian prospective study, patients with anti-RNA-PolIII positive and anti-RNA-PolIII negative antibodies had the same percentage of cancer (13%) but the diagnosis of cancer within 5 years after the diagnosis of scleroderma was more frequent in anti-RNA-PolIII positive patients (13 vs. 3.9%).	('anti-RNA-PolIII', 'Var', (263, 278))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (288, 296))	('scleroderma', 'Disease', 'MESH:D012595', (230, 241))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Disease', (151, 157))	('scleroderma', 'Disease', (230, 241))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('scleroderma', 'Phenotype', 'HP:0100324', (230, 241))	('cancer', 'Disease', (185, 191))
639251	30687318	Rosen's team has shown that patients with anti-scl70 antibodies were associated with short cancer-scleroderma interval.	('cancer-scleroderma interval', 'Disease', (91, 118))	('associated', 'Reg', (69, 79))	('scleroderma', 'Phenotype', 'HP:0100324', (98, 109))	('cancer-scleroderma interval', 'Disease', 'MESH:D009369', (91, 118))	('anti-scl70', 'Var', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('patients', 'Species', '9606', (28, 36))
639253	30687318	An Italian team has demonstrated that anti-Scl70 antibodies were associated with lung cancer.	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('anti-Scl70 antibodies', 'Var', (38, 59))	('associated', 'Reg', (65, 75))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('rat', 'Species', '10116', (27, 30))	('antibodies', 'Var', (49, 59))
639277	30687318	In SSc, this concept has recently been thoroughly demonstrated in patients with anti-RNA-PolIII antibodies and contributes to the possibility of scleroderma being a paraneoplastic disease.	('scleroderma', 'Phenotype', 'HP:0100324', (145, 156))	('paraneoplastic disease', 'Disease', 'MESH:D010257', (165, 187))	('SSc', 'Disease', (3, 6))	('rat', 'Species', '10116', (57, 60))	('antibodies', 'Var', (96, 106))	('scleroderma', 'Disease', 'MESH:D012595', (145, 156))	('paraneoplastic disease', 'Disease', (165, 187))	('anti-RNA-PolIII', 'Protein', (80, 95))	('patients', 'Species', '9606', (66, 74))	('scleroderma', 'Disease', (145, 156))
639278	30687318	Several recent studies conducted by the team of Rosen, Casciola-Rosen and Shah (Johns Hopkins University School of Medicine, Baltimore, USA) among others, have shown that the anti-RNA-PolIII antibodies were associated with cancer in SSc, with a temporal clustering between the two conditions suggestive of a paraneoplastic disease and a common underlying mechanism.	('antibodies', 'Var', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('paraneoplastic disease', 'Disease', (308, 330))	('SSc', 'Disease', (233, 236))	('anti-RNA-PolIII antibodies', 'Var', (175, 201))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('paraneoplastic disease', 'Disease', 'MESH:D010257', (308, 330))	('cancer', 'Disease', (223, 229))	('associated with', 'Reg', (207, 222))
639279	30687318	Patients with anti-RNA-PolIII antibodies are indeed 5.08 (95% CI 1.60-16.1) times more likely to develop cancer within 2 years of SSc onset.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('antibodies', 'Var', (30, 40))	('develop', 'PosReg', (97, 104))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('anti-RNA-PolIII antibodies', 'Var', (14, 40))
639283	30687318	Hence, the presence of this mutated auto-antigen in malignant cells could be the primum movens triggering autoimmunity in these patients, inducing cellular and humoral responses, with the production of anti-RNA-PolIII autoantibodies.	('inducing', 'PosReg', (138, 146))	('autoimmunity', 'Disease', 'MESH:D001327', (106, 118))	('presence', 'Var', (11, 19))	('autoimmunity', 'Phenotype', 'HP:0002960', (106, 118))	('autoimmunity', 'Disease', (106, 118))	('patients', 'Species', '9606', (128, 136))
639286	30687318	These alterations would next trigger a mutant-specific clonal immune response that could subsequently spread to wt antigens in healthy cells, contributing to autoimmune-mediated tissue damage in SSc (Figure 2).	('alterations', 'Var', (6, 17))	('trigger', 'Reg', (29, 36))	('SSc', 'Disease', (195, 198))	('contributing to', 'Reg', (142, 157))	('rat', 'Species', '10116', (10, 13))
639294	30687318	Even if the beneficial effects in terms of overall survival in the scleroderma population remain to be demonstrated, a strategy based on repeated and more aggressive screening in patients with specific autoantibodies subsets (i.e., anti-RNA-PolIII, Pm/Scl or RNPC3) or in seronegative patients may be tantalizing.	('rat', 'Species', '10116', (110, 113))	('Pm/Scl', 'Gene', (249, 255))	('scleroderma', 'Disease', (67, 78))	('scleroderma', 'Phenotype', 'HP:0100324', (67, 78))	('RNPC3', 'Gene', (259, 264))	('sero', 'Chemical', '-', (272, 276))	('RNPC3', 'Gene', '55599', (259, 264))	('patients', 'Species', '9606', (285, 293))	('patients', 'Species', '9606', (179, 187))	('scleroderma', 'Disease', 'MESH:D012595', (67, 78))	('Pm/Scl', 'Gene', '5394', (249, 255))	('anti-RNA-PolIII', 'Var', (232, 247))	('rat', 'Species', '10116', (121, 124))
639432	30288052	Each multivariate logistic regression model contained four independent variables: gender, CCRT, position parameter, and one of the dosimetric variables including mean dose and V10-V60.	('CRT', 'Gene', (91, 94))	('V10-V60', 'Var', (176, 183))	('CRT', 'Gene', '811', (91, 94))
639516	26176243	The two patients that presented cervical fistula caused by dehiscence of the cervical esophagogastric anastomosis, progressed to stenosis between the 29th to 47th postoperative day, confirmed by contrasted X-ray and endoscopy.	('fistula', 'Disease', 'MESH:D005402', (41, 48))	('dehiscence', 'Var', (59, 69))	('patients', 'Species', '9606', (8, 16))	('fistula', 'Disease', (41, 48))	('esophagogastric anastomosis', 'Phenotype', 'HP:0100628', (86, 113))
639573	26519812	The disease was diagnosed as ESCC with IMS, T3N0M1b Stage IVB, according to the classification of the Union for International Cancer Control (UICC, version 7).	('ESCC', 'Disease', (29, 33))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('IMS', 'Chemical', '-', (39, 42))	('T3N0M1b', 'Var', (44, 51))
639600	26519812	DCF also led to improvement in both rapid tumor shrinkage and the survival benefit.	('tumor', 'Disease', (42, 47))	('survival benefit', 'CPA', (66, 82))	('improvement', 'PosReg', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('DCF', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('DCF', 'Chemical', '-', (0, 3))
639629	24979040	However, numerous studies have shown that some patients with thoracic esophageal squamous cell carcinoma (SCC) and cervical lymph node metastasis (CLNM) could have better long-time survival than patients with visceral metastasis, which suggests that CLNM should be regarded as regional spread rather than distant metastasis.	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (115, 145))	('thoracic esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (61, 104))	('CLNM', 'Phenotype', 'HP:0025289', (250, 254))	('visceral metastasis', 'Disease', 'MESH:D009362', (209, 228))	('CLNM', 'Chemical', '-', (250, 254))	('SCC', 'Gene', '6317', (106, 109))	('better', 'PosReg', (164, 170))	('CLNM', 'Phenotype', 'HP:0025289', (147, 151))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('cervical lymph node metastasis', 'Var', (115, 145))	('patients', 'Species', '9606', (47, 55))	('CLNM', 'Chemical', '-', (147, 151))	('thoracic esophageal squamous cell carcinoma', 'Disease', (61, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('patients', 'Species', '9606', (195, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('visceral metastasis', 'Disease', (209, 228))	('SCC', 'Gene', (106, 109))
639658	24979040	The 3-year OS rate was significantly higher in patients with CLNM than in patients with distant organ metastasis (p = 0.027).	('CLNM', 'Phenotype', 'HP:0025289', (61, 65))	('CLNM', 'Var', (61, 65))	('higher', 'PosReg', (37, 43))	('CLNM', 'Chemical', '-', (61, 65))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (47, 55))	('OS rate', 'MPA', (11, 18))
639674	24979040	The above results suggest that the prognosis of esophageal cancer patients with CLNM might be better than that of patients with distant metastases.	('esophageal cancer', 'Disease', (48, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('CLNM', 'Chemical', '-', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('metastases', 'Disease', (136, 146))	('CLNM', 'Phenotype', 'HP:0025289', (80, 84))	('CLNM', 'Var', (80, 84))	('patients', 'Species', '9606', (114, 122))	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('patients', 'Species', '9606', (66, 74))
639677	24979040	In nasopharyngeal carcinoma patients, unilateral CLNM has been associated with better distant metastasis-free survival rates than bilateral CLNM on univariate analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('nasopharyngeal carcinoma', 'Disease', (3, 27))	('CLNM', 'Phenotype', 'HP:0025289', (140, 144))	('CLNM', 'Phenotype', 'HP:0025289', (49, 53))	('CLNM', 'Chemical', '-', (140, 144))	('better', 'PosReg', (79, 85))	('CLNM', 'Chemical', '-', (49, 53))	('unilateral CLNM', 'Var', (38, 53))	('distant metastasis-free survival rates', 'CPA', (86, 124))	('patients', 'Species', '9606', (28, 36))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (3, 27))
639682	24979040	The pairwise comparisons showed that unilateral CLNM (group B) had a similar prognosis to that of patients with regional disease (group A), and had a better prognosis than that of patients with other distant metastases (group C).	('metastases', 'Disease', (208, 218))	('patients', 'Species', '9606', (98, 106))	('unilateral', 'Var', (37, 47))	('metastases', 'Disease', 'MESH:D009362', (208, 218))	('CLNM', 'Phenotype', 'HP:0025289', (48, 52))	('CLNM', 'Chemical', '-', (48, 52))	('patients', 'Species', '9606', (180, 188))
639704	24979040	In our study, T1/2 patients had a higher survival rate than did T3 patients, and the prognosis of T3 patients was better than that of T4 patients.	('survival rate', 'CPA', (41, 54))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (67, 75))	('higher', 'PosReg', (34, 40))	('patients', 'Species', '9606', (137, 145))	('T1/2', 'Var', (14, 18))
639716	32808385	Amplification of the TAZ gene occurred in 2.5%-3.2% of esophageal cancers.	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('TAZ', 'Gene', (21, 24))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('esophageal cancers', 'Disease', (55, 73))	('esophageal cancers', 'Disease', 'MESH:D004938', (55, 73))
639717	32808385	In addition, the CpG islands of the TAZ gene were demethylated in esophageal cancer under thymine DNA glycosylase (TDG) regulation.	('TDG', 'Gene', '6996', (115, 118))	('thymine DNA glycosylase', 'Gene', '6996', (90, 113))	('esophageal cancer', 'Disease', (66, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('thymine DNA glycosylase', 'Gene', (90, 113))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TDG', 'Gene', (115, 118))	('demethylated', 'Var', (50, 62))
639721	32808385	Thymine DNA glycosylase (TDG) acted as a regulator of the aberrant TAZ expression by demethylating its CpG islands, and further participated in radiation resistance by regulating expression of a broad range of nonhomologous end joining (NHEJ)-related genes.	('expression', 'MPA', (179, 189))	('Thymine DNA glycosylase', 'Gene', '6996', (0, 23))	('TDG', 'Gene', (25, 28))	('demethylating', 'Var', (85, 98))	('regulating', 'Reg', (168, 178))	('radiation resistance', 'CPA', (144, 164))	('participated', 'Reg', (128, 140))	('Thymine DNA glycosylase', 'Gene', (0, 23))	('TDG', 'Gene', '6996', (25, 28))
639733	32808385	17 ,  18  Dysregulated TDG could result in abnormal DNA methylation and pathogenic expression of oncorelated genes in cancers.	('cancers', 'Disease', (118, 125))	('abnormal', 'Reg', (43, 51))	('TDG', 'Gene', (23, 26))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('oncorelated genes', 'Gene', (97, 114))	('TDG', 'Gene', '6996', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('result', 'Reg', (33, 39))	('expression', 'MPA', (83, 93))	('DNA methylation', 'MPA', (52, 67))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('Dysregulated', 'Var', (10, 22))
639763	32808385	Survival analysis showed that patients with high TAZ expression had a higher risk of death (hazard ratio [HR] = 1.747) and a shorter median overall survival (mOS, 20.0 vs 42.1 months) than those with low TAZ expression (Figure 1D).	('high', 'Var', (44, 48))	('mOS', 'Gene', '17451', (158, 161))	('death', 'Disease', 'MESH:D003643', (85, 90))	('death', 'Disease', (85, 90))	('TAZ', 'Gene', (49, 52))	('patients', 'Species', '9606', (30, 38))	('shorter', 'NegReg', (125, 132))	('overall survival', 'MPA', (140, 156))	('mOS', 'Gene', (158, 161))
639768	32808385	The median progression-free survival and mOS in patients with TAZ (++/+++) expression were only 22.5 and 30.0 months, whereas those of other patients were up to 38.0 and 45.0 months.	('mOS', 'Gene', (41, 44))	('mOS', 'Gene', '17451', (41, 44))	('TAZ (++/+++) expression', 'Var', (62, 85))	('progression-free survival', 'CPA', (11, 36))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (141, 149))
639795	32808385	In addition, we applied McrBC, an endonuclease that cleaves DNA containing methylcytosine, to detect the methylation modification in the CpG islands of the TAZ gene.	('TAZ', 'Gene', (156, 159))	('methylation', 'Var', (105, 116))	('methylcytosine', 'Chemical', '-', (75, 89))
639800	32808385	Overexpression of TAZ completely rescued the anchorage-independent growth and invasion caused by TDG knockdown (all P > .05; Figure 6B,C).	('TDG', 'Gene', '6996', (97, 100))	('invasion', 'CPA', (78, 86))	('anchorage-independent growth', 'CPA', (45, 73))	('TDG', 'Gene', (97, 100))	('knockdown', 'Var', (101, 110))
639803	32808385	Knockdown of TDG significantly elevated the level of gamma-H2AX at 6 hours post-irradiation, indicating a deficient DSB repair (Figure 6E).	('deficient', 'NegReg', (106, 115))	('level', 'MPA', (44, 49))	('Knockdown', 'Var', (0, 9))	('TDG', 'Gene', (13, 16))	('DSB', 'Disease', (116, 119))	('TDG', 'Gene', '6996', (13, 16))	('elevated', 'PosReg', (31, 39))	('gamma-H2AX', 'Chemical', '-', (53, 63))	('gamma-H2AX', 'MPA', (53, 63))
639804	32808385	In addition, TDG knockdown also reduced levels of several key NHEJ components, including PRKDC (DNA-PKcs), TP53BP1 (53BP1), and XRCC6 (Ku80) (Figure 6F,G).	('TP53BP1', 'Gene', (107, 114))	('53BP1', 'Gene', '7158', (116, 121))	('TDG', 'Gene', (13, 16))	('53BP1', 'Gene', '7158', (109, 114))	('TDG', 'Gene', '6996', (13, 16))	('PRKDC', 'Gene', '5591', (89, 94))	('levels', 'MPA', (40, 46))	('DNA-PKcs', 'Gene', (96, 104))	('53BP1', 'Gene', (116, 121))	('XRCC6', 'Gene', (128, 133))	('53BP1', 'Gene', (109, 114))	('PRKDC', 'Gene', (89, 94))	('Ku80', 'Gene', '7520', (135, 139))	('reduced', 'NegReg', (32, 39))	('Ku80', 'Gene', (135, 139))	('DNA-PKcs', 'Gene', '5591', (96, 104))	('knockdown', 'Var', (17, 26))	('TP53BP1', 'Gene', '7158', (107, 114))	('XRCC6', 'Gene', '2547', (128, 133))
639805	32808385	These effects of TDG knockdown on NHEJ were further validated by complementation experiments using an shTDG-resistant TDG plasmid (Figure 6E-G).	('TDG', 'Gene', '6996', (118, 121))	('TDG', 'Gene', (17, 20))	('TDG', 'Gene', (104, 107))	('TDG', 'Gene', '6996', (17, 20))	('TDG', 'Gene', (118, 121))	('knockdown', 'Var', (21, 30))	('TDG', 'Gene', '6996', (104, 107))
639820	32808385	29  For example, mutations in the tyrosine kinase domain of epidermal growth factor receptor could contribute to cellular radiosensitivity by delaying NHEJ in non-small-cell lung cancer.	('NHEJ', 'Disease', (151, 155))	('lung cancer', 'Disease', (174, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('contribute', 'Reg', (99, 109))	('epidermal growth factor receptor', 'Gene', '1956', (60, 92))	('cellular radiosensitivity', 'Phenotype', 'HP:0010997', (113, 138))	('delaying', 'NegReg', (142, 150))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (163, 185))	('mutations in', 'Var', (17, 29))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (159, 185))	('epidermal growth factor receptor', 'Gene', (60, 92))
639824	32808385	Of note, BRCA1, a central regulator of homologous recombination competing with NHEJ, was upregulated by TAZ knockdown.	('knockdown', 'Var', (108, 117))	('upregulated', 'PosReg', (89, 100))	('BRCA1', 'Gene', '672', (9, 14))	('TAZ', 'Gene', (104, 107))	('BRCA1', 'Gene', (9, 14))
639826	32808385	8 ,  14 ,  32 ,  33  At the mRNA level, TAZ expression efficiency is regulated by multiple microRNAs (miRNAs), including miR-125a-5p, miR-9-3p, and miR-141.	('expression', 'MPA', (44, 54))	('TAZ', 'Gene', (40, 43))	('miR-9-3p', 'Gene', (134, 142))	('miR-141', 'Gene', (148, 155))	('miR-141', 'Gene', '406933', (148, 155))	('miR-125a-5p', 'Var', (121, 132))	('regulated', 'Reg', (69, 78))	('miR-9-3p', 'Gene', '407051', (134, 142))
639832	32808385	A recent study revealed that TDG is also required for melanoma proliferation and survival, potentially by epigenetic modification and by disrupting DNA repair.	('DNA repair', 'MPA', (148, 158))	('epigenetic modification', 'Var', (106, 129))	('disrupting', 'NegReg', (137, 147))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('TDG', 'Gene', '6996', (29, 32))	('melanoma proliferation', 'Disease', 'MESH:D008545', (54, 76))	('melanoma proliferation', 'Disease', (54, 76))	('TDG', 'Gene', (29, 32))
639839	32060969	Association between BTLA polymorphisms and susceptibility to esophageal squamous cell carcinoma in the Chinese population Growing evidence suggested that B- and T-lymphocyte attenuator (BTLA) polymorphisms raised the susceptibility to a wide range of cancers.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('squamous cell carcinoma', 'Disease', (72, 95))	('BTLA', 'Gene', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('BTLA', 'Gene', '151888', (20, 24))	('polymorphisms', 'Var', (192, 205))	('cancers', 'Disease', (251, 258))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('BTLA', 'Gene', (186, 190))	('BTLA', 'Gene', '151888', (186, 190))	('B- and T-lymphocyte attenuator', 'Gene', '151888', (154, 184))	('raised', 'PosReg', (206, 212))
639840	32060969	This study aimed to evaluate whether BTLA variants were related to the risk of esophageal squamous cell carcinoma (ESCC).	('BTLA', 'Gene', (37, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('variants', 'Var', (42, 50))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('related', 'Reg', (56, 63))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))
639841	32060969	A total of 721 ESCC patients and 1208 matched non-cancer controls were included in this research, and four tagging BTLA polymorphisms (rs2171513 G > A, rs3112270 A > G, rs1982809 G > A, and rs16859629 T > C) were selected and genotyped using SNPscan  Assays.	('ESCC', 'Disease', (15, 19))	('rs16859629', 'Mutation', 'rs16859629', (190, 200))	('rs2171513 G > A', 'Var', (135, 150))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('rs1982809', 'Mutation', 'rs1982809', (169, 178))	('rs1982809 G > A', 'Var', (169, 184))	('rs2171513', 'Mutation', 'rs2171513', (135, 144))	('rs3112270', 'Mutation', 'rs3112270', (152, 161))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('rs16859629 T > C', 'Var', (190, 206))	('rs3112270 A > G', 'Var', (152, 167))	('BTLA', 'Gene', (115, 119))
639842	32060969	However, stratified analyses suggested that the variant of BTLA rs3112270 A > G reduced the risk of ESCC in the male subgroup (AG vs AA: adjusted OR = 0.78, 95% CI = 0.61-0.99, P = .042), BMI < 24 kg/m2 subgroup (AG vs AA: adjusted OR = 0.72, 95% CI = 0.55-0.93, P = .012; AG/GG vs AA: adjusted OR = 0.77, 95% CI = 0.60-0.98, P = .032), and ever drinking subgroup (AG vs AA: adjusted OR = 0.61, 95% CI = 0.38-0.97, P = .037).	('rs3112270 A > G', 'Var', (64, 79))	('rs3112270', 'Mutation', 'rs3112270', (64, 73))	('BTLA', 'Gene', (59, 63))	('reduced', 'NegReg', (80, 87))	('ESCC', 'Disease', (100, 104))
639843	32060969	But when stratified by BMI >= 24 kg/m2, the rs3112270 A > G polymorphism increased the susceptibility to ESCC (GG vs AA: adjusted OR = 1.91, 95% CI = 1.02-3.59, P = .045).	('increased', 'PosReg', (73, 82))	('rs3112270 A > G', 'Var', (44, 59))	('ESCC', 'Disease', (105, 109))	('susceptibility', 'MPA', (87, 101))	('rs3112270', 'Mutation', 'rs3112270', (44, 53))
639844	32060969	Besides, we demonstrated that BTLA rs2171513 G > A polymorphism was protective of ESCC in the ever drinking subgroup (GA/AA vs GG: adjusted OR = 0.62, 95% CI = 0.39-0.97, P = .037).	('ESCC', 'Disease', (82, 86))	('rs2171513 G > A', 'Var', (35, 50))	('BTLA', 'Gene', (30, 34))	('rs2171513', 'Mutation', 'rs2171513', (35, 44))
639845	32060969	Taken together, our initial investigation postulated that the rs3112270 A > G and rs2171513 G > A variants in the BTLA gene are candidates for the risk of ESCC, which might be helpful for the early diagnosis and treatment of ESCC.	('BTLA', 'Gene', (114, 118))	('risk', 'Reg', (147, 151))	('rs3112270 A > G', 'Var', (62, 77))	('rs2171513 G > A', 'Var', (82, 97))	('rs3112270', 'Mutation', 'rs3112270', (62, 71))	('rs2171513', 'Mutation', 'rs2171513', (82, 91))	('ESCC', 'Disease', (155, 159))
639849	32060969	9 And the role of BTLA-HVEM pathway has also been identified in BTLA-deficient mouse models,10 where the absence of BTLA gene could enhance sensitivity to antigen-specific immune response and therefore develop autoimmune diseases, as well as HVEM-deficient mice,11 which, on another level, showed the negative effect of BTLA-HVEM pathway on the immune microenvironment.	('mouse', 'Species', '10090', (79, 84))	('autoimmune diseases', 'Disease', 'MESH:D001327', (210, 229))	('absence', 'Var', (105, 112))	('develop', 'PosReg', (202, 209))	('mice', 'Species', '10090', (257, 261))	('BTLA gene', 'Gene', (116, 125))	('autoimmune diseases', 'Disease', (210, 229))	('enhance', 'PosReg', (132, 139))	('sensitivity to antigen-specific immune response', 'MPA', (140, 187))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (210, 229))
639850	32060969	In recent years, accumulating studies have focused on the genetic polymorphisms of immune molecules with susceptibility to the various tumors, including BTLA.12, 13, 14, 15 Fu et al12 genotyped five SNPs and found that BTLA rs1844089, rs2705535, and rs2633562 polymorphisms were associated with the pathological features of breast cancer.	('rs2633562', 'Var', (250, 259))	('rs2705535', 'Var', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('rs1844089', 'Mutation', 'rs1844089', (224, 233))	('rs2633562', 'Mutation', 'rs2633562', (250, 259))	('associated', 'Reg', (279, 289))	('BTLA', 'Gene', (219, 223))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('breast cancer', 'Disease', 'MESH:D001943', (324, 337))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('rs1844089', 'Var', (224, 233))	('rs2705535', 'Mutation', 'rs2705535', (235, 244))	('breast cancer', 'Disease', (324, 337))	('breast cancer', 'Phenotype', 'HP:0003002', (324, 337))
639851	32060969	Partyka et al13 chose seven variants and revealed the rs1982809G allele contributed to a higher-grade stage of renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('contributed', 'Reg', (72, 83))	('higher-grade', 'PosReg', (89, 101))	('rs1982809', 'Mutation', 'rs1982809', (54, 63))	('rs1982809G', 'Var', (54, 64))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (111, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('renal cell carcinoma', 'Disease', (111, 131))
639852	32060969	Recently, there was a basic study demonstrating that the change from T to C in the BTLA rs1982809 variant could interfere with the activity of BTLA 3'UTR and regulate BTLA expression in peripheral blood T lymphocytes, which might be considered as a potential biomarker in predicting the process of sepsis and multiple organ dysfunction syndrome.16 In addition, Karabon et al14 enrolled a total of ten polymorphisms and demonstrated that the presence of BTLA rs1982809 polymorphism was related to a lower level of BTLA mRNA, and the variant might be deemed as a low-risk factor for the development of chronic lymphocytic leukemia.	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (600, 628))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (600, 628))	('multiple organ dysfunction syndrome', 'Disease', 'MESH:D009102', (309, 344))	('sepsis', 'Disease', (298, 304))	('presence', 'Var', (441, 449))	('sepsis', 'Phenotype', 'HP:0100806', (298, 304))	('lower', 'NegReg', (498, 503))	('chronic lymphocytic leukemia', 'Disease', (600, 628))	('BTLA', 'Gene', (453, 457))	('sepsis', 'Disease', 'MESH:D018805', (298, 304))	('rs1982809', 'Mutation', 'rs1982809', (458, 467))	('rs1982809', 'Mutation', 'rs1982809', (88, 97))	('leukemia', 'Phenotype', 'HP:0001909', (620, 628))	('multiple organ dysfunction syndrome', 'Disease', (309, 344))	('rs1982809', 'Var', (458, 467))
639854	32060969	Concerning the tremendous value of co-signaling molecules in anti-tumor therapy, and to better understand this issue, we conducted this case-control study to clarify the detailed relationship of four tagging BTLA polymorphisms with the risk of ESCC in the eastern Chinese Han population.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('polymorphisms', 'Var', (213, 226))	('ESCC', 'Disease', (244, 248))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('BTLA', 'Gene', (208, 212))
639862	32060969	Overall, four candidate BTLA SNPs, including rs2171513 G > A, rs3112270 A > G, rs1982809 G > A, and rs16859629 T > C, were enrolled in this research to evaluate the effect of BTLA polymorphisms on the susceptibility to ESCC.	('rs1982809', 'Mutation', 'rs1982809', (79, 88))	('rs2171513', 'Mutation', 'rs2171513', (45, 54))	('rs16859629 T > C', 'Var', (100, 116))	('rs3112270 A > G', 'Var', (62, 77))	('rs1982809 G > A', 'Var', (79, 94))	('rs3112270', 'Mutation', 'rs3112270', (62, 71))	('ESCC', 'Disease', (219, 223))	('rs16859629', 'Mutation', 'rs16859629', (100, 110))	('rs2171513 G > A', 'Var', (45, 60))
639865	32060969	After adjusting for age, gender, smoking status, and alcohol consumption, the potential associations between BTLA variants and the risk of ESCC were examined by the multivariate logistic regression analyses and described by calculating the adjusted odds ratio (OR) with 95% confidence intervals (CIs).	('variants', 'Var', (114, 122))	('BTLA', 'Gene', (109, 113))	('alcohol', 'Chemical', 'MESH:D000438', (53, 60))	('ESCC', 'Disease', (139, 143))
639866	32060969	We found that BTLA rs2171513 G > A, rs3112270 A > G, and rs1982809 G > A SNPs were not correlated with the susceptibility to the entire cohorts (all P > .05).	('rs3112270', 'Mutation', 'rs3112270', (36, 45))	('rs2171513 G > A', 'Var', (19, 34))	('rs1982809', 'Mutation', 'rs1982809', (57, 66))	('BTLA', 'Gene', (14, 18))	('rs2171513', 'Mutation', 'rs2171513', (19, 28))	('rs1982809 G > A', 'Var', (57, 72))	('rs3112270 A > G', 'Var', (36, 51))
639867	32060969	Nevertheless, we showed that the BTLA rs16859629 T > C variant significantly decreased the risk of ESCC (TC vs TT: adjusted OR = 0.75, 95% CI = 0.57-0.99, P = .044; TC/CC vs TT: adjusted OR = 0.75, 95% CI = 0.57-0.98, P = .035).	('TC', 'Chemical', 'MESH:D013667', (105, 107))	('rs16859629 T > C', 'Var', (38, 54))	('ESCC', 'Disease', (99, 103))	('TC', 'Chemical', 'MESH:D013667', (165, 167))	('rs16859629', 'Mutation', 'rs16859629', (38, 48))	('decreased', 'NegReg', (77, 86))	('BTLA', 'Gene', (33, 37))
639868	32060969	But the significant statistical distribution of BTLA rs16859629 T > C SNP disappeared after adjusting for the confounding factors, including age, sex, smoking, and alcohol status (P > .05).	('rs16859629 T', 'Var', (53, 65))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('BTLA', 'Gene', (48, 52))	('rs16859629', 'Mutation', 'rs16859629', (53, 63))
639870	32060969	As presented in Table 4, when stratified by alcoholic use, in the ever drinking subgroup, we found that the rs2171513 G > A variant in BTLA gene might be a protective variable against the progression of ESCC (GA/AA vs GG: adjusted OR = 0.62, 95% CI = 0.39-0.97, P = .037).	('rs2171513 G > A', 'Var', (108, 123))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('rs2171513', 'Mutation', 'rs2171513', (108, 117))	('ESCC', 'Disease', (203, 207))	('BTLA', 'Gene', (135, 139))
639871	32060969	As exhibited in Table 5, there was a close correlation between BTLA rs3112270 A > G and the risk of ESCC in some certain subgroups.	('ESCC', 'Disease', (100, 104))	('BTLA', 'Gene', (63, 67))	('rs3112270', 'Mutation', 'rs3112270', (68, 77))	('rs3112270 A', 'Var', (68, 79))
639872	32060969	In the male population, results demonstrated that the genotype of AG in BTLA rs3112270 lowered the ESCC risk when using AA genotype as a reference (AG vs AA: adjusted OR = 0.78, 95% CI = 0.61-0.99, P = .042).	('rs3112270', 'Mutation', 'rs3112270', (77, 86))	('rs3112270', 'Var', (77, 86))	('ESCC', 'Disease', (99, 103))	('lowered', 'NegReg', (87, 94))	('BTLA', 'Gene', (72, 76))
639873	32060969	When stratified by BMI, analyses showed that the rs3112270 A > G variant decreased the genetic susceptibility to ESCC in the BMI < 24 kg/m2 subgroup (AG vs AA: adjusted OR = 0.72, 95% CI = 0.55-0.93, P = .012; AG/GG vs AA: adjusted OR = 0.77, 95% CI = 0.60-0.98, P = .032).	('ESCC', 'Disease', (113, 117))	('rs3112270', 'Mutation', 'rs3112270', (49, 58))	('rs3112270 A > G', 'Var', (49, 64))	('decreased', 'NegReg', (73, 82))
639874	32060969	However, as shown in Tables 6 and 7, our results identified that there was no significant difference of distribution in BTLA rs1982809 G > A and rs16859629 T > C variants among any ESCC subgroup and age-/sex-matched controls (all P > .05).	('rs16859629', 'Mutation', 'rs16859629', (145, 155))	('BTLA', 'Gene', (120, 124))	('rs1982809', 'Mutation', 'rs1982809', (125, 134))	('rs1982809 G > A', 'Var', (125, 140))	('rs16859629 T > C', 'Var', (145, 161))
639876	32060969	But stratified analyses found a significant relationship between the two candidate SNPs of rs3112270 A > G and rs2171513 G > A and ESCC risk, which indicated the two polymorphisms in BTLA gene might be involved in the etiology of ESCC.	('rs3112270 A > G', 'Var', (91, 106))	('rs2171513 G > A', 'Var', (111, 126))	('rs3112270', 'Mutation', 'rs3112270', (91, 100))	('involved', 'Reg', (202, 210))	('rs2171513', 'Mutation', 'rs2171513', (111, 120))	('ESCC', 'Disease', (230, 234))	('BTLA', 'Gene', (183, 187))	('ESCC', 'Disease', (131, 135))
639877	32060969	The pathogenesis of ESCC is complex, where the interrelationship between environmental exposures and individual genetic mutations could result in the deterioration of ESCC.23, 24, 25 As revealed in our study, there were possible gene-environment interactions for the polymorphisms of BTLA rs3112270 A > G with ESCC susceptibility; especially for the individuals with different BMI settings, their corresponding risk of ESCC was different.	('BTLA', 'Gene', (284, 288))	('ESCC', 'Disease', (310, 314))	('rs3112270 A > G', 'Var', (289, 304))	('interactions', 'Reg', (246, 258))	('rs3112270', 'Mutation', 'rs3112270', (289, 298))
639878	32060969	Although the mechanism between BMI and ESCC development remained unclear, and concerning that BMI could reflect the status of body nutrition, there was some possible evidence proving that obesity was correlated with the increased level of cancer-related hormones, such as insulin-like growth factor, which could be involved in the regulation of cell cycle.26 Additionally, the site of this SNP was located at the promoter region of BTLA gene, where this region could bind to some proteins and further affect the process of DNA transcription and translation in vitro,27, 28 which might explain the mutation from A to G in BTLA gene could influence the progression of ESCC.	('influence', 'Reg', (637, 646))	('obesity', 'Phenotype', 'HP:0001513', (188, 195))	('mutation', 'Var', (597, 605))	('obesity', 'Disease', 'MESH:D009765', (188, 195))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('BTLA', 'Gene', (621, 625))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('obesity', 'Disease', (188, 195))	('cancer', 'Disease', (239, 245))	('ESCC', 'Disease', (666, 670))	('affect', 'Reg', (501, 507))	('progression', 'CPA', (651, 662))
639881	32060969	Taken together, we postulated that the genetic mutation occurred in the exon 5 of BTLA gene might influence the function of BTLA-HVEM pathway, where this signaling pathway has been proven to decrease local immune response in the tumor tissue of ESCC.33 In the future, more replicated studies about this SNP are required to confirm our hypothesis in esophageal carcinogenesis.	('influence', 'Reg', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('carcinogenesis', 'Disease', 'MESH:D063646', (360, 374))	('BTLA', 'Gene', (82, 86))	('mutation', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('carcinogenesis', 'Disease', (360, 374))	('genetic mutation', 'Var', (39, 55))	('tumor', 'Disease', (229, 234))	('local immune response', 'MPA', (200, 221))	('decrease', 'NegReg', (191, 199))	('function', 'MPA', (112, 120))
639883	32060969	Despite these limitations, our preliminary findings suggest that the two tagging variants of rs3112270 A > G and rs2171513 G > A in the BTLA gene might contribute to the progression of ESCC in the eastern Chinese population, which is the first study for the involvement of the co-inhibitory BTLA SNPs in ESCC to our knowledge.	('contribute', 'Reg', (152, 162))	('BTLA', 'Gene', (136, 140))	('rs2171513 G > A', 'Var', (113, 128))	('rs3112270 A > G', 'Var', (93, 108))	('ESCC', 'Disease', (185, 189))	('rs3112270', 'Mutation', 'rs3112270', (93, 102))	('rs2171513', 'Mutation', 'rs2171513', (113, 122))
639969	31658709	Many studies have reported that lung volumes that receive >20.00 Gy and MLD are prone to radiation pneumonitis.	('pneumonitis', 'Disease', (99, 110))	('MLD', 'Var', (72, 75))	('pneumonitis', 'Disease', 'MESH:D011014', (99, 110))	('prone', 'Reg', (80, 85))
639971	31658709	in the United States; comparing long-term outcomes between 3D-CRT and IMRT, overall survival rates were significantly higher, locoregional control was significantly higher, and cardiac death was significantly lower after IMRT than after 3D-CRT.	('higher', 'PosReg', (118, 124))	('locoregional control', 'CPA', (126, 146))	('lower', 'NegReg', (209, 214))	('cardiac death', 'Disease', (177, 190))	('higher', 'PosReg', (165, 171))	('overall survival rates', 'CPA', (76, 98))	('cardiac death', 'Phenotype', 'HP:0001645', (177, 190))	('cardiac death', 'Disease', 'MESH:D003643', (177, 190))	('IMRT', 'Var', (221, 225))
640023	31429521	PD-L1 expression and CD8+ and CD4+ lymphocyte rate were significantly higher in patients who had ypCR compared to those who had not (10 (0-55) vs 0 (0-0), P = 0.004, 73 (36-147) vs 21 (7-47), P = 0.0006 and 39 (23-74) vs 5 (0-13), P < 0.0001 respectively).	('CD4', 'Gene', (30, 33))	('patients', 'Species', '9606', (80, 88))	('ypCR', 'Var', (97, 101))	('expression', 'MPA', (6, 16))	('CD8', 'Gene', (21, 24))	('CD8', 'Gene', '925', (21, 24))	('PD-L1', 'Gene', (0, 5))	('higher', 'PosReg', (70, 76))	('CD4', 'Gene', '920', (30, 33))	('PD-L1', 'Gene', '29126', (0, 5))
640049	31429521	Commonly, a total dose of 45-50 Gy was administered (1.8 Gy daily) with a target field involving +-5 cm over the tumor extension, +-2 cm over pathologic lymph nodes, mediastinum and supraclavicular fossa.	('+-2', 'Var', (130, 133))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
640075	31429521	G1/G2 grading was more frequent in ypCR patients (95.7% in yCR vs 75.4% in yPPD, P = 0.03; Table 1).	('ypCR', 'Disease', (35, 39))	('patients', 'Species', '9606', (40, 48))	('yCR', 'Disease', (59, 62))	('G1/G2', 'Var', (0, 5))
640147	30183753	The values of mean dose (Dmean), D2% (dose received by 2% of the volume), D98% (dose received by 98% of the volume) and V107% (volume of target receiving at least 107% of the PD) were investigated for target coverage.	('D98%', 'Var', (74, 78))	('PD', 'Disease', 'MESH:D010300', (175, 177))	('V107%', 'Var', (120, 125))
640148	30183753	D98% and D2% for PTV were defined as metrics for minimum and maximum doses.	('D2%', 'Var', (9, 12))	('PTV', 'Chemical', '-', (17, 20))	('D98%', 'Var', (0, 4))
640159	30183753	In total MUs, jaw tracking plans in groups of large field IMRT resulted in about 7% increase compared to fixed jaw plans (P <0.001), while it was about 6% increase for groups of small field IMRT plans (P <0.001).	('increase', 'PosReg', (84, 92))	('jaw plans', 'Disease', 'MESH:D007571', (111, 120))	('jaw plans', 'Disease', (111, 120))	('large field IMRT', 'Var', (46, 62))
640253	29854663	Inhibiting DAXX activity or DAXX accumulation could be a promising therapeutic strategy to enhance the effects of radiotherapy and chemotherapy in esophageal cancer patients.	('esophageal cancer', 'Disease', (147, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('Inhibiting', 'Var', (0, 10))	('patients', 'Species', '9606', (165, 173))	('enhance', 'PosReg', (91, 98))	('DAXX', 'Enzyme', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
640256	29435035	Expression levels of CD147, PTTG and CD44v6 were higher in tumor tissues than in matched adjacent tissues.	('CD44', 'Gene', '960', (37, 41))	('CD147', 'Var', (21, 26))	('tumor', 'Disease', (59, 64))	('PTTG', 'Gene', '9232', (28, 32))	('Expression levels', 'MPA', (0, 17))	('CD44', 'Gene', (37, 41))	('PTTG', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('higher', 'PosReg', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('CD147', 'Chemical', '-', (21, 26))
640270	29435035	CD147 is a heavily glycosylated type I transmembrane glycoprotein; its overexpression of CD147 was significantly associated with various malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('overexpression', 'PosReg', (71, 85))	('associated with', 'Reg', (113, 128))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('malignant tumors', 'Disease', (137, 153))	('malignant tumors', 'Disease', 'MESH:D018198', (137, 153))	('CD147', 'Var', (89, 94))	('CD147', 'Chemical', '-', (0, 5))	('CD147', 'Chemical', '-', (89, 94))
640308	29435035	Kaplan-Meier curves were generated for patients with ESCC categorized patients according to the expression of CD147, PTTG and CD44v6.	('CD147', 'Var', (110, 115))	('patients', 'Species', '9606', (70, 78))	('CD147', 'Chemical', '-', (110, 115))	('patients', 'Species', '9606', (39, 47))	('PTTG', 'Gene', '9232', (117, 121))	('CD44', 'Gene', '960', (126, 130))	('CD44', 'Gene', (126, 130))	('PTTG', 'Gene', (117, 121))
640310	29435035	The results also indicated that the duration of survival was significantly associated with positive PTTG expression (Fig.	('PTTG', 'Gene', (100, 104))	('positive', 'Var', (91, 99))	('PTTG', 'Gene', '9232', (100, 104))
640313	29435035	Regarding co-expression, patients with positive staining for CD147 and PTTG demonstrated lower OS rates (Fig.	('lower', 'NegReg', (89, 94))	('PTTG', 'Gene', (71, 75))	('positive staining', 'Var', (39, 56))	('CD147', 'Gene', (61, 66))	('CD147', 'Chemical', '-', (61, 66))	('OS rates', 'CPA', (95, 103))	('patients', 'Species', '9606', (25, 33))	('PTTG', 'Gene', '9232', (71, 75))
640314	29435035	Furthermore, the combination of CD147 and CD44v6 expression suggested that the overall survival of these subgroups had a statistical difference (Fig.	('CD147', 'Chemical', '-', (32, 37))	('CD44', 'Gene', '960', (42, 46))	('CD44', 'Gene', (42, 46))	('CD147', 'Var', (32, 37))
640322	29435035	Furthermore, when these features were subjected to Kaplan-Meier analysis, the expression of CD147 was associated with lower OS rates.	('OS rates', 'CPA', (124, 132))	('CD147', 'Gene', (92, 97))	('expression', 'Var', (78, 88))	('CD147', 'Chemical', '-', (92, 97))	('lower', 'NegReg', (118, 123))
640333	29435035	The results of the present study indicated that the overexpression of CD44v6 was a useful marker for patient prognosis; the combination of CD44v6 and CD147 was associated with reduced OS rate.	('CD44', 'Gene', (70, 74))	('CD44', 'Gene', (139, 143))	('reduced', 'NegReg', (176, 183))	('CD147', 'Var', (150, 155))	('CD147', 'Chemical', '-', (150, 155))	('patient', 'Species', '9606', (101, 108))	('CD44', 'Gene', '960', (70, 74))	('CD44', 'Gene', '960', (139, 143))
640339	29435035	In conclusion, the overexpression of CD147, PTTG and CD44v6, individually, was associated with the development of ESSC and was significantly associated with OS rate, which indicated that these proteins are potential biomarkers for prognosis.	('overexpression', 'PosReg', (19, 33))	('CD147', 'Var', (37, 42))	('PTTG', 'Gene', (44, 48))	('CD44', 'Gene', '960', (53, 57))	('CD147', 'Chemical', '-', (37, 42))	('OS rate', 'Disease', (157, 164))	('associated with', 'Reg', (79, 94))	('CD44', 'Gene', (53, 57))	('ESSC', 'Disease', (114, 118))	('associated', 'Reg', (141, 151))	('PTTG', 'Gene', '9232', (44, 48))
640342	26478746	Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma Clinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (191, 211))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (271, 275))	('gastro-esophageal junctional carcinoma', 'Disease', 'MESH:D005764', (73, 111))	('esophageal', 'Disease', 'MESH:D004941', (80, 90))	('esophageal', 'Disease', 'MESH:D004941', (191, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('epidermal growth factor receptor', 'Gene', (148, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('epidermal growth factor receptor', 'Gene', '1956', (148, 180))	('copy number aberrations', 'Var', (31, 54))	('esophageal', 'Disease', (58, 68))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (191, 211))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', '1956', (271, 275))	('EGFR', 'Gene', (182, 186))	('esophageal junctional carcinoma', 'Phenotype', 'HP:0011459', (80, 111))	('gastro-esophageal junctional carcinoma', 'Disease', (73, 111))	('esophageal carcinoma', 'Disease', (191, 211))	('esophageal', 'Disease', (80, 90))	('esophageal', 'Disease', 'MESH:D004941', (58, 68))	('esophageal', 'Disease', (191, 201))
640343	26478746	Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small.	('increases', 'PosReg', (29, 38))	('copy number', 'Var', (47, 58))	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (42, 46))
640344	26478746	A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients.	('copy number', 'Var', (87, 98))	('EGFR', 'Gene', (143, 147))	('EGFR', 'Gene', (82, 86))	('patients', 'Species', '9606', (171, 179))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', '1956', (143, 147))	('EGFR', 'Gene', '1956', (82, 86))	('gain', 'PosReg', (99, 103))	('EGFR', 'Gene', (22, 26))
640346	26478746	Dual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6).	('paraffin', 'Chemical', 'MESH:D010232', (35, 43))	('low polysomy', 'Var', (187, 199))	('formalin', 'Chemical', 'MESH:D005557', (20, 28))	('disomy', 'Disease', (116, 122))	('high polysomy', 'Var', (213, 226))	('high trisomy', 'Var', (161, 173))	('low trisomy', 'Var', (136, 147))
640347	26478746	EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %).	('high polysomy', 'Var', (84, 97))	('EGFR', 'Gene', (0, 4))	('tumours', 'Disease', (70, 77))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('EGFR', 'Gene', '1956', (0, 4))	('amplification', 'Var', (117, 130))
640349	26478746	EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03).	('amplification', 'Var', (5, 18))	('worse', 'NegReg', (39, 44))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
640351	26478746	EGFR amplification, which is found in 6.3 %, is associated with poor survival.	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
640367	26478746	The tyrosine kinase inhibitor gefitinib has demonstrated survival benefit in EGFR mutated non-small cell lung cancer and cetuximab, an anti-EGFR monoclonal antibody, improves survival in KRAS wild type colorectal cancer.	('gefitinib', 'Chemical', 'MESH:D000077156', (30, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('non-small cell lung cancer', 'Disease', (90, 116))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('cetuximab', 'Chemical', 'MESH:D000068818', (121, 130))	('EGFR', 'Gene', (140, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (90, 116))	('colorectal cancer', 'Disease', (202, 219))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutated', 'Var', (82, 89))	('EGFR', 'Gene', '1956', (77, 81))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (90, 116))	('EGFR', 'Gene', (77, 81))	('EGFR', 'Gene', '1956', (140, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))	('improves', 'PosReg', (166, 174))
640373	26478746	Gene copy number changes are frequent in EC in comparison to other tumour types including tumours in the gastrointestinal tract, even in the stomach.	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours in the gastrointestinal tract', 'Phenotype', 'HP:0007378', (90, 127))	('frequent', 'Reg', (29, 37))	('tumour', 'Disease', (67, 73))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumours in the gastrointestinal tract', 'Disease', (90, 127))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumours in the gastrointestinal tract', 'Disease', 'MESH:D004067', (90, 127))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('tumour', 'Disease', (90, 96))	('Gene copy number changes', 'Var', (0, 24))
640376	26478746	EGFR copy number gain, including amplification, in esophageal and gastric cancers has been identified using several different methods, which used differing levels of gain for reporting EGFR amplification and inconsistent results regarding whether this confers a poor prognosis (Table 1).	('amplification', 'MPA', (33, 46))	('copy number', 'Var', (5, 16))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (185, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('EGFR', 'Gene', '1956', (185, 189))	('gastric cancers', 'Phenotype', 'HP:0012126', (66, 81))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (51, 81))	('EGFR', 'Gene', '1956', (0, 4))	('gain', 'PosReg', (17, 21))
640377	26478746	Differing classification systems for significant copy number gain or amplification, distinct biological differences between gastric cancer and EC, and some studies not assessing correlation between EGFR copy number and survival may account for reported disparities.	('gastric cancer', 'Disease', (124, 138))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('amplification', 'MPA', (69, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('EGFR', 'Gene', '1956', (198, 202))	('copy number', 'Var', (49, 60))	('EGFR', 'Gene', (198, 202))	('gain', 'PosReg', (61, 65))
640379	26478746	No previous study has provided a classification for EGFR copy number in EC to the degree that has become routine practice in other tumour types.	('copy number', 'Var', (57, 68))	('tumour', 'Disease', (131, 137))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))
640380	26478746	FISH is widely recognised as the "gold standard" diagnostic method for assessing gene copy number gain in human cancers.	('human', 'Species', '9606', (106, 111))	('gene copy number', 'Var', (81, 97))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
640381	26478746	FISH for EGFR copy number alterations has been most extensively studied in formalin fixed paraffin embedded (FFPE) non-small cell lung cancer samples.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('non-small cell lung cancer', 'Disease', (115, 141))	('copy number alterations', 'Var', (14, 37))	('paraffin', 'Chemical', 'MESH:D010232', (90, 98))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (115, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('formalin', 'Chemical', 'MESH:D005557', (75, 83))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (119, 141))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (115, 141))
640383	26478746	Significant correlation between EGFR gene copy number by FISH and EGFR protein expression by immunohistochemistry was identified (p < 0.001); high gene copy number also showed a trend towards poorer prognosis.	('EGFR', 'Gene', '1956', (66, 70))	('high gene copy number', 'Var', (142, 163))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (32, 36))
640384	26478746	This principle of gene copy number classification in lung cancer was developed further by Cappuzzo et al, categorising EGFR FISH status into six categories with precise inclusion criteria of FISH positive cases comprising either high polysomy (>=40 % of cells with >= 4 copies of the EGFR gene) or amplification.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('EGFR', 'Gene', '1956', (284, 288))	('EGFR', 'Gene', '1956', (119, 123))	('amplification', 'Var', (298, 311))	('EGFR', 'Gene', (284, 288))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('EGFR', 'Gene', (119, 123))
640393	26478746	In the EGFR FISH negative group, disomy was present in 45 cases (28.1 %); low trisomy in 47 (29.4 %); high trisomy in two cases (1.3 %) and low polysomy in 34 cases (21.3 %).	('high trisomy', 'Var', (102, 114))	('EGFR', 'Gene', (7, 11))	('disomy', 'Disease', (33, 39))	('low trisomy', 'Var', (74, 85))	('low polysomy', 'Var', (140, 152))	('EGFR', 'Gene', '1956', (7, 11))
640395	26478746	A homogenous staining region is caused by amplicon clustering on a chromosome whereas double minute amplification is due to multiple copies of non-centromeric chromosomal fragments containing EGFR, seen as disseminated signals.	('double minute amplification', 'MPA', (86, 113))	('amplicon', 'Var', (42, 50))	('caused by', 'Reg', (32, 41))	('homogenous staining', 'MPA', (2, 21))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (192, 196))
640399	26478746	In order to remove the effects of treatment interaction, the relationship between EGFR gene copy number and overall survival in the 79 of 160 patients that received no further treatment was examined.	('EGFR', 'Gene', '1956', (82, 86))	('patients', 'Species', '9606', (142, 150))	('EGFR', 'Gene', (82, 86))	('copy number', 'Var', (92, 103))
640407	26478746	The frequency of EGFR amplification present in 6.3 % (ten cases) is consistent with previous reports (6.25-49 %).	('amplification', 'Var', (22, 35))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
640412	26478746	Cases meeting our EGFR amplification criteria have significantly worse overall survival compared with non-amplified cases (median overall survival 1.76 v 3.17 months, p = 0.03), in patients not treated with anti-cancer therapies, confirming EGFR amplification as a therapy independent prognostic biomarker in EC and supporting the use of dual colour EGFR FISH as a robust method of analysis of EGFR gene copy number.	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('EGFR', 'Gene', (350, 354))	('worse', 'NegReg', (65, 70))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', '1956', (241, 245))	('EGFR', 'Gene', (394, 398))	('amplification', 'Var', (246, 259))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', (241, 245))	('cancer', 'Disease', (212, 218))	('overall survival', 'MPA', (71, 87))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('patients', 'Species', '9606', (181, 189))	('EGFR', 'Gene', '1956', (350, 354))	('EGFR', 'Gene', '1956', (394, 398))
640413	26478746	Further studies are required to determine whether EGFR amplification in EC is useful as a predictive biomarker to identify patients suitable for anti-EGFR targeted therapy and we suggest that the method and scoring system described here is fit for this purpose.	('amplification', 'Var', (55, 68))	('EGFR', 'Gene', (150, 154))	('patients', 'Species', '9606', (123, 131))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', '1956', (150, 154))
640418	26478746	Previous studies of EGFR copy number in EC are summarised in Table 1.	('copy number', 'Var', (25, 36))	('EGFR', 'Gene', '1956', (20, 24))	('EGFR', 'Gene', (20, 24))
640419	26478746	A variety of techniques have been employed to investigate the frequency of EGFR copy number gain or amplification in esophago-gastric cancer, yielding a frequency of 6.25- 49 % (Table 1).	('amplification', 'Var', (100, 113))	('esophago-gastric cancer', 'Disease', 'MESH:D013274', (117, 140))	('EGFR', 'Gene', '1956', (75, 79))	('copy number', 'Var', (80, 91))	('gain', 'PosReg', (92, 96))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('esophago-gastric cancer', 'Disease', (117, 140))	('EGFR', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
640420	26478746	Of the studies using FISH to evaluate EGFR copy number change or amplification, two were in gastric cancer patients, demonstrating poor survival in the 4.88 % of European patients with amplification, however survival outcome was not assessed in 29 % EGFR amplified Chinese gastric cancer patients.	('EGFR', 'Gene', '1956', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('amplified', 'Var', (255, 264))	('EGFR', 'Gene', (38, 42))	('gastric cancer', 'Disease', (92, 106))	('gastric cancer', 'Disease', (273, 287))	('patients', 'Species', '9606', (288, 296))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('copy number', 'Var', (43, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (273, 287))	('patients', 'Species', '9606', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('EGFR', 'Gene', '1956', (250, 254))	('gastric cancer', 'Phenotype', 'HP:0012126', (273, 287))	('amplification', 'Var', (185, 198))	('patients', 'Species', '9606', (107, 115))	('EGFR', 'Gene', (250, 254))
640422	26478746	The distinct biological and molecular features of gastric cancer and EC, in particular the different frequencies of gene copy number changes, as well as the lack of a validated classification system for significant EGFR copy number gain or amplification, may account for inconsistencies in results.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('EGFR', 'Gene', '1956', (215, 219))	('EGFR', 'Gene', (215, 219))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('copy number', 'Var', (220, 231))	('gain', 'PosReg', (232, 236))
640423	26478746	In addition, the majority of previous studies have been small and undertaken in patients of differing ethnicities and several studies were performed with technology that is no longer in widespread clinical use, making it unclear whether EGFR amplification does result in poorer survival.	('EGFR', 'Gene', '1956', (237, 241))	('patients', 'Species', '9606', (80, 88))	('amplification', 'Var', (242, 255))	('poorer', 'NegReg', (271, 277))	('EGFR', 'Gene', (237, 241))	('survival', 'MPA', (278, 286))
640424	26478746	The frequency of EGFR amplification may be lower in European and North American populations (6.5 -12.5 %) when compared to studies in Asian patients (7-49 %), implying a significant ethnic component to EGFR dysregulation in esophago-gastric cancer.	('EGFR', 'Gene', (202, 206))	('gastric cancer', 'Phenotype', 'HP:0012126', (233, 247))	('esophago-gastric cancer', 'Disease', 'MESH:D013274', (224, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('amplification', 'Var', (22, 35))	('patients', 'Species', '9606', (140, 148))	('EGFR', 'Gene', '1956', (17, 21))	('esophago-gastric cancer', 'Disease', (224, 247))	('EGFR', 'Gene', '1956', (202, 206))	('EGFR', 'Gene', (17, 21))
640425	26478746	Ethnic differences in molecular abnormalities have been identified in NSCLC where patients of Asian origin are more likely than Caucasians (35 v 11 %) to harbour the EGFR mutations inferring increased benefit from anti-EGFR therapy.	('increased benefit', 'PosReg', (191, 208))	('EGFR', 'Gene', '1956', (219, 223))	('EGFR', 'Gene', (219, 223))	('NSCLC', 'Disease', (70, 75))	('patients', 'Species', '9606', (82, 90))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('molecular abnormalities', 'Disease', (22, 45))	('mutations', 'Var', (171, 180))	('molecular abnormalities', 'Disease', 'MESH:C567116', (22, 45))
640427	26478746	Trastuzumab, a monoclonal antibody against HER-2, has demonstrated activity in combination with platinum doublet chemotherapy in the 10-15 % patients with gastric cancer and tumour HER-2 protein overexpression or amplification, compared to chemotherapy alone.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('amplification', 'Var', (213, 226))	('HER-2', 'Gene', '2064', (43, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (155, 169))	('overexpression', 'PosReg', (195, 209))	('HER-2', 'Gene', (43, 48))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (0, 11))	('tumour', 'Disease', (174, 180))	('activity', 'MPA', (67, 75))	('HER-2', 'Gene', '2064', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('HER-2', 'Gene', (181, 186))	('gastric cancer', 'Disease', (155, 169))	('patients', 'Species', '9606', (141, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (155, 169))
640432	26478746	In conclusion, we have shown that EGFR amplification assessed using our standardised FISH scoring system is a therapy independent prognostic biomarker of poor outcome in EC and represents a practical, robust assay useful for clinical research and clinical practice, particularly for investigation as a predictive biomarker for anti-EGFR therapies in clinical trials.	('EGFR', 'Gene', (332, 336))	('EGFR', 'Gene', (34, 38))	('amplification', 'Var', (39, 52))	('EGFR', 'Gene', '1956', (332, 336))	('EGFR', 'Gene', '1956', (34, 38))
640444	26478746	EGFR FISH scores were assigned for FISH negative: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3) and low polysomy (score = 4) and for FISH positive: high polysomy (score = 5) and amplification (score =6) (Table 2).	('low polysomy', 'Var', (124, 136))	('EGFR', 'Gene', (0, 4))	('low trisomy', 'Var', (70, 81))	('high trisomy', 'Var', (95, 107))	('disomy', 'Var', (50, 56))	('EGFR', 'Gene', '1956', (0, 4))
640445	26478746	Relationships between baseline clinico-pathological features and EGFR mutation status were analysed using Pearson Chi2 or Fisher's exact test when cell counts were <=5.	('mutation', 'Var', (70, 78))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))
640446	26478746	Hazard ratios with 95 % confidence intervals, log rank test and Kaplan-Meier curves were constructed comparing overall survival, defined as time from diagnosis to death) and progression free survival (defined as time from diagnosis to progression or death) in EGFR FISH positive and negative cases, and EGFR amplified cases versus all other cases in the 79 patients who did not receive further systemic treatment for their disease.	('negative', 'NegReg', (283, 291))	('EGFR', 'Gene', (260, 264))	('EGFR', 'Gene', '1956', (303, 307))	('death', 'Disease', 'MESH:D003643', (250, 255))	('death', 'Disease', (250, 255))	('progression free survival', 'CPA', (174, 199))	('EGFR', 'Gene', (303, 307))	('patients', 'Species', '9606', (357, 365))	('amplified', 'Var', (308, 317))	('EGFR', 'Gene', '1956', (260, 264))	('death', 'Disease', (163, 168))	('death', 'Disease', 'MESH:D003643', (163, 168))	('positive', 'Var', (270, 278))
640500	24386361	Genetic Variant rs401681 at 5p15.33 Modifies Susceptibility to Lung Cancer but Not Esophageal Squamous Cell Carcinoma The human 5p15.33 locus contains two well-known genes, the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes, which have been implicated in carcinogenesis.	('human', 'Species', '9606', (122, 127))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('telomerase reverse transcriptase', 'Gene', (177, 209))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (83, 117))	('CLPTM1L', 'Gene', (264, 271))	('TERT', 'Gene', (211, 215))	('Lung Cancer', 'Phenotype', 'HP:0100526', (63, 74))	('TERT', 'Gene', '7015', (211, 215))	('Cancer', 'Disease', (68, 74))	('Variant rs401681', 'Var', (8, 24))	('telomerase reverse transcriptase', 'Gene', '7015', (177, 209))	('rs401681', 'Var', (16, 24))	('Esophageal Squamous Cell Carcinoma', 'Disease', (83, 117))	('Carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('cleft lip and palate', 'Phenotype', 'HP:0000202', (221, 241))	('cleft lip and palate', 'Disease', 'MESH:D002971', (221, 241))	('Modifies', 'Reg', (36, 44))	('carcinogenesis', 'Disease', (310, 324))	('cleft lip', 'Phenotype', 'HP:0410030', (221, 230))	('CLPTM1L', 'Gene', '81037', (264, 271))	('carcinogenesis', 'Disease', 'MESH:D063646', (310, 324))	('rs401681', 'Mutation', 'rs401681', (16, 24))
640501	24386361	A common sequence variant, rs401681, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study.	('rs401681', 'Var', (27, 35))	('lung cancer', 'Disease', (119, 130))	('associated', 'Reg', (103, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('CLPTM1L', 'Gene', '81037', (70, 77))	('CLPTM1L', 'Gene', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('rs401681', 'Mutation', 'rs401681', (27, 35))
640502	24386361	In addition, genetic variants at 5p15.33, including rs401681, have been shown to be involved in the susceptibility to multiple malignancies.	('malignancies', 'Disease', 'MESH:D009369', (127, 139))	('rs401681', 'Var', (52, 60))	('malignancies', 'Disease', (127, 139))	('rs401681', 'Mutation', 'rs401681', (52, 60))	('susceptibility', 'Reg', (100, 114))	('involved', 'Reg', (84, 92))
640503	24386361	Nevertheless, the role of these TERT-CLPTM1L variants in the etiology of esophageal squamous cell carcinoma (ESCC) remains unknown.	('TERT', 'Gene', '7015', (32, 36))	('CLPTM1L', 'Gene', '81037', (37, 44))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (73, 107))	('CLPTM1L', 'Gene', (37, 44))	('variants', 'Var', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('esophageal squamous cell carcinoma', 'Disease', (73, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('TERT', 'Gene', (32, 36))
640504	24386361	We genotyped the rs401681 polymorphism using TaqMan methodology and analyzed its association with the risk of lung cancer and ESCC in a case-control study of 1,479 cancer patients (726 with lung cancer and 753 with ESCC) and 860 healthy individuals.	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('lung cancer', 'Disease', (110, 121))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('lung cancer', 'Disease', (190, 201))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('patients', 'Species', '9606', (171, 179))	('rs401681', 'Mutation', 'rs401681', (17, 25))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Disease', (195, 201))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('cancer', 'Disease', (164, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('association', 'Interaction', (81, 92))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ESCC', 'Disease', (126, 130))	('rs401681', 'Var', (17, 25))
640505	24386361	Logistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR = 0.782, 95% CI = 0.625-0.978, P = 0.031; CT/TT vs. CC: adjusted OR = 0.786; 95% CI = 0.635-0.972, P = 0.026).	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('decreased', 'NegReg', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rs401681', 'Mutation', 'rs401681', (43, 51))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('rs401681 T', 'Var', (43, 53))
640506	24386361	Stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('reduced', 'NegReg', (115, 122))	('rs401681', 'Mutation', 'rs401681', (57, 65))	('rs401681 T', 'Var', (57, 67))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
640507	24386361	Furthermore, no significant association was observed between rs401681 and the risk of ESCC (CT vs. CC: adjusted OR = 0.910, 95% CI = 0.734-1.129, P = 0.392; TT vs. CC: adjusted OR = 0.897, 95%CI = 0.624-1.290, P = 0.558; CT/TT vs. CC: adjusted OR = 0.908, 95% CI = 0.740-1.114, P = 0.355).	('rs401681', 'Mutation', 'rs401681', (61, 69))	('rs401681', 'Var', (61, 69))	('ESCC', 'Disease', (86, 90))
640508	24386361	Our findings provide further evidence supporting rs401681 as a genetic variant associated with the risk of lung cancer.	('rs401681', 'Var', (49, 57))	('associated', 'Reg', (79, 89))	('rs401681', 'Mutation', 'rs401681', (49, 57))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
640509	24386361	In addition, we investigated the correlation between the rs401681 variant and the risk of ESCC in a Han Chinese population, and our results suggest that this genetic variant may not be involved in ESCC risk.	('rs401681', 'Var', (57, 65))	('ESCC', 'Disease', (90, 94))	('rs401681', 'Mutation', 'rs401681', (57, 65))	('ESCC', 'Disease', (197, 201))
640513	24386361	Recently, genome-wide association studies (GWASs) have shown that common TERT-CLPTM1L variants at 5p15.33 may influence the risk of developing lung cancer as well as other types of cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('CLPTM1L', 'Gene', '81037', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('CLPTM1L', 'Gene', (78, 85))	('TERT', 'Gene', '7015', (73, 77))	('lung cancer', 'Disease', (143, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('variants', 'Var', (86, 94))	('influence', 'Reg', (110, 119))	('TERT', 'Gene', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('cancer', 'Disease', (181, 187))
640516	24386361	TERT encodes the catalytic subunit of telomerase, an enzyme that maintains telomere ends by adding the telomere repeat TTAGGG.	('adding', 'PosReg', (92, 98))	('TTAGGG', 'Var', (119, 125))	('TERT', 'Gene', (0, 4))	('telomere', 'MPA', (75, 83))	('TERT', 'Gene', '7015', (0, 4))
640519	24386361	The rs401681 polymorphism, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study.	('CLPTM1L', 'Gene', '81037', (60, 67))	('lung cancer', 'Disease', (109, 120))	('rs401681', 'Mutation', 'rs401681', (4, 12))	('CLPTM1L', 'Gene', (60, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('associated', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('rs401681', 'Var', (4, 12))
640520	24386361	found that rs401681 was significantly associated with lung cancer risk in the Asian population, whereas another study examining 501 lung cancer cases and 576 cancer-free controls detected no association between this genetic variant and risk of lung cancer in a population of the same ethnicity.	('rs401681', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (249, 255))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', (54, 65))	('associated', 'Reg', (38, 48))	('lung cancer', 'Disease', (244, 255))	('cancer', 'Disease', (158, 164))	('lung cancer', 'Disease', (132, 143))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('rs401681', 'Mutation', 'rs401681', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (244, 255))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('cancer', 'Disease', (59, 65))
640521	24386361	Additionally, a study in a Korean population found that rs401681 was associated with a significantly decreased risk of lung cancer under a dominant model for the variant allele.	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('rs401681', 'Var', (56, 64))	('decreased', 'NegReg', (101, 110))	('rs401681', 'Mutation', 'rs401681', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))
640524	24386361	In most cases, the common genetic variants that have been associated with cancer risk seem to be specific to a particular cancer type.	('variants', 'Var', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
640525	24386361	However, single-nucleotide polymorphisms (SNPs) in the TERT-CLPTM1L region, including rs401681, have shown possible associations in multiple cancers.	('CLPTM1L', 'Gene', '81037', (60, 67))	('single-nucleotide polymorphisms', 'Var', (9, 40))	('multiple cancers', 'Disease', (132, 148))	('CLPTM1L', 'Gene', (60, 67))	('rs401681', 'Var', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rs401681', 'Mutation', 'rs401681', (86, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (132, 148))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('associations', 'Reg', (116, 128))
640526	24386361	Recently, rs401681[C] was reported to be associated with an increased risk of basal cell carcinoma and lung, urinary bladder, prostate and cervix cancers.	('rs401681', 'Mutation', 'rs401681', (10, 18))	('associated', 'Reg', (41, 51))	('lung', 'Disease', (103, 107))	('cervix cancers', 'Phenotype', 'HP:0030079', (139, 153))	('prostate', 'Disease', (126, 134))	('rs401681[', 'Var', (10, 19))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (78, 98))	('basal cell carcinoma', 'Disease', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('urinary bladder', 'Disease', (109, 124))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (78, 98))	('cervix cancers', 'Disease', 'MESH:D002583', (139, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cervix cancers', 'Disease', (139, 153))
640527	24386361	Conversely, rs401681[C] appears to confer protection against cutaneous melanoma.	('rs401681[', 'Var', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('rs401681', 'Mutation', 'rs401681', (12, 20))	('cutaneous melanoma', 'Disease', (61, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))
640528	24386361	Moreover, a recent GWAS demonstrated that rs401681 may modify individual susceptibility to pancreatic cancer.	('rs401681', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs401681', 'Mutation', 'rs401681', (42, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('pancreatic cancer', 'Disease', (91, 108))	('modify', 'Reg', (55, 61))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
640529	24386361	The rs401681 polymorphism has been widely studied in different ethnicities and cancer types.	('rs401681', 'Mutation', 'rs401681', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('rs401681', 'Var', (4, 12))
640541	24386361	The associations between the rs401681 polymorphism and cancer risk were estimated by computing the odds ratios (ORs) and their 95% confidence intervals (CIs) through logistic regression analyses for crude ORs and adjusted ORs when adjusting for age, sex and smoking and drinking status.	('associations', 'Interaction', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rs401681', 'Mutation', 'rs401681', (29, 37))	('rs401681', 'Var', (29, 37))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
640547	24386361	The genotype and allele frequencies of the rs401681 polymorphism in the lung cancer and ESCC patients and healthy controls are presented in Table 2.	('ESCC', 'Disease', (88, 92))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('rs401681', 'Mutation', 'rs401681', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rs401681', 'Var', (43, 51))	('patients', 'Species', '9606', (93, 101))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
640550	24386361	As shown in Table 3, logistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR = 0.782, 95% CI = 0.625-0.978, P = 0.031; CT/TT vs. CC: adjusted OR = 0.786; 95% CI = 0.635-0.972, P = 0.026).	('lung cancer', 'Disease', (140, 151))	('rs401681 T', 'Var', (64, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('rs401681', 'Mutation', 'rs401681', (64, 72))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('decreased', 'NegReg', (122, 131))
640551	24386361	Moreover, the rs401681 T allele was borderline significantly associated with a lower risk of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs401681', 'Mutation', 'rs401681', (14, 22))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('rs401681 T', 'Var', (14, 24))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))
640552	24386361	We further evaluated the association between rs401681 and lung cancer risk stratified by histology type.	('rs401681', 'Mutation', 'rs401681', (45, 53))	('rs401681', 'Var', (45, 53))	('evaluated', 'Reg', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
640553	24386361	As shown in Figure 1, stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma, but not with small-cell carcinoma.	('rs401681', 'Mutation', 'rs401681', (79, 87))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 200))	('small-cell carcinoma', 'Disease', 'MESH:D018288', (215, 235))	('rs401681 T', 'Var', (79, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('small-cell carcinoma', 'Phenotype', 'HP:0030357', (215, 235))	('small-cell carcinoma', 'Disease', (215, 235))	('reduced', 'NegReg', (137, 144))
640554	24386361	For the patients with esophageal carcinoma, the genotype frequencies of the rs401681 variant were not significantly different between the cases and controls.	('rs401681', 'Mutation', 'rs401681', (76, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('rs401681', 'Var', (76, 84))	('esophageal carcinoma', 'Disease', (22, 42))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (22, 42))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (22, 42))	('patients', 'Species', '9606', (8, 16))
640555	24386361	In addition, the rs401681 T allele was less frequent among cases than among controls, though this difference was not statistically significant (Table 2).	('rs401681', 'Mutation', 'rs401681', (17, 25))	('rs401681 T', 'Var', (17, 27))	('less', 'NegReg', (39, 43))
640556	24386361	Following adjustment for age, sex and smoking and drinking status in a multivariate logistic regression analysis, no significant association was observed between rs401681 and the susceptibility to esophageal carcinoma (CT vs. CC: adjusted OR = 0.910, 95%CI = 0.734-1.129; TT vs. CC: adjusted OR = 0.897, 95%CI = 0.624-1.290; CT/TT vs. CC: adjusted OR = 0.908, 95%CI = 0.740-1.114) (Table 3).	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (197, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('rs401681', 'Var', (162, 170))	('rs401681', 'Mutation', 'rs401681', (162, 170))	('esophageal carcinoma', 'Disease', (197, 217))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (197, 217))
640558	24386361	A previous study indicated that telomere dysfunction may act as both a potent tumor suppressor and promoter in the lung epithelial compartment, depending on the status of the telomere dysfunction-induced checkpoint.	('telomere dysfunction', 'Var', (32, 52))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
640561	24386361	The exact functional relevance of the rs401681 polymorphism regarding its association with lung cancer currently remains unclear, but some previous studies provide a link to this association.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('rs401681', 'Mutation', 'rs401681', (38, 46))	('rs401681', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('association', 'Interaction', (74, 85))	('lung cancer', 'Disease', (91, 102))
640563	24386361	For example, CLPTM1L rs402710, which is in strong LD with rs401681, has been reported to be associated with significantly higher levels of bulky aromatic/hydrophobic DNA adducts in lung tissue adjacent to tumors.	('rs402710', 'Mutation', 'rs402710', (21, 29))	('rs401681', 'Var', (58, 66))	('rs402710', 'Var', (21, 29))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('rs401681', 'Mutation', 'rs401681', (58, 66))	('CLPTM1L', 'Gene', '81037', (13, 20))	('higher', 'PosReg', (122, 128))	('CLPTM1L', 'Gene', (13, 20))	('bulky aromatic/hydrophobic DNA adducts', 'MPA', (139, 177))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))
640564	24386361	Moreover, rs401681[C] has been shown to be associated with shorter telomeres.	('shorter', 'NegReg', (59, 66))	('rs401681[', 'Var', (10, 19))	('rs401681', 'Mutation', 'rs401681', (10, 18))
640565	24386361	Consistent with previous observations from a pooled analysis, the results of our case-control study suggested that rs401681 T genotypes were associated with a significantly reduced risk of both lung adenocarcinoma and squamous cell carcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (194, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 241))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (218, 241))	('reduced', 'NegReg', (173, 180))	('lung adenocarcinoma', 'Disease', (194, 213))	('rs401681', 'Mutation', 'rs401681', (115, 123))	('rs401681 T', 'Var', (115, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (194, 213))
640566	24386361	confirmed that two independent susceptibility variants at 5p15.33 (TERT rs2736100 and CLPTM1L rs401681) act as determinants of lung cancer risk, differentially impacting lung cancer histology.	('TERT', 'Gene', (67, 71))	('lung cancer', 'Disease', (127, 138))	('TERT', 'Gene', '7015', (67, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('CLPTM1L', 'Gene', '81037', (86, 93))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('rs401681', 'Var', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('rs401681', 'Mutation', 'rs401681', (94, 102))	('CLPTM1L', 'Gene', (86, 93))	('rs2736100', 'Mutation', 'rs2736100', (72, 81))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('lung cancer', 'Disease', (170, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('impacting', 'Reg', (160, 169))
640567	24386361	The risk associated with rs2736100 is largely confined to adenocarcinoma.	('rs2736100', 'Var', (25, 34))	('adenocarcinoma', 'Disease', (58, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (58, 72))	('rs2736100', 'Mutation', 'rs2736100', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
640568	24386361	However, rs401681 influences the risk of all lung cancer histologies, but its strongest effect is on squamous cell carcinoma.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('influences', 'Reg', (18, 28))	('lung cancer', 'Disease', (45, 56))	('rs401681', 'Mutation', 'rs401681', (9, 17))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('rs401681', 'Var', (9, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('squamous cell carcinoma', 'Disease', (101, 124))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
640569	24386361	A recent meta-analysis by cancer type demonstrated that rs401681 [T] carriers show a modestly increased risk of pancreatic carcinoma and skin melanoma.	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (112, 132))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('rs401681', 'Mutation', 'rs401681', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('pancreatic carcinoma', 'Disease', (112, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('skin melanoma', 'Disease', 'MESH:D008545', (137, 150))	('rs401681 [T', 'Var', (56, 67))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('skin melanoma', 'Disease', (137, 150))
640571	24386361	In the present case-control study, the rs401681 T allele was less frequent among the esophageal cancer cases than the controls, though this difference was not statistically significant.	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('less', 'NegReg', (61, 65))	('rs401681', 'Mutation', 'rs401681', (39, 47))	('rs401681 T', 'Var', (39, 49))	('esophageal cancer', 'Disease', (85, 102))
640572	24386361	Following adjustment for age, sex and smoking and drinking status in a multivariate logistic regression analysis, no significant association was found between rs401681 and the susceptibility to ESCC.	('rs401681', 'Var', (159, 167))	('ESCC', 'Disease', (194, 198))	('rs401681', 'Mutation', 'rs401681', (159, 167))
640573	24386361	Several studies have reported an association between short telomeres and an increased risk of esophageal cancer.	('esophageal cancer', 'Disease', (94, 111))	('short telomeres', 'Phenotype', 'HP:0031413', (53, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('short telomeres', 'Var', (53, 68))
640574	24386361	A previous genome-wide association study demonstrated that four SNPs (rs621559 on 1p34.2, rs398652 on 14q21, rs6028466 on 20q11.22 and rs654128 on 6q22.1) were associated with leukocyte telomere length in Caucasian populations.	('rs621559', 'Var', (70, 78))	('rs398652', 'Mutation', 'rs398652', (90, 98))	('rs654128', 'Mutation', 'rs654128', (135, 143))	('rs654128 on', 'Var', (135, 146))	('rs6028466 on', 'Var', (109, 121))	('leukocyte', 'MPA', (176, 185))	('rs6028466', 'Mutation', 'rs6028466', (109, 118))	('rs621559', 'Mutation', 'rs621559', (70, 78))	('rs398652 on', 'Var', (90, 101))	('associated', 'Reg', (160, 170))
640576	24386361	found that both rs621559 and rs398652 were significantly associated with ESCC risk in additive, recessive or dominant genetic models.	('rs621559', 'Mutation', 'rs621559', (16, 24))	('rs398652', 'Mutation', 'rs398652', (29, 37))	('rs621559', 'Var', (16, 24))	('rs398652', 'Var', (29, 37))	('ESCC', 'Disease', (73, 77))	('associated', 'Reg', (57, 67))
640577	24386361	However, in the present study, we detected no association between rs401681 and the risk of ESCC, although rs401681[C] has been reported to be associated with shorter telomeres with nominal significance.	('shorter', 'NegReg', (158, 165))	('rs401681', 'Mutation', 'rs401681', (106, 114))	('rs401681', 'Var', (66, 74))	('ESCC', 'Disease', (91, 95))	('rs401681', 'Mutation', 'rs401681', (66, 74))	('rs401681[', 'Var', (106, 115))
640579	24386361	In summary, our findings suggested that rs401681 may modify susceptibility to lung cancer but not ESCC.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('modify', 'Reg', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rs401681', 'Var', (40, 48))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('rs401681', 'Mutation', 'rs401681', (40, 48))
640721	31711920	We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('associated', 'Reg', (79, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (95, 120))	('esophageal adenocarcinoma or squamous cell carcinoma', 'Disease', 'MESH:D000077277', (95, 147))	('single-nucleotide variants', 'Var', (41, 67))
640726	31711920	A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P=.03).	('mutations', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
640729	31711920	In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival.	('metastasis', 'CPA', (176, 186))	('tumor', 'Disease', (157, 162))	('cancer', 'Disease', (110, 116))	('detection', 'Var', (118, 127))	('disease-specific survival', 'CPA', (192, 217))	('ctDNA', 'Gene', (131, 136))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('associated with', 'Reg', (141, 156))	('age', 'Gene', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('age', 'Gene', '5973', (104, 107))
640751	31711920	The set of mutations identified from tumor genotyping was assessed as a group in blood samples according to a previously described Monte Carlo framework .	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutations', 'Var', (11, 20))
640754	31711920	Mutations were defined as putative emergent mutations if they met the following criteria: Non-synonymous No variant reads in matched germline, pre-CRT plasma, or tumor and maximum of 1 variant read in the plasma of 20 healthy controls >=1500X deduped depth in pre- and post-CRT plasma, >= 500X depth in matched germline, >= 100X depth in tumor Recurrently mutated ESCA gene (> 5% of ESCA cBioportal samples) or >= 2 duplex reads Not in TP53 (known clonal hematopoiesis-associated gene) Our primary aim was to test the hypothesis that detection of ctDNA post-CRT is associated with high risk of recurrence.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('detection', 'Var', (534, 543))	('TP53', 'Gene', (436, 440))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (338, 343))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('hematopoiesis', 'Disease', (455, 468))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('associated', 'Reg', (565, 575))	('ctDNA', 'Gene', (547, 552))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('hematopoiesis', 'Disease', 'MESH:C536227', (455, 468))	('TP53', 'Gene', '7157', (436, 440))
640762	31711920	To interrogate the genetic alterations that are commonly found in ESCA, we developed a 185-kb cancer personalized profiling by deep sequencing (CAPP-Seq) panel targeting 802 regions from 607 genes harboring recurrent single-nucleotide variants (SNVs) in both EAC and ESCC (Table S2) by applying our previously described panel design strategy  to two published ESCA whole-exome datasets .	('ESCC', 'Disease', (267, 271))	('EAC', 'Disease', (259, 262))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('single-nucleotide variants', 'Var', (217, 243))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
640768	31711920	For the tumor-informed strategy, which is similar to that used in prior ctDNA MRD studies in other tumor types, we identified somatic variants in tumor biopsies after consideration of germline alleles within matched leukocytes.	('tumor', 'Disease', (99, 104))	('variants', 'Var', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
640780	31711920	To further explore factors affecting detectability of mutations in plasma, we next asked whether lower VAF tumor mutations were less likely to be detected in plasma than higher VAF tumor mutations.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('VAF tumor', 'Disease', 'MESH:D009369', (177, 186))	('VAF tumor', 'Disease', (177, 186))	('mutations', 'Var', (113, 122))	('lower', 'NegReg', (97, 102))	('VAF tumor', 'Disease', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('VAF tumor', 'Disease', 'MESH:D009369', (103, 112))
640781	31711920	Among patients with detectable ctDNA, we observed that tumor VAF was significantly higher for mutations present in cfDNA compared to mutations that were not.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mutations', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cfDNA', 'Gene', (115, 120))	('tumor', 'Disease', (55, 60))	('patients', 'Species', '9606', (6, 14))	('higher', 'PosReg', (83, 89))
640792	31711920	In order to minimize the likelihood of detecting mutations due to clonal hematopoiesis , we excluded mutations in TP53, the only gene in our panel implicated as being recurrently involved in clonal hematopoiesis as well as any mutations that were also observed in the matched leukocyte sample (see Methods).	('hematopoiesis', 'Disease', 'MESH:C536227', (198, 211))	('mutations', 'Var', (101, 110))	('hematopoiesis', 'Disease', 'MESH:C536227', (73, 86))	('hematopoiesis', 'Disease', (73, 86))	('TP53', 'Gene', '7157', (114, 118))	('hematopoiesis', 'Disease', (198, 211))	('TP53', 'Gene', (114, 118))
640795	31711920	Notably, unlike the other four patients with putative emergent mutations, EP30 underwent surgery 28 days following the post-CRT blood draw and was found to have residual tumor cells.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('patients', 'Species', '9606', (31, 39))	('EP30', 'Var', (74, 78))	('underwent', 'Reg', (79, 88))
640800	31711920	Emergent mutation analysis revealed a new ARID1A G696V mutation that was absent from the pre-CRT plasma, tumor, and matched leukocyte DNA.	('G696V', 'Var', (49, 54))	('ARID1A', 'Gene', '8289', (42, 48))	('ARID1A', 'Gene', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('G696V', 'Mutation', 'p.G696V', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
640820	31711920	Patients with detectable ctDNA post-CRT or DeltaTLG >= -48.5% had significantly increased risk of disease progression (P = .001; Fig.	('disease progression', 'CPA', (98, 117))	('Patients', 'Species', '9606', (0, 8))	('DeltaTLG', 'Var', (43, 51))
640831	31711920	Specifically, we found that detection of ctDNA MRD following CRT was strongly prognostic for FFP and DSS.	('FFP', 'Disease', (93, 96))	('ctDNA MRD', 'Var', (41, 50))	('prognostic', 'Reg', (78, 88))	('DSS', 'Chemical', '-', (101, 104))	('DSS', 'Disease', (101, 104))
640833	31711920	In this case, mutations detected following CRT were absent in post-surgery plasma and this patient did not develop recurrence, suggesting resection contributed to oncologic control.	('CRT', 'Gene', (43, 46))	('patient', 'Species', '9606', (91, 98))	('mutations', 'Var', (14, 23))
640850	31711920	Lastly, our observation of putative emergent mutations in a subset of patients must be interpreted with caution given that we cannot be entirely certain that these mutations are originating from tumor cells.	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
640851	31711920	However, given the strong association with disease recurrence it seems likely that the majority of emergent mutations arise from clonal selection of residual tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mutations', 'Var', (108, 117))
640882	31249757	The genetic hallmark of these tumors is supernumerary ring chromosomes that contain amplification of chromosome 12q13-15.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('amplification', 'Var', (84, 97))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('supernumerary ring chromosomes', 'CPA', (40, 70))
640923	30964241	pointed out that MPMNs share common genetic pathways with central nervous system meningiomas.8 On the other hand, several studies have indicated that MPMNs might be associated with chronic lung or serious cardiac diseases, such as thromboemboli, cardiac failure, chronic bronchitis and emphysema, and atypical adenomatous hyperplasia.9, 10 These diseases may stimulate the lung by stretching or stiffening the alveolar septa, or by causing hypoxia, ischemia, parenchymal destruction, or some combination of these factors, and then induce the formation of MPMNs, which is a nonspecific hyperplastic response to many forms of injury to the pulmonary interstitium.	('cardiac diseases', 'Disease', 'MESH:D006331', (205, 221))	('emphysema', 'Phenotype', 'HP:0002097', (286, 295))	('injury to the pulmonary', 'Disease', 'MESH:D055370', (624, 647))	('chronic lung', 'Disease', 'MESH:D055370', (181, 193))	('MPMN', 'Disease', 'None', (555, 559))	('hypoxia', 'Disease', 'MESH:D000860', (440, 447))	('diseases', 'Var', (346, 354))	('injury to the pulmonary', 'Disease', (624, 647))	('bronchitis', 'Disease', 'MESH:D001991', (271, 281))	('central nervous system meningiomas', 'Disease', 'MESH:D002493', (58, 92))	('cardiac failure', 'Disease', (246, 261))	('thromboemboli', 'Disease', 'MESH:D013923', (231, 244))	('ischemia', 'Disease', (449, 457))	('meningioma', 'Phenotype', 'HP:0002858', (81, 91))	('cardiac failure', 'Disease', 'MESH:D006333', (246, 261))	('cardiac failure', 'Phenotype', 'HP:0001635', (246, 261))	('thromboemboli', 'Disease', (231, 244))	('alveolar septa', 'Disease', (410, 424))	('induce', 'Reg', (531, 537))	('MPMN', 'Disease', 'None', (17, 21))	('stiffening', 'CPA', (395, 405))	('MPMN', 'Disease', (555, 559))	('emphysema', 'Disease', 'MESH:D004646', (286, 295))	('MPMN', 'Disease', (150, 154))	('alveolar septa', 'Disease', 'MESH:D002282', (410, 424))	('bronchitis', 'Phenotype', 'HP:0012387', (271, 281))	('parenchymal destruction', 'CPA', (459, 482))	('causing', 'Reg', (432, 439))	('meningiomas', 'Phenotype', 'HP:0002858', (81, 92))	('bronchitis', 'Disease', (271, 281))	('adenomatous hyperplasia', 'Disease', (310, 333))	('cardiac diseases', 'Disease', (205, 221))	('ischemia', 'Disease', 'MESH:D007511', (449, 457))	('central nervous system meningiomas', 'Disease', (58, 92))	('pulmonary interstitium', 'Phenotype', 'HP:0006530', (638, 660))	('chronic lung', 'Disease', (181, 193))	('emphysema', 'Disease', (286, 295))	('adenomatous hyperplasia', 'Disease', 'MESH:D011125', (310, 333))	('chronic bronchitis', 'Phenotype', 'HP:0004469', (263, 281))	('lung', 'CPA', (373, 377))	('hypoxia', 'Disease', (440, 447))	('MPMN', 'Disease', 'None', (150, 154))	('stimulate', 'PosReg', (359, 368))	('MPMN', 'Disease', (17, 21))
640949	30964241	3 was a 63-year-old woman diagnosed with cT3N1M1 stage IV squamous cell carcinoma of the lower thoracic esophagus (bilateral lung metastases).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (58, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinoma', 'Disease', (58, 81))	('woman', 'Species', '9606', (20, 25))	('bilateral lung metastases', 'Disease', (115, 140))	('cT3N1M1', 'Var', (41, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('bilateral lung metastases', 'Disease', 'MESH:D009362', (115, 140))
640991	30046565	Since aberrant expressions of miRNAs are found in gastroenterological cancers and miRNAs have been shown to regulate antitumor immunity, the combination therapy combining the traditional antibody-based immunotherapy and novel miRNA-based immunotherapy is promising for achieving clinical success.	('expressions', 'MPA', (15, 26))	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('miR', 'Gene', '220972', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('miR', 'Gene', (82, 85))	('gastroenterological cancers', 'Disease', (50, 77))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('aberrant', 'Var', (6, 14))	('tumor', 'Disease', (121, 126))	('miR', 'Gene', '220972', (226, 229))	('miR', 'Gene', (226, 229))	('gastroenterological cancers', 'Disease', 'MESH:D009369', (50, 77))	('regulate', 'Reg', (108, 116))	('gastroenterological cancer', 'Phenotype', 'HP:0007378', (50, 76))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
641000	30046565	The monoclonal antibodies antagonizing these cell growth driver molecules have achieved improved response rate (RR), progression-free survival (PFS), and overall survival (OS), demonstrating varying levels of success in colorectal and gastroesophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('antagonizing', 'Var', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('colorectal and gastroesophageal cancers', 'Disease', 'MESH:D015179', (220, 259))	('improved', 'PosReg', (88, 96))	('overall', 'MPA', (154, 161))	('response', 'MPA', (97, 105))
641005	30046565	The aberrant expressions of genetically or epigenetically altered proteins in cancers produce cancer specific antigens.	('epigenetically altered', 'Var', (43, 65))	('proteins', 'Protein', (66, 74))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('aberrant expressions', 'Var', (4, 24))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('genetically', 'Var', (28, 39))	('produce', 'Reg', (86, 93))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
641013	30046565	Therefore, immunotherapy using monoclonal antibody antagonizing the immunosuppressive cytokines or inactivating immunosuppressive cells can enhance anticancer immunity and inhibit tumor growth.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('enhance', 'PosReg', (140, 147))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('antagonizing', 'Var', (51, 63))	('inhibit', 'NegReg', (172, 179))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
641025	30046565	In gastroenterological cancers, expression of PD-L1 is linked to higher alpha-fetoprotein level, blood vessel invasion, and overall poor prognosis of hepatocellular carcinoma.	('PD-L1', 'Gene', (46, 51))	('gastroenterological cancer', 'Phenotype', 'HP:0007378', (3, 29))	('blood vessel invasion', 'CPA', (97, 118))	('expression', 'Var', (32, 42))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('gastroenterological cancers', 'Disease', (3, 30))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (150, 174))	('gastroenterological cancers', 'Disease', 'MESH:D009369', (3, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('higher', 'PosReg', (65, 71))	('hepatocellular carcinoma', 'Disease', (150, 174))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (150, 174))	('alpha-fetoprotein level', 'MPA', (72, 95))	('higher alpha-fetoprotein level', 'Phenotype', 'HP:0006254', (65, 95))
641028	30046565	Therefore, PD-L1 blockade can relieve tumor suppression, enhance tumor antigen-specific immunity, and improve prognosis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('prognosis', 'CPA', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('improve', 'PosReg', (102, 109))	('blockade', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('PD-L1', 'Gene', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('relieve', 'PosReg', (30, 37))	('enhance', 'PosReg', (57, 64))
641036	30046565	Peptide intratumor injection has been shown to enhance tumor cell antigenicity for specific cytotoxic T lymphocyte activity and be effective in inhibiting tumor growth and prolonging survival time.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (13, 18))	('enhance', 'PosReg', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('prolonging', 'PosReg', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('inhibiting', 'NegReg', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('Peptide', 'Var', (0, 7))	('survival time', 'CPA', (183, 196))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
641037	30046565	MicroRNAs (miRNAs) are a group of short (~ 22 nt), evolutionally conserved, single stranded noncoding RNA molecules that regulate expression of target genes by either cleaving mRNAs or destabilizing the translational system through interacting with sites of imperfect complementarity at 3' untranslated region (UTR) of target mRNAs.	('expression', 'MPA', (130, 140))	('regulate', 'Reg', (121, 129))	('interacting', 'Interaction', (232, 243))	('miR', 'Gene', '220972', (11, 14))	('mRNAs', 'MPA', (176, 181))	('cleaving', 'Var', (167, 175))	('miR', 'Gene', (11, 14))	('men', 'Species', '9606', (274, 277))	('translational system', 'MPA', (203, 223))	('destabilizing', 'NegReg', (185, 198))
641040	30046565	Dysregulation of miRNAs is associated with various diseases including Schizophrenia, obesity, alcoholism, and heart disease.	('heart disease', 'Disease', 'MESH:D006331', (110, 123))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('obesity', 'Disease', 'MESH:D009765', (85, 92))	('associated', 'Reg', (27, 37))	('alcoholism', 'Disease', (94, 104))	('Schizophrenia', 'Disease', 'MESH:D012559', (70, 83))	('Schizophrenia', 'Disease', (70, 83))	('obesity', 'Disease', (85, 92))	('heart disease', 'Disease', (110, 123))	('alcoholism', 'Disease', 'MESH:D000437', (94, 104))	('alcoholism', 'Phenotype', 'HP:0030955', (94, 104))	('obesity', 'Phenotype', 'HP:0001513', (85, 92))	('Schizophrenia', 'Phenotype', 'HP:0100753', (70, 83))
641041	30046565	Notably, dysregulation of miRNA expression profiles is common in most malignancies, and the deregulation of miRNAs may lead to creation of favorable environment for the development of hallmarks of cancer.	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('hallmarks of cancer', 'Disease', (184, 203))	('lead to', 'Reg', (119, 126))	('men', 'Species', '9606', (156, 159))	('men', 'Species', '9606', (176, 179))	('malignancies', 'Disease', 'MESH:D009369', (70, 82))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('deregulation', 'Var', (92, 104))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (184, 203))	('malignancies', 'Disease', (70, 82))	('dysregulation', 'Var', (9, 22))
641057	30046565	reported that the differentiation of FOXP3+CD4+ T regulatory cells and the tolerogenic property of dendritic cells could be enhanced by miR-23b through repressing the expression of NOTCH1 and the NF-kappaB (21406206).	('miR-23b', 'Gene', (136, 143))	('21406206', 'Var', (207, 215))	('NF-kappaB', 'Gene', '4790', (196, 205))	('differentiation', 'CPA', (18, 33))	('CD4', 'Gene', '920', (43, 46))	('repressing', 'NegReg', (152, 162))	('enhanced', 'PosReg', (124, 132))	('FOXP3', 'Gene', (37, 42))	('tolerogenic property of dendritic cells', 'CPA', (75, 114))	('NF-kappaB', 'Gene', (196, 205))	('NOTCH1', 'Gene', '4851', (181, 187))	('NOTCH1', 'Gene', (181, 187))	('CD4', 'Gene', (43, 46))	('expression', 'MPA', (167, 177))	('miR-23b', 'Gene', '407011', (136, 143))	('FOXP3', 'Gene', '50943', (37, 42))
641061	30046565	For each type of cancers, miRNAs possessing the following functions will be featured: (1) directly modulating the activation of immune cells (macrophages, CD+4 or CD+8 T cells, Tregs, NK cells, dendritic cells, etc.)	('Tregs', 'CPA', (177, 182))	('type of cancers', 'Disease', (9, 24))	('modulating', 'Reg', (99, 109))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('CD+8', 'Var', (163, 167))	('type of cancers', 'Disease', 'MESH:D009369', (9, 24))	('CD+4', 'Var', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
641072	30046565	Therefore, the new strategy that combines anti-PD-1 antibody and PD-L1 expression knockout would further remove the immune blockage imposed by PD-1/PD-L1 pathway.	('PD-1', 'Gene', (47, 51))	('PD-1', 'Gene', (143, 147))	('PD-1', 'Gene', '5133', (47, 51))	('remove', 'NegReg', (105, 111))	('PD-1', 'Gene', '5133', (143, 147))	('immune blockage', 'MPA', (116, 131))	('knockout', 'Var', (82, 90))	('PD-L1', 'Gene', (65, 70))	('immune blockage', 'Phenotype', 'HP:0002721', (116, 131))
641083	30046565	Inactivation of STAT3 leads to downregulation of miR-146a, which subsequently alters aforementioned STAT3-associated immunosuppressive cytokines profile and restores the function of NK cells and antitumor lymphocytes.	('tumor', 'Disease', (199, 204))	('STAT3', 'Gene', (100, 105))	('alters', 'Reg', (78, 84))	('men', 'Species', '9606', (90, 93))	('STAT3', 'Gene', '6774', (16, 21))	('NK cells', 'CPA', (182, 190))	('miR-146a', 'Gene', (49, 57))	('restores', 'PosReg', (157, 165))	('STAT3', 'Gene', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('STAT3', 'Gene', '6774', (100, 105))	('function', 'MPA', (170, 178))	('downregulation', 'NegReg', (31, 45))	('Inactivation', 'Var', (0, 12))	('miR-146a', 'Gene', '406938', (49, 57))
641087	30046565	These MICA/B-targeting miRNAs have been found to contribute to immune response evasion, and the epigenetic downregulation of MICA/B-targeting miRNAs by histone deacetylase inhibitor sensitizes HCC cells to the cytolytic effect of NK cells.	('MICA', 'Gene', (6, 10))	('epigenetic', 'Var', (96, 106))	('HCC', 'Gene', '619501', (193, 196))	('miR', 'Gene', '220972', (23, 26))	('MICA', 'Gene', (125, 129))	('miR', 'Gene', (23, 26))	('MICA', 'Gene', '100507436', (6, 10))	('MICA', 'Gene', '100507436', (125, 129))	('HCC', 'Phenotype', 'HP:0001402', (193, 196))	('downregulation', 'NegReg', (107, 121))	('sensitizes', 'Reg', (182, 192))	('HCC', 'Gene', (193, 196))	('miR', 'Gene', (142, 145))	('contribute', 'Reg', (49, 59))	('miR', 'Gene', '220972', (142, 145))	('immune response evasion', 'MPA', (63, 86))	('cytolytic', 'CPA', (210, 219))
641098	30046565	miR-122 inhibits HBV replication by suppressing the expression of cyclin G1, which can negatively regulate p53-mediated inhibition of HBV transcription.	('suppressing', 'NegReg', (36, 47))	('HBV', 'Gene', (17, 20))	('p53', 'Gene', (107, 110))	('cyclin G1', 'Gene', (66, 75))	('inhibits', 'NegReg', (8, 16))	('p53', 'Gene', '7157', (107, 110))	('expression', 'MPA', (52, 62))	('cyclin G1', 'Gene', '900', (66, 75))	('miR-122', 'Var', (0, 7))
641099	30046565	In addition, miR-122 has been found to suppress the interferon-stimulated response element (ISRE) mediated gene expression by enhancing methylation at gene promoter of suppressor of cytokine signaling 3 (SOCS3) and subsequently increasing expression of SOCS3 in liver cells.	('SOCS3', 'Gene', (253, 258))	('expression', 'MPA', (239, 249))	('men', 'Species', '9606', (86, 89))	('increasing', 'PosReg', (228, 238))	('suppressor of cytokine signaling 3', 'Gene', (168, 202))	('enhancing', 'PosReg', (126, 135))	('SOCS3', 'Gene', '9021', (204, 209))	('miR-122', 'Var', (13, 20))	('suppress', 'NegReg', (39, 47))	('SOCS3', 'Gene', '9021', (253, 258))	('suppressor of cytokine signaling 3', 'Gene', '9021', (168, 202))	('methylation', 'MPA', (136, 147))	('SOCS3', 'Gene', (204, 209))
641100	30046565	Therefore, silencing miR-122 can improve response of liver cells to interferon-alpha in treatment against hepatic B or C, which are major causes of liver cirrhosis and cancer.	('silencing', 'Var', (11, 20))	('improve', 'PosReg', (33, 40))	('liver cirrhosis', 'Disease', (148, 163))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (148, 163))	('men', 'Species', '9606', (93, 96))	('cirrhosis', 'Phenotype', 'HP:0001394', (154, 163))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('response', 'MPA', (41, 49))	('hepatic', 'Disease', (106, 113))	('liver cirrhosis', 'Disease', 'MESH:D008103', (148, 163))	('cancer', 'Disease', (168, 174))	('miR-122', 'Gene', (21, 28))
641105	30046565	The expression of miR-122 is downregulated in human HCC patients, and the deletion of miR-122 in hepatocytes leads to progressive development of stages of liver cancer: steatohepatitis, inflammation, hepatocyte regeneration, fibrosis, cirrhosis, and primary and metastatic HCC.	('HCC', 'Gene', (273, 276))	('patients', 'Species', '9606', (56, 64))	('liver cancer', 'Phenotype', 'HP:0002896', (155, 167))	('expression', 'MPA', (4, 14))	('liver cancer', 'Disease', (155, 167))	('hepatocyte regeneration', 'CPA', (200, 223))	('men', 'Species', '9606', (137, 140))	('fibrosis', 'Disease', 'MESH:D005355', (225, 233))	('fibrosis', 'Disease', (225, 233))	('hepatitis', 'Phenotype', 'HP:0012115', (175, 184))	('inflammation', 'Disease', 'MESH:D007249', (186, 198))	('cirrhosis', 'Disease', 'MESH:D005355', (235, 244))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('human', 'Species', '9606', (46, 51))	('steatohepatitis', 'Disease', 'MESH:D005234', (169, 184))	('leads to', 'Reg', (109, 117))	('cirrhosis', 'Phenotype', 'HP:0001394', (235, 244))	('miR-122', 'Gene', (18, 25))	('primary', 'Disease', (250, 257))	('inflammation', 'Disease', (186, 198))	('cirrhosis', 'Disease', (235, 244))	('steatohepatitis', 'Disease', (169, 184))	('downregulated', 'NegReg', (29, 42))	('HCC', 'Gene', '619501', (52, 55))	('miR-122', 'Gene', (86, 93))	('HCC', 'Phenotype', 'HP:0001402', (52, 55))	('deletion', 'Var', (74, 82))	('HCC', 'Gene', '619501', (273, 276))	('liver cancer', 'Disease', 'MESH:D006528', (155, 167))	('HCC', 'Gene', (52, 55))	('HCC', 'Phenotype', 'HP:0001402', (273, 276))
641106	30046565	The loss of miR-122 has been associated with metastasis and poor prognosis of HCCs, whereas the restoration of ectopic miR-122 suppresses cell replication and invasion, inhibits angiogenesis, and sensitizes the liver cancer cells to sorafenib.	('miR-122', 'Gene', (12, 19))	('liver cancer', 'Phenotype', 'HP:0002896', (211, 223))	('liver cancer', 'Disease', (211, 223))	('HCC', 'Gene', '619501', (78, 81))	('HCC', 'Phenotype', 'HP:0001402', (78, 81))	('associated', 'Reg', (29, 39))	('loss', 'Var', (4, 8))	('metastasis', 'CPA', (45, 55))	('HCC', 'Gene', (78, 81))	('ectopic', 'Var', (111, 118))	('sorafenib', 'Chemical', 'MESH:D000077157', (233, 242))	('restoration', 'Var', (96, 107))	('miR-122', 'Gene', (119, 126))	('suppresses', 'NegReg', (127, 137))	('sensitizes', 'Reg', (196, 206))	('angiogenesis', 'CPA', (178, 190))	('cell replication', 'CPA', (138, 154))	('liver cancer', 'Disease', 'MESH:D006528', (211, 223))	('inhibits', 'NegReg', (169, 177))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
641108	30046565	Mice with miR-122 knockout develops chronic inflammation that progresses to HCC since miR-122 deletion leads to upregulation of chemokine (C-C motif) ligand 2 (CCL2) in liver.	('HCC', 'Gene', '619501', (76, 79))	('miR-122', 'Gene', (86, 93))	('deletion', 'Var', (94, 102))	('HCC', 'Phenotype', 'HP:0001402', (76, 79))	('inflammation', 'Disease', 'MESH:D007249', (44, 56))	('upregulation', 'PosReg', (112, 124))	('inflammation', 'Disease', (44, 56))	('HCC', 'Gene', (76, 79))	('Mice', 'Species', '10090', (0, 4))	('chemokine (C-C motif) ligand 2', 'Gene', '20296', (128, 158))
641145	30046565	A common G/C SNP polymorphism rs2910164, which is located in the crucial seed sequence of the mir-146a, is found to affect the expression of mature miR-146a and is correlated to the increased chronic pancreatitis risk.	('correlated to', 'Reg', (164, 177))	('pancreatitis', 'Phenotype', 'HP:0001733', (200, 212))	('expression', 'MPA', (127, 137))	('miR-146a', 'Gene', '406938', (148, 156))	('pancreatitis', 'Disease', 'MESH:D010195', (200, 212))	('mir-146a', 'Gene', (94, 102))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (192, 212))	('affect', 'Reg', (116, 122))	('rs2910164', 'Var', (30, 39))	('rs2910164', 'Mutation', 'rs2910164', (30, 39))	('miR-146a', 'Gene', (148, 156))	('mir-146a', 'Gene', '406938', (94, 102))	('pancreatitis', 'Disease', (200, 212))
641211	30046565	The inflammatory response to lysolecithin disrupts the extracellular microenvironment causing an influx in inflammatory cytokines.	('extracellular microenvironment', 'MPA', (55, 85))	('lysolecithin', 'Chemical', 'MESH:D008244', (29, 41))	('influx in inflammatory cytokines', 'MPA', (97, 129))	('lysolecithin', 'Var', (29, 41))
641215	30046565	However, such an inflammatory response can thus lead to mutations and overexpression of cell-cycle associated proteins such as p53 and MUCI.	('MUCI', 'Gene', (135, 139))	('mutations', 'Var', (56, 65))	('lead to', 'Reg', (48, 55))	('p53', 'Gene', '7157', (127, 130))	('overexpression', 'PosReg', (70, 84))	('p53', 'Gene', (127, 130))
641216	30046565	The implications of p53 mutations has been shown to potentiate atypical hyperplasia, thus resulting in lesions and subsequent malignancy.	('hyperplasia', 'Disease', (72, 83))	('p53', 'Gene', (20, 23))	('malignancy', 'Disease', 'MESH:D009369', (126, 136))	('p53', 'Gene', '7157', (20, 23))	('malignancy', 'Disease', (126, 136))	('lesions', 'Disease', (103, 110))	('hyperplasia', 'Disease', 'MESH:D006965', (72, 83))	('potentiate', 'PosReg', (52, 62))	('resulting in', 'Reg', (90, 102))	('mutations', 'Var', (24, 33))
641221	30046565	demonstrated that, along with P53, K-ras mutations have also been studied as biomarkers in GBC with PBM, with K-ras being a well understood and studied prooncogene.	('mutations', 'Var', (41, 50))	('K-ras', 'Gene', (35, 40))	('K-ras', 'Gene', '3845', (35, 40))	('P53', 'Gene', (30, 33))	('K-ras', 'Gene', (110, 115))	('P53', 'Gene', '7157', (30, 33))	('K-ras', 'Gene', '3845', (110, 115))	('GBC', 'Disease', (91, 94))	('PBM', 'Disease', (100, 103))	('PBM', 'Chemical', '-', (100, 103))
641244	30046565	In EAC it was found that the lncRNA AFAP1-AS1 was subsequently overexpressed due to hypomethylated DNA regions in the transcriptome of EAC cells.	('AS1', 'Gene', '5729', (42, 45))	('overexpressed', 'PosReg', (63, 76))	('AP', 'Phenotype', 'HP:0001735', (38, 40))	('AFAP1', 'Gene', (36, 41))	('hypomethylated', 'Var', (84, 98))	('AFAP1', 'Gene', '60312', (36, 41))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('AS1', 'Gene', (42, 45))	('EAC', 'Phenotype', 'HP:0011459', (135, 138))
641252	30046565	These mi-RNAs were shown to target MALAT1 consequentially silencing its tumor-promoting action.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('MALAT1', 'Gene', '378938', (35, 41))	('tumor', 'Disease', (72, 77))	('MALAT1', 'Gene', (35, 41))	('mi-RNAs', 'Var', (6, 13))	('silencing', 'NegReg', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
641274	30046565	This expression was notably downregulated by the mutant p53 variant.	('expression', 'MPA', (5, 15))	('mutant', 'Var', (49, 55))	('p53', 'Gene', (56, 59))	('variant', 'Var', (60, 67))	('downregulated', 'NegReg', (28, 41))	('p53', 'Gene', '7157', (56, 59))
641275	30046565	Through the patient specific regulation of the wild type p53/p21 pathway miR-34a can be used as a diagnostic marker for therapeutic effectiveness in p53 mutant ESCC.	('miR-34a', 'Gene', '407040', (73, 80))	('p53', 'Gene', '7157', (57, 60))	('p53', 'Gene', (149, 152))	('p21', 'Gene', '644914', (61, 64))	('p53', 'Gene', '7157', (149, 152))	('miR-34a', 'Gene', (73, 80))	('mutant', 'Var', (153, 159))	('p53', 'Gene', (57, 60))	('patient', 'Species', '9606', (12, 19))	('p21', 'Gene', (61, 64))
641342	27788489	This study demonstrated the value of LNM in DLNS in predicting prognosis in surgical ESCC patients, which outperformed those from N-DLNS.	('patients', 'Species', '9606', (90, 98))	('LNM', 'Var', (37, 40))	('DLNS', 'Var', (44, 48))	('surgical ESCC', 'Disease', (76, 89))
641368	27788489	We excluded 13 cases with HLN<16 in the Kaplan-Meier survival analysis and Cox regression to reduce potential interference from inaccurate staging in our results.	('Cox', 'Gene', '1351', (75, 78))	('Cox', 'Gene', (75, 78))	('HLN<16', 'Var', (26, 32))
641370	27788489	The survival curves generated by the Cox regression modeling for the association of LNM in DLNS and N-DLNS with prognosis, Table 3, also demonstrate a poorer prognosis for DLNS+ groups than for N-DLNS+ groups (Figure 3C and 3D).	('DLNS+', 'Var', (172, 177))	('poorer', 'NegReg', (151, 157))	('Cox', 'Gene', '1351', (37, 40))	('Cox', 'Gene', (37, 40))
641371	27788489	Furthermore, the model illustrates that N-DLNS+ did not indicate poorer survival when compared with pN0 cases (P=0.348, P=0.714 for OS and DFS, respectively), while DLNS metastases reduced the survival rate (for OS, HR=1.720, 95% CI=1.017-2.911, P<0.001; for DFS, HR=1.767, 95% CI=1.099-2.840, P=0.001).	('reduced', 'NegReg', (181, 188))	('survival', 'MPA', (193, 201))	('DLNS', 'Var', (165, 169))	('metastases', 'Disease', (170, 180))	('metastases', 'Disease', 'MESH:D009362', (170, 180))
641456	28250904	Recently, modified POEM with shorter submucosal tunnel was confirmed to have good safety and excellent short-term efficacy for achalasia, even for the sigmoid-type.	('achalasia', 'Disease', 'MESH:D004931', (127, 136))	('achalasia', 'Phenotype', 'HP:0002571', (127, 136))	('modified', 'Var', (10, 18))	('achalasia', 'Disease', (127, 136))
641489	26456220	After HMBOX1 siRNA knockdown for 24 h, some cells detached from the substratum and became round.	('knockdown', 'Var', (19, 28))	('HMBOX1', 'Gene', (6, 12))	('rat', 'Species', '10116', (73, 76))
641491	26456220	With HMBOX1 siRNA knockdown, cells showed nuclear condensation and fragmentation, characteristics of apoptosis by the acridine orange (AO) and Hoechst stainings (Fig.	('knockdown', 'Var', (18, 27))	('AO', 'Chemical', 'MESH:D000165', (135, 137))	('HMBOX1', 'Gene', (5, 11))	('Hoechst', 'Chemical', '-', (143, 150))	('nuclear condensation', 'CPA', (42, 62))	('acridine orange', 'Chemical', 'MESH:D000165', (118, 133))
641493	26456220	In addition, HMBOX1 knockdown induced cleaved caspase-8 level, but not cleaved caspase-9 level as compared with scramble siRNA treatment (Supplementary Fig.	('induced', 'Reg', (30, 37))	('caspase-8', 'Gene', (46, 55))	('HMBOX1', 'Gene', (13, 19))	('caspase-9', 'Gene', '842', (79, 88))	('knockdown', 'Var', (20, 29))	('caspase-8', 'Gene', '841', (46, 55))	('caspase-9', 'Gene', (79, 88))
641494	26456220	We also used AnnexinV-FITC/PI staining and flow cytometry assay to determine the the extent of apoptosis after HMBOX1 knockdown.	('HMBOX1', 'Gene', (111, 117))	('AnnexinV-FITC', 'Chemical', '-', (13, 26))	('knockdown', 'Var', (118, 127))
641499	26456220	HUVECs were transfected with pCMV-HMBOX1 for 24 h, and then deprived of FGF-2 for 6 or 12 h to induce apoptosis.	('pCMV-HMBOX1', 'Var', (29, 40))	('induce', 'Reg', (95, 101))	('FGF-2', 'Gene', (72, 77))	('FGF-2', 'Gene', '2247', (72, 77))
641504	26456220	In addition, the results from AnnexinV-FITC/PI staining and flow cytometry assay also showed that the proportion of apoptotic cells decreased to 7.4% with pCMV-HMBOX1 after FGF-2 deprivation for 12 h, from 22.7% with pRC-CMV (Fig.	('apoptotic cells', 'CPA', (116, 131))	('FGF-2', 'Gene', (173, 178))	('AnnexinV-FITC', 'Chemical', '-', (30, 43))	('to 7', 'Species', '1214577', (142, 146))	('decreased', 'NegReg', (132, 141))	('pCMV-HMBOX1', 'Var', (155, 166))	('FGF-2', 'Gene', '2247', (173, 178))
641507	26456220	Consistently, immunofluorescence assay showed decreased proportion of cells containing LC3B puncta (>5) in cells transfected with HMBOX1 siRNA and increased in cells with pCMV-HMBOX1 transfection (Fig.	('increased', 'PosReg', (147, 156))	('LC3B', 'Gene', (87, 91))	('decreased', 'NegReg', (46, 55))	('LC3B', 'Gene', '81631', (87, 91))	('HMBOX1', 'Var', (130, 136))
641508	26456220	Moreover, the phosphorylation of 4E-binding protein 1 (4EBP1) and p70S6K, downstream targets of mTOR, was increased with HMBOX1 siRNA (Fig.	('mTOR', 'Gene', (96, 100))	('4EBP1', 'Gene', '1978', (55, 60))	('HMBOX1', 'Var', (121, 127))	('4EBP1', 'Gene', (55, 60))	('phosphorylation', 'MPA', (14, 29))	('p70S6K', 'Gene', '6198', (66, 72))	('p70S6K', 'Gene', (66, 72))	('mTOR', 'Gene', '2475', (96, 100))	('increased', 'PosReg', (106, 115))	('4E-binding protein 1', 'Gene', '1978', (33, 53))	('4E-binding protein 1', 'Gene', (33, 53))
641519	26456220	HMBOX1 siRNA treatment decreased the level of intracellular free zinc and pCMV-HMBOX1 overexpression increased labile zinc concentration by almost two-fold as compared with pRC-CMV treatment (Fig.	('level of intracellular free zinc', 'MPA', (37, 69))	('labile zinc concentration', 'MPA', (111, 136))	('pCMV-HMBOX1', 'Var', (74, 85))	('increased', 'PosReg', (101, 110))	('rat', 'Species', '10116', (130, 133))	('decreased', 'NegReg', (23, 32))
641525	26456220	And without MT2A, pCMV-HMBOX1 overexpression could no longer increase the zinc level (Fig.	('zinc level', 'MPA', (74, 84))	('MT2A', 'Gene', '4502', (12, 16))	('increase', 'PosReg', (61, 69))	('MT2A', 'Gene', (12, 16))	('pCMV-HMBOX1', 'Var', (18, 29))
641527	26456220	With MT2A knockdown, the level of intracellular zinc could not be increased by HMBOX1 overexpression in HUVECs.	('MT2A', 'Gene', '4502', (5, 9))	('knockdown', 'Var', (10, 19))	('MT2A', 'Gene', (5, 9))
641529	26456220	HUVECs were transfected with pCMV-HMBOX1 for 24 h, then FGF-2-deprived for 12 h to induce cell apoptosis.	('pCMV-HMBOX1', 'Var', (29, 40))	('induce', 'Reg', (83, 89))	('FGF-2', 'Gene', (56, 61))	('FGF-2', 'Gene', '2247', (56, 61))
641534	26456220	Consistently, immunofluorescence assay revealed an increased proportion of cells with LC3B puncta (>5) induced by pCMV-HMBOX1, which was reversed with TPEN (Fig.	('TPEN', 'Chemical', '-', (151, 155))	('increased', 'PosReg', (51, 60))	('LC3B', 'Gene', (86, 90))	('pCMV-HMBOX1', 'Var', (114, 125))	('LC3B', 'Gene', '81631', (86, 90))
641557	26456220	With HMBOX1 knockdown, the interacting MT2A proteins were separated to bind zinc in the cytoplasm, which decreased the intracellular free zinc level.	('HMBOX1', 'Gene', (5, 11))	('intracellular free zinc level', 'MPA', (119, 148))	('knockdown', 'Var', (12, 21))	('bind', 'Interaction', (71, 75))	('rat', 'Species', '10116', (62, 65))	('MT2A', 'Gene', '4502', (39, 43))	('decreased', 'NegReg', (105, 114))	('MT2A', 'Gene', (39, 43))
641567	26456220	beta-actin (A5441) and MT2A (SAB1402848) from Sigma-Aldrich (USA); antibodies for caspase-8 (9746), caspase-9 (9502), poly (ADP-ribose) polymerase (PARP, 9542S), LC3B (2775S), phospho-p70S6K (p-p70S6K; 9206S), p70S6K (9202S), p-4EBP1 (9459S), and 4EBP1 (9452S) were from Cell Signaling Technology (USA).	('9202S', 'Var', (218, 223))	('poly (ADP-ribose) polymerase', 'Gene', (118, 146))	('poly (ADP-ribose) polymerase', 'Gene', '142', (118, 146))	('PARP', 'Gene', '142', (148, 152))	('beta-actin', 'Gene', (0, 10))	('LC3B', 'Gene', (162, 166))	('4EBP1', 'Gene', (228, 233))	('caspase-9', 'Gene', '842', (100, 109))	('PARP', 'Gene', (148, 152))	('caspase-8', 'Gene', (82, 91))	('4EBP1', 'Gene', '1978', (247, 252))	('MT2A', 'Gene', (23, 27))	('p70S6K', 'Gene', '6198', (194, 200))	('LC3B', 'Gene', '81631', (162, 166))	('beta-actin', 'Gene', '728378', (0, 10))	('p70S6K', 'Gene', '6198', (210, 216))	('p70S6K', 'Gene', '6198', (184, 190))	('caspase-9', 'Gene', (100, 109))	('4EBP1', 'Gene', '1978', (228, 233))	('9746', 'Var', (93, 97))	('p70S6K', 'Gene', (194, 200))	('4EBP1', 'Gene', (247, 252))	('caspase-8', 'Gene', '841', (82, 91))	('2775S', 'Var', (168, 173))	('p70S6K', 'Gene', (210, 216))	('p70S6K', 'Gene', (184, 190))	('MT2A', 'Gene', '4502', (23, 27))
641572	26456220	TPEN (P4413) and Bafilomycin A1 (B1793) purchased from Sigma-Aldrich (USA).	('Bafilomycin A1', 'Chemical', 'MESH:C040929', (17, 31))	('B1793', 'Var', (33, 38))	('P4413', 'Var', (6, 11))	('TPEN', 'Chemical', '-', (0, 4))
641600	26456220	The cDNA constructs encoding wild-type HMBOX1 subunit (pCMV-HMBOX1) (Origene, SC319800), empty vector (pRC-CMV), pEGFP or pEGFP-MT2A (Origene, RG202748) were transfected by use of Lipofectamine 2000 reagent (Invitrogen, 11668-019).	('MT2A', 'Gene', (128, 132))	('pEGFP', 'Var', (113, 118))	('Lipofectamine 2000 reagent', 'Chemical', '-', (180, 206))	('MT2A', 'Gene', '4502', (128, 132))
641609	26160986	Furthermore, in a combined analysis, patients with low EphA7-expressing tumors showed a shorter overall survival than those with high expression, resulting in a five-year overall survival rate of 47.4% vs. 52.6%, respectively (p=0.016).	('shorter', 'NegReg', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('patients', 'Species', '9606', (37, 45))	('EphA7', 'Gene', '2045', (55, 60))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('overall survival', 'MPA', (96, 112))	('low', 'Var', (51, 54))	('EphA7', 'Gene', (55, 60))
641661	26160986	Significant association between low cytoplasmic EphA7 expression and lymph node metastasis was observed (rs=0.344; p<0.001).	('EphA7', 'Gene', '2045', (48, 53))	('low cytoplasmic', 'Var', (32, 47))	('EphA7', 'Gene', (48, 53))	('lymph node metastasis', 'CPA', (69, 90))
641666	26160986	The survival rate of patients with low EphA7 expression was significantly lower than in patients with high EphA7 expression (5-year survival rate 52.6% vs 47.4%, respectively; p=0.016; Fig.	('EphA7', 'Gene', (39, 44))	('EphA7', 'Gene', '2045', (107, 112))	('patients', 'Species', '9606', (88, 96))	('survival', 'CPA', (4, 12))	('patients', 'Species', '9606', (21, 29))	('EphA7', 'Gene', '2045', (39, 44))	('low', 'Var', (35, 38))	('lower', 'NegReg', (74, 79))	('EphA7', 'Gene', (107, 112))
641672	26160986	It has been reported that high EphA2 expression results in poor survival in ESCC.	('EphA2', 'Gene', (31, 36))	('high', 'Var', (26, 30))	('survival', 'MPA', (64, 72))	('EphA2', 'Gene', '1969', (31, 36))	('poor', 'NegReg', (59, 63))	('expression', 'MPA', (37, 47))	('ESCC', 'Disease', (76, 80))
641682	26160986	We speculate that the result was attributed to truncated EphA7 protein expression in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EphA7', 'Gene', (57, 62))	('EphA7', 'Gene', '2045', (57, 62))	('truncated', 'Var', (47, 56))	('esophageal cancer', 'Disease', (85, 102))
641685	26160986	Previous studies demonstrated that high EphA7 expression was closely related to carcinogenesis, progression, clinical biological behaviors, and prognosis of glioblastoma multiforme and gallbladder adenocarcinoma.	('gallbladder adenocarcinoma', 'Disease', (185, 211))	('EphA7', 'Gene', '2045', (40, 45))	('glioblastoma multiforme', 'Disease', (157, 180))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (157, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('EphA7', 'Gene', (40, 45))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (185, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))	('related', 'Reg', (69, 76))	('carcinogenesis', 'Disease', (80, 94))
641689	26160986	Tyrosine phosphorylation of Eph/Eprin system promotes cellular transformation, invasion, proliferation, and also inhibits cellular spread or migration mediated via JAK2, PI3K or ILK signal transduction pathways.	('proliferation', 'CPA', (89, 102))	('Eph', 'Gene', '2041', (28, 31))	('JAK2', 'Gene', '3717', (164, 168))	('Tyrosine phosphorylation', 'Var', (0, 24))	('cellular spread', 'CPA', (122, 137))	('Eph', 'Gene', (28, 31))	('ILK', 'Gene', (178, 181))	('cellular transformation', 'CPA', (54, 77))	('promotes', 'PosReg', (45, 53))	('JAK2', 'Gene', (164, 168))	('Tyrosine', 'Chemical', 'MESH:D014443', (0, 8))	('ILK', 'Gene', '3611', (178, 181))	('invasion', 'CPA', (79, 87))	('inhibits', 'NegReg', (113, 121))
641690	26160986	However, downregulation of EphA7 resulting from methylation in human colorectal cancer leads to biological and histopathological effects associated with carcinogenesis and differentiation.	('downregulation', 'NegReg', (9, 23))	('carcinogenesis', 'Disease', (153, 167))	('EphA7', 'Gene', '2045', (27, 32))	('human', 'Species', '9606', (63, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (153, 167))	('colorectal cancer', 'Disease', (69, 86))	('EphA7', 'Gene', (27, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('methylation', 'Var', (48, 59))
641700	20951943	Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity.	('Fbx4', 'Gene', (50, 54))	('nuclear cyclin D1 accumulation', 'MPA', (89, 119))	('human', 'Species', '9606', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('increased', 'PosReg', (124, 133))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('mutations', 'Var', (37, 46))	('PRMT5 activity', 'CPA', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
641714	20951943	Association of cyclin D1T286A with PRMT5 in concert with previous work demonstrating that cyclin D1T286A reduces CUL4A/B expression in a CDK4-dependent manner suggested a potential regulatory relationship involving cyclin D1T286A and chromatin modifying proteins.	('cyclin', 'Var', (90, 96))	('CUL4A/B', 'Gene', '8451;8450', (113, 120))	('CUL4A/B', 'Gene', (113, 120))	('expression', 'MPA', (121, 131))	('reduces', 'NegReg', (105, 112))
641715	20951943	To interrogate this putative relationship, we co-expressed Myc-PRMT5 together with CDK4 and either wild type cyclin D1 or D1T286A in HeLa cells.	('T286', 'Chemical', '-', (124, 128))	('Myc', 'Gene', '4609', (59, 62))	('D1T286A', 'Var', (122, 129))	('Myc', 'Gene', (59, 62))	('HeLa', 'CellLine', 'CVCL:0030', (133, 137))
641725	20951943	Knockdown of PRMT5 also reduced H4R3 and H3R8 methylation but did not change levels of PRMT1, 2, and 7 (Figure 2E).	('Knockdown', 'Var', (0, 9))	('H4R3', 'Protein', (32, 36))	('reduced', 'NegReg', (24, 31))	('H3R8', 'Protein', (41, 45))	('PRMT1', 'Gene', '3276', (87, 92))	('PRMT1', 'Gene', (87, 92))	('methylation', 'MPA', (46, 57))	('PRMT5', 'Gene', (13, 18))
641726	20951943	We confirmed previous observations that regulation of CUL4 and CDT1 requires the kinase activity of CDK4 as expression of a kinase defective mutant, CDK4(K35M), does not support cyclin D1T286A-dependent CUL4 loss and eliminates the impact of PRMT5 knockdown (Figure 2F).	('CDK4', 'Var', (149, 153))	('T286', 'Chemical', '-', (187, 191))	('CDT1', 'Gene', (63, 67))	('K35M', 'Mutation', 'p.K35M', (154, 158))	('CUL4', 'Chemical', '-', (203, 207))	('eliminates', 'NegReg', (217, 227))	('loss', 'NegReg', (208, 212))	('CUL4', 'Chemical', '-', (54, 58))	('CDT1', 'Gene', '81620', (63, 67))
641727	20951943	Further supporting a role for PRMT5 activity downstream of cyclin D1, esophageal cancer cells harboring the mutant cyclin D1 P287A exhibited increased CDT1, decreased CUL4A, and increased H4R3 methylation compared to cells with wild type cyclin D1 (Figure S2F).	('P287A', 'Mutation', 'rs367567016', (125, 130))	('CDT1', 'Gene', (151, 155))	('P287A', 'Var', (125, 130))	('cyclin D1', 'Gene', (115, 124))	('esophageal cancer', 'Disease', (70, 87))	('increased', 'PosReg', (141, 150))	('H4R3', 'Protein', (188, 192))	('mutant', 'Var', (108, 114))	('methylation', 'MPA', (193, 204))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('CDT1', 'Gene', '81620', (151, 155))	('CUL4A', 'Gene', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('decreased', 'NegReg', (157, 166))	('CUL4A', 'Gene', '8451', (167, 172))	('increased', 'PosReg', (178, 187))
641728	20951943	Since attenuation of PRMT5 relieves CUL4 repression, we questioned whether cyclin D1T286A regulates HDAC activity, contributing to CUL4 repression.	('relieves', 'NegReg', (27, 35))	('HDAC', 'Gene', '9734', (100, 104))	('CUL4 repression', 'MPA', (131, 146))	('CUL4', 'Chemical', '-', (131, 135))	('CUL4 repression', 'MPA', (36, 51))	('CUL4', 'Chemical', '-', (36, 40))	('PRMT5', 'Gene', (21, 26))	('HDAC', 'Gene', (100, 104))	('attenuation', 'Var', (6, 17))
641732	20951943	Methylated H3R8 was elevated in tumors compared to non-transgenic controls (Figures 3A and S3A; see Figure S3C for H3R8 antibody specificity).	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('H3R8', 'Protein', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('elevated', 'PosReg', (20, 28))	('Methylated', 'Var', (0, 10))	('tumors', 'Disease', (32, 38))	('transgenic', 'Species', '10090', (55, 65))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
641736	20951943	Given the increase in total H4R3/H3R8 methylation, we determined whether there was an increase in H4R3/H3R8 methylation on the proximal CUL4A/B promoter regions by ChIP using antibodies detecting di-methylated H4R3 and di-methylated H3R8 (see Figure S3D for primer design).	('methylation', 'MPA', (38, 49))	('increase', 'PosReg', (86, 94))	('CUL4A/B', 'Gene', '8451;8450', (136, 143))	('di-methylated', 'Var', (219, 232))	('CUL4A/B', 'Gene', (136, 143))	('di-methylated', 'Var', (196, 209))	('methylation', 'MPA', (108, 119))	('H4R3/H3R8', 'Gene', (28, 37))	('increase', 'PosReg', (10, 18))
641737	20951943	We observed an ~2-3 fold increase in methylation of both H4R3 and H3R8 at the proximal promoter regions (~500bp upstream of the first coding exon) of CUL4A (Figure 3D) and CUL4B (Figure S3E) in the presence of cyclin D1T286A/CDK4 as compared to cyclin D1/CDK4 or untransfected controls in S-phase HeLa cells.	('CUL4A', 'Gene', '8451', (150, 155))	('CUL4B', 'Gene', '8450', (172, 177))	('HeLa', 'CellLine', 'CVCL:0030', (297, 301))	('H4R3', 'Gene', (57, 61))	('cyclin D1T286A/CDK4', 'Var', (210, 229))	('CUL4A', 'Gene', (150, 155))	('increase', 'PosReg', (25, 33))	('T286', 'Chemical', '-', (219, 223))	('H3R8', 'Gene', (66, 70))	('methylation', 'MPA', (37, 48))	('CUL4B', 'Gene', (172, 177))
641740	20951943	Critically, siRNA-mediated knockdown of PRMT5 resulted in significant attenuation of cyclin D1T286A/CDK4 dependent H4R3/H3R8 methylation at CUL4A/B promoter regions during S-phase (Figure 3E).	('knockdown', 'Var', (27, 36))	('CUL4A/B', 'Gene', '8451;8450', (140, 147))	('H4R3/H3R8', 'Protein', (115, 124))	('methylation', 'MPA', (125, 136))	('PRMT5', 'Gene', (40, 45))	('CUL4A/B', 'Gene', (140, 147))	('attenuation', 'NegReg', (70, 81))	('cyclin D1T286A/CDK4', 'Protein', (85, 104))
641747	20951943	MEP50 contains four putative CDK phosphorylation sites: Thr-5, Ser-176, Ser-264, and Ser-306 (Figure S4A).	('Ser', 'Chemical', 'MESH:D012694', (63, 66))	('Ser-176', 'Var', (63, 70))	('Ser-306', 'Var', (85, 92))	('Ser', 'Chemical', 'MESH:D012694', (72, 75))	('Ser', 'Chemical', 'MESH:D012694', (85, 88))	('Thr', 'Chemical', 'MESH:D013912', (56, 59))	('Ser-264', 'Var', (72, 79))
641748	20951943	Consistent with MEP50 being a direct substrate, recombinant MEP50 was phosphorylated by cyclin D1/CDK4 and D1T286A/CDK4 in vitro (Figure 4B; S4B).	('cyclin D1/CDK4', 'Protein', (88, 102))	('phosphorylated', 'MPA', (70, 84))	('T286', 'Chemical', '-', (109, 113))	('D1T286A/CDK4', 'Var', (107, 119))	('MEP50', 'Gene', (60, 65))
641751	20951943	We generated recombinant MEP50 proteins harboring alanine substitutions at all four putative CDK phosphorylation sites and used these as substrates.	('alanine substitutions', 'Var', (50, 71))	('MEP50', 'Gene', (25, 30))	('alanine', 'Chemical', 'MESH:D000409', (50, 57))
641752	20951943	Mutation of Thr-5 dramatically reduced phosphate incorporation; mutation of Ser-264 and Ser-306 also resulted in a moderate reduction while Ser-176A had no apparent effect (Figure 4C).	('Ser', 'Chemical', 'MESH:D012694', (140, 143))	('reduction', 'NegReg', (124, 133))	('reduced', 'NegReg', (31, 38))	('mutation', 'Var', (64, 72))	('Mutation', 'Var', (0, 8))	('phosphate', 'Chemical', 'MESH:D010710', (39, 48))	('Ser', 'Chemical', 'MESH:D012694', (76, 79))	('phosphate incorporation', 'MPA', (39, 62))	('Ser-306', 'Gene', (88, 95))	('Ser-264', 'Gene', (76, 83))	('Thr-5', 'Gene', (12, 17))	('Ser', 'Chemical', 'MESH:D012694', (88, 91))	('Thr', 'Chemical', 'MESH:D013912', (12, 15))
641753	20951943	If CUL4 repression and CDT1 stabilization depends upon MEP50 phosphorylation by cyclin D1T286A/CDK4, we reasoned that overexpression of key non-phosphorylatable MEP50 mutants should be inhibitory.	('CUL4', 'Chemical', '-', (3, 7))	('CDT1', 'Gene', '81620', (23, 27))	('CDT1', 'Gene', (23, 27))	('MEP50', 'Gene', (161, 166))	('mutants', 'Var', (167, 174))	('MEP50', 'MPA', (55, 60))
641754	20951943	Indeed, expression of myc-tagged MEP50-T5A and to a lesser degree MEP50-S264A interfered with cyclin D1T286A-dependent CDT1 stabilization and CUL4 loss during S-phase (Figure 4D).	('myc', 'Gene', '4609', (22, 25))	('MEP50-S264A', 'Var', (66, 77))	('CUL4 loss', 'MPA', (142, 151))	('CDT1', 'Gene', '81620', (119, 123))	('myc', 'Gene', (22, 25))	('CUL4', 'Chemical', '-', (142, 146))	('S264A', 'Mutation', 'p.S264A', (72, 77))	('MEP50-T5A', 'Var', (33, 42))	('T5A', 'Mutation', 'rs1390555280', (39, 42))	('CDT1', 'Gene', (119, 123))	('interfered', 'NegReg', (78, 88))
641758	20951943	Additionally, increased PRMT5/MEP50 SAM-dependent methyltransferase activity directed towards histone H4 was readily apparent following incubation of PRMT5/MEP50 complexes purified from HeLa cells with cyclin D1T286A/CDK4 and to a lesser degree with cyclin D1/CDK4 (Figure 5B).	('increased', 'PosReg', (14, 23))	('HeLa', 'CellLine', 'CVCL:0030', (186, 190))	('SAM-dependent methyltransferase', 'Gene', (36, 67))	('SAM-dependent methyltransferase', 'Gene', '80745', (36, 67))	('T286', 'Chemical', '-', (211, 215))	('activity', 'MPA', (68, 76))	('cyclin', 'Var', (202, 208))
641759	20951943	Expression of MEP50-T5A maintained basal methyltransferase activity in vitro, but was refractory to the CDK4-dependent increase of PRMT5 activation (Figure 5C).	('activity', 'MPA', (59, 67))	('methyltransferase', 'Enzyme', (41, 58))	('MEP50-T5A', 'Var', (14, 23))	('T5A', 'Mutation', 'rs1390555280', (20, 23))
641760	20951943	Serine-264 to alanine substitution also attenuated the response to cyclin D1T286A/CDK4 whereas alanine substitution at 176/306 was without influence.	('alanine', 'Chemical', 'MESH:D000409', (95, 102))	('Serine-264 to alanine substitution', 'Var', (0, 34))	('Serine-264 to alanine', 'Mutation', 'p.S264A', (0, 21))	('alanine', 'Chemical', 'MESH:D000409', (14, 21))	('response to cyclin D1T286A/CDK4', 'MPA', (55, 86))	('attenuated', 'NegReg', (40, 50))
641762	20951943	Cyclin D1T286A/CDK4 expression induces re-replication in a CDT1-dependent fashion.	('CDT1', 'Gene', (59, 63))	('induces', 'Reg', (31, 38))	('re-replication', 'CPA', (39, 53))	('CDT1', 'Gene', '81620', (59, 63))	('Cyclin', 'Var', (0, 6))	('D1T286A/CDK4', 'Gene', (7, 19))
641763	20951943	Consistent with this hypothesis, we observed a dramatic reduction of >4N population from 26.8% to 2.28% with PRMT5 knockdown in T286A/CDK4/CDT1 transfected HeLa cells (Figure 6A-B).	('CDT1', 'Gene', '81620', (139, 143))	('HeLa', 'CellLine', 'CVCL:0030', (156, 160))	('T286A', 'SUBSTITUTION', 'None', (128, 133))	('PRMT5', 'Gene', (109, 114))	('CDT1', 'Gene', (139, 143))	('reduction', 'NegReg', (56, 65))	('T286A', 'Var', (128, 133))	('knockdown', 'Var', (115, 124))
641764	20951943	We next determined whether PRMT5 mediates cyclin D1T286A-dependent transformation by knockdown of PRMT5 in murine fibroblasts, concurrent with expression of oncogenic RasV12 and cyclin D1T286A.	('T286', 'Chemical', '-', (187, 191))	('PRMT5', 'Gene', (98, 103))	('knockdown', 'Var', (85, 94))	('T286', 'Chemical', '-', (51, 55))	('murine', 'Species', '10090', (107, 113))
641765	20951943	In addition, PRMT5 knockdown did not significantly attenuate transformation mediated by Ras plus c-Myc, suggesting mechanistic specificity between PRMT5-dependent methyltransferase activity and constitutively nuclear cyclin D1 (Figure 6C).	('knockdown', 'Var', (19, 28))	('c-Myc', 'Gene', (97, 102))	('c-Myc', 'Gene', '4609', (97, 102))
641770	20951943	To examine the role of MEP50 phosphorylation in cyclin D1T286A-dependent transformation, wild type or phosphorylation-deficient T5A or S264A mutant MEP50 was co-expressed with RasV12 and cyclin D1T286A in NIH3T3 cells.	('mutant', 'Var', (141, 147))	('MEP50', 'Gene', (148, 153))	('T5A', 'Mutation', 'rs1390555280', (128, 131))	('T286', 'Chemical', '-', (57, 61))	('NIH3T3', 'CellLine', 'CVCL:0594', (205, 211))	('T286', 'Chemical', '-', (196, 200))	('S264A', 'Mutation', 'p.S264A', (135, 140))
641771	20951943	Compared to wild type MEP50, expression of the T5A or S264A MEP50 mutant significantly reduced foci number, suggesting that phosphorylation of MEP50 and subsequent increase in PRMT5 activity is a driving force for cellular transformation in the presence of cyclin D1T286A (Figure 6E).	('activity', 'MPA', (182, 190))	('cellular transformation', 'CPA', (214, 237))	('mutant', 'Var', (66, 72))	('T286', 'Chemical', '-', (266, 270))	('S264A', 'Mutation', 'p.S264A', (54, 59))	('reduced', 'NegReg', (87, 94))	('foci number', 'CPA', (95, 106))	('MEP50', 'Gene', (60, 65))	('increase', 'PosReg', (164, 172))	('T5A', 'Mutation', 'rs1390555280', (47, 50))
641772	20951943	While mutations directly targeting cyclin D1 do occur in human cancer, they occur infrequently relative to inactivation of the cyclin D1 E3 ligase.	('cyclin D1', 'Gene', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('human', 'Species', '9606', (57, 62))	('mutations', 'Var', (6, 15))
641774	20951943	Fbx4 knockdown increased cyclin D1 and CDT1 and decreased CUL4A/B; critically, the level of H4R3 methylation was dramatically increased (Figure 7A).	('knockdown', 'Var', (5, 14))	('H4R3 methylation', 'MPA', (92, 108))	('CDT1', 'Gene', '81620', (39, 43))	('CUL4A/B', 'Gene', '8451;8450', (58, 65))	('decreased', 'NegReg', (48, 57))	('increased', 'PosReg', (15, 24))	('CUL4A/B', 'Gene', (58, 65))	('cyclin', 'MPA', (25, 31))	('Fbx4', 'Gene', (0, 4))	('CDT1', 'Gene', (39, 43))	('increased', 'PosReg', (126, 135))
641775	20951943	Previous work identified esophageal tumors harboring inactivating mutations in Fbx4 that resulted in strong cyclin D1 overexpression.	('overexpression', 'PosReg', (118, 132))	('esophageal tumors', 'Disease', 'MESH:D004938', (25, 42))	('esophageal tumors', 'Phenotype', 'HP:0100751', (25, 42))	('inactivating mutations', 'Var', (53, 75))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Fbx4', 'Gene', (79, 83))	('esophageal tumor', 'Phenotype', 'HP:0100751', (25, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('cyclin D1', 'MPA', (108, 117))	('esophageal tumors', 'Disease', (25, 42))
641778	20951943	Because our analysis was restricted to tumors with known Fbx4 mutations and tissue availability for IHC (n=4), our analysis did not achieve statistical significance.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('Fbx4', 'Gene', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('mutations', 'Var', (62, 71))
641779	20951943	To support this analysis, we analyzed an esophageal tumor cell line harboring a mutant Fbx4, Fbx4(S8R) (TE10) and another expressing both wild type Fbx4 and cyclin D1 (TE15) and found that inactive Fbx4 correlates with increased CDT1 and methylated H4R3 (Figure 7C).	('methylated', 'MPA', (238, 248))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CDT1', 'Gene', '81620', (229, 233))	('mutant', 'Var', (80, 86))	('esophageal tumor', 'Disease', 'MESH:D004938', (41, 57))	('H4R3', 'Protein', (249, 253))	('esophageal tumor', 'Disease', (41, 57))	('CDT1', 'Gene', (229, 233))	('Fbx4', 'Gene', (87, 91))	('esophageal tumor', 'Phenotype', 'HP:0100751', (41, 57))	('increased', 'PosReg', (219, 228))	('Fbx4', 'Gene', (93, 97))
641782	20951943	Previous work revealed that aberrant nuclear accumulation of cyclin D1 during S-phase promotes transformation in vitro and drives both B-cell lymphomas and mammary carcinomas in mice.	('carcinomas', 'Disease', (164, 174))	('carcinomas', 'Disease', 'MESH:D002277', (164, 174))	('aberrant nuclear', 'Var', (28, 44))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (135, 151))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (135, 151))	('drives', 'PosReg', (123, 129))	('B-cell lymphomas', 'Disease', (135, 151))	('mice', 'Species', '10090', (178, 182))	('lymphomas', 'Phenotype', 'HP:0002665', (142, 151))	('transformation', 'CPA', (95, 109))	('promotes', 'PosReg', (86, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('lymphoma', 'Phenotype', 'HP:0002665', (142, 150))	('cyclin D1', 'Protein', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
641786	20951943	While PRMT5/MEP50 was identified through affinity purification of D1T286A complexes, it is the demonstration that MEP50 is a direct substrate for D-type cyclin dependent kinase that contributes a key advance in our understanding of cyclin D1-driven tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('T286', 'Chemical', '-', (68, 72))	('MEP50', 'Var', (114, 119))	('tumor', 'Disease', (249, 254))
641787	20951943	Phosphorylation of MEP50 on Thr-5 by D1T286A/CDK4 is necessary and sufficient to increase the intrinsic methyltransferase activity of PRMT5, resulting in increased H4R3/H3R8 methylation and repression of the CUL4A/B expression.	('D1T286A/CDK4', 'Var', (37, 49))	('H4R3/H3R8', 'Protein', (164, 173))	('intrinsic', 'MPA', (94, 103))	('CUL4A/B', 'Gene', '8451;8450', (208, 215))	('CUL4A/B', 'Gene', (208, 215))	('PRMT5', 'Gene', (134, 139))	('T286', 'Chemical', '-', (39, 43))	('Thr', 'Chemical', 'MESH:D013912', (28, 31))	('increase', 'PosReg', (81, 89))	('increased', 'PosReg', (154, 163))	('repression', 'NegReg', (190, 200))	('methylation', 'MPA', (174, 185))
641788	20951943	Notably, although we did not detect phosphorylation of Ser-264 in vivo, mutation of Ser-264 to alanine in MEP50 reduced cyclin D1-dependent induction of PRMT5 activity, suggesting that phosphorylation of this site may also contribute.	('Ser-264 to alanine', 'Mutation', 'p.S264A', (84, 102))	('Ser', 'Chemical', 'MESH:D012694', (55, 58))	('cyclin D1-dependent induction', 'MPA', (120, 149))	('Ser', 'Chemical', 'MESH:D012694', (84, 87))	('PRMT5 activity', 'MPA', (153, 167))	('reduced', 'NegReg', (112, 119))	('Ser-264', 'Gene', (84, 91))	('MEP50', 'Gene', (106, 111))	('mutation', 'Var', (72, 80))
641790	20951943	PRMT5 methylates arginines in multiple proteins including myelin basic protein, SM proteins and p53.	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('myelin basic protein', 'Gene', '4155', (58, 78))	('methylates', 'Var', (6, 16))	('SM proteins', 'Protein', (80, 91))	('arginines', 'Chemical', 'MESH:D001120', (17, 26))	('myelin basic protein', 'Gene', (58, 78))	('arginines', 'Protein', (17, 26))
641793	20951943	The data provided demonstrate that phosphorylation of Thr-5, and perhaps Ser-264, of MEP50 contributes to increased PRMT5/MEP50 methyltransferase activity in cells harboring nuclear cyclin D1/CDK4.	('PRMT5/MEP50 methyltransferase', 'Enzyme', (116, 145))	('Thr', 'Chemical', 'MESH:D013912', (54, 57))	('activity', 'MPA', (146, 154))	('Ser', 'Chemical', 'MESH:D012694', (73, 76))	('nuclear', 'Var', (174, 181))	('phosphorylation', 'MPA', (35, 50))	('increased', 'PosReg', (106, 115))	('MEP50', 'Gene', (85, 90))
641801	20951943	In addition, we questioned the possibility that cyclin D1T286A might result in the recruitment of histone deacetylases and thereby impact CUL4 expression.	('recruitment', 'MPA', (83, 94))	('CUL4', 'Gene', (138, 142))	('histone deacetylase', 'Gene', (98, 117))	('CUL4', 'Chemical', '-', (138, 142))	('result', 'Reg', (69, 75))	('impact', 'Reg', (131, 137))	('cyclin', 'Var', (48, 54))	('histone deacetylase', 'Gene', '9734', (98, 117))
641803	20951943	Cyclin D1T286A/CDK4 increases PRMT5 methyltransferase activity in vivo through MEP50, revealing a pathway where PRMT5 facilitates cyclin D1T286A/CDK4 dependent re-replication and survival of murine tumors harboring a lymphoid-specific D1T286A transgene.	('murine', 'Species', '10090', (191, 197))	('T286', 'Chemical', '-', (9, 13))	('D1T286A transgene', 'Var', (235, 252))	('survival', 'CPA', (179, 187))	('T286', 'Chemical', '-', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('re-replication', 'CPA', (160, 174))	('facilitates', 'PosReg', (118, 129))	('activity', 'MPA', (54, 62))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('T286', 'Chemical', '-', (237, 241))
641804	20951943	First, knockdown of Fbx4, the specificity component of the cyclin D1 E3 ligase, stabilizes nuclear cyclin D1/CDK4 complexes in the nucleus during S-phase and thereby increases PRMT5-dependent histone methylation resulting in CUL4 loss.	('nuclear cyclin D1/CDK4 complexes', 'Protein', (91, 123))	('PRMT5-dependent histone methylation', 'MPA', (176, 211))	('increases', 'PosReg', (166, 175))	('Fbx4', 'Gene', (20, 24))	('CUL4', 'Chemical', '-', (225, 229))	('CUL4', 'MPA', (225, 229))	('knockdown', 'Var', (7, 16))	('loss', 'NegReg', (230, 234))	('stabilizes', 'PosReg', (80, 90))
641805	20951943	Second, human tumors harboring inactivating mutations in Fbx4 and subsequent nuclear accumulation of endogenous cyclin D1-dependent kinase, exhibit a dramatic increase in H4R3 methylation.	('Fbx4', 'Gene', (57, 61))	('inactivating mutations', 'Var', (31, 53))	('tumors', 'Disease', (14, 20))	('methylation', 'MPA', (176, 187))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('H4R3', 'Protein', (171, 175))	('nuclear accumulation', 'MPA', (77, 97))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('human', 'Species', '9606', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('increase', 'PosReg', (159, 167))
641806	20951943	Finally, cyclin D1/CDK4-MEP50/PRMT5 complexes are observed in esophageal carcinoma cell lines harboring cyclin D1P287A.	('esophageal carcinoma', 'Disease', (62, 82))	('observed', 'Reg', (50, 58))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (62, 82))	('P287A', 'Mutation', 'rs367567016', (113, 118))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (62, 82))	('cyclin D1P287A', 'Var', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
641807	20951943	These independent findings implicate aberrant nuclear cyclin D1 in transcriptional repression of CUL4.	('nuclear cyclin D1', 'Protein', (46, 63))	('transcriptional repression', 'MPA', (67, 93))	('CUL4', 'Gene', (97, 101))	('implicate', 'Reg', (27, 36))	('CUL4', 'Chemical', '-', (97, 101))	('aberrant', 'Var', (37, 45))
641809	20951943	Our functional analysis revealed that PRMT5 is necessary for cyclin D1-mediated cell transformation and further that tumors harboring dysregulated cyclin D1 exhibit increased PRMT5-dependent histone methylation.	('PRMT5-dependent histone methylation', 'MPA', (175, 210))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('dysregulated', 'Var', (134, 146))	('increased', 'PosReg', (165, 174))	('cyclin D1', 'Gene', (147, 156))
641812	20951943	Human MEP50 Myc-tagged vector was generated by PCR of human MEP50 with primers designed for directional cloning into pcDNA3 plasmid (in frame with 1X Myc tag at the N terminus of MEP50).	('Myc', 'Gene', '4609', (150, 153))	('Human', 'Species', '9606', (0, 5))	('Myc', 'Gene', (150, 153))	('PCR', 'Var', (47, 50))	('Myc', 'Gene', '4609', (12, 15))	('Myc', 'Gene', (12, 15))	('MEP50', 'Gene', (60, 65))	('human', 'Species', '9606', (54, 59))
641826	20951943	Human esophageal tumors harboring Fbx4 mutations and normal esophageal tissue were obtained with informed consent and with Institutional Review Board approval from the University of Pennsylvania (IRB #803902), Fox Chase Cancer Center (IRB #98-53), and University of Fukui, Japan (IRB #H190228-155).	('Human', 'Species', '9606', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('RB', 'Gene', '5925', (281, 283))	('esophageal tumors', 'Disease', 'MESH:D004938', (6, 23))	('mutations', 'Var', (39, 48))	('Cancer', 'Disease', (220, 226))	('esophageal tumors', 'Disease', (6, 23))	('esophageal tumors', 'Phenotype', 'HP:0100751', (6, 23))	('RB', 'Gene', '5925', (197, 199))	('Fbx4', 'Gene', (34, 38))	('RB', 'Gene', '5925', (236, 238))	('Cancer', 'Disease', 'MESH:D009369', (220, 226))	('esophageal tumor', 'Phenotype', 'HP:0100751', (6, 22))	('Cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
641829	20951943	Purified GST-MEP50 wild type, GST-T5A, S176A, S264A, S306A mutants and GST-RB were used as substrates for in vitro kinase reactions.	('T5A', 'Mutation', 'rs1390555280', (34, 37))	('S306A', 'Var', (53, 58))	('S306A', 'Mutation', 'p.S306A', (53, 58))	('GST-MEP50', 'Gene', (9, 18))	('S176A', 'Var', (39, 44))	('RB', 'Gene', '5925', (75, 77))	('S264A', 'Mutation', 'p.S264A', (46, 51))	('S264A', 'Var', (46, 51))	('S176A', 'Mutation', 'p.S176A', (39, 44))
641840	20951943	For MEP50 overexpression assays, NIH3T3 cells were transfected with 2ug of wt MEP50 or phosphorylation-deficient MEP50 mutant T5A or S264A, along with empty vector or Ras V12 and cyclin D1T286A constructs as indicated.	('T5A', 'Mutation', 'rs1390555280', (126, 129))	('S264A', 'Mutation', 'p.S264A', (133, 138))	('T286', 'Chemical', '-', (188, 192))	('NIH3T3', 'CellLine', 'CVCL:0594', (33, 39))	('MEP50', 'Gene', (113, 118))	('mutant', 'Var', (119, 125))
641865	33621787	However, accumulation of ROS/RNS causes oxidative stress that poses potential damage to the cells by attacking macromolecules such as DNA, RNA, proteins and lipids.	('macromolecules', 'MPA', (111, 125))	('lipids', 'Chemical', 'MESH:D008055', (157, 163))	('RNS', 'Chemical', 'MESH:D026361', (29, 32))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('lipids', 'MPA', (157, 163))	('DNA', 'MPA', (134, 137))	('oxidative stress', 'MPA', (40, 56))	('RNA', 'MPA', (139, 142))	('accumulation', 'Var', (9, 21))	('ROS/RNS', 'Var', (25, 32))	('proteins', 'Protein', (144, 152))	('oxidative stress', 'Phenotype', 'HP:0025464', (40, 56))	('attacking', 'PosReg', (101, 110))
641899	33621787	Among genes encoding anti-oxidant enzymes, variants of GSTP1 (such as rs1695 A>G missense variant), results in reduced enzymatic activity, frequently linked to risks of BE and EAC.	('EAC', 'Disease', (176, 179))	('rs1695', 'Mutation', 'rs1695', (70, 76))	('rs1695 A>G missense variant', 'Var', (70, 97))	('GSTP1', 'Gene', (55, 60))	('reduced', 'NegReg', (111, 118))	('linked to', 'Reg', (150, 159))	('variants', 'Var', (43, 51))	('enzymatic activity', 'MPA', (119, 137))	('GSTP1', 'Gene', '2950', (55, 60))
641900	33621787	Variants of GSTT2 were different in African Americans, as compared with European Americans.	('GSTT2', 'Gene', (12, 17))	('Variants', 'Var', (0, 8))	('GSTT2', 'Gene', '2953', (12, 17))
641905	33621787	Dysfunction of these anti-oxidant enzymes makes esophageal cells more sensitive to ABS exposure.	('sensitive', 'MPA', (70, 79))	('more', 'PosReg', (65, 69))	('Dysfunction', 'Var', (0, 11))	('ABS', 'Chemical', '-', (83, 86))
641909	33621787	Therefore, dysfunction of these antioxidant enzymes not only compromises cellular antioxidant capacity but also favors tumor cell growth, a major contribution to Barrett's tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (119, 124))	('cellular antioxidant capacity', 'MPA', (73, 102))	('tumor', 'Disease', (172, 177))	('dysfunction', 'Var', (11, 22))	('compromises', 'NegReg', (61, 72))	('favors', 'PosReg', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
641931	33621787	Our analysis of COSMIC (Catalogue of Somatic Mutations in Cancers) database indicated low incidence of mutation of NFE2L2 and KEAP1 in EAC (NFE2L2 in 6.6% (38/576) whereas KEAP1 in 1.22% (7/576)).	('NFE2L2', 'Gene', '4780', (140, 146))	('Cancers', 'Disease', (58, 65))	('KEAP1', 'Gene', '9817', (172, 177))	('KEAP1', 'Gene', (126, 131))	('Cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NFE2L2', 'Gene', (140, 146))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CO', 'Chemical', 'MESH:D002248', (16, 18))	('Cancers', 'Disease', 'MESH:D009369', (58, 65))	('KEAP1', 'Gene', (172, 177))	('NFE2L2', 'Gene', '4780', (115, 121))	('mutation', 'Var', (103, 111))	('KEAP1', 'Gene', '9817', (126, 131))	('NFE2L2', 'Gene', (115, 121))
641948	33621787	This is consistent with early discoveries using NRF2 knockout mice which demonstrated that NRF2 knockout mice were more susceptible to chemical-induced tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mice', 'Species', '10090', (62, 66))	('tumor', 'Disease', (152, 157))	('susceptible', 'Reg', (120, 131))	('knockout', 'Var', (96, 104))	('NRF2', 'Gene', (91, 95))	('mice', 'Species', '10090', (105, 109))
641960	33621787	In almost all cancer types, overexpression NRF2 is associated with poor prognosis and drug- or radio-resistance.	('cancer', 'Disease', (14, 20))	('overexpression', 'Var', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('drug-', 'CPA', (86, 91))	('NRF2', 'Gene', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
641970	33621787	For example, the Alpha-Tocopherol Beta Carotene (ATBC) Cancer Prevention Study reported that male smokers receiving b-carotene had an 18% increase in lung cancer incidence.	('increase', 'PosReg', (138, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('Alpha-Tocopherol', 'Chemical', 'MESH:D024502', (17, 33))	('lung cancer', 'Disease', (150, 161))	('b-carotene', 'Var', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('b-carotene', 'Chemical', '-', (116, 126))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('Cancer', 'Disease', (55, 61))	('ATBC', 'Chemical', '-', (49, 53))	('Beta Carotene', 'Chemical', 'MESH:D019207', (34, 47))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))
641981	33621787	The major concern for modulating NRF2 using NRF2 activators relies on the fact that NRF2 functions are hijacked by tumor cells to favor their growth and progression.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('growth', 'CPA', (142, 148))	('modulating', 'Var', (22, 32))	('NRF2', 'Gene', (84, 88))	('favor', 'PosReg', (130, 135))	('progression', 'CPA', (153, 164))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
641984	33621787	tested modulation of NRF2 in several in vivo mouse models and demonstrated that NRF2 activation prevented initiation of chemically induced cancer, and promoted progression of pre-existing tumors regardless of a chemical or genetic etiology.	('modulation', 'Var', (7, 17))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('promoted', 'PosReg', (151, 159))	('mouse', 'Species', '10090', (45, 50))	('NRF2', 'Gene', (80, 84))	('prevented', 'NegReg', (96, 105))	('activation', 'PosReg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('progression', 'CPA', (160, 171))	('cancer', 'Disease', (139, 145))
641990	33621787	In addition to brusatol, other investigational compounds are capable to inhibit NRF2 activity, such as AME1, ML385, trigonelline, malabaricone A, ochratoxin A, and wogonin.	('brusatol', 'Chemical', 'MESH:C020237', (15, 23))	('AME1', 'Gene', '3291', (103, 107))	('wogonin', 'Chemical', 'MESH:C085514', (164, 171))	('trigonelline', 'Chemical', 'MESH:C009560', (116, 128))	('ochratoxin A', 'Chemical', 'MESH:C025589', (146, 158))	('NRF2', 'Gene', (80, 84))	('ML385', 'Chemical', '-', (109, 114))	('AME1', 'Gene', (103, 107))	('inhibit', 'NegReg', (72, 79))	('malabaricone A', 'Chemical', 'MESH:C522672', (130, 144))	('ML385', 'Var', (109, 114))	('activity', 'MPA', (85, 93))
641993	33621787	Therefore, from a hypothetical point of view, NRF2 activators may benefit patients and reduce risks for EAC development.	('EAC development', 'Disease', (104, 119))	('benefit', 'PosReg', (66, 73))	('patients', 'Species', '9606', (74, 82))	('men', 'Species', '9606', (115, 118))	('NRF2', 'Gene', (46, 50))	('reduce', 'NegReg', (87, 93))	('activators', 'Var', (51, 61))
642047	33511071	Some reports have shown that AI-related technologies in medicine could impair the efficacy of patient consultation which may lead to anomalous situations, such as missing out important clinical signs while focusing more on technological appliances.	('missing out', 'NegReg', (163, 174))	('lead', 'Reg', (125, 129))	('AI-related', 'Var', (29, 39))	('efficacy', 'MPA', (82, 90))	('patient', 'Species', '9606', (94, 101))	('impair', 'NegReg', (71, 77))
642136	30789414	It is of interest however to note that all cases of high Aurora Kinase A also had moderate to high expression of c-MYC.	('expression', 'MPA', (99, 109))	('c-MYC', 'Gene', '4609', (113, 118))	('high', 'Var', (52, 56))	('Aurora', 'Gene', (57, 63))	('c-MYC', 'Gene', (113, 118))
642139	30789414	Ramicirumab an antibody director to the vascular endothelial growth factor-2(VEGF-2) has resulted in improvement in survival when combined with paclitaxel for patients with GE junction adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('antibody', 'Var', (15, 23))	('VEGF-2', 'Gene', (77, 83))	('GE junction adenocarcinoma', 'Disease', 'MESH:D000230', (173, 199))	('improvement', 'PosReg', (101, 112))	('Ramicirumab', 'Chemical', '-', (0, 11))	('survival', 'MPA', (116, 124))	('patients', 'Species', '9606', (159, 167))	('paclitaxel', 'Chemical', 'MESH:D017239', (144, 154))	('GE junction adenocarcinoma', 'Disease', (173, 199))
642170	30696879	Epigenetic changes are increasingly considered as valuable targets for cancer therapies.	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('Epigenetic changes', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
642173	30696879	Although the exact mechanisms remain elusive, DNA methylation abnormalities in cancer cells are intimately linked to aberrant expression and function of DNA methylation machinery.	('abnormalities', 'Var', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('linked', 'Reg', (107, 113))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
642177	30696879	Multiple mechanisms, including inactivation of the pRB pathway, activation of E2F family transcription factors and desregulation of p53, SP1 and SP3 can lead to elevated DNMT1 expression.	('pRB', 'Gene', '5925', (51, 54))	('desregulation', 'Var', (115, 128))	('DNMT1', 'Gene', (170, 175))	('inactivation', 'NegReg', (31, 43))	('p53', 'Gene', (132, 135))	('SP3', 'Gene', (145, 148))	('p53', 'Gene', '7157', (132, 135))	('E2F family transcription factors', 'Protein', (78, 110))	('pRB', 'Gene', (51, 54))	('SP1', 'Gene', (137, 140))	('elevated', 'PosReg', (161, 169))	('activation', 'PosReg', (64, 74))	('expression', 'MPA', (176, 186))	('SP3', 'Gene', '6670', (145, 148))
642181	30696879	Aberrant UHRF1 expression in cancer cells has been reported to be regulated transcriptionally by transcription factors such as E2F1, E2F8, SP1 and FOXM1, and post-transcriptionally by micro RNAs.	('E2F8', 'Gene', '79733', (133, 137))	('cancer', 'Disease', (29, 35))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('E2F8', 'Gene', (133, 137))	('expression', 'MPA', (15, 25))	('FOXM1', 'Gene', '2305', (147, 152))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('FOXM1', 'Gene', (147, 152))	('UHRF1', 'Gene', (9, 14))
642186	30696879	In many types of tumors, this signaling pathway is activated owing to mutations in KRAS, NRAS, and BRAF.	('KRAS', 'Gene', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (70, 79))	('NRAS', 'Gene', '4893', (89, 93))	('KRAS', 'Gene', '3845', (83, 87))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('NRAS', 'Gene', (89, 93))	('activated', 'PosReg', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
642194	30696879	Furthermore, addition of MG132, a proteasome inhibitor, 6 hours before cell harvest could fully restore the level of UHRF1 in 2i medium to the level of UHRF1 in serum plus LIF medium (Fig.	('MG132', 'Chemical', 'MESH:C072553', (25, 30))	('restore', 'PosReg', (96, 103))	('MG132', 'Var', (25, 30))
642201	30696879	Thus, while 2i-treatment down-regulated UHRF1 and DNMT1 primarily at the post-transcriptional level in mESCs, it negatively regulated UHRF1 and DNMT1 in HCT116 cells mainly at the level of transcription.	('UHRF1', 'Gene', (134, 139))	('UHRF1', 'Gene', (40, 45))	('2i-treatment', 'Var', (12, 24))	('DNMT1', 'Gene', (50, 55))	('down-regulated', 'NegReg', (25, 39))	('DNMT1', 'Gene', (144, 149))	('negatively regulated', 'NegReg', (113, 133))	('HCT116', 'CellLine', 'CVCL:0291', (153, 159))
642203	30696879	Furthermore, we surmised whether downregulation of UHRF1/DNMT1 by 2i could be explored for targeting aberrant DNA methylation in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('UHRF1/DNMT1', 'Gene', (51, 62))	('aberrant', 'Var', (101, 109))	('downregulation', 'NegReg', (33, 47))
642207	30696879	Notably, 2i treatment also markedly down-regulated the levels of UHRF1 and DNMT1 proteins in all esophageal cancer cells (KYSE150, KYSE410, KYSE140, KYSE520, KYSE30, and KYSE450) with the only one exception of KYSE510, in which UHRF1 protein level was unchanged (Fig.	('KYSE410', 'Var', (131, 138))	('KYSE30', 'Var', (158, 164))	('KYSE140', 'Var', (140, 147))	('levels', 'MPA', (55, 61))	('KYSE520', 'CellLine', 'CVCL:1355', (149, 156))	('esophageal cancer', 'Disease', (97, 114))	('DNMT1', 'Gene', (75, 80))	('UHRF1', 'Gene', (65, 70))	('KYSE520', 'Var', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('proteins', 'Protein', (81, 89))	('KYSE150', 'Var', (122, 129))	('down-regulated', 'NegReg', (36, 50))
642212	30696879	In support of this idea, we found that addition of MG132 could not rescued 2i-induced downregulation of UHRF1 and DNMT1 in A549, HeLa and KYSE70 cells (data not shown).	('DNMT1', 'Gene', (114, 119))	('HeLa', 'CellLine', 'CVCL:0030', (129, 133))	('MG132', 'Chemical', 'MESH:C072553', (51, 56))	('MG132', 'Var', (51, 56))	('downregulation', 'NegReg', (86, 100))	('A549', 'CellLine', 'CVCL:0023', (123, 127))	('UHRF1', 'Gene', (104, 109))
642216	30696879	The 2i contains small molecular inhibitors CHIR99021 and PD0325901 that target GSK3beta and MEK1/2, respectively.	('PD0325901', 'Var', (57, 66))	('CHIR99021', 'Var', (43, 52))	('PD0325901', 'Chemical', 'MESH:C506614', (57, 66))	('GSK3beta', 'Protein', (79, 87))
642219	30696879	We found that similar to 2i treatment, PD0325901 alone reduced the levels of UHRF1 and DNMT1 proteins, and this reduction was not blocked by the proteasome inhibitor MG132 (Fig.	('UHRF1', 'Protein', (77, 82))	('levels of', 'MPA', (67, 76))	('PD0325901', 'Var', (39, 48))	('reduced', 'NegReg', (55, 62))	('MG132', 'Chemical', 'MESH:C072553', (166, 171))	('PD0325901', 'Chemical', 'MESH:C506614', (39, 48))	('DNMT1', 'Gene', (87, 92))
642220	30696879	Furthermore, PD0325901 treatment caused an essentially equivalent reduction of UHRF1 and DNMT1 mRNAs as 2i, whereas CHIR99021 treatment alone had no effect (Fig.	('PD0325901', 'Var', (13, 22))	('UHRF1', 'Gene', (79, 84))	('DNMT1', 'Gene', (89, 94))	('PD0325901', 'Chemical', 'MESH:C506614', (13, 22))	('reduction', 'NegReg', (66, 75))
642221	30696879	By western blotting analysis using an antibody reacting with Thr202/Tyr204 phosphorylated and active form of ERK1/2 (P-ERK1/2), the downstream target of MEK1/2, we confirmed PD0325901 and 2i effectively inhibited MEK1/2 activity (Fig.	('Tyr204', 'Chemical', '-', (68, 74))	('MEK1/2', 'Enzyme', (213, 219))	('PD0325901', 'Var', (174, 183))	('Thr202', 'Chemical', '-', (61, 67))	('inhibited', 'NegReg', (203, 212))	('PD0325901', 'Chemical', 'MESH:C506614', (174, 183))	('activity', 'MPA', (220, 228))
642224	30696879	HCT116 cells were treated without or with 2i, PD0325901 and CHIR99021 for 0, 6, 12, 24, 36 and 48 hours, respectively.	('PD0325901', 'Chemical', 'MESH:C506614', (46, 55))	('PD0325901', 'Var', (46, 55))	('CHIR99021', 'Var', (60, 69))	('HCT116', 'CellLine', 'CVCL:0291', (0, 6))
642225	30696879	The subsequent western blotting analysis showed that both PD0325901 and 2i induced a time-dependent decrease of UHRF1 and DNMT1 proteins, with reduction of UHRF1 observed at 6 hours and peak at 36 hours and reduction of DNMT1 at 12 hours and peak around 36 hours (Fig.	('proteins', 'Protein', (128, 136))	('PD0325901', 'Var', (58, 67))	('decrease', 'NegReg', (100, 108))	('DNMT1 proteins', 'Protein', (122, 136))	('PD0325901', 'Chemical', 'MESH:C506614', (58, 67))	('UHRF1', 'Protein', (112, 117))
642226	30696879	Simultaneous RT-PCR analysis revealed that both PD0325901 and 2i induced a time-dependent progressive reduction of UHRF1 and DNMT1 mRNAs, with reduction of UHRF1 mRNA observed from 6 hours and DNMT1 from 12 hours (Fig.	('PD0325901', 'Var', (48, 57))	('reduction', 'NegReg', (102, 111))	('PD0325901', 'Chemical', 'MESH:C506614', (48, 57))
642227	30696879	Additional time-course experiments showed that PD0325901 markedly inhibited ERK1/2 phosphorylation ~ 1.5 hours (Supplementary Fig.	('ERK1/2', 'Protein', (76, 82))	('PD0325901', 'Var', (47, 56))	('PD0325901', 'Chemical', 'MESH:C506614', (47, 56))	('phosphorylation', 'MPA', (83, 98))	('inhibited', 'NegReg', (66, 75))
642229	30696879	Furthermore, although both 2i and PD0325901 inhibited cell proliferation and increased G0/G1 population of cells, we found that the levels of UHRF1 and DNMT1 mRNAs were not affected by cell cycle in HCT116 cells (Supplementary Fig.	('cell proliferation', 'CPA', (54, 72))	('G0/G1 population of cells', 'CPA', (87, 112))	('inhibited', 'NegReg', (44, 53))	('PD0325901', 'Var', (34, 43))	('HCT116', 'CellLine', 'CVCL:0291', (199, 205))	('UHRF1', 'Gene', (142, 147))	('PD0325901', 'Chemical', 'MESH:C506614', (34, 43))	('increased', 'PosReg', (77, 86))	('DNMT1', 'Gene', (152, 157))
642230	30696879	Given that reduced UHRF1 expression induced by both PD0325901 and 2i was observed within 6 hours treatment, we concluded that MEK/ERK pathway is most likely to directly regulate UHRF1 transcription, although we could not exclude the possibility that the MEK/ERK pathway could also regulate DNMT1 transcription indirectly.	('UHRF1', 'Gene', (19, 24))	('reduced', 'NegReg', (11, 18))	('ERK', 'Gene', (258, 261))	('MEK', 'Gene', (254, 257))	('MEK', 'Gene', (126, 129))	('expression', 'MPA', (25, 35))	('MEK', 'Gene', '5609', (126, 129))	('UHRF1', 'Gene', (178, 183))	('ERK', 'Gene', '5594', (130, 133))	('MEK', 'Gene', '5609', (254, 257))	('PD0325901', 'Var', (52, 61))	('ERK', 'Gene', (130, 133))	('ERK', 'Gene', '5594', (258, 261))	('PD0325901', 'Chemical', 'MESH:C506614', (52, 61))
642231	30696879	To test that inhibition of MEK directly affects UHRF1 and DNMT1 transcription, we cloned the DNA fragments containing UHRF1 proximal promoter region (-295 bp to + 1113 bp) or DNMT1 proximal promoter region (-475 bp to + 1381 bp) into a promoter-less PGL3-basic luciferase reporter.	('PGL3', 'Gene', '6391', (250, 254))	('MEK', 'Gene', (27, 30))	('PGL3', 'Gene', (250, 254))	('MEK', 'Gene', '5609', (27, 30))	('DNMT1', 'Gene', (175, 180))	('-295 bp', 'Var', (150, 157))	('UHRF1', 'Gene', (118, 123))
642232	30696879	Subsequent luciferase reporter assay in HCT116 cells showed that addition of PD0325901 inhibited transcriptional activity from the UHRF1 reporters (Fig.	('PD0325901', 'Var', (77, 86))	('HCT116', 'CellLine', 'CVCL:0291', (40, 46))	('PD0325901', 'Chemical', 'MESH:C506614', (77, 86))	('inhibited', 'NegReg', (87, 96))	('transcriptional activity', 'MPA', (97, 121))	('UHRF1', 'Gene', (131, 136))
642236	30696879	To this end, we treated A549, HeLa and KYSE70 cells with CHIR99021, PD0325901 or both respectively.	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('PD0325901', 'Var', (68, 77))	('HeLa', 'CellLine', 'CVCL:0030', (30, 34))	('CHIR99021', 'Var', (57, 66))	('PD0325901', 'Chemical', 'MESH:C506614', (68, 77))
642237	30696879	Subsequent western blotting analysis revealed that, like 2i, PD0325901 but not CHIR99021 was sufficient to induce down-regulation of UHRF1 and DNMT1, but not DNMT3A in all three cell lines (Fig.	('UHRF1', 'Gene', (133, 138))	('PD0325901', 'Var', (61, 70))	('PD0325901', 'Chemical', 'MESH:C506614', (61, 70))	('DNMT1', 'Gene', (143, 148))	('down-regulation', 'NegReg', (114, 129))
642238	30696879	Addition of MG132 rescued neither 2i- nor PD0325901-induced down-regulation of UHRF1 and DNMT1 proteins (Fig.	('down-regulation', 'NegReg', (60, 75))	('UHRF1', 'Gene', (79, 84))	('DNMT1 proteins', 'Protein', (89, 103))	('MG132', 'Chemical', 'MESH:C072553', (12, 17))	('PD0325901', 'Chemical', 'MESH:C506614', (42, 51))	('PD0325901-induced', 'Var', (42, 59))
642239	30696879	Furthermore, simultaneous RT-PCR analysis showed that PD0325901 inhibited UHRF1 and DNMT1 transcription to the similar extent as 2i (Fig.	('PD0325901', 'Chemical', 'MESH:C506614', (54, 63))	('DNMT1', 'Gene', (84, 89))	('inhibited', 'NegReg', (64, 73))	('transcription', 'MPA', (90, 103))	('PD0325901', 'Var', (54, 63))	('UHRF1', 'Gene', (74, 79))
642240	30696879	We also confirmed, as expected, that PD0325901 treatment drastically inhibited the level of P-ERK1/2 in these cells (Fig.	('level of P-ERK1/2', 'MPA', (83, 100))	('PD0325901', 'Chemical', 'MESH:C506614', (37, 46))	('PD0325901', 'Var', (37, 46))	('inhibited', 'NegReg', (69, 78))
642243	30696879	We found that for 7 esophageal cancer cell lines PD0325901 treatment down-regulated both UHRF1 and DNMT1 at the level of proteins (Fig.	('esophageal cancer', 'Disease', (20, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('PD0325901', 'Chemical', 'MESH:C506614', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('UHRF1', 'Gene', (89, 94))	('DNMT1', 'Gene', (99, 104))	('down-regulated', 'NegReg', (69, 83))	('PD0325901', 'Var', (49, 58))
642244	30696879	As expected, we found that PD0325901 treatment markedly inhibited the level of phosphorylated ERK1/2 in all these cells without affecting the level of ERK1/2 proteins (Fig.	('inhibited', 'NegReg', (56, 65))	('PD0325901', 'Var', (27, 36))	('level of phosphorylated ERK1/2', 'MPA', (70, 100))	('PD0325901', 'Chemical', 'MESH:C506614', (27, 36))
642247	30696879	Also similar to the results of 2i, PD0325901 treatment did reduce the level of UHRF1 and DNMT1 transcription in Bel7402 cells (Supplementary Fig.	('UHRF1', 'Gene', (79, 84))	('PD0325901', 'Var', (35, 44))	('DNMT1', 'Gene', (89, 94))	('reduce', 'NegReg', (59, 65))	('Bel7402', 'CellLine', 'CVCL:5492', (112, 119))	('PD0325901', 'Chemical', 'MESH:C506614', (35, 44))
642250	30696879	As expected, SCH772984 inhibited ERK1/2 activity in HCT116 cells in a dose-dependent manner (Fig.	('SCH772984', 'Var', (13, 22))	('inhibited', 'NegReg', (23, 32))	('HCT116', 'CellLine', 'CVCL:0291', (52, 58))	('activity', 'MPA', (40, 48))	('SCH772984', 'Chemical', 'MESH:C587178', (13, 22))	('ERK1/2', 'Enzyme', (33, 39))
642251	30696879	Like PD0325901, SCH772984 also induced down-regulation of UHRF1 and DNMT1 proteins and mRNAs (Fig.	('PD0325901', 'Chemical', 'MESH:C506614', (5, 14))	('down-regulation', 'NegReg', (39, 54))	('SCH772984', 'Chemical', 'MESH:C587178', (16, 25))	('mRNAs', 'MPA', (87, 92))	('UHRF1', 'Gene', (58, 63))	('DNMT1', 'Gene', (68, 73))	('PD0325901', 'Var', (5, 14))	('SCH772984', 'Var', (16, 25))
642253	30696879	Note that, like PD0325901, SCH772984-induced downregulation of UHRF1 and DNMT1 proteins was not rescued by MG132 (Fig.	('proteins', 'Protein', (79, 87))	('DNMT1', 'Gene', (73, 78))	('UHRF1', 'Gene', (63, 68))	('MG132', 'Chemical', 'MESH:C072553', (107, 112))	('PD0325901', 'Chemical', 'MESH:C506614', (16, 25))	('downregulation', 'NegReg', (45, 59))	('SCH772984', 'Chemical', 'MESH:C587178', (27, 36))	('SCH772984-induced', 'Var', (27, 44))
642254	30696879	Similarly, we found that like PD0325901, SCH772984 also down-regulated UHRF1 and DNMT1 expression in A549 and KYSE70 cells (Fig.	('UHRF1', 'Gene', (71, 76))	('SCH772984', 'Var', (41, 50))	('A549', 'CellLine', 'CVCL:0023', (101, 105))	('DNMT1', 'Gene', (81, 86))	('down-regulated', 'NegReg', (56, 70))	('expression', 'MPA', (87, 97))	('PD0325901', 'Chemical', 'MESH:C506614', (30, 39))	('SCH772984', 'Chemical', 'MESH:C587178', (41, 50))
642255	30696879	Thus, inhibition of either MEK1/2 or ERK1/2 down-regulated UHRF1 and DNMT1 expression in these cancer cells.	('down-regulated', 'NegReg', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('ERK1/2', 'Gene', (37, 43))	('UHRF1', 'Gene', (59, 64))	('inhibition', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('DNMT1', 'Gene', (69, 74))	('expression', 'MPA', (75, 85))
642267	30696879	We found that knockdown of each of the transcription factors led to reduced levels of UHRF1 and DNMT1 transcription, with more severe reduction of both UHRF1 and DNMT1 observed when E2F1, SP1 or STAT3 were knocked down (Fig.	('levels', 'MPA', (76, 82))	('E2F1', 'Gene', (182, 186))	('knocked down', 'Var', (206, 218))	('STAT3', 'Gene', '6774', (195, 200))	('SP1', 'Gene', (188, 191))	('reduced', 'NegReg', (68, 75))	('UHRF1', 'Gene', (86, 91))	('knockdown', 'Var', (14, 23))	('STAT3', 'Gene', (195, 200))	('DNMT1', 'Gene', (96, 101))
642274	30696879	7g,h, ectopic expression of E2F1 or SP1 markedly enhanced the luciferase activity from the UHRF1-luc reporter but not the control PGL3 reporter.	('activity', 'MPA', (73, 81))	('enhanced', 'PosReg', (49, 57))	('SP1', 'Gene', (36, 39))	('PGL3', 'Gene', '6391', (130, 134))	('PGL3', 'Gene', (130, 134))	('E2F1', 'Var', (28, 32))	('luciferase', 'Enzyme', (62, 72))
642275	30696879	Addition of PD0325901 inhibited transcriptional activation by E2F1 and SP1.	('E2F1', 'Gene', (62, 66))	('inhibited', 'NegReg', (22, 31))	('SP1', 'Gene', (71, 74))	('PD0325901', 'Chemical', 'MESH:C506614', (12, 21))	('transcriptional activation', 'MPA', (32, 58))	('PD0325901', 'Var', (12, 21))
642276	30696879	Thus, E2F1 and SP1 can activate UHRF1 and DNMT1 expression by binding to their proximal promoters and this activity is stimulated by the MEK/ERK pathway.	('activate', 'PosReg', (23, 31))	('MEK', 'Gene', (137, 140))	('ERK', 'Gene', (141, 144))	('UHRF1', 'Gene', (32, 37))	('MEK', 'Gene', '5609', (137, 140))	('binding', 'Interaction', (62, 69))	('expression', 'MPA', (48, 58))	('E2F1', 'Var', (6, 10))	('DNMT1', 'Gene', (42, 47))	('ERK', 'Gene', '5594', (141, 144))
642285	30696879	As the MEK/ERK pathway is widely activated, as a result of RAS or BRAF mutations and others, in human cancer cells, our finding provides a reasonable explanation for widespread transcriptional overexpression of UHRF1 (DNMT1 as well) in various cancers.	('MEK', 'Gene', (7, 10))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('ERK', 'Gene', (11, 14))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('human', 'Species', '9606', (96, 101))	('mutations', 'Var', (71, 80))	('overexpression', 'PosReg', (193, 207))	('activated', 'PosReg', (33, 42))	('RAS', 'Gene', (59, 62))	('UHRF1', 'Gene', (211, 216))	('cancer', 'Disease', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('cancers', 'Disease', (244, 251))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MEK', 'Gene', '5609', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('BRAF', 'Gene', '673', (66, 70))	('ERK', 'Gene', '5594', (11, 14))	('BRAF', 'Gene', (66, 70))
642296	30696879	Alternatively, it is also possible that although 2i or PD0325901 treatment markedly down-regulated the levels of UHRF1 and DNMT1, it had yet to reach a low threshold level of UHRF1 and/or DNMT1 that is sufficient for maintaining DNA methylation in cells.	('PD0325901', 'Var', (55, 64))	('PD0325901', 'Chemical', 'MESH:C506614', (55, 64))	('down-regulated', 'NegReg', (84, 98))
642300	30696879	It is noteworthy that throughout the study we generally observed a more severe effect of 2i or PD0325901 on expression of UHRF1 than DNMT1.	('PD0325901', 'Chemical', 'MESH:C506614', (95, 104))	('PD0325901', 'Var', (95, 104))	('expression', 'MPA', (108, 118))	('UHRF1', 'Gene', (122, 127))
642303	30696879	The reagents used in this study were as follows: MEK inhibitor PD0325901 (S1036) and GSK-3 inhibitor CHIR99021 (S2924) were purchased from Selleckchem (Houston, TX), ERK1/2 inhibitor SCH772984 (HY-50846) from MCE (Monmouth Junction, NJ), MG132 (M8699) from Sigma (St. Louis, MO) and Actinomycin D (HY-17559) from MCE(Monmouth Junction, NJ).	('SCH772984', 'Chemical', 'MESH:C587178', (183, 192))	('HY-17559', 'Var', (298, 306))	('MEK', 'Gene', (49, 52))	('Actinomycin D', 'Chemical', 'MESH:D003609', (283, 296))	('MEK', 'Gene', '5609', (49, 52))	('S1036', 'Var', (74, 79))	('SCH772984', 'Var', (183, 192))	('PD0325901', 'Chemical', 'MESH:C506614', (63, 72))	('MG132', 'Chemical', 'MESH:C072553', (238, 243))	('S2924', 'Var', (112, 117))
642305	30696879	A549, LNCaP, KYSE30, KYSE70, KYSE140, KYSE150, KYSE410, KYSE450, KYSE510 and KYSE520 cells were cultured in 1640 medium (Gibco).	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('KYSE30', 'Var', (13, 19))	('KYSE520', 'CellLine', 'CVCL:1355', (77, 84))	('KYSE510', 'Var', (65, 72))	('KYSE70', 'Var', (21, 27))	('KYSE410', 'Var', (47, 54))	('LNCaP', 'CellLine', 'CVCL:0395', (6, 11))	('KYSE450', 'Var', (56, 63))	('KYSE140', 'Var', (29, 36))	('KYSE150', 'Var', (38, 45))
642310	30696879	For inhibitors treatment, PD0325901 was in general used at a final concentration of 1 muM and CHIR99021 was 3 muM otherwise as indicated.	('muM', 'Gene', '56925', (86, 89))	('PD0325901', 'Var', (26, 35))	('muM', 'Gene', '56925', (110, 113))	('muM', 'Gene', (86, 89))	('PD0325901', 'Chemical', 'MESH:C506614', (26, 35))	('muM', 'Gene', (110, 113))
642332	30089078	From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227).	('CRT', 'Gene', '799', (179, 182))	('CRT', 'Gene', (179, 182))	('patients', 'Species', '9606', (37, 45))	('CRT', 'Gene', '799', (155, 158))	('T1-4N1M0/T4N0M0', 'Var', (110, 125))	('CRT', 'Gene', (155, 158))	('thoracic ESCC', 'Disease', (74, 87))
642378	30089078	Covariates included treatment, age (<= 60 years v > 60 years), sex, tumor location, clinical T stage (T1 to T2 v T3 v T4) and clinical N stage (Appendix Fig A1, online only).	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('T1', 'Var', (102, 104))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
642383	30089078	Reasons for not undergoing surgery after chemoradiotherapy (38 of 224 [17.0%]) were patient refusal (n = 29), disease progression (n = 2), unsatisfactory performance status for surgery (n = 2), cerebral infarction (n = 1), death as a result of pneumonia (n = 1), death as a result of esophageal hemorrhage (n = 2), and death as a result of a car accident (n = 1).	('disease', 'Disease', (110, 117))	('pneumonia', 'Disease', (244, 253))	('pneumonia', 'Disease', 'MESH:D011014', (244, 253))	('cerebral infarction', 'Disease', 'MESH:D002544', (194, 213))	('esophageal hemorrhage', 'Disease', (284, 305))	('unsatisfactory', 'Var', (139, 153))	('death', 'Disease', 'MESH:D003643', (319, 324))	('death', 'Disease', (319, 324))	('death', 'Disease', 'MESH:D003643', (223, 228))	('death', 'Disease', (223, 228))	('esophageal hemorrhage', 'Disease', 'MESH:D006470', (284, 305))	('pneumonia', 'Phenotype', 'HP:0002090', (244, 253))	('patient', 'Species', '9606', (84, 91))	('cerebral infarction', 'Disease', (194, 213))	('death', 'Disease', 'MESH:D003643', (263, 268))	('death', 'Disease', (263, 268))
642509	28367236	In addition to environmental or life-style associated factors, family history of malignancy was traced in 26.4% in the current study, suggesting a potential role of gene mutations and polymorphisms in the development of MPC.	('MPC', 'Chemical', '-', (220, 223))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('MPC', 'Disease', (220, 223))	('polymorphisms', 'Var', (184, 197))	('malignancy', 'Disease', (81, 91))
642524	28367236	Some authors figured out, even if the rate of radical resection of esophageal lesion was comparable, the presence of additional head and neck tumors was associated with a worse long-term prognosis.	('esophageal lesion', 'Disease', (67, 84))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('presence', 'Var', (105, 113))	('neck tumors', 'Disease', 'MESH:D006258', (137, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('head and neck tumors', 'Phenotype', 'HP:0012288', (128, 148))	('neck tumors', 'Disease', (137, 148))	('esophageal lesion', 'Disease', 'MESH:D004935', (67, 84))
642536	28367236	Since low BMI has been identified as a significant inverse prognostic factor, how to reduce treatment toxicity became a vital question.	('toxicity', 'Disease', 'MESH:D064420', (102, 110))	('toxicity', 'Disease', (102, 110))	('low BMI', 'Phenotype', 'HP:0045082', (6, 13))	('low', 'Var', (6, 9))	('BMI', 'MPA', (10, 13))
642663	22520270	The transfer of the TNF-alpha gene to regional lymph nodes may serve to eliminate or control metastases to regional lymph nodes.	('TNF-alpha', 'Gene', (20, 29))	('metastases', 'Disease', (93, 103))	('metastases', 'Disease', 'MESH:D009362', (93, 103))	('transfer', 'Var', (4, 12))	('TNF-alpha', 'Gene', '7124', (20, 29))
642673	22520270	Patients were excluded if they had a history of malignancies within the past 2 years except carcinoma in situ, esophageal cancer extending beyond 2 cm into the stomach, liver function test results greater than 2 times the upper limit of normal, coagulopathy with an international normalized ratio >1.5, renal insufficiency, significant anemia, thrombocytopenia or leucopenia, a contraindication to endoscopy including obstructive lesions that could not be dilated to pass the endoscope, or clinical evidence of active infection of any type or were pregnant or lactating, were taking experimental medications within the 4 weeks before day 1 of treatment, were on long-term systemic corticosteroid use, or had significant concurrent medical or psychiatric illness.	('psychiatric illness', 'Phenotype', 'HP:0000708', (742, 761))	('anemia', 'Phenotype', 'HP:0001903', (336, 342))	('thrombocytopenia', 'Disease', 'MESH:D013921', (344, 360))	('psychiatric illness', 'Disease', (742, 761))	('carcinoma', 'Disease', 'MESH:D002277', (92, 101))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (344, 360))	('psychiatric illness', 'Disease', 'MESH:D001523', (742, 761))	('renal insufficiency', 'Disease', (303, 322))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (92, 109))	('anemia', 'Disease', (336, 342))	('coagulopathy', 'Disease', 'MESH:D001778', (245, 257))	('coagulopathy', 'Disease', (245, 257))	('infection', 'Disease', (518, 527))	('infection', 'Disease', 'MESH:D007239', (518, 527))	('men', 'Species', '9606', (589, 592))	('malignancies', 'Disease', 'MESH:D009369', (48, 60))	('Patients', 'Species', '9606', (0, 8))	('leucopenia', 'Disease', (364, 374))	('renal insufficiency', 'Disease', 'MESH:D051437', (303, 322))	('malignancies', 'Disease', (48, 60))	('renal insufficiency', 'Phenotype', 'HP:0000083', (303, 322))	('leucopenia', 'Disease', 'MESH:C536227', (364, 374))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('thrombocytopenia', 'Disease', (344, 360))	('carcinoma', 'Disease', (92, 101))	('anemia', 'Disease', 'MESH:D000740', (336, 342))	('greater', 'Var', (197, 204))	('esophageal cancer', 'Disease', (111, 128))	('coagulopathy', 'Phenotype', 'HP:0003256', (245, 257))	('men', 'Species', '9606', (648, 651))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
642735	22520270	At the top dose of 4 x 1011 PU, TEs were noted in 5 of 8 patients (63%) compared with only 3 of 16 patients (19%) at the lower doses of 4 x 108 to 4 x 1010 PU.	('TEs', 'Phenotype', 'HP:0001907', (32, 35))	('patients', 'Species', '9606', (57, 65))	('TEs', 'Chemical', '-', (32, 35))	('patients', 'Species', '9606', (99, 107))	('4 x 1011 PU', 'Var', (19, 30))	('TEs', 'Disease', (32, 35))
642755	22520270	The top dose of 4 x 1011 PU was associated with thromboembolic complications and should probably be avoided in patients with esophageal cancer who receive concomitant treatment with chemoradiotherapy.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('esophageal cancer', 'Disease', (125, 142))	('thromboembolic complications', 'Disease', (48, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('thromboembolic complications', 'Disease', 'MESH:D013923', (48, 76))	('thromboembolic complications', 'Phenotype', 'HP:0001907', (48, 76))	('men', 'Species', '9606', (172, 175))	('4 x 1011 PU', 'Var', (16, 27))	('patients', 'Species', '9606', (111, 119))
642834	33226481	Heart irradiation may cause microvascular damage, leading to an early phase of inflammation followed by the onset of fibrosis, both processes causing an increase in ECV.	('cause', 'Reg', (22, 27))	('microvascular damage', 'Disease', (28, 48))	('microvascular damage', 'Disease', 'MESH:D017566', (28, 48))	('leading to', 'Reg', (50, 60))	('fibrosis', 'Disease', (117, 125))	('increase', 'PosReg', (153, 161))	('fibrosis', 'Disease', 'MESH:D005355', (117, 125))	('inflammation', 'Disease', 'MESH:D007249', (79, 91))	('Heart irradiation', 'Var', (0, 17))	('ECV', 'MPA', (165, 168))	('inflammation', 'Disease', (79, 91))
642858	31673653	Ten observers delineated primary esophageal tumor GTVs of 6 patients on FDG-PET/CT, T2W-MRI, and T2W + DW-MRI.	('esophageal tumor', 'Disease', (33, 49))	('patients', 'Species', '9606', (60, 68))	('esophageal tumor', 'Disease', 'MESH:D004941', (33, 49))	('esophageal tumor', 'Phenotype', 'HP:0100751', (33, 49))	('FDG', 'Chemical', 'MESH:D019788', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('T2W + DW-MRI', 'Var', (97, 109))	('T2W-MRI', 'Var', (84, 91))
642861	31673653	In the 2 tumors involving the gastroesophageal junction, addition of DW-MRI to T2W-MRI significantly decreased caudal border variation.	('gastroesophageal junction', 'Disease', (30, 55))	('caudal border variation', 'MPA', (111, 134))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (30, 55))	('T2W-MRI', 'Var', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('decreased', 'NegReg', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
642863	31673653	Most variation was seen at cranial-caudal borders, and addition of DW-MRI to T2W-MRI may reduce caudal delineation variation of gastroesophageal junction tumors.	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('caudal', 'MPA', (96, 102))	('gastroesophageal junction tumors', 'Disease', 'MESH:D008309', (128, 160))	('reduce', 'NegReg', (89, 95))	('gastroesophageal junction tumors', 'Disease', (128, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('T2W-MRI', 'Var', (77, 84))
642877	31673653	A previous study showed that longitudinal tumor lengths of esophageal cancers are more accurately delineated using DW-MRI compared with CT or T2-weighted (T2W) MRI only.	('DW-MRI', 'Var', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('longitudinal tumor', 'Disease', 'MESH:D017887', (29, 47))	('longitudinal tumor', 'Disease', (29, 47))	('esophageal cancers', 'Disease', (59, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('esophageal cancers', 'Disease', 'MESH:D004938', (59, 77))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
642880	31673653	Because of the increasing interest in integrating MRI into radiation treatment, the aim of this study is to evaluate target delineation on T2W-MRI and T2W + DW-MRI compared with current-practice FDG-PET/CT.	('T2W + DW-MRI', 'Var', (151, 163))	('FDG', 'Chemical', 'MESH:D019788', (195, 198))	('T2W-MRI', 'Var', (139, 146))
642913	31673653	The 10 observers delineated significantly smaller absolute GTVs on T2W-MRI and T2W + DW-MRI compared with FDG-PET/CT (P = .07 for T2W-MRI vs FDG-PET/CT and P = .01 for T2W + DW-MRI vs FDG-PET/CT; Table 2).	('FDG', 'Chemical', 'MESH:D019788', (141, 144))	('smaller', 'NegReg', (42, 49))	('FDG', 'Chemical', 'MESH:D019788', (184, 187))	('T2W + DW-MRI', 'Var', (79, 91))	('T2W-MRI', 'Var', (67, 74))	('GTVs', 'MPA', (59, 63))	('T2W-MRI', 'Var', (130, 137))	('FDG', 'Chemical', 'MESH:D019788', (106, 109))
642916	31673653	On T2W + DW-MRI, the mean GTV decreased to 32.7 cm3 (SD-per-patient range, 1.7-8.2 cm3).	('patient', 'Species', '9606', (60, 67))	('GTV', 'MPA', (26, 29))	('decreased', 'NegReg', (30, 39))	('T2W + DW-MRI', 'Var', (3, 15))
642920	31673653	Figure 1 visualizes slice variation at the proximal and distal border for delineations on FDG-PET/CT, T2W-MRI, and T2W + DW-MRI.	('T2W-MRI', 'Var', (102, 109))	('FDG', 'Chemical', 'MESH:D019788', (90, 93))	('FDG-PET/CT', 'Var', (90, 100))	('T2W + DW-MRI', 'Var', (115, 127))
642923	31673653	In case 3 and 4 with gastroesophageal junction (GEJ) involvement, a significant decrease in caudal border variation was observed on T2W + DW-MRI compared with T2W-MRI (P = .04 in case 3, P = .01 in case 4; Table 3).	('gastroesophageal junction', 'Disease', (21, 46))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (21, 46))	('caudal border variation', 'MPA', (92, 115))	('GEJ', 'Disease', (48, 51))	('GEJ', 'Disease', 'MESH:D008309', (48, 51))	('T2W + DW-MRI', 'Var', (132, 144))	('decrease', 'NegReg', (80, 88))
642924	31673653	Figure 2 shows an example of GTV delineation variation at the GEJ on T2W-MRI (Fig 2a) and T2W + DW-MRI (Fig 2c), displaying improved delineation agreement at the caudal border after addition of DW-MRI.	('improved', 'PosReg', (124, 132))	('T2W-MRI', 'Var', (69, 76))	('GEJ', 'Disease', (62, 65))	('GEJ', 'Disease', 'MESH:D008309', (62, 65))	('variation', 'Var', (45, 54))	('delineation', 'MPA', (133, 144))	('T2W + DW-MRI', 'Var', (90, 102))
642926	31673653	The main variation is seen at the cranial and caudal tumor border, whereas centrally, differences in tumor delineations were small on T2W and T2W + DW-MRI.	('T2W', 'Var', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('T2W + DW-MRI', 'Var', (142, 154))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
642927	31673653	The addition of DW-MRI to T2W-MRI in the 2 GEJ-involving tumors significantly reduced the SD of the most caudal delineated slice, showing the potential value of DW-MRI for delineation of the caudal border in GEJ-involving cases.	('GEJ', 'Disease', 'MESH:D008309', (43, 46))	('GEJ', 'Disease', (208, 211))	('T2W-MRI', 'Var', (26, 33))	('DW-MRI', 'Var', (16, 22))	('GEJ', 'Disease', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('reduced', 'NegReg', (78, 85))	('SD of the most caudal delineated slice', 'MPA', (90, 128))	('tumors', 'Disease', (57, 63))	('GEJ', 'Disease', 'MESH:D008309', (208, 211))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
642928	31673653	To our knowledge, this is the first study comparing GTV delineation variability on T2W-MRI and T2W + DW-MRI to FDG-PET/CT for esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('T2W + DW-MRI', 'Var', (95, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('FDG', 'Chemical', 'MESH:D019788', (111, 114))	('esophageal cancer', 'Disease', (126, 143))
642935	31673653	In this study, GTVs were significantly smaller on MRI compared with FDG-PET/CT.	('MRI', 'Var', (50, 53))	('GTVs', 'MPA', (15, 19))	('FDG', 'Chemical', 'MESH:D019788', (68, 71))	('smaller', 'NegReg', (39, 46))
642937	31673653	They compared longitudinal length accuracy of esophageal cancer cases on T2W-MRI and DW-MRI to CT and found that DW-MRI resulted in the smallest tumor lengths.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('DW-MRI', 'Var', (113, 119))	('esophageal cancer', 'Disease', (46, 63))	('tumor', 'Disease', (145, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('smallest', 'NegReg', (136, 144))
642939	31673653	In prostate and cervical cancer, delineations on DW-MRI resulted in slightly smaller GTVs compared with histopathology.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('GTVs', 'MPA', (85, 89))	('prostate', 'Disease', (3, 11))	('cancer', 'Disease', (25, 31))	('DW-MRI', 'Var', (49, 55))	('smaller', 'NegReg', (77, 84))
642951	31673653	To ensure accurate GTV delineation of the macroscopic tumor and mirror clinical practice, we recommend further delineation studies on anatomic T2W-MRI combined with DW-MRI.	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('T2W-MRI', 'Var', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
642953	31673653	The addition of DW-MRI to T2W-MRI potentially facilitates delineation of the caudal border in GEJ tumors.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('GEJ tumors', 'Disease', 'MESH:D008309', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('T2W-MRI', 'Var', (26, 33))	('GEJ tumors', 'Disease', (94, 104))	('facilitates', 'PosReg', (46, 57))
642965	31231212	Histamine acts through four different receptor subtypes: H1, H2, H3, and H4 receptors (H1R, H2R, H3R, and H4R).	('H3R', 'Gene', (97, 100))	('H1R', 'Gene', (87, 90))	('Histamine', 'Chemical', 'MESH:D006632', (0, 9))	('H2R', 'Gene', '3274', (92, 95))	('H3R', 'Gene', '11255', (97, 100))	('H4 receptors', 'Protein', (73, 85))	('H4R', 'Var', (106, 109))	('H2R', 'Gene', (92, 95))	('H1R', 'Gene', '3269', (87, 90))
642975	31231212	The discovery of the first selective and potent H4R antagonist JNJ7777120 by Johnson & Johnson Research and Development (now Janssen Pharmaceuticals, Inc.) was essential for evaluating the role of H4R in pathophysiology, including immune reaction-associated pruritus and inflammation.	('pruritus', 'Phenotype', 'HP:0000989', (258, 266))	('including immune reaction-associated', 'Disease', (221, 257))	('men', 'Species', '9606', (115, 118))	('and', 'Disease', (267, 270))	('pruritus', 'Disease', 'MESH:D011537', (258, 266))	('pruritus', 'Disease', (258, 266))	('inflammation', 'Disease', 'MESH:D007249', (271, 283))	('JNJ7777120', 'Var', (63, 73))	('inflammation', 'Disease', (271, 283))	('JNJ7777120', 'Chemical', 'MESH:C484309', (63, 73))
642978	31231212	Recently, the compound JNJ39758979 was developed as a more potent and selective H4R antagonist than JNJ7777120 and it also shows preclinical anti-inflammatory and antipruritic effects.	('JNJ7777120', 'Chemical', 'MESH:C484309', (100, 110))	('antipruritic effects', 'CPA', (163, 183))	('anti-inflammatory', 'CPA', (141, 158))	('JNJ39758979', 'Var', (23, 34))	('H4R antagonist', 'Protein', (80, 94))
642982	31231212	JNJ39758979 was also tested in a phase 2a trial in adults with uncontrolled asthma without reaching the primary efficacy endpoint.	('asthma', 'Disease', (76, 82))	('asthma', 'Disease', 'MESH:D001249', (76, 82))	('JNJ39758979', 'Var', (0, 11))	('asthma', 'Phenotype', 'HP:0002099', (76, 82))
642989	31231212	A recent phase 2a clinical trial was carried out with the selective H4R antagonist ZPL-3893787, administered orally in patients with moderate to severe atopic dermatitis.	('patients', 'Species', '9606', (119, 127))	('H4R', 'Protein', (68, 71))	('ZPL-3893787', 'Var', (83, 94))	('dermatitis', 'Phenotype', 'HP:0011123', (159, 169))	('rat', 'Species', '10116', (137, 140))	('atopic dermatitis', 'Disease', 'MESH:D003876', (152, 169))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (152, 169))	('ZPL-3893787', 'Chemical', '-', (83, 94))	('atopic dermatitis', 'Disease', (152, 169))
643007	31231212	Patients with high protein expression of H4R in tumor cells exhibited a larger primary tumor size and a greater number of lymph node metastases than those with lower expression.	('larger', 'PosReg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (48, 53))	('high protein expression', 'Var', (14, 37))	('tumor', 'Disease', (87, 92))	('H4R', 'Protein', (41, 44))	('Patients', 'Species', '9606', (0, 8))	('metastases', 'Disease', (133, 143))	('greater number of lymph node', 'Phenotype', 'HP:0032536', (104, 132))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('metastases', 'Disease', 'MESH:D009362', (133, 143))
643017	31231212	Furthermore, authors demonstrated that deletion and downregulation of H4R gene take place in the progression but not the initiation of stomach cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('H4R', 'Gene', (70, 73))	('stomach cancer', 'Phenotype', 'HP:0012126', (135, 149))	('initiation of stomach cancer', 'Disease', (121, 149))	('deletion', 'Var', (39, 47))	('downregulation', 'NegReg', (52, 66))	('initiation of stomach cancer', 'Disease', 'MESH:D013274', (121, 149))	('rat', 'Species', '10116', (28, 31))
643026	31231212	On the other hand, a previous study showed that JNJ7777120 inhibited histamine-induced cell growth of human CRC cell lines.	('histamine', 'Chemical', 'MESH:D006632', (69, 78))	('inhibited', 'NegReg', (59, 68))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('JNJ7777120', 'Var', (48, 58))	('JNJ7777120', 'Chemical', 'MESH:C484309', (48, 58))	('human', 'Species', '9606', (102, 107))
643029	31231212	In addition, it was reported that histidine decarboxylase (HDC) deficiency promoted inflammation-associated CRC.	('HDC', 'Gene', (59, 62))	('histidine decarboxylase', 'Gene', '3067', (34, 57))	('deficiency', 'Var', (64, 74))	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('promoted', 'PosReg', (75, 83))	('inflammation', 'Disease', (84, 96))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('HDC', 'Gene', '3067', (59, 62))	('histidine decarboxylase', 'Gene', (34, 57))
643032	31231212	Administration of L. reuteri and not of an isogenic HDC-deficient L. reuteri mutant that was unable to generate histamine, suppressed carcinogenesis, cancer-associated cytokines, and decreased the relative number of splenic CD11b+Gr-1+ immature myeloid cells, which confirmed the potential antitumorigenic effect of histamine.	('carcinogenesis', 'Disease', 'MESH:D063646', (134, 148))	('rat', 'Species', '10116', (8, 11))	('HDC', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('CD11b', 'Gene', '3684', (224, 229))	('CD11b', 'Gene', (224, 229))	('decreased', 'NegReg', (183, 192))	('cancer', 'Disease', (150, 156))	('HDC', 'Gene', '3067', (52, 55))	('histamine', 'Chemical', 'MESH:D006632', (112, 121))	('L. reuteri', 'Species', '1598', (66, 76))	('L. reuteri', 'Gene', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('mutant', 'Var', (77, 83))	('rat', 'Species', '10116', (107, 110))	('tumor', 'Disease', (294, 299))	('L. reuteri', 'Species', '1598', (18, 28))	('suppressed', 'NegReg', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('carcinogenesis', 'Disease', (134, 148))	('histamine', 'Chemical', 'MESH:D006632', (316, 325))	('tumor', 'Disease', 'MESH:D009369', (294, 299))
643047	31231212	To confirm the exclusive participation of the H4R in these processes, studies were performed in cells with genetic knockdown of the H3R and overexpression of H4R.	('overexpression', 'PosReg', (140, 154))	('H3R', 'Gene', '11255', (132, 135))	('H3R', 'Gene', (132, 135))	('knockdown', 'Var', (115, 124))
643058	31231212	It is important to highlight that high expression of H4R in tumor specimens was associated with increased OS in pancreatic cancer (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('H4R', 'Protein', (53, 56))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('high expression', 'Var', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('men', 'Species', '9606', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('pancreatic cancer', 'Disease', (112, 129))	('tumor', 'Disease', (60, 65))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('OS', 'Chemical', '-', (106, 108))
643096	31231212	Further supporting the critical role of H4R in breast cancer development and progression, He and coworkers demonstrated the presence of polymorphisms of the H4R gene (rs623590, rs11662595, and rs1421125 genotypes of H4R gene) in Chinese Han population, which were associated with the risk of developing breast cancer and the malignant degree of the tumor.	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('rs11662595', 'Var', (177, 187))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('rs623590', 'Var', (167, 175))	('breast cancer', 'Disease', (47, 60))	('rs11662595', 'Mutation', 'rs11662595', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('H4R', 'Gene', (157, 160))	('rs623590', 'Mutation', 'rs623590', (167, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', (349, 354))	('rat', 'Species', '10116', (114, 117))	('associated', 'Reg', (264, 274))	('rs1421125', 'Mutation', 'rs1421125', (193, 202))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('rs1421125', 'Var', (193, 202))	('men', 'Species', '9606', (68, 71))
643098	31231212	All the studies, using different H4R ligands and also genetic down-regulation of H4R, demonstrated that the principal receptor subtype involved in the histamine-induced reduction of proliferation was the H4R.	('proliferation', 'CPA', (182, 195))	('H4R', 'Protein', (81, 84))	('H4R', 'Protein', (204, 207))	('reduction', 'NegReg', (169, 178))	('histamine', 'Chemical', 'MESH:D006632', (151, 160))	('down-regulation', 'NegReg', (62, 77))	('rat', 'Species', '10116', (189, 192))	('genetic', 'Var', (54, 61))	('rat', 'Species', '10116', (93, 96))
643099	31231212	The in vivo administration of histamine or H4R agonists (e.g., JNJ28610244) diminished the tumor growth of human triple negative breast cancer (TNBC) developed in immune-deficient nude mice with MDA-MB-231 cells.	('breast cancer', 'Disease', (129, 142))	('nude mice', 'Species', '10090', (180, 189))	('histamine', 'Chemical', 'MESH:D006632', (30, 39))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (195, 205))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('human', 'Species', '9606', (107, 112))	('JNJ28610244', 'Var', (63, 74))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('diminished', 'NegReg', (76, 86))	('rat', 'Species', '10116', (20, 23))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('tumor', 'Disease', (91, 96))	('TNBC', 'Disease', 'None', (144, 148))	('TNBC', 'Disease', (144, 148))
643100	31231212	On the other hand, tumor doubling time was not significantly modified while mean survival was reduced after the treatment with the H4R antagonist JNJ10191584.	('JNJ10191584', 'Chemical', 'MESH:C506811', (146, 157))	('JNJ10191584', 'Var', (146, 157))	('reduced', 'NegReg', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('men', 'Species', '9606', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('mean survival', 'CPA', (76, 89))
643116	31231212	Furthermore, patients with tumors showing low/medium H4R expression presented a higher OS compared to those with high expression levels (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('H4R', 'Protein', (53, 56))	('low/medium', 'Var', (42, 52))	('patients', 'Species', '9606', (13, 21))	('OS', 'Chemical', '-', (87, 89))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('higher', 'PosReg', (80, 86))
643130	31231212	Likewise, results described in breast cancer, genetic variations of H4R gene were found in a large number of Chinese NSCLC patients.	('NSCLC', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('found', 'Reg', (82, 87))	('genetic variations', 'Var', (46, 64))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('H4R', 'Gene', (68, 71))	('breast cancer', 'Disease', (31, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))
643131	31231212	In particular, the loss-of-function polymorphism rs11662595, associated to a higher invasive behavior, was linked to the prognosis, the degree of malignancy, and the metastatic potential of NSCLC.	('rs11662595', 'Mutation', 'rs11662595', (49, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (190, 195))	('invasive behavior', 'CPA', (84, 101))	('higher', 'PosReg', (77, 83))	('metastatic potential', 'CPA', (166, 186))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('rs11662595', 'Var', (49, 59))	('NSCLC', 'Disease', (190, 195))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('malignancy', 'Disease', (146, 156))	('loss-of-function', 'NegReg', (19, 35))
643153	31231212	Antagonist JNJ7777120, as mentioned before, shows high selectivity for the human, mouse and rat H4R.	('human', 'Species', '9606', (75, 80))	('rat', 'Species', '10116', (92, 95))	('JNJ7777120', 'Var', (11, 21))	('H4R', 'Protein', (96, 99))	('men', 'Species', '9606', (26, 29))	('JNJ7777120', 'Chemical', 'MESH:C484309', (11, 21))	('mouse', 'Species', '10090', (82, 87))
643160	31231212	Human H4R isoforms are the result of alternative splicing.	('alternative splicing', 'Var', (37, 57))	('Human H4R', 'Protein', (0, 9))	('Human', 'Species', '9606', (0, 5))
643163	31231212	Some polymorphisms of H4R have been reported in cancer, which were associated to malignancy of the disease in a Chinese Han population.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('H4R', 'Gene', (22, 25))	('reported', 'Reg', (36, 44))	('associated', 'Reg', (67, 77))	('cancer', 'Disease', (48, 54))	('malignancy of the disease', 'Disease', 'MESH:D009369', (81, 106))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('malignancy of the disease', 'Disease', (81, 106))	('polymorphisms', 'Var', (5, 18))
643165	31231212	In addition, the study of the alteration frequency of H4R gene in the main cancer types, with available data from cBioPortal, indicated that H4R gene alterations occurred in different percentage depending on cancer type.	('cancer', 'Disease', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('H4R gene', 'Gene', (141, 149))	('rat', 'Species', '10116', (154, 157))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('alterations', 'Var', (150, 161))	('rat', 'Species', '10116', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
643166	31231212	Amplifications and mutations comprised the major types of H4R gene alterations (Figure 3).	('Amplifications', 'Var', (0, 14))	('H4R', 'Gene', (58, 61))	('mutations', 'Var', (19, 28))	('rat', 'Species', '10116', (71, 74))
643167	31231212	The significance of the genomics alterations of H4R in cancer tissue is still unknown and deserves further investigation.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rat', 'Species', '10116', (37, 40))	('alterations', 'Var', (33, 44))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('H4R', 'Gene', (48, 51))	('cancer', 'Disease', (55, 61))
643179	31231212	In this context, H4R gene alterations (e.g., mutation, deletions, and amplifications) in different cancer types should be studied.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('rat', 'Species', '10116', (30, 33))	('cancer', 'Disease', (99, 105))	('H4R', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('deletions', 'Var', (55, 64))
643191	31231212	H4R ligands exhibit a complex pharmacology, which is related to numerous factors including tissue variability in histamine-induced signaling pathways, functional selectivity, intra and interspecies differences in potency and selectivity, structural homology with H3R, splice variant isoforms, and polymorphisms that could preclude H4R function, together with impairment expression in pathological conditions.	('histamine', 'Chemical', 'MESH:D006632', (113, 122))	('polymorphisms', 'Var', (297, 310))	('men', 'Species', '9606', (365, 368))	('H3R', 'Gene', (263, 266))	('H3R', 'Gene', '11255', (263, 266))
643208	30934987	For cervical ESCC, T4b and high tumor grade were independent prognostic factors of a worse overall survival (OS) in univariate and multivariate analyses.	('T4b', 'Var', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('high', 'Var', (27, 31))	('overall', 'MPA', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('OS', 'Chemical', '-', (109, 111))	('tumor', 'Disease', (32, 37))	('cervical ESCC', 'Disease', (4, 17))
643234	30934987	With respect to OS, there were no significant differences in terms of age (<60 versus >=60 years), N status (N0-1 versus N2-3), and tumor stage (stage IIIA-B versus stage IIIC) in a univariate analysis.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('OS', 'Chemical', '-', (16, 18))	('N0-1', 'Var', (109, 113))
643235	30934987	Meanwhile, the 19 patients with non-T4b (T2-4a) status had a significantly better OS than that of the 44 patients with T4b disease (26.1 versus 17.3 months, p = 0.035).	('better', 'PosReg', (75, 81))	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (18, 26))	('OS', 'Chemical', '-', (82, 84))	('non-T4b', 'Var', (32, 39))
643237	30934987	Multivariate analysis showed that non-T4b status (p = 0.044, hazard ratio: 0.47, 95% confidence interval: 0.23-0.98) and grade 1-2 disease (p = 0.023, hazard ratio: 0.42, 95% confidence interval: 0.20-0.89) remained the independent prognostic factors of a superior OS.	('non-T4b status', 'Var', (34, 48))	('superior OS', 'Disease', (256, 267))	('OS', 'Chemical', '-', (265, 267))
643262	30934987	Previous studies have shown that surgical resection as an initial treatment strategy does not improve the outcome of esophageal cancer patients with T4b status.	('patients', 'Species', '9606', (135, 143))	('esophageal cancer', 'Disease', (117, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('T4b status', 'Var', (149, 159))
643304	30934987	This work was supported by grants from the National Science Council of Taiwan (MOST 105-2314-B-182A-029, MOST 106-2314-B-182A-159-MY3, MOST 106-2320-B-182A-015 and MOST 107-2314-B-182A-156-MY3) and Chang Gung Memorial Hospital (CMRPG8I0201).	('106-2314-B-182A-159-MY3', 'Var', (110, 133))	('OS', 'Chemical', '-', (165, 167))	('OS', 'Chemical', '-', (80, 82))	('OS', 'Chemical', '-', (136, 138))	('OS', 'Chemical', '-', (106, 108))	('107-2314-B-182A-156-MY3', 'Var', (169, 192))
643305	30705370	Identification of recurrent fusion genes across multiple cancer types Chromosome changes are one of the hallmarks of human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('human', 'Species', '9606', (117, 122))	('cancer', 'Disease', (57, 63))	('fusion', 'Var', (28, 34))	('malignancies', 'Disease', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
643306	30705370	Chromosomal rearrangement is frequent in human cancers.	('human', 'Species', '9606', (41, 46))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Chromosomal rearrangement', 'Var', (0, 25))
643307	30705370	One of the consequences of chromosomal rearrangement is gene fusions in the cancer genome.	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('gene fusions', 'Var', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
643308	30705370	We have previously identified a panel of fusion genes in aggressive prostate cancers.	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('prostate cancers', 'Phenotype', 'HP:0012125', (68, 84))	('aggressive prostate cancers', 'Disease', (57, 84))	('fusion genes', 'Var', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('aggressive prostate cancers', 'Disease', 'MESH:D011471', (57, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))
643310	30705370	Among them, the CCNH-C5orf30 and TRMT11-GRIK2 gene fusions were found in breast cancer, colon cancer, non-small cell lung cancer, esophageal adenocarcinoma, glioblastoma multiforme, ovarian cancer and liver cancer, with frequencies ranging from 12.9% to 85%.	('ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('liver cancer', 'Disease', 'MESH:D006528', (201, 213))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (106, 128))	('CCNH', 'Gene', (16, 20))	('colon cancer', 'Phenotype', 'HP:0003003', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (102, 128))	('glioblastoma multiforme', 'Disease', (157, 180))	('liver cancer', 'Phenotype', 'HP:0002896', (201, 213))	('C5orf30', 'Gene', '90355', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (157, 180))	('fusions', 'Var', (51, 58))	('liver cancer', 'Disease', (201, 213))	('C5orf30', 'Gene', (21, 28))	('CCNH', 'Gene', '902', (16, 20))	('TRMT11', 'Gene', (33, 39))	('colon cancer', 'Disease', 'MESH:D015179', (88, 100))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (130, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('ovarian cancer', 'Disease', 'MESH:D010051', (182, 196))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('non-small cell lung cancer', 'Disease', (102, 128))	('TRMT11', 'Gene', '60487', (33, 39))	('GRIK2', 'Gene', (40, 45))	('found', 'Reg', (64, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (130, 155))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('esophageal adenocarcinoma', 'Disease', (130, 155))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('colon cancer', 'Disease', (88, 100))	('breast cancer', 'Disease', (73, 86))	('GRIK2', 'Gene', '2898', (40, 45))	('ovarian cancer', 'Disease', (182, 196))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (102, 128))
643319	30705370	These five types of cancers are projected to account for 305710 deaths in 2018 or over 50% of all cancer-related deaths in the US.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('305710', 'Var', (57, 63))	('death', 'Disease', 'MESH:D003643', (64, 69))	('death', 'Disease', 'MESH:D003643', (113, 118))	('death', 'Disease', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('death', 'Disease', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
643354	30705370	The KDM4-AC011523.2 fusion was only found in 3 breast cancer and 3 lung cancer samples.	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('KDM4-AC011523.2', 'Var', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('found', 'Reg', (36, 41))	('lung cancer', 'Disease', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
643355	30705370	Interestingly, ductal type breast cancers positive for TRMT11-GRIK2 were associated with a lower likelihood of developing local lymph node metastasis (46.7% versus 93.3%, p = 0.014).	('lower', 'NegReg', (91, 96))	('GRIK2', 'Gene', (62, 67))	('GRIK2', 'Gene', '2898', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('ductal type breast cancers', 'Disease', (15, 41))	('breast cancers', 'Phenotype', 'HP:0003002', (27, 41))	('local lymph node metastasis', 'CPA', (122, 149))	('positive', 'Var', (42, 50))	('TRMT11', 'Gene', '60487', (55, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('ductal type breast cancers', 'Disease', 'MESH:D001943', (15, 41))	('TRMT11', 'Gene', (55, 61))
643356	30705370	Liver cancers positive for TRMT11-GRIK2 were also associated with a higher rate of overall survival (41.7% versus 6.9%, p = 0.006).	('TRMT11', 'Gene', '60487', (27, 33))	('overall', 'MPA', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Liver cancers', 'Phenotype', 'HP:0002896', (0, 13))	('higher', 'PosReg', (68, 74))	('Liver cancers', 'Disease', 'MESH:D006528', (0, 13))	('positive', 'Var', (14, 22))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('TRMT11', 'Gene', (27, 33))	('Liver cancers', 'Disease', (0, 13))	('GRIK2', 'Gene', (34, 39))	('GRIK2', 'Gene', '2898', (34, 39))
643357	30705370	KDM4-AC011523.2 was only detected in lobular type breast cancer and adenocarcinoma of the lung.	('KDM4-AC011523.2', 'Var', (0, 15))	('lobular type breast cancer', 'Disease', (37, 63))	('adenocarcinoma of the lung', 'Disease', (68, 94))	('lobular type breast cancer', 'Disease', 'MESH:D013274', (37, 63))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (68, 94))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
643371	30705370	Almost all cancer-specific gene fusions are the result of chromosomal rearrangements or translocations.	('fusions', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('result', 'Reg', (48, 54))	('translocations', 'Var', (88, 102))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('chromosomal rearrangements', 'Var', (58, 84))
643372	30705370	There is increasing evidence suggesting that gene fusions are some of the key drivers of human cancer development.	('human', 'Species', '9606', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('gene fusions', 'Var', (45, 57))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
643382	30705370	The expression of this fusion gene induced spontaneous liver cancer in mice by ectopically phosphorylating the EGFR extracellular domain and activating its signaling pathways.	('mice', 'Species', '10090', (71, 75))	('signaling pathways', 'Pathway', (156, 174))	('EGFR extracellular', 'Protein', (111, 129))	('liver cancer', 'Phenotype', 'HP:0002896', (55, 67))	('liver cancer', 'Disease', 'MESH:D006528', (55, 67))	('activating', 'Reg', (141, 151))	('induced', 'Reg', (35, 42))	('liver cancer', 'Disease', (55, 67))	('expression', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
643385	30705370	The TMEM135-CCDC67, mTOR-TP53BP1 and TRMT11-GRIK2 gene fusions are equivalent to the functional deletion of CCDC67, TP53BP1 and GRIK2, respectively.	('TRMT11', 'Gene', (37, 43))	('TP53BP1', 'Gene', (25, 32))	('TMEM135', 'Gene', (4, 11))	('CCDC67', 'Gene', '159989', (108, 114))	('GRIK2', 'Gene', (44, 49))	('TRMT11', 'Gene', '60487', (37, 43))	('CCDC67', 'Gene', '159989', (12, 18))	('mTOR', 'Gene', '2475', (20, 24))	('TMEM135', 'Gene', '65084', (4, 11))	('GRIK2', 'Gene', '2898', (44, 49))	('GRIK2', 'Gene', (128, 133))	('TP53BP1', 'Gene', '7158', (116, 123))	('CCDC67', 'Gene', (108, 114))	('CCDC67', 'Gene', (12, 18))	('GRIK2', 'Gene', '2898', (128, 133))	('TP53BP1', 'Gene', (116, 123))	('deletion', 'Var', (96, 104))	('TP53BP1', 'Gene', '7158', (25, 32))	('mTOR', 'Gene', (20, 24))
643386	30705370	Deletions of these genes have been shown to promote the aggressive behaviors of cancers.	('aggressive behaviors of cancers', 'Disease', 'MESH:D001523', (56, 87))	('aggressive behaviors', 'Phenotype', 'HP:0000718', (56, 76))	('promote', 'PosReg', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('aggressive behaviors of cancers', 'Disease', (56, 87))	('Deletions', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
643397	30705370	The absence of TRMT11 may produce less efficient and unstable translation of mRNA into protein in cancer cells due to tRNA defects.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TRMT11', 'Gene', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('less', 'NegReg', (34, 38))	('tRNA', 'MPA', (118, 122))	('cancer', 'Disease', (98, 104))	('TRMT11', 'Gene', '60487', (15, 21))	('absence', 'Var', (4, 11))	('translation of mRNA into protein', 'MPA', (62, 94))
643398	30705370	The lack of GRIK2 may accelerate cell cycle progression and promote cell migration.	('accelerate', 'PosReg', (22, 32))	('cell migration', 'CPA', (68, 82))	('promote', 'PosReg', (60, 67))	('GRIK2', 'Gene', (12, 17))	('GRIK2', 'Gene', '2898', (12, 17))	('cell cycle progression', 'CPA', (33, 55))	('lack', 'Var', (4, 8))
643403	30705370	The CCNH-C5orf30 gene fusion produces a truncated cyclin H protein with the deletion of its H5' and HC domains.	('deletion', 'Var', (76, 84))	('C5orf30', 'Gene', '90355', (9, 16))	('CCNH', 'Gene', '902', (4, 8))	('C5orf30', 'Gene', (9, 16))	('cyclin H', 'Gene', (50, 58))	('cyclin H', 'Gene', '902', (50, 58))	('CCNH', 'Gene', (4, 8))
643404	30705370	A study showed that CCNH mutants lacking the HC domain do not activate cdk7.	('CCNH', 'Gene', (20, 24))	('not', 'NegReg', (58, 61))	('mutants', 'Var', (25, 32))	('cdk7', 'Gene', (71, 75))	('CCNH', 'Gene', '902', (20, 24))	('activate', 'PosReg', (62, 70))	('HC domain', 'MPA', (45, 54))	('cdk7', 'Gene', '1022', (71, 75))	('lacking', 'NegReg', (33, 40))
643405	30705370	As a result, the truncated CCNH from the gene fusion may have a negative impact on the functions of RNA polymerase and TFIIH.	('functions', 'MPA', (87, 96))	('TFIIH', 'Gene', (119, 124))	('CCNH', 'Gene', '902', (27, 31))	('truncated', 'Var', (17, 26))	('TFIIH', 'Gene', '2967', (119, 124))	('RNA', 'Protein', (100, 103))	('negative', 'NegReg', (64, 72))	('CCNH', 'Gene', (27, 31))
643408	30705370	The CCNH-C5orf30 gene fusion places C5orf30 expression under the CCNH promoter and may promote its expression.	('expression', 'MPA', (99, 109))	('CCNH', 'Gene', (65, 69))	('expression', 'MPA', (44, 54))	('C5orf30', 'Gene', '90355', (9, 16))	('CCNH', 'Gene', '902', (65, 69))	('CCNH', 'Gene', '902', (4, 8))	('C5orf30', 'Gene', '90355', (36, 43))	('C5orf30', 'Gene', (9, 16))	('C5orf30', 'Gene', (36, 43))	('promote', 'PosReg', (87, 94))	('CCNH', 'Gene', (4, 8))	('fusion', 'Var', (22, 28))
643478	30313035	In addition, we also explored the relationship between low NDRG1 expression and clinicopathological features of DSCs.	('NDRG1', 'Gene', '10397', (59, 64))	('expression', 'MPA', (65, 75))	('low', 'Var', (55, 58))	('NDRG1', 'Gene', (59, 64))	('DSCs', 'Disease', (112, 116))
643498	30313035	Inversely, the in vitro studies verified that NDRG1 overexpression inhibited cell proliferation and invasiveness and induced G1 cell cycle arrest and early apoptosis in gastric cancer.	('gastric cancer', 'Disease', (169, 183))	('NDRG1', 'Gene', (46, 51))	('inhibited', 'NegReg', (67, 76))	('overexpression', 'Var', (52, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('NDRG1', 'Gene', '10397', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('G1 cell cycle arrest', 'CPA', (125, 145))	('invasiveness', 'CPA', (100, 112))	('induced', 'Reg', (117, 124))	('cell proliferation', 'CPA', (77, 95))
643501	30313035	Moreover, it was demonstrated that NDRG1 overexpression could inhibit the invasion, metastasis and epithelial-mesenchymal transition (EMT) of colorectal cancer via multiple pathways, including NF-kappaB and nuclear beta-catenin signaling pathways.	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('NDRG1', 'Gene', (35, 40))	('invasion', 'CPA', (74, 82))	('overexpression', 'Var', (41, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('metastasis', 'CPA', (84, 94))	('NDRG1', 'Gene', '10397', (35, 40))	('beta-catenin', 'Gene', (215, 227))	('colorectal cancer', 'Disease', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('inhibit', 'NegReg', (62, 69))	('rectal cancer', 'Phenotype', 'HP:0100743', (146, 159))	('epithelial-mesenchymal transition', 'CPA', (99, 132))	('beta-catenin', 'Gene', '1499', (215, 227))
643507	30313035	A most recent study by Sevinsky et al reported that high NDRG1 expression was associated with worse prognosis in breast cancer patients, and they demonstrated that NDRG1 promoted breast cancer aggressiveness by regulating the fate of lipids in cells.	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('NDRG1', 'Gene', (164, 169))	('NDRG1', 'Gene', '10397', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('aggressiveness', 'Phenotype', 'HP:0000718', (193, 207))	('breast cancer aggressiveness', 'Disease', 'MESH:D001943', (179, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('breast cancer aggressiveness', 'Disease', (179, 207))	('regulating', 'Reg', (211, 221))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('lipids', 'Chemical', 'MESH:D008055', (234, 240))	('expression', 'MPA', (63, 73))	('NDRG1', 'Gene', (57, 62))	('high', 'Var', (52, 56))	('fate of lipids in cells', 'MPA', (226, 249))	('promoted', 'PosReg', (170, 178))	('NDRG1', 'Gene', '10397', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('patients', 'Species', '9606', (127, 135))
643566	29745062	Patients with high GAS5 expression and low GAS5 expression showed no significant difference in overall survival (Figure 1C).	('GAS5', 'Gene', (19, 23))	('GAS5', 'Gene', (43, 47))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('GAS5', 'Gene', '60674', (19, 23))	('GAS5', 'Gene', '60674', (43, 47))
643570	29745062	GAS5 can inhibit the proliferation and promote the apoptosis of multiple cell types and is a promising diagnostic and prognostic cancer biomarker.11, 12, 14 To study the biological function of GAS5 in esophageal cancer, we silenced GAS5 in 2 esophageal cancer cell lines, KYSE30 and KYSE180 which showed medium GAS5 expression, using lentivirus-mediated knockdown (Figure 2A,B).	('GAS5', 'Gene', '60674', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('esophageal cancer', 'Disease', 'MESH:D004938', (201, 218))	('esophageal cancer', 'Disease', 'MESH:D004938', (242, 259))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('GAS5', 'Gene', (232, 236))	('GAS5', 'Gene', (311, 315))	('esophageal cancer', 'Disease', (201, 218))	('GAS5', 'Gene', (0, 4))	('esophageal cancer', 'Disease', (242, 259))	('GAS5', 'Gene', (193, 197))	('GAS5', 'Gene', '60674', (193, 197))	('silenced', 'Var', (223, 231))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (253, 259))	('cancer', 'Disease', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('GAS5', 'Gene', '60674', (232, 236))	('GAS5', 'Gene', '60674', (311, 315))	('KYSE180', 'CellLine', 'CVCL:1349', (283, 290))
643571	29745062	We next performed transwell assays to evaluate the effects of GAS5 on cell mobility; knockdown of GAS5 increased the migration and invasion of ESCC cells (Figure 2C,D).	('invasion', 'CPA', (131, 139))	('GAS5', 'Gene', '60674', (62, 66))	('migration', 'CPA', (117, 126))	('increased', 'PosReg', (103, 112))	('GAS5', 'Gene', (98, 102))	('ESCC', 'Disease', (143, 147))	('knockdown', 'Var', (85, 94))	('GAS5', 'Gene', '60674', (98, 102))	('GAS5', 'Gene', (62, 66))
643572	29745062	These results indicated that knockdown of the lncRNA GAS5 could promote ESCC cell proliferation, migration, and invasion.	('GAS5', 'Gene', (53, 57))	('migration', 'CPA', (97, 106))	('promote', 'PosReg', (64, 71))	('knockdown', 'Var', (29, 38))	('invasion', 'CPA', (112, 120))	('GAS5', 'Gene', '60674', (53, 57))	('ESCC', 'Disease', (72, 76))
643584	29745062	The results indicated that ruxolitinib could abrogate the upregulation of known ISGs, including ISG15 (interferon-stimulated gene 15), Mx1 (IFN-induced GTP-binding protein Mx1) and viperin (Figure 4B) and the lncRNA GAS5 (Figure 4C).	('ISG15', 'Gene', '9636', (96, 101))	('Mx1', 'Gene', (135, 138))	('GAS5', 'Gene', (216, 220))	('IFN', 'Gene', (140, 143))	('Mx1', 'Gene', (172, 175))	('interferon-stimulated gene 15', 'Gene', '9636', (103, 132))	('ISG15', 'Gene', (96, 101))	('GTP', 'Chemical', 'MESH:D006160', (152, 155))	('abrogate', 'NegReg', (45, 53))	('ruxolitinib', 'Var', (27, 38))	('viperin', 'Gene', (181, 188))	('viperin', 'Gene', '91543', (181, 188))	('GAS5', 'Gene', '60674', (216, 220))	('interferon-stimulated gene 15', 'Gene', (103, 132))	('IFN', 'Gene', '3439', (140, 143))	('ruxolitinib', 'Chemical', 'MESH:C540383', (27, 38))	('Mx1', 'Gene', '4599', (135, 138))	('upregulation', 'PosReg', (58, 70))	('Mx1', 'Gene', '4599', (172, 175))
643591	29745062	These genes were downregulated by GAS5 knockdown (Figure 5A) and upregulated by over-expression of GAS5 (Figure 5B) in 2 esophageal cancer cell lines.	('GAS5', 'Gene', '60674', (34, 38))	('knockdown', 'Var', (39, 48))	('esophageal cancer', 'Disease', (121, 138))	('downregulated', 'NegReg', (17, 30))	('over-expression', 'PosReg', (80, 95))	('GAS5', 'Gene', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('GAS5', 'Gene', (34, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('GAS5', 'Gene', '60674', (99, 103))	('upregulated', 'PosReg', (65, 76))
643592	29745062	To further elucidate the feedback regulation of IFN responses by the lncRNA GAS5, we detected the mRNA expression levels of known IFN-stimulated genes, including the antitumor effectors FASLG(Fas ligand), CDKN1A(cyclin-dependent kinase inhibitor 1), and TNFSF10(TNF-related apoptosis-inducing ligand)19 and the antiviral effectors viperin(Virus inhibitory protein), ISG15(Interferon-stimulated gene 15), Mx1(Interferon-induced GTP-binding protein Mx1) and IFIT1(Interferon-induced protein with tetratricopeptide repeats 1).24, 25 These genes were down-regulated by GAS5 knockdown (Figure 5C) and up-regulated by over-expression of GAS5 (Figure 5D).	('Interferon', 'Gene', '3439', (372, 382))	('IFN', 'Gene', '3439', (130, 133))	('down-regulated', 'NegReg', (547, 561))	('tumor', 'Disease', (170, 175))	('GAS5', 'Gene', (565, 569))	('TNFSF10', 'Gene', (254, 261))	('FASLG', 'Gene', (186, 191))	('ISG15', 'Gene', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('Interferon', 'Gene', (372, 382))	('cyclin-dependent kinase inhibitor 1', 'Gene', '1026', (212, 247))	('IFN', 'Gene', (130, 133))	('IFN', 'Gene', '3439', (48, 51))	('Interferon', 'Gene', '3439', (408, 418))	('GAS5', 'Gene', '60674', (631, 635))	('TNFSF10', 'Gene', '8743', (254, 261))	('Fas ligand', 'Gene', '356', (192, 202))	('Interferon', 'Gene', '3439', (462, 472))	('GAS5', 'Gene', '60674', (76, 80))	('IFIT1', 'Gene', (456, 461))	('FASLG', 'Gene', '356', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('viperin', 'Gene', (331, 338))	('IFN', 'Gene', (48, 51))	('Interferon', 'Gene', (408, 418))	('Fas ligand', 'Gene', (192, 202))	('Mx1(Interferon-induced GTP-binding protein Mx1', 'Gene', '4599', (404, 450))	('Interferon-induced protein with tetratricopeptide repeats 1', 'Gene', '3434', (462, 521))	('CDKN1A', 'Gene', (205, 211))	('up-regulated', 'PosReg', (596, 608))	('CDKN1A', 'Gene', '1026', (205, 211))	('Interferon', 'Gene', (462, 472))	('cyclin-dependent kinase inhibitor 1', 'Gene', (212, 247))	('viperin', 'Gene', '91543', (331, 338))	('GAS5', 'Gene', (631, 635))	('GAS5', 'Gene', '60674', (565, 569))	('knockdown', 'Var', (570, 579))	('IFIT1', 'Gene', '3434', (456, 461))	('GAS5', 'Gene', (76, 80))	('ISG15', 'Gene', '9636', (366, 371))
643594	29745062	The expression levels of IFN pathway-associated genes were slightly higher in ESCC tissue than in normal tissue in GSE53624 (Figure 6A) and obviously higher in GSE23400 (Figure 6B); these results were in accordance with the GAS5 expression level in ESCC.	('expression levels', 'MPA', (4, 21))	('GSE23400', 'Var', (160, 168))	('GSE53624', 'Var', (115, 123))	('ESCC', 'Disease', (78, 82))	('higher', 'PosReg', (150, 156))	('IFN', 'Gene', '3439', (25, 28))	('higher', 'PosReg', (68, 74))	('IFN', 'Gene', (25, 28))	('GAS5', 'Gene', (224, 228))	('GAS5', 'Gene', '60674', (224, 228))
643617	29745062	Crosstalk between the tumor suppressor gene GAS5 and the IFN signaling pathway forms a positive feedback loop that plays an antitumor role in ESCC.	('GAS5', 'Gene', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('IFN', 'Gene', '3439', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('IFN', 'Gene', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Crosstalk', 'Var', (0, 9))	('GAS5', 'Gene', '60674', (44, 48))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (128, 133))	('ESCC', 'Disease', (142, 146))
643802	29390464	To avoid misdiagnosis of spinal venous obstruction induced by SVCS, clinicians should be reminded that SVCS can induce systemic and spinal cord diseases through affecting the venous return.	('affecting', 'Reg', (161, 170))	('venous obstruction', 'Phenotype', 'HP:0025322', (32, 50))	('SVCS', 'Var', (103, 107))	('spinal cord diseases', 'Disease', (132, 152))	('venous return', 'MPA', (175, 188))	('spinal venous obstruction', 'Disease', (25, 50))	('spinal cord diseases', 'Phenotype', 'HP:0002143', (132, 152))	('spinal venous obstruction', 'Disease', 'MESH:D006502', (25, 50))	('spinal cord diseases', 'Disease', 'MESH:D013118', (132, 152))	('induce', 'Reg', (112, 118))
643868	25293388	Patients were scanned with the Hologic Discovery Wi QDR Series (S/N 84566; fan-beam, switched pulse dual-energy x-ray tube, operating at 100 kV and 140 kV) or the Hologic Discovery A QDR series 4500A (S/N 45018; fan-beam) in the General Hospital Groeninge (AZG) and the Ghent University hospital (UZG) respectively.	('S/N 45018', 'Var', (201, 210))	('S/N 84566', 'SUBSTITUTION', 'None', (64, 73))	('S/N 45018', 'SUBSTITUTION', 'None', (201, 210))	('S/N 84566', 'Var', (64, 73))	('Patients', 'Species', '9606', (0, 8))
643925	25293388	Recently, n-3 LCPUFA EPA under the form of fish oil has demonstrated anti-inflammatory properties that improved nutritional parameters in cancer patients.	('anti-inflammatory properties', 'MPA', (69, 97))	('patients', 'Species', '9606', (145, 153))	('cancer', 'Disease', (138, 144))	('EPA', 'Chemical', 'MESH:D015118', (21, 24))	('nutritional parameters', 'MPA', (112, 134))	('improved', 'PosReg', (103, 111))	('n-3 LCPUFA', 'Chemical', '-', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('n-3', 'Var', (10, 13))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('oil', 'Chemical', 'MESH:D009821', (48, 51))
643935	25293388	The large variability that is seen in FA changes over time, could be related to variations in supplement adherence as well as the significant decline in caloric intake in general, and lipid intake in specific, hampering n-3 PUFA uptake.	('hampering', 'NegReg', (210, 219))	('PUFA', 'Gene', '9933', (224, 228))	('decline', 'NegReg', (142, 149))	('caloric intake', 'MPA', (153, 167))	('PUFA', 'Gene', (224, 228))	('lipid', 'Chemical', 'MESH:D008055', (184, 189))	('variations', 'Var', (80, 90))	('lipid', 'MPA', (184, 189))
644000	19655439	The treatment for locally advanced esophageal cancer that does not have distant metastases and is potentially resectable (T3-4aN0, T1-4aN1M0) is highly variable in practice.	('metastases', 'Disease', (80, 90))	('T1-4aN1M0', 'Var', (131, 140))	('esophageal cancer', 'Disease', (35, 52))	('metastases', 'Disease', 'MESH:D009362', (80, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('T3-4aN0', 'Var', (122, 129))
644002	19655439	For patients with pN+ adenocarcinoma who are treated primarily with surgical resection, the National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant chemoradiation.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('pN+', 'Var', (18, 21))	('adenocarcinoma', 'Disease', 'MESH:D000230', (22, 36))	('patients', 'Species', '9606', (4, 12))	('Cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Cancer', 'Disease', (115, 121))	('Cancer', 'Disease', 'MESH:D009369', (115, 121))	('adenocarcinoma', 'Disease', (22, 36))
644037	19655439	In this study of 556 patients with adenocarcinoma of the stomach or cardia, 85% of whom had pathologic nodal disease, patients given adjuvant chemoradiation (45 Gy combined with 5-FU and leucovorin) had significantly better three year survival compared to patients treated with surgery alone (50% versus 41%, hazard ratio 1.32, p=0.0046).	('better', 'PosReg', (217, 223))	('nodal disease', 'Disease', (103, 116))	('5-FU', 'Chemical', 'MESH:D005472', (178, 182))	('patients', 'Species', '9606', (256, 264))	('adenocarcinoma of the stomach or cardia', 'Disease', 'MESH:D004938', (35, 74))	('patients', 'Species', '9606', (21, 29))	('adenocarcinoma of the stomach', 'Phenotype', 'HP:0006753', (35, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('leucovorin', 'Chemical', 'MESH:D002955', (187, 197))	('45 Gy', 'Var', (158, 163))	('adenocarcinoma of the stomach or cardia', 'Disease', (35, 74))	('patients', 'Species', '9606', (118, 126))	('nodal disease', 'Disease', 'MESH:D013611', (103, 116))
644081	24980814	ESCC is believed to develop due to a variety of risk factors including the accumulation of genetic mutations, tobacco and alcohol consumption, obesity, and diet.	('obesity', 'Phenotype', 'HP:0001513', (143, 150))	('genetic mutations', 'Var', (91, 108))	('obesity', 'Disease', 'MESH:D009765', (143, 150))	('ESCC', 'Disease', (0, 4))	('alcohol', 'Chemical', 'MESH:D000438', (122, 129))	('tobacco', 'Species', '4097', (110, 117))	('obesity', 'Disease', (143, 150))
644097	24980814	Correlating NUMB-1 expression to patient prognosis, we discovered that the low NUMB-1 group experienced a significantly shorter event-free survival (EFS) (median EFS: 16 months vs 45 months, p=0.023, log-rank test) and overall survival (OS) (median OS: 24 months vs 49 months, p=0.012, log-rank test) compared with patients in the high NUMB-1 group (Fig.	('NUMB', 'Gene', '8650', (336, 340))	('overall survival', 'CPA', (219, 235))	('NUMB', 'Gene', (79, 83))	('shorter', 'NegReg', (120, 127))	('patient', 'Species', '9606', (33, 40))	('patient', 'Species', '9606', (315, 322))	('low', 'Var', (75, 78))	('NUMB', 'Gene', '8650', (79, 83))	('patients', 'Species', '9606', (315, 323))	('NUMB', 'Gene', (12, 16))	('event-free survival', 'CPA', (128, 147))	('NUMB', 'Gene', (336, 340))	('NUMB', 'Gene', '8650', (12, 16))
644105	24980814	Migration and invasion of KYSE150 cells were dramatically decreased in NUMB-1 overexpressed cells as assessed by the scratch wound healing assay and Boyden chamber invasion assay, respectively (Fig.	('decreased', 'NegReg', (58, 67))	('overexpressed', 'Var', (78, 91))	('NUMB', 'Gene', (71, 75))	('invasion of KYSE150 cells', 'CPA', (14, 39))	('NUMB', 'Gene', '8650', (71, 75))	('KYSE150', 'CellLine', 'CVCL:1348', (26, 33))	('Boyden chamber invasion assay', 'CPA', (149, 178))
644131	24980814	In order to test whether the interaction between Aurora A and NUMB-1 is p53 dependent, we utilized siRNA to knockdown p53 expression.	('knockdown', 'Var', (108, 117))	('NUMB', 'Gene', (62, 66))	('p53', 'Gene', (118, 121))	('Aurora A', 'Gene', '6790', (49, 57))	('NUMB', 'Gene', '8650', (62, 66))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', '7157', (118, 121))	('Aurora A', 'Gene', (49, 57))
644132	24980814	S2, we successfully knockdown over 80% of endogenous p53, and still were able to detect interaction between Aurora A and NUMB-1.	('NUMB', 'Gene', (121, 125))	('Aurora A', 'Gene', '6790', (108, 116))	('NUMB', 'Gene', '8650', (121, 125))	('knockdown', 'Var', (20, 29))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('detect', 'Reg', (81, 87))	('interaction', 'Interaction', (88, 99))	('Aurora A', 'Gene', (108, 116))
644152	24980814	Cyclin B1, cdc2, and p21 (cell-cycle related proteins) were all upregulated and an increase in aneuploidy was observed upon ectopic expression of NUMB-1.	('cdc2', 'Gene', '983', (11, 15))	('p21', 'Gene', (21, 24))	('Cyclin B1', 'Gene', (0, 9))	('ectopic expression', 'Var', (124, 142))	('p21', 'Gene', '644914', (21, 24))	('aneuploidy', 'Disease', 'MESH:D000782', (95, 105))	('NUMB', 'Gene', (146, 150))	('upregulated', 'PosReg', (64, 75))	('NUMB', 'Gene', '8650', (146, 150))	('aneuploidy', 'Disease', (95, 105))	('Cyclin B1', 'Gene', '891', (0, 9))	('cdc2', 'Gene', (11, 15))
644153	24980814	Studies from the literature have shown that high expression of cyclin B1-cdc2 only occurs in the mitotic (M) phase, not the G2 phase, and that mitotic entry and exit are controlled by cyclin B1-cdc2 activation and inactivation, respectively.	('inactivation', 'Var', (214, 226))	('cyclin B1-cdc2', 'Gene', (184, 198))	('cyclin B1-cdc2', 'Gene', (63, 77))	('exit', 'CPA', (161, 165))	('cyclin B1-cdc2', 'Gene', '891;983', (63, 77))	('cyclin B1-cdc2', 'Gene', '891;983', (184, 198))	('mitotic entry', 'CPA', (143, 156))
644155	24980814	This is consistent with a previous study in which overexpression of NUMB by deletion of Musashi, a known repressor of NUMB translation, resulted in glioma cells arresting in M phase.	('deletion', 'Var', (76, 84))	('overexpression', 'PosReg', (50, 64))	('glioma', 'Disease', (148, 154))	('Musashi', 'Gene', (88, 95))	('NUMB', 'Gene', (118, 122))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('NUMB', 'Gene', '8650', (118, 122))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('NUMB', 'Gene', (68, 72))	('NUMB', 'Gene', '8650', (68, 72))
644156	24980814	In contrast, a recent study in human melanoma cells demonstrated that a targeted knockdown of NUMB expression disrupts its ability to interact with the serine/threonine polo-like kinase Plk1 thereby causing G2-M arrest and reducing cell growth.	('Plk1', 'Gene', (186, 190))	('causing', 'Reg', (199, 206))	('G2-M arrest', 'CPA', (207, 218))	('ability', 'MPA', (123, 130))	('cell growth', 'CPA', (232, 243))	('NUMB', 'Gene', (94, 98))	('threonine', 'Chemical', 'MESH:D013912', (159, 168))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('reducing', 'NegReg', (223, 231))	('human', 'Species', '9606', (31, 36))	('disrupts', 'NegReg', (110, 118))	('knockdown', 'Var', (81, 90))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('NUMB', 'Gene', '8650', (94, 98))	('Plk1', 'Gene', '5347', (186, 190))	('serine', 'Chemical', 'MESH:D012694', (152, 158))	('interact', 'Interaction', (134, 142))
644158	24980814	It is possible that the biologic effect of NUMB is isoform specific, as supported by a recent study which found that alternative splicing of NUMB produces functionally distinct protein isoforms that influence the proliferation of lung cancer cells differently.	('alternative splicing', 'Var', (117, 137))	('proliferation', 'CPA', (213, 226))	('lung cancer', 'Disease', (230, 241))	('NUMB', 'Gene', (141, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('NUMB', 'Gene', '8650', (141, 145))	('influence', 'Reg', (199, 208))	('NUMB', 'Gene', (43, 47))	('NUMB', 'Gene', '8650', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))
644165	24980814	Interestingly, in Drosophila neural precursor cells, activation of Aurora-A was shown to trigger phosphorylation of Numb and was responsible for the asymmetric localization of Numb during mitosis.	('Aurora-A', 'Gene', (67, 75))	('responsible', 'Reg', (129, 140))	('mitosis', 'Disease', (188, 195))	('activation', 'Var', (53, 63))	('phosphorylation', 'MPA', (97, 112))	('mitosis', 'Disease', 'None', (188, 195))	('Drosophila', 'Species', '7227', (18, 28))
644173	24980814	Of interest, we also found overexpression of NUMB-1 inhibits tumor growth in KYSE30 cell line and KYSE150 cell line, harboring mutant and wild type p53 respectively, which suggested the tumor suppressor function for NUMB-1 is p53 independent.	('mutant', 'Var', (127, 133))	('NUMB', 'Gene', (45, 49))	('tumor', 'Disease', (61, 66))	('p53', 'Gene', '7157', (226, 229))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('NUMB', 'Gene', '8650', (216, 220))	('NUMB', 'Gene', '8650', (45, 49))	('p53', 'Gene', (148, 151))	('KYSE150', 'CellLine', 'CVCL:1348', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('p53', 'Gene', '7157', (148, 151))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('inhibits', 'NegReg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('overexpression', 'PosReg', (27, 41))	('p53', 'Gene', (226, 229))	('NUMB', 'Gene', (216, 220))
644202	24980814	ESCC cell lines (KYSE150, KYSE30, KYSE180, and TE-1) were provided by Professors Guan XY, which were obtained from DSMZ, the German Resource Center for Biological Material, and cultured in RPMI-1640 (Invitrogen, USA) or DMEM supplemented with 10% FBS in a humidified incubator at 37 C, 5% CO2.	('CO2', 'Chemical', '-', (289, 292))	('DMEM', 'Chemical', '-', (220, 224))	('KYSE30', 'Var', (26, 32))	('FBS', 'Disease', 'MESH:D005198', (247, 250))	('RPMI-1640', 'Chemical', '-', (189, 198))	('KYSE180', 'CellLine', 'CVCL:1349', (34, 41))	('KYSE180', 'Var', (34, 41))	('FBS', 'Disease', (247, 250))	('KYSE150', 'CellLine', 'CVCL:1348', (17, 24))
644244	24212953	They reported that the rate of squamous carcinoma was 25-30% for rats with either DMNM or MNAN alone, and 20% for rats with induced gastroesophageal reflux plus DMNM, while the rate of malignant change rose up to 67-80% in rats with induced duodenoesophageal reflux plus either nitrosamine.	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (132, 155))	('gastroesophageal reflux plus DMNM', 'Disease', 'MESH:D005764', (132, 165))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (31, 49))	('nitrosamine', 'Chemical', 'MESH:D009602', (278, 289))	('squamous carcinoma', 'Disease', 'MESH:D002294', (31, 49))	('DMNM', 'Var', (82, 86))	('malignant change', 'Phenotype', 'HP:0002664', (185, 201))	('duodenoesophageal reflux', 'Phenotype', 'HP:0002020', (241, 265))	('rat', 'Species', '10116', (223, 226))	('DMNM', 'Chemical', 'MESH:C014130', (82, 86))	('DMNM', 'Chemical', 'MESH:C014130', (161, 165))	('rat', 'Species', '10116', (23, 26))	('rats', 'Species', '10116', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('MNAN', 'Chemical', 'MESH:C025033', (90, 94))	('rats', 'Species', '10116', (114, 118))	('rats', 'Species', '10116', (223, 227))	('squamous carcinoma', 'Disease', (31, 49))	('rat', 'Species', '10116', (114, 117))	('rat', 'Species', '10116', (177, 180))	('gastroesophageal reflux plus DMNM', 'Disease', (132, 165))	('rat', 'Species', '10116', (65, 68))
644284	24212953	On the other hand, CpG island hypermethylations in various genes rather than gene mutations involve the development of BE into EAC.	('EAC', 'Phenotype', 'HP:0011459', (127, 130))	('involve', 'Reg', (92, 99))	('BE', 'Phenotype', 'HP:0100580', (119, 121))	('hypermethylations', 'Var', (30, 47))	('BE into EAC', 'Disease', (119, 130))	('rat', 'Species', '10116', (65, 68))
644307	24212953	Epidemiologic studies showed that long-term use of PPI was associated with lower rates of dysplasia and adenocarcinoma in patients with Barrett's esophagus.	('lower', 'NegReg', (75, 80))	("Barrett's esophagus", 'Disease', (136, 155))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (136, 155))	('rat', 'Species', '10116', (81, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('patients', 'Species', '9606', (122, 130))	('PPI', 'Var', (51, 54))	('dysplasia and adenocarcinoma', 'Disease', 'MESH:D000230', (90, 118))
644318	24212953	Incidences of BE and EAC in the TPRO group were 67% and 17%, while they were 94% and 69% in the control group.	('BE', 'Phenotype', 'HP:0100580', (14, 16))	('EAC', 'Phenotype', 'HP:0011459', (21, 24))	('TPRO', 'Chemical', 'MESH:C003438', (32, 36))	('TPRO', 'Var', (32, 36))	('EAC', 'Disease', (21, 24))
644319	24212953	These results suggested that TPRO could prevent only development from BE to adenocarcinoma, but could not suppress inflammation or BE.	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('BE', 'Phenotype', 'HP:0100580', (70, 72))	('BE', 'Phenotype', 'HP:0100580', (131, 133))	('inflammation', 'Disease', (115, 127))	('TPRO', 'Var', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('TPRO', 'Chemical', 'MESH:C003438', (29, 33))	('adenocarcinoma', 'Disease', (76, 90))
644321	24212953	They showed that the incidence of EAC in the control group was 38.9% compared to no adenocarcinoma in the TPRO group and iNOS protein was overexpressed in BE of both groups, speculating that TPRO inhibited the production of not only nitroso-compounds by nitrate-reducing bacteria but also reactive nitrogen species, such as NO, ONOO- and N-nitroso-compounds, derived from duodenal refluxate.	('inhibited', 'NegReg', (196, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('adenocarcinoma', 'Disease', (84, 98))	('EAC', 'Disease', (34, 37))	('reactive nitrogen species', 'Chemical', 'MESH:D026361', (289, 314))	('reactive nitrogen species', 'MPA', (289, 314))	('nitroso-compounds', 'Chemical', 'MESH:D009603', (233, 250))	('TPRO', 'Chemical', 'MESH:C003438', (106, 110))	('duodenal reflux', 'Phenotype', 'HP:0002020', (372, 387))	('adenocarcinoma', 'Disease', 'MESH:D000230', (84, 98))	('TPRO', 'Chemical', 'MESH:C003438', (191, 195))	('nitrate', 'Chemical', 'MESH:D009566', (254, 261))	('ONOO-', 'Chemical', '-', (328, 333))	('N-nitroso-compounds', 'Chemical', '-', (338, 357))	('nitroso-compounds', 'Chemical', 'MESH:D009603', (340, 357))	('TPRO', 'Var', (191, 195))	('EAC', 'Phenotype', 'HP:0011459', (34, 37))	('production', 'MPA', (210, 220))	('BE', 'Phenotype', 'HP:0100580', (155, 157))
644331	24212953	More recently, it was demonstrated that unconjugated bile acids such as chenodeoxycholic acid and deoxycholic acid induced CREB and AP-1 dependant COX-2 expression in BE and EAC through PI3K/AKT and ERK 1/2 pathway.	('chenodeoxycholic acid', 'Var', (72, 93))	('CREB', 'Gene', '81646', (123, 127))	('EAC', 'Phenotype', 'HP:0011459', (174, 177))	('ERK 1/2', 'Gene', '50689;116590', (199, 206))	('expression', 'MPA', (153, 163))	('AP-1', 'Gene', '24516', (132, 136))	('BE', 'Phenotype', 'HP:0100580', (167, 169))	('CREB', 'Gene', (123, 127))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (77, 93))	('rat', 'Species', '10116', (29, 32))	('bile acids', 'Chemical', 'MESH:D001647', (53, 63))	('AKT', 'Gene', '24185', (191, 194))	('AP-1', 'Gene', (132, 136))	('ERK 1/2', 'Gene', (199, 206))	('COX-2', 'Gene', (147, 152))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (98, 114))	('AKT', 'Gene', (191, 194))	('deoxycholic acid', 'Var', (98, 114))	('chenodeoxycholic acid', 'Chemical', 'MESH:D002635', (72, 93))
644341	24212953	(Table 1) Three hypotheses accounting for reduced incidence of esophageal cancer by COX-2 inhibitor are suggested, that is, to inhibit the development of BE from reflux esophagitis, to inhibit the development of dysplasia in BE, or to inhibit the process of carcinogenesis in dysplasia.	('carcinogenesis in dysplasia', 'Disease', (258, 285))	('esophagitis', 'Phenotype', 'HP:0100633', (169, 180))	('reflux esophagitis', 'Disease', 'MESH:D005764', (162, 180))	('inhibit', 'NegReg', (127, 134))	('BE', 'Phenotype', 'HP:0100580', (154, 156))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('reduced', 'NegReg', (42, 49))	('COX-2', 'Gene', (84, 89))	('BE', 'Phenotype', 'HP:0100580', (225, 227))	('carcinogenesis in dysplasia', 'Disease', 'MESH:D063646', (258, 285))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('dysplasia', 'Disease', (276, 285))	('inhibit', 'NegReg', (235, 242))	('dysplasia', 'Disease', 'MESH:D004476', (276, 285))	('dysplasia', 'Disease', (212, 221))	('dysplasia', 'Disease', 'MESH:D004476', (212, 221))	('esophageal cancer', 'Disease', (63, 80))	('inhibitor', 'Var', (90, 99))	('inhibit', 'NegReg', (185, 192))	('reflux esophagitis', 'Disease', (162, 180))
644350	24212953	It demonstrated that the area of Barrett's involvement in the CLX group showed larger reduction than in the placebo group.	('reduction', 'NegReg', (86, 95))	('CLX', 'Chemical', 'MESH:D000068579', (62, 65))	('rat', 'Species', '10116', (10, 13))	('CLX', 'Var', (62, 65))
644376	22044848	A cohort study in Iowa found elevated incidence of esophageal and stomach cancer associated with high intake of heme iron but not total dietary iron.	('stomach cancer', 'Phenotype', 'HP:0012126', (66, 80))	('iron', 'Chemical', 'MESH:D007501', (144, 148))	('high intake', 'Var', (97, 108))	('iron', 'Chemical', 'MESH:D007501', (117, 121))	('heme', 'Chemical', 'MESH:D006418', (112, 116))	('esophageal and stomach cancer', 'Disease', 'MESH:D013274', (51, 80))	('heme', 'Protein', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
644418	22044848	In an analysis of heme iron intake in the NIH-AARP Diet and Health Study cohort, using the same database, heme iron was positively associated with esophageal adenocarcinoma (highest versus lowest quartile HR = 1.47, 95 % CI: 0.99 - 2.20, P for trend = 0.063).	('iron', 'Chemical', 'MESH:D007501', (111, 115))	('associated', 'Reg', (131, 141))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (147, 172))	('esophageal adenocarcinoma', 'Disease', (147, 172))	('heme', 'Chemical', 'MESH:D006418', (106, 110))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (147, 172))	('iron', 'Chemical', 'MESH:D007501', (23, 27))	('heme', 'Chemical', 'MESH:D006418', (18, 22))	('heme', 'Var', (106, 110))
644452	21846596	Nutrition-related deficiencies in vitamins, minerals, and other micronutrients have also been linked to the elevated risk of esophageal and gastric cancer in these areas.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('esophageal', 'Disease', 'MESH:D004941', (125, 135))	('linked', 'Reg', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('deficiencies', 'Var', (18, 30))	('gastric cancer', 'Disease', (140, 154))	('esophageal', 'Disease', (125, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))
644493	21846596	Moldy food intake was also associated with a greater than 50% increased risk for all three cancers.	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Disease', (91, 98))	('Moldy', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
644511	21846596	Similarly, lower education has also been associated with increased risk for these cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lower education', 'Var', (11, 26))	('lower education', 'Phenotype', 'HP:0001249', (11, 26))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))
644552	20808250	The FcepsilonRI-positive cell count varied by diagnosis (proximal biopsies EoE 32.6 +-19.0 cells/HPF, RE 26.7 +-16.6, controls 15.6 +-8.3, ANOVA p=0.005; distal biopsies EoE 24.2 +-16.2, RE 35.7 +-27.6, controls 15.3 +-8.4, p=0.006).	('FcepsilonRI', 'Gene', (4, 15))	('EoE', 'Var', (170, 173))	('FcepsilonRI', 'Gene', '2205', (4, 15))	('EoE', 'Var', (75, 78))
644709	31429766	Therefore, elucidating the genetic and epigenetic molecular alterations associated with HNSCC is extremely important to improving the diagnosis, appropriate treatment and prognosis of patients with HNSCC.	('patients', 'Species', '9606', (184, 192))	('si', 'Chemical', 'MESH:D012825', (177, 179))	('epigenetic molecular', 'Var', (39, 59))	('HNSCC', 'Disease', (88, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (198, 203))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('si', 'Chemical', 'MESH:D012825', (140, 142))
644734	31429766	LINC00460 and PRDX1 lentiviral expression vectors (wild-type and mutant) were constructed by HanYin Biotechnology Co., Ltd.	('LINC00460', 'Gene', (0, 9))	('LINC00460', 'Gene', '728192', (0, 9))	('PRDX1', 'Gene', (14, 19))	('mutant', 'Var', (65, 71))	('PRDX1', 'Gene', '5052', (14, 19))	('expression vectors', 'Species', '29278', (31, 49))
644750	31429766	After being blocked in 3% BSA for 30 min, the cells were incubated with E-cadherin (Cat# ab15148, 1:100) or Vimentin antibodies (Cat# D21H3, 1:100) overnight at 4  C, washed with PBST and then incubated with an Alexa Fluor 549-conjugated anti-goat IgG F (ab')2 fragment (1:200, Invitrogen) for 1 h at room temperature in the dark.	('Cat#', 'Var', (84, 88))	('Cat#', 'Var', (129, 133))	('Vimentin', 'Gene', (108, 116))	('goat', 'Species', '9925', (243, 247))	('PBS', 'Chemical', 'MESH:D007854', (179, 182))	('Vimentin', 'Gene', '7431', (108, 116))	('Alexa Fluor 549', 'Chemical', '-', (211, 226))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))
644765	31429766	To assess whether LINC00460 knockdown could inhibit tumorigenic capacity in vivo, we established a xenograft tumor mouse model using cholesterol-conjugated LINC00460 siRNA (si-LINC00460) for in vivo siRNA delivery.	('tumor', 'Disease', (52, 57))	('LINC00460', 'Gene', '728192', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('LINC00460', 'Gene', '728192', (18, 27))	('si', 'Chemical', 'MESH:D012825', (199, 201))	('knockdown', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('LINC00460', 'Gene', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('si', 'Chemical', 'MESH:D012825', (173, 175))	('inhibit', 'NegReg', (44, 51))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('mouse', 'Species', '10090', (115, 120))	('cholesterol', 'Chemical', 'MESH:D002784', (133, 144))	('LINC00460', 'Gene', '728192', (156, 165))	('LINC00460', 'Gene', (18, 27))	('LINC00460', 'Gene', (176, 185))	('tumor', 'Disease', (109, 114))
644792	31429766	The CCK-8 assay and colony formation assay results showed that LINC00460 knockdown suppressed cell proliferation in CAL-27 and HN30 cells (Fig.	('CAL-27', 'CellLine', 'CVCL:1107', (116, 122))	('HN30', 'CellLine', 'CVCL:5525', (127, 131))	('LINC00460', 'Gene', '728192', (63, 72))	('LINC00460', 'Gene', (63, 72))	('cell proliferation in CAL-27', 'CPA', (94, 122))	('suppressed', 'NegReg', (83, 93))	('knockdown', 'Var', (73, 82))
644794	31429766	The results of transwell assays demonstrated that LINC00460 knockdown suppressed cell migration and invasion in CAL-27 and HN30 cells (Fig.	('CAL-27', 'CellLine', 'CVCL:1107', (112, 118))	('HN30', 'CellLine', 'CVCL:5525', (123, 127))	('suppressed', 'NegReg', (70, 80))	('LINC00460', 'Gene', (50, 59))	('knockdown', 'Var', (60, 69))	('invasion', 'CPA', (100, 108))	('LINC00460', 'Gene', '728192', (50, 59))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('cell migration', 'CPA', (81, 95))
644799	31429766	LINC00460 knockdown significantly increased the levels of E-cadherin but decreased those of N-cadherin, Vimentin, ZEB1 and ZEB2 in CAL-27 and HN30 cells, whereas LINC00460 overexpression significantly decreased the levels of E-cadherin but increased those of N-cadherin, Vimentin, ZEB1 and ZEB2 in CAL-27 and SCC-9 cells, as determined by Western blot (Fig.	('levels', 'MPA', (48, 54))	('Vimentin', 'Gene', (104, 112))	('LINC00460', 'Gene', (0, 9))	('N-cadherin', 'Gene', '1000', (92, 102))	('decreased', 'NegReg', (73, 82))	('ZEB1', 'Gene', '6935', (281, 285))	('SCC-9', 'CellLine', 'CVCL:1685', (309, 314))	('levels', 'MPA', (215, 221))	('HN30', 'CellLine', 'CVCL:5525', (142, 146))	('N-cadherin', 'Gene', '1000', (259, 269))	('LINC00460', 'Gene', '728192', (0, 9))	('ZEB2', 'Gene', (290, 294))	('ZEB2', 'Gene', (123, 127))	('ZEB1', 'Gene', '6935', (114, 118))	('E-cadherin', 'Gene', (58, 68))	('E-cadherin', 'Gene', '999', (58, 68))	('si', 'Chemical', 'MESH:D012825', (182, 184))	('increased', 'PosReg', (34, 43))	('knockdown', 'Var', (10, 19))	('CAL-27', 'CellLine', 'CVCL:1107', (131, 137))	('increased', 'PosReg', (240, 249))	('ZEB2', 'Gene', '9839', (290, 294))	('ZEB2', 'Gene', '9839', (123, 127))	('E-cadherin', 'Gene', (225, 235))	('E-cadherin', 'Gene', '999', (225, 235))	('expression', 'Species', '29278', (176, 186))	('CAL-27', 'CellLine', 'CVCL:1107', (298, 304))	('LINC00460', 'Gene', (162, 171))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('ZEB1', 'Gene', (281, 285))	('Vimentin', 'Gene', '7431', (271, 279))	('si', 'Chemical', 'MESH:D012825', (187, 189))	('ZEB1', 'Gene', (114, 118))	('Vimentin', 'Gene', '7431', (104, 112))	('decreased', 'NegReg', (201, 210))	('LINC00460', 'Gene', '728192', (162, 171))	('N-cadherin', 'Gene', (259, 269))	('Vimentin', 'Gene', (271, 279))	('N-cadherin', 'Gene', (92, 102))
644805	31429766	The results showed that si-LINC00460-1 was the most effective in knocking down LINC00460 expression (Additional file 8: Figure S3).	('expression', 'MPA', (89, 99))	('knocking', 'Var', (65, 73))	('LINC00460', 'Gene', (79, 88))	('LINC00460', 'Gene', (27, 36))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('LINC00460', 'Gene', '728192', (79, 88))	('LINC00460', 'Gene', '728192', (27, 36))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('expression', 'Species', '29278', (89, 99))
644815	31429766	The presence of metastatic nodules in the mouse lungs was confirmed by H&E and Ki-67 staining, and the mice injected with A549 cells transduced with LINC00460 vector formed more nodules on their lung surfaces than the control group (Fig.	('cells', 'Var', (127, 132))	('Ki-67', 'Gene', (79, 84))	('mouse', 'Species', '10090', (42, 47))	('mice', 'Species', '10090', (103, 107))	('Ki-67', 'Gene', '17345', (79, 84))	('LINC00460', 'Gene', '728192', (149, 158))	('LINC00460', 'Gene', (149, 158))	('H&E', 'Chemical', '-', (71, 74))	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('more nodules', 'CPA', (173, 185))
644824	31429766	After the K at aa 120 was mutated to arginine (R), the ability of PRDX1 to bind LINC00460 was significantly weakened, which suggested that the K at aa 120 of PRDX1 was important for interaction with LINC00460 (Fig.	('interaction', 'Interaction', (182, 193))	('PRDX1', 'Gene', (158, 163))	('LINC00460', 'Gene', '728192', (199, 208))	('LINC00460', 'Gene', (199, 208))	('PRDX1', 'Gene', (66, 71))	('PRDX1', 'Gene', '5052', (158, 163))	('LINC00460', 'Gene', (80, 89))	('mutated', 'Var', (26, 33))	('bind', 'Interaction', (75, 79))	('PRDX1', 'Gene', '5052', (66, 71))	('LINC00460', 'Gene', '728192', (80, 89))	('ability', 'MPA', (55, 62))	('weakened', 'NegReg', (108, 116))	('si', 'Chemical', 'MESH:D012825', (94, 96))	('arginine', 'Chemical', 'MESH:D001120', (37, 45))
644826	31429766	Based on the results obtained with the fourth RIP primer, we speculate that nucleotide 323 of LINC00460 might be responsible for binding with PRDX1.	('nucleotide 323', 'Var', (76, 90))	('PRDX1', 'Gene', (142, 147))	('responsible', 'Reg', (113, 124))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('LINC00460', 'Gene', '728192', (94, 103))	('LINC00460', 'Gene', (94, 103))	('PRDX1', 'Gene', '5052', (142, 147))	('binding', 'Interaction', (129, 136))
644833	31429766	4m and Additional file 10: Figure S5E) showed that PRDX1 knockdown suppressed cell proliferation in CAL-27 and HN30 cells (p < 0.05).	('HN30', 'CellLine', 'CVCL:5525', (111, 115))	('knockdown', 'Var', (57, 66))	('PRDX1', 'Gene', (51, 56))	('CAL-27', 'CellLine', 'CVCL:1107', (100, 106))	('PRDX1', 'Gene', '5052', (51, 56))	('suppressed', 'NegReg', (67, 77))
644834	31429766	In addition, the results of the transwell assays demonstrated that PRDX1 knockdown suppressed cell migration in both CAL-27 and HN30 cells (p < 0.05) (Fig.	('PRDX1', 'Gene', '5052', (67, 72))	('cell migration in', 'CPA', (94, 111))	('CAL-27', 'CellLine', 'CVCL:1107', (117, 123))	('HN30', 'CellLine', 'CVCL:5525', (128, 132))	('PRDX1', 'Gene', (67, 72))	('suppressed', 'NegReg', (83, 93))	('knockdown', 'Var', (73, 82))
644835	31429766	PRDX1 knockdown significantly increased the levels of E-cadherin and decreased the levels of N-cadherin, Vimentin, ZEB1 and ZEB2 in CAL-27 and HN30 cells, whereas the levels of E-cadherin were decreased and the levels of N-cadherin, Vimentin, ZEB1 and ZEB2 were increased in CAL-27 and HN30 cells stably transduced with PRDX1, as determined by Western blot analysis (Fig.	('N-cadherin', 'Gene', '1000', (221, 231))	('ZEB1', 'Gene', '6935', (115, 119))	('E-cadherin', 'Gene', (54, 64))	('E-cadherin', 'Gene', '999', (54, 64))	('HN30', 'CellLine', 'CVCL:5525', (143, 147))	('N-cadherin', 'Gene', (93, 103))	('increased', 'PosReg', (30, 39))	('ZEB2', 'Gene', (124, 128))	('decreased', 'NegReg', (193, 202))	('HN30', 'CellLine', 'CVCL:5525', (286, 290))	('N-cadherin', 'Gene', '1000', (93, 103))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('ZEB2', 'Gene', (252, 256))	('ZEB2', 'Gene', '9839', (124, 128))	('ZEB1', 'Gene', (243, 247))	('CAL-27', 'CellLine', 'CVCL:1107', (275, 281))	('CAL-27', 'CellLine', 'CVCL:1107', (132, 138))	('ZEB2', 'Gene', '9839', (252, 256))	('ZEB1', 'Gene', (115, 119))	('E-cadherin', 'Gene', (177, 187))	('decreased', 'NegReg', (69, 78))	('E-cadherin', 'Gene', '999', (177, 187))	('levels', 'MPA', (44, 50))	('PRDX1', 'Gene', (320, 325))	('PRDX1', 'Gene', '5052', (320, 325))	('Vimentin', 'Gene', '7431', (105, 113))	('PRDX1', 'Gene', (0, 5))	('si', 'Chemical', 'MESH:D012825', (362, 364))	('Vimentin', 'Gene', '7431', (233, 241))	('ZEB1', 'Gene', '6935', (243, 247))	('PRDX1', 'Gene', '5052', (0, 5))	('Vimentin', 'Gene', (105, 113))	('levels', 'MPA', (167, 173))	('knockdown', 'Var', (6, 15))	('N-cadherin', 'Gene', (221, 231))	('Vimentin', 'Gene', (233, 241))
644836	31429766	PRDX1 knockdown significantly decreased the levels of N-cadherin, Vimentin, ZEB1 and ZEB2 in CAL-27 (Fig.	('PRDX1', 'Gene', (0, 5))	('N-cadherin', 'Gene', (54, 64))	('ZEB1', 'Gene', '6935', (76, 80))	('ZEB2', 'Gene', '9839', (85, 89))	('ZEB1', 'Gene', (76, 80))	('N-cadherin', 'Gene', '1000', (54, 64))	('Vimentin', 'Gene', (66, 74))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('PRDX1', 'Gene', '5052', (0, 5))	('Vimentin', 'Gene', '7431', (66, 74))	('ZEB2', 'Gene', (85, 89))	('knockdown', 'Var', (6, 15))	('CAL-27', 'CellLine', 'CVCL:1107', (93, 99))	('decreased', 'NegReg', (30, 39))
644848	31429766	Silencing of PRDX1 using si-PRDX1-1 (si-PRDX1) in CAL-27 cells significantly blocked the ability of LINC00460 to promote cell proliferation (Fig.	('blocked', 'NegReg', (77, 84))	('promote', 'PosReg', (113, 120))	('PRDX1', 'Gene', '5052', (40, 45))	('cell proliferation', 'CPA', (121, 139))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('Silencing', 'Var', (0, 9))	('PRDX1', 'Gene', (13, 18))	('PRDX1', 'Gene', (28, 33))	('ability', 'MPA', (89, 96))	('PRDX1', 'Gene', '5052', (13, 18))	('PRDX1', 'Gene', '5052', (28, 33))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('PRDX1-1', 'Gene', (28, 35))	('LINC00460', 'Gene', (100, 109))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('CAL-27', 'CellLine', 'CVCL:1107', (50, 56))	('LINC00460', 'Gene', '728192', (100, 109))	('PRDX1-1', 'Gene', '5052', (28, 35))	('PRDX1', 'Gene', (40, 45))
644872	31429766	Some studies have investigated the effects of miRNAs on LINC00460 and its functions, revealing that LINC00460 promotes cell proliferation and migration by upregulating the expression of the miR-149-5p-targeted genes IL6 in nasopharyngeal carcinoma and CUL4A in colorectal cancer, by targeting miR-342-3p/KDM2a in gastric cancer, by regulating miR-338-3p in epithelial ovarian cancer, by targeting miR-302c-5p/FOXA1 in human lung adenocarcinoma, by sponging miR-613 in papillary thyroid carcinoma, and by targeting miR-539/MMP-9 in meningioma.	('MMP-9', 'Gene', '4318', (522, 527))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('KDM2a', 'Gene', (304, 309))	('migration', 'CPA', (142, 151))	('MMP-9', 'Gene', (522, 527))	('IL6', 'Gene', '3569', (216, 219))	('miR-539', 'Gene', '664612', (514, 521))	('gastric cancer', 'Phenotype', 'HP:0012126', (313, 327))	('colorectal cancer', 'Phenotype', 'HP:0003003', (261, 278))	('miR-342', 'Gene', (293, 300))	('LINC00460', 'Gene', (56, 65))	('epithelial ovarian cancer', 'Disease', (357, 382))	('KDM2a', 'Gene', '22992', (304, 309))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('carcinoma', 'Phenotype', 'HP:0030731', (486, 495))	('targeting', 'Reg', (504, 513))	('IL6', 'Gene', (216, 219))	('nasopharyngeal carcinoma', 'Disease', (223, 247))	('FOXA1', 'Gene', '3169', (409, 414))	('LINC00460', 'Gene', '728192', (56, 65))	('expression', 'Species', '29278', (172, 182))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (468, 495))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('lung adenocarcinoma', 'Disease', (424, 443))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (357, 382))	('sponging', 'Var', (448, 456))	('gastric cancer', 'Disease', (313, 327))	('miR-149', 'Gene', (190, 197))	('papillary thyroid carcinoma', 'Disease', (468, 495))	('colorectal cancer', 'Disease', 'MESH:D015179', (261, 278))	('FOXA1', 'Gene', (409, 414))	('meningioma', 'Disease', (531, 541))	('cell proliferation', 'CPA', (119, 137))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (223, 247))	('miR-342', 'Gene', '442909', (293, 300))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (468, 495))	('meningioma', 'Phenotype', 'HP:0002858', (531, 541))	('targeting', 'Var', (387, 396))	('carcinoma', 'Phenotype', 'HP:0030731', (434, 443))	('miR-613', 'Gene', '693198', (457, 464))	('ovarian cancer', 'Phenotype', 'HP:0100615', (368, 382))	('LINC00460', 'Gene', (100, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (424, 443))	('colorectal cancer', 'Disease', (261, 278))	('gastric cancer', 'Disease', 'MESH:D013274', (313, 327))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (478, 495))	('human', 'Species', '9606', (418, 423))	('miR-149', 'Gene', '406941', (190, 197))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (424, 443))	('miR-613', 'Gene', (457, 464))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (223, 247))	('expression', 'MPA', (172, 182))	('upregulating', 'PosReg', (155, 167))	('meningioma', 'Disease', 'MESH:D008577', (531, 541))	('promotes', 'PosReg', (110, 118))	('LINC00460', 'Gene', '728192', (100, 109))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (357, 382))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('miR-539', 'Gene', (514, 521))
644881	31429766	When the predicted binding sites (K at aa 120 of PRDX1 or nucleotides positions 320-326 of LINC00460) were mutated respectively, the binding capacity between PRDX1 and LINC00460 decreased, suggesting that the predicted binding sites played an important role in maintaining the binding of PRDX1 and LINC00460.	('binding', 'Interaction', (277, 284))	('PRDX1', 'Gene', (158, 163))	('decreased', 'NegReg', (178, 187))	('LINC00460', 'Gene', '728192', (91, 100))	('LINC00460', 'Gene', '728192', (298, 307))	('LINC00460', 'Gene', (168, 177))	('PRDX1', 'Gene', '5052', (158, 163))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('LINC00460', 'Gene', '728192', (168, 177))	('binding', 'Interaction', (19, 26))	('binding', 'Interaction', (133, 140))	('mutated', 'Var', (107, 114))	('si', 'Chemical', 'MESH:D012825', (227, 229))	('LINC00460', 'Gene', (91, 100))	('PRDX1', 'Gene', (288, 293))	('LINC00460', 'Gene', (298, 307))	('PRDX1', 'Gene', '5052', (288, 293))	('PRDX1', 'Gene', (49, 54))	('PRDX1', 'Gene', '5052', (49, 54))	('si', 'Chemical', 'MESH:D012825', (27, 29))
644882	31429766	In our study, after PRDX1 knockdown in LINC00460-overexpressing cells or LINC00460 knockdown in PRDX1-overexpressing cells, cell proliferation and migration were significantly suppressed.	('PRDX1', 'Gene', (20, 25))	('LINC00460', 'Gene', '728192', (39, 48))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('PRDX1', 'Gene', (96, 101))	('PRDX1', 'Gene', '5052', (20, 25))	('LINC00460', 'Gene', '728192', (73, 82))	('LINC00460', 'Gene', (73, 82))	('suppressed', 'NegReg', (176, 186))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('knockdown', 'Var', (26, 35))	('PRDX1', 'Gene', '5052', (96, 101))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('LINC00460', 'Gene', (39, 48))
644883	31429766	When LINC00460 or PRDX1 was knocked down or overexpressed in HNSCC cells, the expression of EMT-associated genes were significantly altered.	('si', 'Chemical', 'MESH:D012825', (118, 120))	('expression', 'MPA', (78, 88))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('PRDX1', 'Gene', (18, 23))	('altered', 'Reg', (132, 139))	('PRDX1', 'Gene', '5052', (18, 23))	('knocked down', 'Var', (28, 40))	('HNSCC', 'Phenotype', 'HP:0012288', (61, 66))	('LINC00460', 'Gene', '728192', (5, 14))	('LINC00460', 'Gene', (5, 14))	('overexpressed', 'PosReg', (44, 57))	('expression', 'Species', '29278', (78, 88))
644896	31429766	Aberrant PRDX1 expression occurs in numerous cancers.	('occurs', 'Reg', (26, 32))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('numerous cancers', 'Disease', (36, 52))	('expression', 'Species', '29278', (15, 25))	('expression', 'MPA', (15, 25))	('PRDX1', 'Gene', (9, 14))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('PRDX1', 'Gene', '5052', (9, 14))	('numerous cancers', 'Disease', 'MESH:D009369', (36, 52))
644909	31429766	This study was supported by grants from the National Program on Key Research Project of China (2016YFC0902700), the National Natural Science Foundation of China (81772933, 81874126 and 81472515), the Shanghai Science and Technology Commission (18JC1413700 and 18DZ2291500) and the 64th Post-doctoral Science Foundation of China (2018 M642049).	('si', 'Chemical', 'MESH:D012825', (238, 240))	('18JC1413700', 'Var', (244, 255))	('81874126', 'Var', (172, 180))	('81472515', 'Var', (185, 193))	('81772933', 'Var', (162, 170))
644925	30379973	MiRNA abnormalities are crucial for the formation and development of cancer and have a regulatory effect on the sensitivity of various cancer treatments.	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('abnormalities', 'Var', (6, 19))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', (69, 75))	('MiRNA', 'MPA', (0, 5))
644928	30379973	Although miRNAs do not encode proteins, they can be used to regulate the expression level of a target gene by base-pairing with the transcripts of the target protein-encoding gene to reduce or inhibit the target gene.	('expression level', 'MPA', (73, 89))	('inhibit', 'NegReg', (193, 200))	('base-pairing', 'Var', (110, 122))	('reduce', 'NegReg', (183, 189))	('miR', 'Gene', '220972', (9, 12))	('regulate', 'MPA', (60, 68))	('miR', 'Gene', (9, 12))
644937	30379973	The following retrieval models are used for retrieval, search terms were: microrna-375 OR miR-375 OR mirna-375 OR hsa-miR-375 OR MicroRNA375.	('miR-375', 'Gene', (90, 97))	('miR-375', 'Gene', (118, 125))	('microrna-375', 'Var', (74, 86))	('mirna-375', 'Var', (101, 110))	('miR-375', 'Gene', '494324', (118, 125))	('A375', 'CellLine', 'CVCL:0132', (136, 140))	('miR-375', 'Gene', '494324', (90, 97))
644954	30379973	Study 4 (GSE77790) determined potential miR-375 target genes in pancreatic cancer and esophageal cancer (Panc-1 and sw1990 & TE8 and TE9).	('sw1990', 'CellLine', 'CVCL:7347', (116, 122))	('miR-375', 'Gene', '494324', (40, 47))	('sw1990 &', 'Var', (116, 124))	('GSE', 'Chemical', '-', (9, 12))	('esophageal cancer', 'Disease', (86, 103))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('miR-375', 'Gene', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))	('Panc-1', 'CellLine', 'CVCL:0480', (105, 111))
644955	30379973	The study collected miR-375 target genes with GPL20844 and included 62,976 probes.	('miR-375', 'Gene', '494324', (20, 27))	('miR-375', 'Gene', (20, 27))	('GPL20844', 'Var', (46, 54))
644966	30379973	KEGG pathway enrichment found that these genes had regulatory effects in amino acid biosynthesis and metabolic pathway, e.g, cysteine and methionine metabolism and metabolic pathways (Table 3).	('metabolic pathway', 'Pathway', (101, 118))	('metabolic pathways', 'Pathway', (164, 182))	('KEGG', 'Chemical', '-', (0, 4))	('regulatory effects', 'Reg', (51, 69))	('cysteine', 'Chemical', 'MESH:D003545', (125, 133))	('amino acid biosynthesis', 'MPA', (73, 96))	('genes', 'Var', (41, 46))	('methionine', 'Chemical', 'MESH:D008715', (138, 148))
644994	30379973	The extracellular domain of VASN is composed of leucine-rich tandem repeats, epidermal growth factor (EGF) -like motifs and fibronectin type iii motifs.	('VASN', 'Gene', (28, 32))	('leucine-rich tandem repeats', 'Var', (48, 75))	('VASN', 'Gene', '114990', (28, 32))
645004	30379973	Both MAT2B variants (overexpressed V1, V2) interact with GIT1.	('interact', 'Reg', (43, 51))	('MAT2B', 'Gene', '27430', (5, 10))	('V1, V2', 'Gene', '136319;6983', (35, 41))	('variants', 'Var', (11, 19))	('GIT1', 'Gene', '28964', (57, 61))	('MAT2B', 'Gene', (5, 10))	('GIT1', 'Gene', (57, 61))
645012	30379973	The expression level of miR-375 was inhibited in DU145 and PC-3 cell lines and clinical samples, and cell proliferation and invasion were inhibited by targeting Sec23 homolog A and yes-associated protein 1(SEC23A and YAP1), while inducing apoptosis and ectopic recovery of cell cycle arrest.	('clinical samples', 'Species', '191496', (79, 95))	('YAP1', 'Gene', (217, 221))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (273, 290))	('inhibited', 'NegReg', (138, 147))	('miR-375', 'Gene', '494324', (24, 31))	('SEC23A', 'Gene', (206, 212))	('ectopic recovery', 'CPA', (253, 269))	('inhibited', 'NegReg', (36, 45))	('miR-375', 'Gene', (24, 31))	('SEC23A', 'Gene', '10484', (206, 212))	('Sec23', 'Gene', (161, 166))	('targeting', 'Var', (151, 160))	('DU145', 'CellLine', 'CVCL:0105', (49, 54))	('expression level', 'MPA', (4, 20))	('inducing', 'NegReg', (230, 238))	('apoptosis', 'CPA', (239, 248))	('YAP1', 'Gene', '10413', (217, 221))	('invasion', 'CPA', (124, 132))	('PC-3', 'CellLine', 'CVCL:0035', (59, 63))	('cell proliferation', 'CPA', (101, 119))
645019	30379973	In her2-positive breast cancer and oral squamous cell carcinoma, silencing of miR-375 leads to up-regulation of IGF1R, which was found to be a direct target of miR-375.	('miR-375', 'Gene', '494324', (160, 167))	('silencing', 'Var', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 63))	('IGF1R', 'Gene', (112, 117))	('breast cancer', 'Disease', (17, 30))	('miR-375', 'Gene', '494324', (78, 85))	('IGF1R', 'Gene', '3480', (112, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('miR-375', 'Gene', (160, 167))	('her2', 'Gene', '2064', (3, 7))	('miR-375', 'Gene', (78, 85))	('oral squamous cell carcinoma', 'Disease', (35, 63))	('up-regulation', 'PosReg', (95, 108))	('her2', 'Gene', (3, 7))
645027	30379973	Targeting small nucleotide siRNA or aptamer of VASN may be a promising drug therapy for HCC.	('VASN', 'Gene', (47, 51))	('small nucleotide', 'Var', (10, 26))	('HCC', 'Disease', (88, 91))	('VASN', 'Gene', '114990', (47, 51))	('aptamer', 'Var', (36, 43))
645044	30379973	In addition to interacting with MAT II, the mutations of MAT2B can interact with other else proteins, for example, including HuR.	('interact', 'Reg', (67, 75))	('MAT2B', 'Gene', '27430', (57, 62))	('interacting', 'Reg', (15, 26))	('HuR', 'Gene', '1994', (125, 128))	('HuR', 'Gene', (125, 128))	('MAT II', 'Gene', (32, 38))	('mutations', 'Var', (44, 53))	('MAT II', 'Gene', '27430', (32, 38))	('MAT2B', 'Gene', (57, 62))
645100	30105511	In addition, dissection of retroperitoneal attachments behind the duodenum (Kocher maneuver) could have also caused the hiatal hernia, by shortening the length between the gastroesophageal junction and the duodenum, which is peculiar in Billroth I anastomosis reconstruction.	('dissection', 'Var', (13, 23))	('gastroesophageal junction', 'Disease', (172, 197))	('hiatal hernia', 'Phenotype', 'HP:0002036', (120, 133))	('hernia', 'Phenotype', 'HP:0100790', (127, 133))	('shortening', 'NegReg', (138, 148))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (172, 197))	('caused', 'Reg', (109, 115))	('Billroth I anastomosis', 'Disease', (237, 259))	('Billroth I anastomosis', 'Disease', 'MESH:C563598', (237, 259))	('hiatal hernia', 'Disease', 'MESH:D006551', (120, 133))	('hiatal hernia', 'Disease', (120, 133))	('man', 'Species', '9606', (83, 86))
645127	27517748	It emerged a statistically significant association between hERG1 expression status and risk of progression to EA.	('hERG1', 'Gene', '3757', (59, 64))	('expression status', 'Var', (65, 82))	('EA', 'Phenotype', 'HP:0011459', (110, 112))	('significant association', 'Reg', (27, 50))	('hERG1', 'Gene', (59, 64))
645152	27517748	As shown in Figure 1, a clear positivity for hERG1 can be observed in the metaplastic cells characterizing BE lesions (Figure 1C), while no hERG1 expression could be detected either in normal squamous epithelium (Figure 1A) or in areas displaying signs of esophagitis (Figure 1B).	('hERG1', 'Gene', '3757', (45, 50))	('hERG1', 'Gene', (45, 50))	('lesions', 'Var', (110, 117))	('esophagitis', 'Disease', (256, 267))	('esophagitis', 'Phenotype', 'HP:0100633', (256, 267))	('hERG1', 'Gene', '3757', (140, 145))	('hERG1', 'Gene', (140, 145))	('BE', 'Phenotype', 'HP:0100580', (107, 109))	('esophagitis', 'Disease', 'MESH:D004941', (256, 267))
645184	27517748	The analysis of the case-control study indicated a statistically significant association between BE hERG1 expression status and risk of progression to adenocarcinoma (odds ratio = 3.70, 95% CI: 1.40-9.82; P = 0.006) (Table 1).	('hERG1', 'Gene', '3757', (100, 105))	('hERG1', 'Gene', (100, 105))	('BE', 'Phenotype', 'HP:0100580', (97, 99))	('adenocarcinoma', 'Disease', (151, 165))	('adenocarcinoma', 'Disease', 'MESH:D000230', (151, 165))	('significant association', 'Reg', (65, 88))	('status', 'Var', (117, 123))
645187	27517748	Those 20 BE samples that were hERG1 positive maintained their positivity and increased the scoring in the ED/EA lesions (mean values 161.8 +- 31.3 and 237.3 +- 16.9, respectively).	('EA lesions', 'Disease', 'MESH:D051437', (109, 119))	('positivity', 'MPA', (62, 72))	('scoring', 'MPA', (91, 98))	('ED', 'Chemical', '-', (106, 108))	('hERG1', 'Gene', '3757', (30, 35))	('EA lesions', 'Disease', (109, 119))	('BE', 'Phenotype', 'HP:0100580', (9, 11))	('increased', 'PosReg', (77, 86))	('positive', 'Var', (36, 44))	('hERG1', 'Gene', (30, 35))	('EA', 'Phenotype', 'HP:0011459', (109, 111))
645215	27517748	The mis-expression of hERG1 in esophageal mucosa, even at early stages of esophageal cancerogenesis, could in turn modify cellular behavior switching on survival and pro-angiogenic signals, which in turn promote proliferation of BE metaplastic cells.	('promote', 'PosReg', (204, 211))	('modify', 'Reg', (115, 121))	('esophageal cancerogenesis', 'Disease', (74, 99))	('esophageal cancerogenesis', 'Disease', 'MESH:D004941', (74, 99))	('esophageal mucosa', 'Disease', (31, 48))	('mis-expression', 'Var', (4, 18))	('esophageal mucosa', 'Disease', 'MESH:D004941', (31, 48))	('BE', 'Phenotype', 'HP:0100580', (229, 231))	('hERG1', 'Gene', '3757', (22, 27))	('cellular behavior switching on survival', 'MPA', (122, 161))	('hERG1', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('proliferation of BE metaplastic cells', 'CPA', (212, 249))
645339	26908564	Preclinical studies demonstrated that a combination of a cytotoxic bile acid cocktail and low pH induces oxidative stress and oxidative DNA damage in cultured esophageal cells and in BE biopsies ex vivo.	('oxidative stress', 'Phenotype', 'HP:0025464', (105, 121))	('oxidative stress', 'MPA', (105, 121))	('bile acid', 'Chemical', 'MESH:D001647', (67, 76))	('rat', 'Species', '10116', (27, 30))	('induces', 'Reg', (97, 104))	('oxidative DNA damage', 'MPA', (126, 146))	('low', 'Var', (90, 93))
645341	26908564	Ursodeoxycholic acid (UDCA), the most hydrophilic of the bile acids, was shown to protect against bile acid and low pH induced oxidative stress and oxidative DNA damage and modulate expression of enzymes associated with protection against oxidative stress in cultured esophageal cells.	('bile acid', 'MPA', (98, 107))	('oxidative stress', 'Phenotype', 'HP:0025464', (239, 255))	('expression', 'MPA', (182, 192))	('oxidative stress', 'Phenotype', 'HP:0025464', (127, 143))	('modulate', 'Reg', (173, 181))	('oxidative DNA damage', 'MPA', (148, 168))	('Ursodeoxycholic acid', 'Chemical', 'MESH:D014580', (0, 20))	('low', 'Var', (112, 115))	('bile acid', 'Chemical', 'MESH:D001647', (98, 107))	('bile acid', 'Chemical', 'MESH:D001647', (57, 66))	('UDCA', 'Chemical', 'MESH:D014580', (22, 26))	('bile acids', 'Chemical', 'MESH:D001647', (57, 67))	('enzymes', 'Enzyme', (196, 203))
645352	26908564	The central hypothesis to be tested in the clinical study is that supplementation with UDCA would alter bile acid composition in the refluxate and subsequently decrease oxidative DNA damage, and cell proliferation and increase apoptosis in the BE epithelium.	('decrease', 'NegReg', (160, 168))	('alter', 'Reg', (98, 103))	('rat', 'Species', '10116', (207, 210))	('cell proliferation', 'CPA', (195, 213))	('bile acid', 'Chemical', 'MESH:D001647', (104, 113))	('men', 'Species', '9606', (72, 75))	('oxidative DNA damage', 'MPA', (169, 189))	('UDCA', 'Chemical', 'MESH:D014580', (87, 91))	('bile acid composition in the refluxate', 'MPA', (104, 142))	('increase', 'PosReg', (218, 226))	('apoptosis', 'CPA', (227, 236))	('supplementation', 'Var', (66, 81))	('UDCA', 'Gene', (87, 91))
645384	26908564	The percent of nuclei stained positive for Ki67, CC3, and 8OHdG in the selected regions was quantified by Aperio Spectrum software and confirmed by a trained pathologist.	('Ki67', 'Var', (43, 47))	('CC3', 'Gene', '6358', (49, 52))	('CC3', 'Gene', (49, 52))	('8OHdG', 'Chemical', 'MESH:C067134', (58, 63))	('Ki67', 'Chemical', '-', (43, 47))
645434	26908564	The PPI treatment may have contributed to the lack of UDCA effects on tissue markers of oxidative DNA damage, cell proliferation, and apoptosis.	('tissue markers of oxidative DNA damage', 'MPA', (70, 108))	('apoptosis', 'CPA', (134, 143))	('PPI', 'Var', (4, 7))	('rat', 'Species', '10116', (122, 125))	('cell proliferation', 'CPA', (110, 128))	('UDCA', 'Chemical', 'MESH:D014580', (54, 58))	('men', 'Species', '9606', (13, 16))
645436	26908564	High-dose PPI treatment in patients with BE that results in effective esophageal acid suppression has been shown to decrease the markers of cell proliferation and inflammation and increase apoptosis.	('inflammation', 'Disease', (163, 175))	('rat', 'Species', '10116', (152, 155))	('increase', 'PosReg', (180, 188))	('decrease', 'NegReg', (116, 124))	('apoptosis', 'CPA', (189, 198))	('PPI', 'Var', (10, 13))	('patients', 'Species', '9606', (27, 35))	('markers of cell', 'MPA', (129, 144))	('men', 'Species', '9606', (19, 22))	('esophageal acid suppression', 'MPA', (70, 97))	('inflammation', 'Disease', 'MESH:D007249', (163, 175))
645437	26908564	PPI treatment reduces the acidity and the volume of the refluxate, which may diminish the exposure of esophagus to cytotoxic bile acids.	('reduces', 'NegReg', (14, 21))	('men', 'Species', '9606', (9, 12))	('volume of the refluxate', 'MPA', (42, 65))	('bile acids', 'Chemical', 'MESH:D001647', (125, 135))	('diminish', 'NegReg', (77, 85))	('PPI', 'Var', (0, 3))	('acidity', 'MPA', (26, 33))	('exposure', 'MPA', (90, 98))
645439	26908564	Furthermore, bile acids that are cytotoxic to the mucosa in an acidic environment may lose their damaging activity at neutral pH from PPI treatment.	('bile acids', 'Chemical', 'MESH:D001647', (13, 23))	('bile', 'Protein', (13, 17))	('lose', 'NegReg', (86, 90))	('damaging activity at neutral pH', 'MPA', (97, 128))	('men', 'Species', '9606', (77, 80))	('PPI treatment', 'Var', (134, 147))	('men', 'Species', '9606', (143, 146))
645457	26414697	Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved.	('esophageal adenocarcinoma', 'Disease', (170, 195))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (170, 195))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (170, 195))	('Polymorphisms', 'Var', (0, 13))	('EAC', 'Gene', '1540', (197, 200))	('EAC', 'Gene', (197, 200))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (83, 108))	("Barrett's esophagus", 'Disease', (59, 78))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (59, 78))	('esophageal adenocarcinoma', 'Disease', (83, 108))	("Barrett's esophagus", 'Disease', (141, 160))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (141, 160))	('androgen', 'Pathway', (30, 38))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (83, 108))
645458	26414697	We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC.	('single nucleotide polymorphisms', 'Var', (21, 52))	('influence', 'Reg', (84, 93))	('EAC', 'Gene', '1540', (120, 123))	('EAC', 'Gene', (120, 123))	('androgen pathway', 'Pathway', (67, 83))
645461	26414697	SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p=0.002) and in males (p=0.003), but not in females separately (p=0.3).	('SNPs', 'Var', (0, 4))	('CYP17A1', 'Gene', (21, 28))	('associated', 'Reg', (34, 44))	('CYP17A1', 'Gene', '1586', (21, 28))
645463	26414697	SNPs within JMJD1C were associated with risk of EAC in females (p=0.001).	('associated', 'Reg', (24, 34))	('EAC', 'Gene', (48, 51))	('SNPs', 'Var', (0, 4))	('JMJD1C', 'Gene', '221037', (12, 18))	('JMJD1C', 'Gene', (12, 18))	('EAC', 'Gene', '1540', (48, 51))
645470	26414697	However, a recent case-control study found an increased risk of BE among participants with high levels of free testosterone and low levels of estrone sulfate.	('low levels of estrone', 'Phenotype', 'HP:0025140', (128, 149))	('low', 'Var', (128, 131))	('estrone sulfate', 'Chemical', 'MESH:C017296', (142, 157))	('high levels of free testosterone', 'Phenotype', 'HP:0030088', (91, 123))	('participants', 'Species', '9606', (73, 85))	('free testosterone', 'MPA', (106, 123))	('testosterone', 'Chemical', 'MESH:D013739', (111, 123))
645472	26414697	However, to the best of our knowledge no study has evaluated single nucleotide polymorphisms (SNPs) in genes coding for the androgen pathway in relation to risk of BE or EAC.	('single nucleotide polymorphisms', 'Var', (61, 92))	('EAC', 'Gene', (170, 173))	('EAC', 'Gene', '1540', (170, 173))
645473	26414697	We conducted a large genetic-epidemiologic study to test whether SNPs in 16 genes encoding components of the androgen pathway are associated with the risk of developing BE or EAC.	('SNPs in', 'Var', (65, 72))	('EAC', 'Gene', '1540', (175, 178))	('EAC', 'Gene', (175, 178))	('associated with', 'Reg', (130, 145))
645499	26414697	In both genders combined, SNPs in CYP17A1 were statistically significantly associated with risk of BE (p=0.002; Table 2).	('associated', 'Reg', (75, 85))	('SNPs', 'Var', (26, 30))	('CYP17A1', 'Gene', (34, 41))	('CYP17A1', 'Gene', '1586', (34, 41))
645501	26414697	SNPs in CYP17A1 were associated with BE risk in males only (p = 0.003; Table 4), and an analysis stratified for tobacco smoking revealed an association between SNPs in CYP17A1 and risk of BE in smokers (p=0.003), but not in non-smokers (Supplementary Table 2a).	('CYP17A1', 'Gene', '1586', (168, 175))	('tobacco', 'Species', '4097', (112, 119))	('CYP17A1', 'Gene', (8, 15))	('CYP17A1', 'Gene', '1586', (8, 15))	('SNPs', 'Var', (0, 4))	('men', 'Species', '9606', (243, 246))	('SNPs in', 'Var', (160, 167))	('CYP17A1', 'Gene', (168, 175))
645502	26414697	We also revealed an association between SNPs in CYP17A1 and BE risk in participants not suffering from reflux disease (p=0.004), but not in participants with reflux (Supplementary Table 2a).	('reflux disease', 'Phenotype', 'HP:0002020', (103, 117))	('CYP17A1', 'Gene', (48, 55))	('reflux disease', 'Disease', (103, 117))	('CYP17A1', 'Gene', '1586', (48, 55))	('SNPs', 'Var', (40, 44))	('reflux disease', 'Disease', 'MESH:D005764', (103, 117))	('participants', 'Species', '9606', (71, 83))	('participants', 'Species', '9606', (140, 152))	('men', 'Species', '9606', (172, 175))
645506	26414697	We analyzed the replication set to examine the positive associations between SNPs in CYP17A1 and risk of BE and SNPs in JMJD1C and risk of EAC in females found in the discovery set.	('SNPs', 'Var', (77, 81))	('SNPs', 'Var', (112, 116))	('EAC', 'Gene', '1540', (139, 142))	('EAC', 'Gene', (139, 142))	('CYP17A1', 'Gene', (85, 92))	('CYP17A1', 'Gene', '1586', (85, 92))	('JMJD1C', 'Gene', '221037', (120, 126))	('JMJD1C', 'Gene', (120, 126))
645507	26414697	No statistically significant association was found for SNPs in CYP17A1 in males and females with BE (p=0.19) or for SNPs in CYP17A1 and BE in males (p=0.27; Supplementary Table 3).	('CYP17A1', 'Gene', '1586', (63, 70))	('CYP17A1', 'Gene', (124, 131))	('CYP17A1', 'Gene', (63, 70))	('men', 'Species', '9606', (163, 166))	('CYP17A1', 'Gene', '1586', (124, 131))	('SNPs', 'Var', (55, 59))
645508	26414697	The association found between SNPs in JMJD1C and risk of EAC in females was not significant in the replication set (p=0.53; Supplementary Table 3).	('JMJD1C', 'Gene', (38, 44))	('SNPs', 'Var', (30, 34))	('EAC', 'Gene', '1540', (57, 60))	('EAC', 'Gene', (57, 60))	('men', 'Species', '9606', (130, 133))	('JMJD1C', 'Gene', '221037', (38, 44))
645509	26414697	This study found an association between SNPs in the androgen-related genes CYP17A1 and risk of BE in males and both sex combined and JMJD1C and risk of EAC in females, but these associations were not found in the replication set.	('JMJD1C', 'Gene', '221037', (133, 139))	('JMJD1C', 'Gene', (133, 139))	('EAC', 'Gene', '1540', (152, 155))	('SNPs', 'Var', (40, 44))	('EAC', 'Gene', (152, 155))	('CYP17A1', 'Gene', (75, 82))	('CYP17A1', 'Gene', '1586', (75, 82))
645511	26414697	Strengths of this study include the population-based design, the extensive data on genetic variants through the assessment of SNPs of relevant genes, and sample sizes that exceed those of most previous studies of BE and EAC.	('EAC', 'Gene', '1540', (220, 223))	('variants', 'Var', (91, 99))	('men', 'Species', '9606', (118, 121))	('EAC', 'Gene', (220, 223))
645519	26414697	The potential associations with SNPs in CYP17A1 might be interesting, since at least one functional SNP in this gene (rs743572) has been found to be of carcinogenic relevance in some tumors.	('SNPs', 'Var', (32, 36))	('associations', 'Interaction', (14, 26))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('CYP17A1', 'Gene', (40, 47))	('rs743572', 'Mutation', 'rs743572', (118, 126))	('CYP17A1', 'Gene', '1586', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('carcinogenic', 'Disease', 'MESH:D063646', (152, 164))	('tumors', 'Disease', (183, 189))	('carcinogenic', 'Disease', (152, 164))
645521	26414697	Moreover, the SNP with the lowest p-value in this study (rs4919686) has been associated with androgen-related disease occurrence.	('rs4919686', 'Var', (57, 66))	('androgen-related disease', 'Disease', (93, 117))	('rs4919686', 'Mutation', 'rs4919686', (57, 66))	('associated', 'Reg', (77, 87))
645523	26414697	Regarding SNPs in the gene JMJD1C, GWAS-studies have found associations with testosterone levels and sex-hormone binding globulin levels, and such SNPs might also be of relevance for carcinogenesis.	('associations', 'Interaction', (59, 71))	('testosterone', 'Chemical', 'MESH:D013739', (77, 89))	('carcinogenesis', 'Disease', (183, 197))	('JMJD1C', 'Gene', '221037', (27, 33))	('JMJD1C', 'Gene', (27, 33))	('testosterone levels', 'MPA', (77, 96))	('SNPs', 'Var', (10, 14))	('sex-hormone binding globulin levels', 'MPA', (101, 136))	('carcinogenesis', 'Disease', 'MESH:D063646', (183, 197))
645529	26414697	In conclusion, although this large-scale genetic-epidemiological study does not provide strong overall support for polymorphisms in the androgen pathway being strongly associated with the risk of BE or EAC, it cannot dismiss the hypothesis that polymorphisms in CYP17A1 and JMJD1C might be associated with these diseases.	('JMJD1C', 'Gene', (274, 280))	('associated', 'Reg', (168, 178))	('androgen pathway', 'Pathway', (136, 152))	('CYP17A1', 'Gene', (262, 269))	('CYP17A1', 'Gene', '1586', (262, 269))	('JMJD1C', 'Gene', '221037', (274, 280))	('EAC', 'Gene', '1540', (202, 205))	('EAC', 'Gene', (202, 205))	('associated', 'Reg', (290, 300))	('polymorphisms', 'Var', (245, 258))
645532	26414697	The results show that genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively.	('risk', 'Reg', (113, 117))	('EAC', 'Gene', (128, 131))	('CYP17A1', 'Gene', (69, 76))	('genetic variants', 'Var', (22, 38))	('CYP17A1', 'Gene', '1586', (69, 76))	('associated', 'Reg', (97, 107))	('JMJD1C', 'Gene', '221037', (81, 87))	('JMJD1C', 'Gene', (81, 87))	('EAC', 'Gene', '1540', (128, 131))
645537	25321468	In this study, we showed that knockdown of PC4 substantially increased ESCC cell sensitivity to ionizing radiation (IR) both in vitro and in vivo and enhanced radiation-induced apoptosis and mitotic catastrophe (MC).	('PC4', 'Gene', '10923', (43, 46))	('mitotic catastrophe', 'CPA', (191, 210))	('enhanced', 'PosReg', (150, 158))	('radiation-induced apoptosis', 'CPA', (159, 186))	('ESCC', 'Disease', (71, 75))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (81, 114))	('MC', 'Chemical', '-', (212, 214))	('increased', 'PosReg', (61, 70))	('knockdown', 'Var', (30, 39))	('PC4', 'Gene', (43, 46))	('increased ESCC', 'Phenotype', 'HP:0003565', (61, 75))
645538	25321468	Importantly, we demonstrated that silencing of PC4 suppressed NHEJ by downregulating the expression of XLF in ESCC cells, whereas reconstituting the expression of XLF protein in the PC4-knockdown ESCC cells restored NHEJ activity and radioresistance.	('XLF', 'Gene', (103, 106))	('PC4', 'Gene', '10923', (47, 50))	('expression', 'MPA', (89, 99))	('XLF', 'Gene', (163, 166))	('PC4', 'Gene', '10923', (182, 185))	('XLF', 'Gene', '79840', (103, 106))	('downregulating', 'NegReg', (70, 84))	('XLF', 'Gene', '79840', (163, 166))	('activity', 'MPA', (221, 229))	('radioresistance', 'CPA', (234, 249))	('NHEJ', 'Disease', (62, 66))	('restored', 'PosReg', (207, 215))	('suppressed', 'NegReg', (51, 61))	('PC4', 'Gene', (47, 50))	('silencing', 'Var', (34, 43))	('PC4', 'Gene', (182, 185))
645539	25321468	Moreover, high expression of PC4 positively correlated with ESCC resistance to CRT and was an independent predictor for short disease-specific survival of ESCC patients in both of our cohorts.	('patients', 'Species', '9606', (160, 168))	('CR', 'Chemical', '-', (79, 81))	('ESCC', 'Disease', (60, 64))	('correlated', 'Reg', (44, 54))	('PC4', 'Gene', (29, 32))	('high', 'Var', (10, 14))	('PC4', 'Gene', '10923', (29, 32))	('ESCC', 'Disease', (155, 159))
645545	25321468	DNA double-strand breaks (DSBs) are considered the most lethal DNA lesions produced by ionizing radiation (IR).	('DSBs', 'Chemical', '-', (26, 30))	('double-strand', 'Var', (4, 17))	('DNA', 'Disease', (0, 3))
645563	25321468	Our results showed that knockdown of PC4 increased the radiosensitivity of ESCC cells both in vitro and in vivo and suppressed cell NHEJ activity by downregulating expression of XLF.	('increased', 'PosReg', (41, 50))	('suppressed', 'NegReg', (116, 126))	('radiosensitivity', 'CPA', (55, 71))	('downregulating', 'NegReg', (149, 163))	('cell NHEJ activity', 'CPA', (127, 145))	('expression', 'MPA', (164, 174))	('XLF', 'Gene', (178, 181))	('XLF', 'Gene', '79840', (178, 181))	('PC4', 'Gene', (37, 40))	('knockdown', 'Var', (24, 33))	('PC4', 'Gene', '10923', (37, 40))
645564	25321468	In addition, high expression of PC4 positively correlated with ESCC resistance to CRT and was a strong and independent predictor for poor disease-specifical survival of ESCC patients.	('high', 'Var', (13, 17))	('PC4', 'Gene', (32, 35))	('correlated', 'Reg', (47, 57))	('patients', 'Species', '9606', (174, 182))	('PC4', 'Gene', '10923', (32, 35))	('ESCC', 'Disease', (63, 67))	('CR', 'Chemical', '-', (82, 84))
645570	25321468	The colony formation and proliferation assay showed that knockdown of PC4 had no significant impact on the proliferative activity and colony formation capacity of untreated ESCC cells (Figures 1b and c).	('PC4', 'Gene', (70, 73))	('knockdown', 'Var', (57, 66))	('colony formation capacity', 'CPA', (134, 159))	('PC4', 'Gene', '10923', (70, 73))	('proliferative activity', 'CPA', (107, 129))
645577	25321468	Our result showed that silencing PC4 did not appear to induce cellular apoptosis in both cell lines.	('PC4', 'Gene', (33, 36))	('PC4', 'Gene', '10923', (33, 36))	('silencing', 'Var', (23, 32))
645580	25321468	In this study, we therefore analyzed whether or not silencing PC4 affected ESCC cell response to IR-induced MC.	('PC4', 'Gene', '10923', (62, 65))	('silencing', 'Var', (52, 61))	('affected', 'Reg', (66, 74))	('MC', 'Chemical', '-', (108, 110))	('PC4', 'Gene', (62, 65))
645586	25321468	We subsequently investigated whether PC4 knockdown could affect ESCC cell response to IR in vivo.	('ESCC', 'Disease', (64, 68))	('affect', 'Reg', (57, 63))	('PC4', 'Gene', (37, 40))	('knockdown', 'Var', (41, 50))	('PC4', 'Gene', '10923', (37, 40))
645589	25321468	Our results showed that knockdown of PC4 did not affect tumor growth of the untreated group.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('PC4', 'Gene', (37, 40))	('knockdown', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('PC4', 'Gene', '10923', (37, 40))
645596	25321468	Inhibition of PC4 expression did not affect the expressions of XRCC4 and DNA ligase IV; however, as measured by both protein and mRNA levels, we showed that XLF was downregulated by PC4 knockdown in Kyse30 and TE-1 cells (Figures 5a and b).	('PC4', 'Gene', (14, 17))	('knockdown', 'Var', (186, 195))	('PC4', 'Gene', '10923', (182, 185))	('downregulated', 'NegReg', (165, 178))	('PC4', 'Gene', '10923', (14, 17))	('TE-1', 'CellLine', 'CVCL:1759', (210, 214))	('XRCC4', 'Gene', (63, 68))	('DNA ligase IV', 'Gene', '3981', (73, 86))	('DNA ligase IV', 'Gene', (73, 86))	('XRCC4', 'Gene', '7518', (63, 68))	('XLF', 'Gene', (157, 160))	('PC4', 'Gene', (182, 185))	('XLF', 'Gene', '79840', (157, 160))
645603	25321468	Our result showed that silencing of PC4 (Figure 6a) indeed attenuated rejoining of noncomplementary DNA ends, as detected by the presence of 430 bp amplicons (Figure 6b).	('attenuated', 'NegReg', (59, 69))	('PC4', 'Gene', (36, 39))	('silencing', 'Var', (23, 32))	('PC4', 'Gene', '10923', (36, 39))	('rejoining of noncomplementary DNA ends', 'CPA', (70, 108))
645605	25321468	Collectively, these data suggest that PC4 knockdown attenuates the NHEJ by downregulating XLF expression, which may be responsible for enhancing the radiosensitivity of ESCC cells.	('XLF', 'Gene', (90, 93))	('PC4', 'Gene', (38, 41))	('attenuates', 'NegReg', (52, 62))	('XLF', 'Gene', '79840', (90, 93))	('PC4', 'Gene', '10923', (38, 41))	('downregulating', 'NegReg', (75, 89))	('radiosensitivity', 'CPA', (149, 165))	('enhancing', 'PosReg', (135, 144))	('NHEJ', 'Disease', (67, 71))	('knockdown', 'Var', (42, 51))
645612	25321468	In univariate analysis, high PC4 expression was evaluated to correlate closely with poor disease-specific survival (DSS) for both learning and validation cohorts (Figures 7c and d).	('disease-specific survival', 'CPA', (89, 114))	('poor', 'NegReg', (84, 88))	('PC4', 'Gene', (29, 32))	('DSS', 'Gene', (116, 119))	('high', 'Var', (24, 28))	('expression', 'MPA', (33, 43))	('DSS', 'Gene', '5376', (116, 119))	('PC4', 'Gene', '10923', (29, 32))
645618	25321468	In the current study, our results clearly showed that PC4 knockdown could substantially increase ESCC cells' therapeutic response to IR in vitro and in vivo.	('ESCC', 'Gene', (97, 101))	('increase', 'PosReg', (88, 96))	('PC4', 'Gene', (54, 57))	('increase ESCC', 'Phenotype', 'HP:0003565', (88, 101))	('PC4', 'Gene', '10923', (54, 57))	('therapeutic response', 'CPA', (109, 129))	('knockdown', 'Var', (58, 67))
645622	25321468	Using flow cytometry, we found that inhibition of PC4 could enhance apoptotic cell death induced by IR.	('inhibition', 'Var', (36, 46))	('apoptotic cell death', 'CPA', (68, 88))	('PC4', 'Gene', (50, 53))	('enhance', 'PosReg', (60, 67))	('PC4', 'Gene', '10923', (50, 53))
645626	25321468	Inhibition of NHEJ can be used as a means for making cancer cells hypersensitive to radiation.	('hypersensitive', 'Disease', 'MESH:D004342', (66, 80))	('hypersensitive to radiation', 'Phenotype', 'HP:0011133', (66, 93))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('hypersensitive', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Inhibition', 'Var', (0, 10))	('NHEJ', 'Protein', (14, 18))
645635	25321468	In this present study, we observed that after knockdown of PC4, XLF was downregulated, leading to a decrease in both XLF foci formation and the recruitment of this protein to DSBs under IR-induced DNA damage.	('XLF', 'Gene', (117, 120))	('PC4', 'Gene', (59, 62))	('knockdown', 'Var', (46, 55))	('XLF', 'Gene', '79840', (117, 120))	('PC4', 'Gene', '10923', (59, 62))	('decrease', 'NegReg', (100, 108))	('recruitment', 'MPA', (144, 155))	('XLF', 'Gene', (64, 67))	('DSBs', 'Chemical', '-', (175, 179))	('downregulated', 'NegReg', (72, 85))	('XLF', 'Gene', '79840', (64, 67))
645637	25321468	However, the foci formation and recruitment of XRCC4 and DNA ligase IV were not affected by PC4 knockdown (Supplementary Figure S1).	('DNA ligase IV', 'Gene', (57, 70))	('XRCC4', 'Gene', (47, 52))	('knockdown', 'Var', (96, 105))	('XRCC4', 'Gene', '7518', (47, 52))	('PC4', 'Gene', (92, 95))	('PC4', 'Gene', '10923', (92, 95))	('DNA ligase IV', 'Gene', '3981', (57, 70))
645642	25321468	These findings, collectively, suggest that PC4 knockdown sensitizes ESCC cells to IR-induced DNA damage at least in part by negatively impacting the XLF-mediated NHEJ.	('PC4', 'Gene', '10923', (43, 46))	('XLF', 'Gene', (149, 152))	('XLF', 'Gene', '79840', (149, 152))	('sensitizes', 'Reg', (57, 67))	('knockdown', 'Var', (47, 56))	('PC4', 'Gene', (43, 46))	('negatively impacting', 'NegReg', (124, 144))
645643	25321468	Interestingly, PC4 knockdown without IR treatment had no impact on the tumorigencity of ESCC cells in vitro or in vivo.	('ESCC', 'Disease', (88, 92))	('knockdown', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('PC4', 'Gene', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('PC4', 'Gene', '10923', (15, 18))	('tumor', 'Disease', (71, 76))
645648	25321468	In the cohorts of our ESCC patients, high expression was found to correlate positively with ESCC resistance to CRT, and PC4 expression was a strong and independent predictor for short DSS of the disease.	('DSS', 'Gene', (184, 187))	('PC4', 'Gene', '10923', (120, 123))	('ESCC', 'Disease', (92, 96))	('high', 'Var', (37, 41))	('resistance to CRT', 'MPA', (97, 114))	('DSS', 'Gene', '5376', (184, 187))	('CR', 'Chemical', '-', (111, 113))	('patients', 'Species', '9606', (27, 35))	('PC4', 'Gene', (120, 123))
645650	25321468	Furthermore, we found that PC4 knockdown could also enhance ESCC cell sensitivity to cisplatin, which is the standard chemotherapeutic agent used in the CRT regimen of our clinical ESCC cohort (Supplementary Figure S2).	('PC4', 'Gene', '10923', (27, 30))	('ESCC', 'Disease', (60, 64))	('CR', 'Chemical', '-', (153, 155))	('sensitivity to cisplatin', 'MPA', (70, 94))	('enhance', 'PosReg', (52, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('knockdown', 'Var', (31, 40))	('PC4', 'Gene', (27, 30))
645651	25321468	In summary, our reports describe, for the first time, that PC4 knockdown enhanced ESCC cell response to IR in vitro and in vivo.	('PC4', 'Gene', (59, 62))	('PC4', 'Gene', '10923', (59, 62))	('enhanced', 'PosReg', (73, 81))	('ESCC cell response to IR', 'MPA', (82, 106))	('knockdown', 'Var', (63, 72))
645653	25321468	Moreover, our results provided a basis for the concept that high expression of PC4 may be a novel predictor of aggressive ESCC with CRT resistance and an independent prognostic factor for ESCC patients who are treated with definitive CRT.	('CR', 'Chemical', '-', (234, 236))	('PC4', 'Gene', (79, 82))	('patients', 'Species', '9606', (193, 201))	('high expression', 'Var', (60, 75))	('ESCC', 'Disease', (188, 192))	('CR', 'Chemical', '-', (132, 134))	('PC4', 'Gene', '10923', (79, 82))	('aggressive ESCC', 'Disease', (111, 126))	('CRT resistance', 'MPA', (132, 146))
645654	25321468	Thus, targeting PC4 may represent a new therapeutic strategy to improve the CRT effect and survival for ESCC patients.	('survival', 'CPA', (91, 99))	('improve', 'PosReg', (64, 71))	('CR', 'Chemical', '-', (76, 78))	('patients', 'Species', '9606', (109, 117))	('PC4', 'Gene', (16, 19))	('targeting', 'Var', (6, 15))	('CRT effect', 'CPA', (76, 86))	('ESCC', 'Disease', (104, 108))	('PC4', 'Gene', '10923', (16, 19))
645656	25321468	ESCC cell lines Kyse30, Kyse140, Kyse410, Kyse510 and TE-1 were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ, Braunschweig, Germany), the German Resource Centre for Biological Material.	('Kyse410', 'Var', (33, 40))	('von', 'Disease', 'MESH:D014842', (96, 99))	('TE-1', 'CellLine', 'CVCL:1759', (54, 58))	('von', 'Disease', (96, 99))
645711	25435989	A preponderance of either type of protein is indicative of gene inactivation, which is a predominant mechanism of tumorigenesis.	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('gene inactivation', 'Var', (59, 76))
645713	25435989	In the present study, human RIZ1 and PR domain eukaryotic expression vectors were constructed to investigate whether the PR domain of the tumor suppressor RIZ1 has the ability to induce apoptosis and reduce cell invasion ability in esophageal carcinoma cells.	('esophageal carcinoma', 'Disease', (232, 252))	('RIZ1', 'Gene', '7799', (28, 32))	('RIZ1', 'Gene', '7799', (155, 159))	('RIZ1', 'Gene', (28, 32))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (232, 252))	('RIZ1', 'Gene', (155, 159))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('induce', 'PosReg', (179, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('expression vectors', 'Species', '29278', (58, 76))	('reduce', 'NegReg', (200, 206))	('PR domain', 'Var', (121, 130))	('human', 'Species', '9606', (22, 27))	('apoptosis', 'CPA', (186, 195))	('cell invasion ability', 'CPA', (207, 228))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (232, 252))
645733	25435989	Briefly, initial denaturation was performed at 95 C for 2 min, followed by 45 cycles of denaturation at 95 C for 15 sec, annealing for the RIZ1/PR domain at 63 C for 15 sec or for GAPDH at 60 C for 15 sec, and extension at 72 C for 40 sec, followed by the production of thermal melting curves.	('GAPDH', 'Gene', '2597', (180, 185))	('RIZ1', 'Gene', (139, 143))	('annealing', 'Var', (121, 130))	('RIZ1', 'Gene', '7799', (139, 143))	('GAPDH', 'Gene', (180, 185))
645746	25435989	The RIZ1 and PR domain mRNA and protein expression levels in TE13 cells transfected with pcDNA3.1(+)/RIZ1 or pcDNA3.1(+)/PR were significantly higher compared with untransfected and empty vector-transfected cells (negative control groups) (P<0.05; Fig.	('RIZ1', 'Gene', (101, 105))	('RIZ1', 'Gene', '7799', (101, 105))	('expression', 'Species', '29278', (40, 50))	('higher', 'PosReg', (143, 149))	('TE13', 'CellLine', 'CVCL:4463', (61, 65))	('RIZ1', 'Gene', (4, 8))	('RIZ1', 'Gene', '7799', (4, 8))	('pcDNA3.1(+)/PR', 'Var', (109, 123))
645748	25435989	The Matrigel invasion ability of the TE13 cells transfected with pcDNA3.1(+)/RIZ1 or pcDNA3.1(+)/PR domain was significantly reduced compared with the invasion ability of the negative controls (P<0.05; Fig.	('Matrigel invasion ability', 'CPA', (4, 29))	('pcDNA3.1', 'Var', (85, 93))	('RIZ1', 'Gene', '7799', (77, 81))	('pcDNA3.1', 'Var', (65, 73))	('reduced', 'NegReg', (125, 132))	('TE13', 'CellLine', 'CVCL:4463', (37, 41))	('RIZ1', 'Gene', (77, 81))
645750	25435989	In addition to gross chromosomal instability and the instability of small repetitive DNA sequences, epigenetic silencing is also considered to contribute significantly to human carcinogenesis.	('carcinogenesis', 'Disease', (177, 191))	('human', 'Species', '9606', (171, 176))	('epigenetic silencing', 'Var', (100, 120))	('chromosomal instability', 'Phenotype', 'HP:0040012', (21, 44))	('contribute', 'Reg', (143, 153))	('carcinogenesis', 'Disease', 'MESH:D063646', (177, 191))
645751	25435989	TSG silencing by the methylation of CpG-rich promoter regions has been reported in numerous types of human cancer.	('TSG', 'Gene', '57045', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('methylation', 'Var', (21, 32))	('human', 'Species', '9606', (101, 106))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('TSG', 'Gene', (0, 3))	('silencing', 'NegReg', (4, 13))	('cancer', 'Disease', (107, 113))
645758	25435989	Chromosomal and microsatellite instability deactivates the RIZ1 gene, resulting in frameshift mutation, point mutations and heterozygous deficiency.	('deficiency', 'Disease', (137, 147))	('point', 'MPA', (104, 109))	('frameshift mutation', 'Var', (83, 102))	('deficiency', 'Disease', 'MESH:D007153', (137, 147))	('deactivates', 'NegReg', (43, 54))	('RIZ1', 'Gene', '7799', (59, 63))	('RIZ1', 'Gene', (59, 63))
645761	25435989	This indicated that inactivation of RIZ1 may be important in the progression of esophageal cancer.	('important', 'Reg', (48, 57))	('RIZ1', 'Gene', (36, 40))	('inactivation', 'Var', (20, 32))	('RIZ1', 'Gene', '7799', (36, 40))	('esophageal cancer', 'Disease', (80, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
645767	25435989	The cell invasion assay revealed that the invasion ability was significantly reduced in the TE13 cells transfected with pcDNA3.1(+)/RIZ1 or pcDNA3.1(+)/PR-domain (P<0.05).	('pcDNA3.1(+)/PR-domain', 'Var', (140, 161))	('RIZ1', 'Gene', (132, 136))	('TE13', 'CellLine', 'CVCL:4463', (92, 96))	('invasion ability', 'CPA', (42, 58))	('cell invasion assay', 'CPA', (4, 23))	('reduced', 'NegReg', (77, 84))	('RIZ1', 'Gene', '7799', (132, 136))
645781	22489266	Among the patients with lower third esophageal tumors, none of those with T1b tumors had cervical metastasis, whereas 16% of those with T2-T4 tumors did.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('esophageal tumors', 'Disease', (36, 53))	('T2-T4 tumors', 'Disease', 'MESH:C535434', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal tumors', 'Disease', 'MESH:D004938', (36, 53))	('cervical metastasis', 'CPA', (89, 108))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('esophageal tumors', 'Phenotype', 'HP:0100751', (36, 53))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('patients', 'Species', '9606', (10, 18))	('T1b', 'Var', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('T2-T4 tumors', 'Disease', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
645810	21951621	PPL knockdown appeared to decrease tumor cell growth together with G2/M phase accumulation in cells attached to a culture dish.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('G2/M phase accumulation', 'CPA', (67, 90))	('decrease', 'NegReg', (26, 34))	('PPL', 'Gene', (0, 3))	('tumor', 'Disease', (35, 40))	('PPL', 'Gene', '5493', (0, 3))	('knockdown', 'Var', (4, 13))
645811	21951621	Importantly, PPL knockdown suppressed cellular movement and attachment to the culture dish accompanied by decreased pAktSer473 phosphorylation.	('decreased', 'NegReg', (106, 115))	('cellular movement', 'CPA', (38, 55))	('suppressed', 'NegReg', (27, 37))	('PPL', 'Gene', '5493', (13, 16))	('attachment to the culture dish', 'CPA', (60, 90))	('knockdown', 'Var', (17, 26))	('pAktSer473 phosphorylation', 'MPA', (116, 142))	('PPL', 'Gene', (13, 16))
645812	21951621	Additionally, LY294002, a PI3K inhibitor that dephosphorylates pAktSer473, significantly suppressed D562 cell migration.	('LY294002', 'Var', (14, 22))	('suppressed', 'NegReg', (89, 99))	('D562', 'CellLine', 'CVCL:X233', (100, 104))	('LY294002', 'Chemical', 'MESH:C085911', (14, 22))	('D562 cell migration', 'CPA', (100, 119))
645814	21951621	PPL knockdown is related to reduced cellular movement and attachment activity in association with PI3K/Akt axis suppression, rather than malignant progression in pharyngeal cancer cells.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('reduced', 'NegReg', (28, 35))	('cellular movement', 'CPA', (36, 53))	('cancer', 'Disease', (173, 179))	('Akt', 'Gene', (103, 106))	('PPL', 'Gene', (0, 3))	('Akt', 'Gene', '207', (103, 106))	('PPL', 'Gene', '5493', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('attachment activity', 'CPA', (58, 77))	('knockdown', 'Var', (4, 13))	('suppression', 'NegReg', (112, 123))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (162, 179))
645826	21951621	We found that PPL knockdown was related to a reduction in cellular movement and attachment activity, and was accompanied by PI3K/Akt axis suppression in pharyngeal cancer cells; it was potentially related to EMT promotion.	('knockdown', 'Var', (18, 27))	('attachment activity', 'CPA', (80, 99))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Akt', 'Gene', '207', (129, 132))	('PPL', 'Gene', (14, 17))	('cellular movement', 'CPA', (58, 75))	('suppression', 'NegReg', (138, 149))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (153, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('Akt', 'Gene', (129, 132))	('PPL', 'Gene', '5493', (14, 17))	('reduction', 'NegReg', (45, 54))
645836	21951621	Thus, knockdown of PPL reduced the S population and increased the G2/M population (Figure 2C).	('S population', 'CPA', (35, 47))	('increased', 'PosReg', (52, 61))	('PPL', 'Gene', '5493', (19, 22))	('G2/M population', 'CPA', (66, 81))	('knockdown', 'Var', (6, 15))	('reduced', 'NegReg', (23, 30))	('PPL', 'Gene', (19, 22))
645848	21951621	These data suggest that knockdown of PPL decreases cellular adhesion to ECM in D562 cells.	('PPL', 'Gene', '5493', (37, 40))	('decreases', 'NegReg', (41, 50))	('cellular adhesion to', 'CPA', (51, 71))	('D562', 'CellLine', 'CVCL:X233', (79, 83))	('knockdown', 'Var', (24, 33))	('PPL', 'Gene', (37, 40))
645862	21951621	These data indicate that knockdown of PPL significantly decreases cellular migration in D562 cells, at least partly via the PI3K/Akt axis.	('Akt', 'Gene', '207', (129, 132))	('cellular migration', 'CPA', (66, 84))	('decreases', 'NegReg', (56, 65))	('PPL', 'Gene', (38, 41))	('PPL', 'Gene', '5493', (38, 41))	('Akt', 'Gene', (129, 132))	('knockdown', 'Var', (25, 34))	('D562', 'CellLine', 'CVCL:X233', (88, 92))
645869	21951621	Further experiments are needed to determine how PPL relates to EMT, including investigations of whether PPL knockdown affects the expression of mesenchymal markers, such as E-cahderin, fibronectin and/or N-cadherin.	('affects', 'Reg', (118, 125))	('knockdown', 'Var', (108, 117))	('expression', 'MPA', (130, 140))	('fibronectin', 'Gene', (185, 196))	('PPL', 'Gene', (48, 51))	('PPL', 'Gene', (104, 107))	('PPL', 'Gene', '5493', (104, 107))	('E-cahderin', 'Chemical', '-', (173, 183))	('N-cadherin', 'Gene', (204, 214))	('fibronectin', 'Gene', '2335', (185, 196))	('PPL', 'Gene', '5493', (48, 51))	('N-cadherin', 'Gene', '1000', (204, 214))
645873	21951621	If PPL knockdown reduces cell adhesion activity, PPL may be associated with proliferation and/or cell death because homeostasis in epithelial cells is enforced by their structural characteristics.	('PPL', 'Gene', (3, 6))	('reduces', 'NegReg', (17, 24))	('PPL', 'Gene', (49, 52))	('PPL', 'Gene', '5493', (3, 6))	('PPL', 'Gene', '5493', (49, 52))	('cell death', 'CPA', (97, 107))	('knockdown', 'Var', (7, 16))	('associated', 'Reg', (60, 70))	('cell adhesion activity', 'CPA', (25, 47))
645874	21951621	Furthermore, distortion of these balances by PPL siRNA, which interferes with cell adhesion to ECM, is often associated with epithelial tumorigenesis.	('associated', 'Reg', (109, 119))	('distortion', 'Var', (13, 23))	('PPL', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cell adhesion', 'CPA', (78, 91))	('PPL', 'Gene', '5493', (45, 48))	('tumor', 'Disease', (136, 141))
645878	21951621	LY294002, a PI3K inhibitor, suppressed cellular migration activity in D562 cell (Additional file 5).	('LY294002', 'Var', (0, 8))	('cellular migration activity', 'CPA', (39, 66))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('suppressed', 'NegReg', (28, 38))	('D562', 'CellLine', 'CVCL:X233', (70, 74))
645886	21951621	Thus, knockdown of PPL reduced ECM attachment and cellular proliferation.	('PPL', 'Gene', '5493', (19, 22))	('cellular proliferation', 'CPA', (50, 72))	('ECM attachment', 'CPA', (31, 45))	('knockdown', 'Var', (6, 15))	('reduced', 'NegReg', (23, 30))	('PPL', 'Gene', (19, 22))
645890	21951621	PPL knockdown is therefore related to reduced cellular movement and attachment activity rather than malignant progression, that is, PPL potentially participates in EMT in pharyngeal cancer cells.	('PPL', 'Gene', '5493', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('participates', 'Reg', (148, 160))	('reduced', 'NegReg', (38, 45))	('PPL', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('PPL', 'Gene', (132, 135))	('PPL', 'Gene', '5493', (0, 3))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (171, 188))	('cellular movement', 'CPA', (46, 63))	('attachment activity', 'CPA', (68, 87))	('cancer', 'Disease', (182, 188))	('EMT', 'CPA', (164, 167))	('knockdown', 'Var', (4, 13))
645911	21951621	Cells were transfected with PPL siRNA or pretreated for 2 h with PI3K inhibitor, LY294002 (Wako, Osaka, Japan).	('PPL', 'Gene', '5493', (28, 31))	('LY294002', 'Var', (81, 89))	('LY294002', 'Chemical', 'MESH:C085911', (81, 89))	('PPL', 'Gene', (28, 31))
645982	20616411	Out of these two false negative cases, one had SLN at a distance of 6 cm from the primary lower esophageal tumor with metastases present in one of the paraesophageal lymph nodes.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('esophageal tumor', 'Disease', 'MESH:D004938', (96, 112))	('metastases', 'Disease', (118, 128))	('esophageal tumor', 'Disease', (96, 112))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('SLN', 'Var', (47, 50))	('esophageal tumor', 'Phenotype', 'HP:0100751', (96, 112))
645997	20616411	The detection of SLN in our study was higher in lower esophageal tumors (85%) than in mid-esophageal tumors (75%), but it was not statistically significant (P value >0.05).	('esophageal tumors', 'Phenotype', 'HP:0100751', (54, 71))	('esophageal tumors', 'Phenotype', 'HP:0100751', (90, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('esophageal tumors', 'Disease', (54, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('esophageal tumor', 'Phenotype', 'HP:0100751', (54, 70))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mid-esophageal tumors', 'Disease', (86, 107))	('esophageal tumors', 'Disease', 'MESH:D004938', (90, 107))	('SLN', 'Var', (17, 20))	('esophageal tumor', 'Phenotype', 'HP:0100751', (90, 106))	('mid-esophageal tumors', 'Disease', 'MESH:D004938', (86, 107))	('esophageal tumors', 'Disease', 'MESH:D004938', (54, 71))
646006	20616411	The incidence of metastasis was significantly higher in SLNs than in SLN-negative patients (76.92% vs. 33.34%) and was statistically significant (P < 0.005).	('patients', 'Species', '9606', (82, 90))	('metastasis', 'CPA', (17, 27))	('SLNs', 'Var', (56, 60))	('higher', 'PosReg', (46, 52))
646069	31053115	Intronic polymorphisms in genes LRFN2 (rs2494938) and DNAH11 (rs2285947) are prognostic indicators of esophageal squamous cell carcinoma Genome wide association study (GWAS) has become the major means to screen for the genetic variants associated with risk and prognosis of different diseases.	('LRFN2', 'Gene', (32, 37))	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('rs2494938', 'Var', (39, 48))	('DNAH11', 'Gene', (54, 60))	('LRFN2', 'Gene', '57497', (32, 37))	('rs2285947', 'Var', (62, 71))	('rs2494938', 'Mutation', 'rs2494938', (39, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('DNAH11', 'Gene', '8701', (54, 60))	('rs2285947', 'Mutation', 'rs2285947', (62, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
646070	31053115	A recent GWAS has discovered three novel intronic single nucleotide polymorphisms in genes LRFN2 (rs2494938), DNAH11 (rs2285947) and PLCXD2 (rs2399395) that are associated with altered risk of esophageal squamous cell carcinoma (ESCC) among Han Chinese populations.	('LRFN2', 'Gene', (91, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('rs2285947', 'Mutation', 'rs2285947', (118, 127))	('rs2494938', 'Var', (98, 107))	('rs2399395', 'Mutation', 'rs2399395', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('rs2399395', 'Var', (141, 150))	('DNAH11', 'Gene', '8701', (110, 116))	('rs2285947', 'Var', (118, 127))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (193, 227))	('rs2494938', 'Mutation', 'rs2494938', (98, 107))	('LRFN2', 'Gene', '57497', (91, 96))	('DNAH11', 'Gene', (110, 116))	('PLCXD2', 'Gene', '257068', (133, 139))	('PLCXD2', 'Gene', (133, 139))	('esophageal squamous cell carcinoma', 'Disease', (193, 227))
646071	31053115	To investigate the association of three novel single nucleotide polymorphisms (rs2494938, rs2285947, rs2399395) with the prognosis of ESCC patients, we recruited 287 ESCC patients treated with surgical resection and evaluated the potential significance of the three polymorphisms through Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazards regression models.	('Cox', 'Gene', '1351', (339, 342))	('rs2494938', 'Mutation', 'rs2494938', (79, 88))	('patients', 'Species', '9606', (139, 147))	('Cox', 'Gene', (339, 342))	('rs2399395', 'Mutation', 'rs2399395', (101, 110))	('patients', 'Species', '9606', (171, 179))	('rs2399395', 'Var', (101, 110))	('rs2285947', 'Var', (90, 99))	('rs2494938', 'Var', (79, 88))	('ESCC', 'Disease', (166, 170))	('rs2285947', 'Mutation', 'rs2285947', (90, 99))
646073	31053115	In addition, rs2494938 at 6p21.1 was independently associated with overall survival of ESCC patients in recessive model [AA vs. GG/GA, HR = 3.12, 95% CI = 1.43-6.83, P = 0.004], rs2285947 at 7p15.3 was independently associated with overall survival of ESCC patients in both dominant model [AA/GA vs. GG, HR = 1.59, 95% CI = 1.02-2.49, P = 0.042] and additive model [AA vs. GA vs. GG, HR = 1.45, 95% CI = 1.05-2.01, P = 0.025].	('ESCC', 'Disease', (252, 256))	('rs2285947', 'Var', (178, 187))	('associated with', 'Reg', (216, 231))	('patients', 'Species', '9606', (92, 100))	('rs2285947', 'Mutation', 'rs2285947', (178, 187))	('associated', 'Reg', (51, 61))	('patients', 'Species', '9606', (257, 265))	('rs2494938', 'Mutation', 'rs2494938', (13, 22))	('rs2494938', 'Var', (13, 22))
646074	31053115	This study demonstrated that the polymorphisms rs2494938 at 6p21.1 and rs2285947 at 7p15.3 may serve as independent prognostic biomarkers for ESCC, implying the potential biological role of their related genes (LRFN2 and DNAH11) in the process of ESCC development.	('LRFN2', 'Gene', (211, 216))	('DNAH11', 'Gene', (221, 227))	('rs2285947', 'Mutation', 'rs2285947', (71, 80))	('LRFN2', 'Gene', '57497', (211, 216))	('DNAH11', 'Gene', '8701', (221, 227))	('rs2494938', 'Var', (47, 56))	('rs2494938', 'Mutation', 'rs2494938', (47, 56))	('ESCC', 'Disease', (142, 146))	('rs2285947', 'Var', (71, 80))
646077	31053115	Nowadays, data generated by GWAS have expanded our understanding of genetic variants that also can act as prognostic markers for multiple cancers, such as the SNP rs10484761 in gastric cancer, SNP of XRCC1 Arg399Gln both in non-small cell lung cancer and breast cancer, the GNAS1 T393C polymorphism in gastric cancer, laryngeal carcinoma and breast cancer.	('breast cancer', 'Disease', (342, 355))	('laryngeal carcinoma', 'Disease', (318, 337))	('rs10484761', 'Var', (163, 173))	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('XRCC1', 'Gene', '7515', (200, 205))	('gastric cancer', 'Disease', 'MESH:D013274', (177, 191))	('breast cancer', 'Disease', (255, 268))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (224, 250))	('gastric cancer', 'Disease', 'MESH:D013274', (302, 316))	('GNAS1', 'Gene', '2778', (274, 279))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Arg399Gln', 'SUBSTITUTION', 'None', (206, 215))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('multiple cancers', 'Disease', (129, 145))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (318, 337))	('gastric cancer', 'Phenotype', 'HP:0012126', (177, 191))	('rs10484761', 'Mutation', 'rs10484761', (163, 173))	('GNAS1', 'Gene', (274, 279))	('non-small cell lung cancer', 'Disease', (224, 250))	('gastric cancer', 'Phenotype', 'HP:0012126', (302, 316))	('Arg399Gln', 'Var', (206, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (318, 337))	('T393C', 'Mutation', 'rs758272654', (280, 285))	('XRCC1', 'Gene', (200, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (342, 355))	('gastric cancer', 'Disease', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (228, 250))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (224, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('gastric cancer', 'Disease', (302, 316))	('multiple cancers', 'Disease', 'MESH:D009369', (129, 145))	('breast cancer', 'Disease', 'MESH:D001943', (342, 355))
646078	31053115	For example, polymorphism rs4919510 within miR-608 was deemed to predict the survival of ESCC.	('predict', 'Reg', (65, 72))	('rs4919510', 'Mutation', 'rs4919510', (26, 35))	('miR-608', 'Gene', '693193', (43, 50))	('polymorphism rs4919510', 'Var', (13, 35))	('ESCC', 'Disease', (89, 93))	('miR-608', 'Gene', (43, 50))
646079	31053115	Another SNP C8092A at ERCC1 showed an association with ESCC patients' survival although the association is not statistically significant.	('patients', 'Species', '9606', (60, 68))	('C8092A', 'Var', (12, 18))	('C8092A', 'Mutation', 'rs3212986', (12, 18))	('association', 'Reg', (38, 49))	('ESCC', 'Disease', (55, 59))	('ERCC1', 'Gene', '2067', (22, 27))	('ERCC1', 'Gene', (22, 27))
646080	31053115	Additionally, Genome-wide association study identified several polymorphisms in SLC39A6 that were associated with length of survival in ESCC.	('SLC39A6', 'Gene', '25800', (80, 87))	('ESCC', 'Disease', (136, 140))	('polymorphisms', 'Var', (63, 76))	('SLC39A6', 'Gene', (80, 87))	('associated', 'Reg', (98, 108))
646081	31053115	performed a GWAS study and discovered that three novel intronic susceptibility loci in the genes LRFN2 (rs2494938 at 6p21.1), DNAH11 (rs2285947 at 7p15.3) and PLCXD2 (rs2399395 at 3q13.2) were associated with the risk of ESCC in Han Chinese populations.	('rs2494938', 'Var', (104, 113))	('rs2285947', 'Var', (134, 143))	('rs2494938', 'Mutation', 'rs2494938', (104, 113))	('rs2285947', 'Mutation', 'rs2285947', (134, 143))	('LRFN2', 'Gene', '57497', (97, 102))	('PLCXD2', 'Gene', '257068', (159, 165))	('PLCXD2', 'Gene', (159, 165))	('DNAH11', 'Gene', (126, 132))	('ESCC', 'Disease', (221, 225))	('DNAH11', 'Gene', '8701', (126, 132))	('rs2399395', 'Mutation', 'rs2399395', (167, 176))	('LRFN2', 'Gene', (97, 102))	('rs2399395', 'Var', (167, 176))
646082	31053115	In present study, we further explored the association between three SNPs and overall survival in ESCC and discovered that rs2494938 in LRFN2 and rs2285947 in DNAH11 might emerge as potential prognostic factors of ESCC in a Chinese population.	('LRFN2', 'Gene', '57497', (135, 140))	('rs2285947', 'Mutation', 'rs2285947', (145, 154))	('DNAH11', 'Gene', (158, 164))	('rs2494938', 'Var', (122, 131))	('ESCC', 'Disease', (213, 217))	('rs2285947', 'Var', (145, 154))	('rs2494938', 'Mutation', 'rs2494938', (122, 131))	('LRFN2', 'Gene', (135, 140))	('DNAH11', 'Gene', '8701', (158, 164))
646099	31053115	Kaplan-Meier curves were used to assess the association of patients' survival with polymorphisms rs2494938, rs2285947 and rs2399395 (Fig.	('rs2494938', 'Var', (97, 106))	('rs2399395', 'Var', (122, 131))	('rs2494938', 'Mutation', 'rs2494938', (97, 106))	('rs2285947', 'Var', (108, 117))	('patients', 'Species', '9606', (59, 67))	('rs2285947', 'Mutation', 'rs2285947', (108, 117))	('rs2399395', 'Mutation', 'rs2399395', (122, 131))
646100	31053115	Significant difference in survival rate was discovered in ESCC patients with different genotypes at rs2494938 (Fig.	('rs2494938', 'Mutation', 'rs2494938', (100, 109))	('patients', 'Species', '9606', (63, 71))	('rs2494938', 'Var', (100, 109))	('ESCC', 'Disease', (58, 62))
646104	31053115	Consistently, ESCC patients carrying G allele (GG + GA) at rs2494938 had better prognosis (Fig.	('better', 'PosReg', (73, 79))	('rs2494938', 'Var', (59, 68))	('patients', 'Species', '9606', (19, 27))	('rs2494938', 'Mutation', 'rs2494938', (59, 68))
646105	31053115	What's more, ESCC patients harboring genotype AA at rs2285947 had shorter survival time than those with genotype GG (Fig.	('shorter', 'NegReg', (66, 73))	('ESCC', 'Disease', (13, 17))	('rs2285947', 'Var', (52, 61))	('patients', 'Species', '9606', (18, 26))	('rs2285947', 'Mutation', 'rs2285947', (52, 61))	('survival time', 'CPA', (74, 87))
646107	31053115	The above suggested that A allele of rs2494938 or rs2285947 was an independent risk factor for overall survival in ESCC patients.	('ESCC', 'Disease', (115, 119))	('rs2285947', 'Mutation', 'rs2285947', (50, 59))	('rs2494938', 'Var', (37, 46))	('rs2494938', 'Mutation', 'rs2494938', (37, 46))	('patients', 'Species', '9606', (120, 128))	('rs2285947', 'Var', (50, 59))
646109	31053115	SNP rs2494938 was consistently demonstrated to be independently associated with overall survival in recessive model (HR = 3.12, 95% CI = 1.43-6.83, P = 0.004), so was rs2285947 in both dominant model (HR = 1.59, 95% CI = 1.02-2.49, P = 0.042) and additive model (HR = 1.45, 95% CI = 1.05-2.01, P = 0.025).	('associated', 'Reg', (64, 74))	('rs2285947', 'Var', (167, 176))	('recessive model', 'Disease', (100, 115))	('rs2285947', 'Mutation', 'rs2285947', (167, 176))	('overall survival', 'MPA', (80, 96))	('SNP rs2494938', 'Var', (0, 13))	('rs2494938', 'Mutation', 'rs2494938', (4, 13))
646111	31053115	In the present study, we evaluated the SNPs (rs2494938, rs2285947 and rs2399395) which were potentially involved in the carcinogenesis of ESCC, and identified three genetic variations associated with prognosis of ESCC patients in Chinese populations.	('patients', 'Species', '9606', (218, 226))	('rs2399395', 'Mutation', 'rs2399395', (70, 79))	('rs2285947', 'Var', (56, 65))	('involved', 'Reg', (104, 112))	('rs2494938', 'Mutation', 'rs2494938', (45, 54))	('rs2399395', 'Var', (70, 79))	('associated', 'Reg', (184, 194))	('ESCC', 'Disease', (213, 217))	('rs2285947', 'Mutation', 'rs2285947', (56, 65))	('rs2494938', 'Var', (45, 54))
646112	31053115	Herein, for the first time, we demonstrated the prognostic significance of rs2494938 and rs2285947 in ESCC.	('rs2285947', 'Var', (89, 98))	('ESCC', 'Disease', (102, 106))	('rs2285947', 'Mutation', 'rs2285947', (89, 98))	('rs2494938', 'Var', (75, 84))	('rs2494938', 'Mutation', 'rs2494938', (75, 84))
646113	31053115	In this study, the AA homozygous genotype of SNP rs2494938 in LRFN2 was significantly associated with worse survival outcome of ESCC.	('SNP rs2494938', 'Var', (45, 58))	('rs2494938', 'Mutation', 'rs2494938', (49, 58))	('associated', 'Reg', (86, 96))	('ESCC', 'Disease', (128, 132))	('LRFN2', 'Gene', (62, 67))	('LRFN2', 'Gene', '57497', (62, 67))	('survival', 'MPA', (108, 116))
646114	31053115	Genetic variants at 6p21.1, where SNP rs2494938 locates and its amplification has been frequently detected in human cancers, have been discovered as independent prognostic markers for cancers, such as SNP rs10484761 for gastric cancer and SNP rs2494938 for laryngeal carcinoma.	('gastric cancer', 'Phenotype', 'HP:0012126', (220, 234))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('rs10484761', 'Mutation', 'rs10484761', (205, 215))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (257, 276))	('rs2494938', 'Mutation', 'rs2494938', (38, 47))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('SNP rs10484761', 'Var', (201, 215))	('cancers', 'Disease', (184, 191))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('rs2494938', 'Mutation', 'rs2494938', (243, 252))	('gastric cancer', 'Disease', (220, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('human', 'Species', '9606', (110, 115))	('SNP rs2494938', 'Var', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('laryngeal carcinoma', 'Disease', (257, 276))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (220, 234))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', (116, 123))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (257, 276))
646115	31053115	The rs2494938 is located in the intron region of LRFN2 (Leucine-rich repeat and fibronectin type III domain-containing protein 2).	('LRFN2', 'Gene', '57497', (49, 54))	('Leucine-rich repeat and fibronectin type III domain-containing protein 2', 'Gene', '57497', (56, 128))	('rs2494938', 'Var', (4, 13))	('rs2494938', 'Mutation', 'rs2494938', (4, 13))	('LRFN2', 'Gene', (49, 54))
646118	31053115	Also, aberrant methylation of the NMDAR2B abrogated gene transcription leading to cellular resistance to apoptosis, which was strongly related to clinical outcomes of ESCC.	('abrogated', 'NegReg', (42, 51))	('related', 'Reg', (135, 142))	('gene transcription', 'MPA', (52, 70))	('ESCC', 'Disease', (167, 171))	('NMDAR2B', 'Gene', (34, 41))	('aberrant methylation', 'Var', (6, 26))	('cellular resistance to apoptosis', 'CPA', (82, 114))	('NMDAR2B', 'Gene', '2904', (34, 41))
646120	31053115	Until now, evidences have confirmed the association of the polymorphism rs2285947 in DNAH11 with the higher risk of human cancers, such as ovarian cancer, head and neck cancer, lung cancer, non-cardia gastric cancer and esophageal squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('head and neck cancer', 'Phenotype', 'HP:0012288', (155, 175))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('DNAH11', 'Gene', (85, 91))	('association', 'Reg', (40, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('rs2285947', 'Var', (72, 81))	('cancers', 'Disease', (122, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('rs2285947', 'Mutation', 'rs2285947', (72, 81))	('non-cardia gastric cancer', 'Disease', (190, 215))	('ovarian cancer', 'Disease', (139, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('ovarian cancer', 'Phenotype', 'HP:0100615', (139, 153))	('gastric cancer', 'Phenotype', 'HP:0012126', (201, 215))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (190, 215))	('head and neck cancer', 'Disease', 'MESH:D006258', (155, 175))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('esophageal squamous cell carcinoma', 'Disease', (220, 254))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('lung cancer', 'Disease', (177, 188))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('human', 'Species', '9606', (116, 121))	('DNAH11', 'Gene', '8701', (85, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (139, 153))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (220, 254))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
646121	31053115	We found that the GA/AA genotype of rs2285947 exhibited a significant association with poorer survival than the GG genotype among ESCC patients.	('rs2285947', 'Var', (36, 45))	('patients', 'Species', '9606', (135, 143))	('rs2285947', 'Mutation', 'rs2285947', (36, 45))	('ESCC', 'Disease', (130, 134))	('poorer', 'NegReg', (87, 93))
646122	31053115	The rs2285947 at 7p15.3 is located in the intron region of DNAH11 (Dynein, axonemal, heavy chain11) which encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family.	('DNAH11', 'Gene', '8701', (59, 65))	('rs2285947', 'Var', (4, 13))	('rs2285947', 'Mutation', 'rs2285947', (4, 13))	('Dynein, axonemal, heavy chain11', 'Gene', '8701', (67, 98))	('DNAH11', 'Gene', (59, 65))
646124	31053115	Thus, the polymorphism rs2285947 may play an important role on the expression of gene DNAH11.	('rs2285947', 'Mutation', 'rs2285947', (23, 32))	('DNAH11', 'Gene', (86, 92))	('DNAH11', 'Gene', '8701', (86, 92))	('rs2285947', 'Var', (23, 32))
646125	31053115	Based upon our study, further functional investigations are warranted to figure out the potential biological importance of the cancer prognosis-related locus of rs2494938 and rs2285947 in ESCC.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs2285947', 'Var', (175, 184))	('ESCC', 'Disease', (188, 192))	('cancer', 'Disease', (127, 133))	('rs2285947', 'Mutation', 'rs2285947', (175, 184))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('rs2494938', 'Var', (161, 170))	('rs2494938', 'Mutation', 'rs2494938', (161, 170))
646126	31053115	First, the sample size of this research was small, particularly in subgroup carrying AA genotype of rs2494938 and TT genotype of rs2399395.	('rs2494938', 'Mutation', 'rs2494938', (100, 109))	('rs2399395', 'Mutation', 'rs2399395', (129, 138))	('rs2399395', 'Var', (129, 138))	('rs2494938', 'Var', (100, 109))
646128	31053115	Taken together, we discovered that rs2494938 at 6p21.1 and rs2285947 at 7p15.3 may play important roles in the survival in ESCC patients.	('rs2494938', 'Var', (35, 44))	('rs2494938', 'Mutation', 'rs2494938', (35, 44))	('roles', 'Reg', (98, 103))	('rs2285947', 'Var', (59, 68))	('ESCC', 'Disease', (123, 127))	('rs2285947', 'Mutation', 'rs2285947', (59, 68))	('play', 'Reg', (83, 87))	('patients', 'Species', '9606', (128, 136))
646129	31053115	The present study confirmed that the polymorphisms rs2494938 in LRFN2 and rs2285947 in DNAH11 may become independent prognostic markers for ESCC in Chinese population.	('rs2285947', 'Var', (74, 83))	('rs2494938', 'Var', (51, 60))	('rs2494938', 'Mutation', 'rs2494938', (51, 60))	('rs2285947', 'Mutation', 'rs2285947', (74, 83))	('LRFN2', 'Gene', (64, 69))	('ESCC', 'Disease', (140, 144))	('DNAH11', 'Gene', '8701', (87, 93))	('LRFN2', 'Gene', '57497', (64, 69))	('DNAH11', 'Gene', (87, 93))
646130	31053115	DNAH11 Dynein, axonemal, heavy chain11 ESCC Esophageal squamous cell carcinoma GWAS Genome wide association study LRFN2 Leucine-rich repeat and fibronectin type III domain-containing protein 2 MAPK Mitogen-activated protein kinase NMDAR N-methyl-D-aspartate receptor SNP Single nucleotide polymorphism JW, QW and BW carried out all the experiments, data analysis and manuscript preparation.	('Esophageal squamous cell carcinoma', 'Disease', (44, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('DNAH11', 'Gene', '8701', (0, 6))	('Leucine-rich repeat and fibronectin type III domain-containing protein 2', 'Gene', '57497', (120, 192))	('LRFN2', 'Gene', '57497', (114, 119))	('Dynein, axonemal, heavy chain11', 'Gene', '8701', (7, 38))	('Single nucleotide polymorphism', 'Var', (271, 301))	('DNAH11', 'Gene', (0, 6))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (44, 78))	('LRFN2', 'Gene', (114, 119))
646262	30137686	However, in Japan, following promising results of good tolerability and strong antitumor activity from a phase II study that investigated NACRT with CF,47 a three-arm phase III trial (JCOG1109) is now ongoing to confirm DCF or CRT with CF as superior to CF as neoadjuvant therapy for ESCC.48 In the near future, NACRT could become one of the standard treatment options for resectable ESCC, depending on the result of JCOG1109, and, therefore, NACRT with DNF might also need to be evaluated, as well as DNF, for NAC.	('NAC', 'Gene', (312, 315))	('NAC', 'Gene', (511, 514))	('NACRT', 'Chemical', '-', (138, 143))	('tumor', 'Disease', (83, 88))	('CRT', 'Gene', '799', (445, 448))	('CRT', 'Gene', (445, 448))	('NACRT', 'Chemical', '-', (312, 317))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('NAC', 'Gene', (443, 446))	('JCOG1109', 'Var', (417, 425))	('DNF', 'Chemical', '-', (454, 457))	('NAC', 'Gene', '6622', (138, 141))	('DNF', 'Chemical', '-', (502, 505))	('ESCC', 'Disease', (384, 388))	('NAC', 'Gene', '6622', (511, 514))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('NAC', 'Gene', '6622', (312, 315))	('men', 'Species', '9606', (356, 359))	('CRT', 'Gene', '799', (140, 143))	('NAC', 'Gene', '6622', (443, 446))	('NACRT', 'Chemical', '-', (443, 448))	('CRT', 'Gene', (140, 143))	('DCF', 'Chemical', '-', (220, 223))	('CRT', 'Gene', '799', (227, 230))	('CRT', 'Gene', (227, 230))	('CRT', 'Gene', '799', (314, 317))	('NAC', 'Gene', (138, 141))	('CRT', 'Gene', (314, 317))
646338	27129592	speculated that a small subset of GISTs that are negative for the KIT- and PDGFRA-activating mutations may be inherited and may occur as part of a multi-neoplastic disease.	('neoplastic disease', 'Phenotype', 'HP:0002664', (153, 171))	('mutations', 'Var', (93, 102))	('multi-neoplastic disease', 'Disease', 'MESH:C564969', (147, 171))	('occur', 'Reg', (128, 133))	('multi-neoplastic disease', 'Disease', (147, 171))	('PDGFRA', 'Gene', (75, 81))	('PDGFRA', 'Gene', '5156', (75, 81))
646349	26267323	Non-hematopoietic CTCs with heteroploid chromosome 8 were detected in 87-92% of lung, esophageal and gastric cancer patients.	('detected', 'Reg', (58, 66))	('gastric cancer', 'Disease', (101, 115))	('heteroploid chromosome', 'Var', (28, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('patients', 'Species', '9606', (116, 124))	('esophageal', 'Disease', (86, 96))	('lung', 'Disease', (80, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
646362	26267323	Similar to the caspase cleaved soluble extracellular CK18 fragment, a serum biomarker for tumor cell apoptosis, intracellular intact CK18 appears to be a significant tumor biomarker with clinical utilities.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('CK18', 'Var', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('intracellular intact CK18', 'Var', (112, 137))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
646367	26267323	It has been reported that ectopic expression of vimentin and loss of CK, indicating EMT, in 2, 517 breast cancer patient samples was associated with a higher tumor grade and mitotic index.	('patient', 'Species', '9606', (113, 120))	('tumor', 'Disease', (158, 163))	('vimentin', 'Gene', '7431', (48, 56))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('ectopic expression', 'Var', (26, 44))	('mitotic index', 'CPA', (174, 187))	('vimentin', 'Gene', (48, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('higher', 'PosReg', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('loss', 'NegReg', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
646388	26267323	Of 2 CK18+ pancreatic cancer CTCs, one stained positively for both CK18+ and CD133+, potentially representing a CTSC.	('CK18+', 'Var', (5, 10))	('pancreatic cancer', 'Disease', 'MESH:D010190', (11, 28))	('pancreatic cancer', 'Disease', (11, 28))	('CK18+', 'Var', (67, 72))	('stained', 'Reg', (39, 46))	('CD133', 'Gene', (77, 82))	('CD133', 'Gene', '8842', (77, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (11, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
646389	26267323	Results of in situ phenotyping and karyotyping CTCs (in situ PK CTC) in Figure 2C reveals non-hematopoietic heteroploid CTCs identified by CK18-iFISH in a non-small cell lung cancer (NSCLC) patient's blood.	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (159, 181))	('iFISH', 'Chemical', '-', (144, 149))	('CK18-iFISH', 'Var', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('NSCLC', 'Disease', (183, 188))	('SCLC', 'Phenotype', 'HP:0030357', (184, 188))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (155, 181))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (155, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('non-small cell lung cancer', 'Disease', (155, 181))	('patient', 'Species', '9606', (190, 197))
646394	26267323	As revealed in Figures 2E, EpCAM-iFISH demonstrates heteroploid chromosome 8 and strong EpCAM expression in enriched breast cancer cells SK-BR-3.	('heteroploid chromosome', 'Var', (52, 74))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('EpCAM', 'Gene', (88, 93))	('SK-BR-3', 'CellLine', 'CVCL:0033', (137, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('expression', 'MPA', (94, 104))	('iFISH', 'Chemical', '-', (33, 38))
646396	26267323	Figure 2G shows a non-hematopoietic (CD45-) CTC enriched from a NSCLC patient has triploid chromosome 8 and visible EMT marker vimentin.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('SCLC', 'Phenotype', 'HP:0030357', (65, 69))	('triploid chromosome', 'Var', (82, 101))	('patient', 'Species', '9606', (70, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('CD45', 'Gene', (37, 41))	('vimentin', 'Gene', '7431', (127, 135))	('NSCLC', 'Disease', (64, 69))	('vimentin', 'Gene', (127, 135))	('CD45', 'Gene', '5788', (37, 41))
646414	26267323	Figure 3C illustrates microscopically verified triploid CK18+ or CK18- gastric cancer cells identified by iFISH.	('iFISH', 'Chemical', '-', (106, 111))	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('triploid CK18+', 'Var', (47, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('CK18+', 'Var', (56, 61))	('CK18-', 'Var', (65, 70))
646423	26267323	As revealed in Figure 4B, further analysis of CK18 expression on lung cancer CTCs indicated that in a total of 623 detected CTCs, 86% cells (537/623, black) were CK18-, while 14% (86/623, grey) had detectable CK18+.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('CK18-', 'Var', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))
646424	26267323	Of the 165 CTCs isolated from patients with esophageal cancer, 76% (126/165, black) were CK18-, whereas the remaining 24% (39/165, grey) were CK18+.	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patients', 'Species', '9606', (30, 38))	('esophageal cancer', 'Disease', (44, 61))	('CK18-', 'Var', (89, 94))
646427	26267323	About 38% of esophageal cancer CTCs were triploid chromosome 8, and among this population, 6.7% were CK18+, and 30.9% were CK18-.	('CK18+', 'Var', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (13, 30))	('triploid chromosome', 'Var', (41, 60))	('CK18-', 'Var', (123, 128))	('esophageal cancer', 'Disease', (13, 30))
646436	26267323	In addition, EGFR mutation analysis performed on lung cancer CTCs was reported to be more sensitive than conventional serum nucleic acid analysis.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', '1956', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('EGFR', 'Gene', (13, 17))
646445	26267323	In this study, we developed a novel in situ strategy combining FDA-approved karyotypic CEP8-FISH and simultaneous phenotypic immunofluorescent staining of tumor biomarkers with either intracellular or extracellular antigenic epitopes (such as HER2, CK, EpCAM, CD133, Vimentin, CD44V6, etc.)	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('CD44V6', 'Var', (277, 283))	('tumor', 'Disease', (155, 160))	('HER2', 'Gene', (243, 247))	('CD133', 'Gene', (260, 265))	('HER2', 'Gene', '2064', (243, 247))	('CD133', 'Gene', '8842', (260, 265))	('Vimentin', 'Protein', (267, 275))
646451	26267323	It has been recently recognized that CK18 is a "tumor biomarker" with distinct clinical significance in cancer cells.	('tumor', 'Disease', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('CK18', 'Var', (37, 41))
646456	26267323	Indeed, one of the anticipated clinical significance of CTC subtypes has been confirmed in our recent studies performed on the advanced gastric cancer patients, showing that among CK18 negative CTCs, trisomy in chromosome 8 CTC may possess intrinsic resistance to the chemotherapeutic drug cisplatin, compared to the tetra- and/or pentasomy subtype which developed the acquired cisplatin resistance.	('CTC', 'Gene', (224, 227))	('tetra', 'Species', '42554', (317, 322))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cisplatin resistance', 'MPA', (378, 398))	('patients', 'Species', '9606', (151, 159))	('gastric cancer', 'Disease', (136, 150))	('CK18', 'Gene', (180, 184))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('trisomy in chromosome', 'Var', (200, 221))	('cisplatin', 'Chemical', 'MESH:D002945', (290, 299))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (378, 387))
646489	26267323	CTC is defined as DAPI+, CD45-, heteroploid CEP8 signal with or without visible CK18 or other tumor biomarkers.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CD45', 'Gene', '5788', (25, 29))	('DAPI', 'Chemical', 'MESH:C007293', (18, 22))	('tumor', 'Disease', (94, 99))	('CD45', 'Gene', (25, 29))	('CEP8', 'Gene', (44, 48))	('heteroploid', 'Var', (32, 43))
646562	25328408	However, the YY1 protein level was significantly higher in ESCC tissues with lymph node metastasis than those without lymph node metastasis (P=0.042).	('YY1', 'Gene', '7528', (13, 16))	('lymph node metastasis', 'Var', (77, 98))	('YY1', 'Gene', (13, 16))	('ESCC', 'Disease', (59, 63))	('higher', 'PosReg', (49, 55))
646565	25328408	The Transwell assay revealed that the overexpression of YY1 promoted the invasion ability of TE-1 cells and the inhibition of YY1 could reverse this promotion.	('invasion ability of TE-1 cells', 'CPA', (73, 103))	('inhibition', 'Var', (112, 122))	('YY1', 'Gene', (56, 59))	('Tran', 'Gene', '7154', (4, 8))	('promoted', 'PosReg', (60, 68))	('YY1', 'Gene', '7528', (126, 129))	('Tran', 'Gene', (4, 8))	('TE-1', 'CellLine', 'CVCL:1759', (93, 97))	('overexpression', 'PosReg', (38, 52))	('YY1', 'Gene', '7528', (56, 59))	('YY1', 'Gene', (126, 129))
646571	25328408	Transcription factors have been reported to play important roles in cell growth, development, and differentiation, and there is substantial evidence that transcription factor dysfunction leads to detrimental outcomes, even tumorigenesis.	('Tran', 'Gene', '7154', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('dysfunction', 'Var', (175, 186))	('Tran', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('transcription', 'Protein', (154, 167))
646572	25328408	Massive evidence indicates that transcription factors act as important players in human cancer development and progression, and it has been shown that the dysregulation of many transcription factors, such as Oct3/4, Sox2, KLF4, and EGR-1, is involved in the occurrence and development of esophageal cancer.	('cancer', 'Disease', (88, 94))	('EGR-1', 'Gene', (232, 237))	('Sox2', 'Gene', '6657', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('dysregulation', 'Var', (155, 168))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('esophageal cancer', 'Disease', 'MESH:D004938', (288, 305))	('KLF4', 'Gene', (222, 226))	('esophageal cancer', 'Disease', (288, 305))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', (299, 305))	('involved', 'Reg', (242, 250))	('Sox2', 'Gene', (216, 220))	('KLF4', 'Gene', '9314', (222, 226))	('Oct3/4', 'Gene', '5460', (208, 214))	('Oct3/4', 'Gene', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('EGR-1', 'Gene', '1958', (232, 237))	('human', 'Species', '9606', (82, 87))
646610	25328408	Conversely, the protein level of YY1 was significantly higher in ESCC tissues with lymph node metastasis than in those without lymph node metastasis (P=0.042, Figure 2).	('YY1', 'Gene', '7528', (33, 36))	('YY1', 'Gene', (33, 36))	('ESCC', 'Disease', (65, 69))	('protein level', 'MPA', (16, 29))	('lymph node metastasis', 'Var', (83, 104))	('higher', 'PosReg', (55, 61))
646614	25328408	It was found that the protein level of YY1 was significantly higher in ESCC tissues with lymph node metastasis than those without lymph node metastasis.	('YY1', 'Gene', '7528', (39, 42))	('ESCC', 'Disease', (71, 75))	('YY1', 'Gene', (39, 42))	('higher', 'PosReg', (61, 67))	('lymph node metastasis', 'Var', (89, 110))	('protein level', 'MPA', (22, 35))
646616	25328408	The results showed that the number of TE-1 cells migrating through the membrane increased after transfection with a YY1 overexpression vector, and significantly decreased after silencing with small hairpin RNA, indicating that YY1 increased the invasive ability of TE-1 cells and the inhibition of YY1 could reverse this promotion (Figure 4).	('YY1', 'Gene', '7528', (298, 301))	('decreased', 'NegReg', (161, 170))	('YY1', 'Gene', '7528', (116, 119))	('TE-1', 'CellLine', 'CVCL:1759', (38, 42))	('increased', 'PosReg', (231, 240))	('invasive ability', 'CPA', (245, 261))	('YY1', 'Gene', (298, 301))	('silencing', 'Var', (177, 186))	('YY1', 'Gene', '7528', (227, 230))	('YY1', 'Gene', (116, 119))	('TE-1', 'CellLine', 'CVCL:1759', (265, 269))	('YY1', 'Gene', (227, 230))
646632	25328408	In the present study, we found that YY1 promoted the invasion of ESCC cells and the inhibition of YY1 could reverse this promotion.	('YY1', 'Gene', (36, 39))	('YY1', 'Gene', '7528', (98, 101))	('YY1', 'Gene', '7528', (36, 39))	('promoted', 'PosReg', (40, 48))	('invasion of ESCC cells', 'CPA', (53, 75))	('YY1', 'Gene', (98, 101))	('inhibition', 'Var', (84, 94))
646865	19698122	Since THBS1, Cyr61 or CTGF expression was shown to have significant impact on the overall survival of patients with ESCC, we included the expressions of these genes in further prognostic value analysis.	('THBS1', 'Gene', (6, 11))	('Cyr61', 'Gene', '3491', (13, 18))	('ESCC', 'Disease', (116, 120))	('patients', 'Species', '9606', (102, 110))	('THBS1', 'Gene', '7057', (6, 11))	('impact', 'Reg', (68, 74))	('CTGF', 'Gene', '1490', (22, 26))	('Cyr61', 'Gene', (13, 18))	('expression', 'Var', (27, 37))	('CTGF', 'Gene', (22, 26))
646882	19698122	Methylation-induced silencing of THBS1 expression correlated with impaired TGF-beta signaling as indicated by decreased Smad2 phosphorylation and nuclear localization.	('impaired', 'NegReg', (66, 74))	('silencing', 'NegReg', (20, 29))	('THBS1', 'Gene', '7057', (33, 38))	('THBS1', 'Gene', (33, 38))	('Smad2', 'Gene', '4087', (120, 125))	('phosphorylation', 'MPA', (126, 141))	('nuclear localization', 'MPA', (146, 166))	('decreased', 'NegReg', (110, 119))	('Smad2', 'Gene', (120, 125))	('TGF-beta', 'Gene', '7040', (75, 83))	('Methylation-induced', 'Var', (0, 19))	('expression', 'MPA', (39, 49))	('TGF-beta', 'Gene', (75, 83))
646884	19698122	Recently, it is reported that loss of THBS1 expression was also significantly associated with distal location, vascular invasion and distant metastasis in gastric cancer and with unfavourable histological grade and shorter overall survival in penile squamous cell carcinoma.	('associated', 'Reg', (78, 88))	('THBS1', 'Gene', (38, 43))	('vascular invasion', 'CPA', (111, 128))	('overall', 'MPA', (223, 230))	('gastric cancer', 'Phenotype', 'HP:0012126', (155, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (250, 273))	('THBS1', 'Gene', '7057', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('distant metastasis', 'CPA', (133, 151))	('penile squamous cell carcinoma', 'Disease', 'MESH:D004414', (243, 273))	('shorter', 'NegReg', (215, 222))	('penile squamous cell carcinoma', 'Disease', (243, 273))	('gastric cancer', 'Disease', (155, 169))	('loss', 'Var', (30, 34))	('distal location', 'CPA', (94, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (155, 169))
646914	17896144	In vitro, paclitaxel-mediated blockade at the G2/M has shown to activate cell-cycle control pathways that induce apoptosis independent of p53.	('p53', 'Gene', (138, 141))	('apoptosis', 'CPA', (113, 122))	('paclitaxel', 'Chemical', 'MESH:D017239', (10, 20))	('blockade', 'Var', (30, 38))	('p53', 'Gene', '7157', (138, 141))	('cell-cycle control pathways', 'Pathway', (73, 100))	('activate', 'PosReg', (64, 72))
646922	17896144	Further eligibility criteria included: patient age between 18 and 75 years, WHO performance status <=2, written informed consent, central venous catheter, and adequate hematological, renal, and hepatic functions defined as white blood cell count > 3.5 x 109/L, platelet count > 100 x 109/L, creatinine level < 120 mumol/L and/or creatinine clearance > 60 mL/min, and normal hepatic enzyme levels.	('patient', 'Species', '9606', (39, 46))	('hepatic enzyme levels', 'MPA', (374, 395))	('creatinine level', 'MPA', (291, 307))	('> 3.5', 'Var', (246, 251))	('> 100 x 109/L', 'Var', (276, 289))	('creatinine', 'Chemical', 'MESH:D003404', (291, 301))	('creatinine clearance', 'MPA', (329, 349))	('creatinine', 'Chemical', 'MESH:D003404', (329, 339))
646971	17896144	The ypTNM stages of the remaining patients were: pT1N0M0 in six patients (12.8%), pT2-3N0M0 in 12 patients (25.5%), pT1-2N1M0 in four patients (8.5%), and pT3N1M0/pT4N0-1M0 in seven patients (14.9%).	('patients', 'Species', '9606', (64, 72))	('pT3N1M0/pT4N0-1M0', 'Var', (155, 172))	('patients', 'Species', '9606', (134, 142))	('patients', 'Species', '9606', (98, 106))	('pT1N0M0', 'Var', (49, 56))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (182, 190))	('pT2-3N0M0', 'Var', (82, 91))	('pT1-2N1M0', 'Var', (116, 125))
647024	32207410	PIK3C3 Acts as a Tumor Suppressor in Esophageal Squamous Cell Carcinoma and Was Regulated by MiR-340-5p Esophageal squamous cell carcinoma (ESCC), a major histological subtype of esophageal cancer, is a common cause of tumor-related deaths in the world.	('tumor', 'Disease', (219, 224))	('Tumor', 'Phenotype', 'HP:0002664', (17, 22))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (48, 71))	('Carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (115, 138))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cancer', 'Disease', (190, 196))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('MiR-340-5p', 'Var', (93, 103))	('squamous cell carcinoma', 'Disease', (115, 138))	('MiR-340-5p', 'Chemical', '-', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('deaths', 'Disease', (233, 239))	('Squamous Cell Carcinoma', 'Disease', (48, 71))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('deaths', 'Disease', 'MESH:D003643', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('PIK3C3', 'Gene', '5289', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('PIK3C3', 'Gene', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))
647029	32207410	In addition, miR-340-5p was revealed to directly bind and negatively modulate PIK3C3 expression in ESCC.	('bind', 'Interaction', (49, 53))	('PIK3C3', 'Gene', (78, 84))	('expression', 'MPA', (85, 95))	('ESCC', 'Disease', (99, 103))	('miR-340-5p', 'Chemical', '-', (13, 23))	('miR-340-5p', 'Var', (13, 23))	('modulate', 'Reg', (69, 77))	('negatively', 'NegReg', (58, 68))
647030	32207410	Blockage of miR-340-5p promoted ESCC cell proliferation, while rescue of PIK3C3 reversed this effect.	('miR-340-5p', 'Chemical', '-', (12, 22))	('Blockage', 'Var', (0, 8))	('miR-340-5p', 'Var', (12, 22))	('promoted', 'PosReg', (23, 31))	('PIK3C3', 'Gene', (73, 79))	('ESCC cell proliferation', 'CPA', (32, 55))
647031	32207410	MiR-340-5p was highly expressed in ESCC tissue and it exhibited a negative correlation with PIK3C3 expression.	('expression', 'MPA', (99, 109))	('MiR-340-5p', 'Var', (0, 10))	('MiR-340-5p', 'Chemical', '-', (0, 10))	('negative', 'NegReg', (66, 74))	('PIK3C3', 'Gene', (92, 98))
647032	32207410	MiR-340-5p functioned as an oncogene of ESCC by directly binding and repressing the expression of PIK3C3.	('repressing', 'NegReg', (69, 79))	('binding', 'Interaction', (57, 64))	('MiR-340-5p', 'Var', (0, 10))	('PIK3C3', 'Gene', (98, 104))	('MiR-340-5p', 'Chemical', '-', (0, 10))	('expression', 'MPA', (84, 94))
647038	32207410	PI3Ks has been reported to be correlated with multiple cellular processes, including cell growth, differentiation, apoptosis, and intracellular trafficking, which in turn have been associated with tumor development.	('associated', 'Reg', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('PI3Ks', 'Var', (0, 5))	('cell growth', 'CPA', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('apoptosis', 'CPA', (115, 124))	('differentiation', 'CPA', (98, 113))	('intracellular', 'MPA', (130, 143))
647044	32207410	In conclusion, our findings suggested that PIK3C3 serves as a tumor repressor by interacting with miR-340-5p in ESCC cells in vitro.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('miR-340-5p', 'Chemical', '-', (98, 108))	('interacting', 'Interaction', (81, 92))	('miR-340-5p', 'Var', (98, 108))	('tumor', 'Disease', (62, 67))	('PIK3C3', 'Gene', (43, 49))
647065	32207410	The wild type (WT) and mutant (Mut) parts of PIK3C3 3'-UTR containing the miR-340-5p binding sequences were inserted into the pCMV6 (Origene, Rockville, MD, USA) to form pCMV6/PIK3C3-wt and pCMV6/PIK3C3-mut, respectively.	('miR-340-5p', 'Chemical', '-', (74, 84))	('mutant', 'Var', (23, 29))	('PIK3C3', 'Gene', (45, 51))
647066	32207410	pCMV6/PIK3C3-wt or pCMV6/PIK3C3-mut was co-transfected into KYSE-150 and TE-12 cells with miR-340-5p mimics or miR-340-5p ASO.	('KYSE', 'Chemical', '-', (60, 64))	('TE-12', 'CellLine', 'CVCL:1762', (73, 78))	('miR-340-5p', 'Chemical', '-', (111, 121))	('miR-340-5p', 'Chemical', '-', (90, 100))	('miR-340-5p', 'Var', (111, 121))	('miR-340-5p', 'Var', (90, 100))
647083	32207410	MiR-381-3p and miR-340-5p were identified by all the 3 software (Figure 4A).	('miR-340-5p', 'Chemical', '-', (15, 25))	('MiR-381-3p', 'Var', (0, 10))	('miR-340-5p', 'Var', (15, 25))
647085	32207410	Results suggested that the expression of miR-340-5p or miR-381-3p was negatively or positively correlated with PIK3C3 expression in ESCC samples, and the Pearson's correlation coefficient was -0.076 and 0.017, respectively (Figure 4B).	('negatively', 'NegReg', (70, 80))	('positively', 'PosReg', (84, 94))	('PIK3C3', 'Gene', (111, 117))	('miR-340-5p', 'Chemical', '-', (41, 51))	('correlated', 'Reg', (95, 105))	('miR-340-5p', 'Var', (41, 51))	('expression', 'MPA', (118, 128))	('ESCC', 'Disease', (132, 136))	('miR-381-3p', 'Var', (55, 65))
647089	32207410	As results indicated that co-transfection of miR-340-5p ASO and PIK3C3-3'-UTR-wt markedly increased the luciferase activity, while co-transfection of miR-340-5p mimics and PIK3C3-3'-UTR-wt markedly attenuated the luciferase intensity (* P<0.05, Figure 4C).	('luciferase', 'Enzyme', (104, 114))	('increased', 'PosReg', (90, 99))	('intensity', 'MPA', (224, 233))	('miR-340-5p', 'Chemical', '-', (150, 160))	('activity', 'MPA', (115, 123))	('luciferase', 'Enzyme', (213, 223))	('attenuated', 'NegReg', (198, 208))	('miR-340-5p', 'Chemical', '-', (45, 55))	('miR-340-5p', 'Var', (45, 55))
647090	32207410	The luciferase intensity of cells driven by PIK3C3-3'-UTR-mut was not affected by miR-340-5p mimics and ASO.	('luciferase', 'Enzyme', (4, 14))	('miR-340-5p', 'Var', (82, 92))	('miR-340-5p', 'Chemical', '-', (82, 92))	("PIK3C3-3'-UTR-mut", 'Var', (44, 61))
647092	32207410	Transfecting KYSE-150 and TE-12 cells with miR-340-5p mimics resulted in a significant downregulation of PIK3C3, while transfection of miR-340-5p ASO exhibited an opposite effect on PIK3C3 expression (* P<0.05, Figure 4D).	('miR-340-5p', 'Chemical', '-', (43, 53))	('KYSE', 'Chemical', '-', (13, 17))	('miR-340-5p mimics', 'Var', (43, 60))	('downregulation', 'NegReg', (87, 101))	('TE-12', 'CellLine', 'CVCL:1762', (26, 31))	('miR-340-5p', 'Chemical', '-', (135, 145))	('PIK3C3', 'Gene', (105, 111))
647093	32207410	Next, we examined the function of miR-340-5p in ESCC cell proliferation by silencing its expression in vitro.	('expression', 'MPA', (89, 99))	('miR-340-5p', 'Chemical', '-', (34, 44))	('silencing', 'NegReg', (75, 84))	('miR-340-5p', 'Var', (34, 44))	('ESCC', 'Disease', (48, 52))
647094	32207410	By using MTT assay, we found that cell viability of KYSE-150 and TE-12 cells treated with anti-miR-340-5p were markedly increased compared to control group (* P<0.05, Figure 5A, 5B).	('miR-340-5p', 'Chemical', '-', (95, 105))	('anti-miR-340-5p', 'Var', (90, 105))	('KYSE', 'Chemical', '-', (52, 56))	('increased', 'PosReg', (120, 129))	('MTT', 'Chemical', 'MESH:C070243', (9, 12))	('TE-12', 'CellLine', 'CVCL:1762', (65, 70))	('cell viability', 'CPA', (34, 48))
647095	32207410	Moreover, co-transfection of anti-miR-340-5p and PIK3C3 reversed the upregulation of cell viability of KYSE-150 and TE-12 cells induced by miR-340-5p knockdown (Figure 5A, 5B).	('upregulation', 'PosReg', (69, 81))	('miR-340-5p knockdown', 'Var', (139, 159))	('miR-340-5p', 'Chemical', '-', (34, 44))	('knockdown', 'Var', (150, 159))	('PIK3C3', 'Gene', (49, 55))	('KYSE', 'Chemical', '-', (103, 107))	('TE-12', 'CellLine', 'CVCL:1762', (116, 121))	('cell viability', 'CPA', (85, 99))	('miR-340-5p', 'Chemical', '-', (139, 149))
647096	32207410	In the colony formation experiment, we demonstrated that miR-340-5p knockdown could remarkably increase the colony number in KYSE-150 and TE-12 cells, however, co-transfection of anti-miR-340-5p and PIK3C3 blocked this phenomenon (* P<0.05, Figure 5C, 5D).	('TE-12', 'CellLine', 'CVCL:1762', (138, 143))	('miR-340-5p', 'Chemical', '-', (57, 67))	('anti-miR-340-5p', 'Var', (179, 194))	('increase', 'PosReg', (95, 103))	('knockdown', 'Var', (68, 77))	('KYSE', 'Chemical', '-', (125, 129))	('miR-340-5p knockdown', 'Var', (57, 77))	('miR-340-5p', 'Chemical', '-', (184, 194))
647097	32207410	qRT-PCR analysis showed that miR-340-5p was markedly upregulated in the ESCC tissue samples compared to the normal counterparts (* P<0.05, Figure 5E).	('miR-340-5p', 'Var', (29, 39))	('miR-340-5p', 'Chemical', '-', (29, 39))	('upregulated', 'PosReg', (53, 64))	('ESCC', 'Disease', (72, 76))
647099	32207410	In addition, a negative correlation was observed between the level of miR-340-5p and PIK3C3 in ESCC samples (Figure 5F).	('PIK3C3', 'Gene', (85, 91))	('ESCC', 'Disease', (95, 99))	('miR-340-5p', 'Chemical', '-', (70, 80))	('negative', 'NegReg', (15, 23))	('miR-340-5p', 'Var', (70, 80))
647100	32207410	These results indicated that PIK3C3 could reverse the promotive effects of miR-340-5p on ESCC cell proliferation.	('miR-340-5p', 'Var', (75, 85))	('ESCC', 'Disease', (89, 93))	('miR-340-5p', 'Chemical', '-', (75, 85))
647101	32207410	PIK3C3 is known as an autophagy-related protein, inhibition of PIK3C3 was reported to prevent autophagy and synergize with MTOR inhibition in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('autophagy', 'CPA', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('MTOR', 'Gene', (123, 127))	('prevent', 'NegReg', (86, 93))	('PIK3C3', 'Gene', (63, 69))	('inhibition', 'Var', (49, 59))	('MTOR', 'Gene', '2475', (123, 127))	('cancer', 'Disease', (142, 148))
647105	32207410	Moreover, repressing PIK3C3 via SAR405 could suppress the process of autophagy caused by nutrient starvation.	('suppress', 'NegReg', (45, 53))	('PIK3C3', 'Gene', (21, 27))	('SAR405', 'Chemical', 'MESH:C000594652', (32, 38))	('SAR405', 'Var', (32, 38))	('process of autophagy', 'CPA', (58, 78))
647108	32207410	In a pilot case-control research of ESCC patients and matched controls, a total of 38 single nucleotide polymorphisms correlated with ESCC were found in 33 genes, which including PIK3C3.	('PIK3C3', 'Gene', (179, 185))	('patients', 'Species', '9606', (41, 49))	('ESCC', 'Disease', (134, 138))	('single nucleotide polymorphisms', 'Var', (86, 117))
647110	32207410	To further identify the mechanism of PIK3C3 in ESCC, we predicted its target miRNAs through bioinformatics methods, and miR-340-5p was screened and proven to directly bind to the 3'-UTR area of PIK3C3.	('ESCC', 'Disease', (47, 51))	('miR-340-5p', 'Chemical', '-', (120, 130))	('miR-340-5p', 'Var', (120, 130))	('bind', 'Interaction', (167, 171))	('PIK3C3', 'Gene', (194, 200))	('PIK3C3', 'Gene', (37, 43))
647111	32207410	MiR-340-5p was previously demonstrated to affect the progression of various human cancers, such as glioblastoma, non-small cell lung cancer, and osteosarcoma, through multiple distinct mechanisms.	('MiR-340-5p', 'Var', (0, 10))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('MiR-340-5p', 'Chemical', '-', (0, 10))	('cancers', 'Disease', (82, 89))	('osteosarcoma', 'Phenotype', 'HP:0002669', (145, 157))	('glioblastoma', 'Disease', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('affect', 'Reg', (42, 48))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('osteosarcoma', 'Disease', (145, 157))	('osteosarcoma', 'Disease', 'MESH:D012516', (145, 157))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('human', 'Species', '9606', (76, 81))	('lung cancer', 'Disease', (128, 139))
647113	32207410	The implication of miR-340-5p in ESCC has not been reported so far.	('miR-340-5p', 'Chemical', '-', (19, 29))	('ESCC', 'Disease', (33, 37))	('miR-340-5p', 'Var', (19, 29))
647114	32207410	In this study, miR-340-5p was found to negatively regulated the expression of PIK3C3, and overexpression of PIK3C3 was shown to abolish the promotive influences of miR-340-5p on ESCC cell proliferation in vitro.	('PIK3C3', 'Gene', (78, 84))	('expression', 'MPA', (64, 74))	('abolish', 'NegReg', (128, 135))	('ESCC cell proliferation in vitro', 'CPA', (178, 210))	('PIK3C3', 'Var', (108, 114))	('miR-340-5p', 'Chemical', '-', (164, 174))	('negatively', 'NegReg', (39, 49))	('miR-340-5p', 'Var', (164, 174))	('promotive influences', 'MPA', (140, 160))	('miR-340-5p', 'Chemical', '-', (15, 25))	('overexpression', 'PosReg', (90, 104))
647162	31681453	In preliminary goodness-of-fit analyses of survival time in the esophageal cancer data, we explored a set of distributions for FW, and chose the extreme value distribution, characterized by density function fW(w) = exp(w - ew), -  < w <  .	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('fW(w', 'Var', (207, 211))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
647189	31681453	For priors on betaR, betaD, xi, mu, and zeta, we assume betaR ~ Np(betaR, SigmaR), betaD ~ Nq(betaD, SigmaD), xi ~ Gamma(axi, bxi), zeta ~ N(zeta, omega2) and mu ~ N(mu, tau2).	('eta', 'Gene', (68, 71))	('eta', 'Gene', '1909', (41, 44))	('eta', 'Gene', '1909', (95, 98))	('eta', 'Gene', '1909', (57, 60))	('eta', 'Gene', (41, 44))	('Ga', 'Chemical', 'MESH:C043055', (115, 117))	('eta', 'Gene', '1909', (142, 145))	('eta', 'Gene', '1909', (15, 18))	('eta', 'Gene', '1909', (22, 25))	('eta', 'Gene', (95, 98))	('eta', 'Gene', '1909', (133, 136))	('eta', 'Gene', (57, 60))	('eta', 'Gene', (142, 145))	('eta', 'Gene', (22, 25))	('eta', 'Gene', '1909', (84, 87))	('eta', 'Gene', '1909', (68, 71))	('eta', 'Gene', (15, 18))	('eta', 'Gene', (133, 136))	('mu ~ N', 'Var', (159, 165))	('eta', 'Gene', (84, 87))
647222	31681453	For example, (Bias, Ave. CI length, Coverage) are (-0.322, 0.392, 28.8%) for betaR3 and (0.216, 0.509, 60.6%) for betaD3 under the Joint-logNormal model.	('eta', 'Gene', '1909', (115, 118))	('eta', 'Gene', (115, 118))	('-0.322', 'Var', (51, 57))	('0.216', 'Var', (89, 94))	('eta', 'Gene', '1909', (78, 81))	('eta', 'Gene', (78, 81))
647229	31681453	Although the performance of the Joint-logNormal is inferior to that of the Joint-DP model, the Joint-logNormal model gives much more reliable estimates of betaR and betaD compared to the R-logNormal and S-logNormal models.	('eta', 'Gene', '1909', (166, 169))	('eta', 'Gene', (156, 159))	('eta', 'Gene', '1909', (156, 159))	('eta', 'Gene', (166, 169))	('Joint-logNormal', 'Var', (95, 110))
647240	31681453	On average, IMRT decreases the effusion rate by a multiplicative factor of exp(-0.82) = 0.442, and decreases the hazard of death by a multiplicative factor of 0.468.	('decreases', 'NegReg', (99, 108))	('IMRT', 'Var', (12, 16))	('decreases', 'NegReg', (17, 26))	('death', 'Disease', 'MESH:D003643', (123, 128))	('death', 'Disease', (123, 128))	('effusion rate', 'MPA', (31, 44))
647241	31681453	These inferences agree with previous findings in that IMRT is significantly associated with better clinical outcomes, such as decreased toxicity in the lungs and heart and longer survival.	('IMRT', 'Var', (54, 58))	('decreased toxicity', 'Disease', (126, 144))	('decreased toxicity', 'Disease', 'MESH:D064420', (126, 144))
647253	31681453	The posterior estimates of xi are considerably different under the Joint-DP and R-DP models, with much smaller xi under the R-DP model.	('R-DP', 'Gene', (124, 128))	('R-DP', 'Gene', (80, 84))	('R-DP', 'Gene', '1800', (124, 128))	('R-DP', 'Gene', '1800', (80, 84))	('Joint-DP', 'Var', (67, 75))
647264	31423241	The effect of silencing CCAT2 (si-CCAT2) and inhibiting Wnt signaling (using the inhibitor FH535) on the proliferation, migration and invasion of Eca-109 cells was measured by MTT, wound-healing and Transwell invasion assays.	('si', 'Chemical', 'MESH:D012825', (14, 16))	('silencing', 'Var', (14, 23))	('si', 'Chemical', 'MESH:D012825', (138, 140))	('CCAT2', 'Gene', (34, 39))	('CCAT2', 'Gene', (24, 29))	('FH535', 'Chemical', 'MESH:C575430', (91, 96))	('invasion', 'CPA', (134, 142))	('inhibiting', 'NegReg', (45, 55))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('migration', 'CPA', (120, 129))	('Wnt signaling', 'Pathway', (56, 69))	('CCAT2', 'Gene', '101805488', (34, 39))	('si', 'Chemical', 'MESH:D012825', (213, 215))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('MTT', 'Chemical', 'MESH:C070243', (176, 179))	('CCAT2', 'Gene', '101805488', (24, 29))
647272	31423241	In summary, lncRNA CCAT2 is upregulated in esophageal cancer cells and the knockdown of lncRNA CCAT2 inhibits their proliferation, migration and invasion via the Wnt signaling pathway.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('si', 'Chemical', 'MESH:D012825', (149, 151))	('migration', 'CPA', (131, 140))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('CCAT2', 'Gene', '101805488', (19, 24))	('knockdown', 'Var', (75, 84))	('proliferation', 'CPA', (116, 129))	('CCAT2', 'Gene', '101805488', (95, 100))	('inhibits', 'NegReg', (101, 109))	('upregulated', 'PosReg', (28, 39))	('CCAT2', 'Gene', (19, 24))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('invasion', 'CPA', (145, 153))	('CCAT2', 'Gene', (95, 100))
647280	31423241	Long non-coding (lnc)RNA colon cancer-associated transcript 2 (CCAT2) was first identified as a region within the 8q24 chromosomal location containing a single nucleotide polymorphism and expressed in microsatellite-stable colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('si', 'Chemical', 'MESH:D012825', (153, 155))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CCAT2', 'Gene', (63, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (223, 240))	('colon cancer-associated transcript 2', 'Gene', (25, 61))	('colorectal cancer', 'Disease', (223, 240))	('colon cancer', 'Phenotype', 'HP:0003003', (25, 37))	('single nucleotide polymorphism', 'Var', (153, 183))	('CCAT2', 'Gene', '101805488', (63, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (223, 240))	('colon cancer-associated transcript 2', 'Gene', '101805488', (25, 61))
647283	31423241	The results demonstrated that the silencing of CCAT2 inhibits proliferation and invasion of NSCLC, SCLC, glioma, ovarian cancer, bladder cancer, breast cancer and even tamoxifen-resistant breast cancer cells.	('SCLC', 'Disease', (93, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('bladder cancer', 'Disease', (129, 143))	('tamoxifen', 'Chemical', 'MESH:D013629', (168, 177))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('breast cancer', 'Disease', (188, 201))	('proliferation', 'CPA', (62, 75))	('glioma', 'Disease', (105, 111))	('CCAT2', 'Gene', '101805488', (47, 52))	('SCLC', 'Disease', (99, 103))	('NSCLC', 'Disease', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('inhibits', 'NegReg', (53, 61))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('si', 'Chemical', 'MESH:D012825', (180, 182))	('CCAT2', 'Gene', (47, 52))	('SCLC', 'Disease', 'MESH:D018288', (93, 97))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('ovarian cancer', 'Disease', (113, 127))	('silencing', 'Var', (34, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('invasion', 'CPA', (80, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('SCLC', 'Disease', 'MESH:D018288', (99, 103))	('breast cancer', 'Disease', (145, 158))
647286	31423241	Moreover, it has been reported to regulate cancer cell metabolism via alternative splicing of glutaminase by selecting the poly(A) site in intron 14 of the precursor mRNA.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('poly', 'Var', (123, 127))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('regulate', 'Reg', (34, 42))	('poly(A)', 'Chemical', 'MESH:D011061', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
647289	31423241	Lymph node metastasis, advanced lymph node metastasis and Myc amplification were also associated with high lncRNA CCAT2 expression.	('si', 'Chemical', 'MESH:D012825', (18, 20))	('expression', 'MPA', (120, 130))	('Myc', 'Gene', '4609', (58, 61))	('CCAT2', 'Gene', '101805488', (114, 119))	('Myc', 'Gene', (58, 61))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('advanced lymph node metastasis', 'CPA', (23, 53))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('CCAT2', 'Gene', (114, 119))	('high lncRNA', 'Var', (102, 113))	('Lymph node metastasis', 'CPA', (0, 21))
647302	31423241	The sequences of the control and lncRNA CCAT2 siRNAs were as follows: si-CCAT2 sense strand, 5'-GCCUGUAGGAAGAGUCAAATT-3'; si-CCAT2 antisense strand, 5'-UUUGACUCUUCCUACAGGCTT-3'; si-NC sense strand, 5'-UUCUCCGAACGUGUCACGUTT-3'; and si-NC antisense strand, 5'-ACGUGACACGUUCGGAGAATT-3'.	('CCAT2', 'Gene', (40, 45))	('si-NC antisense', 'Var', (231, 246))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('CCAT2', 'Gene', '101805488', (125, 130))	('si-NC', 'Var', (178, 183))	('CCAT2', 'Gene', '101805488', (73, 78))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('si', 'Chemical', 'MESH:D012825', (231, 233))	('CCAT2', 'Gene', '101805488', (40, 45))	('CCAT2', 'Gene', (125, 130))	('si', 'Chemical', 'MESH:D012825', (178, 180))	('CCAT2', 'Gene', (73, 78))
647332	31423241	ab53154), anti-APC (ab15270, Abcam), anti-cyclin D1 (cat.	('ab15270', 'Var', (20, 27))	('APC', 'Gene', '324', (15, 18))	('APC', 'Gene', (15, 18))	('cyclin D1', 'Gene', '595', (42, 51))	('cyclin D1', 'Gene', (42, 51))
647345	31423241	The RT-qPCR data showed no off-target effect occurring, and the knockdown of lncRNA CCAT2 was successfully performed (Fig.	('CCAT2', 'Gene', (84, 89))	('CCAT2', 'Gene', '101805488', (84, 89))	('knockdown', 'Var', (64, 73))
647364	31423241	FH535 is an inhibitor of beta-catenin, which inhibits cyclin D1 and survivin and decreases the proliferation of human colorectal cancer cells, liver cancer stem cells, hepatocellular carcinoma cells and HepG2 cells.	('beta-catenin', 'Gene', '1499', (25, 37))	('FH535', 'Chemical', 'MESH:C575430', (0, 5))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('proliferation', 'CPA', (95, 108))	('human', 'Species', '9606', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cyclin D1', 'Gene', (54, 63))	('inhibits', 'NegReg', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('survivin', 'Protein', (68, 76))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (168, 192))	('cyclin D1', 'Gene', '595', (54, 63))	('liver cancer', 'Disease', 'MESH:D006528', (143, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colorectal cancer', 'Disease', (118, 135))	('HepG2', 'CellLine', 'CVCL:0027', (203, 208))	('decreases', 'NegReg', (81, 90))	('FH535', 'Var', (0, 5))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (168, 192))	('liver cancer', 'Phenotype', 'HP:0002896', (143, 155))	('liver cancer', 'Disease', (143, 155))	('beta-catenin', 'Gene', (25, 37))	('hepatocellular carcinoma', 'Disease', (168, 192))
647365	31423241	FH535 enhances imatinib-induced apoptosis, decreases S phase cells, arrests the cell cycle and suppresses the proliferation of cancer cells by targeting the Wnt signaling pathway.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('S phase cells', 'CPA', (53, 66))	('si', 'Chemical', 'MESH:D012825', (38, 40))	('imatinib', 'Chemical', 'MESH:D000068877', (15, 23))	('suppresses', 'NegReg', (95, 105))	('targeting', 'Reg', (143, 152))	('arrests', 'CPA', (68, 75))	('FH535', 'Chemical', 'MESH:C575430', (0, 5))	('enhances', 'PosReg', (6, 14))	('cell cycle', 'CPA', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('imatinib-induced', 'MPA', (15, 31))	('decreases', 'NegReg', (43, 52))	('FH535', 'Var', (0, 5))	('si', 'Chemical', 'MESH:D012825', (161, 163))
647369	31423241	Furthermore, the population of apoptotic cells, quantified by annexin V staining, increased significantly following knockdown of lncRNA CCAT2.	('knockdown', 'Var', (116, 125))	('CCAT2', 'Gene', '101805488', (136, 141))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('increased', 'PosReg', (82, 91))	('CCAT2', 'Gene', (136, 141))
647393	31109341	Furthermore, tumor-infiltrating NK cells with high Tim-3 expression exhibited a phenotype with enhanced dysfunction.	('tumor', 'Disease', (13, 18))	('high', 'Var', (46, 50))	('dysfunction', 'MPA', (104, 115))	('Tim-3', 'Gene', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('enhanced', 'PosReg', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
647404	31109341	NK cells within tumor microenvironment are often impaired by many different mechanisms, such as reduced numbers, imbalances between activating and inhibitory receptors, and immunosuppressive cytokines.	('imbalances', 'Phenotype', 'HP:0002172', (113, 123))	('inhibitory', 'Protein', (147, 157))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('imbalances', 'Var', (113, 123))	('tumor', 'Disease', (16, 21))	('activating and', 'MPA', (132, 146))	('numbers', 'CPA', (104, 111))	('reduced', 'NegReg', (96, 103))
647406	31109341	It has been reported that programmed cell death protein 1 (PD-1) on NK cells indicates poor survival of esophageal cancer and blockade of PD-1 signaling restores NK cell function.	('restores', 'PosReg', (153, 161))	('programmed cell death protein 1', 'Gene', (26, 57))	('programmed cell death protein 1', 'Gene', '100533201', (26, 57))	('blockade', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))
647411	31109341	Recent studies reported that a high percentage of Tim-3+ NK cells was associated with poor prognosis in patients with gastric cancer and lung adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('gastric cancer', 'Disease', (118, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('Tim-3+ NK cells', 'Var', (50, 65))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (137, 156))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('lung adenocarcinoma', 'Disease', (137, 156))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (137, 156))	('patients', 'Species', '9606', (104, 112))
647449	31109341	In tumor-infiltrating lymphocytes, Tim-3+ NK cells exhibited a greater tendency toward apoptosis compared with the Tim-3- NK cells (Fig.	('tumor', 'Disease', (3, 8))	('Tim-3+ NK', 'Var', (35, 44))	('apoptosis', 'CPA', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
647482	31109341	We observed a significant reduction of average body weight in animals exposed to 4-NQO (Fig.	('reduction', 'NegReg', (26, 35))	('4-NQO', 'Var', (81, 86))	('4-NQO', 'Chemical', 'MESH:D015112', (81, 86))	('average body weight', 'CPA', (39, 58))
647485	31109341	The percentage of NK cells statistically decreased in 4-NQO-treated mice, but there was no significant difference of CD8+ T cells or CD4+ T cells (Fig.	('4-NQO-treated', 'Var', (54, 67))	('mice', 'Species', '10090', (68, 72))	('CD4', 'Gene', '12504', (133, 136))	('decreased', 'NegReg', (41, 50))	('CD8', 'Gene', (117, 120))	('4-NQO', 'Chemical', 'MESH:D015112', (54, 59))	('CD4', 'Gene', (133, 136))	('CD8', 'Gene', '925', (117, 120))	('NK cells', 'CPA', (18, 26))
647486	31109341	Meanwhile, we found that the frequency of Tim-3+ NK cells from 4NQO-treated mice was also higher than that from control mice (Fig.	('mice', 'Species', '10090', (120, 124))	('4NQO-treated', 'Var', (63, 75))	('mice', 'Species', '10090', (76, 80))	('4NQO', 'Chemical', 'MESH:D015112', (63, 67))	('higher', 'PosReg', (90, 96))
647497	31109341	These data suggest that Tim-3+ NK cells may be a potential prognostic for esophageal cancer patients.	('patients', 'Species', '9606', (92, 100))	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Tim-3+ NK', 'Var', (24, 33))
647503	31109341	PD-1 was reported as a marker of exhausted NK cells in digestive cancer patients, and blocking PD-1/PD-L1 signaling can restore the functions of NK cells.	('PD-L1', 'Gene', '29126', (100, 105))	('restore', 'PosReg', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('functions', 'MPA', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('blocking', 'Var', (86, 94))	('cancer', 'Disease', (65, 71))	('PD-L1', 'Gene', (100, 105))	('patients', 'Species', '9606', (72, 80))
647504	31109341	Recent studies have reported Tim-3 is an exhaustion maker for NK cells and blocking Tim-3 signaling can increase the antitumor activity of NK cells in lung adenocarcinoma and melanoma.	('increase', 'PosReg', (104, 112))	('Tim-3 signaling', 'Gene', (84, 99))	('blocking', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (151, 170))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('lung adenocarcinoma and melanoma', 'Disease', 'MESH:D000077192', (151, 183))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
647508	31109341	It has been reported that co-expression of PD-1 and Tim-3 was associated with functionally exhausted NK cells in colon cancer tissues.	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('co-expression', 'Var', (26, 39))	('PD-1', 'Gene', (43, 47))	('Tim-3', 'Gene', (52, 57))	('associated', 'Reg', (62, 72))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('colon cancer', 'Disease', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
647526	31109341	Our analyses of human cancer samples clearly indicate that Tim-3+ NK cells are significantly associated with pathological parameters for poor prognosis of esophageal cancer.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('esophageal cancer', 'Disease', (155, 172))	('cancer', 'Disease', (22, 28))	('associated', 'Reg', (93, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('human', 'Species', '9606', (16, 21))	('Tim-3+ NK cells', 'Var', (59, 74))
647527	31109341	This implies that the dysfunction of NK cells may contribute to the progression of the disease in esophageal cancer patients.	('contribute', 'Reg', (50, 60))	('patients', 'Species', '9606', (116, 124))	('esophageal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('dysfunction', 'Var', (22, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
647541	30984350	For the patients who had residual tumors in LNs, the 5-year OS rates were 28.2% in Group C and 39.5% in Group D. The patients in Groups A+B had a significantly better outcome than the patients in Groups C+D (P < 0.01).	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (117, 125))	('A+B', 'Var', (136, 139))	('better', 'PosReg', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('patients', 'Species', '9606', (8, 16))
647641	30642253	Serum markers of hepatitis B virus at admission: HBsAg (+), anti-HBe (+), and anti-HBc (+).	('hepatitis B virus', 'Species', '10407', (17, 34))	('hepatitis B', 'Disease', (17, 28))	('anti-HBc', 'Var', (78, 86))	('hepatitis', 'Phenotype', 'HP:0012115', (17, 26))
647657	30642253	Hepatitis B serum markers: HBsAg (+), anti-HBe (+), and anti-HBc (+).	('anti-HBc', 'Var', (56, 64))	('anti-HBe', 'Var', (38, 46))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('Hepatitis', 'Disease', 'MESH:D056486', (0, 9))	('Hepatitis', 'Disease', (0, 9))	('HBsAg', 'Disease', (27, 32))
647872	24774510	Clinicopathological features and prognostic roles of KRAS, BRAF, PIK3CA and NRAS mutations in advanced gastric cancer RAS-RAF-MEK-ERK and PI3K-AKT pathways form a significant cascade for potential molecular target therapy in advanced cancer.	('RAF', 'Gene', '22882', (122, 125))	('NRAS', 'Gene', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('MEK', 'Gene', '5609', (126, 129))	('ERK', 'Gene', '5594', (130, 133))	('KRAS', 'Gene', '3845', (53, 57))	('KRAS', 'Gene', (53, 57))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('PIK3CA', 'Gene', '5290', (65, 71))	('RAF', 'Gene', (122, 125))	('MEK', 'Gene', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('AKT', 'Gene', '207', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('ERK', 'Gene', (130, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('NRAS', 'Gene', '4893', (76, 80))	('PIK3CA', 'Gene', (65, 71))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('RAF', 'Gene', '22882', (60, 63))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('RAF', 'Gene', (60, 63))	('gastric cancer', 'Disease', (103, 117))	('cancer', 'Disease', (234, 240))	('AKT', 'Gene', (143, 146))
647873	24774510	The clinical significance of mutations in these genes in advanced gastric cancer (AGC) is uncertain.	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('mutations', 'Var', (29, 38))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
647875	24774510	We retrospectively investigated the clinicopathological features of these mutations in AGC patients, and selected patients with metastatic gastric cancer.	('gastric cancer', 'Disease', (139, 153))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('mutations', 'Var', (74, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('patients', 'Species', '9606', (114, 122))
647876	24774510	Among 167 AGC patients, mutations of KRAS codons 12/13 (N = 8/164, 4.9%), PIK3CA (N = 9/163, 5.5%), and NRAS codon 12/13(N = 3/159, 1.9%) were detected.	('NRAS', 'Gene', '4893', (104, 108))	('PIK3CA', 'Gene', '5290', (74, 80))	('KRAS', 'Gene', (37, 41))	('NRAS', 'Gene', (104, 108))	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (14, 22))	('KRAS', 'Gene', '3845', (37, 41))	('PIK3CA', 'Gene', (74, 80))
647877	24774510	Comparison of the clinicopathological features of the mutated KRAS, PIK3CA, NRAS genes with an all-wild type of these genes showed that the frequency of the intestinal type was significantly higher in patients whose tumor tissue contained KRAS mutations (P = 0.014).	('tumor', 'Disease', (216, 221))	('higher', 'PosReg', (191, 197))	('KRAS', 'Gene', (62, 66))	('NRAS', 'Gene', (76, 80))	('PIK3CA', 'Gene', (68, 74))	('patients', 'Species', '9606', (201, 209))	('KRAS', 'Gene', '3845', (62, 66))	('NRAS', 'Gene', '4893', (76, 80))	('PIK3CA', 'Gene', '5290', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('KRAS', 'Gene', (239, 243))	('KRAS', 'Gene', '3845', (239, 243))	('mutations', 'Var', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
647878	24774510	Among 125 patients with metastatic gastric cancer, patients with NRAS codon 12/13 mutations in their tumors had shorter overall survival compared with NRAS wild-type patients (MST: 14.7 vs 8.8 months, P = 0.011).	('NRAS', 'Gene', '4893', (65, 69))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('patients', 'Species', '9606', (166, 174))	('mutations', 'Var', (82, 91))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (51, 59))	('NRAS', 'Gene', '4893', (151, 155))	('NRAS', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', (101, 107))	('gastric cancer', 'Disease', (35, 49))	('overall survival', 'MPA', (120, 136))	('shorter', 'NegReg', (112, 119))	('NRAS', 'Gene', (65, 69))
647880	24774510	Our study indicated that mutations of KRAS, PIK3CA and NRAS were rare in AGC.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (25, 34))	('KRAS', 'Gene', '3845', (38, 42))	('NRAS', 'Gene', '4893', (55, 59))	('PIK3CA', 'Gene', '5290', (44, 50))	('NRAS', 'Gene', (55, 59))	('KRAS', 'Gene', (38, 42))
647881	24774510	NRAS mutations were likely to associate with poor prognosis in metastatic state of AGC patients, but further validation of other research is required.	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (0, 4))	('metastatic state', 'Disease', (63, 79))	('patients', 'Species', '9606', (87, 95))	('NRAS', 'Gene', '4893', (0, 4))
647891	24774510	Ras mutations are found in up to 30% of all cancers and are particularly common in pancreatic and colon cancers.	('pancreatic and colon cancers', 'Disease', 'MESH:D010190', (83, 111))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('common', 'Reg', (73, 79))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('colon cancers', 'Phenotype', 'HP:0003003', (98, 111))	('found', 'Reg', (18, 23))	('mutations', 'Var', (4, 13))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('Ras', 'Gene', (0, 3))
647893	24774510	BRAF mutations have a narrow distribution, but are prevalent in a few specific malignancies such as melanoma, papillary thyroid cancer, and low-grade ovarian cancer.	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (110, 134))	('prevalent', 'Reg', (51, 60))	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('ovarian cancer', 'Phenotype', 'HP:0100615', (150, 164))	('mutations', 'Var', (5, 14))	('low-grade ovarian cancer', 'Disease', 'MESH:D008228', (140, 164))	('thyroid cancer', 'Phenotype', 'HP:0002890', (120, 134))	('BRAF', 'Gene', '673', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('papillary thyroid cancer', 'Disease', (110, 134))	('BRAF', 'Gene', (0, 4))	('low-grade ovarian cancer', 'Disease', (140, 164))	('malignancies', 'Disease', (79, 91))	('melanoma', 'Disease', (100, 108))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (110, 134))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
647895	24774510	These genetic alterations of PIK3CA consist exclusively of somatic missense mutations clustered in two "hotspot" regions in exons 9 and 20, corresponding to the helical and kinase domains of p110alpha, respectively.	('alterations', 'Var', (14, 25))	('p110alpha', 'Gene', (191, 200))	('p110alpha', 'Gene', '5290', (191, 200))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('missense mutations', 'Var', (67, 85))
647897	24774510	Several small-scale biomarker analyses of KRAS, BRAF and PIK3CA mutations were reported previously in AGC.	('KRAS', 'Gene', (42, 46))	('PIK3CA', 'Gene', '5290', (57, 63))	('AGC', 'Disease', (102, 105))	('KRAS', 'Gene', '3845', (42, 46))	('mutations', 'Var', (64, 73))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('PIK3CA', 'Gene', (57, 63))
647898	24774510	The clinical significance of these mutations in AGC patients is not already clarified, and further investigations of these intracellular molecular changes are required.	('AGC', 'Disease', (48, 51))	('patients', 'Species', '9606', (52, 60))	('mutations', 'Var', (35, 44))
647899	24774510	In the present study, we conducted a genomic analysis of KRAS, BRAF, PIK3CA and NRAS mutations in order to investigate the clinicopathological features and prognostic role of gene mutations in AGC patients.	('NRAS', 'Gene', (80, 84))	('patients', 'Species', '9606', (197, 205))	('NRAS', 'Gene', '4893', (80, 84))	('KRAS', 'Gene', (57, 61))	('mutations', 'Var', (85, 94))	('PIK3CA', 'Gene', (69, 75))	('BRAF', 'Gene', '673', (63, 67))	('KRAS', 'Gene', '3845', (57, 61))	('PIK3CA', 'Gene', '5290', (69, 75))	('BRAF', 'Gene', (63, 67))
647917	24774510	We evaluated the proportion of each KRAS, BRAF, PIK3CA and NRAS mutation in whole cohort and the prognostic values of these mutations, which were adjusted variables of patients' characteristics in terms of overall survival (OS) in metastatic group B. OS was defined as the interval from initiation of first-line chemotherapy to death or last follow up.	('BRAF', 'Gene', '673', (42, 46))	('mutation', 'Var', (64, 72))	('death', 'Disease', (328, 333))	('metastatic group B. OS', 'Disease', (231, 253))	('PIK3CA', 'Gene', (48, 54))	('KRAS', 'Gene', (36, 40))	('KRAS', 'Gene', '3845', (36, 40))	('patients', 'Species', '9606', (168, 176))	('NRAS', 'Gene', (59, 63))	('PIK3CA', 'Gene', '5290', (48, 54))	('BRAF', 'Gene', (42, 46))	('NRAS', 'Gene', '4893', (59, 63))	('death', 'Disease', 'MESH:D003643', (328, 333))
647919	24774510	Mutations of KRAS codon 12 (3.7%, n = 6/164) and KRAS codon 13 (1.2%, n = 2/164), PIK3CA exon 9 (4.9%, n = 8/163), PIK3CA exon 20 (0.6%, n = 1/163) and NRAS mutations (1.9%, n = 3/159) were detected.	('KRAS', 'Gene', '3845', (49, 53))	('PIK3CA', 'Gene', (82, 88))	('NRAS', 'Gene', (152, 156))	('NRAS', 'Gene', '4893', (152, 156))	('PIK3CA', 'Gene', '5290', (82, 88))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', (115, 121))	('KRAS', 'Gene', (13, 17))	('PIK3CA', 'Gene', '5290', (115, 121))	('KRAS', 'Gene', '3845', (13, 17))	('KRAS', 'Gene', (49, 53))
647921	24774510	KRAS codon 12 mutations consisted of G12D (35G > A, n = 4), G12S (34G > A; n = 1) and G12N (34 35GG > AA; n = 1), and codon 13 mutations consisted of G13S (37G > A; n = 1) and G13V (38 39GC > TT; n = 1).	('34 35GG > AA', 'Var', (92, 104))	('37G > A', 'Mutation', 'rs121913535', (156, 163))	('KRAS', 'Gene', '3845', (0, 4))	('G12S', 'Mutation', 'rs121913250', (60, 64))	('38 39GC > TT', 'Mutation', 'c.3839GC>TT', (182, 194))	('G12S (34G > A', 'Var', (60, 73))	('G13S (37G > A', 'Var', (150, 163))	('G12D', 'Mutation', 'rs121913529', (37, 41))	('G13V (38 39GC > TT', 'Var', (176, 194))	('35G > A', 'Mutation', 'rs121913529', (43, 50))	('G13V', 'Mutation', 'rs112445441', (176, 180))	('G13S', 'Mutation', 'rs121913535', (150, 154))	('KRAS', 'Gene', (0, 4))	('34G > A', 'Mutation', 'rs121913530', (66, 73))	('G12N', 'Mutation', 'p.G12N', (86, 90))
647922	24774510	PIK3CA exon 9 mutations consisted of E542K (1624G > A; n = 2), E545K (1633G > A; n = 5), and E545D (1635G > C; n = 1), and exon 20 mutations consisted of H1047R (3140A > G; n = 1).	('E542K', 'Mutation', 'rs121913273', (37, 42))	('H1047R (3140A > G', 'Var', (154, 171))	('1635G > C', 'Mutation', 'rs121913275', (100, 109))	('E545K', 'Mutation', 'rs104886003', (63, 68))	('PIK3CA', 'Gene', (0, 6))	('E545D (1635G > C', 'Var', (93, 109))	('PIK3CA', 'Gene', '5290', (0, 6))	('3140A > G', 'Mutation', 'g.3140A>G', (162, 171))	('1624G > A', 'Mutation', 'rs121913273', (44, 53))	('1633G > A', 'Mutation', 'rs104886003', (70, 79))	('H1047R', 'Mutation', 'rs121913279', (154, 160))	('E545D', 'Mutation', 'rs121913275', (93, 98))
647923	24774510	NRAS mutations consisted of G12S (34G > A; n = 1) and G13S (37G > A; n = 1).	('34G > A', 'Mutation', 'rs121913530', (34, 41))	('37G > A', 'Mutation', 'rs121913535', (60, 67))	('G13S', 'Mutation', 'rs121913535', (54, 58))	('G12S', 'Mutation', 'rs121913250', (28, 32))	('NRAS', 'Gene', (0, 4))	('G12S (34G > A', 'Var', (28, 41))	('NRAS', 'Gene', '4893', (0, 4))
647926	24774510	The median ages of patients whose tumor tissue contained mutations of KRAS, PIK3CA and NRAS (54.5, 58.0 and 56.0 years, respectively) were lower than that of patients containing all-wild types of KRAS, BRAF, PIK3CA and NRAS (median age, 64.0 years).	('NRAS', 'Gene', '4893', (87, 91))	('KRAS', 'Gene', (70, 74))	('PIK3CA', 'Gene', (76, 82))	('mutations', 'Var', (57, 66))	('lower', 'NegReg', (139, 144))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PIK3CA', 'Gene', (208, 214))	('NRAS', 'Gene', (87, 91))	('NRAS', 'Gene', '4893', (219, 223))	('patients', 'Species', '9606', (19, 27))	('BRAF', 'Gene', '673', (202, 206))	('BRAF', 'Gene', (202, 206))	('KRAS', 'Gene', '3845', (196, 200))	('PIK3CA', 'Gene', '5290', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('KRAS', 'Gene', '3845', (70, 74))	('KRAS', 'Gene', (196, 200))	('NRAS', 'Gene', (219, 223))	('PIK3CA', 'Gene', '5290', (208, 214))
647934	24774510	Patients whose tumor tissue contained a NRAS codon 12/13 mutation had a significantly shorter OS compared with those carrying the NRAS wild type (8.8 month vs. 14.7 months, p = 0.011, log-rank test).	('mutation', 'Var', (57, 65))	('NRAS', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('shorter', 'NegReg', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Patients', 'Species', '9606', (0, 8))	('NRAS', 'Gene', '4893', (40, 44))	('tumor', 'Disease', (15, 20))	('NRAS', 'Gene', (130, 134))	('NRAS', 'Gene', '4893', (130, 134))
647935	24774510	On the other hand, there was no significant difference in OS between patients with wild type or mutant type of KRAS codon 12/13 (13.2 vs. 15.2 months, p = 0.775) and PIK3CA exon 9/20 (13.6 vs. 9.4 months, p = 0.286).	('PIK3CA', 'Gene', '5290', (166, 172))	('KRAS', 'Gene', (111, 115))	('KRAS', 'Gene', '3845', (111, 115))	('patients', 'Species', '9606', (69, 77))	('PIK3CA', 'Gene', (166, 172))	('mutant type', 'Var', (96, 107))
647938	24774510	Among these mutations, the NRAS codon 12/13 mutation was an independent value in prediction of shorter OS by multivariate analysis (adjusted HR: 5.607, 95% CI: 1.637-19.203).	('NRAS', 'Gene', '4893', (27, 31))	('shorter OS', 'Disease', (95, 105))	('mutations', 'Var', (12, 21))	('NRAS', 'Gene', (27, 31))
647939	24774510	Our analysis suggested that mutations of KRAS codon 12/13 and PIK3CA exon 9/20 (codons 542, 545 and 1047) were not observed frequently in AGC patients, and BRAF mutations (V600E) were not detected.	('V600E', 'Var', (172, 177))	('KRAS', 'Gene', '3845', (41, 45))	('BRAF', 'Gene', (156, 160))	('PIK3CA', 'Gene', (62, 68))	('AGC', 'Disease', (138, 141))	('PIK3CA', 'Gene', '5290', (62, 68))	('V600E', 'Mutation', 'rs113488022', (172, 177))	('KRAS', 'Gene', (41, 45))	('patients', 'Species', '9606', (142, 150))	('BRAF', 'Gene', '673', (156, 160))
647942	24774510	Interestingly, the intestinal type of adenocarcinoma was found more frequently in patients whose tumor tissue contained KRAS codon 12/13 mutations and diffuse type of adenocarcinoma was observed in all 3 patients whose tumor tissue contained NRAS codon 12/13 mutations.	('NRAS', 'Gene', (242, 246))	('tumor', 'Disease', (219, 224))	('adenocarcinoma', 'Disease', (38, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (167, 181))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('patients', 'Species', '9606', (204, 212))	('intestinal type of adenocarcinoma', 'Disease', 'MESH:D007414', (19, 52))	('intestinal type of adenocarcinoma', 'Disease', (19, 52))	('found', 'Reg', (57, 62))	('adenocarcinoma', 'Disease', 'MESH:D000230', (38, 52))	('tumor', 'Disease', (97, 102))	('KRAS', 'Gene', '3845', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('patients', 'Species', '9606', (82, 90))	('KRAS', 'Gene', (120, 124))	('NRAS', 'Gene', '4893', (242, 246))	('adenocarcinoma', 'Disease', (167, 181))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutations', 'Var', (137, 146))
647943	24774510	In addition, NRAS mutations were likely to be associated with shorter OS in metastatic GC patients.	('shorter', 'Disease', (62, 69))	('metastatic GC', 'Disease', (76, 89))	('NRAS', 'Gene', (13, 17))	('NRAS', 'Gene', '4893', (13, 17))	('patients', 'Species', '9606', (90, 98))	('mutations', 'Var', (18, 27))
647945	24774510	In advanced gastro-esophageal adenocarcinoma, the frequency of KRAS codon 12/13 mutations was approximately 3.4 to 9.4% according to biomarker analyses of small-size clinical trials of anti-EGFR antibodies treatment.	('KRAS', 'Gene', '3845', (63, 67))	('mutations', 'Var', (80, 89))	('EGFR', 'Gene', '1956', (190, 194))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (19, 44))	('gastro-esophageal adenocarcinoma', 'Disease', (12, 44))	('to 9', 'Species', '1214577', (112, 116))	('EGFR', 'Gene', (190, 194))	('gastro-esophageal adenocarcinoma', 'Disease', 'MESH:D005764', (12, 44))	('KRAS', 'Gene', (63, 67))
647946	24774510	Our study indicated that KRAS mutations were observed in 4.9% of AGC patients, which is similar to the results of these clinical trials.	('AGC', 'Disease', (65, 68))	('mutations', 'Var', (30, 39))	('observed', 'Reg', (45, 53))	('patients', 'Species', '9606', (69, 77))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
647947	24774510	Several retrospective analyses have reported on frequencies and clinicopathological features of KRAS mutations in gastric cancer.	('KRAS', 'Gene', '3845', (96, 100))	('gastric cancer', 'Disease', (114, 128))	('mutations', 'Var', (101, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('KRAS', 'Gene', (96, 100))
647948	24774510	According to these reports, the most common mutation of KRAS codon 12 was G12D, and all mutations of KRAS codon 13 were G13D.	('KRAS', 'Gene', (56, 60))	('KRAS', 'Gene', (101, 105))	('G12D', 'Var', (74, 78))	('KRAS', 'Gene', '3845', (56, 60))	('KRAS', 'Gene', '3845', (101, 105))	('G12D', 'Mutation', 'rs121913529', (74, 78))	('G13D', 'Mutation', 'rs112445441', (120, 124))
647949	24774510	Our study also indicated that G12D mutations were the most common mutations, and we found in 4 of 6 tumor tissue samples containing the KRAS codon 12 mutations.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('G12D mutations', 'Var', (30, 44))	('KRAS', 'Gene', (136, 140))	('G12D', 'Mutation', 'rs121913529', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('KRAS', 'Gene', '3845', (136, 140))
647952	24774510	suggested that there were significant differences in the presence of KRAS mutations according to tumor site (antrum vs. non-antrum, p = 0.002) and status of microsatellite instability (MSI) (MSI-high vs. MSI-loss, p = 0.000076).	('KRAS', 'Gene', (69, 73))	('MSI', 'Disease', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('MSI', 'Disease', 'None', (185, 188))	('KRAS', 'Gene', '3845', (69, 73))	('MSI-loss', 'Disease', 'MESH:D015431', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutations', 'Var', (74, 83))	('MSI-loss', 'Disease', (204, 212))	('tumor', 'Disease', (97, 102))	('MSI', 'Disease', 'None', (191, 194))	('MSI', 'Disease', (185, 188))	('MSI', 'Disease', 'None', (204, 207))	('MSI', 'Disease', (204, 207))
647955	24774510	Recently, the randomized, multicenter, phase II/III REAL-3 trial, which tested the addition of panitumumab to a modified epirubicin, oxaliplatin, and capecitabine (EOC) regimen, was reported, and a multivariate biomarker analysis of 200 patients indicated that KRAS mutation was a prognostic factor for OS.	('capecitabine', 'Chemical', 'MESH:D000069287', (150, 162))	('epirubicin', 'Chemical', 'MESH:D015251', (121, 131))	('KRAS', 'Gene', (261, 265))	('EOC', 'Chemical', '-', (164, 167))	('panitumumab', 'Chemical', 'MESH:D000077544', (95, 106))	('KRAS', 'Gene', '3845', (261, 265))	('patients', 'Species', '9606', (237, 245))	('mutation', 'Var', (266, 274))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (133, 144))
647956	24774510	In a large-scale clinical trial of treatment of gastric-esophageal cancer with anti-EGFR antibodies, KRAS mutations also appeared to have significant prognostic value, but we need to verify this result by further biomarker analyses of the treatment of molecular therapy in AGC.	('KRAS', 'Gene', (101, 105))	('gastric-esophageal cancer', 'Disease', 'MESH:D013274', (48, 73))	('gastric-esophageal cancer', 'Disease', (48, 73))	('KRAS', 'Gene', '3845', (101, 105))	('EGFR', 'Gene', '1956', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (106, 115))	('EGFR', 'Gene', (84, 88))
647957	24774510	Gene amplifications, deletions and more recently, somatic missense mutations in the PIK3CA gene have been reported in several malignancies, including cancers of the colon, breast, lung, brain, liver and stomach.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('brain', 'Disease', (186, 191))	('breast', 'Disease', (172, 178))	('liver', 'Disease', (193, 198))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('reported', 'Reg', (106, 114))	('stomach', 'Disease', (203, 210))	('PIK3CA', 'Gene', '5290', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('lung', 'Disease', (180, 184))	('deletions', 'Var', (21, 30))	('malignancies', 'Disease', (126, 138))	('missense mutations', 'Var', (58, 76))	('PIK3CA', 'Gene', (84, 90))	('cancers of the colon', 'Disease', (150, 170))	('cancers of the colon', 'Disease', 'MESH:D015179', (150, 170))
647958	24774510	In gastric cancer, previous reports indicated that the frequency of PIK3CA mutations (exons 9 and 20) was 2.5 to 10.6%.	('PIK3CA', 'Gene', (68, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('PIK3CA', 'Gene', '5290', (68, 74))	('mutations', 'Var', (75, 84))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
647959	24774510	Nine of 168 AGC patients (4.5%) had PIK3CA mutations in our study, and there was no great difference compared with previous reports.	('mutations', 'Var', (43, 52))	('PIK3CA', 'Gene', (36, 42))	('patients', 'Species', '9606', (16, 24))	('PIK3CA', 'Gene', '5290', (36, 42))
647960	24774510	Some previous reports suggested a better prognosis for breast cancer patients with PIK3CA mutations, whereas others suggested that PIK3CA mutations were associated with a worse prognosis in colorectal cancer, endometrial cancer and lung cancer.	('mutations', 'Var', (90, 99))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PIK3CA', 'Gene', (131, 137))	('patients', 'Species', '9606', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('better', 'PosReg', (34, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (190, 207))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('PIK3CA', 'Gene', (83, 89))	('breast cancer', 'Disease', (55, 68))	('colorectal cancer', 'Disease', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('endometrial cancer', 'Phenotype', 'HP:0012114', (209, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('PIK3CA', 'Gene', '5290', (131, 137))	('endometrial cancer', 'Disease', (209, 227))	('lung cancer', 'Disease', (232, 243))	('mutations', 'Var', (138, 147))	('endometrial cancer', 'Disease', 'MESH:D016889', (209, 227))	('colorectal cancer', 'Phenotype', 'HP:0003003', (190, 207))	('PIK3CA', 'Gene', '5290', (83, 89))
647961	24774510	Multivariate analyses of the REAL-3 trial indicated that PIK3CA mutations indicated poor OS prognosis in the treatment with anti-EGFR antibodies in gastro-esophageal cancer.	('PIK3CA', 'Gene', '5290', (57, 63))	('EGFR', 'Gene', '1956', (129, 133))	('mutations', 'Var', (64, 73))	('gastro-esophageal cancer', 'Disease', 'MESH:D005764', (148, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('gastro-esophageal cancer', 'Disease', (148, 172))	('EGFR', 'Gene', (129, 133))	('PIK3CA', 'Gene', (57, 63))
647962	24774510	Our data suggested that PIK3CA mutation was not associated with the prognosis in mGC patients treated with systemic chemotherapy, although this study was not a large-scale analysis.	('PIK3CA', 'Gene', (24, 30))	('mutation', 'Var', (31, 39))	('patients', 'Species', '9606', (85, 93))	('PIK3CA', 'Gene', '5290', (24, 30))	('mGC', 'Disease', (81, 84))
647964	24774510	NRAS mutations have been mainly described in melanoma and leukemia, but the prognostic significance in these malignancies has been unclear.	('malignancies', 'Disease', (109, 121))	('leukemia', 'Phenotype', 'HP:0001909', (58, 66))	('mutations', 'Var', (5, 14))	('melanoma and leukemia', 'Disease', 'MESH:D008545', (45, 66))	('described', 'Reg', (32, 41))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))	('NRAS', 'Gene', '4893', (0, 4))
647965	24774510	Some previous reports have suggested an association between NRAS mutations and a poor prognosis in melanoma and a poor response to anti-EGFR antibodies in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('NRAS', 'Gene', (60, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('NRAS', 'Gene', '4893', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('colorectal cancer', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))	('mutations', 'Var', (65, 74))
647966	24774510	Our study indicated that the frequency of NRAS mutations (codons 12 and 13) was 1.9% in AGC and was lower than that seen in other malignancies.	('NRAS', 'Gene', '4893', (42, 46))	('malignancies', 'Disease', (130, 142))	('mutations', 'Var', (47, 56))	('NRAS', 'Gene', (42, 46))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))	('AGC', 'Disease', (88, 91))
647967	24774510	Interestingly, multivariate analyses showed that small groups of NRAS mutations had poor prognosis in metastatic gastric cancer patients who received systemic chemotherapy in present study.	('mutations', 'Var', (70, 79))	('NRAS', 'Gene', '4893', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('patients', 'Species', '9606', (128, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('NRAS', 'Gene', (65, 69))
647968	24774510	We must consider a probable bias of small sample size of NRAS mutations.	('NRAS', 'Gene', '4893', (57, 61))	('NRAS', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
647969	24774510	On the other hand, patient's characteristics of NRAS mutations were younger and smaller number of metastasis site than all wild-type patients.	('patient', 'Species', '9606', (19, 26))	('NRAS', 'Gene', '4893', (48, 52))	('patient', 'Species', '9606', (133, 140))	('patients', 'Species', '9606', (133, 141))	('mutations', 'Var', (53, 62))	('smaller', 'NegReg', (80, 87))	('NRAS', 'Gene', (48, 52))
647970	24774510	There was no significant difference in chemotherapeutic regimens and number of key drugs between patients with NRAS mutations and all-wild type patients.	('NRAS', 'Gene', (111, 115))	('NRAS', 'Gene', '4893', (111, 115))	('patients', 'Species', '9606', (144, 152))	('mutations', 'Var', (116, 125))	('patients', 'Species', '9606', (97, 105))
647971	24774510	Previously, NRAS mutations have not been investigated routinely as a prognostic biomarker in clinical trials of AGC.	('NRAS', 'Gene', '4893', (12, 16))	('NRAS', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
647972	24774510	In addition to having prognostic significance, that NRAS mutations as well as KRAS, BRAF and PIK3CA mutations would be better to be discussed as potential target for molecular therapy in AGC patients.	('NRAS', 'Gene', (52, 56))	('PIK3CA', 'Gene', '5290', (93, 99))	('patients', 'Species', '9606', (191, 199))	('BRAF', 'Gene', '673', (84, 88))	('NRAS', 'Gene', '4893', (52, 56))	('BRAF', 'Gene', (84, 88))	('KRAS', 'Gene', (78, 82))	('mutations', 'Var', (57, 66))	('AGC', 'Disease', (187, 190))	('PIK3CA', 'Gene', (93, 99))	('KRAS', 'Gene', '3845', (78, 82))
647973	24774510	Second, we could not conclude definitely from the data in our study alone that NRAS mutations have prognostic significance because of the low frequencies of NRAS mutations and the large confidence intervals.	('mutations', 'Var', (162, 171))	('NRAS', 'Gene', '4893', (79, 83))	('mutations', 'Var', (84, 93))	('NRAS', 'Gene', (157, 161))	('NRAS', 'Gene', (79, 83))	('NRAS', 'Gene', '4893', (157, 161))
647976	24774510	NRAS mutations were rare in AGC patients, but may have a prognostic value in mGC patients who receive systemic chemotherapy.	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (81, 89))	('mutations', 'Var', (5, 14))	('mGC', 'Disease', (77, 80))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
648005	21984436	In mouse esophagus, when basal cells become differentiated, p63 is down-regulated and eventually turned off in terminally differentiated superficial cells.	('p63', 'Var', (60, 63))	('down-regulated', 'NegReg', (67, 81))	('mouse', 'Species', '10090', (3, 8))
648011	21984436	Sox2 mutations are associated with esophageal atresia in anophthalmia-esophageal-genital syndrome.	('Sox2', 'Gene', (0, 4))	('esophageal atresia', 'Phenotype', 'HP:0002032', (35, 53))	('anophthalmia', 'Phenotype', 'HP:0000528', (57, 69))	('genital syndrome', 'Phenotype', 'HP:0000078', (81, 97))	('anophthalmia-esophageal-genital syndrome', 'Disease', 'MESH:C565948', (57, 97))	('mutations', 'Var', (5, 14))	('esophageal atresia', 'Disease', 'MESH:D004933', (35, 53))	('esophageal atresia', 'Disease', (35, 53))	('anophthalmia-esophageal-genital syndrome', 'Disease', (57, 97))	('associated with', 'Reg', (19, 34))
648022	21984436	Loss of Pax9 impairs terminal differentiation of squamous epithelial cells of mouse tongue.	('squamous epithelia', 'Disease', (49, 67))	('impairs', 'NegReg', (13, 20))	('mouse', 'Species', '10090', (78, 83))	('Pax9', 'Gene', (8, 12))	('squamous epithelia', 'Phenotype', 'HP:0002860', (49, 67))	('Loss', 'Var', (0, 4))	('squamous epithelia', 'Disease', 'MESH:D002294', (49, 67))
648026	21984436	Two independent studies have shown that stomach-specific Cdx2 transgenic overexpression induced intestinal metaplasia in the mouse stomach within weeks after birth.	('intestinal metaplasia', 'Disease', (96, 117))	('induced', 'Reg', (88, 95))	('mouse', 'Species', '10090', (125, 130))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (96, 117))	('Cdx2', 'Gene', (57, 61))	('transgenic', 'Species', '10090', (62, 72))	('overexpression', 'PosReg', (73, 87))	('transgenic', 'Var', (62, 72))
648038	21984436	For example, Math1 (also called Atoh1 or Hath1) is a transcriptional target of Cdx2, and plays a critical role in the development of goblet cells: Cdx2 transfection into IEC6 cells and human esophageal squamous epithelial cells upregulates Math1.	('squamous epithelia', 'Disease', (202, 220))	('upregulates', 'PosReg', (228, 239))	('Atoh1', 'Gene', (32, 37))	('Math1', 'Gene', (240, 245))	('Atoh1', 'Gene', '500156', (32, 37))	('human', 'Species', '9606', (185, 190))	('squamous epithelia', 'Phenotype', 'HP:0002860', (202, 220))	('IEC6', 'CellLine', 'CVCL:0343', (170, 174))	('squamous epithelia', 'Disease', 'MESH:D002294', (202, 220))	('transfection', 'Var', (152, 164))	('Cdx2', 'Gene', (147, 151))
648039	21984436	Knockout of Hes1, a direct upstream negative regulator of Math1, leads to an increased number of goblet cells in mouse small intestine, whereas loss of Math1 completely prevents the development of goblet cells in mouse intestine.	('loss', 'Var', (144, 148))	('prevents', 'NegReg', (169, 177))	('Hes1', 'Gene', (12, 16))	('mouse', 'Species', '10090', (213, 218))	('Math1', 'Gene', (152, 157))	('increased', 'PosReg', (77, 86))	('mouse', 'Species', '10090', (113, 118))
648041	21984436	5) Transfection of Cdx2 into human esophageal squamous epithelial cells induces metaplastic changes in morphology and gene expression.	('human', 'Species', '9606', (29, 34))	('squamous epithelia', 'Phenotype', 'HP:0002860', (46, 64))	('induces', 'Reg', (72, 79))	('squamous epithelia', 'Disease', 'MESH:D002294', (46, 64))	('Cdx2', 'Gene', (19, 23))	('squamous epithelia', 'Disease', (46, 64))	('Transfection', 'Var', (3, 15))	('gene expression', 'MPA', (118, 133))	('metaplastic changes in morphology', 'CPA', (80, 113))
648042	21984436	HET1A cells with stable transfection of human Cdx2 form crypt-like structures in vitro.	('human', 'Species', '9606', (40, 45))	('Cdx2', 'Gene', (46, 50))	('transfection', 'Var', (24, 36))	('crypt-like structures', 'CPA', (56, 77))	('HET1A', 'CellLine', 'CVCL:3702', (0, 5))
648043	21984436	Microarray analysis and quantitative real-time PCR showed that stable transfection of Cdx2 up-regulated differentiation markers of intestinal columnar epithelial cells and goblet cells in HET1A cells.	('Cdx2', 'Gene', (86, 90))	('up-regulated', 'PosReg', (91, 103))	('transfection', 'Var', (70, 82))	('HET1A', 'CellLine', 'CVCL:3702', (188, 193))	('differentiation markers', 'CPA', (104, 127))
648048	21984436	Embryonic mouse esophagus has the keratin 8 promoter methylated when columnar epithelium transdifferentiates into squamous epithelium during embryogeneis.	('rat', 'Species', '10116', (36, 39))	('keratin 8', 'Protein', (34, 43))	('methylated', 'Var', (53, 63))	('mouse', 'Species', '10090', (10, 15))
648049	21984436	Many genes on the TGFbeta and WNT signaling pathways are frequently hyper- or hypomethylated in BE.	('TGFbeta', 'Gene', '7040', (18, 25))	('WNT', 'Gene', '7472', (30, 33))	('hyper-', 'Var', (68, 74))	('hypomethylated', 'Var', (78, 92))	('WNT', 'Gene', (30, 33))	('TGFbeta', 'Gene', (18, 25))
648069	21984436	Knockout of HNF3beta in the lung suppressed alveolarization and induced goblet cell hyperplasia.	('HNF3beta', 'Gene', (12, 20))	('induced', 'Reg', (64, 71))	('HNF3beta', 'Gene', '3170', (12, 20))	('lung suppressed alveolarization', 'Phenotype', 'HP:0002791', (28, 59))	('Knockout', 'Var', (0, 8))	('goblet cell hyperplasia', 'Disease', 'MESH:D002276', (72, 95))	('goblet cell hyperplasia', 'Disease', (72, 95))	('suppressed', 'NegReg', (33, 43))	('alveolarization', 'CPA', (44, 59))
648081	21984436	Aberrant promoter methylation and gene amplification of GATA4 and GATA6 have been reported in human EAC.	('GATA4', 'Gene', (56, 61))	('GATA6', 'Gene', '2627', (66, 71))	('Aberrant', 'Var', (0, 8))	('promoter methylation', 'MPA', (9, 29))	('human', 'Species', '9606', (94, 99))	('GATA6', 'Gene', (66, 71))	('reported', 'Reg', (82, 90))	('gene', 'MPA', (34, 38))	('EAC', 'Disease', (100, 103))	('GATA4', 'Gene', '2626', (56, 61))
648091	21984436	Although mutations of APC and beta-catenin are rare in EAC, promoter hypermethylation (APC, SFRP1), downregulation of E-cadherin, nuclear translocation of beta-catenin and WNT2 overexpression, are commonly seen in EAC.	('promoter hypermethylation', 'MPA', (60, 85))	('WNT2', 'Gene', (172, 176))	('WNT2', 'Gene', '7472', (172, 176))	('E-cadherin', 'Gene', (118, 128))	('overexpression', 'PosReg', (177, 191))	('E-cadherin', 'Gene', '999', (118, 128))	('mutations', 'Var', (9, 18))	('EAC', 'Disease', (214, 217))	('APC', 'Disease', 'MESH:D011125', (87, 90))	('SFRP1', 'Gene', '6422', (92, 97))	('APC', 'Disease', 'MESH:D011125', (22, 25))	('downregulation', 'NegReg', (100, 114))	('APC', 'Disease', (87, 90))	('nuclear translocation', 'MPA', (130, 151))	('SFRP1', 'Gene', (92, 97))	('APC', 'Disease', (22, 25))
648096	21984436	Cells overexpressing exogenous Cdx2 may inhibit beta-catenin/TCF4-mediated transcriptional activation of target genes probably through indirect mechanisms.	('TCF4', 'Gene', '6925', (61, 65))	('inhibit', 'NegReg', (40, 47))	('Cdx2', 'Gene', (31, 35))	('transcriptional activation', 'MPA', (75, 101))	('exogenous', 'Var', (21, 30))	('TCF4', 'Gene', (61, 65))
648114	21984436	Genetic disruption of Notch signaling results in increased number of goblet cells in mouse small intestine.	('mouse', 'Species', '10090', (85, 90))	('Notch', 'Gene', '4851;4854;4855', (22, 27))	('increased', 'PosReg', (49, 58))	('Genetic disruption', 'Var', (0, 18))	('Notch', 'Gene', (22, 27))
648116	21984436	Ectopic Notch signaling in adult intestinal progenitor cells leads to bias against secretory fates.	('Notch', 'Gene', '4851;4854;4855', (8, 13))	('bias', 'CPA', (70, 74))	('Ectopic', 'Var', (0, 7))	('Notch', 'Gene', (8, 13))	('secretory fates', 'MPA', (83, 98))
648122	21984436	These data suggest that inhibition of Notch signaling pathways favors goblet cell differentiation and potentially promote BE.	('goblet cell differentiation', 'CPA', (70, 97))	('Notch', 'Gene', (38, 43))	('inhibition', 'Var', (24, 34))	('Notch', 'Gene', '4851;4854;4855', (38, 43))	('favors', 'PosReg', (63, 69))	('promote', 'PosReg', (114, 121))
648143	21984436	RUNX3 is frequently silenced in gastric cancer through promoter methylation or protein mislocalization, and loss of RUNX3 allows gastric epithelial cells to differentiate into intestinal cell types, suggesting that loss of RUNX3 may play a similar role in the development of BE.	('RUNX3', 'Gene', '864', (116, 121))	('RUNX3', 'Gene', (223, 228))	('RUNX3', 'Gene', '864', (223, 228))	('gastric cancer', 'Disease', (32, 46))	('promoter', 'MPA', (55, 63))	('loss', 'Var', (108, 112))	('protein', 'Protein', (79, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('silenced', 'NegReg', (20, 28))	('RUNX3', 'Gene', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
648158	21984436	BE Barrett's esophagus BMP bone morphogenetic protein EAC esophageal adenocarcinoma GERD gastroesophageal reflux disease HNF hepatocyte nuclear factor KLF Kruppel-like factor RUNX3 runt-related transcriptional factor 3 SNP single nucleotide polymorphism Spdef SAM pointed domain-containing Ets transcription factor TGF transforming growth factor	('RUNX3', 'Gene', (175, 180))	('Spdef', 'Gene', (254, 259))	('single nucleotide polymorphism', 'Var', (223, 253))	('gastroesophageal reflux disease', 'Disease', (89, 120))	('BMP', 'Gene', '649', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('SAM pointed domain-containing Ets transcription factor', 'Gene', '25803', (260, 314))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (58, 83))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (89, 120))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (89, 112))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (3, 22))	('BMP', 'Gene', (23, 26))	('esophageal adenocarcinoma', 'Disease', (58, 83))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (58, 83))	('RUNX3', 'Gene', '864', (175, 180))	('KLF', 'Chemical', '-', (151, 154))
648161	19460136	The aim of this study was to analyze the frequency and timing of LOH at the TS locus in Barrett-associated adenocarcinoma (BA) and its precursory lesions, such as intestinal metaplasia (IM) and dysplasia.	('intestinal metaplasia', 'Disease', (163, 184))	('LOH', 'Var', (65, 68))	('dysplasia', 'Disease', (194, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('dysplasia', 'Disease', 'MESH:D004476', (194, 203))	('TS', 'Gene', '7298', (76, 78))	('adenocarcinoma', 'Disease', (107, 121))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (163, 184))	('BA', 'Chemical', '-', (123, 125))
648166	19460136	However, 6 out of 21 samples (28.6%) had LOH in IM, 2 of 7 (28.6%) in dysplasia, and 10 of 25 (40.0%) in BA.	('BA', 'Chemical', '-', (105, 107))	('dysplasia', 'Disease', 'MESH:D004476', (70, 79))	('LOH', 'Var', (41, 44))	('dysplasia', 'Disease', (70, 79))
648174	19460136	Recently, another polymorphism, a 6 bp insertion/deletion at bp 1494 in the 3'-untranslated region (3'-UTR) of TS gene, was identified and is thought to influence the intratumoral TS mRNA level in vivo .	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('insertion/deletion', 'Var', (39, 57))	('tumor', 'Disease', (172, 177))	('TS', 'Gene', '7298', (180, 182))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('influence', 'Reg', (153, 162))	('TS', 'Gene', '7298', (111, 113))
648212	19460136	Although no samples from GERD patients with LOH at the TS locus were observed in the lower esophageal mucosa (0/22 samples)), 6 out of 21 samples (28.6%) had LOH in IM, 2 out of 7 (28.6%) in dysplasia, and 10 out of 25 (40.0%) in BA.	('LOH', 'Var', (158, 161))	('GERD', 'Disease', (25, 29))	('BA', 'Chemical', '-', (230, 232))	('GERD', 'Disease', 'MESH:D005764', (25, 29))	('dysplasia', 'Disease', (191, 200))	('patients', 'Species', '9606', (30, 38))	('dysplasia', 'Disease', 'MESH:D004476', (191, 200))	('TS', 'Gene', '7298', (55, 57))
648215	19460136	There were 3 patients who had LOH at the 5'-UTR locus and also had a heterozygous genotype at the 3'-UTR locus, and all 3 patients additionally showed LOH at the 3'-UTR locus.	('LOH', 'Var', (30, 33))	('LOH', 'Var', (151, 154))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (122, 130))
648221	19460136	When patients were classified as 2R group patients (2R/2R, 2R/loss), 3R group (3R/3R, loss/3R), and 2R/3R group, according to the number of repeats, no difference of median TS mRNA levels was observed between the groups (p = 0.69).	('TS', 'Gene', '7298', (173, 175))	('patients', 'Species', '9606', (5, 13))	('loss/3R', 'NegReg', (86, 93))	('3R/3R', 'Var', (79, 84))	('patients', 'Species', '9606', (42, 50))
648222	19460136	When patients were classified in the 3RG group, the genotype that contained the 3RG allele, (2R/3RG, 3RC/3RG, 3RG/3RG) and the non-3RG group (2R/2R, 2R/3R, 3RC/3RC) according to the number of repeats and the G/C SNP, there was also no significant difference in median TS mRNA levels between these 2 groups (p = 0.66).	('2R/2R', 'Var', (142, 147))	('patients', 'Species', '9606', (5, 13))	('2R/3RG', 'Var', (93, 99))	('TS', 'Gene', '7298', (268, 270))	('3RG/3RG', 'Var', (110, 117))
648224	19460136	LOH in tumor suppressor gene loci, such as 17p (p53), 18q (DCC), 9p (CDKN2/p16), 5q (APC), and 10q (PTEN), has been reported to be a common genetic alteration in the metaplasia-dysplasia-carcinoma sequence in Barrett's esophagus.	('PTEN', 'Gene', (100, 104))	('p16', 'Gene', '1029', (75, 78))	('CDKN2', 'Gene', (69, 74))	('DCC', 'Gene', '1630', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('APC', 'Disease', 'MESH:D011125', (85, 88))	('PTEN', 'Gene', '5728', (100, 104))	('LOH', 'Var', (0, 3))	('p53', 'Gene', '7157', (48, 51))	('17p', 'Var', (43, 46))	('APC', 'Disease', (85, 88))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (209, 228))	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (166, 196))	('metaplasia-dysplasia-carcinoma', 'Disease', (166, 196))	('18q', 'Var', (54, 57))	('DCC', 'Gene', (59, 62))	('p53', 'Gene', (48, 51))	('CDKN2', 'Gene', '1029', (69, 74))	('10q', 'Var', (95, 98))	('tumor', 'Disease', (7, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('p16', 'Gene', (75, 78))
648226	19460136	In this study, we observed 28.6% of LOH at the TS 5'-UTR locus even in IM tissue, which indicates that this genetic alteration may occur at some early stage of carcinogenesis.	('LOH', 'Var', (36, 39))	('carcinogenesis', 'Disease', (160, 174))	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('TS', 'Gene', '7298', (47, 49))
648236	19460136	One of these regions is estimated to be located in between the two markers DS18S59 and D18S476, where the whole TS gene is located.	('TS', 'Gene', '7298', (112, 114))	('D18S476', 'Var', (87, 94))	('DS18S59', 'Var', (75, 82))
648239	19460136	Whether TS polymorphisms in 5'-UTR or 3'-UTR are associated with TS mRNA expression levels has been a controversial topic for some years.	('polymorphisms', 'Var', (11, 24))	('associated', 'Reg', (49, 59))	('TS', 'Gene', '7298', (65, 67))	('TS', 'Gene', '7298', (8, 10))
648241	19460136	found an association between TS mRNA expression and 5'-UTR polymorphism.	("5'-UTR", 'MPA', (52, 58))	('association', 'Interaction', (9, 20))	('polymorphism', 'Var', (59, 71))	('TS', 'Gene', '7298', (29, 31))
648243	19460136	reported that 6 bp deletion constructs had significantly decreased mRNA stability compared with 6 bp insertion constructs in vitro, and that the patients with an ins/ins genotype had significantly higher TS mRNA levels compared with those with del/del genotype in vivo .	('patients', 'Species', '9606', (145, 153))	('ins/ins', 'Var', (162, 169))	('higher', 'PosReg', (197, 203))	('deletion', 'Var', (19, 27))	('mRNA stability', 'MPA', (67, 81))	('TS', 'Gene', '7298', (204, 206))	('decreased', 'NegReg', (57, 66))
648247	19460136	Our next question is whether patients with LOH at the TS locus in their precursor tissue have a higher cancer risk than those who do not have LOH.	('patients', 'Species', '9606', (29, 37))	('TS', 'Gene', '7298', (54, 56))	('LOH', 'Var', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
648257	31647967	Using an in vitro esophageal epithelial 3-dimensional model system revealed that ANO1 undergoes chromatin modification and rapid upregulation of expression after IL-13 stimulation, that ANO1 is the primary apical IL-13-induced Cl- transport mechanism within the esophageal epithelium, and that loss of ANO1-dependent Cl- transport abrogated esophageal epithelial proliferation.	('i', 'Chemical', 'MESH:D007455', (126, 127))	('i', 'Chemical', 'MESH:D007455', (373, 374))	('i', 'Chemical', 'MESH:D007455', (31, 32))	('esophageal epithelial proliferation', 'CPA', (341, 376))	('expression', 'MPA', (145, 155))	('i', 'Chemical', 'MESH:D007455', (252, 253))	('i', 'Chemical', 'MESH:D007455', (109, 110))	('ANO1', 'Gene', (81, 85))	('i', 'Chemical', 'MESH:D007455', (13, 14))	('i', 'Chemical', 'MESH:D007455', (219, 220))	('abrogated', 'NegReg', (331, 340))	('i', 'Chemical', 'MESH:D007455', (138, 139))	('i', 'Chemical', 'MESH:D007455', (275, 276))	('i', 'Chemical', 'MESH:D007455', (170, 171))	('i', 'Chemical', 'MESH:D007455', (354, 355))	('i', 'Chemical', 'MESH:D007455', (115, 116))	('i', 'Chemical', 'MESH:D007455', (43, 44))	('i', 'Chemical', 'MESH:D007455', (36, 37))	('i', 'Chemical', 'MESH:D007455', (359, 360))	('i', 'Chemical', 'MESH:D007455', (176, 177))	('i', 'Chemical', 'MESH:D007455', (9, 10))	('i', 'Chemical', 'MESH:D007455', (208, 209))	('i', 'Chemical', 'MESH:D007455', (200, 201))	('i', 'Chemical', 'MESH:D007455', (2, 3))	('i', 'Chemical', 'MESH:D007455', (280, 281))	('i', 'Chemical', 'MESH:D007455', (247, 248))	('i', 'Chemical', 'MESH:D007455', (367, 368))	('i', 'Chemical', 'MESH:D007455', (48, 49))	('i', 'Chemical', 'MESH:D007455', (255, 256))	('i', 'Chemical', 'MESH:D007455', (111, 112))	('i', 'Chemical', 'MESH:D007455', (103, 104))	('upregulation', 'PosReg', (129, 141))	('esophageal epithelial proliferation', 'Phenotype', 'HP:0012859', (341, 376))	('loss', 'Var', (294, 298))	('i', 'Chemical', 'MESH:D007455', (152, 153))	('i', 'Chemical', 'MESH:D007455', (191, 192))
648258	31647967	Mechanistically, ANO1-dependent regulation of basal cell proliferation was associated with modulation of TP63 expression and phosphorylated cyclin-dependent kinase 2 levels.	('i', 'Chemical', 'MESH:D007455', (158, 159))	('TP63', 'Gene', '8626', (105, 109))	('i', 'Chemical', 'MESH:D007455', (117, 118))	('basal cell proliferation', 'Phenotype', 'HP:0002671', (46, 70))	('modulation', 'Var', (91, 101))	('i', 'Chemical', 'MESH:D007455', (61, 62))	('cyclin-dependent kinase 2', 'Gene', '1017', (140, 165))	('i', 'Chemical', 'MESH:D007455', (67, 68))	('cyclin-dependent kinase 2', 'Gene', (140, 165))	('basal cell proliferation', 'CPA', (46, 70))	('i', 'Chemical', 'MESH:D007455', (98, 99))	('i', 'Chemical', 'MESH:D007455', (9, 10))	('expression', 'MPA', (110, 120))	('i', 'Chemical', 'MESH:D007455', (144, 145))	('i', 'Chemical', 'MESH:D007455', (87, 88))	('TP63', 'Gene', (105, 109))	('i', 'Chemical', 'MESH:D007455', (80, 81))	('i', 'Chemical', 'MESH:D007455', (39, 40))	('i', 'Chemical', 'MESH:D007455', (6, 7))
648273	31647967	The functional implication of BZH in the symptomatology of EoE is not yet fully delineated; however, BZH is thought to contribute to esophageal barrier dysfunction and chronic inflammation, which in turn could lead to an associated functional phenotype associated with EoE.	('i', 'Chemical', 'MESH:D007455', (237, 238))	('esophageal barrier dysfunction', 'Disease', (133, 163))	('BZ', 'Chemical', '-', (101, 103))	('BZH', 'Var', (101, 104))	('i', 'Chemical', 'MESH:D007455', (173, 174))	('i', 'Chemical', 'MESH:D007455', (226, 227))	('i', 'Chemical', 'MESH:D007455', (196, 197))	('i', 'Chemical', 'MESH:D007455', (258, 259))	('i', 'Chemical', 'MESH:D007455', (83, 84))	('i', 'Chemical', 'MESH:D007455', (124, 125))	('lead', 'Reg', (210, 214))	('i', 'Chemical', 'MESH:D007455', (148, 149))	('EoE', 'Disease', (269, 272))	('i', 'Chemical', 'MESH:D007455', (19, 20))	('i', 'Chemical', 'MESH:D007455', (34, 35))	('inflammation', 'Disease', 'MESH:D007249', (176, 188))	('i', 'Chemical', 'MESH:D007455', (185, 186))	('i', 'Chemical', 'MESH:D007455', (265, 266))	('i', 'Chemical', 'MESH:D007455', (176, 177))	('i', 'Chemical', 'MESH:D007455', (9, 10))	('i', 'Chemical', 'MESH:D007455', (105, 106))	('i', 'Chemical', 'MESH:D007455', (63, 64))	('i', 'Chemical', 'MESH:D007455', (192, 193))	('inflammation', 'Disease', (176, 188))	('contribute', 'Reg', (119, 129))	('i', 'Chemical', 'MESH:D007455', (15, 16))	('BZ', 'Chemical', '-', (30, 32))	('i', 'Chemical', 'MESH:D007455', (23, 24))	('i', 'Chemical', 'MESH:D007455', (160, 161))
648281	31647967	Notably, induction of ANO1 was linked to increased esophageal epithelial proliferation and BZ hyperplasia, and both pharmacologic inhibition and gene silencing of ANO1 attenuated IL-13-induced esophageal epithelial proliferation.	('i', 'Chemical', 'MESH:D007455', (127, 128))	('i', 'Chemical', 'MESH:D007455', (151, 152))	('i', 'Chemical', 'MESH:D007455', (206, 207))	('BZ', 'Chemical', '-', (91, 93))	('i', 'Chemical', 'MESH:D007455', (133, 134))	('i', 'Chemical', 'MESH:D007455', (77, 78))	('hyperplasia', 'Disease', (94, 105))	('attenuated', 'NegReg', (168, 178))	('i', 'Chemical', 'MESH:D007455', (219, 220))	('i', 'Chemical', 'MESH:D007455', (83, 84))	('i', 'Chemical', 'MESH:D007455', (69, 70))	('hyperplasia', 'Disease', 'MESH:D006965', (94, 105))	('i', 'Chemical', 'MESH:D007455', (225, 226))	('i', 'Chemical', 'MESH:D007455', (130, 131))	('gene silencing', 'Var', (145, 159))	('i', 'Chemical', 'MESH:D007455', (211, 212))	('i', 'Chemical', 'MESH:D007455', (156, 157))	('i', 'Chemical', 'MESH:D007455', (185, 186))	('i', 'Chemical', 'MESH:D007455', (9, 10))	('esophageal epithelial proliferation', 'Phenotype', 'HP:0012859', (51, 86))	('ANO1', 'Gene', (22, 26))	('esophageal epithelial proliferation', 'Phenotype', 'HP:0012859', (193, 228))	('i', 'Chemical', 'MESH:D007455', (137, 138))	('increased', 'PosReg', (41, 50))	('i', 'Chemical', 'MESH:D007455', (41, 42))	('i', 'Chemical', 'MESH:D007455', (103, 104))	('esophageal epithelial proliferation', 'CPA', (51, 86))	('i', 'Chemical', 'MESH:D007455', (15, 16))	('i', 'Chemical', 'MESH:D007455', (135, 136))	('ANO1', 'Gene', (163, 167))	('i', 'Chemical', 'MESH:D007455', (32, 33))	('induction', 'Var', (9, 18))	('i', 'Chemical', 'MESH:D007455', (64, 65))
648282	31647967	These studies identify ANO1 as a key regulator of esophageal proliferation and BZH in EoE and identify modification of ANO1 activity as a possible therapeutic strategy for attenuation of esophageal remodeling and EoE severity.	('i', 'Chemical', 'MESH:D007455', (127, 128))	('i', 'Chemical', 'MESH:D007455', (14, 15))	('i', 'Chemical', 'MESH:D007455', (180, 181))	('i', 'Chemical', 'MESH:D007455', (94, 95))	('i', 'Chemical', 'MESH:D007455', (205, 206))	('ANO1', 'Gene', (119, 123))	('i', 'Chemical', 'MESH:D007455', (83, 84))	('EoE', 'Disease', (213, 216))	('EoE', 'Disease', (86, 89))	('i', 'Chemical', 'MESH:D007455', (108, 109))	('esophageal', 'Disease', (187, 197))	('i', 'Chemical', 'MESH:D007455', (19, 20))	('i', 'Chemical', 'MESH:D007455', (156, 157))	('i', 'Chemical', 'MESH:D007455', (99, 100))	('i', 'Chemical', 'MESH:D007455', (106, 107))	('i', 'Chemical', 'MESH:D007455', (10, 11))	('activity', 'MPA', (124, 132))	('modification', 'Var', (103, 115))	('i', 'Chemical', 'MESH:D007455', (112, 113))	('BZ', 'Chemical', '-', (79, 81))	('i', 'Chemical', 'MESH:D007455', (129, 130))	('i', 'Chemical', 'MESH:D007455', (142, 143))	('i', 'Chemical', 'MESH:D007455', (65, 66))	('i', 'Chemical', 'MESH:D007455', (222, 223))	('i', 'Chemical', 'MESH:D007455', (71, 72))
648316	31647967	After 5 days of ALI culture, EPC2 cells were treated with IL-13 (100 ng/mL) for 4, 12, or 48 hours for H3K4me3 or 30 minutes for STAT6 ChIP.	('ALI', 'Chemical', '-', (16, 19))	('i', 'Chemical', 'MESH:D007455', (118, 119))	('STAT6', 'Gene', (129, 134))	('H3K4me3', 'Var', (103, 110))	('i', 'Chemical', 'MESH:D007455', (54, 55))	('STAT6', 'Gene', '6778', (129, 134))
648320	31647967	Anti-H3K4me3 (1 muL; ChIPAb+ Trimethyl-Histone H3 [Lys4]; Millipore, Temecula, Calif) or anti-STAT6 (2.5 mug; sc-621; Santa Cruz Biotechnology, Santa Cruz, Calif) were bound to 20 muL of Dynabeads Protein G magnetic beads (Life Technologies) for 1 hour at RT on a rotating wheel.	('i', 'Chemical', 'MESH:D007455', (213, 214))	('i', 'Chemical', 'MESH:D007455', (31, 32))	('i', 'Chemical', 'MESH:D007455', (62, 63))	('i', 'Chemical', 'MESH:D007455', (237, 238))	('bound', 'Interaction', (168, 173))	('Calif', 'Gene', '9337', (156, 161))	('i', 'Chemical', 'MESH:D007455', (269, 270))	('i', 'Chemical', 'MESH:D007455', (92, 93))	('i', 'Chemical', 'MESH:D007455', (59, 60))	('Anti-H3K4me3', 'Var', (0, 12))	('STAT6', 'Gene', (94, 99))	('i', 'Chemical', 'MESH:D007455', (130, 131))	('Calif', 'Gene', '9337', (79, 84))	('i', 'Chemical', 'MESH:D007455', (82, 83))	('Dynabeads Protein G magnetic', 'Protein', (187, 215))	('Calif', 'Gene', (156, 161))	('i', 'Chemical', 'MESH:D007455', (3, 4))	('i', 'Chemical', 'MESH:D007455', (202, 203))	('STAT6', 'Gene', '6778', (94, 99))	('i', 'Chemical', 'MESH:D007455', (224, 225))	('i', 'Chemical', 'MESH:D007455', (159, 160))	('Calif', 'Gene', (79, 84))	('i', 'Chemical', 'MESH:D007455', (40, 41))
648332	31647967	ANO1-mediated changes in Isc were determined with the addition of T16Ainh-A01 to the luminal reservoir.	('Isc', 'MPA', (25, 28))	('T16Ainh-A01', 'Chemical', 'MESH:C578466', (66, 77))	('T16Ainh-A01', 'Var', (66, 77))	('i', 'Chemical', 'MESH:D007455', (100, 101))	('i', 'Chemical', 'MESH:D007455', (70, 71))	('i', 'Chemical', 'MESH:D007455', (8, 9))	('i', 'Chemical', 'MESH:D007455', (46, 47))	('i', 'Chemical', 'MESH:D007455', (88, 89))	('i', 'Chemical', 'MESH:D007455', (57, 58))	('i', 'Chemical', 'MESH:D007455', (22, 23))	('i', 'Chemical', 'MESH:D007455', (40, 41))	('luminal', 'Chemical', 'MESH:D010634', (85, 92))	('i', 'Chemical', 'MESH:D007455', (59, 60))
648349	31647967	Slides were then blocked by 10% normal donkey serum for 1 hour, followed by overnight incubation of primary antibodies diluted in 10% normal donkey serum at a final concentration of 1 mug/mL: anti-ANO1 (DOG-1; Thermo Fisher Scientific), anti-KRT5 (ab24647; Abcam, Cambridge, United Kingdom), and cytokeratin (CK) 13 (Invitrogen, Carlsbad, Calif).	('i', 'Chemical', 'MESH:D007455', (127, 128))	('i', 'Chemical', 'MESH:D007455', (93, 94))	('i', 'Chemical', 'MESH:D007455', (86, 87))	('i', 'Chemical', 'MESH:D007455', (269, 270))	('i', 'Chemical', 'MESH:D007455', (283, 284))	('i', 'Chemical', 'MESH:D007455', (226, 227))	('cytokeratin (CK) 13', 'Gene', (296, 315))	('i', 'Chemical', 'MESH:D007455', (277, 278))	('i', 'Chemical', 'MESH:D007455', (195, 196))	('anti-ANO1', 'Var', (192, 201))	('i', 'Chemical', 'MESH:D007455', (115, 116))	('Calif', 'Gene', (339, 344))	('i', 'Chemical', 'MESH:D007455', (218, 219))	('i', 'Chemical', 'MESH:D007455', (305, 306))	('i', 'Chemical', 'MESH:D007455', (240, 241))	('KRT5', 'Gene', '100687760', (242, 246))	('i', 'Chemical', 'MESH:D007455', (320, 321))	('i', 'Chemical', 'MESH:D007455', (232, 233))	('i', 'Chemical', 'MESH:D007455', (2, 3))	('i', 'Chemical', 'MESH:D007455', (342, 343))	('i', 'Chemical', 'MESH:D007455', (81, 82))	('ab24647;', 'Var', (248, 256))	('KRT5', 'Gene', (242, 246))	('i', 'Chemical', 'MESH:D007455', (175, 176))	('i', 'Chemical', 'MESH:D007455', (120, 121))	('i', 'Chemical', 'MESH:D007455', (230, 231))	('i', 'Chemical', 'MESH:D007455', (111, 112))	('Calif', 'Gene', '9337', (339, 344))	('i', 'Chemical', 'MESH:D007455', (160, 161))	('i', 'Chemical', 'MESH:D007455', (102, 103))
648412	31647967	Together, these data reveal that enhanced ANO1 expression is an early event after IL-13 stimulation mediated by epigenetic modification and STAT6 promoter interaction (Fig 3, E).	('i', 'Chemical', 'MESH:D007455', (126, 127))	('ANO1', 'Gene', (42, 46))	('i', 'Chemical', 'MESH:D007455', (54, 55))	('epigenetic modification', 'Var', (112, 135))	('enhanced', 'PosReg', (33, 41))	('i', 'Chemical', 'MESH:D007455', (163, 164))	('i', 'Chemical', 'MESH:D007455', (155, 156))	('i', 'Chemical', 'MESH:D007455', (132, 133))	('STAT6', 'Gene', (140, 145))	('expression', 'MPA', (47, 57))	('i', 'Chemical', 'MESH:D007455', (58, 59))	('i', 'Chemical', 'MESH:D007455', (90, 91))	('i', 'Chemical', 'MESH:D007455', (169, 170))	('i', 'Chemical', 'MESH:D007455', (114, 115))	('i', 'Chemical', 'MESH:D007455', (120, 121))	('STAT6', 'Gene', '6778', (140, 145))	('i', 'Chemical', 'MESH:D007455', (96, 97))	('i', 'Chemical', 'MESH:D007455', (103, 104))	('i', 'Chemical', 'MESH:D007455', (128, 129))
648432	31647967	As decreased TP63 expression has been associated with cell-cycle arrest in the G0/G1 phase and loss of proliferative capacity, we hypothesized that ablation of ANO1-dependent Cl- transport in EPC2 cells would lead to decreased TP63 expression, causing cell-cycle arrest.	('i', 'Chemical', 'MESH:D007455', (189, 190))	('decreased', 'NegReg', (217, 226))	('decreased', 'NegReg', (3, 12))	('arrest', 'Disease', 'MESH:D006323', (263, 269))	('expression', 'MPA', (232, 242))	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('i', 'Chemical', 'MESH:D007455', (107, 108))	('i', 'Chemical', 'MESH:D007455', (138, 139))	('TP63', 'Gene', (13, 17))	('expression', 'MPA', (18, 28))	('i', 'Chemical', 'MESH:D007455', (43, 44))	('i', 'Chemical', 'MESH:D007455', (122, 123))	('ANO1-dependent Cl- transport', 'MPA', (160, 188))	('i', 'Chemical', 'MESH:D007455', (248, 249))	('TP63', 'Gene', '8626', (13, 17))	('i', 'Chemical', 'MESH:D007455', (153, 154))	('arrest', 'Disease', (263, 269))	('i', 'Chemical', 'MESH:D007455', (50, 51))	('ablation', 'Var', (148, 156))	('i', 'Chemical', 'MESH:D007455', (113, 114))	('TP63', 'Gene', (227, 231))	('i', 'Chemical', 'MESH:D007455', (25, 26))	('i', 'Chemical', 'MESH:D007455', (72, 73))	('arrest', 'Disease', (65, 71))	('i', 'Chemical', 'MESH:D007455', (239, 240))	('TP63', 'Gene', '8626', (227, 231))
648435	31647967	Notably, in the presence of T16Ainh-A01, IL-13 induced p-CDK2, and proliferation in EPC2-ALI cells was attenuated (Fig 6, C, and Fig 7, D and E).	('attenuated', 'NegReg', (103, 113))	('i', 'Chemical', 'MESH:D007455', (77, 78))	('IL-13', 'Gene', (41, 46))	('CDK2', 'Gene', '1017', (57, 61))	('i', 'Chemical', 'MESH:D007455', (9, 10))	('induced', 'Reg', (47, 54))	('ALI', 'Chemical', '-', (89, 92))	('T16Ainh-A01', 'Chemical', 'MESH:C578466', (28, 39))	('proliferation', 'CPA', (67, 80))	('T16Ainh-A01', 'Var', (28, 39))	('i', 'Chemical', 'MESH:D007455', (32, 33))	('i', 'Chemical', 'MESH:D007455', (130, 131))	('i', 'Chemical', 'MESH:D007455', (47, 48))	('i', 'Chemical', 'MESH:D007455', (81, 82))	('i', 'Chemical', 'MESH:D007455', (71, 72))	('i', 'Chemical', 'MESH:D007455', (116, 117))	('CDK2', 'Gene', (57, 61))
648440	31647967	Using an established esophageal epithelial culture system, we show that (1) ANO1 mRNA and protein expression is rapidly induced by an IL-13-STAT6 mechanism; (2) IL-13 induced an increase in [Cl-]i levels in esophageal cells; (3) ANO1 is the predominant transport pathway of IL-13-induced Cl- efflux in esophageal cells; and (4) IL-13-induced ANO1-mediated Cl- transport is required for esophageal epithelial proliferation.	('i', 'Chemical', 'MESH:D007455', (412, 413))	('i', 'Chemical', 'MESH:D007455', (204, 205))	('i', 'Chemical', 'MESH:D007455', (109, 110))	('i', 'Chemical', 'MESH:D007455', (370, 371))	('i', 'Chemical', 'MESH:D007455', (418, 419))	('i', 'Chemical', 'MESH:D007455', (234, 235))	('i', 'Chemical', 'MESH:D007455', (195, 196))	('i', 'Chemical', 'MESH:D007455', (299, 300))	('i', 'Chemical', 'MESH:D007455', (115, 116))	('i', 'Chemical', 'MESH:D007455', (187, 188))	('increase', 'PosReg', (178, 186))	('STAT6', 'Gene', (140, 145))	('IL-13', 'Var', (161, 166))	('i', 'Chemical', 'MESH:D007455', (34, 35))	('esophageal epithelial proliferation', 'Phenotype', 'HP:0012859', (386, 421))	('i', 'Chemical', 'MESH:D007455', (178, 179))	('i', 'Chemical', 'MESH:D007455', (377, 378))	('i', 'Chemical', 'MESH:D007455', (399, 400))	('i', 'Chemical', 'MESH:D007455', (2, 3))	('i', 'Chemical', 'MESH:D007455', (95, 96))	('i', 'Chemical', 'MESH:D007455', (280, 281))	('i', 'Chemical', 'MESH:D007455', (105, 106))	('i', 'Chemical', 'MESH:D007455', (350, 351))	('i', 'Chemical', 'MESH:D007455', (167, 168))	('i', 'Chemical', 'MESH:D007455', (120, 121))	('STAT6', 'Gene', '6778', (140, 145))	('i', 'Chemical', 'MESH:D007455', (247, 248))	('[Cl-]i levels', 'MPA', (190, 203))	('i', 'Chemical', 'MESH:D007455', (15, 16))	('ANO1', 'Gene', (76, 80))	('i', 'Chemical', 'MESH:D007455', (334, 335))	('i', 'Chemical', 'MESH:D007455', (404, 405))	('i', 'Chemical', 'MESH:D007455', (152, 153))	('i', 'Chemical', 'MESH:D007455', (39, 40))
648447	31647967	These studies demonstrated that IL-4 receptor-mediated induction of ANO1 mRNA expression was dependent on STAT6 because mutation of the STAT6 consensus sequence or small interfering RNA-mediated knockdown of STAT6 ablated IL-4 receptor-mediated induction of ANO1.	('STAT6', 'Gene', '6778', (106, 111))	('i', 'Chemical', 'MESH:D007455', (189, 190))	('i', 'Chemical', 'MESH:D007455', (55, 56))	('i', 'Chemical', 'MESH:D007455', (125, 126))	('i', 'Chemical', 'MESH:D007455', (61, 62))	('STAT6', 'Gene', '6778', (208, 213))	('i', 'Chemical', 'MESH:D007455', (85, 86))	('STAT6', 'Gene', '6778', (136, 141))	('i', 'Chemical', 'MESH:D007455', (251, 252))	('i', 'Chemical', 'MESH:D007455', (170, 171))	('mRNA expression', 'MPA', (73, 88))	('i', 'Chemical', 'MESH:D007455', (10, 11))	('i', 'Chemical', 'MESH:D007455', (178, 179))	('mutation', 'Var', (120, 128))	('ANO1', 'MPA', (258, 262))	('IL-4 receptor', 'Gene', (32, 45))	('IL-4 receptor', 'Gene', (222, 235))	('ANO1', 'Gene', (68, 72))	('IL-4 receptor', 'Gene', '3566', (32, 45))	('STAT6', 'Gene', (106, 111))	('IL-4 receptor', 'Gene', '3566', (222, 235))	('i', 'Chemical', 'MESH:D007455', (49, 50))	('STAT6', 'Gene', (208, 213))	('i', 'Chemical', 'MESH:D007455', (245, 246))	('STAT6', 'Gene', (136, 141))	('ablated', 'NegReg', (214, 221))	('i', 'Chemical', 'MESH:D007455', (239, 240))
648456	31647967	Notably, an 8-week course of PPI therapy significantly decreased ANO1 mRNA expression in these subjects.	('PPI', 'Var', (29, 32))	('i', 'Chemical', 'MESH:D007455', (42, 43))	('ANO1 mRNA expression', 'MPA', (65, 85))	('i', 'Chemical', 'MESH:D007455', (86, 87))	('i', 'Chemical', 'MESH:D007455', (45, 46))	('decreased', 'NegReg', (55, 64))	('i', 'Chemical', 'MESH:D007455', (47, 48))	('i', 'Chemical', 'MESH:D007455', (82, 83))
648458	31647967	We examined the effect of PPIs on IL-13-induced ANO1 mRNA expression in EPC2-ALI cells in vitro and showed that PPI exposure significantly reduced IL-13-mediated ANO1 mRNA expression (see Fig E1 in this article's Online Repository at www.jacionline.org).	('i', 'Chemical', 'MESH:D007455', (126, 127))	('i', 'Chemical', 'MESH:D007455', (189, 190))	('PPI', 'Var', (112, 115))	('i', 'Chemical', 'MESH:D007455', (7, 8))	('i', 'Chemical', 'MESH:D007455', (206, 207))	('reduced', 'NegReg', (139, 146))	('i', 'Chemical', 'MESH:D007455', (195, 196))	('i', 'Chemical', 'MESH:D007455', (179, 180))	('i', 'Chemical', 'MESH:D007455', (69, 70))	('i', 'Chemical', 'MESH:D007455', (131, 132))	('i', 'Chemical', 'MESH:D007455', (225, 226))	('i', 'Chemical', 'MESH:D007455', (156, 157))	('i', 'Chemical', 'MESH:D007455', (91, 92))	('i', 'Chemical', 'MESH:D007455', (241, 242))	('i', 'Chemical', 'MESH:D007455', (200, 201))	('i', 'Chemical', 'MESH:D007455', (129, 130))	('ALI', 'Chemical', '-', (77, 80))	('i', 'Chemical', 'MESH:D007455', (87, 88))	('i', 'Chemical', 'MESH:D007455', (216, 217))	('IL-13-mediated ANO1 mRNA expression', 'MPA', (147, 182))	('i', 'Chemical', 'MESH:D007455', (65, 66))	('i', 'Chemical', 'MESH:D007455', (245, 246))	('i', 'Chemical', 'MESH:D007455', (40, 41))
648459	31647967	This was not specific to ANO1 because PPI also inhibited IL-13-mediated CCL26 mRNA expression (see Fig E1).	('CCL26', 'Gene', '10344', (72, 77))	('inhibited', 'NegReg', (47, 56))	('i', 'Chemical', 'MESH:D007455', (17, 18))	('i', 'Chemical', 'MESH:D007455', (47, 48))	('i', 'Chemical', 'MESH:D007455', (52, 53))	('i', 'Chemical', 'MESH:D007455', (100, 101))	('i', 'Chemical', 'MESH:D007455', (66, 67))	('i', 'Chemical', 'MESH:D007455', (90, 91))	('CCL26', 'Gene', (72, 77))	('i', 'Chemical', 'MESH:D007455', (2, 3))	('i', 'Chemical', 'MESH:D007455', (50, 51))	('PPI', 'Var', (38, 41))	('i', 'Chemical', 'MESH:D007455', (19, 20))
648460	31647967	Collectively, these studies suggest that PPIs can act directly on esophageal epithelial cells and downregulate IL-13-induced ANO1 mRNA expression and suggest that these effects are independent on esophageal inflammation.	('i', 'Chemical', 'MESH:D007455', (79, 80))	('inflammation', 'Disease', 'MESH:D007249', (207, 219))	('i', 'Chemical', 'MESH:D007455', (24, 25))	('i', 'Chemical', 'MESH:D007455', (142, 143))	('i', 'Chemical', 'MESH:D007455', (216, 217))	('inflammation', 'Disease', (207, 219))	('i', 'Chemical', 'MESH:D007455', (7, 8))	('downregulate', 'NegReg', (98, 110))	('i', 'Chemical', 'MESH:D007455', (117, 118))	('i', 'Chemical', 'MESH:D007455', (55, 56))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (196, 219))	('i', 'Chemical', 'MESH:D007455', (84, 85))	('i', 'Chemical', 'MESH:D007455', (207, 208))	('PPIs', 'Var', (41, 45))	('i', 'Chemical', 'MESH:D007455', (181, 182))
648462	31647967	Notably, PPI trial in patients with PPI-REE led to a significant reduction in ANO1 expression; however, ANO1 mRNA levels remained significantly greater than those observed in healthy control subjects, indicating that ANO1 expression is in part responsive to PPI therapy.	('greater', 'PosReg', (144, 151))	('i', 'Chemical', 'MESH:D007455', (125, 126))	('i', 'Chemical', 'MESH:D007455', (204, 205))	('expression', 'MPA', (83, 93))	('i', 'Chemical', 'MESH:D007455', (236, 237))	('i', 'Chemical', 'MESH:D007455', (54, 55))	('i', 'Chemical', 'MESH:D007455', (59, 60))	('i', 'Chemical', 'MESH:D007455', (172, 173))	('i', 'Chemical', 'MESH:D007455', (251, 252))	('i', 'Chemical', 'MESH:D007455', (131, 132))	('patients', 'Species', '9606', (22, 30))	('ANO1 mRNA levels', 'MPA', (104, 120))	('ANO1', 'Gene', (78, 82))	('i', 'Chemical', 'MESH:D007455', (19, 20))	('i', 'Chemical', 'MESH:D007455', (75, 76))	('reduction', 'NegReg', (65, 74))	('i', 'Chemical', 'MESH:D007455', (233, 234))	('i', 'Chemical', 'MESH:D007455', (90, 91))	('i', 'Chemical', 'MESH:D007455', (208, 209))	('i', 'Chemical', 'MESH:D007455', (201, 202))	('PPI-REE', 'Var', (36, 43))	('i', 'Chemical', 'MESH:D007455', (57, 58))	('i', 'Chemical', 'MESH:D007455', (136, 137))	('i', 'Chemical', 'MESH:D007455', (25, 26))	('i', 'Chemical', 'MESH:D007455', (15, 16))	('i', 'Chemical', 'MESH:D007455', (229, 230))	('i', 'Chemical', 'MESH:D007455', (32, 33))	('i', 'Chemical', 'MESH:D007455', (71, 72))	('i', 'Chemical', 'MESH:D007455', (134, 135))
648464	31647967	Previous studies have demonstrated that the ANO1 gene is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in patients with cancer, and that inhibition of ANO1 activity in interstitial cells of Cajal and tumor cell lines inhibited cell proliferation, indicating an important potential contribution for this transporter in cell proliferation.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('i', 'Chemical', 'MESH:D007455', (373, 374))	('i', 'Chemical', 'MESH:D007455', (268, 269))	('i', 'Chemical', 'MESH:D007455', (300, 301))	('i', 'Chemical', 'MESH:D007455', (125, 126))	('i', 'Chemical', 'MESH:D007455', (323, 324))	('i', 'Chemical', 'MESH:D007455', (86, 87))	('i', 'Chemical', 'MESH:D007455', (379, 380))	('i', 'Chemical', 'MESH:D007455', (149, 150))	('cell proliferation', 'CPA', (273, 291))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('i', 'Chemical', 'MESH:D007455', (293, 294))	('i', 'Chemical', 'MESH:D007455', (205, 206))	('i', 'Chemical', 'MESH:D007455', (346, 347))	('i', 'Chemical', 'MESH:D007455', (54, 55))	('i', 'Chemical', 'MESH:D007455', (4, 5))	('i', 'Chemical', 'MESH:D007455', (13, 14))	('i', 'Chemical', 'MESH:D007455', (188, 189))	('i', 'Chemical', 'MESH:D007455', (258, 259))	('i', 'Chemical', 'MESH:D007455', (282, 283))	('i', 'Chemical', 'MESH:D007455', (69, 70))	('i', 'Chemical', 'MESH:D007455', (162, 163))	('i', 'Chemical', 'MESH:D007455', (155, 156))	('i', 'Chemical', 'MESH:D007455', (186, 187))	('i', 'Chemical', 'MESH:D007455', (361, 362))	('i', 'Chemical', 'MESH:D007455', (307, 308))	('i', 'Chemical', 'MESH:D007455', (266, 267))	('i', 'Chemical', 'MESH:D007455', (211, 212))	('i', 'Chemical', 'MESH:D007455', (336, 337))	('inhibition', 'Var', (183, 193))	('i', 'Chemical', 'MESH:D007455', (123, 124))	('inhibited', 'NegReg', (263, 272))	('cancer', 'Disease', (166, 172))	('i', 'Chemical', 'MESH:D007455', (296, 297))	('i', 'Chemical', 'MESH:D007455', (66, 67))	('i', 'Chemical', 'MESH:D007455', (263, 264))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', (246, 251))	('ANO1', 'Gene', (197, 201))	('ANO1', 'Gene', (44, 48))	('activity', 'MPA', (202, 210))	('patients', 'Species', '9606', (152, 160))	('i', 'Chemical', 'MESH:D007455', (288, 289))	('i', 'Chemical', 'MESH:D007455', (144, 145))	('i', 'Chemical', 'MESH:D007455', (223, 224))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('i', 'Chemical', 'MESH:D007455', (221, 222))	('i', 'Chemical', 'MESH:D007455', (183, 184))	('i', 'Chemical', 'MESH:D007455', (214, 215))	('i', 'Chemical', 'MESH:D007455', (207, 208))	('i', 'Chemical', 'MESH:D007455', (190, 191))	('i', 'Chemical', 'MESH:D007455', (332, 333))
648469	31647967	We show that ANO1 is the primary apical Cl- transporter in EPC2-ALI cells and that blockade of ANO1 expression and function reduced the level of IL-13-induced EPC2 cell proliferation, suggesting that ANO1-dependent Cl- efflux might be important in EPC2 cell proliferation.	('i', 'Chemical', 'MESH:D007455', (151, 152))	('i', 'Chemical', 'MESH:D007455', (268, 269))	('blockade', 'Var', (83, 91))	('i', 'Chemical', 'MESH:D007455', (173, 174))	('i', 'Chemical', 'MESH:D007455', (179, 180))	('i', 'Chemical', 'MESH:D007455', (107, 108))	('i', 'Chemical', 'MESH:D007455', (227, 228))	('i', 'Chemical', 'MESH:D007455', (235, 236))	('ANO1', 'Gene', (95, 99))	('level', 'MPA', (136, 141))	('i', 'Chemical', 'MESH:D007455', (18, 19))	('i', 'Chemical', 'MESH:D007455', (27, 28))	('ALI', 'Chemical', '-', (64, 67))	('i', 'Chemical', 'MESH:D007455', (35, 36))	('i', 'Chemical', 'MESH:D007455', (120, 121))	('i', 'Chemical', 'MESH:D007455', (262, 263))	('reduced', 'NegReg', (124, 131))	('i', 'Chemical', 'MESH:D007455', (56, 57))	('i', 'Chemical', 'MESH:D007455', (245, 246))	('i', 'Chemical', 'MESH:D007455', (191, 192))
648476	31647967	CDK2 is required for alleviating retinoblastoma protein-mediated inhibition of E2F and S phase entry and DNA synthesis, and loss of CDK2 activity leads to cell-cycle arrest at the G1/S checkpoint.	('inhibition', 'NegReg', (65, 75))	('i', 'Chemical', 'MESH:D007455', (70, 71))	('i', 'Chemical', 'MESH:D007455', (29, 30))	('arrest', 'Disease', (166, 172))	('i', 'Chemical', 'MESH:D007455', (53, 54))	('i', 'Chemical', 'MESH:D007455', (116, 117))	('i', 'Chemical', 'MESH:D007455', (59, 60))	('i', 'Chemical', 'MESH:D007455', (140, 141))	('loss', 'Var', (124, 128))	('retinoblastoma', 'Disease', 'MESH:D012175', (33, 47))	('CDK2', 'Gene', '1017', (0, 4))	('i', 'Chemical', 'MESH:D007455', (12, 13))	('i', 'Chemical', 'MESH:D007455', (5, 6))	('i', 'Chemical', 'MESH:D007455', (36, 37))	('E2F', 'MPA', (79, 82))	('i', 'Chemical', 'MESH:D007455', (68, 69))	('CDK2', 'Gene', (0, 4))	('arrest', 'Disease', 'MESH:D006323', (166, 172))	('i', 'Chemical', 'MESH:D007455', (26, 27))	('CDK2', 'Gene', '1017', (132, 136))	('retinoblastoma', 'Phenotype', 'HP:0009919', (33, 47))	('DNA synthesis', 'MPA', (105, 118))	('i', 'Chemical', 'MESH:D007455', (192, 193))	('S phase entry', 'MPA', (87, 100))	('i', 'Chemical', 'MESH:D007455', (142, 143))	('i', 'Chemical', 'MESH:D007455', (72, 73))	('retinoblastoma', 'Disease', (33, 47))	('i', 'Chemical', 'MESH:D007455', (65, 66))	('CDK2', 'Gene', (132, 136))	('activity', 'MPA', (137, 145))
648479	31647967	Consistent with this, genetic ablation of TP63 in mature human keratinocytes leads to cell-cycle arrest.	('i', 'Chemical', 'MESH:D007455', (4, 5))	('i', 'Chemical', 'MESH:D007455', (68, 69))	('i', 'Chemical', 'MESH:D007455', (18, 19))	('i', 'Chemical', 'MESH:D007455', (27, 28))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('i', 'Chemical', 'MESH:D007455', (35, 36))	('arrest', 'Disease', (97, 103))	('i', 'Chemical', 'MESH:D007455', (12, 13))	('i', 'Chemical', 'MESH:D007455', (47, 48))	('TP63', 'Gene', (42, 46))	('genetic ablation', 'Var', (22, 38))	('TP63', 'Gene', '8626', (42, 46))	('human', 'Species', '9606', (57, 62))
648482	31647967	Alternatively, ANO1 can directly inhibit TP63 expression and decrease proliferative capacity, an area of current investigation.	('i', 'Chemical', 'MESH:D007455', (38, 39))	('inhibit', 'NegReg', (33, 40))	('TP63', 'Gene', '8626', (41, 45))	('i', 'Chemical', 'MESH:D007455', (53, 54))	('decrease', 'NegReg', (61, 69))	('i', 'Chemical', 'MESH:D007455', (74, 75))	('i', 'Chemical', 'MESH:D007455', (36, 37))	('ANO1', 'Var', (15, 19))	('proliferative capacity', 'CPA', (70, 92))	('i', 'Chemical', 'MESH:D007455', (123, 124))	('i', 'Chemical', 'MESH:D007455', (33, 34))	('expression', 'MPA', (46, 56))	('i', 'Chemical', 'MESH:D007455', (113, 114))	('i', 'Chemical', 'MESH:D007455', (89, 90))	('i', 'Chemical', 'MESH:D007455', (25, 26))	('i', 'Chemical', 'MESH:D007455', (8, 9))	('i', 'Chemical', 'MESH:D007455', (80, 81))	('TP63', 'Gene', (41, 45))	('i', 'Chemical', 'MESH:D007455', (119, 120))
648489	31647967	Notably, EoE endotype 3 was associated with a fibrostenotic (rings, narrowing, or strictures) phenotype and the greatest degree of endoscopic and histologic severity.	('i', 'Chemical', 'MESH:D007455', (154, 155))	('EoE endotype 3', 'Var', (9, 23))	('i', 'Chemical', 'MESH:D007455', (147, 148))	('i', 'Chemical', 'MESH:D007455', (62, 63))	('i', 'Chemical', 'MESH:D007455', (47, 48))	('associated', 'Reg', (28, 38))	('i', 'Chemical', 'MESH:D007455', (162, 163))	('fibrostenotic', 'Disease', (46, 59))	('i', 'Chemical', 'MESH:D007455', (139, 140))	('strictures', 'Disease', (82, 92))	('i', 'Chemical', 'MESH:D007455', (74, 75))	('i', 'Chemical', 'MESH:D007455', (57, 58))	('i', 'Chemical', 'MESH:D007455', (33, 34))	('i', 'Chemical', 'MESH:D007455', (40, 41))	('i', 'Chemical', 'MESH:D007455', (85, 86))
648499	31647967	Mechanistically, we identified a previously undescribed role for ANO1 in esophageal epithelial proliferation and provided data to indicate that ANO1 counterregulates the basal keratinocyte-specific proliferative protein TP63 and the cell-cycle protein CDK2.	('ANO1', 'Gene', (65, 69))	('i', 'Chemical', 'MESH:D007455', (86, 87))	('i', 'Chemical', 'MESH:D007455', (117, 118))	('i', 'Chemical', 'MESH:D007455', (70, 71))	('esophageal epithelial proliferation', 'CPA', (73, 108))	('i', 'Chemical', 'MESH:D007455', (37, 38))	('i', 'Chemical', 'MESH:D007455', (133, 134))	('i', 'Chemical', 'MESH:D007455', (195, 196))	('i', 'Chemical', 'MESH:D007455', (20, 21))	('ANO1', 'Var', (144, 148))	('i', 'Chemical', 'MESH:D007455', (249, 250))	('i', 'Chemical', 'MESH:D007455', (130, 131))	('TP63', 'Gene', (220, 224))	('i', 'Chemical', 'MESH:D007455', (99, 100))	('i', 'Chemical', 'MESH:D007455', (91, 92))	('i', 'Chemical', 'MESH:D007455', (217, 218))	('i', 'Chemical', 'MESH:D007455', (202, 203))	('i', 'Chemical', 'MESH:D007455', (27, 28))	('i', 'Chemical', 'MESH:D007455', (9, 10))	('i', 'Chemical', 'MESH:D007455', (51, 52))	('i', 'Chemical', 'MESH:D007455', (208, 209))	('i', 'Chemical', 'MESH:D007455', (193, 194))	('TP63', 'Gene', '8626', (220, 224))	('i', 'Chemical', 'MESH:D007455', (105, 106))	('CDK2', 'Gene', (252, 256))	('i', 'Chemical', 'MESH:D007455', (25, 26))	('CDK2', 'Gene', '1017', (252, 256))	('esophageal epithelial proliferation', 'Phenotype', 'HP:0012859', (73, 108))	('i', 'Chemical', 'MESH:D007455', (181, 182))	('i', 'Chemical', 'MESH:D007455', (6, 7))
648500	31647967	Collectively, these studies provide a rationale for the therapeutic use of ANO1 antagonists for reduction in BZH and reduction in associated esophageal dysfunction in patients with EoE.	('reduction', 'NegReg', (117, 126))	('i', 'Chemical', 'MESH:D007455', (127, 128))	('antagonists', 'Var', (80, 91))	('i', 'Chemical', 'MESH:D007455', (7, 8))	('i', 'Chemical', 'MESH:D007455', (164, 165))	('i', 'Chemical', 'MESH:D007455', (170, 171))	('i', 'Chemical', 'MESH:D007455', (123, 124))	('i', 'Chemical', 'MESH:D007455', (106, 107))	('EoE', 'Disease', (181, 184))	('i', 'Chemical', 'MESH:D007455', (177, 178))	('esophageal dysfunction', 'Disease', 'MESH:D004938', (141, 163))	('reduction', 'NegReg', (96, 105))	('BZH', 'MPA', (109, 112))	('i', 'Chemical', 'MESH:D007455', (24, 25))	('ANO1', 'Gene', (75, 79))	('i', 'Chemical', 'MESH:D007455', (87, 88))	('esophageal dysfunction', 'Disease', (141, 163))	('i', 'Chemical', 'MESH:D007455', (41, 42))	('patients', 'Species', '9606', (167, 175))	('i', 'Chemical', 'MESH:D007455', (65, 66))	('i', 'Chemical', 'MESH:D007455', (135, 136))	('BZ', 'Chemical', '-', (109, 111))	('i', 'Chemical', 'MESH:D007455', (32, 33))	('i', 'Chemical', 'MESH:D007455', (160, 161))	('i', 'Chemical', 'MESH:D007455', (102, 103))
648502	31647967	IL-13 rapidly induces ANO1 expression by means of epigenetic modification and STAT6 promoter interaction.	('epigenetic modification', 'Var', (50, 73))	('i', 'Chemical', 'MESH:D007455', (58, 59))	('i', 'Chemical', 'MESH:D007455', (14, 15))	('i', 'Chemical', 'MESH:D007455', (93, 94))	('i', 'Chemical', 'MESH:D007455', (52, 53))	('i', 'Chemical', 'MESH:D007455', (66, 67))	('i', 'Chemical', 'MESH:D007455', (70, 71))	('i', 'Chemical', 'MESH:D007455', (101, 102))	('ANO1', 'Gene', (22, 26))	('expression', 'MPA', (27, 37))	('STAT6', 'Gene', (78, 83))	('interaction', 'Interaction', (93, 104))	('induces', 'Reg', (14, 21))	('i', 'Chemical', 'MESH:D007455', (9, 10))	('STAT6', 'Gene', '6778', (78, 83))	('IL-13', 'Gene', (0, 5))	('i', 'Chemical', 'MESH:D007455', (64, 65))	('i', 'Chemical', 'MESH:D007455', (34, 35))
648505	31647967	ANO1-dependent regulation of basal cell proliferation was associated with modulation of TP63 expression and p-CDK2 levels.	('i', 'Chemical', 'MESH:D007455', (63, 64))	('TP63', 'Gene', (88, 92))	('TP63', 'Gene', '8626', (88, 92))	('CDK2', 'Gene', (110, 114))	('i', 'Chemical', 'MESH:D007455', (22, 23))	('i', 'Chemical', 'MESH:D007455', (100, 101))	('i', 'Chemical', 'MESH:D007455', (70, 71))	('basal cell proliferation', 'Phenotype', 'HP:0002671', (29, 53))	('expression', 'MPA', (93, 103))	('CDK2', 'Gene', '1017', (110, 114))	('i', 'Chemical', 'MESH:D007455', (50, 51))	('i', 'Chemical', 'MESH:D007455', (81, 82))	('modulation', 'Var', (74, 84))	('basal cell proliferation', 'CPA', (29, 53))	('i', 'Chemical', 'MESH:D007455', (44, 45))
648529	32330123	The 3' untranslated regions (UTR) of PCDH8 containing wild-type (WT) or mutant (MT) miR-200c binding sites were cloned between the xhoI and NotI sites of the psicheck2 Dual luciferase vector (Promega, WI, USA).	('miR-200c', 'Gene', (84, 92))	('mutant', 'Var', (72, 78))	('miR-200c', 'Gene', '406985', (84, 92))	('PCDH8', 'Gene', (37, 42))
648530	32330123	A total of 3x104 293T cells were seeded on 24-well culture plates 24 h prior to transfection, and then co-transfected with 0.5 mug of wild-type or mutated psicheck2-PCDH8 vectors and 20 muM of miR-200c mimics or scrambled control (Riobio, Guangzhou, China).	('miR-200c', 'Gene', (193, 201))	('miR-200c', 'Gene', '406985', (193, 201))	('psicheck2-PCDH8', 'Gene', (155, 170))	('mutated', 'Var', (147, 154))	('293T', 'CellLine', 'CVCL:0063', (17, 21))
648577	32330123	The tumor weight after treatment also exhibited a similar pattern and was lighter in mice with PCDH8 overexpression compared with control (P<0.001).	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (85, 89))	('lighter', 'NegReg', (74, 81))	('PCDH8', 'Gene', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('overexpression', 'Var', (101, 115))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
648583	32330123	Luciferase activity was significantly decreased in cells co-transfected with wild-type 3'UTR of PCDH8 and miR-200c mimic (P<0.001, Figure 5), whereas mutant 3'UTR of PCDH8 reporter did not exhibit any difference in relative luciferase activity between cells transfected with mock and miR-200c mimic.	('decreased', 'NegReg', (38, 47))	('activity', 'MPA', (11, 19))	('miR-200c', 'Gene', (284, 292))	('miR-200c', 'Gene', '406985', (284, 292))	('miR-200c', 'Gene', (106, 114))	('miR-200c', 'Gene', '406985', (106, 114))	('Luciferase', 'Enzyme', (0, 10))	('mutant', 'Var', (150, 156))
648590	32330123	PCDH8 is usually downregulated in many types of cancer, including ovarian, breast, and lung cancers, due to mutation and epigenetic alteration.	('ovarian', 'Disease', 'MESH:D010049', (66, 73))	('ovarian', 'Disease', (66, 73))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('lung cancers', 'Disease', (87, 99))	('downregulated', 'NegReg', (17, 30))	('PCDH8', 'Gene', (0, 5))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mutation', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lung cancers', 'Disease', 'MESH:D008175', (87, 99))	('lung cancers', 'Phenotype', 'HP:0100526', (87, 99))	('breast', 'Disease', (75, 81))	('epigenetic alteration', 'Var', (121, 142))
648591	32330123	Inactivating PCDH8 may be a key step in the acquisition of malignant phenotype due to its high frequency in cancer.	('malignant', 'Disease', 'MESH:D009369', (59, 68))	('Inactivating', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('malignant', 'Disease', (59, 68))	('PCDH8', 'Gene', (13, 18))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
648592	32330123	Low expression and hypermethylation of PCDH8 are associated with poor prognosis of cancer patients.	('patients', 'Species', '9606', (90, 98))	('associated', 'Reg', (49, 59))	('PCDH8', 'Gene', (39, 44))	('expression', 'MPA', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('hypermethylation', 'Var', (19, 35))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Low', 'NegReg', (0, 3))	('cancer', 'Disease', (83, 89))
648608	32330123	PCDH8 overexpression inhibited ESCC growth, invasion, metastasis, and angiogenesis and induced apoptosis, which is consistent with previous studies conducted in other types of cancer.	('invasion', 'CPA', (44, 52))	('overexpression', 'Var', (6, 20))	('ESCC growth', 'CPA', (31, 42))	('apoptosis', 'CPA', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('PCDH8', 'Gene', (0, 5))	('inhibited', 'NegReg', (21, 30))	('metastasis', 'CPA', (54, 64))	('induced', 'Reg', (87, 94))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('angiogenesis', 'CPA', (70, 82))
648613	32330123	PCDH8 overexpression suppresses EMT progression of ESCC cells through upregulation of E-cadherin and downregulation of N-cadherin and Vimentin.	('downregulation', 'NegReg', (101, 115))	('N-cadherin', 'Gene', (119, 129))	('Vimentin', 'Gene', '7431', (134, 142))	('upregulation', 'PosReg', (70, 82))	('EMT progression', 'CPA', (32, 47))	('overexpression', 'Var', (6, 20))	('N-cadherin', 'Gene', '1000', (119, 129))	('PCDH8', 'Gene', (0, 5))	('suppresses', 'NegReg', (21, 31))	('ESCC', 'Disease', (51, 55))	('Vimentin', 'Gene', (134, 142))	('E-cadherin', 'Gene', (86, 96))	('E-cadherin', 'Gene', '999', (86, 96))
648724	32323780	The human KYSE-70, EC109, KYSE-510, TE1, TE13, EC1 and EC9706 ESCC cell lines and the normal esophageal squamous epithelium HET-1A cell line were provided by Basic Medical Sciences of Zhengzhou University (Zhengzhou, China).	('EC1', 'Gene', (47, 50))	('HET-1A', 'CellLine', 'CVCL:3702', (124, 130))	('EC1', 'Gene', (19, 22))	('human', 'Species', '9606', (4, 9))	('EC9706', 'Var', (55, 61))	('ESCC', 'Disease', 'MESH:C562729', (62, 66))	('EC1', 'Gene', '4819', (47, 50))	('KYSE-510', 'CellLine', 'CVCL:1354', (26, 34))	('EC109', 'CellLine', 'CVCL:6898', (19, 24))	('EC9706', 'CellLine', 'CVCL:E307', (55, 61))	('ESCC', 'Disease', (62, 66))	('EC1', 'Gene', '4819', (19, 22))
648752	32323780	Moreover, silencing of NLRP3 significantly decreased tumor cell invasion in the TE13 cells (P<0.0001) and KYSE-70 (P=0.0002) cells, as well as migration in the TE13 (P<0.0001) and KYSE-70 (P=0.0037) cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('migration', 'CPA', (143, 152))	('decreased', 'NegReg', (43, 52))	('silencing', 'Var', (10, 19))	('NLRP3', 'Gene', (23, 28))
648754	32323780	As compared with the pcDNA-3.1(+) plasmid-transfected cells, the CCK-8 assay results showed that pcDNA-3.1(+)-NLRP3-transfected (OE-NLRP3) KYSE-510 cells had an increased viability (P=0.002), however, EC9706 cells showed no significant increase in viability (P=0.60) (Fig.	('increased', 'PosReg', (161, 170))	('pcDNA-3.1(+)-NLRP3-transfected', 'Var', (97, 127))	('KYSE-510', 'CellLine', 'CVCL:1354', (139, 147))	('EC9706', 'CellLine', 'CVCL:E307', (201, 207))
648755	32323780	Consistently, the wound-healing capability of the cells was also strongly increased in the EC9706 (P=0.045) and KYSE-510 (P=0.021) cells following NLRP3 overexpression (Fig.	('overexpression', 'PosReg', (153, 167))	('KYSE-510', 'CellLine', 'CVCL:1354', (112, 120))	('NLRP3', 'Gene', (147, 152))	('increased', 'PosReg', (74, 83))	('EC9706', 'Var', (91, 97))	('wound-healing capability of the cells', 'CPA', (18, 55))	('EC9706', 'CellLine', 'CVCL:E307', (91, 97))
648767	32323780	These data indicate that patients with a high NLRP3 expression may have a more malignant clinical phenotype.	('NLRP3', 'Gene', (46, 51))	('expression', 'MPA', (52, 62))	('patients', 'Species', '9606', (25, 33))	('high', 'Var', (41, 45))
648799	31650035	Postoperative recovery was uneventful except for a minor chylous leak which settled with a brief period (5 days) of conservative treatment, medium chain triglyceride based diet and feeds through the feeding jejunostomy.	('chylous leak', 'Disease', (57, 69))	('medium chain', 'Var', (140, 152))	('triglyceride', 'Chemical', 'MESH:D014280', (153, 165))
648829	31432128	Dysregulations in metabolism are one of the hallmarks of cancer cells.	('metabolism', 'MPA', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('Dysregulations', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
648868	31432128	SREBP2, HMGCR and c-Myc expression in ESCC cell lines was downregulated via lentiviral transduction.	('expression', 'Species', '29278', (24, 34))	('ESCC', 'Disease', 'MESH:C562729', (38, 42))	('SREBP2', 'Gene', '6721', (0, 6))	('expression', 'MPA', (24, 34))	('c-Myc', 'Gene', (18, 23))	('SREBP2', 'Gene', (0, 6))	('ESCC', 'Disease', (38, 42))	('downregulated', 'NegReg', (58, 71))	('HMGCR', 'Gene', (8, 13))	('lentiviral transduction', 'Var', (76, 99))	('HMGCR', 'Gene', '3156', (8, 13))	('c-Myc', 'Gene', '4609', (18, 23))
648908	31432128	2F, knockdown of HMGCR expression inhibited the anchorage-independent growth of KYSE180 cells compared with the control cells.	('HMGCR', 'Gene', (17, 22))	('inhibited', 'NegReg', (34, 43))	('HMGCR', 'Gene', '3156', (17, 22))	('anchorage-independent growth of KYSE180 cells', 'CPA', (48, 93))	('expression', 'Species', '29278', (23, 33))	('knockdown', 'Var', (4, 13))
648911	31432128	3B and C, SREBP2 knockdown significantly inhibited the anchorage-independent growth and migration of ESCC cells compared with the control (Fig.	('SREBP2', 'Gene', (10, 16))	('SREBP2', 'Gene', '6721', (10, 16))	('knockdown', 'Var', (17, 26))	('ESCC', 'Disease', 'MESH:C562729', (101, 105))	('migration', 'CPA', (88, 97))	('inhibited', 'NegReg', (41, 50))	('anchorage-independent growth', 'CPA', (55, 83))	('ESCC', 'Disease', (101, 105))
648922	31432128	5A; P<0.01), whereas, knockdown of c-Myc expression significantly inhibited HMGCR expression compared with the control (Fig.	('expression', 'Species', '29278', (82, 92))	('c-Myc', 'Gene', '4609', (35, 40))	('expression', 'Species', '29278', (41, 51))	('HMGCR', 'Gene', (76, 81))	('knockdown', 'Var', (22, 31))	('c-Myc', 'Gene', (35, 40))	('inhibited', 'NegReg', (66, 75))	('HMGCR', 'Gene', '3156', (76, 81))
648930	31432128	Dysregulation of the MVA pathway has been demonstrated in numerous types of cancer.	('MVA pathway', 'Pathway', (21, 32))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
648939	31432128	For example, mutant P53 interacts with SREBP and promotes the activation of the MVA pathway in breast cancer cells, suggesting that the MVA pathway is altered by oncogenes and tumor suppressors.	('mutant', 'Var', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast cancer', 'Disease', (95, 108))	('MVA pathway', 'Pathway', (80, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('tumor', 'Disease', (176, 181))	('P53', 'Gene', (20, 23))	('promotes', 'PosReg', (49, 57))	('interacts', 'Interaction', (24, 33))	('activation', 'PosReg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
648949	30948501	Then, we found high expression of GHET1 is a useful biomarker to discriminate cervical cancer tissues from non-tumorous tissues, and associated with advanced clinical stage, lymph node metastasis, distant metastasis and poor histological grade in cervical cancer patients.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('high expression', 'Var', (15, 30))	('associated with', 'Reg', (133, 148))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (263, 271))	('distant metastasis', 'CPA', (197, 215))	('cervical cancer', 'Disease', 'MESH:D002583', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cervical cancer', 'Disease', 'MESH:D002583', (247, 262))	('tumor', 'Disease', (111, 116))	('cervical cancer', 'Disease', (78, 93))	('GHET1', 'Gene', '102723099', (34, 39))	('cervical cancer', 'Disease', (247, 262))	('lymph node metastasis', 'CPA', (174, 195))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('GHET1', 'Gene', (34, 39))
648950	30948501	The survival analysis showed high GHET1 expression was an independent unfavorable prognostic factor in cervical cancer patients.	('high', 'Var', (29, 33))	('expression', 'MPA', (40, 50))	('patients', 'Species', '9606', (119, 127))	('GHET1', 'Gene', '102723099', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('GHET1', 'Gene', (34, 39))	('cervical cancer', 'Disease', (103, 118))	('cervical cancer', 'Disease', 'MESH:D002583', (103, 118))
648952	30948501	The loss-of-function study indicated knockdown of GHET1 expression markedly inhibits cervical cancer cell proliferation, migration, and invasion.	('migration', 'CPA', (121, 130))	('loss-of-function', 'NegReg', (4, 20))	('cervical cancer', 'Disease', 'MESH:D002583', (85, 100))	('knockdown', 'Var', (37, 46))	('GHET1', 'Gene', '102723099', (50, 55))	('cervical cancer', 'Disease', (85, 100))	('inhibits', 'NegReg', (76, 84))	('invasion', 'CPA', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('GHET1', 'Gene', (50, 55))
648988	30948501	As shown in Table 1, high expression of GHET1 was associated with advanced clinical stage (I-IIA vs IIB-IV, P<0.001), lymph node metastasis (absent vs present, P<0.001), distant metastasis (absent vs present vs, P=0.010) and poor histological grade (well vs moderately/poorly, P=0.003).	('distant metastasis', 'CPA', (170, 188))	('lymph node metastasis', 'CPA', (118, 139))	('GHET1', 'Gene', '102723099', (40, 45))	('advanced clinical stage', 'CPA', (66, 89))	('high expression', 'Var', (21, 36))	('GHET1', 'Gene', (40, 45))	('poor histological', 'CPA', (225, 242))
648991	30948501	In addition, the univariate Cox regression analysis suggested that advanced clinical stage (P=0.012), lymph node metastasis (P=0.001), distant metastasis (P=0.010), poor histological grade (P=0.012), and high GHET1 expression (P<0.001) were poor prognostic factors for overall survival in patients with cervical cancer (Table 2).	('patients', 'Species', '9606', (289, 297))	('expression', 'MPA', (215, 225))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('GHET1', 'Gene', '102723099', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('GHET1', 'Gene', (209, 214))	('cervical cancer', 'Disease', (303, 318))	('cervical cancer', 'Disease', 'MESH:D002583', (303, 318))	('high', 'Var', (204, 208))
648992	30948501	Then, high GHET1 expression was identified as an independent unfavorable prognostic factor in cervical cancer patients through multivariate Cox regression analysis (P=0.001, Table 2).	('GHET1', 'Gene', (11, 16))	('Cox', 'Gene', '1351', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('expression', 'MPA', (17, 27))	('Cox', 'Gene', (140, 143))	('high', 'Var', (6, 10))	('cervical cancer', 'Disease', 'MESH:D002583', (94, 109))	('GHET1', 'Gene', '102723099', (11, 16))	('cervical cancer', 'Disease', (94, 109))	('patients', 'Species', '9606', (110, 118))
648997	30948501	The results showed the migratory and invasive capabilities of cervical cancer cells were dramatically decreased after transfecting with si-GHET1 (P<0.001, Figure 4C,D).	('GHET1', 'Gene', '102723099', (139, 144))	('transfecting', 'Var', (118, 130))	('GHET1', 'Gene', (139, 144))	('cervical cancer', 'Disease', (62, 77))	('cervical cancer', 'Disease', 'MESH:D002583', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('decreased', 'NegReg', (102, 111))
649012	30948501	indicated that high levels of GHET1 were associated with advanced clinical stage, larger tumor size, and present lymph node metastasis in breast cancer patients.	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('GHET1', 'Gene', '102723099', (30, 35))	('GHET1', 'Gene', (30, 35))	('patients', 'Species', '9606', (152, 160))	('breast cancer', 'Disease', (138, 151))	('high levels', 'Var', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
649018	30948501	In our research, we found that cervical cancer patients with high expression of GHET1 had a worse overall survival time than patients with low expression of GHET1 through Kaplan-Meier method and log-rank test, and high GHET1 expression was identified as an independent unfavorable prognostic factor in cervical cancer patients through univariate and multivariate Cox regression analysis.	('patients', 'Species', '9606', (47, 55))	('cervical cancer', 'Disease', (31, 46))	('cervical cancer', 'Disease', 'MESH:D002583', (31, 46))	('worse', 'NegReg', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('patients', 'Species', '9606', (125, 133))	('Cox', 'Gene', (363, 366))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('GHET1', 'Gene', '102723099', (80, 85))	('GHET1', 'Gene', (80, 85))	('overall survival time', 'CPA', (98, 119))	('GHET1', 'Gene', '102723099', (157, 162))	('GHET1', 'Gene', (157, 162))	('high expression', 'Var', (61, 76))	('patients', 'Species', '9606', (318, 326))	('cervical cancer', 'Disease', 'MESH:D002583', (302, 317))	('GHET1', 'Gene', '102723099', (219, 224))	('cervical cancer', 'Disease', (302, 317))	('Cox', 'Gene', '1351', (363, 366))	('GHET1', 'Gene', (219, 224))
649019	30948501	Similar results in non-small cell lung cancer, patients with high GHET1 expression had short overall survival time and high GHET1 expression was an independent unfavorable prognostic predictor for overall survival.	('GHET1', 'Gene', '102723099', (124, 129))	('overall survival', 'MPA', (93, 109))	('non-small cell lung cancer', 'Disease', (19, 45))	('GHET1', 'Gene', (66, 71))	('high', 'Var', (119, 123))	('high', 'Var', (61, 65))	('GHET1', 'Gene', (124, 129))	('short', 'NegReg', (87, 92))	('patients', 'Species', '9606', (47, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (23, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (19, 45))	('GHET1', 'Gene', '102723099', (66, 71))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (19, 45))
649020	30948501	showed that hepatocellular carcinoma cases with high GHET1 expression had poor prognosis and high GHET1 expression was an independent poor prognostic factor for overall survival.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('GHET1', 'Gene', '102723099', (53, 58))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (12, 36))	('GHET1', 'Gene', (53, 58))	('GHET1', 'Gene', (98, 103))	('hepatocellular carcinoma', 'Disease', (12, 36))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (12, 36))	('GHET1', 'Gene', '102723099', (98, 103))	('high', 'Var', (48, 52))
649022	30948501	Generally, high GHET1 expression is an unfavorable biomarker for most human cancers.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('GHET1', 'Gene', '102723099', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('GHET1', 'Gene', (16, 21))	('high', 'Var', (11, 15))	('expression', 'MPA', (22, 32))
649026	30948501	In our results, we preliminarily found that knockdown of GHET1 expression markedly inhibited cell proliferation, migration, and invasion in cervical cancer, which was consistent with its function in other cancers.	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancers', 'Disease', (205, 212))	('cervical cancer', 'Disease', (140, 155))	('cervical cancer', 'Disease', 'MESH:D002583', (140, 155))	('cell proliferation', 'CPA', (93, 111))	('inhibited', 'NegReg', (83, 92))	('GHET1', 'Gene', (57, 62))	('GHET1', 'Gene', '102723099', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('knockdown', 'Var', (44, 53))	('migration', 'CPA', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('invasion', 'CPA', (128, 136))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
649038	28928817	Notably, the protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) signaling pathway, an important negative regulator of autophagy, was demonstrated to be suppressed by DCA treatment.	('Akt', 'Gene', (31, 34))	('DCA', 'Var', (177, 180))	('Akt', 'Gene', '207', (31, 34))	('suppressed', 'NegReg', (163, 173))	('DCA', 'Chemical', 'MESH:D003999', (177, 180))
649041	28928817	It has been reported that the inhibition of mTOR and PI3K-mTOR can activate autophagy in glioma cells, which may promote glioma cell survival.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('inhibition', 'Var', (30, 40))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('autophagy', 'CPA', (76, 85))	('promote', 'PosReg', (113, 120))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Disease', (121, 127))	('mTOR', 'Gene', (44, 48))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('glioma', 'Disease', (89, 95))	('PI3K-mTOR', 'Var', (53, 62))	('activate', 'PosReg', (67, 75))
649075	28928817	Taken together, these results indicate that the autophagic flux which occurs in TE-1 cells is enhanced by DCA treatment.	('autophagic flux', 'CPA', (48, 63))	('DCA', 'Var', (106, 109))	('DCA', 'Chemical', 'MESH:D003999', (106, 109))	('TE-1', 'CellLine', 'CVCL:1759', (80, 84))	('enhanced', 'PosReg', (94, 102))
649088	28928817	3C-D, cell number and viability were significantly reduced in cells knocked down for Atg5 in the DCA- and 5-FU-treated conditions.	('knocked down', 'Var', (68, 80))	('Atg5', 'Gene', (85, 89))	('5-FU', 'Chemical', 'MESH:D005472', (106, 110))	('reduced', 'NegReg', (51, 58))	('DCA', 'Chemical', 'MESH:D003999', (97, 100))	('Atg5', 'Gene', '9474', (85, 89))
649089	28928817	In addition, apoptosis was markedly increased in cells treated with the DCA and 5-FU combination treatment, indicating that inhibition of Atg5 expression could enhance drug sensitivity.	('Atg5', 'Gene', '9474', (138, 142))	('apoptosis', 'CPA', (13, 22))	('Atg5', 'Gene', (138, 142))	('drug sensitivity', 'CPA', (168, 184))	('increased', 'PosReg', (36, 45))	('5-FU', 'Chemical', 'MESH:D005472', (80, 84))	('inhibition', 'Var', (124, 134))	('enhance', 'PosReg', (160, 167))	('drug sensitivity', 'Phenotype', 'HP:0020174', (168, 184))	('DCA', 'Chemical', 'MESH:D003999', (72, 75))
649091	28928817	The phosphorylation status of both Akt and mTOR was significantly decreased in DCA-treated cells compared with the control.	('decreased', 'NegReg', (66, 75))	('mTOR', 'Protein', (43, 47))	('DCA', 'Chemical', 'MESH:D003999', (79, 82))	('Akt', 'Gene', '207', (35, 38))	('DCA-treated', 'Var', (79, 90))	('phosphorylation status', 'MPA', (4, 26))	('Akt', 'Gene', (35, 38))
649100	28928817	In the present study, we found that DCA induced autophagy in human esophageal squamous carcinoma cells with minimal apoptosis and induced high levels of autophagy-related proteins.	('autophagy', 'CPA', (48, 57))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (78, 96))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (67, 96))	('DCA', 'Var', (36, 39))	('autophagy-related', 'MPA', (153, 170))	('esophageal squamous carcinoma', 'Disease', (67, 96))	('human', 'Species', '9606', (61, 66))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (67, 96))	('DCA', 'Chemical', 'MESH:D003999', (36, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
649106	28928817	Lin et al reported that DCA induced autophagy was accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced kPL and increased NAD+/NADH ratio in colorectal carcinoma cells, which was consistent with our findings.	('colorectal carcinoma', 'Disease', (173, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('NAD+', 'Chemical', 'MESH:D009243', (154, 158))	('DCA', 'Var', (24, 27))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (173, 193))	('DCA', 'Chemical', 'MESH:D003999', (24, 27))	('lactate excretion', 'MPA', (109, 126))	('reduced', 'NegReg', (128, 135))	('lactate', 'Chemical', 'MESH:D019344', (109, 116))	('kPL', 'MPA', (136, 139))	('autophagy', 'CPA', (36, 45))	('mTOR', 'MPA', (84, 88))	('increased', 'PosReg', (144, 153))	('NAD+/NADH ratio', 'MPA', (154, 169))	('ROS production', 'MPA', (65, 79))	('reduced', 'NegReg', (101, 108))	('inhibition', 'NegReg', (89, 99))	('NADH', 'Chemical', 'MESH:D009243', (159, 163))
649107	28928817	In conclusion, DCA inhibits glycolysis and reduces lactate accumulation, which destroys the acidified tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('lactate accumulation', 'MPA', (51, 71))	('DCA', 'Chemical', 'MESH:D003999', (15, 18))	('lactate', 'Chemical', 'MESH:D019344', (51, 58))	('glycolysis', 'MPA', (28, 38))	('DCA', 'Var', (15, 18))	('inhibits', 'NegReg', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('reduces', 'NegReg', (43, 50))
649114	28122340	The median OS of patients with advanced AJCC stage or low AUC-CSH was also significantly shorter than that of patients with stage I & II or high AUC-CSH (P = 0.021, 0.009).	('low AUC-CSH', 'Var', (54, 65))	('AUC-CSH', 'Chemical', '-', (145, 152))	('AUC-CSH', 'Chemical', '-', (58, 65))	('patients', 'Species', '9606', (17, 25))	('shorter', 'NegReg', (89, 96))	('patients', 'Species', '9606', (110, 118))
649149	28122340	The frequencies of distant metastasis in the low AUC-CSH group were more than twice higher than in the high AUC-CSH group (Table 4).	('distant metastasis', 'CPA', (19, 37))	('low AUC-CSH', 'Var', (45, 56))	('AUC-CSH', 'Chemical', '-', (49, 56))	('AUC-CSH', 'Chemical', '-', (108, 115))	('higher', 'PosReg', (84, 90))
649176	28122340	Additionally, tumor recurrence observed in low AUC-CSH group was 3 times higher than high AUC-CSH group in our research.	('tumor', 'Disease', (14, 19))	('AUC-CSH', 'Chemical', '-', (47, 54))	('low AUC-CSH', 'Var', (43, 54))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('AUC-CSH', 'Chemical', '-', (90, 97))	('higher', 'PosReg', (73, 79))
649178	28122340	In this study, we also found smaller MTV (<= 13.6) was associated with improved RFS in univariate analysis.	('MTV', 'Var', (37, 40))	('MTV', 'Chemical', '-', (37, 40))	('improved', 'PosReg', (71, 79))	('RFS', 'Disease', (80, 83))
649308	22493560	The self renewal and pluripotency are the hallmarks of the embryonic stem cells and it has been observed that deregulation of these pathways involved in differentiation and maintenance of proliferation.	('pluripotency', 'Disease', 'None', (21, 33))	('deregulation', 'Var', (110, 122))	('self renewal', 'CPA', (4, 16))	('involved', 'Reg', (141, 149))	('pluripotency', 'Disease', (21, 33))
649319	22493560	Moreover, ectopic expression of Oct-4 in heterologous cell system has been shown to transform nontumorigenic cells and induces tumorigenecity in nude mice, implicating its possible role in neoplastic process.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('transform', 'Reg', (84, 93))	('induces', 'Reg', (119, 126))	('nude mice', 'Species', '10090', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Oct-4', 'Gene', (32, 37))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('neoplastic process', 'Phenotype', 'HP:0002664', (189, 207))	('tumor', 'Disease', (97, 102))	('ectopic expression', 'Var', (10, 28))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
649416	31640802	Although the level of serum cholesterol was found to be related with the occurrence of esophageal fistula, patients with less than 170 mg/dl were 14.7 times more likely to develop arterio-esophageal fistula after chemoradiotherapy than those with high cholesterol; only 48 samples were included in the study.	('develop', 'PosReg', (172, 179))	('arterio-esophageal fistula', 'Disease', 'MESH:D001159', (180, 206))	('cholesterol', 'Chemical', 'MESH:D002784', (252, 263))	('esophageal fistula', 'Disease', 'MESH:D004937', (188, 206))	('high cholesterol', 'Phenotype', 'HP:0003124', (247, 263))	('less than 170 mg/dl', 'Var', (121, 140))	('arterio-esophageal fistula', 'Disease', (180, 206))	('esophageal fistula', 'Disease', 'MESH:D004937', (87, 105))	('cholesterol', 'Chemical', 'MESH:D002784', (28, 39))	('esophageal fistula', 'Disease', (87, 105))	('patients', 'Species', '9606', (107, 115))
649434	30836148	PEP is the direct phospho-donor to poHis58-FAK within a known "HG" motif for histidine phosphorylation.	('poHis58', 'Chemical', '-', (35, 42))	('poHis58-FAK', 'Var', (35, 46))	('histidine', 'Chemical', 'MESH:D006639', (77, 86))	('PEP', 'Gene', (0, 3))	('donor', 'Species', '9606', (26, 31))	('PEP', 'Chemical', 'MESH:D010728', (0, 3))
649447	30836148	In addition, ESCCs exhibit high frequencies of genomic amplifications of the oncogenic drivers, CCND1, SOX2, and TP63, which are also associated with enhanced glycolysis and ESCC progression.	('SOX2', 'Gene', (103, 107))	('enhanced', 'PosReg', (150, 158))	('CCND1', 'Gene', '595', (96, 101))	('TP63', 'Gene', (113, 117))	('genomic amplifications', 'Var', (47, 69))	('TP63', 'Gene', '8626', (113, 117))	('ESCC', 'Disease', (174, 178))	('glycolysis', 'MPA', (159, 169))	('CCND1', 'Gene', (96, 101))	('SOX2', 'Gene', '6657', (103, 107))
649482	30836148	2-NBDG, a cell-permeable glucose analog that cannot be metabolized via glycolysis, did not induce DNA synthesis in ESCC, whereas glucose did (Figure 3A).	('DNA synthesis', 'MPA', (98, 111))	('glucose', 'Chemical', 'MESH:D005947', (129, 136))	('2-NBDG', 'Chemical', 'MESH:C098340', (0, 6))	('glucose', 'Chemical', 'MESH:D005947', (25, 32))	('2-NBDG', 'Var', (0, 6))
649501	30836148	Thus, we treated KYSE70 with increasing concentrations of exogenous PEP in serum-free conditions and showed that PEP induces DNA synthesis (BrdU incorporation over controls) at a median effective concentration of 6 mumol/L but no change in viability (WST1) (Figure 4B).	('BrdU', 'Chemical', 'MESH:D001973', (140, 144))	('PEP', 'Chemical', 'MESH:D010728', (68, 71))	('induces', 'Reg', (117, 124))	('PEP', 'Chemical', 'MESH:D010728', (113, 116))	('PEP', 'Var', (113, 116))	('DNA synthesis', 'MPA', (125, 138))
649509	30836148	In addition, treatment of ESCC cells, KYSE70 and TE9, with PEP mimicked the ability of glucose to induce the poHis-FAK band (Figure 4H).	('glucose', 'Chemical', 'MESH:D005947', (87, 94))	('poHis-FAK', 'MPA', (109, 118))	('poHis', 'Chemical', 'MESH:C005436', (109, 114))	('KYSE70', 'Var', (38, 44))	('PEP', 'Gene', (59, 62))	('PEP', 'Chemical', 'MESH:D010728', (59, 62))
649510	30836148	These results indicate that glucose or PEP likely induces FAK poHis.	('FAK poHis', 'Disease', (58, 67))	('PEP', 'Chemical', 'MESH:D010728', (39, 42))	('poHis', 'Chemical', 'MESH:C005436', (62, 67))	('PEP', 'Var', (39, 42))	('glucose', 'Chemical', 'MESH:D005947', (28, 35))	('induces', 'Reg', (50, 57))
649512	30836148	First, PEP, but not ATP or pyruvate, induced histidine phosphorylation of recombinant FAK (Figure 5A).	('pyruvate', 'Chemical', 'MESH:D019289', (27, 35))	('induced', 'Reg', (37, 44))	('histidine phosphorylation', 'MPA', (45, 70))	('ATP', 'Chemical', 'MESH:D000255', (20, 23))	('PEP', 'Chemical', 'MESH:D010728', (7, 10))	('histidine', 'Chemical', 'MESH:D006639', (45, 54))	('PEP', 'Var', (7, 10))
649531	30836148	Indeed, the relative glucose-induced poHis level of ectopically expressed FAKH58A was significantly lower than that of WT-FAK in KYSE70 cells (Figure 6G).	('poHis', 'Chemical', 'MESH:C005436', (37, 42))	('FAKH58A', 'Chemical', '-', (74, 81))	('lower', 'NegReg', (100, 105))	('FAKH58A', 'Var', (74, 81))	('glucose', 'Chemical', 'MESH:D005947', (21, 28))	('glucose-induced poHis level', 'MPA', (21, 48))
649532	30836148	We noted that KYSE70 cells stably expressing FAKH58A exhibited decreased glucose consumption and altered cell morphology (small and round shape), compared with those expressing WT-FAK (Figure 6H and I).	('FAKH58A', 'Var', (45, 52))	('altered', 'Reg', (97, 104))	('decreased glucose consumption', 'Disease', (63, 92))	('FAKH58A', 'Chemical', '-', (45, 52))	('decreased glucose consumption', 'Disease', 'MESH:D014397', (63, 92))
649533	30836148	Glucose consumption was decreased in FAK KO SCC cells re-expressing FAKH58A, indicating that H58A inhibition of poHis-FAK signaling decreased utilization of glucose for biomass synthesis (Figure 6H).	('decreased', 'NegReg', (24, 33))	('Glucose consumption', 'Disease', (0, 19))	('H58A', 'SUBSTITUTION', 'None', (71, 75))	('poHis', 'Chemical', 'MESH:C005436', (112, 117))	('H58A', 'Var', (71, 75))	('FAKH58A', 'Chemical', '-', (68, 75))	('Glucose consumption', 'Disease', 'MESH:D014397', (0, 19))	('decreased', 'NegReg', (132, 141))	('utilization of glucose for biomass synthesis', 'MPA', (142, 186))	('glucose', 'Chemical', 'MESH:D005947', (157, 164))	('H58A', 'SUBSTITUTION', 'None', (93, 97))	('H58A', 'Var', (93, 97))
649534	30836148	Furthermore, individual KYSE70-[FAKH58A] clones showed a correlation between FAKH58A expression levels and decreased proliferation (Figure 6J).	('FAKH58A', 'Gene', (77, 84))	('expression levels', 'MPA', (85, 102))	('proliferation', 'CPA', (117, 130))	('KYSE70-[', 'Var', (24, 32))	('decreased', 'NegReg', (107, 116))	('FAKH58A', 'Chemical', '-', (32, 39))	('FAKH58A', 'Chemical', '-', (77, 84))
649537	30836148	To determine whether poY397 is required for glucose-induced poHis58, we mutated Y397 to F397 to prevent Y397 phosphorylation.	('Y397', 'Var', (80, 84))	('mutated Y397', 'Var', (72, 84))	('prevent', 'NegReg', (96, 103))	('glucose', 'Chemical', 'MESH:D005947', (44, 51))	('poY397', 'Chemical', '-', (21, 27))	('poHis58', 'Chemical', '-', (60, 67))	('Y397 phosphorylation', 'MPA', (104, 124))
649538	30836148	The stable expression of FAKY397F did not attenuate glucose-increased poHis-FAK levels in KYSE70 cells (Figure 7A).	('glucose-increased poHis-FAK levels', 'MPA', (52, 86))	('glucose', 'Chemical', 'MESH:D005947', (52, 59))	('attenuate', 'NegReg', (42, 51))	('FAKY397F', 'Var', (25, 33))	('poHis', 'Chemical', 'MESH:C005436', (70, 75))
649541	30836148	Moreover, FAKY397F attenuated growth factor-induced but not glucose-induced proliferation (Figure 7C).	('growth factor-induced', 'CPA', (30, 51))	('glucose', 'Chemical', 'MESH:D005947', (60, 67))	('glucose-induced proliferation', 'CPA', (60, 89))	('FAKY397F', 'Var', (10, 18))	('attenuated', 'NegReg', (19, 29))
649542	30836148	Furthermore, loss of kinase activity (FAK454R, kinase dead) only slightly attenuated the ability of FAKHis58E-454R to induce proliferation in the absence of glucose (Figure 7D).	('FAKHis58E-454R', 'Var', (100, 114))	('proliferation', 'CPA', (125, 138))	('glucose', 'Chemical', 'MESH:D005947', (157, 164))	('loss', 'NegReg', (13, 17))	('induce', 'PosReg', (118, 124))	('attenuated', 'NegReg', (74, 84))	('kinase activity', 'MPA', (21, 36))
649543	30836148	These data indicate that poHis58-FAK promotes glucose-stimulated proliferation independent of poY397-mediated FAK kinase activity.	('poHis58-FAK', 'Var', (25, 36))	('mul', 'Gene', (57, 60))	('poHis58', 'Chemical', '-', (25, 32))	('glucose', 'Chemical', 'MESH:D005947', (46, 53))	('poY397', 'Chemical', '-', (94, 100))	('mul', 'Gene', '4591', (57, 60))	('promotes', 'PosReg', (37, 45))
649547	30836148	In addition, there was also an increase in the relative phospho-levels of FGFR1, EGFR, and FAKpoY925, the latter a known Src phosphorylation site, and corresponding to a small increase in relative SrcpoY418 levels (Table 1).	('Src', 'Gene', (197, 200))	('Src', 'Gene', '6714', (197, 200))	('Src', 'Gene', '6714', (121, 124))	('increase', 'PosReg', (176, 184))	('FGFR1', 'Gene', '2260', (74, 79))	('EGFR', 'Gene', '1956', (81, 85))	('FAKpoY925', 'Var', (91, 100))	('phospho-levels', 'MPA', (56, 70))	('Src', 'Gene', (121, 124))	('SrcpoY418', 'Chemical', '-', (197, 206))	('increase', 'PosReg', (31, 39))	('FGFR1', 'Gene', (74, 79))	('EGFR', 'Gene', (81, 85))
649550	30836148	Indeed, glucose could induce poHis-FAK and poAKT increases in a dose-dependent manner in KYSE70 (ESCC) (Figure 9A) but not in FLO1 (EAC) cells (Figure 9B) under serum-free conditions.	('poHis-FAK', 'CPA', (29, 38))	('poHis', 'Chemical', 'MESH:C005436', (29, 34))	('AKT', 'Gene', (45, 48))	('glucose', 'Chemical', 'MESH:D005947', (8, 15))	('KYSE70', 'Var', (89, 95))	('increases', 'PosReg', (49, 58))	('EAC', 'Chemical', '-', (132, 135))	('FLO1', 'Chemical', '-', (126, 130))	('AKT', 'Gene', '207', (45, 48))
649552	30836148	In addition, inhibition of PI3K or AKT by wortmannin or AZD5363, respectively, decreased serum- or glucose-stimulated proliferation (Figure 9E).	('decreased serum- or glucose', 'Phenotype', 'HP:0011972', (79, 106))	('AZD5363', 'Chemical', 'MESH:C575618', (56, 63))	('AKT', 'Gene', (35, 38))	('decreased', 'NegReg', (79, 88))	('AZD5363', 'Var', (56, 63))	('mul', 'Gene', '4591', (110, 113))	('wortmannin', 'Chemical', 'MESH:D000077191', (42, 52))	('mul', 'Gene', (110, 113))	('glucose', 'Chemical', 'MESH:D005947', (99, 106))	('inhibition', 'NegReg', (13, 23))	('PI3K', 'Pathway', (27, 31))	('AKT', 'Gene', '207', (35, 38))
649553	30836148	In contrast, the MEK1 inhibitor, PD98059, did not impact FBS- or glucose-induced proliferation (Figure 9E).	('glucose-induced proliferation', 'CPA', (65, 94))	('MEK1', 'Gene', '5604', (17, 21))	('PD98059', 'Chemical', 'MESH:C093973', (33, 40))	('FBS', 'Disease', 'MESH:D005198', (57, 60))	('MEK1', 'Gene', (17, 21))	('FBS', 'Disease', (57, 60))	('PD98059', 'Var', (33, 40))	('glucose', 'Chemical', 'MESH:D005947', (65, 72))
649556	30836148	To determine whether poHis58-FAK plays a role in ESCC tumor progression in vivo, under conditions that combine glucose and growth factor stimulation, SCID mice were injected subcutaneously with KYSE70 cells stably expressing either WT- or H58A-FAK.	('mul', 'Gene', '4591', (140, 143))	('H58A', 'Var', (239, 243))	('mul', 'Gene', (140, 143))	('glucose', 'Chemical', 'MESH:D005947', (111, 118))	('H58A', 'SUBSTITUTION', 'None', (239, 243))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('SCID', 'Disease', 'MESH:D053632', (150, 154))	('SCID', 'Disease', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mice', 'Species', '10090', (155, 159))	('ESCC', 'Disease', (49, 53))	('tumor', 'Disease', (54, 59))	('poHis58', 'Chemical', '-', (21, 28))
649557	30836148	KYSE70-[FAKH58A] tumors grew slower than those expressing WT-FAK (Figure 10A), producing smaller tumors (Figure 10B and C).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (97, 103))	('FAKH58A', 'Chemical', '-', (8, 15))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('KYSE70-[FAKH58A', 'Var', (0, 15))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('smaller', 'NegReg', (89, 96))
649558	30836148	Importantly, the KYSE70-[FAKH58A] tumors had lower relative poHis-FAK and poAKT levels compared with those in KYSE70-[WT-FAK] tumors (Figure 10D), strongly suggesting that loss of poHis58-FAK inhibits ESCC tumor growth by attenuating PI3K/AKT signaling.	('AKT', 'Gene', '207', (76, 79))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('poHis58', 'Chemical', '-', (180, 187))	('lower', 'NegReg', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ESCC', 'Disease', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Disease', (126, 132))	('tumor', 'Disease', (34, 39))	('poHis', 'Chemical', 'MESH:C005436', (60, 65))	('AKT', 'Gene', '207', (239, 242))	('attenuating', 'NegReg', (222, 233))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('loss', 'Var', (172, 176))	('FAKH58A', 'Chemical', '-', (25, 32))	('AKT', 'Gene', (76, 79))	('poHis58-FAK', 'Var', (180, 191))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (126, 131))	('inhibits', 'NegReg', (192, 200))	('tumors', 'Disease', (34, 40))	('tumor', 'Disease', (206, 211))	('KYSE70-[FAKH58A]', 'Var', (17, 33))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('AKT', 'Gene', (239, 242))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('poHis', 'Chemical', 'MESH:C005436', (180, 185))
649561	30836148	The proliferation of most normal cell types ceases on removal of growth factors, yet many tumors have developed GFIP through the induction of autocrine pathways stimulated by pro-oncogenic mutations.	('mul', 'Gene', '4591', (164, 167))	('mul', 'Gene', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('autocrine pathways', 'Pathway', (142, 160))	('mutations', 'Var', (189, 198))
649566	30836148	Our studies demonstrate that glycolytic PEP modification of FAK on His58 contributes to glucose-dependent growth of ESCC cells.	('PEP', 'Chemical', 'MESH:D010728', (40, 43))	('His58', 'Var', (67, 72))	('His58', 'Chemical', '-', (67, 72))	('glucose', 'Chemical', 'MESH:D005947', (88, 95))	('contributes', 'Reg', (73, 84))	('glucose-dependent growth', 'CPA', (88, 112))	('glycolytic PEP', 'MPA', (29, 43))
649571	30836148	Our data demonstrate that PEP elevation in ESCC cells stimulates DNA synthesis and induces poHis58-FAK.	('mul', 'Gene', (57, 60))	('PEP', 'Gene', (26, 29))	('PEP', 'Chemical', 'MESH:D010728', (26, 29))	('elevation', 'Var', (30, 39))	('poHis58-FAK', 'Disease', (91, 102))	('poHis58', 'Chemical', '-', (91, 98))	('induces', 'Reg', (83, 90))	('DNA synthesis', 'MPA', (65, 78))	('mul', 'Gene', '4591', (57, 60))
649574	30836148	Mutation of the Y397-FAK autophosphorylation site did not alter glucose-induced poHis and did not reduce glucose-induced proliferation but did inhibit growth factor-dependent proliferation.	('poHis', 'Chemical', 'MESH:C005436', (80, 85))	('growth factor-dependent proliferation', 'CPA', (151, 188))	('Y397-FAK', 'Var', (16, 24))	('glucose-induced poHis', 'CPA', (64, 85))	('glucose', 'Chemical', 'MESH:D005947', (105, 112))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('inhibit', 'NegReg', (143, 150))
649577	30836148	We have shown that induction of poHis FAK results in PI3K/AKT activation.	('poHis', 'Chemical', 'MESH:C005436', (32, 37))	('poHis', 'Var', (32, 37))	('AKT', 'Gene', '207', (58, 61))	('activation', 'PosReg', (62, 72))	('AKT', 'Gene', (58, 61))
649592	30836148	Moreover, these inhibitors are likely aimed to patients where the target pathway is activated by mutation and/or gene amplification.	('gene amplification', 'Var', (113, 131))	('activated', 'PosReg', (84, 93))	('patients', 'Species', '9606', (47, 55))	('mutation', 'Var', (97, 105))
649595	30836148	Although these FAK kinase inhibitors (GSK2256098 or VS-6063 also known as defactinib or PF-045548778) greatly decreased poY397 levels to ~80% from baseline, minor responses or disease stabilization were observed in only 13%-33% of patients with advanced solid tumors including esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (277, 294))	('PF-045548778', 'Var', (88, 100))	('GSK2256098', 'Chemical', 'MESH:C000600809', (38, 48))	('patients', 'Species', '9606', (231, 239))	('poY397', 'Chemical', '-', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('VS-6063', 'Var', (52, 59))	('solid tumors', 'Disease', (254, 266))	('decreased', 'NegReg', (110, 119))	('defactinib', 'Chemical', 'MESH:C584510', (74, 84))	('poY397 levels', 'MPA', (120, 133))	('esophageal cancer', 'Disease', (277, 294))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('GSK2256098', 'Var', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('solid tumors', 'Disease', 'MESH:D009369', (254, 266))
649614	30836148	Receptor tyrosine kinase inhibitors, BMS-754807, BIBW2992, Ponatinib, and Dasatinib, were purchased from Selleck Chemicals (Houston, TX).	('Dasatinib', 'Chemical', 'MESH:D000069439', (74, 83))	('BMS-754807', 'Var', (37, 47))	('Ponatinib', 'Chemical', 'MESH:C545373', (59, 68))	('BIBW2992', 'Gene', (49, 57))	('Receptor tyrosine kinase', 'Gene', (0, 24))	('Receptor tyrosine kinase', 'Gene', '5979', (0, 24))
649632	30836148	Mutagenesis primers for H58A were the following: forward, 5'-C AGT ATT ATC AGG GCA GGA GAT GCT ACT GAT G and reverse, 5'-C ATC AGT AGC ATC TCC TGC CCT GAT AAT ACT G; for H58E: forward, 5'-C AGT ATT ATC AGG GAG GGA GAT GCT ACT GAT G and reverse, 5'-C ATC AGT AGC ATC TCC CTC CCT GAT AAT ACT G (the underlined triplets are those that are mutated).	('H58A', 'Var', (24, 28))	('H58E', 'SUBSTITUTION', 'None', (170, 174))	('H58E', 'Var', (170, 174))	('H58A', 'SUBSTITUTION', 'None', (24, 28))
649680	30836148	KYSE70 cells (1.5 x 106 cells, 100 muL/mouse) expressing the GFP-FAK-WT or GFP-FAK-H58A gene were mixed with 50% Matrigel Matrix (Fisher Scientific, Corning #356234) and injected into the right (H58A) and left (WT) axilla of 6-week-old female SCID mice (obtained from Roswell Park Comprehensive Cancer Center), respectively.	('SCID', 'Disease', 'MESH:D053632', (243, 247))	('SCID', 'Disease', (243, 247))	('Roswell Park Comprehensive Cancer', 'Disease', (268, 301))	('Cancer', 'Phenotype', 'HP:0002664', (295, 301))	('H58A', 'Var', (195, 199))	('mice', 'Species', '10090', (248, 252))	('H58A', 'Var', (83, 87))	('H58A', 'SUBSTITUTION', 'None', (195, 199))	('H58A', 'SUBSTITUTION', 'None', (83, 87))	('mouse', 'Species', '10090', (39, 44))	('Roswell Park Comprehensive Cancer', 'Disease', 'MESH:D013341', (268, 301))
649724	30899637	Functionalized GNRs were used in order to actively enhance specific tumor targeting efficiency rather than relying exclusively on the preferential passive accumulation of nanoparticles in tumors as a result of EPR.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (188, 193))	('EPR', 'Var', (210, 213))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('enhance', 'PosReg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('GNR', 'Chemical', '-', (15, 18))
649754	30899637	to demonstrate an over-expression of EGFR, which naturally became the source of targeting esophageal tumors by conjugating anti-EGFR-antibodies onto our GNRs.	('esophageal tumors', 'Phenotype', 'HP:0100751', (90, 107))	('GNR', 'Chemical', '-', (153, 156))	('anti-EGFR-antibodies', 'Var', (123, 143))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('over-expression', 'PosReg', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('esophageal tumor', 'Disease', 'MESH:D004938', (90, 106))	('esophageal tumor', 'Disease', (90, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('EGFR', 'Gene', (37, 41))	('esophageal tumor', 'Phenotype', 'HP:0100751', (90, 106))	('tumors', 'Disease', (101, 107))
649815	30899637	Thus this provided conclusive evidence that anti-EGFR-antibody-GNRs injected intratumorally became endocytosed within cancer cells, where they were optimally poised for subsequent PTT.	('cancer', 'Disease', (118, 124))	('anti-EGFR-antibody-GNRs', 'Var', (44, 67))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('endocytosed', 'MPA', (99, 110))	('GNR', 'Chemical', '-', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('PTT', 'Chemical', '-', (180, 183))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
649823	30899637	Intravenously administered GNRs resulted in a higher accumulation of Au in all studied organs compared to IT delivery, except within the tumor itself.	('accumulation', 'MPA', (53, 65))	('tumor', 'Disease', (137, 142))	('GNRs', 'Var', (27, 31))	('GNR', 'Chemical', '-', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('IT', 'Chemical', '-', (106, 108))	('Au', 'Chemical', 'MESH:D006046', (69, 71))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
649838	30899637	Blood tests carried out on mice receiving PTT with both IV and IT routes of administration did not demonstrate any hematological or biochemical deviations from normal parameters occurring as a consequence of GNRs or PTT at the end of the study (see Supplementary Tab.	('GNRs', 'Var', (208, 212))	('GNR', 'Chemical', '-', (208, 211))	('mice', 'Species', '10090', (27, 31))	('PTT', 'Chemical', '-', (216, 219))	('PTT', 'Chemical', '-', (42, 45))	('IT', 'Chemical', '-', (63, 65))	('PTT', 'Var', (216, 219))
649865	30899637	Controversy exists regarding the superiority of PTT over photodynamic therapy (PDT) with regards to their respective efficacies in ablating esophageal tumor in several in vitro as well as pre-clinical in vivo experiments.	('PTT', 'Var', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('esophageal tumor', 'Disease', 'MESH:D004938', (140, 156))	('esophageal tumor', 'Disease', (140, 156))	('esophageal tumor', 'Phenotype', 'HP:0100751', (140, 156))	('PTT', 'Chemical', '-', (48, 51))
649954	30706229	Patients with resectable AEG, clinical stage T1, N1-3 or T2-4a, or N0-3 received neoadjuvant treatment.	('T2-4a', 'Var', (57, 62))	('AEG', 'Disease', (25, 28))	('Patients', 'Species', '9606', (0, 8))	('N1-3', 'Var', (49, 53))	('AEG', 'Chemical', '-', (25, 28))
649972	30706229	The Kaplan-Meier survival analysis showed that high MCV, MCH, and MCHC all were associated with poor OS and DFS for all the patients (all P < 0.001) (Fig.	('MCHC', 'Phenotype', 'HP:0025548', (66, 70))	('MCH', 'Gene', (57, 60))	('poor OS', 'Disease', (96, 103))	('high', 'Var', (47, 51))	('MCV', 'Gene', (52, 55))	('DFS', 'Disease', (108, 111))	('MCHC', 'Gene', (66, 70))	('patients', 'Species', '9606', (124, 132))
650011	23894660	IBTs were defined as regimens that included interferon- alfa, pegylated interferon- alfa -2a, or pegylated interferon- alfa -2b for at least 3 months.	('interferon', 'Gene', (72, 82))	('interferon', 'Gene', (107, 117))	('interferon', 'Gene', '3439', (44, 54))	('interferon', 'Gene', '3439', (107, 117))	('interferon', 'Gene', (44, 54))	('interferon', 'Gene', '3439', (72, 82))	('IBT', 'Chemical', '-', (0, 3))	('pegylated', 'Var', (97, 106))
650013	23894660	The 8-year incidence rate for HCC was 3.9% among patients who received IBT and 5.6% among those who did not.	('HCC', 'Disease', (30, 33))	('IBT', 'Chemical', '-', (71, 74))	('HCC', 'Phenotype', 'HP:0001402', (30, 33))	('IBT', 'Var', (71, 74))	('patients', 'Species', '9606', (49, 57))
650015	23894660	Similarly, the event-free survival rates for esophageal variceal bleeding (adjusted HR, 0.45; 95% CI, 0.22-0.91; P = .026), hepatic encephalopathy (adjusted HR, 0.38; 95% CI, 0.21-0.69; P = .001), ascites (adjusted HR, 0.28; 95% CI, 0.14-0.57; P<.001), and cirrhosis (adjusted HR, 0.63; 95% CI, 0.44-0.91; P = .013) were significantly higher among patients who received IBT than those who did not, after adjustment for associated factors.	('patients', 'Species', '9606', (348, 356))	('IBT', 'Var', (370, 373))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (124, 146))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (124, 146))	('hepatic encephalopathy', 'Disease', (124, 146))	('cirrhosis', 'Disease', (257, 266))	('higher', 'PosReg', (335, 341))	('esophageal variceal bleeding', 'Disease', (45, 73))	('ascites', 'Disease', 'MESH:D001201', (197, 204))	('encephalopathy', 'Phenotype', 'HP:0001298', (132, 146))	('esophageal variceal bleeding', 'Phenotype', 'HP:0002040', (45, 73))	('ascites', 'Phenotype', 'HP:0001541', (197, 204))	('cirrhosis', 'Phenotype', 'HP:0001394', (257, 266))	('cirrhosis', 'Disease', 'MESH:D005355', (257, 266))	('IBT', 'Chemical', '-', (370, 373))	('esophageal variceal bleeding', 'Disease', 'MESH:D004932', (45, 73))	('ascites', 'Disease', (197, 204))
650038	23894660	IBT was identified by drug codes for interferon alfa, pegylated interferon alfa-2a, pegylated interferon alfa-2b with or without ribavirin (Table S2).	('pegylated', 'Var', (54, 63))	('interferon', 'Gene', (94, 104))	('interferon', 'Gene', '3439', (64, 74))	('interferon', 'Gene', (37, 47))	('ribavirin', 'Chemical', 'MESH:D012254', (129, 138))	('interferon', 'Gene', '3439', (94, 104))	('interferon', 'Gene', (64, 74))	('IBT', 'Chemical', '-', (0, 3))	('interferon', 'Gene', '3439', (37, 47))
650061	23894660	The overall person-years of follow-up for different clinical outcomes-HCC, esophageal varices bleeding, hepatic encephalopathy, ascites, cirrhosis, and "any cirrhosis complication" were 48217.4, 52671.4, 52294.0, 51635.9, 41724.7, and 49754.4, respectively.	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (104, 126))	('esophageal varices bleeding', 'Disease', 'MESH:D004932', (75, 102))	('outcomes-HCC', 'Disease', (61, 73))	('cirrhosis complication', 'Disease', 'MESH:D008103', (157, 179))	('51635.9', 'Var', (213, 220))	('cirrhosis', 'Disease', 'MESH:D005355', (157, 166))	('52671.4', 'Var', (195, 202))	('esophageal varices bleeding', 'Disease', (75, 102))	('cirrhosis', 'Phenotype', 'HP:0001394', (157, 166))	('41724.7', 'Var', (222, 229))	('cirrhosis', 'Disease', (157, 166))	('52294.0', 'Var', (204, 211))	('ascites', 'Disease', (128, 135))	('HCC', 'Phenotype', 'HP:0001402', (70, 73))	('cirrhosis', 'Disease', 'MESH:D005355', (137, 146))	('esophageal varices', 'Phenotype', 'HP:0002040', (75, 93))	('cirrhosis complication', 'Disease', (157, 179))	('ascites', 'Disease', 'MESH:D001201', (128, 135))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (104, 126))	('cirrhosis', 'Phenotype', 'HP:0001394', (137, 146))	('hepatic encephalopathy', 'Disease', (104, 126))	('encephalopathy', 'Phenotype', 'HP:0001298', (112, 126))	('person', 'Species', '9606', (12, 18))	('cirrhosis', 'Disease', (137, 146))	('ascites', 'Phenotype', 'HP:0001541', (128, 135))
650091	23894660	Similarly, IBT was associated with a 55%, 62%, 72%, 37%, and 65% reduction of risk for esophageal varices bleeding, hepatic encephalopathy, ascites, cirrhosis, and any cirrhosis-associated complication, respectively, after adjustment for prognostic factors.	('ascites', 'Disease', (140, 147))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (116, 138))	('cirrhosis', 'Phenotype', 'HP:0001394', (168, 177))	('hepatic encephalopathy', 'Disease', (116, 138))	('cirrhosis', 'Disease', 'MESH:D005355', (149, 158))	('cirrhosis', 'Disease', (168, 177))	('ascites', 'Disease', 'MESH:D001201', (140, 147))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (116, 138))	('IBT', 'Chemical', '-', (11, 14))	('reduction', 'NegReg', (65, 74))	('cirrhosis', 'Phenotype', 'HP:0001394', (149, 158))	('IBT', 'Var', (11, 14))	('encephalopathy', 'Phenotype', 'HP:0001298', (124, 138))	('ascites', 'Phenotype', 'HP:0001541', (140, 147))	('cirrhosis', 'Disease', (149, 158))	('esophageal varices bleeding', 'Disease', 'MESH:D004932', (87, 114))	('esophageal varices bleeding', 'Disease', (87, 114))	('cirrhosis', 'Disease', 'MESH:D005355', (168, 177))	('esophageal varices', 'Phenotype', 'HP:0002040', (87, 105))
650115	23894660	In conclusion, our nationwide long-term cohort study demonstrated that IBT was associated with a 50% reduction of risk of HCC and 37% to 72% reductions of risk for complications of cirrhosis in chronic hepatitis C patients, independent of other confounders.	('hepatitis', 'Phenotype', 'HP:0012115', (202, 211))	('reductions', 'NegReg', (141, 151))	('reduction', 'NegReg', (101, 110))	('patients', 'Species', '9606', (214, 222))	('cirrhosis in chronic hepatitis C', 'Disease', (181, 213))	('cirrhosis', 'Phenotype', 'HP:0001394', (181, 190))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (194, 211))	('IBT', 'Chemical', '-', (71, 74))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('IBT', 'Var', (71, 74))	('HCC', 'Disease', (122, 125))	('cirrhosis in chronic hepatitis C', 'Disease', 'MESH:D019698', (181, 213))	('complications', 'Disease', (164, 177))
650140	18637088	It describes the common pathway taken by the neoplasms that arise as a result of the progressive accumulation of genetic changes.	('neoplasms', 'Disease', (45, 54))	('neoplasms', 'Phenotype', 'HP:0002664', (45, 54))	('neoplasms', 'Disease', 'MESH:D009369', (45, 54))	('genetic changes', 'Var', (113, 128))
650141	18637088	Mutation of the APC gene, which is common to both inherited and sporadic CRCs, happens early, whereas P53 mutations happen late in the process.	('CRCs', 'Disease', (73, 77))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))	('Mutation', 'Var', (0, 8))	('APC', 'Disease', 'MESH:D011125', (16, 19))	('APC', 'Disease', (16, 19))
650142	18637088	Ras mutations are found in up to 50% of sporadic CRCs, and 50% of colonic adenomas larger than 1 cm.	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('CRCs', 'Disease', (49, 53))	('colonic adenomas', 'Disease', 'MESH:D000236', (66, 82))	('found', 'Reg', (18, 23))	('colonic adenomas', 'Disease', (66, 82))	('mutations', 'Var', (4, 13))	('Ras', 'Gene', (0, 3))
650143	18637088	Familial adnenomatous polyposis (FAP) is a dominantly inherited syndrome caused by a germline mutation in the APC gene.	('FAP', 'Disease', 'MESH:C567782', (33, 36))	('inherited syndrome', 'Disease', (54, 72))	('inherited syndrome', 'Disease', 'None', (54, 72))	('germline mutation', 'Var', (85, 102))	('Familial adnenomatous polyposis', 'Disease', (0, 31))	('FAP', 'Disease', (33, 36))	('APC', 'Disease', 'MESH:D011125', (110, 113))	('caused by', 'Reg', (73, 82))	('APC', 'Disease', (110, 113))	('Familial adnenomatous polyposis', 'Disease', 'MESH:D011125', (0, 31))
650149	18637088	A mutation in any of the four mismatch repair (MMR) genes (MSH2, MLH1, MSH6, and PMS2) is the cause of Lynch syndrome.	('Lynch syndrome', 'Disease', (103, 117))	('MSH6', 'Gene', '2956', (71, 75))	('mutation', 'Var', (2, 10))	('Lynch syndrome', 'Disease', 'MESH:D003123', (103, 117))	('MSH2', 'Gene', (59, 63))	('PMS2', 'Gene', '5395', (81, 85))	('MSH2', 'Gene', '4436', (59, 63))	('MLH1', 'Gene', '4292', (65, 69))	('MSH6', 'Gene', (71, 75))	('MLH1', 'Gene', (65, 69))	('MMR', 'Gene', (47, 50))	('cause', 'Reg', (94, 99))	('PMS2', 'Gene', (81, 85))
650158	18637088	For example, raised or pedunculated polyps are more likely to have mutations in the K-ras gene.	('polyps', 'Disease', (36, 42))	('raised', 'Disease', (13, 19))	('polyps', 'Disease', 'MESH:D011127', (36, 42))	('K-ras', 'Gene', (84, 89))	('K-ras', 'Gene', '3845', (84, 89))	('mutations', 'Var', (67, 76))
650170	18637088	P53 gene mutation is also found in 85-89% in esophageal adenocarcinoma and increases with higher degrees of dysplasia in Barrett's esophagus.	('mutation', 'Var', (9, 17))	('dysplasia', 'Disease', (108, 117))	('dysplasia', 'Disease', 'MESH:D004476', (108, 117))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (121, 140))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (45, 70))	('P53', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('esophageal adenocarcinoma', 'Disease', (45, 70))	("Barrett's esophagus", 'Disease', (121, 140))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (45, 70))	('increases', 'PosReg', (75, 84))
650171	18637088	Although P16 gene mutations are less frequent, there is a high prevalence of hypermethylation in the promoter region of P16 in patients with dysplasia or adenocarcinoma of the esophagus, which also leads to loss of gene transcription and function.	('dysplasia or adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (141, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('loss', 'NegReg', (207, 211))	('P16', 'Gene', (120, 123))	('patients', 'Species', '9606', (127, 135))	('function', 'MPA', (238, 246))	('dysplasia or adenocarcinoma of the esophagus', 'Disease', (141, 185))	('P16', 'Gene', (9, 12))	('hypermethylation', 'Var', (77, 93))	('gene transcription', 'MPA', (215, 233))
650182	18637088	Some pancreatic juice genetic and epigenetic markers that have been looked at include K-ras, P53, and P16 mutations, mitochondrial DNA mutations, and DNA hypermethylation.	('P16', 'Gene', (102, 105))	('K-ras', 'Gene', (86, 91))	('K-ras', 'Gene', '3845', (86, 91))	('pancreatic', 'Disease', 'MESH:D010195', (5, 15))	('pancreatic', 'Disease', (5, 15))	('mutations', 'Var', (106, 115))	('P53', 'Gene', (93, 96))
650183	18637088	Mitochondrial mutations are common in pancreatic cancer, and preliminary results of the use of these as biomarkers of pancreatic cancer in pancreatic juice and urine needs further confirmation.	('pancreatic', 'Disease', 'MESH:D010195', (139, 149))	('pancreatic cancer', 'Disease', (38, 55))	('common', 'Reg', (28, 34))	('pancreatic', 'Disease', 'MESH:D010195', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('pancreatic cancer', 'Disease', 'MESH:D010190', (38, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (38, 55))	('pancreatic', 'Disease', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('pancreatic', 'Disease', (118, 128))	('pancreatic', 'Disease', 'MESH:D010195', (38, 48))	('pancreatic cancer', 'Disease', (118, 135))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('pancreatic', 'Disease', (38, 48))	('Mitochondrial mutations', 'Var', (0, 23))	('mutations', 'Var', (14, 23))
650184	18637088	Another promising diagnostic strategy that will require further investigation is the detection of aberrant gene methylation like P16, cyclin D2, TSLC1, SPARC, and others in the pancreatic juice.	('pancreatic', 'Disease', 'MESH:D010195', (177, 187))	('cyclin D2', 'Gene', '894', (134, 143))	('TSLC1', 'Gene', '23705', (145, 150))	('TSLC1', 'Gene', (145, 150))	('pancreatic', 'Disease', (177, 187))	('SPARC', 'Gene', '6678', (152, 157))	('cyclin D2', 'Gene', (134, 143))	('SPARC', 'Gene', (152, 157))	('aberrant gene methylation', 'Var', (98, 123))	('P16', 'Gene', (129, 132))
650186	18637088	K-ras is readily detected using molecular assays, and mutations in this gene are present in the majority of ductal adenocarcinoma.	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (108, 129))	('mutations', 'Var', (54, 63))	('ductal adenocarcinoma', 'Disease', (108, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('K-ras', 'Gene', (0, 5))	('K-ras', 'Gene', '3845', (0, 5))	('present', 'Reg', (81, 88))
650187	18637088	In fact, it is thought that pancreatic cancers evolve through the sequential appearance of intraepithelial neoplastic lesions (PanINs), which appear to be mediated by the sequential appearance of K-ras mutations, inactivation of P16, followed by inactivation of P53 genes and genes on chromosome 18q called the DPC genes (deleted in pancreatic cancer).	('intraepithelial neoplastic lesions', 'Disease', 'MESH:D002278', (91, 125))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (107, 125))	('inactivation', 'Var', (213, 225))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('K-ras', 'Gene', (196, 201))	('pancreatic cancer', 'Disease', (333, 350))	('intraepithelial neoplastic lesions', 'Disease', (91, 125))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (28, 46))	('pancreatic cancer', 'Disease', 'MESH:D010190', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('pancreatic cancers', 'Disease', (28, 46))	('P16', 'Gene', (229, 232))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (333, 350))	('inactivation', 'Var', (246, 258))	('pancreatic cancers', 'Disease', 'MESH:D010190', (28, 46))	('P53 genes', 'Gene', (262, 271))	('K-ras', 'Gene', '3845', (196, 201))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (28, 45))	('pancreatic cancer', 'Disease', 'MESH:D010190', (333, 350))	('mutations', 'Var', (202, 211))
650188	18637088	Unfortunately, K-ras mutations are not specific for invasive pancreatic cancer and could be found in patients with chronic pancreatitis, in smokers, and in patients with PanINs.	('patients', 'Species', '9606', (156, 164))	('invasive pancreatic cancer', 'Disease', 'MESH:D010190', (52, 78))	('patients', 'Species', '9606', (101, 109))	('pancreatitis', 'Disease', (123, 135))	('invasive pancreatic cancer', 'Disease', (52, 78))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (115, 135))	('found', 'Reg', (92, 97))	('PanINs', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('K-ras', 'Gene', (15, 20))	('K-ras', 'Gene', '3845', (15, 20))	('pancreatitis', 'Phenotype', 'HP:0001733', (123, 135))	('pancreatitis', 'Disease', 'MESH:D010195', (123, 135))	('mutations', 'Var', (21, 30))
650212	32235869	Moreover, inhibition of tumor initiation from cells that have already accumulated transforming mutations could provide a novel method for cancer prevention.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Disease', (138, 144))	('inhibition', 'NegReg', (10, 20))	('tumor initiation', 'Disease', (24, 40))	('tumor initiation', 'Disease', 'MESH:D009369', (24, 40))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
650213	32235869	To achieve this, it is important to fully understand and define the cells of origin for each cancer subtype and determine under which conditions a cell harboring transforming mutations is able to proliferate, invade surrounding tissues, and evade immune surveillance, leading to malignant cancer behavior.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('rat', 'Species', '10116', (203, 206))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('malignant cancer', 'Disease', 'MESH:D009369', (279, 295))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('malignant cancer', 'Disease', (279, 295))	('mutations', 'Var', (175, 184))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('leading to', 'Reg', (268, 278))	('cancer', 'Disease', (289, 295))
650233	32235869	On the other hand, genetic inhibition of the tumor suppressor Patched 1 (PTCH1) using Ptch1+/- mice or expression of mutant GLI family zinc-finger 2 (GLI2, also known as glioma-associated oncogene family zinc-finger 2) using Rosa26-LSL-rtTA; tetO-GLI2DeltaN mice demonstrated a significant contribution of keratin 15 (KRT15), keratin 19 (KRT19) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)-positive hair follicle stem cells in BCC development.	('mice', 'Species', '10090', (95, 99))	('keratin 15', 'Gene', '16665', (306, 316))	('rat', 'Species', '10116', (270, 273))	('BCC development', 'CPA', (453, 468))	('tumor', 'Disease', (45, 50))	('KRT15', 'Gene', '16665', (318, 323))	('PTCH1', 'Gene', (73, 78))	('tet', 'Chemical', 'MESH:C010349', (242, 245))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('Ptch1', 'Gene', '19206', (86, 91))	('keratin 19', 'Gene', '16669', (326, 336))	('Rosa26', 'Gene', '14910', (225, 231))	('GLI2', 'Gene', '14633', (150, 154))	('glioma', 'Disease', (170, 176))	('rat', 'Species', '10116', (308, 311))	('mice', 'Species', '10090', (258, 262))	('KRT19', 'Gene', (338, 343))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('GLI2', 'Gene', (150, 154))	('LGR5', 'Gene', '14160', (410, 414))	('BCC', 'Phenotype', 'HP:0002671', (453, 456))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('keratin 19', 'Gene', (326, 336))	('mutant', 'Var', (117, 123))	('leucine-rich repeat-containing G protein-coupled receptor 5', 'Gene', '14160', (349, 408))	('KRT19', 'Gene', '16669', (338, 343))	('GLI family zinc-finger 2', 'Gene', '14633', (124, 148))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('GLI2', 'Gene', '14633', (247, 251))	('LGR5', 'Gene', (410, 414))	('PTCH1', 'Gene', '19206', (73, 78))	('KRT15', 'Gene', (318, 323))	('rat', 'Species', '10116', (328, 331))	('Rosa26', 'Gene', (225, 231))	('GLI2', 'Gene', (247, 251))	('GLI family zinc-finger 2', 'Gene', (124, 148))	('keratin 15', 'Gene', (306, 316))	('Ptch1', 'Gene', (86, 91))
650237	32235869	Tumorigenesis associated with the cutaneous application of 7,12-dimethylbenzanthracene and 12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA), the most common chemical treatment used to induce SCC in a murine model system, is primarily caused by mutations in Hras.	('7,12-dimethylbenzanthracene', 'Chemical', 'MESH:D015127', (59, 86))	('Hras', 'Gene', (256, 260))	('Tumorigenesis', 'CPA', (0, 13))	('12-O-tetradecanoylphorbol-13-acetate', 'Chemical', 'MESH:D013755', (91, 127))	('DMBA/TPA', 'Chemical', '-', (129, 137))	('murine', 'Species', '10090', (199, 205))	('mutations', 'Var', (243, 252))	('SCC', 'Phenotype', 'HP:0002860', (190, 193))	('caused by', 'Reg', (233, 242))	('Hras', 'Gene', '15461', (256, 260))	('SCC', 'Disease', (190, 193))
650238	32235869	Kras mutations are also induced by this chemical mutagen but at a significantly lower frequency.	('Kras', 'Gene', (0, 4))	('Kras', 'Gene', '16653', (0, 4))	('induced', 'Reg', (24, 31))	('mutations', 'Var', (5, 14))
650241	32235869	In addition, the expression of KrasG12D together with loss of function of the tumor suppressor p53 (oncogenic Ras/p53 combination) significantly accelerates tumor transformation from benign papillomatous tumors to invasive, spindle cell SCCs.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('p53', 'Gene', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('benign papillomatous tumors', 'Disease', (183, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('rat', 'Species', '10116', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('KrasG12D', 'Var', (31, 39))	('SCC', 'Phenotype', 'HP:0002860', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('SCCs', 'Phenotype', 'HP:0002860', (237, 241))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '22059', (114, 117))	('tumor', 'Disease', (78, 83))	('loss of function', 'NegReg', (54, 70))	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('benign papillomatous tumors', 'Disease', 'MESH:D058066', (183, 210))	('tumor', 'Disease', (204, 209))	('p53', 'Gene', '22059', (95, 98))	('accelerates', 'PosReg', (145, 156))	('papilloma', 'Phenotype', 'HP:0012740', (190, 199))
650242	32235869	Intriguingly, upon oncogenic Ras/p53 expression, while Krt5-CreER and Krt14-CreER basal progenitors at the interfollicular epidermis primarily develop into papillomatous tumors, Lgr5-CreER, Krt15-CrePR, and Krt19-CreER hair follicle stem cells develop into invasive, mesenchymal-type SCCs.	('Krt14', 'Gene', (70, 75))	('Krt14', 'Gene', '16664', (70, 75))	('Krt15', 'Gene', (190, 195))	('Krt5', 'Gene', (55, 59))	('SCCs', 'Phenotype', 'HP:0002860', (284, 288))	('papilloma', 'Phenotype', 'HP:0012740', (156, 165))	('Krt19', 'Gene', (207, 212))	('Krt19', 'Gene', '16669', (207, 212))	('p53', 'Gene', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (284, 287))	('Lgr5', 'Gene', '14160', (178, 182))	('Lgr5', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('papillomatous tumors', 'Disease', (156, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('p53', 'Gene', '22059', (33, 36))	('papillomatous tumors', 'Disease', 'MESH:D058066', (156, 176))	('Krt5', 'Gene', '110308', (55, 59))	('Krt15', 'Gene', '16665', (190, 195))	('oncogenic', 'Var', (19, 28))
650246	32235869	Benign nevi may be precursor lesions that can progress to malignant melanocytic tumors when they gain additional mutations or genetic alterations.	('rat', 'Species', '10116', (138, 141))	('malignant melanocytic tumors', 'Disease', 'MESH:D009369', (58, 86))	('nevi', 'Phenotype', 'HP:0003764', (7, 11))	('malignant melanocytic tumor', 'Phenotype', 'HP:0002861', (58, 85))	('malignant melanocytic tumors', 'Disease', (58, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('malignant melanocytic tumors', 'Phenotype', 'HP:0002861', (58, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('gain', 'PosReg', (97, 101))	('mutations', 'Var', (113, 122))	('progress', 'PosReg', (46, 54))	('Benign nevi', 'Disease', (0, 11))	('genetic alterations', 'Var', (126, 145))
650247	32235869	Constitutive activation of the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathways by oncogenic mutations in RAS and rapidly accelerated fibrosarcoma (RAF) genes (e.g., mutant BrafV600E expression) often causes oncogenic senescence in melanocytes.	('RAF', 'Gene', (196, 199))	('causes', 'Reg', (249, 255))	('RAF', 'Gene', '109880', (196, 199))	('rat', 'Species', '10116', (176, 179))	('ERK', 'Gene', (114, 117))	('BrafV600E', 'Gene', (221, 230))	('mutations', 'Var', (141, 150))	('fibrosarcoma', 'Disease', (182, 194))	('ERK', 'Gene', '26413', (114, 117))	('mutant', 'Var', (214, 220))	('activation', 'PosReg', (13, 23))	('oncogenic senescence', 'Disease', (256, 276))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (182, 194))	('fibrosarcoma', 'Disease', 'MESH:D005354', (182, 194))	('RAS', 'Gene', (154, 157))	('extracellular signal-regulated kinase', 'Gene', (75, 112))	('BrafV600E', 'Mutation', 'rs113488022', (221, 230))	('extracellular signal-regulated kinase', 'Gene', '26413', (75, 112))
650249	32235869	The additional genetic alterations help benign melanocytic nevi cells overcome oncogenic senescence to become malignant melanocytic tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('malignant melanocytic tumor', 'Phenotype', 'HP:0002861', (110, 137))	('genetic alterations', 'Var', (15, 34))	('malignant melanocytic tumor', 'Disease', (110, 137))	('rat', 'Species', '10116', (27, 30))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (47, 63))	('nevi', 'Phenotype', 'HP:0003764', (59, 63))	('malignant melanocytic tumor', 'Disease', 'MESH:D009369', (110, 137))
650252	32235869	Recent studies driven by independent groups have experimentally demonstrated that melanoma can directly originate from melanocyte stem cells using Tyr-CreER and c-Kit-CreER promoters.	('rat', 'Species', '10116', (71, 74))	('c-Kit', 'Gene', (161, 166))	('c-Kit', 'Gene', '16590', (161, 166))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('Tyr-CreER', 'Var', (147, 156))
650263	32235869	These studies experimentally demonstrated the importance of extrinsic influences, since tissue injury and/or aberrant stem cell activation can significantly shorten the tumor latency period related to mutant stem cells.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('shorten', 'NegReg', (157, 164))	('rat', 'Species', '10116', (36, 39))	('stem cell activation', 'CPA', (118, 138))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mutant', 'Var', (201, 207))	('tumor', 'Disease', (169, 174))	('aberrant', 'Var', (109, 117))
650268	32235869	Experimentally, we have demonstrated that quiescent follicular melanocyte stem cells are less likely to develop cutaneous melanoma even when they express oncogenic mutations, BrafV600E together with Pten loss of function mutations.	('BrafV600E', 'Mutation', 'rs113488022', (175, 184))	('BrafV600E', 'Var', (175, 184))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('Pten', 'Gene', (199, 203))	('loss of function', 'NegReg', (204, 220))	('Pten', 'Gene', '19211', (199, 203))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('rat', 'Species', '10116', (31, 34))
650272	32235869	Intriguingly, the study found that suppressed tumor formation was dependent on the phosphoinositide 3-kinase-protein kinase B/Akt (PI3K/Akt) pathway, as Pten conditional knockout in tumor-prone, quiescent hair follicle stem cells directly induced SCC formation even during the stem cell quiescent period.	('Pten', 'Gene', (153, 157))	('SCC', 'Phenotype', 'HP:0002860', (247, 250))	('Pten', 'Gene', '19211', (153, 157))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('induced', 'Reg', (239, 246))	('SCC', 'Disease', (247, 250))	('tumor', 'Disease', (46, 51))	('Akt', 'Gene', '11651', (126, 129))	('conditional knockout', 'Var', (158, 178))	('Akt', 'Gene', '11651', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('Akt', 'Gene', (136, 139))	('Akt', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
650276	32235869	It is well known that Cox-2 overexpression can increase tumor growth, decrease apoptosis, and advance progression through mechanisms including immune evasion and increased invasiveness through epithelial-mesenchymal transition (EMT)-like processes.	('invasiveness', 'CPA', (172, 184))	('overexpression', 'Var', (28, 42))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('immune evasion', 'MPA', (143, 157))	('increased', 'PosReg', (162, 171))	('progression', 'CPA', (102, 113))	('tumor', 'Disease', (56, 61))	('Cox-2', 'Gene', '19225', (22, 27))	('apoptosis', 'CPA', (79, 88))	('epithelial-mesenchymal transition', 'CPA', (193, 226))	('Cox-2', 'Gene', (22, 27))	('increase', 'PosReg', (47, 55))	('decrease', 'NegReg', (70, 78))	('advance', 'PosReg', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
650283	32235869	The tumor-promoting role of Cox-2 can partly work through each EP receptor, and inhibition of the receptor pathways has the potential to prevent cutaneous SCCs.	('tumor', 'Disease', (4, 9))	('cutaneous SCCs', 'Disease', (145, 159))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('SCCs', 'Phenotype', 'HP:0002860', (155, 159))	('EP receptor', 'Protein', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('inhibition', 'Var', (80, 90))	('Cox-2', 'Gene', (28, 33))	('Cox-2', 'Gene', '19225', (28, 33))
650288	32235869	Earlier studies demonstrated that Cox-2 inhibitors suppress UV-induced murine SCC formation.	('suppress', 'NegReg', (51, 59))	('murine', 'Species', '10090', (71, 77))	('inhibitors', 'Var', (40, 50))	('rat', 'Species', '10116', (23, 26))	('UV-induced', 'Disease', (60, 70))	('Cox-2', 'Gene', '19225', (34, 39))	('Cox-2', 'Gene', (34, 39))	('SCC', 'Phenotype', 'HP:0002860', (78, 81))
650290	32235869	More recently, Cox-2 knockout in Krt14-Cre+ epidermal basal cells induced a significant reduction in chemical carcinogen-induced tumorigenic potential.	('Cox-2', 'Gene', '19225', (15, 20))	('reduction', 'NegReg', (88, 97))	('Krt14', 'Gene', (33, 38))	('Krt14', 'Gene', '16664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('knockout', 'Var', (21, 29))	('Cox-2', 'Gene', (15, 20))	('tumor', 'Disease', (129, 134))
650291	32235869	Similarly, cell-type-specific Cox-2 knockout in Krt14-Cre+ epidermal basal cells significantly suppressed UV-mediated tumor formation in mouse skin.	('knockout', 'Var', (36, 44))	('suppressed', 'NegReg', (95, 105))	('Krt14', 'Gene', '16664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('mouse', 'Species', '10090', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Cox-2', 'Gene', '19225', (30, 35))	('tumor', 'Disease', (118, 123))	('Cox-2', 'Gene', (30, 35))	('Krt14', 'Gene', (48, 53))
650292	32235869	Using a Cox-2 conditional knockout model (Ptgs2flox/flox) developed by the Herschman group, we have also recently determined the role of cell-type-specific Cox-2 expression in Krt15-CrePR+ tumor-prone hair follicle stem cells expressing KrasG12D together with a p53 loss of function mutation.	('Krt15', 'Gene', (176, 181))	('mutation', 'Var', (283, 291))	('tumor', 'Disease', (189, 194))	('prone hair', 'Phenotype', 'HP:0002299', (195, 205))	('KrasG12D', 'Var', (237, 245))	('Ptgs2', 'Gene', (42, 47))	('p53', 'Gene', (262, 265))	('p53', 'Gene', '22059', (262, 265))	('Cox-2', 'Gene', '19225', (8, 13))	('Cox-2', 'Gene', '19225', (156, 161))	('Ptgs2', 'Gene', '19225', (42, 47))	('Cox-2', 'Gene', (8, 13))	('Krt15', 'Gene', '16665', (176, 181))	('Cox-2', 'Gene', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('loss of function', 'NegReg', (266, 282))
650294	32235869	Additionally, Cox-2 inhibition could have suppressive effects on the development of tumors from mutant hair follicle stem cells, as Akt pathway activation enhances SCC formation.	('Cox-2', 'Gene', (14, 19))	('mutant', 'Var', (96, 102))	('SCC', 'Phenotype', 'HP:0002860', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('activation enhances', 'PosReg', (144, 163))	('Akt', 'Gene', (132, 135))	('inhibition', 'NegReg', (20, 30))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('SCC formation', 'CPA', (164, 177))	('Cox-2', 'Gene', '19225', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('Akt', 'Gene', '11651', (132, 135))
650295	32235869	Intriguingly, genetic inhibition of Cox-2 suppressed tumor development and inhibited EMT-like properties during tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('inhibited', 'NegReg', (75, 84))	('genetic inhibition', 'Var', (14, 32))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('suppressed', 'NegReg', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Cox-2', 'Gene', '19225', (36, 41))	('Cox-2', 'Gene', (36, 41))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (112, 117))
650296	32235869	Oncogenic Ras/p53 expression significantly and directly induces invasive, mesenchymal-like SCC formation from Krt15-positive stem cells, which tend to show loss of epithelial markers (e.g., E-cad) but overexpression of mesenchymal markers (e.g., vimentin and N-cad).	('overexpression', 'PosReg', (201, 215))	('E-cad', 'Gene', (190, 195))	('Krt15', 'Gene', (110, 115))	('N-cad', 'Gene', (259, 264))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '22059', (14, 17))	('loss', 'NegReg', (156, 160))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('vimentin', 'Gene', '22352', (246, 254))	('induces', 'Reg', (56, 63))	('E-cad', 'Gene', '12550', (190, 195))	('vimentin', 'Gene', (246, 254))	('N-cad', 'Gene', '12558', (259, 264))	('Krt15', 'Gene', '16665', (110, 115))	('expression', 'Var', (18, 28))	('epithelial', 'MPA', (164, 174))
650297	32235869	However, the same stem cell populations with a lack of Cox-2 expression tend to form less aggressive or typical epithelial-type SCCs (in contrast to spindle-type SCCs) that are typically well demarcated from the dermis.	('epithelial-type', 'Disease', (112, 127))	('Cox-2', 'Gene', '19225', (55, 60))	('Cox-2', 'Gene', (55, 60))	('lack', 'Var', (47, 51))	('SCCs', 'Phenotype', 'HP:0002860', (128, 132))	('SCCs', 'Phenotype', 'HP:0002860', (162, 166))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))
650299	32235869	In cutaneous melanoma, we have also reported that dexamethasone treatment suppresses UV-induced melanoma formation from mutant, tumor-prone follicular melanocyte stem cells.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('suppresses', 'NegReg', (74, 84))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('tumor', 'Disease', (128, 133))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('dexamethasone', 'Chemical', 'MESH:D003907', (50, 63))	('melanoma', 'Disease', (96, 104))	('mutant', 'Var', (120, 126))
650311	32235869	Oncogenic mutations can induce hyperplastic to papillomatous tumors and SCCs from basal progenitors expressing Krt5, Krt15, p63, and SRY-box2 (Sox-2).	('SRY-box2', 'Gene', (133, 141))	('papilloma', 'Phenotype', 'HP:0012740', (47, 56))	('Sox-2', 'Gene', (143, 148))	('Krt15', 'Gene', '16665', (117, 122))	('SRY-box2', 'Gene', '20674', (133, 141))	('SCCs', 'Phenotype', 'HP:0002860', (72, 76))	('Krt5', 'Gene', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('Krt15', 'Gene', (117, 122))	('induce', 'Reg', (24, 30))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('p63', 'Gene', (124, 127))	('papillomatous tumors', 'Disease', 'MESH:D058066', (47, 67))	('papillomatous tumors', 'Disease', (47, 67))	('Sox-2', 'Gene', '20674', (143, 148))	('p63', 'Gene', '22061', (124, 127))	('SCCs from', 'CPA', (72, 81))	('mutations', 'Var', (10, 19))	('Krt5', 'Gene', '110308', (111, 115))
650321	32235869	Experimental studies consistently demonstrate that Cox-2 inhibition has the potential to suppress esophageal SCC formation.	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('Cox-2', 'Gene', '19225', (51, 56))	('inhibition', 'Var', (57, 67))	('Cox-2', 'Gene', (51, 56))	('esophageal SCC formation', 'Disease', (98, 122))	('rat', 'Species', '10116', (41, 44))	('suppress', 'NegReg', (89, 97))
650324	32235869	Similarly, a diet containing a selective Cox-2 inhibitor, L-748706 (L-706), suppressed NMBA-induced tumor development.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('L-748706', 'CellLine', 'CVCL:0462', (58, 66))	('Cox-2', 'Gene', (41, 46))	('tumor', 'Disease', (100, 105))	('L-706', 'CellLine', 'CVCL:1V41', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('suppressed', 'NegReg', (76, 86))	('NMBA', 'Chemical', 'MESH:C014707', (87, 91))	('L-748706', 'Var', (58, 66))	('Cox-2', 'Gene', '19225', (41, 46))
650325	32235869	In addition, genetic knockdown of Cox-2 in human esophageal SCC cell lines suppressed tumor formation in vivo in xenograft mice.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('suppressed', 'NegReg', (75, 85))	('tumor', 'Disease', (86, 91))	('human', 'Species', '9606', (43, 48))	('Cox-2', 'Gene', '19225', (34, 39))	('knockdown', 'Var', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))	('Cox-2', 'Gene', (34, 39))	('mice', 'Species', '10090', (123, 127))
650331	32235869	However, cell-type-specific knockout of Cox-2 suppresses oncogenic Ras/p53-mediated tumor formation in a genetically engineered mouse model and in 3D organoids.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('suppresses', 'NegReg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Cox-2', 'Gene', '19225', (40, 45))	('p53', 'Gene', (71, 74))	('tumor', 'Disease', (84, 89))	('mouse', 'Species', '10090', (128, 133))	('p53', 'Gene', '22059', (71, 74))	('knockout', 'Var', (28, 36))	('Cox-2', 'Gene', (40, 45))
650334	32235869	Since Cox-2 can be upregulated in response to various extrinsic and intrinsic stress factors, it is important to note that not only mutations but also inflammatory conditions associated with these stress factors (e.g., inflammation induced by individual behaviors such as smoking cigarettes and drinking alcohol) can further accelerate tumor formation from mutant stem/progenitor cells in a Cox-2-dependent manner.	('mutant', 'Var', (357, 363))	('accelerate', 'PosReg', (325, 335))	('inflammation', 'Disease', (219, 231))	('alcohol', 'Chemical', 'MESH:D000438', (304, 311))	('rat', 'Species', '10116', (331, 334))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('inflammation', 'Disease', 'MESH:D007249', (219, 231))	('Cox-2', 'Gene', '19225', (6, 11))	('Cox-2', 'Gene', '19225', (391, 396))	('Cox-2', 'Gene', (391, 396))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (336, 341))	('Cox-2', 'Gene', (6, 11))
650339	32235869	Since bile acid can induce esophagitis in a short timeframe and metaplastic changes in the long term, surgical techniques such as esophagojejunostomy are often used to generate models in both mice and rats.	('induce', 'Reg', (20, 26))	('bile acid', 'Chemical', 'MESH:D001647', (6, 15))	('mice', 'Species', '10090', (192, 196))	('rat', 'Species', '10116', (201, 204))	('esophagitis', 'Phenotype', 'HP:0100633', (27, 38))	('esophagitis', 'Disease', (27, 38))	('metaplastic changes', 'CPA', (64, 83))	('rats', 'Species', '10116', (201, 205))	('rat', 'Species', '10116', (172, 175))	('bile acid', 'Var', (6, 15))	('esophagitis', 'Disease', 'MESH:D004938', (27, 38))
650341	32235869	In the surgery-induced model, pharmacological inhibition of Cox-2 has shown potential to inhibit the carcinogenic effects of GERD.	('Cox-2', 'Gene', '19225', (60, 65))	('pharmacological inhibition', 'Var', (30, 56))	('inhibit', 'NegReg', (89, 96))	('carcinogenic', 'Disease', 'MESH:D063646', (101, 113))	('Cox-2', 'Gene', (60, 65))	('carcinogenic', 'Disease', (101, 113))
650360	32235869	We and others also reported that cell-type-specific Cox-2 knockout in stem/progenitor cells may suppress tumor-promoting inflammation in the niche of cancer cells of origin.	('inflammation', 'Disease', 'MESH:D007249', (121, 133))	('Cox-2', 'Gene', (52, 57))	('inflammation', 'Disease', (121, 133))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Disease', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('knockout', 'Var', (58, 66))	('tumor', 'Disease', (105, 110))	('suppress', 'NegReg', (96, 104))	('Cox-2', 'Gene', '19225', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
650517	31960110	PD-1, TIM-3 and LAG-3 inhibitors are able to enhance the T-cell response to tumor antigens.	('LAG-3', 'Gene', '3902', (16, 21))	('TIM-3', 'Gene', '84868', (6, 11))	('inhibitors', 'Var', (22, 32))	('PD-1', 'Gene', (0, 4))	('enhance', 'PosReg', (45, 52))	('LAG-3', 'Gene', (16, 21))	('PD-1', 'Gene', '5133', (0, 4))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('T-cell response', 'CPA', (57, 72))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('TIM-3', 'Gene', (6, 11))
650518	31960110	Moreover a synergistic function of the above mentioned could enhance the response in combinatorial therapies.	('enhance', 'PosReg', (61, 68))	('synergistic', 'Var', (11, 22))	('response', 'CPA', (73, 81))	('men', 'Species', '9606', (45, 48))
650537	30833958	Results: We identified 84 pathogenic/likely pathogenic mutations and 51 rare variants of uncertain significance (VUS).	('VUS', 'Chemical', '-', (113, 116))	('pathogenic', 'Reg', (44, 54))	('pathogenic/likely', 'Reg', (26, 43))	('mutations', 'Var', (55, 64))
650539	30833958	CYP21A2 was the most frequently mutated gene, and the p.Gln319* variant was identified in 6.5% (5/77) of patients.	('CYP21A2', 'Gene', (0, 7))	('CYP21A2', 'Gene', '1589', (0, 7))	('patients', 'Species', '9606', (105, 113))	('p.Gln319*', 'Mutation', 'p.Q319*', (54, 63))	('p.Gln319*', 'Var', (54, 63))
650540	30833958	The TP53 p.V197E mutation, located within the DNA binding domain, was found in 1.3% (1/77) of patients.	('p.V197E', 'Mutation', 'p.V197E', (9, 16))	('patients', 'Species', '9606', (94, 102))	('TP53', 'Gene', (4, 8))	('p.V197E', 'Var', (9, 16))	('TP53', 'Gene', '7157', (4, 8))
650541	30833958	In total, the 11.7% (9/77) of individuals with homologous recombination (HR) VUS were more likely to have well-differentiated tumors than those without (P = 0.003).	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('VUS', 'Var', (77, 80))	('homologous recombination', 'Var', (47, 71))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('VUS', 'Chemical', '-', (77, 80))
650542	30833958	The degree of lymph node metastasis was correlated with homologous recombination deficiency (HRD) and VUS group (P < 0.05).	('VUS', 'Chemical', '-', (102, 105))	('HRD', 'Disease', (93, 96))	('homologous recombination deficiency', 'Var', (56, 91))	('HRD', 'Disease', 'None', (93, 96))	('lymph node metastasis', 'CPA', (14, 35))
650543	30833958	Moreover, the 10.4% (8/77) of individuals with mismatch repair (MMR) VUS had a higher tumor mutational burden (TMB), although the correlation was not significant.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('VUS', 'Chemical', '-', (69, 72))	('TMB', 'Chemical', '-', (111, 114))	('higher', 'PosReg', (79, 85))	('mismatch repair', 'Var', (47, 62))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
650560	30833958	We integrated all variants of uncertain significance (VUS) from the 77 ESCC cases and determined alterations in the homologous recombination arm of the DNA repair pathway (GO_RECOMBINATIONAL_REPAIR) and the DNA mismatch repair pathway (GO_MISMATCH_REPAIR).	('homologous recombination', 'MPA', (116, 140))	('DNA mismatch repair pathway', 'Pathway', (207, 234))	('alterations', 'Reg', (97, 108))	('ESCC', 'Disease', (71, 75))	('DNA repair pathway', 'Pathway', (152, 170))	('variants', 'Var', (18, 26))	('VUS', 'Chemical', '-', (54, 57))
650561	30833958	Germline alterations in the patients included VUS in HR pathway genes, VUS in MMR pathway genes, rare VUS in SLX4, rare VUS in TSC2, pathogenic mutations in CYP21A2, the rare VUS carrier group and the pathogenic mutation carrier group.	('TSC2', 'Gene', (127, 131))	('VUS', 'Chemical', '-', (46, 49))	('VUS', 'Chemical', '-', (175, 178))	('VUS', 'Chemical', '-', (102, 105))	('VUS', 'Chemical', '-', (120, 123))	('patients', 'Species', '9606', (28, 36))	('SLX4', 'Gene', '84464', (109, 113))	('TSC2', 'Gene', '7249', (127, 131))	('MMR pathway genes', 'Gene', (78, 95))	('SLX4', 'Gene', (109, 113))	('mutations', 'Var', (144, 153))	('VUS', 'Chemical', '-', (71, 74))	('CYP21A2', 'Gene', (157, 164))	('CYP21A2', 'Gene', '1589', (157, 164))
650568	30833958	We identified 84 pathogenic/likely pathogenic mutations in 46 individuals [(59.7%, 46/77):a detection rate of 6.5% (5/77) for CYP21A2 p.Gln319*, 2.6% (2/77) for SPINK1 c.194+2T>C, 2.6% (2/77) for OTOA p.Glu1048*, 2.6% (2/77) for PRAMEF7/8 c.863+1G>T, and 2.6% (2/7) for PRAMEF10/33P c.866+2T>C] (Figure 2).	('PRAMEF10', 'Gene', (270, 278))	('c.863+1G>T', 'Mutation', 'c.863+1G>T', (239, 249))	('pathogenic/likely', 'Reg', (17, 34))	('p.Gln319*', 'Mutation', 'p.Q319*', (134, 143))	('p.Gln319*', 'Var', (134, 143))	('c.866+2T>C', 'Mutation', 'c.866+2T>C', (283, 293))	('OTOA', 'Gene', (196, 200))	('SPINK1', 'Gene', (161, 167))	('OTOA', 'Gene', '146183', (196, 200))	('SPINK1', 'Gene', '6690', (161, 167))	('CYP21A2', 'Gene', (126, 133))	('c.863+1G>T', 'Var', (239, 249))	('pathogenic', 'Reg', (35, 45))	('PRAMEF10', 'Gene', '343071', (270, 278))	('PRAMEF7', 'Gene', (229, 236))	('CYP21A2', 'Gene', '1589', (126, 133))	('PRAMEF7', 'Gene', '441871', (229, 236))	('c.194+2T>C', 'Mutation', 'rs148954387', (168, 178))	('p.Glu1048*', 'Var', (201, 211))	('p.Glu1048*', 'Mutation', 'p.E1048*', (201, 211))
650570	30833958	Pathogenic mutations in CYP21A2 were the most prevalent, while the second most common mutations were in the SPINK1, OTOA, PRAMEF7/8, and PRAMEF10/33P genes.	('OTOA', 'Gene', '146183', (116, 120))	('mutations', 'Var', (11, 20))	('PRAMEF10', 'Gene', (137, 145))	('CYP21A2', 'Gene', (24, 31))	('PRAMEF10', 'Gene', '343071', (137, 145))	('CYP21A2', 'Gene', '1589', (24, 31))	('Pathogenic', 'Reg', (0, 10))	('SPINK1', 'Gene', (108, 114))	('SPINK1', 'Gene', '6690', (108, 114))	('PRAMEF7', 'Gene', '441871', (122, 129))	('PRAMEF7', 'Gene', (122, 129))	('OTOA', 'Gene', (116, 120))
650572	30833958	Rare VUS in SLX4 were the most prevalent, accounting for 7.8% (6/77) of missense mutation carriers.	('SLX4', 'Gene', (12, 16))	('SLX4', 'Gene', '84464', (12, 16))	('missense mutation', 'Var', (72, 89))	('VUS', 'Chemical', '-', (5, 8))
650573	30833958	TSC2 was the second most commonly mutated gene, with a 6.5% (5/77) carrier rate including 3 missense mutations and 2 splice site variants.	('TSC2', 'Gene', '7249', (0, 4))	('TSC2', 'Gene', (0, 4))	('missense mutations', 'Var', (92, 110))
650574	30833958	Two patients in the study cohort were carriers of the MSH3 p.A57_A58delins mutation supporting pathogenicity (PP), which was correlated with hereditary susceptibility to ESCC.	('p.A57_A58del', 'DELETION', 'None', (59, 71))	('MSH3', 'Gene', (54, 58))	('p.A57_A58del', 'Var', (59, 71))	('patients', 'Species', '9606', (4, 12))	('ESCC', 'Disease', (170, 174))
650576	30833958	Among these mutations, the TP53 missense mutation p.V197E, which is located in the DNA binding domain, was deleterious and demonstrated a probable contribution to ESCC progression (Table 4).	('TP53', 'Gene', '7157', (27, 31))	('ESCC', 'Disease', (163, 167))	('TP53', 'Gene', (27, 31))	('p.V197E', 'Var', (50, 57))	('p.V197E', 'Mutation', 'p.V197E', (50, 57))	('contribution', 'Reg', (147, 159))
650580	30833958	Other cancer characteristics did not show statistically significant associations with germline mutation status.	('germline mutation status', 'Var', (86, 110))	('cancer', 'Disease', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))
650582	30833958	Among those patients, the two who were carriers of MSH3 p.A57_A58delinsPP had a much higher TMB (5.82 and 4.47), and one patient who was a carrier of PMS2 p.S587N and p.V302F had a TMB of 6.47.	('p.V302F', 'Var', (167, 174))	('PMS2', 'Gene', (150, 154))	('patients', 'Species', '9606', (12, 20))	('higher', 'PosReg', (85, 91))	('TMB', 'Chemical', '-', (181, 184))	('PMS2', 'Gene', '5395', (150, 154))	('p.V302F', 'Mutation', 'rs755960629', (167, 174))	('TMB', 'MPA', (92, 95))	('MSH3', 'Gene', (51, 55))	('p.A57_A58delinsPP', 'DELETION_INSERTION', 'None', (56, 73))	('patient', 'Species', '9606', (12, 19))	('patient', 'Species', '9606', (121, 128))	('TMB', 'Chemical', '-', (92, 95))	('p.S587N', 'Mutation', 'rs762100304', (155, 162))	('p.A57_A58delinsPP', 'Var', (56, 73))
650585	30833958	We identified 84 pathogenic/likely pathogenic mutations and 51 rare VUS in our study cohort.	('pathogenic/likely', 'Reg', (17, 34))	('VUS', 'Chemical', '-', (68, 71))	('pathogenic', 'Reg', (35, 45))	('mutations', 'Var', (46, 55))
650589	30833958	In our study, the TP53 p.V197E mutation is located within the DNA binding domain and may contribute to ESCC progression, an observation that accounts for the improper DNA binding and disruption of transcriptional activity that was observed.	('TP53', 'Gene', '7157', (18, 22))	('p.V197E', 'Var', (23, 30))	('p.V197E', 'Mutation', 'p.V197E', (23, 30))	('ESCC progression', 'Disease', (103, 119))	('TP53', 'Gene', (18, 22))	('contribute to', 'Reg', (89, 102))
650590	30833958	The TP53 V197E mutant was also found to bind to PBF and promote colorectal tumorigenesis (Read et al.,).	('PBF', 'Gene', '754', (48, 51))	('TP53', 'Gene', (4, 8))	('bind', 'Interaction', (40, 44))	('V197E', 'Var', (9, 14))	('V197E', 'Mutation', 'p.V197E', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('PBF', 'Gene', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('promote', 'PosReg', (56, 63))	('tumor', 'Disease', (75, 80))	('TP53', 'Gene', '7157', (4, 8))
650591	30833958	Individuals carrying germline mutations who smoke cigarettes may be a high-risk population for esophageal cancer (Supplementary Figure 3).	('germline mutations', 'Var', (21, 39))	('esophageal cancer', 'Disease', (95, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
650594	30833958	CYP21A2 p.Gln319* was the most prevalent mutation in our study.	('p.Gln319*', 'Var', (8, 17))	('CYP21A2', 'Gene', '1589', (0, 7))	('CYP21A2', 'Gene', (0, 7))	('p.Gln319*', 'Mutation', 'p.Q319*', (8, 17))
650595	30833958	Steroid 21-hydroxylase deficiency due to CYP21A2 gene mutations, including p.Gln319*, is seen in more than 90% of all congenital adrenal hyperplasia cases (Prado et al.,).	('Steroid', 'Disease', (0, 7))	('CYP21A2', 'Gene', '1589', (41, 48))	('21-hydroxylase deficiency', 'Disease', 'MESH:C535979', (8, 33))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (129, 148))	('CYP21A2', 'Gene', (41, 48))	('p.Gln319*', 'Var', (75, 84))	('p.Gln319*', 'Mutation', 'p.Q319*', (75, 84))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (118, 148))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (118, 148))	('congenital adrenal hyperplasia', 'Disease', (118, 148))	('21-hydroxylase deficiency', 'Disease', (8, 33))
650596	30833958	We hypothesized that CYP21A2 p.Gln319* may affect the metabolism of tobacco and participate in the development of ESCC (Supplementary Figure 3).	('participate', 'Reg', (80, 91))	('ESCC', 'Disease', (114, 118))	('p.Gln319*', 'Mutation', 'p.Q319*', (29, 38))	('tobacco', 'Species', '4097', (68, 75))	('metabolism of tobacco', 'MPA', (54, 75))	('affect', 'Reg', (43, 49))	('p.Gln319*', 'Var', (29, 38))	('CYP21A2', 'Gene', (21, 28))	('CYP21A2', 'Gene', '1589', (21, 28))
650602	30833958	Defects in the homologous recombination (HR) DNA repair pathway sensitize tumors to therapeutics that target this pathway.	('Defects', 'Var', (0, 7))	('HR', 'Gene', (41, 43))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('sensitize', 'Reg', (64, 73))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
650603	30833958	In breast cancer, patients with mutations in the HR pathway are more likely to achieve a pathologic complete response (pCR) than non-deficient patients (Telli et al.,).	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('HR pathway', 'Pathway', (49, 59))	('non-deficient', 'Disease', (129, 142))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('patients', 'Species', '9606', (143, 151))	('non-deficient', 'Disease', 'MESH:C580335', (129, 142))	('mutations', 'Var', (32, 41))	('patients', 'Species', '9606', (18, 26))
650604	30833958	The literature shows that as many as one in four ovarian cancer cases exhibit germline mutations, the majority of which result in HRD (Frey and Pothuri,).	('exhibit', 'Reg', (70, 77))	('HRD', 'Disease', 'None', (130, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('germline mutations', 'Var', (78, 96))	('result in', 'Reg', (120, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('HRD', 'Disease', (130, 133))	('ovarian cancer', 'Disease', (49, 63))
650609	30833958	In our study, we found that individuals who carried MMR VUS have higher TMB than those who did not.	('TMB', 'MPA', (72, 75))	('MMR VUS', 'Var', (52, 59))	('VUS', 'Chemical', '-', (56, 59))	('TMB', 'Chemical', '-', (72, 75))	('higher', 'PosReg', (65, 71))
650610	30833958	E09211 and E12230, who carried MSH3 p.A57_A58delinsPP, had TMB of 5.82 and 4.47, respectively.	('E12230', 'Var', (11, 17))	('p.A57_A58delinsPP', 'DELETION_INSERTION', 'None', (36, 53))	('TMB', 'Chemical', '-', (59, 62))	('p.A57_A58delinsPP', 'Var', (36, 53))	('E09211', 'Var', (0, 6))
650611	30833958	E10308, who carried PMS2 p.S587N and p.V302F, had a TMB of 6.47.	('p.V302F', 'Var', (37, 44))	('PMS2', 'Gene', (20, 24))	('p.V302F', 'Mutation', 'rs755960629', (37, 44))	('PMS2', 'Gene', '5395', (20, 24))	('TMB', 'Chemical', '-', (52, 55))	('E10308', 'Var', (0, 6))	('p.S587N', 'Mutation', 'rs762100304', (25, 32))	('p.S587N', 'Var', (25, 32))
650614	30833958	Our results were consistent with those of previous studies, which demonstrated that loss-of-function mutations in mismatch repair pathway genes correlate with a high TMB (Duval and Hamelin,; Peltomaki,).	('loss-of-function', 'NegReg', (84, 100))	('Peltomaki', 'Disease', (191, 200))	('mutations', 'Var', (101, 110))	('mismatch repair pathway genes', 'Gene', (114, 143))	('TMB', 'MPA', (166, 169))	('TMB', 'Chemical', '-', (166, 169))	('Hamelin', 'Disease', (181, 188))
650666	30684971	The median DFS was 36 months in PD-L1 positive tumor-infiltrating immune cells patients and 34 months in PD-L1 negative patients, respectively.	('PD-L1', 'Gene', (32, 37))	('PD-L1', 'Gene', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('positive', 'Var', (38, 46))	('PD-L1', 'Gene', '29126', (32, 37))	('PD-L1', 'Gene', '29126', (105, 110))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
650667	30684971	The median OS was 53 months in PD-L1 positive tumor-infiltrating immune cells patients and 47 months in PD-L1 negative patients, respectively.	('positive', 'Var', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('OS', 'Chemical', '-', (11, 13))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PD-L1', 'Gene', '29126', (31, 36))	('PD-L1', 'Gene', '29126', (104, 109))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', (46, 51))	('patients', 'Species', '9606', (78, 86))	('PD-L1', 'Gene', (31, 36))	('PD-L1', 'Gene', (104, 109))
650670	30684971	In the current study, we found that 29.9% of T2-T4a ESCC cases were positive for PD-L1 in tumor cells and 40.2% positive in tumor-infiltrating immune cells.	('positive', 'Reg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('T2-T4a', 'Var', (45, 51))	('PD-L1', 'Gene', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (124, 129))	('PD-L1', 'Gene', '29126', (81, 86))	('ESCC', 'Disease', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
650689	30684971	Most of studies found that PD-L1 expression was significantly related with worse overall survival or disease free survival.	('expression', 'Var', (33, 43))	('disease free survival', 'CPA', (101, 122))	('overall survival', 'CPA', (81, 97))	('PD-L1', 'Gene', (27, 32))	('PD-L1', 'Gene', '29126', (27, 32))
650690	30684971	However, a few studies reported that PD-L1 positivity was associated with a favorable prognosis.	('PD-L1', 'Gene', '29126', (37, 42))	('positivity', 'Var', (43, 53))	('PD-L1', 'Gene', (37, 42))
650696	30684971	We analyzed the prognostic relevance of PD-L1 expression in tumor-infiltrating immune cells and showed that the median OS and DFS were longer in patients with PD-L1 expression in tumor-infiltrating immune cells, which was consistent with recent study by Zhang et al..	('patients', 'Species', '9606', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('PD-L1', 'Gene', '29126', (159, 164))	('PD-L1', 'Gene', (40, 45))	('median OS', 'MPA', (112, 121))	('DFS', 'MPA', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('OS', 'Chemical', '-', (119, 121))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('PD-L1', 'Gene', '29126', (40, 45))	('tumor', 'Disease', (60, 65))	('longer', 'PosReg', (135, 141))	('expression', 'Var', (165, 175))	('PD-L1', 'Gene', (159, 164))	('tumor', 'Disease', (179, 184))
650714	30519392	TUG1 confers cisplatin resistance in esophageal squamous cell carcinoma by epigenetically suppressing PDCD4 expression via EZH2 Increasing evidence has suggested the involvement of long non-coding RNA taurine upregulated gene 1 (TUG1) in chemoresistance of cancer treatment.	('si', 'Chemical', 'MESH:D012825', (114, 116))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (37, 71))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('TUG1', 'Gene', '55000', (0, 4))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('TUG1', 'Gene', '55000', (229, 233))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('taurine upregulated gene 1', 'Gene', (201, 227))	('suppressing', 'NegReg', (90, 101))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('taurine upregulated gene 1', 'Gene', '55000', (201, 227))	('cisplatin resistance', 'MPA', (13, 33))	('PDCD4', 'Gene', (102, 107))	('si', 'Chemical', 'MESH:D012825', (245, 247))	('confers', 'Reg', (5, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('esophageal squamous cell carcinoma', 'Disease', (37, 71))	('epigenetically', 'Var', (75, 89))	('TUG1', 'Gene', (0, 4))	('PDCD4', 'Gene', '27250', (102, 107))	('TUG1', 'Gene', (229, 233))	('expression', 'MPA', (108, 118))	('cancer', 'Disease', (257, 263))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))
650718	30519392	High TUG1 expression was correlated with poor prognosis of ESCC patients.	('patients', 'Species', '9606', (64, 72))	('High', 'Var', (0, 4))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('expression', 'MPA', (10, 20))	('ESCC', 'Disease', (59, 63))	('si', 'Chemical', 'MESH:D012825', (52, 54))
650719	30519392	TUG1 knockdown improved the sensitivity of ECA109/DDP and EC9706/DDP cells to DDP.	('DDP', 'Gene', (78, 81))	('TUG1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('DDP', 'Gene', '1678', (50, 53))	('EC9706', 'CellLine', 'CVCL:E307', (58, 64))	('sensitivity', 'MPA', (28, 39))	('DDP', 'Gene', (65, 68))	('DDP', 'Gene', '1678', (78, 81))	('improved', 'PosReg', (15, 23))	('DDP', 'Gene', '1678', (65, 68))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('DDP', 'Gene', (50, 53))
650720	30519392	Moreover, TUG1 could epigenetically suppress PDCD4 expression via recruiting enhancer of zeste homolog 2.	('enhancer of zeste homolog 2', 'Gene', (77, 104))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('suppress', 'NegReg', (36, 44))	('enhancer of zeste homolog 2', 'Gene', '2146', (77, 104))	('epigenetically', 'Var', (21, 35))	('expression', 'MPA', (51, 61))	('PDCD4', 'Gene', (45, 50))
650722	30519392	PDCD4 knockdown counteracted the inductive effect of TUG1 inhibition on DDP sensitivity of ECA109/DDP and EC9706/DDP cells.	('si', 'Chemical', 'MESH:D012825', (79, 81))	('DDP', 'Gene', (98, 101))	('DDP', 'Gene', '1678', (72, 75))	('PDCD4', 'Gene', (0, 5))	('EC9706', 'CellLine', 'CVCL:E307', (106, 112))	('DDP', 'Gene', '1678', (113, 116))	('DDP', 'Gene', (72, 75))	('DDP', 'Gene', '1678', (98, 101))	('inhibition', 'NegReg', (58, 68))	('knockdown', 'Var', (6, 15))	('TUG1', 'Gene', (53, 57))	('DDP', 'Gene', (113, 116))
650723	30519392	Furthermore, TUG1 knockdown facilitated DDP sensitivity of DDP-resistant ESCC cells in vivo.	('knockdown', 'Var', (18, 27))	('DDP', 'Gene', '1678', (40, 43))	('DDP', 'Gene', (59, 62))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('facilitated', 'PosReg', (28, 39))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('DDP', 'Gene', '1678', (59, 62))	('TUG1', 'Gene', (13, 17))	('DDP', 'Gene', (40, 43))
650724	30519392	TUG1 knockdown overcame DDP resistance of ESCC by epigenetically silencing PDCD4, providing a novel therapeutic target for ESCC.	('PDCD4', 'Gene', (75, 80))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('DDP', 'Gene', (24, 27))	('epigenetically silencing', 'Var', (50, 74))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('DDP', 'Gene', '1678', (24, 27))	('overcame', 'PosReg', (15, 23))
650731	30519392	Dysregulated lncRNAs could act as oncogenic molecules and tumor suppressors in malignant tumors, closely associated with tumorigenesis, metastasis, diagnosis or prognosis.	('si', 'Chemical', 'MESH:D012825', (167, 169))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (121, 126))	('Dysregulated', 'Var', (0, 12))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('malignant tumors', 'Disease', 'MESH:D018198', (79, 95))	('si', 'Chemical', 'MESH:D012825', (131, 133))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('lncRNAs', 'Protein', (13, 20))	('malignant tumors', 'Disease', (79, 95))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('associated', 'Reg', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
650734	30519392	Recently, increasing evidence had suggested that aberrant TUG1 expression was associated with non-small cell lung cancer, hepatocellular carcinoma, and ESCC.	('hepatocellular carcinoma', 'Disease', (122, 146))	('associated', 'Reg', (78, 88))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (122, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('non-small cell lung cancer', 'Disease', (94, 120))	('TUG1', 'Gene', (58, 62))	('aberrant', 'Var', (49, 57))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('expression', 'MPA', (63, 73))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (94, 120))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (122, 146))	('ESCC', 'Disease', (152, 156))	('si', 'Chemical', 'MESH:D012825', (69, 71))
650735	30519392	Although a previous study reported that high TUG1 expression was significantly correlated with chemotherapy resistance in ESCC, the function and mechanism of TUG1 in cisplatin (DDP) resistance of ESCC remains uncertain.	('high', 'Var', (40, 44))	('chemotherapy resistance', 'MPA', (95, 118))	('DDP', 'Gene', (177, 180))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('si', 'Chemical', 'MESH:D012825', (184, 186))	('TUG1', 'Gene', (45, 49))	('ESCC', 'Disease', (122, 126))	('DDP', 'Gene', '1678', (177, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('correlated', 'Reg', (79, 89))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('expression', 'MPA', (50, 60))
650738	30519392	Functionally, TUG1 knockdown improved the sensitivity of DDP-resistant ESCC cells to DDP.	('DDP', 'Gene', (57, 60))	('TUG1', 'Gene', (14, 18))	('knockdown', 'Var', (19, 28))	('sensitivity', 'MPA', (42, 53))	('DDP', 'Gene', '1678', (85, 88))	('improved', 'PosReg', (29, 37))	('DDP', 'Gene', '1678', (57, 60))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('DDP', 'Gene', (85, 88))
650739	30519392	Mechanically, TUG1 improved the sensitivity of ESCC cells to DDP through epigenetically suppressing PDCD4 expression through recruiting enhancer of zeste homolog 2 (EZH2).	('DDP', 'Gene', (61, 64))	('enhancer of zeste homolog 2', 'Gene', (136, 163))	('EZH2', 'Gene', (165, 169))	('suppressing', 'NegReg', (88, 99))	('EZH2', 'Gene', '2146', (165, 169))	('expression', 'MPA', (106, 116))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('enhancer of zeste homolog 2', 'Gene', '2146', (136, 163))	('DDP', 'Gene', '1678', (61, 64))	('PDCD4', 'Gene', (100, 105))	('epigenetically', 'Var', (73, 87))	('sensitivity', 'MPA', (32, 43))	('improved', 'PosReg', (19, 27))	('si', 'Chemical', 'MESH:D012825', (35, 37))
650748	30519392	TUG1 or PDCD4 overexpressing vector pcDNA3.1-TUG1 or pcDNA3.1-PDCD4 (TUG1 or PDCD4), small interfering RNAs against TUG1 (si-TUG1 #1 or si-TUG1 #2) or PDCD4 (si-PDCD4) and their scramble negative control (si-con) were chemically synthesized by Genepharma (Shanghai, China).	('small interfering', 'Var', (85, 102))	('si', 'Chemical', 'MESH:D012825', (205, 207))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('si-TUG1', 'Var', (122, 129))	('si', 'Chemical', 'MESH:D012825', (235, 237))	('si', 'Chemical', 'MESH:D012825', (158, 160))	('si-TUG1 #2', 'Gene', (136, 146))	('si-TUG1 #2', 'Gene', '55000', (136, 146))	('si', 'Chemical', 'MESH:D012825', (24, 26))
650769	30519392	The primary antibodies anti-EZH2, anti-PDCD4 and anti-GAPDH were obtained from Cell Signaling Technology (Danvers, MA, USA).	('EZH2', 'Gene', '2146', (28, 32))	('EZH2', 'Gene', (28, 32))	('anti-PDCD4', 'Var', (34, 44))	('GAPDH', 'Gene', '2597', (54, 59))	('GAPDH', 'Gene', (54, 59))
650773	30519392	One week later, mice were intraperitoneally injected with 6 mg/kg DDP or same volume of PBS every week according to indicated groups (n = 5 each group): sh-con + PBS, sh-TUG1 + PBS, sh-con + DDP, sh-TUG1 + DDP.	('sh-TUG1 + PBS', 'Var', (167, 180))	('PBS', 'Chemical', 'MESH:D007854', (88, 91))	('DDP', 'Gene', '1678', (206, 209))	('DDP', 'Gene', (206, 209))	('DDP', 'Gene', '1678', (191, 194))	('sh-con + PBS', 'Var', (153, 165))	('DDP', 'Gene', (66, 69))	('DDP', 'Gene', (191, 194))	('PBS', 'Chemical', 'MESH:D007854', (162, 165))	('mice', 'Species', '10090', (16, 20))	('PBS', 'Chemical', 'MESH:D007854', (177, 180))	('DDP', 'Gene', '1678', (66, 69))
650787	30519392	Kaplan-Meier survival analysis revealed that patients with high TUG1 level (n = 21) had a low overall survival (P = 0.0079) compared with that with low TUG1 level (n = 21) (Fig.	('overall survival', 'MPA', (94, 110))	('high TUG1 level', 'Var', (59, 74))	('patients', 'Species', '9606', (45, 53))	('low', 'NegReg', (90, 93))	('si', 'Chemical', 'MESH:D012825', (27, 29))
650793	30519392	Remarkably, TUG1 knockdown heightened the sensitivity of ECA109/DDP and EC9706/DDP cells to DDP (Fig.	('DDP', 'Gene', (92, 95))	('DDP', 'Gene', (64, 67))	('heightened', 'PosReg', (27, 37))	('DDP', 'Gene', (79, 82))	('EC9706', 'CellLine', 'CVCL:E307', (72, 78))	('sensitivity', 'MPA', (42, 53))	('DDP', 'Gene', '1678', (64, 67))	('DDP', 'Gene', '1678', (92, 95))	('DDP', 'Gene', '1678', (79, 82))	('knockdown', 'Var', (17, 26))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('TUG1', 'Gene', (12, 16))
650796	30519392	Together, silencing of TUG1 enhanced DDP sensitivity in ESCC cells.	('si', 'Chemical', 'MESH:D012825', (10, 12))	('enhanced', 'PosReg', (28, 36))	('DDP', 'Gene', '1678', (37, 40))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('TUG1', 'Gene', (23, 27))	('DDP', 'Gene', (37, 40))	('silencing', 'Var', (10, 19))
650799	30519392	Hence, we further investigated whether TUG1 epigenetically suppressed PDCD4 in DDP-resistant ESCC cells by recruiting EZH2.	('epigenetically', 'Var', (44, 58))	('DDP', 'Gene', (79, 82))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('recruiting', 'PosReg', (107, 117))	('PDCD4', 'Gene', (70, 75))	('EZH2', 'Gene', (118, 122))	('EZH2', 'Gene', '2146', (118, 122))	('DDP', 'Gene', '1678', (79, 82))
650803	30519392	Western blot analysis showed that TUG1 knockdown significantly raised PDCD4 expression in ECA109/DDP cells (Fig.	('raised', 'PosReg', (63, 69))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('DDP', 'Gene', '1678', (97, 100))	('TUG1', 'Gene', (34, 38))	('knockdown', 'Var', (39, 48))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('expression', 'MPA', (76, 86))	('DDP', 'Gene', (97, 100))	('PDCD4', 'Gene', (70, 75))	('si', 'Chemical', 'MESH:D012825', (49, 51))
650804	30519392	Moreover, si-EZH2 transfection suppressed EZH2 and up-regulated PDCD4 expression in ECA109/DDP cells (Fig.	('EZH2', 'Gene', (13, 17))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('EZH2', 'Gene', '2146', (13, 17))	('up-regulated', 'PosReg', (51, 63))	('PDCD4', 'Gene', (64, 69))	('DDP', 'Gene', '1678', (91, 94))	('EZH2', 'Gene', '2146', (42, 46))	('EZH2', 'Gene', (42, 46))	('expression', 'MPA', (70, 80))	('transfection', 'Var', (18, 30))	('suppressed', 'NegReg', (31, 41))	('DDP', 'Gene', (91, 94))	('si', 'Chemical', 'MESH:D012825', (10, 12))
650809	30519392	To further confirm whether TUG1 transcriptionally repressed PDCD4 expression through enrichment of EZH2 and H3K27me3 on the PDCD4 promoter, ChIP assays were performed in ECA109/DDP cells.	('EZH2', 'Gene', '2146', (99, 103))	('PDCD4', 'Gene', (60, 65))	('EZH2', 'Gene', (99, 103))	('DDP', 'Gene', '1678', (177, 180))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('DDP', 'Gene', (177, 180))	('H3K27me3', 'Var', (108, 116))
650810	30519392	The results revealed that TUG1 knockdown dramatically decreased EZH2 recruitment and H3K27me3 levels on the PDCD4 promoter in ECA109/DDP cells (Fig.	('DDP', 'Gene', (133, 136))	('H3K27me3 levels', 'MPA', (85, 100))	('DDP', 'Gene', '1678', (133, 136))	('decreased', 'NegReg', (54, 63))	('TUG1', 'Gene', (26, 30))	('EZH2', 'Gene', (64, 68))	('knockdown', 'Var', (31, 40))	('EZH2', 'Gene', '2146', (64, 68))
650812	30519392	As expected, TUG1 knockdown could enhance the activity of PDCD4 promoter, oppositely, TUG1 overexpression led to reduction of the promoter activity (Fig.	('knockdown', 'Var', (18, 27))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('enhance', 'PosReg', (34, 41))	('promoter activity', 'MPA', (130, 147))	('activity', 'MPA', (46, 54))	('reduction', 'NegReg', (113, 122))	('PDCD4 promoter', 'Gene', (58, 72))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('TUG1', 'Gene', (13, 17))
650824	30519392	To further study whether TUG1 exerted its functional role in DDP resistance of ESCC cells through regulating PDCD4 expression, ECA109/DDP and EC9706/DDP cells were transfected with si-con, si-TUG1 or si-TUG1 + si-PDCD4.	('DDP', 'Gene', (61, 64))	('si-TUG1', 'Var', (200, 207))	('DDP', 'Gene', '1678', (149, 152))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('PDCD4', 'Gene', (109, 114))	('DDP', 'Gene', (134, 137))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('DDP', 'Gene', (149, 152))	('expression', 'MPA', (115, 125))	('DDP', 'Gene', '1678', (61, 64))	('si-TUG1', 'Var', (189, 196))	('EC9706', 'CellLine', 'CVCL:E307', (142, 148))	('si-con', 'Var', (181, 187))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('DDP', 'Gene', '1678', (134, 137))	('si', 'Chemical', 'MESH:D012825', (210, 212))	('si', 'Chemical', 'MESH:D012825', (200, 202))	('si', 'Chemical', 'MESH:D012825', (189, 191))
650826	30519392	MTT assay revealed that down-regulation of TUG1 improved DDP sensitivity of ECA109/DDP and EC9706/DDP cells, nevertheless, the inductive effect of TUG1 inhibition on DDP sensitivity was strikingly eliminated by PDCD4 silencing (Fig.	('silencing', 'Var', (217, 226))	('DDP', 'Gene', (98, 101))	('DDP', 'Gene', (57, 60))	('DDP', 'Gene', '1678', (83, 86))	('si', 'Chemical', 'MESH:D012825', (173, 175))	('improved', 'PosReg', (48, 56))	('DDP', 'Gene', '1678', (166, 169))	('si', 'Chemical', 'MESH:D012825', (217, 219))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('DDP', 'Gene', (83, 86))	('DDP', 'Gene', '1678', (98, 101))	('DDP', 'Gene', '1678', (57, 60))	('MTT', 'Chemical', '-', (0, 3))	('DDP', 'Gene', (166, 169))	('TUG1', 'Gene', (43, 47))	('down-regulation', 'NegReg', (24, 39))	('EC9706', 'CellLine', 'CVCL:E307', (91, 97))
650827	30519392	Furthermore, introduction of si-PDCD4 particularly demolished the inductive effect of down-regulated TUG1 on apoptosis in ECA109/DDP and EC9706/DDP cells (Fig.	('EC9706', 'CellLine', 'CVCL:E307', (137, 143))	('demolished', 'NegReg', (51, 61))	('DDP', 'Gene', (129, 132))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('si-PDCD4', 'Var', (29, 37))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('apoptosis', 'CPA', (109, 118))	('DDP', 'Gene', (144, 147))	('TUG1', 'Gene', (101, 105))	('DDP', 'Gene', '1678', (129, 132))	('down-regulated', 'NegReg', (86, 100))	('inductive effect', 'MPA', (66, 82))	('DDP', 'Gene', '1678', (144, 147))
650828	30519392	Collectively, these results confirmed that TUG1 knockdown facilitated DDP sensitivity of ESCC cells through elevating PDCD4 expression.	('DDP', 'Gene', '1678', (70, 73))	('elevating', 'PosReg', (108, 117))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('facilitated', 'PosReg', (58, 69))	('expression', 'MPA', (124, 134))	('DDP', 'Gene', (70, 73))	('TUG1', 'Gene', (43, 47))	('PDCD4', 'Gene', (118, 123))	('knockdown', 'Var', (48, 57))
650830	30519392	The data revealed that TUG1 knockdown or DDP treatment significantly suppressed tumor growth, evidenced by the diminished tumor volume (Fig.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('DDP', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('DDP', 'Gene', '1678', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', (80, 85))	('suppressed', 'NegReg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('knockdown', 'Var', (28, 37))	('diminished', 'NegReg', (111, 121))	('tumor', 'Disease', (122, 127))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('TUG1', 'Gene', (23, 27))
650833	30519392	Additionally, qRT-PCR assay revealed that TUG1 mRNA levels were lowered, while PDCD4 expression was elevated in tumors after sh-TUG1 introduction or DDP treatment (Fig.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('expression', 'MPA', (85, 95))	('DDP', 'Gene', '1678', (149, 152))	('lowered', 'NegReg', (64, 71))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PDCD4', 'Gene', (79, 84))	('DDP', 'Gene', (149, 152))	('sh-TUG1', 'Var', (125, 132))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('elevated', 'PosReg', (100, 108))	('TUG1 mRNA levels', 'MPA', (42, 58))	('tumors', 'Disease', (112, 118))
650836	30519392	The combination of TUG1 knockdown and DDP exposure led to much higher PDCD4 protein expression (Fig.	('si', 'Chemical', 'MESH:D012825', (90, 92))	('DDP', 'Gene', (38, 41))	('PDCD4', 'Gene', (70, 75))	('TUG1', 'Gene', (19, 23))	('higher', 'PosReg', (63, 69))	('DDP', 'Gene', '1678', (38, 41))	('knockdown', 'Var', (24, 33))
650837	30519392	All these data proved that TUG1 knockdown improved DDP sensitivity of ESCC cells in vivo.	('DDP', 'Gene', '1678', (51, 54))	('TUG1', 'Gene', (27, 31))	('improved', 'PosReg', (42, 50))	('knockdown', 'Var', (32, 41))	('DDP', 'Gene', (51, 54))	('si', 'Chemical', 'MESH:D012825', (58, 60))
650841	30519392	Moreover, TUG1 knockdown re-sensitized ECA109/DDP and EC9706/DDP cells to DDP by promoting DDP-induced apoptosis.	('DDP', 'Gene', (61, 64))	('knockdown', 'Var', (15, 24))	('DDP', 'Gene', '1678', (46, 49))	('TUG1', 'Gene', (10, 14))	('DDP', 'Gene', '1678', (91, 94))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('DDP', 'Gene', '1678', (74, 77))	('DDP', 'Gene', '1678', (61, 64))	('DDP', 'Gene', (46, 49))	('promoting', 'PosReg', (81, 90))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('DDP', 'Gene', (91, 94))	('EC9706', 'CellLine', 'CVCL:E307', (54, 60))	('DDP', 'Gene', (74, 77))
650842	30519392	More importantly, TUG1 conferred DPP resistance to ESCC cells via epigenetically silencing PDCD4 via EZH2.	('DPP resistance', 'MPA', (33, 47))	('PDCD4', 'Gene', (91, 96))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('DPP', 'Chemical', 'MESH:C038694', (33, 36))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('epigenetically silencing', 'Var', (66, 90))	('EZH2', 'Gene', (101, 105))	('EZH2', 'Gene', '2146', (101, 105))
650846	30519392	Apart from our findings, dysregulated TUG1 has been reported to be implicated with chemoresistance in other cancers.	('chemoresistance', 'CPA', (83, 98))	('TUG1', 'Gene', (38, 42))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('implicated', 'Reg', (67, 77))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))	('dysregulated', 'Var', (25, 37))
650847	30519392	For example, TUG1 was overexpressed in small cell lung cancer, and TUG1 down-regulation sensitized lung cancer cells to chemotherapeutic drugs (DDP, Adriamycin and Etoposide) by epigenetically suppressing LIM-kinase 2b (LIMK2b) expression through EZH2.	('EZH2', 'Gene', (247, 251))	('EZH2', 'Gene', '2146', (247, 251))	('si', 'Chemical', 'MESH:D012825', (169, 171))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('DDP', 'Gene', (144, 147))	('small cell lung cancer', 'Disease', 'MESH:D055752', (39, 61))	('small cell lung cancer', 'Disease', (39, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Adriamycin', 'Chemical', 'MESH:D004317', (149, 159))	('si', 'Chemical', 'MESH:D012825', (200, 202))	('TUG1', 'Gene', (67, 71))	('suppressing', 'NegReg', (193, 204))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (39, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))	('Etoposide', 'Chemical', 'MESH:D005047', (164, 173))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('epigenetically', 'Var', (178, 192))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('LIMK2b', 'Gene', (220, 226))	('overexpressed', 'PosReg', (22, 35))	('si', 'Chemical', 'MESH:D012825', (234, 236))	('DDP', 'Gene', '1678', (144, 147))	('down-regulation', 'NegReg', (72, 87))
650848	30519392	Moreover, TUG1 knockdown re-sensitized MTX-resistant colorectal cell lines to MTX through acting as a competitive endogenous RNA (ceRNA) to sponge miR-186 and release the miRNA target CPEB2.	('knockdown', 'Var', (15, 24))	('CPEB2', 'Gene', '132864', (184, 189))	('TUG1', 'Gene', (10, 14))	('MTX', 'Chemical', 'MESH:D008727', (39, 42))	('miR-186', 'Gene', '406962', (147, 154))	('MTX', 'Chemical', 'MESH:D008727', (78, 81))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('miR-186', 'Gene', (147, 154))	('CPEB2', 'Gene', (184, 189))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('release', 'MPA', (159, 166))
650857	30519392	Our western blot assays indicated that TUG1 or EZH2 knockdown elevated PDCD4 protein levels.	('EZH2', 'Gene', (47, 51))	('PDCD4 protein levels', 'MPA', (71, 91))	('TUG1', 'Gene', (39, 43))	('knockdown', 'Var', (52, 61))	('elevated', 'PosReg', (62, 70))	('EZH2', 'Gene', '2146', (47, 51))
650859	30519392	ChIP and luciferase reporter assays further proved that TUG1 knockdown enhanced the promoter activity of PDCD4 by attenuating the recruiting of EZH2 on PDCD4 promoter region.	('attenuating', 'NegReg', (114, 125))	('enhanced', 'PosReg', (71, 79))	('PDCD4', 'Gene', (105, 110))	('EZH2', 'Gene', (144, 148))	('promoter activity', 'MPA', (84, 101))	('recruiting', 'MPA', (130, 140))	('EZH2', 'Gene', '2146', (144, 148))	('TUG1', 'Gene', (56, 60))	('knockdown', 'Var', (61, 70))
650860	30519392	These data demonstrated that TUG1 epigenetically silencing PDCD4 via recruiting EZH2 in ECA109/DDP cells.	('epigenetically silencing', 'Var', (34, 58))	('DDP', 'Gene', '1678', (95, 98))	('PDCD4', 'Gene', (59, 64))	('recruiting', 'PosReg', (69, 79))	('EZH2', 'Gene', (80, 84))	('EZH2', 'Gene', '2146', (80, 84))	('DDP', 'Gene', (95, 98))	('si', 'Chemical', 'MESH:D012825', (49, 51))
650862	30519392	Moreover, PDCD4 could improve the sensitivity of cancer cells to chemotherapy drugs such as docetaxel and cisplatin.	('improve', 'PosReg', (22, 29))	('sensitivity', 'MPA', (34, 45))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('PDCD4', 'Var', (10, 15))	('cancer', 'Disease', (49, 55))	('docetaxel', 'Chemical', 'MESH:D000077143', (92, 101))
650865	30519392	Furthermore, PDCD4 inhibition reversed the inductive effect of TUG1 knockdown on the sensitivity of ECA109/DDP and EC9706/DDP to DDP.	('DDP', 'Gene', '1678', (107, 110))	('DDP', 'Gene', (129, 132))	('DDP', 'Gene', (122, 125))	('TUG1', 'Gene', (63, 67))	('DDP', 'Gene', '1678', (129, 132))	('EC9706', 'CellLine', 'CVCL:E307', (115, 121))	('DDP', 'Gene', (107, 110))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('knockdown', 'Var', (68, 77))	('DDP', 'Gene', '1678', (122, 125))	('sensitivity', 'MPA', (85, 96))
650866	30519392	All these data demonstrated that TUG1 inhibition sensitized DDP-resistant ESCC cells to DDP through epigenetically silencing PDCD4 in ESCC.	('si', 'Chemical', 'MESH:D012825', (115, 117))	('epigenetically silencing', 'Var', (100, 124))	('DDP', 'Gene', (88, 91))	('sensitized', 'Reg', (49, 59))	('DDP', 'Gene', '1678', (60, 63))	('DDP', 'Gene', '1678', (88, 91))	('inhibition', 'NegReg', (38, 48))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('PDCD4', 'Gene', (125, 130))	('DDP', 'Gene', (60, 63))
650867	30519392	In conclusion, our study demonstrated that TUG1 knockdown enhanced DDP sensitivity of ESCC cells.	('DDP', 'Gene', '1678', (67, 70))	('enhanced', 'PosReg', (58, 66))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('DDP', 'Gene', (67, 70))	('TUG1', 'Gene', (43, 47))	('knockdown', 'Var', (48, 57))
650868	30519392	Importantly, the enhancive effect of TUG1 inhibition on DDP sensitivity might be mediated by PDCD4 through an epigenetic mechanism in ESCC cells, providing a promising therapeutic strategy to overcome DDP resistance in ESCC.	('epigenetic', 'Var', (110, 120))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('DDP', 'Gene', '1678', (56, 59))	('si', 'Chemical', 'MESH:D012825', (207, 209))	('DDP', 'Gene', '1678', (201, 204))	('enhancive', 'PosReg', (17, 26))	('PDCD4', 'Gene', (93, 98))	('DDP', 'Gene', (201, 204))	('DDP', 'Gene', (56, 59))	('inhibition', 'NegReg', (42, 52))	('TUG1', 'Gene', (37, 41))	('si', 'Chemical', 'MESH:D012825', (63, 65))
650932	29207620	In this study, we detected a significant association between the rs408014 and rs7771314 SNPs at the TXNDC5 locus and cervical carcinoma using the Taqman genotyping method.	('TXNDC5', 'Gene', '81567', (100, 106))	('rs408014', 'Var', (65, 73))	('cervical carcinoma', 'Disease', (117, 135))	('rs7771314', 'Mutation', 'rs7771314', (78, 87))	('cervical carcinoma', 'Disease', 'MESH:D002575', (117, 135))	('rs408014', 'Mutation', 'rs408014', (65, 73))	('rs7771314', 'Var', (78, 87))	('TXNDC5', 'Gene', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
650934	29207620	Additionally, inhibition of TXNDC5 expression using siRNA prevented tube-like structure formation, an experimental indicator of vasculogenic mimicry and metastasis, in HeLa cervical tumor cells.	('TXNDC5', 'Gene', '81567', (28, 34))	('HeLa cervical tumor', 'Disease', (168, 187))	('prevented', 'NegReg', (58, 67))	('TXNDC5', 'Gene', (28, 34))	('cervical tumor', 'Phenotype', 'HP:0030159', (173, 187))	('tube-like structure formation', 'CPA', (68, 97))	('HeLa cervical tumor', 'Disease', 'MESH:D002583', (168, 187))	('inhibition', 'Var', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
650935	29207620	Inhibiting TXNDC5 expression simultaneously led to the increased expression of SERPINF1 (serpin peptidase inhibitor, clade F) and TRAF1 (TNF receptor-associated factor 1), which have been reported to inhibit angiogenesis and metastasis as well as induce apoptosis.	('TNF receptor-associated factor 1', 'Gene', (137, 169))	('TRAF1', 'Gene', '7185', (130, 135))	('induce', 'Reg', (247, 253))	('Inhibiting', 'Var', (0, 10))	('inhibit', 'NegReg', (200, 207))	('TNF receptor-associated factor 1', 'Gene', '7185', (137, 169))	('increased', 'PosReg', (55, 64))	('SERPINF1', 'Gene', (79, 87))	('TRAF1', 'Gene', (130, 135))	('apoptosis', 'CPA', (254, 263))	('expression', 'MPA', (65, 75))	('TXNDC5', 'Gene', (11, 17))	('TXNDC5', 'Gene', '81567', (11, 17))
650939	29207620	The present study suggests that TXNDC5 is a susceptibility gene in cervical cancer, and high expression of this gene contributes to abnormal angiogenesis, vasculogenic mimicry and metastasis by down-regulating SERPINF1 and TRAF1 expression.	('TXNDC5', 'Gene', (32, 38))	('metastasis', 'CPA', (180, 190))	('cervical cancer', 'Disease', (67, 82))	('high expression', 'Var', (88, 103))	('SERPINF1', 'Protein', (210, 218))	('vasculogenic mimicry', 'CPA', (155, 175))	('TRAF1', 'Gene', '7185', (223, 228))	('contributes', 'Reg', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('down-regulating', 'NegReg', (194, 209))	('TXNDC5', 'Gene', '81567', (32, 38))	('abnormal angiogenesis', 'CPA', (132, 153))	('TRAF1', 'Gene', (223, 228))	('cervical cancer', 'Disease', 'MESH:D002583', (67, 82))	('expression', 'MPA', (229, 239))
650953	29207620	A case-control analysis revealed a significant association of rs9505298, rs7771314, rs2815128, rs13210097 and rs9392182 SNPs in the TXNDC5 gene with cervical carcinoma, esophageal carcinoma, and liver cancer, but the results were not verified in independent cohorts with large numbers of samples using other genotyping method.	('rs13210097', 'Mutation', 'rs13210097', (95, 105))	('liver cancer', 'Disease', 'MESH:D006528', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cervical carcinoma', 'Disease', 'MESH:D002575', (149, 167))	('rs9392182', 'Mutation', 'rs9392182', (110, 119))	('TXNDC5', 'Gene', (132, 138))	('liver cancer', 'Phenotype', 'HP:0002896', (195, 207))	('liver cancer', 'Disease', (195, 207))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (169, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('rs7771314', 'Mutation', 'rs7771314', (73, 82))	('rs9505298', 'Var', (62, 71))	('TXNDC5', 'Gene', '81567', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('rs7771314', 'Var', (73, 82))	('esophageal carcinoma', 'Disease', (169, 189))	('rs2815128', 'Mutation', 'rs2815128', (84, 93))	('rs9505298', 'Mutation', 'rs9505298', (62, 71))	('rs9392182 SNPs', 'Var', (110, 124))	('rs13210097', 'Var', (95, 105))	('rs2815128', 'Var', (84, 93))	('cervical carcinoma', 'Disease', (149, 167))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (169, 189))
650955	29207620	Five SNPs in the TXNDC5 locus, including rs2815128, rs408014, rs4959462, rs7763203 and rs7771314, were genotyped using the Taqman genotyping method in patient cohorts of breast cancer, cervical carcinoma, colorectal cancer, esophageal carcinoma, gastric carcinoma, liver cancer, lung cancer, and rectal carcinoma as well as healthy controls.	('liver cancer', 'Disease', 'MESH:D006528', (265, 277))	('rectal carcinoma', 'Disease', (296, 312))	('rs408014', 'Var', (52, 60))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (224, 244))	('rs4959462', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('gastric carcinoma', 'Disease', 'MESH:D013274', (246, 263))	('lung cancer', 'Disease', 'MESH:D008175', (279, 290))	('gastric carcinoma', 'Disease', (246, 263))	('colorectal cancer', 'Disease', 'MESH:D015179', (205, 222))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('liver cancer', 'Phenotype', 'HP:0002896', (265, 277))	('rs2815128', 'Mutation', 'rs2815128', (41, 50))	('cervical carcinoma', 'Disease', (185, 203))	('rectal carcinoma', 'Disease', 'MESH:D012004', (296, 312))	('patient', 'Species', '9606', (151, 158))	('liver cancer', 'Disease', (265, 277))	('rs4959462', 'Mutation', 'rs4959462', (62, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (279, 290))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (246, 263))	('colorectal cancer', 'Disease', (205, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('rs2815128', 'Var', (41, 50))	('cervical carcinoma', 'Disease', 'MESH:D002575', (185, 203))	('TXNDC5', 'Gene', (17, 23))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (224, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('rs7763203', 'Mutation', 'rs7763203', (73, 82))	('breast cancer', 'Disease', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('rs7771314', 'Mutation', 'rs7771314', (87, 96))	('esophageal carcinoma', 'Disease', (224, 244))	('rs7763203', 'Var', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('rs7771314', 'Var', (87, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (205, 222))	('lung cancer', 'Disease', (279, 290))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (296, 312))	('TXNDC5', 'Gene', '81567', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('rs408014', 'Mutation', 'rs408014', (52, 60))
650956	29207620	The case-control analysis exhibited a significant difference in the allele frequency of rs408014 (odds ratio = 1.328862; 95% CI = [1.035893~1.704689], p = 0.025157) between cervical carcinoma patients and controls.	('rs408014', 'Mutation', 'rs408014', (88, 96))	('patients', 'Species', '9606', (192, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('cervical carcinoma', 'Disease', 'MESH:D002575', (173, 191))	('cervical carcinoma', 'Disease', (173, 191))	('rs408014', 'Var', (88, 96))
650957	29207620	The analysis also revealed a significant difference in the allele frequency (odds ratio=0.512561; 95% CI = [0.303152~0.866624], p = 0.011327) and the gene frequency (p = 0.033817) of rs7771314 between cervical carcinoma patients and the controls.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('rs7771314', 'Mutation', 'rs7771314', (183, 192))	('difference', 'Reg', (41, 51))	('patients', 'Species', '9606', (220, 228))	('rs7771314', 'Var', (183, 192))	('cervical carcinoma', 'Disease', 'MESH:D002575', (201, 219))	('cervical carcinoma', 'Disease', (201, 219))
650958	29207620	In addition, the analysis revealed a significant difference in the allele frequency (odds ratio = 0.553230; 95% CI = [0.323325~0.946612], p = 0.028771) of rs2815128 between breast cancer patients and controls.	('patients', 'Species', '9606', (187, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('rs2815128', 'Var', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('rs2815128', 'Mutation', 'rs2815128', (155, 164))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Disease', (173, 186))
650960	29207620	Significant differences in the allelic or genotypic frequencies of rs4959462 and rs7763203 (p > 0.05) were not detected by genotyping among patients with breast cancer, cervical carcinoma, colorectal cancer, esophageal carcinoma, gastric carcinoma, liver cancer, lung cancer or rectal carcinoma and the controls.	('gastric carcinoma', 'Disease', 'MESH:D013274', (230, 247))	('colorectal cancer', 'Phenotype', 'HP:0003003', (189, 206))	('lung cancer', 'Disease', (263, 274))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('gastric carcinoma', 'Disease', (230, 247))	('liver cancer', 'Disease', 'MESH:D006528', (249, 261))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (230, 247))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (278, 294))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (208, 228))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('rectal carcinoma', 'Disease', (278, 294))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('patients', 'Species', '9606', (140, 148))	('liver cancer', 'Phenotype', 'HP:0002896', (249, 261))	('colorectal cancer', 'Disease', 'MESH:D015179', (189, 206))	('cervical carcinoma', 'Disease', (169, 187))	('liver cancer', 'Disease', (249, 261))	('rs4959462', 'Var', (67, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('rectal carcinoma', 'Disease', 'MESH:D012004', (278, 294))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('colorectal cancer', 'Disease', (189, 206))	('cervical carcinoma', 'Disease', 'MESH:D002575', (169, 187))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (208, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('rs4959462', 'Mutation', 'rs4959462', (67, 76))	('breast cancer', 'Disease', (154, 167))	('rs7763203', 'Mutation', 'rs7763203', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('esophageal carcinoma', 'Disease', (208, 228))	('rs7763203', 'Var', (81, 90))
650979	29207620	HeLa cells treated with anti-TXNDC5 and anti-SERPINF1; anti-TXNDC5 and TRAF1 siRNA; or anti-TXNDC5, anti-SERPINF1 and TRAF1 siRNA exhibited significantly increased tube-like structures compared with cells treated with anti-TXNDC5 alone.	('TXNDC5', 'Gene', '81567', (223, 229))	('TRAF1', 'Gene', '7185', (71, 76))	('TXNDC5', 'Gene', (92, 98))	('anti-SERPINF1', 'Var', (40, 53))	('TRAF1', 'Gene', (118, 123))	('TXNDC5', 'Gene', (60, 66))	('TXNDC5', 'Gene', '81567', (29, 35))	('TRAF1', 'Gene', (71, 76))	('TXNDC5', 'Gene', (223, 229))	('tube-like structures', 'CPA', (164, 184))	('increased', 'PosReg', (154, 163))	('TXNDC5', 'Gene', '81567', (92, 98))	('TXNDC5', 'Gene', '81567', (60, 66))	('anti-SERPINF1', 'Var', (100, 113))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('TRAF1', 'Gene', '7185', (118, 123))	('TXNDC5', 'Gene', (29, 35))
651001	29207620	In the present study, Taqman genotyping demonstrated a significant association between rs408014 and rs7771314 in the TXNDC5 locus and cervical carcinoma.	('rs7771314', 'Mutation', 'rs7771314', (100, 109))	('cervical carcinoma', 'Disease', 'MESH:D002575', (134, 152))	('cervical carcinoma', 'Disease', (134, 152))	('rs408014', 'Var', (87, 95))	('rs7771314', 'Var', (100, 109))	('TXNDC5', 'Gene', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('rs408014', 'Mutation', 'rs408014', (87, 95))	('TXNDC5', 'Gene', '81567', (117, 123))
651004	29207620	This case-control analysis revealed a significant difference in allele frequencies and genotype frequencies for rs9505298, rs7771314, rs2815128, rs13210097 and rs9392182 among patients with breast cancer, cervical carcinoma, esophageal carcinoma, gastric carcinoma and liver cancer.	('cervical carcinoma', 'Disease', (205, 223))	('gastric carcinoma and liver cancer', 'Disease', 'MESH:D013274', (247, 281))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('rs9505298', 'Var', (112, 121))	('cervical carcinoma', 'Disease', 'MESH:D002575', (205, 223))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (247, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('rs9505298', 'Mutation', 'rs9505298', (112, 121))	('rs7771314', 'Mutation', 'rs7771314', (123, 132))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (225, 245))	('rs2815128', 'Mutation', 'rs2815128', (134, 143))	('rs13210097', 'Var', (145, 155))	('rs7771314', 'Var', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('esophageal carcinoma', 'Disease', (225, 245))	('rs13210097', 'Mutation', 'rs13210097', (145, 155))	('rs2815128', 'Var', (134, 143))	('rs9392182', 'Mutation', 'rs9392182', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('rs9392182', 'Var', (160, 169))	('patients', 'Species', '9606', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('liver cancer', 'Phenotype', 'HP:0002896', (269, 281))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (225, 245))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
651005	29207620	The results of the current study, which were completed using the Taqman genotyping method, are consistent with results of previous studies and confirms the strong association between rs7771314 and cervical tumor risk.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('rs7771314', 'Mutation', 'rs7771314', (183, 192))	('tumor', 'Disease', (206, 211))	('rs7771314', 'Var', (183, 192))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('cervical tumor', 'Phenotype', 'HP:0030159', (197, 211))
651015	29207620	found that the proportion of poorly differentiated gastric adenocarcinomas was significantly increased in tumors with high TXNDC5 expression compared with specimens with low TXNDC5 expression.	('high', 'Var', (118, 122))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('TXNDC5', 'Gene', (174, 180))	('increased', 'PosReg', (93, 102))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('TXNDC5', 'Gene', (123, 129))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (51, 74))	('gastric adenocarcinomas', 'Disease', (51, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('TXNDC5', 'Gene', '81567', (123, 129))	('TXNDC5', 'Gene', '81567', (174, 180))
651016	29207620	Lymph node metastasis and the depth of tumor invasion were significantly increased in specimens that exhibited high TXNDC5 expression compared with specimens with low TXNDC5 expression.	('increased', 'PosReg', (73, 82))	('TXNDC5', 'Gene', (116, 122))	('TXNDC5', 'Gene', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('TXNDC5', 'Gene', '81567', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('TXNDC5', 'Gene', '81567', (167, 173))	('tumor', 'Disease', (39, 44))	('Lymph node metastasis', 'CPA', (0, 21))	('high', 'Var', (111, 115))
651017	29207620	A survival analysis by the same group revealed that the prognosis of patients who exhibited high TXNDC5 expression was significantly poorer than that of patients who exhibited low TXNDC5 expression.	('poorer', 'NegReg', (133, 139))	('TXNDC5', 'Gene', '81567', (180, 186))	('high', 'Var', (92, 96))	('patients', 'Species', '9606', (153, 161))	('TXNDC5', 'Gene', '81567', (97, 103))	('TXNDC5', 'Gene', (180, 186))	('patients', 'Species', '9606', (69, 77))	('TXNDC5', 'Gene', (97, 103))
651022	29207620	The silencing of TXNDC5 expression also restrains the growth and proliferation of gastric cancer cells.	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('TXNDC5', 'Gene', (17, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('restrains', 'NegReg', (40, 49))	('gastric cancer', 'Disease', (82, 96))	('TXNDC5', 'Gene', '81567', (17, 23))	('silencing', 'Var', (4, 13))
651056	29207620	To confirm the pathway from TXNDC5 to SERPINF1 and TRAF1 that stimulates cell migration and vasculogenic mimicry, we simultaneously transfected HeLa cells with anti-TXNDC5, anti-SERPINF1 and TRAF1 siRNA and observed tube-like structure formation.	('anti-SERPINF1', 'Var', (173, 186))	('TRAF1', 'Gene', (51, 56))	('TXNDC5', 'Gene', '81567', (28, 34))	('TXNDC5', 'Gene', '81567', (165, 171))	('observed', 'Reg', (207, 215))	('TRAF1', 'Gene', (191, 196))	('TXNDC5', 'Gene', (165, 171))	('cell migration', 'CPA', (73, 87))	('TXNDC5', 'Gene', (28, 34))	('TRAF1', 'Gene', '7185', (51, 56))	('HeLa', 'CellLine', 'CVCL:0030', (144, 148))	('TRAF1', 'Gene', '7185', (191, 196))	('tube-like structure formation', 'CPA', (216, 245))
651057	29207620	We found that the treatment of these cells with anti-TXNDC5 and anti-SERPINF1 or anti-TXNDC5 and TRAF1 siRNA considerably rescued the ability to form tube-like structures compared with treatment with anti-TXNDC5 siRNA alone.	('TXNDC5', 'Gene', (205, 211))	('TXNDC5', 'Gene', '81567', (86, 92))	('anti-SERPINF1', 'Var', (64, 77))	('rescued', 'PosReg', (122, 129))	('TXNDC5', 'Gene', '81567', (205, 211))	('TRAF1', 'Gene', '7185', (97, 102))	('TXNDC5', 'Gene', '81567', (53, 59))	('TXNDC5', 'Gene', (86, 92))	('TRAF1', 'Gene', (97, 102))	('TXNDC5', 'Gene', (53, 59))
651061	29207620	Inactivation of NR4A1 decreased TXNDC5 expression, resulting in activation of the ROS/endoplasmic reticulum stress and proapoptotic pathways.	('TXNDC5', 'Gene', (32, 38))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('TXNDC5', 'Gene', '81567', (32, 38))	('proapoptotic pathways', 'Pathway', (119, 140))	('NR4A1', 'Gene', (16, 21))	('activation', 'PosReg', (64, 74))	('NR4A1', 'Gene', '3164', (16, 21))	('Inactivation', 'Var', (0, 12))	('decreased', 'NegReg', (22, 31))
651072	29207620	The tag SNPs rs2815128, rs408014, rs4959462, rs7763203 and rs7771314 were selected on the basis of linkage disequilibrium patterns that were observed in samples obtained from the Han Chinese population of Beijing, which was genotyped as part of the International HapMap Project.	('rs2815128', 'Var', (13, 22))	('rs2815128', 'Mutation', 'rs2815128', (13, 22))	('rs7771314', 'Var', (59, 68))	('rs7763203', 'Var', (45, 54))	('rs408014', 'Var', (24, 32))	('rs4959462', 'Var', (34, 43))	('rs4959462', 'Mutation', 'rs4959462', (34, 43))	('rs408014', 'Mutation', 'rs408014', (24, 32))	('rs7763203', 'Mutation', 'rs7763203', (45, 54))	('rs7771314', 'Mutation', 'rs7771314', (59, 68))
651107	29207620	To confirm the pathogenic pathway of TXNDC5, we simultaneously transfected HeLa cells with anti-TXNDC5, anti-SERPINF1 or anti-TRAF1 siRNA and observed the tube-like formation ability of the treated cells.	('tube-like formation ability', 'CPA', (155, 182))	('TXNDC5', 'Gene', (37, 43))	('TXNDC5', 'Gene', '81567', (96, 102))	('TRAF1', 'Gene', '7185', (126, 131))	('TXNDC5', 'Gene', '81567', (37, 43))	('HeLa', 'CellLine', 'CVCL:0030', (75, 79))	('TRAF1', 'Gene', (126, 131))	('TXNDC5', 'Gene', (96, 102))	('anti-SERPINF1', 'Var', (104, 117))
651108	29207620	The targeting sequence of anti- SERPINF1S siRNA is 5' CCAGAATTTGACCTTGATA 3', and the targeting sequence of anti-TRAF1 siRNA is 5' GAACCCATCTGTCGCTCTT 3'.	('anti-', 'Var', (26, 31))	('TRAF1', 'Gene', '7185', (113, 118))	('TRAF1', 'Gene', (113, 118))
651122	28854977	Manipulating CASC9 expression in ESCC cells altered both PDCD4 mRNA and protein levels and cell cycle arrest caused by CASC9 knockdown could be rescued by suppressing PDCD4 expression.	('knockdown', 'Var', (125, 134))	('PDCD4', 'Gene', (57, 62))	('CASC9', 'Gene', '101805492', (119, 124))	('PDCD4', 'Gene', (167, 172))	('PDCD4', 'Gene', '27250', (57, 62))	('CASC9', 'Gene', (119, 124))	('PDCD4', 'Gene', '27250', (167, 172))	('CASC9', 'Gene', '101805492', (13, 18))	('altered', 'Reg', (44, 51))	('suppressing', 'NegReg', (155, 166))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('expression', 'MPA', (173, 183))	('cell cycle arrest', 'CPA', (91, 108))	('CASC9', 'Gene', (13, 18))
651132	28854977	Long noncoding RNAs (lncRNAs) have been reported to drive many important cancer phenotypes by multiple ways, containing epigenetic modification, transcription regulation, RNA decay, miRNA sponging and so on.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('epigenetic modification', 'Var', (120, 143))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('drive', 'Reg', (52, 57))	('transcription regulation', 'MPA', (145, 169))	('RNA decay', 'MPA', (171, 180))
651135	28854977	has studied the lncRNA expression profile of ESCC by microarray including 119 pairs of tumor and normal tissues and found that a three-lncRNA signature (including the lncRNAs ENST00000435885.1, XLOC_013014 and ENST00000547963.1) is significantly associated with the overall survival of ESCC patients.	('ENST00000547963.1', 'Var', (210, 227))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('patients', 'Species', '9606', (291, 299))	('ENST00000435885.1', 'Var', (175, 192))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('XLOC_013014', 'Var', (194, 205))	('associated with', 'Reg', (246, 261))	('ESCC', 'Disease', (286, 290))
651154	28854977	Total RNA from the KYSE450 cells with CASC9 knockdown and control KYSE450 cells was isolated and quantified.	('knockdown', 'Var', (44, 53))	('CASC9', 'Gene', (38, 43))	('CASC9', 'Gene', '101805492', (38, 43))
651181	28854977	The chromatin was immunoprecipitated using 2 mug anti-Ezh2 (CST), 2 mug anti-H3K27me3 (Millipore) and 2 mug corresponding IgG with rotation overnight at 4  C. Then 30 mul magnetic beads were added to each tube and incubated with rotation for 2 h at 4  C. The immunoprecipitated chromatin was washed with low salt solution three times and high salt solution once.	('Ezh2', 'Gene', (54, 58))	('anti-H3K27me3', 'Var', (72, 85))	('low salt', 'Chemical', '-', (304, 312))	('Ezh2', 'Gene', '2146', (54, 58))	('CST', 'Gene', '106478911', (60, 63))	('high salt solution', 'Phenotype', 'HP:0003228', (338, 356))	('salt', 'Chemical', 'MESH:D012492', (343, 347))	('salt', 'Chemical', 'MESH:D012492', (308, 312))	('CST', 'Gene', (60, 63))
651182	28854977	The antibodies used were specific for EZH2 (1:1000, CST), PDCD4 (1:4000, CST), CCNE2 (1:1000, CST) and CDK6 (1:1000, CST).	('CST', 'Gene', '106478911', (73, 76))	('CST', 'Gene', '106478911', (52, 55))	('CST', 'Gene', '106478911', (94, 97))	('CST', 'Gene', '106478911', (117, 120))	('EZH2', 'Gene', '2146', (38, 42))	('1:1000', 'Var', (86, 92))	('PDCD4', 'Gene', (58, 63))	('EZH2', 'Gene', (38, 42))	('CST', 'Gene', (73, 76))	('PDCD4', 'Gene', '27250', (58, 63))	('1:4000', 'Var', (65, 71))	('CDK6', 'Gene', (103, 107))	('CST', 'Gene', (52, 55))	('CST', 'Gene', (94, 97))	('CST', 'Gene', (117, 120))	('CCNE2', 'Gene', (79, 84))	('CDK6', 'Gene', '1021', (103, 107))	('CCNE2', 'Gene', '9134', (79, 84))
651186	28854977	We randomly selected 3 up-regulated lncRNAs (BC017398, RP5-907D15, RP11-417E7) and 3 down-regulated lncRNAs (CCAT1, LINC00443, NR_038940) to detect their expression in ESCC and normal tissues by qRT-PCR.	('RP5-907D15', 'Var', (55, 65))	('LINC00443', 'Gene', '100874173', (116, 125))	('RP11-417E7) and 3', 'Gene', '22924', (67, 84))	('up-regulated', 'PosReg', (23, 35))	('CCAT1', 'Gene', '100507056', (109, 114))	('ESCC', 'Disease', (168, 172))	('BC017398', 'Var', (45, 53))	('CCAT1', 'Gene', (109, 114))	('LINC00443', 'Gene', (116, 125))
651191	28854977	Almost no H3K27Ac and H3K4me1 histones modification signals were found in the CASC9 genome according to UCSC prediction, which indicated CASC9 was not an enhancer-like RNA.	('CASC9', 'Gene', '101805492', (137, 142))	('H3K4me1', 'Var', (22, 29))	('CASC9', 'Gene', (78, 83))	('CASC9', 'Gene', '101805492', (78, 83))	('CASC9', 'Gene', (137, 142))	('H3K27Ac', 'Var', (10, 17))
651210	28854977	The CCK-8 assays showed that knockdown of CASC9 expression inhibited cell growth in both ESCC cell lines (Fig.	('CASC9', 'Gene', (42, 47))	('CASC9', 'Gene', '101805492', (42, 47))	('knockdown', 'Var', (29, 38))	('inhibited', 'NegReg', (59, 68))	('cell growth in', 'CPA', (69, 83))
651212	28854977	Thus knockdown of CASC9 inhibited cell growth in vitro and in vivo.	('CASC9', 'Gene', '101805492', (18, 23))	('CASC9', 'Gene', (18, 23))	('knockdown', 'Var', (5, 14))	('inhibited', 'NegReg', (24, 33))	('cell growth', 'CPA', (34, 45))
651213	28854977	Next, we investigated the effects of CASC9 knockdown on cell proliferation, apoptosis and cell cycle, which contributed to cell growth by different ways.	('knockdown', 'Var', (43, 52))	('cell cycle', 'CPA', (90, 100))	('CASC9', 'Gene', (37, 42))	('CASC9', 'Gene', '101805492', (37, 42))	('investigated', 'Reg', (9, 21))	('cell proliferation', 'CPA', (56, 74))	('apoptosis', 'CPA', (76, 85))
651214	28854977	48 h after SI2-CASC9 transfection, proliferative cells labeled by Edu were significantly decreased (Fig.	('SI2-CASC9', 'Disease', (11, 20))	('SI2-CASC9', 'Disease', 'None', (11, 20))	('transfection', 'Var', (21, 33))	('proliferative cells labeled', 'CPA', (35, 62))	('decreased', 'NegReg', (89, 98))
651215	28854977	The cell cycle analysis demonstrated that inhibiting CASC9 expression led to cell cycle arrest in G1 phase and reduced the cell proportion in S phase (Fig.	('inhibiting', 'Var', (42, 52))	('CASC9', 'Gene', (53, 58))	('CASC9', 'Gene', '101805492', (53, 58))	('reduced', 'NegReg', (111, 118))	('expression', 'MPA', (59, 69))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('cell proportion in S phase', 'CPA', (123, 149))	('cell cycle arrest in G1 phase', 'CPA', (77, 106))
651216	28854977	Nevertheless, there was no statistical difference in apoptotic cells between CASC9 knockdown and control groups (Additional file 2: Fig.	('CASC9', 'Gene', (77, 82))	('CASC9', 'Gene', '101805492', (77, 82))	('knockdown', 'Var', (83, 92))
651227	28854977	Furthermore, knockdown of CASC9 elevated the PDCD expression at protein level in KYSE150 and KYSE450 (Fig.	('PDCD expression', 'MPA', (45, 60))	('elevated', 'PosReg', (32, 40))	('CASC9', 'Gene', '101805492', (26, 31))	('CASC9', 'Gene', (26, 31))	('knockdown', 'Var', (13, 22))
651238	28854977	The tumor-suppressor role of PDCD4 has been characterized well, and PDCD4 knockdown could significantly promote cell growth.	('tumor', 'Disease', (4, 9))	('PDCD4', 'Gene', '27250', (29, 34))	('PDCD4', 'Gene', (68, 73))	('knockdown', 'Var', (74, 83))	('PDCD4', 'Gene', '27250', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('promote', 'PosReg', (104, 111))	('cell growth', 'CPA', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('PDCD4', 'Gene', (29, 34))
651239	28854977	Thus it is reasonable to hypothesize that the suppressive effect of CASC9 knockdown on cell growth could be rescued by suppressing PDCD4.	('PDCD4', 'Gene', '27250', (131, 136))	('CASC9', 'Gene', '101805492', (68, 73))	('suppressing', 'NegReg', (119, 130))	('knockdown', 'Var', (74, 83))	('PDCD4', 'Gene', (131, 136))	('CASC9', 'Gene', (68, 73))
651240	28854977	By cell cycle assays, we found that interfering PDCD4 partly rescued cell cycle G1/S arrest caused by CASC9 knockdown (Fig.	('knockdown', 'Var', (108, 117))	('rescued', 'NegReg', (61, 68))	('PDCD4', 'Gene', (48, 53))	('S arrest', 'Disease', (83, 91))	('S arrest', 'Disease', 'MESH:D006323', (83, 91))	('PDCD4', 'Gene', '27250', (48, 53))	('CASC9', 'Gene', '101805492', (102, 107))	('CASC9', 'Gene', (102, 107))
651243	28854977	To investigate the potential mechanism of CASC9 regulating PDCD4 expression in ESCC, we first performed bioinformatic analysis and found that the promoter region of PDCD4 was enriched in the repressive mark H3K27me3 and EZH2 binding sites in various cells (Additional file 2: Fig.	('CASC9', 'Gene', (42, 47))	('CASC9', 'Gene', '101805492', (42, 47))	('H3K27me3', 'Var', (207, 215))	('EZH2', 'Gene', '2146', (220, 224))	('EZH2', 'Gene', (220, 224))	('PDCD4', 'Gene', (165, 170))	('PDCD4', 'Gene', '27250', (165, 170))	('PDCD4', 'Gene', (59, 64))	('ESCC', 'Disease', (79, 83))	('PDCD4', 'Gene', '27250', (59, 64))	('binding', 'Interaction', (225, 232))
651255	28854977	Using ChIP and qRT-PCR assays, we found that CASC9 knockdown decreased the enrichment of EZH2 and H3K27me3 in the PDCD4 promoter region (Fig.	('EZH2', 'Gene', '2146', (89, 93))	('H3K27me3', 'Protein', (98, 106))	('CASC9', 'Gene', (45, 50))	('EZH2', 'Gene', (89, 93))	('CASC9', 'Gene', '101805492', (45, 50))	('decreased', 'NegReg', (61, 70))	('PDCD4', 'Gene', '27250', (114, 119))	('PDCD4', 'Gene', (114, 119))	('enrichment', 'MPA', (75, 85))	('knockdown', 'Var', (51, 60))
651281	28854977	Our previous work has also revealed that suppression of PDCD4 promotes G1/S transition of ESCC cells, which is consistent with present results in CASC9 knockdown cells.	('CASC9', 'Gene', '101805492', (146, 151))	('CASC9', 'Gene', (146, 151))	('PDCD4', 'Gene', '27250', (56, 61))	('G1/S transition', 'CPA', (71, 86))	('promotes', 'PosReg', (62, 70))	('PDCD4', 'Gene', (56, 61))	('suppression', 'Var', (41, 52))
651282	28854977	In this study, we further observed that suppression of PDCD4 rescued the cell cycle arrest caused by CASC9 knockdown, further sustaining the viewpoint that CASC9 performs in a PDCD4-dependent manner.	('knockdown', 'Var', (107, 116))	('PDCD4', 'Gene', '27250', (176, 181))	('CASC9', 'Gene', (101, 106))	('CASC9', 'Gene', '101805492', (101, 106))	('cell cycle arrest', 'CPA', (73, 90))	('suppression', 'NegReg', (40, 51))	('CASC9', 'Gene', (156, 161))	('CASC9', 'Gene', '101805492', (156, 161))	('PDCD4', 'Gene', (176, 181))	('PDCD4', 'Gene', (55, 60))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (73, 90))	('PDCD4', 'Gene', '27250', (55, 60))
651285	28854977	We found that knockdown of CASC9 reduced the expression of CDK6, and CCNE2, and this could be dampened by knockdown of PDCD4.	('CCNE2', 'Gene', '9134', (69, 74))	('CASC9', 'Gene', (27, 32))	('CASC9', 'Gene', '101805492', (27, 32))	('PDCD4', 'Gene', (119, 124))	('CDK6', 'Gene', (59, 63))	('PDCD4', 'Gene', '27250', (119, 124))	('expression', 'MPA', (45, 55))	('CDK6', 'Gene', '1021', (59, 63))	('reduced', 'NegReg', (33, 40))	('knockdown', 'Var', (14, 23))	('CCNE2', 'Gene', (69, 74))
651290	28854977	EZH2 is a subunit of polycomb repressive complex 2 (PRC2), which has an effect of H3K27me3 and leads to repressing gene expression.	('EZH2', 'Gene', '2146', (0, 4))	('repressing gene expression', 'MPA', (104, 130))	('EZH2', 'Gene', (0, 4))	('H3K27me3', 'Var', (82, 90))	('leads to', 'Reg', (95, 103))
651294	28854977	Finally, we verified that knockdown of CASC9 interfered the binding affinity of EZH2 to the promoter of PDCD4 and decreased the H3K27me3 level of its promoters.	('interfered', 'NegReg', (45, 55))	('binding affinity', 'Interaction', (60, 76))	('CASC9', 'Gene', '101805492', (39, 44))	('H3K27me3 level', 'MPA', (128, 142))	('decreased', 'NegReg', (114, 123))	('knockdown', 'Var', (26, 35))	('CASC9', 'Gene', (39, 44))	('EZH2', 'Gene', (80, 84))	('EZH2', 'Gene', '2146', (80, 84))	('PDCD4', 'Gene', (104, 109))	('PDCD4', 'Gene', '27250', (104, 109))
651411	23874925	We conducted a retrospective review of 141 patients with limited-disease esophageal small cell carcinoma from 3 institutions in China who underwent treatment between July 1994 and September 2008, July 1994 and July 2011, and June 2004 and December 2010, respectively.	('patients', 'Species', '9606', (43, 51))	('limited-disease esophageal small cell carcinoma', 'Disease', 'MESH:D018288', (57, 104))	('July 1994', 'Var', (196, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('esophageal small cell carcinoma', 'Phenotype', 'HP:0011459', (73, 104))	('limited-disease esophageal small cell carcinoma', 'Disease', (57, 104))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (84, 104))
651421	23874925	The data from these 3 centers were collected from the patients who were diagnosed between July 1994 and September 2008, July 1994 and July 2011, and June2004 and December 2010, respectively.	('July 1994', 'Var', (120, 129))	('patients', 'Species', '9606', (54, 62))	('July 2011', 'Var', (134, 143))
651485	21923918	Over half of all patients with metastatic disease involving five or more organs have lesions in the spleen (often microscopic), and these patients represent 2-7% of those who die from end-stage metastatic disease.	('metastatic disease', 'Disease', (31, 49))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (138, 146))	('lesions', 'Var', (85, 92))
651574	19834547	Fifty-six ESCC patients were enrolled in this study based on the following criteria: 1) ESCC treated at Kobe University Hospital from August 2002 to June 2006; 2) clinical stage T1 to T4, N0 or N1, and M0 or M1a according to the International Union Against Cancer tumor node metastasis (TNM) classification; 3) age less than 85 years; 4) an Eastern Cooperative Oncology Group performance status of 0 to 2; 5) adequate bone marrow, marrow, renal, and hepatic function; 6) no prior chemotherapy; 7) no severe medical complications; and 8) no other active malignancies (except early cancer).	('Oncology', 'Phenotype', 'HP:0002664', (361, 369))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('ESCC', 'Disease', (88, 92))	('patients', 'Species', '9606', (15, 23))	('M0 or', 'Var', (202, 207))	('cancer', 'Disease', 'MESH:D009369', (580, 586))	('cancer', 'Disease', (580, 586))	('malignancies', 'Disease', 'MESH:D009369', (553, 565))	('Cancer', 'Phenotype', 'HP:0002664', (257, 263))	('malignancies', 'Disease', (553, 565))	('cancer', 'Phenotype', 'HP:0002664', (580, 586))	('Cancer tumor node metastasis', 'Disease', 'MESH:D009362', (257, 285))	('Cancer tumor node metastasis', 'Disease', (257, 285))
651610	19834547	The circadian rhythm in plasma concentrations of 5-FU observed with CDDP was altered when NDP was used instead, and clinical response can be predicted on the basis of the plasma concentrations of 5-FU in the CDDP group, but not in the NDP group.	('NDP', 'Chemical', 'MESH:C053989', (235, 238))	('5-FU', 'Chemical', 'MESH:D005472', (196, 200))	('5-FU', 'Chemical', 'MESH:D005472', (49, 53))	('CDDP', 'Chemical', '-', (68, 72))	('altered', 'Reg', (77, 84))	('CDDP', 'Chemical', '-', (208, 212))	('NDP', 'Chemical', 'MESH:C053989', (90, 93))	('circadian', 'MPA', (4, 13))	('CDDP', 'Var', (208, 212))
651614	33335531	However, we recently found that patients with peanut allergy may have asymptomatic esophageal eosinophilia at baseline and that peanut OIT induces transient esophageal eosinophilia in most subjects.	('patients', 'Species', '9606', (32, 40))	('esophageal eosinophilia', 'Disease', (157, 180))	('allergy', 'Phenotype', 'HP:0012393', (53, 60))	('allergy', 'Disease', (53, 60))	('peanut', 'Var', (128, 134))	('eosinophilia', 'Phenotype', 'HP:0001880', (94, 106))	('allergy', 'Disease', 'MESH:D004342', (53, 60))	('esophageal eosinophilia', 'Disease', (83, 106))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (157, 180))	('peanut', 'Species', '3818', (128, 134))	('eosinophilia', 'Phenotype', 'HP:0001880', (168, 180))	('peanut', 'Species', '3818', (46, 52))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (83, 106))
651647	33335531	Among the endotypes, EoEe1 is the most benign, while EoEe2 is associated with marked type 2 inflammation.	('EoEe2', 'Var', (53, 58))	('EoE', 'Phenotype', 'HP:0410151', (53, 56))	('associated', 'Reg', (62, 72))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('EoE', 'Phenotype', 'HP:0410151', (21, 24))	('inflammation', 'Disease', (92, 104))	('EoEe1', 'Var', (21, 26))
651652	33335531	Benralizumab binds to IL-5Ralpha blocking interaction with IL-5 and promoting antibody-dependent cellular cytotoxicity (ADCC) and deletion of eosinophils.	('IL-5Ralpha', 'Gene', '3568', (22, 32))	('IL-5Ralpha', 'Gene', (22, 32))	('interaction', 'Interaction', (42, 53))	('AD', 'Disease', 'MESH:D000544', (120, 122))	('cytotoxicity', 'Disease', (106, 118))	('Benralizumab', 'Chemical', 'MESH:C571386', (0, 12))	('deletion', 'Var', (130, 138))	('AD', 'Disease', (120, 122))	('blocking', 'NegReg', (33, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (106, 118))	('promoting', 'PosReg', (68, 77))
651655	33335531	Ligation of siglec-8 induces apoptosis of eosinophils and inhibits mast cell activity.	('apoptosis', 'CPA', (29, 38))	('Ligation', 'Var', (0, 8))	('siglec-8', 'Gene', (12, 20))	('induces', 'Reg', (21, 28))	('siglec-8', 'Gene', '27181', (12, 20))	('inhibits', 'NegReg', (58, 66))	('mast cell activity', 'CPA', (67, 85))
651701	33335531	The eosinophil microenvironment may become problematic for the epithelium with chronic inflammation:for example, eosinophil oxygen metabolism may induce tissue hypoxia resulting in barrier impairment.	('inflammation', 'Disease', (87, 99))	('hypoxia', 'Disease', (160, 167))	('hypoxia', 'Disease', 'MESH:D000860', (160, 167))	('eosinophil oxygen metabolism', 'Var', (113, 141))	('barrier', 'MPA', (181, 188))	('induce', 'Reg', (146, 152))	('oxygen', 'Chemical', 'MESH:D010100', (124, 130))	('inflammation', 'Disease', 'MESH:D007249', (87, 99))
651729	33052138	Association between the pri-miR-26a-1 rs7372209 C>T polymorphism and cancer susceptibility: multivariate analysis and trial sequential analysis MiR-26 has been suggested to play a tumor-suppressive role in cancer development, which could be influenced by the mutate pri-miR-26a-1.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('miR-26a-1', 'Gene', (28, 37))	('miR-26a-1', 'Gene', '407015', (270, 279))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('miR-26a-1', 'Gene', '407015', (28, 37))	('tumor', 'Disease', (180, 185))	('rs7372209', 'Mutation', 'rs7372209', (38, 47))	('mutate', 'Var', (259, 265))	('miR-26a-1', 'Gene', (270, 279))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (206, 212))	('influenced', 'Reg', (241, 251))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('MiR-26', 'Gene', (144, 150))	('cancer', 'Disease', (69, 75))
651730	33052138	Molecular epidemiological studies have demonstrated some inconsistent associations between pri-miR-26a-1 rs7372209 C>T polymorphism and cancer risk.	('miR-26a-1', 'Gene', '407015', (95, 104))	('rs7372209', 'Mutation', 'rs7372209', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('rs7372209 C>T', 'Var', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('miR-26a-1', 'Gene', (95, 104))
651731	33052138	We therefore performed this meta-analysis with multivariate statistic method to comprehensively evaluate the associations between rs7372209 C>T polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('rs7372209 C>T', 'Var', (130, 143))	('rs7372209', 'Mutation', 'rs7372209', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))
651734	33052138	Overall, our results indicated that the pri-miR-26a-1 rs7372209 C>T polymorphism may not be a potential risk for cancer development.	('rs7372209 C>T', 'Var', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('miR-26a-1', 'Gene', '407015', (44, 53))	('cancer', 'Disease', (113, 119))	('rs7372209', 'Mutation', 'rs7372209', (54, 63))	('miR-26a-1', 'Gene', (44, 53))
651742	33052138	The aberrant expression of related genes in a cell causes abnormalities in cell proliferation and cancer development.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('aberrant expression', 'Var', (4, 23))	('cancer', 'Disease', (98, 104))	('cell proliferation', 'CPA', (75, 93))
651743	33052138	MiRNA-26a is a new microRNA that plays a tumor-suppressive role during cell cycle by inhibiting cancer cell proliferation, invasion, and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('inhibiting', 'NegReg', (85, 95))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('invasion', 'CPA', (123, 131))	('MiRNA-26a', 'Chemical', '-', (0, 9))	('MiRNA-26a', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cancer', 'Disease', (96, 102))
651745	33052138	Single nucleotide polymorphism (SNP) is one of the most common type of gene mutation, and the SNPs in pri-miRNA genes can change spatial structure, affect the miRNA-mRNA interaction network, activate the aberrant expression of target genes and increase the risk of cancer.	('change', 'Reg', (122, 128))	('SNPs', 'Var', (94, 98))	('increase', 'PosReg', (244, 252))	('pri-miRNA', 'Gene', (102, 111))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('affect', 'Reg', (148, 154))	('miRNA-mRNA interaction network', 'MPA', (159, 189))	('Single nucleotide polymorphism', 'Var', (0, 30))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('spatial structure', 'MPA', (129, 146))	('activate', 'PosReg', (191, 199))	('cancer', 'Disease', (265, 271))	('aberrant expression', 'MPA', (204, 223))
651746	33052138	For pri-miR-26a-1, rs7372209 C>T is the most common locus that has attracted more attentions.	('rs7372209', 'Mutation', 'rs7372209', (19, 28))	('rs7372209 C>T', 'Var', (19, 32))	('miR-26a-1', 'Gene', '407015', (8, 17))	('miR-26a-1', 'Gene', (8, 17))
651747	33052138	published the first case-control study of Chinese population and results did not show any significant association between the pri-miR-26a-1 rs7372209 C>T polymorphism and bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('miR-26a-1', 'Gene', '407015', (130, 139))	('rs7372209 C>T polymorphism', 'Var', (140, 166))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('bladder cancer', 'Disease', 'MESH:D001749', (171, 185))	('bladder cancer', 'Disease', (171, 185))	('rs7372209', 'Mutation', 'rs7372209', (140, 149))	('miR-26a-1', 'Gene', (130, 139))
651748	33052138	Subsequently, numerous epidemiological studies have been performed to examine the relationship between the pri-miR-26a-1 rs7372209 C>T polymorphism and the risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('miR-26a-1', 'Gene', (111, 120))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('rs7372209 C>T', 'Var', (121, 134))	('rs7372209', 'Mutation', 'rs7372209', (121, 130))	('miR-26a-1', 'Gene', '407015', (111, 120))
651749	33052138	Therefore, this meta-analysis aimed to conduct a precise and comprehensive assessment of the association between the pri-miR-26a-1 rs7372209 C>T polymorphism and the risk of cancer.	('miR-26a-1', 'Gene', (121, 130))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('miR-26a-1', 'Gene', '407015', (121, 130))	('association', 'Interaction', (93, 104))	('rs7372209', 'Mutation', 'rs7372209', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('rs7372209 C>T', 'Var', (131, 144))
651753	33052138	Then, the remaining genetic models were assessed via univariate analyses, and no significant association was found between the pri-miR-26a-1 rs7372209 C>T polymorphism and the risk of cancer in the whole population (Supplementary Table 1).	('cancer', 'Disease', (184, 190))	('miR-26a-1', 'Gene', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('rs7372209', 'Mutation', 'rs7372209', (141, 150))	('miR-26a-1', 'Gene', '407015', (131, 140))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('rs7372209 C>T', 'Var', (141, 154))
651755	33052138	These data indicated that the cumulative evidence on the pri-miR-26a-1 rs7372209 C>T polymorphism was not adequate and more trials were required (Figure 6).	('rs7372209 C>T', 'Var', (71, 84))	('rs7372209', 'Mutation', 'rs7372209', (71, 80))	('miR-26a-1', 'Gene', '407015', (61, 70))	('miR-26a-1', 'Gene', (61, 70))
651756	33052138	The aberrant mutation of pri-miRNAs could change the nucleotide sequence and spatial structure of the corresponding miRNAs, thereby interfering with the normal physiological processes of the cells and consequently leading to the formation and proliferation of abnormal tumor cells.	('leading to', 'Reg', (214, 224))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('change', 'Reg', (42, 48))	('pri-miRNAs', 'Gene', (25, 35))	('abnormal tumor', 'Phenotype', 'HP:0002664', (260, 274))	('abnormal tumor', 'Disease', (260, 274))	('interfering', 'NegReg', (132, 143))	('aberrant mutation', 'Var', (4, 21))	('proliferation', 'CPA', (243, 256))	('normal physiological processes of the', 'MPA', (153, 190))	('spatial structure', 'MPA', (77, 94))	('formation', 'CPA', (229, 238))	('abnormal tumor', 'Disease', 'MESH:D009369', (260, 274))	('nucleotide sequence', 'MPA', (53, 72))
651758	33052138	The pri-miR-26a-1 gene is located in the human chromosome 3q21.3, and rs7372209 C>T polymorphism is the most important SNP locus in the pri-miR-26a-1 gene, which significantly associated with susceptibility to various types of cancers.	('miR-26a-1', 'Gene', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('susceptibility', 'Reg', (192, 206))	('human', 'Species', '9606', (41, 46))	('miR-26a-1', 'Gene', '407015', (140, 149))	('associated', 'Reg', (176, 186))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('miR-26a-1', 'Gene', '407015', (8, 17))	('miR-26a-1', 'Gene', (8, 17))	('rs7372209 C>T', 'Var', (70, 83))	('rs7372209', 'Mutation', 'rs7372209', (70, 79))	('cancers', 'Disease', (227, 234))	('cancers', 'Disease', 'MESH:D009369', (227, 234))
651760	33052138	(2008) first analyzed the frequency of rs7372209 C>T polymorphism in individuals with bladder cancer and indicated less susceptibility in dominant model (OR=1.10, 95% CI=0.89-1.36, P=0.38) in US.	('less', 'NegReg', (115, 119))	('bladder cancer', 'Disease', (86, 100))	('rs7372209 C>T', 'Var', (39, 52))	('rs7372209', 'Mutation', 'rs7372209', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('susceptibility', 'MPA', (120, 134))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))
651761	33052138	studied the rs7372209 C>T polymorphism to identify its effect on esophageal cancer susceptibility among Chinese and showed that there was no significant difference between the control and case groups in genotypic distribution in 2013 and 2014 separately (for dominant model: OR=0.89, 95% CI=0.67-1.18, P=0.42; OR=1.03, 95% CI=0.87-1.21, P=0.73), indicating no significant risk for esophageal cancer.	('esophageal cancer', 'Disease', (381, 398))	('rs7372209 C>T', 'Var', (12, 25))	('rs7372209', 'Mutation', 'rs7372209', (12, 21))	('esophageal cancer', 'Disease', (65, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (381, 398))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))
651762	33052138	reported that South Africans with rs7372209 C>T polymorphism had a significantly reduced risk for esophageal squamous cell carcinoma in the additive model (OR=0.47, 95% CI=0.28-0.78, P=0.003) and the dominant genetic model (OR=0.44, 95% CI=0.26-0.74, P=0.002) in the mixed ancestry group in 2013.	('esophageal squamous cell carcinoma', 'Disease', (98, 132))	('rs7372209 C>T', 'Var', (34, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('rs7372209', 'Mutation', 'rs7372209', (34, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('reduced', 'NegReg', (81, 88))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (98, 132))
651763	33052138	investigated the association between rs7372209 C>T polymorphism and the risk of lung cancer and found that the subjects with T allele of rs7372209 C>T polymorphism had an increased risk of cancer development (OR=1.27, 95% CI=1.07-1.50, P=0.01).	('rs7372209', 'Mutation', 'rs7372209', (37, 46))	('rs7372209', 'Var', (37, 46))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('rs7372209 C>T', 'Var', (137, 150))	('rs7372209', 'Mutation', 'rs7372209', (137, 146))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Disease', (85, 91))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (189, 195))
651764	33052138	focused on the correlation between rs7372209 C>T polymorphism and lung cancer.	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs7372209', 'Mutation', 'rs7372209', (35, 44))	('rs7372209 C>T', 'Var', (35, 48))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
651766	33052138	conducted a case-control study on the association between rs7372209 C>T polymorphism and the risk of cervical cancer among southern Chinese women.	('cancer', 'Disease', (110, 116))	('association', 'Interaction', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rs7372209 C>T', 'Var', (58, 71))	('women', 'Species', '9606', (140, 145))	('rs7372209', 'Mutation', 'rs7372209', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
651767	33052138	However, this study did not identify any significant relationship between the polymorphic loci and the risk of cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('polymorphic loci', 'Var', (78, 94))
651768	33052138	evaluated the association between rs7372209 C>T polymorphism and the risk of breast cancer among Chinese women, and results showed that there was no significant association between them.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('rs7372209 C>T', 'Var', (34, 47))	('women', 'Species', '9606', (105, 110))	('rs7372209', 'Mutation', 'rs7372209', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
651769	33052138	revealed that the rs7372209 C>T polymorphism was not significantly associated with colorectal cancer in 2016.	('colorectal cancer', 'Disease', 'MESH:D015179', (83, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('colorectal cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('associated', 'Reg', (67, 77))	('rs7372209 C>T', 'Var', (18, 31))	('rs7372209', 'Mutation', 'rs7372209', (18, 27))
651770	33052138	In addition, the protective effect of rs7372209 in the dominant model was observed in advanced-stage oral squamous cell carcinoma in the study of Yang et al.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (106, 129))	('rs7372209', 'Var', (38, 47))	('rs7372209', 'Mutation', 'rs7372209', (38, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('squamous cell carcinoma', 'Disease', (106, 129))
651771	33052138	Hence, we conducted a meta-analysis of 11 publications (12 independent case-control studies) involving 12,223 participants to assess the association between rs7372209 C>T polymorphism and cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('rs7372209 C>T', 'Var', (157, 170))	('rs7372209', 'Mutation', 'rs7372209', (157, 166))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('participants', 'Species', '9606', (110, 122))
651774	33052138	In the current meta-analysis, we comprehensively summarized data on the relationship between rs7372209 C>T polymorphism and the risk of cancer, and no significant association was found between rs7372209 C>T polymorphism and cancer in the whole population and in the subgroup with the finest genetic model.	('rs7372209', 'Mutation', 'rs7372209', (193, 202))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('rs7372209 C', 'Var', (193, 204))	('cancer', 'Disease', (136, 142))	('rs7372209 C>T', 'Var', (93, 106))	('rs7372209', 'Mutation', 'rs7372209', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
651776	33052138	Furthermore, some univariate analyses revealed that Chinese have increased risks of rs7372209 C>T polymorphism and cancer.	('rs7372209', 'Mutation', 'rs7372209', (84, 93))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rs7372209 C>T polymorphism', 'Var', (84, 110))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
651777	33052138	The co-dominant and recessive models indicated that the TT mutant homozygote was associated with a 19% increased risk of cancer development in Chinese, but not in Caucasians.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutant', 'Var', (59, 65))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))
651779	33052138	Variations in a single gene and locus might not play a decisive role in tumorigenesis affecting the entire signaling pathway, so did the rs7372209 C>T polymorphism too.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('rs7372209 C>T', 'Var', (137, 150))	('rs7372209', 'Mutation', 'rs7372209', (137, 146))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
651781	33052138	Then, the analysis indicated that the over-dominant genetic model could be the most appropriate choice and the results revealed there was no significant association between rs7372209 C>T polymorphism and cancers in the general and subgroup analyses.	('rs7372209', 'Mutation', 'rs7372209', (173, 182))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('rs7372209 C>T', 'Var', (173, 186))
651782	33052138	To date, this study conducted the first meta-analysis on the association between rs7372209 C>T polymorphism and the risk of cancer.	('cancer', 'Disease', (124, 130))	('rs7372209 C>T', 'Var', (81, 94))	('rs7372209', 'Mutation', 'rs7372209', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('association', 'Interaction', (61, 72))
651784	33052138	In summary, the pri-miR-26a-1 rs7372209 C>T polymorphism may not be an independent risk factor for tumorigenesis and the development of cancer.	('tumor', 'Disease', (99, 104))	('rs7372209 C>T', 'Var', (30, 43))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('rs7372209', 'Mutation', 'rs7372209', (30, 39))	('miR-26a-1', 'Gene', '407015', (20, 29))	('cancer', 'Disease', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('miR-26a-1', 'Gene', (20, 29))
651785	33052138	Relevant studies were searched in online databases (such as Science Citation Index, Embase, PubMed, CNKI and Wanfang) to investigate the relationship between the pri-miR-26a-1 rs7372209 C>T polymorphism and the risk of cancer from inception to June 1, 2019.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('miR-26a-1', 'Gene', (166, 175))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('rs7372209', 'Mutation', 'rs7372209', (176, 185))	('cancer', 'Disease', (219, 225))	('rs7372209 C>T', 'Var', (176, 189))	('miR-26a-1', 'Gene', '407015', (166, 175))
651786	33052138	The following search terms and strategy were used (e.g., PubMed database): #1 pri-miR-26a-1 #2 microRNA-26a #3 miR-26a #4 miR-26a-1 #5 rs7372209 #6 #1 OR #2 OR #3 OR #4 OR #5 #7 mutation #8 variant #9 polymorphism #10 #7 OR #8 OR #9 #11 neoplasm #12 tumor #13 cancer #14 #11 OR #12 OR #13 #15 #6 AND #10 AND #14 The inclusion criteria were as follows: (1) case-control studies that investigated the association between the pri-miR-26a-1 rs7372209 C>T polymorphism and the risk of cancer; (2) those with a sufficient number of data on genotype distribution that can be utilized to examine the crude odds ratios (ORs) and 95% confidence intervals (CIs); (3) those written in English and Chinese only; and (4) those in which the largest or most recently sample data were adopted in cases of multiple publications with duplicate or overlapping data on the same theme.	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('neoplasm', 'Phenotype', 'HP:0002664', (237, 245))	('tumor', 'Disease', (250, 255))	('miR-26a-1', 'Gene', '407015', (427, 436))	('cancer', 'Disease', 'MESH:D009369', (480, 486))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('rs7372209 C>T polymorphism', 'Var', (437, 463))	('rs7372209', 'Mutation', 'rs7372209', (135, 144))	('miR-26a-1', 'Gene', '407015', (82, 91))	('rs7372209', 'Mutation', 'rs7372209', (437, 446))	('neoplasm', 'Disease', 'MESH:D009369', (237, 245))	('miR-26a-1', 'Gene', '407015', (122, 131))	('cancer', 'Disease', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('miR-26a-1', 'Gene', (427, 436))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('neoplasm', 'Disease', (237, 245))	('cancer', 'Disease', (480, 486))	('miR-26a-1', 'Gene', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (480, 486))	('miR-26a-1', 'Gene', (122, 131))
651787	33052138	Meanwhile, the exclusion criteria were as follows: (1) case series, meta-analyses or reviews; (2) duplicate publications; (3) case-control studies that did not focus on pri-miR-26a-1 rs7372209 C>T locus; (4) unrelated studies; and (5) studies with insufficient data.	('miR-26a-1', 'Gene', '407015', (173, 182))	('miR-26a-1', 'Gene', (173, 182))	('rs7372209 C>T', 'Var', (183, 196))	('rs7372209', 'Mutation', 'rs7372209', (183, 192))
651789	33052138	The ORs and 95% CIs were calculated to examine the relationship between the pri-miR-26a-1 rs7372209 C>T polymorphism and the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('miR-26a-1', 'Gene', (80, 89))	('cancer', 'Disease', (133, 139))	('miR-26a-1', 'Gene', '407015', (80, 89))	('rs7372209 C>T', 'Var', (90, 103))	('rs7372209', 'Mutation', 'rs7372209', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
651803	33228549	Many studies showed that endoscopic screening might be associated with reduced mortality on EC and GC in some high-risk areas of Asia.	('mortality', 'Disease', 'MESH:D003643', (79, 88))	('reduced', 'NegReg', (71, 78))	('endoscopic screening', 'Var', (25, 45))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('mortality', 'Disease', (79, 88))
651859	33228549	However, many other studies showed endoscopic screening may be associated with reduced GC mortality in Japan, South Korea and rural China.	('mortality', 'Disease', (90, 99))	('reduced', 'NegReg', (79, 86))	('GC', 'Phenotype', 'HP:0012126', (87, 89))	('mortality', 'Disease', 'MESH:D003643', (90, 99))	('endoscopic screening', 'Var', (35, 55))
651901	32884352	Mutations in SLC39A6, EP300 (10%), and FAM135B (6.8%) as well as amplification or overexpression of EGFR were associated with a poor prognosis of ESCC.	('FAM135B', 'Gene', (39, 46))	('EP300', 'Gene', (22, 27))	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))	('FAM135B', 'Gene', '51059', (39, 46))	('associated with', 'Reg', (110, 125))	('Mutations', 'Var', (0, 9))	('SLC39A6', 'Gene', '25800', (13, 20))	('EP300', 'Gene', '2033', (22, 27))	('ESCC', 'Disease', (146, 150))	('SLC39A6', 'Gene', (13, 20))
651902	32884352	Moreover, many genes involved in cell cycle regulation, DNA repair and apoptosis were mutated or amplified in 99% of cases, including TP53 (93%), CCND1 (33%), CDK4/CDK6 (23.6%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%).	('RB1', 'Gene', '5925', (209, 212))	('CDK4', 'Gene', (159, 163))	('mutated', 'Var', (86, 93))	('TP53', 'Gene', (134, 138))	('NFE2L2', 'Gene', '4780', (192, 198))	('CDK4', 'Gene', '1019', (159, 163))	('amplified', 'Var', (97, 106))	('CDK6', 'Gene', (164, 168))	('CCND1', 'Gene', '595', (146, 151))	('NFE2L2', 'Gene', (192, 198))	('CDKN2A', 'Gene', (178, 184))	('CDK6', 'Gene', '1021', (164, 168))	('RB1', 'Gene', (209, 212))	('CDKN2A', 'Gene', '1029', (178, 184))	('TP53', 'Gene', '7157', (134, 138))	('CCND1', 'Gene', (146, 151))
651903	32884352	As the highest frequency of mutated gene, mutation of TP53 in the DNA binding domain has been regarded as the main cause for p53 inactivation and proposed as a key factor in driving ESCC progression.	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('TP53', 'Gene', '7157', (54, 58))	('mutation', 'Var', (42, 50))	('ESCC', 'Disease', (182, 186))	('inactivation', 'NegReg', (129, 141))	('TP53', 'Gene', (54, 58))
651904	32884352	Two compounds (ie, APR-246, COTI-2) that can reactivate missense-mutant p53 protein have been tested in clinical Phase I/II trials.	('missense-mutant', 'Var', (56, 71))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('protein', 'Protein', (76, 83))	('reactivate', 'MPA', (45, 55))
651906	32884352	Importantly, the tumor-promoting functions of p53 mutations also depend on the shorter p53 isoforms from the mutated FLp53 in some specific conditions, like missense mutations.	('tumor', 'Disease', (17, 22))	('p53', 'Gene', (87, 90))	('p53', 'Gene', (46, 49))	('mutations', 'Var', (50, 59))	('p53', 'Gene', '7157', (87, 90))	('missense mutations', 'Var', (157, 175))	('p53', 'Gene', '7157', (119, 122))	('p53', 'Gene', '7157', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('p53', 'Gene', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
651914	32884352	Circulating p53 mutations were significantly associated with drug resistance and disease progression of patients with metastatic breast cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('mutations', 'Var', (16, 25))	('p53', 'Gene', (12, 15))	('associated', 'Reg', (45, 55))	('p53', 'Gene', '7157', (12, 15))	('disease progression', 'CPA', (81, 100))	('drug resistance', 'CPA', (61, 76))	('drug resistance', 'Phenotype', 'HP:0020174', (61, 76))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
651955	32884352	Pearson's correlation coefficient analysis revealed that serum Delta133p53, FLp53 and Delta133p53/FLp53 ratio were positively correlated with their tissue expression, and Pearson's correlation coefficients were 0.7019 (P < 0.0001) (Figure 2A), 0.4030 (P < 0.0001) (Figure 2B) and 0.4137 (P < 0.0001) (Figure 2C), respectively.	('0.4030', 'Var', (244, 250))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('0.4137', 'Var', (280, 286))	('tissue expression', 'MPA', (148, 165))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (100, 103))	('p53', 'Gene', '7157', (71, 74))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (78, 81))	('p53', 'Gene', (100, 103))
651969	32884352	The AUC values of tissue and serum Delta133p53/FLp53 ratio in the Cox regression model for OS were 0.695 (P = 0.0351) and 0.641 (P = 0.0360), respectively (Figure 3A), and 0.692 (P = 0.0337) and 0.649 (P = 0.0340) for PFS, respectively (Figure 3B).	('p53', 'Gene', (49, 52))	('0.641', 'Var', (122, 127))	('p53', 'Gene', '7157', (49, 52))	('0.649', 'Var', (195, 200))	('PFS', 'Disease', (218, 221))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('0.692', 'Var', (172, 177))
651981	32884352	The best cutoff value of the serum Delta133p53/FLp53 ratio to distinguish ESCC patients from healthy donors was 0.6798 (Sensitivity: 76.11%; Specificity: 77.55%, AUC = 0.8376), which was also less than 2.9160 (Figure S4E).	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('ESCC', 'Disease', (74, 78))	('patients', 'Species', '9606', (79, 87))	('p53', 'Gene', (43, 46))	('0.6798', 'Var', (112, 118))	('p53', 'Gene', '7157', (43, 46))
652013	32884352	ESCC, esophageal squamous cell carcinoma; FLp53, full-length p53; OS, overall survival; PFS, progression-free survival; ROC, receiver-operating characteristic curve; CNAs, copy number alterations; TTR, time to relapse; VSMC, vascular smooth muscle cell.	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('copy number alterations', 'Var', (172, 195))	('esophageal squamous cell carcinoma', 'Disease', (6, 40))	('p53', 'Gene', (44, 47))	('ESCC', 'Disease', (0, 4))	('p53', 'Gene', '7157', (44, 47))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (6, 40))
652029	31207904	Nab-paclitaxel has a favorable toxicity profile compared to conventional taxanes, and has shown non-inferiority to solvent-based paclitaxel with less toxicity in the second-line treatment of gastric carcinoma.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('gastric carcinoma', 'Disease', (191, 208))	('taxanes', 'Chemical', 'MESH:D043823', (73, 80))	('toxicity', 'Disease', 'MESH:D064420', (150, 158))	('Nab-paclitaxel', 'Var', (0, 14))	('toxicity', 'Disease', (150, 158))	('toxicity', 'Disease', 'MESH:D064420', (31, 39))	('toxicity', 'Disease', (31, 39))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (191, 208))	('paclitaxel', 'Chemical', 'MESH:D017239', (129, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('gastric carcinoma', 'Disease', 'MESH:D013274', (191, 208))
652030	31207904	The primary aim of this study was to determine the recommended dose for phase II testing (RP2D) of nab-paclitaxel combined with capecitabine and oxaliplatin (CapOx), and to assess its feasibility in terms of toxicity.	('paclitaxel', 'Chemical', 'MESH:D017239', (103, 113))	('CapOx', 'Chemical', '-', (158, 163))	('nab', 'Chemical', '-', (99, 102))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (145, 156))	('nab-paclitaxel', 'Var', (99, 113))	('capecitabine', 'Chemical', 'MESH:D000069287', (128, 140))	('toxicity', 'Disease', 'MESH:D064420', (208, 216))	('toxicity', 'Disease', (208, 216))
652034	31207904	Previous research has shown that CAFs are associated with a worse prognosis in esophageal cancer and precede the deposition of collagen:another main component of the stroma.	('CAFs', 'Var', (33, 37))	('esophageal cancer', 'Disease', (79, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
652079	31207904	Baseline tumor burden (median 111.16 mL; range 2.34-3475.45 mL) was not correlated with baseline ADAM12 and IL-6 concentrations (p = 0.29 and p = 0.28, respectively), indicating that the poor survival of patients with high baseline ADAM12 levels was not merely due to a higher tumor burden (see Figure S5 for representative images for primary tumor and metastases segmentation).	('IL-6', 'Gene', '3569', (108, 112))	('metastases segmentation', 'Disease', 'MESH:D009362', (353, 376))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('IL-6', 'Gene', (108, 112))	('patients', 'Species', '9606', (204, 212))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (343, 348))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('ADAM12', 'Gene', '8038', (232, 238))	('ADAM12', 'Gene', (232, 238))	('tumor', 'Disease', (277, 282))	('high', 'Var', (218, 222))	('ADAM12', 'Gene', '8038', (97, 103))	('metastases segmentation', 'Disease', (353, 376))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('ADAM12', 'Gene', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))
652123	31207904	Any DLT was considered to be related to nab-paclitaxel alone or in combination with oxaliplatin and capecitabine, and unrelated to disease progression, inter-current illness, or concomitant medications.	('capecitabine', 'Chemical', 'MESH:D000069287', (100, 112))	('nab', 'Chemical', '-', (40, 43))	('nab-paclitaxel', 'Var', (40, 54))	('paclitaxel', 'Chemical', 'MESH:D017239', (44, 54))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (84, 95))	('DLT', 'Disease', (4, 7))
652382	31156297	More than 5 kg weight loss is the indicator of poor prognosis, while albumin <30 g/L increase the risk of postoperative anastomosis leakage.	('weight loss', 'Phenotype', 'HP:0001824', (15, 26))	('albumin', 'Protein', (69, 76))	('postoperative anastomosis leakage', 'Disease', (106, 139))	('loss', 'NegReg', (22, 26))	('postoperative anastomosis leakage', 'Disease', 'MESH:D010149', (106, 139))	('<30 g/L', 'Var', (77, 84))
652395	31156297	For patients with T1-3N0-1M0 esophageal carcinoma, right transthoracic MIE is recommended, especially for those have underwent neoadjuvant radio/chemotherapy.	('T1-3N0-1M0', 'Var', (18, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('patients', 'Species', '9606', (4, 12))	('esophageal carcinoma', 'Disease', (29, 49))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (29, 49))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (29, 49))
652404	31156297	However, three-field dissection is associated with more complications, especially recurrent laryngeal nerve paralysis, anastomosis leakage, and aspiration pneumonia.	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (144, 164))	('anastomosis leakage', 'Disease', (119, 138))	('paralysis', 'Phenotype', 'HP:0003470', (108, 117))	('laryngeal nerve paralysis', 'Disease', 'MESH:D014826', (92, 117))	('laryngeal nerve paralysis', 'Disease', (92, 117))	('laryngeal nerve paralysis', 'Phenotype', 'HP:0001605', (92, 117))	('aspiration pneumonia', 'Disease', (144, 164))	('aspiration', 'Phenotype', 'HP:0002835', (144, 154))	('three-field', 'Var', (9, 20))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (144, 164))	('pneumonia', 'Phenotype', 'HP:0002090', (155, 164))
652408	31156297	For example: upper segment of thoracic esophageal cancer, or when cervical lymph nodes metastasis is suspected before surgery, or fast biopsy confirmed metastasis of any recurrent laryngeal nerve lymph nodes (left or right).	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('thoracic esophageal cancer', 'Disease', (30, 56))	('metastasis', 'Var', (152, 162))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (30, 56))
652430	31156297	(2) Adjuvant radiotherapy/concurrent radiochemotherapy 1) R1 (include circular edge) or R2 resection; 2) For squamous carcinoma, R0 resection, pathologically N+, or T4N0, lymph node capsule involved.	('squamous carcinoma', 'Disease', (109, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('R0 resection', 'Var', (129, 141))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (109, 127))	('squamous carcinoma', 'Disease', 'MESH:D002294', (109, 127))	('T4N0', 'Var', (165, 169))
652431	31156297	For adenocarcinoma, pathologically N+, or N3-4aN0, or T2N0 lower segment of thoracic esophageal/esophagogastric junction adenocarcinoma with risk factor(s) (e.g.	('N3-4aN0', 'Var', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('thoracic esophageal/esophagogastric junction adenocarcinoma', 'Disease', 'MESH:D013899', (76, 135))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (96, 135))	('adenocarcinoma', 'Disease', (121, 135))	('adenocarcinoma', 'Disease', (4, 18))	('T2N0', 'Var', (54, 58))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('adenocarcinoma', 'Disease', 'MESH:D000230', (121, 135))
652470	31156297	Concurrent radiochemotherapy V20<=28%; (2) Heart: V30<=40%, V40<=30%; (3) Cord PRV: Dmax<=45 Gy;  (4) Stomach: V40<=40%, Dmax<=55-60 Gy;  (5) Intestine: V40<=40%, Dmax<=55 Gy;  (6) Kidneys: V20<=30%; (7) Liver: V30<=30%.	('Dmax<=55-60', 'Var', (121, 132))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('V20', 'Var', (190, 193))	('V40<=40%', 'Var', (111, 119))	('V20', 'Var', (29, 32))	('V40<=40%', 'Var', (153, 161))
652524	31156297	Based on current available large randomized controlled clinical studies on esophageal cancer, we recommend neoadjuvant chemotherapy for patients with clinically T3-4N0M0 or T1-3N1-3M0 resectable esophageal cancer to increase theen-bloc (R0) dissection rate and improve overall survival (OS), without increasing postoperative complications.	('esophageal cancer', 'Disease', (195, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('T1-3N1-3M0', 'Var', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('T3-4N0M0', 'Var', (161, 169))	('improve', 'PosReg', (261, 268))	('overall', 'MPA', (269, 276))	('patients', 'Species', '9606', (136, 144))	('esophageal cancer', 'Disease', (75, 92))	('increase', 'PosReg', (216, 224))
652527	31156297	We recommend neoadjuvant chemotherapy for patients with resectable adenocarcinoma locating in lower segment of esophagus or esophagogastric junction to improve 5-year survival without increasing postoperative mortality and morbidity.	('adenocarcinoma', 'Disease', (67, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('locating', 'Var', (82, 90))	('improve', 'PosReg', (152, 159))	('patients', 'Species', '9606', (42, 50))
652576	31156297	Further research indicates the patients with EGFR mutation may be potentially benefit from EGFR-TKIs.	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', (45, 49))	('patients', 'Species', '9606', (31, 39))	('benefit', 'PosReg', (78, 85))	('EGFR', 'Gene', '1956', (91, 95))	('EGFR', 'Gene', '1956', (45, 49))	('mutation', 'Var', (50, 58))
652641	31156297	The threshold of 0-I subtype and 0-IIa subtype is 1.0 mm of elevation (the single cup of openned biopsy forceps is approximately 1.2 mm), while the thresholds of 0-III and 0-IIc is 0.5 mm of depression (half of one cup of biopsy forceps is approximately 0.6 mm).	('elevation', 'PosReg', (60, 69))	('0-IIa', 'Var', (33, 38))	('depression', 'Phenotype', 'HP:0000716', (191, 201))	('depression', 'Disease', 'MESH:D000275', (191, 201))	('depression', 'Disease', (191, 201))
652658	31156297	For those with lymph node metastasis, or with distant metastasis, or limited SM2/SM3 esophageal cancer with high-risk of lymph node metastasis, surgery is still the preferred treatment.	('SM2/SM3', 'Var', (77, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('distant metastasis', 'CPA', (46, 64))	('lymph node metastasis', 'CPA', (15, 36))	('esophageal cancer', 'Disease', (85, 102))
652663	31156297	On diagnosis of regional lymph node metastasis, the sensitivity of EUS is 80%, obviously higher than CT (50%) and PET (57%).	('higher', 'PosReg', (89, 95))	('P', 'Chemical', 'MESH:D010758', (114, 115))	('regional lymph node', 'Disease', (16, 35))	('EUS', 'Var', (67, 70))
652672	31156297	Indications for esophageal squamous carcinoma (a) Absolute indications: 1) T1a esophageal squamous carcinoma limited in epithelium (M1) or lamina propria mucosa (M2), without evidence of lymph node metastasis; 2) Precancerous lesions.	('esophageal squamous carcinoma', 'Disease', (79, 108))	('Precancerous lesions', 'Disease', 'MESH:D011230', (213, 233))	('T1a', 'Var', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Precancerous lesions', 'Disease', (213, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (16, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (27, 45))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (90, 108))	('esophageal squamous carcinoma', 'Disease', (16, 45))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (79, 108))
652679	31156297	Relative contraindications: 1) Positive non-lift sign; 2) Patients with coagulation disorders that not corrected, or those who is taking anti-coagulate agents; 3) Lesion invades to deep layer of submucosa; patients refuse or are not suitable for surgery.	('coagulation disorders', 'Disease', 'MESH:D025861', (72, 93))	('P', 'Chemical', 'MESH:D010758', (58, 59))	('coagulation disorders', 'Disease', (72, 93))	('P', 'Chemical', 'MESH:D010758', (31, 32))	('patients', 'Species', '9606', (206, 214))	('coagulation disorders', 'Phenotype', 'HP:0001928', (72, 93))	('Patients', 'Species', '9606', (58, 66))	('Lesion', 'Var', (163, 169))
652768	31156297	We do not recommend postoperative adjuvant radiotherapy or chemotherapy for completely resected (R0 resection) T2-3N0M0 esophageal squamous carcinoma or T2N0M0 esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (160, 185))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (131, 149))	('esophageal adenocarcinoma', 'Disease', (160, 185))	('esophageal squamous carcinoma', 'Disease', (120, 149))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (160, 185))	('T2N0M0', 'Var', (153, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('T2-3N0M0', 'Var', (111, 119))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (120, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
652769	31156297	For pathological T4N0 or T1-4N1-3M0 esophageal squamous carcinoma underwent R0 resection, postoperative adjuvant radiotherapy or chemotherapy can be considered.	('squamous carcinoma', 'Phenotype', 'HP:0002860', (47, 65))	('T1-4N1-3M0', 'Var', (25, 35))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (36, 65))	('esophageal squamous carcinoma', 'Disease', (36, 65))	('T4N0', 'Var', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
652770	31156297	Fluorouracil-based postoperative radiochemotherapy is the choice for R0 resected T3N0M0 and T1-2N1M0, or R1/R2 resected esophageal adenocarcinoma.	('R1/R2', 'Gene', '910;6241', (105, 110))	('Fluorouracil', 'Chemical', 'MESH:D005472', (0, 12))	('R1/R2', 'Gene', (105, 110))	('T1-2N1M0', 'Var', (92, 100))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (120, 145))	('esophageal adenocarcinoma', 'Disease', (120, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (120, 145))	('T3N0M0', 'Var', (81, 87))
652771	31156297	For T1-3N1-2M0 and some resectable T4aN0-1M0 esophageal cancer, preoperative neoadjuvant radiochemotherapy/radiotherapy/chemotherapy and post-therapy reassessment are recommended.	('T4aN0-1M0', 'Var', (35, 44))	('esophageal cancer', 'Disease', (45, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
652785	29660222	Aberrant methylation of EYA4 promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma EYA4, one of the four members of the EYA gene family, is associated with several human cancers.	('esophageal squamous cell carcinoma', 'Disease', (75, 109))	('EYA', 'Gene', '33916', (110, 113))	('EYA', 'Gene', '33916', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('promotes', 'PosReg', (29, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('EYA', 'Gene', (147, 150))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (75, 109))	('human', 'Species', '9606', (191, 196))	('EYA', 'Gene', '33916', (147, 150))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancers', 'Disease', (197, 204))	('Aberrant methylation', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('EYA4', 'Gene', (110, 114))	('EYA4', 'Gene', (24, 28))	('epithelial-mesenchymal transition', 'CPA', (38, 71))	('EYA4', 'Gene', '2070', (110, 114))	('EYA4', 'Gene', '2070', (24, 28))	('EYA', 'Gene', (24, 27))	('associated', 'Reg', (167, 177))	('EYA', 'Gene', (110, 113))
652787	29660222	In the present study, we found that EYA4 was underexpressed and hypermethylated in most of the ESCC cell lines tested (85.7%, 6/7).	('hypermethylated', 'Var', (64, 79))	('EYA4', 'Gene', '2070', (36, 40))	('EYA4', 'Gene', (36, 40))
652791	29660222	Conversely, the overexpression of EYA4 in KYSE180 and KYSE450 promoted an epithelial phenotype, which consisted of decreased migration and invasion abilities and a decrease in TGF-beta1-induced epithelial-mesenchymal transition.	('EYA4', 'Gene', (34, 38))	('overexpression', 'PosReg', (16, 30))	('epithelial phenotype', 'CPA', (74, 94))	('EYA4', 'Gene', '2070', (34, 38))	('KYSE450', 'CellLine', 'CVCL:1353', (54, 61))	('TGF-beta1', 'Gene', '7040', (176, 185))	('KYSE180', 'Var', (42, 49))	('decreased', 'NegReg', (115, 124))	('TGF-beta1', 'Gene', (176, 185))	('decrease', 'NegReg', (164, 172))	('promoted', 'PosReg', (62, 70))	('KYSE450', 'Var', (54, 61))
652794	29660222	In summary, EYA4 is frequently hypermethylated in ESCC and may function as a tumor suppressor gene in the development of ESCC.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ESCC', 'Disease', (121, 125))	('EYA4', 'Gene', (12, 16))	('tumor', 'Disease', (77, 82))	('EYA4', 'Gene', '2070', (12, 16))	('hypermethylated', 'Var', (31, 46))	('ESCC', 'Disease', (50, 54))
652799	29660222	In this study, we primarily revealed the epigenetic changes and the expression of EYA4 in ESCC.	('EYA4', 'Gene', (82, 86))	('ESCC', 'Gene', (90, 94))	('epigenetic changes', 'Var', (41, 59))	('revealed', 'Reg', (28, 36))	('EYA4', 'Gene', '2070', (82, 86))
652822	29660222	For the drug treatment, cells were preincubated with TGF-beta1 (5 ng/mL) or LY294002 (20 mumol/L, Cell Signaling Technology, USA) for 24 hours in a CO2 incubator.	('CO2', 'Chemical', '-', (148, 151))	('LY294002', 'Var', (76, 84))	('TGF-beta1', 'Gene', '7040', (53, 62))	('TGF-beta1', 'Gene', (53, 62))	('LY294002', 'Chemical', 'MESH:C085911', (76, 84))
652837	29660222	EYA4 mRNA expression were restored after treatment with 5-aza-dC and/or TSA in 3 ESCC cell lines including KYSE150, KYSE450 and KYSE510 (Figure 1D,E).	('EYA4', 'Gene', (0, 4))	('restored', 'PosReg', (26, 34))	('EYA4', 'Gene', '2070', (0, 4))	('KYSE150', 'Var', (107, 114))	('5-aza-dC', 'Var', (56, 64))	('KYSE450', 'CellLine', 'CVCL:1353', (116, 123))	('KYSE510', 'Var', (128, 135))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (56, 64))	('TSA', 'Chemical', 'MESH:C012589', (72, 75))
652839	29660222	Methylation of EYA4 was detected in 39 of 50 (78%) primary ESCC and only 29 of 50 (58%) adjacent non-tumor tissues (Figure 2A).	('detected', 'Reg', (24, 32))	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('EYA4', 'Gene', (15, 19))	('ESCC', 'Disease', (59, 63))	('EYA4', 'Gene', '2070', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
652841	29660222	EYA4 was downregulated in KYSE150 and KYSE510 with an average methylation density of approximately 93.5% and 97.4%, respectively.	('EYA4', 'Gene', (0, 4))	('methylation', 'MPA', (62, 73))	('EYA4', 'Gene', '2070', (0, 4))	('KYSE150', 'Var', (26, 33))	('KYSE510', 'Var', (38, 45))	('downregulated', 'NegReg', (9, 22))
652842	29660222	Similarly, we detected a significantly higher density of methylated CpG sites in primary ESCC tissues compared with adjacent non-tumor tissues (Figure 2C).	('higher', 'PosReg', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ESCC', 'Disease', (89, 93))	('tumor', 'Disease', (129, 134))	('methylated', 'Var', (57, 67))
652843	29660222	Next, we integrated the methylation data with paired mRNA expression data from ESCC tissue samples and found that samples with EYA4 hypermethylation were more likely to have reduced EYA4 expression than samples without EYA4 methylation (Figure 2D).	('EYA4', 'Gene', (182, 186))	('EYA4', 'Gene', (219, 223))	('EYA4', 'Gene', '2070', (182, 186))	('EYA4', 'Gene', '2070', (219, 223))	('hypermethylation', 'Var', (132, 148))	('expression', 'MPA', (187, 197))	('reduced', 'NegReg', (174, 181))	('EYA4', 'Gene', (127, 131))	('EYA4', 'Gene', '2070', (127, 131))
652845	29660222	No significant association was found between the methylation of EYA4 and differentiation, tumor size or TNM stage (Table 1).	('differentiation', 'CPA', (73, 88))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('TNM', 'Gene', '10178', (104, 107))	('methylation', 'Var', (49, 60))	('TNM', 'Gene', (104, 107))	('EYA4', 'Gene', '2070', (64, 68))	('EYA4', 'Gene', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
652848	29660222	Next, the relationship between EYA4 expression and clinicopathological characteristics were analyzed (Table 2), and we found that the expression of EYA4 was significantly associated with TNM stage and lymph node metastases, which suggests that the epigenetic silencing of EYA4 gene is correlated with the loss or reduction of EYA4 expression in ESCC and may play a critical role in epithelial-mesenchymal transition (EMT) during esophageal squamous cell carcinoma development and tumor aggressiveness.	('EYA4', 'Gene', (31, 35))	('EYA4', 'Gene', (148, 152))	('EYA4', 'Gene', '2070', (31, 35))	('EYA4', 'Gene', '2070', (148, 152))	('TNM', 'Gene', '10178', (187, 190))	('tumor aggressiveness', 'Disease', (480, 500))	('reduction', 'NegReg', (313, 322))	('TNM', 'Gene', (187, 190))	('esophageal squamous cell carcinoma', 'Disease', (429, 463))	('aggressiveness', 'Phenotype', 'HP:0000718', (486, 500))	('epithelial-mesenchymal transition', 'CPA', (382, 415))	('loss', 'NegReg', (305, 309))	('associated', 'Reg', (171, 181))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (480, 500))	('EYA4', 'Gene', (272, 276))	('EYA4', 'Gene', '2070', (272, 276))	('tumor', 'Phenotype', 'HP:0002664', (480, 485))	('EYA4', 'Gene', (326, 330))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (429, 463))	('EYA4', 'Gene', '2070', (326, 330))	('metastases', 'Disease', 'MESH:D009362', (212, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (440, 463))	('epigenetic silencing', 'Var', (248, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (454, 463))	('metastases', 'Disease', (212, 222))	('expression', 'MPA', (331, 341))	('play', 'Reg', (358, 362))
652853	29660222	Transwell assays revealed that the knockdown of EYA4 in KYSE30 and KYSE70 cells led to a significant increase of cell migration and invasion ability (Figure 3C,D).	('knockdown', 'Var', (35, 44))	('EYA4', 'Gene', (48, 52))	('increase', 'PosReg', (101, 109))	('EYA4', 'Gene', '2070', (48, 52))	('invasion ability', 'CPA', (132, 148))	('cell migration', 'CPA', (113, 127))
652854	29660222	Similarly, wound healing assays demonstrated that ESCC cells exhibited faster rates of wound healing when EYA4 was silenced (Figure 3E).	('EYA4', 'Gene', '2070', (106, 110))	('wound healing', 'CPA', (87, 100))	('faster', 'PosReg', (71, 77))	('silenced', 'Var', (115, 123))	('EYA4', 'Gene', (106, 110))
652862	29660222	Transwell assay showed that EYA4 overexpression in KYSE180 and KYSE450 cells was associated with decreased migratory ability (Figure 4B).	('overexpression', 'PosReg', (33, 47))	('EYA4', 'Gene', (28, 32))	('KYSE450', 'Var', (63, 70))	('EYA4', 'Gene', '2070', (28, 32))	('decreased', 'NegReg', (97, 106))	('migratory ability', 'CPA', (107, 124))	('KYSE450', 'CellLine', 'CVCL:1353', (63, 70))
652865	29660222	Furthermore, the staining of slug is predominantly nuclear in EYA4 knockdown cells.	('slug', 'Gene', (29, 33))	('knockdown', 'Var', (67, 76))	('slug', 'Gene', '6591', (29, 33))	('EYA4', 'Gene', (62, 66))	('EYA4', 'Gene', '2070', (62, 66))
652871	29660222	To confirm whether Akt/GSK-3beta/slug inactiviation mediated the suppression of EYA4 on cell migration, we detected cell migration after LY294002 treatment in EYA4 knockdown cells and found that LY294002 significantly decreased KYSE30-shEYA4 cell migration (Figure 5D).	('LY294002', 'Var', (195, 203))	('EYA4', 'Gene', (237, 241))	('EYA4', 'Gene', '2070', (237, 241))	('LY294002', 'Var', (137, 145))	('detected', 'Reg', (107, 115))	('slug', 'Gene', '6591', (33, 37))	('decreased', 'NegReg', (218, 227))	('LY294002', 'Chemical', 'MESH:C085911', (195, 203))	('LY294002', 'Chemical', 'MESH:C085911', (137, 145))	('Akt', 'Gene', (19, 22))	('GSK-3beta', 'Gene', '2932', (23, 32))	('Akt', 'Gene', '207', (19, 22))	('slug', 'Gene', (33, 37))	('EYA4', 'Gene', (80, 84))	('EYA4', 'Gene', (159, 163))	('EYA4', 'Gene', '2070', (80, 84))	('EYA4', 'Gene', '2070', (159, 163))	('GSK-3beta', 'Gene', (23, 32))	('cell migration', 'CPA', (116, 130))
652872	29660222	Western blotting also showed that LY294002 effectively decreased the expression of p-Akt, p-GSK-3beta and slug induced by the silencing of EYA4 in KYSE30 cells (Figure 5E).	('LY294002', 'Var', (34, 42))	('Akt', 'Gene', '207', (85, 88))	('expression', 'MPA', (69, 79))	('slug', 'Gene', (106, 110))	('decreased', 'NegReg', (55, 64))	('Akt', 'Gene', (85, 88))	('LY294002', 'Chemical', 'MESH:C085911', (34, 42))	('GSK-3beta', 'Gene', (92, 101))	('GSK-3beta', 'Gene', '2932', (92, 101))	('EYA4', 'Gene', (139, 143))	('EYA4', 'Gene', '2070', (139, 143))	('slug', 'Gene', '6591', (106, 110))	('silencing', 'Var', (126, 135))
652882	29660222	Deregulation of EYA4 has previously been reported to have an impact on DNA damage repair, such as double-stranded breaks, in other types of cancer cells.	('DNA damage repair', 'MPA', (71, 88))	('impact', 'Reg', (61, 67))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('double-stranded breaks', 'MPA', (98, 120))	('EYA4', 'Gene', (16, 20))	('EYA4', 'Gene', '2070', (16, 20))
652888	29660222	Numerous studies have indicated that EYA4 is aberrantly expressed in a variety of cancers, such as hepatocellular carcinoma, intrahepatic cholangio-carcinoma, colorectal cancer and acute lymphoblastic leukemia.16, 19, 20, 21, 22 Consistent with these findings, in the present study, we found that EYA4 was aberrantly hypermethylated in both ESCC specimens and cell lines.	('acute lymphoblastic leukemia', 'Disease', (181, 209))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cancers', 'Disease', (82, 89))	('intrahepatic cholangio-carcinoma', 'Disease', (125, 157))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (181, 209))	('EYA4', 'Gene', (37, 41))	('EYA4', 'Gene', '2070', (37, 41))	('aberrantly', 'Var', (306, 316))	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (99, 123))	('colorectal cancer', 'Disease', (159, 176))	('EYA4', 'Gene', (297, 301))	('cholangio-carcinoma', 'Phenotype', 'HP:0030153', (138, 157))	('EYA4', 'Gene', '2070', (297, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('hepatocellular carcinoma', 'Disease', (99, 123))	('intrahepatic cholangio-carcinoma', 'Disease', 'MESH:D002780', (125, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))
652889	29660222	Then, we assessed the expression of EYA4 in ESCC cell lines and found that reduced EYA4 expression in 6 of 7 ESCC cell lines was associated with methylation status.	('methylation status', 'Var', (145, 163))	('EYA4', 'Gene', (83, 87))	('EYA4', 'Gene', '2070', (83, 87))	('reduced', 'NegReg', (75, 82))	('EYA4', 'Gene', '2070', (36, 40))	('EYA4', 'Gene', (36, 40))	('expression', 'MPA', (88, 98))
652890	29660222	In vitro assays showed that EYA4 knockdown promoted tumor cell migration and invasiveness, whereas the overexpression of EYA4 resulted in inverse effects.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('promoted', 'PosReg', (43, 51))	('tumor', 'Disease', (52, 57))	('knockdown', 'Var', (33, 42))	('EYA4', 'Gene', (28, 32))	('EYA4', 'Gene', (121, 125))	('EYA4', 'Gene', '2070', (28, 32))	('EYA4', 'Gene', '2070', (121, 125))	('invasiveness', 'CPA', (77, 89))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
652891	29660222	Experimental metastasis assays confirmed that EYA4 knockdown promoted ESCC cell metastasis to the lung in vivo.	('promoted', 'PosReg', (61, 69))	('EYA4', 'Gene', (46, 50))	('EYA4', 'Gene', '2070', (46, 50))	('ESCC', 'Disease', (70, 74))	('knockdown', 'Var', (51, 60))
652998	33912703	MiRNA-20b/SUFU/Wnt axis accelerates gastric cancer cell proliferation, migration and EMT Previous research has found that miRNA-20b is highly expressed in gastric cancer (GC), however, its function and underlying mechanism are not clear.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('SUFU', 'Gene', (10, 14))	('gastric cancer', 'Disease', (36, 50))	('miRNA-20b', 'Var', (122, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (155, 169))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('SUFU', 'Gene', '51684', (10, 14))	('migration', 'CPA', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('accelerates', 'PosReg', (24, 35))	('GC', 'Phenotype', 'HP:0012126', (171, 173))	('miRNA-20b', 'Chemical', '-', (122, 131))	('GC', 'Gene', '14473', (171, 173))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('gastric cancer', 'Disease', (155, 169))	('gastric cancer', 'Disease', 'MESH:D013274', (155, 169))
653003	33912703	Moreover, additional knockdown of SUFU alleviated the inhibitory effect on Wnt pathway activity, EMT, cell proliferation/migration and colony formation caused by miRNA-20b inhibition.	('inh', 'Chemical', '-', (54, 57))	('Wnt', 'Gene', (75, 78))	('miRNA-20b', 'Gene', (162, 171))	('cell proliferation/migration', 'CPA', (102, 130))	('colony formation', 'CPA', (135, 151))	('alleviated', 'NegReg', (39, 49))	('miRNA-20b', 'Chemical', '-', (162, 171))	('EMT', 'CPA', (97, 100))	('inh', 'Chemical', '-', (172, 175))	('Wnt', 'Gene', 'None', (75, 78))	('knockdown', 'Var', (21, 30))	('inhibition', 'NegReg', (172, 182))
653004	33912703	In summary, miRNA-20b is an oncogenic miRNA and promoted cell proliferation, migration and EMT in GC partially by activating Wnt pathway via targeting SUFU.	('GC', 'Phenotype', 'HP:0012126', (98, 100))	('miRNA-20b', 'Var', (12, 21))	('SUFU', 'Protein', (151, 155))	('migration', 'CPA', (77, 86))	('Wnt', 'Gene', 'None', (125, 128))	('miRNA-20b', 'Chemical', '-', (12, 21))	('GC', 'Gene', '14473', (98, 100))	('activating', 'PosReg', (114, 124))	('promoted', 'PosReg', (48, 56))	('cell proliferation', 'CPA', (57, 75))	('Wnt', 'Gene', (125, 128))
653011	33912703	Previous research has found that in GC miRNA-20b is overexpressed and its high level predicts poor overall survival in GC patients.	('GC', 'Phenotype', 'HP:0012126', (119, 121))	('miRNA-20b', 'Var', (39, 48))	('overexpressed', 'PosReg', (52, 65))	('patients', 'Species', '9606', (122, 130))	('GC', 'Gene', '14473', (36, 38))	('miRNA-20b', 'Chemical', '-', (39, 48))	('GC', 'Phenotype', 'HP:0012126', (36, 38))	('overall', 'MPA', (99, 106))	('GC', 'Gene', '14473', (119, 121))	('poor', 'NegReg', (94, 98))
653015	33912703	Dysregulated canonical Wnt pathway has been implicated in GC.	('Wnt', 'Gene', (23, 26))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('implicated', 'Reg', (44, 54))	('Dysregulated', 'Var', (0, 12))	('Wnt', 'Gene', 'None', (23, 26))	('GC', 'Gene', '14473', (58, 60))
653019	33912703	In addition, TCGA study highlights the significance of Wnt pathway mutations in GCs.	('GC', 'Gene', '14473', (80, 82))	('Wnt', 'Gene', 'None', (55, 58))	('GC', 'Phenotype', 'HP:0012126', (80, 82))	('mutations', 'Var', (67, 76))	('Wnt', 'Gene', (55, 58))
653022	33912703	We hypothesize that miRNA-20b enhances Wnt pathway activity and induces EMT (Epithelial-Mesenchymal Transition).	('miRNA-20b', 'Chemical', '-', (20, 29))	('Wnt', 'Gene', (39, 42))	('enhances', 'PosReg', (30, 38))	('miRNA-20b', 'Var', (20, 29))	('Wnt', 'Gene', 'None', (39, 42))	('induces', 'PosReg', (64, 71))
653023	33912703	Furthermore, we would like to approve that SUFU (Suppressor of Fused) is the target of miRNA-20b.	('Suppressor of Fused', 'Gene', (49, 68))	('miRNA-20b', 'Var', (87, 96))	('miRNA-20b', 'Chemical', '-', (87, 96))	('Suppressor of Fused', 'Gene', '51684', (49, 68))
653028	33912703	Specific primers (#PN4427975 60C04, #PN4427975 82D07) for miRNA-20b detection were synthesized by Applied Biosystems.	('#PN4427975 82D07', 'Var', (36, 52))	('#PN4427975 60C04', 'Var', (18, 34))	('miRNA-20b', 'Chemical', '-', (58, 67))
653050	33912703	To further investigate how miRNA-20b activates Wnt signaling, target genes of miR-20b were predicted using miRwalk website (http://mirwalk.umm.uni-heidelberg.de/).	('miRNA-20b', 'Chemical', '-', (27, 36))	('Wnt', 'Gene', (47, 50))	('activates', 'PosReg', (37, 46))	('miRNA-20b', 'Var', (27, 36))	('miR-20b', 'Gene', (78, 85))	('Wnt', 'Gene', 'None', (47, 50))
653056	33912703	The expression of miRNA-20b was significant up-regulated in HFE145 with 20b-mimic transfection while down-regulated in BGC823 with 20b-inhibitor transfection (Figure 1B).	('miRNA-20b', 'Gene', (18, 27))	('BGC823', 'CellLine', 'CVCL:3360', (119, 125))	('miRNA-20b', 'Chemical', '-', (18, 27))	('transfection', 'Var', (82, 94))	('expression', 'MPA', (4, 14))	('HFE145', 'Var', (60, 66))	('20b', 'Chemical', '-', (24, 27))	('up-regulated', 'PosReg', (44, 56))	('down-regulated', 'NegReg', (101, 115))	('20b', 'Chemical', '-', (72, 75))	('20b', 'Chemical', '-', (131, 134))	('GC', 'Phenotype', 'HP:0012126', (120, 122))
653058	33912703	Inhibition of miRNA-20b results in reduced relative TCF dependent transcriptional activity, suggesting that miRNA-20b sustains Wnt signaling (Figure 1C, P = 0.014).	('miRNA-20b', 'Chemical', '-', (14, 23))	('Wnt', 'Gene', 'None', (127, 130))	('reduced', 'NegReg', (35, 42))	('TCF', 'Gene', (52, 55))	('miRNA-20b', 'Chemical', '-', (108, 117))	('Wnt', 'Gene', (127, 130))	('Inhibition', 'Var', (0, 10))	('TCF', 'Gene', '51176;3172', (52, 55))	('miRNA-20b', 'Var', (108, 117))	('miRNA-20b', 'Gene', (14, 23))
653062	33912703	In agreement with the immunoblotting results, miRNA-20b inhibitors cause beta-catenin preferentially localized to cell membrane compared to the control (Figure 1E).	('beta-catenin', 'Gene', (73, 85))	('preferentially', 'PosReg', (86, 100))	('miRNA-20b', 'Gene', (46, 55))	('beta-catenin', 'Gene', '1499', (73, 85))	('miRNA-20b', 'Chemical', '-', (46, 55))	('inhibitors', 'Var', (56, 66))	('inh', 'Chemical', '-', (56, 59))
653064	33912703	As shown in Figure 1F, inhibition of miRNA-20b consequently downregulated a set of Wnt target genes including cyclin D1(CCND1), TCF-1(HNF1A), c-Jun (JUN), LEF1 (LEF1), MMP7(MMP7).	('LEF1', 'MPA', (155, 159))	('miRNA-20b', 'Chemical', '-', (37, 46))	('CCND1', 'Gene', '595', (120, 125))	('inh', 'Chemical', '-', (23, 26))	('MMP7', 'Gene', '4316', (173, 177))	('CCND1', 'Gene', (120, 125))	('TCF-1', 'Gene', '6927', (128, 133))	('MMP7', 'Gene', (168, 172))	('Wnt', 'Gene', (83, 86))	('cyclin D1', 'Gene', (110, 119))	('Wnt', 'Gene', 'None', (83, 86))	('miRNA-20b', 'Gene', (37, 46))	('downregulated', 'NegReg', (60, 73))	('MMP7', 'Gene', (173, 177))	('cyclin D1', 'Gene', '595', (110, 119))	('HNF1A', 'Gene', '6927', (134, 139))	('inhibition', 'Var', (23, 33))	('HNF1A', 'Gene', (134, 139))	('MMP7', 'Gene', '4316', (168, 172))	('TCF-1', 'Gene', (128, 133))	('c-Jun', 'MPA', (142, 147))
653065	33912703	Conversely, overexpression of miRNA-20b in HFE145 cells induced the expression of these genes, suggesting that miRNA-20b truly activates the Wnt/beta-catenin activity in turn upregulates the downstream gene expression.	('miRNA-20b', 'Chemical', '-', (30, 39))	('expression', 'MPA', (68, 78))	('beta-catenin', 'Gene', (145, 157))	('Wnt', 'Gene', 'None', (141, 144))	('miRNA-20b', 'Chemical', '-', (111, 120))	('Wnt', 'Gene', (141, 144))	('beta-catenin', 'Gene', '1499', (145, 157))	('upregulates', 'PosReg', (175, 186))	('activates', 'PosReg', (127, 136))	('expression', 'MPA', (207, 217))	('miRNA-20b', 'Var', (111, 120))
653069	33912703	On the other hand, enforced overexpression of miRNA-20b resulted in a remarkable enhancement of N-cadherin, Claudin, Vimentin, ZEB and Snail expression and a decrease in E-cadherin expression.	('miRNA-20b', 'Var', (46, 55))	('ZEB', 'Protein', (127, 130))	('E-cadherin', 'Gene', (170, 180))	('E-cadherin', 'Gene', '999', (170, 180))	('N-cadherin', 'Gene', (96, 106))	('Vimentin', 'Protein', (117, 125))	('decrease', 'NegReg', (158, 166))	('enhancement', 'PosReg', (81, 92))	('miRNA-20b', 'Chemical', '-', (46, 55))	('Claudin', 'Protein', (108, 115))	('overexpression', 'PosReg', (28, 42))	('Snail expression', 'CPA', (135, 151))	('N-cadherin', 'Gene', '1000', (96, 106))
653070	33912703	Aberrantly activated Wnt signaling elevates the Snail expression level in CRC (Colorectal Cancer) cells.	('Colorectal Cancer', 'Disease', 'MESH:D015179', (79, 96))	('Wnt', 'Gene', 'None', (21, 24))	('elevates', 'PosReg', (35, 43))	('Colorectal Cancer', 'Disease', (79, 96))	('Wnt', 'Gene', (21, 24))	('CRC', 'Disease', (74, 77))	('Snail expression level', 'MPA', (48, 70))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (79, 96))	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('CRC', 'Disease', 'MESH:D015179', (74, 77))	('Aberrantly activated', 'Var', (0, 20))
653072	33912703	Here, we found that miRNA-20b only influences Snail expression but not Slug.	('Snail expression', 'MPA', (46, 62))	('miRNA-20b', 'Var', (20, 29))	('miRNA-20b', 'Chemical', '-', (20, 29))	('influences', 'Reg', (35, 45))
653074	33912703	To further investigate how miRNA-20b activates Wnt signaling, we have integrated miRNA target prediction using miRwalk (http://mirwalk.umm.uni-heidelberg.de/) and analysis of Wnt pathway associated genes.	('Wnt', 'Gene', 'None', (175, 178))	('miRNA-20b', 'Chemical', '-', (27, 36))	('Wnt', 'Gene', (47, 50))	('Wnt', 'Gene', (175, 178))	('miRNA-20b', 'Var', (27, 36))	('Wnt', 'Gene', 'None', (47, 50))
653075	33912703	We identified SUFU, negatively regulating Wnt pathway, potentially targeted by miRNA-20b.	('miRNA-20b', 'Chemical', '-', (79, 88))	('Wnt', 'Gene', (42, 45))	('Wnt', 'Gene', 'None', (42, 45))	('miRNA-20b', 'Var', (79, 88))	('negatively regulating', 'NegReg', (20, 41))
653076	33912703	The prediction was confirmed by the experimental results revealing that transfection of inhibitors of miRNA-20b enhanced the SUFU expression in BGC823 cells and forced overexpression of miRNA-20b mimics decreased the expression of SUFU in HFE145 cells (Figure 2A).	('enhanced', 'PosReg', (112, 120))	('inh', 'Chemical', '-', (88, 91))	('decreased', 'NegReg', (203, 212))	('expression', 'MPA', (217, 227))	('miRNA-20b', 'Chemical', '-', (186, 195))	('GC', 'Phenotype', 'HP:0012126', (145, 147))	('miRNA-20b', 'Gene', (102, 111))	('SUFU expression', 'MPA', (125, 140))	('BGC823', 'CellLine', 'CVCL:3360', (144, 150))	('miRNA-20b', 'Chemical', '-', (102, 111))	('inhibitors', 'Var', (88, 98))
653078	33912703	Subsequently, the reporters containing wild type or mutant binding site for miRNA-20b were constructed (Figure 2B).	('miRNA-20b', 'Chemical', '-', (76, 85))	('miRNA-20b', 'Gene', (76, 85))	('mutant', 'Var', (52, 58))
653079	33912703	MiRNA-20b suppressed the activity of the SUFU 3'UTR reporter containing WT (wild type) binding site of miRNA-20b in HFE145 cells (Figure 2C, P = 0.000), but not the mutant reporter.	('miRNA-20b', 'Chemical', '-', (103, 112))	("SUFU 3'UTR reporter", 'MPA', (41, 60))	('MiRNA-20b', 'Chemical', '-', (0, 9))	('suppressed', 'NegReg', (10, 20))	('miRNA-20b', 'Var', (103, 112))	('activity', 'MPA', (25, 33))
653080	33912703	Agreeably, transfection of inhibitors of miRNA-20b elevated the luciferase expression of the reporter containing WT 3'UTR of SUFU in BGC823 cells, but not the mutant reporter (Figure 2C, P = 0.000).	('miRNA-20b', 'Gene', (41, 50))	('miRNA-20b', 'Chemical', '-', (41, 50))	('inh', 'Chemical', '-', (27, 30))	('inhibitors', 'Var', (27, 37))	('luciferase', 'Enzyme', (64, 74))	('GC', 'Phenotype', 'HP:0012126', (134, 136))	('elevated', 'PosReg', (51, 59))	('BGC823', 'CellLine', 'CVCL:3360', (133, 139))	('expression', 'MPA', (75, 85))
653082	33912703	To determine if miRNA-20b activates Wnt pathway and EMT via targeting SUFU, we performed the rescue experiment by knocking down SUFU meanwhile inhibiting miRNA-20b.	('Wnt', 'Gene', (36, 39))	('miRNA-20b', 'Var', (16, 25))	('SUFU', 'Gene', (128, 132))	('inhibiting', 'NegReg', (143, 153))	('inh', 'Chemical', '-', (143, 146))	('activates', 'PosReg', (26, 35))	('knocking down', 'Var', (114, 127))	('Wnt', 'Gene', 'None', (36, 39))	('miRNA-20b', 'Gene', (154, 163))	('miRNA-20b', 'Chemical', '-', (16, 25))	('miRNA-20b', 'Chemical', '-', (154, 163))
653083	33912703	The reduction of Topflash/Fopflash induced by inhibitors of miRNA-20b was rescued (Figure 3A, NSC vs 20-inh, P = 0.000; 20-inh vs 20-inh + SUFU si, P = 0.022).	('inh', 'Chemical', '-', (46, 49))	('20-inh', 'Chemical', '-', (130, 136))	('inhibitors', 'Var', (46, 56))	('inh', 'Chemical', '-', (133, 136))	('inh', 'Chemical', '-', (123, 126))	('Topflash/Fopflash', 'MPA', (17, 34))	('20-inh', 'Chemical', '-', (120, 126))	('inh', 'Chemical', '-', (104, 107))	('reduction', 'NegReg', (4, 13))	('NSC', 'Chemical', '-', (94, 97))	('miRNA-20b', 'Gene', (60, 69))	('20-inh', 'Chemical', '-', (101, 107))	('miRNA-20b', 'Chemical', '-', (60, 69))
653084	33912703	Inhibition of beta-catenin nuclear translocation triggered by miRNA-20b inhibitors was relieved after introducing SUFU siRNAs to miRNA-20b inhibitors as revealed by immuno-blotting after subcellular fractionation (Figure 3B).	('beta-catenin', 'Gene', (14, 26))	('inh', 'Chemical', '-', (139, 142))	('beta-catenin', 'Gene', '1499', (14, 26))	('miRNA-20b', 'Chemical', '-', (62, 71))	('inh', 'Chemical', '-', (72, 75))	('inhibitors', 'Var', (72, 82))	('miRNA-20b', 'Chemical', '-', (129, 138))	('miRNA-20b', 'Gene', (62, 71))
653091	33912703	CCK8 data showed that knockdown of SUFU rescued part of the proliferation rate reduction caused by miRNA-20b inhibitors (Figure 4A, NSC vs 20-inh, P = 0.000; 20-inh vs 20-inh + SUFU si, P = 0.005).	('inh', 'Chemical', '-', (109, 112))	('20-inh', 'Chemical', '-', (158, 164))	('inh', 'Chemical', '-', (161, 164))	('20-inh', 'Chemical', '-', (168, 174))	('inh', 'Chemical', '-', (171, 174))	('knockdown', 'Var', (22, 31))	('miRNA-20b', 'Gene', (99, 108))	('proliferation rate', 'CPA', (60, 78))	('inh', 'Chemical', '-', (142, 145))	('20-inh', 'Chemical', '-', (139, 145))	('NSC', 'Chemical', '-', (132, 135))	('reduction', 'NegReg', (79, 88))	('miRNA-20b', 'Chemical', '-', (99, 108))
653092	33912703	Cell migration suppressed by miRNA-20b inhibitors was enhanced by SUFU siRNAs as demonstrated in transwell and wound healing assay (Figure 4B, NSC vs 20-inh, P = 0.000; 20-inh vs 20-inh + SUFU si, P = 0.000, and Figure 4C).	('inhibitors', 'Var', (39, 49))	('inh', 'Chemical', '-', (39, 42))	('Cell migration', 'CPA', (0, 14))	('wound healing assay', 'CPA', (111, 130))	('20-inh', 'Chemical', '-', (150, 156))	('NSC', 'Chemical', '-', (143, 146))	('miRNA-20b', 'Gene', (29, 38))	('inh', 'Chemical', '-', (182, 185))	('20-inh', 'Chemical', '-', (179, 185))	('inh', 'Chemical', '-', (172, 175))	('miRNA-20b', 'Chemical', '-', (29, 38))	('20-inh', 'Chemical', '-', (169, 175))	('enhanced', 'PosReg', (54, 62))	('inh', 'Chemical', '-', (153, 156))
653093	33912703	Cell colony formation capacity was decreased in miRNA-20b inhibitors treated cells and rescued in coupled SUFU siRNAs transfected counterparts (Figure 4D, NSC vs 20-inh, P = 0.000; 20-inh vs 20-inh + SUFU si, P = 0.008).	('20-inh', 'Chemical', '-', (191, 197))	('inh', 'Chemical', '-', (194, 197))	('miRNA-20b', 'Gene', (48, 57))	('Cell colony formation capacity', 'CPA', (0, 30))	('inh', 'Chemical', '-', (58, 61))	('miRNA-20b', 'Chemical', '-', (48, 57))	('inh', 'Chemical', '-', (165, 168))	('20-inh', 'Chemical', '-', (181, 187))	('decreased', 'NegReg', (35, 44))	('NSC', 'Chemical', '-', (155, 158))	('inhibitors', 'Var', (58, 68))	('20-inh', 'Chemical', '-', (162, 168))	('inh', 'Chemical', '-', (184, 187))
653102	33912703	Inhibition of miR-20b reduces tumor volume of breast cancer cells in nude mice.	('miR-20b', 'Gene', (14, 21))	('nude mice', 'Species', '10090', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('reduces', 'NegReg', (22, 29))	('Inhibition', 'Var', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Disease', (46, 59))	('tumor', 'Disease', (30, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
653104	33912703	Aberrant expression of miRNA-20b increases tumor growth in in vivo study, together providing the rationale to target miRNA-20b in esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (130, 150))	('Aberrant expression', 'Var', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (130, 150))	('miRNA-20b', 'Chemical', '-', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('increases', 'PosReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('miRNA-20b', 'Gene', (23, 32))	('miRNA-20b', 'Chemical', '-', (23, 32))	('tumor', 'Disease', (43, 48))	('esophageal carcinoma', 'Disease', (130, 150))
653119	33912703	Here, we show that SUFU is also inhibited by miRNA-20b to enhance cell proliferation and EMT in GC.	('enhance', 'PosReg', (58, 65))	('GC', 'Phenotype', 'HP:0012126', (96, 98))	('inhibited', 'NegReg', (32, 41))	('miRNA-20b', 'Chemical', '-', (45, 54))	('cell proliferation', 'CPA', (66, 84))	('miRNA-20b', 'Var', (45, 54))	('EMT', 'CPA', (89, 92))	('inh', 'Chemical', '-', (32, 35))	('GC', 'Gene', '14473', (96, 98))
653125	33912703	Here, we also demonstrate that miRNA-20b activates Wnt pathway through suppressing SUFU expression.	('activates', 'PosReg', (41, 50))	('Wnt', 'Gene', 'None', (51, 54))	('miRNA-20b', 'Chemical', '-', (31, 40))	('SUFU', 'Protein', (83, 87))	('miRNA-20b', 'Var', (31, 40))	('Wnt', 'Gene', (51, 54))	('suppressing', 'NegReg', (71, 82))
653126	33912703	The findings are consistent with the fact that miRNA-20b generally activates Wnt signaling pathway through modulating Wnt associated negative regulators.	('Wnt', 'Gene', (118, 121))	('Wnt', 'Gene', (77, 80))	('modulating', 'Reg', (107, 117))	('miRNA-20b', 'Var', (47, 56))	('activates', 'PosReg', (67, 76))	('Wnt', 'Gene', 'None', (118, 121))	('Wnt', 'Gene', 'None', (77, 80))	('miRNA-20b', 'Chemical', '-', (47, 56))
653137	33481352	Functionally, knockdown of SIX4 inhibited cell proliferation and induced apoptosis in ESCC.	('si', 'Chemical', 'MESH:D012825', (79, 81))	('inhibited', 'NegReg', (32, 41))	('cell proliferation', 'CPA', (42, 60))	('apoptosis', 'CPA', (73, 82))	('knockdown', 'Var', (14, 23))	('induced', 'Reg', (65, 72))	('SIX4', 'Gene', (27, 31))
653138	33481352	In addition, the silencing of SIX4 inhibited cell migration, invasion and EMT in ESCC.	('cell migration', 'CPA', (45, 59))	('ESCC', 'Disease', (81, 85))	('invasion', 'CPA', (61, 69))	('EMT', 'CPA', (74, 77))	('SIX4', 'Gene', (30, 34))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('inhibited', 'NegReg', (35, 44))	('silencing', 'Var', (17, 26))	('si', 'Chemical', 'MESH:D012825', (65, 67))
653212	33481352	The relationship between abnormal expressions of SIX4 and clinical features in ESCC patients was analyzed.	('abnormal', 'Var', (25, 33))	('patients', 'Species', '9606', (84, 92))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('abnormal expressions', 'Phenotype', 'HP:0100022', (25, 45))	('ESCC', 'Disease', (79, 83))
653213	33481352	As shown in Table 1, SIX4 expression was associated with lymph node metastasis in ESCC patients (p < 0.05, Table 1).	('ESCC', 'Disease', (82, 86))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('associated with', 'Reg', (41, 56))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('lymph node metastasis', 'CPA', (57, 78))	('SIX4 expression', 'Var', (21, 36))	('patients', 'Species', '9606', (87, 95))
653216	33481352	Compared with normal esophageal cells Het-1A, upregulation of SIX4 was identified in ESCC cell lines KYSE150 and KYSE450 (p < 0.01, Figure 2(a)).	('upregulation', 'PosReg', (46, 58))	('KYSE450', 'CellLine', 'CVCL:1353', (113, 120))	('ESCC', 'Disease', (85, 89))	('SIX4', 'Enzyme', (62, 66))	('KYSE450', 'Var', (113, 120))
653218	33481352	Then, si-SIX4 or si-NC was transfected into KYSE450 ESCC cells.	('KYSE450', 'CellLine', 'CVCL:1353', (44, 51))	('si-NC', 'Var', (17, 22))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('si-SIX4', 'Var', (6, 13))
653219	33481352	RT-qPCR showed that SIX4 expression was significantly reduced by si-SIX4 in KYSE450 cells (p < 0.01, Figure 2(b)).	('KYSE450', 'CellLine', 'CVCL:1353', (76, 83))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('reduced', 'NegReg', (54, 61))	('SIX4', 'Gene', (20, 24))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('si-SIX4', 'Var', (65, 72))
653220	33481352	Functionally, knockdown of SIX4 was found to inhibit cell proliferation in KYSE450 cells (p < 0.01, Figure 2(c)).	('cell proliferation in KYSE450 cells', 'CPA', (53, 88))	('KYSE450', 'CellLine', 'CVCL:1353', (75, 82))	('knockdown', 'Var', (14, 23))	('inhibit', 'NegReg', (45, 52))	('SIX4', 'Gene', (27, 31))
653221	33481352	The colony formation assay showed that had considerably cell colonies in si-SIX4 group was fewer than that of si-NC group (p < 0.05, Figure 2(d)).	('si', 'Chemical', 'MESH:D012825', (73, 75))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('si-SIX4', 'Var', (73, 80))	('colony formation assay', 'CPA', (4, 26))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('cell colonies', 'CPA', (56, 69))	('fewer', 'NegReg', (91, 96))
653224	33481352	We found that si-SIX4 promoted Bax expression and decreased the survival gene Bcl-2 expression (p < 0.05, Figure 2(f)).	('si', 'Chemical', 'MESH:D012825', (14, 16))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('si-SIX4', 'Var', (14, 21))	('Bax', 'Gene', '581', (31, 34))	('promoted', 'PosReg', (22, 30))	('decreased', 'NegReg', (50, 59))	('Bcl-2', 'Gene', (78, 83))	('Bcl-2', 'Gene', '596', (78, 83))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('expression', 'MPA', (84, 94))	('Bax', 'Gene', (31, 34))
653225	33481352	All these results indicated that SIX4 could promote cell proliferation and inhibit apoptosis in ESCC.	('promote', 'PosReg', (44, 51))	('SIX4', 'Var', (33, 37))	('inhibit', 'NegReg', (75, 82))	('cell proliferation', 'CPA', (52, 70))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('ESCC', 'Disease', (96, 100))	('apoptosis', 'CPA', (83, 92))
653227	33481352	Wound healing assay showed that silencing of SIX4 significantly decreased the velocity of cell movements.	('velocity of cell movements', 'CPA', (78, 104))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('silencing', 'Var', (32, 41))	('SIX4', 'Gene', (45, 49))	('decreased', 'NegReg', (64, 73))
653228	33481352	The percentage of wound closure at 24 h was decreased from 62.3% in the si-NC group to 12.1% in the si-SIX4 group (p < 0.05, Figure 3(a)).	('si-SIX4', 'Var', (100, 107))	('si-NC', 'Var', (72, 77))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('wound closure at 24 h', 'CPA', (18, 39))	('decreased', 'NegReg', (44, 53))	('si', 'Chemical', 'MESH:D012825', (100, 102))
653229	33481352	In addition, transwell assay showed that knockdown of SIX4 restrained cell migration and invasion in KYSE450 cells (p < 0.01, Figure 3(b), (c)).	('si', 'Chemical', 'MESH:D012825', (93, 95))	('KYSE450', 'CellLine', 'CVCL:1353', (101, 108))	('restrained', 'NegReg', (59, 69))	('SIX4', 'Gene', (54, 58))	('cell migration', 'CPA', (70, 84))	('invasion in KYSE450 cells', 'CPA', (89, 114))	('knockdown', 'Var', (41, 50))
653231	33481352	The results showed that knockdown of SIX4 reduced N-cadherin and vimentin expression and increased E-cadherin expression (Figure 3(d)).	('expression', 'MPA', (74, 84))	('vimentin', 'Gene', (65, 73))	('reduced', 'NegReg', (42, 49))	('N-cadherin', 'Gene', '1000', (50, 60))	('SIX4', 'Gene', (37, 41))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))	('increased', 'PosReg', (89, 98))	('knockdown', 'Var', (24, 33))	('vimentin', 'Gene', '7431', (65, 73))	('N-cadherin', 'Gene', (50, 60))	('si', 'Chemical', 'MESH:D012825', (80, 82))
653232	33481352	These findings imply that silencing of SIX4 inhibits cell metastasis and EMT in ESCC.	('EMT', 'CPA', (73, 76))	('SIX4', 'Gene', (39, 43))	('cell metastasis', 'CPA', (53, 68))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('silencing', 'Var', (26, 35))	('inhibits', 'NegReg', (44, 52))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('ESCC', 'Disease', (80, 84))
653234	33481352	Compared with the control group, the tumor volume was increased in mice with SIX4 vector (Figure 4(a)).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('SIX4 vector', 'Var', (77, 88))	('increased', 'PosReg', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mice', 'Species', '10090', (67, 71))
653237	33481352	However, PI3K and AKT expressions were not affected by SIX4 in KYSE450 cells.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('SIX4', 'Var', (55, 59))	('PI3K', 'CPA', (9, 13))	('AKT', 'Gene', (18, 21))	('KYSE450', 'CellLine', 'CVCL:1353', (63, 70))	('AKT', 'Gene', '207', (18, 21))
653241	33481352	16  Mice doubly deficient in homeobox genes Six4 and Six5 showed ventral body wall defects as those seen in human omphalocele.	('deficient', 'NegReg', (16, 25))	('omphalocele', 'Phenotype', 'HP:0001539', (114, 125))	('Six5', 'Gene', (53, 57))	('Mice', 'Species', '10090', (4, 8))	('homeobox', 'Protein', (29, 37))	('Six4', 'Gene', '20474', (44, 48))	('Six4', 'Gene', (44, 48))	('human', 'Species', '9606', (108, 113))	('Six5', 'Gene', '20475', (53, 57))	('ventral body wall defects', 'CPA', (65, 90))	('doubly', 'Var', (9, 15))
653243	33481352	In addition, the silencing of SIX4 inhibited cell migration and invasion in ESCC.	('si', 'Chemical', 'MESH:D012825', (68, 70))	('SIX4', 'Gene', (30, 34))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('inhibited', 'NegReg', (35, 44))	('ESCC', 'Disease', (76, 80))	('silencing', 'Var', (17, 26))
653248	33481352	found that knockdown of SIX4 inhibited cell growth, invasion, and the EMT of glioblastoma.	('inhibited', 'NegReg', (29, 38))	('glioblastoma', 'Disease', (77, 89))	('EMT', 'CPA', (70, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('cell growth', 'CPA', (39, 50))	('SIX4', 'Gene', (24, 28))	('invasion', 'CPA', (52, 60))	('knockdown', 'Var', (11, 20))
653253	33481352	22  Here, we found that knockdown of SIX4 reduced N-cadherin and vimentin expression and increased E-cadherin expression, indicating that SIX4 promotes EMT in ESCC.	('expression', 'MPA', (74, 84))	('vimentin', 'Gene', (65, 73))	('reduced', 'NegReg', (42, 49))	('N-cadherin', 'Gene', '1000', (50, 60))	('SIX4', 'Gene', (37, 41))	('EMT', 'CPA', (152, 155))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('promotes', 'PosReg', (143, 151))	('SIX4', 'Var', (138, 142))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('increased', 'PosReg', (89, 98))	('vimentin', 'Gene', '7431', (65, 73))	('N-cadherin', 'Gene', (50, 60))	('ESCC', 'Disease', (159, 163))
653254	33481352	Consistent with our results, SIX4 has been proposed to promote metastasis in breast cancer by activating EMT.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('breast cancer', 'Disease', (77, 90))	('metastasis', 'CPA', (63, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('SIX4', 'Var', (29, 33))	('EMT', 'CPA', (105, 108))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('activating', 'PosReg', (94, 104))	('promote', 'PosReg', (55, 62))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
653255	33481352	9  In addition, SIX4 was found to activate AKT and promote tumor angiogenesis in solid tumor progression.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('activate', 'PosReg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('AKT', 'Gene', '207', (43, 46))	('tumor', 'Disease', (87, 92))	('SIX4', 'Var', (16, 20))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('promote', 'PosReg', (51, 58))	('AKT', 'Gene', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('si', 'Chemical', 'MESH:D012825', (100, 102))
653256	33481352	also reported that SIX4 promoted cell metastasis via activation of the PI3K-AKT pathway in colorectal cancer.	('colorectal cancer', 'Disease', (91, 108))	('AKT', 'Gene', '207', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('activation', 'PosReg', (53, 63))	('SIX4', 'Var', (19, 23))	('AKT', 'Gene', (76, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('cell metastasis', 'CPA', (33, 48))	('promoted', 'PosReg', (24, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('si', 'Chemical', 'MESH:D012825', (45, 47))
653399	32165590	The total number of mutations occurring in a tumor specimen is termed tumor mutation burden (TMB), which sketches out the status of genomic mutation.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (45, 50))	('TMB', 'Chemical', '-', (93, 96))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
653405	32165590	In the presented study, we analyzed the difference of clinical features, such as ages, genders, tumor grades, tumor stages, races and radiation, between high TMB (TMB-H) and low TMB (TMB-L) groups.	('TMB', 'Chemical', '-', (158, 161))	('TMB', 'Chemical', '-', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TMB-H', 'Chemical', '-', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (110, 115))	('TMB', 'Chemical', '-', (163, 166))	('TMB', 'Chemical', '-', (183, 186))	('high TMB', 'Var', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
653426	32165590	The TMB-H group had significantly increased Tregs cell infiltration in EC patients who did not receive radiotherapy (P = 0.033), while there was no significantly different infiltration of 22 kinds of immune cells among patients receiving radiotherapy (Figure 5).	('patients', 'Species', '9606', (74, 82))	('TMB-H', 'Var', (4, 9))	('Tregs cell infiltration', 'CPA', (44, 67))	('TMB-H', 'Chemical', '-', (4, 9))	('patients', 'Species', '9606', (219, 227))	('increased', 'PosReg', (34, 43))
653431	32165590	As a tumor with high mutational loads, EC was estimated to have 3,000 to 300,000 mutations per tumor.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutational', 'Var', (21, 31))	('tumor', 'Disease', (95, 100))
653452	32165590	The Treg cells were inclined to be upregulated in the TMB-L subtype of various cancer types, however, we found that high TMB was associated with elevated Treg cell infiltration in EC patients without radiotherapy.	('elevated', 'PosReg', (145, 153))	('TMB', 'Gene', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('high', 'Var', (116, 120))	('Treg cell infiltration', 'CPA', (154, 176))	('TMB', 'Chemical', '-', (121, 124))	('TMB', 'Chemical', '-', (54, 57))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('patients', 'Species', '9606', (183, 191))
653453	32165590	Some studies suggested that high TMB resulted in numerous neoantigens that incited anti-tumor immune responses, and that high TMB was associated with genomic instability, resulting in induced anti-tumor immune responses.	('induced', 'Reg', (184, 191))	('TMB', 'Chemical', '-', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('high TMB', 'Var', (28, 36))	('incited', 'Reg', (75, 82))	('high TMB', 'Var', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('neoantigens', 'MPA', (58, 69))	('TMB', 'Chemical', '-', (33, 36))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (197, 202))
653464	32165590	All SNVs were classified into 96 possible mutation categories based on the 6 base substitutions (C > A, C > G, C > T, T > A, T > C and T > G) and 16 possible combinations of neighboring bases within the trinucleotide sequence context.	('C > T', 'Var', (111, 116))	('C > A', 'Var', (97, 102))	('T > A', 'Var', (118, 123))	('T > C and T > G', 'Var', (125, 140))	('trinucleotide', 'Chemical', '-', (203, 216))	('C > G', 'Var', (104, 109))
653490	31516546	P.gingivalis is an important pathogenic bacterium that mediates the local inflammatory response of periodontitis, adhere to and invade gingival epithelial cells, interfere with normal physiological metabolism, and inhibit apoptosis, which is a potential risk factor for cancer.	('normal physiological metabolism', 'MPA', (177, 208))	('periodontitis', 'Disease', 'MESH:D010518', (99, 112))	('inhibit', 'NegReg', (214, 221))	('apoptosis', 'CPA', (222, 231))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('P.gingivalis', 'Species', '837', (0, 12))	('periodontitis', 'Phenotype', 'HP:0000704', (99, 112))	('periodontitis', 'Disease', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('interfere', 'NegReg', (162, 171))	('P.gingivalis', 'Var', (0, 12))	('local inflammatory response of periodontitis', 'Phenotype', 'HP:0011059', (68, 112))
653500	31516546	On the basis of different antibody levels of P. gingivalis IgG in vivo, periodontitis is divided into none or light(<69EU(Enzyme-linked immunosorbent assay unit)),medium (69.1-119.0 EU) and severe (> 119.0 EU).	('P. gingivalis', 'Species', '837', (45, 58))	('<69EU', 'Var', (116, 121))	('periodontitis', 'Disease', 'MESH:D010518', (72, 85))	('periodontitis', 'Phenotype', 'HP:0000704', (72, 85))	('periodontitis', 'Disease', (72, 85))
653503	31516546	The mortality rate of patients with periodontitis generally increases with the increase in P.gingivalis IgG level.	('increase', 'PosReg', (79, 87))	('periodontitis', 'Disease', 'MESH:D010518', (36, 49))	('periodontitis', 'Phenotype', 'HP:0000704', (36, 49))	('periodontitis', 'Disease', (36, 49))	('patients', 'Species', '9606', (22, 30))	('P.gingivalis', 'Var', (91, 103))	('increases', 'PosReg', (60, 69))	('P.gingivalis', 'Species', '837', (91, 103))
653512	31516546	After long-term and repeated exposure to P. gingivalis, the invasiveness of OSCC cells increases either by IL-8 and MMPs upregulation of or by obtaining stem cell characteristics.	('MMPs', 'Protein', (116, 120))	('P. gingivalis', 'Species', '837', (41, 54))	('P. gingivalis', 'Var', (41, 54))	('increases', 'PosReg', (87, 96))	('stem cell characteristics', 'CPA', (153, 178))	('invasiveness of OSCC cells', 'CPA', (60, 86))	('upregulation of', 'PosReg', (121, 136))
653514	31516546	The possibility of carcinogenesis increases after the primary cell of a human being is infected by P. gingivalis.	('carcinogenesis increases', 'Disease', (19, 43))	('P. gingivalis', 'Species', '837', (99, 112))	('P. gingivalis', 'Var', (99, 112))	('human', 'Species', '9606', (72, 77))	('carcinogenesis increases', 'Disease', 'MESH:D063646', (19, 43))
653521	31516546	Peters B A et al further revealed the increasing P. gingivalis can increase the risk of getting ESCC.	('P. gingivalis', 'Species', '837', (49, 62))	('P. gingivalis', 'Var', (49, 62))	('ESCC', 'Disease', (96, 100))	('gingivalis can increase', 'Phenotype', 'HP:0000212', (52, 75))
653522	31516546	Chinese scholars Gao et al discovered that the positive rates of P. gingivalis in ESCC, adjacent tissues and normal esophageal tissues were 61, 12% and 0, respectively.	('ESCC', 'Disease', (82, 86))	('P. gingivalis', 'Species', '837', (65, 78))	('P. gingivalis', 'Var', (65, 78))
653525	31516546	The sensitivity/specificity of P. gingivalis IgG, IgA, and IgG+ IgA for the diagnosis of ESCC is 29.17%/96.90, 52.10%/70.81, and 68.75%/68.46%, respectively.	('ESCC', 'Disease', (89, 93))	('P. gingivalis', 'Species', '837', (31, 44))	('P. gingivalis', 'Var', (31, 44))
653526	31516546	P. gingivalis IgA exhibits better diagnostic performance for early ESCC than IgG (54.54% vs. 20.45%).	('P. gingivalis', 'Var', (0, 13))	('early ESCC', 'Disease', (61, 71))	('P. gingivalis', 'Species', '837', (0, 13))
653527	31516546	In addition, ESCC patients with high levels of P. gingivalis IgG or IgA have poor prognosis, especially those with stage 0-II or lymph node metastasis; furthermore, patients have positive P. gingivalis IgG+ IgA present poor prognosis.	('P. gingivalis', 'Species', '837', (47, 60))	('P. gingivalis', 'Var', (47, 60))	('P. gingivalis', 'Species', '837', (188, 201))	('ESCC', 'Disease', (13, 17))	('patients', 'Species', '9606', (165, 173))	('patients', 'Species', '9606', (18, 26))	('P. gingivalis', 'Var', (188, 201))
653547	31516546	P. gingivalis is a pathogenic bacterium that possibly participates in liver diseases formation.	('liver disease', 'Phenotype', 'HP:0001392', (70, 83))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('participates', 'Reg', (54, 66))	('liver diseases', 'Disease', 'MESH:D008107', (70, 84))	('liver diseases', 'Phenotype', 'HP:0001392', (70, 84))	('liver diseases', 'Disease', (70, 84))
653548	31516546	In 2009, Nishihara R et al discovered that after KKAy diabetes mice are inoculated with P. gingivalis, their blood glucose, serum tumor necrosis factor alpha (TNF-alpha), and interleukin - 6 (IL-6) are significantly increased,whereas adiponectin is significantly reduced to 35.7%.	('TNF-alpha', 'Gene', '21926', (159, 168))	('necrosis', 'Disease', 'MESH:D009336', (136, 144))	('diabetes', 'Disease', 'MESH:D003920', (54, 62))	('glucose', 'Chemical', 'MESH:D005947', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mice', 'Species', '10090', (63, 67))	('reduced', 'NegReg', (263, 270))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('blood glucose', 'MPA', (109, 122))	('TNF-alpha', 'Gene', (159, 168))	('diabetes', 'Disease', (54, 62))	('P. gingivalis', 'Var', (88, 101))	('adiponectin', 'MPA', (234, 245))	('tumor', 'Disease', (130, 135))	('increased', 'PosReg', (216, 225))	('P. gingivalis', 'Species', '837', (88, 101))	('necrosis', 'Disease', (136, 144))
653569	31516546	The authors speculate that peptide-based arginine deaminase (PAD) enzymes secreted by oral bacterial flora including P. gingivalis, Forsythia bacillus and Treponema pallidum probably cause the gene mutation of P53 and K-ras, which in turn trigger PC.	('gene mutation', 'Var', (193, 206))	('trigger', 'Reg', (239, 246))	('P. gingivalis', 'Species', '837', (117, 130))	('P53', 'Gene', (210, 213))	('K-ras', 'Protein', (218, 223))	('cause', 'Reg', (183, 188))	('Treponema pallidum', 'Species', '160', (155, 173))
653578	31516546	The overall survival rate of Extrahepatic cholangiocarcinoma was greatly lower than those of other cancers.Meta-analysis showed that the risk of gallbladder cancer was associated with Salmonella typhi, and no related reports on P. gingivalis and extrahepatic cholangiocarcinoma were found.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (42, 60))	('gallbladder cancer', 'Disease', (145, 163))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('Salmonella typhi', 'Species', '90370', (184, 200))	('P. gingivalis', 'Species', '837', (228, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('Extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (29, 60))	('extrahepatic cholangiocarcinoma', 'Disease', (246, 277))	('associated', 'Interaction', (168, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (259, 277))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('gallbladder cancer', 'Disease', 'MESH:D005706', (145, 163))	('Salmonella typhi', 'Var', (184, 200))	('cancers', 'Disease', (99, 106))	('Extrahepatic cholangiocarcinoma', 'Disease', (29, 60))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (246, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
653582	31516546	P. gingivalis is probably an important risk factor of gastrointestinal cancer, especially for oral cancer, esophageal cancer, colorectal cancer and pancreatic cancer (Fig.	('P. gingivalis', 'Species', '837', (0, 13))	('pancreatic cancer', 'Disease', 'MESH:D010190', (148, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', (107, 124))	('pancreatic cancer', 'Disease', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (54, 77))	('gastrointestinal cancer', 'Disease', (54, 77))	('colorectal cancer', 'Disease', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (54, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (148, 165))	('P. gingivalis', 'Var', (0, 13))	('oral cancer', 'Disease', 'MESH:D009062', (94, 105))	('oral cancer', 'Disease', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
653594	29561760	The BTK gene is located on the X chromosome (Xq21.33-Xq22) and was first described in the setting of X-linked agammaglobulinemia, a disorder characterized by a lack of maturation and development of B lymphocytes and gammaglobulins due to a mutation in BTK.	('BTK', 'Gene', (252, 255))	('X-linked agammaglobulinemia, a disorder', 'Disease', 'MESH:C537409', (101, 140))	('mutation', 'Var', (240, 248))	('BTK', 'Gene', (4, 7))	('men', 'Species', '9606', (190, 193))	('agammaglobulinemia', 'Phenotype', 'HP:0004432', (110, 128))
653618	29561760	Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) comprises approximately 15-20% of non-small cell lung cancer in white populations with higher rates in the order of 22-62% reported in Asian populations.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (117, 143))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (48, 74))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (121, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('EGFR', 'Gene', (34, 38))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (117, 143))	('non-small cell lung cancer', 'Disease', (48, 74))	('NSCLC', 'Disease', (76, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('non-small cell lung cancer', 'Disease', (117, 143))	('EGFR', 'Gene', '1956', (34, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (48, 74))	('mutated', 'Var', (40, 47))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))
653620	29561760	Osimertinib, a third generation EGFR-directed TKI has shown promising first line data, as well as second line data in those who progress on first line treatment that harbor a T790M resistance mutation (more than 50% of cases).	('men', 'Species', '9606', (156, 159))	('EGFR', 'Gene', '1956', (32, 36))	('T790M', 'Mutation', 'rs121434569', (175, 180))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('EGFR', 'Gene', (32, 36))	('T790M resistance', 'Var', (175, 191))
653625	29561760	A more recent study confirmed that ibrutinib inhibits mutant EGFR kinases through formation of a covalent bond with Cys797 similar to other irreversible EGFR TKIs such as gefitinib and erlotinib.	('ibrutinib', 'Chemical', 'MESH:C551803', (35, 44))	('inhibits', 'NegReg', (45, 53))	('covalent bond', 'MPA', (97, 110))	('EGFR', 'Gene', '1956', (153, 157))	('EGFR', 'Gene', (153, 157))	('Cys797', 'Chemical', '-', (116, 122))	('erlotinib', 'Chemical', 'MESH:D000069347', (185, 194))	('Cys797', 'Var', (116, 122))	('mutant', 'Var', (54, 60))	('EGFR', 'Gene', '1956', (61, 65))	('gefitinib', 'Chemical', 'MESH:D000077156', (171, 180))	('EGFR', 'Gene', (61, 65))
653627	29561760	The ibrutinib activity against EGFR mutant cell lines was similar to that of erlotinib in one comparative study, but also with preserved activity against T790M mutated cell lines which were not sensitive to erlotinib.	('EGFR', 'Gene', '1956', (31, 35))	('T790M', 'Mutation', 'rs121434569', (154, 159))	('EGFR', 'Gene', (31, 35))	('erlotinib', 'Chemical', 'MESH:D000069347', (207, 216))	('erlotinib', 'Chemical', 'MESH:D000069347', (77, 86))	('activity', 'MPA', (137, 145))	('T790M', 'Var', (154, 159))	('mutant', 'Var', (36, 42))	('ibrutinib', 'Chemical', 'MESH:C551803', (4, 13))
653630	29561760	Ibrutinib also slowed tumor progression in a T790M mutation mouse model.	('slowed', 'NegReg', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('T790M mutation', 'Var', (45, 59))	('tumor', 'Disease', (22, 27))	('Ibrutinib', 'Chemical', 'MESH:C551803', (0, 9))	('mouse', 'Species', '10090', (60, 65))	('T790M', 'Mutation', 'rs121434569', (45, 50))
653654	29561760	In subsequent experiments, knockdown of BTK expression selectively inhibited the growth of gastric cancer cells, but not the normal mucosal epithelium.	('knockdown', 'Var', (27, 36))	('inhibited', 'NegReg', (67, 76))	('gastric cancer', 'Disease', (91, 105))	('BTK', 'Gene', (40, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (91, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('growth', 'CPA', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('men', 'Species', '9606', (20, 23))
653662	29561760	MYC amplification is described in 32% of esophageal adenocarcinomas and 23% of squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('MYC', 'Gene', (0, 3))	('esophageal adenocarcinomas', 'Disease', (41, 67))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (79, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('squamous cell carcinomas', 'Disease', (79, 103))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (41, 67))	('amplification', 'Var', (4, 17))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (79, 103))	('MYC', 'Gene', '4609', (0, 3))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))
653680	29561760	Loss of function studies demonstrated that BTK knockdown led to reduced expression of JAK2 and STAT3 targets:with comparable efficacy to BTK knockdown demonstrated with ibrutinib treatment.	('ibrutinib', 'Chemical', 'MESH:C551803', (169, 178))	('knockdown', 'Var', (47, 56))	('expression', 'MPA', (72, 82))	('STAT3', 'Gene', '6774', (95, 100))	('men', 'Species', '9606', (184, 187))	('reduced', 'NegReg', (64, 71))	('JAK2', 'Gene', '3717', (86, 90))	('STAT3', 'Gene', (95, 100))	('JAK2', 'Gene', (86, 90))
653688	29561760	Microarray results show that inhibiting BTK increases expression of the apoptosis-related marker Asp175.	('expression', 'MPA', (54, 64))	('BTK', 'Gene', (40, 43))	('Asp175', 'Chemical', '-', (97, 103))	('inhibiting', 'Var', (29, 39))	('Asp175', 'Gene', (97, 103))	('increases', 'PosReg', (44, 53))
653734	29561760	In solid tumors this combination is also the subject of several active clinical trials of colon cancer, melanoma, renal cell carcinoma, non-small cell lung cancer, breast cancer and pancreatic cancer (NCT03332498, NCT02899078, NCT03021460, NCT02403271).	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (182, 199))	('NCT03332498', 'Var', (201, 212))	('NCT02899078', 'Var', (214, 225))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (136, 162))	('NCT02403271', 'Var', (240, 251))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('colon cancer', 'Phenotype', 'HP:0003003', (90, 102))	('renal cell carcinoma', 'Disease', (114, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('pancreatic cancer', 'Disease', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('non-small cell lung cancer', 'Disease', (136, 162))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('colon cancer', 'Disease', 'MESH:D015179', (90, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('solid tumors', 'Disease', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('breast cancer', 'Disease', (164, 177))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (136, 162))	('colon cancer', 'Disease', (90, 102))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (114, 134))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('NCT03021460', 'Var', (227, 238))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (140, 162))	('solid tumors', 'Disease', 'MESH:D009369', (3, 15))
653788	27405645	Axial images were reconstructed in 2 mm increments using both B19S and B50F kernels.	('B50F', 'Var', (71, 75))	('B50F', 'SUBSTITUTION', 'None', (71, 75))	('B19S', 'Var', (62, 66))	('B19S', 'SUBSTITUTION', 'None', (62, 66))
653800	27405645	Despite the fact that the parameter large-and-medium large nodes gave the best sensitivity (21.7%), it proved the worst specificity (74.8%) and accuracy (62.0%), which therefore made it the least reliable for detection of metastases.	('metastases', 'Disease', 'MESH:D009362', (222, 232))	('metastases', 'Disease', (222, 232))	('large-and-medium', 'Var', (36, 52))
653810	27405645	FDG-PET/CT is a hybrid diagnostic tool where metabolic information provided by PET enhances the anatomic one provided by CT and vice versa.	('metabolic information', 'MPA', (45, 66))	('anatomic one', 'MPA', (96, 108))	('PET', 'Var', (79, 82))	('FDG', 'Gene', '23583', (0, 3))	('enhances', 'PosReg', (83, 91))	('FDG', 'Gene', (0, 3))
653898	26447543	It has been shown that loss of members of the TGFbeta signaling cascade, such as Smad4 and beta2 spectrin, can contribute to the initiation of Barrett's esophagus and the progression to esophageal adenocarcinoma through concomitant upregulation of Notch targets Hes1 and Jagged1.	('Hes1', 'Gene', '3280', (262, 266))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (186, 211))	('TGFbeta', 'Gene', (46, 53))	('beta2 spectrin', 'Protein', (91, 105))	("initiation of Barrett's esophagus", 'Disease', (129, 162))	('Jagged1', 'Gene', '182', (271, 278))	('upregulation', 'PosReg', (232, 244))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (186, 211))	("initiation of Barrett's esophagus", 'Disease', 'MESH:D001471', (129, 162))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (143, 162))	('Hes1', 'Gene', (262, 266))	('Smad4', 'Gene', (81, 86))	('Smad4', 'Gene', '4089', (81, 86))	('contribute', 'Reg', (111, 121))	('Jagged1', 'Gene', (271, 278))	('loss', 'Var', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('esophageal adenocarcinoma', 'Disease', (186, 211))
653900	26447543	The disruption of TGFbeta/Smad-dependent signaling during the progression of esophageal adenocarcinoma was confirmed by a report that showed Smad4 mRNA expression was progressively reduced in the metaplasia-dysplasia-adenocarcinoma sequence by promoter methylation.	('Smad', 'Gene', '4089;4086;4089;4090;4093', (26, 30))	('promoter methylation', 'Var', (244, 264))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', 'MESH:D008679', (196, 231))	('reduced', 'NegReg', (181, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('Smad', 'Gene', (141, 145))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', (196, 231))	('Smad4', 'Gene', (141, 146))	('Smad4', 'Gene', '4089', (141, 146))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (77, 102))	('Smad', 'Gene', '4089;4086;4089;4090;4093', (141, 145))	('mRNA expression', 'MPA', (147, 162))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (77, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('esophageal adenocarcinoma', 'Disease', (77, 102))	('Smad', 'Gene', (26, 30))
653930	26447543	Interestingly, when normalized to the number of cells at the end of the collection period (48 hours), Activin A concentration was higher in OE33 INHBA cells than CPB INHBA cells, while FLO-1 INHBA cells secreted the highest levels of Activin A overall.	('INHBA', 'Gene', (166, 171))	('Activin', 'Gene', (102, 109))	('INHBA', 'Gene', (145, 150))	('Activin', 'Gene', (234, 241))	('INHBA', 'Gene', '3624', (191, 196))	('higher', 'PosReg', (130, 136))	('CPB', 'Gene', '1360', (162, 165))	('INHBA', 'Gene', (191, 196))	('OE33', 'Var', (140, 144))	('Activin', 'Gene', '83729', (102, 109))	('Activin', 'Gene', '83729', (234, 241))	('INHBA', 'Gene', '3624', (166, 171))	('FLO-1', 'Chemical', '-', (185, 190))	('INHBA', 'Gene', '3624', (145, 150))	('CPB', 'Gene', (162, 165))
653933	26447543	As the function and availability of Activin A can be regulated by secreted factors, such as the antagonists Follistatin and Inhibin A, we also measured the concentrations of Follistatin (pan-antibody recognizing all three Follistatin isoforms FS288, FS300 and FS315) and Inhibin A in the collected conditioned media by ELISA.	('Follistatin', 'Gene', (222, 233))	('FS315', 'Var', (260, 265))	('Activin', 'Gene', '83729', (36, 43))	('Follistatin', 'Gene', '10468', (108, 119))	('FS300', 'Var', (250, 255))	('Inhibin A', 'Gene', (271, 280))	('Follistatin', 'Gene', (108, 119))	('FS288', 'Var', (243, 248))	('Inhibin A', 'Gene', (124, 133))	('Inhibin A', 'Gene', '3623', (271, 280))	('Activin', 'Gene', (36, 43))	('Follistatin', 'Gene', '10468', (174, 185))	('Follistatin', 'Gene', '10468', (222, 233))	('Follistatin', 'Gene', (174, 185))	('Inhibin A', 'Gene', '3623', (124, 133))
653941	26447543	In FLO-1 cells pSmad1,5,8 was suppressed by INHBA overexpression, but present in control cells treated with TGFbeta1 or Follistatin-288.	('Follistatin', 'Gene', (120, 131))	('INHBA', 'Gene', '3624', (44, 49))	('suppressed', 'NegReg', (30, 40))	('Smad1,5,8', 'Gene', '4086;4090;4093', (16, 25))	('INHBA', 'Gene', (44, 49))	('TGFbeta1', 'Gene', '7040', (108, 116))	('TGFbeta1', 'Gene', (108, 116))	('FLO-1', 'Chemical', '-', (3, 8))	('overexpression', 'Var', (50, 64))	('Follistatin', 'Gene', '10468', (120, 131))
653983	26447543	The addition of A83-01 had no effect on TGFbeta1 secretion in in all three cell lines.	('TGFbeta1', 'Gene', '7040', (40, 48))	('TGFbeta1', 'Gene', (40, 48))	('secretion', 'MPA', (49, 58))	('A83-01', 'Var', (16, 22))
653989	26447543	Again, overall pERK1/2 was higher in CPB and OE33 cells compared to FLO-1, similar to our observations in the INHBA overexpression model (Figure 2C).	('INHBA', 'Gene', (110, 115))	('CPB', 'Gene', (37, 40))	('pERK1/2', 'MPA', (15, 22))	('OE33', 'Var', (45, 49))	('CPB', 'Gene', '1360', (37, 40))	('higher', 'PosReg', (27, 33))	('FLO-1', 'Chemical', '-', (68, 73))	('INHBA', 'Gene', '3624', (110, 115))
654006	26447543	When we studied the response to Activin A in scratch assays, we found that while OE33 had the highest migratory potential in the scratch assays, Activin A stimulation had no effect compared to untreated controls (Figure 5B).	('Activin', 'Gene', '83729', (32, 39))	('OE33', 'Var', (81, 85))	('Activin', 'Gene', (145, 152))	('migratory potential', 'CPA', (102, 121))	('Activin', 'Gene', (32, 39))	('Activin', 'Gene', '83729', (145, 152))
654016	26447543	This hypothesis is supported by the variable regulation of Activin A-dependent functions in the presence of Follistatin or Activin A neutralizing antibody, but will require additional experimentation.	('Activin', 'Gene', (123, 130))	('Activin', 'Gene', (59, 66))	('neutralizing', 'Var', (133, 145))	('Follistatin', 'Gene', '10468', (108, 119))	('Follistatin', 'Gene', (108, 119))	('Activin', 'Gene', '83729', (123, 130))	('Activin', 'Gene', '83729', (59, 66))
654023	26447543	CK8, however, could be detected and increased following treatment with Activin A and A83-01 (Figure 6B).	('Activin', 'Gene', '83729', (71, 78))	('CK8', 'Gene', '3856', (0, 3))	('CK8', 'Gene', (0, 3))	('A83-01', 'Var', (85, 91))	('increased', 'PosReg', (36, 45))	('Activin', 'Gene', (71, 78))
654036	26447543	TGFbeta inhibition by A83-01 decreased nuclear SOX9 in the CPB cultures, but did not inhibit SOX9 nuclear localization in the FLO-1 cells (Figure 7C).	('SOX9', 'Gene', (47, 51))	('SOX9', 'Gene', '6662', (47, 51))	('inhibition', 'NegReg', (8, 18))	('CPB', 'Gene', '1360', (59, 62))	('TGFbeta', 'Gene', (0, 7))	('A83-01', 'Var', (22, 28))	('SOX9', 'Gene', (93, 97))	('decreased', 'NegReg', (29, 38))	('CPB', 'Gene', (59, 62))	('FLO-1', 'Chemical', '-', (126, 131))	('SOX9', 'Gene', '6662', (93, 97))
654038	26447543	In FLO-1 cells, which showed an increased number of SOX9-positive nuclei upon Activin A and A83-01 treatments, we still detected an increase in SOX9-postitive nuclei in INHBA-overexpressing cells (Figure 7B), but not to the same extent as in cultures treated with recombinant Activin A (Figure 7C).	('SOX9', 'Gene', (144, 148))	('INHBA', 'Gene', (169, 174))	('Activin', 'Gene', '83729', (276, 283))	('SOX9', 'Gene', (52, 56))	('SOX9', 'Gene', '6662', (144, 148))	('A83-01', 'Var', (92, 98))	('Activin', 'Gene', '83729', (78, 85))	('Activin', 'Gene', (276, 283))	('SOX9', 'Gene', '6662', (52, 56))	('increased', 'PosReg', (32, 41))	('Activin', 'Gene', (78, 85))	('FLO-1', 'Chemical', '-', (3, 8))	('INHBA', 'Gene', '3624', (169, 174))
654050	26447543	This has been shown by deletions of TGFbeta2, TGFbeta3 and Inhibin betaA, which all result in cleft palate defects in the respective mouse model.	('deletions', 'Var', (23, 32))	('TGFbeta3', 'Gene', (46, 54))	('cleft palate', 'Phenotype', 'HP:0000175', (94, 106))	('TGFbeta2', 'Gene', '21808', (36, 44))	('result in', 'Reg', (84, 93))	('TGFbeta2', 'Gene', (36, 44))	('cleft palate defects', 'Disease', (94, 114))	('Inhibin betaA', 'Gene', '16323', (59, 72))	('mouse', 'Species', '10090', (133, 138))	('cleft palate defects', 'Disease', 'MESH:D002972', (94, 114))	('palate defects', 'Phenotype', 'HP:0000174', (100, 114))	('Inhibin betaA', 'Gene', (59, 72))
654051	26447543	Similar to a 10-bp polyadenine tract within the TGFbeta receptor type II gene (TGFBR2) that is prone to frameshift mutations in gastrointestinal cancers, mutations in ACVR2 have been identified in colorectal and pancreatic cancers.	('frameshift', 'Var', (104, 114))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (212, 230))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('polyadenine', 'Chemical', 'MESH:C000628261', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('TGFBR2', 'Gene', (79, 85))	('colorectal and pancreatic cancers', 'Disease', 'MESH:D010190', (197, 230))	('ACVR2', 'Gene', '92', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (212, 229))	('identified', 'Reg', (183, 193))	('ACVR2', 'Gene', (167, 172))	('mutations', 'Var', (154, 163))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (128, 152))	('TGFBR2', 'Gene', '7048', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('gastrointestinal cancers', 'Disease', (128, 152))
654052	26447543	Additionally, ACVR1B is commonly mutated in pancreatic cancer, and in a majority of sporadic colorectal cancers BMPR2 expression is impaired.	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('impaired', 'NegReg', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('colorectal cancers', 'Disease', 'MESH:D015179', (93, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('mutated', 'Var', (33, 40))	('ACVR1B', 'Gene', '91', (14, 20))	('ACVR1B', 'Gene', (14, 20))	('BMPR2', 'Gene', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('colorectal cancers', 'Disease', (93, 111))	('expression', 'MPA', (118, 128))	('pancreatic cancer', 'Disease', (44, 61))	('BMPR2', 'Gene', '659', (112, 117))
654054	26447543	Exome and whole-genome sequencing of EAC has identified recurrent driver events with high frequency, such as mutations in TP53 and CDKN2A, but also PTEN and SMAD4.	('PTEN', 'Gene', (148, 152))	('EAC', 'Phenotype', 'HP:0011459', (37, 40))	('TP53', 'Gene', (122, 126))	('PTEN', 'Gene', '5728', (148, 152))	('CDKN2A', 'Gene', '1029', (131, 137))	('SMAD4', 'Gene', (157, 162))	('mutations', 'Var', (109, 118))	('TP53', 'Gene', '7157', (122, 126))	('CDKN2A', 'Gene', (131, 137))	('SMAD4', 'Gene', '4089', (157, 162))
654062	26447543	Our previous study showed that while cell invasion was increased upon Activin A stimulation in a premalignant cell model, inhibition of Activin A and TGFbeta1 further enhanced cell invasion.	('enhanced', 'PosReg', (167, 175))	('inhibition', 'Var', (122, 132))	('Activin', 'Gene', (70, 77))	('TGFbeta1', 'Gene', '7040', (150, 158))	('increased', 'PosReg', (55, 64))	('TGFbeta1', 'Gene', (150, 158))	('Activin', 'Gene', '83729', (136, 143))	('cell invasion', 'CPA', (176, 189))	('Activin', 'Gene', '83729', (70, 77))	('Activin', 'Gene', (136, 143))	('cell invasion', 'CPA', (37, 50))
654065	26447543	Invasion of CPB and FLO-1 cells was increased upon INHBA overexpression, but was not affected by stimulation.	('Invasion', 'CPA', (0, 8))	('CPB', 'Gene', '1360', (12, 15))	('increased', 'PosReg', (36, 45))	('FLO-1', 'Chemical', '-', (20, 25))	('INHBA', 'Gene', '3624', (51, 56))	('overexpression', 'Var', (57, 71))	('CPB', 'Gene', (12, 15))	('INHBA', 'Gene', (51, 56))
654087	26447543	Additional support that SOX9 may be an important early event in the development of Barrett's tumorigenesis is seen in the activation of SOX9 following loss of beta2-spectrin, which induces a TGFbeta signaling switch from tumor suppressor in normal cells to tumor promoter in fibroblasts and EACs.	('SOX9', 'Gene', '6662', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('SOX9', 'Gene', '6662', (24, 28))	('activation', 'PosReg', (122, 132))	('tumor', 'Disease', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('induces', 'Reg', (181, 188))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('beta2-spectrin', 'Chemical', '-', (159, 173))	('EAC', 'Phenotype', 'HP:0011459', (291, 294))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('SOX9', 'Gene', (136, 140))	('SOX9', 'Gene', (24, 28))	('tumor', 'Disease', (93, 98))	('beta2-spectrin', 'Protein', (159, 173))	('TGFbeta signaling switch', 'MPA', (191, 215))	('loss', 'Var', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
654148	22542127	Forty micrograms of total protein extracts were separated on 3% to 8% Tris-acetate and 4% to 12% Bis-Tris gels for detection of MUC16 (500-5000 kDa) and beta-actin (42 kDa), respectively.	('beta-actin', 'Gene', '728378', (153, 163))	('beta-actin', 'Gene', (153, 163))	('MUC16', 'Protein', (128, 133))	('Tris-acetate', 'Chemical', '-', (70, 82))	('500-5000 kDa', 'Var', (135, 147))	('Bis-Tris', 'Chemical', 'MESH:C026272', (97, 105))
654223	19939248	Therefore, mRNA expression of the genotype of these cells, in theory, can improve the sensitivity of detection of early cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('improve', 'PosReg', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('mRNA', 'Var', (11, 15))
654228	19939248	Recently, the value of methylated EYA4 as a marker for Barrette's esophagus and esophageal adenocarcinoma has been suggested.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (80, 105))	('methylated', 'Var', (23, 33))	('EYA4', 'Gene', (34, 38))	('EYA4', 'Gene', '2070', (34, 38))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	("Barrette's esophagus", 'Phenotype', 'HP:0100580', (55, 75))	('esophageal adenocarcinoma', 'Disease', (80, 105))
654329	33633453	A gene is a resistant candidate if it exists within primary tumor (23cm) post-IR and did not exist within a high-mutation burden pre-IR cell or the percentage of post-IR cells with the mutation is greater than non-high mutational burden primary tumor (23cm) pre-IR cells.	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mutation', 'Var', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (245, 250))	('tumor', 'Disease', (60, 65))
654342	33633453	The criteria of identifying IR-resistant gene candidates were defined as genes which were mutated in multiple post-IR cells and either: 1) not mutated in any potential sensitive cell or 2) the percentage of cells with a gene mutated post-IR is greater than the percentage of cells with it mutated in pre-IR primary tumor (23cm) cells with less than 62 mutations.	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', (315, 320))	('mutated', 'Var', (225, 232))
654343	33633453	Interestingly, mutations in LAMA5 and CHEK2 co-occur with PTEN and AHNAK2 mutations in cancer cells.	('cancer', 'Disease', (87, 93))	('PTEN', 'Gene', '5728', (58, 62))	('CHEK2', 'Gene', (38, 43))	('AHNAK2', 'Gene', '113146', (67, 73))	('LAMA5', 'Gene', '3911', (28, 33))	('mutations', 'Var', (15, 24))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CHEK2', 'Gene', '11200', (38, 43))	('LAMA5', 'Gene', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('AHNAK2', 'Gene', (67, 73))	('co-occur', 'Reg', (44, 52))	('PTEN', 'Gene', (58, 62))
654344	33633453	However, there was no cancer cell carried both LAMA5 and CHEK2 mutations at single-cell level, suggesting mutations in LAMA5 and CHEK2 may represent different radioresistant subclones within AHNAK2mutPTENmut cells (Figure 1A and B).	('AHNAK2', 'Gene', '113146', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('PTEN', 'Gene', '5728', (200, 204))	('cancer', 'Disease', (22, 28))	('LAMA5', 'Gene', (47, 52))	('PTEN', 'Gene', (200, 204))	('LAMA5', 'Gene', (119, 124))	('CHEK2', 'Gene', '11200', (129, 134))	('mutations', 'Var', (106, 115))	('CHEK2', 'Gene', '11200', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('AHNAK2', 'Gene', (191, 197))	('LAMA5', 'Gene', '3911', (47, 52))	('CHEK2', 'Gene', (129, 134))	('CHEK2', 'Gene', (57, 62))	('LAMA5', 'Gene', '3911', (119, 124))
654347	33633453	We observed that 65% (35/54) of patients with mutations in AHNAK2, 19% (10/54) with mutations in EVPL and 2% (1/54) of patients with mutations in LAMA5 that were persistent during their radiotherapy (Figure 2A).	('EVPL', 'Gene', (97, 101))	('patients', 'Species', '9606', (32, 40))	('mutations', 'Var', (46, 55))	('LAMA5', 'Gene', '3911', (146, 151))	('EVPL', 'Gene', '2125', (97, 101))	('patients', 'Species', '9606', (119, 127))	('AHNAK2', 'Gene', (59, 65))	('AHNAK2', 'Gene', '113146', (59, 65))	('LAMA5', 'Gene', (146, 151))
654348	33633453	Collectively, the results suggested that mutations in AHNAK2, EVPL and LAMA5 may potentially contribute to the radioresistance of ESCC.	('mutations', 'Var', (41, 50))	('contribute', 'Reg', (93, 103))	('AHNAK2', 'Gene', (54, 60))	('EVPL', 'Gene', '2125', (62, 66))	('ESCC', 'Disease', (130, 134))	('LAMA5', 'Gene', (71, 76))	('AHNAK2', 'Gene', '113146', (54, 60))	('LAMA5', 'Gene', '3911', (71, 76))	('radioresistance', 'CPA', (111, 126))	('EVPL', 'Gene', (62, 66))
654352	33633453	The colony formation assay with siRNA transfected TE-1 cells also exhibited that more colonies were formed in the AHNAK2-RNAi and EVPL-RNAi ESCC cells (Figure 3E), which indicated that knockdown of AHNAK2 and EVPL could induce radioresistance.	('colonies', 'CPA', (86, 94))	('induce', 'PosReg', (220, 226))	('knockdown', 'Var', (185, 194))	('radioresistance', 'CPA', (227, 242))	('EVPL', 'Gene', (130, 134))	('AHNAK2', 'Gene', (114, 120))	('EVPL', 'Gene', (209, 213))	('EVPL', 'Gene', '2125', (209, 213))	('EVPL', 'Gene', '2125', (130, 134))	('AHNAK2', 'Gene', (198, 204))	('AHNAK2', 'Gene', '113146', (114, 120))	('AHNAK2', 'Gene', '113146', (198, 204))
654357	33633453	To further investigate the role of these genes in radioresistance, we conducted siRNA knockdown of AHNAK2, EVPL and LAMA5 in ESCC cell lines and performed RNA-seq to identify the potential influenced signaling pathways.	('EVPL', 'Gene', (107, 111))	('knockdown', 'Var', (86, 95))	('AHNAK2', 'Gene', (99, 105))	('EVPL', 'Gene', '2125', (107, 111))	('AHNAK2', 'Gene', '113146', (99, 105))	('LAMA5', 'Gene', (116, 121))	('LAMA5', 'Gene', '3911', (116, 121))
654363	33633453	These results showed that knockdown of AHNAK2 and EVPL may have similar transcriptional influence, in which the NF-kappa B signaling pathway and TNF signaling pathway were significantly repressed in KYSE-150 cells.	('AHNAK2', 'Gene', (39, 45))	('TNF', 'Gene', (145, 148))	('AHNAK2', 'Gene', '113146', (39, 45))	('repressed', 'NegReg', (186, 195))	('NF-kappa B', 'Gene', '4790', (112, 122))	('EVPL', 'Gene', (50, 54))	('EVPL', 'Gene', '2125', (50, 54))	('TNF', 'Gene', '7124', (145, 148))	('knockdown', 'Var', (26, 35))	('KYSE-150', 'CellLine', 'CVCL:1348', (199, 207))	('NF-kappa B', 'Gene', (112, 122))
654372	33633453	In summary, these results suggested that knockdown of AHNAK2 and EVPL in KYSE-150 cells will repress the potential immune response of cancer cells through controlling the expression of interleukins and chemokines by inhibiting the NF-kappaB and TNF signaling pathways.	('EVPL', 'Gene', (65, 69))	('expression', 'MPA', (171, 181))	('EVPL', 'Gene', '2125', (65, 69))	('AHNAK2', 'Gene', (54, 60))	('NF-kappaB', 'Gene', (231, 240))	('inhibiting', 'NegReg', (216, 226))	('cancer', 'Disease', (134, 140))	('repress', 'NegReg', (93, 100))	('TNF', 'Gene', (245, 248))	('AHNAK2', 'Gene', '113146', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('controlling', 'Reg', (155, 166))	('NF-kappaB', 'Gene', '4790', (231, 240))	('TNF', 'Gene', '7124', (245, 248))	('knockdown', 'Var', (41, 50))	('KYSE-150', 'CellLine', 'CVCL:1348', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
654377	33633453	In the present work, we reported three newly identified radioresistant genes - AHNAK2, EVPL and LAMA5, in which the mutations in these genes may cause loss of function and contributed to radioresistance.	('EVPL', 'Gene', '2125', (87, 91))	('loss of function', 'NegReg', (151, 167))	('LAMA5', 'Gene', '3911', (96, 101))	('AHNAK2', 'Gene', (79, 85))	('mutations', 'Var', (116, 125))	('radioresistance', 'CPA', (187, 202))	('AHNAK2', 'Gene', '113146', (79, 85))	('LAMA5', 'Gene', (96, 101))	('contributed', 'Reg', (172, 183))	('EVPL', 'Gene', (87, 91))
654379	33633453	Although the mutations (or reductions) of AHNAK2 or EVPL could significantly cause the radioresistance of cancer cells, the transcriptional changes of these cancer cells may play vital roles in the resistance of cancer during radiotherapy.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('EVPL', 'Gene', (52, 56))	('EVPL', 'Gene', '2125', (52, 56))	('cause', 'Reg', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('AHNAK2', 'Gene', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('AHNAK2', 'Gene', '113146', (42, 48))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('play', 'Reg', (174, 178))	('mutations', 'Var', (13, 22))	('reductions', 'NegReg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
654385	33633453	In summary, we demonstrated that mutations in AHNAK2, LAMA5 and EVPL genes were correlated with radioresistance in ESCC and provided a mechanistic clue that loss of function in specific gene may reshape the transcriptome profiles in tumor cells and reduce their potential immune response and thereby impact the overall resistance to radiotherapy.	('LAMA5', 'Gene', (54, 59))	('loss of function', 'Var', (157, 173))	('mutations', 'Var', (33, 42))	('immune response', 'CPA', (272, 287))	('EVPL', 'Gene', (64, 68))	('LAMA5', 'Gene', '3911', (54, 59))	('ESCC', 'Disease', (115, 119))	('tumor', 'Disease', (233, 238))	('reshape', 'Reg', (195, 202))	('EVPL', 'Gene', '2125', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('correlated', 'Reg', (80, 90))	('impact', 'Reg', (300, 306))	('transcriptome profiles', 'MPA', (207, 229))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('resistance to radiotherapy', 'CPA', (319, 345))	('radioresistance', 'Disease', (96, 111))	('reduce', 'NegReg', (249, 255))	('AHNAK2', 'Gene', '113146', (46, 52))	('AHNAK2', 'Gene', (46, 52))
654391	29805590	The hUCMSC-CM also attenuated the migratory abilities of the two tumor cell types.	('tumor', 'Disease', (65, 70))	('hUCMSC-CM', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('attenuated', 'NegReg', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
654405	29805590	By contrast, other studies have indicated that hUCMSCs may promote tumor proliferation in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('hUCMSCs', 'Var', (47, 54))	('promote', 'PosReg', (59, 66))	('tumor', 'Disease', (67, 72))
654438	29805590	The results for BEL7402 cells treated with hUCMSC-CM were different, with an increased cell number in the S phase and a corresponding reduction in the G1 phase population (Fig.	('hUCMSC-CM', 'Var', (43, 52))	('G1 phase population', 'CPA', (151, 170))	('reduction', 'NegReg', (134, 143))	('cell number in the S phase', 'CPA', (87, 113))	('increased', 'PosReg', (77, 86))	('BEL7402', 'CellLine', 'CVCL:5492', (16, 23))
654439	29805590	Overall, analysis of the cell cycle distribution revealed that hUCMSC-CM inhibited the proliferation of tumor cells by arresting the cell cycle in specific phases.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('hUCMSC-CM', 'Var', (63, 72))	('inhibited', 'NegReg', (73, 82))	('arresting', 'NegReg', (119, 128))	('cell cycle', 'CPA', (133, 143))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
654441	29805590	The results revealed that fewer A549 and BEL7402 cells were able to cross the membrane following treatment with hUCMSC-CM, compared with the control group (P<0.05; Fig.	('BEL7402', 'CellLine', 'CVCL:5492', (41, 48))	('A549', 'CellLine', 'CVCL:0023', (32, 36))	('fewer', 'NegReg', (26, 31))	('hUCMSC-CM', 'Var', (112, 121))
654442	29805590	Therefore, hUCMSC-CM markedly reduced the migratory abilities of A549 and BEL7402 tumor cells.	('A549', 'CellLine', 'CVCL:0023', (65, 69))	('BEL7402', 'CellLine', 'CVCL:5492', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('hUCMSC-CM', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('reduced', 'NegReg', (30, 37))	('migratory abilities', 'CPA', (42, 61))	('tumor', 'Disease', (82, 87))
654443	29805590	hUCMSC-CM induces the apoptosis of A549 and BEL7402 cells.	('apoptosis', 'CPA', (22, 31))	('hUCMSC-CM', 'Var', (0, 9))	('BEL7402', 'CellLine', 'CVCL:5492', (44, 51))	('A549', 'CellLine', 'CVCL:0023', (35, 39))
654445	29805590	1C, incubation with hUCMSC-CM induced a significant increase in the percentage of apoptotic cells, with 46.27+-9.96% of A549 tumor cells and 18.23+-6.66% of BEL7402 tumor cells in late-stage apoptosis (P<0.05; Fig.	('apoptotic cells', 'CPA', (82, 97))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('A549 tumor', 'Disease', 'MESH:D009369', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('increase', 'PosReg', (52, 60))	('BEL7402', 'CellLine', 'CVCL:5492', (157, 164))	('hUCMSC-CM', 'Var', (20, 29))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('A549 tumor', 'Disease', (120, 130))	('tumor', 'Disease', (165, 170))
654446	29805590	Taken together, these results demonstrated that hUCMSC-CM induced the apoptosis of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('hUCMSC-CM', 'Var', (48, 57))	('apoptosis', 'CPA', (70, 79))	('cancer', 'Disease', (83, 89))
654447	29805590	The results of western blot analysis revealed that hUCMSC-CM slightly increased the expression of EphA5, which has been identified as a biomarker of cancer cell dormancy.	('cancer', 'Disease', (149, 155))	('increased', 'PosReg', (70, 79))	('EphA5', 'Gene', (98, 103))	('EphA5', 'Gene', '2044', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('hUCMSC-CM', 'Var', (51, 60))	('expression', 'MPA', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
654448	29805590	hUCMSC-CM also resulted in the downregulation of Bcl-2 and caspase-7 in these two tumor cell types (Fig.	('hUCMSC-CM', 'Var', (0, 9))	('Bcl-2', 'Gene', (49, 54))	('Bcl-2', 'Gene', '596', (49, 54))	('caspase-7', 'Gene', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('caspase-7', 'Gene', '840', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('downregulation', 'NegReg', (31, 45))	('tumor', 'Disease', (82, 87))
654464	29805590	Zhang et al reported that modified hUCMSCs that were transfected with the inerleukin-21 gene inhibited the proliferation of ovarian cancer cells in vitro and in vivo.	('proliferation', 'CPA', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (124, 138))	('ovarian cancer', 'Disease', 'MESH:D010051', (124, 138))	('inerleukin-21', 'Gene', (74, 87))	('gene', 'Var', (88, 92))	('inhibited', 'NegReg', (93, 102))	('ovarian cancer', 'Disease', (124, 138))
654468	29805590	When cell cycle analysis was conducted, significantly more tumor cells were observed in the G1/S phase following treatment with hUCMSC-CM in vitro.	('more', 'PosReg', (54, 58))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('G1/S phase', 'CPA', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('hUCMSC-CM', 'Var', (128, 137))
654474	29805590	The present study demonstrated that hUCMSCs also significantly inhibited the migratory behavior of the two types of tumor cells in Transwell chambers.	('hUCMSCs', 'Var', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('inhibited', 'NegReg', (63, 72))	('tumor', 'Disease', (116, 121))
654475	29805590	Furthermore, it was revealed that hUCMSC-CM significantly increased the proportion of Annexin V/PI-positive cells.	('Annexin V', 'Gene', (86, 95))	('hUCMSC-CM', 'Var', (34, 43))	('increased', 'PosReg', (58, 67))	('Annexin V', 'Gene', '308', (86, 95))
654476	29805590	Consistently, the western blot analysis revealed that hUCMSC-CM inhibited the expression of apoptosis-related proteins, including Bcl-2 and pro caspase-7, in A549 and BEL7402 cells.	('A549', 'CellLine', 'CVCL:0023', (158, 162))	('expression', 'MPA', (78, 88))	('caspase-7', 'Gene', (144, 153))	('inhibited', 'NegReg', (64, 73))	('caspase-7', 'Gene', '840', (144, 153))	('BEL7402', 'CellLine', 'CVCL:5492', (167, 174))	('Bcl-2', 'Gene', (130, 135))	('hUCMSC-CM', 'Var', (54, 63))	('apoptosis-related proteins', 'Gene', (92, 118))	('Bcl-2', 'Gene', '596', (130, 135))
654486	29805590	The results of western blot analysis in the present study demonstrated that the treatment of A549 and BEL7402 cells with hUCMSC-CM resulted in the downregulation of beta-catenin.	('beta-catenin', 'Gene', '1499', (165, 177))	('BEL7402', 'CellLine', 'CVCL:5492', (102, 109))	('A549', 'CellLine', 'CVCL:0023', (93, 97))	('downregulation', 'NegReg', (147, 161))	('hUCMSC-CM', 'Var', (121, 130))	('beta-catenin', 'Gene', (165, 177))
654488	29805590	Consistent with the observed reduction in beta-catenin, the expression levels of c-Myc in these two tumor cell types receiving hUCMSC-CM were also downregulated.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('beta-catenin', 'Gene', (42, 54))	('downregulated', 'NegReg', (147, 160))	('beta-catenin', 'Gene', '1499', (42, 54))	('tumor', 'Disease', (100, 105))	('reduction', 'NegReg', (29, 38))	('hUCMSC-CM', 'Var', (127, 136))	('c-Myc', 'Gene', '4609', (81, 86))	('c-Myc', 'Gene', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
654494	29805590	At the beginning of the present study, it was observed that hUCMSCs induced cell cycle arrest, an increase in apoptosis and a decrease in the migration of A549 and BEL7402 tumor cells, which indicated the possible involvement of dormancy mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('migration', 'CPA', (142, 151))	('hUCMSCs', 'Var', (60, 67))	('tumor', 'Disease', (172, 177))	('cell cycle arrest', 'CPA', (76, 93))	('BEL7402', 'CellLine', 'CVCL:5492', (164, 171))	('decrease', 'NegReg', (126, 134))	('A549', 'CellLine', 'CVCL:0023', (155, 159))	('increase', 'PosReg', (98, 106))	('apoptosis', 'CPA', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
654516	29805590	In summary, the results of the present study suggested that hUCMSCs may inhibit the malignant biological behaviors of human lung cancer and hepatocellular cancer cells in vitro by activating cell apoptosis and inhibiting Wnt signaling.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cell apoptosis', 'CPA', (191, 205))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('hUCMSCs', 'Var', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('activating', 'Reg', (180, 190))	('human', 'Species', '9606', (118, 123))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (140, 161))	('hepatocellular cancer', 'Disease', (140, 161))	('inhibiting', 'NegReg', (210, 220))	('inhibit', 'NegReg', (72, 79))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (140, 161))	('Wnt signaling', 'Pathway', (221, 234))
654535	29616200	Genomic profiling of UGT malignancies has yielded compendia of mutations, regions of loss of heterogeneity, gene fusions/translocations, and copy-number alterations responsible for pathogenesis, disease recurrence, and drug resistance.	('mutations', 'Var', (63, 72))	('drug resistance', 'Phenotype', 'HP:0020174', (219, 234))	('UGT malignancies', 'Disease', 'MESH:D009369', (21, 37))	('copy-number alterations', 'Var', (141, 164))	('UGT malignancies', 'Disease', (21, 37))
654556	29616200	The N-terminal of the ICP10 gene of HSV2 was modified by deleting a protein-kinase domain.	('deleting', 'Var', (57, 65))	('HSV2', 'Species', '10310', (36, 40))	('protein-kinase domain', 'MPA', (68, 89))	('HSV2', 'Gene', (36, 40))
654558	29616200	They used four drugs and a modified Ad5, with deletion of the 55 kDa-encoding E1B region and a part of the E3 region, generating the vector Ad-delE1B55.	('deletion', 'Var', (46, 54))	('E1B', 'Gene', (78, 81))	('Ad5', 'Gene', (36, 39))	('Ad5', 'Gene', '8081', (36, 39))
654560	29616200	5FU enhanced the cell cycle at the S phase and then induced G2-M phase entry, whereas CDDP induced G1 phase arrest.	('G2-M phase', 'CPA', (60, 70))	('enhanced', 'PosReg', (4, 12))	('CDDP', 'Chemical', 'MESH:D002945', (86, 90))	('cell cycle at the S phase', 'CPA', (17, 42))	('induced', 'Reg', (52, 59))	('5FU', 'Chemical', 'MESH:D005472', (0, 3))	('5FU', 'Var', (0, 3))
654561	29616200	Ad-delE1B55 also induced the S phase and G2/M phase such that G1 phase arrest by CDDP was inhibitory to Ad-mediated cell-cycle progression and as a result was unfavorable to Ad-mediated toxicities.	('G1 phase arrest', 'CPA', (62, 77))	('G2/M phase', 'CPA', (41, 51))	('Ad-delE1B55', 'Var', (0, 11))	('toxicities', 'Disease', (186, 196))	('induced', 'Reg', (17, 24))	('inhibitory', 'NegReg', (90, 100))	('CDDP', 'Gene', (81, 85))	('toxicities', 'Disease', 'MESH:D064420', (186, 196))	('CDDP', 'Chemical', 'MESH:D002945', (81, 85))	('S phase', 'CPA', (29, 36))
654581	29616200	It was found that N-acetyl cysteine improved killing of neighboring uninfected cells using the NV1066 platform.	('N-acetyl', 'Var', (18, 26))	('improved', 'PosReg', (36, 44))	('killing', 'CPA', (45, 52))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (18, 35))
654583	29616200	midkine and cyclooxygenases (Cox2M and Cox2L) promoters demonstrated high transcriptional activity in gastric cancer cells, and the Cox2CR-Ad showed a potent oncolytic effect.	('oncolytic effect', 'CPA', (158, 174))	('oxygen', 'Chemical', 'MESH:D010100', (17, 23))	('gastric cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('Cox2CR-Ad', 'Var', (132, 141))	('transcriptional activity', 'MPA', (74, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))
654589	29616200	The vector Ad5LucRGD also had polylysine motifs - pK7 and pK21 - that bound to heparan sulfates, which are overexpressed in gastric cancers.	('Ad5', 'Gene', '8081', (11, 14))	('bound', 'Interaction', (70, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('polylysine', 'Chemical', 'MESH:D011107', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('gastric cancers', 'Disease', 'MESH:D013274', (124, 139))	('heparan sulfates', 'Protein', (79, 95))	('heparan sulfates', 'Chemical', 'MESH:D006497', (79, 95))	('gastric cancers', 'Disease', (124, 139))	('gastric cancers', 'Phenotype', 'HP:0012126', (124, 139))	('Ad5', 'Gene', (11, 14))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('pK21 -', 'Var', (58, 64))
654593	29616200	This AdE2F-p16 replicated preferentially in tumor cells with the desired specificity, while sparing normal cells.	('p16', 'Gene', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('replicated', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('preferentially', 'PosReg', (26, 40))	('p16', 'Gene', '1029', (11, 14))	('tumor', 'Disease', (44, 49))
654610	29616200	This study demonstrated that cell-cycle mobilization and S/G2/M phase trapping could be induced by adenoviral infection.	('adenoviral infection', 'Disease', (99, 119))	('induced', 'Reg', (88, 95))	('cell-cycle mobilization', 'CPA', (29, 52))	('adenoviral infection', 'Disease', 'MESH:D007239', (99, 119))	('S/G2', 'Var', (57, 61))	('S/G2', 'SUBSTITUTION', 'None', (57, 61))
654629	29616200	Initially, such vectors as ONYX015 (Ad with E1B 55 kDa deletion) developed to treat other malignancies were evaluated in pancreatic tumor cancer cells.	('malignancies', 'Disease', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('E1B', 'Var', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic tumor cancer', 'Disease', (121, 144))	('pancreatic tumor cancer', 'Disease', 'MESH:D010190', (121, 144))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (121, 137))
654652	29616200	Ad Sur-SYE resulted in potent oncolysis in PDAC and superior efficiency when compared to the non-targeting virus AdSur for neuroendocrine pancreatic tumors when administrated intratumorally.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('oncolysis', 'MPA', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (138, 154))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('PDAC', 'Phenotype', 'HP:0006725', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (138, 155))	('tumor', 'Disease', (180, 185))	('efficiency', 'MPA', (61, 71))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', (149, 154))	('Ad Sur-SYE', 'Var', (0, 10))	('neuroendocrine pancreatic tumors', 'Disease', (123, 155))	('PDAC', 'Chemical', '-', (43, 47))	('neuroendocrine pancreatic tumors', 'Disease', 'MESH:D018358', (123, 155))
654682	29616200	Melittin can induce HCC apoptosis, and the vector QG511-HA-melittin exerted an inhibitory effect in HCC and was described as triple-targeting mechanism addressing AFP-positive cells, cells in a hypoxic environment, and cells with p53 deficiency.	('AFP', 'Gene', '174', (163, 166))	('HCC apoptosis', 'CPA', (20, 33))	('inhibitory effect', 'MPA', (79, 96))	('HCC', 'Phenotype', 'HP:0001402', (20, 23))	('QG511-HA-melittin', 'Var', (50, 67))	('p53', 'Gene', '7157', (230, 233))	('AFP', 'Gene', (163, 166))	('p53', 'Gene', (230, 233))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))
654696	29616200	In this study, virotherapy was found to induce antivascular cytokines and was associated with tumor vascular shutdown.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('virotherapy', 'Var', (15, 26))	('antivascular cytokines', 'MPA', (47, 69))	('induce', 'PosReg', (40, 46))
654705	29616200	Continued VSV genome engineering yielded improved vector safety using an MDelta51 deletion in the viral genome.	('vector safety', 'MPA', (50, 63))	('improved', 'PosReg', (41, 49))	('VSV', 'Species', '11276', (10, 13))	('MDelta51 deletion', 'Var', (73, 90))
654713	29616200	An NDV vector harboring an L289A mutation within the F gene resulted in enhanced fusion and cytotoxicity of HCC cells in vitro compared to an rNDV/F3aa control virus.	('L289A', 'Var', (27, 32))	('HCC', 'Phenotype', 'HP:0001402', (108, 111))	('cytotoxicity', 'Disease', (92, 104))	('NDV', 'Species', '11176', (3, 6))	('L289A', 'Mutation', 'p.L289A', (27, 32))	('NDV', 'Species', '11176', (143, 146))	('enhanced', 'PosReg', (72, 80))	('fusion', 'CPA', (81, 87))	('cytotoxicity', 'Disease', 'MESH:D064420', (92, 104))
654735	27323819	The results showed that RGZ suppressed proliferation and induced apoptosis of esophageal cancer cells, which could be partly restored by inactivation of PPARgamma.	('inactivation', 'Var', (137, 149))	('induced', 'Reg', (57, 64))	('suppressed', 'NegReg', (28, 38))	('proliferation', 'CPA', (39, 52))	('apoptosis', 'CPA', (65, 74))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('PPARgamma', 'Gene', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
654738	27323819	In conclusion, our data suggested that activation of PPARgamma suppressed proliferation and induced apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway.	('TLR4', 'Gene', (151, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('inhibiting', 'NegReg', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('suppressed', 'NegReg', (63, 73))	('proliferation', 'CPA', (74, 87))	('PPARgamma', 'Protein', (53, 62))	('activation', 'Var', (39, 49))	('TLR4', 'Gene', '7099', (151, 155))	('apoptosis', 'CPA', (100, 109))	('esophageal cancer', 'Disease', (113, 130))
654761	27323819	We observed that GW9662 enhanced the proliferation of EC109 cells compared with the control group.	('GW9662', 'Var', (17, 23))	('GW9662', 'Chemical', 'MESH:C457499', (17, 23))	('enhanced', 'PosReg', (24, 32))	('EC109', 'CellLine', 'CVCL:6898', (54, 59))	('proliferation', 'CPA', (37, 50))
654765	27323819	We observed that siRNA-mediated knockdown of RXRalpha in EC109 cells blunted the ability of RGZ to repress cell proliferation (Figure 1E).	('RXRalpha', 'Gene', '6256', (45, 53))	('ability', 'MPA', (81, 88))	('knockdown', 'Var', (32, 41))	('cell proliferation', 'CPA', (107, 125))	('EC109', 'CellLine', 'CVCL:6898', (57, 62))	('blunted', 'NegReg', (69, 76))	('RXRalpha', 'Gene', (45, 53))
654766	27323819	To further confirm the role of PPARgamma, western blot analysis was conducted to detect the expression status of Ki67 and PCNA.	('PCNA', 'Gene', (122, 126))	('PCNA', 'Gene', '5111', (122, 126))	('Ki67', 'Var', (113, 117))
654767	27323819	The expression levels of Ki67 and PCNA were decreased in response to PPARgamma activation in EC109 and TE10 cells (Figure 1B and 1D), but increased in the presence of GW9662 or when knockdown of PPARgamma or RXRalpha (Figure 1F).	('expression levels', 'MPA', (4, 21))	('GW9662', 'Chemical', 'MESH:C457499', (167, 173))	('increased', 'PosReg', (138, 147))	('TE10', 'CellLine', 'CVCL:1760', (103, 107))	('EC109', 'CellLine', 'CVCL:6898', (93, 98))	('RXRalpha', 'Gene', (208, 216))	('RXRalpha', 'Gene', '6256', (208, 216))	('PCNA', 'Gene', (34, 38))	('activation', 'PosReg', (79, 89))	('PPARgamma', 'Gene', (69, 78))	('GW9662', 'Var', (167, 173))	('knockdown', 'Var', (182, 191))	('PCNA', 'Gene', '5111', (34, 38))	('decreased', 'NegReg', (44, 53))
654770	27323819	As shown in Figures 2A, 2B, 2D and 2E, RGZ induced apoptosis, reduced Bcl-2 expression level, and elevated Bax and cleaved caspase-3 expression levels in EC109 and TE10 cells.	('RGZ', 'Var', (39, 42))	('TE10', 'CellLine', 'CVCL:1760', (164, 168))	('Bcl-2', 'Gene', (70, 75))	('Bcl-2', 'Gene', '596', (70, 75))	('Bax', 'Gene', '581', (107, 110))	('elevated', 'PosReg', (98, 106))	('cleaved caspase-3 expression levels', 'MPA', (115, 150))	('apoptosis', 'CPA', (51, 60))	('EC109', 'CellLine', 'CVCL:6898', (154, 159))	('Bax', 'Gene', (107, 110))	('reduced', 'NegReg', (62, 69))
654776	27323819	We found that LPS increased the expression levels of TLR4, MyD88, and TRAF6, but the levels were inhibited by RGZ or enhanced by GW9662.	('MyD88', 'Gene', (59, 64))	('GW9662', 'Var', (129, 135))	('increased', 'PosReg', (18, 27))	('GW9662', 'Chemical', 'MESH:C457499', (129, 135))	('LPS increased', 'Phenotype', 'HP:0003141', (14, 27))	('TRAF6', 'Gene', (70, 75))	('MyD88', 'Gene', '4615', (59, 64))	('TRAF6', 'Gene', '7189', (70, 75))	('LPS', 'Chemical', 'MESH:D008070', (14, 17))	('TLR4', 'Gene', '7099', (53, 57))	('enhanced', 'PosReg', (117, 125))	('inhibited', 'NegReg', (97, 106))	('TLR4', 'Gene', (53, 57))	('expression levels', 'MPA', (32, 49))
654778	27323819	The results showed that PPARgamma knockdown promoted LPS-induced TLR4, MyD88, and TRAF6 expression in EC109 cells (Figure 3).	('MyD88', 'Gene', '4615', (71, 76))	('promoted', 'PosReg', (44, 52))	('TLR4', 'Gene', (65, 69))	('MyD88', 'Gene', (71, 76))	('PPARgamma', 'Gene', (24, 33))	('TRAF6', 'Gene', (82, 87))	('knockdown', 'Var', (34, 43))	('TRAF6', 'Gene', '7189', (82, 87))	('LPS', 'Chemical', 'MESH:D008070', (53, 56))	('expression', 'MPA', (88, 98))	('EC109', 'CellLine', 'CVCL:6898', (102, 107))	('TLR4', 'Gene', '7099', (65, 69))
654781	27323819	To explore whether ERK, JNK and p38 was inhibited by PPARgamma activation, EC109 cells were treated with RGZ (20 muM) or GW9662 (10 muM) for 0, 24, and 48 h. As shown in Figure 4A, GW9662 significantly induced p-ERK, p-JNK, and p-p38 activation, but RGZ inhibited the MAPK pathway in EC109 cells.	('p-ERK', 'Gene', '9451', (210, 215))	('ERK', 'Gene', '5594', (19, 22))	('p-ERK', 'Gene', (210, 215))	('p38', 'Gene', '5594', (230, 233))	('GW9662', 'Chemical', 'MESH:C457499', (181, 187))	('muM', 'Gene', '56925', (113, 116))	('activation', 'PosReg', (234, 244))	('JNK', 'Gene', (24, 27))	('muM', 'Gene', (113, 116))	('JNK', 'Gene', '5599', (24, 27))	('GW9662', 'Chemical', 'MESH:C457499', (121, 127))	('ERK', 'Gene', (19, 22))	('GW9662', 'Var', (181, 187))	('p38', 'Gene', (32, 35))	('ERK', 'Gene', '5594', (212, 215))	('muM', 'Gene', (132, 135))	('inhibited', 'NegReg', (254, 263))	('EC109', 'CellLine', 'CVCL:6898', (284, 289))	('JNK', 'Gene', (219, 222))	('p38', 'Gene', (230, 233))	('JNK', 'Gene', '5599', (219, 222))	('MAPK pathway', 'Pathway', (268, 280))	('muM', 'Gene', '56925', (132, 135))	('EC109', 'CellLine', 'CVCL:6898', (75, 80))	('ERK', 'Gene', (212, 215))	('p38', 'Gene', '5594', (32, 35))
654784	27323819	PPARgamma-knockdown EC109 cells was treated with 10 muM of GW9662 for 0, 24, and 48 h, the levels of p-ERK, p-JNK, and p-p38 was significantly increased compared to the si-control or si-PPARgamma groups (Figure 4B).	('increased', 'PosReg', (143, 152))	('JNK', 'Gene', (110, 113))	('p38', 'Gene', (121, 124))	('JNK', 'Gene', '5599', (110, 113))	('p-ERK', 'Gene', '9451', (101, 106))	('muM', 'Gene', '56925', (52, 55))	('GW9662', 'Var', (59, 65))	('GW9662', 'Chemical', 'MESH:C457499', (59, 65))	('levels', 'MPA', (91, 97))	('p-ERK', 'Gene', (101, 106))	('muM', 'Gene', (52, 55))	('p38', 'Gene', '5594', (121, 124))	('EC109', 'CellLine', 'CVCL:6898', (20, 25))
654790	27323819	Figure 6A and 6C showed that silence of TLR4, MyD88, ERK, JNK, and p38 inhibited proliferation of EC109 cells.	('JNK', 'Gene', '5599', (58, 61))	('p38', 'Gene', (67, 70))	('MyD88', 'Gene', (46, 51))	('inhibited', 'NegReg', (71, 80))	('ERK', 'Gene', '5594', (53, 56))	('TLR4', 'Gene', '7099', (40, 44))	('ERK', 'Gene', (53, 56))	('TLR4', 'Gene', (40, 44))	('MyD88', 'Gene', '4615', (46, 51))	('silence', 'Var', (29, 36))	('EC109', 'CellLine', 'CVCL:6898', (98, 103))	('JNK', 'Gene', (58, 61))	('proliferation', 'CPA', (81, 94))	('p38', 'Gene', '5594', (67, 70))
654791	27323819	Silence of TLR4, MyD88, ERK, JNK, and p38 also suppressed the expression of Ki67 and PCNA (Figure 6B and 6D).	('Ki67', 'Gene', (76, 80))	('suppressed', 'NegReg', (47, 57))	('TLR4', 'Gene', '7099', (11, 15))	('TLR4', 'Gene', (11, 15))	('expression', 'MPA', (62, 72))	('PCNA', 'Gene', (85, 89))	('MyD88', 'Gene', '4615', (17, 22))	('JNK', 'Gene', (29, 32))	('JNK', 'Gene', '5599', (29, 32))	('p38', 'Gene', '5594', (38, 41))	('PCNA', 'Gene', '5111', (85, 89))	('Silence', 'Var', (0, 7))	('ERK', 'Gene', '5594', (24, 27))	('ERK', 'Gene', (24, 27))	('p38', 'Gene', (38, 41))	('MyD88', 'Gene', (17, 22))
654792	27323819	As expected, knockdown of TLR4, MyD88, ERK, JNK, and p38 induced apoptosis of EC109 cells (Figure 6E and 6G).	('p38', 'Gene', '5594', (53, 56))	('MyD88', 'Gene', '4615', (32, 37))	('ERK', 'Gene', '5594', (39, 42))	('JNK', 'Gene', (44, 47))	('TLR4', 'Gene', '7099', (26, 30))	('EC109', 'CellLine', 'CVCL:6898', (78, 83))	('ERK', 'Gene', (39, 42))	('p38', 'Gene', (53, 56))	('MyD88', 'Gene', (32, 37))	('apoptosis', 'CPA', (65, 74))	('JNK', 'Gene', '5599', (44, 47))	('TLR4', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))
654793	27323819	Western blot analysis suggested that silence of TLR4, MyD88, ERK, JNK, and p38 decreased Bcl-2 expression level and increased Bax and cleaved caspase-3 expression levels, consistent with the FCM analysis results (Figure 6F and 6H).	('increased', 'PosReg', (116, 125))	('MyD88', 'Gene', '4615', (54, 59))	('p38', 'Gene', '5594', (75, 78))	('Bax', 'Gene', '581', (126, 129))	('JNK', 'Gene', '5599', (66, 69))	('cleaved caspase-3 expression levels', 'MPA', (134, 169))	('decreased', 'NegReg', (79, 88))	('p38', 'Gene', (75, 78))	('TLR4', 'Gene', (48, 52))	('ERK', 'Gene', '5594', (61, 64))	('Bax', 'Gene', (126, 129))	('MyD88', 'Gene', (54, 59))	('JNK', 'Gene', (66, 69))	('Bcl-2', 'Gene', (89, 94))	('Bcl-2', 'Gene', '596', (89, 94))	('silence', 'Var', (37, 44))	('TLR4', 'Gene', '7099', (48, 52))	('ERK', 'Gene', (61, 64))
654794	27323819	Taken together, these data suggest that activation of PPARgamma inhibits proliferation and induces apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('TLR4', 'Gene', (150, 154))	('activation', 'Var', (40, 50))	('proliferation', 'CPA', (73, 86))	('PPARgamma', 'Protein', (54, 63))	('apoptosis', 'CPA', (99, 108))	('TLR4', 'Gene', '7099', (150, 154))	('esophageal cancer', 'Disease', (112, 129))	('inhibits', 'NegReg', (64, 72))	('induces', 'Reg', (91, 98))	('inhibiting', 'NegReg', (139, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
654801	27323819	Moreover, RGZ induced apoptosis of esophageal cancer cells.	('apoptosis', 'CPA', (22, 31))	('esophageal cancer', 'Disease', (35, 52))	('RGZ', 'Var', (10, 13))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
654804	27323819	TLR4 is associated with lymph node metastasis, and stimulation of TLR4 with LPS has been displayed to accelerate migration and adhesion of esophageal squamous cell carcinoma cells.	('TLR4', 'Gene', '7099', (66, 70))	('accelerate', 'PosReg', (102, 112))	('TLR4', 'Gene', (0, 4))	('stimulation', 'Var', (51, 62))	('TLR4', 'Gene', (66, 70))	('LPS', 'Chemical', 'MESH:D008070', (76, 79))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (139, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('migration', 'CPA', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('adhesion', 'CPA', (127, 135))	('TLR4', 'Gene', '7099', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', (139, 173))
654811	27323819	Our data in this study showed that inactivation of MAPK inhibited viability and induced apoptosis of esophageal cancer cells by PPARgamma agonist or siRNA targeting ERK, JNK, and p38, which are consistent with these results.	('apoptosis', 'CPA', (88, 97))	('induced', 'Reg', (80, 87))	('JNK', 'Gene', (170, 173))	('MAPK', 'Gene', (51, 55))	('inactivation', 'Var', (35, 47))	('ERK', 'Gene', '5594', (165, 168))	('viability', 'CPA', (66, 75))	('esophageal cancer', 'Disease', (101, 118))	('PPARgamma', 'Protein', (128, 137))	('p38', 'Gene', '5594', (179, 182))	('JNK', 'Gene', '5599', (170, 173))	('inhibited', 'NegReg', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('ERK', 'Gene', (165, 168))	('p38', 'Gene', (179, 182))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))
654817	27323819	In general, our data suggested that activation of PPARgamma suppressed proliferation and induced apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway.	('TLR4', 'Gene', '7099', (148, 152))	('suppressed', 'NegReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('inhibiting', 'NegReg', (137, 147))	('TLR4', 'Gene', (148, 152))	('PPARgamma', 'Protein', (50, 59))	('esophageal cancer', 'Disease', (110, 127))	('proliferation', 'CPA', (71, 84))	('activation', 'Var', (36, 46))	('apoptosis', 'CPA', (97, 106))
654820	27323819	This research highlighted that ERK, JNK, and p38 MAPK activation was regulated by TLR4 pathway, and that inhibition of TLR4, MyD88, ERK, JNK, and p38 attenuated proliferation and induced apoptosis esophageal cancer cells in vitro.	('p38', 'Gene', (45, 48))	('ERK', 'Gene', (132, 135))	('MyD88', 'Gene', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('apoptosis esophageal cancer', 'Disease', (187, 214))	('TLR4', 'Gene', '7099', (119, 123))	('TLR4', 'Gene', (119, 123))	('inhibition', 'Var', (105, 115))	('p38', 'Gene', (146, 149))	('p38', 'Gene', '5594', (45, 48))	('ERK', 'Gene', '5594', (31, 34))	('attenuated', 'NegReg', (150, 160))	('JNK', 'Gene', (36, 39))	('JNK', 'Gene', '5599', (36, 39))	('MyD88', 'Gene', '4615', (125, 130))	('p38', 'Gene', '5594', (146, 149))	('proliferation', 'CPA', (161, 174))	('ERK', 'Gene', '5594', (132, 135))	('ERK', 'Gene', (31, 34))	('induced', 'Reg', (179, 186))	('TLR4', 'Gene', '7099', (82, 86))	('JNK', 'Gene', (137, 140))	('apoptosis esophageal cancer', 'Disease', 'MESH:D004938', (187, 214))	('TLR4', 'Gene', (82, 86))	('JNK', 'Gene', '5599', (137, 140))
654823	27323819	For RNAi experiments, EC109 and TE10 cells (1 x 105 per well) were seeded in 6-well plates and incubated for 24 h. Cells were transfected with 100 nM specific siRNAs targeting RXRalpha, PPARgamma, TLR4, MyD88, ERK, JNK, and p38 or control siRNA (si-control) with lipofectamine 2000 Reagent (Invitrogen) following the manufacturer's instructions.	('p38', 'Gene', (224, 227))	('MyD88', 'Gene', (203, 208))	('RXRalpha', 'Gene', (176, 184))	('JNK', 'Gene', (215, 218))	('lipofectamine 2000', 'Chemical', 'MESH:C086724', (263, 281))	('MyD88', 'Gene', '4615', (203, 208))	('RXRalpha', 'Gene', '6256', (176, 184))	('TLR4', 'Gene', '7099', (197, 201))	('TE10', 'CellLine', 'CVCL:1760', (32, 36))	('EC109', 'CellLine', 'CVCL:6898', (22, 27))	('JNK', 'Gene', '5599', (215, 218))	('ERK', 'Gene', '5594', (210, 213))	('p38', 'Gene', '5594', (224, 227))	('PPARgamma', 'Var', (186, 195))	('ERK', 'Gene', (210, 213))	('TLR4', 'Gene', (197, 201))
654824	27323819	Cells treated with different concentrations of RGZ or/and 10 muM of GW9662 were collected to detect the expression levels of Ki67, PCNA, Bcl-2, Bax, and phospho-caspase-3 proteins using western blot analysis.	('PCNA', 'Gene', '5111', (131, 135))	('muM', 'Gene', (61, 64))	('GW9662', 'Chemical', 'MESH:C457499', (68, 74))	('Bax', 'Gene', '581', (144, 147))	('Ki67', 'Var', (125, 129))	('expression', 'MPA', (104, 114))	('Bax', 'Gene', (144, 147))	('Bcl-2', 'Gene', (137, 142))	('Bcl-2', 'Gene', '596', (137, 142))	('PCNA', 'Gene', (131, 135))	('muM', 'Gene', '56925', (61, 64))
654865	24147754	Citrated-blood was left to stabilize for 30 minutes after collection before TEG measurements, a fixed time point after sampling was chosen to minimize interassay variation.20 TEG was performed using a computerized thromboelastograph1 according to a previously described method using human recombinant tissue factor2 as the activator.20 Thromboelastograms were obtained for 90 minutes at 37 C. Recorded TEG variables included time to initiation of clot formation (R), time for the tracing to achieve a predetermined clot strength (K), speed of clot propagation (alpha), greatest clot strength (MA), calculated G value and degree of fibrinolysis at 30 and 60 minutes after MA was reached (Ly30 and Ly60, respectively; Fig 1).	('Ly60', 'Var', (696, 700))	('tissue factor', 'Gene', (301, 314))	('G value', 'MPA', (609, 616))	('factor2', 'Gene', (308, 315))	('tissue factor', 'Gene', '490153', (301, 314))	('factor2', 'Gene', '8458', (308, 315))	('human', 'Species', '9606', (283, 288))	('greatest', 'MPA', (569, 577))
654883	24147754	There was no significant difference between groups for R, LY30 and LY60.	('LY30', 'Chemical', '-', (58, 62))	('LY30', 'Var', (58, 62))	('LY60', 'Chemical', '-', (67, 71))	('LY60', 'Var', (67, 71))
654885	24147754	The median CRP and fibrinogen concentrations were significantly increased in the neoplastic group compared to the non-neoplastic group (P < .01) as well as between the neoplastic and control group (P < .01; Table 1).	('increased', 'PosReg', (64, 73))	('fibrinogen', 'Gene', '2244', (19, 29))	('fibrinogen', 'Gene', (19, 29))	('neoplastic', 'Var', (81, 91))
654905	24147754	The concentrations for CRP and fibrinogen were significantly increased in the neoplastic group, and both showed strong positive correlation with MA.	('fibrinogen', 'Gene', '2244', (31, 41))	('concentrations', 'MPA', (4, 18))	('fibrinogen', 'Gene', (31, 41))	('neoplastic', 'Var', (78, 88))	('increased', 'PosReg', (61, 70))	('CRP', 'Protein', (23, 26))
655023	26494763	Furthermore, breastfeeding has been found to decrease the risk for esophageal and gastric junction adenocarcinoma.	('breastfeeding', 'Var', (13, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal', 'Disease', 'MESH:D004941', (67, 77))	('decrease', 'NegReg', (45, 53))	('gastric junction adenocarcinoma', 'Disease', 'MESH:D013274', (82, 113))	('esophageal', 'Disease', (67, 77))	('gastric junction adenocarcinoma', 'Disease', (82, 113))
655024	26494763	In males, levels of free testosterone and dihydrotestosterone have been positively associated with an increased risk of Barrett's esophagus.	('dihydrotestosterone', 'Chemical', 'MESH:D013196', (42, 61))	('dihydrotestosterone', 'Var', (42, 61))	('testosterone', 'Chemical', 'MESH:D013739', (49, 61))	('testosterone', 'Chemical', 'MESH:D013739', (25, 37))	("Barrett's esophagus", 'Disease', (120, 139))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (120, 139))	('associated', 'Reg', (83, 93))
655094	26366380	However, there was a trend that hospital length of stay and hospital expense were reduced in the MIE group than OE group.	('MIE', 'Chemical', '-', (97, 100))	('MIE', 'Var', (97, 100))	('hospital length of stay', 'CPA', (32, 55))	('hospital expense', 'CPA', (60, 76))	('reduced', 'NegReg', (82, 89))	('OE', 'Chemical', '-', (112, 114))
655114	24892549	Knock-down of YAP1 mimicked the phenotype induced by miR-375 over-expression indicating that miR-375 most likely exerts its pro-apoptotic role through YAP1 and its anti-apoptotic down-stream targets BIRC5 and BCL2L1.	('YAP1', 'Gene', (151, 155))	('YAP1', 'Gene', '10413', (151, 155))	('YAP1', 'Gene', (14, 18))	('YAP1', 'Gene', '10413', (14, 18))	('pro-apoptotic', 'MPA', (124, 137))	('BCL2L1', 'Gene', (209, 215))	('miR-375', 'Gene', (53, 60))	('BIRC5', 'Gene', '332', (199, 204))	('BIRC5', 'Gene', (199, 204))	('BCL2L1', 'Gene', '598', (209, 215))	('over-expression', 'PosReg', (61, 76))	('miR-375', 'Var', (93, 100))
655118	24892549	Chromosomal instability leading to allelic imbalance accounts for 70-85% of the tumors whereas 20-15% have DNA mismatch repair defects leading to microsatellite instability.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('microsatellite instability', 'MPA', (146, 172))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('imbalance', 'Phenotype', 'HP:0002172', (43, 52))	('Chromosomal', 'Var', (0, 11))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('allelic imbalance', 'MPA', (35, 52))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))
655122	24892549	Finally, functional screening has identified clinically relevant miRNAs in pancreatic and testicular germ cell tumors.	('miRNAs', 'Var', (65, 71))	('pancreatic', 'Disease', 'MESH:D010195', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('pancreatic', 'Disease', (75, 85))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('germ cell tumors', 'Phenotype', 'HP:0100728', (101, 117))	('clinical', 'Species', '191496', (45, 53))
655129	24892549	Finally, lymphoid-specific helicase (HELLS) and nucleolar and coiled-body phosphor protein 1 (NOLC1) were identified as down-stream targets of miR-375 potentially playing a role in cell cycle regulating pathways.	('NOLC1', 'Gene', (94, 99))	('cell', 'CPA', (181, 185))	('NOLC1', 'Gene', '9221', (94, 99))	('miR-375', 'Var', (143, 150))	('lymphoid-specific helicase', 'Gene', (9, 35))	('down-stream', 'NegReg', (120, 131))	('HELLS', 'Gene', (37, 42))	('lymphoid-specific helicase', 'Gene', '3070', (9, 35))	('HELLS', 'Gene', '3070', (37, 42))
655151	24892549	The IDs of the CpG sites in close proximity to MIR-375 were as follows CpG1; cg00215432, CpG2; cg00218620, CpG3; cg00705280, CpG4; cg02257674, CpG5; cg04348419, CpG6; cg06214770, CpG7; cg14358282, CpG8; cg21615583, CpG9; cg22306928, CpG10; cg01822124 and CpG11; cg26394220.	('cg00215432', 'Var', (77, 87))	('cg00218620', 'Var', (95, 105))	('MIR-375', 'Gene', (47, 54))	('MIR-375', 'Gene', '494324', (47, 54))	('cg01822124', 'Var', (240, 250))	('cg06214770', 'Var', (167, 177))	('cg14358282', 'Var', (185, 195))	('CpG10; cg01822124', 'Var', (233, 250))	('cg22306928', 'Var', (221, 231))	('cg21615583', 'Var', (203, 213))	('cg00705280', 'Var', (113, 123))	('CpG3', 'Var', (107, 111))	('cg26394220', 'Var', (262, 272))	('CpG11', 'Var', (255, 260))
655152	24892549	The mRNA profiling of miR-375 transfected HCT116 cells and the clinical samples are described in the Supplementary Material (Methods S1).	('clinical samples', 'Species', '191496', (63, 79))	('transfected', 'Var', (30, 41))	('miR-375', 'Gene', (22, 29))	('HCT116', 'CellLine', 'CVCL:0291', (42, 48))
655158	24892549	Selected fragments of the 3'UTRs of HELLS (NM_018063) and NOLC1 (NM_004741) containing putative miR-375 binding sites were amplified from normal human genomic DNA and cloned downstream of the Renilla Luciferase gene in the siCHECK-2 vector (Promega, Fitchburg, WI, USA).	('NM_018063', 'Var', (43, 52))	('NM_004741', 'Var', (65, 74))	('human', 'Species', '9606', (145, 150))	('NOLC1', 'Gene', (58, 63))	('HELLS', 'Gene', (36, 41))	('HELLS', 'Gene', '3070', (36, 41))	('NOLC1', 'Gene', '9221', (58, 63))
655167	24892549	The tRFP fluorescence marker was used as a surrogate to sort for cell populations expressing the highest level miR-375 after induction of dox.	('tRFP', 'Gene', (4, 8))	('miR-375', 'Var', (111, 118))	('dox', 'Chemical', 'MESH:D004318', (138, 141))	('tRFP', 'Gene', '9477', (4, 8))
655170	24892549	The HCT116_miR-375H cells were phenotypically characterized using xCELLigence (Roche Applied Science), Caspase 3/7 assays and YAP1 Western blotting (details in Supplementary Material (Methods S1)).	('YAP1', 'Gene', (126, 130))	('YAP1', 'Gene', '10413', (126, 130))	('HCT116_miR-375H', 'Var', (4, 19))	('HCT116', 'CellLine', 'CVCL:0291', (4, 10))	('Caspase 3', 'Gene', (103, 112))	('Caspase 3', 'Gene', '836', (103, 112))
655187	24892549	To validate the identified phenotypes, the miRNAs that were down-regulated in clinical samples and Top-40 ranked in the phenotype screen (miR-150, miR-375, miR23b, miR-138, miR-139-5p and miR-9) were subjected to detailed functional analysis using HCT116, HT29, LS174T TR4, DLD1 TR7 and SW480 colon cancer cell lines.	('miR23b', 'Var', (156, 162))	('miR-138', 'Var', (164, 171))	('down-regulated', 'NegReg', (60, 74))	('colon cancer', 'Disease', (293, 305))	('TR4', 'Gene', (269, 272))	('TR4', 'Gene', '7182', (269, 272))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('HT29', 'CellLine', 'CVCL:0320', (256, 260))	('clinical samples', 'Species', '191496', (78, 94))	('miR-375', 'Var', (147, 154))	('colon cancer', 'Phenotype', 'HP:0003003', (293, 305))	('HCT116', 'CellLine', 'CVCL:0291', (248, 254))	('miR-150', 'Gene', (138, 145))	('colon cancer', 'Disease', 'MESH:D015179', (293, 305))	('miR-150', 'Gene', '406942', (138, 145))	('SW480', 'CellLine', 'CVCL:0546', (287, 292))
655188	24892549	The ectopic expression of miR-375, miR-9 and miR-138 significantly reduced the viability of more than one cell line (MTT reduction >20% and p<=0.05) (Figure 2A (HCT116) and Figure S2), possible due to a general anti-proliferative or pro-apoptotic role of these miRNAs.	('miR-9', 'Gene', (35, 40))	('pro-apoptotic', 'CPA', (233, 246))	('MTT', 'Chemical', '-', (117, 120))	('miR-375', 'Var', (26, 33))	('miR-138', 'Gene', (45, 52))	('HCT116', 'CellLine', 'CVCL:0291', (161, 167))	('reduced', 'NegReg', (67, 74))	('viability of more than one cell line', 'CPA', (79, 115))	('reduction', 'NegReg', (121, 130))
655191	24892549	MiR-375 increased Caspase 3/7 activity and demonstrated coincident increase in cellular death (LDH release) in both HCT116 and DLD1 TR7 (Figures 2B and C, and Figure S3).	('HCT116', 'CellLine', 'CVCL:0291', (116, 122))	('MiR-375', 'Gene', (0, 7))	('Caspase 3', 'Gene', '836', (18, 27))	('MiR-375', 'Gene', '494324', (0, 7))	('cellular death', 'CPA', (79, 93))	('increase', 'PosReg', (67, 75))	('increased', 'PosReg', (8, 17))	('Caspase 3', 'Gene', (18, 27))	('DLD1', 'Var', (127, 131))	('activity', 'MPA', (30, 38))
655192	24892549	Furthermore, the apoptotic death induced by miR-375 could be inhibited with z-DEVD-fmk (Caspase 3/7 inhibitor) (Figure 2D) demonstrating that the induced apoptosis is dependent on Caspase 3/7 activity.	('Caspase 3', 'Gene', (180, 189))	('apoptotic death', 'CPA', (17, 32))	('inhibited', 'NegReg', (61, 70))	('Caspase 3', 'Gene', (88, 97))	('miR-375', 'Var', (44, 51))	('Caspase 3', 'Gene', '836', (180, 189))	('Caspase 3', 'Gene', '836', (88, 97))	('z-DEVD-fmk', 'Chemical', 'MESH:C110772', (76, 86))
655194	24892549	Finally, miR-375, miR-138 and miR-9 were selected for further analysis due to their down-regulation in clinical samples and their ability to induced phenotypic changes in vitro.	('miR-375', 'Var', (9, 16))	('clinical samples', 'Species', '191496', (103, 119))	('miR-9', 'Var', (30, 35))	('down-regulation', 'NegReg', (84, 99))	('miR-138', 'Var', (18, 25))
655195	24892549	To elucidate the cellular origin of miR-375, miR-138 and miR-9, we measured their expression in laser captured microdissected colorectal adenocarcinomas and adjacent normal colon mucosa (Figure 2E and Figure S4).	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (126, 152))	('expression', 'MPA', (82, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('colon mucosa', 'Disease', (173, 185))	('miR-138', 'Var', (45, 52))	('miR-9', 'Gene', (57, 62))	('miR-375', 'Gene', (36, 43))	('colorectal adenocarcinomas', 'Disease', (126, 152))	('colon mucosa', 'Disease', 'MESH:D015179', (173, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
655207	24892549	Previous studies have shown that miR-375 is indeed down-regulated due to hypermethylation in esophageal and breast cancer.	('hypermethylation', 'Var', (73, 89))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('down-regulated', 'NegReg', (51, 65))	('miR-375', 'Gene', (33, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('esophageal and breast cancer', 'Disease', 'MESH:D004938', (93, 121))
655208	24892549	Hypermethylation of MIR-375 has also been demonstrated in melanoma and in the CRC cell line HCT116 cell.	('demonstrated', 'Reg', (42, 54))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('HCT116', 'CellLine', 'CVCL:0291', (92, 98))	('Hypermethylation', 'Var', (0, 16))	('MIR-375', 'Gene', '494324', (20, 27))	('MIR-375', 'Gene', (20, 27))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
655215	24892549	These results indicate that epigenetic silencing of MIR-375 is not the general mechanism of miR-375 down-regulation in CRC.	('epigenetic silencing', 'Var', (28, 48))	('CRC', 'Disease', (119, 122))	('MIR-375', 'Gene', '494324', (52, 59))	('miR-375', 'Gene', (92, 99))	('down-regulation', 'NegReg', (100, 115))	('MIR-375', 'Gene', (52, 59))
655226	24892549	Interestingly, six of these known miR-375 targets were also significantly down-regulated in HCT116 upon miR-375 ectopic expression.	('HCT116', 'CellLine', 'CVCL:0291', (92, 98))	('miR-375', 'Gene', (104, 111))	('down-regulated', 'NegReg', (74, 88))	('ectopic expression', 'Var', (112, 130))	('HCT116', 'Gene', (92, 98))
655229	24892549	Most strikingly, YAP1 was found to be negatively correlated to miR-375 in CRC tissue samples indicating that targeting of YAP1 by miR-375 is also relevant for the tumorigenesis of colorectal cancer (Table 3 and Table S7 in File S1).	('YAP1', 'Gene', (17, 21))	('YAP1', 'Gene', '10413', (17, 21))	('colorectal cancer', 'Disease', 'MESH:D015179', (180, 197))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('targeting', 'Var', (109, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (180, 197))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('miR-375', 'Gene', (130, 137))	('tumor', 'Disease', (163, 168))	('YAP1', 'Gene', '10413', (122, 126))	('colorectal cancer', 'Disease', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('YAP1', 'Gene', (122, 126))
655235	24892549	Initial analysis confirmed the down-regulation of HELLS, NOLC1 and YAP1 at the mRNA and protein level in response to ectopic miR-375 expression in HCT116 cells (Figures 4D-F).	('miR-375', 'Var', (125, 132))	('HELLS', 'Gene', (50, 55))	('NOLC1', 'Gene', (57, 62))	('HCT116', 'CellLine', 'CVCL:0291', (147, 153))	('NOLC1', 'Gene', '9221', (57, 62))	('YAP1', 'Gene', (67, 71))	('down-regulation', 'NegReg', (31, 46))	('ectopic miR-375', 'Var', (117, 132))	('YAP1', 'Gene', '10413', (67, 71))	('HELLS', 'Gene', '3070', (50, 55))
655239	24892549	These analyses clearly demonstrate an Ago2 dependent immunoprecipitation of YAP1 and showed that the amount of immunoprecipitated YAP1 is enriched in the miR-375 transfected cells compared to Scr transfected cells (Figures 4G (input) and H (IP)).	('Ago2', 'Gene', (38, 42))	('immunoprecipitation', 'MPA', (53, 72))	('YAP1', 'Gene', (76, 80))	('YAP1', 'Gene', '10413', (76, 80))	('miR-375 transfected', 'Var', (154, 173))	('YAP1', 'Gene', '10413', (130, 134))	('YAP1', 'Gene', (130, 134))	('Ago2', 'Gene', '27161', (38, 42))
655241	24892549	We next sought to elucidate whether HELLS and NOLC1 were directly or indirectly targeted by miR-375.	('NOLC1', 'Gene', '9221', (46, 51))	('miR-375', 'Var', (92, 99))	('HELLS', 'Gene', (36, 41))	('HELLS', 'Gene', '3070', (36, 41))	('NOLC1', 'Gene', (46, 51))
655245	24892549	Furthermore, like miR-375 ectopic expression, silencing of YAP1 resulted in down-regulation of BIRC5 (~30%) and BCL2L1 (~40-50%) further emphasizing the role of miR-375 and YAP1 in the regulation of these molecules in HCT116 cells (Figure 5A).	('YAP1', 'Gene', (59, 63))	('BCL2L1', 'Gene', (112, 118))	('YAP1', 'Gene', '10413', (59, 63))	('silencing', 'Var', (46, 55))	('YAP1', 'Gene', '10413', (173, 177))	('BCL2L1', 'Gene', '598', (112, 118))	('BIRC5', 'Gene', '332', (95, 100))	('BIRC5', 'Gene', (95, 100))	('YAP1', 'Gene', (173, 177))	('down-regulation', 'NegReg', (76, 91))	('HCT116', 'CellLine', 'CVCL:0291', (218, 224))
655246	24892549	Next we analyzed whether the silencing of YAP1could reduce the viability of HCT116 cells through induction of apoptosis thus mimicking the phenotype induced by miR-375.	('YAP1', 'Gene', (42, 46))	('viability', 'CPA', (63, 72))	('silencing', 'Var', (29, 38))	('YAP1', 'Gene', '10413', (42, 46))	('reduce', 'NegReg', (52, 58))	('HCT116', 'CellLine', 'CVCL:0291', (76, 82))
655247	24892549	Indeed, elimination of YAP1 significantly reduced the viability and induced Caspase 3/7 dependent apoptotic death in HCT116 cells (Figures 5C-E).	('reduced', 'NegReg', (42, 49))	('Caspase 3', 'Gene', '836', (76, 85))	('apoptotic death', 'CPA', (98, 113))	('induced', 'Reg', (68, 75))	('HCT116', 'CellLine', 'CVCL:0291', (117, 123))	('elimination', 'Var', (8, 19))	('viability', 'CPA', (54, 63))	('YAP1', 'Gene', '10413', (23, 27))	('YAP1', 'Gene', (23, 27))	('Caspase 3', 'Gene', (76, 85))
655248	24892549	The phenotype induced by the miR-375 mimic was more pronounced than that induced by the YAP1 siRNAs, probably reflecting that YAP1 only represents one out of a number of critical nodes in the pleiotropic miR-375 network.	('YAP1', 'Gene', (126, 130))	('mimic', 'Var', (37, 42))	('YAP1', 'Gene', '10413', (126, 130))	('miR-375', 'Gene', (29, 36))	('YAP1', 'Gene', (88, 92))	('YAP1', 'Gene', '10413', (88, 92))
655251	24892549	Next we analyzed whether knock-down of HELLS and NOLC1 could reduce the viability of HCT116 and induce a pro-apoptotic phenotype, thus mimicking the phenotype induced by miR-375.	('viability', 'MPA', (72, 81))	('NOLC1', 'Gene', '9221', (49, 54))	('reduce', 'NegReg', (61, 67))	('HCT116', 'CellLine', 'CVCL:0291', (85, 91))	('induce', 'Reg', (96, 102))	('knock-down', 'Var', (25, 35))	('HELLS', 'Gene', (39, 44))	('NOLC1', 'Gene', (49, 54))	('HCT116', 'Gene', (85, 91))	('pro-apoptotic phenotype', 'MPA', (105, 128))	('HELLS', 'Gene', '3070', (39, 44))
655252	24892549	Indeed, individual elimination of HELLS and NOLCL1 reduced the viability and induced cellular death in a manner similar to miR-375 ectopic expression (Figures 6C and D) but did not induce apoptotic death (Figure 6E) and hence other miR-375 targets such as YAP1 are responsible for the apoptotic phenotype.	('ectopic expression', 'Var', (131, 149))	('YAP1', 'Gene', '10413', (256, 260))	('HELLS', 'Gene', (34, 39))	('reduced', 'NegReg', (51, 58))	('induced', 'Reg', (77, 84))	('viability', 'CPA', (63, 72))	('HELLS', 'Gene', '3070', (34, 39))	('cellular death', 'CPA', (85, 99))	('miR-375', 'Gene', (123, 130))	('YAP1', 'Gene', (256, 260))
655258	24892549	While no miR-375 expression was observed in the HCT116_ScrH cells +/- dox, a minor level of miR-375 expression was observed in the untreated HCT116_miR-375H cells (Figure 7A), which could indicate a minor leakage from the miR-375-tRFP expression cassette in the absence of dox.	('tRFP', 'Gene', (230, 234))	('dox', 'Chemical', 'MESH:D004318', (70, 73))	('miR-375', 'Var', (92, 99))	('HCT116', 'CellLine', 'CVCL:0291', (48, 54))	('HCT116', 'CellLine', 'CVCL:0291', (141, 147))	('dox', 'Chemical', 'MESH:D004318', (273, 276))	('tRFP', 'Gene', '9477', (230, 234))
655259	24892549	However, the phenotypic characterization of HCT116_miR-375H cells clearly showed that dox treatment significantly reduced the cell proliferation and induced Caspase 3/7 dependent apoptosis in the HCT116_miR-375H cells when compared to HCT116-ScrH cells or untreated HCT116-miR-375H cells (Figures 7B-D).	('HCT116', 'CellLine', 'CVCL:0291', (44, 50))	('HCT116', 'CellLine', 'CVCL:0291', (266, 272))	('HCT116_miR-375H', 'Var', (196, 211))	('cell proliferation', 'CPA', (126, 144))	('reduced', 'NegReg', (114, 121))	('Caspase 3', 'Gene', (157, 166))	('apoptosis', 'CPA', (179, 188))	('HCT116', 'CellLine', 'CVCL:0291', (196, 202))	('Caspase 3', 'Gene', '836', (157, 166))	('HCT116', 'CellLine', 'CVCL:0291', (235, 241))	('dox', 'Chemical', 'MESH:D004318', (86, 89))
655264	24892549	All together, the above results strongly indicate that miR-375 has the ability to suppress tumor growth through the induction of apoptosis.	('miR-375', 'Var', (55, 62))	('apoptosis', 'CPA', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('suppress', 'NegReg', (82, 90))	('tumor', 'Disease', (91, 96))
655276	24892549	Originally, MIR-375 hypermethylation was reported in cell lines originating from breast and gastric cancer.	('reported', 'Reg', (41, 49))	('hypermethylation', 'Var', (20, 36))	('MIR-375', 'Gene', '494324', (12, 19))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('breast', 'Disease', (81, 87))	('MIR-375', 'Gene', (12, 19))
655280	24892549	Thorough analysis of MIR-375 methylation and expression in CRC cell lines and tissue samples only identified MIR-375 promoter methylation and concurrent miR-375 down-regulation in three CRC cell lines including HCT116.	('HCT116', 'CellLine', 'CVCL:0291', (211, 217))	('MIR-375', 'Gene', (109, 116))	('MIR-375', 'Gene', '494324', (109, 116))	('miR-375', 'Gene', (153, 160))	('methylation', 'Var', (126, 137))	('MIR-375', 'Gene', (21, 28))	('MIR-375', 'Gene', '494324', (21, 28))	('down-regulation', 'NegReg', (161, 176))
655284	24892549	In the present study, miR-375 was shown to reduce viability and to induce Caspase 3/7 dependent apoptotic death in CRC cell lines.	('reduce', 'NegReg', (43, 49))	('Caspase 3', 'Gene', (74, 83))	('apoptotic death', 'CPA', (96, 111))	('miR-375', 'Var', (22, 29))	('Caspase 3', 'Gene', '836', (74, 83))	('viability', 'CPA', (50, 59))	('induce', 'PosReg', (67, 73))
655293	24892549	Additionally, knockdown of YAP1 using siRNAs mimicked the apoptotic phenotype induced by miR-375.	('knockdown', 'Var', (14, 23))	('YAP1', 'Gene', '10413', (27, 31))	('YAP1', 'Gene', (27, 31))	('miR-375', 'Var', (89, 96))
655295	24892549	These analyses showed that YAP1 is enriched in immunoprecipitates from miR-375 transfected cells compared to Scr transfected cells in an Ago2 dependent manner, thus providing strong evidence that YAP1 is indeed a direct miR-375 target in CRC cells.	('Ago2', 'Gene', (137, 141))	('YAP1', 'Gene', (196, 200))	('YAP1', 'Gene', '10413', (196, 200))	('YAP1', 'Gene', (27, 31))	('YAP1', 'Gene', '10413', (27, 31))	('transfected', 'Var', (79, 90))	('Ago2', 'Gene', '27161', (137, 141))	('miR-375', 'Gene', (71, 78))
655301	24892549	miR-375 has also been shown to inhibit G1/S transition in HCT116.	('inhibit', 'NegReg', (31, 38))	('G1/S transition', 'MPA', (39, 54))	('miR-375', 'Var', (0, 7))	('HCT116', 'CellLine', 'CVCL:0291', (58, 64))
655305	24892549	In conclusion, combing high-throughput functional screening with miRNA profiling of CRC tissue samples, we have identified clinically relevant miRNAs in colorectal cancer including miR-375.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('miRNAs', 'Var', (143, 149))	('miR-375', 'Var', (181, 188))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('clinical', 'Species', '191496', (123, 131))	('colorectal cancer', 'Disease', (153, 170))
655325	23845841	Chemotherapy was often administered in combinations of 5-flurouracil and taxane or with platinum-based compounds.	('5-flurouracil', 'Chemical', '-', (55, 68))	('5-flurouracil', 'Var', (55, 68))	('taxane', 'Chemical', 'MESH:C080625', (73, 79))	('platinum', 'Chemical', 'MESH:D010984', (88, 96))	('combinations', 'Interaction', (39, 51))
655347	23845841	When comparing among the 3 different types of radiation modalities, there was a significant increase in postoperative pulmonary complications for 3D-CRT compared to IMRT (odds ratio [OR], 4.097; 95% confidence interval [CI], 1.366-12.286) and for 3D-CRT versus PBT (OR, 9.127; 95% CI, 1.834-45.424) but not for IMRT compared to PBT (OR, 2.228; 95% CI, 0.863-5.755) after adjusting for pre-RT DLCO level (Table 2).	('pulmonary complications', 'Phenotype', 'HP:0006532', (118, 141))	('increase', 'PosReg', (92, 100))	('3D-CRT', 'Var', (146, 152))	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (104, 141))	('postoperative pulmonary complications', 'Disease', (104, 141))
655349	23845841	After adjusting for tumor location, surgery type, radiation modality, and year of surgery, postoperative GI complications were marginally increased in patients treated with 3D-CRT versus those treated with IMRT (OR, 2.255; 95% CI, 0.951-5.349) and marginally increased in patients treated with 3D-CRT versus PBT (OR, 2.311; 95% CI, 0.690, 7.740), but not for IMRT versus PBT (OR, 1.025; 95% CI, 0.467-2.249) (Table 2).	('increased', 'PosReg', (138, 147))	('patients', 'Species', '9606', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('postoperative GI complications', 'Disease', (91, 121))	('3D-CRT', 'Var', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('patients', 'Species', '9606', (272, 280))	('postoperative GI complications', 'Disease', 'MESH:D011183', (91, 121))	('tumor', 'Disease', (20, 25))
655375	23845841	While perioperative cardiac toxicities were not different among the 3 radiation modalities, perhaps late complications (such as myocardial infarction) could be affected by heart dose differences between 3D-CRT versus IMRT.	('3D-CRT', 'Var', (203, 209))	('myocardial infarction', 'Disease', (128, 149))	('cardiac toxicities', 'Disease', 'MESH:D066126', (20, 38))	('affected by', 'Reg', (160, 171))	('myocardial infarction', 'Disease', 'MESH:D009203', (128, 149))	('cardiac toxicities', 'Disease', (20, 38))	('myocardial infarction', 'Phenotype', 'HP:0001658', (128, 149))
655377	23845841	For example, Lin et al compared IMRT versus 3D-CRT in 676 esophageal cancer patients treated with CRTand found that overall survival (OS), locoregional control, and noncancer-related mortality rates were significantly better in patients treated with IMRT than with 3D-CRT.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('patients', 'Species', '9606', (76, 84))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('IMRT', 'Var', (250, 254))	('patients', 'Species', '9606', (228, 236))	('locoregional control', 'CPA', (139, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('overall survival', 'CPA', (116, 132))	('cancer', 'Disease', (69, 75))	('better', 'PosReg', (218, 224))
655393	33174687	In this review, we have summarized the dual role of aberrant miR-423 expression and its mechanisms in tumorigenesis, and the therapeutic potential of miR-423 in human tumors.	('human', 'Species', '9606', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('miR-423', 'Gene', (61, 68))	('miR-423', 'Gene', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('aberrant', 'Var', (52, 60))	('miR-423', 'Gene', '494335', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('miR-423', 'Gene', '494335', (61, 68))	('tumor', 'Disease', (102, 107))	('tumors', 'Disease', (167, 173))	('tumor', 'Disease', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
655399	33174687	2 ,  3   Dysregulation of microRNAs (miRNAs) in human cancers has been significantly involved in various signaling pathways and the pathogenesis.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('signaling pathways', 'Pathway', (105, 123))	('microRNAs', 'Protein', (26, 35))	('cancers', 'Disease', (54, 61))	('human', 'Species', '9606', (48, 53))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('involved', 'Reg', (85, 93))	('Dysregulation', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
655401	33174687	15  There is much evidence that dysregulated expression of various miRNAs in cells can ultimately enhance chemoresistance by affecting cell survival, apoptosis, and autophagy, thereby pushing normal cells toward cancerous cells.	('pushing', 'PosReg', (184, 191))	('enhance', 'PosReg', (98, 105))	('apoptosis', 'CPA', (150, 159))	('dysregulated', 'Var', (32, 44))	('cell survival', 'CPA', (135, 148))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('affecting', 'Reg', (125, 134))	('chemoresistance', 'CPA', (106, 121))	('autophagy', 'CPA', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
655402	33174687	16  In some cases, aberrant expression of miRNAs has been shown to be associated with tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor metastasis', 'Disease', 'MESH:D009362', (86, 102))	('associated', 'Reg', (70, 80))	('miRNAs', 'Protein', (42, 48))	('tumor metastasis', 'Disease', (86, 102))	('aberrant expression', 'Var', (19, 38))
655403	33174687	17  As regulators of the human genome, 18  the vast majority of miRNAs are located in cancer-related genomic regions and participate in tumor progression in the form of tumor suppressor genes or proto-oncogenes.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('human', 'Species', '9606', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('miRNAs', 'Var', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (169, 174))	('participate in', 'Reg', (121, 135))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', (136, 141))	('cancer', 'Disease', (86, 92))
655410	33174687	The potential value of single nucleotide polymorphisms (SNPs) in pre-miR-423 (rs6505162) as a diagnostic biomarker, and a therapeutic target, are also discussed.	('rs6505162', 'Mutation', 'rs6505162', (78, 87))	('miR-423', 'Gene', '494335', (69, 76))	('rs6505162', 'Var', (78, 87))	('miR-423', 'Gene', (69, 76))
655417	33174687	34  Furthermore, inhibition of miR-423-5p expression upregulates gene associated with GRIM-19 expression and decreases BCL-2 expression to inhibit prostate cancer cell proliferation and promote apoptosis.	('prostate cancer', 'Disease', 'MESH:D011471', (147, 162))	('promote', 'PosReg', (186, 193))	('prostate cancer', 'Phenotype', 'HP:0012125', (147, 162))	('prostate cancer', 'Disease', (147, 162))	('GRIM-19', 'Gene', (86, 93))	('decreases', 'NegReg', (109, 118))	('inhibition', 'Var', (17, 27))	('apoptosis', 'CPA', (194, 203))	('BCL-2', 'Gene', '596', (119, 124))	('miR-423', 'Gene', '494335', (31, 38))	('upregulates', 'PosReg', (53, 64))	('GRIM-19', 'Gene', '51079', (86, 93))	('BCL-2', 'Gene', (119, 124))	('BC', 'Phenotype', 'HP:0003002', (119, 121))	('expression', 'MPA', (125, 135))	('expression', 'MPA', (94, 104))	('inhibit', 'NegReg', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('miR-423', 'Gene', (31, 38))	('gene', 'MPA', (65, 69))
655419	33174687	36  Furthermore, the miR-423 chain promotes BC cell growth by enhancing the expression of mutant p53 and proliferating cell nuclear antigen (PCNA).	('p53', 'Gene', (97, 100))	('proliferating cell nuclear antigen', 'Gene', '5111', (105, 139))	('PCNA', 'Gene', '5111', (141, 145))	('BC', 'Phenotype', 'HP:0003002', (44, 46))	('mutant', 'Var', (90, 96))	('p53', 'Gene', '7157', (97, 100))	('promotes', 'PosReg', (35, 43))	('enhancing', 'PosReg', (62, 71))	('miR-423', 'Gene', (21, 28))	('expression', 'MPA', (76, 86))	('BC cell growth', 'CPA', (44, 58))	('PCNA', 'Gene', (141, 145))	('proliferating cell nuclear antigen', 'Gene', (105, 139))	('miR-423', 'Gene', '494335', (21, 28))
655430	33174687	43  MiR-423-3p has similar functional effects in hepatocellular carcinoma (HCC), whereas miR-423-5p does not.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (49, 73))	('hepatocellular carcinoma', 'Disease', (49, 73))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (49, 73))	('MiR-423-3p', 'Chemical', '-', (4, 14))	('HCC', 'Phenotype', 'HP:0001402', (75, 78))	('miR-423', 'Gene', (89, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('MiR-423-3p', 'Var', (4, 14))	('miR-423', 'Gene', '494335', (89, 96))
655433	33174687	Inhibition of apoptosis can promote tumor progression.	('apoptosis', 'Protein', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('promote', 'PosReg', (28, 35))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
655445	33174687	49  Similarly, Knockdown expression of beta-catenin can downregulate miR-423-5p expression, thereby promoting gastric cancer apoptosis.	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('miR-423', 'Gene', '494335', (69, 76))	('promoting', 'PosReg', (100, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('beta-catenin', 'Gene', (39, 51))	('downregulate', 'NegReg', (56, 68))	('beta-catenin', 'Gene', '1499', (39, 51))	('Knockdown', 'Var', (15, 24))	('miR-423', 'Gene', (69, 76))
655458	33174687	56  In laryngeal cancer, miR-423-3p has been confirmed to affect tumor cell metastasis by regulating AdipoR2.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('AdipoR2', 'Gene', (101, 108))	('miR-423-3p', 'Chemical', '-', (25, 35))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('AdipoR2', 'Gene', '79602', (101, 108))	('miR-423-3p', 'Var', (25, 35))	('cancer', 'Disease', (17, 23))	('regulating', 'Reg', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (7, 23))	('affect', 'Reg', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
655459	33174687	57  Furthermore, TAR DNA binding protein (TDP-43) promotes lung cancer cell metastasis by upregulating the expression of oncogenic miR-423-3p.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('expression', 'MPA', (107, 117))	('lung cancer', 'Disease', (59, 70))	('TDP-43', 'Gene', '23435', (42, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('TAR DNA binding protein', 'Gene', '23435', (17, 40))	('miR-423-3p', 'Chemical', '-', (131, 141))	('upregulating', 'PosReg', (90, 102))	('TDP-43', 'Gene', (42, 48))	('miR-423-3p', 'Var', (131, 141))	('promotes', 'PosReg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('TAR DNA binding protein', 'Gene', (17, 40))
655467	33174687	64  Thus, it is clear that abnormal expression of miR-423 can affect cancer cell metastasis of human tumors, miR-423 may be a promising prognostic and therapeutic marker for patients with metastatic cancer.	('abnormal', 'Var', (27, 35))	('affect', 'Reg', (62, 68))	('human', 'Species', '9606', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('miR-423', 'Gene', (50, 57))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('miR-423', 'Gene', (109, 116))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('miR-423', 'Gene', '494335', (50, 57))	('miR-423', 'Gene', '494335', (109, 116))	('cancer', 'Disease', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('tumors', 'Disease', (101, 107))
655480	33174687	68  Similarly, the abnormal exosomal miR-423-5p expression affects the therapeutic effect of cisplatin in triple negative BC.	('triple negative BC', 'Disease', (106, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('BC', 'Phenotype', 'HP:0003002', (122, 124))	('miR-423', 'Gene', (37, 44))	('affects', 'Reg', (59, 66))	('abnormal', 'Var', (19, 27))	('miR-423', 'Gene', '494335', (37, 44))	('therapeutic effect of cisplatin', 'MPA', (71, 102))
655486	33174687	LncRNA expression mutations can promote tumor occurrence and metastasis.	('LncRNA expression', 'Gene', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('promote', 'PosReg', (32, 39))	('mutations', 'Var', (18, 27))
655510	33174687	89 ,  90  A meta-analysis of miR-423 polymorphisms and cancer prognosis suggests that rs6505162 is a prognostic marker of all common human cancers.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('rs6505162', 'Mutation', 'rs6505162', (86, 95))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('miR-423', 'Gene', (29, 36))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rs6505162', 'Var', (86, 95))	('miR-423', 'Gene', '494335', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('human', 'Species', '9606', (133, 138))	('cancer', 'Disease', (55, 61))	('cancer', 'Disease', (139, 145))
655511	33174687	91  According to another meta-analysis, rs6505162 may participate in the prevention of cancers such as lung cancer and colorectal cancer, but does not reduce the risk of breast cancer, esophageal cancer and gastric cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('gastric cancer', 'Disease', (207, 221))	('lung cancer', 'Disease', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('rs6505162', 'Var', (40, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (185, 202))	('gastric cancer', 'Disease', 'MESH:D013274', (207, 221))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancers', 'Disease', (87, 94))	('esophageal cancer', 'Disease', (185, 202))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('participate', 'Reg', (54, 65))	('colorectal cancer', 'Disease', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (207, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('breast cancer', 'Disease', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('rs6505162', 'Mutation', 'rs6505162', (40, 49))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
655512	33174687	92  These polymorphisms have the potential to lead to metabolic abnormalities and changes in cancer susceptibility (Table 3).	('lead to', 'Reg', (46, 53))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('metabolic abnormalities', 'Phenotype', 'HP:0001939', (54, 77))	('metabolic abnormalities', 'Disease', 'MESH:D008659', (54, 77))	('changes', 'Reg', (82, 89))	('metabolic abnormalities', 'Disease', (54, 77))	('polymorphisms', 'Var', (10, 23))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
655513	33174687	The rs6505162 C>A polymorphism, mapping to chromosome 17 at 17q11.2, is situated in the pre-miRNA region of miR-423.	('miR-423', 'Gene', '494335', (108, 115))	('rs6505162', 'Mutation', 'rs6505162', (4, 13))	('rs6505162 C>A', 'Var', (4, 17))	('miR-423', 'Gene', (108, 115))
655515	33174687	22   Growing evidence supports the association between rs6505162 and the cancer risk of several cancers, as well as the susceptibility of individuals to cancer, although the results are contradictory.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('rs6505162', 'Var', (55, 64))	('rs6505162', 'Mutation', 'rs6505162', (55, 64))	('association', 'Interaction', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
655517	33174687	36  The rs6505162 SNP has been reported to affect the risk of esophageal cancer.	('esophageal cancer', 'Disease', (62, 79))	('rs6505162', 'Mutation', 'rs6505162', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('affect', 'Reg', (43, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('rs6505162', 'Var', (8, 17))
655518	33174687	106  Many reports have also linked rs6505162 to environmental exposure to cancer.	('rs6505162', 'Mutation', 'rs6505162', (35, 44))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('rs6505162', 'Var', (35, 44))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('environmental exposure to cancer', 'Phenotype', 'HP:0031437', (48, 80))
655519	33174687	A recent study conducted in South Africa indicated that rs6505162 is associated with environmental exposure to smoke and can increase the risk of esophageal squamous cell carcinoma.	('rs6505162', 'Mutation', 'rs6505162', (56, 65))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (146, 180))	('increase', 'PosReg', (125, 133))	('rs6505162', 'Var', (56, 65))	('associated', 'Reg', (69, 79))	('esophageal squamous cell carcinoma', 'Disease', (146, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))
655521	33174687	108 ,  109  Nevertheless, a recent study demonstrated that there is no correlation between any genetic model of miR-423 (including rs6505162) and susceptibility to esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (164, 198))	('miR-423', 'Gene', '494335', (112, 119))	('rs6505162', 'Mutation', 'rs6505162', (131, 140))	('miR-423', 'Gene', (112, 119))	('esophageal squamous cell carcinoma', 'Disease', (164, 198))	('rs6505162', 'Var', (131, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (175, 198))	('susceptibility', 'Reg', (146, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
655522	33174687	110  Similarly, there is no biological association between rs6505162 and passive smoking exposure in Chinese women with lung cancer.	('rs6505162', 'Var', (59, 68))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('women', 'Species', '9606', (109, 114))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('rs6505162', 'Mutation', 'rs6505162', (59, 68))
655523	33174687	111  The rs6505162 SNP is associated with genetic susceptibility to lung cancer and lung adenocarcinoma, 102  The rs6505162 SNP also has implications for the prognosis of patients with completely resected non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('lung adenocarcinoma', 'Disease', (84, 103))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('lung cancer', 'Disease', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('patients', 'Species', '9606', (171, 179))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('implications', 'Reg', (137, 149))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('lung cancer', 'Disease', (68, 79))	('rs6505162', 'Mutation', 'rs6505162', (9, 18))	('rs6505162', 'Mutation', 'rs6505162', (114, 123))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('rs6505162', 'Var', (114, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('rs6505162', 'Var', (9, 18))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('associated', 'Reg', (26, 36))
655524	33174687	112  Two recent meta-analyses, indicated that rs6505162 significantly decreased the risk of lung cancer, suggesting that this miR-423 polymorphism is an effective protective factor against lung cancer.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('miR-423', 'Gene', '494335', (126, 133))	('rs6505162', 'Mutation', 'rs6505162', (46, 55))	('decreased', 'NegReg', (70, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('lung cancer', 'Disease', (189, 200))	('rs6505162', 'Var', (46, 55))	('miR-423', 'Gene', (126, 133))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))
655525	33174687	104 ,  113  Analysis using association methods revealed that the CC genotype of rs6505162 reduced the risk of breast cancer development.	('reduced', 'NegReg', (90, 97))	('rs6505162', 'Mutation', 'rs6505162', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rs6505162', 'Var', (80, 89))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
655527	33174687	114  The rs6505162 SNP was found to affect the risk of familial breast cancer in a study conducted in South America.	('familial breast cancer', 'Disease', 'MESH:D001943', (55, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('familial breast cancer', 'Disease', (55, 77))	('rs6505162', 'Mutation', 'rs6505162', (9, 18))	('rs6505162', 'Var', (9, 18))	('affect', 'Reg', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
655528	33174687	99  Rah et al reported that breast cancer-related microRNA polymorphisms, including rs6505162, are connected with increased primary ovarian insufficiency risk via interactions with miR-423 A variants.	('miR-423', 'Gene', '494335', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('interactions', 'Interaction', (163, 175))	('rs6505162', 'Mutation', 'rs6505162', (84, 93))	('breast cancer', 'Disease', (28, 41))	('miR-423', 'Gene', (181, 188))	('rs6505162', 'Var', (84, 93))	('increased primary ovarian insufficiency', 'Disease', (114, 153))	('primary ovarian insufficiency', 'Phenotype', 'HP:0008209', (124, 153))	('increased primary ovarian insufficiency', 'Disease', 'MESH:D016649', (114, 153))
655530	33174687	116  Dozens of colorectal cancer susceptibility bases have been identified by genome-wide association analysis (GWAS), and rs6505162 has been shown to affect the prognosis of colorectal cancer patients following chemotherapy.	('affect', 'Reg', (151, 157))	('patients', 'Species', '9606', (193, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('rs6505162', 'Var', (123, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (15, 32))	('colorectal cancer', 'Disease', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('colorectal cancer', 'Disease', (15, 32))	('rs6505162', 'Mutation', 'rs6505162', (123, 132))	('prognosis', 'CPA', (162, 171))
655531	33174687	63 ,  117  Similarly, rs6505162 has been identified as a biomarker of colorectal cancer metastasis.	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('colorectal cancer', 'Disease', (70, 87))	('rs6505162', 'Mutation', 'rs6505162', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('rs6505162', 'Var', (22, 31))
655532	33174687	118  Another study indicated that rs6505162 has a negative impact on susceptibility to Wilms tumor, especially in Chinese children.	('rs6505162', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Wilms tumor', 'Disease', (87, 98))	('Wilms tumor', 'Phenotype', 'HP:0002667', (87, 98))	('susceptibility', 'MPA', (69, 83))	('children', 'Species', '9606', (122, 130))	('rs6505162', 'Mutation', 'rs6505162', (34, 43))	('negative', 'NegReg', (50, 58))	('Wilms tumor', 'Disease', 'MESH:D009396', (87, 98))
655534	33174687	120 ,  121  The miR-423 rs6505162 polymorphism is considered to be a tumor-related susceptibility gene.	('rs6505162', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('miR-423', 'Gene', (16, 23))	('tumor', 'Disease', (69, 74))	('miR-423', 'Gene', '494335', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('rs6505162', 'Mutation', 'rs6505162', (24, 33))
655541	33174687	60  The combination of miR-423-3p and the three other miRNAs (miR-148b, miR-221 and miR-23b) has proved to be a novel and non-invasive marker for lung cancer detection, with an area under curve (AUC) of 0.885.	('miR-148b', 'Gene', '442892', (62, 70))	('miR-23b', 'Gene', (84, 91))	('miR-423-3p', 'Chemical', '-', (23, 33))	('miR-148b', 'Gene', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('miR-423-3p', 'Var', (23, 33))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('miR-221', 'Gene', '407006', (72, 79))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('miR-23b', 'Gene', '407011', (84, 91))	('miR-221', 'Gene', (72, 79))
655545	33174687	127  The combination of miR-423-3p with miR-151-5p and miR-152-3p is also a clinically effective marker for cervical cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('miR-1', 'Gene', (55, 60))	('miR-1', 'Gene', '79187', (40, 45))	('miR-423-3p', 'Chemical', '-', (24, 34))	('miR-151', 'Gene', '442893', (40, 47))	('miR-151', 'Gene', (40, 47))	('miR-423-3p', 'Var', (24, 34))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('miR-1', 'Gene', '79187', (55, 60))	('miR-1', 'Gene', (40, 45))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (124, 132))
655550	33174687	114  It has been reported that 70.1% of hereditary breast cancers can be distinguished from non-hereditary breast cancer on the basis of miR-423-3p expression.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('miR-423-3p', 'Chemical', '-', (137, 147))	('hereditary breast cancers', 'Disease', 'MESH:D061325', (40, 65))	('breast cancers', 'Phenotype', 'HP:0003002', (51, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('hereditary breast cancers', 'Disease', (40, 65))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('non-hereditary breast cancer', 'Disease', (92, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('miR-423-3p expression', 'Var', (137, 158))	('non-hereditary breast cancer', 'Disease', 'MESH:D061325', (92, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
655600	32048046	According to a meta-analysis by Hulscher et al., transhiatal esophagectomy was associated with fewer pulmonary complications, but trans-transthoracic esophagectomy showed a trend towards improved survival.	('pulmonary complications', 'Phenotype', 'HP:0006532', (101, 124))	('trans-transthoracic', 'Var', (130, 149))	('pulmonary complications', 'Disease', (101, 124))	('transhiatal', 'Var', (49, 60))	('pulmonary complications', 'Disease', 'MESH:D008171', (101, 124))	('improved', 'PosReg', (187, 195))	('fewer', 'NegReg', (95, 100))
655690	29379302	RACKI induces chemotherapy resistance in esophageal carcinoma by upregulating the PI3K/AKT pathway and Bcl-2 expression Accumulating evidence indicates that RACK1 is involved in the progression of tumors.	('Bcl-2', 'Gene', '596', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('esophageal carcinoma', 'Disease', (41, 61))	('AKT', 'Gene', (87, 90))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (41, 61))	('chemotherapy resistance', 'MPA', (14, 37))	('induces', 'Reg', (6, 13))	('upregulating', 'PosReg', (65, 77))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (41, 61))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('RACKI', 'Var', (0, 5))	('tumors', 'Disease', (197, 203))	('AKT', 'Gene', '207', (87, 90))	('Bcl-2', 'Gene', (103, 108))
655694	29379302	Furthermore, we found that RACK1 could activate the PI3K/AKT pathway and increase the expression level of Bcl-2 in ESCC, which leads to the enhancement of chemoresistance in ESCC.	('chemoresistance', 'CPA', (155, 170))	('expression level', 'MPA', (86, 102))	('RACK1', 'Var', (27, 32))	('increase', 'PosReg', (73, 81))	('ESCC', 'Disease', (174, 178))	('AKT', 'Gene', '207', (57, 60))	('enhancement', 'PosReg', (140, 151))	('Bcl-2', 'Gene', (106, 111))	('Bcl-2', 'Gene', '596', (106, 111))	('AKT', 'Gene', (57, 60))	('activate', 'PosReg', (39, 47))
655704	29379302	Eca109 and EC9706 cells were cultured in Roswell Park Memorial Institute (RPMI) 1640 medium with 10% fetal bovine serum, 100 mug/mL streptomycin, and 100 U/mL penicillin in a 5% CO2 atmosphere at 37 C. Plasmid with shRNA, nonsense shRNA for negative control (shNC), or open reading frame (ORF) targeting RACK1 gene was transfected into Eca109 and EC9706 cell lines with Lipofectamine  2000 Reagent (Thermo Fisher Scientific, Waltham, MA, USA).	('RACK1 gene', 'Gene', (304, 314))	('streptomycin', 'Chemical', 'MESH:D013307', (132, 144))	('EC9706', 'CellLine', 'CVCL:E307', (347, 353))	('bovine', 'Species', '9913', (107, 113))	('EC9706', 'CellLine', 'CVCL:E307', (11, 17))	('Lipofectamine', 'Chemical', 'MESH:C086724', (370, 383))	('open reading frame', 'Var', (269, 287))	('CO2', 'Chemical', '-', (178, 181))	('penicillin', 'Chemical', 'MESH:D010406', (159, 169))
655724	29379302	It was upregulated in overexpression Eca109 cells (6.76+-1.46, P=0.0209) and EC9706 cells (7.76+-0.31, P=0.0007) compared to control cells.	('EC9706', 'Var', (77, 83))	('upregulated', 'PosReg', (7, 18))	('EC9706', 'CellLine', 'CVCL:E307', (77, 83))
655726	29379302	The RACK1 expression level increased in both clone E109-overexpression and E9706-overexpression groups compared to the control cells.	('expression level', 'MPA', (10, 26))	('increased', 'PosReg', (27, 36))	('E9706-overexpression', 'Var', (75, 95))	('E9706', 'CellLine', 'CVCL:E307', (75, 80))	('RACK1', 'Gene', (4, 9))
655727	29379302	Additionally, after transfection by shRACK1, RACK1 protein level reduced to 65 and 44% compared to the control group in both Eca109 and EC9706 cells (Figure 1A and B).	('EC9706', 'CellLine', 'CVCL:E307', (136, 142))	('reduced', 'NegReg', (65, 72))	('transfection', 'Var', (20, 32))	('RACK1 protein level', 'MPA', (45, 64))	('shRACK1', 'Gene', (36, 43))
655729	29379302	The results showed that downregulation of RACK1 by shRACK1 transfection significantly suppressed cell proliferation in human esophageal carcinoma cells (Eca109: 254+-11 vs 343+-15, P=0.0013; EC9706: 187+-23 vs 353+-7, P=0.0003, Figure 2A and B).	('human', 'Species', '9606', (119, 124))	('cell proliferation in human', 'CPA', (97, 124))	('shRACK1', 'Gene', (51, 58))	('downregulation', 'NegReg', (24, 38))	('transfection', 'Var', (59, 71))	('esophageal carcinoma', 'Disease', (125, 145))	('suppressed', 'NegReg', (86, 96))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (125, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('EC9706', 'CellLine', 'CVCL:E307', (191, 197))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (125, 145))	('RACK1', 'Gene', (42, 47))
655730	29379302	Moreover, the number of formation colony increased in clone E109-overexpression (393+-14 vs 343+-15, P=0.0148) and E9706-overexpression (369+-12 vs 353+-7, P=0.0280) groups compared with the control one (Figure 2A and B).	('E9706', 'CellLine', 'CVCL:E307', (115, 120))	('E109-overexpression', 'Var', (60, 79))	('increased', 'PosReg', (41, 50))	('E9706-overexpression', 'Var', (115, 135))
655731	29379302	Eca109 and EC9706 were exposed to different concentrations of cisplatin (0-320 muM) or 5-fluorouracil (Eca109, 0-10 muM; EC9706, 0-320 muM) for 48 and 72 h, respectively.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('muM', 'Gene', (116, 119))	('muM', 'Gene', '56925', (79, 82))	('EC9706', 'CellLine', 'CVCL:E307', (121, 127))	('muM', 'Gene', '56925', (116, 119))	('EC9706', 'CellLine', 'CVCL:E307', (11, 17))	('muM', 'Gene', '56925', (135, 138))	('muM', 'Gene', (79, 82))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (87, 101))	('muM', 'Gene', (135, 138))	('EC9706', 'Var', (121, 127))
655747	29379302	Recently, Ruan et al showed that aberrant expression of RACK1 involved in chemoresistance in vitro as well as tumor growth of HCC in vivo.	('RACK1', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('chemoresistance', 'CPA', (74, 89))	('tumor', 'Disease', (110, 115))	('HCC', 'Phenotype', 'HP:0001402', (126, 129))	('involved in', 'Reg', (62, 73))	('aberrant expression', 'Var', (33, 52))
655749	29379302	Our findings also showed that RACK1 could activate PI3K/AKT pathway and upregulate the expression of Bcl-2, which subsequently led to chemotherapy resistance.	('led to', 'Reg', (127, 133))	('AKT', 'Gene', '207', (56, 59))	('Bcl-2', 'Gene', (101, 106))	('Bcl-2', 'Gene', '596', (101, 106))	('activate', 'PosReg', (42, 50))	('AKT', 'Gene', (56, 59))	('expression', 'MPA', (87, 97))	('RACK1', 'Var', (30, 35))	('upregulate', 'PosReg', (72, 82))	('chemotherapy resistance', 'CPA', (134, 157))
655750	29379302	There is accumulating evidence showing that aberrant activation of the protein kinase B (AKT) pathway plays a pivotal role in tumor development, progression, and chemoresistance.	('chemoresistance', 'CPA', (162, 177))	('AKT', 'Gene', (89, 92))	('activation', 'PosReg', (53, 63))	('AKT', 'Gene', '207', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('aberrant', 'Var', (44, 52))	('tumor', 'Disease', (126, 131))
655754	29379302	Moreover, we demonstrated that knockdown of RACK1 inhibited the phosphorylation of AKT and ERK in the Eca109 and EC9706 cells to a certain extent.	('AKT', 'Gene', '207', (83, 86))	('phosphorylation', 'MPA', (64, 79))	('EC9706', 'CellLine', 'CVCL:E307', (113, 119))	('ERK', 'Gene', '5594', (91, 94))	('AKT', 'Gene', (83, 86))	('ERK', 'Gene', (91, 94))	('knockdown', 'Var', (31, 40))	('RACK1', 'Gene', (44, 49))	('inhibited', 'NegReg', (50, 59))
655756	29379302	The expression of Bcl-2 could be upregulated by phosphorylating AKT.	('upregulated', 'PosReg', (33, 44))	('Bcl-2', 'Gene', (18, 23))	('expression', 'MPA', (4, 14))	('AKT', 'Gene', '207', (64, 67))	('phosphorylating', 'Var', (48, 63))	('AKT', 'Gene', (64, 67))	('Bcl-2', 'Gene', '596', (18, 23))
655761	29379302	Although we have a more profound understanding about the impact of RACK1 in ESCC, it is possible that RACK1 may lead to the chemotherapy resistance through other mechanisms except for the PI3K/AKT and Bcl-2 pathways; further investigations are certainly necessary to understand the complete mechanism.	('AKT', 'Gene', '207', (193, 196))	('lead to', 'Reg', (112, 119))	('Bcl-2', 'Gene', (201, 206))	('AKT', 'Gene', (193, 196))	('Bcl-2', 'Gene', '596', (201, 206))	('chemotherapy resistance', 'MPA', (124, 147))	('RACK1', 'Var', (102, 107))	('ESCC', 'Disease', (76, 80))
655805	27731548	For ypN0 cancers, survival decreased distinctively and monotonically only for ypT3 and ypT4a cancers (Fig.	('cancers', 'Disease', (93, 100))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('T4a', 'Gene', (89, 92))	('ypT3', 'Gene', (78, 82))	('decreased', 'NegReg', (27, 36))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ypN0', 'Var', (4, 8))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('T4a', 'Gene', '6317', (89, 92))
655837	27731548	Frequency of histologic grade in decreasing order for SCC was G1, G2, and G3; the inverse was reported for adenocarcinoma.	('SCC', 'Gene', '6317', (54, 57))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('adenocarcinoma', 'Disease', (107, 121))	('G3', 'Var', (74, 76))	('SCC', 'Gene', (54, 57))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))
655844	27731548	Survival was substantially different for ypN0 patients versus those with N+.	('different', 'Reg', (27, 36))	('ypN0', 'Var', (41, 45))	('patients', 'Species', '9606', (46, 54))
655845	27731548	Similarly, survival was substantially different for ypM0 patients versus those with ypM+.	('survival', 'MPA', (11, 19))	('patients', 'Species', '9606', (57, 65))	('different', 'Reg', (38, 47))	('ypM0', 'Var', (52, 56))
656037	27703377	The study by Priola et al demonstrated that, in patients with thymoma, patients with higher ADC have a significantly higher disease-free survival than patients with lower ADC.	('ADC', 'Var', (92, 95))	('patients', 'Species', '9606', (71, 79))	('thymoma', 'Disease', 'MESH:D013945', (62, 69))	('disease-free survival', 'CPA', (124, 145))	('patients', 'Species', '9606', (151, 159))	('thymoma', 'Disease', (62, 69))	('higher', 'PosReg', (117, 123))	('thymoma', 'Phenotype', 'HP:0100522', (62, 69))	('patients', 'Species', '9606', (48, 56))
656051	27703377	Combination of earlier studies may partly explain the observation that low ADC value predicted worse outcome in patients with ESCC.	('ADC value', 'MPA', (75, 84))	('low', 'Var', (71, 74))	('patients', 'Species', '9606', (112, 120))	('ESCC', 'Disease', (126, 130))
656052	27703377	However, low ADC value does not always predict worse outcome in other types of cancer.	('low', 'Var', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ADC value', 'MPA', (13, 22))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
656097	27215366	In a study of PET in identifying metastatic disease and evaluating the prognostic potential of standard uptake value (SUV) in 123 patients, PET was more sensitive in identifying pancreatic metastatic lesions than CT or MRI; however, it had a lower specificity (differentiating benign from malignant pancreatic masses), lower positive predictive value and, in some cases, delayed definitive surgical management.	('lower', 'NegReg', (242, 247))	('PET', 'Var', (140, 143))	('lower', 'NegReg', (319, 324))	('pancreatic', 'Disease', (299, 309))	('malignant pancreatic', 'Disease', (289, 309))	('specificity', 'MPA', (248, 259))	('malignant pancreatic', 'Disease', 'MESH:D010190', (289, 309))	('patients', 'Species', '9606', (130, 138))	('pancreatic', 'Disease', 'MESH:D010195', (178, 188))	('pancreatic', 'Disease', 'MESH:D010195', (299, 309))	('positive predictive value', 'MPA', (325, 350))	('pancreatic', 'Disease', (178, 188))
656134	27215366	Therefore, tests of pelvic floor dysfunction yield the correct diagnosis, impact selection of physical therapy and obviate the need for low yield or invasive and expensive testing involving imaging, as well as avoiding prolonged periods of ineffective treatments for constipation.	('constipation', 'Disease', (267, 279))	('pelvic floor dysfunction', 'Disease', 'MESH:D059952', (20, 44))	('constipation', 'Phenotype', 'HP:0002019', (267, 279))	('tests', 'Var', (11, 16))	('constipation', 'Disease', 'MESH:D003248', (267, 279))	('pelvic floor dysfunction', 'Disease', (20, 44))
656187	26198208	Several studies on humans and animals have suggested that extrinsic causes such as lesions located in the central nervous system (CNS) may produce manometric findings of achalasia.	('achalasia', 'Disease', (170, 179))	('achalasia', 'Disease', 'MESH:D004931', (170, 179))	('produce', 'Reg', (139, 146))	('humans', 'Species', '9606', (19, 25))	('manometric', 'MPA', (147, 157))	('lesions', 'Var', (83, 90))	('achalasia', 'Phenotype', 'HP:0002571', (170, 179))	('lesions located in the central nervous system', 'Phenotype', 'HP:0100006', (83, 128))
656190	26198208	Studies have suggested that loss of VIP and NO secreting neurons leads to an imbalance between the excitatory and inhibitory neurons of the myenteric plexus, producing irreversible manometric changes in such patients.	('loss', 'Var', (28, 32))	('patients', 'Species', '9606', (208, 216))	('imbalance', 'Phenotype', 'HP:0002172', (77, 86))	('VIP', 'Gene', '7432', (36, 39))	('manometric changes', 'MPA', (181, 199))	('VIP', 'Gene', (36, 39))
656195	26198208	Mutation of the ALADIN 12q13 gene is a commonly reported cause of achalasia in children.	('achalasia', 'Disease', (66, 75))	('cause', 'Reg', (57, 62))	('Mutation', 'Var', (0, 8))	('achalasia', 'Phenotype', 'HP:0002571', (66, 75))	('children', 'Species', '9606', (79, 87))	('ALADIN 12q13', 'Gene', (16, 28))	('achalasia', 'Disease', 'MESH:D004931', (66, 75))
656198	26198208	Recent studies have also shown multiple genetic mutations such as nitric oxide synthase 1 gene (NOS1), VIP receptor 1, IL23R, IL10 promoter, IL33, and protein tyrosine phosphatase non-receptor 22 (PTPN22) to be associated with the development of achalasia.	('NOS1', 'Gene', (96, 100))	('nitric oxide synthase 1', 'Gene', '4842', (66, 89))	('achalasia', 'Disease', (246, 255))	('VIP', 'Gene', '7432', (103, 106))	('IL23R', 'Gene', '149233', (119, 124))	('PTPN22', 'Gene', '26191', (197, 203))	('mutations', 'Var', (48, 57))	('achalasia', 'Phenotype', 'HP:0002571', (246, 255))	('protein tyrosine phosphatase non-receptor 22', 'Gene', (151, 195))	('IL23R', 'Gene', (119, 124))	('IL10', 'Gene', (126, 130))	('protein tyrosine phosphatase non-receptor 22', 'Gene', '26191', (151, 195))	('VIP', 'Gene', (103, 106))	('PTPN22', 'Gene', (197, 203))	('IL33', 'Gene', '90865', (141, 145))	('IL10', 'Gene', '3586', (126, 130))	('nitric oxide synthase 1', 'Gene', (66, 89))	('IL33', 'Gene', (141, 145))	('associated', 'Reg', (211, 221))	('achalasia', 'Disease', 'MESH:D004931', (246, 255))	('NOS1', 'Gene', '4842', (96, 100))
656342	31701262	Human DNAJB6 has two spliced isoforms: isoform a (2.5 kb, NM_058246) and isoform b (1.6 kb, NM_005494).	('NM_058246', 'Var', (58, 67))	('Human', 'Species', '9606', (0, 5))	('DNAJB6', 'Gene', (6, 12))	('DNAJB6', 'Gene', '10049', (6, 12))
656406	31701262	These results imply that DNAJB6 dysregulation may play a significant role in the progress of the ESCC.	('DNAJB6', 'Gene', '10049', (25, 31))	('dysregulation', 'Var', (32, 45))	('play', 'Reg', (50, 54))	('DNAJB6', 'Gene', (25, 31))	('ESCC', 'Disease', (97, 101))
656415	31701262	And previous study showed that GPX4 suppresses ferroptosis; in return, inhibiting GPX4 increases lipid peroxidation, which contributes to ferroptotic cancer death.	('GPX4', 'Gene', (82, 86))	('increases', 'PosReg', (87, 96))	('lipid peroxidation', 'MPA', (97, 115))	('contributes', 'Reg', (123, 134))	('ferroptotic', 'Disease', (138, 149))	('suppresses', 'NegReg', (36, 46))	('GPX4', 'Gene', '2879', (82, 86))	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('cancer death', 'Disease', (150, 162))	('GPX4', 'Gene', (31, 35))	('inhibiting', 'Var', (71, 81))	('GPX4', 'Gene', '2879', (31, 35))	('ferroptosis', 'CPA', (47, 58))	('cancer death', 'Disease', 'MESH:D009369', (150, 162))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
656422	31701262	Therefore, we can conclude that overexpressing DNAJB6a can promote ferroptosis.	('overexpressing', 'Var', (32, 46))	('DNAJB6', 'Gene', (47, 53))	('promote', 'PosReg', (59, 66))	('ferroptosis', 'CPA', (67, 78))	('DNAJB6', 'Gene', '10049', (47, 53))
656616	30127961	The changes in TP53 and RB1 mutations were used to quantify the circulating tumor DNA (ctDNA) using Bio-Rad QX200 droplet digital PCR system during treatment with radiation and Pembrolizumab.	('Pembrolizumab', 'Chemical', 'MESH:C582435', (177, 190))	('RB1', 'Gene', (24, 27))	('RB1', 'Gene', '5925', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
656618	30127961	Approximately 49 days after the start of the combination therapy, abundances of TP53 mutation dropped from 13-4%, abundances of RB1 mutation dropped from 9-1%.	('RB1', 'Gene', (128, 131))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))	('RB1', 'Gene', '5925', (128, 131))	('dropped', 'NegReg', (141, 148))	('dropped', 'NegReg', (94, 101))
656683	29548582	The covariates included age, sex, comorbidities (pulmonary, cardiac, diabetes, previous cancer), previous chest radiation, tumor location, histological grade (poor vs. well/moderate), clinical stage (II vs. III), induction chemotherapy, chemotherapy duration, and radiation dose (>=5040 vs. <5040 cGy).	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('diabetes', 'Disease', (69, 77))	('tumor', 'Disease', (123, 128))	('cardiac', 'Disease', (60, 67))	('diabetes', 'Disease', 'MESH:D003920', (69, 77))	('>=5040', 'Var', (280, 286))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
656717	29548582	In multivariable analysis, trimodality treatment was significantly associated with improved OS (HR 0.57, 95% CI 0.34-0.97, P=0.039), after year of treatment was controlled for.	('trimodality treatment', 'Var', (27, 48))	('improved', 'PosReg', (83, 91))	('OS', 'Chemical', '-', (92, 94))
656736	29548582	and the Japan Clinical Oncology Group (JCOG) pooled data from two previous prospective trials of patients with locally advanced esophageal SCC treated with either definitive CRT (JCOG9906) or trimodality treatment (JCOG9907) and reported significantly improved progression-free survival and OS for patients treated with esophagectomy (definitive CRT vs trimodality: adjusted HR 1.76 [95% CI 1.3-2.5] vs 1.72 [95% CI 1.2-2.5]).	('JCOG9906', 'Var', (179, 187))	('Oncology', 'Phenotype', 'HP:0002664', (23, 31))	('esophageal SCC', 'Disease', (128, 142))	('progression-free survival', 'CPA', (261, 286))	('patients', 'Species', '9606', (298, 306))	('esophageal SCC', 'Disease', 'MESH:D004941', (128, 142))	('OS', 'Chemical', '-', (291, 293))	('JCOG9906', 'CellLine', 'None', (179, 187))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('JCOG9907', 'Var', (215, 223))	('improved', 'PosReg', (252, 260))	('patients', 'Species', '9606', (97, 105))
656773	29559669	Qingzhen is a county in Guizhou Province (N24 30-29 13, E103 1-109 30, 1100 m above sea level, subtropical humid climate) in southwestern China, located in the Miaoling mountains.	('sea', 'Gene', '6395', (84, 87))	('E103 1-109 30', 'Var', (56, 69))	('sea', 'Gene', (84, 87))	('N24 30-29', 'Var', (42, 51))
656791	29559669	Because of the coordination effect between EC and factors such as the living environment, dietary habits, smoking history, alcohol drinking, low social and economic status, poor standard of living and inadequate knowledge related to EC, the combination of carcinogenic factors and cellular genetic factors may result in gradual accumulation of genetic mutations in cells responsible for malignant tumors.	('genetic mutations', 'Var', (344, 361))	('carcinogenic', 'Disease', 'MESH:D063646', (256, 268))	('alcohol drinking', 'Phenotype', 'HP:0030955', (123, 139))	('carcinogenic', 'Disease', (256, 268))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('alcohol', 'Chemical', 'MESH:D000438', (123, 130))	('malignant tumors', 'Disease', (387, 403))	('tumors', 'Phenotype', 'HP:0002664', (397, 403))	('malignant tumors', 'Disease', 'MESH:D018198', (387, 403))	('accumulation', 'PosReg', (328, 340))	('result in', 'Reg', (310, 319))
656794	29559669	Pickled vegetables, pickles, sauerkraut and barbecued food contain N-nitroso-compounds (NOCs), which have been found in animal models to induce malignant tumors, including EC.	('induce', 'PosReg', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('N-nitroso-compounds', 'Var', (67, 86))	('NOC', 'Gene', (88, 91))	('malignant tumors', 'Disease', (144, 160))	('N-nitroso-compounds', 'Chemical', '-', (67, 86))	('NOC', 'Gene', '25819', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('malignant tumors', 'Disease', 'MESH:D018198', (144, 160))
656829	28553369	We subsequently demonstrated that L-748706, a selective COX-2 inhibitor, and S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), a selective iNOS inhibitor, significantly inhibit NMBA-induced rat esophageal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('PBIT', 'Chemical', 'MESH:C118852', (132, 136))	('L-748706', 'Chemical', 'MESH:C505055', (34, 42))	('rat', 'Species', '10116', (23, 26))	('NMBA', 'Chemical', 'MESH:C014707', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('inhibit', 'NegReg', (181, 188))	("S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea", 'Chemical', 'MESH:C118852', (77, 130))	('rat', 'Species', '10116', (202, 205))	('L-748706', 'Var', (34, 42))
656861	28553369	To assess whether these agents could modulate COX-2, iNOS and associated cell signaling, KYSE-270 cells were treated with C3R, C3G, C3S, P3R, PCA, 4HBA, celecoxib and PBIT alone or in combination.	('C3R', 'Var', (122, 125))	('C3G', 'Var', (127, 130))	('P3R', 'Chemical', '-', (137, 140))	('P3R', 'Var', (137, 140))	('C3G', 'Chemical', 'MESH:C114438', (127, 130))	('COX-2', 'Enzyme', (46, 51))	('modulate', 'Reg', (37, 45))	('4HBA', 'Chemical', 'MESH:C038193', (147, 151))	('KYSE-270', 'CellLine', 'CVCL:1350', (89, 97))	('C3R', 'Chemical', 'MESH:C428983', (122, 125))	('C3S', 'Var', (132, 135))	('C3S', 'Chemical', '-', (132, 135))	('celecoxib', 'Chemical', 'MESH:D000068579', (153, 162))	('PBIT', 'Chemical', 'MESH:C118852', (167, 171))	('cell signaling', 'MPA', (73, 87))	('PCA', 'Chemical', 'MESH:C009091', (142, 145))
656883	28553369	The other anthocyanins identified in BRB include cyaniding-3-xylorutinoside (C3X; 18.2%), C3G (4.9%), C3S; 2.1% and P3R (0.8%).	('C3S', 'Var', (102, 105))	('C3G', 'Chemical', 'MESH:C114438', (90, 93))	('C3X', 'Chemical', '-', (77, 80))	('P3R', 'Chemical', '-', (116, 119))	('anthocyanins', 'Chemical', 'MESH:D000872', (10, 22))	('C3G', 'Var', (90, 93))	('cyaniding-3-xylorutinoside', 'Chemical', '-', (49, 75))	('C3S', 'Chemical', '-', (102, 105))
656887	28553369	The animals fed BRB or celecoxib + PBIT showed a greater percentage of area exhibiting normal and esophageal hyperplasia compared to those fed the control diet (Figure 2B).	('celecoxib + PBIT', 'Var', (23, 39))	('PBIT', 'Chemical', 'MESH:C118852', (35, 39))	('esophageal hyperplasia', 'Disease', 'MESH:D006965', (98, 120))	('esophageal hyperplasia', 'Disease', (98, 120))	('celecoxib', 'Chemical', 'MESH:D000068579', (23, 32))
656890	28553369	Moreover, the phosphorylation of nuclear factor kappa B (NFkappaB), mitogen-activated protein kinase (MAPK; P < 0.05) and AKT (P < 0.01) are suppressed by BRB (Figure 4).	('NFkappaB', 'Gene', (57, 65))	('NFkappaB', 'Gene', '4790', (57, 65))	('mitogen-activated', 'Protein', (68, 85))	('phosphorylation', 'MPA', (14, 29))	('BRB', 'Var', (155, 158))	('AKT', 'Pathway', (122, 125))	('suppressed', 'NegReg', (141, 151))
656892	28553369	As indicated in Figures 5A to 5C, BRB anthocyanins (C3R, C3G, C3S and P3R), cyanidin and pelargonidin anthocyanin metabolites (PCA and 4HBA), celecoxib and PBIT, inhibit KYSE-270 cell proliferation in a dose-dependent manner.	('KYSE-270 cell proliferation', 'CPA', (170, 197))	('rat', 'Species', '10116', (191, 194))	('anthocyanin', 'Chemical', 'MESH:D000872', (102, 113))	('C3G', 'Chemical', 'MESH:C114438', (57, 60))	('P3R', 'Chemical', '-', (70, 73))	('4HBA', 'Chemical', 'MESH:C038193', (135, 139))	('C3G', 'Var', (57, 60))	('cyanidin', 'Chemical', 'MESH:C017154', (76, 84))	('P3R', 'Var', (70, 73))	('PBIT', 'Chemical', 'MESH:C118852', (156, 160))	('celecoxib', 'Chemical', 'MESH:D000068579', (142, 151))	('anthocyanins', 'Chemical', 'MESH:D000872', (38, 50))	('C3S', 'Chemical', '-', (62, 65))	('C3R', 'Chemical', 'MESH:C428983', (52, 55))	('KYSE-270', 'CellLine', 'CVCL:1350', (170, 178))	('anthocyanin', 'Chemical', 'MESH:D000872', (38, 49))	('pelargonidin', 'Chemical', 'MESH:C066957', (89, 101))	('inhibit', 'NegReg', (162, 169))	('C3S', 'Var', (62, 65))	('PCA', 'Chemical', 'MESH:C009091', (127, 130))
656894	28553369	As indicated in Figure 5E, C3R downregulates COX-2 and iNOS protein, and suppresses the activation of extracellular receptor kinase (ERK) and AKT.	('C3R', 'Var', (27, 30))	('ERK', 'Gene', '5594', (133, 136))	('ERK', 'Gene', (133, 136))	('iNOS protein', 'Protein', (55, 67))	('C3R', 'Chemical', 'MESH:C428983', (27, 30))	('downregulates', 'NegReg', (31, 44))	('COX-2', 'Protein', (45, 50))	('AKT', 'Pathway', (142, 145))	('suppresses', 'NegReg', (73, 83))
656896	28553369	At the IC50 value shown in Figure 5F, C3R decreases the protein expression levels of p-ERK, p-AKT, COX-2 and iNOS.	('ERK', 'Gene', (87, 90))	('ERK', 'Gene', '5594', (87, 90))	('C3R', 'Var', (38, 41))	('decreases', 'NegReg', (42, 51))	('iNOS', 'MPA', (109, 113))	('p-AKT', 'MPA', (92, 97))	('C3R', 'Chemical', 'MESH:C428983', (38, 41))	('protein expression levels', 'MPA', (56, 81))	('COX-2', 'MPA', (99, 104))
656916	28553369	In this study, we found that C3R inhibits cell proliferation, downregulates COX-2 and iNOS, and suppresses the activation of ERK and AKT in KYSE-270 cells.	('C3R', 'Var', (29, 32))	('ERK', 'Gene', '5594', (125, 128))	('COX-2', 'Gene', (76, 81))	('AKT', 'Pathway', (133, 136))	('C3R', 'Chemical', 'MESH:C428983', (29, 32))	('ERK', 'Gene', (125, 128))	('cell proliferation', 'CPA', (42, 60))	('KYSE-270', 'CellLine', 'CVCL:1350', (140, 148))	('rat', 'Species', '10116', (54, 57))	('inhibits', 'NegReg', (33, 41))	('downregulates', 'NegReg', (62, 75))	('iNOS', 'Protein', (86, 90))	('suppresses', 'NegReg', (96, 106))
656918	28553369	We observed a reduction on protein expression of COX-2 and iNOS by celecoxib and PBIT when its dose was increased to IC50 value.	('celecoxib', 'Var', (67, 76))	('iNOS', 'Gene', (59, 63))	('protein expression', 'MPA', (27, 45))	('COX-2', 'Enzyme', (49, 54))	('PBIT', 'Chemical', 'MESH:C118852', (81, 85))	('reduction', 'NegReg', (14, 23))	('celecoxib', 'Chemical', 'MESH:D000068579', (67, 76))
656976	28123302	PET/CT-based GTVs of the primary tumor were automatically contoured by using nine different methods: SUV >=2.0, >=2.5, >=3.0, >=3.5; >=20%, >=25%, >=30%, >=35%, >=40% of the maximum SUVmax, and visual contouring.	('>=30%', 'Var', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('GTV', 'Chemical', '-', (13, 16))	('>=20%', 'Var', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('>=35%', 'Var', (154, 159))	('tumor', 'Disease', (33, 38))	('>=25%', 'Var', (140, 145))
656980	28123302	Then target centroid shift in the left-right (LR), anterior-posterior (AP), and cranial-caudal (CC) directions between GTVPET and IGTV10 was obtained as Deltax, Deltay, and Deltaz, respectively.	('GTVPET', 'Gene', (119, 125))	('GTV', 'Chemical', '-', (119, 122))	('Deltax', 'Var', (153, 159))	('Deltaz', 'Var', (173, 179))	('Deltay', 'Var', (161, 167))	('IGTV10', 'Gene', (130, 136))	('GTV', 'Chemical', '-', (131, 134))
656993	28123302	Wang et al compared GTV determined from average 4DPET and average 4DCT, and proved that GTVPET at SUV2.5, SUV20% correlated well with GTVCT in tumor length, VR, and CI, but the CIs (0.58, 0.57) were also not ideal.	('GTV', 'Chemical', '-', (88, 91))	('tumor', 'Disease', (143, 148))	('SUV20%', 'Var', (106, 112))	('GTV', 'Chemical', '-', (134, 137))	('GTV', 'Chemical', '-', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
656997	28123302	First, considering that the change of tumor geometry or size and a potential increase in the likelihood of a mismatch between IGTV10 and GTVPET because of the treatment or long time interval during PET-CT and 4DCT, all the patients enrolled in this study performed PET-CT and 4DCT simulation scans on the same day without any treatment.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('GTVPET', 'Gene', (137, 143))	('change', 'Reg', (28, 34))	('GTV', 'Chemical', '-', (137, 140))	('GTV', 'Chemical', '-', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('mismatch', 'Var', (109, 117))	('patients', 'Species', '9606', (223, 231))	('IGTV10', 'Gene', (126, 132))
657097	27187472	Leaves extracts of Shepherdia argentea:a deciduous shrub commonly known as silver buffaloberry:were reported as a good reserve of gluconic acid core carrying the potential anti-HIV novel ET, such as hippophaenin A, shephagenin A and shephagenin B. Tannins are unique secondary metabolites of plant phenolics with relatively higher molecular weight (300-30,000 Da) and bear the ability to generate complexes with some macromolecules, like proteins and carbohydrates.	('higher', 'PosReg', (324, 330))	('rat', 'Species', '10116', (392, 395))	('carbohydrates', 'Chemical', 'MESH:D002241', (451, 464))	('phenolics', 'Chemical', '-', (298, 307))	('Shepherdia argentea', 'Species', '72158', (19, 38))	('rat', 'Species', '10116', (459, 462))	('gluconic acid', 'Chemical', 'MESH:C030691', (130, 143))	('proteins', 'Protein', (438, 446))	('ET,', 'Chemical', 'MESH:D047348', (187, 190))	('I', 'Chemical', 'MESH:D007455', (178, 179))	('complexes', 'Interaction', (397, 406))	('300-30,000', 'Var', (349, 359))
657104	27187472	ETs (hydrolysable tannins) on their hydrolysis yield gallic acid and ellagic acid from the compounds carrying gallyol groups and HHDP groups, respectively.	('gallyol groups', 'Var', (110, 124))	('tannins', 'Chemical', 'MESH:D013634', (18, 25))	('HHDP', 'Chemical', '-', (129, 133))	('gallic acid', 'Chemical', 'MESH:D005707', (53, 64))	('ET', 'Chemical', 'MESH:D047348', (0, 2))	('ellagic acid', 'Chemical', 'MESH:D004610', (69, 81))	('gallic acid', 'MPA', (53, 64))	('ellagic acid', 'MPA', (69, 81))	('hydrolysis', 'MPA', (36, 46))
657115	27187472	Variation in HHDP group originates by linking (C-C or C-O) one or more galloyl groups to HHDP unit.	('C-C', 'Var', (47, 50))	('HHDP', 'Chemical', '-', (13, 17))	('C-O', 'Var', (54, 57))	('HHDP', 'Chemical', '-', (89, 93))	('galloyl', 'Protein', (71, 78))	('linking', 'Interaction', (38, 45))
657207	27187472	Targeting the PI3K pathway with small molecule inhibitors has been studied for therapeutic purposes, and inhibitors such as GDC-0941 or GDC-0980 have entered preclinical trials.	('GDC-0941', 'Var', (124, 132))	('I', 'Chemical', 'MESH:D007455', (15, 16))	('GDC-0941', 'Chemical', 'MESH:C532162', (124, 132))	('GDC-0980', 'Var', (136, 144))	('GDC-0980', 'Chemical', 'MESH:C569670', (136, 144))	('PI3K pathway', 'Pathway', (14, 26))
657228	27187472	Lyophilized strawberries (LS), which carry 42.9% ET and their derivatives and 48.8% anthocyanins, have been referred as an effective option to prevent oral carcinogenesis: indeed a diet containing 5% LS reduced the number of 7,12-dimethylbenz[a]anthracene (DMBA)-induced cheek pouch tumors in hamsters inhibiting Ras/Raf/ERK-dependent cell proliferation, VEGF-dependent angiogenesis, 5-LOX/LTB4 pathway, and prevented oxidative damage; LS was also found to modulate the genetic signature related to DMBA-induced tumor development, such as p13Arf, p16, p53, and Bcl-2.	('hamster', 'Species', '10034', (293, 300))	('VEGF', 'Gene', (355, 359))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('p13Arf', 'Var', (539, 545))	('Bcl-2', 'Gene', (561, 566))	('reduced', 'NegReg', (203, 210))	('tumor', 'Disease', (512, 517))	('ERK', 'Gene', (321, 324))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('tumor', 'Disease', 'MESH:D009369', (512, 517))	('modulate', 'Reg', (457, 465))	('Bcl-2', 'Gene', '596', (561, 566))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('tumors', 'Disease', (283, 289))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (151, 170))	('Raf', 'Gene', (317, 320))	('rat', 'Species', '10116', (347, 350))	('tumor', 'Phenotype', 'HP:0002664', (512, 517))	('p16', 'Gene', (547, 550))	('inhibiting', 'NegReg', (302, 312))	('oral carcinogenesis', 'Disease', (151, 170))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('p53', 'Gene', '7157', (552, 555))	('p16', 'Gene', '1029', (547, 550))	('anthocyanins', 'Chemical', 'MESH:D000872', (84, 96))	('ERK', 'Gene', '5594', (321, 324))	('Raf', 'Gene', '22882', (317, 320))	('VEGF', 'Gene', '7422', (355, 359))	('ET', 'Chemical', 'MESH:D047348', (49, 51))	('tumor', 'Disease', (283, 288))	('p53', 'Gene', (552, 555))
657229	27187472	In the same experimental model of hamster buccal pouch carcinoma, it was demonstrated that dietary supplementation of ellagic acid (up to 0.4%) modulated the expression profiles of 37 genes involved in DMBA-induced oral carcinogenesis, blocked the development of carcinomas by suppression of Wnt/beta-catenin signaling associated with the inactivation of NF-kappaB and modulation of key components of the mitochondrial apoptotic network, and prevented angiogenesis by abrogating hypoxia-driven PI3K/Akt/mTOR, MAPK, and VEGF/VEGFR2 signaling pathways.	('carcinoma', 'Disease', 'MESH:D002277', (55, 64))	('Akt', 'Gene', (499, 502))	('beta-catenin', 'Gene', (296, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('hypoxia', 'Disease', (479, 486))	('blocked', 'NegReg', (236, 243))	('VEGF', 'Gene', '7422', (519, 523))	('carcinomas', 'Phenotype', 'HP:0030731', (263, 273))	('beta-catenin', 'Gene', '1499', (296, 308))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('carcinomas', 'Disease', 'MESH:D002277', (263, 273))	('Akt', 'Gene', '207', (499, 502))	('carcinoma', 'Disease', (263, 272))	('ellagic acid', 'Chemical', 'MESH:D004610', (118, 130))	('VEGF', 'Gene', (519, 523))	('hypoxia', 'Disease', 'MESH:D000860', (479, 486))	('rat', 'Species', '10116', (80, 83))	('inactivation', 'Var', (339, 351))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (215, 234))	('MAPK', 'Gene', (509, 513))	('suppression', 'NegReg', (277, 288))	('prevented', 'NegReg', (442, 451))	('modulated', 'Reg', (144, 153))	('NF-kappaB', 'Gene', (355, 364))	('VEGF', 'Gene', '7422', (524, 528))	('modulation', 'Reg', (369, 379))	('carcinoma', 'Disease', 'MESH:D002277', (263, 272))	('MAPK', 'Gene', '5594', (509, 513))	('oral carcinogenesis', 'Disease', (215, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('NF-kappaB', 'Gene', '4790', (355, 364))	('VEGF', 'Gene', (524, 528))	('carcinomas', 'Disease', (263, 273))	('angiogenesis', 'CPA', (452, 464))	('carcinoma', 'Disease', (55, 64))	('hamster', 'Species', '10034', (34, 41))	('abrogating', 'NegReg', (468, 478))	('expression profiles', 'MPA', (158, 177))	('I', 'Chemical', 'MESH:D007455', (495, 496))
657248	27187472	Furthermore, thonningianin A significantly downregulated the NF-kappaB cell survival pathway concomitantly with the upregulation of the expression level of phosphorylated P38 and downregulation of the expression level of phosphorylated ERK.	('thonningianin A', 'Chemical', 'MESH:C411320', (13, 28))	('P38', 'Gene', (171, 174))	('downregulated', 'NegReg', (43, 56))	('thonningianin', 'Var', (13, 26))	('ERK', 'Gene', '5594', (236, 239))	('P38', 'Gene', '1432', (171, 174))	('expression level', 'MPA', (201, 217))	('NF-kappaB', 'Gene', (61, 70))	('ERK', 'Gene', (236, 239))	('downregulation', 'NegReg', (179, 193))	('upregulation', 'PosReg', (116, 128))	('expression level', 'MPA', (136, 152))	('NF-kappaB', 'Gene', '4790', (61, 70))
657281	27187472	Animal studies further confirmed the chemopreventive and anticancer activity of ET-rich pomegranate extract: in a UVB initiation-promotion protocol, SKH-1 hairless mice receiving oral pomegranate extract supplementation showed reduced tumor incidence, prolonged latency periods of tumor appearance, and lower tumor body burden compared to that of unsupplemented UVB-irradiated control animals.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('reduced', 'NegReg', (227, 234))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (281, 286))	('mice', 'Species', '10090', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Disease', (309, 314))	('latency periods', 'CPA', (262, 277))	('SKH-1 hairless', 'Disease', 'MESH:C565162', (149, 163))	('cancer', 'Disease', (61, 67))	('lower', 'NegReg', (303, 308))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (235, 240))	('pomegranate', 'Species', '22663', (184, 195))	('ET', 'Chemical', 'MESH:D047348', (80, 82))	('pomegranate', 'Species', '22663', (88, 99))	('SKH-1 hairless', 'Disease', (149, 163))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('supplementation', 'Var', (204, 219))
657285	27187472	In Chinese hamster B14 cells, ellagic acid and gallic acid caused the production of DNA single-strand breaks with no relation to the concentration used, cytotoxic effects and increased lipid bilayer fluidity, an event which the authors suggested as contributing to DNA single-strand breakage.	('Chinese hamster', 'Species', '10029', (3, 18))	('lipid', 'MPA', (185, 190))	('ellagic acid', 'Chemical', 'MESH:D004610', (30, 42))	('lipid', 'Chemical', 'MESH:D008055', (185, 190))	('rat', 'Species', '10116', (140, 143))	('increased lipid', 'Phenotype', 'HP:0003077', (175, 190))	('increased', 'PosReg', (175, 184))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('gallic acid', 'Chemical', 'MESH:D005707', (47, 58))	('DNA single-strand breaks', 'MPA', (84, 108))	('ellagic acid', 'Var', (30, 42))
657296	27187472	For example, a 90-day sub-chronic toxicity study performed in F344 rats showed that ellagic acid NOEL was 3011 mg/kg b.w./day for males and the NOAEL and NOEL in females were 3254 mg/kg b.w./day and <=778 mg/kg b.w./day, respectively, and there were no obvious histopathological changes in any of the groups.	('rats', 'Species', '10116', (67, 71))	('3011 mg/kg', 'Var', (106, 116))	('toxicity', 'Disease', 'MESH:D064420', (34, 42))	('toxicity', 'Disease', (34, 42))	('ellagic acid', 'Chemical', 'MESH:D004610', (84, 96))
657351	25963088	Univariate analysis showed that the presence of ESCC, male gender, older age, higher BMI, and higher serum triglyceride level were significant risk factors for CRN.	('CRN', 'Disease', (160, 163))	('ESCC', 'Gene', (48, 52))	('serum triglyceride level', 'MPA', (101, 125))	('higher serum triglyceride level', 'Phenotype', 'HP:0002155', (94, 125))	('presence', 'Var', (36, 44))	('BMI', 'MPA', (85, 88))	('higher', 'PosReg', (94, 100))	('triglyceride', 'Chemical', 'MESH:D014280', (107, 119))
657352	25963088	In patients with advanced CRN, univariate analysis showed that the presence of ESCC, older age, history of diabetes, and serum total cholesterol level were significant risk factors.	('diabetes', 'Disease', (107, 115))	('cholesterol', 'Chemical', 'MESH:D002784', (133, 144))	('diabetes', 'Disease', 'MESH:D003920', (107, 115))	('presence', 'Var', (67, 75))	('patients', 'Species', '9606', (3, 11))	('ESCC', 'Disease', (79, 83))	('serum total cholesterol level', 'MPA', (121, 150))
657354	25963088	In the univariate analysis, the ESCC patients with CRN were significantly older than were those without CRN, but this difference was not significant in the multivariate analysis.	('CRN', 'Var', (51, 54))	('ESCC', 'Disease', (32, 36))	('patients', 'Species', '9606', (37, 45))
657356	25963088	When the CRN risk in ESCC patients who were at stage T1N0 were compared with controls, subjects with T1N0 had a significantly higher risk of CRN (OR, 3.347; 95% CI, 1.331 to 8.420; p=0.010).	('higher', 'PosReg', (126, 132))	('ESCC', 'Disease', (21, 25))	('patients', 'Species', '9606', (26, 34))	('CRN', 'CPA', (141, 144))	('T1N0', 'Var', (101, 105))	('CRN', 'CPA', (9, 12))
657413	22847786	Other requirements included age 18-75, Zubrod performance status (PS) of 0-2, absolute neutrophil count (ANC) >=1,500/mm3, platelet count >= 100,000/mm3, creatinine clearance >=60 ml/min per the Cockcroft-Gault equation, total bilirubin <=1.5x the institutional upper limit of normal, and SGOT/SGPT <=2.5x the upper limit of normal.	('creatinine', 'Chemical', 'MESH:D003404', (154, 164))	('total bilirubin', 'MPA', (221, 236))	('SGOT/SGPT', 'MPA', (289, 298))	('bilirubin', 'Chemical', 'MESH:D001663', (227, 236))	('>=60', 'Var', (175, 179))	('creatinine clearance', 'MPA', (154, 174))
657417	22847786	Within the three-dimensional conformal treatment planning system, a gross tumor volume (GTV) was created based on abnormalities noted in the esophagus, proximal stomach, and regional lymph nodes on pretreatment diagnostic upper endoscopy, CT scan and barium swallow.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('abnormalities', 'Var', (114, 127))	('abnormalities noted in the esophagus', 'Phenotype', 'HP:0002031', (114, 150))	('tumor', 'Disease', (74, 79))	('barium', 'Chemical', 'MESH:D001464', (251, 257))
657472	22847786	Neoangiogenesis is a vital process in malignancy and inhibitors of pro-angiogenic cytokines such as VEGF have demonstrated a clinical benefit in a wide range of solid tumors.	('inhibitors', 'Var', (53, 63))	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('Neoangiogenesis', 'CPA', (0, 15))	('solid tumors', 'Disease', (161, 173))	('malignancy', 'Disease', (38, 48))	('benefit', 'PosReg', (134, 141))	('solid tumors', 'Disease', 'MESH:D009369', (161, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('VEGF', 'Gene', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
657542	25123079	With NOD2 deficiency, dysbiosis alone was sufficient for CRC development in mice.	('CRC', 'Phenotype', 'HP:0003003', (57, 60))	('CRC development', 'CPA', (57, 72))	('mice', 'Species', '10090', (76, 80))	('NOD2', 'Gene', (5, 9))	('deficiency', 'Var', (10, 20))	('dysbiosis', 'Disease', (22, 31))	('dysbiosis', 'Disease', 'MESH:D064806', (22, 31))
657543	25123079	reveals that NOD2-associated dysbiosis can be overcome by co-housing NOD2 mutants with wild type mice.	('NOD2', 'Gene', (69, 73))	('NOD2-associated', 'Gene', (13, 28))	('mice', 'Species', '10090', (97, 101))	('dysbiosis', 'Disease', (29, 38))	('dysbiosis', 'Disease', 'MESH:D064806', (29, 38))	('mutants', 'Var', (74, 81))
657586	25123079	Eradication of H. pylori has been shown to correlate with a decrease in incidence of gastric cancer.	('decrease', 'NegReg', (60, 68))	('gastric cancer', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Eradication', 'Var', (0, 11))	('H. pylori', 'Gene', (15, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))	('H. pylori', 'Species', '210', (15, 24))
657595	25123079	In infected mucosa, H. pylori phosphorylates RKIP, removing apoptotic control and inducing proliferation by removing control of the cell cycle.	('RKIP', 'Gene', (45, 49))	('H. pylori', 'Species', '210', (20, 29))	('proliferation', 'CPA', (91, 104))	('infected mucosa', 'Disease', 'MESH:D018442', (3, 18))	('apoptotic control', 'MPA', (60, 77))	('infected mucosa', 'Disease', (3, 18))	('rat', 'Species', '10116', (98, 101))	('control', 'MPA', (117, 124))	('inducing', 'PosReg', (82, 90))	('H. pylori', 'Var', (20, 29))	('removing', 'NegReg', (51, 59))	('removing', 'NegReg', (108, 116))	('RKIP', 'Gene', '5037', (45, 49))
657601	25123079	However, in tumors that do not involve the gastric cardia, H. pylori is associated with a lowered risk of tumor development.	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('H. pylori', 'Var', (59, 68))	('H. pylori', 'Species', '210', (59, 68))	('gastric cardia', 'Disease', (43, 57))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('gastric cardia', 'Disease', 'MESH:D004938', (43, 57))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', (12, 18))	('tumor', 'Disease', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('lowered', 'NegReg', (90, 97))	('tumor', 'Disease', (106, 111))
657614	25123079	In addition, bile culture-positivity is associated with increase in gallbladder carcinogenesis, especially positivity for the Vi antigen (a capsular antigen associated with Salmonella).	('gallbladder carcinogenesis', 'Disease', (68, 94))	('positivity', 'Var', (107, 117))	('increase', 'PosReg', (56, 64))	('gallbladder carcinogenesis', 'Disease', 'MESH:D063646', (68, 94))
657640	25123079	Recent evidence points to bacteria in Clostridium cluster IX as a possible source of increased DCA and cancer risk in obese mice.	('obese', 'Disease', 'MESH:D009765', (118, 123))	('bacteria', 'Var', (26, 34))	('DCA', 'Chemical', 'MESH:D003999', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('obese', 'Disease', (118, 123))	('Clostridium', 'Species', '1496', (38, 49))	('mice', 'Species', '10090', (124, 128))	('DCA', 'Disease', (95, 98))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
657777	24139225	G3 neutropenia was more common in docetaxel-based group, where occurred in 11 out of 44 patients (36.7%) compared with 6 out of 39 patients (23.1%) in cisplatin plus 5-Fu group.	('patients', 'Species', '9606', (131, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('neutropenia', 'Disease', 'MESH:D009503', (3, 14))	('patients', 'Species', '9606', (88, 96))	('neutropenia', 'Phenotype', 'HP:0001875', (3, 14))	('5-Fu', 'Chemical', 'MESH:D005472', (166, 170))	('docetaxel-based', 'Var', (34, 49))	('neutropenia', 'Disease', (3, 14))	('docetaxel', 'Chemical', 'MESH:D000077143', (34, 43))
657785	24139225	reported that the OS of all 73 recurrent ESCC patients was 46.7% and 4.7% at 1 and 3 years respectively, and patients receiving CCRT had better OS than those receiving RT alone with 1-year OS 62.5% in CCRT group vs. 33.8% in RT alone group, 3-year OS 10.5% in CCRT group vs. 0% in RT alone group .	('CR', 'Chemical', '-', (261, 263))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (109, 117))	('OS', 'Chemical', '-', (189, 191))	('OS', 'Chemical', '-', (248, 250))	('SCC', 'Gene', (42, 45))	('OS', 'Chemical', '-', (18, 20))	('SCC', 'Gene', '6317', (42, 45))	('CCRT', 'Var', (128, 132))	('CR', 'Chemical', '-', (129, 131))	('OS', 'Chemical', '-', (144, 146))	('CR', 'Chemical', '-', (202, 204))
657792	24139225	Although clinical CR after CCRT may not be significantly correlated to pathologic CR , maximizing the CR rate is likely to increase the proportion of patients with most favorable outcome and potentially affect survival of the group as a whole.	('CR', 'Chemical', '-', (28, 30))	('CR', 'Chemical', '-', (18, 20))	('CR', 'Chemical', '-', (82, 84))	('patients', 'Species', '9606', (150, 158))	('affect', 'Reg', (203, 209))	('CR', 'Chemical', '-', (102, 104))	('maximizing', 'Var', (87, 97))
657812	24139225	This might because the anastomotic recurrence is more likely to cause dysphagia and be diagnosed earlier.	('cause', 'Reg', (64, 69))	('dysphagia', 'Disease', (70, 79))	('anastomotic', 'Var', (23, 34))	('dysphagia', 'Phenotype', 'HP:0002015', (70, 79))	('dysphagia', 'Disease', 'MESH:D003680', (70, 79))
657837	33579377	With the further understanding of miRNAs, researchers find miRNAs can function as oncogenes or tumor suppressors to modulate tumor cell proliferation, apoptosis, immune response, and reshape microenvronment.	('miRNAs', 'Var', (59, 65))	('immune response', 'CPA', (162, 177))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('modulate', 'Reg', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('apoptosis', 'CPA', (151, 160))	('tumor', 'Disease', (95, 100))
657841	33579377	Loss of E-cadherin has been recognized to be related to cancer metastasis and the poor prognosis since nearly 20 years ago, then how to activate EMT draws considerable attention.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('related', 'Reg', (45, 52))	('cancer', 'Disease', (56, 62))	('Loss', 'Var', (0, 4))
657864	33579377	However, how the precursor of miR-514 becomes the mature miR-514b-3p and miR-514b-5p with distinct roles remains to be further investigated.	('miR-514', 'Var', (30, 37))	('miR-514b', 'Gene', (73, 81))	('miR-514b', 'Gene', '100422847', (57, 65))	('miR-514b', 'Gene', (57, 65))	('miR-514b', 'Gene', '100422847', (73, 81))
657881	33579377	Furthermore, miR-138-5p that can be downregulated by TGF-beta also targets vimentin to enhance the chemosensitivity to 5-FU in pancreatic cancer.	('TGF-beta', 'Gene', '7039', (53, 61))	('pancreatic cancer', 'Disease', (127, 144))	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('targets', 'Reg', (67, 74))	('chemosensitivity to 5-FU', 'MPA', (99, 123))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('enhance', 'PosReg', (87, 94))	('vimentin', 'Gene', (75, 83))	('vimentin', 'Gene', '7431', (75, 83))	('miR-138-5p', 'Chemical', '-', (13, 23))	('miR-138-5p', 'Var', (13, 23))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('TGF-beta', 'Gene', (53, 61))	('downregulated', 'NegReg', (36, 49))
657882	33579377	It was reported that miR-30a, miR-153, and miR-363 all targeted Snail to enhance chemotherapy sensitivity.	('Snail', 'Gene', (64, 69))	('miR-363', 'Gene', '574031', (43, 50))	('miR-30a', 'Gene', (21, 28))	('Snail', 'Gene', '6615', (64, 69))	('miR-153', 'Var', (30, 37))	('enhance', 'PosReg', (73, 80))	('miR-363', 'Gene', (43, 50))	('chemotherapy sensitivity', 'CPA', (81, 105))	('miR-30a', 'Gene', '407029', (21, 28))
657886	33579377	Twist, another key EMT-TF, can be suppressed by miR-181a with the increased cisplatin sensitivity simultaneously.	('miR-181a', 'Var', (48, 56))	('Twist', 'Gene', '7291', (0, 5))	('increased', 'PosReg', (66, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('Twist', 'Gene', (0, 5))	('suppressed', 'NegReg', (34, 44))	('cisplatin sensitivity', 'MPA', (76, 97))
657888	33579377	As for ZEB, miR-708-3p acts as a ZEB1 suppressor to increase drug resistance in breast cancer.	('miR-708-3p', 'Chemical', '-', (12, 22))	('ZEB', 'Gene', (33, 36))	('ZEB1', 'Gene', (33, 37))	('drug resistance', 'MPA', (61, 76))	('ZEB', 'Gene', (7, 10))	('increase', 'PosReg', (52, 60))	('ZEB1', 'Gene', '6935', (33, 37))	('ZEB', 'Gene', '9839', (33, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('ZEB', 'Gene', '9839', (7, 10))	('drug resistance', 'Phenotype', 'HP:0020174', (61, 76))	('miR-708-3p', 'Var', (12, 22))
657898	33579377	Overexpression of miR-25-3p and miR-31-3p can target Semaphorin 4 C to reverse EMT in cisplatin-resistance cervical cancer cells.	('miR-31', 'Gene', '407035', (32, 38))	('cancer', 'Disease', (116, 122))	('reverse', 'PosReg', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('miR-25-3p', 'Var', (18, 27))	('Semaphorin 4 C', 'Gene', '54910', (53, 67))	('cisplatin-resistance', 'MPA', (86, 106))	('miR-31', 'Gene', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Semaphorin 4 C', 'Gene', (53, 67))
657902	33579377	It was found that miR-296-3p could suppress the expression of MAPK activated protein kinase 2 to inhibit the Ras/Braf/Erk/Mek/c-Myc pathway, ultimately reversing the chemoresistance in NPC.	('c-Myc', 'Gene', (126, 131))	('inhibit', 'NegReg', (97, 104))	('chemoresistance', 'CPA', (166, 181))	('NPC', 'Disease', (185, 188))	('miR-296-3p', 'Var', (18, 28))	('Mek', 'Gene', (122, 125))	('Braf', 'Gene', (113, 117))	('expression', 'MPA', (48, 58))	('Erk', 'Gene', (118, 121))	('Braf', 'Gene', '673', (113, 117))	('Mek', 'Gene', '5609', (122, 125))	('MAPK activated protein kinase 2', 'Gene', (62, 93))	('reversing', 'NegReg', (152, 161))	('c-Myc', 'Gene', '4609', (126, 131))	('MAPK activated protein kinase 2', 'Gene', '9261', (62, 93))	('Erk', 'Gene', '5594', (118, 121))	('miR-296-3p', 'Chemical', '-', (18, 28))	('suppress', 'NegReg', (35, 43))
657903	33579377	In lung adenocarcinoma, miR-296-3p also contributes to the inhibition of Ras, leading to the increased chemotherapy sensitivity.	('inhibition', 'NegReg', (59, 69))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('increased', 'PosReg', (93, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('Ras', 'Protein', (73, 76))	('miR-296-3p', 'Chemical', '-', (24, 34))	('chemotherapy sensitivity', 'MPA', (103, 127))	('miR-296-3p', 'Var', (24, 34))	('lung adenocarcinoma', 'Disease', (3, 22))
657905	33579377	Intriguingly, miR-95 knockdown could repress EMT and CSCs phenotype through dual specificity phosphatase 5-dependent MAPK pathway.	('knockdown', 'Var', (21, 30))	('repress', 'NegReg', (37, 44))	('miR-95', 'Gene', '407052', (14, 20))	('miR-95', 'Gene', (14, 20))
657908	33579377	For example, derived from intestinal epithelial cells, exosomal miR-128-3p shows the outstanding capability to increase chemosensitivity to oxaliplatin in colorectal cancer.	('chemosensitivity to oxaliplatin', 'MPA', (120, 151))	('increase', 'PosReg', (111, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('miR-128-3p', 'Var', (64, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('colorectal cancer', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (140, 151))	('miR-128-3p', 'Chemical', '-', (64, 74))
657909	33579377	Mechanically, miR-128-3p can prevent the efflux of oxaliplatin via repressing the drug transporter multidrug resistant protein 5 and reverse the oxaliplatin-induced EMT.	('drug transporter multidrug resistant protein 5', 'MPA', (82, 128))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (51, 62))	('oxaliplatin-induced', 'MPA', (145, 164))	('repressing', 'NegReg', (67, 77))	('miR-128-3p', 'Chemical', '-', (14, 24))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (145, 156))	('miR-128-3p', 'Var', (14, 24))	('reverse', 'NegReg', (133, 140))	('prevent', 'NegReg', (29, 36))	('efflux of oxaliplatin', 'MPA', (41, 62))
657911	33579377	Apart from promoting EMT that is aforementioned, miR-125b can directly regulate CSCs phenotype to induce chemoresistance.	('CSCs', 'CPA', (80, 84))	('induce', 'PosReg', (98, 104))	('regulate', 'Reg', (71, 79))	('chemoresistance', 'CPA', (105, 120))	('miR-125b', 'Var', (49, 57))	('miR-125b', 'Chemical', '-', (49, 57))
657912	33579377	observed the phenomenon that miR-125b confers the chemoresistant capability of breast cancer by maintaining CSCs state.	('CSCs state', 'MPA', (108, 118))	('miR-125b', 'Chemical', '-', (29, 37))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('chemoresistant capability', 'CPA', (50, 75))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('miR-125b', 'Var', (29, 37))	('maintaining', 'PosReg', (96, 107))
657914	33579377	found miR-455-3p as an oncomiR can maintain CSCs state to reinforce the chemoresistance in esophageal cancer by activating Wnt/beta-catenin and TGF-beta signaling.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TGF-beta', 'Gene', '7039', (144, 152))	('cancer', 'Disease', (102, 108))	('miR-455-3p', 'Chemical', '-', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('beta-catenin', 'Gene', (127, 139))	('beta-catenin', 'Gene', '1499', (127, 139))	('miR-455-3p', 'Var', (6, 16))	('reinforce', 'PosReg', (58, 67))	('chemoresistance', 'CPA', (72, 87))	('TGF-beta', 'Gene', (144, 152))	('activating', 'PosReg', (112, 122))
657915	33579377	Remarkably, treatment with the miR-455-3p antagomir significantly sensitized esophageal cancer in vitro, which provided a novel therapeutic strategy for esophageal cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('sensitized', 'Reg', (66, 76))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('miR-455-3p', 'Chemical', '-', (31, 41))	('miR-455-3p', 'Var', (31, 41))
657931	33579377	MiR-9-5p, miR-195-5p, and miR-203a-3p carried by exosomes all target One Cut Homeobox 2 (ONECUT2) to enhance the stemness of breast cancer.	('stemness of breast cancer', 'Disease', (113, 138))	('One Cut Homeobox 2', 'Gene', (69, 87))	('MiR-9-5p', 'Gene', (0, 8))	('stemness of breast cancer', 'Disease', 'MESH:D001943', (113, 138))	('miR-203a-3p', 'Var', (26, 37))	('miR-195', 'Gene', (10, 17))	('miR-195', 'Gene', '406971', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('One Cut Homeobox 2', 'Gene', '9480', (69, 87))	('ONECUT2', 'Gene', (89, 96))	('enhance', 'PosReg', (101, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('MiR-9-5p', 'Gene', '407052', (0, 8))	('ONECUT2', 'Gene', '9480', (89, 96))
657938	33579377	Therefore, the blockage of the TGF-beta pathway may be an effective approach in preventing the initiation of EMT and overcome drug resistance.	('TGF-beta', 'Gene', (31, 39))	('preventing', 'NegReg', (80, 90))	('drug resistance', 'Phenotype', 'HP:0020174', (126, 141))	('blockage', 'Var', (15, 23))	('initiation of EMT', 'CPA', (95, 112))	('TGF-beta', 'Gene', '7039', (31, 39))
657950	33579377	It was found that Axl was significantly upregulated during the process of EMT and knockdown of Axl by siRNA inhibited the metastasis and increased the overall survival in breast cancer.	('overall survival', 'CPA', (151, 167))	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('Axl', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('Axl', 'Gene', (95, 98))	('Axl', 'Gene', '558', (18, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('knockdown', 'Var', (82, 91))	('increased', 'PosReg', (137, 146))	('metastasis', 'CPA', (122, 132))	('Axl', 'Gene', '558', (95, 98))	('inhibited', 'NegReg', (108, 117))	('upregulated', 'PosReg', (40, 51))
657956	33579377	The downregulation of miR-129-5p and miR-532-3p are associated with the poor prognosis in manifold cancer types, which are involved in the EMT program.	('miR-532-3p', 'Var', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('miR-129-5p', 'Gene', (22, 32))	('miR-129-5p', 'Gene', '100302178', (22, 32))	('cancer', 'Disease', (99, 105))	('downregulation', 'NegReg', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
657957	33579377	used miR-129-5p and miR-532-3p mimics, respectively, to enhance the chemosensitivity in vivo.	('miR-532-3p mimics', 'Var', (20, 37))	('enhance', 'PosReg', (56, 63))	('miR-129-5p', 'Gene', (5, 15))	('miR-129-5p', 'Gene', '100302178', (5, 15))	('chemosensitivity', 'CPA', (68, 84))
657959	33579377	On the contrary, miR-224 is responsible for the poor response of 5-FU, and silencing miR-224 by antagomir achieves the desired effect in colorectal cancer cells.	('colorectal cancer', 'Disease', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('5-FU', 'Chemical', 'MESH:D005472', (65, 69))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('miR-224', 'Gene', '407009', (85, 92))	('miR-224', 'Gene', (85, 92))	('miR-224', 'Gene', '407009', (17, 24))	('silencing', 'Var', (75, 84))	('miR-224', 'Gene', (17, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))
657968	30881375	Dietary Compounds as Epigenetic Modulating Agents in Cancer Epigenetic mechanisms control gene expression during normal development and their aberrant regulation may lead to human diseases including cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Cancer', 'Disease', 'MESH:D009369', (53, 59))	('human', 'Species', '9606', (174, 179))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('control', 'Reg', (82, 89))	('aberrant regulation', 'Var', (142, 161))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('gene expression', 'MPA', (90, 105))	('cancer', 'Disease', (199, 205))	('lead to', 'Reg', (166, 173))	('human diseases', 'Disease', (174, 188))	('Cancer', 'Disease', (53, 59))
657973	30881375	Modulation of epigenetic activities by phytochemicals will allow the discovery of novel biomarkers for cancer prevention, and highlights its potential as an alternative therapeutic approach in cancer.	('Modulation', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('epigenetic activities', 'MPA', (14, 35))
657975	30881375	Cancer is caused by the accumulation of genetic and epigenetic alterations, which induce alterations in the expression of oncogenes and tumor suppressor genes.	('epigenetic alterations', 'Var', (52, 74))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('oncogenes', 'Gene', (122, 131))	('alterations', 'Reg', (89, 100))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('expression', 'MPA', (108, 118))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (136, 141))
657976	30881375	The main epigenetic mechanisms studied in mammalian cells are DNA methylation and histones modifications which induce remodeling of chromatin resulting in changes of cellular phenotypes.	('remodeling', 'MPA', (118, 128))	('cellular phenotypes', 'MPA', (166, 185))	('histones', 'Protein', (82, 90))	('changes', 'Reg', (155, 162))	('modifications', 'Var', (91, 104))	('mammalian', 'Species', '9606', (42, 51))
657977	30881375	In cancer cells, diverse epigenetic alterations of cancer-related genes occur in the early stages of tumor development.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('occur', 'Reg', (72, 77))	('cancer', 'Disease', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (3, 9))	('epigenetic alterations', 'Var', (25, 47))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
657981	30881375	Remarkably, phytochemicals may act through epigenetic mechanisms such as modulation of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) activities.	('HDAC', 'Gene', '9734', (144, 148))	('histone deacetylases', 'Enzyme', (122, 142))	('DNMT', 'Gene', (111, 115))	('activities', 'MPA', (151, 161))	('modulation', 'Var', (73, 83))	('DNA methyltransferases', 'Enzyme', (87, 109))	('DNMT', 'Gene', '1786', (111, 115))	('HDAC', 'Gene', (144, 148))
657985	30881375	In this review, we first provided an overview of the most frequent epigenetic alterations in human cancers, then we described the most studied dietary phytochemicals and their potential use in the reversion of cancer hallmarks through epigenetic mechanisms, and finally we discussed their potential use as an alternative strategy for cancer therapy.	('epigenetic alterations', 'Var', (67, 89))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('cancers', 'Disease', (99, 106))	('cancer', 'Disease', (99, 105))	('epigenetic', 'Var', (235, 245))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (334, 340))
657986	30881375	Importantly, dysregulation of these cellular events is frequently found during early and late stages of tumorigenesis.	('dysregulation', 'Var', (13, 26))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
657988	30881375	Aberrant DNA methylation patterns play a crucial role in genomic instability, activation of oncogenes and silencing of tumor suppressor genes involved in cell proliferation, cell cycle, DNA repair, stress response and apoptosis.	('tumor', 'Disease', (119, 124))	('Aberrant', 'Var', (0, 8))	('oncogenes', 'Gene', (92, 101))	('silencing', 'NegReg', (106, 115))	('activation', 'PosReg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('genomic instability', 'CPA', (57, 76))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
657990	30881375	Several studies have showed the impact of hypomethylation or hypermethylation of DNA sequences associated with the transcriptional regulation of cancer-related genes.	('cancer', 'Disease', (145, 151))	('hypomethylation', 'Var', (42, 57))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('DNA sequences', 'Gene', (81, 94))	('hypermethylation', 'Var', (61, 77))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('associated', 'Reg', (95, 105))	('transcriptional regulation', 'MPA', (115, 141))
657991	30881375	For instance, LINE-1 gene hypomethylation is associated with different clinical-pathological characteristics in lung cancer; early carcinogenesis in breast cancer, and metastasis in colorectal adenocarcinoma.	('carcinogenesis', 'Disease', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('LINE-1', 'Gene', (14, 20))	('colorectal adenocarcinoma', 'Disease', (182, 207))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('associated', 'Reg', (45, 55))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (182, 207))	('breast cancer', 'Disease', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('hypomethylation', 'Var', (26, 41))	('metastasis', 'CPA', (168, 178))
657992	30881375	On the other hand, hypomethylation of specific genes like TTF-3, MUC4, and CT45 frequently occur in prostate, pancreatic and ovarian cancers.	('occur', 'Reg', (91, 96))	('TTF-3', 'Gene', (58, 63))	('MUC4', 'Gene', (65, 69))	('pancreatic and ovarian cancers', 'Disease', 'MESH:D010190', (110, 140))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('CT45', 'Gene', '2577', (75, 79))	('prostate', 'Disease', (100, 108))	('ovarian cancers', 'Phenotype', 'HP:0100615', (125, 140))	('CT45', 'Gene', (75, 79))	('hypomethylation', 'Var', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('MUC4', 'Gene', '4585', (65, 69))
657993	30881375	The hypermethylation of RASSF1A gene has been identified as a diagnostic marker in lung cancer, whereas it contributes to increased mortality in women with breast cancer.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('RASSF1A', 'Gene', (24, 31))	('breast cancer', 'Disease', (156, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('lung cancer', 'Disease', (83, 94))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('RASSF1A', 'Gene', '11186', (24, 31))	('contributes', 'Reg', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('increased', 'PosReg', (122, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('women', 'Species', '9606', (145, 150))	('hypermethylation', 'Var', (4, 20))
657994	30881375	Hypermethylation of RASSF1A also has been related with high risk of ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (68, 82))	('RASSF1A', 'Gene', (20, 27))	('Hypermethylation', 'Var', (0, 16))	('ovarian cancer', 'Disease', 'MESH:D010051', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ovarian cancer', 'Disease', (68, 82))	('RASSF1A', 'Gene', '11186', (20, 27))	('related', 'Reg', (42, 49))
657995	30881375	Other studies showed that hypermethylation of PDE3A gene modulated the response to therapy in cisplatin-resistant non-small cell lung cancer (NSCLC).	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('PDE3A', 'Gene', '5139', (46, 51))	('NSCLC', 'Disease', (142, 147))	('modulated', 'Reg', (57, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (118, 140))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('cell lung cancer', 'Disease', (124, 140))	('PDE3A', 'Gene', (46, 51))	('hypermethylation', 'Var', (26, 42))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (114, 140))	('cell lung cancer', 'Disease', 'MESH:D008175', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('response to therapy', 'MPA', (71, 90))
657996	30881375	In addition, hypermethylation of genes such as NDN activated the WNT signaling pathway contributing to cell proliferation of colorectal cancer cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('NDN', 'Gene', (47, 50))	('WNT', 'Gene', (65, 68))	('cell proliferation', 'CPA', (103, 121))	('WNT', 'Gene', '7474', (65, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('NDN', 'Gene', '4692', (47, 50))	('colorectal cancer', 'Disease', (125, 142))	('hypermethylation', 'Var', (13, 29))	('activated', 'PosReg', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
657997	30881375	These examples illustrate the impact of alterations in epigenetic mechanisms in the development of diverse types of human cancers.	('epigenetic', 'Var', (55, 65))	('alterations', 'Var', (40, 51))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('human', 'Species', '9606', (116, 121))
658001	30881375	In cancer cells, histones modifications at specific amino acids residues are related to transcription activation or repression.	('repression', 'CPA', (116, 126))	('related', 'Reg', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('activation', 'PosReg', (102, 112))	('cancer', 'Disease', (3, 9))	('modifications', 'Var', (26, 39))	('histones', 'Protein', (17, 25))	('transcription', 'MPA', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
658002	30881375	In most species, histone H3 is primarily acetylated at lysines 9, 14, 18, 23, and 56, methylated at arginine 2 and lysines 4, 9, 27, 36, and 79, and phosphorylated at ser10, ser28, Thr3, and Thr11.	('lysines', 'Chemical', 'MESH:D008239', (55, 62))	('Thr3', 'Var', (181, 185))	('ser10', 'Var', (167, 172))	('ser10', 'Chemical', '-', (167, 172))	('lysines', 'Chemical', 'MESH:D008239', (115, 122))	('Thr3', 'Chemical', '-', (181, 185))	('Thr11', 'Chemical', '-', (191, 196))	('arginine', 'Chemical', 'MESH:D001120', (100, 108))	('lysines', 'Var', (55, 62))	('histone H3', 'Protein', (17, 27))	('ser28', 'Chemical', '-', (174, 179))	('acetylated', 'MPA', (41, 51))	('ser28', 'Var', (174, 179))	('lysines', 'Var', (115, 122))
658004	30881375	In prostate cancer, H3K9me2 and H3Ac marks distinguish between tumors from non-malignant tissues, and the H3K4me1 modification was established as a biomarker of tumor progression and a predictor of recurrence after radical prostatectomy.	('tumor', 'Disease', (63, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('prostate cancer', 'Disease', (3, 18))	('tumors', 'Disease', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('H3K4me1', 'Var', (106, 113))	('tumor', 'Disease', (161, 166))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
658006	30881375	In early-stage of colon cancer (TNM stage I and II) low nuclear expression of H3K4me3 and high expression of H3K9me3 and H4K20me3 were associated with good prognosis.	('colon cancer', 'Disease', 'MESH:D015179', (18, 30))	('colon cancer', 'Disease', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('nuclear expression', 'MPA', (56, 74))	('H3K4me3', 'Protein', (78, 85))	('colon cancer', 'Phenotype', 'HP:0003003', (18, 30))	('H3K9me3', 'Protein', (109, 116))	('low', 'NegReg', (52, 55))	('H4K20me3', 'Var', (121, 129))	('high', 'PosReg', (90, 94))
658042	30881375	It has been reported that EGCG epigenetically reactivated p21/waf1, Bax and PUMA in prostate cancer cells, leading to cell cycle arrest and apoptosis mediated by proteasomal degradation of class I HDACs.	('p21', 'Gene', (58, 61))	('prostate cancer', 'Disease', (84, 99))	('p21', 'Gene', '644914', (58, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('apoptosis', 'CPA', (140, 149))	('proteasomal degradation', 'MPA', (162, 185))	('EGCG', 'Chemical', 'MESH:C045651', (26, 30))	('PUMA in prostate', 'Phenotype', 'HP:0000024', (76, 92))	('epigenetically reactivated', 'Var', (31, 57))	('HDAC', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('HDAC', 'Gene', '9734', (197, 201))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('EGCG', 'Gene', (26, 30))	('cell cycle arrest', 'CPA', (118, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))
658045	30881375	Remarkably, EGCG is a potential epigenetic modifier of DNMTs and HDACs and restores epigenetically silenced genes in skin and cervical cancers.	('epigenetically silenced genes', 'MPA', (84, 113))	('DNMT', 'Gene', (55, 59))	('HDAC', 'Gene', (65, 69))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('EGCG', 'Var', (12, 16))	('HDAC', 'Gene', '9734', (65, 69))	('EGCG', 'Chemical', 'MESH:C045651', (12, 16))	('restores', 'PosReg', (75, 83))	('skin and cervical cancers', 'Disease', 'MESH:D012878', (117, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('DNMT', 'Gene', '1786', (55, 59))
658047	30881375	In esophageal cancer, EGCG induced apoptosis and inhibited cell growth of ECa109 cells through p16 gene demethylation.	('cell growth of ECa109 cells', 'CPA', (59, 86))	('demethylation', 'Var', (104, 117))	('esophageal cancer', 'Disease', (3, 20))	('EGCG', 'Chemical', 'MESH:C045651', (22, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('p16', 'Gene', '1029', (95, 98))	('ECa109', 'CellLine', 'CVCL:6898', (74, 80))	('EGCG', 'Gene', (22, 26))	('apoptosis', 'CPA', (35, 44))	('inhibited', 'NegReg', (49, 58))	('p16', 'Gene', (95, 98))
658064	30881375	Also, curcumin impeded differentiation of astrocytes and promoted neural differentiation associated with hypoacetylation of H3 and H4.	('hypoacetylation', 'Var', (105, 120))	('impeded', 'NegReg', (15, 22))	('promoted', 'PosReg', (57, 65))	('curcumin', 'Chemical', 'MESH:D003474', (6, 14))	('differentiation of astrocytes', 'CPA', (23, 52))	('neural differentiation', 'CPA', (66, 88))
658070	30881375	Additionally, curcumin restored p15INK4b expression by hypomethylation of its promoter inducing cell cycle arrest at G1 phase and apoptosis in vitro.	('cell cycle arrest at G1 phase', 'CPA', (96, 125))	('p15INK4b', 'Gene', (32, 40))	('apoptosis', 'CPA', (130, 139))	('expression', 'MPA', (41, 51))	('inducing', 'Reg', (87, 95))	('hypomethylation', 'Var', (55, 70))	('p15INK4b', 'Gene', '1030', (32, 40))	('curcumin', 'Chemical', 'MESH:D003474', (14, 22))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))
658073	30881375	Also, curcumin promoted apoptosis of LNCaP cells inhibiting JNK signaling and repressing H3K4me3 epigenetic mark.	('LNCaP', 'CellLine', 'CVCL:0395', (37, 42))	('JNK', 'Gene', (60, 63))	('apoptosis', 'CPA', (24, 33))	('JNK', 'Gene', '5599', (60, 63))	('inhibiting', 'NegReg', (49, 59))	('H3K4me3 epigenetic', 'Var', (89, 107))	('repressing', 'NegReg', (78, 88))	('curcumin', 'Chemical', 'MESH:D003474', (6, 14))
658081	30881375	On the other hand, showed that quercetin inhibited tumor growth by activation of p16INK4a induced by promoter demethylation in colorectal cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('activation', 'PosReg', (67, 77))	('p16INK4a', 'Gene', (81, 89))	('tumor', 'Disease', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('promoter demethylation', 'Var', (101, 123))	('p16INK4a', 'Gene', '1029', (81, 89))	('inhibited', 'NegReg', (41, 50))	('quercetin', 'Chemical', 'MESH:D011794', (31, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
658086	30881375	In esophageal cancer, combinations of quercetin and sodium butyrate repress tumor growth and cell proliferation which was associated with downregulation of DNMT1, NF-kappaBp65, HDAC1, and cyclin D1.	('tumor', 'Disease', (76, 81))	('HDAC1', 'Gene', '3065', (177, 182))	('DNMT1', 'Gene', '1786', (156, 161))	('repress', 'NegReg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('combinations', 'Var', (22, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('NF-kappaBp65', 'Gene', '5970', (163, 175))	('esophageal cancer', 'Disease', (3, 20))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cell proliferation', 'CPA', (93, 111))	('DNMT1', 'Gene', (156, 161))	('quercetin', 'Chemical', 'MESH:D011794', (38, 47))	('downregulation', 'NegReg', (138, 152))	('cyclin D1', 'Gene', (188, 197))	('HDAC1', 'Gene', (177, 182))	('sodium butyrate', 'Chemical', 'MESH:D020148', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cyclin D1', 'Gene', '595', (188, 197))	('NF-kappaBp65', 'Gene', (163, 175))
658091	30881375	In DU145 (mutant p53) and LNCaP (wild type p53) prostate cancer cell lines, resveratrol downregulated the Metastasis Associated Protein 1 (MTA1) leading to destabilization of MTA1/NuRD, a nucleosome remodeling deacetylation (NuRD) corepressor complex that mediates posttranslational modifications of histones and non-histone proteins resulting in transcriptional repression.	('MTA1/NuRD', 'Gene', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('p53', 'Gene', (43, 46))	('MTA1/NuRD', 'Gene', '9112', (175, 184))	('p53', 'Gene', (17, 20))	('downregulated', 'NegReg', (88, 101))	('transcriptional', 'MPA', (347, 362))	('Metastasis Associated Protein 1', 'Gene', (106, 137))	('DU145', 'CellLine', 'CVCL:0105', (3, 8))	('MTA1', 'Gene', (139, 143))	('resveratrol', 'Var', (76, 87))	('prostate cancer', 'Disease', 'MESH:D011471', (48, 63))	('MTA1', 'Gene', '9112', (139, 143))	('destabilization', 'MPA', (156, 171))	('Metastasis Associated Protein 1', 'Gene', '9112', (106, 137))	('prostate cancer', 'Phenotype', 'HP:0012125', (48, 63))	('prostate cancer', 'Disease', (48, 63))	('resveratrol', 'Chemical', 'MESH:D000077185', (76, 87))	('LNCaP', 'CellLine', 'CVCL:0395', (26, 31))	('MTA1', 'Gene', (175, 179))	('p53', 'Gene', '7157', (43, 46))	('p53', 'Gene', '7157', (17, 20))	('MTA1', 'Gene', '9112', (175, 179))
658100	30881375	In addition, these combinations induced the reactivation of ER-alpha expression in ER-alpha negative breast cancer cells, sensitizing tumor cells to 17beta-estradiol treatment which was associated to an increase in H3K9 and H4 marks in the ERalpha promoter.	('ERalpha', 'Gene', (240, 247))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('ER-alpha', 'Gene', (60, 68))	('ERalpha', 'Gene', '2099', (240, 247))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('ER-alpha', 'Gene', (83, 91))	('ER-alpha', 'Gene', '2099', (60, 68))	('breast cancer', 'Disease', (101, 114))	('combinations', 'Var', (19, 31))	('H4 marks', 'Protein', (224, 232))	('increase', 'PosReg', (203, 211))	('ER-alpha', 'Gene', '2099', (83, 91))	('tumor', 'Disease', (134, 139))	('H3K9', 'Protein', (215, 219))	('reactivation', 'MPA', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (149, 165))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))
658111	30881375	Interestingly, SFN restored the miR-9-3 expression through epigenetic regulation attenuating the DNMT1 activity and DNMT3a, HDAC1, HDAC3, HDAC6, and CDH1 protein expression.	('miR-9-3', 'Gene', (32, 39))	('DNMT3a', 'Gene', '1788', (116, 122))	('HDAC6', 'Gene', '10013', (138, 143))	('CDH1', 'Gene', '999', (149, 153))	('DNMT1', 'Gene', '1786', (97, 102))	('CDH1', 'Gene', (149, 153))	('HDAC3', 'Gene', (131, 136))	('SFN', 'Chemical', 'MESH:C016766', (15, 18))	('epigenetic regulation', 'Var', (59, 80))	('HDAC1', 'Gene', (124, 129))	('HDAC6', 'Gene', (138, 143))	('protein', 'Protein', (154, 161))	('DNMT1', 'Gene', (97, 102))	('miR-9-3', 'Gene', '407051', (32, 39))	('HDAC1', 'Gene', '3065', (124, 129))	('HDAC3', 'Gene', '8841', (131, 136))	('attenuating', 'NegReg', (81, 92))	('expression', 'MPA', (162, 172))	('DNMT3a', 'Gene', (116, 122))
658114	30881375	The downregulation of DNMTs in response to SFN induced CpG demethylation of hTERT thereby facilitating CTCF binding associated with hTERT repression.	('facilitating', 'PosReg', (90, 102))	('hTERT', 'Gene', '7015', (76, 81))	('binding', 'Interaction', (108, 115))	('CTCF', 'Gene', (103, 107))	('hTERT', 'Gene', '7015', (132, 137))	('demethylation', 'Var', (59, 72))	('DNMT', 'Gene', '1786', (22, 26))	('SFN', 'Chemical', 'MESH:C016766', (43, 46))	('hTERT', 'Gene', (76, 81))	('downregulation', 'NegReg', (4, 18))	('DNMT', 'Gene', (22, 26))	('hTERT', 'Gene', (132, 137))	('CTCF', 'Gene', '10664', (103, 107))
658115	30881375	SFN increased the level of active chromatin markers H3K9ac and acetyl-H4, and suppressed H3K9me3 and H3K27me3 in hTERT promoter.	('hTERT', 'Gene', (113, 118))	('H3K27me3', 'Var', (101, 109))	('level of active chromatin', 'MPA', (18, 43))	('H3K9ac', 'MPA', (52, 58))	('suppressed', 'NegReg', (78, 88))	('H3K9me3', 'MPA', (89, 96))	('acetyl-H4', 'MPA', (63, 72))	('SFN increased', 'Phenotype', 'HP:0002922', (0, 13))	('hTERT', 'Gene', '7015', (113, 118))	('SFN', 'Chemical', 'MESH:C016766', (0, 3))	('increased', 'PosReg', (4, 13))
658116	30881375	Altogether, these epigenetic events induced breast cancer cells death.	('induced', 'Reg', (36, 43))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('epigenetic events', 'Var', (18, 35))
658121	30881375	Also, SFN induced methylation and inhibited the HDAC activities of hTERT promoter associated with H3K4me2, H3K9me3 and H3K27me3 epigenetic marks.	('HDAC', 'Gene', (48, 52))	('HDAC', 'Gene', '9734', (48, 52))	('H3K27me3 epigenetic marks', 'Var', (119, 144))	('induced', 'Reg', (10, 17))	('inhibited', 'NegReg', (34, 43))	('methylation', 'MPA', (18, 29))	('H3K4me2', 'Var', (98, 105))	('hTERT', 'Gene', '7015', (67, 72))	('H3K9me3', 'Var', (107, 114))	('SFN', 'Chemical', 'MESH:C016766', (6, 9))	('hTERT', 'Gene', (67, 72))
658123	30881375	These modifications were linked with high risk of prostate cancer recurrence.	('modifications', 'Var', (6, 19))	('prostate cancer', 'Disease', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))
658125	30881375	SFN also caused demethylation of CpGs islands of Nrf2 gene promoter, which acts as regulator in the cellular oxidative stress decreasing the carcinogen-induced tumorigenesis, in TRAMP C1 cells.	('oxidative stress', 'Phenotype', 'HP:0025464', (109, 125))	('demethylation', 'MPA', (16, 29))	('decreasing', 'NegReg', (126, 136))	('Nrf2', 'Gene', '18024', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('TRAMP', 'Gene', (178, 183))	('TRAMP', 'Gene', '85030', (178, 183))	('Nrf2', 'Gene', (49, 53))	('tumor', 'Disease', (160, 165))	('SFN', 'Chemical', 'MESH:C016766', (0, 3))	('SFN', 'Var', (0, 3))
658187	29384871	Furthermore, we analyzed the prognostic factors of SRC in patients with lymph node recurrence after radical surgery of esophageal cancer and found that PRC significantly reduced the efficacy of SRC in patients with lymph node recurrence.	('patients', 'Species', '9606', (201, 209))	('PRC', 'Var', (152, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('reduced', 'NegReg', (170, 177))	('efficacy', 'MPA', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('patients', 'Species', '9606', (58, 66))	('PRC', 'Chemical', '-', (152, 155))	('esophageal cancer', 'Disease', (119, 136))
658189	29384871	In our study, many patients with postoperative pathology positive lymph nodes underwent PRC, which partly explain why univariate analysis revealed a decline in overall survival in patients who received PRC (Fig.	('PRC', 'Chemical', '-', (88, 91))	('patients', 'Species', '9606', (19, 27))	('PRC', 'Var', (88, 91))	('decline', 'NegReg', (149, 156))	('overall survival', 'MPA', (160, 176))	('PRC', 'Chemical', '-', (202, 205))	('PRC', 'Var', (202, 205))	('patients', 'Species', '9606', (180, 188))
658200	29384871	However, our study suggests that further research is necessary to determine whether patients receiving PRC have higher survival rates than those who do not undergo PRC but receive SRC for recurrence.	('higher', 'PosReg', (112, 118))	('patients', 'Species', '9606', (84, 92))	('PRC', 'Chemical', '-', (164, 167))	('survival', 'MPA', (119, 127))	('PRC', 'Chemical', '-', (103, 106))	('PRC', 'Var', (103, 106))
658204	29384871	Further research is necessary to determine whether patients receiving PRC have higher survival rates than those who do not undergo PRC but receive SRC after recurrence.	('PRC', 'Var', (70, 73))	('survival', 'MPA', (86, 94))	('patients', 'Species', '9606', (51, 59))	('PRC', 'Chemical', '-', (131, 134))	('PRC', 'Chemical', '-', (70, 73))	('higher', 'PosReg', (79, 85))
658213	29021479	ELP can cause stricture, ulceration, and squamous cell carcinoma.	('cause', 'Reg', (8, 13))	('squamous cell carcinoma', 'Disease', (41, 64))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('ulceration', 'Disease', (25, 35))	('stricture', 'Disease', (14, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))	('ELP', 'Var', (0, 3))
658338	26673551	In the Dunn's test, the Barthel Index score differed significantly between mGPS 0 and mGPS 2.	('mGPS 2', 'Gene', (86, 92))	('differed', 'Reg', (44, 52))	('mGPS', 'Var', (75, 79))	('Barthel Index score', 'MPA', (24, 43))	('mGPS 2', 'Gene', '56310', (86, 92))
658352	26673551	Malnutrition can cause dysphagia and has been associated with dysphagia and head lifting strength which reflects the strength of the suprahyoid muscles.	('head lifting strength', 'CPA', (76, 97))	('Malnutrition', 'Var', (0, 12))	('Malnutrition', 'Phenotype', 'HP:0004395', (0, 12))	('dysphagia', 'Disease', (62, 71))	('dysphagia', 'Disease', 'MESH:D003680', (23, 32))	('dysphagia', 'Phenotype', 'HP:0002015', (62, 71))	('cause', 'Reg', (17, 22))	('dysphagia', 'Phenotype', 'HP:0002015', (23, 32))	('dysphagia', 'Disease', (23, 32))	('dysphagia', 'Disease', 'MESH:D003680', (62, 71))	('associated', 'Reg', (46, 56))
658399	24736077	The most common esophagectomy procedure was Ivor Lewis, while a few patients also received transhiatal, left thoracotomy, radical (en block) resection, or minimally invasive esophagectomy.	('esophagectomy', 'Disease', (16, 29))	('patients', 'Species', '9606', (68, 76))	('transhiatal', 'Var', (91, 102))	('left thoracotomy', 'Disease', (104, 120))
658404	24736077	A total of 285 patients diagnosed with esophageal cancer and treated with neoadjuvant chemoradiation followed by esophagectomy were included in our analysis; 158 patients were treated with 3D-CRT and 127 were treated with IMRT.	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (15, 23))	('3D-CRT', 'Var', (189, 195))	('esophageal cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('CR', 'Chemical', '-', (192, 194))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))
658442	24736077	reported a 5.6% anastomotic leak rate in their study showing the significance of D50 to the gastric fundus (the total dose delivered to 50% of the volume) as a risk factor for anastomotic complications.	('anastomotic leak', 'Disease', (16, 32))	('D50', 'Var', (81, 84))	('anastomotic leak', 'Disease', 'MESH:D057868', (16, 32))
658524	23935622	found that narrow-band imaging was more likely 2 folds than conventional white-light evaluation to detect pharyngeal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('squamous cell carcinoma', 'Disease', (117, 140))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 140))	('narrow-band', 'Var', (11, 22))	('pharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (106, 140))
658539	23629646	Genome-wide association studies in China showed that variants in several chromosome regions conferred increased risk, but only genetic variants in alcohol-metabolizing genes were significantly associated with ESCC risk in Japan.	('Japan', 'Disease', (222, 227))	('SCC', 'Gene', (210, 213))	('alcohol', 'Chemical', 'MESH:D000438', (147, 154))	('SCC', 'Gene', '6317', (210, 213))	('variants', 'Var', (53, 61))	('associated', 'Reg', (193, 203))
658580	23629646	Polymorphisms in the genes that encode alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH):2 important enzymes in the alcohol-metabolizing pathway:may contribute to variation in the amount of acetaldehyde produced.	('acetaldehyde', 'Chemical', 'MESH:D000079', (71, 83))	('alcohol dehydrogenase', 'Gene', '10327', (39, 60))	('alcohol', 'Chemical', 'MESH:D000438', (39, 46))	('Polymorphisms', 'Var', (0, 13))	('amount of acetaldehyde produced', 'MPA', (196, 227))	('acetaldehyde', 'Chemical', 'MESH:D000079', (206, 218))	('ADH', 'Gene', (62, 65))	('ADH', 'Gene', '10327', (62, 65))	('contribute', 'Reg', (165, 175))	('alcohol dehydrogenase', 'Gene', (39, 60))	('alcohol', 'Chemical', 'MESH:D000438', (132, 139))
658581	23629646	Differences in the activity of these enzymes, and the potential of acetaldehyde to cause mutations, may explain why ESCC risk varies among individuals with the same level of alcohol consumption.	('acetaldehyde', 'Chemical', 'MESH:D000079', (67, 79))	('alcohol', 'Chemical', 'MESH:D000438', (174, 181))	('SCC', 'Gene', (117, 120))	('activity', 'MPA', (19, 27))	('cause', 'Reg', (83, 88))	('SCC', 'Gene', '6317', (117, 120))	('mutations', 'Var', (89, 98))
658583	23629646	Since 2009, there have been 2 genome-wide association (GWA) studies reporting functional variants that were significantly associated with susceptibility to esophageal cancer in the Japanese population., The first GWA study identified 4q21-23 and 12q24 as susceptibility loci, in which 2 functional variants in ADH1B and ALDH2 showed significant associations with ESCC risk (Table 3).	('ADH1B', 'Gene', '125', (310, 315))	('SCC', 'Gene', (364, 367))	('esophageal cancer', 'Disease', (156, 173))	('associations', 'Reg', (345, 357))	('SCC', 'Gene', '6317', (364, 367))	('ALDH2', 'Gene', '217', (320, 325))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('variants', 'Var', (298, 306))	('ADH1B', 'Gene', (310, 315))	('ALDH2', 'Gene', (320, 325))
658586	23629646	The second GWA study reported similar findings, ie, clear synergistic effects of ADH1B and ALDH2 SNPs, alcohol consumption, and cigarette smoking on ESCC risk.	('SCC', 'Gene', '6317', (150, 153))	('ADH1B', 'Gene', (81, 86))	('ALDH2', 'Gene', (91, 96))	('ADH1B', 'Gene', '125', (81, 86))	('SCC', 'Gene', (150, 153))	('alcohol', 'Chemical', 'MESH:D000438', (103, 110))	('SNPs', 'Var', (97, 101))	('ALDH2', 'Gene', '217', (91, 96))
658593	23629646	Overall, alcohol consumption and cigarette smoking have been shown to be associated with increased ESCC risk in the Chinese population.	('alcohol', 'Chemical', 'MESH:D000438', (9, 16))	('SCC', 'Gene', (100, 103))	('alcohol consumption', 'Var', (9, 28))	('SCC', 'Gene', '6317', (100, 103))	('increased ESCC', 'Phenotype', 'HP:0003565', (89, 103))
658609	23629646	Studies in Linxian found that general malnutrition, as well as deficiencies in selenium, zinc, folate, riboflavin, and vitamins A, C, E, and B12, was associated with increased risk of ESCC.	('SCC', 'Gene', (185, 188))	('deficiencies', 'Var', (63, 75))	('riboflavin', 'Chemical', 'MESH:D012256', (103, 113))	('SCC', 'Gene', '6317', (185, 188))	('B12', 'Gene', (141, 144))	('riboflavin', 'Protein', (103, 113))	('malnutrition', 'Phenotype', 'HP:0004395', (38, 50))	('selenium', 'Gene', (79, 87))	('B12', 'Gene', '4709', (141, 144))	('folate', 'Chemical', 'MESH:D005492', (95, 101))	('selenium', 'Chemical', 'MESH:D012643', (79, 87))
658622	23629646	Variants at 10q23 in PLCE1 were significantly associated with ESCC and gastric cardia cancer in GWA studies by Wang et al and Abnet et al., PLCE1 encodes a phospholipase and is involved in regulating cell growth, differentiation, apoptosis, and angiogenesis.	('gastric cardia cancer', 'Disease', 'MESH:D013274', (71, 92))	('SCC', 'Gene', (63, 66))	('gastric cardia cancer', 'Disease', (71, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('PLCE1', 'Gene', (140, 145))	('SCC', 'Gene', '6317', (63, 66))	('Variants at', 'Var', (0, 11))	('PLCE1', 'Gene', '51196', (140, 145))	('associated', 'Reg', (46, 56))	('PLCE1', 'Gene', (21, 26))	('PLCE1', 'Gene', '51196', (21, 26))	('involved', 'Reg', (177, 185))
658626	23629646	Epidemiologic studies in China suggest that gastric cardia adenocarcinoma (GCA) and ESCC have a similar geographic distribution in incidence and common risk factors.,- In particular, GCA was more prevalent in ESCC high-risk areas such as Linxian and Cixian., Case-control and cohort studies in high-risk areas reported that family history of esophageal cancer, low socioeconomic status, and low intake of vegetables and fruit were significant risk factors for GCA and ESCC., Interestingly, in the GWA studies by Wang et al and Abnet et al, variants in PLCE1 were also significantly associated with GCA risk., These findings strongly suggest that the pathogenic processes of ESCC and GCA are similar.	('esophageal cancer', 'Disease', 'MESH:D004938', (342, 359))	('SCC', 'Gene', '6317', (469, 472))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (44, 73))	('SCC', 'Gene', '6317', (85, 88))	('SCC', 'Gene', (210, 213))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('gastric cardia adenocarcinoma', 'Disease', (44, 73))	('PLCE1', 'Gene', (552, 557))	('SCC', 'Gene', '6317', (210, 213))	('SCC', 'Gene', (675, 678))	('PLCE1', 'Gene', '51196', (552, 557))	('variants', 'Var', (540, 548))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('esophageal cancer', 'Disease', (342, 359))	('SCC', 'Gene', (469, 472))	('SCC', 'Gene', (85, 88))	('SCC', 'Gene', '6317', (675, 678))
658639	23629646	Fifth, GWA studies in China showed that variants in several chromosome regions confer increased risk, suggesting the involvement of multiple genes in the carcinogenic process.	('men', 'Species', '9606', (124, 127))	('variants', 'Var', (40, 48))	('carcinogenic process', 'Disease', (154, 174))	('carcinogenic process', 'Disease', 'MESH:D009385', (154, 174))
658640	23629646	However, GWA studies in Japan found that ESCC risk was associated only with genetic variants in alcohol-metabolizing genes.	('genetic variants', 'Var', (76, 92))	('SCC', 'Gene', (42, 45))	('SCC', 'Gene', '6317', (42, 45))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))
658650	23629646	While GWA studies in the Japanese population found that the major susceptibility variants are located in alcohol-metabolizing genes, GWA studies in the Chinese population did not replicate this finding.	('susceptibility', 'Reg', (66, 80))	('alcohol-metabolizing genes', 'Gene', (105, 131))	('alcohol', 'Chemical', 'MESH:D000438', (105, 112))	('variants', 'Var', (81, 89))
658651	23629646	Instead, susceptibility to esophageal cancer may be determined by many variants in different genes that have mostly small effects.	('variants', 'Var', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('esophageal cancer', 'Disease', (27, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))
658661	23629646	Third, while there is convincing evidence that H. pylori is strongly associated with increased risk of noncardia gastric cancer, studies of its association with ESCC have been limited and have yielded inconsistent results.	('H. pylori', 'Species', '210', (47, 56))	('increased risk of noncardia gastric cancer', 'Phenotype', 'HP:0006753', (85, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('noncardia gastric cancer', 'Disease', (103, 127))	('associated', 'Reg', (69, 79))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (103, 127))	('H. pylori', 'Var', (47, 56))	('SCC', 'Gene', (162, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('SCC', 'Gene', '6317', (162, 165))
658722	22482920	The number (mean [standard deviation]) of buried glands per patient in the post-CE-IM group (7.1 [9.3]) was significantly lower compared with the pre-CE-IM group (34.4 [44.6]; P = .02).	('lower', 'NegReg', (122, 127))	('CE-IM', 'Chemical', '-', (150, 155))	('patient', 'Species', '9606', (60, 67))	('CE-IM', 'Chemical', '-', (80, 85))	('post-CE-IM', 'Var', (75, 85))	('buried glands', 'CPA', (42, 55))
658776	22482920	Furthermore, as shown in Figure 4, the number of buried glands per patient observed in the post-CE-IM group (7.1 [9.3], median = 5) is significantly lower compared with the number of buried glands per patient observed in the pre-CE-IM group (34.4 [44.6], median = 26.5; P = .02).	('CE-IM', 'Chemical', '-', (96, 101))	('post-CE-IM', 'Var', (91, 101))	('CE-IM', 'Chemical', '-', (229, 234))	('patient', 'Species', '9606', (201, 208))	('lower', 'NegReg', (149, 154))	('patient', 'Species', '9606', (67, 74))
658847	22084683	As illustrated in Figure 3, CM proteins derived from [12C6]-lysine labelled myoblasts (light) and [13C6]-lysine labelled myotubes (heavy) were mixed in equal amounts and subjected to one-dimensional gel electrophoresis (1D-SDS PAGE), followed by trypsin digestion.	('13C6', 'Chemical', '-', (99, 103))	('12C6', 'Chemical', '-', (54, 58))	('lysine', 'Chemical', 'MESH:D008239', (105, 111))	('1D-SDS', 'Chemical', '-', (220, 226))	('lysine', 'Chemical', 'MESH:D008239', (60, 66))	('[13C6]-lysine', 'Var', (98, 111))	('[12C6]-lysine', 'Var', (53, 66))
658860	22084683	Expression level of Prx1 was shown to positively correlate with cancer progression; knocking down Prx1 not only attenuated malignancy, but also sensitized the cancer cells to chemotherapy and improved survival.	('improved', 'PosReg', (192, 200))	('Prx1', 'Gene', (20, 24))	('sensitized', 'Reg', (144, 154))	('cancer', 'Disease', (159, 165))	('Prx1', 'Gene', '5052', (20, 24))	('attenuated malignancy', 'Disease', (112, 133))	('attenuated malignancy', 'Disease', 'MESH:C538265', (112, 133))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('knocking down', 'Var', (84, 97))	('survival', 'CPA', (201, 209))	('chemotherapy', 'CPA', (175, 187))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('Prx1', 'Gene', (98, 102))	('Prx1', 'Gene', '5052', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
658895	21386808	Treatment with ablation might delay the diagnosis of invasive cancer, but is unlikely to change the poor prognosis of nodal disease.	('delay', 'NegReg', (30, 35))	('ablation', 'Var', (15, 23))	('nodal disease', 'Disease', 'MESH:D013611', (118, 131))	('invasive cancer', 'Disease', 'MESH:D009362', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('nodal disease', 'Disease', (118, 131))	('invasive cancer', 'Disease', (53, 68))
658916	30057856	Furthermore, studies have shown that higher mortality in SSc is linked to HLA alleles DRB1*0802 and DQA1*0501.	('DRB1', 'Gene', '3123', (86, 90))	('DRB1', 'Gene', (86, 90))	('higher', 'PosReg', (37, 43))	('SSc', 'Disease', (57, 60))	('DQA1*0501', 'Var', (100, 109))
658917	30057856	Among exogenous triggers, gadolinium, L-tryptophane, viruses and fungi are linked to SSc.	('SSc', 'Disease', (85, 88))	('gadolinium', 'Chemical', 'MESH:D005682', (26, 36))	('gadolinium', 'MPA', (26, 36))	('L-tryptophane', 'Chemical', 'MESH:D014364', (38, 51))	('linked', 'Reg', (75, 81))	('L-tryptophane', 'Var', (38, 51))
658919	30057856	DNA methylation, in particular hypomethylation can lead to overexpression of integrins which in turn favor myofibroblast differentiation and activation of transforming growth factor beta (TGF-beta).	('favor', 'PosReg', (101, 106))	('hypomethylation', 'Var', (31, 46))	('transforming growth factor beta', 'Gene', '7040', (155, 186))	('lead', 'Reg', (51, 55))	('TGF-beta', 'Gene', '7040', (188, 196))	('overexpression', 'PosReg', (59, 73))	('transforming growth factor beta', 'Gene', (155, 186))	('myofibroblast differentiation', 'CPA', (107, 136))	('integrins', 'Protein', (77, 86))	('TGF-beta', 'Gene', (188, 196))	('activation', 'PosReg', (141, 151))
658944	30057856	Currently, these antibodies, among other autoantibodies, have been linked to disease complications such as pulmonary hypertension, renal failure and abnormalities in GI motility.	('pulmonary hypertension', 'Disease', (107, 129))	('renal failure and abnormalities in GI motility', 'Disease', 'MESH:D051437', (131, 177))	('renal failure', 'Phenotype', 'HP:0000083', (131, 144))	('abnormalities in GI', 'Phenotype', 'HP:0011024', (149, 168))	('abnormalities in GI motility', 'Phenotype', 'HP:0030895', (149, 177))	('linked', 'Reg', (67, 73))	('antibodies', 'Var', (17, 27))	('hypertension', 'Phenotype', 'HP:0000822', (117, 129))	('pulmonary hypertension', 'Disease', 'MESH:D006976', (107, 129))
659122	30057856	Lastly, in severe cases supplementing fiber can lead to fecal impaction.	('fecal', 'Disease', (56, 61))	('supplementing fiber', 'Var', (24, 43))	('fiber', 'Chemical', 'MESH:D004043', (38, 43))	('men', 'Species', '9606', (30, 33))	('lead to', 'Reg', (48, 55))
659152	30057856	Diet modification can mediate gut motility and integrity of the IAS, improving fecal incontinence.	('fecal incontinence', 'Phenotype', 'HP:0002607', (79, 97))	('fecal incontinence', 'Disease', 'MESH:D005242', (79, 97))	('improving', 'PosReg', (69, 78))	('Diet modification', 'Var', (0, 17))	('gut motility', 'CPA', (30, 42))	('fecal incontinence', 'Disease', (79, 97))
659176	30057856	The antinuclear antibodies, anti-gp210 and anti-sp100, are highly specific for PBC and serve as PBC markers in individuals who are AMA negative.	('AMA', 'Phenotype', 'HP:0030167', (131, 134))	('PBC', 'Phenotype', 'HP:0002613', (79, 82))	('PBC', 'Phenotype', 'HP:0002613', (96, 99))	('antinuclear antibodies', 'Phenotype', 'HP:0003493', (4, 26))	('PBC', 'Gene', (96, 99))	('PBC', 'Gene', '1737', (79, 82))	('PBC', 'Gene', '1737', (96, 99))	('anti-gp210', 'Var', (28, 38))	('PBC', 'Gene', (79, 82))	('anti-sp100', 'Var', (43, 53))
659178	30057856	Thus, when screening SSc patients for PBC (SSc-PBC), the more specific anti-sp100 was shown to be useful.	('PBC', 'Gene', '1737', (47, 50))	('PBC', 'Phenotype', 'HP:0002613', (38, 41))	('PBC', 'Gene', (47, 50))	('PBC', 'Gene', (38, 41))	('PBC', 'Gene', '1737', (38, 41))	('anti-sp100', 'Var', (71, 81))	('patients', 'Species', '9606', (25, 33))	('PBC', 'Phenotype', 'HP:0002613', (47, 50))
659179	30057856	In a study of 817 patients with SSc, the combination of AMA and anti-sp100 increased the sensitivity for detection of PBC from 81.3% to 100%.	('AMA', 'Phenotype', 'HP:0030167', (56, 59))	('PBC', 'Phenotype', 'HP:0002613', (118, 121))	('PBC', 'Gene', '1737', (118, 121))	('patients', 'Species', '9606', (18, 26))	('PBC', 'Gene', (118, 121))	('increased', 'PosReg', (75, 84))	('anti-sp100', 'Var', (64, 74))
659200	30057856	SSc causes exocrine pancreatic insufficiency, that is rarely clinically significant.	('exocrine pancreatic insufficiency', 'Phenotype', 'HP:0001738', (11, 44))	('pancreatic insufficiency', 'Disease', 'MESH:D010188', (20, 44))	('causes', 'Reg', (4, 10))	('pancreatic insufficiency', 'Phenotype', 'HP:0001738', (20, 44))	('pancreatic insufficiency', 'Disease', (20, 44))	('SSc', 'Var', (0, 3))
659213	30057856	Gastroparesis and gastric non-compliance leads to early satiety, nausea and vomiting, bloating, and/or abdominal pain.	('Gastroparesis', 'Phenotype', 'HP:0002578', (0, 13))	('vomiting', 'Disease', (76, 84))	('vomiting', 'Disease', 'MESH:D014839', (76, 84))	('leads to', 'Reg', (41, 49))	('abdominal pain', 'Phenotype', 'HP:0002027', (103, 117))	('abdominal pain', 'Disease', (103, 117))	('nausea', 'Phenotype', 'HP:0002018', (65, 71))	('pain', 'Phenotype', 'HP:0012531', (113, 117))	('nausea', 'Disease', (65, 71))	('nausea', 'Disease', 'MESH:D009325', (65, 71))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (65, 84))	('abdominal pain', 'Disease', 'MESH:D015746', (103, 117))	('Gastroparesis', 'Disease', (0, 13))	('vomiting', 'Phenotype', 'HP:0002013', (76, 84))	('bloating', 'Disease', (86, 94))	('non-compliance', 'Var', (26, 40))	('early satiety', 'Disease', (50, 63))	('bloating', 'Phenotype', 'HP:0003270', (86, 94))
659221	30057856	Additionally, SSc also causes severe fatigue and myalgia which further contribute to a declining functional status by impairing activities of daily living such as cooking.	('fatigue', 'Phenotype', 'HP:0012378', (37, 44))	('causes', 'Reg', (23, 29))	('myalgia', 'Disease', (49, 56))	('impairing', 'NegReg', (118, 127))	('activities', 'MPA', (128, 138))	('cooking', 'Disease', (163, 170))	('myalgia', 'Disease', 'MESH:D063806', (49, 56))	('myalgia', 'Phenotype', 'HP:0003326', (49, 56))	('fatigue', 'Disease', 'MESH:D005221', (37, 44))	('fatigue', 'Disease', (37, 44))	('impairing activities of daily living', 'Phenotype', 'HP:0031058', (118, 154))	('SSc', 'Var', (14, 17))
659252	30057856	Antibodies against M3-R were shown to induce damage to the myenteric neurons; vascular endothelial alteration favoring fibrosis and collagen deposition have been shown to affect the neural pathways and smooth muscle activity in the GI tract resulting in the various clinical manifestations of the disease including loss of normal peristalsis, hypotonia, wall rigidity and muscular atrophy leading to paresis, dilatation, small bowel bacterial overgrowth, CIPO, diarrhea and eventually malnutrition.	('muscular atrophy', 'Disease', 'MESH:D009133', (372, 388))	('Antibodies', 'Var', (0, 10))	('CIPO', 'Disease', (455, 459))	('overgrowth', 'Phenotype', 'HP:0001548', (443, 453))	('normal peristalsis', 'MPA', (323, 341))	('diarrhea', 'Disease', 'MESH:D003967', (461, 469))	('affect', 'Reg', (171, 177))	('neural pathways', 'Pathway', (182, 197))	('rigidity', 'Disease', 'MESH:D009127', (359, 367))	('loss', 'NegReg', (315, 319))	('hypotonia', 'Phenotype', 'HP:0001290', (343, 352))	('hypotonia', 'Disease', 'MESH:D009123', (343, 352))	('rigidity', 'Disease', (359, 367))	('malnutrition', 'Phenotype', 'HP:0004395', (485, 497))	('dilatation', 'Disease', (409, 419))	('hypotonia', 'Disease', (343, 352))	('paresis', 'Disease', (400, 407))	('fibrosis', 'Disease', 'MESH:D005355', (119, 127))	('fibrosis', 'Disease', (119, 127))	('dilatation', 'Phenotype', 'HP:0002617', (409, 419))	('malnutrition', 'Disease', (485, 497))	('rigidity', 'Phenotype', 'HP:0002063', (359, 367))	('diarrhea', 'Phenotype', 'HP:0002014', (461, 469))	('muscular atrophy', 'Disease', (372, 388))	('CIPO', 'Chemical', '-', (455, 459))	('M3-R', 'Gene', (19, 23))	('wall', 'Disease', (354, 358))	('small bowel bacterial overgrowth', 'Disease', (421, 453))	('collagen', 'Var', (132, 140))	('small bowel bacterial overgrowth', 'Disease', 'MESH:D001765', (421, 453))	('diarrhea', 'Disease', (461, 469))	('muscular atrophy', 'Phenotype', 'HP:0003202', (372, 388))
659274	29849819	It was reported that M2BP has a role in galectin-1 function and modulates cell aggregation by this lectin.	('modulates', 'Reg', (64, 73))	('galectin-1', 'Gene', (40, 50))	('function', 'MPA', (51, 59))	('galectin-1', 'Gene', '3956', (40, 50))	('M2BP', 'Var', (21, 25))	('cell aggregation', 'CPA', (74, 90))
659275	29849819	Researches claimed that M2BP stimulates monocytes and increases IL-2 levels.	('M2BP', 'Var', (24, 28))	('IL-2', 'Gene', (64, 68))	('increases', 'PosReg', (54, 63))	('IL-2', 'Gene', '3558', (64, 68))	('monocytes', 'CPA', (40, 49))	('stimulates', 'PosReg', (29, 39))
659278	29849819	As a matrix protein, M2BP, which seems to be mediated by beta1 integrins and is independent of galectin-3, may play a strong role in apoptosis of cancer cells by means of cellular interactions.	('play', 'Reg', (111, 115))	('apoptosis', 'CPA', (133, 142))	('beta1', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('interactions', 'Interaction', (180, 192))	('cellular', 'CPA', (171, 179))	('M2BP', 'Var', (21, 25))	('beta1', 'Gene', '3779', (57, 62))
659331	29731639	The cumulative incidences of fistula for patients with CEA >2.87 ng/mL and CEA <=2.87 ng/mL were 18.46% and 6.8%, respectively (p=0.016) (Figure 4).	('CEA', 'Gene', (55, 58))	('CEA', 'Gene', '1084', (55, 58))	('CEA', 'Gene', (75, 78))	('patients', 'Species', '9606', (41, 49))	('CEA', 'Gene', '1084', (75, 78))	('fistula', 'Disease', 'MESH:D005402', (29, 36))	('fistula', 'Disease', (29, 36))	('>2.87', 'Var', (59, 64))
659339	29731639	The incidence for patients with CEA >2.87 ng/mL was 18.46%, whereas for those with CEA <=2.87 ng/mL it was only 6.80%.	('CEA', 'Gene', (83, 86))	('CEA', 'Gene', '1084', (83, 86))	('CEA', 'Gene', (32, 35))	('CEA', 'Gene', '1084', (32, 35))	('patients', 'Species', '9606', (18, 26))	('>2.87', 'Var', (36, 41))
659491	29125237	Suspected confounders were tested in the unconditional logistic regression models including age, sex, place of residence (Gonbad rural, Gonbad urban, Kalaleh, and Aq Qala), smoking (pack-years), opium use (ever, never), socioeconomic status (determined by a composite score) 24, formal education (none, any), ethnicity (non-Turkmen, Turkmen), body mass index (BMI) (<18.5, 18.5 to <25, 25 to <30, >=30), family history of esophageal or gastric cancer in first-degree relatives (yes, no), physical activity level at work (irregular nonintense, regular nonintense, irregular intense, or regular intense) 17, and the daily intake of fruits and vegetables (grams/day).	('Aq', 'Chemical', '-', (163, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (436, 450))	('esophageal', 'Disease', (422, 432))	('cancer', 'Phenotype', 'HP:0002664', (444, 450))	('irregular nonintense', 'Var', (521, 541))	('gastric cancer', 'Disease', (436, 450))	('gastric cancer', 'Disease', 'MESH:D013274', (436, 450))
659527	29125237	Methylmercury compounds have been reported to be associated with lung, brain, and prostate cancer 15.	('prostate cancer', 'Disease', 'MESH:D011471', (82, 97))	('lung', 'Disease', (65, 69))	('associated', 'Reg', (49, 59))	('brain', 'Disease', (71, 76))	('prostate cancer', 'Disease', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))	('mercury', 'Chemical', 'MESH:D008628', (6, 13))	('Methylmercury', 'Var', (0, 13))
659594	27785689	The new anastomoses/connections in the small intestine and resulting internal hernia defect (i.e., Peterson's space) may increase the risk for small bowel complications.	('anastomoses/connections', 'Var', (8, 31))	('small bowel complications', 'Disease', 'MESH:D015212', (143, 168))	('internal hernia', 'Phenotype', 'HP:0025195', (69, 84))	('hernia', 'Phenotype', 'HP:0100790', (78, 84))	('internal hernia defect', 'Disease', 'MESH:D006547', (69, 91))	('internal hernia defect', 'Disease', (69, 91))	('small bowel complications', 'Disease', (143, 168))
659607	26678488	 Anaplastic Lymphoma Kinase Rearrangement in Digestive Tract Cancer: Implication for Targeted Therapy in Chinese Population Anaplastic lymphoma kinase (ALK) rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition.	('Cancer', 'Disease', (61, 67))	('Anaplastic lymphoma kinase', 'Gene', '238', (124, 150))	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))	('cancer', 'Disease', (198, 204))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('Tract Cancer', 'Disease', 'MESH:D014571', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Anaplastic Lymphoma Kinase', 'Gene', (1, 27))	('Anaplastic lymphoma kinase', 'Gene', (124, 150))	('rearrangements', 'Var', (157, 171))	('lymphoma', 'Phenotype', 'HP:0002665', (135, 143))	('ALK', 'Gene', '238', (152, 155))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (124, 143))	('lung cancer', 'Disease', (193, 204))	('ALK', 'Gene', (152, 155))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Lymphoma', 'Phenotype', 'HP:0002665', (12, 20))	('Tract Cancer', 'Disease', (55, 67))	('Anaplastic Lymphoma Kinase', 'Gene', '238', (1, 27))	('Digestive Tract Cancer', 'Phenotype', 'HP:0007378', (45, 67))	('Anaplastic Lymphoma', 'Phenotype', 'HP:0012193', (1, 20))
659612	26678488	The incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric and esophageal cancers', 'Disease', 'MESH:D013274', (94, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('gene fusion', 'Var', (26, 37))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('esophageal cancer', 'Disease', (106, 123))	('ALK', 'Gene', (22, 25))	('cancers', 'Disease', (117, 124))
659614	26678488	Since the original description in 1994, other ALK gene alterations have been subsequently reported in the literature, and this gene has been found to be rearranged, mutated, or amplified in several types of solid tumors, such as inflammatory myofibroblastic tumor, lung cancer and colorectal cancer (CRC).	('colorectal cancer', 'Disease', (281, 298))	('solid tumors', 'Disease', 'MESH:D009369', (207, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Disease', (258, 263))	('lung cancer', 'Phenotype', 'HP:0100526', (265, 276))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (229, 263))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('colorectal cancer', 'Phenotype', 'HP:0003003', (281, 298))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (242, 263))	('inflammatory myofibroblastic tumor', 'Disease', (229, 263))	('rectal cancer', 'Phenotype', 'HP:0100743', (285, 298))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('lung cancer', 'Disease', (265, 276))	('solid tumors', 'Disease', (207, 219))	('ALK gene', 'Gene', (46, 54))	('tumor', 'Disease', (213, 218))	('alterations', 'Var', (55, 66))	('tumor', 'Disease', 'MESH:D009369', (213, 218))
659635	26678488	This method showed high sensitivity and specificity of 100% and 98% respectively, for detecting ALK rearrangement in primary lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (125, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('rearrangement', 'Var', (100, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('ALK', 'Gene', (96, 99))	('detecting', 'Reg', (86, 95))
659641	26678488	Although crizotinib is initially approved as a targeted therapy for NSCLC, a study focusing on inflammatory myofibroblastic tumors reported a partial response to it in a patient with ALK translocation, while there was no observed activity in another patient without the translocation.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('myofibroblastic tumors', 'Disease', (108, 130))	('myofibroblastic tumors', 'Disease', 'MESH:D009369', (108, 130))	('ALK translocation', 'Var', (183, 200))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (108, 129))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (108, 130))
659643	26678488	Crizotinib was also able to inhibit proliferation and ALK-mediated signaling in a neuroblastoma cell line.	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('neuroblastoma', 'Disease', 'MESH:D009447', (82, 95))	('Crizotinib', 'Var', (0, 10))	('neuroblastoma', 'Disease', (82, 95))	('neuroblastoma', 'Phenotype', 'HP:0003006', (82, 95))	('proliferation', 'CPA', (36, 49))	('inhibit', 'NegReg', (28, 35))	('ALK-mediated signaling', 'MPA', (54, 76))
659647	26678488	SPTBN1 gene fusions have been reported in atypical myeloproliferative disorders (MPDs) and atypical chronic myeloid leukemia.	('SPTBN1', 'Gene', (0, 6))	('fusions', 'Var', (12, 19))	('reported', 'Reg', (30, 38))	('leukemia', 'Phenotype', 'HP:0001909', (116, 124))	('chronic myeloid leukemia', 'Disease', (100, 124))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (100, 124))	('myeloproliferative disorders', 'Disease', (51, 79))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (100, 124))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (51, 79))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (108, 124))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (51, 79))
659648	26678488	In one MPDs case, SPTBN1 was fused to the platelet-derived growth factor receptor beta gene (PDGFRB), a member of the type III receptor tyrosine kinase family.	('platelet-derived growth factor receptor beta', 'Gene', '5159', (42, 86))	('SPTBN1', 'Gene', (18, 24))	('PDGFRB', 'Gene', '5159', (93, 99))	('fused', 'Var', (29, 34))	('PDGFRB', 'Gene', (93, 99))	('platelet-derived growth factor receptor beta', 'Gene', (42, 86))
659655	24828664	TGM2 expression in neoadjuvantly treated EACs and following small interfering RNA-mediated knockdown in cisplatin-treated EAC cells was used to determine its possible role in chemoresistance.	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('TGM2', 'Gene', '7052', (0, 4))	('TGM2', 'Gene', (0, 4))	('knockdown', 'Var', (91, 100))
659676	24828664	In other epithelial cancers cell lines, expression of TGM2 has been linked to cisplatin and doxorubicin drug resistance with knockdown of TGM2 causing increased chemosensitivity.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('linked', 'Reg', (68, 74))	('TGM2', 'Gene', (54, 58))	('epithelial cancers', 'Disease', (9, 27))	('knockdown', 'Var', (125, 134))	('increased', 'PosReg', (151, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (92, 103))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('epithelial cancers', 'Disease', 'MESH:D000077216', (9, 27))	('chemosensitivity', 'MPA', (161, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('TGM2', 'Gene', '7052', (138, 142))	('TGM2', 'Gene', (138, 142))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('TGM2', 'Gene', '7052', (54, 58))
659700	24828664	All primers were designed using NCBI Primer-BLAST and the primer sequences for TGM2 are: TGM2 all isoforms, forward CCAACTACAACTCGGCCCAT, and reverse CTGGTCATCCACGACTCCAC targeting between exons 7 and 8; long isoform (NCBI NM_004613), forward GCAGGGGAGGAAGTTAAGGTGAGAA, and reverse GGCGGGGCCAATGATGACA targeting exon 13; common short isoform (NCBI NM_198951), forward GGTAAAGCCCTGTGTTCCTG, and reverse AGCGCCATGTAAGTGTCTGTG targeting its unique portion in exon 10.	('TGM2', 'Gene', (89, 93))	('TGM2', 'Gene', '7052', (89, 93))	('TGM2', 'Gene', '7052', (79, 83))	('TGM2', 'Gene', (79, 83))	('NCBI NM_198951', 'Var', (343, 357))
659721	24828664	There are two major TGM2 isoforms, a long form (NM_004613) containing 3937 base pairs (687AA) and the shorter form (NM_198951) truncated at the 3' UTR and containing only 1879 base pairs (548AA) with a unique C-terminus.	('TGM2', 'Gene', '7052', (20, 24))	('TGM2', 'Gene', (20, 24))	('NM_004613', 'Var', (48, 57))
659741	24828664	In breast cancer and in non-small-cell lung cancers, TGM2 promoter hypermethylation seem to influence TGM2 expression and chemosensitivity.	('influence', 'Reg', (92, 101))	('TGM2', 'Gene', '7052', (53, 57))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('TGM2', 'Gene', (53, 57))	('TGM2', 'Gene', '7052', (102, 106))	('lung cancers', 'Disease', 'MESH:D008175', (39, 51))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('TGM2', 'Gene', (102, 106))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('expression', 'MPA', (107, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('lung cancers', 'Phenotype', 'HP:0100526', (39, 51))	('lung cancers', 'Disease', (39, 51))	('promoter hypermethylation', 'Var', (58, 83))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
659755	24828664	The data suggest that increased TGM2 copy number partially accounts for, in addition to epigenetic and TGFbeta regulation, upregulated expression of TGM2.	('TGM2', 'Gene', '7052', (149, 153))	('TGM2', 'Gene', '7052', (32, 36))	('TGFbeta', 'Gene', '7040', (103, 110))	('upregulated', 'PosReg', (123, 134))	('copy number', 'Var', (37, 48))	('increased', 'PosReg', (22, 31))	('expression', 'MPA', (135, 145))	('TGFbeta', 'Gene', (103, 110))	('TGM2', 'Gene', (149, 153))	('TGM2', 'Gene', (32, 36))
659761	24828664	We observed that siRNA knockdown significantly decreased cell viability in OE33 (high baseline TGM2 expression) when compared with nontargeting siRNA (Fig.	('TGM2', 'Gene', (95, 99))	('TGM2', 'Gene', '7052', (95, 99))	('knockdown', 'Var', (23, 32))	('expression', 'MPA', (100, 110))	('cell viability', 'CPA', (57, 71))	('decreased', 'NegReg', (47, 56))
659763	24828664	When OE33 cells were treated with cisplatin in addition to siRNA knockdown of TGM2, cellular viability increased significantly when compared with mock-transfected cultures at each level of cisplatin concentration tested (Supplementary Figure 4, SDC 1, http://links.lww.com/JTO/A609).	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('SDC 1', 'Gene', '6382', (245, 250))	('TGM2', 'Gene', '7052', (78, 82))	('increased', 'PosReg', (103, 112))	('TGM2', 'Gene', (78, 82))	('SDC 1', 'Gene', (245, 250))	('knockdown', 'Var', (65, 74))	('cellular viability', 'CPA', (84, 102))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))
659780	24828664	Because not all tumors that overexpress TGM2 showed high gene copy number, other transcriptional or posttranslational mechanisms may be involved in the regulation of TGM2 expression in these cancers.	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('high gene copy number', 'Var', (52, 73))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Disease', (191, 198))	('TGM2', 'Gene', '7052', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Disease', (16, 22))	('TGM2', 'Gene', (40, 44))	('TGM2', 'Gene', (166, 170))	('TGM2', 'Gene', '7052', (40, 44))
659784	24828664	Dysregulation of TGFbeta expression has been observed in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (57, 63))	('TGFbeta', 'Gene', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('observed', 'Reg', (45, 53))	('TGFbeta', 'Gene', '7040', (17, 24))
659787	24828664	We hypothesized that TGM2 knockdown or enzymatic inhibition may sensitize or lead to drug-induced apoptosis in resistant tumors; however, the opposite was observed in OE33 cells (Supplementary Figure 4, SDC 1, http://links.lww.com/JTO/A609) and may not reflect accurately the complexity of tumor biology.	('lead to', 'Reg', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('SDC 1', 'Gene', (203, 208))	('TGM2', 'Gene', (21, 25))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (121, 126))	('TGM2', 'Gene', '7052', (21, 25))	('drug-induced apoptosis', 'MPA', (85, 107))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('knockdown', 'Var', (26, 35))	('SDC 1', 'Gene', '6382', (203, 208))	('sensitize', 'Reg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('inhibition', 'NegReg', (49, 59))	('tumor', 'Disease', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
659788	24828664	Because TGM2 knockdown reduced cell growth, it is possible that cisplatin that has high cytotoxicity in S phase was less effective in reducing cell viability when TGM2 is reduced.	('TGM2', 'Gene', '7052', (8, 12))	('cytotoxicity', 'Disease', (88, 100))	('cytotoxicity', 'Disease', 'MESH:D064420', (88, 100))	('cell growth', 'CPA', (31, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('reduced', 'NegReg', (23, 30))	('TGM2', 'Gene', '7052', (163, 167))	('knockdown', 'Var', (13, 22))	('TGM2', 'Gene', (163, 167))	('TGM2', 'Gene', (8, 12))
659831	23915238	RT-PCR results showed that STAT5 Bcl-2 and Cyclin D1 mRNA expression in STAT5 siRNA group were significantly inhibited compared to siRNA control and blank control group as shown in Table 2.	('Cyclin D1', 'Gene', '595', (43, 52))	('Bcl-2', 'Gene', (33, 38))	('inhibited', 'NegReg', (109, 118))	('Bcl-2', 'Gene', '596', (33, 38))	('Cyclin D1', 'Gene', (43, 52))	('STAT5 siRNA', 'Var', (72, 83))
659833	23915238	The result showed that silencing the STAT5 depresses the proliferation of esophageal carcinoma cell line Eca-109 (Figure 1B).	('esophageal carcinoma', 'Disease', 'MESH:D004938', (74, 94))	('depresses', 'NegReg', (43, 52))	('silencing', 'Var', (23, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('STAT5', 'Gene', (37, 42))	('proliferation', 'CPA', (57, 70))	('esophageal carcinoma', 'Disease', (74, 94))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (74, 94))
659834	23915238	The result showed that silencing the STAT5 induced the apoptosis and suppressed invasion and metastasis of esophageal carcinoma cell line Eca-109 as shown in Table 4.	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('silencing', 'Var', (23, 32))	('metastasis of esophageal carcinoma', 'Disease', (93, 127))	('suppressed', 'NegReg', (69, 79))	('STAT5', 'Gene', (37, 42))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (107, 127))	('metastasis of esophageal carcinoma', 'Disease', 'MESH:D009362', (93, 127))	('apoptosis', 'CPA', (55, 64))
659844	23915238	Zhao Zhengjun e.tal approved silencing the STAT5 of liver carcinoma cell SMMC27721 induced the cell apoptosis,using siRNA.	('silencing', 'Var', (29, 38))	('liver carcinoma', 'Disease', 'MESH:D006528', (52, 67))	('cell apoptosis', 'CPA', (95, 109))	('liver carcinoma', 'Disease', (52, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('liver carcinoma', 'Phenotype', 'HP:0001402', (52, 67))
659845	23915238	Duan zhao e.tal approved silencing the STAT5 depressed the proliferation of cervical carcinoma cell HeLa and induced the cell apoptosis.	('silencing', 'Var', (25, 34))	('depressed', 'NegReg', (45, 54))	('induced', 'Reg', (109, 116))	('cervical carcinoma cell HeLa', 'Disease', 'MESH:D002575', (76, 104))	('STAT5', 'Gene', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cervical carcinoma cell HeLa', 'Disease', (76, 104))	('cell apoptosis', 'CPA', (121, 135))
659853	23915238	The study first approved silencing the STAT5 of esophageal carcinoma cell line Eca-109 induced the apoptosis and supressed the proliferation,invasion and metastasis, which indicated STAT5 might be a novel therapeutic strategy for the human ESCC.	('silencing', 'Var', (25, 34))	('supressed', 'NegReg', (113, 122))	('proliferation', 'CPA', (127, 140))	('esophageal carcinoma', 'Disease', (48, 68))	('human', 'Species', '9606', (234, 239))	('apoptosis', 'CPA', (99, 108))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (48, 68))	('STAT5', 'Gene', (39, 44))	('ESCC', 'Disease', (240, 244))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (48, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
659915	23289488	Although incidence of nodal metastasis in pT1 tumor was significantly lower in the type G tumor group than the other type tumor groups, there was no significant difference in pT2, pT3 and pT4 tumors among 4 tumor groups.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Disease', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (122, 127))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('pT3', 'Gene', '7694', (180, 183))	('pT1', 'Gene', '58492', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (192, 197))	('pT1', 'Gene', (42, 45))	('type G', 'Var', (83, 89))	('tumor', 'Disease', (46, 51))	('nodal metastasis', 'CPA', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('lower', 'NegReg', (70, 75))	('pT3', 'Gene', (180, 183))
659978	33466369	Using the Dual-Index Degenerate Adaptor-Sequencing (DIDA-Seq) error-correction method, we serially interrogated plasma cell-free DNA at 28-41 tumor-specific genomic loci throughout therapy and in surveillance with an average limit of detection of 0.016% mutant allele frequency.	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('mutant', 'Var', (254, 260))
659984	33466369	Undetectable ctDNA following definitive treatment has been shown to be associated with pathologic complete response (pCR) and improved outcomes, particularly in the neoadjuvant setting for breast cancer; however, the feasibility of serial ctDNA measurements in the neoadjuvant setting for rectal and esophageal cancer has not been previously reported.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('esophageal cancer', 'Disease', (300, 317))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('esophageal cancer', 'Disease', 'MESH:D004938', (300, 317))	('breast cancer', 'Disease', (189, 202))	('Undetectable', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
659985	33466369	Our ctDNA monitoring technique, called DIDA-Seq (Dual-Indexed, Degenerate Adaptor-Sequencing), combines unique-molecular indexing (UMI)-based error correction with custom hybridization capture at many genomic loci of somatic variants previously identified by whole-exome sequencing of the patient's tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('variants', 'Var', (225, 233))	('tumor', 'Disease', (299, 304))
659992	33466369	SNVs were filtered by frequency (requiring >1% variant allele frequency and >3 supporting reads in the tumor, and <2% variant allele frequency in the matched normal) and depth (requiring >=30X coverage in the tumor and >=14X coverage in the matched normal) and were further assessed and hand-curated using Oncotator and IGV software.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', (103, 108))	('variant', 'Var', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
659997	33466369	Patient 1 is a 33 year old female who presented with cT3N1M0 distal rectal adenocarcinoma and enrolled on an unrelated phase II trial evaluating the efficacy of total neoadjuvant therapy (eight cycles of FOLFOX chemotherapy and long-course chemoradiation) followed by non-operative management for clinical complete responders based on MRI and endoscopy (NCT02008656).	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('cT3N1M0', 'Var', (53, 60))	('adenocarcinoma', 'Disease', 'MESH:D000230', (75, 89))	('FOLFOX', 'Chemical', '-', (204, 210))	('adenocarcinoma', 'Disease', (75, 89))
659999	33466369	Patient 2 is a 59 year old male who presented with cT2N1M0 mid-rectal adenocarcinoma and enrolled on the aforementioned phase II study.	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('adenocarcinoma', 'Disease', 'MESH:D000230', (70, 84))	('adenocarcinoma', 'Disease', (70, 84))	('cT2N1M0', 'Var', (51, 58))
660007	33466369	Patient 4 is a 61 year old male with a history of cT2N0M0 distal esophageal adenocarcinoma who underwent neoadjuvant chemoradiation and esophagectomy.	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (65, 90))	('cT2N0M0', 'Var', (50, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('adenocarcinoma', 'Disease', (76, 90))
660008	33466369	CtDNA levels declined during neoadjuvant therapy, associated with reduced tumor size and avidity on PET-CT, and were near the limit of detection (i.e., indeterminate as compared negative control values, see Methods) with 5 mutant reads in 114k total reads immediately prior to surgery, and 29 mutant reads in 137k total reads immediately following surgery (Figure 4A).	('reduced', 'NegReg', (66, 73))	('mutant', 'Var', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('declined', 'NegReg', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CtDNA levels', 'MPA', (0, 12))	('tumor', 'Disease', (74, 79))	('avidity', 'MPA', (89, 96))
660009	33466369	Patient 5 is a 69 year old male with cT3N0M0 distal esophageal adenocarcinoma who received neoadjuvant chemoradiation prior to esophagectomy with surgical pathology confirming a near-complete response.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (52, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cT3N0M0', 'Var', (37, 44))	('adenocarcinoma', 'Disease', (63, 77))	('adenocarcinoma', 'Disease', 'MESH:D000230', (63, 77))
660024	33466369	In a similar study for Stage II and III rectal cancer patients receiving tri-modality therapy with planned surgery, the presence of tumor-specific ctDNA during post-neoadjuvant chemoradiation was highly predictive for disease recurrence despite adjustment for stage, CEA levels, and use of adjuvant therapy.	('predictive for', 'Reg', (203, 217))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Disease', (47, 53))	('rectal cancer', 'Phenotype', 'HP:0100743', (40, 53))	('tumor', 'Disease', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('presence', 'Var', (120, 128))	('ctDNA', 'Gene', (147, 152))	('disease recurrence', 'CPA', (218, 236))
660025	33466369	Additionally, in a heterogeneous cohort of esophageal cancer patients receiving chemoradiation either in the neoadjuvant or definitive setting, post-chemoradiation panel-based mutation detection of ctDNA was associated with tumor progression, metastasis, and shorter survival.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('mutation detection', 'Var', (176, 194))	('tumor', 'Disease', (224, 229))	('ctDNA', 'Gene', (198, 203))	('associated with', 'Reg', (208, 223))	('metastasis', 'CPA', (243, 253))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('shorter', 'NegReg', (259, 266))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
660029	33466369	As sequencing costs decrease, it may be feasible to routinely monitor cell-free DNA for every mutation identified by exome- or whole-genome sequencing of tumor biopsies, potentially mitigating such issues.	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mutation', 'Var', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
660047	31491899	These miRNAs are able to target numerous genes by their seed sequence (nucleotides 2-8), as well as by base pairing in the central region (nucleotides 9-12) resulting in an amplification of their biological effects.	('biological effects', 'MPA', (196, 214))	('nucleotides 2-8', 'Chemical', 'MESH:D009711', (71, 86))	('miR', 'Gene', '220972', (6, 9))	('miR', 'Gene', (6, 9))	('amplification', 'PosReg', (173, 186))	('base pairing', 'Var', (103, 115))
660105	31491899	They used qPCR to identify the best internal RGs between miR-16, miR-638, snRNAU6, 18S rRNA, Let-7a and miR-92a.	('miR', 'Gene', '220972', (57, 60))	('miR-638', 'Gene', (65, 72))	('miR', 'Gene', (57, 60))	('snRNAU6', 'Var', (74, 81))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('miR-16', 'Gene', (57, 63))	('miR', 'Gene', '220972', (104, 107))	('miR', 'Gene', (104, 107))	('miR-16', 'Gene', '51573', (57, 63))	('miR-638', 'Gene', '693223', (65, 72))
660108	31491899	They evaluated six miRNAs (let-7a, miR-16, miR-93, miR-103, miR-192 and miR-451) and one small nuclear RNA (RNU6B) according to literature searches and suggestions from Exiqon.	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (60, 63))	('miR', 'Gene', (51, 54))	('miR', 'Gene', (35, 38))	('RNU6B', 'Gene', (108, 113))	('miR-192', 'Gene', '406967', (60, 67))	('let-7a', 'Var', (27, 33))	('miR', 'Gene', (19, 22))	('miR', 'Gene', (43, 46))	('rat', 'Species', '10116', (132, 135))	('miR-16', 'Gene', (35, 41))	('miR-451', 'Gene', '574411', (72, 79))	('RNU6B', 'Gene', '26826', (108, 113))	('miR', 'Gene', '220972', (72, 75))	('miR-93', 'Gene', (43, 49))	('miR-93', 'Gene', '407051', (43, 49))	('miR-16', 'Gene', '51573', (35, 41))	('miR', 'Gene', (72, 75))	('miR-192', 'Gene', (60, 67))	('miR-451', 'Gene', (72, 79))
660136	31491899	The authors investigated the expression stability of eight miRNAs (miR-16, miR-103, miR-191, let-7a, miR-26a, miR-221, miR-181a and miR-451) and two small RNAs (5S and U6), according to previous reports of their reliability as RGs for qPCR assay of hepatopathy patients.	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', '220972', (84, 87))	('hepatopathy', 'Disease', (249, 260))	('hepatopathy', 'Disease', 'None', (249, 260))	('miR', 'Gene', '220972', (59, 62))	('miR-191', 'Gene', '406966', (84, 91))	('miR-191', 'Gene', (84, 91))	('miR', 'Gene', (132, 135))	('miR-451', 'Gene', '574411', (132, 139))	('miR', 'Gene', (67, 70))	('miR', 'Gene', (101, 104))	('miR-221', 'Gene', (110, 117))	('miR', 'Gene', (75, 78))	('miR', 'Gene', (84, 87))	('let-7a', 'Var', (93, 99))	('miR', 'Gene', (59, 62))	('miR-221', 'Gene', '407006', (110, 117))	('miR-16', 'Gene', (67, 73))	('miR-26a', 'Gene', (101, 108))	('miR', 'Gene', '220972', (119, 122))	('miR-451', 'Gene', (132, 139))	('miR-26a', 'Gene', '407015', (101, 108))	('miR', 'Gene', '220972', (110, 113))	('miR-16', 'Gene', '51573', (67, 73))	('miR', 'Gene', (119, 122))	('miR', 'Gene', '220972', (132, 135))	('patients', 'Species', '9606', (261, 269))	('miR', 'Gene', (110, 113))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', '220972', (101, 104))
660145	31491899	analyzed the serum exosomal levels of miR-26a, miR-21, miR-22*, miR-181a, miR-181c, miR-16, miR-103, miR-191, let-7a, 5SrRNA and U6snRNA by using qPCR.	('miR', 'Gene', '220972', (84, 87))	('let-7a', 'Var', (110, 116))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (47, 50))	('miR-191', 'Gene', '406966', (101, 108))	('miR-16', 'Gene', (84, 90))	('miR-191', 'Gene', (101, 108))	('miR', 'Gene', (38, 41))	('miR', 'Gene', (101, 104))	('miR-181c', 'Gene', '406957', (74, 82))	('miR', 'Gene', (84, 87))	('miR', 'Gene', '220972', (74, 77))	('miR', 'Gene', (92, 95))	('miR-26a', 'Gene', (38, 45))	('miR-16', 'Gene', '51573', (84, 90))	('miR', 'Gene', (74, 77))	('miR-26a', 'Gene', '407015', (38, 45))	('miR', 'Gene', '220972', (64, 67))	('miR-21', 'Gene', '406991', (47, 53))	('miR', 'Gene', '220972', (55, 58))	('miR-181c', 'Gene', (74, 82))	('miR', 'Gene', '220972', (47, 50))	('miR-22', 'Gene', '407004', (55, 61))	('miR', 'Gene', (64, 67))	('miR-22', 'Gene', (55, 61))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (55, 58))	('miR', 'Gene', '220972', (101, 104))	('miR-21', 'Gene', (47, 53))
660195	31491899	From this analysis, 11 miRNAs (miR-25-3p, miR-520f, miR-149-5p, let-7a-5p, miR-2682-5p, miR-612, miR-222-3p, miR-598, miR-188-5p, miR-489 and lastly miR-1183) were selected for a subsequent validation step by qPCR and Digital Droplet PCR (ddPCR) in pooled plasma samples.	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (109, 112))	('miR', 'Gene', (23, 26))	('miR-520f', 'Gene', '574464', (42, 50))	('miR-612', 'Gene', (88, 95))	('let-7a-5p', 'Var', (64, 73))	('miR', 'Gene', '220972', (52, 55))	('miR-489', 'Gene', (130, 137))	('miR', 'Gene', (75, 78))	('miR-598', 'Gene', '693183', (109, 116))	('miR-222', 'Gene', (97, 104))	('miR', 'Gene', '220972', (130, 133))	('miR-25', 'Gene', (31, 37))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (52, 55))	('miR', 'Gene', '220972', (88, 91))	('miR-520f', 'Gene', (42, 50))	('188-5p', 'Chemical', 'MESH:C490816', (122, 128))	('miR', 'Gene', (130, 133))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', '220972', (149, 152))	('miR-1183', 'Gene', '100302122', (149, 157))	('Digital Droplet', 'Disease', (218, 233))	('miR', 'Gene', (42, 45))	('miR-222', 'Gene', '407007', (97, 104))	('miR', 'Gene', '220972', (118, 121))	('miR', 'Gene', (97, 100))	('miR-1183', 'Gene', (149, 157))	('miR', 'Gene', (88, 91))	('miR', 'Gene', '220972', (109, 112))	('miR', 'Gene', '220972', (23, 26))	('miR-612', 'Gene', '693197', (88, 95))	('miR-25', 'Gene', '407014', (31, 37))	('miR', 'Gene', (31, 34))	('Digital Droplet', 'Disease', 'MESH:D058066', (218, 233))	('miR-598', 'Gene', (109, 116))	('miR', 'Gene', (149, 152))	('miR-489', 'Gene', '574442', (130, 137))	('miR', 'Gene', (118, 121))
660247	28810885	Hence, the high conformality of IMRT could theoretically afford fewer toxicities to these organs-at-risk (OARs), especially in the setting of relative dose-escalation with dCRT, but supportive data are currently lacking.	('OAR', 'Gene', '4936', (106, 109))	('toxicities', 'Disease', (70, 80))	('OAR', 'Gene', (106, 109))	('dCRT', 'Gene', (172, 176))	('dCRT', 'Gene', '45841', (172, 176))	('high conformality', 'Var', (11, 28))	('toxicities', 'Disease', 'MESH:D064420', (70, 80))	('fewer', 'NegReg', (64, 69))
660312	27857024	We evaluated the efficacy and safety of leucovorin and 5-fluorouracil (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX) combination chemotherapies administered adjuvantly for curatively-resected, node-positive ESCC.	('SCC', 'Gene', '6317', (207, 210))	('LV5FU2', 'Var', (83, 89))	('FOLFOX', 'Chemical', '-', (108, 114))	('SCC', 'Gene', (207, 210))	('SCC', 'Phenotype', 'HP:0002860', (207, 210))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (95, 106))	('leucovorin', 'Chemical', 'MESH:D002955', (40, 50))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (55, 69))
660313	27857024	Patients with pathologically node-positive esophageal cancer after curative R0 resection were enrolled and randomly assigned to receive LV5FU2 or FOLFOX biweekly for up to eight cycles.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('FOLFOX', 'Chemical', '-', (146, 152))	('Patients', 'Species', '9606', (0, 8))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('LV5FU2', 'Var', (136, 142))
660316	27857024	The DFS rate at 12 months was 67% in the LV5FU2 group and 63% in the FOLFOX group with a hazard ratio of 1.3 (95% confidence interval [CI], 0.66 to 2.62).	('DFS', 'Disease', (4, 7))	('FOLFOX', 'Chemical', '-', (69, 75))	('LV5FU2', 'Var', (41, 47))
660318	27857024	Grade 3 or 4 neutropenia was more frequent in patients in the FOLFOX arm than the LV5FU2 arm (20.0% vs. 3.1%).	('FOLFOX', 'Var', (62, 68))	('FOLFOX', 'Chemical', '-', (62, 68))	('patients', 'Species', '9606', (46, 54))	('neutropenia', 'Disease', 'MESH:D009503', (13, 24))	('neutropenia', 'Phenotype', 'HP:0001875', (13, 24))	('neutropenia', 'Disease', (13, 24))
660354	27857024	Approximately 70% of patients had stage III disease, and the upper esophagus tumors represented 20% of patients in the LV5FU2 group and 33% of the FOLFOX group.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('upper esophagus tumors', 'Disease', 'MESH:D004938', (61, 83))	('FOLFOX', 'Chemical', '-', (147, 153))	('esophagus tumors', 'Phenotype', 'HP:0100751', (67, 83))	('upper esophagus tumors', 'Disease', (61, 83))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('stage III disease', 'Disease', (34, 51))	('patients', 'Species', '9606', (103, 111))	('LV5FU2', 'Var', (119, 125))
660355	27857024	The DFS rate at 12 months, which was the primary endpoint in this study, was 67% (95% confidence interval [CI], 50.7 to 83.3) in the LV5FU2 group and 63% (95% CI, 45.7 to 80.3) in the FOLFOX group with a hazard ratio (HR) of 1.3 (95% CI, 0.66 to 2.62).	('FOLFOX', 'Chemical', '-', (184, 190))	('LV5FU2', 'Var', (133, 139))	('DFS', 'MPA', (4, 7))
660365	27857024	Grade 3 or higher neutropenia was more frequent in patients in the FOLFOX arm compared with the LV5FU2 arm (20.0% vs. 3.1%), but no patients exhibited febrile neutropenia.	('neutropenia', 'Disease', (159, 170))	('neutropenia', 'Disease', (18, 29))	('febrile neutropenia', 'Disease', (151, 170))	('febrile neutropenia', 'Disease', 'MESH:D009503', (151, 170))	('FOLFOX', 'Var', (67, 73))	('Grade 3', 'Disease', (0, 7))	('neutropenia', 'Disease', 'MESH:D009503', (18, 29))	('FOLFOX', 'Chemical', '-', (67, 73))	('neutropenia', 'Disease', 'MESH:D009503', (159, 170))	('neutropenia', 'Phenotype', 'HP:0001875', (18, 29))	('patients', 'Species', '9606', (51, 59))	('neutropenia', 'Phenotype', 'HP:0001875', (159, 170))	('patients', 'Species', '9606', (132, 140))
660369	27857024	Treatment completion rates were similarly high in both groups (84% in the LV5FU2 arm and 70% in the FOLFOX arm, p=0.230).	('FOLFOX', 'Chemical', '-', (100, 106))	('LV5FU2', 'Var', (74, 80))	('Treatment completion', 'CPA', (0, 20))
660458	28226185	We titrate down our p53 antibody using two formalin-fixed and paraffin-embedded cell lines one know to harbor p53 mutation (and overexpress p53) while the other has wild-type p53.	('p53', 'Gene', (20, 23))	('p53', 'Gene', (175, 178))	('p53', 'Gene', (110, 113))	('p53', 'Gene', '7157', (20, 23))	('paraffin', 'Chemical', 'MESH:D010232', (62, 70))	('p53', 'Gene', '7157', (110, 113))	('formalin', 'Chemical', 'MESH:D005557', (43, 51))	('overexpress', 'PosReg', (128, 139))	('mutation', 'Var', (114, 122))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('p53', 'Gene', '7157', (175, 178))
660459	28226185	We optimized our staining conditions to produce strong nuclear staining in the cell line with p53 mutation and no staining in the cell line with wild type p53, and this may have resulted in our inability to detect wild type p53 in our cases.	('p53', 'Gene', (224, 227))	('p53', 'Gene', (155, 158))	('p53', 'Gene', (94, 97))	('mutation', 'Var', (98, 106))	('p53', 'Gene', '7157', (224, 227))	('p53', 'Gene', '7157', (155, 158))	('p53', 'Gene', '7157', (94, 97))	('nuclear staining', 'MPA', (55, 71))
660460	28226185	Furthermore, because of its detection largely in cases with HGD/EAC it is likely that absent p53 stating pattern is a late event in the neoplastic progression in BM, and may not be valuable as a predictive marker.	('p53', 'Gene', '7157', (93, 96))	('p53', 'Gene', (93, 96))	('absent', 'Var', (86, 92))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))
660533	28384225	Blurring or irregular Z-lines in 28 NERD patients (58.3%) were the most common i-scan endoscopic findings of minimal changes in this study.	('patients', 'Species', '9606', (41, 49))	('irregular', 'Var', (12, 21))	('Blurring', 'Var', (0, 8))
660762	20602752	Our results show that GST pi expression is down regulated in the squamous esophageal carcinoma, and that the lack of GST pi expression is associated with poor prognosis.	('GST pi', 'Gene', (22, 28))	('squamous esophageal carcinoma', 'Disease', (65, 94))	('lack', 'Var', (109, 113))	('squamous esophageal carcinoma', 'Disease', 'MESH:D000077277', (65, 94))	('GST pi', 'Gene', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('down regulated', 'NegReg', (43, 57))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (74, 94))
660775	20602752	As to the alternation of GST pi in development of esophageal carcinoma, several studies have been performed on Barrett's metaplasia and adenocarcinoma with results suggesting deficiency of GST pi may contribute to an increased cancer risk.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('adenocarcinoma', 'Disease', (136, 150))	('deficiency', 'Var', (175, 185))	('men', 'Species', '9606', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('adenocarcinoma', 'Disease', 'MESH:D000230', (136, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('esophageal carcinoma', 'Disease', (50, 70))	('GST pi', 'Gene', (189, 195))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('metaplasia', 'Disease', 'MESH:D008679', (121, 131))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (50, 70))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (50, 70))	('contribute', 'Reg', (200, 210))	('metaplasia', 'Disease', (121, 131))
660778	20602752	Our study confirms a down-regulated GST pi expression in this type of tumor, and demonstrates the deficiency of GST pi protein expression is significantly associated with a shorter overall survival.	('deficiency', 'Var', (98, 108))	('GST pi', 'Gene', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('expression', 'MPA', (127, 137))	('tumor', 'Disease', (70, 75))	('down-regulated', 'NegReg', (21, 35))	('shorter', 'NegReg', (173, 180))	('GST', 'Protein', (36, 39))	('expression', 'MPA', (43, 53))	('overall survival', 'MPA', (181, 197))
660815	20602752	Hypermethylation of GST pi gene, although happened at a low frequency, has been reported in esophageal adenocarcinomas.	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (92, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('GST pi', 'Gene', (20, 26))	('Hypermethylation', 'Var', (0, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('esophageal adenocarcinomas', 'Disease', (92, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (92, 117))	('reported', 'Reg', (80, 88))
660817	20602752	We speculate that epigenetic alterations may happen in squamous esophageal carcinomas and results in a decreased GST pi expression in this type of tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('squamous esophageal carcinomas', 'Disease', 'MESH:D000077277', (55, 85))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (64, 84))	('decreased', 'NegReg', (103, 112))	('GST pi', 'Protein', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('happen', 'Reg', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('epigenetic alterations', 'Var', (18, 40))	('squamous esophageal carcinomas', 'Disease', (55, 85))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (64, 85))
660820	20602752	On the other side, due to the redox-mediated damages on DNA molecules, they could initiate a cascade of mutational events which promoted the development or progression of malignancy.	('damages', 'Var', (45, 52))	('men', 'Species', '9606', (148, 151))	('development', 'CPA', (141, 152))	('promoted', 'PosReg', (128, 136))	('initiate', 'Reg', (82, 90))	('malignancy', 'Disease', 'MESH:D009369', (171, 181))	('DNA molecules', 'Protein', (56, 69))	('malignancy', 'Disease', (171, 181))
660825	20602752	As to development and progression of squamous esophageal carcinoma, we speculate that lack or loss of GST pi protein expression may predispose a normal cell to undergo further genetic alternations, raising risks of malignant changes ultimately and even tumor progression.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('loss', 'NegReg', (94, 98))	('GST pi', 'Gene', (102, 108))	('squamous esophageal carcinoma', 'Disease', 'MESH:D000077277', (37, 66))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (46, 66))	('squamous esophageal carcinoma', 'Disease', (37, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('malignant changes', 'Phenotype', 'HP:0002664', (215, 232))	('tumor', 'Disease', (253, 258))	('men', 'Species', '9606', (13, 16))	('lack', 'Var', (86, 90))	('malignant changes', 'CPA', (215, 232))
660835	30891423	In subgroup analyses, high PD-L2 expression revealed an unfavorable prognostic prediction for OS in hepatocellular carcinoma (HCC) (HR = 1.60, 95% CI = 1.12-2.29, P = 0.011) and for DFS/PFS in HCC (HR = 1.50, 95%CI = 1.04-2.16, P = 0.031) as well as clear cell renal cell carcinoma (HR = 1.45, 95% CI = 1.03-2.03, P = 0.033).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('HCC', 'Disease', (193, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('HCC', 'Phenotype', 'HP:0001402', (193, 196))	('high', 'Var', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (250, 281))	('clear cell renal cell carcinoma', 'Disease', (250, 281))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (261, 281))	('OS in hepatocellular carcinoma', 'Disease', 'MESH:C567932', (94, 124))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (250, 281))	('DFS/PFS', 'Var', (182, 189))	('HCC', 'Phenotype', 'HP:0001402', (126, 129))	('PD-L2', 'Gene', (27, 32))	('OS in hepatocellular carcinoma', 'Disease', (94, 124))
660836	30891423	Conclusion: High PD-L2 expression may promote tumor metastasis and predict unfavorable prognosis in solid cancer patients after surgery, especially in HCC.	('solid cancer', 'Disease', (100, 112))	('PD-L2', 'Protein', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('solid cancer', 'Disease', 'MESH:D009369', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (113, 121))	('HCC', 'Disease', (151, 154))	('promote', 'PosReg', (38, 45))	('tumor metastasis', 'Disease', 'MESH:D009362', (46, 62))	('HCC', 'Phenotype', 'HP:0001402', (151, 154))	('High', 'Var', (12, 16))	('tumor metastasis', 'Disease', (46, 62))	('expression', 'MPA', (23, 33))
660842	30891423	Akin to PD-L1, PD-L2 interacts with PD-1 and suppresses T cell proliferation and cytokine release.	('PD-L2', 'Var', (15, 20))	('T cell proliferation', 'CPA', (56, 76))	('interacts', 'Interaction', (21, 30))	('suppresses', 'NegReg', (45, 55))	('PD-1', 'Gene', (36, 40))	('PD-1', 'Gene', '5133', (36, 40))
660853	30891423	We found that PD-L2 was a negative predictor for prognosis among solid cancer patients.	('solid cancer', 'Disease', (65, 77))	('negative', 'NegReg', (26, 34))	('solid cancer', 'Disease', 'MESH:D009369', (65, 77))	('patients', 'Species', '9606', (78, 86))	('PD-L2', 'Var', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
660872	30891423	Subgroup analyses regarding cancer type clarified that high PD-L2 expression had a unfavorable prognostic value for OS in patients with HCC (HR = 1.60, 95% CI = 1.12-2.29, P = 0.011), while no significant association was observed in RCC, esophageal cancer or gastric cancer (OS for RCC: HR = 1.86, 95% CI = 0.55-6.27, P = 0.315; esophageal cancer: HR = 0.91, 95% CI = 0.60-1.38, P = 0.647; gastric cancer: HR = 1.33, 95% CI = 0.81-2.17).	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('gastric cancer', 'Disease', (390, 404))	('cancer', 'Disease', (249, 255))	('cancer', 'Disease', (398, 404))	('HCC', 'Disease', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (340, 346))	('high', 'Var', (55, 59))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('HCC', 'Phenotype', 'HP:0001402', (136, 139))	('RCC', 'Disease', (233, 236))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('gastric cancer', 'Disease', (259, 273))	('esophageal cancer', 'Disease', 'MESH:D004938', (329, 346))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('RCC', 'Phenotype', 'HP:0005584', (282, 285))	('PD-L2', 'Gene', (60, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (390, 404))	('esophageal cancer', 'Disease', (329, 346))	('cancer', 'Disease', (267, 273))	('gastric cancer', 'Disease', 'MESH:D013274', (259, 273))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (398, 404))	('OS', 'Chemical', '-', (116, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (390, 404))	('esophageal cancer', 'Disease', 'MESH:D004938', (238, 255))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', (340, 346))	('OS', 'Chemical', '-', (275, 277))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (259, 273))	('esophageal cancer', 'Disease', (238, 255))
660877	30891423	The pooled results revealed that PD-L2 was a negative predictor for OS among studies adjusted for PD-1 expression or PD-L1 expression (HR = 1.42, 95% CI = 1.05-1.90, P = 0.021), whereas it was not significantly correlated with OS among studies not adjusted for PD-1/PD-L1 (HR = 1.39, 95% CI = 0.84-2.30, P = 0.201).	('PD-1', 'Gene', (98, 102))	('PD-1', 'Gene', '5133', (98, 102))	('OS', 'Chemical', '-', (227, 229))	('negative', 'NegReg', (45, 53))	('PD-1', 'Gene', (261, 265))	('PD-1', 'Gene', '5133', (261, 265))	('PD-L1', 'Gene', (117, 122))	('OS', 'Chemical', '-', (68, 70))	('PD-L2', 'Var', (33, 38))
660883	30891423	The results of subgroup analysis regarding the model for DFS/PFS was consistent with those of OS, namely, PD-L2 was an unfavorable predictor for DFS/PFS among studies adjusted for PD-1/PD-L1 (HR = 1.62, 95% CI = 1.24-2.13, P < 0.001), whereas it was not significantly correlated with DFS/PFS among studies not adjusted for PD-1/PD-L1 (HR = 1.12, 95% CI = 0.75-1.67, P = 0.591) (Figure 3B).	('PD-L2', 'Var', (106, 111))	('OS', 'Chemical', '-', (94, 96))	('DFS/PFS', 'Disease', (145, 152))	('PD-1', 'Gene', (323, 327))	('PD-1', 'Gene', '5133', (323, 327))	('PD-1', 'Gene', (180, 184))	('PD-1', 'Gene', '5133', (180, 184))
660893	30891423	A transcriptomic analysis performed by Danilova and colleagues used The Cancer Genome Atlas datasets and found that PD-L2 mRNA expression indicated good prognosis in skin cutaneous melanoma (SKCM) but had no prognostic role in other 8 tumors.	('skin cutaneous melanoma', 'Disease', (166, 189))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumors', 'Disease', (235, 241))	('PD-L2', 'Gene', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (166, 189))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cancer', 'Disease', (72, 78))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('Cancer', 'Disease', 'MESH:D009369', (72, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (171, 189))	('mRNA expression', 'Var', (122, 137))
660897	30891423	Taken together, high PD-L2 expression might promote tumor metastasis and predict unfavorable prognosis in solid cancer patients after surgery, especially in HCC.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('solid cancer', 'Disease', 'MESH:D009369', (106, 118))	('predict', 'Reg', (73, 80))	('promote', 'PosReg', (44, 51))	('high', 'Var', (16, 20))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('expression', 'MPA', (27, 37))	('HCC', 'Disease', (157, 160))	('tumor metastasis', 'Disease', 'MESH:D009362', (52, 68))	('HCC', 'Phenotype', 'HP:0001402', (157, 160))	('tumor metastasis', 'Disease', (52, 68))	('PD-L2', 'Gene', (21, 26))	('solid cancer', 'Disease', (106, 118))
660899	30891423	In esophageal squamous cell carcinoma (ESCC), PD-L2 was shown to negatively associate with the number of PD-1+ tumor infiltrating lymphocytes (TILs), indicating that PD-L2 expressed on ESCC cells might restrain PD-1+ TILs activity, ultimately facilitating immune escape.	('PD-1+ tumor', 'Disease', (105, 116))	('PD-1', 'Gene', '5133', (105, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('PD-1+ tumor', 'Disease', 'MESH:D010300', (105, 116))	('PD-L2', 'Var', (166, 171))	('immune escape', 'CPA', (256, 269))	('PD-1', 'Gene', '5133', (211, 215))	('activity', 'MPA', (222, 230))	('PD-1', 'Gene', (211, 215))	('facilitating', 'Reg', (243, 255))	('restrain', 'NegReg', (202, 210))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))	('PD-1', 'Gene', (105, 109))
660900	30891423	Recently, a multivariate analysis revealed that in CRC, high tumor PD-L2 expression was correlated with a weak Crohn's-like lymphoid reaction, which was deemed to play a significant role in adaptive immune responses against tumors, suggesting that PD-L2 expression might reduce Crohn's-like lymphoid reactions to suppress antitumor immunity.	('suppress', 'NegReg', (313, 321))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('lymphoid reaction', 'Disease', 'MESH:D004342', (124, 141))	('PD-L2', 'Gene', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	("Crohn's-", 'Phenotype', 'HP:0100280', (278, 286))	("Crohn's-", 'Phenotype', 'HP:0100280', (111, 119))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (326, 331))	('lymphoid reaction', 'Disease', 'MESH:D004342', (291, 308))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('tumor', 'Disease', (224, 229))	('PD-L2', 'Var', (248, 253))	('lymphoid reaction', 'Disease', (124, 141))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('lymphoid reaction', 'Disease', (291, 308))	('reduce', 'NegReg', (271, 277))	('weak Crohn', 'Phenotype', 'HP:0100280', (106, 116))	('tumor', 'Disease', (61, 66))
660902	30891423	As tumor hypoxia is generally recognized as a contributor to immune resistance in the tumor microenvironment, it is conceivable that PD-L2 may potentially mediate immune resistance via promoting tumor hypoxia.	('tumor hypoxia', 'Disease', 'MESH:D000860', (195, 208))	('PD-L2', 'Var', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (3, 8))	('tumor hypoxia', 'Disease', (3, 16))	('tumor hypoxia', 'Disease', (195, 208))	('tumor hypoxia', 'Disease', 'MESH:D000860', (3, 16))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mediate', 'Reg', (155, 162))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('promoting', 'PosReg', (185, 194))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
660903	30891423	Furthermore, high PD-L2 expression in tumor tissue was independently associated with better clinical response to pembrolizumab in patients with head and neck squamous cell carcinoma, suggesting that PD-L2 expression in tumor tissue may exert a vital role in response to PD-1 blockade therapy, although this study was not included in our meta-analysis.	('better', 'PosReg', (85, 91))	('tumor', 'Disease', (219, 224))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('pembrolizumab', 'Chemical', 'MESH:C582435', (113, 126))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('PD-L2', 'Gene', (18, 23))	('PD-1', 'Gene', (270, 274))	('PD-1', 'Gene', '5133', (270, 274))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('clinical response', 'MPA', (92, 109))	('patients', 'Species', '9606', (130, 138))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (144, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('tumor', 'Disease', (38, 43))	('neck squamous cell carcinoma', 'Disease', (153, 181))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (153, 181))
660906	30891423	Blockade of PD-L2 in a pancreatic murine model also displayed evident anti-tumor effects with decreased tumor outgrowth rates.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', (104, 109))	('PD-L2', 'Gene', (12, 17))	('murine', 'Species', '10090', (34, 40))	('pancreatic', 'Disease', 'MESH:D010195', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('pancreatic', 'Disease', (23, 33))	('decreased', 'NegReg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
660912	30891423	However, in esophageal cancer, high PD-L2 expression implied a favorable prognosis trend, although with no statistical significance.	('expression', 'MPA', (42, 52))	('esophageal cancer', 'Disease', (12, 29))	('high', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('PD-L2', 'Protein', (36, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (12, 29))
660928	30891423	In conclusion, our study has clinical significance because it clarifies the correlation between high PD-L2 expression and unfavorable prognosis for solid cancer patients after surgery, especially in HCC.	('expression', 'MPA', (107, 117))	('solid cancer', 'Disease', 'MESH:D009369', (148, 160))	('solid cancer', 'Disease', (148, 160))	('patients', 'Species', '9606', (161, 169))	('high', 'Var', (96, 100))	('HCC', 'Disease', (199, 202))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('HCC', 'Phenotype', 'HP:0001402', (199, 202))	('PD-L2', 'Gene', (101, 106))
660937	30809093	Meanwhile, we demonstrated that eHsp90alpha promoted migration and invasion of ECA109 and ECA9706 in vitro.	('ECA9706', 'Var', (90, 97))	('promoted', 'PosReg', (44, 52))	('invasion', 'CPA', (67, 75))	('ECA9706', 'CellLine', 'CVCL:E307', (90, 97))	('Hsp90alpha', 'Gene', (33, 43))	('Hsp90alpha', 'Gene', '3320', (33, 43))	('migration', 'CPA', (53, 62))
660988	30809093	The proportion of patients with positive LN metastasis in high and low Hsp90alpha groups was 53.7% and 36.9%, respectively.	('low', 'Var', (67, 70))	('LN metastasis', 'CPA', (41, 54))	('Hsp90alpha', 'Gene', '3320', (71, 81))	('high', 'Var', (58, 62))	('patients', 'Species', '9606', (18, 26))	('Hsp90alpha', 'Gene', (71, 81))
661001	30809093	Subsequently, the amount of Hsp90alpha in CM and TCL from ECA109 and ECA9706 was analyzed when treated with IgG control or Hsp90alpha Ab.	('Hsp90alpha', 'Gene', (28, 38))	('Hsp90alpha', 'Gene', '3320', (28, 38))	('ECA9706', 'CellLine', 'CVCL:E307', (69, 76))	('Hsp90alpha', 'Gene', (123, 133))	('Hsp90alpha', 'Gene', '3320', (123, 133))	('ECA9706', 'Var', (69, 76))
661009	30809093	All the data demonstrated that eHsp90alpha promoted migration and invasion in ESCC cell lines, and the blockage of secreted Hsp90alpha can efficiently suppress this function.	('migration', 'CPA', (52, 61))	('promoted', 'PosReg', (43, 51))	('blockage', 'Var', (103, 111))	('Hsp90alpha', 'Gene', (124, 134))	('Hsp90alpha', 'Gene', '3320', (124, 134))	('Hsp90alpha', 'Gene', (32, 42))	('Hsp90alpha', 'Gene', '3320', (32, 42))	('invasion', 'CPA', (66, 74))	('suppress', 'NegReg', (151, 159))
661030	30809093	An interesting feature of our study is the existence of a statistically significant (P=0.027) correlation between high serum Hsp90alpha level and positive LN metastasis.	('Hsp90alpha', 'Gene', (125, 135))	('Hsp90alpha', 'Gene', '3320', (125, 135))	('high', 'Var', (114, 118))	('positive LN metastasis', 'CPA', (146, 168))
661046	30809093	Moreover, the migration and invasion of ECA109 and ECA9706 were increased upon treatment with rHsp90alpha, while Hsp90alpha Ab showed an obvious inhibitory effect.	('migration', 'CPA', (14, 23))	('ECA9706', 'CellLine', 'CVCL:E307', (51, 58))	('Hsp90alpha', 'Gene', (113, 123))	('Hsp90alpha', 'Gene', (95, 105))	('invasion', 'CPA', (28, 36))	('Hsp90alpha', 'Gene', '3320', (95, 105))	('increased', 'PosReg', (64, 73))	('Hsp90alpha', 'Gene', '3320', (113, 123))	('ECA9706', 'Var', (51, 58))	('ECA109', 'CPA', (40, 46))
661048	30809093	Accordingly, inhibition of eHsp90alpha could simultaneously disrupt multiple signaling pathways that are responsible for increasing tumor cell movement also making eHsp90alpha an attractive target for drug therapy to limit ESCC cells' migration and invasion.	('Hsp90alpha', 'Gene', (28, 38))	('Hsp90alpha', 'Gene', (165, 175))	('signaling pathways', 'Pathway', (77, 95))	('invasion', 'CPA', (249, 257))	('Hsp90alpha', 'Gene', '3320', (28, 38))	('Hsp90alpha', 'Gene', '3320', (165, 175))	('limit', 'NegReg', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('inhibition', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('ESCC', 'Disease', (223, 227))	('tumor', 'Disease', (132, 137))	('disrupt', 'NegReg', (60, 67))
661066	30809093	Therefore, inhibition of eHsp90alpha may have clinical utility in preventing LN metastasis to improve ESCC control and patient outcome.	('patient', 'Species', '9606', (119, 126))	('ESCC control', 'Disease', (102, 114))	('inhibition', 'Var', (11, 21))	('improve', 'PosReg', (94, 101))	('Hsp90alpha', 'Gene', (26, 36))	('Hsp90alpha', 'Gene', '3320', (26, 36))
661067	30361064	miR-424 coordinates multilayered regulation of cell cycle progression to promote esophageal squamous cell carcinoma cell proliferation Dysregulation of the cell cycle has been implicated in esophageal squamous cell carcinoma (ESCC) progression.	('miR-424', 'Gene', (0, 7))	('esophageal squamous cell carcinoma', 'Disease', (81, 115))	('miR-424', 'Gene', '494336', (0, 7))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (190, 224))	('implicated', 'Reg', (176, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (81, 115))	('Dysregulation', 'Var', (135, 148))	('promote', 'PosReg', (73, 80))	('Dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (135, 166))	('esophageal squamous cell carcinoma', 'Disease', (190, 224))
661089	30361064	Impaired function of critical gatekeepers of cell cycle progression caused by the accumulation of alterations involving the cell-cycle regulatory machinery will allow unscheduled persistent cell proliferation, which is a hallmark of cancer.	('Impaired', 'NegReg', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('hallmark of cancer', 'Disease', (221, 239))	('gatekeepers', 'Species', '111938', (30, 41))	('hallmark of cancer', 'Disease', 'MESH:D009369', (221, 239))	('function', 'MPA', (9, 17))	('alterations', 'Var', (98, 109))
661106	30361064	Puromycin (Cat# P9620), thymidine (Cat# T18S95), nocodazole (Cat# M1404), propidium iodide (Cat# P4170), cycloheximide (Cat# C7698), and crystal violet (Cat# C6158) were purchased from Sigma-Aldrich Corporation (St. Louis, MO, USA).	('thymidine', 'Chemical', 'MESH:D013936', (24, 33))	('Cat# C7698', 'Var', (120, 130))	('cycloheximide', 'Chemical', 'MESH:D003513', (105, 118))	('Puromycin', 'Chemical', 'MESH:D011691', (0, 9))	('propidium iodide', 'Chemical', 'MESH:D011419', (74, 90))	('crystal violet', 'Chemical', 'MESH:D005840', (137, 151))	('nocodazole', 'Chemical', 'MESH:D015739', (49, 59))	('Cat# P4170', 'Var', (92, 102))	('Cat# C6158', 'Var', (153, 163))	('Cat# P9620', 'Var', (11, 21))	('Cat# M1404', 'Var', (61, 71))
661109	30361064	The horseradish peroxidase-conjugated secondary antibodies anti-rabbit (Cat# NA934) and anti-mouse (Cat# NA931) IgG were purchased from GE Healthcare (Little Chalfont, UK).	('Cat# NA931', 'Var', (100, 110))	('Cat# NA934', 'Var', (72, 82))	('mouse', 'Species', '10090', (93, 98))	('rabbit', 'Species', '9986', (64, 70))	('horseradish', 'Species', '3704', (4, 15))
661113	30361064	All cell lines were cultured in a humidified incubator containing 5% CO2 at 37  C. Lentiviral constructs expressing miRZip-424 (System Biosciences, Palo Alto, CA, USA: Cat# MZIP424-PP-1), which knocks down miR-424 functionally, lenti-miR-424 (System Biosciences; Cat# PMIRH424PP-1), which expresses the miR-424 precursor, or the corresponding controls (System Biosciences; Cat# MZIP000-PP-1 and PMIRH000PP-1) were packaged using the ViraPower Lentiviral Packaging Mix (Life Technologies/Thermo Fisher Scientific; Cat# K497500) in 293FT cells, respectively.	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', '220972', (234, 237))	('knocks', 'Var', (194, 200))	('miR-424', 'Gene', (234, 241))	('Mix', 'Gene', '83881', (464, 467))	('miR', 'Gene', (116, 119))	('miR-424', 'Gene', '494336', (234, 241))	('miR', 'Gene', (234, 237))	('miR', 'Gene', '220972', (303, 306))	('Mix', 'Gene', (464, 467))	('miR-424', 'Gene', (303, 310))	('miR', 'Gene', '220972', (206, 209))	('miR-424', 'Gene', '494336', (303, 310))	('miR', 'Gene', (303, 306))	('miR-424', 'Gene', (206, 213))	('miR-424', 'Gene', '494336', (206, 213))	('293FT', 'CellLine', 'CVCL:6911', (530, 535))	('miR', 'Gene', (206, 209))	('CO2', 'Chemical', '-', (69, 72))
661160	30361064	However, both univariate and multivariate survival analyses revealed that high miR-424 expression was significantly associated with poor patient prognosis (p < 0 05 by Kaplan-Meier method with log-rank test for univariate survival analysis and Cox's proportional hazards regression analysis for multivariate survival analysis, Fig.	('patient', 'Species', '9606', (137, 144))	('high', 'Var', (74, 78))	('miR-424', 'Gene', (79, 86))	('Cox', 'Gene', '1351', (244, 247))	('miR-424', 'Gene', '494336', (79, 86))	('expression', 'MPA', (87, 97))	('Cox', 'Gene', (244, 247))
661166	30361064	2b, miR-424 overexpression significantly promoted KYSE-410, KYSE-510, and NE1 cell growth, whereas miR-424 knockdown significantly retarded the growth rate of KYSE-410 and KYSE-510 cells (Fig.	('knockdown', 'Var', (107, 116))	('retarded', 'Disease', 'MESH:D008607', (131, 139))	('miR-424', 'Gene', (4, 11))	('KYSE-510', 'CellLine', 'CVCL:1354', (60, 68))	('miR-424', 'Gene', '494336', (4, 11))	('promoted', 'PosReg', (41, 49))	('NE1', 'CellLine', 'CVCL:E306', (74, 77))	('KYSE-410', 'CPA', (50, 58))	('KYSE-510', 'CPA', (60, 68))	('retarded', 'Disease', (131, 139))	('miR-424', 'Gene', (99, 106))	('KYSE-510', 'CellLine', 'CVCL:1354', (172, 180))	('miR-424', 'Gene', '494336', (99, 106))	('growth rate', 'CPA', (144, 155))
661169	30361064	2d, the tumors formed by miR-424-knockdown KYSE-410 or KYSE-510 cells were smaller than the tumors formed by control cells.	('miR-424', 'Gene', (25, 32))	('KYSE-510', 'Var', (55, 63))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('KYSE-410', 'Var', (43, 51))	('miR-424', 'Gene', '494336', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('KYSE-510', 'CellLine', 'CVCL:1354', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('smaller', 'NegReg', (75, 82))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
661187	30361064	Taken together, the cell cycle analyses of ESCC cells after synchronization and release from different cell cycle phases provided evidence that knockdown or overexpression of miR-424 respectively negatively or positively regulates G1/S transition in KYSE-410 cells and G2/M transition in both KYSE-410 and KYSE-510 cells.	('negatively', 'NegReg', (196, 206))	('miR-424', 'Gene', '494336', (175, 182))	('G1/S transition', 'CPA', (231, 246))	('G2/M transition', 'CPA', (269, 284))	('overexpression', 'PosReg', (157, 171))	('knockdown', 'Var', (144, 153))	('regulates', 'Reg', (221, 230))	('positively', 'PosReg', (210, 220))	('KYSE-510', 'CellLine', 'CVCL:1354', (306, 314))	('miR-424', 'Gene', (175, 182))
661201	30361064	As expected, knockdown of E2F1 decreased the expression of pri-miR-424, pre-miR-424, and mature miR-424 in ESCC KYSE-410 cells (Fig.	('miR-424', 'Gene', (96, 103))	('miR-424', 'Gene', (63, 70))	('miR-424', 'Gene', '494336', (96, 103))	('decreased', 'NegReg', (31, 40))	('miR-424', 'Gene', (76, 83))	('expression', 'MPA', (45, 55))	('miR-424', 'Gene', '494336', (63, 70))	('E2F1', 'Gene', (26, 30))	('miR-424', 'Gene', '494336', (76, 83))	('knockdown', 'Var', (13, 22))
661202	30361064	To confirm the direct binding between E2F1 and the miR-424 promoter, a ChIP assay with 5 pairs of primers within the putative promoter region was performed to investigate the presence of E2F1 in the endogenous putative promoter in KYSE-410 cells 8 h after release from G0/G1-phase.	('miR-424', 'Gene', (51, 58))	('E2F1', 'Var', (187, 191))	('miR-424', 'Gene', '494336', (51, 58))
661203	30361064	To evaluate the role of the putative E2F1-binding sites in the upregulation of miR-424 transcription during G1/S progression, a 1750-bp fragment of the putative promoter region encompassing the wild type or mutant E2F1 binding sites was inserted into pEZX-LvPG04, a GLuc-ON transcriptional response element lentiviral clone, using a secreted Gaussia luciferase (GLuc) as the reporter.	('miR-424', 'Gene', (79, 86))	('E2F1', 'Gene', (214, 218))	('secreted Gaussia luciferase', 'Disease', 'MESH:D002640', (333, 360))	('miR-424', 'Gene', '494336', (79, 86))	('mutant', 'Var', (207, 213))	('secreted Gaussia luciferase', 'Disease', (333, 360))	('upregulation', 'PosReg', (63, 75))
661206	30361064	Taken together, these data demonstrated that E2F1 binds to the miR-424 promoter and directly activates its transcription during the G1/S transition.	('activates', 'PosReg', (93, 102))	('miR-424', 'Gene', (63, 70))	('transcription', 'MPA', (107, 120))	('miR-424', 'Gene', '494336', (63, 70))	('E2F1', 'Var', (45, 49))	('binds', 'Interaction', (50, 55))
661212	30361064	During G1/S progression, western blotting revealed that knockdown of miR-424 clearly elevated PRKCD protein in KYSE-410 (Fig.	('miR-424', 'Gene', (69, 76))	('elevated', 'PosReg', (85, 93))	('miR-424', 'Gene', '494336', (69, 76))	('PRKCD protein', 'Protein', (94, 107))	('knockdown', 'Var', (56, 65))
661214	30361064	However, no obvious changes in LATS2, PDCD4, CDC25A, cyclin D1, and cyclin E1 expression caused by miR-424 knockdown were observed in either KYSE-410 (Fig.	('knockdown', 'Var', (107, 116))	('expression', 'MPA', (78, 88))	('miR-424', 'Gene', (99, 106))	('PDCD4', 'Gene', (38, 43))	('cyclin D1', 'Gene', '595', (53, 62))	('cyclin', 'MPA', (68, 74))	('cyclin D1', 'Gene', (53, 62))	('CDC25A', 'Gene', (45, 51))	('LATS2', 'Gene', (31, 36))	('LATS2', 'Gene', '26524', (31, 36))	('miR-424', 'Gene', '494336', (99, 106))
661220	30361064	A luciferase assay showed that overexpression of miR-424 attenuated the reporter activities driven by the 3'UTRs of PRKCD and WEE1 transcripts, but knockdown of miR-424 elevated these reporter activities.	('miR-424', 'Gene', (49, 56))	('elevated', 'PosReg', (169, 177))	('miR-424', 'Gene', '494336', (161, 168))	('reporter activities', 'MPA', (72, 91))	('miR-424', 'Gene', '494336', (49, 56))	('attenuated', 'NegReg', (57, 67))	('knockdown', 'Var', (148, 157))	('miR-424', 'Gene', (161, 168))
661221	30361064	However, dysregulation of miR-424 did not result in alterations in the reporter activities driven by the mutated 3'UTRs of these transcripts within the miR-424-binding-regions (Fig.	('miR-424', 'Gene', (152, 159))	('reporter activities', 'MPA', (71, 90))	('miR-424', 'Gene', (26, 33))	('miR-424', 'Gene', '494336', (152, 159))	('dysregulation', 'Var', (9, 22))	('miR-424', 'Gene', '494336', (26, 33))
661223	30361064	Enrichment of the PRKCD transcript significantly increased in miR-424-overexpressing KYSE-410 cells after release from G0/G1 for 12 h, while WEE1 enrichment increased in both miR-424-overexpressing KYSE-410 and KYSE-510 cells after release from the onset of S-phase for 9 h, compared with the levels in control cells, respectively (Fig.	('miR-424', 'Gene', (62, 69))	('KYSE-510', 'CellLine', 'CVCL:1354', (211, 219))	('Enrichment', 'MPA', (0, 10))	('miR-424', 'Gene', '494336', (175, 182))	('miR-424', 'Gene', '494336', (62, 69))	('increased', 'PosReg', (49, 58))	('PRKCD', 'Gene', (18, 23))	('KYSE-410', 'Var', (85, 93))	('increased', 'PosReg', (157, 166))	('miR-424', 'Gene', (175, 182))
661228	30361064	In ESCC cells, our miRNP-IP assay proved that circLARP4 could be enriched in miR-424-overexpressing KYSE-410 and KYSE-510 cells at G1/S transition, and the effect was more profound in KYSE-510 cells (Fig.	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (77, 80))	('miR', 'Gene', (19, 22))	('KYSE-510', 'CellLine', 'CVCL:1354', (184, 192))	('KYSE-510', 'CellLine', 'CVCL:1354', (113, 121))	('KYSE-510', 'Var', (184, 192))	('miR-424', 'Gene', (77, 84))	('miR-424', 'Gene', '494336', (77, 84))	('miR', 'Gene', '220972', (77, 80))
661230	30361064	However, knockdown of miR-424 had no influence on the expression of circLARP4 (Supplementary Fig.	('expression', 'MPA', (54, 64))	('knockdown', 'Var', (9, 18))	('miR-424', 'Gene', (22, 29))	('circLARP4', 'Gene', (68, 77))	('miR-424', 'Gene', '494336', (22, 29))
661235	30361064	During G1/S transition, western blotting showed that knocking down miR-424 in KYSE-410 cells increased p21Cip1 protein expression and decreased p-CDK2 (Thr160) levels, which represent the activated state of CDK2 (Fig.	('decreased', 'NegReg', (134, 143))	('p21Cip1', 'Gene', (103, 110))	('increased', 'PosReg', (93, 102))	('miR-424', 'Gene', (67, 74))	('p21Cip1', 'Gene', '1026', (103, 110))	('Thr160', 'Chemical', '-', (152, 158))	('knocking down', 'Var', (53, 66))	('miR-424', 'Gene', '494336', (67, 74))
661237	30361064	However, another member of the CIP/KIP family, p27Kip1, did not exhibit expression changes during G1/S transition in miR-424-knockdown KYSE-410 cells (Fig.	('p27Kip1', 'Var', (47, 54))	('miR-424', 'Gene', (117, 124))	('CIP', 'Disease', (31, 34))	('CIP', 'Disease', 'MESH:D010259', (31, 34))	('miR-424', 'Gene', '494336', (117, 124))
661238	30361064	The negative regulation of p21Cip1 by miR-424 did not occur at the transcriptional level, as the mRNA level of p21Cip1 was not altered by miR-424 knockdown in KYSE-410 cells (Supplementary Fig.	('knockdown', 'Var', (146, 155))	('miR-424', 'Gene', (138, 145))	('miR-424', 'Gene', (38, 45))	('p21Cip1', 'Gene', (27, 34))	('miR-424', 'Gene', '494336', (38, 45))	('p21Cip1', 'Gene', (111, 118))	('miR-424', 'Gene', '494336', (138, 145))	('p21Cip1', 'Gene', '1026', (27, 34))	('p21Cip1', 'Gene', '1026', (111, 118))
661239	30361064	However, knockdown of miR-424 delayed p21Cip1 protein degradation when KYSE-410 cells were cultured with cycloheximide to inhibit de novo protein synthesis (Fig.	('delayed', 'NegReg', (30, 37))	('de novo protein synthesis', 'MPA', (130, 155))	('p21Cip1', 'Gene', (38, 45))	('knockdown', 'Var', (9, 18))	('cycloheximide', 'Chemical', 'MESH:D003513', (105, 118))	('p21Cip1', 'Gene', '1026', (38, 45))	('miR-424', 'Gene', (22, 29))	('inhibit', 'NegReg', (122, 129))	('miR-424', 'Gene', '494336', (22, 29))
661243	30361064	The mitotic kinase CDC2/Cyclin B is critical for G2/M transition and is maintained in an inactive state until the dephosphorylation of Thr-14 and Tyr-15 at the G2/M border activates CDC2.	('activates', 'PosReg', (172, 181))	('Cyclin', 'Gene', '5111', (24, 30))	('Tyr', 'Chemical', 'MESH:D014443', (146, 149))	('CDC2', 'Gene', (182, 186))	('G2/M', 'Disease', (49, 53))	('dephosphorylation', 'MPA', (114, 131))	('Tyr-15', 'Var', (146, 152))	('Cyclin', 'Gene', (24, 30))	('Thr', 'Chemical', 'MESH:D013912', (135, 138))
661244	30361064	WEE1 is the kinase responsible for phosphorylating Tyr-15 of CDC2 and hence inhibits CDC2 activity.	('CDC2', 'Gene', (61, 65))	('Tyr', 'Chemical', 'MESH:D014443', (51, 54))	('Tyr-15', 'Var', (51, 57))	('phosphorylating', 'MPA', (35, 50))	('inhibits', 'NegReg', (76, 84))	('CDC2 activity', 'MPA', (85, 98))
661245	30361064	6d, knockdown of miR-424 in KYSE-410 cells increased WEE1 expression and CDC2 phosphorylation at Tyr-15 when the cells were at the G2/M border (6 h after release from the onset of S-phase by double-thymidine treatment) compared with control cells.	('phosphorylation at', 'MPA', (78, 96))	('miR-424', 'Gene', '494336', (17, 24))	('expression', 'MPA', (58, 68))	('CDC2', 'Gene', (73, 77))	('Tyr', 'Chemical', 'MESH:D014443', (97, 100))	('WEE1', 'Gene', (53, 57))	('miR-424', 'Gene', (17, 24))	('increased', 'PosReg', (43, 52))	('thymidine', 'Chemical', 'MESH:D013936', (198, 207))	('knockdown', 'Var', (4, 13))
661247	30361064	On the other hand, the WEE1 upregulation induced by knockdown of miR-424 maintained the inactivation of CDC2 to postpone G2/M transition in ESCC.	('miR-424', 'Gene', (65, 72))	('CDC2', 'Gene', (104, 108))	('ESCC', 'Disease', (140, 144))	('miR-424', 'Gene', '494336', (65, 72))	('WEE1', 'Gene', (23, 27))	('inactivation', 'MPA', (88, 100))	('knockdown', 'Var', (52, 61))	('upregulation', 'PosReg', (28, 40))
661252	30361064	miR-424 is commonly lost in aggressive breast cancers, and the loss of miR-424 promotes breast tumorigenesis and chemoresistance by up-regulating two of its targets: BCL-2 and IGF1R.	('IGF1R', 'Gene', '3480', (176, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('up-regulating', 'PosReg', (132, 145))	('loss', 'Var', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IGF1R', 'Gene', (176, 181))	('BCL-2', 'Gene', '596', (166, 171))	('BCL-2', 'Gene', (166, 171))	('aggressive breast cancers', 'Disease', 'MESH:D001943', (28, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('miR-424', 'Gene', (71, 78))	('breast', 'Disease', (88, 94))	('chemoresistance', 'CPA', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('miR-424', 'Gene', '494336', (71, 78))	('tumor', 'Disease', (95, 100))	('miR-424', 'Gene', (0, 7))	('miR-424', 'Gene', '494336', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('promotes', 'PosReg', (79, 87))	('breast cancers', 'Phenotype', 'HP:0003002', (39, 53))	('aggressive breast cancers', 'Disease', (28, 53))
661261	30361064	This is probably due to the phenomenon of field cancerization, in which some morphologically normal cells acquire pro-tumorigenic genetic or epigenetic mutations, leading to the increased expression of miR-424 in NEs.	('epigenetic mutations', 'Var', (141, 161))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('expression', 'MPA', (188, 198))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('miR-424', 'Gene', '494336', (202, 209))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('miR-424', 'Gene', (202, 209))	('increased', 'PosReg', (178, 187))
661263	30361064	The poor survival of patients with high miR-424 expression may be attributable to intrinsic characteristics of the tumor cells that are partly determined by miR-424, although no significant correlation was observed between miR-424 expression and patient clinicopathological characteristics, such as tumor pathological stage or differentiation.	('miR-424', 'Gene', '494336', (157, 164))	('tumor', 'Disease', (115, 120))	('patients', 'Species', '9606', (21, 29))	('poor', 'NegReg', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('patient', 'Species', '9606', (246, 253))	('expression', 'MPA', (48, 58))	('determined', 'Reg', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patient', 'Species', '9606', (21, 28))	('miR-424', 'Gene', (40, 47))	('miR-424', 'Gene', '494336', (40, 47))	('tumor', 'Disease', (299, 304))	('miR-424', 'Gene', (223, 230))	('miR-424', 'Gene', '494336', (223, 230))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('high', 'Var', (35, 39))	('miR-424', 'Gene', (157, 164))
661264	30361064	Consistent with the clinical data, knockdown of miR-424 in ESCC cells remarkably suppressed ESCC proliferation in vitro and tumor formation in a mouse model, while the opposite results were observed after overexpressing miR-424.	('miR-424', 'Gene', (220, 227))	('knockdown', 'Var', (35, 44))	('suppressed', 'NegReg', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('miR-424', 'Gene', (48, 55))	('mouse', 'Species', '10090', (145, 150))	('tumor', 'Disease', (124, 129))	('miR-424', 'Gene', '494336', (220, 227))	('miR-424', 'Gene', '494336', (48, 55))	('ESCC proliferation in vitro', 'CPA', (92, 119))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
661285	30361064	However, the reason why circLARP4 completely abrogated miR-424 binding to PRKCD in KYSE-510 but not KYSE-410 cells is unknown.	('PRKCD', 'Protein', (74, 79))	('circLARP4', 'Var', (24, 33))	('abrogated', 'NegReg', (45, 54))	('miR-424', 'Gene', (55, 62))	('binding', 'Interaction', (63, 70))	('miR-424', 'Gene', '494336', (55, 62))	('KYSE-510', 'CellLine', 'CVCL:1354', (83, 91))
661301	30361064	These results suggest a positive feedback loop in which miR-424 is one of the G1/S genes that are activated by the transcription factor E2F1 and elevation of miR-424 further increases cyclin-CDK activity and decreases CDK-inhibitory proteins, leading to irreversible cell cycle commitment.	('cyclin', 'Gene', (184, 190))	('increases', 'PosReg', (174, 183))	('miR-424', 'Gene', '494336', (158, 165))	('miR-424', 'Gene', (56, 63))	('decreases', 'NegReg', (208, 217))	('CDK-inhibitory proteins', 'MPA', (218, 241))	('miR-424', 'Gene', '494336', (56, 63))	('cyclin', 'Gene', '5111', (184, 190))	('miR-424', 'Gene', (158, 165))	('elevation', 'Var', (145, 154))	('activity', 'MPA', (195, 203))
661340	29581534	In non-small cell lung cancer, high Notch2 mRNA expression predicted better overall survival in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (96, 115))	('Notch2', 'Gene', (36, 42))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (96, 115))	('overall survival', 'MPA', (76, 92))	('mRNA expression', 'MPA', (43, 58))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('Notch2', 'Gene', '4853', (36, 42))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (96, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('better', 'PosReg', (69, 75))	('high', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('non-small cell lung cancer', 'Disease', (3, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
661355	29581534	1E,F, using qRT-PCR, we found that the miR-1 level in the miR-1 mimics group was significantly higher than that in the NC group in both TE-1 and KYSE410 cells.	('miR', 'Gene', '220972', (39, 42))	('mimics', 'Var', (64, 70))	('miR', 'Gene', (39, 42))	('KYSE410', 'CellLine', 'CVCL:1352', (145, 152))	('higher', 'PosReg', (95, 101))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))
661358	29581534	In addition, the proliferation ability of cells in the miR-1 inhibitor group was significantly higher than that of cells in the inhibitor NC group (p < 0.05).	('inhibitor', 'Var', (61, 70))	('proliferation ability', 'CPA', (17, 38))	('higher', 'PosReg', (95, 101))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))
661366	29581534	Luciferase activity was significantly higher in miR-1 inhibitor than that for cells transfected with inhibitor NC in the Notch2-3'UTR-WT group (**p < 0.01).	('Notch2', 'Gene', '4853', (121, 127))	('activity', 'MPA', (11, 19))	('Notch2', 'Gene', (121, 127))	('higher', 'PosReg', (38, 44))	('miR', 'Gene', '220972', (48, 51))	('inhibitor', 'Var', (54, 63))	('miR', 'Gene', (48, 51))	('Luciferase', 'Enzyme', (0, 10))
661370	29581534	Expression of Notch2 protein in the miR-1 mimics group was lower than that in the NC group (Fig.	('Notch2', 'Gene', '4853', (14, 20))	('Expression', 'MPA', (0, 10))	('lower', 'NegReg', (59, 64))	('mimics', 'Var', (42, 48))	('Notch2', 'Gene', (14, 20))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (36, 39))	('protein', 'Protein', (21, 28))
661393	29581534	Overexpression of miR-1 in prostate cells led to growth inhibition and down-regulation of genes in pathways that regulate cell cycle progression, mitosis, and DNA replication/repair and participate in dynamics.	('mitosis', 'Disease', (146, 153))	('mitosis', 'Disease', 'None', (146, 153))	('down-regulation', 'NegReg', (71, 86))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('Overexpression', 'Var', (0, 14))	('growth inhibition', 'CPA', (49, 66))	('genes', 'Gene', (90, 95))	('cell cycle', 'CPA', (122, 132))
661457	29581534	TE-1 and KYSE410 cells were co-transfected with the Wt or Mut vector and miR-1 mimics, NC, miR-1 inhibitor, or inhibitor NC using the Attractene Transfection Reagent (Qiagen).	('miR', 'Gene', (91, 94))	('mimics', 'Var', (79, 85))	('KYSE410', 'CellLine', 'CVCL:1352', (9, 16))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))	('miR', 'Gene', '220972', (91, 94))
661531	28643456	IRF6 expression in basal epithelium partially rescues Irf6 knockout mice Mutations in IRF6, CHUK (IKKA) and RIPK4 can lead to a disease spectrum that includes cutaneous, limb and craniofacial malformations.	('lead to', 'Reg', (118, 125))	('RIPK4', 'Gene', '72388', (108, 113))	('CHUK', 'Gene', '12675', (92, 96))	('Mutations', 'Var', (73, 82))	('IRF6', 'Gene', (86, 90))	('IRF6', 'Gene', '54139', (86, 90))	('RIPK4', 'Gene', (108, 113))	('Irf6', 'Gene', '54139', (54, 58))	('craniofacial malformations', 'Disease', 'MESH:D019465', (179, 205))	('Irf6', 'Gene', (54, 58))	('IKKA', 'Gene', (98, 102))	('CHUK', 'Gene', (92, 96))	('cutaneous', 'Disease', (159, 168))	('IKKA', 'Gene', '12675', (98, 102))	('craniofacial malformations', 'Disease', (179, 205))	('disease spectrum', 'Disease', (128, 144))	('IRF6', 'Gene', (0, 4))	('IRF6', 'Gene', '54139', (0, 4))	('craniofacial malformations', 'Phenotype', 'HP:0004484', (179, 205))
661541	28643456	In this work, we show that altering the expression level of IRF6 dramatically modified this phenotype in utero.	('altering', 'Var', (27, 35))	('IRF6', 'Gene', (60, 64))	('IRF6', 'Gene', '54139', (60, 64))	('expression level', 'MPA', (40, 56))	('modified', 'Reg', (78, 86))
661542	28643456	Mutations in IRF6 lead to Van der Woude Syndrome (VWS OMIM #119300) and Popliteal Pterygium Syndrome (PPS OMIM #119500).	('Popliteal Pterygium', 'Phenotype', 'HP:0009756', (72, 91))	('VWS', 'Disease', (50, 53))	('Popliteal Pterygium Syndrome', 'Disease', (72, 100))	('PPS', 'Chemical', 'MESH:D010426', (102, 105))	('IRF6', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IRF6', 'Gene', '54139', (13, 17))	('Pterygium', 'Phenotype', 'HP:0001059', (82, 91))	('VWS', 'Disease', 'None', (50, 53))	('lead to', 'Reg', (18, 25))	('Van der Woude Syndrome', 'Disease', (26, 48))	('Van der Woude Syndrome', 'Disease', 'MESH:C536528', (26, 48))
661544	28643456	Common variants within the IRF6 locus also increase risk for isolated or nonsyndromic orofacial clefting (iCLP).	('increase', 'Reg', (43, 51))	('nonsyndromic orofacial clefting', 'Disease', (73, 104))	('variants', 'Var', (7, 15))	('nonsyndromic orofacial clefting', 'Disease', 'MESH:C566121', (73, 104))	('IRF6', 'Gene', (27, 31))	('IRF6', 'Gene', '54139', (27, 31))
661545	28643456	Loss of IRF6 expression in epithelial cells is also associated with skin and head and neck squamous cell carcinoma.	('IRF6', 'Gene', (8, 12))	('IRF6', 'Gene', '54139', (8, 12))	('neck squamous cell carcinoma', 'Disease', (86, 114))	('associated', 'Reg', (52, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (77, 114))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (86, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('Loss', 'Var', (0, 4))
661546	28643456	Loss of Irf6 in the mouse leads to skin, limb and craniofacial defects.	('craniofacial defects', 'Disease', (50, 70))	('leads to', 'Reg', (26, 34))	('Irf6', 'Gene', '54139', (8, 12))	('skin', 'CPA', (35, 39))	('Irf6', 'Gene', (8, 12))	('craniofacial defects', 'Disease', 'MESH:D019465', (50, 70))	('Loss', 'Var', (0, 4))	('mouse', 'Species', '10090', (20, 25))
661548	28643456	Furthermore, mutations in RIPK4 result in a similar but more severe form of PPS, called Bartsocas-Papas Syndrome (BPS OMIM # 263650).	('BPS', 'Disease', 'MESH:C564874', (114, 117))	('PPS', 'Chemical', 'MESH:D010426', (76, 79))	('PPS', 'Disease', (76, 79))	('result in', 'Reg', (32, 41))	('RIPK4', 'Gene', '72388', (26, 31))	('RIPK4', 'Gene', (26, 31))	('BPS', 'Disease', (114, 117))	('mutations', 'Var', (13, 22))	('Bartsocas-Papas Syndrome', 'Disease', (88, 112))
661549	28643456	Mutations in CHUK result in a similar but more severe form of BPS, called Severe Fetal Encasement Malformation or Cocoon Syndrome (OMIM # 613630).	('CHUK', 'Gene', '12675', (13, 17))	('CHUK', 'Gene', (13, 17))	('BPS', 'Disease', (62, 65))	('Fetal Encasement Malformation or Cocoon Syndrome', 'Disease', (81, 129))	('Mutations', 'Var', (0, 9))	('Fetal Encasement Malformation or Cocoon Syndrome', 'Disease', 'OMIM:613630', (81, 129))	('BPS', 'Disease', 'MESH:C564874', (62, 65))
661577	28643456	These differences were driven by fewer than expected Irf6 knockout (predicted 22; actual 9) and heterozygous embryos (predicted 44; actual 25).	('knockout', 'Var', (58, 66))	('Irf6', 'Gene', '54139', (53, 57))	('Irf6', 'Gene', (53, 57))
661581	28643456	Most strikingly, while Irf6 knockout pups died, rescue pups survived the perinatal period.	('Irf6', 'Gene', (23, 27))	('knockout', 'Var', (28, 36))	('Irf6', 'Gene', '54139', (23, 27))
661584	28643456	Like Ikka, Irf6 knockout embryos have severe skeletal malformations, which are thought to be secondary to cutaneous defects.	('cutaneous defects', 'Disease', (106, 123))	('cutaneous defects', 'Disease', 'MESH:D018366', (106, 123))	('Ikka', 'Gene', (5, 9))	('Irf6', 'Gene', (11, 15))	('knockout', 'Var', (16, 24))	('Ikka', 'Gene', '12675', (5, 9))	('malformations', 'Disease', 'MESH:D000014', (54, 67))	('malformations', 'Disease', (54, 67))	('skeletal malformations', 'Phenotype', 'HP:0000924', (45, 67))	('Irf6', 'Gene', '54139', (11, 15))
661586	28643456	Second, while prior work showed Irf6 knockout embryos have a bifid xiphoid, rescue pups had an intermediately affected xiphoid, suggesting partial rescue (Fig.	('Irf6', 'Gene', '54139', (32, 36))	('knockout', 'Var', (37, 45))	('Irf6', 'Gene', (32, 36))	('bifid xiphoid', 'Phenotype', 'HP:0100891', (61, 74))
661589	28643456	In the epidermis, loss of Irf6 leads to an expanded, hyper-proliferative epidermis that lacks stratification and differentiation.	('leads to', 'Reg', (31, 39))	('Irf6', 'Gene', '54139', (26, 30))	('loss', 'Var', (18, 22))	('Irf6', 'Gene', (26, 30))
661601	28643456	Furthermore, Irf6 knockout embryo (Fig.	('knockout', 'Var', (18, 26))	('Irf6', 'Gene', (13, 17))	('Irf6', 'Gene', '54139', (13, 17))
661603	28643456	Prior work shows that Irf6 knockout embryos have cleft palate with ubiquitous oral and esophageal adhesions.	('cleft palate', 'Disease', 'MESH:D002972', (49, 61))	('cleft palate', 'Phenotype', 'HP:0000175', (49, 61))	('Irf6', 'Gene', '54139', (22, 26))	('knockout', 'Var', (27, 35))	('Irf6', 'Gene', (22, 26))	('cleft palate', 'Disease', (49, 61))
661607	28643456	3H), a phenotype previously undocumented in Irf6 knockout embryos.	('knockout', 'Var', (49, 57))	('Irf6', 'Gene', '54139', (44, 48))	('Irf6', 'Gene', (44, 48))
661628	28643456	We used a transgenic mouse line expressing IRF6 under the control of the KRT14 promoter to test the role of IRF6 in basal epithelial cells of Irf6 knockout embryos.	('IRF6', 'Gene', '54139', (108, 112))	('Irf6', 'Gene', '54139', (142, 146))	('transgenic', 'Species', '10090', (10, 20))	('mouse', 'Species', '10090', (21, 26))	('IRF6', 'Gene', (43, 47))	('Irf6', 'Gene', (142, 146))	('KRT14', 'Gene', (73, 78))	('IRF6', 'Gene', '54139', (43, 47))	('KRT14', 'Gene', '16664', (73, 78))	('knockout', 'Var', (147, 155))	('IRF6', 'Gene', (108, 112))
661642	28643456	Importantly, loss of GRHL3 can lead to Van der Woude Syndrome and these results might provide some mechanistic insight into how a cleft palate forms in vivo.	('GRHL3', 'Gene', (21, 26))	('cleft palate', 'Phenotype', 'HP:0000175', (130, 142))	('GRHL3', 'Gene', '230824', (21, 26))	('lead to', 'Reg', (31, 38))	('cleft palate', 'Disease', (130, 142))	('loss', 'Var', (13, 17))	('Van der Woude Syndrome', 'Disease', (39, 61))	('Van der Woude Syndrome', 'Disease', 'MESH:C536528', (39, 61))	('cleft palate', 'Disease', 'MESH:D002972', (130, 142))
661646	28643456	In support of this model, we recently showed that all Grhl3 knockout embryos have bilateral oral adhesions between the mandible and maxilla but that clefting only resulted when lingual-palatal adhesions were also present.	('Grhl3', 'Gene', (54, 59))	('bilateral oral adhesions', 'CPA', (82, 106))	('Grhl3', 'Gene', '230824', (54, 59))	('knockout', 'Var', (60, 68))
661651	28643456	Therefore, while an examination of earlier timepoints might show a delay in these milestones, the phenotype observed at P0 can be traced back to a defect at E15.5.	('defect', 'Var', (147, 153))	('E15', 'Gene', '114730', (157, 160))	('E15', 'Gene', (157, 160))
661653	28643456	In addition, we found that replacing IRF6 in basal epithelial cells is sufficient for cutaneous epidermal stratification.	('IRF6', 'Gene', (37, 41))	('IRF6', 'Gene', '54139', (37, 41))	('replacing', 'Var', (27, 36))	('cutaneous epidermal stratification', 'Disease', (86, 120))
661659	28643456	DNA variants in MCS9.7 are associated with risk for nonsyndromic cleft lip and palate and VWS.	('nonsyndromic cleft lip and palate', 'Disease', 'MESH:C566121', (52, 85))	('MCS9.7', 'Gene', (16, 22))	('variants', 'Var', (4, 12))	('associated', 'Reg', (27, 37))	('VWS', 'Disease', 'None', (90, 93))	('cleft lip', 'Phenotype', 'HP:0410030', (65, 74))	('VWS', 'Disease', (90, 93))
661664	28643456	Consistent with a peripheral role in this gene regulatory network, Ripk4 knockouts are less severely affected when compared to Ikka, Irf6, Sfn and Kdf1 knockout mice.	('mice', 'Species', '10090', (161, 165))	('Sfn', 'Gene', (139, 142))	('Ikka', 'Gene', (127, 131))	('Kdf1', 'Gene', '69073', (147, 151))	('Ikka', 'Gene', '12675', (127, 131))	('Ripk4', 'Gene', (67, 72))	('Irf6', 'Gene', '54139', (133, 137))	('Sfn', 'Gene', '104444', (139, 142))	('Kdf1', 'Gene', (147, 151))	('Irf6', 'Gene', (133, 137))	('knockouts', 'Var', (73, 82))	('Ripk4', 'Gene', '72388', (67, 72))
661668	28643456	We first inter-crossed Irf6+/- and TgKrt14::Irf6 to produce Irf6+/-;TgKrt14::Irf6.	('TgKrt14', 'Var', (68, 75))	('Irf6', 'Gene', '54139', (44, 48))	('Irf6', 'Gene', '54139', (23, 27))	('Irf6', 'Gene', '54139', (60, 64))	('Irf6', 'Gene', '54139', (77, 81))	('Irf6', 'Gene', (23, 27))	('Irf6', 'Gene', (60, 64))	('Irf6', 'Gene', (44, 48))	('Irf6', 'Gene', (77, 81))
661689	28643456	Following incubation, skeletons were stained in Alcian blue for cartilage (Sigma, A5268-10G).	('Alcian blue', 'Chemical', 'MESH:D000423', (48, 59))	('A5268-10G', 'SUBSTITUTION', 'None', (82, 91))	('A5268-10G', 'Var', (82, 91))	('cartilage', 'Disease', (64, 73))	('cartilage', 'Disease', 'MESH:D002357', (64, 73))
661695	28643456	To make cDNA, we used Oligo dT primers (18418-012, Invitrogen), dNTP mix (18427-013, Invitrogen), SuperScriptIII Reverse Transcriptase (18080-093, Invitrogen) and Recombinant RNasin Ribonuclease Inhibitor (N2511, Promega).	('Ribonuclease Inhibitor', 'Gene', (182, 204))	('18418-012', 'Var', (40, 49))	('18427-013', 'Var', (74, 83))	('dNTP', 'Chemical', 'MESH:D010278', (64, 68))	('Ribonuclease Inhibitor', 'Gene', '107702', (182, 204))
661721	20631636	Specifically, monoclonal antibodies to EGFR have been shown to inhibit the proliferation of cells that produce both Transforming Growth Factor (TGF) and Epidermal Growth Factor (EGF).	('EGF', 'Gene', (39, 42))	('EGF', 'Gene', '1950', (178, 181))	('EGF', 'Gene', (178, 181))	('EGF', 'Gene', '1950', (39, 42))	('monoclonal antibodies', 'Var', (14, 35))	('proliferation of cells', 'CPA', (75, 97))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('inhibit', 'NegReg', (63, 70))	('Epidermal Growth Factor', 'MPA', (153, 176))
661767	20631636	Polymorphisms, as performed in this trial, were not found to be associated with response, overall survival, progression-free survival, time to treatment failure or toxicity for any of the genes tested.	('toxicity', 'Disease', 'MESH:D064420', (164, 172))	('toxicity', 'Disease', (164, 172))	('Polymorphisms', 'Var', (0, 13))
661783	20631636	Low frequency of Kras mutations have also been observed in squamous cell carcinoma of the esophagus (0%) and gastric adenocarcinoma (11%).	('squamous cell carcinoma of the esophagus', 'Disease', (59, 99))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (109, 131))	('gastric adenocarcinoma', 'Disease', (109, 131))	('Kras', 'Gene', (17, 21))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (59, 99))	('Kras', 'Gene', '3845', (17, 21))	('mutations', 'Var', (22, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
661832	18437209	Although it has been assumed that intestinal metaplasia in Barrett's esophagus is an adaptive response to chronic gastroesophageal reflux, the differences of chemokine expression, especially IL-4, between patients with reflux esophagitis and those with Barrett's esophagus may influence the development of intestinal metaplasia in the esophagus.	('esophagitis', 'Phenotype', 'HP:0100633', (226, 237))	('IL-4', 'Gene', '3565', (191, 195))	('chemokine', 'MPA', (158, 167))	('patients', 'Species', '9606', (205, 213))	('influence', 'Reg', (277, 286))	('intestinal metaplasia', 'Disease', (34, 55))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (114, 137))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (253, 272))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (114, 137))	('gastroesophageal reflux', 'Disease', (114, 137))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (34, 55))	('reflux esophagitis', 'Disease', (219, 237))	('intestinal metaplasia', 'Disease', (306, 327))	('reflux esophagitis', 'Disease', 'MESH:D005764', (219, 237))	('IL-4', 'Gene', (191, 195))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (59, 78))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (306, 327))	('differences', 'Var', (143, 154))
661836	18437209	It has also been reported that patients with GERD show an increase of superoxide dismutase (SOD), an antioxidant enzyme, in the esophageal mucosa, although the activity of this enzyme is decreased due to nitration of tyrosine residues.	('increase', 'PosReg', (58, 66))	('superoxide dismutase', 'Gene', '6647', (70, 90))	('tyrosine', 'Chemical', 'MESH:D014443', (217, 225))	('rat', 'Species', '10116', (207, 210))	('GERD', 'Disease', (45, 49))	('SOD', 'Gene', '6647', (92, 95))	('superoxide dismutase', 'Gene', (70, 90))	('activity', 'MPA', (160, 168))	('nitration', 'Var', (204, 213))	('patients', 'Species', '9606', (31, 39))	('SOD', 'Gene', (92, 95))	('increase of superoxide dismutase', 'Phenotype', 'HP:0031836', (58, 90))
661844	18437209	Interestingly, our data revealed that conjugated bile acids in acidic media resulted in remarkable increase in IL-8 production compared with those in neural -pH media.	('IL-8', 'Gene', (111, 115))	('bile acids', 'Chemical', 'MESH:D001647', (49, 59))	('conjugated bile acids', 'Var', (38, 59))	('IL-8', 'Gene', '3576', (111, 115))	('increase', 'PosReg', (99, 107))
661866	18437209	used esophagoduodenal anastomosis to create a rat model of esophagitis in which iron supplementation considerably enhanced oxidative damage to DNA, protein, and lipid, and also induced the development of inflammation and esophageal adenocarcinoma.	('induced', 'Reg', (177, 184))	('esophageal adenocarcinoma', 'Disease', (221, 246))	('rat', 'Species', '10116', (46, 49))	('inflammation', 'Disease', 'MESH:D007249', (204, 216))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (221, 246))	('esophagitis', 'Disease', (59, 70))	('esophagitis', 'Phenotype', 'HP:0100633', (59, 70))	('supplementation', 'Var', (85, 100))	('esophagitis', 'Disease', 'MESH:D004941', (59, 70))	('inflammation', 'Disease', (204, 216))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (221, 246))	('enhanced', 'PosReg', (114, 122))	('iron', 'Chemical', 'MESH:D007501', (80, 84))	('esophagoduodenal anastomosis', 'Phenotype', 'HP:0100628', (5, 33))	('lipid', 'Chemical', 'MESH:D008055', (161, 166))	('oxidative damage to DNA', 'MPA', (123, 146))
661889	18437209	It has recently been demonstrated that PPIs also have other effects beyond the suppression of acid secretion.	('acid secretion', 'MPA', (94, 108))	('PPIs', 'Var', (39, 43))	('rat', 'Species', '10116', (28, 31))
661892	18437209	Furthermore, it has been reported that PPIs inhibit free radical production by neutrophils and block neutrophil degranulation, though at relatively high concentrations (10-4-10-5 M).	('rat', 'Species', '10116', (160, 163))	('inhibit', 'NegReg', (44, 51))	('free radical production', 'MPA', (52, 75))	('free radical', 'Chemical', 'MESH:D005609', (52, 64))	('PPIs', 'Var', (39, 43))	('neutrophil degranulation', 'MPA', (101, 125))	('block', 'NegReg', (95, 100))
661893	18437209	Taken altogether, these evidences suggest that PPIs not only inhibit acid secretion but also reduce inflammation and oxidative stress in the gastric and esophageal mucosa by inhibiting the activation of neutrophils and endothelial cells.	('inflammation', 'Disease', (100, 112))	('activation', 'CPA', (189, 199))	('inhibiting', 'NegReg', (174, 184))	('acid secretion', 'MPA', (69, 83))	('inhibit', 'NegReg', (61, 68))	('PPIs', 'Var', (47, 51))	('oxidative stress', 'Phenotype', 'HP:0025464', (117, 133))	('inflammation', 'Disease', 'MESH:D007249', (100, 112))	('reduce', 'NegReg', (93, 99))
661894	18437209	Actually, in our study described above, PPI therapy rapidly reduced IL-8 levels in the human esophageal mucosa.	('PPI', 'Var', (40, 43))	('IL-8', 'Gene', '3576', (68, 72))	('human', 'Species', '9606', (87, 92))	('IL-8', 'Gene', (68, 72))	('reduced', 'NegReg', (60, 67))
661895	18437209	In an animal model of chronic esophagitis due to acid reflux, PPI therapy markedly inhibited the expression of adhesion molecules and inflammatory cytokines in the esophageal mucosa.	('expression of adhesion molecules', 'MPA', (97, 129))	('acid reflux', 'Phenotype', 'HP:0002020', (49, 60))	('PPI', 'Var', (62, 65))	('inhibited', 'NegReg', (83, 92))	('inflammatory cytokines', 'MPA', (134, 156))	('esophagitis', 'Phenotype', 'HP:0100633', (30, 41))	('acid reflux', 'MPA', (49, 60))	('esophagitis', 'Disease', (30, 41))	('esophagitis', 'Disease', 'MESH:D004941', (30, 41))
661897	18437209	In fact, we have demonstrated that the anti-inflammatory and anti-oxidant effects of PPI are partly related to suppression of intracellular calcium metabolism and to blocking the activation of transcription factors.	('anti-inflammatory', 'MPA', (39, 56))	('activation', 'MPA', (179, 189))	('transcription factors', 'Pathway', (193, 214))	('intracellular calcium metabolism', 'MPA', (126, 158))	('PPI', 'Var', (85, 88))	('suppression', 'NegReg', (111, 122))	('blocking', 'NegReg', (166, 174))	('calcium', 'Chemical', 'MESH:D002118', (140, 147))	('rat', 'Species', '10116', (24, 27))	('anti-oxidant', 'MPA', (61, 73))
661899	18437209	We previously reported that in a rat model of mixed reflux esophagitis, intraduodenal rebamipide significantly inhibited the increased expression of mRNA and protein for CINC-1 and TNF-alpha, as well as neutrophil infiltration and lipid peroxidation in the esophageal mucosa, and consequently prevented the development of mucosal lesions both histologically and macroscopically.	('TNF-alpha', 'Gene', (181, 190))	('neutrophil', 'CPA', (203, 213))	('increased', 'PosReg', (125, 134))	('esophagitis', 'Phenotype', 'HP:0100633', (59, 70))	('intraduodenal', 'Var', (72, 85))	('rat', 'Species', '10116', (33, 36))	('rebamipide', 'Chemical', 'MESH:C052785', (86, 96))	('reflux esophagitis', 'Disease', 'MESH:D005764', (52, 70))	('lipid', 'Chemical', 'MESH:D008055', (231, 236))	('mucosal lesions', 'Disease', (322, 337))	('expression', 'MPA', (135, 145))	('rat', 'Species', '10116', (220, 223))	('prevented', 'NegReg', (293, 302))	('CINC-1', 'Gene', (170, 176))	('mucosal lesions', 'Disease', 'MESH:D009059', (322, 337))	('inhibited', 'NegReg', (111, 120))	('CINC-1', 'Gene', '81503', (170, 176))	('lipid peroxidation', 'MPA', (231, 249))	('reflux esophagitis', 'Disease', (52, 70))	('TNF-alpha', 'Gene', '24835', (181, 190))
661922	31058109	The process of esophageal healing and stricture formation after endoscopic resection involves three stages: the first stage is an injury of epithelium, resulting in the damage of the barrier of the epithelial and making the submucosal layers exposed to food boluses, acid, or bile reflux and esophageal fungal or bacterial flora.	('injury', 'Var', (130, 136))	('damage', 'NegReg', (169, 175))	('esophageal fungal', 'Disease', (292, 309))	('esophageal fungal', 'Disease', 'MESH:D004941', (292, 309))	('barrier of the', 'CPA', (183, 197))
662125	28028355	The pathogenesis of squamous cell carcinoma is highly complex, involving an accumulation of genetic modifications within the esophageal mucosa, causing progressive changes that result in invasive carcinoma.	('causing', 'Reg', (144, 151))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('squamous cell carcinoma', 'Disease', (20, 43))	('genetic modifications', 'Var', (92, 113))	('invasive carcinoma', 'Disease', 'MESH:D009361', (187, 205))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('esophageal mucosa', 'Disease', (125, 142))	('result in', 'Reg', (177, 186))	('invasive carcinoma', 'Disease', (187, 205))	('esophageal mucosa', 'Disease', 'MESH:D004941', (125, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))
662127	28028355	Genetic mutations within cyclin D1 and the tumour suppressor gene, TP53, are among the most frequently isolated genetic abnormalities from esophageal squamous cell carcinomas.	('genetic abnormalities', 'Disease', (112, 133))	('tumour', 'Disease', (43, 49))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (150, 174))	('esophageal squamous cell carcinomas', 'Disease', (139, 174))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (139, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('TP53', 'Gene', '7157', (67, 71))	('genetic abnormalities', 'Disease', 'MESH:D030342', (112, 133))	('TP53', 'Gene', (67, 71))	('Genetic mutations', 'Var', (0, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('cyclin D1', 'Gene', '595', (25, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('cyclin D1', 'Gene', (25, 34))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
662129	28028355	TP53 mutations have been reported in as little as 10% and up to 80% of esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('mutations', 'Var', (5, 14))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))
662130	28028355	Additionally, mutations to the TP53 gene are also found in dysplastic lesions, indicating TP53 mutations may be an event in the early stages of esophageal squamous cell carcinoma carcinogenesis.	('event', 'Reg', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (31, 35))	('dysplastic lesions', 'Disease', 'MESH:D021782', (59, 77))	('TP53', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))	('dysplastic lesions', 'Disease', (59, 77))	('esophageal squamous cell carcinoma carcinogenesis', 'Disease', (144, 193))	('esophageal squamous cell carcinoma carcinogenesis', 'Disease', 'MESH:D000077277', (144, 193))	('mutations', 'Var', (14, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
662131	28028355	TP53 mutations produce abnormal TP53 protein that accumulates in the nuclei of cells which may be identified by immunohistochemistry.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('accumulates', 'PosReg', (50, 61))	('TP53', 'Gene', '7157', (32, 36))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', (32, 36))	('protein', 'Protein', (37, 44))
662132	28028355	Positive p53 staining has been demonstrated in the non-cancerous cells adjacent to tumors and in cells lacking the commonly identified TP53 mutations; indicating poor specificity and sensitivity of the technique and potentially additional mutations within the gene accounting for the positive staining.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('non-cancer', 'Disease', 'MESH:D009369', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('TP53', 'Gene', '7157', (135, 139))	('tumors', 'Disease', (83, 89))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', (135, 139))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('mutations', 'Var', (140, 149))	('non-cancer', 'Disease', (51, 61))
662155	28028355	p53 mutations can cause accumulation of non-functional protein that has increased stability and a longer half-life than the native protein.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('increased', 'PosReg', (72, 81))	('accumulation', 'PosReg', (24, 36))	('stability', 'MPA', (82, 91))	('mutations', 'Var', (4, 13))	('non-functional protein', 'MPA', (40, 62))
662193	28028355	Developing a risk prediction model, the authors reported eight significant predictors for adenocarcinoma: decanal, nonanal, phenol, ethyl phenol, methyl phenol, hexanoic acid, heptanal, and butyric acid, with sensitivity and specificity of 98% and 91.7% respectively when compared to normal upper GI tract.	('hexanoic', 'MPA', (161, 169))	('ethyl phenol', 'Chemical', '-', (132, 144))	('phenol', 'Chemical', 'MESH:D019800', (138, 144))	('phenol', 'Chemical', 'MESH:D019800', (124, 130))	('heptanal', 'MPA', (176, 184))	('phenol', 'Chemical', 'MESH:D019800', (153, 159))	('hexanoic acid', 'Chemical', 'MESH:C037652', (161, 174))	('methyl phenol', 'Var', (146, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('ethyl phenol', 'Var', (132, 144))	('adenocarcinoma', 'Disease', (90, 104))	('methyl phenol', 'Chemical', 'MESH:C077977', (146, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('ethyl phenol', 'Chemical', '-', (147, 159))	('butyric acid', 'Chemical', 'MESH:D020148', (190, 202))	('heptanal', 'Chemical', 'MESH:C046204', (176, 184))
662229	25823933	It is estimated that one third of the genes in the human genome are regulated by miRNAs and, to date, >1,800 miRNA genes have been identified (miRBase release 20.0; http://www.mirbase.org/), including several that are involved in key cellular processes, including apoptosis, proliferation and differentiation.. MiRNA misexpression or mutation results in a gain or loss of miRNA function and, therefore, a downregulation or upregulation of the target protein.	('upregulation', 'PosReg', (423, 435))	('miR', 'Gene', '220972', (109, 112))	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (81, 84))	('miR', 'Gene', (109, 112))	('downregulation', 'NegReg', (405, 419))	('misexpression', 'Var', (317, 330))	('function', 'MPA', (378, 386))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', (143, 146))	('human', 'Species', '9606', (51, 56))	('gain', 'Disease', (356, 360))	('MiRNA', 'Gene', (311, 316))	('gain', 'Disease', 'MESH:D015430', (356, 360))	('miR', 'Gene', '220972', (372, 375))	('mutation', 'Var', (334, 342))	('miR', 'Gene', (372, 375))	('loss', 'NegReg', (364, 368))
662259	25823933	The most enriched pathways targeted by dysregulated mRNAs included the phosphatidylinositol signaling system, ECM-receptor interaction and focal adhesion pathways and the peroxisome proliferator activated receptor signaling pathway.	('mRNAs', 'Var', (52, 57))	('dysregulated mRNAs', 'Var', (39, 57))	('phosphatidylinositol signaling system', 'Pathway', (71, 108))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (71, 91))	('focal adhesion pathways', 'Pathway', (139, 162))	('peroxisome proliferator', 'Pathway', (171, 194))
662275	25823933	In the present study, a total of 17 aberrantly expressed miRNAs were identified in the ESCC samples, compared to adjacent normal tissues.	('aberrantly expressed', 'Var', (36, 56))	('ESCC', 'Disease', (87, 91))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))
662285	25823933	Pathway analysis can reveal distinct biological processes and identify the significant pathways that dysregulated mRNAs are involved in, which can provide a comprehensive understanding of the interactions of genes, their functions and the association between up- and down-stream genes, and can identify genes, which may be regulated by miRNAs.	('miR', 'Gene', '220972', (336, 339))	('miR', 'Gene', (336, 339))	('dysregulated', 'Var', (101, 113))	('interactions', 'Interaction', (192, 204))
662366	20955586	We previously characterized genomic instability in esophageal squamous cell carcinomas (ESCC) in terms of loss of heterozygosity (LOH) and copy number (CN) changes in tumors using the Affymetrix GeneChip Human Mapping 500K array in 30 cases from a high-risk region of China.	('changes', 'Var', (156, 163))	('copy number', 'Var', (139, 150))	('esophageal squamous cell carcinomas', 'Disease', (51, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (51, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (62, 86))	('heterozygosity', 'MPA', (114, 128))	('Human', 'Species', '9606', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('loss', 'NegReg', (106, 110))	('tumors', 'Disease', (167, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
662367	20955586	In the current study we focused on copy number neutral (CN = 2) LOH (CNNLOH) and its relation to gene expression in ESCC.	('ESCC', 'Disease', (116, 120))	('CN = 2', 'Gene', (56, 62))	('copy number neutral', 'Var', (35, 54))	('CN = 2', 'Gene', '55748', (56, 62))
662371	20955586	Genomic instability is important for cancer development and can manifest as copy number (CN) gain or loss as well as loss of heterozygosity (LOH).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('loss', 'NegReg', (117, 121))	('loss', 'NegReg', (101, 105))	('cancer', 'Disease', (37, 43))	('gain', 'PosReg', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('copy number', 'Var', (76, 87))
662372	20955586	Copy number neutral LOH (CNNLOH) has been observed in tumors following the widespread application of SNP array technology.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('Copy number neutral', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
662377	20955586	Previously, we identified several regions of LOH and CN alteration in ESCC using microsatellite markers and low- and high-density SNP arrays, where the majority of ESCC patients from this high-risk population were found to have high genomic instability and high frequency of LOH on several chromosome arms.	('ESCC', 'Disease', (70, 74))	('patients', 'Species', '9606', (169, 177))	('alteration', 'Var', (56, 66))	('ESCC', 'Disease', (164, 168))
662378	20955586	For example, 82% of 56 ESCCs showed LOH when tested with four microsatellite markers flanking ANXA1 (9q11-q21), but no somatic mutations were detected in these patients.	('ANXA1', 'Gene', '301', (94, 99))	('ANXA1', 'Gene', (94, 99))	('LOH', 'Var', (36, 39))	('patients', 'Species', '9606', (160, 168))
662379	20955586	Another example is BRCA2, which also showed frequent LOH in ESCC (57% for D13S260, 83% for D13S767), but only infrequent somatic mutations in these cancer patients (2/56, 3.5%).	('cancer', 'Disease', (148, 154))	('D13S260', 'Var', (74, 81))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('LOH', 'NegReg', (53, 56))	('BRCA2', 'Gene', (19, 24))	('ESCC', 'Disease', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('BRCA2', 'Gene', '675', (19, 24))	('D13S767', 'Var', (91, 98))	('D13S260', 'Chemical', '-', (74, 81))	('D13S767', 'Chemical', '-', (91, 98))	('patients', 'Species', '9606', (155, 163))
662381	20955586	In the present study, we analyzed DNA from 30 micro-dissected ESCC tumors, adjacent normal tissue, and blood DNA from the same patient using the Affymetrix 500K SNP array to identify the distribution of complex DNA alterations, including CNNLOH, and we related CNNLOH to expression of the genes affected as assessed with the Affymetrix U133A 2.0 array in these patients.	('patients', 'Species', '9606', (361, 369))	('ESCC tumors', 'Disease', (62, 73))	('patient', 'Species', '9606', (127, 134))	('alterations', 'Var', (215, 226))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ESCC tumors', 'Disease', 'MESH:D004938', (62, 73))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('patient', 'Species', '9606', (361, 368))
662391	20955586	Copy number (CN) loss or gain was based on comparisons of either adjacent normal to germ-line DNA or tumor to germ-line DNA.	('gain', 'PosReg', (25, 29))	('Copy number', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('loss', 'NegReg', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
662401	20955586	In the present study we determined copy number and loss of heterozygosity (LOH) status in DNA isolated from germ-line and micro-dissected tumor and matched adjacent normal samples from 30 ESCC patients using the Affymetrix 500 K SNP array.	('patients', 'Species', '9606', (193, 201))	('tumor', 'Disease', (138, 143))	('ESCC', 'Disease', (188, 192))	('loss of heterozygosity', 'NegReg', (51, 73))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('copy number', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
662410	20955586	For example, in colon cancer and basal cell carcinoma nearly all LOH was associated with copy number neutral regions.	('colon cancer', 'Disease', (16, 28))	('copy number neutral regions', 'Var', (89, 116))	('associated', 'Reg', (73, 83))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (33, 53))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (33, 53))	('basal cell carcinoma', 'Disease', (33, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (16, 28))	('colon cancer', 'Disease', 'MESH:D015179', (16, 28))
662414	20955586	For example, JAK2 V617F, FLT3-ITD, AML1/RUNX1, WT1, and NPM1 mutations were all found in CNNLOH regions in AML.	('AML', 'Disease', (35, 38))	('WT1', 'Gene', '7490', (47, 50))	('AML', 'Disease', (107, 110))	('NPM1', 'Gene', (56, 60))	('JAK2', 'Gene', '3717', (13, 17))	('V617F', 'SUBSTITUTION', 'None', (18, 23))	('AML1', 'Gene', '861', (35, 39))	('FLT3', 'Gene', (25, 29))	('found', 'Reg', (80, 85))	('FLT3', 'Gene', '2322', (25, 29))	('JAK2', 'Gene', (13, 17))	('AML1', 'Gene', (35, 39))	('NPM1', 'Gene', '4869', (56, 60))	('V617F', 'Var', (18, 23))	('WT1', 'Gene', (47, 50))	('RUNX1', 'Gene', (40, 45))	('AML', 'Disease', 'MESH:D015470', (35, 38))	('RUNX1', 'Gene', '861', (40, 45))	('AML', 'Disease', 'MESH:D015470', (107, 110))
662418	20955586	SNP: single nucleotide polymorphism; ESCC: esophageal squamous cell carcinoma; (CNNLOH): copy number neutral loss of heterozygosity; CN: copy number.	('esophageal squamous cell carcinoma', 'Disease', (43, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (43, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('single nucleotide polymorphism', 'Var', (5, 35))	('loss of heterozygosity', 'NegReg', (109, 131))
662421	19302219	p53 Arg72Pro, MDM2 T309G and CCND1 G870A polymorphisms are not associated with susceptibility to esophageal adenocarcinoma p53 Arg72Pro, MDM2 T309G, and CCND1 G870A are functional single nucleotide polymorphisms (SNPs) in key genes that regulate apoptosis and cell cycle.	('esophageal adenocarcinoma', 'Disease', (97, 122))	('CCND1', 'Gene', '595', (153, 158))	('MDM2', 'Gene', '4193', (14, 18))	('G870A', 'Mutation', 'rs603965', (159, 164))	('p53', 'Gene', '7157', (0, 3))	('T309G', 'Mutation', 'rs2279744', (19, 24))	('CCND1', 'Gene', (153, 158))	('MDM2', 'Gene', (137, 141))	('G870A', 'Var', (159, 164))	('p53', 'Gene', (0, 3))	('MDM2', 'Gene', '4193', (137, 141))	('CCND1', 'Gene', '595', (29, 34))	('T309G', 'Mutation', 'rs2279744', (142, 147))	('p53', 'Gene', '7157', (123, 126))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (97, 122))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (97, 122))	('CCND1', 'Gene', (29, 34))	('G870A', 'Mutation', 'rs603965', (35, 40))	('p53', 'Gene', (123, 126))	('MDM2', 'Gene', (14, 18))
662422	19302219	Variant genotypes of these SNPs have been associated with increased risk and earlier age of onset in some cancers.	('associated', 'Reg', (42, 52))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('Variant genotypes', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
662426	19302219	In contrast to the results of smaller published studies, no association between p53 Arg72Pro, MDM2 T309G, and CCND1 G870A SNPs and susceptibility to esophageal adenocarcinoma, age of onset, or stage of disease at diagnosis was detected.	('MDM2', 'Gene', (94, 98))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (149, 174))	('T309G', 'Var', (99, 104))	('esophageal adenocarcinoma', 'Disease', (149, 174))	('CCND1', 'Gene', (110, 115))	('G870A', 'Var', (116, 121))	('T309G', 'Mutation', 'rs2279744', (99, 104))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (149, 174))	('p53', 'Gene', (80, 83))	('CCND1', 'Gene', '595', (110, 115))	('p53', 'Gene', '7157', (80, 83))	('G870A', 'Mutation', 'rs603965', (116, 121))	('MDM2', 'Gene', '4193', (94, 98))
662428	19302219	p53, its negative regulator MDM2, and cyclin D1 (CCND1) are important regulators of cell cycle and apoptosis; and each contains functional single nucleotide polymorphisms (SNPs) (p53 Arg72Pro, MDM2 T309G, and CCND1 G870A) that have been implicated in the susceptibility and outcome of various human malignancies.	('p53', 'Gene', (179, 182))	('CCND1', 'Gene', (209, 214))	('MDM2', 'Gene', (28, 32))	('G870A', 'Mutation', 'rs603965', (215, 220))	('MDM2', 'Gene', (193, 197))	('p53', 'Gene', '7157', (0, 3))	('CCND1', 'Gene', '595', (49, 54))	('MDM2', 'Gene', '4193', (28, 32))	('T309G', 'Var', (198, 203))	('MDM2', 'Gene', '4193', (193, 197))	('cyclin D1', 'Gene', (38, 47))	('CCND1', 'Gene', (49, 54))	('Arg72Pro', 'Var', (183, 191))	('p53', 'Gene', (0, 3))	('G870A', 'Var', (215, 220))	('malignancies', 'Disease', 'MESH:D009369', (299, 311))	('contains', 'Reg', (119, 127))	('malignancies', 'Disease', (299, 311))	('human', 'Species', '9606', (293, 298))	('cyclin D1', 'Gene', '595', (38, 47))	('implicated', 'Reg', (237, 247))	('T309G', 'Mutation', 'rs2279744', (198, 203))	('p53', 'Gene', '7157', (179, 182))	('CCND1', 'Gene', '595', (209, 214))
662429	19302219	The variants alleles of both p53 Arg72Pro and MDM2 T309G putatively impair apoptosis, which could contribute to esophageal carcinogenesis: p53 Pro72 codes for a protein with reduced apoptotic potential, while MDM2 309G is a promoter SNP that results in the upregulation of MDM2 and the consequent downregulation of the p53 pathway.	('variants', 'Var', (4, 12))	('T309G', 'Var', (51, 56))	('p53', 'Gene', (139, 142))	('p53', 'Gene', (319, 322))	('MDM2', 'Gene', (273, 277))	('MDM2', 'Gene', (209, 213))	('reduced', 'NegReg', (174, 181))	('T309G', 'Mutation', 'rs2279744', (51, 56))	('downregulation', 'NegReg', (297, 311))	('MDM2', 'Gene', '4193', (273, 277))	('impair', 'NegReg', (68, 74))	('apoptosis', 'CPA', (75, 84))	('MDM2', 'Gene', '4193', (209, 213))	('Arg72Pro', 'Var', (33, 41))	('p53', 'Gene', '7157', (29, 32))	('upregulation', 'PosReg', (257, 269))	('MDM2', 'Gene', (46, 50))	('esophageal carcinogenesis', 'Disease', (112, 137))	('apoptotic potential', 'CPA', (182, 201))	('p53', 'Gene', (29, 32))	('p53', 'Gene', '7157', (139, 142))	('p53', 'Gene', '7157', (319, 322))	('MDM2', 'Gene', '4193', (46, 50))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (112, 137))
662430	19302219	CCND1 G870A alters a transcriptional splice site, with the resulting transcript leading to constitutive nuclear cyclin D1 localization and an increased in vitro transforming capacity through mechanisms not fully elucidated.	('alters', 'Reg', (12, 18))	('G870A', 'Mutation', 'rs603965', (6, 11))	('increased', 'PosReg', (142, 151))	('G870A', 'Var', (6, 11))	('cyclin D1', 'Gene', '595', (112, 121))	('cyclin D1', 'Gene', (112, 121))	('CCND1', 'Gene', (0, 5))	('transcriptional splice site', 'MPA', (21, 48))	('CCND1', 'Gene', '595', (0, 5))	('leading to', 'Reg', (80, 90))
662431	19302219	Two studies, with conflicting findings, have evaluated the association between CCND1 G870A and EA risk.	('CCND1', 'Gene', '595', (79, 84))	('G870A', 'Mutation', 'rs603965', (85, 90))	('G870A', 'Var', (85, 90))	('CCND1', 'Gene', (79, 84))	('EA', 'Phenotype', 'HP:0011459', (95, 97))
662432	19302219	p53 Arg72Pro and MDM2 T309G have not been studied in this disease despite the importance of the p53 pathway in esophageal cancer, and associations with risk in other aerodigestive cancers.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('T309G', 'Mutation', 'rs2279744', (22, 27))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('MDM2', 'Gene', '4193', (17, 21))	('esophageal cancer', 'Disease', (111, 128))	('MDM2', 'Gene', (17, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('Arg72Pro', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('associations', 'Interaction', (134, 146))
662439	19302219	Genotyping for p53 Arg72Pro (rs1042522), MDM2 T309G (rs2279744) and CCND1 G870A (rs603965) were performed as previously described using Taqman assays.	('CCND1', 'Gene', '595', (68, 73))	('T309G (rs2279744', 'Var', (46, 62))	('rs1042522', 'Mutation', 'rs1042522', (29, 38))	('rs603965', 'Var', (81, 89))	('rs603965', 'Mutation', 'rs603965', (81, 89))	('p53', 'Gene', (15, 18))	('MDM2', 'Gene', '4193', (41, 45))	('p53', 'Gene', '7157', (15, 18))	('rs2279744', 'Mutation', 'rs2279744', (53, 62))	('MDM2', 'Gene', (41, 45))	('G870A (rs603965', 'Var', (74, 89))	('Arg72Pro (rs1042522', 'Var', (19, 38))	('rs1042522', 'Var', (29, 38))	('CCND1', 'Gene', (68, 73))	('rs2279744', 'Var', (53, 62))	('G870A', 'Mutation', 'rs603965', (74, 79))	('T309G', 'Mutation', 'rs2279744', (46, 51))
662442	19302219	In a large esophageal adenocarcinoma genetic case-control study, we found no association between p53 Arg72Pro, MDM2 T309G or CCND1 G870A and EA susceptibility.	('CCND1', 'Gene', (125, 130))	('T309G', 'Var', (116, 121))	('p53', 'Gene', (97, 100))	('CCND1', 'Gene', '595', (125, 130))	('T309G', 'Mutation', 'rs2279744', (116, 121))	('p53', 'Gene', '7157', (97, 100))	('EA', 'Phenotype', 'HP:0011459', (141, 143))	('G870A', 'Mutation', 'rs603965', (131, 136))	('esophageal adenocarcinoma', 'Disease', (11, 36))	('G870A', 'Var', (131, 136))	('MDM2', 'Gene', '4193', (111, 115))	('MDM2', 'Gene', (111, 115))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (11, 36))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (11, 36))
662445	19302219	The lack of association between p53 Arg72Pro, MDM2 T309G and risk or age of onset in EA is important and adds to the growing literature about p53 pathway SNPs and cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('EA', 'Phenotype', 'HP:0011459', (85, 87))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('T309G', 'Var', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('MDM2', 'Gene', '4193', (46, 50))	('cancer', 'Disease', (163, 169))	('T309G', 'Mutation', 'rs2279744', (51, 56))	('MDM2', 'Gene', (46, 50))
662449	19302219	Our null result for CCND1 G870A and EA risk contrasts with one small case-control study (cases, n=56; OR 5.99, 95% CI 1.89-18.96, for A/A vs. G/G), but consistent with another (n=56) that did not find a significant association.	('G870A', 'Mutation', 'rs603965', (26, 31))	('G870A', 'Var', (26, 31))	('A/A', 'Var', (134, 137))	('CCND1', 'Gene', (20, 25))	('EA', 'Phenotype', 'HP:0011459', (36, 38))	('CCND1', 'Gene', '595', (20, 25))
662450	19302219	In addition, we did not confirm the results of a case series (n=124) that found a positive association between CCND1 A/- genotypes and both age of onset and frequency of distant metastases at diagnosis.	('CCND1', 'Gene', (111, 116))	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('CCND1', 'Gene', '595', (111, 116))	('metastases', 'Disease', (178, 188))	('A/- genotypes', 'Var', (117, 130))
662452	19302219	In conclusion, our findings do not support an association between p53 Arg72Pro, MDM2 T309G, and CCND1 G870A SNPs and esophageal adenocarcinoma susceptibility in a North American Caucasian-predominant population.	('MDM2', 'Gene', (80, 84))	('MDM2', 'Gene', '4193', (80, 84))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (117, 142))	('T309G', 'Var', (85, 90))	('p53', 'Gene', '7157', (66, 69))	('G870A', 'Var', (102, 107))	('CCND1', 'Gene', '595', (96, 101))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (117, 142))	('T309G', 'Mutation', 'rs2279744', (85, 90))	('esophageal adenocarcinoma', 'Disease', (117, 142))	('G870A', 'Mutation', 'rs603965', (102, 107))	('CCND1', 'Gene', (96, 101))	('p53', 'Gene', (66, 69))
662463	33711961	Results from IHC staining and western blot further proved that markers of Th2 and M2 cell were significantly increased in gastric cancer patients with high ITGA5 expression levels.	('Th2', 'Chemical', '-', (74, 77))	('high', 'Var', (151, 155))	('patients', 'Species', '9606', (137, 145))	('gastric cancer', 'Disease', (122, 136))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('ITGA5', 'Gene', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ITGA5', 'Gene', '3678', (156, 161))	('increased', 'PosReg', (109, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
662516	33711961	Specifically, the cohorts (GSE17536) included 177 samples at different stages of colorectal cancer and showed a remarkable association between high ITGA5 expression levels and poor prognosis (OS HR = 1.66, 95% CI = 1.16 to 2.37, Cox P = 0.005; DFS HR = 2.97, 95% CI = 1.70 to 5.21, Cox P = 0.0004) (Figs.	('colorectal cancer', 'Disease', (81, 98))	('ITGA5', 'Gene', (148, 153))	('high', 'Var', (143, 147))	('ITGA5', 'Gene', '3678', (148, 153))	('poor', 'Disease', (176, 180))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('expression levels', 'MPA', (154, 171))
662519	33711961	High expression of ITGA5 was also associated with poor prognosis in lung cancer (OS HR = 1.6, 95% CI = 1.4 to 1.81, P = 5.9e-13; DFS HR = 1.75, 95% CI = 1.44 to 2.12, P = 1.2e-08) and breast cancer (OS HR = 1.21, 95% CI = 0.96 to 1.52, P = 0.11; DFS HR = 1.28, 95% CI = 1.14 to 1.44, P = 4.1e-05) (Additional file: Fig.	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('High', 'Var', (0, 4))	('ITGA5', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', (184, 197))	('ITGA5', 'Gene', '3678', (19, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))
662520	33711961	Similarly, the cohorts (GSE26712) showed that high ITGA5 expression levels were correlated with poor prognosis (OS HR = 1.58, 95% CI = 1.06 to 2.36, Cox P = 0.025; DFS HR = 1.54, 95% CI = 1.06 to 2.24, Cox P = 0.025) in ovarian cancers (Additional file: Fig.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('high', 'Var', (46, 50))	('ITGA5', 'Gene', (51, 56))	('ovarian cancer', 'Phenotype', 'HP:0100615', (220, 234))	('ITGA5', 'Gene', '3678', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('ovarian cancers', 'Phenotype', 'HP:0100615', (220, 235))	('ovarian cancers', 'Disease', (220, 235))	('ovarian cancers', 'Disease', 'MESH:D010051', (220, 235))	('expression levels', 'MPA', (57, 74))
662536	33711961	In addition, stage I through IV cancer patients with high expression levels of ITGA5 showed worse OS (P < 0.05) (Table 2).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('patients', 'Species', '9606', (39, 47))	('cancer', 'Disease', (32, 38))	('ITGA5', 'Gene', '3678', (79, 84))	('stage I', 'Disease', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('high expression levels', 'Var', (53, 75))	('ITGA5', 'Gene', (79, 84))
662537	33711961	Similarly, high expression levels of ITGA5 were associated with worse PFS in stage II through IV gastric cancer patients (P < 0.05) but not in stage I gastric cancer patients (Table 2).	('gastric cancer', 'Disease', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('high', 'Var', (11, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('stage II', 'Disease', (77, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('patients', 'Species', '9606', (112, 120))	('ITGA5', 'Gene', (37, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('PFS', 'MPA', (70, 73))	('gastric cancer', 'Disease', (151, 165))	('ITGA5', 'Gene', '3678', (37, 42))	('patients', 'Species', '9606', (166, 174))
662539	33711961	Moreover, high ITGA5 levels express the highest HR value of N1 with OS and PFS among four N categories (Table 2).	('ITGA5', 'Gene', (15, 20))	('HR value', 'MPA', (48, 56))	('high', 'Var', (10, 14))	('ITGA5', 'Gene', '3678', (15, 20))
662543	33711961	In addition, these results revealed that the expression levels of CD163 (chi2 = 8.750, P = 0.003), STAT6 (chi2 = 8.174, P = 0.004) and GATA3 (chi2 = 5.079, P = 0.024) in the ITGA5 high-expression group were significantly higher than what was observed in the ITGA5 low-expression group (Table 3).	('high-expression', 'Var', (180, 195))	('ITGA5', 'Gene', '3678', (174, 179))	('STAT6', 'Gene', '6778', (99, 104))	('expression levels', 'MPA', (45, 62))	('GATA3', 'Gene', (135, 140))	('ITGA5', 'Gene', '3678', (258, 263))	('CD163', 'Gene', '9332', (66, 71))	('GATA3', 'Gene', '2625', (135, 140))	('CD163', 'Gene', (66, 71))	('STAT6', 'Gene', (99, 104))	('ITGA5', 'Gene', (174, 179))	('ITGA5', 'Gene', (258, 263))	('higher', 'PosReg', (221, 227))
662558	33711961	Although the results did not show statistical significance, esophageal cancer patients with high ITGA5 expression levels still showed a trend of high survival risk.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('high', 'Var', (92, 96))	('ITGA5', 'Gene', (97, 102))	('cancer', 'Disease', (71, 77))	('expression', 'MPA', (103, 113))	('patients', 'Species', '9606', (78, 86))	('ITGA5', 'Gene', '3678', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
662573	33711961	Subsequently, IHC and western blot were performed on adjacent normal and tumor tissues extracted from gastric cancer patients to find that Th2 cell markers such as STAT6, GATA3 and the M2 cell polarization marker CD163 were significantly increased in patients with high ITGA5 expression levels.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('gastric cancer', 'Disease', (102, 116))	('CD163', 'Gene', (213, 218))	('ITGA5', 'Gene', (270, 275))	('patients', 'Species', '9606', (251, 259))	('patients', 'Species', '9606', (117, 125))	('ITGA5', 'Gene', '3678', (270, 275))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('Th2', 'Chemical', '-', (139, 142))	('STAT6', 'Gene', (164, 169))	('GATA3', 'Gene', '2625', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', (73, 78))	('GATA3', 'Gene', (171, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('CD163', 'Gene', '9332', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('STAT6', 'Gene', '6778', (164, 169))	('increased', 'PosReg', (238, 247))	('high', 'Var', (265, 269))
662608	32332600	Kanglaite injection (Z10970091, China Food and Drug Administration), which is extracted from Coix seed, is an effective anti-cancer treatment in traditional Chinese medicine.	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Z10970091', 'Var', (21, 30))
662848	30944559	A single-channel endoscope (GIF-H260Z; Olympus Medical Systems Corp., Tokyo, Japan) was used to mark dots using magnifying narrow-band imaging, and another single-channel endoscope (GIF-Q260J; Olympus Medical Systems Corp., Tokyo, Japan) was used for mucosal incision and submucosal dissection.	('H260Z', 'Var', (32, 37))	('H260Z', 'SUBSTITUTION', 'None', (32, 37))	('Q260J', 'SUBSTITUTION', 'None', (186, 191))	('Q260J', 'Var', (186, 191))
662954	27861759	Furthermore, MetS could increase risk of EA by increasing the risk of the precursor lesion, BE, or by increasing risk of BE progression to cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('increasing', 'PosReg', (47, 57))	('MetS', 'Var', (13, 17))	('EA', 'Phenotype', 'HP:0011459', (41, 43))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BE', 'Phenotype', 'HP:0100580', (92, 94))	('BE', 'Phenotype', 'HP:0100580', (121, 123))	('cancer', 'Disease', (139, 145))
662961	27861759	BE controls identified with ICD-9-CM code 530.85 were excluded if they had a prior diagnosis with ICD-9-CM 530.2 (ulcer of the esophagus) which has previously been used for BE but is non-specific.	('ICD-9-CM 530.2', 'Var', (98, 112))	('ulcer of the esophagus', 'Disease', (114, 136))	('ulcer of the esophagus', 'Disease', 'MESH:D014456', (114, 136))	('BE', 'Phenotype', 'HP:0100580', (173, 175))	('ulcer of the esophagus', 'Phenotype', 'HP:0004791', (114, 136))	('BE', 'Phenotype', 'HP:0100580', (0, 2))
662995	27861759	In addition to demonstrating that MetS increases risk of EA, it is also of interest to the field whether the association is driven by increasing the risk of the precursor lesion, BE, or by increasing risk of BE progression to cancer.	('increasing', 'PosReg', (134, 144))	('BE', 'Phenotype', 'HP:0100580', (208, 210))	('MetS', 'Var', (34, 38))	('rat', 'Species', '10116', (22, 25))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('EA', 'Phenotype', 'HP:0011459', (57, 59))	('BE', 'Phenotype', 'HP:0100580', (179, 181))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
662996	27861759	No studies have directly addressed the issue, however, a review hypothesized that MetS may be a risk factor for carcinogenic progression of BE.	('risk factor', 'Reg', (96, 107))	('carcinogenic', 'Disease', 'MESH:D063646', (112, 124))	('MetS', 'Var', (82, 86))	('carcinogenic', 'Disease', (112, 124))	('BE', 'Phenotype', 'HP:0100580', (140, 142))
663000	27861759	Indeed, our results support a mechanism by which MetS increases risk of EA possibly through increasing risk of BE and not by increasing the carcinogenic progression of BE.	('BE', 'Phenotype', 'HP:0100580', (111, 113))	('carcinogenic', 'Disease', 'MESH:D063646', (140, 152))	('EA', 'Phenotype', 'HP:0011459', (72, 74))	('MetS', 'Var', (49, 53))	('carcinogenic', 'Disease', (140, 152))	('BE', 'Phenotype', 'HP:0100580', (168, 170))
663005	27861759	Using administrative data, a cost-effective approach to study risk factors of cancer, we are the first to demonstrate that MetS is associated with an increased risk of EA in men in the absence of GERD and women regardless of GERD status in an older population.	('MetS', 'Var', (123, 127))	('women', 'Species', '9606', (205, 210))	('EA', 'Phenotype', 'HP:0011459', (168, 170))	('cancer', 'Disease', (78, 84))	('men', 'Species', '9606', (207, 210))	('rat', 'Species', '10116', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('men', 'Species', '9606', (174, 177))	('rat', 'Species', '10116', (14, 17))
663012	27987372	SIX1  cDNA transfection induced overexpression of transforming growth factors (TGFB1 and TGFB2) and its receptor (TGFBR2).	('overexpression', 'PosReg', (32, 46))	('TGFB2', 'Gene', '7042', (89, 94))	('TGFB1', 'Gene', (79, 84))	('TGFB2', 'Gene', (89, 94))	('TGFBR2', 'Gene', (114, 120))	('transfection', 'Var', (11, 23))	('TGFBR2', 'Gene', '7048', (114, 120))	('TGFB1', 'Gene', '7040', (79, 84))
663016	27987372	Finally, TGF-beta signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN-positive tumor basal cell population.	('tumor basal cell', 'Phenotype', 'HP:0002671', (116, 132))	('TGF-beta', 'Gene', '7040', (9, 17))	('TGF-beta', 'Gene', (9, 17))	('blockade', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('reduction', 'NegReg', (89, 98))	('tumor basal cell', 'Disease', 'MESH:D002280', (116, 132))	('tumor basal cell', 'Disease', (116, 132))	('ESCC', 'Disease', (48, 52))	('PDPN', 'Gene', '10630', (102, 106))	('PDPN', 'Gene', (102, 106))	('suppressed', 'NegReg', (37, 47))
663051	27987372	We first investigated SIX1 and PDPN mRNA expression in eight ESCC cell lines (TE1, TE3, TE5, TE6, TE8, TE10, T.Tn, and KYSE510) and normal esophageal epithelium that was divided into basal, epibasal, and differentiated cell layers by laser-captured microdissection.	('TE6', 'Var', (93, 96))	('PDPN', 'Gene', '10630', (31, 35))	('PDPN', 'Gene', (31, 35))
663053	27987372	Accordingly, the high SIX1 expression was significantly correlated with the poor prognosis of ESCC patients received by surgery alone (Fig.	('high', 'Var', (17, 21))	('expression', 'MPA', (27, 37))	('SIX1', 'Protein', (22, 26))	('patients', 'Species', '9606', (99, 107))	('ESCC', 'Disease', (94, 98))	('correlated', 'Reg', (56, 66))
663058	27987372	Interestingly, a series of the TGF-beta related genes (TGFBI and TGFB2) and their receptor genes (TGFBR1 and 2) were highly expressed accompanying SIX1 overexpression (Fig.	('TGF-beta', 'Gene', (31, 39))	('SIX1', 'Var', (147, 151))	('overexpression', 'PosReg', (152, 166))	('TGFBR1 and 2', 'Gene', '7046;7048', (98, 110))	('TGFB2', 'Gene', '7042', (65, 70))	('highly expressed', 'PosReg', (117, 133))	('TGFB2', 'Gene', (65, 70))	('TGF-beta', 'Gene', '7040', (31, 39))	('TGFBI', 'Gene', '7045', (55, 60))	('TGFBI', 'Gene', (55, 60))
663078	27987372	Although transient transfection of SIX1 cDNA or siRNA did not alter PDPN expression (data not shown), these results indicate that SIX1 cannot directly induce PDPN expression, but can accelerate self-renewal of PDPN-positive tumor basal cells both in vitro (Fig.	('self-renewal', 'CPA', (194, 206))	('PDPN', 'Gene', (210, 214))	('PDPN', 'Gene', '10630', (158, 162))	('PDPN', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('PDPN', 'Gene', '10630', (210, 214))	('tumor basal cells', 'Phenotype', 'HP:0002671', (224, 241))	('tumor basal cell', 'Phenotype', 'HP:0002671', (224, 240))	('tumor basal cell', 'Disease', 'MESH:D002280', (224, 240))	('accelerate', 'PosReg', (183, 193))	('PDPN', 'Gene', '10630', (68, 72))	('PDPN', 'Gene', (68, 72))	('tumor basal cell', 'Disease', (224, 240))	('SIX1', 'Var', (130, 134))
663090	27987372	After exposure to small molecular inhibitor of TGF-beta receptor A-83-0123 for 7 days, the relative viability was significantly decreased in all of the four ESCC cell lines (TE3, TE8, T.Tn, and KYSE510) harboring a high PDPN-positive cell population (Fig.	('PDPN', 'Gene', '10630', (220, 224))	('PDPN', 'Gene', (220, 224))	('relative viability', 'CPA', (91, 109))	('A-83-0123', 'Var', (65, 74))	('decreased', 'NegReg', (128, 137))	('TGF-beta', 'Gene', '7040', (47, 55))	('TGF-beta', 'Gene', (47, 55))
663091	27987372	In TE3 and KYSE510 highly sensitive to A-83-01, its PDPN-positive cell population was significantly reduced by A-83-01(Fig.	('PDPN', 'Gene', '10630', (52, 56))	('PDPN', 'Gene', (52, 56))	('reduced', 'NegReg', (100, 107))	('KYSE510', 'Var', (11, 18))	('A-83-01', 'Var', (111, 118))	('A-83-01', 'Var', (39, 46))
663103	27987372	On the contrary, in ESCC patients who received definitive CRT, no significant difference is found, though cases with high SIX1 expression had a tendency for a worse prognosis (data not shown).	('high SIX1 expression', 'Var', (117, 137))	('ESCC', 'Disease', (20, 24))	('patients', 'Species', '9606', (25, 33))
663107	27987372	In accordance with previous findings in breast cancers, SIX1 activated TGF-beta (Fig.	('breast cancers', 'Disease', (40, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('activated', 'PosReg', (61, 70))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('SIX1', 'Var', (56, 60))	('TGF-beta', 'Gene', '7040', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (40, 54))	('TGF-beta', 'Gene', (71, 79))	('breast cancers', 'Disease', 'MESH:D001943', (40, 54))
663108	27987372	Furthermore, we investigated whether SIX1 induces a cancer stem cell phenotype, since EMT is often accompanied by cancer stem cell properties.5 We first found that SIX1 induces some genes selectively expressed at the normal basal layer where esophageal tissue stem cells are thought to reside (Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('SIX1', 'Var', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('genes', 'Gene', (182, 187))	('induces', 'Reg', (169, 176))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (114, 120))
663117	27987372	reported that immortalized esophageal epithelial cells underwent EMT through TGF-beta.35 Our data showed that TGFB was upregulated by SIX1 (Fig.	('TGFB', 'Gene', '7040', (110, 114))	('SIX1', 'Var', (134, 138))	('upregulated', 'PosReg', (119, 130))	('TGFB', 'Gene', (110, 114))	('TGF-beta', 'Gene', '7040', (77, 85))	('TGF-beta', 'Gene', (77, 85))
663123	27987372	In conclusion, our study demonstrated that aberrant expression of SIX1 is correlated with metastasis and poor survival in ESCC patients.	('metastasis', 'CPA', (90, 100))	('aberrant expression', 'Var', (43, 62))	('ESCC', 'Disease', (122, 126))	('patients', 'Species', '9606', (127, 135))	('SIX1', 'Gene', (66, 70))	('correlated', 'Reg', (74, 84))
663124	27987372	We also found that SIX1 accelerates self-renewal of cancer stem cells of ESCCs.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('accelerates', 'PosReg', (24, 35))	('SIX1', 'Var', (19, 23))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
663125	27987372	This process is dependent on TGF-beta signaling, and TGF-beta receptor inhibitors may be effective in highly malignant ESCC with high SIX1 expression.	('ESCC', 'Disease', (119, 123))	('TGF-beta', 'Gene', '7040', (29, 37))	('TGF-beta', 'Gene', '7040', (53, 61))	('TGF-beta', 'Gene', (29, 37))	('high SIX1 expression', 'Var', (129, 149))	('TGF-beta', 'Gene', (53, 61))
663132	27517497	Univariate survival analysis demonstrated that high preoperative FC score (1/2) was significantly associated with impaired disease free survival (DFS) [hazard ratio (HR), 1.650; 95% confidence interval (CI), 1.181-2.303; P = 0.003] and overall survival (OS) (HR, 1.879; 95% CI, 1.333-2.648; P<0.001), and it remained an independent predictor for both DFS (HR, 1.468; 95% CI, 1.043-2.067; P=0.028) and OS (HR, 2.070; 95% CI, 1.266-3.385; P=0.004) in multivariate Cox regression analysis.	('high', 'Var', (47, 51))	('FC', 'Chemical', '-', (65, 67))	('impaired disease', 'Disease', (114, 130))	('impaired disease', 'Disease', 'MESH:D030342', (114, 130))	('overall survival', 'CPA', (236, 252))
663161	27517497	After adjusting for other confounding variables, we found that high FC score could also serve as an independent predictor for OS (HR, 2.070; 95% CI, 1.266-3.385; P=0.004).	('FC score', 'Gene', (68, 76))	('FC', 'Chemical', '-', (68, 70))	('high', 'Var', (63, 67))
663164	27517497	The present study demonstrated that preoperative FC score was significantly correlated with the clinical stage and postoperative long-term survival, suggesting that those with high preoperative FC scores have more advanced and progressive disease, as well as impaired prognosis.	('FC scores', 'Gene', (194, 203))	('high', 'Var', (176, 180))	('FC', 'Chemical', '-', (49, 51))	('FC', 'Chemical', '-', (194, 196))	('advanced', 'CPA', (214, 222))
663179	27517497	Furthermore, as an systematic inflammation response marker, CPR has also been identified as an independent prognostic indicator for various malignancies.	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('CPR', 'Var', (60, 63))	('malignancies', 'Disease', (140, 152))	('inflammation', 'Disease', 'MESH:D007249', (30, 42))	('inflammation', 'Disease', (30, 42))
663403	16796747	For the evaluation of the Ep-CAM staining we used standardized criteria to evaluate membranous staining specified by Dako for interpretation of the HercepTest for p185HER2 expression.	('p185HER2', 'Var', (163, 171))	('Ep-CAM', 'Gene', '4072', (26, 32))	('Ep-CAM', 'Gene', (26, 32))
663420	16796747	The median cumulative disease-specific survival of the patients was 17.0 months for Ep-CAM 1+ - 3+ positive tumors and 24.0 months for Ep-CAM negative tumors (log rank, p = 0.3491; relapse-free survival: Ep-CAM 1+ - 3+ 16.0 months vs. Ep-CAM negative 43.0 months; log rank, p = 0.5993).	('1+ - 3+ positive', 'Var', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Ep-CAM', 'Gene', (204, 210))	('Ep-CAM', 'Gene', '4072', (135, 141))	('Ep-CAM', 'Gene', (135, 141))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('Ep-CAM', 'Gene', '4072', (84, 90))	('Ep-CAM', 'Gene', (84, 90))	('Ep-CAM', 'Gene', '4072', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('Ep-CAM', 'Gene', (235, 241))	('Ep-CAM', 'Gene', '4072', (235, 241))	('patients', 'Species', '9606', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
663448	16796747	Although Ep-CAM expression is low in normal gastric mucosa and an increasing expression was observed in intestinal metaplasia, loss of Ep-CAM expression is a strong prognostic factor for poor survival in gastric cancer.	('expression', 'MPA', (77, 87))	('gastric cancer', 'Disease', 'MESH:D013274', (204, 218))	('metaplasia', 'Disease', (115, 125))	('Ep-CAM', 'Gene', (9, 15))	('Ep-CAM', 'Gene', '4072', (135, 141))	('Ep-CAM', 'Gene', (135, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (204, 218))	('Ep-CAM', 'Gene', '4072', (9, 15))	('increasing', 'PosReg', (66, 76))	('loss', 'Var', (127, 131))	('metaplasia', 'Disease', 'MESH:D008679', (115, 125))	('gastric cancer', 'Disease', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
663451	16796747	The biology behind these observations can be explained by in vitro and in vivo experiments demonstrating reduced motility, invasiveness and metastatic capability of Ep-CAM transfected cells.	('Ep-CAM', 'Gene', '4072', (165, 171))	('transfected', 'Var', (172, 183))	('Ep-CAM', 'Gene', (165, 171))	('metastatic capability', 'CPA', (140, 161))	('reduced', 'NegReg', (105, 112))	('invasiveness', 'CPA', (123, 135))	('motility', 'CPA', (113, 121))
663504	31918536	Varices were present in 52.2% of patients who received endoscopy for variceal screening, and the incidence of varices was significantly higher in patients with Child-Pugh class B/C than in those with Child-Pugh class A (35-43% vs. 48-72%).	('Child-Pugh class B/C', 'Var', (160, 180))	('patients', 'Species', '9606', (33, 41))	('higher', 'PosReg', (136, 142))	('Child', 'Species', '9606', (200, 205))	('varices', 'Disease', (110, 117))	('patients', 'Species', '9606', (146, 154))	('Child', 'Species', '9606', (160, 165))
663524	31918536	The Baveno VI criteria suggest that endoscopic surveillance can be avoided in cACLD patients with a liver stiffness <20 kPa and a platelet count >150x109/L because they are at very low risk for varices that need to be treated.	('varices', 'Disease', (194, 201))	('>150x109/L', 'Var', (145, 155))	('liver stiffness', 'MPA', (100, 115))	('patients', 'Species', '9606', (84, 92))
663525	31918536	expanded the Baveno VI criteria to say that endoscopic surveillance can be avoided in cACLD patients with liver stiffness <25 kPa and a platelet count >110x109/L.	('>110x109/L', 'Var', (151, 161))	('liver stiffness', 'MPA', (106, 121))	('patients', 'Species', '9606', (92, 100))
663569	31918536	In a multicenter RCT comparing the efficacy of carvedilol and EVL in preventing first variceal bleeding in cirrhotic patients with large EVs, carvedilol had lower rates of first variceal bleeding (10% vs. 23%, P=0.04), but there was no significant difference in overall mortality or bleeding-related mortality during follow up.	('bleeding', 'Disease', (187, 195))	('mortality', 'Disease', (300, 309))	('bleeding', 'Disease', 'MESH:D006470', (95, 103))	('mortality', 'Disease', 'MESH:D003643', (270, 279))	('bleeding', 'Disease', 'MESH:D006470', (283, 291))	('bleeding', 'Disease', (95, 103))	('bleeding', 'Disease', (283, 291))	('carvedilol', 'Chemical', 'MESH:D000077261', (142, 152))	('mortality', 'Disease', (270, 279))	('EVL', 'Chemical', '-', (62, 65))	('carvedilol', 'Var', (142, 152))	('mortality', 'Disease', 'MESH:D003643', (300, 309))	('carvedilol', 'Chemical', 'MESH:D000077261', (47, 57))	('patients', 'Species', '9606', (117, 125))	('lower', 'NegReg', (157, 162))	('bleeding', 'Disease', 'MESH:D006470', (187, 195))
663596	31918536	Discontinuing NSBBs can increase the risk of variceal bleeding and mortality.	('NSBBs', 'Chemical', '-', (14, 19))	('bleeding', 'Disease', 'MESH:D006470', (54, 62))	('bleeding', 'Disease', (54, 62))	('mortality', 'Disease', (67, 76))	('NSBBs', 'Gene', (14, 19))	('Discontinuing', 'Var', (0, 13))	('mortality', 'Disease', 'MESH:D003643', (67, 76))
663636	31918536	In a previous RCT comparing intravenous ceftriaxone (1 g every 24 hours) and oral norfloxacin (400 mg every 12 hours) for the prophylaxis of bacterial infection in cirrhotic patients with gastrointestinal bleeding, the incidence of proven or possible infections (11% vs. 33%, P=0.003), proven infections (11% vs. 26%, P=0.03), and spontaneous bacterial peritonitis or bacteremia (2% vs. 12%, P=0.03) was significantly lower in the ceftriaxone group.	('bacterial peritonitis or bacteremia', 'Disease', 'MESH:D016920', (343, 378))	('lower', 'NegReg', (418, 423))	('bacterial infection', 'Disease', 'MESH:D001424', (141, 160))	('ceftriaxone', 'Var', (431, 442))	('ceftriaxone', 'Chemical', 'MESH:D002443', (431, 442))	('bacterial infection', 'Phenotype', 'HP:0002718', (141, 160))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (188, 213))	('infections', 'Disease', 'MESH:D007239', (293, 303))	('ceftriaxone', 'Chemical', 'MESH:D002443', (40, 51))	('proven', 'Disease', (232, 238))	('infections', 'Disease', (293, 303))	('infections', 'Disease', 'MESH:D007239', (251, 261))	('norfloxacin', 'Chemical', 'MESH:D009643', (82, 93))	('bacterial peritonitis or bacteremia', 'Disease', (343, 378))	('infections', 'Disease', (251, 261))	('bacteremia', 'Phenotype', 'HP:0031864', (368, 378))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (188, 213))	('gastrointestinal bleeding', 'Disease', (188, 213))	('patients', 'Species', '9606', (174, 182))	('bacterial infection', 'Disease', (141, 160))	('peritonitis', 'Phenotype', 'HP:0002586', (353, 364))
663687	31918536	NSBBs, which reduce portal pressure, have been reported to be more effective than placebo at preventing rebleeding in several RCTs.	('bleeding', 'Disease', 'MESH:D006470', (106, 114))	('portal pressure', 'MPA', (20, 35))	('bleeding', 'Disease', (106, 114))	('NSBBs', 'Var', (0, 5))	('NSBBs', 'Chemical', '-', (0, 5))
663695	31918536	A recent meta-analysis demonstrated that the rebleeding rate decreased (RR, 0.44; 95% CI, 0.28-0.69) and the mortality rate during follow-up tended to decrease with the combination of EVL plus a NSBBs (RR, 0.58; 95% CI, 0.33-1.03) compared with EVL alone.	('EVL', 'Var', (184, 187))	('mortality', 'Disease', 'MESH:D003643', (109, 118))	('bleeding', 'Disease', 'MESH:D006470', (47, 55))	('decrease', 'NegReg', (151, 159))	('EVL', 'Chemical', '-', (245, 248))	('EVL', 'Chemical', '-', (184, 187))	('mortality', 'Disease', (109, 118))	('bleeding', 'Disease', (47, 55))	('decreased', 'NegReg', (61, 70))	('combination', 'Interaction', (169, 180))	('NSBBs', 'Chemical', '-', (195, 200))
663704	31918536	An RCT comparing TIPS placement with a combination of EVL plus an NSBBs to prevent variceal rebleeding found a lower variceal rebleeding rate in the TIPS group (0% vs. 29%, P=0.001), but the incidence of HE within 1 year in that group was higher (35% vs. 14%, P=0.035).	('bleeding', 'Disease', (128, 136))	('bleeding', 'Disease', 'MESH:D006470', (94, 102))	('bleeding', 'Disease', (94, 102))	('NSBBs', 'Chemical', '-', (66, 71))	('EVL', 'Chemical', '-', (54, 57))	('lower', 'NegReg', (111, 116))	('bleeding', 'Disease', 'MESH:D006470', (128, 136))	('TIPS', 'Var', (149, 153))
663756	31918536	Complications, such as HE and stent occlusion, and medical costs were higher with the TIPS than with EVO.	('higher', 'PosReg', (70, 76))	('EVO', 'Chemical', '-', (101, 104))	('medical costs', 'CPA', (51, 64))	('TIPS', 'Var', (86, 90))
663787	31918536	Both GOV2s and IGV1s are usually called gastric fundic varices.	('GOV2s', 'Chemical', '-', (5, 10))	('gastric fundic varices', 'Disease', (40, 62))	('GOV2s', 'Var', (5, 10))
663800	31918536	However, the rebleeding rate was significantly lower in the BRTO group than the EVO group (15.4% vs. 71.4%, P<0.01).	('bleeding', 'Disease', 'MESH:D006470', (15, 23))	('lower', 'NegReg', (47, 52))	('EVO', 'Chemical', '-', (80, 83))	('bleeding', 'Disease', (15, 23))	('BRTO', 'Var', (60, 64))	('BRTO', 'Chemical', '-', (60, 64))
663806	31918536	However, a recent retrospective study showed that PPI use decreased the rebleeding risk following EVO (OR, 0.554; 95% CI, 0.352-0.873).	('PPI', 'Var', (50, 53))	('bleeding', 'Disease', 'MESH:D006470', (74, 82))	('decreased', 'NegReg', (58, 67))	('bleeding', 'Disease', (74, 82))	('EVO', 'Chemical', '-', (98, 101))
663938	31918536	Because BCAAs, such as valine, leucine, and isoleucine, are absorbed in the peripheral tissue, patients with cirrhosis have a lower concentration of the BCAAs and a higher concentration of the aromatic amino acids in the blood compared with healthy people.	('leucine', 'Chemical', 'MESH:D007930', (47, 54))	('lower', 'NegReg', (126, 131))	('patients', 'Species', '9606', (95, 103))	('cirrhosis', 'Phenotype', 'HP:0001394', (109, 118))	('isoleucine', 'Chemical', 'MESH:D007532', (44, 54))	('leucine', 'Chemical', 'MESH:D007930', (31, 38))	('cirrhosis', 'Disease', 'MESH:D005355', (109, 118))	('isoleucine', 'Var', (44, 54))	('concentration', 'MPA', (132, 145))	('aromatic amino acids', 'Chemical', 'MESH:D024322', (193, 213))	('valine', 'Chemical', 'MESH:D014633', (23, 29))	('higher', 'PosReg', (165, 171))	('BCAAs', 'Chemical', 'MESH:D000597', (8, 13))	('BCAAs', 'Chemical', 'MESH:D000597', (153, 158))	('people', 'Species', '9606', (249, 255))	('BCAAs', 'MPA', (153, 158))	('cirrhosis', 'Disease', (109, 118))	('aromatic amino acids', 'MPA', (193, 213))
663986	31918536	However, exercise can temporarily increase the portal pressure in OHE patients, and it could increase the risk of a fall or fracture in malnourished patients.	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (149, 157))	('increase', 'PosReg', (93, 101))	('fall', 'Phenotype', 'HP:0002527', (116, 120))	('exercise', 'Var', (9, 17))	('fracture', 'Disease', 'MESH:D050723', (124, 132))	('portal pressure', 'MPA', (47, 62))	('fracture', 'Disease', (124, 132))	('fall', 'CPA', (116, 120))	('increase', 'PosReg', (34, 42))	('OHE', 'Chemical', '-', (66, 69))
664047	31918536	The presence of OHE negatively affects both mental and physical functioning, whereas MHE mainly has negative effects on mental health.	('presence', 'Var', (4, 12))	('negatively', 'NegReg', (20, 30))	('OHE', 'Chemical', '-', (16, 19))	('affects', 'Reg', (31, 38))
664048	31918536	Several studies have shown that the HRQoL of patients with MHE is lower than that of patients without HE.	('MHE', 'Var', (59, 62))	('HRQoL', 'MPA', (36, 41))	('lower', 'NegReg', (66, 71))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (45, 53))
664063	31918536	One study of 160 cirrhotic patients undergoing liver transplantation found that patients with MHE or OHE had a lower MCS than patients without HE.	('patients', 'Species', '9606', (80, 88))	('MHE', 'Var', (94, 97))	('MCS', 'Gene', (117, 120))	('OHE', 'Chemical', '-', (101, 104))	('OHE', 'Var', (101, 104))	('patients', 'Species', '9606', (27, 35))	('lower MCS', 'Phenotype', 'HP:0025066', (111, 120))	('lower', 'NegReg', (111, 116))	('patients', 'Species', '9606', (126, 134))	('MCS', 'Gene', '4183', (117, 120))
664070	31918536	Patients with MHE report a decrease in the quality of their sleep and in their physical and mental HRQoL.	('MHE', 'Var', (14, 17))	('decrease', 'NegReg', (27, 35))	('mental HRQoL', 'Disease', (92, 104))	('Patients', 'Species', '9606', (0, 8))	('quality', 'MPA', (43, 50))	('mental HRQoL', 'Disease', 'MESH:D001523', (92, 104))
664102	28529620	Furthermore, clinical development of these HPV-induced tumors, related to the treatment response and overall survival, is favorable when compared to HPV negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('HPV', 'Species', '10566', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('men', 'Species', '9606', (83, 86))	('clinical development', 'CPA', (13, 33))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('HPV-induced', 'Var', (43, 54))	('tumors', 'Disease', (55, 61))	('clinical', 'Species', '191496', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', (162, 168))	('men', 'Species', '9606', (29, 32))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('HPV', 'Species', '10566', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
664173	28529620	In South America, HPV types most often found in the cervix are HPV 16, 58, 18, 45 and 31, whereas, only HPV types 16, 18 and 31 are cited as frequently in cervical and esophageal cancer.	('HPV 16', 'Species', '333760', (63, 69))	('esophageal cancer', 'Disease', (168, 185))	('HPV', 'Species', '10566', (104, 107))	('HPV', 'Species', '10566', (18, 21))	('HPV', 'Species', '10566', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('cervical', 'Disease', (155, 163))	('HPV 16', 'Var', (63, 69))
664188	28529620	Among suggested hypotheses, one of them states that esophageal carcinogenesis may involve a high rate of p16 methylation promoters, thus inhibiting its expression in the oncogenic HPV infection.	('p16', 'Gene', (105, 108))	('methylation', 'Var', (109, 120))	('inhibiting', 'NegReg', (137, 147))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (52, 77))	('oncogenic HPV infection', 'Disease', (170, 193))	('p16', 'Gene', '1029', (105, 108))	('esophageal carcinogenesis', 'Disease', (52, 77))	('oncogenic HPV infection', 'Disease', 'MESH:D030361', (170, 193))	('expression', 'MPA', (152, 162))
664191	28529620	(2013) reported that 20% of esophageal tumors were p16-/HPV+, and that most of these tumors showed methylation of the p16 gene promoter.	('methylation', 'Var', (99, 110))	('p16', 'Gene', '1029', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('p16', 'Gene', '1029', (118, 121))	('HPV', 'Species', '10566', (56, 59))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('esophageal tumors', 'Disease', 'MESH:D004938', (28, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('p16', 'Gene', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal tumors', 'Disease', (28, 45))	('esophageal tumors', 'Phenotype', 'HP:0100751', (28, 45))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p16', 'Gene', (118, 121))	('tumors', 'Disease', (39, 45))	('tumors', 'Disease', (85, 91))
664231	26976915	The AHA endorses 7 metrics of ideal health that include a combination of health behaviors (not smoking, physical activity, low body mass index [BMI, defined as the weight in kilograms divided by the square of the height in meters], and healthy diet) and health factors (blood sugar, blood pressure, and total cholesterol).	('physical activity', 'Disease', (104, 121))	('blood sugar', 'Chemical', 'MESH:D001786', (270, 281))	('low', 'Var', (123, 126))	('cholesterol', 'Chemical', 'MESH:D002784', (309, 320))	('low body mass', 'Phenotype', 'HP:0004325', (123, 136))	('low body mass index', 'Phenotype', 'HP:0045082', (123, 142))
664235	26976915	The World Health Organization (WHO) estimates that more than 30% of cancer deaths could be prevented by modifying or avoiding certain risk factors including tobacco use, obesity, unhealthy diets low in fruit and vegetable intake, inactivity, alcohol use, sexually transmitted HPV-infection, urban air pollution, and indoor smoke from solid fuels.	('obesity', 'Disease', 'MESH:D009765', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('alcohol', 'Chemical', 'MESH:D000438', (242, 249))	('obesity', 'Disease', (170, 177))	('tobacco', 'Species', '4097', (157, 164))	('cancer deaths', 'Disease', 'MESH:D003643', (68, 81))	('cancer deaths', 'Disease', (68, 81))	('HPV-infection', 'Disease', 'MESH:D030361', (276, 289))	('HPV-infection', 'Disease', (276, 289))	('alcohol use', 'Phenotype', 'HP:0030955', (242, 253))	('modifying', 'Var', (104, 113))	('obesity', 'Phenotype', 'HP:0001513', (170, 177))	('inactivity', 'Disease', (230, 240))	('alcohol use', 'Disease', (242, 253))
664255	26976915	Overexpression of IL-6 has been shown to inhibit cancer cell apoptosis, stimulate angiogenesis, and have a role in drug resistance, leading to tumor progression.	('IL-6', 'Gene', '3569', (18, 22))	('leading to', 'Reg', (132, 142))	('tumor', 'Disease', (143, 148))	('role', 'Reg', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('angiogenesis', 'CPA', (82, 94))	('drug resistance', 'Phenotype', 'HP:0020174', (115, 130))	('inhibit', 'NegReg', (41, 48))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('stimulate', 'PosReg', (72, 81))	('IL-6', 'Gene', (18, 22))	('cancer', 'Disease', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
664268	26976915	Meta-analyses have shown an increased risk of colorectal cancer, prostate cancer, and premenopausal breast cancer associated with high serum levels of IGF.	('colorectal cancer', 'Disease', 'MESH:D015179', (46, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (65, 80))	('high', 'Var', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('IGF', 'Protein', (151, 154))	('colorectal cancer', 'Disease', (46, 63))	('breast cancer', 'Disease', (100, 113))	('men', 'Species', '9606', (89, 92))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (86, 113))	('prostate cancer', 'Disease', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
664298	26976915	Similar to estrogen, which has well-known pleiotropic effects on the cardiovascular system, emerging murine studies also demonstrate that 27HC has cardiovascular effects.	('27HC', 'Var', (138, 142))	('murine', 'Species', '10090', (101, 107))	('cardiovascular effects', 'MPA', (147, 169))	('27HC', 'Chemical', 'MESH:C076996', (138, 142))
664310	26976915	In vitro animal models have found that nicotine can inhibit apoptosis and enhance angiogenesis, which raises concern about the role of nicotine itself in both diseases.	('inhibit', 'NegReg', (52, 59))	('nicotine', 'Chemical', 'MESH:D009538', (135, 143))	('angiogenesis', 'CPA', (82, 94))	('apoptosis', 'CPA', (60, 69))	('nicotine', 'Chemical', 'MESH:D009538', (39, 47))	('nicotine', 'Var', (39, 47))	('enhance', 'PosReg', (74, 81))
664318	26976915	A probable decreased risk exists between the following: non-starchy vegetables with oropharygneal, laryngeal, esophageal and stomach cancer; garlic with colorectal cancer; fruits with oropharygneal, laryngeal, esophageal, lung and stomach cancer; and high calcium diets and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('colorectal cancer', 'Disease', (274, 291))	('decreased', 'NegReg', (11, 20))	('stomach cancer', 'Disease', 'MESH:D013274', (231, 245))	('esophageal', 'Disease', (110, 120))	('stomach cancer', 'Phenotype', 'HP:0012126', (231, 245))	('colorectal cancer', 'Disease', (153, 170))	('stomach cancer', 'Disease', 'MESH:D013274', (125, 139))	('stomach cancer', 'Phenotype', 'HP:0012126', (125, 139))	('calcium', 'Chemical', 'MESH:D002118', (256, 263))	('lung', 'Disease', (222, 226))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('colorectal cancer', 'Phenotype', 'HP:0003003', (274, 291))	('garlic', 'Species', '4682', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('esophageal', 'Disease', (210, 220))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('stomach cancer', 'Disease', (231, 245))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('stomach cancer', 'Disease', (125, 139))	('colorectal cancer', 'Disease', 'MESH:D015179', (274, 291))	('laryngeal', 'Disease', (99, 108))	('oropharygneal', 'Var', (184, 197))
664320	26976915	Genetic mutations in the folate metabolism pathway, in conjunction with inadequate folate intake, are associated with increased risk of both CVD and colorectal cancer.	('associated', 'Reg', (102, 112))	('folate', 'Chemical', 'MESH:D005492', (25, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('inadequate folate', 'Phenotype', 'HP:0100507', (72, 89))	('folate', 'Chemical', 'MESH:D005492', (83, 89))	('inadequate folate intake', 'Phenotype', 'HP:0100507', (72, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CVD', 'Disease', (141, 144))	('Genetic mutations', 'Var', (0, 17))	('folate metabolism pathway', 'Pathway', (25, 50))	('colorectal cancer', 'Disease', (149, 166))	('CVD', 'Phenotype', 'HP:0001626', (141, 144))
664321	26976915	Aberrant methylation due to folate deficiency is hypothesized to contribute to atherosclerosis, as this may modulate the expression of a variety of genes involved in proliferation and migration capabilities within the smooth muscle of coronary vessels.	('modulate', 'Reg', (108, 116))	('atherosclerosis', 'Disease', (79, 94))	('folate deficiency', 'Disease', (28, 45))	('folate deficiency', 'Disease', 'MESH:C562799', (28, 45))	('Aberrant', 'Var', (0, 8))	('migration', 'CPA', (184, 193))	('atherosclerosis', 'Disease', 'MESH:D050197', (79, 94))	('expression', 'MPA', (121, 131))	('methylation', 'MPA', (9, 20))	('atherosclerosis', 'Phenotype', 'HP:0002621', (79, 94))	('folate deficiency', 'Phenotype', 'HP:0100507', (28, 45))	('contribute', 'Reg', (65, 75))
664322	26976915	In rapidly dividing tissues such as the epithelium of the gastrointestinal tract, inadequate folate causes inadequate thymidylate production, impairing DNA synthesis and producing genomic instability and subsequent carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (215, 229))	('impairing', 'NegReg', (142, 151))	('folate', 'MPA', (93, 99))	('thymidylate production', 'MPA', (118, 140))	('carcinogenesis', 'Disease', (215, 229))	('genomic instability', 'CPA', (180, 199))	('folate', 'Chemical', 'MESH:D005492', (93, 99))	('gastrointestinal tract', 'Disease', (58, 80))	('inadequate folate', 'Phenotype', 'HP:0100507', (82, 99))	('DNA synthesis', 'MPA', (152, 165))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (58, 80))	('inadequate', 'NegReg', (107, 117))	('inadequate', 'Var', (82, 92))	('producing', 'Reg', (170, 179))
664326	26976915	nitrosamines) that can act directly on DNA and cause point mutations, deletions, and insertions.	('insertions', 'Var', (85, 95))	('cause', 'Reg', (47, 52))	('nitrosamines', 'Chemical', 'MESH:D009602', (0, 12))	('deletions', 'Var', (70, 79))	('point mutations', 'Var', (53, 68))
664327	26976915	Consumption of polyphenols, found primarily in fruits, vegetables, and certain plants, has been associated with a reduction in both CVD and cancer, presumably due to their affect on several metabolic pathways, including MAP-kinases, P13-kinases, IGF-1, NF-kB and ROS.	('polyphenols', 'Chemical', 'MESH:D059808', (15, 26))	('IGF-1', 'Gene', '3479', (246, 251))	('P13-kinases', 'Enzyme', (233, 244))	('reduction', 'NegReg', (114, 123))	('metabolic pathways', 'Pathway', (190, 208))	('polyphenols', 'Var', (15, 26))	('MAP-kinases', 'Enzyme', (220, 231))	('IGF-1', 'Gene', (246, 251))	('CVD', 'Phenotype', 'HP:0001626', (132, 135))	('cancer', 'Disease', (140, 146))	('NF-kB', 'Gene', (253, 258))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('CVD', 'Disease', (132, 135))	('ROS', 'Chemical', 'MESH:D017382', (263, 266))	('affect', 'Reg', (172, 178))
664331	26976915	In patients with established cardiovascular disease, meta-analyzed data (8 observational studies) of 16,351 patients found moderate alcohol consumption to be associated with reduced CVD- and all-cause mortality.	('cardiovascular disease', 'Disease', (29, 51))	('moderate alcohol consumption', 'Var', (123, 151))	('patients', 'Species', '9606', (3, 11))	('CVD', 'Phenotype', 'HP:0001626', (182, 185))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (29, 51))	('patients', 'Species', '9606', (108, 116))	('reduced', 'NegReg', (174, 181))	('alcohol', 'Chemical', 'MESH:D000438', (132, 139))	('cardiovascular disease', 'Disease', 'MESH:D002318', (29, 51))
664334	26976915	Higher alcohol levels are associated with increased mortality, CVD, elevated triglycerides, hypertension, atrial fibrillation, cardiomyopathy, and stroke.	('Higher alcohol', 'Var', (0, 14))	('hypertension', 'Disease', (92, 104))	('stroke', 'Phenotype', 'HP:0001297', (147, 153))	('alcohol', 'Chemical', 'MESH:D000438', (7, 14))	('elevated', 'PosReg', (68, 76))	('atrial fibrillation', 'Disease', 'MESH:D001281', (106, 125))	('atrial fibrillation', 'Disease', (106, 125))	('stroke', 'Disease', 'MESH:D020521', (147, 153))	('mortality', 'Disease', (52, 61))	('hypertension', 'Phenotype', 'HP:0000822', (92, 104))	('stroke', 'Disease', (147, 153))	('triglycerides', 'Chemical', 'MESH:D014280', (77, 90))	('CVD', 'Phenotype', 'HP:0001626', (63, 66))	('increased', 'PosReg', (42, 51))	('cardiomyopathy', 'Disease', (127, 141))	('triglycerides', 'MPA', (77, 90))	('CVD', 'Disease', (63, 66))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (106, 125))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (127, 141))	('cardiomyopathy', 'Disease', 'MESH:D009202', (127, 141))	('hypertension', 'Disease', 'MESH:D006973', (92, 104))	('elevated triglycerides', 'Phenotype', 'HP:0002155', (68, 90))
664346	26976915	The AICR/WCRF reports that there is convincing evidence that physical activity reduces colorectal cancer risk, and there is probable evidence that it reduces postmenopausal breast and endometrial cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('endometrial cancers', 'Disease', 'MESH:D016889', (184, 203))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('postmenopausal breast', 'Disease', (158, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('reduces', 'NegReg', (79, 86))	('men', 'Species', '9606', (162, 165))	('physical', 'Var', (61, 69))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('endometrial cancer', 'Phenotype', 'HP:0012114', (184, 202))	('colorectal cancer', 'Disease', (87, 104))	('reduces', 'NegReg', (150, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))	('endometrial cancers', 'Disease', (184, 203))
664352	26976915	While environment and cultural practices may impart disease patterns among members of specific ethnicities, genetic components of race pre-dispose individuals toward some of the aforementioned modifiable risk factors.	('impart', 'Reg', (45, 51))	('men', 'Species', '9606', (183, 186))	('pre-dispose', 'Reg', (135, 146))	('genetic', 'Var', (108, 115))	('men', 'Species', '9606', (13, 16))
664361	26976915	Metformin has been thought to reduce the risk of cancer and has a plausible biological mechanism, although population studies have demonstrated mixed results.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('reduce', 'NegReg', (30, 36))	('Metformin', 'Var', (0, 9))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
664362	26976915	Metformin activates adenosine monophosphate-activated protein kinase (AMPK) in hepatocytes, a major cellular regulator of lipid and glucose metabolism, and AMPK is associated with several tumor suppressors.	('tumor', 'Disease', (188, 193))	('adenosine monophosphate-activated protein kinase', 'Gene', '5563', (20, 68))	('AMPK', 'Gene', (156, 160))	('lipid', 'Chemical', 'MESH:D008055', (122, 127))	('activates', 'PosReg', (10, 19))	('AMPK', 'Gene', '5563', (156, 160))	('glucose metabolism', 'Disease', 'MESH:D044882', (132, 150))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Metformin', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('AMPK', 'Gene', '5563', (70, 74))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('adenosine monophosphate-activated protein kinase', 'Gene', (20, 68))	('glucose metabolism', 'Disease', (132, 150))	('AMPK', 'Gene', (70, 74))
664368	26976915	Additional studies have adjusted for hypertension, still showing a weakened, albeit statistically significant, association between diuretics and RCC; more convincingly, diuretics have been shown to increase the risk of RCC in normotensive patients taking diuretics for alternative indications.	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('hypertension', 'Disease', (37, 49))	('increase', 'PosReg', (198, 206))	('patients', 'Species', '9606', (239, 247))	('hypertension', 'Phenotype', 'HP:0000822', (37, 49))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('hypertension', 'Disease', 'MESH:D006973', (37, 49))	('RCC', 'Disease', (219, 222))	('diuretics', 'Var', (169, 178))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', 'MESH:C538614', (219, 222))
664375	26976915	Statin inhibition of HMG-CoA reductase decreases levels of mevalonate and its downstream products, including not only cholesterol but additional factors that are critical for cancer growth and progression.	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('levels of mevalonate', 'MPA', (49, 69))	('inhibition', 'Var', (7, 17))	('cholesterol', 'MPA', (118, 129))	('decreases', 'NegReg', (39, 48))	('mevalonate', 'Chemical', 'MESH:D008798', (59, 69))	('HMG-CoA', 'Gene', (21, 28))	('cholesterol', 'Chemical', 'MESH:D002784', (118, 129))
664386	26976915	A large prospective study showed NSAIDs to be associated with reduced risk of several alcohol-related, infection-related, obesity-related, and smoking-related cancers.	('cancers', 'Disease', (159, 166))	('obesity', 'Phenotype', 'HP:0001513', (122, 129))	('infection', 'Disease', (103, 112))	('NSAIDs', 'Var', (33, 39))	('obesity', 'Disease', 'MESH:D009765', (122, 129))	('infection', 'Disease', 'MESH:D007239', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('alcohol-related', 'Disease', (86, 101))	('alcohol', 'Chemical', 'MESH:D000438', (86, 93))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('obesity', 'Disease', (122, 129))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('reduced', 'NegReg', (62, 69))
664409	26976915	Nonetheless, the results from the EPIC and Rasmussen-Torvik studies demonstrate that adherence to several of the health measures combined is associated with a reduced risk of incident cancer over time.	('cancer', 'Disease', (184, 190))	('adherence', 'Var', (85, 94))	('reduced', 'NegReg', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
664511	25373738	To date, several transcriptional co-activators have been reported to befrequently overexpressed in ESCC including deleted in breast cancer 1 (DBC1), p300, beta-catenin, amplified in breast cancer 1 (AIB1).	('beta-catenin', 'Gene', (155, 167))	('p300', 'Gene', '2033', (149, 153))	('AIB1', 'Gene', (199, 203))	('AIB1', 'Gene', '63897', (199, 203))	('DBC1', 'Gene', '57805', (142, 146))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('DBC1', 'Gene', (142, 146))	('beta-catenin', 'Gene', '1499', (155, 167))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('amplified in breast cancer 1', 'Gene', (169, 197))	('deleted in', 'Var', (114, 124))	('breast cancer', 'Disease', (125, 138))	('p300', 'Gene', (149, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('amplified in breast cancer 1', 'Gene', '63897', (169, 197))
664522	25373738	Of note, the high ZNF282 expression was significantly correlated with advanced T stage (p=0.019).	('high', 'Var', (13, 17))	('expression', 'MPA', (25, 35))	('ZNF282', 'Gene', (18, 24))	('ZNF282', 'Gene', '8427', (18, 24))
664523	25373738	This correlation between high ZNF282 expression and advanced T stage was more distinctly observed in the small size (<4cm) tumor group (p=0.0005).	('tumor', 'Disease', (123, 128))	('ZNF282', 'Gene', (30, 36))	('high', 'Var', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('expression', 'MPA', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('ZNF282', 'Gene', '8427', (30, 36))
664524	25373738	1E) of patients with high expression of ZNF282 were significantly lower than those of patients with low expression (p<0.001 for both).	('ZNF282', 'Gene', '8427', (40, 46))	('ZNF282', 'Gene', (40, 46))	('lower', 'NegReg', (66, 71))	('high expression', 'Var', (21, 36))	('patients', 'Species', '9606', (7, 15))	('patients', 'Species', '9606', (86, 94))
664525	25373738	Moreover, high expression of ZNF282 was identified as an independent prognostic factor for both OS [HR: 2.>56 (95% CI 1.54-4.26), p<0.001] and DFS [HR:2.28 (95% CI 1.43-3.62, p<0.001], in the multivariate analysis (Table 2).	('ZNF282', 'Gene', '8427', (29, 35))	('high expression', 'Var', (10, 25))	('DFS', 'Disease', (143, 146))	('ZNF282', 'Gene', (29, 35))
664531	25373738	ZNF282 knockdown in TE9 cells increased late apoptotic compartment (17.55 %) compared to control group (12.63 %), while no significant difference in the proportion of early apoptotic cells between shZNF282 group (11.19 %)and control group (10.14 %) (Figure.	('ZNF282', 'Gene', '8427', (199, 205))	('ZNF282', 'Gene', '8427', (0, 6))	('late apoptotic compartment', 'CPA', (40, 66))	('ZNF282', 'Gene', (199, 205))	('ZNF282', 'Gene', (0, 6))	('increased', 'PosReg', (30, 39))	('knockdown', 'Var', (7, 16))
664560	25373738	To further assess the physiological role of ZNF282 as an E2F1 co-activator, we determined the effect of ZNF282 depletion on the expression of the endogenous E2F1 target genes including E2F1 itself.	('ZNF282', 'Gene', (44, 50))	('ZNF282', 'Gene', '8427', (104, 110))	('depletion', 'Var', (111, 120))	('expression', 'MPA', (128, 138))	('ZNF282', 'Gene', (104, 110))	('ZNF282', 'Gene', '8427', (44, 50))
664561	25373738	When ZNF282 protein and mRNA levels were specifically reduced in TE10 cells by siRNA transfection (Figure 3G and 3H), the expression of well characterized E2F1 target genes such as CCND2, CCNA1, CDC2, and CDC6 was significantly inhibited compared with the results using a NS siRNA (Figure 3I).	('CDC2', 'Gene', (195, 199))	('expression', 'MPA', (122, 132))	('CDC6', 'Gene', (205, 209))	('inhibited', 'NegReg', (228, 237))	('ZNF282', 'Gene', (5, 11))	('TE10', 'CellLine', 'CVCL:1760', (65, 69))	('transfection', 'Var', (85, 97))	('protein', 'Protein', (12, 19))	('CCND2', 'Gene', (181, 186))	('reduced', 'NegReg', (54, 61))	('mRNA levels', 'MPA', (24, 35))	('CCNA1', 'Gene', (188, 193))	('ZNF282', 'Gene', '8427', (5, 11))
664563	25373738	Having demonstrated that ZNF282 depletion reduces the expression of a subset of E2F1-responsive genes, we next performed chromatin immunoprecipitation (ChIP) assays in TE10 cells to examine whether ZNF282 is recruited to the target gene promoters.	('expression', 'MPA', (54, 64))	('E2F1-responsive genes', 'Gene', (80, 101))	('ZNF282', 'Gene', (198, 204))	('depletion', 'Var', (32, 41))	('TE10', 'CellLine', 'CVCL:1760', (168, 172))	('reduces', 'NegReg', (42, 49))	('ZNF282', 'Gene', '8427', (25, 31))	('ZNF282', 'Gene', (25, 31))	('ZNF282', 'Gene', '8427', (198, 204))
664570	25373738	The prognostic effect of ZNF282 in OS and DFS was more significant in E2F1 high-expression group than in low-expression group (OS, p=0.021 vs p=0.438; DFS, p=0.049 vs p=0.458) (Figure 4C-F).	('high-expression', 'Var', (75, 90))	('ZNF282', 'Gene', '8427', (25, 31))	('ZNF282', 'Gene', (25, 31))	('E2F1', 'Gene', (70, 74))
664575	25373738	Besides, we demonstrated that knockdown of ZNF282 induced apoptosis and cell cycle arrest as well as decreased migration, invasion, and tumorigenenicity in vitro,and inhibited growth of ESCC xenograft tumor in nude mice.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('ZNF282', 'Gene', (43, 49))	('migration', 'CPA', (111, 120))	('growth', 'CPA', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('inhibited', 'NegReg', (166, 175))	('invasion', 'CPA', (122, 130))	('decreased', 'NegReg', (101, 110))	('cell cycle arrest', 'CPA', (72, 89))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('knockdown', 'Var', (30, 39))	('apoptosis', 'CPA', (58, 67))	('tumor', 'Disease', (201, 206))	('ZNF282', 'Gene', '8427', (43, 49))	('tumor', 'Disease', (136, 141))	('nude mice', 'Species', '10090', (210, 219))
664589	25373738	Although there is increasing evidence that E2F1 is associated with ESCCaggressiveness and poor clinical outcomes, the underlying mechanisms ofE2F1-mediated transcriptional regulation in ESCC are not well defined.	('ESCCaggressiveness', 'Disease', (67, 85))	('E2F1', 'Var', (43, 47))	('associated', 'Reg', (51, 61))	('ESCCaggressiveness', 'Disease', 'None', (67, 85))	('ESCC', 'Disease', (186, 190))
664591	25373738	ZNF282 depletion increased apoptosis and inhibited cell cycle progression at G1/S.	('increased', 'PosReg', (17, 26))	('cell cycle progression at G1/S', 'CPA', (51, 81))	('ZNF282', 'Gene', '8427', (0, 6))	('depletion', 'Var', (7, 16))	('ZNF282', 'Gene', (0, 6))	('inhibited', 'NegReg', (41, 50))	('apoptosis', 'CPA', (27, 36))
664592	25373738	Because E2F1 facilitates cell cycle progression by stimulating G1/S transition, these results suggest that ZNF282 has a critical role as an E2F1 co-activator in cell cycle control of ESCC cells.	('facilitates', 'PosReg', (13, 24))	('E2F1', 'Var', (8, 12))	('cell cycle progression', 'CPA', (25, 47))	('G1/S transition', 'MPA', (63, 78))	('ZNF282', 'Gene', '8427', (107, 113))	('stimulating', 'PosReg', (51, 62))	('ZNF282', 'Gene', (107, 113))
664645	25030066	Compared with SA, CRTS was associated with significantly decreased postoperative mortality, local recurrence and distant metastasis rates, with RR (95% CI) = 0.64 (0.49-0.84), 0.53 (0.39-0.73), 0.82 (0.68-0.98); p = 0.001, <0.00001, =0.03, respectively.	('local recurrence', 'CPA', (92, 108))	('CRTS', 'Var', (18, 22))	('SA', 'Chemical', '-', (14, 16))	('decreased', 'NegReg', (57, 66))	('distant metastasis rates', 'CPA', (113, 137))	('postoperative mortality', 'CPA', (67, 90))
664675	25030066	Previous studies have demonstrated that CRTS significantly improves the long-term survival rate of esophageal cancer compared with SA alone.	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('CRTS', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('improves', 'PosReg', (59, 67))	('esophageal cancer', 'Disease', (99, 116))	('SA', 'Chemical', '-', (131, 133))
664710	25013469	Three cases indicated pleomorphism and Ki-67 was locally positive.	('indicated', 'Reg', (12, 21))	('Ki-67', 'Chemical', '-', (39, 44))	('pleomorphism', 'Var', (22, 34))
664769	25013469	Negative markers, which include CD117, CD34, desmin, CK, SMA, glial fibrillary acidic protein, inhibin-alpha, myoglobin, fibronectin and carcinoembryonic antigen, have also been reported.	('fibronectin', 'Gene', (121, 132))	('carcinoembryonic', 'Disease', 'None', (137, 153))	('desmin', 'Gene', (45, 51))	('myoglobin', 'Gene', '4151', (110, 119))	('CD34', 'Gene', (39, 43))	('CD34', 'Gene', '947', (39, 43))	('CD117', 'Var', (32, 37))	('SMA', 'Chemical', '-', (57, 60))	('desmin', 'Gene', '1674', (45, 51))	('glial', 'MPA', (62, 67))	('fibronectin', 'Gene', '2335', (121, 132))	('myoglobin', 'Gene', (110, 119))	('carcinoembryonic', 'Disease', (137, 153))	('SMA', 'Phenotype', 'HP:0003262', (57, 60))
664836	24373621	Microarray analysis was performed on primary HNSCC cell cultures followed by validation of deregulated miRNAs via qRT-PCR.	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('deregulated', 'Var', (91, 102))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))
664848	24373621	During the last decade alterations in miRNA expression have been associated with a number of human diseases, including cancer (reviewed in ).	('human', 'Species', '9606', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('associated', 'Reg', (65, 75))	('cancer', 'Disease', (119, 125))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('alterations', 'Var', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
664911	24373621	In order to further investigate whether the plasma miRNA changes following tumor therapy originate from the tumor cells we established an in vitro radiochemotherapy model using primary HNSCC from two different patients, HN1957 and HN2092 (Table  2).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('HN2092', 'Var', (231, 237))	('HNSCC', 'Phenotype', 'HP:0012288', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('HN1957', 'Var', (220, 226))	('tumor', 'Disease', (108, 113))	('miR', 'Gene', '220972', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('miR', 'Gene', (51, 54))	('HN2092', 'CellLine', 'CVCL:K854', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('patients', 'Species', '9606', (210, 218))	('HN1957', 'CellLine', 'CVCL:M493', (220, 226))	('tumor', 'Disease', (75, 80))
664913	24373621	HN2092 cells showed higher sensitivity to ionizing radiation but lower sensitivity to 5-FU treatment compared to HN1957 cells.	('5-FU', 'Chemical', 'MESH:D005472', (86, 90))	('sensitivity to ionizing radiation', 'MPA', (27, 60))	('lower', 'NegReg', (65, 70))	('higher', 'PosReg', (20, 26))	('sensitivity to 5-FU treatment', 'MPA', (71, 100))	('HN1957', 'CellLine', 'CVCL:M493', (113, 119))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (27, 60))	('HN2092', 'Var', (0, 6))	('HN2092', 'CellLine', 'CVCL:K854', (0, 6))
664916	24373621	MiRNA profiling using Agilent microarrays in the sham-irradiated and DMSO-treated control cells compared to cells treated with in vitro radiochemotherapy revealed several miRNAs that differentiate control cells and treated cells for HN1957 and HN2092 (Additional files 5 and 6).	('MiR', 'Gene', (0, 3))	('MiR', 'Gene', '220972', (0, 3))	('HN1957', 'Var', (233, 239))	('HN2092', 'CellLine', 'CVCL:K854', (244, 250))	('miR', 'Gene', '220972', (171, 174))	('miR', 'Gene', (171, 174))	('HN1957', 'CellLine', 'CVCL:M493', (233, 239))	('DMSO', 'Chemical', 'MESH:D004121', (69, 73))	('HN2092', 'Var', (244, 250))
664950	24373621	The current study strongly suggests that alterations of miRNAs following radiochemotherapy in the blood plasma are associated with the tumor response to therapy and therefore might represent novel biomarkers for therapy monitoring.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('associated with', 'Reg', (115, 130))	('alterations', 'Var', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
665075	23735112	Tumors in the mice were established using human colorectal cancer cell lines with high (SW480) or low (SW620) expression of EGFR.	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('EGFR', 'Gene', '1956', (124, 128))	('human', 'Species', '9606', (42, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))	('mice', 'Species', '10090', (14, 18))	('low', 'NegReg', (98, 101))	('colorectal cancer', 'Disease', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('EGFR', 'Gene', (124, 128))	('SW480', 'Var', (88, 93))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('expression', 'MPA', (110, 120))	('SW620', 'Var', (103, 108))	('SW480', 'CellLine', 'CVCL:0546', (88, 93))
665079	23735112	Mice with a tumor containing the SW480 line were found to have significantly higher mean fluorescence intensity (1.92 +- 0.22) than mice with SW620 tumors (0.59 +- 0.21).	('fluorescence intensity', 'MPA', (89, 111))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('higher', 'PosReg', (77, 83))	('tumor', 'Disease', (148, 153))	('SW480', 'Var', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('SW620 tumors', 'Disease', (142, 154))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mice', 'Species', '10090', (132, 136))	('SW620 tumors', 'Disease', 'MESH:D009369', (142, 154))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('SW480', 'CellLine', 'CVCL:0546', (33, 38))
665120	23506629	The changes in lung V20, V30, esophageal V50 and V55 were statistically significant (Ps< 0.05 for all), while the differences in mean lung dose, lung V5, V10, V15, heart V30, mean esophageal dose, esophagus Dmax, and spinal cord Dmax were not significant (Ps> 0.05 for all).	('lung dose', 'MPA', (134, 143))	('lung', 'MPA', (15, 19))	('esophageal', 'MPA', (30, 40))	('V15', 'Gene', '28814', (159, 162))	('V15', 'Gene', (159, 162))	('V55', 'Var', (49, 52))	('V30', 'Var', (25, 28))
665145	23506629	(1) GTVCT and GTVPET-CT calculated automatically on the workstation; (2) Dose-volume histogram (DVH) parameters, including mean lung dose (MLD), lung V5, V10, V15, V20 and V30, mean heart dose (MHD), heart V30, esophageal V50 and V55, esophageal Dmax, and spinal cord Dmax.	('esophageal', 'Disease', (211, 221))	('V30', 'Var', (172, 175))	('MLD', 'Disease', 'MESH:D007966', (139, 142))	('mean heart dose', 'MPA', (177, 192))	('MLD', 'Disease', (139, 142))	('spinal cord Dmax', 'CPA', (256, 272))	('V55', 'MPA', (230, 233))	('V15', 'Gene', '28814', (159, 162))	('MHD', 'Disease', 'None', (194, 197))	('V10', 'Var', (154, 157))	('MHD', 'Disease', (194, 197))	('V20', 'Var', (164, 167))	('heart', 'Disease', (200, 205))	('V15', 'Gene', (159, 162))	('esophageal', 'CPA', (235, 245))
665149	23506629	The changes in lung V20, V30, esophageal V50 and V55 were statistically significant (Ps< 0.05 for all), while the differences in MLD, lung V5, V10, V15, heart V30, MHD, esophageal Dmax, and spinal cord Dmax were not statistically significant (Ps> 0.05 for all).	('V15', 'Gene', (148, 151))	('MLD', 'Disease', 'MESH:D007966', (129, 132))	('MLD', 'Disease', (129, 132))	('V15', 'Gene', '28814', (148, 151))	('MHD', 'Disease', 'None', (164, 167))	('MHD', 'Disease', (164, 167))	('V55', 'Var', (49, 52))	('V30', 'Var', (25, 28))
665157	23506629	The changes in lung V20, V30, esophageal V50 and V55 were statistically significant (Ps< 0.05 for all), while the differences in MLD, lung V5, V10, V15, heart V30, MHD, esophageal Dmax, and spinal cord Dmax were not significant (Ps> 0.05 for all).	('V15', 'Gene', (148, 151))	('lung', 'MPA', (15, 19))	('esophageal', 'MPA', (30, 40))	('MLD', 'Disease', 'MESH:D007966', (129, 132))	('MLD', 'Disease', (129, 132))	('V15', 'Gene', '28814', (148, 151))	('MHD', 'Disease', 'None', (164, 167))	('MHD', 'Disease', (164, 167))	('V55', 'Var', (49, 52))	('V30', 'Var', (25, 28))
665162	23506629	In a study involving 99 NSCLC patients performed by Graham et al., univariate analysis showed that the V20 and MLD were closely associated with the development of acute radiation-induced lung injury (grade 2 or higher), and multivariate analysis showed that the V20 was the only independent predictive factor for acute radiation-induced lung injury.	('NSCLC', 'Disease', (24, 29))	('V20', 'Var', (103, 106))	('MLD', 'Disease', 'MESH:D007966', (111, 114))	('MLD', 'Disease', (111, 114))	('lung injury', 'Disease', 'MESH:D055370', (337, 348))	('lung injury', 'Disease', 'MESH:D055370', (187, 198))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('lung injury', 'Disease', (337, 348))	('lung injury', 'Disease', (187, 198))	('patients', 'Species', '9606', (30, 38))	('associated with', 'Reg', (128, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))
665164	23506629	demonstrated that the V30 was a factor associated with the development of acute radiation-induced lung injury.	('lung injury', 'Disease', (98, 109))	('V30', 'Var', (22, 25))	('associated', 'Reg', (39, 49))	('lung injury', 'Disease', 'MESH:D055370', (98, 109))
665295	32398863	Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities.	('oncogenic activities', 'CPA', (184, 204))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('impaired', 'NegReg', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (138, 143))	('ESCC', 'Disease', (82, 86))	('NFE2L2', 'Gene', (109, 115))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('conferred', 'Reg', (174, 183))	('mutations', 'Var', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
665296	32398863	We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival.	('correlated', 'Reg', (128, 138))	('SLC35E2', 'Gene', (110, 117))	('mutations', 'Var', (74, 83))	('hotspot', 'PosReg', (66, 73))	('SLC35E2', 'Gene', '9906', (110, 117))
665297	32398863	Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies.	('mutations', 'Var', (86, 95))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
665302	32398863	Recent whole-genome and -exome analyses in ESCC revealed a complex mutational landscape and identified significantly mutated genes (SMGs) including TP53, ZNF750, NOTCH1, FAT1, NFE2L2, recurrent copy number amplifications occurring in SOX2, TERT, FGFR1, MDM2, and common deletions of RB1.	('SOX2', 'Gene', '6657', (234, 238))	('MDM2', 'Gene', '4193', (253, 257))	('NOTCH1', 'Gene', '4851', (162, 168))	('TP53', 'Gene', (148, 152))	('FGFR1', 'Gene', (246, 251))	('FAT1', 'Gene', (170, 174))	('RB1', 'Gene', (283, 286))	('ZNF750', 'Gene', '79755', (154, 160))	('ZNF750', 'Gene', (154, 160))	('TP53', 'Gene', '7157', (148, 152))	('copy number amplifications', 'Var', (194, 220))	('TERT', 'Gene', (240, 244))	('TERT', 'Gene', '7015', (240, 244))	('RB1', 'Gene', '5925', (283, 286))	('deletions', 'Var', (270, 279))	('NOTCH1', 'Gene', (162, 168))	('FAT1', 'Gene', '2195', (170, 174))	('MDM2', 'Gene', (253, 257))	('FGFR1', 'Gene', '2260', (246, 251))	('SOX2', 'Gene', (234, 238))
665323	32398863	Cluster 1 (100 patients) was dominated by APOBEC-associated signatures (S1 and S2) while cluster 3 (312 patients) was correlated with mismatch repair deficiency (S3) and spontaneous deamination of 5-methylcytosine (S4), and cluster 2 (96 patients) shared features with deficient homologous recombination repair signatures (S11 and S6).	('APOBEC', 'Gene', '80287', (42, 48))	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (238, 246))	('S11', 'Gene', '6267', (323, 326))	('mismatch', 'Var', (134, 142))	('spontaneous deamination', 'MPA', (170, 193))	('S11', 'Gene', (323, 326))	('APOBEC', 'Gene', (42, 48))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (197, 213))	('deficiency', 'Disease', (150, 160))	('patients', 'Species', '9606', (104, 112))	('deficiency', 'Disease', 'MESH:D007153', (150, 160))
665327	32398863	In addition, we found that ZNF750 mutations were highly enriched in cluster 1 (Fisher Exact Test, P = 2.42e-09, FDR = 4.35e-08) whereas mutations of FAT2 (Fisher Exact Test, P = 0.0117, FDR = 0.21) and CASP8 (Fisher Exact Test, P = 0.041, FDR = 0.39) showed a weak depletion in cluster 2 (Fig.	('ZNF750', 'Gene', (27, 33))	('CASP8', 'Gene', (202, 207))	('CASP8', 'Gene', '841', (202, 207))	('mutations', 'Var', (136, 145))	('FAT2', 'Gene', '2196', (149, 153))	('FAT2', 'Gene', (149, 153))	('ZNF750', 'Gene', '79755', (27, 33))	('mutations', 'Var', (34, 43))
665331	32398863	Patients with high TMB (TMB-H) generally had a better response to immunotherapy than those with low TMB.	('better', 'PosReg', (47, 53))	('TMB', 'Chemical', '-', (100, 103))	('high TMB', 'Var', (14, 22))	('response', 'CPA', (54, 62))	('TMB', 'Chemical', '-', (24, 27))	('Patients', 'Species', '9606', (0, 8))	('TMB', 'Chemical', '-', (19, 22))	('TMB-H', 'Chemical', '-', (24, 29))
665333	32398863	As expected, TMB-H tended to occur in patients with nonsynonymous mutations in DNA mismatch repair (MMR) genes (Fisher Exact Test, P = 3.72e-5) or patients with high microsatellite instability (MSI-H) (Fisher Exact Test, P = 0.00102) (Fig.	('nonsynonymous mutations', 'Var', (52, 75))	('DNA', 'Gene', (79, 82))	('patients', 'Species', '9606', (147, 155))	('TMB-H', 'Chemical', '-', (13, 18))	('patients', 'Species', '9606', (38, 46))	('occur', 'Reg', (29, 34))	('TMB-H', 'Disease', (13, 18))	('MMR) genes', 'Gene', (100, 110))
665334	32398863	In addition, TMB-H patients also exhibited a significantly higher proportion of the APOBEC-associated S2 mutations (Wilcoxon Test, P = 3.999e-05, Fig.	('patients', 'Species', '9606', (19, 27))	('higher', 'PosReg', (59, 65))	('APOBEC', 'Gene', '80287', (84, 90))	('mutations', 'Var', (105, 114))	('TMB-H', 'Chemical', '-', (13, 18))	('APOBEC', 'Gene', (84, 90))
665335	32398863	Furthermore, the TMB was significantly larger in patients enriched with APOBEC-associated mutations within the TpCpW motif (Wilcoxon Test, P = 2.2e-16, Supplementary information, Fig.	('TMB', 'Chemical', '-', (17, 20))	('mutations', 'Var', (90, 99))	('APOBEC', 'Gene', '80287', (72, 78))	('larger', 'PosReg', (39, 45))	('APOBEC', 'Gene', (72, 78))	('patients', 'Species', '9606', (49, 57))	('TMB', 'MPA', (17, 20))
665339	32398863	Importantly, the TMB-H patients had significantly worse OS than other patients (Kaplan-Meier analysis, log rank P = 0.011, HR = 1.87, 95% CI, 1.141-3.078, Fig.	('patients', 'Species', '9606', (70, 78))	('TMB-H', 'Var', (17, 22))	('patients', 'Species', '9606', (23, 31))	('TMB-H', 'Chemical', '-', (17, 22))	('worse', 'NegReg', (50, 55))
665341	32398863	NFE2L2 (also known as NRF2) was predicted to have a total of 31 missense mutations, with the most frequent hotspot at p.R34P and R34Q, followed by p.E79K and E79Q within the DLG and ETGE protein domains, respectively, that bind to KEAP1 (Fig.	('E79Q', 'Var', (158, 162))	('p.E79K', 'Mutation', 'rs1057519922', (147, 153))	('R34Q', 'SUBSTITUTION', 'None', (129, 133))	('bind', 'Interaction', (223, 227))	('KEAP1', 'Gene', '9817', (231, 236))	('E79Q', 'Mutation', 'rs1057519922', (158, 162))	('p.R34P', 'Var', (118, 124))	('NRF2', 'Gene', '4780', (22, 26))	('NFE2L2', 'Gene', (0, 6))	('p.R34P', 'Mutation', 'p.R34P', (118, 124))	('R34Q', 'Var', (129, 133))	('KEAP1', 'Gene', (231, 236))	('NRF2', 'Gene', (22, 26))	('p.E79K', 'Var', (147, 153))
665342	32398863	Although the oncogenic role of NFE2L2 mutations that inactivate KEAP1-binding site was well established in several squamous cell carcinomas, the biological function of NFE2L2 and its mutations in ESCC have not been systematically determined.	('inactivate', 'NegReg', (53, 63))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (115, 139))	('KEAP1', 'Gene', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('ESCC', 'Gene', (196, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('NFE2L2', 'Gene', (168, 174))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (115, 139))	('squamous cell carcinomas', 'Disease', (115, 139))	('NFE2L2', 'Gene', (31, 37))	('mutations', 'Var', (38, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('KEAP1', 'Gene', '9817', (64, 69))
665343	32398863	Among the 22 SMGs, we found that patients with NFE2L2 mutations had a much worse prognosis (Kaplan-Meier analysis, log rank P = 0.00035, FDR = 0.0081; Cox regression, P = 0.001, HR = 2.21, 95% CI, 1.349-3.325, Fig.	('NFE2L2', 'Gene', (47, 53))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (33, 41))
665346	32398863	Cell proliferation assay showed that a reduction of endogenous wild-type NFE2L2 (NFE2L2-wt) level in KYSE410 and KYSE450 cells led to increased cell proliferation whereas ablation of mutant NFE2L2 (NFE2L2-mut) in KYSE70 and KYSE180 cells caused decreased cell proliferation (Supplementary information, Fig.	('cell proliferation', 'CPA', (144, 162))	('endogenous', 'MPA', (52, 62))	('cell proliferation', 'CPA', (255, 273))	('KYSE450', 'CellLine', 'CVCL:1353', (113, 120))	('mutant', 'Var', (183, 189))	('reduction', 'NegReg', (39, 48))	('KYSE180', 'CellLine', 'CVCL:1349', (224, 231))	('decreased', 'NegReg', (245, 254))	('ablation', 'Var', (171, 179))	('increased', 'PosReg', (134, 143))	('NFE2L2', 'Gene', (190, 196))
665347	32398863	Further studies verified the promotion of cell proliferation by stable NFE2L2 knockdown in KYSE450 cells (Supplementary information, Fig.	('KYSE450', 'CellLine', 'CVCL:1353', (91, 98))	('NFE2L2', 'Gene', (71, 77))	('knockdown', 'Var', (78, 87))	('promotion', 'PosReg', (29, 38))	('cell proliferation', 'CPA', (42, 60))
665349	32398863	Notably, NFE2L2 mutants (p.R34Q, p.E79K, p.K438E, p.R569H) completely interfered with the suppressive activity of NFE2L2, and some NFE2L2 mutants (p.R34Q, p.E79K) even exerted an oncogenic role (Supplementary information, Fig.	('p.E79K', 'Var', (155, 161))	('interfered', 'NegReg', (70, 80))	('p.R569H', 'Mutation', 'rs765321668', (50, 57))	('p.R34Q', 'Var', (147, 153))	('p.K438E', 'Var', (41, 48))	('p.R34Q', 'Var', (25, 31))	('p.E79K', 'Var', (33, 39))	('oncogenic', 'MPA', (179, 188))	('p.E79K', 'Mutation', 'rs1057519922', (155, 161))	('p.K438E', 'Mutation', 'p.K438E', (41, 48))	('exerted', 'Reg', (168, 175))	('p.E79K', 'Mutation', 'rs1057519922', (33, 39))	('p.R569H', 'Var', (50, 57))	('suppressive activity', 'MPA', (90, 110))	('p.R34Q', 'Mutation', 'p.R34Q', (147, 153))	('p.R34Q', 'Mutation', 'p.R34Q', (25, 31))	('NFE2L2', 'Gene', (131, 137))	('NFE2L2', 'Gene', (9, 15))
665350	32398863	Consistently, xenograft mouse model showed that NFE2L2-wt ablation promoted tumor growth whereas NFE2L2-wt overexpression suppressed tumor growth.	('mouse', 'Species', '10090', (24, 29))	('promoted', 'PosReg', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('ablation', 'Var', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
665351	32398863	Some NFE2L2 mutants (p.R34Q, p.E79K) significantly promoted tumor growth, while other NFE2L2 mutants (p.K438E, p.R569H) had no significant effect on tumor growth compared with the vector control (Fig.	('p.R569H', 'Mutation', 'rs765321668', (111, 118))	('p.K438E', 'Var', (102, 109))	('p.R34Q', 'Var', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('p.E79K', 'Var', (29, 35))	('NFE2L2', 'Gene', (5, 11))	('p.R569H', 'Var', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('p.E79K', 'Mutation', 'rs1057519922', (29, 35))	('p.K438E', 'Mutation', 'p.K438E', (102, 109))	('mutants', 'Var', (12, 19))	('promoted', 'PosReg', (51, 59))	('tumor', 'Disease', (149, 154))	('p.R34Q', 'Mutation', 'p.R34Q', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
665352	32398863	Taken with our genetic observations, these functional data indicate that NFE2L2 may act as a tumor suppressor in ESCC; mutations in NFE2L2, which serve as a poor prognosis biomarker, probably impaired its tumor-suppressive function, or even conferred oncogenic activities.	('conferred', 'Reg', (241, 250))	('ESCC', 'Disease', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', (93, 98))	('oncogenic activities', 'CPA', (251, 271))	('impaired', 'NegReg', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('mutations', 'Var', (119, 128))	('NFE2L2', 'Gene', (132, 138))
665358	32398863	Amplification of 11q13.3 was significantly associated with patients' poor outcomes (Kaplan-Meier analysis, log rank P = 0.016, HR = 1.38, 95% CI, 1.058-1.805, Fig.	('11q13.3', 'Gene', (17, 24))	('Amplification', 'Var', (0, 13))	('patients', 'Species', '9606', (59, 67))	('associated', 'Reg', (43, 53))
665359	32398863	Intriguingly, we identified, for the first time, that losses of 13q12.11, 13q14.2, 17q25.3 and 22q13.33 were significantly associated with patients' poor outcomes (log rank P in Supplementary information, Table S13).	('patients', 'Species', '9606', (139, 147))	('22q13.33', 'Gene', (95, 103))	('13q12.11', 'Var', (64, 72))	('17q25.3', 'Gene', (83, 90))	('losses', 'Var', (54, 60))
665362	32398863	Recurrent noncoding hotspot mutation analysis identified 13 hotspots including hotspots in the promoter of WDR74 that were previously reported in multiple human cancer types (Fig.	('WDR74', 'Gene', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('WDR74', 'Gene', '54663', (107, 112))	('human', 'Species', '9606', (155, 160))	('mutation', 'Var', (28, 36))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('hotspots', 'MPA', (79, 87))	('cancer', 'Disease', (161, 167))
665364	32398863	Survival analysis revealed that the hotspot mutation at the promoter of SLC35E2 was correlated with a worse prognosis (Kaplan-Meier analysis, log rank P = 0.0025, FDR = 0.0058, HR = 3.24, 95% CI, 0.984-3.507, Fig.	('SLC35E2', 'Gene', '9906', (72, 79))	('SLC35E2', 'Gene', (72, 79))	('mutation', 'Var', (44, 52))
665365	32398863	Meanwhile, 3.9% (20 of 508) ESCC samples had the A30G hotspot mutation at the transcript lncRNA RP11-69I8.2-003 that has not been previously linked to cancer (Supplementary information, Fig.	('RP11', 'Gene', '26121', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('A30G', 'Mutation', 'c.30A>G', (49, 53))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('ESCC', 'Disease', (28, 32))	('A30G', 'Var', (49, 53))	('RP11', 'Gene', (96, 100))
665371	32398863	We identified 107 NEAT1 mutations in 94 patients (FDR = 7.38e-16) and 67 MALAT1 mutations in 54 patients (FDR = 7.38e-16).	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (40, 48))	('NEAT1', 'Gene', '283131', (18, 23))	('MALAT1', 'Gene', '378938', (73, 79))	('NEAT1', 'Gene', (18, 23))	('MALAT1', 'Gene', (73, 79))	('patients', 'Species', '9606', (96, 104))	('mutations', 'Var', (24, 33))
665379	32398863	EGFR amplification was the most prevalent actionable alteration (31 cases, 6.1%), followed by FGFR1 amplification (26 cases, 5.12%).	('FGFR1', 'Gene', '2260', (94, 99))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('FGFR1', 'Gene', (94, 99))	('EGFR', 'Gene', '1956', (0, 4))
665381	32398863	Although not significant, patients harboring either EGFR or FGFR1 amplification (57 patients) showed poorer prognosis (Supplementary information, Fig.	('amplification', 'Var', (66, 79))	('patients', 'Species', '9606', (84, 92))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('FGFR1', 'Gene', (60, 65))	('FGFR1', 'Gene', '2260', (60, 65))	('patients', 'Species', '9606', (26, 34))	('poorer', 'NegReg', (101, 107))
665383	32398863	Importantly, amplifications in the RTK-RAS pathway, a pathway containing many actionable alterations including EGFR and FGFR1, were significantly correlated with the patients' worse survival (Kaplan-Meier analysis, log rank P = 0.0032, HR = 1.54, 95% CI, 1.178-2.009, Fig.	('RTK-RAS pathway', 'Pathway', (35, 50))	('FGFR1', 'Gene', (120, 125))	('EGFR', 'Gene', '1956', (111, 115))	('amplifications', 'Var', (13, 27))	('FGFR1', 'Gene', '2260', (120, 125))	('EGFR', 'Gene', (111, 115))	('patients', 'Species', '9606', (166, 174))
665384	32398863	Correlation of the RTK-RAS signaling-related amplifications with worse survival was also observed in gastric cancer.	('gastric cancer', 'Disease', (101, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('amplifications', 'Var', (45, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('RTK-RAS', 'MPA', (19, 26))
665386	32398863	The RTK-RAS pathway-related amplifications showed significant co-occurrence with amplifications of the MYC pathway and cell cycle pathway; meanwhile, amplifications of the RTK-RAS pathway tended to co-occur with deletion of cell cycle pathway (Fisher Exact Test, all P < 1e-7).	('deletion', 'Var', (212, 220))	('MYC', 'Gene', (103, 106))	('cell cycle pathway', 'Pathway', (224, 242))	('RTK-RAS pathway', 'Pathway', (172, 187))	('MYC', 'Gene', '4609', (103, 106))
665387	32398863	Amplification of the MYC pathway was also significantly correlated with patient's survival (Kaplan-Meier analysis, log rank P = 0.017, HR = 1.40, 95% CI, 1.058-1.847, Fig.	('MYC', 'Gene', (21, 24))	('Amplification', 'Var', (0, 13))	('patient', 'Species', '9606', (72, 79))	('MYC', 'Gene', '4609', (21, 24))	('correlated', 'Reg', (56, 66))
665388	32398863	For cell cycle pathway, CDKN2A/B were mostly altered by deletions whereas CCND1, located in 11q13.3, was frequently amplified.	('altered', 'Reg', (45, 52))	('CDKN2A/B', 'Gene', (24, 32))	('cell cycle pathway', 'Pathway', (4, 22))	('CCND1', 'Gene', (74, 79))	('deletions', 'Var', (56, 65))	('CCND1', 'Gene', '595', (74, 79))	('CDKN2A/B', 'Gene', '1029;1030', (24, 32))
665389	32398863	Interestingly, CCND1 also harbored promoter mutations in 17 samples and patients with promoter mutations showed much worse prognosis than those with amplifications (Supplementary information, Fig.	('CCND1', 'Gene', (15, 20))	('CCND1', 'Gene', '595', (15, 20))	('mutations', 'Var', (95, 104))	('patients', 'Species', '9606', (72, 80))
665390	32398863	Additionally, within the NRF2 pathway, NFE2L2 was mutated in an exclusive manner with CUL3 and KEAP1 as previously reported.	('NFE2L2', 'Gene', (39, 45))	('NRF2', 'Gene', (25, 29))	('KEAP1', 'Gene', (95, 100))	('mutated', 'Var', (50, 57))	('CUL3', 'Gene', '8452', (86, 90))	('NRF2', 'Gene', '4780', (25, 29))	('CUL3', 'Gene', (86, 90))	('KEAP1', 'Gene', '9817', (95, 100))
665393	32398863	Although the MYC pathway-related amplification was significantly correlated with survival, the selection probability of MYC pathway was only 0.53, partly due to its high co-occurrence with RTK-RAS amplification (Fisher Exact Test, P = 2e-9).	('MYC', 'Gene', (120, 123))	('amplification', 'Var', (33, 46))	('MYC', 'Gene', '4609', (13, 16))	('MYC', 'Gene', '4609', (120, 123))	('correlated', 'Reg', (65, 75))	('MYC', 'Gene', (13, 16))
665396	32398863	Replacing the RTK-RAS amplification with the RTK-RAS-MYC amplification in the Cox regression model controlling clinical features led to an increase of the R-square from 0.165 to 0.173, and both NFE2L2 mutation and RTK-RAS-MYC amplification were highly significant (P = 1.25e-05 and 5.11e-4, respectively, Supplementary information, Table S16b).	('NFE2L2', 'Gene', (194, 200))	('R-square', 'MPA', (155, 163))	('MYC', 'Gene', '4609', (53, 56))	('MYC', 'Gene', '4609', (222, 225))	('increase', 'PosReg', (139, 147))	('mutation', 'Var', (201, 209))	('MYC', 'Gene', (222, 225))	('MYC', 'Gene', (53, 56))
665397	32398863	We classified the tumors into three distinct subtypes, NFE2L2-mutated, RTK-RAS-MYC-amplified, and double-negative subtypes (Fig.	('MYC', 'Gene', (79, 82))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('MYC', 'Gene', '4609', (79, 82))	('NFE2L2-mutated', 'Var', (55, 69))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
665398	32398863	The NFE2L2-mutated subtype consisted of tumors with NFE2L2 mutations, the RTK-RAS-MYC-amplified subtype included tumors with the RTK-RAS-MYC amplifications but without NFE2L2 mutations, and the double-negative subtype was all other tumors.	('tumors', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('MYC', 'Gene', (137, 140))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('tumors', 'Disease', (40, 46))	('MYC', 'Gene', (82, 85))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('NFE2L2', 'Gene', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('MYC', 'Gene', '4609', (82, 85))	('MYC', 'Gene', '4609', (137, 140))	('mutations', 'Var', (59, 68))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', (232, 238))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('NFE2L2-mutated', 'Disease', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
665399	32398863	The NFE2L2-mutated subtype had the worst survival, followed by the RTK-RAS-MYC-amplified subtype (Kaplan-Meier analysis, log rank P = 9.1e-07, Fig.	('MYC', 'Gene', '4609', (75, 78))	('worst', 'NegReg', (35, 40))	('survival', 'CPA', (41, 49))	('NFE2L2-mutated', 'Var', (4, 18))	('MYC', 'Gene', (75, 78))
665402	32398863	A set of functional assays confirmed NFE2L2 and RP11-69I8.2-003 mutations as oncogenic drivers for ESCC progression.	('RP11', 'Gene', (48, 52))	('NFE2L2', 'Gene', (37, 43))	('RP11', 'Gene', '26121', (48, 52))	('ESCC', 'Disease', (99, 103))	('mutations', 'Var', (64, 73))
665404	32398863	We found that a significant portion of ESCC patients had actionable mutations and may potentially benefit from targeted therapies.	('mutations', 'Var', (68, 77))	('patients', 'Species', '9606', (44, 52))	('ESCC', 'Disease', (39, 43))
665405	32398863	Most importantly, available clinical data allowed us to identify potential prognostic biomarkers such as NFE2L2 mutations, SLC35E2 promoter mutations, clusters of mutation signatures, TMB-H, and RTK-RAS-MYC amplification.	('TMB-H', 'Chemical', '-', (184, 189))	('NFE2L2', 'Gene', (105, 111))	('MYC', 'Gene', (203, 206))	('mutations', 'Var', (112, 121))	('MYC', 'Gene', '4609', (203, 206))	('mutations', 'Var', (140, 149))	('SLC35E2', 'Gene', (123, 130))	('SLC35E2', 'Gene', '9906', (123, 130))
665410	32398863	These noncoding mutations and rare driver-coding mutations may improve the understanding of ESCC tumorigenesis and can be used for genetic counseling, to predict patients' outcome and to determine the most optimal treatment for ESCC patients.	('patients', 'Species', '9606', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('ESCC', 'Disease', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('improve', 'PosReg', (63, 70))	('patients', 'Species', '9606', (233, 241))	('noncoding mutations', 'Var', (6, 25))
665411	32398863	APOBEC cytidine deaminase activity is an endogenous mutagen and APOBEC signature mutations can accumulate by the ongoing APOBEC activity, consistent with our observation that late-stage tumor tended to have more APOBEC signature mutations.	('APOBEC', 'Gene', '80287', (0, 6))	('APOBEC', 'Gene', '80287', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('APOBEC', 'Gene', '80287', (121, 127))	('APOBEC', 'Gene', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('mutations', 'Var', (229, 238))	('APOBEC', 'Gene', (212, 218))	('APOBEC', 'Gene', (121, 127))	('tumor', 'Disease', (186, 191))	('APOBEC', 'Gene', (0, 6))	('APOBEC', 'Gene', '80287', (64, 70))
665416	32398863	Hence, immunotherapy may be a better therapeutic option for patients enriched with APOBEC signature mutations.	('mutations', 'Var', (100, 109))	('patients', 'Species', '9606', (60, 68))	('APOBEC', 'Gene', '80287', (83, 89))	('APOBEC', 'Gene', (83, 89))
665418	32398863	Forced expression of mutant EGFR and KRAS can be synthetic lethal, implying that the second explanation may be more likely for the mutual exclusivity of RTK-RAS-related alterations.	('EGFR', 'Gene', '1956', (28, 32))	('mutant', 'Var', (21, 27))	('EGFR', 'Gene', (28, 32))	('KRAS', 'Gene', (37, 41))	('KRAS', 'Gene', '3845', (37, 41))
665423	32398863	In this study, we uncover NFE2L2 mutation and the RTK-RAS-MYC pathway amplification as better molecular features in predicting ESCC patients' poor survival.	('MYC', 'Gene', (58, 61))	('mutation', 'Var', (33, 41))	('NFE2L2', 'Gene', (26, 32))	('ESCC', 'Disease', (127, 131))	('MYC', 'Gene', '4609', (58, 61))	('patients', 'Species', '9606', (132, 140))
665426	32398863	Although EAC and ESCC share a number of recurrent driver alterations, such as frequent TP53 mutation and CDKN2A deletion, their genomic landscapes are substantially different.	('TP53', 'Gene', '7157', (87, 91))	('mutation', 'Var', (92, 100))	('CDKN2A', 'Gene', (105, 111))	('TP53', 'Gene', (87, 91))	('deletion', 'Var', (112, 120))	('CDKN2A', 'Gene', '1029', (105, 111))
665427	32398863	GATA4/6 and SMAD4 alterations were much more frequent in EAC.	('alterations', 'Var', (18, 29))	('GATA4/6', 'Gene', '2626;2627', (0, 7))	('SMAD4', 'Gene', (12, 17))	('GATA4/6', 'Gene', (0, 7))	('EAC', 'Disease', (57, 60))	('frequent', 'Reg', (45, 53))	('SMAD4', 'Gene', '4089', (12, 17))
665429	32398863	Interestingly, clinical biomarkers were also different, such as NFE2L2 mutation and RTK-RAS-MYC amplification in ESCC, and GATA4 amplification and SMAD4 alteration in EAC.	('alteration', 'Var', (153, 163))	('ESCC', 'Disease', (113, 117))	('mutation', 'Var', (71, 79))	('NFE2L2', 'Gene', (64, 70))	('SMAD4', 'Gene', '4089', (147, 152))	('MYC', 'Gene', '4609', (92, 95))	('EAC', 'Disease', (167, 170))	('GATA4', 'Gene', '2626', (123, 128))	('SMAD4', 'Gene', (147, 152))	('MYC', 'Gene', (92, 95))	('GATA4', 'Gene', (123, 128))
665447	32398863	The molecular features included the 22 SMGs, the 5 prognosis-related focal deletions/amplifications, TMB-H status, MSI-H status, somatic mutations at dMMR-related genes, APOBEC enrichment status, the NMF cluster, the CNV cluster and mutation status, amplification status and deletion status of the seven key cancer pathways (Nrf2, RTK-RAS, Myc, Cell cycle, Notch, Wnt, Chromatin remodeling).	('Notch', 'Pathway', (357, 362))	('Nrf2', 'Gene', (325, 329))	('Wnt', 'Pathway', (364, 367))	('Myc', 'Gene', (340, 343))	('Myc', 'Gene', '4609', (340, 343))	('deletions/amplifications', 'Var', (75, 99))	('Chromatin', 'Disease', (369, 378))	('TMB-H', 'Chemical', '-', (101, 106))	('APOBEC', 'Gene', '80287', (170, 176))	('RTK-RAS', 'Disease', (331, 338))	('cancer', 'Disease', (308, 314))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('deletion', 'Var', (275, 283))	('Nrf2', 'Gene', '4780', (325, 329))	('Cell cycle', 'CPA', (345, 355))	('APOBEC', 'Gene', (170, 176))
665568	32903788	Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents.	('BRCA2', 'Gene', (33, 38))	('loss of function', 'NegReg', (171, 187))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('BRCA1', 'Gene', '672', (156, 161))	('BRCA1', 'Gene', (156, 161))	('Alterations', 'Var', (47, 58))	('HRD', 'Disease', (236, 239))	('deficiency', 'Disease', 'MESH:D007153', (224, 234))	('BRCA2', 'Gene', '675', (33, 38))	('Cancer', 'Disease', (4, 10))	('poly (ADP-ribose) polymerase', 'Gene', '142', (265, 293))	('BRCA2', 'Gene', (165, 170))	('HRD', 'Disease', 'None', (236, 239))	('poly (ADP-ribose) polymerase', 'Gene', (265, 293))	('homologous', 'MPA', (199, 209))	('Loss', 'NegReg', (133, 137))	('deficiency', 'Disease', (224, 234))	('Genomic', 'MPA', (86, 93))	('PARP', 'Gene', '142', (295, 299))	('BRCA1', 'Gene', '672', (23, 28))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('BRCA1', 'Gene', (23, 28))	('BRCA2', 'Gene', '675', (165, 170))	('PARP', 'Gene', (295, 299))
665569	32903788	In cancers associated with germline BRCA1/2 alterations (BRCA1/2-associated cancers: breast, ovarian, pancreatic, prostate), BRCA1/2 alterations result in HRD and are biomarkers for PARP inhibitor use.	('result in', 'Reg', (145, 154))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('BRCA1/2', 'Gene', (125, 132))	('cancers', 'Disease', (76, 83))	('HRD', 'Disease', 'None', (155, 158))	('BRCA1/2', 'Gene', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PARP', 'Gene', (182, 186))	('alterations', 'Var', (44, 55))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('PARP', 'Gene', '142', (182, 186))	('alterations', 'Var', (133, 144))	('breast, ovarian, pancreatic', 'Disease', 'MESH:D010195', (85, 112))	('HRD', 'Disease', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
665570	32903788	In other (non-BRCA1/2-associated) cancer types, the association between BRCA1/2 alteration and HRD is less clear.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('BRCA1/2', 'Gene', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('HRD', 'Disease', (95, 98))	('cancer', 'Disease', (34, 40))	('alteration', 'Var', (80, 90))	('HRD', 'Disease', 'None', (95, 98))
665573	32903788	BRCA1/2 mutations were predicted germline in 57.4% of BRCA1/2-associated and 37.2% of non-BRCA1/2-associated cancers.	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('BRCA1/2', 'Gene', (0, 7))	('BRCA1/2-associated', 'Gene', (54, 72))
665575	32903788	Differences in tissue distribution of biallelic BRCA1 versus BRCA2 alterations were noted, including a higher rate of biallelic BRCA2 alteration in prostate cancer.	('BRCA1', 'Gene', '672', (48, 53))	('biallelic', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('BRCA2', 'Gene', (128, 133))	('alteration', 'Var', (134, 144))	('BRCA1', 'Gene', (48, 53))	('alterations', 'Var', (67, 78))	('BRCA2', 'Gene', (61, 66))	('prostate cancer', 'Disease', 'MESH:D011471', (148, 163))	('BRCA2', 'Gene', '675', (128, 133))	('prostate cancer', 'Phenotype', 'HP:0012125', (148, 163))	('BRCA2', 'Gene', '675', (61, 66))	('prostate cancer', 'Disease', (148, 163))
665576	32903788	Biallelic BRCA1/2 alteration was observed at a 3.2% frequency (BRCA1/2-associated cancers, 8.9%; non-BRCA1/2-associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancers', 'Disease', (82, 89))	('cancer', 'Disease', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancers', 'Disease', (120, 127))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('alteration', 'Var', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
665577	32903788	Across cancer types, biallelic BRCA1/2 alteration was associated with increased gLOH versus monoallelic or wild-type BRCA1/2; predicted germline or somatic mutations were both associated with elevated gLOH.	('alteration', 'Var', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('gLOH', 'MPA', (80, 84))	('increased', 'PosReg', (70, 79))	('cancer', 'Disease', (7, 13))	('biallelic', 'Var', (21, 30))	('BRCA1/2', 'Gene', (31, 38))
665578	32903788	Biallelic BRCA1/2 alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with BRCA1/2 cancer syndromes.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('alterations', 'Var', (18, 29))	('BRCA1/2 cancer', 'Disease', 'OMIM:612555', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gLOH', 'MPA', (60, 64))	('BRCA1/2 cancer', 'Disease', (140, 154))	('elevated', 'PosReg', (51, 59))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('BRCA1/2', 'Gene', (10, 17))
665579	32903788	Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('PARP', 'Gene', (26, 30))	('HRD', 'Disease', (236, 239))	('biallelic', 'Var', (129, 138))	('cancer', 'Disease', (193, 199))	('PARP', 'Gene', (244, 248))	('BRCA1/2', 'Gene', (139, 146))	('PARP', 'Gene', '142', (26, 30))	('alteration', 'Var', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('HRD', 'Disease', 'None', (236, 239))	('PARP', 'Gene', '142', (244, 248))
665581	32903788	Germline BRCA1/2 (gBRCA1/2) alterations are associated with elevated risk for breast, ovarian, pancreatic, and prostate cancer (BRCA1/2-associated cancers), and tumors that arise in BRCA1/2 mutation carriers have often lost the wild-type allele.	('mutation', 'Var', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', (161, 167))	('alterations', 'Var', (28, 39))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('gBRCA1/2', 'Gene', (18, 26))	('BRCA1/2 (gBRCA1/2', 'Gene', (9, 26))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('BRCA1/2', 'Gene', (182, 189))	('cancers', 'Disease', (147, 154))	('breast, ovarian, pancreatic', 'Disease', 'MESH:D010195', (78, 105))
665583	32903788	Companion diagnostic testing for gBRCA1/2 and somatic BRCA1/2 (sBRCA1/2) alteration can guide PARPi therapy selection.	('guide', 'Reg', (88, 93))	('PARP', 'Gene', '142', (94, 98))	('sBRCA1/2', 'Gene', (63, 71))	('PARP', 'Gene', (94, 98))	('alteration', 'Var', (73, 83))
665584	32903788	Key Objective BRCA1/2 loss-of-function alterations result in homologous recombination deficiency (HRD) and are biomarkers for poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity in breast, ovarian, prostate, and pancreatic cancer.	('homologous', 'MPA', (61, 71))	('HRD', 'Disease', 'None', (98, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (218, 235))	('PARP', 'Gene', '142', (156, 160))	('poly (ADP-ribose) polymerase', 'Gene', '142', (126, 154))	('poly (ADP-ribose) polymerase', 'Gene', (126, 154))	('PARP', 'Gene', (156, 160))	('ovarian', 'Disease', (195, 202))	('breast', 'Disease', (187, 193))	('pancreatic cancer', 'Disease', 'MESH:D010190', (218, 235))	('prostate', 'Disease', (204, 212))	('deficiency', 'Disease', 'MESH:D007153', (86, 96))	('loss-of-function', 'NegReg', (22, 38))	('pancreatic cancer', 'Disease', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('BRCA1/2', 'Gene', (14, 21))	('deficiency', 'Disease', (86, 96))	('HRD', 'Disease', (98, 101))	('alterations', 'Var', (39, 50))
665585	32903788	To determine the relevance of BRCA1/2 alterations across cancer types, we evaluated the pan-cancer landscape of BRCA1/2 alterations and their association with the genome-wide loss-of-heterozygosity (gLOH) marker of HRD.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('HRD', 'Disease', 'None', (215, 218))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('HRD', 'Disease', (215, 218))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BRCA1/2', 'Gene', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('alterations', 'Var', (120, 131))	('loss-of-heterozygosity', 'NegReg', (175, 197))
665586	32903788	Knowledge Generated The fraction of BRCA1/2 alterations that were biallelic differed by cancer type and predicted germline/somatic status.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('predicted', 'Reg', (104, 113))	('BRCA1/2', 'Gene', (36, 43))	('alterations', 'Var', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
665587	32903788	BRCA1/2 alterations were most frequently biallelic in breast, ovarian, prostate, and pancreatic cancer; in other cancer types, 44% of BRCA1/2 alterations were biallelic.	('pancreatic cancer', 'Disease', (85, 102))	('ovarian', 'Disease', (62, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('alterations', 'Var', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('alterations', 'Var', (8, 19))	('prostate', 'Disease', (71, 79))	('BRCA1/2', 'Gene', (134, 141))	('cancer', 'Disease', (113, 119))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('breast', 'Disease', (54, 60))	('BRCA1/2', 'Gene', (0, 7))	('cancer', 'Disease', (96, 102))
665588	32903788	Across cancer types, biallelic BRCA1/2 alteration was associated with elevated gLOH compared with monoallelic or wild-type BRCA1/2; this association with HRD was observed irrespective of predicted germline or somatic status.	('alteration', 'Var', (39, 49))	('elevated', 'PosReg', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('HRD', 'Disease', (154, 157))	('biallelic', 'Var', (21, 30))	('cancer', 'Disease', (7, 13))	('HRD', 'Disease', 'None', (154, 157))	('BRCA1/2', 'Gene', (31, 38))	('gLOH', 'MPA', (79, 83))
665589	32903788	Relevance BRCA1/2 biallelic alteration is associated with HRD across tumor types and should be broadly evaluated as a biomarker in trials of PARP inhibitors and other agents that target HRD.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('HRD', 'Disease', 'None', (58, 61))	('PARP', 'Gene', '142', (141, 145))	('associated with', 'Reg', (42, 57))	('HRD across tumor', 'Disease', 'MESH:D009369', (58, 74))	('HRD', 'Disease', (186, 189))	('PARP', 'Gene', (141, 145))	('HRD', 'Disease', (58, 61))	('HRD across tumor', 'Disease', (58, 74))	('HRD', 'Disease', 'None', (186, 189))	('biallelic alteration', 'Var', (18, 38))	('BRCA1/2', 'Gene', (10, 17))
665591	32903788	BRCA1 and BRCA2 have distinct functions in the homology-mediated repair process, and their inactivation leads to different patterns of rearrangements, with BRCA1 loss of function associated with tandem duplications and BRCA2 loss of function associated with deletions.	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', '675', (219, 224))	('BRCA2', 'Gene', '675', (10, 15))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA2', 'Gene', (219, 224))	('tandem duplications', 'Var', (195, 214))	('deletions', 'Var', (258, 267))	('loss of function', 'NegReg', (162, 178))	('BRCA1', 'Gene', '672', (156, 161))	('BRCA2', 'Gene', (10, 15))	('BRCA1', 'Gene', (156, 161))	('loss of function', 'NegReg', (225, 241))
665593	32903788	In clinical trials of ovarian cancer, high gLOH (gLOH-high) was associated with improved benefit from the PARPi rucaparib; therefore, gLOH measurement may guide therapeutic decision making.	('ovarian cancer', 'Disease', 'MESH:D010051', (22, 36))	('PARP', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('rucaparib', 'Chemical', 'MESH:C531549', (112, 121))	('ovarian cancer', 'Disease', (22, 36))	('improved', 'PosReg', (80, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('PARP', 'Gene', '142', (106, 110))	('high gLOH', 'Var', (38, 47))	('benefit', 'MPA', (89, 96))
665594	32903788	Emerging data from clinical trials suggest that BRCA1/2 genomic alteration status may also be a predictive biomarker for PARPi in prostate cancer.	('BRCA1/2', 'Gene', (48, 55))	('PARP', 'Gene', '142', (121, 125))	('prostate cancer', 'Disease', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('prostate cancer', 'Disease', 'MESH:D011471', (130, 145))	('PARP', 'Gene', (121, 125))	('prostate cancer', 'Phenotype', 'HP:0012125', (130, 145))	('genomic alteration status', 'Var', (56, 81))
665595	32903788	However, PARPi has limited activity in other cancer types with BRCA1/2 alteration.	('PARP', 'Gene', (9, 13))	('alteration', 'Var', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('PARP', 'Gene', '142', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('activity', 'MPA', (27, 35))	('BRCA1/2', 'Gene', (63, 70))
665596	32903788	Here, we assessed a genomic data set of 234,154 tumor specimens to determine the landscape of BRCA1/2 biallelic alterations and their association with gLOH to understand the potential clinical relevance of BRCA1/2 alterations across cancer types.	('association', 'Interaction', (134, 145))	('BRCA1/2', 'Gene', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', (48, 53))	('biallelic', 'Var', (102, 111))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
665598	32903788	BRCA1/2 genomic alterations were defined (Appendix) as likely pathogenic alterations or variants of unknown significance (VUSs; not counted as BRCA1/2 alterations).	('alterations', 'Var', (73, 84))	('VUSs', 'Disease', 'None', (122, 126))	('VUSs', 'Disease', (122, 126))	('pathogenic', 'Reg', (62, 72))	('BRCA1/2', 'Gene', (0, 7))
665599	32903788	Zygosity and somatic/germline status for mutations was computationally predicted without matched normal tissue; in validation testing of 480 tumor-only predictions against matched normal specimens, accuracy was 95% for somatic and 99% for germline predictions.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))
665600	32903788	BRCA1/2 alterations were categorized as biallelic (mutations with LOH of the wild-type allele, homozygous deletion, or two or more BRCA1 or BRCA2 alterations in a sample), monoallelic (heterozygous mutations with retained wild-type allele), or unknown (alterations where zygosity status could not be determined).	('BRCA1', 'Gene', (0, 5))	('mutations', 'Var', (51, 60))	('alterations', 'Var', (146, 157))	('BRCA1', 'Gene', '672', (131, 136))	('BRCA2', 'Gene', (140, 145))	('deletion', 'Var', (106, 114))	('BRCA1', 'Gene', (131, 136))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA2', 'Gene', '675', (140, 145))
665603	32903788	Overall, BRCA1/2 alterations were observed in 4.7% of cases (BRCA1, 2.1%; BRCA2, 2.7%; Fig 1A; Appendix Fig A1).	('BRCA1', 'Gene', (61, 66))	('Appendix', 'Disease', (95, 103))	('BRCA2', 'Gene', (74, 79))	('BRCA1', 'Gene', '672', (9, 14))	('BRCA2', 'Gene', '675', (74, 79))	('BRCA1', 'Gene', (9, 14))	('BRCA1', 'Gene', '672', (61, 66))	('alterations', 'Var', (17, 28))
665604	32903788	As expected, BRCA1/2 alterations were most frequently identified in BRCA1/2-associated cancers (BRCA1/2-associated group, 9.9%; ovarian, 15.2%; prostate, 10.7%; breast, 8.8%; pancreatic, 5.2%).	('breast', 'Disease', (161, 167))	('cancers', 'Disease', (87, 94))	('BRCA1/2-associated', 'Gene', (68, 86))	('ovarian', 'Disease', (128, 135))	('pancreatic', 'Disease', 'MESH:D010195', (175, 185))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('identified', 'Reg', (54, 64))	('pancreatic', 'Disease', (175, 185))	('prostate', 'Disease', (144, 152))	('BRCA1/2', 'Gene', (13, 20))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('alterations', 'Var', (21, 32))
665605	32903788	BRCA1 and BRCA2 alterations were most frequent in ovarian (10.5%) and prostate cancer (9.6%), respectively; unlike BRCA2, BRCA1 alterations were infrequent in prostate cancer.	('BRCA2', 'Gene', '675', (115, 120))	('BRCA1', 'Gene', '672', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('BRCA1', 'Gene', (122, 127))	('BRCA2', 'Gene', '675', (10, 15))	('prostate cancer', 'Disease', 'MESH:D011471', (159, 174))	('prostate cancer', 'Phenotype', 'HP:0012125', (159, 174))	('ovarian', 'Disease', (50, 57))	('prostate cancer', 'Disease', (159, 174))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA1', 'Gene', (0, 5))	('prostate cancer', 'Disease', 'MESH:D011471', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('alterations', 'Var', (16, 27))	('prostate cancer', 'Disease', (70, 85))	('frequent', 'Reg', (38, 46))	('BRCA2', 'Gene', (115, 120))	('BRCA2', 'Gene', (10, 15))
665606	32903788	BRCA1/2 homozygous deletions were infrequent except in prostate cancer, where BRCA2 deletions were observed at a 2.6% frequency and accounted for 25% of BRCA1/2-altered cases.	('prostate cancer', 'Disease', 'MESH:D011471', (55, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (55, 70))	('BRCA2', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('BRCA2', 'Gene', '675', (78, 83))	('BRCA1/2', 'Gene', (0, 7))	('prostate cancer', 'Disease', (55, 70))	('deletions', 'Var', (84, 93))
665608	32903788	First, in a subset of 23 tumor samples from Rutgers Cancer Institute of New Jersey that arose in patients with gBRCA1/2 variants identified by genetic testing, computational methods correctly identified 21 (91%) as predicted germline variants.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('variants', 'Var', (120, 128))	('tumor', 'Disease', (25, 30))	('gBRCA1/2', 'Gene', (111, 119))	('Cancer', 'Disease', (52, 58))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('patients', 'Species', '9606', (97, 105))
665610	32903788	Overall, 98.1% of mutations (51 of 52) were observed in cfDNA at allele frequencies consistent with germline/somatic predictions from tumor-only sequencing (Appendix Figs A3A and A3B).	('A3B', 'Gene', '9582', (179, 182))	('observed', 'Reg', (44, 52))	('A3B', 'Gene', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cfDNA', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('mutations', 'Var', (18, 27))
665611	32903788	Overall, 47.8% of BRCA1/2 mutations (BRCA1, 51.6%; BRCA2, 45.3%) were predicted to be germline (Figs 1B and 1C; Appendix Figs A3C-A3E).	('BRCA1', 'Gene', '672', (18, 23))	('BRCA2', 'Gene', (51, 56))	('BRCA1', 'Gene', (18, 23))	('A3C', 'Mutation', 'c.3A>C', (126, 129))	('BRCA2', 'Gene', '675', (51, 56))	('mutations', 'Var', (26, 35))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA1', 'Gene', (37, 42))
665612	32903788	As expected, the majority of mutations were predicted to be germline in BRCA1/2-associated cancers (BRCA1, 58.1%; BRCA2, 56.8%), but predicted sBRCA1/2 mutations comprised an appreciable proportion of BRCA1/2 mutations.	('BRCA1', 'Gene', '672', (100, 105))	('mutations', 'Var', (152, 161))	('BRCA1', 'Gene', '672', (72, 77))	('BRCA2', 'Gene', (114, 119))	('BRCA1', 'Gene', (144, 149))	('cancers', 'Disease', (91, 98))	('mutations', 'Var', (29, 38))	('BRCA1', 'Gene', '672', (144, 149))	('BRCA2', 'Gene', '675', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('BRCA1', 'Gene', (72, 77))	('BRCA1', 'Gene', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('BRCA1', 'Gene', '672', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('BRCA1', 'Gene', (201, 206))
665613	32903788	In prostate cancer, 51.7% of BRCA2 v 34.4% of BRCA1 mutations were predicted to be germline.	('mutations', 'Var', (52, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('BRCA1', 'Gene', '672', (46, 51))	('BRCA2', 'Gene', (29, 34))	('prostate cancer', 'Disease', (3, 18))	('BRCA1', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('BRCA2', 'Gene', '675', (29, 34))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
665614	32903788	In non-BRCA1/2-associated cancer types, BRCA1/2 mutations were less frequently predicted to be germline (37.2%).	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('BRCA1/2', 'Gene', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (48, 57))
665615	32903788	Predicted somatic mutations were frequent in skin squamous cell carcinoma (SCC) and melanoma, which accounted for 90.7% and 75.8% of BRCA1/2 mutations, respectively.	('SCC', 'Gene', '6317', (75, 78))	('skin squamous cell carcinoma', 'Disease', (45, 73))	('mutations', 'Var', (141, 150))	('frequent', 'Reg', (33, 41))	('skin squamous cell carcinoma', 'Phenotype', 'HP:0006739', (45, 73))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('skin squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('BRCA1/2', 'Gene', (133, 140))	('SCC', 'Gene', (75, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
665616	32903788	As expected, predicted sBRCA1/2 mutations in these cancer types were often found in a mutational context of ultraviolet light exposure (skin SCC, 45% [14 of 31]; melanoma, 81% [50 of 62]).	('sBRCA1/2', 'Gene', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('SCC', 'Gene', (141, 144))	('found', 'Reg', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('mutations', 'Var', (32, 41))	('SCC', 'Gene', '6317', (141, 144))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
665622	32903788	Biallelic BRCA1/2 alteration was found in 3.2% of all cases and greatest in BRCA1/2-associated cancers (8.9%).	('found', 'Reg', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('alteration', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRCA1/2', 'Gene', (10, 17))
665624	32903788	For BRCA1/2-associated cancers, both predicted gBRCA1/2 (90.8%) and sBRCA1/2 (81.2%) mutations were frequently biallelic, whereas in non-BRCA1/2-associated cancers, fewer predicted gBRCA1/2 (46.4%) and sBRCA1/2 (25.4%) mutations were biallelic.	('gBRCA1/2', 'Gene', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('BRCA1/2-associated', 'Gene', (4, 22))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('sBRCA1/2', 'Gene', (68, 76))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('biallelic', 'Var', (111, 120))
665626	32903788	In ovarian and breast cancer, the majority of BRCA1 and BRCA2 mutations were biallelic, both for predicted germline and somatic mutations.	('ovarian and breast cancer', 'Disease', 'MESH:D001943', (3, 28))	('BRCA2', 'Gene', '675', (56, 61))	('BRCA1', 'Gene', '672', (46, 51))	('BRCA1', 'Gene', (46, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('BRCA2', 'Gene', (56, 61))	('mutations', 'Var', (62, 71))
665627	32903788	In prostate cancer, the majority of BRCA2 (gBRCA2, 87.6%; sBRCA2, 75.0%) mutations were biallelic, but BRCA1 (gBRCA1, 40.0%; sBRCA1, 22.2%) mutations were less frequently biallelic.	('BRCA2', 'Gene', '675', (59, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('BRCA1', 'Gene', (126, 131))	('BRCA1', 'Gene', '672', (103, 108))	('BRCA1', 'Gene', '672', (111, 116))	('BRCA2', 'Gene', (36, 41))	('BRCA1', 'Gene', (103, 108))	('prostate cancer', 'Disease', (3, 18))	('BRCA2', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('BRCA1', 'Gene', (111, 116))	('BRCA2', 'Gene', (59, 64))	('BRCA2', 'Gene', '675', (44, 49))	('BRCA2', 'Gene', '675', (36, 41))	('BRCA1', 'Gene', '672', (126, 131))	('mutations', 'Var', (73, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
665628	32903788	In pancreatic cancer, predicted gBRCA1/2 mutations were frequently biallelic (gBRCA1, 79.2%; gBRCA2, 79.7%) compared with sBRCA1/2 mutations (sBRCA1, 52.9%; sBRCA2, 46.0%).	('mutations', 'Var', (41, 50))	('BRCA1', 'Gene', '672', (123, 128))	('BRCA1', 'Gene', '672', (143, 148))	('BRCA1', 'Gene', '672', (79, 84))	('pancreatic cancer', 'Disease', (3, 20))	('BRCA2', 'Gene', (94, 99))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('BRCA1', 'Gene', (123, 128))	('BRCA1', 'Gene', (143, 148))	('BRCA1', 'Gene', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('BRCA2', 'Gene', '675', (94, 99))	('BRCA1', 'Gene', '672', (33, 38))	('BRCA2', 'Gene', (158, 163))	('BRCA1', 'Gene', (33, 38))	('BRCA2', 'Gene', '675', (158, 163))
665629	32903788	Among non-BRCA1/2-associated cancers, predicted gBRCA1 mutations were most frequently biallelic in endometrial (87.1%), unknown primary (66.7%), bladder/urothelial (63.6%), and neuroendocrine (60.0%) cancer; predicted gBRCA2 mutations were most frequently biallelic in salivary gland (85.7%), unknown primary (71.7%), biliary tract (65.0%), and endometrial (58.1%) cancer; and predicted sBRCA1/2 mutations were infrequently biallelic except for biliary tract cancer (sBRCA1, 50.0% [2 of 4]; sBRCA2, 61.5% [24 of 39]), endometrial cancer (sBRCA1, 48.7% [19 of 39]), and esophageal SCC (sBRCA1, 80% [4 of 5]; Appendix Figs A5B and A5C).	('BRCA2', 'Gene', '675', (219, 224))	('endometrial cancer', 'Disease', 'MESH:D016889', (518, 536))	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (445, 465))	('biliary tract cancer', 'Disease', 'MESH:D001661', (445, 465))	('BRCA2', 'Gene', (492, 497))	('cancer', 'Disease', (365, 371))	('BRCA1', 'Gene', '672', (10, 15))	('SCC', 'Phenotype', 'HP:0002860', (580, 583))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('BRCA1', 'Gene', (10, 15))	('A5C', 'Mutation', 'c.5A>C', (629, 632))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (530, 536))	('BRCA1', 'Gene', '672', (468, 473))	('cancer', 'Disease', (29, 35))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (530, 536))	('SCC', 'Gene', '6317', (580, 583))	('BRCA1', 'Gene', (468, 473))	('cancer', 'Disease', (459, 465))	('BRCA2', 'Gene', '675', (492, 497))	('BRCA1', 'Gene', '672', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('BRCA1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (459, 465))	('BRCA2', 'Gene', (219, 224))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('BRCA1', 'Gene', '672', (388, 393))	('BRCA1', 'Gene', '672', (586, 591))	('BRCA1', 'Gene', '672', (539, 544))	('SCC', 'Gene', (580, 583))	('endometrial cancer', 'Phenotype', 'HP:0012114', (518, 536))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('biliary tract cancer', 'Disease', (445, 465))	('BRCA1', 'Gene', (586, 591))	('mutations', 'Var', (225, 234))	('BRCA1', 'Gene', (539, 544))	('BRCA1', 'Gene', (388, 393))	('cancers', 'Disease', (29, 36))	('endometrial cancer', 'Disease', (518, 536))	('cancer', 'Disease', 'MESH:D009369', (530, 536))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (200, 206))
665632	32903788	Biallelic BRCA1/2 alterations were associated with gLOH-high across every cancer type examined.	('alterations', 'Var', (18, 29))	('gLOH-high', 'Disease', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('associated', 'Reg', (35, 45))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('BRCA1/2', 'Gene', (10, 17))
665634	32903788	Biallelic BRCA1/2 mutations were associated with gLOH-high irrespective of predicted germline or somatic status (Appendix Figs A6B and A6C).	('A6C', 'Mutation', 'c.6A>C', (135, 138))	('mutations', 'Var', (18, 27))	('gLOH-high', 'Disease', (49, 58))	('associated', 'Reg', (33, 43))	('BRCA1/2', 'Gene', (10, 17))
665635	32903788	In some cancer types, significant but modest elevation in tumor mutational burden (TMB) was observed for biallelic BRCA1/2-mutated cases (predicted germline or somatic) versus wild type; however, the association with TMB was not consistent across cancer types (Appendix Fig A7).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('BRCA1/2-mutated', 'Gene', (115, 130))	('cancer', 'Disease', (8, 14))	('biallelic', 'Var', (105, 114))	('TMB', 'Chemical', '-', (83, 86))	('TMB', 'Chemical', '-', (217, 220))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('elevation', 'PosReg', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
665636	32903788	Monoallelic sBRCA1/2-mutated (but not gBRCA1/2) cases were commonly associated with elevated TMB versus wild type, and such mutations may be a consequence of increased mutation rate.	('elevated', 'PosReg', (84, 92))	('TMB', 'MPA', (93, 96))	('Monoallelic', 'Var', (0, 11))	('sBRCA1/2-mutated', 'Gene', (12, 28))	('TMB', 'Chemical', '-', (93, 96))
665637	32903788	Although biallelic BRCA1/2 status was consistently associated with gLOH-high, the magnitude was variable for each cancer type, with the greatest association observed in pancreatic (OR, 22.5), biliary (OR, 21.5), endometrial (OR, 17.2), unknown primary (OR, 16.1), and ovarian (OR, 14.9) cancer (Fig 4A).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('biallelic', 'Var', (9, 18))	('biliary', 'Disease', (192, 199))	('cancer', 'Disease', (287, 293))	('gLOH-high', 'Gene', (67, 76))	('unknown primary', 'Disease', (236, 251))	('pancreatic', 'Disease', (169, 179))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('BRCA1/2', 'Gene', (19, 26))	('ovarian', 'Disease', (268, 275))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('endometrial', 'Disease', (212, 223))	('pancreatic', 'Disease', 'MESH:D010195', (169, 179))	('cancer', 'Disease', (114, 120))
665638	32903788	More than 75% of cases with biallelic BRCA1/2 alterations were gLOH-high for ovarian, breast, pancreatic, unknown primary, and endometrial cancer, whereas fewer than half were gLOH-high for prostate and colorectal cancer.	('pancreatic', 'Disease', 'MESH:D010195', (94, 104))	('endometrial cancer', 'Phenotype', 'HP:0012114', (127, 145))	('prostate', 'Disease', (190, 198))	('unknown primary', 'Disease', (106, 121))	('breast', 'Disease', (86, 92))	('pancreatic', 'Disease', (94, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (127, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('colorectal cancer', 'Phenotype', 'HP:0003003', (203, 220))	('alterations', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('colorectal cancer', 'Disease', (203, 220))	('ovarian', 'Disease', (77, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (203, 220))	('endometrial cancer', 'Disease', (127, 145))	('BRCA1/2', 'Gene', (38, 45))
665641	32903788	Consistent with the findings using a gLOH cutoff-based approach, gLOH scores were higher in BRCA1/2 biallelic versus wild-type cases across all cancer types evaluated; increased gLOH score was also observed when biallelic BRCA1 and BRCA2 were evaluated independently.	('BRCA1', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BRCA2', 'Gene', (232, 237))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('higher', 'PosReg', (82, 88))	('cancer', 'Disease', (144, 150))	('BRCA1', 'Gene', '672', (222, 227))	('BRCA1', 'Gene', '672', (92, 97))	('BRCA2', 'Gene', '675', (232, 237))	('BRCA1', 'Gene', (222, 227))	('gLOH', 'MPA', (65, 69))	('biallelic', 'Var', (100, 109))
665644	32903788	To inform rational cancer type-specific gLOH-high cutoffs, we assessed the performance of different gLOH-high thresholds to classify biallelic BRCA1/2 compared with wild-type cases.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('biallelic', 'Var', (133, 142))	('cancer', 'Disease', (19, 25))	('BRCA1/2', 'Disease', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
665648	32903788	Emerging clinical trial data suggest that BRCA1/2 alteration may also be predictive of PARPi response in prostate cancer.	('BRCA1/2', 'Gene', (42, 49))	('alteration', 'Var', (50, 60))	('prostate cancer', 'Disease', (105, 120))	('PARP', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('PARP', 'Gene', '142', (87, 91))
665650	32903788	To understand the landscape and phenotypic consequence of BRCA1/2 alterations, we assessed our data set of 234,154 cancer specimens sequenced using a clinical-grade CGP assay.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('BRCA1/2', 'Gene', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('alterations', 'Var', (66, 77))
665651	32903788	BRCA1/2 alterations were frequent in BRCA1/2-associated cancers but also observed in a significant fraction (3%) of non-BRCA1/2-associated cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('alterations', 'Var', (8, 19))	('cancers', 'Disease', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('frequent', 'Reg', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BRCA1/2', 'Gene', (0, 7))
665652	32903788	Predicted germline mutations comprised the majority of BRCA1/2 mutations in BRCA1/2-associated cancers; however, it is notable that 43% were predicted somatic (of which 81% were biallelic) given data that support sBRCA1/2 alteration as a biomarker for PARPi in ovarian and prostate cancer.	('mutations', 'Var', (63, 72))	('PARP', 'Gene', (252, 256))	('BRCA1/2', 'Gene', (55, 62))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('BRCA1/2-associated', 'Gene', (76, 94))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('PARP', 'Gene', '142', (252, 256))	('ovarian and prostate cancer', 'Disease', 'MESH:D011472', (261, 288))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (273, 288))
665653	32903788	Of note, although monoallelic alteration in BRCA1/2 mutation carriers may have a subtle haploinsufficient phenotype, it does not lead to severe HRD or sensitivity to platinum-based chemotherapy.	('subtle haploinsufficient', 'Disease', 'MESH:D058495', (81, 105))	('lead to', 'Reg', (129, 136))	('platinum', 'Chemical', 'MESH:D010984', (166, 174))	('HRD', 'Disease', 'None', (144, 147))	('BRCA1/2', 'Gene', (44, 51))	('monoallelic alteration', 'Var', (18, 40))	('subtle haploinsufficient', 'Disease', (81, 105))	('HRD', 'Disease', (144, 147))
665654	32903788	Consistent with the established role of BRCA1/2 in the pathogenesis of BRCA1/2-associated cancers, 90% of BRCA1/2-altered cases were biallelic with high biallelic fraction both for predicted gBRCA1/2 and sBRCA1/2.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('biallelic', 'Var', (133, 142))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('BRCA1/2-associated', 'Gene', (71, 89))	('BRCA1/2-altered', 'Gene', (106, 121))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
665658	32903788	To determine whether BRCA1/2 alterations lead to HRD in both BRCA1/2-associated and non-BRCA1/2-associated cancers, we evaluated gLOH in BRCA1/2-altered versus wild-type cases.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('BRCA1/2-associated', 'Disease', (61, 79))	('HRD', 'Disease', 'None', (49, 52))	('alterations', 'Var', (29, 40))	('lead to', 'Reg', (41, 48))	('BRCA1/2', 'Gene', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('HRD', 'Disease', (49, 52))
665659	32903788	Across every cancer type evaluated, biallelic BRCA1/2 alteration was associated with increased gLOH.	('alteration', 'Var', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('BRCA1/2', 'Gene', (46, 53))	('biallelic', 'Var', (36, 45))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('increased', 'PosReg', (85, 94))	('gLOH', 'Disease', (95, 99))
665660	32903788	Therefore, biallelic BRCA1/2 alterations broadly result in the gLOH signature for HRD and may represent a therapeutic vulnerability targetable by PARPi.	('result in', 'Reg', (49, 58))	('HRD', 'Disease', 'None', (82, 85))	('PARP', 'Gene', '142', (146, 150))	('alterations', 'Var', (29, 40))	('HRD', 'Disease', (82, 85))	('PARP', 'Gene', (146, 150))	('BRCA1/2', 'Gene', (21, 28))
665661	32903788	Monoallelic alterations may be found in sporadic cancers from gBRCA1/2 carriers or as somatic passenger mutations.	('sporadic cancers', 'Disease', (40, 56))	('Monoallelic alterations', 'Var', (0, 23))	('gBRCA1/2', 'Gene', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('found', 'Reg', (31, 36))	('sporadic cancers', 'Disease', 'MESH:D009369', (40, 56))
665662	32903788	Distinguishing biallelic from monoallelic status may be an important consideration for refining BRCA1/2 alteration as a predictive biomarker for PARPi.	('PARP', 'Gene', '142', (145, 149))	('alteration', 'Var', (104, 114))	('PARP', 'Gene', (145, 149))	('BRCA1/2', 'Gene', (96, 103))
665665	32903788	The lack of PARPi clinical activity in non-BRCA1/2-associated cancers reported previously could be explained by grouped analysis of biallelic and monoallelic BRCA1/2 alterations.	('biallelic', 'Var', (132, 141))	('non-BRCA1/2-associated', 'Disease', (39, 61))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('alterations', 'Var', (166, 177))	('PARP', 'Gene', '142', (12, 16))	('BRCA1/2', 'Gene', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('monoallelic', 'Var', (146, 157))	('cancers', 'Disease', (62, 69))	('PARP', 'Gene', (12, 16))
665666	32903788	Because of lower rates of biallelic alteration in non-BRCA1/2-associated cancers, PARPi clinical trials will likely require patient selection strategies that incorporate methods to discriminate biallelic from monoallelic BRCA1/2 alterations.	('cancers', 'Disease', (73, 80))	('non-BRCA1/2-associated', 'Gene', (50, 72))	('PARP', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('biallelic', 'Var', (26, 35))	('lower', 'NegReg', (11, 16))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('PARP', 'Gene', '142', (82, 86))	('patient', 'Species', '9606', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
665667	32903788	Our findings are consistent with a recent study that demonstrated an elevated HRD composite score in biallelic but not heterozygous BRCA1/2 cases relative to wild type in an aggregate set of non-BRCA1/2-associated cancers.	('HRD', 'Disease', 'None', (78, 81))	('BRCA1/2', 'Gene', (132, 139))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('HRD', 'Disease', (78, 81))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('elevated', 'PosReg', (69, 77))	('biallelic', 'Var', (101, 110))
665668	32903788	A strength of the current study was that the large data set size enabled analysis of biallelic BRCA1/2 separately from monoallelic alterations, independent assessment of BRCA1 and BRCA2, and evaluation of non-BRCA1/2-associated cancers as individual cancer types rather than in aggregate, which may have enabled identification of associations between biallelic BRCA1/2 alterations and an HRD signature across cancer types not previously described.	('cancer', 'Phenotype', 'HP:0002664', (409, 415))	('HRD signature across cancer', 'Disease', 'MESH:D009369', (388, 415))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('BRCA1', 'Gene', '672', (361, 366))	('BRCA1', 'Gene', '672', (170, 175))	('BRCA1', 'Gene', (361, 366))	('BRCA1', 'Gene', (170, 175))	('BRCA1', 'Gene', '672', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('BRCA1', 'Gene', (209, 214))	('alterations', 'Var', (369, 380))	('cancer', 'Disease', 'MESH:D009369', (409, 415))	('BRCA2', 'Gene', (180, 185))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('cancer', 'Disease', (228, 234))	('cancers', 'Disease', (228, 235))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('BRCA1', 'Gene', '672', (95, 100))	('HRD signature across cancer', 'Disease', (388, 415))	('BRCA1', 'Gene', (95, 100))	('associations', 'Interaction', (330, 342))	('BRCA2', 'Gene', '675', (180, 185))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', (409, 415))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
665669	32903788	If BRCA1/2 biallelic alterations functionally result in HRD, they should represent a targetable vulnerability to PARPi and platinum-based chemotherapy, irrespective of whether they are drivers of disease pathogenesis or bystander passenger alterations.	('HRD', 'Disease', (56, 59))	('biallelic alterations', 'Var', (11, 32))	('result in', 'Reg', (46, 55))	('PARP', 'Gene', '142', (113, 117))	('platinum', 'Chemical', 'MESH:D010984', (123, 131))	('HRD', 'Disease', 'None', (56, 59))	('BRCA1/2', 'Gene', (3, 10))	('PARP', 'Gene', (113, 117))
665670	32903788	Our data demonstrate that biallelic BRCA1/2 alteration in non-BRCA1/2-associated cancers are associated with the gLOH-high signature of HRD and, therefore, warrant investigation in PARPi trials.	('HRD', 'Disease', 'None', (136, 139))	('alteration', 'Var', (44, 54))	('PARP', 'Gene', (181, 185))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Disease', (81, 88))	('BRCA1/2', 'Gene', (36, 43))	('biallelic', 'Var', (26, 35))	('associated', 'Reg', (93, 103))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('PARP', 'Gene', '142', (181, 185))	('HRD', 'Disease', (136, 139))
665671	32903788	Biallelic BRCA1/2 alteration was observed in 1.6% of non-BRCA1/2-associated cancer and at > 1% frequency in at least 13 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('observed', 'Reg', (33, 41))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('alteration', 'Var', (18, 28))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('BRCA1/2', 'Gene', (10, 17))
665672	32903788	Although biallelic BRCA1/2 alterations occur at low prevalence in non-BRCA1/2-associated cancers, basket trials that led to the tumor-agnostic approvals of NTRK inhibitors for NTRK fusion-positive tumors and pembrolizumab for microsatellite instability-high tumors demonstrate feasibility of therapeutic development for rare pan-cancer biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('microsatellite instability-high tumors', 'Disease', (226, 264))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', (258, 263))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('pembrolizumab', 'Chemical', 'MESH:C582435', (208, 221))	('BRCA1/2', 'Gene', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancers', 'Disease', (89, 96))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('alterations', 'Var', (27, 38))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Disease', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('microsatellite instability-high tumors', 'Disease', 'MESH:D053842', (226, 264))	('tumor', 'Disease', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', (329, 335))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Disease', (197, 202))
665674	32903788	Although gLOH-high is associated with clinical benefit from rucaparib in ovarian cancer, understanding of the gLOH biomarker in other cancer types is required.	('benefit', 'PosReg', (47, 54))	('ovarian cancer', 'Disease', (73, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('rucaparib', 'Chemical', 'MESH:C531549', (60, 69))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('gLOH-high', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ovarian cancer', 'Disease', 'MESH:D010051', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
665681	32903788	Third, using BRCA1/2 biallelic versus wild-type status to refine gLOH-high cutoffs is confounded by some BRCA1/2 wild-type gLOH-high cases that are HRD because of BRCA1/2 alteration-independent mechanisms, such as BRCA1/2 methylation or alteration in other HR genes.	('HRD', 'Disease', (148, 151))	('BRCA1/2', 'Gene', (163, 170))	('methylation', 'Var', (222, 233))	('HR genes', 'Gene', (257, 265))	('BRCA1/2', 'Gene', (214, 221))	('HRD', 'Disease', 'None', (148, 151))	('alteration-independent', 'Reg', (171, 193))	('alteration', 'Reg', (237, 247))
665682	32903788	Another study evaluated a group of 102 HR pathway genes and found that biallelic alterations were associated with HRD.	('HRD', 'Disease', (114, 117))	('HRD', 'Disease', 'None', (114, 117))	('associated', 'Reg', (98, 108))	('biallelic alterations', 'Var', (71, 92))
665684	32903788	Finally, clinical outcomes data that associate PARPi response with biallelic BRCA1/2 alteration and gLOH were not available and require evaluation in clinical trials.	('PARP', 'Gene', (47, 51))	('biallelic', 'Var', (67, 76))	('alteration', 'Var', (85, 95))	('BRCA1/2', 'Gene', (77, 84))	('PARP', 'Gene', '142', (47, 51))
665685	32903788	We demonstrate that biallelic BRCA1/2 alterations are associated with elevated gLOH across all cancer types evaluated and may therefore represent a therapeutic vulnerability targetable by PARPi.	('elevated', 'PosReg', (70, 78))	('PARP', 'Gene', (188, 192))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('BRCA1/2', 'Gene', (30, 37))	('cancer', 'Disease', (95, 101))	('PARP', 'Gene', '142', (188, 192))	('alterations', 'Var', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gLOH', 'MPA', (79, 83))
665686	32903788	Biomarker development for PARPi should reliably distinguish biallelic/monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated as a pan-cancer biomarker in PARPi clinical trials.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('PARP', 'Gene', (26, 30))	('PARP', 'Gene', (188, 192))	('alteration', 'Var', (120, 130))	('biallelic', 'Var', (102, 111))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('PARP', 'Gene', '142', (26, 30))	('PARP', 'Gene', '142', (188, 192))	('cancer', 'Disease', (168, 174))
665691	32903788	In validation testing of 480 tumor-only sequencing calls against matched normal specimens, accuracy was 95% for somatic and 99% for germline calls (Sun JX, et al: PLOS Comput Biol 14:e1005965, 2018); in assessment of zygosity calls, significant enrichment in mutations with loss of heterozygosity (LOH) was observed for tumor suppressor genes (Sun JX, et al: PLOS Comput Biol 14:e1005965, 2018).	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutations', 'Var', (259, 268))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', (29, 34))	('loss of heterozygosity', 'NegReg', (274, 296))
665695	32903788	Biallelic alterations were mutations with LOH of the wild-type allele, as determined by zygosity status (Sun JX, et al: PLOS Comput Biol 14:e1005965, 2018); homozygous deletion; or >= 2 BRCA1 or >= 2 BRCA2 alterations in a sample.	('alterations', 'Reg', (206, 217))	('BRCA2', 'Gene', (200, 205))	('BRCA1', 'Gene', '672', (186, 191))	('BRCA2', 'Gene', '675', (200, 205))	('BRCA1', 'Gene', (186, 191))	('deletion', 'Var', (168, 176))
665702	32903788	An ultraviolet signature trinucleotide context was defined as the top-weighted alteration classes in COSMIC Signature 7 (A[C>T]C, C[C>T]A, C[C>T]C, C[C>T]G, C[C>T]T, G[C>T]C, G[C>T]T, T[C>T]A, T[C>T]C, T[C>T]G, T[C>T]T; https://cancer.sanger.ac.uk/cosmic/signatures_v2; Alexandrov LB, et al: Nature 500:415-421, 2013).	('cancer', 'Disease', (228, 234))	('C[C>T]', 'Var', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('G[C>T]C', 'Var', (166, 173))	('C[C>T]T', 'Var', (157, 164))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
665710	31987972	A c-statistic of 0.84 was obtained for a model with DeltaADCduring, DeltaSUVmean,post and histology in classifying patients as pCR (versus 0.82 for DeltaADCduring and 0.79 for DeltaSUVmean,post alone).	('patients', 'Species', '9606', (115, 123))	('pCR', 'Disease', (127, 130))	('DeltaADCduring', 'Var', (52, 66))
665732	31987972	The following tumor regression groups were scored: absence of residual cancer cells (TRG 1), 1-10% residual cancer cells (TRG 2), 10-50% residual cancer cells (TRG 3) and >50% residual cancer cells (TRG 4).	('cancer', 'Disease', (146, 152))	('TRG 4', 'Gene', (199, 204))	('TRG 4', 'Gene', '64717', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('TRG 2', 'Gene', (122, 127))	('cancer', 'Disease', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (71, 77))	('10-50', 'Var', (130, 135))	('TRG 3', 'Gene', '7197', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Disease', (14, 19))	('TRG 3', 'Gene', (160, 165))	('TRG 1', 'Gene', (85, 90))	('TRG 2', 'Gene', '7196', (122, 127))	('TRG 1', 'Gene', '7195', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
665760	31987972	Furthermore, the model with DeltaADCduring DeltaSUVmean,post and histology also demonstrated the best global model fit in terms of the lowest AIC (Supplementary Table 2).	('AIC', 'Disease', 'MESH:D058540', (142, 145))	('AIC', 'Disease', (142, 145))	('DeltaADCduring', 'Var', (28, 42))	('lowest', 'NegReg', (135, 141))
665761	31987972	ROC curve analyses of 18F-FDG PET/CT and DW-MRI parameters acquired during treatment for prediction of GR did not demonstrate complementary value of DeltaADCduring and DeltaSUVmax,during, but demonstrated a high bootstrapped c-statistic for DeltaADCduring with histology (0.82 [95% CI: 0.75 - 0.94] for DeltaADCduring and DeltaSUVmax,during, versus 0.83 [95% CI: 0.73 - 0.92] for DeltaADCduring and 0.74 [95% CI: 0.60 - 0.88] for DeltaSUVmax,during, all models with histology, Table 3 and Figure 3b).	('FDG', 'Gene', (26, 29))	('DeltaADCduring', 'Var', (241, 255))	('FDG', 'Gene', '23583', (26, 29))
665762	31987972	The model with DeltaSUVmax,during and histology demonstrated the best global model fit in terms lowest AIC (Supplementary Table 2).	('AIC', 'Disease', 'MESH:D058540', (103, 106))	('AIC', 'Disease', (103, 106))	('DeltaSUVmax', 'Var', (15, 26))
665818	31908393	During the development of esophageal cancer, the rs11473 polymorphism of the miR-483-5p binding site plays a vital role in the 3'-untranslated region of the basigin gene.	('basigin', 'Gene', (157, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (26, 43))	('rs11473', 'DBSNP_MENTION', 'None', (49, 56))	('esophageal cancer', 'Disease', (26, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('rs11473', 'Var', (49, 56))	('basigin', 'Gene', '682', (157, 164))	('miR-483-5p', 'Gene', (77, 87))
665819	31908393	Single nucleotide polymorphisms in telomerase reverse transcriptase may be associated with susceptibility to esophageal cancer and contribute to the development of esophageal cancer.	('esophageal cancer', 'Disease', (164, 181))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('telomerase reverse transcriptase', 'Enzyme', (35, 67))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))	('associated', 'Reg', (75, 85))	('contribute to', 'Reg', (131, 144))
665837	31908393	We believe that the presence of these differentially expressed genes is closely related to the development of various stages of esophageal cancer.	('related', 'Reg', (80, 87))	('esophageal cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('presence', 'Var', (20, 28))
128220	31908393	Importantly, positive CPLX2 expression is associated with lymphatic invasion, pathological staging, and adverse disease-specific survival in LNET patients.	('positive', 'Var', (13, 21))	('associated', 'Reg', (42, 52))	('expression', 'MPA', (28, 38))	('pathological staging', 'CPA', (78, 98))	('CPLX2', 'Gene', (22, 27))	('CPLX2', 'Gene', '10814', (22, 27))	('patients', 'Species', '9606', (146, 154))	('lymphatic invasion', 'CPA', (58, 76))
665862	31908393	After knocking out the DPEP1 gene, cells (SW480 and HCT116) exhibited increased apoptosis and attenuated cell proliferation and cell invasion.	('knocking out', 'Var', (6, 18))	('increased', 'PosReg', (70, 79))	('SW480', 'CellLine', 'CVCL:0546', (42, 47))	('HCT116', 'CellLine', 'CVCL:0291', (52, 58))	('attenuated', 'NegReg', (94, 104))	('cell invasion', 'CPA', (128, 141))	('DPEP1', 'Gene', (23, 28))	('DPEP1', 'Gene', '1800', (23, 28))	('cell proliferation', 'CPA', (105, 123))
665867	31908393	In the study of hepatocellular carcinoma, Su et al found that knockdown of THBS4 inhibited migration and invasion of hepatocellular carcinoma cells as well as hemangiocarcinoma-induced angiogenesis.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (117, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('hepatocellular carcinoma', 'Disease', (117, 141))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (117, 141))	('Su', 'Chemical', 'MESH:C035067', (42, 44))	('THBS4', 'Gene', '7060', (75, 80))	('inhibited', 'NegReg', (81, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('hemangiocarcinoma', 'Disease', (159, 176))	('THBS4', 'Gene', (75, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('hepatocellular carcinoma', 'Disease', (16, 40))	('hemangiocarcinoma', 'Disease', 'None', (159, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('knockdown', 'Var', (62, 71))
665871	31908393	Jin et al found that hypermethylation of the SST promoter is common and is associated with early tumor progression in Barrett's esophagus.	('hypermethylation', 'Var', (21, 37))	('associated with', 'Reg', (75, 90))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (118, 137))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('SST promoter', 'Gene', (45, 57))	('tumor', 'Disease', (97, 102))	("Barrett's esophagus", 'Disease', (118, 137))
665872	31908393	It also may play an important role in the regulation of esophageal cancer by methylation modification.	('esophageal cancer', 'Disease', (56, 73))	('methylation modification', 'Var', (77, 101))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))
665873	31908393	Ghosh et al studied the effect of SH3GL2 methylation on the pathogenesis of head and neck squamous cell carcinoma, and abnormal SH3GL2 is an independent pathway for early developmental abnormalities of the head and neck.	('SH3GL2', 'Gene', (128, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (76, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (171, 198))	('developmental abnormalities of the head', 'Disease', (171, 210))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (76, 113))	('SH3GL2', 'Gene', '6456', (128, 134))	('SH3GL2', 'Gene', (34, 40))	('abnormalities of the head', 'Phenotype', 'HP:0000234', (185, 210))	('abnormalities of the head and neck', 'Phenotype', 'HP:0000152', (185, 219))	('developmental abnormalities of the head', 'Disease', 'MESH:D006130', (171, 210))	('SH3GL2', 'Gene', '6456', (34, 40))	('abnormal', 'Var', (119, 127))
665958	30277016	prospectively collected data from the United Kingdom carcinoma network and showed that the two and five-year OS rates were similar in the CRT + surgery and CRT groups.25 However, patients administered non-surgical-based therapies had more than double the incidence of local relapse compared to patients administered surgical-based therapies.	('CR', 'Gene', '109732', (156, 158))	('carcinoma', 'Disease', 'MESH:D002277', (53, 62))	('patients', 'Species', '9606', (294, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('non-surgical-based therapies', 'Var', (201, 229))	('patients', 'Species', '9606', (179, 187))	('OS', 'Chemical', '-', (109, 111))	('carcinoma', 'Disease', (53, 62))	('CR', 'Gene', '109732', (138, 140))	('local relapse', 'CPA', (268, 281))
665969	29100401	The Kaplan-Meier survival curves indicated that patients with NRS >= 3 had worse overall survival (OS) compared to patients with NRS < 3 (P<0.001).	('patients', 'Species', '9606', (115, 123))	('NRS >= 3', 'Var', (62, 70))	('patients', 'Species', '9606', (48, 56))	('overall survival', 'MPA', (81, 97))	('worse', 'NegReg', (75, 80))
666001	29100401	In further analyses, NRS >= 3 was significantly associated with shorter OS for patients who received S1 based chemotherapy (P=0.005, Figure 2A) and patients who received paclitaxel based chemotherapy (P<0.001, Figure 2B).	('patients', 'Species', '9606', (148, 156))	('paclitaxel', 'Chemical', 'MESH:D017239', (170, 180))	('patients', 'Species', '9606', (79, 87))	('shorter OS', 'Disease', (64, 74))	('NRS >= 3', 'Var', (21, 29))
666003	29100401	Similarly, NRS >= 3 was significantly associated with shorter OS for female patients (P<0.001, Figure 3A) and male patients (P=0.016, Figure 3B).	('shorter', 'Disease', (54, 61))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (76, 84))	('NRS >= 3', 'Var', (11, 19))
666005	29100401	Patients with NRS >= 3 had an elevated risk of death compared to those with NRS < 3.	('death', 'Disease', (47, 52))	('Patients', 'Species', '9606', (0, 8))	('NRS >= 3', 'Var', (14, 22))	('death', 'Disease', 'MESH:D003643', (47, 52))
666009	29100401	The patients in the validation cohort with NRS >= 3 exhibited decreased OS (P=0.016) compared with the patients who had NRS < 3 (Figure 4).	('patients', 'Species', '9606', (103, 111))	('decreased', 'NegReg', (62, 71))	('patients', 'Species', '9606', (4, 12))	('NRS >= 3', 'Var', (43, 51))
666017	29100401	In our study, tumor markers (CEA, CA125, CA199 and CA724) were not associated with overall survival according to univariate analysis (P>0.05).	('tumor', 'Disease', (14, 19))	('CA125', 'Gene', '94025', (34, 39))	('CA724', 'Var', (51, 56))	('CEA', 'Gene', (29, 32))	('CEA', 'Gene', '5670', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('CA125', 'Gene', (34, 39))	('CA199', 'Var', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
666029	29100401	The median PFS in patients received paclitaxel-based regimens were significantly longer than in patients received S1-based regimens (13.0 m Vs 6.5 m, P=0.034).	('longer', 'PosReg', (81, 87))	('PFS', 'MPA', (11, 14))	('paclitaxel-based', 'Var', (36, 52))	('paclitaxel', 'Chemical', 'MESH:D017239', (36, 46))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (18, 26))
666048	29100401	Blood samples were taken from each patient routinely before treatment to measure serum albumin, hemoglobin and tumor markers (CEA, CA125 and CA199).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('hemoglobin', 'MPA', (96, 106))	('CA125', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patient', 'Species', '9606', (35, 42))	('tumor', 'Disease', (111, 116))	('serum albumin', 'MPA', (81, 94))	('CA125', 'Gene', '94025', (131, 136))	('CEA', 'Gene', (126, 129))	('CA199', 'Var', (141, 146))	('CEA', 'Gene', '5670', (126, 129))
666102	28969011	Other hypotheses, such as the induction of Th17 response and molecular mimicry, have also been proposed to explain the mechanism by which C. albicans might promote cancer progression.	('C. albicans', 'Species', '5476', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('C. albicans', 'Var', (138, 149))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('promote', 'PosReg', (156, 163))
666198	28458564	The Kwint model, derived from 139 patients after CCRT treatment for non-small cell lung cancer (NSCLC), demonstrated a sigmoid-shaped relationship between grade >=2 AET and V50.	('V50', 'Disease', (173, 176))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (72, 94))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (68, 94))	('NSCLC', 'Disease', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('AET', 'Chemical', '-', (165, 168))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (68, 94))	('patients', 'Species', '9606', (34, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('grade >=2 AET', 'Var', (155, 168))	('non-small cell lung cancer', 'Disease', (68, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
666207	28458564	The DE-IMRT plan resulted in a 28.4% dose escalation to the GTV on average compared with the NE-IMRT plan (65.9 Gy versus 51.3 Gy).	('DE-IMRT', 'Var', (4, 11))	('GTV', 'Chemical', '-', (60, 63))	('dose', 'MPA', (37, 41))
666218	28458564	The results of this study are consistent with previously reported dosimetric data, which identified an improvement in dose escalation to the tumor using the DE-IMRT strategy.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('improvement', 'PosReg', (103, 114))	('tumor', 'Disease', (141, 146))	('dose escalation', 'MPA', (118, 133))	('DE-IMRT', 'Var', (157, 164))
666220	28458564	They found that the use of DE-IMRT produced a 28% dose escalation (from 52 Gy to 66.9 Gy) to the GTV, while providing a comparable dose to the lungs and a slightly higher dose to the spinal cord compared with the conventional dose plan.	('dose', 'MPA', (50, 54))	('higher', 'PosReg', (164, 170))	('dose', 'MPA', (171, 175))	('GTV', 'Chemical', '-', (97, 100))	('DE-IMRT', 'Var', (27, 34))
666259	28458564	In summary, our study has demonstrated the benefits of using the DE-IMRT strategy to significantly improve tumor control with minor side effects, or clinically acceptable toxicities for UTEC patients.	('toxicities', 'Disease', 'MESH:D064420', (171, 181))	('patients', 'Species', '9606', (191, 199))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('improve', 'PosReg', (99, 106))	('tumor', 'Disease', (107, 112))	('clinical', 'Species', '191496', (149, 157))	('toxicities', 'Disease', (171, 181))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('DE-IMRT', 'Var', (65, 72))
666270	27766776	Silencing Akt1 could reverse cisplatin resistance in Eca109 and TE-1.	('Akt1', 'Gene', (10, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('Akt1', 'Gene', '207', (10, 14))	('Silencing', 'Var', (0, 9))	('cisplatin resistance', 'MPA', (29, 49))	('reverse', 'NegReg', (21, 28))
666321	27766776	We then used cell flow cytometry and Hoechst staining to detect the role of RUNX3 on the apoptosis and cell cycle of ESCC cell lines, and the results showed that heterologous RUNX3 could promote apoptosis, induce G1 arrest, and decrease G2/M compared with the control (Fig 3d,e,f).	('promote', 'PosReg', (187, 194))	('heterologous', 'Var', (162, 174))	('RUNX3', 'Gene', (175, 180))	('decrease', 'NegReg', (228, 236))	('apoptosis', 'CPA', (195, 204))	('Hoechst', 'Chemical', '-', (37, 44))	('G2/M', 'CPA', (237, 241))	('induce', 'PosReg', (206, 212))	('G1 arrest', 'CPA', (213, 222))
666323	27766776	Western blot showed a decreasing level of Akt1 and phospho (p)-Akt in Eca109PR-R3 and TE-1PR-R3 compared with the control group, and a consistent change of downstream genes in the Akt pathway, which are involved in the cell cycle and apoptosis; bcl-2, bcl-xl, cyclinD1 and p21 were also observed (Fig 4a).	('p21', 'Gene', '644914', (273, 276))	('decreasing', 'NegReg', (22, 32))	('Akt1', 'Gene', (42, 46))	('Akt', 'Gene', '207', (63, 66))	('bcl-2', 'Gene', (245, 250))	('bcl-xl', 'Gene', (252, 258))	('bcl-xl', 'Gene', '598', (252, 258))	('Akt', 'Gene', (180, 183))	('Akt1', 'Gene', '207', (42, 46))	('Akt', 'Gene', '207', (180, 183))	('cyclinD1', 'Gene', '595', (260, 268))	('bcl-2', 'Gene', '596', (245, 250))	('TE-1PR-R3', 'Var', (86, 95))	('change', 'Reg', (146, 152))	('Akt', 'Gene', (42, 45))	('p21', 'Gene', (273, 276))	('Akt', 'Gene', '207', (42, 45))	('Eca109PR-R3', 'Var', (70, 81))	('cyclinD1', 'Gene', (260, 268))	('Akt', 'Gene', (63, 66))
666326	27766776	The IC50 cisplatin value was significantly decreased in Eca109PR-small interfering (si)Akt1 and TE-1PR-siAkt1 compared with the control group.	('Akt1', 'Gene', '207', (105, 109))	('IC50 cisplatin value', 'MPA', (4, 24))	('Akt1', 'Gene', (87, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('Eca109PR-small interfering', 'Var', (56, 82))	('Akt1', 'Gene', '207', (87, 91))	('Akt1', 'Gene', (105, 109))	('decreased', 'NegReg', (43, 52))
666331	27766776	Tumors derived from Eca109PR-RUNX3 cells grew more slowly when compared with NC-transfected cells.	('Eca109PR-RUNX3', 'Var', (20, 34))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('slowly', 'NegReg', (51, 57))	('grew', 'CPA', (41, 45))
666346	27766776	All of these results confirm that RUNX3 improves cisplatin sensitivity in ESCC patients.	('improves', 'PosReg', (40, 48))	('RUNX3', 'Var', (34, 39))	('ESCC', 'Disease', (74, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('cisplatin sensitivity', 'MPA', (49, 70))	('patients', 'Species', '9606', (79, 87))
666356	27766776	confirmed that an activated Akt pathway could inhibit apoptosis induced by cisplatin.32 Chen found that suppression of the phosphoinositide 3-kinase/Akt and signal transducer and activator of transcription 3 pathways could enhance cisplatin sensitivity in ESCC cells.33 In our study, silencing Akt1 significantly reversed cisplatin resistance in two cell lines.	('Akt', 'Gene', (28, 31))	('cisplatin resistance', 'MPA', (322, 342))	('Akt', 'Gene', (149, 152))	('Akt1', 'Gene', '207', (294, 298))	('Akt', 'Gene', '207', (294, 297))	('cisplatin', 'Chemical', 'MESH:D002945', (231, 240))	('silencing', 'Var', (284, 293))	('cisplatin', 'Chemical', 'MESH:D002945', (322, 331))	('Akt', 'Gene', (294, 297))	('signal transducer and activator of transcription 3', 'Gene', '6774', (157, 207))	('Akt', 'Gene', '207', (28, 31))	('Akt', 'Gene', '207', (149, 152))	('reversed', 'NegReg', (313, 321))	('Akt1', 'Gene', (294, 298))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))
666359	27766776	In conclusion, our findings confirmed that RUNX3 expression correlated with chemotherapeutic effect in ESCC patients, and heterologous RUNX3 could reverse cisplatin resistance in ESCC cell lines via suppression of the Akt pathway.	('suppression', 'NegReg', (199, 210))	('patients', 'Species', '9606', (108, 116))	('Akt', 'Gene', '207', (218, 221))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('RUNX3', 'Var', (135, 140))	('cisplatin resistance', 'MPA', (155, 175))	('Akt', 'Gene', (218, 221))	('heterologous', 'Var', (122, 134))	('RUNX3', 'Gene', (43, 48))	('reverse', 'NegReg', (147, 154))
666367	27008696	In cancers, high nuclear and cytoplasmic staining of TLR4 associated with metastatic disease and poor prognosis.	('associated', 'Reg', (58, 68))	('high', 'Var', (12, 16))	('metastatic disease', 'Disease', (74, 92))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('TLR4', 'Gene', '7099', (53, 57))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('TLR4', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
666409	27008696	In cancers, ligands of these TLRs have been shown to stimulate inflammatory cytokines, but also to induce tumor regression.	('inflammatory cytokines', 'MPA', (63, 85))	('induce', 'PosReg', (99, 105))	('stimulate', 'PosReg', (53, 62))	('TLRs', 'Gene', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancers', 'Disease', (3, 10))	('ligands', 'Var', (12, 19))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
666420	27008696	TLR4 knockdown attenuates tumor growth in lung cancer.	('TLR4', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('attenuates', 'NegReg', (15, 25))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (26, 31))	('TLR4', 'Gene', '7099', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
666421	27008696	Supporting role of TLR4 activation in pathogenesis of esophageal inflammation and carcinoma, TLR4 activation has been shown to induce Interleukin-8 and NF-kB in esophageal epithelial cells and, more pronouncedly so, in Barrett's esophagus.	('NF-kB', 'Protein', (152, 157))	('Interleukin-8', 'Gene', '3576', (134, 147))	('TLR4', 'Gene', '7099', (93, 97))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (54, 77))	('induce', 'PosReg', (127, 133))	('carcinoma', 'Disease', 'MESH:D002277', (82, 91))	("Barrett's esophagus", 'Disease', (219, 238))	('TLR4', 'Gene', (93, 97))	('esophageal inflammation', 'Disease', 'MESH:D007249', (54, 77))	('TLR4', 'Gene', '7099', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma', 'Disease', (82, 91))	('Interleukin-8', 'Gene', (134, 147))	('esophageal inflammation', 'Disease', (54, 77))	('TLR4', 'Gene', (19, 23))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (219, 238))	('activation', 'Var', (98, 108))
666453	25175076	Specifically, miR-141 and miR-200b were upregulated, whereas miR-376a was downregulated after PPI treatment in both tumour types.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('miR-141', 'Gene', '406933', (14, 21))	('miR-376a', 'Var', (61, 69))	('tumour', 'Disease', (116, 122))	('miR-200b', 'Var', (26, 34))	('miR-376', 'Chemical', '-', (61, 68))	('miR-141', 'Gene', (14, 21))	('downregulated', 'NegReg', (74, 87))	('upregulated', 'PosReg', (40, 51))
666454	25175076	Our study demonstrates for the first time that PPIs impact on tumour cell survival, metastatic potential and sensitivity towards chemotherapy in esophageal cancer cell lines.	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('metastatic potential', 'CPA', (84, 104))	('esophageal cancer', 'Disease', (145, 162))	('sensitivity towards chemotherapy', 'MPA', (109, 141))	('impact', 'Reg', (52, 58))	('PPIs', 'Var', (47, 51))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Disease', (62, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))
666455	25175076	Furthermore, we observed that in this tumour entity, PPIs do not lead to intracellular acidification, but affect the expression of resistance-relevant miRNAs.	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('PPIs', 'Var', (53, 57))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('expression of resistance-relevant miRNAs', 'MPA', (117, 157))	('tumour', 'Disease', (38, 44))	('affect', 'Reg', (106, 112))
666468	25175076	PPI pretreatment has been shown to sensitize various cell lines derived from primary tumours, including colon and ovarian adenocarcinomas, to cisplatin, 5-FU and vinblastine.	('primary tumours', 'Disease', (77, 92))	('primary tumours', 'Disease', 'MESH:D009369', (77, 92))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('vinblastine', 'Chemical', 'MESH:D014747', (162, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('colon and ovarian adenocarcinomas', 'Disease', 'MESH:D010051', (104, 137))	('PPI', 'Var', (0, 3))	('5-FU', 'Chemical', 'MESH:D005472', (153, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('sensitize', 'Reg', (35, 44))
666512	25175076	Namely, we selected miR-16, miR-21, miR-23a, miR-24, miR-26a, miR-106, miR-141, miR-155, miR-196a, miR-200a, miR-200b, miR-200c, miR-221, miR-222, miR-296-5p, miR-376a, miR-429 and let-7i for this study.	('miR-222', 'Gene', (138, 145))	('miR-221', 'Gene', '407006', (129, 136))	('miR-200a', 'Gene', '406983', (99, 107))	('miR-106', 'Gene', (62, 69))	('miR-429', 'Gene', (169, 176))	('miR-155', 'Gene', (80, 87))	('miR-26a', 'Gene', (53, 60))	('miR-16', 'Gene', (20, 26))	('miR-21', 'Gene', (28, 34))	('miR-200b', 'Var', (109, 117))	('let-7i', 'Gene', '406891', (181, 187))	('miR-155', 'Gene', '406947', (80, 87))	('miR-26a', 'Gene', '407015', (53, 60))	('miR-222', 'Gene', '407007', (138, 145))	('miR-141', 'Gene', '406933', (71, 78))	('miR-106', 'Gene', '406899', (62, 69))	('miR-16', 'Gene', '51573', (20, 26))	('miR-141', 'Gene', (71, 78))	('miR-200a', 'Gene', (99, 107))	('miR-200c', 'Gene', '406985', (119, 127))	('miR-429', 'Gene', '554210', (169, 176))	('let-7i', 'Gene', (181, 187))	('miR-376', 'Chemical', '-', (159, 166))	('miR-23a', 'Gene', '407010', (36, 43))	('miR-23a', 'Gene', (36, 43))	('miR-200c', 'Gene', (119, 127))	('miR-24', 'Var', (45, 51))	('miR-196a', 'Var', (89, 97))	('miR-296-5p', 'Var', (147, 157))	('miR-221', 'Gene', (129, 136))	('miR-21', 'Gene', '406991', (28, 34))
666524	25175076	After 15, 30, 60 and 90 minutes of PPI treatment, the ability of tumour cells to adhere to coated wells under the stimulation of TGF-?2 was significantly reduced in both tumour entities compared to untreated controls (p???0.025).	('reduced', 'NegReg', (154, 161))	('tumour', 'Disease', (170, 176))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('adhere', 'CPA', (81, 87))	('tumour entities', 'Disease', 'MESH:D009369', (170, 185))	('tumour entities', 'Disease', (170, 185))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('PPI', 'Var', (35, 38))	('tumour', 'Disease', 'MESH:D009369', (170, 176))	('tumour', 'Disease', (65, 71))	('TGF-?2', 'Gene', (129, 135))
666525	25175076	Furthermore, the ability of tumour cells (SCC and EAC) to migrate through 8-?m pores in a coated Boyden Chamber was significantly reduced after PPI treatment compared to controls (p?<?0.0001).	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('SCC', 'Gene', (42, 45))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('reduced', 'NegReg', (130, 137))	('tumour', 'Disease', (28, 34))	('SCC', 'Gene', '6317', (42, 45))	('PPI treatment', 'Var', (144, 157))	('migrate', 'CPA', (58, 65))
666533	25175076	However, this additional effect of esomeprazole on the cytotoxicity of chemotherapeutics was higher in cisplatin treated cells (resulting in an overall cytotoxicity of 88-99% after combined treatment) than in 5 FU-treated cells (resulting in an overall cytotoxicity of only about 80-97% after combined treatment; p?<?0.05).	('higher', 'PosReg', (93, 99))	('cytotoxicity', 'Disease', (253, 265))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('cytotoxicity', 'Disease', 'MESH:D064420', (152, 164))	('cytotoxicity', 'Disease', (55, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (253, 265))	('esomeprazole', 'Chemical', 'MESH:D064098', (35, 47))	('cisplatin', 'Var', (103, 112))	('cytotoxicity', 'Disease', (152, 164))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))
666534	25175076	The literature suggests that PPIs mediate their effects on tumour cells via disruption of the intra-extracellular pH-gradient and accumulation of protons in the cytosol of cancer cells.	('accumulation', 'PosReg', (130, 142))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('PPIs', 'Var', (29, 33))	('disruption of the intra-extracellular pH-gradient', 'MPA', (76, 125))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (172, 178))	('tumour', 'Disease', (59, 65))
666544	25175076	After PPI treatment, we observed significant deregulation of 8 of these miRNAs in SCC cells and 9 of these miRNAs in EAC cells.	('SCC', 'Gene', (82, 85))	('SCC', 'Gene', '6317', (82, 85))	('PPI', 'Var', (6, 9))	('deregulation', 'MPA', (45, 57))
666545	25175076	Most interestingly, 3 of these resistance-relevant miRNA candidates showed a similar pattern of deregulation in both tumour types: miR-141 and miR-200b were significanty upregulated whereas miR-376a was significantly downregulated (see Table 1 and Figure 6).	('miR-141', 'Gene', (131, 138))	('miR-376', 'Chemical', '-', (190, 197))	('downregulated', 'NegReg', (217, 230))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('miR-200b', 'Var', (143, 151))	('miR-141', 'Gene', '406933', (131, 138))	('miR-376a', 'Var', (190, 198))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('tumour', 'Disease', (117, 123))	('upregulated', 'PosReg', (170, 181))
666550	25175076	Based on the highly promising results in other tumour entities,?, we hypothesized that PPIs might impact on tumour cell survival, metastatic potential and chemotherapy resistance in esophageal cancer.	('tumour', 'Disease', (108, 114))	('tumour entities', 'Disease', (47, 62))	('PPIs', 'Var', (87, 91))	('esophageal cancer', 'Disease', (182, 199))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('chemotherapy resistance', 'CPA', (155, 178))	('impact', 'Reg', (98, 104))	('tumour', 'Disease', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('metastatic potential', 'CPA', (130, 150))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('tumour entities', 'Disease', 'MESH:D009369', (47, 62))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
666563	25175076	Specifically, PPI treatment led to upregulation of miR-141 and miR-200b and downregulaton of miR-376a in SCC and EAC cells.	('miR-376', 'Chemical', '-', (93, 100))	('downregulaton', 'NegReg', (76, 89))	('miR-141', 'Gene', '406933', (51, 58))	('miR-376a', 'MPA', (93, 101))	('PPI', 'Var', (14, 17))	('SCC', 'Gene', (105, 108))	('miR-200b', 'Gene', (63, 71))	('miR-141', 'Gene', (51, 58))	('upregulation', 'PosReg', (35, 47))	('SCC', 'Gene', '6317', (105, 108))
666568	25175076	In addition, a number of authors demonstrated an effect of PPIs or other V-ATPase inhibitors on cancer treatment.	('effect', 'Reg', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('V-ATPase', 'Protein', (73, 81))	('PPIs', 'Var', (59, 63))	('cancer', 'Disease', (96, 102))	('ATP', 'Chemical', 'MESH:D000255', (75, 78))
666569	25175076	For example, PPIs were shown to increase the sensitivity of colon adenocarcinoma derived cells towards chemotherapeutic drugs, or specific inhibitors of V-ATPase were demonstrated to impair the preferential accumulation of daunomycin in lysosomes and to reverse the resistance towards anthracyclines in drug-resistant renal epithelial cells.	('inhibitors', 'Var', (139, 149))	('increase', 'PosReg', (32, 40))	('preferential accumulation', 'MPA', (194, 219))	('sensitivity', 'MPA', (45, 56))	('daunomycin', 'Chemical', 'MESH:D003630', (223, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('ATP', 'Chemical', 'MESH:D000255', (155, 158))	('PPIs', 'Var', (13, 17))	('resistance towards anthracyclines', 'MPA', (266, 299))	('colon adenocarcinoma', 'Disease', (60, 80))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (60, 80))	('impair', 'NegReg', (183, 189))	('reverse', 'Reg', (254, 261))	('V-ATPase', 'Gene', (153, 161))	('anthracyclines', 'Chemical', 'MESH:D018943', (285, 299))
666571	25175076	Further evidence for the role of V-ATPases in chemoresistance was reported from targeted molecular studies: small interfering RNA against the ATP6L subunit of proton pump V-ATPase was shown to attenuate chemoresistance of breast cancer cells and hepatocellular carcinoma xenografts.	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('breast cancer', 'Disease', (222, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('hepatocellular carcinoma xenografts', 'Disease', (246, 281))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (246, 270))	('proton pump', 'Gene', (159, 170))	('ATP', 'Chemical', 'MESH:D000255', (35, 38))	('ATP', 'Chemical', 'MESH:D000255', (142, 145))	('ATP6L', 'Gene', '527', (142, 147))	('hepatocellular carcinoma xenografts', 'Disease', 'MESH:D006528', (246, 281))	('ATP6L', 'Gene', (142, 147))	('proton pump', 'Gene', '495', (159, 170))	('attenuate', 'NegReg', (193, 202))	('ATP', 'Chemical', 'MESH:D000255', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('small interfering', 'Var', (108, 125))	('chemoresistance', 'CPA', (203, 218))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))
666576	25175076	Consequently, inhibition of proton pumps via PPIs should impair the ability of the cell to eliminate protons from the intracellular space, subsequently leading to an accumulation of protons in the cytosol of the cells with a decrease of pHi, and an increase of pHe.	('pHi', 'Gene', '2821', (237, 240))	('ability', 'MPA', (68, 75))	('increase', 'PosReg', (249, 257))	('proton pump', 'Gene', (28, 39))	('pHe', 'MPA', (261, 264))	('pHi', 'Gene', (237, 240))	('accumulation', 'PosReg', (166, 178))	('inhibition', 'Var', (14, 24))	('pHe', 'Chemical', 'MESH:D010649', (261, 264))	('impair', 'NegReg', (57, 63))	('proton pump', 'Gene', '495', (28, 39))	('decrease', 'NegReg', (225, 233))
666577	25175076	observed a decrease of pHi and an increase of pHe in a human gastric cell line after PPI treatment.	('pHi', 'Gene', (23, 26))	('pHe', 'Chemical', 'MESH:D010649', (46, 49))	('PPI', 'Var', (85, 88))	('human', 'Species', '9606', (55, 60))	('decrease', 'NegReg', (11, 19))	('increase', 'PosReg', (34, 42))	('pHe', 'MPA', (46, 49))	('pHi', 'Gene', '2821', (23, 26))
666578	25175076	Moreover, Luciani and colleagues demonstrated that PPI pretreatment of melanoma, colon adenocarcinoma, breast cancer and ovarian carcinoma cell lines was associated with an increase of both, pHe and the pH of lysosomal organelles.	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('breast cancer', 'Disease', (103, 116))	('colon adenocarcinoma', 'Disease', (81, 101))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (121, 138))	('ovarian carcinoma', 'Disease', (121, 138))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('increase', 'PosReg', (173, 181))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (121, 138))	('pHe', 'Chemical', 'MESH:D010649', (191, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('PPI', 'Var', (51, 54))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (81, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('pH of lysosomal organelles', 'MPA', (203, 229))	('pHe', 'MPA', (191, 194))
666579	25175076	Furthermore, there is some evidence in the current literature that changes in pHi and pHe impact on prognosis, invasiveness and metastasis formation, activation of extracellular metalloproteases that influence tumour cell motility, proliferation and metastasis, and resistance towards irradiation and chemotherapy drugs.	('resistance', 'CPA', (266, 276))	('changes', 'Var', (67, 74))	('pHe', 'Chemical', 'MESH:D010649', (86, 89))	('invasiveness', 'CPA', (111, 123))	('pHi', 'Gene', (78, 81))	('activation', 'PosReg', (150, 160))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('metastasis', 'CPA', (250, 260))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('proliferation', 'CPA', (232, 245))	('pHe', 'Gene', (86, 89))	('pHi', 'Gene', '2821', (78, 81))	('extracellular metalloproteases', 'Enzyme', (164, 194))	('metastasis formation', 'CPA', (128, 148))	('impact', 'Reg', (90, 96))	('prognosis', 'CPA', (100, 109))	('tumour', 'Disease', (210, 216))	('influence', 'Reg', (200, 209))
666580	25175076	For example, acidic pHe in tumours can lead to an extracellular accumulation of weakly basic chemotherapeutics such as anthracyclines, anthraquinones and vinca alkaloid which subsequently fail to reach their intracellular targets.	('lead to', 'Reg', (39, 46))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('anthracyclines', 'Chemical', 'MESH:D018943', (119, 133))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('anthraquinones', 'Chemical', 'MESH:D000880', (135, 149))	('vinca alkaloid', 'Chemical', 'MESH:D014748', (154, 168))	('acidic pHe', 'Var', (13, 23))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumours', 'Disease', (27, 34))	('pHe', 'Chemical', 'MESH:D010649', (20, 23))
666582	25175076	In contrast to these reports, we found that pHi increased and pHe decreased after PPI treatment in esophageal cancer cell lines.	('increased', 'PosReg', (48, 57))	('pHi', 'Gene', (44, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('decreased', 'NegReg', (66, 75))	('pHe', 'MPA', (62, 65))	('PPI treatment', 'Var', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pHe', 'Chemical', 'MESH:D010649', (62, 65))	('pHi', 'Gene', '2821', (44, 47))	('esophageal cancer', 'Disease', (99, 116))
666584	25175076	However, our data provide the first reported evidence that in esophageal cancer cell lines, PPI treatment does not lead to an intracellular accumulation of protons and an inability to eliminate protons in the extracellular compartment.	('PPI', 'Var', (92, 95))	('esophageal cancer', 'Disease', (62, 79))	('eliminate protons in the extracellular compartment', 'MPA', (184, 234))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('inability', 'NegReg', (171, 180))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))
666585	25175076	Our data suggest that the observed effect of PPI treatment in our study might at least in part not be mediated by the inhibition of proton pumps.	('proton pump', 'Gene', '495', (132, 143))	('PPI', 'Var', (45, 48))	('proton pump', 'Gene', (132, 143))
666588	25175076	Most interestingly, we found three miRNAs (namely miR-141, miR-200b and miR-376a) to be deregulated in a similar fashion in both tumour subtypes, implying that these miRNAs might in general be affected by PPI treatment.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('deregulated', 'MPA', (88, 99))	('miR-376a', 'Var', (72, 80))	('tumour subtypes', 'Disease', (129, 144))	('miR-141', 'Gene', (50, 57))	('miR-141', 'Gene', '406933', (50, 57))	('miR-200b', 'Var', (59, 67))	('tumour subtypes', 'Disease', 'MESH:C535673', (129, 144))	('miR-376', 'Chemical', '-', (72, 79))
666601	25175076	However, as several other authors observed that PPI treatment lead to intracellular acidification, in our opinion the absence of this accumulation of protons in the intracellular space in our experiments justifies the conclusion that this is not the main effect of action of esomeprazole in esophageal cancer cell lines.	('esophageal cancer', 'Disease', 'MESH:D004938', (291, 308))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('esomeprazole', 'Chemical', 'MESH:D064098', (275, 287))	('lead to', 'Reg', (62, 69))	('intracellular acidification', 'MPA', (70, 97))	('esophageal cancer', 'Disease', (291, 308))	('PPI treatment', 'Var', (48, 61))
666604	25175076	The current study provides for the very first time evidence that PPIs impact on tumour cell survival, metastatic potential and sensitivity towards chemotherapeutic drugs in esophageal cancer cell lines, as has previously been demonstrated in other malignancies.	('tumour', 'Disease', (80, 86))	('sensitivity', 'MPA', (127, 138))	('impact', 'Reg', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('malignancies', 'Disease', 'MESH:D009369', (248, 260))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('malignancies', 'Disease', (248, 260))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('esophageal cancer', 'Disease', (173, 190))	('metastatic potential', 'CPA', (102, 122))	('PPIs', 'Var', (65, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (173, 190))
666606	25175076	Most interestingly, we found, that the expression of resistance-relevant miRNAs in esophageal cancer cells (SCC and EAC) is affected by PPI treatment.	('esophageal cancer', 'Disease', (83, 100))	('SCC', 'Gene', (108, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('PPI treatment', 'Var', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('SCC', 'Gene', '6317', (108, 111))	('affected', 'Reg', (124, 132))	('expression', 'MPA', (39, 49))
666617	24146905	Inhibition of PAR-2 activation or siRNA PAR-2 knockdown in EACs prior to treatment with 5 FU reduced cell viability of EACs by an additional 30% (P<0.01) compared to chemotherapy alone.	('EA', 'Phenotype', 'HP:0011459', (119, 121))	('EAC', 'Phenotype', 'HP:0011459', (119, 122))	('knockdown', 'Var', (46, 55))	('reduced', 'NegReg', (93, 100))	('PAR-2', 'Gene', (40, 45))	('EA', 'Phenotype', 'HP:0011459', (59, 61))	('PAR-2', 'Gene', '2150', (40, 45))	('cell viability', 'CPA', (101, 115))	('EAC', 'Phenotype', 'HP:0011459', (59, 62))	('PAR-2', 'Gene', (14, 19))	('PAR-2', 'Gene', '2150', (14, 19))
666629	24146905	Trypsin cleaves and activates PAR-2 more efficiently than any other PAR members (PAR-1, PAR-3 and PAR-4).	('PAR', 'Gene', (88, 91))	('PAR-4', 'Gene', (98, 103))	('cleaves', 'Var', (8, 15))	('PAR', 'Gene', '10899', (30, 33))	('PAR-3', 'Gene', (88, 93))	('PAR-1', 'Gene', '2149', (81, 86))	('PAR', 'Gene', (30, 33))	('PAR-3', 'Gene', '2151', (88, 93))	('PAR', 'Gene', '10899', (68, 71))	('PAR-1', 'Gene', (81, 86))	('PAR-2', 'Gene', (30, 35))	('PAR-2', 'Gene', '2150', (30, 35))	('PAR', 'Gene', (68, 71))	('PAR', 'Gene', '10899', (81, 84))	('PAR', 'Gene', '10899', (98, 101))	('activates', 'MPA', (20, 29))	('PAR', 'Gene', (81, 84))	('PAR-4', 'Gene', '9002', (98, 103))	('PAR', 'Gene', (98, 101))	('PAR', 'Gene', '10899', (88, 91))
666636	24146905	We have also shown that inhibition of PAR-2 by various approaches sensitizes EAC cells to cytotoxic agents.	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('EAC', 'Disease', (77, 80))	('inhibition', 'Var', (24, 34))	('PAR-2', 'Gene', (38, 43))	('PAR-2', 'Gene', '2150', (38, 43))	('EA', 'Phenotype', 'HP:0011459', (77, 79))	('sensitizes', 'Reg', (66, 76))
666637	24146905	Our results suggest that potent PAR-2 inhibitors could be new auxiliary therapeutic agents for esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('PAR-2', 'Gene', (32, 37))	('PAR-2', 'Gene', '2150', (32, 37))	('inhibitors', 'Var', (38, 48))	('esophageal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
666666	24146905	Figure 2C showed that 10 nM trypsin significantly induced proliferation in OE19 and OE33 over a 4-days time course and BART cells over a 1-day time course [an average fold-increase of ATP levels of 2.19+-0.29, 1.73+-0.07, and 2.46+-0.12 respectively (p<0.01)], while FLO1 did not exhibit a significant response to 10 nM trypsin stimulation.	('OE33', 'Var', (84, 88))	('ATP', 'Gene', (184, 187))	('proliferation', 'CPA', (58, 71))	('FLO1', 'Chemical', '-', (267, 271))	('ATP', 'Gene', '51761', (184, 187))
666687	24146905	In order to determine whether PAR-2 activation might also provide survival signaling in EAC, we used siRNA to knockdown PAR-2 expression in EAC followed by apoptosis analysis.	('knockdown', 'Var', (110, 119))	('EA', 'Phenotype', 'HP:0011459', (140, 142))	('EA', 'Phenotype', 'HP:0011459', (88, 90))	('EAC', 'Phenotype', 'HP:0011459', (88, 91))	('EAC', 'Phenotype', 'HP:0011459', (140, 143))	('PAR-2', 'Gene', (30, 35))	('PAR-2', 'Gene', (120, 125))	('PAR-2', 'Gene', '2150', (30, 35))	('PAR-2', 'Gene', '2150', (120, 125))
666688	24146905	In three separate experiments, the fraction of early apoptotic cells in OE19 increased from 5.85+-1.05% (scrambled control) to 19.35+-0.55% (PAR-2 siRNA knockdown, p<0.01).	('PAR-2', 'Gene', (141, 146))	('PAR-2', 'Gene', '2150', (141, 146))	('OE19', 'Var', (72, 76))
666689	24146905	OE33 cells showed a similar trend from 7.30+-1.10% (scrambled control) to 24.5+-0.30% (PAR-2 siRNA knockdown, p<0.01).	('PAR-2', 'Gene', (87, 92))	('PAR-2', 'Gene', '2150', (87, 92))	('knockdown', 'Var', (99, 108))
666690	24146905	Interestingly, given the lower level of PAR-2 expression and trypsin secretion, PAR-2 siRNA knockdown in FLO1 cells did not alter its apoptotic rate (figure 5A).	('PAR-2', 'Gene', (80, 85))	('PAR-2', 'Gene', '2150', (80, 85))	('FLO1', 'Chemical', '-', (105, 109))	('knockdown', 'Var', (92, 101))	('PAR-2', 'Gene', (40, 45))	('PAR-2', 'Gene', '2150', (40, 45))	('trypsin secretion', 'MPA', (61, 78))	('expression', 'MPA', (46, 56))
666691	24146905	To confirm these results, we inhibited trypsin with the protease inhibitor leupeptin which also resulted in a significant increase in the fraction of apopotic cells in both OE33 and OE19, but not FLO1 (figure 5B).	('inhibited', 'NegReg', (29, 38))	('OE33', 'Var', (173, 177))	('OE19', 'Var', (182, 186))	('leupeptin', 'Chemical', 'MESH:C032854', (75, 84))	('FLO1', 'Chemical', '-', (196, 200))	('trypsin', 'Protein', (39, 46))	('increase', 'PosReg', (122, 130))
666693	24146905	At 72 hrs after knockdown of PAR-2 expression, cell viability was decreased to 45.64+-8.69% in OE19 cells and to 56.96+-11.37% in OE33 cells compared to scrambled control cells (figure 5C).	('PAR-2', 'Gene', (29, 34))	('PAR-2', 'Gene', '2150', (29, 34))	('decreased', 'NegReg', (66, 75))	('knockdown', 'Var', (16, 25))	('cell viability', 'CPA', (47, 61))	('expression', 'Var', (35, 45))
666698	24146905	Based on our observation of a blunted proliferation response of EA cells to exogenous trypsin, and the observation that PAR-2 inhibition reduced baseline proliferation and increased baseline apoptosis in EA cells, we speculated that they might secrete trypsin in an autocrine fashion.	('EA', 'Phenotype', 'HP:0011459', (64, 66))	('baseline proliferation', 'CPA', (145, 167))	('baseline', 'CPA', (182, 190))	('increased', 'PosReg', (172, 181))	('inhibition', 'Var', (126, 136))	('PAR-2', 'Gene', (120, 125))	('EA', 'Phenotype', 'HP:0011459', (204, 206))	('PAR-2', 'Gene', '2150', (120, 125))	('reduced', 'NegReg', (137, 144))
666703	24146905	DNA sequence mismatches with type 1 (gene ID: PRSS1, NM_002769) and type 2 (gene ID: PRSS2, NM_002770) trypsinogen sequences were observed (figure S1).	('NM_002770', 'Var', (92, 101))	('NM_002769', 'Var', (53, 62))	('PRSS1', 'Gene', '5644', (46, 51))	('PRSS2', 'Gene', '5645', (85, 90))	('PRSS2', 'Gene', (85, 90))	('PRSS1', 'Gene', (46, 51))
666708	24146905	We speculated that inactivation of PAR-2 may resensitize EAC to 5FU via inhibiting cell proliferation and/or inducing apoptosis.	('apoptosis', 'CPA', (118, 127))	('PAR-2', 'Gene', '2150', (35, 40))	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('cell proliferation', 'CPA', (83, 101))	('inhibiting', 'NegReg', (72, 82))	('EA', 'Phenotype', 'HP:0011459', (57, 59))	('5FU', 'Chemical', 'MESH:D005472', (64, 67))	('inducing', 'Reg', (109, 117))	('inactivation', 'Var', (19, 31))	('PAR-2', 'Gene', (35, 40))
666715	24146905	These data indicated that inhibition of PAR-2 activity rendered OE19 and OE33 cells more sensitive to chemotherapeutic agent 5FU.	('sensitive to', 'MPA', (89, 101))	('5FU', 'Chemical', 'MESH:D005472', (125, 128))	('inhibition', 'Var', (26, 36))	('PAR-2', 'Gene', (40, 45))	('activity', 'MPA', (46, 54))	('PAR-2', 'Gene', '2150', (40, 45))	('more', 'PosReg', (84, 88))
666719	24146905	These data further support our hypothesis that inhibition of the trypsin/PAR-2 network could facilitate the effect of chemotherapeutic treatment in EA cells.	('PAR-2', 'Gene', (73, 78))	('inhibition', 'Var', (47, 57))	('PAR-2', 'Gene', '2150', (73, 78))	('facilitate', 'PosReg', (93, 103))	('EA', 'Phenotype', 'HP:0011459', (148, 150))
666722	24146905	Our data suggest that secreted trypsin acting on the PAR-2 receptor can function as an autocrine survival signal, and that targeting this axis can increase sensitivity to chemotherapy in esophageal adenocarcinoma cell lines.	('esophageal adenocarcinoma', 'Disease', (187, 212))	('PAR-2', 'Gene', (53, 58))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (187, 212))	('autocrine survival signal', 'MPA', (87, 112))	('PAR-2', 'Gene', '2150', (53, 58))	('targeting', 'Var', (123, 132))	('increase', 'PosReg', (147, 155))	('sensitivity to chemotherapy', 'MPA', (156, 183))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (187, 212))
666732	24146905	Over-expression of PRSS3 has been shown to promote pancreatic cancer cell proliferation as well as invasion in vitro, and tumor progression and metastasis in vivo .	('PRSS3', 'Gene', (19, 24))	('promote', 'PosReg', (43, 50))	('PRSS3', 'Gene', '5646', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('pancreatic cancer', 'Disease', (51, 68))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('invasion', 'CPA', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Over-expression', 'Var', (0, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))	('tumor', 'Disease', (122, 127))
666746	24146905	In vitro studies showed that activation of PAR-2 enhances the growth of two gastric cancer cell lines AGS and MKN28 via EGFR trans-activation.	('growth', 'CPA', (62, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('gastric cancer', 'Disease', (76, 90))	('AGS', 'Disease', (102, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('PAR-2', 'Gene', (43, 48))	('PAR-2', 'Gene', '2150', (43, 48))	('AGS', 'Disease', 'MESH:C535607', (102, 105))	('trans-activation', 'PosReg', (125, 141))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('EGFR', 'Gene', '1956', (120, 124))	('activation', 'Var', (29, 39))	('enhances', 'PosReg', (49, 57))	('EGFR', 'Gene', (120, 124))
666748	24146905	Treating human colon cancer cell HT-29 with 0.1-1.0 nM trypsin elicited a highly significant increase of cell number in vitro.	('colon cancer', 'Phenotype', 'HP:0003003', (15, 27))	('HT-29', 'CellLine', 'CVCL:0320', (33, 38))	('colon cancer', 'Disease', 'MESH:D015179', (15, 27))	('cell number', 'CPA', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('increase', 'PosReg', (93, 101))	('colon cancer', 'Disease', (15, 27))	('human', 'Species', '9606', (9, 14))	('0.1-1.0 nM', 'Var', (44, 54))
666754	24146905	This study is the first report that PAR-2 inhibition not only blocked cell proliferation in EACs and BART cells, also induced apoptosis in EACs.	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('PAR-2', 'Gene', (36, 41))	('apoptosis', 'CPA', (126, 135))	('cell proliferation', 'CPA', (70, 88))	('inhibition', 'Var', (42, 52))	('EAC', 'Phenotype', 'HP:0011459', (139, 142))	('EA', 'Phenotype', 'HP:0011459', (139, 141))	('PAR-2', 'Gene', '2150', (36, 41))	('blocked', 'NegReg', (62, 69))	('EA', 'Phenotype', 'HP:0011459', (92, 94))	('induced', 'Reg', (118, 125))
666756	24146905	By inactivating PAR-2 either with its antagonist ENMD or PAR-2 antibody SAM-11 or siRNA depletion of PAR-2, we were able to demonstrate that inhibition of PAR-2 activation sensitized EACs to the current chemotherapeutical agent 5FU and conferred a synergistic cell killing effect in vitro.	('PAR-2', 'Gene', (101, 106))	('PAR-2', 'Gene', (155, 160))	('PAR-2', 'Gene', '2150', (101, 106))	('synergistic cell killing effect', 'CPA', (248, 279))	('PAR-2', 'Gene', '2150', (155, 160))	('sensitized', 'Reg', (172, 182))	('PAR-2', 'Gene', (16, 21))	('5FU', 'Chemical', 'MESH:D005472', (228, 231))	('PAR-2', 'Gene', '2150', (16, 21))	('PAR-2', 'Gene', (57, 62))	('EA', 'Phenotype', 'HP:0011459', (183, 185))	('PAR-2', 'Gene', '2150', (57, 62))	('SAM-11', 'Chemical', '-', (72, 78))	('EAC', 'Phenotype', 'HP:0011459', (183, 186))	('inhibition', 'Var', (141, 151))	('inactivating', 'Var', (3, 15))
666757	24146905	We reason that potent PAR-2 antagonists/inhibitors may provide chemotherapeutic sensitization in cancer patients by blocking trypsin mediated survival signaling and sensitizing cells to other apoptosis inducing compounds such as chemotheraputic agents.	('antagonists/inhibitors', 'Var', (28, 50))	('cancer', 'Disease', (97, 103))	('trypsin mediated survival signaling', 'MPA', (125, 160))	('PAR-2', 'Gene', (22, 27))	('PAR-2', 'Gene', '2150', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('blocking', 'NegReg', (116, 124))	('sensitizing', 'Reg', (165, 176))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
666762	24146905	In summary, we have shown that PAR-2 was constitutively expressed in cultured EACs and BART cells and trypsin exposure resulted in increased cell proliferation via trans-activation of ERK MAPK pathway.	('PAR-2', 'Gene', '2150', (31, 36))	('ERK', 'Gene', '5594', (184, 187))	('increased', 'PosReg', (131, 140))	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('trypsin', 'Var', (102, 109))	('ERK', 'Gene', (184, 187))	('cell proliferation', 'CPA', (141, 159))	('EA', 'Phenotype', 'HP:0011459', (78, 80))	('PAR-2', 'Gene', (31, 36))
666763	24146905	More importantly, we provided clear evidence that targeting PAR-2 increases apoptosis in EACs and consequently confers chemo-sensitization of EACs.	('EAC', 'Phenotype', 'HP:0011459', (89, 92))	('increases', 'PosReg', (66, 75))	('PAR-2', 'Gene', (60, 65))	('PAR-2', 'Gene', '2150', (60, 65))	('EA', 'Phenotype', 'HP:0011459', (142, 144))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))	('apoptosis', 'CPA', (76, 85))	('targeting', 'Var', (50, 59))	('EA', 'Phenotype', 'HP:0011459', (89, 91))
666775	23420329	The U.S. study reported an inverse association with vitamin C, vitamin E, and beta-carotene whereas the FINBAR study found that the overall antioxidant index, a measure of the combined intake of vitamin C, vitamin E, total carotenoids, and selenium, was associated with a reduced risk of EAC, but not of BE.	('vitamin C', 'Chemical', 'MESH:D001205', (195, 204))	('vitamin', 'Var', (52, 59))	('carotenoids', 'Chemical', 'MESH:D002338', (223, 234))	('reduced', 'NegReg', (272, 279))	('beta-carotene', 'Chemical', 'MESH:D019207', (78, 91))	('vitamin E', 'Chemical', 'MESH:D014810', (63, 72))	('EAC', 'Disease', (288, 291))	('vitamin C', 'Chemical', 'MESH:D001205', (52, 61))	('inverse', 'NegReg', (27, 34))	('vitamin E', 'Chemical', 'MESH:D014810', (206, 215))	('selenium', 'Chemical', 'MESH:D012643', (240, 248))
666796	23420329	For example, a subject with an antioxidant intake in the first decile for each of the eight micronutrients (vitamin C, vitamin E, alpha-carotene, beta-carotene, selenium, cryptoxanthin, lutein and lycopene) had an antioxidant score equal to 4, while a subject in the tenth decile for each micronutrient had an antioxidant score equal to 40, as previously described.	('alpha-carotene', 'Var', (130, 144))	('vitamin E', 'Chemical', 'MESH:D014810', (119, 128))	('cryptoxanthin', 'Chemical', 'MESH:D065366', (171, 184))	('vitamin C', 'Chemical', 'MESH:D001205', (108, 117))	('beta-carotene', 'Var', (146, 159))	('lutein', 'Chemical', 'MESH:D014975', (186, 192))	('alpha-carotene', 'Chemical', 'MESH:C041635', (130, 144))	('antioxidant score', 'MPA', (310, 327))	('selenium', 'Chemical', 'MESH:D012643', (161, 169))	('antioxidant score', 'MPA', (214, 231))	('lycopene', 'Chemical', 'MESH:D000077276', (197, 205))	('beta-carotene', 'Chemical', 'MESH:D019207', (146, 159))
666831	23420329	A meta-analysis showed that high folate intake is significantly associated with a reduced risk of EAC.	('high folate intake', 'Phenotype', 'HP:0032164', (28, 46))	('EAC', 'Disease', (98, 101))	('folate', 'Chemical', 'MESH:D005492', (33, 39))	('high', 'Var', (28, 32))	('reduced', 'NegReg', (82, 89))
666859	18076764	Prevalence and patterns of soft tissue metastasis: detection with true whole-body F-18 FDG PET/CT The aim of this retrospective study was to report the prevalence and patterns of soft tissue (ST) metastasis detected with true whole-body (TWB) F-18 FDG PET/CT acquired from the top of the skull through the bottom of the feet and to compare such findings to that of the typically acquired skull-base to upper-thigh, thus limited whole-body (LWB) field of view (FOV).	('FDG', 'Chemical', 'MESH:D019788', (248, 251))	('FDG', 'Chemical', 'MESH:D019788', (87, 90))	('F-18 FDG', 'Var', (243, 251))	('FDG', 'Var', (248, 251))
666868	18076764	There is a growing body of literature regarding the added value of F-18 FDG PET/CT in cancer patient management.	('F-18 FDG', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('FDG', 'Chemical', 'MESH:D019788', (72, 75))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
667021	33297391	In comparison of the highest vs. lowest intakes, refined grain consumption was not associated with colorectal cancer but was associated with a 27% higher risk of colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('refined grain consumption', 'Var', (49, 74))	('colon cancer', 'Disease', (162, 174))	('colorectal cancer', 'Disease', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('higher', 'PosReg', (147, 153))	('rectal cancer', 'Phenotype', 'HP:0100743', (103, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (162, 174))	('colon cancer', 'Disease', 'MESH:D015179', (162, 174))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
667093	33276470	Indeed, HO-1 induction and/or impairment has been associated with a huge variety of diseases such as cancer, neurodegenerative, and cardiovascular diseases, among others.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('neurodegenerative', 'Disease', (109, 126))	('HO-1', 'Gene', (8, 12))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (132, 155))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cardiovascular diseases', 'Disease', (132, 155))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (132, 155))	('rat', 'Species', '10116', (120, 123))	('associated', 'Reg', (50, 60))	('impairment', 'Var', (30, 40))
667094	33276470	In this review we summarize the essential role of HO-1 and its end-products for ensuring the gastrointestinal tract health and how its dysfunction lead to several disorders of the esophagus, stomach, pancreas, liver, and gut.	('gastrointestinal tract health', 'Phenotype', 'HP:0011024', (93, 122))	('esophagus', 'Disease', (180, 189))	('lead to', 'Reg', (147, 154))	('stomach', 'Disease', (191, 198))	('disorders of the esophagus', 'Phenotype', 'HP:0002031', (163, 189))	('pancreas', 'Disease', (200, 208))	('disorder', 'Disease', 'MESH:D030342', (163, 171))	('liver', 'Disease', (210, 215))	('dysfunction', 'Var', (135, 146))	('disorder', 'Disease', (163, 171))
667106	33276470	These changes prevent Bach1 binding to StREs and lead to Bach1 export from the nucleus, and its ubiquitination by E3 ubiquitin ligase HOIL-1 and proteosomal degradation.	('proteosomal', 'MPA', (145, 156))	('HOIL-1', 'Gene', '10616', (134, 140))	('ubiquitination', 'MPA', (96, 110))	('Bach1', 'Gene', '571', (22, 27))	('binding', 'Interaction', (28, 35))	('HOIL-1', 'Gene', (134, 140))	('Bach1', 'Gene', (22, 27))	('changes', 'Var', (6, 13))	('prevent', 'NegReg', (14, 21))	('Bach1', 'Gene', (57, 62))	('StREs', 'Protein', (39, 44))	('lead to', 'Reg', (49, 56))	('export from the nucleus', 'MPA', (63, 86))	('Bach1', 'Gene', '571', (57, 62))	('E3 ubiquitin ligase', 'Protein', (114, 133))
667117	33276470	In addition, the oxidative damage may trigger heme release from hemoproteins, which in turn may contribute to boost the oxidative state.	('boost', 'PosReg', (110, 115))	('heme', 'Chemical', 'MESH:D006418', (46, 50))	('heme release', 'MPA', (46, 58))	('hemoproteins', 'Protein', (64, 76))	('trigger', 'Reg', (38, 45))	('oxidative state', 'MPA', (120, 135))	('oxidative', 'Var', (17, 26))
667133	33276470	Recent epidemiological studies highlight the potential of bilirubin to be employed as therapeutic target for stress-related diseases, since high levels of bilirubin have been associated with lower risk of stroke, diabetes, and non-alcoholic fatty liver disease.	('liver disease', 'Phenotype', 'HP:0001392', (247, 260))	('diabetes', 'Disease', (213, 221))	('stroke', 'Disease', (205, 211))	('high levels of bilirubin', 'Phenotype', 'HP:0003573', (140, 164))	('bilirubin', 'Chemical', 'MESH:D001663', (58, 67))	('diabetes', 'Disease', 'MESH:D003920', (213, 221))	('non-alcoholic fatty liver disease', 'Disease', (227, 260))	('stroke', 'Disease', 'MESH:D020521', (205, 211))	('bilirubin', 'Chemical', 'MESH:D001663', (155, 164))	('alcoholic fatty liver', 'Phenotype', 'HP:0006573', (231, 252))	('fatty liver', 'Phenotype', 'HP:0001397', (241, 252))	('stroke', 'Phenotype', 'HP:0001297', (205, 211))	('lower', 'NegReg', (191, 196))	('non-alcoholic fatty liver disease', 'Disease', 'MESH:D065626', (227, 260))	('high levels', 'Var', (140, 151))
667171	33276470	An increment of those stimuli may lead to inflammation of the esophagus, and, ultimately, derived into disorders.	('inflammation', 'Disease', (42, 54))	('inflammation of the esophagus', 'Phenotype', 'HP:0100633', (42, 71))	('lead to', 'Reg', (34, 41))	('disorder', 'Disease', 'MESH:D030342', (103, 111))	('increment', 'Var', (3, 12))	('inflammation', 'Disease', 'MESH:D007249', (42, 54))	('disorder', 'Disease', (103, 111))
667193	33276470	Interestingly, NSAIDs themselves also may induce HO-1 expression to protect gastric mucosa from NSAID-induced apoptosis, since inhibitor of HO-stimulated NSAID exacerbates ulcers.	('exacerbates', 'PosReg', (160, 171))	('ulcers', 'Disease', (172, 178))	('inhibitor', 'Var', (127, 136))	('ulcers', 'Disease', 'MESH:D014456', (172, 178))
667194	33276470	In fact, several studies describe how the induction of HO-1 ameliorates peptic ulcers by means of the reduction of pro-inflammatory cytokines, cell adhesion, and stimulation of anti-oxidative state.	('pro-inflammatory cytokines', 'MPA', (115, 141))	('HO-1', 'Gene', (55, 59))	('ulcers', 'Disease', (79, 85))	('induction', 'Var', (42, 51))	('ulcers', 'Disease', 'MESH:D014456', (79, 85))	('ameliorates', 'PosReg', (60, 71))	('anti-oxidative state', 'MPA', (177, 197))	('reduction', 'NegReg', (102, 111))	('peptic ulcers', 'Phenotype', 'HP:0004398', (72, 85))	('stimulation', 'PosReg', (162, 173))	('rat', 'Species', '10116', (66, 69))	('cell adhesion', 'CPA', (143, 156))
667219	33276470	Indeed, patients with necrotizing AP, the most severe form of AP, more frequently are carriers of long GT repeats genotype compared with those who has mild AP, or with healthy patients, associated with lower HO-1 expression.	('patients', 'Species', '9606', (176, 184))	('expression', 'MPA', (213, 223))	('AP', 'Gene', '16870', (156, 158))	('lower', 'NegReg', (202, 207))	('AP', 'Gene', '16870', (34, 36))	('AP', 'Gene', '16870', (62, 64))	('HO-1', 'Protein', (208, 212))	('long GT repeats', 'Var', (98, 113))	('patients', 'Species', '9606', (8, 16))
667242	33276470	As well as in other inflammatory diseases, individuals carrying longer GT repeats at HMOX1 promoter are more likely to develop T2DM.	('inflammatory diseases', 'Disease', 'MESH:D007249', (20, 41))	('longer GT repeats', 'Var', (64, 81))	('inflammatory diseases', 'Disease', (20, 41))	('HMOX1', 'Gene', (85, 90))	('HMOX1', 'Gene', '3162', (85, 90))	('T2DM', 'Disease', (127, 131))
667249	33276470	Interestingly, the authors observed how the restoration of HO-1 expression reduced the incidence of T1DM.	('T1DM', 'Disease', (100, 104))	('expression', 'MPA', (64, 74))	('reduced', 'NegReg', (75, 82))	('restoration', 'Var', (44, 55))	('rat', 'Species', '10116', (49, 52))	('HO-1', 'Gene', (59, 63))
667263	33276470	A recent study pointed out that HO-1 expression may protect hepatocytes by suppressing ROS-dependent endoplasmic reticulum stress and related apoptosis.	('suppressing', 'NegReg', (75, 86))	('expression', 'Var', (37, 47))	('protect hepatocytes', 'MPA', (52, 71))	('HO-1', 'Gene', (32, 36))	('ROS', 'Chemical', 'MESH:D017382', (87, 90))	('ROS-dependent endoplasmic reticulum stress', 'MPA', (87, 129))	('apoptosis', 'CPA', (142, 151))
667273	33276470	During reperfusion, the cells may recover from the ischemic insult, but they generate ROS which aggravates the inflammatory immune response.	('inflammatory immune response', 'CPA', (111, 139))	('aggravates', 'PosReg', (96, 106))	('ROS', 'Var', (86, 89))	('rat', 'Species', '10116', (81, 84))	('ROS', 'Chemical', 'MESH:D017382', (86, 89))
667276	33276470	In accordance with the latter, a more recent work found that liver macrophages are the major HO-1 producers, and that high expression in human OLT at reperfusion phase are associated with better survival and hepatocellular function.	('human', 'Species', '9606', (137, 142))	('hepatocellular function', 'CPA', (208, 231))	('better', 'PosReg', (188, 194))	('survival', 'CPA', (195, 203))	('high expression', 'Var', (118, 133))
667280	33276470	This role is supported by a study in which the deficiency of ATF3, a stress-induced transcription factor, depressed HO-1 signaling conducing to a TLR4-driven inflammatory response and liver injury increase.	('liver injury increase', 'Disease', (184, 205))	('HO-1 signaling', 'MPA', (116, 130))	('TLR4', 'Gene', '7099', (146, 150))	('liver injury increase', 'Disease', 'MESH:D017093', (184, 205))	('ATF3', 'Gene', '467', (61, 65))	('TLR4', 'Gene', (146, 150))	('ATF3', 'Gene', (61, 65))	('depressed', 'NegReg', (106, 115))	('deficiency', 'Var', (47, 57))
667287	33276470	The immune system tolerates the gut microbiota maintaining a continue cross-talk between them, so an imbalance in these microbiota-immunity interactions under certain environmental context may lead to oxidative stress and the development of inflammatory diseases.	('imbalance', 'Var', (101, 110))	('interactions', 'Interaction', (140, 152))	('oxidative stress', 'MPA', (201, 217))	('rat', 'Species', '10116', (22, 25))	('imbalance', 'Phenotype', 'HP:0002172', (101, 110))	('iron', 'Chemical', 'MESH:D007501', (170, 174))	('inflammatory diseases', 'Disease', 'MESH:D007249', (241, 262))	('oxidative stress', 'Phenotype', 'HP:0025464', (201, 217))	('inflammatory diseases', 'Disease', (241, 262))	('lead to', 'Reg', (193, 200))
667299	33276470	Independently of the type of immune response, the overall response is mediated by an inappropriate mucosal immune response against the gut microbiota by means of polarization from Treg towards Th cells promoting an inflammatory state.	('mucosal immune response against the gut microbiota', 'MPA', (99, 149))	('inflammatory', 'MPA', (215, 227))	('polarization', 'Var', (162, 174))	('Treg', 'Chemical', '-', (180, 184))
667302	33276470	Interestingly, they found how the induction of HO-1 before the onset of inflammation ameliorates colitis, although the induction has no effects once inflammation is already established.	('inflammation ameliorates colitis', 'Disease', (72, 104))	('inflammation', 'Disease', (72, 84))	('induction', 'Var', (34, 43))	('inflammation', 'Disease', 'MESH:D007249', (149, 161))	('inflammation', 'Disease', 'MESH:D007249', (72, 84))	('inflammation', 'Disease', (149, 161))	('HO-1', 'Gene', (47, 51))	('colitis', 'Phenotype', 'HP:0002583', (97, 104))	('inflammation ameliorates colitis', 'Disease', 'MESH:D007249', (72, 104))
667328	33276470	Moreover, normally, high HO-1 expression is associated with poor prognosis, lower survival rate and, especially, less responsiveness to treatments.	('expression', 'MPA', (30, 40))	('rat', 'Species', '10116', (91, 94))	('lower', 'NegReg', (76, 81))	('high', 'Var', (20, 24))	('HO-1', 'Gene', (25, 29))	('survival rate', 'CPA', (82, 95))
667329	33276470	For instance, in colorectal cancer, some studies highlight a better long-term survival and less metastases when HO-1 is expressed, and lower HO-1 expression at high grade stages; meanwhile other studies observed that the high HO-1 expression in colorectal cancer cells is linked to tumor progression and metastasis, by inhibiting apoptosis and promoting angiogenesis and immunological scape.	('tumor', 'Disease', (282, 287))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('high', 'Var', (221, 225))	('expression', 'MPA', (146, 156))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('colorectal cancer', 'Disease', (17, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (245, 262))	('immunological scape', 'CPA', (371, 390))	('apoptosis', 'CPA', (330, 339))	('metastases', 'Disease', (96, 106))	('colorectal cancer', 'Disease', (245, 262))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('inhibiting', 'NegReg', (319, 329))	('promoting', 'PosReg', (344, 353))	('lower', 'NegReg', (135, 140))	('angiogenesis', 'CPA', (354, 366))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (245, 262))	('HO-1', 'Gene', (226, 230))
667339	33276470	Indeed, Nrf2 is overexpressed in pancreatic and hepatic cancer, and mutations in its inhibitor, keap1, also have been described in colorectal cancer.	('Nrf2', 'Gene', (8, 12))	('hepatic cancer', 'Phenotype', 'HP:0002896', (48, 62))	('keap1', 'Gene', (96, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('described', 'Reg', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('pancreatic and hepatic cancer', 'Disease', 'MESH:D010190', (33, 62))	('overexpressed', 'PosReg', (16, 29))	('mutations', 'Var', (68, 77))	('colorectal cancer', 'Disease', (131, 148))	('keap1', 'Gene', '9817', (96, 101))
667349	33276470	Inhibition of HO-1 has been used for pancreatic cancer, enhancing the response to chemotherapy and reducing cell proliferation.	('reducing', 'NegReg', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('pancreatic cancer', 'Disease', (37, 54))	('enhancing', 'PosReg', (56, 65))	('Inhibition', 'Var', (0, 10))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))	('rat', 'Species', '10116', (120, 123))	('cell proliferation', 'CPA', (108, 126))	('HO-1', 'Gene', (14, 18))	('response', 'CPA', (70, 78))
667352	33276470	Controversially, some studies point out the induction of HO-1 stimulate pro-apoptotic effects through CO production and endoplasmic reticular stress.	('induction', 'Var', (44, 53))	('pro-apoptotic effects', 'CPA', (72, 93))	('CO', 'Chemical', 'MESH:D002248', (102, 104))	('HO-1', 'Gene', (57, 61))
667363	33276470	Studies carried out in healthy volunteers have focused on the effect of dietary supplements on the expression of HO-1 (Table 1), to finally demonstrate the possibility of their use as an alternative in the treatment of diseases in which dysregulation of HO-1 expression has been implicated in their development.	('rat', 'Species', '10116', (147, 150))	('HO-1', 'Gene', (113, 117))	('dysregulation', 'Var', (237, 250))	('HO-1', 'Gene', (254, 258))
667372	33276470	The trial NCT00842205 concluded that microsatellite variations in the HMOX1 gene are not associated with liver injury in chronic hepatitis C virus (HCV) after treatment with rivabirin and/or pegylated interferon.	('associated with', 'Reg', (89, 104))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (121, 138))	('microsatellite variations', 'Var', (37, 62))	('liver injury', 'Disease', (105, 117))	('HMOX1', 'Gene', '3162', (70, 75))	('chronic hepatitis C virus', 'Disease', (121, 146))	('rivabirin', 'Chemical', '-', (174, 183))	('HCV', 'Species', '11103', (148, 151))	('hepatitis', 'Phenotype', 'HP:0012115', (129, 138))	('liver injury', 'Disease', 'MESH:D017093', (105, 117))	('chronic hepatitis C virus', 'Disease', 'MESH:D019698', (121, 146))	('HMOX1', 'Gene', (70, 75))
667379	33276470	At the NCT01050712 trial, researchers hypothesized that inhaling CO before and after colon surgery would shorten the length of normal post-operative ileus (POI), a temporary paralysis of the intestines that could appears after colon surgery, and decrease the occurrence of POI complications with minimal side effects.	('decrease', 'NegReg', (246, 254))	('paralysis of the intestines', 'Phenotype', 'HP:0005214', (174, 201))	('shorten', 'NegReg', (105, 112))	('rat', 'Species', '10116', (142, 145))	('CO', 'Chemical', 'MESH:D002248', (65, 67))	('paralysis', 'Disease', (174, 183))	('POI', 'Disease', (273, 276))	('paralysis', 'Phenotype', 'HP:0003470', (174, 183))	('length', 'MPA', (117, 123))	('inhaling', 'Var', (56, 64))	('temporary paralysis', 'Phenotype', 'HP:0002385', (164, 183))	('ileus', 'Phenotype', 'HP:0002595', (149, 154))	('paralysis', 'Disease', 'MESH:D010243', (174, 183))
667415	31821313	A previous study reported younger age, poor differentiation, adenoma type, and more distant metastatic sites were significantly correlated with worse prognosis.	('adenoma type', 'Disease', (61, 73))	('poor', 'Var', (39, 43))	('adenoma type', 'Disease', 'MESH:D000236', (61, 73))
667442	31821313	Patients younger than 67 years, grade III, N1-N3, histological subtype of EAC or others, and lung metastases were more likely to have BM occurrence, while unmarried patients were associated with worse survival (Figure 3).	('grade III', 'Var', (32, 41))	('lung metastases', 'Disease', 'MESH:D009362', (93, 108))	('lung metastases', 'Disease', (93, 108))	('EAC', 'Disease', (74, 77))	('N1-N3', 'Var', (43, 48))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (165, 173))	('BM occurrence', 'Disease', (134, 147))
667446	31821313	Investigating the risk factors was important for identifying patients at high risk for distant metastases Results in our study revealed that patients with age younger than 67 years, male sex, T4 stage grade III, N1-3, histological subtype of EAC or others, and metastasis to liver, lung, and brain were more likely to have BM.	('EAC', 'Disease', (242, 245))	('patients', 'Species', '9606', (61, 69))	('metastasis', 'Var', (261, 271))	('metastases', 'Disease', (95, 105))	('N1-3', 'Var', (212, 216))	('metastases', 'Disease', 'MESH:D009362', (95, 105))	('patients', 'Species', '9606', (141, 149))
667497	30697606	Splenectomy can be done safely even in laparoscopic surgery by experienced surgeons, and the procedure itself is feasible with good short-term outcomes.32, 33, 34 Several recent retrospective reports, however, showed that splenectomy in open total gastrectomy could increase postoperative morbidity and mortality35, 36 without survival benefit.37, 38 In 2017, a multi-institutional RCT comparing splenectomy with spleen preservation in proximal gastric cancer was conducted in Japan.39 Splenectomy was associated with higher morbidity and greater blood loss, but had no survival benefit.	('cancer', 'Phenotype', 'HP:0002664', (453, 459))	('blood loss', 'Disease', 'MESH:D006473', (547, 557))	('gastric cancer', 'Disease', 'MESH:D013274', (445, 459))	('blood loss', 'Disease', (547, 557))	('gastric cancer', 'Disease', (445, 459))	('gastric cancer', 'Phenotype', 'HP:0012126', (445, 459))	('Splenectomy', 'Var', (486, 497))
667549	28639581	At an obvious area of leukoplakia, magnifying narrow-band imaging (NBI) endoscopy showed Type B1 intrapapillary capillary loops (IPCLs), demonstrating dilatation, tortuosity, caliber change, and distinct morphology [Figure 1b].	('IPCLs', 'Chemical', '-', (129, 134))	('leukoplakia', 'Disease', (22, 33))	('Type B1', 'Var', (89, 96))	('dilatation', 'Phenotype', 'HP:0002617', (151, 161))	('tortuosity', 'CPA', (163, 173))	('dilatation', 'CPA', (151, 161))	('caliber change', 'CPA', (175, 189))	('leukoplakia', 'Disease', 'MESH:D007971', (22, 33))
667566	28639581	In addition, basal-layer-type SCC might be detected by TP53 mutation and cyclin D1 amplification and a high Ki-67 labeling index.	('cyclin D1', 'Gene', (73, 82))	('SCC', 'Gene', '6317', (30, 33))	('mutation', 'Var', (60, 68))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('detected', 'Reg', (43, 51))	('SCC', 'Gene', (30, 33))	('cyclin D1', 'Gene', '595', (73, 82))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))
667579	28099899	The results of present meta-analysis showed that concurrent NCRT was associated with improved overall survival, progression-free survival, and R0 resection rate in patients with esophageal cancer.	('esophageal cancer', 'Disease', (178, 195))	('improved', 'PosReg', (85, 93))	('overall survival', 'CPA', (94, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('NCRT', 'Var', (60, 64))	('patients', 'Species', '9606', (164, 172))	('progression-free survival', 'CPA', (112, 137))	('R0 resection rate', 'CPA', (143, 160))
667627	28123601	In vivo, intra-peritoneal injection of BM-MSCs significantly increases the overall survival of xenograft models in nude-SCID mice.	('BM-MSCs', 'Var', (39, 46))	('SCID', 'Disease', 'MESH:D053632', (120, 124))	('SCID', 'Disease', (120, 124))	('mice', 'Species', '10090', (125, 129))	('increases', 'PosReg', (61, 70))
667628	28123601	AT-MSCs inhibit the growth of EL4 murine T-cell lymphoma by altering cell-cycle progression and inducing apoptosis in vitro, and can migrate to tumor sites and inhibit tumor growth in tumor-bearing nude mice and prolong their survival time.	('inhibit', 'NegReg', (8, 15))	('inducing', 'Reg', (96, 104))	('inhibit', 'NegReg', (160, 167))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (41, 56))	('cell-cycle progression', 'CPA', (69, 91))	('T-cell lymphoma', 'Disease', (41, 56))	('altering', 'Reg', (60, 68))	('EL4', 'Gene', '111979', (30, 33))	('survival time', 'CPA', (226, 239))	('nude mice', 'Species', '10090', (198, 207))	('tumor', 'Disease', (184, 189))	('cell lymphoma', 'Phenotype', 'HP:0012191', (43, 56))	('lymphoma', 'Phenotype', 'HP:0002665', (48, 56))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (168, 173))	('murine', 'Species', '10090', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('growth', 'CPA', (20, 26))	('prolong', 'PosReg', (212, 219))	('EL4', 'Gene', (30, 33))	('apoptosis', 'CPA', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (41, 56))	('AT-MSCs', 'Var', (0, 7))	('migrate', 'CPA', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
667652	28123601	However, AT-MSCs significantly suppressed the proliferation of colorectal adenocarcinoma (HT-29) in vitro and in mice xenografts.	('HT-29', 'CellLine', 'CVCL:0320', (90, 95))	('AT-MSCs', 'Var', (9, 16))	('colorectal adenocarcinoma', 'Disease', (63, 88))	('proliferation', 'CPA', (46, 59))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (63, 88))	('suppressed', 'NegReg', (31, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('mice', 'Species', '10090', (113, 117))
667653	28123601	Other reports showed that AT-MSCs enhance the metastatic capacity of colon cancer cell lines (HCT116, LoVo cells, SW480, LS174T and CCD-18Co) in a colon cancer cell co-culture model.	('colon cancer', 'Disease', (69, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (69, 81))	('AT-MSCs', 'Var', (26, 33))	('enhance', 'PosReg', (34, 41))	('colon cancer', 'Phenotype', 'HP:0003003', (147, 159))	('colon cancer', 'Disease', 'MESH:D015179', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('LoVo', 'CellLine', 'CVCL:0399', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('HCT116', 'CellLine', 'CVCL:0291', (94, 100))	('colon cancer', 'Disease', (147, 159))	('SW480', 'CellLine', 'CVCL:0546', (114, 119))	('colon cancer', 'Disease', 'MESH:D015179', (69, 81))	('metastatic capacity', 'CPA', (46, 65))
667654	28123601	AT-MSCs also promote the expression of the growth marker, proliferation cell nuclear antigen, but inhibit apoptosis markers and single-stranded DNA in the well- and poorly differentiated types of gastric adenocarcinoma cell lines (MKN28 and MKN45).	('proliferation cell nuclear antigen', 'Protein', (58, 92))	('expression', 'MPA', (25, 35))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (196, 218))	('promote', 'PosReg', (13, 20))	('gastric adenocarcinoma', 'Disease', (196, 218))	('inhibit', 'NegReg', (98, 105))	('single-stranded DNA', 'Var', (128, 147))	('apoptosis markers', 'MPA', (106, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))
667656	28123601	However, artificial fusion of MSCs with esophageal carcinoma cell line EC9706 resulted in hybrids with declined cell growth, increased apoptosis and suppressed tumorigenicity.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (40, 60))	('apoptosis', 'CPA', (135, 144))	('increased', 'PosReg', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cell growth', 'CPA', (112, 123))	('esophageal carcinoma', 'Disease', (40, 60))	('EC9706', 'CellLine', 'CVCL:E307', (71, 77))	('suppressed', 'NegReg', (149, 159))	('tumor', 'Disease', (160, 165))	('declined', 'NegReg', (103, 111))	('hybrids', 'Var', (90, 97))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (40, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
667657	28123601	UC-MSCs promote the proliferation of mouse pancreatic cancer cell line Pan02 in vivo, however, MSCs producing IL-15 eradicate established pancreatic tumors in syngeneic mice.	('pancreatic tumors', 'Disease', 'MESH:D010190', (138, 155))	('pancreatic tumors', 'Disease', (138, 155))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('eradicate', 'NegReg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (138, 155))	('MSCs', 'Var', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('mouse', 'Species', '10090', (37, 42))	('mice', 'Species', '10090', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('IL-15', 'Gene', '16168', (110, 115))	('pancreatic cancer', 'Disease', (43, 60))	('IL-15', 'Gene', (110, 115))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))
667660	28123601	However, another study showed that AT-MSCs do not affect the proliferation of lung adenocarcinoma cell line (A549) in vitro or promote tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('promote', 'PosReg', (127, 134))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('AT-MSCs', 'Var', (35, 42))	('proliferation', 'CPA', (61, 74))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 97))	('lung adenocarcinoma', 'Disease', (78, 97))
667663	28123601	AT-MSCs can inhibit the proliferation and induce the apoptosis of both androgen-responsive (LNCaP) and androgen-nonresponsive (PC3) human prostate cancer cells.	('PC3', 'Gene', '3853', (127, 130))	('proliferation', 'CPA', (24, 37))	('apoptosis', 'CPA', (53, 62))	('inhibit', 'NegReg', (12, 19))	('prostate cancer', 'Disease', 'MESH:D011471', (138, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('induce', 'PosReg', (42, 48))	('LNCaP', 'CellLine', 'CVCL:0395', (92, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('PC3', 'Gene', (127, 130))	('AT-MSCs', 'Var', (0, 7))	('human', 'Species', '9606', (132, 137))	('prostate cancer', 'Disease', (138, 153))
667664	28123601	Another study showed that AT-MSCs increase cell viability of prostate tumor cell lines LNCaP and LNCaP-Bic, but no effect was observed for Du145 or PC3.	('PC3', 'Gene', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('prostate tumor', 'Disease', (61, 75))	('AT-MSCs', 'Var', (26, 33))	('PC3', 'Gene', '3853', (148, 151))	('LNCaP', 'CellLine', 'CVCL:0395', (87, 92))	('prostate tumor', 'Phenotype', 'HP:0100787', (61, 75))	('increase', 'PosReg', (34, 42))	('prostate tumor', 'Disease', 'MESH:D011471', (61, 75))	('cell viability', 'CPA', (43, 57))	('LNCaP', 'CellLine', 'CVCL:0395', (97, 102))
667673	28123601	Co-injection of MSCs with U87MG promotes tumor growth in vivo and also induces a reduction in apoptotic cell death.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('U87MG', 'CellLine', 'CVCL:0022', (26, 31))	('reduction', 'NegReg', (81, 90))	('U87MG', 'Var', (26, 31))	('promotes', 'PosReg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('apoptotic cell death', 'CPA', (94, 114))
667678	28123601	AT-MSCs inhibit the growth of human melanoma cell lines (A375SM and A375P) by inducing apoptosis and altering cell-cycle distribution in vitro.	('human', 'Species', '9606', (30, 35))	('inhibit', 'NegReg', (8, 15))	('A375', 'CellLine', 'CVCL:0132', (57, 61))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('cell-cycle distribution', 'CPA', (110, 133))	('apoptosis', 'CPA', (87, 96))	('altering', 'Reg', (101, 109))	('A375', 'CellLine', 'CVCL:0132', (68, 72))	('growth', 'CPA', (20, 26))	('inducing', 'NegReg', (78, 86))	('A375P', 'Var', (68, 73))
667711	28123601	The depletion of CAFs leads to increased tumor invasion associated with decreased survival in transgenic mice with the ability to delete alphaSMA (+) myofibroblasts in pancreatic ductal adenocarcinoma; fewer myofibroblasts in these tumors also correlated with reduced survival in patients with invasive pancreatic adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('increased', 'PosReg', (31, 40))	('delete', 'Var', (130, 136))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (168, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('transgenic mice', 'Species', '10090', (94, 109))	('invasive pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (294, 328))	('decreased', 'NegReg', (72, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('pancreatic ductal adenocarcinoma', 'Disease', (168, 200))	('tumor', 'Disease', (232, 237))	('patients', 'Species', '9606', (280, 288))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (168, 200))	('invasive pancreatic adenocarcinoma', 'Disease', (294, 328))	('reduced', 'NegReg', (260, 267))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (303, 328))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('alphaSMA', 'MPA', (137, 145))	('survival', 'CPA', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('depletion', 'MPA', (4, 13))	('tumors', 'Disease', (232, 238))
667714	28123601	BM-MSCs have been shown to induce gastric cancer cell EMT and promote transwell and trans-endothelial migration in vitro, as well as remarkably increase tumor mass and liver metastasis in vivo.	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('increase tumor', 'Disease', (144, 158))	('induce', 'PosReg', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('gastric cancer', 'Disease', (34, 48))	('promote', 'PosReg', (62, 69))	('BM-MSCs', 'Var', (0, 7))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('trans-endothelial migration', 'CPA', (84, 111))	('increase tumor', 'Disease', 'MESH:D009369', (144, 158))	('liver metastasis', 'CPA', (168, 184))
667742	28123601	Fusion of BM-MSCs with SU3 glioma cells contributes to glioma neovascularization.	('glioma', 'Disease', (55, 61))	('glioma', 'Disease', (27, 33))	('Fusion', 'Var', (0, 6))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))
667748	28123601	The artificial fusion of UC-MSCs with esophageal cancer cell line EC9706 resulted in hybrids with decreased cell growth, increased apoptosis and suppressed tumorigenicity.	('esophageal cancer', 'Disease', (38, 55))	('cell growth', 'CPA', (108, 119))	('increased', 'PosReg', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('EC9706', 'CellLine', 'CVCL:E307', (66, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('hybrids', 'Var', (85, 92))	('suppressed', 'NegReg', (145, 155))	('apoptosis', 'CPA', (131, 140))	('decreased', 'NegReg', (98, 107))
667772	28123601	Direct co-cultures of human glioblastoma cell lines (8-MGBA, 42-MG-BA and U-118 MG) with AT-MSCs transfected with herpes simplex virus-thymidine kinase and the prodrug ganciclovir (TK-MSC/GCV) resulted in a substantial decrease in viability in vitro through the formation of gap junctions between MSCs and glioblastoma cells; however, the inability of breast adenocarcinoma cell line MCF7 and cervical epitheloid carcinoma cell line HeLa to form gap junctions with MSCs renders these cells refractory to TK-MSC/GCV-mediated cytotoxicity.	('glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (306, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (413, 422))	('cytotoxicity', 'Disease', (524, 536))	('herpes simplex', 'Phenotype', 'HP:0012302', (114, 128))	('transfected', 'Var', (97, 108))	('glioblastoma', 'Disease', (28, 40))	('inability of breast adenocarcinoma', 'Disease', 'MESH:D016388', (339, 373))	('epitheloid carcinoma', 'Disease', (402, 422))	('cytotoxicity', 'Disease', 'MESH:D064420', (524, 536))	('inability of breast adenocarcinoma', 'Disease', (339, 373))	('MCF7', 'CellLine', 'CVCL:0031', (384, 388))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (364, 373))	('glioblastoma', 'Disease', (306, 318))	('glioblastoma', 'Phenotype', 'HP:0012174', (306, 318))	('U-118', 'Var', (74, 79))	('human', 'Species', '9606', (22, 27))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (352, 373))	('epitheloid carcinoma', 'Disease', 'MESH:D002277', (402, 422))	('epitheloid carcinoma', 'Phenotype', 'HP:0031492', (402, 422))	('HeLa', 'CellLine', 'CVCL:0030', (433, 437))
667775	28123601	Despite constant doubt about the antitumor properties of MSCs, application of MSCs is a burgeoning strategy for cancer treatment in clinical settings Some studies reviewed here have shown that MSCs can promote the growth of tumors.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('MSCs', 'Var', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumor', 'Disease', (224, 229))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('promote', 'PosReg', (202, 209))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
667805	28123601	The inhibition rate of leukemia MSCs was significantly higher with the MSCs of umbilical cord blood than with the MSCs of normal BM.	('leukemia MSCs', 'Disease', 'MESH:D007938', (23, 36))	('leukemia MSCs', 'Disease', (23, 36))	('leukemia', 'Phenotype', 'HP:0001909', (23, 31))	('MSCs of umbilical cord blood', 'Var', (71, 99))	('inhibition', 'NegReg', (4, 14))	('higher', 'PosReg', (55, 61))
667809	28123601	Researchers in the same group reported that MSC1s are anti-tumorigenic while MSC2s are pro-tumorigenic in nature.	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (91, 96))	('MSC1s', 'Var', (44, 49))
667828	28103913	Although patients with a major response (defined by the presence of less than 10% of vital cells in the primary tumor) and ypN0 had a 5-year survival rate of 64%, the rate was only 18% in those with a minor response and ypN(+).	('patients', 'Species', '9606', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('ypN0', 'Var', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))
667860	28103913	Patients with any of TRG2/3, LVI(+) or PNI(+) were characterized as having poor primary tumor factors, whereas patients with either ypN(+) or ECI (+) were regarded as having poor lymph node factors.	('PNI(+', 'Var', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (111, 119))	('ECI', 'Chemical', '-', (142, 145))	('Patients', 'Species', '9606', (0, 8))	('TRG2', 'Gene', '7196', (21, 25))	('LVI(+', 'Var', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('TRG2', 'Gene', (21, 25))
667862	28103913	Using Cox regression model, we demonstrated that these factors have additional effect; which means, patients with 1, 2, and 3 poor factors had HR of 1.576, 1.728, and 3.130 compared to those without any poor factor in the overall survival analysis (p = 0.048).	('Cox', 'Gene', '1351', (6, 9))	('Cox', 'Gene', (6, 9))	('1.728', 'Var', (156, 161))	('patients', 'Species', '9606', (100, 108))
667885	28103913	The presence of ECI seems to have negative additive impact on DFS, regardless of the pN stage.	('presence', 'Var', (4, 12))	('negative', 'NegReg', (34, 42))	('ECI', 'Chemical', '-', (16, 19))	('DFS', 'MPA', (62, 65))
667919	27829391	Analysis of ESCC patient samples indicated that patients with high stromal Activin A expression had low epithelial ACVRIB, the Activin type I receptor.	('Activin A', 'Gene', (75, 84))	('Activin', 'Gene', (127, 134))	('Activin A', 'Gene', '29200', (75, 84))	('Activin', 'Gene', '83729', (75, 82))	('patient', 'Species', '9606', (17, 24))	('ACVRIB', 'Chemical', '-', (115, 121))	('patient', 'Species', '9606', (48, 55))	('Activin', 'Gene', '83729', (127, 134))	('low', 'NegReg', (100, 103))	('Activin', 'Gene', (75, 82))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))	('epithelial ACVRIB', 'MPA', (104, 121))
667931	27829391	In vivo knock-down of inhibin betaA in mice leads to incomplete development and defects in squamous tissue wound healing.	('inhibin', 'Gene', (22, 29))	('defects', 'NegReg', (80, 87))	('incomplete', 'NegReg', (53, 63))	('squamous tissue wound healing', 'CPA', (91, 120))	('knock-down', 'Var', (8, 18))	('mice', 'Species', '10090', (39, 43))
667948	27829391	Primary esophageal keratinocytes expressing dominant-negative mutants of E-cadherin and TbetaRII (ECdnT), established as previously described, were cultured in keratinocyte serum-free media (KSFM) supplemented with 40 mug/mL bovine pituitary extract, 1 ng/mL epidermal growth factor (EGF), and 1 % P/S (Gibco).	('rat', 'Species', '10116', (162, 165))	('EGF', 'Gene', (284, 287))	('mutants', 'Var', (62, 69))	('P', 'Chemical', 'MESH:D010758', (298, 299))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('EGF', 'Gene', '521832', (284, 287))	('epidermal growth factor', 'Gene', (259, 282))	('epidermal growth factor', 'Gene', '521832', (259, 282))	('rat', 'Species', '10116', (21, 24))	('E-cadherin and TbetaRII', 'Gene', '282637', (73, 96))	('bovine', 'Species', '9913', (225, 231))
668001	27829391	Similarly, A83-01 treatment, while increasing cell invasion in the ECdnT cultures with empty vector control, could not restore cell invasion in the Fibro-ActA cultures (Fig.	('cell invasion', 'CPA', (127, 140))	('cell invasion', 'CPA', (46, 59))	('increasing', 'PosReg', (35, 45))	('A83-01', 'Var', (11, 17))	('A83-01', 'Chemical', 'MESH:C507011', (11, 17))
668005	27829391	Laminin 5gamma2 was upregulated in the Fibro-ActA cultures treated with both nAb and A83-01, the only tested marker to do so (Fig.	('Laminin 5gamma2', 'Protein', (0, 15))	('nAb', 'Var', (77, 80))	('upregulated', 'PosReg', (20, 31))	('A83-01', 'Var', (85, 91))	('A83-01', 'Chemical', 'MESH:C507011', (85, 91))
668007	27829391	Epithelial cell proliferation, measured by Ki67, was inhibited with the addition of A83-01 to all cultures, but was unaltered in the presence of nAb (Fig.	('inhibited', 'NegReg', (53, 62))	('A83-01', 'Var', (84, 90))	('rat', 'Species', '10116', (23, 26))	('A83-01', 'Chemical', 'MESH:C507011', (84, 90))	('Epithelial cell proliferation', 'CPA', (0, 29))	('Ki67', 'Chemical', '-', (43, 47))
668029	27829391	Deposition of collagen IV, a common characteristic of cancer cells, was increased overall in TE-11 (Fig.	('TE-11', 'Var', (93, 98))	('increased', 'PosReg', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('Deposition of collagen IV', 'MPA', (0, 25))	('TE', 'Chemical', 'MESH:D013691', (93, 95))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
668051	27829391	ACVR2 mutations have been described to attenuate Activin A signaling in prostate cancer and microsatellite unstable colon cancer.	('microsatellite unstable colon cancer', 'Disease', 'MESH:D015179', (92, 128))	('prostate cancer', 'Disease', 'MESH:D011471', (72, 87))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('microsatellite unstable colon cancer', 'Disease', (92, 128))	('ACVR2', 'Gene', '92', (0, 5))	('prostate cancer', 'Phenotype', 'HP:0012125', (72, 87))	('Activin A', 'Gene', (49, 58))	('Activin A', 'Gene', '29200', (49, 58))	('prostate cancer', 'Disease', (72, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ACVR2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('attenuate', 'NegReg', (39, 48))	('mutations', 'Var', (6, 15))
668052	27829391	The mutations identified are similar to the well-characterized frameshift mutations in TGFBR2.	('TGFBR2', 'Gene', (87, 93))	('frameshift mutations', 'Var', (63, 83))	('TGFBR2', 'Gene', '7048', (87, 93))
668053	27829391	Inactivation of ACVRIB so far has only been identified in pancreatic cancer as a consequence of a somatic mutation, and homologous deletion is associated with an aggressive phenotype in pancreatic cancer.	('pancreatic cancer', 'Disease', (58, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('associated with', 'Reg', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ACVRIB', 'Gene', (16, 22))	('pancreatic cancer', 'Disease', (186, 203))	('ACVRIB', 'Chemical', '-', (16, 22))	('pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))	('homologous deletion', 'Var', (120, 139))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))	('Inactivation', 'Var', (0, 12))
668064	27829391	This inhibition is a consequence of intact Activin A signaling; however, loss of ACVRIB allows esophageal cancer cells, such as TE-11 cells, to escape Activin A-dependent regulation.	('Activin A', 'Gene', '29200', (43, 52))	('loss', 'Var', (73, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Activin A', 'Gene', '29200', (151, 160))	('Activin A', 'Gene', (151, 160))	('ACVRIB', 'Gene', (81, 87))	('TE', 'Chemical', 'MESH:D013691', (128, 130))	('ACVRIB', 'Chemical', '-', (81, 87))	('esophageal cancer', 'Disease', (95, 112))	('Activin A', 'Gene', (43, 52))
668093	27829391	Dysregulation of the Activin A pathway may be a way in which cancer cells can adapt to circumvent inhibitory environmental factors.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Dysregulation', 'Var', (0, 13))	('Activin A', 'Gene', '29200', (21, 30))	('Activin A', 'Gene', (21, 30))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
668126	21328345	In gender-combined analyses, added sugars were positively associated with risk of esophageal adenocarcinoma (HRQ5 vs. Q1: 1.62, 95% CI: 1.07-2.45; Ptrend = 0.01); added fructose was associated with risk of small intestine cancer (HRQ5 vs. Q1: 2.20, 95% CI: 1.16-4.16; Ptrend = 0.009); and all investigated sugars were associated with increased risk of pleural cancer.	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('added', 'Var', (163, 168))	('cancer', 'Disease', (222, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (82, 107))	('cancer', 'Disease', (360, 366))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('esophageal adenocarcinoma', 'Disease', (82, 107))	('pleural cancer', 'Disease', (352, 366))	('fructose', 'Chemical', 'MESH:D005632', (169, 177))	('pleural cancer', 'Disease', 'MESH:D010995', (352, 366))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('sugars', 'Chemical', 'MESH:D000073893', (306, 312))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (82, 107))	('small intestine cancer', 'Phenotype', 'HP:0100833', (206, 228))	('sugars', 'Chemical', 'MESH:D000073893', (35, 41))
668198	21328345	There was a statistically significant positive association between added sugars intake and risk of esophageal cancer.	('added sugars', 'Var', (67, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('esophageal cancer', 'Disease', (99, 116))	('sugars', 'Chemical', 'MESH:D000073893', (73, 79))
668244	21328345	In our cohort, education was strongly associated with added sugars intake, but less so with total sugars.	('associated', 'Reg', (38, 48))	('sugars', 'Chemical', 'MESH:D000073893', (60, 66))	('added sugars intake', 'MPA', (54, 73))	('education', 'Var', (15, 24))	('sugars', 'Chemical', 'MESH:D000073893', (98, 104))
668247	21328345	In women, total sugars, added sugars and added fructose intakes were positively associated with risk of leukemia, and high fructose intake was associated with increased risk of bladder cancer.	('sugars', 'Chemical', 'MESH:D000073893', (16, 22))	('bladder cancer', 'Disease', 'MESH:D001749', (177, 191))	('bladder cancer', 'Disease', (177, 191))	('sugars', 'Chemical', 'MESH:D000073893', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('high fructose', 'Var', (118, 131))	('leukemia', 'Disease', (104, 112))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('leukemia', 'Disease', 'MESH:D007938', (104, 112))	('women', 'Species', '9606', (3, 8))	('fructose', 'Chemical', 'MESH:D005632', (123, 131))	('fructose', 'Chemical', 'MESH:D005632', (47, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (177, 191))
668284	21328345	Although it may be theoretically possible that the measurement error could have inflated the risk estimates for some of the cancers for which we are seeing significant results, it is much more likely that measurement error attenuated their true risk estimates, which in reality are even stronger; whereas for the cancers with weaker true association with sugars, it may have attenuated the association towards null.	('sugars', 'Chemical', 'MESH:D000073893', (355, 361))	('cancers', 'Disease', (313, 320))	('cancers', 'Disease', 'MESH:D009369', (313, 320))	('attenuated', 'NegReg', (223, 233))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (313, 320))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('measurement error', 'Var', (205, 222))	('cancers', 'Disease', (124, 131))	('men', 'Species', '9606', (58, 61))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('men', 'Species', '9606', (212, 215))
668292	23136537	Severe acute toxicities, including leukopenia, stomatitis, and cheilitis, were evaluated according to 6 single nucleotide polymorphisms (SNPs) in the gene; the intronic SNPs of rs7635707 G/T, rs6787255 A/C, rs9812034 G/T, and rs9310738 C/T and the SNPs in the 3'-untranslated region (3'-UTR) of rs844107 C/T and rs1349265 G/A.	('rs844107 C/T', 'Var', (295, 307))	('leukopenia', 'Disease', 'MESH:D007970', (35, 45))	('rs7635707 G/T', 'Var', (177, 190))	('leukopenia', 'Phenotype', 'HP:0001882', (35, 45))	('leukopenia', 'Disease', (35, 45))	('stomatitis', 'Phenotype', 'HP:0010280', (47, 57))	('rs9310738', 'Mutation', 'rs9310738', (226, 235))	('rs9310738 C/T', 'Var', (226, 239))	('rs844107', 'Mutation', 'rs844107', (295, 303))	('rs1349265', 'Mutation', 'rs1349265', (312, 321))	('rs6787255', 'Mutation', 'rs6787255', (192, 201))	('acute toxicities', 'Disease', 'MESH:D000208', (7, 23))	('cheilitis', 'Disease', 'MESH:D002613', (63, 72))	('rs9812034 G/T', 'Var', (207, 220))	('rs9812034', 'Mutation', 'rs9812034', (207, 216))	('rs1349265 G/A', 'Var', (312, 325))	('rs7635707', 'Mutation', 'rs7635707', (177, 186))	('acute toxicities', 'Disease', (7, 23))	('cheilitis', 'Phenotype', 'HP:0100825', (63, 72))	('cheilitis', 'Disease', (63, 72))	('rs6787255 A/C', 'Var', (192, 205))	('stomatitis', 'Disease', 'MESH:D013280', (47, 57))	('stomatitis', 'Disease', (47, 57))
668295	23136537	Frequency of haplotype of the 4 intronic SNPs reached approximately 97% with the 2 major haplotypes G-A-G-C (73.4%) and T-C-T-T (23.5%).	('T-C-T-T', 'Disease', (120, 127))	('G-A-G-C', 'Var', (100, 107))	('T-C-T-T', 'Disease', 'MESH:D001260', (120, 127))
668305	23136537	Because of the narrow therapeutic index of chemotherapeutic agents, pharmacogenomics has drawn increasing attention in the field of tailored medicine, ranging from gene expression profiles in tumor tissues to genetic signatures, including single nucleotide polymorphisms (SNPs).	('single nucleotide polymorphisms', 'Var', (239, 270))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
668306	23136537	The application of SNP genotyping to anticancer therapy is an attractive approach, and serious toxicities have been explained by SNPs in well-known drug-metabolizing enzyme- or drug-transporter-related genes.	('toxicities', 'Disease', 'MESH:D064420', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('SNPs', 'Var', (129, 133))	('explained', 'Reg', (116, 125))	('toxicities', 'Disease', (95, 105))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
668329	23136537	To date, 4 TRbeta mRNA variants have been identified, and all encode a common protein and have a common non-coding exon 2 (Fig.	('TRbeta', 'Gene', '6957', (11, 17))	('variants', 'Var', (23, 31))	('encode', 'Reg', (62, 68))	('protein', 'Protein', (78, 85))	('TRbeta', 'Gene', (11, 17))
668330	23136537	2), which led to the hypothesis that SNPs in introns adjacent to exon 2 may influence TRbeta mRNA and protein expression.	('TRbeta', 'Gene', (86, 92))	('TRbeta', 'Gene', '6957', (86, 92))	('SNPs', 'Var', (37, 41))	('influence', 'Reg', (76, 85))
668332	23136537	Four SNPs, reference SNP (rs) 7635707, rs6787255, rs9812034, and rs9310738, met the selection criteria described above.	('rs6787255', 'Mutation', 'rs6787255', (39, 48))	('rs9812034', 'Var', (50, 59))	('rs9310738', 'Var', (65, 74))	('rs6787255', 'Var', (39, 48))	('rs9812034', 'Mutation', 'rs9812034', (50, 59))	('rs9310738', 'Mutation', 'rs9310738', (65, 74))
668333	23136537	The SNPs rs7635707 and rs6787255 are located in intron 1, and rs9812034 and rs9310738 in intron 2.	('rs9310738', 'Mutation', 'rs9310738', (76, 85))	('rs6787255', 'Mutation', 'rs6787255', (23, 32))	('rs7635707', 'Var', (9, 18))	('rs6787255', 'Var', (23, 32))	('rs9812034', 'Mutation', 'rs9812034', (62, 71))	('rs9310738', 'Var', (76, 85))	('rs9812034', 'Var', (62, 71))	('rs7635707', 'Mutation', 'rs7635707', (9, 18))
668334	23136537	Considering a possible role in TRbeta mRNA stability, additional candidate SNPs in the 3'-untranslated region (3'-UTR), rs844107 and rs1349265, were also selected.	('TRbeta', 'Gene', '6957', (31, 37))	('rs1349265', 'Var', (133, 142))	('rs844107', 'Mutation', 'rs844107', (120, 128))	('rs1349265', 'Mutation', 'rs1349265', (133, 142))	('rs844107', 'Var', (120, 128))	('TRbeta', 'Gene', (31, 37))
668335	23136537	Haplotype frequencies of the SNPs of rs7635707 G/T, rs6787255 A/C, rs9812034 G/T and rs9310738 C/T were estimated.	('rs9812034 G/T', 'Var', (67, 80))	('rs7635707', 'Mutation', 'rs7635707', (37, 46))	('rs9310738 C/T', 'Var', (85, 98))	('rs9310738', 'Mutation', 'rs9310738', (85, 94))	('rs6787255', 'Mutation', 'rs6787255', (52, 61))	('rs7635707 G/T', 'Var', (37, 50))	('rs6787255 A/C', 'Var', (52, 65))	('rs9812034', 'Mutation', 'rs9812034', (67, 76))
668340	23136537	The genotype frequencies of wild-type homozygotes, heterozygotes, and homozygote variants of the SNPs rs7635707, rs6787255, rs9812034, and rs9310738 were 29/49, 16/49, and 4/49, respectively.	('rs9812034', 'Var', (124, 133))	('rs9310738', 'Mutation', 'rs9310738', (139, 148))	('rs6787255', 'Mutation', 'rs6787255', (113, 122))	('rs7635707', 'Mutation', 'rs7635707', (102, 111))	('rs6787255', 'Var', (113, 122))	('rs7635707', 'Var', (102, 111))	('rs9812034', 'Mutation', 'rs9812034', (124, 133))	('rs9310738', 'Var', (139, 148))	('SNPs', 'Gene', (97, 101))
668341	23136537	Frequencies of the CC, CT, and TT genotypes and C allele of the SNP rs844107 were 21/49, 19/49, 9/49, and 61/98, respectively.	('SNP', 'Gene', (64, 67))	('rs844107', 'Var', (68, 76))	('rs844107', 'Mutation', 'rs844107', (68, 76))
668344	23136537	With the major 2 haplotypes, the frequency reached approximately 97%: G-A-G-C (73.4%) and T-C-T-T (23.5%).	('T-C-T-T', 'Disease', (90, 97))	('T-C-T-T', 'Disease', 'MESH:D001260', (90, 97))	('G-A-G-C', 'Var', (70, 77))
668345	23136537	T-A-G-C (1.0%), G-C-G-C (1.0%), and G-A-T-T (1.0%) were rare, and other haplotypes were not statistically inferred with a frequency >0.1% in the present population.	('A-T-T', 'Disease', 'MESH:D001260', (38, 43))	('T-A-G-C', 'Var', (0, 7))	('G-C-G-C', 'Var', (16, 23))	('A-T-T', 'Disease', (38, 43))	('T-A-G-C', 'Chemical', '-', (0, 7))	('G-C-G-C', 'Chemical', '-', (16, 23))
668349	23136537	Subjects with the GG genotype of rs7635707 SNP, the AA genotype of rs6787255, the GG genotype of rs9812034, and the CC genotype of rs9310738 were at a lower risk of developing severe acute leukopenia.	('rs6787255', 'Mutation', 'rs6787255', (67, 76))	('rs7635707 SNP', 'Var', (33, 46))	('rs7635707', 'Mutation', 'rs7635707', (33, 42))	('acute leukopenia', 'Disease', 'MESH:D007970', (183, 199))	('acute leukopenia', 'Phenotype', 'HP:0002488', (183, 199))	('leukopenia', 'Phenotype', 'HP:0001882', (189, 199))	('rs9812034', 'Mutation', 'rs9812034', (97, 106))	('rs6787255', 'Var', (67, 76))	('rs9310738', 'Var', (131, 140))	('acute leukopenia', 'Disease', (183, 199))	('rs9812034', 'Var', (97, 106))	('rs9310738', 'Mutation', 'rs9310738', (131, 140))
668351	23136537	Analysis of the relationship between leukopenia and haplotypes revealed a lower rate of leukopenia in subjects with the G-A-G-C haplotype.	('G-A-G-C', 'Var', (120, 127))	('leukopenia', 'Phenotype', 'HP:0001882', (37, 47))	('leukopenia', 'Disease', (88, 98))	('leukopenia', 'Disease', (37, 47))	('leukopenia', 'Disease', 'MESH:D007970', (88, 98))	('leukopenia', 'Disease', 'MESH:D007970', (37, 47))	('lower', 'NegReg', (74, 79))	('leukopenia', 'Phenotype', 'HP:0001882', (88, 98))
668355	23136537	In the current study, we demonstrated that ESCC patients with the GG genotype of the THRB rs7635707 SNP, the AA genotype of rs6787255, the GG genotype of rs9812034, and the CC genotype of rs9310738 have a lower probability of severe acute leukopenia than those with the other genotypes.	('THRB', 'Gene', '7068', (85, 89))	('THRB', 'Gene', (85, 89))	('rs9812034', 'Mutation', 'rs9812034', (154, 163))	('rs6787255', 'Var', (124, 133))	('rs9310738', 'Var', (188, 197))	('ESCC', 'Disease', (43, 47))	('acute leukopenia', 'Disease', 'MESH:D007970', (233, 249))	('leukopenia', 'Phenotype', 'HP:0001882', (239, 249))	('acute leukopenia', 'Disease', (233, 249))	('rs9812034', 'Var', (154, 163))	('rs9310738', 'Mutation', 'rs9310738', (188, 197))	('rs6787255', 'Mutation', 'rs6787255', (124, 133))	('rs7635707 SNP', 'Var', (90, 103))	('patients', 'Species', '9606', (48, 56))	('rs7635707', 'Mutation', 'rs7635707', (90, 99))	('acute leukopenia', 'Phenotype', 'HP:0002488', (233, 249))
668356	23136537	Germline mutations in THRB have been identified in association with resistance to thyroid hormone, which is quite a rare disease.	('Germline mutations', 'Var', (0, 18))	('association', 'Reg', (51, 62))	('THRB', 'Gene', (22, 26))	('THRB', 'Gene', '7068', (22, 26))	('identified', 'Reg', (37, 47))	('resistance to thyroid hormone', 'Phenotype', 'HP:0002930', (68, 97))	('resistance to thyroid hormone', 'MPA', (68, 97))
668357	23136537	Such patients harbor missense mutations or defects that correspond to amino acid alterations in the ligand-binding domain.	('amino acid alterations', 'Var', (70, 92))	('patients', 'Species', '9606', (5, 13))	('ligand-binding domain', 'MPA', (100, 121))	('missense mutations', 'Var', (21, 39))	('defects', 'Var', (43, 50))
668358	23136537	Somatic mutations and aberrant expression have been detected in cancers of different organs, including breast, thyroid, kidney, lung, liver, and colon, suggesting a suppressive role in carcinogenesis and metastasis.	('aberrant', 'Var', (22, 30))	('kidney', 'Disease', (120, 126))	('lung', 'Disease', (128, 132))	('detected', 'Reg', (52, 60))	('liver', 'Disease', (134, 139))	('breast', 'Disease', (103, 109))	('carcinogenesis', 'Disease', 'MESH:D063646', (185, 199))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('carcinogenesis', 'Disease', (185, 199))	('thyroid', 'Disease', (111, 118))	('cancers', 'Disease', (64, 71))	('expression', 'MPA', (31, 41))	('colon', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
668360	23136537	The present study is the first to demonstrate that the intronic SNPs in THRB could have a clinical impact.	('THRB', 'Gene', '7068', (72, 76))	('THRB', 'Gene', (72, 76))	('intronic SNPs', 'Var', (55, 68))
668361	23136537	Given the burden of cost and time, analysis of only one of the 4 intronic SNPs can be a strong predictor of severe acute leukopenia.	('acute leukopenia', 'Disease', (115, 131))	('acute leukopenia', 'Disease', 'MESH:D007970', (115, 131))	('acute leukopenia', 'Phenotype', 'HP:0002488', (115, 131))	('analysis', 'Var', (35, 43))	('leukopenia', 'Phenotype', 'HP:0001882', (121, 131))
668363	23136537	These SNPs were located across exon 2, which is common among the THRB transcript variants.	('THRB', 'Gene', '7068', (65, 69))	('THRB', 'Gene', (65, 69))	('variants', 'Var', (81, 89))
668366	23136537	An intron control region regulates TRbeta2 expression in the central nervous system, and 3'- and 5'-UTR variants regulate TRbeta1 expression in renal cell cancer, but this region is not mentioned in these reports.	('renal cell cancer', 'Disease', (144, 161))	('beta2', 'Gene', (37, 42))	('expression', 'MPA', (130, 140))	('TRbeta', 'Gene', (35, 41))	('regulate', 'Reg', (113, 121))	('beta2', 'Gene', '10242', (37, 42))	('TRbeta', 'Gene', '6957', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('renal cell cancer', 'Phenotype', 'HP:0005584', (144, 161))	('variants', 'Var', (104, 112))	('TRbeta', 'Gene', (122, 128))	('regulates', 'Reg', (25, 34))	('TRbeta', 'Gene', '6957', (122, 128))	('renal cell cancer', 'Disease', 'MESH:C538614', (144, 161))
668374	23136537	PI3K also plays a role in TRbeta-regulated cellular survival and proliferation.	('proliferation', 'CPA', (65, 78))	('PI3K', 'Var', (0, 4))	('TRbeta', 'Gene', (26, 32))	('TRbeta', 'Gene', '6957', (26, 32))	('cellular survival', 'CPA', (43, 60))
668375	23136537	Finally, aberrant TRbeta expression in liver and kidney may influence the pharmacokinetics of 5-FU and CDDP.	('TRbeta', 'Gene', (18, 24))	('pharmacokinetics of 5-FU', 'MPA', (74, 98))	('CDDP', 'Chemical', 'MESH:D002945', (103, 107))	('influence', 'Reg', (60, 69))	('TRbeta', 'Gene', '6957', (18, 24))	('aberrant', 'Var', (9, 17))	('5-FU', 'Chemical', 'MESH:D005472', (94, 98))	('CDDP', 'MPA', (103, 107))
668381	23136537	Our pilot study shows the potential utility of THRB polymorphisms in ESCC patients receiving a definitive 5-FU/CDDP-based CRT, suggesting that specific SNPs in THRB provide pre-treatment warning of severe acute myelotoxicity.	('SNPs', 'Var', (152, 156))	('THRB', 'Gene', (47, 51))	('acute myelotoxicity', 'Disease', 'MESH:D059787', (205, 224))	('5-FU', 'Chemical', 'MESH:D005472', (106, 110))	('patients', 'Species', '9606', (74, 82))	('acute myelotoxicity', 'Disease', (205, 224))	('CDDP', 'Chemical', 'MESH:D002945', (111, 115))	('acute myelotoxicity', 'Phenotype', 'HP:0004808', (205, 224))	('THRB', 'Gene', '7068', (160, 164))	('ESCC', 'Disease', (69, 73))	('THRB', 'Gene', (160, 164))	('THRB', 'Gene', '7068', (47, 51))
668384	33246288	Evaluation of 99mTc-CN5DG as a broad-spectrum SPECT probe for tumor imaging 99mTc-CN5DG exhibited high tumor uptake, tumor/muscle and tumor/blood ratios in different kinds of tumor models.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('99mTc-CN5DG', 'Var', (76, 87))	('99mTc-CN5DG', 'Chemical', '-', (14, 25))	('99mTc-CN5DG', 'Chemical', '-', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('high tumor', 'Disease', (98, 108))	('high tumor', 'Disease', 'MESH:D009369', (98, 108))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
668385	33246288	99mTc-CN5DG was stable in blood and tumors in vivo and rapidly cleared from blood.	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('99mTc-CN5DG', 'Var', (0, 11))	('99mTc-CN5DG', 'Chemical', '-', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
668389	33246288	The biodistribution data showed that 99mTc-CN5DG had a similar biodistribution pattern in four tumor models at 2 h post-injection with high accumulation in tumors and kidneys.	('99mTc-CN5DG', 'Chemical', '-', (37, 48))	('99mTc-CN5DG', 'Var', (37, 48))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('accumulation', 'MPA', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (156, 161))	('tumors', 'Disease', (156, 162))	('tumor', 'Disease', (95, 100))
668390	33246288	The tumor/muscle ratios (from 4.08 +- 0.42 to 9.63 +- 3.53) and tumor/blood ratios (from 17.18 +- 7.40 to 53.17 +- 16.16) of 99mTc-CN5DG in four tumor models were high.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('99mTc-CN5DG', 'Var', (125, 136))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('99mTc-CN5DG', 'Chemical', '-', (125, 136))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
668394	33246288	All of the above results demonstrated that 99mTc-CN5DG could be a broad-spectrum SPECT probe for tumor imaging and its further clinical application is warranted.	('99mTc-CN5DG', 'Chemical', '-', (43, 54))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('99mTc-CN5DG', 'Var', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))
668403	33246288	Preliminary studies in A549 tumor xenografts demonstrated that 99mTc-CN5DG would be a powerful tool as a SPECT probe for tumor detection.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('99mTc-CN5DG', 'Var', (63, 74))	('tumor', 'Disease', (121, 126))	('99mTc-CN5DG', 'Chemical', '-', (63, 74))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
668433	33246288	The tumor/muscle ratios in U87 MG, HCT-116, PANC-1 and TE-1 were 4.02 +- 0.42, 4.53 +- 0.54, 9.63 +- 3.53 and 9.35 +- 3.38, respectively.	('tumor', 'Disease', (4, 9))	('PANC-1', 'CellLine', 'CVCL:0480', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('U87 MG', 'CellLine', 'CVCL:0022', (27, 33))	('U87 MG', 'Var', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('HCT-116', 'CellLine', 'CVCL:0291', (35, 42))
668435	33246288	The high tumor/blood ratios in all four tumor models indicated that 99mTc-CN5DG has low blood uptake.	('99mTc-CN5DG', 'Chemical', '-', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('blood uptake', 'MPA', (88, 100))	('high tumor', 'Disease', 'MESH:D009369', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('high tumor', 'Disease', (4, 14))	('99mTc-CN5DG', 'Var', (68, 79))
668436	33246288	Taken together, these results demonstrated that 99mTc-CN5DG had a significant uptake in a variety of tumors and would be more suitable for the detection of PANC-1 and TE-1 tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('TE-1 tumors', 'Disease', (167, 178))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('TE-1 tumors', 'Disease', 'MESH:D009369', (167, 178))	('PANC-1', 'CellLine', 'CVCL:0480', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('PANC-1', 'Disease', (156, 162))	('uptake', 'MPA', (78, 84))	('99mTc-CN5DG', 'Var', (48, 59))	('99mTc-CN5DG', 'Chemical', '-', (48, 59))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
668439	33246288	The ROI ratios of the tumor sites versus corresponding non-tumor sites for U87 MG, HCT-116, PANC-1 and TE-1 were 3.09 +- 0.19, 4.73 +- 0.15, 5.51 +- 0.79 and 6.01 +- 1.37, respectively.	('HCT-116', 'CellLine', 'CVCL:0291', (83, 90))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('PANC-1', 'CellLine', 'CVCL:0480', (92, 98))	('U87 MG', 'Var', (75, 81))	('U87 MG', 'CellLine', 'CVCL:0022', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
668440	33246288	These results were in consistence with the biodistribution data and verified that 99mTc-CN5DG holds potential for the diagnosis of glioma, colon cancer, pancreatic cancer and esophageal cancer.	('cancer', 'Disease', (145, 151))	('glioma', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('colon cancer', 'Disease', 'MESH:D015179', (139, 151))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('99mTc-CN5DG', 'Var', (82, 93))	('99mTc-CN5DG', 'Chemical', '-', (82, 93))	('colon cancer', 'Disease', (139, 151))	('cancer', 'Disease', (164, 170))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))	('cancer', 'Disease', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('pancreatic cancer', 'Disease', (153, 170))	('colon cancer', 'Phenotype', 'HP:0003003', (139, 151))
668448	33246288	Combined with our previous studies, we concluded that 99mTc-CN5DG was transported into tumor cells through glucose transporters and was not further metabolized in tumors.	('99mTc-CN5DG', 'Chemical', '-', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('glucose', 'Chemical', 'MESH:D005947', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Disease', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('glucose transporters', 'MPA', (107, 127))	('99mTc-CN5DG', 'Var', (54, 65))
668451	33246288	These data suggested that 99mTc-CN5DG had a fast clearance rate in blood in vivo.	('99mTc-CN5DG', 'Chemical', '-', (26, 37))	('clearance', 'MPA', (49, 58))	('99mTc-CN5DG', 'Var', (26, 37))
668454	33246288	In our previous studies, 99mTc-CN5DG was evaluated in nude mice bearing A549 tumor and would be a potential agent for tumor imaging.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('99mTc-CN5DG', 'Var', (25, 36))	('99mTc-CN5DG', 'Chemical', '-', (25, 36))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
668461	33246288	In our previous biodistribution studies in A549 tumor bearing mice, 99mTc-CN5DG had the highest uptake in tumors at 30 min post-injection and the tumor/muscle ratio was high at 60 min post-injection, but the uptakes in blood and other tissues (such as heart, stomach) were also high at 60 min.	('99mTc-CN5DG', 'Chemical', '-', (68, 79))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('uptake', 'MPA', (96, 102))	('A549', 'CellLine', 'CVCL:0023', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (106, 111))	('99mTc-CN5DG', 'Var', (68, 79))
668464	33246288	The biodistribution data in four tumor models revealed that 99mTc-CN5DG had a moderate tumor uptake (from 0.42 +- 0.07%ID/g to 1.24 +- 0.28%ID/g) and high tumor/muscle (from 4.08+- 0.42 to 9.63 +- 3.53), tumor/blood ratios (from 17.18 +- 7.40 to 53.17 +- 16.16).	('99mTc-CN5DG', 'Var', (60, 71))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('99mTc-CN5DG', 'Chemical', '-', (60, 71))	('high tumor', 'Disease', 'MESH:D009369', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('high tumor', 'Disease', (150, 160))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
668466	33246288	The uptake of 99mTc-CN5DG in U87 MG tumor was significantly lower than that in other three kinds of tumors, possibly because the amounts of Gluts that transport the tracer into U87 MG tumor cells are lower than those on the other three tumor cell lines.	('U87 MG', 'CellLine', 'CVCL:0022', (29, 35))	('MG tumor', 'Disease', (33, 41))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('99mTc-CN5DG', 'Var', (14, 25))	('99mTc-CN5DG', 'Chemical', '-', (14, 25))	('uptake', 'MPA', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (36, 41))	('lower', 'NegReg', (60, 65))	('MG tumor', 'Disease', 'MESH:D000080343', (33, 41))	('MG tumor', 'Disease', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('U87 MG', 'CellLine', 'CVCL:0022', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumors', 'Disease', (100, 106))	('MG tumor', 'Disease', 'MESH:D000080343', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumor', 'Disease', (236, 241))
668467	33246288	The SPECT/CT images of 99mTc-CN5DG verified its broad-spectrum application in U87 MG, HCT-116, PANC-1 and TE-1 tumor models.	('99mTc-CN5DG', 'Chemical', '-', (23, 34))	('99mTc-CN5DG', 'Var', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TE-1 tumor', 'Disease', (106, 116))	('U87 MG', 'CellLine', 'CVCL:0022', (78, 84))	('PANC-1', 'CellLine', 'CVCL:0480', (95, 101))	('TE-1 tumor', 'Disease', 'MESH:D009369', (106, 116))	('HCT-116', 'CellLine', 'CVCL:0291', (86, 93))
668468	33246288	The ROIs (regions of interest drawn from SPECT images) ratios of the tumor sites versus corresponding non-tumor sites for U87 MG, HCT-116, PANC-1 and TE-1 were 3.09 +- 0.19, 4.73 +- 0.15, 5.51 +- 0.79 and 6.01 +- 1.37, respectively.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('PANC-1', 'CellLine', 'CVCL:0480', (139, 145))	('tumor', 'Disease', (69, 74))	('U87 MG', 'Var', (122, 128))	('U87 MG', 'CellLine', 'CVCL:0022', (122, 128))	('HCT-116', 'CellLine', 'CVCL:0291', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('HCT-116', 'Gene', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (106, 111))
668474	33246288	These results warranted the early tumor detection ability of 99mTc-CN5DG in other three kinds of tumor models (HCT-116, PANC-1 and TE-1).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (34, 39))	('HCT-116', 'CellLine', 'CVCL:0291', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('PANC-1', 'CellLine', 'CVCL:0480', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('99mTc-CN5DG', 'Var', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('99mTc-CN5DG', 'Chemical', '-', (61, 72))
668475	33246288	When compared to [18F]FDG, 99mTc-CN5DG has very low physiological uptake in the brain (0.02%ID/g).	('physiological uptake', 'MPA', (52, 72))	('FDG', 'Chemical', 'MESH:D019788', (22, 25))	('99mTc-CN5DG', 'Var', (27, 38))	('99mTc-CN5DG', 'Chemical', '-', (27, 38))	('low', 'NegReg', (48, 51))
668479	33246288	As a result, the tumor/brain ratio of 99mTc-CN5DG in U87 MG tumor bearing mice was high (19.00 +- 0.71).	('MG tumor', 'Disease', (57, 65))	('tumor', 'Disease', (17, 22))	('U87 MG', 'CellLine', 'CVCL:0022', (53, 59))	('99mTc-CN5DG', 'Var', (38, 49))	('99mTc-CN5DG', 'Chemical', '-', (38, 49))	('MG tumor', 'Disease', 'MESH:D000080343', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
668482	33246288	In this study, 99mTc-CN5DG was also found to be stable in blood and had no other metabolite in A549 tumors, suggesting it exhibited high stability in vivo.	('99mTc-CN5DG', 'Chemical', '-', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('99mTc-CN5DG', 'Var', (15, 26))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
668483	33246288	The significant tumor uptake, fast blood clearance and good safety of 99mTc-CN5DG warranted its further clinical application for cancer diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('99mTc-CN5DG', 'Var', (70, 81))	('99mTc-CN5DG', 'Chemical', '-', (70, 81))	('tumor', 'Disease', (16, 21))	('blood clearance', 'CPA', (35, 50))
668484	33246288	In this study, 99mTc-CN5DG exhibited moderate tumor uptake, tumor/muscle and tumor/blood ratios in U87 MG, HCT-116, PANC-1 and TE-1 tumor models.	('99mTc-CN5DG', 'Chemical', '-', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', (132, 137))	('TE-1 tumor', 'Disease', 'MESH:D009369', (127, 137))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('TE-1 tumor', 'Disease', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('U87 MG', 'CellLine', 'CVCL:0022', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('HCT-116', 'CellLine', 'CVCL:0291', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('PANC-1', 'CellLine', 'CVCL:0480', (116, 122))	('tumor', 'Disease', (77, 82))	('99mTc-CN5DG', 'Var', (15, 26))
668485	33246288	Moreover, 99mTc-CN5DG was stable in blood and tumors in vivo and rapidly cleared from blood.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('99mTc-CN5DG', 'Var', (10, 21))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('99mTc-CN5DG', 'Chemical', '-', (10, 21))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
668486	33246288	These findings verified 99mTc-CN5DG could be used as a promising broad-spectrum tumor imaging agent and had potential for clinical translation.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('99mTc-CN5DG', 'Var', (24, 35))	('99mTc-CN5DG', 'Chemical', '-', (24, 35))	('tumor', 'Disease', (80, 85))
668514	31485658	All primary antibodies, including those against E-cadherin (3195), beta-catenin (8480), vimentin (5741), Twist1 (46702) and GAPDH (5174) were purchased from Cell Signaling Technology, Inc.	('46702', 'Var', (113, 118))	('5741', 'Var', (98, 102))	('Twist1', 'Gene', '7291', (105, 111))	('vimentin', 'Gene', '7431', (88, 96))	('GAPDH', 'Gene', '2597', (124, 129))	('GAPDH', 'Gene', (124, 129))	('8480', 'Var', (81, 85))	('Twist1', 'Gene', (105, 111))	('5174', 'Var', (131, 135))	('E-cadherin', 'Gene', (48, 58))	('vimentin', 'Gene', (88, 96))	('beta-catenin', 'Gene', (67, 79))	('E-cadherin', 'Gene', '999', (48, 58))	('beta-catenin', 'Gene', '1499', (67, 79))
668574	31485658	Accumulating evidence has indicated that miRNAs participate in the progression of several types of cancer by targeting multiple genes involved in cancer progression and metastasis, and the aberrant expression of miRNAs contributes to the pathogenesis of malignancies in humans.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('aberrant', 'Var', (189, 197))	('malignancies', 'Disease', 'MESH:D009369', (254, 266))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('contributes', 'Reg', (219, 230))	('humans', 'Species', '9606', (270, 276))	('cancer', 'Disease', (99, 105))	('miRNAs', 'Gene', (212, 218))	('malignancies', 'Disease', (254, 266))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('expression', 'MPA', (198, 208))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
668601	31485658	In conclusion, the results from the present study demonstrate that miR-212 facilitates ESCC cell migration and invasion rather than proliferation, and berberine is a potential therapeutic drug against metastasis of ESCC in patients with high miR-212 expression.	('miR-212', 'Gene', (242, 249))	('miR-212', 'Gene', (67, 74))	('ESCC', 'Disease', (215, 219))	('patients', 'Species', '9606', (223, 231))	('ESCC', 'Disease', 'MESH:C562729', (87, 91))	('metastasis of ESCC', 'Disease', 'MESH:C562729', (201, 219))	('metastasis of ESCC', 'Disease', (201, 219))	('ESCC', 'Disease', (87, 91))	('ESCC', 'Disease', 'MESH:C562729', (215, 219))	('berberine', 'Chemical', 'MESH:D001599', (151, 160))	('miR-212', 'Gene', '406994', (242, 249))	('high', 'Var', (237, 241))	('miR-212', 'Gene', '406994', (67, 74))	('invasion', 'CPA', (111, 119))	('facilitates', 'PosReg', (75, 86))
668612	29587347	The most recent developments, such as dominant-negative survivin mutants, RNA interference, anti-sense oligonucleotides, small-molecule inhibitors, and peptide-based immunotherapy, seem to be helpful for effectively downregulating survivin expression and reducing tumor growth potential, increasing the apoptotic rate, and sensitizing tumor cells to chemo- and radiotherapy.	('reducing', 'NegReg', (255, 263))	('RNA interference', 'MPA', (74, 90))	('survivin', 'Gene', (231, 239))	('survivin', 'Gene', '11799', (231, 239))	('tumor', 'Disease', (264, 269))	('survivin', 'Gene', (56, 64))	('expression', 'MPA', (240, 250))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', (335, 340))	('survivin', 'Gene', '11799', (56, 64))	('mutants', 'Var', (65, 72))	('apoptotic rate', 'CPA', (303, 317))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('oligonucleotides', 'Chemical', 'MESH:D009841', (103, 119))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('sensitizing', 'Reg', (323, 334))	('downregulating', 'NegReg', (216, 230))	('increasing', 'PosReg', (288, 298))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))
668632	29587347	These alterations promote progression from normal epithelial cells to clinically evident cancerous lesions capable of producing metastases.	('alterations', 'Var', (6, 17))	('metastases', 'Disease', (128, 138))	('progression', 'CPA', (26, 37))	('cancerous lesions', 'Disease', (89, 106))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancerous lesions', 'Disease', 'MESH:D009062', (89, 106))
668634	29587347	Many molecular markers have been discovered in SCCs and several important similarities have been found among the major groups of SCCs, including abnormalities in cell cycle regulatory proteins (p53 family and Ki-67) and signal transduction proteins (EGFR).	('SCC', 'Gene', '6317', (129, 132))	('SCCs', 'Phenotype', 'HP:0002860', (47, 51))	('SCC', 'Gene', '6317', (47, 50))	('abnormalities', 'Var', (145, 158))	('abnormalities in cell cycle', 'Phenotype', 'HP:0011018', (145, 172))	('SCC', 'Gene', (47, 50))	('cell cycle', 'CPA', (162, 172))	('p53', 'Gene', (194, 197))	('p53', 'Gene', '7157', (194, 197))	('EGFR', 'Gene', '1956', (250, 254))	('SCC', 'Gene', (129, 132))	('Ki-67', 'Protein', (209, 214))	('EGFR', 'Gene', (250, 254))	('SCCs', 'Phenotype', 'HP:0002860', (129, 133))
668637	29587347	Mutations in p53 is a critical step in the development on non-melanoma skin cancer and is also commonly observed in HNSCC, esophageal cancer, and NSCLC.	('esophageal cancer', 'Disease', (123, 140))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('non-melanoma skin cancer', 'Disease', (58, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('NSCLC', 'Disease', (146, 151))	('SCC', 'Gene', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (116, 121))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (58, 82))	('skin cancer', 'Phenotype', 'HP:0008069', (71, 82))	('p53', 'Gene', (13, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('SCC', 'Gene', '6317', (118, 121))	('p53', 'Gene', '7157', (13, 16))	('observed', 'Reg', (104, 112))
668647	29587347	Any alteration in this sophisticated molecular mechanism can cause abnormal inhibition of cell death and tumorigenesis, as well as an increase in chemoresistance.	('inhibition', 'NegReg', (76, 86))	('tumor', 'Disease', (105, 110))	('chemoresistance', 'CPA', (146, 161))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('alteration', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('increase', 'PosReg', (134, 142))	('cell death', 'CPA', (90, 100))
668648	29587347	Almost 25 years ago, a protein family named inhibitor of apoptosis (IAP) proteins was discovered that encodes a group of proteins such as X-linked inhibitor of apoptosis (XIAP), c-IAP, and survivin.	('survivin', 'Gene', (189, 197))	('X-linked inhibitor of apoptosis', 'Gene', '331', (138, 169))	('XIAP', 'Gene', (171, 175))	('survivin', 'Gene', '11799', (189, 197))	('X-linked inhibitor of apoptosis', 'Gene', (138, 169))	('XIAP', 'Gene', '331', (171, 175))	('c-IAP', 'Var', (178, 183))
668660	29587347	It is still unclear whether alternative splicing variants of survivin are the consequence of tumor adaptation used to support their proliferation and avoid detection by the immune system, and further investigations are needed.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('survivin', 'Gene', '11799', (61, 69))	('tumor', 'Disease', (93, 98))	('alternative splicing variants', 'Var', (28, 57))	('survivin', 'Gene', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
668684	29587347	Interference with survivin functions induces programmed cell death and cell division defects, suggesting a dual role of this protein in apoptosis control and mitotic cell division.	('survivin', 'Gene', (18, 26))	('survivin', 'Gene', '11799', (18, 26))	('Interference', 'Var', (0, 12))	('programmed cell death', 'CPA', (45, 66))	('cell division defects', 'CPA', (71, 92))
668703	29587347	The idea that prompted research in anticancer gene therapy is that this approach has several appealing aspects, particularly in those tumors with specific genetic alterations in which conventional treatment modalities have been largely unsuccessful.	('alterations', 'Var', (163, 174))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
668704	29587347	Among the gene therapy approaches targeting survivin, plasmids or viral vectors have been successfully used to deliver dominant-negative survivin mutants to tumor cells.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('mutants', 'Var', (146, 153))	('survivin', 'Gene', '11799', (44, 52))	('survivin', 'Gene', '11799', (137, 145))	('survivin', 'Gene', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('survivin', 'Gene', (137, 145))
668705	29587347	first demonstrated that transfecting a model keratinocyte cell line, HaCat cells, with a green fluorescent protein-conjugated survivin dominant negative mutant carrying a cysteine 84/alanine (Cys84Ala) mutation in the survivin baculovirus IAP repeat domain resulted in spontaneous apoptosis with a five-fold increase in the sub-G0/G1 fraction, corresponding to apoptotic cells.	('survivin', 'Gene', (126, 134))	('Cys84Ala', 'Var', (192, 200))	('Cys84Ala', 'SUBSTITUTION', 'None', (192, 200))	('alanine', 'Chemical', 'MESH:D000409', (183, 190))	('survivin', 'Gene', '11799', (218, 226))	('survivin', 'Gene', '11799', (126, 134))	('resulted in', 'Reg', (257, 268))	('increase', 'PosReg', (308, 316))	('HaCat', 'CellLine', 'CVCL:6758', (69, 74))	('cysteine', 'Chemical', 'MESH:D003545', (171, 179))	('survivin', 'Gene', (218, 226))	('sub-G0/G1 fraction', 'MPA', (324, 342))
668706	29587347	The effectiveness of the survivin mutant (Cys84Ala) was also demonstrated in melanoma, colon, and gastric cancer cell lines.	('survivin', 'Gene', (25, 33))	('Cys84Ala', 'Var', (42, 50))	('gastric cancer', 'Disease', (98, 112))	('Cys84Ala', 'SUBSTITUTION', 'None', (42, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('melanoma', 'Disease', (77, 85))	('colon', 'Disease', (87, 92))	('survivin', 'Gene', '11799', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
668709	29587347	The phosphorylation-defective Thr34/alanine (Thr34/Ala, or T34A) mutant is the most studied survivin mutation, suggesting its role in promoting sensitivity to chemo- and radiotherapy through apoptosis enhancement.	('apoptosis', 'CPA', (191, 200))	('enhancement', 'PosReg', (201, 212))	('survivin', 'Gene', '11799', (92, 100))	('phosphorylation-defective', 'Disease', (4, 29))	('Thr34/alanine', 'SUBSTITUTION', 'None', (30, 43))	('Thr34/alanine', 'Var', (30, 43))	('T34A', 'Mutation', 'rs756919605', (59, 63))	('promoting', 'PosReg', (134, 143))	('Thr34/Ala', 'Mutation', 'rs761129000', (45, 54))	('survivin', 'Gene', (92, 100))
668710	29587347	showed that modification of T34 in the HeLa cell line has both a positive and a negative impact on survivin function.	('survivin', 'Gene', (99, 107))	('T34', 'Gene', (28, 31))	('HeLa', 'CellLine', 'CVCL:0030', (39, 43))	('survivin', 'Gene', '11799', (99, 107))	('negative', 'NegReg', (80, 88))	('modification', 'Var', (12, 24))
668711	29587347	In fact, cancer cells harboring survivin T34A mutant forms are not protected against death-inducing signals, but show growth acceleration.	('cancer', 'Disease', (9, 15))	('survivin', 'Gene', '11799', (32, 40))	('T34A mutant', 'Var', (41, 52))	('acceleration', 'PosReg', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('growth', 'CPA', (118, 124))	('mutant', 'Var', (46, 52))	('growth acceleration', 'Phenotype', 'HP:0001510', (118, 137))	('survivin', 'Gene', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('T34A', 'Mutation', 'rs756919605', (41, 45))
668712	29587347	In contrast, the phosphomimetic form of T34 (T34E) retards mitosis and it significantly enhances cell resistance to death-inducing signals.	('enhances', 'PosReg', (88, 96))	('T34E', 'Mutation', 'p.T34E', (45, 49))	('cell resistance to death-inducing', 'CPA', (97, 130))	('retards mitosis', 'Disease', 'MESH:D008607', (51, 66))	('T34 (T34E', 'Var', (40, 49))	('retards mitosis', 'Disease', (51, 66))
668714	29587347	Results from several studies investigating survivin-T34A in cancer cells and xenograft models suggest that the role of this mutant form is to promote sensitivity to chemo- and radiotherapy through apoptosis enhancement.	('apoptosis', 'CPA', (197, 206))	('T34A', 'Mutation', 'rs756919605', (52, 56))	('survivin', 'Gene', '11799', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('mutant', 'Var', (124, 130))	('enhancement', 'PosReg', (207, 218))	('cancer', 'Disease', (60, 66))	('promote', 'PosReg', (142, 149))	('survivin', 'Gene', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
668717	29587347	Subsequently, many different studies have highlighted that it is possible to reduce the proliferative potential in different human tumor cells through survivin knockdown by using siRNAs or plasmid/viral vectors encoding for short hairpin RNAs (shRNAs).	('survivin', 'Gene', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('reduce', 'NegReg', (77, 83))	('knockdown', 'Var', (160, 169))	('proliferative potential', 'CPA', (88, 111))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('human', 'Species', '9606', (125, 130))	('tumor', 'Disease', (131, 136))	('survivin', 'Gene', '11799', (151, 159))
668721	29587347	The same results were achieved by transfecting a plasmid-containing survivin shRNA into an OSCC tongue cell line: shRNA inhibited the expression of survivin at both the protein and mRNA level, inhibited cell proliferation via caspase-3 activity induction, and enhanced chemosensitivity to cisplatin.	('survivin', 'Gene', '11799', (148, 156))	('caspase-3', 'Gene', '836', (226, 235))	('expression', 'MPA', (134, 144))	('cell proliferation', 'CPA', (203, 221))	('chemosensitivity', 'CPA', (269, 285))	('inhibited', 'NegReg', (193, 202))	('enhanced', 'PosReg', (260, 268))	('SCC', 'Gene', '6317', (92, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (289, 298))	('inhibited', 'NegReg', (120, 129))	('survivin', 'Gene', '11799', (68, 76))	('shRNA', 'Var', (114, 119))	('caspase-3', 'Gene', (226, 235))	('survivin', 'Gene', (148, 156))	('survivin', 'Gene', (68, 76))	('SCC', 'Gene', (92, 95))
668726	29587347	The ability of RNAi-mediated survivin knockdown to reduce the formation of new tumors and to hinder the growth of already established lesions in vivo was confirmed in BALB/c nude mice bearing OSCC treated with a lentiviral vector encoding shRNA targeting survivin.	('survivin', 'Gene', '11799', (29, 37))	('survivin', 'Gene', (255, 263))	('growth', 'CPA', (104, 110))	('survivin', 'Gene', '11799', (255, 263))	('tumors', 'Disease', (79, 85))	('nude mice', 'Species', '10090', (174, 183))	('SCC', 'Gene', (193, 196))	('survivin', 'Gene', (29, 37))	('reduce', 'NegReg', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('hinder', 'NegReg', (93, 99))	('knockdown', 'Var', (38, 47))	('SCC', 'Gene', '6317', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
668741	29587347	A phase I study established tolerability of 750 mg of LY2181308, another ASO, followed by two other phase I trials in patients with advanced cancers.	('LY2181308', 'Chemical', 'MESH:C529350', (54, 63))	('ASO', 'Chemical', 'MESH:D016376', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('LY2181308', 'Var', (54, 63))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('patients', 'Species', '9606', (118, 126))	('cancers', 'Disease', (141, 148))
668743	29587347	Indeed, it was established that the anti-neoplastic activity of LY2181308 is related to survivin inhibition and reduced expression of survivin mRNA and protein in tumor cell lines.	('expression', 'MPA', (120, 130))	('LY2181308', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('survivin', 'Gene', '11799', (88, 96))	('inhibition', 'NegReg', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('LY2181308', 'Chemical', 'MESH:C529350', (64, 73))	('protein', 'Protein', (152, 159))	('survivin', 'Gene', '11799', (134, 142))	('tumor', 'Disease', (163, 168))	('survivin', 'Gene', (88, 96))	('anti-neoplastic activity', 'CPA', (36, 60))	('reduced', 'NegReg', (112, 119))	('survivin', 'Gene', (134, 142))
668744	29587347	treated 40 patients with LY2181308 at doses ranging from 100 to 1000 mg; the patients had different tumors including breast, colon, and melanoma.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('breast', 'Disease', (117, 123))	('LY2181308', 'Var', (25, 34))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('patients', 'Species', '9606', (77, 85))	('colon', 'Disease', (125, 130))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('patients', 'Species', '9606', (11, 19))	('LY2181308', 'Chemical', 'MESH:C529350', (25, 34))
668749	29587347	The major results of the study were the demonstration that ASO accumulates within tumor tissues, reduces survivin gene and protein expression by 20%, and restores apoptotic signaling in tumor cells in vivo.	('ASO', 'Chemical', 'MESH:D016376', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('survivin', 'Gene', '11799', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('restores', 'PosReg', (154, 162))	('tumor', 'Disease', (186, 191))	('ASO', 'Var', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('reduces', 'NegReg', (97, 104))	('survivin', 'Gene', (105, 113))	('tumor', 'Disease', (82, 87))	('apoptotic signaling', 'MPA', (163, 182))
668751	29587347	In the second phase I trial, the tolerability, pharmacokinetics, and anti-cancer activity of LY2181308 were evaluated in 14 patients with advanced cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('LY2181308', 'Var', (93, 102))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancer', 'Disease', (147, 153))	('cancers', 'Disease', (147, 154))	('patients', 'Species', '9606', (124, 132))	('LY2181308', 'Chemical', 'MESH:C529350', (93, 102))
668756	29587347	Despite the data on the clinical response, the results from both trials showing favorable toxicity and pharmacokinetic profiles of LY2181308 have to be considered as positives.	('toxicity', 'Disease', 'MESH:D064420', (90, 98))	('LY2181308', 'Var', (131, 140))	('toxicity', 'Disease', (90, 98))	('LY2181308', 'Chemical', 'MESH:C529350', (131, 140))
668757	29587347	In fact, LY2181308 was not designed as a single-agent therapy; it was expected to facilitate the effects of pro-apoptotic treatments and thus have activity in conjunction with apoptosis-inducing agents, such as chemo- and/or radiotherapy.	('facilitate', 'PosReg', (82, 92))	('LY2181308', 'Chemical', 'MESH:C529350', (9, 18))	('effects', 'MPA', (97, 104))	('LY2181308', 'Var', (9, 18))	('activity', 'MPA', (147, 155))
668762	29587347	showed that treatment with YM155 resulted also in the ability to sensitize NSCLC cells to radiation and to platinum-based compounds (cisplatin and carboplatin) both in vitro and in vivo.	('platinum', 'Chemical', 'MESH:D010984', (107, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('carboplatin', 'Chemical', 'MESH:D016190', (147, 158))	('NSCLC', 'Disease', (75, 80))	('YM155', 'Var', (27, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('YM155', 'Chemical', 'MESH:C523798', (27, 32))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('sensitize', 'Reg', (65, 74))
668763	29587347	These preclinical results and pharmacokinetic evaluation demonstrated a rapid elimination half-life in mice, rapid distribution to tissues, and a 20-fold increase in tumor tissue concentrations as compared with plasma, leading to clinical development of YM155 with two phase I trials.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Disease', (166, 171))	('YM155', 'Var', (254, 259))	('YM155', 'Chemical', 'MESH:C523798', (254, 259))	('increase', 'PosReg', (154, 162))
668769	29587347	Recently, two phase II trials evaluating YM155 have been completed: an open-label, multicenter trial consisting of administration of YM155 as a single-agent therapy in patients with unresectable stage III-IV melanoma and a multicenter study of YM155 as a single-agent therapy in patients with refractory previously-treated, advanced NSCLC.	('YM155', 'Chemical', 'MESH:C523798', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (333, 338))	('YM155', 'Chemical', 'MESH:C523798', (133, 138))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('YM155', 'Var', (133, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (333, 338))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('YM155', 'Chemical', 'MESH:C523798', (244, 249))	('patients', 'Species', '9606', (279, 287))	('patients', 'Species', '9606', (168, 176))	('NSCLC', 'Disease', (333, 338))
668771	29587347	Cyclin-dependent kinase (CDK) inhibitors such as purvalanol A have been developed with the aim of blocking the phosphorylation of survivin on Thr34, leading to increased protein destruction and thereby counteracting its function.	('survivin', 'Gene', (130, 138))	('increased', 'PosReg', (160, 169))	('Thr34', 'Var', (142, 147))	('Thr34', 'Chemical', '-', (142, 147))	('purvalanol A', 'Chemical', 'MESH:C471843', (49, 61))	('survivin', 'Gene', '11799', (130, 138))	('protein destruction', 'MPA', (170, 189))	('blocking', 'NegReg', (98, 106))	('phosphorylation', 'MPA', (111, 126))
668772	29587347	reported that the addition of the novel CDK inhibitor NU6140 to paclitaxel-treated HeLa cervical carcinoma cells resulted in significantly increased cytotoxic effect and apoptotic response in comparison with the paclitaxel-purvalanol A combination, resulting in abrogation of the expression of the survivin active form.	('expression', 'MPA', (280, 290))	('paclitaxel', 'Chemical', 'MESH:D017239', (64, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('increased', 'PosReg', (139, 148))	('NU6140', 'Var', (54, 60))	('survivin', 'Gene', '11799', (298, 306))	('NU6140', 'Chemical', 'MESH:C506606', (54, 60))	('apoptotic response', 'CPA', (170, 188))	('purvalanol A', 'Chemical', 'MESH:C471843', (223, 235))	('HeLa cervical carcinoma', 'Disease', 'MESH:D002575', (83, 106))	('cytotoxic effect', 'CPA', (149, 165))	('HeLa cervical carcinoma', 'Disease', (83, 106))	('abrogation', 'NegReg', (262, 272))	('paclitaxel', 'Chemical', 'MESH:D017239', (212, 222))	('survivin', 'Gene', (298, 306))
668801	29587347	abolished survivin expression from the hematopoietic compartment of mice, showing that inducible deletion causes defects in erythropoiesis in a subset of the animals, which emphasizes the sensibility of the hematopoietic system to survivin disruption.	('mice', 'Species', '10090', (68, 72))	('survivin', 'Gene', (10, 18))	('survivin', 'Gene', '11799', (231, 239))	('defects', 'NegReg', (113, 120))	('defects in erythropoiesis', 'Phenotype', 'HP:0010972', (113, 138))	('erythropoiesis', 'Disease', 'MESH:C563479', (124, 138))	('survivin', 'Gene', '11799', (10, 18))	('survivin', 'Gene', (231, 239))	('deletion', 'Var', (97, 105))	('erythropoiesis', 'Disease', (124, 138))
668805	29587347	However, in agreement with Altieri, there is the possibility that targeting survivin might preferentially affect the qualitatively different molecular networks in cancer cells, leaving survivin functions intact in normal tissues.	('survivin', 'Gene', '11799', (76, 84))	('qualitatively', 'MPA', (117, 130))	('survivin', 'Gene', (185, 193))	('survivin', 'Gene', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('targeting', 'Var', (66, 75))	('survivin', 'Gene', '11799', (185, 193))	('affect', 'Reg', (106, 112))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
668808	29587347	Since inhibition of mechanisms underlying apoptosis events can promote tumorigenesis and increase resistance to chemo- and radiotherapy, induction of apoptosis has been considered a promising method for anticancer therapy.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('inhibition', 'Var', (6, 16))	('promote', 'PosReg', (63, 70))	('tumor', 'Disease', (71, 76))	('increase', 'PosReg', (89, 97))
668813	29587347	These strategies interfere at different levels with survivin expression and include ASO, RNAi, ribozymes, dominant-negative mutants, SMI, vaccines, and adoptive cell therapy (Figure 4).	('ribozymes', 'Enzyme', (95, 104))	('interfere', 'Reg', (17, 26))	('dominant-negative mutants', 'Var', (106, 131))	('ASO', 'Chemical', 'MESH:D016376', (84, 87))	('survivin', 'Gene', (52, 60))	('survivin', 'Gene', '11799', (52, 60))	('expression', 'MPA', (61, 71))
668817	29587347	Conditionally replicative recombinant adenoviral vectors encoding dominant-negative survivin mutants have been successfully used to elicit spontaneous and enhanced drug-induced apoptosis in cell lines of different tumor origins and in cancer xenograft models in nude mice.	('survivin', 'Gene', (84, 92))	('drug-induced apoptosis', 'CPA', (164, 186))	('survivin', 'Gene', '11799', (84, 92))	('cancer', 'Disease', (235, 241))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('mutants', 'Var', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('enhanced', 'PosReg', (155, 163))	('tumor', 'Disease', (214, 219))	('elicit', 'Reg', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('nude mice', 'Species', '10090', (262, 271))
668819	29587347	However, as the survivin gene is transcriptionally repressed by wild-type p53 protein and the loss of wild-type p53 in tumors can lead directly to survivin expression, the administration of rAd-p53 agents may be considered as an approach that indirectly hits survivin.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('p53', 'Gene', (74, 77))	('p53', 'Gene', (194, 197))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('p53', 'Gene', '7157', (112, 115))	('p53', 'Gene', '7157', (74, 77))	('tumors', 'Disease', (119, 125))	('loss', 'Var', (94, 98))	('p53', 'Gene', (112, 115))	('survivin', 'Gene', (16, 24))	('lead', 'Reg', (130, 134))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('survivin', 'Gene', '11799', (16, 24))	('survivin', 'Gene', (259, 267))	('survivin', 'Gene', (147, 155))	('survivin', 'Gene', '11799', (259, 267))	('survivin', 'Gene', '11799', (147, 155))	('p53', 'Gene', '7157', (194, 197))	('expression', 'MPA', (156, 166))
668821	29587347	Despite survivin knockdown by RNAs resulting in proliferation inhibition, apoptosis, and chemosensitivity enhancement in both in vitro and in vivo models, the hope to use this gene-silencing technique has yet to be realized.	('apoptosis', 'CPA', (74, 83))	('chemosensitivity', 'CPA', (89, 105))	('survivin', 'Gene', (8, 16))	('knockdown', 'Var', (17, 26))	('enhancement', 'PosReg', (106, 117))	('proliferation inhibition', 'CPA', (48, 72))	('survivin', 'Gene', '11799', (8, 16))
668824	29587347	Another strategy concerns the use of gene therapy to transfer genes that augment the immune response against cancer cells.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('augment', 'PosReg', (73, 80))	('genes', 'Var', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
668826	29587347	LY2181308, a second-generation ASO designed to complementarily bind to human survivin mRNA, showed in two dose-escalation studies a favorable safety profile.	('ASO', 'Chemical', 'MESH:D016376', (31, 34))	('LY2181308', 'Var', (0, 9))	('LY2181308', 'Chemical', 'MESH:C529350', (0, 9))	('survivin', 'Gene', '11799', (77, 85))	('survivin', 'Gene', (77, 85))	('human', 'Species', '9606', (71, 76))
668827	29587347	Despite the fact that only one patient with esophageal SCC was enrolled and showed limited clinical response, results from both trials are encouraging for the future use of LY2181308 as a complementary therapy.	('SCC', 'Gene', (55, 58))	('LY2181308', 'Chemical', 'MESH:C529350', (173, 182))	('patient', 'Species', '9606', (31, 38))	('SCC', 'Gene', '6317', (55, 58))	('LY2181308', 'Var', (173, 182))
668831	29587347	However, this approach has been recently tested with the use of YM155, a novel SMI that directly affects the survivin gene expression via inhibition of its promoter.	('inhibition', 'NegReg', (138, 148))	('expression', 'MPA', (123, 133))	('survivin', 'Gene', '11799', (109, 117))	('YM155', 'Chemical', 'MESH:C523798', (64, 69))	('promoter', 'MPA', (156, 164))	('YM155', 'Var', (64, 69))	('survivin', 'Gene', (109, 117))	('affects', 'Reg', (97, 104))
668839	29587347	However, despite the better toxicity profile than YM155 or LY2181308, only marginal immunological and clinical responses were achieved.	('LY2181308', 'Var', (59, 68))	('YM155', 'Chemical', 'MESH:C523798', (50, 55))	('toxicity', 'Disease', 'MESH:D064420', (28, 36))	('LY2181308', 'Chemical', 'MESH:C529350', (59, 68))	('toxicity', 'Disease', (28, 36))
668845	29587347	For example, YM155 was evaluated in phase I/II trials giving results similar to those obtained in SCC patients.	('SCC', 'Gene', '6317', (98, 101))	('patients', 'Species', '9606', (102, 110))	('YM155', 'Chemical', 'MESH:C523798', (13, 18))	('YM155', 'Var', (13, 18))	('SCC', 'Gene', (98, 101))
668846	29587347	Regarding gynecological tumors, several phase I/II trials have been conducted using LY2181308, but the results obtained were unsatisfactory.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (24, 30))	('LY2181308', 'Chemical', 'MESH:C529350', (84, 93))	('LY2181308', 'Var', (84, 93))
668924	29290655	The current standard of care for early stage esophageal cancer includes EMR for T1aN0 disease and upfront surgery for T1bN0 and T2N0 disease.	('esophageal cancer', 'Disease', (45, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('T1aN0', 'Var', (80, 85))
668950	29290655	Of the 139 patients with clinical T1N0 or T2N0 esophageal cancer, 62 patients had a PET included as part of their clinical workup.	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('T2N0', 'Var', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('T1N0', 'Var', (34, 38))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (11, 19))	('esophageal cancer', 'Disease', (47, 64))
668956	29290655	Interestingly, in a SEER study, the authors noted that EUS and/or CT-PET was associated with improved overall survival, probably due to the improvement in staging and receipt of therapies for patients undergoing these procedures.	('improved', 'PosReg', (93, 101))	('patients', 'Species', '9606', (192, 200))	('CT-PET', 'Gene', (66, 72))	('staging', 'CPA', (155, 162))	('overall survival', 'MPA', (102, 118))	('EUS', 'Var', (55, 58))	('improvement', 'PosReg', (140, 151))
668975	29290655	Therefore, current treatment algorithms of clinical stageT1N0 and T2N0 esophageal cancer should be re-evaluated so that appropriate therapy is administered, without over- or under-treatment.	('T2N0', 'Var', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('esophageal cancer', 'Disease', (71, 88))
669027	19959033	Further analysis of the same St. Jude cohort showed that the 20-year cumulative incidence of CNS tumors increased in conjunction with radiation dose: 1% at 10-21Gy; 1.7% at >21-30 Gy; and 3.2% at >30Gy.	('CNS tumors', 'Disease', (93, 103))	('10-21Gy', 'Var', (156, 163))	('CNS tumors', 'Disease', 'MESH:D009369', (93, 103))	('increased', 'PosReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))
669032	19959033	Secondary leukemias associated with high dose alkylating agent exposure usually occur in older children, have a latency of 4-10 years, and are associated with myelodysplasia and deletions in chromosomes 5 and 7.	('myelodysplasia', 'Disease', 'MESH:D009190', (159, 173))	('myelodysplasia', 'Disease', (159, 173))	('associated', 'Reg', (143, 153))	('leukemias', 'Disease', 'MESH:D007938', (10, 19))	('deletions', 'Var', (178, 187))	('leukemia', 'Phenotype', 'HP:0001909', (10, 18))	('children', 'Species', '9606', (95, 103))	('myelodysplasia', 'Phenotype', 'HP:0002863', (159, 173))	('leukemias', 'Phenotype', 'HP:0001909', (10, 19))	('leukemias', 'Disease', (10, 19))
669033	19959033	In contrast, topoisomerase II-induced secondary leukemias are typically diagnosed in younger children, have a short latency period (median 1-3 years), and are associated with balanced chromosomal translocation 11q23, or less frequently 21q22.	('children', 'Species', '9606', (93, 101))	('leukemias', 'Disease', 'MESH:D007938', (48, 57))	('secondary leukemia', 'Disease', 'MESH:D060085', (38, 56))	('leukemia', 'Phenotype', 'HP:0001909', (48, 56))	('secondary leukemia', 'Disease', (38, 56))	('leukemias', 'Phenotype', 'HP:0001909', (48, 57))	('topoisomerase II-induced', 'Enzyme', (13, 37))	('21q22', 'Var', (236, 241))	('leukemias', 'Disease', (48, 57))
669036	19959033	In addition, the administration schedule of epipdophyllotoxins appears to contribute to the risk of secondary leukemias, as prolonged infusions were found to be an independent risk factor.	('epipdophyllotoxins', 'Var', (44, 62))	('leukemias', 'Phenotype', 'HP:0001909', (110, 119))	('leukemias', 'Disease', (110, 119))	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('leukemias', 'Disease', 'MESH:D007938', (110, 119))	('epipdophyllotoxins', 'Chemical', '-', (44, 62))	('secondary leukemia', 'Disease', 'MESH:D060085', (100, 118))	('secondary leukemia', 'Disease', (100, 118))
669041	19959033	Approximately 40% of cases of RB are hereditary, with an identifiable germline deletion in the Rb-1 tumor suppressor gene which confers a genetic predisposition to subsequent neoplasms.	('neoplasms', 'Disease', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('neoplasm', 'Phenotype', 'HP:0002664', (175, 183))	('RB', 'Phenotype', 'HP:0009919', (30, 32))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('neoplasms', 'Phenotype', 'HP:0002664', (175, 184))	('Rb-1', 'Gene', (95, 99))	('deletion', 'Var', (79, 87))	('RB', 'Gene', '5925', (30, 32))	('neoplasms', 'Disease', 'MESH:D009369', (175, 184))
669042	19959033	The specific secondary malignancies for which survivors with hereditary RB are at the highest risk include soft tissue sarcomas, bone sarcomas, and malignant melanoma.	('bone sarcomas', 'Disease', 'MESH:D001847', (129, 142))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (107, 127))	('bone sarcomas', 'Disease', (129, 142))	('bone sarcomas', 'Phenotype', 'HP:0002669', (129, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('bone sarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('RB', 'Phenotype', 'HP:0009919', (72, 74))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('malignancies', 'Disease', 'MESH:D009369', (23, 35))	('malignant melanoma', 'Disease', (148, 166))	('hereditary', 'Var', (61, 71))	('malignancies', 'Disease', (23, 35))	('RB', 'Gene', '5925', (72, 74))	('soft tissue sarcomas', 'Disease', (107, 127))	('malignant melanoma', 'Phenotype', 'HP:0002861', (148, 166))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('malignant melanoma', 'Disease', 'MESH:D008545', (148, 166))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (107, 127))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (107, 126))
669049	19959033	In general, survivors of nonhereditary RB are not considered to be at increased risk of secondary malignancies except for soft tissue sarcomas (SIR 21.9, 95% CI 4.5-63.7), and female breast cancer (SIR 2.8, 95% CI 1.1-5.9).	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (122, 142))	('soft tissue sarcomas', 'Disease', (122, 142))	('malignancies', 'Disease', (98, 110))	('RB', 'Phenotype', 'HP:0009919', (39, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('RB', 'Gene', '5925', (39, 41))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (122, 142))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (122, 141))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Disease', (183, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('nonhereditary', 'Var', (25, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))
669101	19959033	While alkylating agent chemotherapy for HL is associated with a subsequently reduced risk of breast cancer through a deleterious effect on ovarian function, increased risks of lung cancer risk ensue.	('HL', 'Phenotype', 'HP:0012189', (40, 42))	('alkylating agent', 'Var', (6, 22))	('ovarian', 'MPA', (139, 146))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('HL', 'CellLine', 'CVCL:2492', (40, 42))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('reduced', 'NegReg', (77, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('lung cancer', 'Disease', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
669135	19959033	When the dose-response analyses were focused on patients <45 years of age when irradiated, women treated with postlumpectomy radiation (which was associated with higher doses to the contralateral breast) had a significantly 1.5-fold increased risk of contralateral breast cancer compared with patients treated with postmastectomy radiation therapy.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('contralateral breast cancer', 'Disease', (251, 278))	('patients', 'Species', '9606', (293, 301))	('women', 'Species', '9606', (91, 96))	('postlumpectomy radiation', 'Var', (110, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (265, 278))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (251, 278))	('patients', 'Species', '9606', (48, 56))
669274	24167366	Furthermore, siRNA-mediated knockdown of FXYD-3 showed a reduction in the proliferative activity of both PC-3 and LNCaP prostate cancer cells and T3 M4 pancreatic cancer cells in vitro.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('LNCaP', 'CellLine', 'CVCL:0395', (114, 119))	('proliferative activity', 'CPA', (74, 96))	('FXYD-3', 'Gene', (41, 47))	('PC-3', 'Gene', (105, 109))	('reduction', 'NegReg', (57, 66))	('M4', 'CellLine', 'CVCL:U812', (149, 151))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('PC-3', 'Gene', '3853', (105, 109))	('knockdown', 'Var', (28, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))
669287	22745369	The Annexin-V staining and Western blot analysis indicated that t-DARPP effectively abrogated trastuzumab-induced apoptosis, inhibited cleavage of caspase-3 and blocked trastuzumab-induced dephosphorylation of ERBB2 and AKT proteins.	('AKT', 'Gene', (220, 223))	('dephosphorylation', 'MPA', (189, 206))	('caspase-3', 'Gene', '836', (147, 156))	('t-DARPP', 'Var', (64, 71))	('Annexin-V', 'Gene', '308', (4, 13))	('ERBB2', 'Gene', (210, 215))	('abrogated', 'NegReg', (84, 93))	('trastuzumab', 'Chemical', 'MESH:D000068878', (169, 180))	('trastuzumab', 'Chemical', 'MESH:D000068878', (94, 105))	('ERBB2', 'Gene', '2064', (210, 215))	('AKT', 'Gene', '207', (220, 223))	('blocked', 'NegReg', (161, 168))	('inhibited', 'NegReg', (125, 134))	('Annexin-V', 'Gene', (4, 13))	('caspase-3', 'Gene', (147, 156))	('apoptosis', 'CPA', (114, 123))	('cleavage', 'MPA', (135, 143))	('trastuzumab-induced', 'MPA', (94, 113))
669288	22745369	The knockdown of endogenous t-DARPP reversed these effects and sensitized cells to trastuzumab (p<0.01).	('trastuzumab', 'Chemical', 'MESH:D000068878', (83, 94))	('knockdown', 'Var', (4, 13))	('sensitized', 'Reg', (63, 73))	('t-DARPP', 'Protein', (28, 35))
669291	22745369	Using EAC-xenografted mouse model, t-DARPP enhanced tumor growth and rendered tumors unresponsive to trastuzumab.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('enhanced', 'PosReg', (43, 51))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('trastuzumab', 'Chemical', 'MESH:D000068878', (101, 112))	('tumor', 'Disease', (78, 83))	('mouse', 'Species', '10090', (22, 27))	('t-DARPP', 'Var', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
669297	22745369	Chromosomal amplification at the 17q21 region is a frequent finding in adenocarcinomas of the stomach and esophagus.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('adenocarcinomas of the stomach', 'Disease', 'MESH:D013274', (71, 101))	('Chromosomal amplification at', 'Var', (0, 28))	('adenocarcinomas of the stomach', 'Phenotype', 'HP:0006753', (71, 101))	('esophagus', 'Disease', (106, 115))	('adenocarcinomas of the stomach', 'Disease', (71, 101))
669373	22745369	While t-DARPP protein was highly expressed in OE33 cells, it was undetectable in OE19 cells (Figure 1D, right panel), suggesting that t-DARPP expression was associated with increased trastuzumab resistance in esophageal cancer cells.	('esophageal cancer', 'Disease', (209, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('t-DARPP', 'Var', (134, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (209, 226))	('OE19', 'CellLine', 'CVCL:1622', (81, 85))	('trastuzumab resistance', 'MPA', (183, 205))	('increased', 'PosReg', (173, 182))	('trastuzumab', 'Chemical', 'MESH:D000068878', (183, 194))
669390	22745369	In accordance with these data, we demonstrated by immunofluorescence analysis that ERBB2 expression on the cell surface was approximately 2 fold higher in t-DARPP-expressing cells than control cells (p<0.01) (Supplemental Figure 1).	('expression', 'MPA', (89, 99))	('t-DARPP-expressing', 'Var', (155, 173))	('ERBB2', 'Gene', (83, 88))	('ERBB2', 'Gene', '2064', (83, 88))	('men', 'Species', '9606', (215, 218))	('higher', 'PosReg', (145, 151))
669394	22745369	These data clearly demonstrated that t-DARPP expression maintained ERBB2 phosphorylation and activated the downstream AKT survival pathway in response to trastuzumab treatment.	('trastuzumab', 'Chemical', 'MESH:D000068878', (154, 165))	('ERBB2', 'Gene', '2064', (67, 72))	('AKT', 'Gene', '207', (118, 121))	('ERBB2', 'Gene', (67, 72))	('response to trastuzumab treatment', 'MPA', (142, 175))	('t-DARPP', 'Gene', (37, 44))	('AKT', 'Gene', (118, 121))	('maintained', 'PosReg', (56, 66))	('phosphorylation', 'MPA', (73, 88))	('men', 'Species', '9606', (171, 174))	('expression', 'Var', (45, 55))	('activated', 'PosReg', (93, 102))
669396	22745369	The Western blot analysis data indicated that knockdown of t-DARPP and treatment with trastuzumab significantly decreased p-ERBB2(Y1248) and p-AKT(S473) protein levels relative to controls (Figure 5A).	('AKT', 'Gene', (143, 146))	('knockdown', 'Var', (46, 55))	('trastuzumab', 'Chemical', 'MESH:D000068878', (86, 97))	('men', 'Species', '9606', (76, 79))	('AKT', 'Gene', '207', (143, 146))	('t-DARPP', 'Gene', (59, 66))	('ERBB2', 'Gene', '2064', (124, 129))	('decreased', 'NegReg', (112, 121))	('ERBB2', 'Gene', (124, 129))
669397	22745369	Knocking down t-DARPP alone, without treatment with trastuzumab, decreased p-AKT(S473) protein level in OE33 cells (Figure 5A).	('Knocking down', 'Var', (0, 13))	('AKT', 'Gene', '207', (77, 80))	('men', 'Species', '9606', (42, 45))	('decreased', 'NegReg', (65, 74))	('trastuzumab', 'Chemical', 'MESH:D000068878', (52, 63))	('t-DARPP', 'Gene', (14, 21))	('AKT', 'Gene', (77, 80))
669398	22745369	The CellTiter-Glo viability assay results revealed that knockdown of t-DARPP in combination with trastuzumab treatment decreased cell survival by 30% relative to control (p<0.01) (Figure 5B).	('decreased', 'NegReg', (119, 128))	('men', 'Species', '9606', (114, 117))	('cell survival', 'CPA', (129, 142))	('trastuzumab', 'Chemical', 'MESH:D000068878', (97, 108))	('t-DARPP', 'Gene', (69, 76))	('knockdown', 'Var', (56, 65))
669399	22745369	These results clearly demonstrated that knocking down endogenous t-DARPP in OE33 cells significantly sensitized cells to trastuzumab.	('trastuzumab', 'Chemical', 'MESH:D000068878', (121, 132))	('cells', 'CPA', (112, 117))	('t-DARPP', 'Protein', (65, 72))	('sensitized', 'Reg', (101, 111))	('endogenous', 'MPA', (54, 64))	('knocking down', 'Var', (40, 53))
669406	22745369	The immunofluorescence staining results showed that the trastuzumab-bound ERBB2 protein level was approximately 5 fold lower in t-DARPP-expressing cells than control cells (p<0.01) (Supplemental Figure 2).	('ERBB2', 'Gene', (74, 79))	('lower', 'NegReg', (119, 124))	('t-DARPP-expressing', 'Var', (128, 146))	('trastuzumab', 'Chemical', 'MESH:D000068878', (56, 67))	('men', 'Species', '9606', (188, 191))	('ERBB2', 'Gene', '2064', (74, 79))
669408	22745369	Of note, cells expressing higher levels of t-DARPP showed stronger ERBB2 signal (Supplemental Figure 2C).	('ERBB2', 'Gene', '2064', (67, 72))	('men', 'Species', '9606', (87, 90))	('ERBB2', 'Gene', (67, 72))	('t-DARPP', 'Var', (43, 50))	('stronger', 'PosReg', (58, 66))
669411	22745369	Of note, t-DARPP expression significantly increased tumor growth rate (p<0.01) as compared to control (Figure 7C, left panel).	('increased', 'PosReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('expression', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('t-DARPP', 'Protein', (9, 16))
669417	22745369	Amplification and overexpression of ERBB2 has been identified in 15-20% of primary EAC tumor specimens and their corresponding metastases.	('Amplification', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ERBB2', 'Gene', (36, 41))	('men', 'Species', '9606', (98, 101))	('ERBB2', 'Gene', '2064', (36, 41))	('metastases', 'Disease', 'MESH:D009362', (127, 137))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('metastases', 'Disease', (127, 137))	('overexpression', 'PosReg', (18, 32))
669429	22745369	Based on these data, we hypothesized that t-DARPP and ERBB2 may have a functional relationship where t-DARPP-mediated activation of AKT could lead to resistance to trastuzumab.	('activation', 'PosReg', (118, 128))	('t-DARPP-mediated', 'Var', (101, 117))	('AKT', 'Gene', '207', (132, 135))	('ERBB2', 'Gene', '2064', (54, 59))	('trastuzumab', 'Chemical', 'MESH:D000068878', (164, 175))	('ERBB2', 'Gene', (54, 59))	('AKT', 'Gene', (132, 135))	('resistance to trastuzumab', 'MPA', (150, 175))	('lead to', 'Reg', (142, 149))
669436	22745369	While we and others have previously shown that t-DARPP can lead to activation of AKT and resistance to trastuzumab in breast cancer cells in vitro, the mechanism by which t-DARPP activates the AKT survival pathway was not fully identified.	('AKT', 'Gene', '207', (193, 196))	('activation', 'PosReg', (67, 77))	('AKT', 'Gene', '207', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('t-DARPP', 'Var', (47, 54))	('AKT', 'Gene', (193, 196))	('t-DARPP', 'Var', (171, 178))	('trastuzumab', 'Chemical', 'MESH:D000068878', (103, 114))	('resistance to trastuzumab', 'MPA', (89, 114))	('AKT', 'Gene', (81, 84))	('activates', 'PosReg', (179, 188))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
669437	22745369	In the current study, our data clearly indicated that t-DARPP expression, without treatment with trastuzumab, significantly increased ERBB2, p-ERBB2(Y1248), and p-AKT(S473) protein levels relative to control cells.	('AKT', 'Gene', '207', (163, 166))	('men', 'Species', '9606', (87, 90))	('ERBB2', 'Gene', '2064', (134, 139))	('increased', 'PosReg', (124, 133))	('AKT', 'Gene', (163, 166))	('ERBB2', 'Gene', (134, 139))	('ERBB2', 'Gene', (143, 148))	('ERBB2', 'Gene', '2064', (143, 148))	('trastuzumab', 'Chemical', 'MESH:D000068878', (97, 108))	('expression', 'Var', (62, 72))	('t-DARPP', 'Protein', (54, 61))
669442	22745369	Several mechanisms have been suggested such as activating mutations in the PI3KCA, deletions of PTEN, overexpression of cMET, and overexpression of ERBB3.	('PTEN', 'Gene', '5728', (96, 100))	('mutations', 'Var', (58, 67))	('ERBB3', 'Gene', '2065', (148, 153))	('overexpression', 'PosReg', (102, 116))	('deletions', 'Var', (83, 92))	('ERBB3', 'Gene', (148, 153))	('PI3KCA', 'Gene', (75, 81))	('cMET', 'Gene', (120, 124))	('cMET', 'Gene', '4233', (120, 124))	('PTEN', 'Gene', (96, 100))	('activating', 'PosReg', (47, 57))
669443	22745369	In an attempt to elucidate the mechanistic role of t-DARPP in trastuzumab resistance in EAC, we found that t-DARPP associated with ERBB2 in a protein complex.	('trastuzumab', 'Chemical', 'MESH:D000068878', (62, 73))	('ERBB2', 'Gene', '2064', (131, 136))	('ERBB2', 'Gene', (131, 136))	('associated', 'Interaction', (115, 125))	('t-DARPP', 'Var', (107, 114))
669446	22745369	The immunofluorescence data clearly indicated that t-DARPP expression was cytosolic (Supplemental Figure 2C); strongly suggesting that t-DARPP interaction with ERBB2 cytosolic domain could alter ERBB2 protein folding and conformation, thereby interfering with trastuzumab binding to ERBB2 extracellular domain.	('trastuzumab', 'Chemical', 'MESH:D000068878', (260, 271))	('ERBB2', 'Gene', (283, 288))	('ERBB2', 'Gene', '2064', (160, 165))	('t-DARPP', 'Var', (135, 142))	('ERBB2', 'Gene', (160, 165))	('ERBB2', 'Gene', (195, 200))	('ERBB2', 'Gene', '2064', (195, 200))	('alter', 'Reg', (189, 194))	('conformation', 'MPA', (221, 233))	('binding', 'Interaction', (272, 279))	('folding', 'MPA', (209, 216))	('protein', 'Protein', (201, 208))	('men', 'Species', '9606', (91, 94))	('trastuzumab', 'MPA', (260, 271))	('interfering', 'NegReg', (243, 254))	('interaction', 'Interaction', (143, 154))	('ERBB2', 'Gene', '2064', (283, 288))
669587	33391449	Besides, LOXL1-AS1 knockdown impaired ESCC cells proliferation, migration and invasion capabilities in vitro.	('LOXL1', 'Gene', (9, 14))	('impaired', 'NegReg', (29, 37))	('invasion capabilities', 'CPA', (78, 99))	('knockdown', 'Var', (19, 28))	('AS1', 'Gene', (15, 18))	('AS1', 'Gene', '5729', (15, 18))	('ESCC', 'Disease', (38, 42))	('migration', 'CPA', (64, 73))	('LOXL1', 'Gene', '4016', (9, 14))
669588	33391449	Furthermore, inhibiting LOXL1-AS1 in ESCC cells increased the percentage of cells at the G1 phase, accompanied by reducing in S phase in contrast to scramble control, and silencing of LOXL1-AS1 evoked ESCC cell apoptosis.	('increased', 'PosReg', (48, 57))	('ESCC cell apoptosis', 'CPA', (201, 220))	('AS1', 'Gene', '5729', (190, 193))	('AS1', 'Gene', (190, 193))	('S phase', 'MPA', (126, 133))	('AS1', 'Gene', (30, 33))	('AS1', 'Gene', '5729', (30, 33))	('reducing', 'NegReg', (114, 122))	('LOXL1', 'Gene', '4016', (24, 29))	('LOXL1', 'Gene', (24, 29))	('silencing', 'Var', (171, 180))	('LOXL1', 'Gene', (184, 189))	('inhibiting', 'Var', (13, 23))	('LOXL1', 'Gene', '4016', (184, 189))	('evoked', 'Reg', (194, 200))
669598	33391449	Furthermore, accumulating evidence indicated that dysregulated lncRNAs could act as tumor suppressors or oncogenes to participate in cancer progression.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('participate', 'Reg', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', (84, 89))	('dysregulated', 'Var', (50, 62))	('cancer', 'Disease', (133, 139))	('lncRNAs', 'Protein', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
669600	33391449	Additionally, knockdown lncRNA FOXD3-AS1 inhibited cutaneous malignant melanoma cells proliferation, invasion and migration via regulating miR-325/MAP3K2 axis.	('malignant melanoma', 'Disease', (61, 79))	('FOXD3', 'Gene', '27022', (31, 36))	('malignant melanoma', 'Disease', 'MESH:D008545', (61, 79))	('MAP3K2', 'Gene', (147, 153))	('MAP3K2', 'Gene', '10746', (147, 153))	('AS1', 'Gene', '5729', (37, 40))	('AS1', 'Gene', (37, 40))	('FOXD3', 'Gene', (31, 36))	('inhibited', 'NegReg', (41, 50))	('knockdown', 'Var', (14, 23))	('miR-325', 'Gene', (139, 146))	('regulating', 'Reg', (128, 138))	('malignant melanoma', 'Phenotype', 'HP:0002861', (61, 79))	('miR-325', 'Gene', '442899', (139, 146))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (51, 79))
669604	33391449	For example, knockdown of LOXL1-AS1 dramatically inhibited osteosarcoma cell proliferation, migration and invasion through suppressing PI3K-AKT pathway.	('AKT', 'Gene', (140, 143))	('osteosarcoma', 'Phenotype', 'HP:0002669', (59, 71))	('osteosarcoma', 'Disease', (59, 71))	('suppressing', 'NegReg', (123, 134))	('AS1', 'Gene', (32, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (59, 71))	('LOXL1', 'Gene', '4016', (26, 31))	('LOXL1', 'Gene', (26, 31))	('AS1', 'Gene', '5729', (32, 35))	('invasion', 'CPA', (106, 114))	('migration', 'CPA', (92, 101))	('AKT', 'Gene', '207', (140, 143))	('knockdown', 'Var', (13, 22))	('inhibited', 'NegReg', (49, 58))
669637	33391449	The results showed that knockdown of LOXL1-AS1 could efficiently inhibit ESCC cell proliferation (Fig.	('LOXL1', 'Gene', '4016', (37, 42))	('LOXL1', 'Gene', (37, 42))	('AS1', 'Gene', '5729', (43, 46))	('AS1', 'Gene', (43, 46))	('inhibit', 'NegReg', (65, 72))	('ESCC', 'Disease', (73, 77))	('knockdown', 'Var', (24, 33))
669640	33391449	To this end, transwell assays were carried out and we found ESCC cell migration and invasion abilities were decreased when knocking down of LOXL1-AS1 in KYSE30 and EC109 cells (Fig.	('AS1', 'Gene', '5729', (146, 149))	('AS1', 'Gene', (146, 149))	('ESCC cell migration', 'CPA', (60, 79))	('LOXL1', 'Gene', '4016', (140, 145))	('LOXL1', 'Gene', (140, 145))	('decreased', 'NegReg', (108, 117))	('invasion abilities', 'CPA', (84, 102))	('EC109', 'CellLine', 'CVCL:6898', (164, 169))	('knocking down', 'Var', (123, 136))
669643	33391449	The results manifested that inhibiting LOXL1-AS1 in KYSE30 cells increased the percentage of cells at the G1 phase, accompanied by reducing in S phase in contrast to scramble control (Fig.	('AS1', 'Gene', '5729', (45, 48))	('increased', 'PosReg', (65, 74))	('LOXL1', 'Gene', '4016', (39, 44))	('LOXL1', 'Gene', (39, 44))	('inhibiting', 'Var', (28, 38))	('S phase', 'MPA', (143, 150))	('reducing', 'NegReg', (131, 139))	('cells at the G1 phase', 'CPA', (93, 114))	('AS1', 'Gene', (45, 48))
669645	33391449	Using the Annexin V/PI double-staining method to measure the apoptotic percentage, flow cytometry assays demonstrated that silencing of LOXL1-AS1 induced ESCC cell apoptosis (Fig.	('AS1', 'Gene', (142, 145))	('Annexin V', 'Gene', '308', (10, 19))	('Annexin V', 'Gene', (10, 19))	('LOXL1', 'Gene', '4016', (136, 141))	('ESCC', 'Disease', (154, 158))	('LOXL1', 'Gene', (136, 141))	('silencing', 'Var', (123, 132))	('AS1', 'Gene', '5729', (142, 145))
669654	33391449	Moreover, we performed qRT-PCR to measure the expression of DESC1 after silencing of LOXL1-AS1 and observed that DESC1 was markedly elevated in ESCC cells (Fig.	('elevated', 'PosReg', (132, 140))	('DESC1', 'Gene', (60, 65))	('silencing', 'Var', (72, 81))	('AS1', 'Gene', '5729', (91, 94))	('AS1', 'Gene', (91, 94))	('LOXL1', 'Gene', '4016', (85, 90))	('LOXL1', 'Gene', (85, 90))	('ESCC', 'Disease', (144, 148))	('DESC1', 'MPA', (113, 118))
669664	33391449	For example, LOXL1-AS1 acted as a ceRNA to upregulate USF1 via sponging miR-708-5p and facilitated the tumorigenesis and stemness of gastric carcinoma.	('miR-708', 'Gene', (72, 79))	('facilitated', 'PosReg', (87, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('sponging', 'Var', (63, 71))	('upregulate', 'PosReg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('AS1', 'Gene', '5729', (19, 22))	('AS1', 'Gene', (19, 22))	('stemness of gastric carcinoma', 'Disease', 'MESH:D013274', (121, 150))	('LOXL1', 'Gene', '4016', (13, 18))	('LOXL1', 'Gene', (13, 18))	('USF1', 'Gene', (54, 58))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (133, 150))	('USF1', 'Gene', '7391', (54, 58))	('miR-708', 'Gene', '100126333', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('stemness of gastric carcinoma', 'Disease', (121, 150))
669667	33391449	Silencing of LOXL1-AS1 apparently inhibited ESCC cells proliferation, migration and invasion capabilities.	('invasion capabilities', 'CPA', (84, 105))	('ESCC', 'Disease', (44, 48))	('migration', 'CPA', (70, 79))	('AS1', 'Gene', '5729', (19, 22))	('inhibited', 'NegReg', (34, 43))	('AS1', 'Gene', (19, 22))	('LOXL1', 'Gene', '4016', (13, 18))	('LOXL1', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))
669669	33391449	Meanwhile, silencing of LOXL1-AS1 accelerated ESCC cell apoptosis.	('silencing', 'Var', (11, 20))	('ESCC', 'Disease', (46, 50))	('AS1', 'Gene', '5729', (30, 33))	('accelerated', 'PosReg', (34, 45))	('AS1', 'Gene', (30, 33))	('LOXL1', 'Gene', '4016', (24, 29))	('LOXL1', 'Gene', (24, 29))
669716	32468882	Patients with leakage often first presented with a postoperative fever or leukocytosis.	('leakage', 'Var', (14, 21))	('presented', 'Reg', (34, 43))	('leukocytosis', 'Disease', 'MESH:D007964', (74, 86))	('leukocytosis', 'Phenotype', 'HP:0001974', (74, 86))	('Patients', 'Species', '9606', (0, 8))	('leukocytosis', 'Disease', (74, 86))	('postoperative fever', 'Disease', 'MESH:D005334', (51, 70))	('fever', 'Phenotype', 'HP:0001945', (65, 70))	('postoperative fever', 'Disease', (51, 70))
669724	32468882	In addition, the patients in the low-fat nutrition group had a shorter operation time than the patients in the control group (164.5 +- 34.0 vs. 172.7 +- 33.2 min, respectively; p = 0.011).	('low-fat nutrition', 'Var', (33, 50))	('patients', 'Species', '9606', (17, 25))	('shorter', 'NegReg', (63, 70))	('patients', 'Species', '9606', (95, 103))
669795	32178324	Moreover, polymethoxyflavones have a strong cytotoxicity and are constituents of chemo-preventive and chemotherapy drugs.	('polymethoxyflavones', 'Var', (10, 29))	('polymethoxyflavones', 'Chemical', '-', (10, 29))	('cytotoxicity', 'Disease', 'MESH:D064420', (44, 56))	('cytotoxicity', 'Disease', (44, 56))
669796	32178324	C-3' and C-5 hydroxy, as well as C-3 and C-4' methoxy groups in the casticin molecule, consist of significant antiproliferative activity, resulting in a proliferative disadvantage:a desirable characteristic of anticancer drugs.	('antiproliferative activity', 'CPA', (110, 136))	('cancer', 'Disease', (214, 220))	('rat', 'Species', '10116', (160, 163))	('proliferative', 'MPA', (153, 166))	('rat', 'Species', '10116', (121, 124))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('C-5 hydroxy', 'Var', (9, 20))	("C-3'", 'Var', (0, 4))	("C-4'", 'Var', (41, 45))	('casticin', 'Chemical', 'MESH:C054133', (68, 76))	('C-3', 'Var', (33, 36))
669816	32178324	Reverse transcriptase polymerase chain reaction (RT-PCR) is used to encode gene mechanisms, such as FoxM1, amplifying the gene and searching for any mutations within the DNA.	('FoxM1', 'Gene', '2305', (100, 105))	('amplifying', 'Var', (107, 117))	('FoxM1', 'Gene', (100, 105))
669869	32178324	It is important to note that the casticin samples used in this study were pretreated with a JNK pathway inhibitor, SP600125, which may have minimized the effect of the compound itself on the cell line.	('SP600125', 'Chemical', 'MESH:C432165', (115, 123))	('SP600125', 'Var', (115, 123))	('casticin', 'Chemical', 'MESH:C054133', (33, 41))	('JNK', 'Gene', (92, 95))	('JNK', 'Gene', '5599', (92, 95))
669912	32178324	Moreover, there was significant accumulation of cells in the G2/M phase at 12 h, which gradually declined towards 48 h, suggesting the maximal activity of casticin in this study occurred at 12 h. The compound also upregulated P21waf1, P27kip1 and AV-positive PI-negative cells.	('casticin', 'Chemical', 'MESH:C054133', (155, 163))	('upregulated', 'PosReg', (214, 225))	('AV-positive PI-negative cells', 'CPA', (247, 276))	('P27kip1', 'Gene', '1027', (235, 242))	('P21waf1', 'Var', (226, 233))	('cline', 'Chemical', '-', (99, 104))	('P27kip1', 'Gene', (235, 242))
669952	32178324	Concentrations tested were 2.5 microM, 5.0 microM and 10.0 microM for 24 h, and it was found that casticin induced apoptosis through the inactivation of the FoxM1 gene.	('inactivation', 'Var', (137, 149))	('FoxM1', 'Gene', '2305', (157, 162))	('FoxM1', 'Gene', (157, 162))	('rat', 'Species', '10116', (7, 10))	('casticin', 'Chemical', 'MESH:C054133', (98, 106))	('apoptosis', 'CPA', (115, 124))
669978	32178324	Twist overexpression in LCSCs attenuated casticin-induced regulation of E-cadherin and N-cadherin protein expression, as well as EMT capacity.	('E-cadherin', 'Protein', (72, 82))	('overexpression', 'Var', (6, 20))	('N-cadherin', 'Protein', (87, 97))	('regulation', 'MPA', (58, 68))	('casticin', 'Chemical', 'MESH:C054133', (41, 49))	('EMT capacity', 'CPA', (129, 141))	('attenuated', 'NegReg', (30, 40))
670034	31454136	Here, we highlight that targeting valosin-containing protein (VCP) improves radiation sensitivity in esophageal squamous cell carcinoma (ESCC) cell lines and show the potential of using VCP as a prognosis marker in locally advanced ESCC treated with radiation therapy.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (101, 135))	('radiation sensitivity', 'MPA', (76, 97))	('valosin-containing protein', 'Gene', (34, 60))	('ESCC', 'Disease', (232, 236))	('improves', 'PosReg', (67, 75))	('targeting', 'Var', (24, 33))	('ESCC', 'Disease', (137, 141))	('VCP', 'Gene', (62, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('esophageal squamous cell carcinoma', 'Disease', (101, 135))	('ESCC', 'Disease', 'MESH:C562729', (137, 141))	('ESCC', 'Disease', 'MESH:C562729', (232, 236))	('valosin-containing protein', 'Gene', '7415', (34, 60))
670051	31454136	KYSE70, KYSE140, KYSE150, KYSE410, KYSE450, and KYSE510 cells were maintained in RPMI-1640, 10% FBS, and 1% streptomycin/penicillin.	('KYSE510', 'CellLine', 'CVCL:1354', (48, 55))	('KYSE410', 'Var', (26, 33))	('KYSE450', 'Var', (35, 42))	('KYSE150', 'Var', (17, 24))	('KYSE140', 'Var', (8, 15))	('KYSE510', 'Var', (48, 55))	('penicillin', 'Chemical', 'MESH:D010406', (121, 131))
670058	31454136	Cells were seeded (400 cells/well for KYSE140; 200 cells/well for KYSE70) in 6-well plates in 2 mL medium and incubated for 24 hours at 37 C in a 5% CO2 incubator.	('KYSE70', 'Var', (66, 72))	('CO2', 'Chemical', 'MESH:D002245', (149, 152))	('KYSE140', 'Var', (38, 45))
670079	31454136	Among the 7 different ESCC cells, KYSE140 is associated with the highest expression of VCP (Figure 1A,B).	('KYSE140', 'Var', (34, 41))	('ESCC', 'Disease', (22, 26))	('expression', 'MPA', (73, 83))	('ESCC', 'Disease', 'MESH:C562729', (22, 26))	('VCP', 'Gene', (87, 90))
670085	31454136	To evaluate the efficacy of VCP inhibitor in combination with radiation therapy, colony formation assays were undertaken in ESCC cells (KYSE70 and KYSE140).	('ESCC', 'Disease', 'MESH:C562729', (124, 128))	('KYSE140', 'Var', (147, 154))	('ESCC', 'Disease', (124, 128))	('KYSE70', 'Var', (136, 142))
670089	31454136	Together, these data suggested that inhibition of VCP sensitizes ESCC cells to radiation therapy.	('inhibition', 'Var', (36, 46))	('ESCC', 'Disease', 'MESH:C562729', (65, 69))	('sensitizes', 'Reg', (54, 64))	('ESCC', 'Disease', (65, 69))	('VCP', 'Protein', (50, 53))
670095	31454136	Collectively, these data suggested that VCP inhibition enhanced radiation-mediated apoptosis and this enhancement was tumor cell-specific.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('inhibition', 'Var', (44, 54))	('radiation-mediated apoptosis', 'CPA', (64, 92))	('enhanced', 'PosReg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('VCP', 'Protein', (40, 43))
670096	31454136	An accumulation of unfolded proteins and misfolded proteins resulted in ER stress response in tumor cells.25 The ER stress response is an adaptive mechanism that contributes to cell survival; however, increased ER stress is associated with CHOP overexpression, and would predispose the cells to ER stress-mediated apoptosis.26, 27 Previous studies described radiation-induced ER stress in cancer cells.27, 28, 29 Valosin-containing protein inhibitors have been reported to trigger the misfolded protein accumulation and activate the UPR in various cancer cell lines.30 Therefore, we presumed that inhibiting a key component of the ER stress response might result in an elevated level of protein burden in the ER of tumor cells.	('inhibiting', 'Var', (597, 607))	('tumor', 'Disease', 'MESH:D009369', (715, 720))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Valosin-containing protein', 'Gene', '7415', (413, 439))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (715, 720))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('tumor', 'Disease', (715, 720))	('tumor', 'Disease', (94, 99))	('cancer', 'Disease', (548, 554))	('Valosin-containing protein', 'Gene', (413, 439))	('cancer', 'Disease', 'MESH:D009369', (548, 554))	('cancer', 'Phenotype', 'HP:0002664', (548, 554))	('level of protein burden', 'MPA', (678, 701))	('elevated', 'PosReg', (669, 677))	('cancer', 'Disease', (389, 395))	('cancer', 'Disease', 'MESH:D009369', (389, 395))
670107	31454136	Patients with low VCP expression had better survival than those in the high VCP expression group.	('survival', 'CPA', (44, 52))	('VCP', 'Protein', (18, 21))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (37, 43))	('low', 'Var', (14, 17))
670108	31454136	Based on univariate analyses, high expression of VCP (P = .005, HR = 0.457 [95% CI, 0.265-0.789]) and lymph node metastases (P = .001, HR = 0.255 [95% CI, 0.123-0.527]) were statistically significant predictors for poor survival.	('poor', 'NegReg', (215, 219))	('high', 'Var', (30, 34))	('VCP', 'Gene', (49, 52))	('metastases', 'Disease', (113, 123))	('metastases', 'Disease', 'MESH:D009362', (113, 123))
670131	31454136	Yamamoto et al15, 16 reported that high expression of VCP was associated with increased incidence of cancer progression in gastric carcinoma and esophageal cancer patients who received surgical resection.	('gastric carcinoma and esophageal cancer', 'Disease', 'MESH:D013274', (123, 162))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('VCP', 'Gene', (54, 57))	('patients', 'Species', '9606', (163, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', (101, 107))	('high expression', 'Var', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (123, 140))
670165	28659182	Genetic silencing of Mcl-1 sensitizes a spectrum of cancers, such as melanoma, non-small cell lung and hepatocellular cancers to chemotherapy.	('cancers', 'Disease', (118, 125))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('cancers', 'Disease', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('Mcl-1', 'Gene', '4170', (21, 26))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Genetic silencing', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('hepatocellular cancers', 'Disease', (103, 125))	('Mcl-1', 'Gene', (21, 26))	('melanoma', 'Disease', (69, 77))	('hepatocellular cancers', 'Disease', 'MESH:D006528', (103, 125))	('non-small cell lung', 'Disease', (79, 98))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('sensitizes', 'Reg', (27, 37))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
670167	28659182	For instance, microRNA-193b enhances the cytotoxicity of cisplatin to hepatocellular carcinoma cells by targeting Mcl-1.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (70, 94))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 94))	('Mcl-1', 'Gene', '4170', (114, 119))	('hepatocellular carcinoma', 'Disease', (70, 94))	('cytotoxicity', 'Disease', (41, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('enhances', 'PosReg', (28, 36))	('Mcl-1', 'Gene', (114, 119))	('microRNA-193b', 'Var', (14, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))
670171	28659182	Knockdown of MCL-1 also enhances sensitivity to cisplatin in gastric cancer cells expressing high levels of MCL-1.	('MCL-1', 'Gene', (13, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('Knockdown', 'Var', (0, 9))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('sensitivity to cisplatin', 'MPA', (33, 57))	('enhances', 'PosReg', (24, 32))
670175	28659182	The combination of UMI-77 and cisplatin induced apoptosis more significantly compared with treatment of UMI-77 or cisplatin alone by causing caspase-3 activation and PARP cleavage.	('caspase-3', 'Gene', (141, 150))	('UMI-77', 'Chemical', 'MESH:C000592878', (19, 25))	('caspase-3', 'Gene', '836', (141, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('PARP', 'Gene', '1302', (166, 170))	('PARP', 'Gene', (166, 170))	('UMI-77', 'Chemical', 'MESH:C000592878', (104, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('apoptosis', 'CPA', (48, 57))	('activation', 'PosReg', (151, 161))	('UMI-77', 'Var', (19, 25))
670176	28659182	In addition, the results demonstrated that UMI-77 prevented MCL-1/BAX and MCL-1/BAK complexes formation.	('UMI-77', 'Chemical', 'MESH:C000592878', (43, 49))	('BAX', 'Gene', (66, 69))	('BAK', 'Gene', (80, 83))	('BAX', 'Gene', '581', (66, 69))	('prevented', 'NegReg', (50, 59))	('BAK', 'Gene', '578', (80, 83))	('UMI-77', 'Var', (43, 49))
670187	28659182	The KYSE150, KYSE510, Eca109, and TE-1 ESCC cell lines were obtained and grown in RPMI-1640 medium supplemented with 10% FBS and 1% antibiotics as previously reported.	('KYSE510', 'Var', (13, 20))	('FBS', 'Disease', (121, 124))	('RPMI-1640 medium', 'Chemical', '-', (82, 98))	('KYSE510', 'CellLine', 'CVCL:1354', (13, 20))	('FBS', 'Disease', 'MESH:D005198', (121, 124))
670200	28659182	Primary antibodies were used for immunoblotting: MCL-1 (#5453), cleaved caspase-3 (#9664), cleaved PARP (#5625), BCL-2 (#2870), BCL-xL (#2764), BAX (#5023) and BAK (#6947) from Cell Signaling Technology; beta-actin (A5316) from Sigma-Aldrich; GAPDH (sc-47,724) from Santa Cruz Biotechnology.	('GAPDH', 'Gene', (243, 248))	('#5625', 'Var', (105, 110))	('BCL-2', 'Gene', '596', (113, 118))	('beta-actin', 'Gene', '728378', (204, 214))	('PARP', 'Gene', (99, 103))	('BCL-2', 'Gene', (113, 118))	('PARP', 'Gene', '1302', (99, 103))	('BAK', 'Gene', '578', (160, 163))	('BAX', 'Gene', (144, 147))	('caspase-3', 'Gene', '836', (72, 81))	('BCL-xL', 'Gene', (128, 134))	('BAX', 'Gene', '581', (144, 147))	('BAK', 'Gene', (160, 163))	('#2870', 'Var', (120, 125))	('BCL-xL', 'Gene', '598', (128, 134))	('caspase-3', 'Gene', (72, 81))	('GAPDH', 'Gene', '2597', (243, 248))	('beta-actin', 'Gene', (204, 214))
670201	28659182	Secondary antibodies were anti-rabbit IgG HRP (#7074) and anti-mouse IgG HRP (#7076) and purchased from Cell Signaling Technology.	('rabbit', 'Species', '9986', (31, 37))	('mouse', 'Species', '10090', (63, 68))	('#7076', 'Var', (78, 83))	('#7074', 'Var', (47, 52))
670211	28659182	Immunocomplexes were resolved by SDS-PAGE and co-immunoprecipitated proteins were detected using anti-BAX (#5023, Cell Signaling Technology) and anti-BAK (#6947, Cell Signaling Technology) antibodies, respectively.	('#5023', 'Var', (107, 112))	('BAK', 'Gene', '578', (150, 153))	('BAX', 'Gene', (102, 105))	('SDS', 'Chemical', 'MESH:D012967', (33, 36))	('BAX', 'Gene', '581', (102, 105))	('BAK', 'Gene', (150, 153))	('#6947', 'Var', (155, 160))
670214	28659182	old) were randomly divided into two groups (n = 10) and subcutaneously injected in the flank with KYSE150-shGFP or KYSE150-shMCL-1#2 esophageal carcinoma cells (2 x 106).	('esophageal carcinoma', 'Disease', 'MESH:D004938', (133, 153))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (133, 153))	('KYSE150-shGFP', 'Var', (98, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('KYSE150-shMCL-1', 'Var', (115, 130))	('esophageal carcinoma', 'Disease', (133, 153))
670241	28659182	The results demonstrate that diminishment of MCL-1 expression significantly reduces the tumorigenic properties of esophageal squamous cancer cells in vitro.	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (114, 140))	('esophageal squamous cancer', 'Disease', (114, 140))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('MCL-1', 'Gene', (45, 50))	('diminishment', 'Var', (29, 41))	('reduces', 'NegReg', (76, 83))	('expression', 'MPA', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('squamous cancer', 'Phenotype', 'HP:0002860', (125, 140))	('tumor', 'Disease', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
670242	28659182	We next determined whether knockdown of MCL-1 could suppress tumor growth in vivo.	('knockdown', 'Var', (27, 36))	('suppress', 'NegReg', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MCL-1', 'Gene', (40, 45))	('tumor', 'Disease', (61, 66))
670243	28659182	The results showed that the tumor in the KYSE150-shGFP group grew faster than that in the KYSE150-shMCL-1 group (Fig.	('KYSE150-shGFP', 'Var', (41, 54))	('tumor', 'Disease', (28, 33))	('faster', 'PosReg', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('grew', 'CPA', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
670244	28659182	The tumor volumes were decreased in the KYSE150-shMCL-1 group (Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('decreased', 'NegReg', (23, 32))	('KYSE150-shMCL-1', 'Var', (40, 55))
670245	28659182	The tumor weights were decreased in the KYSE150-shMCL-1 group (Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('decreased', 'NegReg', (23, 32))	('KYSE150-shMCL-1', 'Var', (40, 55))
670246	28659182	The IHC results showed that knockdown of MCL-1 dramatically decreased Ki67 staining in tumor tissue, which indicated that down-regulation of MCL-1 inhibited tumor cell proliferation in vivo (Fig.	('Ki67', 'Gene', (70, 74))	('tumor', 'Disease', (157, 162))	('decreased', 'NegReg', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('MCL-1', 'Gene', (141, 146))	('inhibited', 'NegReg', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (87, 92))	('Ki67', 'Gene', '17345', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('knockdown', 'Var', (28, 37))	('down-regulation', 'NegReg', (122, 137))
670247	28659182	These results suggest that blocking MCL-1 expression significantly reduces the tumorigenic properties of esophageal squamous cancer cells in vivo.	('tumor', 'Disease', (79, 84))	('blocking', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (105, 131))	('esophageal squamous cancer', 'Disease', (105, 131))	('squamous cancer', 'Phenotype', 'HP:0002860', (116, 131))	('MCL-1', 'Gene', (36, 41))	('reduces', 'NegReg', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
670253	28659182	The results demonstrated that knockdown of MCL-1 combined treatment with cisplatin enhanced cleavage of caspase-3 and PARP in both KYSE150 (Fig.	('cleavage', 'MPA', (92, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('enhanced', 'PosReg', (83, 91))	('caspase-3', 'Gene', '836', (104, 113))	('PARP', 'Gene', '1302', (118, 122))	('knockdown', 'Var', (30, 39))	('MCL-1', 'Gene', (43, 48))	('PARP', 'Gene', (118, 122))	('caspase-3', 'Gene', (104, 113))
670258	28659182	The results indicate that suppression of MCL-1 effectively enhances the sensitivity of ESCC cells to cisplatin and suggest that manipulating antiapoptotic proteins such as MCL-1 can potentiate the anticancer effect of common chemotherapeutic drug cisplatin.	('MCL-1', 'Gene', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (247, 256))	('cancer', 'Disease', (201, 207))	('potentiate', 'PosReg', (182, 192))	('MCL-1', 'Gene', (41, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('sensitivity', 'MPA', (72, 83))	('suppression', 'NegReg', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('enhances', 'PosReg', (59, 67))	('manipulating', 'Var', (128, 140))
670259	28659182	Since attenuation of MCL-1 by RNA interference lowered the threshold at which KYSE150 and KYSE510 cells undergo apoptosis and led to sensitization of these cells to undergo apoptosis triggered by cisplatin (Figs.	('cisplatin', 'Chemical', 'MESH:D002945', (196, 205))	('apoptosis', 'CPA', (173, 182))	('apoptosis', 'CPA', (112, 121))	('lowered', 'NegReg', (47, 54))	('KYSE510', 'Var', (90, 97))	('attenuation', 'NegReg', (6, 17))	('RNA interference', 'MPA', (30, 46))	('threshold', 'MPA', (59, 68))	('KYSE510', 'CellLine', 'CVCL:1354', (90, 97))	('sensitization', 'Reg', (133, 146))
670273	28659182	For instance, various CDK inhibitors, such as flavopiridol, roscovitine , and SNS-032, diminish MCL-1 levels and induce apoptosis in a variety of cell types.	('CDK', 'Protein', (22, 25))	('diminish', 'NegReg', (87, 95))	('SNS-032', 'Var', (78, 85))	('diminish MCL', 'Phenotype', 'HP:0025066', (87, 99))	('induce', 'PosReg', (113, 119))	('SNS-032', 'Chemical', 'MESH:C484864', (78, 85))	('apoptosis', 'CPA', (120, 129))	('flavopiridol', 'Chemical', 'MESH:C077990', (46, 58))	('MCL-1 levels', 'MPA', (96, 108))	('roscovitine', 'Chemical', 'MESH:D000077546', (60, 71))
670274	28659182	AZD8055, an mTORC1/2 inhibitor, reduces MCL-1 expression in KRAS- and BRAF-mutant colorectal cancer cells.	('colorectal cancer', 'Disease', (82, 99))	('AZD8055', 'Var', (0, 7))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('mTORC1/2', 'Gene', '74343;382056', (12, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('reduces', 'NegReg', (32, 39))	('MCL-1 expression', 'MPA', (40, 56))	('KRAS', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (60, 64))	('BRAF', 'Gene', '673', (70, 74))	('mTORC1/2', 'Gene', (12, 20))	('BRAF', 'Gene', (70, 74))
670275	28659182	The USP9X inhibitor WP1130 lowers MCL-1 levels in chronic myelogenous leukemia and enhances sensitivity to apoptosis by facilitating MCL-1 degradation.	('WP1130', 'Var', (20, 26))	('lowers', 'NegReg', (27, 33))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (58, 78))	('USP9X', 'Gene', (4, 9))	('sensitivity to apoptosis', 'MPA', (92, 116))	('USP9X', 'Gene', '8239', (4, 9))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (50, 78))	('WP1130', 'Chemical', 'MESH:C519751', (20, 26))	('MCL-1 levels', 'MPA', (34, 46))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('enhances', 'PosReg', (83, 91))	('chronic myelogenous leukemia', 'Disease', (50, 78))	('MCL-1 degradation', 'MPA', (133, 150))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (50, 78))
670281	28659182	Our results indicated that UMI-77 also induced apoptosis in ESCC cells when administrated as single agent (Figs.	('UMI-77', 'Var', (27, 33))	('apoptosis', 'CPA', (47, 56))	('UMI-77', 'Chemical', 'MESH:C000592878', (27, 33))
670290	28659182	reported that (-)-Gossypol enhances the antitumor efficacy of cisplatin through inhibition of APE1 repair and redox activity in non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('APE1', 'Gene', (94, 98))	('inhibition', 'NegReg', (80, 90))	('non-small cell lung cancer', 'Disease', (128, 154))	('APE1', 'Gene', '328', (94, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('-)-Gossypol', 'Var', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('enhances', 'PosReg', (27, 35))	('(-)-Gossypol', 'Chemical', 'MESH:D006072', (14, 26))	('redox activity', 'MPA', (110, 124))	('tumor', 'Disease', (44, 49))
670291	28659182	Furthermore, synergistic antitumor effects have been observed when MCL-1 inhibitors combined not only with cytoxic drugs but also with other chemotherapeutic agents.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('combined', 'Interaction', (84, 92))	('MCL-1', 'Gene', (67, 72))	('inhibitors', 'Var', (73, 83))
670294	28659182	Our results demonstrated that UMI-77 synergistically enhanced cisplatin-induced apoptosis in both KYSE150 and KYSE510 cells (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('cisplatin-induced', 'MPA', (62, 79))	('UMI-77', 'Chemical', 'MESH:C000592878', (30, 36))	('KYSE510', 'CellLine', 'CVCL:1354', (110, 117))	('UMI-77', 'Var', (30, 36))	('enhanced', 'PosReg', (53, 61))
670296	28659182	The enhanced apoptosis when cisplatin in combination with MCL-1 knockdown (Figs.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('MCL-1', 'Gene', (58, 63))	('enhanced', 'PosReg', (4, 12))	('apoptosis', 'CPA', (13, 22))	('knockdown', 'Var', (64, 73))
670304	28659182	reported that the combination of ABT-263 and AZD8055, an mTORC1/2 inhibitor that reduced MCL-1 protein levels, potently suppresses tumor progression across a variety of preclinical small cell lung cancer experimental models.	('mTORC1/2', 'Gene', (57, 65))	('small cell lung cancer', 'Disease', (181, 203))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mTORC1/2', 'Gene', '74343;382056', (57, 65))	('ABT-263', 'Chemical', 'MESH:C528561', (33, 40))	('MCL-1 protein levels', 'MPA', (89, 109))	('AZD8055', 'Var', (45, 52))	('suppresses', 'NegReg', (120, 130))	('AZD8055', 'Chemical', 'MESH:C546624', (45, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('small cell lung cancer', 'Disease', 'MESH:D055752', (181, 203))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (181, 203))	('reduced', 'NegReg', (81, 88))	('reduced MCL', 'Phenotype', 'HP:0025066', (81, 92))
670305	28659182	Potent and selective small-molecule MCL-1 inhibitors A-1210477 synergizes with the BCL-2 and BCL-xL inhibitor ABT-263 to kill a variety of cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('ABT-263', 'Chemical', 'MESH:C528561', (110, 117))	('BCL-2', 'Gene', '596', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('inhibitors A-1210477', 'Var', (42, 62))	('BCL-xL', 'Gene', '598', (93, 99))	('BCL-xL', 'Gene', (93, 99))	('BCL-2', 'Gene', (83, 88))	('MCL-1', 'Gene', (36, 41))	('A-1210477', 'Var', (53, 62))	('cancer', 'Disease', (139, 145))
670324	28659182	Our results suggests that MCL-1 contributes to the development of ESCC and provide insights into the potential role of MCL-1 as a therapeutic target in ESCC chemotherapy and show that antagonizing MCL-1 function with RNAi-mediated knockdown or small molecule MCL-1 inhibitor UMI-77 sensitizes ESCC cells to cisplatin-induced apoptosis.	('cisplatin-induced apoptosis', 'CPA', (307, 334))	('antagonizing', 'Var', (184, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (307, 316))	('ESCC', 'Disease', (66, 70))	('ESCC', 'Disease', (293, 297))	('sensitizes', 'Reg', (282, 292))	('UMI-77', 'Chemical', 'MESH:C000592878', (275, 281))
670333	27956773	Cancer is a fatal disease characterized by abnormal proliferation of cells as a result of genetic mutation.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('rat', 'Species', '10116', (59, 62))	('genetic mutation', 'Var', (90, 106))	('abnormal proliferation of cells', 'Phenotype', 'HP:0031377', (43, 74))
670360	27956773	Esophageal adenocarcinoma can be induced by insertion of interleukin-1beta cDNA into the Epstein-Barr virus ED-L2 leading to columnar metaplasia similar to that observed in Barrett's esophagitis.	('Epstein-Barr virus', 'Species', '10376', (89, 107))	('Esophageal adenocarcinoma', 'Disease', (0, 25))	("Barrett's esophagitis", 'Disease', (173, 194))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (0, 25))	("Barrett's esophagitis", 'Phenotype', 'HP:0100580', (173, 194))	('columnar metaplasia', 'Disease', (125, 144))	('induced', 'Reg', (33, 40))	('insertion', 'Var', (44, 53))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('esophagitis', 'Phenotype', 'HP:0100633', (183, 194))	("Barrett's esophagitis", 'Disease', 'MESH:D001471', (173, 194))	('columnar metaplasia', 'Disease', 'MESH:D008679', (125, 144))
670363	27956773	Several human esophageal cell lines are available such as KYSE-270, KYSE-30, and KYSE-70 that produce esophageal squamous cell carcinoma and OACM5.1 C, SK-GT-4, etc., that produce adenocarcinoma.	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('KYSE-70', 'Var', (81, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('SK-GT-4', 'Chemical', '-', (152, 159))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('adenocarcinoma', 'Disease', (180, 194))	('human', 'Species', '9606', (8, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('adenocarcinoma', 'Disease', 'MESH:D000230', (180, 194))
670391	27956773	The animals develop inflammation as a result of the acid, which in turn triggers adenocarcinoma mimicking that of Barrett's esophagus.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('adenocarcinoma', 'Disease', (81, 95))	('adenocarcinoma', 'Disease', 'MESH:D000230', (81, 95))	('develop', 'PosReg', (12, 19))	('acid', 'Var', (52, 56))	('inflammation', 'Disease', 'MESH:D007249', (20, 32))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (114, 133))	('inflammation', 'Disease', (20, 32))	("Barrett's esophagus", 'Disease', (114, 133))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (114, 133))	('triggers', 'Reg', (72, 80))
670403	26788120	P. gingivalis was detected immunohistochemically in 61 % of cancerous tissues, 12 % of adjacent tissues and was undetected in normal esophageal mucosa.	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('cancerous', 'Disease', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancerous', 'Disease', 'MESH:D009369', (60, 69))
670406	26788120	These findings demonstrate for the first time that P. gingivalis infects the epithelium of the esophagus of ESCC patients, establish an association between infection with P. gingivalis and the progression of ESCC, and suggest P. gingivalis infection could be a biomarker for this disease.	('P. gingivalis', 'Species', '837', (226, 239))	('ESCC', 'Disease', (208, 212))	('P. gingivalis infection', 'Disease', 'MESH:C000656865', (226, 249))	('P. gingivalis', 'Species', '837', (171, 184))	('patients', 'Species', '9606', (113, 121))	('P. gingivalis', 'Var', (51, 64))	('P. gingivalis', 'Species', '837', (51, 64))	('P. gingivalis infection', 'Disease', (226, 249))	('association', 'Interaction', (136, 147))
670421	26788120	Since esophageal squamous cells are histologically similar to oral squamous cells and esophageal infection arising from the oral niche is highly plausible, we hypothesized that P. gingivalis may be associated with ESCC.	('ESCC', 'Disease', (214, 218))	('esophageal infection', 'Disease', (86, 106))	('esophageal infection', 'Disease', 'MESH:D004941', (86, 106))	('associated', 'Reg', (198, 208))	('P. gingivalis', 'Var', (177, 190))	('P. gingivalis', 'Species', '837', (177, 190))
670422	26788120	1, P. gingivalis was detected in cancerous and adjacent esophageal mucosa, but not healthy mucosa.	('P. gingivalis', 'Species', '837', (3, 16))	('P. gingivalis', 'Var', (3, 16))	('cancerous', 'Disease', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancerous', 'Disease', 'MESH:D009369', (33, 42))
670436	26788120	Since an association between P. gingivalis infection and ESCC had been demonstrated, we next sought to determine if the presence of P. gingivalis antigens is associated with the progression of esophageal cancer.	('associated with', 'Reg', (158, 173))	('P. gingivalis infection', 'Disease', (29, 52))	('ESCC', 'Disease', (57, 61))	('P. gingivalis infection', 'Disease', 'MESH:C000656865', (29, 52))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('esophageal cancer', 'Disease', (193, 210))	('presence', 'Var', (120, 128))	('P. gingivalis', 'Species', '837', (29, 42))	('P. gingivalis', 'Species', '837', (132, 145))	('association', 'Interaction', (9, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))
670438	26788120	While the presence of P. gingivalis was not significantly associated with age, gender, or smoking history of the patients, the presence of P. gingivalis was positively related to differentiation, lymph node metastasis and the TNM stage of ESCC (p < 0.05).	('P. gingivalis', 'Species', '837', (22, 35))	('differentiation', 'CPA', (179, 194))	('patients', 'Species', '9606', (113, 121))	('ESCC', 'Disease', (239, 243))	('related', 'Reg', (168, 175))	('P. gingivalis', 'Var', (139, 152))	('TNM stage', 'CPA', (226, 235))	('lymph node metastasis', 'CPA', (196, 217))	('P. gingivalis', 'Species', '837', (139, 152))	('presence', 'Var', (127, 135))
670439	26788120	A positive immunohistochemical signal for P. gingivalis was 90 % in the poorly differentiated tissues, which was significantly higher than that of well or moderately differentiated samples (p < 0.05) (Table 5).	('P. gingivalis', 'Var', (42, 55))	('higher', 'PosReg', (127, 133))	('P. gingivalis', 'Species', '837', (42, 55))
670442	26788120	Additionally, the presence of P. gingivalis was closely related to the TNM stage of ESCC.	('P. gingivalis', 'Var', (30, 43))	('P. gingivalis', 'Species', '837', (30, 43))	('ESCC', 'Disease', (84, 88))	('TNM stage', 'Disease', (71, 80))	('related', 'Reg', (56, 63))
670447	26788120	However, the mean survival time for patients with positive P. gingivalis antigen expression was 20.139 months, significantly lower than that of P. gingivalis negative group (25.971 months) or all patients (23.981 months) (both p < 0.05) (Table 6).	('positive P. gingivalis', 'Var', (50, 72))	('P. gingivalis', 'Species', '837', (144, 157))	('patients', 'Species', '9606', (36, 44))	('P. gingivalis', 'Species', '837', (59, 72))	('patients', 'Species', '9606', (196, 204))	('survival time', 'CPA', (18, 31))	('lower', 'NegReg', (125, 130))
670453	26788120	Moreover, our analysis indicates that the presence of P. gingivalis correlates with multiple clinicopathologic factors, including cancer cell differentiation, metastasis, and overall survival ESCC rate.	('P. gingivalis', 'Species', '837', (54, 67))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('metastasis', 'CPA', (159, 169))	('ESCC rate', 'PosReg', (192, 201))	('cancer', 'Disease', (130, 136))	('presence', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('P. gingivalis', 'Var', (54, 67))	('overall survival', 'CPA', (175, 191))
670457	26788120	In this regard, both our group and others have demonstrated that P. gingivalis activates JAK2 and GSK3beta pathways, thus increasing the production of IL-6 in epithelial cells.	('production of IL-6', 'MPA', (137, 155))	('P. gingivalis', 'Species', '837', (65, 78))	('P. gingivalis', 'Var', (65, 78))	('increasing', 'PosReg', (122, 132))	('GSK3beta pathways', 'Pathway', (98, 115))	('activates', 'PosReg', (79, 88))
670462	26788120	Thirdly, P. gingivalis inhibits epithelial cell apoptosis by a number of mechanisms, including activation of Jak1/Akt/Stat3, enhancing the Bcl2 (antiapoptotic): Bax (proapoptotic) ratio, blocking the release of the apoptosis effector cytochrome c, and the activation of downstream caspases.	('release', 'MPA', (200, 207))	('apoptosis effector cytochrome c', 'MPA', (215, 246))	('epithelial cell apoptosis', 'CPA', (32, 57))	('blocking', 'NegReg', (187, 195))	('activation', 'PosReg', (256, 266))	('activation', 'PosReg', (95, 105))	('enhancing', 'PosReg', (125, 134))	('P. gingivalis', 'Species', '837', (9, 22))	('P. gingivalis', 'Var', (9, 22))	('Jak1/Akt/Stat3', 'Pathway', (109, 123))	('inhibits', 'NegReg', (23, 31))
670463	26788120	Moreover, P. gingivalis can upregulate microRNAs, such as miR-203, which suppress apoptosis in primary gingival epithelial cells.	('suppress', 'NegReg', (73, 81))	('P. gingivalis', 'Var', (10, 23))	('miR-203', 'Chemical', '-', (58, 65))	('apoptosis', 'CPA', (82, 91))	('P. gingivalis', 'Species', '837', (10, 23))	('miR-203', 'Gene', (58, 65))	('upregulate', 'PosReg', (28, 38))
670465	26788120	Lastly, in oral squamous cell carcinoma (OSCC) cells, P. gingivalis promotes cellular migration through activation of the ERK1/2-Ets1, p38/HSP27, and PAR2/NF-kappaB pathways to induce pro-matrix metalloproteinase (MMP)-9 expression.	('p38/HSP27', 'Protein', (135, 144))	('activation', 'PosReg', (104, 114))	('promotes', 'PosReg', (68, 76))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (11, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('oral squamous cell carcinoma', 'Disease', (11, 39))	('PAR2/NF-kappaB pathways', 'Pathway', (150, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('P. gingivalis', 'Var', (54, 67))	('expression', 'MPA', (221, 231))	('induce', 'PosReg', (177, 183))	('cellular migration', 'CPA', (77, 95))	('P. gingivalis', 'Species', '837', (54, 67))	('ERK1/2-Ets1', 'Pathway', (122, 133))	('MMP)-9', 'Gene', (214, 220))
670470	26788120	Should P. gingivalis prove to cause ESCC, the implications are enormous.	('cause', 'Reg', (30, 35))	('P. gingivalis', 'Species', '837', (7, 20))	('P. gingivalis', 'Var', (7, 20))	('ESCC', 'Disease', (36, 40))
670477	26788120	Dysbiosis of the microbiota in the esophagus could potentially cause or exacerbate the severity of esophageal disorders.	('esophageal disorders', 'Disease', 'MESH:D004935', (99, 119))	('cause', 'Reg', (63, 68))	('esophageal disorders', 'Disease', (99, 119))	('exacerbate', 'PosReg', (72, 82))	('severity', 'MPA', (87, 95))	('Dysbiosis', 'Var', (0, 9))
670478	26788120	Thus, a further possibility to be tested is that esophageal infection with P. gingivalis leads to shift in the microbiome involved in the development of esophageal cancer.	('P. gingivalis', 'Species', '837', (75, 88))	('P. gingivalis', 'Var', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('esophageal infection', 'Disease', (49, 69))	('shift', 'Reg', (98, 103))	('esophageal infection', 'Disease', 'MESH:D004941', (49, 69))	('esophageal cancer', 'Disease', (153, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
670527	25674530	The patient underwent an Ivor-Lewis esophagectomy with regional lymph node dissection for recurrent multifocal esophageal neoplasia, and the final pathologic staging was TisN0M0 (stage 0).	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (111, 131))	('patient', 'Species', '9606', (4, 11))	('multifocal esophageal neoplasia', 'Disease', 'None', (100, 131))	('multifocal esophageal neoplasia', 'Disease', (100, 131))	('TisN0M0', 'Var', (170, 177))	('neoplasia', 'Phenotype', 'HP:0002664', (122, 131))
670560	23093236	They showed that triangular-stapled anastomosis had a lower frequency of anastomotic failure and stenosis than that of hand-sewn or circular stapler anastomosis.	('anastomotic failure', 'Disease', (73, 92))	('triangular-stapled', 'Var', (17, 35))	('stenosis', 'CPA', (97, 105))	('anastomotic failure', 'Disease', 'MESH:D057868', (73, 92))	('lower', 'NegReg', (54, 59))
670590	23093236	reported that the anastomotic stenosis was observed in 8.3 % at triangulating stapled anastomosis, which was lower than that observed for hand-sewn or circular stapled anastomosis.	('anastomotic stenosis', 'Disease', (18, 38))	('anastomotic stenosis', 'Disease', 'MESH:D057868', (18, 38))	('triangulating stapled', 'Var', (64, 85))
670625	20507544	The presence of IEM was associated with delayed esophageal acid clearance.	('IEM', 'Gene', (16, 19))	('IEM', 'Chemical', '-', (16, 19))	('esophageal acid', 'Chemical', '-', (48, 63))	('presence', 'Var', (4, 12))	('delayed esophageal acid clearance', 'MPA', (40, 73))
670646	20507544	Therefore, it can be hypothesized that even small amounts of aspiration could lead to significant injury, particularly with multiple repeated episodes over time.	('injury', 'Disease', (98, 104))	('lead to', 'Reg', (78, 85))	('aspiration', 'Phenotype', 'HP:0002835', (61, 71))	('injury', 'Disease', 'MESH:D058186', (98, 104))	('aspiration', 'Var', (61, 71))	('rat', 'Species', '10116', (65, 68))
670663	20507544	However, with reflux into the proximal esophagus, symptoms are likely related to microaspiration.	('aspiration', 'Phenotype', 'HP:0002835', (86, 96))	('microaspiration', 'Disease', (81, 96))	('reflux', 'Var', (14, 20))	('related', 'Reg', (70, 77))	('symptoms', 'Disease', (50, 58))	('rat', 'Species', '10116', (90, 93))
670687	20507544	However, 70% of the patients with BOS had bile in BALF, compared with 31% of stable patients.	('patients', 'Species', '9606', (84, 92))	('BOS', 'Chemical', '-', (34, 37))	('bile in BALF', 'MPA', (42, 54))	('BOS', 'Var', (34, 37))	('patients', 'Species', '9606', (20, 28))
670693	20507544	Freedom from BOS was reduced in patients with abnormal (proximal and/or distal) pH findings or BALF bile acids.	('reduced', 'NegReg', (21, 28))	('patients', 'Species', '9606', (32, 40))	('bile acids', 'Chemical', 'MESH:D001647', (100, 110))	('BOS', 'Chemical', '-', (13, 16))	('BALF', 'Var', (95, 99))
670699	20507544	However, both nocturnal esophageal volume exposure and the number of nocturnal weakly acidic reflux events were significantly higher in patients who had bile acids in BALF.	('bile acids', 'Var', (153, 163))	('reflux events', 'Phenotype', 'HP:0002020', (93, 106))	('higher', 'PosReg', (126, 132))	('bile acids', 'Chemical', 'MESH:D001647', (153, 163))	('patients', 'Species', '9606', (136, 144))	('weakly acidic reflux events', 'MPA', (79, 106))	('acidic reflux', 'Phenotype', 'HP:0002020', (86, 99))
670708	20507544	Edelbroek et al has shown that erythromycin increases the rate of total and proximal stomach emptying of both solids and liquids.	('erythromycin', 'Chemical', 'MESH:D004917', (31, 43))	('stomach emptying', 'Phenotype', 'HP:0002578', (85, 101))	('total and', 'MPA', (66, 75))	('erythromycin', 'Var', (31, 43))	('rat', 'Species', '10116', (58, 61))	('increases', 'PosReg', (44, 53))
670718	20507544	were the first group to demonstrate improvement in pulmonary function after fundoplication in a lung transplant recipient.	('fundoplication', 'Var', (76, 90))	('pulmonary function', 'MPA', (51, 69))	('improvement', 'PosReg', (36, 47))	('improvement in pulmonary function', 'Phenotype', 'HP:0005952', (36, 69))	('rat', 'Species', '10116', (31, 34))
670807	32280752	2), although cross-sectional imaging depicted high suspicion of malignancy in view of asymmetrical thickening or mass (Fig.	('asymmetrical thickening', 'Phenotype', 'HP:0001528', (86, 109))	('malignancy', 'Disease', (64, 74))	('malignancy', 'Disease', 'MESH:D009369', (64, 74))	('asymmetrical', 'Var', (86, 98))
670845	31903058	Several studies have examined body mass index (BMI) as well as measures of abdominal obesity; Kramer et al demonstrated that high waist-to-hip ratio but not BMI is associated with increased risk of Barrett esophagus.	('abdominal obesity', 'Phenotype', 'HP:0012743', (75, 92))	('high waist-to-hip ratio', 'Phenotype', 'HP:0031819', (125, 148))	('abdominal obesity', 'Disease', (75, 92))	('Barrett esophagus', 'Disease', (198, 215))	('high waist-to-hip', 'Var', (125, 142))	('abdominal obesity', 'Disease', 'MESH:D056128', (75, 92))	('obesity', 'Phenotype', 'HP:0001513', (85, 92))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (198, 215))
670847	31903058	The risk of developing esophageal adenocarcinoma in individuals with a BMI >=30 kg/m2 is an estimated 2.4 to 2.8 times higher than the risk for those with normal BMI (18.5-24.9 kg/m2).	('>=30 kg/m2', 'Var', (75, 85))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (23, 48))	('esophageal adenocarcinoma', 'Disease', (23, 48))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (23, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))
670915	31772236	In the OE19 EAC cell line with mainly HER2 phosphorylation, and the ESO51 EAC cell line with mainly MET phosphorylation, profound cell growth inhibition with induction of apoptosis was observed in response to single agent with lack of enhanced growth inhibition when the two agents were combined.	('HER2', 'Protein', (38, 42))	('EAC', 'Phenotype', 'HP:0011459', (74, 77))	('EAC', 'Disease', 'MESH:D004941', (12, 15))	('EAC', 'Disease', (12, 15))	('EAC', 'Disease', (74, 77))	('apoptosis', 'CPA', (171, 180))	('cell growth', 'CPA', (130, 141))	('phosphorylation', 'Var', (43, 58))	('EAC', 'Disease', 'MESH:D004941', (74, 77))	('EAC', 'Phenotype', 'HP:0011459', (12, 15))
670932	31772236	Recent studies indicated that EAC is driven by amplification of c-MET and HER2 in a subset of patients who may be resistant to lapatinib therapy.	('lapatinib', 'Chemical', 'MESH:C490728', (127, 136))	('c-MET', 'Gene', '4233', (64, 69))	('patients', 'Species', '9606', (94, 102))	('EAC', 'Phenotype', 'HP:0011459', (30, 33))	('EAC', 'Disease', (30, 33))	('amplification', 'Var', (47, 60))	('EAC', 'Disease', 'MESH:D004941', (30, 33))	('HER2', 'Protein', (74, 78))	('c-MET', 'Gene', (64, 69))
670935	31772236	In this study, we therefore hypothesized that MET activation may lead to lapatinib resistance in HER2-driven esophageal adenocarcinoma, and tested the feasibility of MET targeting by small-molecule inhibitor Foretinib in EAC cells.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('Foretinib', 'Chemical', 'MESH:C544831', (208, 217))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (109, 134))	('esophageal adenocarcinoma', 'Disease', (109, 134))	('lapatinib', 'Chemical', 'MESH:C490728', (73, 82))	('EAC', 'Disease', 'MESH:D004941', (221, 224))	('EAC', 'Disease', (221, 224))	('activation', 'PosReg', (50, 60))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (109, 134))	('MET', 'Var', (46, 49))	('tested', 'Reg', (140, 146))	('lapatinib resistance', 'MPA', (73, 93))	('lead to', 'Reg', (65, 72))	('EAC', 'Phenotype', 'HP:0011459', (221, 224))
670952	31772236	The nitrocellulose membranes were blocked for 1 hour in PBS-T at room temperature and then incubated overnight at 4  C with the following primary antibodies: cleaved poly (ADP-ribose) polymerase-1 (c-PARP) (Catalog #5625), cleaved caspase-3 (Catalog #5664), total MET (Catalog #8198) and phospho-MET(Catalog #3077), total HER2 (Catalog #2165) and phospho-HER2 (Catalog #2243) (all from Cell Signaling Technology, Beverly, MA) and beta-actin (Sigma-Aldrich, St. Louis, MO) (Catalog #A1978).	('poly (ADP-ribose) polymerase-1', 'Gene', '142', (166, 196))	('poly (ADP-ribose) polymerase-1', 'Gene', (166, 196))	('c-PARP', 'Gene', '142', (198, 204))	('c-PARP', 'Gene', (198, 204))	('Catalog #5664', 'Var', (242, 255))	('Catalog #2165', 'Var', (328, 341))	('beta-actin', 'Gene', '728378', (430, 440))	('Catalog #3077', 'Var', (300, 313))	('phospho-MET', 'Chemical', 'MESH:C098756', (288, 299))	('beta-actin', 'Gene', (430, 440))	('Catalog #2243', 'Var', (361, 374))	('Catalog #8198', 'Var', (269, 282))
670972	31772236	On the other hand, ESO51 cells with predominately MET phosphorylation showed significant cell growth inhibition with single-agent MET-targeting foretinib at 0.1 muM, and co-administration of lapatinib with foretinib didn't further enhance ESO 51 cell growth inhibition (Fig.	('foretinib', 'Chemical', 'MESH:C544831', (206, 215))	('cell growth inhibition', 'CPA', (89, 111))	('muM', 'Gene', (161, 164))	('muM', 'Gene', '56925', (161, 164))	('phosphorylation', 'Var', (54, 69))	('lapatinib', 'Chemical', 'MESH:C490728', (191, 200))	('ESO 51 cell growth inhibition', 'CPA', (239, 268))	('MET phosphorylation', 'Var', (50, 69))	('foretinib', 'Chemical', 'MESH:C544831', (144, 153))	('MET-targeting', 'Var', (130, 143))
670975	31772236	Immunoblot analysis to determine the effect of lapatinib on HER signaling and foretinib on MET signaling revealed that lapatinib blocked the expression of phospho-HER2 (pHER2), and foretinib blocked the expression of phospho-MET (pMET) (Fig.	('blocked', 'NegReg', (191, 198))	('lapatinib', 'Chemical', 'MESH:C490728', (119, 128))	('pMET', 'Chemical', 'MESH:C098756', (230, 234))	('phospho-HER2', 'Var', (155, 167))	('expression', 'MPA', (203, 213))	('blocked', 'NegReg', (129, 136))	('foretinib', 'Chemical', 'MESH:C544831', (78, 87))	('expression', 'MPA', (141, 151))	('foretinib', 'Chemical', 'MESH:C544831', (181, 190))	('phospho-MET', 'Chemical', 'MESH:C098756', (217, 228))	('lapatinib', 'Chemical', 'MESH:C490728', (47, 56))
670985	31772236	Net tumor growth inhibition in lapatinib (L), foretinib (F), L + F, CP (carboplatin) + PT (paclitaxel), CP + PT + L + F groups was 3%, 12.5%, 56.3%, 59.4%, and 65.5% as compared with the control.	('tumor', 'Disease', (4, 9))	('PT', 'Chemical', 'MESH:D017239', (109, 111))	('lapatinib', 'Chemical', 'MESH:C490728', (31, 40))	('foretinib', 'Chemical', 'MESH:C544831', (46, 55))	('carboplatin', 'Chemical', 'MESH:D016190', (72, 83))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('paclitaxel', 'Chemical', 'MESH:D017239', (91, 101))	('PT', 'Chemical', 'MESH:D017239', (87, 89))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CP + PT + L + F', 'Var', (104, 119))
670988	31772236	In addition, compared to control, lapatinib (0.38426 g vs. 0.3847 g, p = 0.9867) and foretinib (0.38426 g vs. 0.3891 g, p = 0.22684) didn't significantly decrease mean tumor weight as monotherapy but significantly decreased mean tumor weight as combination therapy (0.38426 g vs. 0.22347 g, p = 0.00013) with further enhancement in reducing mean tumor weight when lapatinib plus foretinib was combined with CP plus PT (0.22347 g vs. 0.1795 g, p = 0.0466) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('PT', 'Chemical', 'MESH:D017239', (415, 417))	('0.22347 g', 'Var', (419, 428))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('lapatinib', 'Chemical', 'MESH:C490728', (364, 373))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('decreased', 'NegReg', (214, 223))	('reducing', 'NegReg', (332, 340))	('tumor', 'Disease', (168, 173))	('decrease', 'NegReg', (154, 162))	('combined', 'Interaction', (393, 401))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('lapatinib', 'Chemical', 'MESH:C490728', (34, 43))	('foretinib', 'Chemical', 'MESH:C544831', (379, 388))	('mean', 'MPA', (163, 167))	('foretinib', 'Chemical', 'MESH:C544831', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', (346, 351))
670994	31772236	6d) of OE33 tumor xenografts with an antibody that recognizes carcinoma cells expressing the proliferative marker Ki-67, showed significantly lower number of carcinoma cells expressing Ki-67 per 100 total number of cells (proliferative index) in the lapatinib plus foretinib combination therapy group compared to that of the control, lapatinib or foretinib treatment groups.	('foretinib', 'Chemical', 'MESH:C544831', (347, 356))	('carcinoma', 'Disease', (158, 167))	('Ki-67', 'Var', (185, 190))	('foretinib', 'Chemical', 'MESH:C544831', (265, 274))	('carcinoma', 'Disease', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lower', 'NegReg', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('lapatinib', 'Chemical', 'MESH:C490728', (334, 343))	('carcinoma', 'Disease', 'MESH:D002277', (158, 167))	('carcinoma', 'Disease', 'MESH:D002277', (62, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('tumor', 'Disease', (12, 17))	('lapatinib', 'Chemical', 'MESH:C490728', (250, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
671009	31772236	Using only in-vitro studies, it has been suggested that MET activation may confer lapatinib resistance in EAC.	('EAC', 'Phenotype', 'HP:0011459', (106, 109))	('EAC', 'Disease', 'MESH:D004941', (106, 109))	('EAC', 'Disease', (106, 109))	('MET activation', 'Var', (56, 70))	('lapatinib', 'Chemical', 'MESH:C490728', (82, 91))	('lapatinib resistance', 'MPA', (82, 102))
671016	31772236	It has been reported that In-vitro targeting of HER2 in EAC cell lines with lapatinib resulted in inhibition of the phosphorylated HER2 receptor and downstream signaling with the development of lapatinib resistance due to MET amplification.	('EAC cell lines', 'Disease', (56, 70))	('inhibition', 'NegReg', (98, 108))	('lapatinib', 'Chemical', 'MESH:C490728', (76, 85))	('downstream signaling', 'MPA', (149, 169))	('EAC cell lines', 'Disease', 'MESH:D002292', (56, 70))	('lapatinib', 'Chemical', 'MESH:C490728', (194, 203))	('phosphorylated', 'MPA', (116, 130))	('EAC', 'Phenotype', 'HP:0011459', (56, 59))	('HER2 receptor', 'Protein', (131, 144))	('MET amplification', 'Var', (222, 239))
671024	31772236	Similarly, MET phosphorylation in MET driven ESO51 EAC cells rendered ESO51 cells more sensitive to single-agent foretinib induced cell growth inhibition and apoptosis than that of lapatinib.	('EAC', 'Disease', 'MESH:D004941', (51, 54))	('lapatinib', 'Chemical', 'MESH:C490728', (181, 190))	('MET phosphorylation', 'Var', (11, 30))	('ESO51', 'Gene', (45, 50))	('apoptosis', 'CPA', (158, 167))	('foretinib', 'Chemical', 'MESH:C544831', (113, 122))	('sensitive', 'MPA', (87, 96))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('cell growth inhibition', 'CPA', (131, 153))	('EAC', 'Disease', (51, 54))
671026	31772236	HER2 and MET co-activation rendered OE33 EAC cells less sensitive to single-agent lapatinib or foretinib induced cell growth inhibition and apoptosis, but enhanced growth inhibition with apoptosis was noted when combining lapatinib with foretinib.	('EAC', 'Disease', 'MESH:D004941', (41, 44))	('co-activation', 'Var', (13, 26))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('cell growth inhibition', 'CPA', (113, 135))	('apoptosis', 'CPA', (140, 149))	('less', 'NegReg', (51, 55))	('foretinib', 'Chemical', 'MESH:C544831', (237, 246))	('foretinib', 'Chemical', 'MESH:C544831', (95, 104))	('EAC', 'Disease', (41, 44))	('sensitive', 'MPA', (56, 65))	('lapatinib', 'Chemical', 'MESH:C490728', (82, 91))	('HER2', 'Protein', (0, 4))	('lapatinib', 'Chemical', 'MESH:C490728', (222, 231))
671037	31772236	The combination of anti-MET therapy with anti-HER2 therapy could have a direct clinical benefit in a subset of EAC patients.	('patients', 'Species', '9606', (115, 123))	('anti-MET', 'Var', (19, 27))	('EAC', 'Disease', (111, 114))	('EAC', 'Disease', 'MESH:D004941', (111, 114))	('EAC', 'Phenotype', 'HP:0011459', (111, 114))
671082	31152823	GERD can lead to further accumulation of genetic alterations in BE cells and progression to EAC at a rate approximately 0.12%-0.6% per year.	('genetic alterations', 'Var', (41, 60))	('rat', 'Species', '10116', (101, 104))	('accumulation', 'PosReg', (25, 37))	('EAC', 'Disease', (92, 95))	('rat', 'Species', '10116', (53, 56))	('BE', 'Phenotype', 'HP:0100580', (64, 66))
671083	31152823	In this review, we will discuss genetic and epigenetic changes that play an integral role in the progression of Barrett's esophagus to esophageal adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (146, 160))	("Barrett's esophagus", 'Disease', (112, 131))	('epigenetic changes', 'Var', (44, 62))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (112, 131))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (135, 160))	('adenocarcinoma', 'Disease', (146, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
671085	31152823	Based on a comprehensive comparison across more than 3000 cancers and 27 tumor types, EAC was included in a group of tumors with the most frequent copy-number alterations (CNA).	('rat', 'Species', '10116', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('copy-number alterations', 'Var', (147, 170))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', (73, 78))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('EAC', 'Disease', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
671088	31152823	This frequency translates into a median of 26,161(range of 18,881-66,225) mutations across the genome per tumor.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
671091	31152823	Recurrent structural rearrangements at 1p, 3q, 11p, and 22p and frequent mutations in the TP53 gene, which encodes p53, a well-known tumor suppressor, have also been found.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('TP53', 'Gene', '7157', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('TP53', 'Gene', (90, 94))	('tumor', 'Disease', (133, 138))	('men', 'Species', '9606', (30, 33))	('mutations', 'Var', (73, 82))
671092	31152823	Fluorescent in situ Hybridization (FISH) has helped to identify additional numeric changes in chromosomes 4, 6, 7, 8, 9, 10, 11, 12, 17, 18, Y, and X that were found to be an early change in dysplastic regions.	('dysplastic', 'Disease', (191, 201))	('changes', 'Var', (83, 90))	('dysplastic', 'Disease', 'MESH:D004416', (191, 201))
671095	31152823	Chromosomal alterations were also found in BE adjacent to cancer sites.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Chromosomal alterations', 'Var', (0, 23))	('rat', 'Species', '10116', (16, 19))	('BE', 'Phenotype', 'HP:0100580', (43, 45))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
671096	31152823	Several studies have suggested that recurrent gains (8q, 6p, 10q) and losses (13q, Y, 9p, 17p) occur in Barrett's metaplastic cells even in the absence of dysplasia and adenocarcinoma, although to a lesser extend.	('adenocarcinoma', 'Disease', 'MESH:D000230', (169, 183))	('gains', 'PosReg', (46, 51))	('absence of dysplasia', 'Disease', 'MESH:D004832', (144, 164))	('absence of dysplasia', 'Disease', (144, 164))	('13q', 'Var', (78, 81))	('8q', 'Var', (53, 55))	('adenocarcinoma', 'Disease', (169, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('losses', 'NegReg', (70, 76))
671100	31152823	The initial systematic NGS study by Dulak et al, which included 149 EAC tumor - normal pairs, found mutations in 8,331 genes, of which 199 were mutated in 5% or more of the EACs.	('mutations', 'Var', (100, 109))	('mutated', 'Var', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('genes', 'Gene', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('EACs', 'Chemical', 'MESH:D015119', (173, 177))
671102	31152823	Seventy two percent of EACs carry p53 mutations.	('p53', 'Gene', (34, 37))	('EACs', 'Chemical', 'MESH:D015119', (23, 27))	('p53', 'Gene', '7157', (34, 37))	('mutations', 'Var', (38, 47))
671103	31152823	Similar frequencies of p53 mutations (71-72%) were reported in studies conducted by the Cancer Genome Atlas (TCGA) Research Network and the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Study Group.	('mutations', 'Var', (27, 36))	('Cancer', 'Disease', (152, 158))	('Cancer', 'Disease', 'MESH:D009369', (88, 94))	('Cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('rat', 'Species', '10116', (184, 187))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))	('Cancer', 'Disease', (88, 94))
671104	31152823	High frequency of mutations was also found in the CDKN2 gene, which is known to regulate the cell cycle.	('CDKN2', 'Gene', '1029', (50, 55))	('CDKN2', 'Gene', (50, 55))	('mutations', 'Var', (18, 27))
671105	31152823	The TCGA studies revealed that the CDKN2A gene is inactivated by deletions, epigenetic silencing, or mutations in 76% of EACs.	('CDKN2A', 'Gene', '1029', (35, 41))	('mutations', 'Var', (101, 110))	('epigenetic silencing', 'Var', (76, 96))	('EACs', 'Chemical', 'MESH:D015119', (121, 125))	('inactivated', 'NegReg', (50, 61))	('deletions', 'Var', (65, 74))	('CDKN2A', 'Gene', (35, 41))
671106	31152823	Cell cycle regulation is affected not only by inactivation of CDKN2A but also by amplification of CDK6, CCNE1 and CCND1 genes, which encode cell division protein kinase 6 (CDK6) and cyclins E1 and D1, respectively (Figure 1).	('CDK6', 'Gene', (98, 102))	('cyclin', 'Gene', '5111', (182, 188))	('E1 and D1', 'Gene', '6080;1896', (190, 199))	('CCND1', 'Gene', '595', (114, 119))	('CCNE1', 'Gene', '898', (104, 109))	('CCND1', 'Gene', (114, 119))	('Cell cycle', 'CPA', (0, 10))	('cyclin', 'Gene', (182, 188))	('cell division protein kinase 6', 'Gene', (140, 170))	('cell division protein kinase 6', 'Gene', '1021', (140, 170))	('amplification', 'Var', (81, 94))	('CDKN2A', 'Gene', (62, 68))	('CDK6', 'Gene', '1021', (172, 176))	('affected', 'Reg', (25, 33))	('CDK6', 'Gene', '1021', (98, 102))	('CDK6', 'Gene', (172, 176))	('inactivation', 'Var', (46, 58))	('CDKN2A', 'Gene', '1029', (62, 68))	('CCNE1', 'Gene', (104, 109))
671109	31152823	Amplification of the ERBB2 gene is the most prominent receptor alteration in EACs that was found in 32% of tumors.	('EACs', 'Chemical', 'MESH:D015119', (77, 81))	('Amplification', 'Var', (0, 13))	('rat', 'Species', '10116', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('ERBB2', 'Gene', '2064', (21, 26))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('ERBB2', 'Gene', (21, 26))
671111	31152823	The phosphatidylinositol-3-kinase (PI3K) pathway was the most frequently altered oncogenic pathway by mutations and CNAs found in 24% of tumors.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('altered', 'Reg', (73, 80))	('phosphatidylinositol-3-kinase', 'Gene', '5293', (4, 33))	('mutations', 'Var', (102, 111))	('phosphatidylinositol-3-kinase', 'Gene', (4, 33))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
671112	31152823	In addition to ERBB2 and EGFR gene amplifications, which can potentially activate the PI3K pathway, mutations were reported in PI3KCA, PI3KR1, PTEN and other related genes.	('mutations', 'Var', (100, 109))	('ERBB2', 'Gene', (15, 20))	('PI3K pathway', 'Pathway', (86, 98))	('EGFR', 'Gene', (25, 29))	('PI3KCA', 'Gene', (127, 133))	('activate', 'PosReg', (73, 81))	('PTEN', 'Gene', (143, 147))	('PTEN', 'Gene', '5728', (143, 147))	('EGFR', 'Gene', '1956', (25, 29))	('ERBB2', 'Gene', '2064', (15, 20))	('PI3KR1', 'Gene', (135, 141))
671114	31152823	The Rho family GTPase, RAC1, is also frequently activated primarily by mutations in DOCK2 and ELM01 genes that are important regulators of RAC1.	('RAC1', 'Gene', '5879', (139, 143))	('DOCK2', 'Gene', (84, 89))	('RAC1', 'Gene', '5879', (23, 27))	('RAC1', 'Gene', (139, 143))	('ELM01', 'CellLine', 'CVCL:X174', (94, 99))	('RAC1', 'Gene', (23, 27))	('mutations', 'Var', (71, 80))	('DOCK2', 'Gene', '1794', (84, 89))	('activated', 'PosReg', (48, 57))	('ELM01', 'Gene', (94, 99))
671115	31152823	Given that dysregulation of DOCK2 and ELMO1 is associated in cancers with enhanced cell migration and invasion, it may help to explain the highly invasive nature of EACs.	('rat', 'Species', '10116', (91, 94))	('cell migration', 'CPA', (83, 97))	('EACs', 'Chemical', 'MESH:D015119', (165, 169))	('invasion', 'CPA', (102, 110))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('DOCK2', 'Gene', '1794', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('ELMO1', 'Gene', '9844', (38, 43))	('dysregulation', 'Var', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('associated', 'Reg', (47, 57))	('enhanced', 'PosReg', (74, 82))	('DOCK2', 'Gene', (28, 33))	('ELMO1', 'Gene', (38, 43))
671116	31152823	In addition, EACs shows amplifications of VEGFA, FGFR2, IGF1R, and MET genes (Figure 1).	('IGF1R', 'Gene', '3480', (56, 61))	('MET genes', 'Gene', (67, 76))	('amplifications', 'Var', (24, 38))	('EACs', 'Chemical', 'MESH:D015119', (13, 17))	('FGFR2', 'Gene', (49, 54))	('FGFR2', 'Gene', '2263', (49, 54))	('VEGFA', 'Gene', '7422', (42, 47))	('IGF1R', 'Gene', (56, 61))	('VEGFA', 'Gene', (42, 47))
671117	31152823	NGS analyses also revealed dysregulation of the TGFbeta pathway.	('TGFbeta', 'Gene', '7039', (48, 55))	('dysregulation', 'Var', (27, 40))	('TGFbeta', 'Gene', (48, 55))
671120	31152823	Interestingly, SMAD4 is primarily mutated in EAC, but not in high grade dysplasia (HGD) providing a genetic distinction between EAC and HGD.	('SMAD4', 'Gene', (15, 20))	('dysplasia', 'Disease', (72, 81))	('SMAD4', 'Gene', '4089', (15, 20))	('dysplasia', 'Disease', 'MESH:C536170', (72, 81))	('EAC', 'Disease', (45, 48))	('mutated', 'Var', (34, 41))
671121	31152823	In addition, some EACs showed activation of the WNT/beta-catenin pathway by mutations or loss of AXIN1, APC or CDH1 genes, although dysregulation of this pathway was less frequent than in other tumor types.	('mutations', 'Var', (76, 85))	('beta-catenin', 'Gene', (52, 64))	('AXIN1', 'Gene', '8312', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('CDH1', 'Gene', (111, 115))	('WNT', 'Gene', (48, 51))	('activation', 'PosReg', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('AXIN1', 'Gene', (97, 102))	('EACs', 'Chemical', 'MESH:D015119', (18, 22))	('APC', 'Disease', 'MESH:D011125', (104, 107))	('tumor', 'Disease', (194, 199))	('APC', 'Disease', (104, 107))	('CDH1', 'Gene', '999', (111, 115))	('beta-catenin', 'Gene', '1499', (52, 64))	('WNT', 'Gene', '7472', (48, 51))	('loss', 'NegReg', (89, 93))
671122	31152823	Mutations of the CTNNB1 gene, which encodes beta-catenin, were found to be relatively uncommon.	('CTNNB1', 'Gene', (17, 23))	('beta-catenin', 'Gene', (44, 56))	('CTNNB1', 'Gene', '1499', (17, 23))	('Mutations', 'Var', (0, 9))	('beta-catenin', 'Gene', '1499', (44, 56))
671123	31152823	EAC also shows loss-of-function mutations and CNAs of ARID1A, ARID2, SMARCA4, and PBRM1 genes that encode components of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin-remodelling complex (Figure 1).	('ARID1A', 'Gene', (54, 60))	('ARID2', 'Gene', (62, 67))	('PBRM1', 'Gene', (82, 87))	('men', 'Species', '9606', (155, 158))	('PBRM1', 'Gene', '55193', (82, 87))	('Sucrose', 'Chemical', 'MESH:D013395', (140, 147))	('ARID2', 'Gene', '196528', (62, 67))	('SMARCA4', 'Gene', (69, 76))	('SMARCA4', 'Gene', '6597', (69, 76))	('mutations', 'Var', (32, 41))	('loss-of-function', 'NegReg', (15, 31))	('ARID1A', 'Gene', '8289', (54, 60))
671124	31152823	Alterations of the SWI/SNF complex are not unique to EAC and are found in over 20% of human malignancies.	('malignancies', 'Disease', (92, 104))	('Alterations', 'Var', (0, 11))	('human', 'Species', '9606', (86, 91))	('rat', 'Species', '10116', (4, 7))	('malignancies', 'Disease', 'MESH:D009369', (92, 104))
671125	31152823	Among other prominent alterations were amplifications of GATA4/6 genes, deletions of RUNX1, WWOX, FHIT genes that have potential tumor suppressor roles, and mutations in genes that regulate the adherens junctions, CDH1, HEWCW 1, AJAP1, and inflammatory response, TLR4.	('WWOX', 'Gene', '51741', (92, 96))	('TLR4', 'Gene', '7099', (263, 267))	('CDH1', 'Gene', (214, 218))	('RUNX1', 'Gene', (85, 90))	('AJAP1', 'Gene', (229, 234))	('tumor', 'Disease', (129, 134))	('RUNX1', 'Gene', '861', (85, 90))	('TLR4', 'Gene', (263, 267))	('amplifications', 'Var', (39, 53))	('GATA4/6', 'Gene', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('mutations', 'Var', (157, 166))	('FHIT', 'Gene', (98, 102))	('WWOX', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('deletions', 'Var', (72, 81))	('GATA4/6', 'Gene', '2626;2627', (57, 64))	('rat', 'Species', '10116', (26, 29))	('AJAP1', 'Gene', '55966', (229, 234))	('FHIT', 'Gene', '2272', (98, 102))	('CDH1', 'Gene', '999', (214, 218))
671127	31152823	The mutational signatures revealed three distinct molecular subtypes for EAC: (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint.	('C>A/T', 'Var', (285, 290))	('associated', 'Reg', (213, 223))	('neoantigen burden', 'MPA', (256, 273))	('defects', 'NegReg', (127, 134))	('men', 'Species', '9606', (88, 91))	('homologous recombination pathway', 'Pathway', (142, 174))	('mutational load', 'MPA', (236, 251))	('BRCA', 'Disease', (97, 101))
671129	31152823	It was reported that early stages of disease and BE often have a higher rate of mutations than many common dysplastic tumors.	('rat', 'Species', '10116', (72, 75))	('mutations', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('dysplastic tumors', 'Disease', 'MESH:C562393', (107, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('dysplastic tumors', 'Disease', (107, 124))	('BE', 'Phenotype', 'HP:0100580', (49, 51))
671132	31152823	It was shown that approximately a third of EAC cases (32%) are characterized by massive localized chromosome translocations (chromothripsis) that may cause rapid activation of oncogenes and inactivation of tumor suppressors.	('chromosome translocations', 'Var', (98, 123))	('oncogenes', 'Protein', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('chromothripsis', 'Disease', (125, 139))	('tumor', 'Disease', (206, 211))	('chromothripsis', 'Disease', 'MESH:D000072837', (125, 139))	('inactivation', 'NegReg', (190, 202))	('EAC', 'Disease', (43, 46))	('activation', 'PosReg', (162, 172))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
671134	31152823	Similar to other tumor types, genetic alterations in EAC are accompanied by significant changes of the epigenome.	('tumor', 'Disease', (17, 22))	('epigenome', 'MPA', (103, 112))	('changes', 'Reg', (88, 95))	('genetic alterations', 'Var', (30, 49))	('EAC', 'Gene', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('rat', 'Species', '10116', (42, 45))
671137	31152823	Comparison with other types of normal tissues suggests that epigenetic alterations in BE may reflect the actual tumorigenic process, rather than simply due to acquisition of metaplastic phenotype.	('BE', 'Phenotype', 'HP:0100580', (86, 88))	('rat', 'Species', '10116', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('rat', 'Species', '10116', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('epigenetic alterations', 'Var', (60, 82))	('tumor', 'Disease', (112, 117))
671139	31152823	It was shown that the promoter hypermethylation of MGMT, p16/ RUNX3/HPP1, HPP1/p16/RUNX3, TIPM3/APC/TERT genes or gene combinations such as SLC22A18+PIGR+GJA2+RIN2, p16+APC, RUNX3+p16+HPP1+NELL1+TAC1+SST+AKAP12+CDH13 and hypomethylation of ORF3A4 gene may help to stratify the risk of cancer development in patients with non-dysplastic BE.	('RIN2', 'Gene', (159, 163))	('CDH13', 'Gene', (211, 216))	('p16', 'Gene', '1029', (180, 183))	('RUNX3', 'Gene', '864', (83, 88))	('PIGR', 'Gene', (149, 153))	('TERT', 'Gene', (100, 104))	('HPP1', 'Gene', (74, 78))	('TERT', 'Gene', '7015', (100, 104))	('MGMT', 'Gene', (51, 55))	('SLC22A18', 'Gene', '5002', (140, 148))	('patients', 'Species', '9606', (307, 315))	('AKAP12', 'Gene', (204, 210))	('RUNX3', 'Gene', (174, 179))	('TAC1', 'Gene', '6863', (195, 199))	('dysplastic', 'Disease', 'MESH:D004416', (325, 335))	('SST', 'Gene', '6750', (200, 203))	('RUNX3', 'Gene', (62, 67))	('HPP1', 'Gene', (184, 188))	('NELL1', 'Gene', (189, 194))	('BE', 'Phenotype', 'HP:0100580', (336, 338))	('cancer', 'Disease', (285, 291))	('p16', 'Gene', '1029', (165, 168))	('NELL1', 'Gene', '4745', (189, 194))	('dysplastic', 'Disease', (325, 335))	('SLC22A18', 'Gene', (140, 148))	('p16', 'Gene', (57, 60))	('RUNX3', 'Gene', (83, 88))	('HPP1', 'Gene', '780897', (68, 72))	('AKAP12', 'Gene', '9590', (204, 210))	('rat', 'Species', '10116', (266, 269))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('p16', 'Gene', (79, 82))	('CDH13', 'Gene', '1012', (211, 216))	('APC', 'Disease', 'MESH:D011125', (169, 172))	('p16', 'Gene', '1029', (57, 60))	('PIGR', 'Gene', '5284', (149, 153))	('APC', 'Disease', (169, 172))	('MGMT', 'Gene', '4255', (51, 55))	('ORF3A4', 'Gene', (240, 246))	('RUNX3', 'Gene', '864', (174, 179))	('p16', 'Gene', '1029', (79, 82))	('RUNX3', 'Gene', '864', (62, 67))	('men', 'Species', '9606', (299, 302))	('TAC1', 'Gene', (195, 199))	('HPP1', 'Gene', '780897', (74, 78))	('RIN2', 'Gene', '54453', (159, 163))	('p16', 'Gene', (165, 168))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('SST', 'Gene', (200, 203))	('HPP1', 'Gene', (68, 72))	('APC', 'Disease', (96, 99))	('hypomethylation', 'Var', (221, 236))	('p16', 'Gene', (180, 183))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('HPP1', 'Gene', '780897', (184, 188))
671140	31152823	Among other critical epigenetic alterations that contribute to the development and progression of EAC are posttranslational modifications of histones and alterations of multiple non-coding RNAs, including microRNA and lncRNA.	('histones', 'Protein', (141, 149))	('rat', 'Species', '10116', (36, 39))	('EAC', 'Disease', (98, 101))	('rat', 'Species', '10116', (158, 161))	('alterations', 'Var', (154, 165))	('men', 'Species', '9606', (74, 77))	('non-coding RNAs', 'Protein', (178, 193))
671150	31152823	ROS is also thought to induce mutations in mitochondrial DNA in Barrett's metaplasia.	('mutations', 'Var', (30, 39))	('mitochondrial', 'Gene', (43, 56))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	("Barrett's metaplasia", 'Disease', (64, 84))
671154	31152823	It was also shown that induction of bile reflux increases the mutational rate (primarily transitions C to T and G to A) in the rat esophagus.	('increases', 'PosReg', (48, 57))	('rat', 'Species', '10116', (73, 76))	('bile reflux increases', 'Phenotype', 'HP:0002020', (36, 57))	('G to A', 'Var', (112, 118))	('rat', 'Species', '10116', (127, 130))	('bile reflux', 'MPA', (36, 47))	('mutational rate', 'MPA', (62, 77))
671155	31152823	These data are consistent with the preponderance of C to T transitions in human esophageal adenocarcinomas, suggesting that reflux may be responsible for their generation.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('adenocarcinomas', 'Disease', 'MESH:D000230', (91, 106))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('rat', 'Species', '10116', (164, 167))	('human', 'Species', '9606', (74, 79))	('C to T transitions', 'Var', (52, 70))	('adenocarcinomas', 'Disease', (91, 106))
671158	31152823	Double strand breaks of DNA are even more detrimental as these lesions are extremely difficult to repair resulting in highly cytotoxic and mutagenic effects.	('mutagenic effects', 'CPA', (139, 156))	('men', 'Species', '9606', (47, 50))	('Double strand breaks', 'Var', (0, 20))
671164	31152823	For example, levels of DDR enzymes MUTYH and OGG1, which are involved in repair of oxidative DNA damage, were significantly decreased after treatment of esophageal cells with bile acid.	('men', 'Species', '9606', (145, 148))	('MUTYH', 'Var', (35, 40))	('decreased', 'NegReg', (124, 133))	('OGG1', 'Gene', (45, 49))	('levels', 'MPA', (13, 19))	('bile acid', 'Chemical', 'MESH:D001647', (175, 184))	('OGG1', 'Gene', '4968', (45, 49))
671166	31152823	MGMT protein, which is involved in repair of alkylated DNA lesions, is downregulated by promoter hypermethylation in BE.	('MGMT', 'Gene', (0, 4))	('downregulated', 'NegReg', (71, 84))	('promoter hypermethylation', 'Var', (88, 113))	('BE', 'Phenotype', 'HP:0100580', (117, 119))	('MGMT', 'Gene', '4255', (0, 4))
671177	31152823	As discussed above, p53 is frequently inactivated by mutations, which typically occur during transition from non-dysplastic BE to high-grade dysplasia.	('p53', 'Gene', (20, 23))	('dysplasia', 'Disease', (141, 150))	('dysplastic', 'Disease', 'MESH:D004416', (113, 123))	('p53', 'Gene', '7157', (20, 23))	('mutations', 'Var', (53, 62))	('BE', 'Phenotype', 'HP:0100580', (124, 126))	('dysplasia', 'Disease', 'MESH:C536170', (141, 150))	('dysplastic', 'Disease', (113, 123))	('inactivated', 'NegReg', (38, 49))
671178	31152823	TP53gene mutations in BE tissues increased the adjusted risk of progression 13.8-fold (95% confidence interval, 3.2-61.0; p < 0.001).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (9, 18))	('BE', 'Phenotype', 'HP:0100580', (22, 24))	('increased', 'PosReg', (33, 42))
671179	31152823	The comparison of BE tissues from patients with or without later progression to HGD or EAC found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression.	('BE', 'Phenotype', 'HP:0100580', (18, 20))	('TP53', 'Gene', '7157', (129, 133))	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (134, 143))	('patients', 'Species', '9606', (155, 163))	('TP53', 'Gene', (129, 133))	('BE', 'Phenotype', 'HP:0100580', (147, 149))
671180	31152823	These mutations are primarily missense variants that inhibit the binding of p53 protein to DNA causing inhibition of p53-dependent transcription.	('inhibit', 'NegReg', (53, 60))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('p53', 'Gene', (76, 79))	('binding', 'Interaction', (65, 72))	('p53', 'Gene', '7157', (76, 79))	('mutations', 'Var', (6, 15))	('inhibition', 'NegReg', (103, 113))
671188	31152823	Given the important role played by p53 in tumor suppression and chemotherapeutic drug response, a number of compounds, such as STIMA-1, PRIMA-1, MIRA-1, RITA and others, have been identified to restore activity of mutant p53 (reviewed in).	('tumor', 'Disease', (42, 47))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('PRIMA-1', 'Gene', (136, 143))	('RITA', 'Gene', '84934', (153, 157))	('mutant', 'Var', (214, 220))	('p53', 'Gene', (221, 224))	('p53', 'Gene', '7157', (221, 224))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('PRIMA-1', 'Gene', '145270', (136, 143))	('RITA', 'Gene', (153, 157))	('activity', 'MPA', (202, 210))	('restore', 'PosReg', (194, 201))
671190	31152823	APR-246 was tested in EAC cells harboring mutant p53 and found to upregulate p53 target genes and induce apoptosis.	('mutant', 'Var', (42, 48))	('induce', 'PosReg', (98, 104))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('apoptosis', 'CPA', (105, 114))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('APR-246', 'Chemical', 'MESH:C533410', (0, 7))	('upregulate', 'PosReg', (66, 76))
671200	31152823	However, some DeltaN isoforms, such as DeltaNp63alpha retain transcriptional activity through additional transactivation domains (reviewed in).	('DeltaNp63alpha', 'Var', (39, 53))	('transcriptional activity', 'MPA', (61, 85))	('DeltaNp63', 'Chemical', '-', (39, 48))	('transactivation domains', 'MPA', (105, 128))
671215	31152823	Another CDK inhibitor, p27KIP1, which regulates the cell cycle by inhibiting the cyclin E/CDK2 and cyclin D/CDK4 complexes, is also affected in BE and EAC.	('cyclin', 'Gene', (81, 87))	('CDK', 'Gene', '1017;1019;1021', (90, 93))	('CDK', 'Gene', (8, 11))	('CDK4', 'Gene', '1019', (108, 112))	('inhibiting', 'NegReg', (66, 76))	('BE', 'Phenotype', 'HP:0100580', (144, 146))	('affected', 'Reg', (132, 140))	('cyclin E/CDK2', 'Gene', (81, 94))	('CDK', 'Gene', '1017;1019;1021', (8, 11))	('cyclin', 'Gene', '5111', (99, 105))	('CDK', 'Gene', (108, 111))	('p27KIP1', 'Var', (23, 30))	('cyclin E/CDK2', 'Gene', '1017', (81, 94))	('cyclin', 'Gene', '5111', (81, 87))	('cell cycle', 'CPA', (52, 62))	('regulates', 'Reg', (38, 47))	('cyclin', 'Gene', (99, 105))	('CDK4', 'Gene', (108, 112))	('CDK', 'Gene', '1017;1019;1021', (108, 111))	('CDK', 'Gene', (90, 93))
671220	31152823	Amplifications of both genes are associated with poor survival of EAC patients.	('patients', 'Species', '9606', (70, 78))	('EAC', 'Disease', (66, 69))	('associated', 'Reg', (33, 43))	('Amplifications', 'Var', (0, 14))
671226	31152823	The same study found amplification of the CCNE1 gene, which encodes cyclin E1, in 19.0% of EAC cases.	('cyclin E1', 'Gene', '898', (68, 77))	('CCNE1', 'Gene', '898', (42, 47))	('CCNE1', 'Gene', (42, 47))	('EAC', 'Disease', (91, 94))	('cyclin E1', 'Gene', (68, 77))	('amplification', 'Var', (21, 34))
671243	31152823	Several studies have reported K-RAS activating mutations and amplifications of the K-RAS gene.	('K-RAS', 'Gene', '3845', (83, 88))	('K-RAS', 'Gene', (83, 88))	('K-RAS', 'Gene', '3845', (30, 35))	('amplifications', 'Var', (61, 75))	('activating', 'PosReg', (36, 46))	('K-RAS', 'Gene', (30, 35))
671262	31152823	Elevated Notch signaling is thought to promote cancer stem cell phenotype, increases cancer cell survival and resistance to chemotherapy.	('resistance to chemotherapy', 'CPA', (110, 136))	('promote', 'PosReg', (39, 46))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('Notch signaling', 'MPA', (9, 24))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', (85, 91))	('increases cancer', 'Disease', (75, 91))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Elevated', 'Var', (0, 8))	('increases cancer', 'Disease', 'MESH:D009369', (75, 91))
671271	31152823	Aberrant activation of the Wnt/beta-catenin signaling is a common event during the late stages of BE neoplastic transformation (Figure 3).	('activation', 'PosReg', (9, 19))	('beta-catenin', 'Gene', (31, 43))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', '1499', (31, 43))	('Wnt', 'Gene', (27, 30))	('Wnt', 'Gene', '7472', (27, 30))	('BE', 'Phenotype', 'HP:0100580', (98, 100))
671275	31152823	In contrast to colonic and other tumors, dysregulation of the Wnt/beta-catenin pathway is rarely caused by mutations in the APC, AXIN1, CDH1 or the beta-catenin genes.	('beta-catenin', 'Gene', (66, 78))	('beta-catenin', 'Gene', '1499', (66, 78))	('Wnt', 'Gene', '7472', (62, 65))	('AXIN1', 'Gene', '8312', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('colonic', 'Disease', (15, 22))	('caused', 'Reg', (97, 103))	('APC', 'Disease', 'MESH:D011125', (124, 127))	('APC', 'Disease', (124, 127))	('colonic', 'Disease', 'MESH:D003110', (15, 22))	('beta-catenin', 'Gene', (148, 160))	('beta-catenin', 'Gene', '1499', (148, 160))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('AXIN1', 'Gene', (129, 134))	('CDH1', 'Gene', '999', (136, 140))	('mutations', 'Var', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Wnt', 'Gene', (62, 65))	('tumors', 'Disease', (33, 39))	('CDH1', 'Gene', (136, 140))
671281	31152823	Since inhibition of COX-2 activity suppresses inflammation and induce apoptosis, COX2 is considered as a target for prevention and treatment of esophageal cancer.	('inflammation', 'Disease', 'MESH:D007249', (46, 58))	('men', 'Species', '9606', (136, 139))	('activity', 'MPA', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('inflammation', 'Disease', (46, 58))	('COX2', 'Gene', (81, 85))	('COX2', 'Gene', '4513', (81, 85))	('induce', 'PosReg', (63, 69))	('inhibition', 'Var', (6, 16))	('apoptosis', 'CPA', (70, 79))	('COX-2', 'Gene', (20, 25))	('COX-2', 'Gene', '5743', (20, 25))	('suppresses', 'NegReg', (35, 45))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
671295	31152823	However, most of the studies did not find significant survival benefits for anti-EGFR antibodies and small molecule inhibitors in patients with esophageal and gastroesophageal junction carcinomas.	('esophageal', 'Disease', (144, 154))	('gastroesophageal junction carcinomas', 'Disease', 'MESH:D008309', (159, 195))	('gastroesophageal junction carcinomas', 'Disease', (159, 195))	('patients', 'Species', '9606', (130, 138))	('antibodies', 'Var', (86, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
671296	31152823	Multiple factors may contribute to negative outcomes of these trials: EGFR mutations that prevents binding of inhibitors, RAS mutations, deletion of PTEN, amplifications of HER2 and MET, activation of downstream mediators such as PI3KCA and MAPK-ERK and/or activation of alternative oncogenic pathways in response to EGFR inhibition.	('HER2', 'Gene', (173, 177))	('activation', 'PosReg', (187, 197))	('PTEN', 'Gene', (149, 153))	('EGFR', 'Gene', '1956', (317, 321))	('activation', 'PosReg', (257, 267))	('binding', 'Interaction', (99, 106))	('ERK', 'Gene', '5594', (246, 249))	('MET', 'Gene', (182, 185))	('EGFR', 'Gene', '1956', (70, 74))	('PTEN', 'Gene', '5728', (149, 153))	('mutations', 'Var', (126, 135))	('alternative oncogenic pathways', 'Pathway', (271, 301))	('ERK', 'Gene', (246, 249))	('HER2', 'Gene', '2064', (173, 177))	('EGFR', 'Gene', (317, 321))	('PI3KCA', 'Pathway', (230, 236))	('prevents', 'NegReg', (90, 98))	('RAS', 'Gene', (122, 125))	('inhibitors', 'Protein', (110, 120))	('deletion', 'Var', (137, 145))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))
671322	31428123	Variants in these genes have been shown to increase susceptibility to ESCC development, and they are also associated with alcohol consumption.	('Variants', 'Var', (0, 8))	('associated', 'Reg', (106, 116))	('alcohol consumption', 'Disease', (122, 141))	('ESCC development', 'Disease', (70, 86))	('alcohol', 'Chemical', 'MESH:D000438', (122, 129))
671324	31428123	Genes with variants implicated in the development of ESCC in these populations include phospholipase c epsilon 1 (PLCE1), caspase 8 (CAP8), tumor protein 53 (TP53), and human leukocyte antigen (HLA).	('TP53', 'Gene', '7157', (158, 162))	('PLCE1', 'Gene', (114, 119))	('TP53', 'Gene', (158, 162))	('phospholipase c epsilon 1', 'Gene', '51196', (87, 112))	('PLCE1', 'Gene', '51196', (114, 119))	('ESCC', 'Disease', (53, 57))	('tumor protein 53', 'Gene', '7157', (140, 156))	('variants', 'Var', (11, 19))	('PLCE', 'Gene', '51196', (114, 118))	('CAP8', 'Gene', (133, 137))	('CAP8', 'Gene', '841', (133, 137))	('caspase 8', 'Gene', '841', (122, 131))	('PLCE', 'Gene', (114, 118))	('human', 'Species', '9606', (169, 174))	('phospholipase c epsilon 1', 'Gene', (87, 112))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('caspase 8', 'Gene', (122, 131))	('tumor protein 53', 'Gene', (140, 156))
671330	31428123	The AR gene regulates the sex hormones, androgens, while CYP2E1 and CYP3A5 are involved in steroid, cholesterol, and lipid synthesis.	('regulates', 'Reg', (12, 21))	('CYP3A5', 'Var', (68, 74))	('CYP2E1', 'Var', (57, 63))	('lipid', 'Chemical', 'MESH:D008055', (117, 122))	('steroid', 'Chemical', 'MESH:D013256', (91, 98))	('involved', 'Reg', (79, 87))	('androgens', 'MPA', (40, 49))	('cholesterol', 'Chemical', 'MESH:D002784', (100, 111))	('steroid', 'MPA', (91, 98))	('sex hormones', 'MPA', (26, 38))
671333	31428123	Six of the 16 SNPs were reported to reduce the risk of ESCC, and they are the following: ADH1B (Arg48His; rs1229984), ALDH2 (+82 A > G; rs886205), GSTT2B (deletion allele), NAT2 (341T > C; rs1801280), PTGS2 (-1195 A > G; rs689466), and PLCE1 (Arg548Leu; rs17417407).	('+82 A > G', 'Mutation', 'rs886205', (125, 134))	('rs1801280', 'Mutation', 'rs1801280', (189, 198))	('Arg48His', 'Var', (96, 104))	('-1195 A > G; rs689466', 'Var', (208, 229))	('Arg548Leu', 'SUBSTITUTION', 'None', (243, 252))	('341T > C', 'Mutation', 'rs1801280', (179, 187))	('rs17417407', 'Mutation', 'rs17417407', (254, 264))	('Arg548Leu', 'Var', (243, 252))	('rs886205', 'Var', (136, 144))	('-1195 A > G', 'Mutation', 'rs689466', (208, 219))	('ESCC', 'Disease', (55, 59))	('Arg48His', 'SUBSTITUTION', 'None', (96, 104))	('rs1229984', 'Mutation', 'rs1229984', (106, 115))	('rs689466', 'Mutation', 'rs689466', (221, 229))	('rs886205', 'DBSNP_MENTION', 'None', (136, 144))
671334	31428123	The remaining 10 SNPs were reported to increase the risk of ESCC: ALDH2 (ALDH2*1/*2), CASP8 (Asp302His; rs1045485), CHEK2 (rs4822983 C > T, and rs1033667, C > T), CYP2E1 (7632T > A), MGMT (Leu84Phe; rs12917), MLH3 (Arg797His; rs28756991), MSH3 (Ala1045Thr; rs26279), PMS1 (c.-21+639G > A; rs5742938), and RUNX1 (rs2014300).	('7632T > A', 'Mutation', 'rs6413432', (171, 180))	('ESCC', 'Disease', (60, 64))	('Asp302His; rs1045485', 'Var', (93, 113))	('Arg797His; rs28756991', 'Var', (215, 236))	('rs5742938', 'Mutation', 'rs5742938', (289, 298))	('Asp302His', 'Mutation', 'rs1045485', (93, 102))	('rs1045485', 'Mutation', 'rs1045485', (104, 113))	('rs28756991', 'Mutation', 'rs28756991', (226, 236))	('rs12917', 'Mutation', 'rs12917', (199, 206))	('rs1033667', 'Mutation', 'rs1033667', (144, 153))	('Ala1045Thr', 'Mutation', 'rs26279', (245, 255))	('rs2014300', 'Var', (312, 321))	('Leu84Phe', 'Mutation', 'rs12917', (189, 197))	('rs1033667', 'Var', (144, 153))	('c.-21+639G > A', 'Mutation', 'rs5742938', (273, 287))	('c.-21+639G > A; rs5742938', 'Var', (273, 298))	('rs2014300', 'Mutation', 'rs2014300', (312, 321))	('rs4822983', 'Mutation', 'rs4822983', (123, 132))	('Arg797His', 'Mutation', 'rs28756991', (215, 224))	('rs4822983 C > T', 'Var', (123, 138))	('rs26279', 'Mutation', 'rs26279', (257, 264))
671337	31428123	The specific locus positions with the corresponding microsatellite markers are as follows: 2p (D2S123), 3p13 (D3S659), 3p24.2-25 (D3S1255), 4q12 (Bat 25), 2p21-p16.3 (Bat 26), and 1p12-13.3 (Bat 40).	('p16', 'Gene', '1029', (160, 163))	('p16', 'Gene', (160, 163))	('D3S1255', 'Var', (130, 137))
671341	31428123	SULT1A1 variants were associated with smoking status only.	('SULT1A1', 'Gene', (0, 7))	('associated', 'Reg', (22, 32))	('SULT1A1', 'Gene', '6817', (0, 7))	('variants', 'Var', (8, 16))
671342	31428123	Other interaction studies included wood/charcoal use and mutations in the GST genes, as well as red and white meat intake and SNPs in NAT1/2 genes.	('NAT1/2', 'Gene', '122830;9;10', (134, 140))	('NAT1/2', 'Gene', (134, 140))	('interaction', 'Interaction', (6, 17))	('GST genes', 'Gene', (74, 83))	('mutations', 'Var', (57, 66))	('SNPs', 'Var', (126, 130))	('charcoal', 'Chemical', 'MESH:D002606', (40, 48))
671352	23117882	Elevating AXL in non-overexpressing cells doubled the sensitivity to CDDP cytotoxicity and increased cell survival 3-fold, whereas attenuating AXL in ovexpressing cells reduced survival 2-fold.	('cytotoxicity', 'Disease', (74, 86))	('CDDP', 'Chemical', 'MESH:D002945', (69, 73))	('AXL', 'Gene', '558', (143, 146))	('cell survival', 'CPA', (101, 114))	('cytotoxicity', 'Disease', 'MESH:D064420', (74, 86))	('Elevating', 'Var', (0, 9))	('AXL', 'Gene', '558', (10, 13))	('increased', 'PosReg', (91, 100))	('AXL', 'Gene', (143, 146))	('AXL', 'Gene', (10, 13))	('attenuating', 'Var', (131, 142))
671353	23117882	The effects of AXL modulation on cell survival associated with changes in cellular and molecular markers of apoptosis.	('AXL', 'Gene', (15, 18))	('cell survival', 'CPA', (33, 46))	('changes', 'Reg', (63, 70))	('modulation', 'Var', (19, 29))	('AXL', 'Gene', '558', (15, 18))
671361	23117882	Although deficient p53 expression renders cancer cells less responsive to cisplatin-based chemotherapy, drug resistance is not complete.	('responsive to cisplatin-based chemotherapy', 'MPA', (60, 102))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('p53', 'Gene', (19, 22))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('p53', 'Gene', '7157', (19, 22))	('deficient', 'Var', (9, 18))	('less', 'NegReg', (55, 59))	('expression', 'MPA', (23, 33))
671364	23117882	Yuan et al, demonstrated that c-ABL binds and phosphorylates the p73 protein on a tyrosine residue (Y99) in response to DNA damage, and disruption of the c-ABL/p73 interaction blocked apoptosis.	('p73', 'Gene', '7161', (65, 68))	('interaction', 'Interaction', (164, 175))	('p73', 'Gene', (65, 68))	('phosphorylates', 'MPA', (46, 60))	('disruption', 'Var', (136, 146))	('blocked', 'NegReg', (176, 183))	('p73', 'Gene', '7161', (160, 163))	('c-ABL', 'Gene', '25', (30, 35))	('p73', 'Gene', (160, 163))	('c-ABL', 'Gene', '25', (154, 159))	('response to DNA damage', 'MPA', (108, 130))	('tyrosine', 'Chemical', 'MESH:D014443', (82, 90))	('c-ABL', 'Gene', (30, 35))	('binds', 'Interaction', (36, 41))	('c-ABL', 'Gene', (154, 159))	('apoptosis', 'CPA', (184, 193))
671366	23117882	In addition to aberrant p53 expression, negative regulation of p73 could potentially play a significant role in promoting cisplatin resistance.	('p73', 'Gene', '7161', (63, 66))	('p53', 'Gene', (24, 27))	('cisplatin resistance', 'MPA', (122, 142))	('p73', 'Gene', (63, 66))	('p53', 'Gene', '7157', (24, 27))	('expression', 'MPA', (28, 38))	('aberrant', 'Var', (15, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('promoting', 'PosReg', (112, 121))	('negative', 'NegReg', (40, 48))
671367	23117882	This is of major importance given the fact that the majority of EACs are deficient or mutant in p53.	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('mutant', 'Var', (86, 92))	('deficient', 'NegReg', (73, 82))
671414	23117882	In cells harboring non-functional p53, activated endogenous p73 protein binds to the p53 binding site, thereby transcription is induced and the reporter gene is expressed.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('binds', 'Interaction', (72, 77))	('induced', 'PosReg', (128, 135))	('transcription', 'MPA', (111, 124))	('p53', 'Gene', '7157', (85, 88))	('p73', 'Gene', '7161', (60, 63))	('non-functional', 'Var', (19, 33))	('p53', 'Gene', (85, 88))	('p73', 'Gene', (60, 63))
671429	23117882	The results clearly indicated that knockdown of endogenous AXL significantly sensitized cells to CDDP (p<0.001) (Figure 2B).	('knockdown', 'Var', (35, 44))	('AXL', 'Gene', (59, 62))	('CDDP', 'Chemical', 'MESH:D002945', (97, 101))	('AXL', 'Gene', '558', (59, 62))	('sensitized', 'Reg', (77, 87))
671433	23117882	Conversely, knockdown of endogenous AXL in FLO-1 cells decreased cell survival by approximately 2-fold relative to control (p=0.01) in response to CDDP (Figure 2D).	('CDDP', 'Chemical', 'MESH:D002945', (147, 151))	('AXL', 'Gene', '558', (36, 39))	('cell survival', 'CPA', (65, 78))	('FLO-1', 'CellLine', 'CVCL:2045', (43, 48))	('knockdown', 'Var', (12, 21))	('AXL', 'Gene', (36, 39))	('decreased', 'NegReg', (55, 64))	('CDDP', 'MPA', (147, 151))
671436	23117882	In contrast, knockdown of endogenous AXL in FLO-1 cells increased early apoptosis by 73.5% relative to control (p<0.01) in response to CDDP (Figure 3C).	('AXL', 'Gene', '558', (37, 40))	('increased', 'PosReg', (56, 65))	('CDDP', 'MPA', (135, 139))	('FLO-1', 'CellLine', 'CVCL:2045', (44, 49))	('AXL', 'Gene', (37, 40))	('early apoptosis', 'CPA', (66, 81))	('CDDP', 'Chemical', 'MESH:D002945', (135, 139))	('knockdown', 'Var', (13, 22))
671437	23117882	Accordingly, Western blot analysis results showed that knockdown of endogenous AXL significantly increased protein levels of cleaved forms of caspase-9 and -3, and PARP relative to control in response to CDDP (Figure 3D).	('knockdown', 'Var', (55, 64))	('AXL', 'Gene', (79, 82))	('PARP', 'Gene', '1302', (164, 168))	('increased', 'PosReg', (97, 106))	('PARP', 'Gene', (164, 168))	('AXL', 'Gene', '558', (79, 82))	('protein levels of cleaved forms', 'MPA', (107, 138))	('CDDP', 'Chemical', 'MESH:D002945', (204, 208))	('caspase-9 and -3', 'Gene', '842;836', (142, 158))
671440	23117882	Accordingly, protein expression of p73 downstream transcriptional targets PUMA and HDM2 was significantly induced by CDDP in control cells but not in AXL-expressing cells (Figures 4A&4B).	('induced', 'PosReg', (106, 113))	('protein expression', 'MPA', (13, 31))	('p73', 'Gene', '7161', (35, 38))	('p73', 'Gene', (35, 38))	('AXL', 'Gene', '558', (150, 153))	('PUMA', 'Gene', (74, 78))	('CDDP', 'Chemical', 'MESH:D002945', (117, 121))	('HDM2', 'Gene', (83, 87))	('AXL', 'Gene', (150, 153))	('CDDP', 'Var', (117, 121))
671452	23117882	Conversely, AXL expression substantially attenuated CDDP-induced phosphorylation of c-ABL and p73beta proteins in OE33/AXL cells (Figure 5A).	('attenuated', 'NegReg', (41, 51))	('p73', 'Gene', '7161', (94, 97))	('expression', 'Var', (16, 26))	('c-ABL', 'Gene', '25', (84, 89))	('p73', 'Gene', (94, 97))	('AXL', 'Gene', '558', (119, 122))	('AXL', 'Gene', (12, 15))	('CDDP', 'Chemical', 'MESH:D002945', (52, 56))	('AXL', 'Gene', (119, 122))	('phosphorylation', 'MPA', (65, 80))	('c-ABL', 'Gene', (84, 89))	('AXL', 'Gene', '558', (12, 15))
671474	23117882	Our results clearly indicated that reconstitution of AXL expression enhanced survival and attenuated apoptosis after treatment with CDDP.	('reconstitution', 'Var', (35, 49))	('enhanced', 'PosReg', (68, 76))	('AXL', 'Gene', '558', (53, 56))	('survival', 'CPA', (77, 85))	('CDDP', 'Chemical', 'MESH:D002945', (132, 136))	('attenuated', 'NegReg', (90, 100))	('AXL', 'Gene', (53, 56))	('apoptosis', 'CPA', (101, 110))
671475	23117882	Conversely, knockdown of endogenous AXL sensitized cells to CDDP.	('AXL', 'Gene', '558', (36, 39))	('knockdown', 'Var', (12, 21))	('AXL', 'Gene', (36, 39))	('endogenous', 'Protein', (25, 35))	('CDDP', 'Chemical', 'MESH:D002945', (60, 64))	('sensitized', 'Reg', (40, 50))
671478	23117882	However, CDDP can also induce apoptosis in p53-deficient cells through activation of the p73 protein, a member of the p53 family.	('induce', 'PosReg', (23, 29))	('p53', 'Gene', (118, 121))	('activation', 'PosReg', (71, 81))	('apoptosis', 'CPA', (30, 39))	('CDDP', 'Chemical', 'MESH:D002945', (9, 13))	('p53', 'Gene', '7157', (118, 121))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('p73', 'Gene', '7161', (89, 92))	('p73', 'Gene', (89, 92))	('CDDP', 'Var', (9, 13))
671479	23117882	This is particularly of major importance, given the majority of EACs are deficient or mutant in p53.	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('mutant', 'Var', (86, 92))	('deficient', 'NegReg', (73, 82))
671481	23117882	Indeed, our data showed that the reconstitution of AXL expression significantly attenuated CDDP-induced transcriptional activation of endogenous p73beta as confirmed by decreased levels of p73beta, PUMA, and HDM2 proteins, and PG13-luc luciferase activity.	('p73', 'Gene', (189, 192))	('levels', 'MPA', (179, 185))	('AXL', 'Gene', (51, 54))	('p73', 'Gene', '7161', (145, 148))	('transcriptional', 'MPA', (104, 119))	('CDDP-induced', 'Gene', (91, 103))	('p73', 'Gene', (145, 148))	('reconstitution', 'Var', (33, 47))	('PG13-luc luciferase', 'Enzyme', (227, 246))	('activation', 'PosReg', (120, 130))	('attenuated', 'NegReg', (80, 90))	('AXL', 'Gene', '558', (51, 54))	('p73', 'Gene', '7161', (189, 192))	('decreased', 'NegReg', (169, 178))	('activity', 'MPA', (247, 255))	('endogenous', 'MPA', (134, 144))	('CDDP', 'Chemical', 'MESH:D002945', (91, 95))
671494	23117882	Phosphorylation of p73 (Y99) promotes tight interaction with the SH2 domain of c-ABL that may enhance p73 protein stability.	('c-ABL', 'Gene', (79, 84))	('tight', 'MPA', (38, 43))	('Phosphorylation', 'Var', (0, 15))	('enhance', 'PosReg', (94, 101))	('p73', 'Gene', '7161', (19, 22))	('c-ABL', 'Gene', '25', (79, 84))	('p73', 'Gene', (19, 22))	('p73', 'Gene', '7161', (102, 105))	('p73', 'Gene', (102, 105))	('interaction', 'Interaction', (44, 55))	('promotes', 'PosReg', (29, 37))
671547	29670922	The median tumor size was larger with GCC than that with EC (5.92 +- 2.22 versus 4.98 +- 1.51 cm; P = 0.001) (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('GCC', 'Var', (38, 41))	('tumor', 'Disease', (11, 16))	('GCC', 'Chemical', '-', (38, 41))	('larger', 'PosReg', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
671621	29670922	Confirming the potential role of TLR4 in the progression of gastric lesions, some studies associated TLR4 polymorphisms with the risk of gastric cancer.	('polymorphisms', 'Var', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('TLR4', 'Gene', (101, 105))	('gastric lesions', 'Disease', 'MESH:D013272', (60, 75))	('associated', 'Reg', (90, 100))	('gastric cancer', 'Disease', (137, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('gastric lesions', 'Disease', (60, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
671622	29670922	TLR4+896A>G polymorphism was reported as a risk factor for NGCC and its precursors.	('risk', 'Reg', (43, 47))	('NGCC', 'Disease', (59, 63))	('GCC', 'Chemical', '-', (60, 63))	('TLR4+896A>G', 'Var', (0, 11))
671623	29670922	In contrast, prevalence of TLR4+896G was not significantly increased in GCC.	('GCC', 'Chemical', '-', (72, 75))	('GCC', 'Disease', (72, 75))	('TLR4+896G', 'Var', (27, 36))
671649	29435022	Metformin inhibits the migration and invasion of esophageal squamous cell carcinoma cells by downregulating the protein kinase B signaling pathway Previous studies have suggested that metformin, a biguanide family member widely used as an oral antidiabetic drug, may inhibit proliferation and induce apoptosis in certain types of cancer cell.	('migration', 'CPA', (23, 32))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('apoptosis', 'CPA', (300, 309))	('downregulating', 'NegReg', (93, 107))	('esophageal squamous cell carcinoma', 'Disease', (49, 83))	('metformin', 'Var', (184, 193))	('metformin', 'Chemical', 'MESH:D008687', (184, 193))	('proliferation', 'CPA', (275, 288))	('inhibit', 'NegReg', (267, 274))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('induce', 'PosReg', (293, 299))	('cancer', 'Disease', (330, 336))	('protein kinase B', 'Gene', '2185', (112, 128))	('inhibits', 'NegReg', (10, 18))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (49, 83))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('protein kinase B', 'Gene', (112, 128))
671653	29435022	A Transwell assay and western blot analysis revealed that metformin inhibited the migration and invasion of EC109 cells, nuclear factor-kappaB activation, matrix metallopeptidase 9 and N-cadherin expression in a phosphorylated-AKT dependent manner.	('nuclear', 'Protein', (121, 128))	('matrix metallopeptidase 9', 'Gene', (155, 180))	('N-cadherin', 'Gene', (185, 195))	('AKT', 'Gene', (227, 230))	('EC109', 'CellLine', 'CVCL:6898', (108, 113))	('expression', 'MPA', (196, 206))	('inhibited', 'NegReg', (68, 77))	('metformin', 'Var', (58, 67))	('matrix metallopeptidase 9', 'Gene', '4318', (155, 180))	('N-cadherin', 'Gene', '1000', (185, 195))	('metformin', 'Chemical', 'MESH:D008687', (58, 67))	('activation', 'PosReg', (143, 153))	('AKT', 'Gene', '207', (227, 230))
671669	29435022	In 2005, Evans et al demonstrated that in addition to its antidiabetic function, metformin may significantly decrease tumor incidence among patients with type 2 diabetes.	('decrease', 'NegReg', (109, 117))	('type 2 diabetes', 'Disease', (154, 169))	('metformin', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('type 2 diabetes', 'Disease', 'MESH:D003924', (154, 169))	('metformin', 'Chemical', 'MESH:D008687', (81, 90))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (154, 169))	('tumor', 'Disease', (118, 123))	('patients', 'Species', '9606', (140, 148))
671670	29435022	Previously, multiple studies have demonstrated that metformin may inhibit proliferation, induce apoptosis and arrest the cell cycle in ESCC cells.	('induce', 'PosReg', (89, 95))	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('cell cycle', 'CPA', (121, 131))	('arrest', 'Disease', 'MESH:D006323', (110, 116))	('metformin', 'Var', (52, 61))	('arrest', 'Disease', (110, 116))	('apoptosis', 'CPA', (96, 105))	('inhibit', 'NegReg', (66, 73))	('proliferation', 'CPA', (74, 87))	('metformin', 'Chemical', 'MESH:D008687', (52, 61))	('SCC', 'CellLine', 'CVCL:1R13', (136, 139))
671671	29435022	Furthermore, metformin may inhibit malignant cell migration, and the invasion of ovarian, pancreatic cancer and melanoma cells in vitro.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('metformin', 'Var', (13, 22))	('pancreatic cancer', 'Disease', (90, 107))	('ovarian', 'Disease', 'MESH:D010051', (81, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('malignant cell migration', 'CPA', (35, 59))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('invasion', 'CPA', (69, 77))	('melanoma', 'Disease', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian', 'Disease', (81, 88))	('inhibit', 'NegReg', (27, 34))
671675	29435022	EC109 cells were treated with 100 nM insulin [a protein kinase B (AKT) activator] and 10 microM LY294002 (a PI3K inhibitor) dissolved in dimethyl sulfoxide (DMSO) for 30 min or 24 h at 37 C in a humidified, 5% CO2 atmosphere, separately or in combination.	('protein kinase B', 'Gene', (48, 64))	('LY294002', 'Var', (96, 104))	('AKT', 'Gene', (66, 69))	('insulin', 'Gene', (37, 44))	('DMSO', 'Chemical', 'MESH:D004121', (157, 161))	('insulin', 'Gene', '3630', (37, 44))	('protein kinase B', 'Gene', '2185', (48, 64))	('LY294002', 'Chemical', 'MESH:C085911', (96, 104))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (137, 155))	('CO2', 'Chemical', '-', (210, 213))	('EC109', 'CellLine', 'CVCL:6898', (0, 5))	('AKT', 'Gene', '207', (66, 69))
671678	29435022	Metformin and LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, were purchased from Sigma-Aldrich; Merck KGaA (Darmstadt, Germany).	('phosphoinositide 3-kinase', 'Gene', (26, 51))	('LY294002', 'Var', (14, 22))	('LY294002', 'Chemical', 'MESH:C085911', (14, 22))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('phosphoinositide 3-kinase', 'Gene', '5295', (26, 51))
671708	29435022	The results of the present study indicated that MMP9 transcription was dose-dependently decreased by metformin (Fig.	('MMP9', 'Gene', '4318', (48, 52))	('MMP9', 'Gene', (48, 52))	('metformin', 'Var', (101, 110))	('decreased', 'NegReg', (88, 97))	('metformin', 'Chemical', 'MESH:D008687', (101, 110))
671712	29435022	To further explore whether the AKT signaling pathway is associated with EC109 cell migration and invasion, EC109 cells were treated with 100 nM insulin (an AKT activator) and 10 microM LY294002 (a PI3K inhibitor) for 30 min or 24 h, separately or in combination.	('AKT', 'Gene', '207', (156, 159))	('LY294002', 'Var', (185, 193))	('EC109', 'CellLine', 'CVCL:6898', (72, 77))	('AKT', 'Gene', (31, 34))	('EC109', 'CellLine', 'CVCL:6898', (107, 112))	('AKT', 'Gene', (156, 159))	('insulin', 'Gene', (144, 151))	('LY294002', 'Chemical', 'MESH:C085911', (185, 193))	('insulin', 'Gene', '3630', (144, 151))	('AKT', 'Gene', '207', (31, 34))
671714	29435022	The results of the present study demonstrated that LY294002 inhibited the migration and invasion of the EC109 cells (Fig.	('LY294002', 'Var', (51, 59))	('EC109', 'CellLine', 'CVCL:6898', (104, 109))	('invasion of the EC109 cells', 'CPA', (88, 115))	('inhibited', 'NegReg', (60, 69))	('LY294002', 'Chemical', 'MESH:C085911', (51, 59))
671717	29435022	EC109 cells were treated with LY294002 for 24 h or with insulin for 30 min, separately or in combination.	('insulin', 'Gene', '3630', (56, 63))	('LY294002', 'Chemical', 'MESH:C085911', (30, 38))	('EC109', 'CellLine', 'CVCL:6898', (0, 5))	('insulin', 'Gene', (56, 63))	('LY294002', 'Var', (30, 38))
671719	29435022	2B), the protein expression of MMP9 and N-cadherin was downregulated, and the expression of E-cadherin was increased in LY294002-treated cells (Fig.	('N-cadherin', 'Gene', (40, 50))	('LY294002-treated', 'Var', (120, 136))	('expression', 'MPA', (78, 88))	('E-cadherin', 'Gene', (92, 102))	('increased', 'PosReg', (107, 116))	('MMP9', 'Gene', (31, 35))	('N-cadherin', 'Gene', '1000', (40, 50))	('E-cadherin', 'Gene', '999', (92, 102))	('MMP9', 'Gene', '4318', (31, 35))	('LY294002', 'Chemical', 'MESH:C085911', (120, 128))	('protein expression', 'MPA', (9, 27))	('downregulated', 'NegReg', (55, 68))
671727	29435022	Previous studies have evaluated the effects metformin may induce through AMP-activated protein kinase-dependent mechanisms, and have demonstrated that metformin decreases the expression of p-AKT in bladder cancer, NRAS proto-oncogene mutant melanoma cell line DO4 and squamous cell carcinoma (SCC) cell line A431.	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('mutant', 'Var', (234, 240))	('melanoma', 'Disease', (241, 249))	('squamous cell carcinoma', 'Disease', (268, 291))	('AMP-activated', 'MPA', (73, 86))	('NRAS', 'Gene', '4893', (214, 218))	('expression', 'MPA', (175, 185))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('AKT', 'Gene', '207', (191, 194))	('SCC', 'CellLine', 'CVCL:1R13', (293, 296))	('bladder cancer', 'Disease', (198, 212))	('metformin', 'Chemical', 'MESH:D008687', (44, 53))	('SCC', 'Phenotype', 'HP:0002860', (293, 296))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('decreases', 'NegReg', (161, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (268, 291))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('NRAS', 'Gene', (214, 218))	('A431', 'CellLine', 'CVCL:0037', (308, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('metformin', 'Var', (151, 160))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (268, 291))	('AKT', 'Gene', (191, 194))	('metformin', 'Chemical', 'MESH:D008687', (151, 160))
671730	29435022	Consistent with these previous studies, the results of the present study suggested that metformin inhibited invasion in EC109 cells by inhibiting AKT activation.	('AKT', 'Gene', '207', (146, 149))	('metformin', 'Chemical', 'MESH:D008687', (88, 97))	('inhibited', 'NegReg', (98, 107))	('AKT', 'Gene', (146, 149))	('inhibiting', 'NegReg', (135, 145))	('EC109', 'CellLine', 'CVCL:6898', (120, 125))	('metformin', 'Var', (88, 97))	('invasion', 'CPA', (108, 116))	('activation', 'MPA', (150, 160))
671731	29435022	The present study also demonstrated that the PI3K inhibitor LY294002 inhibited EC109 cell migration and invasion, while the AKT activator insulin decreased metformin-induced metastasis inhibition in EC109 cells.	('EC109', 'CellLine', 'CVCL:6898', (79, 84))	('metformin', 'Chemical', 'MESH:D008687', (156, 165))	('LY294002', 'Chemical', 'MESH:C085911', (60, 68))	('EC109', 'CellLine', 'CVCL:6898', (199, 204))	('AKT', 'Gene', (124, 127))	('insulin', 'Gene', (138, 145))	('inhibited', 'NegReg', (69, 78))	('invasion', 'CPA', (104, 112))	('LY294002', 'Var', (60, 68))	('insulin', 'Gene', '3630', (138, 145))	('AKT', 'Gene', '207', (124, 127))
671733	29435022	To the best of our knowledge, the present study is the first to demonstrate in vitro that metformin inhibits ESCC metastasis by inhibiting AKT activation.	('inhibits', 'NegReg', (100, 108))	('ESCC', 'Disease', (109, 113))	('AKT', 'Gene', '207', (139, 142))	('SCC', 'CellLine', 'CVCL:1R13', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('metformin', 'Var', (90, 99))	('AKT', 'Gene', (139, 142))	('activation', 'PosReg', (143, 153))	('inhibiting', 'NegReg', (128, 138))	('metformin', 'Chemical', 'MESH:D008687', (90, 99))
671737	29435022	In the gastric cancer cell line BGC-823, the overexpression of death associated protein kinase 3 (DAPK3) induced AKT activation and increased the phosphorylation of IKKalpha, NFKBIA and NF-kappaB, while the AKT inhibitor LY294002 significantly decreased the phosphorylation of IKKalpha, NFKBIA, NF-kappaB, and prevented DAPK3-induced BGC-823 cell migration and invasion.	('LY294002', 'Chemical', 'MESH:C085911', (221, 229))	('DAPK3', 'Gene', '1613', (320, 325))	('NF-kappaB', 'Gene', (295, 304))	('AKT', 'Gene', '207', (113, 116))	('gastric cancer', 'Disease', (7, 21))	('prevented', 'NegReg', (310, 319))	('death associated protein kinase 3', 'Gene', (63, 96))	('invasion', 'CPA', (361, 369))	('death associated protein kinase 3', 'Gene', '1613', (63, 96))	('AKT', 'Gene', '207', (207, 210))	('NF-kappaB', 'Gene', '4790', (295, 304))	('increased', 'PosReg', (132, 141))	('NFKBIA', 'Gene', (287, 293))	('BGC-823', 'Gene', (334, 341))	('IKKalpha', 'Gene', '1147', (277, 285))	('NFKBIA', 'Gene', (175, 181))	('NFKBIA', 'Gene', '4792', (287, 293))	('IKKalpha', 'Gene', '1147', (165, 173))	('gastric cancer', 'Disease', 'MESH:D013274', (7, 21))	('NFKBIA', 'Gene', '4792', (175, 181))	('DAPK3', 'Gene', (98, 103))	('decreased', 'NegReg', (244, 253))	('LY294002', 'Var', (221, 229))	('BGC-823', 'CellLine', 'CVCL:3360', (334, 341))	('DAPK3', 'Gene', (320, 325))	('IKKalpha', 'Gene', (277, 285))	('AKT', 'Gene', (113, 116))	('activation', 'PosReg', (117, 127))	('IKKalpha', 'Gene', (165, 173))	('BGC-823', 'CellLine', 'CVCL:3360', (32, 39))	('NF-kappaB', 'Gene', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (7, 21))	('AKT', 'Gene', (207, 210))	('DAPK3', 'Gene', '1613', (98, 103))	('phosphorylation', 'MPA', (258, 273))	('NF-kappaB', 'Gene', '4790', (186, 195))	('phosphorylation', 'MPA', (146, 161))
671738	29435022	In the present study, NF-kappaB (p65) expression was decreased in the EC109 cells treated with metformin or LY294002, but increased in insulin-treated EC109 cells pretreated with or without metformin.	('insulin', 'Gene', (135, 142))	('LY294002', 'Var', (108, 116))	('EC109', 'CellLine', 'CVCL:6898', (70, 75))	('p65', 'Gene', (33, 36))	('expression', 'MPA', (38, 48))	('EC109', 'CellLine', 'CVCL:6898', (151, 156))	('insulin', 'Gene', '3630', (135, 142))	('NF-kappaB', 'Gene', (22, 31))	('metformin', 'Chemical', 'MESH:D008687', (95, 104))	('p65', 'Gene', '5970', (33, 36))	('increased', 'PosReg', (122, 131))	('decreased', 'NegReg', (53, 62))	('LY294002', 'Chemical', 'MESH:C085911', (108, 116))	('metformin', 'Chemical', 'MESH:D008687', (190, 199))	('NF-kappaB', 'Gene', '4790', (22, 31))
671740	29435022	Since AKT promoted invasion in the human fibrosarcoma cell line HT1080 by increasing cell motility and MMP9 expression in a previous study, LY294002-induced suppression of MMP9 expression may have resulted in the inhibition of EC109 cell invasion demonstrated in the present study.	('MMP9', 'Gene', '4318', (103, 107))	('MMP9', 'Gene', (103, 107))	('human', 'Species', '9606', (35, 40))	('HT1080', 'CellLine', 'CVCL:0317', (64, 70))	('fibrosarcoma', 'Disease', 'MESH:D005354', (41, 53))	('expression', 'MPA', (177, 187))	('AKT', 'Gene', (6, 9))	('cell motility', 'CPA', (85, 98))	('LY294002-induced', 'Var', (140, 156))	('invasion', 'CPA', (19, 27))	('fibrosarcoma', 'Disease', (41, 53))	('LY294002', 'Chemical', 'MESH:C085911', (140, 148))	('suppression', 'NegReg', (157, 168))	('MMP9', 'Gene', '4318', (172, 176))	('MMP9', 'Gene', (172, 176))	('AKT', 'Gene', '207', (6, 9))	('EC109', 'CellLine', 'CVCL:6898', (227, 232))	('increasing', 'PosReg', (74, 84))	('promoted', 'PosReg', (10, 18))	('expression', 'MPA', (108, 118))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (41, 53))
671753	27882512	Between July 2005 and December 2015, a linear-stapled side-to-side esophagojejunostomy with hand-sewn closure of the common enterotomy (modified Orringer technique) was used for Roux-en-Y reconstruction after prophylactic total gastrectomy in 22 germline CDH1 mutation carriers and after therapeutic total gastrectomy in 18 patients diagnosed with gastric adenocarcinoma.	('gastric adenocarcinoma', 'Disease', (348, 370))	('CDH1', 'Gene', (255, 259))	('patients', 'Species', '9606', (324, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('CDH1', 'Gene', '999', (255, 259))	('mutation', 'Var', (260, 268))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (348, 370))
671760	27882512	A small percentage of gastric adenocarcinomas (Lauren diffuse type) arise in individuals with germline mutation of the CDH1 gene, which encodes the E-cadherin cell adhesion protein.	('CDH1', 'Gene', '999', (119, 123))	('E-cadherin', 'Gene', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('gastric adenocarcinomas', 'Disease', (22, 45))	('E-cadherin', 'Gene', '999', (148, 158))	('arise', 'Reg', (68, 73))	('CDH1', 'Gene', (119, 123))	('mutation', 'Var', (103, 111))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (22, 45))
671761	27882512	For germline CDH1 mutation carriers, the cumulative risk of developing diffuse gastric adenocarcinoma by 80 years of age is up to 80%, and the average age of diagnosis is 38 years old.	('CDH1', 'Gene', '999', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (79, 101))	('gastric adenocarcinoma', 'Disease', (79, 101))	('mutation', 'Var', (18, 26))	('CDH1', 'Gene', (13, 17))
671762	27882512	Prophylactic total gastrectomy is recommended in healthy individuals with germline CDH1 mutation.	('mutation', 'Var', (88, 96))	('CDH1', 'Gene', (83, 87))	('CDH1', 'Gene', '999', (83, 87))
671769	27882512	In this article, we report a single surgeon's experience with a modified version of the Orringer anastomosis in 22 CDH1 mutation carriers who underwent prophylactic total gastrectomy and 18 patients diagnosed with gastric adenocarinoma who underwent therapeutic total gastrectomy.	('patients', 'Species', '9606', (190, 198))	('gastric adenocarinoma', 'Disease', (214, 235))	('mutation', 'Var', (120, 128))	('CDH1', 'Gene', (115, 119))	('gastric adenocarinoma', 'Disease', 'MESH:D013274', (214, 235))	('CDH1', 'Gene', '999', (115, 119))
671784	27882512	Thirty-two patients who underwent prophylactic total gastrectomy for germline CDH1 mutation were identified from the examined time period.	('mutation', 'Var', (83, 91))	('patients', 'Species', '9606', (11, 19))	('CDH1', 'Gene', '999', (78, 82))	('CDH1', 'Gene', (78, 82))
671811	27882512	In this article, we describe a single surgeon's experience with a linear-stapled side-to-side esophagojejunostomy reconstruction in 22 consecutive patients who underwent prophylactic total gastrectomy for CDH1 mutation and 18 consecutive patients who underwent therapeutic total gastrectomy for gastric adenocarcinoma.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (295, 317))	('gastric adenocarcinoma', 'Disease', (295, 317))	('CDH1', 'Gene', (205, 209))	('esophagojejunostomy reconstruction', 'Phenotype', 'HP:0100628', (94, 128))	('mutation', 'Var', (210, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('patients', 'Species', '9606', (147, 155))	('CDH1', 'Gene', '999', (205, 209))	('patients', 'Species', '9606', (238, 246))
671819	27882512	While similar anastomosis-related outcomes were achieved in patients who received therapeutic total gastrectomy, it is important to note that CDH1 mutation carriers represent a unique population.	('mutation', 'Var', (147, 155))	('CDH1', 'Gene', (142, 146))	('patients', 'Species', '9606', (60, 68))	('CDH1', 'Gene', '999', (142, 146))
671822	27882512	The post-operative quality of life for the patient is critically important, particularly for patients with germline CDH1 mutation as they often receive prophylactic total gastrectomy before any appreciable gastrointestinal symptoms arise.	('CDH1', 'Gene', '999', (116, 120))	('gastrointestinal symptoms', 'Disease', (206, 231))	('patients', 'Species', '9606', (93, 101))	('patient', 'Species', '9606', (43, 50))	('patient', 'Species', '9606', (93, 100))	('mutation', 'Var', (121, 129))	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (206, 231))	('CDH1', 'Gene', (116, 120))
671825	27882512	No statistically significant differences in post-gastrectomy dumping syndrome, persistent reflux symptoms, or weight loss were identified when comparing patients who received modified Orringer anastomosis to patients who received a completely hand-sewn anastomosis.	('weight loss', 'Disease', 'MESH:D015431', (110, 121))	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (153, 161))	('reflux symptoms', 'Phenotype', 'HP:0002020', (90, 105))	('weight loss', 'Disease', (110, 121))	('modified', 'Var', (175, 183))	('weight loss', 'Phenotype', 'HP:0001824', (110, 121))
671827	27882512	This manuscript describes one of the largest Western experiences in the operative management of CDH1 mutation carriers.	('CDH1', 'Gene', (96, 100))	('mutation', 'Var', (101, 109))	('CDH1', 'Gene', '999', (96, 100))
671900	25674529	One or 2 days after the ingestion of alkaline substances, destruction of the mucosa is exacerbated by thrombosis in small vessels and the production of heat.	('alkaline', 'Var', (37, 45))	('thrombosis', 'Disease', 'MESH:D013927', (102, 112))	('exacerbated', 'PosReg', (87, 98))	('destruction of the mucosa', 'CPA', (58, 83))	('thrombosis', 'Disease', (102, 112))
671904	25674529	On the other hand, dissolving picosulfate in a low volume of water produces a more strongly acidic liquid, which more frequently leads to corrosive esophagitis.	('dissolving', 'Var', (19, 29))	('water', 'Chemical', 'MESH:D014867', (61, 66))	('picosulfate', 'Chemical', 'MESH:C005701', (30, 41))	('esophagitis', 'Phenotype', 'HP:0100633', (148, 159))	('corrosive esophagitis', 'Disease', (138, 159))	('corrosive esophagitis', 'Disease', 'MESH:D004941', (138, 159))	('leads to', 'Reg', (129, 137))
671915	24396446	The following parameters were found to be reduced following the use of methylprednisolone: Interleukin (IL)-6 immediately following surgery and on postoperative days (PODs) 1 and 3; IL-8 immediately following surgery; and PaO2/FiO2 on POD 3.	('reduced', 'NegReg', (42, 49))	('PaO2/FiO2', 'Var', (222, 231))	('methylprednisolone', 'Chemical', 'MESH:D008775', (71, 89))	('Interleukin (IL)-6', 'Gene', (91, 109))	('IL-8', 'Gene', '3576', (182, 186))	('Interleukin (IL)-6', 'Gene', '3569', (91, 109))	('IL-8', 'Gene', (182, 186))	('FiO2', 'Chemical', '-', (227, 231))	('PaO2', 'Chemical', '-', (222, 226))
671947	24396446	For example, while the preoperative levels of IL-6 were not different between the control and methylprednisolone-treated groups, the postoperative IL-6 levels in patients treated with methylprednisolone were significantly lower on PODs 1 and 3.	('patients', 'Species', '9606', (162, 170))	('IL-6', 'Gene', (46, 50))	('methylprednisolone', 'Chemical', 'MESH:D008775', (184, 202))	('methylprednisolone', 'Chemical', 'MESH:D008775', (94, 112))	('methylprednisolone', 'Var', (184, 202))	('IL-6', 'Gene', '3569', (46, 50))	('IL-6', 'Gene', (147, 151))	('PODs 1 and 3', 'Gene', '6943', (231, 243))	('lower', 'NegReg', (222, 227))	('IL-6', 'Gene', '3569', (147, 151))
671968	24396446	The current meta-analysis showed that morbidity associated with organ failure was lower in the methylprednisolone-treated group compared with the control group, with the exception of renal and hepatic failure, which showed no significant difference.	('hepatic failure', 'Phenotype', 'HP:0001399', (193, 208))	('methylprednisolone-treated', 'Var', (95, 121))	('methylprednisolone', 'Chemical', 'MESH:D008775', (95, 113))	('organ failure', 'Disease', (64, 77))	('organ failure', 'Disease', 'MESH:D009102', (64, 77))	('renal and hepatic failure', 'Disease', 'MESH:D051437', (183, 208))	('morbidity', 'CPA', (38, 47))	('lower', 'NegReg', (82, 87))
671993	19183436	Additionally, PADI4 and cAT levels were significantly associated with higher levels of known tumor markers.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('cAT', 'MPA', (24, 27))	('PADI4', 'Var', (14, 19))	('higher', 'PosReg', (70, 76))	('cAT', 'Chemical', '-', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
671996	19183436	had found that citrullination by PADI4 prevents arginine methylation of histones H3 and H4 during transcriptional activation of estrogen-responsive genes.	('histones H3', 'Protein', (72, 83))	('prevents', 'NegReg', (39, 47))	('PADI4', 'Gene', (33, 38))	('arginine', 'Chemical', 'MESH:D001120', (48, 56))	('arginine methylation', 'MPA', (48, 68))	('citrullination', 'Var', (15, 29))
672085	19183436	In the present study, high cAT production was specifically and primarily detected in blood of most malignant tumor types, but not in blood of benign tumors or non-tumor diseases, suggesting that citrullination of antithrombin may be involved in promoting carcinogenesis.	('involved', 'Reg', (233, 241))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('cAT', 'Chemical', '-', (27, 30))	('cAT production', 'MPA', (27, 41))	('blood of benign tumors', 'Disease', (133, 155))	('blood of benign tumors', 'Disease', 'MESH:D009383', (133, 155))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('malignant tumor', 'Disease', (99, 114))	('malignant tumor', 'Disease', 'MESH:D018198', (99, 114))	('citrullination', 'Var', (195, 209))	('detected', 'Reg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('non-tumor diseases', 'Disease', (159, 177))	('antithrombin', 'Gene', (213, 225))	('carcinogenesis', 'Disease', (255, 269))	('antithrombin', 'Gene', '462', (213, 225))	('carcinogenesis', 'Disease', 'MESH:D063646', (255, 269))	('promoting', 'PosReg', (245, 254))	('non-tumor diseases', 'Disease', 'MESH:D009369', (159, 177))
672086	19183436	Therefore, it is formally possible that deregulated thrombin activity drives thrombin-related tumorigenesis, including malignant proliferation, invasion and metastasis of tumor cells, as well as abnormal angiogenesis and fibrin deposition in tumor tissues.	('thrombin', 'Gene', '2147', (77, 85))	('deregulated', 'Var', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('fibrin deposition', 'CPA', (221, 238))	('angiogenesis', 'CPA', (204, 216))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('thrombin', 'Gene', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('invasion', 'CPA', (144, 152))	('thrombin', 'Gene', '2147', (52, 60))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('malignant proliferation', 'CPA', (119, 142))	('thrombin', 'Gene', (77, 85))	('tumor', 'Disease', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
672090	19183436	These modifications consequently interrupt apoptosis and cell cycle progression, which are primary features of tumorigenic cells.	('modifications', 'Var', (6, 19))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('apoptosis', 'CPA', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('cell cycle progression', 'CPA', (57, 79))	('interrupt', 'NegReg', (33, 42))
672098	19183436	Our results implicate the importance of PADI4 and citrullination in the promotion of tumorigenesis.	('citrullination', 'Var', (50, 64))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
672139	17603896	Cox Proportional Hazard Model (R0-resections) for decade I revealed pN-category (HR:2.444; 95%CI:1.219-4.901) as the only independent prognostic factor of overall survival, whereas pT-category, distant metastases, grading, age, gender and ASA-classification were not significant (p > 0.05) (multivariate analysis).	('pN-category', 'Var', (68, 79))	('metastases', 'Disease', 'MESH:D009362', (202, 212))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('overall survival', 'MPA', (155, 171))	('ASA', 'Chemical', 'MESH:D001241', (239, 242))	('metastases', 'Disease', (202, 212))
672207	33123474	The radiation dose was P-GTV 60.2-66 Gy/28-33 fractions and P-CTV 50.4-59.4 Gy/28-33 fractions.	('P-GTV', 'Chemical', '-', (23, 28))	('P-CTV', 'Var', (60, 65))	('P-GTV', 'Var', (23, 28))
672466	32304170	Ectopic Sox2 expression induces stomach-like differentiation in intestinal epithelium in embryonic mice, demonstrating its importance in epithelial specification of the foregut.	('mice', 'Species', '10090', (99, 103))	('stomach-like differentiation', 'CPA', (32, 60))	('induces', 'Reg', (24, 31))	('rat', 'Species', '10116', (112, 115))	('Sox2', 'Gene', (8, 12))	('Ectopic', 'Var', (0, 7))
672493	32304170	In theory, however, loss of lymphatic drainage through trauma or occlusion could cause swelling and decreased functionality of tissue in the GEJ.	('loss of lymphatic drainage', 'Phenotype', 'HP:0001004', (20, 46))	('occlusion', 'Var', (65, 74))	('trauma', 'Disease', (55, 61))	('trauma', 'Disease', 'MESH:D014947', (55, 61))	('swelling', 'Disease', (87, 95))	('decreased', 'NegReg', (100, 109))	('swelling', 'Disease', 'MESH:D004487', (87, 95))	('lymphatic drainage', 'CPA', (28, 46))	('loss', 'NegReg', (20, 24))	('functionality of tissue', 'CPA', (110, 133))
672596	31839819	In recent years, investigations based on genetic sequencing have revealed the emerging role of ADCY1 mutations in affecting drug efficiency in various cancers such as lung cancer, esophageal cancer and colorectal cancer.	('drug efficiency', 'MPA', (124, 139))	('lung cancer', 'Disease', (167, 178))	('esophageal cancer', 'Disease', (180, 197))	('colorectal cancer', 'Disease', (202, 219))	('ADCY1', 'Gene', (95, 100))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('cancers', 'Disease', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (101, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('affecting', 'Reg', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('esophageal cancer', 'Disease', 'MESH:D004938', (180, 197))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))
672613	31839819	ADCY1 was hypermethylated in glioblastoma and associated with the survival time of the patients with malignant glioma.	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('malignant glioma', 'Disease', (101, 117))	('malignant glioma', 'Disease', 'MESH:D005910', (101, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('ADCY1', 'Gene', (0, 5))	('associated with', 'Reg', (46, 61))	('hypermethylated', 'Var', (10, 25))	('patients', 'Species', '9606', (87, 95))	('glioblastoma', 'Disease', (29, 41))
672634	31839819	The EPAC/Rap1 signaling is associated with the complex network of EMT signaling; whose dysfunction may cause lung cancer.	('Rap1', 'Gene', (9, 13))	('EPAC', 'Gene', (4, 8))	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('EPAC', 'Gene', '10411', (4, 8))	('Rap1', 'Gene', '5906', (9, 13))	('dysfunction', 'Var', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('cause', 'Reg', (103, 108))
672648	31839819	The abnormity of DNA damage and repair process can lead to cellular dysfunction and tumor development.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('abnormity', 'Var', (4, 13))	('cellular dysfunction', 'CPA', (59, 79))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('lead to', 'Reg', (51, 58))
672662	31839819	The expression and polymorphisms of XRCC1 play an important role in DNA repair and it may be a prognosis biomarker for lung cancer patients treated with radiation or chemotherapy.	('patients', 'Species', '9606', (131, 139))	('polymorphisms', 'Var', (19, 32))	('lung cancer', 'Disease', (119, 130))	('DNA repair', 'CPA', (68, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('XRCC1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('XRCC1', 'Gene', '7515', (36, 41))
672686	31839819	OSU03013, a derivative of celecoxib, can compete with ATP to bind to cAMP-dependent protein kinase, and cause dephosphorylation of glycogen synthase kinase 3-beta (GSK3beta), leading to beta-catenin (beta-catenin) degradation.	('GSK3beta', 'Gene', (164, 172))	('ATP', 'Chemical', 'MESH:D000255', (54, 57))	('GSK3beta', 'Gene', '2931', (164, 172))	('glycogen synthase kinase 3-beta', 'Gene', '2932', (131, 162))	('beta-catenin', 'Gene', (200, 212))	('beta-catenin', 'Gene', (186, 198))	('dephosphorylation', 'MPA', (110, 127))	('OSU03013', 'Chemical', 'MESH:C528969', (0, 8))	('beta-catenin', 'Gene', '1499', (200, 212))	('beta-catenin', 'Gene', '1499', (186, 198))	('bind', 'Interaction', (61, 65))	('cause', 'Reg', (104, 109))	('cAMP', 'Chemical', 'MESH:D000242', (69, 73))	('glycogen synthase kinase 3-beta', 'Gene', (131, 162))	('OSU03013', 'Var', (0, 8))	('celecoxib', 'Chemical', 'MESH:D000068579', (26, 35))
672704	31839819	Loss of LKB1 will promote cancer progression and influence therapeutic responses in preclinical investigations, due to its effect on drug efficacy through the regulation of MDR1 expression.	('LKB1', 'Gene', '6794', (8, 12))	('MDR1', 'Gene', (173, 177))	('MDR1', 'Gene', '5243', (173, 177))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('expression', 'MPA', (178, 188))	('LKB1', 'Gene', (8, 12))	('therapeutic responses', 'CPA', (59, 80))	('regulation', 'Reg', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('effect', 'Reg', (123, 129))	('influence', 'Reg', (49, 58))	('Loss', 'Var', (0, 4))	('promote', 'PosReg', (18, 25))	('drug efficacy', 'MPA', (133, 146))
672715	31839819	Alteration of the expression of MEG3 is also correlated with cis-platinum resistance in lung adenocarcinoma.	('cis-platinum resistance', 'MPA', (61, 84))	('MEG3', 'Gene', (32, 36))	('Alteration', 'Var', (0, 10))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('MEG3', 'Gene', '55384', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('expression', 'MPA', (18, 28))	('lung adenocarcinoma', 'Disease', (88, 107))	('cis-platinum', 'Chemical', 'MESH:D002945', (61, 73))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('correlated', 'Reg', (45, 55))
672721	31839819	Mutations of ADCY1 were revealed to be associated with hearing impairment or other disorders in the nervous system.	('hearing impairment', 'Phenotype', 'HP:0000365', (55, 73))	('hearing impairment or other disorders', 'Disease', (55, 92))	('Mutations', 'Var', (0, 9))	('ADCY1', 'Gene', (13, 18))	('associated', 'Reg', (39, 49))	('hearing impairment or other disorders', 'Disease', 'MESH:D034381', (55, 92))
672747	31871456	In addition, although several studies had reported the association between RAS or HER-2 or PIK3CA mutation and brain metastases from digestive cancers, the present study did not address the effects of genes mutations on brain metastases from digestive cancers since our cohort included many patients prior to the establishment of routine genetic analyses.	('PIK3CA', 'Gene', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('brain', 'Disease', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('mutation', 'Var', (98, 106))	('HER-2', 'Gene', '2064', (82, 87))	('PIK3CA', 'Gene', '5290', (91, 97))	('HER-2', 'Gene', (82, 87))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('association', 'Interaction', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('RAS', 'Gene', (75, 78))
672826	30425526	To date, circRNA_100876 has been found to be highly expressed in lung cancer, with its high expression being negatively correlated with the prognosis of non-small-cell lung cancer, suggesting that circRNA_100876 promotes metastatic potential.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('metastatic potential', 'CPA', (221, 241))	('lung cancer', 'Disease', (168, 179))	('promotes', 'PosReg', (212, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('negatively', 'NegReg', (109, 119))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('circRNA_100876', 'Var', (197, 211))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))
672827	30425526	The expression pattern and biological function of circRNA_100876 in esophageal squamous cell carcinoma (ESCC) remain unknown.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('esophageal squamous cell carcinoma', 'Disease', (68, 102))	('circRNA_100876', 'Var', (50, 64))
672852	30425526	Using the medium expression value of circRNA_100876 as the cut-off point for the Pearson chi-squared test and Kaplan-Meier's plot, it was found that circRNA_100876 expression was strongly correlated with tumor invasion depth (P=0.017), lymph node metastasis (P=0.027), and vascular invasion (P=0.036; Table 2).	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('lymph node metastasis', 'CPA', (236, 257))	('vascular invasion', 'CPA', (273, 290))	('circRNA_100876', 'Var', (149, 163))	('correlated', 'Reg', (188, 198))
672853	30425526	Patients with higher circRNA_100876 expression had shorter recurrence-free survival (median, 41 vs 23 months; P=0.029; Figure 1C) and overall survival time (median, 46 vs 30 months; P=0.021; Figure 1D) than those with lower circRNA_100876 expression, indicating that circRNA_100876 expression was linked to the clinical progression of ESCC and might represent a promising prognostic biomarker.	('circRNA_100876 expression', 'Var', (21, 46))	('shorter', 'NegReg', (51, 58))	('linked', 'Reg', (297, 303))	('recurrence-free survival', 'CPA', (59, 83))	('overall survival time', 'CPA', (134, 155))	('Patients', 'Species', '9606', (0, 8))	('ESCC', 'Disease', (335, 339))
672858	30425526	The average volume of xenograft tumors grown from circRNA_100876-knockdown TE-1 cells was 75.27+-7.51 mm3 at day 16, while that of the mice inoculated with NC sequence-infected TE-1 cells was 472.20+-142.71 mm3, which was significantly larger than that of circRNA_100876 silencing group (P<0.05; Figure 2D).	('circRNA_100876-knockdown', 'Var', (50, 74))	('larger', 'PosReg', (236, 242))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mice', 'Species', '10090', (135, 139))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
672861	30425526	Hence, circRNA_100876 depletion restricted ESCC progression, partially by eliminating cell cycle arrest and inhibiting apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('ESCC', 'Disease', (43, 47))	('depletion', 'Var', (22, 31))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('restricted', 'NegReg', (32, 42))	('eliminating', 'NegReg', (74, 85))	('apoptosis', 'CPA', (119, 128))	('arrest', 'Disease', (97, 103))	('inhibiting', 'NegReg', (108, 118))
672862	30425526	CircRNA_100876 promotes extracellular matrix degradation by competing with MMP13 for miR-136.	('MMP13', 'Gene', (75, 80))	('MMP13', 'Gene', '4322', (75, 80))	('miR-136', 'Gene', (85, 92))	('extracellular matrix degradation', 'CPA', (24, 56))	('miR-136', 'Gene', '406927', (85, 92))	('CircRNA_100876', 'Var', (0, 14))	('promotes', 'PosReg', (15, 23))
672863	30425526	The EMT process was also restrained after circRNA_100876 knockdown, which was characterized by upregulation of epithelial-phenotype E-cadherin and downregulation of mesenchymal-phenotype N-cadherin, vimentin, and the EMT-associated transcription factor Snail (Figure 4B).	('N-cadherin', 'Gene', '1000', (187, 197))	('epithelial-phenotype', 'CPA', (111, 131))	('E-cadherin', 'Gene', (132, 142))	('mesenchymal-phenotype', 'CPA', (165, 186))	('E-cadherin', 'Gene', '999', (132, 142))	('knockdown', 'Var', (57, 66))	('EMT process', 'CPA', (4, 15))	('downregulation', 'NegReg', (147, 161))	('upregulation', 'PosReg', (95, 107))	('vimentin', 'Protein', (199, 207))	('N-cadherin', 'Gene', (187, 197))	('circRNA_100876 knockdown', 'Var', (42, 66))	('restrained', 'NegReg', (25, 35))
672864	30425526	Therefore, we concluded that circRNA_100876 promoted cell migration, invasion, and EMT progression in ESCC, thus facilitating cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('promoted', 'PosReg', (44, 52))	('cancer metastasis', 'Disease', 'MESH:D009362', (126, 143))	('ESCC', 'Disease', (102, 106))	('facilitating', 'PosReg', (113, 125))	('circRNA_100876', 'Var', (29, 43))	('invasion', 'CPA', (69, 77))	('cell migration', 'CPA', (53, 67))	('EMT progression', 'CPA', (83, 98))	('cancer metastasis', 'Disease', (126, 143))
672867	30425526	Altered circ_100876 expression has been identified in lung squamous cell carcinoma.	('Altered', 'Var', (0, 7))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('identified', 'Reg', (40, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
672868	30425526	Circ_100876 expression levels in ESCC tissues were markedly higher than those in the corresponding noncancerous tissues.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ESCC', 'Disease', (33, 37))	('higher', 'PosReg', (60, 66))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('expression levels', 'MPA', (12, 29))	('Circ_100876', 'Var', (0, 11))
672869	30425526	Moreover, there was a significant correlation between elevated circ_100876 expression and the presence of lymph node metastasis, advanced tumor staging, and poor prognosis of ESCC patients.	('tumor', 'Disease', (138, 143))	('circ_100876', 'Var', (63, 74))	('elevated', 'PosReg', (54, 62))	('patients', 'Species', '9606', (180, 188))	('ESCC', 'Disease', (175, 179))	('lymph node metastasis', 'CPA', (106, 127))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('expression', 'MPA', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
672870	30425526	Our findings indicate that circRNA_100876 should be considered as a crucial molecular marker for ESCC patients.	('patients', 'Species', '9606', (102, 110))	('ESCC', 'Disease', (97, 101))	('circRNA_100876', 'Var', (27, 41))
672872	30425526	CircRNA_100876 depletion reduced tumor growth in nude mice.	('depletion', 'Var', (15, 24))	('nude mice', 'Species', '10090', (49, 58))	('reduced', 'NegReg', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
672873	30425526	These findings coupled with our discovery of the positive relationship between tissue circRNA_100876 expression and lymph node metastasis suggested that elevated circRNA_100876 expression in ESCC tissues might enhance distant metastasis and thus result in unfavorable outcomes in ESCC patients.	('ESCC', 'Disease', (280, 284))	('elevated', 'PosReg', (153, 161))	('distant metastasis', 'CPA', (218, 236))	('circRNA_100876', 'Var', (162, 176))	('enhance', 'PosReg', (210, 217))	('result in', 'Reg', (246, 255))	('patients', 'Species', '9606', (285, 293))
672876	30425526	In the current study, we found that circRNA_100876 depletion led to upregulation of the protein levels of E-cadherin and downregulation of N-cadherin and vimentin in ESCC cells, suggesting that absence of circRNA_100876 might reverse EMT process.	('protein levels', 'MPA', (88, 102))	('EMT process', 'CPA', (234, 245))	('upregulation', 'PosReg', (68, 80))	('E-cadherin', 'Gene', (106, 116))	('downregulation', 'NegReg', (121, 135))	('vimentin', 'Protein', (154, 162))	('N-cadherin', 'Gene', (139, 149))	('depletion', 'Var', (51, 60))	('E-cadherin', 'Gene', '999', (106, 116))	('circRNA_100876', 'Var', (36, 50))	('N-cadherin', 'Gene', '1000', (139, 149))
672879	30425526	Additional studies to elucidate the functional mechanisms of circRNA_100876 in ESCC and other cancers are essential.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ESCC', 'Disease', (79, 83))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('circRNA_100876', 'Var', (61, 75))	('cancers', 'Disease', (94, 101))
672914	29029485	Among the 252 ESCC patients, in 165 cases of strong or moderate FZD7 expression, the median survival time was 19 months and the 5-year survival rate was 6.0%, whereas in 87 cases of low FZD7 expression, the median survival time was 30 months and the 5-year survival rate was 11.2% (P=0.001; Figure 2C).	('patients', 'Species', '9606', (19, 27))	('expression', 'Var', (69, 79))	('ESCC', 'Disease', (14, 18))	('strong', 'Var', (45, 51))	('moderate', 'Var', (55, 63))	('FZD7', 'Gene', (64, 68))
672916	29029485	As shown in the Kaplan-Meier survival curves, PATIENTS WITH high FZD7 expression in early stage had significantly shorter survival TIME (median survival time: 24 months) than those with low FZD7 expression (median survival time: >60 months, P=0.0004, Supplementary Figure 2A).	('high', 'Var', (60, 64))	('survival TIME', 'CPA', (122, 135))	('PATIENTS', 'Species', '9606', (46, 54))	('FZD7', 'Gene', (65, 69))	('shorter', 'NegReg', (114, 121))	('expression', 'Var', (70, 80))
672922	29029485	In the animal experimental model, swelling popliteal lymph nodes (LNs) were observed in 4 out of 5 mice two months after the injection of EC109-FZD7 cells at the foot pads of SCID mice, whereas only one swelling popliteal LN was observed in 5 mice injected with EC109-vec cells.	('mice', 'Species', '10090', (99, 103))	('swelling popliteal LN', 'Disease', 'MESH:D011151', (203, 224))	('mice', 'Species', '10090', (243, 247))	('SCID', 'Disease', 'MESH:D053632', (175, 179))	('swelling popliteal lymph', 'Phenotype', 'HP:0001004', (34, 58))	('SCID', 'Disease', (175, 179))	('mice', 'Species', '10090', (180, 184))	('EC109-FZD7 cells', 'Var', (138, 154))	('swelling popliteal LN', 'Disease', (203, 224))	('swelling popliteal lymph nodes', 'Disease', (34, 64))	('swelling popliteal lymph nodes', 'Disease', 'MESH:D000072717', (34, 64))	('EC109-FZD7', 'CellLine', 'CVCL:6898', (138, 148))
672923	29029485	(Figure 3E) To further examine whether inhibition of FZD7 expression could suppress the ESCC cell mobility and tumor metastasis in mouse model, we knocked down the endogenous FZD7 expression in KYSE30 and KYSE410 cells (KYSE30/KYSE410-sh1/3) by lentiviral transduction.	('knocked', 'Reg', (147, 154))	('ESCC cell mobility', 'CPA', (88, 106))	('inhibition', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('FZD7', 'Gene', (175, 179))	('mouse', 'Species', '10090', (131, 136))	('suppress', 'NegReg', (75, 83))	('tumor metastasis', 'Disease', 'MESH:D009362', (111, 127))	('tumor metastasis', 'Disease', (111, 127))
672924	29029485	In vivo metastasis studies further showed that only one SCID mouse injected with KYSE30-shFZD7 cells showed popliteal LN metastasis, whereas LN metastasis appeared in 4 out of 5 mice injected with KYSE30-NTC cells (Figure 4E).	('popliteal LN metastasis', 'CPA', (108, 131))	('mice', 'Species', '10090', (178, 182))	('KYSE30-shFZD7 cells', 'Var', (81, 100))	('mouse', 'Species', '10090', (61, 66))	('SCID', 'Disease', (56, 60))	('SCID', 'Disease', 'MESH:D053632', (56, 60))
672927	29029485	The results showed that both non-phosphorylated beta-catenin and its downstream targets such as LEF and MMP7 were repressed by knockdown of FZD7, even under WNT3A stimulation (Figure 5A).	('FZD7', 'Gene', (140, 144))	('MMP7', 'Gene', (104, 108))	('MMP7', 'Gene', '4316', (104, 108))	('knockdown', 'Var', (127, 136))	('beta-catenin', 'Protein', (48, 60))
672929	29029485	The results showed that beta-catenin could accumulate into nucleus much more efficiently in EC109-FZD7 cells than control cells under WNT3A stimulation, suggesting that FZD7 could induce the canonical WNT/beta-catenin pathway in ESCC cells (Supplementary Figure 3).	('canonical WNT/beta-catenin pathway', 'Pathway', (191, 225))	('induce', 'PosReg', (180, 186))	('EC109-FZD7', 'CellLine', 'CVCL:6898', (92, 102))	('FZD7', 'Var', (169, 173))
672939	29029485	Overexpression of FZD7 has also been reported to be significantly associated with tumor cell proliferation in colorectal cancer and glioma.	('glioma', 'Disease', (132, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('associated', 'Reg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('FZD7', 'Gene', (18, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('Overexpression', 'Var', (0, 14))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('tumor', 'Disease', (82, 87))	('colorectal cancer', 'Disease', (110, 127))
672941	29029485	In the animal model for tumor metastasis, introduction of exogenous FZD7 in ESCC cells could result in increased popliteal lymph nodes metastasis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('FZD7', 'Gene', (68, 72))	('increased', 'PosReg', (103, 112))	('increased popliteal lymph nodes metastasis', 'Phenotype', 'HP:0025043', (103, 145))	('popliteal lymph nodes metastasis', 'CPA', (113, 145))	('tumor metastasis', 'Disease', 'MESH:D009362', (24, 40))	('tumor metastasis', 'Disease', (24, 40))	('exogenous', 'Var', (58, 67))
672968	29029485	EC109-FZD7/vec and KYSE30-NTC/shFZD7 cells (2x105) were injected subcutaneously into foot pads of 4-week-old male SCID mice (n=5), respectively.	('mice', 'Species', '10090', (119, 123))	('SCID', 'Disease', 'MESH:D053632', (114, 118))	('SCID', 'Disease', (114, 118))	('EC109-FZD7', 'CellLine', 'CVCL:6898', (0, 10))	('KYSE30-NTC/shFZD7', 'Var', (19, 36))
672996	27006592	As early as 1988, Tartter alluded to the possible immunosuppressive effects of perioperative BTs, resulting in an increased incidence of postoperative complications and infections, where of the 134 patients who received RBC transfusions, 33 patients (24.6%) developed infectious complications compared with 9 (4.3%) of the 209 patients who were not transfused (P < 0.0001).	('postoperative complications and infections', 'Disease', 'MESH:D011183', (137, 179))	('infectious complications', 'Disease', 'MESH:D003141', (268, 292))	('patients', 'Species', '9606', (198, 206))	('infectious complications', 'Disease', (268, 292))	('transfusions', 'Var', (224, 236))	('patients', 'Species', '9606', (327, 335))	('patients', 'Species', '9606', (241, 249))
672999	27006592	Furthermore, in 292 patients undergoing liver resection for colorectal liver metastases, allogeneic RBT was significantly associated with reduced recurrence-free survival (RFS; 32 vs. 72 months; P = 0.008).	('reduced', 'NegReg', (138, 145))	('allogeneic', 'Var', (89, 99))	('patients', 'Species', '9606', (20, 28))	('colorectal liver metastases', 'Disease', 'MESH:D009362', (60, 87))	('recurrence-free survival', 'CPA', (146, 170))	('colorectal liver metastases', 'Disease', (60, 87))
673013	27006592	Furthermore, allogeneic BT given before radiotherapy may be associated with higher incidence of distant metastases and decreased survival in patients with stage IIB cervical cancer, but not for stage Ib.	('decreased', 'NegReg', (119, 128))	('metastases', 'Disease', (104, 114))	('survival', 'CPA', (129, 137))	('metastases', 'Disease', 'MESH:D009362', (104, 114))	('cancer', 'Disease', (174, 180))	('allogeneic', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('higher', 'PosReg', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('patients', 'Species', '9606', (141, 149))
673016	27006592	Five-year OS was also substantially decreased in patients receiving RBT (85% compared to 63%; P = 0.0035).	('RBT', 'Var', (68, 71))	('patients', 'Species', '9606', (49, 57))	('decreased', 'NegReg', (36, 45))
673021	27006592	A study of the effect of allogeneic BT on specific immunological functions in mice and human subjects has demonstrated decreases in (a) interleukin 2 secretion, (b) natural killer (NK) cell activity and, hence, lymphokine-activated killer (LAK) cell activity and immune surveillance against malignancy, (c) delayed-type hypersensitivity responses, (d) CD4/CD8 ratios, and (e) macrophage function.	('malignancy', 'Disease', (291, 301))	('decreases', 'NegReg', (119, 128))	('hypersensitivity', 'Disease', (320, 336))	('macrophage function', 'CPA', (376, 395))	('hypersensitivity', 'Disease', 'MESH:D004342', (320, 336))	('delayed-type hypersensitivity responses', 'Phenotype', 'HP:0002972', (307, 346))	('human', 'Species', '9606', (87, 92))	('CD8', 'Gene', (356, 359))	('CD4', 'Gene', (352, 355))	('CD8', 'Gene', '925', (356, 359))	('allogeneic', 'Var', (25, 35))	('malignancy', 'Disease', 'MESH:D009369', (291, 301))	('CD4', 'Gene', '920', (352, 355))	('immune surveillance', 'CPA', (263, 282))	('mice', 'Species', '10090', (78, 82))
673023	27006592	The sharing of HLA between donor and recipient cells persists in the recipient (microchimerism state) and therefore induces a specific tolerance or results from the production of anti-idiotype antibodies or is caused by BT-inducing lymphocyte anergy.	('specific tolerance', 'CPA', (126, 144))	('donor', 'Species', '9606', (27, 32))	('induces', 'Reg', (116, 123))	('sharing', 'Var', (4, 11))	('HLA', 'Protein', (15, 18))	('anti-idiotype antibodies', 'Protein', (179, 203))	('results from', 'Reg', (148, 160))
673040	27006592	Fresh plasma and cryoprecipitate are often transfused to patients with cancer in the context of surgeries or to revert warfarin effect or normalize the prothrombin time in anticipation of interventional procedures particularly related to the liver.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('warfarin effect', 'MPA', (119, 134))	('cancer', 'Disease', (71, 77))	('patients', 'Species', '9606', (57, 65))	('revert', 'Var', (112, 118))	('prothrombin time', 'MPA', (152, 168))	('normalize', 'Reg', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('warfarin', 'Chemical', 'MESH:D014859', (119, 127))
673137	25505718	The rate of nodal involvement is 0% to 2% in cases of esophageal adenocarcinoma invading the mucosa (T1a) with an M1 or M2 lesion, which have no significant risk of lymph node metastasis.	('M2 lesion', 'Var', (120, 129))	('T1a', 'Gene', (101, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (54, 79))	('T1a', 'Gene', '10630', (101, 104))	('nodal', 'Gene', (12, 17))	('esophageal adenocarcinoma', 'Disease', (54, 79))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (54, 79))	('nodal', 'Gene', '4838', (12, 17))
673143	25505718	reported that G1/G2 histology was associated with a lower rate of lymph node metastasis compared with G3 in early esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('lower', 'NegReg', (52, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('G1/G2 histology', 'Var', (14, 29))	('lymph node metastasis', 'CPA', (66, 87))
673241	21507583	Intergroup (INT) 0122 attempted to improve locoregional control through the addition of three cycles of induction chemotherapy (5-FU, cisplatin) and intensification of radiotherapy (5-FU, cisplatin, and 64.8 Gy).	('5-FU', 'Var', (182, 186))	('5-FU', 'Chemical', 'MESH:D005472', (182, 186))	('cisplatin', 'Var', (188, 197))	('5-FU', 'Chemical', 'MESH:D005472', (128, 132))	('locoregional control', 'CPA', (43, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (188, 197))
673283	20565814	P66shc is phosphorylated at ser36 in its CH2 domain under various stress signals such as H2O2, UV radiation and exposure to chemicals, such as Taxol, and thus could serve as an apoptotic sensitizer to stress signals.	('ser36', 'Var', (28, 33))	('ser36', 'Chemical', '-', (28, 33))	('P66shc', 'Gene', (0, 6))	('P66shc', 'Gene', '20416', (0, 6))	('Taxol', 'Chemical', 'MESH:D017239', (143, 148))	('H2O2', 'Chemical', 'MESH:D006861', (89, 93))
673314	20565814	This notion is further supported by the observations that raising intracellular ROS level increases the expression of p66shc protein, for example, by H2O2 treatment.	('raising', 'PosReg', (58, 65))	('p66shc', 'Gene', (118, 124))	('p66shc', 'Gene', '20416', (118, 124))	('increases', 'PosReg', (90, 99))	('expression', 'MPA', (104, 114))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('H2O2', 'Chemical', 'MESH:D006861', (150, 154))	('H2O2', 'Var', (150, 154))	('raising intracellular ROS level', 'Phenotype', 'HP:0025464', (58, 89))
673416	31966000	In terms of racial differences, our analysis of the three models showed that the cumulative esophageal carcinoma-specific mortality rate was higher in patients of African-American ethnicity when compared with Caucasians (Figure 2B), which may be associated with socioeconomic factors and lower surgical rates.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (92, 112))	('African-American ethnicity', 'Var', (163, 189))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (92, 112))	('patients', 'Species', '9606', (151, 159))	('higher', 'PosReg', (141, 147))	('esophageal carcinoma', 'Disease', (92, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
673442	31822288	Tea constituents, including polyphenols (such as epigallocatechin-3 gallate, epigallocatechin), lipids, vitamins and minerals, may act at numerous points of carcinogenesis, including cancer cell growth, apoptosis and metastasis.	('lipids', 'Chemical', 'MESH:D008055', (96, 102))	('cancer', 'Disease', (183, 189))	('epigallocatechin-3', 'Var', (49, 67))	('epigallocatechin', 'Chemical', 'MESH:C057580', (77, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (157, 171))	('epigallocatechin-3 gallate', 'Chemical', 'MESH:C045651', (49, 75))	('epigallocatechin', 'Var', (77, 93))	('apoptosis', 'CPA', (203, 212))	('polyphenols', 'Chemical', 'MESH:D059808', (28, 39))	('act', 'Reg', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('epigallocatechin', 'Chemical', 'MESH:C057580', (49, 65))	('carcinogenesis', 'Disease', (157, 171))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('metastasis', 'CPA', (217, 227))
673491	31822288	Pickled food contained N-nitroso compounds, which had the potential to induce the occurrence of EC.	('induce', 'PosReg', (71, 77))	('N-nitroso compounds', 'Chemical', '-', (23, 42))	('N-nitroso', 'Var', (23, 32))
673544	31080898	Heart and lung doses were associated with cardiac and pulmonary complications.	('cardiac and pulmonary complications', 'Disease', 'MESH:D005117', (42, 77))	('Heart', 'Var', (0, 5))	('associated', 'Reg', (26, 36))	('pulmonary complications', 'Phenotype', 'HP:0006532', (54, 77))
673551	31080898	Heart V30 >45% and mean lung dose (MLD) >10 Gy were found to be independently associated with worse survival after adjustment for other clinical and dosimetric factors (P < 0.05).	('>45%', 'Var', (10, 14))	('worse', 'NegReg', (94, 99))	('MLD', 'Disease', 'MESH:D007966', (35, 38))	('Heart V30 >45%', 'Var', (0, 14))	('MLD', 'Disease', (35, 38))
673552	31080898	Heart and lung doses were also found to be risk factors for radiation-induced cardiac and pulmonary complications (P < 0.05): 8.5% of patients with heart V30 <=45% had cardiac complications vs. 15% for V30 >45% (P = 0.046); 18.8% of patients with MLD <=10 Gy had pulmonary complications vs. 27% for MLD >10 Gy (P = 0.020).	('pulmonary complications', 'Phenotype', 'HP:0006532', (263, 286))	('pulmonary complications', 'Phenotype', 'HP:0006532', (90, 113))	('pulmonary complications', 'Disease', (263, 286))	('pulmonary complications', 'Disease', 'MESH:D008171', (90, 113))	('cardiac complications', 'Disease', 'MESH:D005117', (168, 189))	('patients', 'Species', '9606', (233, 241))	('pulmonary complications', 'Disease', 'MESH:D008171', (263, 286))	('patients', 'Species', '9606', (134, 142))	('MLD', 'Disease', (247, 250))	('MLD', 'Disease', 'MESH:D007966', (247, 250))	('pulmonary complications', 'Disease', (90, 113))	('cardiac complications', 'Disease', (168, 189))	('MLD', 'Disease', 'MESH:D007966', (299, 302))	('MLD', 'Disease', (299, 302))	('cardiac and pulmonary complications', 'Disease', 'MESH:D005117', (78, 113))	('V30 <=45%', 'Var', (154, 163))
673583	31080898	Clinical factors associated with inferior OS in UVA were age >70 years, pre-existing cardiac disease, squamous cell cancer, stage III/IV disease, poor differentiation, lack of surgery, and PTV >574 cm3 (all P < 0.05).	('poor differentiation', 'CPA', (146, 166))	('IV disease', 'Disease', (134, 144))	('OS', 'Chemical', '-', (42, 44))	('cardiac disease', 'Disease', 'MESH:D006331', (85, 100))	('squamous cell cancer', 'Disease', 'MESH:D002294', (102, 122))	('squamous cell cancer', 'Disease', (102, 122))	('IV disease', 'Disease', 'MESH:D020432', (134, 144))	('cardiac disease', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('PTV >574 cm3', 'Var', (189, 201))	('inferior OS in UVA', 'Disease', (33, 51))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (102, 122))
673585	31080898	All dosimetric variables were associated with worse OS on UVA (all P < 0.05), except for low heart doses (heart V5 and V10).	('OS', 'Chemical', '-', (52, 54))	('V10', 'Var', (119, 122))	('UVA', 'Disease', (58, 61))
673586	31080898	All clinical and dosimetric covariates with P < 0.1 in UVA for OS were entered into the MVA model, age >70 years (hazard ratio [HR] 1.390, 95% confidence interval [CI] 1.069-1.809, P = 0.014); stage III/IV disease (HR 1.577, 95% CI 1.225-2.028, P < 0.001); poor differentiation (HR 1.485, 95% CI 1.180-1.868, P = 0.001); lack of surgery (HR 0.479, 95% CI 0.380-0.603, P < 0.001); heart V30 >45% (HR 1.402, 95% CI 1.077-1.826, P = 0.012); and MLD >10 Gy (HR 1.355, 95% CI 1.068-1.720, P = 0.012) were all associated with worse survival.	('OS', 'Chemical', '-', (63, 65))	('IV disease', 'Disease', 'MESH:D020432', (203, 213))	('MLD', 'Disease', 'MESH:D007966', (442, 445))	('MLD', 'Disease', (442, 445))	('heart V30 >45%', 'Var', (380, 394))	('IV disease', 'Disease', (203, 213))
673589	31080898	Heart V15, V20, V25, V30, V35, and MHD were found to be significant independent predictors of OS (Table 1).	('Heart V15', 'Var', (0, 9))	('V30', 'Var', (21, 24))	('V35', 'Gene', '28474', (26, 29))	('MHD', 'Disease', 'None', (35, 38))	('MHD', 'Disease', (35, 38))	('OS', 'Chemical', '-', (94, 96))	('V35', 'Gene', (26, 29))	('V25', 'Var', (16, 19))	('V20', 'Var', (11, 14))
673594	31080898	Patients who experienced RICC had worse survival than those who did not, with corresponding 5-year OS rates of 27.6% and 43.2% (P = 0.012) (Fig.	('worse', 'NegReg', (34, 39))	('RICC', 'Chemical', '-', (25, 29))	('RICC', 'Var', (25, 29))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (99, 101))
673598	31080898	Lung V20, V25, and MLD were found to be significant independent predictors of OS (Table 2), but lung V5-15 and lung V30-50 were not (all P > 0.05) (Table 3).	('V25', 'Var', (10, 13))	('MLD', 'Disease', 'MESH:D007966', (19, 22))	('MLD', 'Disease', (19, 22))	('OS', 'Chemical', '-', (78, 80))
673606	31080898	In the surgery cohort, heart V30 remained independently associated with OS after adjusting other variables (P = 0.001), while MLD trended toward significance (P = 0.060).	('OS', 'Chemical', '-', (72, 74))	('heart V30', 'Var', (23, 32))	('MLD', 'Disease', 'MESH:D007966', (126, 129))	('associated with', 'Reg', (56, 71))	('MLD', 'Disease', (126, 129))
673607	31080898	In the non-surgery cohort, MLD remained independently associated with OS after adjusting other variables (P = 0.028), and heart V30 trended towards significance (P = 0.088).	('OS', 'Chemical', '-', (70, 72))	('heart V30', 'Var', (122, 131))	('MLD', 'Disease', 'MESH:D007966', (27, 30))	('MLD', 'Disease', (27, 30))	('associated', 'Reg', (54, 64))
673609	31080898	Specifically, heart V30 and MLD were the strongest predictors of the heart and lung metrics, and they remained to be the independent predictors in both surgery and non-surgery cohorts.	('heart V30', 'Var', (14, 23))	('MLD', 'Disease', (28, 31))	('MLD', 'Disease', 'MESH:D007966', (28, 31))
673610	31080898	Cut point analysis revealed that keeping heart V30 <=45% and MLD <=10 Gy was associated with 6.5% and 8.2% absolute decrease in RICC and RIPC, respectively.	('heart V30 <=45%', 'Var', (41, 56))	('RICC', 'MPA', (128, 132))	('decrease', 'NegReg', (116, 124))	('RICC', 'Chemical', '-', (128, 132))	('MLD', 'Disease', 'MESH:D007966', (61, 64))	('RIPC', 'Chemical', '-', (137, 141))	('MLD', 'Disease', (61, 64))	('RIPC', 'MPA', (137, 141))
673620	31080898	Numerous studies have reported heart dose as being independently associated with inferior OS in lung cancer.	('inferior OS in lung cancer', 'Disease', (81, 107))	('inferior OS in lung cancer', 'Disease', 'MESH:C567932', (81, 107))	('associated', 'Reg', (65, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('heart', 'Var', (31, 36))
673622	31080898	Although heart V30 was the strongest heart variable, heart V15-25, V35, and MHD each contributed to survival when analyzed alone.	('survival', 'MPA', (100, 108))	('V35', 'Gene', (67, 70))	('MHD', 'Disease', 'None', (76, 79))	('MHD', 'Disease', (76, 79))	('heart V15-25', 'Var', (53, 65))	('contributed', 'Reg', (85, 96))	('V35', 'Gene', '28474', (67, 70))
673624	31080898	In one such study of 112 patients with NSCLC from several prospective trials, heart dose was associated with RICC in both UVA and MVA, but was not associated with OS.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('RICC in', 'MPA', (109, 116))	('OS', 'Chemical', '-', (163, 165))	('heart dose', 'Var', (78, 88))	('patients', 'Species', '9606', (25, 33))	('NSCLC', 'Disease', (39, 44))	('RICC', 'Chemical', '-', (109, 113))	('associated', 'Interaction', (93, 103))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
673633	31080898	Many cardiac dosimetry measures have been linked with RICC in thoracic cancer, including MHD, heart V5, V30, and V50, among others, which also supports the need to consider heart dosimetry as a whole rather than emphasize a single variable.	('V30', 'Var', (104, 107))	('thoracic cancer', 'Disease', (62, 77))	('MHD', 'Disease', 'None', (89, 92))	('heart', 'Disease', (94, 99))	('V50', 'Var', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('RICC', 'Chemical', '-', (54, 58))	('MHD', 'Disease', (89, 92))	('linked', 'Reg', (42, 48))	('thoracic cancer', 'Disease', 'MESH:D009369', (62, 77))
673636	31080898	In the current study, patients with heart V30 >45% had a much higher RICC rate than those with heart V30 <=45%.	('heart V30', 'Var', (36, 45))	('RICC', 'Chemical', '-', (69, 73))	('patients', 'Species', '9606', (22, 30))	('higher', 'PosReg', (62, 68))	('RICC rate', 'MPA', (69, 78))
673639	31080898	Patients who experienced RICC had greatly inferior survival compared with those without RICC (5-year OS rates 27.6% vs. 43.2%, P = 0.012).	('RICC', 'Chemical', '-', (25, 29))	('RICC', 'Var', (25, 29))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (101, 103))	('inferior', 'NegReg', (42, 50))	('RICC', 'Chemical', '-', (88, 92))	('survival', 'MPA', (51, 59))
673665	28042534	showed that knockdown of LDH1 in tumor cells decreased ability of cell proliferation under hypoxic conditions, and thus repressed tumorigenicity.	('hypoxic conditions', 'Disease', 'MESH:D009135', (91, 109))	('knockdown', 'Var', (12, 21))	('decreased', 'NegReg', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumorigenicity', 'MPA', (130, 144))	('LDH1', 'Gene', (25, 29))	('hypoxic conditions', 'Disease', (91, 109))
673667	28042534	suggested that SB-204990 (the chemical inhibitor for ATP citrate lyase) could increase citrate level, which in turn inhibited aerobic glycolysis, thereby producing anti-cancer effects.	('SB-204990', 'Var', (15, 24))	('citrate level', 'MPA', (87, 100))	('anti-cancer effects', 'CPA', (164, 183))	('inhibited', 'NegReg', (116, 125))	('ATP citrate lyase', 'Gene', '47', (53, 70))	('increase citrate level', 'Phenotype', 'HP:0012406', (78, 100))	('ATP citrate lyase', 'Gene', (53, 70))	('increase', 'PosReg', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('aerobic glycolysis', 'MPA', (126, 144))	('SB-204990', 'Chemical', 'MESH:C112852', (15, 24))
673683	28042534	Loss of MMP was thought to be associated with mitochondrial dysfunction, leading to apoptosis.	('apoptosis', 'CPA', (84, 93))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (46, 71))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (46, 71))	('MMP', 'Gene', (8, 11))	('mitochondrial dysfunction', 'Disease', (46, 71))	('Loss', 'Var', (0, 4))
673766	25634542	We recently demonstrated that analysis for TP53 mutations in Cytosponge samples can be used to diagnose high grade dysplasia (HGD) when compared with samples from patients without BE and patients with BE who had never developed dysplasia over a median follow-up of 6 y.	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (163, 171))	('dysplasia', 'Disease', (115, 124))	('dysplasia', 'Disease', (228, 237))	('BE', 'Phenotype', 'HP:0100580', (201, 203))	('dysplasia', 'Disease', 'MESH:D004476', (115, 124))	('dysplasia', 'Disease', 'MESH:D004476', (228, 237))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('BE', 'Phenotype', 'HP:0100580', (180, 182))
673767	25634542	To understand the broader context of the Cytosponge-TFF3 test and stratified risk using detection of TP53 mutations, we have modeled this in a hypothetical population of 10,000 individuals attending primary care for investigation of reflux symptoms.	('reflux symptoms', 'Phenotype', 'HP:0002020', (233, 248))	('TP53', 'Gene', '7157', (101, 105))	('TFF3', 'Gene', (52, 56))	('TP53', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('reflux', 'Disease', (233, 239))	('TFF3', 'Gene', '7033', (52, 56))
673768	25634542	We used a sensitivity of 79.9% and a specificity of 92.4% for detection of any length of BE; for TP53 mutation detection we performed the calculations using a sensitivity of 86% (95% CI 65%-96%) and a specificity of 100% (95% CI 94.6%-100%) for detection of HGD.	('TP53', 'Gene', '7157', (97, 101))	('mutation', 'Var', (102, 110))	('TP53', 'Gene', (97, 101))	('BE', 'Phenotype', 'HP:0100580', (89, 91))	('HGD', 'Disease', (258, 261))
673786	25634542	3 shows examples of TFF3 staining for a case with widespread TFF3 positivity and for a case with a single TFF3-positive goblet cell, which was also categorized as positive.	('TFF3', 'Gene', (61, 65))	('TFF3', 'Gene', (106, 110))	('TFF3', 'Gene', (20, 24))	('positivity', 'Var', (66, 76))	('TFF3', 'Gene', '7033', (61, 65))	('TFF3', 'Gene', '7033', (106, 110))	('TFF3', 'Gene', '7033', (20, 24))
673794	25634542	Indeed, using an exquisitely sensitive (down to an allele fraction of 0.6%) next-generation sequencing approach, we recently demonstrated that screening for TP53 mutations in Cytosponge samples can be used to diagnose HGD.	('TP53', 'Gene', (157, 161))	('mutations', 'Var', (162, 171))	('HGD', 'Disease', (218, 221))	('TP53', 'Gene', '7157', (157, 161))
673798	25634542	Those testing negative for TP53 mutations would be scheduled for a repeat Cytosponge, expected to be between 2 and 5 y later, but the optimal interval is still to be determined.	('TP53', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('TP53', 'Gene', '7157', (27, 31))
673799	25634542	Similarly, for the true TFF3-positive patients with BE (prevalence 3%), between two and 14 cases would test positive for TP53 mutations, and approximately two of these would be confirmed dysplastic at endoscopy.	('BE', 'Phenotype', 'HP:0100580', (52, 54))	('TP53', 'Gene', '7157', (121, 125))	('patients', 'Species', '9606', (38, 46))	('TFF3', 'Gene', (24, 28))	('TP53', 'Gene', (121, 125))	('dysplastic', 'Disease', 'MESH:D004416', (187, 197))	('dysplastic', 'Disease', (187, 197))	('mutations', 'Var', (126, 135))	('TFF3', 'Gene', '7033', (24, 28))
673898	21886457	The relative refractive index of the nuclei in these tissues was found to be 1.047 +- 0.0051 for the normal tissues and 1.041+-0.0038 for the dysplastic tissues.	('dysplastic', 'Disease', 'MESH:D004416', (142, 152))	('dysplastic', 'Disease', (142, 152))	('1.041+-0.0038', 'Var', (120, 133))
673900	21886457	The relative refractive index of the nuclei in these tissues was found to be 1.057+-0.0068 for the normal tissues and 1.051+-0.0094 for the dysplastic tissues.	('dysplastic', 'Disease', 'MESH:D004416', (140, 150))	('dysplastic', 'Disease', (140, 150))	('1.051+-0.0094', 'Var', (118, 131))
673960	32317029	This task force clearly derives evidence from published studies with validated PET findings (either by histopathology or clinical course) in the setting of diagnosis, biopsy, surgery, radiotherapy and response assessment, and shows superiority of amino acid PET such as 18F-FET or 11C-MET PET over 18F-FDG PET.	('C-MET', 'Gene', '4233', (283, 288))	('FDG', 'Gene', (302, 305))	('18F-FET', 'Var', (270, 277))	('C-MET', 'Gene', (283, 288))	('FDG', 'Gene', '23583', (302, 305))
673961	32317029	In a recent study, the combination of 18F-FET-PET and T1w MRI was shown to carry the most information for prediction of patterns of failure following chemo-radiation therapy of glioblastoma patients.	('glioblastoma', 'Disease', (177, 189))	('18F-FET-PET', 'Var', (38, 49))	('patients', 'Species', '9606', (190, 198))	('T1w', 'Var', (54, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (177, 189))	('glioblastoma', 'Phenotype', 'HP:0012174', (177, 189))
673976	32317029	For primary staging, the use of PET/CT leads to a change of about 10% in every TNM category and similarly, a major change in treatment strategy in about 10% of patients.	('patients', 'Species', '9606', (160, 168))	('TNM', 'Gene', '10178', (79, 82))	('TNM', 'Gene', (79, 82))	('change', 'Reg', (115, 121))	('change', 'Reg', (50, 56))	('PET/CT', 'Var', (32, 38))
673978	32317029	Moreover, first data suggests that the use of PET/CT for radiation planning could significantly improve the local tumor control, regional control and even survival.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('improve', 'PosReg', (96, 103))	('regional control', 'CPA', (129, 145))	('survival', 'CPA', (155, 163))	('tumor', 'Disease', (114, 119))	('PET/CT', 'Var', (46, 52))
674017	32317029	89Zr-durvalumab or 89Zr-pembrolizumab to determine SUV of radiolabeled IO uptake in tumor lesions, correlate between tumor uptake and PD-L1 expression as determined by immunohistochemistry and potentially predict response rate (NCT03829007), (NCT03853187), (NCT02760225).	('NCT02760225', 'Var', (258, 269))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (117, 122))	('PD-L1', 'Gene', (134, 139))	('predict', 'Reg', (205, 212))	('pembrolizumab', 'Chemical', 'MESH:C582435', (24, 37))	('durvalumab', 'Chemical', 'MESH:C000613593', (5, 15))	('NCT03853187', 'Var', (243, 254))	('tumor', 'Disease', (84, 89))	('IO', 'Chemical', '-', (71, 73))	('PD-L1', 'Gene', '29126', (134, 139))	('tumor lesions', 'Disease', (84, 97))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor lesions', 'Disease', 'MESH:D009369', (84, 97))	('NCT03829007', 'Var', (228, 239))
674170	32250567	The risk of pneumonia onset during hospitalization was significantly lower in the postintroduction group than in the preintroduction group, with an odds ratio of 0.44 (95% confidence interval [CI]: 0.35-0.55, p < .001).	('pneumonia', 'Phenotype', 'HP:0002090', (12, 21))	('postintroduction', 'Var', (82, 98))	('lower', 'NegReg', (69, 74))	('pneumonia', 'Disease', (12, 21))	('pneumonia', 'Disease', 'MESH:D011014', (12, 21))
674191	32250567	Although this is only a comparison of the period before and after introduction, as we could not examine whether POM was actually performed or not in this study, POM intervention was considered to be the independent risk factor for developing pneumonia in cancer patients who underwent surgery.	('intervention', 'Var', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('pneumonia', 'Phenotype', 'HP:0002090', (242, 251))	('pneumonia', 'Disease', (242, 251))	('pneumonia', 'Disease', 'MESH:D011014', (242, 251))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('patients', 'Species', '9606', (262, 270))
674224	32075129	We observed no correlation between DKK2 or miRNA-221 expression and clinico-pathological data DKK2 expression was correlated with TP53 mutations and amplification of GATA6.	('GATA6', 'Gene', '2627', (166, 171))	('correlated', 'Reg', (114, 124))	('amplification', 'Var', (149, 162))	('mutations', 'Var', (135, 144))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('GATA6', 'Gene', (166, 171))
674235	32075129	So far, it has been assumed that DKK2 is a Wnt-antagonist and that, accordingly, inactivation of DKK2 increases Wnt activity with accelerating tumor progression.	('inactivation', 'Var', (81, 93))	('accelerating', 'PosReg', (130, 142))	('tumor', 'Disease', (143, 148))	('DKK2', 'Gene', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('Wnt activity', 'MPA', (112, 124))	('increases', 'PosReg', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
545832	32075129	Cases were further evaluated only when normal tissue nuclei displayed one or two clearly distinct signals of green GATA6 and orange CEN18.	('orange CEN18', 'Var', (125, 137))	('GATA6', 'Gene', '2627', (115, 120))	('GATA6', 'Gene', (115, 120))
674259	32075129	A total of 175 patients of 192 on the TMA were immunohistochemically interpretable for DKK2 and 176 patients for miRNA-221.	('patients', 'Species', '9606', (15, 23))	('miRNA-221', 'Var', (113, 122))	('DKK2', 'Gene', (87, 91))	('patients', 'Species', '9606', (100, 108))	('TMA', 'Chemical', '-', (38, 41))
674271	32075129	However, in patients receiving neoadjuvant treatment, tumors with DKK2 expression showed a significant shortened OS compared to patients without DKK2 expression.	('patients', 'Species', '9606', (12, 20))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('men', 'Species', '9606', (48, 51))	('expression', 'Var', (71, 81))	('shortened', 'NegReg', (103, 112))	('DKK2', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('patients', 'Species', '9606', (128, 136))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
674274	32075129	Amplification of GATA6 did not serve as prognostic marker, either for the entire patients group or stratified in patients with or without neoadjuvant treatment.	('men', 'Species', '9606', (155, 158))	('Amplification', 'Var', (0, 13))	('patients', 'Species', '9606', (113, 121))	('patients', 'Species', '9606', (81, 89))	('GATA6', 'Gene', (17, 22))	('GATA6', 'Gene', '2627', (17, 22))
674279	32075129	We observed a strong correlation between DKK2 and GATA6 genomic alterations on genomic level supporting the immunohistochemical and FISH data on our own data set.	('GATA6', 'Gene', '2627', (50, 55))	('GATA6', 'Gene', (50, 55))	('alterations', 'Var', (64, 75))	('DKK2', 'Gene', (41, 45))
674287	32075129	Patients after neoadjuvant radiochemotherapy showed a worsened overall survival depending on DKK2 expression than patients without DKK2 detection.	('overall survival', 'MPA', (63, 79))	('expression', 'Var', (98, 108))	('worsened', 'NegReg', (54, 62))	('Patients', 'Species', '9606', (0, 8))	('DKK2', 'Gene', (93, 97))	('patients', 'Species', '9606', (114, 122))
674292	32075129	Recent studies have shown an influence on the cell cycle in gastric carcinoma, where a depletion of GATA6 led to a cycle arrest in the M-phase and thus to significantly slower tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('gastric carcinoma', 'Disease', (60, 77))	('tumor', 'Disease', (176, 181))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (60, 77))	('GATA6', 'Gene', '2627', (100, 105))	('depletion', 'Var', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('GATA6', 'Gene', (100, 105))	('cycle arrest in the', 'CPA', (115, 134))	('gastric carcinoma', 'Disease', 'MESH:D013274', (60, 77))	('slower', 'NegReg', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
674327	30834294	Risk of lymph node metastasis in patients with a histological tumor grade of T1a-MM or T1b-SM2 is about 10 % to 54 %   , so additional treatment is generally recommended in these patients.	('T1a-MM', 'Var', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('SM2', 'Gene', '53366', (91, 94))	('lymph node metastasis', 'CPA', (8, 29))	('SM2', 'Gene', (91, 94))
674500	28443203	Colorectal cancer detection rate was slightly higher in FOBT twice positive than once positive or negative.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('higher', 'PosReg', (46, 52))	('FOBT twice positive', 'Var', (56, 75))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('rectal cancer', 'Phenotype', 'HP:0100743', (4, 17))	('Colorectal cancer', 'Disease', (0, 17))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))
674566	27741117	They found that PORT use was associated with an increase in the hazard for heart disease mortality (hazard ratio [HR], 1.30).	('PORT use', 'Var', (16, 24))	('heart disease', 'Disease', 'MESH:D006331', (75, 88))	('heart disease', 'Disease', (75, 88))
674637	27741117	In Hardy et al work, radiotherapy was only associated with the risk of cardiac dysfunction (HR, 1.54), but not significantly associated with other heart diseases.	('radiotherapy', 'Var', (21, 33))	('cardiac dysfunction', 'Disease', (71, 90))	('heart diseases', 'Disease', 'MESH:D006331', (147, 161))	('heart diseases', 'Disease', (147, 161))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (71, 90))
674692	26068491	These toxicities occurred at D0.01 cc of 51.5 and 52 Gy, both below the Radiation Therapy Oncology Group (RTOG) 0813 specified maximum esophageal constraint of 52.5 Gy.	('toxicities', 'Disease', 'MESH:D064420', (6, 16))	('Oncology', 'Phenotype', 'HP:0002664', (90, 98))	('D0.01 cc', 'Var', (29, 37))	('toxicities', 'Disease', (6, 16))
674722	26068491	Selective irradiation of endothelial cells did not cause additional crypt stem cell loss beyond whole body radiation, and genetic deletion of proapoptic Bax and Bak1 from endothelial cells did not protect mice from irradiation-induced GI syndrome.	('GI syndrome', 'Disease', (235, 246))	('genetic deletion', 'Var', (122, 138))	('Bax', 'Gene', (153, 156))	('Bak1', 'Gene', '12018', (161, 165))	('mice', 'Species', '10090', (205, 209))	('Bax', 'Gene', '12028', (153, 156))	('Bak1', 'Gene', (161, 165))	('GI syndrome', 'Disease', 'MESH:D005767', (235, 246))
674725	26068491	Crypt base columnar cells, which are believed to be Lgr5+ (Leucine-rich repeat-containing G-protein coupled receptor + 5) intestinal stem cells, have been found to undergo increased apoptosis at 10 Gy compared with 1 Gy.	('Lgr5', 'Gene', (52, 56))	('Lgr5', 'Gene', '8549', (52, 56))	('Crypt base', 'Phenotype', 'HP:0000384', (0, 10))	('Leucine-rich repeat-containing G-protein coupled receptor + 5', 'Gene', '8549', (59, 120))	('10 Gy', 'Var', (195, 200))
674727	26068491	As just described, radiation can result in a complex wound, which may be more likely to result from SBRT and higher BEDs, and it may be that antiangiogenic treatment simply inhibits the healing process (Fig.	('healing process', 'CPA', (186, 201))	('BEDs', 'Disease', (116, 120))	('radiation', 'Var', (19, 28))	('BEDs', 'Disease', 'MESH:D003668', (116, 120))	('result in', 'Reg', (33, 42))	('SBRT', 'Chemical', '-', (100, 104))	('inhibits', 'NegReg', (173, 181))
674731	26068491	Finally, VEGF inhibition may worsen ischemic injury caused by radiation.	('ischemic injury', 'Disease', (36, 51))	('VEGF', 'Protein', (9, 13))	('inhibition', 'Var', (14, 24))	('ischemic injury', 'Disease', 'MESH:D003324', (36, 51))	('worsen', 'PosReg', (29, 35))
674732	26068491	Cholesterol emboli syndrome resulting from VEGF inhibition has been hypothesized to cause thromboembolic events in atherosclerotic patients that may result in mesenteric ischemia and GI perforation.	('ischemia', 'Disease', (170, 178))	('thromboembolic', 'Disease', (90, 104))	('patients', 'Species', '9606', (131, 139))	('ischemia', 'Disease', 'MESH:D007511', (170, 178))	('inhibition', 'Var', (48, 58))	('atherosclerotic', 'Disease', (115, 130))	('Cholesterol', 'Chemical', 'MESH:D002784', (0, 11))	('thromboembolic', 'Disease', 'MESH:D013923', (90, 104))	('thromboembolic events', 'Phenotype', 'HP:0001907', (90, 111))	('atherosclerotic', 'Disease', 'MESH:D050197', (115, 130))	('emboli syndrome', 'Disease', 'MESH:D020766', (12, 27))	('GI perforation', 'CPA', (183, 197))	('cause', 'Reg', (84, 89))	('VEGF', 'Protein', (43, 47))	('emboli syndrome', 'Disease', (12, 27))
674734	26068491	They showed that anti-VEGF antibody enhances intestinal damage, leading to decreased mucosal surface, shortened villi, and edema and inflammation, as early as 24 hours after total body irradiation with 12 Gy.	('mucosal surface', 'CPA', (85, 100))	('enhances', 'PosReg', (36, 44))	('anti-VEGF', 'Protein', (17, 26))	('inflammation', 'Disease', 'MESH:D007249', (133, 145))	('edema', 'Disease', (123, 128))	('edema', 'Phenotype', 'HP:0000969', (123, 128))	('inflammation', 'Disease', (133, 145))	('intestinal damage', 'CPA', (45, 62))	('shortened villi', 'CPA', (102, 117))	('antibody', 'Var', (27, 35))	('edema', 'Disease', 'MESH:D004487', (123, 128))	('decreased', 'NegReg', (75, 84))
674736	26068491	Thus, if SBRT is more likely to result in GI mucosal injury, VEGF inhibitors and more severe may prevent normal tissue recovery in the post-SBRT period and thus make SBRT-related toxicity more likely.	('result', 'Reg', (32, 38))	('SBRT', 'Chemical', '-', (140, 144))	('normal tissue recovery', 'MPA', (105, 127))	('toxicity', 'Disease', 'MESH:D064420', (179, 187))	('toxicity', 'Disease', (179, 187))	('SBRT', 'Chemical', '-', (9, 13))	('GI mucosal injury', 'Disease', 'MESH:D052016', (42, 59))	('SBRT', 'Chemical', '-', (166, 170))	('GI mucosal injury', 'Disease', (42, 59))	('VEGF', 'Gene', (61, 65))	('inhibitors', 'Var', (66, 76))	('SBRT', 'Disease', (9, 13))	('prevent', 'NegReg', (97, 104))
674815	26623443	Iron excess results in oxidative stress, lipid peroxidation, and DNA damage, all of which contribute to oncogenesis.	('DNA damage', 'MPA', (65, 75))	('results in', 'Reg', (12, 22))	('oxidative stress', 'Phenotype', 'HP:0025464', (23, 39))	('oxidative stress', 'MPA', (23, 39))	('lipid', 'Chemical', 'MESH:D008055', (41, 46))	('Iron', 'Chemical', 'MESH:D007501', (0, 4))	('lipid peroxidation', 'MPA', (41, 59))	('Iron excess', 'Var', (0, 11))	('contribute', 'Reg', (90, 100))
674822	26623443	One study demonstrated that zinc induces growth arrest in colon cancer cells in vitro, while in vivo studies have demonstrated that zinc supplementation confers a chemoprotective effect against chemically-induced colonic carcinogenesis in rats, supporting the role of zinc as a protective antioxidant.	('growth arrest', 'Disease', (41, 54))	('chemoprotective effect', 'CPA', (163, 185))	('colonic carcinogenesis', 'Disease', (213, 235))	('zinc', 'Var', (28, 32))	('growth arrest', 'Disease', 'MESH:D006323', (41, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('growth arrest', 'Phenotype', 'HP:0001510', (41, 54))	('colonic carcinogenesis', 'Disease', 'MESH:D063646', (213, 235))	('colon cancer', 'Disease', 'MESH:D015179', (58, 70))	('colon cancer', 'Disease', (58, 70))	('rats', 'Species', '10116', (239, 243))
674833	26623443	This classification yielded four subtypes, including MSI, TP53+, TP53-, and epithelial-to-mesenchymal transition (EMT).	('MSI', 'Disease', (53, 56))	('epithelial-to-mesenchymal transition', 'CPA', (76, 112))	('TP53-', 'Var', (65, 70))	('TP53+', 'Var', (58, 63))	('MSI', 'Disease', 'None', (53, 56))
674834	26623443	MSI or microsatellite-unstable tumors exhibited the best overall prognosis and the lowest frequency of recurrence.	('MSI', 'Disease', 'None', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('microsatellite-unstable', 'Var', (7, 30))	('MSI', 'Disease', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (31, 37))
674847	26623443	Non-phosphorylated CagA also exerts numerous effects within gastric epithelial cells that contribute to pathogenesis.	('effects', 'MPA', (45, 52))	('CagA', 'Gene', '20201', (19, 23))	('CagA', 'Gene', (19, 23))	('Non-phosphorylated', 'Var', (0, 18))
674849	26623443	In addition, non-phosphorylated CagA disrupts adherens junctions leading to mislocalization and aberrant activation of beta-catenin (Figure 2A), a response associated with oncogenesis.	('non-phosphorylated', 'Var', (13, 31))	('activation', 'PosReg', (105, 115))	('adherens junctions', 'Protein', (46, 64))	('beta-catenin', 'Protein', (119, 131))	('mislocalization', 'MPA', (76, 91))	('CagA', 'Gene', '20201', (32, 36))	('CagA', 'Gene', (32, 36))	('disrupts', 'NegReg', (37, 45))
674905	24800852	Targeted Knockdown of IQGAP1 Inhibits the Progression of Esophageal Squamous Cell Carcinoma In Vitro and In Vivo IQGAP1 is a scaffolding protein that can regulate several distinct signaling pathways.	('Inhibits', 'NegReg', (29, 37))	('Carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('Esophageal Squamous Cell Carcinoma', 'Disease', (57, 91))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (57, 91))	('regulate', 'Reg', (154, 162))	('IQGAP1', 'Gene', '8826', (22, 28))	('IQGAP1', 'Gene', (22, 28))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('Progression', 'CPA', (42, 53))	('IQGAP1', 'Gene', (113, 119))	('Knockdown', 'Var', (9, 18))	('IQGAP1', 'Gene', '8826', (113, 119))
674909	24800852	Importantly, by using RNA interference (RNAi) technology we successfully silenced IQGAP1 gene in two ESCC cell lines, EC9706 and KYSE150, and for the first time found that suppressing IQGAP1 expression not only obviously reduced the tumor cell growth, migration and invasion in vitro but also markedly inhibited the tumor growth, invasion, lymph node and lung metastasis in xenograft mice.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('lung metastasis', 'Disease', (355, 370))	('suppressing', 'Var', (172, 183))	('IQGAP1', 'Gene', (184, 190))	('mice', 'Species', '10090', (384, 388))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('tumor cell growth', 'CPA', (233, 250))	('EC9706', 'CellLine', 'CVCL:E307', (118, 124))	('invasion', 'CPA', (330, 338))	('reduced', 'NegReg', (221, 228))	('migration', 'CPA', (252, 261))	('tumor growth', 'CPA', (316, 328))	('IQGAP1', 'Gene', (82, 88))	('inhibited', 'NegReg', (302, 311))	('lung metastasis', 'Disease', 'MESH:D009362', (355, 370))	('invasion', 'CPA', (266, 274))
674910	24800852	IQGAP1 silencing may therefore develop into a promising novel anticancer therapy.	('IQGAP1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('silencing', 'Var', (7, 16))	('cancer', 'Disease', (66, 72))
674940	24800852	Two IQGAP1 knockdown stable clones in EC9706 (E1 and E2 clones) or KYSE150 cells (K1 and K2 clones) and corresponding one vector control clone (EC9706/control or KYSE150/control clone) were selected for further analysis (Figure 2C).	('EC9706', 'Var', (38, 44))	('E1 and E2', 'Gene', '6080', (46, 55))	('IQGAP1', 'Gene', (4, 10))
674943	24800852	Further, 3 (or 2) mice developed lymph node metastases in EC9706/control (or KYSE150/control) group (Figure 6E), whereas in IQGAP1 knockdown groups, no gross or microscopic lymph nodes were observed, which showed that the incidence of lymph node metastasis were significantly inhibited by downregulation of IQGAP1 expression.	('lymph node metastases', 'Disease', 'MESH:D009362', (33, 54))	('lymph node metastasis', 'CPA', (235, 256))	('EC9706/control', 'Var', (58, 72))	('lymph node metastases', 'Disease', (33, 54))	('IQGAP1', 'Gene', (307, 313))	('metastases', 'Disease', (44, 54))	('KYSE150/control', 'Var', (77, 92))	('expression', 'MPA', (314, 324))	('metastases', 'Disease', 'MESH:D009362', (44, 54))	('downregulation', 'NegReg', (289, 303))	('inhibited', 'NegReg', (276, 285))
674948	24800852	Recently, evidence also indicates that increasing IQGAP1 expression in breast cancer MCF-7 cells promotes cell proliferation and invasion, siRNA-induced knockdown of IQGAP1 reduces the proliferation and invasion of thyroid cancer and MCF-7 cells.	('cell proliferation', 'CPA', (106, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('thyroid cancer', 'Phenotype', 'HP:0002890', (215, 229))	('invasion', 'CPA', (203, 211))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('breast cancer', 'Disease', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('invasion', 'CPA', (129, 137))	('IQGAP1', 'Gene', (50, 56))	('knockdown', 'Var', (153, 162))	('MCF-7', 'CellLine', 'CVCL:0031', (85, 90))	('MCF-7', 'CellLine', 'CVCL:0031', (234, 239))	('reduces', 'NegReg', (173, 180))	('thyroid cancer', 'Disease', (215, 229))	('promotes', 'PosReg', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('proliferation', 'CPA', (185, 198))	('IQGAP1', 'Gene', (166, 172))	('thyroid cancer', 'Disease', 'MESH:D013964', (215, 229))
674990	20637198	This sequence of glycines (G) and alanines (A), terminated with lysine, has the same size as that of the candidate peptides, but does not have functional groups on the amino acid side chains to enable binding.	('alanines', 'Var', (34, 42))	('lysine', 'Chemical', 'MESH:D008239', (64, 70))	('glycines', 'Chemical', 'MESH:D005998', (17, 25))	('binding', 'Interaction', (201, 208))	('alanines', 'Chemical', 'MESH:D000409', (34, 42))
675024	20637198	for binding of the SNFYMPL phage to the Q-hTERT cells is 0.231+-0.063 compared to that of 0.225+-0.030 and 0.210+-0.011 for the WT-phage (p>0.05) and for no phage (p>0.05), respectively.	('binding', 'Interaction', (4, 11))	('0.231+-0.063', 'Var', (57, 69))	('SNFYMPL', 'Chemical', '-', (19, 26))	('hTERT cells', 'CellLine', 'CVCL:4388', (42, 53))
675028	20637198	We observed that the addition of 100, 200, 400, and 800 muM of the unlabeled SNFYMPL peptide with GGGSK linker (SNFYMPLGGGSK) resulted in a significant reduction in the number of bound phage, corresponding to values of 680+-22x103, 22+-4x103, 6+-2x103, and 0 (p<0.01), respectively.	('bound', 'Interaction', (179, 184))	('muM', 'Gene', '56925', (56, 59))	('SNFYMPLGGGSK', 'Chemical', '-', (112, 124))	('GGGSK', 'Var', (98, 103))	('SNFYMPL peptide', 'Chemical', '-', (77, 92))	('muM', 'Gene', (56, 59))	('reduction', 'NegReg', (152, 161))
675046	20637198	HGD (expanded view of black box in 6E) is identified histologically by large, non-uniform stratified nuclei and lack of cytoplasmic mucin, magnification 40x (Fig.	('magnification 40x', 'Var', (139, 156))	('mucin', 'Gene', (132, 137))	('mucin', 'Gene', '100508689', (132, 137))
675063	20564104	Epigenetic and Genetic Silencing of CHFR in Esophageal Adenocarcinomas The checkpoint with Forkhead-associated domain (FHA) and Ring finger domain (CHFR) is a mitotic checkpoint protein with tumor-suppressor functions.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('CHFR', 'Gene', (148, 152))	('FHA', 'Disease', (119, 122))	('Genetic Silencing', 'Var', (15, 32))	('CHFR', 'Gene', '55743', (148, 152))	('CHFR', 'Gene', (36, 40))	('FHA', 'Disease', 'MESH:D052456', (119, 122))	('Epigenetic', 'Var', (0, 10))	('Esophageal Adenocarcinomas', 'Disease', (44, 70))	('tumor', 'Disease', (191, 196))	('Esophageal Adenocarcinomas', 'Disease', 'MESH:D004938', (44, 70))	('CHFR', 'Gene', '55743', (36, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))
675068	20564104	We detected significant CHFR promoter DNA hypermethylation in 31% of tumor samples (18/58), as compared to normal samples (P<.001).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('hypermethylation', 'Var', (42, 58))	('CHFR', 'Gene', '55743', (24, 28))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CHFR', 'Gene', (24, 28))
482427	20564104	Aberrant DNA methylation, namely overall DNA hypomethylation and regional DNA hypermethylation has been linked to carcinogenesis of various organs.	('Aberrant', 'Var', (0, 8))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('carcinogenesis', 'Disease', (114, 128))	('linked', 'Reg', (104, 110))
675079	20564104	Aberrant DNA hypermethylation of CpG islands in the promoter region has been associated with gene silencing of several genes in cancer such as p16, hMLH1 and CDH1 genes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('gene', 'MPA', (93, 97))	('Aberrant', 'Var', (0, 8))	('p16', 'Gene', '1029', (143, 146))	('cancer', 'Disease', (128, 134))	('CDH1', 'Gene', '999', (158, 162))	('p16', 'Gene', (143, 146))	('hMLH1', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('hMLH1', 'Gene', '4292', (148, 153))	('CDH1', 'Gene', (158, 162))	('associated', 'Reg', (77, 87))
675083	20564104	In this study, we have examined the epigenetic and genetic mechanism of silencing of CHFR in esophageal adenocarcinomas.	('esophageal adenocarcinomas', 'Disease', (93, 119))	('CHFR', 'Gene', (85, 89))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (93, 118))	('silencing', 'Var', (72, 81))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (93, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('CHFR', 'Gene', '55743', (85, 89))
675124	20564104	As shown in figure 3A, samples with hypermethylation (>=20%) had significant down-regulation for CHFR expression (p<=0.05) as compared to samples with absence or low promoter DNA methylation level (<=20%).	('expression', 'MPA', (102, 112))	('down-regulation', 'NegReg', (77, 92))	('CHFR', 'Gene', '55743', (97, 101))	('CHFR', 'Gene', (97, 101))	('hypermethylation', 'Var', (36, 52))
675126	20564104	These results suggest that the hypermethylation of the CHFR promoter region is one of the factors involved in suppression of its mRNA expression in EACs.	('suppression', 'NegReg', (110, 121))	('hypermethylation', 'Var', (31, 47))	('CHFR', 'Gene', '55743', (55, 59))	('CHFR', 'Gene', (55, 59))	('mRNA expression', 'MPA', (129, 144))
675129	20564104	The 5-Aza treatment but not DMSO or TSA led to reduction in the DNA methylation level from 80% to 45% and a 13-fold increase in mRNA expression (Figure 3C).	('reduction', 'NegReg', (47, 56))	('5-Aza', 'Var', (4, 9))	('increase', 'PosReg', (116, 124))	('DMSO', 'Chemical', 'MESH:D004121', (28, 32))	('DNA methylation level', 'MPA', (64, 85))	('5-Aza', 'Chemical', 'MESH:D001374', (4, 9))	('TSA', 'Chemical', 'MESH:C012589', (36, 39))	('mRNA expression', 'MPA', (128, 143))
675131	20564104	These findings prompted us to find out whether loss of copy numbers could be a contributing factor in silencing CHFR expression.	('expression', 'MPA', (117, 127))	('silencing', 'NegReg', (102, 111))	('CHFR', 'Gene', (112, 116))	('copy numbers', 'Var', (55, 67))	('CHFR', 'Gene', '55743', (112, 116))
675134	20564104	This interplay of epigenetic and genetic mechanisms for silencing CHFR suggests that silencing of CHFR is a critical alteration for EACs.	('silencing', 'Var', (56, 65))	('CHFR', 'Gene', '55743', (98, 102))	('CHFR', 'Gene', (66, 70))	('CHFR', 'Gene', '55743', (66, 70))	('silencing', 'Var', (85, 94))	('CHFR', 'Gene', (98, 102))	('EACs', 'Disease', (132, 136))
675137	20564104	In this study, we have shown that silencing of CHFR expression in esophageal adenocarcinomas is mediated by both epigenetic and genetic mechanisms.	('esophageal adenocarcinomas', 'Disease', (66, 92))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (66, 91))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (66, 92))	('CHFR', 'Gene', '55743', (47, 51))	('CHFR', 'Gene', (47, 51))	('silencing', 'Var', (34, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))
675139	20564104	In this context, our findings that CHFR expression is frequently lost in EACs further confirm the reports showing that loss of CHFR is critical for cellular transformation and carcinogenesis.	('CHFR', 'Gene', '55743', (127, 131))	('cellular transformation', 'CPA', (148, 171))	('loss', 'Var', (119, 123))	('CHFR', 'Gene', (35, 39))	('CHFR', 'Gene', '55743', (35, 39))	('lost', 'NegReg', (65, 69))	('carcinogenesis', 'Disease', 'MESH:D063646', (176, 190))	('CHFR', 'Gene', (127, 131))	('carcinogenesis', 'Disease', (176, 190))
675140	20564104	Previous studies have demonstrated variable results for CHFR methylation (10 -40%) in carcinomas of the colon, head and neck, lung, and stomach.	('carcinomas of the colon', 'Disease', 'MESH:D015179', (86, 109))	('lung', 'Disease', (126, 130))	('methylation', 'Var', (61, 72))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('CHFR', 'Gene', (56, 60))	('carcinomas of the colon', 'Disease', (86, 109))	('CHFR', 'Gene', '55743', (56, 60))	('stomach', 'Disease', (136, 143))
675146	20564104	Taken together, our data confirm that aberrant hypermethylation of the 5'CpG island of the CHFR gene is closely associated with the transcriptional inactivation and might be involved in tumor development.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('involved', 'Reg', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('transcriptional', 'MPA', (132, 147))	('tumor', 'Disease', (186, 191))	('aberrant hypermethylation', 'Var', (38, 63))	('CHFR', 'Gene', (91, 95))	('associated', 'Reg', (112, 122))	('CHFR', 'Gene', '55743', (91, 95))
675161	20564104	Indeed, we and others have shown that chromosomal instability and DNA copy number variations are common features of esophageal adenocarcinomas, pointing out the disruption of key mechanisms that regulate mitosis and chromosomal segregation.	('variations', 'Var', (82, 92))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (116, 142))	('mitosis', 'Disease', (204, 211))	('chromosomal instability', 'Phenotype', 'HP:0040012', (38, 61))	('mitosis', 'Disease', 'None', (204, 211))	('DNA', 'Gene', (66, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (116, 141))	('esophageal adenocarcinomas', 'Disease', (116, 142))
675163	20564104	Taken together, our data indicate interplay between epigenetic and genetic mechanisms for inactivation of CHFR, suggesting its involvement in development and progression of esophageal adenocarcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('CHFR', 'Gene', '55743', (106, 110))	('esophageal adenocarcinomas', 'Disease', (173, 199))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (173, 199))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (173, 198))	('involvement', 'Reg', (127, 138))	('inactivation', 'Var', (90, 102))	('CHFR', 'Gene', (106, 110))
675195	19534809	Alterations in MAPK signaling have been correlated with malignant progression in humans.	('MAPK', 'Protein', (15, 19))	('Alterations', 'Var', (0, 11))	('humans', 'Species', '9606', (81, 87))	('correlated', 'Reg', (40, 50))	('rat', 'Species', '10116', (4, 7))	('malignant progression', 'CPA', (56, 77))
675201	19534809	In addition, CREB-specific siRNA and dominant-negative AP-1 (TAM67) blocked deoxycholate- and chenodeoxycholate - induced COX-2 induction.	('TAM67', 'Chemical', '-', (61, 66))	('deoxycholate', 'Chemical', 'MESH:D003840', (76, 88))	('blocked', 'NegReg', (68, 75))	('deoxycholate', 'Chemical', 'MESH:D003840', (99, 111))	('chenodeoxycholate', 'Chemical', 'MESH:D002635', (94, 111))	('AP-1', 'Gene', (55, 59))	('COX-2', 'Gene', (122, 127))	('COX-2', 'Gene', '5743', (122, 127))	('dominant-negative', 'Var', (37, 54))
675202	19534809	In the present study, we investigated the molecular mechanisms underlying DCA stimulated COX-2 signaling pathway in esophageal adenocarcinoma cells and their possible contribution to deregulated cell survival and apoptosis.	('esophageal adenocarcinoma', 'Disease', (116, 141))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (116, 141))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (116, 141))	('DCA', 'Var', (74, 77))	('COX-2', 'Gene', (89, 94))	('COX-2', 'Gene', '5743', (89, 94))	('DCA', 'Chemical', 'MESH:D003840', (74, 77))	('stimulated', 'Reg', (78, 88))
675217	19534809	Membranes were incubated with specific antibodies against Erk1/2, p38 and JNK (at a dilution of 1:1000) (Santa Cruz, CA) or their corresponding phosphorylated forms Erk1/2 (p-Tyr204-Erk1/2), JNK (p-Thr-183/Tyr-185-JNK) (Santa Cruz, CA) and p38 (p-Thr180/Tyr182-p38) (at a dilution of 1:50) (New England Biolabs, Hertfordshire, UK) overnight at 4 C. Antibodies against COX-2 (Cayman chemicals, Alexis Corp, UK) and PARP (Biosource International UK) (at a dilution of 1:100) were also used and incubated overnight at 4 C. Membranes were then incubated with corresponding secondary horseradish peroxidase-conjugated antibodies (Dako, Bucks, UK) (at a dilution of 1:2000) for 1 h at room temperature.	('Thr-183/Tyr', 'Var', (198, 209))	('JNK', 'Gene', (191, 194))	('p38', 'Gene', '1432', (261, 264))	('JNK', 'Gene', '5599', (191, 194))	('Thr180', 'Chemical', '-', (247, 253))	('p38', 'Gene', (66, 69))	('JNK', 'Gene', (214, 217))	('rat', 'Species', '10116', (689, 692))	('JNK', 'Gene', '5599', (214, 217))	('COX-2', 'Gene', (368, 373))	('p38', 'Gene', (240, 243))	('PARP', 'Gene', '142', (414, 418))	('p38', 'Gene', '1432', (66, 69))	('horseradish', 'Species', '3704', (579, 590))	('Thr-183/Tyr', 'SUBSTITUTION', 'None', (198, 209))	('Tyr182', 'Chemical', '-', (254, 260))	('PARP', 'Gene', (414, 418))	('p38', 'Gene', (261, 264))	('COX-2', 'Gene', '5743', (368, 373))	('Tyr204', 'Chemical', '-', (175, 181))	('JNK', 'Gene', (74, 77))	('JNK', 'Gene', '5599', (74, 77))	('p38', 'Gene', '1432', (240, 243))
675248	19534809	On the other hand, DCA induces a weak and more transient activation of c-Jun, which is maximal at 4 hr and is consistently weak and even negligible at 6 hr (Figure 1C).	('c-Jun', 'MPA', (71, 76))	('activation', 'PosReg', (57, 67))	('weak', 'NegReg', (123, 127))	('DCA', 'Var', (19, 22))	('DCA', 'Chemical', 'MESH:D003840', (19, 22))
675251	19534809	Therefore, the possible types of early induced complexes are c-Jun/c-Jun, c-Jun/JunB, c-Jun/Fra-1, JunB/Fra-1 or JunB/JunB, while only the latter two would be present at later stages.	('Fra-1', 'Gene', (104, 109))	('Fra-1', 'Gene', '8061', (104, 109))	('Fra-1', 'Gene', (92, 97))	('Fra-1', 'Gene', '8061', (92, 97))	('c-Jun/JunB', 'Var', (74, 84))	('c-Jun/c-Jun', 'Var', (61, 72))
675258	19534809	The presence of basal expression levels together with the matching kinetics of enhanced protein expression and those of DNA binding activity for Fra-1, JunB and c-Jun, suggest that DCA induces AP-1 DNA binding activity through activation of pre-existing molecules as well as either induction of de novo protein synthesis or increased protein stability.	('activity', 'MPA', (210, 218))	('DCA', 'Var', (181, 184))	('increased', 'PosReg', (324, 333))	('Fra-1', 'Gene', '8061', (145, 150))	('DCA', 'Chemical', 'MESH:D003840', (181, 184))	('activation', 'PosReg', (227, 237))	('protein', 'Protein', (303, 310))	('enhanced', 'PosReg', (79, 87))	('Fra-1', 'Gene', (145, 150))	('protein expression', 'MPA', (88, 106))	('protein', 'MPA', (334, 341))	('AP-1', 'Gene', (193, 197))
675265	19534809	We therefore examined the ability of DCA to activate Erk1/2, p38 and JNK in SKGT4 cells using Western blot analysis with specific antibodies that recognize the active phosphorylated forms of these proteins: Erk1/2 (p-Tyr204-Erk1/2), p38 (p-Thr180/Tyr182-p38) and JNK (p-Thr-183/Tyr-185-JNK).	('JNK', 'Gene', (263, 266))	('p-Tyr204-Erk1/2', 'Var', (215, 230))	('p38', 'Gene', '1432', (254, 257))	('p38', 'Gene', (233, 236))	('JNK', 'Gene', '5599', (263, 266))	('Thr180', 'Chemical', '-', (240, 246))	('p38', 'Gene', (61, 64))	('JNK', 'Gene', (286, 289))	('JNK', 'Gene', '5599', (286, 289))	('Thr-183/Tyr', 'SUBSTITUTION', 'None', (270, 281))	('SKGT4', 'CellLine', 'CVCL:2195', (76, 81))	('JNK', 'Gene', (69, 72))	('Tyr204', 'Chemical', '-', (217, 223))	('p38', 'Gene', '1432', (61, 64))	('JNK', 'Gene', '5599', (69, 72))	('p38', 'Gene', '1432', (233, 236))	('Tyr182', 'Chemical', '-', (247, 253))	('p38', 'Gene', (254, 257))	('Thr-183/Tyr', 'Var', (270, 281))	('DCA', 'Chemical', 'MESH:D003840', (37, 40))
675271	19534809	SKGT4 cells were incubated with 50 muM PD98059 or 2 muM of the SB203580 for 30 minutes prior to the addition of 300 muM DCA.	('muM', 'Gene', '56925', (35, 38))	('DCA', 'Chemical', 'MESH:D003840', (120, 123))	('PD98059', 'Chemical', 'MESH:C093973', (39, 46))	('muM', 'Gene', (116, 119))	('muM', 'Gene', '56925', (52, 55))	('SKGT4', 'CellLine', 'CVCL:2195', (0, 5))	('muM', 'Gene', '56925', (116, 119))	('muM', 'Gene', (35, 38))	('SB203580', 'Chemical', 'MESH:C093642', (63, 71))	('muM', 'Gene', (52, 55))	('SB203580', 'Gene', (63, 71))	('PD98059', 'Var', (39, 46))
675272	19534809	PD98059 completely abolishes basal, PdBu and DCA-induced Erk1/2 activity at all the time points tested (Figure 3B).	('PdBu', 'Chemical', 'MESH:D015240', (36, 40))	('abolishes', 'NegReg', (19, 28))	('Erk1/2', 'Enzyme', (57, 63))	('PD98059', 'Var', (0, 7))	('DCA', 'Chemical', 'MESH:D003840', (45, 48))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))	('activity', 'MPA', (64, 72))
675273	19534809	Similarly, the SB203580 compound inhibits the activation of p38 in response to DCA and to anisomycin at all tested time points (Figure 3D).	('response to DCA', 'MPA', (67, 82))	('anisomycin', 'Chemical', 'MESH:D000841', (90, 100))	('p38', 'Gene', '1432', (60, 63))	('DCA', 'Chemical', 'MESH:D003840', (79, 82))	('SB203580 compound', 'Var', (15, 32))	('p38', 'Gene', (60, 63))	('inhibits', 'NegReg', (33, 41))	('SB203580', 'Chemical', 'MESH:C093642', (15, 23))	('activation', 'MPA', (46, 56))
675276	19534809	SKGT4 cells were pre-treated with 10 muM PD98059 or 2 muM SB203580 for 30 min prior to stimulation with 300 muM DCA for 6 hr and DNA affinity precipitation assays were performed.	('muM', 'Gene', (54, 57))	('PD98059', 'Var', (41, 48))	('muM', 'Gene', '56925', (108, 111))	('SKGT4', 'CellLine', 'CVCL:2195', (0, 5))	('PD98059', 'Chemical', 'MESH:C093973', (41, 48))	('SB203580', 'Chemical', 'MESH:C093642', (58, 66))	('muM', 'Gene', '56925', (37, 40))	('muM', 'Gene', '56925', (54, 57))	('muM', 'Gene', (108, 111))	('SB203580', 'Gene', (58, 66))	('DCA', 'Chemical', 'MESH:D003840', (112, 115))	('muM', 'Gene', (37, 40))
675277	19534809	Pre-treatment of SKGT4 cells with 10 muM PD98059 impairs and diminishes DCA-induced activation of Fra-1 and JunB, respectively (Figure 3F).	('PD98059', 'Var', (41, 48))	('SKGT4', 'CellLine', 'CVCL:2195', (17, 22))	('DCA', 'Chemical', 'MESH:D003840', (72, 75))	('impairs', 'NegReg', (49, 56))	('PD98059', 'Chemical', 'MESH:C093973', (41, 48))	('muM', 'Gene', '56925', (37, 40))	('Fra-1', 'Gene', (98, 103))	('DCA-induced activation', 'MPA', (72, 94))	('diminishes', 'NegReg', (61, 71))	('Fra-1', 'Gene', '8061', (98, 103))	('JunB', 'MPA', (108, 112))	('muM', 'Gene', (37, 40))
675278	19534809	The SB203580 compound completely abolishes DCA-induced Fra-1 DNA binding while having no effect on DCA-induced JunB DNA binding (Figure 3F).	('abolishes', 'NegReg', (33, 42))	('Fra-1', 'Gene', '8061', (55, 60))	('SB203580', 'Chemical', 'MESH:C093642', (4, 12))	('Fra-1', 'Gene', (55, 60))	('SB203580', 'Var', (4, 12))	('DNA binding', 'Interaction', (61, 72))	('DCA', 'Chemical', 'MESH:D003840', (43, 46))	('DCA', 'Chemical', 'MESH:D003840', (99, 102))
675295	19534809	Taken together, these data show that DCA induces a reduction in cell proliferation, which is accompanied by low levels of apoptosis.	('reduction', 'NegReg', (51, 60))	('rat', 'Species', '10116', (76, 79))	('cell proliferation', 'CPA', (64, 82))	('DCA', 'Chemical', 'MESH:D003840', (37, 40))	('DCA', 'Var', (37, 40))
675299	19534809	SKGT4 cells were pretreated for 1 hr with 50 muM of either Z-VAD-FMK or Z-DEVD-FMK and stimulated with 400 muM DCA, a concentration which induced significant levels of PARP cleavage (Figure 4) for 6 hr.	('Z-DEVD-FMK', 'Var', (72, 82))	('rat', 'Species', '10116', (125, 128))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (59, 68))	('muM', 'Gene', '56925', (45, 48))	('muM', 'Gene', '56925', (107, 110))	('SKGT4', 'CellLine', 'CVCL:2195', (0, 5))	('PARP', 'Gene', (168, 172))	('muM', 'Gene', (45, 48))	('muM', 'Gene', (107, 110))	('Z-DEVD-FMK', 'Chemical', 'MESH:C110772', (72, 82))	('DCA', 'Chemical', 'MESH:D003840', (111, 114))	('PARP', 'Gene', '142', (168, 172))
675301	19534809	Both Z-VAD-FMK and Z-DEVD-FMK completely abolished DCA-induced PARP cleavage while partially inhibiting DNA fragmentation (Figures 5A and 5B).	('PARP', 'Gene', '142', (63, 67))	('Z-DEVD-FMK', 'Chemical', 'MESH:C110772', (19, 29))	('abolished', 'NegReg', (41, 50))	('PARP', 'Gene', (63, 67))	('DCA', 'Chemical', 'MESH:D003840', (51, 54))	('Z-DEVD-FMK', 'Var', (19, 29))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (5, 14))	('inhibiting', 'NegReg', (93, 103))	('DNA fragmentation', 'MPA', (104, 121))
675312	19534809	SKGT4 cells were pre-treated with 10 muM PD98059, 2 muM SB203580 or 1 muM Go6976 for 30 minutes prior to addition of 300 muM DCA for 6 hr.	('PD98059', 'Var', (41, 48))	('muM', 'Gene', '56925', (121, 124))	('muM', 'Gene', '56925', (52, 55))	('SKGT4', 'CellLine', 'CVCL:2195', (0, 5))	('muM', 'Gene', '56925', (70, 73))	('Go6976', 'Chemical', 'MESH:C081021', (74, 80))	('DCA', 'Chemical', 'MESH:D003840', (125, 128))	('PD98059', 'Chemical', 'MESH:C093973', (41, 48))	('muM', 'Gene', (121, 124))	('muM', 'Gene', '56925', (37, 40))	('muM', 'Gene', (52, 55))	('SB203580', 'Chemical', 'MESH:C093642', (56, 64))	('SB203580', 'Var', (56, 64))	('Go6976', 'Var', (74, 80))	('muM', 'Gene', (70, 73))	('muM', 'Gene', (37, 40))
675313	19534809	(GO6976 was used as a positive control in this experiment as it has previously been shown to inhibit COX-2 expression.	('inhibit', 'NegReg', (93, 100))	('GO6976', 'Var', (1, 7))	('COX-2', 'Gene', (101, 106))	('COX-2', 'Gene', '5743', (101, 106))	('expression', 'MPA', (107, 117))	('GO6976', 'Chemical', 'MESH:C081021', (1, 7))
675322	19534809	These data show that inhibition of COX-2 expression readily enhances the apoptotic markers induced upon DCA exposure, confirming a potential anti-apoptotic role of COX-2 in this system.	('COX-2', 'Gene', (35, 40))	('enhances', 'PosReg', (60, 68))	('COX-2', 'Gene', '5743', (35, 40))	('DCA', 'Chemical', 'MESH:D003840', (104, 107))	('inhibition', 'Var', (21, 31))	('COX-2', 'Gene', (164, 169))	('apoptotic markers induced', 'MPA', (73, 98))	('COX-2', 'Gene', '5743', (164, 169))
675326	19534809	Alterations in gene expression underlie the ability of deoxycholate to deregulate biochemical processes and control the fate of the cells.	('Alterations', 'Var', (0, 11))	('deregulate biochemical processes', 'MPA', (71, 103))	('rat', 'Species', '10116', (4, 7))	('control', 'Reg', (108, 115))	('deoxycholate', 'Chemical', 'MESH:D003840', (55, 67))
675341	19534809	reported that the unconjugated bile acids chenodoxycholate and deoxycholate potently upregulate ROS production in the esophagus, leading to activation of the PI3K and ERK1/2 signaling pathways, with a subsequent CREB- and AP-1-dependent COX-2 expression.	('COX-2', 'Gene', '5743', (237, 242))	('upregulate ROS production', 'Phenotype', 'HP:0025464', (85, 110))	('expression', 'MPA', (243, 253))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('bile acids', 'Chemical', 'MESH:D001647', (31, 41))	('upregulate', 'PosReg', (85, 95))	('ROS production', 'MPA', (96, 110))	('chenodoxycholate', 'Chemical', '-', (42, 58))	('chenodoxycholate', 'Var', (42, 58))	('activation', 'PosReg', (140, 150))	('deoxycholate', 'Var', (63, 75))	('deoxycholate', 'Chemical', 'MESH:D003840', (63, 75))	('COX-2', 'Gene', (237, 242))
675344	19534809	Furthermore, DCA induces a dose- and time-dependent increase in COX-2 expression that parallels with PARP cleavage and DNA fragmentation.	('DCA', 'Chemical', 'MESH:D003840', (13, 16))	('PARP', 'Gene', '142', (101, 105))	('increase', 'PosReg', (52, 60))	('expression', 'MPA', (70, 80))	('PARP', 'Gene', (101, 105))	('COX-2', 'Gene', (64, 69))	('COX-2', 'Gene', '5743', (64, 69))	('DCA', 'Var', (13, 16))
675365	19534809	COX-2 expression was completely blocked by the PD98059 and SB203580 compounds demonstrating the involvement of Raf-Mek1/2-Erk1/2 and MMK3/6-p38 pathways in DCA-induced COX-2 expression.	('Raf', 'Gene', (111, 114))	('PD98059', 'Var', (47, 54))	('Mek1/2', 'Gene', (115, 121))	('p38', 'Gene', (140, 143))	('COX-2', 'Gene', '5743', (168, 173))	('expression', 'MPA', (6, 16))	('PD98059', 'Chemical', 'MESH:C093973', (47, 54))	('SB203580', 'Chemical', 'MESH:C093642', (59, 67))	('p38', 'Gene', '1432', (140, 143))	('Mek1/2', 'Gene', '5604;5605', (115, 121))	('Raf', 'Gene', '22882', (111, 114))	('DCA', 'Chemical', 'MESH:D003840', (156, 159))	('rat', 'Species', '10116', (85, 88))	('SB203580', 'Gene', (59, 67))	('COX-2', 'Gene', '5743', (0, 5))	('COX-2', 'Gene', (168, 173))	('COX-2', 'Gene', (0, 5))
675367	19534809	However, MAPKs inhibitors such as PD98059 and SB203580 are well-established specific inhibitors of ERK and p38 pathway, respectively, and have been tested in many systems for their specificity in inhibiting MAPKs activity.	('MAPKs', 'Gene', (9, 14))	('activity', 'MPA', (213, 221))	('p38', 'Gene', (107, 110))	('PD98059', 'Var', (34, 41))	('inhibiting', 'NegReg', (196, 206))	('ERK', 'Gene', '5594', (99, 102))	('ERK', 'Gene', (99, 102))	('PD98059', 'Chemical', 'MESH:C093973', (34, 41))	('MAPKs', 'Enzyme', (207, 212))	('SB203580', 'Chemical', 'MESH:C093642', (46, 54))	('p38', 'Gene', '1432', (107, 110))	('SB203580', 'Var', (46, 54))
675387	33693959	Upregulated long non-coding RNA LincIN promotes tumor progression via the regulation of nuclear factor 90/microRNA-7/HOXB13 in esophageal squamous cell carcinoma Long non-coding RNA LincIN has been reported to be overexpressed and to be involved in the metastasis of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (267, 280))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (127, 161))	('LincIN', 'Chemical', '-', (32, 38))	('promotes', 'PosReg', (39, 47))	('Long non-coding RNA', 'Var', (162, 181))	('tumor', 'Disease', (48, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('esophageal squamous cell carcinoma', 'Disease', (127, 161))	('involved', 'Reg', (237, 245))	('LincIN', 'Chemical', '-', (182, 188))	('HOXB13', 'Gene', '10481', (117, 123))	('breast cancer', 'Disease', 'MESH:D001943', (267, 280))	('HOXB13', 'Gene', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('breast cancer', 'Disease', (267, 280))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
675398	33693959	The overexpression of miR-7 or the depletion of HOXB13 both attenuated the tumor-promoting roles of LincIN in ESCC cell growth, migration and invasion.	('attenuated', 'NegReg', (60, 70))	('miR-7', 'Chemical', '-', (22, 27))	('HOXB13', 'Gene', '10481', (48, 54))	('miR-7', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('LincIN', 'Protein', (100, 106))	('LincIN', 'Chemical', '-', (100, 106))	('HOXB13', 'Gene', (48, 54))	('ESCC', 'Disease', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('overexpression', 'PosReg', (4, 18))	('depletion', 'Var', (35, 44))	('invasion', 'CPA', (142, 150))	('tumor', 'Disease', (75, 80))
675429	33693959	TE-1 has a mutation at codon 272 of p53, leading to p53 activity impairment.	('TE-1', 'CellLine', 'CVCL:1759', (0, 4))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (36, 39))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (52, 55))	('mutation at codon', 'Var', (11, 28))	('activity impairment', 'MPA', (56, 75))
675471	33693959	CCK-8 and EdU incorporation assays revealed that the knockdown of LincIN inhibited ESCC cell growth (Fig.	('LincIN', 'Gene', (66, 72))	('knockdown', 'Var', (53, 62))	('LincIN', 'Chemical', '-', (66, 72))	('inhibited', 'NegReg', (73, 82))	('EdU', 'Chemical', 'MESH:C031086', (10, 13))	('ESCC', 'Disease', (83, 87))	('CCK-8', 'Chemical', '-', (0, 5))
675472	33693959	Transwell migration and invasion assays also revealed that the knockdown of LincIN inhibited ESCC cell migration and invasion (Fig.	('LincIN', 'Gene', (76, 82))	('inhibited', 'NegReg', (83, 92))	('LincIN', 'Chemical', '-', (76, 82))	('knockdown', 'Var', (63, 72))	('invasion', 'CPA', (117, 125))	('ESCC cell migration', 'CPA', (93, 112))
675473	33693959	Collectively, these results suggested that the knockdown of LincIN inhibited ESCC cell growth, migration and invasion.	('invasion', 'CPA', (109, 117))	('inhibited', 'NegReg', (67, 76))	('ESCC', 'Disease', (77, 81))	('LincIN', 'Chemical', '-', (60, 66))	('knockdown', 'Var', (47, 56))	('LincIN', 'Gene', (60, 66))	('migration', 'CPA', (95, 104))
675480	33693959	RIP assays revealed that the overexpression of LincIN promoted, while the knockdown of LincIN suppressed the binding between NF90 and pri-miR-7 (Fig.	('LincIN', 'Chemical', '-', (47, 53))	('NF90', 'Gene', (125, 129))	('knockdown', 'Var', (74, 83))	('LincIN', 'Gene', (87, 93))	('suppressed', 'NegReg', (94, 104))	('LincIN', 'Chemical', '-', (87, 93))	('NF90', 'Gene', '3609', (125, 129))	('miR-7', 'Chemical', '-', (138, 143))	('binding', 'Interaction', (109, 116))
675489	33693959	HOXB13 was previously identified as a critical target of miR-7 and it was found to mediate the tumor suppressive roles of miR-7.	('miR-7', 'Var', (122, 127))	('miR-7', 'Chemical', '-', (57, 62))	('miR-7', 'Chemical', '-', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('HOXB13', 'Gene', '10481', (0, 6))	('miR-7', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('HOXB13', 'Gene', (0, 6))	('tumor', 'Disease', (95, 100))
675492	33693959	Reciprocally, the knockdown of LincIN significantly reduced the 3'UTR activity of HOXB13 (Fig.	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (52, 59))	('HOXB13', 'Gene', '10481', (82, 88))	('LincIN', 'Gene', (31, 37))	('LincIN', 'Chemical', '-', (31, 37))	('HOXB13', 'Gene', (82, 88))
675494	33693959	Reciprocally, the knockdown of LincIN significantly reduced the HOXB13 mRNA level (Fig.	('knockdown', 'Var', (18, 27))	('HOXB13', 'Gene', '10481', (64, 70))	('reduced', 'NegReg', (52, 59))	('LincIN', 'Gene', (31, 37))	('LincIN', 'Chemical', '-', (31, 37))	('HOXB13', 'Gene', (64, 70))
675496	33693959	Reciprocally, the knockdown of LincIN markedly reduced the HOXB13 protein level (Fig.	('knockdown', 'Var', (18, 27))	('HOXB13', 'Gene', (59, 65))	('LincIN', 'Gene', (31, 37))	('HOXB13', 'Gene', '10481', (59, 65))	('LincIN', 'Chemical', '-', (31, 37))	('reduced', 'NegReg', (47, 54))
675503	33693959	Whole-exome sequencings have identified a number of mutations in ESCC, including TP53, CCND1, CDKN2A, NFE2L2, RB1, KMT2D, KMT2C, EP300, FAT1, NOTCH1 and others.	('CDKN2A', 'Gene', '1029', (94, 100))	('RB1', 'Gene', (110, 113))	('NFE2L2', 'Gene', '4780', (102, 108))	('KMT2C', 'Gene', '58508', (122, 127))	('KMT2C', 'Gene', (122, 127))	('FAT1', 'Gene', '2195', (136, 140))	('TP53', 'Gene', '7157', (81, 85))	('EP300', 'Gene', '2033', (129, 134))	('NOTCH1', 'Gene', (142, 148))	('KMT2D', 'Gene', '8085', (115, 120))	('CCND1', 'Gene', '595', (87, 92))	('NFE2L2', 'Gene', (102, 108))	('RB1', 'Gene', '5925', (110, 113))	('ESCC', 'Gene', (65, 69))	('NOTCH1', 'Gene', '4851', (142, 148))	('CCND1', 'Gene', (87, 92))	('EP300', 'Gene', (129, 134))	('FAT1', 'Gene', (136, 140))	('CDKN2A', 'Gene', (94, 100))	('TP53', 'Gene', (81, 85))	('mutations', 'Var', (52, 61))	('KMT2D', 'Gene', (115, 120))
675506	33693959	CCAT1 binds and recruits EZH2 and SUV39H1 to epigenetically silence SPRY4.	('SUV39H1', 'Gene', '6839', (34, 41))	('EZH2', 'Gene', '2146', (25, 29))	('SPRY4', 'Gene', (68, 73))	('EZH2', 'Gene', (25, 29))	('SPRY4', 'Gene', '81848', (68, 73))	('CCAT1', 'Gene', '100507056', (0, 5))	('epigenetically', 'Var', (45, 59))	('CCAT1', 'Gene', (0, 5))	('binds', 'Interaction', (6, 11))	('SUV39H1', 'Gene', (34, 41))
675518	33693959	The knockdown of LincIN inhibited ESCC cell growth, migration and invasion.	('LincIN', 'Gene', (17, 23))	('migration', 'CPA', (52, 61))	('knockdown', 'Var', (4, 13))	('LincIN', 'Chemical', '-', (17, 23))	('inhibited', 'NegReg', (24, 33))	('ESCC', 'Disease', (34, 38))	('invasion', 'CPA', (66, 74))
675532	33693959	By repressing miR-7, LincIN was verified to upregulate HOXB13 expression in ESCC cells.	('expression', 'MPA', (62, 72))	('miR-7', 'Var', (14, 19))	('upregulate', 'PosReg', (44, 54))	('LincIN', 'Chemical', '-', (21, 27))	('miR-7', 'Chemical', '-', (14, 19))	('HOXB13', 'Gene', '10481', (55, 61))	('HOXB13', 'Gene', (55, 61))
675533	33693959	Functional rescue assays demonstrated that the overexpression of miR-7 or depletion of HOXB13 attenuated the promoting effects of LincIN on ESCC cell growth, migration and invasion, which further suggested that miR-7/HOXB13 are critical mediators of the oncogenic roles of LincIN in ESCC.	('depletion', 'Var', (74, 83))	('HOXB13', 'Gene', (87, 93))	('LincIN', 'Chemical', '-', (130, 136))	('miR-7', 'Chemical', '-', (211, 216))	('overexpression', 'PosReg', (47, 61))	('ESCC', 'Disease', (283, 287))	('HOXB13', 'Gene', '10481', (217, 223))	('migration', 'CPA', (158, 167))	('ESCC', 'Disease', (140, 144))	('attenuated', 'NegReg', (94, 104))	('invasion', 'CPA', (172, 180))	('miR-7', 'Chemical', '-', (65, 70))	('HOXB13', 'Gene', '10481', (87, 93))	('HOXB13', 'Gene', (217, 223))	('miR-7', 'Gene', (65, 70))	('LincIN', 'Chemical', '-', (273, 279))
675537	33693959	In conclusion, the present study demonstrates that lncRNA LincIN is highly expressed in ESCC, and is associated with an advanced clinical stage and a poor prognosis of patients with ESCC.	('lncRNA', 'Var', (51, 57))	('ESCC', 'Disease', (88, 92))	('lncRNA LincIN', 'Chemical', '-', (51, 64))	('patients', 'Species', '9606', (168, 176))	('associated', 'Reg', (101, 111))
675616	33643529	The results of this review also suggest that MIE might give older patients a chance at curative resection without a higher risk of mortality as compared to younger patients.	('MIE', 'Var', (45, 48))	('mortality', 'Disease', 'MESH:D003643', (131, 140))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (66, 74))	('mortality', 'Disease', (131, 140))
675632	31164716	Subsequently, we investigated the relationship between mutations and copy number alterations in prominin genes and various types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('investigated', 'Reg', (17, 29))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('mutations', 'Var', (55, 64))	('prominin genes', 'Gene', (96, 110))	('rat', 'Species', '10116', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('copy number alterations', 'Var', (69, 92))	('S', 'Chemical', 'MESH:D012694', (0, 1))
675640	31164716	Cumulative genetic alterations in the form of base insertions, deletions, substitutions, duplications, and translocations can be considered as the basis of cancer.	('translocations', 'Var', (107, 121))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('rat', 'Species', '10116', (23, 26))	('duplications', 'Var', (89, 101))	('substitutions', 'Var', (74, 87))	('deletions', 'Var', (63, 72))	('base insertions', 'Var', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
675647	31164716	Recent studies suggest that PROM1 is upregulated in non-small cell lung cancer tissue compared to normal lung tissue, and mutations in PROM1 are associated with poor prognosis.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (56, 78))	('upregulated', 'PosReg', (37, 48))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (52, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('associated', 'Reg', (145, 155))	('mutations', 'Var', (122, 131))	('PROM1', 'Gene', (28, 33))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('PROM1', 'Gene', (135, 140))
675650	31164716	It can also regulate the activation of stem cells by orchestrating ciliary dynamics, and the absence of PROM1 allows stem cells to resist the effects of sonic hedgehog (SHH) on growth stimulation, thereby disrupting stem cell activation.	('absence', 'Var', (93, 100))	('disrupting', 'NegReg', (205, 215))	('sonic hedgehog', 'Gene', '6469', (153, 167))	('rat', 'Species', '10116', (60, 63))	('SHH', 'Gene', (169, 172))	('resist', 'NegReg', (131, 137))	('ciliary', 'CPA', (67, 74))	('sonic hedgehog', 'Gene', (153, 167))	('SHH', 'Gene', '6469', (169, 172))	('PROM1', 'Gene', (104, 109))	('stem cell activation', 'CPA', (216, 236))
675654	31164716	Furthermore, PROM2 causes cell protrusions that recruit cholesterol with the aid of lipid rafts and subsequently, increase the phosphorylation of caveolin-1 in membrane microdomains.	('PROM2', 'Var', (13, 18))	('increase', 'PosReg', (114, 122))	('phosphorylation', 'MPA', (127, 142))	('caveolin-1', 'Gene', (146, 156))	('recruit', 'PosReg', (48, 55))	('cell protrusions', 'CPA', (26, 42))	('cholesterol', 'MPA', (56, 67))	('caveolin-1', 'Gene', '857', (146, 156))	('lipid', 'Chemical', 'MESH:D008055', (84, 89))	('cholesterol', 'Chemical', 'MESH:D002784', (56, 67))
675700	31164716	The primary search parameters included alterations (amplifications, deep deletions, and missense mutations), copy number alterations (CNAs) from GISTIC, and RNA sequencing data, using the default settings.	('S', 'Chemical', 'MESH:D012694', (147, 148))	('rat', 'Species', '10116', (125, 128))	('rat', 'Species', '10116', (43, 46))	('deep deletions', 'Var', (68, 82))	('missense mutations', 'Var', (88, 106))	('copy number alterations', 'Var', (109, 132))
675731	31164716	Moreover, PROM1+ ovarian CSCs are highly tumorigenic, chemo-resistant, and metastatic and they promote the adhesion capabilities of the ovarian cancer metastatic niche.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('ovarian CSCs', 'Disease', (17, 29))	('promote', 'PosReg', (95, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (136, 150))	('tumor', 'Disease', (41, 46))	('ovarian cancer', 'Disease', (136, 150))	('ovarian CSCs', 'Disease', 'MESH:D010049', (17, 29))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('adhesion capabilities', 'CPA', (107, 128))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PROM1+', 'Var', (10, 16))
675740	31164716	In addition, low levels of PROM1 expression were correlated with poor overall survival (OS) in prostate and lung cancers (Fig.	('overall survival', 'MPA', (70, 86))	('prostate', 'Disease', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lung cancers', 'Disease', (108, 120))	('low levels', 'Var', (13, 23))	('lung cancers', 'Phenotype', 'HP:0100526', (108, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('expression', 'MPA', (33, 43))	('lung cancers', 'Disease', 'MESH:D008175', (108, 120))	('PROM1', 'Gene', (27, 32))	('poor', 'NegReg', (65, 69))	('S', 'Chemical', 'MESH:D012694', (89, 90))
675747	31164716	In addition, we found that high PROM1 expression was associated with poor OS in patients with esophageal cancers and mixed Ewing sarcoma (Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('PROM1', 'Protein', (32, 37))	('patients', 'Species', '9606', (80, 88))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('expression', 'MPA', (38, 48))	('Ewing sarcoma', 'Disease', (123, 136))	('high', 'Var', (27, 31))	('poor OS', 'Disease', (69, 76))	('esophageal cancers', 'Disease', (94, 112))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (123, 136))	('S', 'Chemical', 'MESH:D012694', (75, 76))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (123, 136))	('esophageal cancers', 'Disease', 'MESH:D004938', (94, 112))
675750	31164716	Similarly, in gastric, liver, and ovarian cancer patients, high levels of PROM1 expression were associated with poor OS (Fig.	('PROM1', 'Gene', (74, 79))	('high levels', 'Var', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ovarian cancer', 'Phenotype', 'HP:0100615', (34, 48))	('associated', 'Reg', (96, 106))	('S', 'Chemical', 'MESH:D012694', (118, 119))	('ovarian cancer', 'Disease', 'MESH:D010051', (34, 48))	('expression', 'MPA', (80, 90))	('ovarian cancer', 'Disease', (34, 48))	('patients', 'Species', '9606', (49, 57))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('poor OS', 'Disease', (112, 119))
675774	31164716	We also observed that both low and high levels of PROM2 expression were associated with poor survival in ovarian cancer patients (Fig.	('ovarian cancer', 'Disease', 'MESH:D010051', (105, 119))	('poor', 'NegReg', (88, 92))	('ovarian cancer', 'Disease', (105, 119))	('high levels', 'Var', (35, 46))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('patients', 'Species', '9606', (120, 128))	('PROM2', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
675780	31164716	While high PROM1 expression was common in esophageal and liver cancers, based on data from Oncomine, R2, and SurvExpress (see Figs.	('liver cancers', 'Phenotype', 'HP:0002896', (57, 70))	('liver cancers', 'Disease', (57, 70))	('esophageal', 'Disease', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('expression', 'MPA', (17, 27))	('Oncomine', 'Chemical', '-', (91, 99))	('R2', 'Gene', '913', (101, 103))	('common', 'Reg', (32, 38))	('high', 'Var', (6, 10))	('S', 'Chemical', 'MESH:D012694', (109, 110))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('PROM1', 'Gene', (11, 16))	('liver cancers', 'Disease', 'MESH:D006528', (57, 70))	('liver cancer', 'Phenotype', 'HP:0002896', (57, 69))
675790	31164716	The clinical prognosis data were then used to prepare a multivariate survival plot to assess the effect of high/high, high/low, low/high, and low/low expression of PROM1 and PROM2 in each cancer.	('high/low', 'Var', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('PROM1', 'Gene', (164, 169))	('low/high', 'Var', (128, 136))	('cancer', 'Disease', (188, 194))	('low/low', 'Var', (142, 149))	('PROM2', 'Gene', (174, 179))
675796	31164716	The multivariate survival analysis revealed a significant association between low/high expression of PROM1/PROM2 and poorer prognosis of patients with kidney renal clear cell carcinoma (KIRC) compared to patients with high/high, low/low, or high/low expression patterns (Fig.	('patients', 'Species', '9606', (204, 212))	('kidney renal clear cell carcinoma', 'Disease', (151, 184))	('low/high', 'Var', (78, 86))	('patients', 'Species', '9606', (137, 145))	('expression', 'MPA', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('PROM1/PROM2', 'Gene', (101, 112))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (151, 184))
675797	31164716	This result suggested that the partial-co-expression of PROM1 and PROM2 may regulate cancer prognosis.	('PROM2', 'Gene', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('regulate', 'Reg', (76, 84))	('partial-co-expression', 'Var', (31, 52))	('PROM1', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
675798	31164716	In the case of kidney renal papillary cell carcinoma (KIRP), the low/low expression pattern of PROM1/PROM2 was associated with poor prognosis compared to the high/high, high/low, and low/high patterns (see Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('kidney renal papillary cell carcinoma', 'Disease', (15, 52))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (15, 52))	('low/low', 'Var', (65, 72))	('expression', 'MPA', (73, 83))	('PROM1/PROM2', 'Gene', (95, 106))
675806	31164716	Several studies have shown that mutations in PROM1 are associated with photoreceptor degeneration in mice and this photoreceptor degeneration is regulated through interactions between PROM1 and PCDH21.	('photoreceptor degeneration', 'Disease', 'MESH:D012162', (115, 141))	('PCDH21', 'Gene', (194, 200))	('associated', 'Reg', (55, 65))	('interactions', 'Interaction', (163, 175))	('PCDH21', 'Gene', '170677', (194, 200))	('photoreceptor degeneration', 'Disease', (115, 141))	('mutations', 'Var', (32, 41))	('mice', 'Species', '10090', (101, 105))	('photoreceptor degeneration', 'Disease', 'MESH:D012162', (71, 97))	('PROM1', 'Gene', (45, 50))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('photoreceptor degeneration', 'Disease', (71, 97))
675808	31164716	In silico studies suggest that PROM2 transcription may be regulated by several proteins, including E74A, HFH-2, Snail, and Spz1.	('Snail', 'Gene', '6615', (112, 117))	('Snail', 'Gene', (112, 117))	('Spz1', 'Gene', (123, 127))	('PROM2', 'Gene', (31, 36))	('E74A', 'Mutation', 'p.E74A', (99, 103))	('E74A', 'Var', (99, 103))	('HFH-2', 'Gene', (105, 110))	('Spz1', 'Gene', '84654', (123, 127))	('regulated', 'Reg', (58, 67))	('transcription', 'MPA', (37, 50))	('HFH-2', 'Gene', '27022', (105, 110))
675816	31164716	The database was first queried for PROM1 gene mutations in 56,250 samples from 215 studies that covered the entire set of available cancers.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PROM1 gene', 'Gene', (35, 45))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
675818	31164716	We also observed that PROM1 mutations primarily occurred in uterine cancer and spanned the prominin domain, with a hotspot in N566Ifs*29/Kfs*2.	('occurred', 'Reg', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PROM1', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('Kfs*2', 'Gene', (137, 142))	('uterine cancer', 'Phenotype', 'HP:0010784', (60, 74))	('mutations', 'Var', (28, 37))	('Kfs*2', 'Gene', '4222', (137, 142))
675819	31164716	Unlike PROM1, PROM2 mutations primarily occurred in skin cancer.	('skin cancer', 'Disease', 'MESH:D012878', (52, 63))	('PROM2', 'Gene', (14, 19))	('occurred', 'Reg', (40, 48))	('skin cancer', 'Phenotype', 'HP:0008069', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('skin cancer', 'Disease', (52, 63))	('mutations', 'Var', (20, 29))
675820	31164716	They also spanned the prominin domain, with hotspots in Q508R and R582Q/W (Fig.	('R582Q', 'SUBSTITUTION', 'None', (66, 71))	('Q508R', 'Var', (56, 61))	('Q508R', 'SUBSTITUTION', 'None', (56, 61))	('R582Q', 'Var', (66, 71))
675825	31164716	The alterations occurred mostly in neuroendocrine prostate cancer (NEPC).	('neuroendocrine prostate cancer', 'Disease', (35, 65))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (35, 65))	('alterations', 'Var', (4, 15))	('rat', 'Species', '10116', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('occurred', 'Reg', (16, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))
675835	31164716	In both cases, alterations largely occurred due to amplifications.	('alterations', 'Reg', (15, 26))	('amplifications', 'Var', (51, 65))	('occurred', 'Reg', (35, 43))	('rat', 'Species', '10116', (19, 22))
675842	31164716	This analysis confirmed the statistical significance of the co-occurrence of alterations in PROM1 and each gene in the associated set (Fig.	('alterations', 'Var', (77, 88))	('rat', 'Species', '10116', (81, 84))	('PROM1', 'Gene', (92, 97))
675843	31164716	A similar analysis was performed for PROM2, which also shows the statistically significant co-occurrence of alterations of each pair of PROM2 and its partner genes (Fig.	('rat', 'Species', '10116', (112, 115))	('PROM2', 'Gene', (136, 141))	('alterations', 'Var', (108, 119))
675849	31164716	Its dysregulation has a potential role in tumorigenesis.	('dysregulation', 'Var', (4, 17))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
675881	31164716	PROM2 can cause cellular protrusions and enhance phosphorylation of caveolin-1 to promote endocytosis.	('caveolin-1', 'Gene', '857', (68, 78))	('PROM2', 'Var', (0, 5))	('enhance', 'PosReg', (41, 48))	('cellular protrusions', 'CPA', (16, 36))	('promote', 'PosReg', (82, 89))	('cause', 'Reg', (10, 15))	('phosphorylation', 'MPA', (49, 64))	('endocytosis', 'MPA', (90, 101))	('caveolin-1', 'Gene', (68, 78))
675891	31164716	In general, high PROM1 expression was associated with poor survival in mixed Ewing sarcoma and brain, esophageal, gastric, liver, and ovarian cancers.	('Ewing sarcoma', 'Disease', (77, 90))	('ovarian cancer', 'Phenotype', 'HP:0100615', (134, 148))	('esophageal', 'Disease', (102, 112))	('high', 'Var', (12, 16))	('ovarian cancers', 'Phenotype', 'HP:0100615', (134, 149))	('poor', 'NegReg', (54, 58))	('ovarian cancers', 'Disease', (134, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (77, 90))	('liver', 'Disease', (123, 128))	('brain', 'Disease', (95, 100))	('ovarian cancers', 'Disease', 'MESH:D010051', (134, 149))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (77, 90))	('PROM1', 'Gene', (17, 22))	('gastric', 'Disease', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('expression', 'MPA', (23, 33))
675894	31164716	For example, PROM1 upregulation has been reported in ovarian cancer and targeting this gene retards ovarian cancer development in an in vivo model.	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('retards ovarian cancer', 'Disease', (92, 114))	('ovarian cancer', 'Disease', (53, 67))	('retards ovarian cancer', 'Disease', 'MESH:D010051', (92, 114))	('upregulation', 'PosReg', (19, 31))	('PROM1', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancer', 'Disease', 'MESH:D010051', (100, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('targeting', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('men', 'Species', '9606', (122, 125))
675901	31164716	The results suggested that the co-expression of PROM1 and PROM2 may impact clinical outcomes in patients with certain types of cancers.	('PROM2', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('clinical outcomes', 'CPA', (75, 92))	('co-expression', 'Var', (31, 44))	('impact', 'Reg', (68, 74))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('PROM1', 'Gene', (48, 53))	('patients', 'Species', '9606', (96, 104))	('cancers', 'Disease', (127, 134))
675903	31164716	It is primarily influenced by four major factors - somatically acquired genetic, epigenetic, transcriptomic, and proteomic alterations.	('influenced', 'Reg', (16, 26))	('epigenetic', 'Var', (81, 91))	('rat', 'Species', '10116', (127, 130))
675904	31164716	Somatic loss-of-function or gain-of-function alterations occur in particular genomic regions involved in potential inhibitory or carcinogenic effects, respectively.	('alterations', 'Var', (45, 56))	('carcinogenic', 'Disease', 'MESH:D063646', (129, 141))	('carcinogenic', 'Disease', (129, 141))	('gain-of-function', 'PosReg', (28, 44))	('loss-of-function', 'NegReg', (8, 24))	('rat', 'Species', '10116', (49, 52))	('S', 'Chemical', 'MESH:D012694', (0, 1))
675905	31164716	Therefore, we used cBioPortal to determine human cancers with CNAs and mutations in prominin genes.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('prominin', 'Gene', (84, 92))	('mutations', 'Var', (71, 80))	('CNAs', 'Gene', (62, 66))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('human', 'Species', '9606', (43, 48))
675906	31164716	Mutations in PROM1 were mainly missense and truncating mutations, including p.R373C, p.Y452fsX12, p.G614fsX626, and p.Q576X in the prominin domain, which are associated with human inherited diseases.	('p.Q576X', 'Mutation', 'rs137853005', (116, 123))	('p.R373C', 'Mutation', 'rs137853006', (76, 83))	('human', 'Species', '9606', (174, 179))	('p.Y452fsX12', 'Mutation', 'rs543698823', (85, 96))	('p.Q576X', 'Var', (116, 123))	('inherited diseases', 'Disease', (180, 198))	('truncating', 'MPA', (44, 54))	('p.R373C', 'Var', (76, 83))	('PROM1', 'Gene', (13, 18))	('p.G614fsX626', 'Var', (98, 110))	('p.Y452fsX12', 'Var', (85, 96))	('inherited diseases', 'Disease', 'MESH:D030342', (180, 198))	('p.G614fsX626', 'Mutation', 'rs886037612', (98, 110))
675907	31164716	A recent study reported the identification of a point mutation at p.S281R (serine [S] changed to arginine [R] due the mutation of thymine [T] to guanine [G]) in the prominin domain of the PROM1 protein in 8/555 lung cancer patients.	('serine', 'Chemical', 'MESH:D012694', (75, 81))	('S', 'Chemical', 'MESH:D012694', (68, 69))	('thymine', 'Chemical', 'MESH:D013941', (130, 137))	('S', 'Chemical', 'MESH:D012694', (83, 84))	('guanine', 'Chemical', 'MESH:D006147', (145, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('arginine [R]', 'MPA', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('arginine', 'Chemical', 'MESH:D001120', (97, 105))	('p.S281R', 'Var', (66, 73))	('patients', 'Species', '9606', (223, 231))	('p.S281R', 'Mutation', 'rs182096110', (66, 73))	('lung cancer', 'Disease', (211, 222))
675908	31164716	In our systematic analysis, we also found several missense and truncating mutations within PROM1 and PROM2 protein-coding sequences, especially in the prominin domain, in various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PROM2', 'Gene', (101, 106))	('PROM1', 'Gene', (91, 96))	('truncating mutations', 'Var', (63, 83))	('missense', 'Var', (50, 58))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))
675910	31164716	Specifically, PROM1 mutations mainly occurred in uterine pan-cancer and consisted of several frame-shift insertion or deletion mutations in a hotspot at position p.N566Ifs*29/Kfs*2 in the prominin domain.	('p.N566Ifs*29', 'Var', (162, 174))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('deletion mutations', 'Var', (118, 136))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('consisted', 'Reg', (72, 81))	('cancer', 'Disease', (61, 67))	('frame-shift insertion', 'Var', (93, 114))	('occurred', 'Reg', (37, 45))	('PROM1', 'Gene', (14, 19))	('Kfs*2', 'Gene', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Kfs*2', 'Gene', '4222', (175, 180))	('mutations', 'Var', (20, 29))	('p.N566Ifs*29', 'FRAMESHIFT', 'None', (162, 174))
675911	31164716	PROM2 mutations were mainly found in skin cancers and predominantly consisted of point mutations of a hotspot at position p.Q508R and p.R582Q/W in the prominin domain.	('skin cancers', 'Disease', (37, 49))	('p.R582Q', 'Var', (134, 141))	('consisted', 'Reg', (68, 77))	('p.R582Q', 'SUBSTITUTION', 'None', (134, 141))	('skin cancer', 'Phenotype', 'HP:0008069', (37, 48))	('p.Q508R', 'Var', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('p.Q508R', 'Mutation', 'rs12992066', (122, 129))	('skin cancers', 'Disease', 'MESH:D012878', (37, 49))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('found', 'Reg', (28, 33))	('PROM2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('skin cancers', 'Phenotype', 'HP:0008069', (37, 49))
675912	31164716	These mutations have a potential role in the regulation of cancer progression and prognosis, but this is yet to be confirmed.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (6, 15))
675913	31164716	PPIs trigger the majority of biological processes, including signaling and disease development.	('signaling', 'CPA', (61, 70))	('disease development', 'CPA', (75, 94))	('biological processes', 'CPA', (29, 49))	('men', 'Species', '9606', (90, 93))	('trigger', 'Reg', (5, 12))	('PPIs', 'Var', (0, 4))
675914	31164716	With a cross-cancer viewpoint for both, as Subsequent analysis using cBioPortal showed that genetic alterations of the ten genes in the PROM1 and PROM2 signatures, mainly occurred in NEPC, with alteration frequencies of 25.27-52.34% and 20.2-44.9%, respectively.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('rat', 'Species', '10116', (104, 107))	('PROM2', 'Gene', (146, 151))	('PROM1', 'Gene', (136, 141))	('alterations', 'Var', (100, 111))	('rat', 'Species', '10116', (198, 201))	('cross-cancer', 'Disease', (7, 19))	('S', 'Chemical', 'MESH:D012694', (43, 44))	('cross-cancer', 'Disease', 'MESH:D009369', (7, 19))	('occurred', 'Reg', (171, 179))	('NEPC', 'Disease', (183, 187))
675940	32084010	PD-1 gene rs10204525 and rs7421861 polymorphisms are associated with increased risk and clinical features of esophageal cancer in a Chinese Han population Programmed death-1 (PD-1) polymorphisms have been associated with esophageal cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Programmed death-1', 'Gene', '5133', (155, 173))	('PD-1', 'Gene', (175, 179))	('PD-1', 'Gene', (0, 4))	('rs10204525', 'Mutation', 'rs10204525', (10, 20))	('PD-1', 'Gene', '5133', (175, 179))	('PD-1', 'Gene', '5133', (0, 4))	('esophageal cancer', 'Disease', (221, 238))	('rs7421861', 'Var', (25, 34))	('rs10204525', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('esophageal cancer', 'Disease', (109, 126))	('rs7421861', 'Mutation', 'rs7421861', (25, 34))	('associated', 'Reg', (205, 215))	('esophageal cancer', 'Disease', 'MESH:D004938', (221, 238))	('Programmed death-1', 'Gene', (155, 173))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
675941	32084010	Here, the aims of this case-control study were to explore whether three PD-1 polymorphisms (rs10204525, rs7421861, and rs36084323) were related with the risk and clinical features of esophageal cancer in Chinese Han subjects (n = 814 cases and 961 controls).	('rs7421861', 'Mutation', 'rs7421861', (104, 113))	('related', 'Reg', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('rs10204525', 'Mutation', 'rs10204525', (92, 102))	('esophageal cancer', 'Disease', (183, 200))	('PD-1', 'Gene', (72, 76))	('rs7421861', 'Var', (104, 113))	('rs36084323', 'Mutation', 'rs36084323', (119, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (183, 200))	('rs36084323', 'Var', (119, 129))	('rs10204525', 'Var', (92, 102))
675942	32084010	We found that rs10204525 and rs7421861, but not rs36084323, conferred increased susceptibility to esophageal cancer.	('rs36084323', 'Mutation', 'rs36084323', (48, 58))	('rs7421861', 'Mutation', 'rs7421861', (29, 38))	('rs10204525', 'Mutation', 'rs10204525', (14, 24))	('esophageal cancer', 'Disease', (98, 115))	('rs10204525', 'Var', (14, 24))	('susceptibility', 'Reg', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('rs7421861', 'Var', (29, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
675943	32084010	Subgroup analysis revealed that all three loci increased the risk of esophageal cancer among men, and that rs10204525 and rs7421861 correlated with increased risk among patients >= 60 years old.	('rs7421861', 'Var', (122, 131))	('patients', 'Species', '9606', (169, 177))	('esophageal cancer', 'Disease', (69, 86))	('rs10204525', 'Mutation', 'rs10204525', (107, 117))	('men', 'Species', '9606', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('rs7421861', 'Mutation', 'rs7421861', (122, 131))	('rs10204525', 'Var', (107, 117))	('increased', 'PosReg', (47, 56))
675944	32084010	The rs10204525 and rs7421861 polymorphisms were associated with higher TNM stage, and rs10204525 was associated with distant metastasis.	('TNM', 'Gene', (71, 74))	('rs10204525', 'Mutation', 'rs10204525', (4, 14))	('rs7421861', 'Mutation', 'rs7421861', (19, 28))	('rs10204525', 'Mutation', 'rs10204525', (86, 96))	('higher', 'PosReg', (64, 70))	('rs10204525', 'Var', (4, 14))	('TNM', 'Gene', '10178', (71, 74))	('rs10204525', 'Var', (86, 96))	('associated', 'Reg', (101, 111))	('distant metastasis', 'CPA', (117, 135))	('rs7421861', 'Var', (19, 28))
675945	32084010	The combination of smoking and either the rs10204525 or rs7421861 genotype conferred an increased risk to esophageal cancer, which is indicative of potential gene-environment interactions.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rs10204525', 'Var', (42, 52))	('rs7421861', 'Var', (56, 65))	('men', 'Species', '9606', (170, 173))	('rs7421861', 'Mutation', 'rs7421861', (56, 65))	('esophageal cancer', 'Disease', (106, 123))	('rs10204525', 'Mutation', 'rs10204525', (42, 52))
675946	32084010	The rs10204525 and rs7421861 polymorphisms correlated with increased PD-1 gene and protein levels, and Kaplan-Meier survival curves showed higher PD-1 gene expression was related to poorer overall survival.	('rs10204525', 'Mutation', 'rs10204525', (4, 14))	('rs7421861', 'Var', (19, 28))	('rs7421861', 'Mutation', 'rs7421861', (19, 28))	('overall survival', 'CPA', (189, 205))	('poorer', 'NegReg', (182, 188))	('increased PD', 'Phenotype', 'HP:0008151', (59, 71))	('PD-1', 'Gene', (146, 150))	('rs10204525', 'Var', (4, 14))	('expression', 'MPA', (156, 166))	('increased', 'PosReg', (59, 68))	('higher', 'PosReg', (139, 145))
675947	32084010	These data indicate the rs10204525 and rs7421861 polymorphisms of PD-1 gene confer an increased risk of esophageal cancer among Chinese Han individuals.	('rs10204525', 'Mutation', 'rs10204525', (24, 34))	('rs7421861', 'Var', (39, 48))	('rs7421861', 'Mutation', 'rs7421861', (39, 48))	('rs10204525', 'Var', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('PD-1', 'Gene', (66, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))
675957	32084010	Additional chemotherapy methods include capecitabine, S-1, infusional 5-fluorouracil (5-FU) and other 5-FU pro-drugs, and oxaliplatin or cisplatin.	('5-FU', 'Chemical', 'MESH:D005472', (102, 106))	('S-1', 'Var', (54, 57))	('capecitabine', 'Disease', (40, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('5-FU', 'Chemical', 'MESH:D005472', (86, 90))	('capecitabine', 'Chemical', 'MESH:D000069287', (40, 52))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (70, 84))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (122, 133))
675966	32084010	Interestingly, polymorphisms in the programmed death-1 (PD-1) gene (located in chromosome 2q37.3) have been associated with esophageal cancer risk and prognosis.	('esophageal cancer', 'Disease', (124, 141))	('programmed death-1', 'Gene', (36, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('programmed death-1', 'Gene', '5133', (36, 54))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('associated', 'Reg', (108, 118))	('PD-1', 'Gene', (56, 60))	('polymorphisms', 'Var', (15, 28))
675972	32084010	Biomarkers including density of tumor infiltrating lymphocyte, mismatch-repair deficiency, PD-L1 expression, and tumor mutational burden, predicted treatment effect of anti-PD-1 therapy.	('tumor', 'Disease', (113, 118))	('PD-L1', 'Gene', (91, 96))	('deficiency', 'Var', (79, 89))	('mismatch-repair', 'Protein', (63, 78))	('predicted', 'Reg', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('men', 'Species', '9606', (153, 156))	('PD-L1', 'Gene', '29126', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (32, 37))	('expression', 'MPA', (97, 107))
675973	32084010	PD-1 gene polymorphisms were associated with the risk of various cancers.	('PD-1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('polymorphisms', 'Var', (10, 23))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('associated', 'Reg', (29, 39))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))
675975	32084010	For example, the rs2227981, rs2227982, and rs3608432 polymorphisms were related to lung adenocarcinoma risk and prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('rs2227982', 'Mutation', 'rs2227982', (28, 37))	('rs3608432', 'Mutation', 'rs3608432', (43, 52))	('lung adenocarcinoma', 'Disease', (83, 102))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('rs2227981', 'Mutation', 'rs2227981', (17, 26))	('rs3608432', 'Var', (43, 52))	('related', 'Reg', (72, 79))	('rs2227982', 'Var', (28, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('rs2227981', 'Var', (17, 26))
675977	32084010	The PD-1.5 C/T polymorphism increased the risk of cervical, lung, gastric, colon, thyroid cancers.	('increased', 'PosReg', (28, 37))	('colon', 'Disease', (75, 80))	('thyroid cancers', 'Disease', 'MESH:D013964', (82, 97))	('gastric', 'Disease', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PD-1.5', 'Gene', (4, 10))	('colon', 'Disease', 'MESH:D015179', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('polymorphism', 'Var', (15, 27))	('lung', 'Disease', (60, 64))	('cervical', 'Disease', (50, 58))	('thyroid cancers', 'Disease', (82, 97))
675978	32084010	The rs2227982 C>T polymorphism associated with gastric cardia adenocarcinoma risk.	('rs2227982', 'Mutation', 'rs2227982', (4, 13))	('rs2227982 C>T', 'Var', (4, 17))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (47, 76))	('associated', 'Reg', (31, 41))	('gastric cardia adenocarcinoma', 'Disease', (47, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
675980	32084010	mentioned that PD-1 gene polymorphisms may regulate the breast cancer susceptibility and prognosis in Chinese individuals, while inconsistent findings were obtained in the study by Haghshenas et al..	('regulate', 'Reg', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('polymorphisms', 'Var', (25, 38))	('prognosis', 'CPA', (89, 98))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('PD-1', 'Gene', (15, 19))	('men', 'Species', '9606', (0, 3))
675981	32084010	Data summarized that PD-1 rs11568821 and rs2227981 polymorphisms decreased the overall cancer risk, and PD-1 rs7421861 polymorphism was associated with an increased risk of overall cancer.	('rs11568821', 'Var', (26, 36))	('cancer', 'Disease', (87, 93))	('rs7421861', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('decreased', 'NegReg', (65, 74))	('PD-1', 'Gene', (21, 25))	('rs7421861', 'Mutation', 'rs7421861', (109, 118))	('rs11568821', 'Mutation', 'rs11568821', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('PD-1', 'Gene', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('rs2227981', 'Mutation', 'rs2227981', (41, 50))	('rs2227981', 'Var', (41, 50))
675982	32084010	No significant association between some SNPs (rs2227982, rs10204525, rs36084323, and rs2890658 polymorphisms) and overall cancer risk was obtained.	('rs2890658', 'Var', (85, 94))	('rs36084323', 'Mutation', 'rs36084323', (69, 79))	('rs36084323', 'Var', (69, 79))	('rs2227982', 'Var', (46, 55))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('rs2227982', 'Mutation', 'rs2227982', (46, 55))	('rs2890658', 'Mutation', 'rs2890658', (85, 94))	('rs10204525', 'Mutation', 'rs10204525', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('rs10204525', 'Var', (57, 67))
675985	32084010	The aims of this case-control study were to investigate whether three PD-1 gene polymorphisms (rs10204525, rs36084323, and rs7421861) were related with esophageal cancer risk and clinical features in Chinese subjects.	('rs36084323', 'Mutation', 'rs36084323', (107, 117))	('rs10204525', 'Var', (95, 105))	('related', 'Reg', (139, 146))	('rs36084323', 'Var', (107, 117))	('esophageal cancer', 'Disease', (152, 169))	('rs7421861', 'Var', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('rs7421861', 'Mutation', 'rs7421861', (123, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('PD-1', 'Gene', (70, 74))	('rs10204525', 'Mutation', 'rs10204525', (95, 105))
675990	32084010	We evaluated the associations between three polymorphisms in PD-1 (rs10204525, rs7421861, and rs36084323) and the risk of esophageal cancer.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('rs36084323', 'Var', (94, 104))	('PD-1', 'Gene', (61, 65))	('rs36084323', 'Mutation', 'rs36084323', (94, 104))	('rs7421861', 'Var', (79, 88))	('rs10204525', 'Mutation', 'rs10204525', (67, 77))	('rs7421861', 'Mutation', 'rs7421861', (79, 88))	('rs10204525', 'Var', (67, 77))	('associations', 'Interaction', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
675991	32084010	The distributions of the genotypes of the PD-1 variants among the case and control populations are presented in Table 2 and Supplementary Figure 1.	('variants', 'Var', (47, 55))	('men', 'Species', '9606', (130, 133))	('PD-1', 'Gene', (42, 46))
675992	32084010	The GG genotype of rs10204525 polymorphism increased the risk of esophageal cancer compared to the more common AA genotype (GG vs. AA: adjusted odds ratio [OR] = 1.65, 95% confidence interval [CI] = 1.12-2.45; P = 0.012).	('rs10204525', 'Var', (19, 29))	('esophageal cancer', 'Disease', (65, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('increased', 'PosReg', (43, 52))	('rs10204525', 'Mutation', 'rs10204525', (19, 29))
675993	32084010	The TT genotype of rs7421861 was related with a 1.45-fold higher risk of esophageal cancer compared to the CC genotype (TT vs. CC: OR = 1.45, 95% CI = 1.06-1.99); P = 0.022).	('rs7421861', 'Mutation', 'rs7421861', (19, 28))	('esophageal cancer', 'Disease', (73, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rs7421861', 'Var', (19, 28))
675994	32084010	We did not observe an association between rs36084323 polymorphism and esophageal cancer risk.	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('rs36084323', 'Var', (42, 52))	('rs36084323', 'Mutation', 'rs36084323', (42, 52))
675997	32084010	The association between rs10204525 polymorphism and the esophageal cancer risk was stronger among men, those who smoked or consumed alcohol, and those >= 60 years old (Table 3).	('rs10204525', 'Mutation', 'rs10204525', (24, 34))	('esophageal cancer', 'Disease', (56, 73))	('rs10204525', 'Var', (24, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('stronger', 'PosReg', (83, 91))	('men', 'Species', '9606', (98, 101))	('alcohol', 'Chemical', 'MESH:D000438', (132, 139))
675998	32084010	The rs7421861 polymorphism demonstrated a significant association with esophageal cancer risk among men and among smokers (Table 3).	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('men', 'Species', '9606', (100, 103))	('rs7421861', 'Var', (4, 13))	('rs7421861', 'Mutation', 'rs7421861', (4, 13))	('esophageal cancer', 'Disease', (71, 88))
675999	32084010	The rs36084323 polymorphism was only related to esophageal cancer risk among men.	('rs36084323', 'Mutation', 'rs36084323', (4, 14))	('esophageal cancer', 'Disease', (48, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('related', 'Reg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('men', 'Species', '9606', (77, 80))	('rs36084323', 'Var', (4, 14))
676000	32084010	Finally, rs10204525 and rs7421861 polymorphisms increased the risk of ESCC (Supplementary Tables 1 and 2).	('increased', 'PosReg', (48, 57))	('ESCC', 'Disease', 'MESH:D000077277', (70, 74))	('rs10204525', 'Mutation', 'rs10204525', (9, 19))	('rs7421861', 'Var', (24, 33))	('rs7421861', 'Mutation', 'rs7421861', (24, 33))	('rs10204525', 'Var', (9, 19))	('ESCC', 'Disease', (70, 74))	('men', 'Species', '9606', (82, 85))
676001	32084010	We next analyzed the joint effects of the PD-1 polymorphisms and either smoking or alcohol consumption on esophageal cancer risk (Table 4).	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('polymorphisms', 'Var', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PD-1', 'Gene', (42, 46))	('alcohol', 'Chemical', 'MESH:D000438', (83, 90))	('esophageal cancer', 'Disease', (106, 123))
676002	32084010	The GG genotype of rs10204525 did not confer an increased risk to esophageal cancer.	('rs10204525', 'Var', (19, 29))	('esophageal cancer', 'Disease', (66, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rs10204525', 'Mutation', 'rs10204525', (19, 29))
676004	32084010	However, smokers with the GG genotype of rs10204525 polymorphism showed an increased risk of esophageal cancer compared to non-smokers with the AA genotype (OR = 1.93, 95% CI = 1.13-3.28; P = 0.014).	('rs10204525', 'Mutation', 'rs10204525', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('rs10204525', 'Var', (41, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))
676006	32084010	The TT genotype of rs7421861 was also not associated with an increased risk of esophageal cancer.	('rs7421861', 'Mutation', 'rs7421861', (19, 28))	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('rs7421861', 'Var', (19, 28))
676007	32084010	However, smokers with the TT genotype of rs7421861 had a significantly increased risk of esophageal cancer.	('esophageal cancer', 'Disease', (89, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rs7421861', 'Var', (41, 50))	('rs7421861', 'Mutation', 'rs7421861', (41, 50))
676009	32084010	We next investigated the relationship between PD-1 gene polymorphisms and the clinical characteristics of esophageal cancer patients (Table 5).	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('investigated', 'Reg', (8, 20))	('PD-1', 'Gene', (46, 50))	('polymorphisms', 'Var', (56, 69))	('esophageal cancer', 'Disease', (106, 123))	('patients', 'Species', '9606', (124, 132))
676010	32084010	The GG genotype of rs10204525 polymorphism increased the risk of distant metastasis (OR = 2.21, 95% CI = 1.16-4.23; P = 0.014) and higher TNM stage (OR = 1.81, 95% CI = 1.05-3.12; P = 0.032).	('rs10204525', 'Var', (19, 29))	('distant metastasis', 'CPA', (65, 83))	('TNM', 'Gene', '10178', (138, 141))	('rs10204525', 'Mutation', 'rs10204525', (19, 29))	('TNM', 'Gene', (138, 141))
676011	32084010	The AG genotype of rs10204525 was related to an increased risk of ESCC (OR = 1.61, 95% CI = 1.05-2.46; P = 0.029).	('rs10204525', 'Var', (19, 29))	('ESCC', 'Disease', 'MESH:D000077277', (66, 70))	('rs10204525', 'Mutation', 'rs10204525', (19, 29))	('ESCC', 'Disease', (66, 70))
676012	32084010	Finally, the TT genotype of rs7421861was associated with higher TNM stage.	('higher', 'PosReg', (57, 63))	('TNM', 'Gene', (64, 67))	('rs7421861was', 'Var', (28, 40))	('rs7421861', 'Mutation', 'rs7421861', (28, 37))	('TNM', 'Gene', '10178', (64, 67))
676013	32084010	The PD-1 expression levels were measured by qRT-PCR and ELISA in 150 esophageal cancer patients with different genotypes of rs10204525 and rs7421861 polymorphisms.	('rs7421861', 'Mutation', 'rs7421861', (139, 148))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('rs10204525', 'Mutation', 'rs10204525', (124, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('expression levels', 'MPA', (9, 26))	('rs10204525', 'Var', (124, 134))	('patients', 'Species', '9606', (87, 95))	('rs7421861', 'Var', (139, 148))
676016	32084010	Thus, the mutant genotype of rs10204525 or rs7421861 polymorphism might contribute to worse survival of esophageal cancer patients by increasing the PD-1 expression.	('rs7421861', 'Var', (43, 52))	('increasing', 'PosReg', (134, 144))	('rs7421861', 'Mutation', 'rs7421861', (43, 52))	('rs10204525', 'Mutation', 'rs10204525', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('PD-1', 'Protein', (149, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('patients', 'Species', '9606', (122, 130))	('rs10204525', 'Var', (29, 39))	('contribute', 'Reg', (72, 82))	('expression', 'MPA', (154, 164))
676017	32084010	In this study, we investigated the relationship between PD-1 gene variants and the risk of esophageal cancer and found PD-1 gene rs7421861 and rs10204525 polymorphisms increased the risk of esophageal cancer in Chinese individuals.	('rs7421861', 'Var', (129, 138))	('rs10204525', 'Mutation', 'rs10204525', (143, 153))	('increased', 'PosReg', (168, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs7421861', 'Mutation', 'rs7421861', (129, 138))	('polymorphisms', 'Var', (154, 167))	('esophageal cancer', 'Disease', (190, 207))	('esophageal cancer', 'Disease', 'MESH:D004938', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('esophageal cancer', 'Disease', (91, 108))	('rs10204525 polymorphisms', 'Var', (143, 167))	('PD-1', 'Gene', (119, 123))
676019	32084010	In addition, genotypes of rs10204525 and rs7421861 polymorphisms were shown to be associated with increased PD-1 gene and protein levels.	('rs10204525', 'Var', (26, 36))	('increased PD', 'Phenotype', 'HP:0008151', (98, 110))	('PD-1', 'Gene', (108, 112))	('increased', 'PosReg', (98, 107))	('rs7421861', 'Var', (41, 50))	('rs10204525', 'Mutation', 'rs10204525', (26, 36))	('rs7421861', 'Mutation', 'rs7421861', (41, 50))
676024	32084010	Overexpression of PD-1 was also observed in hepatocellular carcinoma and adjacent tissue, and was correlated with the rs10204525 polymorphism in PD-1.	('observed', 'Reg', (32, 40))	('rs10204525', 'Mutation', 'rs10204525', (118, 128))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (44, 68))	('PD-1', 'Gene', (18, 22))	('correlated', 'Reg', (98, 108))	('hepatocellular carcinoma', 'Disease', (44, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (44, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('rs10204525', 'Var', (118, 128))
676026	32084010	As reported, PD-1 gene rs2227982 C>T polymorphism other than rs10204525 A>G or rs7421861 T>C polymorphism was associated with gastric cardia adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('PD-1 gene', 'Gene', (13, 22))	('rs7421861 T>C', 'Var', (79, 92))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (126, 155))	('associated', 'Reg', (110, 120))	('rs2227982', 'Mutation', 'rs2227982', (23, 32))	('rs7421861', 'Mutation', 'rs7421861', (79, 88))	('rs2227982 C>T', 'Var', (23, 36))	('rs10204525 A>G', 'Var', (61, 75))	('gastric cardia adenocarcinoma', 'Disease', (126, 155))	('rs10204525', 'Mutation', 'rs10204525', (61, 71))
676027	32084010	PD-1 was highly expressed on liver cancer tissues and adjacent tissues and the PD-1 level was remarkably associated with PD-1 gene rs10204525 polymorphism.	('polymorphism', 'Var', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('rs10204525', 'Mutation', 'rs10204525', (131, 141))	('PD-1', 'Gene', (121, 125))	('liver cancer', 'Disease', 'MESH:D006528', (29, 41))	('rs10204525 polymorphism', 'Var', (131, 154))	('liver cancer', 'Phenotype', 'HP:0002896', (29, 41))	('associated', 'Reg', (105, 115))	('liver cancer', 'Disease', (29, 41))	('PD-1 level', 'MPA', (79, 89))
676029	32084010	Moreover, the PD-L1 8923 A/C polymorphism and PD-1.5 C/T polymorphism are risky factors of non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('PD-L1', 'Gene', '29126', (14, 19))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (91, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('non-small cell lung cancer', 'Disease', (91, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('C/T polymorphism', 'Var', (53, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (95, 117))	('PD-1.5', 'Gene', (46, 52))	('PD-L1', 'Gene', (14, 19))	('polymorphism', 'Var', (57, 69))	('8923 A/C', 'Mutation', 'g.8923A>C', (20, 28))	('NSCLC', 'Disease', (119, 124))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (91, 117))
676030	32084010	Another study observed a significant link between the PD-1 gene rs2227982 polymorphism and breast cancer risk in northwest Chinese women.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('women', 'Species', '9606', (131, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('rs2227982 polymorphism', 'Var', (64, 86))	('polymorphism', 'Var', (74, 86))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('PD-1', 'Gene', (54, 58))	('rs2227982', 'Mutation', 'rs2227982', (64, 73))
676031	32084010	A meta-analysis concluded the PD-1 gene rs36084323 polymorphism decreased cancer risk among Asians.	('PD-1 gene', 'Gene', (30, 39))	('rs36084323 polymorphism', 'Var', (40, 63))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('rs36084323', 'Mutation', 'rs36084323', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('decreased', 'NegReg', (64, 73))
676032	32084010	The AA genotype of rs10204525 in PD-1 gene was previously associated with an increased risk of esophageal cancer and proposed to be a predictive biomarker for ESCC.	('rs10204525', 'Var', (19, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('rs10204525', 'Mutation', 'rs10204525', (19, 29))	('ESCC', 'Disease', 'MESH:D000077277', (159, 163))	('PD-1', 'Gene', (33, 37))	('esophageal cancer', 'Disease', (95, 112))	('ESCC', 'Disease', (159, 163))
676033	32084010	The rs36084323 T>C polymorphism previously reduced the risk of esophagogastric junction adenocarcinoma (EGJA) while the rs7421861 polymorphism increased the risk of EGJA in Chinese subjects.	('EGJA', 'Disease', 'MESH:C537006', (165, 169))	('rs36084323', 'Mutation', 'rs36084323', (4, 14))	('increased', 'PosReg', (143, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('rs7421861', 'Var', (120, 129))	('EGJA', 'Disease', 'MESH:C537006', (104, 108))	('rs7421861', 'Mutation', 'rs7421861', (120, 129))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (63, 102))	('esophagogastric junction adenocarcinoma', 'Disease', (63, 102))	('rs36084323 T>C', 'Var', (4, 18))	('EGJA', 'Disease', (165, 169))	('reduced', 'NegReg', (43, 50))	('esophagogastric junction adenocarcinoma', 'Disease', 'MESH:C537006', (63, 102))	('EGJA', 'Disease', (104, 108))
676034	32084010	In addition, the PD-1 Trs10204525Grs2227982Crs36084323Ars7421861 haplotype significantly associated with a decreased risk of EGJA.	('PD-1', 'Gene', (17, 21))	('EGJA', 'Disease', (125, 129))	('rs7421861', 'Mutation', 'rs7421861', (55, 64))	('Trs10204525Grs2227982Crs36084323Ars7421861', 'Var', (22, 64))	('decreased', 'NegReg', (107, 116))	('EGJA', 'Disease', 'MESH:C537006', (125, 129))	('rs36084323', 'Mutation', 'rs36084323', (44, 54))	('rs10204525', 'Mutation', 'rs10204525', (23, 33))	('rs2227982', 'Mutation', 'rs2227982', (34, 43))
676035	32084010	The rs10204525 polymorphism was not related to ESCC risk in the full cohort.	('rs10204525', 'Mutation', 'rs10204525', (4, 14))	('rs10204525', 'Var', (4, 14))	('ESCC', 'Disease', (47, 51))	('ESCC', 'Disease', 'MESH:D000077277', (47, 51))
676037	32084010	Here we found PD-1 rs10204525 and rs7421861 polymorphisms, but not rs36084323, increased the risk for esophageal cancer, which are obviously inconsistent with the above studies.	('rs10204525', 'Var', (19, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('rs36084323', 'Mutation', 'rs36084323', (67, 77))	('rs7421861', 'Var', (34, 43))	('PD-1', 'Gene', (14, 18))	('increased', 'Reg', (79, 88))	('rs7421861', 'Mutation', 'rs7421861', (34, 43))	('rs10204525', 'Mutation', 'rs10204525', (19, 29))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
676041	32084010	The rs10204525, rs36084323, rs7421861 polymorphisms increased the risk of esophageal cancer among men in our study.	('rs10204525', 'Mutation', 'rs10204525', (4, 14))	('increased', 'PosReg', (52, 61))	('rs7421861', 'Var', (28, 37))	('rs36084323', 'Var', (16, 26))	('rs36084323', 'Mutation', 'rs36084323', (16, 26))	('rs10204525', 'Var', (4, 14))	('esophageal cancer', 'Disease', (74, 91))	('rs7421861', 'Mutation', 'rs7421861', (28, 37))	('men', 'Species', '9606', (98, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
676042	32084010	Subgroup analysis revealed that rs10204525 polymorphism elevated the risk of esophageal cancer among patients who consumed alcohol and among patients >= 60 years old.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('elevated', 'PosReg', (56, 64))	('patients', 'Species', '9606', (101, 109))	('alcohol', 'Chemical', 'MESH:D000438', (123, 130))	('rs10204525', 'Mutation', 'rs10204525', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('patients', 'Species', '9606', (141, 149))	('rs10204525', 'Var', (32, 42))
676043	32084010	Cross-over analysis indicated that smoking in combination with either the rs10204525 or rs7421861 polymorphism significantly contributed to an increased risk of esophageal cancer.	('rs7421861', 'Var', (88, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('rs10204525', 'Var', (74, 84))	('rs7421861', 'Mutation', 'rs7421861', (88, 97))	('rs10204525', 'Mutation', 'rs10204525', (74, 84))	('esophageal cancer', 'Disease', (161, 178))
676044	32084010	Next, we explored the associations between PD-1 gene polymorphisms and clinical features of esophageal cancer.	('PD-1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('esophageal cancer', 'Disease', (92, 109))	('associations', 'Interaction', (22, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))	('polymorphisms', 'Var', (53, 66))
676045	32084010	It was found that rs7421861 and rs10204525 polymorphisms were associated with distant metastasis, and that rs7421861 was also associated with higher TNM stage.	('rs7421861', 'Mutation', 'rs7421861', (107, 116))	('associated', 'Reg', (126, 136))	('associated', 'Reg', (62, 72))	('TNM', 'Gene', '10178', (149, 152))	('distant metastasis', 'CPA', (78, 96))	('rs7421861', 'Var', (107, 116))	('rs7421861', 'Var', (18, 27))	('rs10204525', 'Mutation', 'rs10204525', (32, 42))	('TNM', 'Gene', (149, 152))	('rs7421861', 'Mutation', 'rs7421861', (18, 27))	('higher', 'PosReg', (142, 148))	('rs10204525', 'Var', (32, 42))
676046	32084010	However, rs36084323 polymorphism was not associated with esophageal cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs36084323', 'Mutation', 'rs36084323', (9, 19))	('esophageal cancer metastasis', 'Disease', (57, 85))	('rs36084323', 'Var', (9, 19))	('esophageal cancer metastasis', 'Disease', 'MESH:D009362', (57, 85))
676047	32084010	Interestingly, both the rs10204525 and rs7421861 polymorphisms were associated with higher PD-1 gene and plasma levels in esophageal cancer patients.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('rs10204525', 'Mutation', 'rs10204525', (24, 34))	('rs7421861', 'Var', (39, 48))	('PD-1', 'Gene', (91, 95))	('rs7421861', 'Mutation', 'rs7421861', (39, 48))	('rs10204525', 'Var', (24, 34))	('plasma levels', 'MPA', (105, 118))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('higher', 'PosReg', (84, 90))
676049	32084010	These results are in line with those of previous studies, which demonstrated associations between PD-L1 polymorphisms and poor prognosis and survival among lung cancer patients.	('poor prognosis', 'CPA', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PD-L1', 'Gene', (98, 103))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('patients', 'Species', '9606', (168, 176))	('PD-L1', 'Gene', '29126', (98, 103))	('polymorphisms', 'Var', (104, 117))	('associations', 'Interaction', (77, 89))	('lung cancer', 'Disease', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
676050	32084010	Thus, we assumed PD-1 gene variants increased the PD-1 gene levels, thereby contributing to esophageal cancer metastasis and worse survival.	('variants', 'Var', (27, 35))	('PD-1', 'Gene', (17, 21))	('esophageal cancer metastasis', 'Disease', (92, 120))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('PD-1 gene levels', 'MPA', (50, 66))	('worse', 'NegReg', (125, 130))	('increased', 'PosReg', (36, 45))	('contributing to', 'Reg', (76, 91))	('esophageal cancer metastasis', 'Disease', 'MESH:D009362', (92, 120))
676051	32084010	First, the limited sample size of this study could not exactly uncover the relationship of the PD-1 gene rs7421861, rs10204525, rs36084323 polymorphisms with esophageal cancer susceptibility.	('rs7421861', 'Var', (105, 114))	('rs36084323', 'Mutation', 'rs36084323', (128, 138))	('rs10204525', 'Var', (116, 126))	('PD-1 gene', 'Gene', (95, 104))	('rs36084323', 'Var', (128, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('rs7421861', 'Mutation', 'rs7421861', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('rs10204525', 'Mutation', 'rs10204525', (116, 126))	('esophageal cancer', 'Disease', (158, 175))
676053	32084010	Third, further functional analyses were necessary to uncover how the PD-1 gene polymorphisms affect esophageal cancer.	('esophageal cancer', 'Disease', (100, 117))	('affect', 'Reg', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('PD-1', 'Gene', (69, 73))	('polymorphisms', 'Var', (79, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))
676054	32084010	Fourth, we could not perform related experiments to explore the underlying mechanisms by which the PD-1 variants conferred an increased risk to esophageal cancer.	('PD-1', 'Gene', (99, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('variants', 'Var', (104, 112))	('men', 'Species', '9606', (43, 46))	('esophageal cancer', 'Disease', (144, 161))
676056	32084010	In summary, the rs7421861 and rs10204525 polymorphisms in PD-1 gene increase the risk of esophageal cancer in a Chinese Han population.	('rs10204525', 'Var', (30, 40))	('esophageal cancer', 'Disease', (89, 106))	('rs7421861', 'Var', (16, 25))	('rs7421861', 'Mutation', 'rs7421861', (16, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PD-1', 'Gene', (58, 62))	('increase', 'PosReg', (68, 76))	('rs10204525', 'Mutation', 'rs10204525', (30, 40))
676114	30450409	When administrated through drinking water or liquid diet, NNN administration resulted in oral, esophageal, and nasal tumors.10  An animal study investigated the carcinogenic effects of NNN enantiomers.11 In this study, it was demonstrated that S-NNN, when administered through drinking water, resulted in significantly higher rates of oral cavity tumors and esophageal tumors as compared to those receiving R-NNN.	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('nasal tumors', 'Disease', 'MESH:D009669', (111, 123))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('rat', 'Species', '10116', (326, 329))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('esophageal tumors', 'Disease', (358, 375))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('drinking water', 'Chemical', 'MESH:D060766', (277, 291))	('carcinogenic', 'Disease', (161, 173))	('nasal tumors', 'Disease', (111, 123))	('tumors', 'Disease', (347, 353))	('tumors', 'Disease', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (369, 375))	('rat', 'Species', '10116', (13, 16))	('esophageal tumors', 'Disease', 'MESH:D004938', (358, 375))	('nasal tumors', 'Phenotype', 'HP:0012720', (111, 123))	('rat', 'Species', '10116', (70, 73))	('carcinogenic', 'Disease', 'MESH:D063646', (161, 173))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (369, 375))	('R-NNN', 'Chemical', '-', (407, 412))	('rat', 'Species', '10116', (233, 236))	('esophageal tumors', 'Phenotype', 'HP:0100751', (358, 375))	('S-NNN', 'Chemical', 'MESH:C008655', (244, 249))	('higher', 'PosReg', (319, 325))	('drinking water', 'Chemical', 'MESH:D060766', (27, 41))	('S-NNN', 'Var', (244, 249))	('tumors', 'Disease', 'MESH:D009369', (369, 375))
676115	30450409	The S-NNN group had 4.5 oral cavity tumors per rat as compared to 0.25 per rat in those receiving the R enantiomer.	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('rat', 'Species', '10116', (75, 78))	('S-NNN', 'Var', (4, 9))	('S-NNN', 'Chemical', 'MESH:C008655', (4, 9))	('rat', 'Species', '10116', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
676136	30450409	When binding and mutation occurs at critical genes (ie, tumor suppressor), the mutations can result in carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('carcinoma', 'Disease', (103, 112))	('mutation', 'Var', (17, 25))	('binding', 'Interaction', (5, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinoma', 'Disease', 'MESH:D002277', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('mutations', 'Var', (79, 88))	('result in', 'Reg', (93, 102))
676183	28594085	The dose differences between Edose reconstructions and TPS calculations were within 3% for D95%, D98%, and Dmean in each PTV, with the exception that the D98% of the PTV-clinical target volume (CTV) in esophageal carcinoma cases was (3.21 +- 2.33)%.	('esophageal carcinoma', 'Disease', (202, 222))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (202, 222))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (202, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('D98%', 'Var', (154, 158))
676201	28594085	The values of the parameters applied in this study were c = 0.00013, mu 1 = 11.3000, mu 3 = 15.000, C r = 0.028, epsilon = 6.000, and sigma = 5.000.	('C r = 0.028', 'Var', (100, 111))	('mu 1', 'Gene', '2944', (69, 73))	('mu 1', 'Gene', (69, 73))	('sigma =', 'Var', (134, 141))	('c = 0.00013', 'Var', (56, 67))	('mu 3 =', 'Var', (85, 91))	('epsilon =', 'Var', (113, 122))
676214	28594085	CTV-N-L (or R) represents left (or right) of lymph nodes with a low risk of occult metastases.	('CTV-N-L', 'Var', (0, 7))	('occult metastases', 'Disease', (76, 93))	('occult metastases', 'Disease', 'MESH:D009362', (76, 93))
676221	28594085	For example, in NPC plans, the values of  Dmax were (-6.12 +- 5.28)% and (-2.41 +- 6.82)% for eye-lens-L and optic-nerve-L, respectively.	('-2.41', 'Var', (74, 79))	('NPC plans', 'Disease', 'MESH:D052556', (16, 25))	('NPC', 'Phenotype', 'HP:0100630', (16, 19))	('eye-lens-L', 'Disease', (94, 104))	('NPC plans', 'Disease', (16, 25))
676233	28380431	A six-miRNA signature including up-regulated miR-106a, miR-18a, miR-20b, miR-486-5p, miR-584 and down-regulated miR-223-3p in ESCC was identified.	('miR-584', 'Gene', '693169', (85, 92))	('miR-18a', 'Gene', (55, 62))	('up-regulated', 'PosReg', (32, 44))	('miR-20b', 'Gene', '574032', (64, 71))	('miR-223', 'Gene', '407008', (112, 119))	('miR-106a', 'Gene', '406899', (45, 53))	('miR-584', 'Gene', (85, 92))	('miR-20b', 'Gene', (64, 71))	('miR-18a', 'Gene', '406953', (55, 62))	('miR-106a', 'Gene', (45, 53))	('down-regulated', 'NegReg', (97, 111))	('miR-486-5p', 'Var', (73, 83))	('miR-223', 'Gene', (112, 119))
676245	28380431	Numerous studies have indicated that dysregulation of miRNAs is involved in the tumorigenesis and progression of various cancers.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancers', 'Disease', (121, 128))	('involved', 'Reg', (64, 72))	('dysregulation', 'Var', (37, 50))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('miRNAs', 'Protein', (54, 60))	('progression', 'CPA', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
676258	28380431	Combined results of the two stages showed that miR-106a, miR-18a, miR-20b, miR-486-5p and miR-584 were significantly up-regulated, while miR-223-3p was down-regulated in plasma of ESCC patients compared with NCs (Table 2; Figure 2).	('miR-20b', 'Gene', (66, 73))	('miR-584', 'Gene', (90, 97))	('miR-223', 'Gene', (137, 144))	('miR-106a', 'Gene', '406899', (47, 55))	('miR-486-5p', 'Var', (75, 85))	('up-regulated', 'PosReg', (117, 129))	('miR-18a', 'Gene', '406953', (57, 64))	('miR-584', 'Gene', '693169', (90, 97))	('miR-106a', 'Gene', (47, 55))	('miR-223', 'Gene', '407008', (137, 144))	('patients', 'Species', '9606', (185, 193))	('miR-20b', 'Gene', '574032', (66, 73))	('down-regulated', 'NegReg', (152, 166))	('miR-18a', 'Gene', (57, 64))	('ESCC', 'Disease', (180, 184))
676259	28380431	The data from the training and testing stage were combined to calculate the optimal cutoff values for miR-106a, miR-18a, miR-20b, miR-223-3p, miR-486-5p and miR-584.	('miR-486-5p', 'Var', (142, 152))	('miR-20b', 'Gene', '574032', (121, 128))	('miR-106a', 'Gene', '406899', (102, 110))	('miR-18a', 'Gene', '406953', (112, 119))	('miR-584', 'Gene', '693169', (157, 164))	('miR-223', 'Gene', '407008', (130, 137))	('miR-20b', 'Gene', (121, 128))	('miR-106a', 'Gene', (102, 110))	('miR-584', 'Gene', (157, 164))	('miR-18a', 'Gene', (112, 119))	('miR-223', 'Gene', (130, 137))
676260	28380431	The corresponding areas under the ROC curve (AUCs) were 0.639 (95% confidence interval (CI): 0.574-0.703), 0.661 (95% CI: 0.586-0.735), 0.627 (95% CI: 0.562-0.691), 0.649 (95% CI: 0.586-0.711), 0.688 (95% CI: 0.627-0.749) and 0.659 (95% CI: 0.595-0.723) for miR-106a, miR-18a, miR-20b, miR-223-3p, miR-486-5p and miR-584, respectively (Supplementary Figure 2 online).	('0.627', 'Var', (136, 141))	('miR-584', 'Gene', (313, 320))	('0.661', 'Var', (107, 112))	('miR-18a', 'Gene', (268, 275))	('miR-223', 'Gene', (286, 293))	('miR-486-5p', 'Var', (298, 308))	('miR-20b', 'Gene', '574032', (277, 284))	('miR-106a', 'Gene', '406899', (258, 266))	('miR-584', 'Gene', '693169', (313, 320))	('miR-106a', 'Gene', (258, 266))	('miR-20b', 'Gene', (277, 284))	('miR-18a', 'Gene', '406953', (268, 275))	('miR-223', 'Gene', '407008', (286, 293))
676264	28380431	MiR-106a, miR-18a, miR-20b, miR-486-5p and miR-584 were significantly up-regulated and miR-223-3p was down-regulated in plasma of ESCC patients which was identical to the results in the training and testing stage (Supplementary Table 3 online).	('down-regulated', 'NegReg', (102, 116))	('miR-18a', 'Gene', (10, 17))	('patients', 'Species', '9606', (135, 143))	('miR-20b', 'Gene', '574032', (19, 26))	('MiR-106a', 'Gene', (0, 8))	('miR-584', 'Gene', '693169', (43, 50))	('up-regulated', 'PosReg', (70, 82))	('ESCC', 'Disease', (130, 134))	('miR-223', 'Gene', (87, 94))	('miR-20b', 'Gene', (19, 26))	('miR-486-5p', 'Var', (28, 38))	('miR-584', 'Gene', (43, 50))	('miR-18a', 'Gene', '406953', (10, 17))	('miR-223', 'Gene', '407008', (87, 94))	('MiR-106a', 'Gene', '406899', (0, 8))
676268	28380431	The corresponding AUCs for ESCC patients with stage I, II and III were 0.92 (95% CI: 0.834-0.992), 0.925 (95% CI: 0.87-0.979) and 0.936 (95% CI: 0.9-0.972), respectively (Supplementary Figure 3 online).	('ESCC', 'Disease', (27, 31))	('0.936', 'Var', (130, 135))	('0.925', 'Var', (99, 104))	('patients', 'Species', '9606', (32, 40))
676274	28380431	While miR-20b and miR-486-5p were significantly down-regulated in exosomes from ESCC patients compared with NCs.	('exosomes', 'MPA', (66, 74))	('down-regulated', 'NegReg', (48, 62))	('patients', 'Species', '9606', (85, 93))	('miR-20b', 'Gene', '574032', (6, 13))	('miR-20b', 'Gene', (6, 13))	('ESCC', 'Disease', (80, 84))	('miR-486-5p', 'Var', (18, 28))
676288	28380431	In the following training and testing stages, a miRNA signature including five up-regulated (miR-106a, miR-18a, miR-20b, miR-486-5p and miR-584) and one down-regulated (miR-223-3p) plasma miRNAs were identified and could act as a biomarker in diagnosis of ESCC.	('up-regulated', 'PosReg', (79, 91))	('ESCC', 'Disease', (256, 260))	('miR-18a', 'Gene', (103, 110))	('miR-20b', 'Gene', '574032', (112, 119))	('miR-18a', 'Gene', '406953', (103, 110))	('miR-106a', 'Gene', '406899', (93, 101))	('miR-584', 'Gene', (136, 143))	('miR-223', 'Gene', (169, 176))	('down-regulated', 'NegReg', (153, 167))	('miR-20b', 'Gene', (112, 119))	('miR-486-5p', 'Var', (121, 131))	('miR-106a', 'Gene', (93, 101))	('miR-223', 'Gene', '407008', (169, 176))	('miR-584', 'Gene', '693169', (136, 143))
676298	28380431	High expression of miR-18a could promote proliferation of ESCC cells and predict worse outcomes of ESCC patients.	('promote', 'PosReg', (33, 40))	('miR-18a', 'Gene', '406953', (19, 26))	('High', 'Var', (0, 4))	('ESCC', 'Disease', (99, 103))	('miR-18a', 'Gene', (19, 26))	('ESCC', 'Disease', (58, 62))	('patients', 'Species', '9606', (104, 112))	('proliferation', 'CPA', (41, 54))
676303	28380431	On the other hand, down-regulation of miR-223-3p was also found in ESCC tissues, and ectopic expression of the miRNA could decrease migration and invasion of ESCC cells.	('ESCC', 'Disease', (67, 71))	('decrease', 'NegReg', (123, 131))	('down-regulation', 'NegReg', (19, 34))	('miRNA', 'Var', (111, 116))	('miR-223', 'Gene', (38, 45))	('ESCC', 'Disease', (158, 162))	('ectopic expression', 'Var', (85, 103))	('miR-223', 'Gene', '407008', (38, 45))
676317	28380431	Interestingly, miR-20b and miR-486-5p was down-regulated in exosomes of ESCC patients which was opposite to the expression levels of the two miRNAs in plasma.	('miR-20b', 'Gene', '574032', (15, 22))	('down-regulated', 'NegReg', (42, 56))	('patients', 'Species', '9606', (77, 85))	('miR-20b', 'Gene', (15, 22))	('miR-486-5p', 'Var', (27, 37))	('ESCC', 'Disease', (72, 76))
676319	28380431	We assumed that the majority of the four miRNAs (especially miR-20b and miR-486-5p) might bind to proteins in plasma of ESCC patients.	('bind', 'Interaction', (90, 94))	('miR-20b', 'Gene', '574032', (60, 67))	('ESCC', 'Disease', (120, 124))	('miR-20b', 'Gene', (60, 67))	('proteins', 'Protein', (98, 106))	('miR-486-5p', 'Var', (72, 82))	('patients', 'Species', '9606', (125, 133))
676377	28235650	Several mechanisms of impairment of cardial continence are attributed to sleeve, like lost of angle of His' flap valve, reduced lower esophageal sphincter (LES) pressure, cardial dilatation, damage of sling fibers, alteration of esophageal outflow secondary to increased intragastric pressure, etc.	('dilatation', 'Phenotype', 'HP:0002617', (179, 189))	('cardial dilatation', 'Disease', (171, 189))	('esophageal sphincter', 'Disease', (134, 154))	('lost', 'Var', (86, 90))	('esophageal outflow', 'MPA', (229, 247))	('esophageal sphincter', 'Disease', 'MESH:D009122', (134, 154))	('cardial dilatation', 'Phenotype', 'HP:0004942', (171, 189))	('impairment of cardial continence', 'Disease', 'MESH:D009422', (22, 54))	('increased intragastric pressure', 'Phenotype', 'HP:0007906', (261, 292))	('alteration', 'Reg', (215, 225))	('impairment of cardial continence', 'Disease', (22, 54))	('cardial continence', 'Phenotype', 'HP:0031064', (36, 54))	('damage', 'Var', (191, 197))	('reduced', 'NegReg', (120, 127))
676461	21679712	The 1 year outcomes of this trial demonstrated CE-D in 85.7% by intention-to-treat analysis (92.3% per protocol), CE-IM in 77.4% of subjects by intention-to-treat analysis (83.3% per protocol), and decreased rates of disease progression and cancer incidence in the treated groups.	('CE-D', 'Chemical', '-', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('CE-IM', 'Chemical', '-', (114, 119))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('decreased', 'NegReg', (198, 207))	('disease progression', 'CPA', (217, 236))	('CE-IM', 'Var', (114, 119))	('CE-D', 'Var', (47, 51))
676576	21679712	In conclusion, follow-up of the subjects from the AIM Dysplasia trial to an average of 3.05 years demonstrates that a high percentage of subjects with both low-grade and high-grade dysplasia retain complete eradication of dysplasia and intestinal metaplasia after treatment.	('AIM Dysplasia', 'Disease', 'MESH:D004476', (50, 63))	('dysplasia retain complete eradication of dysplasia and intestinal metaplasia', 'Disease', 'MESH:D008679', (181, 257))	('AIM Dysplasia', 'Disease', (50, 63))	('low-grade', 'Var', (156, 165))
676704	33341909	In advanced tumor stages, due to local (T3-T4) or regional extension (N1-3) the 5-year overall survival rates vary between 20 and 50%.	('T3-T4', 'Var', (40, 45))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))
676712	33341909	Trials using cetuximab instead of cisplatin as de-escalation strategy for HPV-positive OPSCC showed inferior 2-year overall survival rates for cetuximab compared to cisplatin.	('cetuximab', 'Chemical', 'MESH:D000068818', (13, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('OPSCC', 'Phenotype', 'HP:0012182', (87, 92))	('OPSCC', 'Disease', (87, 92))	('inferior', 'NegReg', (100, 108))	('cetuximab', 'Var', (143, 152))	('overall survival', 'MPA', (116, 132))	('HPV', 'Species', '10566', (74, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))	('cetuximab', 'Chemical', 'MESH:D000068818', (143, 152))
676726	33341909	Surgery may comprise resection of important swallowing structures, involving muscles and nerves leading to sensory-motor dysfunction and incoordination of swallowing, whereas (C)RT may lead to other pathophysiological changes.	('resection', 'Var', (21, 30))	('lead to', 'Reg', (185, 192))	('incoordination', 'Phenotype', 'HP:0002311', (137, 151))	('incoordination', 'Disease', 'MESH:D001259', (137, 151))	('sensory-motor dysfunction', 'Disease', (107, 132))	('incoordination', 'Disease', (137, 151))	('sensory-motor dysfunction', 'Disease', 'MESH:D015417', (107, 132))	('leading to', 'Reg', (96, 106))
676729	33341909	Combined resections of the soft palate and tonsillar pillars may affect pharyngeal bolus transport causing nasopharyngeal reflux and pharyngeal residue.	('affect', 'Reg', (65, 71))	('soft palate', 'Disease', (27, 38))	('nasopharyngeal reflux', 'Disease', (107, 128))	('tonsillar pillars', 'Disease', 'MESH:D014067', (43, 60))	('soft palate', 'Disease', 'MESH:C562950', (27, 38))	('tonsillar pillars', 'Disease', (43, 60))	('pharyngeal reflux', 'Phenotype', 'HP:0002020', (111, 128))	('pharyngeal bolus transport', 'MPA', (72, 98))	('resections', 'Var', (9, 19))	('pharyngeal residue', 'Disease', (133, 151))
676744	33341909	HNC treatment can lead to lymphedema, fibrosis, and adhesion or synechia formation of the laryngeal mucosal membrane, which can compromise ventilation.	('lymphedema', 'Phenotype', 'HP:0001004', (26, 36))	('edema', 'Phenotype', 'HP:0000969', (31, 36))	('HNC', 'Phenotype', 'HP:0012288', (0, 3))	('lymphedema', 'Disease', (26, 36))	('adhesion', 'CPA', (52, 60))	('HNC treatment', 'Var', (0, 13))	('fibrosis', 'Disease', (38, 46))	('fibrosis', 'Disease', 'MESH:D005355', (38, 46))	('men', 'Species', '9606', (9, 12))	('synechia', 'Disease', (64, 72))	('lead to', 'Reg', (18, 25))	('lymphedema', 'Disease', 'MESH:D008209', (26, 36))	('synechia', 'Disease', 'MESH:D006175', (64, 72))
676882	33341909	Evidence suggests that such changes have further negative impacts on employment opportunities, ability to work and return to the workplace (see "Reimbursement of head and neck cancer related oropharyngeal dysphagia costs in European countries" section).	('employment opportunities', 'CPA', (69, 93))	('dysphagia costs', 'Disease', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('men', 'Species', '9606', (75, 78))	('dysphagia costs', 'Disease', 'MESH:D003680', (205, 220))	('men', 'Species', '9606', (154, 157))	('head and neck cancer', 'Phenotype', 'HP:0012288', (162, 182))	('changes', 'Var', (28, 35))	('dysphagia', 'Phenotype', 'HP:0002015', (205, 214))	('oropharyngeal dysphagia', 'Phenotype', 'HP:0200136', (191, 214))	('head and neck cancer', 'Disease', 'MESH:D006258', (162, 182))
677075	33341909	Neck dissections sacrificing the hypoglossal nerve, mandibular branch of the facial nerve, mylohyoid branches of the trigeminal nerve or the auricular branch of the facial nerve may also result in OD often with aspiration.	('OD often', 'Disease', (197, 205))	('hypoglossal nerve', 'Phenotype', 'HP:0011394', (33, 50))	('result in', 'Reg', (187, 196))	('OD', 'Phenotype', 'HP:0200136', (197, 199))	('aspiration', 'Phenotype', 'HP:0002835', (211, 221))	('aspiration', 'Disease', (211, 221))	('auricular branch of the facial nerve', 'Disease', (141, 177))	('auricular branch of the facial nerve', 'Disease', 'MESH:D004428', (141, 177))	('sacrificing', 'Var', (17, 28))	('dissections sacrificing', 'Var', (5, 28))	('auricular branch', 'Phenotype', 'HP:0030021', (141, 157))
677168	32319588	The Wnt/beta-catenin signaling pathway plays an important role in the process of cell proliferation and differentiation, while abnormal activation of this pathway can lead to tumor.	('cell proliferation', 'CPA', (81, 99))	('abnormal', 'Var', (127, 135))	('tumor', 'Disease', (175, 180))	('lead to', 'Reg', (167, 174))	('differentiation', 'CPA', (104, 119))	('activation', 'PosReg', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
677230	32319588	3C, cell proliferation was higher following DJ-1 overexpression compared with the control group, as the Edu staining was stronger.	('DJ-1', 'Gene', (44, 48))	('cell proliferation', 'CPA', (4, 22))	('overexpression', 'Var', (49, 63))	('higher', 'PosReg', (27, 33))	('stronger', 'PosReg', (121, 129))	('Edu staining', 'CPA', (104, 116))	('Edu', 'Chemical', '-', (104, 107))
677233	32319588	To further confirm the effects of DJ-1 in tumor metastasis and EMT of ESCC, lentivirus vectors encoding siRNAs targeting DJ-1 were used to knockdown DJ-1 expression in ECA-109 cells.	('knockdown', 'Var', (139, 148))	('tumor metastasis', 'Disease', 'MESH:D009362', (42, 58))	('tumor metastasis', 'Disease', (42, 58))	('DJ-1', 'Gene', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('DJ-1', 'Gene', (149, 153))
677239	32319588	7A, the proliferation of LV-DJ-1 cells treated with XAV939 was decreased compared with LV-DJ-1 cells.	('XAV939', 'Chemical', 'MESH:C544261', (52, 58))	('proliferation', 'CPA', (8, 21))	('decreased', 'NegReg', (63, 72))	('XAV939', 'Var', (52, 58))
677240	32319588	In the colony formation assay, cells treated with XAV939 had a significantly smaller number of colonies compared with the control LV-DJ-1 cells (P<0.01; Fig.	('colony formation assay', 'CPA', (7, 29))	('XAV939', 'Var', (50, 56))	('smaller', 'NegReg', (77, 84))	('XAV939', 'Chemical', 'MESH:C544261', (50, 56))
677241	32319588	In the Transwell assay, LV-DJ-1 cells treated with XAV939 demonstrated significantly reduced abilities to migrate and invade compared with LV-con group (P<0.01; Fig.	('XAV939', 'Var', (51, 57))	('reduced', 'NegReg', (85, 92))	('XAV939', 'Chemical', 'MESH:C544261', (51, 57))
677242	32319588	Similarly, the adhesion ability was significantly decreased in the XAV939 group compared with the LV-con group (P<0.01; Fig.	('decreased', 'NegReg', (50, 59))	('adhesion ability', 'CPA', (15, 31))	('XAV939', 'Var', (67, 73))	('XAV939', 'Chemical', 'MESH:C544261', (67, 73))
677243	32319588	Western blotting results demonstrated that XAV939 treatment could signifi-cantly increase the E-cadherin, while it significantly reduced the vimentin and N-cadherin expression levels compared with the untreated LV-DJ-1 cells (P<0.01; Fig.	('XAV939', 'Chemical', 'MESH:C544261', (43, 49))	('E-cadherin', 'Protein', (94, 104))	('XAV939', 'Var', (43, 49))	('vimentin', 'MPA', (141, 149))	('increase', 'PosReg', (81, 89))	('reduced', 'NegReg', (129, 136))
677244	32319588	7E), which indicates XAV939 inhibited the EMT process promoted by DJ-1.	('XAV939', 'Var', (21, 27))	('XAV939', 'Chemical', 'MESH:C544261', (21, 27))	('inhibited', 'NegReg', (28, 37))	('EMT process', 'CPA', (42, 53))	('DJ-1', 'Gene', (66, 70))
677246	32319588	7F), These data suggest XAV939 could reverse tumor malignant behavior induced by overexpression of DJ-1.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor malignant behavior', 'Disease', (45, 69))	('XAV939', 'Chemical', 'MESH:C544261', (24, 30))	('DJ-1', 'Gene', (99, 103))	('overexpression', 'PosReg', (81, 95))	('reverse', 'NegReg', (37, 44))	('XAV939', 'Var', (24, 30))	('tumor malignant behavior', 'Disease', 'MESH:D009369', (45, 69))
677252	32319588	Notably, liver metastases in the LV-DJ-1 group exhibited a larger volume and contained a larger number of nodules (Fig.	('LV-DJ-1', 'Var', (33, 40))	('larger', 'PosReg', (59, 65))	('liver metastases', 'Disease', (9, 25))	('larger', 'PosReg', (89, 95))	('liver metastases', 'Disease', 'MESH:D009362', (9, 25))
677266	32319588	A mutated Wnt pathway leads to multiple growth-related pathologies and cancer.	('leads to', 'Reg', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('mutated', 'Var', (2, 9))	('Wnt pathway', 'Pathway', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('growth-related pathologies', 'CPA', (40, 66))
677270	32319588	Tung et al identified that regulation of LRP6 could promote hepato-carcinogenesis and enhance cell invasion.	('hepato-carcinogenesis', 'Disease', (60, 81))	('enhance', 'PosReg', (86, 93))	('LRP6', 'Protein', (41, 45))	('hepato-carcinogenesis', 'Disease', 'MESH:D063646', (60, 81))	('regulation', 'Var', (27, 37))	('cell invasion', 'CPA', (94, 107))	('promote', 'PosReg', (52, 59))
677274	32319588	XAV939 is a novel small molecule inhibitor of the Wnt signaling pathway, which may restrain the abnormal activation of Wnt/beta-catenin and does not affect CRE, NF-kappaB or TGF-beta.	('TGF-beta', 'Gene', '7039', (174, 182))	('restrain', 'NegReg', (83, 91))	('NF-kappaB', 'Gene', '4790', (161, 170))	('XAV939', 'Var', (0, 6))	('NF-kappaB', 'Gene', (161, 170))	('XAV939', 'Chemical', 'MESH:C544261', (0, 6))	('Wnt/beta-catenin', 'Pathway', (119, 135))	('TGF-beta', 'Gene', (174, 182))	('activation', 'MPA', (105, 115))
677275	32319588	Guo et al  found that XAV939 could suppress the viability of small cell lung cancer NCI-H446 cells and induce apoptosis.	('viability', 'CPA', (48, 57))	('small cell lung cancer', 'Disease', 'MESH:D055752', (61, 83))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('induce', 'PosReg', (103, 109))	('XAV939', 'Var', (22, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('NCI-H446', 'CellLine', 'CVCL:1562', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('apoptosis', 'CPA', (110, 119))	('small cell lung cancer', 'Disease', (61, 83))	('suppress', 'NegReg', (35, 43))	('XAV939', 'Chemical', 'MESH:C544261', (22, 28))
677310	31467538	Regression after chemotherapy was determined using haematoxylin- and eosin-(H&E-) stained slides and rated according to the system devised by Becker et al.. Regression grades 1a and 1b were considered as having responded to therapy (responder group), while regression grade 3 was considered nonresponsive (nonresponder group).	('eosin', 'Chemical', 'MESH:D004801', (69, 74))	('haematoxylin', 'Chemical', 'MESH:D006416', (51, 63))	('having responded to', 'MPA', (204, 223))	('.. Regression grades', 'Var', (154, 174))	('H&E', 'Chemical', 'MESH:D006371', (76, 79))
677357	31467538	In ovarian cancer, chemoresistance is increased by modulation of specific calcium-regulated potassium channels.	('modulation', 'Var', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('chemoresistance', 'CPA', (19, 34))	('increased', 'PosReg', (38, 47))	('ovarian cancer', 'Disease', (3, 17))	('specific', 'Protein', (65, 73))
677373	31467538	Multiple analyses have focused on cell lines where overexpression is commonly associated with chemoresistance and knockdown restores chemo- and/or radio sensitivity and induces tumor cell apoptosis.	('chemoresistance', 'Disease', (94, 109))	('knockdown', 'Var', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('induces', 'Reg', (169, 176))	('chemo- and/or radio sensitivity', 'MPA', (133, 164))	('tumor', 'Disease', (177, 182))	('restores', 'PosReg', (124, 132))
677393	31467538	In addition, overexpression has been found to inhibit growth and proliferation in gastric cancer cell lines and esophageal squamous cell carcinoma.	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('esophageal squamous cell carcinoma', 'Disease', (112, 146))	('inhibit', 'NegReg', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('gastric cancer', 'Disease', (82, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (112, 146))	('overexpression', 'Var', (13, 27))
677405	30635339	Activation of WNT/beta-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNAs) in beta-catenin signaling elements including CTNNB1, APC, APC2, AXIN1, AXIN2; pathway prediction from RNAseq gene expression; and inverse correlation of beta-catenin protein levels with the T cell-inflamed gene expression signature.	('APC2', 'Gene', '10297', (197, 201))	('mutations', 'Var', (86, 95))	('AXIN1', 'Gene', '8312', (203, 208))	('APC', 'Disease', 'MESH:D011125', (192, 195))	('AXIN1', 'Gene', (203, 208))	('APC', 'Disease', (197, 200))	('CTNNB1', 'Gene', '1499', (184, 190))	('APC', 'Disease', (192, 195))	('AXIN2', 'Gene', (210, 215))	('AXIN2', 'Gene', '8313', (210, 215))	('beta-catenin', 'MPA', (142, 154))	('CTNNB1', 'Gene', (184, 190))	('alterations', 'Var', (119, 130))	('APC2', 'Gene', (197, 201))	('APC', 'Disease', 'MESH:D011125', (197, 200))
677408	30635339	Mutations of beta-catenin signaling molecules in non-T cell-inflamed tumors were enriched three-fold relative to T cell-inflamed tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Mutations', 'Var', (0, 9))	('beta-catenin', 'Protein', (13, 25))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
677410	30635339	This included target molecule expression from somatic mutations and/or SCNAs of beta-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased beta-catenin protein levels (20 tumors, 65%).	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('increased', 'PosReg', (169, 178))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('SCNAs', 'Var', (71, 76))	('14 tumors', 'Disease', 'OMIM:615513', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('14 tumors', 'Disease', (148, 157))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', (211, 217))	('beta-catenin protein levels', 'MPA', (179, 206))
677423	30635339	In syngeneic murine models of B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma, and Renca renal adenocarcinoma, blocking beta-catenin pathway signaling via RNA interference resulted in influx of CD8+ T cells and increase in interferon-gamma-associated gene targets.	('CD8', 'Gene', '925', (208, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (51, 68))	('carcinoma', 'Disease', 'MESH:D009369', (59, 68))	('carcinoma', 'Disease', (114, 123))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('neuroblastoma', 'Disease', (78, 91))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (103, 123))	('murine', 'Species', '10090', (13, 19))	('neuroblastoma', 'Phenotype', 'HP:0003006', (78, 91))	('blocking', 'Var', (125, 133))	('influx', 'PosReg', (198, 204))	('carcinoma', 'Disease', 'MESH:D009369', (114, 123))	('CD8', 'Gene', (208, 211))	('neuroblastoma', 'Disease', 'MESH:D009447', (78, 91))	('increase', 'PosReg', (225, 233))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('beta-catenin pathway signaling', 'Pathway', (134, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('carcinoma', 'Disease', (59, 68))	('Renca renal adenocarcinoma', 'Disease', 'MESH:C538614', (97, 123))	('Renca renal adenocarcinoma', 'Disease', (97, 123))	('interferon-gamma', 'Gene', '15978', (237, 253))	('interferon-gamma', 'Gene', (237, 253))	('RNA interference', 'MPA', (169, 185))
677437	30635339	In this system, the threshold for non-T cell-inflamed and T cell-inflamed tumors was beta0 = 0.1.	('beta0 =', 'Var', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
677439	30635339	As each gene score has values of -1, 0, or +1, the summation of all gene scores ranges from -160 (if all genes are downregulated) to +160 (if all genes are upregulated), where tumors of < -80 score summation were categorized as non-T cell-inflamed, > +80 score summation as T-cell inflamed, and the rest as intermediate.	('> +80 score summation', 'Var', (249, 270))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('downregulated', 'NegReg', (115, 128))	('upregulated', 'PosReg', (156, 167))	('non-T cell-inflamed', 'Disease', (228, 247))
677450	30635339	Combining all cancer types within TCGA, 3137/9244 (33.9%) samples showed a non-T cell-inflamed gene expression signature, with 2946/9244 (31.9%) scoring as intermediate and 3161/9244 (34.2%) displaying the T cell-inflamed phenotype (Supplementary Figure 2).	('cancer', 'Disease', (14, 20))	('3161/9244', 'Var', (173, 182))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))
677459	30635339	beta-catenin pathway activation was addressed on three levels: somatic mutations or copy number alterations in CTNNB1 and other regulators predicted to yield pathway activation, expression of downstream target genes indicative of beta-catenin signaling, and beta-catenin protein levels as assessed by reverse phase protein array (RPPA).	('CTNNB1', 'Gene', '1499', (111, 117))	('activation', 'PosReg', (166, 176))	('expression', 'MPA', (178, 188))	('mutations', 'Var', (71, 80))	('CTNNB1', 'Gene', (111, 117))	('beta-catenin protein levels', 'MPA', (258, 285))	('copy number alterations', 'Var', (84, 107))
677461	30635339	For CTNNB1, we defined relevant mutations as those affecting exon 3 (amino acid position 29 to 49) corresponding to the phosphorylation site by GSK3beta which normally leads to proteolytic degradation of beta-catenin (Figure 2A).	('leads to', 'Reg', (168, 176))	('CTNNB1', 'Gene', (4, 10))	('mutations', 'Var', (32, 41))	('proteolytic degradation', 'MPA', (177, 200))	('GSK3beta', 'Gene', (144, 152))	('GSK3beta', 'Gene', '2931', (144, 152))	('beta-catenin', 'MPA', (204, 216))	('CTNNB1', 'Gene', '1499', (4, 10))
677462	30635339	Across the aggregate TCGA cohort, we observed a statistically significant three-fold enrichment (p<0.0001, two-sided Fisher's exact test) of these mutations in non-T cell-inflamed versus T cell-inflamed tumors (Figure 2B, black bars).	('mutations', 'Var', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('non-T cell-inflamed', 'Disease', (160, 179))
677463	30635339	Mutations were most commonly missense mutations effecting serine or threonine residues as previously published.	('serine or threonine residues', 'MPA', (58, 86))	('serine', 'Chemical', 'MESH:D012694', (58, 64))	('Mutations', 'Var', (0, 9))	('missense mutations', 'Var', (29, 47))	('effecting', 'Reg', (48, 57))	('threonine', 'Chemical', 'MESH:D013912', (68, 77))
677466	30635339	Across non-T cell-inflamed tumors we observed 15.21% of samples as harboring mutations predicted to activate beta-catenin signaling, somatic CN alterations (SCNAs) in pathway genes or both (Figure 2C; Supplementary Figure 3A-B) as opposed to 10.06% in T cell-inflamed tumors (Supplementary Figure 3C-E).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('activate', 'PosReg', (100, 108))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (268, 274))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('mutations', 'Var', (77, 86))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('beta-catenin', 'MPA', (109, 121))	('pathway genes', 'Gene', (167, 180))
677467	30635339	These mutations and high-level SCNAs were predominately non-overlapping and were dominated by activating mutations in CTNNB1 and damaging mutations in APC.	('CTNNB1', 'Gene', '1499', (118, 124))	('APC', 'Disease', 'MESH:D011125', (151, 154))	('APC', 'Disease', (151, 154))	('damaging mutations', 'Var', (129, 147))	('mutations', 'Var', (105, 114))	('CTNNB1', 'Gene', (118, 124))
677468	30635339	Consistent with those disrupting GSK3beta-phosphorylation sites in exon 3, those additional mutations showed a strong anti-correlation with the T cell-inflamed expression signature (10 in non-T cell-inflamed, 7 in intermediate, and 1 in T cell-inflamed group), potentially by reducing APC/AXIN1/AXIN2 binding or affecting ubiquitin-mediated protein degradation pathways.	('AXIN2', 'Gene', (295, 300))	('disrupting', 'NegReg', (22, 32))	('anti-correlation', 'MPA', (118, 134))	('affecting', 'Reg', (312, 321))	('AXIN2', 'Gene', '8313', (295, 300))	('GSK3beta', 'Gene', (33, 41))	('AXIN1', 'Gene', '8312', (289, 294))	('GSK3beta', 'Gene', '2931', (33, 41))	('mutations', 'Var', (92, 101))	('AXIN1', 'Gene', (289, 294))	('APC', 'Disease', 'MESH:D011125', (285, 288))	('reducing', 'NegReg', (276, 284))	('APC', 'Disease', (285, 288))	('binding', 'Interaction', (301, 308))	('ubiquitin-mediated protein degradation pathways', 'Pathway', (322, 369))
677469	30635339	We acknowledge our analysis is likely an underestimated assessment of somatic mutations that drive beta-catenin signaling activation, considering that mutations in genes other than CTNNB1, APC, APC2, AXIN1, and AXIN2 may also be contributors.	('CTNNB1', 'Gene', '1499', (181, 187))	('APC', 'Disease', (194, 197))	('beta-catenin signaling', 'MPA', (99, 121))	('APC2', 'Gene', '10297', (194, 198))	('CTNNB1', 'Gene', (181, 187))	('AXIN1', 'Gene', '8312', (200, 205))	('AXIN1', 'Gene', (200, 205))	('AXIN2', 'Gene', '8313', (211, 216))	('APC', 'Disease', (189, 192))	('APC', 'Disease', 'MESH:D011125', (189, 192))	('APC2', 'Gene', (194, 198))	('APC', 'Disease', 'MESH:D011125', (194, 197))	('mutations', 'Var', (151, 160))	('AXIN2', 'Gene', (211, 216))
677471	30635339	Across individual tumors, 19 cancer types showed a higher fraction of beta-catenin pathway mutations, high-level SCNAs or both associated with non-T cell-inflamed as compared with T cell-inflamed tumors (Figure 2D; Supplementary Figure 5).	('cancer', 'Disease', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('associated', 'Reg', (127, 137))	('non-T cell-inflamed', 'Disease', (143, 162))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('beta-catenin pathway', 'Pathway', (70, 90))	('mutations', 'Var', (91, 100))	('tumors', 'Disease', (18, 24))	('high-level SCNAs', 'Disease', (102, 118))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
677472	30635339	Additionally, we compared the expression of the T cell-inflamed gene expression signature with the fraction of beta-catenin pathway altered samples (mutations or high-level SCNA changes in CTNNB1, APC, APC2, AXIN1, and AXIN2) per tumor type (Supplementary Figure 6).	('tumor', 'Disease', (230, 235))	('APC', 'Disease', (197, 200))	('APC2', 'Gene', (202, 206))	('mutations', 'Var', (149, 158))	('APC2', 'Gene', '10297', (202, 206))	('AXIN2', 'Gene', (219, 224))	('AXIN2', 'Gene', '8313', (219, 224))	('APC', 'Disease', 'MESH:D011125', (202, 205))	('APC', 'Disease', (202, 205))	('AXIN1', 'Gene', '8312', (208, 213))	('CTNNB1', 'Gene', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('AXIN1', 'Gene', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('APC', 'Disease', 'MESH:D011125', (197, 200))	('CTNNB1', 'Gene', '1499', (189, 195))
677473	30635339	We found a weak and statistically in-significant correlation across TCGA and within specific tumor types, suggesting that direct genomic activation of beta-catenin by mutation or high-level SCNAs may not be the main driver of non-T cell-inflamed phenotype.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutation', 'Var', (167, 175))	('tumor', 'Disease', (93, 98))	('activation', 'PosReg', (137, 147))	('beta-catenin', 'Protein', (151, 163))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
677474	30635339	However, the results should be interpreted with caution considering the limited sample size for beta-catenin pathway mutations or high-level SCNAs within each tumor type.	('mutations', 'Var', (117, 126))	('beta-catenin pathway', 'Pathway', (96, 116))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
677488	30635339	From the 14 tumor types where WNT/beta-catenin activation by pathway analysis was observed, we identified 291/348 (83.6%) as mutated or copy number altered and activated in non-T cell-inflamed as compared with 127/225 (56.4%) in T cell-inflamed tumors (Supplemental Figure 11).	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('activated', 'PosReg', (160, 169))	('mutated', 'Var', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (245, 250))	('copy number altered', 'Var', (136, 155))	('tumor', 'Disease', (12, 17))	('tumors', 'Disease', (245, 251))
677489	30635339	This demonstrates a significantly higher concordance between mutated samples and activated samples with a low level of T cell inflammation (p<0.0001, odds ratio=3.93, two-sided Fisher's exact test).	('higher', 'PosReg', (34, 40))	('concordance', 'MPA', (41, 52))	('inflammation', 'Disease', 'MESH:D007249', (126, 138))	('mutated', 'Var', (61, 68))	('inflammation', 'Disease', (126, 138))	('low level of T cell', 'Phenotype', 'HP:0005403', (106, 125))
677501	30635339	We inferred beta-catenin pathway activation using three approaches: 1) somatic pathway mutations or high-level SCNAs, where 19 cancers showed a higher proportion of mutated samples in non-T cell-inflamed group relative to inflamed; 2) pathway target gene expression, where 14 cancers showed predicted beta-catenin activation based on upregulation of known target molecules in non-T cell-inflamed group relative to inflamed 3) beta-catenin protein level by RPPA, where 20 cancers showed significant anti-correlation between beta-catenin protein level and T-cell inflamed gene expression.	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (471, 477))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('cancers', 'Disease', (276, 283))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('anti-correlation', 'NegReg', (498, 514))	('cancers', 'Disease', 'MESH:D009369', (471, 478))	('cancers', 'Phenotype', 'HP:0002664', (471, 478))	('beta-catenin protein level', 'MPA', (426, 452))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancers', 'Disease', (471, 478))	('mutations', 'Var', (87, 96))
677505	30635339	Activating mutations in the beta-catenin gene itself, as well as inactivating mutations in negative regulators of the beta-catenin pathway, are likely restricted to the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('Activating mutations', 'Var', (0, 20))	('inactivating mutations', 'Var', (65, 87))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('beta-catenin gene', 'Gene', (28, 45))	('tumor', 'Disease', (169, 174))
677508	30635339	Future biomarker development to document the degree of beta-catenin pathway activation should incorporate somatic mutations and SCNAs of the pathway coupled with immunohistochemical analysis of CD8+ T cells along with stabilized beta-catenin protein levels within tumor cells.	('CD8', 'Gene', (194, 197))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('CD8', 'Gene', '925', (194, 197))	('mutations', 'Var', (114, 123))	('tumor', 'Disease', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (264, 269))
677518	30635339	In bladder cancer, activating mutations in FGFR3, as well as molecular evidence for PPAR-gamma activation, have been associated with the non-T cell-inflamed tumor microenvironment.	('tumor', 'Disease', (157, 162))	('activating', 'PosReg', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('associated', 'Reg', (117, 127))	('FGFR3', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('PPAR-gamma', 'Gene', (84, 94))	('activation', 'PosReg', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mutations', 'Var', (30, 39))	('FGFR3', 'Gene', '2261', (43, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('PPAR-gamma', 'Gene', '5468', (84, 94))
677528	30635339	We have analyzed activated WNT/beta-catenin signaling by somatic mutations, copy number alterations, gene expression, and reverse phase protein array showing a pan-cancer association of this signaling pathway with immune-exclusion.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('copy number alterations', 'Var', (76, 99))
677549	27716366	This suggests that modulating LPO may be an effective way to control the development of RE.	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('development of RE', 'CPA', (73, 90))	('modulating', 'Var', (19, 29))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('LPO', 'Protein', (30, 33))
677554	27716366	However, n-6 PUFA is believed to be a pro-inflammatory substance.	('PUFA', 'Gene', '9933', (13, 17))	('PUFA', 'Gene', (13, 17))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n-6', 'Var', (9, 12))	('n', 'Chemical', 'MESH:D009584', (9, 10))
677555	27716366	In this study, we observed the effect of intraperitoneally administered n-3 or n-6 PUFA on the expression of inflammatory factors and LPO indices, along with the underlying protective mechanisms, in rats with acute RE.	('n', 'Chemical', 'MESH:D009584', (42, 43))	('PUFA', 'Gene', (83, 87))	('n', 'Chemical', 'MESH:D009584', (131, 132))	('n-6', 'Var', (79, 82))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('LPO indices', 'Gene', (134, 145))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('expression', 'MPA', (95, 105))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('rats', 'Species', '10116', (199, 203))	('PUFA', 'Gene', '9933', (83, 87))	('n', 'Chemical', 'MESH:D009584', (189, 190))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (197, 198))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (163, 164))	('n', 'Chemical', 'MESH:D009584', (139, 140))	('n', 'Chemical', 'MESH:D009584', (170, 171))
677622	27716366	Ranked data was compared using LSD test and significant difference was found between n-3 PUFA and n-6 PUFA (P = 0.007), n-3 PUFA and control group (P = 0.042).	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('PUFA', 'Gene', '9933', (89, 93))	('n-3', 'Var', (85, 88))	('PUFA', 'Gene', '9933', (102, 106))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('PUFA', 'Gene', '9933', (124, 128))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('PUFA', 'Gene', (89, 93))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('PUFA', 'Gene', (102, 106))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('PUFA', 'Gene', (124, 128))	('n-3', 'Var', (120, 123))
677635	27716366	Its level was lowest in the n-3 PUFAs group and highest in the control group and a significant difference was found when compared with other groups (P < 0.05).	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('PUFAs', 'Chemical', 'MESH:D005231', (32, 37))	('n-3 PUFAs', 'Var', (28, 37))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('lowest', 'NegReg', (14, 20))	('n', 'Chemical', 'MESH:D009584', (65, 66))
677641	27716366	TC levels were significantly lower in the n-3 PUFAs group compared with other groups (P < 0.005), while no significant differences were found in other groups (P > 0.05, Table 5).	('PUFAs', 'Chemical', 'MESH:D005231', (46, 51))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('TC', 'Chemical', '-', (0, 2))	('n-3 PUFAs', 'Var', (42, 51))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('TC levels', 'MPA', (0, 9))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('lower', 'NegReg', (29, 34))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (139, 140))
677647	27716366	In this experiment, the morphological grading of the esophagus and histological grading H&E stained esophageal sections showed that esophageal damage and inflammation were markedly decreased in the n-3 PUFA group (P < 0.05), while the proportion of grade III damage in n-6 PUFAs group was significantly higher than other RE model groups (7/8, 87.5 %), which suggested that n-3 PUFA reduced inflammation and reflux-related damage, while n-6 PUFA increased inflammation.	('n', 'Chemical', 'MESH:D009584', (43, 44))	('PUFA', 'Gene', (377, 381))	('PUFA', 'Gene', (202, 206))	('n', 'Chemical', 'MESH:D009584', (391, 392))	('PUFA', 'Gene', (440, 444))	('n', 'Chemical', 'MESH:D009584', (298, 299))	('n', 'Chemical', 'MESH:D009584', (456, 457))	('and', 'CPA', (150, 153))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('PUFA', 'Gene', (273, 277))	('markedly', 'NegReg', (172, 180))	('inflammation', 'Disease', 'MESH:D007249', (455, 467))	('and reflux-related', 'MPA', (403, 421))	('n', 'Chemical', 'MESH:D009584', (192, 193))	('inflammation', 'Disease', 'MESH:D007249', (154, 166))	('reduced', 'MPA', (382, 389))	('n', 'Chemical', 'MESH:D009584', (446, 447))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('H&E', 'Chemical', '-', (88, 91))	('increased', 'MPA', (445, 454))	('n', 'Chemical', 'MESH:D009584', (198, 199))	('n', 'Chemical', 'MESH:D009584', (404, 405))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('PUFA', 'Gene', '9933', (377, 381))	('inflammation', 'Disease', 'MESH:D007249', (390, 402))	('PUFA', 'Gene', '9933', (202, 206))	('inflammation', 'Disease', (455, 467))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('PUFA', 'Gene', '9933', (440, 444))	('n', 'Chemical', 'MESH:D009584', (165, 166))	('n-6 PUFAs', 'Chemical', '-', (269, 278))	('n', 'Chemical', 'MESH:D009584', (373, 374))	('n', 'Chemical', 'MESH:D009584', (151, 152))	('n', 'Chemical', 'MESH:D009584', (436, 437))	('n', 'Chemical', 'MESH:D009584', (244, 245))	('n', 'Chemical', 'MESH:D009584', (292, 293))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (269, 270))	('inflammation', 'Disease', (154, 166))	('that', 'MPA', (127, 131))	('PUFA', 'Gene', '9933', (273, 277))	('esophageal damage', 'Disease', (132, 149))	('n', 'Chemical', 'MESH:D009584', (267, 268))	('n', 'Chemical', 'MESH:D009584', (466, 467))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('n', 'Chemical', 'MESH:D009584', (401, 402))	('inflammation', 'Disease', (390, 402))	('the', 'Var', (194, 197))	('esophageal damage', 'Disease', 'MESH:D004935', (132, 149))	('n', 'Chemical', 'MESH:D009584', (313, 314))	('n', 'Chemical', 'MESH:D009584', (155, 156))
677662	27716366	Moreover, IL-8 and IL-1beta consequently results in esophageal damage and RE progression.	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('esophageal damage', 'Disease', 'MESH:D004935', (52, 69))	('RE progression', 'CPA', (74, 88))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('IL-8', 'Gene', (10, 14))	('results in', 'Reg', (41, 51))	('esophageal damage', 'Disease', (52, 69))	('IL-1beta', 'Var', (19, 27))
677686	27716366	For example, ROS could induce the expression of IL-6, IL-1beta and IL-8 by activating NF-kB signaling and damage the esophageal mucosa.	('IL-1beta', 'Gene', (54, 62))	('expression', 'MPA', (34, 44))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('IL-8', 'Gene', (67, 71))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('damage', 'NegReg', (106, 112))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('activating', 'Reg', (75, 85))	('ROS', 'Var', (13, 16))	('NF-kB', 'Gene', (86, 91))	('induce', 'PosReg', (23, 29))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('NF-kB', 'Gene', '81736', (86, 91))	('IL-6', 'Gene', (48, 52))	('esophageal', 'MPA', (117, 127))
677694	27716366	On the contrary, the SOD level was significantly higher after n-3 PUFAs treatment, but not n-6 PUFAs, which suggested that n-3 PUFAs remove free radicals by up-regulating antioxidant mechanisms.	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('PUFAs', 'Chemical', 'MESH:D005231', (95, 100))	('PUFAs', 'Chemical', 'MESH:D005231', (127, 132))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('antioxidant mechanisms', 'MPA', (171, 193))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('up-regulating', 'PosReg', (157, 170))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('SOD level', 'MPA', (21, 30))	('free radicals', 'Chemical', 'MESH:D005609', (140, 153))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (180, 181))	('PUFAs', 'Chemical', 'MESH:D005231', (66, 71))	('n', 'Chemical', 'MESH:D009584', (188, 189))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('free radicals', 'MPA', (140, 153))	('n-6 PUFAs', 'Chemical', '-', (91, 100))	('n-3', 'Var', (62, 65))	('higher', 'PosReg', (49, 55))
677695	27716366	Additionally, n-3 PUFAs could inhibit pro-inflammatory factors induced by ROS and consequently inhibit acute RE.	('ROS', 'Protein', (74, 77))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('inhibit', 'NegReg', (30, 37))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('inhibit', 'NegReg', (95, 102))	('pro-inflammatory factors', 'MPA', (38, 62))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('acute RE', 'CPA', (103, 111))	('PUFAs', 'Chemical', 'MESH:D005231', (18, 23))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('n-3', 'Var', (14, 17))
677698	27716366	However, we found that the levels of TC and TG were significantly lower in n-3 PUFAs group compared with controls or other acute RE models (P < 0.05), which suggested that n-3 PUFAs had an effect on lowering TG and TC levels.	('n', 'Chemical', 'MESH:D009584', (75, 76))	('lowering', 'NegReg', (199, 207))	('TG', 'Chemical', 'MESH:D014280', (208, 210))	('n-3', 'Var', (75, 78))	('lower', 'NegReg', (66, 71))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('TC', 'Chemical', '-', (215, 217))	('n', 'Chemical', 'MESH:D009584', (15, 16))	('n', 'Chemical', 'MESH:D009584', (73, 74))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('levels', 'MPA', (27, 33))	('TC', 'Chemical', '-', (37, 39))	('PUFAs', 'Chemical', 'MESH:D005231', (176, 181))	('TC levels', 'MPA', (215, 224))	('n', 'Chemical', 'MESH:D009584', (197, 198))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n', 'Chemical', 'MESH:D009584', (205, 206))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('n', 'Chemical', 'MESH:D009584', (212, 213))	('PUFAs', 'Chemical', 'MESH:D005231', (79, 84))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('TG', 'Chemical', 'MESH:D014280', (44, 46))	('n', 'Chemical', 'MESH:D009584', (187, 188))
677773	26956511	In this study, we found no thoracic duct injury based on the above modifications of the TLE.	('thoracic duct injury', 'Disease', (27, 47))	('modifications', 'Var', (67, 80))	('TLE', 'Chemical', '-', (88, 91))
677830	23251087	This is potentially provided by the alteration in the structure of the docetaxel backbone and substitution of the hydroxyl groups by the dimethyloxy side chains causing alteration of the P-glycoprotein (P-gp) affinity characteristic of docetaxel which is thought to be responsible in part for the development of resistance to docetaxel and other taxanes.	('P-gp', 'Gene', '5243', (203, 207))	('substitution', 'Var', (94, 106))	('alteration', 'Reg', (169, 179))	('P-glycoprotein', 'Gene', '5243', (187, 201))	('P-glycoprotein', 'Gene', (187, 201))	('P-gp', 'Gene', (203, 207))	('alteration', 'Reg', (36, 46))	('men', 'Species', '9606', (304, 307))	('docetaxel', 'Chemical', 'MESH:D000077143', (71, 80))	('affinity', 'MPA', (209, 217))	('docetaxel', 'Chemical', 'MESH:D000077143', (236, 245))	('docetaxel', 'Chemical', 'MESH:D000077143', (326, 335))	('taxanes', 'Chemical', 'MESH:D043823', (346, 353))
677831	23251087	Furthermore the presence of the extra methyloxy side chains theoretically elicits the ability of cabazitaxel to cross the blood-brain barrier.	('cabazitaxel', 'Chemical', 'MESH:C552428', (97, 108))	('methyloxy', 'Protein', (38, 47))	('ability', 'MPA', (86, 93))	('presence', 'Var', (16, 24))	('elicits', 'Reg', (74, 81))
677846	23251087	Efficacy of DJ-927 was compared in vitro and in vivo to paclitaxel and docetaxel and DJ-927 was found to be more potent with higher cytotoxicity than paclitaxel and docetaxel in various tumor cell lines, but especially in P-gp-expressing tumor cell lines.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('paclitaxel', 'Chemical', 'MESH:D017239', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('P-gp', 'Gene', (222, 226))	('cytotoxicity', 'Disease', 'MESH:D064420', (132, 144))	('DJ-927', 'Chemical', 'MESH:C479543', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (238, 243))	('docetaxel', 'Chemical', 'MESH:D000077143', (71, 80))	('DJ-927', 'Chemical', 'MESH:C479543', (85, 91))	('higher', 'PosReg', (125, 131))	('DJ-927', 'Var', (85, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (150, 160))	('P-gp', 'Gene', '5243', (222, 226))	('cytotoxicity', 'Disease', (132, 144))	('docetaxel', 'Chemical', 'MESH:D000077143', (165, 174))
677848	23251087	In addition the intracellular accumulation of DJ-927 was much higher than those of paclitaxel or docetaxel, particularly in P-gp-positive cells.	('paclitaxel', 'Chemical', 'MESH:D017239', (83, 93))	('docetaxel', 'Chemical', 'MESH:D000077143', (97, 106))	('P-gp', 'Gene', '5243', (124, 128))	('DJ-927', 'Chemical', 'MESH:C479543', (46, 52))	('DJ-927', 'Var', (46, 52))	('higher', 'PosReg', (62, 68))	('intracellular accumulation', 'MPA', (16, 42))	('P-gp', 'Gene', (124, 128))
677849	23251087	Pharmacokinetic analysis in a human Phase I study with DJ-927 27 mg/m2 orally every 3 weeks showed that the median area under the curve (t = 0-168 hours) was 1752 +- 1355 ng/mL/hour and the half-life was 167 +- 77 hours.	('1752 +- 1355 ng/mL/hour', 'Var', (158, 181))	('DJ-927', 'Chemical', 'MESH:C479543', (55, 61))	('DJ-927', 'Gene', (55, 61))	('human', 'Species', '9606', (30, 35))
677851	23251087	The majority of 36 patients received cisplatin and gemcitabine before entering this study, the overall response rate was 5.6%, 47% of patients had disease stabilization for >6 weeks, median TTP was 97 days, and the median survival time 120 days.	('patients', 'Species', '9606', (19, 27))	('cisplatin', 'Var', (37, 46))	('gemcitabine', 'Chemical', 'MESH:C056507', (51, 62))	('disease stabilization', 'CPA', (147, 168))	('patients', 'Species', '9606', (134, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))
677855	23251087	The starting dose was DJ-927 18 mg/m2 and capecitabine 1,250 mg/m2/day with the plan to escalate the dose if tolerated and based on a prespecified protocol dose escalation schema.	('capecitabine', 'Chemical', 'MESH:D000069287', (42, 54))	('schema', 'Disease', 'None', (172, 178))	('DJ-927', 'Chemical', 'MESH:C479543', (22, 28))	('DJ-927', 'Var', (22, 28))	('schema', 'Disease', (172, 178))
677871	23251087	When compared to docetaxel in the second-line treatment of NSCLC, PPX produced similar survival rates with reduced alopecia, grade 3-4 neutropenia and febrile neutropenia, but increased grade 3-4 neurotoxicity rates.	('neutropenia', 'Phenotype', 'HP:0001875', (135, 146))	('neurotoxicity', 'Disease', (196, 209))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('docetaxel', 'Chemical', 'MESH:D000077143', (17, 26))	('increased', 'PosReg', (176, 185))	('men', 'Species', '9606', (51, 54))	('PPX', 'Chemical', 'MESH:C509139', (66, 69))	('reduced', 'NegReg', (107, 114))	('alopecia', 'MPA', (115, 123))	('neutropenia and febrile neutropenia', 'Disease', 'MESH:D009503', (135, 170))	('alopecia', 'Phenotype', 'HP:0001596', (115, 123))	('neurotoxicity', 'Disease', 'MESH:D020258', (196, 209))	('neutropenia', 'Phenotype', 'HP:0001875', (159, 170))	('PPX', 'Var', (66, 69))	('NSCLC', 'Disease', (59, 64))
677884	23251087	A Phase II RCT of gemcitabine +- EndoTAG-1 showed that the combination of gemcitabine with EndoTAG-1 in chemotherapy-naive locally advanced or metastatic pancreatic cancer was well tolerated with improved disease-control rate, PFS and OS compared to gemcitabine alone.	('gemcitabine', 'Chemical', 'MESH:C056507', (74, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('combination', 'Var', (59, 70))	('EndoTAG-1', 'Gene', (91, 100))	('gemcitabine', 'Chemical', 'MESH:C056507', (18, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('locally advanced', 'Disease', (123, 139))	('PFS', 'CPA', (227, 230))	('disease-control rate', 'CPA', (205, 225))	('gemcitabine', 'Chemical', 'MESH:C056507', (250, 261))	('improved', 'PosReg', (196, 204))	('pancreatic cancer', 'Disease', (154, 171))
677911	23251087	In the M109 mouse tumor model, DHA-paclitaxel was less toxic than paclitaxel and with greater therapeutic index possibly due to the alteration of the pharmacokinetics of the drug by the fatty acid and to increased area under the curve (AUC) in tumors and decreased AUC in normal cells.	('fatty acid', 'Chemical', 'MESH:D005227', (186, 196))	('DHA-paclitaxel', 'Chemical', 'MESH:C528070', (31, 45))	('area under the curve', 'MPA', (214, 234))	('increased', 'PosReg', (204, 213))	('AUC', 'MPA', (265, 268))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('paclitaxel', 'Chemical', 'MESH:D017239', (66, 76))	('tumor', 'Disease', (18, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (35, 45))	('alteration', 'Reg', (132, 142))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('pharmacokinetics', 'MPA', (150, 166))	('tumors', 'Disease', (244, 250))	('mouse', 'Species', '10090', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('DHA-paclitaxel', 'Var', (31, 45))	('tumor', 'Disease', (244, 249))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
677912	23251087	The concentrations of paclitaxel and DHA-paclitaxel were analyzed in vivo in mouse models (M109) and showed that DHA delivers paclitaxel to tumors; tumor AUCs were 61-fold higher for DHA-paclitaxel than for paclitaxel at equitoxic doses and eightfold higher at equimolar doses.	('paclitaxel', 'Chemical', 'MESH:D017239', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('DHA-paclitaxel', 'Chemical', 'MESH:C528070', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('higher', 'PosReg', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mouse', 'Species', '10090', (77, 82))	('DHA', 'Chemical', 'MESH:D004281', (37, 40))	('paclitaxel', 'Chemical', 'MESH:D017239', (41, 51))	('DHA-paclitaxel', 'Var', (183, 197))	('tumors', 'Disease', (140, 146))	('paclitaxel', 'Chemical', 'MESH:D017239', (207, 217))	('paclitaxel', 'Chemical', 'MESH:D017239', (126, 136))	('DHA', 'Chemical', 'MESH:D004281', (113, 116))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Disease', (148, 153))	('paclitaxel', 'Chemical', 'MESH:D017239', (22, 32))	('DHA', 'Chemical', 'MESH:D004281', (183, 186))	('DHA-paclitaxel', 'Chemical', 'MESH:C528070', (183, 197))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (140, 145))
677913	23251087	These findings were consistent with the increase in therapeutic index of DHA-paclitaxel relative to paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (100, 110))	('DHA-paclitaxel', 'Var', (73, 87))	('increase', 'PosReg', (40, 48))	('DHA-paclitaxel', 'Chemical', 'MESH:C528070', (73, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (77, 87))	('therapeutic index', 'MPA', (52, 69))
677918	23251087	The mean (+-standard deviation) area under the curve of unbound paclitaxel increased nonlinearly with dose from 0.089 +- 0.029 mug   hour/mL (at 660 mg/m2) to 0.624 +- 0.216 mug   hour/mL (at 1100 mg/m2), and was associated with the dose-limiting neutropenia.	('area', 'MPA', (32, 36))	('neutropenia', 'Disease', 'MESH:D009503', (247, 258))	('neutropenia', 'Phenotype', 'HP:0001875', (247, 258))	('unbound', 'MPA', (56, 63))	('paclitaxel', 'Chemical', 'MESH:D017239', (64, 74))	('neutropenia', 'Disease', (247, 258))	('increased', 'PosReg', (75, 84))	('0.624 +- 0.216 mug', 'Var', (159, 177))
677933	23251087	Safety results of the two drugs were acceptable, myelosuppression was more common with DHA-paclitaxel.	('DHA-paclitaxel', 'Var', (87, 101))	('DHA-paclitaxel', 'Chemical', 'MESH:C528070', (87, 101))	('myelosuppression', 'Disease', 'MESH:D001855', (49, 65))	('myelosuppression', 'Disease', (49, 65))
677936	23251087	In a Phase II study in malignant melanoma patients, the most common grade 3-4 toxicities of DHA-paclitaxel were neutropenia (10%), musculoskeletal pain (10%), while fatigue (73%), skin rash (70%), and diarrhea (60%) were the most common side effects.	('neutropenia', 'Phenotype', 'HP:0001875', (112, 123))	('neutropenia', 'Disease', 'MESH:D009503', (112, 123))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('diarrhea', 'Phenotype', 'HP:0002014', (201, 209))	('skin rash', 'Disease', 'MESH:D005076', (180, 189))	('DHA-paclitaxel', 'Chemical', 'MESH:C528070', (92, 106))	('skin rash', 'Phenotype', 'HP:0000988', (180, 189))	('fatigue', 'Disease', (165, 172))	('fatigue', 'Phenotype', 'HP:0012378', (165, 172))	('diarrhea', 'Disease', (201, 209))	('malignant melanoma', 'Phenotype', 'HP:0002861', (23, 41))	('musculoskeletal pain', 'Disease', (131, 151))	('malignant melanoma', 'Disease', 'MESH:D008545', (23, 41))	('musculoskeletal pain', 'Disease', 'MESH:D059352', (131, 151))	('neutropenia', 'Disease', (112, 123))	('diarrhea', 'Disease', 'MESH:D003967', (201, 209))	('patients', 'Species', '9606', (42, 50))	('fatigue', 'Disease', 'MESH:D005221', (165, 172))	('toxicities', 'Disease', 'MESH:D064420', (78, 88))	('skin rash', 'Disease', (180, 189))	('DHA-paclitaxel', 'Var', (92, 106))	('pain', 'Phenotype', 'HP:0012531', (147, 151))	('toxicities', 'Disease', (78, 88))	('malignant melanoma', 'Disease', (23, 41))
677939	23251087	Preclinical studies showed that BMS-184476 was not only innately more potent than paclitaxel in assays of tubulin polymerization and against taxane-sensitive neoplasms, but was also more active against tumors that were typically taxane resistant.	('taxane', 'Chemical', 'MESH:C080625', (141, 147))	('tubulin polymerization', 'MPA', (106, 128))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('neoplasms', 'Phenotype', 'HP:0002664', (158, 167))	('taxane', 'Chemical', 'MESH:C080625', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('paclitaxel', 'Chemical', 'MESH:D017239', (82, 92))	('neoplasms', 'Disease', 'MESH:D009369', (158, 167))	('BMS-184476', 'Var', (32, 42))	('neoplasms', 'Disease', (158, 167))
677941	23251087	This compound was also more active than paclitaxel against tumor cells with acquired taxane resistance mediated by tubulin mutations such as human ovarian cancer cells A2780/tax22 with taxane resistance caused by a tubulin mutation which express ninefold resistance to BMS-184467 and 32-fold to paclitaxel.	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('mediated by', 'Reg', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('ovarian cancer', 'Disease', 'MESH:D010051', (147, 161))	('taxane resistance', 'MPA', (85, 102))	('mutation', 'Var', (223, 231))	('taxane', 'Chemical', 'MESH:C080625', (85, 91))	('human', 'Species', '9606', (141, 146))	('paclitaxel', 'Chemical', 'MESH:D017239', (40, 50))	('caused by', 'Reg', (203, 212))	('paclitaxel', 'Chemical', 'MESH:D017239', (295, 305))	('tubulin', 'Gene', (115, 122))	('ovarian cancer', 'Disease', (147, 161))	('mutations', 'Var', (123, 132))	('taxane', 'Chemical', 'MESH:C080625', (185, 191))
677943	23251087	BMS-184476 was more soluble than conventional paclitaxel in water based solvents containing polyoxyethylated castor oil.	('more', 'PosReg', (15, 19))	('polyoxyethylated castor oil', 'Chemical', '-', (92, 119))	('paclitaxel', 'Chemical', 'MESH:D017239', (46, 56))	('BMS-184476', 'Var', (0, 10))	('water', 'Chemical', 'MESH:D014867', (60, 65))	('soluble', 'MPA', (20, 27))
677947	23251087	Preclinical studies were conducted and demonstrated that the BMS-184476 can enhance the effects of radiation in human lung cancer cells both in vitro and in vivo and also supported the hypothesis that a G2/M block is involved in the radiosensitization caused by the taxanes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BMS-184476', 'Var', (61, 71))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('taxanes', 'Chemical', 'MESH:D043823', (266, 273))	('effects of', 'MPA', (88, 98))	('lung cancer', 'Disease', (118, 129))	('enhance', 'PosReg', (76, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('human', 'Species', '9606', (112, 117))
677955	23251087	Weekly schedules of BMS-184476 were also evaluated with BMS-184476 IV on days 1, 8, and 15 without premedication, the maximum administered dose was 60 mg/m2/week, and the MTD was 50 mg/m2/week with neutropenia as the main toxicity and DLT.	('neutropenia', 'Disease', 'MESH:D009503', (198, 209))	('toxicity', 'Disease', 'MESH:D064420', (222, 230))	('toxicity', 'Disease', (222, 230))	('neutropenia', 'Phenotype', 'HP:0001875', (198, 209))	('BMS-184476', 'Var', (56, 66))	('neutropenia', 'Disease', (198, 209))
677959	23251087	In a Phase II study in patients with advanced NSCLC progressing or relapsing after >=1 prior chemotherapy regimen with BMS-184476 at a dose of 60 mg/m2 IV over 1 h every 21 days, 14.3% patients had PR and 58.9% stable disease.	('stable disease', 'Disease', (211, 225))	('BMS-184476', 'Var', (119, 129))	('men', 'Species', '9606', (110, 113))	('patients', 'Species', '9606', (23, 31))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('patients', 'Species', '9606', (185, 193))
677960	23251087	BMS-184476 was well tolerated at the dose of 60 mg/m2 and showed evidence of antitumor activity in previously treated NSCLC.	('BMS-184476', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('NSCLC', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('tumor', 'Disease', (81, 86))
677971	23251087	In a Phase II study of BMS-184476 and carboplatin, neutropenia was the DLT.	('neutropenia', 'Disease', (51, 62))	('BMS-184476', 'Var', (23, 33))	('carboplatin', 'Chemical', 'MESH:D016190', (38, 49))	('neutropenia', 'Disease', 'MESH:D009503', (51, 62))	('neutropenia', 'Phenotype', 'HP:0001875', (51, 62))
677974	23251087	The toxicities seen in the combination of BMS-184476 and doxorubicin include neutropenia (DLT), loss of appetite, asthenia, and mild, cumulative peripheral neuropathy.	('toxicities', 'Disease', (4, 14))	('asthenia', 'Disease', 'MESH:D001247', (114, 122))	('neutropenia', 'Phenotype', 'HP:0001875', (77, 88))	('asthenia', 'Disease', (114, 122))	('doxorubicin', 'Chemical', 'MESH:D004317', (57, 68))	('asthenia', 'Phenotype', 'HP:0025406', (114, 122))	('loss of appetite', 'Disease', (96, 112))	('BMS-184476', 'Var', (42, 52))	('toxicities', 'Disease', 'MESH:D064420', (4, 14))	('neutropenia', 'Disease', (77, 88))	('loss of appetite', 'Phenotype', 'HP:0004396', (96, 112))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (145, 166))	('neuropathy', 'Phenotype', 'HP:0009830', (156, 166))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (145, 166))	('peripheral neuropathy', 'Disease', (145, 166))	('neutropenia', 'Disease', 'MESH:D009503', (77, 88))	('loss of appetite', 'Disease', 'MESH:D001068', (96, 112))
677997	19149902	Survival of patients was followed up for two years after treatment and survival rate of patients with methylated APC promoter was compared with that of unmethylated patients.	('men', 'Species', '9606', (62, 65))	('patients', 'Species', '9606', (12, 20))	('methylated', 'Var', (102, 112))	('patients', 'Species', '9606', (88, 96))	('APC promoter', 'Gene', (113, 125))	('patients', 'Species', '9606', (165, 173))	('APC', 'Phenotype', 'HP:0005227', (113, 116))
677998	19149902	Assessment of APC promoter methylation revealed that normal tissues were unmethylated, while twenty out of forty five (44.4%) tumor tissues were hypermethylated either in one or both alleles of APC.	('tumor', 'Disease', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('APC', 'Phenotype', 'HP:0005227', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('APC', 'Phenotype', 'HP:0005227', (194, 197))	('hypermethylated', 'Var', (145, 160))	('men', 'Species', '9606', (6, 9))
677999	19149902	Analyzing two-year survival rate of patients with respect to promoter hypermethylation showed a lower rate of survival for patients with methylated APC promoter following their treatment.	('survival', 'MPA', (110, 118))	('patients', 'Species', '9606', (36, 44))	('methylated', 'Var', (137, 147))	('lower', 'NegReg', (96, 101))	('patients', 'Species', '9606', (123, 131))	('APC', 'Phenotype', 'HP:0005227', (148, 151))	('APC', 'Gene', (148, 151))	('men', 'Species', '9606', (182, 185))
678002	19149902	In addition, the higher rate of two-year survival for patients with unmethylated APC promoter as well as its relationship with tumor differentiation would suggest that this tumor suppressor could be an appropriate candidate molecular marker for evaluating tumor malignancy and predicting survival of patients subsequent to treatment.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', (127, 132))	('patients', 'Species', '9606', (54, 62))	('tumor malignancy', 'Disease', (256, 272))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('APC promoter', 'Gene', (81, 93))	('higher', 'PosReg', (17, 23))	('tumor', 'Disease', (173, 178))	('APC', 'Phenotype', 'HP:0005227', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('men', 'Species', '9606', (328, 331))	('unmethylated', 'Var', (68, 80))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor malignancy', 'Disease', 'MESH:D018198', (256, 272))	('tumor', 'Disease', (256, 261))	('patients', 'Species', '9606', (300, 308))
678005	19149902	Several genetic and epigenetic alterations have been suggested to play an important role in the carcinogenesis of esophageal and other gastrointestinal (GI) tumors; affecting different oncogenes, tumor suppressor genes, apoptosis regulating genes or mismatch repair genes such as APC, P53, P16, DCC, RB, MCC, BRCA and MTS1/CDK41 .	('tumor', 'Disease', (196, 201))	('BRCA', 'Gene', (309, 313))	('affecting', 'Reg', (165, 174))	('P53', 'Gene', (285, 288))	('oncogenes', 'Gene', (185, 194))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('MTS1', 'Gene', (318, 322))	('P53', 'Gene', '7157', (285, 288))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('MCC', 'Gene', '4163', (304, 307))	('P16', 'Gene', '1029', (290, 293))	('MCC', 'Gene', (304, 307))	('DCC', 'Gene', '1630', (295, 298))	('APC', 'Phenotype', 'HP:0005227', (280, 283))	('apoptosis regulating genes', 'Gene', (220, 246))	('P16', 'Gene', (290, 293))	('tumor', 'Disease', (157, 162))	('alterations', 'Var', (31, 42))	('BRCA', 'Gene', '672', (309, 313))	('mismatch repair genes', 'Gene', (250, 271))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('DCC', 'Gene', (295, 298))	('carcinogenesis of esophageal and other gastrointestinal (GI) tumors', 'Disease', 'MESH:D004067', (96, 163))	('MTS1', 'Gene', '1029', (318, 322))	('APC', 'Gene', (280, 283))
678006	19149902	Hypermethylation of CpG islands in promoter regions of genes is a common epigenetic event of gene silencing in both types of esophageal cancers and impacts a wide range of important genes such as those involved in matrix remodeling like TIMP3 , ligand dependent suppressor genes for instance DCC , cell adhesion genes including cadherins (CDH1) and integrins, cell cycle regulator genes such as p14, p16 , apoptosis associated genes like DAPK, DNA repair and mismatch repair genes such as MGM, hMLH1 , xenobiotic metabolism engaged genes for instance GSTP1  and nel-like1gene.	('GSTP1', 'Gene', '2950', (551, 556))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('p14', 'Gene', (395, 398))	('Hypermethylation', 'Var', (0, 16))	('GSTP1', 'Gene', (551, 556))	('xenobiotic metabolism', 'Disease', 'MESH:D008659', (502, 523))	('p16', 'Gene', (400, 403))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('CDH1', 'Gene', '999', (339, 343))	('silencing', 'NegReg', (98, 107))	('p16', 'Gene', '1029', (400, 403))	('xenobiotic metabolism', 'Disease', (502, 523))	('CDH1', 'Gene', (339, 343))	('nel-like1gene', 'Gene', (562, 575))	('esophageal cancers', 'Disease', (125, 143))	('TIMP3', 'Gene', (237, 242))	('TIMP3', 'Gene', '7078', (237, 242))	('DCC', 'Gene', '1630', (292, 295))	('MGM', 'Gene', (489, 492))	('hMLH1', 'Gene', (494, 499))	('hMLH1', 'Gene', '4292', (494, 499))	('p14', 'Gene', '1029', (395, 398))	('esophageal cancers', 'Disease', 'MESH:D004938', (125, 143))	('DCC', 'Gene', (292, 295))
678007	19149902	Epigenetic silencing of tumor suppressor genes has been shown to be associated with tumor invasiveness, growth, neovascularization, metastatic behavior and in particular, might be the cause of tumor recurrence after treatment, impacting overall patient survival.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('neovascularization', 'CPA', (112, 130))	('tumor invasiveness', 'Disease', 'MESH:D009369', (84, 102))	('growth', 'CPA', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (193, 198))	('patient', 'Species', '9606', (245, 252))	('metastatic behavior', 'CPA', (132, 151))	('tumor', 'Disease', (24, 29))	('tumor invasiveness', 'Disease', (84, 102))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('men', 'Species', '9606', (221, 224))	('Epigenetic silencing', 'Var', (0, 20))	('impacting', 'Reg', (227, 236))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('associated', 'Reg', (68, 78))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cause', 'Reg', (184, 189))
678013	19149902	This indicates that inactivation of APC plays a key role in the carcinogenesis of esophageal cancers and could be considered as a candidate molecular marker.	('carcinogenesis of esophageal cancers', 'Disease', (64, 100))	('inactivation', 'Var', (20, 32))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('carcinogenesis of esophageal cancers', 'Disease', 'MESH:D063646', (64, 100))	('APC', 'Protein', (36, 39))	('APC', 'Phenotype', 'HP:0005227', (36, 39))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
678015	19149902	While loss of heterozygosity along with mutational inactivation has been suggested for APC in esophageal cancer, nevertheless, mutations in APC are rare in this cancer.	('loss', 'NegReg', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('APC', 'Phenotype', 'HP:0005227', (140, 143))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('esophageal cancer', 'Disease', (94, 111))	('APC', 'Phenotype', 'HP:0005227', (87, 90))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (127, 136))
678016	19149902	Investigations have shown that inactivation of APC leads to increased beta-catenin transcriptional activity and subsequent loss of cellular growth control.	('APC', 'Gene', (47, 50))	('inactivation', 'Var', (31, 43))	('beta-catenin', 'Gene', (70, 82))	('beta-catenin', 'Gene', '1499', (70, 82))	('loss', 'NegReg', (123, 127))	('cellular growth control', 'CPA', (131, 154))	('increased', 'PosReg', (60, 69))	('APC', 'Phenotype', 'HP:0005227', (47, 50))
678018	19149902	In contrast, loss of APC results in nuclear accumulation of beta-catenin, which subsequently binds to Tcf-Lef (T cell factor/lymphoid enhancer factor) family of transcription factors, culminating in the activation of transcription and ultimately uncontrolled cell growth.	('APC', 'Phenotype', 'HP:0005227', (21, 24))	('APC', 'Gene', (21, 24))	('binds', 'Interaction', (93, 98))	('transcription', 'MPA', (217, 230))	('nuclear accumulation', 'MPA', (36, 56))	('beta-catenin', 'Gene', (60, 72))	('loss', 'Var', (13, 17))	('beta-catenin', 'Gene', '1499', (60, 72))	('activation', 'PosReg', (203, 213))	('Tcf-Lef', 'Gene', (102, 109))
678020	19149902	This is the first effort that has focused on epigenetic regulation of APC as an example of tumor suppressor genes such as P15INKb.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('P15INKb', 'Var', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('APC', 'Phenotype', 'HP:0005227', (70, 73))	('APC', 'Gene', (70, 73))	('tumor', 'Disease', (91, 96))
678064	19149902	In contrast, achievement of 98 bp amplification products for 20 out of 45 tumor tissues points out that 44.4% of tumor tissues are methylated either in one or both alleles of APC.	('tumor', 'Disease', (113, 118))	('APC', 'Phenotype', 'HP:0005227', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (74, 79))	('methylated', 'Var', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('men', 'Species', '9606', (20, 23))
678072	19149902	Among poorly differentiated tumors, 13 (41%) were methylated, while 19 (59%) were unmethylated.	('methylated', 'Var', (50, 60))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
678073	19149902	This condition was also true for moderately differentiated tissue samples in which 2 out of 5 (40%) tumors were methylated while 3(60%) others displayed unmethylated tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('methylated', 'Var', (112, 122))
678077	19149902	This statistic (X2 = 6.86), at 2 degree of freedom (df), revealed that there is a significant association (p < 0:001) between presence of hypermethylated APC promoter and mortality rate among SCCE patients.	('APC promoter', 'Protein', (154, 166))	('patients', 'Species', '9606', (197, 205))	('mortality', 'CPA', (171, 180))	('presence', 'Var', (126, 134))	('APC', 'Phenotype', 'HP:0005227', (154, 157))	('hypermethylated', 'Var', (138, 153))
678079	19149902	Moreover, as differentiation status turns from well to poor, survival rate of patients with methylated promoters increases, while the converse is true for unmethylated promoters.	('methylated promoters', 'Var', (92, 112))	('increases', 'PosReg', (113, 122))	('survival', 'CPA', (61, 69))	('patients', 'Species', '9606', (78, 86))
678083	19149902	Epigenetic regulation of gene expression through promoter methylation is one of the key means of controlling genes during development and also transcriptional silencing of tumor suppressor genes in cellular transformation.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('silencing', 'NegReg', (159, 168))	('tumor', 'Disease', (172, 177))	('Epigenetic', 'Var', (0, 10))	('men', 'Species', '9606', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
678085	19149902	The highest occurrence of methylation has been observed in GI cancers involving both sporadic and inherited types.	('methylation', 'Var', (26, 37))	('GI cancers', 'Disease', 'MESH:D009369', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('GI cancers', 'Disease', (59, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))
678087	19149902	Inactivation of APC has been shown to be an early event in tumorigenesis of colorectal and gastric cancer, as could be observed with histopathological examinations and particularly in intestinal tumors in which sufficient levels of DNA methyltransferase activity play a role in the early polyp formation in APCMin/+ mice.	('intestinal tumors', 'Disease', (184, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (59, 64))	('intestinal tumors', 'Disease', 'MESH:D007414', (184, 201))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('colorectal and gastric cancer', 'Disease', 'MESH:D013274', (76, 105))	('APC', 'Phenotype', 'HP:0005227', (307, 310))	('mice', 'Species', '10090', (316, 320))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('APC', 'Phenotype', 'HP:0005227', (16, 19))	('APC', 'Gene', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Inactivation', 'Var', (0, 12))
678090	19149902	Eads and colleagues have previously shown APC promoter hypermethylation in Barrett's epithelium, either in metaplasia, dysplasia and adenocarcinoma of esophagus.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('promoter hypermethylation', 'Var', (46, 71))	('adenocarcinoma of esophagus', 'Disease', (133, 160))	('APC', 'Phenotype', 'HP:0005227', (42, 45))	('APC', 'Gene', (42, 45))	('metaplasia, dysplasia', 'Disease', 'MESH:D008679', (107, 128))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (138, 160))	('adenocarcinoma of esophagus', 'Disease', 'MESH:C562730', (133, 160))
678092	19149902	Their study showed 92% hypermethylation of APC in adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('adenocarcinoma', 'Disease', 'MESH:D000230', (50, 64))	('APC', 'Protein', (43, 46))	('hypermethylation', 'Var', (23, 39))	('APC', 'Phenotype', 'HP:0005227', (43, 46))	('adenocarcinoma', 'Disease', (50, 64))
678095	19149902	Further study on the mucosa of patients at risk for developing Barrett's esophagus, a condition which progresses to adenocarcinoma of esophagus, has shown 88% methylation of APC promoter.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('adenocarcinoma of esophagus', 'Disease', (116, 143))	('APC', 'Phenotype', 'HP:0005227', (174, 177))	("Barrett's esophagus", 'Disease', (63, 82))	('patients', 'Species', '9606', (31, 39))	('adenocarcinoma of esophagus', 'Disease', 'MESH:C562730', (116, 143))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (121, 143))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (63, 82))	('methylation', 'Var', (159, 170))	('APC', 'Protein', (174, 177))
678096	19149902	Moreover, in recent studies APC methylation has been found to be an appropriate molecular marker for monitoring tumor recurrence in lung and bladder cancer in which the presence of hypermethylated APC in the serum of patients correlates with worse clinicopathological features of malignancy.	('malignancy', 'Disease', (280, 290))	('bladder cancer', 'Disease', (141, 155))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('lung', 'Disease', (132, 136))	('APC', 'Phenotype', 'HP:0005227', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('APC', 'Protein', (197, 200))	('malignancy', 'Disease', 'MESH:D009369', (280, 290))	('hypermethylated', 'Var', (181, 196))	('tumor', 'Disease', (112, 117))	('patients', 'Species', '9606', (217, 225))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))	('APC', 'Phenotype', 'HP:0005227', (197, 200))
678097	19149902	Results indicate that 44.4% of patients with SCCE exhibited hypermethylation in the APC promoter.	('APC promoter', 'Gene', (84, 96))	('exhibited', 'Reg', (50, 59))	('hypermethylation', 'Var', (60, 76))	('patients', 'Species', '9606', (31, 39))	('APC', 'Phenotype', 'HP:0005227', (84, 87))
678100	19149902	Achieving a 44.4% methylation of APC promoter might well point to the involvement of the same possible molecular alterations in the etiology of SCCE in the Iranian population as in other parts of the world.	('point', 'Reg', (57, 62))	('men', 'Species', '9606', (77, 80))	('SCCE', 'Disease', (144, 148))	('methylation', 'Var', (18, 29))	('APC', 'Phenotype', 'HP:0005227', (33, 36))	('involvement', 'Reg', (70, 81))
678104	19149902	In addition, inactivation of APC, which results in beta-catenin transcriptional activation, seems to be among prerequisites for esophageal carcinogenesis.	('inactivation', 'Var', (13, 25))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (128, 153))	('beta-catenin', 'Gene', '1499', (51, 63))	('transcriptional', 'MPA', (64, 79))	('esophageal carcinogenesis', 'Disease', (128, 153))	('APC', 'Phenotype', 'HP:0005227', (29, 32))	('APC', 'Gene', (29, 32))	('beta-catenin', 'Gene', (51, 63))	('activation', 'PosReg', (80, 90))
678106	19149902	Our study also shows lower survival rate of patients with APC hypermethylation.	('patients', 'Species', '9606', (44, 52))	('APC hypermethylation', 'Var', (58, 78))	('APC', 'Phenotype', 'HP:0005227', (58, 61))	('lower', 'NegReg', (21, 26))	('survival', 'MPA', (27, 35))
678107	19149902	The higher mortality rate of patients with methylated APC promoter indicates that APC is among determinant genes in esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (116, 141))	('patients', 'Species', '9606', (29, 37))	('esophageal carcinogenesis', 'Disease', (116, 141))	('APC', 'Phenotype', 'HP:0005227', (54, 57))	('APC', 'Phenotype', 'HP:0005227', (82, 85))	('APC', 'Gene', (54, 57))	('methylated', 'Var', (43, 53))
678114	19149902	Identifying correlation between differentiation status and APC promoter methylation in conjunction with lower survival rate of patients with hypermethylated APC promoter implies the importance of epigenetic control of tumor suppressor genes in the tumorigenesis of SCCE, as well as the significant indicatory role of APC hypermetylation for evaluating tumor malignancy and predicting survival of SCCE patients subsequent to treatment.	('APC', 'Phenotype', 'HP:0005227', (317, 320))	('tumor', 'Disease', (218, 223))	('APC', 'Phenotype', 'HP:0005227', (157, 160))	('tumor', 'Disease', (248, 253))	('tumor malignancy', 'Disease', (352, 368))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('patients', 'Species', '9606', (401, 409))	('tumor', 'Disease', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('SCCE', 'Disease', (265, 269))	('men', 'Species', '9606', (429, 432))	('APC', 'Gene', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('APC', 'Phenotype', 'HP:0005227', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('hypermethylated', 'Var', (141, 156))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('patients', 'Species', '9606', (127, 135))	('tumor malignancy', 'Disease', 'MESH:D018198', (352, 368))
678125	32252688	There was no significant homozygous loss and the most recurrent hemizygous deletion involved the B3GAT1 gene on chromosome 11q25.	('deletion', 'Var', (75, 83))	('B3GAT1', 'Gene', '27087', (97, 103))	('B3GAT1', 'Gene', (97, 103))
678142	32252688	Apart from copy number aberrations, mutational analyses have shown recurrent inactivating mutations in TP53, and NOTCH1 as well as activating events in PIK3CA.	('TP53', 'Gene', '7157', (103, 107))	('PIK3CA', 'Gene', '5290', (152, 158))	('cop', 'Gene', '114769', (11, 14))	('TP53', 'Gene', (103, 107))	('NOTCH1', 'Gene', '4851', (113, 119))	('NOTCH1', 'Gene', (113, 119))	('activating', 'PosReg', (131, 141))	('cop', 'Gene', (11, 14))	('PIK3CA', 'Gene', (152, 158))	('inactivating mutations', 'Var', (77, 99))
678143	32252688	A single genomic study, performed on African patients from Malawi, recapitulated patterns of gene mutations and copy number changes (gains of CCND1, TP63, MYC, ERBB2, EGFR, MYCL1 and losses of CDKN2A/CDKN2B), similar to those observed in Asian and North American ESCC patients .	('MYCL1', 'Gene', '4610', (173, 178))	('CDKN2B', 'Gene', '1030', (200, 206))	('gains', 'PosReg', (133, 138))	('cop', 'Gene', (112, 115))	('patients', 'Species', '9606', (45, 53))	('MYC', 'Gene', '4609', (155, 158))	('patients', 'Species', '9606', (268, 276))	('CDKN2A', 'Gene', (193, 199))	('ERBB2', 'Gene', (160, 165))	('CCND1', 'Gene', '595', (142, 147))	('EGFR', 'Gene', (167, 171))	('CCND1', 'Gene', (142, 147))	('TP63', 'Gene', (149, 153))	('ERBB2', 'Gene', '2064', (160, 165))	('losses', 'NegReg', (183, 189))	('CDKN2A', 'Gene', '1029', (193, 199))	('MYC', 'Gene', (173, 176))	('cop', 'Gene', '114769', (112, 115))	('CDKN2B', 'Gene', (200, 206))	('TP63', 'Gene', '8626', (149, 153))	('MYC', 'Gene', (155, 158))	('MYCL1', 'Gene', (173, 178))	('mutations', 'Var', (98, 107))	('EGFR', 'Gene', '1956', (167, 171))	('MYC', 'Gene', '4609', (173, 176))
678173	32252688	Although the function of the TPRG1 gene is not well established, amplification and/or activating mutations in Cis regulatory elements of this gene associated with its increased expression have recently been reported in diffuse large B-cell lymphomas, suggesting potential oncogenic activity.	('mutations', 'Var', (97, 106))	('TPRG1', 'Gene', (29, 34))	('lymphomas', 'Phenotype', 'HP:0002665', (240, 249))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (233, 249))	('activating', 'PosReg', (86, 96))	('increased', 'PosReg', (167, 176))	('lymphoma', 'Phenotype', 'HP:0002665', (240, 248))	('cell lymphoma', 'Phenotype', 'HP:0012191', (235, 248))	('amplification', 'Var', (65, 78))	('expression', 'MPA', (177, 187))	('lymphomas', 'Disease', (240, 249))	('TPRG1', 'Gene', '285386', (29, 34))	('lymphomas', 'Disease', 'MESH:D008223', (240, 249))
678187	32252688	Twenty-six tumor samples were assessed for Shank2, cortactin and cyclin D1 protein expression; of these, 22 cases had DNA gain of all three genes and 19/22 (86%) overexpressed Shank2 (score3), 16/22 (72%) overexpressed cortactin, while only 5/22 cases (22%) overexpressed cyclin D1, (score of 3).	('cyclin D1', 'Gene', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Shank2', 'Gene', '22941', (43, 49))	('cyclin D1', 'Gene', '595', (65, 74))	('Shank2', 'Gene', '22941', (176, 182))	('cortactin', 'Gene', '2017', (51, 60))	('DNA', 'Var', (118, 121))	('tumor', 'Disease', (11, 16))	('overexpressed', 'PosReg', (162, 175))	('Shank2', 'Gene', (43, 49))	('overexpressed', 'PosReg', (205, 218))	('cyclin D1', 'Gene', '595', (272, 281))	('cortactin', 'Gene', (219, 228))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cortactin', 'Gene', (51, 60))	('cyclin D1', 'Gene', (272, 281))	('cortactin', 'Gene', '2017', (219, 228))	('Shank2', 'Gene', (176, 182))
678194	32252688	Co-amplification of CTTN, SHANK2 and CCND1 genes has been reported previously in oral squamous cell carcinoma.	('CTTN', 'Gene', '2017', (20, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('SHANK2', 'Gene', (26, 32))	('SHANK2', 'Gene', '22941', (26, 32))	('oral squamous cell carcinoma', 'Disease', (81, 109))	('CCND1', 'Gene', (37, 42))	('reported', 'Reg', (58, 66))	('CCND1', 'Gene', '595', (37, 42))	('CTTN', 'Gene', (20, 24))	('Co-amplification', 'Var', (0, 16))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 109))
678212	32252688	CTTN gain/ increased expression alone has been associated with ESCC metastasis and functional studies further demonstrated that inhibition of CTTN expression decreased tumor growth and lung metastasis.	('CTTN', 'Gene', (142, 146))	('decreased tumor', 'Disease', 'MESH:D002303', (158, 173))	('CTTN', 'Gene', '2017', (142, 146))	('gain/', 'PosReg', (5, 10))	('expression', 'MPA', (21, 31))	('CTTN', 'Gene', (0, 4))	('ESCC', 'Disease', (63, 67))	('lung metastasis', 'CPA', (185, 200))	('decreased tumor', 'Disease', (158, 173))	('inhibition', 'Var', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('CTTN', 'Gene', '2017', (0, 4))
678220	32252688	Although this gene has not been linked to ESCC pathogenesis, its distal neighbor gene, TP63 showed gains in a wider peak region, in 20 of the 21 cases with gains at 3q28.	('gains', 'PosReg', (99, 104))	('ESCC', 'Disease', (42, 46))	('TP63', 'Gene', (87, 91))	('TP63', 'Gene', '8626', (87, 91))	('gains', 'Var', (156, 161))
678222	32252688	Of note, TPRG1 is highly expressed in normal esophageal tissue and an intergenic susceptibility locus (rs6791479) was identified in a genome-wide association study of cutaneous squamous cell carcinoma in between the TP63 and TPRG1 genes.	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('TP63', 'Gene', '8626', (216, 220))	('rs6791479', 'Mutation', 'rs6791479', (103, 112))	('cutaneous squamous cell carcinoma', 'Disease', (167, 200))	('TP63', 'Gene', (216, 220))	('TPRG1', 'Gene', '285386', (225, 230))	('TPRG1', 'Gene', (9, 14))	('rs6791479', 'Var', (103, 112))	('TPRG1', 'Gene', '285386', (9, 14))	('TPRG1', 'Gene', (225, 230))
678233	32252688	BAC Bacterial artificial chromosome ESCC Esophageal squamous carcinoma FFPE Formalin fixed paraffin embedded FISH Fluorescence in situ hybridisation GEO Gene Expression Omnibus GISTIC Genomic Identification of Significant Targets in Cancer IHC Immunohistochemistry PCR Polymerase chain reaction SCNV Somatic cop number variants SNP Single nucleotide polymorphism SSC Saline sodium citrate Supplementary information accompanies this paper at 10.1186/s12885-020-06788-3.	('variants', 'Var', (319, 327))	('Saline sodium citrate', 'Chemical', '-', (367, 388))	('squamous carcinoma', 'Disease', 'MESH:D002294', (52, 70))	('Cancer', 'Disease', 'MESH:D009369', (233, 239))	('cop', 'Gene', (308, 311))	('Cancer', 'Disease', (233, 239))	('squamous carcinoma', 'Disease', (52, 70))	('Formalin', 'Chemical', 'MESH:D005557', (76, 84))	('cop', 'Gene', '114769', (308, 311))	('Esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (41, 70))	('paraffin', 'Chemical', 'MESH:D010232', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('Cancer', 'Phenotype', 'HP:0002664', (233, 239))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (52, 70))
678238	31118947	Previous genome-wide association studies (GWAS) in Chinese populations have identified several ESCC susceptibility loci, including variants on chromosome 2q33 and 6p21, but the contribution of these loci to risk in African populations is unknown.	('variants', 'Var', (131, 139))	('ESCC', 'Disease', (95, 99))	('p21', 'Gene', (164, 167))	('p21', 'Gene', '644914', (164, 167))
678239	31118947	Variants at 2q33 (rs3769823, rs10931936, rs13016963, rs7578456, rs2244438) and 6p21 (rs911178, rs3763338, rs2844695, rs17533090, rs1536501) were genotyped in a set of Black Xhosa (463 cases and 480 controls) and Mixed Ancestry (269 cases and 288 controls) individuals.	('Mix', 'Gene', '83881', (212, 215))	('Mix', 'Gene', (212, 215))	('rs2244438', 'Mutation', 'rs2244438', (64, 73))	('rs911178', 'Var', (85, 93))	('rs3769823', 'Mutation', 'rs3769823', (18, 27))	('rs13016963', 'Mutation', 'rs13016963', (41, 51))	('rs7578456', 'Var', (53, 62))	('rs1536501', 'Mutation', 'rs1536501', (129, 138))	('p21', 'Gene', (80, 83))	('rs2844695', 'Mutation', 'rs2844695', (106, 115))	('p21', 'Gene', '644914', (80, 83))	('rs911178', 'Mutation', 'rs911178', (85, 93))	('rs3769823', 'Var', (18, 27))	('rs2844695', 'Var', (106, 115))	('rs17533090', 'Var', (117, 127))	('rs3763338', 'Mutation', 'rs3763338', (95, 104))	('rs10931936', 'Var', (29, 39))	('rs2244438', 'Var', (64, 73))	('rs1536501', 'Var', (129, 138))	('rs7578456', 'Mutation', 'rs7578456', (53, 62))	('rs13016963', 'Var', (41, 51))	('rs10931936', 'Mutation', 'rs10931936', (29, 39))	('rs17533090', 'Mutation', 'rs17533090', (117, 127))	('rs3763338', 'Var', (95, 104))
678241	31118947	The 2q33 variants rs10931936, rs7578456, and rs2244438 were marginally associated with higher risk of ESCC in the Mixed Ancestry population (ORs = 1.39-1.58, p <= 0.035), of which rs7578456 and rs2244438 remained significant after multiple correction (p < 0.005).	('rs7578456', 'Mutation', 'rs7578456', (180, 189))	('Mix', 'Gene', (114, 117))	('ESCC', 'Disease', (102, 106))	('Mix', 'Gene', '83881', (114, 117))	('rs10931936', 'Mutation', 'rs10931936', (18, 28))	('rs7578456', 'Mutation', 'rs7578456', (30, 39))	('rs2244438', 'Var', (45, 54))	('rs2244438', 'Mutation', 'rs2244438', (45, 54))	('rs7578456', 'Var', (30, 39))	('rs10931936', 'Var', (18, 28))	('rs2244438', 'Mutation', 'rs2244438', (194, 203))
678242	31118947	The associations with rs7578456 and rs2244438 were also observed across strata of tobacco smoking (ORs = 1.47-2.75, p <= 0.035) and alcohol consumption (ORs = 1.45-2.06, p <= 0.085) status.	('rs2244438', 'Var', (36, 45))	('tobacco', 'Species', '4097', (82, 89))	('rs7578456', 'Mutation', 'rs7578456', (22, 31))	('rs7578456', 'Var', (22, 31))	('alcohol', 'Chemical', 'MESH:D000438', (132, 139))	('rs2244438', 'Mutation', 'rs2244438', (36, 45))
678243	31118947	However, only the association with rs2244438, which lies within an exon of TRAK2, remained significant after adjustment for the other variants in the region.	('TRAK2', 'Gene', (75, 80))	('TRAK2', 'Gene', '66008', (75, 80))	('rs2244438', 'Var', (35, 44))	('rs2244438', 'Mutation', 'rs2244438', (35, 44))
678248	31118947	More than 200 xenobiotic-metabolizing enzymes are responsible for the metabolism and detoxification of dietary and environmental carcinogens, which if not removed, can bind to DNA and may lead to cancer causing mutations.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('mutations', 'Var', (211, 220))	('lead to', 'Reg', (188, 195))	('DNA', 'Protein', (176, 179))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('xenobiotic-', 'Phenotype', 'HP:0031838', (14, 25))	('bind', 'Interaction', (168, 172))
678250	31118947	The development of genome-wide association studies (GWAS) has had a major impact in the discovery of multiple susceptibility loci for ESCC in Asian and Caucasian populations, including variants in PLCE1, C20orf54, PDE4D, RUNX1, and CASP8.	('CASP8', 'Gene', (232, 237))	('RUNX1', 'Gene', (221, 226))	('variants', 'Var', (185, 193))	('ESCC', 'Disease', (134, 138))	('PLCE1', 'Gene', (197, 202))	('RUNX1', 'Gene', '861', (221, 226))	('PLCE1', 'Gene', '51196', (197, 202))	('C20orf54', 'Gene', (204, 212))	('C20orf54', 'Gene', '113278', (204, 212))	('PDE4D', 'Gene', '5144', (214, 219))	('CASP8', 'Gene', '841', (232, 237))	('PDE4D', 'Gene', (214, 219))
678252	31118947	A recent GWAS in a northern Chinese population identified common genetic variants on chromosome 2q33 that increased the risk for both ESCC and lung cancer.	('increased', 'Reg', (106, 115))	('lung cancer', 'Disease', (143, 154))	('variants', 'Var', (73, 81))	('ESCC', 'Disease', (134, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))
678253	31118947	These variants are therefore strong candidates for the study of pivotal biological mechanisms and pleiotropic effects associated with carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (134, 148))	('variants', 'Var', (6, 14))	('carcinogenesis', 'Disease', (134, 148))
678256	31118947	In this study we investigated whether single nucleotide polymorphisms (SNPs) at 2q33 and 6p21 reported to be associated with ESCC in the northern Chinese populations also contributed to the increased risk of ESCC in the South African populations.	('associated', 'Reg', (109, 119))	('ESCC', 'Disease', (208, 212))	('single nucleotide polymorphisms', 'Var', (38, 69))	('p21', 'Gene', (90, 93))	('p21', 'Gene', '644914', (90, 93))	('ESCC', 'Disease', (125, 129))
678270	31118947	For the 2q33 locus, we selected five SNPs (rs3769823, rs10931936, rs13016963, rs7578456, and rs2244438) that were significantly associated (p < 0.05) with both esophageal and lung cancer risk in a northern Chinese population.	('rs3769823', 'Var', (43, 52))	('rs7578456', 'Mutation', 'rs7578456', (78, 87))	('rs10931936', 'Var', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('rs7578456', 'Var', (78, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('rs13016963', 'Var', (66, 76))	('with', 'Reg', (150, 154))	('rs2244438', 'Var', (93, 102))	('associated', 'Reg', (128, 138))	('rs2244438', 'Mutation', 'rs2244438', (93, 102))	('rs13016963', 'Mutation', 'rs13016963', (66, 76))	('rs3769823', 'Mutation', 'rs3769823', (43, 52))	('esophageal and lung cancer', 'Disease', 'MESH:D004938', (160, 186))	('rs10931936', 'Mutation', 'rs10931936', (54, 64))
678272	31118947	We removed one SNP at 6p21 (rs6901869) that failed the frequency test (<5% frequency in African populations) as we would have limited power to detect any association of this SNP with ESCC.	('association', 'Interaction', (154, 165))	('rs6901869', 'Var', (28, 37))	('rs6901869', 'Mutation', 'rs6901869', (28, 37))	('ESCC', 'Disease', (183, 187))	('p21', 'Gene', (23, 26))	('p21', 'Gene', '644914', (23, 26))
678273	31118947	Since rs17533090 at 6p21 was highly correlated with rs35399661 in both Chinese and African populations (D' = 1/r2 = 1 in 1000 Genome Project data), only rs17533090 was genotyped as a proxy for rs35399661.	('p21', 'Gene', (21, 24))	('rs35399661', 'Mutation', 'rs35399661', (52, 62))	('p21', 'Gene', '644914', (21, 24))	('rs17533090', 'Mutation', 'rs17533090', (153, 163))	('rs35399661', 'Mutation', 'rs35399661', (193, 203))	('rs35399661', 'Var', (52, 62))	('rs17533090', 'Mutation', 'rs17533090', (6, 16))	('rs17533090', 'Var', (6, 16))
678274	31118947	Finally, five SNPs from the 6p21 locus (rs17533090, rs911178, rs2844695, rs1536501, and rs3763338) were selected for genotyping.	('rs2844695', 'Var', (62, 71))	('rs1536501', 'Mutation', 'rs1536501', (73, 82))	('rs17533090', 'Mutation', 'rs17533090', (40, 50))	('rs3763338', 'Var', (88, 97))	('rs911178', 'Var', (52, 60))	('rs911178', 'Mutation', 'rs911178', (52, 60))	('rs17533090', 'Var', (40, 50))	('rs3763338', 'Mutation', 'rs3763338', (88, 97))	('p21', 'Gene', (29, 32))	('rs1536501', 'Var', (73, 82))	('p21', 'Gene', '644914', (29, 32))	('rs2844695', 'Mutation', 'rs2844695', (62, 71))
678281	31118947	Three of the five 2q33 variants tested were marginally associated with a higher risk of ESCC in the Mixed Ancestry population.	('ESCC', 'Disease', (88, 92))	('Mix', 'Gene', '83881', (100, 103))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('2q33', 'Gene', (18, 22))	('variants', 'Var', (23, 31))	('Mix', 'Gene', (100, 103))
678282	31118947	These were CASP8 rs10931936 (OR = 1.39, 95% CI = 1.02-1.90, p = 3.52 x 10-2), TRAK2 rs7578456 (OR = 1.58, 95% CI = 1.22-2.05, p = 2.59 x 10-4), and TRAK2 rs2244438 (OR = 1.55, 95% CI = 1.16-2.07, p = 2.30 x 10-3).	('TRAK2', 'Gene', (148, 153))	('rs7578456', 'Mutation', 'rs7578456', (84, 93))	('rs2244438', 'Var', (154, 163))	('rs10931936', 'Mutation', 'rs10931936', (17, 27))	('rs2244438', 'Mutation', 'rs2244438', (154, 163))	('TRAK2', 'Gene', (78, 83))	('CASP8', 'Gene', '841', (11, 16))	('rs7578456', 'Var', (84, 93))	('TRAK2', 'Gene', '66008', (148, 153))	('rs10931936', 'Var', (17, 27))	('CASP8', 'Gene', (11, 16))	('TRAK2', 'Gene', '66008', (78, 83))
678283	31118947	Of these, rs7578456 and rs2244438 remained significant after Bonferroni multiple testing correction (P < 0.005).	('rs2244438', 'Mutation', 'rs2244438', (24, 33))	('rs7578456', 'Mutation', 'rs7578456', (10, 19))	('rs7578456', 'Var', (10, 19))	('rs2244438', 'Var', (24, 33))
678284	31118947	A suggestive association was also noted for CASP8 rs3769823 (OR = 1.26, 95% CI = 0.97-1.63, p = 0.076).	('rs3769823', 'Var', (50, 59))	('CASP8', 'Gene', '841', (44, 49))	('CASP8', 'Gene', (44, 49))	('rs3769823', 'Mutation', 'rs3769823', (50, 59))
678286	31118947	An analysis of alcohol consumption and cigarette smoking showed that there was no significant difference in association with rs10931936, rs7578456, and rs2244438 in the Mixed Ancestry sample across strata for tobacco smoking or alcohol consumption status, except for rs7578456 that was statistically significantly associated with risk in alcohol drinkers (OR = 1.61; 95% CI = 1.18-2.20, p = 0.003) but not in non-alcohol drinkers (OR = 1.55, 95% CI = 0.94-2.55, p = 0.085) (Table 3).	('alcohol drinkers', 'Disease', (338, 354))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (413, 429))	('rs7578456', 'Mutation', 'rs7578456', (137, 146))	('alcohol', 'Chemical', 'MESH:D000438', (228, 235))	('alcohol', 'Chemical', 'MESH:D000438', (15, 22))	('tobacco', 'Species', '4097', (209, 216))	('Mix', 'Gene', '83881', (169, 172))	('rs7578456', 'Var', (267, 276))	('rs2244438', 'Var', (152, 161))	('alcohol', 'Chemical', 'MESH:D000438', (338, 345))	('Mix', 'Gene', (169, 172))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (338, 354))	('associated', 'Reg', (314, 324))	('rs7578456', 'Var', (137, 146))	('rs10931936', 'Var', (125, 135))	('rs7578456', 'Mutation', 'rs7578456', (267, 276))	('rs10931936', 'Mutation', 'rs10931936', (125, 135))	('rs2244438', 'Mutation', 'rs2244438', (152, 161))	('alcohol', 'Chemical', 'MESH:D000438', (413, 420))
678288	31118947	Notably, there was a moderate correlation between rs3769823 and rs7578456 (r2 = 0.59) and between rs10931936 and rs2244438 (r2 = 0.53) in Africans, suggesting that the association of these variants with ESCC risk in the current study may be driven by one or two independent association signals.	('rs2244438', 'Var', (113, 122))	('rs3769823', 'Var', (50, 59))	('rs2244438', 'Mutation', 'rs2244438', (113, 122))	('rs10931936', 'Var', (98, 108))	('rs7578456', 'Mutation', 'rs7578456', (64, 73))	('ESCC', 'Disease', (203, 207))	('rs3769823', 'Mutation', 'rs3769823', (50, 59))	('rs7578456', 'Var', (64, 73))	('rs10931936', 'Mutation', 'rs10931936', (98, 108))
678291	31118947	Haplotype analysis of the five SNPs at 6p21 showed no evidence of association with ESCC in both the Black and Mixed Ancestry samples (p >= 0.09; Supplementary Table 2).	('Haplotype', 'Var', (0, 9))	('Mix', 'Gene', (110, 113))	('Mix', 'Gene', '83881', (110, 113))	('association', 'Interaction', (66, 77))	('ESCC', 'Disease', (83, 87))	('p21', 'Gene', (40, 43))	('p21', 'Gene', '644914', (40, 43))
678292	31118947	The multivariate logistic regression analysis revealed marginal associations with rs2244438 in the Mixed Ancestry sample after we controlled for the effect of the other SNPs in the region (rs3769823, rs10931936, rs13016963, rs7578456), although none of these associations were statistically significant after Bonferroni correction (highest OR = 1.19, smallest p = 0.008) (Table 4).	('rs2244438', 'Var', (82, 91))	('rs3769823', 'Mutation', 'rs3769823', (189, 198))	('rs13016963', 'Var', (212, 222))	('rs10931936', 'Mutation', 'rs10931936', (200, 210))	('Mix', 'Gene', '83881', (99, 102))	('rs3769823', 'Var', (189, 198))	('rs7578456', 'Mutation', 'rs7578456', (224, 233))	('associations', 'Interaction', (64, 76))	('rs13016963', 'Mutation', 'rs13016963', (212, 222))	('Mix', 'Gene', (99, 102))	('rs2244438', 'Mutation', 'rs2244438', (82, 91))	('rs10931936', 'Var', (200, 210))
678293	31118947	Conversely, rs7578456 and rs10931936 were no longer significantly associated with risk after adjusting for rs2244438 (p = 0.399 and 0.354, respectively), indicating that rs2244438 was the variant driving the association at 2p33.	('rs7578456', 'Mutation', 'rs7578456', (12, 21))	('rs10931936', 'Var', (26, 36))	('rs2244438', 'Mutation', 'rs2244438', (107, 116))	('rs7578456', 'Var', (12, 21))	('rs2244438', 'Mutation', 'rs2244438', (170, 179))	('rs2244438', 'Var', (170, 179))	('rs10931936', 'Mutation', 'rs10931936', (26, 36))
678295	31118947	These variants were previously reported to be associated with higher risk for both ESCC and other cancer types in the Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('variants', 'Var', (6, 14))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('ESCC', 'Disease', (83, 87))
678296	31118947	Our analysis revealed three SNPs at 2q33 (rs10931936, rs7578456, rs2244438) that conferred an increased risk of ESCC in the Mixed Ancestry population, thus replicating the association signals identified in the Chinese study.	('Mix', 'Gene', (124, 127))	('rs10931936', 'Mutation', 'rs10931936', (42, 52))	('Mix', 'Gene', '83881', (124, 127))	('rs7578456', 'Var', (54, 63))	('rs10931936', 'Var', (42, 52))	('rs2244438', 'Var', (65, 74))	('ESCC', 'Disease', (112, 116))	('rs2244438', 'Mutation', 'rs2244438', (65, 74))	('rs7578456', 'Mutation', 'rs7578456', (54, 63))
678298	31118947	Of these, rs2244438 that maps to a genomic region harboring TRAK2 was independently associated with ESCC risk after adjusting for the other SNPs at 2q33.	('associated with', 'Reg', (84, 99))	('rs2244438', 'Var', (10, 19))	('rs2244438', 'Mutation', 'rs2244438', (10, 19))	('TRAK2', 'Gene', (60, 65))	('ESCC', 'Disease', (100, 104))	('TRAK2', 'Gene', '66008', (60, 65))
678299	31118947	We should also note that rs2244438, unlike rs7578456 and rs10931936, lies within an exon of TRAK2 and therefore is more likely to have a functional effect on the encoded protein.	('rs10931936', 'Var', (57, 67))	('rs7578456', 'Mutation', 'rs7578456', (43, 52))	('TRAK2', 'Gene', (92, 97))	('rs2244438', 'Var', (25, 34))	('rs2244438', 'Mutation', 'rs2244438', (25, 34))	('rs10931936', 'Mutation', 'rs10931936', (57, 67))	('TRAK2', 'Gene', '66008', (92, 97))
678305	31118947	This is the first study to report that SNPs mapping to TRAK2 were significantly associated with ESCC risk in African populations and support previous findings of an association between rs2244438 and ESCC and lung cancer risk in the Chinese.	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('TRAK2', 'Gene', (55, 60))	('rs2244438', 'Var', (185, 194))	('association', 'Interaction', (165, 176))	('rs2244438', 'Mutation', 'rs2244438', (185, 194))	('SNPs mapping', 'Var', (39, 51))	('TRAK2', 'Gene', '66008', (55, 60))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('associated with', 'Reg', (80, 95))	('ESCC', 'Disease', (96, 100))	('ESCC', 'Disease', (199, 203))	('lung cancer', 'Disease', (208, 219))
678308	31118947	The variant rs2244438 is located within an exon with evolutionary constraints, and the G to A transition at this site results in the nonsynonymous change from threonine (Thr) to isoleucine (Ile) at the residue position of 528 on TRAK2.	('Thr', 'Chemical', 'MESH:D013912', (170, 173))	('results in', 'Reg', (118, 128))	('TRAK2', 'Gene', (229, 234))	('threonine', 'Chemical', 'MESH:D013912', (159, 168))	('Ile', 'Chemical', 'MESH:D007532', (190, 193))	('TRAK2', 'Gene', '66008', (229, 234))	('rs2244438', 'Var', (12, 21))	('rs2244438', 'Mutation', 'rs2244438', (12, 21))	('isoleucine', 'Chemical', 'MESH:D007532', (178, 188))
678311	31118947	The TRAK2 gene at 2q33 is therefore a credible candidate for containing the causal variant driving the association at this locus, and the effect of rs2244438 on gene expression will require functional follow-up to determine its potential pathogenic effect on the protein.	('rs2244438', 'Var', (148, 157))	('TRAK2', 'Gene', '66008', (4, 9))	('rs2244438', 'Mutation', 'rs2244438', (148, 157))	('TRAK2', 'Gene', (4, 9))
678313	31118947	Loss of heterozygosity and DNA hypermethylation in the MHC region resulting in the downregulation of HLA class I and class II genes are common and well-recognized event in esophageal tumors.	('MHC', 'Gene', (55, 58))	('Loss of heterozygosity', 'Var', (0, 22))	('HLA', 'Gene', (101, 104))	('downregulation', 'NegReg', (83, 97))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('esophageal tumors', 'Disease', 'MESH:D004938', (172, 189))	('class II genes', 'Gene', (117, 131))	('esophageal tumors', 'Phenotype', 'HP:0100751', (172, 189))	('HLA', 'Gene', '3117', (101, 104))	('esophageal tumors', 'Disease', (172, 189))
678314	31118947	Our study suggests that genetic risk variants at the 2q33 locus are shared between the Chinese populations and the Mixed Ancestry population of South Africa.	('variants', 'Var', (37, 45))	('2q33', 'Gene', (53, 57))	('Mix', 'Gene', '83881', (115, 118))	('Mix', 'Gene', (115, 118))
678318	31118947	As an example, the five SNPs at 2q33 tested in this study were in lower LD in Africans (max r2 = 0.59) compared with the Chinese (max r2 = 0.96), and the number of private haplotypes was higher in Black individuals as compared with Mixed Ancestry individuals.	('lower', 'NegReg', (66, 71))	('Mix', 'Gene', (232, 235))	('Mix', 'Gene', '83881', (232, 235))	('2q33', 'Gene', (32, 36))	('SNPs at', 'Var', (24, 31))
678321	31118947	These variants may also represent novel targets for functional follow-up aimed at elucidating the underlying biological mechanisms of esophageal carcinogenesis and identifying targeted therapies tailored toward ESCC patients with specific genetic markers.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (134, 159))	('ESCC', 'Disease', (211, 215))	('variants', 'Var', (6, 14))	('esophageal carcinogenesis', 'Disease', (134, 159))	('patients', 'Species', '9606', (216, 224))
678352	29928130	Moreover, in the liver, SIRT4 inhibition increased gene expression of mitochondrial and fatty acid metabolism-related enzymes, thereby suggesting that SIRT4 inhibition increased fat oxidative capacity.	('fat oxidative capacity', 'MPA', (178, 200))	('increased', 'PosReg', (168, 177))	('mitochondrial', 'Enzyme', (70, 83))	('increased', 'PosReg', (41, 50))	('fatty acid metabolism-related enzymes', 'Enzyme', (88, 125))	('inhibition', 'Var', (30, 40))	('SIRT4', 'Gene', (24, 29))	('fatty acid', 'Chemical', 'MESH:D005227', (88, 98))	('inhibition', 'Var', (157, 167))	('gene expression', 'MPA', (51, 66))
678367	29928130	In vivo studies in nude mice have shown that knockout of SIRT4 in mouse embryonic fibroblast cells forms larger tumors.	('SIRT4', 'Gene', (57, 62))	('nude mice', 'Species', '10090', (19, 28))	('mouse', 'Species', '10090', (66, 71))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('knockout', 'Var', (45, 53))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
678386	29928130	Previous studies on SIRT4 indicated that SIRT4 inhibited tumor metabolism, particularly the glutamine metabolism, suggesting that SIRT4 may function as a tumor suppressor.	('inhibited', 'NegReg', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('SIRT4', 'Var', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('glutamine', 'Chemical', 'MESH:D005973', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('glutamine metabolism', 'MPA', (92, 112))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (154, 159))
678389	29928130	Overexpression of SIRT4 can inhibit glutamine consumption and ammonia production in Myc-induced B cell lymphoma.	('ammonia', 'Chemical', 'MESH:D000641', (62, 69))	('glutamine', 'Chemical', 'MESH:D005973', (36, 45))	('SIRT4', 'Gene', (18, 23))	('B cell lymphoma', 'Disease', 'MESH:D016393', (96, 111))	('B cell lymphoma', 'Disease', (96, 111))	('glutamine consumption', 'MPA', (36, 57))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (96, 111))	('Overexpression', 'Var', (0, 14))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('ammonia production', 'MPA', (62, 80))	('Myc', 'Gene', (84, 87))	('inhibit', 'NegReg', (28, 35))	('Myc', 'Gene', '4609', (84, 87))
678396	29928130	These findings were in line with the notion that SIRT4 inhibited the glutamine metabolism and indicated that SIRT4 inhibited the glucose metabolism in colorectal cancer cells.	('glutamine', 'Chemical', 'MESH:D005973', (69, 78))	('glutamine metabolism', 'MPA', (69, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('colorectal cancer', 'Disease', (151, 168))	('glucose', 'Chemical', 'MESH:D005947', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (151, 168))	('SIRT4', 'Var', (109, 114))	('inhibited', 'NegReg', (115, 124))	('glucose metabolism', 'MPA', (129, 147))	('inhibited', 'NegReg', (55, 64))
678420	29928130	Overexpression of SIRT4 increased the sensitivity of Burkitt lymphoma cells to glucose deprivation and increased cell death that was associated with glucose metabolism inhibitor treatment.	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (53, 69))	('sensitivity', 'MPA', (38, 49))	('Burkitt lymphoma', 'Disease', (53, 69))	('increased', 'PosReg', (103, 112))	('glucose', 'Chemical', 'MESH:D005947', (149, 156))	('cell death', 'CPA', (113, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('SIRT4', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (53, 69))	('glucose deprivation', 'Disease', 'MESH:D012892', (79, 98))	('increased', 'PosReg', (24, 33))	('glucose deprivation', 'Disease', (79, 98))	('glucose', 'Chemical', 'MESH:D005947', (79, 86))
678423	29928130	In our previous study, we showed that 5-FU increased the sensitivity of colorectal cancer cells to chemotherapy drugs by delaying the cell cycle.	('cell cycle', 'CPA', (134, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('5-FU', 'Chemical', 'MESH:D005472', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('delaying', 'NegReg', (121, 129))	('increased', 'PosReg', (43, 52))	('sensitivity', 'MPA', (57, 68))	('colorectal cancer', 'Disease', (72, 89))	('5-FU', 'Var', (38, 42))
678515	28521405	CpG methylation resulting in the loss of TSG functions is a major epigenetic alteration that leads to tumor development and progression.	('TSG', 'Gene', '57045', (41, 44))	('functions', 'MPA', (45, 54))	('loss', 'NegReg', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('methylation', 'Var', (4, 15))	('leads to', 'Reg', (93, 101))	('TSG', 'Gene', (41, 44))	('progression', 'CPA', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
678517	28521405	However, a previous study reported that CMTM3 was methylated in 3% of esophageal carcinomas.	('methylated', 'Var', (50, 60))	('CMTM3', 'Gene', (40, 45))	('esophageal carcinomas', 'Disease', (70, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('CMTM3', 'Gene', '123920', (40, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (70, 91))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (70, 91))
678543	27650268	However, KPE in infants with cirrhosis and ascites may precipitate hepatic decompensation.	('cirrhosis', 'Disease', 'MESH:D005355', (29, 38))	('ascites', 'Disease', 'MESH:D001201', (43, 50))	('ascites', 'Disease', (43, 50))	('ascites', 'Phenotype', 'HP:0001541', (43, 50))	('hepatic decompensation', 'Disease', (67, 89))	('KPE', 'Var', (9, 12))	('precipitate', 'Reg', (55, 66))	('cirrhosis', 'Disease', (29, 38))	('infants', 'Species', '9606', (16, 23))	('cirrhosis', 'Phenotype', 'HP:0001394', (29, 38))
678648	27650268	Platelet transfusions should be reserved for severe variceal bleeding or clinically significant bleeding from other sources in the setting of significant thrombocytopenia (<20-60 x109/L).	('variceal', 'Disease', (52, 60))	('thrombocytopenia', 'Disease', (154, 170))	('bleeding', 'Disease', 'MESH:D006470', (61, 69))	('<20-60', 'Var', (172, 178))	('bleeding', 'Disease', 'MESH:D006470', (96, 104))	('bleeding', 'Disease', (61, 69))	('bleeding', 'Disease', (96, 104))	('thrombocytopenia', 'Disease', 'MESH:D013921', (154, 170))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (154, 170))
678662	27650268	Patients with neurologic symptoms or severe hyponatremia (<115-120 mequ/L) may benefit from significant fluid restriction.	('hyponatremia', 'Phenotype', 'HP:0002902', (44, 56))	('fluid restriction', 'Phenotype', 'HP:0011032', (104, 121))	('neurologic symptoms', 'Disease', (14, 33))	('<115-120 mequ/L', 'Var', (58, 73))	('hyponatremia', 'Disease', (44, 56))	('hyponatremia', 'Disease', 'MESH:D007010', (44, 56))	('Patients', 'Species', '9606', (0, 8))	('neurologic symptoms', 'Disease', 'MESH:D009422', (14, 33))
678679	27650268	Although redo KPE may theoretically make future transplantation more difficult (due to adhesions, increased blood loss, and increased surgical time), in select cases redo-KPE may offer patients long-term survival with their native liver.	('blood loss', 'Disease', 'MESH:D006473', (108, 118))	('patients', 'Species', '9606', (185, 193))	('redo-KPE', 'Var', (166, 174))	('blood loss', 'Disease', (108, 118))
678701	27650268	Some believe that LDT as young as 6 months of age, before patients show signs of significant malnutrition and hepatic decompensation, may avoid complications of cirrhosis and allow for even better post-transplant outcomes.	('LDT', 'Var', (18, 21))	('cirrhosis', 'Phenotype', 'HP:0001394', (161, 170))	('cirrhosis', 'Disease', 'MESH:D005355', (161, 170))	('malnutrition', 'Disease', (93, 105))	('malnutrition', 'Disease', 'MESH:D044342', (93, 105))	('patients', 'Species', '9606', (58, 66))	('cirrhosis', 'Disease', (161, 170))	('malnutrition', 'Phenotype', 'HP:0004395', (93, 105))
678723	26039359	Using data from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA.	('affect', 'Reg', (240, 246))	('biogenesis', 'MPA', (251, 261))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (34, 59))	('microRNAs', 'MPA', (288, 297))	('cancers', 'Disease', 'MESH:D009369', (406, 413))	('biological activity', 'MPA', (265, 284))	('cancers', 'Phenotype', 'HP:0002664', (406, 413))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('cancers', 'Disease', (406, 413))	('deregulated', 'Reg', (386, 397))	('single nucleotide polymorphisms', 'Var', (184, 215))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('Esophageal Adenocarcinoma', 'Disease', (34, 59))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (34, 59))
678724	26039359	None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity).	('variants', 'Var', (136, 144))	('EA/BE', 'Disease', (179, 184))	('obesity', 'Disease', 'MESH:D009765', (198, 205))	('obesity', 'Disease', (198, 205))	('obesity', 'Phenotype', 'HP:0001513', (198, 205))
678729	26039359	Candidate-gene-based studies have associated altered risk of EA or BE with DNA polymorphisms in genes that function in a wide range of biological pathways (inflammation, detoxification, DNA repair, angiogenesis, and apoptosis), while a recent linkage-based genetic analysis of sibling pairs provided preliminary evidence for several novel germline mutations.	('polymorphisms', 'Var', (79, 92))	('inflammation', 'Disease', (156, 168))	('inflammation', 'Disease', 'MESH:D007249', (156, 168))
678730	26039359	A large body of work has established that microRNAs (miRNAs), small non-coding RNAs that function in post-transcriptional gene regulation, act as oncogenes or tumor suppressors in a variety of tissues, and their deregulation can lead to cancer.	('lead to', 'Reg', (229, 236))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('deregulation', 'Var', (212, 224))
678734	26039359	A previous case-control study of 346 esophageal cancer cases (86% EA) and an equal number of matched controls reported that seven miRNA-related SNPs from a panel of 41 total SNPs tested were associated with altered risk of esophageal carcinoma, with the association of one SNP in the pre-miRNA-423 region remaining statistically significant after correction for multiple comparisons.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('esophageal carcinoma', 'Disease', (223, 243))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (223, 243))	('SNPs', 'Var', (144, 148))	('esophageal cancer', 'Disease', (37, 54))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (223, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
678746	26039359	A literature search was also conducted to identify miRNA-related SNPs shown to be associated with cancer susceptibility (S2 Table).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('associated', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('miRNA-related', 'Gene', (51, 64))	('SNPs', 'Var', (65, 69))
678750	26039359	Three SNPs satisfied P<0.05 in both analyses (EA and BE): RDH8 rs1644730 T>A, miR-3117 rs7526812 T>C, and miR-4467 rs12534337 G>A.	('rs12534337 G>A', 'Var', (115, 129))	('rs1644730 T>A', 'Var', (63, 76))	('rs1644730', 'Mutation', 'rs1644730', (63, 72))	('rs7526812 T>C', 'Var', (87, 100))	('RDH8', 'Gene', '50700', (58, 62))	('miR-4467', 'Gene', '100616367', (106, 114))	('miR-3117', 'Gene', '100422871', (78, 86))	('RDH8', 'Gene', (58, 62))	('miR-3117', 'Gene', (78, 86))	('rs12534337', 'Mutation', 'rs12534337', (115, 125))	('miR-4467', 'Gene', (106, 114))	('rs7526812', 'Mutation', 'rs7526812', (87, 96))
678751	26039359	Assessment of all 568 variants revealed multiple nominally-significant interactions with smoking history or BMI, but none remained significant after correction for multiple comparisons (FDR q>0.05).	('interactions', 'Interaction', (71, 83))	('variants', 'Var', (22, 30))	('men', 'Species', '9606', (6, 9))
678752	26039359	One variant (rs595055 T>C) in the biogenesis gene EIF2C1 exhibited a borderline-significant interaction (P = 0.0001, q = 0.057) with BMI in relation to risk of BE, with elevated disease risk seen only among obese individuals.	('elevated disease', 'Disease', 'MESH:D006937', (169, 185))	('elevated disease', 'Disease', (169, 185))	('obese', 'Disease', (207, 212))	('rs595055 T>C', 'Var', (13, 25))	('rs595055', 'Mutation', 'rs595055', (13, 21))	('EIF2C1', 'Gene', '26523', (50, 56))	('EIF2C1', 'Gene', (50, 56))	('obese', 'Disease', 'MESH:D009765', (207, 212))
678753	26039359	Aberrant expression of miRNAs has been reported in many cancers, and several studies have described miRNA expression changes at specific stages in the development of EA, which may be associated with progression or prognosis.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('Aberrant', 'Var', (0, 8))	('miRNAs', 'Gene', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('associated', 'Reg', (183, 193))	('expression', 'MPA', (9, 19))	('changes', 'Reg', (117, 124))	('reported', 'Reg', (39, 47))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('miRNA expression', 'MPA', (100, 116))	('men', 'Species', '9606', (158, 161))
678755	26039359	The largest previous study included 386 esophageal cancer cases (86% EA, n = 296), and identified seven SNPs significantly associated with cancer risk, five of which were associated specifically with EA.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('associated with', 'Reg', (123, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('SNPs', 'Var', (104, 108))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('esophageal cancer', 'Disease', (40, 57))	('cancer', 'Disease', (139, 145))
678757	26039359	For each of the three variants reaching P<0.05 in both analyses (RDH8 rs1644730 T>A, miR-3117 rs7526812 T>C, and miR-4467 rs12534337 G>A), the direction and magnitude of the OR was very similar for BE and EA (S4 Table), raising the possibility that the association with risk of BE might account for the association with risk of EA.	('rs1644730 T>A', 'Var', (70, 83))	('rs1644730', 'Mutation', 'rs1644730', (70, 79))	('rs12534337', 'Mutation', 'rs12534337', (122, 132))	('RDH8', 'Gene', '50700', (65, 69))	('RDH8', 'Gene', (65, 69))	('miR-3117', 'Gene', '100422871', (85, 93))	('miR-4467', 'Gene', (113, 121))	('miR-3117', 'Gene', (85, 93))	('miR-4467', 'Gene', '100616367', (113, 121))	('rs7526812', 'Mutation', 'rs7526812', (94, 103))
678758	26039359	When EA and BE cases were combined into a single case group and compared to the same set of controls, all three of these variants were highly-ranked among the set of 31 nominally significant SNPs (S7 Table), and two of the three (rs7526812 T>C, rs12534337 G>A) had smaller P values than observed in the individual analyses, without reaching Bonferroni or FDR significance thresholds.	('rs7526812', 'Mutation', 'rs7526812', (230, 239))	('rs12534337', 'Mutation', 'rs12534337', (245, 255))	('rs7526812 T>C', 'Var', (230, 243))	('rs12534337 G>A', 'Var', (245, 259))
678759	26039359	rs1644730 T>A is located within a predicted miR-630 binding site in the 3'UTR of all-trans-retinol dehydrogenase 8 (RDH8), which encodes a short-chain dehydrogenase/reductase enzyme involved in rhodopsin regeneration in the vision pathway.	('rs1644730 T>A', 'Var', (0, 13))	('RDH8', 'Gene', (116, 120))	('rhodopsin', 'Gene', '6010', (194, 203))	('RDH8', 'Gene', '50700', (116, 120))	('rs1644730', 'Mutation', 'rs1644730', (0, 9))	('all-trans-retinol dehydrogenase 8', 'Gene', '50700', (81, 114))	('rhodopsin', 'Gene', (194, 203))	('all-trans-retinol dehydrogenase 8', 'Gene', (81, 114))
678762	26039359	An intriguing hypothesis relates to whether the suggested inverse association observed in this study for rs1644730 T>A may reflect impaired miRNA-mediated repression of RDH8 and consequent elevations in estrogen synthesis.	('estrogen synthesis', 'MPA', (203, 221))	('impaired', 'NegReg', (131, 139))	('inverse', 'NegReg', (58, 65))	('rs1644730 T>A', 'Var', (105, 118))	('RDH8', 'Gene', '50700', (169, 173))	('elevations', 'PosReg', (189, 199))	('rs1644730', 'Mutation', 'rs1644730', (105, 114))	('RDH8', 'Gene', (169, 173))	('miRNA-mediated repression', 'MPA', (140, 165))
678763	26039359	In exploratory analyses stratified by sex, the inverse association of this variant with risk of EA appeared stronger among males (OR = 0.86, p = 0.00057, q = 0.23) relative to the overall study sample (OR = 0.88, p = 0.0011, q = 0.54), and was not evident among the limited pool (n = 1200) of female participants (OR = 0.97, p = 0.79).	('variant', 'Var', (75, 82))	('participants', 'Species', '9606', (300, 312))	('inverse', 'NegReg', (47, 54))
678764	26039359	rs12534337 G>A is located in the miR-4467 precursor, identified by deep sequencing of the small RNA transcriptome of normal and malignant B cells, and paired normal and tumor breast tissue (68, 69).	('miR-4467', 'Gene', '100616367', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('rs12534337', 'Mutation', 'rs12534337', (0, 10))	('rs12534337 G>A', 'Var', (0, 14))	('miR-4467', 'Gene', (33, 41))	('tumor', 'Disease', (169, 174))
678768	26039359	rs7526812 T>C is located ~15kb downstream from, and is in strong linkage disequilibrium (r 2 = 1.0) with, a variant in the miR-3117 gene locus (rs12402181).	('miR-3117', 'Gene', '100422871', (123, 131))	('rs12402181', 'Mutation', 'rs12402181', (144, 154))	('miR-3117', 'Gene', (123, 131))	('rs7526812', 'Mutation', 'rs7526812', (0, 9))	('rs12402181', 'Var', (144, 154))	('rs7526812 T>C', 'Var', (0, 13))
678769	26039359	rs7526812 T>C is also a missense polymorphism situated within an exon of the SGIP gene, which has been genetically linked to fat mass.	('SGIP', 'Gene', (77, 81))	('rs7526812', 'Mutation', 'rs7526812', (0, 9))	('linked', 'Reg', (115, 121))	('rs7526812 T>C', 'Var', (0, 13))
678771	26039359	were included in our analysis of genotyped SNPs from the BEACON GWAS, including their single SNP (pre-miR-423 rs6505162) reported as significant after correction for multiple comparisons.	('miR-423', 'Gene', (102, 109))	('rs6505162', 'Mutation', 'rs6505162', (110, 119))	('rs6505162', 'Var', (110, 119))	('miR-423', 'Gene', '494335', (102, 109))
678772	26039359	Three of these five SNPs had been associated with EA (miR-423 rs6505162, miR-196a-2 rs11614913, and RAN rs14035), while two reached borderline significance (XPO5 rs11077 and pri-miR-219-1 rs213210).	('associated', 'Reg', (34, 44))	('rs6505162', 'Mutation', 'rs6505162', (62, 71))	('rs14035', 'Mutation', 'rs14035', (104, 111))	('miR-423', 'Gene', (54, 61))	('rs6505162', 'Var', (62, 71))	('RAN', 'Gene', '5901', (100, 103))	('miR-219-1', 'Gene', (178, 187))	('rs11614913', 'Var', (84, 94))	('miR-219-1', 'Gene', '407002', (178, 187))	('miR-196a-2', 'Gene', (73, 83))	('miR-196a-2', 'Gene', '406973', (73, 83))	('XPO5', 'Gene', (157, 161))	('XPO5', 'Gene', '57510', (157, 161))	('miR-423', 'Gene', '494335', (54, 61))	('rs213210', 'Mutation', 'rs213210', (188, 196))	('rs11614913', 'Mutation', 'rs11614913', (84, 94))	('RAN', 'Gene', (100, 103))	('rs11077', 'Mutation', 'rs11077', (162, 169))
678773	26039359	Re-analysis of these five SNPs using the alternative models resulted in one polymorphism reaching borderline significance (pri-miR-219-1 rs213210 T>C, dominant model, EA OR 1.17, 95% CI 1.01-1.47, P = 0.06), in the same direction as the previously published results (OR 1.61, P = 0.058).	('miR-219-1', 'Gene', '407002', (127, 136))	('rs213210', 'Mutation', 'rs213210', (137, 145))	('miR-219-1', 'Gene', (127, 136))	('rs213210 T>C', 'Var', (137, 149))
678775	26039359	Inclusion of both BE and EA cases allowed for a comparison of the genetic variation associated with risk of a neoplastic precursor lesion and the cancer that arises from it.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('genetic variation', 'Var', (66, 83))	('neoplastic precursor lesion', 'Disease', (110, 137))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
678779	25292432	A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant Asian Americans are one of the fastest-growing populations in the United States.	('Variant', 'Var', (89, 96))	('Aldehyde Dehydrogenase 2', 'Gene', (62, 86))	('Aldehyde Dehydrogenase 2', 'Gene', '217', (62, 86))
678780	25292432	A relatively large subset of this population carries a unique loss-of-function point mutation in aldehyde dehydrogenase 2 (ALDH2), ALDH2*2.	('aldehyde dehydrogenase 2', 'Gene', (97, 121))	('point mutation', 'Var', (79, 93))	('loss-of-function', 'NegReg', (62, 78))	('ALDH2', 'Gene', (123, 128))	('ALDH2*2', 'Gene', (131, 138))	('aldehyde dehydrogenase 2', 'Gene', '217', (97, 121))
678782	25292432	Furthermore, this variant is associated with a higher risk for several diseases affecting many organ systems, including a particularly high incidence relative to the general population of esophageal cancer, myocardial infarction, and osteoporosis.	('esophageal cancer', 'Disease', 'MESH:D004938', (188, 205))	('myocardial infarction', 'Phenotype', 'HP:0001658', (207, 228))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('osteoporosis', 'Disease', 'MESH:D010024', (234, 246))	('osteoporosis', 'Disease', (234, 246))	('myocardial infarction', 'Disease', 'MESH:D009203', (207, 228))	('myocardial infarct', 'Phenotype', 'HP:0001658', (207, 225))	('myocardial infarction', 'Disease', (207, 228))	('osteoporosis', 'Phenotype', 'HP:0000939', (234, 246))	('esophageal cancer', 'Disease', (188, 205))	('variant', 'Var', (18, 25))
678783	25292432	In this review, we discuss the pathophysiology associated with the ALDH2*2 variant, describe why this variant needs to be considered when selecting drug treatments, and suggest a personalized medicine approach for Asian American carriers of this variant.	('variant', 'Var', (75, 82))	('men', 'Species', '9606', (158, 161))	('ALDH2*2', 'Gene', (67, 74))
678785	25292432	Hospital data for Asian Americans suggest their outcomes appear poorer compared to Caucasians; for example, Asian Americans have an increased risk for cardiac events during an inpatient stay.	('patient', 'Species', '9606', (178, 185))	('Asian Americans', 'Var', (108, 123))	('cardiac', 'CPA', (151, 158))
678787	25292432	The point mutation in aldehyde dehydrogenase 2 (ALDH2), identified as ALDH2*2, is the most frequent variant in humans and is present in 8% of the world's population, or approximately 560 million people.	('aldehyde dehydrogenase 2', 'Gene', '217', (22, 46))	('aldehyde dehydrogenase 2', 'Gene', (22, 46))	('point mutation', 'Var', (4, 18))	('ALDH2', 'Gene', (48, 53))	('people', 'Species', '9606', (195, 201))	('humans', 'Species', '9606', (111, 117))
678788	25292432	The ALDH2*2 variant is more common than other highly studied human point mutations, including those leading to sickle cell anemia, cystic fibrosis, and glucose-6-phosphate dehydrogenase.	('common', 'Reg', (28, 34))	('variant', 'Var', (12, 19))	('ALDH2*2', 'Gene', (4, 11))	('glucose-6-phosphate dehydrogenase', 'Gene', (152, 185))	('cystic fibrosis', 'Disease', 'MESH:D003550', (131, 146))	('anemia', 'Disease', 'MESH:D000740', (123, 129))	('anemia', 'Disease', (123, 129))	('glucose-6-phosphate dehydrogenase', 'Gene', '2539', (152, 185))	('leading to', 'Reg', (100, 110))	('cystic fibrosis', 'Disease', (131, 146))	('human', 'Species', '9606', (61, 66))	('anemia', 'Phenotype', 'HP:0001903', (123, 129))
678793	25292432	Other East Asian ethnicities in the United States may also carry the ALDH2*2 variant at a lower frequency, including the Hmong natives of Laos and a small percentage of Filipino and Thai people.	('ALDH2*2', 'Gene', (69, 76))	('people', 'Species', '9606', (187, 193))	('variant', 'Var', (77, 84))
678802	25292432	The ALDH2*2 point mutation occurs at nucleotide 1459, where an adenine is substituted for a guanine (rs671).	('adenine', 'Chemical', 'MESH:D000225', (63, 70))	('ALDH2*2', 'Gene', (4, 11))	('rs671', 'Var', (101, 106))	('guanine', 'Chemical', 'MESH:D006147', (92, 99))	('rs671', 'Mutation', 'rs671', (101, 106))
678804	25292432	When it forms a tetrameric complex with the wild-type ALDH2*1 enzyme, ALDH2*2 dominantly inhibits catalysis and increases ALDH2 enzyme turnover.	('increases ALDH2 enzyme turnover', 'Disease', 'MESH:D008661', (112, 143))	('inhibits', 'NegReg', (89, 97))	('ALDH2*2', 'Var', (70, 77))	('catalysis', 'MPA', (98, 107))	('increases ALDH2 enzyme turnover', 'Disease', (112, 143))
678805	25292432	Alternatively, a two-question screening tool predicted the ALDH2*2 variant with 90% sensitivity and 88% specificity in a general population of Japanese men (Figure 3); this questionnaire could be used in locations with minimal genotyping resources.	('variant', 'Var', (67, 74))	('ALDH2*2', 'Gene', (59, 66))	('men', 'Species', '9606', (152, 155))
678807	25292432	However, when compared to the questionnaire, the sensitivity and specificity of the ethanol patch test was much lower, and the test may perhaps be the least useful screening method for the ALDH2*2 variant.	('ALDH2*2', 'Gene', (189, 196))	('ethanol', 'Chemical', 'MESH:D000431', (84, 91))	('lower', 'NegReg', (112, 117))	('variant', 'Var', (197, 204))
678808	25292432	Although ALDH2*2 is classically known for its effect on limiting alcohol consumption and protection from developing alcoholism, this variant has only recently been recognized as having a major impact on human health and disease.	('alcoholism', 'Phenotype', 'HP:0030955', (116, 126))	('human', 'Species', '9606', (203, 208))	('alcohol', 'Chemical', 'MESH:D000438', (116, 123))	('variant', 'Var', (133, 140))	('alcohol', 'Chemical', 'MESH:D000438', (65, 72))	('ALDH2*2', 'Gene', (9, 16))
678809	25292432	Here we focus on clinical and translational studies that investigate what impact the ALDH2*2 variant may have on human health (Figure 4).	('ALDH2*2', 'Gene', (85, 92))	('variant', 'Var', (93, 100))	('human', 'Species', '9606', (113, 118))
678817	25292432	After consuming alcohol, homozygotes and heterozygotes for the ALDH2*2 variant accumulate high acetaldehyde blood levels.	('accumulate', 'PosReg', (79, 89))	('acetaldehyde', 'Chemical', 'MESH:D000079', (95, 107))	('variant', 'Var', (71, 78))	('ALDH2*2', 'Gene', (63, 70))	('high acetaldehyde blood levels', 'MPA', (90, 120))	('high acetaldehyde', 'Phenotype', 'HP:0003533', (90, 107))	('alcohol', 'Chemical', 'MESH:D000438', (16, 23))
678821	25292432	Genotyping of 250 heroin-dependent Han Chinese patients in Taiwan revealed that 60.8% were either ALDH2*1/*2 or ALDH2*2/*2, 10.2% higher than in population controls.	('ALDH2*1/*2', 'Var', (98, 108))	('higher', 'PosReg', (130, 136))	('patients', 'Species', '9606', (47, 55))	('ALDH2*2/*2', 'Var', (112, 122))	('heroin', 'Chemical', 'MESH:D003932', (18, 24))
678823	25292432	Thus, human ALDH2*2 carriers may have a higher risk of cognitive impairment and decline, dementia, and Alzheimer's disease by accumulating aldehyde-induced damage to brain cells.	('accumulating', 'PosReg', (126, 138))	('human', 'Species', '9606', (6, 11))	('aldehyde', 'Chemical', 'MESH:D000447', (139, 147))	('damage to brain cells', 'Phenotype', 'HP:0002529', (156, 177))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (103, 122))	('dementia', 'Phenotype', 'HP:0000726', (89, 97))	('cognitive impairment', 'Phenotype', 'HP:0100543', (55, 75))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (103, 122))	('cognitive impairment', 'Disease', (55, 75))	('dementia', 'Disease', (89, 97))	("Alzheimer's disease", 'Disease', (103, 122))	('aldehyde-induced damage', 'MPA', (139, 162))	('decline', 'CPA', (80, 87))	('ALDH2*2', 'Gene', (12, 19))	('cognitive impairment', 'Disease', 'MESH:D003072', (55, 75))	('carriers', 'Var', (20, 28))	('dementia', 'Disease', 'MESH:D003704', (89, 97))
678824	25292432	Most initial studies in humans focused on how the ALDH2*2 variant affects Alzheimer's disease.	('humans', 'Species', '9606', (24, 30))	('variant', 'Var', (58, 65))	('affects', 'Reg', (66, 73))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (74, 93))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (74, 93))	('ALDH2*2', 'Gene', (50, 57))	("Alzheimer's disease", 'Disease', (74, 93))
678831	25292432	Although rs671 single nucleotide polymorphism (SNP) incidence was too low to study, the haplotypes that increased Parkinson's disease risk 2-5-fold in patients who had been exposed to pesticides all possessed an ALDH2 minor allele variant rs737280 that reduces ALDH2 enzymatic activity.	("Parkinson's disease", 'Disease', 'MESH:D010300', (114, 133))	('increased', 'PosReg', (104, 113))	('ALDH2', 'Gene', (212, 217))	('patients', 'Species', '9606', (151, 159))	('rs737280', 'Var', (239, 247))	('ALDH2', 'Protein', (261, 266))	('enzymatic activity', 'MPA', (267, 285))	('rs671', 'Mutation', 'rs671', (9, 14))	('reduces', 'NegReg', (253, 260))	('rs737280', 'Mutation', 'rs737280', (239, 247))	("Parkinson's disease", 'Disease', (114, 133))
678837	25292432	Although further studies are needed in humans, these rodent studies provide evidence that the ALDH2*2 variant contributes to nociception, providing a potential genetic basis for the differences in pain behavior observed in humans.	('humans', 'Species', '9606', (39, 45))	('nociception', 'MPA', (125, 136))	('pain', 'Phenotype', 'HP:0012531', (197, 201))	('contributes', 'Reg', (110, 121))	('ALDH2*2', 'Gene', (94, 101))	('variant', 'Var', (102, 109))	('pain', 'Disease', 'MESH:D010146', (197, 201))	('pain', 'Disease', (197, 201))	('humans', 'Species', '9606', (223, 229))
678839	25292432	The ALDH2*2 variant may modify blood glucose control, affecting the development of noninsulin-dependent diabetes mellitus.	('diabetes mellitus', 'Phenotype', 'HP:0000819', (104, 121))	('variant', 'Var', (12, 19))	('-dependent diabetes mellitus', 'Phenotype', 'HP:0100651', (93, 121))	('diabetes mellitus', 'Disease', (104, 121))	('noninsulin-dependent diabetes', 'Phenotype', 'HP:0005978', (83, 112))	('ALDH2*2', 'Gene', (4, 11))	('modify', 'Reg', (24, 30))	('diabetes mellitus', 'Disease', 'MESH:D003920', (104, 121))	('men', 'Species', '9606', (75, 78))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('blood glucose control', 'MPA', (31, 52))	('affecting', 'Reg', (54, 63))
678840	25292432	Individuals with the ALDH2*2 variant who consume alcohol have higher hemoglobin A1C values compared to those with the ALDH2*1/*1 enzyme.	('higher hemoglobin A1C', 'Phenotype', 'HP:0040217', (62, 83))	('hemoglobin A1C values', 'MPA', (69, 90))	('A1C', 'Mutation', 'c.1A>C', (80, 83))	('ALDH2*2', 'Gene', (21, 28))	('variant', 'Var', (29, 36))	('higher hemoglobin', 'Phenotype', 'HP:0001900', (62, 79))	('higher', 'PosReg', (62, 68))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))
678841	25292432	In Han Chinese patients with coronary artery disease, the ALDH2*2 variant is a potential risk factor for diabetes in females.	('patients', 'Species', '9606', (15, 23))	('coronary artery disease', 'Disease', (29, 52))	('ALDH2*2', 'Gene', (58, 65))	('diabetes', 'Disease', (105, 113))	('risk factor', 'Reg', (89, 100))	('coronary artery disease', 'Disease', 'MESH:D003324', (29, 52))	('variant', 'Var', (66, 73))	('diabetes', 'Disease', 'MESH:D003920', (105, 113))
678845	25292432	As discussed below, an increased incidence of myocardial infarction and coronary artery disease is strongly associated with the ALDH2*2 variant.	('myocardial infarction', 'Phenotype', 'HP:0001658', (46, 67))	('variant', 'Var', (136, 143))	('coronary artery disease', 'Disease', 'MESH:D003324', (72, 95))	('associated', 'Reg', (108, 118))	('myocardial infarction', 'Disease', (46, 67))	('myocardial infarction', 'Disease', 'MESH:D009203', (46, 67))	('myocardial infarct', 'Phenotype', 'HP:0001658', (46, 64))	('ALDH2*2', 'Gene', (128, 135))	('coronary artery disease', 'Disease', (72, 95))
678847	25292432	A Japanese study of 342 men with a myocardial infarction and 1,820 cardiac disease-free men identified a 1.56 higher odds ratio for myocardial infarction in those homozygous for the ALDH2*2 variant.	('men', 'Species', '9606', (24, 27))	('myocardial infarction', 'Phenotype', 'HP:0001658', (35, 56))	('variant', 'Var', (190, 197))	('cardiac disease', 'Disease', (67, 82))	('myocardial infarct', 'Phenotype', 'HP:0001658', (35, 53))	('myocardial infarction', 'Disease', (132, 153))	('ALDH2*2', 'Gene', (182, 189))	('myocardial infarction', 'Disease', (35, 56))	('myocardial infarction', 'Disease', 'MESH:D009203', (132, 153))	('myocardial infarction', 'Disease', 'MESH:D009203', (35, 56))	('myocardial infarction', 'Phenotype', 'HP:0001658', (132, 153))	('myocardial infarct', 'Phenotype', 'HP:0001658', (132, 150))	('rat', 'Species', '10116', (122, 125))	('men', 'Species', '9606', (88, 91))	('higher', 'PosReg', (110, 116))	('cardiac disease', 'Disease', 'MESH:D006331', (67, 82))
678848	25292432	A GWAS in Japanese men also found the ALDH2*2 variant increased the risk of coronary artery disease and myocardial infarction.	('myocardial infarction', 'Phenotype', 'HP:0001658', (104, 125))	('variant', 'Var', (46, 53))	('myocardial infarct', 'Phenotype', 'HP:0001658', (104, 122))	('myocardial infarction', 'Disease', (104, 125))	('myocardial infarction', 'Disease', 'MESH:D009203', (104, 125))	('ALDH2*2', 'Gene', (38, 45))	('increased', 'PosReg', (54, 63))	('coronary artery disease', 'Disease', 'MESH:D003324', (76, 99))	('men', 'Species', '9606', (19, 22))	('coronary artery disease', 'Disease', (76, 99))
678849	25292432	A recent meta-analysis of nine case-control studies further supported the hypothesis that the ALDH2*2 variant increases patients' odds ratios for coronary artery disease and myocardial infarction.	('myocardial infarction', 'Disease', (174, 195))	('myocardial infarction', 'Disease', 'MESH:D009203', (174, 195))	('coronary artery disease', 'Disease', (146, 169))	('rat', 'Species', '10116', (135, 138))	('increases', 'PosReg', (110, 119))	('ALDH2*2', 'Gene', (94, 101))	('variant', 'Var', (102, 109))	('patients', 'Species', '9606', (120, 128))	('myocardial infarction', 'Phenotype', 'HP:0001658', (174, 195))	('coronary artery disease', 'Disease', 'MESH:D003324', (146, 169))	('myocardial infarct', 'Phenotype', 'HP:0001658', (174, 192))
678852	25292432	Thus, the ALDH2*2 variant, with reduced enzymatic activity, may mitigate the remote ischemic conditioning benefits during cardiac bypass surgery.	('ALDH2*2', 'Gene', (10, 17))	('ischemic', 'Disease', 'MESH:D007511', (84, 92))	('mitigate', 'NegReg', (64, 72))	('ischemic', 'Disease', (84, 92))	('variant', 'Var', (18, 25))
678853	25292432	People with the ALDH2*2 variant showed reductions in forearm blood flow response to acetylcholine after remote preconditioning followed by ischemia-reperfusion that were less than those seen in people with the ALDH2*1/*1 genotype.	('forearm blood flow response to acetylcholine', 'MPA', (53, 97))	('ischemia', 'Disease', (139, 147))	('reductions', 'NegReg', (39, 49))	('people', 'Species', '9606', (194, 200))	('People', 'Species', '9606', (0, 6))	('ischemia', 'Disease', 'MESH:D007511', (139, 147))	('acetylcholine', 'Chemical', 'MESH:D000109', (84, 97))	('variant', 'Var', (24, 31))	('ALDH2*2', 'Gene', (16, 23))
678855	25292432	Biopsies of myocardial tissue in children with cyanotic heart disease, including tetralogy of Fallot, transposition of the great arteries, and double outlet right ventricle, showed less ALDH2 activity for either the wild type or ALDH2*2 variant compared to noncyanotic controls.	('ALDH2*2', 'Gene', (229, 236))	('cyanotic heart disease', 'Disease', (47, 69))	('double outlet right ventricle', 'Phenotype', 'HP:0001719', (143, 172))	('tetralogy of Fallot', 'Disease', (81, 100))	('cyanotic heart disease', 'Disease', 'MESH:D006331', (47, 69))	('ALDH2', 'Enzyme', (186, 191))	('transposition of the great arteries', 'Phenotype', 'HP:0001669', (102, 137))	('less', 'NegReg', (181, 185))	('children', 'Species', '9606', (33, 41))	('variant', 'Var', (237, 244))	('activity', 'MPA', (192, 200))	('transposition of the great', 'Phenotype', 'HP:0011540', (102, 128))	('transposition', 'Disease', (102, 115))	('tetralogy of Fallot', 'Phenotype', 'HP:0001636', (81, 100))
678856	25292432	The ALDH2*2 variant may require compensatory measures to improve outcomes when cyanosis is present at birth.	('variant', 'Var', (12, 19))	('cyanosis', 'Disease', 'MESH:D003490', (79, 87))	('cyanosis', 'Phenotype', 'HP:0000961', (79, 87))	('ALDH2*2', 'Gene', (4, 11))	('cyanosis', 'Disease', (79, 87))
678862	25292432	Because people with the ALDH2*2 variant limit or abstain from alcohol use because of the side effects such as facial flushing and increased heart rate, the variant may protect them against alcohol-induced stroke.	('facial flushing', 'Disease', (110, 125))	('heart rate', 'MPA', (140, 150))	('alcohol', 'Chemical', 'MESH:D000438', (62, 69))	('flush', 'Phenotype', 'HP:0031284', (117, 122))	('protect', 'Reg', (168, 175))	('stroke', 'Disease', (205, 211))	('variant', 'Var', (32, 39))	('alcohol use', 'Phenotype', 'HP:0030955', (62, 73))	('people', 'Species', '9606', (8, 14))	('increased', 'PosReg', (130, 139))	('alcohol', 'Chemical', 'MESH:D000438', (189, 196))	('increased heart', 'Phenotype', 'HP:0001640', (130, 145))	('stroke', 'Phenotype', 'HP:0001297', (205, 211))	('rat', 'Species', '10116', (146, 149))	('stroke', 'Disease', 'MESH:D020521', (205, 211))	('ALDH2*2', 'Gene', (24, 31))	('facial flushing', 'Disease', 'MESH:D005483', (110, 125))	('flushing', 'Phenotype', 'HP:0031284', (117, 125))	('increased heart rate', 'Phenotype', 'HP:0001649', (130, 150))
678863	25292432	A study in Japanese men reported those with the ALDH2*2 variant had fewer multiple lacunar infarcts compared to ALDH2*1 individuals.	('variant', 'Var', (56, 63))	('infarcts', 'Disease', (91, 99))	('infarcts', 'Disease', 'MESH:D007238', (91, 99))	('ALDH2*2', 'Gene', (48, 55))	('fewer', 'NegReg', (68, 73))	('men', 'Species', '9606', (20, 23))
678864	25292432	The ALDH2*2 variant also associates with other factors that may contribute to a stroke, including hypertension and alcohol-induced increases in triglyceride levels.	('stroke', 'Disease', 'MESH:D020521', (80, 86))	('variant', 'Var', (12, 19))	('hypertension', 'Disease', 'MESH:D006973', (98, 110))	('hypertension', 'Disease', (98, 110))	('increases', 'PosReg', (131, 140))	('contribute', 'Reg', (64, 74))	('stroke', 'Phenotype', 'HP:0001297', (80, 86))	('ALDH2*2', 'Gene', (4, 11))	('hypertension', 'Phenotype', 'HP:0000822', (98, 110))	('increases in triglyceride levels', 'Phenotype', 'HP:0002155', (131, 163))	('stroke', 'Disease', (80, 86))	('triglyceride', 'Chemical', 'MESH:D014280', (144, 156))	('triglyceride levels', 'MPA', (144, 163))	('alcohol', 'Chemical', 'MESH:D000438', (115, 122))	('associates', 'Reg', (25, 35))
678869	25292432	As discussed below, the ALDH2*2 variant may also influence outcomes related to reactive airway disease and lung cancer.	('airway disease', 'Disease', 'MESH:D000402', (88, 102))	('variant', 'Var', (32, 39))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('airway disease', 'Disease', (88, 102))	('ALDH2*2', 'Gene', (24, 31))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('influence', 'Reg', (49, 58))	('reactive airway disease', 'Phenotype', 'HP:0002099', (79, 102))
678871	25292432	Compared to the Asian ALDH2*1/*1 genotype, Asian patients with an ALDH2*2 variant have a greater tendency to trigger an asthma exacerbation after alcohol consumption.	('asthma', 'Phenotype', 'HP:0002099', (120, 126))	('trigger', 'Reg', (109, 116))	('variant', 'Var', (74, 81))	('ALDH2*2', 'Gene', (66, 73))	('patients', 'Species', '9606', (49, 57))	('asthma', 'Disease', (120, 126))	('alcohol', 'Chemical', 'MESH:D000438', (146, 153))	('asthma', 'Disease', 'MESH:D001249', (120, 126))
678876	25292432	A case-control study of 718 patients with lung cancer in Japan identified an association between a history of smoking more than 15 packs per year and a higher risk of lung cancer for those with the homozygous ALDH2*2 mutation compared to patients with the ALDH2*1/*1 genotype.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('ALDH2*2', 'Gene', (209, 216))	('lung cancer', 'Disease', (167, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('mutation', 'Var', (217, 225))	('lung cancer', 'Disease', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (238, 246))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
678879	25292432	People with the ALDH2*2 variant who are exposed to both alcohol and cigarettes are at the highest risk for developing cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('People', 'Species', '9606', (0, 6))	('variant', 'Var', (24, 31))	('alcohol', 'Chemical', 'MESH:D000438', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('ALDH2*2', 'Gene', (16, 23))
678881	25292432	The activity ratios may suggest why patients with the ALDH2*2 variant have a clear risk for esophageal cancer.	('ALDH2*2', 'Gene', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (36, 44))	('esophageal cancer', 'Disease', (92, 109))	('rat', 'Species', '10116', (13, 16))	('variant', 'Var', (62, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
678886	25292432	For East Asians, four factors increase esophageal cancer risk: (a) a history of smoking cigarettes, (b) a history of drinking alcohol, (c) the presence of the ALDH2*2 mutation, or (d) the presence of a mutation in alcohol dehydrogenase (ADH1B, rs1229984) that causes a rapid conversion of alcohol to acetaldehyde.	('conversion', 'MPA', (275, 285))	('presence', 'Reg', (188, 196))	('rs1229984', 'Var', (244, 253))	('alcohol dehydrogenase', 'Gene', '10327', (214, 235))	('alcohol', 'Chemical', 'MESH:D000438', (214, 221))	('rs1229984', 'Mutation', 'rs1229984', (244, 253))	('rapid conversion of alcohol to acetaldehyde', 'Phenotype', 'HP:0003533', (269, 312))	('alcohol', 'Chemical', 'MESH:D000438', (126, 133))	('increase esophageal cancer', 'Disease', 'MESH:D004938', (30, 56))	('ALDH2*2', 'Gene', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ADH1B', 'Gene', (237, 242))	('increase esophageal cancer', 'Disease', (30, 56))	('alcohol', 'Chemical', 'MESH:D000438', (289, 296))	('acetaldehyde', 'Chemical', 'MESH:D000079', (300, 312))	('alcohol dehydrogenase', 'Gene', (214, 235))	('ADH1B', 'Gene', '125', (237, 242))
678889	25292432	Stomach cancer development among individuals with the ALDH2*2 variant may depend highly on smoking and drinking habits.	('ALDH2*2', 'Gene', (54, 61))	('Stomach cancer', 'Phenotype', 'HP:0012126', (0, 14))	('Stomach cancer', 'Disease', (0, 14))	('Stomach cancer', 'Disease', 'MESH:D013274', (0, 14))	('men', 'Species', '9606', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('variant', 'Var', (62, 69))
678891	25292432	Another study suggested that both alcohol and the ALDH2*2 variant may contribute to an increased risk for pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('ALDH2*2', 'Gene', (50, 57))	('alcohol', 'Chemical', 'MESH:D000438', (34, 41))	('variant', 'Var', (58, 65))	('pancreatic cancer', 'Disease', (106, 123))	('increased risk for pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 123))
678897	25292432	Case reports describe dermatitis or skin irritation after alcohol application for people of Asian descent, with a possible link to the ALDH2*2 variant.	('skin irritation', 'Disease', (36, 51))	('alcohol', 'Chemical', 'MESH:D000438', (58, 65))	('dermatitis', 'Disease', 'MESH:D003872', (22, 32))	('dermatitis', 'Disease', (22, 32))	('variant', 'Var', (143, 150))	('dermatitis', 'Phenotype', 'HP:0011123', (22, 32))	('ALDH2*2', 'Gene', (135, 142))	('people', 'Species', '9606', (82, 88))	('skin irritation', 'Disease', 'MESH:D012871', (36, 51))
678907	25292432	ALDH2 converts glyceryl trinitrate (nitroglycerin) to nitric oxide through an esterase-mediated mechanism requiring Cys302 at the enzymatic catalytic core.	('Cys302', 'Var', (116, 122))	('glyceryl trinitrate', 'MPA', (15, 34))	('ALDH2', 'Gene', (0, 5))	('nitric oxide', 'Chemical', 'MESH:D009569', (54, 66))	('nitroglycerin', 'Chemical', 'MESH:D005996', (36, 49))	('glyceryl trinitrate', 'Chemical', 'MESH:D005996', (15, 34))	('Cys302', 'Chemical', '-', (116, 122))
678908	25292432	Subjects with an ALDH2*1/*2 genotype compared to the ALDH2*1/*1 genotype had 33% less vasodilation, as assessed by forearm blood flow, when nitroglycerin was infused at 1 microg/min.	('nitroglycerin', 'Chemical', 'MESH:D005996', (140, 153))	('vasodilation', 'MPA', (86, 98))	('less', 'NegReg', (81, 85))	('ALDH2*1/*2', 'Var', (17, 27))
678909	25292432	The human ALDH2*2 variant has a catalytic efficiency 10-fold less for nitroglycerin compared to wild-type ALDH2.	('nitroglycerin', 'Chemical', 'MESH:D005996', (70, 83))	('human', 'Species', '9606', (4, 9))	('ALDH2*2', 'Gene', (10, 17))	('less', 'NegReg', (61, 65))	('catalytic efficiency', 'MPA', (32, 52))	('variant', 'Var', (18, 25))
678913	25292432	However, researchers need to examine whether nitroglycerin administration is beneficial during ischemia for patients with the ALDH2*2 variant; it may be detrimental, as shown by a rodent myocardial ischemia study.	('ischemia', 'Disease', (198, 206))	('ischemia', 'Disease', (95, 103))	('ether', 'Chemical', 'MESH:D004986', (39, 44))	('rat', 'Species', '10116', (67, 70))	('myocardial ischemia', 'Phenotype', 'HP:0002637', (187, 206))	('variant', 'Var', (134, 141))	('myocardial ischemia', 'Disease', (187, 206))	('myocardial ischemia', 'Disease', 'MESH:D003324', (187, 206))	('ischemia', 'Disease', 'MESH:D007511', (95, 103))	('ALDH2*2', 'Gene', (126, 133))	('ischemia', 'Disease', 'MESH:D007511', (198, 206))	('patients', 'Species', '9606', (108, 116))	('amine', 'Chemical', 'MESH:D000588', (31, 36))	('men', 'Species', '9606', (158, 161))	('nitroglycerin', 'Chemical', 'MESH:D005996', (45, 58))
678924	25292432	Because 5-nitrofuran is being investigated for treating medulloblastoma and neuroblastoma, further studies will be needed to investigate whether this drug is effective in treating these diseases in patients with the ALDH2*2 variant.	('ether', 'Chemical', 'MESH:D004986', (139, 144))	('5-nitrofuran', 'Chemical', '-', (8, 20))	('medulloblastoma', 'Disease', (56, 71))	('neuroblastoma', 'Disease', (76, 89))	('patients', 'Species', '9606', (198, 206))	('ALDH2*2', 'Gene', (216, 223))	('neuroblastoma', 'Phenotype', 'HP:0003006', (76, 89))	('medulloblastoma', 'Phenotype', 'HP:0002885', (56, 71))	('medulloblastoma', 'Disease', 'MESH:D008527', (56, 71))	('variant', 'Var', (224, 231))	('neuroblastoma', 'Disease', 'MESH:D009447', (76, 89))
678930	25292432	This leads to the question of whether acetaminophen administration may be detrimental to preserving tissue following ischemic injury, particularly in patients with the ALDH2*2 variant.	('men', 'Species', '9606', (79, 82))	('ether', 'Chemical', 'MESH:D004986', (32, 37))	('variant', 'Var', (176, 183))	('ischemic injury', 'Disease', 'MESH:D003324', (117, 132))	('acetaminophen', 'Chemical', 'MESH:D000082', (38, 51))	('rat', 'Species', '10116', (60, 63))	('ALDH2*2', 'Gene', (168, 175))	('patients', 'Species', '9606', (150, 158))	('ischemic injury', 'Disease', (117, 132))
678934	25292432	For individuals with the ALDH2*2 variant, exposure to environmental aldehydes could lead to a higher risk of developing various pathologies relative to wild-type individuals.	('lead', 'Reg', (84, 88))	('aldehydes', 'Chemical', 'MESH:D000447', (68, 77))	('ALDH2*2', 'Gene', (25, 32))	('variant', 'Var', (33, 40))	('men', 'Species', '9606', (61, 64))
678942	25292432	However, chronic exposure to ethyl tertiary-butyl ether (ETBE), a common gasoline additive, may be more damaging for people with the ALDH2*2 variant.	('people', 'Species', '9606', (117, 123))	('ALDH2*2', 'Gene', (133, 140))	('ETBE', 'Chemical', 'MESH:C098546', (57, 61))	('variant', 'Var', (141, 148))	('ethyl tertiary-butyl ether', 'Chemical', 'MESH:C098546', (29, 55))
678951	25292432	Physicians can use the two-part questionnaire to generate a discussion regarding the ALDH2*2 variant during an annual physical exam (Figure 3).	('rat', 'Species', '10116', (53, 56))	('ALDH2*2', 'Gene', (85, 92))	('variant', 'Var', (93, 100))
678952	25292432	For patients with the ALDH2*2 variant, physicians should conduct a more detailed family history of diseases commonly associated with the variant.	('patients', 'Species', '9606', (4, 12))	('variant', 'Var', (30, 37))	('ALDH2*2', 'Gene', (22, 29))
678961	25292432	Animal models with specific variants seen in the Asian American population, such as the transgenic knock-in mouse for ALDH2*2 our group has created, can be used to test observations witnessed in the clinic.	('mouse', 'Species', '10090', (108, 113))	('variants', 'Var', (28, 36))	('ALDH2*2', 'Gene', (118, 125))	('transgenic', 'Species', '10090', (88, 98))
678967	25292432	ALDH2 aldehyde dehydrogenase 2 ALDH2*2 the East Asian variant of ALDH2, resulting from a base pair substitution of guanine to adenine ALDH2*1/*1 a homozygous genotype for ALDH2 that does not possess the East Asian variant ALDH2*1/*2 a heterozygous genotype for the East Asian variant of ALDH2 that reduces enzymatic activity of the enzyme by approximately 60% to 80% ALDH2*2/*2 a homozygous genotype for the East Asian variant of ALDH2 that reduces ALDH2 activity to approximately 4% compared to wild type rs671 SNP for the ALDH2 East Asian variant; can be homozygous (A;A) or heterozygous (G;A) for the variant or may not possess it (G;G) ADH alcohol dehydrogenase GWAS genome-wide association study Fanconi anemia a disease associated with a mutation in one of 15 proteins mediating DNA repair Radiation dermatitis an inflammatory reaction of the skin secondary to ionizing radiation CMMG 9-carboxymethoxymethylguanine, a metabolite of acyclovir NAPQI N-acetyl-p-benzoquinonimine, a metabolite of acetaminophen Asian Americans are one of the fastest-growing populations in the United States and will consist of 25 million people by 2035.	('acyclovir', 'Chemical', 'MESH:D000212', (938, 947))	('guanine', 'Chemical', 'MESH:D006147', (115, 122))	('N-acetyl-p-benzoquinonimine', 'Chemical', 'MESH:C028473', (954, 981))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (701, 715))	('adenine', 'Chemical', 'MESH:D000225', (126, 133))	('CMMG', 'Chemical', 'MESH:C035400', (886, 890))	('ADH', 'Gene', '10327', (640, 643))	('skin secondary to ionizing radiation', 'Phenotype', 'HP:0011133', (849, 885))	('aldehyde dehydrogenase 2', 'Gene', '217', (6, 30))	('dermatitis', 'Disease', 'MESH:D003872', (806, 816))	('dermatitis', 'Disease', (806, 816))	('rs671', 'Mutation', 'rs671', (506, 511))	('alcohol dehydrogenase', 'Gene', (644, 665))	('alcohol dehydrogenase', 'Gene', '10327', (644, 665))	('guanine', 'Chemical', 'MESH:D006147', (913, 920))	('acetaminophen', 'Chemical', 'MESH:D000082', (999, 1012))	('aldehyde dehydrogenase 2', 'Gene', (6, 30))	('inflammatory reaction of the skin', 'Phenotype', 'HP:0011123', (820, 853))	('Fanconi anemia', 'Disease', (701, 715))	('9-carboxymethoxymethylguanine', 'Chemical', 'MESH:C035400', (891, 920))	('associated', 'Reg', (726, 736))	('dermatitis', 'Phenotype', 'HP:0011123', (806, 816))	('NAPQI', 'Chemical', 'MESH:C028473', (948, 953))	('ADH', 'Gene', (640, 643))	('Fanconi anemia', 'Disease', 'MESH:D005199', (701, 715))	('people', 'Species', '9606', (1124, 1130))	('mutation', 'Var', (744, 752))	('anemia', 'Phenotype', 'HP:0001903', (709, 715))
678971	25292432	People with the ALDH2*2 genetic variant clearly have a higher associative risk for diseases such as esophageal cancer, coronary artery disease, myocardial infarction, and osteoporosis.	('myocardial infarction', 'Disease', (144, 165))	('myocardial infarction', 'Disease', 'MESH:D009203', (144, 165))	('variant', 'Var', (32, 39))	('esophageal cancer', 'Disease', (100, 117))	('coronary artery disease', 'Disease', 'MESH:D003324', (119, 142))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('People', 'Species', '9606', (0, 6))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('osteoporosis', 'Phenotype', 'HP:0000939', (171, 183))	('myocardial infarct', 'Phenotype', 'HP:0001658', (144, 162))	('coronary artery disease', 'Disease', (119, 142))	('myocardial infarction', 'Phenotype', 'HP:0001658', (144, 165))	('osteoporosis', 'Disease', 'MESH:D010024', (171, 183))	('ALDH2*2', 'Gene', (16, 23))	('osteoporosis', 'Disease', (171, 183))
678972	25292432	Other health problems, including addiction, Alzheimer's disease, pain, diabetes, stroke, Fanconi anemia, and dermatitis, may also be associated with the variant.	('variant', 'Var', (153, 160))	('diabetes', 'Disease', 'MESH:D003920', (71, 79))	('pain', 'Disease', (65, 69))	('anemia', 'Phenotype', 'HP:0001903', (97, 103))	('stroke', 'Phenotype', 'HP:0001297', (81, 87))	('pain', 'Phenotype', 'HP:0012531', (65, 69))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (89, 103))	('stroke', 'Disease', 'MESH:D020521', (81, 87))	('dermatitis', 'Disease', 'MESH:D003872', (109, 119))	('dermatitis', 'Disease', (109, 119))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (44, 63))	('diabetes', 'Disease', (71, 79))	('associated', 'Reg', (133, 143))	("Alzheimer's disease", 'Disease', (44, 63))	('stroke', 'Disease', (81, 87))	('pain', 'Disease', 'MESH:D010146', (65, 69))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (44, 63))	('dermatitis', 'Phenotype', 'HP:0011123', (109, 119))	('addiction', 'Disease', (33, 42))	('Fanconi anemia', 'Disease', (89, 103))	('Fanconi anemia', 'Disease', 'MESH:D005199', (89, 103))
678973	25292432	The ALDH2*2 variant causes altered responses to commonly used drugs, including nitroglycerin, acyclovir, and 5-nitrofuran.	('acyclovir', 'MPA', (94, 103))	('variant', 'Var', (12, 19))	('altered', 'Reg', (27, 34))	('5-nitrofuran', 'Chemical', '-', (109, 121))	('ALDH2*2', 'Gene', (4, 11))	('acyclovir', 'Chemical', 'MESH:D000212', (94, 103))	('responses to commonly used drugs', 'MPA', (35, 67))	('nitroglycerin', 'Chemical', 'MESH:D005996', (79, 92))
678977	25292432	A personalized medicine approach based on genotyping Asian Americans for the ALDH2*2 genetic variant should be implemented and will ultimately improve the care and health of this large population.	('improve', 'PosReg', (143, 150))	('ALDH2*2', 'Gene', (77, 84))	('variant', 'Var', (93, 100))	('men', 'Species', '9606', (116, 119))
678978	25292432	As many behavioral associations exist for the ALDH2*2 variant, how does ALDH2*2 affect human behavior?	('human', 'Species', '9606', (87, 92))	('variant', 'Var', (54, 61))	('affect', 'Reg', (80, 86))	('ALDH2*2', 'Gene', (46, 53))
678979	25292432	What role does the ALDH2*2 variant play in cardiac disease, particularly regarding remote conditioning and in general outcomes after cardiac bypass surgery and myocardial infarction in adults and children?	('myocardial infarction', 'Phenotype', 'HP:0001658', (160, 181))	('cardiac disease', 'Disease', 'MESH:D006331', (43, 58))	('myocardial infarct', 'Phenotype', 'HP:0001658', (160, 178))	('cardiac disease', 'Disease', (43, 58))	('myocardial infarction', 'Disease', (160, 181))	('children', 'Species', '9606', (196, 204))	('myocardial infarction', 'Disease', 'MESH:D009203', (160, 181))	('variant', 'Var', (27, 34))	('ALDH2*2', 'Gene', (19, 26))
678981	25292432	Is nitroglycerin use during acute ischemic events such as myocardial infarction or stroke less effective or detrimental for patients with the ALDH2*2 variant?	('stroke', 'Disease', 'MESH:D020521', (83, 89))	('myocardial infarction', 'Disease', (58, 79))	('myocardial infarction', 'Disease', 'MESH:D009203', (58, 79))	('ischemic', 'Disease', (34, 42))	('myocardial infarct', 'Phenotype', 'HP:0001658', (58, 76))	('stroke', 'Phenotype', 'HP:0001297', (83, 89))	('variant', 'Var', (150, 157))	('stroke', 'Disease', (83, 89))	('nitroglycerin', 'Chemical', 'MESH:D005996', (3, 16))	('men', 'Species', '9606', (113, 116))	('ischemic', 'Disease', 'MESH:D007511', (34, 42))	('myocardial infarction', 'Phenotype', 'HP:0001658', (58, 79))	('ALDH2*2', 'Gene', (142, 149))	('patients', 'Species', '9606', (124, 132))	('acute ischemic events', 'Phenotype', 'HP:0002637', (28, 49))
678983	25292432	Given the common use of acetaminophen, does this drug alter the activity of the ALDH2*2 variant?	('alter', 'Reg', (54, 59))	('acetaminophen', 'Chemical', 'MESH:D000082', (24, 37))	('variant', 'Var', (88, 95))	('activity', 'MPA', (64, 72))	('ALDH2*2', 'Gene', (80, 87))
678984	25292432	How does environmental exposure to aldehydes such as pesticides, solvents, cigarette smoke, and air pollution alter the risk of developing or accelerating disease processes in people with the ALDH2*2 variant?	('disease', 'Disease', (155, 162))	('ALDH2*2', 'Gene', (192, 199))	('rat', 'Species', '10116', (148, 151))	('variant', 'Var', (200, 207))	('people', 'Species', '9606', (176, 182))	('developing', 'CPA', (128, 138))	('men', 'Species', '9606', (16, 19))	('accelerating', 'PosReg', (142, 154))	('aldehydes', 'Chemical', 'MESH:D000447', (35, 44))
678987	25433484	Recent studies investigating the association between hsa-mir-499 polymorphism (rs3746444) and cancer risk have yielded conflicting results.	('mir-499', 'Gene', '574501', (57, 64))	('mir-499', 'Gene', (57, 64))	('rs3746444', 'Var', (79, 88))	('rs3746444', 'Mutation', 'rs3746444', (79, 88))	('hsa', 'Gene', '213', (53, 56))	('hsa', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
678988	25433484	In this meta-analysis, we conducted a search of case-control studies on the associations of SNP rs3746444 with susceptibility to cancer in electronic databases.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('rs3746444', 'Var', (96, 105))	('rs3746444', 'Mutation', 'rs3746444', (96, 105))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('associations', 'Interaction', (76, 88))	('SNP', 'Gene', (92, 95))
678990	25433484	Overall, significant association between rs3746444 polymorphism and susceptibility to cancer was identified in TC versus TT and TC/CC versus TT (dominant) models.	('rs3746444', 'Var', (41, 50))	('TC', 'Chemical', 'MESH:D013667', (128, 130))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs3746444', 'Mutation', 'rs3746444', (41, 50))	('TC/CC', 'Disease', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('TC', 'Chemical', 'MESH:D013667', (111, 113))	('cancer', 'Disease', (86, 92))
678993	25433484	Our meta-analysis suggested that hsa-mir-499 rs3746444 T > C polymorphism is associated with the risk of cancer in Asians, mainly in Iranian and Chinese population.	('mir-499', 'Gene', '574501', (37, 44))	('mir-499', 'Gene', (37, 44))	('rs3746444 T > C', 'Var', (45, 60))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('rs3746444', 'Mutation', 'rs3746444', (45, 54))	('hsa', 'Gene', '213', (33, 36))	('hsa', 'Gene', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('associated', 'Reg', (77, 87))
678994	25433484	However, rs3746444 T > C polymorphism is negatively associated with the risk of esophageal cancer.	('negatively', 'NegReg', (41, 51))	('esophageal cancer', 'Disease', (80, 97))	('rs3746444 T > C', 'Var', (9, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rs3746444', 'Mutation', 'rs3746444', (9, 18))
678995	25433484	In early 1990s, microRNAs (miRNAs) were first discovered through analysis of developmental timing mutants in C. elegans by several groups, simultaneously .	('C. elegans', 'Species', '6239', (109, 119))	('developmental timing', 'Gene', (77, 97))	('mutants', 'Var', (98, 105))
679001	25433484	rs4846049 (G > T) of MTHFR gene is associated with increased risk for coronary heart diseases, and the potentially pathogenetic mechanism may be SNP-modified posttranscriptional gene regulation by miRNA-149 to MTHFR.	('rs4846049 (G > T', 'Var', (0, 16))	('MTHFR', 'Gene', '4524', (21, 26))	('rs4846049', 'Mutation', 'rs4846049', (0, 9))	('coronary heart diseases', 'Disease', 'MESH:D003324', (70, 93))	('coronary heart diseases', 'Disease', (70, 93))	('MTHFR', 'Gene', '4524', (210, 215))	('MTHFR', 'Gene', (21, 26))	('MTHFR', 'Gene', (210, 215))
679004	25433484	The A to G base change of rs999885 may provide a protective effect against chronic HBV infection but an increased risk for HCC in HBV persistent carriers by altering the expression of the miR-106b-25 cluster.	('HBV', 'Gene', (130, 133))	('miR-106b', 'Gene', (188, 196))	('altering', 'Reg', (157, 165))	('miR-106b', 'Gene', '406900', (188, 196))	('HCC', 'Disease', (123, 126))	('HBV infection', 'Disease', (83, 96))	('HBV infection', 'Disease', 'MESH:D006509', (83, 96))	('rs999885', 'Var', (26, 34))	('rs999885', 'Mutation', 'rs999885', (26, 34))	('expression', 'MPA', (170, 180))
679005	25433484	miR-200b/200c/429-binding site polymorphism in the 3'-UTR of AP-2alpha gene is associated with cisplatin resistance, suggesting that SNP (rs1045385) A > C variation may be a potential prognostic marker for cisplatin treatment.	('AP-2alpha', 'Gene', (61, 70))	('associated', 'Reg', (79, 89))	('SNP (rs1045385) A > C', 'Var', (133, 154))	('miR-200b', 'Gene', '406984', (0, 8))	('miR-200b', 'Gene', (0, 8))	('AP-2alpha', 'Gene', '160', (61, 70))	('cisplatin resistance', 'MPA', (95, 115))	('rs1045385', 'Mutation', 'rs1045385', (138, 147))
679006	25433484	To date, many studies explored the association between rs3746444 T > C SNP in hsa-mir-499 and susceptibility to diseases, such as breast cancer, lung cancer, congenital heart disease, dilated cardiomyopathy, gallbladder cancer, squamous cell carcinoma of the head and neck, chronic obstructive pulmonary disease, liver cancer, rheumatoid arthritis, coronary artery disease, and colorectal cancer.	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (242, 272))	('mir-499', 'Gene', (82, 89))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('liver cancer', 'Disease', 'MESH:D006528', (313, 325))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (184, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (282, 311))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (327, 347))	('congenital heart disease', 'Disease', 'MESH:D006331', (158, 182))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colorectal cancer', 'Phenotype', 'HP:0003003', (378, 395))	('coronary artery disease', 'Disease', 'MESH:D003324', (349, 372))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (228, 251))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('liver cancer', 'Phenotype', 'HP:0002896', (313, 325))	('hsa', 'Gene', '213', (78, 81))	('gallbladder cancer', 'Disease', (208, 226))	('liver cancer', 'Disease', (313, 325))	('coronary artery disease', 'Disease', (349, 372))	('dilated cardiomyopathy', 'Disease', (184, 206))	('arthritis', 'Phenotype', 'HP:0001369', (338, 347))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (274, 311))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (274, 311))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('rheumatoid arthritis', 'Disease', (327, 347))	('association', 'Interaction', (35, 46))	('congenital heart disease', 'Disease', (158, 182))	('lung cancer', 'Disease', (145, 156))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (228, 251))	('rs3746444', 'Mutation', 'rs3746444', (55, 64))	('chronic obstructive pulmonary disease', 'Disease', (274, 311))	('colorectal cancer', 'Disease', 'MESH:D015179', (378, 395))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (184, 206))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (192, 206))	('congenital heart disease', 'Phenotype', 'HP:0001627', (158, 182))	('breast cancer', 'Disease', (130, 143))	('mir-499', 'Gene', '574501', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('colorectal cancer', 'Disease', (378, 395))	('bladder cancer', 'Phenotype', 'HP:0009725', (212, 226))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (327, 347))	('hsa', 'Gene', (78, 81))	('squamous cell carcinoma', 'Disease', (228, 251))	('gallbladder cancer', 'Disease', 'MESH:D005706', (208, 226))	('rs3746444 T > C SNP', 'Var', (55, 74))
679007	25433484	Especially, one study suggested that miR-499 rs3746444*T alleles might be protective for breast cancer, but another found that the miR-499 rs3746444 C allele increased cancer risk in the allelic contrast model and in the dominant model, especially in breast cancer, while another study showed that no significant associations were observed between rs3746444 in miR-499 and breast cancer susceptibility.	('breast cancer', 'Disease', (373, 386))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', 'MESH:D001943', (373, 386))	('breast cancer', 'Disease', (89, 102))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('miR-499', 'Gene', '574501', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (380, 386))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('miR-499', 'Gene', '574501', (131, 138))	('miR-499', 'Gene', '574501', (361, 368))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('miR-499', 'Gene', (37, 44))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('miR-499', 'Gene', (361, 368))	('breast cancer', 'Disease', (251, 264))	('miR-499', 'Gene', (131, 138))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('rs3746444', 'Mutation', 'rs3746444', (348, 357))	('cancer', 'Disease', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('breast cancer', 'Phenotype', 'HP:0003002', (373, 386))	('cancer', 'Disease', 'MESH:D009369', (380, 386))	('rs3746444', 'Mutation', 'rs3746444', (45, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('rs3746444 C', 'Var', (139, 150))	('rs3746444', 'Mutation', 'rs3746444', (139, 148))	('increased', 'PosReg', (158, 167))
679008	25433484	Recently, a meta-analysis suggested that polymorphism of hsa-mir-499 rs3746444 T > C was not associated with increased susceptibility to cancers, while other systematic analysis supported that hsa-mir-499 rs3746444 polymorphism contributed to the susceptibility to cancers.	('rs3746444 T > C', 'Var', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('hsa', 'Gene', '213', (57, 60))	('cancers', 'Disease', (137, 144))	('rs3746444', 'Var', (205, 214))	('mir-499', 'Gene', '574501', (197, 204))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('hsa', 'Gene', (193, 196))	('mir-499', 'Gene', (197, 204))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('mir-499', 'Gene', '574501', (61, 68))	('rs3746444', 'Mutation', 'rs3746444', (69, 78))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('hsa', 'Gene', (57, 60))	('rs3746444', 'Mutation', 'rs3746444', (205, 214))	('mir-499', 'Gene', (61, 68))	('hsa', 'Gene', '213', (193, 196))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('cancers', 'Disease', (265, 272))
679009	25433484	In the present study, we conducted a meta-analysis in order to derive more precise and more comprehensive estimation of the associations between the SNP hsa-mir-499 rs3746444 T > C and susceptibility to cancers to quantify the potential between-study heterogeneity.	('mir-499', 'Gene', (157, 164))	('associations', 'Interaction', (124, 136))	('rs3746444 T > C', 'Var', (165, 180))	('rs3746444', 'Mutation', 'rs3746444', (165, 174))	('mir-499', 'Gene', '574501', (157, 164))	('hsa', 'Gene', (153, 156))	('hsa', 'Gene', '213', (153, 156))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
679010	25433484	We performed a publication search in PubMed, EMBASE, ISI Web of Science, The Cochrane Library, ScienceDirect, EBSCO, Ovid, Wiley Online Library, and HighWire databases with the following search terms: (miR-499 OR rs3746444) AND (cancer), by two independent investigators (Chen Chen and Shenglan Yang, last search update: June 29, 2014).	('rs3746444', 'Var', (213, 222))	('miR-499', 'Gene', (202, 209))	('rs3746444', 'Mutation', 'rs3746444', (213, 222))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('miR-499', 'Gene', '574501', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
679011	25433484	Studies included in current meta-analysis had to meet all the following criteria: (1) evaluated the associations between the hsa-mir-499 rs3746444 polymorphism and cancer risk; (2) studied on human beings; (3) diseases were confirmed by histology, imaging or pathology; (4) a case-control design; (5) detailed genotype data were provided for the calculation of odds ratio (OR) and 95% confidence interval (CIs); (6) if serial studies of the same population from the same group were reported, the latest study was included.	('mir-499', 'Gene', '574501', (129, 136))	('hsa', 'Gene', (125, 128))	('mir-499', 'Gene', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('hsa', 'Gene', '213', (125, 128))	('human', 'Species', '9606', (192, 197))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('rs3746444', 'Var', (137, 146))	('rs3746444', 'Mutation', 'rs3746444', (137, 146))
679014	25433484	For each study, the departure of frequencies of hsa-mir-499 polymorphism from expectation under Hardy-Weinberg equilibrium (HWE) was assessed by the goodness-of-fit chi-square test in controls.	('polymorphism', 'Var', (60, 72))	('mir-499', 'Gene', (52, 59))	('mir-499', 'Gene', '574501', (52, 59))	('hsa', 'Gene', '213', (48, 51))	('hsa', 'Gene', (48, 51))
679015	25433484	OR corresponding to 95% CI was used to assess the strength of association between hsa-miR-499 rs3746444 T > C polymorphism and susceptibility to cancer risk.	('cancer', 'Disease', (145, 151))	('miR-499', 'Gene', (86, 93))	('rs3746444 T > C', 'Var', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('rs3746444', 'Mutation', 'rs3746444', (94, 103))	('hsa', 'Gene', '213', (82, 85))	('miR-499', 'Gene', '574501', (86, 93))	('hsa', 'Gene', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
679020	25433484	The association between hsa-mir-499 rs3746444 polymorphism and susceptibility to cancer was analyzed in 31 independent studies.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('mir-499', 'Gene', '574501', (28, 35))	('cancer', 'Disease', (81, 87))	('mir-499', 'Gene', (28, 35))	('rs3746444', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('hsa', 'Gene', (24, 27))	('rs3746444', 'Mutation', 'rs3746444', (36, 45))	('hsa', 'Gene', '213', (24, 27))
679021	25433484	Significant association between rs3746444 polymorphism and susceptibility to cancer was identified in TC versus TT and TC/CC versus TT (dominant) models, when all the eligible studies were pooled (C versus T: OR = 1.08, 95% CI 0.99-1.17, P = 0.08; TC versus TT: OR = 1.11, 95% CI 1.00-1.23, P = 0.04; CC versus TT: OR = 1.02, 95% CI 0.85-1.22, P = 0.85; TC/CC versus TT (dominant): OR = 1.11, 95% CI 1.01-1.23, P = 0.03; CC versus TC/TT (recessive): OR = 0.98, 95% CI 0.81-1.17, P = 0.79).	('rs3746444', 'Mutation', 'rs3746444', (32, 41))	('TC', 'Chemical', 'MESH:D013667', (431, 433))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('TC', 'Chemical', 'MESH:D013667', (119, 121))	('TC', 'Chemical', 'MESH:D013667', (102, 104))	('rs3746444', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TC', 'Chemical', 'MESH:D013667', (248, 250))	('TC', 'Chemical', 'MESH:D013667', (354, 356))
679024	25433484	However, no significant association between hsa-mir-499 rs3746444 T > C polymorphism and cancer risk was found in Caucasians in any of the genetic models tested.	('rs3746444 T > C', 'Var', (56, 71))	('rs3746444', 'Mutation', 'rs3746444', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('hsa', 'Gene', '213', (44, 47))	('hsa', 'Gene', (44, 47))	('cancer', 'Disease', (89, 95))	('mir-499', 'Gene', '574501', (48, 55))	('mir-499', 'Gene', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
679026	25433484	In the present study, hsa-mir-499 rs3746444 polymorphism and susceptibility to cancer was evaluated in different genetic models in 12799 cancer cases and 14507 controls.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mir-499', 'Gene', '574501', (26, 33))	('rs3746444', 'Mutation', 'rs3746444', (34, 43))	('hsa', 'Gene', '213', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hsa', 'Gene', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('mir-499', 'Gene', (26, 33))	('rs3746444', 'Var', (34, 43))
679027	25433484	Significant association between rs3746444 polymorphism and susceptibility to cancer was identified in TC versus TT and TC/CC versus TT (dominant) models.	('TC/CC', 'Disease', (119, 124))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('TC', 'Chemical', 'MESH:D013667', (119, 121))	('TC', 'Chemical', 'MESH:D013667', (102, 104))	('rs3746444', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rs3746444', 'Mutation', 'rs3746444', (32, 41))
679031	25433484	hsa-mir-499 rs3746444 polymorphism is located in the seed region of the mature miR-499 sequence.	('mir-499', 'Gene', (4, 11))	('mir-499', 'Gene', '574501', (4, 11))	('miR-499', 'Gene', (79, 86))	('miR-499', 'Gene', '574501', (79, 86))	('rs3746444', 'Var', (12, 21))	('hsa', 'Gene', (0, 3))	('rs3746444', 'Mutation', 'rs3746444', (12, 21))	('hsa', 'Gene', '213', (0, 3))
679032	25433484	Several case-control studies have investigated the association between rs3746444 polymorphism and risks of various cancers.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rs3746444', 'Var', (71, 80))	('rs3746444', 'Mutation', 'rs3746444', (71, 80))
679033	25433484	In this meta-analysis, we first found that rs3746444 polymorphism was associated with increased cancer risk mainly in Asian population, especially in Chinese and Iranians.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('rs3746444', 'Var', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('rs3746444', 'Mutation', 'rs3746444', (43, 52))	('cancer', 'Disease', (96, 102))
679034	25433484	It is important to notice that, although rs3746444 polymorphism contributes to cancer risk in Chinese and Iranians, the genetic models are different.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('rs3746444', 'Var', (41, 50))	('rs3746444', 'Mutation', 'rs3746444', (41, 50))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
679035	25433484	Interestingly, we also found that rs3746444 polymorphism showed a decreased risk in esophageal cancer.	('rs3746444', 'Mutation', 'rs3746444', (34, 43))	('decreased', 'NegReg', (66, 75))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('rs3746444', 'Var', (34, 43))
679036	25433484	This means that rs3746444 polymorphism may contribute to single gene function in certain disease model at molecular level.	('contribute', 'Reg', (43, 53))	('rs3746444', 'Mutation', 'rs3746444', (16, 25))	('rs3746444', 'Var', (16, 25))
679037	25433484	When taken together in epidemiological studies of populations, various effects of rs3746444 polymorphism on different genes may result in different associations with diseases at phenotype level.	('diseases', 'Disease', (166, 174))	('result in', 'Reg', (128, 137))	('associations', 'Interaction', (148, 160))	('effects', 'Reg', (71, 78))	('rs3746444', 'Var', (82, 91))	('rs3746444', 'Mutation', 'rs3746444', (82, 91))
679040	25433484	In summary, though with limitations, our meta-analysis suggested that hsa-mir-499 rs3746444 T > C polymorphism is associated with the risk of cancer, especially in Asians, mainly in Chinese and Iranians.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('hsa', 'Gene', '213', (70, 73))	('mir-499', 'Gene', '574501', (74, 81))	('hsa', 'Gene', (70, 73))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rs3746444', 'Mutation', 'rs3746444', (82, 91))	('associated', 'Reg', (114, 124))	('rs3746444 T > C', 'Var', (82, 97))	('mir-499', 'Gene', (74, 81))
679041	25433484	Larger studies from different ethnic groups and studying different types of cancers with detailed information are needed to further clarify the association between rs3746444 polymorphism and cancer risk.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('rs3746444', 'Mutation', 'rs3746444', (164, 173))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('rs3746444', 'Var', (164, 173))
679130	24762549	When patients were stratified based on the extent of tumor budding, there was a significant difference in survival associated with the extent of tumor budding.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('patients', 'Species', '9606', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (145, 150))	('extent', 'Var', (135, 141))	('tumor', 'Disease', (53, 58))	('survival', 'MPA', (106, 114))
679140	24762549	When patients with focal budding were compared to those with no tumor budding, the modest difference in time to recurrence was not significant (p=0.096).	('tumor', 'Disease', (64, 69))	('patients', 'Species', '9606', (5, 13))	('focal budding', 'Var', (19, 32))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
679142	24762549	Extensive tumor budding was associated with a 3.2-fold increased risk of recurrence (95% confidence interval 1.4-7.0, p=0.005), independent of T and N stage in the multivariate analysis.	('recurrence', 'CPA', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('Extensive', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
679176	24762549	We illustrate how the relationship between other risk factors and nodal metastasis is modified by the extent of tumor budding such that T1b-superficial, low grade tumors and tumors without angiolymphatic invasion had dramatically higher rates of nodal metastasis in the presence of extensive tumor budding.	('tumor', 'Disease', (163, 168))	('higher', 'PosReg', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('tumors', 'Disease', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('nodal metastasis', 'CPA', (246, 262))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Disease', (112, 117))	('T1b-superficial', 'Var', (136, 151))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('low grade', 'Var', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
679188	23735443	We used the Surveillance Epidemiology and End Results database to identify 1618 patients with Tis or T1 N0M0 EAC, from 1998 through 2009.	('T1 N0M0 EAC', 'Var', (101, 112))	('Tis', 'Var', (94, 97))	('patients', 'Species', '9606', (80, 88))	('EAC', 'Phenotype', 'HP:0011459', (109, 112))
679239	23735443	The HR of overall survival and cancer-specific survival associated with T1b tumor compared to Tis/T1a tumor was 1.37 (95% CI 1.12-1.69) and 1.65 (95% CI 1.28-2.16), respectively.	('overall survival', 'CPA', (10, 26))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('T1a', 'Gene', (98, 101))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('T1a', 'Gene', '10630', (98, 101))	('T1b', 'Var', (72, 75))	('cancer', 'Disease', (31, 37))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
679240	23735443	In subgroup analyses stratified by tumor stage, overall survival and esophageal cancer-specific survival of patients with Tis/T1a and T1b tumor were not significantly different between the two groups (Table 4) (Supplement table s2).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('esophageal cancer', 'Disease', (69, 86))	('T1b', 'Var', (134, 137))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (35, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('T1a', 'Gene', '10630', (126, 129))	('T1a', 'Gene', (126, 129))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
679288	18852079	There is no serosa to serve as a barrier between the esophagus and the surrounding structures; lack of a serosa facilitates tumor spread through the esophageal wall into adjacent structures.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('lack', 'Var', (95, 99))	('tumor', 'Disease', (124, 129))	('facilitates', 'PosReg', (112, 123))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
679330	18852079	Published studies have found that the use of PET-CT helps in more precisely defining the location of FDG avidity in the region of the primary tumor, thereby improving regional lymph node staging accuracy[ (Fig.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('avidity', 'Var', (105, 112))	('tumor', 'Disease', (142, 147))	('improving', 'PosReg', (157, 166))	('regional lymph node staging accuracy', 'CPA', (167, 203))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('FDG', 'Protein', (101, 104))
679347	18852079	At some institutions, patients with T1N0 disease on EUS and M0 disease on CT and PET will undergo endoscopic therapy or surgery, whereas those with deeper extent of tumor and/or tumor involved regional lymph nodes will undergo neoadjuvant chemoradiation therapy followed by surgery.	('T1N0 disease', 'Var', (36, 48))	('tumor', 'Disease', (178, 183))	('patients', 'Species', '9606', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (165, 170))
679353	33805149	Landscape of Chimeric RNAs in Non-Cancerous Cells Gene fusions and their products (RNA and protein) have been traditionally recognized as unique features of cancer cells and are used as ideal biomarkers and drug targets for multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Disease', (157, 163))	('Chimeric', 'Var', (13, 21))
679355	33805149	Finally, we examined a number of validated chimeric RNAs in different cancer and non-cancer cells, including blood from healthy donors, and demonstrated their ubiquitous expression pattern.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('non-cancer', 'Disease', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('chimeric', 'Var', (43, 51))	('non-cancer', 'Disease', 'MESH:D009369', (81, 91))	('RNAs', 'Protein', (52, 56))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
679356	33805149	Chimeric fusion RNAs and their encoded proteins were once thought to be features unique to cancer, some of which have been successfully used as cancer diagnostic markers and therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('Chimeric fusion', 'Var', (0, 15))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('RNAs', 'Protein', (16, 20))
679358	33805149	Compared to non-cancer tissues and cells, most of these chimeric RNAs are significantly over-expressed in cancer.	('chimeric', 'Var', (56, 64))	('non-cancer', 'Disease', (12, 22))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('non-cancer', 'Disease', 'MESH:D009369', (12, 22))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('over-expressed', 'PosReg', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
679361	33805149	ADCK4-NUMBL, C15orf57-CBX3, ARL10-HIGD2A, and other fusions are detected in GTEx samples and knockdown of ADCK4-NUMBL and C15orf57-CBX decrease cell proliferation and/or cell motility in non-cancerous cells.	('knockdown', 'Var', (93, 102))	('NUMBL', 'Gene', (112, 117))	('NUMBL', 'Gene', '9253', (112, 117))	('HIGD2A', 'Gene', (34, 40))	('C15orf57', 'Gene', '90416', (13, 21))	('ARL10', 'Gene', (28, 33))	('ADCK4', 'Gene', '79934', (106, 111))	('cell proliferation', 'CPA', (144, 162))	('C15orf57', 'Gene', (13, 21))	('non-cancer', 'Disease', 'MESH:D009369', (187, 197))	('NUMBL', 'Gene', (6, 11))	('NUMBL', 'Gene', '9253', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ADCK4', 'Gene', '79934', (0, 5))	('non-cancer', 'Disease', (187, 197))	('ADCK4', 'Gene', (106, 111))	('C15orf57', 'Gene', '90416', (122, 130))	('CBX3', 'Gene', '11335', (22, 26))	('C15orf57', 'Gene', (122, 130))	('CBX3', 'Gene', (22, 26))	('ADCK4', 'Gene', (0, 5))	('HIGD2A', 'Gene', '192286', (34, 40))	('decrease', 'NegReg', (135, 143))	('ARL10', 'Gene', '285598', (28, 33))
679363	33805149	We also explored four of the validated chimeric RNAs in other cells and tissues, including esophageal and prostate cancer and non-cancerous cell lines, as well as healthy blood samples.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('non-cancer', 'Disease', 'MESH:D009369', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('chimeric', 'Var', (39, 47))	('non-cancer', 'Disease', (126, 136))	('prostate cancer', 'Disease', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))	('esophageal', 'Disease', (91, 101))
679387	33805149	When the M/M-type fusions were filtered out, the INTERCHR group shrunk (1% in HEK-293T, 25% in HUVEC, and 16% in LO2), and Read-Through and INTRA-Others became more abundant (70% and 29% in HEK-293T, 47% and 28% in HUVEC, and 41% and 43% in LO2, respectively).	('HEK-293T', 'CellLine', 'CVCL:0063', (190, 198))	('HEK-293T', 'Var', (190, 198))	('HEK-293T', 'CellLine', 'CVCL:0063', (78, 86))	('HEK-293T', 'Var', (78, 86))	('Read-Through', 'CPA', (123, 135))
679388	33805149	Among all the fusions, the most prominent category was E/E fusions: 64% in HEK-293T, while M/M (25%), M/E (8%), and E/M (3%) were much less common in HEK-293T.	('HEK-293T', 'Disease', (75, 83))	('M/E', 'Var', (102, 105))	('HEK-293T', 'CellLine', 'CVCL:0063', (75, 83))	('HEK-293T', 'CellLine', 'CVCL:0063', (150, 158))	('M/M', 'Var', (91, 94))
679389	33805149	After filtering out the M/M-type, E/E fusions were significantly enriched (85% in HEK-293T, 59% in HUVEC, and 72% in LO2).	('HEK-293T', 'CellLine', 'CVCL:0063', (82, 90))	('HEK-293T', 'Var', (82, 90))	('E/E fusions', 'Var', (34, 45))
679391	33805149	Removal of M/M-type fusions seemed to enrich in-frame (18% in HEK-293T, 22% in HUVEC, and no change in LO2) and frame-shift (41% in HEK-293T, 13% in HUVEC, and 26% in LO2) classifications, while reducing fusions with NA classification (39% in HEK-293T, 65% in HUVEC, and 63% in LO2).	('HEK-293T', 'Var', (132, 140))	('frame-shift', 'Var', (112, 123))	('HEK-293T', 'CellLine', 'CVCL:0063', (243, 251))	('enrich', 'PosReg', (38, 44))	('HEK-293T', 'Disease', (62, 70))	('HEK-293T', 'CellLine', 'CVCL:0063', (62, 70))	('HEK-293T', 'CellLine', 'CVCL:0063', (132, 140))	('fusions', 'MPA', (204, 211))
679399	33805149	Based on bioinformatics analysis, MSANTD3-TMEFF1 is in-frame, RAD51AP1-DYRK4, and TPD5112-DNAJC5 are frame-shift, and SUMO3-UBE2G2 is NA, according to their reading frames which are described above.	('DNAJC5', 'Gene', (90, 96))	('UBE2G2', 'Gene', (124, 130))	('RAD51AP1', 'Gene', (62, 70))	('DYRK4', 'Gene', (71, 76))	('MSANTD3-TMEFF1', 'Var', (34, 48))	('DYRK4', 'Gene', '8798', (71, 76))	('UBE2G2', 'Gene', '7327', (124, 130))	('DNAJC5', 'Gene', '80331', (90, 96))	('MSANTD3-TMEFF1', 'CellLine', 'CVCL:3570', (34, 48))	('RAD51AP1', 'Gene', '10635', (62, 70))	('SUMO3', 'Gene', (118, 123))	('SUMO3', 'Gene', '6612', (118, 123))
679405	33805149	Chimeric RNAs caused by chromosomal rearrangements are well known cancer-causing genetic events and are actively used in clinical cancer diagnoses.	('chromosomal rearrangements', 'Var', (24, 50))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('RNAs', 'Gene', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Chimeric', 'Var', (0, 8))	('cancer', 'Disease', (66, 72))
679407	33805149	However, there has been increasing evidence of chimeric RNAs in non-cancer tissues and cells.	('non-cancer', 'Disease', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('non-cancer', 'Disease', 'MESH:D009369', (64, 74))	('chimeric RNAs', 'Var', (47, 60))
679408	33805149	However, it is important to realize that not all chimeric RNAs detected in cancer cells or tissues are cancer specific.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('chimeric RNAs', 'Var', (49, 62))
679413	33805149	In conclusion, instead of being unique features of cancer, chimeric RNAs are widely spread in non-cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('non-cancer', 'Disease', (94, 104))	('non-cancer', 'Disease', 'MESH:D009369', (94, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (98, 104))	('chimeric RNAs', 'Var', (59, 72))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
679451	32425979	A large number of miRNAs have been confirmed to be associated with esophageal neoplasms.	('miRNAs', 'Var', (18, 24))	('esophageal neoplasms', 'Disease', (67, 87))	('neoplasms', 'Phenotype', 'HP:0002664', (78, 87))	('esophageal neoplasms', 'Disease', 'MESH:D004938', (67, 87))	('associated', 'Reg', (51, 61))	('esophageal neoplasms', 'Phenotype', 'HP:0100751', (67, 87))
679458	32425979	Take Mir-199a-3p (the 3p arm of the pre-miRNA for miR-199a) as an example, it is highly expressed in colonic neoplasms tissues, resulting in significantly reduced survival rate of patients.	('Mir-199a-3p', 'Gene', (5, 16))	('reduced', 'NegReg', (155, 162))	('miR-199a', 'Var', (50, 58))	('neoplasms', 'Phenotype', 'HP:0002664', (109, 118))	('colonic neoplasms', 'Disease', 'MESH:D003110', (101, 118))	('colonic neoplasms', 'Phenotype', 'HP:0100273', (101, 118))	('survival rate', 'CPA', (163, 176))	('colonic neoplasms', 'Disease', (101, 118))	('Mir-199a-3p', 'Gene', '406977', (5, 16))	('patients', 'Species', '9606', (180, 188))
679464	32425979	An example of miRNAs related with lymphoma is miR-125b.	('lymphoma', 'Disease', 'MESH:D008223', (34, 42))	('miR-125b', 'Var', (46, 54))	('lymphoma', 'Phenotype', 'HP:0002665', (34, 42))	('lymphoma', 'Disease', (34, 42))
679507	30984290	In longitudinal studies, higher CRP confers a corresponding incremental AF risk.	('CRP', 'Gene', (32, 35))	('AF', 'Disease', 'MESH:D001281', (72, 74))	('CRP', 'Gene', '1401', (32, 35))	('higher', 'Var', (25, 31))	('AF', 'Phenotype', 'HP:0005110', (72, 74))
679558	30984290	Whereas the mechanism linking NAFLD with autonomic dysfunction is not well described, alterations in the autonomic nervous system may promote initiation and maintenance of AF.	('promote', 'PosReg', (134, 141))	('autonomic dysfunction', 'Phenotype', 'HP:0012332', (41, 62))	('AF', 'Disease', 'MESH:D001281', (172, 174))	('AF', 'Disease', 'MESH:D001281', (31, 33))	('AF', 'Phenotype', 'HP:0005110', (172, 174))	('AF', 'Phenotype', 'HP:0005110', (31, 33))	('autonomic dysfunction', 'Disease', 'MESH:D001342', (41, 62))	('autonomic dysfunction', 'Disease', (41, 62))	('alterations in the autonomic nervous system', 'Phenotype', 'HP:0012332', (86, 129))	('alterations', 'Var', (86, 97))
679572	30984290	TMAO is associated with atherosclerosis and cardiovascular events, possibly by increasing the production of pro-inflammatory cytokines.	('cardiovascular events', 'Disease', (44, 65))	('atherosclerosis', 'Disease', (24, 39))	('increasing', 'PosReg', (79, 89))	('TMAO', 'Chemical', 'MESH:C005855', (0, 4))	('associated', 'Reg', (8, 18))	('atherosclerosis', 'Phenotype', 'HP:0002621', (24, 39))	('cardiovascular events', 'Phenotype', 'HP:0001626', (44, 65))	('atherosclerosis', 'Disease', 'MESH:D050197', (24, 39))	('production of pro-inflammatory cytokines', 'MPA', (94, 134))	('TMAO', 'Var', (0, 4))
679578	30984290	AF patients with high lipopolysaccharides also had increased risk of major adverse cardiovascular events compared with those with low lipopolysaccharides levels.	('cardiovascular events', 'Phenotype', 'HP:0001626', (83, 104))	('AF', 'Disease', 'MESH:D001281', (0, 2))	('high lipopolysaccharides', 'Var', (17, 41))	('lipopolysaccharides', 'Chemical', 'MESH:D008070', (22, 41))	('major', 'Disease', (69, 74))	('patients', 'Species', '9606', (3, 11))	('lipopolysaccharides', 'Chemical', 'MESH:D008070', (134, 153))	('AF', 'Phenotype', 'HP:0005110', (0, 2))
679629	30984290	In a large Canadian administrative database, DOACs were not associated with an increased risk of severe liver injury compared with warfarin.	('liver injury', 'Disease', (104, 116))	('DOACs', 'Var', (45, 50))	('warfarin', 'Chemical', 'MESH:D014859', (131, 139))	('DOACs', 'Chemical', '-', (45, 50))	('liver injury', 'Disease', 'MESH:D056486', (104, 116))
679653	30984290	In a systematic review of 28 studies, apixaban was the only DOAC to have lower rates of gastrointestinal hemorrhage compared with warfarin (HR 0.63, 95% CI 0.42-0.95).	('apixaban', 'Var', (38, 46))	('gastrointestinal hemorrhage', 'Disease', (88, 115))	('apixaban', 'Chemical', 'MESH:C522181', (38, 46))	('gastrointestinal hemorrhage', 'Phenotype', 'HP:0002239', (88, 115))	('gastrointestinal hemorrhage', 'Disease', 'MESH:D006471', (88, 115))	('lower', 'NegReg', (73, 78))	('warfarin', 'Chemical', 'MESH:D014859', (130, 138))	('DOAC', 'Chemical', '-', (60, 64))
679657	30984290	Though trials directly comparing the DOACs are not available, the existing 'real world' data and multiple meta-analyses on gastrointestinal bleeding suggest that apixaban may have fewer major bleeding complications compared with dabigatran and rivaroxaban, and may be the optimal treatment for patients with an underlying history of gastrointestinal hemorrhage, or those at increased risk of bleeding.	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (123, 148))	('fewer', 'NegReg', (180, 185))	('dabigatran', 'Chemical', 'MESH:D000069604', (229, 239))	('bleeding', 'Disease', 'MESH:D006470', (192, 200))	('gastrointestinal bleeding', 'Disease', (123, 148))	('apixaban', 'Var', (162, 170))	('bleeding', 'Disease', (140, 148))	('DOACs', 'Chemical', '-', (37, 42))	('bleeding', 'Disease', (392, 400))	('rivaroxaban', 'Chemical', 'MESH:D000069552', (244, 255))	('bleeding', 'Disease', (192, 200))	('gastrointestinal hemorrhage', 'Phenotype', 'HP:0002239', (333, 360))	('gastrointestinal hemorrhage', 'Disease', 'MESH:D006471', (333, 360))	('bleeding complications', 'Disease', 'MESH:D006470', (192, 214))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (123, 148))	('bleeding complications', 'Disease', (192, 214))	('patients', 'Species', '9606', (294, 302))	('apixaban', 'Chemical', 'MESH:C522181', (162, 170))	('bleeding', 'Disease', 'MESH:D006470', (140, 148))	('gastrointestinal hemorrhage', 'Disease', (333, 360))	('bleeding', 'Disease', 'MESH:D006470', (392, 400))
679683	30644002	Injury to an anomalous V2 can cause severe hemorrhage during subcarinal lymph node dissection in esophagectomy.	('cause', 'Reg', (30, 35))	('hemorrhage', 'Disease', (43, 53))	('anomalous', 'Var', (13, 22))	('hemorrhage', 'Disease', 'MESH:D006470', (43, 53))	('Injury', 'Var', (0, 6))
679689	30644002	Although lymph node dissection might be technically possible without recognizing the RSPV anomaly preoperatively, injury to this vein would cause severe hemorrhage and be fatal.	('RSPV anomaly', 'Disease', 'MESH:D000014', (85, 97))	('cause', 'Reg', (140, 145))	('RSPV anomaly', 'Disease', (85, 97))	('hemorrhage', 'Disease', (153, 163))	('hemorrhage', 'Disease', 'MESH:D006470', (153, 163))	('injury', 'Var', (114, 120))
679699	30644002	During the preoperative examination, contrast-enhanced CT imaging revealed that the anomalous V2 drained into the RSPV, which ran behind the intermediate bronchus (Fig.	('ran', 'Gene', '5901', (126, 129))	('RSPV', 'Chemical', '-', (114, 118))	('anomalous', 'Var', (84, 93))	('ran', 'Gene', (126, 129))
679705	30644002	The pathological diagnosis on TNM staging was pT3 pN3 cM0 pStage IVA.	('TNM', 'Gene', (30, 33))	('pT3 pN3 cM0', 'Var', (46, 57))	('IVA', 'Disease', (65, 68))	('IVA', 'Disease', 'MESH:C538167', (65, 68))	('TNM', 'Gene', '10178', (30, 33))
679711	30644002	reported that anomalous V2 was found in 14 (7.4%) of 189 patients on three-dimensional CT angiography (3-D CTA).	('anomalous', 'Var', (14, 23))	('patients', 'Species', '9606', (57, 65))	('CTA', 'Chemical', 'MESH:C569473', (107, 110))	('found', 'Reg', (31, 36))
679719	30644002	3-D CTA Three-dimensional computed tomographic angiography Anomalous V2 Anomaly of the superior posterior pulmonary vein in the right upper lobe CT Computed tomography NACRT Neoadjuvant chemoradiotherapy POD Postoperative day RSPV Right superior pulmonary vein YO is the first and corresponding author of this manuscript.	('man', 'Species', '9606', (310, 313))	('Anomalous', 'Var', (59, 68))	('Anomaly', 'Disease', 'MESH:D000014', (72, 79))	('CTA', 'Chemical', 'MESH:C569473', (4, 7))	('NACRT', 'Chemical', '-', (168, 173))	('Anomaly', 'Disease', (72, 79))	('RSPV', 'Chemical', '-', (226, 230))
679777	26922374	Although the complete response rate of patients with uT1 lesions was higher than that of patients with uT2 lesions, the difference was not significant (71.4 % vs. 50.0 %, P = 0.263).	('lesions', 'Var', (57, 64))	('patients', 'Species', '9606', (39, 47))	('uT2', 'Gene', '8170', (103, 106))	('uT1', 'Gene', (53, 56))	('uT2', 'Gene', (103, 106))	('complete response', 'CPA', (13, 30))	('patients', 'Species', '9606', (89, 97))	('uT1', 'Gene', '6563', (53, 56))	('higher', 'PosReg', (69, 75))
679790	26922374	The 5-year LRFS rate of patients with cT1-2 lesions was higher than that of patients with cT3-4 lesions, but the difference was not significant (67.2 % vs. 50.2 %, P = 0.065 [log-rank test]).	('lesions', 'Var', (44, 51))	('LRFS rate', 'CPA', (11, 20))	('patients', 'Species', '9606', (76, 84))	('cT3-4', 'Gene', '27120', (90, 95))	('cT1-2', 'Gene', (38, 43))	('cT3-4', 'Gene', (90, 95))	('patients', 'Species', '9606', (24, 32))	('higher', 'PosReg', (56, 62))	('cT1-2', 'Gene', '266740', (38, 43))
679791	26922374	The 5-year LRFS rate of patients with uT1 lesions was higher than that of patients with uT2 lesions, but the difference was not significant (62.2 % vs. 50.0 %, P = 0.062 [log-rank test]).	('LRFS rate', 'CPA', (11, 20))	('higher', 'PosReg', (54, 60))	('uT1', 'Gene', '6563', (38, 41))	('patients', 'Species', '9606', (74, 82))	('lesions', 'Var', (42, 49))	('patients', 'Species', '9606', (24, 32))	('uT1', 'Gene', (38, 41))	('uT2', 'Gene', (88, 91))	('uT2', 'Gene', '8170', (88, 91))
679792	26922374	The 5-year LRFS rate of patients with lesions occupying an esophageal circumference smaller than 1/4 was significantly higher than that of patients with lesions occupying an esophageal circumference of 1/4 or larger (73.5 % vs. 38.3 %, P = 0.001 [log-rank test]) (Fig.	('patients', 'Species', '9606', (139, 147))	('higher', 'PosReg', (119, 125))	('lesions', 'Var', (38, 45))	('patients', 'Species', '9606', (24, 32))	('LRFS', 'CPA', (11, 15))
679795	26922374	The 5-year OS rate of patients with cT1-2 lesions was significantly higher than that of patients with cT3-4 lesions (59.5 % vs. 34.7 %, P = 0.018 [log-rank test]).	('cT3-4', 'Gene', (102, 107))	('OS', 'Chemical', '-', (11, 13))	('cT1-2', 'Gene', (36, 41))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (22, 30))	('higher', 'PosReg', (68, 74))	('lesions', 'Var', (42, 49))	('cT1-2', 'Gene', '266740', (36, 41))	('OS rate', 'MPA', (11, 18))	('cT3-4', 'Gene', '27120', (102, 107))
679797	26922374	Though the 5-year OS rate of patients with lesions occupying an esophageal circumference smaller than 1/4 was higher than those with lesions occupying an esophageal circumference of 1/4 or larger, the difference was not significant (54.2 % vs. 40.4 %, P = 0.108 [log-rank test]) (Fig.	('patients', 'Species', '9606', (29, 37))	('higher', 'PosReg', (110, 116))	('lesions', 'Var', (43, 50))	('OS', 'Chemical', '-', (18, 20))
679925	22269708	That is probably the likely cause, because there is a bias at our institution to do transhiatals, and I would bet, again, with the two groups, that most of them were transhiatals as opposed to Ivor Lewises.	('transhiatals', 'Var', (166, 178))	('bet', 'Gene', (110, 113))	('bet', 'Gene', '92737', (110, 113))
679938	22269708	So to summarize, in patients that we find a longer length T2 tumor that would translate to a higher risk on our nomogram of underdiagnosis, these are the patients we focus on giving neoadjuvant chemoradiation.	('patients', 'Species', '9606', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('longer', 'Var', (44, 50))
679944	25085003	We analyze whether expression of APOBEC1 induces a mutator phenotype in vertebrate cells, likely through direct targeting of genomic DNA.	('APOBEC1', 'Gene', (33, 40))	('mutator phenotype', 'MPA', (51, 68))	('expression', 'Var', (19, 29))	('induces', 'Reg', (41, 48))	('rat', 'Species', '10116', (78, 81))
679945	25085003	We show its ability to increase the inactivation of a stably inserted reporter gene in a chicken cell line that lacks any other AID/APOBEC proteins, and to increase the number of imatinib-resistant clones in a human cellular model for chronic myeloid leukemia through induction of mutations in the BCR-ABL1 fusion gene.	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (235, 259))	('chronic myeloid leukemia', 'Disease', (235, 259))	('chicken', 'Species', '9031', (89, 96))	('leukemia', 'Phenotype', 'HP:0001909', (251, 259))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (243, 259))	('induction', 'Reg', (268, 277))	('increase', 'PosReg', (156, 164))	('BCR-ABL1', 'Gene', (298, 306))	('inactivation', 'MPA', (36, 48))	('human', 'Species', '9606', (210, 215))	('increase', 'PosReg', (23, 31))	('mutations', 'Var', (281, 290))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (235, 259))	('imatinib-resistant clones', 'MPA', (179, 204))	('imatinib', 'Chemical', 'MESH:D000068877', (179, 187))	('BCR-ABL1', 'Gene', '613;25', (298, 306))
679946	25085003	Moreover, we find the presence of an AID/APOBEC mutational signature in esophageal adenocarcinomas, a type of tumor where APOBEC1 is expressed, that mimics the one preferred by APOBEC1 in vitro.	('esophageal adenocarcinomas', 'Disease', (72, 98))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (72, 97))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mutational', 'Var', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (72, 98))	('APOBEC1', 'Gene', (122, 129))	('AID/APOBEC', 'Gene', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
679950	25085003	APOBEC1 (Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1) is part of the RNA editing complex that physiologically deaminates C6666 to U in the transcript of human Apolipoprotein B, a major component in lipid transport.	('lipid', 'Chemical', 'MESH:D008055', (216, 221))	('C6666', 'Var', (139, 144))	('Apolipoprotein B', 'Gene', (9, 25))	('Apolipoprotein B', 'Gene', (177, 193))	('Apolipoprotein B', 'Gene', '338', (9, 25))	('APOBEC1', 'Gene', (0, 7))	('Apolipoprotein B', 'Gene', '338', (177, 193))	('human', 'Species', '9606', (171, 176))
679956	25085003	This hypothesis is corroborated by the evidence that aberrant activity of other AID/APOBECs underlies the onset of genetic alterations in human cancer.	('aberrant activity', 'Var', (53, 70))	('Cs', 'Chemical', 'MESH:D002586', (89, 91))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('rat', 'Species', '10116', (26, 29))	('human', 'Species', '9606', (138, 143))	('cancer', 'Disease', (144, 150))	('rat', 'Species', '10116', (127, 130))	('genetic alterations', 'MPA', (115, 134))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
679962	25085003	Indeed, the sequence context of the mutations at cytosine residues observed in the EGFP reflects that observed in vitro and in bacteria for APOBEC1, especially with regard to the preference for a thymine directly upstream to the mutated C and the avoidance of adenines (Figure 1D; Additional file 2).	('or a', 'Gene', '100170843', (191, 195))	('mutations', 'Var', (36, 45))	('APOBEC1', 'Gene', (140, 147))	('cytosine', 'Chemical', 'MESH:D003596', (49, 57))	('or a', 'Gene', (191, 195))	('adenines', 'Chemical', 'MESH:D000225', (260, 268))
679966	25085003	Sequence analysis of the rpoB gene from rifampicin-resistant clones shows that the mutations induced by human APOBEC1 closely resemble those induced by the rat homologue (Figure 2B).	('rpoB', 'Gene', (25, 29))	('mutations', 'Var', (83, 92))	('rat', 'Species', '10116', (156, 159))	('human', 'Species', '9606', (104, 109))	('rifampicin', 'Chemical', 'MESH:D012293', (40, 50))	('APOBEC1', 'Gene', (110, 117))
679970	25085003	Mutations in BCR-ABL1 can produce imatinib-resistant clones: it has been shown that exogenous overexpression of AID induces mutations that can confer resistance to the drug by disrupting the interaction of BCR-ABL1 with the drug.	('BCR-ABL1', 'Gene', '613;25', (206, 214))	('mutations', 'Var', (124, 133))	('resistance', 'MPA', (150, 160))	('imatinib', 'Chemical', 'MESH:D000068877', (34, 42))	('Mutations', 'Var', (0, 9))	('BCR-ABL1', 'Gene', (13, 21))	('interaction', 'Interaction', (191, 202))	('disrupting', 'NegReg', (176, 186))	('BCR-ABL1', 'Gene', '613;25', (13, 21))	('BCR-ABL1', 'Gene', (206, 214))
679975	25085003	Sequence analysis of individual clones confirmed the presence of mutations in the ABL1 tyrosine kinase domain, mostly located at residues near the catalytic pocket (Table 1).	('ABL1', 'Gene', '25', (82, 86))	('located', 'Reg', (118, 125))	('ABL1', 'Gene', (82, 86))	('mutations', 'Var', (65, 74))
679976	25085003	This is in line with previous studies in which A/T mutations represented 33 to 50% of all unique BCR-ABL1 mutations induced by AID.	('BCR-ABL1', 'Gene', '613;25', (97, 105))	('BCR-ABL1', 'Gene', (97, 105))	('mutations', 'Var', (51, 60))	('mutations', 'Var', (106, 115))
679988	25085003	In human tumors derived from mature B cells there are characteristic chromosomal translocations and other mutations that can be regarded as a veritable AID mutational signature.	('chromosomal translocations', 'Var', (69, 95))	('human', 'Species', '9606', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (106, 115))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
679991	25085003	Based on this, we have looked at the data from a recent study on EACs in which at least two mutational signatures had been observed: A to C transversions in the context of the ApA dinucleotide, and C to T transitions at CpG sites.	('EAC', 'Gene', (65, 68))	('Cs', 'Chemical', 'MESH:D002586', (67, 69))	('A to C transversions', 'Var', (133, 153))	('EAC', 'Gene', '1540', (65, 68))	('ApA dinucleotide', 'Chemical', '-', (176, 192))	('C to T', 'Var', (198, 204))
679992	25085003	Our re-analysis shows that mutations at non-CpG sites represent about 55% of all mutations at Cs, and the sequence context observed in these non-CpG mutations is similar to that ascribed to AID/APOBEC action (Figure 4B).	('mutations', 'Var', (27, 36))	('Cs', 'Chemical', 'MESH:D002586', (94, 96))	('mutations', 'Var', (149, 158))	('mutations', 'Var', (81, 90))
679995	25085003	Indeed, the pyrimidine/purine ratio in EACs is the lowest among the different tumors, with the tumors with high expression of APOBEC3B displaying the highest ratio (Additional file 5).	('APOBEC3B', 'Gene', '9582', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('purine', 'Chemical', 'MESH:C030985', (23, 29))	('rat', 'Species', '10116', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('high expression', 'Var', (107, 122))	('tumors', 'Disease', (95, 101))	('pyrimidine', 'Chemical', 'MESH:C030986', (12, 22))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('rat', 'Species', '10116', (30, 33))	('pyrimidine/purine ratio', 'MPA', (12, 35))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('EAC', 'Gene', '1540', (39, 42))	('APOBEC3B', 'Gene', (126, 134))	('EAC', 'Gene', (39, 42))	('Cs', 'Chemical', 'MESH:D002586', (41, 43))	('lowest', 'NegReg', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
679997	25085003	Indeed, a recent analysis of the somatic mutations in Barrett's esophagus reports that 71% of all mutations are targeted to C/G base pairs, with a strong bias towards transition mutations (Ts/Tv ratio at CpH sites of 1.69).	('transition mutations', 'Var', (167, 187))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (54, 73))	('mutations', 'Var', (98, 107))	('rat', 'Species', '10116', (195, 198))	('targeted', 'Reg', (112, 120))
680003	25085003	It is possible, therefore, that these changes, associated with APOBEC1 mutagenic activity, may also be boosting its oncogenic potential and drive both the onset and the progression of cancer.	('cancer', 'Disease', (184, 190))	('oncogenic potential', 'CPA', (116, 135))	('APOBEC1', 'Gene', (63, 70))	('drive', 'PosReg', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutagenic activity', 'Var', (71, 89))	('changes', 'Var', (38, 45))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('boosting', 'PosReg', (103, 111))
680024	25085003	In our sequencing we found evidence for at least five variants of the PCR-amplified BCR-ABL1 fragment, only one of which could translate a proper BCR-ABL1 fusion protein.	('BCR-ABL1', 'Gene', (146, 154))	('BCR-ABL1', 'Gene', (84, 92))	('BCR-ABL1', 'Gene', '613;25', (146, 154))	('BCR-ABL1', 'Gene', '613;25', (84, 92))	('variants', 'Var', (54, 62))	('or a', 'Gene', (37, 41))	('or a', 'Gene', '100170843', (37, 41))
680031	25085003	The trinucleotide representing the local context of mutations at C either from the DT40 experiments, from the EAC data, or from the control exome were then fed into the weblogo interface.	('mutations', 'Var', (52, 61))	('EAC', 'Gene', (110, 113))	('trinucleotide', 'Chemical', '-', (4, 17))	('DT40', 'Gene', (83, 87))	('EAC', 'Gene', '1540', (110, 113))
680040	23420099	The inhibitory effects of ABCC2 with MK571 did not correspond to those observed in the correlation analysis.	('MK571', 'Var', (37, 42))	('MK571', 'Chemical', 'MESH:C059141', (37, 42))	('ABCC2', 'Gene', '1244', (26, 31))	('ABCC2', 'Gene', (26, 31))
680068	23420099	Relative sensitivity was calculated as follows: Relative sensitivity = IC50 (without gimeracil or MK571)/IC50 (with gimeracil or MK571).	('MK571', 'Var', (129, 134))	('MK571', 'Chemical', 'MESH:C059141', (129, 134))	('MK571', 'Chemical', 'MESH:C059141', (98, 103))	('MK571', 'Var', (98, 103))	('gimeracil', 'Chemical', 'MESH:C104201', (85, 94))	('gimeracil', 'Chemical', 'MESH:C104201', (116, 125))	('gimeracil', 'Var', (116, 125))
680081	23420099	The sensitivity of KYSE30 cells to 5-FU was enhanced by gimeracil, but in the other cell lines gimeracil had no observable effect (Table VI).	('gimeracil', 'Chemical', 'MESH:C104201', (56, 65))	('sensitivity', 'MPA', (4, 15))	('gimeracil', 'Var', (56, 65))	('5-FU', 'Chemical', 'MESH:D005472', (35, 39))	('gimeracil', 'Chemical', 'MESH:C104201', (95, 104))	('enhanced', 'PosReg', (44, 52))
680082	23420099	In addition, gimeracil showed a tendency to decrease the sensitivity of all the cell lines to CDDP.	('gimeracil', 'Chemical', 'MESH:C104201', (13, 22))	('decrease', 'NegReg', (44, 52))	('CDDP', 'Chemical', '-', (94, 98))	('gimeracil', 'Var', (13, 22))	('sensitivity', 'MPA', (57, 68))
680084	23420099	However, the sensitivity of KYSE70 cells to 5-FU was substantially accelerated by the presence of MK571, and the sensitivity of OE33 cells to 5-FU was markedly decreased.	('accelerated', 'PosReg', (67, 78))	('sensitivity', 'MPA', (13, 24))	('presence', 'Var', (86, 94))	('MK571', 'Chemical', 'MESH:C059141', (98, 103))	('5-FU', 'Chemical', 'MESH:D005472', (142, 146))	('decreased', 'NegReg', (160, 169))	('MK571', 'Var', (98, 103))	('5-FU', 'Chemical', 'MESH:D005472', (44, 48))	('sensitivity', 'MPA', (113, 124))
680085	23420099	However, MK571 showed a tendency to decrease sensitivity to CDDP, with the exception of the KYSE30 and KYSE150 cell lines.	('sensitivity to CDDP', 'MPA', (45, 64))	('MK571', 'Var', (9, 14))	('MK571', 'Chemical', 'MESH:C059141', (9, 14))	('CDDP', 'Chemical', '-', (60, 64))	('decrease', 'NegReg', (36, 44))
680091	23420099	These findings suggest that sensitivity to 5-FU and CDDP was influenced by the growth activity of cells, although cytotoxic agents such as 5-FU and CDDP are known to be more toxic in cells with higher growth activity.	('5-FU', 'Chemical', 'MESH:D005472', (43, 47))	('CDDP', 'Chemical', '-', (52, 56))	('CDDP', 'Chemical', '-', (148, 152))	('influenced', 'Reg', (61, 71))	('CDDP', 'Var', (148, 152))	('5-FU', 'Chemical', 'MESH:D005472', (139, 143))
680108	23420099	Finally, the roles of ABCC2 and DPYD in sensitivity to 5-FU and CDDP were examined, since the knock-down of MSH2 in SW460 and HeLa cells has been reported to have no influence on sensitivity to 5-FU.	('ABCC2', 'Gene', (22, 27))	('DPYD', 'Gene', (32, 36))	('DPYD', 'Gene', '1806', (32, 36))	('SW460', 'CellLine', 'CVCL:0459', (116, 121))	('5-FU', 'Chemical', 'MESH:D005472', (55, 59))	('knock-down', 'Var', (94, 104))	('CDDP', 'Chemical', '-', (64, 68))	('MSH2', 'Gene', (108, 112))	('sensitivity to 5-FU', 'MPA', (179, 198))	('HeLa', 'CellLine', 'CVCL:0030', (126, 130))	('MSH2', 'Gene', '4436', (108, 112))	('5-FU', 'Chemical', 'MESH:D005472', (194, 198))	('ABCC2', 'Gene', '1244', (22, 27))
680112	23420099	The concomitant administration of 50 muM MK571, a representative ABCC2 inhibitor, was found to decrease the sensitivity of OE33 and KYSE150 cells to 5-FU.	('decrease', 'NegReg', (95, 103))	('MK571', 'Var', (41, 46))	('MK571', 'Chemical', 'MESH:C059141', (41, 46))	('ABCC2', 'Gene', (65, 70))	('ABCC2', 'Gene', '1244', (65, 70))	('sensitivity', 'MPA', (108, 119))	('muM', 'Gene', '56925', (37, 40))	('5-FU', 'Chemical', 'MESH:D005472', (149, 153))	('muM', 'Gene', (37, 40))
680116	23420099	These genes have the potential to affect the sensitivity to 5-FU and CDDP.	('genes', 'Var', (6, 11))	('sensitivity to 5-FU', 'MPA', (45, 64))	('affect', 'Reg', (34, 40))	('5-FU', 'Chemical', 'MESH:D005472', (60, 64))	('CDDP', 'MPA', (69, 73))	('CDDP', 'Chemical', '-', (69, 73))
680156	19327566	Opium dross and smoke condensates from opium and morphine cause mutations in S. typhimorium, sister chromatid exchanges in human lymphocytes, and morphological transformations in cultured Syrian hamster embryo cells.	('morphological transformations', 'CPA', (146, 175))	('sister chromatid exchanges', 'CPA', (93, 119))	('human', 'Species', '9606', (123, 128))	('cause', 'Reg', (58, 63))	('Syrian hamster', 'Species', '10036', (188, 202))	('S. typhimorium', 'Gene', (77, 91))	('morphine', 'Chemical', 'MESH:D009020', (49, 57))	('mutations', 'Var', (64, 73))
680175	19327566	Studies have shown that samples of pickled vegetables are mutagenic in the Ames test, can cause sister chromatid exchanges in Syrian hamster, and can also cause cancer when fed to rats.	('cancer', 'Disease', (161, 167))	('Ames test', 'CPA', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('sister chromatid exchanges', 'CPA', (96, 122))	('Syrian hamster', 'Species', '10036', (126, 140))	('mutagenic', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cause', 'Reg', (90, 95))	('rats', 'Species', '10116', (180, 184))	('cause', 'Reg', (155, 160))
680183	19327566	By the early 1980s, both epidemiologists and basic scientists had obtained intriguing evidence that vitamin and micronutrient deficiencies may play important roles in the etiology of EC and several other cancers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('deficiencies', 'Var', (126, 138))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))
680228	19327566	Oncogenic types of HPV, most notably HPV 16 and HPV 18, are necessary causes of cervical cancer, and also play an important role in the etiology of the epithelial cancers of the vulva, anus, penis, and oropharyngeal cavity.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('HPV', 'Species', '10566', (48, 51))	('HPV 16', 'Species', '333760', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('epithelial cancers of the vulva', 'Disease', 'MESH:D014846', (152, 183))	('causes', 'Reg', (70, 76))	('epithelial cancers of the vulva', 'Disease', (152, 183))	('HPV', 'Species', '10566', (19, 22))	('HPV 16', 'Var', (37, 43))	('cancers of the vulva', 'Phenotype', 'HP:0030416', (163, 183))	('HPV', 'Species', '10566', (37, 40))	('cervical cancer', 'Disease', (80, 95))	('cervical cancer', 'Disease', 'MESH:D002583', (80, 95))	('HPV 18', 'Var', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
680267	19327566	In vitro, acetaldehyde causes point mutations in human lymphocytes, sister chromatic exchanges, cellular proliferation, and inhibits DNA repair.	('point mutations', 'Var', (30, 45))	('causes', 'Reg', (23, 29))	('inhibits', 'NegReg', (124, 132))	('DNA repair', 'MPA', (133, 143))	('sister chromatic exchanges', 'CPA', (68, 94))	('human', 'Species', '9606', (49, 54))	('acetaldehyde', 'Chemical', 'MESH:D000079', (10, 22))	('cellular proliferation', 'CPA', (96, 118))
680269	19327566	Since then, genetic polymorphisms in ADH genes and ALDH2 that favor the accumulation of acetaldehyde have been observed to increase ESCC risk, thus adding to the evidence of acetaldehyde carcinogenicity in humans.	('increase ESCC', 'Phenotype', 'HP:0003565', (123, 136))	('ADH', 'Gene', (37, 40))	('ADH', 'Gene', '10327', (37, 40))	('acetaldehyde', 'Chemical', 'MESH:D000079', (88, 100))	('accumulation of acetaldehyde', 'MPA', (72, 100))	('acetaldehyde', 'Chemical', 'MESH:D000079', (174, 186))	('polymorphisms', 'Var', (20, 33))	('ALDH2', 'Gene', '217', (51, 56))	('increase', 'PosReg', (123, 131))	('carcinogenic', 'Disease', 'MESH:D063646', (187, 199))	('accumulation of acetaldehyde', 'Phenotype', 'HP:0003533', (72, 100))	('carcinogenic', 'Disease', (187, 199))	('ALDH2', 'Gene', (51, 56))	('humans', 'Species', '9606', (206, 212))	('ESCC', 'Disease', (132, 136))
680315	19327566	If these associations are indeed causal, there are several mechanistic hypotheses: (a) changes in oral microbial flora which result in both poor oral health and in increased production of carcinogens such as nitrosamines and acetaldehyde; (b) physical irritation and damage to the esophageal epithelium due to swallowing unchewed food; (c) change in dietary patterns and nutrient intake due to poor dentition; (d) infection of the esophageal mucosa with an oral microorganism; (e) genetic factors that affect both oral health and EC.	('esophageal', 'Disease', (431, 441))	('esophageal', 'Disease', (281, 291))	('infection of the esophageal mucosa', 'Disease', 'MESH:D004941', (414, 448))	('acetaldehyde', 'Chemical', 'MESH:D000079', (225, 237))	('irritation', 'Disease', (252, 262))	('nitrosamines', 'Chemical', 'MESH:D009602', (208, 220))	('esophageal', 'Disease', 'MESH:D004941', (431, 441))	('esophageal', 'Disease', 'MESH:D004941', (281, 291))	('irritation', 'Disease', 'MESH:D001523', (252, 262))	('poor oral', 'Phenotype', 'HP:0000160', (140, 149))	('infection of the esophageal mucosa', 'Disease', (414, 448))	('changes', 'Var', (87, 94))
680328	19327566	Absence of H. pylori in the stomach is also becoming increasingly recognized as a risk factor.	('Absence', 'Var', (0, 7))	('H. pylori', 'Protein', (11, 20))	('H. pylori', 'Species', '210', (11, 20))
680341	16277658	In conclusion, results of the present study suggest that alterations of retinoic acid receptors protein may contribute in the development of SCC in esophagus and that in some patients life style (e.g.	('esophagus', 'Disease', (148, 157))	('SCC', 'Gene', (141, 144))	('alterations', 'Var', (57, 68))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('SCC', 'Gene', '6317', (141, 144))	('patients', 'Species', '9606', (175, 183))	('retinoic', 'Protein', (72, 80))	('retinoic acid', 'Chemical', 'MESH:D014212', (72, 85))	('contribute', 'Reg', (108, 118))
680354	16277658	An association between altered expression of nuclear retinoic acid receptors and the malignant transformation of human cells has been demonstrated in several studies.	('malignant transformation of human cells', 'CPA', (85, 124))	('retinoic acid', 'Chemical', 'MESH:D014212', (53, 66))	('expression', 'MPA', (31, 41))	('nuclear retinoic', 'Protein', (45, 61))	('altered', 'Var', (23, 30))	('human', 'Species', '9606', (113, 118))
680429	28548040	In addition, overexpression of PAQR3 downregulated the protein expression levels of RAF1, p-MEK1, and p-ERK1/2 in esophageal cancer cells.	('downregulated', 'NegReg', (37, 50))	('RAF1', 'Gene', (84, 88))	('RAF1', 'Gene', '5894', (84, 88))	('MEK1', 'Gene', '5604', (92, 96))	('p-ERK1/2', 'Var', (102, 110))	('MEK1', 'Gene', (92, 96))	('PAQR3', 'Gene', (31, 36))	('PAQR3', 'Gene', '152559', (31, 36))	('esophageal cancer', 'Disease', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('overexpression', 'PosReg', (13, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('protein expression levels', 'MPA', (55, 80))
680477	28548040	The results revealed that U0126 treatment greatly enhanced the inhibitory effects of PAQR3 on EC9706 cell proliferation (Fig.	('inhibitory effects', 'MPA', (63, 81))	('PAQR3', 'Gene', (85, 90))	('PAQR3', 'Gene', '152559', (85, 90))	('U0126', 'Var', (26, 31))	('enhanced', 'PosReg', (50, 58))	('EC9706', 'CellLine', 'CVCL:E307', (94, 100))	('U0126', 'Chemical', 'MESH:C113580', (26, 31))	('EC9706 cell proliferation', 'CPA', (94, 119))
680574	32212808	Similarly, in the laryngeal cancer group, after adjustment for other confounding factors, alcohol use was associated with an increased risk of laryngeal cancer (Adjusted OR: 5.00; 95% CI: 1.72-14.48).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('alcohol use', 'Var', (90, 101))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('alcohol use', 'Phenotype', 'HP:0030955', (90, 101))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (18, 34))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('men', 'Species', '9606', (54, 57))	('alcohol', 'Chemical', 'MESH:D000438', (90, 97))	('cancer', 'Disease', (28, 34))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (143, 159))
680584	32212808	Evidence provided by this study intensifies the existence of a causal relation between opium use and H and N cancers, as the relation observed in this study was relatively strong and opium use increased the risk of H and N cancers and laryngeal cancer over 12 and about 17 times respectively.	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('H and N cancers', 'Disease', 'MESH:D009369', (215, 230))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Disease', (245, 251))	('cancer', 'Disease', (109, 115))	('H and N cancers', 'Disease', 'MESH:D009369', (101, 116))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('increased', 'PosReg', (193, 202))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (235, 251))	('opium', 'Var', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
680595	32212808	Also pyrolysis and alkaloids of morphine lead to sister chromatic exchange in human lymphocytes and morphological changes in cultured Syrian hamster embryo cells (Perry et al., 1983).	('pyrolysis', 'Var', (5, 14))	('Syrian hamster', 'Species', '10036', (134, 148))	('morphine', 'Chemical', 'MESH:D009020', (32, 40))	('sister chromatic exchange', 'MPA', (49, 74))	('lead to', 'Reg', (41, 48))	('human', 'Species', '9606', (78, 83))	('morphological changes', 'CPA', (100, 121))
680597	32212808	It has also been shown that pyrolysis and aromatic hydrocarbons (PAHs) released from burning opioid substances indirectly lead to DNA damage and, as a result, may stimulate mutagenic mechanisms (Nasrollahzadeh et al., 2008).	('PAHs', 'Chemical', '-', (65, 69))	('lead to', 'Reg', (122, 129))	('DNA damage', 'MPA', (130, 140))	('pyrolysis', 'Var', (28, 37))	('mutagenic mechanisms', 'CPA', (173, 193))	('aromatic hydrocarbons', 'Chemical', 'MESH:D006841', (42, 63))	('D', 'Chemical', 'MESH:D003903', (130, 131))	('stimulate', 'PosReg', (163, 172))
680601	32212808	The non-organic lead in these drugs can cause severe toxic and even carcinogenic effects (Hayatbakhsh et al., 2017).	('cause', 'Reg', (40, 45))	('carcinogenic effects', 'Disease', (68, 88))	('toxic', 'CPA', (53, 58))	('non-organic', 'Var', (4, 15))	('carcinogenic effects', 'Disease', 'MESH:D020018', (68, 88))
680711	32746883	These data suggest that PDCD6 has the potential clinical value as a predictive biomarker for disease diagnosis in CRC and the patients with CRC benefit from the elimination of PDCD6.	('elimination', 'Var', (161, 172))	('PDCD6', 'Gene', (24, 29))	('PDCD6', 'Gene', (176, 181))	('patients', 'Species', '9606', (126, 134))	('CRC', 'Disease', (114, 117))
680713	32746883	Proliferation assays and colony formation assays showed that both cell proliferation and the colony formation ability were decreased in PDCD6-KD HCT116 and HCT15 cells compared with cells expressing the vector control (Fig.	('decreased', 'NegReg', (123, 132))	('cell proliferation', 'CPA', (66, 84))	('HCT15', 'CellLine', 'CVCL:0292', (156, 161))	('colony formation ability', 'CPA', (93, 117))	('HCT116', 'Gene', (145, 151))	('HCT116', 'CellLine', 'CVCL:0291', (145, 151))	('PDCD6-KD', 'Var', (136, 144))
680715	32746883	The tumor sizes of the PDCD6-KD group xenografts were markedly smaller than those in the control group (Fig.	('PDCD6-KD group', 'Var', (23, 37))	('tumor', 'Disease', (4, 9))	('smaller', 'NegReg', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('raf', 'Gene', '22882', (43, 46))	('raf', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
680717	32746883	Accordingly, the weights of tumors originating from PDCD6-KD HCT116 and HCT115 cells decreased more than 2- and 3-fold respectively compared with those originating from the control cells (Fig.	('weights', 'CPA', (17, 24))	('decreased', 'NegReg', (85, 94))	('HCT116', 'CellLine', 'CVCL:0291', (61, 67))	('PDCD6-KD', 'Var', (52, 60))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('HCT115', 'CellLine', 'CVCL:M747', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('HCT116', 'Gene', (61, 67))
680718	32746883	Collectively, these in vitro and in vivo experiments demonstrate that PDCD6 depletion significantly inhibits tumor cell growth.	('inhibits', 'NegReg', (100, 108))	('PDCD6', 'Gene', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('depletion', 'Var', (76, 85))	('tumor', 'Disease', (109, 114))
680723	32746883	The tumor sizes and weights of the PDCD6-OE group xenografts were significantly greater than those of the vector control xenografts (Fig.	('tumor', 'Disease', (4, 9))	('raf', 'Gene', (126, 129))	('raf', 'Gene', '22882', (55, 58))	('raf', 'Gene', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('greater', 'PosReg', (80, 87))	('raf', 'Gene', '22882', (126, 129))	('PDCD6-OE', 'Var', (35, 43))
680726	32746883	To further investigate the functionally grouped networks in CRC, the ClueGO and the CluePedia plugins of in Cytoscape were used to identify the enriched pathways involved in tumorigenesis and to observe a functionally grouped network between the PDCD6-KD and the control groups.	('tumor', 'Disease', (174, 179))	('PDCD6-KD', 'Var', (246, 254))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
680742	32746883	Immunoblotting analysis revealed that increased phosphorylation of MEK and ERK in the PDCD6-OE HCT116 cell line was significantly inhibited by RAF709 and Trametinib (Fig.	('ERK', 'Gene', '5594', (75, 78))	('HCT116', 'CellLine', 'CVCL:0291', (95, 101))	('inhibited', 'NegReg', (130, 139))	('ERK', 'Gene', (75, 78))	('RAF709', 'Chemical', 'MESH:C000621808', (143, 149))	('phosphorylation', 'MPA', (48, 63))	('MEK', 'Gene', (67, 70))	('Trametinib', 'Chemical', 'MESH:C560077', (154, 164))	('RAF709', 'Var', (143, 149))	('MEK', 'Gene', '5609', (67, 70))
680743	32746883	Furthermore, we compared the inhibition function by PDCD6-KD and c-Raf KD, and their combination in the MAPK pathway.	('MAPK pathway', 'Pathway', (104, 116))	('PDCD6-KD', 'Var', (52, 60))	('inhibition', 'NegReg', (29, 39))	('c-Raf', 'Gene', '5894', (65, 70))	('c-Raf', 'Gene', (65, 70))
680744	32746883	The results showed the inhibition effect of PDCD6-KD and c-Raf-KD was obviously, in which p- MEK and p-ERK were decreased dramatically.	('ERK', 'Gene', (103, 106))	('PDCD6-KD', 'Var', (44, 52))	('MEK', 'Gene', (93, 96))	('c-Raf', 'Gene', '5894', (57, 62))	('c-Raf', 'Gene', (57, 62))	('MEK', 'Gene', '5609', (93, 96))	('decreased', 'NegReg', (112, 121))	('ERK', 'Gene', '5594', (103, 106))
680748	32746883	RAF709 and Trametinib could also inhibited cell proliferation (Supplementary Fig.	('Trametinib', 'Chemical', 'MESH:C560077', (11, 21))	('RAF709', 'Chemical', 'MESH:C000621808', (0, 6))	('RAF709', 'Var', (0, 6))	('cell proliferation', 'CPA', (43, 61))	('inhibited', 'NegReg', (33, 42))
680752	32746883	Immunohistochemical examination of the tumor xenografts revealed that the phosphorylation of c-Raf/MEK/ERK was markedly suppressed in PDCD6-KD HCT116 cells xenografts, whereas c-Raf/MEK/ERK phosphorylation was markedly enhanced in the PDCD6-OE compared with the vector control cell xenografts.	('phosphorylation', 'MPA', (74, 89))	('ERK', 'Gene', '5594', (186, 189))	('suppressed', 'NegReg', (120, 130))	('MEK', 'Gene', (182, 185))	('c-Raf', 'Gene', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('raf', 'Gene', (50, 53))	('c-Raf', 'Gene', '5894', (93, 98))	('raf', 'Gene', (161, 164))	('MEK', 'Gene', '5609', (99, 102))	('ERK', 'Gene', (186, 189))	('raf', 'Gene', (287, 290))	('ERK', 'Gene', '5594', (103, 106))	('MEK', 'Gene', (99, 102))	('c-Raf', 'Gene', (93, 98))	('HCT116', 'CellLine', 'CVCL:0291', (143, 149))	('raf', 'Gene', '22882', (50, 53))	('raf', 'Gene', '22882', (161, 164))	('tumor', 'Disease', (39, 44))	('PDCD6-KD HCT116', 'Var', (134, 149))	('c-Raf', 'Gene', '5894', (176, 181))	('ERK', 'Gene', (103, 106))	('MEK', 'Gene', '5609', (182, 185))	('enhanced', 'PosReg', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('raf', 'Gene', '22882', (287, 290))
680768	32746883	The functional experiments showed that PDCD6 depletion significantly inhibited colorectal cancer tumorigenesis and PDCD6 overexpression enhanced the proliferation and tumor growth of CRC cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('enhanced', 'PosReg', (136, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('colorectal cancer', 'Disease', (79, 96))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (97, 102))	('proliferation', 'CPA', (149, 162))	('PDCD6', 'Gene', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('inhibited', 'NegReg', (69, 78))	('depletion', 'Var', (45, 54))	('tumor', 'Disease', (167, 172))
680786	32746883	RAF709 and Trametinib, which are effective MAPK pathway effective inhibitors, have been shown to be anticancer agents in multiple tumor types.	('tumor', 'Disease', (130, 135))	('Trametinib', 'Chemical', 'MESH:C560077', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('RAF709', 'Var', (0, 6))	('RAF709', 'Chemical', 'MESH:C000621808', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
680788	32746883	Moreover, these findings suggest the potential for antagonizing Raf/MEK/ERK signaling as a strategy to inhibit the growth of tumors hyperactivated by PDCD6.	('PDCD6', 'Gene', (150, 155))	('ERK', 'Gene', (72, 75))	('tumors hyperactivated', 'Disease', 'MESH:D011504', (125, 146))	('MEK', 'Gene', '5609', (68, 71))	('Raf', 'Gene', '22882', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Raf', 'Gene', (64, 67))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('antagonizing', 'Var', (51, 63))	('tumors hyperactivated', 'Disease', (125, 146))	('growth', 'MPA', (115, 121))	('ERK', 'Gene', '5594', (72, 75))	('inhibit', 'NegReg', (103, 110))	('MEK', 'Gene', (68, 71))
680802	32746883	2018YFC1003500), the National Natural Science Foundation of China (81672472, 81672461, and 31725013), the National Key Basic Research Program of China (2015CB943001), the State Key Project on Infection Diseases of China (2017ZX10201021-007-003), and the State Key Laboratory Special fund from the Ministry of Science (2060204).	('81672461', 'Var', (77, 85))	('Infection', 'Disease', (192, 201))	('31725013', 'Var', (91, 99))	('Infection', 'Disease', 'MESH:D007239', (192, 201))	('81672472', 'Var', (67, 75))
680808	31636510	CircPVT1-specific siRNA or plasmids were used to knock down or overexpression the target RNA.	('PVT1', 'Gene', (4, 8))	('knock down', 'Var', (49, 59))	('PVT1', 'Gene', '5820', (4, 8))	('overexpression', 'PosReg', (63, 77))
680814	31636510	In addition, overexpressing circPVT1 in TE-10 cell promoted invasive ability of cancer cell.	('PVT1', 'Gene', '5820', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('promoted', 'PosReg', (51, 59))	('overexpressing', 'Var', (13, 27))	('PVT1', 'Gene', (32, 36))	('cir', 'Gene', (28, 31))	('cancer', 'Disease', (80, 86))	('cir', 'Gene', '9541', (28, 31))
680815	31636510	In contrast, siRNA knockdown of circPVT1 inhibited this phenomenon, leading to increased apoptosis levels of TE-10 cell.	('increased', 'PosReg', (79, 88))	('cir', 'Gene', (32, 35))	('PVT1', 'Gene', '5820', (36, 40))	('cir', 'Gene', '9541', (32, 35))	('knockdown', 'Var', (19, 28))	('apoptosis levels', 'MPA', (89, 105))	('inhibited', 'NegReg', (41, 50))	('PVT1', 'Gene', (36, 40))
680828	31636510	Whereas, the disordered expression of circRNAs leads to a variety of diseases including tumors.	('leads to', 'Reg', (47, 55))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('cir', 'Gene', '9541', (38, 41))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('cir', 'Gene', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('disordered', 'Var', (13, 23))	('tumors', 'Disease', (88, 94))	('diseases', 'Disease', (69, 77))
680880	31636510	The number of positive cells was up-regulated by siRNAs, indicating that silencing circ-PVT1 subsequently reduced the survival ability of cancer cells (Fig.	('silencing', 'Var', (73, 82))	('cancer', 'Disease', (138, 144))	('cir', 'Gene', '9541', (83, 86))	('PVT1', 'Gene', '5820', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cir', 'Gene', (83, 86))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('reduced', 'NegReg', (106, 113))	('PVT1', 'Gene', (88, 92))
680881	31636510	Taken together, these data suggested that circPVT1 knockdown by siRNA might partially impeded the proliferation of EC cells and leaded to apoptosis in vitro.	('PVT1', 'Gene', '5820', (46, 50))	('leaded to', 'Reg', (128, 137))	('EC', 'Phenotype', 'HP:0011459', (115, 117))	('EC', 'Disease', 'MESH:D004938', (115, 117))	('impeded', 'NegReg', (86, 93))	('apoptosis', 'CPA', (138, 147))	('PVT1', 'Gene', (46, 50))	('cir', 'Gene', (42, 45))	('cir', 'Gene', '9541', (42, 45))	('knockdown', 'Var', (51, 60))
680886	31636510	To confirm whether this enhanced invasive ability was caused by over-expressed circPVT1, the overexpression plasmid was transfected wi siRNA and it was found that the invasive ability of tumor cells was inhibited and returned to the level of the control group (Fig.	('cir', 'Gene', '9541', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('invasive ability', 'CPA', (33, 49))	('PVT1', 'Gene', (83, 87))	('enhanced', 'PosReg', (24, 32))	('inhibited', 'NegReg', (203, 212))	('tumor', 'Disease', (187, 192))	('invasive ability', 'CPA', (167, 183))	('over-expressed', 'Var', (64, 78))	('cir', 'Gene', (79, 82))	('PVT1', 'Gene', '5820', (83, 87))
680915	31636510	CircPVT1 has flanks two long introns (35269 bp and 41466 bp), which contains many Alu repeats.	('35269 bp', 'Var', (38, 46))	('PVT1', 'Gene', (4, 8))	('PVT1', 'Gene', '5820', (4, 8))	('41466 bp', 'Var', (51, 59))
680921	31636510	The result showed that circPVT1 knockdown by siRNA might partly impeded the proliferation of EC cells and leaded to apoptosis in vitro, overexpression of circ-PVT1 can increase the invasive ability of TE-10 cells, and this phenomenon disappeared after knockdown of circ-PVT.	('increase', 'PosReg', (168, 176))	('leaded to', 'Reg', (106, 115))	('invasive ability of TE-10 cells', 'CPA', (181, 212))	('PVT1', 'Gene', (159, 163))	('EC', 'Phenotype', 'HP:0011459', (93, 95))	('PVT1', 'Gene', '5820', (159, 163))	('apoptosis', 'CPA', (116, 125))	('impeded', 'NegReg', (64, 71))	('EC', 'Disease', 'MESH:D004938', (93, 95))	('cir', 'Gene', '9541', (23, 26))	('cir', 'Gene', (23, 26))	('PVT1', 'Gene', (27, 31))	('overexpression', 'PosReg', (136, 150))	('cir', 'Gene', '9541', (154, 157))	('PVT1', 'Gene', '5820', (27, 31))	('cir', 'Gene', '9541', (265, 268))	('cir', 'Gene', (154, 157))	('knockdown', 'Var', (32, 41))	('cir', 'Gene', (265, 268))
680977	27330313	Molecular epidemiological studies suggest that HOTAIR polymorphisms may be associated with cancer susceptibility, but the results remain controversial.	('polymorphisms', 'Var', (54, 67))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('HOTAIR', 'Gene', (47, 53))	('HOTAIR', 'Gene', '100124700', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (75, 85))
680978	27330313	To derive a more precise evaluation, we performed a meta-analysis focused on the associations between HOTAIR polymorphisms and cancer risk for the first time.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('polymorphisms', 'Var', (109, 122))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('HOTAIR', 'Gene', (102, 108))	('cancer', 'Disease', (127, 133))	('associations', 'Interaction', (81, 93))	('HOTAIR', 'Gene', '100124700', (102, 108))
680979	27330313	Odds ratios (ORs) with 95% confidence interval (CI) were applied to assess the association between HOTAIR rs920778 C>T, rs4759314 A>G, rs7958904 G>C, and rs1899663 G>T polymorphisms and cancer susceptibility.	('rs920778', 'Mutation', 'rs920778', (106, 114))	('rs7958904', 'Mutation', 'rs7958904', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('rs1899663', 'Mutation', 'rs1899663', (154, 163))	('association', 'Interaction', (79, 90))	('HOTAIR', 'Gene', (99, 105))	('rs4759314 A>G', 'Var', (120, 133))	('rs920778 C>T', 'Var', (106, 118))	('HOTAIR', 'Gene', '100124700', (99, 105))	('rs1899663 G>T', 'Var', (154, 167))	('rs7958904 G>C', 'Var', (135, 148))	('rs4759314', 'Mutation', 'rs4759314', (120, 129))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
680981	27330313	Significant associations between the HOTAIR rs920778 polymorphism and cancer risk were observed (T vs C: OR =1.33, 95% CI =1.17-1.53; TT vs TC + CC: OR =1.55, 95% CI =1.21-2.00; TC + TT vs CC: OR =1.33, 95% CI =1.11-1.59; TT vs CC: OR =2.02, 95% CI =1.31-3.10) in the total population, as well as in subgroup analyses.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('HOTAIR', 'Gene', (37, 43))	('TC', 'Chemical', 'MESH:D013667', (140, 142))	('TC', 'Chemical', 'MESH:D013667', (178, 180))	('HOTAIR', 'Gene', '100124700', (37, 43))	('rs920778 polymorphism', 'Var', (44, 65))	('polymorphism', 'Var', (53, 65))	('rs920778', 'Mutation', 'rs920778', (44, 52))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
680982	27330313	For rs4759314 A>G polymorphism, a similarly increased risk was found in the gastric cancer group.	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('gastric cancer', 'Disease', (76, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('rs4759314 A>G', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rs4759314', 'Mutation', 'rs4759314', (4, 13))
680983	27330313	However, significant decreases in cancer risk were observed both in the overall population and colorectal cancer group for rs7958904 G>C polymorphism.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('colorectal cancer', 'Disease', (95, 112))	('decreases', 'NegReg', (21, 30))	('rs7958904 G>C', 'Var', (123, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', (34, 40))	('rs7958904', 'Mutation', 'rs7958904', (123, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
680984	27330313	In addition, no significant association was detected between rs1899663 G>T polymorphism and cancer susceptibility.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('rs1899663', 'Mutation', 'rs1899663', (61, 70))	('rs1899663 G>T', 'Var', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
680985	27330313	In conclusion, our meta-analyses suggest that HOTAIR polymorphisms may be associated with the risk of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('HOTAIR', 'Gene', (46, 52))	('cancer', 'Disease', (102, 108))	('HOTAIR', 'Gene', '100124700', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('polymorphisms', 'Var', (53, 66))	('associated', 'Reg', (74, 84))
680995	27330313	Therefore, increasing studies have investigated the single nucleotide polymorphisms (SNPs) in the HOTAIR locus with cancer risk.	('single nucleotide polymorphisms', 'Var', (52, 83))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('HOTAIR', 'Gene', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HOTAIR', 'Gene', '100124700', (98, 104))
680996	27330313	Thus, a comprehensive meta-analysis involving the related studies was performed to assess the possible association between HOTAIR polymorphisms and cancer susceptibility.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('polymorphisms', 'Var', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('HOTAIR', 'Gene', (123, 129))	('HOTAIR', 'Gene', '100124700', (123, 129))
680997	27330313	The PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases were searched to identify studies that examined the association between HOTAIR polymorphisms and cancer susceptibility prior to January 31, 2016.	('HOTAIR', 'Gene', (155, 161))	('HOTAIR', 'Gene', '100124700', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('polymorphisms', 'Var', (162, 175))	('cancer', 'Disease', (180, 186))
680998	27330313	The following medical subject heading terms were used: (HOTAIR OR HOX transcript antisense RNA OR long noncoding RNA OR lncRNA OR lincRNA) AND (cancer OR carcinoma OR tumor OR neoplasia OR neoplasm) AND (polymorphism OR genotype OR allele OR variant OR SNP).	('HOTAIR', 'Gene', (56, 62))	('carcinoma OR tumor', 'Disease', (154, 172))	('neoplasia', 'Phenotype', 'HP:0002664', (176, 185))	('neoplasia OR neoplasm', 'Disease', 'MESH:D009369', (176, 197))	('HOTAIR', 'Gene', '100124700', (56, 62))	('neoplasia OR neoplasm', 'Disease', (176, 197))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('antisense', 'Var', (81, 90))	('cancer', 'Disease', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinoma OR tumor', 'Disease', 'MESH:D009369', (154, 172))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
681001	27330313	ORs with 95% CIs were used to assess the strength of the association between the HOTAIR polymorphisms and cancer risk.	('polymorphisms', 'Var', (88, 101))	('HOTAIR', 'Gene', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('association', 'Interaction', (57, 68))	('HOTAIR', 'Gene', '100124700', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
681002	27330313	For the HOTAIR rs920778 C>T polymorphism, the pooled ORs were obtained for allele (T vs C), recessive (TT vs TC + CC), dominant (TC + TT vs CC), and homozygous (co-dominant) model (TT vs CC).	('HOTAIR', 'Gene', (8, 14))	('rs920778 C>T', 'Var', (15, 27))	('TC', 'Chemical', 'MESH:D013667', (109, 111))	('TC', 'Chemical', 'MESH:D013667', (129, 131))	('HOTAIR', 'Gene', '100124700', (8, 14))	('rs920778', 'Mutation', 'rs920778', (15, 23))
681003	27330313	Similar genetic models were also assessed for HOTAIR rs4759314 A>G, rs7958904 G>C, and rs1899663 G>T variants.	('rs1899663', 'Mutation', 'rs1899663', (87, 96))	('rs1899663 G>T', 'Var', (87, 100))	('HOTAIR', 'Gene', (46, 52))	('rs4759314 A>G', 'Var', (53, 66))	('rs7958904 G>C', 'Var', (68, 81))	('HOTAIR', 'Gene', '100124700', (46, 52))	('rs4759314', 'Mutation', 'rs4759314', (53, 62))	('rs7958904', 'Mutation', 'rs7958904', (68, 77))
681005	27330313	Ultimately, eight eligible articles were selected with adequate data, including eight studies on rs920778 C>T, eight studies on rs4759314 A>G, three publications on rs1899663 G>T, and three studies on rs7958904 G>C, respectively.	('rs4759314 A>G', 'Var', (128, 141))	('rs7958904', 'Mutation', 'rs7958904', (201, 210))	('rs920778 C>T', 'Var', (97, 109))	('rs920778', 'Mutation', 'rs920778', (97, 105))	('rs4759314', 'Mutation', 'rs4759314', (128, 137))	('rs1899663 G>T', 'Var', (165, 178))	('rs1899663', 'Mutation', 'rs1899663', (165, 174))
681006	27330313	The genotype distribution was in agreement with HWE in all studies except for one study of HOTAIR rs920778 C>T polymorphism.	('HOTAIR', 'Gene', (91, 97))	('HOTAIR', 'Gene', '100124700', (91, 97))	('rs920778 C>T', 'Var', (98, 110))	('rs920778', 'Mutation', 'rs920778', (98, 106))
681007	27330313	A total of eight relevant studies, consisting of 3,627 patients and 4,585 controls, were examined for the association between the HOTAIR rs920778 C>T polymorphism and cancer risk.	('association', 'Interaction', (106, 117))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('HOTAIR', 'Gene', (130, 136))	('rs920778 C>T', 'Var', (137, 149))	('HOTAIR', 'Gene', '100124700', (130, 136))	('patients', 'Species', '9606', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('rs920778', 'Mutation', 'rs920778', (137, 145))
681010	27330313	Enhanced cancer risk was also observed in the subgroup analysis with genotyping method of restriction fragment length polymorphism under all four genetic models.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('restriction fragment length polymorphism', 'Var', (90, 130))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('Enhanced', 'PosReg', (0, 8))
681013	27330313	Eight studies consisting of 5,526 cases and 6,659 controls were included in the analysis to determine whether the HOTAIR rs4759314 A>G polymorphism was associated with cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('HOTAIR', 'Gene', (114, 120))	('rs4759314', 'Mutation', 'rs4759314', (121, 130))	('HOTAIR', 'Gene', '100124700', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('rs4759314 A>G', 'Var', (121, 134))	('associated', 'Reg', (152, 162))
681014	27330313	Only two genetic models (for G vs A, OR =1.29, 95% CI =1.10-1.51, P=0.002, I2=43.5%; for GA + GG vs AA, OR =1.32, 95% CI =1.12-1.56, P=0.001, I2=44.0%) revealed increased risk in the gastric cancer group.	('gastric cancer', 'Disease', (183, 197))	('gastric cancer', 'Disease', 'MESH:D013274', (183, 197))	('GA + GG', 'Var', (89, 96))	('gastric cancer', 'Phenotype', 'HP:0012126', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
681015	27330313	Three eligible studies including 2,487 cases and 2,912 controls focused on the association of HOTAIR rs7958904 G>C polymorphism with cancer.	('rs7958904', 'Mutation', 'rs7958904', (101, 110))	('HOTAIR', 'Gene', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('HOTAIR', 'Gene', '100124700', (94, 100))	('association', 'Interaction', (79, 90))	('cancer', 'Disease', (133, 139))	('rs7958904 G>C', 'Var', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
681016	27330313	A significant decrease in cancer risk was observed in the overall population (C vs G: OR =0.85, 95% CI =0.78-0.93, P<0.001, I2=0%; CG + CC vs GG: OR =0.84, 95% CI =0.76-0.94, P=0.002, I2=0; CC vs GG: OR =0.72, 95% CI =0.58-0.89, P=0.002, I2=0; Table 2).	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('CG', 'Chemical', 'MESH:C028505', (131, 133))	('decrease', 'NegReg', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('CG + CC', 'Var', (131, 138))
681019	27330313	Three studies with 2,002 cases and 2,504 controls were included in the HOTAIR rs1899663 G>T polymorphism and cancer risk research.	('rs1899663 G>T polymorphism', 'Var', (78, 104))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('HOTAIR', 'Gene', (71, 77))	('cancer', 'Disease', (109, 115))	('HOTAIR', 'Gene', '100124700', (71, 77))	('rs1899663', 'Mutation', 'rs1899663', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
681022	27330313	SNPs in several lncRNAs previously identified to be involved in carcinogenesis have been reported to be associated with cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('lncRNAs', 'Gene', (16, 23))	('cancer', 'Disease', (120, 126))	('carcinogenesis', 'Disease', (64, 78))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('SNPs', 'Var', (0, 4))	('associated', 'Reg', (104, 114))
681023	27330313	Recently, several molecular epidemiological studies have been conducted to evaluate the association between polymorphisms of HOTAIR and the risk of cancer development, but results have remained conflicting.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('HOTAIR', 'Gene', '100124700', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('polymorphisms', 'Var', (108, 121))	('HOTAIR', 'Gene', (125, 131))
681024	27330313	Regarding the HOTAIR rs920778 C>T polymorphism, Pan et al reported that the TT carriers had a 1.66- and 1.87-fold increased gastric cancer risk in Jinan and Huaian populations of People's Republic of China compared with the CC carriers.	('gastric cancer', 'Disease', (124, 138))	('rs920778', 'Mutation', 'rs920778', (21, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('HOTAIR', 'Gene', '100124700', (14, 20))	('increased gastric', 'Phenotype', 'HP:0005207', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('People', 'Species', '9606', (179, 185))	('rs920778 C>T', 'Var', (21, 33))	('increased gastric cancer', 'Phenotype', 'HP:0006753', (114, 138))	('HOTAIR', 'Gene', (14, 20))
681027	27330313	To our knowledge, this is the first meta-analysis to date focused on the association between polymorphisms in lncRNA HOTAIR and cancer susceptibility specially.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('HOTAIR', 'Gene', '100124700', (117, 123))	('HOTAIR', 'Gene', (117, 123))	('lncRNA', 'Gene', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('polymorphisms', 'Var', (93, 106))	('cancer', 'Disease', (128, 134))
681029	27330313	Overall, significant increased risk of cancer was observed for the HOTAIR rs920778 C>T polymorphism.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('HOTAIR', 'Gene', (67, 73))	('HOTAIR', 'Gene', '100124700', (67, 73))	('rs920778 C>T', 'Var', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('rs920778', 'Mutation', 'rs920778', (74, 82))
681030	27330313	In subgroup analyses by ethnicity, we found that individuals with the T allele and mutated genotypes had a significant increased cancer risk in Asian populations, suggesting that the increased cancer risk may be ethno-specific.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutated', 'Var', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('T allele', 'Var', (70, 78))
681032	27330313	Similarly, the result that rs4759314 A>G polymorphism just increased the risk of gastric cancer rather than other types of cancers was revealed in our meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('increased the risk of gastric cancer', 'Phenotype', 'HP:0006753', (59, 95))	('rs4759314', 'Mutation', 'rs4759314', (27, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('gastric cancer', 'Disease', (81, 95))	('cancers', 'Disease', (123, 130))	('rs4759314 A>G', 'Var', (27, 40))	('increased', 'PosReg', (59, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
681033	27330313	While significant decreases in cancer risk were observed both in overall population and colorectal cancer group, indicating that rs7958904 G>C polymorphism might be a protective factor especially for colorectal cancer.	('colorectal cancer', 'Disease', (88, 105))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('decreases', 'NegReg', (18, 27))	('colorectal cancer', 'Disease', 'MESH:D015179', (200, 217))	('rs7958904 G>C', 'Var', (129, 142))	('rs7958904', 'Mutation', 'rs7958904', (129, 138))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (211, 217))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (200, 217))	('colorectal cancer', 'Disease', (200, 217))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
681036	27330313	First, heterogeneity across studies existed for rs920778 and rs4759314 polymorphisms.	('rs4759314', 'Var', (61, 70))	('rs920778', 'Var', (48, 56))	('rs4759314', 'Mutation', 'rs4759314', (61, 70))	('rs920778', 'Mutation', 'rs920778', (48, 56))
681038	27330313	Nevertheless, subgroup analyses were successfully used to relieve moderate heterogeneity bias in the rs4759314 polymorphism analysis within the population-based control group and the genotyping method of restriction fragment length polymorphism group, suggesting that control sources and genotyping method may influence heterogeneity.	('rs4759314', 'Mutation', 'rs4759314', (101, 110))	('influence', 'Reg', (310, 319))	('rs4759314', 'Var', (101, 110))
681040	27330313	Finally, cancer is a multi-factorial malignant disease that likely arises from complex interactions between genetic mutations, environmental changes, lifestyle, diet, age, and sex.	('cancer', 'Disease', (9, 15))	('multi-factorial malignant disease', 'Disease', 'MESH:D009369', (21, 54))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('multi-factorial malignant disease', 'Disease', (21, 54))
681042	27330313	In conclusion, the current meta-analysis indicated that three functional polymorphisms of HOTAIR rs920778 C>T, rs4759314 A>G, and rs7958904 G>C may play an important role in the development of cancer.	('HOTAIR', 'Gene', (90, 96))	('play', 'Reg', (148, 152))	('rs920778 C>T', 'Var', (97, 109))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('HOTAIR', 'Gene', '100124700', (90, 96))	('cancer', 'Disease', (193, 199))	('rs7958904 G>C', 'Var', (130, 143))	('rs920778', 'Mutation', 'rs920778', (97, 105))	('rs4759314', 'Mutation', 'rs4759314', (111, 120))	('rs7958904', 'Mutation', 'rs7958904', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('rs4759314 A>G', 'Var', (111, 124))
681043	27330313	Large-scale, case-control studies with rigorous designs should be conducted to confirm the association of above functional polymorphisms in lncRNA HOTAIR and cancer risk in the future.	('rigorous', 'Disease', (39, 47))	('lncRNA', 'Gene', (140, 146))	('HOTAIR', 'Gene', '100124700', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('polymorphisms', 'Var', (123, 136))	('cancer', 'Disease', (158, 164))	('HOTAIR', 'Gene', (147, 153))	('rigorous', 'Disease', 'MESH:D012298', (39, 47))	('association', 'Interaction', (91, 102))
681054	26493335	High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone.	('resistance to cisplatin', 'MPA', (35, 58))	('gastric cancer', 'Disease', (84, 98))	('High', 'Var', (0, 4))	('protein', 'Protein', (11, 18))	('SPHK1', 'Gene', '8877', (5, 10))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('patients', 'Species', '9606', (136, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('patients', 'Species', '9606', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('SPHK1', 'Gene', (5, 10))
681085	26493335	The panel of drug resistant cell lines generated in this way were AGSCIS5, AGSOX8, AGSDOC6, OE33CIS4, OE33OX4 and OE21OX4 with the subscript denoting the drug and final concentration of drug (muM) that cells were exposed to.	('OE21OX4', 'Var', (114, 121))	('AGS', 'Disease', (75, 78))	('OE33OX4', 'Var', (102, 109))	('AGS', 'Disease', 'MESH:C535607', (83, 86))	('muM', 'Gene', (192, 195))	('AGS', 'Disease', 'MESH:C535607', (75, 78))	('OE33CIS4', 'Var', (92, 100))	('AGS', 'Disease', (66, 69))	('AGS', 'Disease', 'MESH:C535607', (66, 69))	('AGS', 'Disease', (83, 86))	('muM', 'Gene', '56925', (192, 195))
681097	26493335	Gene expression was performed using RNA isolated from AGS, AGSCIS5, AGSOX8, AGSDOC6, OE33, OE33CIS4, OE33OX4, OE21, OE21OX4 (Fig.	('AGS', 'Disease', 'MESH:C535607', (76, 79))	('AGS', 'Disease', (54, 57))	('OE21', 'Var', (110, 114))	('AGS', 'Disease', 'MESH:C535607', (54, 57))	('AGS', 'Disease', (68, 71))	('OE33', 'Var', (85, 89))	('OE33CIS4', 'Var', (91, 99))	('AGS', 'Disease', 'MESH:C535607', (68, 71))	('OE21OX4', 'Var', (116, 123))	('OE33OX4', 'Var', (101, 108))	('AGS', 'Disease', (59, 62))	('AGS', 'Disease', 'MESH:C535607', (59, 62))	('AGS', 'Disease', (76, 79))
681098	26493335	This analysis identified differentially expressed genes for drug resistant gastric adenocarcinoma [AGSCIS5 (n = 1298), AGSOX8 (n = 466), AGSDOC6 (n = 2251)], esophageal adenocarcinoma [OE33OX4 (n = 2107), OE33CIS4 (n = 2613)] and esophageal squamous cell carcinoma [OE21OX4 (n = 859)] cell lines compared to the sensitive parental line.	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (75, 97))	('AGS', 'Disease', (99, 102))	('AGS', 'Disease', (119, 122))	('esophageal squamous cell carcinoma', 'Disease', (230, 264))	('OE33CIS4', 'Var', (205, 213))	('gastric adenocarcinoma', 'Disease', (75, 97))	('AGS', 'Disease', (137, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('AGS', 'Disease', 'MESH:C535607', (99, 102))	('esophageal adenocarcinoma', 'Disease', (158, 183))	('AGS', 'Disease', 'MESH:C535607', (119, 122))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (158, 183))	('AGS', 'Disease', 'MESH:C535607', (137, 140))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (158, 183))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (230, 264))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (241, 264))
681111	26493335	In addition, preclinical investigations in cancer and non-cancer cells demonstrate that increased SPHK1 is associated with increased production of sphingosine-1-phosphate (S1P) in cancer cells and S1P promotes cell proliferation and angiogenesis, and inhibits cell death.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cell proliferation', 'CPA', (210, 228))	('non-cancer', 'Disease', 'MESH:D009369', (54, 64))	('angiogenesis', 'CPA', (233, 245))	('SPHK1', 'Gene', (98, 103))	('inhibits', 'NegReg', (251, 259))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('sphingosine-1-phosphate', 'Chemical', 'MESH:C060506', (147, 170))	('non-cancer', 'Disease', (54, 64))	('SPHK1', 'Gene', '8877', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('promotes', 'PosReg', (201, 209))	('cancer', 'Disease', (180, 186))	('increased', 'PosReg', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('increased', 'PosReg', (88, 97))	('cell death', 'CPA', (260, 270))	('cancer', 'Disease', (43, 49))	('S1P', 'Var', (197, 200))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (58, 64))
681114	26493335	Recently, in prostate cancer, an inverse relationship between expression of SPHK1 and SGPL1 was noted and down regulation of SGPL1 increased production of S1P and was associated with resistance to docetaxel.	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))	('increased', 'PosReg', (131, 140))	('associated with', 'Reg', (167, 182))	('down regulation', 'Var', (106, 121))	('production of S1P', 'MPA', (141, 158))	('SGPL1', 'Gene', (86, 91))	('resistance', 'MPA', (183, 193))	('SGPL1', 'Gene', (125, 130))	('SGPL1', 'Gene', '8879', (86, 91))	('prostate cancer', 'Disease', 'MESH:D011471', (13, 28))	('prostate cancer', 'Disease', (13, 28))	('SGPL1', 'Gene', '8879', (125, 130))	('docetaxel', 'Chemical', 'MESH:D000077143', (197, 206))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('SPHK1', 'Gene', (76, 81))	('SPHK1', 'Gene', '8877', (76, 81))
681116	26493335	In order to test this hypothesis we examined the relationship between the cellular levels of S1P and the ratio of SPHK1 and SGPL1 mRNA expression and drug resistance in the 4 drug resistant cell lines that demonstrated increased SPHK1 together with decreased SGPL1 - AGSCIS5, AGSDOC6,OE33OX4, OE33CIS4.	('SPHK1', 'Gene', '8877', (114, 119))	('SGPL1', 'Gene', '8879', (259, 264))	('OE33CIS4', 'Var', (293, 301))	('AGS', 'Disease', (267, 270))	('AGS', 'Disease', 'MESH:C535607', (276, 279))	('SPHK1', 'Gene', '8877', (229, 234))	('AGS', 'Disease', 'MESH:C535607', (267, 270))	('SGPL1', 'Gene', (124, 129))	('SGPL1', 'Gene', (259, 264))	('SGPL1', 'Gene', '8879', (124, 129))	('decreased', 'NegReg', (249, 258))	('OE33OX4', 'Var', (284, 291))	('SPHK1', 'Gene', (114, 119))	('SPHK1', 'Gene', (229, 234))	('AGS', 'Disease', (276, 279))	('increased', 'PosReg', (219, 228))	('drug resistance', 'Phenotype', 'HP:0020174', (150, 165))
681140	26493335	In drug resistant gastroesophageal cancer cell lines we observed increased levels of sphingosine metabolite, S1P and increased cisplatin sensitivity in response to pharmacological inhibition of SPHK1, a kinase required for metabolism of sphingosine to S1P, as well as correlation between SPHK1 protein expression and cisplatin sensitivity in an independent gastric cancer cell line panel.	('gastroesophageal cancer', 'Disease', (18, 41))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (18, 41))	('increased', 'PosReg', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cisplatin sensitivity', 'MPA', (127, 148))	('sphingosine', 'Chemical', 'MESH:D013110', (237, 248))	('gastric cancer', 'Disease', (357, 371))	('SPHK1', 'Gene', (194, 199))	('sphingosine', 'Chemical', 'MESH:D013110', (85, 96))	('SPHK1', 'Gene', '8877', (194, 199))	('cisplatin', 'Chemical', 'MESH:D002945', (317, 326))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('gastric cancer', 'Disease', 'MESH:D013274', (357, 371))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('increased', 'PosReg', (65, 74))	('S1P', 'MPA', (109, 112))	('SPHK1', 'Gene', (288, 293))	('levels', 'MPA', (75, 81))	('SPHK1', 'Gene', '8877', (288, 293))	('inhibition', 'Var', (180, 190))	('gastric cancer', 'Phenotype', 'HP:0012126', (357, 371))	('sphingosine metabolite', 'MPA', (85, 107))
681146	26493335	In addition, investigations in cancer and non-cancer cells demonstrate that increased SPHK1 is associated with increased production of S1P in cells and S1P promotes cell proliferation, angiogenesis and inhibits cell death all of which could promote cell survival following cytotoxic drug insult and hence induce resistance.	('induce', 'PosReg', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cell death', 'CPA', (211, 221))	('cell survival', 'CPA', (249, 262))	('angiogenesis', 'CPA', (185, 197))	('promotes', 'PosReg', (156, 164))	('resistance', 'CPA', (312, 322))	('increased', 'PosReg', (76, 85))	('non-cancer', 'Disease', 'MESH:D009369', (42, 52))	('cancer', 'Disease', (31, 37))	('inhibits', 'NegReg', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', (46, 52))	('S1P', 'Var', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('non-cancer', 'Disease', (42, 52))	('increased', 'PosReg', (111, 120))	('cell proliferation', 'CPA', (165, 183))	('promote', 'PosReg', (241, 248))	('production', 'MPA', (121, 131))	('SPHK1', 'Gene', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('SPHK1', 'Gene', '8877', (86, 91))
681158	26493335	Our finding of an inverse relationship between SPHK1 and SGPL1 expression in gastroesophageal cancer associated with increased levels of S1P and cytotoxic drug resistance is consistent with a recent report in prostate cancer, where a similar inverse relationship between expression of SPHK1 and SGPL1 was noted leading to increased production of S1P and an association with resistance to docetaxel.	('SGPL1', 'Gene', '8879', (295, 300))	('prostate cancer', 'Phenotype', 'HP:0012125', (209, 224))	('increased', 'PosReg', (117, 126))	('association', 'Interaction', (357, 368))	('drug resistance', 'Phenotype', 'HP:0020174', (155, 170))	('prostate cancer', 'Disease', (209, 224))	('S1P', 'MPA', (137, 140))	('cytotoxic drug resistance', 'MPA', (145, 170))	('increased', 'PosReg', (322, 331))	('SGPL1', 'Gene', '8879', (57, 62))	('levels', 'MPA', (127, 133))	('gastroesophageal cancer', 'Disease', (77, 100))	('expression', 'Var', (63, 73))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (77, 100))	('docetaxel', 'Chemical', 'MESH:D000077143', (388, 397))	('production', 'MPA', (332, 342))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('SGPL1', 'Gene', (57, 62))	('inverse', 'NegReg', (18, 25))	('SGPL1', 'Gene', (295, 300))	('SPHK1', 'Gene', (47, 52))	('resistance to docetaxel', 'MPA', (374, 397))	('SPHK1', 'Gene', '8877', (47, 52))	('S1P', 'MPA', (346, 349))	('SPHK1', 'Gene', (285, 290))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('prostate cancer', 'Disease', 'MESH:D011471', (209, 224))	('SPHK1', 'Gene', '8877', (285, 290))
681162	26493335	A previous study by Li et al., demonstrated that high SPHK1 expression in resected gastric cancers was associated with worse survival.	('SPHK1', 'Gene', (54, 59))	('expression', 'MPA', (60, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('SPHK1', 'Gene', '8877', (54, 59))	('gastric cancers', 'Disease', (83, 98))	('gastric cancers', 'Disease', 'MESH:D013274', (83, 98))	('gastric cancers', 'Phenotype', 'HP:0012126', (83, 98))	('high', 'Var', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
681177	26493335	There are a number of SPHK1 and S1P inhibitors in clinical development as anti-cancer agents that confer increased sensitivity to cytotoxic drugs, targeted agents or radiotherapy and/or have single agent activity in preclinical cancer models (Table 2).	('cancer', 'Disease', (228, 234))	('inhibitors', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('S1P', 'Gene', (32, 35))	('SPHK1', 'Gene', '8877', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('increased', 'PosReg', (105, 114))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('SPHK1', 'Gene', (22, 27))	('sensitivity to cytotoxic drugs', 'MPA', (115, 145))
681188	26493335	Further pre-clincial experiments with specific SPHK1 inhibitors and siRNA mediated knockdown of SHK1 would allow additional exploration of the potential of SPHK1 as a target and the usefulness of combining with other cytotoxic and targeted drugs.	('SPHK1', 'Gene', (47, 52))	('SPHK1', 'Gene', '8877', (47, 52))	('SPHK1', 'Gene', '8877', (156, 161))	('SHK1', 'Gene', (96, 100))	('knockdown', 'Var', (83, 92))	('SPHK1', 'Gene', (156, 161))
681195	26083936	Deep sequencing, a method of optimizing the high throughput capacity of NGS technologies, allows for the detection of genetic aberrations in small subsets of premalignant and/or tumor cells in noncancerous chronically inflamed tissues.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (178, 183))	('genetic aberrations', 'Var', (118, 137))	('cancerous', 'Disease', 'MESH:D009369', (196, 205))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancerous', 'Disease', (196, 205))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
681199	26083936	In fact, whole-exome sequencing (WES) and whole-genome sequencing (WGS) of various cancers using NGS technologies have led to the identification of many genetic alterations in cancerous tissues.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Disease', (83, 90))	('genetic alterations', 'Var', (153, 172))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancerous', 'Disease', 'MESH:D009369', (176, 185))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancerous', 'Disease', (176, 185))
681200	26083936	Most of these genetic alterations might be passenger mutations that do not contribute to carcinogenesis, but some recurrently observed mutations are likely to be oncogenic driver mutations.	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('genetic alterations', 'Var', (14, 33))	('carcinogenesis', 'Disease', (89, 103))	('mutations', 'Var', (135, 144))
681205	26083936	Hepatocellular carcinomas also have mutations of genes in several pathways, including the p53/RB pathway (TP53 and CDKN2A), WNT pathway (CTNNB1 and AXIN1), and chromatin remodeling complex (ARID1A and ARID2).	('CDKN2A', 'Gene', (115, 121))	('p53', 'Gene', (90, 93))	('ARID2', 'Gene', '196528', (201, 206))	('CTNNB1', 'Gene', '1499', (137, 143))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))	('CDKN2A', 'Gene', '1029', (115, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('AXIN1', 'Gene', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('ARID2', 'Gene', (201, 206))	('Hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (0, 25))	('ARID1A', 'Gene', (190, 196))	('TP53', 'Gene', (106, 110))	('CTNNB1', 'Gene', (137, 143))	('ARID1A', 'Gene', '8289', (190, 196))	('Hepatocellular carcinomas', 'Disease', 'MESH:D006528', (0, 25))	('AXIN1', 'Gene', '8312', (148, 153))	('p53', 'Gene', '7157', (90, 93))	('mutations', 'Var', (36, 45))	('WNT pathway', 'Pathway', (124, 135))	('Hepatocellular carcinomas', 'Disease', (0, 25))	('TP53', 'Gene', '7157', (106, 110))
681209	26083936	Identifying somatic mutations contained in noncancerous tissues by such (ultra-) deep sequencing could provide clues to elucidating carcinogenic mechanisms because those mutations might contribute to carcinogenesis at an early stage of tumor development.	('contribute to', 'Reg', (186, 199))	('cancerous', 'Disease', (46, 55))	('mutations', 'Var', (170, 179))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('cancerous', 'Disease', 'MESH:D009369', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('carcinogenic', 'Disease', 'MESH:D063646', (132, 144))	('carcinogenesis', 'Disease', 'MESH:D063646', (200, 214))	('carcinogenic', 'Disease', (132, 144))	('tumor', 'Disease', (236, 241))	('carcinogenesis', 'Disease', (200, 214))
681215	26083936	Germline mutations of some tumor suppressor genes strongly predispose to tumor development, as seen in familial polyposis coli and Li-Fraumeni syndrome.	('Germline mutations', 'Var', (0, 18))	('familial polyposis coli', 'Disease', (103, 126))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('predispose', 'Reg', (59, 69))	('tumor', 'Disease', (27, 32))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (131, 151))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('familial polyposis coli', 'Disease', 'MESH:D011125', (103, 126))	('Li-Fraumeni syndrome', 'Disease', (131, 151))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
681219	26083936	Cancer is a genome disease, and the accumulation of genetic aberrations in tumor-related genes is a critical step in malignant transformation.	('genome disease', 'Disease', (12, 26))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('genome disease', 'Disease', 'MESH:D042822', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (75, 80))	('genetic aberrations', 'Var', (52, 71))
681221	26083936	Thus, it is reasonable to assume that chronically inflamed epithelial cells play a role as the origin of inflammation-associated cancers through the accumulation of genetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('inflammation-associated cancers', 'Disease', (105, 136))	('epithelia', 'Disease', 'None', (59, 68))	('epithelia', 'Disease', (59, 68))	('inflammation-associated cancers', 'Disease', 'MESH:D007249', (105, 136))	('genetic alterations', 'Var', (165, 184))
681223	26083936	It is possible that mutations latently accumulated in premalignant tissues also include putative driver mutations, which could contribute to the early stage of carcinogenesis.	('contribute', 'Reg', (127, 137))	('carcinogenesis', 'Disease', (160, 174))	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('mutations', 'Var', (104, 113))
681226	26083936	For example, Barrett's esophagus epithelium represents premalignant lesions of esophageal adenocarcinoma with somatic mutations in TP53 and CDKN2A genes, both of which are key tumor suppressor genes involved in the development of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('CDKN2A', 'Gene', (140, 146))	("Barrett's esophagus", 'Disease', (13, 32))	('mutations', 'Var', (118, 127))	('TP53', 'Gene', '7157', (131, 135))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (13, 32))	('TP53', 'Gene', (131, 135))	('esophageal adenocarcinoma', 'Disease', (230, 255))	('CDKN2A', 'Gene', '1029', (140, 146))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (230, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('esophageal adenocarcinoma', 'Disease', (79, 104))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (230, 255))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))
681227	26083936	Chronic hepatitis tissues with HCV infection, which predisposes to hepatocellular carcinoma, bear TP53 mutations at frequencies of 4-15 nucleotides per 104 nucleotides.	('mutations', 'Var', (103, 112))	('HCV infection', 'Disease', 'MESH:D006526', (31, 44))	('Chronic hepatitis', 'Disease', 'MESH:D056487', (0, 17))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('hepatocellular carcinoma', 'Disease', (67, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('hepatitis', 'Phenotype', 'HP:0012115', (8, 17))	('Chronic hepatitis', 'Disease', (0, 17))	('TP53', 'Gene', '7157', (98, 102))	('HCV infection', 'Disease', (31, 44))	('Chronic hepatitis', 'Phenotype', 'HP:0200123', (0, 17))	('TP53', 'Gene', (98, 102))
681228	26083936	A sequencing study of colon crypts isolated by laser capture microdissection revealed TP53 mutations in both premalignant dysplasia and nondysplastic inflamed colon crypts of patients with ulcerative colitis.	('ulcerative colitis', 'Disease', 'MESH:D003093', (189, 207))	('TP53', 'Gene', '7157', (86, 90))	('premalignant dysplasia and nondysplastic inflamed colon', 'Disease', 'MESH:C531841', (109, 164))	('TP53', 'Gene', (86, 90))	('patients', 'Species', '9606', (175, 183))	('mutations', 'Var', (91, 100))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (189, 207))	('ulcerative colitis', 'Disease', (189, 207))	('colitis', 'Phenotype', 'HP:0002583', (200, 207))
681230	26083936	Because of the low frequencies of cells with mutated genes in noncancerous tissues (Figure 1), however, identifying pro-oncogenic mutations in noncancerous tissues by the Sanger method requires much time and effort, and is still insufficient.	('cancerous', 'Disease', (146, 155))	('insufficient', 'Disease', (229, 241))	('cancerous', 'Disease', 'MESH:D009369', (146, 155))	('cancerous', 'Disease', 'MESH:D009369', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancerous', 'Disease', (65, 74))	('insufficient', 'Disease', 'MESH:D000309', (229, 241))
681231	26083936	Taking advantage of the high sensitivity of NGS for the detection of low-abundance mutations, recent studies identified somatic mutations of cancer-related genes in noncancerous tissues with chronic inflammation in various organs.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('cancerous', 'Disease', 'MESH:D009369', (168, 177))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('inflammation', 'Disease', 'MESH:D007249', (199, 211))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancerous', 'Disease', (168, 177))	('inflammation', 'Disease', (199, 211))
681232	26083936	TP53 mutations are most frequently detected in gastric cancer genomes, followed by ARID1A, CTNNB1, and PIK3CA.	('TP53', 'Gene', '7157', (0, 4))	('detected', 'Reg', (35, 43))	('TP53', 'Gene', (0, 4))	('CTNNB1', 'Gene', (91, 97))	('gastric cancer', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('ARID1A', 'Gene', '8289', (83, 89))	('mutations', 'Var', (5, 14))	('PIK3CA', 'Gene', (103, 109))	('ARID1A', 'Gene', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('CTNNB1', 'Gene', '1499', (91, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('PIK3CA', 'Gene', '5290', (103, 109))
681234	26083936	In the gastritis mucosa of 28 patients with gastric cancer, non-synonymous low-abundance mutations in TP53 and ARID1A were detected in 11 cases (39.3%) and four cases (14.3%), respectively.	('TP53', 'Gene', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('gastritis mucosa', 'Disease', (7, 23))	('gastritis', 'Phenotype', 'HP:0005263', (7, 16))	('ARID1A', 'Gene', '8289', (111, 117))	('gastric cancer', 'Disease', (44, 58))	('ARID1A', 'Gene', (111, 117))	('patients', 'Species', '9606', (30, 38))	('detected', 'Reg', (123, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('mutations', 'Var', (89, 98))	('gastritis mucosa', 'Disease', 'MESH:D005756', (7, 23))	('TP53', 'Gene', '7157', (102, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))
681235	26083936	Interestingly, non-synonymous low-abundance mutations in TP53 and ARID1A were also detected in the gastritis mucosa of patients without gastric cancer.	('gastritis mucosa', 'Disease', (99, 115))	('detected', 'Reg', (83, 91))	('gastritis', 'Phenotype', 'HP:0005263', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('patients', 'Species', '9606', (119, 127))	('low-abundance', 'NegReg', (30, 43))	('gastritis mucosa', 'Disease', 'MESH:D005756', (99, 115))	('gastric cancer', 'Disease', (136, 150))	('ARID1A', 'Gene', (66, 72))	('ARID1A', 'Gene', '8289', (66, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))
681237	26083936	Consistent with our findings, other recent studies revealed that the majority of recurrent mutations in cancer-related genes detected in esophageal adenocarcinoma were found in Barrett's esophagus.	("Barrett's esophagus", 'Disease', (177, 196))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (177, 196))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (137, 162))	('esophageal adenocarcinoma', 'Disease', (137, 162))	('mutations', 'Var', (91, 100))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (137, 162))	('found', 'Reg', (168, 173))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
681240	26083936	Furthermore, the vast majority of detected mutations had similar mutation frequencies among the three disease stages, while TP53 was mutated exclusively in high-grade dysplasia and esophageal adenocarcinoma, but not in never-dysplastic Barrett's esophagus.	('TP53', 'Gene', '7157', (124, 128))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (236, 255))	('TP53', 'Gene', (124, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('dysplasia', 'Disease', (167, 176))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (181, 206))	('mutations', 'Var', (43, 52))	('esophageal adenocarcinoma', 'Disease', (181, 206))	("dysplastic Barrett's esophagus", 'Disease', (225, 255))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (181, 206))	('dysplasia', 'Disease', 'MESH:D004476', (167, 176))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (225, 255))
681241	26083936	Combined with accessional analyses, the TP53 mutation status was found to differentiate never-dysplastic Barrett's esophagus from high-grade dysplasia and esophageal adenocarcinoma.	('dysplasia', 'Disease', (141, 150))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (155, 180))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (94, 124))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (105, 124))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (155, 180))	('dysplasia', 'Disease', 'MESH:D004476', (141, 150))	('TP53', 'Gene', '7157', (40, 44))	('mutation', 'Var', (45, 53))	('TP53', 'Gene', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	("dysplastic Barrett's esophagus", 'Disease', (94, 124))	('esophageal adenocarcinoma', 'Disease', (155, 180))
681242	26083936	With regard to hepatobiliary tumors, we demonstrated that many genetic alterations accumulate in the cirrhotic liver following HCV-related chronic hepatitis, a predisposing condition to hepatocellular carcinoma.	('HCV', 'Species', '11103', (127, 130))	('genetic alterations', 'Var', (63, 82))	('hepatitis', 'Phenotype', 'HP:0012115', (147, 156))	('cirrhotic liver', 'Disease', (101, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('cirrhotic liver', 'Disease', 'MESH:D008103', (101, 116))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (101, 116))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (139, 156))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (186, 210))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('hepatocellular carcinoma', 'Disease', (186, 210))	('hepatobiliary tumors', 'Disease', (15, 35))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (186, 210))	('chronic hepatitis', 'Disease', 'MESH:D056487', (139, 156))	('accumulate', 'Reg', (83, 93))	('hepatobiliary tumors', 'Disease', 'MESH:D004066', (15, 35))	('chronic hepatitis', 'Disease', (139, 156))
681243	26083936	Whole exome sequencing on nontumorous cirrhotic liver tissues led to the identification of nucleotide alterations in a large quantity, comparable to those of hepatocellular carcinoma, while the mutation frequencies in cirrhotic tissues tended to be lower than those in the matched tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('nucleotide alterations', 'Var', (91, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (38, 53))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('cirrhotic liver', 'Disease', (38, 53))	('tumor', 'Disease', (29, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (158, 182))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('cirrhotic liver', 'Disease', 'MESH:D008103', (38, 53))	('hepatocellular carcinoma', 'Disease', (158, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (158, 182))	('tumor', 'Disease', (281, 286))
681244	26083936	Although the majority of the mutated genes detected in cirrhotic tissues were thought to be passenger mutations, the leptin receptor gene (LEPR) was identified as a putative cancer-related gene mutated in both cirrhotic tissues and hepatocellular carcinoma.	('LEPR', 'Gene', (139, 143))	('leptin receptor', 'Gene', '3953', (117, 132))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (232, 256))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (232, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('mutated', 'Var', (194, 201))	('hepatocellular carcinoma', 'Disease', (232, 256))	('LEPR', 'Gene', '3953', (139, 143))	('leptin receptor', 'Gene', (117, 132))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
681245	26083936	Additional deep sequencing analyses on TP53, CTNNB1, and LEPR genes revealed low-abundance mutations in more than half of the nontumorous cirrhotic tissues analyzed.	('CTNNB1', 'Gene', '1499', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('LEPR', 'Gene', (57, 61))	('CTNNB1', 'Gene', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mutations', 'Var', (91, 100))	('TP53', 'Gene', '7157', (39, 43))	('LEPR', 'Gene', '3953', (57, 61))	('tumor', 'Disease', (129, 134))	('TP53', 'Gene', (39, 43))
681246	26083936	reported whole exome sequencing on one dysplastic nodule and two hepatocellular carcinomas in the same patient with HBV infection, and, consistent with our results, several mutations were detected in dysplastic nodules as well as tumor tissues, although there was no overlap in the mutations between dysplastic nodules and hepatocellular carcinomas.	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (65, 90))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (323, 347))	('dysplastic', 'Disease', (200, 210))	('dysplastic', 'Disease', 'MESH:D004416', (39, 49))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (65, 90))	('HBV infection', 'Disease', (116, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('dysplastic nodules', 'Disease', 'MESH:D004416', (300, 318))	('dysplastic', 'Disease', 'MESH:D004416', (300, 310))	('hepatocellular carcinomas', 'Disease', (65, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('dysplastic', 'Disease', (39, 49))	('patient', 'Species', '9606', (103, 110))	('dysplastic nodules', 'Disease', (200, 218))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))	('tumor', 'Disease', (230, 235))	('HBV infection', 'Disease', 'MESH:D006509', (116, 129))	('dysplastic', 'Disease', (300, 310))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (323, 348))	('mutations', 'Var', (173, 182))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (323, 348))	('dysplastic nodules and hepatocellular carcinomas', 'Disease', 'MESH:D006528', (300, 348))	('carcinoma', 'Phenotype', 'HP:0030731', (338, 347))	('carcinomas', 'Phenotype', 'HP:0030731', (338, 348))	('dysplastic nodules', 'Disease', 'MESH:D004416', (200, 218))	('dysplastic', 'Disease', 'MESH:D004416', (200, 210))	('detected', 'Reg', (188, 196))	('hepatocellular carcinomas', 'Disease', (323, 348))	('dysplastic nodules', 'Disease', (300, 318))
681247	26083936	These findings indicate that oncogenic mutations of genes related to hepatocarcinogenesis latently accumulate in cirrhotic livers with viral infection.	('hepatocarcinogenesis latently', 'Disease', (69, 98))	('cirrhotic liver', 'Disease', (113, 128))	('hepatocarcinogenesis latently', 'Disease', 'MESH:D055985', (69, 98))	('mutations', 'Var', (39, 48))	('cirrhotic liver', 'Disease', 'MESH:D008103', (113, 128))	('viral infection', 'Disease', 'MESH:D001102', (135, 150))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (113, 128))	('cirrhotic livers', 'Phenotype', 'HP:0001394', (113, 129))	('accumulate', 'PosReg', (99, 109))	('viral infection', 'Disease', (135, 150))
681248	26083936	Thus, deep sequencing analyses on inflamed noncancerous tissues have elucidated the accumulation of putative pro-oncogenic mutations of cancer-related genes in the noncancerous tissues of various organs during the process of inflammation-associated carcinogenesis.	('carcinogenesis', 'Disease', (249, 263))	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancerous', 'Disease', (46, 55))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', (167, 173))	('inflammation', 'Disease', (225, 237))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancerous', 'Disease', (167, 176))	('cancer', 'Disease', (136, 142))	('cancerous', 'Disease', 'MESH:D009369', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancerous', 'Disease', 'MESH:D009369', (167, 176))	('carcinogenesis', 'Disease', 'MESH:D063646', (249, 263))	('mutations', 'Var', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
681250	26083936	Several studies clarified that C:G>T:A transitions at XpCpG trinucleotides (X: any nucleotide, under bar: mutated nucleotide) are the most prominent mutational signature in many types of cancers, particularly gastrointestinal cancers (Figure 2).	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('trinucleotides', 'Chemical', '-', (60, 74))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancers', 'Disease', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('C:G>T', 'Var', (31, 36))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (209, 233))	('cancers', 'Disease', (226, 233))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('gastrointestinal cancers', 'Disease', (209, 233))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
681252	26083936	In gastric cancer, C:G>T:A transitions at XpCpG sites as well as GpCpX sites are dominantly observed, and high rates of T:A>G:C transversions at XpTpT sites (specifically at CpTpT sites) were also recently observed in some microsatellite-stable gastric cancers.	('gastric cancers', 'Disease', (245, 260))	('gastric cancers', 'Disease', 'MESH:D013274', (245, 260))	('gastric cancers', 'Phenotype', 'HP:0012126', (245, 260))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('C:G>T:A', 'Var', (19, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (245, 259))	('T:A>G:C transversions', 'Var', (120, 141))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('XpTpT', 'Gene', (145, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (245, 259))	('observed', 'Reg', (206, 214))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
681255	26083936	While T:A>G:C transversions at XpTpT sites are most frequently observed in esophageal adenocarcinomas similar to some gastric cancers, C:G>T:A transitions at XpCpG trinucleotides are the most predominant patterns in esophageal squamous cell carcinoma, followed by C:G>G:C transversions and C:G>T:A transitions at TpCpX motifs.	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (75, 101))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('C:G>T:A', 'Var', (135, 142))	('trinucleotides', 'Chemical', '-', (164, 178))	('esophageal squamous cell carcinoma', 'Disease', (216, 250))	('gastric cancers', 'Phenotype', 'HP:0012126', (118, 133))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('esophageal adenocarcinomas', 'Disease', (75, 101))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (75, 100))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (216, 250))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('gastric cancers', 'Disease', (118, 133))	('gastric cancers', 'Disease', 'MESH:D013274', (118, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('observed', 'Reg', (63, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (227, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
681256	26083936	Hepatocellular carcinoma has unique mutational signatures, such as T:A>C:G transitions in ApTpX sequences and T:A>A:T transversions in CpTpG sequences, in addition to C:G>T:A transitions in XpCpG motifs.	('T:A>A:T transversions', 'Var', (110, 131))	('transversions', 'Var', (118, 131))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (0, 24))	('transitions', 'Reg', (75, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('T:A>C:G', 'Var', (67, 74))	('CpTpG sequences', 'Gene', (135, 150))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('ApTpX', 'Gene', (90, 95))	('CpTpG', 'Chemical', '-', (135, 140))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))
681261	26083936	Tumors with microsatellite instability in many cancer types have numerous substitutions and indels due to defects of mismatch repair function caused by promoter methylation of MLH1 or mutations of MSH2, MSH3, and MSH6.	('mutations', 'Var', (184, 193))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MSH6', 'Gene', (213, 217))	('cancer', 'Disease', (47, 53))	('MSH6', 'Gene', '2956', (213, 217))	('Tumors', 'Disease', (0, 6))	('MSH3', 'Gene', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('MSH3', 'Gene', '4437', (203, 207))	('MSH2', 'Gene', (197, 201))	('substitutions', 'Var', (74, 87))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('MLH1', 'Gene', (176, 180))	('MSH2', 'Gene', '4436', (197, 201))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('promoter', 'MPA', (152, 160))	('mismatch repair function', 'MPA', (117, 141))	('defects', 'NegReg', (106, 113))	('MLH1', 'Gene', '4292', (176, 180))
681262	26083936	Tumors with mutations in POLE or POLD1 have extreme numbers of mutations due to an impaired proofreading function of DNA polymerases.	('mutations', 'Var', (63, 72))	('POLE', 'Gene', (25, 29))	('POLD1', 'Gene', (33, 38))	('mutations', 'Var', (12, 21))	('POLD1', 'Gene', '5424', (33, 38))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('proofreading function', 'MPA', (92, 113))	('DNA polymerases', 'Enzyme', (117, 132))	('impaired', 'NegReg', (83, 91))
681263	26083936	Some tumors with inactivating mutations of BRCA1 or BRCA2, such as some breast and pancreatic cancers, have substantial numbers of larger deletions (up to 50 bp) with overlapping microhomology at breakpoint junctions.	('BRCA1', 'Gene', (43, 48))	('BRCA2', 'Gene', (52, 57))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('inactivating mutations', 'Var', (17, 39))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (83, 101))	('breast', 'Disease', (72, 78))	('BRCA2', 'Gene', '675', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('BRCA1', 'Gene', '672', (43, 48))	('pancreatic cancers', 'Disease', 'MESH:D010190', (83, 101))	('pancreatic cancers', 'Disease', (83, 101))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
681264	26083936	Ultraviolet light, a well-known extrinsic mutagen, mainly induces C:G>T:A transitions in dipyrimidines, and accordingly this mutation pattern is predominant in melanoma and basal cell carcinoma, providing evidence that ultraviolet light is a causative factor in the development of these tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('dipyrimidines', 'Chemical', '-', (89, 102))	('C:G>T:A transitions', 'Var', (66, 85))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('basal cell carcinoma', 'Disease', (173, 193))	('melanoma', 'Disease', (160, 168))	('induces', 'Reg', (58, 65))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (173, 193))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (173, 193))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumors', 'Disease', (287, 293))
681265	26083936	Benzo[a]pyrene, a convincingly established carcinogen contained in tobacco, is likely to cause C:G>A:T transversions, and this mutation pattern is dominantly observed in lung cancers, especially in those associated with smokers.	('Benzo[a]pyrene', 'Chemical', 'MESH:D001564', (0, 14))	('cause', 'Reg', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('C:G>A:T transversions', 'Var', (95, 116))	('lung cancers', 'Phenotype', 'HP:0100526', (170, 182))	('lung cancers', 'Disease', (170, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('tobacco', 'Species', '4097', (67, 74))	('lung cancers', 'Disease', 'MESH:D008175', (170, 182))
681268	26083936	On the other hand, inflammatory stimulation elicits aberrant AID expression in epithelial cells and overexpressed AID could induce mutations in various non-immunoglobulin genes and trigger inflammation-associated tumorigenesis, including gastric carcinogenesis associated with H. pylori-related gastritis and hepatocarcinogenesis associated with chronic hepatitis C. AID deaminates C to U, resulting in the generation of a U:G mismatch.	('trigger', 'Reg', (181, 188))	('non-immunoglobulin', 'Gene', (152, 170))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('epithelia', 'Disease', (79, 88))	('resulting in', 'Reg', (390, 402))	('inflammation', 'Disease', (189, 201))	('chronic hepatitis C', 'Disease', (346, 365))	('H. pylori', 'Species', '210', (277, 286))	('gastritis', 'Phenotype', 'HP:0005263', (295, 304))	('gastritis and hepatocarcinogenesis', 'Disease', 'MESH:D005756', (295, 329))	('gastric carcinogenesis', 'Disease', (238, 260))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (346, 363))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (238, 260))	('tumor', 'Disease', (213, 218))	('mutations', 'Var', (131, 140))	('hepatitis', 'Phenotype', 'HP:0012115', (354, 363))	('chronic hepatitis C', 'Disease', 'MESH:D019698', (346, 365))	('U:G mismatch', 'MPA', (423, 435))	('induce', 'Reg', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('epithelia', 'Disease', 'None', (79, 88))	('inflammation', 'Disease', 'MESH:D007249', (189, 201))
681269	26083936	Such AID-induced mutagenesis is genome-widely confirmed by experimental models in which AID predominantly caused C:G>T:A transitions in the known preferred AID target sequence, i.e., WRCY motifs (W = A or T, R = A or G, and Y = C or T) or RpCpX trinucleotides.	('trinucleotides', 'Chemical', '-', (245, 259))	('caused', 'Reg', (106, 112))	('W = A', 'Var', (196, 201))
681271	26083936	In contrast to AID, APOBEC3B exhibits a strong preference for deaminating C residues flanked by T. Although the function of APOBEC3B in normal conditions is unknown, APOBEC3B expression is correlated with frequencies of C:G>T:A transitions or C:G>G:C transversions in TpCpX motifs in several types of cancer, including breast cancer and lung cancer.	('breast cancer', 'Disease', 'MESH:D001943', (319, 332))	('correlated', 'Reg', (189, 199))	('lung cancer', 'Disease', 'MESH:D008175', (337, 348))	('breast cancer', 'Disease', (319, 332))	('cancer', 'Disease', (342, 348))	('lung cancer', 'Phenotype', 'HP:0100526', (337, 348))	('APOBEC3B', 'Gene', '9582', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('TpCpX motifs', 'Gene', (268, 280))	('C:G>T:A transitions', 'Var', (220, 239))	('cancer', 'Disease', (301, 307))	('cancer', 'Disease', (326, 332))	('APOBEC3B', 'Gene', '9582', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('APOBEC3B', 'Gene', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('C:G>G:C transversions', 'Var', (243, 264))	('APOBEC3B', 'Gene', (124, 132))	('lung cancer', 'Disease', (337, 348))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('breast cancer', 'Phenotype', 'HP:0003002', (319, 332))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('APOBEC3B', 'Gene', (20, 28))	('APOBEC3B', 'Gene', '9582', (166, 174))
681279	26083936	In gastric cancers, the most common mutation is C:G>T:A transitions, more than half of which occur in XpCpG trinucleotides.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancers', 'Disease', 'MESH:D013274', (3, 18))	('common', 'Reg', (29, 35))	('gastric cancers', 'Disease', (3, 18))	('gastric cancers', 'Phenotype', 'HP:0012126', (3, 18))	('trinucleotides', 'Chemical', '-', (108, 122))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('C:G>T:A', 'Var', (48, 55))
681281	26083936	In addition, gastric cancers also have a preponderance of C:G>T:A transitions at non-CpG sites, especially at GpCpX sequences.	('gastric cancer', 'Phenotype', 'HP:0012126', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('gastric cancers', 'Disease', 'MESH:D013274', (13, 28))	('gastric cancers', 'Disease', (13, 28))	('gastric cancers', 'Phenotype', 'HP:0012126', (13, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('C:G>T:A', 'Var', (58, 65))
681283	26083936	Moreover, deep sequencing on selected cancer-related genes in nontumorous gastritis mucosa revealed a strong preference for C:G>T:A transitions at GpCpX sequences, similar to those in gastric cancer tissues.	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('nontumorous gastritis mucosa', 'Disease', 'MESH:D005756', (62, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('nontumorous gastritis mucosa', 'Disease', (62, 90))	('gastritis', 'Phenotype', 'HP:0005263', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', (38, 44))	('gastric cancer', 'Disease', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('C:G>T:A', 'Var', (124, 131))
681285	26083936	In esophageal adenocarcinomas, the predominant mutational signature is T:A>G:C transversions with striking enrichment at the CpTpT site.	('esophageal adenocarcinomas', 'Disease', (3, 29))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (3, 28))	('T:A>G:C transversions', 'Var', (71, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (3, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))
681286	26083936	This mutational signature is relatively rare in other cancers, but some microsatellite-stable gastric cancers exhibit the same pattern.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('microsatellite-stable', 'Var', (72, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('gastric cancers', 'Disease', 'MESH:D013274', (94, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('gastric cancers', 'Disease', (94, 109))	('gastric cancers', 'Phenotype', 'HP:0012126', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
681289	26083936	On the other hand, the predominant mutational signature of esophageal squamous cell carcinoma is C:G>T:A transitions at XpCpG and TpCpX sites, followed by C:G>G:C transversions.	('C:G>T:A', 'Var', (97, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('esophageal squamous cell carcinoma', 'Disease', (59, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (59, 93))
681291	26083936	Interestingly, C:G>A:T transversions, which are dominantly detected in lung squamous cell carcinoma, are not predominant patterns in esophageal squamous cell carcinoma.	('detected', 'Reg', (59, 67))	('esophageal squamous cell carcinoma', 'Disease', (133, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('lung squamous cell carcinoma', 'Disease', (71, 99))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (71, 99))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (133, 167))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('C:G>A:T transversions', 'Var', (15, 36))
681294	26083936	In addition to C:G>T:A transitions in XpCpG contexts, T:A>C:G transitions in ApTpX contexts and T:A>A:T transversions in CpTpG contexts are characteristic patterns in hepatocellular carcinoma.	('T:A>', 'Var', (54, 58))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (167, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('hepatocellular carcinoma', 'Disease', (167, 191))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (167, 191))	('CpTpG', 'Chemical', '-', (121, 126))
681295	26083936	While C:G>T:A transitions in XpCpG contexts are commonly observed across all ancestry and sexes, T:A>C:G transitions in ApTpA contexts and T:A>A:T transversions in CpTpG contexts are especially increased in Japanese males and US-Asian cases, respectively.	('T:A>C:G', 'Var', (97, 104))	('CpTpG', 'Chemical', '-', (164, 169))	('T:A>A', 'Var', (139, 144))	('ApTpA', 'Gene', (120, 125))
681299	26083936	For example, in gastric cancers, microsatellite-stable cancers exhibit chromosomal instability and T:A>G:C transversions at the CpTpT site; microsatellite-instable cancers have features of chromosomal stability and a large number of single nucleotide substitutions with relatively high T:A>C:G transition rates; diffuse-type cancers have relatively fewer single nucleotide variants and copy number aberrations.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('diffuse-type', 'Disease', (312, 324))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('chromosomal instability', 'Phenotype', 'HP:0040012', (71, 94))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancers', 'Phenotype', 'HP:0002664', (325, 332))	('cancers', 'Disease', (325, 332))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('gastric cancers', 'Disease', 'MESH:D013274', (16, 31))	('cancers', 'Disease', (24, 31))	('cancers', 'Disease', (55, 62))	('gastric cancers', 'Disease', (16, 31))	('gastric cancers', 'Phenotype', 'HP:0012126', (16, 31))	('single nucleotide substitutions', 'Var', (233, 264))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('gastric cancer', 'Phenotype', 'HP:0012126', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (325, 332))	('cancers', 'Disease', 'MESH:D009369', (24, 31))
681302	26083936	Moreover, mutational signatures determined by NGS also provide the footprints of carcinogenic processes.	('carcinogenic processes', 'Disease', 'MESH:D009385', (81, 103))	('mutational', 'Var', (10, 20))	('carcinogenic processes', 'Disease', (81, 103))
681304	26083936	There are various patterns of mutational signatures observed in human cancers whose mutagenic processes are not yet explained.	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutational', 'Var', (30, 40))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Disease', (70, 77))
681376	23563888	Abnet and colleagues examined the association between serum 25(OH)D and esophageal squamous cell dysplasia in the same population used by Chen et al..	('esophageal squamous cell dysplasia', 'Disease', 'MESH:D000077277', (72, 106))	('esophageal squamous cell dysplasia', 'Disease', (72, 106))	('25(OH)D', 'Chemical', '-', (60, 67))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (83, 106))	('serum 25(OH)D', 'Var', (54, 67))
681463	22893750	Role of XPC, XPD, XRCC1, GSTP genetic polymorphisms and Barrett's esophagus in a cohort of Italian subjects.	('GSTP', 'Gene', '2950', (25, 29))	('XRCC1', 'Gene', '7515', (18, 23))	('GSTP', 'Gene', (25, 29))	('XPC', 'Gene', (8, 11))	('XPD', 'Gene', '2068', (13, 16))	('XPC', 'Gene', '7508', (8, 11))	('polymorphisms', 'Var', (38, 51))	('XRCC1', 'Gene', (18, 23))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (56, 75))	('XPD', 'Gene', (13, 16))
681477	22893750	van Lieshout et al studied the frequencies of polymorphic variants in glutathione S-transferase P1 (GSTP1) among 247 blood donors, 98 BE patients, and 34 subjects with OAC.	('GSTP1', 'Gene', '2950', (100, 105))	('patients', 'Species', '9606', (137, 145))	('glutathione S-transferase P1', 'Gene', '2950', (70, 98))	('OAC', 'Chemical', '-', (168, 171))	('GSTP1', 'Gene', (100, 105))	('donor', 'Species', '9606', (123, 128))	('BE', 'Phenotype', 'HP:0100580', (134, 136))	('polymorphic variants', 'Var', (46, 66))	('glutathione S-transferase P1', 'Gene', (70, 98))
681481	22893750	They studied the frequency of the same GSTP1 variant but found no association between GSTP1 and risk of OAC in 27 patients.	('GSTP1', 'Gene', '2950', (86, 91))	('GSTP1', 'Gene', '2950', (39, 44))	('GSTP1', 'Gene', (86, 91))	('OAC', 'Disease', (104, 107))	('variant', 'Var', (45, 52))	('patients', 'Species', '9606', (114, 122))	('OAC', 'Chemical', '-', (104, 107))	('GSTP1', 'Gene', (39, 44))
681484	22893750	In addition, the authors observed the genetic polymorphisms in XRCC1 associated with an increased risk of developing squamous cell carcinoma in a Chinese population.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('squamous cell carcinoma', 'Disease', (117, 140))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 140))	('associated', 'Reg', (69, 79))	('XRCC1', 'Gene', (63, 68))	('genetic polymorphisms', 'Var', (38, 59))	('XRCC1', 'Gene', '7515', (63, 68))
681485	22893750	Several other studies have reported an association between DNA repair genes and the pathogenesis of BE and OAC with a higher frequency of xeroderma pigmentosum complementation group C (XPC), poly AT insertion/deletion in OAC, a lower frequency of xeroderma pigmentosum complementary group D (XPD), and XRCC1 homozygous variants in BE, as compared with normal controls.	('BE', 'Phenotype', 'HP:0100580', (100, 102))	('xeroderma pigmentosum complementation group C', 'Gene', (138, 183))	('OAC', 'Chemical', '-', (221, 224))	('poly AT insertion/deletion', 'Var', (191, 217))	('XPD', 'Gene', (292, 295))	('BE', 'Phenotype', 'HP:0100580', (331, 333))	('XPC', 'Gene', '7508', (185, 188))	('XRCC1', 'Gene', '7515', (302, 307))	('DNA repair genes', 'Gene', (59, 75))	('xeroderma pigmentosum complementation group C', 'Gene', '7508', (138, 183))	('XPD', 'Gene', '2068', (292, 295))	('xeroderma pigmentosum complementary group D', 'Gene', (247, 290))	('xeroderma pigmentosum complementary group D', 'Gene', '2068', (247, 290))	('XRCC1', 'Gene', (302, 307))	('OAC', 'Disease', (107, 110))	('OAC', 'Chemical', '-', (107, 110))	('XPC', 'Gene', (185, 188))	('association', 'Interaction', (39, 50))
681494	22893750	Six different single nucleotide polymorphisms (SNPs) were investigated: XRCC1 arg194trp; XRCC1 arg399gln; XPC poly AT insertion/deletion indicated as pat; XPD arg156arg (allele C or A); GSTP1 Ile105Val; and Ala114Val.	('Ala114Val', 'SUBSTITUTION', 'None', (207, 216))	('GSTP1', 'Gene', '2950', (186, 191))	('arg399gln', 'Var', (95, 104))	('GSTP1', 'Gene', (186, 191))	('XRCC1', 'Gene', '7515', (89, 94))	('Ile105Val', 'Var', (192, 201))	('poly AT insertion/deletion', 'Var', (110, 136))	('XRCC1', 'Gene', '7515', (72, 77))	('arg156arg', 'Chemical', '-', (159, 168))	('XPD', 'Gene', (155, 158))	('XPC', 'Gene', '7508', (106, 109))	('Ala114Val', 'Var', (207, 216))	('arg194trp', 'Chemical', '-', (78, 87))	('arg194trp', 'Var', (78, 87))	('arg399gln', 'Chemical', '-', (95, 104))	('XPC', 'Gene', (106, 109))	('Ile105Val', 'SUBSTITUTION', 'None', (192, 201))	('XRCC1', 'Gene', (89, 94))	('XPD', 'Gene', '2068', (155, 158))	('XRCC1', 'Gene', (72, 77))
681498	22893750	The XPD PCR product was digested with Thermus filiformis, whereas restriction enzymes Proteus vulgaris 2 and methylation-specific PCR 1 were used to detect exon 6 and exon 10 polymorphisms in the XRCC1 gene, respectively (New England BioLabs GmbH, Frankfurt, Germany).	('XRCC1', 'Gene', '7515', (196, 201))	('XPD', 'Gene', (4, 7))	('exon 6', 'Var', (156, 162))	('polymorphisms', 'Var', (175, 188))	('Proteus vulgaris', 'Species', '585', (86, 102))	('XPD', 'Gene', '2068', (4, 7))	('XRCC1', 'Gene', (196, 201))	('Thermus filiformis', 'Species', '276', (38, 56))	('exon 10 polymorphisms', 'Var', (167, 188))
681499	22893750	The GSTP1 polymorphisms in exon 5 and in exon 6 were assayed according to the methods and enzymes previously described.	('GSTP1', 'Gene', (4, 9))	('GSTP1', 'Gene', '2950', (4, 9))	('polymorphisms', 'Var', (10, 23))
681515	22893750	A prominent feature of most cancers including Barrett's adenocarcinoma is genetic instability, which is associated with the development and progression of the disease.	('cancers', 'Disease', (28, 35))	("Barrett's adenocarcinoma", 'Disease', (46, 70))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('men', 'Species', '9606', (131, 134))	('associated', 'Reg', (104, 114))	('genetic instability', 'Var', (74, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	("Barrett's adenocarcinoma", 'Disease', 'MESH:D001471', (46, 70))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
681518	22893750	Defects in DNA repair have been demonstrated to be a critical mechanism in human carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('DNA', 'Gene', (11, 14))	('Defects', 'Var', (0, 7))	('carcinogenesis', 'Disease', (81, 95))	('human', 'Species', '9606', (75, 80))
681519	22893750	In addition, a reduced DNA repair capacity caused by genetic polymorphism is associated with an increased cancer risk.	('DNA repair capacity', 'MPA', (23, 42))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('genetic polymorphism', 'Var', (53, 73))	('reduced', 'NegReg', (15, 22))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
681520	22893750	In this sense, numerous DNA polymorphisms have been identified in DNA repair genes, and many of them have been shown to contribute to genetic instability and error accumulation due to reduced protein activity.	('error accumulation', 'Disease', (158, 176))	('contribute', 'Reg', (120, 130))	('reduced', 'NegReg', (184, 191))	('polymorphisms', 'Var', (28, 41))	('error accumulation', 'Disease', 'MESH:C579880', (158, 176))	('DNA repair genes', 'Gene', (66, 82))	('protein', 'Protein', (192, 199))	('genetic instability', 'MPA', (134, 153))
681522	22893750	To date, a large number of case-control studies to explore the association between DNA repair gene polymorphisms and the increasing risk of cancer have been performed.	('polymorphisms', 'Var', (99, 112))	('DNA repair', 'Gene', (83, 93))	('cancer', 'Disease', (140, 146))	('association', 'Interaction', (63, 74))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
681523	22893750	Several reports have shown an association between polymorphisms in the XPC and XPD genes and the increased risk of developing different types of cancer, with some XPD allelic variants related to an increased risk of lung cancer, squamous cell carcinoma of the head and neck, and breast cancer.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('XPD', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (243, 273))	('breast cancer', 'Disease', 'MESH:D001943', (279, 292))	('breast cancer', 'Disease', (279, 292))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('cancer', 'Disease', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (229, 252))	('association', 'Reg', (30, 41))	('XPD', 'Gene', (163, 166))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('variants', 'Var', (175, 183))	('cancer', 'Disease', (221, 227))	('related to', 'Reg', (184, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('XPD', 'Gene', '2068', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('XPC', 'Gene', '7508', (71, 74))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (229, 252))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('lung cancer', 'Disease', (216, 227))	('XPC', 'Gene', (71, 74))	('XPD', 'Gene', '2068', (163, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (279, 292))	('squamous cell carcinoma', 'Disease', (229, 252))	('polymorphisms', 'Var', (50, 63))
681525	22893750	BER genes play a key role in removing DNA damage from oxidation, deamination, and ring fragmentation, and exposure to tobacco smoking induces oxidative damage by generating reactive oxygen species; polymorphisms in BER genes have been shown to be associated with lung cancer.	('lung cancer', 'Disease', (263, 274))	('associated', 'Reg', (247, 257))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (173, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('oxidative damage', 'MPA', (142, 158))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('men', 'Species', '9606', (91, 94))	('BE', 'Phenotype', 'HP:0100580', (0, 2))	('BE', 'Phenotype', 'HP:0100580', (215, 217))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('reactive oxygen species', 'MPA', (173, 196))	('tobacco', 'Species', '4097', (118, 125))	('BER', 'Gene', (215, 218))	('polymorphisms', 'Var', (198, 211))
681526	22893750	Furthermore, given that exposure of esophageal epithelium to luminal toxic agents likely plays a crucial role, several studies have analyzed the association between polymorphisms in the detoxifying enzyme glutathione S-transferase and the risk of developing BE or OAC.	('polymorphisms', 'Var', (165, 178))	('glutathione S-transferase', 'Gene', (205, 230))	('OAC', 'Chemical', '-', (264, 267))	('BE or OAC', 'Disease', (258, 267))	('glutathione S-transferase', 'Gene', '373156', (205, 230))	('BE', 'Phenotype', 'HP:0100580', (258, 260))
681536	32661924	SHANK2 is a frequently amplified oncogene with evolutionarily conserved roles in regulating Hippo signaling Dysfunction of the Hippo pathway enables cells to evade contact inhibition and provides advantages for cancerous overgrowth.	('overgrowth', 'Phenotype', 'HP:0001548', (221, 231))	('cancerous overgrowth', 'Disease', 'MESH:D009369', (211, 231))	('Dysfunction', 'Var', (108, 119))	('cancerous overgrowth', 'Disease', (211, 231))	('Hippo', 'Gene', (127, 132))	('Hippo', 'Gene', '37247', (92, 97))	('advantages', 'PosReg', (196, 206))	('SHANK2', 'Gene', (0, 6))	('SHANK2', 'Gene', '22941', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('Hippo', 'Gene', '37247', (127, 132))	('Hippo', 'Gene', (92, 97))	('evade', 'NegReg', (158, 163))
681542	32661924	Further studies in multiple human cell lines confirmed that SHANK2 overexpression causes deregulation of Hippo signaling through competitive binding for a LATS1 activator, and as a potential oncogene, SHANK2 promotes cellular transformation and tumor formation in vivo.	('promotes', 'PosReg', (208, 216))	('Hippo', 'Gene', (105, 110))	('SHANK2', 'Gene', (60, 66))	('human', 'Species', '9606', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('binding', 'Interaction', (141, 148))	('Hippo', 'Gene', '37247', (105, 110))	('SHANK2', 'Var', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cellular transformation', 'CPA', (217, 240))	('overexpression', 'Var', (67, 81))	('deregulation', 'MPA', (89, 101))	('tumor', 'Disease', (245, 250))	('LATS1', 'Gene', (155, 160))	('LATS1', 'Gene', '9113', (155, 160))
681543	32661924	In cancer cell lines with deregulated Hippo pathway, depletion of SHANK2 restores Hippo signaling and ceases cellular proliferation.	('Hippo', 'Gene', (82, 87))	('deregulated', 'Var', (26, 37))	('depletion', 'Var', (53, 62))	('Hippo', 'Gene', (38, 43))	('Hippo', 'Gene', '37247', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cellular proliferation', 'CPA', (109, 131))	('SHANK2', 'Gene', (66, 72))	('cancer', 'Disease', (3, 9))	('ceases', 'NegReg', (102, 108))	('Hippo', 'Gene', '37247', (38, 43))	('restores', 'PosReg', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
681550	32661924	Later studies in mammalian system reached similar conclusions and showed that deregulation of the Hippo pathway causes cancer (Zender et al.,; Dong et al.,; Zhou et al.,; Atkins et al.,).	('causes', 'Reg', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('Hippo', 'Gene', '37247', (98, 103))	('cancer', 'Disease', (119, 125))	('deregulation', 'Var', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('Hippo', 'Gene', (98, 103))	('mammalian', 'Species', '9606', (17, 26))
681552	32661924	Phosphorylation of YAP/TAZ by LATS1/2 leads to cytoplasmic sequestration and degradation of these transcription cofactors, thereby stopping cell growth and proliferation (Liu et al.,; Zhao et al.,).	('TAZ', 'Gene', (23, 26))	('LATS1/2', 'Gene', (30, 37))	('TAZ', 'Gene', '6901', (23, 26))	('Phosphorylation', 'Var', (0, 15))	('leads to', 'Reg', (38, 46))	('cytoplasmic sequestration', 'MPA', (47, 72))	('YAP', 'Gene', '10413', (19, 22))	('cell growth', 'CPA', (140, 151))	('degradation', 'MPA', (77, 88))	('YAP', 'Gene', (19, 22))	('LATS1/2', 'Gene', '9113;26524', (30, 37))	('stopping', 'NegReg', (131, 139))
681554	32661924	However, analysis of human cancer genomes suggests that abnormalities of core components of the Hippo pathway, including mutations involving GNAQ (Yu et al.,; Feng et al.,), GNA11 (Yu et al.,) and NF2 (Xiao et al.,; Zhang et al.,; Yin et al.,), deletions involving VGLL4 (Jiao et al.,; Zhang et al.,), MST1 (Zhou et al.,; Song et al.,) and LATS1 (Yu et al.,), as well as amplifications involving YAP and TAZ (Overholtzer et al.,; Zender et al.,; Fernandez-L et al.,; Song et al.,), occur in a relatively small fraction of human cancer (Sanchez-Vega et al.,).	('TAZ', 'Gene', (404, 407))	('MST1', 'Gene', '4485', (302, 306))	('cancer', 'Phenotype', 'HP:0002664', (528, 534))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('VGLL4', 'Gene', '9686', (265, 270))	('GNA11', 'Gene', (174, 179))	('GNAQ', 'Gene', '2776', (141, 145))	('YAP', 'Gene', (396, 399))	('GNAQ', 'Gene', (141, 145))	('NF2', 'Gene', '4771', (197, 200))	('cancer', 'Disease', 'MESH:D009369', (528, 534))	('Hippo', 'Gene', (96, 101))	('NF2', 'Gene', (197, 200))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('Hippo', 'Gene', '37247', (96, 101))	('YAP', 'Gene', '10413', (396, 399))	('Sanchez-Vega', 'Disease', (536, 548))	('human', 'Species', '9606', (522, 527))	('MST1', 'Gene', (302, 306))	('LATS1', 'Gene', (340, 345))	('LATS1', 'Gene', '9113', (340, 345))	('GNA11', 'Gene', '2767', (174, 179))	('Sanchez-Vega', 'Disease', 'MESH:C535577', (536, 548))	('deletions', 'Var', (245, 254))	('VGLL4', 'Gene', (265, 270))	('human', 'Species', '9606', (21, 26))	('cancer', 'Disease', (528, 534))	('cancer', 'Disease', (27, 33))	('TAZ', 'Gene', '6901', (404, 407))
681555	32661924	Epigenetic silencing of MST1/2 and LATS1/2 has also been observed in mesothelioma (Maille et al.,) and sarcomas (Seidel et al.,; Merritt et al.,), as well as lung (Malik et al.,) and colorectal cancer (Wierzbicki et al.,).	('lung', 'Disease', (158, 162))	('MST1/2', 'Gene', '4485;6788', (24, 30))	('sarcomas', 'Disease', 'MESH:D012509', (103, 111))	('LATS1/2', 'Gene', '9113;26524', (35, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (103, 111))	('observed', 'Reg', (57, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (183, 200))	('sarcomas', 'Disease', (103, 111))	('mesothelioma', 'Disease', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('colorectal cancer', 'Phenotype', 'HP:0003003', (183, 200))	('Epigenetic silencing', 'Var', (0, 20))	('LATS1/2', 'Gene', (35, 42))	('MST1/2', 'Gene', (24, 30))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('colorectal cancer', 'Disease', (183, 200))
681563	32661924	Among the fly lines with the most pronounced effect in this screen, two independent Drosophila lines, A569 (EP-1) and A723 (EP-2) both exhibited p-element insertion at the 5' UTR region of the Prosap gene (Fig.	('A723', 'Var', (118, 122))	('Drosophila', 'Species', '7227', (84, 94))	('exhibited', 'Reg', (135, 144))	('Prosap', 'Gene', '50225', (193, 199))	('p-element insertion', 'Var', (145, 164))	('Prosap', 'Gene', (193, 199))
681572	32661924	S1C and S1D), and RNAi knockdown of Prosap caused reduction of wing size (Fig.	('Prosap', 'Gene', (36, 42))	('reduction', 'NegReg', (50, 59))	('knockdown', 'Var', (23, 32))	('wing size', 'CPA', (63, 72))	('Prosap', 'Gene', '50225', (36, 42))
681580	32661924	Lastly, Prosap knockdown could not suppress eye overgrowth phenotype induced by yki overexpression (Fig.	('eye overgrowth', 'Disease', (44, 58))	('overexpression', 'PosReg', (84, 98))	('knockdown', 'Var', (15, 24))	('overgrowth', 'Phenotype', 'HP:0001548', (48, 58))	('Prosap', 'Gene', '50225', (8, 14))	('eye overgrowth', 'Disease', 'MESH:D019214', (44, 58))	('Prosap', 'Gene', (8, 14))
681595	32661924	SHANK2 expression also caused YAP nuclear retention and high YAP activity despite high cell density (Figs.	('YAP', 'Gene', '10413', (30, 33))	('YAP', 'Gene', '10413', (61, 64))	('YAP', 'Gene', (30, 33))	('SHANK2', 'Gene', (0, 6))	('expression', 'Var', (7, 17))	('YAP', 'Gene', (61, 64))	('caused', 'Reg', (23, 29))
681608	32661924	Such a genetic combination resulted in one small liver tumor in three mice.	('liver tumor', 'Phenotype', 'HP:0002896', (49, 60))	('liver tumor', 'Disease', (49, 60))	('genetic combination', 'Var', (7, 26))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mice', 'Species', '10090', (70, 74))	('resulted in', 'Reg', (27, 38))	('liver tumor', 'Disease', 'MESH:D008113', (49, 60))
681609	32661924	When SHANK2 is also included in the experiment, numerous huge liver tumors were observed in 4 weeks after hydrodynamic injection in all three mice, demonstrating that SHANK2 indeed potently promotes cancer formation in vivo (Fig.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('liver tumors', 'Disease', 'MESH:D008113', (62, 74))	('mice', 'Species', '10090', (142, 146))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('liver tumors', 'Disease', (62, 74))	('cancer', 'Disease', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('liver tumors', 'Phenotype', 'HP:0002896', (62, 74))	('huge liver', 'Phenotype', 'HP:0002240', (57, 67))	('SHANK2', 'Var', (167, 173))	('promotes', 'PosReg', (190, 198))	('liver tumor', 'Phenotype', 'HP:0002896', (62, 73))
681611	32661924	3F'', S4C, and S4D), indicating enhanced YAP activity.	('S4D', 'Var', (15, 18))	('YAP', 'Gene', (41, 44))	('enhanced', 'PosReg', (32, 40))	('YAP', 'Gene', '10413', (41, 44))
681631	32661924	Importantly, DeltaPDZ SHANK2 could not interfere with ARHGEF7-LATS1 binding (Fig.	('LATS1', 'Gene', (62, 67))	('binding', 'Interaction', (68, 75))	('LATS1', 'Gene', '9113', (62, 67))	('DeltaPDZ', 'Var', (13, 21))
681632	32661924	Deletion of PDZ from SHANK2 also diminished its ability to deregulate the phosphorylation, localization and activity of YAP (Fig.	('phosphorylation', 'MPA', (74, 89))	('diminished', 'NegReg', (33, 43))	('activity', 'MPA', (108, 116))	('deregulate', 'MPA', (59, 69))	('SHANK2', 'Gene', (21, 27))	('localization', 'MPA', (91, 103))	('YAP', 'Gene', '10413', (120, 123))	('ability', 'MPA', (48, 55))	('YAP', 'Gene', (120, 123))	('PDZ', 'Gene', (12, 15))	('Deletion', 'Var', (0, 8))
681636	32661924	We asked whether knockdown of SHANK2 could restore Hippo signaling in these cell lines and reduce their proliferation.	('Hippo', 'Gene', '37247', (51, 56))	('reduce', 'NegReg', (91, 97))	('restore', 'PosReg', (43, 50))	('SHANK2', 'Gene', (30, 36))	('proliferation', 'CPA', (104, 117))	('Hippo', 'Gene', (51, 56))	('knockdown', 'Var', (17, 26))
681637	32661924	In multiple human cancer cell lines that overexpress SHANK2, upon SHANK2 knockdown, YAP phosphorylation was restored at high cell density, and YAP were sequestered in cytoplasm under such conditions (Fig.	('phosphorylation', 'MPA', (88, 103))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('YAP', 'Gene', '10413', (84, 87))	('restored', 'PosReg', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('YAP', 'Gene', '10413', (143, 146))	('SHANK2', 'Gene', (66, 72))	('human', 'Species', '9606', (12, 17))	('YAP', 'Gene', (84, 87))	('cancer', 'Disease', (18, 24))	('knockdown', 'Var', (73, 82))	('YAP', 'Gene', (143, 146))
681638	32661924	This indicated that SHANK2 knockdown restored Hippo signaling in such cells.	('knockdown', 'Var', (27, 36))	('Hippo', 'Gene', '37247', (46, 51))	('SHANK2', 'Gene', (20, 26))	('Hippo', 'Gene', (46, 51))	('restored', 'PosReg', (37, 45))
681640	32661924	When injected into nude mice, SHANK2 depletion also severely reduced the ability to form tumor in vivo (Fig.	('depletion', 'Var', (37, 46))	('SHANK2', 'Gene', (30, 36))	('nude mice', 'Species', '10090', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('reduced', 'NegReg', (61, 68))	('tumor', 'Disease', (89, 94))
681668	32661924	1C) and the Broad cancer gene copy number analysis (Table S1) of the 11q13 tumor amplicon clearly indicates a selection for SHANK2 amplification.	('amplification', 'Var', (131, 144))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SHANK2', 'Gene', (124, 130))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Disease', (75, 80))
681674	32661924	Our results, and the recent finding that cancerous SWI/SNF mutations cause YAP activation (Chang et al.,) will further expand the picture of Hippo pathway's broad involvement in human cancer.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('YAP', 'Gene', '10413', (75, 78))	('human', 'Species', '9606', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancerous SWI', 'Disease', (41, 54))	('cause', 'Reg', (69, 74))	('Hippo', 'Gene', (141, 146))	('cancer', 'Disease', (41, 47))	('YAP', 'Gene', (75, 78))	('mutations', 'Var', (59, 68))	('cancerous SWI', 'Disease', 'MESH:D009369', (41, 54))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('Hippo', 'Gene', '37247', (141, 146))
681676	32661924	Several studies noted SHANK2's amplification in esophageal and oropharyngeal cancer and its association with poor prognosis (Carneiro et al.,; Qin et al.,; Barros-Filho et al.,; Yu et al.,; Brown et al.,).	('SHANK2', 'Gene', (22, 28))	('esophageal', 'Disease', (48, 58))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Qin', 'Gene', '2290', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Qin', 'Gene', (143, 146))	('amplification', 'Var', (31, 44))
681680	32661924	SHANK2 mutation has been recently linked to autism (Berkel et al.,; Won et al.,; Schneider et al.,), and SHANK2 expression is mostly restricted to the nervous system (Naisbitt et al.,; Hayashi et al.,; Berkel et al.,; Won et al.,; Schneider et al.,).	('autism', 'Disease', (44, 50))	('SHANK2', 'Gene', (105, 111))	('autism', 'Phenotype', 'HP:0000717', (44, 50))	('mutation', 'Var', (7, 15))	('SHANK2', 'Gene', (0, 6))	('autism', 'Disease', 'MESH:D001321', (44, 50))	('linked', 'Reg', (34, 40))
681700	32661924	Our data suggests that deletion of PDZ domains from SHANK2 abolished its ability to regulate LATS1/2.	('abolished', 'NegReg', (59, 68))	('deletion', 'Var', (23, 31))	('LATS1/2', 'Gene', '9113;26524', (93, 100))	('SHANK2', 'Gene', (52, 58))	('ability', 'MPA', (73, 80))	('LATS1/2', 'Gene', (93, 100))
681730	33584065	Low FVC has been implicated as a risk prognostic predictor in gastric cancer, and low VC also predicts the poor survival in Japanese esophageal cancer in previous limited studies.	('low VC', 'Disease', 'MESH:D009800', (82, 88))	('low VC', 'Disease', (82, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Low FVC', 'Phenotype', 'HP:0032341', (0, 7))	('gastric cancer', 'Disease', (62, 76))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Low', 'Var', (0, 3))
681760	33584065	Stratification analysis by age at diagnosis and tumor length accordingly showed that patients with coMVV-HALP score = 0 had a worse overall survival than patients with coMVV-HALP score = 1 or 2 in groups with age < 60 (n = 379, P < 0.001, Figure 5), age >= 60 (n = 420, P < 0.001, Figure 5), tumor length < 4 cm (n = 374, P = 0.002, Figure 5) and tumor length >= 4 cm (n = 425, P < 0.001, Figure 5).	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('worse', 'NegReg', (126, 131))	('tumor', 'Disease', (48, 53))	('overall survival', 'MPA', (132, 148))	('tumor', 'Disease', (347, 352))	('tumor', 'Disease', (292, 297))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('coMVV-HALP score = 0', 'Var', (99, 119))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))
681762	33584065	However, we found that, among patients in stage II (n = 437, P < 0.001, Figure 6) and III (n = 264, P < 0.001, Figure 6), those with coMVV-HALP score = 0 had a worse overall survival than those with coMVV-HALP score = 1 or 2.	('coMVV-HALP score = 0', 'Var', (133, 153))	('patients', 'Species', '9606', (30, 38))	('overall survival', 'MPA', (166, 182))	('worse', 'NegReg', (160, 165))
681769	33584065	In this study, we found that low MVV was an independent risk factor for the overall survival of Chinese ESCC patients.	('MVV', 'MPA', (33, 36))	('low', 'Var', (29, 32))	('patients', 'Species', '9606', (109, 117))
681770	33584065	Although the mechanism of this association between lung function and cancer prognosis is unclear, multiple studies have demonstrated that impaired lung function is associated with mortality risk in the general population.	('impaired lung function', 'Phenotype', 'HP:0005952', (138, 160))	('mortality', 'Disease', (180, 189))	('associated', 'Reg', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mortality', 'Disease', 'MESH:D003643', (180, 189))	('impaired', 'Var', (138, 146))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
681771	33584065	Additionally, Sarkar et al elaborated a mechanism in which abnormal function of the respiratory system could lead to the development of hypoxemia and its detrimental consequences.	('abnormal', 'Var', (59, 67))	('lead to', 'Reg', (109, 116))	('hypoxemia', 'Phenotype', 'HP:0012418', (136, 145))	('hypoxemia', 'Disease', (136, 145))	('abnormal function of the respiratory system', 'Phenotype', 'HP:0002086', (59, 102))	('hypoxemia', 'Disease', 'MESH:D000860', (136, 145))
681776	33584065	Therefore, MVV may influence the capacity of oxygen supply for the body and then further affect the prognosis.	('affect', 'Reg', (89, 95))	('influence', 'Reg', (19, 28))	('oxygen', 'Chemical', 'MESH:D010100', (45, 51))	('MVV', 'Var', (11, 14))
681782	33584065	A low preoperative lymphocyte count could serve as a risk factor for a variety of cancers including ESCC; and (4) Platelets may protect tumor cells from immunosurveillance and mediate cancer metastasis.	('cancer', 'Disease', (184, 190))	('protect', 'NegReg', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancers', 'Disease', (82, 89))	('cancer', 'Disease', (82, 88))	('ESCC', 'Disease', (100, 104))	('Platelets', 'Var', (114, 123))	('mediate', 'Reg', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (136, 141))
681798	32580338	ICIs increased antitumor T cells' responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('acquired immune system tolerance', 'CPA', (82, 114))	('reducing', 'NegReg', (69, 77))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ICIs', 'Var', (0, 4))	('increased', 'PosReg', (5, 14))	('tumor', 'Disease', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
681805	32580338	Chemotherapy was the first identified therapeutic approach that systemically delivered chemical agents into tumor tissue and destroyed the large mass, but did not eliminate the disease.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('large mass', 'MPA', (139, 149))	('destroyed', 'NegReg', (125, 134))	('chemical agents', 'Var', (87, 102))
681825	32580338	CTLA-4 is the earliest known immune checkpoint and in vivo experiments showed that mice died after 3-4 weeks CTLA-4 deletion for immunosuppression, showing its important roles in immune responses and T cell activation.	('mice', 'Species', '10090', (83, 87))	('deletion', 'Var', (116, 124))	('died', 'Disease', (88, 92))	('CTLA-4', 'Gene', (109, 115))	('died', 'Disease', 'MESH:D003643', (88, 92))
681832	32580338	Recently, monoclonal antibodies against CTLA-4, ipilimumab, and tremelimumab, alone or in combination with PD-1/L-1 inhibitors, significantly increased antitumor effects and improved the survival of several malignancies (Figure 1).	('L-1', 'Gene', (112, 115))	('malignancies', 'Disease', (207, 219))	('ipilimumab', 'Chemical', 'MESH:D000074324', (48, 58))	('L-1', 'Gene', '28938', (112, 115))	('increased', 'PosReg', (142, 151))	('tremelimumab', 'Chemical', 'MESH:C520704', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('CTLA-4', 'Gene', (40, 46))	('malignancies', 'Disease', 'MESH:D009369', (207, 219))	('monoclonal antibodies', 'Var', (10, 31))	('improved', 'PosReg', (174, 182))
681858	32580338	Hepatic side effects (elevated AST (28%), elevated alkaline phosphatase (22%), elevated ALT (16%)) appear along with gastrointestinal side effects (diarrhea or colitis (21%)), respiratory side effects (cough (17%), upper respiratory tract infection (17%)), cardiovascular side effects (peripheral edema (10%)), and endocrine side effects (hypothyroidism and hyperthyroidism) (Figure 2).	('Hepatic side effects', 'MPA', (0, 20))	('AST', 'Gene', '26503', (31, 34))	('colitis', 'Disease', (160, 167))	('diarrhea', 'Disease', (148, 156))	('hypothyroidism', 'Phenotype', 'HP:0000821', (339, 353))	('ALT', 'MPA', (88, 91))	('elevated', 'Var', (79, 87))	('upper respiratory tract infection', 'Disease', (215, 248))	('upper respiratory tract infection', 'Disease', 'MESH:D012141', (215, 248))	('colitis', 'Disease', 'MESH:D003092', (160, 167))	('edema', 'Phenotype', 'HP:0000969', (297, 302))	('cough', 'Disease', 'MESH:D003371', (202, 207))	('diarrhea', 'Disease', 'MESH:D003967', (148, 156))	('elevated', 'PosReg', (42, 50))	('cough', 'Disease', (202, 207))	('hyperthyroidism', 'Phenotype', 'HP:0000836', (358, 373))	('upper respiratory tract infection', 'Phenotype', 'HP:0002788', (215, 248))	('AST', 'Gene', (31, 34))	('elevated ALT', 'Phenotype', 'HP:0031964', (79, 91))	('edema', 'Disease', 'MESH:D004487', (297, 302))	('peripheral edema', 'Phenotype', 'HP:0012398', (286, 302))	('respiratory tract infection', 'Phenotype', 'HP:0011947', (221, 248))	('edema', 'Disease', (297, 302))	('colitis', 'Phenotype', 'HP:0002583', (160, 167))	('elevated alkaline phosphatase', 'Phenotype', 'HP:0003155', (42, 71))	('diarrhea', 'Phenotype', 'HP:0002014', (148, 156))	('cough', 'Phenotype', 'HP:0012735', (202, 207))	('hypothyroidism and hyperthyroidism', 'Disease', 'MESH:D006980', (339, 373))	('gastrointestinal', 'MPA', (117, 133))
681874	32580338	Their results showed that OS was increased by 15.1 months in patients who received ipilimumab as compared to 7.8 months in other patients.	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (61, 69))	('ipilimumab', 'Chemical', 'MESH:D000074324', (83, 93))	('increased', 'PosReg', (33, 42))	('ipilimumab', 'Var', (83, 93))
681991	32580338	Genetic modifications of the PD-L1/PD-L2 along with JAK2 locus in the 9p24.1 region have been described and could contribute to the overexpression of PD-L1 and PD-L2.	('PD-L2', 'Gene', (35, 40))	('PD-L2', 'Gene', '80380', (35, 40))	('overexpression', 'PosReg', (132, 146))	('modifications', 'Var', (8, 21))	('PD-L2', 'Gene', (160, 165))	('JAK2', 'Gene', '3717', (52, 56))	('PD-L2', 'Gene', '80380', (160, 165))	('JAK2', 'Gene', (52, 56))	('contribute', 'Reg', (114, 124))
682038	32580338	Based on the evidence, up to 90% of patients treated with an anti-CTLA-4 antibody and 70% of patients treated with a PD-1/PD-L1 antibody develop irAEs, which affect any of the body organs including thyroiditis, dermatitis, pneumonitis, colitis, hepatitis, hypophysitis, uveitis, polyneuritis, and pancreatitis.	('pancreatitis', 'Disease', (297, 309))	('polyneuritis', 'Phenotype', 'HP:0031003', (279, 291))	('PD-1/PD-L1', 'Disease', (117, 127))	('polyneuritis', 'Disease', (279, 291))	('hypophysitis', 'Disease', 'MESH:D000072659', (256, 268))	('patients', 'Species', '9606', (93, 101))	('thyroiditis', 'Disease', (198, 209))	('patients', 'Species', '9606', (36, 44))	('anti-CTLA-4', 'Gene', (61, 72))	('hepatitis', 'Phenotype', 'HP:0012115', (245, 254))	('colitis', 'Disease', (236, 243))	('hepatitis', 'Disease', 'MESH:D056486', (245, 254))	('anti-CTLA-4', 'Var', (61, 72))	('uveitis', 'Disease', 'MESH:D014605', (270, 277))	('pneumonitis', 'Disease', 'MESH:D011014', (223, 234))	('uveitis', 'Disease', (270, 277))	('pancreatitis', 'Phenotype', 'HP:0001733', (297, 309))	('thyroiditis', 'Disease', 'MESH:D013959', (198, 209))	('dermatitis', 'Disease', (211, 221))	('colitis', 'Disease', 'MESH:D003092', (236, 243))	('hepatitis', 'Disease', (245, 254))	('dermatitis', 'Disease', 'MESH:D003872', (211, 221))	('pneumonitis', 'Disease', (223, 234))	('hypophysitis', 'Disease', (256, 268))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (117, 127))	('thyroiditis', 'Phenotype', 'HP:0100646', (198, 209))	('pancreatitis', 'Disease', 'MESH:D010195', (297, 309))	('uveitis', 'Phenotype', 'HP:0000554', (270, 277))	('polyneuritis', 'Disease', 'MESH:D009443', (279, 291))	('affect', 'Reg', (158, 164))	('dermatitis', 'Phenotype', 'HP:0011123', (211, 221))	('colitis', 'Phenotype', 'HP:0002583', (236, 243))
682040	32580338	Rash and erythema are the most common cutaneous irAE (40%) for patients who are treated with combination therapy compared to 25% in anti-CTLA-4, and 15% in anti-PD1 monotherapies.	('erythema', 'Phenotype', 'HP:0010783', (9, 17))	('erythema', 'Disease', 'MESH:D004890', (9, 17))	('erythema', 'Disease', (9, 17))	('Rash', 'Disease', (0, 4))	('combination', 'Var', (93, 104))	('patients', 'Species', '9606', (63, 71))	('PD1', 'Gene', '5133', (161, 164))	('Rash', 'Disease', 'MESH:D005076', (0, 4))	('Rash', 'Phenotype', 'HP:0000988', (0, 4))	('PD1', 'Gene', (161, 164))
682048	32580338	In addition, hepatitis is higher in patients who were treated with combination therapy (14-18%) than patients who were treated with anti-CTLA4 (4-9%) or anti-PD1 (1-4%) monotherapy.	('hepatitis', 'Disease', (13, 22))	('patients', 'Species', '9606', (101, 109))	('CTLA4', 'Gene', '1493', (137, 142))	('hepatitis', 'Phenotype', 'HP:0012115', (13, 22))	('higher', 'PosReg', (26, 32))	('patients', 'Species', '9606', (36, 44))	('CTLA4', 'Gene', (137, 142))	('hepatitis', 'Disease', 'MESH:D056486', (13, 22))	('combination', 'Var', (67, 78))	('PD1', 'Gene', (158, 161))	('PD1', 'Gene', '5133', (158, 161))
682076	32580338	For example, PD-L1 expression, high mutational load, selective CD8+ T cell infiltration, and distribution at tumor invasive margins correlate with clinical response to anti-PD-1/PD-L1treatment.	('expression', 'MPA', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('high mutational load', 'Var', (31, 51))	('CD8', 'Gene', (63, 66))	('PD-L1', 'Gene', (13, 18))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (173, 183))	('CD8', 'Gene', '925', (63, 66))	('PD-1/PD-L1', 'Disease', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
682307	30619771	In addition, some studies have shown higher zinc intake was significantly associated with reduced risk of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('reduced', 'NegReg', (90, 97))	('colorectal cancer', 'Disease', (106, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('zinc', 'Var', (44, 48))
682439	29416809	When 4EBP1 is phosphorylated and deactivated by upstream signals at several sites (Thr37/46, Thr70, Ser65, etc.	('Ser65', 'Var', (100, 105))	('Thr37', 'Chemical', '-', (83, 88))	('Ser65', 'Chemical', '-', (100, 105))	('Thr70', 'Var', (93, 98))	('Thr70', 'Chemical', '-', (93, 98))	('4EBP1', 'Gene', '1978', (5, 10))	('deactivated', 'NegReg', (33, 44))	('4EBP1', 'Gene', (5, 10))	('Thr37/46', 'Var', (83, 91))
682442	29416809	Research have shown that loss of 4EBP1 function (phosphorylation of 4EBP1) can induce epithelial-mesenchymal transformation, migration, and invasion by cancer cells.	('cancer', 'Disease', (152, 158))	('loss', 'Var', (25, 29))	('migration', 'CPA', (125, 134))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('4EBP1', 'Gene', '1978', (33, 38))	('induce', 'PosReg', (79, 85))	('4EBP1', 'Gene', (33, 38))	('4EBP1', 'Gene', '1978', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('epithelial-mesenchymal transformation', 'CPA', (86, 123))	('4EBP1', 'Gene', (68, 73))
682456	29416809	Our pooled analyses suggested that p-4EBP1 underexpression was a favorable indicator of 5-year overall survival among cancer patients, in contrast to those with redundant p-4EBP1 (P < 0.00001) (Figure 3).	('cancer', 'Disease', (118, 124))	('underexpression', 'Var', (43, 58))	('4EBP1', 'Gene', '1978', (173, 178))	('4EBP1', 'Gene', '1978', (37, 42))	('4EBP1', 'Gene', (173, 178))	('4EBP1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('overall', 'MPA', (95, 102))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('patients', 'Species', '9606', (125, 133))
682457	29416809	Furthermore, there was a correlation between patients with higher p-4EBP1 positivity and limited 10-year overall survival (P = 0.03) (Figure 4).	('positivity', 'Var', (74, 84))	('4EBP1', 'Gene', '1978', (68, 73))	('patients', 'Species', '9606', (45, 53))	('p-4EBP1 positivity', 'Phenotype', 'HP:0030859', (66, 84))	('higher', 'PosReg', (59, 65))	('limited', 'NegReg', (89, 96))	('4EBP1', 'Gene', (68, 73))
682462	29416809	Similarly, p-4EBP1 underexpression was a beneficial indicator of 5-year overall survival among patients with esophageal cancer (P = 0.0005), nasopharyngeal cancer (P = 0.0005), pancreatic cancer (P = 0.001), and other types (P = 0.01).	('underexpression', 'Var', (19, 34))	('beneficial', 'PosReg', (41, 51))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (141, 162))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (141, 162))	('nasopharyngeal cancer', 'Disease', (141, 162))	('overall', 'MPA', (72, 79))	('patients', 'Species', '9606', (95, 103))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('pancreatic cancer', 'Disease', (177, 194))	('esophageal cancer', 'Disease', (109, 126))	('4EBP1', 'Gene', '1978', (13, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))	('pancreatic cancer', 'Disease', 'MESH:D010190', (177, 194))	('4EBP1', 'Gene', (13, 18))
682465	29416809	Additionally, underexpression of p-4EBP1 predicted a longer 5-year disease-free survival in breast cancer (P = 0.008) and renal cancer (P = 0.004) but not in other types of cancer (P = 0.15) (Supplementary Figure 4).	('4EBP1', 'Gene', '1978', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('underexpression', 'Var', (14, 29))	('cancer', 'Disease', (128, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('renal cancer', 'Disease', (122, 134))	('breast cancer', 'Disease', (92, 105))	('cancer', 'Disease', (173, 179))	('renal cancer', 'Phenotype', 'HP:0009726', (122, 134))	('4EBP1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('disease-free survival', 'CPA', (67, 88))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('renal cancer', 'Disease', 'MESH:D007680', (122, 134))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('longer', 'PosReg', (53, 59))
682477	29416809	Evidence indicates that the disruption of protein synthesis at the level of 4EBP1/eIF4E downstream of mTORC1 stimulates tumor formation.	('eIF4E', 'Gene', '1977', (82, 87))	('4EBP1', 'Gene', '1978', (76, 81))	('mTORC1', 'Gene', '382056', (102, 108))	('4EBP1', 'Gene', (76, 81))	('stimulates', 'PosReg', (109, 119))	('disruption', 'Var', (28, 38))	('mTORC1', 'Gene', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('eIF4E', 'Gene', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('protein synthesis', 'MPA', (42, 59))	('tumor', 'Disease', (120, 125))
682489	29416809	In different tumor types, underexpression of p-4EBP1 consistently acted as an indicator of better prognosis among patients with breast cancer, cholangiocarcinoma, esophageal cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, and renal cancer.	('tumor', 'Disease', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('renal cancer', 'Disease', (244, 256))	('ovarian cancer', 'Disease', (205, 219))	('pancreatic cancer', 'Disease', (221, 238))	('renal cancer', 'Phenotype', 'HP:0009726', (244, 256))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('ovarian cancer', 'Phenotype', 'HP:0100615', (205, 219))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('better', 'PosReg', (91, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('4EBP1', 'Gene', '1978', (47, 52))	('esophageal cancer', 'Disease', (163, 180))	('renal cancer', 'Disease', 'MESH:D007680', (244, 256))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (182, 203))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (221, 238))	('underexpression', 'Var', (26, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (143, 161))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('ovarian cancer', 'Disease', 'MESH:D010051', (205, 219))	('cholangiocarcinoma', 'Disease', (143, 161))	('nasopharyngeal cancer', 'Disease', (182, 203))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (143, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (221, 238))	('4EBP1', 'Gene', (47, 52))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (182, 203))
682512	28426276	This work identified the global DNA methylation dysregulation patterns across 14 cancer types showing a higher impact for the non-CpG island areas.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('dysregulation', 'Var', (48, 61))
682515	28426276	Typically, cancers include hundreds of somatic alterations to DNA, overcoming programs that control replication and apoptosis to allow survival and growth.	('cancers', 'Disease', (11, 18))	('DNA', 'Gene', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('alterations', 'Var', (47, 58))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
682519	28426276	Recently, pan-cancer analyses have reported functional mutations, immunogenomic signature, and copy number alterations.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('copy number alterations', 'Var', (95, 118))
682525	28426276	Diverse methylomes within tumor type have been associated with tumor characteristics and patient prognosis.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('patient', 'Species', '9606', (89, 96))	('methylomes', 'Var', (8, 18))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('associated', 'Reg', (47, 57))
682551	28426276	Extending our assessment to summary measures of genetic somatic alterations, overall copy number alterations:represented by the fraction of the genome altered (FGA):median was 17.4%, though this had a wide IQR (4.75 to 34.3%).	('copy number alterations', 'Var', (85, 108))	('FGA', 'Gene', (160, 163))	('FGA', 'Gene', '2243', (160, 163))
682557	28426276	In contrast, the summary measures of genetic somatic alterations FGA and MCB, also presented in the figure, showed a different order and magnitude across cancer types.	('MCB', 'Gene', (73, 76))	('cancer', 'Disease', (154, 160))	('alterations', 'Var', (53, 64))	('FGA', 'Gene', '2243', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('FGA', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('MCB', 'Chemical', '-', (73, 76))
682561	28426276	Next, we visualized the gcMDI for all samples using unsupervised clustering and for each cancer type set four classes: high dysregulation, high-intermediate dysregulation, low-intermediate dysregulation, and low dysregulation (Fig.	('high dysregulation', 'Var', (119, 137))	('low-intermediate dysregulation', 'Var', (172, 202))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('low', 'Disease', (208, 211))	('cancer', 'Disease', (89, 95))	('high-intermediate dysregulation', 'Var', (139, 170))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
682590	28426276	Several CpG sites were related to long noncoding RNA or antisense genes (OTX2-AS1, LINC00466, TFAP2A-AS1, LHX5-AS1, LOC100507443, LIN28B-AS1, PAUPAR, DKFZp686K1684), transcription and regulatory factors (TFAP2B, USP44), and genes encoding tumor suppressor proteins (TRIM15, CASZ1).	('LINC00466', 'Gene', '199899', (83, 92))	('AS1', 'Gene', (111, 114))	('USP44', 'Gene', (212, 217))	('TRIM15', 'Gene', (266, 272))	('PAUPAR', 'Gene', '103157000', (142, 148))	('AS1', 'Gene', (78, 81))	('LINC00466', 'Gene', (83, 92))	('AS1', 'Gene', '5729', (137, 140))	('LOC100507443', 'Gene', (116, 128))	('CASZ1', 'Gene', (274, 279))	('AS1', 'Gene', (101, 104))	('LHX5-AS1', 'Gene', '104355219;64211;5729', (106, 114))	('CASZ1', 'Gene', '54897', (274, 279))	('tumor', 'Disease', (239, 244))	('TRIM15', 'Gene', '89870', (266, 272))	('USP44', 'Gene', '84101', (212, 217))	('TFAP2A-AS1', 'Gene', '100130275;7020;5729', (94, 104))	('AS1', 'Gene', '5729', (111, 114))	('LIN28B', 'Gene', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('TFAP2A-AS1', 'Gene', (94, 104))	('TFAP2B', 'Gene', '7021', (204, 210))	('AS1', 'Gene', '5729', (78, 81))	('AS1', 'Gene', (137, 140))	('LHX5-AS1', 'Gene', (106, 114))	('LOC100507443', 'Gene', '100507443', (116, 128))	('OTX2-AS1', 'Gene', (73, 81))	('TFAP2B', 'Gene', (204, 210))	('AS1', 'Gene', '5729', (101, 104))	('PAUPAR', 'Gene', (142, 148))	('OTX2-AS1', 'Gene', '100309464;5015;5729', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('LIN28B', 'Gene', '389421', (130, 136))	('DKFZp686K1684', 'Var', (150, 163))
682591	28426276	In addition, several commonly altered CpG sites were located in enhancer elements (cg10903903, cg17754510, cg22797031, cg13539545, cg08443563) and a few were spatially near to the histone related cluster of chromosome 6 (cg10903903-HIST1H2BL, and cg01518607-PRSS16).	('cg17754510', 'Var', (95, 105))	('cg22797031', 'Var', (107, 117))	('cg10903903', 'Var', (83, 93))	('PRSS16', 'Gene', (258, 264))	('enhancer', 'PosReg', (64, 72))	('HIST1H2BL', 'Gene', '8340', (232, 241))	('HIST1H2BL', 'Gene', (232, 241))	('PRSS16', 'Gene', '10279', (258, 264))	('cg08443563', 'Var', (131, 141))	('cg13539545', 'Var', (119, 129))
682595	28426276	Globally, the amount of dysregulation was lower in CpG island regions compared with other genomic regions, such as CpG island shores and shelves, and those in less CpG dense regions across tumor types.	('tumor', 'Disease', (189, 194))	('lower', 'NegReg', (42, 47))	('dysregulation', 'MPA', (24, 37))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('CpG', 'Var', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
682597	28426276	This finding was further supported when analyzing the specific loci dysregulation, in which these cancer types cluster together; three of the four showed a pattern of loci dysregulation associated to specific metabolic genes, proto-oncogenes and oncogenes.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('dysregulation', 'Var', (172, 185))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
682599	28426276	In contrast, age was consistently associated with MDI in breast cancer and hepatocellular carcinoma globally and across the different genomic contexts.	('breast cancer', 'Disease', (57, 70))	('associated', 'Reg', (34, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('hepatocellular carcinoma globally', 'Disease', (75, 108))	('hepatocellular carcinoma globally', 'Disease', 'MESH:D006528', (75, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('MDI', 'Var', (50, 53))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
682608	28426276	Specific reported mutations associated with differential methylation (CIMP phenotypes) differ by cancer subtype, which precludes an integrative analysis of specific mutation signatures for all the samples.	('mutations', 'Var', (18, 27))	('CIMP', 'Chemical', '-', (70, 74))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('differential methylation', 'MPA', (44, 68))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
682617	28426276	This work contributes to the understanding of the impact of epigenetic alterations from a pan-cancer perspective.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('epigenetic alterations', 'Var', (60, 82))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
682626	28426276	Although copy number alterations do not bias DNA methylation signals, biologically they are drivers of other cancer alterations which may alter DNA methylation levels, and were therefore included in our models.	('DNA methylation levels', 'MPA', (144, 166))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('alter', 'Reg', (138, 143))	('copy number alterations', 'Var', (9, 32))
682627	28426276	Information on the fraction of the genome with copy number alterations (FGA) and mutation count burden (MCB) were retrieved from cBioportal.	('FGA', 'Gene', (72, 75))	('MCB', 'Chemical', '-', (104, 107))	('FGA', 'Gene', '2243', (72, 75))	('copy number alterations', 'Var', (47, 70))
682628	28426276	FGA was measured using Affymetrix SNP arrays and corresponds to the fraction of the genome affected by copy number alterations, which is equivalent to the number of bases in segments with mean log2 greater than 0.2 or smaller than -0.2 divided by the number of bases in all segments profiled by the array.	('FGA', 'Gene', '2243', (0, 3))	('alterations', 'Var', (115, 126))	('copy number alterations', 'Var', (103, 126))	('affected by', 'Reg', (91, 102))	('FGA', 'Gene', (0, 3))
682745	28806937	For LSR, the exact mechanisms underlying the association remain unclear: one explanation is that the change in LSR levels is associated with subclinical inflammation, which may result in continued damage of tissue precipitating some noninfectious diseases.	('damage', 'MPA', (197, 203))	('LSR', 'Gene', (111, 114))	('inflammation', 'Disease', 'MESH:D007249', (153, 165))	('inflammation', 'Disease', (153, 165))	('associated', 'Reg', (125, 135))	('change', 'Var', (101, 107))
682837	26989390	The overall response rate was 19% in the cetuximab group compared with 13% in the standard treatment group, and there was a signal for improved efficacy regarding survival end points.	('improved', 'PosReg', (135, 143))	('cetuximab', 'Chemical', 'MESH:D000068818', (41, 50))	('cetuximab', 'Var', (41, 50))
683020	24914102	Of the six patients with non-T4 disease, five patients had extracapsular LNs that invaded the esophagus, and the other patients received a second course of RT.	('patients', 'Species', '9606', (46, 54))	('extracapsular', 'Disease', (59, 72))	('patients', 'Species', '9606', (119, 127))	('non-T4', 'Var', (25, 31))	('patients', 'Species', '9606', (11, 19))
683033	24914102	Patients with age younger than 60 years old, KPS <=70, T4 stage, a second course of RT, extracapsular LNs involving the esophagus, CRT and a total dose >100 Gy (BED-10) were at higher risk of perforation in the univariate analysis (details in Table 1).	('perforation', 'Disease', (192, 203))	('Patients', 'Species', '9606', (0, 8))	('KPS <=70', 'Var', (45, 53))
683085	23426606	The 2-year overall survival rate of patients expressing high levels of MIB-1 was 71% (+-17%) compared with 0% (P=0.019) for those expressing low levels.	('high levels', 'Var', (56, 67))	('patients', 'Species', '9606', (36, 44))	('MIB-1', 'Gene', (71, 76))
683088	23426606	The 2-year disease-free survival rates of HER2/neu and ER were 0% for patients expressing high levels compared with 56% (+-17%) for those with low levels (P=0.027).	('patients', 'Species', '9606', (70, 78))	('high levels', 'Var', (90, 101))	('ER', 'Gene', '2099', (55, 57))	('disease-free survival', 'CPA', (11, 32))	('ER', 'Gene', '2099', (43, 45))	('HER2/neu', 'Gene', '2064', (42, 50))	('HER2/neu', 'Gene', (42, 50))
683119	23426606	The TNM classifications were as follows: T1/T2/T3/T4, 2/3/5/0; N0/N1, 3/7; M0/M1a/M1b, 7/0/3; and stages I/II/III/IV, 2/2/3/3, respectively.	('TNM', 'Gene', '10178', (4, 7))	('M0/M1a/M1b', 'Var', (75, 85))	('TNM', 'Gene', (4, 7))	('N0/N1', 'Var', (63, 68))	('T1/T2/T3/T4', 'Disease', (41, 52))
683149	23426606	Blocking NF-kappaB causes tumor cells to stop proliferating, die or become more sensitive to the action of antitumor agents.	('NF-kappaB', 'Gene', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('die', 'CPA', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Blocking', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('stop', 'PosReg', (41, 45))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('NF-kappaB', 'Gene', '4790', (9, 18))
683151	23426606	Izzo et al reported that activated NF-kappaB prior to therapy in 80 patients with esophageal cancer was associated with the lack of a complete pathological response, which supports the present result showing that patients with high expression levels of NF-kappaB had significantly poorer OS and DFS rates than those showing low levels.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('NF-kappaB', 'Gene', (253, 262))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('DFS rates', 'CPA', (295, 304))	('high expression levels', 'Var', (227, 249))	('NF-kappaB', 'Gene', '4790', (35, 44))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (213, 221))	('esophageal cancer', 'Disease', (82, 99))	('activated', 'PosReg', (25, 34))	('NF-kappaB', 'Gene', (35, 44))	('poorer', 'NegReg', (281, 287))	('NF-kappaB', 'Gene', '4790', (253, 262))
683154	23426606	In addition to breast cancer, HER2 overexpression and gene amplification have also been reported in carcinomas of the colon, bladder, ovary, endometrium, lung, head and neck, esophagus and stomach.	('lung', 'Disease', (154, 158))	('stomach', 'Disease', (189, 196))	('HER2', 'Gene', (30, 34))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('breast cancer', 'Disease', (15, 28))	('esophagus', 'Disease', (175, 184))	('carcinomas of the colon', 'Disease', 'MESH:D015179', (100, 123))	('bladder', 'Disease', (125, 132))	('carcinomas of the colon', 'Disease', (100, 123))	('reported', 'Reg', (88, 96))	('overexpression', 'PosReg', (35, 49))	('gene amplification', 'Var', (54, 72))	('ovary', 'Disease', (134, 139))	('endometrium', 'Disease', (141, 152))	('ovary', 'Disease', 'MESH:D010051', (134, 139))	('HER2', 'Gene', '2064', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
683296	32512917	The receptor on epithelial cancer cells, referred to as type II IL-4 receptor, consist of IL-4Ralpha and IL-13Ralpha1.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('IL-13Ralpha1', 'Var', (105, 117))	('epithelial cancer', 'Phenotype', 'HP:0031492', (16, 33))	('IL-4 receptor', 'Gene', (64, 77))	('IL-4Ralpha', 'Gene', (90, 100))	('cancer', 'Disease', (27, 33))	('IL-4 receptor', 'Gene', '3566', (64, 77))	('IL-4Ralpha', 'Gene', '3566', (90, 100))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
683323	32512917	Interestingly, positive correlation between tumor grade and fold-change in IL-4 protein concentration in ESCC patients resulted from a negative correlation observed in adjacent non-cancerous tissue (rho = -0.60, p = 0.009) and not from an increasing IL-4 accumulation in tumor.	('fold-change', 'Var', (60, 71))	('ESCC', 'Disease', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('IL-4', 'Gene', (75, 79))	('tumor', 'Disease', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Disease', (181, 187))	('tumor', 'Disease', (44, 49))	('patients', 'Species', '9606', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (271, 276))
683358	32512917	Fold-change in expression ratio of IL4Ra positively correlated with fold-change in ACTA2, CCL2, CDKN1A, PTGS2, TJP1, and VEGFA and tended to positively correlate with HIF1A but was inversely related to CLDN2 and Ki67.	('correlated', 'Reg', (52, 62))	('HIF1A', 'Gene', (167, 172))	('VEGFA', 'Gene', (121, 126))	('TJP1', 'Gene', (111, 115))	('CCL2', 'Gene', '6347', (90, 94))	('CLDN2', 'Gene', '9075', (202, 207))	('fold-change', 'Var', (68, 79))	('PTGS2', 'Gene', (104, 109))	('CDKN1A', 'Gene', (96, 102))	('VEGFA', 'Gene', '7422', (121, 126))	('CDKN1A', 'Gene', '1026', (96, 102))	('HIF1A', 'Gene', '3091', (167, 172))	('Ki67', 'Chemical', '-', (212, 216))	('CLDN2', 'Gene', (202, 207))	('CCL2', 'Gene', (90, 94))	('TJP1', 'Gene', '7082', (111, 115))	('IL4Ra', 'Gene', (35, 40))	('ACTA2', 'Gene', (83, 88))	('correlate', 'Reg', (152, 161))	('IL4Ra', 'Gene', '3566', (35, 40))	('ACTA2', 'Gene', '59', (83, 88))	('expression ratio', 'MPA', (15, 31))	('PTGS2', 'Gene', '5743', (104, 109))
683359	32512917	Fold-change in IL4 tended to be positively correlated with fold-change in ACTA2 (Table 9).	('fold-change', 'Var', (59, 70))	('ACTA2', 'Gene', (74, 79))	('ACTA2', 'Gene', '59', (74, 79))	('IL4', 'Gene', '3565', (15, 18))	('IL4', 'Gene', (15, 18))
683381	32512917	In addition, IL4Ra expression in SW620 was higher than in SW480 cells.	('expression', 'MPA', (19, 29))	('SW620', 'Var', (33, 38))	('higher', 'PosReg', (43, 49))	('SW480', 'CellLine', 'CVCL:0546', (58, 63))	('IL4Ra', 'Gene', (13, 18))	('IL4Ra', 'Gene', '3566', (13, 18))
683382	32512917	IL13Ra1 expression was significantly higher in HT-29 and SW620 than in HCT 116 and SW480 cells (Figure 10).	('IL13Ra1', 'Gene', '3597', (0, 7))	('higher', 'PosReg', (37, 43))	('SW620', 'Var', (57, 62))	('HT-29', 'CellLine', 'CVCL:0320', (47, 52))	('SW480', 'CellLine', 'CVCL:0546', (83, 88))	('IL13Ra1', 'Gene', (0, 7))	('expression', 'MPA', (8, 18))
683432	32512917	Correspondingly, others have shown that high IL-4Ralpha protein expression in CRC was associated with lower incidence of lymph node metastasis.	('lower', 'NegReg', (102, 107))	('high', 'Var', (40, 44))	('lymph node metastasis', 'CPA', (121, 142))	('expression', 'MPA', (64, 74))	('IL-4Ralpha', 'Gene', (45, 55))	('IL-4Ralpha', 'Gene', '3566', (45, 55))	('lower incidence of lymph node metastasis', 'Phenotype', 'HP:0002732', (102, 142))
683442	32512917	Moreover, the authors showed an inhibition of colonic cancer cell proliferation induced by IL-13 by silencing IL13Ra1, but not IL13Ra2 gene.	('IL13Ra1', 'Gene', (110, 117))	('IL-13', 'Gene', '3596', (91, 96))	('IL13Ra1', 'Gene', '3597', (110, 117))	('silencing', 'Var', (100, 109))	('inhibition', 'NegReg', (32, 42))	('IL13Ra2', 'Gene', (127, 134))	('colonic cancer', 'Disease', (46, 60))	('colonic cancer', 'Disease', 'MESH:D015179', (46, 60))	('IL13Ra2', 'Gene', '3598', (127, 134))	('colonic cancer', 'Phenotype', 'HP:0003003', (46, 60))	('IL-13', 'Gene', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
683480	32512917	In CRC, high systemic IL-13 translated into better prognosis and accompanied less advanced cancers in terms of the overall disease stage and lymph node and distant metastases.	('metastases', 'Disease', 'MESH:D009362', (164, 174))	('better', 'PosReg', (44, 50))	('high', 'Var', (8, 12))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('IL-13', 'Gene', (22, 27))	('metastases', 'Disease', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('IL-13', 'Gene', '3596', (22, 27))
683486	32512917	One of the important findings of this study is the observation that some of the alterations concerning interleukins are happening in the tumor-adjacent tissue and not the tumor itself.	('alterations', 'Var', (80, 91))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('interleukins', 'Gene', (103, 115))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
683515	32512917	Neutralizing antibodies to IL-4 have inhibited tumor growth in xenograft models by reducing expression of anti-apoptotic Bcl-xL and Bcl-2.	('inhibited', 'NegReg', (37, 46))	('IL-4', 'Gene', (27, 31))	('reducing', 'NegReg', (83, 91))	('Bcl-xL', 'Gene', '598', (121, 127))	('Bcl-2', 'Gene', (132, 137))	('Bcl-xL', 'Gene', (121, 127))	('Bcl-2', 'Gene', '596', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Neutralizing', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('expression', 'MPA', (92, 102))
683528	32512917	In addition to already mentioned slightly greater sensitivity of HCT 116 to pro-survival activity of IL-13 during prolonged stimulation, the migratory properties of those cells were more markedly improved by IL-4.	('IL-13', 'Gene', (101, 106))	('IL-13', 'Gene', '3596', (101, 106))	('IL-4', 'Var', (208, 212))	('improved', 'PosReg', (196, 204))	('migratory properties of', 'CPA', (141, 164))
683604	31428901	Specifically, it has been reported that the rates of RLN palsy after such extensive nodal dissections could be as high as 60%:potentially impairing quality of life, predisposing to serious postoperative complications (e.g., aspiration pneumonia), and even resulting in postoperative deaths.	('aspiration pneumonia', 'Disease', 'MESH:D011015', (224, 244))	('predisposing', 'Reg', (165, 177))	('pneumonia', 'Phenotype', 'HP:0002090', (235, 244))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (224, 244))	('impairing', 'NegReg', (138, 147))	('quality of life', 'CPA', (148, 163))	('RLN palsy', 'Disease', 'MESH:D010243', (53, 62))	('nodal', 'Gene', (84, 89))	('deaths', 'Disease', 'MESH:D003643', (283, 289))	('aspiration', 'Phenotype', 'HP:0002835', (224, 234))	('deaths', 'Disease', (283, 289))	('nodal', 'Gene', '4838', (84, 89))	('dissections', 'Var', (90, 101))	('RLN palsy', 'Disease', (53, 62))	('aspiration pneumonia', 'Disease', (224, 244))
683732	30327774	F806 Suppresses the Invasion and Metastasis of Esophageal Squamous Cell Carcinoma via Downregulating F-Actin Assembly-Related Rho Family Proteins Invasion and metastasis are critical pathological and mortal processes in esophageal squamous cell carcinoma (ESCC).	('F-Actin Assembly-Related', 'Protein', (101, 125))	('F806', 'Chemical', '-', (0, 4))	('F806', 'Var', (0, 4))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('Downregulating', 'NegReg', (86, 100))	('esophageal squamous cell carcinoma', 'Disease', (220, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('Suppresses', 'NegReg', (5, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('Carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('Metastasis of Esophageal Squamous Cell Carcinoma', 'Disease', (33, 81))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (220, 254))	('Metastasis of Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (33, 81))
683734	30327774	A novel natural macrolide F806 specifically promotes apoptosis of various ESCC cells.	('promotes', 'PosReg', (44, 52))	('apoptosis', 'CPA', (53, 62))	('macrolide', 'Chemical', 'MESH:D018942', (16, 25))	('F806', 'Var', (26, 30))	('F806', 'Chemical', '-', (26, 30))
683735	30327774	However, whether F806 can inhibit metastasis of ESCC cells needs further evaluation.	('F806', 'Chemical', '-', (17, 21))	('inhibit', 'NegReg', (26, 33))	('metastasis', 'CPA', (34, 44))	('ESCC', 'Disease', (48, 52))	('F806', 'Var', (17, 21))
683736	30327774	Here, our data showed that F806 inhibits dynamic F-actin assembly and then suppresses the migration of ESCC cells in vitro and their invasion and metastasis in vivo.	('F806', 'Var', (27, 31))	('F806', 'Chemical', '-', (27, 31))	('migration', 'CPA', (90, 99))	('dynamic F-actin assembly', 'MPA', (41, 65))	('suppresses', 'NegReg', (75, 85))	('inhibits', 'NegReg', (32, 40))	('ESCC', 'Disease', (103, 107))
683737	30327774	The correlation between cancer migration and actin cytoskeleton assembly was consistent with the ability of F806 to prevent the aggregation of Paxillin, an essential protein for focal adhesion formation through binding to the ends of actin filaments.	('Paxillin', 'Gene', '5829', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('prevent', 'NegReg', (116, 123))	('F806', 'Var', (108, 112))	('Paxillin', 'Gene', (143, 151))	('F806', 'Chemical', '-', (108, 112))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('binding', 'Interaction', (211, 218))	('aggregation', 'MPA', (128, 139))
683738	30327774	Furthermore, F806 downregulated the expression and activity of the Rho family proteins cell division cycle 42 (CDC42), RAC family small GTPase 1 (RAC1), and RAS homolog family member A (RHOA).	('RAC', 'Gene', '207', (119, 122))	('activity', 'MPA', (51, 59))	('RAC1', 'Gene', (146, 150))	('RAC', 'Gene', (146, 149))	('RHOA', 'Gene', '387', (186, 190))	('GTP', 'Chemical', 'MESH:D006160', (136, 139))	('RHOA', 'Gene', (186, 190))	('CDC42', 'Gene', '998', (111, 116))	('RAC1', 'Gene', '5879', (146, 150))	('downregulated', 'NegReg', (18, 31))	('RAC', 'Gene', '207', (146, 149))	('RAC', 'Gene', (119, 122))	('CDC42', 'Gene', (111, 116))	('F806', 'Var', (13, 17))	('expression', 'MPA', (36, 46))	('F806', 'Chemical', '-', (13, 17))
683739	30327774	Taken together, these results suggest that F806 can suppress cancer invasion and metastasis via interrupting the assembly of migration components involving F-actin.	('suppress', 'NegReg', (52, 60))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('assembly of', 'MPA', (113, 124))	('cancer', 'Disease', (61, 67))	('interrupting', 'NegReg', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('F806', 'Var', (43, 47))	('F-actin', 'Protein', (156, 163))	('F806', 'Chemical', '-', (43, 47))
683746	30327774	Our previous research suggested that the novel macrolide analog F806 has higher selectivity and sensitivity for the apoptosis of ESCC cells than that of normal cells ( and Supplementary Figure S1), making it a possible candidate target drug.	('macrolide', 'Chemical', 'MESH:D018942', (47, 56))	('ESCC', 'Disease', (129, 133))	('apoptosis', 'CPA', (116, 125))	('sensitivity', 'MPA', (96, 107))	('selectivity', 'MPA', (80, 91))	('F806', 'Var', (64, 68))	('F806', 'Chemical', '-', (64, 68))	('higher', 'PosReg', (73, 79))
683747	30327774	However, it is not clear whether F806 has pharmacological functions to inhibit the invasion and metastasis of ESCC cells.	('inhibit', 'NegReg', (71, 78))	('F806', 'Var', (33, 37))	('F806', 'Chemical', '-', (33, 37))	('invasion', 'CPA', (83, 91))	('ESCC', 'Disease', (110, 114))
683748	30327774	F806 can downregulate expression of integrin beta 1 (ITGB1) and growth factor receptor bound protein 2 (GRB2), resulting in ESCC cell apoptosis.	('F806', 'Chemical', '-', (0, 4))	('F806', 'Var', (0, 4))	('ITGB1', 'Gene', '3688', (53, 58))	('growth factor receptor bound protein 2', 'Gene', '2885', (64, 102))	('GRB2', 'Gene', '2885', (104, 108))	('growth factor receptor bound protein 2', 'Gene', (64, 102))	('integrin beta 1', 'Gene', '3688', (36, 51))	('ITGB1', 'Gene', (53, 58))	('GRB2', 'Gene', (104, 108))	('ESCC', 'Disease', (124, 128))	('expression', 'MPA', (22, 32))	('downregulate', 'NegReg', (9, 21))	('integrin beta 1', 'Gene', (36, 51))
683751	30327774	Therefore, we hypothesized that F806 may have a new function of disrupting the actin cytoskeleton assembly and focal adhesion, leading to inhibition of cancer cell metastasis.	('inhibition', 'NegReg', (138, 148))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('disrupting', 'NegReg', (64, 74))	('actin cytoskeleton', 'MPA', (79, 97))	('F806', 'Var', (32, 36))	('focal adhesion', 'CPA', (111, 125))	('F806', 'Chemical', '-', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
683752	30327774	To prove this hypothesis, we firstly characterize the pharmacological function of F806 in inhibiting ESCC migration and metastasis in vitro and in vivo and then display an antimetastasis mechanism of F806 in this study.	('F806', 'Var', (200, 204))	('inhibiting', 'NegReg', (90, 100))	('F806', 'Chemical', '-', (200, 204))	('F806', 'Var', (82, 86))	('F806', 'Chemical', '-', (82, 86))
683770	30327774	Briefly, cells grown on coverslips in 24-well plate were treated with F806 (20 muM) for 24 hrs.	('muM', 'Gene', '56925', (79, 82))	('F806', 'Var', (70, 74))	('muM', 'Gene', (79, 82))	('F806', 'Chemical', '-', (70, 74))
683775	30327774	Briefly, after the treatment with or without F806 (20 muM) for 24 hrs, cells were homogenized in lysis buffer and F-actin stabilization buffers, followed by centrifugation for 1 hr at 100,000 xg at 37 C to pellet F-actin.	('muM', 'Gene', (54, 57))	('muM', 'Gene', '56925', (54, 57))	('F806', 'Chemical', '-', (45, 49))	('F806', 'Var', (45, 49))
683776	30327774	After the treatment with F806 (20 muM) for 24 hrs, cells were homogenized.	('muM', 'Gene', '56925', (34, 37))	('F806', 'Chemical', '-', (25, 29))	('muM', 'Gene', (34, 37))	('F806', 'Var', (25, 29))
683780	30327774	The potential of F806 to inhibit the migration of EC109 and KYSE510 cells was initially examined in a transwell cell migration assay.	('F806', 'Chemical', '-', (17, 21))	('KYSE510', 'CellLine', 'CVCL:1354', (60, 67))	('migration', 'CPA', (37, 46))	('inhibit', 'NegReg', (25, 32))	('F806', 'Var', (17, 21))
683781	30327774	F806 (20 muM) reduced the number of cell colonies on the bottom surface of the chamber (Figure 1(a)).	('F806', 'Chemical', '-', (0, 4))	('F806', 'Var', (0, 4))	('reduced', 'NegReg', (14, 21))	('muM', 'Gene', '56925', (9, 12))	('muM', 'Gene', (9, 12))
683782	30327774	Cell migration was reduced by about 52% and 66% in F806-treated EC109 and KYSE510 cells, respectively (Figure 1(b)).	('F806', 'Chemical', '-', (51, 55))	('Cell migration', 'CPA', (0, 14))	('KYSE510', 'CellLine', 'CVCL:1354', (74, 81))	('reduced', 'NegReg', (19, 26))	('F806-treated', 'Var', (51, 63))
683783	30327774	The results indicated that the migration of ESCC cells in vitro was clearly suppressed by F806.	('F806', 'Chemical', '-', (90, 94))	('suppressed', 'NegReg', (76, 86))	('F806', 'Var', (90, 94))	('migration of ESCC cells in vitro', 'CPA', (31, 63))
683785	30327774	Tumor size was reduced by about 53% or 31% following administration of 4 mg/kg or 8 mg/kg F806, respectively (Figure 2(c)).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('F806', 'Var', (90, 94))	('F806', 'Chemical', '-', (90, 94))	('Tumor size', 'CPA', (0, 10))	('reduced', 'NegReg', (15, 22))
683786	30327774	Similarly, HE stain suggested that the infiltrating cancer cells were distinctly reduced by F806 in the inguinal lymph node area of mice (Figure 2(e)).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('HE', 'Chemical', '-', (11, 13))	('reduced', 'NegReg', (81, 88))	('mice', 'Species', '10090', (132, 136))	('F806', 'Var', (92, 96))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('F806', 'Chemical', '-', (92, 96))
683787	30327774	Therefore, the conclusion is that F806 can markedly inhibit the migration of ESCC cells in vitro and their invasion and metastasis in vivo.	('inhibit', 'NegReg', (52, 59))	('F806', 'Chemical', '-', (34, 38))	('ESCC', 'Disease', (77, 81))	('migration', 'CPA', (64, 73))	('F806', 'Var', (34, 38))
683788	30327774	Previous reports showed that F806 can downregulate expression of ITGB1 and GRB2 proteins that participate in the connection of actin fibers to plasma membrane, in ESCC cell lines.	('ITGB1', 'Gene', (65, 70))	('proteins', 'Protein', (80, 88))	('F806', 'Var', (29, 33))	('expression', 'MPA', (51, 61))	('downregulate', 'NegReg', (38, 50))	('GRB2', 'Gene', (75, 79))	('ITGB1', 'Gene', '3688', (65, 70))	('F806', 'Chemical', '-', (29, 33))	('GRB2', 'Gene', '2885', (75, 79))
683789	30327774	Therefore, we examined whether the inhibitory effect of F806 on ESCC invasion and metastasis was correlated with alterations in F-actin rearrangement.	('ESCC', 'Disease', (64, 68))	('F806', 'Var', (56, 60))	('F806', 'Chemical', '-', (56, 60))	('F-actin', 'MPA', (128, 135))	('metastasis', 'CPA', (82, 92))
683791	30327774	We found that fluorescence intensity was dramatically altered by F806 in accordance with the distinction of fluorescence intensity between G-actin and F-actin (Figure 3(a)).	('fluorescence intensity', 'MPA', (14, 36))	('F806', 'Chemical', '-', (65, 69))	('F806', 'Var', (65, 69))	('altered', 'Reg', (54, 61))
683792	30327774	At the cell level, actin assembly was inhibited by F806, resulting in a significant reduction in the number and length of stress fibers and filopodia after the treatment with F806 (20 muM) for 24 hrs (Figure 3(b)) and after the treatment with F806 (20 muM) for 30 minutes, when the behavior of actin assembly was visualized for following 2 hrs using the live imaging system in a confocal microscope (Figure 3(c) and Supplementary video).	('F806', 'Chemical', '-', (175, 179))	('F806', 'Chemical', '-', (51, 55))	('reduction', 'NegReg', (84, 93))	('actin', 'Protein', (19, 24))	('inhibited', 'NegReg', (38, 47))	('muM', 'Gene', '56925', (252, 255))	('muM', 'Gene', '56925', (184, 187))	('F806', 'Var', (51, 55))	('muM', 'Gene', (252, 255))	('F806', 'Chemical', '-', (243, 247))	('muM', 'Gene', (184, 187))
683793	30327774	At the molecular level, the data indicated that F806 reduced the level of F-actin, suggesting that formation of actin filaments, from G-actin, was suppressed by F806 (Figure 3(d)).	('F806', 'Chemical', '-', (161, 165))	('level of F-actin', 'MPA', (65, 81))	('F806', 'Var', (48, 52))	('formation of actin filaments', 'MPA', (99, 127))	('F806', 'Chemical', '-', (48, 52))	('suppressed', 'NegReg', (147, 157))	('reduced', 'NegReg', (53, 60))	('F806', 'Var', (161, 165))
683794	30327774	Rho family proteins, CDC42, RHOA, and RAC1, are involved in the upstream regulation of actin filament formation, so we tested the effect of F806 on CDC42, RHOA, and RAC1 protein expression.	('RHOA', 'Gene', (28, 32))	('F806', 'Chemical', '-', (140, 144))	('RAC1', 'Gene', (38, 42))	('CDC42', 'Gene', '998', (21, 26))	('RHOA', 'Gene', (155, 159))	('tested', 'Reg', (119, 125))	('CDC42', 'Gene', '998', (148, 153))	('CDC42', 'Gene', (21, 26))	('RAC1', 'Gene', '5879', (165, 169))	('CDC42', 'Gene', (148, 153))	('RAC1', 'Gene', '5879', (38, 42))	('RHOA', 'Gene', '387', (28, 32))	('RHOA', 'Gene', '387', (155, 159))	('RAC1', 'Gene', (165, 169))	('F806', 'Var', (140, 144))
683795	30327774	We found that their expression was reduced by F806 treatment in both EC109 and KYSE510 cells (Figures 4(a) and 4(b)).	('expression', 'MPA', (20, 30))	('reduced', 'NegReg', (35, 42))	('F806', 'Chemical', '-', (46, 50))	('F806 treatment', 'Var', (46, 60))	('KYSE510', 'CellLine', 'CVCL:1354', (79, 86))
683796	30327774	Importantly, the activity form of CDC42 (CDC42-GTP) also decreased in the F806 treatment group compared to the control group.	('CDC42', 'Gene', '998', (34, 39))	('CDC42', 'Gene', '998', (41, 46))	('CDC42', 'Gene', (34, 39))	('F806 treatment', 'Var', (74, 88))	('decreased', 'NegReg', (57, 66))	('CDC42', 'Gene', (41, 46))	('F806', 'Chemical', '-', (74, 78))	('CDC42-GTP', 'Gene', '998', (41, 50))	('activity form', 'MPA', (17, 30))	('CDC42-GTP', 'Gene', (41, 50))
683798	30327774	Western blots showed that F806 lost the ability to reduce Rho family proteins after treatment with MG132, suggesting that F806 inhibited the activity of Rho family proteins by regulating proteasome activity.	('F806', 'Chemical', '-', (122, 126))	('MG132', 'Chemical', 'MESH:C072553', (99, 104))	('activity', 'MPA', (141, 149))	('Rho family proteins', 'Protein', (58, 77))	('inhibited', 'NegReg', (127, 136))	('proteasome activity', 'MPA', (187, 206))	('reduce', 'NegReg', (51, 57))	('regulating', 'Reg', (176, 186))	('F806', 'Var', (122, 126))	('F806', 'Chemical', '-', (26, 30))	('Rho', 'Protein', (153, 156))
683800	30327774	The results suggested that F806 interfered with Paxillin aggregation at the ends of actin filaments (Figure 4(d)).	('F806', 'Var', (27, 31))	('F806', 'Chemical', '-', (27, 31))	('Paxillin', 'Gene', '5829', (48, 56))	('interfered', 'NegReg', (32, 42))	('Paxillin', 'Gene', (48, 56))
683801	30327774	Thus, we conclude that F806 suppresses the assembly of actin filaments and their linkage to Paxillin via inhibiting the expression of Rho family.	('inhibiting', 'NegReg', (105, 115))	('expression', 'MPA', (120, 130))	('Paxillin', 'Gene', (92, 100))	('F806', 'Chemical', '-', (23, 27))	('suppresses', 'NegReg', (28, 38))	('linkage', 'Interaction', (81, 88))	('F806', 'Var', (23, 27))	('Paxillin', 'Gene', '5829', (92, 100))	('assembly', 'MPA', (43, 51))	('Rho family', 'Protein', (134, 144))
683804	30327774	We previously showed that F806 displays greater specificity and stronger lethality toward ESCC cells, but not for normal immortalized epithelia cells (Supplementary Figure 1).	('stronger', 'PosReg', (64, 72))	('specificity', 'MPA', (48, 59))	('lethality', 'MPA', (73, 82))	('F806', 'Var', (26, 30))	('ESCC', 'Disease', (90, 94))	('F806', 'Chemical', '-', (26, 30))
683806	30327774	Our previous studies showed that F806 suppresses cancer progression; though it downregulates the protein expression of actin cytoskeleton linkers ITGB1 and GRB2, proteins are involved in the formation of focal adhesions, which implies F806 can control dynamic changes of the cytoskeleton.	('GRB2', 'Gene', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('F806', 'Var', (33, 37))	('F806', 'Chemical', '-', (235, 239))	('downregulates', 'NegReg', (79, 92))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('GRB2', 'Gene', '2885', (156, 160))	('ITGB1', 'Gene', (146, 151))	('F806', 'Chemical', '-', (33, 37))	('suppresses', 'NegReg', (38, 48))	('actin cytoskeleton linkers', 'MPA', (119, 145))	('protein expression', 'MPA', (97, 115))	('ITGB1', 'Gene', '3688', (146, 151))	('cancer', 'Disease', (49, 55))
683807	30327774	We determined whether F806 could take part in the regulation of actin assembly and cancer metastasis by analyzing the function of F806-downregulating proteins in the above two biological processes.	('F806-downregulating', 'Var', (130, 149))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('F806', 'Var', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('F806', 'Chemical', '-', (22, 26))	('proteins', 'Protein', (150, 158))	('cancer', 'Disease', (83, 89))	('F806', 'Chemical', '-', (130, 134))
683808	30327774	Nevertheless, we have previously paid close attention to the therapeutic efficacy of F806 for ESCC survival and growth, but its regulation for ESCC migration processes had yet to be explored.	('close attention', 'Phenotype', 'HP:0000736', (38, 53))	('F806', 'Var', (85, 89))	('ESCC', 'Disease', (94, 98))	('F806', 'Chemical', '-', (85, 89))
683809	30327774	Our results firstly suggest that F806, as a potential candidate compound, suppresses ESCC migration in vitro and in vivo (Figures 1 and 2).	('F806', 'Var', (33, 37))	('F806', 'Chemical', '-', (33, 37))	('suppresses', 'NegReg', (74, 84))	('ESCC', 'Disease', (85, 89))
683810	30327774	Because F806 may have pleiotropic effects on inhibiting ESCC development, it needs to be further confirmed that the inhibitory effect of F806 on ESCC migration independent of its suppression on ESCC growth.	('F806', 'Chemical', '-', (8, 12))	('inhibiting', 'NegReg', (45, 55))	('F806', 'Var', (8, 12))	('F806', 'Var', (137, 141))	('ESCC development', 'CPA', (56, 72))	('F806', 'Chemical', '-', (137, 141))	('ESCC', 'Disease', (145, 149))
683811	30327774	The results showed that the dose-response of F806-mediated inhibition of metastasis was not completely identical with inhibition of tumor size (Figures 2(c) and 2(e)), which suggested that F806-mediated suppression of ESCC metastasis did not completely rely on F806 against ESCC proliferation.	('F806-mediated', 'Var', (189, 202))	('F806', 'Chemical', '-', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('suppression', 'NegReg', (203, 214))	('ESCC', 'Disease', (218, 222))	('metastasis', 'CPA', (73, 83))	('F806-mediated', 'Var', (45, 58))	('F806', 'Chemical', '-', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('F806', 'Chemical', '-', (261, 265))	('tumor', 'Disease', (132, 137))
683812	30327774	Based on the correlation of the above mentioned ESCC metastasis-related processes mediated by F806, F806 inhibition of actin assembly was supported by our demonstration that F806 disturbs actin assembly (Figure 3).	('disturbs', 'Reg', (179, 187))	('F806', 'Var', (100, 104))	('F806', 'Chemical', '-', (174, 178))	('actin', 'MPA', (119, 124))	('F806', 'Chemical', '-', (100, 104))	('inhibition', 'NegReg', (105, 115))	('F806', 'Var', (94, 98))	('actin assembly', 'MPA', (188, 202))	('F806', 'Chemical', '-', (94, 98))	('ESCC', 'Disease', (48, 52))	('F806', 'Var', (174, 178))
683813	30327774	Although we understand that F806 suppresses ESCC migration and disturbs the dynamic actin assembly, we needed to determine the proteins regulating above two physiological processes.	('ESCC migration', 'CPA', (44, 58))	('F806', 'Var', (28, 32))	('suppresses', 'NegReg', (33, 43))	('F806', 'Chemical', '-', (28, 32))	('disturbs', 'NegReg', (63, 71))	('dynamic actin assembly', 'MPA', (76, 98))
683815	30327774	Examination of the effects of F806 on their expression showed that F806 inhibits their activity via reducing their expression (Figures 4(a) and 4(b)).	('F806', 'Chemical', '-', (30, 34))	('activity', 'MPA', (87, 95))	('reducing', 'NegReg', (100, 108))	('inhibits', 'NegReg', (72, 80))	('expression', 'MPA', (115, 125))	('F806', 'Var', (67, 71))	('F806', 'Chemical', '-', (67, 71))
683819	30327774	When ESCC cells were exposed to F806, the aggregation of Paxillin was blocked at the ends of actin filaments close to the interior surface of plasma membranes; the depolymerization of actin filaments was promoted (Figure 4(c)).	('Paxillin', 'Gene', (57, 65))	('depolymerization of actin filaments', 'MPA', (164, 199))	('F806', 'Var', (32, 36))	('F806', 'Chemical', '-', (32, 36))	('aggregation', 'MPA', (42, 53))	('blocked', 'NegReg', (70, 77))	('Paxillin', 'Gene', '5829', (57, 65))	('promoted', 'PosReg', (204, 212))
683820	30327774	In addition, we previously showed that ITGB1, a constituent of the focal adhesion complex, is also reduced by F806.	('ITGB1', 'Gene', '3688', (39, 44))	('F806', 'Var', (110, 114))	('F806', 'Chemical', '-', (110, 114))	('reduced', 'NegReg', (99, 106))	('ITGB1', 'Gene', (39, 44))
683821	30327774	The loss of ITGB1 may result in the separation of Paxillin from the intracellular surface of cell adhesion sites.	('Paxillin', 'Gene', (50, 58))	('ITGB1', 'Gene', '3688', (12, 17))	('result in', 'Reg', (22, 31))	('separation', 'MPA', (36, 46))	('ITGB1', 'Gene', (12, 17))	('Paxillin', 'Gene', '5829', (50, 58))	('loss', 'Var', (4, 8))
683822	30327774	Because Paxillin plays an important role in the recruitment of an array of GTPase activators to sites of cell adhesion, loss of Paxillin at these sites may in turn further inhibit CDC42, RAC1, and RHOA activity.	('RAC1', 'Gene', (187, 191))	('loss', 'Var', (120, 124))	('RAC1', 'Gene', '5879', (187, 191))	('GTP', 'Chemical', 'MESH:D006160', (75, 78))	('RHOA', 'Gene', '387', (197, 201))	('Paxillin', 'Gene', '5829', (128, 136))	('Paxillin', 'Gene', '5829', (8, 16))	('CDC42', 'Gene', '998', (180, 185))	('RHOA', 'Gene', (197, 201))	('inhibit', 'NegReg', (172, 179))	('Paxillin', 'Gene', (128, 136))	('CDC42', 'Gene', (180, 185))	('Paxillin', 'Gene', (8, 16))
683823	30327774	Therefore, we examined CDC42, RAC1, and RHOA as potential target proteins of F806 based on their role in the formation and turnover of actin filaments, as well as cancer invasion and metastasis.	('CDC42', 'Gene', (23, 28))	('RHOA', 'Gene', '387', (40, 44))	('metastasis', 'CPA', (183, 193))	('RAC1', 'Gene', '5879', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('RHOA', 'Gene', (40, 44))	('CDC42', 'Gene', '998', (23, 28))	('RAC1', 'Gene', (30, 34))	('F806', 'Var', (77, 81))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('F806', 'Chemical', '-', (77, 81))
683824	30327774	F806 may also regulate other upstream signal complexes involved in cytoskeletal organization, cancer apoptosis, and autophagy.	('cytoskeletal', 'CPA', (67, 79))	('F806', 'Chemical', '-', (0, 4))	('F806', 'Var', (0, 4))	('autophagy', 'CPA', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('regulate', 'Reg', (14, 22))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
683826	30327774	In conclusion, our results demonstrated that the therapeutic effects of F806 on invasion and metastasis of ESCC via inhibiting the function of Rho family proteins for regulating F-actin assemble and the combination of Paxillin with F-actin ends.	('inhibiting', 'NegReg', (116, 126))	('invasion', 'CPA', (80, 88))	('Paxillin', 'Gene', (218, 226))	('metastasis', 'CPA', (93, 103))	('F806', 'Var', (72, 76))	('Rho family proteins', 'Protein', (143, 162))	('regulating F-actin assemble', 'MPA', (167, 194))	('F806', 'Chemical', '-', (72, 76))	('combination', 'Interaction', (203, 214))	('function', 'MPA', (131, 139))	('ESCC', 'Disease', (107, 111))	('Paxillin', 'Gene', '5829', (218, 226))
683827	30327774	Therefore, it can be said that we found the novel efficacy of F806 interrupting Rho family proteins/F-actin assembly/ESCC migration pathway in metastatic ESCC.	('metastatic ESCC', 'Disease', (143, 158))	('F806', 'Chemical', '-', (62, 66))	('F806', 'Var', (62, 66))
683965	26211420	using the same model as Ellis et al., showed that flavopiridol, a cyclin-dependent kinase inhibitor could reduce the prevalence of BE and EAC in p27 knockout mice by almost two-thirds, further highlighting the importance of P27 gene in EAC pathogenesis.	('EAC', 'Gene', (138, 141))	('EAC', 'Gene', '74256', (236, 239))	('knockout', 'Var', (149, 157))	('mice', 'Species', '10090', (158, 162))	('EAC', 'Gene', (236, 239))	('P27', 'Gene', (224, 227))	('reduce', 'NegReg', (106, 112))	('p27', 'Gene', (145, 148))	('flavopiridol', 'Chemical', 'MESH:C077990', (50, 62))	('EAC', 'Phenotype', 'HP:0011459', (138, 141))	('P27', 'Gene', '12576', (224, 227))	('BE and EAC', 'Gene', '74256', (131, 141))	('EAC', 'Gene', '74256', (138, 141))	('p27', 'Gene', '12576', (145, 148))	('EAC', 'Phenotype', 'HP:0011459', (236, 239))
683967	26211420	However, they are created by single gene insertion or deletion in all cells of the whole body or a whole organ, which is a rather oversimplification of the process of clonal evolution naturally occurring in the carcinogenic field.	('deletion', 'Var', (54, 62))	('rat', 'Species', '10116', (123, 126))	('carcinogenic field', 'Disease', 'MESH:D005128', (211, 229))	('carcinogenic field', 'Disease', (211, 229))
683970	26211420	They reported occasional development of BE mice defective for thrombospondin-1 but no development of EAC was found.	('mice', 'Species', '10090', (43, 47))	('EAC', 'Gene', '74256', (101, 104))	('thrombospondin-1', 'Gene', '21825', (62, 78))	('thrombospondin-1', 'Gene', (62, 78))	('EAC', 'Gene', (101, 104))	('defective', 'Var', (48, 57))	('EAC', 'Phenotype', 'HP:0011459', (101, 104))	('BE', 'Chemical', 'MESH:D001608', (40, 42))
684035	32884296	Stromal FAP-alpha expression was significantly associated with poor survival in univariable (HR 2.009; 95% CI 1.259-3.205; p=0.003) and multivariable analysis (HR 1.833; 95% CI 1.144-2.937; p=0.012).	('FAP-alpha', 'Gene', (8, 17))	('FAP-alpha', 'Gene', '2191', (8, 17))	('expression', 'Var', (18, 28))	('poor', 'NegReg', (63, 67))
684050	32884296	FAP-alpha was shown to predict survival, for example, high FAP-alpha being a marker for poor survival in oral squamous cell carcinoma, gastric cancer, and pancreatic ductal adenocarcinoma.	('gastric cancer', 'Disease', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (155, 187))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('high', 'Var', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('oral squamous cell carcinoma', 'Disease', (105, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (155, 187))	('FAP-alpha', 'Gene', '2191', (0, 9))	('FAP-alpha', 'Gene', '2191', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))	('pancreatic ductal adenocarcinoma', 'Disease', (155, 187))	('FAP-alpha', 'Gene', (0, 9))	('FAP-alpha', 'Gene', (59, 68))
684051	32884296	Subsequently, another study investigated the role of epithelial FAP-alpha in distal cholangiocarcinoma and found that positive of this marker protein correlates with better survival.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('cholangiocarcinoma', 'Disease', (84, 102))	('positive', 'Var', (118, 126))	('FAP-alpha', 'Gene', '2191', (64, 73))	('better', 'PosReg', (166, 172))	('FAP-alpha', 'Gene', (64, 73))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
684057	32884296	For this study, the following criteria were required for inclusion: surgery with the radical operation, histopathologically confirmed ESCC, the pathological stage was T3N0-3M0, the degree of differentiation was G2, no history of neoadjuvant treatment, no early (30-d) postoperative mortality, complete clinical information, complete follow-up information, formalin-fixed paraffin-embedded tissue from primary resection available in the archives at the Department of Pathology, First Affiliated Hospital of Bengbu Medical College.	('mortality', 'Disease', (282, 291))	('T3N0-3M0', 'Var', (167, 175))	('ESCC', 'Disease', (134, 138))	('formalin', 'Chemical', 'MESH:D005557', (356, 364))	('mortality', 'Disease', 'MESH:D003643', (282, 291))	('rat', 'Species', '10116', (96, 99))	('rat', 'Species', '10116', (275, 278))	('paraffin', 'Chemical', 'MESH:D010232', (371, 379))
684086	32884296	There was no statistically significant difference between high and low FAP-alpha expression in stromal concerning age, gender, tumor location (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('FAP-alpha', 'Gene', '2191', (71, 80))	('FAP-alpha', 'Gene', (71, 80))	('high', 'Var', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('low', 'NegReg', (67, 70))
684089	32884296	Multivariate cox regression analyses showed that lymph node metastases and high expression of FAP-alpha remained independent prognostic factors for survival (Table 3).	('FAP-alpha', 'Gene', '2191', (94, 103))	('high', 'Var', (75, 79))	('FAP-alpha', 'Gene', (94, 103))	('metastases', 'Disease', (60, 70))	('metastases', 'Disease', 'MESH:D009362', (60, 70))
684091	32884296	Kaplan-Meier analysis with associated Log rank test showed that the overall survival and disease-free survival of patients with FAP-alpha high expression group were significantly lower than that of FAP-alpha low expression group (mean survival time, 26.5 vs. 52.9 months, P =0.002) (Figure 2A and B).	('disease-free survival', 'CPA', (89, 110))	('lower', 'NegReg', (179, 184))	('FAP-alpha', 'Gene', '2191', (128, 137))	('FAP-alpha', 'Gene', '2191', (198, 207))	('FAP-alpha', 'Gene', (128, 137))	('FAP-alpha', 'Gene', (198, 207))	('overall survival', 'CPA', (68, 84))	('high expression', 'Var', (138, 153))	('patients', 'Species', '9606', (114, 122))
684114	32884296	There are indications that high FAP-alpha expression is associated with higher tumor grade and poorer overall survival rate in most tumors.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (79, 84))	('expression', 'MPA', (42, 52))	('FAP-alpha', 'Gene', '2191', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('rat', 'Species', '10116', (119, 122))	('high', 'Var', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('higher', 'PosReg', (72, 78))	('tumors', 'Disease', (132, 138))	('FAP-alpha', 'Gene', (32, 41))	('overall survival', 'CPA', (102, 118))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('poorer', 'NegReg', (95, 101))
684115	32884296	A meta-analysis including 9 kinds of solid tumors reported that high FAP-alpha expression is related to poor overall survival.	('FAP-alpha', 'Gene', (69, 78))	('high', 'Var', (64, 68))	('expression', 'MPA', (79, 89))	('FAP-alpha', 'Gene', '2191', (69, 78))	('solid tumors', 'Disease', 'MESH:D009369', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('poor', 'NegReg', (104, 108))	('overall', 'MPA', (109, 116))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('solid tumors', 'Disease', (37, 49))
684116	32884296	In oral squamous cell carcinoma, high FAP-alpha expression correlated to lymph node metastasis and poor overall survival.	('FAP-alpha', 'Gene', (38, 47))	('high', 'Var', (33, 37))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('expression', 'MPA', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('FAP-alpha', 'Gene', '2191', (38, 47))	('lymph node metastasis', 'CPA', (73, 94))
684117	32884296	In gastric cancer, high stromal FAP-alpha expression was reported to correlate with adverse clinic-pathological characteristics including higher grade, lymph node, and peritoneal invasion, advanced TNM stage, and worse overall survival.	('peritoneal invasion', 'CPA', (168, 187))	('overall survival', 'CPA', (219, 235))	('high', 'Var', (19, 23))	('higher grade', 'CPA', (138, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TNM', 'Gene', '10178', (198, 201))	('TNM', 'Gene', (198, 201))	('FAP-alpha', 'Gene', '2191', (32, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('gastric cancer', 'Disease', (3, 17))	('FAP-alpha', 'Gene', (32, 41))	('lymph node', 'CPA', (152, 162))
684119	32884296	In ovarian cancer, high FAP-alpha was significantly associated with shorter disease-free survival.	('FAP-alpha', 'Gene', (24, 33))	('high', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Disease', (3, 17))	('FAP-alpha', 'Gene', '2191', (24, 33))	('disease-free survival', 'CPA', (76, 97))	('shorter', 'NegReg', (68, 75))
684139	32884296	The combination of PT-100 and oxaliplatin can reduce tumor growth and improve survival enhance by enhancing the effect of chemotherapy and reducing CAF markers.	('enhancing', 'PosReg', (98, 107))	('reduce', 'NegReg', (46, 52))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (30, 41))	('PT-100', 'Chemical', 'MESH:C514044', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('effect', 'MPA', (112, 118))	('CAF markers', 'MPA', (148, 159))	('PT-100', 'Var', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('improve', 'PosReg', (70, 77))	('tumor', 'Disease', (53, 58))	('reducing', 'NegReg', (139, 147))	('survival enhance', 'CPA', (78, 94))
684186	29221517	Administration of the 13C-labeled urea pill, collection of the breath sample, and measurement of the 13C-labeled CO2 in the collected breath sample were performed by X.D.W., D.G.W., Y.Y., Y.T.C., and G.Y.W.	('Y.T.C.', 'Var', (188, 194))	('CO2', 'Chemical', 'MESH:D002245', (113, 116))	('13C', 'Chemical', 'MESH:C000615229', (22, 25))	('collected breath', 'Phenotype', 'HP:0002098', (124, 140))	('13C', 'Chemical', 'MESH:C000615229', (101, 104))	('D.G.W.', 'Var', (174, 180))	('urea', 'Chemical', 'MESH:D014508', (34, 38))	('X.D.W.', 'Var', (166, 172))	('men', 'Species', '9606', (89, 92))	('Y.Y.', 'Var', (182, 186))
684305	31201145	LINC00184 silencing inhibits glycolysis and restores mitochondrial oxidative phosphorylation in esophageal cancer through demethylation of PTEN Total lesion glycolysis has been reported to be a satisfactory predictor of survival in patients with locally advanced esophageal cancer (EC).	('Total lesion glycolysis', 'Disease', 'MESH:C564972', (144, 167))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('glycolysis', 'MPA', (29, 39))	('restores', 'PosReg', (44, 52))	('inhibits', 'NegReg', (20, 28))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('LINC00184', 'Gene', '100302691', (0, 9))	('PTEN', 'Gene', (139, 143))	('demethylation', 'MPA', (122, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('mitochondrial oxidative phosphorylation', 'MPA', (53, 92))	('esophageal cancer', 'Disease', (263, 280))	('LINC00184', 'Gene', (0, 9))	('Total lesion glycolysis', 'Disease', (144, 167))	('silencing', 'Var', (10, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (263, 280))
684309	31201145	Silencing of LINC00184 was observed to inhibit the proliferation, migration, invasion, colony formation, and glycolysis of EC cells and tumour growth, while the mitochondrial OXPHOS was restored.	('colony formation', 'CPA', (87, 103))	('tumour growth', 'Disease', (136, 149))	('migration', 'CPA', (66, 75))	('inhibit', 'NegReg', (39, 46))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumour growth', 'Disease', 'MESH:D006130', (136, 149))	('invasion', 'CPA', (77, 85))	('LINC00184', 'Gene', '100302691', (13, 22))	('proliferation', 'CPA', (51, 64))	('mitochondrial OXPHOS', 'MPA', (161, 181))	('Silencing', 'Var', (0, 9))	('LINC00184', 'Gene', (13, 22))	('glycolysis', 'CPA', (109, 119))
684311	31201145	Inhibition of PTEN promoter methylation suppressed EC glycolysis, whereas, improved mitochondrial OXPHOS.	('improved', 'PosReg', (75, 83))	('PTEN', 'Gene', (14, 18))	('PTEN', 'Gene', '5728', (14, 18))	('suppressed', 'NegReg', (40, 50))	('mitochondrial OXPHOS', 'MPA', (84, 104))	('EC glycolysis', 'MPA', (51, 64))	('methylation', 'Var', (28, 39))
684313	31201145	After blockage of Akt signaling pathway by an Akt inhibitor, LY294002, the regulatory effects of LINC00184 on the glycolysis and mitochondrial OXPHOS of EC cells were reversed.	('glycolysis', 'MPA', (114, 124))	('Akt', 'Gene', '207', (46, 49))	('LINC00184', 'Gene', (97, 106))	('Akt', 'Gene', (18, 21))	('Akt', 'Gene', (46, 49))	('LY294002', 'Chemical', 'MESH:C085911', (61, 69))	('mitochondrial OXPHOS', 'MPA', (129, 149))	('Akt', 'Gene', '207', (18, 21))	('LINC00184', 'Gene', '100302691', (97, 106))	('LY294002', 'Var', (61, 69))
684321	31201145	Taken together, targeting LINC00184 might be a promising therapeutic strategy for EC.	('targeting', 'Var', (16, 25))	('LINC00184', 'Gene', (26, 35))	('LINC00184', 'Gene', '100302691', (26, 35))
684328	31201145	Strikingly, long noncoding RNAs (lncRNAs), a set of transcripts in length longer than 200 nucleotides, are able to control glucose metabolism in cancer cells.	('glucose metabolism in cancer', 'Disease', 'MESH:D044882', (123, 151))	('glucose metabolism in cancer', 'Disease', (123, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('long noncoding', 'Var', (12, 26))
684348	31201145	An Akt inhibitor, LY294002 (L9908; Sigma-Aldrich) and a DNA methyltransferase inhibitor, 5-aza-2'deoxycytidine (5-Aza-dC; A3656; Sigma-Aldrich) were applied to block the Akt signaling pathway and inhibit DNA methylation, respectively, and dimethylsulfoxide (DMSO) worked as the control.	('L9908', 'Var', (28, 33))	('5-aza', 'Chemical', 'MESH:D001374', (89, 94))	('Akt', 'Gene', '207', (170, 173))	('Akt', 'Gene', '207', (3, 6))	('Akt', 'Gene', (170, 173))	('inhibit', 'NegReg', (196, 203))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))	('block', 'NegReg', (160, 165))	('Akt', 'Gene', (3, 6))	('DNA methylation', 'MPA', (204, 219))
684374	31201145	The membranes were blocked with 5% skim milk for 1 h at room temperature and then incubated with diluted primary antibodies of rabbit antibody to PTEN (1:10000, ab32199), DNMT1 (1:1000, ab19905), Akt (1:500, ab8805), p-Akt (1:700, ab38449), COMPLEXII-SDHB (1:1000, ab84622), COHPLEXIII-UQCRC2 (1:2000, ab203832), COMPLEXIV-COXII (1:5000, ab79393), COMPLEXV-ATP5A (1:2000, ab176569), and GAPDH (internal reference, 1:2500, ab9485) at 4  C overnight.	('PTEN', 'Gene', (146, 150))	('UQCRC2', 'Gene', (286, 292))	('1:2000', 'Var', (294, 300))	('PTEN', 'Gene', '5728', (146, 150))	('UQCRC2', 'Gene', '7385', (286, 292))	('ATP5A', 'Gene', (357, 362))	('GAPDH', 'Gene', (387, 392))	('1:2000', 'Var', (364, 370))	('ATP5A', 'Gene', '522', (357, 362))	('DNMT1', 'Gene', (171, 176))	('Akt', 'Gene', '207', (196, 199))	('1:5000', 'Var', (330, 336))	('Akt', 'Gene', '207', (219, 222))	('rabbit', 'Species', '9986', (127, 133))	('GAPDH', 'Gene', '2597', (387, 392))	('DNMT1', 'Gene', '1786', (171, 176))	('Akt', 'Gene', (196, 199))	('Akt', 'Gene', (219, 222))
684406	31201145	When cells grew into 80% - 90%, the cells transfected with oe-NC, sh-NC, oe-LINC00184, or sh-LINC00184 were washed with PBS, resuspended, and counted with the concentration adjusted to 1 x 107 cells/mL.	('sh-NC', 'Var', (66, 71))	('sh-LINC00184', 'Gene', '100302691', (90, 102))	('LINC00184', 'Gene', (93, 102))	('LINC00184', 'Gene', (76, 85))	('PBS', 'Chemical', '-', (120, 123))	('LINC00184', 'Gene', '100302691', (76, 85))	('LINC00184', 'Gene', '100302691', (93, 102))	('sh-LINC00184', 'Gene', (90, 102))
684419	31201145	In order to explore the role of LINC00184 in EC cell proliferation, migration, invasion, and colony formation, KYSE450 cells and Eca-109 cells were transfected with oe-LINC00184 or sh-LINC00184 to either over-express or knock down LINC00184.	('knock down', 'Var', (220, 230))	('KYSE450', 'CellLine', 'CVCL:1353', (111, 118))	('LINC00184', 'Gene', (184, 193))	('LINC00184', 'Gene', '100302691', (32, 41))	('LINC00184', 'Gene', (231, 240))	('sh-LINC00184', 'Gene', (181, 193))	('LINC00184', 'Gene', (32, 41))	('sh-LINC00184', 'Gene', '100302691', (181, 193))	('LINC00184', 'Gene', '100302691', (168, 177))	('LINC00184', 'Gene', '100302691', (184, 193))	('over-express', 'PosReg', (204, 216))	('LINC00184', 'Gene', (168, 177))	('LINC00184', 'Gene', '100302691', (231, 240))
684426	31201145	The results revealed that with time went by, the mice injected with oe-LINC00184-transfected KYSE450 cells or Eca-109 cells had lager tumours with increased tumour weight (p < .05) while the mice injected with sh-LINC00184-transfected KYSE450 cells or Eca-109 cells exhibited smaller tumours with decreased tumour weight (p < .05) (Fig.	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Phenotype', 'HP:0002664', (307, 313))	('decreased tumour weight', 'Disease', 'MESH:D015431', (297, 320))	('tumours', 'Disease', (134, 141))	('sh-LINC00184', 'Gene', '100302691', (210, 222))	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('tumours', 'Disease', 'MESH:D009369', (134, 141))	('increased tumour weight', 'Disease', 'MESH:D015431', (147, 170))	('mice', 'Species', '10090', (49, 53))	('tumours', 'Disease', (284, 291))	('decreased tumour weight', 'Disease', (297, 320))	('mice', 'Species', '10090', (191, 195))	('KYSE450', 'CellLine', 'CVCL:1353', (93, 100))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('LINC00184', 'Gene', '100302691', (71, 80))	('tumours', 'Phenotype', 'HP:0002664', (284, 291))	('increased tumour weight', 'Disease', (147, 170))	('tumours', 'Disease', 'MESH:D009369', (284, 291))	('KYSE450', 'CellLine', 'CVCL:1353', (235, 242))	('LINC00184', 'Gene', '100302691', (213, 222))	('LINC00184', 'Gene', (71, 80))	('KYSE450', 'Var', (93, 100))	('sh-LINC00184', 'Gene', (210, 222))	('LINC00184', 'Gene', (213, 222))	('tumour', 'Phenotype', 'HP:0002664', (284, 290))
684427	31201145	These results suggest that LINC00184 silencing inhibits the EC progression in vitro and suppresses tumour growth in vivo.	('suppresses', 'NegReg', (88, 98))	('LINC00184', 'Gene', (27, 36))	('tumour growth', 'Disease', (99, 112))	('tumour growth', 'Disease', 'MESH:D006130', (99, 112))	('silencing', 'Var', (37, 46))	('LINC00184', 'Gene', '100302691', (27, 36))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('inhibits', 'NegReg', (47, 55))
684434	31201145	We found that over-expression of LINC00184 noticeably increased glucose consumption and lactic acid production in KYSE450 cells and Eca-109 cells, while silencing of LINC00184 exhibited inhibitory effects on those (Fig.	('KYSE450', 'CellLine', 'CVCL:1353', (114, 121))	('glucose consumption', 'MPA', (64, 83))	('lactic acid', 'Chemical', 'MESH:D019344', (88, 99))	('over-expression', 'PosReg', (14, 29))	('LINC00184', 'Gene', (166, 175))	('LINC00184', 'Gene', (33, 42))	('increased glucose', 'Phenotype', 'HP:0003074', (54, 71))	('silencing', 'Var', (153, 162))	('lactic acid production', 'MPA', (88, 110))	('increased', 'PosReg', (54, 63))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('LINC00184', 'Gene', '100302691', (166, 175))	('LINC00184', 'Gene', '100302691', (33, 42))
684435	31201145	These results indicate that silencing of LINC00184 could inhibit the glycolysis in EC cells.	('glycolysis', 'MPA', (69, 79))	('LINC00184', 'Gene', (41, 50))	('inhibit', 'NegReg', (57, 64))	('LINC00184', 'Gene', '100302691', (41, 50))	('silencing', 'Var', (28, 37))
684437	31201145	It was found that silencing of LINC00184 decreased the proportion of glucose for glycolysis in the total glucose consumption (Fig.	('LINC00184', 'Gene', (31, 40))	('glucose', 'Chemical', 'MESH:D005947', (69, 76))	('silencing', 'Var', (18, 27))	('decreased', 'NegReg', (41, 50))	('glucose', 'Chemical', 'MESH:D005947', (105, 112))	('proportion of glucose for glycolysis', 'MPA', (55, 91))	('LINC00184', 'Gene', '100302691', (31, 40))
684438	31201145	These results suggested that the glucose consumption for OXPHOS may increase after silencing LINC00184 and mitochondrial OXPHOS may be partially restored.	('mitochondrial', 'MPA', (107, 120))	('LINC00184', 'Gene', (93, 102))	('glucose', 'Chemical', 'MESH:D005947', (33, 40))	('increase', 'PosReg', (68, 76))	('LINC00184', 'Gene', '100302691', (93, 102))	('glucose consumption for OXPHOS', 'MPA', (33, 63))	('silencing', 'Var', (83, 92))
684441	31201145	In contrast, silencing of LINC00184 increased the expression of those mitochondrial COMPLEX II, III, IV and V subunits (Fig.	('LINC00184', 'Gene', '100302691', (26, 35))	('increased', 'PosReg', (36, 45))	('LINC00184', 'Gene', (26, 35))	('expression', 'MPA', (50, 60))	('silencing', 'Var', (13, 22))
684442	31201145	It was suggested that silencing LINC00184 could restore the expression of the key proteins of mitochondrial complex.	('LINC00184', 'Gene', '100302691', (32, 41))	('LINC00184', 'Gene', (32, 41))	('silencing', 'Var', (22, 31))	('restore', 'PosReg', (48, 55))	('expression of', 'MPA', (60, 73))
684443	31201145	Furthermore, ATP level in KYSE450 cells and Eca-109 cells was reduced dramatically after up-regulation of LINC00184, but increased dramatically by silencing of LINC00184 (Fig.	('ATP', 'Chemical', 'MESH:D000255', (13, 16))	('increased', 'PosReg', (121, 130))	('LINC00184', 'Gene', (160, 169))	('LINC00184', 'Gene', '100302691', (106, 115))	('KYSE450', 'CellLine', 'CVCL:1353', (26, 33))	('LINC00184', 'Gene', (106, 115))	('LINC00184', 'Gene', '100302691', (160, 169))	('up-regulation', 'PosReg', (89, 102))	('reduced', 'NegReg', (62, 69))	('silencing', 'Var', (147, 156))
684444	31201145	Taken together, LINC00184 could mediate the metabolic level of EC cells, and silencing of LINC00184 exerts an inhibitory effect on the abnormal aerobic glycolysis of EC cells and restores mitochondrial OXPHOS function, thus reversing the abnormal glucose metabolism that occurs in the EC cells.	('LINC00184', 'Gene', '100302691', (16, 25))	('abnormal aerobic glycolysis', 'MPA', (135, 162))	('abnormal glucose metabolism', 'Disease', (238, 265))	('LINC00184', 'Gene', (90, 99))	('reversing', 'NegReg', (224, 233))	('silencing', 'Var', (77, 86))	('LINC00184', 'Gene', (16, 25))	('inhibitory', 'NegReg', (110, 120))	('restores', 'PosReg', (179, 187))	('abnormal glucose metabolism', 'Disease', 'MESH:D044882', (238, 265))	('abnormal glucose', 'Phenotype', 'HP:0001952', (238, 254))	('abnormal aerobic glycolysis', 'Phenotype', 'HP:0004366', (135, 162))	('mitochondrial OXPHOS function', 'MPA', (188, 217))	('LINC00184', 'Gene', '100302691', (90, 99))
684450	31201145	It was displayed that the expression of PTEN in EC cells was reduced dramatically after up-regulation of LINC00184 but remarkably elevated by silencing of LINC00184 (Fig.	('expression', 'MPA', (26, 36))	('silencing', 'Var', (142, 151))	('LINC00184', 'Gene', (155, 164))	('LINC00184', 'Gene', '100302691', (105, 114))	('PTEN', 'Gene', (40, 44))	('PTEN', 'Gene', '5728', (40, 44))	('up-regulation', 'PosReg', (88, 101))	('elevated', 'PosReg', (130, 138))	('LINC00184', 'Gene', '100302691', (155, 164))	('LINC00184', 'Gene', (105, 114))	('reduced', 'NegReg', (61, 68))
684461	31201145	Next, in order to study the enrichment of DNMT1 in the promoter region of PTEN, the CHIP assay was conducted after over-expression and silencing of LINC00184 in EC cells.	('LINC00184', 'Gene', (148, 157))	('silencing', 'Var', (135, 144))	('PTEN', 'Gene', (74, 78))	('PTEN', 'Gene', '5728', (74, 78))	('DNMT1', 'Gene', (42, 47))	('over-expression', 'PosReg', (115, 130))	('LINC00184', 'Gene', '100302691', (148, 157))	('DNMT1', 'Gene', '1786', (42, 47))
684467	31201145	The data revealed that the methylation level of PTEN in EC cells decreased and the expression of PTEN increased noticeably after treatment with 5-aza-dc.	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('5-aza-dc', 'Var', (144, 152))	('PTEN', 'Gene', (97, 101))	('decreased', 'NegReg', (65, 74))	('PTEN', 'Gene', '5728', (97, 101))	('methylation level', 'MPA', (27, 44))	('5-aza-dc', 'Chemical', 'MESH:D000077209', (144, 152))	('expression', 'MPA', (83, 93))	('increased', 'PosReg', (102, 111))
684470	31201145	When treated with 5-aza-dc, the proliferation and migration of EC cells slowed down dramatically, abnormal aerobic glycolysis was inhibited, and mitochondrial OXPHOS capacity was recovered.	('abnormal aerobic glycolysis', 'Phenotype', 'HP:0004366', (98, 125))	('inhibited', 'NegReg', (130, 139))	('5-aza-dc', 'Chemical', 'MESH:D000077209', (18, 26))	('5-aza-dc', 'Var', (18, 26))	('slowed down', 'NegReg', (72, 83))	('mitochondrial OXPHOS capacity', 'MPA', (145, 174))	('proliferation', 'CPA', (32, 45))	('recovered', 'PosReg', (179, 188))	('aerobic glycolysis', 'MPA', (107, 125))
684473	31201145	All these results indicate that over-expression of LINC00184 induced PTEN promoter methylation, while inhibition of PTEN methylation suppresses proliferation, migration and abnormal aerobic glycolysis of EC cells and promotes mitochondrial OXPHOS recovery.	('mitochondrial OXPHOS recovery', 'MPA', (226, 255))	('LINC00184', 'Gene', (51, 60))	('PTEN', 'Gene', '5728', (69, 73))	('methylation', 'MPA', (83, 94))	('abnormal aerobic glycolysis', 'MPA', (173, 200))	('inhibition', 'Var', (102, 112))	('migration', 'CPA', (159, 168))	('suppresses', 'NegReg', (133, 143))	('promotes', 'PosReg', (217, 225))	('over-expression', 'PosReg', (32, 47))	('abnormal aerobic glycolysis', 'Phenotype', 'HP:0004366', (173, 200))	('PTEN', 'Gene', (116, 120))	('LINC00184', 'Gene', '100302691', (51, 60))	('PTEN', 'Gene', '5728', (116, 120))	('proliferation', 'CPA', (144, 157))	('PTEN', 'Gene', (69, 73))
684476	31201145	Silencing of LINC00184 reduced the extent of Akt phosphorylation in EC cells.	('Akt', 'Gene', (45, 48))	('LINC00184', 'Gene', '100302691', (13, 22))	('Akt', 'Gene', '207', (45, 48))	('reduced', 'NegReg', (23, 30))	('Silencing', 'Var', (0, 9))	('LINC00184', 'Gene', (13, 22))
684479	31201145	The results showed that additional treatment of LY294002 inhibited noticeably the proliferation and migration of EC cells over-expressing LINC00184 (Fig.	('LINC00184', 'Gene', (138, 147))	('migration', 'CPA', (100, 109))	('LY294002', 'Var', (48, 56))	('inhibited', 'NegReg', (57, 66))	('LINC00184', 'Gene', '100302691', (138, 147))	('over-expressing', 'PosReg', (122, 137))	('proliferation', 'CPA', (82, 95))	('LY294002', 'Chemical', 'MESH:C085911', (48, 56))
684482	31201145	In this study, the loss of LINC00184 was found to increase COMPLEX II-SDHB, COHPLEX III-UQCRC2, COMPLEX IV-COXII, and COMPLEX V-ATP5A as well as ATP, suggesting LINC00184 regulated the glycometabolism in EC.	('COMPLEX II-SDHB', 'MPA', (59, 74))	('LINC00184', 'Gene', (27, 36))	('UQCRC2', 'Gene', (88, 94))	('LINC00184', 'Gene', '100302691', (161, 170))	('regulated', 'Reg', (171, 180))	('increase', 'PosReg', (50, 58))	('ATP', 'Chemical', 'MESH:D000255', (128, 131))	('ATP', 'Chemical', 'MESH:D000255', (145, 148))	('loss', 'Var', (19, 23))	('UQCRC2', 'Gene', '7385', (88, 94))	('LINC00184', 'Gene', '100302691', (27, 36))	('ATP5A', 'Gene', (128, 133))	('LINC00184', 'Gene', (161, 170))	('ATP5A', 'Gene', '522', (128, 133))
684487	31201145	Similarly, the present study provides evidence that LINC00184 silencing contributed to improve OXPHOS and repressed aerobic glycolysis in EC cells.	('silencing', 'Var', (62, 71))	('LINC00184', 'Gene', (52, 61))	('LINC00184', 'Gene', '100302691', (52, 61))	('improve', 'PosReg', (87, 94))	('OXPHOS', 'MPA', (95, 101))	('repressed aerobic glycolysis', 'MPA', (106, 134))
684491	31201145	Consistently, epigenetic silencing of PTEN gene by promoter hypermethylation is frequently demonstrated as a significant mechanism of PTEN deletion in ESCC.	('PTEN', 'Gene', '5728', (38, 42))	('deletion', 'Var', (139, 147))	('epigenetic silencing', 'Var', (14, 34))	('ESCC', 'Disease', (151, 155))	('PTEN', 'Gene', '5728', (134, 138))	('PTEN', 'Gene', (134, 138))	('PTEN', 'Gene', (38, 42))
684498	31201145	PTEN deletion status has been found to be closely correlated with activation of Akt phosphorylation in prostate cancer.	('Akt', 'Gene', '207', (80, 83))	('deletion', 'Var', (5, 13))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Akt', 'Gene', (80, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('prostate cancer', 'Disease', (103, 118))	('activation', 'PosReg', (66, 76))
684501	31201145	Since insulin-stimulated metabolic responses are principally accomplished through PI3K, PTEN exerts a critical function over regulating glucose uptake.	('PI3K', 'Var', (82, 86))	('glucose uptake', 'MPA', (136, 150))	('glucose', 'Chemical', 'MESH:D005947', (136, 143))	('PTEN', 'Gene', (88, 92))	('PTEN', 'Gene', '5728', (88, 92))	('accomplished', 'Reg', (61, 73))
684506	31201145	Consistently, our study suggested that inhibition of PTEN methylation or suppression of Akt phosphorylation rescued the abnormal glucose metabolism regulated by LINC00184.	('inhibition', 'Var', (39, 49))	('Akt', 'Gene', '207', (88, 91))	('abnormal glucose', 'Phenotype', 'HP:0001952', (120, 136))	('suppression', 'NegReg', (73, 84))	('LINC00184', 'Gene', '100302691', (161, 170))	('abnormal glucose metabolism', 'Disease', (120, 147))	('Akt', 'Gene', (88, 91))	('PTEN', 'Gene', (53, 57))	('rescued', 'PosReg', (108, 115))	('PTEN', 'Gene', '5728', (53, 57))	('LINC00184', 'Gene', (161, 170))	('abnormal glucose metabolism', 'Disease', 'MESH:D044882', (120, 147))
684509	31201145	LINC00184 knockdown reversed abnormal glycometabolism in EC, thus suggesting a promise target for therapies protecting against EC.	('LINC00184', 'Gene', (0, 9))	('glycometabolism', 'MPA', (38, 53))	('knockdown', 'Var', (10, 19))	('LINC00184', 'Gene', '100302691', (0, 9))
684558	30762804	The OS of patients was significantly longer in the low NLR group compared with that in the high NLR group (P = .025, Fig.	('longer', 'PosReg', (37, 43))	('low', 'Var', (51, 54))	('OS', 'Chemical', '-', (4, 6))	('patients', 'Species', '9606', (10, 18))
684559	30762804	And there was a significantly better OS in patients with NLR/PA <= 0.01 than patients with NLR/PA > 0.1 (P = .001, Fig.	('better', 'PosReg', (30, 36))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (77, 85))	('OS', 'Chemical', '-', (37, 39))	('NLR/PA <= 0.01', 'Var', (57, 71))
684564	30762804	The AUC area was 0.600, 0.575, 0.614, 0.611, and 0.643 for NLR, Alb, PA, NLR/Alb, and NLR/PA, respectively.	('NLR/Alb', 'Gene', (73, 80))	('Alb', 'Gene', (64, 67))	('NLR/Alb', 'Gene', '213', (73, 80))	('0.643', 'Var', (49, 54))	('Alb', 'Gene', '213', (77, 80))	('Alb', 'Gene', '213', (64, 67))	('Alb', 'Gene', (77, 80))
684565	30762804	As shown in Table 3 and Figure 3, the index of NLR/ PA had a higher AUC area than that of the index of NLR or NLR/Alb (P = .032).	('NLR/Alb', 'Gene', (110, 117))	('NLR/Alb', 'Gene', '213', (110, 117))	('higher', 'PosReg', (61, 67))	('AUC area', 'MPA', (68, 76))	('NLR/ PA', 'Var', (47, 54))
684568	30762804	As shown in Figure 4A, in stage I-II, the index of NLR/ PA (AUC = 0.685) had a higher AUC area than that of the index of NLR (AUC = 0.515, P = .037) or NLR/Alb (AUC = 0.568, P < .001).	('NLR/ PA', 'Var', (51, 58))	('AUC area', 'MPA', (86, 94))	('NLR/Alb', 'Gene', (152, 159))	('NLR/Alb', 'Gene', '213', (152, 159))	('higher', 'PosReg', (79, 85))
684581	30762804	A meta analysis involving 1633 patients with EC demonstrated that high NLR was significantly associated with poor OS and disease-free survive (DFS).	('OS', 'Chemical', '-', (114, 116))	('patients', 'Species', '9606', (31, 39))	('high', 'Var', (66, 70))	('disease-free survive', 'CPA', (121, 141))	('poor OS', 'Disease', (109, 116))	('NLR', 'Gene', (71, 74))
684615	28937628	Integrative Pathway Analysis of Genes and Metabolites Reveals Metabolism Abnormal Subpathway Regions and Modules in Esophageal Squamous Cell Carcinoma Aberrant metabolism is one of the main driving forces in the initiation and development of ESCC.	('Metabolism Abnormal Subpathway Regions', 'Disease', 'MESH:D008659', (62, 100))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('ESCC', 'Disease', (242, 246))	('Aberrant', 'Var', (151, 159))	('Esophageal Squamous Cell Carcinoma', 'Disease', (116, 150))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (116, 150))	('Metabolism Abnormal', 'Phenotype', 'HP:0001939', (62, 81))	('Metabolism Abnormal Subpathway Regions', 'Disease', (62, 100))	('Carcinoma', 'Phenotype', 'HP:0030731', (141, 150))
684637	28937628	Valine, leucine and isoleucine were located at the starting region of three sub-regions of the pathway, and all of them were differential in ESCC.	('leucine', 'Var', (8, 15))	('Valine', 'Chemical', 'MESH:D014633', (0, 6))	('Valine', 'Var', (0, 6))	('isoleucine', 'Var', (20, 30))	('differential', 'Reg', (125, 137))	('leucine', 'Chemical', 'MESH:D007930', (8, 15))	('isoleucine', 'Chemical', 'MESH:D007532', (20, 30))	('ESCC', 'Disease', (141, 145))	('leucine', 'Chemical', 'MESH:D007930', (23, 30))
684643	28937628	Although they were not reported in ESCC, beta-alanine, a center metabolite of the pathway, displayed potential anti-cancer effects in renal and cervical tumor cells.	('beta-alanine', 'Var', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('beta-alanine', 'Chemical', 'MESH:D015091', (41, 53))	('cervical tumor', 'Phenotype', 'HP:0030159', (144, 158))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('renal', 'Disease', (134, 139))
684644	28937628	Histidine was previously reported by us to be associated with prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('Histidine', 'Chemical', 'MESH:D006639', (0, 9))	('prostate cancer', 'Disease', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Histidine', 'Var', (0, 9))	('associated', 'Reg', (46, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))
684653	28937628	SHMT1 1420C/T genotype can significantly reduce susceptibility to ESCC.	('1420C/T', 'Var', (6, 13))	('susceptibility', 'MPA', (48, 62))	('reduce', 'NegReg', (41, 47))	('SHMT1', 'Gene', '6470', (0, 5))	('SHMT1', 'Gene', (0, 5))	('ESCC', 'Disease', (66, 70))	('1420C/T', 'Mutation', 'rs1979277', (6, 13))
684681	28937628	The mutation of all these genes was highly associated with cancer initiation and progression, suggesting importance of these genes in ESCC.	('progression', 'CPA', (81, 92))	('ESCC', 'Disease', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutation', 'Var', (4, 12))	('cancer initiation', 'Disease', 'MESH:D009369', (59, 76))	('associated', 'Reg', (43, 53))	('cancer initiation', 'Disease', (59, 76))
684685	28937628	Patients with high GPT expression had a significantly shorter survival time than those with low expression (p = 0.000019) (Figure 6).	('GPT', 'Gene', (19, 22))	('survival time', 'CPA', (62, 75))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (54, 61))	('GPT', 'Gene', '2875', (19, 22))
684718	29538372	Also, DEK overexpression in human keratinocytes, the cell of origin for SCC, was sufficient to cause hyperplasia in 3D organotypic raft cultures that mimic human skin, thus linking high DEK expression in keratinocytes to oncogenic phenotypes.	('cause', 'Reg', (95, 100))	('hyperplasia', 'Disease', (101, 112))	('human', 'Species', '9606', (28, 33))	('expression', 'Species', '29278', (14, 24))	('hyperplasia', 'Disease', 'MESH:D006965', (101, 112))	('SCC', 'Gene', (72, 75))	('expression', 'Species', '29278', (190, 200))	('overexpression', 'PosReg', (10, 24))	('SCC', 'Gene', '6317', (72, 75))	('human', 'Species', '9606', (156, 161))	('DEK', 'Var', (6, 9))
684728	29538372	High DEK expression causes cancer related phenotypes such as increased cellular proliferation, migration, and invasion in vitro.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cellular proliferation', 'CPA', (71, 93))	('expression', 'Species', '29278', (9, 19))	('increased', 'PosReg', (61, 70))	('cancer', 'Disease', (27, 33))	('High DEK expression', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('invasion', 'CPA', (110, 118))	('migration', 'CPA', (95, 104))
684729	29538372	Despite the well documented link between high DEK expression and cancer, the consequences of Dek overexpression in vivo are poorly understood.	('Dek', 'Gene', (93, 96))	('DEK', 'Protein', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('high', 'Var', (41, 45))	('Dek', 'Gene', '110052', (93, 96))	('expression', 'Species', '29278', (101, 111))	('expression', 'Species', '29278', (50, 60))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
684737	29538372	Additionally, high DEK expression is associated with poor prognosis in melanoma, gastric, ovarian, breast, prostate, bladder, lung, pancreatic, skin cancer, and head and neck SCC.	('pancreatic', 'Disease', 'MESH:D010195', (132, 142))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('expression', 'Species', '29278', (23, 33))	('gastric', 'Disease', (81, 88))	('bladder', 'Disease', (117, 124))	('skin cancer', 'Disease', (144, 155))	('ovarian', 'Disease', (90, 97))	('pancreatic', 'Disease', (132, 142))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('DEK', 'Protein', (19, 22))	('high', 'Var', (14, 18))	('ovarian', 'Disease', 'MESH:D010051', (90, 97))	('breast', 'Disease', (99, 105))	('skin cancer', 'Phenotype', 'HP:0008069', (144, 155))	('lung', 'Disease', (126, 130))	('SCC', 'Gene', '6317', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('prostate', 'Disease', (107, 115))	('SCC', 'Gene', (175, 178))	('skin cancer', 'Disease', 'MESH:D012878', (144, 155))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))
684746	29538372	DEK overexpression occurs through various mechanisms including gene amplification, increased transcription, and mutations in microRNAs and ubiquitin ligases responsible for DEK mRNA and protein degradation, respectively.	('increased', 'PosReg', (83, 92))	('microRNAs', 'Gene', (125, 134))	('transcription', 'MPA', (93, 106))	('mutations', 'Var', (112, 121))	('expression', 'Species', '29278', (8, 18))	('protein degradation', 'MPA', (186, 205))	('ubiquitin ligases', 'Enzyme', (139, 156))
684757	29538372	4NQO is a chemical carcinogen that mimics the effects of tobacco smoke by forming DNA adducts and mutations similar to those seen in human HNSCC and ESCC.	('SCC', 'Gene', '6317', (150, 153))	('tobacco', 'Species', '4097', (57, 64))	('SCC', 'Gene', (141, 144))	('4NQO', 'Chemical', 'MESH:D015112', (0, 4))	('mutations', 'Var', (98, 107))	('DNA adducts', 'MPA', (82, 93))	('SCC', 'Gene', '6317', (141, 144))	('SCC', 'Gene', (150, 153))	('al', 'Chemical', 'MESH:D000535', (16, 18))	('human', 'Species', '9606', (133, 138))
684758	29538372	When administered in drinking water, 4NQO stimulates susceptibility to squamous cell carcinomas in the tongue, oral cavity, and esophagus.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (71, 95))	('4NQO', 'Chemical', 'MESH:D015112', (37, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('stimulates', 'PosReg', (42, 52))	('drinking water', 'Chemical', 'MESH:D060766', (21, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('esophagus', 'Disease', (128, 137))	('4NQO', 'Var', (37, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('susceptibility', 'MPA', (53, 67))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (71, 95))	('al', 'Chemical', 'MESH:D000535', (113, 115))	('squamous cell carcinomas', 'Disease', (71, 95))
684809	29538372	Exposure of mice to drinking water containing the soluble quinoline derivative 4NQO promotes the development of oral and/or esophageal cancer.	('4NQO', 'Var', (79, 83))	('esophageal cancer', 'Disease', (124, 141))	('quinoline', 'Chemical', 'MESH:C037219', (58, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('drinking water', 'Chemical', 'MESH:D060766', (20, 34))	('al', 'Chemical', 'MESH:D000535', (132, 134))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('4NQO', 'Chemical', 'MESH:D015112', (79, 83))	('al', 'Chemical', 'MESH:D000535', (114, 116))	('mice', 'Species', '10090', (12, 16))	('promotes', 'PosReg', (84, 92))
684846	29538372	Here we demonstrate that Dek overexpression targeted to the epithelium stimulates proliferation specifically in the presence of 4NQO in the tongue and also in the esophagus.	('overexpression', 'PosReg', (29, 43))	('stimulates', 'PosReg', (71, 81))	('4NQO', 'Var', (128, 132))	('al', 'Chemical', 'MESH:D000535', (104, 106))	('Dek', 'Gene', '110052', (25, 28))	('al', 'Chemical', 'MESH:D000535', (151, 153))	('expression', 'Species', '29278', (33, 43))	('4NQO', 'Chemical', 'MESH:D015112', (128, 132))	('proliferation', 'CPA', (82, 95))	('Dek', 'Gene', (25, 28))
684853	29538372	Interestingly, C57BL/6 and FVB/N harbor variations in immune phenotype, raising the intriguing possibility that immune surveillance and/or evasion account at least in part for the differing tumor phenotypes in mice with ubiquitous versus epithelial cell targeted Dek overexpression.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mice', 'Species', '10090', (210, 214))	('variations', 'Reg', (40, 50))	('expression', 'Species', '29278', (271, 281))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('Dek', 'Gene', (263, 266))	('tumor', 'Disease', (190, 195))	('al', 'Chemical', 'MESH:D000535', (246, 248))	('C57BL/6', 'Var', (15, 22))	('Dek', 'Gene', '110052', (263, 266))
684858	29538372	The complexity of DEK functions in vivo is exemplified in studies of non-vertebrate organisms For instance, in Arabidopsis, DEK3 overexpression decreases germination efficiency under high salinity conditions, and conversely, plants deficient in DEK3 germinated significantly better compared to wild-type plants suggesting DEK3 levels are crucial for stress tolerance.	('decreases', 'NegReg', (144, 153))	('germination efficiency', 'CPA', (154, 176))	('DEK3', 'Gene', (124, 128))	('overexpression', 'PosReg', (129, 143))	('deficient', 'Var', (232, 241))	('expression', 'Species', '29278', (133, 143))	('al', 'Chemical', 'MESH:D000535', (189, 191))	('better', 'PosReg', (275, 281))	('DEK3', 'Gene', '828770', (124, 128))	('DEK3', 'Gene', (245, 249))	('Arabidopsis', 'Species', '3702', (111, 122))	('DEK3', 'Gene', (322, 326))	('DEK3', 'Gene', '828770', (245, 249))	('germinated', 'CPA', (250, 260))	('al', 'Chemical', 'MESH:D000535', (343, 345))	('DEK3', 'Gene', '828770', (322, 326))
684974	28029663	Preclinical studies showed that the combination of 5-FU and hyperthermia could promote tumor cell apoptosis and increase the thermotolerance, consequently improves prognosis and reduces side effects of chemotherapy.	('reduces', 'NegReg', (178, 185))	('5-FU', 'Var', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('hyperthermia', 'Disease', 'MESH:D005334', (60, 72))	('side effects', 'CPA', (186, 198))	('tumor', 'Disease', (87, 92))	('5-FU', 'Chemical', 'MESH:D005472', (51, 55))	('increase the thermotolerance', 'Phenotype', 'HP:0002046', (112, 140))	('hyperthermia', 'Phenotype', 'HP:0001945', (60, 72))	('hyperthermia', 'Disease', (60, 72))	('increase', 'PosReg', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('promote', 'PosReg', (79, 86))	('prognosis', 'CPA', (164, 173))	('improves', 'PosReg', (155, 163))	('thermotolerance', 'CPA', (125, 140))
685128	25450480	Furthermore, Cdc2, CDK2 and Cdc25C were inhibited due to phosphorylation on Tyr15, Thr160 and Ser216, respectively, following Jaridonin treatment with a slight decrease in total Cdc2 and CDK2 level (Fig.	('Ser216', 'Var', (94, 100))	('CDK2', 'Gene', '1017', (19, 23))	('Cdc2', 'Gene', (178, 182))	('Thr160', 'Chemical', '-', (83, 89))	('Cdc2', 'Gene', '983', (13, 17))	('CDK2', 'Gene', (19, 23))	('Thr160', 'Var', (83, 89))	('Tyr15', 'Chemical', '-', (76, 81))	('Ser216', 'Chemical', '-', (94, 100))	('Cdc2', 'Gene', '983', (28, 32))	('Cdc25C', 'Gene', '995', (28, 34))	('men', 'Species', '9606', (141, 144))	('Cdc2', 'Gene', (13, 17))	('Jaridonin', 'Chemical', 'MESH:C587044', (126, 135))	('Cdc25C', 'Gene', (28, 34))	('Tyr15', 'Var', (76, 81))	('Cdc2', 'Gene', '983', (178, 182))	('CDK2', 'Gene', '1017', (187, 191))	('decrease', 'NegReg', (160, 168))	('inhibited', 'NegReg', (40, 49))	('Cdc2', 'Gene', (28, 32))	('CDK2', 'Gene', (187, 191))	('phosphorylation', 'MPA', (57, 72))
685137	25450480	We have shown previously that Jaridonin causes DNA damage of EC9706 and EC109 human esophageal cancer cells.	('EC9706', 'CellLine', 'CVCL:E307', (61, 67))	('EC109', 'CellLine', 'CVCL:6898', (72, 77))	('Jaridonin', 'Chemical', 'MESH:C587044', (30, 39))	('DNA damage', 'MPA', (47, 57))	('EC9706', 'Var', (61, 67))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('human', 'Species', '9606', (78, 83))
685146	25450480	Negative regulation of Cdc25C by phosphorylation at Ser216 is an important regulatory mechanism used by cells to block mitotic entry under normal cell cycle progression or after DNA damage.	('Negative regulation', 'NegReg', (0, 19))	('phosphorylation', 'Var', (33, 48))	('Ser216', 'Chemical', '-', (52, 58))	('Cdc25C', 'Gene', (23, 29))	('Cdc25C', 'Gene', '995', (23, 29))	('mitotic entry', 'CPA', (119, 132))	('block', 'NegReg', (113, 118))
685147	25450480	The findings discussed above suggested that Jaridonin-induced ATM checkpoint signaling followed by Chk1/Chk2 activation possibly results in phosphorylation of the Cdc25C phosphatase at Ser216 and associated negative regulation, which in turn produces accumulation of inactive phosphorylated Cdc2 at Tyr15.	('ATM', 'Gene', '472', (62, 65))	('Tyr15', 'Chemical', '-', (299, 304))	('Jaridonin', 'Chemical', 'MESH:C587044', (44, 53))	('Ser216', 'Chemical', '-', (185, 191))	('Cdc2', 'Gene', '983', (291, 295))	('ATM', 'Gene', (62, 65))	('Chk2', 'Gene', (104, 108))	('phosphorylation', 'MPA', (140, 155))	('Cdc2', 'Gene', '983', (163, 167))	('Cdc25C', 'Gene', '995', (163, 169))	('Chk1', 'Gene', (99, 103))	('Chk1', 'Gene', '1111', (99, 103))	('Ser216', 'Var', (185, 191))	('Cdc25C', 'Gene', (163, 169))	('Cdc2', 'Gene', (291, 295))	('accumulation', 'PosReg', (251, 263))	('negative regulation', 'MPA', (207, 226))	('Chk2', 'Gene', '11200', (104, 108))	('Cdc2', 'Gene', (163, 167))	('inactive phosphorylated', 'MPA', (267, 290))
685148	25450480	Consistent with this hypothesis, we observed that Jaridonin induces the phosphorylation of Cdc25C at Ser216 (Fig.	('Ser216', 'Var', (101, 107))	('Cdc25C', 'Gene', (91, 97))	('phosphorylation', 'MPA', (72, 87))	('Cdc25C', 'Gene', '995', (91, 97))	('Jaridonin', 'Chemical', 'MESH:C587044', (50, 59))	('Ser216', 'Chemical', '-', (101, 107))
685150	25450480	5B), clearly suggesting the role of ATM-mediated Chk1/2 kinase pathway for inhibitory phosphorylation of Cdc25C (Ser216).	('Chk1/2', 'Gene', '1111;11200', (49, 55))	('inhibitory phosphorylation', 'MPA', (75, 101))	('ATM', 'Gene', (36, 39))	('Ser216', 'Chemical', '-', (113, 119))	('Cdc25C', 'Gene', (105, 111))	('Ser216', 'Var', (113, 119))	('ATM', 'Gene', '472', (36, 39))	('Cdc25C', 'Gene', '995', (105, 111))	('Chk1/2', 'Gene', (49, 55))
685155	25450480	To further confirm this observation, KU55933, a potent ATM inhibitor, was used again for examining this finding.	('KU55933', 'Chemical', 'MESH:C495818', (37, 44))	('ATM', 'Gene', '472', (55, 58))	('ATM', 'Gene', (55, 58))	('KU55933', 'Var', (37, 44))
685156	25450480	Similar to caffeine, KU55933 (10 microM) pretreatment of cells almost completely reversed Jaridonin induced G2/M phase arrest in EC9706 cells (Fig.	('men', 'Species', '9606', (49, 52))	('EC9706', 'CellLine', 'CVCL:E307', (129, 135))	('caffeine', 'Chemical', 'MESH:D002110', (11, 19))	('Jaridonin', 'Chemical', 'MESH:C587044', (90, 99))	('G2/M phase arrest', 'CPA', (108, 125))	('KU55933', 'Var', (21, 28))	('KU55933', 'Chemical', 'MESH:C495818', (21, 28))
685158	25450480	It has been shown previously that exposure of 293T cells to H2O2 causes activation of ATM.	('activation', 'PosReg', (72, 82))	('ATM', 'Gene', '472', (86, 89))	('H2O2', 'Chemical', 'MESH:D006861', (60, 64))	('293T', 'CellLine', 'CVCL:0063', (46, 50))	('H2O2', 'Var', (60, 64))	('ATM', 'Gene', (86, 89))
685203	25450480	At the onset of mitosis, Cdc2 cyclin-dependent kinase and Cyclin B complexes are activated by Cdc25C-mediated dephosphorylation of the inhibitory sites on Cdc2.	('mitosis', 'Disease', (16, 23))	('dephosphorylation', 'Var', (110, 127))	('Cdc2', 'Gene', (25, 29))	('mitosis', 'Disease', 'None', (16, 23))	('Cdc2', 'Gene', '983', (94, 98))	('Cdc25C', 'Gene', '995', (94, 100))	('activated', 'PosReg', (81, 90))	('Cyclin B complexes', 'Enzyme', (58, 76))	('Cdc2', 'Gene', (155, 159))	('Cdc2', 'Gene', (94, 98))	('Cdc2', 'Gene', '983', (25, 29))	('Cdc2', 'Gene', '983', (155, 159))	('Cdc25C', 'Gene', (94, 100))
685206	25450480	We also showed that ATM activation by Jaridonin induces phosphorylation of Chk1 (Ser345) and Chk2 (Ser516) followed by that of Cdc25C (Ser216) and Cdc2 (Tyr15).	('Chk2', 'Gene', (93, 97))	('Ser516', 'Chemical', '-', (99, 105))	('Ser216', 'Chemical', '-', (135, 141))	('Cdc25C', 'Gene', '995', (127, 133))	('Cdc2', 'Gene', (127, 131))	('Ser516', 'Var', (99, 105))	('Cdc2', 'Gene', '983', (147, 151))	('phosphorylation', 'MPA', (56, 71))	('Cdc25C', 'Gene', (127, 133))	('Ser345', 'Chemical', '-', (81, 87))	('Chk2', 'Gene', '11200', (93, 97))	('ATM', 'Gene', '472', (20, 23))	('Jaridonin', 'Chemical', 'MESH:C587044', (38, 47))	('Chk1', 'Gene', (75, 79))	('Chk1', 'Gene', '1111', (75, 79))	('Tyr15', 'Chemical', '-', (153, 158))	('Ser216', 'Var', (135, 141))	('Cdc2', 'Gene', (147, 151))	('ATM', 'Gene', (20, 23))	('Cdc2', 'Gene', '983', (127, 131))	('Ser345', 'Var', (81, 87))
685233	23925665	Conversely, ANGPTL4 is also implicated as a pro-angiogenic factor, and tumor-derived ANGPTL4 has been shown to promote metastasis by disrupting vascular integrity.	('disrupting', 'NegReg', (133, 143))	('ANGPTL4', 'Var', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('metastasis', 'CPA', (119, 129))	('vascular integrity', 'CPA', (144, 162))	('promote', 'PosReg', (111, 118))
685252	23925665	1f, the 2-year progression-free survival (PFS) in ESCC patients with high/moderate expression of ANGPTL4 protein was inferior to that with low/negative expression [mean 16.7 months (95 % CI 14.510-18.839) vs. 20.1 months (95 % CI 18.340-21.946), P = 0.028].	('protein', 'Protein', (105, 112))	('high/moderate expression', 'Var', (69, 93))	('patients', 'Species', '9606', (55, 63))	('ANGPTL4', 'Gene', (97, 104))	('inferior', 'NegReg', (117, 125))	('ESCC', 'Disease', (50, 54))
685253	23925665	Results showed that high/moderate expression of ANGPTL4 protein, apart from lymph metastasis, was independent factor for predicting an adverse 2-year PFS for ESCC patients (Table 2).	('patients', 'Species', '9606', (163, 171))	('protein', 'Protein', (56, 63))	('ESCC', 'Disease', (158, 162))	('ANGPTL4', 'Gene', (48, 55))	('high/moderate', 'Var', (20, 33))
685263	23925665	found that ANGPTL4 was a genetically and epigenetically inactivated secreted tumor suppressor and inhibited tumor angiogenesis in gastric cancer.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('inhibited', 'NegReg', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ANGPTL4', 'Gene', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('gastric cancer', 'Disease', (130, 144))	('tumor', 'Disease', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('epigenetically', 'Var', (41, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))
685419	33841566	Comprehensive molecular analyses have recently elucidated various genetic and epigenetic alterations in several types of cancer, and numerous studies in which circulating cell-free nucleic acids have been analyzed have reported the potential utility of blood molecular biomarkers.	('epigenetic', 'Var', (78, 88))	('cancer', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))
685479	33841566	3; Table SI), who was not determined as a correct cancerous characteristic, the patient had no specific characteristics observed besides pathological findings of T3N2M0 and non-elevation of both CEA and CA19-9.	('CEA', 'Gene', '1084', (195, 198))	('cancerous', 'Disease', (50, 59))	('T3N2M0', 'Var', (162, 168))	('cancerous', 'Disease', 'MESH:D009369', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('CEA', 'Gene', (195, 198))	('CA19-9', 'Chemical', 'MESH:C086528', (203, 209))	('patient', 'Species', '9606', (80, 87))
685512	32424351	By middle age, normal human tissues including the esophageal epithelium (EE) become a patchwork of mutant clones.	('age', 'Gene', (10, 13))	('age', 'Gene', '5973', (10, 13))	('age', 'Gene', (55, 58))	('mutant', 'Var', (99, 105))	('human', 'Species', '9606', (22, 27))	('age', 'Gene', '5973', (55, 58))
685515	32424351	Deep sequencing identified numerous mutant clones with multiple genes under positive selection including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium.	('age', 'Gene', '5973', (169, 172))	('Notch2', 'Gene', (113, 119))	('human', 'Species', '9606', (158, 163))	('Trp53', 'Gene', (124, 129))	('mutant', 'Var', (36, 42))	('Notch1', 'Gene', (105, 111))	('age', 'Gene', (169, 172))
685517	32424351	Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells.	('age', 'Gene', '5973', (84, 87))	('age', 'Gene', (84, 87))	('mutations', 'Var', (121, 130))
685518	32424351	When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal appearing epithelium.	('mutant', 'Var', (54, 60))	('competitive fitness', 'Disease', (25, 44))	('homeostasis', 'MPA', (87, 98))	('competitive fitness', 'Disease', 'MESH:D012640', (25, 44))
685519	32424351	Normal adult human tissues are a patchwork of clones carrying somatic mutations that progressively accumulate with age and are linked to neoplasia and other diseases .	('mutations', 'Var', (70, 79))	('human', 'Species', '9606', (13, 18))	('age', 'Gene', '5973', (115, 118))	('neoplasia', 'Disease', (137, 146))	('neoplasia', 'Phenotype', 'HP:0002664', (137, 146))	('neoplasia', 'Disease', 'MESH:D009369', (137, 146))	('linked to', 'Reg', (127, 136))	('accumulate', 'PosReg', (99, 109))	('age', 'Gene', (115, 118))
685520	32424351	This process is exemplified by human esophageal epithelium (EE), in which mutant clones colonize the majority of normal epithelium by middle age .	('age', 'Gene', '5973', (141, 144))	('human', 'Species', '9606', (31, 36))	('age', 'Gene', (42, 45))	('age', 'Gene', (141, 144))	('mutant', 'Var', (74, 80))	('age', 'Gene', '5973', (42, 45))
685521	32424351	This argues that selected mutant genes confer a competitive advantage over wild-type cells in normal esophageal epithelium .	('mutant genes', 'Var', (26, 38))	('age', 'Gene', (106, 109))	('age', 'Gene', (66, 69))	('age', 'Gene', '5973', (106, 109))	('age', 'Gene', '5973', (66, 69))
685525	32424351	Importantly, mouse esophageal epithelium progenitors lie in a continuous sheet with no barriers to limit the lateral expansion of mutant clones, which may eventually collide and compete with each other as well as with wild-type cells .	('mouse', 'Species', '10090', (13, 18))	('age', 'Gene', (24, 27))	('mutant', 'Var', (130, 136))	('lateral expansion', 'CPA', (109, 126))	('age', 'Gene', '5973', (24, 27))
685526	32424351	We used oral administration of diethylnitrosamine (DEN), a well characterized mutagen found in tobacco smoke, to generate a patchwork of mutant clones in the mouse esophageal epithelium resembling that of older humans .	('age', 'Gene', '5973', (169, 172))	('mouse', 'Species', '10090', (158, 163))	('age', 'Gene', (81, 84))	('tobacco', 'Species', '4097', (95, 102))	('age', 'Gene', '5973', (81, 84))	('humans', 'Species', '9606', (211, 217))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (31, 49))	('DEN', 'Chemical', 'MESH:D004052', (51, 54))	('age', 'Gene', (169, 172))	('mutant', 'Var', (137, 143))
685528	32424351	Once an expanding mutant clone collides with cells of similar 'fitness', its proliferative advantage decreases, reverting towards the balanced proliferation and differentiation that characterizes tissue homeostasis.	('fitness', 'Disease', (63, 70))	('age', 'Gene', '5973', (97, 100))	('fitness', 'Disease', 'MESH:D012640', (63, 70))	('decreases', 'NegReg', (101, 110))	('mutant', 'Var', (18, 24))	('age', 'Gene', (97, 100))
685535	32424351	Functionally, most mutations were protein-altering, with missense SNVs being the commonest in both DEN-treated and control samples (Fig.	('DEN', 'Chemical', 'MESH:D004052', (99, 102))	('mutations', 'Var', (19, 28))	('missense SNVs', 'Var', (57, 70))
685536	32424351	The mutational spectrum after DEN treatment was dominated by T>A/A>T, T>C/A>G and C>T/G>A alterations (~82% of total substitutions), with few C>G/G>C SNVs (~0.8%), typical of the DEN signature (Fig.	('T>A/A>', 'Var', (61, 67))	('DEN', 'Chemical', 'MESH:D004052', (179, 182))	('C>G/G>', 'Var', (142, 148))	('C>T/G>A', 'Var', (82, 89))	('T>C/A>G', 'Var', (70, 77))	('DEN', 'Chemical', 'MESH:D004052', (30, 33))
685537	32424351	Thus, DEN administration generates a dense patchwork of mutant clones in mouse esophageal epithelium, which appears to function normally despite a remarkably high mutation burden.	('DEN', 'Chemical', 'MESH:D004052', (6, 9))	('age', 'Gene', '5973', (84, 87))	('mutant', 'Var', (56, 62))	('mouse', 'Species', '10090', (73, 78))	('age', 'Gene', (84, 87))
685541	32424351	Protein-altering mutations that have no effect on cell behavior will have the same chance as being detected as silent mutations in the same gene, yielding dN/dS ratios of 1.	('dS', 'Chemical', 'MESH:D003903', (158, 160))	('mutations', 'Var', (17, 26))	('dN/dS', 'MPA', (155, 160))	('dN', 'Chemical', 'MESH:C022306', (155, 157))
685542	32424351	Values of dN/dS<1 would indicate negative selection, resulting in clonal loss.	('dN', 'Chemical', 'MESH:C022306', (10, 12))	('dS', 'Chemical', 'MESH:D003903', (13, 15))	('clonal', 'CPA', (66, 72))	('dN/dS', 'Var', (10, 15))
685543	32424351	Conversely, values of dN/dS>1 indicate the mutated gene confers a competitive advantage.	('age', 'Gene', '5973', (84, 87))	('dN', 'Chemical', 'MESH:C022306', (22, 24))	('dS', 'Chemical', 'MESH:D003903', (25, 27))	('mutated', 'Var', (43, 50))	('age', 'Gene', (84, 87))
685547	32424351	We estimated clones carrying Notch1 mutations colonized over 80% of the DEN-treated esophageal epithelium, whereas the remaining selected genes each covered between 1.7%-19% (Fig.	('age', 'Gene', (89, 92))	('mutations', 'Var', (36, 45))	('age', 'Gene', '5973', (89, 92))	('Notch1', 'Gene', (29, 35))	('DEN', 'Chemical', 'MESH:D004052', (72, 75))
685549	32424351	A second cluster of mutations was seen in the Notch negative regulatory region, which is cleaved by Adam10 following ligand binding (Figs.	('Adam10', 'Gene', (100, 106))	('Adam10', 'Gene', '11487', (100, 106))	('mutations', 'Var', (20, 29))
685551	32424351	Notch1 mutations were similarly distributed to those in DEN-treated mice (Extended Data 2c).	('Notch1', 'Gene', (0, 6))	('DEN', 'Chemical', 'MESH:D004052', (56, 59))	('mice', 'Species', '10090', (68, 72))	('mutations', 'Var', (7, 16))
685552	32424351	However, mutations in the 8 positively selected genes occupied only 1.6-3.2% of the control esophageal epithelium, suggesting the tissue predominantly behaves neutrally, in agreement with published lineage tracing experiments .	('age', 'Gene', '5973', (97, 100))	('mutations', 'Var', (9, 18))	('age', 'Gene', (202, 205))	('age', 'Gene', (97, 100))	('age', 'Gene', '5973', (202, 205))
685553	32424351	Comparing our results with sequencing of aging normal human esophagus showed that Notch1, Trp53, Notch2, Cul3 and Arid1a were positively selected in both species (Extended Data 1e, 2d; Supplementary Tables 4,5) .	('Notch1', 'Var', (82, 88))	('Notch2', 'Gene', (97, 103))	('human', 'Species', '9606', (54, 59))	('Trp53', 'Gene', (90, 95))
685554	32424351	The similarities of the most strongly selected genes, together with the predominance and clustering of Notch 1 mutations, indicate that genetic selection in normal esophageal epithelium is convergent in mutagen-treated mouse and aging humans, despite the large differences in time scale and mutational spectrum (Extended Data 2e-h).	('mutations', 'Var', (111, 120))	('age', 'Gene', '5973', (169, 172))	('Notch 1', 'Gene', (103, 110))	('mouse', 'Species', '10090', (219, 224))	('age', 'Gene', (206, 209))	('humans', 'Species', '9606', (235, 241))	('Notch 1', 'Gene', '18128', (103, 110))	('age', 'Gene', (169, 172))	('age', 'Gene', '5973', (206, 209))
685561	32424351	Of note, we observed a small proportion of unexpectedly large clones that may result from spontaneous mutations conferring a competitive advantage i.e.	('age', 'Gene', '5973', (143, 146))	('mutations', 'Var', (102, 111))	('age', 'Gene', (143, 146))
685564	32424351	This indicates that the mutational landscape that evolves after DEN treatment develops from strong clonal competition causing the increased growth of "winner" mutant clones, thence eliminating more clones than in control esophageal epithelium (Supplementary Note).	('age', 'Gene', (226, 229))	('mutant', 'Var', (159, 165))	('DEN', 'Chemical', 'MESH:D004052', (64, 67))	('growth', 'MPA', (140, 146))	('age', 'Gene', '5973', (226, 229))	('eliminating', 'NegReg', (181, 192))	('increased', 'PosReg', (130, 139))	('clones', 'MPA', (198, 204))
685566	32424351	As most of the mutagenized esophageal epithelium was eventually colonized by positively selected mutant clones, we expected that the behavior of most progenitor cells would diverge from normal.	('age', 'Gene', '5973', (18, 21))	('age', 'Gene', '5973', (32, 35))	('mutant', 'Var', (97, 103))	('age', 'Gene', (18, 21))	('age', 'Gene', (32, 35))
685575	32424351	Adam10 mutations were significantly more likely to occur in Notch1 wild-type clones (p= 1.5 x 10-5, Fisher's exact test with multiple test correction), consistent with Adam10 mutations being an alternative route to decreasing Notch signaling (Fig.	('Adam10', 'Gene', (168, 174))	('Adam10', 'Gene', (0, 6))	('decreasing', 'NegReg', (215, 225))	('Adam10', 'Gene', '11487', (168, 174))	('mutations', 'Var', (175, 184))	('Adam10', 'Gene', '11487', (0, 6))	('Notch signaling', 'MPA', (226, 241))	('mutations', 'Var', (7, 16))
685576	32424351	This may reflect the late time points analyzed, and we may speculate that at an early stage, strongly selected mutant clones would be expanding in a background of cells of lower competitive fitness and that clone size may indeed reflect the fitness conferred by the mutation(s) it carries .	('fitness', 'Disease', 'MESH:D012640', (241, 248))	('mutant', 'Var', (111, 117))	('fitness', 'Disease', (190, 197))	('fitness', 'Disease', 'MESH:D012640', (190, 197))	('age', 'Gene', '5973', (88, 91))	('competitive fitness', 'Disease', 'MESH:D012640', (178, 197))	('competitive fitness', 'Disease', (178, 197))	('fitness', 'Disease', (241, 248))	('age', 'Gene', (88, 91))
685579	32424351	Collectively, these findings confirm that clones carrying positively selected mutations spread widely in the esophageal epithelium.	('age', 'Gene', '5973', (114, 117))	('age', 'Gene', (114, 117))	('mutations', 'Var', (78, 87))
685581	32424351	To further explore cellular mechanisms of competition we drew on previous insights into normal and mutant progenitor cell behavior in murine esophageal epithelium.	('age', 'Gene', (146, 149))	('mutant', 'Var', (99, 105))	('age', 'Gene', '5973', (146, 149))	('murine', 'Species', '10090', (134, 140))
685582	32424351	A common feature of transgenic Notch and p53 mutant keratinocytes in a background of wild-type cells is an imbalance in division outcome, so the average mutant cell division produces more progenitor than differentiating daughters, thus increasing the mutant population .	('age', 'Gene', '5973', (149, 152))	('mutant', 'Var', (45, 51))	('increasing', 'PosReg', (236, 246))	('imbalance', 'Phenotype', 'HP:0002172', (107, 116))	('mutant', 'Var', (153, 159))	('age', 'Gene', (149, 152))	('more', 'PosReg', (183, 187))	('p53', 'Gene', '22059', (41, 44))	('p53', 'Gene', (41, 44))
685583	32424351	This gives mutant clones an advantage even if the rate of cell division is unchanged (Extended Data 1a).	('age', 'Gene', (34, 37))	('mutant', 'Var', (11, 17))	('age', 'Gene', '5973', (34, 37))
685585	32424351	A second key observation from Notch and p53 mutant progenitors is that, in the long term, their fate reverts towards the balance of normal homeostasis.	('mutant', 'Var', (44, 50))	('Notch', 'Gene', (30, 35))	('p53', 'Gene', '22059', (40, 43))	('p53', 'Gene', (40, 43))
685589	32424351	We compared the results of this simulation with a transgenic mouse experiment in which the highly competitive dominant negative mutant allele of Maml-1 fused to GFP (DN-Maml1), that inhibits Notch signaling, was induced in single progenitors (Figs.	('negative', 'NegReg', (119, 127))	('Notch signaling', 'MPA', (191, 206))	('inhibits', 'NegReg', (182, 190))	('mutant', 'Var', (128, 134))	('Maml1', 'Gene', (169, 174))	('Maml1', 'Gene', '103806', (169, 174))	('mouse', 'Species', '10090', (61, 66))	('Maml-1', 'Gene', '103806', (145, 151))	('Maml-1', 'Gene', (145, 151))
685592	32424351	A simple setting, in which mutant cells were assigned the same fitness value, produced results consistent with the behavior of YFP-labelled clones in DEN-treated esophageal epithelium, both in terms of clone size and the proportion of clones that persisted over time (Figs.	('fitness value', 'Disease', (63, 76))	('mutant', 'Var', (27, 33))	('age', 'Gene', (167, 170))	('fitness value', 'Disease', 'MESH:D012640', (63, 76))	('age', 'Gene', '5973', (167, 170))	('DEN', 'Chemical', 'MESH:D004052', (150, 153))
685594	32424351	Taken together, simulated and experimental data argue that the dynamics of mutant clones in the mutagen treated esophageal epithelium are driven by neighbor-constrained fitness.	('fitness', 'Disease', (169, 176))	('age', 'Gene', '5973', (117, 120))	('age', 'Gene', (99, 102))	('fitness', 'Disease', 'MESH:D012640', (169, 176))	('age', 'Gene', '5973', (99, 102))	('mutant', 'Var', (75, 81))	('age', 'Gene', (117, 120))
685595	32424351	One prediction is that the expansion of mutant clones will vary according to the surrounding mutational patchwork, as their growth is conditional on their fitness relative to adjacent clones (Figs.	('mutant', 'Var', (40, 46))	('fitness', 'Disease', (155, 162))	('fitness', 'Disease', 'MESH:D012640', (155, 162))
685596	32424351	To test this, we performed lineage tracing in conditional DN-Maml1 mice, tracking the expansion of the highly competitive DN-Maml1 mutant clones in animals previously treated with DEN (Fig.	('mutant', 'Var', (131, 137))	('Maml1', 'Gene', (125, 130))	('Maml1', 'Gene', '103806', (125, 130))	('DEN', 'Chemical', 'MESH:D004052', (180, 183))	('age', 'Gene', (31, 34))	('Maml1', 'Gene', (61, 66))	('Maml1', 'Gene', '103806', (61, 66))	('mice', 'Species', '10090', (67, 71))	('age', 'Gene', '5973', (31, 34))
685598	32424351	This was presumably due to DN-Maml1 mutant clones colliding with other clones carrying DEN-induced mutations of similar competitive fitness, such as those carrying Notch1 mutations (Fig.	('Notch1', 'Gene', (164, 170))	('DEN', 'Chemical', 'MESH:D004052', (87, 90))	('Maml1', 'Gene', '103806', (30, 35))	('competitive fitness', 'Disease', (120, 139))	('mutant', 'Var', (36, 42))	('Maml1', 'Gene', (30, 35))	('mutations', 'Var', (171, 180))	('competitive fitness', 'Disease', 'MESH:D012640', (120, 139))
685606	32424351	Taken together, the results above show that the NCF model defines and predicts the global dynamics and behaviour of clones in mutated epithelium, arguing that the competitive 'fitness' of mutant cells depends on the properties of their neighbors.	('fitness', 'Disease', (176, 183))	('fitness', 'Disease', 'MESH:D012640', (176, 183))	('mutant', 'Var', (188, 194))
685612	32424351	This is despite the esophageal epithelium being extensively colonized by cells carrying mutations that promote clone expansion as evidenced by strongly positive dN/dS ratios.	('dN', 'Chemical', 'MESH:C022306', (161, 163))	('age', 'Gene', (25, 28))	('mutations', 'Var', (88, 97))	('dS', 'Chemical', 'MESH:D003903', (164, 166))	('dN/dS ratios', 'MPA', (161, 173))	('age', 'Gene', '5973', (25, 28))	('positive', 'Reg', (152, 160))
685613	32424351	The mutations under selection in mice include the commonest drivers in human esophageal epithelium.	('age', 'Gene', (82, 85))	('age', 'Gene', '5973', (82, 85))	('mice', 'Species', '10090', (33, 37))	('mutations', 'Var', (4, 13))	('human', 'Species', '9606', (71, 76))
685614	32424351	Notably, Notch1 mutants replace the majority of esophageal epithelium in both mice and older humans, and the distribution of missense mutants across the protein is almost identical.	('age', 'Gene', (53, 56))	('humans', 'Species', '9606', (93, 99))	('mutants', 'Var', (16, 23))	('Notch1', 'Gene', (9, 15))	('age', 'Gene', '5973', (53, 56))	('mice', 'Species', '10090', (78, 82))
685617	32424351	These may include mutant cells driving the differentiation of neighbors, a type of 'super competition' observed with Notch inhibiting mutant clones in esophageal epithelium .	('age', 'Gene', '5973', (156, 159))	('age', 'Gene', (156, 159))	('mutant', 'Var', (134, 140))	('inhibiting', 'NegReg', (123, 133))
685621	32424351	If, as seems likely, the risk of transformation varies with the size of the population of cells carrying mutations that promote malignancy, reducing the burden of oncogenic mutants may have long term benefit in cutting cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('reducing', 'NegReg', (140, 148))	('malignancy', 'Disease', 'MESH:D009369', (128, 138))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('mutations', 'Var', (105, 114))	('malignancy', 'Disease', (128, 138))	('cancer', 'Disease', (219, 225))
685622	32424351	Reducing competitive fitness of one such mutant, p53, in a wild-type background results in loss of p53 mutant clones as they are displaced by adjacent wild-type cells with a relative proliferative advantage .	('p53', 'Gene', (49, 52))	('competitive fitness', 'Disease', 'MESH:D012640', (9, 28))	('p53', 'Gene', '22059', (49, 52))	('competitive fitness', 'Disease', (9, 28))	('mutant', 'Var', (103, 109))	('p53', 'Gene', '22059', (99, 102))	('age', 'Gene', (203, 206))	('loss', 'NegReg', (91, 95))	('p53', 'Gene', (99, 102))	('age', 'Gene', '5973', (203, 206))
685670	31304826	The preparation and storing processes produce N-nitroso compounds, which have been proven to be carcinogenic in animals and possibly in humans.	('N-nitroso compounds', 'Chemical', '-', (46, 65))	('carcinogenic', 'Disease', 'MESH:D063646', (96, 108))	('carcinogenic', 'Disease', (96, 108))	('humans', 'Species', '9606', (136, 142))	('N-nitroso compounds', 'Var', (46, 65))
685681	27835987	Dysregulation of mTOR contributes to tumorigenesis, angiogenesis, cellular growth and metastasis but its roles in esophageal squamous cell carcinoma (ESCC) are controversial.	('contributes', 'Reg', (22, 33))	('angiogenesis', 'CPA', (52, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Dysregulation', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (114, 148))	('cellular growth', 'CPA', (66, 81))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('esophageal squamous cell carcinoma', 'Disease', (114, 148))	('metastasis', 'CPA', (86, 96))
685696	27835987	In response to extracellular stimuli, mTOR is activated by the phosphorylation of Ser2448 through the PI3K/Akt/mTOR pathway, and it then activates the eukaryotic translation factor 4E (elF4E) and p70 ribosomal S6 kinase (p70S6 kinase).	('elF4', 'Gene', '2000', (185, 189))	('activated', 'PosReg', (46, 55))	('Akt', 'Gene', (107, 110))	('Ser2448', 'Var', (82, 89))	('eukaryotic', 'Enzyme', (151, 161))	('elF4', 'Gene', (185, 189))	('mTOR', 'Gene', '2475', (111, 115))	('PI3', 'Gene', '5266', (102, 105))	('mTOR', 'Gene', (111, 115))	('p70', 'Enzyme', (196, 199))	('mTOR', 'Gene', '2475', (38, 42))	('activates', 'PosReg', (137, 146))	('Ser2448', 'Chemical', '-', (82, 89))	('PI3', 'Gene', (102, 105))	('Akt', 'Gene', '207', (107, 110))	('mTOR', 'Gene', (38, 42))	('phosphorylation', 'Var', (63, 78))
685697	27835987	mTOR consists of two independent functional complexes, mTORC1 and mTORC2, and the dysregulation of mTOR plays a crucial role in tumorigenesis, angiogenesis, cellular growth and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mTOR', 'Gene', (99, 103))	('mTORC2', 'Gene', '74343', (66, 72))	('mTOR', 'Gene', (66, 70))	('dysregulation', 'Var', (82, 95))	('angiogenesis', 'CPA', (143, 155))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', (0, 4))	('mTOR', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (66, 70))	('cellular growth', 'CPA', (157, 172))	('tumor', 'Disease', (128, 133))	('mTOR', 'Gene', '2475', (0, 4))	('mTORC1', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mTOR', 'Gene', '2475', (55, 59))	('mTORC1', 'Gene', '382056', (55, 61))	('metastasis', 'CPA', (177, 187))	('mTORC2', 'Gene', (66, 72))
685725	27835987	There was also a substantial difference in antibody use (Ser2448 or Rabbit anti-mTOR antibody) and the corresponding dilution (ranged from 1:200 to 1:50) between studies (Tables 1 and 2).	('Ser2448', 'Var', (57, 64))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('Ser2448', 'Chemical', '-', (57, 64))	('Rabbit', 'Species', '9986', (68, 74))
685752	27835987	In 1991, mTOR was firstly discovered as a mammalian homolog of the target of rapamycin (TOR) proteins in yeast mutants.	('yeast', 'Species', '4932', (105, 110))	('rapamycin', 'Chemical', 'MESH:D020123', (77, 86))	('mTOR', 'Gene', (9, 13))	('mTOR', 'Gene', '2475', (9, 13))	('mutants', 'Var', (111, 118))	('mammalian', 'Species', '9606', (42, 51))
685753	27835987	TOR is generally regarded as a target of the macrolide fungicide rapamycin according to the growth resistance of these mutants to rapamycin, and mTOR is the structurally and functionally conserved mammalian counterpart.	('mTOR', 'Gene', (145, 149))	('mTOR', 'Gene', '2475', (145, 149))	('mammalian', 'Species', '9606', (197, 206))	('rapamycin', 'Chemical', 'MESH:D020123', (130, 139))	('macrolide', 'Chemical', 'MESH:D018942', (45, 54))	('mutants', 'Var', (119, 126))	('rapamycin', 'Chemical', 'MESH:D020123', (65, 74))
685766	27835987	In the classical upstream PI3K/Akt/mTOR pathway, stimulation of class I P13K activates its downstream effector AKT, and then leads to the phosphorylation of Ser2448 which plays a key role in activating the mTOR (p-mTOR).	('PI3', 'Gene', '5266', (26, 29))	('Akt', 'Gene', (31, 34))	('P13K', 'Mutation', 'p.P13K', (72, 76))	('Akt', 'Gene', '207', (31, 34))	('AKT', 'Gene', (111, 114))	('p-mTOR', 'Gene', (212, 218))	('p-mTOR', 'Gene', '2475', (212, 218))	('mTOR', 'Gene', (35, 39))	('PI3', 'Gene', (26, 29))	('Ser2448', 'Chemical', '-', (157, 164))	('activates', 'PosReg', (77, 86))	('mTOR', 'Gene', (206, 210))	('AKT', 'Gene', '207', (111, 114))	('mTOR', 'Gene', '2475', (35, 39))	('Ser2448', 'Var', (157, 164))	('mTOR', 'Gene', (214, 218))	('leads to', 'Reg', (125, 133))	('mTOR', 'Gene', '2475', (206, 210))	('P13K', 'Var', (72, 76))	('mTOR', 'Gene', '2475', (214, 218))	('phosphorylation', 'MPA', (138, 153))
685770	27835987	In the downstream mTOR signaling pathways, p-mTOR can improve the translation efficiency of 5'-TOR mRNA and accelerate protein synthesis by phosphorylating its downstream receptors during the translation process, such as elF4E and p70S6 kinase.	('mTOR', 'Gene', (18, 22))	('mTOR', 'Gene', '2475', (18, 22))	('p-mTOR', 'Gene', (43, 49))	('p70S6 kinase', 'Var', (231, 243))	('elF4', 'Gene', '2000', (221, 225))	('elF4', 'Gene', (221, 225))	('p-mTOR', 'Gene', '2475', (43, 49))	('protein synthesis', 'MPA', (119, 136))	('accelerate', 'PosReg', (108, 118))	('phosphorylating', 'MPA', (140, 155))	('mTOR', 'Gene', '2475', (45, 49))	('translation efficiency', 'MPA', (66, 88))	('improve', 'PosReg', (54, 61))	('mTOR', 'Gene', (45, 49))
685773	27835987	Aberrant activation of mTOR pathway induced by the loss of tumor suppressors and oncogene stimulation can significantly promote tumor growth, angiogenesis and metastasis.	('activation', 'PosReg', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('loss', 'Var', (51, 55))	('promote', 'PosReg', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (23, 27))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
685774	27835987	The mutations in mTOR gene confer a probability of constitutive activation of mTOR signaling pathways, even under nutrient starvation conditions.	('mTOR', 'Gene', (78, 82))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (78, 82))	('activation', 'PosReg', (64, 74))	('mutations', 'Var', (4, 13))	('mTOR', 'Gene', '2475', (17, 21))
685787	27835987	Their laboratorial evidence also indicated that inhibition of mTOR could sensitize ESCC cell lines to chemotherapy, suggesting that the mTOR inhibitor could enhance the efficacy of NIT.	('mTOR', 'Gene', '2475', (62, 66))	('efficacy', 'MPA', (169, 177))	('enhance', 'PosReg', (157, 164))	('mTOR', 'Gene', (62, 66))	('NIT', 'MPA', (181, 184))	('inhibition', 'Var', (48, 58))	('NIT', 'Chemical', '-', (181, 184))	('mTOR', 'Gene', (136, 140))	('mTOR', 'Gene', '2475', (136, 140))
685806	27184424	KLF4 transcriptionally activates non-canonical WNT5A to control epithelial stratification Epithelial differentiation and stratification are essential for normal homeostasis, and disruption of these processes leads to both injury and cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('disruption', 'Var', (178, 188))	('KLF4', 'Gene', (0, 4))	('KLF4', 'Gene', '16600', (0, 4))	('WNT5A', 'Gene', (47, 52))	('leads to', 'Reg', (208, 216))	('WNT5A', 'Gene', '22418', (47, 52))	('injury and cancer', 'Disease', 'MESH:D009369', (222, 239))
685813	27184424	As such, perturbation of the pathways of normal esophageal squamous epithelial differentiation contributes to both esophageal injury and cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('contributes', 'Reg', (95, 106))	('esophageal injury and cancer', 'Disease', 'MESH:D004938', (115, 143))	('perturbation', 'Var', (9, 21))	('squamous epithelia', 'Disease', (59, 77))	('squamous epithelia', 'Disease', 'MESH:D002294', (59, 77))	('squamous epithelia', 'Phenotype', 'HP:0002860', (59, 77))
685817	27184424	Indicative of this, KLF4 is highly expressed in differentiating esophageal epithelial cells, and genetic ablation of Klf4 results in defective squamous epithelial differentiation.	('squamous epithelia', 'Disease', (143, 161))	('defective', 'NegReg', (133, 142))	('Klf4', 'Gene', (117, 121))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (64, 84))	('squamous epithelia', 'Phenotype', 'HP:0002860', (143, 161))	('squamous epithelia', 'Disease', 'MESH:D002294', (143, 161))	('esophageal epithelia', 'Disease', (64, 84))	('esophageal epithelia', 'Disease', 'MESH:D004941', (64, 84))	('genetic ablation', 'Var', (97, 113))
685818	27184424	In skin, Klf4 deletion leads to loss of barrier function and defective late-stage differentiation, with early lethality by postnatal day 1 due to these barrier defects, and in the esophagus, Klf4 ablation results in delayed differentiation, abnormal stratification, and the development of precancerous squamous cell dysplasia.	('delayed differentiation', 'CPA', (216, 239))	('abnormal stratification', 'CPA', (241, 264))	('defective', 'NegReg', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('barrier', 'MPA', (40, 47))	('loss', 'NegReg', (32, 36))	('precancerous squamous cell dysplasia', 'Disease', (289, 325))	('ablation', 'Var', (196, 204))	('Klf4', 'Gene', (9, 13))	('precancerous squamous cell dysplasia', 'Disease', 'MESH:D011230', (289, 325))	('deletion', 'Var', (14, 22))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (302, 325))	('late-stage differentiation', 'CPA', (71, 97))
685824	27184424	Previously, we identified the non-canonical Wnt ligand Wnt5a as a gene that is differentially expressed in esophageal squamous epithelial cells of mice with esophageal specific deletion of Klf4, compared to controls, suggesting that Wnt5a might be a target of KLF4 in squamous epithelia.	('Wnt', 'Gene', '7474;22418', (44, 47))	('mice', 'Species', '10090', (147, 151))	('Wnt', 'Gene', (44, 47))	('squamous epithelia', 'Disease', 'MESH:D002294', (118, 136))	('Klf4', 'Gene', (189, 193))	('squamous epithelia', 'Disease', (268, 286))	('deletion', 'Var', (177, 185))	('Wnt', 'Gene', '7474;22418', (233, 236))	('squamous epithelia', 'Disease', (118, 136))	('Wnt', 'Gene', (233, 236))	('Wnt', 'Gene', '7474;22418', (55, 58))	('squamous epithelia', 'Disease', 'MESH:D002294', (268, 286))	('Wnt', 'Gene', (55, 58))	('squamous epithelia', 'Phenotype', 'HP:0002860', (268, 286))	('squamous epithelia', 'Phenotype', 'HP:0002860', (118, 136))
685830	27184424	Using primary keratinocytes in organotypic culture, we show that loss of KLF4 impairs squamous epithelial differentiation and demonstrate functionally that WNT5A rescues the effects of KLF4 loss on differentiation and stratification.	('loss', 'Var', (65, 69))	('impairs', 'NegReg', (78, 85))	('squamous epithelia', 'Disease', (86, 104))	('loss', 'NegReg', (190, 194))	('KLF4', 'Gene', (73, 77))	('KLF4', 'Gene', (185, 189))	('squamous epithelia', 'Disease', 'MESH:D002294', (86, 104))	('squamous epithelia', 'Phenotype', 'HP:0002860', (86, 104))
685832	27184424	ED-L2-Cre/Klf4loxp/loxp mice have hyperplastic esophageal epithelia with evidence of abnormal differentiation and stratification.	('mice', 'Species', '10090', (24, 28))	('ED-L2-Cre/Klf4loxp/loxp', 'Var', (0, 23))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (47, 67))	('hyperplastic esophageal epithelia', 'Disease', (34, 67))	('hyperplastic esophageal epithelia', 'Disease', 'MESH:D004941', (34, 67))
685833	27184424	Non-canonical Wnt5a was reduced 3-fold on microarray studies of murine esophagus with Klf4 deletion, and we postulated that Wnt5a loss might be critical for the effects of Klf4 loss.	('deletion', 'Var', (91, 99))	('reduced', 'NegReg', (24, 31))	('Klf4', 'Gene', (86, 90))	('murine', 'Species', '10090', (64, 70))	('Non-canonical', 'MPA', (0, 13))
685838	27184424	Klf4 knockdown decreased Wnt5a mRNA by nearly 60% in primary mouse esophageal keratinocytes (Fig.	('Klf4', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (15, 24))	('mouse', 'Species', '10090', (61, 66))	('Wnt5a mRNA', 'MPA', (25, 35))
685839	27184424	1D), and KLF4 knockdown decreased WNT5A mRNA by more than 30% in primary human esophageal keratinocytes (Fig.	('decreased', 'NegReg', (24, 33))	('human', 'Species', '9606', (73, 78))	('WNT5A mRNA', 'MPA', (34, 44))	('knockdown', 'Var', (14, 23))	('KLF4', 'Gene', (9, 13))
685845	27184424	In contrast, KLF4 knockdown in EPC2-hTERT cells in organotypic culture yielded hyperplastic epithelia and rounded, immature-appearing cells with discernible nuclei in the suprabasal and superficial layers (Fig.	('knockdown', 'Var', (18, 27))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (31, 41))	('hyperplastic epithelia', 'Disease', (79, 101))	('hyperplastic epithelia', 'Disease', 'MESH:D054514', (79, 101))
685846	27184424	Thus, KLF4 knockdown in esophageal keratinocytes in organotypic culture recapitulated the esophageal phenotype of the ED-L2-Cre/Klf4loxp/loxp mice (Figure S2).	('mice', 'Species', '10090', (142, 146))	('knockdown', 'Var', (11, 20))	('esophageal', 'Disease', (90, 100))
685849	27184424	2D) while WNT5A treatment restored normal stratification of EPC2-hTERT cells with KLF4 knockdown (Fig.	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (60, 70))	('stratification', 'MPA', (42, 56))	('knockdown', 'Var', (87, 96))
685850	27184424	As such, we sought to determine whether WNT5A corrected defective keratinocyte differentiation resulting from KLF4 knockdown by examining the expression patterns of keratin 14, which marks immature, proliferative keratinocytes typically located in the basal layer, and keratin 4, a marker of keratinocyte differentiation.	('keratin 14', 'Gene', '16664', (165, 175))	('keratin 4', 'Gene', '16682', (269, 278))	('keratin 14', 'Gene', (165, 175))	('keratin 4', 'Gene', (269, 278))	('KLF4', 'Gene', (110, 114))	('knockdown', 'Var', (115, 124))
685851	27184424	3A), esophageal epithelia from organotypic cultures with KLF4 knockdown had marked expansion of keratin 14 expression indicative of more immature keratinocytes (Fig.	('keratin 14', 'Gene', '16664', (96, 106))	('KLF4', 'Gene', (57, 61))	('expansion', 'PosReg', (83, 92))	('keratin 14', 'Gene', (96, 106))	('expression', 'MPA', (107, 117))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (5, 25))	('esophageal epithelia', 'Disease', 'MESH:D004941', (5, 25))	('esophageal epithelia', 'Disease', (5, 25))	('knockdown', 'Var', (62, 71))
685852	27184424	3D), the localization of keratin 14 positive cells was similar to untreated cultures; WNT5A treatment of organotypic cultures with KLF4 knockdown resulted in a reduction of keratin 14 expressing cells and a more normal pattern of keratin 14 expression (Fig.	('reduction', 'NegReg', (160, 169))	('keratin 14', 'Gene', (25, 35))	('keratin 14', 'Gene', (230, 240))	('keratin 14', 'Gene', '16664', (173, 183))	('expression', 'MPA', (241, 251))	('knockdown', 'Var', (136, 145))	('keratin 14', 'Gene', '16664', (230, 240))	('keratin 14', 'Gene', (173, 183))	('KLF4', 'Gene', (131, 135))	('keratin 14', 'Gene', '16664', (25, 35))
685854	27184424	However, WNT5A treatment was sufficient to rescue the effects of KLF4 knockdown on keratin 4 expression and therefore esophageal epithelial differentiation (Fig.	('esophageal epithelia', 'Phenotype', 'HP:0012859', (118, 138))	('knockdown', 'Var', (70, 79))	('keratin 4', 'Gene', (83, 92))	('esophageal epithelia', 'Disease', 'MESH:D004941', (118, 138))	('esophageal epithelia', 'Disease', (118, 138))	('KLF4', 'Gene', (65, 69))	('expression', 'MPA', (93, 103))	('keratin 4', 'Gene', '16682', (83, 92))
685859	27184424	The Kruppel-like factor family member KLF4 is critical for the regulation of epithelial homeostasis and disease, including in the squamous esophagus and skin, and mice with Klf4 deletion in esophageal keratinocytes develop altered cell morphology, delayed differentiation, and abnormal stratification, leading to precancerous esophageal squamous cell dysplasia.	('epithelial homeostasis and disease', 'Disease', 'MESH:D002277', (77, 111))	('precancerous esophageal squamous cell dysplasia', 'Disease', (313, 360))	('squamous esophagus', 'Disease', (130, 148))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('delayed differentiation', 'CPA', (248, 271))	('deletion', 'Var', (178, 186))	('mice', 'Species', '10090', (163, 167))	('cell morphology', 'CPA', (231, 246))	('precancerous esophageal squamous cell dysplasia', 'Disease', 'MESH:D000077277', (313, 360))	('Klf4', 'Gene', (173, 177))	('squamous esophagus', 'Disease', 'MESH:D004938', (130, 148))	('leading to', 'Reg', (302, 312))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (337, 360))
685861	27184424	Wnt5a deletion in mice compromises differentiation of the hair follicle, and in the interfollicular epidermis, WNT5A activation induces keratinocyte differentiation during wound healing, consistent with a role for WNT5A in tissue repair seen in other contexts.	('WNT5A', 'Gene', (111, 116))	('Wnt5a', 'Gene', (0, 5))	('mice', 'Species', '10090', (18, 22))	('compromises', 'NegReg', (23, 34))	('differentiation of the hair follicle', 'CPA', (35, 71))	('deletion', 'Var', (6, 14))	('keratinocyte differentiation', 'CPA', (136, 164))	('induces', 'Reg', (128, 135))
685886	27184424	Mouse primary esophageal keratinocytes were transfected with either pCDNA3.1 or pCDNA3-Flag-Klf4 and with either pGL4 or Wnt5a-luc at 70% confluence in triplicate on 24-well plates using Turbofect transfection reagent (Thermo Fisher Scientific).	('pCDNA3.1', 'Var', (68, 76))	('Mouse', 'Species', '10090', (0, 5))	('pCDNA3-Flag-Klf4', 'Var', (80, 96))
685888	27184424	KLF4 knockdown was induced with 4 mug/ml of doxycycline from days 7-15, and recombinant WNT5A was added from days 11-15.	('knockdown', 'Var', (5, 14))	('doxycycline', 'Chemical', 'MESH:D004318', (44, 55))	('KLF4', 'Gene', (0, 4))
685962	26500452	From the integration of findings, we summarize that anti-inflammatory mechanism of XNT involved inhibition of IL-6 and TNF-alpha, and suppression of COX-2 and iNOS expression via NF-kB pathway resulting PGE2 and NO reduction.	('iNOS', 'Protein', (159, 163))	('XNT', 'Chemical', 'MESH:C120248', (83, 86))	('COX-2', 'Gene', (149, 154))	('COX-2', 'Gene', '19225', (149, 154))	('PGE2', 'Chemical', 'MESH:D015232', (203, 207))	('NF-kB', 'Gene', '81736', (179, 184))	('TNF-alpha', 'Protein', (119, 128))	('suppression', 'NegReg', (134, 145))	('PGE2', 'Var', (203, 207))	('IL-6', 'Protein', (110, 114))	('NF-kB', 'Gene', (179, 184))	('anti-inflammatory', 'MPA', (52, 69))	('rat', 'Species', '10116', (14, 17))
685972	26500452	We suggest that XNT might be subjected to further investigation in cardiovascular disorders because high LDL antioxidant activity could reduce the risk of heart attack.	('cardiovascular disorders', 'Phenotype', 'HP:0001626', (67, 91))	('XNT', 'Chemical', 'MESH:C120248', (16, 19))	('reduce', 'NegReg', (136, 142))	('high', 'Var', (100, 104))	('heart attack', 'Phenotype', 'HP:0001658', (155, 167))	('cardiovascular disorders', 'Disease', 'MESH:D002318', (67, 91))	('heart attack', 'Disease', (155, 167))	('high LDL', 'Phenotype', 'HP:0003141', (100, 108))	('cardiovascular disorders', 'Disease', (67, 91))
686059	26500452	It has been shown that XNT inhibited H2O2-induced lipid peroxidation in rat brain homogenates, glutamate-induced neurotoxicity, LDL peroxidation and ROS production.	('glutamate', 'Chemical', 'MESH:D018698', (95, 104))	('rat', 'Species', '10116', (72, 75))	('H2O2-induced', 'Var', (37, 49))	('LDL peroxidation', 'MPA', (128, 144))	('neurotoxicity', 'Disease', 'MESH:D020258', (113, 126))	('H2O2', 'Chemical', 'MESH:D006861', (37, 41))	('ROS', 'Chemical', 'MESH:D017382', (149, 152))	('XNT', 'Chemical', 'MESH:C120248', (23, 26))	('inhibited', 'NegReg', (27, 36))	('ROS production', 'MPA', (149, 163))	('neurotoxicity', 'Disease', (113, 126))	('lipid', 'Chemical', 'MESH:D008055', (50, 55))
686070	26500452	Improper upregulation can cause certain human cancers and inflammatory disorders.	('inflammatory disorders', 'Disease', 'MESH:D015212', (58, 80))	('cause', 'Reg', (26, 31))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('upregulation', 'PosReg', (9, 21))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('inflammatory disorders', 'Disease', (58, 80))	('human', 'Species', '9606', (40, 45))	('Improper', 'Var', (0, 8))
686080	26500452	and Handayani et al., where increased expression of p53 did not induce Bax expression, but reduced Bcl-2 level in MCF-7 breast cancer and HepG2 liver cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('liver cancer', 'Phenotype', 'HP:0002896', (144, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('Bax', 'Gene', (71, 74))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('HepG2 liver cancer', 'Disease', 'MESH:D006528', (138, 156))	('expression', 'Var', (38, 48))	('reduced', 'NegReg', (91, 98))	('HepG2 liver cancer', 'Disease', (138, 156))	('Bcl-2', 'Gene', (99, 104))	('Bax', 'Gene', '581', (71, 74))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (114, 133))	('MCF-7 breast cancer', 'Disease', (114, 133))	('Bcl-2', 'Gene', '596', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
686085	26500452	The hallmarks of caspase-dependent apoptosis as shown by XNT in cancer cells include increased mitochondrial membrane permeability and cytosolic release of cytochrome c (MDA-MB-231 invasive breast cancer, HCT 116 colon cancer cells), activation of caspase-3 and -9 (HepG2, MDA-MB-231, HCT 116 cells), reduced Bcl-XL expression (HepG2, HCT116 cancer cells), reduced Bcl-2 expression (MCF-7, HepG2, Tca8113 tongue cancer cells), truncation of Bid (HepG2, HCT116 cancer cells) and cleavage of DNA repair enzyme poly-(ADP-ribose) polymerase (PARP) (HepG2, MCF-7, MDA-MB-231, HCT116 cancer cells).	('PARP', 'Gene', (538, 542))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('tongue cancer', 'Disease', (405, 418))	('cancer', 'Disease', (342, 348))	('mitochondrial membrane permeability', 'MPA', (95, 130))	('cytochrome c', 'Gene', (156, 168))	('Bcl-2', 'Gene', '596', (365, 370))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('invasive breast cancer', 'Disease', 'MESH:D001943', (181, 203))	('increased', 'PosReg', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('activation', 'PosReg', (234, 244))	('colon cancer', 'Disease', (213, 225))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (273, 283))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (559, 569))	('HCT116', 'CellLine', 'CVCL:0291', (335, 341))	('cancer', 'Disease', (64, 70))	('HCT116', 'CellLine', 'CVCL:0291', (453, 459))	('tongue cancer', 'Disease', 'MESH:D014062', (405, 418))	('truncation', 'Var', (427, 437))	('reduced', 'NegReg', (301, 308))	('caspase', 'Gene', (17, 24))	('cancer', 'Disease', (412, 418))	('HepG2', 'CellLine', 'CVCL:0027', (390, 395))	('Bcl-XL', 'Gene', '598', (309, 315))	('caspase-3 and -9', 'Gene', '836;842', (248, 264))	('HCT116', 'CellLine', 'CVCL:0291', (571, 577))	('cancer', 'Disease', (460, 466))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (170, 180))	('HCT 116', 'CellLine', 'CVCL:0291', (285, 292))	('caspase', 'Gene', (248, 255))	('Bcl-XL', 'Gene', (309, 315))	('reduced', 'NegReg', (357, 364))	('caspase', 'Gene', '841;842', (17, 24))	('Bid', 'Gene', '637', (441, 444))	('cancer', 'Disease', (578, 584))	('HCT 116', 'CellLine', 'CVCL:0291', (205, 212))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('MCF-7', 'CellLine', 'CVCL:0031', (552, 557))	('cancer', 'Phenotype', 'HP:0002664', (412, 418))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cleavage', 'Var', (478, 486))	('cancer', 'Disease', (197, 203))	('caspase', 'Gene', '841;842', (248, 255))	('colon cancer', 'Phenotype', 'HP:0003003', (213, 225))	('XNT', 'Chemical', 'MESH:C120248', (57, 60))	('ADP', 'Chemical', 'MESH:D000244', (514, 517))	('HepG2', 'CellLine', 'CVCL:0027', (545, 550))	('cytochrome c', 'Gene', '54205', (156, 168))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('HepG2', 'CellLine', 'CVCL:0027', (266, 271))	('Bcl-2', 'Gene', (365, 370))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('HepG2', 'CellLine', 'CVCL:0027', (328, 333))	('HepG2', 'CellLine', 'CVCL:0027', (446, 451))	('colon cancer', 'Disease', 'MESH:D015179', (213, 225))	('PARP', 'Gene', '142', (538, 542))	('cancer', 'Disease', 'MESH:D009369', (412, 418))	('cancer', 'Disease', 'MESH:D009369', (460, 466))	('MCF-7', 'CellLine', 'CVCL:0031', (383, 388))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('cancer', 'Disease', 'MESH:D009369', (578, 584))	('invasive breast cancer', 'Disease', (181, 203))	('Bid', 'Gene', (441, 444))
686097	26500452	Although Akt inhibition activated GSK3beta and subsequently enhanced NAG-1 expression, the exact molecular mechanisms of Akt/GSK3beta/mTOR signaling on NAG-1-induced apoptosis are yet to be explored.	('Akt', 'Protein', (9, 12))	('GSK3beta', 'Gene', (125, 133))	('NAG-1', 'Gene', '9518', (69, 74))	('inhibition', 'Var', (13, 23))	('NAG-1', 'Gene', '9518', (152, 157))	('GSK3beta', 'Gene', '2932', (125, 133))	('NAG-1', 'Gene', (69, 74))	('mTOR', 'Gene', '2475', (134, 138))	('activated', 'PosReg', (24, 33))	('mTOR', 'Gene', (134, 138))	('NAG-1', 'Gene', (152, 157))	('GSK3beta', 'Gene', (34, 42))	('enhanced', 'PosReg', (60, 68))	('expression', 'MPA', (75, 85))	('GSK3beta', 'Gene', '2932', (34, 42))
686103	26500452	Since excessive accumulation of ROS in the cells can stimulate MAPK pathway, it is concluded that XNT induced caspase-independent apoptosis through ROS-mediated p38 MAPK and JNK activation in SCC-15 OSCC cells.	('JNK', 'MPA', (174, 177))	('caspase', 'Gene', '841;842', (110, 117))	('XNT', 'Chemical', 'MESH:C120248', (98, 101))	('activation', 'PosReg', (178, 188))	('p38', 'Var', (161, 164))	('ROS', 'Chemical', 'MESH:D017382', (148, 151))	('ROS', 'Chemical', 'MESH:D017382', (32, 35))	('SCC-15 OSCC', 'CellLine', 'CVCL:L894', (192, 203))	('caspase', 'Gene', (110, 117))	('MAPK pathway', 'Pathway', (63, 75))
686112	26500452	Since Akt is a NF-kB upstream signal factor, Akt phosphorylation can activate IkappaB kinase (IKK) followed by NF-kB, which promotes cell survival pathway.	('NF-kB', 'Gene', '81736', (15, 20))	('NF-kB', 'Gene', (111, 116))	('activate', 'PosReg', (69, 77))	('NF-kB', 'Gene', (15, 20))	('cell survival pathway', 'CPA', (133, 154))	('promotes', 'PosReg', (124, 132))	('NF-kB', 'Gene', '81736', (111, 116))	('phosphorylation', 'Var', (49, 64))
686126	26500452	In HCT116 colon cancer cells, XNT was found to inhibit the cell cycle in the G1 or G2/M phase by triggering cyclin-dependent kinase inhibitors (CDKIs) such as p21 and p27.	('XNT', 'Var', (30, 33))	('cyclin-dependent', 'MPA', (108, 124))	('p27', 'Var', (167, 170))	('HCT116', 'CellLine', 'CVCL:0291', (3, 9))	('p21', 'Gene', (159, 162))	('XNT', 'Chemical', 'MESH:C120248', (30, 33))	('p21', 'Gene', '644914', (159, 162))	('inhibit', 'NegReg', (47, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (10, 22))	('cell cycle in the G1', 'CPA', (59, 79))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('colon cancer', 'Disease', 'MESH:D015179', (10, 22))	('colon cancer', 'Disease', (10, 22))	('triggering', 'Reg', (97, 107))
686127	26500452	Cell cycle arrest in the G0/G1 and G2/M phase and increased sub-G1 peaks were closely associated with under-expression of cell cycle regulatory proteins such as cyclin A, B1, D1, cyclin-dependent kinase 1 (CDK1), CDK2, CDK4 and proliferating cell nuclear antigen (PCNA), which is a biomarker for the cell proliferation.	('G2/M phase', 'CPA', (35, 45))	('PCNA', 'Gene', (264, 268))	('Cell cycle arrest', 'CPA', (0, 17))	('CDK4', 'Gene', (219, 223))	('cyclin-dependent kinase 1', 'Gene', '983', (179, 204))	('proliferating cell nuclear antigen', 'Gene', '5111', (228, 262))	('increased', 'PosReg', (50, 59))	('cyclin A', 'Gene', '890', (161, 169))	('sub-G1', 'Gene', (60, 66))	('under-expression', 'Var', (102, 118))	('cyclin-dependent kinase 1', 'Gene', (179, 204))	('CDK4', 'Gene', '1019', (219, 223))	('PCNA', 'Gene', '5111', (264, 268))	('cyclin A', 'Gene', (161, 169))	('rat', 'Species', '10116', (235, 238))	('CDK1', 'Gene', (206, 210))	('CDK1', 'Gene', '983', (206, 210))	('CDK2', 'Gene', '1017', (213, 217))	('proliferating cell nuclear antigen', 'Gene', (228, 262))	('CDK2', 'Gene', (213, 217))	('rat', 'Species', '10116', (312, 315))	('G0/G1', 'CPA', (25, 30))
686151	26500452	However, in vivo results reflected that XNT interacted with tamoxifen causing increased tumor volumes, tumor size, tumor weight and protein expression of p27 (kip1) and p38 in the MCF-7 implanted athymic nude mice model.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('p27', 'Var', (154, 157))	('nude mice', 'Species', '10090', (204, 213))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tamoxifen', 'Chemical', 'MESH:D013629', (60, 69))	('tumor', 'Disease', (103, 108))	('XNT', 'Chemical', 'MESH:C120248', (40, 43))	('tumor', 'Disease', (115, 120))	('MCF-7', 'CellLine', 'CVCL:0031', (180, 185))	('increased', 'PosReg', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('protein expression', 'MPA', (132, 150))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('p38', 'Var', (169, 172))
686153	26500452	Since p27(kip1) was upregulated in XNT + tamoxifen group compared to the tamoxifen-alone group, it was postulated that XNT may inactivate the functional properties of p27(kip1) resulting increased tumor growth.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('p27', 'Var', (167, 170))	('upregulated', 'PosReg', (20, 31))	('inactivate', 'NegReg', (127, 137))	('XNT', 'Chemical', 'MESH:C120248', (119, 122))	('increased', 'PosReg', (187, 196))	('tamoxifen', 'Chemical', 'MESH:D013629', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tamoxifen', 'Chemical', 'MESH:D013629', (41, 50))	('p27(kip1', 'Protein', (6, 14))	('tumor', 'Disease', (197, 202))	('functional properties', 'MPA', (142, 163))	('XNT', 'Chemical', 'MESH:C120248', (35, 38))
686154	26500452	p27(kip1) is expelled from the nucleus rendering cell growth inhibition due to phosphorylation occurs at Ser of p27(kip 1).	('phosphorylation', 'MPA', (79, 94))	('Ser', 'Chemical', 'MESH:D012694', (105, 108))	('Ser', 'Var', (105, 108))	('cell growth', 'CPA', (49, 60))
686157	26500452	It exerts the pro-apoptotic action by phosphorylating and translocating Bcl-2 family's proteins, thus causing the mitochondrial release of cytochrome c. Since p27(kip1) and p38 were over-expressed in this study, in vivo tumor-promoting effect of XNT-tamoxifen interaction may be probably due to the mutation occurred leading to protein p27(kip1) and p38 malfunction.	('protein p27(kip1', 'Protein', (328, 344))	('p38', 'Protein', (350, 353))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tamoxifen', 'Chemical', 'MESH:D013629', (250, 259))	('over-expressed', 'PosReg', (182, 196))	('Bcl-2', 'Gene', (72, 77))	('Bcl-2', 'Gene', '596', (72, 77))	('malfunction', 'PosReg', (354, 365))	('tumor', 'Disease', (220, 225))	('XNT', 'Chemical', 'MESH:C120248', (246, 249))	('cytochrome c', 'Gene', (139, 151))	('mutation', 'Var', (299, 307))	('cytochrome c', 'Gene', '54205', (139, 151))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
686188	26132559	Functional BCL-2 regulatory genetic variants contribute to susceptibility of esophageal squamous cell carcinoma B-cell lymphoma-2 (BCL-2) prevents apoptosis and its overexpression could promote cancer cell survival.	('promote', 'PosReg', (186, 193))	('BCL-2', 'Gene', '596', (11, 16))	('BCL-2', 'Gene', (11, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('overexpression', 'PosReg', (165, 179))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('lymphoma', 'Phenotype', 'HP:0002665', (119, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('B-cell lymphoma-2', 'Gene', '596', (112, 129))	('apoptosis', 'CPA', (147, 156))	('cancer', 'Disease', (194, 200))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('BCL-2', 'Gene', '596', (131, 136))	('BCL-2', 'Gene', (131, 136))	('variants', 'Var', (36, 44))	('B-cell lymphoma-2', 'Gene', (112, 129))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (112, 127))
686189	26132559	Multiple functional BCL-2 genetic polymorphisms, such as rs2279115, rs1801018 and rs1564483, have been identified previously and might be involved in cancer development through deregulating BCL-2 expression.	('rs1801018', 'Var', (68, 77))	('rs1564483', 'Var', (82, 91))	('rs1564483', 'Mutation', 'rs1564483', (82, 91))	('BCL-2', 'Gene', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('expression', 'MPA', (196, 206))	('rs2279115', 'Var', (57, 66))	('involved', 'Reg', (138, 146))	('cancer', 'Disease', (150, 156))	('BCL-2', 'Gene', '596', (190, 195))	('rs1801018', 'Mutation', 'rs1801018', (68, 77))	('rs2279115', 'Mutation', 'rs2279115', (57, 66))	('deregulating', 'NegReg', (177, 189))	('BCL-2', 'Gene', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('BCL-2', 'Gene', '596', (20, 25))
686192	26132559	The impact of the rs2279115 polymorphism on BCL-2 expression was detected using esophagus tissues.	('rs2279115', 'Mutation', 'rs2279115', (18, 27))	('BCL-2', 'Gene', '596', (44, 49))	('rs2279115', 'Var', (18, 27))	('BCL-2', 'Gene', (44, 49))
686193	26132559	Our results demonstrated that the BCL-2 rs2279115 AA genotype was significantly associated with decreased ESCC risk compared with the CC genotype (OR = 0.72, 95% CI = 0.57-0.90, P = 0.005), especially in nonsmokers (OR = 0.42, 95% CI = 0.29-0.59, P = 0.001) or nondrinkers (OR = 0.44, 95% CI = 0.32-0.62, P = 0.002).	('rs2279115', 'Mutation', 'rs2279115', (40, 49))	('rs2279115 AA', 'Var', (40, 52))	('BCL-2', 'Gene', '596', (34, 39))	('decreased', 'NegReg', (96, 105))	('ESCC', 'Disease', (106, 110))	('BCL-2', 'Gene', (34, 39))	('decreased ESCC', 'Phenotype', 'HP:0025022', (96, 110))
686194	26132559	Genotype-phenotype correlation studies demonstrated that subjects with the rs2279115 CA and AA genotypes had a statistically significant decrease of BCL-2 mRNA expression compared to the CC genotype in both normal and cancerous esophagus tissues.	('decrease', 'NegReg', (137, 145))	('cancerous esophagus', 'Disease', (218, 237))	('rs2279115', 'Var', (75, 84))	('BCL-2', 'Gene', '596', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancerous esophagus', 'Phenotype', 'HP:0100751', (218, 237))	('cancerous esophagus', 'Disease', 'MESH:D004938', (218, 237))	('rs2279115', 'Mutation', 'rs2279115', (75, 84))	('BCL-2', 'Gene', (149, 154))
686195	26132559	Our results indicate that the BCL-2 rs2279115 polymorphism contributes to ESCC susceptibility in Chinese populations.	('rs2279115', 'Mutation', 'rs2279115', (36, 45))	('BCL-2', 'Gene', (30, 35))	('ESCC', 'Disease', (74, 78))	('rs2279115', 'Var', (36, 45))	('BCL-2', 'Gene', '596', (30, 35))
686196	26132559	Deregulations of apoptosis lead to either inappropriate killing of vital cells or survival of unwanted cells, which has been considered to be a hallmark of most cancers.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Deregulations', 'Var', (0, 13))	('apoptosis', 'CPA', (17, 26))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('lead to', 'Reg', (27, 34))	('cancers', 'Disease', (161, 168))	('survival of unwanted cells', 'CPA', (82, 108))
686204	26132559	For example, ESCC genome-wide association studies (GWAS) highlight the involvement of single nucleotide polymorphisms (SNP) in cancer development, alone and in combination with environmental risk factors.	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('single nucleotide polymorphisms', 'Var', (86, 117))	('cancer', 'Disease', (127, 133))
686210	26132559	Interestingly, the rs2279115 A allele may render a better interaction with TP53, leading to a decrease in the BCL2 expression, an up-regulated programmed cell death or reduced longevity of transformed cells, and thus a subsequent decrease in the risk of malignances, such as squamous cell carcinoma of the head and neck (SCCHN).	('squamous cell carcinoma', 'Disease', (275, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('decrease', 'NegReg', (94, 102))	('reduced', 'NegReg', (168, 175))	('rs2279115 A', 'Var', (19, 30))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (289, 319))	('programmed cell death', 'CPA', (143, 164))	('TP53', 'Gene', (75, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (275, 298))	('BCL2', 'Gene', '596', (110, 114))	('interaction', 'Interaction', (58, 69))	('up-regulated', 'PosReg', (130, 142))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (275, 298))	('BCL2', 'Gene', (110, 114))	('decrease', 'NegReg', (230, 238))	('longevity', 'CPA', (176, 185))	('expression', 'MPA', (115, 125))	('rs2279115', 'Mutation', 'rs2279115', (19, 28))	('TP53', 'Gene', '7157', (75, 79))
686211	26132559	Considering the importance of BCL-2 in tumorigenesis, we hypothesized that the BCL-2 functional polymorphisms (rs2279115, rs1801018 and rs1564483) might be also involved in ESCC development through deregulating BCL-2 expression.	('BCL-2', 'Gene', (211, 216))	('rs1801018', 'Mutation', 'rs1801018', (122, 131))	('deregulating', 'PosReg', (198, 210))	('ESCC', 'Disease', (173, 177))	('involved', 'Reg', (161, 169))	('expression', 'MPA', (217, 227))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('BCL-2', 'Gene', '596', (79, 84))	('BCL-2', 'Gene', (79, 84))	('rs2279115', 'Mutation', 'rs2279115', (111, 120))	('rs1801018', 'Var', (122, 131))	('tumor', 'Disease', (39, 44))	('BCL-2', 'Gene', '596', (30, 35))	('rs2279115', 'Var', (111, 120))	('BCL-2', 'Gene', (30, 35))	('rs1564483', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('rs1564483', 'Mutation', 'rs1564483', (136, 145))	('BCL-2', 'Gene', '596', (211, 216))
686212	26132559	To validate the biological function of BCL-2 rs2279115 genetic variant in vivo, we detected the association between its genotypes and BCL-2 mRNA expression levels in normal and cancerous esophagus tissues.	('rs2279115', 'Var', (45, 54))	('BCL-2', 'Gene', (39, 44))	('BCL-2', 'Gene', (134, 139))	('rs2279115', 'Mutation', 'rs2279115', (45, 54))	('association', 'Interaction', (96, 107))	('cancerous esophagus', 'Disease', (177, 196))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('BCL-2', 'Gene', '596', (39, 44))	('cancerous esophagus', 'Phenotype', 'HP:0100751', (177, 196))	('cancerous esophagus', 'Disease', 'MESH:D004938', (177, 196))	('BCL-2', 'Gene', '596', (134, 139))
686218	26132559	To reduce the costs of the study, we genotyped the BCL-2 rs2279115 SNP in the validation set using PCR-based restriction fragment length polymorphism (RFLP).	('rs2279115', 'Mutation', 'rs2279115', (57, 66))	('rs2279115 SNP', 'Var', (57, 70))	('BCL-2', 'Gene', '596', (51, 56))	('BCL-2', 'Gene', (51, 56))
686229	26132559	During calculating associations between functional SNP candidates in BCL-2 and ESCC risk in Huaian case-control set, we used the common genotypes of rs2279115 (CC), rs1801018 (AA) and rs1564483 (GG) as the reference genotype.	('rs1801018', 'Mutation', 'rs1801018', (165, 174))	('rs1801018', 'Var', (165, 174))	('rs1564483', 'Mutation', 'rs1564483', (184, 193))	('BCL-2', 'Gene', '596', (69, 74))	('rs2279115', 'Mutation', 'rs2279115', (149, 158))	('ESCC', 'Disease', (79, 83))	('BCL-2', 'Gene', (69, 74))	('rs1564483', 'Var', (184, 193))
686231	26132559	The genotype frequencies of BCL-2 candidate SNPs (rs2279115 C > A, rs1801018 A > G and rs1564483 G > A) are summarized in Table 2.	('rs2279115 C > A', 'Var', (50, 65))	('rs1801018 A > G', 'Var', (67, 82))	('BCL-2', 'Gene', '596', (28, 33))	('rs1564483 G > A', 'Var', (87, 102))	('BCL-2', 'Gene', (28, 33))	('rs1564483', 'Mutation', 'rs1564483', (87, 96))	('rs1801018', 'Mutation', 'rs1801018', (67, 76))	('rs2279115', 'Mutation', 'rs2279115', (50, 59))
686232	26132559	The allele frequencies for rs2279115 C, rs1801018 G and rs1564483 A were 0.362, 0.084, and 0.375 in ESCC cases and 0.410, 0.098, and 0.338 in control subjects in Huaian training case-control set.	('rs1564483 A', 'Var', (56, 67))	('rs2279115 C', 'Var', (27, 38))	('rs2279115', 'Mutation', 'rs2279115', (27, 36))	('rs1801018', 'Mutation', 'rs1801018', (40, 49))	('ESCC', 'Disease', (100, 104))	('rs1564483', 'Mutation', 'rs1564483', (56, 65))	('rs1801018 G', 'Var', (40, 51))
686233	26132559	Distributions of the rs2279115, rs1801018 and rs1564483 genotypes were then compared among patients and controls.	('rs1564483', 'Var', (46, 55))	('rs1564483', 'Mutation', 'rs1564483', (46, 55))	('patients', 'Species', '9606', (91, 99))	('rs2279115', 'Mutation', 'rs2279115', (21, 30))	('rs1801018', 'Mutation', 'rs1801018', (32, 41))	('rs1801018', 'Var', (32, 41))	('rs2279115', 'Var', (21, 30))
686234	26132559	Frequencies of rs2279115 CC, CA, and AA genotypes among ESCC cases differed significantly from those among controls (chi2 = 8.68, P = 0.013, df = 2), with the frequency of AA homozygote being significantly lower among patients than among controls (13.7% vs. 15.0%).	('ESCC', 'Disease', (56, 60))	('patients', 'Species', '9606', (218, 226))	('rs2279115 CC', 'Var', (15, 27))	('lower', 'NegReg', (206, 211))	('rs2279115', 'Mutation', 'rs2279115', (15, 24))
686235	26132559	However, no statistically significant differences of rs1801018 and rs1564483 genotypes were observed between cases and control subjects (both P > 0.05) (Table 2).	('rs1564483', 'Mutation', 'rs1564483', (67, 76))	('rs1564483', 'Var', (67, 76))	('rs1801018', 'Var', (53, 62))	('rs1801018', 'Mutation', 'rs1801018', (53, 62))
686236	26132559	Associations between genotypes of BCL-2 rs2279115 C > A SNP and ESCC risk were calculated using unconditional logistic regression analyses (Table 3).	('rs2279115', 'Mutation', 'rs2279115', (40, 49))	('rs2279115 C > A', 'Var', (40, 55))	('ESCC', 'Disease', (64, 68))	('BCL-2', 'Gene', '596', (34, 39))	('BCL-2', 'Gene', (34, 39))
686237	26132559	The BCL-2 rs2279115 A allele was shown to be a protective allele.	('rs2279115', 'Mutation', 'rs2279115', (10, 19))	('BCL-2', 'Gene', '596', (4, 9))	('rs2279115 A', 'Var', (10, 21))	('BCL-2', 'Gene', (4, 9))
686239	26132559	However, the rs2279115 AA genotypes had a marginally decreased risk for ESCC compared with the rs2279115 CC genotype (OR = 0.85, 95% CI = 0.70-1.03, P = 0.095).	('ESCC', 'Disease', (72, 76))	('rs2279115', 'Mutation', 'rs2279115', (13, 22))	('rs2279115 AA', 'Var', (13, 25))	('decreased', 'NegReg', (53, 62))	('rs2279115', 'Mutation', 'rs2279115', (95, 104))
686240	26132559	In Jinan set, carriers of the rs2279115 CA or AA genotypes were significantly associated with decreased ESCC risk (OR = 0.62, 95% CI = 0.50-0.77, P = 0.002, or OR = 0.49, 95% CI = 0.36-0.66, P = 4.2 x 10-4) (Table 3).	('rs2279115', 'Mutation', 'rs2279115', (30, 39))	('decreased ESCC', 'Phenotype', 'HP:0025022', (94, 108))	('decreased', 'NegReg', (94, 103))	('ESCC', 'Disease', (104, 108))	('rs2279115', 'Var', (30, 39))
686241	26132559	In the pooled analyses, we observed that only individuals with the rs2279115 AA genotype had a 0.72-fold decreased risk to develop ESCC compared to the CC genotype carriers (95% CI = 0.57-0.90, P = 0.005) (Table 3).	('rs2279115', 'Mutation', 'rs2279115', (67, 76))	('decreased', 'NegReg', (105, 114))	('rs2279115', 'Var', (67, 76))	('ESCC', 'Disease', (131, 135))
686242	26132559	Associations between genotypes of BCL-2 rs2279115 genetic variant and ESCC risk was further examined by stratifying for age, sex, smoking and alcohol drinking status using the pooled data of two Chinese case-control sets (Table 4).	('rs2279115', 'Mutation', 'rs2279115', (40, 49))	('BCL-2', 'Gene', '596', (34, 39))	('alcohol', 'Chemical', 'MESH:D000438', (142, 149))	('rs2279115', 'Var', (40, 49))	('BCL-2', 'Gene', (34, 39))	('alcohol drinking', 'Phenotype', 'HP:0030955', (142, 158))	('ESCC', 'Disease', (70, 74))
686243	26132559	Compared with the BCL-2 rs2279115 CC genotype, a significantly decreased risk of ESCC was associated with AA genotypes only among males (OR = 0.70, 95% CI = 0.54-0.91, P = 0.008), but not among females (OR = 0.74, 95% CI = 0.42-1.32, P = 0.309).	('rs2279115 CC', 'Var', (24, 36))	('BCL-2', 'Gene', '596', (18, 23))	('rs2279115', 'Mutation', 'rs2279115', (24, 33))	('decreased', 'NegReg', (63, 72))	('ESCC', 'Disease', (81, 85))	('BCL-2', 'Gene', (18, 23))
686244	26132559	However, the BCL-2 rs2279115 CC genotype was not significantly associated with ESCC susceptibility in males or females (OR = 0.86, 95% CI = 0.71-1.04, P = 0.123, or OR = 0.97, 95% CI = 0.66-1.42, P = 0.868).	('BCL-2', 'Gene', '596', (13, 18))	('BCL-2', 'Gene', (13, 18))	('rs2279115 CC', 'Var', (19, 31))	('ESCC', 'Disease', (79, 83))	('rs2279115', 'Mutation', 'rs2279115', (19, 28))
686245	26132559	In age-stratified analyses, either rs2279115 CA or AA genotype was significantly associated with decreased risk in subjects aged older than 57 years (OR = 0.76, 95% CI = 0.60-0.96, P = 0.021, or, OR = 0.56, 95% CI = 0.40-0.78, P = 0.001).	('decreased', 'NegReg', (97, 106))	('rs2279115 CA', 'Var', (35, 47))	('rs2279115', 'Mutation', 'rs2279115', (35, 44))
686246	26132559	However, among subjects aged 57 years or younger, neither rs2279115 CA nor AA genotype showed impacts on ESCC risk (OR = 0.56, 95% CI = 0.40-0.78, P = 0.001, or, OR = 0.92, 95% CI = 0.65-1.29, P = 0.619).	('impacts', 'Reg', (94, 101))	('rs2279115', 'Mutation', 'rs2279115', (58, 67))	('ESCC', 'Disease', (105, 109))	('rs2279115 CA', 'Var', (58, 70))
686247	26132559	Because tobacco smoking and alcohol drinking are both risk factors for ESCC, we then examined whether the BCL-2 rs2279115 genetic variant influence ESCC susceptibility in combination with these pathogenic factors (Table 4).	('ESCC', 'Disease', (71, 75))	('BCL-2', 'Gene', (106, 111))	('alcohol drinking', 'Phenotype', 'HP:0030955', (28, 44))	('alcohol', 'Chemical', 'MESH:D000438', (28, 35))	('rs2279115', 'Mutation', 'rs2279115', (112, 121))	('rs2279115', 'Var', (112, 121))	('ESCC', 'Disease', (148, 152))	('influence', 'Reg', (138, 147))	('tobacco', 'Species', '4097', (8, 15))	('BCL-2', 'Gene', '596', (106, 111))
686248	26132559	In nonsmokers, compared with the rs2279115 CC carriers, individuals with CA or AA genotype had a 0.70-fold or 0.42-fold decreased risk to develop ESCC (95% CI = 0.54-0.92, P = 0.010, or 95% CI = 0.29-0.59, P = 0.001).	('decreased', 'NegReg', (120, 129))	('ESCC', 'Disease', (146, 150))	('rs2279115', 'Var', (33, 42))	('rs2279115', 'Mutation', 'rs2279115', (33, 42))
686249	26132559	Nondrinkers carrying rs2279115 CA or AA genotype showed significantly decreased risk to develop ESCC compared with CC carriers who did not drink (OR = 0.78, 95% CI = 0.61-0.99, P = 0.041, or OR = 0.44, 95% CI = 0.32-0.62, P = 0.002).	('rs2279115', 'Mutation', 'rs2279115', (21, 30))	('decreased', 'NegReg', (70, 79))	('rs2279115 CA', 'Var', (21, 33))	('ESCC', 'Disease', (96, 100))
686250	26132559	However, there were no association between rs2279115 CA and AA genotypes and ESCC risk in drinkers (both P > 0.05) (Table 4).	('ESCC', 'Disease', (77, 81))	('rs2279115', 'Mutation', 'rs2279115', (43, 52))	('rs2279115', 'Var', (43, 52))
686251	26132559	Due to rs2279115 C-to-A change could influence BCL-2 P2 promoter activity and gene expression in cancer cells, we investigated whether there is an allele-specific effect of rs2279115 SNP on BCL-2 expression in esophagus tissues.	('influence', 'Reg', (37, 46))	('cancer', 'Disease', (97, 103))	('rs2279115', 'Mutation', 'rs2279115', (7, 16))	('BCL-2', 'Gene', (47, 52))	('gene expression', 'MPA', (78, 93))	('BCL-2', 'Gene', '596', (47, 52))	('rs2279115', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('BCL-2', 'Gene', '596', (190, 195))	('rs2279115', 'Mutation', 'rs2279115', (173, 182))	('BCL-2', 'Gene', (190, 195))	('rs2279115', 'Var', (7, 16))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
686252	26132559	We found that there were significantly lower BCL-2 mRNA levels (mean +- SE) among carriers of the rs2279115 CA and AA genotypes compared to carriers of the CC genotype in normal esophagus tissues (0.083 +- 0.012 [n = 17] vs. 0.109 +- 0.021 [n = 12], P = 0.031) (Table 5).	('BCL-2', 'Gene', '596', (45, 50))	('rs2279115', 'Var', (98, 107))	('BCL-2', 'Gene', (45, 50))	('rs2279115', 'Mutation', 'rs2279115', (98, 107))	('lower', 'NegReg', (39, 44))
686253	26132559	Similar results have also been observed in ESCC tissues (the rs2279115 CA and AA genotypes: 0.153 +- 0.022 [n = 17] vs. the CC genotype: 0.184 +- 0.045 [n = 12], P = 0.040) (Table 5).	('ESCC', 'Disease', (43, 47))	('rs2279115', 'Var', (61, 70))	('rs2279115', 'Mutation', 'rs2279115', (61, 70))
686255	26132559	We found that only BCL-2 rs2279115 polymorphism is significantly associated with decreased ESCC susceptibility in Chinese populations, with the rs2279115 AA genotype as the protective genotype.	('decreased', 'NegReg', (81, 90))	('rs2279115', 'Var', (25, 34))	('BCL-2', 'Gene', (19, 24))	('rs2279115', 'Mutation', 'rs2279115', (144, 153))	('ESCC', 'Disease', (91, 95))	('rs2279115', 'Mutation', 'rs2279115', (25, 34))	('decreased ESCC', 'Phenotype', 'HP:0025022', (81, 95))	('BCL-2', 'Gene', '596', (19, 24))	('rs2279115', 'Var', (144, 153))
686256	26132559	Our data support the hypothesis that SNPs in gene expression regulatory elements of tumor suppressor genes or oncogenes might impact genetic susceptibility of cancers.	('cancers', 'Disease', (159, 166))	('oncogenes', 'Gene', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('impact', 'Reg', (126, 132))	('tumor', 'Disease', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('genetic susceptibility', 'MPA', (133, 155))	('SNPs in', 'Var', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
686257	26132559	The BCL-2 rs2279115 polymorphism has been extensively studied in multiple cancer types, including ESCC.	('BCL-2', 'Gene', '596', (4, 9))	('rs2279115', 'Mutation', 'rs2279115', (10, 19))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('BCL-2', 'Gene', (4, 9))	('ESCC', 'Disease', (98, 102))	('cancer', 'Disease', (74, 80))	('rs2279115', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
686259	26132559	They found that the BCL-2 rs2279115 AA genotype was significantly associated with increased risk of developing esophageal cancer.	('rs2279115', 'Mutation', 'rs2279115', (26, 35))	('rs2279115 AA', 'Var', (26, 38))	('BCL-2', 'Gene', (20, 25))	('associated', 'Reg', (66, 76))	('esophageal cancer', 'Disease', (111, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BCL-2', 'Gene', '596', (20, 25))
686260	26132559	In contrast, we found that subjects with the rs2279115 AA genotype have significantly decreased risk to develop ESCC in both Northern and Southern Chinese populations.	('decreased', 'NegReg', (86, 95))	('rs2279115 AA', 'Var', (45, 57))	('ESCC', 'Disease', (112, 116))	('rs2279115', 'Mutation', 'rs2279115', (45, 54))
686261	26132559	only recruited 205 esophageal cancer patients to evaluate association between rs2279115 and esophageal cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (37, 45))	('rs2279115', 'Var', (78, 87))	('esophageal cancer', 'Disease', (19, 36))	('esophageal cancer', 'Disease', (92, 109))	('rs2279115', 'Mutation', 'rs2279115', (78, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (19, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
686265	26132559	Our results are consistent to functional relevance of rs2279115 polymorphism in SCCHN.	('SCCHN', 'Disease', (80, 85))	('rs2279115', 'Mutation', 'rs2279115', (54, 63))	('rs2279115', 'Var', (54, 63))
686266	26132559	That is, the rs2279115 AA genotype may result in decreased BCL-2 expression, elevated apoptosis rates of cancer cells, and thus decreased risk of malignances.	('malignances', 'CPA', (146, 157))	('BCL-2', 'Gene', '596', (59, 64))	('rs2279115', 'Mutation', 'rs2279115', (13, 22))	('rs2279115 AA', 'Var', (13, 25))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('apoptosis rates', 'CPA', (86, 101))	('decreased', 'NegReg', (49, 58))	('BCL-2', 'Gene', (59, 64))	('elevated', 'PosReg', (77, 85))	('decreased', 'NegReg', (128, 137))	('expression', 'MPA', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
686268	26132559	Therefore, it is biologically plausible that the functional BCL-2 rs2279115 polymorphism influence ESCC genetics thoroughly through regulating BCL-2 expression and apoptosis in vivo.	('BCL-2', 'Gene', (60, 65))	('BCL-2', 'Gene', '596', (143, 148))	('rs2279115', 'Mutation', 'rs2279115', (66, 75))	('influence', 'Reg', (89, 98))	('ESCC', 'Disease', (99, 103))	('apoptosis', 'CPA', (164, 173))	('BCL-2', 'Gene', (143, 148))	('expression', 'MPA', (149, 159))	('BCL-2', 'Gene', '596', (60, 65))	('regulating', 'Reg', (132, 142))	('rs2279115', 'Var', (66, 75))
686269	26132559	The BCL-2 rs2279115 polymorphism showed a consistent association with ESCC risk in two independent case-control cohorts.	('BCL-2', 'Gene', '596', (4, 9))	('association', 'Reg', (53, 64))	('rs2279115', 'Mutation', 'rs2279115', (10, 19))	('BCL-2', 'Gene', (4, 9))	('rs2279115', 'Var', (10, 19))	('ESCC', 'Disease', (70, 74))
686271	26132559	In conclusion, we demonstrated that functional BCL-2 rs2279115 SNP was associated with a significantly decreased risk of ESCC in Chinese populations, especially in nonsmokers or nondrinkers.	('rs2279115', 'Mutation', 'rs2279115', (53, 62))	('BCL-2', 'Gene', (47, 52))	('decreased', 'NegReg', (103, 112))	('rs2279115 SNP', 'Var', (53, 66))	('ESCC', 'Disease', (121, 125))	('BCL-2', 'Gene', '596', (47, 52))
686272	26132559	Functional BCL-2 regulatory genetic variants contribute to susceptibility of esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('BCL-2', 'Gene', '596', (11, 16))	('susceptibility', 'Reg', (59, 73))	('BCL-2', 'Gene', (11, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('variants', 'Var', (36, 44))
686273	23707461	Central Adiposity Is Associated With Increased Risk of Esophageal Inflammation, Metaplasia, and Adenocarcinoma: A Systematic Review and Meta-analysis Central adiposity has been implicated as a risk factor for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), possibly promoting the progression from inflammation to metaplasia and neoplasia.	('esophageal adenocarcinoma', 'Disease', (238, 263))	('Metaplasia', 'Disease', 'MESH:D008679', (80, 90))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (238, 263))	('Adenocarcinoma', 'Disease', (96, 110))	('Esophageal Inflammation', 'Disease', (55, 78))	("Barrett's esophagus", 'Disease', (209, 228))	('inflammation to metaplasia and neoplasia', 'Disease', 'MESH:D007249', (311, 351))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (209, 228))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (96, 110))	('Esophageal Inflammation', 'Disease', 'MESH:D007249', (55, 78))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (238, 263))	('EAC', 'Phenotype', 'HP:0011459', (265, 268))	('Metaplasia', 'Disease', (80, 90))	('neoplasia', 'Phenotype', 'HP:0002664', (342, 351))	('BE', 'Phenotype', 'HP:0100580', (230, 232))	('Central', 'Var', (150, 157))	('Esophageal Inflammation', 'Phenotype', 'HP:0100633', (55, 78))
686302	23707461	The relation between central adiposity was stronger for long-segment BE as compared with shortsegment BE, which was based on pooled analysis of 5 studies.	('BE', 'Phenotype', 'HP:0100580', (69, 71))	('stronger', 'Reg', (43, 51))	('central adiposity', 'MPA', (21, 38))	('men', 'Species', '9606', (97, 100))	('long-segment', 'Var', (56, 68))	('men', 'Species', '9606', (64, 67))	('BE', 'Phenotype', 'HP:0100580', (102, 104))
686338	23826241	PLCE1 Polymorphism and Upper Gastrointestinal Cancer Risk: A Meta-Analysis In recent years, the PLCE1 rs2274223 polymorphism has been extensively investigated as a potential risk factor for upper gastrointestinal cancers, including squamous cell carcinoma (ESCC) and gastric cancer.	('PLCE1', 'Gene', '51196', (96, 101))	('Upper Gastrointestinal Cancer', 'Disease', (23, 52))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (232, 255))	('gastric cancer', 'Disease', (267, 281))	('Upper Gastrointestinal Cancer', 'Disease', 'MESH:D004067', (23, 52))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (190, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('squamous cell carcinoma', 'Disease', (232, 255))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('gastric cancer', 'Disease', 'MESH:D013274', (267, 281))	('rs2274223', 'Mutation', 'rs2274223', (102, 111))	('rs2274223', 'Var', (102, 111))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('Gastrointestinal Cancer', 'Phenotype', 'HP:0007378', (29, 52))	('risk', 'Reg', (174, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (232, 255))	('upper gastrointestinal cancers', 'Disease', (190, 220))	('PLCE1', 'Gene', (0, 5))	('gastric cancer', 'Phenotype', 'HP:0012126', (267, 281))	('PLCE1', 'Gene', '51196', (0, 5))	('PLCE1', 'Gene', (96, 101))
686339	23826241	A meta-analysis of 13 case-control studies was performed including more than 11,000 subjects with genotyped PLCE1 rs2274223 polymorphisms.	('PLCE1', 'Gene', (108, 113))	('PLCE1', 'Gene', '51196', (108, 113))	('rs2274223', 'Mutation', 'rs2274223', (114, 123))	('rs2274223 polymorphisms', 'Var', (114, 137))	('polymorphisms', 'Var', (124, 137))
686340	23826241	Odds ratios (OR) with 95% confidence intervals (CI) were employed to assess the association of the PLCE1 rs2274223 polymorphism with a susceptibility to ESCC or gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (161, 175))	('rs2274223', 'Mutation', 'rs2274223', (105, 114))	('rs2274223', 'Var', (105, 114))	('association', 'Interaction', (80, 91))	('PLCE1', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('gastric cancer', 'Disease', (161, 175))	('PLCE1', 'Gene', '51196', (99, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (161, 175))	('ESCC', 'Disease', (153, 157))
686341	23826241	A statistically significant increase in the risk of ESCC was associated with the PLCE1 rs2274223 polymorphism.	('rs2274223', 'Var', (87, 96))	('PLCE1', 'Gene', (81, 86))	('PLCE1', 'Gene', '51196', (81, 86))	('ESCC', 'Disease', (52, 56))	('rs2274223', 'Mutation', 'rs2274223', (87, 96))
686343	23826241	In a subgroup analysis, the PLCE1 rs2274223 polymorphism was found to be a very sensitive marker for gastric cardia cancer as shown by the homozygous genetic model (OR = 2.23), heterozygous genetic model(OR = 1.59) and allelic genetic model (OR = 1.47).	('gastric cardia cancer', 'Disease', (101, 122))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (101, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rs2274223', 'Mutation', 'rs2274223', (34, 43))	('rs2274223', 'Var', (34, 43))	('PLCE1', 'Gene', (28, 33))	('PLCE1', 'Gene', '51196', (28, 33))
686346	23826241	In this meta-analysis, the PLCE1 rs2274223 polymorphism was confirmed to have a statistically significant association with an increasing risk of ESCC and gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('rs2274223', 'Mutation', 'rs2274223', (33, 42))	('rs2274223', 'Var', (33, 42))	('association', 'Reg', (106, 117))	('gastric cancer', 'Disease', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (154, 168))	('PLCE1', 'Gene', (27, 32))	('PLCE1', 'Gene', '51196', (27, 32))	('ESCC', 'Disease', (145, 149))
686359	23826241	found that PLCE1 gene variants cause an early onset nephrotic syndrome in humans.	('nephrotic syndrome', 'Disease', 'MESH:D009404', (52, 70))	('nephrotic syndrome', 'Disease', (52, 70))	('nephrotic syndrome', 'Phenotype', 'HP:0000100', (52, 70))	('humans', 'Species', '9606', (74, 80))	('cause', 'Reg', (31, 36))	('PLCE1', 'Gene', (11, 16))	('variants', 'Var', (22, 30))	('PLCE1', 'Gene', '51196', (11, 16))
686361	23826241	In 2010, two large-scale GWASs simultaneously reported that a new susceptibility locus (rs2274223: A5780G), located in exon 26 of PLCE1, was strongly associated with the risk of ESCC and gastric cancer in Chinese populations.	('gastric cancer', 'Disease', (187, 201))	('gastric cancer', 'Disease', 'MESH:D013274', (187, 201))	('rs2274223', 'Mutation', 'rs2274223', (88, 97))	('rs2274223: A5780G', 'Var', (88, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (187, 201))	('PLCE1', 'Gene', (130, 135))	('PLCE1', 'Gene', '51196', (130, 135))	('ESCC', 'Disease', (178, 182))	('A5780G', 'Mutation', 'rs2274223', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('associated with', 'Reg', (150, 165))
686362	23826241	found that the rs2274223 polymorphism in PLCE1 was associated with a reduced risk of ESCC.	('PLCE1', 'Gene', (41, 46))	('PLCE1', 'Gene', '51196', (41, 46))	('rs2274223', 'Mutation', 'rs2274223', (15, 24))	('reduced', 'NegReg', (69, 76))	('rs2274223', 'Var', (15, 24))	('ESCC', 'Disease', (85, 89))
686363	23826241	Further, no association with gastric cancer was found in either a Polish or a US study  In this study, a systematic review and meta-analysis were performed to clarify these inconsistencies and to establish a comprehensive picture of the relationship between PLCE1 gene variants and the risk of ESCC and gastric cancer.	('gastric cancer', 'Disease', (303, 317))	('gastric cancer', 'Disease', (29, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (303, 317))	('ESCC', 'Disease', (294, 298))	('gastric cancer', 'Disease', 'MESH:D013274', (29, 43))	('gastric cancer', 'Phenotype', 'HP:0012126', (303, 317))	('variants', 'Var', (269, 277))	('gastric cancer', 'Phenotype', 'HP:0012126', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('PLCE1', 'Gene', (258, 263))	('PLCE1', 'Gene', '51196', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
686364	23826241	In addition, recent studies reported that a series of gene mutation such as adenosine diphosphate ribosyltransferase (ADPRT) and X-ray repair cross-complementing 1 (XRCC1), matrix metalloproteinases 2 (MMP-2), and cyclooxygenase-2 (COX-2) were only associated with the gastric cardia cancer.	('ADPRT', 'Gene', (118, 123))	('gastric cardia cancer', 'Disease', (269, 290))	('XRCC1', 'Gene', (165, 170))	('cyclooxygenase-2', 'Gene', '5743', (214, 230))	('mutation', 'Var', (59, 67))	('COX-2', 'Gene', '5743', (232, 237))	('adenosine diphosphate ribosyltransferase', 'Gene', (76, 116))	('X-ray repair cross-complementing 1', 'Gene', '7515', (129, 163))	('cyclooxygenase-2', 'Gene', (214, 230))	('matrix metalloproteinases 2', 'Gene', (173, 200))	('MMP-2', 'Gene', '4313', (202, 207))	('XRCC1', 'Gene', '7515', (165, 170))	('matrix metalloproteinases 2', 'Gene', '4313', (173, 200))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('X-ray repair cross-complementing 1', 'Gene', (129, 163))	('adenosine diphosphate ribosyltransferase', 'Gene', '142', (76, 116))	('COX-2', 'Gene', (232, 237))	('MMP-2', 'Gene', (202, 207))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (269, 290))	('ADPRT', 'Gene', '142', (118, 123))	('associated', 'Reg', (249, 259))
686365	23826241	So in this article we also made a stratified analysis and found that PLCE1 polymorphism is significantly associated with gastric cardia cancer but not with gastric non-cardia cancer.	('polymorphism', 'Var', (75, 87))	('gastric non-cardia cancer', 'Disease', 'MESH:D013274', (156, 181))	('gastric non-cardia cancer', 'Disease', (156, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (121, 142))	('associated', 'Reg', (105, 115))	('PLCE1', 'Gene', (69, 74))	('gastric cardia cancer', 'Disease', (121, 142))	('PLCE1', 'Gene', '51196', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
686366	23826241	The combination of key words was as follows: 'PLCE1 polymorphism', 'rs2274223', 'esophageal squamous cell carcinoma' or 'ESCC' and 'gastric cancer'.	("'gastric cancer", 'Disease', 'MESH:D013274', (131, 146))	('PLCE1', 'Gene', (46, 51))	('PLCE1', 'Gene', '51196', (46, 51))	('polymorphism', 'Var', (52, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	("'gastric cancer", 'Disease', (131, 146))	("'esophageal squamous cell carcinoma'", 'Disease', (80, 116))	('rs2274223', 'Mutation', 'rs2274223', (68, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	("'ESCC'", 'Disease', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	("'esophageal squamous cell carcinoma'", 'Disease', 'MESH:D000077277', (80, 116))
686367	23826241	The studies were selected based on the following inclusion criteria: 1) the studies evaluated the PLCE1 polymorphism and the risk of ESCC or gastric cancer; 2) all patients were histo-pathologically diagnosed as primary ESCC or gastric cancer; 3) the studies were case-control design; 4) the genotype distributions for both the cases and the controls were available for estimating odds ratios (OR) and 95% confidence intervals (CI); and 5) the studies met the assumptions for Hardy-Weinberg equilibrium (HWE).	('polymorphism', 'Var', (104, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (228, 242))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('gastric cancer', 'Disease', (228, 242))	('ESCC', 'Disease', (133, 137))	('Hardy-Weinberg equilibrium', 'Disease', (476, 502))	('PLCE1', 'Gene', (98, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (228, 242))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('PLCE1', 'Gene', '51196', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('patients', 'Species', '9606', (164, 172))	('gastric cancer', 'Disease', (141, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))
686368	23826241	The ORs and their corresponding 95% CIs were used to evaluate the association between the PLCE1 polymorphisms and the risk of ESCC or gastric cancer.	('PLCE1', 'Gene', (90, 95))	('PLCE1', 'Gene', '51196', (90, 95))	('association', 'Interaction', (66, 77))	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('ESCC', 'Disease', (126, 130))	('polymorphisms', 'Var', (96, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))
686371	23826241	Eight studies examining ESCC were included for the evaluation of the association with the PLCE1 rs2274223 polymorphism.	('rs2274223', 'Mutation', 'rs2274223', (96, 105))	('rs2274223', 'Var', (96, 105))	('PLCE1', 'Gene', (90, 95))	('PLCE1', 'Gene', '51196', (90, 95))	('association', 'Interaction', (69, 80))	('ESCC', 'Disease', (24, 28))
686373	23826241	Statistically significant associations were found between the occurrence of the rs2274223 polymorphism and increased gastric cancer risk under the homozygous genetic model (GG vs. AA: OR = 1.52, 95% CI: 1.12-2.06, p = 0.007), and the heterozygous genetic model (GA vs. AA: OR = 1.29, 95% CI: 1.16-1.44, p = 0.000).	('rs2274223', 'Mutation', 'rs2274223', (80, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('rs2274223', 'Var', (80, 89))	('increased gastric', 'Phenotype', 'HP:0005207', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastric cancer', 'Disease', (117, 131))	('increased gastric cancer', 'Phenotype', 'HP:0006753', (107, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))
686375	23826241	Consequently, analyses were performed examining the association between the rs2274223 polymorphism and the risk of both gastric cardia cancer and non-cardia gastric cancer.	('non-cardia gastric cancer', 'Disease', (146, 171))	('gastric cancer', 'Phenotype', 'HP:0012126', (157, 171))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (120, 141))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('rs2274223', 'Var', (76, 85))	('gastric cardia cancer', 'Disease', (120, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('association', 'Interaction', (52, 63))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (146, 171))	('rs2274223', 'Mutation', 'rs2274223', (76, 85))
686379	23826241	The results of the meta-analysis result showed that the rs2274223 polymorphism genotype might have an association with decreased non-cardia gastric cancer risk.	('rs2274223', 'Var', (56, 65))	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('decreased', 'NegReg', (119, 128))	('non-cardia gastric cancer', 'Disease', (129, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (129, 154))	('rs2274223', 'Mutation', 'rs2274223', (56, 65))
686383	23826241	Because mutations in the RAS gene family are associated with approximately 30% of all human cancers, several studies have investigated the possible role of PLCE1 mutations in cancer development and progression.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('human', 'Species', '9606', (86, 91))	('mutations', 'Var', (8, 17))	('associated', 'Reg', (45, 55))	('PLCE1', 'Gene', (156, 161))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('PLCE1', 'Gene', '51196', (156, 161))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
686384	23826241	PLCE1 has been reported to have multiple mutation points such as rs2274223, rs11187870 and rs3765524.	('rs3765524', 'Var', (91, 100))	('rs11187870', 'Var', (76, 86))	('PLCE1', 'Gene', (0, 5))	('rs3765524', 'Mutation', 'rs3765524', (91, 100))	('rs11187870', 'Mutation', 'rs11187870', (76, 86))	('PLCE1', 'Gene', '51196', (0, 5))	('rs2274223', 'Mutation', 'rs2274223', (65, 74))	('rs2274223', 'Var', (65, 74))
686385	23826241	All these studies discussed the relationship between the rs2274223 gene variant and the ESCC or gastric cancer risk.	('ESCC', 'Disease', (88, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs2274223', 'Mutation', 'rs2274223', (57, 66))	('rs2274223', 'Var', (57, 66))	('gastric cancer', 'Disease', (96, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))
686386	23826241	However, the rs11187870 and rs3765524 gene variants have been studied less.	('rs11187870', 'Mutation', 'rs11187870', (13, 23))	('rs3765524', 'Var', (28, 37))	('rs11187870', 'Var', (13, 23))	('rs3765524', 'Mutation', 'rs3765524', (28, 37))
686387	23826241	This meta-analysis only examines the association between the rs2274223 gene variant and the ESCC and gastric cancer risk.	('ESCC', 'Disease', (92, 96))	('gastric cancer', 'Disease', (101, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('rs2274223', 'Mutation', 'rs2274223', (61, 70))	('rs2274223', 'Var', (61, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
686388	23826241	PLCE1 rs2274223 is a non-synonymous SNP with an A to G transition in exon 26, which results in the substitution of a histidine for an arginine.	('substitution', 'Var', (99, 111))	('arginine', 'Chemical', 'MESH:D001120', (134, 142))	('rs2274223', 'Mutation', 'rs2274223', (6, 15))	('PLCE1', 'Gene', (0, 5))	('PLCE1', 'Gene', '51196', (0, 5))	('rs2274223', 'Var', (6, 15))	('histidine', 'Chemical', 'MESH:D006639', (117, 126))	('histidine', 'MPA', (117, 126))
686389	23826241	In this meta-analysis, we confirmed that PLCE1 rs2274223 was associated with an increase in the risk of ESCC under all the genetic models including the homozygous genetic model (OR = 1.46), heterozygous genetic model (OR = 1.25) and allelic genetic model (OR = 1.23).	('PLCE1', 'Gene', (41, 46))	('PLCE1', 'Gene', '51196', (41, 46))	('rs2274223', 'Mutation', 'rs2274223', (47, 56))	('rs2274223', 'Var', (47, 56))	('ESCC', 'Disease', (104, 108))
686390	23826241	Furthermore, it was also demonstrated that PLCE1 rs2274223 was a notable signal for susceptibility to gastric cancer under the homozygous genetic model (OR = 1.52) and the heterozygous genetic model (OR = 1.29).	('rs2274223', 'Mutation', 'rs2274223', (49, 58))	('rs2274223', 'Var', (49, 58))	('PLCE1', 'Gene', (43, 48))	('gastric cancer', 'Disease', (102, 116))	('PLCE1', 'Gene', '51196', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('susceptibility', 'Reg', (84, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (84, 116))
686394	23826241	This meta-analysis confirmed that PLCE1 rs2274223 was associated with an increase in the risks of ESCC and gastric cancer, especially gastric cardia cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('rs2274223', 'Mutation', 'rs2274223', (40, 49))	('ESCC', 'Disease', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('especially gastric cardia cancer', 'Disease', (123, 155))	('rs2274223', 'Var', (40, 49))	('PLCE1', 'Gene', (34, 39))	('gastric cancer', 'Disease', (107, 121))	('PLCE1', 'Gene', '51196', (34, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))	('especially gastric cardia cancer', 'Disease', 'MESH:D013274', (123, 155))
686395	23826241	Recently, another study found that PLCE1 rs2274223 was associated with survival following a gastric cancer diagnosis.	('PLCE1', 'Gene', '51196', (35, 40))	('rs2274223', 'Var', (41, 50))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('associated with', 'Reg', (55, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('rs2274223', 'Mutation', 'rs2274223', (41, 50))	('PLCE1', 'Gene', (35, 40))
686396	23826241	These investigators examined a total of 938 gastric cancer patients and found that individuals carrying the PLCE1 rs2274223 AG/GG genotype had a higher survival rate than those carrying the AA genotype.	('PLCE1', 'Gene', (108, 113))	('PLCE1', 'Gene', '51196', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('rs2274223', 'Mutation', 'rs2274223', (114, 123))	('gastric cancer', 'Disease', (44, 58))	('survival rate', 'CPA', (152, 165))	('patients', 'Species', '9606', (59, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('rs2274223 AG/GG', 'Var', (114, 129))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('higher', 'PosReg', (145, 151))
686397	23826241	This suggested that the rs2274223 G allele might be associated with better prognosis in gastric cancer patients.	('rs2274223 G', 'Var', (24, 35))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('patients', 'Species', '9606', (103, 111))	('rs2274223', 'Mutation', 'rs2274223', (24, 33))
686398	23826241	It appears that although PLCE1 rs2274223 was associated with a high risk of gastric cancer, carriers of this genotypealso had a long survival.	('rs2274223', 'Var', (31, 40))	('high risk of gastric cancer', 'Phenotype', 'HP:0006753', (63, 90))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('PLCE1', 'Gene', '51196', (25, 30))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('PLCE1', 'Gene', (25, 30))	('rs2274223', 'Mutation', 'rs2274223', (31, 40))	('gastric cancer', 'Disease', (76, 90))
686399	23826241	However, the reason for this effect of the PLCE1 rs2274223 gene polymorphism is still unclear.	('rs2274223', 'Mutation', 'rs2274223', (49, 58))	('PLCE1', 'Gene', '51196', (43, 48))	('rs2274223', 'Var', (49, 58))	('PLCE1', 'Gene', (43, 48))
686400	23826241	found that the rs2274223 gene variant was more evident in males, non-smokers, non-drinkers and gastric cardia cancer patients.	('gastric cardia cancer', 'Disease', 'MESH:D013274', (95, 116))	('rs2274223', 'Mutation', 'rs2274223', (15, 24))	('rs2274223', 'Var', (15, 24))	('gastric cardia cancer', 'Disease', (95, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('patients', 'Species', '9606', (117, 125))
686401	23826241	In conclusion, this meta-analysis indicated that the PLCE1 rs2274223 polymorphism is associated with both ESCC and gastric cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('PLCE1', 'Gene', (53, 58))	('PLCE1', 'Gene', '51196', (53, 58))	('ESCC', 'Disease', (106, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('rs2274223', 'Mutation', 'rs2274223', (59, 68))	('rs2274223', 'Var', (59, 68))	('associated', 'Reg', (85, 95))	('gastric cancer', 'Disease', (115, 129))
686403	23826241	This meta-analysis found that the PLCE1 rs2274223 gene variant was linked to greater susceptibility for gastric cardia cancer.	('gastric cardia cancer', 'Disease', (104, 125))	('susceptibility', 'Reg', (85, 99))	('rs2274223', 'Mutation', 'rs2274223', (40, 49))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (104, 125))	('rs2274223', 'Var', (40, 49))	('PLCE1', 'Gene', (34, 39))	('PLCE1', 'Gene', '51196', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
686443	23349998	The persistent immune activation induced by T. cruzi has been related to a sustained increase in HIV replication, with several studies showing an increase in plasma HIV-1 viral load in patients with parasitemia, indicating reactivation of T. cruzi infection.	('cruzi infection', 'Disease', (242, 257))	('immune', 'MPA', (15, 21))	('plasma', 'MPA', (158, 164))	('T. cruzi', 'Var', (44, 52))	('HIV', 'Species', '12721', (165, 168))	('increase', 'PosReg', (146, 154))	('T. cruzi', 'Species', '5693', (239, 247))	('T. cruzi', 'Species', '5693', (44, 52))	('HIV replication', 'MPA', (97, 112))	('activation', 'PosReg', (22, 32))	('HIV', 'Species', '12721', (97, 100))	('parasitemia', 'Disease', (199, 210))	('parasitemia', 'Disease', 'MESH:D018512', (199, 210))	('patients', 'Species', '9606', (185, 193))	('HIV-1', 'Species', '11676', (165, 170))	('increase', 'PosReg', (85, 93))	('cruzi infection', 'Disease', 'MESH:D014355', (242, 257))
686444	23349998	Reactivation in immunosuppressed patients is usually associated with more severe clinical manifestations (e.g., central nervous system [CNS] involvement, chagomas, meningoencephalitis, and severe myocarditis) than those observed in immunocompetent patients with acute Chagas disease.	('myocarditis', 'Disease', (196, 207))	('patients', 'Species', '9606', (33, 41))	('central nervous system [', 'Disease', (112, 136))	('patients', 'Species', '9606', (248, 256))	('myocarditis', 'Phenotype', 'HP:0012819', (196, 207))	('encephalitis', 'Phenotype', 'HP:0002383', (171, 183))	('meningoencephalitis', 'Disease', (164, 183))	('Reactivation', 'Var', (0, 12))	('man', 'Species', '9606', (90, 93))	('meningoencephalitis', 'Disease', 'MESH:D008590', (164, 183))	('acute Chagas disease', 'Disease', 'MESH:D014355', (262, 282))	('myocarditis', 'Disease', 'MESH:D009205', (196, 207))	('chagomas', 'Disease', (154, 162))	('acute Chagas disease', 'Disease', (262, 282))
686522	23349998	(1999) Reactivation of Trypanosoma cruzi infection in patients with acquired immunodeficiency syndrome.	('Trypanosoma cruzi infection', 'Disease', 'MESH:D014355', (23, 50))	('patients', 'Species', '9606', (54, 62))	('Trypanosoma cruzi infection', 'Disease', (23, 50))	('Reactivation', 'Var', (7, 19))	('immunodeficiency syndrome', 'Disease', (77, 102))	('immunodeficiency', 'Phenotype', 'HP:0002721', (77, 93))	('immunodeficiency syndrome', 'Disease', 'MESH:D007153', (77, 102))
686625	31989043	The sepsis population was identified by secondary diagnoses using ICD-9-CM codes, namely 038, 038.0, 038.1, 038.2, 038.3, 038.4, 038.8, 038.9, 038.10, 038.11, 038.19, 038.40, 038.41, 038.42, 038.43, 038.44, 038.49, 790.7, and 996.62.	('sepsis', 'Disease', (4, 10))	('038.43', 'Var', (191, 197))	('sepsis', 'Phenotype', 'HP:0100806', (4, 10))	('sepsis', 'Disease', 'MESH:D018805', (4, 10))	('996.62', 'Var', (226, 232))
686650	31989043	In the 18-44 age group, the following characteristics of patients were associated with a relatively high risk of postoperative sepsis: male sex, low income, remote township, pancreatic surgery, diabetes, and cardiovascular dysfunction.	('postoperative sepsis', 'Disease', 'MESH:D018805', (113, 133))	('cardiovascular dysfunction', 'Phenotype', 'HP:0001626', (208, 234))	('patients', 'Species', '9606', (57, 65))	('sepsis', 'Phenotype', 'HP:0100806', (127, 133))	('pancreatic', 'Disease', 'MESH:D010195', (174, 184))	('diabetes', 'Disease', (194, 202))	('postoperative sepsis', 'Disease', (113, 133))	('cardiovascular dysfunction', 'Disease', (208, 234))	('cardiovascular dysfunction', 'Disease', 'MESH:D012735', (208, 234))	('pancreatic', 'Disease', (174, 184))	('associated', 'Reg', (71, 81))	('diabetes', 'Disease', 'MESH:D003920', (194, 202))	('low income', 'Var', (145, 155))
686652	31989043	In the >=65 age group, the high-risk characteristics postoperative sepsis were male sex, low income, agricultural town, splenic surgery, chronic renal disease, and cardiovascular dysfunction.	('cardiovascular dysfunction', 'Disease', (164, 190))	('postoperative sepsis', 'Disease', 'MESH:D018805', (53, 73))	('cardiovascular dysfunction', 'Disease', 'MESH:D012735', (164, 190))	('postoperative sepsis', 'Disease', (53, 73))	('low income', 'Var', (89, 99))	('chronic renal disease', 'Disease', 'MESH:D051436', (137, 158))	('cardiovascular dysfunction', 'Phenotype', 'HP:0001626', (164, 190))	('splenic surgery', 'Disease', (120, 135))	('chronic renal disease', 'Disease', (137, 158))	('chronic renal disease', 'Phenotype', 'HP:0003774', (137, 158))	('sepsis', 'Phenotype', 'HP:0100806', (67, 73))	('renal disease', 'Phenotype', 'HP:0000112', (145, 158))
686810	31417273	They also provide the evidence that Fusobacterium nucleatum DNA positivity is significantly associated with tumor stage and cancer-specific survival.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cancer', 'Disease', (124, 130))	('positivity', 'Var', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('Fusobacterium nucleatum', 'Species', '851', (36, 59))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Fusobacterium nucleatum', 'Gene', (36, 59))	('associated', 'Reg', (92, 102))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
686833	31417273	Individuals who have high levels of antibodies against Porphyromonas gingivalis ATTC 53,978 are at higher risk of pancreatic cancer.	('antibodies', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancer', 'Disease', (114, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('Porphyromonas gingivalis', 'Species', '837', (55, 79))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))
686834	31417273	Mitsuhashi et al find that Fusobacterium, an anaerobic, oral bacterium, can be detected in pancreatic cancer tissues and the presence of Fusobacterium colonization means shorter survival.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Fusobacterium', 'Species', '76859', (137, 150))	('presence', 'Var', (125, 133))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('shorter', 'NegReg', (170, 177))	('Fusobacterium', 'Species', '76859', (27, 40))	('pancreatic cancer', 'Disease', (91, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
686845	31417273	Porphyromonas gingivalis, and other oral bacteria, may have a significant role in the diseases of distant organs by causing inflammation and promoting tissue degenerative processes.	('causing', 'Reg', (116, 123))	('inflammation', 'Disease', (124, 136))	('Porphyromonas', 'Var', (0, 13))	('promoting', 'PosReg', (141, 150))	('tissue degenerative processes', 'CPA', (151, 180))	('Porphyromonas gingivalis', 'Species', '837', (0, 24))	('inflammation', 'Disease', 'MESH:D007249', (124, 136))
686853	31417273	In addition, Porphyromonas gingivalis could also induce inhibition of the host's immune system.	('Porphyromonas', 'Var', (13, 26))	('inhibition', 'CPA', (56, 66))	('Porphyromonas gingivalis', 'Species', '837', (13, 37))
686890	30816445	Effects of miR-106b-3p on cell proliferation and epithelial-mesenchymal transition, and targeting of ZNRF3 in esophageal squamous cell carcinoma Previous studies have demonstrated that the dysregulation of microRNAs (miRs) is frequently associated with cancer progression.	('ZNRF3', 'Gene', (101, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('associated', 'Reg', (237, 247))	('epithelial-mesenchymal transition', 'CPA', (49, 82))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('dysregulation', 'Var', (189, 202))	('miR-106b', 'Gene', (11, 19))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (110, 144))	('cancer', 'Disease', (253, 259))	('ZNRF3', 'Gene', '84133', (101, 106))	('microRNAs', 'Protein', (206, 215))	('miR-106b', 'Gene', '406900', (11, 19))	('esophageal squamous cell carcinoma', 'Disease', (110, 144))	('cell proliferation', 'CPA', (26, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
686905	30816445	miRNA (miR)-106b-3p has been reported to be deregulated in some types of cancer, including increased in laryngeal carcinoma, bladder cancer, hepatocellular carcinoma and renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (104, 123))	('cancer', 'Disease', (73, 79))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (170, 190))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('increased', 'PosReg', (91, 100))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (104, 123))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('cancer', 'Disease', (133, 139))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (141, 165))	('hepatocellular carcinoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (141, 190))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('miRNA (miR)-106b-3p', 'Var', (0, 19))	('laryngeal carcinoma', 'Disease', (104, 123))
686909	30816445	Increasing evidence has demonstrated that aberrant activation of the Wnt/beta-catenin signaling pathway promotes tumor progression in various types of human cancer.	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('beta-catenin', 'Gene', (73, 85))	('human', 'Species', '9606', (151, 156))	('aberrant', 'Var', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('beta-catenin', 'Gene', '1499', (73, 85))	('promotes', 'PosReg', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Disease', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('activation', 'PosReg', (51, 61))
686973	30816445	2D); the data demonstrated that the proliferation rate of cells was markedly increased by the transfection of miR-106b-3p mimics compared with the negative control, while that of cells in the miR-106b-3p inhibitors group was decreased.	('miR-106b', 'Gene', (192, 200))	('miR-106b', 'Gene', '406900', (192, 200))	('miR-106b', 'Gene', (110, 118))	('miR-106b', 'Gene', '406900', (110, 118))	('increased', 'PosReg', (77, 86))	('proliferation rate of cells', 'CPA', (36, 63))	('transfection', 'Var', (94, 106))
686975	30816445	These results indicated that miR-106b-3p silencing could suppress the proliferation of ESCC cells.	('miR-106b', 'Gene', '406900', (29, 37))	('silencing', 'Var', (41, 50))	('proliferation of', 'CPA', (70, 86))	('suppress', 'NegReg', (57, 65))	('ESCC', 'Disease', (87, 91))	('miR-106b', 'Gene', (29, 37))
686985	30816445	In addition, miR-106b-3p inhibitors markedly increased the expression of the epithelial marker E-cadherin (Fig.	('increased', 'PosReg', (45, 54))	('E-cadherin', 'Gene', (95, 105))	('miR-106b', 'Gene', '406900', (13, 21))	('E-cadherin', 'Gene', '999', (95, 105))	('expression', 'MPA', (59, 69))	('inhibitors', 'Var', (25, 35))	('miR-106b', 'Gene', (13, 21))
686989	30816445	The wound healing assay demonstrated that miR-106b-3p expression was positively associated with the rates of wound healing, and silencing of miR-106b-3p expression with slower healing (Fig.	('miR-106b', 'Gene', '406900', (141, 149))	('silencing', 'Var', (128, 137))	('miR-106b', 'Gene', (42, 50))	('miR-106b', 'Gene', (141, 149))	('associated', 'Reg', (80, 90))	('miR-106b', 'Gene', '406900', (42, 50))	('slower healing', 'CPA', (169, 183))	('wound healing', 'CPA', (109, 122))
687004	30816445	Inversely, silencing of miR-106b-3p increased p-GSK3 levels.	('silencing', 'Var', (11, 20))	('miR-106b', 'Gene', (24, 32))	('p-GSK3 levels', 'MPA', (46, 59))	('increased', 'PosReg', (36, 45))	('miR-106b', 'Gene', '406900', (24, 32))
687007	30816445	Recent evidence has indicated that alterations of specific miRNAs may be promising translational biomarker candidates in cancer.	('alterations', 'Var', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('miRNAs', 'Protein', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
687026	30816445	Dysregulation of the Wnt/beta-catenin pathway has been observed in various cancer typess and to regulate cancer metastasis.	('cancer metastasis', 'Disease', 'MESH:D009362', (105, 122))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('Dysregulation', 'Var', (0, 13))	('beta-catenin', 'Gene', '1499', (25, 37))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (75, 81))	('cancer metastasis', 'Disease', (105, 122))	('regulate', 'Reg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('observed', 'Reg', (55, 63))	('beta-catenin', 'Gene', (25, 37))
687101	28791287	MC eradication via TK inhibitors may also be a means to treat MC-driven diseases such as asthma.	('asthma', 'Disease', (89, 95))	('eradication', 'Var', (3, 14))	('asthma', 'Disease', 'MESH:D001249', (89, 95))	('asthma', 'Phenotype', 'HP:0002099', (89, 95))
687130	28791287	IL-5 targeting therapies resulted in a reduction of esophageal inflammation, but only in minimal symptom relief.	('targeting therapies', 'Var', (5, 24))	('IL-5', 'Gene', '3567', (0, 4))	('IL-5', 'Gene', (0, 4))	('reduction', 'NegReg', (39, 48))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (52, 75))	('esophageal inflammation', 'Disease', 'MESH:D007249', (52, 75))	('esophageal inflammation', 'Disease', (52, 75))
687196	28791287	Cutaneous mastocytosis is associated with gain-of-function Kit mutations in approximately 8% of cases.	('mutations', 'Var', (63, 72))	('Kit', 'Gene', (59, 62))	('Cutaneous mastocytosis', 'Disease', (0, 22))	('Cutaneous mastocytosis', 'Phenotype', 'HP:0200151', (0, 22))	('Cutaneous mastocytosis', 'Disease', 'MESH:D034701', (0, 22))	('gain-of-function', 'PosReg', (42, 58))	('mastocytosis', 'Phenotype', 'HP:0100495', (10, 22))
687197	28791287	Almost all patients with SM present a somatic mutation in codon 816 (D816V) of the gene encoding the receptor Kit, which leads to the substitution of a valine for an aspartate in the protein.	('valine for an aspartate', 'MPA', (152, 175))	('valine', 'Chemical', 'MESH:D014633', (152, 158))	('D816V', 'Mutation', 'rs121913507', (69, 74))	('leads to', 'Reg', (121, 129))	('substitution', 'Var', (134, 146))	('patients', 'Species', '9606', (11, 19))	('aspartate', 'Chemical', 'MESH:D001224', (166, 175))
687198	28791287	Because of the D816V mutation, Kit is constitutively active, resulting in autophosphorylation and enhancement of MC differentiation and survival.	('survival', 'CPA', (136, 144))	('autophosphorylation', 'MPA', (74, 93))	('D816V', 'Var', (15, 20))	('D816V', 'Mutation', 'rs121913507', (15, 20))	('enhancement', 'PosReg', (98, 109))	('MC differentiation', 'CPA', (113, 131))
687206	28791287	Indeed, even though less dense clusters of MCs compared to the typical multifocal aggregates of D816V Kit+ SM, in some cases MCs exhibited spindle-shaped morphology and aberrant surface expression of CD25, both minor criteria for SM according to the WHO criteria.	('CD25', 'Gene', '3559', (200, 204))	('D816V', 'Mutation', 'rs121913507', (96, 101))	('exhibited', 'Reg', (129, 138))	('aberrant', 'Var', (169, 177))	('CD25', 'Gene', (200, 204))	('spindle-shaped morphology', 'CPA', (139, 164))
687208	28791287	To date, FIP1L1-PDGFRA and D816V Kit mutations appear to be mutually exclusive.	('D816V', 'Var', (27, 32))	('D816V', 'Mutation', 'rs121913507', (27, 32))	('PDGFRA', 'Gene', '5156', (16, 22))	('PDGFRA', 'Gene', (16, 22))	('FIP1L1', 'Gene', '81608', (9, 15))	('FIP1L1', 'Gene', (9, 15))
687209	28791287	In the D816V Kit+ patients, gastrointestinal symptoms, urticaria pigmentosa, thrombocytosis, median serum tryptase value, and the presence of MC dense infiltrates in the bone marrow were increased compared to patients with FIP1L1-PDGFRA mutation.	('PDGFRA', 'Gene', '5156', (230, 236))	('PDGFRA', 'Gene', (230, 236))	('thrombocytosis', 'Disease', 'MESH:D013922', (77, 91))	('urticaria pigmentosa', 'Disease', (55, 75))	('gastrointestinal symptoms', 'Disease', (28, 53))	('increased', 'PosReg', (187, 196))	('thrombocytosis', 'Disease', (77, 91))	('FIP1L1', 'Gene', (223, 229))	('thrombocytosis', 'Phenotype', 'HP:0001894', (77, 91))	('median serum tryptase value', 'MPA', (93, 120))	('D816V', 'Var', (7, 12))	('D816V', 'Mutation', 'rs121913507', (7, 12))	('FIP1L1', 'Gene', '81608', (223, 229))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (18, 26))	('urticaria pigmentosa', 'Disease', 'MESH:D014582', (55, 75))	('urticaria', 'Phenotype', 'HP:0001025', (55, 64))	('Kit+', 'Gene', (13, 17))	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (28, 53))
687211	28791287	Whether a patient with peripheral eosinophilia and increased bone marrow MC infiltration carries a D816V Kit or FIP1L1-PDGFRA mutation is important for guiding therapeutic decisions.	('PDGFRA', 'Gene', '5156', (119, 125))	('FIP1L1', 'Gene', (112, 118))	('D816V', 'Mutation', 'rs121913507', (99, 104))	('FIP1L1', 'Gene', '81608', (112, 118))	('eosinophilia', 'Phenotype', 'HP:0001880', (34, 46))	('patient', 'Species', '9606', (10, 17))	('D816V Kit', 'Var', (99, 108))	('peripheral eosinophilia', 'Disease', (23, 46))	('PDGFRA', 'Gene', (119, 125))	('peripheral eosinophilia', 'Disease', 'MESH:D004802', (23, 46))
687212	28791287	Indeed, FIP1L1-PDGFRA mutation is highly sensitive to imatinib treatment, which induces clinical remission as early as 4 weeks.	('FIP1L1', 'Gene', (8, 14))	('mutation', 'Var', (22, 30))	('imatinib', 'Chemical', 'MESH:D000068877', (54, 62))	('PDGFRA', 'Gene', '5156', (15, 21))	('PDGFRA', 'Gene', (15, 21))	('FIP1L1', 'Gene', '81608', (8, 14))
687213	28791287	By contrast, the vast majority of SM carrying D816V Kit mutation are imatinib resistant and candidate to second-line tyrosine kinase inhibitors or cytoreductive therapy.	('D816V', 'Mutation', 'rs121913507', (46, 51))	('D816V Kit', 'Var', (46, 55))	('imatinib resistant', 'MPA', (69, 87))	('imatinib', 'Chemical', 'MESH:D000068877', (69, 77))
687229	28435293	The patients expressing low GRHL2 and high HIF-1alpha showed significant reduction in both overall survival rate and disease-free survival rate.	('GRHL2', 'Gene', '79977', (28, 33))	('overall survival rate', 'CPA', (91, 112))	('high', 'Var', (38, 42))	('HIF-1alpha', 'Gene', (43, 53))	('disease-free survival', 'CPA', (117, 138))	('patients', 'Species', '9606', (4, 12))	('low', 'Var', (24, 27))	('GRHL2', 'Gene', (28, 33))	('reduction', 'NegReg', (73, 82))	('HIF-1alpha', 'Gene', '3091', (43, 53))
687230	28435293	The results demonstrated that abnormal expression of GRHL2 is common in EC, and low expression of GRHL2 accompanied by a high expression of HIF-1alpha indicates poor prognosis.	('abnormal', 'Var', (30, 38))	('low', 'NegReg', (80, 83))	('GRHL2', 'Gene', (53, 58))	('HIF-1alpha', 'Gene', '3091', (140, 150))	('GRHL2', 'Gene', (98, 103))	('GRHL2', 'Gene', '79977', (53, 58))	('GRHL2', 'Gene', '79977', (98, 103))	('expression', 'MPA', (39, 49))	('expression', 'MPA', (84, 94))	('HIF-1alpha', 'Gene', (140, 150))
687239	28435293	It has been shown that GRHL1 regulates epidermal differentiation, as the Grhl1-/- mice has been found to exhibit palmoplantar keratoderma, impaired hair anchoring, and desmosomal abnormalities, whereas GRHL3 acts as a direct activator of PTEN expression, and deletion of GRHL3 in adult epidermis has been shown to result in aggressive squamous cell carcinoma induced by evoking of PI3K/AKT/mTOR signaling.	('aggressive squamous cell carcinoma', 'Disease', (324, 358))	('desmosomal abnormalities', 'Disease', 'MESH:D000014', (168, 192))	('desmosomal abnormalities', 'Disease', (168, 192))	('Grhl1', 'Gene', (73, 78))	('Grhl1', 'Gene', '195733', (73, 78))	('palmoplantar keratoderma', 'Disease', 'MESH:D007645', (113, 137))	('PTEN', 'Gene', '19211', (238, 242))	('GRHL3', 'Gene', (271, 276))	('mTOR', 'Gene', (390, 394))	('impaired hair anchoring', 'Disease', 'MESH:D009422', (139, 162))	('AKT', 'Gene', (386, 389))	('carcinoma', 'Phenotype', 'HP:0030731', (349, 358))	('mice', 'Species', '10090', (82, 86))	('deletion', 'Var', (259, 267))	('palmoplantar keratoderma', 'Disease', (113, 137))	('aggressive squamous cell carcinoma', 'Disease', 'MESH:D002294', (324, 358))	('impaired hair anchoring', 'Disease', (139, 162))	('AKT', 'Gene', '11651', (386, 389))	('evoking', 'Reg', (370, 377))	('palmoplantar keratoderma', 'Phenotype', 'HP:0000982', (113, 137))	('PTEN', 'Gene', (238, 242))	('mTOR', 'Gene', '56717', (390, 394))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (335, 358))
687258	28435293	Then, the slides were incubated with diluted antibodies (GRHL2, 1:100, ab86611 [Abcam, Cambridge, UK]; HIF-1alpha, 1:100, ab113642 [Abcam]; VEGF, 1:100, 19003-1-AP [Proteintech, Rosemont, IL, USA]; anti- CD34, 1:100, 60180-1-Ig [Proteintech]) overnight at 4 C. After incubation with the secondary antibody for 30 minutes, the sections were stained with 3,3'-diaminobenzidine.	('CD34', 'Gene', (204, 208))	('VEGF', 'Gene', '7422', (140, 144))	('HIF-1alpha', 'Gene', (103, 113))	('CD34', 'Gene', '947', (204, 208))	('GRHL2', 'Gene', (57, 62))	('HIF-1alpha', 'Gene', '3091', (103, 113))	('VEGF', 'Gene', (140, 144))	('ab113642 [', 'Var', (122, 132))	('GRHL2', 'Gene', '79977', (57, 62))
687271	28435293	The median DFS and OS (Figure 3) in low GRHL2 and high HIF-1alpha expression group were significantly shorter than that of other patients (including patients with low GRHL2 and low HIF-1alpha, high GRHL2 and high HIF-1alpha, and high GRHL2 and low HIF-1alpha expression).	('shorter', 'NegReg', (102, 109))	('HIF-1alpha', 'Gene', (55, 65))	('GRHL2', 'Gene', (234, 239))	('GRHL2', 'Gene', '79977', (234, 239))	('patients', 'Species', '9606', (149, 157))	('GRHL2', 'Gene', '79977', (40, 45))	('HIF-1alpha', 'Gene', '3091', (248, 258))	('patients', 'Species', '9606', (129, 137))	('HIF-1alpha', 'Gene', '3091', (181, 191))	('GRHL2', 'Gene', (167, 172))	('DFS', 'MPA', (11, 14))	('HIF-1alpha', 'Gene', '3091', (213, 223))	('GRHL2', 'Gene', '79977', (167, 172))	('HIF-1alpha', 'Gene', '3091', (55, 65))	('high', 'Var', (50, 54))	('HIF-1alpha', 'Gene', (248, 258))	('GRHL2', 'Gene', (198, 203))	('GRHL2', 'Gene', (40, 45))	('GRHL2', 'Gene', '79977', (198, 203))	('HIF-1alpha', 'Gene', (181, 191))	('low', 'NegReg', (177, 180))	('HIF-1alpha', 'Gene', (213, 223))
687309	27818590	Oesophageal Cancer Collaborative Group conducted a quantitative meta-analysis using updated data from these five RCTs comprising 1147 patients to assess whether preoperative radiotherapy improves OS and whether it is differentially effective in patients defined by age, sex and tumour location (Figure 1).	('Oesophageal Cancer', 'Disease', 'MESH:D009369', (0, 18))	('patients', 'Species', '9606', (245, 253))	('tumour', 'Phenotype', 'HP:0002664', (278, 284))	('Oesophageal Cancer', 'Disease', (0, 18))	('patients', 'Species', '9606', (134, 142))	('tumour', 'Disease', 'MESH:D009369', (278, 284))	('radiotherapy', 'Var', (174, 186))	('tumour', 'Disease', (278, 284))	('improves', 'PosReg', (187, 195))	('Cancer', 'Phenotype', 'HP:0002664', (12, 18))	('OS', 'Chemical', '-', (196, 198))
687518	23456798	Silencing of miR-31 is also implicated in the aberrant activation of NF-kappaB signaling in tumors.	('miR-31', 'Gene', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('miR-31', 'Gene', '407035', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('NF-kappaB signaling', 'Pathway', (69, 88))	('Silencing', 'Var', (0, 9))	('tumors', 'Disease', (92, 98))	('activation', 'PosReg', (55, 65))
687519	23456798	Loss of miR-31 has been associated with defects in the p53 pathway and functions in serous ovarian cancer and other cancers.	('functions', 'Reg', (71, 80))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('defects', 'NegReg', (40, 47))	('serous ovarian cancer', 'Disease', (84, 105))	('miR-31', 'Gene', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (84, 105))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('Loss', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('miR-31', 'Gene', '407035', (8, 14))
687522	23456798	Ectopic miR-451 expression suppresses the in vitro proliferation and colony formation of NSCLC cells and the development of tumors in nude mice by enhancing apoptosis, which may be associated with the inactivation of the AKT signal pathway.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('apoptosis', 'CPA', (157, 166))	('miR-451', 'Gene', (8, 15))	('in vitro proliferation', 'CPA', (42, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('nude mice', 'Species', '10090', (134, 143))	('enhancing', 'PosReg', (147, 156))	('tumors', 'Disease', (124, 130))	('Ectopic', 'Var', (0, 7))	('suppresses', 'NegReg', (27, 37))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('NSCLC', 'Disease', (89, 94))
687557	33828156	It is well known that cancer development and progression are triggered by altered activities and dysregulated expression of genes that control cell proliferation and differentiation.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('dysregulated', 'Var', (97, 109))	('cancer', 'Disease', (22, 28))	('progression', 'CPA', (45, 56))	('expression', 'MPA', (110, 120))	('altered', 'Reg', (74, 81))	('triggered', 'Reg', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('activities', 'MPA', (82, 92))
687560	33828156	For example, approximately 20% of stomach and gastroesophageal junction cancers are associated with the amplification of the HER2 gene that is an important therapeutic target and predicts response to trastuzumab.	('HER2', 'Gene', (125, 129))	('HER2', 'Gene', '2064', (125, 129))	('gastroesophageal junction cancers', 'Disease', 'MESH:D009369', (46, 79))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('trastuzumab', 'Chemical', 'MESH:D000068878', (200, 211))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('associated', 'Reg', (84, 94))	('gastroesophageal junction cancers', 'Disease', (46, 79))	('amplification', 'Var', (104, 117))
687619	33828156	Likewise, the AUC of the downregulated genes are 0.9788 (standard deviation 0.0265) and 0.9770 (standard deviation 0.0114) for esophageal and stomach cancers respectively.	('stomach cancers', 'Disease', 'MESH:D013274', (142, 157))	('stomach cancers', 'Disease', (142, 157))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('0.9788', 'Var', (49, 55))	('stomach cancers', 'Phenotype', 'HP:0012126', (142, 157))	('stomach cancer', 'Phenotype', 'HP:0012126', (142, 156))	('esophageal', 'Disease', (127, 137))	('0.9770', 'Var', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
687620	33828156	Meanwhile, the classifier model using the random selected genes has the lowest AUC score 0.9280 with standard deviation of 0.1137 for esophageal cancer and 0.5603 with standard deviation of 0.1664 for stomach cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('0.5603', 'Var', (156, 162))	('stomach cancer', 'Disease', 'MESH:D013274', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('stomach cancer', 'Phenotype', 'HP:0012126', (201, 215))	('AUC score', 'MPA', (79, 88))	('stomach cancer', 'Disease', (201, 215))	('lowest', 'NegReg', (72, 78))	('esophageal cancer', 'Disease', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
687624	33828156	The abnormal gene expression plays a pivotal role in tumor development and progression.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('abnormal gene', 'Var', (4, 17))
687641	33828156	APOC2 mutations could cause hyperlipoproteinemia type IB, characterized by hypertriglyceridemia, xanthomas, and early atherosclerosis.	('cause', 'Reg', (22, 27))	('xanthomas', 'Disease', 'MESH:D014973', (97, 106))	('early atherosclerosis', 'Phenotype', 'HP:0004416', (112, 133))	('hyperlipoproteinemia type IB', 'Disease', 'MESH:D008072', (28, 56))	('atherosclerosis', 'Disease', (118, 133))	('hyperlipoproteinemia', 'Phenotype', 'HP:0010980', (28, 48))	('APOC2', 'Gene', (0, 5))	('hyperlipoproteinemia type IB', 'Disease', (28, 56))	('xanthomas', 'Disease', (97, 106))	('hypertriglyceridemia', 'Phenotype', 'HP:0002155', (75, 95))	('xanthomas', 'Phenotype', 'HP:0001114', (97, 106))	('hypertriglyceridemia', 'Disease', 'MESH:D015228', (75, 95))	('atherosclerosis', 'Phenotype', 'HP:0002621', (118, 133))	('hypertriglyceridemia', 'Disease', (75, 95))	('APOC2', 'Gene', '344', (0, 5))	('mutations', 'Var', (6, 15))	('atherosclerosis', 'Disease', 'MESH:D050197', (118, 133))
687653	33828156	High INHBA gene expression has shown to be associated with significantly poorer 5-year overall survival compared with low expression cases in patients with stomach cancer.	('INHBA', 'Gene', '3624', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('High', 'Var', (0, 4))	('INHBA', 'Gene', (5, 10))	('stomach cancer', 'Disease', 'MESH:D013274', (156, 170))	('poorer', 'NegReg', (73, 79))	('stomach cancer', 'Phenotype', 'HP:0012126', (156, 170))	('patients', 'Species', '9606', (142, 150))	('expression', 'MPA', (16, 26))	('stomach cancer', 'Disease', (156, 170))	('overall survival', 'MPA', (87, 103))
687660	33828156	Mutations in this gene may be involved in skeletal dysplasia and spinal degeneration, however, its role in cancer is not well understood.	('spinal degeneration', 'Disease', (65, 84))	('skeletal dysplasia', 'Phenotype', 'HP:0002652', (42, 60))	('involved', 'Reg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('skeletal dysplasia', 'Disease', (42, 60))	('skeletal dysplasia', 'Disease', 'MESH:C535858', (42, 60))	('spinal degeneration', 'Phenotype', 'HP:0007269', (65, 84))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
687670	33828156	Its dysregulation could promote cancer invasiveness and progression.	('cancer invasiveness', 'Disease', 'MESH:D009362', (32, 51))	('cancer invasiveness', 'Disease', (32, 51))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('promote', 'PosReg', (24, 31))
687673	33828156	Evidence suggests that genetic polymorphisms of this enzyme has been associated with the increased risk of the aerodigestive cancer triggered by alcohol consumption.	('genetic polymorphisms', 'Var', (23, 44))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('associated', 'Reg', (69, 79))	('alcohol', 'Chemical', 'MESH:D000438', (145, 152))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
687678	33828156	Consistent with our observation of its downregulation, promoter hypermethylation and downregulation of GPX3 in melanoma, stomach, head and neck, cervical and lung cancers suggest that GPX3 serves as a tumor suppressor in these cancers.	('GPX3', 'Gene', '2878', (103, 107))	('promoter hypermethylation', 'Var', (55, 80))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('downregulation', 'NegReg', (85, 99))	('tumor', 'Disease', (201, 206))	('cervical', 'Disease', (145, 153))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('lung cancers', 'Phenotype', 'HP:0100526', (158, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('stomach', 'Disease', (121, 128))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('lung cancers', 'Disease', 'MESH:D008175', (158, 170))	('GPX3', 'Gene', (184, 188))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('lung cancers', 'Disease', (158, 170))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('cancers', 'Disease', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('GPX3', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('GPX3', 'Gene', '2878', (184, 188))	('cancers', 'Disease', (227, 234))	('downregulation', 'NegReg', (39, 53))
687680	33828156	Dysregulation of CLEC3B has been reported in various epithelial cancers including stomach cancer.	('CLEC3B', 'Gene', (17, 23))	('CLEC3B', 'Gene', '7123', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('stomach cancer', 'Disease', 'MESH:D013274', (82, 96))	('reported', 'Reg', (33, 41))	('stomach cancer', 'Phenotype', 'HP:0012126', (82, 96))	('stomach cancer', 'Disease', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
687682	33828156	However, when they evaluated 328 patients with early-stage stomach cancer, high intratumoral tetranectin level was significantly associated with tumor invasion, lymph node metastasis, advanced TNM stage, and a shorter overall survival.	('tumor', 'Disease', (85, 90))	('associated with', 'Reg', (129, 144))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('patients', 'Species', '9606', (33, 41))	('stomach cancer', 'Phenotype', 'HP:0012126', (59, 73))	('stomach cancer', 'Disease', (59, 73))	('high', 'Var', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('shorter', 'NegReg', (210, 217))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('overall', 'MPA', (218, 225))	('lymph node metastasis', 'CPA', (161, 182))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tetranectin', 'Gene', '7123', (93, 104))	('tetranectin', 'Gene', (93, 104))	('stomach cancer', 'Disease', 'MESH:D013274', (59, 73))
687684	33828156	Impaired balance of complement activation could promote inflammation and tumorigenesis resulting in malignant cells proliferation, migration, invasiveness and metastasis.	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('migration', 'CPA', (131, 140))	('inflammation', 'Disease', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('malignant cells proliferation', 'CPA', (100, 129))	('tumor', 'Disease', (73, 78))	('promote', 'PosReg', (48, 55))	('Impaired', 'Var', (0, 8))
687725	33644048	These lesions could cause mutations and have detrimental effects on replication and transcription, which are thought to be the crucial antitumor activity of platinum-based drugs and ultimately lead to cellular apoptosis.	('replication', 'CPA', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('cause', 'Reg', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('mutations', 'Var', (26, 35))	('lesions', 'Var', (6, 13))	('platinum', 'Chemical', 'MESH:D010984', (157, 165))	('effects', 'Reg', (57, 64))	('transcription', 'MPA', (84, 97))	('lead to', 'Reg', (193, 200))
687751	33644048	Many factors contribute to the regulation of apoptosis, including the signal pathways (such as MAPK/ERK, PI3k/AKT, NF-kB, Nrf2, p53), the tumor microenvironment (TME) (including hypoxia-inducible factor, HIF), cancer-associated fibroblasts (CAFs), and epigenetic regulation.	('p53', 'Gene', '7157', (128, 131))	('tumor', 'Disease', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('AKT', 'Gene', (110, 113))	('hypoxia', 'Disease', 'MESH:D000860', (178, 185))	('HIF', 'Disease', (204, 207))	('contribute', 'Reg', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('p53', 'Gene', (128, 131))	('Nrf2', 'Gene', (122, 126))	('epigenetic regulation', 'Var', (252, 273))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('signal pathways', 'Pathway', (70, 85))	('apoptosis', 'CPA', (45, 54))	('HIF', 'Disease', 'None', (204, 207))	('AKT', 'Gene', '207', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('ERK', 'Gene', '5594', (100, 103))	('hypoxia', 'Disease', (178, 185))	('cancer', 'Disease', (210, 216))	('Nrf2', 'Gene', '4780', (122, 126))	('ERK', 'Gene', (100, 103))
687769	33644048	Antitumor drug resistance usually concentrates on alteration of drug influx and efflux, enhancement of drug deactivation, and mutation of the drug target.	('tumor', 'Disease', (4, 9))	('drug resistance', 'Phenotype', 'HP:0020174', (10, 25))	('mutation', 'Var', (126, 134))	('enhancement', 'PosReg', (88, 99))	('alteration', 'Reg', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('efflux', 'MPA', (80, 86))	('drug deactivation', 'MPA', (103, 120))	('drug influx', 'MPA', (64, 75))
687782	33644048	Therefore, patients with a mutant genotype associated with decreased MTHFR activity are more sensitive to 5-FU.	('5-FU', 'Chemical', 'MESH:D005472', (106, 110))	('mutant', 'Var', (27, 33))	('decreased', 'NegReg', (59, 68))	('MTHFR', 'Gene', '4524', (69, 74))	('sensitive to 5-FU', 'MPA', (93, 110))	('MTHFR', 'Gene', (69, 74))	('activity', 'MPA', (75, 83))	('patients', 'Species', '9606', (11, 19))
687784	33644048	Previous study has showed that inhibiting autophagy activity could enhance antitumor activity of 5-FU in colorectal cancers.	('tumor', 'Disease', (79, 84))	('colorectal cancers', 'Disease', (105, 123))	('inhibiting', 'Var', (31, 41))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('enhance', 'PosReg', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('5-FU', 'Chemical', 'MESH:D005472', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('colorectal cancers', 'Disease', 'MESH:D015179', (105, 123))	('autophagy activity', 'CPA', (42, 60))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
687802	33644048	The effects of antitumor activity could enhance in relation to drug dose increasing, however, the dose increasing not only promotes the drug's effectiveness but also increases cytotoxicity.	('dose increasing', 'Var', (98, 113))	('promotes', 'PosReg', (123, 131))	('cytotoxicity', 'Disease', 'MESH:D064420', (176, 188))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('increases', 'PosReg', (166, 175))	('effectiveness', 'MPA', (143, 156))	('tumor', 'Disease', (19, 24))	('cytotoxicity', 'Disease', (176, 188))
687809	33644048	In this progress, non-coding RNAs is the most common molecular pathway that dually mediate or inhibit PTX resistance.	('PTX resistance', 'MPA', (102, 116))	('mediate', 'Reg', (83, 90))	('PTX', 'Chemical', 'MESH:D017239', (102, 105))	('inhibit', 'NegReg', (94, 101))	('non-coding RNAs', 'Var', (18, 33))
687820	33644048	The molecular characterization of EAC is divided into four etiological/genetic subtypes based on gastric adenocarcinoma molecular characterization classification: (1) EBV-associated tumors; (2) Microsatellite instability (MSI) tumors commonly with PIK3CA, EGFR and human epidermal growth factor receptor 2 (HER2) mutations; (3) Genomically stable tumors, (4) Chromosomally instability (CIN) tumors with TP53 mutations as well as RTK/RAS, VEGFR, and p110 amplifications.	('HER2', 'Gene', (307, 311))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('adenocarcinoma', 'Disease', 'MESH:D000230', (105, 119))	('tumors', 'Disease', (391, 397))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('instability (CIN) tumors', 'Disease', 'MESH:D043171', (373, 397))	('human', 'Species', '9606', (265, 270))	('PIK3CA', 'Gene', '5290', (248, 254))	('TP53', 'Gene', (403, 407))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('EGFR', 'Gene', (439, 443))	('epidermal growth factor receptor 2', 'Gene', '2064', (271, 305))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', (347, 353))	('tumors', 'Disease', 'MESH:D009369', (391, 397))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('p110', 'Gene', (449, 453))	('EGFR', 'Gene', (256, 260))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('epidermal growth factor receptor 2', 'Gene', (271, 305))	('HER2', 'Gene', '2064', (307, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('p110', 'Gene', '100616443', (449, 453))	('TP53', 'Gene', '7157', (403, 407))	('PIK3CA', 'Gene', (248, 254))	('VEGFR', 'Gene', '3791', (438, 443))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('Chromosomally', 'Disease', (359, 372))	('EGFR', 'Gene', '1956', (439, 443))	('adenocarcinoma', 'Disease', (105, 119))	('tumors', 'Phenotype', 'HP:0002664', (391, 397))	('VEGFR', 'Gene', (438, 443))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('EAC', 'Phenotype', 'HP:0011459', (34, 37))	('EGFR', 'Gene', '1956', (256, 260))	('mutations', 'Var', (408, 417))
687824	33644048	The ESCC genomic characterization are divided into three molecular subtypes by The Cancer Genome Atlas Research Network: (1) the alteration in NrF2 pathway, which regulates adaptation to oxidative stressors including some carcinogens and some chemotherapy agents; (2) higher rates of mutation of NOTCH1 or ZNF750, more frequent inactivating alterations of KDM6A and KDM2D, CDK6 amplification, and inactivation of PTEN or PIK3R1; (3) No evidence for genetic deregulation of the cell cycle and only a few of TP53 mutations.	('NrF2', 'Gene', (143, 147))	('CDK6', 'Gene', '1021', (373, 377))	('KDM6A', 'Gene', '7403', (356, 361))	('TP53', 'Gene', (506, 510))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('PIK3R1', 'Gene', '5295', (421, 427))	('NrF2', 'Gene', '4780', (143, 147))	('ZNF750', 'Gene', '79755', (306, 312))	('CDK6', 'Gene', (373, 377))	('inactivation', 'NegReg', (397, 409))	('oxidative stressors', 'Phenotype', 'HP:0025464', (187, 206))	('ZNF750', 'Gene', (306, 312))	('Cancer', 'Disease', (83, 89))	('oxidative stress', 'Phenotype', 'HP:0025464', (187, 203))	('KDM6A', 'Gene', (356, 361))	('higher', 'PosReg', (268, 274))	('PTEN', 'Gene', (413, 417))	('TP53', 'Gene', '7157', (506, 510))	('PIK3R1', 'Gene', (421, 427))	('NOTCH1', 'Gene', (296, 302))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))	('mutation', 'Var', (284, 292))	('PTEN', 'Gene', '5728', (413, 417))	('NOTCH1', 'Gene', '4851', (296, 302))	('inactivating', 'MPA', (328, 340))
687864	33644048	Although targeted therapy is better tolerated than traditional chemotherapy, it does produce toxicity based on several main mechanisms.	('toxicity', 'Disease', 'MESH:D064420', (93, 101))	('toxicity', 'Disease', (93, 101))	('targeted therapy', 'Var', (9, 25))
687877	33644048	The increased PI3K signaling can be due to loss of function through gene mutations or deletion of NF1 or PTEN, or the activation of a wide range RTKs, EGFR, FGFR1, PGFR-beta etc..	('activation', 'PosReg', (118, 128))	('EGFR', 'Gene', '1956', (151, 155))	('EGFR', 'Gene', (151, 155))	('FGFR1', 'Gene', (157, 162))	('PI3K signaling', 'Pathway', (14, 28))	('PTEN', 'Gene', (105, 109))	('FGFR1', 'Gene', '2260', (157, 162))	('PTEN', 'Gene', '5728', (105, 109))	('NF1', 'Gene', (98, 101))	('NF1', 'Gene', '4763', (98, 101))	('gene mutations', 'Var', (68, 82))	('increased', 'PosReg', (4, 13))	('deletion', 'Var', (86, 94))
687891	33644048	Additional mutations in receptor tyrosine kinases, RAS, and PI3K pathways appear to the mechanism of both intrinsic and acquired resistance to HER2 inhibitor.	('receptor tyrosine kinases', 'Enzyme', (24, 49))	('mutations', 'Var', (11, 20))	('PI3K pathways', 'Pathway', (60, 73))	('HER2', 'Gene', (143, 147))	('HER2', 'Gene', '2064', (143, 147))	('RAS', 'Pathway', (51, 54))
687926	33644048	In previous studies, the most common immune-related adverse events (irAEs) of PD-1 inhibitors (pembrolizumab and nivolumab) were fatigue, pruritus, rash, and diarrhea.	('PD-1', 'Gene', (78, 82))	('rash', 'Disease', (148, 152))	('diarrhea', 'Phenotype', 'HP:0002014', (158, 166))	('nivolumab', 'Chemical', 'MESH:D000077594', (113, 122))	('pruritus', 'Phenotype', 'HP:0000989', (138, 146))	('diarrhea', 'Disease', (158, 166))	('fatigue', 'Disease', 'MESH:D005221', (129, 136))	('diarrhea', 'Disease', 'MESH:D003967', (158, 166))	('pruritus', 'Disease', (138, 146))	('rash', 'Disease', 'MESH:D005076', (148, 152))	('pembrolizumab', 'Chemical', 'MESH:C582435', (95, 108))	('pruritus', 'Disease', 'MESH:D011537', (138, 146))	('fatigue', 'Disease', (129, 136))	('rash', 'Phenotype', 'HP:0000988', (148, 152))	('fatigue', 'Phenotype', 'HP:0012378', (129, 136))	('inhibitors', 'Var', (83, 93))
687931	33644048	Furthermore, the proportion of patients with progressive disease were higher in the nivolumab group than that in chemotherapy group.	('nivolumab', 'Chemical', 'MESH:D000077594', (84, 93))	('progressive disease', 'CPA', (45, 64))	('patients', 'Species', '9606', (31, 39))	('nivolumab', 'Var', (84, 93))	('higher', 'PosReg', (70, 76))
687936	33644048	A variety of intrinsic and extrinsic factors are involved in tumor cell evasion from immune activation at the genetic, enzymatic, and cellular levels, such as the regulation of TME, intracellular protein mutations, oncogene signal transduction pathways, epigenetic changes, etc..	('mutations', 'Var', (204, 213))	('epigenetic changes', 'Var', (254, 272))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('TME', 'Gene', (177, 180))	('tumor', 'Disease', (61, 66))
687941	33644048	The abnormal expression or dysregulation of protein kinases is involved in different hallmarks of cancer including survival, motility, metabolism, angiogenesis, proliferation, resistance to standard therapies, and immunotherapies and escape of antitumor immune responses.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', (248, 253))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('protein kinases', 'Enzyme', (44, 59))	('metabolism', 'CPA', (135, 145))	('involved', 'Reg', (63, 71))	('motility', 'CPA', (125, 133))	('angiogenesis', 'CPA', (147, 159))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('dysregulation', 'Var', (27, 40))	('cancer', 'Disease', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('proliferation', 'CPA', (161, 174))
687942	33644048	PD-L1 overexpression can be a major hinderance for anti-PD-L1 therapy via overexpression tumor specific T-cells and apart from its immunosuppressive function.	('anti-PD-L1', 'Var', (51, 61))	('overexpression', 'PosReg', (74, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
687945	33644048	Either the alterations of receptor kinases in their activity, abundance, cellular distribution and/or regulation can affect the functioning of signal transduction routes and result in the constitutive activation of downstream kinases like PI3K/AKT, MAPK, EGFR, or JAK/STAT.	('alterations', 'Var', (11, 22))	('activation', 'PosReg', (201, 211))	('abundance', 'MPA', (62, 71))	('EGFR', 'Gene', (255, 259))	('EGFR', 'Gene', '1956', (255, 259))	('activity', 'MPA', (52, 60))	('MAPK', 'Pathway', (249, 253))	('AKT', 'Gene', (244, 247))	('JAK', 'Gene', (264, 267))	('AKT', 'Gene', '207', (244, 247))	('regulation', 'MPA', (102, 112))	('affect', 'Reg', (117, 123))	('functioning', 'MPA', (128, 139))	('JAK', 'Gene', '3716;3717', (264, 267))	('signal transduction routes', 'Pathway', (143, 169))
687946	33644048	Loss of B2M and defective IFN-gamma signaling are tightly associated with T cell-resistant phenotype and tumor-intrinsic determinants of resistance to immunotherapies.	('associated', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Loss', 'NegReg', (0, 4))	('T cell-resistant phenotype', 'Disease', (74, 100))	('IFN-gamma', 'Gene', (26, 35))	('B2M', 'Gene', '567', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IFN-gamma', 'Gene', '3458', (26, 35))	('B2M', 'Gene', (8, 11))	('tumor', 'Disease', (105, 110))	('defective', 'Var', (16, 25))
687948	33644048	Defective IFN-gamma signaling, such as through inactivating mutations in Janus kinases (JAK1 or JAK2) or in the interferon-gamma receptor 1 (IFNGR1), has also been suggested to relate to resistance of anti-PD-1 therapy.	('IFN-gamma', 'Gene', (10, 19))	('JAK1', 'Gene', (88, 92))	('Defective', 'NegReg', (0, 9))	('JAK2', 'Gene', '3717', (96, 100))	('JAK1', 'Gene', '3716', (88, 92))	('interferon-gamma receptor 1', 'Gene', '3459', (112, 139))	('IFNGR1', 'Gene', '3459', (141, 147))	('JAK2', 'Gene', (96, 100))	('inactivating mutations', 'Var', (47, 69))	('IFNGR1', 'Gene', (141, 147))	('interferon-gamma receptor 1', 'Gene', (112, 139))	('IFN-gamma', 'Gene', '3458', (10, 19))
688071	31936288	Internal and external factors like smoking, obesity, urbanization, genetic mutations, and prevalence of Helicobacter pylori and Hepatitis B and Hepatitis C viral infections could increase the risk of GI cancer.	('genetic mutations', 'Var', (67, 84))	('obesity', 'Disease', 'MESH:D009765', (44, 51))	('GI cancer', 'Phenotype', 'HP:0007378', (200, 209))	('Hepatitis', 'Phenotype', 'HP:0012115', (144, 153))	('obesity', 'Disease', (44, 51))	('p', 'Chemical', 'MESH:D010758', (117, 118))	('Helicobacter pylori', 'Species', '210', (104, 123))	('p', 'Chemical', 'MESH:D010758', (90, 91))	('p', 'Chemical', 'MESH:D010758', (146, 147))	('GI cancer', 'Disease', 'MESH:D004067', (200, 209))	('GI cancer', 'Disease', (200, 209))	('Hepatitis', 'Phenotype', 'HP:0012115', (128, 137))	('Helicobacter pylori', 'Disease', (104, 123))	('Hepatitis B and Hepatitis C viral infections', 'Disease', 'MESH:D006509', (128, 172))	('obesity', 'Phenotype', 'HP:0001513', (44, 51))	('increase', 'PosReg', (179, 187))	('p', 'Chemical', 'MESH:D010758', (130, 131))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
688084	31936288	The carcinogenesis of GI cancer occurs due to the accumulation of genetic variation of multiple genes such as tumor suppressors, mismatch repair genes, and oncogenes.	('GI cancer', 'Disease', (22, 31))	('p', 'Chemical', 'MESH:D010758', (140, 141))	('mismatch repair genes', 'Gene', (129, 150))	('p', 'Chemical', 'MESH:D010758', (119, 120))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('genetic variation', 'Var', (66, 83))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (4, 18))	('GI cancer', 'Phenotype', 'HP:0007378', (22, 31))	('p', 'Chemical', 'MESH:D010758', (118, 119))	('GI cancer', 'Disease', 'MESH:D004067', (22, 31))	('carcinogenesis', 'Disease', (4, 18))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
688118	31936288	Cancer mutations affect several mechanisms and pathways in the body (Figure 1).	('mutations', 'Var', (7, 16))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('affect', 'Reg', (17, 23))	('p', 'Chemical', 'MESH:D010758', (47, 48))
688159	31936288	A study performed on a Korean population showed an association between dietary lutein and the risk of colorectal cancer.	('colorectal cancer', 'Disease', (102, 119))	('lutein', 'Chemical', 'MESH:D014975', (79, 85))	('association', 'Interaction', (51, 62))	('dietary', 'Var', (71, 78))	('p', 'Chemical', 'MESH:D010758', (8, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('p', 'Chemical', 'MESH:D010758', (32, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('p', 'Chemical', 'MESH:D010758', (30, 31))
688175	31936288	In a gastric-induced carcinogens model, lycopene has been found to block the activity of carcinogenic cells through the upregulation of a reduced glutathione (GSH) dependent hepatic detoxification system, thus protecting cells from oxidative damage.	('lycopene', 'Chemical', 'MESH:D000077276', (40, 48))	('carcinogenic', 'Disease', 'MESH:D063646', (89, 101))	('hepatic detoxification system', 'Disease', (174, 203))	('p', 'Chemical', 'MESH:D010758', (210, 211))	('p', 'Chemical', 'MESH:D010758', (121, 122))	('carcinogenic', 'Disease', (89, 101))	('GSH', 'Chemical', 'MESH:D005978', (159, 162))	('p', 'Chemical', 'MESH:D010758', (176, 177))	('glutathione', 'Chemical', 'MESH:D005978', (146, 157))	('p', 'Chemical', 'MESH:D010758', (166, 167))	('activity', 'CPA', (77, 85))	('block', 'NegReg', (67, 72))	('lycopene', 'Var', (40, 48))	('upregulation', 'PosReg', (120, 132))	('hepatic detoxification system', 'Disease', 'MESH:D056486', (174, 203))	('oxidative damage', 'MPA', (232, 248))	('p', 'Chemical', 'MESH:D010758', (44, 45))
688218	31936288	The mechanisms by which garlic inhibits the growth of carcinogen cells include reduction of DNA adducts, regulation of cellular arrest, activation of metabolizing detoxification enzymes, and induction of differentiation and apoptosis.	('metabolizing', 'Enzyme', (150, 162))	('inhibits', 'NegReg', (31, 39))	('garlic', 'Var', (24, 30))	('differentiation', 'CPA', (204, 219))	('p', 'Chemical', 'MESH:D010758', (227, 228))	('DNA adducts', 'MPA', (92, 103))	('p', 'Chemical', 'MESH:D010758', (225, 226))	('regulation', 'MPA', (105, 115))	('activation', 'PosReg', (136, 146))	('apoptosis', 'CPA', (224, 233))	('cellular arrest', 'MPA', (119, 134))	('growth of carcinogen cells', 'CPA', (44, 70))	('induction', 'Reg', (191, 200))	('reduction', 'NegReg', (79, 88))	('garlic', 'Species', '4682', (24, 30))
688222	31936288	Moreover, consumption of garlic suppresses the activity of NF-kappaB by inhibiting phosphorylated P65 translocation (Figure 2).	('garlic', 'Species', '4682', (25, 31))	('p', 'Chemical', 'MESH:D010758', (34, 35))	('p', 'Chemical', 'MESH:D010758', (83, 84))	('suppresses', 'NegReg', (32, 42))	('NF-kappaB', 'Gene', '4790', (59, 68))	('phosphorylated P65 translocation', 'MPA', (83, 115))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('p', 'Chemical', 'MESH:D010758', (65, 66))	('inhibiting', 'NegReg', (72, 82))	('garlic', 'Var', (25, 31))	('p', 'Chemical', 'MESH:D010758', (35, 36))	('NF-kappaB', 'Gene', (59, 68))	('p', 'Chemical', 'MESH:D010758', (16, 17))	('activity', 'MPA', (47, 55))	('p', 'Chemical', 'MESH:D010758', (64, 65))
688223	31936288	In xenograft nude mice, administration of S-allylmercaptocysteine (SAMC) in combination with rapamycin (a macrolide compound) was found to enhance anticancer ability by suppressing tumor growth and inducing apoptosis (Table 1).	('p', 'Chemical', 'MESH:D010758', (119, 120))	('apoptosis', 'CPA', (207, 216))	('rat', 'Species', '10116', (32, 35))	('S-allylmercaptocysteine', 'Chemical', 'MESH:C086300', (42, 65))	('p', 'Chemical', 'MESH:D010758', (54, 55))	('S-allylmercaptocysteine', 'Var', (42, 65))	('p', 'Chemical', 'MESH:D010758', (171, 172))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('p', 'Chemical', 'MESH:D010758', (172, 173))	('SAMC', 'Gene', (67, 71))	('cancer', 'Disease', (151, 157))	('inducing', 'Reg', (198, 206))	('suppressing', 'NegReg', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('p', 'Chemical', 'MESH:D010758', (210, 211))	('p', 'Chemical', 'MESH:D010758', (208, 209))	('nude mice', 'Species', '10090', (13, 22))	('enhance', 'PosReg', (139, 146))	('rapamycin', 'Chemical', 'MESH:D020123', (93, 102))	('tumor', 'Disease', (181, 186))	('macrolide', 'Chemical', 'MESH:D018942', (106, 115))	('SAMC', 'Gene', '115286', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('p', 'Chemical', 'MESH:D010758', (95, 96))
688225	31936288	A meta-analysis study has indicated that the consumption of garlic is associated with reduced gastric cancer with a 95% confidence interval and a 0.53 odd ratio.	('reduced gastric cancer', 'Phenotype', 'HP:0006753', (86, 108))	('gastric cancer', 'Disease', (94, 108))	('reduced', 'NegReg', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('garlic', 'Var', (60, 66))	('p', 'Chemical', 'MESH:D010758', (51, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('garlic', 'Species', '4682', (60, 66))	('rat', 'Species', '10116', (155, 158))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))
688260	31936288	Gastric cancer cells treated with low molecular weight citrus pectin (LCP) have been found to suppress adhesion, aggregation, and metastasis of cancer cells.	('cancer', 'Disease', (8, 14))	('adhesion', 'CPA', (103, 111))	('suppress', 'NegReg', (94, 102))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('pectin', 'Chemical', 'MESH:D010368', (62, 68))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('metastasis of cancer', 'Disease', (130, 150))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('low molecular weight', 'Var', (34, 54))	('metastasis of cancer', 'Disease', 'MESH:D009362', (130, 150))	('aggregation', 'CPA', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
688289	31936288	In addition, human colorectal adenocarcinoma HT-29 cells treated with inositol hexaphosphate have been shown to induce apoptosis through the upregulation of BAX, caspase-3, and caspase-8 expression, and through the downregulation of Bcl-xl.	('caspase-8', 'Gene', '841', (177, 186))	('p', 'Chemical', 'MESH:D010758', (165, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('p', 'Chemical', 'MESH:D010758', (189, 190))	('downregulation', 'NegReg', (215, 229))	('apoptosis', 'CPA', (119, 128))	('p', 'Chemical', 'MESH:D010758', (180, 181))	('inositol', 'Var', (70, 78))	('induce', 'PosReg', (112, 118))	('p', 'Chemical', 'MESH:D010758', (83, 84))	('colorectal adenocarcinoma HT-29', 'Disease', 'MESH:D015179', (19, 50))	('caspase-8', 'Gene', (177, 186))	('p', 'Chemical', 'MESH:D010758', (122, 123))	('BAX', 'Gene', (157, 160))	('Bcl-xl', 'Gene', '598', (233, 239))	('upregulation', 'PosReg', (141, 153))	('BAX', 'Gene', '581', (157, 160))	('inositol hexaphosphate', 'Chemical', 'MESH:D010833', (70, 92))	('caspase-3', 'Gene', '836', (162, 171))	('Bcl-xl', 'Gene', (233, 239))	('colorectal adenocarcinoma HT-29', 'Disease', (19, 50))	('caspase-3', 'Gene', (162, 171))	('p', 'Chemical', 'MESH:D010758', (120, 121))	('p', 'Chemical', 'MESH:D010758', (142, 143))	('human', 'Species', '9606', (13, 18))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('expression', 'MPA', (187, 197))
688321	31936288	For example, administration of lycopene triggers five mechanisms, namely, it downregulates the NF-kappaB pathway and Wnt/beta-catenin, upregulates MAP-mediated protein kinase, detoxifies enzymes, and induces apoptosis.	('beta-catenin', 'Gene', (121, 133))	('downregulates', 'NegReg', (77, 90))	('p', 'Chemical', 'MESH:D010758', (101, 102))	('beta-catenin', 'Gene', '1499', (121, 133))	('detoxifies enzymes', 'MPA', (176, 194))	('lycopene', 'Var', (31, 39))	('p', 'Chemical', 'MESH:D010758', (100, 101))	('NF-kappaB', 'Gene', (95, 104))	('rat', 'Species', '10116', (21, 24))	('p', 'Chemical', 'MESH:D010758', (211, 212))	('p', 'Chemical', 'MESH:D010758', (209, 210))	('NF-kappaB', 'Gene', '4790', (95, 104))	('upregulates', 'PosReg', (135, 146))	('lycopene', 'Chemical', 'MESH:D000077276', (31, 39))	('p', 'Chemical', 'MESH:D010758', (35, 36))	('p', 'Chemical', 'MESH:D010758', (105, 106))	('p', 'Chemical', 'MESH:D010758', (136, 137))	('apoptosis', 'CPA', (208, 217))	('MAP-mediated protein kinase', 'Pathway', (147, 174))	('p', 'Chemical', 'MESH:D010758', (8, 9))	('p', 'Chemical', 'MESH:D010758', (160, 161))	('induces', 'Reg', (200, 207))
688389	31683690	MCo-3 to MCo-6 are not potent trypsin inhibitors, but can slightly inhibit cancer cell line MDA-MB-231.	('inhibit', 'NegReg', (67, 74))	('MCo-6', 'Gene', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('MCo-6', 'Chemical', '-', (9, 14))	('MCo-3', 'Chemical', '-', (0, 5))	('MCo-3', 'Var', (0, 5))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (92, 102))
688395	31683690	It has been proven that MSE can inhibit different tumors, which are listed in Table 2.	('MSE', 'Var', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('MSE', 'Chemical', '-', (24, 27))	('inhibit', 'NegReg', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
688421	31683690	When the concentration was 264.72 mug mL-1, the inhibitory rate of zebrafish neovascularization was 21.74%, and the apoptosis induction rate was 28.92%.	('mL-1', 'Gene', '23961', (38, 42))	('apoptosis induction', 'CPA', (116, 135))	('rat', 'Species', '10116', (16, 19))	('inhibitory', 'NegReg', (48, 58))	('264.72 mug', 'Var', (27, 37))	('rat', 'Species', '10116', (136, 139))	('rat', 'Species', '10116', (59, 62))	('zebrafish', 'Species', '7955', (67, 76))	('zebrafish neovascularization', 'CPA', (67, 95))	('mL-1', 'Gene', (38, 42))
688464	31683690	The extract induces A549 apoptosis through the mitochondrial pathway and inhibits metastasis by the STAT-3 and MMP-2 pathways.	('MMP-2', 'Gene', '4313', (111, 116))	('inhibits', 'NegReg', (73, 81))	('A549', 'Var', (20, 24))	('MMP-2', 'Gene', (111, 116))	('STAT-3', 'Gene', '6774', (100, 106))	('A549', 'Chemical', '-', (20, 24))	('metastasis', 'CPA', (82, 92))	('mitochondrial pathway', 'Pathway', (47, 68))	('STAT-3', 'Gene', (100, 106))
688472	31683690	It was found that it inhibited the proliferation of Kyse30, TE-13, Ecal09, and Kyse180 at the concentration of 20 mug mL-1.	('rat', 'Species', '10116', (101, 104))	('proliferation', 'CPA', (35, 48))	('mL-1', 'Gene', (118, 122))	('mL-1', 'Gene', '23961', (118, 122))	('Kyse180', 'Var', (79, 86))	('inhibited', 'NegReg', (21, 30))	('TE', 'Chemical', 'MESH:D013691', (60, 62))	('rat', 'Species', '10116', (42, 45))
688477	31683690	Simultaneously, CMSP could decrease the expression levels of C-myc and N-myc in Kyse30 cells dramatically.	('CMSP', 'Chemical', '-', (16, 20))	('C-myc', 'Gene', '4609', (61, 66))	('CMSP', 'Var', (16, 20))	('decrease', 'NegReg', (27, 35))	('C-myc', 'Gene', (61, 66))	('N-myc', 'Gene', '4613', (71, 76))	('expression levels', 'MPA', (40, 57))	('N-myc', 'Gene', (71, 76))
688511	31683690	Ovalbumin and MSE extract act in mice to induce higher specific antibody production, and ovalbumin-specific IgG titers are significantly increased among 50 to 100 mug.	('specific antibody production', 'MPA', (55, 83))	('Ovalbumin', 'Gene', '20723', (0, 9))	('ovalbumin', 'Gene', '20723', (89, 98))	('IgG', 'Gene', '16059', (108, 111))	('MSE extract', 'Chemical', '-', (14, 25))	('IgG', 'Gene', (108, 111))	('Ovalbumin', 'Gene', (0, 9))	('50 to 100 mug', 'Var', (153, 166))	('higher', 'PosReg', (48, 54))	('increased', 'PosReg', (137, 146))	('mice', 'Species', '10090', (33, 37))	('ovalbumin', 'Gene', (89, 98))
688513	31683690	MCoCI also can stimulate the proliferation of spleen cells, spleen lymphocytes, and bone marrow cells in the immune system, and promote the mitosis of spleen cells, which is usually accompanied by the induction of cytokines, such as IL-2.	('IL-2', 'Gene', '3558', (233, 237))	('MCo', 'Species', '3674', (0, 3))	('IL-2', 'Gene', (233, 237))	('rat', 'Species', '10116', (36, 39))	('proliferation', 'CPA', (29, 42))	('mitosis', 'CPA', (140, 147))	('promote', 'PosReg', (128, 135))	('stimulate', 'PosReg', (15, 24))	('MCoCI', 'Var', (0, 5))
688574	31560173	Moreover, SOX2 gain-of-function significantly promotes nuclear YAP1 expression in ESCC cells while silencing of SOX2 expression inhibits YAP1 activation.	('SOX2', 'Gene', (10, 14))	('YAP1', 'Gene', '10413', (137, 141))	('gain-of-function', 'PosReg', (15, 31))	('expression', 'MPA', (68, 78))	('YAP1', 'Gene', (63, 67))	('YAP1', 'Gene', '10413', (63, 67))	('inhibits', 'NegReg', (128, 136))	('nuclear', 'MPA', (55, 62))	('silencing', 'Var', (99, 108))	('promotes', 'PosReg', (46, 54))	('YAP1', 'Gene', (137, 141))
688576	31560173	Disruption of this SOX2-WWC1-YAP1 axis could be a therapeutic strategy for SOX2-dependent tumors.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('YAP1', 'Gene', '10413', (29, 33))	('YAP1', 'Gene', (29, 33))	('WWC1', 'Gene', '23286', (24, 28))	('WWC1', 'Gene', (24, 28))	('Disruption', 'Var', (0, 10))
688592	31560173	After blocking with 5% skimmed milk, the membranes were incubated with primary antibodies against SOX 2 (#2748, 1:500; Cell Signaling Technology), YAP1 (#14074, 1:1000; Cell Signaling Technology), TAZ (#4883, 1:1000; Cell Signaling Technology), beta-actin (1E9A3, 1:1000; ZSGB-BIO), alpha-tubulin (AF0001, Beyotime Biotechnology), Lamin B1 (AF1408, Beyotime Biotechnology), and appropriate peroxidase-conjugated secondary antibodies.	('SOX 2', 'Gene', '6657', (98, 103))	('beta-actin', 'Gene', '728378', (245, 255))	('beta-actin', 'Gene', (245, 255))	('YAP1', 'Gene', (147, 151))	('YAP1', 'Gene', '10413', (147, 151))	('Lamin B1', 'Gene', (331, 339))	('ZSGB', 'Chemical', '-', (272, 276))	('#14074', 'Var', (153, 159))	('alpha-tubulin', 'Gene', (283, 296))	('Lamin B1', 'Gene', '4001', (331, 339))	('alpha-tubulin', 'Gene', '10376', (283, 296))	('SOX 2', 'Gene', (98, 103))
688602	31560173	A substantial proportion of the samples (34 cases; 35.4%) exhibit co-amplification of the SOX2, ACTL6A, and TP63 loci, while WWC1, NF2, and YAP1, components of the Hippo-YAP1 signaling, were barely mutated among these patients (Figure 1A).	('YAP1', 'Gene', (140, 144))	('YAP1', 'Gene', '10413', (140, 144))	('WWC1', 'Gene', '23286', (125, 129))	('WWC1', 'Gene', (125, 129))	('patients', 'Species', '9606', (218, 226))	('Hippo', 'Gene', (164, 169))	('SOX2', 'Gene', (90, 94))	('ACTL6A', 'Gene', '86', (96, 102))	('NF2', 'Gene', (131, 134))	('YAP1', 'Gene', (170, 174))	('YAP1', 'Gene', '10413', (170, 174))	('TP63', 'Gene', '8626', (108, 112))	('Hippo', 'Gene', '37247', (164, 169))	('NF2', 'Gene', '4771', (131, 134))	('ACTL6A', 'Gene', (96, 102))	('co-amplification', 'Var', (66, 82))	('TP63', 'Gene', (108, 112))
688611	31560173	Quantification of this series of samples showed that nuclear YAP1 expression was higher in ESCC with high SOX2 scores than that with low expression of SOX2 (Figure 3C).	('ESCC', 'Disease', (91, 95))	('higher', 'PosReg', (81, 87))	('YAP1', 'Gene', '10413', (61, 65))	('expression', 'MPA', (66, 76))	('high', 'Var', (101, 105))	('nuclear', 'MPA', (53, 60))	('YAP1', 'Gene', (61, 65))
688612	31560173	Furthermore, nuclear YAP1 expression score was positively associated with elevated SOX2 (Pearson r = .313, P = .0025; Spearman r = .233, P = .0262; Figure 3D).	('expression', 'MPA', (26, 36))	('YAP1', 'Gene', (21, 25))	('YAP1', 'Gene', '10413', (21, 25))	('elevated', 'PosReg', (74, 82))	('nuclear', 'Var', (13, 20))	('SOX2', 'MPA', (83, 87))
688614	31560173	Among a panel of ESCC cell lines, the expression of endogenous SOX2 protein was low in Eca109 and EC9706 cells (Figure 4A).	('expression of endogenous', 'MPA', (38, 62))	('EC9706', 'CellLine', 'CVCL:E307', (98, 104))	('low', 'NegReg', (80, 83))	('EC9706', 'Var', (98, 104))
688619	31560173	Conversely, knockdown of SOX2 expression by shRNAs in KYSE150 cells inhibited the nuclear levels of YAP1, but not TAZ (Figure 4E,F), confirming the control of YAP1 localization by SOX2.	('nuclear levels', 'MPA', (82, 96))	('YAP1', 'Gene', (100, 104))	('YAP1', 'Gene', '10413', (100, 104))	('knockdown', 'Var', (12, 21))	('inhibited', 'NegReg', (68, 77))	('YAP1', 'Gene', (159, 163))	('YAP1', 'Gene', '10413', (159, 163))	('KYSE150', 'CellLine', 'CVCL:1348', (54, 61))	('SOX2', 'Gene', (25, 29))
688622	31560173	On the contrary, silencing of SOX2 by shRNA markedly reduced migration and invasion of KYSE150 cells (Figure 5D,E).	('shRNA', 'Gene', (38, 43))	('KYSE150', 'CellLine', 'CVCL:1348', (87, 94))	('reduced', 'NegReg', (53, 60))	('SOX2', 'Protein', (30, 34))	('silencing', 'Var', (17, 26))
688633	31560173	SOX2 has been described to promote tumor growth through activation of the AKT/mTORC1 signaling39 and to promote metastasis by activating the STAT3/HIF-1alpha pathway.40 Targeted silencing of SOX2 by an artificial transcription factor shows an anti-tumor effect in ESCC.41 In the present study, ectopic SOX2 expression promotes migration, invasion, and drug resistance of ESCC cells, while knockdown of SOX2 or WWC1 overexpression diminishes their migration ability and invasive potential.	('AKT', 'Gene', '207', (74, 77))	('migration ability', 'CPA', (447, 464))	('HIF-1alpha', 'Gene', '3091', (147, 157))	('tumor', 'Disease', (248, 253))	('ectopic', 'Var', (294, 301))	('STAT3', 'Gene', (141, 146))	('tumor', 'Disease', (35, 40))	('drug resistance', 'Phenotype', 'HP:0020174', (352, 367))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('HIF-1alpha', 'Gene', (147, 157))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('STAT3', 'Gene', '6774', (141, 146))	('SOX2', 'Gene', (302, 306))	('WWC1', 'Gene', '23286', (410, 414))	('WWC1', 'Gene', (410, 414))	('AKT', 'Gene', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('promotes', 'PosReg', (318, 326))	('invasive potential', 'CPA', (469, 487))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('diminishes', 'NegReg', (430, 440))	('migration', 'CPA', (327, 336))	('mTORC1', 'Gene', (78, 84))	('drug resistance', 'CPA', (352, 367))	('invasion', 'CPA', (338, 346))	('mTORC1', 'Gene', '382056', (78, 84))
688651	28118614	Because inappropriate delivery could potentially cause loco-regional relapse or excess toxicity.	('toxicity', 'Disease', 'MESH:D064420', (87, 95))	('toxicity', 'Disease', (87, 95))	('inappropriate', 'Var', (8, 21))	('cause', 'Reg', (49, 54))	('loco-regional relapse', 'CPA', (55, 76))
688733	27495065	It also induces gene deficiencies in the susceptibility to immune-mediated cholangiopathies, which might easily induce cancer.	('cholangiopathies', 'Disease', 'None', (75, 91))	('induce', 'Reg', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('induces', 'Reg', (8, 15))	('gene deficiencies', 'Var', (16, 33))	('cholangiopathies', 'Disease', (75, 91))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
688763	27495065	The cumulative incidence curve of developing digestive system cancer in individuals with BTI was significantly greater than the incidence curve in those without BTI (P <0.0001, by the log-rank test) (Fig.	('system cancer', 'Disease', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BTI', 'Var', (89, 92))	('greater', 'PosReg', (111, 118))	('BTI', 'Chemical', '-', (89, 92))	('system cancer', 'Disease', 'MESH:D009369', (55, 68))	('BTI', 'Chemical', '-', (161, 164))
688782	27495065	Several studies in cell culture and animal have shown that different kinds of bile acids like taurochenodeoxycholic acid may increase the production of reactive oxygen species (ROS) in cultured gastric carcinoma cells, whereas deoxycholic acid may induce apoptosis in cultured human gastric epithelial cells.	('bile acids', 'Chemical', 'MESH:D001647', (78, 88))	('taurochenodeoxycholic acid', 'Var', (94, 120))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (152, 175))	('increase', 'PosReg', (125, 133))	('induce', 'Reg', (248, 254))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (194, 211))	('ROS', 'Chemical', 'MESH:D017382', (177, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('apoptosis', 'CPA', (255, 264))	('gastric carcinoma', 'Disease', 'MESH:D013274', (194, 211))	('taurochenodeoxycholic acid', 'Chemical', 'MESH:D013655', (94, 120))	('production of reactive oxygen species', 'MPA', (138, 175))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (104, 120))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (227, 243))	('human', 'Species', '9606', (277, 282))	('gastric carcinoma', 'Disease', (194, 211))
688800	27495065	This study shows that patients with BTI may have increased risk of liver cancer (aHR: 1.53; 95% CI: 1.07-2.18).	('liver cancer', 'Disease', (67, 79))	('BTI', 'Var', (36, 39))	('BTI', 'Chemical', '-', (36, 39))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('liver cancer', 'Phenotype', 'HP:0002896', (67, 79))	('liver cancer', 'Disease', 'MESH:D006528', (67, 79))
688803	27495065	This study shows that BTI patients may increase the risk of the pancreatic cancer (aHR: 3.10; 95% CI: 1.20-8.03).	('BTI', 'Var', (22, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('patients', 'Species', '9606', (26, 34))	('BTI', 'Chemical', '-', (22, 25))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))
688808	27495065	An animal study has shown that unconjugated bile acids contribute to peri-ampullary tumor formation in the setting of an Apc mutation.	('Apc', 'Gene', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('Apc', 'Gene', '324', (121, 124))	('bile acids', 'Chemical', 'MESH:D001647', (44, 54))	('mutation', 'Var', (125, 133))
688850	27338463	The results of published epidemiological studies are controversial because most of the studies found no significant association between dietary flavonoid intake and esophageal cancer; whereas two studies showed that flavonoids were associated with had significant reductions in the risk of esophageal cancer.	('esophageal cancer', 'Disease', (165, 182))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('flavonoids', 'Var', (216, 226))	('flavonoids', 'Chemical', 'MESH:D005419', (216, 226))	('flavonoid', 'Chemical', 'MESH:D005419', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('esophageal cancer', 'Disease', (290, 307))	('reductions', 'NegReg', (264, 274))	('flavonoid', 'Chemical', 'MESH:D005419', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('esophageal cancer', 'Disease', 'MESH:D004938', (290, 307))
688887	27338463	The latest publication found that high intake of dietary flavonols was significantly related to a reduced risk of gastric cancer, not of esophageal cancer, which was same as our result of seven studies from four articles.	('gastric cancer', 'Disease', (114, 128))	('reduced', 'NegReg', (98, 105))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('high', 'Var', (34, 38))	('flavonols', 'Chemical', 'MESH:D044948', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('esophageal cancer', 'Disease', (137, 154))
688894	27338463	The present meta-analysis indicated that anthocyanidins intake was significantly reduced the risk of esophageal cancer.	('anthocyanidins', 'Var', (41, 55))	('anthocyanidins', 'Chemical', 'MESH:D000872', (41, 55))	('esophageal cancer', 'Disease', (101, 118))	('reduced', 'NegReg', (81, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
688959	24951515	Although a benign disease, there are reports in which EIPD has been associated with esophageal cancer.	('associated', 'Reg', (68, 78))	('EIPD', 'Var', (54, 58))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
689020	24379990	The ideal threshold value identified from the ROC curve for CEA was >3.34 with a sensitivity of 50% (95% CI: 35.5-64.5) and a specificity of 100% in patients with esophageal cancer.	('patients', 'Species', '9606', (149, 157))	('>3.34', 'Var', (68, 73))	('CEA', 'Gene', (60, 63))	('esophageal cancer', 'Disease', (163, 180))	('CEA', 'Gene', '1084', (60, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
689021	24379990	The ideal threshold value based on the ROC curve for CEA was >3.34 with a sensitivity of 44% (95% CI: 30.0-58.7) and a specificity of 100% in patients with gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('>3.34', 'Var', (61, 66))	('gastric cancer', 'Disease', (156, 170))	('gastric cancer', 'Disease', 'MESH:D013274', (156, 170))	('CEA', 'Gene', (53, 56))	('CEA', 'Gene', '1084', (53, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (156, 170))	('patients', 'Species', '9606', (142, 150))
689022	24379990	The ideal threshold value based on the ROC curve for CEA was >3.34 with a sensitivity of 76% (95% CI: 61.8-86.9) and a specificity of 100% in patients with colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (156, 168))	('colon cancer', 'Disease', 'MESH:D015179', (156, 168))	('>3.34', 'Var', (61, 66))	('colon cancer', 'Disease', (156, 168))	('CEA', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('CEA', 'Gene', '1084', (53, 56))	('patients', 'Species', '9606', (142, 150))
689024	24379990	CA19-9 exceeded the threshold value in 42% of patients with gastric cancer, with NPV of 63.29%, AUC of 0.679 (SE=0.05), and significance level of P<0.0011.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (46, 54))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('gastric cancer', 'Disease', (60, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('CA19-9', 'Var', (0, 6))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))
689025	24379990	CA19-9 was higher than the threshold value in 26% of patients with colon cancer, with NPV of 57.47%, AUC of 0.580 (SE=0.05), and significance level of P=0.1670.	('CA19-9', 'Var', (0, 6))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('patients', 'Species', '9606', (53, 61))	('colon cancer', 'Disease', 'MESH:D015179', (67, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('colon cancer', 'Disease', (67, 79))	('higher', 'PosReg', (11, 17))
689026	24379990	The ideal threshold point identified from the ROC curve for CA19-9 was >21.08, with a sensitivity of 48% (95% CI: 33.7-62.6) and a specificity of 72%.	('>21.08', 'Var', (71, 77))	('CA19-9', 'Chemical', 'MESH:C086528', (60, 66))	('CA19-9', 'Gene', (60, 66))
689027	24379990	The ideal threshold point for CA19-9 was >34.851, with a sensitivity of 44% (95% CI: 30.0-58.7) and a specificity of 100% in patients with gastric cancer.	('gastric cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('CA19-9', 'Gene', (30, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('CA19-9', 'Chemical', 'MESH:C086528', (30, 36))	('>34.851', 'Var', (41, 48))	('patients', 'Species', '9606', (125, 133))
689028	24379990	The ideal threshold point based on the ROC curve for CA19-9 was >34.851, with a sensitivity of 26% (95% CI: 14.6-40.3) and a specificity of 100% in patients with colon cancer.	('patients', 'Species', '9606', (148, 156))	('CA19-9', 'Gene', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colon cancer', 'Disease', (162, 174))	('>34.851', 'Var', (64, 71))	('CA19-9', 'Chemical', 'MESH:C086528', (53, 59))	('colon cancer', 'Phenotype', 'HP:0003003', (162, 174))	('colon cancer', 'Disease', 'MESH:D015179', (162, 174))
689068	24379990	found that patients positive for both CEA and CA19-9 had significantly higher frequencies of lymph node metastasis, deeper invasion by the tumor, lower rates of curative resection, and higher rates of hepatic metastasis.	('CEA', 'Gene', (38, 41))	('higher', 'PosReg', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('hepatic metastasis', 'Disease', (201, 219))	('CEA', 'Gene', '1084', (38, 41))	('CA19-9', 'Var', (46, 52))	('deeper invasion', 'CPA', (116, 131))	('hepatic metastasis', 'Disease', 'MESH:D009362', (201, 219))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('lower', 'NegReg', (146, 151))	('CA19-9', 'Chemical', 'MESH:C086528', (46, 52))	('curative resection', 'CPA', (161, 179))	('patients', 'Species', '9606', (11, 19))	('higher', 'PosReg', (185, 191))	('lymph node metastasis', 'CPA', (93, 114))
689081	24379990	CA19-9 does not cause cancer but rather is a protein shed by tumor cells, making it useful as a tumor marker for monitoring the course of the disease.	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CA19-9', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Disease', (61, 66))
689103	24379990	The decrease in hepatic elimination of CEA and CA19-9 is known to significantly influence the elevation of serum levels of tumor markers during hepatic metastasis.	('tumor', 'Disease', (123, 128))	('hepatic elimination', 'MPA', (16, 35))	('CA19-9', 'Chemical', 'MESH:C086528', (47, 53))	('CA19-9', 'Var', (47, 53))	('hepatic metastasis', 'Disease', (144, 162))	('decrease', 'NegReg', (4, 12))	('CEA', 'Gene', (39, 42))	('hepatic metastasis', 'Disease', 'MESH:D009362', (144, 162))	('CEA', 'Gene', '1084', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('influence', 'Reg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
689117	24379990	The high serum CEA detected through CRC screening programs should be considered a marker of malignancy, especially in patients with appropriate symptoms, which include diarrhoea or constipation, changes in stool consistency, narrow stools, rectal bleeding or blood in the stool, pain, cramps, or gas in the abdomen, pain during bowel movements, Irritable Bowel Syndrome (IBS), change in bowel habits, continual urges to defecate, weakness or fatigue, unexplained weight loss, shortness of breath, and iron deficiency anaemia.	('iron deficiency anaemia', 'Disease', (501, 524))	('IBS', 'Disease', (371, 374))	('weakness', 'Disease', 'MESH:D018908', (430, 438))	('diarrhoea', 'Phenotype', 'HP:0002014', (168, 177))	('pain', 'Disease', (279, 283))	('IBS', 'Disease', 'MESH:D043183', (371, 374))	('weight loss', 'Phenotype', 'HP:0001824', (463, 474))	('pain', 'Disease', 'MESH:D010146', (316, 320))	('cramps', 'Disease', (285, 291))	('CEA', 'Gene', '1084', (15, 18))	('malignancy', 'Disease', 'MESH:D009369', (92, 102))	('blood in the stool', 'Phenotype', 'HP:0025085', (259, 277))	('men', 'Species', '9606', (311, 314))	('shortness of breath', 'Phenotype', 'HP:0002098', (476, 495))	('constipation', 'Disease', 'MESH:D003248', (181, 193))	('high serum CEA', 'Phenotype', 'HP:0031029', (4, 18))	('pain', 'Phenotype', 'HP:0012531', (279, 283))	('weakness', 'Disease', (430, 438))	('Irritable Bowel Syndrome', 'Disease', 'MESH:D043183', (345, 369))	('weight loss', 'Disease', (463, 474))	('shortness of breath', 'Disease', (476, 495))	('iron deficiency anaemia', 'Phenotype', 'HP:0001891', (501, 524))	('bowel habits', 'Disease', 'MESH:D020323', (387, 399))	('changes', 'Var', (195, 202))	('cramps', 'Disease', 'MESH:D009120', (285, 291))	('fatigue', 'Disease', (442, 449))	('malignancy', 'Disease', (92, 102))	('weight loss', 'Disease', 'MESH:D015431', (463, 474))	('fatigue', 'Phenotype', 'HP:0012378', (442, 449))	('rectal bleeding', 'Disease', (240, 255))	('diarrhoea', 'Disease', (168, 177))	('pain', 'Disease', 'MESH:D010146', (279, 283))	('change', 'Reg', (377, 383))	('constipation', 'Disease', (181, 193))	('bowel habits', 'Disease', (387, 399))	('anaemia', 'Phenotype', 'HP:0001903', (517, 524))	('gas in the abdomen', 'Phenotype', 'HP:0001541', (296, 314))	('pain', 'Disease', (316, 320))	('diarrhoea', 'Disease', 'MESH:D003967', (168, 177))	('rectal bleeding', 'Disease', 'MESH:D006470', (240, 255))	('shortness of breath', 'Disease', 'MESH:D004417', (476, 495))	('men', 'Species', '9606', (338, 341))	('pain', 'Phenotype', 'HP:0012531', (316, 320))	('CEA', 'Gene', (15, 18))	('rectal bleeding', 'Phenotype', 'HP:0002573', (240, 255))	('fatigue', 'Disease', 'MESH:D005221', (442, 449))	('bowel movements', 'Disease', 'MESH:D009069', (328, 343))	('Irritable Bowel Syndrome', 'Disease', (345, 369))	('iron deficiency anaemia', 'Disease', 'MESH:D018798', (501, 524))	('constipation', 'Phenotype', 'HP:0002019', (181, 193))	('bowel movements', 'Disease', (328, 343))	('patients', 'Species', '9606', (118, 126))	('Irritable', 'Phenotype', 'HP:0000737', (345, 354))
689126	24379990	CA19-9 has not been advocated as a screening test for colorectal cancer.	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('CA19-9', 'Var', (0, 6))	('colorectal cancer', 'Disease', (54, 71))
689127	24379990	CA19-9 is increased in advanced stages of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('colorectal cancer', 'Disease', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CA19-9', 'Var', (0, 6))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))	('increased', 'PosReg', (10, 19))
689132	24379990	Inclusion of CA19-9, CA242, CA72-4, or hCGbeta in the model exhibited no improvement in diagnostic accuracy.	('CA242', 'Chemical', '-', (21, 26))	('CA72-4', 'Var', (28, 34))	('CA19-9', 'Var', (13, 19))	('men', 'Species', '9606', (80, 83))	('hCGbeta', 'Gene', (39, 46))	('CA242', 'Var', (21, 26))	('CA19-9', 'Chemical', 'MESH:C086528', (13, 19))
689181	21490897	The hypercoagulable state (antithrombin III deficiency, protein C/S deficiency, factor V Leiden mutation, prothrombin mutation, myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, pregnancy, and contraceptive use), tumor invasion, Behcet's disease, trauma, inflammatory bowel disease, and membranous obstruction comprise 75% of cases, and the remaining 25% of cases are idiopathic.	('prothrombin', 'Gene', (106, 117))	("Behcet's disease", 'Disease', 'MESH:D001528', (273, 289))	('membranous obstruction', 'Disease', (331, 353))	('trauma', 'Disease', 'MESH:D014947', (291, 297))	('antiphospholipid syndrome', 'Disease', (195, 220))	('paroxysmal nocturnal hemoglobinuria', 'Phenotype', 'HP:0004818', (158, 193))	('tumor', 'Disease', (257, 262))	('mutation', 'Var', (96, 104))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (299, 325))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (299, 325))	('antithrombin III deficiency', 'Phenotype', 'HP:0001976', (27, 54))	('hypercoagulable', 'Disease', (4, 19))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('inflammatory bowel disease', 'Disease', (299, 325))	('paroxysmal nocturnal hemoglobinuria', 'Disease', 'MESH:D006457', (158, 193))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (128, 156))	('antiphospholipid syndrome', 'Disease', 'MESH:D016736', (195, 220))	('hypercoagulable state', 'Phenotype', 'HP:0100724', (4, 25))	('hemoglobinuria', 'Phenotype', 'HP:0003641', (179, 193))	('factor V Leiden', 'Gene', '2153', (80, 95))	('III deficiency', 'Disease', 'MESH:C536044', (40, 54))	('III deficiency', 'Disease', (40, 54))	('antiphospholipid syndrome', 'Phenotype', 'HP:0003613', (195, 220))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('factor V Leiden', 'Gene', (80, 95))	("Behcet's disease", 'Disease', (273, 289))	('prothrombin', 'Gene', '2147', (106, 117))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (128, 156))	('membranous obstruction', 'Phenotype', 'HP:0031153', (331, 353))	('protein C/S deficiency', 'Disease', (56, 78))	('trauma', 'Disease', (291, 297))	('paroxysmal nocturnal hemoglobinuria', 'Disease', (158, 193))	('myeloproliferative disorders', 'Disease', (128, 156))	('protein C/S deficiency', 'Disease', 'MESH:D018455', (56, 78))
689255	19499338	GAD65 antibodies are found in 80% of patients with type 1 diabetes mellitus (usually in low titer) and in approximately 20% of patients with various organ-specific neurological disorders, including myasthenia gravis, Lambert-Eaton syndrome, autoimmune dysautonomias and encephalopathies.	('autoimmune dysautonomias', 'Disease', (241, 265))	('autoimmune dysautonomias', 'Phenotype', 'HP:0012332', (241, 265))	('patients', 'Species', '9606', (37, 45))	('neurological disorders', 'Disease', 'MESH:D009422', (164, 186))	('myasthenia gravis', 'Disease', (198, 215))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (51, 66))	('type 1 diabetes mellitus', 'Disease', 'MESH:D003922', (51, 75))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (58, 75))	('Lambert-Eaton syndrome', 'Disease', (217, 239))	('myasthenia', 'Phenotype', 'HP:0003473', (198, 208))	('encephalopathies', 'Disease', 'MESH:D001927', (270, 286))	('Lambert-Eaton syndrome', 'Disease', 'MESH:D015624', (217, 239))	('autoimmune dysautonomias', 'Disease', 'MESH:D054969', (241, 265))	('encephalopathies', 'Phenotype', 'HP:0001298', (270, 286))	('GAD65', 'Gene', (0, 5))	('type 1 diabetes mellitus', 'Disease', (51, 75))	('GAD65', 'Gene', '2572', (0, 5))	('encephalopathies', 'Disease', (270, 286))	('patients', 'Species', '9606', (127, 135))	('antibodies', 'Var', (6, 16))	('found', 'Reg', (21, 26))	('myasthenia gravis', 'Disease', 'MESH:D009157', (198, 215))	('neurological disorders', 'Disease', (164, 186))
689268	33179079	CIN85 gene silencing significantly inhibited TE1 cell proliferation, migration and invasion.	('CIN85', 'Gene', (0, 5))	('gene silencing', 'Var', (6, 20))	('invasion', 'CPA', (83, 91))	('inhibited', 'NegReg', (35, 44))	('TE1 cell proliferation', 'CPA', (45, 67))	('CIN85', 'Gene', '30011', (0, 5))	('migration', 'CPA', (69, 78))
689327	33179079	There was no significant difference in the overall survival rate between patients with low and high CIN85 expression.	('CIN85', 'Gene', '30011', (100, 105))	('high', 'Var', (95, 99))	('CIN85', 'Gene', (100, 105))	('patients', 'Species', '9606', (73, 81))	('low', 'Var', (87, 90))
689331	33179079	The mRNA and protein expression levels of CIN85 were decreased significantly in TE1-KD cells, as compared with the controls (Fig.	('decreased', 'NegReg', (53, 62))	('CIN85', 'Gene', (42, 47))	('TE1-KD cells', 'Var', (80, 92))	('CIN85', 'Gene', '30011', (42, 47))
689341	33179079	Tyrosine kinase receptor inhibitors have been used in combination with chemotherapeutic drugs, and inhibitors of vascular EGFR in combination with chemotherapy for the treatment of esophageal cancer; however, the two aforementioned agents have not achieved outstanding results.	('esophageal cancer', 'Disease', (181, 198))	('inhibitors', 'Var', (99, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
689352	33179079	On this basis, the present study further constructed CIN85-knockdown cell lines and found that the proliferation, migration and invasion of ESCC cells were significantly inhibited in the CIN85 knockdown group.	('knockdown', 'Var', (193, 202))	('migration', 'CPA', (114, 123))	('CIN85', 'Gene', '30011', (53, 58))	('CIN85', 'Gene', '30011', (187, 192))	('invasion of', 'CPA', (128, 139))	('CIN85', 'Gene', (53, 58))	('CIN85', 'Gene', (187, 192))	('inhibited', 'NegReg', (170, 179))
689386	32368284	The following histologic subtypes were included (1) adenocarcinoma (8050-8052, 8123, 8140-8147, 8210-8211, 8255, 8260-8263, 8310, 8480-8481, 8490, 8550, 8570-8575) (2) squamous cell carcinomas (8032, 8070-8077, 8083, 8094).	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (168, 192))	('squamous cell carcinomas', 'Disease', (168, 192))	('8140-8147', 'Var', (85, 94))	('8032', 'Var', (194, 198))	('8490', 'Var', (141, 145))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (168, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('adenocarcinoma', 'Disease', (52, 66))	('8050-8052', 'Var', (68, 77))	('8550', 'Var', (147, 151))	('adenocarcinoma', 'Disease', 'MESH:D000230', (52, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))	('8310', 'Var', (124, 128))
689417	31527584	PICOT knockdown led to a reduced H3K27me3 mark and a decrease in EED and EZH2 at the CCND2 gene promoter.	('reduced', 'NegReg', (25, 32))	('decrease', 'NegReg', (53, 61))	('H3K27me3 mark', 'Protein', (33, 46))	('EED', 'MPA', (65, 68))	('EZH2', 'Gene', '2146', (73, 77))	('CCND2', 'Gene', (85, 90))	('EZH2', 'Gene', (73, 77))	('knockdown', 'Var', (6, 15))	('CCND2', 'Gene', '894', (85, 90))
689418	31527584	In agreement, PICOT-deficient T cells exhibited a significant increase in CCND2 mRNA and protein expression.	('CCND2', 'Gene', (74, 79))	('CCND2', 'Gene', '894', (74, 79))	('PICOT-deficient', 'Var', (14, 29))	('expression', 'Species', '29278', (97, 107))	('increase', 'PosReg', (62, 70))
689421	31527584	Furthermore, high expression of PICOT and low expression of CCND2 correlated with poor patient survival in five different types of human tumors.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('patient survival', 'CPA', (87, 103))	('CCND2', 'Gene', (60, 65))	('human', 'Species', '9606', (131, 136))	('poor', 'NegReg', (82, 86))	('expression', 'Species', '29278', (18, 28))	('patient', 'Species', '9606', (87, 94))	('expression', 'MPA', (18, 28))	('expression', 'Species', '29278', (46, 56))	('CCND2', 'Gene', '894', (60, 65))	('low', 'NegReg', (42, 45))	('expression', 'MPA', (46, 56))	('PICOT', 'Var', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
689429	31527584	Its expression is upregulated in cardiac muscles in response to hypertrophic stimuli where PICOT attenuates the pressure overload-induced cardiac hypertrophy and increases ventricular function and cardiomyocyte contractility.	('hypertrophic', 'Disease', (64, 76))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (138, 157))	('expression', 'Species', '29278', (4, 14))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (138, 157))	('increases ventricular function', 'Disease', 'MESH:D018754', (162, 192))	('hypertrophic', 'Disease', 'MESH:D006984', (64, 76))	('pressure overload-induced', 'MPA', (112, 137))	('attenuates', 'NegReg', (97, 107))	('upregulated', 'PosReg', (18, 29))	('cardiac hypertrophy', 'Disease', (138, 157))	('PICOT', 'Var', (91, 96))	('increases ventricular function', 'Disease', (162, 192))	('cardiomyocyte contractility', 'CPA', (197, 224))
689437	31527584	Initial studies supported this hypothesis by demonstrating that PICOT knock-down in Jurkat T cells led to a reduced H3K27me3 at the PRC2 target gene, myelin transcription factor 1 (MYT1).	('H3K27me3', 'Protein', (116, 124))	('reduced', 'NegReg', (108, 115))	('MYT1', 'Gene', (181, 185))	('PICOT', 'Gene', (64, 69))	('knock-down', 'Var', (70, 80))	('myelin transcription factor 1', 'Gene', '4661', (150, 179))	('Jurkat T', 'CellLine', 'CVCL:0065', (84, 92))	('myelin transcription factor 1', 'Gene', (150, 179))	('MYT1', 'Gene', '4661', (181, 185))
689459	31527584	Furthermore, when the ChIP-qPCR was optimized for the PRC2 components, EZH2 and EED, the percentage input value for the PRC2 target genes was significantly higher when using either anti-EED (Fig.	('EZH2', 'Gene', (71, 75))	('EZH2', 'Gene', '2146', (71, 75))	('higher', 'PosReg', (156, 162))	('anti-EED', 'Var', (181, 189))
689461	31527584	Since the trimethylation of H3K27 is catalyzed by EZH2 and further propagated by the help of EED, we further tested whether PICOT knockdown might effect EZH2 and EED presence at PRC2 target genes.	('tested', 'Reg', (109, 115))	('knockdown', 'Var', (130, 139))	('effect', 'Reg', (146, 152))	('EZH2', 'Gene', '2146', (50, 54))	('EZH2', 'Gene', (153, 157))	('EZH2', 'Gene', '2146', (153, 157))	('H3K27', 'Protein', (28, 33))	('EZH2', 'Gene', (50, 54))
689469	31527584	Knock down of PICOT expression in Jurkat T cells increases cyclin D2 mRNA and protein expression levels Since PRC2-mediated trimethyation of H3K27 at specific gene loci can negatively regulate gene transcripiton, we tested whether the lower levels of EED, EZH2, and H3K27me3 at the CCND2 promoter in PICOT-deficient cells would also be reflected at the gene transcription and translation levels.	('EZH2', 'Gene', (256, 260))	('H3K27me3', 'Var', (266, 274))	('CCND2', 'Gene', '894', (282, 287))	('expression', 'Species', '29278', (86, 96))	('increases', 'PosReg', (49, 58))	('cyclin D2', 'Gene', '894', (59, 68))	('cyclin D2', 'Gene', (59, 68))	('tested', 'Reg', (216, 222))	('CCND2', 'Gene', (282, 287))	('Jurkat T', 'CellLine', 'CVCL:0065', (34, 42))	('regulate', 'Reg', (184, 192))	('EZH2', 'Gene', '2146', (256, 260))	('expression', 'Species', '29278', (20, 30))
689476	31527584	The current findings indicate that PICOT deficiency in Jurkat T cells correlates with hypomethylation of H3K27 at the CCND2 promoter, which results in upregulation of CCND2 gene transcription and translation, suggesting that PICOT might have a negative regulatory effect on the synthesis of cyclin D2.	('CCND2', 'Gene', '894', (167, 172))	('cyclin D2', 'Gene', '894', (291, 300))	('CCND2', 'Gene', (118, 123))	('hypomethylation', 'Var', (86, 101))	('transcription', 'MPA', (178, 191))	('CCND2', 'Gene', (167, 172))	('cyclin D2', 'Gene', (291, 300))	('CCND2', 'Gene', '894', (118, 123))	('deficiency', 'Var', (41, 51))	('H3K27', 'Protein', (105, 110))	('translation', 'MPA', (196, 207))	('upregulation', 'PosReg', (151, 163))	('PICOT', 'Gene', (35, 40))	('Jurkat T', 'CellLine', 'CVCL:0065', (55, 63))
689490	31527584	An independent analysis performed on T-ALL data from GSE62156, indicated a correlation of -0.3 (p = 0.016, N = 64; t-test on Pearson's product moment correlation coefficient) between PICOT and CCND2 expression.	('expression', 'Species', '29278', (199, 209))	('CCND2', 'Gene', (193, 198))	('expression', 'MPA', (199, 209))	('GSE62156', 'Var', (53, 61))	('CCND2', 'Gene', '894', (193, 198))
689503	31527584	The observation that PICOT deficiency results in embryonic lethality implicates PICOT in cellular functions that are critical for embryogenesis.	('embryonic lethality', 'Disease', 'MESH:D020964', (49, 68))	('embryonic lethality', 'Disease', (49, 68))	('deficiency', 'Var', (27, 37))	('implicates', 'Reg', (69, 79))	('PICOT', 'Gene', (21, 26))
689504	31527584	In addition, PICOT knockdown led to a slower growth rate of Jurkat T cells (Fig.	('slower', 'NegReg', (38, 44))	('knockdown', 'Var', (19, 28))	('Jurkat T', 'CellLine', 'CVCL:0065', (60, 68))	('PICOT', 'Gene', (13, 18))
689507	31527584	Furthermore, PICOT binding to EED had a positive effect on H3K27 methylation at the MYT1 PRC2 target gene.	('positive', 'PosReg', (40, 48))	('PICOT', 'Var', (13, 18))	('methylation', 'MPA', (65, 76))	('MYT1', 'Gene', '4661', (84, 88))	('H3K27', 'Protein', (59, 64))	('MYT1', 'Gene', (84, 88))
689510	31527584	We demonstrated that PICOT associates with the chromatin-residing EED and that PICOT knock-down leads to a reduced H3K27me3 mark and a decrease in EED and EZH2 at the CCND2 gene promoter.	('knock-down', 'Var', (85, 95))	('EED', 'MPA', (147, 150))	('CCND2', 'Gene', (167, 172))	('reduced', 'NegReg', (107, 114))	('EZH2', 'Gene', '2146', (155, 159))	('PICOT', 'Gene', (79, 84))	('EZH2', 'Gene', (155, 159))	('decrease', 'NegReg', (135, 143))	('CCND2', 'Gene', '894', (167, 172))	('H3K27me3', 'Protein', (115, 123))
689513	31527584	PICOT knockdown did not alter the global levels of H3K27me3 (not shown), as was demonstrated for other PRC2 auxiliary proteins, such as Jumonji and AT-rich interaction domain containing 2 (JARID2).	('knockdown', 'Var', (6, 15))	('JARID2', 'Gene', (189, 195))	('JARID2', 'Gene', '3720', (189, 195))
689514	31527584	A difference in the effect of PICOT knockdown on the two PRC2 target genes, CCND2 and HOXA2, is not surprising, since knockdown of other PRC2 associated proteins, such as the Polycomb-like proteins (PCL), were also found to desilence only selected PRC2 target genes.	('CCND2', 'Gene', (76, 81))	('knockdown', 'Var', (118, 127))	('CCND2', 'Gene', '894', (76, 81))	('HOXA2', 'Gene', (86, 91))	('HOXA2', 'Gene', '3199', (86, 91))
689526	31527584	This effect reflected hypermethylation at the CCND2 gene promoter region which is rarely observed in NAT samples.	('CCND2', 'Gene', '894', (46, 51))	('CCND2', 'Gene', (46, 51))	('reflected', 'Reg', (12, 21))	('hypermethylation', 'Var', (22, 38))
689532	31527584	More important, high expression of PICOT and low expression of CCND2 correlated with poor patient survival in five different types of human cancers, namely lung and pancreatic adenocarcinoma, glioblastoma, and breast and esophageal cancer.	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (165, 190))	('poor', 'NegReg', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('expression', 'Species', '29278', (21, 31))	('glioblastoma', 'Disease', 'MESH:D005909', (192, 204))	('expression', 'MPA', (49, 59))	('CCND2', 'Gene', (63, 68))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('CCND2', 'Gene', '894', (63, 68))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (165, 190))	('human', 'Species', '9606', (134, 139))	('pancreatic adenocarcinoma', 'Disease', (165, 190))	('glioblastoma', 'Disease', (192, 204))	('breast and esophageal cancer', 'Disease', 'MESH:D004938', (210, 238))	('PICOT', 'Var', (35, 40))	('lung', 'Disease', (156, 160))	('low', 'NegReg', (45, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (192, 204))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('expression', 'Species', '29278', (49, 59))	('expression', 'MPA', (21, 31))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('patient', 'Species', '9606', (90, 97))	('cancers', 'Disease', (140, 147))
689542	31527584	Rabbit mAbs anti-EZH2, anti-SUZ12, anti-trimethyl histone H3 (Lys 27, H3K27me3), anti-cyclin D2 and normal rabbit IgG were from Cell Signaling Technology Inc. (Danvers, MA).	('SUZ12', 'Gene', '23512', (28, 33))	('EZH2', 'Gene', (17, 21))	('cyclin D2', 'Gene', (86, 95))	('anti-trimethyl', 'Var', (35, 49))	('trimethyl histone', 'Chemical', '-', (40, 57))	('SUZ12', 'Gene', (28, 33))	('EZH2', 'Gene', '2146', (17, 21))	('Lys', 'Chemical', 'MESH:D008239', (62, 65))	('cyclin D2', 'Gene', '894', (86, 95))	('rabbit', 'Species', '9986', (107, 113))	('Rabbit', 'Species', '9986', (0, 6))
689585	31527584	Probe set 207506_at was used for PICOT and 200951_s_at was used for CCND2.	('200951_s_at', 'Var', (43, 54))	('CCND2', 'Gene', (68, 73))	('CCND2', 'Gene', '894', (68, 73))
689684	31496629	Mutation in ras gene is thought to promote carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (43, 57))	('carcinogenesis', 'Disease', (43, 57))	('ras', 'Gene', (12, 15))	('Mutation', 'Var', (0, 8))	('promote', 'PosReg', (35, 42))
689685	31496629	Victor et al evaluated 27 EC samples from a high incidence are in South Africa, and found no evidence of ras mutation, however the authours conclude that point mutation may not be directly involved but possibly involvement of ras via other mechanisms.	('men', 'Species', '9606', (218, 221))	('involvement', 'Reg', (211, 222))	('point mutation', 'Var', (154, 168))
689687	31496629	A mutation in MSH3 has been shown to promote carcinogenesis of the colon.	('mutation', 'Var', (2, 10))	('promote', 'PosReg', (37, 44))	('carcinogenesis of the colon', 'Disease', 'MESH:D063646', (45, 72))	('MSH3', 'Gene', (14, 18))	('carcinogenesis of the colon', 'Disease', (45, 72))	('MSH3', 'Gene', '4437', (14, 18))
689692	31496629	A mutation in these can result in carcinogenesis.	('mutation', 'Var', (2, 10))	('result in', 'Reg', (24, 33))	('carcinogenesis', 'Disease', (34, 48))	('carcinogenesis', 'Disease', 'MESH:D063646', (34, 48))
689693	31496629	Vogelsang et al, assessed the cumulative effects of polymorphisms in the DNA mismatch repair genes and tobacco smoking in EC risk in a South African population.	('DNA mismatch repair genes', 'Gene', (73, 98))	('tobacco', 'Species', '4097', (103, 110))	('polymorphisms', 'Var', (52, 65))
689694	31496629	In a mixed ancestry group, they found the MSH3 rs26279 G/G vs A/A or A/G genotype was positively associated with cancer (OR = 2.71, 95%CI: 1.34-5.50).	('rs26279 G/G', 'Var', (47, 58))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('associated', 'Reg', (97, 107))	('cancer', 'Disease', (113, 119))	('rs26279', 'Mutation', 'rs26279', (47, 54))	('MSH3', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('MSH3', 'Gene', '4437', (42, 46))
689695	31496629	Similar associations were observed for PMS1 rs5742938 (GG vs AA or AG: OR  =  1.73, 95%CI: 1.07-2.79) and MLH3 rs28756991 (AA or GA vs GG: OR  =  2.07; 95%CI: 1.04-4.12).	('MLH3', 'Gene', '27030', (106, 110))	('rs28756991', 'Var', (111, 121))	('MLH3', 'Gene', (106, 110))	('rs5742938', 'Var', (44, 53))	('PMS1', 'Gene', (39, 43))	('PMS1', 'Gene', '5378', (39, 43))	('rs28756991', 'Mutation', 'rs28756991', (111, 121))	('rs5742938', 'Mutation', 'rs5742938', (44, 53))
689696	31496629	In Black individuals, however, no association between MMR polymorphisms and cancer risk was observed in individual single nucleotide polymorphisms analysis).	('polymorphisms', 'Var', (58, 71))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
689697	31496629	In Blacks, rs6505162 A>C was associated with ESCC under dominant, additive and recessive models with ORs 1.353, 1.404, and 2.858, respectively.	('rs6505162 A>C', 'Var', (11, 24))	('rs6505162', 'Mutation', 'rs6505162', (11, 20))	('ESCC', 'Disease', (45, 49))	('associated', 'Reg', (29, 39))
689768	31496629	Host factors including mutation in genes coding for enzymes responsible for Alcohol and Acetaldehyde metabolism, and handling of oxidative stress in alcohol and contaminated food were found to be associated with EC and are important.	('Alcohol', 'Chemical', 'MESH:D000438', (76, 83))	('Acetaldehyde metabolism', 'Phenotype', 'HP:0003533', (88, 111))	('oxidative stress', 'Phenotype', 'HP:0025464', (129, 145))	('mutation', 'Var', (23, 31))	('associated', 'Reg', (196, 206))	('Acetaldehyde', 'Chemical', 'MESH:D000079', (88, 100))	('alcohol', 'Chemical', 'MESH:D000438', (149, 156))
689770	31496629	Exogenous or endogenous acetaldehyde as a product of alcohol and oral fermentation (poor dental hygiene) is carcinogenic.	('alcohol', 'Chemical', 'MESH:D000438', (53, 60))	('Exogenous', 'Var', (0, 9))	('men', 'Species', '9606', (73, 76))	('dental hygiene', 'Phenotype', 'HP:0000670', (89, 103))	('acetaldehyde', 'Chemical', 'MESH:D000079', (24, 36))	('carcinogenic', 'Disease', 'MESH:D063646', (108, 120))	('carcinogenic', 'Disease', (108, 120))
689773	31496629	ALDH2 polymorphism has been implicated in the development of oesophageal cancer.	('oesophageal cancer', 'Disease', 'MESH:D009369', (61, 79))	('polymorphism', 'Var', (6, 18))	('oesophageal cancer', 'Disease', (61, 79))	('ALDH2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('men', 'Species', '9606', (53, 56))	('implicated', 'Reg', (28, 38))	('ALDH2', 'Gene', '217', (0, 5))
689774	31496629	Genetic polymorphisms associated with modulation of oxidative stress, including N-acetyl transferases NAT1 and NAT2 mutations, Glutathione S transferase GSTT2B have been implicated in development of ESCC.	('GSTT2B', 'Gene', '653689', (153, 159))	('NAT2', 'Gene', '10', (111, 115))	('NAT1', 'Gene', (102, 106))	('implicated', 'Reg', (170, 180))	('GSTT2B', 'Gene', (153, 159))	('men', 'Species', '9606', (191, 194))	('NAT1', 'Gene', '9', (102, 106))	('mutations', 'Var', (116, 125))	('oxidative stress', 'Phenotype', 'HP:0025464', (52, 68))	('ESCC', 'Disease', (199, 203))	('NAT2', 'Gene', (111, 115))
689775	31496629	Somatic mutations including p53 and p16/CDKN2 genes and those associated with genetic polymorphisms associated with DNA repair like RUNX1 rs2014300 have been observed as an independent risk in some small studies.	('p53', 'Gene', (28, 31))	('CDKN2', 'Gene', '1029', (40, 45))	('rs2014300', 'Var', (138, 147))	('p53', 'Gene', '7157', (28, 31))	('CDKN2', 'Gene', (40, 45))	('RUNX1', 'Gene', (132, 137))	('p16', 'Gene', '1029', (36, 39))	('RUNX1', 'Gene', '861', (132, 137))	('rs2014300', 'Mutation', 'rs2014300', (138, 147))	('p16', 'Gene', (36, 39))
689805	31375656	Moreover, recent research has shown that abnormal expression of lncRNAs in malignant tumor cells before and after radiotherapy may participate in the progression of cancers and affect the radiation sensitivity of malignant tumor cells mediated by specific signaling pathways or cell cycle regulation.	('abnormal', 'Var', (41, 49))	('malignant tumor', 'Disease', 'MESH:D018198', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('malignant tumor', 'Disease', 'MESH:D018198', (213, 228))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('participate', 'Reg', (131, 142))	('lncRNAs', 'Protein', (64, 71))	('affect', 'Reg', (177, 183))	('malignant tumor', 'Disease', (75, 90))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('malignant tumor', 'Disease', (213, 228))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancers', 'Disease', (165, 172))	('expression', 'MPA', (50, 60))
689834	31375656	CSCs produce less gamma-H2AX after exposure, suggesting that the DNA repair ability of CSCs is significantly stronger than that of non-CSCs.	('gamma-H2AX', 'Protein', (18, 28))	('CSCs', 'Var', (87, 91))	('gamma-H2AX', 'Chemical', '-', (18, 28))	('less', 'NegReg', (13, 17))	('DNA repair ability', 'CPA', (65, 83))	('stronger', 'PosReg', (109, 117))
689848	31375656	The homologous recombination repair produces functional GFP by importing defect GFP, and silencing the expression of ANRIL reduced homologous recombination repair by 50%, thus we speculated ANRIL is necessary to the homologous recombination pathway.	('homologous recombination repair', 'MPA', (131, 162))	('ANRIL', 'Gene', (190, 195))	('ANRIL', 'Gene', '100048912', (117, 122))	('expression', 'MPA', (103, 113))	('silencing', 'Var', (89, 98))	('ANRIL', 'Gene', '100048912', (190, 195))	('ANRIL', 'Gene', (117, 122))	('reduced', 'NegReg', (123, 130))
689868	31375656	conducted the earliest study on lncRNAs associated with radiosensitivity in ESCC in 2014; they showed that tumor tissues had a relatively low expression of LOC285194 and displayed a larger tumor size, an advanced tumor TNM stage, a poorer histological grade, and more lymph node and distant metastases compared with normal adjacent tissue, and was significantly negatively correlated with the pathological response to radiotherapy, in contrast to the LOC285194-high group.	('tumor', 'Disease', (107, 112))	('CC', 'Phenotype', 'HP:0002664', (78, 80))	('negatively', 'NegReg', (362, 372))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('larger', 'PosReg', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('more', 'PosReg', (263, 267))	('TNM', 'Gene', '10178', (219, 222))	('TNM', 'Gene', (219, 222))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('expression', 'MPA', (142, 152))	('LOC285194', 'Var', (156, 165))	('metastases', 'Disease', 'MESH:D009362', (291, 301))	('correlated', 'Reg', (373, 383))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', (189, 194))	('metastases', 'Disease', (291, 301))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('low', 'NegReg', (138, 141))
689869	31375656	Low LOC285194 expression has been reported to induce radioresistance in EC patients.	('patients', 'Species', '9606', (75, 83))	('Low LOC285194 expression', 'Var', (0, 24))	('radioresistance', 'CPA', (53, 68))	('induce', 'Reg', (46, 52))
689871	31375656	The mutation or deletion of p53 may lead to EC, so the effect of LOC285194 on radiotherapy can be achieved by p53.	('p53', 'Gene', (28, 31))	('lead to', 'Reg', (36, 43))	('p53', 'Gene', (110, 113))	('p53', 'Gene', '7157', (28, 31))	('deletion', 'Var', (16, 24))	('p53', 'Gene', '7157', (110, 113))	('mutation', 'Var', (4, 12))
689873	31375656	ESCC with overexpression of MALAT1 and upregulation of cyclin-dependent kinase subunit (cks1) is radioresistant, and downregulation of MALAT1 can improve the radiotherapeutic effect of ESCC.	('MALAT1', 'Gene', (28, 34))	('MALAT1', 'Gene', '378938', (135, 141))	('radiotherapeutic effect', 'CPA', (158, 181))	('downregulation', 'Var', (117, 131))	('MALAT1', 'Gene', (135, 141))	('upregulation', 'PosReg', (39, 51))	('cks1', 'Gene', '137529', (88, 92))	('overexpression', 'PosReg', (10, 24))	('CC', 'Phenotype', 'HP:0002664', (2, 4))	('improve', 'PosReg', (146, 153))	('CC', 'Phenotype', 'HP:0002664', (187, 189))	('MALAT1', 'Gene', '378938', (28, 34))	('cks1', 'Gene', (88, 92))
689875	31375656	Overexpression of Cks1 in breast cancer has been shown to inhibit DNA damage caused by oncogene activation, resulting in radiotherapy resistance.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('Cks1', 'Gene', '137529', (18, 22))	('activation', 'PosReg', (96, 106))	('resulting in', 'Reg', (108, 120))	('radiotherapy resistance', 'MPA', (121, 144))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Overexpression', 'Var', (0, 14))	('inhibit', 'NegReg', (58, 65))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('oncogene', 'Protein', (87, 95))	('DNA damage', 'MPA', (66, 76))	('Cks1', 'Gene', (18, 22))
689891	31375656	It has been reported that PI3K kinase is associated with 3 known major radioresistance mechanisms: intrinsic radioresistance, tumor cell proliferation, and hypoxia.	('hypoxia', 'Disease', (156, 163))	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('associated', 'Reg', (41, 51))	('intrinsic radioresistance', 'CPA', (99, 124))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('PI3K kinase', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
689892	31375656	Inhibition of PI3K kinase activity can enhance tumor radiosensitivity.	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Inhibition', 'Var', (0, 10))	('PI3K kinase', 'Pathway', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('enhance tumor radiosensitivity', 'Phenotype', 'HP:0010997', (39, 69))	('enhance', 'PosReg', (39, 46))	('tumor', 'Disease', (47, 52))
689893	31375656	PI3K kinase is a downstream effector of WISP1 in the development of ESCC radioresistance.	('WISP1', 'Gene', '8840', (40, 45))	('PI3K', 'Var', (0, 4))	('ESCC', 'Disease', (68, 72))	('WISP1', 'Gene', (40, 45))	('CC', 'Phenotype', 'HP:0002664', (70, 72))
689902	31375656	FAM201A knockdown enhances the radiosensitivity of ECA109/ECA109R cells by upregulating ataxia-telangiectasia-mutated (ATM) and mammalian target of rapamycin (mTOR) expression via the negative regulation of miR-101 expression.	('enhances', 'PosReg', (18, 26))	('upregulating', 'PosReg', (75, 87))	('radiosensitivity', 'CPA', (31, 47))	('ATM', 'Gene', (119, 122))	('telangiectasia', 'Phenotype', 'HP:0001009', (95, 109))	('ataxia-telangiectasia-mutated', 'Gene', (88, 117))	('ataxia', 'Phenotype', 'HP:0001251', (88, 94))	('miR', 'Gene', '220972', (207, 210))	('FAM201A', 'Gene', '158228', (0, 7))	('mTOR', 'Gene', (159, 163))	('mammalian target of rapamycin', 'Gene', '2475', (128, 157))	('FAM201A', 'Gene', (0, 7))	('miR', 'Gene', (207, 210))	('knockdown', 'Var', (8, 17))	('expression', 'MPA', (165, 175))	('mTOR', 'Gene', '2475', (159, 163))	('mammalian target of rapamycin', 'Gene', (128, 157))	('ATM', 'Gene', '472', (119, 122))	('ataxia-telangiectasia-mutated', 'Gene', '472', (88, 117))	('negative regulation', 'NegReg', (184, 203))
689910	31375656	Furthermore, loss of function analysis found that XIST knockdown suppressed proliferation and improved radiosensitivity by inhibiting DNA damage repair in NPC cells.	('XIST', 'Gene', (50, 54))	('knockdown', 'Var', (55, 64))	('inhibiting', 'NegReg', (123, 133))	('PC', 'Phenotype', 'HP:0002894', (156, 158))	('DNA damage repair', 'MPA', (134, 151))	('radiosensitivity', 'MPA', (103, 119))	('proliferation', 'CPA', (76, 89))	('suppressed', 'NegReg', (65, 75))	('improved', 'PosReg', (94, 102))	('XIST', 'Gene', '7503', (50, 54))	('NPC', 'Phenotype', 'HP:0100630', (155, 158))
689916	31375656	Another study showed that knockdown of XIST inhibited cell proliferation and increased radiosensitivity of NPC cells by upregulating miR-29c, suggesting that targeting XIST/miR-29c may be a novel strategy to improve radiotherapy for patients with NPC.	('XIST', 'Gene', (39, 43))	('miR-29c', 'Gene', '407026', (133, 140))	('XIST', 'Gene', '7503', (168, 172))	('increased', 'PosReg', (77, 86))	('PC', 'Phenotype', 'HP:0002894', (248, 250))	('XIST', 'Gene', '7503', (39, 43))	('NPC', 'Phenotype', 'HP:0100630', (107, 110))	('miR-29c', 'Gene', (173, 180))	('radiosensitivity', 'CPA', (87, 103))	('inhibited', 'NegReg', (44, 53))	('miR-29c', 'Gene', (133, 140))	('NPC', 'Phenotype', 'HP:0100630', (247, 250))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (77, 103))	('upregulating', 'PosReg', (120, 132))	('knockdown', 'Var', (26, 35))	('patients', 'Species', '9606', (233, 241))	('PC', 'Phenotype', 'HP:0002894', (108, 110))	('cell proliferation', 'CPA', (54, 72))	('XIST', 'Gene', (168, 172))	('miR-29c', 'Gene', '407026', (173, 180))
689934	31375656	In the Hela cell line, downregulation of HOAIR expression can promote p21 expression, whereas in the C33A cell line, upregulation of HOTAIR expression can significantly inhibit p21 expression.	('Hela', 'CellLine', 'CVCL:0030', (7, 11))	('inhibit', 'NegReg', (169, 176))	('p21', 'Gene', (70, 73))	('p21', 'Gene', (177, 180))	('HOTAIR', 'Gene', (133, 139))	('p21', 'Gene', '644914', (177, 180))	('promote', 'PosReg', (62, 69))	('downregulation', 'Var', (23, 37))	('p21', 'Gene', '644914', (70, 73))	('HOAIR', 'Gene', (41, 46))	('HOTAIR', 'Gene', '100124700', (133, 139))	('upregulation', 'PosReg', (117, 129))
689943	31375656	After downregulated of the expression of MALAT1, the colony formation rate of CaSki and Hela cells decreased and the distribution of G1 phase decreased, while the distribution of G2/M phase increased.	('MALAT1', 'Gene', '378938', (41, 47))	('CaSki', 'CellLine', 'CVCL:1100', (78, 83))	('decreased', 'NegReg', (99, 108))	('colony formation rate of CaSki', 'CPA', (53, 83))	('distribution', 'MPA', (117, 129))	('MALAT1', 'Gene', (41, 47))	('decreased', 'NegReg', (142, 151))	('downregulated', 'NegReg', (6, 19))	('Hela cells', 'CellLine', 'CVCL:0030', (88, 98))	('expression', 'Var', (27, 37))
689944	31375656	Inhibition of the expression of endogenous MALAT1 was shown to decrease the expression of cell cycle regulatory molecules (cyclin D1, cyclin E and CDK6), suggesting that the effect of MALAT1 on radiosensitivity may be related to cell cycle regulation, and that the inhibitory effect of miR-145 may also be associated with the regulation of cell cycle regulatory molecules.	('miR-145', 'Gene', (286, 293))	('MALAT1', 'Gene', '378938', (184, 190))	('miR-145', 'Gene', '406937', (286, 293))	('CDK6', 'Gene', (147, 151))	('MALAT1', 'Gene', '378938', (43, 49))	('CDK6', 'Gene', '1021', (147, 151))	('decrease', 'NegReg', (63, 71))	('expression', 'MPA', (76, 86))	('MALAT1', 'Gene', (184, 190))	('Inhibition', 'Var', (0, 10))	('cyclin D1', 'Gene', '595', (123, 132))	('cyclin D1', 'Gene', (123, 132))	('cyclin E', 'Gene', (134, 142))	('MALAT1', 'Gene', (43, 49))
689947	31375656	Recent studies also found silencing MALAT1 decreased the viable cell ratio, promoted apoptosis, increased G1 phase cells, and decreased G2/M phase cells.	('decreased', 'NegReg', (126, 135))	('G1 phase cells', 'CPA', (106, 120))	('increased', 'PosReg', (96, 105))	('apoptosis', 'CPA', (85, 94))	('MALAT1', 'Gene', '378938', (36, 42))	('G2/M phase cells', 'CPA', (136, 152))	('silencing', 'Var', (26, 35))	('MALAT1', 'Gene', (36, 42))	('promoted', 'PosReg', (76, 84))	('viable cell ratio', 'CPA', (57, 74))	('decreased', 'NegReg', (43, 52))
689949	31375656	Silencing MALAT1 combined with miR-143 plus radiotherapy decreased the viable cell ratio, enhanced apoptosis, increased G1 phase ratio, and decreased the numbers of S or G2/M cells.	('MALAT1', 'Gene', '378938', (10, 16))	('decreased', 'NegReg', (140, 149))	('increased', 'PosReg', (110, 119))	('MALAT1', 'Gene', (10, 16))	('apoptosis', 'CPA', (99, 108))	('miR-143', 'Gene', '406935', (31, 38))	('enhanced', 'PosReg', (90, 98))	('G1 phase ratio', 'CPA', (120, 134))	('miR-143', 'Gene', (31, 38))	('Silencing', 'Var', (0, 9))	('viable cell ratio', 'CPA', (71, 88))	('decreased', 'NegReg', (57, 66))
689961	31375656	The overexpression of NEAT1 promoted proliferation, while the silence of NEAT1 made cell cycle arrest in G0/G1 phase, and triggered more apoptosis, indicating the oncogenic role of NEAT1 in CC.	('NEAT1', 'Gene', (22, 27))	('cell cycle arrest in G0/G1 phase', 'CPA', (84, 116))	('silence', 'Var', (62, 69))	('apoptosis', 'CPA', (137, 146))	('NEAT1', 'Gene', '283131', (181, 186))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('NEAT1', 'Gene', (181, 186))	('proliferation', 'CPA', (37, 50))	('NEAT1', 'Gene', '283131', (73, 78))	('CC', 'Phenotype', 'HP:0002664', (190, 192))	('promoted', 'PosReg', (28, 36))	('NEAT1', 'Gene', '283131', (22, 27))	('NEAT1', 'Gene', (73, 78))	('triggered', 'Reg', (122, 131))
689962	31375656	The mechanistic assays affirmed that NEAT1 could function as a ceRNA to regulate cyclin D1 through sponging miR-193b-3p in CC.	('miR-193b', 'Gene', '574455', (108, 116))	('NEAT1', 'Gene', (37, 42))	('miR-193b', 'Gene', (108, 116))	('CC', 'Phenotype', 'HP:0002664', (123, 125))	('cyclin D1', 'Gene', '595', (81, 90))	('cyclin D1', 'Gene', (81, 90))	('NEAT1', 'Gene', '283131', (37, 42))	('sponging', 'Var', (99, 107))
689983	31375656	Moreover, downregulation of UCA1 plus radiation reduced the expression levels of EMT-associated proteins, indicating that silencing of UCA1 significantly inhibits EMT in CCL244 cells.	('inhibits', 'NegReg', (154, 162))	('UCA1', 'Gene', '652995', (135, 139))	('UCA1', 'Gene', (135, 139))	('reduced', 'NegReg', (48, 55))	('downregulation', 'NegReg', (10, 24))	('silencing', 'Var', (122, 131))	('expression levels of EMT-associated proteins', 'MPA', (60, 104))	('CC', 'Phenotype', 'HP:0002664', (170, 172))	('UCA1', 'Gene', '652995', (28, 32))	('EMT in CCL244 cells', 'CPA', (163, 182))	('UCA1', 'Gene', (28, 32))
689990	31375656	After HOTAIR was knocked out, the expression of Wnt inhibitor 1 (WIF1) was increased and the Wnt/beta-catenin signaling pathway was inhibited, resulting in decreased expression of the EMT-related protein beta-catenin, which increased the radiosensitivity of PDAC cells and increased the cell apoptosis after radiotherapy.	('expression', 'MPA', (34, 44))	('beta-catenin', 'Gene', (97, 109))	('radiosensitivity', 'CPA', (238, 254))	('beta-catenin', 'Gene', '1499', (97, 109))	('inhibited', 'NegReg', (132, 141))	('cell apoptosis', 'CPA', (287, 301))	('increased', 'PosReg', (273, 282))	('PDAC', 'Phenotype', 'HP:0006725', (258, 262))	('increased', 'PosReg', (75, 84))	('increased', 'PosReg', (224, 233))	('WIF1', 'Gene', '11197', (65, 69))	('beta-catenin', 'Gene', (204, 216))	('decreased', 'NegReg', (156, 165))	('beta-catenin', 'Gene', '1499', (204, 216))	('expression', 'MPA', (166, 176))	('HOTAIR', 'Gene', '100124700', (6, 12))	('WIF1', 'Gene', (65, 69))	('knocked', 'Var', (17, 24))	('HOTAIR', 'Gene', (6, 12))
689992	31375656	They identified that HOTAIR knockdown could enhance radiosensitivity and influence autophagy by upregulating ATG7 expression in PC cells.	('autophagy', 'CPA', (83, 92))	('upregulating', 'PosReg', (96, 108))	('radiosensitivity', 'CPA', (52, 68))	('PC', 'Phenotype', 'HP:0002894', (128, 130))	('ATG7', 'Gene', (109, 113))	('expression', 'MPA', (114, 124))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (44, 68))	('knockdown', 'Var', (28, 37))	('influence', 'Reg', (73, 82))	('enhance', 'PosReg', (44, 51))	('HOTAIR', 'Gene', (21, 27))	('HOTAIR', 'Gene', '100124700', (21, 27))	('ATG7', 'Gene', '10533', (109, 113))
690009	31375656	Moreover, ectopic expression of lincRNA-p21 suppressed GC cell proliferation, cell cycle, and migration.	('suppressed', 'NegReg', (44, 54))	('GC cell proliferation', 'CPA', (55, 76))	('lincRNA-p21', 'Gene', (32, 43))	('migration', 'CPA', (94, 103))	('GC', 'Phenotype', 'HP:0012126', (55, 57))	('lincRNA-p21', 'Gene', '102800311', (32, 43))	('ectopic expression', 'Var', (10, 28))	('cell cycle', 'CPA', (78, 88))
690017	31375656	SP1 can induce the upregulation of TINCR, while TINCR can affect the stability and transcription of KLF2 mRNA.	('KLF2', 'Gene', '10365', (100, 104))	('TINCR', 'Gene', (35, 40))	('KLF2', 'Gene', (100, 104))	('transcription', 'MPA', (83, 96))	('stability', 'MPA', (69, 78))	('upregulation', 'PosReg', (19, 31))	('TINCR', 'Gene', '257000', (48, 53))	('SP1', 'Var', (0, 3))	('TINCR', 'Gene', '257000', (35, 40))	('affect', 'Reg', (58, 64))	('TINCR', 'Gene', (48, 53))
690019	31375656	However, the lack of p21 protein can weaken radiation-induced cell cycle arrest.	('p21', 'Gene', (21, 24))	('p21', 'Gene', '644914', (21, 24))	('weaken', 'NegReg', (37, 43))	('lack', 'Var', (13, 17))	('radiation-induced cell cycle arrest', 'CPA', (44, 79))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))
690124	30602370	To improve the efficacy of surgery and regulate the heterochronic relapse, NAC in Eastern Asia along with neoadjuvant chemoradiotherapy in the West is thought to be a standard strategy for treating resectable ESCC.	('NAC', 'Chemical', '-', (75, 78))	('SCC', 'Gene', '6317', (210, 213))	('NAC', 'Var', (75, 78))	('SCC', 'Gene', (210, 213))
690207	28192107	Although alterations in the physiology of the small intestine may allow greater absorption capacity, it is likely that small-bowel absorption adapts to the over-consumption of calories associated with obesity, leading to more rapid absorption without an increase in energy absorption.	('absorption capacity', 'MPA', (80, 99))	('obesity', 'Disease', 'MESH:D009765', (201, 208))	('obesity', 'Disease', (201, 208))	('rapid absorption', 'MPA', (226, 242))	('alterations', 'Var', (9, 20))	('obesity', 'Phenotype', 'HP:0001513', (201, 208))	('more', 'PosReg', (221, 225))
690212	28192107	The higher prevalence of diarrhea could be attributed to several potential mechanisms associated with obesity: changes in bile acids resulting in bile acid diarrhea, accelerated colonic transit, increased mucosal permeability,  or intestinal inflammation as evidenced by increased levels of fecal calprotectin.	('changes', 'Var', (111, 118))	('bile acid', 'Chemical', 'MESH:D001647', (146, 155))	('mucosal permeability', 'MPA', (205, 225))	('obesity', 'Disease', 'MESH:D009765', (102, 109))	('bile acid', 'Chemical', 'MESH:D001647', (122, 131))	('increased', 'PosReg', (195, 204))	('diarrhea', 'Disease', (156, 164))	('diarrhea', 'Phenotype', 'HP:0002014', (25, 33))	('accelerated', 'PosReg', (166, 177))	('intestinal inflammation', 'Disease', (231, 254))	('diarrhea', 'Disease', 'MESH:D003967', (156, 164))	('obesity', 'Phenotype', 'HP:0001513', (102, 109))	('intestinal inflammation', 'Disease', 'MESH:D007249', (231, 254))	('diarrhea', 'Disease', (25, 33))	('colonic transit', 'CPA', (178, 193))	('increased', 'PosReg', (271, 280))	('diarrhea', 'Disease', 'MESH:D003967', (25, 33))	('bile acid', 'MPA', (146, 155))	('bile acids', 'MPA', (122, 132))	('obesity', 'Disease', (102, 109))	('diarrhea', 'Phenotype', 'HP:0002014', (156, 164))	('bile acids', 'Chemical', 'MESH:D001647', (122, 132))
690239	28192107	Obesity is associated with a higher risk of developing diverticulosis, as well as an increased number of diverticuli and increased diverticular bleeding and recurrent diverticulitis compared with normal-weight individuals.	('diverticular bleeding', 'Disease', (131, 152))	('Obesity', 'Var', (0, 7))	('diverticulosis', 'Disease', (55, 69))	('diverticulosis', 'Disease', 'MESH:D004240', (55, 69))	('increased', 'PosReg', (121, 130))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('diverticular bleeding', 'Disease', 'MESH:D000076385', (131, 152))	('diverticulitis', 'Disease', 'MESH:D004238', (167, 181))	('diverticulitis', 'Disease', (167, 181))
690293	28192107	In an analysis of the Surveillance, Epidemiology, and End Results registry in the United States from 2004 to 2009, NAFLD was the third most common underlying cause of HCC after chronic hepatitis C and alcoholic liver disease.	('NAFLD', 'Var', (115, 120))	('alcoholic liver disease', 'Disease', (201, 224))	('HCC', 'Gene', (167, 170))	('hepatitis', 'Phenotype', 'HP:0012115', (185, 194))	('liver disease', 'Phenotype', 'HP:0001392', (211, 224))	('cause', 'Reg', (158, 163))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (177, 194))	('HCC', 'Gene', '619501', (167, 170))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (201, 224))	('chronic hepatitis C', 'Disease', (177, 196))
690304	28192107	In human studies, PNPLA3 rs738409 C>G polymorphism imparted increased risk for HCC in NAFLD, although the magnitude of this risk and mechanism remain to be determined.	('human', 'Species', '9606', (3, 8))	('PNPLA3', 'Gene', (18, 24))	('HCC', 'Gene', (79, 82))	('PNPLA3', 'Gene', '80339', (18, 24))	('rs738409 C>G', 'Var', (25, 37))	('rs738409', 'Mutation', 'rs738409', (25, 33))	('HCC', 'Gene', '619501', (79, 82))
690305	28192107	Thus, experimental studies have linked perturbations of both the adaptive and innate immune systems to increased risk of HCC in NASH.	('HCC', 'Gene', (121, 124))	('perturbations', 'Var', (39, 52))	('HCC', 'Gene', '619501', (121, 124))	('men', 'Species', '9606', (12, 15))
690439	26448015	NF-kappaB expression was associated with poor 3-year OS in both Tumor, Lymph Node, Metastasis stage I-II (OR = 9.11, 95% CI = 2.90-28.68, P = 0.0002) and III-IV (OR = 2.59, 95% CI = 1.61-4.15, P < 0.0001).	('Tumor', 'Phenotype', 'HP:0002664', (64, 69))	('NF-kappaB', 'Gene', '4790', (0, 9))	('Lymph Node', 'CPA', (71, 81))	('NF-kappaB', 'Gene', (0, 9))	('Metastasis', 'Disease', 'MESH:D009362', (83, 93))	('Metastasis', 'Disease', (83, 93))	('III-IV', 'CPA', (154, 160))	('Tumor', 'CPA', (64, 69))	('expression', 'Var', (10, 20))
690447	26448015	The mammalian NF-kappaB family consists of 5 protein members: NF-kappaB1 (p50 and its precursor p105), NF-kappaB2 (p52 and its precursor p100), RelA (p65), RelB, and c-Rel.	('p105', 'Gene', (96, 100))	('NF-kappaB', 'Gene', (103, 112))	('NF-kappaB', 'Gene', '4790', (103, 112))	('NF-kappaB', 'Gene', (14, 23))	('RelB', 'Gene', '5971', (156, 160))	('NF-kappaB', 'Gene', (62, 71))	('mammalian', 'Species', '9606', (4, 13))	('p65', 'Gene', (150, 153))	('c-Rel', 'Gene', '5966', (166, 171))	('p105', 'Gene', '4790', (96, 100))	('RelA', 'Gene', (144, 148))	('NF-kappaB', 'Gene', '4790', (14, 23))	('NF-kappaB', 'Gene', '4790', (62, 71))	('p50', 'Gene', '4790', (74, 77))	('RelB', 'Gene', (156, 160))	('p52', 'Gene', '4791', (115, 118))	('p100', 'Var', (137, 141))	('p50', 'Gene', (74, 77))	('p65', 'Gene', '5970', (150, 153))	('c-Rel', 'Gene', (166, 171))	('RelA', 'Gene', '5970', (144, 148))	('p52', 'Gene', (115, 118))
690448	26448015	Aberrant activation of NF-kappaB has been linked to inflammatory and autoimmune diseases, infection and cancer.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('NF-kappaB', 'Gene', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('autoimmune diseases, infection', 'Disease', 'MESH:D001327', (69, 99))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (69, 88))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('NF-kappaB', 'Gene', '4790', (23, 32))	('linked', 'Reg', (42, 48))
690473	26448015	For NF-kappaB p50 antibody, 4 studies used clone sc114, 1 study used clone sc1190, and 1 study did not report the clone.	('NF-kappaB p50', 'Gene', (4, 17))	('clone sc114', 'Var', (43, 54))	('NF-kappaB p50', 'Gene', '4790', (4, 17))
690474	26448015	For NF-kappaB p65 antibody, 4 studies used clone sc8008, 3 studies used clone G96-337, 6 studies used clone sc109, 1 study each used clone sc372, sc502, D14E12, and 24 studies did not report the clone.	('p65', 'Gene', '5970', (14, 17))	('sc502', 'Var', (146, 151))	('NF-kappaB', 'Gene', '4790', (4, 13))	('clone G96-337', 'Var', (72, 85))	('p65', 'Gene', (14, 17))	('NF-kappaB', 'Gene', (4, 13))	('D14E12', 'Var', (153, 159))
690484	26448015	NF-kappaB expression was associated with poor 3-year OS in both TNM stage I-II (OR = 9.11, 95% CI = 2.90-28.68, P = 0.0002) and III-IV (OR = 2.59, 95% CI = 1.61-4.15, P < 0.0001) (Fig.	('TNM stage I-II', 'Disease', (64, 78))	('NF-kappaB', 'Gene', '4790', (0, 9))	('NF-kappaB', 'Gene', (0, 9))	('III-IV', 'Disease', (128, 134))	('poor', 'NegReg', (41, 45))	('expression', 'Var', (10, 20))
690493	26448015	NF-kappaB expression was associated with a statistically significant worse 3-year DFS (OR = 3.17, 95% CI = 1.87-5.38, P < 0.0001) (Fig.	('NF-kappaB', 'Gene', '4790', (0, 9))	('worse', 'NegReg', (69, 74))	('DFS', 'MPA', (82, 85))	('NF-kappaB', 'Gene', (0, 9))	('expression', 'Var', (10, 20))
690503	26448015	Therefore, targeting NF-kappaB is thought to be a potent node of pharmacological interference against tumors and acquires clinical benefit response.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('NF-kappaB', 'Gene', '4790', (21, 30))	('NF-kappaB', 'Gene', (21, 30))	('targeting', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
690506	26448015	Moreover, NF-kappaB expression is associated with poor survival in both TNM stage I-II and III-IV.	('poor', 'NegReg', (50, 54))	('NF-kappaB', 'Gene', '4790', (10, 19))	('expression', 'Var', (20, 30))	('TNM stage I-II', 'Disease', (72, 86))	('NF-kappaB', 'Gene', (10, 19))	('III-IV', 'Disease', (91, 97))
690508	26448015	Among the tumor types evaluated, the expression of NF-kappaB is associated with worse 3- and 5-year OS for colorectal cancer and esophageal carcinoma, while NF-kappaB is not significantly associated with either 3- or 5-year OS for gastric cancer and ovarian cancer.	('expression', 'Var', (37, 47))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (129, 149))	('ovarian cancer', 'Disease', 'MESH:D010051', (250, 264))	('gastric cancer', 'Disease', (231, 245))	('NF-kappaB', 'Gene', '4790', (51, 60))	('tumor', 'Disease', (10, 15))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('ovarian cancer', 'Disease', (250, 264))	('NF-kappaB', 'Gene', (157, 166))	('gastric cancer', 'Disease', 'MESH:D013274', (231, 245))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('ovarian cancer', 'Phenotype', 'HP:0100615', (250, 264))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (129, 149))	('NF-kappaB', 'Gene', '4790', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (231, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('esophageal carcinoma', 'Disease', (129, 149))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('colorectal cancer', 'Disease', (107, 124))	('NF-kappaB', 'Gene', (51, 60))
690516	26448015	First, it shows that NF-kappaB expression is associated with worse outcome of solid tumors, which suggests that NF-kappaB may be a potential therapeutic target.	('solid tumors', 'Disease', (78, 90))	('NF-kappaB', 'Gene', '4790', (112, 121))	('NF-kappaB', 'Gene', '4790', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('NF-kappaB', 'Gene', (112, 121))	('associated', 'Reg', (45, 55))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('NF-kappaB', 'Gene', (21, 30))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('expression', 'Var', (31, 41))
690529	25613496	Inhibition of MALAT1 suppressed tumor proliferation in vitro and in vivo, as well as the migratory and invasive capacity.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('suppressed', 'NegReg', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('MALAT1', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (32, 37))
690530	25613496	Western-blotting results implicated that the ATM-CHK2 pathway which is associated with G2/M arrest was phosphorylated by MALAT1 knockdown.	('CHK2', 'Gene', '11200', (49, 53))	('ATM', 'Gene', '472', (45, 48))	('knockdown', 'Var', (128, 137))	('MALAT1', 'Gene', (121, 127))	('CHK2', 'Gene', (49, 53))	('ATM', 'Gene', (45, 48))	('G2/M arrest', 'Disease', (87, 98))
690533	25613496	Moreover, amplification of MALAT1 in tumor tissues may play an important role for its up-regulation, and it seems that the gene amplification in tumor tissues emerges during ESCC progression, but is not derived from germline origins.	('up-regulation', 'PosReg', (86, 99))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('MALAT1', 'Gene', (27, 33))	('ESCC', 'Disease', (174, 178))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('amplification', 'Var', (10, 23))
690536	25613496	A growing amount of literature has linked deregulation of lncRNAs with diverse human cancers, such as the well-characterized HOTAIR, MEG3, GAS5, H19, and MALAT1.	('H19', 'Gene', '283120', (145, 148))	('human', 'Species', '9606', (79, 84))	('deregulation', 'Var', (42, 54))	('HOTAIR', 'Gene', '100124700', (125, 131))	('H19', 'Gene', (145, 148))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('MEG3', 'Gene', (133, 137))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('GAS5', 'Gene', '60674', (139, 143))	('cancers', 'Disease', (85, 92))	('MEG3', 'Gene', '55384', (133, 137))	('MALAT1', 'Disease', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('GAS5', 'Gene', (139, 143))	('HOTAIR', 'Gene', (125, 131))
690542	25613496	To our knowledge, the tumor genomes are under frequent DNA damage events and spontaneous genetic mutation, which could activate the cell cycle checkpoints, represented by the ATM-CHK2 pathway.	('cell cycle checkpoints', 'CPA', (132, 154))	('CHK2', 'Gene', '11200', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('CHK2', 'Gene', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('ATM', 'Gene', (175, 178))	('tumor', 'Disease', (22, 27))	('genetic mutation', 'Var', (89, 105))	('activate', 'PosReg', (119, 127))	('ATM', 'Gene', '472', (175, 178))
690544	25613496	Inactivation of this checkpoint may release cells from cycle arrest, and results in accelerating tumor growth.	('accelerating', 'PosReg', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cycle arrest', 'CPA', (55, 67))	('tumor', 'Disease', (97, 102))	('release', 'PosReg', (36, 43))	('Inactivation', 'Var', (0, 12))
690546	25613496	Moreover, the factors that lead to MALAT1 over-expression in tumor tissues remain largely unknown, previous studies have found that the expression level of MALAT1 was controlled by methylation of histone H3, transcriptional factors, and microRNAs; however, evidence to explain its over-expression in diverse tumor tissues is lacking.	('controlled', 'Reg', (167, 177))	('expression', 'MPA', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('methylation', 'Var', (181, 192))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MALAT1', 'Gene', (156, 162))	('tumor', 'Disease', (308, 313))	('tumor', 'Disease', (61, 66))
690553	25613496	MALAT1 depletion activated the ATM-CHK2 pathway, which should be responsible for G2/M arrest.	('MALAT1', 'MPA', (0, 6))	('ATM', 'Gene', '472', (31, 34))	('CHK2', 'Gene', '11200', (35, 39))	('activated', 'PosReg', (17, 26))	('depletion', 'Var', (7, 16))	('ATM', 'Gene', (31, 34))	('CHK2', 'Gene', (35, 39))
690555	25613496	We also found that amplification of MALAT1 in tumor tissues may partially contribute to its over-expression, but the genomic amplification in somatic tissues should be a complex event, instead of being derived from a germline source.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('amplification', 'Var', (19, 32))	('tumor', 'Disease', (46, 51))	('over-expression', 'MPA', (92, 107))	('MALAT1', 'Gene', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
690595	25613496	To assess the role of MALAT1 in ESCC growth, we first silenced MALAT1 expression in EC109 and EC9706 by small interfering RNA.	('EC9706', 'Var', (94, 100))	('silenced', 'NegReg', (54, 62))	('MALAT1', 'Gene', (63, 69))	('expression', 'MPA', (70, 80))	('EC9706', 'CellLine', 'CVCL:E307', (94, 100))
690597	25613496	CCK8 assays revealed that cell growth was suppressed in both cell lines transfected with siRNAs compared with negative control (Figure 2B), colony-formation ability was also reduced by MALAT1 silencing in EC9706 and EC109 cells (Figure 2C).	('cell growth', 'CPA', (26, 37))	('EC9706', 'Var', (205, 211))	('MALAT1', 'Gene', (185, 191))	('suppressed', 'NegReg', (42, 52))	('colony-formation ability', 'CPA', (140, 164))	('EC9706', 'CellLine', 'CVCL:E307', (205, 211))	('reduced', 'NegReg', (174, 181))	('silencing', 'NegReg', (192, 201))
690598	25613496	The inhibitory effect of MALAT1 knockdown on ESCC proliferation was also observed in a nude mice tumor growth model.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('MALAT1', 'Gene', (25, 31))	('inhibitory', 'NegReg', (4, 14))	('knockdown', 'Var', (32, 41))	('tumor', 'Disease', (97, 102))	('ESCC', 'Disease', (45, 49))	('nude mice', 'Species', '10090', (87, 96))
690602	25613496	Similarly, invasion of EC109 and EC9706 cells was reduced by 34.2% and 39.8% separately following silencing of MALAT1 (Figure 3B).	('MALAT1', 'Gene', (111, 117))	('silencing', 'Var', (98, 107))	('invasion', 'CPA', (11, 19))	('reduced', 'NegReg', (50, 57))	('EC9706', 'CellLine', 'CVCL:E307', (33, 39))
690604	25613496	The results showed that the expression level of phosphorylated ATM, CHK2, CDC25C, and CDK1 were significantly increased upon MALAT1 depletion, while no detectable differences were observed for total ATM, CHK2, CDC25C, and CDK1 (Figure 4C).	('ATM', 'Gene', '472', (199, 202))	('ATM', 'Gene', '472', (63, 66))	('MALAT1', 'MPA', (125, 131))	('increased', 'PosReg', (110, 119))	('CHK2', 'Gene', '11200', (204, 208))	('CHK2', 'Gene', '11200', (68, 72))	('depletion', 'Var', (132, 141))	('ATM', 'Gene', (199, 202))	('ATM', 'Gene', (63, 66))	('CDC25C', 'Gene', (210, 216))	('CDC25C', 'Gene', '995', (210, 216))	('expression level', 'MPA', (28, 44))	('CHK2', 'Gene', (204, 208))	('CDC25C', 'Gene', (74, 80))	('CHK2', 'Gene', (68, 72))	('CDK1', 'Gene', (222, 226))	('CDK1', 'Gene', '983', (222, 226))	('CDC25C', 'Gene', '995', (74, 80))	('CDK1', 'Gene', (86, 90))	('CDK1', 'Gene', '983', (86, 90))
690605	25613496	These data suggested that inhibition of MALAT1 may activate the ATM-CHK2 pathway, and eventually lead to G2/M arrest.	('MALAT1', 'Gene', (40, 46))	('CHK2', 'Gene', (68, 72))	('inhibition', 'Var', (26, 36))	('ATM', 'Gene', (64, 67))	('CHK2', 'Gene', '11200', (68, 72))	('activate', 'PosReg', (51, 59))	('G2/M arrest', 'CPA', (105, 116))	('ATM', 'Gene', '472', (64, 67))	('lead to', 'Reg', (97, 104))
690609	25613496	Together these data suggested that high expression of MALAT1 promotes ESCC proliferation by dephosphorylation of the ATM-CHK2 pathway, which may release cells from G2/M arrest, resulting in uncontrolled cell cycle and tumor growth.	('G2/M arrest', 'Protein', (164, 175))	('ATM', 'Gene', '472', (117, 120))	('release', 'PosReg', (145, 152))	('ATM', 'Gene', (117, 120))	('promotes', 'PosReg', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('CHK2', 'Gene', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('high expression', 'Var', (35, 50))	('uncontrolled cell cycle', 'CPA', (190, 213))	('tumor', 'Disease', (218, 223))	('ESCC', 'Disease', (70, 74))	('dephosphorylation', 'MPA', (92, 109))	('MALAT1', 'Gene', (54, 60))	('resulting in', 'Reg', (177, 189))	('CHK2', 'Gene', '11200', (121, 125))
690615	25613496	Here we detected whether the germline copy number variation of MALAT1 may lead to tissue copy number amplification and is associated with ESCC risk in a case-control study, which contained blood samples from the 54 patients mentioned above.	('patients', 'Species', '9606', (215, 223))	('germline copy number variation', 'Var', (29, 59))	('lead to', 'Reg', (74, 81))	('tissue copy number amplification', 'MPA', (82, 114))	('associated with', 'Reg', (122, 137))	('MALAT1', 'Gene', (63, 69))	('ESCC', 'Disease', (138, 142))
690616	25613496	Finally we found no germline copy number gain in whole samples while copy number loss in twelve patients and eight controls (Additional file 4: Figure S1B), suggesting that the amplification in tissues may not come from germline source, and the germline CNV should not be a risk indicator for ESCC (Table 3).	('loss', 'NegReg', (81, 85))	('ESCC', 'Disease', (293, 297))	('copy number', 'Var', (69, 80))	('patients', 'Species', '9606', (96, 104))
690619	25613496	Among these emerging functional stars, MALAT1 has been widely accepted as a key regulator in development and carcinogenesis, which participates in biological events through various mechanisms, such as chromosome modification, mediating mRNA relocation, and alternative splicing.	('participates', 'Reg', (131, 143))	('carcinogenesis', 'Disease', 'MESH:D063646', (109, 123))	('chromosome modification', 'Var', (201, 224))	('carcinogenesis', 'Disease', (109, 123))	('mRNA', 'Var', (236, 240))	('alternative splicing', 'Var', (257, 277))	('MALAT1', 'Gene', (39, 45))
624216	25613496	Inhibition of MALAT1 suppressed tumor growth in vitro and in vivo, as well as cell migratory and invasive capacity, confirming its oncogenic roles in ESCC.	('suppressed', 'NegReg', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('ESCC', 'Disease', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('MALAT1', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (32, 37))
690629	25613496	Results from Western-blotting showed that the phosphorylated forms of ATM, CHK2, CDC25C, and CDK1 were upregulated upon MALAT1 knockdown.	('MALAT1', 'Gene', (120, 126))	('CDK1', 'Gene', '983', (93, 97))	('CHK2', 'Gene', (75, 79))	('ATM', 'Gene', '472', (70, 73))	('CDC25C', 'Gene', '995', (81, 87))	('CHK2', 'Gene', '11200', (75, 79))	('CDK1', 'Gene', (93, 97))	('knockdown', 'Var', (127, 136))	('upregulated', 'PosReg', (103, 114))	('CDC25C', 'Gene', (81, 87))	('ATM', 'Gene', (70, 73))
690630	25613496	As we know, ATM is a key regulator in cell cycle moderating, which may be phosphorylated at Ser1981 in response to environmental disturbance and genome instability, such as toxicant-induced or spontaneous DNA damage.	('ATM', 'Gene', (12, 15))	('Ser1981', 'Chemical', '-', (92, 99))	('ATM', 'Gene', '472', (12, 15))	('Ser1981', 'Var', (92, 99))
690631	25613496	The phosphorylated form of ATM could subsequently activate CHK2 by phosphorylating CHK2 at the Thr68 site, and the activated CHK2 played its role in suppressing CDC25C by phosphorylation on Ser216 of CDC25C.	('CHK2', 'Gene', '11200', (125, 129))	('phosphorylation on Ser216', 'Var', (171, 196))	('ATM', 'Gene', '472', (27, 30))	('CDC25C', 'Gene', (161, 167))	('Ser216', 'Chemical', '-', (190, 196))	('Thr68', 'Chemical', '-', (95, 100))	('CDC25C', 'Gene', (200, 206))	('CHK2', 'Gene', (59, 63))	('CHK2', 'Gene', (83, 87))	('ATM', 'Gene', (27, 30))	('CHK2', 'Gene', '11200', (59, 63))	('CDC25C', 'Gene', '995', (161, 167))	('suppressing', 'NegReg', (149, 160))	('CHK2', 'Gene', '11200', (83, 87))	('CHK2', 'Gene', (125, 129))	('CDC25C', 'Gene', '995', (200, 206))
690632	25613496	The CDC25C was a phosphatase which can direct dephosphorylation of P-CDK1 (Thr14, Tyr15) and triggers entry into mitosis.	('CDC25C', 'Gene', '995', (4, 10))	('Tyr15', 'Var', (82, 87))	('CDC25C', 'Gene', (4, 10))	('dephosphorylation', 'MPA', (46, 63))	('mitosis', 'Disease', (113, 120))	('mitosis', 'Disease', 'None', (113, 120))	('CDK1', 'Gene', (69, 73))	('Thr14', 'Chemical', '-', (75, 80))	('CDK1', 'Gene', '983', (69, 73))	('Tyr15', 'Chemical', '-', (82, 87))	('triggers', 'Reg', (93, 101))
690644	25613496	In this study, we genotyped the copy number of MALAT1 in 201 ESCC patients (the 54 patients mentioned above included) and 193 healthy controls.	('copy number', 'Var', (32, 43))	('ESCC', 'Disease', (61, 65))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (66, 74))	('MALAT1', 'Gene', (47, 53))
690646	25613496	It may promote ESCC growth by moderating the ATM-CHK2 pathway which is involved in cell cycle orchestrating, and the amplification of MALAT1 may be an important cause for its up-regulation in ESCC tissues.	('MALAT1', 'Gene', (134, 140))	('ESCC', 'Disease', (15, 19))	('CHK2', 'Gene', '11200', (49, 53))	('ATM', 'Gene', '472', (45, 48))	('moderating', 'Reg', (30, 40))	('promote', 'PosReg', (7, 14))	('CHK2', 'Gene', (49, 53))	('up-regulation', 'PosReg', (175, 188))	('ATM', 'Gene', (45, 48))	('amplification', 'Var', (117, 130))
690662	20525404	Nonfunctional presentation of tumoral antigen and further suppression of an effective immune response is one of the most important mechanisms of immune evasion which has been targeted in designing a number of immunotherapeutic modalities.	('tumoral', 'Disease', (30, 37))	('tumoral', 'Disease', 'MESH:D009369', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Nonfunctional', 'Var', (0, 13))	('suppression', 'NegReg', (58, 69))
690716	20525404	Taking advantage of their capabilities, DC transfection with nucleic acids encoding tumor specific antigens leads to processing and presenting the antigens and consequently, activating tumor-specific CTLs.	('tumor', 'Disease', (185, 190))	('nucleic', 'Var', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('activating', 'PosReg', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('processing', 'MPA', (117, 127))	('presenting', 'MPA', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
690731	20525404	In summary, we demonstrated that electroporating DCs with tumor mRNA will enhance the cytotoxic effects of T cells against tumor in ESCC patients.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (123, 128))	('patients', 'Species', '9606', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('electroporating', 'Var', (33, 48))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('ESCC', 'Disease', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('enhance', 'PosReg', (74, 81))
690819	19040976	An air-tight closure should be confirmed by deflating the endotracheal tube, flooding the operative field with saline, and having the anesthesiologist perform a Valsalva maneuver.	('Valsalva maneuver', 'Disease', 'None', (161, 178))	('Valsalva maneuver', 'Disease', (161, 178))	('deflating', 'Var', (44, 53))	('saline', 'Chemical', 'MESH:D012965', (111, 117))
690844	19040976	Tubiana and colleagues demonstrated improved local control at 15 years in patients receiving EBRT over 50 Gy for locally invasive well-differentiated thyroid cancer when compared with a cohort of patients who did not receive radiation, despite the larger and more extensive tumors in the EBRT-treated patients.	('local control', 'CPA', (45, 58))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('EBRT', 'Chemical', '-', (288, 292))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (301, 309))	('thyroid cancer', 'Disease', (150, 164))	('patients', 'Species', '9606', (196, 204))	('improved', 'PosReg', (36, 44))	('thyroid cancer', 'Phenotype', 'HP:0002890', (150, 164))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('EBRT', 'Chemical', '-', (93, 97))	('thyroid cancer', 'Disease', 'MESH:D013964', (150, 164))	('EBRT over 50 Gy', 'Var', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', (274, 280))
690864	33810518	Residing at the center of the cascade, E2s largely determine Ub chain topology and are responsible for recruiting E3 ligases and their substrates.	('Ub chain', 'Protein', (61, 69))	('recruiting', 'PosReg', (103, 113))	('determine', 'Reg', (51, 60))	('E2s', 'Var', (39, 42))	('E3', 'Chemical', '-', (114, 116))	('E2s', 'Chemical', 'MESH:D004958', (39, 42))	('E3 ligases', 'Protein', (114, 124))
690866	33810518	showed that increased expression or mutation of UBE2O is common in breast cancer (BC), gastric cancer (GC), renal carcinoma (RC) and ovarian cancer (OC).	('GC', 'Phenotype', 'HP:0012126', (103, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('C', 'Gene', '55832', (104, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('C', 'Gene', '55832', (150, 151))	('renal carcinoma', 'Phenotype', 'HP:0005584', (108, 123))	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('C', 'Gene', '55832', (126, 127))	('BC', 'Phenotype', 'HP:0003002', (82, 84))	('increased', 'PosReg', (12, 21))	('UBE2O', 'Gene', '63893', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('renal carcinoma (RC) and ovarian cancer', 'Disease', 'MESH:C538614', (108, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('C', 'Gene', '55832', (83, 84))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('common', 'Reg', (57, 63))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('RC', 'Phenotype', 'HP:0005584', (125, 127))	('expression', 'MPA', (22, 32))	('breast cancer', 'Disease', (67, 80))	('UBE2O', 'Gene', (48, 53))	('gastric cancer', 'Disease', (87, 101))	('mutation', 'Var', (36, 44))	('OC', 'Phenotype', 'HP:0100615', (149, 151))
690868	33810518	Even UBE2C transgenic mice are more likely to develop spontaneous tumors and tumors induced by carcinogens.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('develop', 'PosReg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('transgenic mice', 'Species', '10090', (11, 26))	('UBE2C', 'Gene', (5, 10))	('transgenic', 'Var', (11, 21))
690884	33810518	Some E2s also play a role outside the traditional Ub transport pathway by regulating the activity of other enzymes.	('regulating', 'Reg', (74, 84))	('E2s', 'Var', (5, 8))	('enzymes', 'Enzyme', (107, 114))	('E2s', 'Chemical', 'MESH:D004958', (5, 8))	('play', 'Reg', (14, 18))	('activity', 'MPA', (89, 97))
690885	33810518	It should be pointed out that Ub contains seven different lysine residues (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63), any of which can be covalently linked with other Ub molecules.	('Lys29', 'Var', (95, 100))	('Lys48', 'Chemical', '-', (109, 114))	('Lys63', 'Var', (120, 125))	('Lys33', 'Var', (102, 107))	('Lys33', 'Chemical', '-', (102, 107))	('Lys48', 'Var', (109, 114))	('Lys63', 'Chemical', '-', (120, 125))	('lysine', 'Chemical', 'MESH:D008239', (58, 64))	('Lys27', 'Var', (88, 93))	('Lys6', 'Var', (75, 79))	('Lys11', 'Var', (81, 86))	('Lys27', 'Chemical', '-', (88, 93))	('Lys29', 'Chemical', '-', (95, 100))	('Lys11', 'Chemical', '-', (81, 86))	('Lys6', 'Chemical', '-', (75, 79))	('Lys6', 'Chemical', '-', (120, 124))
690890	33810518	Generally speaking, Lys48 and Lys11 chains are further involved in proteasome degradation.	('Lys11 chains', 'Var', (30, 42))	('Lys48', 'Var', (20, 25))	('Lys48', 'Chemical', '-', (20, 25))	('proteasome degradation', 'MPA', (67, 89))	('involved', 'Reg', (55, 63))	('Lys11', 'Chemical', '-', (30, 35))
690891	33810518	Proteasome shuttling factors preferentially bind Lys48 chains compared with Lys11 chains.	('preferentially', 'PosReg', (29, 43))	('bind', 'Interaction', (44, 48))	('Lys11', 'Chemical', '-', (76, 81))	('Lys48', 'Chemical', '-', (49, 54))	('Lys48', 'Var', (49, 54))
690892	33810518	M1-linked ubiquitin chains, Lys63 and Lys6 chains are usually involved in non-proteolytic processes, such as immune homoeostasis, DNA repair, signal transduction, and endosomal-lysosomal degradation.	('Lys6', 'Chemical', '-', (38, 42))	('immune homoeostasis', 'Disease', (109, 128))	('Lys63', 'Var', (28, 33))	('Lys6 chains', 'Var', (38, 49))	('Lys6', 'Chemical', '-', (28, 32))	('1', 'Gene', '55832', (1, 2))	('involved', 'Reg', (62, 70))	('Lys63', 'Chemical', '-', (28, 33))	('immune homoeostasis', 'Disease', 'MESH:D007154', (109, 128))
690899	33810518	Ubiquitin-conjugating enzyme variant (UEV) exhibits high similarity with E2s both in structure and amino acid sequence, but lacks the UBC domain and the active-site cysteine residue, and thus is catalytically inactive.	('E2s', 'Chemical', 'MESH:D004958', (73, 76))	('variant', 'Var', (29, 36))	('lacks', 'NegReg', (124, 129))	('UBC', 'Gene', '7316', (134, 137))	('BC', 'Phenotype', 'HP:0003002', (135, 137))	('UBC', 'Gene', (134, 137))	('cysteine', 'Chemical', 'MESH:D003545', (165, 173))
690902	33810518	Although the shallow and exposed nature of the catalytic site make it difficult to target the site directly with small molecules, the distinct regions in which E2s are involved in many protein-protein interactions raise the possibility of additional modes of inhibition.	('protein-protein', 'Protein', (185, 200))	('E2s', 'Var', (160, 163))	('E2s', 'Chemical', 'MESH:D004958', (160, 163))	('interactions', 'Interaction', (201, 213))	('involved in', 'Reg', (168, 179))
690906	33810518	The SUMOylation of Xerderma pigmentosum C by UBE2I is to participate in nucleotide excision repair (NER).	('Xerderma pigmentosum C', 'Disease', (19, 41))	('SUMOylation', 'Var', (4, 15))	('Xerderma pigmentosum C', 'Disease', 'MESH:C567886', (19, 41))	('participate', 'Reg', (57, 68))	('UBE2I', 'Gene', (45, 50))	('nucleotide excision repair', 'MPA', (72, 98))
690910	33810518	The accumulation of unrepaired DNA usually triggers the activation of multiple cell death or carcinogenic pathways, resulting in cell death, senescence, or cancer.	('accumulation', 'Var', (4, 16))	('senescence', 'CPA', (141, 151))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('death', 'Disease', 'MESH:D003643', (134, 139))	('death', 'Disease', (134, 139))	('triggers', 'Reg', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('carcinogenic', 'Disease', 'MESH:D063646', (93, 105))	('death', 'Disease', 'MESH:D003643', (84, 89))	('carcinogenic', 'Disease', (93, 105))	('death', 'Disease', (84, 89))	('activation', 'PosReg', (56, 66))
690912	33810518	DNA damage induces monoubiquitination at Lys164 of PCNA, which is catalyzed by UBA1, RAD6, and RAD18 (which also involved in the activation of FA pathway).	('monoubiquitination', 'MPA', (19, 37))	('UBA1', 'Gene', (79, 83))	('damage', 'Var', (4, 10))	('induces', 'Reg', (11, 18))	('RAD18', 'Gene', (95, 100))	('PCNA', 'Gene', (51, 55))	('RAD18', 'Gene', '56852', (95, 100))	('UBA1', 'Gene', '7317', (79, 83))	('Lys164', 'Var', (41, 47))	('PCNA', 'Gene', '5111', (51, 55))	('Lys164', 'Chemical', '-', (41, 47))
690914	33810518	RAD6 binds to RAD18 to regulate the TLS pathway of mutant DNA in response to genomic damage, including that induced by chemotherapy and radiotherapy.	('regulate', 'Reg', (23, 31))	('DNA', 'Gene', (58, 61))	('mutant', 'Var', (51, 57))	('TLS', 'Disease', (36, 39))	('response to genomic damage', 'MPA', (65, 91))	('TLS', 'Disease', 'None', (36, 39))	('RAD18', 'Gene', (14, 19))	('RAD18', 'Gene', '56852', (14, 19))
690923	33810518	RAP80 recognizes the Lys63 polyUb chain on H2AX and forms a complex with ABRA1 (Abraxas), BRCC36, breast cancer-1 (BRCA1), and BARD to participate in HR (Figure 3C).	('RC', 'Phenotype', 'HP:0005584', (91, 93))	('BRCA1', 'Gene', '672', (115, 120))	('BRCA1', 'Gene', (115, 120))	('H2AX', 'Gene', (43, 47))	('RAP80', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ABRA1', 'Gene', '84142', (73, 78))	('BRCC36', 'Gene', (90, 96))	('CC', 'Phenotype', 'HP:0002664', (92, 94))	('breast cancer-1', 'Gene', '672', (98, 113))	('ABRA1', 'Gene', (73, 78))	('H2AX', 'Gene', '3014', (43, 47))	('C', 'Gene', '55832', (117, 118))	('Lys63', 'Chemical', '-', (21, 26))	('C', 'Gene', '55832', (93, 94))	('Lys63 polyUb', 'Var', (21, 33))	('C', 'Gene', '55832', (92, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('complex', 'Interaction', (60, 67))	('participate', 'Reg', (135, 146))	('C', 'Gene', '55832', (162, 163))	('breast cancer-1', 'Gene', (98, 113))	('RAP80', 'Gene', '51720', (0, 5))	('BRCC36', 'Gene', '79184', (90, 96))	('RC', 'Phenotype', 'HP:0005584', (116, 118))
690930	33810518	The destruction of UBE2T expression leads to FA (a DNA repair defect) by affecting the damage repair response of DNA ICL.	('destruction', 'Var', (4, 15))	('C', 'Gene', '55832', (118, 119))	('affecting', 'Reg', (73, 82))	('leads to', 'Reg', (36, 44))	('UBE2T', 'Gene', '29089', (19, 24))	('damage repair response', 'MPA', (87, 109))	('UBE2T', 'Gene', (19, 24))
690932	33810518	Lyakhovich showed that knocking down FANCD2 increased the sensitivity of cancer cells (BC, Bladder, or LC cell lines) to mitomycin C (MMC) and to a lesser extent, to gamma-rays.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('C', 'Gene', '55832', (136, 137))	('LC', 'Phenotype', 'HP:0100526', (103, 105))	('sensitivity', 'MPA', (58, 69))	('FANCD2', 'Gene', '2177', (37, 43))	('MMC', 'Chemical', 'MESH:D016685', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('FANCD2', 'Gene', (37, 43))	('C', 'Gene', '55832', (104, 105))	('knocking down', 'Var', (23, 36))	('BC', 'Phenotype', 'HP:0003002', (87, 89))	('C', 'Gene', '55832', (131, 132))	('increased', 'PosReg', (44, 53))	('C', 'Gene', '55832', (88, 89))	('C', 'Gene', '55832', (40, 41))
690933	33810518	Importantly, those cell lines with significant FANCD2 depletion revealed a decreased recurrence capacity.	('depletion', 'Var', (54, 63))	('FANCD2', 'Gene', '2177', (47, 53))	('FANCD2', 'Gene', (47, 53))	('recurrence capacity', 'CPA', (85, 104))	('decreased', 'NegReg', (75, 84))
690938	33810518	Overall, in normal cells, E2s are involved in DNA repair and restart of damaged DNA replication forks to maintain genomic integrity and reduce the incidence of cancer.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('E2s', 'Var', (26, 29))	('reduce', 'NegReg', (136, 142))	('E2s', 'Chemical', 'MESH:D004958', (26, 29))	('genomic', 'MPA', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
690941	33810518	RAD6 regulates mutagenic TLS and FA in response to various genomic insults, including chemo and radiation therapy.	('regulates', 'Reg', (5, 14))	('TLS', 'Disease', 'None', (25, 28))	('TLS', 'Disease', (25, 28))	('RAD6', 'Gene', (0, 4))	('mutagenic', 'Var', (15, 24))
690955	33810518	RAD6 influences the transcription of CDK1 by increasing monoubiquitinylation of H2B and trimethylation of H3K4 in the CDK1 promoter region.	('H2B', 'Gene', '8349', (80, 83))	('CDK1', 'Gene', '983', (118, 122))	('CDK1', 'Gene', (37, 41))	('CDK1', 'Gene', (118, 122))	('transcription', 'MPA', (20, 33))	('H3K4', 'Protein', (106, 110))	('CDK1', 'Gene', '983', (37, 41))	('increasing', 'PosReg', (45, 55))	('H2B', 'Gene', (80, 83))	('monoubiquitinylation', 'MPA', (56, 76))	('RAD6', 'Var', (0, 4))	('influences', 'Reg', (5, 15))	('trimethylation', 'MPA', (88, 102))
690958	33810518	In GBM cells, SUMOylation of CDK6 can prevent its ubiquitination and degradation, and ensure its existence in the process of G1/S transformation.	('SUMOylation', 'Var', (14, 25))	('degradation', 'MPA', (69, 80))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('existence', 'MPA', (97, 106))	('ensure', 'Reg', (86, 92))	('prevent', 'NegReg', (38, 45))	('ubiquitination', 'MPA', (50, 64))	('1', 'Gene', '55832', (126, 127))	('CDK6', 'Gene', (29, 33))	('CDK6', 'Gene', '1021', (29, 33))
690961	33810518	Improper SAC results in malignancies or birth defects.	('birth defects', 'Disease', 'MESH:D000014', (40, 53))	('birth defects', 'Disease', (40, 53))	('malignancies', 'Disease', 'MESH:D009369', (24, 36))	('C', 'Gene', '55832', (11, 12))	('results in', 'Reg', (13, 23))	('malignancies', 'Disease', (24, 36))	('Improper', 'Var', (0, 8))
690967	33810518	The heteromorphic Lys11/Lys48 chains mediated by UBE2C and UBE2S in the cell cycle are vital for the orderly and accurate progress of the cell cycle.	('Lys11/Lys48', 'Var', (18, 29))	('UBE2S', 'Gene', (59, 64))	('Lys11', 'Chemical', '-', (18, 23))	('UBE2C', 'Var', (49, 54))	('Lys48', 'Chemical', '-', (24, 29))	('UBE2S', 'Gene', '27338', (59, 64))
690971	33810518	In addition, UBE2C, UBE2D2, UBE2D3, UBE2N, UBE2Q1, UBE2S, and UBE2T can affect the stability and activity of p53 protein to mediate cell cycle arrest.	('arrest', 'Disease', (143, 149))	('stability', 'MPA', (83, 92))	('activity', 'MPA', (97, 105))	('UBE2S', 'Gene', (51, 56))	('UBE2D2', 'Gene', '7322', (20, 26))	('UBE2T', 'Gene', (62, 67))	('UBE2C', 'Var', (13, 18))	('UBE2Q1', 'Gene', '55585', (43, 49))	('UBE2T', 'Gene', '29089', (62, 67))	('mediate', 'Reg', (124, 131))	('UBE2N', 'Gene', '7334', (36, 41))	('p53', 'Gene', '7157', (109, 112))	('arrest', 'Disease', 'MESH:D006323', (143, 149))	('UBE2D2', 'Gene', (20, 26))	('UBE2N', 'Gene', (36, 41))	('p53', 'Gene', (109, 112))	('UBE2S', 'Gene', '27338', (51, 56))	('affect', 'Reg', (72, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (132, 149))	('UBE2Q1', 'Gene', (43, 49))	('UBE2D3', 'Gene', (28, 34))	('protein', 'Protein', (113, 120))	('UBE2D3', 'Gene', '7323', (28, 34))
690973	33810518	Mutation of p53 upregulates CCND1 and downregulates CDKN1A, leading to a highly active CDK4/CDK6 complex and thus ensuring uninterrupted pancreatic cancer cell division and uncontrolled cell proliferation.	('highly', 'PosReg', (73, 79))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (137, 154))	('upregulates', 'PosReg', (16, 27))	('ensuring', 'PosReg', (114, 122))	('CC', 'Phenotype', 'HP:0002664', (28, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (137, 154))	('CDK6', 'Gene', '1021', (92, 96))	('p53', 'Gene', '7157', (12, 15))	('pancreatic cancer', 'Disease', (137, 154))	('CDK4', 'Gene', (87, 91))	('CDK6', 'Gene', (92, 96))	('CCND1', 'Gene', '595', (28, 33))	('Mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CDKN1A', 'Gene', (52, 58))	('p53', 'Gene', (12, 15))	('cell proliferation', 'CPA', (186, 204))	('downregulates', 'NegReg', (38, 51))	('CDKN1A', 'Gene', '1026', (52, 58))	('CCND1', 'Gene', (28, 33))	('CDK4', 'Gene', '1019', (87, 91))
690979	33810518	Disorders of cell cycle progression play a key role in the formation and development of cancer, and the abnormal regulation of the cell cycle often leads to the occurrence and development of cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Disorders of cell cycle', 'Phenotype', 'HP:0011018', (0, 23))	('abnormal', 'Var', (104, 112))	('regulation', 'MPA', (113, 123))	('leads to', 'Reg', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
690982	33810518	UBE2T knockout can significantly inhibit the proliferation and colony formation of bladder cancer cells, induce cell cycle arrest, and increase the rate of apoptosis, which might be related to the fact that UBE2T is the target gene promoted by the E2F transcription factor.	('UBE2T', 'Gene', (207, 212))	('UBE2T', 'Gene', '29089', (0, 5))	('increase', 'PosReg', (135, 143))	('inhibit', 'NegReg', (33, 40))	('induce', 'Reg', (105, 111))	('UBE2T', 'Gene', '29089', (207, 212))	('apoptosis', 'CPA', (156, 165))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (112, 129))	('arrest', 'Disease', (123, 129))	('proliferation', 'CPA', (45, 58))	('E2', 'Chemical', 'MESH:D004958', (209, 211))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('bladder cancer', 'Disease', (83, 97))	('E2', 'Chemical', 'MESH:D004958', (2, 4))	('UBE2T', 'Gene', (0, 5))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('E2', 'Chemical', 'MESH:D004958', (248, 250))	('knockout', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('arrest', 'Disease', 'MESH:D006323', (123, 129))
690983	33810518	Inhibition of UBE2T in GC cells arrested the cell cycle in the G2/M phase, and ultimately inhibited cell proliferation and colony formation.	('cell cycle in the G2/M phase', 'CPA', (45, 73))	('C', 'Gene', '55832', (24, 25))	('UBE2T', 'Gene', (14, 19))	('UBE2T', 'Gene', '29089', (14, 19))	('arrest', 'Disease', 'MESH:D006323', (32, 38))	('cell proliferation', 'CPA', (100, 118))	('Inhibition', 'Var', (0, 10))	('arrest', 'Disease', (32, 38))	('inhibited', 'NegReg', (90, 99))	('GC', 'Phenotype', 'HP:0012126', (23, 25))
690986	33810518	Overexpression of UBE2C can also induce epithelial to mesenchyme transition (EMT) related to cancer cell invasion and metastasis through the APC/C complex and Wnt/beta-catenin, P13K/AKT, and p53 signaling pathways.	('APC', 'Disease', 'MESH:D011125', (141, 144))	('p53', 'Gene', '7157', (191, 194))	('Overexpression', 'Var', (0, 14))	('APC', 'Disease', (141, 144))	('induce', 'PosReg', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('P13K', 'SUBSTITUTION', 'None', (177, 181))	('epithelial to mesenchyme transition', 'CPA', (40, 75))	('C', 'Gene', '55832', (143, 144))	('AKT', 'Gene', '207', (182, 185))	('p53', 'Gene', (191, 194))	('C', 'Gene', '55832', (22, 23))	('beta-catenin', 'Gene', (163, 175))	('beta-catenin', 'Gene', '1499', (163, 175))	('P13K', 'Var', (177, 181))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('C', 'Gene', '55832', (145, 146))	('AKT', 'Gene', (182, 185))
690988	33810518	Silencing UBE2C causes pancreatic ductal adenocarcinoma cells to block in the G1/S phase, and reduces the levels of EMT markers (VIM, E-cadherin).	('1', 'Gene', '55832', (79, 80))	('VIM', 'Gene', '7431', (129, 132))	('UBE2C', 'Gene', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('reduces', 'NegReg', (94, 101))	('E-cadherin', 'Gene', (134, 144))	('pancreatic ductal adenocarcinoma', 'Disease', (23, 55))	('VIM', 'Gene', (129, 132))	('block', 'CPA', (65, 70))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (23, 55))	('E-cadherin', 'Gene', '999', (134, 144))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (23, 55))	('levels of EMT markers', 'MPA', (106, 127))	('Silencing', 'Var', (0, 9))
690993	33810518	However, it can be seen from the above that UBE2C and several special E2s promote the progress of cell cycle.	('promote', 'PosReg', (74, 81))	('E2s', 'Chemical', 'MESH:D004958', (70, 73))	('UBE2C', 'Var', (44, 49))	('progress of cell cycle', 'CPA', (86, 108))
691001	33810518	Knockout of BIRC6 can block the CRC cell cycle in the S phase and increase apoptosis.	('C', 'Gene', '55832', (32, 33))	('RC', 'Phenotype', 'HP:0005584', (33, 35))	('increase', 'PosReg', (66, 74))	('C', 'Gene', '55832', (34, 35))	('apoptosis', 'CPA', (75, 84))	('block', 'NegReg', (22, 27))	('Knockout', 'Var', (0, 8))	('C', 'Gene', '55832', (15, 16))	('RC', 'Phenotype', 'HP:0005584', (14, 16))
691003	33810518	It can be seen that targeting E2 member BIRC6 in cancer cell can release the inhibition and degradation of caspase activity, thus affecting the survival of cancer cell.	('caspase', 'Gene', (107, 114))	('cancer', 'Disease', (156, 162))	('release', 'PosReg', (65, 72))	('affecting', 'Reg', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('caspase', 'Gene', '12371', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('degradation', 'MPA', (92, 103))	('E2 member', 'Var', (30, 39))	('RC', 'Phenotype', 'HP:0005584', (42, 44))	('inhibition', 'MPA', (77, 87))	('cancer', 'Disease', (49, 55))	('BIRC6', 'Gene', (40, 45))	('E2', 'Chemical', 'MESH:D004958', (30, 32))
691004	33810518	Inhibition of apoptosis prevents the death of cancer cells, either associated with carcinogenic initiation or cancer therapy.	('apoptosis', 'Protein', (14, 23))	('cancer', 'Disease', (110, 116))	('death', 'Disease', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('carcinogenic initiation', 'Disease', 'MESH:D011230', (83, 106))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('death', 'Disease', 'MESH:D003643', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('carcinogenic initiation', 'Disease', (83, 106))
691009	33810518	Suppression of UBE2D can stabilize p53, leading to enhanced apoptosis and markedly inhibited proliferation of human LC cells in a p53-dependent manner.	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('proliferation', 'CPA', (93, 106))	('UBE2', 'Gene', '7318', (15, 19))	('Suppression', 'Var', (0, 11))	('apoptosis', 'CPA', (60, 69))	('enhanced', 'PosReg', (51, 59))	('inhibited', 'NegReg', (83, 92))	('UBE2', 'Gene', (15, 19))	('human', 'Species', '9606', (110, 115))	('C', 'Gene', '55832', (117, 118))	('p53', 'Gene', (130, 133))	('LC', 'Phenotype', 'HP:0100526', (116, 118))	('p53', 'Gene', '7157', (130, 133))
691010	33810518	The mutation of BIRC6 led to upregulation of p53, resulting in mitochondrial apoptosis.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('upregulation', 'PosReg', (29, 41))	('mutation', 'Var', (4, 12))	('mitochondrial apoptosis', 'CPA', (63, 86))	('BIRC6', 'Gene', (16, 21))	('RC', 'Phenotype', 'HP:0005584', (18, 20))
691013	33810518	Downregulation of UBE2I decreased the level of the BCL2 protein in HepG2 cells and thus caused HCC cell apoptosis.	('BCL2', 'Gene', '596', (51, 55))	('decreased', 'NegReg', (24, 33))	('HCC cell apoptosis', 'CPA', (95, 113))	('HepG2', 'CellLine', 'CVCL:0027', (67, 72))	('HCC', 'Phenotype', 'HP:0001402', (95, 98))	('Downregulation', 'Var', (0, 14))	('BCL2', 'Gene', (51, 55))	('UBE2I', 'Gene', (18, 23))	('CC', 'Phenotype', 'HP:0002664', (96, 98))	('caused', 'Reg', (88, 94))	('BC', 'Phenotype', 'HP:0003002', (51, 53))
691022	33810518	As a novel activator of the Wnt/beta-catenin signaling pathway, UBE2S modifies beta-catenin at Lys19 via a Lys11-linked polyUb chain.	('modifies', 'Reg', (70, 78))	('UBE2S', 'Gene', (64, 69))	('beta-catenin', 'Gene', '1499', (79, 91))	('Lys11', 'Chemical', '-', (107, 112))	('beta-catenin', 'Gene', (32, 44))	('UBE2S', 'Gene', '27338', (64, 69))	('beta-catenin', 'Gene', '1499', (32, 44))	('Lys11-linked polyUb chain', 'Var', (107, 132))	('Lys19', 'Chemical', '-', (95, 100))	('beta-catenin', 'Gene', (79, 91))
691023	33810518	This modification promotes beta-catenin stabilization through antagonizing its Lys48-linked proteasomal degradation, mediated by the destruction complex/betaTrCP signaling.	('modification', 'Var', (5, 17))	('beta-catenin', 'Gene', '1499', (27, 39))	('Lys48', 'Chemical', '-', (79, 84))	('stabilization', 'MPA', (40, 53))	('Lys48-linked proteasomal degradation', 'MPA', (79, 115))	('antagonizing', 'NegReg', (62, 74))	('promotes', 'PosReg', (18, 26))	('betaTrCP', 'Gene', (153, 161))	('beta-catenin', 'Gene', (27, 39))	('betaTrCP', 'Gene', '8945', (153, 161))
691024	33810518	UBE2B can also stabilize beta-catenin through the Lys63-linked polyUb chain, and silencing UBE2B can inhibit the transcription activity of beta-catenin.	('UBE2B', 'Gene', '7320', (91, 96))	('inhibit', 'NegReg', (101, 108))	('beta-catenin', 'Gene', '1499', (25, 37))	('Lys63', 'Chemical', '-', (50, 55))	('UBE2B', 'Gene', '7320', (0, 5))	('beta-catenin', 'Gene', (139, 151))	('transcription activity', 'MPA', (113, 135))	('stabilize', 'MPA', (15, 24))	('silencing', 'Var', (81, 90))	('UBE2B', 'Gene', (91, 96))	('beta-catenin', 'Gene', '1499', (139, 151))	('beta-catenin', 'Gene', (25, 37))	('UBE2B', 'Gene', (0, 5))
691027	33810518	If the activity of E2 or E3 changes, it will destroy the stability of beta-catenin.	('stability of', 'MPA', (57, 69))	('activity', 'MPA', (7, 15))	('E3', 'Chemical', '-', (25, 27))	('beta-catenin', 'Gene', (70, 82))	('beta-catenin', 'Gene', '1499', (70, 82))	('E3 changes', 'Var', (25, 35))	('E2', 'Chemical', 'MESH:D004958', (19, 21))	('destroy', 'NegReg', (45, 52))
691030	33810518	In addition, since Wnt/beta-catenin signaling is crucial for the activity of epithelial stem cells, it is not surprising that Wnt/beta-catenin pathway mutations are frequently observed in carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('observed', 'Reg', (176, 184))	('beta-catenin', 'Gene', (23, 35))	('beta-catenin', 'Gene', '1499', (23, 35))	('carcinomas', 'Disease', 'MESH:D009369', (188, 198))	('beta-catenin', 'Gene', (130, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('mutations', 'Var', (151, 160))	('carcinomas', 'Disease', (188, 198))	('beta-catenin', 'Gene', '1499', (130, 142))
691038	33810518	E2s participate in signaling pathways by modifying certain key substrates, including mTORC1, PTEN-AKT, TNF, TLR, NLR, RLR, and TCR.	('mTORC1', 'Gene', '382056', (85, 91))	('E2s', 'Chemical', 'MESH:D004958', (0, 3))	('PTEN', 'Gene', (93, 97))	('TCR', 'Gene', '6962', (127, 130))	('AKT', 'Gene', '207', (98, 101))	('TLR', 'Disease', (108, 111))	('PTEN', 'Gene', '5728', (93, 97))	('TCR', 'Gene', (127, 130))	('RLR', 'Gene', (118, 121))	('modifying', 'Reg', (41, 50))	('TNF', 'Gene', (103, 106))	('RC', 'Phenotype', 'HP:0005584', (88, 90))	('RLR', 'Gene', '79132', (118, 121))	('E2s', 'Var', (0, 3))	('signaling pathways', 'Pathway', (19, 37))	('AKT', 'Gene', (98, 101))	('NLR', 'Disease', (113, 116))	('mTORC1', 'Gene', (85, 91))	('TNF', 'Gene', '7124', (103, 106))	('participate', 'Reg', (4, 15))
691047	33810518	UBE2N-UBE2V1, TRAF6, and TRAF2 are involved in the formation of Lys63-linked chain on NF-kappaB essential modifier (NEMO)/IKKgamma and/or RIP1.	('UBE2V1', 'Gene', (6, 12))	('NEMO', 'Gene', (116, 120))	('RIP1', 'Gene', '8737', (138, 142))	('Lys63', 'Chemical', '-', (64, 69))	('TRAF2', 'Gene', (25, 30))	('UBE2V1', 'Gene', '7335', (6, 12))	('TRAF2', 'Gene', '7186', (25, 30))	('Lys63-linked', 'Var', (64, 76))	('RIP1', 'Gene', (138, 142))	('NEMO', 'Gene', '8517', (116, 120))	('IKKgamma', 'Gene', (122, 130))	('UBE2N', 'Gene', '7334', (0, 5))	('IKKgamma', 'Gene', '8517', (122, 130))	('TRAF6', 'Gene', '7189', (14, 19))	('NF-kappaB essential modifier', 'Gene', (86, 114))	('involved', 'Reg', (35, 43))	('NF-kappaB essential modifier', 'Gene', '8517', (86, 114))	('UBE2N', 'Gene', (0, 5))	('TRAF6', 'Gene', (14, 19))
691062	33810518	Overexpression of UBE2V1 can inhibit stress-induced apoptosis of HepG2 cells by activating NF-kappaB signaling.	('NF-kappaB', 'Gene', '4790', (91, 100))	('NF-kappaB', 'Gene', (91, 100))	('UBE2V1', 'Gene', (18, 24))	('inhibit', 'NegReg', (29, 36))	('UBE2V1', 'Gene', '7335', (18, 24))	('Overexpression', 'Var', (0, 14))	('activating', 'PosReg', (80, 90))	('HepG2', 'CellLine', 'CVCL:0027', (65, 70))	('stress-induced apoptosis', 'CPA', (37, 61))
691072	33810518	Therefore, there are many more E2s modified substrates that could participate in the regulation of cancer.	('E2s', 'Chemical', 'MESH:D004958', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('participate', 'Reg', (66, 77))	('E2s modified', 'Var', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
691076	33810518	UBE2T promoted the proliferation of renal cell carcinoma cells by regulating P13K/AKT signaling, suggesting that it might be a novel target for the treatment of patients with renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (175, 195))	('UBE2T', 'Gene', (0, 5))	('renal cell carcinoma', 'Disease', (36, 56))	('P13K', 'SUBSTITUTION', 'None', (77, 81))	('UBE2T', 'Gene', '29089', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (36, 56))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (36, 56))	('AKT', 'Gene', '207', (82, 85))	('renal cell carcinoma', 'Disease', (175, 195))	('proliferation', 'CPA', (19, 32))	('regulating', 'Reg', (66, 76))	('promoted', 'PosReg', (6, 14))	('patients', 'Species', '9606', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (175, 195))	('P13K', 'Var', (77, 81))	('AKT', 'Gene', (82, 85))
691078	33810518	The UBE2D complex is critical to maintain KRAS protein stability, and targeting such a complex might be a unique strategy to degrade mutant KRAS to kill cancer cells.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('KRAS', 'Gene', '3845', (140, 144))	('KRAS', 'Gene', (42, 46))	('UBE2', 'Gene', (4, 8))	('cancer', 'Disease', (153, 159))	('KRAS', 'Gene', '3845', (42, 46))	('UBE2', 'Gene', '7318', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('degrade', 'NegReg', (125, 132))	('mutant', 'Var', (133, 139))	('KRAS', 'Gene', (140, 144))
691079	33810518	Downregulation of UBE2O promoted AMPKalpha2-mediated suppression of the (mTORC1)-HIF-1alpha pathway, which is essential for metabolic "reprogramming" of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('mTORC1', 'Gene', (73, 79))	('HIF-1alpha', 'Gene', '3091', (81, 91))	('AMPKalpha2', 'Gene', '5563', (33, 43))	('cancer', 'Disease', (153, 159))	('suppression', 'NegReg', (53, 64))	('Downregulation', 'Var', (0, 14))	('AMPKalpha2', 'Gene', (33, 43))	('UBE2O', 'Gene', '63893', (18, 23))	('mTORC1', 'Gene', '382056', (73, 79))	('HIF-1alpha', 'Gene', (81, 91))	('UBE2O', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('RC', 'Phenotype', 'HP:0005584', (76, 78))
691081	33810518	Inhibition of CRMP2 SUMOylation could suppress GBM proliferation significantly in vitro.	('SUMOylation', 'Protein', (20, 31))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('CRMP2', 'Gene', '1808', (14, 19))	('CRMP2', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('GBM proliferation', 'CPA', (47, 64))	('suppress', 'NegReg', (38, 46))
691083	33810518	E2s not only promote the overexpression of these "mission critical" events in cancer cells, but also promote the progress of their entire life cycle.	('promote', 'PosReg', (101, 108))	('E2s', 'Chemical', 'MESH:D004958', (0, 3))	('progress', 'CPA', (113, 121))	('entire life cycle', 'CPA', (131, 148))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('promote', 'PosReg', (13, 20))	('E2s', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (25, 39))
691097	33810518	miRNAs, as natural antisense nucleotides, showed reduced immune response and low toxicity compared with plasmid DNA-based gene therapy and protein-based drug molecules.	('immune response', 'CPA', (57, 72))	('toxicity', 'Disease', 'MESH:D064420', (81, 89))	('toxicity', 'Disease', (81, 89))	('reduced', 'NegReg', (49, 56))	('reduced immune response', 'Phenotype', 'HP:0002721', (49, 72))	('miRNAs', 'Var', (0, 6))
691108	33810518	Specific modifications to the reported E2 inhibitors to reduce these shortcomings, optimize their efficacy, and their use in combined applications (chemotherapy drugs and inhibitors or multi-target inhibitors), might achieve unexpected results.	('E2', 'Chemical', 'MESH:D004958', (39, 41))	('efficacy', 'MPA', (98, 106))	('modifications', 'Var', (9, 22))
691138	29617798	We studied NIS data between 1998 and 2013 to obtain frequency of hospital stays where the primary diagnosis was EC in patients with age of 18 or higher using ICD-9 codes (150.0150.1150.2150.3, 150.4, 150.5, 150.8, 150.9, 230.1, V1003).	('NIS', 'Chemical', '-', (11, 14))	('V1003', 'Var', (228, 233))	('EC', 'Disease', 'MESH:D004938', (112, 114))	('150.0150.1150.2150.3', 'Var', (171, 191))	('patients', 'Species', '9606', (118, 126))
691188	29617798	Reasons for this trend are not clear, but one explanation could be that Medicare patients better access and more continuous insurance coverage compared to those with other types of insurance.	('Medicare', 'Var', (72, 80))	('better', 'PosReg', (90, 96))	('patients', 'Species', '9606', (81, 89))	('more', 'PosReg', (108, 112))
691216	31417270	PVS is also associated with an increased risk for upper gastrointestinal tract cancers, the most common being squamous cell carcinoma of the hypopharynx and cervical esophagus.	('carcinoma of the hypopharynx', 'Disease', (124, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('cervical esophagus', 'Disease', (157, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('upper gastrointestinal tract cancers', 'Disease', (50, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('upper gastrointestinal tract cancers', 'Disease', 'MESH:D004067', (50, 86))	('PVS', 'Var', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('carcinoma of the hypopharynx', 'Disease', 'MESH:D002277', (124, 152))
691388	29531468	Possible explanations might be as follows: (1) The stent could provide radial force to fix the PGA sheet, thereby preventing the defluvium of the PGA sheet; and (2) The PGA sheet could increase the friction between the stent and wound surface, reducing stent displacement, and also provide cytoskeleton and carry medicine to accelerate cell repair and wound healing.	('increase', 'PosReg', (185, 193))	('accelerate', 'PosReg', (325, 335))	('preventing', 'NegReg', (114, 124))	('cell repair', 'CPA', (336, 347))	('reducing', 'NegReg', (244, 252))	('friction', 'MPA', (198, 206))	('PGA', 'Chemical', 'MESH:D011100', (146, 149))	('wound healing', 'CPA', (352, 365))	('PGA', 'Chemical', 'MESH:D011100', (169, 172))	('PGA', 'Var', (169, 172))	('defluvium', 'MPA', (129, 138))	('stent displacement', 'CPA', (253, 271))	('provide', 'Reg', (282, 289))	('PGA', 'Chemical', 'MESH:D011100', (95, 98))	('cytoskeleton', 'CPA', (290, 302))
691416	26717375	Association of IL-23R Polymorphisms (rs6682925, rs10889677, rs1884444) With Cancer Risk Although interleukin (IL)-23 receptor (IL-23R) plays an important role in the pathogenesis of multiple cancers, its association with cancer risk is inconsistent across different studies.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('rs1884444', 'Var', (60, 69))	('Cancer', 'Disease', (76, 82))	('rs6682925', 'Mutation', 'rs6682925', (37, 46))	('Association', 'Interaction', (0, 11))	('rs1884444', 'Mutation', 'rs1884444', (60, 69))	('rs6682925', 'Var', (37, 46))	('rs10889677', 'Var', (48, 58))	('multiple cancers', 'Disease', 'MESH:D009369', (182, 198))	('cancer', 'Disease', (191, 197))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('interleukin (IL)-23', 'Gene', '51561', (97, 116))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('IL-23R', 'Gene', (127, 133))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))	('interleukin (IL)-23', 'Gene', (97, 116))	('rs10889677', 'Mutation', 'rs10889677', (48, 58))	('IL-23R', 'Gene', '149233', (127, 133))	('cancer', 'Disease', (221, 227))	('IL-23R', 'Gene', (15, 21))	('IL-23R', 'Gene', '149233', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('multiple cancers', 'Disease', (182, 198))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))
691417	26717375	We therefore conducted a meta-analysis with the aim of resolving the relationship among the 3 common polymorphisms of IL-23R (rs6682925, rs10889677, rs1884444) and cancer risk.	('rs10889677', 'Var', (137, 147))	('rs10889677', 'Mutation', 'rs10889677', (137, 147))	('rs6682925', 'Var', (126, 135))	('IL-23R', 'Gene', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('IL-23R', 'Gene', '149233', (118, 124))	('rs1884444', 'Mutation', 'rs1884444', (149, 158))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('rs6682925', 'Mutation', 'rs6682925', (126, 135))	('rs1884444', 'Var', (149, 158))
691418	26717375	Case-control studies evaluating the association between IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) and cancer risk were searched in the PubMed, Web of Science, and CNKI databases.	('IL-23R', 'Gene', '149233', (56, 62))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('rs1884444', 'Mutation', 'rs1884444', (101, 110))	('rs1884444', 'Var', (101, 110))	('rs6682925', 'Mutation', 'rs6682925', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rs10889677', 'Mutation', 'rs10889677', (89, 99))	('IL-23R', 'Gene', (56, 62))	('rs10889677', 'Var', (89, 99))	('rs6682925', 'Var', (78, 87))
691419	26717375	Data were included in the meta-analysis if they were from original studies adopting a case-control design investigating the association between IL-23R polymorphisms and risk of any cancer; all cancer cases must have been confirmed by histology or pathology, and controls selected from noncancer individuals.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('IL-23R', 'Gene', (144, 150))	('polymorphisms', 'Var', (151, 164))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('IL-23R', 'Gene', '149233', (144, 150))
691420	26717375	Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the relationship of IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) with cancer risk.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('rs6682925', 'Mutation', 'rs6682925', (117, 126))	('rs10889677', 'Var', (128, 138))	('rs10889677', 'Mutation', 'rs10889677', (128, 138))	('rs6682925', 'Var', (117, 126))	('IL-23R', 'Gene', (95, 101))	('rs1884444', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('IL-23R', 'Gene', '149233', (95, 101))	('rs1884444', 'Mutation', 'rs1884444', (140, 149))
691422	26717375	In the overall analysis, the rs10889677 polymorphism was associated with breast cancer (BC) under the allelic, homozygous, dominant, and heterozygous models.	('BC', 'Phenotype', 'HP:0003002', (88, 90))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('rs10889677', 'Var', (29, 39))	('rs10889677', 'Mutation', 'rs10889677', (29, 39))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('associated', 'Reg', (57, 67))
691423	26717375	Rs1884444 polymorphism was relevant to hepatocellular carcinoma (HCC) under the homozygous, recessive, and allelic models.	('HCC', 'Phenotype', 'HP:0001402', (65, 68))	('Rs1884444', 'Mutation', 'Rs1884444', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('Rs1884444', 'Var', (0, 9))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('HCC', 'Gene', (65, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('HCC', 'Gene', '619501', (65, 68))	('hepatocellular carcinoma', 'Disease', (39, 63))
691424	26717375	However, no evidence of a relationship between IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) and cancer risk was found in the overall population.	('rs6682925', 'Mutation', 'rs6682925', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('rs1884444', 'Var', (92, 101))	('rs10889677', 'Var', (80, 90))	('rs10889677', 'Mutation', 'rs10889677', (80, 90))	('IL-23R', 'Gene', (47, 53))	('rs6682925', 'Var', (69, 78))	('rs1884444', 'Mutation', 'rs1884444', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('IL-23R', 'Gene', '149233', (47, 53))	('cancer', 'Disease', (107, 113))
691425	26717375	Our meta-analysis provides no evidence supporting a global association of IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) with the risk of cancer.	('rs10889677', 'Mutation', 'rs10889677', (107, 117))	('rs1884444', 'Mutation', 'rs1884444', (119, 128))	('rs6682925', 'Mutation', 'rs6682925', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('rs10889677', 'Var', (107, 117))	('rs6682925', 'Var', (96, 105))	('IL-23R', 'Gene', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('rs1884444', 'Var', (119, 128))	('IL-23R', 'Gene', '149233', (74, 80))	('cancer', 'Disease', (147, 153))
691426	26717375	However, rs10889677 may be associated with BC susceptibility and rs1884444 had association with HCC risk.	('BC', 'Phenotype', 'HP:0003002', (43, 45))	('rs1884444', 'Mutation', 'rs1884444', (65, 74))	('rs10889677', 'Mutation', 'rs10889677', (9, 19))	('HCC', 'Gene', (96, 99))	('rs10889677', 'Var', (9, 19))	('associated', 'Reg', (27, 37))	('association', 'Interaction', (79, 90))	('HCC', 'Gene', '619501', (96, 99))	('rs1884444', 'Var', (65, 74))	('HCC', 'Phenotype', 'HP:0001402', (96, 99))
691436	26717375	Some studies found that genetic variants of IL-23R may contribute to the pathological development from hepatitis to HCC, and that hepatitis B virus could induce hepatitis by increasing IL-23 expression in a mannose receptor/endocytosis-dependent or -independent manner, and result in liver damage through the IL-23/IL-17 axis.	('induce', 'Reg', (154, 160))	('hepatitis', 'Disease', 'MESH:D056486', (130, 139))	('hepatitis', 'Disease', 'MESH:D056486', (161, 170))	('increasing', 'PosReg', (174, 184))	('hepatitis', 'Disease', (130, 139))	('hepatitis', 'Disease', (161, 170))	('hepatitis', 'Phenotype', 'HP:0012115', (103, 112))	('IL-23', 'Gene', (185, 190))	('result in', 'Reg', (274, 283))	('hepatitis', 'Disease', 'MESH:D056486', (103, 112))	('IL-17', 'Gene', (315, 320))	('IL-17', 'Gene', '3605', (315, 320))	('expression', 'MPA', (191, 201))	('liver damage', 'Disease', (284, 296))	('hepatitis', 'Disease', (103, 112))	('genetic variants', 'Var', (24, 40))	('HCC', 'Gene', '619501', (116, 119))	('HCC', 'Phenotype', 'HP:0001402', (116, 119))	('liver damage', 'Disease', 'MESH:D056486', (284, 296))	('HCC', 'Gene', (116, 119))	('IL-23R', 'Gene', (44, 50))	('hepatitis', 'Phenotype', 'HP:0012115', (130, 139))	('IL-23R', 'Gene', '149233', (44, 50))	('contribute', 'Reg', (55, 65))	('hepatitis', 'Phenotype', 'HP:0012115', (161, 170))	('hepatitis B virus', 'Species', '10407', (130, 147))
691440	26717375	Recently, some case-control studies have investigated the association of IL-23R polymorphisms with the risk of cancer, including esophageal squamous cell carcinoma, bladder cancer, acute myeloid leukemia, gastric cancer, ovarian cancer, breast cancer, lung cancer, colorectal cancer, and nasopharyngeal cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (265, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('ovarian cancer', 'Disease', (221, 235))	('nasopharyngeal cancer', 'Disease', (288, 309))	('acute myeloid leukemia', 'Disease', (181, 203))	('colorectal cancer', 'Disease', (265, 282))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('cancer', 'Disease', (111, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (221, 235))	('lung cancer', 'Disease', (252, 263))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('IL-23R', 'Gene', (73, 79))	('cancer', 'Disease', (303, 309))	('gastric cancer', 'Disease', (205, 219))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('IL-23R', 'Gene', '149233', (73, 79))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (288, 309))	('breast cancer', 'Disease', (237, 250))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (129, 163))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('polymorphisms', 'Var', (80, 93))	('cancer', 'Disease', (213, 219))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (181, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (187, 203))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('association', 'Interaction', (58, 69))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (229, 235))	('leukemia', 'Phenotype', 'HP:0001909', (195, 203))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (181, 203))	('gastric cancer', 'Disease', 'MESH:D013274', (205, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (265, 282))	('lung cancer', 'Disease', 'MESH:D008175', (252, 263))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('bladder cancer', 'Disease', 'MESH:D001749', (165, 179))	('bladder cancer', 'Disease', (165, 179))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('ovarian cancer', 'Disease', 'MESH:D010051', (221, 235))	('cancer', 'Disease', (244, 250))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (288, 309))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('lung cancer', 'Phenotype', 'HP:0100526', (252, 263))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('bladder cancer', 'Phenotype', 'HP:0009725', (165, 179))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('gastric cancer', 'Phenotype', 'HP:0012126', (205, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('cancer', 'Disease', (257, 263))	('esophageal squamous cell carcinoma', 'Disease', (129, 163))
691441	26717375	Wrobel et al found a correlation between the IL-17F rs763780 polymorphism and AML, but no relationship between IL-23R and AML was observed.	('IL-23R', 'Gene', '149233', (111, 117))	('rs763780 polymorphism', 'Var', (52, 73))	('AML', 'Disease', 'MESH:D015470', (78, 81))	('correlation', 'Interaction', (21, 32))	('IL-17F', 'Gene', '112744', (45, 51))	('rs763780', 'Mutation', 'rs763780', (52, 60))	('AML', 'Disease', 'MESH:D015470', (122, 125))	('IL-17F', 'Gene', (45, 51))	('AML', 'Disease', (78, 81))	('IL-23R', 'Gene', (111, 117))	('polymorphism', 'Var', (61, 73))	('AML', 'Disease', (122, 125))
691442	26717375	However, Qian et al reported that genetic variants of IL-23R may contribute to AML risk.	('AML', 'Disease', (79, 82))	('genetic variants', 'Var', (34, 50))	('IL-23R', 'Gene', (54, 60))	('AML', 'Disease', 'MESH:D015470', (79, 82))	('IL-23R', 'Gene', '149233', (54, 60))	('contribute', 'Reg', (65, 75))
691443	26717375	Based on these findings, the effects of IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) have been widely discussed, but no conclusive relationships have been determined.	('rs6682925', 'Mutation', 'rs6682925', (62, 71))	('rs1884444', 'Var', (85, 94))	('rs10889677', 'Var', (73, 83))	('rs10889677', 'Mutation', 'rs10889677', (73, 83))	('IL-23R', 'Gene', (40, 46))	('rs6682925', 'Var', (62, 71))	('IL-23R', 'Gene', '149233', (40, 46))	('rs1884444', 'Mutation', 'rs1884444', (85, 94))
691444	26717375	Therefore, we conducted a meta-analysis to achieve a more comprehensive evaluation of the association among 3 IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) with cancer risk.	('rs10889677', 'Var', (143, 153))	('rs10889677', 'Mutation', 'rs10889677', (143, 153))	('IL-23R', 'Gene', (110, 116))	('rs1884444', 'Mutation', 'rs1884444', (155, 164))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('association', 'Interaction', (90, 101))	('cancer', 'Disease', (171, 177))	('IL-23R', 'Gene', '149233', (110, 116))	('rs6682925', 'Mutation', 'rs6682925', (132, 141))	('rs6682925', 'Var', (132, 141))	('rs1884444', 'Var', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
691445	26717375	A comprehensive literature search was conducted using the following search terms: "Interleukin-23 receptor" or "IL-23R," "polymorphism" or "SNP," "cancer," and "tumor."	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('IL-23R', 'Gene', (112, 118))	('Interleukin-23 receptor', 'Gene', (83, 106))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('IL-23R', 'Gene', '149233', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('polymorphism" or "SNP', 'Var', (122, 143))	('cancer', 'Disease', (147, 153))	('tumor', 'Disease', (161, 166))	('Interleukin-23 receptor', 'Gene', '149233', (83, 106))
691446	26717375	The following criteria were used to select eligible studies for further meta-analysis: (1) original studies; (2) case-control design investigating the association between IL-23R polymorphisms and risk of any cancer; and (3) all cancer cases were confirmed by histology or pathology, and the controls were selected from noncancer individuals.	('cancer', 'Disease', (208, 214))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('association', 'Interaction', (151, 162))	('cancer', 'Disease', (322, 328))	('IL-23R', 'Gene', (171, 177))	('polymorphisms', 'Var', (178, 191))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('IL-23R', 'Gene', '149233', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
691449	26717375	Using the genotype and allele frequencies in cases and controls, we applied crude odds ratios (ORs) with corresponding 95% confidence intervals (CIs) to evaluate the associations between IL-23R (rs6682925, rs10889677, rs1884444) polymorphisms and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('rs1884444', 'Var', (218, 227))	('rs10889677', 'Var', (206, 216))	('rs10889677', 'Mutation', 'rs10889677', (206, 216))	('IL-23R', 'Gene', (187, 193))	('rs6682925', 'Var', (195, 204))	('associations', 'Interaction', (166, 178))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('rs1884444', 'Mutation', 'rs1884444', (218, 227))	('IL-23R', 'Gene', '149233', (187, 193))	('rs6682925', 'Mutation', 'rs6682925', (195, 204))
691450	26717375	As shown in Figure 1, a total of 134 studies were identified that evaluated IL-23R polymorphisms (rs6682925, rs10889677, rs1884444), and 41 of these studies were excluded as duplicate publications.	('IL-23R', 'Gene', '149233', (76, 82))	('rs1884444', 'Mutation', 'rs1884444', (121, 130))	('rs1884444', 'Var', (121, 130))	('rs6682925', 'Mutation', 'rs6682925', (98, 107))	('rs6682925', 'Var', (98, 107))	('rs10889677', 'Var', (109, 119))	('rs10889677', 'Mutation', 'rs10889677', (109, 119))	('IL-23R', 'Gene', (76, 82))
691451	26717375	Finally, a total of 15 studies with 8784 cases and 10,321 cancer-free controls were found to meet the inclusion criteria for assessing the influence of the rs6682925, rs10889677, and rs1884444 polymorphisms on cancer risk.	('rs1884444', 'Var', (183, 192))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('rs1884444', 'Mutation', 'rs1884444', (183, 192))	('rs6682925', 'Mutation', 'rs6682925', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('rs6682925', 'Var', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('rs10889677', 'Var', (167, 177))	('cancer', 'Disease', (58, 64))	('rs10889677', 'Mutation', 'rs10889677', (167, 177))	('cancer', 'Disease', (210, 216))
691454	26717375	Evaluation of the association between the rs6682925 polymorphism and cancer risk is summarized in Table 3 and Figure 2.	('rs6682925', 'Mutation', 'rs6682925', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs6682925', 'Var', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
691455	26717375	There were 10 studies with 4060 cases and 4406 controls evaluating the effect of rs10889677 on cancer risk.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('rs10889677', 'Mutation', 'rs10889677', (81, 91))	('rs10889677', 'Var', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
691456	26717375	However, in the subgroup analyses by cancer type, a significant association was found between rs10889677 polymorphism and BC risk under the allelic, homozygous, dominant, and heterozygous models (C vs A: OR = 0.77, 95% CI = 0.69-0.86, P = 0.000; CC vs AA: OR = 0.56, 95% CI = 0.43-0.73, P = 0.000; AC+CC vs AA: OR = 0.76, 95% CI = 0.66-0.88, P = 0.000; AC vs AA: OR = 0.81, 95% CI = 0.70-0.95, P = 0.007).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('rs10889677', 'Var', (94, 104))	('BC', 'Phenotype', 'HP:0003002', (122, 124))	('rs10889677', 'Mutation', 'rs10889677', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
691457	26717375	Eight studies with 6229 cases and 8109 controls were used to evaluate the relationship between the rs1884444 polymorphism with cancer risk, which is summarized in Table 3 and Figure 4.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs1884444', 'Var', (99, 108))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('rs1884444', 'Mutation', 'rs1884444', (99, 108))
691458	26717375	Further analysis of the studies which were in agreement with HWE also showed no association between rs1884444 polymorphism and cancer risk generally.	('rs1884444 polymorphism', 'Var', (100, 122))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('polymorphism', 'Var', (110, 122))	('rs1884444', 'Mutation', 'rs1884444', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
691459	26717375	However, we found that rs1884444 was significantly associated with HCC risk based on the allelic model, homozygous genetic model, and recessive genetic model (T vs G: OR = 1.18, 95% CI = 1.04-1.33, P = 0.009; TT vs GG: OR = 1.41, 95% CI = 1.08-1.83, P = 0.01; TT vs GG+TG: OR = 1.33, 95% CI = 1.04-1.70, P = 0.02).	('HCC', 'Gene', '619501', (67, 70))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('rs1884444', 'Var', (23, 32))	('associated', 'Reg', (51, 61))	('rs1884444', 'Mutation', 'rs1884444', (23, 32))	('HCC', 'Gene', (67, 70))
691460	26717375	Sensitivity analyses were performed by sequential removal of each eligible study to assess the influence of each individual study on the pooled OR for the respective comparisons of the rs6682925, rs10889677, and rs1884444 polymorphisms.	('rs10889677', 'Var', (196, 206))	('rs10889677', 'Mutation', 'rs10889677', (196, 206))	('rs6682925', 'Var', (185, 194))	('rs1884444', 'Mutation', 'rs1884444', (212, 221))	('rs1884444', 'Var', (212, 221))	('rs6682925', 'Mutation', 'rs6682925', (185, 194))
691461	26717375	There was heterogeneity among studies in both the overall comparisons and the subgroup analyses for all 3 polymorphisms evaluated (rs6682925, rs10889677, and rs1884444).	('rs6682925', 'Mutation', 'rs6682925', (131, 140))	('rs10889677', 'Mutation', 'rs10889677', (142, 152))	('rs10889677', 'Var', (142, 152))	('rs1884444', 'Var', (158, 167))	('rs6682925', 'Var', (131, 140))	('rs1884444', 'Mutation', 'rs1884444', (158, 167))
691462	26717375	The results shown no evidence of heterogeneity coming from the source of control (rs6682925: P = 0.30; rs10889677: P = 0.10; rs1884444: P = 0.06), ethnicity (P = 0.30, 0.68, and 0.68, respectively), and year of publication (P = 0.89, 0.36, and 0.14, respectively).	('rs10889677', 'Var', (103, 113))	('rs10889677', 'Mutation', 'rs10889677', (103, 113))	('rs1884444', 'Mutation', 'rs1884444', (125, 134))	('rs6682925', 'Mutation', 'rs6682925', (82, 91))	('rs1884444', 'Var', (125, 134))	('rs6682925:', 'Var', (82, 92))
691465	26717375	In the present stratified meta-analysis based on cancer type, there was no significant association between rs6682925, rs10889677, or rs1884444 and cancer risk in the overall population.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('rs1884444', 'Var', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('rs6682925', 'Mutation', 'rs6682925', (107, 116))	('rs10889677', 'Var', (118, 128))	('rs10889677', 'Mutation', 'rs10889677', (118, 128))	('rs6682925', 'Var', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('rs1884444', 'Mutation', 'rs1884444', (133, 142))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', (49, 55))
691466	26717375	Our meta-analysis involved 15 independent case-control studies involving 8784 cancer patients and 10,321 cancer-free controls, and the results showed that the rs6682925 polymorphism was not associated with the susceptibility to any cancer and rs10889677 polymorphism may only increase BC susceptibility.	('BC', 'Phenotype', 'HP:0003002', (285, 287))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (232, 238))	('cancer', 'Disease', (105, 111))	('increase', 'PosReg', (276, 284))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('rs6682925', 'Mutation', 'rs6682925', (159, 168))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('rs6682925', 'Var', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rs10889677', 'Var', (243, 253))	('rs10889677', 'Mutation', 'rs10889677', (243, 253))
691467	26717375	Qian et al found that rs6682925 TC/CC variant genotypes were associated with an increased risk of acute myeloid leukemia, and this polymorphism was also proposed to have predictive value for nonsmall-cell lung cancer clinical outcomes.	('rs6682925', 'Var', (22, 31))	('TC/CC', 'Gene', (32, 37))	('leukemia', 'Phenotype', 'HP:0001909', (112, 120))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (98, 120))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('acute myeloid leukemia', 'Disease', (98, 120))	('nonsmall-cell lung cancer', 'Disease', 'MESH:D002289', (191, 216))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (104, 120))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (98, 120))	('nonsmall-cell lung cancer', 'Disease', (191, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('rs6682925', 'Mutation', 'rs6682925', (22, 31))	('nonsmall-cell lung cancer', 'Phenotype', 'HP:0030358', (191, 216))
691468	26717375	Individuals with at least 1 variant C allele of the rs10889677 polymorphism showed a higher risk of developing oral cancer and tumor lymph node metastasis compared with patients carrying the wild-type A/A and C/C homozygous genotypes, and IL23R was suggested to play an important role in the susceptibility and prognosis of ovarian cancer in the Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor lymph node metastasis', 'Disease', 'MESH:D009362', (127, 154))	('developing', 'PosReg', (100, 110))	('ovarian cancer', 'Disease', (324, 338))	('rs10889677', 'Mutation', 'rs10889677', (52, 62))	('patients', 'Species', '9606', (169, 177))	('rs10889677', 'Var', (52, 62))	('IL23R', 'Gene', '149233', (239, 244))	('ovarian cancer', 'Phenotype', 'HP:0100615', (324, 338))	('IL23R', 'Gene', (239, 244))	('oral cancer', 'Disease', 'MESH:D009062', (111, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (324, 338))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor lymph node metastasis', 'Disease', (127, 154))	('oral cancer', 'Disease', (111, 122))
691469	26717375	A recent meta-analysis indicated individuals with AC and CC genotype of rs10889677 polymorphism may decrease risk of multiple solid tumors (P < 0.001).	('rs10889677', 'Mutation', 'rs10889677', (72, 82))	('polymorphism', 'Var', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('multiple solid tumors', 'Disease', (117, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('decrease', 'NegReg', (100, 108))	('rs10889677 polymorphism', 'Var', (72, 95))	('multiple solid tumors', 'Disease', 'MESH:D009369', (117, 138))
691470	26717375	Zheng et al demonstrated rs10889677A > C genotype could affect T-cell proliferation rate, the proportion of Tregs and IL-23R expression, which further influenced cancer susceptibility.	('affect', 'Reg', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('IL-23R', 'Gene', (118, 124))	('rs10889677A > C', 'Var', (25, 40))	('cancer', 'Disease', (162, 168))	('IL-23R', 'Gene', '149233', (118, 124))	('expression', 'MPA', (125, 135))	('T-cell proliferation rate', 'CPA', (63, 88))	('rs10889677A > C', 'DBSNP_MENTION', 'None', (25, 40))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('influenced', 'Reg', (151, 161))
691472	26717375	The present meta-analysis revealed an increased risk of HCC in carriers of the rs1884444 polymorphism; indeed, significant associations were observed between rs1884444 and HCC risk in 3 genotype models, but not the dominant and heterozygous models, in the overall population.	('rs1884444', 'Mutation', 'rs1884444', (79, 88))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('HCC', 'Gene', (172, 175))	('HCC', 'Phenotype', 'HP:0001402', (172, 175))	('rs1884444', 'Var', (158, 167))	('HCC', 'Gene', (56, 59))	('HCC', 'Gene', '619501', (172, 175))	('rs1884444', 'Var', (79, 88))	('rs1884444', 'Mutation', 'rs1884444', (158, 167))	('associations', 'Interaction', (123, 135))	('HCC', 'Gene', '619501', (56, 59))
691476	26717375	Fourth, meta-analysis is the statistical analysis of large collection of analysis from individual studies for the purpose of integrating the findings, but there were few studies evaluated the association between rs10889677 and bladder cancer, HCC, oral cancer and other cancer, rs1884444 and esophageal squamous cell carcinoma, acute myeloid leukemia, esophageal cancer, and other cancer.	('rs10889677', 'Mutation', 'rs10889677', (212, 222))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (292, 326))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (303, 326))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (328, 350))	('cancer', 'Disease', 'MESH:D009369', (363, 369))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', (381, 387))	('esophageal cancer', 'Disease', 'MESH:D004938', (352, 369))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('rs1884444', 'Var', (278, 287))	('rs1884444', 'Mutation', 'rs1884444', (278, 287))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('acute myeloid leukemia', 'Disease', (328, 350))	('HCC', 'Gene', '619501', (243, 246))	('cancer', 'Disease', (363, 369))	('esophageal squamous cell carcinoma', 'Disease', (292, 326))	('oral cancer', 'Disease', 'MESH:D009062', (248, 259))	('HCC', 'Phenotype', 'HP:0001402', (243, 246))	('cancer', 'Disease', (253, 259))	('esophageal cancer', 'Disease', (352, 369))	('oral cancer', 'Disease', (248, 259))	('bladder cancer', 'Disease', 'MESH:D001749', (227, 241))	('bladder cancer', 'Disease', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('HCC', 'Gene', (243, 246))	('association', 'Interaction', (192, 203))	('rs10889677', 'Var', (212, 222))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('bladder cancer', 'Phenotype', 'HP:0009725', (227, 241))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (328, 350))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (334, 350))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('leukemia', 'Phenotype', 'HP:0001909', (342, 350))
691478	26717375	In conclusion, the current evidence does not support a significant association between the rs6682925, rs10889677, and rs1884444 polymorphisms of IL-23R with cancer susceptibility in the overall population, although rs10889677 appears to influence the susceptibility to BC and rs1884444 may increase the risk of HCC.	('IL-23R', 'Gene', (145, 151))	('IL-23R', 'Gene', '149233', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('influence', 'Reg', (237, 246))	('increase', 'PosReg', (290, 298))	('rs10889677', 'Var', (215, 225))	('rs6682925', 'Mutation', 'rs6682925', (91, 100))	('rs6682925', 'Var', (91, 100))	('rs1884444', 'Var', (276, 285))	('rs1884444', 'Mutation', 'rs1884444', (276, 285))	('rs10889677', 'Mutation', 'rs10889677', (215, 225))	('cancer', 'Disease', (157, 163))	('rs10889677', 'Var', (102, 112))	('BC', 'Phenotype', 'HP:0003002', (269, 271))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('rs1884444', 'Var', (118, 127))	('HCC', 'Gene', '619501', (311, 314))	('HCC', 'Phenotype', 'HP:0001402', (311, 314))	('rs1884444', 'Mutation', 'rs1884444', (118, 127))	('rs10889677', 'Mutation', 'rs10889677', (102, 112))	('HCC', 'Gene', (311, 314))
691516	28072858	Considerable heterogeneity was observed in the overall analysis (I2 = 90%), although this was primarily due to the different sample sizes: when the sample size was less than 600, the use of PPIs was strongly associated with a lower risk of dysplasia in patients with BE (OR 0.20, 95% CI 0.09-0.46; I2 = 77%).	('lower', 'NegReg', (226, 231))	('dysplasia', 'Disease', 'MESH:D004476', (240, 249))	('PPIs', 'Var', (190, 194))	('patients', 'Species', '9606', (253, 261))	('BE', 'Phenotype', 'HP:0100580', (267, 269))	('dysplasia', 'Disease', (240, 249))
691522	28072858	This previous article included four cohort and two case-control studies for analysis, as partly described here, involving a total of 2813 patients, and showed that PPI use was associated with a 71% risk reduction in progression to EAC and/or HGD in a duration-dependent manner.	('HGD', 'Disease', (242, 245))	('EAC', 'Disease', (231, 234))	('PPI use', 'Var', (164, 171))	('use', 'Var', (168, 171))	('reduction', 'NegReg', (203, 212))	('patients', 'Species', '9606', (138, 146))	('EAC', 'Phenotype', 'HP:0011459', (231, 234))
691530	28072858	Indeed, in experimental studies, COX-2 inhibitors suppressed the growth of BE cells, potentially through suppression of basic fibroblast growth factor.	('inhibitors', 'Var', (39, 49))	('suppressed', 'NegReg', (50, 60))	('basic', 'Protein', (120, 125))	('COX-2', 'Gene', (33, 38))	('BE', 'Phenotype', 'HP:0100580', (75, 77))	('suppression', 'NegReg', (105, 116))	('COX-2', 'Gene', '5743', (33, 38))	('growth of BE cells', 'CPA', (65, 83))	('men', 'Species', '9606', (17, 20))
691533	28072858	The observation that PPIs may increase the risk of EAC is explained by the treatment indication being a risk factor for EAC, i.e., reverse causation and the phenomenon of 'channeling', where in high-risk patients are being prescribed high-dose PPIs whereas low-risk patients are being prescribed lower doses or not at all.	('patients', 'Species', '9606', (204, 212))	('patients', 'Species', '9606', (266, 274))	('high-dose PPIs', 'Var', (234, 248))	('men', 'Species', '9606', (162, 165))	('EAC', 'Phenotype', 'HP:0011459', (120, 123))	('men', 'Species', '9606', (80, 83))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('PPIs', 'Var', (21, 25))	('PPIs', 'Var', (244, 248))	('EAC', 'Disease', (51, 54))
691535	28072858	Concerns that PPI-induced hypergastrinaemia may increase the risk of adenocarcinoma development have also been expressed.	('hypergastrinaemia', 'Disease', 'None', (26, 43))	('hypergastrinaemia', 'Disease', (26, 43))	('men', 'Species', '9606', (91, 94))	('PPI-induced', 'Var', (14, 25))	('adenocarcinoma', 'Disease', (69, 83))	('hypergastrinaemia may increase', 'Phenotype', 'HP:0500167', (26, 56))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))
691548	28072858	PPIs were found to have no association with the risk of EAC and/or HGD in patients with BE (unadjusted OR 0.43, 95% CI 0.17-1.08).	('EAC', 'Disease', (56, 59))	('HGD', 'Disease', (67, 70))	('patients', 'Species', '9606', (74, 82))	('BE', 'Phenotype', 'HP:0100580', (88, 90))	('PPIs', 'Var', (0, 4))	('EAC', 'Phenotype', 'HP:0011459', (56, 59))
691555	27650456	Univariate analyses demonstrated that TNM pStage (p < 0.0001), tumor size (p = 0.0014), operation time (p = 0.0209), low LMR (p = 0.0008), and high PLR (p = 0.0232) were significant risk factors for poor prognosis.	('tumor', 'Disease', (63, 68))	('low', 'Var', (117, 120))	('TNM', 'Gene', '10178', (38, 41))	('LMR', 'Chemical', '-', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('TNM', 'Gene', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
691557	27650456	In non-elderly patients, univariate analyses demonstrated that TNM pStage (p < 0.0001), tumor size (p = 0.0001), operation time (p = 0.0374), LMR (p < 0.0001), and PLR (p = 0.0189) were significantly associated with a poorer prognosis.	('patients', 'Species', '9606', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('TNM', 'Gene', '10178', (63, 66))	('LMR', 'Chemical', '-', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('TNM', 'Gene', (63, 66))	('PLR', 'Var', (164, 167))	('tumor', 'Disease', (88, 93))
691558	27650456	Multivariate analysis demonstrated that TNM pStage (p = 0.001) and LMR (p = 0.0007) were independent risk factors for a poorer prognosis.	('TNM', 'Gene', '10178', (40, 43))	('LMR', 'Chemical', '-', (67, 70))	('TNM', 'Gene', (40, 43))	('LMR', 'Var', (67, 70))
691560	27650456	LMR was associated with cancer-specific survival (CSS) of esophageal cancer patients after curative esophagectomy.	('LMR', 'Var', (0, 3))	('patients', 'Species', '9606', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('LMR', 'Chemical', '-', (0, 3))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CSS', 'Chemical', '-', (50, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('associated', 'Reg', (8, 18))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
691583	27650456	A value of 4.0 was chosen as the cut-off level for LMR for CSS as associated with a high sensitivity and specificity for CSS (62.5 and 71.3 %, respectively).	('CSS', 'Chemical', '-', (59, 62))	('CSS', 'Gene', (59, 62))	('LMR', 'Var', (51, 54))	('CSS', 'Chemical', '-', (121, 124))	('LMR', 'Chemical', '-', (51, 54))	('CSS', 'Disease', (121, 124))
691598	27650456	Univariate analyses demonstrated that TNM pStage (p < 0.0001), tumor size (p = 0.0014), operation time (p = 0.0209), low LMR (p = 0.0008), and high PLR (p = 0.0232) were significant risk factors for poor prognosis (Table 2).	('tumor', 'Disease', (63, 68))	('low', 'Var', (117, 120))	('TNM', 'Gene', '10178', (38, 41))	('LMR', 'Chemical', '-', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('TNM', 'Gene', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
691599	27650456	TNM pStage (HR, 4.190; 95 % CI, 2.146-8.562; p < 0.0001) and low LMR (HR, 2.372; 95 % CI, 1.198-4.840; p = 0.0129) were found to be independently associated with poor prognosis via multivariate analysis (Table 2).	('TNM', 'Gene', (0, 3))	('TNM', 'Gene', '10178', (0, 3))	('low LMR', 'Var', (61, 68))	('LMR', 'Chemical', '-', (65, 68))
691603	27650456	Multivariate analysis demonstrated that TNM pStage (HR, 4.009; 95 % CI, 1.731-10.162; p = 0.001) and LMR (HR, 4.553; 95 % CI, 1.856-12.516; p = 0.0007) were independent risk factors for a poorer prognosis (Table 4).	('LMR', 'Chemical', '-', (101, 104))	('LMR', 'Var', (101, 104))	('TNM', 'Gene', '10178', (40, 43))	('TNM', 'Gene', (40, 43))
691616	27650456	Additionally, univariate analyses revealed that a low LMR was a significant risk factor for poor prognosis in stage III patients, whereas no prognostic factor was detected in patients with stage I or II cancer.	('low LMR', 'Var', (50, 57))	('stage III', 'Disease', (110, 119))	('II cancer', 'Disease', 'MESH:D009369', (200, 209))	('II cancer', 'Disease', (200, 209))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (120, 128))	('LMR', 'Chemical', '-', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
691656	27650456	In conclusion, our study demonstrated that the LMR and PLR were associated with CSS of esophageal cancer patients after curative esophagectomy.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('associated', 'Reg', (64, 74))	('patients', 'Species', '9606', (105, 113))	('CSS', 'Disease', (80, 83))	('esophageal cancer', 'Disease', (87, 104))	('CSS', 'Chemical', '-', (80, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('LMR', 'Var', (47, 50))	('LMR', 'Chemical', '-', (47, 50))
691678	26828133	With the implementation of DNA microarrays into cancer research, it was possible for the first time to determine the expression of thousands of genes in one assay and detect disease- or resistance-driving mutations in tumor tissue on a large scale.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('expression', 'MPA', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mutations', 'Var', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', (218, 223))
691683	26828133	Inhibitors of the epidermal growth factor receptor (EGFR) were among the first targeted therapeutics whose treatment outcome could be linked to a specific genetic profile including the molecule being targeted as well as downstream pathways, as discussed below.	('EGFR', 'Gene', (52, 56))	('epidermal growth factor receptor', 'Gene', '1956', (18, 50))	('Inhibitors', 'Var', (0, 10))	('epidermal growth factor receptor', 'Gene', (18, 50))
691687	26828133	Tumors expressing wildtype KRAS and BRAF had a significantly higher control rate when cetuximab therapy was applied, while the presence of specific KRAS or BRAF mutations diminished the tumor response.	('KRAS', 'Var', (27, 31))	('KRAS', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('control', 'MPA', (68, 75))	('BRAF', 'Gene', (156, 160))	('diminished', 'NegReg', (171, 181))	('rat', 'Species', '10116', (76, 79))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cetuximab', 'Chemical', 'MESH:D000068818', (86, 95))	('higher', 'PosReg', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (161, 170))
691695	26828133	Interestingly, Komaki and colleagues did not find a correlation between EGFR mutation status and response, although this may be due to the relatively small patient numbers or to different molecular mechanisms with the drug used alone or in combination with radiation.	('mutation', 'Var', (77, 85))	('EGFR', 'Gene', (72, 76))	('patient', 'Species', '9606', (156, 163))
691696	26828133	For example, the BRAF inhibitors vemurafenib and dabrafenib are designed to inhibit only BRAF with a substitution of the amino acid valine at position 600 with glutamic acid (V600E), but not wildtype BRAF.	('dabrafenib', 'Chemical', 'MESH:C561627', (49, 59))	('inhibit', 'NegReg', (76, 83))	('valine at position 600 with glutamic acid', 'Mutation', 'rs113488022', (132, 173))	('V600E', 'Mutation', 'rs113488022', (175, 180))	('vemurafenib', 'Chemical', 'MESH:D000077484', (33, 44))	('BRAF', 'Gene', (89, 93))	('V600E', 'Var', (175, 180))	('substitution', 'Var', (101, 113))
691697	26828133	This V600E mutation is frequently found in melanoma and papillary thyroid carcinoma.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (66, 83))	('melanoma and papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (43, 83))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (56, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('V600E', 'Var', (5, 10))	('found', 'Reg', (34, 39))
691698	26828133	Inhibition of BRAF results in a significant increase of overall and disease-free survival in patients with BRAF-mutant melanoma.	('disease-free survival', 'CPA', (68, 89))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('increase', 'PosReg', (44, 52))	('melanoma', 'Disease', (119, 127))	('BRAF-mutant', 'Gene', (107, 118))	('Inhibition', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('BRAF', 'Gene', (14, 18))	('patients', 'Species', '9606', (93, 101))	('overall', 'CPA', (56, 63))
691701	26828133	Interestingly, all tumors showed no response to the treatment, indicating a radiosensitizing effect on normal tissue with wildtype BRAF, but not on malignant cells harboring BRAF V600E mutations.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('radiosensitizing effect', 'MPA', (76, 99))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('BRAF', 'Gene', (174, 178))	('V600E mutations', 'Var', (179, 194))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
691702	26828133	One possible explanation for this finding is that the effect of radiation on the skin is potentiated by the drug-related cutaneous side effects of BRAF inhibitors including erythema and hand-foot syndrome which are thought to be caused by a paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in wildtype BRAF cells.	('inhibitors', 'Var', (152, 162))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (186, 204))	('erythema', 'Phenotype', 'HP:0010783', (173, 181))	('erythema', 'Disease', 'MESH:D004890', (173, 181))	('effect of radiation on the skin', 'Phenotype', 'HP:0011133', (54, 85))	('activation', 'PosReg', (253, 263))	('erythema', 'Disease', (173, 181))	('BRAF', 'Gene', (147, 151))	('MAPK', 'Gene', '5594', (305, 309))	('hand-foot syndrome', 'Disease', (186, 204))	('MAPK', 'Gene', (305, 309))
691703	26828133	Inhibition of the poly (ADP-ribose) polymerase (PARP), an enzyme involved in repairing DNA single strand breaks (SSBs), has no radiosensitizing effect in normal cells due to an efficient repair of SSBs by homologous recombination (HR).	('SSBs', 'Chemical', '-', (113, 117))	('SSBs', 'Chemical', '-', (197, 201))	('poly (ADP-ribose) polymerase', 'Gene', (18, 46))	('PARP', 'Gene', '142', (48, 52))	('PARP', 'Gene', (48, 52))	('poly (ADP-ribose) polymerase', 'Gene', '142', (18, 46))	('SSBs', 'Var', (197, 201))
691704	26828133	by a frameshift mutation in the breast cancer, early onset [BRCA] 1 or BRCA2 gene), PARP inhibitors strongly reduce cellular radiation survival.	('breast cancer', 'Disease', (32, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('reduce', 'NegReg', (109, 115))	('BRCA2', 'Gene', (71, 76))	('PARP', 'Gene', '142', (84, 88))	('frameshift mutation', 'Var', (5, 24))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('BRCA', 'Gene', (71, 75))	('BRCA', 'Gene', '672', (71, 75))	('cellular radiation survival', 'CPA', (116, 143))	('BRCA', 'Gene', '672', (60, 64))	('BRCA2', 'Gene', '675', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('PARP', 'Gene', (84, 88))	('BRCA', 'Gene', (60, 64))
691705	26828133	As hereditary BRCA mutations promote the development of breast and ovarian cancer, a certain percentage of these tumors are BRCA1 or BRCA2 negative.	('tumors', 'Disease', (113, 119))	('BRCA', 'Gene', '672', (14, 18))	('BRCA1', 'Gene', '672', (124, 129))	('BRCA', 'Gene', '672', (124, 128))	('BRCA1', 'Gene', (124, 129))	('BRCA', 'Gene', (133, 137))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (56, 81))	('BRCA', 'Gene', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('BRCA2', 'Gene', (133, 138))	('BRCA', 'Gene', (124, 128))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('BRCA2', 'Gene', '675', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('promote', 'PosReg', (29, 36))	('mutations', 'Var', (19, 28))	('BRCA', 'Gene', '672', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
691710	26828133	Epigenetic alterations play an important role not only in many physiologic processes including DNA replication and repair, but also in disease development and cancer cell resistance to therapy.	('cancer', 'Disease', (159, 165))	('Epigenetic alterations', 'Var', (0, 22))	('rat', 'Species', '10116', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('repair', 'CPA', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('DNA replication', 'CPA', (95, 110))
691718	26828133	Because most of these studies evaluated the epigenetic modifications only before treatment, changes due to radiation or chemotherapy, which might inform how to adapt treatment based on tumor response, were not taken into account.	('epigenetic', 'Var', (44, 54))	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (185, 190))
691721	26828133	In pancreatic carcinoma, high levels of dimethylated (H3K4me2) or acetylated histone 3 (H3K18ac) are associated with better survival after adjuvant radiochemotherapy, independent of other clinical factors.	('survival', 'MPA', (124, 132))	('H3K4me2', 'Var', (54, 61))	('dimethylated', 'MPA', (40, 52))	('better', 'PosReg', (117, 123))	('pancreatic carcinoma', 'Disease', (3, 23))	('acetylated', 'MPA', (66, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (3, 23))
691734	26828133	Additionally, a high SChLAP1 expression was an independent negative predictive marker and correlated with reduced overall and disease-free survival.	('disease-free survival', 'CPA', (126, 147))	('SChLAP1', 'Gene', (21, 28))	('high', 'Var', (16, 20))	('SChLAP1', 'Gene', '101669767', (21, 28))	('expression', 'MPA', (29, 39))	('reduced', 'NegReg', (106, 113))	('overall', 'CPA', (114, 121))
691751	26828133	Similarly, targeting of beta1 integrin leads to enhanced phosphorylation of EGFR/MAPK associated signaling.	('MAPK', 'Gene', (81, 85))	('beta1 integrin', 'Gene', (24, 38))	('enhanced', 'PosReg', (48, 56))	('targeting', 'Var', (11, 20))	('beta1 integrin', 'Gene', '3688', (24, 38))	('phosphorylation', 'MPA', (57, 72))	('MAPK', 'Gene', '5594', (81, 85))
691754	26828133	An siRNA-mediated knockdown of these activated proteins restored sensitivity to HER2 inhibition.	('knockdown', 'Var', (18, 27))	('HER2', 'Gene', '2064', (80, 84))	('sensitivity to', 'MPA', (65, 79))	('HER2', 'Gene', (80, 84))	('restored', 'PosReg', (56, 64))
691757	26828133	On the one hand this can be caused by intrinsic factors like mutational alterations of important enzymes or differential expression of molecules; on the other hand, also extracellular factors, for example the tumor microenvironment, can have a critical impact on metabolic pathways and metabolite levels.	('caused', 'Reg', (28, 34))	('tumor', 'Disease', (209, 214))	('rat', 'Species', '10116', (76, 79))	('impact', 'Reg', (253, 259))	('expression', 'MPA', (121, 131))	('metabolic', 'MPA', (263, 272))	('mutational', 'Var', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('metabolite levels', 'MPA', (286, 303))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
691760	26828133	One example regarding the impact of cellular metabolite levels on tumor formation and progression is the mutation of the isocitrate dehydrogenase (IDH).	('isocitrate dehydrogenase', 'Gene', (121, 145))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('IDH', 'Gene', '3417', (147, 150))	('mutation', 'Var', (105, 113))	('isocitrate dehydrogenase', 'Gene', '3417', (121, 145))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('IDH', 'Gene', (147, 150))
691761	26828133	IDH mutations found in glioma, chondrosarcoma and hematologic malignancies result in the accumulation of D-2-hydroxyglutarate which inhibits several enzymatic reactions involved in epigenetic modifications and cell signaling.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('IDH', 'Gene', (0, 3))	('chondrosarcoma', 'Disease', (31, 45))	('accumulation', 'PosReg', (89, 101))	('chondrosarcoma', 'Disease', 'MESH:D002813', (31, 45))	('hematologic malignancies', 'Disease', 'MESH:D019337', (50, 74))	('IDH', 'Gene', '3417', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('inhibits', 'NegReg', (132, 140))	('hematologic malignancies', 'Disease', (50, 74))	('glioma', 'Disease', (23, 29))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (105, 125))	('epigenetic modifications', 'MPA', (181, 205))	('D-2-hydroxyglutarate', 'MPA', (105, 125))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (31, 45))	('mutations', 'Var', (4, 13))	('enzymatic reactions', 'MPA', (149, 168))
691763	26828133	Additionally, the development of therapeutics targeting only mutated IDH might be a promising approach for treatment of these tumors.	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('IDH', 'Gene', (69, 72))	('IDH', 'Gene', '3417', (69, 72))	('mutated', 'Var', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
691776	26828133	The discovery of cancer-driving mutations enabled the development of molecular targeted drugs, while the expression profiles of RNA and proteins have already been used to predict treatment outcome and identify patients with high risk for treatment failure.	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (17, 23))	('treatment failure', 'Disease', (238, 255))	('patients', 'Species', '9606', (210, 218))	('treatment failure', 'Disease', 'MESH:D016609', (238, 255))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
691899	27382301	However, when treated with 3 mug/mL and 6 mug/mL cisplatin, the cell survival rates in the mimic group were significantly higher than the rates in the non-T and NC groups (both P<0.05), whereas the rates in the non-T and NC groups were significantly higher than those in the inhibitor group.	('higher', 'PosReg', (122, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('cell survival rates', 'CPA', (64, 83))	('cisplatin', 'Var', (49, 58))
691921	27382301	Our study also showed that Ki67-positive cells displayed brown granules in the nucleus and that there were fewer positive cells in the effective group than in the ineffective group, suggesting that Ki67 may be used as a marker for PGBC proliferation and invasion and that it had certain significance in PGBC prognosis.	('Ki67', 'Var', (198, 202))	('PGBC', 'Chemical', '-', (231, 235))	('PGBC', 'Chemical', '-', (303, 307))	('invasion', 'CPA', (254, 262))
691945	27136592	These changes ultimately resulted in isolated tumor cells showing a uniform phenotype, irrespective of the differentiation of the main tumor mass (i.e., differentiated or undifferentiated carcinomas).	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('differentiated', 'Disease', (153, 167))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', (46, 51))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (171, 198))	('changes', 'Var', (6, 13))	('undifferentiated carcinomas', 'Disease', (171, 198))	('resulted', 'Reg', (25, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
691998	27136592	In CRC, high budding correlated with lower 5-year overall survival (OS) (, although see), 10-year OS, 5-year CSS, and 10-year CSS.	('high', 'Var', (8, 12))	('lower', 'NegReg', (37, 42))	('overall survival', 'MPA', (50, 66))	('OS', 'Chemical', '-', (98, 100))	('OS', 'Chemical', '-', (68, 70))
692004	27136592	In colon cancer, high budding correlated with lower 5-year recurrence-free survival (RFS), 5-year OS (although see), 10-year OS, and 5-year CSS.	('OS', 'Chemical', '-', (125, 127))	('high', 'Var', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('recurrence-free survival', 'CPA', (59, 83))	('lower', 'NegReg', (46, 51))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('OS', 'Chemical', '-', (98, 100))	('colon cancer', 'Disease', (3, 15))
692005	27136592	In RC, high budding correlated with recurrence, both local and distant (most notably liver metastases) and consequently, with lower 5-year DFS.	('lower', 'NegReg', (126, 131))	('liver', 'Disease', (85, 90))	('metastases', 'Disease', (91, 101))	('high', 'Var', (7, 11))	('recurrence', 'Disease', (36, 46))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('DFS', 'MPA', (139, 142))
692006	27136592	High budding also correlated with lower 5-year OS and 10-year OS.	('lower', 'NegReg', (34, 39))	('OS', 'Chemical', '-', (47, 49))	('OS', 'Chemical', '-', (62, 64))	('High', 'Var', (0, 4))
692008	27136592	In CRC patients, high budding correlated with higher overall stage, higher T stage (but see), higher N stage, higher Dukes stage, tumor dedifferentiation, infiltrating growth pattern, lymphatic invasion, venous invasion, lymphovascular invasion, perineural invasion, nodal metastasis, and distant metastasis (but see).	('Dukes', 'MPA', (117, 122))	('patients', 'Species', '9606', (7, 15))	('lymphatic invasion', 'CPA', (184, 202))	('higher', 'PosReg', (46, 52))	('venous invasion', 'CPA', (204, 219))	('higher T stage', 'CPA', (68, 82))	('perineural invasion', 'CPA', (246, 265))	('lymphovascular invasion', 'CPA', (221, 244))	('high', 'Var', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('overall stage', 'CPA', (53, 66))	('nodal metastasis', 'CPA', (267, 283))	('tumor', 'Disease', (130, 135))	('infiltrating growth pattern', 'CPA', (155, 182))	('distant metastasis', 'CPA', (289, 307))
692029	27136592	High budding correlated with lower 5-year DFS, lower 3-year OS and 5-year OS.	('lower', 'NegReg', (47, 52))	('High', 'Var', (0, 4))	('3-year OS', 'MPA', (53, 62))	('DFS', 'MPA', (42, 45))	('lower', 'NegReg', (29, 34))	('OS', 'Chemical', '-', (60, 62))	('OS', 'Chemical', '-', (74, 76))
692035	27136592	Despite this weaker prognostic correlation for adenocarcinoma, one study, which included both patients with squamous cell carcinoma and patients with adenocarcinoma, found that high budding correlated with higher grade, higher T stage, higher overall stage, nodal metastasis, lower inflammatory response, incomplete excision of the tumor, and lower OS.	('adenocarcinoma', 'Disease', (150, 164))	('nodal metastasis', 'CPA', (258, 274))	('high', 'Var', (177, 181))	('squamous cell carcinoma', 'Disease', (108, 131))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('patients', 'Species', '9606', (94, 102))	('adenocarcinoma', 'Disease', 'MESH:D000230', (150, 164))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('higher overall stage', 'CPA', (236, 256))	('higher grade', 'CPA', (206, 218))	('OS', 'Chemical', '-', (349, 351))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('higher T stage', 'CPA', (220, 234))	('lower', 'NegReg', (276, 281))	('tumor', 'Disease', (332, 337))	('lower inflammatory response', 'Phenotype', 'HP:0012648', (276, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('lower OS', 'CPA', (343, 351))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('patients', 'Species', '9606', (136, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('adenocarcinoma', 'Disease', (47, 61))
692041	27136592	High budding also correlated with lower 3-year OS and 5-year OS.	('lower', 'NegReg', (34, 39))	('OS', 'Chemical', '-', (47, 49))	('OS', 'Chemical', '-', (61, 63))	('High', 'Var', (0, 4))
692050	27136592	In oral squamous cell carcinoma, high budding correlated with lower DFS.	('high', 'Var', (33, 37))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('DFS', 'MPA', (68, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('lower', 'NegReg', (62, 67))	('oral squamous cell carcinoma', 'Disease', (3, 31))
692052	27136592	High budding also correlated with lower 5-year OS and lower CSS (reviewed in).	('High', 'Var', (0, 4))	('5-year OS', 'CPA', (40, 49))	('lower', 'NegReg', (34, 39))	('CSS', 'CPA', (60, 63))	('OS', 'Chemical', '-', (47, 49))	('lower', 'NegReg', (54, 59))
692053	27136592	In nasopharyngeal carcinoma, high budding correlated with higher T stage, higher overall clinical stage, lymphatic invasion, vascular invasion, and nodal metastases.	('high', 'Var', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('nasopharyngeal carcinoma', 'Disease', (3, 27))	('vascular invasion', 'CPA', (125, 142))	('nodal metastases', 'Disease', (148, 164))	('lymphatic invasion', 'CPA', (105, 123))	('T stage', 'CPA', (65, 72))	('nodal metastases', 'Disease', 'MESH:D009362', (148, 164))	('higher', 'PosReg', (58, 64))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (3, 27))
692055	27136592	In laryngeal carcinoma, high budding correlated with lower metastatic DFS.	('laryngeal carcinoma', 'Disease', (3, 22))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (3, 22))	('high', 'Var', (24, 28))	('metastatic DFS', 'CPA', (59, 73))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (3, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lower', 'NegReg', (53, 58))
692057	27136592	In lung adenocarcinoma, budding correlated with higher overall pathologic stage, infiltrating growth pattern, schirrhous (i.e., rich in dense connective tissue) stromal type, lymphatic invasion, vascular invasion, pleural invasion, and nodal metastases.	('budding', 'Var', (24, 31))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('schirrhous', 'CPA', (110, 120))	('dense connective tissue', 'Phenotype', 'HP:0009025', (136, 159))	('nodal metastases', 'Disease', 'MESH:D009362', (236, 252))	('pleural invasion', 'Disease', (214, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('pleural invasion', 'Disease', 'MESH:D010995', (214, 230))	('infiltrating growth pattern', 'CPA', (81, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('higher', 'PosReg', (48, 54))	('lymphatic invasion', 'CPA', (175, 193))	('vascular invasion', 'CPA', (195, 212))	('pathologic stage', 'CPA', (63, 79))	('nodal metastases', 'Disease', (236, 252))	('lung adenocarcinoma', 'Disease', (3, 22))
692058	27136592	Budding correlated with lower OS, including lower 5-year OS.	('lower', 'NegReg', (44, 49))	('lower', 'Disease', (24, 29))	('Budding', 'Var', (0, 7))	('OS', 'Chemical', '-', (57, 59))	('OS', 'Chemical', '-', (30, 32))
692060	27136592	Budding also correlated with lower 5-year OS and 5-year CSS.	('lower', 'NegReg', (29, 34))	('OS', 'Chemical', '-', (42, 44))	('Budding', 'Var', (0, 7))
692063	27136592	High budding also correlated with lower 5-year OS and shorter CSS.	('High', 'Var', (0, 4))	('5-year OS', 'CPA', (40, 49))	('lower', 'NegReg', (34, 39))	('shorter', 'NegReg', (54, 61))	('OS', 'Chemical', '-', (47, 49))
692066	27136592	In endometrial cancer, high budding correlated with advanced overall stage (III + IV) and deep invasion of the myometrium (>=50%).	('endometrial cancer', 'Phenotype', 'HP:0012114', (3, 21))	('high', 'Var', (23, 27))	('endometrial cancer', 'Disease', 'MESH:D016889', (3, 21))	('endometrial cancer', 'Disease', (3, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
692067	27136592	High budding also correlated with lower 5-year OS.	('5-year OS', 'CPA', (40, 49))	('lower', 'NegReg', (34, 39))	('OS', 'Chemical', '-', (47, 49))	('High', 'Var', (0, 4))
692096	27136592	Aberrant activation of EMT is considered to be a hallmark of cancer metastasis (reviewed in).	('hallmark of cancer metastasis', 'Disease', (49, 78))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('EMT', 'CPA', (23, 26))	('hallmark of cancer metastasis', 'Disease', 'MESH:D009362', (49, 78))
692208	24235844	EGFR inhibitors have proven efficacious in patients with non-small cell lung, colon, intestinal, and head and neck cancers.	('colon', 'Disease', (78, 83))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('EGFR', 'Gene', (0, 4))	('non-small cell lung', 'Disease', (57, 76))	('intestinal', 'Disease', (85, 95))	('neck cancers', 'Disease', (110, 122))	('inhibitors', 'Var', (5, 15))	('colon', 'Disease', 'MESH:D015179', (78, 83))	('patients', 'Species', '9606', (43, 51))	('neck cancers', 'Disease', 'MESH:D006258', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('head and neck cancer', 'Phenotype', 'HP:0012288', (101, 121))	('head and neck cancers', 'Phenotype', 'HP:0012288', (101, 122))	('EGFR', 'Gene', '1956', (0, 4))
692267	24235844	The immunoreactivity of EGFR was graded into four groups according to the intensity of cell membrane EGFR staining in the whole tumor: high (+++), markedly stronger staining than normal esophageal epithelium; medium (++), moderately stronger staining than normal esophageal epithelium; low (+), staining identical to that of normal epithelium (Figure 2); and negative (-), faint staining.	('EGFR', 'Gene', '1956', (24, 28))	('staining', 'MPA', (242, 250))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('EGFR', 'Gene', (24, 28))	('EGFR', 'Gene', '1956', (101, 105))	('stronger', 'PosReg', (233, 241))	('EGFR', 'Gene', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('staining', 'MPA', (165, 173))	('medium (++', 'Var', (209, 219))	('high (+++', 'Var', (135, 144))	('tumor', 'Disease', (128, 133))	('stronger', 'PosReg', (156, 164))
692269	24235844	EGFR expression at levels (+++), (++) and (+) was found in 13, 7, and 1 patient, respectively.	('patient', 'Species', '9606', (72, 79))	('++', 'Var', (34, 36))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
692285	24235844	However, our study showed that combined radiotherapy and targeted therapy could improve the OS over that achievable with radiotherapy alone.	('improve', 'PosReg', (80, 87))	('targeted', 'Var', (57, 65))	('OS', 'Chemical', '-', (92, 94))
692293	24235844	Targeted therapy has been reported to potentiate radiation-induced cell death.	('potentiate', 'PosReg', (38, 48))	('death', 'Disease', 'MESH:D003643', (72, 77))	('death', 'Disease', (72, 77))	('Targeted therapy', 'Var', (0, 16))
692294	24235844	EGFR inhibitors have become the most common targeted-therapy drug that is combined with radiotherapy.	('EGFR', 'Gene', '1956', (0, 4))	('inhibitors', 'Var', (5, 15))	('EGFR', 'Gene', (0, 4))
692325	20541192	The presence of LN metastases was determined by EUS-FNA cytopathologic results because the high specificity of EUS-FNA obviated the need for surgical LN dissection.	('EUS-FNA', 'Var', (111, 118))	('metastases', 'Disease', 'MESH:D009362', (19, 29))	('metastases', 'Disease', (19, 29))
692382	33759957	On univariate analysis, positive margins (HR=2.395, 95%CI=1.337-4.289, p=0.003), positive lymph nodes (HR=2.373, 95%CI=1.420-3.964, p<0.001), size of the tumor (HR=1.014; 95%CI=1.002-1.027, p=0.023), and operative time (HR=1.003, 95%CI=1.001-1.005, p=0.005) were all associated with increased overall mortality.	('positive', 'Var', (81, 89))	('mortality', 'Disease', (301, 310))	('increased', 'PosReg', (283, 292))	('positive', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mortality', 'Disease', 'MESH:D003643', (301, 310))	('tumor', 'Disease', (154, 159))
692383	33759957	Conversely, NAT (HR=0.245; 95%CI=0.076-0.784, p=0.018) was associated with a 76.5% reduction in overall mortality (Table 4).	('mortality', 'Disease', (104, 113))	('reduction', 'NegReg', (83, 92))	('NAT', 'Var', (12, 15))	('mortality', 'Disease', 'MESH:D003643', (104, 113))
692384	33759957	In the multivariate analysis for overall survival, positive lymph nodes (HR=2.240, 95%CI=1.332-3.769, p=0.002) and prolonged operative time (HR=1.003, 95%CI=1.000-1.005, p=0.019) were the only predictors of increased mortality.	('mortality', 'Disease', (217, 226))	('mortality', 'Disease', 'MESH:D003643', (217, 226))	('positive', 'Var', (51, 59))
692400	33759957	Multivariable analysis revealed a 2.2-fold increase in overall mortality with metastasis to local lymph nodes.	('metastasis', 'Var', (78, 88))	('mortality', 'Disease', (63, 72))	('mortality', 'Disease', 'MESH:D003643', (63, 72))
692415	32875717	Long non-coding RNA CASC8 polymorphisms are associated with the risk of esophageal cancer in a Chinese population Esophageal cancer (EC) is an important disease that threatens public health and safety.	('associated', 'Reg', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('polymorphisms', 'Var', (26, 39))	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (72, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('CASC8', 'Gene', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('EC', 'Disease', 'MESH:D005955', (133, 135))	('cancer', 'Disease', (83, 89))	('CASC8', 'Gene', '727677', (20, 25))
692419	32875717	Here, we examined the genetic susceptibility to ESCC in relation to functional single nucleotide polymorphisms (SNPs) in the long non-coding RNA (lncRNA) CASC8.	('single nucleotide polymorphisms', 'Var', (79, 110))	('CASC8', 'Gene', (154, 159))	('ESCC', 'Disease', (48, 52))	('CASC8', 'Gene', '727677', (154, 159))
692421	32875717	The CASC8 rs1562430 GG genotype was significantly associated with increased ESCC risk in men, patients younger than 63 years, non-smokers, and nondrinkers.	('CASC8', 'Gene', '727677', (4, 9))	('rs1562430', 'Mutation', 'rs1562430', (10, 19))	('patients', 'Species', '9606', (94, 102))	('increased ESCC', 'Phenotype', 'HP:0003565', (66, 80))	('rs1562430 GG', 'Var', (10, 22))	('ESCC', 'Disease', (76, 80))	('men', 'Species', '9606', (89, 92))	('CASC8', 'Gene', (4, 9))
692422	32875717	CASC8 rs1562430 A > G may cause susceptibility to ESCC and CASC8 SNPs may play a vital role in ESCC risk, thereby serving as a potential biomarker for diagnosing ESCC.	('rs1562430', 'Mutation', 'rs1562430', (6, 15))	('rs1562430 A > G', 'Var', (6, 21))	('CASC8', 'Gene', '727677', (59, 64))	('ESCC', 'Disease', (95, 99))	('cause susceptibility', 'Reg', (26, 46))	('CASC8', 'Gene', (0, 5))	('ESCC', 'Disease', (162, 166))	('CASC8', 'Gene', '727677', (0, 5))	('ESCC', 'Disease', (50, 54))	('CASC8', 'Gene', (59, 64))
692423	32875717	CASC8 rs1562430 A>G may cause susceptibility to ESCC and CASC8 SNPs may play a vital role in ESCC risk, thereby serving as a potential biomarker for diagnosing ESCC.	('cause susceptibility', 'Reg', (24, 44))	('ESCC', 'Disease', (160, 164))	('rs1562430 A>G', 'Var', (6, 19))	('CASC8', 'Gene', '727677', (0, 5))	('CASC8', 'Gene', '727677', (57, 62))	('CASC8', 'Gene', (57, 62))	('CASC8', 'Gene', (0, 5))	('ESCC', 'Disease', (48, 52))	('ESCC', 'Disease', (93, 97))	('rs1562430', 'Mutation', 'rs1562430', (6, 15))
692431	32875717	Most disease-related single nucleotide polymorphisms (SNPs) occur in non-coding regions, 12  and many of these SNPs are associated with cancer.	('associated', 'Reg', (120, 130))	('single nucleotide polymorphisms', 'Var', (21, 52))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('disease-related', 'Reg', (5, 20))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
692432	32875717	Polymorphisms in many genes including long non-coding RNAs (lncRNAs) are closely related to tumorigenesis and tumor development.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Polymorphisms', 'Var', (0, 13))	('related', 'Reg', (81, 88))	('tumor', 'Disease', (110, 115))	('men', 'Species', '9606', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (92, 97))	('long', 'Protein', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
692433	32875717	Many studies have investigated the correlation between lncRNAs and the pathogenesis of various diseases, 15  including tumors, 16 ,  17  and the results suggest that SNPs in lncRNA are associated with the susceptibility to cancer.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('SNPs', 'Var', (166, 170))	('lncRNA', 'Gene', (174, 180))	('associated', 'Reg', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))
692436	32875717	22   SNPs in the CASC8 gene, such as rs7837328, rs6983267, and rs7014346, are correlated with the risk of cancer, including prostate, 23  breast, colorectal, and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('colorectal', 'Disease', (146, 156))	('cancer', 'Disease', (170, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('23  breast', 'Disease', (134, 144))	('rs6983267', 'Mutation', 'rs6983267', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (106, 112))	('gastric cancers', 'Disease', (162, 177))	('gastric cancers', 'Disease', 'MESH:D013274', (162, 177))	('gastric cancers', 'Phenotype', 'HP:0012126', (162, 177))	('CASC8', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('CASC8', 'Gene', '727677', (17, 22))	('prostate', 'Disease', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('rs7837328', 'Var', (37, 46))	('correlated with', 'Reg', (78, 93))	('rs7014346', 'Mutation', 'rs7014346', (63, 72))	('rs7837328', 'Mutation', 'rs7837328', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('rs7014346', 'Var', (63, 72))	('rs6983267', 'Var', (48, 57))
692437	32875717	21  The rs10505477, located in the intron of CASC8, is associated with the risk of colorectal cancer 24 ,  25 ,  26  and the prognosis of gastric cancer.	('gastric cancer', 'Disease', (138, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (83, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('CASC8', 'Gene', (45, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('rs10505477', 'Mutation', 'rs10505477', (8, 18))	('associated', 'Reg', (55, 65))	('CASC8', 'Gene', '727677', (45, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('colorectal cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('rs10505477', 'Var', (8, 18))
692446	32875717	Student's t-tests and chi2 tests were performed to detect differences in factors collected in the questionnaire and CASC8 rs10505477 C > T and rs1562430 A > G genotypes.	('rs1562430 A > G', 'Var', (143, 158))	('CASC8', 'Gene', (116, 121))	('rs10505477 C > T', 'Var', (122, 138))	('rs10505477', 'Mutation', 'rs10505477', (122, 132))	('CASC8', 'Gene', '727677', (116, 121))	('rs1562430', 'Mutation', 'rs1562430', (143, 152))
692447	32875717	The relationships between CASC8 rs10505477 C > T and rs1562430 A > G SNPs and risk of ESCC were examined by computing odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analyses, including crude ORs and adjusted ORs, after adjusting for age, sex, smoking, and drinking status.	('rs10505477 C > T', 'Var', (32, 48))	('CASC8', 'Gene', '727677', (26, 31))	('rs10505477', 'Mutation', 'rs10505477', (32, 42))	('rs1562430 A > G', 'Var', (53, 68))	('rs1562430', 'Mutation', 'rs1562430', (53, 62))	('CASC8', 'Gene', (26, 31))	('ESCC', 'Disease', (86, 90))
692449	32875717	As shown in Table 3, the genotype frequencies of CASC8 rs1562430 A > G were 69.65% (AA), 26.99% (AG), and 3.34% (GG) in the cases and 69.12% (AA), 29.08% (AG), and 1.78% (GG) in the healthy controls, demonstrating statistically significant differences between the two subgroups (P = 0.042).	('CASC8', 'Gene', (49, 54))	('CASC8', 'Gene', '727677', (49, 54))	('rs1562430 A > G', 'Var', (55, 70))	('rs1562430', 'Mutation', 'rs1562430', (55, 64))
692450	32875717	In a recessive model using CASC8 rs1562430 AA/GG genotypes as the reference group, the GG homozygous genotype (GG vs. AA/GG: adjusted OR = 2.11, 95% CI: 1.22-3.64, P = 0.007) was significantly associated with increased risk of ESCC, whereas the AG/GG homozygous genotype (AG/GG vs. AA/GG: adjusted OR = 0.97, 95% CI: 0.81-1.16, P = 0.725) was not associated with ESCC risk.	('CASC8', 'Gene', (27, 32))	('CASC8', 'Gene', '727677', (27, 32))	('rs1562430', 'Mutation', 'rs1562430', (33, 42))	('rs1562430', 'Var', (33, 42))	('ESCC', 'Disease', (227, 231))
692451	32875717	However, when the CASC8 rs1562430 AA homozygous genotype was used as the reference group, the GG genotype was significantly associated with increased risk of ESCC (GG vs. AA: adjusted OR = 2.05, 95% CI: 1.18-3.55, P = 0.010), whereas the AG genotype was not associated with ESCC risk (AG vs. AA: adjusted OR = 0.91, 95% CI: 0.75-1.09, P = 0.304).	('CASC8', 'Gene', (18, 23))	('rs1562430', 'Var', (24, 33))	('rs1562430', 'Mutation', 'rs1562430', (24, 33))	('CASC8', 'Gene', '727677', (18, 23))	('ESCC', 'Disease', (274, 278))	('ESCC', 'Disease', (158, 162))
692452	32875717	The CASC8 rs10505477 C > T SNP was not associated with ESCC risk (Table 3).	('CASC8', 'Gene', '727677', (4, 9))	('rs10505477', 'Mutation', 'rs10505477', (10, 20))	('ESCC', 'Disease', (55, 59))	('CASC8', 'Gene', (4, 9))	('rs10505477 C > T', 'Var', (10, 26))
692453	32875717	Stratified analysis was performed to further assess the possible correlation between the CASC8 rs1562430 A > G SNP and ESCC risk in the recessive model (Table 4).	('CASC8', 'Gene', '727677', (89, 94))	('ESCC', 'Disease', (119, 123))	('CASC8', 'Gene', (89, 94))	('rs1562430 A > G', 'Var', (95, 110))	('rs1562430', 'Mutation', 'rs1562430', (95, 104))
692454	32875717	The results showed that the CASC8 rs1562430 GG genotype was significantly associated with increased risk of ESCC among men (GG vs. AA: adjusted OR = 2.47, 95% CI: 1.27-4.81, P = 0.008), patients younger than 63 years (GG vs. AA: adjusted OR = 2.50, 95% CI: 1.26-4.95, P = 0.009), non-smokers (GG vs. AA: adjusted OR = 1.98, 95% CI: 1.05-3.73, P = 0.034), and nondrinkers (GG vs. AA: adjusted OR = 1.98, 95% CI: 1.07-3.66, P = 0.031) (Table 4).	('rs1562430', 'Var', (34, 43))	('CASC8', 'Gene', '727677', (28, 33))	('CASC8', 'Gene', (28, 33))	('men', 'Species', '9606', (119, 122))	('ESCC', 'Disease', (108, 112))	('patients', 'Species', '9606', (186, 194))	('rs1562430', 'Mutation', 'rs1562430', (34, 43))
692455	32875717	In addition, in a recessive model using CASC8 rs1562430 AA/GG genotypes as the reference group, the GG homozygous genotype was significantly associated with increased risk of ESCC among men (GG vs. AA/GG: adjusted OR = 2.62, 95% CI: 1.35-5.10, P = 0.005), patients younger than 63 years (GG vs. AA/GG: adjusted OR = 2.62, 95% CI: 1.33-5.17, P = 0.005), non-smokers (GG vs. AA/GG: adjusted OR = 2.02, 95% CI: 1.07-3.78, P = 0.029), and nondrinkers (GG vs. AA/GG: adjusted OR = 1.98, 95% CI: 1.07-3.66, P = 0.029) (Table 4).	('patients', 'Species', '9606', (256, 264))	('rs1562430', 'Var', (46, 55))	('rs1562430', 'Mutation', 'rs1562430', (46, 55))	('men', 'Species', '9606', (186, 189))	('ESCC', 'Disease', (175, 179))	('CASC8', 'Gene', (40, 45))	('CASC8', 'Gene', '727677', (40, 45))
692457	32875717	In the present study, we investigated the association between SNPs in the lncRNA CASC8 gene and susceptibility to ESCC.	('ESCC', 'Disease', (114, 118))	('association', 'Interaction', (42, 53))	('SNPs', 'Var', (62, 66))	('CASC8', 'Gene', (81, 86))	('CASC8', 'Gene', '727677', (81, 86))
692458	32875717	We found that rs1562430 was significantly associated with increased risk of ESCC.	('rs1562430', 'Mutation', 'rs1562430', (14, 23))	('ESCC', 'Disease', (76, 80))	('rs1562430', 'Var', (14, 23))
692459	32875717	In stratification analyses, we found that the increased ESCC risk was significantly associated with CASC8 rs1562430 GG genotype among subjects for males, never-drinkers, never-smokers and those age < 60.	('ESCC', 'Disease', (56, 60))	('CASC8', 'Gene', (100, 105))	('rs1562430 GG', 'Var', (106, 118))	('CASC8', 'Gene', '727677', (100, 105))	('rs1562430', 'Mutation', 'rs1562430', (106, 115))	('increased ESCC', 'Phenotype', 'HP:0003565', (46, 60))
692461	32875717	29  CASC8 gene polymorphisms play important roles in different cancers.	('CASC8', 'Gene', '727677', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Disease', (63, 70))	('roles', 'Reg', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('polymorphisms', 'Var', (15, 28))	('CASC8', 'Gene', (4, 9))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
692463	32875717	30  The results of this study suggested that the CASC8 SNP rs1562430 could be a predictive biomarker for susceptibility to ESCC.	('CASC8', 'Gene', (49, 54))	('CASC8', 'Gene', '727677', (49, 54))	('rs1562430', 'Var', (59, 68))	('ESCC', 'Disease', (123, 127))	('rs1562430', 'Mutation', 'rs1562430', (59, 68))
692464	32875717	The CASC8 rs10505477 variant is related to the development of numerous cancers including colorectal, 31  gastric, 32  and ovarian cancers.	('numerous cancers', 'Disease', (62, 78))	('CASC8', 'Gene', '727677', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('rs10505477', 'Mutation', 'rs10505477', (10, 20))	('ovarian cancers', 'Phenotype', 'HP:0100615', (122, 137))	('rs10505477', 'Var', (10, 20))	('colorectal', 'Disease', (89, 99))	('related to', 'Reg', (32, 42))	('ovarian cancers', 'Disease', (122, 137))	('ovarian cancers', 'Disease', 'MESH:D010051', (122, 137))	('men', 'Species', '9606', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('numerous cancers', 'Disease', 'MESH:D009369', (62, 78))	('31  gastric', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CASC8', 'Gene', (4, 9))
692465	32875717	reported that the SNP rs6983267 GG genotype was significantly associated with increased lung cancer risk in Han Chinese.	('rs6983267', 'Mutation', 'rs6983267', (22, 31))	('lung cancer', 'Disease', (88, 99))	('SNP', 'Var', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
692466	32875717	34  In the current study, we used the CASC8 rs1562430 AA genotype as the reference group and found that the GG genotype can significantly increase the risk of ESCC.	('increase', 'PosReg', (138, 146))	('CASC8', 'Gene', (38, 43))	('CASC8', 'Gene', '727677', (38, 43))	('rs1562430', 'Mutation', 'rs1562430', (44, 53))	('rs1562430', 'Var', (44, 53))	('ESCC', 'Disease', (159, 163))
692468	32875717	In summary, we explored the effect of the CASC8 rs1562430 polymorphism on ESCC susceptibility and found that functional polymorphisms in CASC8 rs1562430 A > G may affect individual susceptibility to ESCC.	('rs1562430', 'Mutation', 'rs1562430', (143, 152))	('rs1562430 A > G', 'Var', (143, 158))	('rs1562430', 'Mutation', 'rs1562430', (48, 57))	('CASC8', 'Gene', '727677', (42, 47))	('affect', 'Reg', (163, 169))	('CASC8', 'Gene', '727677', (137, 142))	('ESCC', 'Disease', (199, 203))	('CASC8', 'Gene', (42, 47))	('CASC8', 'Gene', (137, 142))
692489	32846774	In ESCC, survivin overexpression is associated with poor clinical outcomes, while inhibition of survivin induces the sensitivity of tumor cells to radiation.	('induces', 'Reg', (105, 112))	('survivin', 'Protein', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('sensitivity', 'MPA', (117, 128))	('inhibition', 'Var', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('survivin', 'Protein', (9, 17))	('ESCC', 'Disease', (3, 7))	('tumor', 'Disease', (132, 137))	('overexpression', 'PosReg', (18, 32))
692492	32846774	p53 mutations and dysfunctions in ESCC are well established and contribute to ESCC development and progression.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('ESCC', 'Disease', (78, 82))	('contribute', 'Reg', (64, 74))	('ESCC', 'Disease', (34, 38))	('dysfunctions', 'Var', (18, 30))	('mutations', 'Var', (4, 13))
692534	32846774	Moreover, expression of SIRT1 and survivin, individually and in combination, was associated with poor OS and PFS among ESCC patients after concurrent chemoradiotherapy.	('survivin', 'Protein', (34, 42))	('ESCC', 'Disease', (119, 123))	('SIRT1', 'Gene', '23411', (24, 29))	('poor OS', 'Disease', (97, 104))	('PFS', 'Disease', (109, 112))	('SIRT1', 'Gene', (24, 29))	('associated', 'Reg', (81, 91))	('patients', 'Species', '9606', (124, 132))	('expression', 'Var', (10, 20))
692538	32846774	SIRT1 overexpression was also shown to be associated with poor ESCC prognosis, and high SIRT1 expression in ESCC was suggested as an independent diagnostic and prognostic marker for ESCC.	('SIRT1', 'Gene', '23411', (88, 93))	('SIRT1', 'Gene', (88, 93))	('SIRT1', 'Gene', '23411', (0, 5))	('SIRT1', 'Gene', (0, 5))	('ESCC', 'Disease', (182, 186))	('overexpression', 'PosReg', (6, 20))	('high', 'Var', (83, 87))	('ESCC', 'Disease', (63, 67))	('expression', 'MPA', (94, 104))
692553	31327664	We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the transgenic mouse esophagus.	('oxidative stress', 'Phenotype', 'HP:0025464', (53, 69))	('low-dose ionizing radiation', 'Phenotype', 'HP:0011133', (75, 102))	('mutant', 'Var', (131, 137))	('LDIR', 'Phenotype', 'HP:0011133', (104, 108))	('mouse', 'Species', '10090', (162, 167))	('LDIR', 'Chemical', '-', (104, 108))	('tested', 'Reg', (3, 9))	('transgenic', 'Species', '10090', (151, 161))	('p53', 'Gene', (127, 130))
692555	31327664	p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure.	('p53', 'Gene', (0, 3))	('LDIR', 'Phenotype', 'HP:0011133', (36, 40))	('mutant', 'Var', (4, 10))	('LDIR', 'Chemical', '-', (36, 40))
692556	31327664	Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population.	('p53', 'Gene', (118, 121))	('LDIR', 'Phenotype', 'HP:0011133', (48, 52))	('LDIR', 'Chemical', '-', (48, 52))	('reducing', 'NegReg', (146, 154))	('promoting', 'PosReg', (75, 84))	('wild-type', 'CPA', (85, 94))	('mutant', 'Var', (122, 128))	('p53 mutant population', 'MPA', (159, 180))
692557	31327664	Cell tracking shows low-dose ionizing radiation drives differentiation in esophagus Low-dose radiation acts via redox stress without activating the DNA repair pathway p53 mutant cells do not differentiate after irradiation and outcompete normal cells Antioxidant plus radiation depletes p53 mutant cells by improving normal cell fitness Normal human esophagus contains p53 mutant progenitors.	('depletes', 'NegReg', (278, 286))	('improving', 'PosReg', (307, 316))	('mutant', 'Var', (373, 379))	('low-dose ionizing radiation', 'Phenotype', 'HP:0011133', (20, 47))	('p53', 'Gene', (369, 372))	('human', 'Species', '9606', (344, 349))	('mutant', 'Var', (171, 177))	('mutant', 'Var', (291, 297))	('p53', 'Gene', (287, 290))
692559	31327664	This process is exemplified by human esophageal epithelium (EE), in which mutations generated by cell-intrinsic processes colonize the majority of normal epithelium by middle age.	('mutations', 'Var', (74, 83))	('esophageal epithelium', 'Disease', (37, 58))	('human', 'Species', '9606', (31, 36))
692560	31327664	In this study, we focused on p53 (human TP53, mouse Trp53) mutations because these are the most enriched during malignant transformation.	('human', 'Species', '9606', (34, 39))	('Trp53', 'Gene', (52, 57))	('mouse', 'Species', '10090', (46, 51))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('mutations', 'Var', (59, 68))	('Trp53', 'Gene', '22059', (52, 57))
692562	31327664	This argues that ESCC emerges from the p53 mutant cell population in normal epithelium and that mutation of p53 is required for cancer development.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('p53', 'Gene', (108, 111))	('ESCC', 'Disease', (17, 21))	('mutant', 'Var', (43, 49))	('p53', 'Gene', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
692565	31327664	Here we apply this technique to test whether the selection of p53 mutant clones is altered by oxidative stress resulting from low-dose ionizing radiation (LDIR) with doses similar to those from medical imaging and environmental contamination.	('mutant', 'Var', (66, 72))	('altered', 'Reg', (83, 90))	('low-dose ionizing radiation', 'Phenotype', 'HP:0011133', (126, 153))	('oxidative', 'MPA', (94, 103))	('LDIR', 'Phenotype', 'HP:0011133', (155, 159))	('LDIR', 'Chemical', '-', (155, 159))	('oxidative stress', 'Phenotype', 'HP:0025464', (94, 110))	('p53', 'Gene', (62, 65))
692566	31327664	We find that LDIR exposure promotes the expansion of p53 mutant clones.	('LDIR', 'Chemical', '-', (13, 17))	('mutant', 'Var', (57, 63))	('p53', 'Gene', (53, 56))	('LDIR', 'Phenotype', 'HP:0011133', (13, 17))
692570	31327664	Yellow fluorescent protein (YFP) expression was induced by genetic recombination in individual progenitor cells in AhcreERTRosa26flEYFP/WT (RYFP) transgenic mice (Figures 2A and S1A).	('expression', 'MPA', (33, 43))	('transgenic mice', 'Species', '10090', (146, 161))	('genetic recombination', 'Var', (59, 80))	('YFP', 'Gene', (28, 31))
692605	31327664	We began by immunostaining EE from irradiated and control mice for phospho-serine40 NRF2 protein, which accumulates in the nucleus of cells following an oxidative challenge.	('mice', 'Species', '10090', (58, 62))	('NRF2', 'Gene', '18024', (84, 88))	('phospho-serine40', 'Var', (67, 83))	('NRF2', 'Gene', (84, 88))
692609	31327664	Having established that LDIR alters wild-type cell dynamics in EE, we set out to see whether it might influence the selection of cells carrying mutations that drive clonal expansion in the human esophagus.	('LDIR', 'Phenotype', 'HP:0011133', (24, 28))	('influence', 'Reg', (102, 111))	('LDIR', 'Chemical', '-', (24, 28))	('human', 'Species', '9606', (189, 194))	('wild-type', 'MPA', (36, 45))	('mutations', 'Var', (144, 153))	('alters', 'Reg', (29, 35))
692611	31327664	In addition, both humans and mice with germline heterozygous p53 mutations are at an increased risk of developing esophageal tumors.	('esophageal tumors', 'Disease', (114, 131))	('humans', 'Species', '9606', (18, 24))	('p53', 'Gene', (61, 64))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('mice', 'Species', '10090', (29, 33))	('esophageal tumors', 'Disease', 'MESH:D004938', (114, 131))	('esophageal tumors', 'Phenotype', 'HP:0100751', (114, 131))	('mutations', 'Var', (65, 74))
692612	31327664	We first investigated the effect of LDIR on p53 mutant clones in EE using lineage tracing in AhcreERTp53flR245W-GFPWT transgenic mice, hereafter called p53*/WT.	('mutant', 'Var', (48, 54))	('transgenic mice', 'Species', '10090', (118, 133))	('R245W', 'Mutation', 'p.R245W', (106, 111))	('p53', 'Gene', (44, 47))	('LDIR', 'Phenotype', 'HP:0011133', (36, 40))	('LDIR', 'Chemical', '-', (36, 40))
692614	31327664	This p53 mutant has properties distinct from a null allele and is frequently found in keratinocyte-derived cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutant', 'Var', (9, 15))	('found', 'Reg', (77, 82))	('p53', 'Gene', (5, 8))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
692616	31327664	We found that p53*/WT clones were significantly larger and had fewer differentiated and more basal cells than both unirradiated p53*/WT mice and p53WT/WT clones in RYFP control animals.	('fewer', 'NegReg', (63, 68))	('mice', 'Species', '10090', (136, 140))	('p53*/WT', 'Var', (14, 21))	('larger', 'PosReg', (48, 54))
692619	31327664	This reveals that a single exposure or multiple LDIR exposures act as positive selective pressure for p53*/WT cells in normal EE, based on the resistance of mutant cells to radiation-induced differentiation.	('positive', 'PosReg', (70, 78))	('LDIR', 'Phenotype', 'HP:0011133', (48, 52))	('p53*/WT', 'Var', (102, 109))	('LDIR', 'Chemical', '-', (48, 52))
692620	31327664	We next investigated the basis of the competitive advantage of p53*/WT over wild-type cells following LDIR, speculating that the mutant cells may be resistant to the radiation-induced alteration in mitochondrial redox state seen in wild-type cells.	('LDIR', 'Phenotype', 'HP:0011133', (102, 106))	('LDIR', 'Chemical', '-', (102, 106))	('mito', 'Species', '262676', (198, 202))	('p53*/WT', 'Var', (63, 70))	('mutant', 'Var', (129, 135))
692621	31327664	In keeping with this hypothesis, primary cultures of p53*/WT EE exhibited lower baseline levels of mitochondrial oxidation than wild-type cells (Figure 5M), and these were little changed in the mutant following exposure to 50 mGy LDIR (Figure 5N).	('baseline levels', 'MPA', (80, 95))	('p53*/WT', 'Var', (53, 60))	('mitochondrial oxidation', 'MPA', (99, 122))	('LDIR', 'Phenotype', 'HP:0011133', (230, 234))	('LDIR', 'Chemical', '-', (230, 234))	('mito', 'Species', '262676', (99, 103))	('lower', 'NegReg', (74, 79))
692622	31327664	This suggested that p53*/WT may express higher levels of cellular antioxidants, protecting them from the effects of LDIR in a manner similar to NAC treatment of wild-type cells.	('LDIR', 'Phenotype', 'HP:0011133', (116, 120))	('LDIR', 'Chemical', '-', (116, 120))	('higher', 'PosReg', (40, 46))	('NAC', 'Chemical', 'MESH:D000111', (144, 147))	('p53*/WT', 'Var', (20, 27))	('levels of cellular antioxidants', 'MPA', (47, 78))
692623	31327664	In keeping with this hypothesis, RNA sequencing (RNA-seq) analysis of mutant cultures revealed minimal change in the global transcriptome or transcription following LDIR (Figures S5A and S5B).	('global transcriptome', 'MPA', (117, 137))	('LDIR', 'Phenotype', 'HP:0011133', (165, 169))	('LDIR', 'Chemical', '-', (165, 169))	('mutant', 'Var', (70, 76))	('transcription', 'MPA', (141, 154))
692624	31327664	We noted that transcription of the p53* allele was unaltered by LDIR and that, in contrast to wild-type cells, differentiation associated transcripts were not upregulated by irradiation of mutant cultures (Figures S5C-S5E).	('mutant', 'Var', (189, 195))	('LDIR', 'Phenotype', 'HP:0011133', (64, 68))	('p53', 'Gene', (35, 38))	('LDIR', 'Chemical', '-', (64, 68))
692625	31327664	Both unirradiated and LDIR-treated p53*/WT cells showed substantially higher levels of transcripts encoding oxidative stress response genes compared with p53WT/WT cells (Figure S5F).	('levels of transcripts encoding', 'MPA', (77, 107))	('LDIR', 'Phenotype', 'HP:0011133', (22, 26))	('LDIR', 'Chemical', '-', (22, 26))	('oxidative stress', 'Phenotype', 'HP:0025464', (108, 124))	('higher', 'PosReg', (70, 76))	('p53*/WT', 'Var', (35, 42))
692627	31327664	The competitive advantage of the p53 mutant cells was abolished by exposing the cultures to NAC.	('NAC', 'Chemical', 'MESH:D000111', (92, 95))	('mutant', 'Var', (37, 43))	('p53', 'Gene', (33, 36))	('competitive advantage', 'CPA', (4, 25))	('abolished', 'NegReg', (54, 63))
692628	31327664	Taken together, the findings above led us to conclude that the heightened resilience of p53 mutant cells to oxidative stress explains their selection over wild-type cells in EE exposed to LDIR.	('resilience', 'MPA', (74, 84))	('LDIR', 'Chemical', '-', (188, 192))	('heightened', 'PosReg', (63, 73))	('p53', 'Gene', (88, 91))	('oxidative stress', 'Phenotype', 'HP:0025464', (108, 124))	('mutant', 'Var', (92, 98))	('LDIR', 'Phenotype', 'HP:0011133', (188, 192))
692631	31327664	Remarkably, however, rather than simply rescuing the effect of LDIR on mutant cell expansion, NAC treatment resulted in a substantial decrease in the proportion of p53*/WT mutant basal cells in EE (Figure 6D).	('LDIR', 'Phenotype', 'HP:0011133', (63, 67))	('decrease', 'NegReg', (134, 142))	('p53*/WT', 'Var', (164, 171))	('LDIR', 'Chemical', '-', (63, 67))	('NAC', 'Chemical', 'MESH:D000111', (94, 97))
692632	31327664	To gain more insight into the cellular mechanisms of p53 mutant clone loss in animals treated with NAC and LDIR, we used short-term lineage tracing with EdU, allowing us to track the fate of proliferating mutant and wild-type cells in the same mouse.	('mouse', 'Species', '10090', (244, 249))	('loss', 'NegReg', (70, 74))	('EdU', 'Chemical', '-', (153, 156))	('NAC', 'Chemical', 'MESH:D000111', (99, 102))	('mutant', 'Var', (57, 63))	('p53', 'Gene', (53, 56))	('LDIR', 'Chemical', '-', (107, 111))	('LDIR', 'Phenotype', 'HP:0011133', (107, 111))
692633	31327664	We found that, 48 h after EdU labeling, the proportion of differentiated EdU-positive cells was significantly higher in mutant than in wild-type cells (Figures 6G and 6H).	('EdU', 'Chemical', '-', (26, 29))	('higher', 'PosReg', (110, 116))	('EdU', 'Chemical', '-', (73, 76))	('mutant', 'Var', (120, 126))
692634	31327664	Correspondingly, we found that the proportion of basal cells expressing the proliferation-associated antigen Ki67 was reduced in mutant compared with wild-type cells (Figure 6I).	('Ki67', 'Gene', '17345', (109, 113))	('mutant', 'Var', (129, 135))	('reduced', 'NegReg', (118, 125))	('Ki67', 'Gene', (109, 113))
692637	31327664	Treating animals with an exogenous antioxidant, NAC, protects wild-type cells from LDIR-induced differentiation and turns the tables on mutant clones, which have an increased likelihood of loss by shedding under these conditions.	('LDIR', 'Phenotype', 'HP:0011133', (83, 87))	('LDIR', 'Chemical', '-', (83, 87))	('NAC', 'Chemical', 'MESH:D000111', (48, 51))	('mutant', 'Var', (136, 142))	('LDIR-induced', 'CPA', (83, 95))
692639	31327664	Antioxidants may also mitigate the effects of planned LDIR exposure on p53 mutant clones.	('p53', 'Gene', (71, 74))	('LDIR', 'Phenotype', 'HP:0011133', (54, 58))	('LDIR', 'Chemical', '-', (54, 58))	('mutant', 'Var', (75, 81))
692642	31327664	In these mice, transcription of a cre mutant estrogen receptor fusion protein (creERT) is induced by beta-naphthoflavone.	('mutant', 'Var', (38, 44))	('transcription', 'MPA', (15, 28))	('beta-naphthoflavone', 'Chemical', 'MESH:D019324', (101, 120))	('mice', 'Species', '10090', (9, 13))
692644	31327664	p53eGFP-R245W/wt mice express the R245W mutant version of p53 and can be detected by GFP expression following cre induction.	('mice', 'Species', '10090', (17, 21))	('R245W', 'Mutation', 'p.R245W', (8, 13))	('R245W', 'Var', (34, 39))	('R245W', 'Mutation', 'p.R245W', (34, 39))	('p53', 'Gene', (58, 61))
692646	31327664	Once the wild-type Trp53 genomic region is deleted by cre both the Trp53 mutant carrying the R245W mutation and the eGFP reporter are transcribed.	('Trp53', 'Gene', '22059', (19, 24))	('Trp53', 'Gene', '22059', (67, 72))	('Trp53', 'Gene', (19, 24))	('R245W', 'Var', (93, 98))	('R245W', 'Mutation', 'p.R245W', (93, 98))	('Trp53', 'Gene', (67, 72))
692694	29259266	Recent studies researched the associations of core genes in the pTEN/AKT/mTOR pathway polymorphisms with the cancer susceptibility; however, the results are inconclusive.	('mTOR', 'Gene', '2475', (73, 77))	('pTEN', 'Gene', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('AKT', 'Gene', (69, 72))	('mTOR', 'Gene', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('pTEN', 'Gene', '5728', (64, 68))	('polymorphisms', 'Var', (86, 99))	('AKT', 'Gene', '207', (69, 72))	('associations', 'Interaction', (30, 42))
692695	29259266	Therefore, a systematically meta-analysis was performed to evaluate the association between the five SNPs (mTOR rs2295080 and rs2536, AKT1 rs2494750 and rs2494752, pTEN rs701848) and cancer risk by systematic review of the literature in 31 eligible studies.	('pTEN', 'Gene', '5728', (164, 168))	('rs2494750', 'Var', (139, 148))	('AKT1', 'Gene', '207', (134, 138))	('cancer', 'Disease', (183, 189))	('rs2494752', 'Mutation', 'rs2494752', (153, 162))	('AKT1', 'Gene', (134, 138))	('pTEN', 'Gene', (164, 168))	('rs2295080', 'Var', (112, 121))	('mTOR', 'Gene', (107, 111))	('mTOR', 'Gene', '2475', (107, 111))	('rs2494750', 'Mutation', 'rs2494750', (139, 148))	('rs701848', 'Mutation', 'rs701848', (169, 177))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('rs2536', 'Mutation', 'rs2536', (126, 132))	('rs2295080', 'Mutation', 'rs2295080', (112, 121))	('rs2536', 'Var', (126, 132))	('rs2494752', 'Var', (153, 162))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
692696	29259266	The results showed a significant decreased risk between rs2295080 TG, GG genotype, and GG/TG genotypes and overall cancer [TG vs.TT: OR(95% CI) = 0.82(0.76, 0.89), GG/TG vs. TT: OR(95% CI) = 0.82(0.76, 0.88), and GG vs. TG/TT: OR(95% CI) = 0.67(0.51, 0.88)] and the subgroup of urinary system cancer and digestive system cancer.	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('system cancer', 'Disease', (314, 327))	('rs2295080', 'Mutation', 'rs2295080', (56, 65))	('decreased', 'NegReg', (33, 42))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('TG', 'Chemical', '-', (220, 222))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('urinary system cancer', 'Disease', (278, 299))	('system cancer', 'Disease', 'MESH:D009369', (286, 299))	('TG', 'Chemical', '-', (123, 125))	('rs2295080', 'Var', (56, 65))	('TG', 'Chemical', '-', (66, 68))	('cancer', 'Disease', (293, 299))	('TG', 'Chemical', '-', (90, 92))	('urinary system cancer', 'Phenotype', 'HP:0010786', (278, 299))	('TG', 'Chemical', '-', (167, 169))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (321, 327))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('urinary system cancer', 'Disease', 'MESH:D001749', (278, 299))	('system cancer', 'Disease', 'MESH:D009369', (314, 327))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))
692697	29259266	Moreover, the SNP rs701848 CC, TC genotype showed significantly increased the overall cancer risk both in dominant model [CC/TC vs. TT: OR(95% CI) = 1.25(1.15, 1.36)] and recessive model [CC vs. TC/TT: OR(95% CI) = 1.20(1.09, 1.32)], and digestive system cancer and urinary system cancer.	('rs701848', 'Mutation', 'rs701848', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('system cancer', 'Disease', 'MESH:D009369', (274, 287))	('SNP', 'Var', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (281, 287))	('system cancer', 'Disease', 'MESH:D009369', (248, 261))	('urinary system cancer', 'Phenotype', 'HP:0010786', (266, 287))	('urinary system cancer', 'Disease', (266, 287))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('increased', 'PosReg', (64, 73))	('system cancer', 'Disease', (248, 261))	('urinary system cancer', 'Disease', 'MESH:D001749', (266, 287))	('cancer', 'Disease', (86, 92))
692698	29259266	In addition, AG genotype and GG/AG genotype of rs2494752 was associated with increased risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('rs2494752', 'Var', (47, 56))	('rs2494752', 'Mutation', 'rs2494752', (47, 56))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
692704	29259266	Therefore, the Single nucleotide polymorphisms (SNPs) of core genes in the pTEN/AKT/mTOR pathway may impact the transcription and expression of the proteins and thus alter the capacity and function of the pathway, which could play a critical role in carcinogenesis.	('pTEN', 'Gene', (75, 79))	('expression', 'MPA', (130, 140))	('impact', 'NegReg', (101, 107))	('AKT', 'Gene', '207', (80, 83))	('function', 'MPA', (189, 197))	('proteins', 'Protein', (148, 156))	('carcinogenesis', 'Disease', (250, 264))	('mTOR', 'Gene', '2475', (84, 88))	('AKT', 'Gene', (80, 83))	('mTOR', 'Gene', (84, 88))	('pTEN', 'Gene', '5728', (75, 79))	('alter', 'Reg', (166, 171))	('Single nucleotide polymorphisms', 'Var', (15, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (250, 264))	('transcription', 'MPA', (112, 125))
692708	29259266	Among those cSNPs, a few potential functional SNPs especially located in the 5'-untranslated regions(5'UTR) and 3'UTR of the candidate genes could affect the carcinogenesis by modulating the transcriptional activity of candidate genes or by interacting with the miRNA binding, such as rs2295080 in the mTOR gene promoter region, rs2494750 and rs2494752 in the AKT1 5'UTR region, rs2536 in the 3'UTR of mTOR  and rs701848 the pTEN 3'UTR region.	('mTOR', 'Gene', (402, 406))	('carcinogenesis', 'Disease', 'MESH:D063646', (158, 172))	('modulating', 'Reg', (176, 186))	('interacting', 'Reg', (241, 252))	('mTOR', 'Gene', '2475', (402, 406))	('rs2536', 'Mutation', 'rs2536', (379, 385))	('rs2295080', 'Mutation', 'rs2295080', (285, 294))	('affect', 'Reg', (147, 153))	('AKT1', 'Gene', '207', (360, 364))	('pTEN', 'Gene', (425, 429))	('mTOR', 'Gene', (302, 306))	('rs2494752', 'Var', (343, 352))	('transcriptional activity', 'MPA', (191, 215))	('rs2494750', 'Mutation', 'rs2494750', (329, 338))	('candidate genes', 'Gene', (219, 234))	('pTEN', 'Gene', '5728', (425, 429))	('rs2295080', 'Var', (285, 294))	('miRNA', 'Protein', (262, 267))	('rs2536', 'Var', (379, 385))	('AKT1', 'Gene', (360, 364))	('mTOR', 'Gene', '2475', (302, 306))	('rs2494752', 'Mutation', 'rs2494752', (343, 352))	('rs2494750', 'Var', (329, 338))	('carcinogenesis', 'Disease', (158, 172))	('rs701848', 'Mutation', 'rs701848', (412, 420))	('rs701848', 'Var', (412, 420))
692709	29259266	Furthermore, previous studies demonstrated that the mTOR rs2295080 TT genotypes carriers showed a much higher mRNA levels of mTOR transcription by increasing the transcriptional activity of mTOR gene in human gastric cancer cell line SGC-7901.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('mTOR', 'Gene', '2475', (125, 129))	('human', 'Species', '9606', (203, 208))	('mTOR', 'Gene', '2475', (190, 194))	('mTOR', 'Gene', (125, 129))	('rs2295080', 'Var', (57, 66))	('mTOR', 'Gene', (190, 194))	('gastric cancer', 'Disease', (209, 223))	('increasing', 'PosReg', (147, 157))	('transcriptional activity', 'MPA', (162, 186))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('gastric cancer', 'Disease', 'MESH:D013274', (209, 223))	('higher', 'PosReg', (103, 109))	('rs2295080', 'Mutation', 'rs2295080', (57, 66))	('SGC-7901', 'CellLine', 'CVCL:0520', (234, 242))	('gastric cancer', 'Phenotype', 'HP:0012126', (209, 223))
692710	29259266	Moreover, carrying the rs2295080 T allele showed increased mTOR mRNA levels compared with the G allele in the patients with renal cell cancer and colorectal cancer.	('renal cell cancer', 'Disease', 'MESH:C538614', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('rs2295080 T', 'Var', (23, 34))	('renal cell cancer', 'Disease', (124, 141))	('increased', 'PosReg', (49, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('renal cell cancer', 'Phenotype', 'HP:0005584', (124, 141))	('colorectal cancer', 'Disease', (146, 163))	('rs2295080', 'Mutation', 'rs2295080', (23, 32))	('mTOR', 'Gene', '2475', (59, 63))	('patients', 'Species', '9606', (110, 118))	('mTOR', 'Gene', (59, 63))
692712	29259266	found that co-transfection of the rs2536 A allele and G allele with miR-767-3p exhibited different promoter activities.	('rs2536', 'Mutation', 'rs2536', (34, 40))	('rs2536 A', 'Var', (34, 42))	('promoter activities', 'MPA', (99, 118))
692713	29259266	Additionally, the polymorphism of pTEN rs701848 was proposed to involve in affecting the activity of micorRNA binding site.	('affecting', 'Reg', (75, 84))	('pTEN', 'Gene', '5728', (34, 38))	('pTEN', 'Gene', (34, 38))	('rs701848', 'Var', (39, 47))	('rs701848', 'Mutation', 'rs701848', (39, 47))	('micorRNA', 'Protein', (101, 109))	('activity', 'MPA', (89, 97))
692714	29259266	Therefore, considering the critical role of the genetic variations in the pTEN/AKT/mTOR pathway, understanding the association between these SNPs and cancer susceptibility are urgently required.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('mTOR', 'Gene', (83, 87))	('AKT', 'Gene', (79, 82))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('pTEN', 'Gene', '5728', (74, 78))	('mTOR', 'Gene', '2475', (83, 87))	('AKT', 'Gene', '207', (79, 82))	('genetic variations', 'Var', (48, 66))	('pTEN', 'Gene', (74, 78))
692715	29259266	To date, numerous studies have investigated the association of genetic polymorphisms of pTEN/AKT/mTOR pathway genes including rs2295080, rs2536 of mTOR gene, rs2494750 and rs2494752 in the AKT1 gene, pTEN rs701848 with cancer susceptibility, however, the results were inconclusive.	('AKT1', 'Gene', '207', (189, 193))	('pTEN', 'Gene', '5728', (200, 204))	('association', 'Interaction', (48, 59))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('pTEN', 'Gene', '5728', (88, 92))	('rs2494752', 'Var', (172, 181))	('mTOR', 'Gene', '2475', (147, 151))	('rs2494750', 'Mutation', 'rs2494750', (158, 167))	('rs2295080', 'Mutation', 'rs2295080', (126, 135))	('AKT', 'Gene', (189, 192))	('AKT', 'Gene', (93, 96))	('mTOR', 'Gene', (97, 101))	('AKT1', 'Gene', (189, 193))	('rs2494750', 'Var', (158, 167))	('rs2494752', 'Mutation', 'rs2494752', (172, 181))	('rs2536', 'Var', (137, 143))	('mTOR', 'Gene', '2475', (97, 101))	('pTEN', 'Gene', (200, 204))	('rs2295080', 'Var', (126, 135))	('cancer', 'Disease', (219, 225))	('AKT', 'Gene', '207', (189, 192))	('AKT', 'Gene', '207', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('rs701848', 'Mutation', 'rs701848', (205, 213))	('rs701848', 'Var', (205, 213))	('rs2536', 'Mutation', 'rs2536', (137, 143))	('mTOR', 'Gene', (147, 151))	('pTEN', 'Gene', (88, 92))
692717	29259266	All the searched eligible original studies and review articles were reviewed carefully to identify the relevant articles by using the following search terms "mTOR rs2295080" or "mTOR rs2536" or "pTEN rs701848" or "AKT1 rs2494750" or "AKT1 rs2494752" and "polymorphism or SNP or single nucleotide polymorphism or variation or mutation" and "cancer or carcinoma or tumor or neoplasm", (the search was updated on Feb 15, 2017).	('rs2536', 'Mutation', 'rs2536', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('cancer', 'Disease', 'MESH:D009369', (340, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (350, 359))	('carcinoma or tumor', 'Disease', (350, 368))	('mTOR', 'Gene', (178, 182))	('AKT1', 'Gene', (214, 218))	('AKT1', 'Gene', '207', (234, 238))	('single nucleotide polymorphism', 'Var', (278, 308))	('neoplasm', 'Disease', 'MESH:D009369', (372, 380))	('rs2494750', 'Mutation', 'rs2494750', (219, 228))	('mTOR', 'Gene', '2475', (178, 182))	('neoplasm', 'Disease', (372, 380))	('variation', 'Var', (312, 321))	('pTEN', 'Gene', (195, 199))	('rs701848', 'Var', (200, 208))	('rs2295080', 'Var', (163, 172))	('rs2536', 'Var', (183, 189))	('rs701848', 'Mutation', 'rs701848', (200, 208))	('AKT1', 'Gene', (234, 238))	('rs2295080', 'Mutation', 'rs2295080', (163, 172))	('carcinoma or tumor', 'Disease', 'MESH:D009369', (350, 368))	('cancer', 'Disease', (340, 346))	('mTOR', 'Gene', (158, 162))	('pTEN', 'Gene', '5728', (195, 199))	('rs2494752', 'Mutation', 'rs2494752', (239, 248))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('AKT1', 'Gene', '207', (214, 218))	('mutation', 'Reg', (325, 333))	('mTOR', 'Gene', '2475', (158, 162))
692718	29259266	In this meta-analysis, selected publications were eligible if they fulfilled the following criteria: (1) a case-control study or cohort study design; (2) evaluated the association of the genetic polymorphisms of mTOR, AKT1, and pTEN gene with the risk of cancer; (3) sufficient genotypic and/or allelic information for estimating the odds ratio (OR) with 95% confidence intervals (CIs) was provided; (4) the samples size of cases or controls were >=20.	('mTOR', 'Gene', '2475', (212, 216))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('association', 'Interaction', (168, 179))	('polymorphisms', 'Var', (195, 208))	('pTEN', 'Gene', '5728', (228, 232))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('mTOR', 'Gene', (212, 216))	('AKT1', 'Gene', '207', (218, 222))	('pTEN', 'Gene', (228, 232))	('AKT1', 'Gene', (218, 222))
692722	29259266	Finally, 31 studies of Asian population were met the inclusion criteria, 13 studies of them evaluated the association of mTOR rs2295080 with cancer risks, 10 studies determined the SNP rs2536 of mTOR gene and cancer susceptibility, 16 publications were pTEN rs701848 polymorphism, 6 reports studied the AKT1 rs2494750 SNP and 3 reports determined AKT1 rs2494752 SNP.	('rs2536', 'Mutation', 'rs2536', (185, 191))	('AKT1', 'Gene', '207', (347, 351))	('rs2494750', 'Mutation', 'rs2494750', (308, 317))	('mTOR', 'Gene', '2475', (195, 199))	('rs2295080', 'Mutation', 'rs2295080', (126, 135))	('pTEN', 'Gene', (253, 257))	('rs701848', 'Mutation', 'rs701848', (258, 266))	('mTOR', 'Gene', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('AKT1', 'Gene', (347, 351))	('pTEN', 'Gene', '5728', (253, 257))	('cancer', 'Disease', (141, 147))	('mTOR', 'Gene', '2475', (121, 125))	('AKT1', 'Gene', '207', (303, 307))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rs2295080', 'Var', (126, 135))	('association', 'Interaction', (106, 117))	('rs2494752', 'Mutation', 'rs2494752', (352, 361))	('AKT1', 'Gene', (303, 307))	('cancer', 'Disease', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('mTOR', 'Gene', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
692726	29259266	In this final meta-analysis 8965 cases and 9868 controls for the mTOR rs2295080, 8411 cases and 8837 controls for the mTOR rs2536, 5882 cases and 6284 controls for the pTEN rs701848, 4332 cases and 4498 controls for the AKT1 rs2494750, and 3187 cases and 3174 controls for the AKT1 rs2494752 were included.	('mTOR', 'Gene', (65, 69))	('pTEN', 'Gene', '5728', (168, 172))	('mTOR', 'Gene', '2475', (65, 69))	('AKT1', 'Gene', (277, 281))	('AKT1', 'Gene', '207', (220, 224))	('rs2295080', 'Mutation', 'rs2295080', (70, 79))	('rs701848', 'Var', (173, 181))	('rs701848', 'Mutation', 'rs701848', (173, 181))	('mTOR', 'Gene', (118, 122))	('AKT1', 'Gene', (220, 224))	('mTOR', 'Gene', '2475', (118, 122))	('rs2494750', 'Mutation', 'rs2494750', (225, 234))	('pTEN', 'Gene', (168, 172))	('AKT1', 'Gene', '207', (277, 281))	('rs2494752', 'Mutation', 'rs2494752', (282, 291))	('rs2536', 'Mutation', 'rs2536', (123, 129))	('rs2295080', 'Var', (70, 79))
692728	29259266	The meta-analysis results for the mTOR rs2295080 and rs2536 polymorphism and cancer susceptibility are illustrated in Tables 2, 3, Fig.	('rs2295080', 'Var', (39, 48))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('rs2536', 'Mutation', 'rs2536', (53, 59))	('rs2536', 'Var', (53, 59))	('rs2295080', 'Mutation', 'rs2295080', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', (34, 38))
692729	29259266	Overall, we observed that carrying mTOR rs2295080 TG or GG genotype and GG/TG genotype showed significant association with decreased cancer risk [TG vs.TT in heterozygote model: OR(95% CI) = 0.82(0.76, 0.89), P < 0.001; GG/TG vs. TT in dominant model: OR(95% CI) = 0.82(0.76, 0.88), P < 0.001; and GG vs.TG/TT in recessive model: OR(95% CI) = 0.67(0.51, 0.88), P = 0.004].	('mTOR', 'Gene', (35, 39))	('TG', 'Chemical', '-', (146, 148))	('rs2295080', 'Var', (40, 49))	('mTOR', 'Gene', '2475', (35, 39))	('decreased cancer', 'Disease', (123, 139))	('TG', 'Chemical', '-', (50, 52))	('TG', 'Chemical', '-', (75, 77))	('TG', 'Chemical', '-', (304, 306))	('decreased cancer', 'Disease', 'MESH:D009369', (123, 139))	('rs2295080', 'Mutation', 'rs2295080', (40, 49))	('TG', 'Chemical', '-', (223, 225))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
692731	29259266	Subsequently, we found that rs2295080 GG genotype, TG genotype, and GG/TG genotypes carriers showed a significantly decreased cancer risk in the stratification analysis of urinary system cancer [GG vs.TT: OR(95% CI) = 0.78(0.62, 0.97), P = 0.029; TG vs. TT: OR(95% CI) = 0.77(0.69, 0.85), P < 0.001; GG/TG vs. TT: OR(95% CI) = 0.77(0.69, 0.85), P < 0.001; and GG vs. TG/TT: OR(95% CI) = 0.79(0.63, 0.98), P = 0.035] and digestive system cancer [GG vs.TT: OR(95% CI) = 0.56(0.40, 0.79), P = 0.001; TG vs. TT: OR(95% CI) = 0.81(0.70, 0.94), P = 0.006; GG/TG vs. TT: OR(95% CI) = 0.77(0.67, 0.89), P = 0.001; and GG vs. TG/TT: OR(95% CI) = 0.55(0.40, 0.77), P = 0.001].	('urinary system cancer', 'Phenotype', 'HP:0010786', (172, 193))	('TG', 'Chemical', '-', (497, 499))	('TG', 'Chemical', '-', (617, 619))	('TG', 'Chemical', '-', (553, 555))	('system cancer', 'Disease', 'MESH:D009369', (430, 443))	('cancer', 'Phenotype', 'HP:0002664', (437, 443))	('urinary system cancer', 'Disease', 'MESH:D001749', (172, 193))	('system cancer', 'Disease', (430, 443))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TG', 'Chemical', '-', (51, 53))	('rs2295080', 'Mutation', 'rs2295080', (28, 37))	('decreased cancer', 'Disease', (116, 132))	('system cancer', 'Disease', 'MESH:D009369', (180, 193))	('TG', 'Chemical', '-', (367, 369))	('decreased cancer', 'Disease', 'MESH:D009369', (116, 132))	('TG', 'Chemical', '-', (247, 249))	('TG', 'Chemical', '-', (303, 305))	('urinary system cancer', 'Disease', (172, 193))	('TG', 'Chemical', '-', (71, 73))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('rs2295080', 'Var', (28, 37))
692733	29259266	For mTOR rs2536 polymorphism, there was no association was observed both in overall analysis and subgroup analysis (Tables 2 and 3).	('rs2536', 'Var', (9, 15))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('rs2536', 'Mutation', 'rs2536', (9, 15))
692734	29259266	The effect of pTEN rs701848 polymorphism on cancer risk in overall and subgroup analysis was shown in Tables 2, 3 and Figs 3 and S2.The SNP rs701848 CC or TC genotype and CC/TC genotype were associated with an increased overall cancer risk [CC vs.TT in homozygote model: OR(95% CI) = 1.35(1.21, 1.51), P < 0.001; TC vs. TT in heterozygote model: OR(95% CI) = 1.21(1.11, 1.32), P < 0.001; CC/TC vs. TT in dominant model: OR(95% CI) = 1.25(1.15, 1.36), P < 0.001; and CC vs. TC/TT in recessive model: OR(95% CI) = 1.20(1.09, 1.32), P < 0.001].	('cancer', 'Disease', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('pTEN', 'Gene', (14, 18))	('rs701848', 'Mutation', 'rs701848', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('SNP rs701848 CC', 'Var', (136, 151))	('rs701848', 'Mutation', 'rs701848', (140, 148))	('pTEN', 'Gene', '5728', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
692735	29259266	In the further stratification analysis, we found that rs701848 CC genotype, TC genotype and CC/TC genotypes were statistically increased association with digestive system cancer [CC vs.TT: OR(95% CI) = 1.51(1.24, 1.84), P < 0.001; TC vs. TT: OR(95% CI) = 1.36(1.19, 1.57), P < 0.001; and CC/TC vs. TT: OR(95% CI) = 1.40(1.22, 1.59), P = 0.017; and CC vs. TC/TT: OR(95% CI) = 1.23(1.04, 1.47), P < 0.001] and urinary system cancer[CC vs. TT: OR(95% CI) = 1.33(1.12, 1.58), P < 0.001; TC vs. TT: OR(95% CI) = 1.14(1.00, 1.31), P = 0.049; and CC/TC vs. TT: OR(95% CI) = 1.20(1.05, 1.36), P = 0.008; and CC vs. TC/TT: OR(95% CI) = 1.23(1.05, 1.43), P = 0.006], however no association was observed between the oral cavity cancer and cancer risk in this concluded studies.	('urinary system cancer', 'Disease', (408, 429))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (717, 723))	('system cancer', 'Disease', 'MESH:D009369', (416, 429))	('cancer', 'Phenotype', 'HP:0002664', (717, 723))	('cancer', 'Disease', 'MESH:D009369', (728, 734))	('cancer', 'Disease', (423, 429))	('urinary system cancer', 'Phenotype', 'HP:0010786', (408, 429))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('CC/TC vs. TT', 'Var', (540, 552))	('cancer', 'Disease', 'MESH:D009369', (717, 723))	('cancer', 'Disease', (171, 177))	('urinary system cancer', 'Disease', 'MESH:D001749', (408, 429))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (423, 429))	('cancer', 'Disease', (728, 734))	('rs701848', 'Mutation', 'rs701848', (54, 62))	('rs701848', 'Var', (54, 62))	('system cancer', 'Disease', 'MESH:D009369', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (728, 734))	('system cancer', 'Disease', (164, 177))	('increased', 'PosReg', (127, 136))
692736	29259266	The association between polymorphisms of AKT1 rs2494750, rs2494752 and cancer risk in overall meta-analysis results was shown in Tables 2, 3 and Fig.	('AKT1', 'Gene', '207', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('rs2494752', 'Var', (57, 66))	('rs2494750', 'Mutation', 'rs2494750', (46, 55))	('cancer', 'Disease', (71, 77))	('rs2494752', 'Mutation', 'rs2494752', (57, 66))	('AKT1', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs2494750', 'Var', (46, 55))
692737	29259266	A significant association was observed between AKT1 rs2494752 and overall cancer risk, and the heterozygous genotype AG and GG/AG genotype of AKT1 rs2494752 were associated with increased cancer risk (AG vs. AA in heterozygote model: OR(95% CI) = 1.13(1.01, 1.25), P = 0.026; and GG/AG vs. AA in dominant model: OR(95% CI) = 1.13(1.02, 1.25), P = 0.017).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('AKT1', 'Gene', '207', (142, 146))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('AKT1', 'Gene', (142, 146))	('rs2494752', 'Var', (52, 61))	('rs2494752', 'Var', (147, 156))	('cancer', 'Disease', (188, 194))	('rs2494752', 'Mutation', 'rs2494752', (147, 156))	('AKT1', 'Gene', '207', (47, 51))	('rs2494752', 'Mutation', 'rs2494752', (52, 61))	('AKT1', 'Gene', (47, 51))
692738	29259266	For AKT1 rs2494750 polymorphism, we have not found the correlation with the cancer susceptibility both in overall analysis and subgroup analysis (Tables 2 and 3).	('rs2494750', 'Var', (9, 18))	('AKT1', 'Gene', '207', (4, 8))	('AKT1', 'Gene', (4, 8))	('rs2494750', 'Mutation', 'rs2494750', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
692739	29259266	No significant heterogeneities were observed for the overall analyses of mTOR rs2536, AKT1 rs2494750 and rs2494752.	('mTOR', 'Gene', '2475', (73, 77))	('mTOR', 'Gene', (73, 77))	('rs2494752', 'Var', (105, 114))	('rs2494750', 'Var', (91, 100))	('AKT1', 'Gene', '207', (86, 90))	('rs2494752', 'Mutation', 'rs2494752', (105, 114))	('AKT1', 'Gene', (86, 90))	('rs2536', 'Mutation', 'rs2536', (78, 84))	('rs2494750', 'Mutation', 'rs2494750', (91, 100))	('rs2536', 'Var', (78, 84))
692740	29259266	However, the highest heterogeneity were observed when all the studies were analyzed for all the cases of mTOR rs2295080 under the dominant model (I 2 = 96.1%) and pTEN rs701848 under the dominant model (I 2 = 62.0%) (Tables S1 and S2).	('rs2295080', 'Mutation', 'rs2295080', (110, 119))	('pTEN', 'Gene', '5728', (163, 167))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (105, 109))	('pTEN', 'Gene', (163, 167))	('rs701848', 'Var', (168, 176))	('rs2295080', 'Var', (110, 119))	('rs701848', 'Mutation', 'rs701848', (168, 176))
692741	29259266	The heterogeneity of mTOR rs2295080 was also present in the subgroup of urinary system cancer and digestive system cancer under the dominant model (Table S2).	('system cancer', 'Disease', (108, 121))	('urinary system cancer', 'Phenotype', 'HP:0010786', (72, 93))	('rs2295080', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('urinary system cancer', 'Disease', (72, 93))	('urinary system cancer', 'Disease', 'MESH:D001749', (72, 93))	('system cancer', 'Disease', 'MESH:D009369', (108, 121))	('rs2295080', 'Mutation', 'rs2295080', (26, 35))	('system cancer', 'Disease', 'MESH:D009369', (80, 93))	('mTOR', 'Gene', (21, 25))	('mTOR', 'Gene', '2475', (21, 25))
692744	29259266	For pTEN rs701848, we found that the heterogeneity of overall and subgroup was significantly decreased after deleting this article of Zhang Y.G.	('pTEN', 'Gene', '5728', (4, 8))	('rs701848', 'Var', (9, 17))	('pTEN', 'Gene', (4, 8))	('rs701848', 'Mutation', 'rs701848', (9, 17))	('decreased', 'NegReg', (93, 102))	('heterogeneity', 'MPA', (37, 50))
692746	29259266	There are no significant publication bias was observed for all the dominant models of the five SNPs (rs2295080: P = 0.200; rs2536: P = 0.176; rs701848: P = 0.218; rs2494750: P = 0.694 and rs2494752: P = 0.696) by the Egger's test.	('rs701848', 'Mutation', 'rs701848', (142, 150))	('rs2494750', 'Mutation', 'rs2494750', (163, 172))	('rs2295080', 'Mutation', 'rs2295080', (101, 110))	('rs2494752', 'Var', (188, 197))	('rs2494752', 'Mutation', 'rs2494752', (188, 197))	('rs2295080:', 'Var', (101, 111))	('rs2536', 'Mutation', 'rs2536', (123, 129))	('rs2536', 'Var', (123, 129))	('rs701848', 'Var', (142, 150))	('rs2494750', 'Var', (163, 172))
692747	29259266	The funnel plots shapes showed obvious symmetry, which were obtained for the association of the SNPs under the dominant model (rs2295080: P = 0.672; rs2536: P = 0.531; rs701848: P = 0.373; rs2494750: P = 1.000 and rs2494752: P = 602) (Fig.	('rs2295080', 'Mutation', 'rs2295080', (127, 136))	('rs2494752', 'Var', (214, 223))	('rs2494752', 'Mutation', 'rs2494752', (214, 223))	('rs2295080:', 'Var', (127, 137))	('rs2536', 'Mutation', 'rs2536', (149, 155))	('rs2536', 'Var', (149, 155))	('rs2494750', 'Var', (189, 198))	('rs701848', 'Var', (168, 176))	('rs2494750', 'Mutation', 'rs2494750', (189, 198))	('rs701848', 'Mutation', 'rs701848', (168, 176))
692748	29259266	The data indicated that no publication bias might have a significant influence on the observed effect of SNPs located at pTEN/AKT/mTOR pathway on the susceptibility of cancer as assessed.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('AKT', 'Gene', (126, 129))	('pTEN', 'Gene', '5728', (121, 125))	('SNPs', 'Var', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('pTEN', 'Gene', (121, 125))	('mTOR', 'Gene', (130, 134))	('cancer', 'Disease', (168, 174))	('AKT', 'Gene', '207', (126, 129))	('mTOR', 'Gene', '2475', (130, 134))
692749	29259266	Overexpression or mutations of key genes of the pTEN/AKT/mTOR pathways were associated with carcinogenesis, invasion, metastasis, and prognosis of a variety of cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('pTEN', 'Gene', '5728', (48, 52))	('carcinogenesis', 'Disease', (92, 106))	('metastasis', 'CPA', (118, 128))	('cancers', 'Disease', (160, 167))	('AKT', 'Gene', '207', (53, 56))	('pTEN', 'Gene', (48, 52))	('associated', 'Reg', (76, 86))	('mTOR', 'Gene', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mTOR', 'Gene', '2475', (57, 61))	('AKT', 'Gene', (53, 56))	('invasion', 'CPA', (108, 116))	('mutations', 'Var', (18, 27))
692751	29259266	The potentially functional SNPs in those key genes, especially in the TFBS or miRNA binding sites may involve in the cancer susceptibility.	('functional', 'Reg', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('TFBS', 'Disease', 'None', (70, 74))	('TFBS', 'Disease', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('involve', 'Reg', (102, 109))	('SNPs', 'Var', (27, 31))	('cancer', 'Disease', (117, 123))
692752	29259266	Therefore, the present meta-analysis analyzed the associations of SNPs in the 5'upstream regulatory or promoter region (mTOR rs2295080, AKT1 rs2494752), and 3'UTR region (mTOR rs2536, pTEN rs701848 and AKT1 rs2494750) in the mTOR signaling pathway (AKT, and PTEN) with cancer risk.	('AKT1', 'Gene', (136, 140))	('AKT', 'Gene', '207', (249, 252))	('pTEN', 'Gene', '5728', (184, 188))	('rs2494750', 'Mutation', 'rs2494750', (207, 216))	('mTOR', 'Gene', (225, 229))	('associations', 'Interaction', (50, 62))	('rs2494752', 'Mutation', 'rs2494752', (141, 150))	('mTOR', 'Gene', '2475', (171, 175))	('PTEN', 'Gene', (258, 262))	('AKT1', 'Gene', '207', (202, 206))	('rs2295080', 'Mutation', 'rs2295080', (125, 134))	('rs2494750', 'Var', (207, 216))	('mTOR', 'Gene', '2475', (225, 229))	('AKT', 'Gene', '207', (136, 139))	('mTOR', 'Gene', (120, 124))	('cancer', 'Disease', (269, 275))	('PTEN', 'Gene', '5728', (258, 262))	('AKT1', 'Gene', (202, 206))	('AKT', 'Gene', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('AKT', 'Gene', (249, 252))	('AKT1', 'Gene', '207', (136, 140))	('mTOR', 'Gene', '2475', (120, 124))	('rs2536', 'Mutation', 'rs2536', (176, 182))	('pTEN', 'Gene', (184, 188))	('rs701848', 'Var', (189, 197))	('AKT', 'Gene', '207', (202, 205))	('mTOR', 'Gene', (171, 175))	('rs2494752', 'Var', (141, 150))	('rs701848', 'Mutation', 'rs701848', (189, 197))	('cancer', 'Disease', 'MESH:D009369', (269, 275))	('AKT', 'Gene', (136, 139))
692753	29259266	Given the crucial function of mTOR in cellular signals from growth factors and energy status, such as in angiogenesis and cell proliferation, growth, differentiation, and apoptosis, our findings of an association between the genetic variations in mTOR gene and cancer risk are biologically plausible and wide, including renal cell cancer, prostate cancer, breast cancer, acute lymphocytic leukemia, gastric cancer, esophageal squamous cell cancer, hepatocellular cancer and colorectal cancer.	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('gastric cancer', 'Disease', 'MESH:D013274', (399, 413))	('colorectal cancer', 'Phenotype', 'HP:0003003', (474, 491))	('variations', 'Var', (233, 243))	('renal cell cancer', 'Disease', (320, 337))	('cancer', 'Disease', (407, 413))	('renal cell cancer', 'Disease', 'MESH:C538614', (320, 337))	('breast cancer', 'Phenotype', 'HP:0003002', (356, 369))	('cancer', 'Disease', 'MESH:D009369', (363, 369))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('mTOR', 'Gene', (247, 251))	('mTOR', 'Gene', '2475', (30, 34))	('renal cell cancer', 'Phenotype', 'HP:0005584', (320, 337))	('cancer', 'Disease', (485, 491))	('breast cancer', 'Disease', 'MESH:D001943', (356, 369))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (415, 446))	('breast cancer', 'Disease', (356, 369))	('cancer', 'Disease', 'MESH:D009369', (463, 469))	('gastric cancer', 'Phenotype', 'HP:0012126', (399, 413))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancer', 'Disease', (261, 267))	('mTOR', 'Gene', '2475', (247, 251))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (426, 446))	('cancer', 'Disease', 'MESH:D009369', (440, 446))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (371, 397))	('colorectal cancer', 'Disease', 'MESH:D015179', (474, 491))	('cancer', 'Disease', (348, 354))	('cancer', 'Disease', 'MESH:D009369', (407, 413))	('acute lymphocytic leukemia', 'Disease', (371, 397))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('colorectal cancer', 'Disease', (474, 491))	('cancer', 'Disease', (363, 369))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('esophageal squamous cell cancer', 'Disease', (415, 446))	('cancer', 'Disease', 'MESH:D009369', (485, 491))	('prostate cancer', 'Disease', 'MESH:D011471', (339, 354))	('prostate cancer', 'Phenotype', 'HP:0012125', (339, 354))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('cancer', 'Disease', (331, 337))	('gastric cancer', 'Disease', (399, 413))	('hepatocellular cancer', 'Disease', (448, 469))	('leukemia', 'Phenotype', 'HP:0001909', (389, 397))	('prostate cancer', 'Disease', (339, 354))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (371, 397))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (448, 469))	('cancer', 'Disease', (463, 469))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cancer', 'Disease', (440, 446))	('mTOR', 'Gene', (30, 34))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (448, 469))
692754	29259266	In this meta-analysis of 13 studies including 8965 cases and 9868 controls for rs2295080, we found a significant decreased of rs2295080 TG, GG genotype, G allele and TG/GG genotype on the overall cancer risk, and the stratification subtype of urinary system cancer and digestive system cancer.	('rs2295080', 'Mutation', 'rs2295080', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('TG', 'Chemical', '-', (166, 168))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('decreased', 'NegReg', (113, 122))	('rs2295080', 'Mutation', 'rs2295080', (126, 135))	('cancer', 'Disease', (286, 292))	('urinary system cancer', 'Disease', 'MESH:D001749', (243, 264))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('system cancer', 'Disease', 'MESH:D009369', (279, 292))	('rs2295080', 'Var', (79, 88))	('system cancer', 'Disease', (279, 292))	('rs2295080', 'Var', (126, 135))	('TG', 'Chemical', '-', (136, 138))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('urinary system cancer', 'Disease', (243, 264))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('system cancer', 'Disease', 'MESH:D009369', (251, 264))	('urinary system cancer', 'Phenotype', 'HP:0010786', (243, 264))
692756	29259266	Up to now, only two meta-analyses focused on mTOR rs2295080 polymorphism and cancer risk.	('rs2295080', 'Var', (50, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('rs2295080', 'Mutation', 'rs2295080', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mTOR', 'Gene', '2475', (45, 49))	('mTOR', 'Gene', (45, 49))
692757	29259266	In one meta-analysis reported that the rs2295080 G allele is associated with decreased risk of cancer, however, only five studies were included.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('rs2295080', 'Mutation', 'rs2295080', (39, 48))	('rs2295080 G', 'Var', (39, 50))	('decreased', 'NegReg', (77, 86))
692759	29259266	Thereafter, another eight studies meta-analysis found that the rs2295080 G allele was associated with a significantly lower risk of genitourinary cancers in the dominant model, and a higher risk of acute leukemia in the recessive model, which consistent with our founding's in overall cancer risk and digestive system cancer.	('cancer', 'Disease', (146, 152))	('genitourinary cancers', 'Disease', (132, 153))	('cancer', 'Disease', (318, 324))	('rs2295080', 'Mutation', 'rs2295080', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('genitourinary cancers', 'Disease', 'MESH:D014565', (132, 153))	('rs2295080 G', 'Var', (63, 74))	('system cancer', 'Disease', 'MESH:D009369', (311, 324))	('acute leukemia', 'Disease', (198, 212))	('system cancer', 'Disease', (311, 324))	('cancer', 'Disease', (285, 291))	('leukemia', 'Phenotype', 'HP:0001909', (204, 212))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('acute leukemia', 'Disease', 'MESH:D015470', (198, 212))	('acute leukemia', 'Phenotype', 'HP:0002488', (198, 212))	('lower', 'NegReg', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
692760	29259266	Likewise, we further founded that carrying rs2295080 GG genotype showed increased 2.25-fold association in the blood system cancer including acute lymphocytic leukemia and acute lymphocytic leukemia which was not explicated in the previous meta-analyses.	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (172, 198))	('rs2295080', 'Mutation', 'rs2295080', (43, 52))	('acute lymphocytic leukemia', 'Disease', (172, 198))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (141, 167))	('blood system cancer', 'Disease', (111, 130))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('acute lymphocytic leukemia', 'Disease', (141, 167))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('blood system cancer', 'Disease', 'MESH:D009369', (111, 130))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (172, 198))	('rs2295080 GG', 'Var', (43, 55))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (141, 167))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))
692761	29259266	Thus, these data indicated that there was an obvious divergence between the SNP rs2295080 and cancer risk in the digestive system and blood system, which might be partially explained by cancer-specificity of rs2295080 polymorphism.	('rs2295080', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('rs2295080', 'Mutation', 'rs2295080', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rs2295080', 'Mutation', 'rs2295080', (208, 217))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
692762	29259266	10 studied of 8411 cases and 8837 controls for rs2536 polymorphism, no significant association was observed between rs2536 and cancer susceptibility after performing stratified analyses by cancer type in this pooled meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('rs2536', 'Mutation', 'rs2536', (116, 122))	('polymorphism', 'Var', (54, 66))	('rs2536', 'Gene', (47, 53))	('rs2536', 'Mutation', 'rs2536', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
692763	29259266	performed a six case-control studies meta-analysis and also reported that there was no association of rs2536 SNP with cancer risk both under dominant and recessive models.	('cancer', 'Disease', (118, 124))	('rs2536 SNP', 'Var', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs2536', 'Mutation', 'rs2536', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
692764	29259266	Furthermore, this present updated meta-analysis also indicated that rs2536 polymorphism was not an important biomarker for predicting cancer risk, although rs2536 was observed associated with the risk of esophageal cancer and prostate cancer, together with interacting with environmental factors such as body mass index.	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('prostate cancer', 'Phenotype', 'HP:0012125', (226, 241))	('rs2536', 'Mutation', 'rs2536', (156, 162))	('rs2536', 'Var', (156, 162))	('cancer', 'Disease', (134, 140))	('esophageal cancer', 'Disease', (204, 221))	('associated', 'Reg', (176, 186))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('prostate cancer', 'Disease', (226, 241))	('esophageal cancer', 'Disease', 'MESH:D004938', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('rs2536', 'Mutation', 'rs2536', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (226, 241))
692765	29259266	The previous foundlings were controversial for the SNP rs2536, partially because of insufficient statistical power and further studies of different cancers are needed for providing a more precise estimation of the associations.	('SNP rs2536', 'Var', (51, 61))	('insufficient statistical', 'Disease', (84, 108))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('rs2536', 'Mutation', 'rs2536', (55, 61))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('insufficient statistical', 'Disease', 'MESH:D000309', (84, 108))
692767	29259266	However, little is known about the association between pTEN rs701848 polymorphism and cancer.	('pTEN', 'Gene', '5728', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pTEN', 'Gene', (55, 59))	('rs701848', 'Var', (60, 68))	('rs701848', 'Mutation', 'rs701848', (60, 68))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
692768	29259266	Specifically, 15 studies of 5882 cases and 6284 controls for rs701848, CC or TC genotype, C allele and CC/TC genotype were associated with significant increased overall cancer risk and in the subgroup of the digestive system cancer and urinary system cancer, but not in oral cavity cancers.	('cancers', 'Disease', (282, 289))	('increased', 'PosReg', (151, 160))	('system cancer', 'Disease', 'MESH:D009369', (218, 231))	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (225, 231))	('rs701848', 'Var', (61, 69))	('system cancer', 'Disease', (218, 231))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('rs701848', 'Mutation', 'rs701848', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('urinary system cancer', 'Disease', 'MESH:D001749', (236, 257))	('cancers', 'Disease', 'MESH:D009369', (282, 289))	('C allele', 'Var', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('system cancer', 'Disease', 'MESH:D009369', (244, 257))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', (282, 288))	('urinary system cancer', 'Disease', (236, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('urinary system cancer', 'Phenotype', 'HP:0010786', (236, 257))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))
692769	29259266	for the first time reported a significant association of pTEN rs701848 with laryngo cancer risk in 2006, more evidences have accumulated regarding the relationship between SNP rs701848 and the risk of various cancers, such as lung cancer, esophageal cancer, breast cancer, prostate cancer, hepatocellular cancer, renal cancer, gastric cancer, and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (347, 364))	('gastric cancer', 'Disease', (327, 341))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('pTEN', 'Gene', '5728', (57, 61))	('prostate cancer', 'Disease', 'MESH:D011471', (273, 288))	('SNP rs701848', 'Var', (172, 184))	('prostate cancer', 'Phenotype', 'HP:0012125', (273, 288))	('gastric cancer', 'Disease', 'MESH:D013274', (327, 341))	('prostate cancer', 'Disease', (273, 288))	('renal cancer', 'Disease', (313, 325))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('renal cancer', 'Phenotype', 'HP:0009726', (313, 325))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))	('colorectal cancer', 'Disease', 'MESH:D015179', (347, 364))	('rs701848', 'Mutation', 'rs701848', (62, 70))	('rs701848', 'Mutation', 'rs701848', (176, 184))	('laryngo cancer', 'Phenotype', 'HP:0012118', (76, 90))	('lung cancer', 'Disease', (226, 237))	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('hepatocellular cancer', 'Disease', (290, 311))	('colorectal cancer', 'Disease', (347, 364))	('breast cancer', 'Disease', (258, 271))	('esophageal cancer', 'Disease', (239, 256))	('gastric cancer', 'Phenotype', 'HP:0012126', (327, 341))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (290, 311))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('renal cancer', 'Disease', 'MESH:D007680', (313, 325))	('laryngo cancer', 'Disease', (76, 90))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (290, 311))	('association', 'Interaction', (42, 53))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('laryngo cancer', 'Disease', 'MESH:D009369', (76, 90))	('cancers', 'Disease', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('pTEN', 'Gene', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
692770	29259266	It should be noted that SNP rs701848 is located within the 3' near gene region, which can be targeted by microRNAs to affecting the miRNA binding site activity, thereby altering pTEN expression by influencing the mRNA stability, and then influence cancer susceptibility.	('cancer', 'Disease', (248, 254))	('affecting', 'Reg', (118, 127))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('pTEN', 'Gene', '5728', (178, 182))	('SNP', 'Var', (24, 27))	('mRNA stability', 'MPA', (213, 227))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('altering', 'Reg', (169, 177))	('pTEN', 'Gene', (178, 182))	('influencing', 'Reg', (197, 208))	('expression', 'MPA', (183, 193))	('miRNA', 'MPA', (132, 137))	('rs701848', 'Mutation', 'rs701848', (28, 36))	('influence', 'Reg', (238, 247))
692772	29259266	In this pooled meta-analysis, 6 studied of 4332 cases and 4498 controls for rs2494750 polymorphism and 3 studied of 3187 cases and 3174 controls for rs2494752 polymorphism were included.	('rs2494752', 'Var', (149, 158))	('rs2494752', 'Mutation', 'rs2494752', (149, 158))	('rs2494750', 'Mutation', 'rs2494750', (76, 85))	('rs2494750 polymorphism', 'Var', (76, 98))	('polymorphism', 'Var', (86, 98))
692773	29259266	A significant association was observed between rs2494752 and overall cancer risk, the heterozygous genotype AG, GG/AG genotype and G allele of rs2494752 SNP was associated with increased cancer risk.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('rs2494752', 'Var', (47, 56))	('rs2494752', 'Mutation', 'rs2494752', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs2494752', 'Var', (143, 152))	('rs2494752', 'Mutation', 'rs2494752', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
692774	29259266	However, we have not found the correlation between rs2494750 polymorphism and the cancer susceptibility both in overall analysis and the stratification analysis.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('rs2494750', 'Mutation', 'rs2494750', (51, 60))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('rs2494750', 'Var', (51, 60))
692777	29259266	These results indicated that the environmental factors were interacted with the genetic variants in the aspect of carcinogenesis.	('carcinogenesis', 'Disease', (114, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('genetic variants', 'Var', (80, 96))
692778	29259266	Most importantly, the SNP rs2494752 is located at the 5' UTR of AKT1 gene, a region predicted to be the transcription factor binding region based on the sequence alignments, which may affect the transcription and translation of AKT1.	('AKT1', 'Gene', (64, 68))	('transcription', 'MPA', (195, 208))	('rs2494752', 'Var', (26, 35))	('affect', 'Reg', (184, 190))	('rs2494752', 'Mutation', 'rs2494752', (26, 35))	('translation', 'MPA', (213, 224))	('AKT1', 'Gene', '207', (228, 232))	('AKT1', 'Gene', '207', (64, 68))	('AKT1', 'Gene', (228, 232))
692779	29259266	It is plausible that the rs2494752 G allele increased the transcription activity of the promoter in the AKT1 gene, then facilitated the cancer development and progression, which may partially explain the cancer risk associated with this SNP.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('AKT1', 'Gene', '207', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('AKT1', 'Gene', (104, 108))	('rs2494752 G', 'Var', (25, 36))	('cancer', 'Disease', (136, 142))	('facilitated', 'PosReg', (120, 131))	('rs2494752', 'Mutation', 'rs2494752', (25, 34))	('increased', 'PosReg', (44, 53))	('transcription activity of the promoter', 'MPA', (58, 96))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
692781	29259266	Second, only 3 studies were included for the SNP rs2494752, therefore considering the limited small size of rs2494752, we cannot rule out the possibility that the results may be by chance, although the number of study participants met the requirement for analysis.	('participants', 'Species', '9606', (218, 230))	('rs2494752', 'Mutation', 'rs2494752', (108, 117))	('rs2494752', 'Mutation', 'rs2494752', (49, 58))	('rs2494752', 'Var', (49, 58))	('rs2494752', 'Var', (108, 117))
692784	29259266	We found that mTOR rs2295080 TG, GG genotype and GG/TG genotype carriers showed an decreased in the overall cancer risk, urinary system cancer and digestive system cancer, nevertheless TT genotype of rs2295080 was associated with increased the risk of blood system cancer.	('mTOR', 'Gene', '2475', (14, 18))	('system cancer', 'Disease', 'MESH:D009369', (129, 142))	('rs2295080', 'Var', (19, 28))	('TG', 'Chemical', '-', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('urinary system cancer', 'Disease', (121, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('TG', 'Chemical', '-', (52, 54))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('rs2295080', 'Var', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('urinary system cancer', 'Phenotype', 'HP:0010786', (121, 142))	('blood system cancer', 'Disease', (252, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('system cancer', 'Disease', 'MESH:D009369', (157, 170))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('system cancer', 'Disease', (157, 170))	('cancer', 'Disease', (164, 170))	('blood system cancer', 'Disease', 'MESH:D009369', (252, 271))	('rs2295080', 'Mutation', 'rs2295080', (19, 28))	('increased', 'PosReg', (230, 239))	('urinary system cancer', 'Disease', 'MESH:D001749', (121, 142))	('mTOR', 'Gene', (14, 18))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('decreased', 'NegReg', (83, 92))	('rs2295080', 'Mutation', 'rs2295080', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('system cancer', 'Disease', 'MESH:D009369', (258, 271))	('cancer', 'Disease', (265, 271))
692785	29259266	Carrying rs701848 CC,TC genotype and CC/TC genotype were associated with an increased overall cancer risk, especially in digestive system cancer and urinary system cancer.	('system cancer', 'Disease', (131, 144))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('system cancer', 'Disease', 'MESH:D009369', (157, 170))	('rs701848', 'Mutation', 'rs701848', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('urinary system cancer', 'Phenotype', 'HP:0010786', (149, 170))	('urinary system cancer', 'Disease', (149, 170))	('system cancer', 'Disease', 'MESH:D009369', (131, 144))	('rs701848 CC', 'Var', (9, 20))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('urinary system cancer', 'Disease', 'MESH:D001749', (149, 170))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
692786	29259266	Moreover, a significant increased association was observed between rs2494752 AG and GG/AG genotype and overall cancer risk.	('rs2494752', 'Var', (67, 76))	('rs2494752', 'Mutation', 'rs2494752', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('increased', 'PosReg', (24, 33))
692788	29259266	In this meta-analysis of Asian population, the carriers of mTOR rs2295080 TG, GG genotype and GG/TG genotypes showed a significantly decreased the risk of overall cancer, the urinary system cancer and digestive system cancer.	('mTOR', 'Gene', '2475', (59, 63))	('rs2295080', 'Mutation', 'rs2295080', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('urinary system cancer', 'Disease', (175, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('decreased', 'NegReg', (133, 142))	('system cancer', 'Disease', 'MESH:D009369', (183, 196))	('urinary system cancer', 'Phenotype', 'HP:0010786', (175, 196))	('rs2295080 TG', 'Var', (64, 76))	('TG', 'Chemical', '-', (74, 76))	('system cancer', 'Disease', 'MESH:D009369', (211, 224))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('system cancer', 'Disease', (211, 224))	('cancer', 'Disease', (218, 224))	('TG', 'Chemical', '-', (97, 99))	('urinary system cancer', 'Disease', 'MESH:D001749', (175, 196))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('mTOR', 'Gene', (59, 63))
692789	29259266	Furthermore, the SNP rs701848 CC, TC genotype and CC/TC genotype of pTEN were observed increased susceptibility of overall cancer and the subgroup of the urinary and digestive cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('CC/TC', 'Var', (50, 55))	('cancer', 'Disease', (123, 129))	('pTEN', 'Gene', '5728', (68, 72))	('rs701848', 'Mutation', 'rs701848', (21, 29))	('susceptibility', 'Reg', (97, 111))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('pTEN', 'Gene', (68, 72))	('SNP rs701848 CC', 'Var', (17, 32))
692790	29259266	Moreover, carrying AKT1 rs2494752 AG and GG/AG genotypes showed an increased overall cancer risk.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('rs2494752 AG', 'Var', (24, 36))	('rs2494752', 'Mutation', 'rs2494752', (24, 33))	('AKT1', 'Gene', '207', (19, 23))	('AKT1', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
692792	24901890	Association between PTEN Gene IVS4 Polymorphism and Risk of Cancer: A Meta-Analysis Phosphatase and tensin homolog (PTEN) is a well established tumor suppressor gene.	('tumor', 'Disease', (144, 149))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('Polymorphism', 'Var', (35, 47))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('PTEN', 'Gene', '5728', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('PTEN', 'Gene', (116, 120))	('Association', 'Interaction', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PTEN', 'Gene', (20, 24))	('PTEN', 'Gene', '5728', (20, 24))
692793	24901890	Recently, increasing studies investigated the association between PTEN IVS4 polymorphism (rs3830675) and risk of various types of cancer.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('PTEN', 'Gene', (66, 70))	('PTEN', 'Gene', '5728', (66, 70))	('cancer', 'Disease', (130, 136))	('rs3830675', 'Mutation', 'rs3830675', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('rs3830675', 'Var', (90, 99))
692794	24901890	The aim of this meta-analysis was to elucidate whether PTEN IVS4 polymorphism was associated with cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('PTEN', 'Gene', '5728', (55, 59))	('associated', 'Reg', (82, 92))	('polymorphism', 'Var', (65, 77))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('PTEN', 'Gene', (55, 59))
692795	24901890	Odds ratios (OR) and their 95% confidence interval (CI) were used to assess the strength of association between PTEN IVS4 polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('polymorphism', 'Var', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PTEN', 'Gene', (112, 116))	('PTEN', 'Gene', '5728', (112, 116))	('cancer', 'Disease', (139, 145))
692797	24901890	The allele analysis revealed that (-) allele was significantly associated with increased risk of cancer (OR = 1.30, 95% CI = 1.12-1.50, P = 0.001) and subgroup of digestive tract cancer (OR = 1.42, 95% CI = 1.16-1.74, P = 0.001) compared with (+) allele.	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tract cancer', 'Disease', 'MESH:D014571', (173, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (163, 185))	('tract cancer', 'Disease', (173, 185))	('-) allele', 'Var', (35, 44))	('cancer', 'Disease', (179, 185))
692799	24901890	PTEN IVS4 (-/-) genotype was significantly associated with increased risk of cancer especially for digestive tract cancer compared with (+/+) genotype.	('-/-) genotype', 'Var', (11, 24))	('cancer', 'Disease', (115, 121))	('genotype', 'Var', (16, 24))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (99, 121))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tract cancer', 'Disease', (109, 121))	('IVS4', 'Gene', (5, 9))	('tract cancer', 'Disease', 'MESH:D014571', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('PTEN', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('PTEN', 'Gene', '5728', (0, 4))
692800	24901890	The (-) allele of PTEN IVS4 (rs3830675) polymorphism was significantly associated with increased risk of cancer especially for digestive tract cancer compared with (+) allele.	('tract cancer', 'Disease', (137, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('PTEN', 'Gene', (18, 22))	('rs3830675', 'Var', (29, 38))	('PTEN', 'Gene', '5728', (18, 22))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (127, 149))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rs3830675', 'Mutation', 'rs3830675', (29, 38))	('tract cancer', 'Disease', 'MESH:D014571', (137, 149))	('associated', 'Reg', (71, 81))
692801	24901890	The recessive effect model and dominant effect model also demonstrated significant association between PTEN IVS4 (rs3830675) polymorphism and increased cancer risk especially for digestive tract cancer.	('PTEN', 'Gene', (103, 107))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('PTEN', 'Gene', '5728', (103, 107))	('tract cancer', 'Disease', 'MESH:D014571', (189, 201))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (179, 201))	('rs3830675', 'Var', (114, 123))	('tract cancer', 'Disease', (189, 201))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('rs3830675', 'Mutation', 'rs3830675', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
692804	24901890	Identification of gene polymorphism that is associated to risk of cancer would largely benefit the early prevention and treatment for cancer.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('benefit', 'Reg', (87, 94))	('polymorphism', 'Var', (23, 35))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (66, 72))
692807	24901890	The 403 amino-acid PTEN protein is a dual phosphatase, acting at both serine-threonine and tyrosine sites.	('protein', 'Protein', (24, 31))	('403 amino-acid', 'Var', (4, 18))	('PTEN', 'Gene', (19, 23))	('serine-threonine', 'Chemical', '-', (70, 86))	('tyrosine', 'Chemical', 'MESH:D014443', (91, 99))	('PTEN', 'Gene', '5728', (19, 23))
692810	24901890	Since its first clone in 1997, somatic PTEN mutations have been widely reported in various types of cancer including prostate cancer, breast cancer, endometrial cancer and so on.	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('endometrial cancer', 'Phenotype', 'HP:0012114', (149, 167))	('PTEN', 'Gene', '5728', (39, 43))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (134, 147))	('endometrial cancer', 'Disease', (149, 167))	('cancer', 'Disease', (126, 132))	('endometrial cancer', 'Disease', 'MESH:D016889', (149, 167))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (100, 106))	('prostate cancer', 'Disease', (117, 132))	('reported', 'Reg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('mutations', 'Var', (44, 53))	('PTEN', 'Gene', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
692812	24901890	PTEN polymorphisms have been reported to be involved in multiple cancers, such as breast cancer, gastric cancer and colon cancer.	('gastric cancer', 'Disease', (97, 111))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('multiple cancers', 'Disease', 'MESH:D009369', (56, 72))	('colon cancer', 'Disease', (116, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('PTEN', 'Gene', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('polymorphisms', 'Var', (5, 18))	('involved', 'Reg', (44, 52))	('breast cancer', 'Disease', (82, 95))	('multiple cancers', 'Disease', (56, 72))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PTEN', 'Gene', '5728', (0, 4))
692813	24901890	PTEN IVS4 polymorphism (rs3830675) with ATCTT insertion at 109 bp downstream of exon 4 in intron 4 was one of the common PTEN polymorphisms.	('PTEN', 'Gene', (121, 125))	('PTEN', 'Gene', '5728', (121, 125))	('rs3830675', 'Mutation', 'rs3830675', (24, 33))	('PTEN', 'Gene', (0, 4))	('rs3830675', 'Var', (24, 33))	('PTEN', 'Gene', '5728', (0, 4))
692814	24901890	Most recently, increasing studies investigated the association between PTEN IVS4 polymorphism (rs3830675) and risk of various types of cancer including breast cancer, colorectal cancer, gastric cancer, esophageal cancer and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('PTEN', 'Gene', '5728', (71, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (167, 184))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (135, 141))	('colorectal cancer', 'Disease', (167, 184))	('prostate cancer', 'Disease', 'MESH:D011471', (224, 239))	('prostate cancer', 'Phenotype', 'HP:0012125', (224, 239))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (202, 219))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rs3830675', 'Var', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (213, 219))	('prostate cancer', 'Disease', (224, 239))	('gastric cancer', 'Disease', (186, 200))	('rs3830675', 'Mutation', 'rs3830675', (95, 104))	('esophageal cancer', 'Disease', (202, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('colorectal cancer', 'Phenotype', 'HP:0003003', (167, 184))	('polymorphism', 'Var', (81, 93))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', (194, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('PTEN', 'Gene', (71, 75))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('breast cancer', 'Disease', (152, 165))
692816	24901890	reported that no significant association was observed between PTEN IVS4 polymorphism and susceptibility to prostate cancer.	('prostate cancer', 'Disease', (107, 122))	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('polymorphism', 'Var', (72, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
692817	24901890	Until now, no meta-analysis has been performed to investigate the association of PTEN IVS4 polymorphism (rs3830675) with susceptibility to cancer.	('rs3830675', 'Mutation', 'rs3830675', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs3830675', 'Var', (105, 114))	('PTEN', 'Gene', (81, 85))	('PTEN', 'Gene', '5728', (81, 85))	('cancer', 'Disease', (139, 145))
692818	24901890	To explore whether PTEN IVS4 polymorphism (rs3830675) was associated with risks of cancer and specific cancer subtypes, we performed a meta-analysis on the association between PTEN IVS4 polymorphism (rs3830675) and cancer risk in the present study.	('rs3830675', 'Var', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (215, 221))	('PTEN', 'Gene', (176, 180))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('PTEN', 'Gene', '5728', (176, 180))	('PTEN', 'Gene', (19, 23))	('rs3830675', 'Var', (43, 52))	('PTEN', 'Gene', '5728', (19, 23))	('rs3830675', 'Mutation', 'rs3830675', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (83, 89))	('rs3830675', 'Mutation', 'rs3830675', (43, 52))
692819	24901890	Electronic databases of Web of Science, PubMed and Chinese National Knowledge Infrastructure (CNKI) were systematically searched using different combinations of the search terms including "phosphatase and tensin homolog/PTEN", "polymorphism/mutation/variant" and "cancer/neoplasm/malignancy".	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('neoplasm', 'Phenotype', 'HP:0002664', (271, 279))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('polymorphism/mutation/variant', 'Var', (228, 257))	('neoplasm/malignancy', 'Disease', (271, 290))	('PTEN', 'Gene', (220, 224))	('PTEN', 'Gene', '5728', (220, 224))	('neoplasm/malignancy', 'Disease', 'MESH:D009369', (271, 290))	('cancer', 'Disease', (264, 270))
692820	24901890	All the included studies must meet the following criteria: case-control study; studies concerning the association between PTEN gene IVS4 polymorphism (rs3830675) and risk of cancer; studies published in English or Chinese; studies with sufficient raw data for estimating odds ratios (OR) and their 95% confidence interval (CI).	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('rs3830675', 'Mutation', 'rs3830675', (151, 160))	('PTEN', 'Gene', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('PTEN', 'Gene', '5728', (122, 126))	('rs3830675', 'Var', (151, 160))
692822	24901890	The following data were extracted from each individual study: first author, publication year, ethnicity of the studied population, cancer type, numbers of each genotype in cases and controls, genotyping methods for PTEN gene IVS4 polymorphism, source of controls.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('PTEN', 'Gene', (215, 219))	('PTEN', 'Gene', '5728', (215, 219))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('polymorphism', 'Var', (230, 242))
692823	24901890	ORs and their 95%CI were used to assess the strength of association between PTEN gene polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('PTEN', 'Gene', (76, 80))	('PTEN', 'Gene', '5728', (76, 80))	('polymorphism', 'Var', (86, 98))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
692831	24901890	As for different ethnicities, carriers of PTEN IVS4 (-/-) genotype were significantly associated with increased risk of cancer in Turkish and Chinese, but not in American population.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PTEN', 'Gene', (42, 46))	('PTEN', 'Gene', '5728', (42, 46))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('IVS4', 'Gene', (47, 51))	('carriers', 'Var', (30, 38))
692834	24901890	However, subgroup analysis based on different cancer type indicated that PTEN IVS4 (+/-) genotype was significantly related with increased risk of digestive tract cancer (OR = 1.33, 95% CI = 1.05-1.68, P = 0.016); while no such association was detected in subgroups of breast cancer or prostate cancer.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Disease', (295, 301))	('IVS4 (+/-', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('breast cancer', 'Phenotype', 'HP:0003002', (269, 282))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('tract cancer', 'Disease', (157, 169))	('breast cancer', 'Disease', 'MESH:D001943', (269, 282))	('breast cancer', 'Disease', (269, 282))	('increased risk of digestive tract', 'Phenotype', 'HP:0011024', (129, 162))	('PTEN', 'Gene', (73, 77))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (147, 169))	('cancer', 'Disease', (46, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (286, 301))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('prostate cancer', 'Phenotype', 'HP:0012125', (286, 301))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (163, 169))	('prostate cancer', 'Disease', (286, 301))	('PTEN', 'Gene', '5728', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tract cancer', 'Disease', 'MESH:D014571', (157, 169))
692836	24901890	The recessive effect model and dominant effect model also demonstrated significant association between PTEN IVS4 (rs3830675) polymorphism and increased cancer risk (-/- vs. (-/+ and +/+): OR = 1.56, 95% CI = 1.19-2.05, P = 0.001, Figure S2; (-/+ and -/-) vs. (+/+): OR = 1.26, 95% CI = 1.06-1.49, P = 0.008, Figure S3) especially for digestive tract cancer (-/- vs. (-/+ and +/+): OR = 1.70, 95% CI = 1.16-2.49, P = 0.007; (-/+ and -/-) vs. (+/+): OR = 1.45, 95% CI = 1.16-1.81, P = 0.001).	('PTEN', 'Gene', (103, 107))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('PTEN', 'Gene', '5728', (103, 107))	('increased', 'PosReg', (142, 151))	('tract cancer', 'Disease', (344, 356))	('tract cancer', 'Disease', 'MESH:D014571', (344, 356))	('cancer', 'Disease', 'MESH:D009369', (350, 356))	('polymorphism', 'Var', (125, 137))	('rs3830675) polymorphism', 'Var', (114, 137))	('cancer', 'Disease', (350, 356))	('rs3830675', 'Mutation', 'rs3830675', (114, 123))	('-/+', 'Var', (424, 427))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (334, 356))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))
692837	24901890	The allele analysis revealed that (-) allele of PTEN IVS4 (rs3830675) polymorphism was significantly associated with increased risk of cancer (OR = 1.30, 95% CI = 1.12-1.50, P = 0.001, Figure 4) and digestive tract cancer (OR = 1.42, 95% CI = 1.16-1.74, P = 0.001) compared with (+) allele.	('tract cancer', 'Disease', 'MESH:D014571', (209, 221))	('PTEN', 'Gene', (48, 52))	('cancer', 'Disease', (135, 141))	('PTEN', 'Gene', '5728', (48, 52))	('tract cancer', 'Disease', (209, 221))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('rs3830675', 'Mutation', 'rs3830675', (59, 68))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (199, 221))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rs3830675', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('-', 'Var', (35, 36))
692842	24901890	Significant publication bias were observed in the allele analysis and recessive effect model analysis of PTEN gene IVS4 (rs3830675) polymorphism.	('rs3830675', 'Var', (121, 130))	('rs3830675', 'Mutation', 'rs3830675', (121, 130))	('PTEN', 'Gene', (105, 109))	('PTEN', 'Gene', '5728', (105, 109))
692844	24901890	Results of previous studies concerning the relationship of PTEN gene IVS4 (rs3830675) polymorphism with cancer risk turn out to be controversial.	('rs3830675', 'Mutation', 'rs3830675', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('PTEN', 'Gene', (59, 63))	('rs3830675', 'Var', (75, 84))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('PTEN', 'Gene', '5728', (59, 63))
692845	24901890	To our best knowledge, this was the first meta-analysis investigating the role of PTEN IVS4 polymorphism in carcinogenesis.	('polymorphism', 'Var', (92, 104))	('PTEN', 'Gene', (82, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('PTEN', 'Gene', '5728', (82, 86))	('carcinogenesis', 'Disease', (108, 122))
692850	24901890	In addition, germline mutations of PTEN predispose carriers to develop Cowden's disease and Bannayan-Zonana syndrome.	('Bannayan-Zonana syndrome', 'Disease', 'MESH:D006223', (92, 116))	("Cowden's disease", 'Disease', 'MESH:D006223', (71, 87))	('PTEN', 'Gene', (35, 39))	('PTEN', 'Gene', '5728', (35, 39))	("Cowden's disease", 'Disease', (71, 87))	('predispose', 'Reg', (40, 50))	('germline mutations', 'Var', (13, 31))	('Bannayan-Zonana syndrome', 'Disease', (92, 116))
692851	24901890	Recently, the association between polymorphisms of PTEN gene and risk of cancer has been investigated in various types of cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (122, 128))	('polymorphisms', 'Var', (34, 47))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PTEN', 'Gene', (51, 55))	('PTEN', 'Gene', '5728', (51, 55))
692852	24901890	One of the most commonly studied polymorphism was PTEN gene IVS4 (rs3830675) polymorphism in intron 4.	('PTEN', 'Gene', '5728', (50, 54))	('rs3830675', 'Var', (66, 75))	('PTEN', 'Gene', (50, 54))	('rs3830675', 'Mutation', 'rs3830675', (66, 75))
692853	24901890	As individual studies demonstrated inconsistent results, we performed the present meta-analysis to elucidate the exact role of PTEN gene IVS4 (rs3830675) polymorphism in carcinogenesis.	('carcinogenesis', 'Disease', (170, 184))	('rs3830675', 'Mutation', 'rs3830675', (143, 152))	('PTEN', 'Gene', (127, 131))	('rs3830675', 'Var', (143, 152))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('PTEN', 'Gene', '5728', (127, 131))
692855	24901890	The recessive effect model and dominant effect model also demonstrated significant association between PTEN IVS4 (rs3830675) polymorphism and increased cancer risk (-/- vs. (-/+ and +/+): OR = 1.56; (-/+ and -/-) vs. (+/+): OR = 1.26) especially for digestive tract cancer.	('PTEN', 'Gene', (103, 107))	('tract cancer', 'Disease', (260, 272))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('increased', 'PosReg', (142, 151))	('PTEN', 'Gene', '5728', (103, 107))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (250, 272))	('cancer', 'Disease', (266, 272))	('rs3830675', 'Var', (114, 123))	('rs3830675', 'Mutation', 'rs3830675', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tract cancer', 'Disease', 'MESH:D014571', (260, 272))
692856	24901890	Similarly, (-) allele of PTEN IVS4 (rs3830675) polymorphism was also significantly associated with increased risk of cancer (OR = 1.30) and digestive tract cancer (OR = 1.42) compared with (+) allele; no such significant association was found in subgroups of breast cancer or prostate cancer.	('rs3830675', 'Mutation', 'rs3830675', (36, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('tract cancer', 'Disease', (150, 162))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (140, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('cancer', 'Disease', (117, 123))	('PTEN', 'Gene', (25, 29))	('cancer', 'Disease', (285, 291))	('breast cancer', 'Disease', (259, 272))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('prostate cancer', 'Disease', 'MESH:D011471', (276, 291))	('prostate cancer', 'Phenotype', 'HP:0012125', (276, 291))	('rs3830675) polymorphism', 'Var', (36, 59))	('PTEN', 'Gene', '5728', (25, 29))	('prostate cancer', 'Disease', (276, 291))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('polymorphism', 'Var', (47, 59))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('tract cancer', 'Disease', 'MESH:D014571', (150, 162))
692857	24901890	Different cancer has its distinct mechanisms of initiation and progression, the obvious different outcome of diverse cancer subtypes in this meta-analysis indicated that PTEN IVS4 (rs3830675) polymorphism might confer altered risks to various types of cancer.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PTEN', 'Gene', (170, 174))	('cancer', 'Disease', (252, 258))	('PTEN', 'Gene', '5728', (170, 174))	('initiation', 'Disease', (48, 58))	('rs3830675', 'Mutation', 'rs3830675', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('initiation', 'Disease', 'MESH:D007319', (48, 58))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('altered risks', 'Reg', (218, 231))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('rs3830675', 'Var', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (10, 16))
692858	24901890	The consistent association between PTEN IVS4 (rs3830675) polymorphism and risk of digestive tract cancer in different genetic models suggested that PTEN might have specific role in the carcinogenesis of digestive tract cancer, which requires further studies to explore.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('PTEN', 'Gene', (148, 152))	('tract cancer', 'Disease', (213, 225))	('tract cancer', 'Disease', 'MESH:D014571', (213, 225))	('PTEN', 'Gene', '5728', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (82, 104))	('rs3830675', 'Var', (46, 55))	('carcinogenesis', 'Disease', 'MESH:D063646', (185, 199))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (203, 225))	('PTEN', 'Gene', (35, 39))	('PTEN', 'Gene', '5728', (35, 39))	('carcinogenesis', 'Disease', (185, 199))	('rs3830675', 'Mutation', 'rs3830675', (46, 55))	('tract cancer', 'Disease', (92, 104))	('tract cancer', 'Disease', 'MESH:D014571', (92, 104))
692859	24901890	As for different ethnicities, PTEN IVS4 (-/-) genotype and (-) allele were associated with increased risk of cancer in both Turkish and Chinese but not in American.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('-/-', 'Var', (41, 44))	('PTEN', 'Gene', (30, 34))	('PTEN', 'Gene', '5728', (30, 34))
692866	24901890	The PTEN IVS4 (rs3830675) polymorphism may lead to a splicing error or may be by linkage disequilibrium with another locus to affect the expression and function of the PTEN.	('PTEN', 'Gene', '5728', (4, 8))	('PTEN', 'Gene', (168, 172))	('expression', 'MPA', (137, 147))	('rs3830675', 'Var', (15, 24))	('PTEN', 'Gene', '5728', (168, 172))	('error', 'Disease', (62, 67))	('lead to', 'Reg', (43, 50))	('affect', 'Reg', (126, 132))	('function', 'MPA', (152, 160))	('rs3830675', 'Mutation', 'rs3830675', (15, 24))	('PTEN', 'Gene', (4, 8))	('error', 'Disease', 'MESH:D012030', (62, 67))
692867	24901890	The alternation of PTEN expression would inevitably change the role of PTEN in maintaining genome stability, and loss of function of this tumor suppressor might therefore leads to carcinogenesis.	('leads to', 'Reg', (171, 179))	('tumor', 'Disease', (138, 143))	('PTEN', 'Gene', (19, 23))	('change', 'Reg', (52, 58))	('genome stability', 'CPA', (91, 107))	('PTEN', 'Gene', '5728', (19, 23))	('PTEN', 'Gene', (71, 75))	('alternation', 'Var', (4, 15))	('PTEN', 'Gene', '5728', (71, 75))	('carcinogenesis', 'Disease', 'MESH:D063646', (180, 194))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('loss of function', 'NegReg', (113, 129))	('carcinogenesis', 'Disease', (180, 194))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
692868	24901890	Although the above-mentioned possible mechanism might partially explain the observed association between PTEN IVS4 (rs3830675) polymorphism and cancer susceptibilities, rare functional study has been carried out and the exact mechanism remain largely elusive.	('rs3830675', 'Mutation', 'rs3830675', (116, 125))	('PTEN', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PTEN', 'Gene', '5728', (105, 109))	('rs3830675', 'Var', (116, 125))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
692869	24901890	Future functional studies are still needed to clarify the exact mechanism of the role of PTEN IVS4 (rs3830675) polymorphism in carcinogenesis.	('rs3830675', 'Var', (100, 109))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('carcinogenesis', 'Disease', (127, 141))	('rs3830675', 'Mutation', 'rs3830675', (100, 109))	('PTEN', 'Gene', (89, 93))	('PTEN', 'Gene', '5728', (89, 93))
692955	24453866	Generally, obliteration of outflow from the portal vein may exacerbate portal hypertension and aggravate ascites and esophageal varices.	('aggravate', 'PosReg', (95, 104))	('ascites', 'Disease', 'MESH:D001201', (105, 112))	('ascites', 'Disease', (105, 112))	('ascites', 'Phenotype', 'HP:0001541', (105, 112))	('esophageal varices', 'Disease', (117, 135))	('hypertension', 'Disease', (78, 90))	('portal hypertension', 'Phenotype', 'HP:0001409', (71, 90))	('hypertension', 'Phenotype', 'HP:0000822', (78, 90))	('obliteration', 'Var', (11, 23))	('esophageal varices', 'Phenotype', 'HP:0002040', (117, 135))	('exacerbate', 'PosReg', (60, 70))	('hypertension', 'Disease', 'MESH:D006973', (78, 90))
692960	24453866	Unlike TIPS, BRTO increases hepatopetal blood flow by obliteration of the hepatofugal shunt vessels, and it may subsequently improve the blood flow in the liver parenchyma.	('obliteration', 'NegReg', (54, 66))	('BRTO', 'Chemical', '-', (13, 17))	('increases hepatopetal blood', 'Disease', 'MESH:D006973', (18, 45))	('liver parenchyma', 'Disease', (155, 171))	('liver parenchyma', 'Disease', 'MESH:D010195', (155, 171))	('BRTO', 'Var', (13, 17))	('shunt vessels', 'Phenotype', 'HP:0001693', (86, 99))	('increases hepatopetal blood', 'Disease', (18, 45))	('improve', 'PosReg', (125, 132))	('blood flow', 'MPA', (137, 147))
692962	24453866	We expected that PTO and the combination of PTO and BRTO would also obliterate hepatofugal shunts and produce similar changes in hemodynamics.	('changes', 'Reg', (118, 125))	('hemodynamics', 'MPA', (129, 141))	('PTO', 'Var', (44, 47))	('obliterate hepatofugal', 'Disease', (68, 90))	('PTO', 'Chemical', '-', (44, 47))	('BRTO', 'Chemical', '-', (52, 56))	('obliterate hepatofugal', 'Disease', 'None', (68, 90))	('PTO', 'Disease', (17, 20))	('combination', 'Var', (29, 40))	('BRTO', 'Gene', (52, 56))	('PTO', 'Chemical', '-', (17, 20))
692967	19584833	DNA promoter hypermethylation of p16 and APC predicts neoplastic progression in Barrett's esophagus Prediction of progression to cancer in patients with Barrett's esophagus is difficult using current techniques.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('p16', 'Gene', (33, 36))	('patients', 'Species', '9606', (139, 147))	('APC', 'Disease', 'MESH:D011125', (41, 44))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (153, 172))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('neoplastic progression', 'CPA', (54, 76))	('APC', 'Disease', (41, 44))	('p16', 'Gene', '1029', (33, 36))	('hypermethylation', 'Var', (13, 29))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (80, 99))	('predicts', 'Reg', (45, 53))
692969	19584833	We first performed a cross-sectional study to evaluate the prevalence of gene hypermethylation in biopsies from patients with normal esophagus (n=17), Barrett's esophagus (n=102), and adenocarcinoma (n=42).	('normal esophagus', 'Disease', (126, 142))	('gene hypermethylation', 'Var', (73, 94))	('patients', 'Species', '9606', (112, 120))	("Barrett's esophagus", 'Disease', (151, 170))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (151, 170))	('adenocarcinoma', 'Disease', (184, 198))	('adenocarcinoma', 'Disease', 'MESH:D000230', (184, 198))
692972	19584833	Hypermethylation was prevalent in Barrett's esophagus without dysplasia or low-grade dysplasia (p16=31% and APC=50%; p<0.01) and high-grade dysplasia or adenocarcinoma (p16=54% and APC=68%; p<0.001) compared to normal esophagus (not detected).	('Hypermethylation', 'Var', (0, 16))	("Barrett's esophagus", 'Disease', (34, 53))	('p16', 'Gene', (169, 172))	('p16', 'Gene', '1029', (169, 172))	('APC', 'Disease', 'MESH:D011125', (181, 184))	('p16', 'Gene', (96, 99))	('APC', 'Disease', 'MESH:D011125', (108, 111))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (34, 53))	('APC', 'Disease', (181, 184))	('APC', 'Disease', (108, 111))	('p16', 'Gene', '1029', (96, 99))	('dysplasia', 'Disease', (140, 149))	('prevalent', 'Reg', (21, 30))	('dysplasia', 'Disease', (62, 71))	('dysplasia or adenocarcinoma', 'Disease', 'MESH:D000230', (140, 167))	('dysplasia', 'Disease', 'MESH:D004476', (62, 71))	('dysplasia or adenocarcinoma', 'Disease', (140, 167))	('dysplasia', 'Disease', (85, 94))	('dysplasia', 'Disease', 'MESH:D004476', (85, 94))	('dysplasia', 'Disease', 'MESH:D004476', (140, 149))
692974	19584833	Hypermethylation of both p16 and APC was a strong predictor of subsequent progression to cancer during a mean follow-up time of 4.1 years (adjusted OR [95% CI]=14.97 [1.73,inf], p=0.01).	('APC', 'Disease', 'MESH:D011125', (33, 36))	('APC', 'Disease', (33, 36))	('Hypermethylation', 'Var', (0, 16))	('p16', 'Gene', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('p16', 'Gene', '1029', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
692976	19584833	Hypermethylation of both p16 and APC strongly predicts progression to high-grade dysplasia or cancer in patients with Barrett's esophagus.	('dysplasia or cancer', 'Disease', (81, 100))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (118, 137))	('APC', 'Disease', 'MESH:D011125', (33, 36))	('APC', 'Disease', (33, 36))	('predicts', 'Reg', (46, 54))	('Hypermethylation', 'Var', (0, 16))	('p16', 'Gene', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('p16', 'Gene', '1029', (25, 28))	('patients', 'Species', '9606', (104, 112))	('dysplasia or cancer', 'Disease', 'MESH:D009369', (81, 100))
692977	19584833	Absence of p16 and APC hypermethylation is associated with a benign course.	('APC', 'Disease', 'MESH:D011125', (19, 22))	('APC', 'Disease', (19, 22))	('p16', 'Gene', (11, 14))	('Absence', 'Var', (0, 7))	('p16', 'Gene', '1029', (11, 14))
692985	19584833	Methylation of the promoter region of a gene results in suppression of gene transcription and has been associated with the development of esophageal cancer.	('esophageal cancer', 'Disease', (138, 155))	('Methylation', 'Var', (0, 11))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('suppression', 'NegReg', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('associated with', 'Reg', (103, 118))	('gene transcription', 'MPA', (71, 89))
692986	19584833	However, to date, few studies have evaluated the role of gene hypermethylation in predicting the progression from BE to esophageal adenocarcinoma in a longitudinal cohort of patients.	('hypermethylation', 'Var', (62, 78))	('patients', 'Species', '9606', (174, 182))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (120, 145))	('esophageal adenocarcinoma', 'Disease', (120, 145))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (120, 145))
693033	19584833	In contrast, those with BE and no dysplasia or low-grade dysplasia had a significantly higher prevalence of promoter hypermethylation for both p16 and APC in their mucosal biopsies (31% and 50%, respectively; p<0.01 for both compared to normal esophagus).	('dysplasia', 'Disease', 'MESH:D004476', (34, 43))	('promoter', 'MPA', (108, 116))	('APC', 'Disease', 'MESH:D011125', (151, 154))	('p16', 'Gene', (143, 146))	('dysplasia', 'Disease', (57, 66))	('APC', 'Disease', (151, 154))	('dysplasia', 'Disease', (34, 43))	('dysplasia', 'Disease', 'MESH:D004476', (57, 66))	('low-grade', 'Var', (47, 56))	('p16', 'Gene', '1029', (143, 146))
693035	19584833	We then analyzed the strength of the association of dysplasia grade with gene hypermethylation in patients with BE by calculating odds ratios (Table 2).	('patients', 'Species', '9606', (98, 106))	('dysplasia', 'Disease', (52, 61))	('gene hypermethylation', 'Var', (73, 94))	('dysplasia', 'Disease', 'MESH:D004476', (52, 61))
693043	19584833	Patients with BE who subsequently progressed from baseline pathology to HGD or adenocarcinoma had a significantly higher prevalence of hypermethylation in their initial esophagus biopsies compared to those who did not progress with respect to both p16 (100% vs. 33%; p=0.008) and APC (86% vs. 40%; p=0.02) (Table 3).	('p16', 'Gene', '1029', (248, 251))	('APC', 'Disease', 'MESH:D011125', (280, 283))	('APC', 'Disease', (280, 283))	('HGD or adenocarcinoma', 'Disease', 'MESH:D000230', (72, 93))	('p16', 'Gene', (248, 251))	('Patients', 'Species', '9606', (0, 8))	('hypermethylation', 'Var', (135, 151))	('HGD or adenocarcinoma', 'Disease', (72, 93))
693044	19584833	Hypermethylation of p16 was a highly significant predictor of subsequent progression from baseline pathology to HGD or adenocarcinoma (OR [95% CI] = 10.02 [1.18,inf], p=0.03) (Table 3, Figure 1).	('Hypermethylation', 'Var', (0, 16))	('p16', 'Gene', (20, 23))	('HGD or adenocarcinoma', 'Disease', (112, 133))	('HGD or adenocarcinoma', 'Disease', 'MESH:D000230', (112, 133))	('p16', 'Gene', '1029', (20, 23))
693045	19584833	The association of APC hypermethylation and subsequent progression to adenocarcinoma was also significant (OR [95% CI] =9.00 [1.01,80.52], p=0.049, Table 3).	('APC', 'Disease', 'MESH:D011125', (19, 22))	('APC', 'Disease', (19, 22))	('association', 'Interaction', (4, 15))	('adenocarcinoma', 'Disease', (70, 84))	('hypermethylation', 'Var', (23, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (70, 84))
693046	19584833	However, the combination of both hypermethylated p16 and APC in baseline esophagus biopsies was the best predictor of subsequent progression to adenocarcinoma (OR [95% CI] =14.97 [1.73,inf], p=0.012).	('APC', 'Disease', 'MESH:D011125', (57, 60))	('APC', 'Disease', (57, 60))	('adenocarcinoma', 'Disease', (144, 158))	('hypermethylated', 'Var', (33, 48))	('p16', 'Gene', (49, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('p16', 'Gene', '1029', (49, 52))
693048	19584833	When we incorporated the length of follow-up time in prediction of outcome, we found statistically significant differences in the probability of progression-free survival when comparing patients who had hypermethylation of p16 or APC in their initial esophagus biopsies versus those who did not (Figures 2A, 2B, 2C).	('p16', 'Gene', '1029', (223, 226))	('hypermethylation', 'Var', (203, 219))	('APC', 'Disease', 'MESH:D011125', (230, 233))	('APC', 'Disease', (230, 233))	('p16', 'Gene', (223, 226))	('patients', 'Species', '9606', (186, 194))
693049	19584833	Patients who had hypermethylation of p16 or APC individually or both genes all had a significantly lower probability of progression-free survival (p<0.05 for all comparisons of presence versus absence of gene hypermethylation by the log-rank test).	('progression-free survival', 'CPA', (120, 145))	('APC', 'Disease', 'MESH:D011125', (44, 47))	('APC', 'Disease', (44, 47))	('lower', 'NegReg', (99, 104))	('Patients', 'Species', '9606', (0, 8))	('p16', 'Gene', '1029', (37, 40))	('hypermethylation', 'Var', (17, 33))	('p16', 'Gene', (37, 40))
693051	19584833	These results suggest that p16 and APC hypermethylation are early events in the neoplastic progression of BE, since even BE patients with no dysplasia or low-grade dysplasia had hypermethylation of p16 and APC ranging from 30-50%.	('dysplasia', 'Disease', (141, 150))	('dysplasia', 'Disease', 'MESH:D004476', (164, 173))	('p16', 'Gene', (198, 201))	('APC', 'Disease', 'MESH:D011125', (206, 209))	('dysplasia', 'Disease', 'MESH:D004476', (141, 150))	('APC', 'Disease', 'MESH:D011125', (35, 38))	('p16', 'Gene', (27, 30))	('APC', 'Disease', (206, 209))	('p16', 'Gene', '1029', (198, 201))	('dysplasia', 'Disease', (164, 173))	('APC', 'Disease', (35, 38))	('hypermethylation', 'Var', (178, 194))	('patients', 'Species', '9606', (124, 132))	('p16', 'Gene', '1029', (27, 30))
693060	19584833	Our results are consistent with a previous study which found p16, RUNX3, and HPP1 hypermethylation to be predictors of progression to the combined endpoint of high-grade dysplasia or adenocarcinoma in BE patients, with the odds ratios for risk of progression being 1.74, 1.80, and 1.77, respectively.	('patients', 'Species', '9606', (204, 212))	('RUNX3', 'Gene', (66, 71))	('dysplasia or adenocarcinoma', 'Disease', (170, 197))	('HPP1', 'Gene', '780897', (77, 81))	('p16', 'Gene', (61, 64))	('RUNX3', 'Gene', '864', (66, 71))	('HPP1', 'Gene', (77, 81))	('p16', 'Gene', '1029', (61, 64))	('hypermethylation', 'Var', (82, 98))	('dysplasia or adenocarcinoma', 'Disease', 'MESH:D000230', (170, 197))
693061	19584833	However, our study differs from this previous study in that our study results show a much stronger association between promoter hypermethylation of both p16 and APC and subsequent progression to HGD or cancer with much higher odds ratios than previously reported.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('APC', 'Disease', 'MESH:D011125', (161, 164))	('p16', 'Gene', '1029', (153, 156))	('promoter hypermethylation', 'Var', (119, 144))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('APC', 'Disease', (161, 164))	('cancer', 'Disease', (202, 208))	('HGD', 'Disease', (195, 198))	('p16', 'Gene', (153, 156))
693062	19584833	The use in our study of the highly sensitive nested methylation-specific PCR assay for detection of gene promoter hypermethylation may explain the high odds ratios and strong associations between promoter hypermethylation of p16 and APC and subsequent progression to cancer which we observed.	('associations', 'Interaction', (175, 187))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('APC', 'Disease', 'MESH:D011125', (233, 236))	('p16', 'Gene', '1029', (225, 228))	('APC', 'Disease', (233, 236))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('promoter hypermethylation', 'Var', (196, 221))	('p16', 'Gene', (225, 228))
693064	19584833	APC, TIMP3, and TERT promoters were hypermethylated in 100%, 91%, and 92% of cases in BE mucosa from patients who had adenocarcinoma.	('TERT', 'Gene', (16, 20))	('adenocarcinoma', 'Disease', 'MESH:D000230', (118, 132))	('patients', 'Species', '9606', (101, 109))	('TIMP3', 'Gene', '7078', (5, 10))	('hypermethylated', 'Var', (36, 51))	('TIMP3', 'Gene', (5, 10))	('TERT', 'Gene', '7015', (16, 20))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('APC', 'Disease', (0, 3))	('adenocarcinoma', 'Disease', (118, 132))
693068	19584833	Our use of the highly sensitive nested methylation-specific PCR assay for detection of gene promoter hypermethylation may explain why we were able to detect p16 hypermethylation as a predictor of progression.	('hypermethylation', 'Var', (161, 177))	('p16', 'Gene', '1029', (157, 160))	('p16', 'Gene', (157, 160))
693070	19584833	In conclusion, we report that promoter hypermethylation of p16 and APC is a frequent and early event in the stepwise progression from normal esophagus through BE to esophageal adenocarcinoma.	('APC', 'Disease', (67, 70))	('p16', 'Gene', '1029', (59, 62))	('esophageal adenocarcinoma', 'Disease', (165, 190))	('p16', 'Gene', (59, 62))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (165, 190))	('promoter hypermethylation', 'Var', (30, 55))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))	('APC', 'Disease', 'MESH:D011125', (67, 70))
693071	19584833	Regardless of baseline dysplasia grade, hypermethylation of both p16 and APC is a strong predictor of subsequent progression from baseline pathology to HGD or esophageal adenocarcinoma in patients with BE even before pathologic changes are evident.	('esophageal adenocarcinoma', 'Disease', (159, 184))	('HGD', 'Disease', (152, 155))	('p16', 'Gene', '1029', (65, 68))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (159, 184))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (159, 184))	('dysplasia', 'Disease', (23, 32))	('patients', 'Species', '9606', (188, 196))	('hypermethylation', 'Var', (40, 56))	('p16', 'Gene', (65, 68))	('APC', 'Disease', 'MESH:D011125', (73, 76))	('dysplasia', 'Disease', 'MESH:D004476', (23, 32))	('APC', 'Disease', (73, 76))
693072	19584833	Meanwhile, the absence of p16 and APC hypermethylation may be equally important in predicting a benign course.	('p16', 'Gene', (26, 29))	('absence', 'Var', (15, 22))	('APC', 'Disease', 'MESH:D011125', (34, 37))	('p16', 'Gene', '1029', (26, 29))	('APC', 'Disease', (34, 37))
693074	19584833	If these results are confirmed, follow-up of BE patients could then be adjusted accordingly, with the highest risk patients who have both p16 and APC hypermethylated undergoing early intervention in the form of more frequent endoscopic surveillance, chemoprevention, ablative therapy, or surgery.	('patients', 'Species', '9606', (115, 123))	('p16', 'Gene', '1029', (138, 141))	('hypermethylated', 'Var', (150, 165))	('p16', 'Gene', (138, 141))	('APC', 'Disease', 'MESH:D011125', (146, 149))	('patients', 'Species', '9606', (48, 56))	('APC', 'Disease', (146, 149))
693078	19584833	A multitude of epigenetic and genetic factors have been studied as potential biomarkers including p53 protein overexpression and allelic loss, aneuploidy or tetraploidy, and gains of proto-oncogenes.	('allelic loss', 'Var', (129, 141))	('aneuploidy or tetraploidy', 'Disease', (143, 168))	('p53', 'Gene', '7157', (98, 101))	('p53', 'Gene', (98, 101))	('aneuploidy or tetraploidy', 'Disease', 'MESH:D057891', (143, 168))	('overexpression', 'PosReg', (110, 124))	('protein', 'Protein', (102, 109))
693188	33318475	KDMs deregulation was associated with tumor aggressiveness and therapy failure.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor aggressiveness', 'Disease', (38, 58))	('therapy failure', 'CPA', (63, 78))	('aggressiveness', 'Phenotype', 'HP:0000718', (44, 58))	('KDMs', 'Gene', (0, 4))	('deregulation', 'Var', (5, 17))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (38, 58))	('associated', 'Reg', (22, 32))
693191	33318475	Effect of JmjC-KDM inhibitor IOX1, as well as KDM3A knockdown, in in vitro functional cell behavior and RT response was assessed in ESCC under hypoxic conditions.	('knockdown', 'Var', (52, 61))	('KDM3A', 'Gene', '55818', (46, 51))	('KDM3A', 'Gene', (46, 51))
693223	33318475	Conversely, H3K9me2 and H3K27me3, repressive histone markers targeted by KDM3A and KDM6B, respectively, were found downregulated under hypoxic conditions, except for Kyse-30 (Fig.	('KDM3A', 'Gene', '55818', (73, 78))	('KDM6B', 'Gene', '23135', (83, 88))	('KDM6B', 'Gene', (83, 88))	('KDM3A', 'Gene', (73, 78))	('H3K27me3', 'Var', (24, 32))	('downregulated', 'NegReg', (115, 128))	('Kyse', 'Chemical', '-', (166, 170))	('H3K9me2', 'Var', (12, 19))
693228	33318475	Concomitantly, D0, Dq and SF2 values were decreased in hypoxia (50 microM CoCl2 or 0.5-1% of O2 levels) combined with IOX1, comparatively with hypoxic conditions alone (Supplementary Table S2).	('SF2', 'Gene', (26, 29))	('50', 'Var', (64, 66))	('decreased', 'NegReg', (42, 51))	('O2', 'Chemical', 'MESH:D010100', (93, 95))	('hypoxia', 'Disease', 'MESH:D000860', (55, 62))	('SF2', 'Gene', '6426', (26, 29))	('hypoxia', 'Disease', (55, 62))	('CoCl2', 'Chemical', 'MESH:C018021', (74, 79))
693229	33318475	Interestingly, IOX1 sensitized hypoxic ESCC cells to RT [SER > 1].	('SER', 'Chemical', '-', (57, 60))	('sensitized', 'Reg', (20, 30))	('IOX1', 'Var', (15, 19))
693231	33318475	Remarkably, for all ESCC cells, IOX1 treatment combined with 2 Gy irradiation significantly increased the % of global DNA fragmentation and cell apoptosis for most of the time points, compared to 50 microM CoCl2 and 0.5-1% O2 conditions (Fig.	('IOX1', 'Var', (32, 36))	('cell apoptosis', 'CPA', (140, 154))	('CoCl2', 'Chemical', 'MESH:C018021', (206, 211))	('increased', 'PosReg', (92, 101))	('O2', 'Chemical', 'MESH:D010100', (223, 225))	('global DNA fragmentation', 'CPA', (111, 135))
693241	33318475	Together, these results indicate that hypoxic-induced JmjC-KDMs modulation promotes ESCC cells' radiosensitization, supporting KDM3A's as a key RT responsiveness mediator.	('KDM3A', 'Gene', '55818', (127, 132))	('ESCC', 'Disease', (84, 88))	('promotes', 'PosReg', (75, 83))	('KDM3A', 'Gene', (127, 132))	('JmjC-KDMs', 'Gene', (54, 63))	('radiosensitization', 'CPA', (96, 114))	('modulation', 'Var', (64, 74))
693273	33318475	Additionally, IOX1 was also shown to have a higher selectivity for Pan-JmjC-KDMs activity inhibition than PHDs.	('PHDs', 'Disease', (106, 110))	('Pan-JmjC-KDMs', 'Disease', (67, 80))	('Pan-JmjC-KDMs', 'Disease', 'MESH:C537931', (67, 80))	('PHDs', 'Disease', 'None', (106, 110))	('IOX1', 'Var', (14, 18))	('activity', 'MPA', (81, 89))
693274	33318475	Indeed, a similar HIF-1alpha expression trend in IOX1 Kyse-410 microtumors may be partially explained by intrinsic expression levels in the control condition and the apparent hypoxic foci in 3D tumors.	('Kyse', 'Chemical', '-', (54, 58))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('HIF-1alpha', 'Gene', (18, 28))	('hypoxic foci', 'Disease', (175, 187))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('hypoxic foci', 'Disease', 'MESH:C565785', (175, 187))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('HIF-1alpha', 'Gene', '3091', (18, 28))	('expression', 'MPA', (29, 39))	('IOX1', 'Var', (49, 53))
693278	33318475	Indeed, KDM3A inhibition decreased estrogen receptor positive breast cancer cells' proliferation whereas it was implicated in stemness and chemoresistance in ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('decreased estrogen receptor', 'Phenotype', 'HP:0008214', (25, 52))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('decreased', 'NegReg', (25, 34))	('KDM3A', 'Gene', '55818', (8, 13))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('estrogen receptor', 'Gene', (35, 52))	('breast cancer', 'Disease', (62, 75))	('stemness and chemoresistance in ovarian cancer', 'Disease', 'MESH:D020526', (126, 172))	('estrogen receptor', 'Gene', '2099', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('KDM3A', 'Gene', (8, 13))	('inhibition', 'Var', (14, 24))
693279	33318475	Furthermore, KDM3A targeting increased response to anti-angiogenic therapies, disclosing a role in tumor angiogenesis Interestingly, in vitro studies in lung and breast cancer cells demonstrated that KDM6A inhibition decreased cell survival and improved RT response, through H3K27me3 enhancement.	('decreased', 'NegReg', (217, 226))	('cell survival', 'CPA', (227, 240))	('increased', 'PosReg', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('KDM6A', 'Gene', (200, 205))	('H3K27me3', 'Protein', (275, 283))	('RT response', 'CPA', (254, 265))	('tumor', 'Disease', (99, 104))	('enhancement', 'PosReg', (284, 295))	('improved', 'PosReg', (245, 253))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('KDM3A', 'Gene', (13, 18))	('response', 'MPA', (39, 47))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('inhibition', 'Var', (206, 216))	('breast cancer', 'Disease', (162, 175))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('KDM6A', 'Gene', '7403', (200, 205))	('KDM3A', 'Gene', '55818', (13, 18))
693284	33318475	In the same vein and as a consequence of DNA damage repair deficiency, gamma-H2AX was independently maintained overtime after cell replication in hypoxic-induced IOX1 cells, suggesting the persistence unrepaired DNA DSBs.	('DSBs', 'Chemical', 'MESH:C007563', (216, 220))	('deficiency', 'Var', (59, 69))	('gamma-H2AX', 'MPA', (71, 81))	('gamma-H2AX', 'Chemical', '-', (71, 81))
693286	33318475	Defects in DNA repair dynamics prevents DDR resolution, due to endless gamma-H2AX activation and impaired recruitment of the major HR and NHEJ repair effectors.	('impaired', 'NegReg', (97, 105))	('Defects', 'Var', (0, 7))	('activation', 'PosReg', (82, 92))	('prevents', 'NegReg', (31, 39))	('gamma-H2AX', 'Protein', (71, 81))	('recruitment', 'MPA', (106, 117))	('gamma-H2AX', 'Chemical', '-', (71, 81))	('DDR resolution', 'Disease', (40, 54))
693289	33318475	Interestingly, deregulation of JmjC-KDMs, including LSD1, KDM3C, KDM4C, KDM7B, and UTX/KDM6A, has been implicated in esophageal carcinogenesis, although published data concerning KDM3A and KDM6B is notoriously lacking.	('JmjC-KDMs', 'Gene', (31, 40))	('deregulation', 'Var', (15, 27))	('KDM6A', 'Gene', (87, 92))	('implicated', 'Reg', (103, 113))	('LSD1', 'Gene', (52, 56))	('UTX', 'Gene', (83, 86))	('KDM3A', 'Gene', (179, 184))	('LSD1', 'Gene', '23028', (52, 56))	('KDM4C', 'Gene', (65, 70))	('KDM6B', 'Gene', (189, 194))	('UTX', 'Gene', '7403', (83, 86))	('KDM4C', 'Gene', '23081', (65, 70))	('KDM6B', 'Gene', '23135', (189, 194))	('KDM3C', 'Gene', (58, 63))	('carcinogenesis', 'Disease', (128, 142))	('KDM3A', 'Gene', '55818', (179, 184))	('KDM6A', 'Gene', '7403', (87, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (128, 142))	('KDM7B', 'Var', (72, 77))
693312	33318475	Except for gamma-H2AX antibody, which was incubated for 1 h at R/T, all remainder antibodies (H3K9me2, H3K27me3, KDM3A, and KDM6B) were incubated overnight at R/T.	('KDM3A', 'Gene', (113, 118))	('gamma-H2AX', 'Chemical', '-', (11, 21))	('KDM6B', 'Gene', '23135', (124, 129))	('KDM3A', 'Gene', '55818', (113, 118))	('H3K9me2', 'Var', (94, 101))	('KDM6B', 'Gene', (124, 129))	('H3K27me3', 'Var', (103, 111))
693314	33318475	Briefly, endogenous peroxidases activity was blocked with 3% H2O2, followed by non-specific linked blockage in horse serum (GIBCO, Invitrogen, USA).	('3% H2O2', 'Var', (58, 65))	('activity', 'MPA', (32, 40))	('H2O2', 'Chemical', 'MESH:D006861', (61, 65))	('H2O2', 'Var', (61, 65))	('blocked', 'NegReg', (45, 52))	('endogenous peroxidases', 'Enzyme', (9, 31))
693398	33301056	For patients with metastatic diseases whose tumors harbor particular genetic profiles, such as the over-expression of the human epidermal growth factor receptor-2 (HER-2) or neurotrophic tropomyosin receptor kinase (NTRK)- gene fusions, microsatellite instability, mismatched repair genes or programmed cell death ligand 1 (PD-L1) over-expression, targeted therapy or immunotherapy may be beneficial.	('human', 'Species', '9606', (122, 127))	('over-expression', 'Var', (331, 346))	('microsatellite instability', 'Var', (237, 263))	('epidermal growth factor receptor-2', 'Gene', (128, 162))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('fusions', 'Var', (228, 235))	('epidermal growth factor receptor-2', 'Gene', '2064', (128, 162))	('NTRK)- gene', 'Gene', (216, 227))	('programmed cell death ligand 1', 'Gene', '29126', (292, 322))	('over-expression', 'PosReg', (99, 114))	('HER-2', 'Gene', '2064', (164, 169))	('patients', 'Species', '9606', (4, 12))	('HER-2', 'Gene', (164, 169))	('PD-L1', 'Gene', (324, 329))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('PD-L1', 'Gene', '29126', (324, 329))	('programmed cell death ligand 1', 'Gene', (292, 322))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('metastatic diseases', 'Disease', (18, 37))	('tumors', 'Disease', (44, 50))	('mismatched repair', 'Var', (265, 282))
693401	33301056	Nanomedicine offers the means to prolong patient viability by using nanoparticle delivery of conjugates such as nab-palitaxel, cisplatin, and capecitabine that are currently being tested in the neoadjuvant setting in a phase 2 clinical trial.	('patient', 'Species', '9606', (41, 48))	('capecitabine', 'Chemical', 'MESH:D000069287', (142, 154))	('nab-palitaxel', 'Var', (112, 125))	('nab-palitaxel', 'Chemical', '-', (112, 125))	('prolong', 'PosReg', (33, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))
693432	33301056	In vivo tumor targeting has utilized antibodies such as transferrin, folic acid, and single-chain antibodies.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('transferrin', 'Gene', '7018', (56, 67))	('transferrin', 'Gene', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('folic acid', 'Chemical', 'MESH:D005492', (69, 79))	('tumor', 'Disease', (8, 13))	('single-chain', 'Var', (85, 97))
693496	33301056	Specifically, nano-encapsulation of Curcumin in liposomes and polymeric NPs has shown increased bioavailability that results in reduced inflammation and apoptotic effects for cancer cells.	('increased', 'PosReg', (86, 95))	('reduced', 'NegReg', (128, 135))	('nano-encapsulation', 'Var', (14, 32))	('cancer', 'Disease', (175, 181))	('polymer', 'Chemical', 'MESH:D011108', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('inflammation', 'Disease', 'MESH:D007249', (136, 148))	('Curcumin', 'Chemical', 'MESH:D003474', (36, 44))	('bioavailability', 'MPA', (96, 111))	('inflammation', 'Disease', (136, 148))	('apoptotic effects', 'CPA', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
693502	33301056	In addition, multiple genetic markers enable differentiation between healthy and cancerous tissues and can, therefore, be used for selective nanodelivery of small interfering RNA (siRNA) or micro-RNA, which either silences or disrupts cancerous genes.	('cancerous', 'Disease', 'MESH:D009369', (81, 90))	('small interfering', 'Var', (157, 174))	('disrupts', 'NegReg', (226, 234))	('cancerous', 'Disease', (235, 244))	('cancerous', 'Disease', (81, 90))	('micro-RNA', 'Var', (190, 199))	('silences', 'NegReg', (214, 222))	('cancerous', 'Disease', 'MESH:D009369', (235, 244))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
693599	32357565	Compared to other plant oils, hemp seed oil has the highest proportion of polyunsaturated fatty acids, which have the potential to reduce the risk of cardiovascular diseases, cancer, rheumatoid arthritis, hypertension, inflammatory and autoimmune diseases.	('hypertension', 'Phenotype', 'HP:0000822', (205, 217))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (150, 173))	('inflammatory', 'Disease', (219, 231))	('cancer', 'Disease', (175, 181))	('polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (74, 101))	('polyunsaturated', 'Var', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (183, 203))	('hemp', 'Species', '3483', (30, 34))	('oil', 'Chemical', 'MESH:D009821', (40, 43))	('seed oil', 'Chemical', '-', (35, 43))	('autoimmune diseases', 'Disease', 'MESH:D001327', (236, 255))	('arthritis', 'Phenotype', 'HP:0001369', (194, 203))	('oil', 'Chemical', 'MESH:D009821', (24, 27))	('reduce', 'NegReg', (131, 137))	('autoimmune diseases', 'Disease', (236, 255))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (150, 173))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (236, 255))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('rheumatoid arthritis', 'Disease', (183, 203))	('hypertension', 'Disease', 'MESH:D006973', (205, 217))	('hypertension', 'Disease', (205, 217))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (183, 203))	('cardiovascular diseases', 'Disease', (150, 173))
693653	32357565	Moreover, at low doses, THC induces mild euphoria, relaxation and reduces anxiety, whereas, at high doses, leads to dysphoria, sensory distortion, hallucinations, and increases anxiety.	('dysphoria', 'Disease', (116, 125))	('reduces', 'NegReg', (66, 73))	('anxiety', 'Disease', 'MESH:D001007', (74, 81))	('relaxation', 'MPA', (51, 61))	('hallucinations', 'Disease', (147, 161))	('hallucinations', 'Phenotype', 'HP:0000738', (147, 161))	('anxiety', 'Disease', 'MESH:D001007', (177, 184))	('sensory distortion', 'Disease', (127, 145))	('hallucinations', 'Disease', 'MESH:D006212', (147, 161))	('anxiety', 'Disease', (177, 184))	('THC', 'Var', (24, 27))	('anxiety', 'Disease', (74, 81))	('increases', 'PosReg', (167, 176))	('THC', 'Chemical', 'MESH:D013759', (24, 27))	('euphoria', 'Phenotype', 'HP:0031844', (41, 49))	('leads to', 'Reg', (107, 115))	('anxiety', 'Phenotype', 'HP:0000739', (177, 184))	('mild euphoria', 'MPA', (36, 49))	('anxiety', 'Phenotype', 'HP:0000739', (74, 81))	('dysphoria', 'Disease', 'MESH:D000068116', (116, 125))
693655	32357565	Specifically, THC induces tachycardia, antispasticity and anti-convulsant effects, bronchodilatation, bronchial irritation, and ocular hypotonicity.	('bronchial irritation', 'Disease', (102, 122))	('anti-convulsant effects', 'CPA', (58, 81))	('ocular hypotonicity', 'Disease', 'MESH:D005128', (128, 147))	('tachycardia', 'Disease', 'MESH:D013610', (26, 37))	('ocular hypotonicity', 'Phenotype', 'HP:0032547', (128, 147))	('ocular hypotonicity', 'Disease', (128, 147))	('spasticity', 'Disease', (43, 53))	('THC', 'Var', (14, 17))	('bronchodilatation', 'Disease', (83, 100))	('spasticity', 'Disease', 'MESH:D009128', (43, 53))	('spasticity', 'Phenotype', 'HP:0001257', (43, 53))	('tachycardia', 'Phenotype', 'HP:0001649', (26, 37))	('THC', 'Chemical', 'MESH:D013759', (14, 17))	('bronchial irritation', 'Disease', 'MESH:D001982', (102, 122))	('tachycardia', 'Disease', (26, 37))
693665	32357565	Moreover, CBD improves sleep disorders and induces mood stabilization.	('induces', 'Reg', (43, 50))	('CBD', 'Chemical', 'MESH:D002185', (10, 13))	('improves sleep', 'Phenotype', 'HP:0002360', (14, 28))	('sleep disorders', 'Disease', (23, 38))	('CBD', 'Var', (10, 13))	('improves', 'PosReg', (14, 22))	('sleep disorders', 'Disease', 'MESH:D012893', (23, 38))	('mood stabilization', 'MPA', (51, 69))
693669	32357565	CBD is an inverse agonist of the receptors GPR3, GPR6, and GPR12.	('CBD', 'Chemical', 'MESH:D002185', (0, 3))	('GPR12', 'Var', (59, 64))	('GPR6', 'Var', (49, 53))	('GPR3', 'Var', (43, 47))
693683	32357565	Moreover, CBG, as CBD, inhibits AEA uptake, MAGL and lysophosphatidylinositol (LPI)-induced GPR55 signaling (see Table 2 for references).	('CBD', 'Chemical', 'MESH:D002185', (18, 21))	('lysophosphatidylinositol', 'Chemical', 'MESH:C025449', (53, 77))	('CBG', 'Var', (10, 13))	('CBG', 'Chemical', 'MESH:C037036', (10, 13))	('GPR55', 'Gene', '9290', (92, 97))	('LPI', 'Chemical', 'MESH:C025449', (79, 82))	('AEA uptake', 'MPA', (32, 42))	('GPR55', 'Gene', (92, 97))	('inhibits', 'NegReg', (23, 31))	('AEA', 'Chemical', '-', (32, 35))
693685	32357565	Similar to CBG, CBC increases AEA (inhibiting its uptake) and MAGL levels (see Table 2 for references).	('MAGL levels', 'MPA', (62, 73))	('CBC', 'Var', (16, 19))	('CBC', 'Chemical', 'MESH:C010695', (16, 19))	('CBG', 'Chemical', 'MESH:C037036', (11, 14))	('AEA', 'MPA', (30, 33))	('AEA', 'Chemical', '-', (30, 33))	('increases', 'PosReg', (20, 29))
693706	32357565	Because of these characteristics, modulation of the ECS might be beneficial for IBS patients.	('patients', 'Species', '9606', (84, 92))	('ECS', 'Chemical', '-', (52, 55))	('IBS', 'Disease', 'MESH:D043183', (80, 83))	('IBS', 'Disease', (80, 83))	('modulation', 'Var', (34, 44))
693708	32357565	Early reports indicated that CBD did not affect intestinal motility (gastric emptying, small intestinal transit and defecation) when tested in normal, healthy, animals, compared with other natural cannabinoids (such as Delta8-THC or Delta9-THC) that elicited inhibitory effects.	('gastric emptying', 'Phenotype', 'HP:0002578', (69, 85))	('CBD', 'Var', (29, 32))	('indica', 'Species', '596366', (14, 20))	('Delta8', 'Mutation', 'c.del8', (219, 225))	('cannabinoids', 'Chemical', 'MESH:D002186', (197, 209))	('THC', 'Chemical', 'MESH:D013759', (226, 229))	('CBD', 'Chemical', 'MESH:D002185', (29, 32))	('Delta9-THC', 'Chemical', '-', (233, 243))	('THC', 'Chemical', 'MESH:D013759', (240, 243))	('small intestinal transit', 'Phenotype', 'HP:0030897', (87, 111))	('intestinal motility', 'CPA', (48, 67))
693718	32357565	Abdominal pain associated with the sensitization of visceral sensory afferents and/or the derangement of sensory processing along the brain-gut axis is a key component of IBS.	('IBS', 'Disease', 'MESH:D043183', (171, 174))	('IBS', 'Disease', (171, 174))	('Abdominal pain', 'Disease', 'MESH:D015746', (0, 14))	('Abdominal pain', 'Disease', (0, 14))	('Abdominal pain', 'Phenotype', 'HP:0002027', (0, 14))	('pain', 'Phenotype', 'HP:0012531', (10, 14))	('derangement', 'Var', (90, 101))
693754	32357565	For instance, CBD reduced the production of reactive oxygen species (ROS) and lipid peroxidation in Caco-2 cells cultures, and counteracted LPS/interferon gamma (IFNgamma)-induced inflammatory-like responses in cultured human-derived colonic biopsies of UC patients.	('IFNgamma', 'Gene', (162, 170))	('Caco-2', 'CellLine', 'CVCL:0025', (100, 106))	('IFNgamma', 'Gene', '3458', (162, 170))	('interferon gamma', 'Gene', (144, 160))	('human', 'Species', '9606', (220, 225))	('CBD', 'Chemical', 'MESH:D002185', (14, 17))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('reduced', 'NegReg', (18, 25))	('lipid peroxidation', 'MPA', (78, 96))	('production of reactive oxygen species', 'MPA', (30, 67))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (44, 67))	('patients', 'Species', '9606', (257, 265))	('CBD', 'Var', (14, 17))	('interferon gamma', 'Gene', '3458', (144, 160))	('lipid', 'Chemical', 'MESH:D008055', (78, 83))
693757	32357565	Furthermore, in in vitro conditions, CBG also reduced nitric oxide (NO) production in macrophages and reduced the formation of ROS in intestinal epithelial cells.	('ROS', 'Chemical', 'MESH:D017382', (127, 130))	('CBG', 'Chemical', 'MESH:C037036', (37, 40))	('nitric oxide', 'Chemical', 'MESH:D009569', (54, 66))	('reduced', 'NegReg', (46, 53))	('formation of ROS', 'MPA', (114, 130))	('CBG', 'Var', (37, 40))	('reduced', 'NegReg', (102, 109))
693796	32357565	Early studies in SW40 colon cancer cells showed that CBD induces phosphatases and phosphatase-dependent apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('CBD', 'Var', (53, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('phosphatases', 'Enzyme', (65, 77))	('CBD', 'Chemical', 'MESH:D002185', (53, 56))	('phosphatase-dependent apoptosis', 'CPA', (82, 113))	('SW40', 'CellLine', 'CVCL:R777', (17, 21))	('colon cancer', 'Disease', (22, 34))	('induces', 'PosReg', (57, 64))
693829	32357565	Although interactions between the multiple phytocannabinoids present in Cannabis sativa have to be taken into consideration, the relevant role that THC seems to play suggests that its substitution (or at least reduction in concentration) by other phytocannabinoids might be beneficial in avoiding CHS.	('THC', 'Chemical', 'MESH:D013759', (148, 151))	('CHS', 'Disease', (297, 300))	('substitution', 'Var', (184, 196))	('CHS', 'Disease', 'MESH:D002609', (297, 300))	('phytocannabinoids', 'Chemical', '-', (43, 60))	('phytocannabinoids', 'Chemical', '-', (247, 264))	('Cannabis sativa', 'Species', '3483', (72, 87))
693884	32038997	We chose the top 25% most variant mRNAs (4,938 mRNAs) and the top 25% most variant lncRNAs (3,712 genes) for constructing networks, while we did not do pretreatment for miRNA expression profile due to the small number of miRNAs (1,881 miRNAs).	('miR', 'Gene', '220972', (235, 238))	('miR', 'Gene', (235, 238))	('variant', 'Var', (26, 33))	('miR', 'Gene', '220972', (169, 172))	('miR', 'Gene', (169, 172))	('miR', 'Gene', '220972', (221, 224))	('miR', 'Gene', (221, 224))
693905	32038997	Then, the common candidate miRNAs with  MM  > 0.4 in hub modules and prediction by TargetScan was defined as real hub miRNAs.	('hub', 'Gene', (53, 56))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('hub', 'Gene', '1993', (114, 117))	('MM  > 0.4', 'Var', (40, 49))	('miR', 'Gene', '220972', (118, 121))	('miR', 'Gene', (118, 121))	('hub', 'Gene', '1993', (53, 56))	('hub', 'Gene', (114, 117))
693942	32038997	Based on the MM of lncRNA co-expression network and the prediction by LncBase (Table 3), 21 lncRNAs (RP11-275I4.2, RP11-327F22.6, LINC01355, CTD-3018O17.3, RP11-504P24.8, RP11-2H3.6, AC016735.1, PSMG3-AS1, C1orf213, RP5-1054A22.4, AC141928.1, XIST, RP11-332H14.2, CTD-2023N9.1, RP5-1125A11.7, RP3-470B24.5, AC226118.1, RP5-1184F4.5, RP11-440L14.1, ETV5-AS1, and RP5-1029K10.2) were considered as hub lncRNAs.	('AS1', 'Gene', '5729', (201, 204))	('RP11', 'Gene', (101, 105))	('RP11', 'Gene', (156, 160))	('CTD', 'Gene', (264, 267))	('ETV5', 'Gene', (348, 352))	('RP11', 'Gene', (171, 175))	('RP5-1184F4.5', 'Var', (319, 331))	('RP5-1125A11.7', 'Var', (278, 291))	('C1orf213', 'Gene', '148898', (206, 214))	('hub', 'Gene', (396, 399))	('XIST', 'Gene', (243, 247))	('RP11', 'Gene', (115, 119))	('C1orf213', 'Gene', (206, 214))	('RP11', 'Gene', (249, 253))	('CTD', 'Gene', (141, 144))	('AS1', 'Gene', (353, 356))	('hub', 'Gene', '1993', (396, 399))	('AS1', 'Gene', (201, 204))	('CTD', 'Gene', '1283', (264, 267))	('ETV5', 'Gene', '2119', (348, 352))	('XIST', 'Gene', '7503', (243, 247))	('RP11', 'Gene', '26121', (333, 337))	('PSMG3', 'Gene', (195, 200))	('RP3', 'Gene', (293, 296))	('RP11', 'Gene', '26121', (156, 160))	('RP11', 'Gene', '26121', (101, 105))	('RP11', 'Gene', '26121', (171, 175))	('LINC01355', 'Gene', (130, 139))	('PSMG3', 'Gene', '84262', (195, 200))	('CTD', 'Gene', '1283', (141, 144))	('LINC01355', 'Gene', '100996511', (130, 139))	('RP11', 'Gene', '26121', (115, 119))	('AS1', 'Gene', '5729', (353, 356))	('RP3', 'Gene', '6990', (293, 296))	('RP11', 'Gene', '26121', (249, 253))	('RP11', 'Gene', (333, 337))
693944	32038997	Eight genes (SPI1, RNASE6, C1QB, C1QC, CSF1R, C1QA, TBC1D2, and ATP6V0E1), seven miRNAs (hsa-miR-519e-5p, hsa-miR-519d-5p, hsa-miR-515-5p, hsa-miR-6756-5p, hsa-miR-6769b-5p, hsa-miR-4707-3p, and hsa-miR-650), and 21 lncRNAs (RP11-275I4.2, RP11-327F22.6, LINC01355, CTD-3018O17.3, RP11-504P24.8, RP11-2H3.6, AC016735.1, PSMG3-AS1, C1orf213, RP5-1054A22.4, AC141928.1, XIST, RP11-332H14.2, CTD-2023N9.1, RP5-1125A11.7, RP3-470B24.5, AC226118.1, RP5-1184F4.5, RP11-440L14.1, ETV5-AS1, and RP5-1029K10.2) were involved in this interaction network.	('SPI1', 'Gene', '6688', (13, 17))	('PSMG3', 'Gene', (319, 324))	('C1QB', 'Gene', (27, 31))	('LINC01355', 'Gene', (254, 263))	('miR', 'Gene', '220972', (178, 181))	('LINC01355', 'Gene', '100996511', (254, 263))	('TBC1D2', 'Gene', (52, 58))	('miR', 'Gene', (93, 96))	('RP11', 'Gene', '26121', (239, 243))	('RP11', 'Gene', '26121', (373, 377))	('RP3', 'Gene', '6990', (417, 420))	('AS1', 'Gene', '5729', (477, 480))	('ATP6V0E1', 'Gene', (64, 72))	('RP11', 'Gene', '26121', (295, 299))	('miR', 'Gene', '220972', (81, 84))	('RP11', 'Gene', (457, 461))	('C1QB', 'Gene', '713', (27, 31))	('CTD', 'Gene', '1283', (265, 268))	('PSMG3', 'Gene', '84262', (319, 324))	('CTD', 'Gene', (388, 391))	('miR', 'Gene', (178, 181))	('AS1', 'Gene', '5729', (325, 328))	('RP11', 'Gene', (280, 284))	('RP11', 'Gene', (225, 229))	('C1QC', 'Gene', '714', (33, 37))	('ETV5', 'Gene', (472, 476))	('C1QC', 'Gene', (33, 37))	('hsa-miR-650', 'Gene', '723778', (195, 206))	('miR', 'Gene', '220972', (160, 163))	('miR', 'Gene', (81, 84))	('TBC1D2', 'Gene', '55357', (52, 58))	('RNASE6', 'Gene', '6039', (19, 25))	('C1orf213', 'Gene', '148898', (330, 338))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', '220972', (127, 130))	('XIST', 'Gene', (367, 371))	('RP11', 'Gene', (239, 243))	('C1orf213', 'Gene', (330, 338))	('SPI1', 'Gene', (13, 17))	('hsa-miR-650', 'Gene', (195, 206))	('miR', 'Gene', '220972', (199, 202))	('RP11', 'Gene', (295, 299))	('RP11', 'Gene', (373, 377))	('CTD', 'Gene', '1283', (388, 391))	('CSF1R', 'Gene', '1436', (39, 44))	('miR', 'Gene', '220972', (110, 113))	('AS1', 'Gene', (477, 480))	('RP5-1125A11.7', 'Var', (402, 415))	('miR', 'Gene', (160, 163))	('ATP6V0E1', 'Gene', '8992', (64, 72))	('XIST', 'Gene', '7503', (367, 371))	('CSF1R', 'Gene', (39, 44))	('RP11', 'Gene', '26121', (457, 461))	('AS1', 'Gene', (325, 328))	('miR', 'Gene', (143, 146))	('CTD', 'Gene', (265, 268))	('miR', 'Gene', (127, 130))	('RP3', 'Gene', (417, 420))	('RNASE6', 'Gene', (19, 25))	('ETV5', 'Gene', '2119', (472, 476))	('RP11', 'Gene', '26121', (280, 284))	('miR', 'Gene', (199, 202))	('RP11', 'Gene', '26121', (225, 229))	('miR', 'Gene', '220972', (93, 96))	('C1QA', 'Gene', '712', (46, 50))	('miR', 'Gene', (110, 113))	('C1QA', 'Gene', (46, 50))
693988	32038997	A recent study demonstrated the abnormal expression of XIST could contribute to esophageal cancer via miR-494/CDK6 axis.	('expression', 'MPA', (41, 51))	('miR-494', 'Gene', (102, 109))	('esophageal cancer', 'Disease', (80, 97))	('CDK6', 'Gene', (110, 114))	('abnormal', 'Var', (32, 40))	('XIST', 'Gene', '7503', (55, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('CDK6', 'Gene', '1021', (110, 114))	('contribute', 'Reg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('XIST', 'Gene', (55, 59))	('miR-494', 'Gene', '574452', (102, 109))
693998	32038997	A lot of cancer-promoting errors may occur during cell division, such as DNA mutations and epigenetic mistakes, chromosome aberrations occurring, and the wrong distribution of cell-fate determinants between the daughter cells.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('chromosome aberrations', 'CPA', (112, 134))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('DNA', 'Disease', (73, 76))	('epigenetic mistakes', 'Var', (91, 110))
694002	32038997	For example, the high expression of EGFR causes the abnormal differentiation of ESCC cells and the decrease in adhesion between cells, and the tumor is prone to lymphatic and distant metastasis.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (143, 148))	('prone', 'Reg', (152, 157))	('high expression', 'Var', (17, 32))	('decrease', 'NegReg', (99, 107))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('EGFR', 'Gene', '1956', (36, 40))	('adhesion between cells', 'CPA', (111, 133))	('EGFR', 'Gene', (36, 40))	('ESCC', 'Disease', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
694046	31715446	Also, short-segment distal esophageal resection may be associated with severe gastroesophageal reflux.	('short-segment', 'Var', (6, 19))	('associated', 'Reg', (55, 65))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (78, 101))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (78, 101))	('gastroesophageal reflux', 'Disease', (78, 101))
694056	30404157	These genes were subsequently knocked down in QH and OE33 cells and the functional effect of siRNA-induced knockdown on reactive oxygen species production, mitochondrial mass, mitochondrial membrane potential and cellular metabolism was investigated.	('knockdown', 'Var', (107, 116))	('reactive oxygen species production', 'MPA', (120, 154))	('mitochondrial membrane potential', 'MPA', (176, 208))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (120, 143))	('mitochondrial mass', 'MPA', (156, 174))
694058	30404157	We also demonstrate that knockdown of BAK1, FIS1 and SFN in vitro resulted in significant alterations in mitochondrial membrane potential; however, no differences in reactive oxygen species or mitochondrial mass were observed.	('alterations', 'Reg', (90, 101))	('FIS1', 'Gene', (44, 48))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (166, 189))	('BAK1', 'Gene', (38, 42))	('mitochondrial membrane potential', 'MPA', (105, 137))	('knockdown', 'Var', (25, 34))	('SFN', 'Gene', (53, 56))
694059	30404157	Furthermore, knockdown of these genes in esophageal adenocarcinoma cells significantly altered cellular metabolism.	('altered', 'Reg', (87, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('esophageal adenocarcinoma', 'Disease', (41, 66))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (41, 66))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (41, 66))	('cellular metabolism', 'MPA', (95, 114))	('knockdown', 'Var', (13, 22))
694060	30404157	In conclusion, we found that differential expression of BAK1, FIS1, and SFN were altered across the Barrett's disease sequence and manipulation of these genes elicited significant effects on mitochondrial membrane potential.	("Barrett's disease", 'Phenotype', 'HP:0100580', (100, 117))	("Barrett's disease", 'Disease', (100, 117))	('expression', 'MPA', (42, 52))	('mitochondrial membrane potential', 'MPA', (191, 223))	("Barrett's disease", 'Disease', 'MESH:D001471', (100, 117))	('effects', 'Reg', (180, 187))	('FIS1', 'Gene', (62, 66))	('SFN', 'Gene', (72, 75))	('altered', 'Reg', (81, 88))	('BAK1', 'Gene', (56, 60))	('manipulation', 'Var', (131, 143))
694085	30404157	Figure 3 shows the functional effect of BAK1 siRNA knockdown on ROS production, mitochondrial mass and MMP in the Barrett's and OAC cell lines.	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('ROS production', 'MPA', (64, 78))	('MMP', 'MPA', (103, 106))	('mitochondrial mass', 'MPA', (80, 98))	('BAK1 siRNA', 'Gene', (40, 50))	('OAC', 'Chemical', '-', (128, 131))	('knockdown', 'Var', (51, 60))
694087	30404157	In contrast, knockdown of BAK1 had no effect on ROS levels (Figure 3D), mitochondrial mass (Figure 3F) or MMP (Figure 3H) in OE33 cells.	('BAK1', 'Gene', (26, 30))	('mitochondrial mass', 'MPA', (72, 90))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))	('knockdown', 'Var', (13, 22))	('ROS levels', 'MPA', (48, 58))	('MMP', 'MPA', (106, 109))
694088	30404157	Figure 4 shows the functional effect of FIS1 siRNA knockdown on ROS production, mitochondrial mass and MMP in the Barrett's and OAC cell lines.	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('ROS production', 'MPA', (64, 78))	('FIS1 siRNA', 'Gene', (40, 50))	('MMP', 'MPA', (103, 106))	('mitochondrial mass', 'MPA', (80, 98))	('OAC', 'Chemical', '-', (128, 131))	('knockdown', 'Var', (51, 60))
694089	30404157	Analogous to the findings with BAK1 in Figure 3, knockdown of FIS1 significantly decreased MMP (Figure 4G) (p = 0.019) but did not alter ROS levels (Figure 4C) or mitochondrial mass (Figure 4E) in QH cells.	('decreased', 'NegReg', (81, 90))	('knockdown', 'Var', (49, 58))	('ROS', 'Chemical', 'MESH:D017382', (137, 140))	('mitochondrial mass', 'MPA', (163, 181))	('FIS1', 'Gene', (62, 66))	('ROS levels', 'MPA', (137, 147))
694090	30404157	Similarly, knockdown of FIS1 did not significantly affect ROS levels (Figure 4D), mitochondrial mass (Figure 4F) or MMP (Figure 4H) in OE33 cells.	('ROS levels', 'MPA', (58, 68))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('affect', 'Reg', (51, 57))	('FIS1', 'Gene', (24, 28))	('MMP', 'MPA', (116, 119))	('knockdown', 'Var', (11, 20))	('mitochondrial mass', 'MPA', (82, 100))
694091	30404157	Figure 5 shows the functional effect of SFN siRNA knockdown on ROS production, mitochondrial mass and MMP in the Barrett's and OAC cell lines.	('mitochondrial mass', 'MPA', (79, 97))	('SFN siRNA', 'Gene', (40, 49))	('knockdown', 'Var', (50, 59))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('OAC', 'Chemical', '-', (127, 130))	('ROS production', 'MPA', (63, 77))	('MMP', 'MPA', (102, 105))
694092	30404157	As with BAK1 and FIS1, knockdown of SFN significantly decreased MMP (Figure 5G) (p = 0.049) but did not alter ROS levels (Figure 5C) or mitochondrial mass (Figure 5E) in QH cells.	('knockdown', 'Var', (23, 32))	('ROS levels', 'MPA', (110, 120))	('ROS', 'Chemical', 'MESH:D017382', (110, 113))	('decreased', 'NegReg', (54, 63))	('SFN', 'Gene', (36, 39))	('mitochondrial mass', 'MPA', (136, 154))
694093	30404157	However, knockdown of SFN significantly decreased MMP (Figure 5H) (p = 0.022) without affecting ROS levels (Figure 5D) or mitochondrial mass (Figure 5F) in OE33 cells.	('knockdown', 'Var', (9, 18))	('ROS levels', 'MPA', (96, 106))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('SFN', 'Gene', (22, 25))	('mitochondrial mass', 'MPA', (122, 140))	('decreased', 'NegReg', (40, 49))
694095	30404157	Supplementary Figure S2 demonstrates the effect of FIS1 and SFN knockdown on oligomycin-induced changes in ECAR (glycolysis) and baseline ECAR in QH and OE33 cells, respectively.	('oligomycin', 'Chemical', 'MESH:D009840', (77, 87))	('FIS1', 'Gene', (51, 55))	('baseline ECAR', 'MPA', (129, 142))	('knockdown', 'Var', (64, 73))	('SFN', 'Gene', (60, 63))
694096	30404157	Upon complex V inhibition with oligomycin, unscrambled control treated OE33 cells increased their glycolytic levels to compensate for the lack of oxidative phosphorylation activity; however, FIS1 knockdown significantly decreased the ability of OE33 cells to increase glycolysis (Supplementary Figure S2B) (P = 0.006).	('decreased', 'NegReg', (220, 229))	('increase', 'PosReg', (259, 267))	('oligomycin', 'Chemical', 'MESH:D009840', (31, 41))	('glycolytic levels', 'MPA', (98, 115))	('increased', 'PosReg', (82, 91))	('knockdown', 'Var', (196, 205))	('glycolysis', 'MPA', (268, 278))	('FIS1', 'Gene', (191, 195))
694097	30404157	No significant effect of BAK1, FIS1 or SFN knockdown was observed on baseline OCR, ATP synthesis or proton leak in both cell lines (p > 0.05).	('ATP synthesis', 'MPA', (83, 96))	('proton leak', 'MPA', (100, 111))	('OCR', 'Chemical', '-', (78, 81))	('knockdown', 'Var', (43, 52))	('BAK1', 'Gene', (25, 29))	('ATP', 'Chemical', 'MESH:D000255', (83, 86))	('FIS1', 'Gene', (31, 35))	('baseline OCR', 'MPA', (69, 81))	('SFN', 'Gene', (39, 42))
694101	30404157	These alterations in mitochondrial function may increase the risk of neoplastic progression from Barrett's metaplasia to OAC.	('alterations', 'Var', (6, 17))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (97, 117))	("Barrett's metaplasia", 'Disease', (97, 117))	('OAC', 'Disease', (121, 124))	('mitochondrial', 'MPA', (21, 34))	('OAC', 'Chemical', '-', (121, 124))	('neoplastic progression', 'CPA', (69, 91))
694104	30404157	Induction of apoptosis through BAK1 activation has previously been shown to have a beneficial effect; specifically, overexpression of BAK1 decreased in vitro growth, decreased cell cycle G0/G1 arrest and induced apoptosis in gastric cancer cells, suggesting BAK1 may be a suitable therapeutic target for treating more proliferative tissue.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('induced', 'Reg', (204, 211))	('gastric cancer', 'Disease', (225, 239))	('apoptosis', 'CPA', (212, 221))	('gastric cancer', 'Disease', 'MESH:D013274', (225, 239))	('arrest', 'Disease', 'MESH:D006323', (193, 199))	('BAK1', 'Gene', (134, 138))	('decreased', 'NegReg', (166, 175))	('decreased', 'NegReg', (139, 148))	('arrest', 'Disease', (193, 199))	('gastric cancer', 'Phenotype', 'HP:0012126', (225, 239))	('overexpression', 'Var', (116, 130))	('BAK1', 'Gene', (31, 35))	('growth', 'CPA', (158, 164))
694105	30404157	BAK1 mediated apoptosis was also shown to correlate with caspase-3 activation and exert its apoptotic effect independent of p53.	('p53', 'Gene', (124, 127))	('activation', 'PosReg', (67, 77))	('BAK1', 'Var', (0, 4))	('p53', 'Gene', '7157', (124, 127))	('caspase-3', 'Gene', (57, 66))	('apoptosis', 'CPA', (14, 23))	('caspase-3', 'Gene', '836', (57, 66))
694107	30404157	Conversely, one study investigating BAK1 in tumor and non-tumor lesions in matched head and neck cancer patients found that loss of BAK1 was associated with a non-tumor phenotype.	('non-tumor', 'Disease', (159, 168))	('non-tumor', 'Disease', (54, 63))	('tumor', 'Disease', (163, 168))	('non-tumor', 'Disease', 'MESH:D009369', (159, 168))	('non-tumor', 'Disease', 'MESH:D009369', (54, 63))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (58, 63))	('loss', 'Var', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('head and neck cancer', 'Phenotype', 'HP:0012288', (83, 103))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('associated', 'Reg', (141, 151))	('neck cancer', 'Disease', 'MESH:D006258', (92, 103))	('neck cancer', 'Disease', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('BAK1', 'Gene', (132, 136))
694108	30404157	Moreover, although deletion of BAK significantly inhibited hepatocyte apoptosis in Mcl-1 knockout mice, deletion resulted in reduced incidences of liver cancer, reduced TNFalpha production, oxidative stress and oxidative DNA damage in non-cancerous livers.	('liver cancer', 'Disease', 'MESH:D006528', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('oxidative DNA damage', 'MPA', (211, 231))	('TNFalpha', 'Gene', (169, 177))	('oxidative stress', 'Phenotype', 'HP:0025464', (190, 206))	('liver cancer', 'Phenotype', 'HP:0002896', (147, 159))	('reduced', 'NegReg', (161, 168))	('BAK', 'Gene', (31, 34))	('liver cancer', 'Disease', (147, 159))	('non-cancerous', 'Disease', 'MESH:D009369', (235, 248))	('Mcl-1', 'Gene', '17210', (83, 88))	('hepatocyte', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('mice', 'Species', '10090', (98, 102))	('non-cancerous', 'Disease', (235, 248))	('Mcl-1', 'Gene', (83, 88))	('inhibited', 'NegReg', (49, 58))	('TNFalpha', 'Gene', '21926', (169, 177))	('oxidative stress', 'MPA', (190, 206))	('deletion', 'Var', (19, 27))	('reduced', 'NegReg', (125, 132))	('deletion', 'Var', (104, 112))
694110	30404157	Therefore, expression of BAK1 may play some role in Barrett's patients by conferring resistance to potential cancer cells by regulating cytochrome c oxidase and mitochondrial energy metabolism, known to be differentially altered across the normal-metaplasia-dysplasia-adenocarcinoma disease sequence in Barrett's esophagus.	('cytochrome c', 'Gene', '54205', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('metaplasia-dysplasia-adenocarcinoma disease', 'Disease', 'MESH:D008679', (247, 290))	('metaplasia-dysplasia-adenocarcinoma disease', 'Disease', (247, 290))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('altered', 'Reg', (221, 228))	('patients', 'Species', '9606', (62, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('regulating', 'Reg', (125, 135))	('BAK1', 'Gene', (25, 29))	('mitochondrial energy metabolism', 'MPA', (161, 192))	('cytochrome c', 'Gene', (136, 148))	('expression', 'Var', (11, 21))	("Barrett's esophagus", 'Disease', (303, 322))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (303, 322))	('conferring', 'Reg', (74, 84))
694112	30404157	Conversely, it is also upregulated in patients with non-metastatic prostate cancer and plays a role in cisplatin resistance in tongue squamous cell carcinoma with cisplatin sensitivity being restored upon knockdown of FIS1.	('tongue squamous cell carcinoma', 'Disease', (127, 157))	('plays', 'Reg', (87, 92))	('upregulated', 'PosReg', (23, 34))	('prostate cancer', 'Disease', (67, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('knockdown', 'Var', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (127, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (67, 82))	('cisplatin resistance', 'MPA', (103, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('patients', 'Species', '9606', (38, 46))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
694113	30404157	It is also speculated that increased levels of FIS1 promotes mitophagy to eliminate defective mitochondria following cellular stress and perhaps supports functional oxidative phosphorylation known to be associated with progression to OAC in Barrett's esophagus.	('mitophagy', 'MPA', (61, 70))	('increased levels', 'Var', (27, 43))	('FIS1', 'Gene', (47, 51))	('OAC', 'Disease', (234, 237))	("Barrett's esophagus", 'Disease', (241, 260))	('functional oxidative phosphorylation', 'MPA', (154, 190))	('promotes', 'PosReg', (52, 60))	('levels', 'Var', (37, 43))	('OAC', 'Chemical', '-', (234, 237))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (241, 260))	('eliminate defective mitochondria following', 'MPA', (74, 116))	('supports', 'PosReg', (145, 153))
694124	30404157	Figure 6 summarizes the effect of BAK1, FIS1 and SFN knockdown on mitochondrial function and cellular metabolism in Barrett's and OAC cells.	('FIS1', 'Gene', (40, 44))	('knockdown', 'Var', (53, 62))	('cellular metabolism', 'MPA', (93, 112))	('SFN', 'Gene', (49, 52))	('mitochondrial function', 'MPA', (66, 88))	('OAC', 'Chemical', '-', (130, 133))	('BAK1', 'Gene', (34, 38))
694132	30404157	Furthermore, we demonstrate that loss of SFN in OAC cells is associated with lower levels of both MMP and glycolysis.	('lower', 'NegReg', (77, 82))	('SFN', 'Gene', (41, 44))	('levels of', 'MPA', (83, 92))	('glycolysis', 'MPA', (106, 116))	('loss', 'Var', (33, 37))	('OAC', 'Chemical', '-', (48, 51))
694133	30404157	As OAC is known to be associated with high levels of glycolysis, targeting SFN may potentially reduce the levels of glycolysis in these highly bioenergetics cells.	('reduce', 'NegReg', (95, 101))	('glycolysis', 'MPA', (53, 63))	('OAC', 'Disease', (3, 6))	('levels of glycolysis in', 'MPA', (106, 129))	('targeting', 'Var', (65, 74))	('OAC', 'Chemical', '-', (3, 6))	('SFN', 'Gene', (75, 78))
694134	30404157	We found that knockdown of these genes had no effect on cell number in both Barrett's and OAC cells.	('cell number', 'CPA', (56, 67))	('OAC', 'Chemical', '-', (90, 93))	('knockdown', 'Var', (14, 23))
694138	30404157	These mitochondrial changes may increase the risk of progression from Barrett's esophagus to OAC.	('changes', 'Var', (20, 27))	("Barrett's esophagus", 'Disease', (70, 89))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (70, 89))	('OAC', 'Disease', (93, 96))	('OAC', 'Chemical', '-', (93, 96))
694175	30344746	Myositis-specific autoantibody expression, specifically anti-TIF1gamma positivity and/or anti-MDA5 negativity, was associated with cancer in patients with DM.	('cancer', 'Disease', (131, 137))	('TIF1gamma', 'Gene', '51592', (61, 70))	('TIF1gamma', 'Gene', (61, 70))	('Myositis', 'Phenotype', 'HP:0100614', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Myositis', 'Disease', (0, 8))	('DM', 'Disease', 'MESH:D009223', (155, 157))	('MDA5', 'Gene', '64135', (94, 98))	('MDA5', 'Gene', (94, 98))	('Myositis', 'Disease', 'MESH:D009220', (0, 8))	('positivity', 'Var', (71, 81))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('associated with', 'Reg', (115, 130))	('patients', 'Species', '9606', (141, 149))
694224	30344746	In contrast, ILD (18.6% vs. 54.59%; P<0.001), arthralgia (18.60% vs. 42.86%; P=0.002), and anti-Jo-1 antibody (0.00% vs. 9.18%; P=0.041) were significantly less common in the malignancy group than in the non-malignancy group.	('ILD', 'Disease', (13, 16))	('malignancy', 'Disease', (175, 185))	('arthralgia', 'Disease', 'MESH:D018771', (46, 56))	('ILD', 'Disease', 'MESH:C562470', (13, 16))	('anti-Jo-1', 'Var', (91, 100))	('malignancy', 'Disease', 'MESH:D009369', (208, 218))	('arthralgia', 'Disease', (46, 56))	('malignancy', 'Disease', (208, 218))	('malignancy', 'Disease', 'MESH:D009369', (175, 185))	('arthralgia', 'Phenotype', 'HP:0002829', (46, 56))
694233	30344746	One patient with cancer was positive for both anti-TIF1gamma and anti-SRP.	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('patient', 'Species', '9606', (4, 11))	('cancer', 'Disease', (17, 23))	('anti-SRP', 'Var', (65, 73))	('TIF1gamma', 'Gene', '51592', (51, 60))	('TIF1gamma', 'Gene', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
694234	30344746	Among the 13 patients with DM without tumors, 6 were positive for anti-RO-52, 2 for anti-SRP, and 2 for both anti-Mi-2alpha and anti-Mi-2beta.	('Mi-2alpha', 'Gene', (114, 123))	('positive', 'Reg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Mi-2beta', 'Gene', (133, 141))	('tumors', 'Disease', (38, 44))	('anti-SRP', 'Var', (84, 92))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('DM', 'Disease', 'MESH:D009223', (27, 29))	('Mi-2beta', 'Gene', '1108', (133, 141))	('Mi-2alpha', 'Gene', '1107', (114, 123))	('anti-RO-52', 'Var', (66, 76))
694235	30344746	In addition, the patients without tumors were positive for anti-Ku or anti-PL-7.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('anti-PL-7', 'Var', (70, 79))	('patients', 'Species', '9606', (17, 25))	('anti-Ku', 'Var', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
694278	30344746	Protective factors include ILD, arthralgia, Raynaud phenomenon, anti-extractable nuclear antigen and anti-Jo-1 antibody.	('anti-Jo-1', 'Var', (101, 110))	('ILD', 'Disease', (27, 30))	('anti-extractable', 'Var', (64, 80))	('Raynaud phenomenon', 'Disease', (44, 62))	('arthralgia', 'Disease', 'MESH:D018771', (32, 42))	('ILD', 'Disease', 'MESH:C562470', (27, 30))	('Raynaud phenomenon', 'Phenotype', 'HP:0030880', (44, 62))	('arthralgia', 'Disease', (32, 42))	('men', 'Species', '9606', (57, 60))	('arthralgia', 'Phenotype', 'HP:0002829', (32, 42))
694294	30344746	Furthermore, the study showed that anti-MDA5 antibodies were associated with intractable ILD, particularly in patients with amyopathic DM.	('amyopathic DM', 'Disease', 'MESH:D009223', (124, 137))	('patients', 'Species', '9606', (110, 118))	('amyopathic DM', 'Disease', (124, 137))	('antibodies', 'Var', (45, 55))	('MDA5', 'Gene', (40, 44))	('MDA5', 'Gene', '64135', (40, 44))	('associated', 'Reg', (61, 71))	('ILD', 'Disease', (89, 92))	('ILD', 'Disease', 'MESH:C562470', (89, 92))
694320	29340044	Our data demonstrated that CEH significantly inhibited ESCC cell proliferation in a dose-dependent manner, induced G2/M phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to cisplatin (cDDP).	('arrest', 'Disease', (137, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (216, 225))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (126, 143))	('increased', 'PosReg', (163, 172))	('ESCC cell proliferation', 'CPA', (55, 78))	('CEH', 'Var', (27, 30))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('cDDP', 'Chemical', '-', (227, 231))	('apoptosis', 'CPA', (148, 157))	('inhibited', 'NegReg', (45, 54))	('CEH', 'Chemical', '-', (27, 30))	('sensitivity', 'MPA', (177, 188))	('induced', 'Reg', (107, 114))
694321	29340044	Mechanistically, CEH inhibited ESCC cell growth and induced apoptosis through activation of c-Jun, thereby inhibiting the expression of P-gp, and enhancing p21 expression via activation of the p53 signaling pathway.	('expression', 'MPA', (160, 170))	('expression', 'MPA', (122, 132))	('P-gp', 'Protein', (136, 140))	('p53', 'Gene', (193, 196))	('CEH', 'Var', (17, 20))	('apoptosis', 'CPA', (60, 69))	('enhancing', 'PosReg', (146, 155))	('p53', 'Gene', '7157', (193, 196))	('p21', 'Gene', (156, 159))	('CEH', 'Chemical', '-', (17, 20))	('inhibiting', 'NegReg', (107, 117))	('activation', 'PosReg', (78, 88))	('inhibited', 'NegReg', (21, 30))	('p21', 'Gene', '644914', (156, 159))	('ESCC', 'Disease', (31, 35))	('induced', 'Reg', (52, 59))	('c-Jun', 'Protein', (92, 97))
694322	29340044	In this study, we observed that growth of xenograft tumors derived from ESCC cell lines in nude mice was also significantly inhibited by combination therapy.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('combination', 'Var', (137, 148))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('nude mice', 'Species', '10090', (91, 100))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('growth', 'CPA', (32, 38))	('inhibited', 'NegReg', (124, 133))
694342	29340044	Then, the cellular morphology of Eca109 and Eca109/CDDP was studied, we found that the morphology of Eca109/CDDP was irregular and misaligned, whereas that of Eca109 was fusiform and in alignment, and that the cell volume of Eca109/CDDP increased compared to that of Eca109 (Figure 1B).	('increased', 'PosReg', (237, 246))	('CDDP', 'Chemical', 'MESH:D002945', (51, 55))	('CDDP', 'Chemical', 'MESH:D002945', (108, 112))	('cell volume', 'CPA', (210, 221))	('CDDP', 'Chemical', 'MESH:D002945', (232, 236))	('Eca109/CDDP', 'Var', (101, 112))	('Eca109/CDDP', 'Var', (225, 236))
694361	29340044	the results showed that CEH significantly increased PARP cleavage, but suppressed anti-apoptotic Bcl-2 expression, consistent with the observed upregulation of p53.	('increased', 'PosReg', (42, 51))	('PARP', 'Gene', '142', (52, 56))	('Bcl-2', 'Gene', (97, 102))	('Bcl-2', 'Gene', '596', (97, 102))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('PARP', 'Gene', (52, 56))	('CEH', 'Var', (24, 27))	('CEH', 'Chemical', '-', (24, 27))	('suppressed', 'NegReg', (71, 81))
694364	29340044	Cyto-c, a necessary cofactor for apoptotic protease activating factor 1 (Apaf- 1) oligomerization and the subsequent activation of caspase-9 and -3.	('activation', 'PosReg', (117, 127))	('caspase-9 and -3', 'Gene', '842;836', (131, 147))	('apoptotic protease activating factor 1', 'Gene', (33, 71))	('Apaf- 1', 'Gene', (73, 80))	('Cyto-c', 'Gene', (0, 6))	('Cyto-c', 'Gene', '54205', (0, 6))	('apoptotic protease activating factor 1', 'Gene', '317', (33, 71))	('oligomerization', 'Var', (82, 97))	('Apaf- 1', 'Gene', '317', (73, 80))
694368	29340044	In order to verify the drug resistance mechanism of Eca109/CDDP, qRT-PCR and western blot analysis were used to quantify the MDR1 mRNA and P-gp protein, respectively (Figure 4A-4E).	('CDDP', 'Chemical', 'MESH:D002945', (59, 63))	('MDR1', 'Gene', (125, 129))	('P-gp', 'MPA', (139, 143))	('Eca109/CDDP', 'Var', (52, 63))	('drug resistance', 'Phenotype', 'HP:0020174', (23, 38))	('MDR1', 'Gene', '5243', (125, 129))
694374	29340044	As shown in Figure 4F and 4G, CEH increase the expression and activation of c-Jun and JNK with a concentration dependent manner.	('JNK', 'MPA', (86, 89))	('CEH', 'Var', (30, 33))	('CEH', 'Chemical', '-', (30, 33))	('activation', 'MPA', (62, 72))	('c-Jun', 'Protein', (76, 81))	('increase', 'PosReg', (34, 42))	('expression', 'MPA', (47, 57))
694375	29340044	Mechanistically, CEH inhibited ESCC cell growth, induced apoptosis through repressing phosphorylation of c-Jun and reduced P-gp expression by the activation of c-Jun/JNK signaling cascades, which led to the reversal of P-gp-mediated cDDP resistance and promotion of mitochondrial-mediated apoptosis.	('P-gp', 'Protein', (123, 127))	('apoptosis', 'CPA', (57, 66))	('mitochondrial-mediated apoptosis', 'CPA', (266, 298))	('reduced', 'NegReg', (115, 122))	('c-Jun/JNK', 'MPA', (160, 169))	('CEH', 'Var', (17, 20))	('phosphorylation', 'MPA', (86, 101))	('cDDP', 'Chemical', '-', (233, 237))	('CEH', 'Chemical', '-', (17, 20))	('induced', 'Reg', (49, 56))	('inhibited', 'NegReg', (21, 30))	('promotion', 'PosReg', (253, 262))	('expression', 'MPA', (128, 138))	('ESCC cell growth', 'CPA', (31, 47))
694377	29340044	As shown in Figure 5A-5D, tretment of SP600125 decreased CEH-induced cell apoptosis.	('SP600125', 'Var', (38, 46))	('CEH', 'Chemical', '-', (57, 60))	('CEH-induced', 'Disease', (57, 68))	('SP600125', 'Chemical', 'MESH:C432165', (38, 46))	('decreased', 'NegReg', (47, 56))
694379	29340044	Furthermore, we found that the tretment of SP600125 sifnificantly reversed the P-gp expression inhibited by CEH (Figure 5K and 5L).	('P-gp expression', 'MPA', (79, 94))	('SP600125', 'Chemical', 'MESH:C432165', (43, 51))	('inhibited', 'NegReg', (95, 104))	('SP600125', 'Var', (43, 51))	('CEH', 'Chemical', '-', (108, 111))
694381	29340044	Together, these findings suggest that CEH increases cell apoptosis and decareses the expressions of MDR1 mRNA and P-gp might be mediated by the activation of JNK and p53 pathways.	('expressions', 'MPA', (85, 96))	('increases', 'PosReg', (42, 51))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('decareses', 'NegReg', (71, 80))	('MDR1', 'Gene', (100, 104))	('CEH', 'Var', (38, 41))	('CEH', 'Chemical', '-', (38, 41))	('cell apoptosis', 'CPA', (52, 66))	('MDR1', 'Gene', '5243', (100, 104))	('P-gp', 'Protein', (114, 118))
694387	29340044	Taken together, these data indicated that CEH could also effectively increase the anti-tumor effect of cDDP in vivo.	('increase', 'PosReg', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('cDDP', 'Gene', (103, 107))	('CEH', 'Var', (42, 45))	('cDDP', 'Chemical', '-', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CEH', 'Chemical', '-', (42, 45))
694403	29340044	This sensitization mechanism might be that CEP restore the sensitivity of tumor cells to chemotherapeutic drugs by affecting the function of the cell membrane and thus lead to the accumulation of drugs in cancer cells.	('accumulation of drugs', 'MPA', (180, 201))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('restore', 'PosReg', (47, 54))	('sensitivity', 'MPA', (59, 70))	('cancer', 'Disease', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('function of the cell membrane', 'MPA', (129, 158))	('CEP', 'Var', (43, 46))	('CEP', 'Chemical', 'MESH:C006947', (43, 46))	('lead to', 'Reg', (168, 175))	('tumor', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('affecting', 'Reg', (115, 124))
694409	29340044	reported that CEH had a direct cytotoxic effect on human chronic myeloid leukemia cell line K562 and K562/ADR, a Dox-resistant cell line with stable MDR phenotype induced by Dox.	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (57, 81))	('myeloid leukemia', 'Disease', (65, 81))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('human', 'Species', '9606', (51, 56))	('Dox', 'Chemical', 'MESH:D004317', (113, 116))	('CEH', 'Var', (14, 17))	('K562', 'CellLine', 'CVCL:0004', (101, 105))	('myeloid leukemia', 'Disease', 'MESH:D007951', (65, 81))	('Dox', 'Chemical', 'MESH:D004317', (174, 177))	('CEH', 'Chemical', '-', (14, 17))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (65, 81))	('K562', 'CellLine', 'CVCL:0004', (92, 96))
694410	29340044	Similarly, we found that CEH could inhibit the growth of esophageal squamous cell lines Eca109 and Eca109/CDDP, and the antineoplastic activity showed concentration dependence.	('CDDP', 'Chemical', 'MESH:D002945', (106, 110))	('CEH', 'Var', (25, 28))	('CEH', 'Chemical', '-', (25, 28))	('esophageal squamous', 'Disease', 'MESH:D000077277', (57, 76))	('esophageal squamous', 'Disease', (57, 76))	('growth', 'CPA', (47, 53))	('inhibit', 'NegReg', (35, 42))
694419	29340044	Inactivation of the p53 tumor suppressor gene occurs in over half of all human tumors, implying that loss of this gene represents a fundamentally important step in the pathogenesis of cancer.	('cancer', 'Disease', (184, 190))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (24, 29))	('loss', 'Var', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('human', 'Species', '9606', (73, 78))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('Inactivation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
694421	29340044	Our data demonstrated that CEH induced a dose-dependent upregulation of p53 and the downstream p21, explaining the mechanism by which CEH can caused cell cycle arrest, inhibited proliferation, and induced apoptosis.	('apoptosis', 'CPA', (205, 214))	('induced', 'Reg', (197, 204))	('upregulation', 'PosReg', (56, 68))	('proliferation', 'CPA', (178, 191))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (149, 166))	('p53', 'Gene', (72, 75))	('CEH', 'Var', (134, 137))	('p53', 'Gene', '7157', (72, 75))	('arrest', 'Disease', 'MESH:D006323', (160, 166))	('CEH', 'Chemical', '-', (134, 137))	('inhibited', 'NegReg', (168, 177))	('arrest', 'Disease', (160, 166))	('CEH', 'Chemical', '-', (27, 30))	('p21', 'Gene', (95, 98))	('p21', 'Gene', '644914', (95, 98))
694422	29340044	In addition, p53 may regulate the sensitivity of chemotherapeutic agents as a clinical study indicated that p53 mutation may contribute to MDR.	('p53', 'Gene', (108, 111))	('mutation', 'Var', (112, 120))	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', (13, 16))	('contribute', 'Reg', (125, 135))	('MDR', 'Disease', (139, 142))	('p53', 'Gene', '7157', (13, 16))
694429	29340044	This result demonstrates that CEH reversed MDR in ESCC by modulating complex signal transduction.	('modulating', 'Reg', (58, 68))	('CEH', 'Var', (30, 33))	('CEH', 'Chemical', '-', (30, 33))	('complex signal transduction', 'MPA', (69, 96))	('ESCC', 'Disease', (50, 54))
694430	29340044	In the ESCC xenograft models, we also discovered that CEH increased the sensitivity of cDDP in ESCC.	('CEH', 'Var', (54, 57))	('increased', 'PosReg', (58, 67))	('CEH', 'Chemical', '-', (54, 57))	('ESCC', 'Disease', (95, 99))	('sensitivity', 'MPA', (72, 83))	('cDDP', 'Chemical', '-', (87, 91))
694433	29340044	Similar to the in vitro results, CEH reversed cDDP resistance in ESCC via activation of c-Jun/JNK signaling pathway in vivo.	('CEH', 'Var', (33, 36))	('c-Jun/JNK signaling pathway', 'Pathway', (88, 115))	('CEH', 'Chemical', '-', (33, 36))	('activation', 'PosReg', (74, 84))	('cDDP', 'Chemical', '-', (46, 50))
694434	29340044	In summary, our study demonstrated that CEH could effectively reverse the MDR-mediated cisplatin resistance of ESCC cells in vitro and vivo, and was able to induce significant apoptosis in human ESCC cell lines Eca109 and its resistant strain Eca109/CDDP, inhibited ESCC cell lines proliferation and induced G2/M phase cell cycle arrest.	('arrest', 'Disease', 'MESH:D006323', (330, 336))	('induce', 'Reg', (157, 163))	('CEH', 'Var', (40, 43))	('MDR-mediated cisplatin resistance', 'MPA', (74, 107))	('reverse', 'NegReg', (62, 69))	('inhibited', 'NegReg', (256, 265))	('CEH', 'Chemical', '-', (40, 43))	('human', 'Species', '9606', (189, 194))	('arrest', 'Disease', (330, 336))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('ESCC cell lines proliferation', 'CPA', (266, 295))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (319, 336))	('apoptosis', 'CPA', (176, 185))	('CDDP', 'Chemical', 'MESH:D002945', (250, 254))	('induced', 'Reg', (300, 307))
694493	28192623	We previously reported that patients with high EGFR expression benefited from postoperative radiotherapy;18 however, the survival rate in these patients was still lower than in those with low EGFR expression who received surgery only.	('survival rate', 'CPA', (121, 134))	('patients', 'Species', '9606', (144, 152))	('high', 'Var', (42, 46))	('lower', 'NegReg', (163, 168))	('patients', 'Species', '9606', (28, 36))	('EGFR', 'Gene', (47, 51))
694519	28192623	Esophageal squamous cell lines with wild-type EGFR expression kyse30, TE1, and CaEs-17 were purchased from ATCC.	('kyse30', 'Var', (62, 68))	('EGFR', 'Gene', (46, 50))	('TC', 'Chemical', '-', (108, 110))
694540	28192623	For the group with positive PD-L1 expression, the 5-year OS rate was 37.6%, with a median survival time of 31.6 months; for the group with negative PD-L1 expression, the 5-year OS rate was 20.5%, with a median survival time of 17.0 months.	('PD-L1', 'Gene', '29126', (28, 33))	('PD-L1', 'Gene', '29126', (148, 153))	('OS', 'Chemical', '-', (177, 179))	('expression', 'Var', (34, 44))	('OS', 'Chemical', '-', (57, 59))	('PD-L1', 'Gene', (28, 33))	('PD-L1', 'Gene', (148, 153))
694548	28192623	We wondered whether we could improve the separation of survival rate between the groups by combining groups with high EGFR and negative PD-L1 expression, which are both associated with lower survival rates, and groups with low EGFR and positive PD-L1 expression, which are both associated with higher survival rates.	('high', 'Var', (113, 117))	('PD-L1', 'Gene', (245, 250))	('lower', 'NegReg', (185, 190))	('negative', 'NegReg', (127, 135))	('survival rates', 'CPA', (191, 205))	('PD-L1', 'Gene', (136, 141))	('PD-L1', 'Gene', '29126', (245, 250))	('EGFR', 'Gene', (118, 122))	('expression', 'MPA', (142, 152))	('PD-L1', 'Gene', '29126', (136, 141))
694560	28192623	AG1478 inhibited radiation-induced PD-L1 expression dramatically, to levels even lower than those found in the un-irradiated controls (Fig.	('PD-L1', 'Gene', '29126', (35, 40))	('expression', 'MPA', (41, 51))	('AG1478', 'Chemical', 'MESH:C101044', (0, 6))	('inhibited', 'NegReg', (7, 16))	('PD-L1', 'Gene', (35, 40))	('AG1478', 'Var', (0, 6))
694561	28192623	Western blot results confirmed that radiation induced phosphorylation of EGFR in all three cell lines, and that AG1478 blocked EGFR phosphorylation.	('AG1478', 'Chemical', 'MESH:C101044', (112, 118))	('EGFR', 'Protein', (73, 77))	('blocked', 'NegReg', (119, 126))	('AG1478', 'Var', (112, 118))	('phosphorylation', 'MPA', (54, 69))
694562	28192623	The level of phosphorylated STAT3 increased after cells were exposed to radiation and decreased after administration of AG1478 only in kyse30 and TE1 cells, not CaEs17 cells (Fig.	('STAT3', 'Gene', (28, 33))	('AG1478', 'Chemical', 'MESH:C101044', (120, 126))	('decreased', 'NegReg', (86, 95))	('AG1478', 'Var', (120, 126))	('STAT3', 'Gene', '6774', (28, 33))	('increased', 'PosReg', (34, 43))
694580	28192623	Activation of the EGFR pathway might involve suppressing the immune response in murine melanoma models, either through activating regulatory T cells or reducing the levels of the T cell chemoattractant.25 It is possible that in patients with high EGFR expression, the endogenous antitumor immune response was inhibited, which could be partially reflected by decreased PD-L1 expression and devote to the high rates of recurrence and metastasis and shorter survival time for these patients.	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('expression', 'Var', (252, 262))	('EGFR', 'Gene', (247, 251))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanoma', 'Disease', (87, 95))	('expression', 'MPA', (374, 384))	('patients', 'Species', '9606', (228, 236))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('decreased', 'NegReg', (358, 367))	('patients', 'Species', '9606', (479, 487))	('inhibited', 'NegReg', (309, 318))	('PD-L1', 'Gene', (368, 373))	('metastasis', 'CPA', (432, 442))	('PD-L1', 'Gene', '29126', (368, 373))	('high', 'Var', (242, 246))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('tumor', 'Disease', (283, 288))	('decreased PD', 'Phenotype', 'HP:0032198', (358, 370))	('murine', 'Species', '10090', (80, 86))
694582	28192623	As patients with low EGFR/positive PD-L1 tumors have their antitumor immune potential, their median OS time was much longer than that of patients with high EGFR/negative PD-L1 expression.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (63, 68))	('PD-L1', 'Gene', (170, 175))	('PD-L1', 'Gene', '29126', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('PD-L1', 'Gene', '29126', (170, 175))	('OS', 'Chemical', '-', (100, 102))	('patients', 'Species', '9606', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('patients', 'Species', '9606', (3, 11))	('low', 'Var', (17, 20))	('PD-L1 tumors', 'Disease', (35, 47))	('PD-L1 tumors', 'Disease', 'MESH:D010300', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PD-L1', 'Gene', (35, 40))
694593	28192623	Accordingly, the negative association between EGFR and PD-L1 expression was found in the tissue samples; and patients with high EGFR/negative PD-L1 expression had much worse survival than that of patients with low EGFR/positive PD-L1 expression.	('worse', 'NegReg', (168, 173))	('survival', 'CPA', (174, 182))	('patients', 'Species', '9606', (109, 117))	('PD-L1', 'Gene', '29126', (55, 60))	('PD-L1', 'Gene', (228, 233))	('PD-L1', 'Gene', '29126', (142, 147))	('high', 'Var', (123, 127))	('patients', 'Species', '9606', (196, 204))	('PD-L1', 'Gene', '29126', (228, 233))	('PD-L1', 'Gene', (55, 60))	('PD-L1', 'Gene', (142, 147))
694598	28192623	In our previous study, we found patients with high EGFR expression would benefit from postoperative radiotherapy.18 However, in the present study, we did not find significant differences of survival among patients who had either positive or negative PD-L1 expression and received postoperative radiotherapy or not (Figs S2, S3).	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (205, 213))	('PD-L1', 'Gene', (250, 255))	('negative', 'NegReg', (241, 249))	('PD-L1', 'Gene', '29126', (250, 255))	('positive', 'Var', (229, 237))	('expression', 'MPA', (256, 266))
694600	28192623	In conclusion, our results show that expression of PD-L1 on tumor-infiltrating ICs is an independent prognostic factor for patients with ESCC and the association between EGFR and PD-L1 is vital to survival.	('expression', 'Var', (37, 47))	('PD-L1', 'Gene', '29126', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ESCC', 'Disease', (137, 141))	('patients', 'Species', '9606', (123, 131))	('PD-L1', 'Gene', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('PD-L1', 'Gene', '29126', (179, 184))	('PD-L1', 'Gene', (51, 56))
694602	28046029	Genetic Variants in MTHFR Gene Predict >= 2 Radiation Pneumonitis in Esophageal Squamous Cell Carcinoma Patients Treated with Thoracic Radiotherapy Reactive oxygen species (ROS), formed as an indirect production of radiotherapy (RT), could cause DNA damage of normal tissues.	('Predict', 'Reg', (31, 38))	('MTHFR', 'Gene', '4524', (20, 25))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('Carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('Genetic Variants', 'Var', (0, 16))	('Reactive oxygen species', 'Chemical', 'MESH:D017382', (148, 171))	('cause', 'Reg', (240, 245))	('MTHFR', 'Gene', (20, 25))	('ROS', 'Chemical', 'MESH:D017382', (173, 176))	('Esophageal Squamous Cell Carcinoma', 'Disease', (69, 103))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (69, 103))	('Patients', 'Species', '9606', (104, 112))
694604	28046029	Therefore, in this prospective cohort study, we explored the association of genetic variants in ROS metabolism and DNA repair pathway-related genes with radiation pneumonitis (RP).	('pneumonitis', 'Disease', (163, 174))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('pneumonitis', 'Disease', 'MESH:D011014', (163, 174))	('genetic variants', 'Var', (76, 92))	('ROS metabolism', 'Gene', (96, 110))	('DNA repair pathway-related genes', 'Gene', (115, 147))	('association', 'Interaction', (61, 72))
694606	28046029	Five functional single nucleotide polymorphisms (SNPs) (rs1695 in GSTP1; rs4880 in SOD2; rs3957356 in GSTA1; and rs1801131, rs1801133 in MTHFR) were genotyped using the MassArray system, and rs1801131 was found to be a predictor of >= 2 RP.	('SOD2', 'Gene', '6648', (83, 87))	('rs1801133', 'Mutation', 'rs1801133', (124, 133))	('rs4880', 'Mutation', 'rs4880', (73, 79))	('rs3957356', 'Var', (89, 98))	('rs4880', 'Var', (73, 79))	('MTHFR', 'Gene', (137, 142))	('GSTA1', 'Gene', (102, 107))	('GSTP1', 'Gene', '2950', (66, 71))	('rs1801131', 'Var', (113, 122))	('GSTP1', 'Gene', (66, 71))	('rs3957356', 'Mutation', 'rs3957356', (89, 98))	('rs1801133', 'Var', (124, 133))	('GSTA1', 'Gene', '2938', (102, 107))	('rs1801131', 'Mutation', 'rs1801131', (113, 122))	('rs1801131', 'Var', (191, 200))	('rs1695', 'Var', (56, 62))	('rs1801131', 'Mutation', 'rs1801131', (191, 200))	('SOD2', 'Gene', (83, 87))	('rs1695', 'Mutation', 'rs1695', (56, 62))
694607	28046029	Our results showed that, compared with TT genotype, patients with GG/GT genotypes of rs1801131 had a notably lower risk of developing >= 2 RP (HR = 0.339, 95% CI = 0.137-0.839, P = 0.019).	('rs1801131', 'Mutation', 'rs1801131', (85, 94))	('developing >= 2 RP', 'MPA', (123, 141))	('lower', 'NegReg', (109, 114))	('rs1801131', 'Var', (85, 94))	('patients', 'Species', '9606', (52, 60))
694616	28046029	Previous study revealed that single nucleotide polymorphisms of genes in ROS metabolism pathway are closely associated with acute skin toxicity for breast cancer patients receiving radiotherapy.	('patients', 'Species', '9606', (162, 170))	('ROS metabolism pathway', 'Pathway', (73, 95))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('ROS', 'Chemical', 'MESH:D017382', (73, 76))	('single nucleotide polymorphisms', 'Var', (29, 60))	('breast cancer', 'Disease', (148, 161))	('associated with', 'Reg', (108, 123))	('skin toxicity', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('skin toxicity', 'Disease', 'MESH:D012871', (130, 143))
694617	28046029	So it is highly plausible these genetic variants could also affect radiation lung injury, however, which has not well been explored.	('radiation lung injury', 'Disease', (67, 88))	('radiation lung injury', 'Disease', 'MESH:D011832', (67, 88))	('affect', 'Reg', (60, 66))	('variants', 'Var', (40, 48))	('genetic variants', 'Var', (32, 48))
694618	28046029	One article reported that single nucleotide polymorphisms in MTHFR gene could exert influence on the incidence of radiation pneumonitis in white lung cancer patients.	('pneumonitis', 'Disease', (124, 135))	('influence', 'Reg', (84, 93))	('MTHFR', 'Gene', (61, 66))	('white lung cancer', 'Disease', (139, 156))	('white lung cancer', 'Disease', 'MESH:D056784', (139, 156))	('patients', 'Species', '9606', (157, 165))	('pneumonitis', 'Disease', 'MESH:D011014', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('single nucleotide polymorphisms', 'Var', (26, 57))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
694619	28046029	In view of the above mentioned, we therefore depended on the existing literature by screening for an association of functional SNPs in SOD2, GSTP1, GSTA1and MTHFR genes with the risk of RP in a prospective cohort of ESCC patients treated with definitive RT.	('GSTA1', 'Gene', (148, 153))	('patients', 'Species', '9606', (221, 229))	('MTHFR', 'Gene', (157, 162))	('SOD2', 'Gene', '6648', (135, 139))	('SNPs', 'Var', (127, 131))	('SOD2', 'Gene', (135, 139))	('ESCC', 'Disease', (216, 220))	('GSTA1', 'Gene', '2938', (148, 153))	('association', 'Interaction', (101, 112))	('GSTP1', 'Gene', (141, 146))	('GSTP1', 'Gene', '2950', (141, 146))
694628	28046029	Genotyping was performed by Sequenom MassArray System (San Diego, USA) on known functional SNPs for candidate genes in ROS metabolism and DNA repair pathways including: 1) glutathione S-transferases pi 1 (GSTP1; rs1695); 2) superoxide dismutase 2 (SOD2; rs4880); 3) glutathione S-transferases alpha 1(GSTA1; rs3957356); 4) methylenetetrahydrofolate reductase (MTHFR; rs1801131 and rs1801133).	('SOD2', 'Gene', (248, 252))	('GSTA1', 'Gene', (301, 306))	('rs1801133', 'Var', (381, 390))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (323, 358))	('rs1801131', 'Mutation', 'rs1801131', (367, 376))	('ROS', 'Chemical', 'MESH:D017382', (119, 122))	('superoxide dismutase 2', 'Gene', (224, 246))	('SOD2', 'Gene', '6648', (248, 252))	('methylenetetrahydrofolate reductase', 'Gene', (323, 358))	('rs1695', 'Mutation', 'rs1695', (212, 218))	('GSTA1', 'Gene', '2938', (301, 306))	('superoxide dismutase 2', 'Gene', '6648', (224, 246))	('rs3957356', 'Mutation', 'rs3957356', (308, 317))	('rs1801133', 'Mutation', 'rs1801133', (381, 390))	('glutathione S-transferases pi 1', 'Gene', '2950', (172, 203))	('glutathione S-transferases pi 1', 'Gene', (172, 203))	('GSTP1', 'Gene', '2950', (205, 210))	('rs4880', 'Mutation', 'rs4880', (254, 260))	('GSTP1', 'Gene', (205, 210))
694640	28046029	We found that rs1801131 of MTHFR was significantly related to the risk of >= 2 RP (HR = 0.285, 95% CI = 0.120-0.676, P = 0.004).	('related', 'Reg', (51, 58))	('rs1801131', 'Var', (14, 23))	('rs1801131', 'Mutation', 'rs1801131', (14, 23))	('MTHFR', 'Gene', (27, 32))
694645	28046029	Patients were divided into four groups according to genotype in rs1801131 and MLD or V20.	('rs1801131', 'Mutation', 'rs1801131', (64, 73))	('rs1801131', 'Var', (64, 73))	('MLD', 'Disease', 'MESH:D007966', (78, 81))	('Patients', 'Species', '9606', (0, 8))	('MLD', 'Disease', (78, 81))
694646	28046029	Patients with TT genotypes in rs1801131 and MLD>11.6 Gy or V20>17.1% had the highest RP risk compared with other groups (P<0.001; P<0.001,respectively,Fig 2).	('rs1801131', 'Mutation', 'rs1801131', (30, 39))	('MLD', 'Disease', 'MESH:D007966', (44, 47))	('MLD', 'Disease', (44, 47))	('rs1801131', 'Var', (30, 39))	('Patients', 'Species', '9606', (0, 8))	('V20>', 'Var', (59, 63))
694647	28046029	However, this difference was not significant in patients who received MLD <= 11.6 Gy or V20 <= 17.1%, suggesting that the effect of genetic variants on the risk of >= 2 RP were independent from dosimetric parameters.	('MLD', 'Disease', (70, 73))	('patients', 'Species', '9606', (48, 56))	('variants', 'Var', (140, 148))	('MLD', 'Disease', 'MESH:D007966', (70, 73))
694648	28046029	In our prospective study, we examined the association between genetic variants in SOD2, GSTP1, GSTA1 and MTHFR genes and the RP risk in ESCC patients.	('MTHFR', 'Gene', (105, 110))	('ESCC', 'Disease', (136, 140))	('GSTP1', 'Gene', '2950', (88, 93))	('association', 'Interaction', (42, 53))	('variants', 'Var', (70, 78))	('SOD2', 'Gene', '6648', (82, 86))	('GSTA1', 'Gene', (95, 100))	('GSTA1', 'Gene', '2938', (95, 100))	('SOD2', 'Gene', (82, 86))	('patients', 'Species', '9606', (141, 149))	('GSTP1', 'Gene', (88, 93))
694649	28046029	We found that rs1801131 of MTHFR gene in the DNA repair pathway maybe a reliable and independent predictor for >= 2 RP.	('rs1801131', 'Var', (14, 23))	('rs1801131', 'Mutation', 'rs1801131', (14, 23))	('MTHFR gene', 'Gene', (27, 37))
694650	28046029	The study indicated that patients with GG/GT genotypes had a decreased risk of >= 2 RP compared with other genotype.	('decreased', 'NegReg', (61, 70))	('GG/GT', 'Var', (39, 44))	('>= 2 RP', 'Disease', (79, 86))	('patients', 'Species', '9606', (25, 33))
694651	28046029	However, genetic variants in ROS metabolism-related genes were not found to be significantly associated with RP risk.	('genetic variants', 'Var', (9, 25))	('ROS metabolism-related genes', 'Gene', (29, 57))	('associated', 'Reg', (93, 103))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))
694655	28046029	The rs1801131 of MTHFR results in a glutamate to alanine substitution at codon 439 in exon 7, which is located in the COOH-terminal regulatory domain of the gene, and results in a 30-40% reduction of enzymatic function in the homozygous variant genotype.	('enzymatic function', 'MPA', (200, 218))	('rs1801131', 'Mutation', 'rs1801131', (4, 13))	('reduction', 'NegReg', (187, 196))	('glutamate', 'MPA', (36, 45))	('rs1801131', 'Var', (4, 13))	('MTHFR', 'Gene', (17, 22))	('glutamate to alanine substitution at codon 439', 'Mutation', 'p.E439A', (36, 82))
694656	28046029	What's more, other research demonstrated that after total body irradiation in mice, MTHFR activity levels decreased while thymidylate synthase activity increased suggesting that the regulation of these enzymes in diverting folate metabolism toward thymidine base synthesis may play an important role in the cellular response to ionizing radiation.In addition, recent investigations have found that genetic variants of MTHFR were related to many diseases.	('diseases', 'Disease', (445, 453))	('folate', 'Chemical', 'MESH:D005492', (223, 229))	('thymidine', 'Chemical', 'MESH:D013936', (248, 257))	('MTHFR', 'Gene', (418, 423))	('genetic variants', 'Var', (398, 414))	('related', 'Reg', (429, 436))	('thymidylate synthase activity increased', 'Phenotype', 'HP:0003240', (122, 161))	('mice', 'Species', '10090', (78, 82))
694657	28046029	A further study conducted by Harvard School of Public Health found that genetic variants in MTHFR gene associated significantly with RP risk for lung cancer patients receiving radiotherapy in white population.	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('associated', 'Reg', (103, 113))	('MTHFR', 'Gene', (92, 97))	('patients', 'Species', '9606', (157, 165))	('lung cancer', 'Disease', (145, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('genetic variants', 'Var', (72, 88))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
694664	28046029	Recent studies also illustrated genetic variants involved in ROS metabolism pathway-related genes could predict radiation-induced skin toxicity for breast cancer patients receiving RT.	('patients', 'Species', '9606', (162, 170))	('predict', 'Reg', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ROS metabolism pathway-related genes', 'Gene', (61, 97))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('skin toxicity', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('variants', 'Var', (40, 48))	('skin toxicity', 'Disease', 'MESH:D012871', (130, 143))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
694665	28046029	However, in our analysis, while CC genotype of rs3957356 in GSTA1 gene shows a relative high risk of RP, the results was still not statistically significant, which further studies are deserved to confirm the results.	('rs3957356', 'Mutation', 'rs3957356', (47, 56))	('rs3957356', 'Var', (47, 56))	('GSTA1', 'Gene', '2938', (60, 65))	('GSTA1', 'Gene', (60, 65))
694668	28046029	In conclusion, our study explored the association between genetic variants in candidate genes involved in ROS metabolism, DNA repair pathways and the risk of RP.	('association', 'Interaction', (38, 49))	('variants', 'Var', (66, 74))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))
694669	28046029	We identified that rs1801131 of MTHFR gene in DNA repair pathway was statistically associated with >= 2 RP.	('rs1801131', 'Var', (19, 28))	('MTHFR', 'Gene', (32, 37))	('DNA repair pathway', 'Pathway', (46, 64))	('associated', 'Reg', (83, 93))	('rs1801131', 'Mutation', 'rs1801131', (19, 28))
694707	25431829	Genetic variants and risk of esophageal squamous cell carcinoma: A GWAS-based pathway analysis This study was designed to identify candidate single-nucleotide polymorphisms (SNPs) that may affect the susceptibility to esophageal squamous cell carcinoma (ESCC) and elucidate their potential mechanisms to generate SNP-to-gene-to-pathway hypotheses.	('single-nucleotide polymorphisms', 'Var', (141, 172))	('affect', 'Reg', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (29, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (229, 252))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (218, 252))	('esophageal squamous cell carcinoma', 'Disease', (29, 63))	('esophageal squamous cell carcinoma', 'Disease', (218, 252))
694709	25431829	The three strongest hypothetical biological mechanisms were as follows: rs4135113   TDG   BASE EXCISION REPAIR; rs1800450   MBL2   MONOSACCHARIDE BINDING; and rs3769823   CASP8   d4gdiPathway.	('MBL2', 'Gene', (124, 128))	('CASP8', 'Gene', (171, 176))	('CASP8', 'Gene', '841', (171, 176))	('rs1800450', 'Mutation', 'rs1800450', (112, 121))	('rs1800450', 'Var', (112, 121))	('TDG', 'Gene', '6996', (84, 87))	('rs3769823', 'Mutation', 'rs3769823', (159, 168))	('rs4135113', 'Mutation', 'rs4135113', (72, 81))	('rs4135113', 'Var', (72, 81))	('MONOSACCHARIDE', 'Chemical', 'MESH:D009005', (131, 145))	('MBL2', 'Gene', '4153', (124, 128))	('rs3769823', 'Var', (159, 168))	('TDG', 'Gene', (84, 87))	('BASE EXCISION REPAIR', 'MPA', (90, 110))
694715	25431829	Single nucleotide polymorphisms (SNPs) are highly associated with the risk of ESCC within genes that encode proteins such as P53, PTEN, HIF-1alpha, VEGF, ATM, and survivin.	('P53', 'Gene', '7157', (125, 128))	('VEGF', 'Gene', (148, 152))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('ESCC', 'Disease', (78, 82))	('HIF-1alpha', 'Gene', '3091', (136, 146))	('ATM', 'Gene', (154, 157))	('PTEN', 'Gene', (130, 134))	('VEGF', 'Gene', '7422', (148, 152))	('ATM', 'Gene', '472', (154, 157))	('HIF-1alpha', 'Gene', (136, 146))	('associated', 'Reg', (50, 60))	('PTEN', 'Gene', '5728', (130, 134))	('P53', 'Gene', (125, 128))
694722	25431829	The top four candidate SNPs were rs1800450 [-log10 (p) = 2.218], rs3769823 [-log10 (p) = 2.610], rs3765524 [-log10 (p) = 7.026], and rs2274223 [-log10 (p) = 6.924].	('rs2274223 [', 'Var', (133, 144))	('rs1800450', 'Var', (33, 42))	('rs3769823', 'Mutation', 'rs3769823', (65, 74))	('rs3765524', 'Mutation', 'rs3765524', (97, 106))	('rs3769823', 'Var', (65, 74))	('rs2274223', 'Mutation', 'rs2274223', (133, 142))	('rs3765524', 'Var', (97, 106))	('rs1800450', 'Mutation', 'rs1800450', (33, 42))
694723	25431829	Two of the five candidate SNPs, i.e., rs1800450 and rs3769823, were not in LD with any SNP.	('rs3769823', 'Var', (52, 61))	('rs1800450', 'Mutation', 'rs1800450', (38, 47))	('rs3769823', 'Mutation', 'rs3769823', (52, 61))	('rs1800450', 'Var', (38, 47))
694724	25431829	SNP rs4135113, which was not represented in the original GWAS metaanalysis, was in LD with rs4135054 (r2 = 1.0).	('rs4135054', 'Var', (91, 100))	('rs4135054', 'Mutation', 'rs4135054', (91, 100))	('rs4135113', 'Var', (4, 13))	('rs4135113', 'Mutation', 'rs4135113', (4, 13))
694725	25431829	rs11187870 and rs647126, which were not represented in the original GWAS metaanalysis, were in LD with rs3781264 and rs590336 (r2 = 1.0).	('rs647126', 'Mutation', 'rs647126', (15, 23))	('rs590336', 'Var', (117, 125))	('rs3781264', 'Var', (103, 112))	('rs11187870', 'Var', (0, 10))	('rs590336', 'Mutation', 'rs590336', (117, 125))	('rs11187870', 'Mutation', 'rs11187870', (0, 10))	('rs647126', 'Var', (15, 23))	('rs3781264', 'Mutation', 'rs3781264', (103, 112))
694726	25431829	For instance, the strongest hypothetical biological mechanism involved the role alteration of thymine DNA glycosylase (TDG) by rs4135113 in the pathways of non-synonymous coding (deleterious) in base excision repair (nominal p < 0.001; FDR = 0.002).	('TDG', 'Gene', (119, 122))	('alteration', 'Reg', (80, 90))	('thymine DNA glycosylase', 'Gene', '6996', (94, 117))	('base excision repair', 'MPA', (195, 215))	('TDG', 'Gene', '6996', (119, 122))	('rs4135113', 'Mutation', 'rs4135113', (127, 136))	('thymine DNA glycosylase', 'Gene', (94, 117))	('rs4135113', 'Var', (127, 136))
694727	25431829	The second strongest mechanism involved rs1 800450 in the monosaccharide binding pathway (nominal p < 0.001; FDR = 0.002).	('rs1', 'Var', (40, 43))	('monosaccharide binding pathway', 'Pathway', (58, 88))	('rs1', 'DBSNP_MENTION', 'None', (40, 43))	('monosaccharide', 'Chemical', 'MESH:D009005', (58, 72))
694728	25431829	The third mechanism involved rs3769823 of CASP8 in the D4-GDI signaling pathway (nominal p < 0.001; FDR = 0.002).	('D4-GDI signaling pathway', 'Pathway', (55, 79))	('CASP8', 'Gene', (42, 47))	('CASP8', 'Gene', '841', (42, 47))	('rs3769823', 'Mutation', 'rs3769823', (29, 38))	('rs3769823', 'Var', (29, 38))
694729	25431829	The fourth mechanism involved rs11187870, rs3765524, and rs2274223 of the PLCE1 gene in the lipid bio-synthetic process pathway (nominal p < 0.001; FDR = 0.005).	('PLCE1', 'Gene', (74, 79))	('rs11187870', 'Mutation', 'rs11187870', (30, 40))	('PLCE1', 'Gene', '51196', (74, 79))	('rs3765524', 'Mutation', 'rs3765524', (42, 51))	('rs3765524', 'Var', (42, 51))	('lipid bio-synthetic process pathway', 'Pathway', (92, 127))	('rs2274223', 'Mutation', 'rs2274223', (57, 66))	('rs2274223', 'Var', (57, 66))	('lipid', 'Chemical', 'MESH:D008055', (92, 97))	('rs11187870', 'Var', (30, 40))
694730	25431829	The fifth mechanism involved rs647126 of UCP3 in the respiratory gaseous exchange pathway (nominal p < 0.001; FDR = 0.006, Tables 1-3).	('rs647126', 'Mutation', 'rs647126', (29, 37))	('UCP3', 'Gene', (41, 45))	('rs647126', 'Var', (29, 37))	('respiratory gaseous exchange pathway', 'Pathway', (53, 89))	('UCP3', 'Gene', '7352', (41, 45))
694737	25431829	The most significant SNP-to-gene-to-effect hypothesis was that rs4135113 alters the role of TDG in base excision repair pathway.	('TDG', 'Gene', (92, 95))	('base excision repair pathway', 'Pathway', (99, 127))	('TDG', 'Gene', '6996', (92, 95))	('rs4135113', 'Mutation', 'rs4135113', (63, 72))	('alters', 'Reg', (73, 79))	('rs4135113', 'Var', (63, 72))
694738	25431829	TDG is a glycosylase to correct G/T or G/U mismatches in BER pathway.	('BER pathway', 'Pathway', (57, 68))	('G/U mismatches', 'Var', (39, 53))	('G/T', 'Var', (32, 35))	('TDG', 'Gene', (0, 3))	('TDG', 'Gene', '6996', (0, 3))
694740	25431829	A mutation of TDG will contribute to colorectal cancer based on various analyses.	('TDG', 'Gene', '6996', (14, 17))	('colorectal cancer', 'Disease', (37, 54))	('mutation', 'Var', (2, 10))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('contribute', 'Reg', (23, 33))	('TDG', 'Gene', (14, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))
694741	25431829	As a coactivator, it could promote beta-catenin/TCF transactivation and functionally cooperates with CBP in Wnt signaling, knocking down TDG could inhibit the proliferation of colon cells, which promoted that TDG may contribute to the risk of digestive cancer.	('TCF', 'Gene', '3172', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('proliferation', 'CPA', (159, 172))	('CBP', 'Gene', (101, 104))	('TDG', 'Gene', (209, 212))	('colon cells', 'CPA', (176, 187))	('contribute', 'Reg', (217, 227))	('TDG', 'Gene', '6996', (209, 212))	('TCF', 'Gene', (48, 51))	('TDG', 'Gene', (137, 140))	('cancer', 'Disease', (253, 259))	('TDG', 'Gene', '6996', (137, 140))	('inhibit', 'NegReg', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('beta-catenin', 'Gene', (35, 47))	('beta-catenin', 'Gene', '1499', (35, 47))	('promote', 'PosReg', (27, 34))	('CBP', 'Gene', '1387', (101, 104))	('knocking down', 'Var', (123, 136))
694742	25431829	In a previous GWAS study, TDG SNP (rs4135054) was associated with the risk of ESCC.	('rs4135054', 'Mutation', 'rs4135054', (35, 44))	('ESCC', 'Disease', (78, 82))	('TDG', 'Gene', '6996', (26, 29))	('associated', 'Reg', (50, 60))	('rs4135054', 'Var', (35, 44))	('TDG', 'Gene', (26, 29))
694743	25431829	However, no close linkage between these previously reported SNPs and rs4135054 (TDG) through LD search was found in that study.	('rs4135054', 'Var', (69, 78))	('TDG', 'Gene', (80, 83))	('TDG', 'Gene', '6996', (80, 83))	('rs4135054', 'Mutation', 'rs4135054', (69, 78))
694744	25431829	In the present study, a candidate causal SNP rs4135113 was found using pathway analysis, suggesting that TDG may have an important role in ESCC risk.	('TDG', 'Gene', (105, 108))	('rs4135113', 'Var', (45, 54))	('TDG', 'Gene', '6996', (105, 108))	('rs4135113', 'Mutation', 'rs4135113', (45, 54))	('ESCC', 'Disease', (139, 143))
694745	25431829	The second strongest mechanism involved the modulation of monosaccharide binding that selectively interacts with any monosaccharide by rs1800450, which may alter the expression of Mannan-Binding Lectin 2 (MBL2).	('MBL2', 'Gene', (205, 209))	('rs1800450', 'Var', (135, 144))	('alter', 'Reg', (156, 161))	('monosaccharide', 'Chemical', 'MESH:D009005', (58, 72))	('monosaccharide', 'Chemical', 'MESH:D009005', (117, 131))	('Mannan-Binding Lectin 2', 'Gene', '4153', (180, 203))	('interacts', 'Interaction', (98, 107))	('expression', 'MPA', (166, 176))	('Mannan-Binding Lectin 2', 'Gene', (180, 203))	('rs1800450', 'Mutation', 'rs1800450', (135, 144))	('MBL2', 'Gene', '4153', (205, 209))
694749	25431829	In previous study, rs1800450 was associated with a higher risk of glioma, here we first report that rs1800450 may contribute to the risk of ESCC.	('glioma', 'Disease', (66, 72))	('rs1800450', 'Var', (19, 28))	('contribute', 'Reg', (114, 124))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('rs1800450', 'Mutation', 'rs1800450', (100, 109))	('rs1800450', 'Var', (100, 109))	('rs1800450', 'Mutation', 'rs1800450', (19, 28))
694772	24098650	Notably, ghrelin is a 28-amino acid peptide hormone, produced predominantly by the P/D1 cells of gastric oxyntic gland and is mainly found in the proximal stomach.	('P/D1', 'Var', (83, 87))	('P/D1', 'SUBSTITUTION', 'None', (83, 87))	('ghrelin', 'Chemical', 'MESH:D054439', (9, 16))	('ghrelin', 'Protein', (9, 16))
694791	24098650	The following ICD-O-3 codes were used to categorize the four cancer groups: for esophageal squamous cell carcinoma, topography C15.0- C15.9, and morphology M8070/3; for esophageal adenocarcinoma, topography C15.0- C15.7, and morphology M8140/2, M8140/3; for gastric cardia and esophagogastric junctional cancer topography C16.0 and morphology M8140/2, M8140/3, M8144/3, and M8145/3; for gastric non-cardia cancer topography C16.1- C16.7, and morphology M8140/2, M8140/3, M8144/3, and M8145/3.	('esophageal adenocarcinoma', 'Disease', (169, 194))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (304, 310))	('M8145/3', 'Var', (484, 491))	('gastric non-cardia cancer', 'Disease', 'MESH:D013274', (387, 412))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('gastric cardia', 'Disease', 'MESH:D004938', (258, 272))	('cancer', 'Disease', (406, 412))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('gastric cardia', 'Disease', (258, 272))	('esophageal squamous cell carcinoma', 'Disease', (80, 114))	('M8140/3', 'Var', (462, 469))	('C16.7', 'CellLine', 'CVCL:0H98', (431, 436))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('cancer', 'Disease', (61, 67))	('gastric non-cardia cancer', 'Disease', (387, 412))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('M8144/3', 'Var', (471, 478))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (169, 194))	('cancer', 'Disease', 'MESH:D009369', (406, 412))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (169, 194))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (80, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
694934	32468021	A dual-luciferase reporter assay was also conducted to analyze the interaction between LINC00473 and miR-497-5p, as well as the interaction between CDC25A and miR-497-5p.	('CDC25A', 'Gene', '993', (148, 154))	('interaction', 'Interaction', (128, 139))	('miR-497-5p', 'Chemical', '-', (159, 169))	('interaction', 'Interaction', (67, 78))	('miR-497-5p', 'Chemical', '-', (101, 111))	('LINC00473', 'Gene', '90632', (87, 96))	('miR-497-5p', 'Var', (101, 111))	('CDC25A', 'Gene', (148, 154))	('LINC00473', 'Gene', (87, 96))
694938	32468021	Moreover, transfection with miR-497-5p inhibitors partially alleviated the inhibitory effects of LINC00473 knockdown on cellular proliferation, and partly reversed the sensitivity of cells to X-ray irradiation induced by LINC00473 knockdown.	('knockdown', 'Var', (107, 116))	('LINC00473', 'Gene', (97, 106))	('sensitivity', 'MPA', (168, 179))	('LINC00473', 'Gene', (221, 230))	('miR-497-5p', 'Chemical', '-', (28, 38))	('cellular proliferation', 'CPA', (120, 142))	('inhibitory effects', 'MPA', (75, 93))	('alleviated', 'NegReg', (60, 70))	('reversed', 'Reg', (155, 163))	('LINC00473', 'Gene', '90632', (97, 106))	('LINC00473', 'Gene', '90632', (221, 230))
694939	32468021	Furthermore, it was confirmed that miR-497-5p was able to bind LINC00473 and the 3'-untranslated region of CDC25A.	('LINC00473', 'Gene', (63, 72))	('bind', 'Interaction', (58, 62))	('miR-497-5p', 'Chemical', '-', (35, 45))	('LINC00473', 'Gene', '90632', (63, 72))	('miR-497-5p', 'Var', (35, 45))	('CDC25A', 'Gene', (107, 113))	('CDC25A', 'Gene', '993', (107, 113))
694945	32468021	lncRNAs can be categorized as oncogenes and/or tumor suppressors depending on the specific malignancy, and the aberrant expression of lncRNAs can be used to evaluate the tumorigenesis, progression and relapse of malignant tumors.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('relapse', 'CPA', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('malignant tumors', 'Disease', (212, 228))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('evaluate', 'Reg', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (170, 175))	('malignant tumors', 'Disease', 'MESH:D009369', (212, 228))	('aberrant', 'Var', (111, 119))	('tumor', 'Disease', (222, 227))	('malignancy', 'Disease', 'MESH:D009369', (91, 101))	('progression', 'CPA', (185, 196))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('malignancy', 'Disease', (91, 101))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Disease', (47, 52))
694951	32468021	The abnormal expression of miRs has been closely associated with the development and progression of tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('associated', 'Reg', (49, 59))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))
694974	32468021	The relative expression levels of LINC00473 and miR-497-5p were calculated using the 2-DeltaDeltaCq method.	('LINC00473', 'Gene', '90632', (34, 43))	('miR-497-5p', 'Chemical', '-', (48, 58))	('miR-497-5p', 'Var', (48, 58))	('LINC00473', 'Gene', (34, 43))
694985	32468021	Wild-type (WT) or mutant-type (MUT) LINC00473 was subcloned into a pGL3 Basic vector (Promega Corporation).	('mutant-type', 'Var', (18, 29))	('LINC00473', 'Gene', '90632', (36, 45))	('LINC00473', 'Gene', (36, 45))	('pGL3', 'Gene', (67, 71))	('pGL3', 'Gene', '6391', (67, 71))
694986	32468021	miR-497-5p or miR-NC were co-transfected with WT or MUT reporter vectors into KYSE-30 and TE-5 cells, respectively, using Lipofectamine  3000.	('miR-497-5p', 'Chemical', '-', (0, 10))	('miR-497-5p', 'Var', (0, 10))	('Lipofectamine', 'Chemical', 'MESH:C086724', (122, 135))	('miR-NC', 'Disease', 'OMIM:617025', (14, 20))	('miR-NC', 'Disease', (14, 20))
694988	32468021	RT-qPCR was conducted to determine the association between the expression levels of LINC00473, miR-497-5p and CDC25A mRNA in 46 paired ESCC and adjacent-normal tissue samples.	('LINC00473', 'Gene', '90632', (84, 93))	('LINC00473', 'Gene', (84, 93))	('CDC25A', 'Gene', '993', (110, 116))	('miR-497-5p', 'Chemical', '-', (95, 105))	('CDC25A', 'Gene', (110, 116))	('miR-497-5p', 'Var', (95, 105))	('association', 'Interaction', (39, 50))
694992	32468021	Moreover, miR-497-5p expression negatively correlated with CDC25A expression (Fig.	('expression', 'MPA', (66, 76))	('miR-497-5p', 'Chemical', '-', (10, 20))	('CDC25A', 'Gene', (59, 65))	('negatively', 'NegReg', (32, 42))	('miR-497-5p', 'Var', (10, 20))	('CDC25A', 'Gene', '993', (59, 65))
694994	32468021	These data suggest a possible regulatory association among LINC00473, miR-497-5p and CDC25A.	('CDC25A', 'Gene', (85, 91))	('CDC25A', 'Gene', '993', (85, 91))	('miR-497-5p', 'Chemical', '-', (70, 80))	('LINC00473', 'Gene', '90632', (59, 68))	('miR-497-5p', 'Var', (70, 80))	('LINC00473', 'Gene', (59, 68))
694998	32468021	RT-qPCR was used to quantify the expression levels of LINC00473 and miR-497-5p in 4 ESCC cell lines (KYSE-30, KYSE-150, KYSE-180 and TE-5).	('miR-497-5p', 'Chemical', '-', (68, 78))	('KYSE-30', 'Var', (101, 108))	('miR-497-5p', 'Var', (68, 78))	('LINC00473', 'Gene', (54, 63))	('LINC00473', 'Gene', '90632', (54, 63))
695002	32468021	2C and D), and that following irradiation, the expression of miR-497-5p was markedly suppressed (Fig.	('miR-497-5p', 'Chemical', '-', (61, 71))	('miR-497-5p', 'Var', (61, 71))	('suppressed', 'NegReg', (85, 95))	('expression', 'MPA', (47, 57))
695003	32468021	These results indicated that the expression of LINC00473 and miR-497-5p was inversely affected by X-ray irradiation.	('LINC00473', 'Gene', '90632', (47, 56))	('LINC00473', 'Gene', (47, 56))	('expression', 'MPA', (33, 43))	('miR-497-5p', 'Chemical', '-', (61, 71))	('miR-497-5p', 'Var', (61, 71))
695008	32468021	A colony formation assay was then performed, and the results indicated that LINC00473 overexpression and knockdown increased and decreased the number of colony-forming units, respectively (Fig.	('LINC00473', 'Gene', (76, 85))	('increased', 'PosReg', (115, 124))	('knockdown', 'Var', (105, 114))	('decreased', 'NegReg', (129, 138))	('LINC00473', 'Gene', '90632', (76, 85))
695010	32468021	Bioinformatics analysis (starBase, v2.0, http://starbase.sysu.edu.cn/) predicted miR-497-5p to be a candidate target of LINC00473, and the potential binding site is illustrated in Fig.	('LINC00473', 'Gene', '90632', (120, 129))	('miR-497-5p', 'Chemical', '-', (81, 91))	('LINC00473', 'Gene', (120, 129))	('miR-497-5p', 'Var', (81, 91))
695012	32468021	S1 and S2), miR-497-5p overexpression was shown to markedly decrease the luciferase activity of pGL3-LINC00473-WT, whereas it did not significantly affect that of pGL3-LINC00473-MUT (Fig.	('luciferase', 'Enzyme', (73, 83))	('decrease', 'NegReg', (60, 68))	('LINC00473', 'Gene', (101, 110))	('pGL3', 'Gene', (163, 167))	('pGL3', 'Gene', '6391', (163, 167))	('miR-497-5p overexpression', 'Var', (12, 37))	('pGL3', 'Gene', '6391', (96, 100))	('overexpression', 'Var', (23, 37))	('LINC00473', 'Gene', '90632', (101, 110))	('activity', 'MPA', (84, 92))	('miR-497-5p', 'Chemical', '-', (12, 22))	('LINC00473', 'Gene', '90632', (168, 177))	('pGL3', 'Gene', (96, 100))	('LINC00473', 'Gene', (168, 177))
695014	32468021	The results suggested that compared with the control group, the expression of miR-497-5p was notably inhibited by LINC00473 overexpression and increased by LINC00473 knockdown, respectively (Fig.	('knockdown', 'Var', (166, 175))	('increased', 'PosReg', (143, 152))	('miR-497-5p', 'Chemical', '-', (78, 88))	('expression', 'MPA', (64, 74))	('miR-497-5p', 'Var', (78, 88))	('LINC00473', 'Gene', '90632', (114, 123))	('LINC00473', 'Gene', (114, 123))	('LINC00473', 'Gene', (156, 165))	('inhibited', 'NegReg', (101, 110))	('LINC00473', 'Gene', '90632', (156, 165))	('overexpression', 'PosReg', (124, 138))
695017	32468021	The inhibitory effects of LINC00473 knockdown on ESCC cell viability were weakened by transfection with miR-497-5p inhibitors, while transfection with miR-497-5p mimics attenuated the promoting effects of LINC00473 on cell proliferation (Fig.	('weakened', 'NegReg', (74, 82))	('LINC00473', 'Gene', '90632', (205, 214))	('miR-497-5p', 'Chemical', '-', (151, 161))	('LINC00473', 'Gene', '90632', (26, 35))	('LINC00473', 'Gene', (205, 214))	('attenuated', 'NegReg', (169, 179))	('knockdown', 'Var', (36, 45))	('LINC00473', 'Gene', (26, 35))	('inhibitory effects', 'MPA', (4, 22))	('miR-497-5p', 'Chemical', '-', (104, 114))	('ESCC', 'Disease', (49, 53))	('cell proliferation', 'CPA', (218, 236))
695019	32468021	Collectively, these data indicate that LINC00473 reduces the radiosensitivity of ESCC cells via miR-497-5p.	('reduces', 'NegReg', (49, 56))	('LINC00473', 'Gene', '90632', (39, 48))	('miR-497-5p', 'Chemical', '-', (96, 106))	('miR-497-5p', 'Var', (96, 106))	('LINC00473', 'Gene', (39, 48))	('radiosensitivity', 'CPA', (61, 77))
695020	32468021	TargetScan predicted that CDC25A was one of the candidate target genes for miR-497-5p, and the speculative binding sites are displayed in Fig.	('miR-497-5p', 'Chemical', '-', (75, 85))	('CDC25A', 'Gene', (26, 32))	('CDC25A', 'Gene', '993', (26, 32))	('miR-497-5p', 'Var', (75, 85))
695022	32468021	The results of the luciferase reporter assay indicated that miR-497-5p could specifically bind to the 3'UTR of CDC25A (Fig.	('miR-497-5p', 'Var', (60, 70))	('bind', 'Interaction', (90, 94))	('CDC25A', 'Gene', (111, 117))	('CDC25A', 'Gene', '993', (111, 117))	('miR-497-5p', 'Chemical', '-', (60, 70))
695023	32468021	The results of western blot analysis revealed that the expression of CDC25A was markedly elevated in the KYSE-30 and TE-5 cells following LINC00473 overexpression, but was reduced after LINC00473 was knocked down (Fig.	('LINC00473', 'Gene', '90632', (186, 195))	('LINC00473', 'Gene', (186, 195))	('expression', 'MPA', (55, 65))	('overexpression', 'Var', (148, 162))	('elevated', 'PosReg', (89, 97))	('LINC00473', 'Gene', '90632', (138, 147))	('CDC25A', 'Gene', (69, 75))	('CDC25A', 'Gene', '993', (69, 75))	('LINC00473', 'Gene', (138, 147))
695024	32468021	Additionally, LINC00473 overexpression reversed the inhibitory effect on CDC25A expression induced by miR-497-5p (Fig.	('CDC25A', 'Gene', '993', (73, 79))	('miR-497-5p', 'Chemical', '-', (102, 112))	('miR-497-5p', 'Var', (102, 112))	('expression', 'MPA', (80, 90))	('LINC00473', 'Gene', '90632', (14, 23))	('CDC25A', 'Gene', (73, 79))	('LINC00473', 'Gene', (14, 23))	('inhibitory', 'MPA', (52, 62))
695026	32468021	Collectively, these data confirm that CDC25A is a downstream gene of miR-497-5p, and that its expression is directly and inversely regulated by miR-497-5p, though indirectly and positively modulated by LINC00473.	('miR-497-5p', 'Chemical', '-', (144, 154))	('miR-497-5p', 'Var', (144, 154))	('miR-497-5p', 'Chemical', '-', (69, 79))	('CDC25A', 'Gene', (38, 44))	('CDC25A', 'Gene', '993', (38, 44))	('LINC00473', 'Gene', '90632', (202, 211))	('expression', 'MPA', (94, 104))	('regulated', 'Reg', (131, 140))	('LINC00473', 'Gene', (202, 211))
695047	32468021	In addition, LINC00473 overexpression was shown to inhibit the expression of miR-497-5p, while LINC00473 knockdown increased the expression level of miR-497-5p.	('expression', 'MPA', (129, 139))	('increased', 'PosReg', (115, 124))	('LINC00473', 'Gene', '90632', (95, 104))	('inhibit', 'NegReg', (51, 58))	('knockdown', 'Var', (105, 114))	('expression', 'MPA', (63, 73))	('miR-497-5p', 'Chemical', '-', (149, 159))	('LINC00473', 'Gene', '90632', (13, 22))	('LINC00473', 'Gene', (95, 104))	('LINC00473', 'Gene', (13, 22))	('miR-497-5p', 'Protein', (77, 87))	('miR-497-5p', 'Chemical', '-', (77, 87))
695049	32468021	Furthermore, colony formation assays revealed that miR-497-5p inhibition reverses the enhanced radiosensitivity caused by LINC00473 knockdown.	('knockdown', 'Var', (132, 141))	('reverses', 'NegReg', (73, 81))	('LINC00473', 'Gene', '90632', (122, 131))	('miR-497-5p', 'Chemical', '-', (51, 61))	('enhanced', 'PosReg', (86, 94))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (86, 111))	('miR-497-5p', 'Var', (51, 61))	('LINC00473', 'Gene', (122, 131))	('radiosensitivity', 'CPA', (95, 111))
695052	32468021	For example, miR-339-5p enhances ESCC radiosensitivity by inhibiting CDC25A.	('ESCC', 'Disease', (33, 37))	('miR-339-5p', 'Chemical', '-', (13, 23))	('inhibiting', 'NegReg', (58, 68))	('miR-339-5p', 'Var', (13, 23))	('CDC25A', 'Gene', (69, 75))	('CDC25A', 'Gene', '993', (69, 75))	('enhances', 'PosReg', (24, 32))
695054	32468021	miR-497-5p also decreased the luciferase activity of WT CDC25A, but not the mutant type.	('miR-497-5p', 'Chemical', '-', (0, 10))	('miR-497-5p', 'Var', (0, 10))	('luciferase', 'Enzyme', (30, 40))	('CDC25A', 'Gene', (56, 62))	('CDC25A', 'Gene', '993', (56, 62))	('activity', 'MPA', (41, 49))	('decreased', 'NegReg', (16, 25))
695056	32468021	Hence, CDC25A was concluded to be directly and reversely regulated by miR-497-5p, as well as positively and indirectly by LINC00473.	('LINC00473', 'Gene', '90632', (122, 131))	('miR-497-5p', 'Chemical', '-', (70, 80))	('CDC25A', 'Gene', (7, 13))	('miR-497-5p', 'Var', (70, 80))	('LINC00473', 'Gene', (122, 131))	('CDC25A', 'Gene', '993', (7, 13))
695057	32468021	Although previous studies have reported that LINC000473 in ESCC tissues and cells is significantly upregulated, and the upregulation of LINC00473 indicated radioresistance and a poor prognosis of patients with ESCC, the findings of the present study highlight a unique lncRNA-regulated mechanism in ESCC, namely that LINC00473 facilitates the radioresistance of ESCC cells through miR-497-5p.	('LINC00473', 'Gene', (317, 326))	('upregulated', 'PosReg', (99, 110))	('radioresistance', 'CPA', (343, 358))	('miR-497-5p', 'Chemical', '-', (381, 391))	('LINC00473', 'Gene', '90632', (136, 145))	('patients', 'Species', '9606', (196, 204))	('miR-497-5p', 'Var', (381, 391))	('facilitates', 'PosReg', (327, 338))	('LINC00473', 'Gene', (136, 145))	('ESCC', 'Disease', (299, 303))	('LINC00473', 'Gene', '90632', (317, 326))	('radioresistance', 'CPA', (156, 171))	('LINC000473', 'Var', (45, 55))
695058	32468021	Secondly, more data are required to prove that in ESCC, miR-497-5p regulated the radiosensitivity of cancer cells by suppressing CDC25A.	('radiosensitivity', 'MPA', (81, 97))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('CDC25A', 'Gene', (129, 135))	('cancer', 'Disease', (101, 107))	('regulated', 'Reg', (67, 76))	('suppressing', 'NegReg', (117, 128))	('CDC25A', 'Gene', '993', (129, 135))	('miR-497-5p', 'Chemical', '-', (56, 66))	('miR-497-5p', 'Var', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
695129	31132430	Upon exposure to stresses, KEAP1 is inactivated, mainly by direct modification of cysteine thiol residues, resulting in decreased NRF2 ubiquitination and degradation.	('decreased', 'NegReg', (120, 129))	('KEAP1', 'Gene', '9817', (27, 32))	('cysteine thiol', 'Chemical', '-', (82, 96))	('NRF2', 'Gene', '4780', (130, 134))	('KEAP1', 'Gene', (27, 32))	('degradation', 'MPA', (154, 165))	('ubiquitination', 'MPA', (135, 149))	('NRF2', 'Gene', (130, 134))	('modification', 'Var', (66, 78))	('cysteine', 'Protein', (82, 90))
695181	31132430	The primary antibodies were: anti-NRF2 antibody (Millipore), Anti-KEAP1 antibody (Proteintech), anti-cleaved caspase 3 and caspase 3 antibodies (Cell Signaling), anti-cleaved PARP and PARP antibodies (Cell Signaling), anti-histone H3 antibody, anti-beta-tubulin antibody (Cell Signaling), and anti-beta-actin antibody (Sigma).	('NRF2', 'Gene', (34, 38))	('PARP', 'Gene', '1302', (175, 179))	('caspase 3', 'Gene', '836', (123, 132))	('PARP', 'Gene', (175, 179))	('anti-beta-tubulin', 'Var', (244, 261))	('KEAP1', 'Gene', '9817', (66, 71))	('NRF2', 'Gene', '4780', (34, 38))	('beta-actin', 'Gene', '728378', (298, 308))	('beta-actin', 'Gene', (298, 308))	('KEAP1', 'Gene', (66, 71))	('PARP', 'Gene', '1302', (184, 188))	('anti-histone', 'Var', (218, 230))	('caspase 3', 'Gene', (109, 118))	('anti-cleaved', 'Var', (162, 174))	('PARP', 'Gene', (184, 188))	('caspase 3', 'Gene', (123, 132))	('caspase 3', 'Gene', '836', (109, 118))
695218	31132430	Knockdown of NRF2 led to a significant decrease in NRF2 target genes, HO-1 and GR (Figure 6B).	('HO-1', 'Gene', (70, 74))	('NRF2', 'Gene', (51, 55))	('Knockdown', 'Var', (0, 9))	('decrease', 'NegReg', (39, 47))	('NRF2', 'Gene', '4780', (51, 55))	('HO-1', 'Gene', '3162', (70, 74))	('NRF2', 'Gene', '4780', (13, 17))	('GR', 'Gene', '2936', (79, 81))	('NRF2', 'Gene', (13, 17))
695219	31132430	Treatment of these cells with ABS induced significantly higher intracellular ROS levels than that in control cells, indicating that knockdown of NRF2 sensitized cells to oxidative stress (Figure 6C).	('NRF2', 'Gene', '4780', (145, 149))	('knockdown', 'Var', (132, 141))	('NRF2', 'Gene', (145, 149))	('ABS', 'Chemical', '-', (30, 33))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('higher', 'PosReg', (56, 62))	('intracellular ROS levels', 'MPA', (63, 87))	('sensitized', 'Reg', (150, 160))	('oxidative stress', 'Phenotype', 'HP:0025464', (170, 186))
695220	31132430	Not surprisingly, the oxidative DNA damage level, as measured by positive 8-oxoguanine lesions, was significantly higher in NRF2 knockdown (NRF2 KD) cells, following exposure to ABS, as compared to control cells (Figure 6 D and E).	('ABS', 'Chemical', '-', (178, 181))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (74, 86))	('NRF2', 'Gene', '4780', (124, 128))	('knockdown', 'Var', (129, 138))	('NRF2', 'Gene', (124, 128))	('NRF2', 'Gene', (140, 144))	('NRF2', 'Gene', '4780', (140, 144))	('higher', 'PosReg', (114, 120))	('oxidative DNA damage level', 'MPA', (22, 48))
695221	31132430	Similarly, knockdown of NRF2 sensitized CPB cells to ABS-induced double strand breaks (Figure 6 F and G).	('CPB', 'Gene', (40, 43))	('NRF2', 'Gene', (24, 28))	('double strand breaks', 'MPA', (65, 85))	('sensitized', 'Reg', (29, 39))	('CPB', 'Gene', '1360', (40, 43))	('ABS', 'Chemical', '-', (53, 56))	('NRF2', 'Gene', '4780', (24, 28))	('knockdown', 'Var', (11, 20))
695222	31132430	To further confirm the protective role of NRF2, we reconstituted NRF2 in CPB cells with stable crispr/cas9 NRF2 knockdown.	('NRF2', 'Gene', '4780', (107, 111))	('NRF2', 'Gene', (65, 69))	('CPB', 'Gene', '1360', (73, 76))	('NRF2', 'Gene', (42, 46))	('NRF2', 'Gene', (107, 111))	('knockdown', 'Var', (112, 121))	('NRF2', 'Gene', '4780', (65, 69))	('CPB', 'Gene', (73, 76))	('NRF2', 'Gene', '4780', (42, 46))
695223	31132430	The reconstitution of NRF2 reduced ABS-induced oxidative DNA damage lesions (Supplementary Figure 4).	('reconstitution', 'Var', (4, 18))	('reduced', 'NegReg', (27, 34))	('ABS', 'Chemical', '-', (35, 38))	('damage lesions', 'Disease', (61, 75))	('damage lesions', 'Disease', 'MESH:D007674', (61, 75))	('NRF2', 'Gene', '4780', (22, 26))	('NRF2', 'Gene', (22, 26))
695262	31132430	Activation of NRF2 protected esophageal cells by suppressing ABS-induced ROS levels, oxidative DNA damage, DNA double strand breaks, and apoptosis.	('ABS', 'Chemical', '-', (61, 64))	('NRF2', 'Gene', (14, 18))	('apoptosis', 'CPA', (137, 146))	('DNA double strand breaks', 'MPA', (107, 131))	('ROS', 'Chemical', 'MESH:D017382', (73, 76))	('suppressing', 'NegReg', (49, 60))	('Activation', 'Var', (0, 10))	('NRF2', 'Gene', '4780', (14, 18))	('oxidative DNA damage', 'MPA', (85, 105))
695278	30308939	Hypermethylation of CCND2 in Lung and Breast Cancer Is a Potential Biomarker and Drug Target Lung and breast cancer are the leading causes of mortality in women worldwide.	('women', 'Species', '9606', (155, 160))	('breast cancer', 'Disease', (102, 115))	('Breast Cancer', 'Phenotype', 'HP:0003002', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('Hypermethylation', 'Var', (0, 16))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Breast Cancer', 'Disease', (38, 51))	('CCND2', 'Gene', (20, 25))	('Breast Cancer', 'Disease', 'MESH:D001943', (38, 51))	('Lung', 'Disease', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CCND2', 'Gene', '894', (20, 25))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
695282	30308939	Genome-wide methylation and quantitative methylation-specific real-time polymerase chain reaction (PCR) showed CCND2 promoter hypermethylation in Taiwanese breast cancer patients.	('patients', 'Species', '9606', (170, 178))	('CCND2', 'Gene', '894', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('CCND2', 'Gene', (111, 116))	('hypermethylation', 'Var', (126, 142))
695285	30308939	The cell model assay indicated that CCND2 expression inhibited cancer cell growth and migration ability.	('inhibited', 'NegReg', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('CCND2', 'Gene', (36, 41))	('expression', 'Var', (42, 52))	('migration ability', 'CPA', (86, 103))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('CCND2', 'Gene', '894', (36, 41))	('cancer', 'Disease', (63, 69))
695288	30308939	The discovery of various molecular, genetic and epigenetic alterations that underlie lung cancer and breast cancer has improved the understanding of their tumorigenesis and it has contributed to the development of specifically targeted therapies employing protein overexpression inhibitors and specific mutation inhibitors, such as epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2).	('epidermal growth factor receptor', 'Gene', '1956', (382, 414))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', (155, 160))	('epidermal growth factor receptor 2', 'Gene', '2064', (382, 416))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('epidermal growth factor receptor', 'Gene', (332, 364))	('alterations', 'Var', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('lung cancer', 'Disease', (85, 96))	('epidermal growth factor receptor 2', 'Gene', (382, 416))	('epidermal growth factor receptor', 'Gene', '1956', (332, 364))	('HER2', 'Gene', '2064', (418, 422))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('overexpression', 'PosReg', (264, 278))	('EGFR', 'Gene', (366, 370))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('HER2', 'Gene', (418, 422))	('human', 'Species', '9606', (376, 381))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('EGFR', 'Gene', '1956', (366, 370))
695298	30308939	The CDK4/6 inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression, and its dysregulation is an important contributor to endocrine therapy resistance in breast cancer.	('breast cancer', 'Disease', (197, 210))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('retinoblastoma', 'Phenotype', 'HP:0009919', (36, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('INK4)-retinoblastoma', 'Disease', 'MESH:D012175', (30, 50))	('dysregulation', 'Var', (120, 133))	('contributor', 'Reg', (150, 161))	('CDK4/6', 'Gene', '1019;1021', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cell cycle progression', 'CPA', (88, 110))	('CDK4', 'Gene', '1019', (24, 28))	('Rb', 'Phenotype', 'HP:0009919', (52, 54))	('CDK4', 'Gene', '1019', (4, 8))	('CDK4', 'Gene', (4, 8))	('CDK4', 'Gene', (24, 28))	('CDK4/6', 'Gene', (4, 10))
695299	30308939	However, hypermethylation of the CCND2 gene is common in many cancers, including lung and breast cancer, and it results in low CCND2 expression.	('expression', 'MPA', (133, 143))	('CCND2', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('low', 'NegReg', (123, 126))	('CCND2', 'Gene', '894', (127, 132))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('hypermethylation', 'Var', (9, 25))	('CCND2', 'Gene', '894', (33, 38))	('breast cancer', 'Disease', (90, 103))	('common', 'Reg', (47, 53))	('CCND2', 'Gene', (127, 132))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancers', 'Disease', (62, 69))	('lung', 'Disease', (81, 85))
695300	30308939	CCND2 hypermethylation is significantly more frequent in invasive peripheral lung adenocarcinoma.	('hypermethylation', 'Var', (6, 22))	('invasive peripheral lung adenocarcinoma', 'Disease', (57, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('invasive peripheral lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 96))	('CCND2', 'Gene', (0, 5))	('frequent', 'Reg', (45, 53))	('CCND2', 'Gene', '894', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
695301	30308939	CCND2 hypermethylation, and, therefore, low CCND2 protein expression are associated with a poor prognosis in epithelial ovarian cell cancer and hepatocellular carcinoma recurrence.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (144, 168))	('hypermethylation', 'Var', (6, 22))	('epithelial ovarian cell cancer', 'Phenotype', 'HP:0025318', (109, 139))	('hepatocellular carcinoma', 'Disease', (144, 168))	('low', 'NegReg', (40, 43))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (144, 168))	('CCND2', 'Gene', (44, 49))	('expression', 'MPA', (58, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('epithelial ovarian cell cancer', 'Disease', 'MESH:D000077216', (109, 139))	('CCND2', 'Gene', (0, 5))	('protein', 'Protein', (50, 57))	('epithelial ovarian cell cancer', 'Disease', (109, 139))	('CCND2', 'Gene', '894', (44, 49))	('CCND2', 'Gene', '894', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
695302	30308939	However, no comprehensive study has investigated the clinical significance of CCND2 alterations and its applications and drug discovery.	('CCND2', 'Gene', (78, 83))	('alterations', 'Var', (84, 95))	('CCND2', 'Gene', '894', (78, 83))
695316	30308939	In our previous study, we observed that antroquinonol D could decrease methylation and induce CCND2 expression in breast cancer MDA-MB-231 cells (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CCND2', 'Gene', '894', (94, 99))	('expression', 'MPA', (100, 110))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('methylation', 'MPA', (71, 82))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (128, 138))	('decrease', 'NegReg', (62, 70))	('antroquinonol D', 'Chemical', 'MESH:C545357', (40, 55))	('induce', 'PosReg', (87, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('CCND2', 'Gene', (94, 99))	('antroquinonol D', 'Var', (40, 55))	('breast cancer', 'Disease', (114, 127))
695318	30308939	Reduced CCND2 expression has been reported in various cancers, and the mechanism underlying CCND2 silencing in these cases was aberrant promoter methylation.	('CCND2', 'Gene', (8, 13))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('aberrant', 'Var', (127, 135))	('cancers', 'Disease', (54, 61))	('silencing', 'NegReg', (98, 107))	('CCND2', 'Gene', (92, 97))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('Reduced', 'NegReg', (0, 7))	('expression', 'MPA', (14, 24))	('CCND2', 'Gene', '894', (8, 13))	('CCND2', 'Gene', '894', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('promoter', 'MPA', (136, 144))
695323	30308939	An increase in the methylation level of the CCND2 promoter CpG site cg22678952 when compared with paired adjacent normal tissues was found in Taiwanese breast cancer patients (Figure 2A).	('CCND2', 'Gene', '894', (44, 49))	('CCND2', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('breast cancer', 'Disease', (152, 165))	('methylation level', 'MPA', (19, 36))	('cg22678952', 'Var', (68, 78))	('patients', 'Species', '9606', (166, 174))	('increase', 'PosReg', (3, 11))
695325	30308939	Notably, hypermethylation of CCND2 was associated with female lung cancer and lung adenocarcinoma (Table S3, p < 0.001).	('CCND2', 'Gene', (29, 34))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('lung cancer', 'Disease', (62, 73))	('CCND2', 'Gene', '894', (29, 34))	('hypermethylation', 'Var', (9, 25))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('associated', 'Reg', (39, 49))	('lung adenocarcinoma', 'Disease', (78, 97))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 97))
695326	30308939	Further analysis of the methylation patterns of other cancer types revealed that the CCND2 promoter hypermethylation was significant in breast cancer, lung adenocarcinoma, and liver cancer (Figure 2C,E, Table 1 and Table S4), but not in esophageal and colon cancers (Figure 2F,G and Table 1).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (151, 170))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('breast cancer', 'Disease', (136, 149))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (151, 170))	('esophageal and colon cancers', 'Disease', 'MESH:D004938', (237, 265))	('liver cancer', 'Disease', 'MESH:D006528', (176, 188))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('hypermethylation', 'Var', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', (54, 60))	('liver cancer', 'Phenotype', 'HP:0002896', (176, 188))	('liver cancer', 'Disease', (176, 188))	('cancer', 'Disease', (258, 264))	('colon cancers', 'Phenotype', 'HP:0003003', (252, 265))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lung adenocarcinoma', 'Disease', (151, 170))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('colon cancer', 'Phenotype', 'HP:0003003', (252, 264))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('CCND2', 'Gene', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('significant', 'Reg', (121, 132))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('CCND2', 'Gene', '894', (85, 90))
695328	30308939	In addition, 63.3% of tumors from breast patients with methylated CCND2 were also characterized by low CCND2 mRNA expression (Table 1).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('mRNA expression', 'MPA', (109, 124))	('CCND2', 'Gene', '894', (66, 71))	('CCND2', 'Gene', '894', (103, 108))	('low', 'NegReg', (99, 102))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('patients', 'Species', '9606', (41, 49))	('methylated', 'Var', (55, 65))	('CCND2', 'Gene', (103, 108))	('tumors', 'Disease', (22, 28))	('CCND2', 'Gene', (66, 71))
695331	30308939	Aberrant methylation in the CCND2 promoter was also associated with a poor prognosis in breast cancer and lung cancer using the log-rank test (Figure 3C,D, p = 0.045 and p = 0.022, respectively).	('CCND2', 'Gene', '894', (28, 33))	('lung cancer', 'Disease', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Aberrant methylation', 'Var', (0, 20))	('CCND2', 'Gene', (28, 33))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
695333	30308939	Aberrant methylation in the CCND2 promoter was also associated with a poor prognosis in lung cancer and breast cancer using multivariate Cox proportional hazard model analysis (Table 2, p = 0.039 and p = 0.009).	('CCND2', 'Gene', '894', (28, 33))	('lung cancer', 'Disease', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('breast cancer', 'Disease', (104, 117))	('Aberrant methylation', 'Var', (0, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('CCND2', 'Gene', (28, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
695335	30308939	In conclusion, alterations of CCND2 serve as a therapeutic target for precision medicine in lung cancer and breast cancer.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('CCND2', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('alterations', 'Var', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('CCND2', 'Gene', '894', (30, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))
695340	30308939	The data revealed that the knockdown of CCND2 increased the growth rate and migration ability of H1299 cells by 2.09-fold and 3.53-fold, respectively (Figure 4B).	('knockdown', 'Var', (27, 36))	('H1299', 'CellLine', 'CVCL:0060', (97, 102))	('increased', 'PosReg', (46, 55))	('CCND2', 'Gene', (40, 45))	('migration ability', 'CPA', (76, 93))	('CCND2', 'Gene', '894', (40, 45))	('growth rate', 'CPA', (60, 71))
695345	30308939	In our previous study, antroquinonol D inhibited MDA-MB-231 breast cancer cell growth and induced DNA demethylation, likely through the inhibition of DNA methyltransferase 1 activity.	('breast cancer', 'Disease', (60, 73))	('inhibited', 'NegReg', (39, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('DNA demethylation', 'MPA', (98, 115))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (49, 59))	('antroquinonol', 'Var', (23, 36))	('MDA-MB-231', 'Gene', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('DNA methyltransferase 1', 'Gene', (150, 173))	('induced', 'Reg', (90, 97))	('antroquinonol D', 'Chemical', 'MESH:C545357', (23, 38))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('DNA methyltransferase 1', 'Gene', '1786', (150, 173))
695347	30308939	CCND2 expression was increased by antroquinonol D in CL1-5 cells and by antroquinonol in H1299 cells.	('increased', 'PosReg', (21, 30))	('antroquinonol', 'Chemical', 'MESH:C545357', (72, 85))	('antroquinonol', 'Chemical', 'MESH:C545357', (34, 47))	('antroquinonol', 'Var', (72, 85))	('expression', 'MPA', (6, 16))	('CL1-5', 'Gene', '9201;100862695;23284;100862696', (53, 58))	('CCND2', 'Gene', (0, 5))	('CL1-5', 'Gene', (53, 58))	('antroquinonol D', 'Chemical', 'MESH:C545357', (34, 49))	('CCND2', 'Gene', '894', (0, 5))	('H1299', 'CellLine', 'CVCL:0060', (89, 94))	('antroquinonol', 'Var', (34, 47))
695359	30308939	In our previous study, antroquinonol D inhibited breast cancer cell proliferation and migration without any damage to normal breast cells.	('inhibited', 'NegReg', (39, 48))	('migration', 'CPA', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('antroquinonol', 'Var', (23, 36))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('antroquinonol D', 'Chemical', 'MESH:C545357', (23, 38))
695361	30308939	Antroquinonol led to 50% cell death in CL1-5 at 1.25 microM and 40% cell death in IMR-90 at a high dose of 20 microM (Figure S5).	('Antroquinonol', 'Chemical', 'MESH:C545357', (0, 13))	('IMR-90', 'CellLine', 'CVCL:0347', (82, 88))	('CL1-5', 'Gene', '9201;100862695;23284;100862696', (39, 44))	('Antroquinonol', 'Var', (0, 13))	('CL1-5', 'Gene', (39, 44))
695364	30308939	The data indicated that antroquinonol D induced G1 phase arrest in CL1-5 lung cancer cells in a dose-dependent manner (Figure 6A upper panel) and antroquinonol induced G1 phase arrest in H1299 lung cancer cells in a dose-dependent manner (Figure 6A lower panel).	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('antroquinonol', 'Chemical', 'MESH:C545357', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('G1 phase arrest', 'CPA', (168, 183))	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('antroquinonol D', 'Chemical', 'MESH:C545357', (24, 39))	('CL1-5', 'Gene', '9201;100862695;23284;100862696', (67, 72))	('H1299 lung cancer', 'Disease', (187, 204))	('G1 phase arrest', 'CPA', (48, 63))	('CL1-5', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('lung cancer', 'Disease', (73, 84))	('H1299 lung cancer', 'Disease', 'MESH:D008175', (187, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('antroquinonol', 'Var', (24, 37))	('antroquinonol', 'Chemical', 'MESH:C545357', (24, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))
695369	30308939	Transwell migration assays revealed that antroquinonol D and antroquinonol decreased the migration ability of CL1-5 cells by 92.46% and 73.6%, respectively (Figure 6C).	('antroquinonol D', 'Chemical', 'MESH:C545357', (41, 56))	('CL1-5', 'Gene', (110, 115))	('CL1-5', 'Gene', '9201;100862695;23284;100862696', (110, 115))	('antroquinonol', 'Chemical', 'MESH:C545357', (61, 74))	('antroquinonol', 'Var', (61, 74))	('antroquinonol', 'Chemical', 'MESH:C545357', (41, 54))	('antroquinonol', 'Var', (41, 54))	('decreased', 'NegReg', (75, 84))
695371	30308939	The cell migration ability increased following CCND2 knockdown (Figure 6B,D and Figure S6), and antroquinonol D was found to significantly suppress the migration ability following CCND2 knockdown (Figure 6D).	('knockdown', 'Var', (186, 195))	('increased', 'PosReg', (27, 36))	('antroquinonol D', 'Chemical', 'MESH:C545357', (96, 111))	('knockdown', 'Var', (53, 62))	('CCND2', 'Gene', (47, 52))	('suppress', 'NegReg', (139, 147))	('CCND2', 'Gene', '894', (180, 185))	('cell migration ability', 'CPA', (4, 26))	('migration ability', 'CPA', (152, 169))	('CCND2', 'Gene', '894', (47, 52))	('CCND2', 'Gene', (180, 185))
695373	30308939	Promoter hypermethylation of CCND2 and low CCND2 expression were associated with a poor prognosis, especially in NSCLC and breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('CCND2', 'Gene', (43, 48))	('CCND2', 'Gene', (29, 34))	('low', 'NegReg', (39, 42))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('breast cancer', 'Disease', (123, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('expression', 'MPA', (49, 59))	('patients', 'Species', '9606', (137, 145))	('associated', 'Reg', (65, 75))	('CCND2', 'Gene', '894', (29, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('CCND2', 'Gene', '894', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('NSCLC', 'Disease', (113, 118))	('Promoter hypermethylation', 'Var', (0, 25))
695379	30308939	Mutations or amplifications of CCND2 genes were found in patients with malignant gliomas or hematologic malignancies.	('amplifications', 'Var', (13, 27))	('CCND2', 'Gene', '894', (31, 36))	('patients', 'Species', '9606', (57, 65))	('hematologic malignancies', 'Disease', 'MESH:D019337', (92, 116))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('Mutations', 'Var', (0, 9))	('hematologic malignancies', 'Disease', (92, 116))	('found', 'Reg', (48, 53))	('CCND2', 'Gene', (31, 36))	('malignant gliomas', 'Disease', (71, 88))	('malignant gliomas', 'Disease', 'MESH:D005910', (71, 88))
695380	30308939	Thr280Ala-mutated CCND2 leads to the increased the phosphorylation of retinoblastoma protein, thereby causing significant cell cycle changes and increased proliferation of acute myeloid leukemia cell lines.	('causing', 'Reg', (102, 109))	('retinoblastoma', 'Disease', (70, 84))	('retinoblastoma', 'Disease', 'MESH:D012175', (70, 84))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (172, 194))	('CCND2', 'Gene', '894', (18, 23))	('proliferation', 'CPA', (155, 168))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (172, 194))	('increased', 'PosReg', (145, 154))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (178, 194))	('leukemia', 'Phenotype', 'HP:0001909', (186, 194))	('Thr280Ala', 'Var', (0, 9))	('phosphorylation', 'MPA', (51, 66))	('cell cycle changes', 'CPA', (122, 140))	('increased', 'PosReg', (37, 46))	('CCND2', 'Gene', (18, 23))	('retinoblastoma', 'Phenotype', 'HP:0009919', (70, 84))	('acute myeloid leukemia', 'Disease', (172, 194))	('Thr280Ala', 'SUBSTITUTION', 'None', (0, 9))
695381	30308939	However, promoter hypermethylation of CCND2 is frequent in several solid cancers, such as breast cancer, lung cancer, and liver cancer (Figure 2).	('promoter hypermethylation', 'Var', (9, 34))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('cancers', 'Disease', (73, 80))	('liver cancer', 'Disease', 'MESH:D006528', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('liver cancer', 'Phenotype', 'HP:0002896', (122, 134))	('liver cancer', 'Disease', (122, 134))	('frequent', 'Reg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CCND2', 'Gene', (38, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('CCND2', 'Gene', '894', (38, 43))	('lung cancer', 'Disease', (105, 116))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))
695383	30308939	CCND2 knockdown in H1299 cells induced cell proliferation and metastasis (Figure 4A,B), suggesting that CCND2 may act as a suppressor gene during solid tumor formation.	('CCND2', 'Gene', (104, 109))	('metastasis', 'CPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('CCND2', 'Gene', '894', (104, 109))	('CCND2', 'Gene', '894', (0, 5))	('H1299', 'CellLine', 'CVCL:0060', (19, 24))	('tumor', 'Disease', (152, 157))	('CCND2', 'Gene', (0, 5))	('induced', 'Reg', (31, 38))	('knockdown', 'Var', (6, 15))	('cell proliferation', 'CPA', (39, 57))
695385	30308939	Promoter hypermethylation of CCND2 and low CCND2 expression were also associated with a poor prognosis in overall lung and breast cancer, likely because most lung and breast cancer patients with a poor survival have lung adenocarcinoma and TNBC, respectively.	('breast cancer', 'Disease', (167, 180))	('CCND2', 'Gene', (43, 48))	('patients', 'Species', '9606', (181, 189))	('lung', 'Disease', (114, 118))	('CCND2', 'Gene', '894', (43, 48))	('Promoter hypermethylation', 'Var', (0, 25))	('expression', 'MPA', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('lung adenocarcinoma', 'Disease', (216, 235))	('lung', 'Disease', (158, 162))	('low', 'NegReg', (39, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (216, 235))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('CCND2', 'Gene', (29, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('breast cancer', 'Disease', (123, 136))	('CCND2', 'Gene', '894', (29, 34))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (216, 235))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
695388	30308939	Aberrantly methylated CCND2 has been reported in breast, lung, gastric, and liver cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('CCND2', 'Gene', (22, 27))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('gastric', 'Disease', (63, 70))	('breast', 'Disease', (49, 55))	('liver cancers', 'Phenotype', 'HP:0002896', (76, 89))	('liver cancer', 'Phenotype', 'HP:0002896', (76, 88))	('lung', 'Disease', (57, 61))	('CCND2', 'Gene', '894', (22, 27))	('liver cancers', 'Disease', (76, 89))	('liver cancers', 'Disease', 'MESH:D006528', (76, 89))	('reported', 'Reg', (37, 45))	('Aberrantly methylated', 'Var', (0, 21))
695393	30308939	Additionally, CCND2 hypermethylation was associated with a poor prognosis in breast and lung cancer patients.	('CCND2', 'Gene', '894', (14, 19))	('hypermethylation', 'Var', (20, 36))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (100, 108))	('CCND2', 'Gene', (14, 19))	('breast and lung cancer', 'Disease', 'MESH:D001943', (77, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
695394	30308939	Multivariate Cox proportional hazard model analysis showed that CCND2 expression was also significantly correlated with a poor survival (Table 2).	('poor survival', 'CPA', (122, 135))	('correlated', 'Reg', (104, 114))	('CCND2', 'Gene', (64, 69))	('CCND2', 'Gene', '894', (64, 69))	('expression', 'Var', (70, 80))
695395	30308939	High frequency (63.3%) of breast patients with methylated CCND2 were also characterized by low CCND2 mRNA expression (Table 1).	('methylated', 'Var', (47, 57))	('low', 'NegReg', (91, 94))	('patients', 'Species', '9606', (33, 41))	('CCND2', 'Gene', (95, 100))	('CCND2', 'Gene', (58, 63))	('CCND2', 'Gene', '894', (95, 100))	('CCND2', 'Gene', '894', (58, 63))	('mRNA expression', 'MPA', (101, 116))
695396	30308939	Hypermethylation of CCND2 could be successfully detected in the plasma of breast cancer patients compared with that in healthy persons.	('breast cancer', 'Disease', (74, 87))	('detected', 'Reg', (48, 56))	('Hypermethylation', 'Var', (0, 16))	('persons', 'Species', '9606', (127, 134))	('patients', 'Species', '9606', (88, 96))	('CCND2', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('CCND2', 'Gene', '894', (20, 25))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
695397	30308939	Therefore, aberrant circulating cell-free DNA methylation of CCND2 may serve as a potential early diagnosis marker and poor prognosis marker in the future.	('CCND2', 'Gene', '894', (61, 66))	('CCND2', 'Gene', (61, 66))	('aberrant', 'Var', (11, 19))
695400	30308939	However, whether detecting the aberrant methylation of CCND2 in the blood samples of patients can be applied as a noninvasive analytical method for early diagnosis, prognosis, or precision medicine in breast cancer and lung cancer patients is worth further massive screening and investigation.	('methylation', 'Var', (40, 51))	('patients', 'Species', '9606', (231, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (219, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('lung cancer', 'Disease', (219, 230))	('CCND2', 'Gene', '894', (55, 60))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('aberrant methylation', 'Var', (31, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('lung cancer', 'Disease', 'MESH:D008175', (219, 230))	('breast cancer', 'Disease', (201, 214))	('CCND2', 'Gene', (55, 60))
695404	30308939	Enzyme activity assays and molecular modeling have revealed that antroquinonol D is bound to the catalytic domain of DNMT1 and it competes for the same binding pocket in the DNMT1 enzyme as the cofactor SAM, but it does not compete for the binding pocket in the DNMT3B enzyme.	('DNMT1', 'Gene', '1786', (117, 122))	('antroquinonol D', 'Chemical', 'MESH:C545357', (65, 80))	('competes', 'NegReg', (130, 138))	('binding', 'Interaction', (152, 159))	('DNMT3B', 'Gene', '1789', (262, 268))	('DNMT1', 'Gene', (174, 179))	('DNMT1', 'Gene', '1786', (174, 179))	('DNMT1', 'Gene', (117, 122))	('antroquinonol', 'Var', (65, 78))	('DNMT3B', 'Gene', (262, 268))
695415	30308939	Antroquinonol D induces CCND2 DNA demethylation, recovery of CCND2 expression, cancer cell death, and metastasis inhibition.	('metastasis inhibition', 'CPA', (102, 123))	('Antroquinonol D', 'Chemical', 'MESH:C545357', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CCND2', 'Gene', (61, 66))	('Antroquinonol', 'Var', (0, 13))	('recovery', 'MPA', (49, 57))	('CCND2', 'Gene', (24, 29))	('expression', 'MPA', (67, 77))	('CCND2', 'Gene', '894', (61, 66))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('CCND2', 'Gene', '894', (24, 29))
695416	30308939	Future studies should verify whether antroquinonol or antroquinonol D could be a potential drug for lung cancer or breast cancer patients with hypermethylation of CCND2 or CCND2 low expression and improve the survival rate in these patients.	('CCND2', 'Gene', (163, 168))	('CCND2', 'Gene', '894', (172, 177))	('CCND2', 'Gene', '894', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hypermethylation', 'Var', (143, 159))	('improve', 'PosReg', (197, 204))	('antroquinonol', 'Chemical', 'MESH:C545357', (54, 67))	('lung cancer', 'Disease', (100, 111))	('antroquinonol D', 'Chemical', 'MESH:C545357', (54, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('survival rate', 'CPA', (209, 222))	('expression', 'MPA', (182, 192))	('patients', 'Species', '9606', (129, 137))	('antroquinonol', 'Chemical', 'MESH:C545357', (37, 50))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('breast cancer', 'Disease', (115, 128))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('patients', 'Species', '9606', (232, 240))	('low', 'NegReg', (178, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('CCND2', 'Gene', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
695437	30308939	Pearson's chi-squared test was used to compare lung and breast cancer patients in terms of CCND2 methylation, RNA expression, and other clinical data, including age, gender, tumor type, TNM tumor stage, race, menopause state, and ER, PR, and HER2 status.	('CCND2', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('CCND2', 'Gene', '894', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('breast cancer', 'Disease', (56, 69))	('patients', 'Species', '9606', (70, 78))	('HER2', 'Gene', (242, 246))	('methylation', 'Var', (97, 108))	('menopause state', 'Phenotype', 'HP:0008209', (209, 224))	('TNM tumor', 'Disease', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', (190, 195))	('RNA expression', 'MPA', (110, 124))	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('HER2', 'Gene', '2064', (242, 246))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('TNM tumor', 'Disease', 'MESH:D009369', (186, 195))
695440	30308939	Multivariate Cox proportional hazards regression analyses (adjusted for age, gender, race, tumor subtype, tumor stage, and menopause) were further used to analyze the correlation between CCND2 hypermethylation or CCND2 expression and survival in lung and breast cancer patients.	('CCND2', 'Gene', (187, 192))	('expression', 'MPA', (219, 229))	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('hypermethylation', 'Var', (193, 209))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('breast cancer', 'Disease', (255, 268))	('CCND2', 'Gene', '894', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CCND2', 'Gene', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('lung', 'Disease', (246, 250))	('tumor', 'Disease', (91, 96))	('CCND2', 'Gene', '894', (213, 218))	('patients', 'Species', '9606', (269, 277))	('tumor', 'Disease', (106, 111))
695464	26716915	On propensity score IPTW-adjusted multivariate analysis, IMRT was not associated with EC-specific mortality (HR 0.93, 95%CI 0.80-1.10) or pulmonary mortality (HR 1.11, 95%CI 0.37-3.36) but was significantly associated with lower all-cause mortality (HR 0.83, 95%CI 0.72-0.95), cardiac mortality (HR 0.18, 95%CI 0.06-0.54) and other cause mortality (HR 0.54, 95%CI 0.35-0.84).	('all-cause mortality', 'CPA', (229, 248))	('lower', 'NegReg', (223, 228))	('IMRT', 'Var', (57, 61))	('cardiac mortality', 'CPA', (277, 294))	('IPTW', 'Chemical', '-', (20, 24))
695510	26716915	We found 5FU-based regimen to exert similar protective effects on overall and EC-specific survival, including cardiac mortality, compared to either no-chemotherapy use or non-5FU based regimen.	('5FU', 'Chemical', 'MESH:D005472', (9, 12))	('5FU-based regimen', 'Var', (9, 26))	('EC-specific survival', 'CPA', (78, 98))	('5FU', 'Chemical', 'MESH:D005472', (175, 178))	('cardiac', 'Disease', (110, 117))
695518	26716915	In this population-based analysis of non-metastatic EC patients treated with radiotherapy, we found that the use of IMRT was associated with lower all-cause mortality, cardiac-specific mortality and other-cause mortality, but not cancer-specific and pulmonary mortality.	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('use', 'Var', (109, 112))	('lower', 'NegReg', (141, 146))	('cancer', 'Disease', (230, 236))	('IMRT', 'Gene', (116, 120))	('patients', 'Species', '9606', (55, 63))	('cardiac-specific mortality', 'MPA', (168, 194))	('all-cause mortality', 'MPA', (147, 166))	('other-cause mortality', 'MPA', (199, 220))
695528	26716915	Low dose radiation to the chest for the treatment of lymphoma in young people can greatly increase the risk to the development of future myocardial infarction.	('lymphoma', 'Disease', (53, 61))	('lymphoma', 'Disease', 'MESH:D008223', (53, 61))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('myocardial infarction', 'Phenotype', 'HP:0001658', (137, 158))	('people', 'Species', '9606', (71, 77))	('Low dose', 'Var', (0, 8))	('future myocardial infarction', 'Disease', (130, 158))	('future myocardial infarction', 'Disease', 'MESH:D009203', (130, 158))
695533	26716915	Since V45 significantly predicts for radiation-induced ischemic changes in the heart, patients treated with 3D likely had heart doses that were substantially above this clinically relevant level compared to IMRT.	('ischemic', 'Disease', 'MESH:D007511', (55, 63))	('ischemic', 'Disease', (55, 63))	('V45', 'Var', (6, 9))	('heart', 'MPA', (122, 127))	('predicts', 'Reg', (24, 32))	('patients', 'Species', '9606', (86, 94))
695546	29665050	Silence of HDAC6 suppressed esophageal squamous cell carcinoma proliferation and migration by disrupting chaperone function of HSP90 Esophageal carcinoma is aggressive in nature and its prognosis is largely dependent on the degree of invasion.	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (133, 153))	('Esophageal carcinoma', 'Disease', (133, 153))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (133, 153))	('HSP90', 'Protein', (127, 132))	('HDAC6', 'Gene', '10013', (11, 16))	('HDAC6', 'Gene', (11, 16))	('esophageal squamous cell carcinoma proliferation', 'Disease', 'MESH:D000077277', (28, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('suppressed', 'NegReg', (17, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('disrupting', 'NegReg', (94, 104))	('esophageal squamous cell carcinoma proliferation', 'Disease', (28, 76))	('chaperone function', 'MPA', (105, 123))	('migration', 'CPA', (81, 90))	('Silence', 'Var', (0, 7))
695550	29665050	Consistently, the microtubulin skeleton was stabilized after HDAC6 knockdown or inhibition.	('inhibition', 'NegReg', (80, 90))	('HDAC6', 'Gene', (61, 66))	('knockdown', 'Var', (67, 76))	('stabilized', 'Reg', (44, 54))	('microtubulin skeleton', 'MPA', (18, 39))	('HDAC6', 'Gene', '10013', (61, 66))
695551	29665050	In addition, acetylation status of HSP90, another HDAC6 target, was also increased towards HDAC6 knockdown or inhibition by co-immunoprecipitation assay.	('HDAC6', 'Gene', '10013', (91, 96))	('increased', 'PosReg', (73, 82))	('inhibition', 'NegReg', (110, 120))	('knockdown', 'Var', (97, 106))	('HDAC6', 'Gene', (91, 96))	('HDAC6', 'Gene', (50, 55))	('HSP90', 'Gene', (35, 40))	('HSP90', 'Gene', '3320', (35, 40))	('HDAC6', 'Gene', '10013', (50, 55))	('acetylation status', 'MPA', (13, 31))
695552	29665050	Besides, co-treatment of HSP90 inhibitor (PU-H71) and HDAC6 inhibitor (tubastatin A) induced a stronger cell migration inhibition compared to administration of either drug alone.	('HDAC6', 'Gene', (54, 59))	('stronger', 'PosReg', (95, 103))	('PU-H71', 'Var', (42, 48))	('cell migration', 'CPA', (104, 118))	('HSP90', 'Gene', (25, 30))	('HSP90', 'Gene', '3320', (25, 30))	('tubastatin A', 'Chemical', 'MESH:C553587', (71, 83))	('PU-H71', 'Chemical', 'MESH:C526550', (42, 48))	('HDAC6', 'Gene', '10013', (54, 59))
695562	29665050	HSP90 serves as a molecular chaperone that is crucial for the stability and function of numerous proteins to maintain cellular protein homeostasis and cell survival.7 Likewise, during oncogenesis, HSP90 is crucial for the stability and function of multiple oncogenic proteins that are indispensable for tumor development.8 In esophageal carcinoma, overexpression of HSP90 was observed in ESCC epithelium compared to normal epithelium, and inhibition of HSP90 by its inhibitor 17-AAG could decrease proliferation of esophageal cancer cell in vitro.9 HSP90 is a substrate of HDAC6, inactivation or knockdown of HDAC6 leads to HSP90 hyper-acetylation and loss of HSP90 chaperone activity.10 In human leukemia cells, combination inhibition of HDAC6 and HSP90 show synergistic effect in anticancer activity.11 Thus, drugging HSP90-HDAC6 may be a promising strategy in esophageal cancer.	('HSP90', 'Gene', (366, 371))	('AAG', 'Gene', (479, 482))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', (549, 554))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('HDAC6', 'Gene', (573, 578))	('HSP90', 'Gene', (453, 458))	('HSP90', 'Gene', (660, 665))	('esophageal cancer', 'Disease', (515, 532))	('HSP90', 'Gene', '3320', (820, 825))	('cancer', 'Phenotype', 'HP:0002664', (526, 532))	('esophageal cancer', 'Disease', (863, 880))	('HDAC6', 'Gene', (739, 744))	('HSP90', 'Gene', '3320', (749, 754))	('HDAC6', 'Gene', (826, 831))	('HSP90', 'Gene', '3320', (0, 5))	('HSP90', 'Gene', '3320', (549, 554))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (326, 346))	('HSP90', 'Gene', '3320', (366, 371))	('cancer', 'Disease', (874, 880))	('leukemia', 'Phenotype', 'HP:0001909', (697, 705))	('human', 'Species', '9606', (691, 696))	('HSP90', 'Gene', '3320', (453, 458))	('HSP90', 'Gene', '3320', (660, 665))	('HDAC6', 'Gene', (609, 614))	('cancer', 'Phenotype', 'HP:0002664', (874, 880))	('cancer', 'Disease', 'MESH:D009369', (526, 532))	('cancer', 'Disease', (786, 792))	('HSP90', 'Gene', (197, 202))	('HSP90', 'Gene', (624, 629))	('HDAC6', 'Gene', '10013', (573, 578))	('cancer', 'Phenotype', 'HP:0002664', (786, 792))	('AAG', 'Gene', '4350', (479, 482))	('leukemia', 'Disease', (697, 705))	('tumor', 'Disease', (303, 308))	('leukemia', 'Disease', 'MESH:D007938', (697, 705))	('HDAC6', 'Gene', '10013', (739, 744))	('HDAC6', 'Gene', '10013', (826, 831))	('HSP90', 'Gene', '3320', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('drugging', 'Var', (811, 819))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (326, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (337, 346))	('HSP90', 'Gene', (820, 825))	('cancer', 'Disease', 'MESH:D009369', (874, 880))	('HSP90', 'Gene', '3320', (624, 629))	('HDAC6', 'Gene', '10013', (609, 614))	('cancer', 'Disease', 'MESH:D009369', (786, 792))	('esophageal cancer', 'Disease', 'MESH:D004938', (515, 532))	('cancer', 'Disease', (526, 532))	('HSP90', 'Gene', (749, 754))	('esophageal carcinoma', 'Disease', (326, 346))	('esophageal cancer', 'Disease', 'MESH:D004938', (863, 880))
695564	29665050	Inhibition or knockdown of HDAC6 could greatly inhibited cell proliferation and cell motility in ESCC cell KYSE140 and KYSE180, which may be correlated to an increase of acetylation of alpha-tubulin.	('acetylation', 'MPA', (170, 181))	('increase', 'PosReg', (158, 166))	('inhibited', 'NegReg', (47, 56))	('knockdown', 'Var', (14, 23))	('HDAC6', 'Gene', '10013', (27, 32))	('HDAC6', 'Gene', (27, 32))	('cell motility', 'CPA', (80, 93))	('cell proliferation', 'CPA', (57, 75))	('alpha-tubulin', 'Protein', (185, 198))
695565	29665050	In addition, acetylation level of HSP90 was also increased in response to HDAC6 inhibition, which may indicated that inhibition of HDAC6 could suppress ESCC proliferation and migration by disrupting chaperone function of HSP90.	('acetylation level', 'MPA', (13, 30))	('HDAC6', 'Gene', '10013', (74, 79))	('HSP90', 'Gene', (34, 39))	('increased', 'PosReg', (49, 58))	('disrupting', 'NegReg', (188, 198))	('HSP90', 'Gene', '3320', (34, 39))	('HDAC6', 'Gene', '10013', (131, 136))	('HDAC6', 'Gene', (131, 136))	('inhibition', 'Var', (117, 127))	('HSP90', 'Gene', (221, 226))	('suppress', 'NegReg', (143, 151))	('HSP90', 'Gene', '3320', (221, 226))	('inhibition', 'Var', (80, 90))	('ESCC proliferation', 'CPA', (152, 170))	('HDAC6', 'Gene', (74, 79))	('chaperone function', 'MPA', (199, 217))
695604	29665050	In both KYSE140 and KYSE180 cells, siRNA transfection successfully inhibited HDAC6 expression (Figures 2A and 2B) by qRT-PCR and Western bolt analysis, and HDAC6 silencing dramatically inhibited cell proliferation (Figure 2C).	('HDAC6', 'Gene', '10013', (77, 82))	('HDAC6', 'Gene', (77, 82))	('inhibited', 'NegReg', (67, 76))	('cell proliferation', 'CPA', (195, 213))	('inhibited', 'NegReg', (185, 194))	('transfection', 'Var', (41, 53))	('expression', 'MPA', (83, 93))	('HDAC6', 'Gene', '10013', (156, 161))	('silencing', 'NegReg', (162, 171))	('HDAC6', 'Gene', (156, 161))
695606	29665050	Indeed, HDAC6 silencing greatly reduced cell number invaded through matrigel indicating its role in regulating cell motility capacity (Figure 2D).	('silencing', 'Var', (14, 23))	('reduced', 'NegReg', (32, 39))	('cell motility capacity', 'CPA', (111, 133))	('cell number invaded through matrigel', 'CPA', (40, 76))	('HDAC6', 'Gene', '10013', (8, 13))	('HDAC6', 'Gene', (8, 13))
695608	29665050	Consistently, Tubastatin A administration had positive inhibitory activity on cell proliferation in both KYSE140 and KYSE180 cells (Figure 2E), and evoked a sharp decrease of cell migration in a dose-dependent manner (Figure 2F).	('Tubastatin A', 'Gene', (14, 26))	('inhibitory activity', 'NegReg', (55, 74))	('Tubastatin A', 'Chemical', 'MESH:C553587', (14, 26))	('cell migration', 'CPA', (175, 189))	('decrease', 'NegReg', (163, 171))	('KYSE180', 'Var', (117, 124))	('cell proliferation', 'CPA', (78, 96))
695610	29665050	In KYSE140 and KYSE180 cells, Tubastatin A, and HDAC6 siRNAs triggered an increase of acetylation of alpha-tubulin in a dose dependent manner (Figures 3A and 3B).	('acetylation of alpha-tubulin', 'MPA', (86, 114))	('HDAC6', 'Gene', '10013', (48, 53))	('KYSE180', 'Var', (15, 22))	('HDAC6', 'Gene', (48, 53))	('increase', 'PosReg', (74, 82))	('Tubastatin A', 'Chemical', 'MESH:C553587', (30, 42))
695616	29665050	EGFR is a client protein of HSP90 and highly expressed in the majority of ESCC cells.12 EGFR signaling through PI3K-AKT and MAPK-ERK to exert its oncogene function.13 In KYSE140 and KYSE180 cells, PU-H71, a kind of HSP90 inhibitor, induced a decrease of EGFR protein level.	('HSP90', 'Gene', (215, 220))	('HSP90', 'Gene', '3320', (215, 220))	('ERK', 'Gene', '5594', (129, 132))	('HSP90', 'Gene', (28, 33))	('HSP90', 'Gene', '3320', (28, 33))	('PU-H71', 'Chemical', 'MESH:C526550', (197, 203))	('ERK', 'Gene', (129, 132))	('PU-H71', 'Var', (197, 203))	('EGFR protein level', 'MPA', (254, 272))	('decrease', 'NegReg', (242, 250))
695617	29665050	Correspondingly, phosphorylation level of AKT and ERK were also decreased in PU-H71-treated cells compared with control group (Figures 5A and 5B).	('ERK', 'Gene', '5594', (50, 53))	('ERK', 'Gene', (50, 53))	('phosphorylation level', 'MPA', (17, 38))	('PU-H71-treated', 'Var', (77, 91))	('PU-H71', 'Chemical', 'MESH:C526550', (77, 83))	('AKT', 'Pathway', (42, 45))	('decreased', 'NegReg', (64, 73))
695620	29665050	In KYSE140 and KYSE180 cells, combination of Tubastatin A and PU-H71 significantly reduced cell proliferation and migration in comparison with treatment of either inhibitor alone (Figures 6A and 6B).	('Tubastatin A', 'Gene', (45, 57))	('reduced', 'NegReg', (83, 90))	('PU-H71', 'Chemical', 'MESH:C526550', (62, 68))	('PU-H71', 'Gene', (62, 68))	('combination', 'Var', (30, 41))	('cell proliferation', 'CPA', (91, 109))	('Tubastatin A', 'Chemical', 'MESH:C553587', (45, 57))
695621	29665050	Consistently, cells treated with both Tubastatin A and PU-H71 exhibited lowest protein level of EGFR, phospho-AKT, and phospho-ERK in comparison with Tubastatin A or PU-H71 treatment alone (Figure 6C).	('Tubastatin A', 'Chemical', 'MESH:C553587', (38, 50))	('protein level', 'MPA', (79, 92))	('PU-H71', 'Chemical', 'MESH:C526550', (55, 61))	('PU-H71', 'Chemical', 'MESH:C526550', (166, 172))	('ERK', 'Gene', '5594', (127, 130))	('PU-H71', 'Var', (55, 61))	('EGFR', 'MPA', (96, 100))	('Tubastatin A', 'Chemical', 'MESH:C553587', (150, 162))	('ERK', 'Gene', (127, 130))	('lowest', 'NegReg', (72, 78))	('phospho-AKT', 'MPA', (102, 113))
695623	29665050	The tumor growth of KYSE140 cells was significantly suppressed in all groups treated with inhibitors compared to control group.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('suppressed', 'NegReg', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('inhibitors', 'Var', (90, 100))
695625	29665050	Consistently, the mice treat with Tubastatin A and PU-H71 exhibited lowest protein level of EGFR, phospho-AKT, and phospho-ERK in comparison with Tubastatin A or PU-H71 treatment alone in tumors (Figure 7C).	('phospho-AKT', 'MPA', (98, 109))	('PU-H71', 'Chemical', 'MESH:C526550', (51, 57))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('Tubastatin A', 'Chemical', 'MESH:C553587', (146, 158))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('ERK', 'Gene', '5594', (123, 126))	('mice', 'Species', '10090', (18, 22))	('lowest', 'NegReg', (68, 74))	('PU-H71', 'Var', (51, 57))	('PU-H71', 'Chemical', 'MESH:C526550', (162, 168))	('EGFR', 'Protein', (92, 96))	('ERK', 'Gene', (123, 126))	('protein level', 'MPA', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Tubastatin A', 'Chemical', 'MESH:C553587', (34, 46))
695640	29665050	Protein level of EGFR, phospho-AKT, and phospho-ERK were downregulated toward PU-H71 or Tubastatin A treatment and to a large extent towards combination treatment of PU-H71 and Tubastatin A.	('PU-H71', 'Var', (78, 84))	('ERK', 'Gene', (48, 51))	('downregulated', 'NegReg', (57, 70))	('Protein level', 'MPA', (0, 13))	('PU-H71', 'Chemical', 'MESH:C526550', (166, 172))	('phospho-AKT', 'MPA', (23, 34))	('Tubastatin A', 'Chemical', 'MESH:C553587', (177, 189))	('Tubastatin A', 'Chemical', 'MESH:C553587', (88, 100))	('PU-H71', 'Chemical', 'MESH:C526550', (78, 84))	('ERK', 'Gene', '5594', (48, 51))
695674	28985034	Tissue sections (4 mum thick) were obtained from paraffin blocks and stained with hematoxylin & eosin or with anti-CD34 (monoclonal rabbit EP373Y; Abcam, Cambridge, UK), aAnti-CD31 (mouse monoclonal cloneJc70A; DakoDenmark A/S, Glostrup, Denmark), or anti-VEGF (rabbit polyclonal to VEGFA; Abcam) and then counterstained with hematoxylin.	('rabbit', 'Species', '9986', (262, 268))	('VEGFA', 'Gene', '7422', (283, 288))	('eosin', 'Chemical', 'MESH:D004801', (96, 101))	('mum', 'Gene', '56925', (19, 22))	('hematoxylin', 'Chemical', 'MESH:D006416', (326, 337))	('paraffin', 'Chemical', 'MESH:D010232', (49, 57))	('rabbit', 'Species', '9986', (132, 138))	('hematoxylin', 'Chemical', 'MESH:D006416', (82, 93))	('mouse', 'Species', '10090', (182, 187))	('VEGFA', 'Gene', (283, 288))	('mum', 'Gene', (19, 22))	('with', 'Var', (105, 109))
695688	28985034	Formalin-fixed adipose tissue samples were paraffin-embedded and serial sections were immunostained with anti-human CD34 (clone QBEnd-10; DakoDenmark A/S), anti-human CD45 and anti-human CD31 (both from Abcam) according to the manufacturer's instructions.	('human', 'Species', '9606', (161, 166))	('anti-human', 'Var', (105, 115))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('human', 'Species', '9606', (181, 186))	('CD45', 'Gene', '5788', (167, 171))	('CD34', 'Gene', (116, 120))	('anti-human', 'Var', (176, 186))	('CD45', 'Gene', (167, 171))	('human', 'Species', '9606', (110, 115))	('CD31', 'Protein', (187, 191))	('paraffin', 'Chemical', 'MESH:D010232', (43, 51))	('anti-human', 'Var', (156, 166))
695721	28985034	We measured the expression of CD34, NSTM, CD90 and OCT-4 in peritumoral adipose tissue of EAC patients and we observed a significantly decreased mRNA expression of CD34, CD90 and NSTM in patients treated with neoadjuvant therapy, in comparison with patients who did not receive neoadjuvant treatment (Fig.	('NSTM', 'Gene', '26354', (179, 183))	('mRNA expression', 'MPA', (145, 160))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (94, 102))	('CD90', 'Gene', (170, 174))	('decreased', 'NegReg', (135, 144))	('expression', 'MPA', (16, 26))	('OCT-4', 'Gene', '5460', (51, 56))	('NSTM', 'Gene', (36, 40))	('CD90', 'Gene', (42, 46))	('patients', 'Species', '9606', (249, 257))	('CD90', 'Gene', '7070', (170, 174))	('NSTM', 'Gene', (179, 183))	('OCT-4', 'Gene', (51, 56))	('CD90', 'Gene', '7070', (42, 46))	('peritumoral', 'Chemical', '-', (60, 71))	('CD34', 'Gene', (30, 34))	('CD34', 'Var', (164, 168))	('NSTM', 'Gene', '26354', (36, 40))
695734	28985034	After 48 h of treatment with CM, the population of CD34+/CD45-/CD31- cells was significantly higher in cells treated with peritumoral adipose tissue CM in comparison with cells treated with omental adipose tissue CM or untreated control cells (Fig.	('higher', 'PosReg', (93, 99))	('CD45', 'Gene', '5788', (57, 61))	('peritumoral adipose tissue CM', 'Var', (122, 151))	('peritumoral', 'Chemical', '-', (122, 133))	('CD45', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
695802	29137232	Individual miRNAs can inhibit multiple target genes or entire signaling pathways, including cell proliferation, differentiation, and apoptosis.	('apoptosis', 'CPA', (133, 142))	('inhibit', 'NegReg', (22, 29))	('entire signaling pathways', 'Pathway', (55, 80))	('miRNAs', 'Var', (11, 17))	('cell proliferation', 'CPA', (92, 110))	('differentiation', 'CPA', (112, 127))	('rat', 'Species', '10116', (104, 107))
695859	29137232	This result is consistent with reports that miR-143 is an essential regulator of cancer glycolysis by targeting HK2 in cancer cells, including lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, and colon cancer cells.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (156, 193))	('lung cancer', 'Disease', (143, 154))	('miR-143', 'Var', (44, 51))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('renal cell carcinoma', 'Disease', (195, 215))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (195, 215))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', (119, 125))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('neck squamous cell carcinoma', 'Disease', (165, 193))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (165, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', (148, 154))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (195, 215))	('targeting', 'Reg', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('HK2', 'Protein', (112, 115))
695893	29137232	Moreover, we showed that miR-143 regulates cancer glycolysis in ZD-induced esophageal neoplasia by targeting HK2 (Figure 3), a result consistent with reports for lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, breast cancer, and prostate cancer.	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('cancer', 'Disease', (167, 173))	('HK2', 'Protein', (109, 112))	('ZD', 'Chemical', '-', (64, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (264, 270))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (75, 95))	('prostate cancer', 'Disease', 'MESH:D011471', (255, 270))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (175, 195))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (255, 270))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('targeting', 'Reg', (99, 108))	('neck squamous cell carcinoma', 'Disease', (206, 234))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (206, 234))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('prostate cancer', 'Disease', (255, 270))	('miR-143', 'Var', (25, 32))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('regulates', 'Reg', (33, 42))	('breast cancer', 'Disease', (236, 249))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('renal cell carcinoma', 'Disease', (175, 195))	('lung cancer', 'Disease', (162, 173))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (175, 195))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (197, 234))	('cancer', 'Disease', (43, 49))	('esophageal neoplasia', 'Disease', (75, 95))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (75, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('cancer', 'Disease', (243, 249))	('neoplasia', 'Phenotype', 'HP:0002664', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('ZD-induced', 'Disease', (64, 74))
696078	27416981	The following data were collected from each study: First author's name, publication year, country, tumor type, sample size, true positive (TP), false positive (FP), false negative (FN), true negative (TN), sensitivity, and specificity.	('tumor', 'Disease', (99, 104))	('false', 'Var', (165, 170))	('false', 'Var', (144, 149))	('true', 'Var', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
696132	25859432	Recent reports, however, have identified specific epigenetic and genetic alterations in EBV-associated GC, which might lead to a distinct treatment approach for this specific subtype of GC in the future.	('lead to', 'Reg', (119, 126))	('EBV-associated GC', 'Gene', (88, 105))	('EBV', 'Species', '10376', (88, 91))	('epigenetic', 'Var', (50, 60))	('genetic alterations', 'Var', (65, 84))
696136	25859432	In this particular histological subtype, the prevalence of EBV positivity is observed in more than 90% of cases.	('EBV', 'Species', '10376', (59, 62))	('positivity', 'Var', (63, 73))	('EBV', 'Gene', (59, 62))
696172	25859432	In the present study, we observed EBV positivity determined by EBER in situ hybridization in 14/465 cases of upper gastrointestinal adenocarcinomas in total.	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('positivity', 'Var', (38, 48))	('EBV', 'Gene', (34, 37))	('upper gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (109, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('upper gastrointestinal adenocarcinomas', 'Disease', (109, 147))	('EBV', 'Species', '10376', (34, 37))
696180	25859432	However, we also observed one case with lymphoepithelioma-like morphology and EBER positivity in the accompanying lymphocytic infiltrate but not in the carcinoma cells.	('EBER positivity', 'Var', (78, 93))	('carcinoma', 'Disease', 'MESH:D002277', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('carcinoma', 'Disease', (152, 161))	('lymphoepithelioma', 'Disease', 'None', (40, 57))	('lymphoepithelioma', 'Disease', (40, 57))
696191	25859432	Epstein-Barr virus-associated tumors are strongly correlated with methylation of CpG islands in the promoter region of cancer-related genes as well as with genome-wide hypermethylation, whereas microsatellite instable (MSI) tumors show other hypermethylation patterns, suggesting a different mechanism leading to epigenetic dysregulation in EBV and MSI tumors.	('Epstein-Barr virus', 'Species', '10376', (0, 18))	('MSI tumors', 'Disease', (349, 359))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', 'MESH:D009369', (353, 359))	('tumors', 'Disease', (224, 230))	('EBV', 'Species', '10376', (341, 344))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('CpG', 'Gene', (81, 84))	('correlated', 'Reg', (50, 60))	('cancer', 'Disease', (119, 125))	('MSI tumors', 'Disease', 'MESH:D009369', (349, 359))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (353, 359))	('tumors', 'Disease', (30, 36))	('methylation', 'Var', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Disease', (353, 359))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('MSI) tumors', 'Disease', 'MESH:D009369', (219, 230))
696192	25859432	This assumption is supported by the fact that EBV positivity in GC has been shown to be mutually exclusive to loss of MLH1 expression and MSI.	('loss', 'NegReg', (110, 114))	('expression', 'MPA', (123, 133))	('MSI', 'Disease', 'None', (138, 141))	('EBV', 'Species', '10376', (46, 49))	('MSI', 'Disease', (138, 141))	('positivity', 'Var', (50, 60))	('MLH1', 'Gene', '4292', (118, 122))	('MLH1', 'Gene', (118, 122))
696195	25859432	Furthermore, the authors confirm the epigenetic differences between EBV-associated and MSI GC.	('epigenetic differences', 'Var', (37, 59))	('MSI', 'Disease', 'None', (87, 90))	('EBV', 'Species', '10376', (68, 71))	('MSI', 'Disease', (87, 90))	('EBV-associated', 'Gene', (68, 82))
696197	25859432	EBV positive carcinomas show recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274, and PDCD1LG2.	('carcinomas', 'Disease', 'MESH:D002277', (13, 23))	('CD274', 'Gene', (114, 119))	('JAK2', 'Gene', (108, 112))	('mutations', 'Var', (46, 55))	('amplification', 'Var', (91, 104))	('EBV', 'Species', '10376', (0, 3))	('PDCD1LG2', 'Gene', (125, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('PIK3CA', 'Gene', (39, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (13, 23))	('carcinomas', 'Disease', (13, 23))
696198	25859432	Aberrations of the latter molecules (also known as PD-L1 and PD-L2) may not only serve for a molecular genetic classification but also as specific targets for immunotherapy.	('PD-L1', 'Gene', '29126', (51, 56))	('PD-L2', 'Gene', (61, 66))	('PD-L2', 'Gene', '80380', (61, 66))	('Aberrations', 'Var', (0, 11))	('PD-L1', 'Gene', (51, 56))
696208	25859432	EBV positivity was further associated with lower mortality rate when adjusted for stage and other confounders.	('mortality rate', 'MPA', (49, 63))	('positivity', 'Var', (4, 14))	('EBV', 'Gene', (0, 3))	('EBV', 'Species', '10376', (0, 3))	('lower', 'NegReg', (43, 48))
696216	25859432	Most recent reports, however, identified different genetic and epigenetic alterations in EBV-associated GC compared to viral negative GC.	('EBV-associated GC', 'Disease', (89, 106))	('EBV', 'Species', '10376', (89, 92))	('epigenetic alterations', 'Var', (63, 85))
696225	25218668	The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs - 14.7% among subjects given placebo; 1-sided P=.80).	('S6K1', 'Gene', (39, 43))	('metformin', 'Var', (115, 124))	('S6K1', 'Gene', '6198', (39, 43))	('metformin', 'Chemical', 'MESH:D008687', (115, 124))
696226	25218668	Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P=.08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P=.06).	('men', 'Species', '9606', (224, 227))	('insulin', 'Gene', (81, 88))	('metformin', 'Chemical', 'MESH:D008687', (287, 296))	('insulin', 'Gene', '3630', (81, 88))	('Metformin', 'Var', (0, 9))	('insulin', 'Gene', (233, 240))	('metformin', 'Var', (124, 133))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('insulin', 'Gene', '3630', (233, 240))	('insulin resistance', 'Phenotype', 'HP:0000855', (233, 251))	('homeostatic model assessments', 'MPA', (200, 229))	('metformin', 'Chemical', 'MESH:D008687', (124, 133))	('reduction', 'NegReg', (52, 61))
696229	25218668	Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues.	('metformin', 'Chemical', 'MESH:D008687', (9, 18))	('insulin resistance', 'Phenotype', 'HP:0000855', (55, 73))	('insulin', 'Gene', (43, 50))	('insulin', 'Gene', '3630', (43, 50))	('insulin', 'Gene', (55, 62))	('reduced', 'NegReg', (19, 26))	('metformin', 'Var', (9, 18))	('insulin', 'Gene', '3630', (55, 62))
696244	25218668	Metformin also has AMPK-independent, indirect anti-proliferative effects related to lower systemic levels of insulin.	('insulin', 'Gene', (109, 116))	('insulin', 'Gene', '3630', (109, 116))	('Metformin', 'Var', (0, 9))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('lower', 'NegReg', (84, 89))	('anti-proliferative', 'NegReg', (46, 64))
696256	25218668	General exclusion criteria were: history of confirmed esophageal high-grade dysplasia, esophageal carcinoma or any cancer; vitamin B12 deficiency; history of lactic acidosis; medication for weight loss <=2 months prior to enrollment; treatment with other oral hypoglycemia agents or biguanides; receipt of other investigational agents <=3 months prior to enrollment; history of allergic reactions attributed to compounds of similar composition to the study agent; elective surgery during the study period; genetic disorders such as family history of hereditary gastrointestinal polyp disorder; or comorbidities that might limit adherence to the study protocol.	('lactic acidosis', 'Disease', (158, 173))	('dysplasia', 'Disease', (76, 85))	('dysplasia', 'Disease', 'MESH:D004476', (76, 85))	('genetic disorders', 'Disease', 'MESH:D030342', (506, 523))	('allergic reactions', 'Disease', 'MESH:D004342', (378, 396))	('esophageal carcinoma', 'Disease', (87, 107))	('bid', 'Gene', (602, 605))	('hereditary gastrointestinal polyp disorder', 'Disease', (550, 592))	('men', 'Species', '9606', (361, 364))	('bid', 'Gene', '637', (602, 605))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('genetic disorders', 'Disease', (506, 523))	('oral hypoglycemia', 'Disease', (255, 272))	('vitamin B12', 'Gene', (123, 134))	('allergic reactions', 'Phenotype', 'HP:0012393', (378, 396))	('hypoglycemia', 'Phenotype', 'HP:0001943', (260, 272))	('men', 'Species', '9606', (239, 242))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('acidosis', 'Phenotype', 'HP:0001941', (165, 173))	('lactic acidosis', 'Phenotype', 'HP:0003128', (158, 173))	('oral hypoglycemia', 'Disease', 'MESH:D007003', (255, 272))	('weight loss', 'Disease', 'MESH:D015431', (190, 201))	('allergic reactions', 'Disease', (378, 396))	('men', 'Species', '9606', (228, 231))	('hereditary gastrointestinal polyp disorder', 'Disease', 'MESH:D011127', (550, 592))	('vitamin B12 deficiency', 'Phenotype', 'HP:0100502', (123, 145))	('weight loss', 'Phenotype', 'HP:0001824', (190, 201))	('cancer', 'Disease', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('biguanide', 'Chemical', 'MESH:D001645', (283, 292))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('lactic acidosis', 'Disease', 'MESH:D000140', (158, 173))	('gastrointestinal polyp', 'Phenotype', 'HP:0200008', (561, 583))	('deficiency', 'Var', (135, 145))	('weight loss', 'Disease', (190, 201))
696275	25218668	The null hypothesis for this study was that the percent change (%Delta) in mean pS6K1 values (from baseline to post-intervention) would be the same or increased for the metformin arm as compared to the placebo arm.	('S6K1', 'Gene', (81, 85))	('increased', 'PosReg', (151, 160))	('S6K1', 'Gene', '6198', (81, 85))	('metformin', 'Var', (169, 178))	('metformin', 'Chemical', 'MESH:D008687', (169, 178))
696276	25218668	The alternative hypothesis was that the percent change in mean pS6K1 values would be decreased in the metformin arm as compared to placebo.	('S6K1', 'Gene', (64, 68))	('metformin', 'Var', (102, 111))	('decreased', 'NegReg', (85, 94))	('metformin', 'Chemical', 'MESH:D008687', (102, 111))	('S6K1', 'Gene', '6198', (64, 68))
696277	25218668	We estimated that the standard deviation for the distribution of %Delta in pS6K1 would be approximately the range of possible values (i.e.	('S6K1', 'Gene', '6198', (76, 80))	('%Delta', 'Var', (65, 71))	('S6K1', 'Gene', (76, 80))
696286	25218668	Intervention arms were evenly balanced at baseline with respect to all factors (Table 1) including sex (p=1.00), length of BE segment (p=1.00), age (p=0.43), BMI (p=0.58), smoking history (p=0.73), NSAID use (p=1.00), and dysplasia status (p=0.57) in the 74 randomized participants who also received study drug (38 metformin; 36 placebo).	('metformin', 'Var', (315, 324))	('dysplasia status', 'Disease', (222, 238))	('metformin', 'Chemical', 'MESH:D008687', (315, 324))	('men', 'Species', '9606', (129, 132))	('participants', 'Species', '9606', (269, 281))	('dysplasia status', 'Disease', 'MESH:D013226', (222, 238))
696288	25218668	The observed overall adverse event (AE) rates were higher for the metformin participants, but none of the differences reached statistical significance (Table 1).	('metformin', 'Chemical', 'MESH:D008687', (66, 75))	('metformin', 'Var', (66, 75))	('adverse event', 'MPA', (21, 34))	('higher', 'PosReg', (51, 57))	('participants', 'Species', '9606', (76, 88))
696293	25218668	When pooling across grades due to the small numbers, metformin treated subjects had a significantly higher rate of grade 1/2 abdominal pain compared to placebo (16% vs. 0%; p=0.025).	('pain', 'Phenotype', 'HP:0012531', (135, 139))	('metformin', 'Chemical', 'MESH:D008687', (53, 62))	('abdominal pain', 'Phenotype', 'HP:0002027', (125, 139))	('abdominal pain', 'Disease', (125, 139))	('abdominal pain', 'Disease', 'MESH:D015746', (125, 139))	('metformin', 'Var', (53, 62))
696304	25218668	Specifically, the median percent change from baseline in pS6K1 values was 1.4% for metformin compared to a decrease of 14.7% in placebo treated participants (Table 2).	('S6K1', 'Gene', (58, 62))	('S6K1', 'Gene', '6198', (58, 62))	('metformin', 'Var', (83, 92))	('participants', 'Species', '9606', (144, 156))	('metformin', 'Chemical', 'MESH:D008687', (83, 92))
696307	25218668	However, metformin had no discernible effects on levels of phosphorylation of S6Kinase1, the intracellular mediator of insulin and IGF activation in Barrett's epithelium, compared to placebo.	('levels', 'MPA', (49, 55))	('metformin', 'Chemical', 'MESH:D008687', (9, 18))	('insulin', 'Gene', (119, 126))	('S6Kinase1', 'Protein', (78, 87))	('phosphorylation', 'MPA', (59, 74))	('insulin', 'Gene', '3630', (119, 126))	('metformin', 'Var', (9, 18))
696339	25337547	Recent high impact studies dealing with EPA and DHA have sparked a renewed interest in using n-3 PUFAs for cancer prevention and cancer treatment, for which n-3 PUFAs may exert their anticancer actions by influencing multiple targets implicated in various stages of cancer development, including cell proliferation, cell survival, angiogenesis, inflammation, and metastasis against various cancers.	('n', 'Chemical', 'MESH:D009584', (69, 70))	('n', 'Chemical', 'MESH:D009584', (211, 212))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('n', 'Chemical', 'MESH:D009584', (360, 361))	('cancer', 'Disease', (129, 135))	('cell proliferation', 'CPA', (296, 314))	('DHA', 'Chemical', 'MESH:D004281', (48, 51))	('n-3', 'Var', (157, 160))	('men', 'Species', '9606', (280, 283))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (184, 185))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancers', 'Phenotype', 'HP:0002664', (390, 397))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('n', 'Chemical', 'MESH:D009584', (287, 288))	('inflammation', 'Disease', 'MESH:D007249', (345, 357))	('cancers', 'Disease', (390, 397))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (390, 396))	('n', 'Chemical', 'MESH:D009584', (199, 200))	('rat', 'Species', '10116', (308, 311))	('metastasis', 'CPA', (363, 373))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('n', 'Chemical', 'MESH:D009584', (338, 339))	('men', 'Species', '9606', (141, 144))	('n', 'Chemical', 'MESH:D009584', (214, 215))	('n', 'Chemical', 'MESH:D009584', (332, 333))	('inflammation', 'Disease', (345, 357))	('n', 'Chemical', 'MESH:D009584', (246, 247))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (356, 357))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (189, 190))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('n', 'Chemical', 'MESH:D009584', (268, 269))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('n-3 PUFAs', 'Chemical', 'MESH:D015525', (157, 166))	('n', 'Chemical', 'MESH:D009584', (206, 207))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('cancer', 'Disease', (107, 113))	('n', 'Chemical', 'MESH:D009584', (293, 294))	('n-3 PUFAs', 'Chemical', 'MESH:D015525', (93, 102))	('angiogenesis', 'CPA', (331, 343))	('n', 'Chemical', 'MESH:D009584', (346, 347))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('cancer', 'Disease', (187, 193))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('cancer', 'Disease', (266, 272))	('cell survival', 'CPA', (316, 329))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('cancers', 'Disease', 'MESH:D009369', (390, 397))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('cancer', 'Disease', 'MESH:D009369', (390, 396))	('n', 'Chemical', 'MESH:D009584', (378, 379))	('influencing', 'Reg', (205, 216))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('EPA', 'Chemical', 'MESH:D015118', (40, 43))	('n', 'Chemical', 'MESH:D009584', (313, 314))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (282, 283))	('n', 'Chemical', 'MESH:D009584', (392, 393))	('n', 'Chemical', 'MESH:D009584', (131, 132))
696348	25337547	Among the FAs, Omega-3 polyunsaturated fatty acids (n-3 PUFA) and omega-6 polyunsaturated fatty acids (n-6 PUFA) have been suggested to decrease and increase several human diseases, respectively.	('human diseases', 'Disease', (166, 180))	('PUFA', 'Gene', '9933', (56, 60))	('n', 'Chemical', 'MESH:D009584', (3, 4))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('PUFA', 'Gene', (107, 111))	('Omega-3 polyunsaturated fatty acids', 'Chemical', '-', (15, 50))	('increase', 'PosReg', (149, 157))	('human', 'Species', '9606', (166, 171))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('omega-6 polyunsaturated fatty acids', 'Chemical', '-', (66, 101))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('PUFA', 'Gene', '9933', (107, 111))	('omega-6 polyunsaturated fatty acids', 'Var', (66, 101))	('PUFA', 'Gene', (56, 60))	('Omega-3 polyunsaturated fatty acids', 'Var', (15, 50))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('FAs', 'Chemical', 'MESH:C038178', (10, 13))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (146, 147))	('n', 'Chemical', 'MESH:D009584', (170, 171))
696352	25337547	n-6 PUFA can induce cardiovascular disease, diabetes, cancer, and age-related disease.	('age-related disease', 'Disease', (66, 85))	('PUFA', 'Gene', '9933', (4, 8))	('induce', 'PosReg', (13, 19))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (20, 42))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('n', 'Chemical', 'MESH:D009584', (0, 1))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('cancer', 'Disease', (54, 60))	('cardiovascular disease', 'Disease', 'MESH:D002318', (20, 42))	('PUFA', 'Gene', (4, 8))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('cardiovascular disease', 'Disease', (20, 42))	('diabetes', 'Disease', 'MESH:D003920', (44, 52))	('diabetes', 'Disease', (44, 52))	('n-6', 'Var', (0, 3))
696357	25337547	Especially, n-3 PUFA has been shown to exert beneficial effects on some chronic degenerative diseases such as cardiovascular disease, rheumatoid arthritis, diabetes, other autoimmune diseases, and cancer.	('n', 'Chemical', 'MESH:D009584', (194, 195))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('n', 'Chemical', 'MESH:D009584', (12, 13))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('diabetes', 'Disease', 'MESH:D003920', (156, 164))	('rat', 'Species', '10116', (86, 89))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (134, 154))	('PUFA', 'Gene', '9933', (16, 20))	('n-3', 'Var', (12, 15))	('beneficial effects', 'PosReg', (45, 63))	('n', 'Chemical', 'MESH:D009584', (199, 200))	('chronic', 'Disease', (72, 79))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (110, 132))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('cardiovascular disease', 'Disease', 'MESH:D002318', (110, 132))	('autoimmune diseases', 'Disease', 'MESH:D001327', (172, 191))	('cardiovascular disease', 'Disease', (110, 132))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('cancer', 'Disease', (197, 203))	('autoimmune diseases', 'Disease', (172, 191))	('diabetes', 'Disease', (156, 164))	('arthritis', 'Phenotype', 'HP:0001369', (145, 154))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (172, 191))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (134, 154))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('n', 'Chemical', 'MESH:D009584', (180, 181))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('PUFA', 'Gene', (16, 20))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('rheumatoid arthritis', 'Disease', (134, 154))
696361	25337547	Recent studies have found a positive association between n-6 PUFA and cancer risk, whereas in the same model, n-3 PUFA were shown to reduce the development of cancer.	('n', 'Chemical', 'MESH:D009584', (67, 68))	('PUFA', 'Gene', (61, 65))	('n', 'Chemical', 'MESH:D009584', (161, 162))	('n-6', 'Var', (57, 60))	('n', 'Chemical', 'MESH:D009584', (153, 154))	('cancer', 'Disease', (159, 165))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('reduce', 'NegReg', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('cancer', 'Disease', (70, 76))	('n', 'Chemical', 'MESH:D009584', (128, 129))	('men', 'Species', '9606', (151, 154))	('PUFA', 'Gene', (114, 118))	('PUFA', 'Gene', '9933', (61, 65))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('PUFA', 'Gene', '9933', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
696376	25337547	suggests that negative associations between n-3 PUFA intake and the risk of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (76, 101))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('PUFA', 'Gene', '9933', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('negative', 'NegReg', (14, 22))	('n-3', 'Var', (44, 47))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('PUFA', 'Gene', (48, 52))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (76, 101))
696391	25337547	In vitro studies have shown that n-3 PUFA inhibited macrophage-enhanced gastric cancer cell migration and attenuated matrix metalloproteinase (MMP)-10 expression through ERK and STAT3 phosphorylation and inhibited the growth of human gastric carcinoma cell via apoptosis and combination with 5-fluorouracil has synergetic effect in inhibiting the proliferation of gastric cancer cells.	('inhibited', 'NegReg', (204, 213))	('PUFA', 'Gene', (37, 41))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('ERK', 'Gene', '5594', (170, 173))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('rat', 'Species', '10116', (95, 98))	('inhibiting', 'NegReg', (332, 342))	('gastric cancer', 'Disease', (364, 378))	('n', 'Chemical', 'MESH:D009584', (272, 273))	('n', 'Chemical', 'MESH:D009584', (359, 360))	('n', 'Chemical', 'MESH:D009584', (201, 202))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('attenuated', 'NegReg', (106, 116))	('n', 'Chemical', 'MESH:D009584', (232, 233))	('macrophage-enhanced', 'Gene', (52, 71))	('n', 'Chemical', 'MESH:D009584', (280, 281))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('proliferation', 'CPA', (347, 360))	('n', 'Chemical', 'MESH:D009584', (137, 138))	('n', 'Chemical', 'MESH:D009584', (374, 375))	('ERK', 'Gene', (170, 173))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('inhibited', 'NegReg', (42, 51))	('n', 'Chemical', 'MESH:D009584', (247, 248))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (364, 378))	('rat', 'Species', '10116', (354, 357))	('PUFA', 'Gene', '9933', (37, 41))	('n', 'Chemical', 'MESH:D009584', (198, 199))	('gastric carcinoma', 'Disease', 'MESH:D013274', (234, 251))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('n', 'Chemical', 'MESH:D009584', (340, 341))	('expression', 'MPA', (151, 161))	('macrophage-enhanced', 'PosReg', (52, 71))	('gastric carcinoma', 'Disease', (234, 251))	('n', 'Chemical', 'MESH:D009584', (333, 334))	('matrix metalloproteinase (MMP)-10', 'Gene', '4319', (117, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('n', 'Chemical', 'MESH:D009584', (285, 286))	('human', 'Species', '9606', (228, 233))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (292, 306))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (234, 251))	('STAT3', 'Gene', (178, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (364, 378))	('n', 'Chemical', 'MESH:D009584', (205, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('n-3', 'Var', (33, 36))	('n', 'Chemical', 'MESH:D009584', (313, 314))	('growth', 'CPA', (218, 224))	('STAT3', 'Gene', '6774', (178, 183))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (330, 331))	('gastric cancer', 'Disease', (72, 86))
696392	25337547	Moreover, n-3 PUFA are beneficial for preventing oxidative stress-induced apoptosis by inhibiting apoptotic gene expression and DNA fragmentation of gastric epithelial cells.	('n', 'Chemical', 'MESH:D009584', (67, 68))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('DNA fragmentation', 'CPA', (128, 145))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('PUFA', 'Gene', '9933', (14, 18))	('apoptotic gene expression', 'MPA', (98, 123))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('men', 'Species', '9606', (136, 139))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n-3', 'Var', (10, 13))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('PUFA', 'Gene', (14, 18))	('oxidative stress', 'Phenotype', 'HP:0025464', (49, 65))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('inhibiting', 'NegReg', (87, 97))
696393	25337547	On the other hand, DHA induced apoptosis of gastric cancer cells by inducing the expression of apoptotic genes in gastric cancer cells.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('apoptotic genes', 'Gene', (95, 110))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('expression', 'MPA', (81, 91))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('n', 'Chemical', 'MESH:D009584', (15, 16))	('gastric cancer', 'Disease', (44, 58))	('DHA', 'Chemical', 'MESH:D004281', (19, 22))	('gastric cancer', 'Disease', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('DHA', 'Var', (19, 22))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('inducing', 'PosReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('n', 'Chemical', 'MESH:D009584', (69, 70))
696397	25337547	Recently, n-3 PUFA have been recognized to have antitumor activity in colon cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('n', 'Chemical', 'MESH:D009584', (74, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (70, 82))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('colon cancer', 'Disease', (70, 82))	('tumor', 'Disease', (52, 57))	('PUFA', 'Gene', '9933', (14, 18))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('PUFA', 'Gene', (14, 18))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('colon cancer', 'Disease', 'MESH:D015179', (70, 82))	('n-3', 'Var', (10, 13))
696420	25337547	Firstly, n-3 PUFA inhibits growth signal transduction.	('PUFA', 'Gene', '9933', (13, 17))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('growth signal transduction', 'CPA', (27, 53))	('PUFA', 'Gene', (13, 17))	('n-3', 'Var', (9, 12))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('inhibits', 'NegReg', (18, 26))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (9, 10))
696422	25337547	Secondly, n-3 PUFA induces cancer cell apoptosis via modulation of peroxisome proliferator-activated receptors (PPARs), the Bcl-2 family, and NF-kappaB cell signaling.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('NF-kappaB', 'Gene', (142, 151))	('modulation', 'Reg', (53, 63))	('Bcl-2', 'Gene', (124, 129))	('PUFA', 'Gene', '9933', (14, 18))	('rat', 'Species', '10116', (85, 88))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('PPARs', 'Gene', (112, 117))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('NF-kappaB', 'Gene', '18033', (142, 151))	('Bcl-2', 'Gene', '12043', (124, 129))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('n-3', 'Var', (10, 13))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('PUFA', 'Gene', (14, 18))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('cancer', 'Disease', (27, 33))	('induces', 'PosReg', (19, 26))	('n', 'Chemical', 'MESH:D009584', (139, 140))
696423	25337547	Thirdly, n-3 PUFA decreases sprouting angiogenesis by suppressing vascular endothelial growth factor (VEGF)- and platelet derived growth factor (PDGF)-stimulated endothelial cell proliferation, migration, and tube formation and by inhibition of MMPs via NO production and NF-kappaB and beta-catenin cell signaling.	('tube formation', 'CPA', (209, 223))	('n', 'Chemical', 'MESH:D009584', (297, 298))	('suppressing', 'NegReg', (54, 65))	('n', 'Chemical', 'MESH:D009584', (266, 267))	('VEGF', 'Gene', '22339', (102, 106))	('inhibition', 'NegReg', (231, 241))	('vascular endothelial growth factor', 'Gene', '22339', (66, 100))	('n', 'Chemical', 'MESH:D009584', (240, 241))	('n', 'Chemical', 'MESH:D009584', (202, 203))	('beta-catenin', 'Gene', '12387', (286, 298))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('PUFA', 'Gene', '9933', (13, 17))	('NF-kappaB', 'Gene', '18033', (272, 281))	('MMPs', 'Gene', (245, 249))	('n', 'Chemical', 'MESH:D009584', (232, 233))	('beta-catenin', 'Gene', (286, 298))	('n', 'Chemical', 'MESH:D009584', (311, 312))	('rat', 'Species', '10116', (197, 200))	('n', 'Chemical', 'MESH:D009584', (295, 296))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (191, 192))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('decreases', 'NegReg', (18, 27))	('n', 'Chemical', 'MESH:D009584', (222, 223))	('migration', 'CPA', (194, 203))	('n', 'Chemical', 'MESH:D009584', (206, 207))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (269, 270))	('n', 'Chemical', 'MESH:D009584', (283, 284))	('n', 'Chemical', 'MESH:D009584', (225, 226))	('sprouting angiogenesis', 'CPA', (28, 50))	('n-3', 'Var', (9, 12))	('PUFA', 'Gene', (13, 17))	('rat', 'Species', '10116', (186, 189))	('vascular endothelial growth factor', 'Gene', (66, 100))	('VEGF', 'Gene', (102, 106))	('NF-kappaB', 'Gene', (272, 281))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (163, 164))	('MMPs', 'Gene', '4319', (245, 249))	('n', 'Chemical', 'MESH:D009584', (307, 308))
696424	25337547	Fourthly, n-3 PUFA also decreases cell-cell adhesion via down regulation of Rho-GTPase, which inhibits cytoskeleton reorganisation, and reduction in intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression.	('expression', 'MPA', (235, 245))	('cell-cell adhesion', 'CPA', (34, 52))	('vascular cell adhesion molecule (VCAM)-1', 'Gene', '22329', (194, 234))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('Rho-GTPase', 'Gene', (76, 86))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('PUFA', 'Gene', '9933', (14, 18))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('down regulation', 'NegReg', (57, 72))	('inhibits', 'NegReg', (94, 102))	('adhesion molecule (ICAM)-1', 'Gene', '15894', (163, 189))	('cytoskeleton reorganisation', 'CPA', (103, 130))	('n', 'Chemical', 'MESH:D009584', (191, 192))	('n', 'Chemical', 'MESH:D009584', (215, 216))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('adhesion molecule (ICAM)-1', 'Gene', (163, 189))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('reduction', 'NegReg', (136, 145))	('n', 'Chemical', 'MESH:D009584', (244, 245))	('n-3', 'Var', (10, 13))	('decreases', 'NegReg', (24, 33))	('PUFA', 'Gene', (14, 18))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('n', 'Chemical', 'MESH:D009584', (170, 171))
696425	25337547	has also proposed the four main anti-tumor actions of n-3 PUFA (i) modulation of COX activity; (ii) alteration of membrane dynamics and cell surface receptor function; (iii) increased cellular oxidative stress and (iiii) derived anti-inflammatory lipid mediators.	('cellular oxidative stress', 'MPA', (184, 209))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('n', 'Chemical', 'MESH:D009584', (211, 212))	('n', 'Chemical', 'MESH:D009584', (235, 236))	('n-3', 'Var', (54, 57))	('cell surface receptor function', 'MPA', (136, 166))	('alteration', 'Reg', (100, 110))	('COX', 'Enzyme', (81, 84))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('n', 'Chemical', 'MESH:D009584', (230, 231))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('PUFA', 'Gene', (58, 62))	('modulation', 'Reg', (67, 77))	('membrane dynamics', 'MPA', (114, 131))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('lipid', 'Chemical', 'MESH:D008055', (247, 252))	('n', 'Chemical', 'MESH:D009584', (165, 166))	('oxidative stress', 'Phenotype', 'HP:0025464', (193, 209))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('PUFA', 'Gene', '9933', (58, 62))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('tumor', 'Disease', (37, 42))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('increased', 'PosReg', (174, 183))	('rat', 'Species', '10116', (104, 107))
696428	25337547	Secondly, incorporation of n-3 PUFA into cell membranes alters the fluidity, structure and/or function of lipid rafts or calveolae.	('n', 'Chemical', 'MESH:D009584', (101, 102))	('incorporation', 'Var', (10, 23))	('lipid', 'Chemical', 'MESH:D008055', (106, 111))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('rat', 'Species', '10116', (17, 20))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('fluidity', 'MPA', (67, 75))	('PUFA', 'Gene', '9933', (31, 35))	('PUFA', 'Gene', (31, 35))	('alters', 'Reg', (56, 62))	('function', 'MPA', (94, 102))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('structure', 'MPA', (77, 86))
696430	25337547	Thirdly, n-3 PUFA may have an anti-tumor effect through alteration in the cellular redox state.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('PUFA', 'Gene', '9933', (13, 17))	('PUFA', 'Gene', (13, 17))	('n-3', 'Var', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('tumor', 'Disease', (35, 40))	('rat', 'Species', '10116', (60, 63))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('cellular redox state', 'MPA', (74, 94))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('alteration', 'Reg', (56, 66))	('n', 'Chemical', 'MESH:D009584', (9, 10))
696432	25337547	Therefore, n-3 PUFA can induce cancer cell apoptosis via elevation of intracellular ROS levels.	('n', 'Chemical', 'MESH:D009584', (22, 23))	('intracellular ROS levels', 'MPA', (70, 94))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('PUFA', 'Gene', '9933', (15, 19))	('induce', 'PosReg', (24, 30))	('elevation', 'PosReg', (57, 66))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n-3', 'Var', (11, 14))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('cancer', 'Disease', (31, 37))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('PUFA', 'Gene', (15, 19))
696433	25337547	Fourthly, n-3 PUFA can be metabolized novel anti-inflammatory lipid mediators including resolvins, protectins and maresins.	('n', 'Chemical', 'MESH:D009584', (50, 51))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('PUFA', 'Gene', '9933', (14, 18))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('PUFA', 'Gene', (14, 18))	('lipid', 'Chemical', 'MESH:D008055', (62, 67))	('metabolized', 'MPA', (26, 37))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('n-3', 'Var', (10, 13))	('anti-inflammatory lipid mediators', 'MPA', (44, 77))
696435	25337547	Besides these multiple anti-tumor actions, it is also reported recently that n-3 PUFA can activate Nrf2 and induced Nrf2-directed gene expression and can suppress lipopolysaccharide-induced inflammation through induction of Nrf2 expression.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('PUFA', 'Gene', '9933', (81, 85))	('tumor', 'Disease', (28, 33))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('Nrf2', 'Gene', (116, 120))	('n-3', 'Var', (77, 80))	('inflammation', 'Disease', (190, 202))	('induced', 'MPA', (108, 115))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('suppress', 'NegReg', (154, 162))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (163, 181))	('n', 'Chemical', 'MESH:D009584', (201, 202))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('Nrf2', 'Gene', (99, 103))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('Nrf2', 'Gene', (224, 228))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Nrf2', 'Gene', '18024', (116, 120))	('n', 'Chemical', 'MESH:D009584', (238, 239))	('n', 'Chemical', 'MESH:D009584', (191, 192))	('n', 'Chemical', 'MESH:D009584', (183, 184))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('PUFA', 'Gene', (81, 85))	('activate', 'PosReg', (90, 98))	('expression', 'MPA', (229, 239))	('Nrf2', 'Gene', '18024', (99, 103))	('inflammation', 'Disease', 'MESH:D007249', (190, 202))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('Nrf2', 'Gene', '18024', (224, 228))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (219, 220))	('n', 'Chemical', 'MESH:D009584', (212, 213))
696436	25337547	Moreover, n-3 PUFA significantly reduces oxidative stress-induced endothelial cell Ca++ influx.	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('PUFA', 'Gene', '9933', (14, 18))	('oxidative stress', 'Phenotype', 'HP:0025464', (41, 57))	('PUFA', 'Gene', (14, 18))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('reduces', 'NegReg', (33, 40))	('n-3', 'Var', (10, 13))
696443	25337547	showed that melanoma formation and growth are reduced in Fat-1 transgenic mice.	('n', 'Chemical', 'MESH:D009584', (29, 30))	('transgenic', 'Var', (63, 73))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('melanoma', 'Disease', (12, 20))	('Fat-1', 'Gene', '14107', (57, 62))	('growth', 'CPA', (35, 41))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('reduced', 'NegReg', (46, 53))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('Fat-1', 'Gene', (57, 62))	('transgenic mice', 'Species', '10090', (63, 78))	('n', 'Chemical', 'MESH:D009584', (55, 56))
696450	25337547	Besides of GI cancers, the growth of hepatocellular carcinoma (HCC) in vivo was significantly reduced in the Fat-1 transgenic mice.	('n', 'Chemical', 'MESH:D009584', (122, 123))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (37, 61))	('GI cancers', 'Disease', 'MESH:D009369', (11, 21))	('HCC', 'Phenotype', 'HP:0001402', (63, 66))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('growth', 'MPA', (27, 33))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (37, 61))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('Fat-1', 'Gene', (109, 114))	('GI cancer', 'Phenotype', 'HP:0007378', (11, 20))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('reduced', 'NegReg', (94, 101))	('Fat-1', 'Gene', '14107', (109, 114))	('hepatocellular carcinoma', 'Disease', (37, 61))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('n', 'Chemical', 'MESH:D009584', (118, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('transgenic', 'Var', (115, 125))	('transgenic mice', 'Species', '10090', (115, 130))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('GI cancers', 'Disease', (11, 21))	('n', 'Chemical', 'MESH:D009584', (69, 70))
696451	25337547	Mice expressing MMTV-neu(ndl)-YD5 and Fat-1, which were bred with mouse mammary tumor virus (MMTV)-neu(ndl)-YD5 mice (an aggressive breast cancer model), displayed significant (P<0.05) reductions in tumor volume (~30%) and multiplicity (~33%).	('MMTV', 'Species', '11757', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('mouse mammary tumor virus', 'Species', '11757', (66, 91))	('Mice', 'Species', '10090', (0, 4))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('n', 'Chemical', 'MESH:D009584', (193, 194))	('Fat-1', 'Gene', (38, 43))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (121, 145))	('Fat-1', 'Gene', '14107', (38, 43))	('reductions', 'NegReg', (185, 195))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', (80, 85))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('aggressive breast cancer', 'Disease', (121, 145))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('mice', 'Species', '10090', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('multiplicity', 'CPA', (223, 235))	('n', 'Chemical', 'MESH:D009584', (197, 198))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('MMTV', 'Species', '11757', (16, 20))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('n', 'Chemical', 'MESH:D009584', (220, 221))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('MMTV-neu(ndl)-YD5', 'Var', (16, 33))
696461	25337547	In addition, using n-3 PUFA in combination with other agents with complementary antitumor action may improve their efficacy in GI cancer prevention.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('PUFA', 'Gene', '9933', (23, 27))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('improve', 'PosReg', (101, 108))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('men', 'Species', '9606', (72, 75))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('GI cancer', 'Disease', (127, 136))	('n-3', 'Var', (19, 22))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('PUFA', 'Gene', (23, 27))	('tumor', 'Disease', (84, 89))	('GI cancer', 'Disease', 'MESH:D009369', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('GI cancer', 'Phenotype', 'HP:0007378', (127, 136))	('n', 'Chemical', 'MESH:D009584', (146, 147))
696543	23346552	Alterations of MEN1 gene (11q13) cause multiple endocrine neoplasia type 1 (MEN1) syndrome.	('cause', 'Reg', (33, 38))	('neoplasia', 'Phenotype', 'HP:0002664', (58, 67))	('Alterations', 'Var', (0, 11))	('MEN1', 'Gene', (76, 80))	('MEN1', 'Gene', '4221', (76, 80))	('MEN1', 'Gene', '4221', (15, 19))	('MEN1', 'Gene', (15, 19))	('multiple endocrine neoplasia type 1 (MEN1) syndrome', 'Disease', 'MESH:D018761', (39, 90))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (48, 67))
696544	23346552	Several sporadic GI-NENs show alterations of MEN1 gene.	('MEN1', 'Gene', (45, 49))	('alterations', 'Var', (30, 41))	('MEN1', 'Gene', '4221', (45, 49))
696545	23346552	The incidence of loss of heterozygosity (LOH) of the MEN1gene is 39% of GI-NENs (Rindi and Bordi,).	('MEN1', 'Gene', (53, 57))	('MEN1', 'Gene', '4221', (53, 57))	('loss', 'Var', (17, 21))
696548	23346552	The incidence of TP53 mutation is 4-44% (Ramnani et al.,; Rindi and Bordi,).	('TP53', 'Gene', '7157', (17, 21))	('mutation', 'Var', (22, 30))	('TP53', 'Gene', (17, 21))
696550	23346552	GI-NENs show frequent methylation of RASSF1A, p14-ARF, retinoic acid receptor beta 2 (RARbeta), O6-methyl-guanine methyltransferase (MGMT), cyclooxygenase 2 (COX-2), thrombospondin 1 (THBS1), estrogen receptor (ER), and hypermethylated in cancer 1 (HIC-1) (Chan et al.,; Liu et al.,; Pizzi et al.,; Zhang et al.,; Arnold et al.,).	('RASSF1A', 'Gene', '11186', (37, 44))	('RARbeta', 'Gene', '5915', (86, 93))	('RARbeta', 'Gene', (86, 93))	('THBS1', 'Gene', (184, 189))	('cyclooxygenase 2', 'Gene', (140, 156))	('COX-2', 'Gene', (158, 163))	('RASSF1A', 'Gene', (37, 44))	('THBS1', 'Gene', '7057', (184, 189))	('methylation', 'Var', (22, 33))	('p14-ARF', 'Gene', (46, 53))	('O6-methyl-guanine methyltransferase', 'Gene', (96, 131))	('cancer', 'Disease', (239, 245))	('MGMT', 'Gene', '4255', (133, 137))	('COX-2', 'Gene', '5743', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('thrombospondin 1', 'Gene', '7057', (166, 182))	('HIC-1', 'Gene', '3090', (249, 254))	('O6-methyl-guanine methyltransferase', 'Gene', '4255', (96, 131))	('cyclooxygenase 2', 'Gene', '5743', (140, 156))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('p14-ARF', 'Gene', '1029', (46, 53))	('HIC-1', 'Gene', (249, 254))	('MGMT', 'Gene', (133, 137))	('thrombospondin 1', 'Gene', (166, 182))
696551	23346552	p16-INK4 methylation is present in 33% of GI-NENs according to the results of several studies (Serrano et al.,; Chan et al.,; Liu et al.,).	('methylation', 'Var', (9, 20))	('INK4', 'Gene', '1029', (4, 8))	('INK4', 'Gene', (4, 8))	('p16', 'Gene', (0, 3))	('p16', 'Gene', '1029', (0, 3))
696553	23346552	The methylation of RASSF1A gene is associated with distant or lymph node metastasis (Liu et al.,; Zhang et al.,).	('RASSF1A', 'Gene', '11186', (19, 26))	('associated', 'Reg', (35, 45))	('methylation', 'Var', (4, 15))	('distant or lymph node metastasis', 'CPA', (51, 83))	('RASSF1A', 'Gene', (19, 26))
696556	23346552	reported that 3 out of 9 cases of GI-NENs showed HER2/neu amplification, and they found a trend of increased HER-2/neu copy number in the more aggressive GI-NENs (Evers et al.,).	('neu', 'Gene', '2064', (115, 118))	('HER2/neu', 'Gene', (49, 57))	('neu', 'Gene', '2064', (54, 57))	('neu', 'Gene', (115, 118))	('HER-2', 'Gene', '2064', (109, 114))	('neu', 'Gene', (54, 57))	('HER-2', 'Gene', (109, 114))	('increased', 'PosReg', (99, 108))	('copy', 'MPA', (119, 123))	('HER2/neu', 'Gene', '2064', (49, 57))	('amplification', 'Var', (58, 71))
696560	23346552	reported mutations in exon 3 of beta-catenin in 38% (27/72 cases) of GI-NENs and 1 mutation in APC (1%, 1/72 case) (Fujimori et al.,).	('APC', 'Disease', (95, 98))	('mutations in', 'Var', (9, 21))	('beta-catenin', 'Gene', (32, 44))	('beta-catenin', 'Gene', '1499', (32, 44))	('APC', 'Phenotype', 'HP:0005227', (95, 98))	('APC', 'Disease', 'MESH:D011125', (95, 98))
696603	23346552	S-100 protein positivity has been reported in sustentacular-like cells in 7% of tumors (Burke et al.,).	('S-100', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('positivity', 'Var', (14, 24))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('S-100', 'Gene', '6271', (0, 5))
696631	18599359	Plasma membrane cation channel autoantibodies were detected in 23 patients: neuronal voltage-gated calcium channel (5 N-type and 1 P/Q-type), acetylcholine receptor (11 ganglionic-type and 4 muscle-type) and neuronal voltage-gated potassium channel autoantibodies (4).	('acetylcholine receptor', 'MPA', (142, 164))	('1 P/Q', 'Var', (129, 134))	('neuronal', 'MPA', (76, 84))	('patients', 'Species', '9606', (66, 74))	('1 P/Q', 'SUBSTITUTION', 'None', (129, 134))
696643	18599359	Mice injected systemically with IgG prepared from serum containing ganglionic-type AChR antibodies develop slowed GI transit, urinary retention, dilated pupils, reduced heart rate variability, and impaired catecholamine response to stress.	('reduced', 'NegReg', (161, 168))	('heart rate variability', 'MPA', (169, 191))	('impaired', 'NegReg', (197, 205))	('catecholamine response to stress', 'MPA', (206, 238))	('AChR', 'Gene', (83, 87))	('catecholamine', 'Chemical', 'MESH:D002395', (206, 219))	('urinary', 'CPA', (126, 133))	('slowed', 'NegReg', (107, 113))	('Mice', 'Species', '10090', (0, 4))	('reduced heart rate variability', 'Phenotype', 'HP:0031861', (161, 191))	('urinary retention', 'Phenotype', 'HP:0000016', (126, 143))	('antibodies', 'Var', (88, 98))	('dilated', 'Disease', (145, 152))	('dilated pupils', 'Phenotype', 'HP:0011499', (145, 159))
696660	18599359	In 22 patients the index autoantibodies detected (Table 2) were neuronal or muscle cation channel autoantibodies: acetylcholine receptor (11 ganglionic-type and 4 muscle-type), neuronal voltage-gated calcium channel (5 N-type and 1 P/Q-type) and neuronal voltage-gated potassium channel autoantibody (3).	('patients', 'Species', '9606', (6, 14))	('1 P/Q', 'Var', (230, 235))	('acetylcholine receptor', 'MPA', (114, 136))	('1 P/Q', 'SUBSTITUTION', 'None', (230, 235))
696676	18599359	He had muscle-type AChR autoantibodies (0.11 nmol/L; normal, 0.02 nmol/L or less), but no evidence of myasthenia gravis by detailed electromyographic evaluation.	('muscle-type AChR autoantibodies', 'Protein', (7, 38))	('myasthenia', 'Phenotype', 'HP:0003473', (102, 112))	('myasthenia gravis', 'Disease', (102, 119))	('0.11', 'Var', (40, 44))	('myasthenia gravis', 'Disease', 'MESH:D009157', (102, 119))
696691	18599359	Following commencement of oral prednisone and 6-mercaptopurine, she reported marked improvement in GI symptoms and quality of life, and her weight stabilized over the next few months.	('6-mercaptopurine', 'Var', (46, 62))	('prednisone', 'Chemical', 'MESH:D011241', (31, 41))	('quality of life', 'CPA', (115, 130))	('6-mercaptopurine', 'Chemical', 'MESH:D015122', (46, 62))	('GI symptoms', 'Disease', (99, 110))	('improvement', 'PosReg', (84, 95))
696727	18599359	Our laboratory recently recognized a 22% frequency of GAD65 autoantibodies in patients with idiopathic achalasia, compared with 2.3% among 171 age-matched control subjects.	('GAD65', 'Gene', '2572', (54, 59))	('idiopathic achalasia', 'Disease', 'MESH:D004931', (92, 112))	('idiopathic achalasia', 'Disease', (92, 112))	('patients', 'Species', '9606', (78, 86))	('achalasia', 'Phenotype', 'HP:0002571', (103, 112))	('autoantibodies', 'Var', (60, 74))	('GAD65', 'Gene', (54, 59))
696739	33176591	Silencing ubiquitin resulted in the suppression of cell growth, chemoresistance, colony formation and cell migration in esophageal squamous cell carcinoma cells.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('cell growth', 'CPA', (51, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('ubiquitin', 'Protein', (10, 19))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('chemoresistance', 'CPA', (64, 79))	('colony formation', 'CPA', (81, 97))	('suppression', 'NegReg', (36, 47))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('Silencing', 'Var', (0, 9))	('cell migration', 'CPA', (102, 116))
696740	33176591	Proteomic analysis in esophageal squamous cell carcinoma cells showed that knockdown of ubiquitin coding genes deregulated the expression of 159 proteins (92 were upregulated and 67 were downregulated) involved in multiple pathways.	('downregulated', 'NegReg', (187, 200))	('deregulated', 'NegReg', (111, 122))	('esophageal squamous cell carcinoma', 'Disease', (22, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('ubiquitin coding genes', 'Gene', (88, 110))	('proteins', 'Protein', (145, 153))	('expression of', 'MPA', (127, 140))	('knockdown', 'Var', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (22, 56))	('upregulated', 'PosReg', (163, 174))
696755	33176591	The UBA52 and RPS27A genes encode the fusion ribosomal proteins L40 and S27a, respectively, and are thought to be essential for protein synthesis.	('RPS27A', 'Gene', '6233', (14, 20))	('UBA52', 'Gene', '7311', (4, 9))	('RPS27A', 'Gene', (14, 20))	('UBA52', 'Gene', (4, 9))	('S27a', 'Var', (72, 76))
696760	33176591	We have previously reported that ubiquitin expression was significantly upregulated in human lung cancer cells and that silencing ubiquitin genes inhibited the proliferation and radioresistance of H1299 xenografts by promoting apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('radioresistance', 'CPA', (178, 193))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('human', 'Species', '9606', (87, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('H1299', 'CellLine', 'CVCL:0060', (197, 202))	('ubiquitin genes', 'Gene', (130, 145))	('inhibited', 'NegReg', (146, 155))	('apoptosis', 'CPA', (227, 236))	('lung cancer', 'Disease', (93, 104))	('ubiquitin expression', 'MPA', (33, 53))	('silencing', 'Var', (120, 129))	('upregulated', 'PosReg', (72, 83))	('promoting', 'PosReg', (217, 226))
696815	33176591	Carbamidomethyl on Cys, TMT-6plex (N-term), and TMT-6plex (K) were specified as fixed modifications, and oxidation on Met was specified as a variable modification.	('Carbamidomethyl', 'Chemical', '-', (0, 15))	('Cys', 'Chemical', 'MESH:D003545', (19, 22))	('TMT-6plex', 'Var', (24, 33))	('TMT-6plex', 'Var', (48, 57))	('Carbamidomethyl', 'Var', (0, 15))
696828	33176591	As measured by real-time PCR analysis, the most effective shRNAs for the knockdown of UBB and UBC were shRNA-1 and shRNA-2, respectively, in both Eca-109 and TE-1 cells (Figures 2B and C).	('UBC', 'Gene', '7316', (94, 97))	('UBC', 'Gene', (94, 97))	('UBB', 'Gene', (86, 89))	('shRNA-2', 'Gene', (115, 122))	('shRNA-1', 'Gene', (103, 110))	('UBB', 'Gene', '7314', (86, 89))	('knockdown', 'Var', (73, 82))
696830	33176591	As shown in the MTT assay (Figure 3A and B), knockdown of UBB/UBC appeared to suppress the cell viability of Eca-109 and TE-1 cells with or without cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('suppress', 'NegReg', (78, 86))	('UBB/UBC', 'Gene', '7314;7316', (58, 65))	('UBB/UBC', 'Gene', (58, 65))	('cell viability', 'CPA', (91, 105))	('knockdown', 'Var', (45, 54))	('MTT', 'Chemical', 'MESH:C070243', (16, 19))
696831	33176591	The combined knockdown of UBB and UBC also significantly decreased the migration and invasion of Eca-109 and TE-1 cells (Figure 3D).	('UBB', 'Gene', (26, 29))	('UBB', 'Gene', '7314', (26, 29))	('migration', 'CPA', (71, 80))	('UBC', 'Gene', (34, 37))	('UBC', 'Gene', '7316', (34, 37))	('knockdown', 'Var', (13, 22))	('decreased', 'NegReg', (57, 66))
696832	33176591	These results indicated that silencing of ubiquitin coding genes (UBB and UBC) abrogated the aggressive phenotypes of ESCC cells.	('ESCC', 'Disease', (118, 122))	('silencing', 'Var', (29, 38))	('UBB', 'Gene', (66, 69))	('UBC', 'Gene', '7316', (74, 77))	('UBC', 'Gene', (74, 77))	('aggressive phenotypes of', 'CPA', (93, 117))	('UBB', 'Gene', '7314', (66, 69))	('abrogated', 'NegReg', (79, 88))
696836	33176591	Dysfunction of ubiquitin has been implicated in a vast array of human diseases, including cancer.	('human', 'Species', '9606', (64, 69))	('Dysfunction', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ubiquitin', 'Protein', (15, 24))	('implicated', 'Reg', (34, 44))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
696845	33176591	Silencing ubiquitin induces apoptotic cell death, indicating that ubiquitin might be a potential target for cancer treatment.	('death', 'Disease', 'MESH:D003643', (43, 48))	('death', 'Disease', (43, 48))	('ubiquitin', 'Protein', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Silencing', 'Var', (0, 9))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
696846	33176591	Consistent with previous studies, we found that knock-down of UBB/UBC resulted in decreased ESCC cell growth, colony formation and migration, suggesting that ubiquitin may be a potent inhibitor in esophageal cancer progression.	('UBB/UBC', 'Gene', (62, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('ESCC', 'Disease', (92, 96))	('migration', 'CPA', (131, 140))	('knock-down', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('decreased ESCC', 'Phenotype', 'HP:0025022', (82, 96))	('UBB/UBC', 'Gene', '7314;7316', (62, 69))	('esophageal cancer', 'Disease', (197, 214))	('colony formation', 'CPA', (110, 126))	('decreased', 'NegReg', (82, 91))
696848	33176591	In this study, we revealed that silencing UBB/UBC contributed to decreased chemoresistance.	('decreased', 'NegReg', (65, 74))	('silencing', 'Var', (32, 41))	('chemoresistance', 'CPA', (75, 90))	('UBB/UBC', 'Gene', '7314;7316', (42, 49))	('UBB/UBC', 'Gene', (42, 49))
696860	33176591	In previous studies, we found that silencing ubiquitin genes inhibited the expression of anti-apoptotic protein Bcl-2 in lung cancer H1299 cells, and silencing ubiquitin genes suppressed the proliferation and radioresistance of H1299 transplanted xenografts by promoting apoptosis.	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('inhibited', 'NegReg', (61, 70))	('promoting', 'PosReg', (261, 270))	('silencing', 'Var', (150, 159))	('H1299', 'CellLine', 'CVCL:0060', (133, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('proliferation', 'CPA', (191, 204))	('H1299', 'CellLine', 'CVCL:0060', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ubiquitin genes', 'Gene', (45, 60))	('lung cancer', 'Disease', (121, 132))	('Bcl-2', 'Gene', (112, 117))	('silencing', 'Var', (35, 44))	('radioresistance', 'CPA', (209, 224))	('ubiquitin', 'Gene', (160, 169))	('suppressed', 'NegReg', (176, 186))	('Bcl-2', 'Gene', '596', (112, 117))	('apoptosis', 'CPA', (271, 280))	('expression', 'MPA', (75, 85))
696899	29532261	The reasons for additional treatment (multiple reasons in some cases) were submucosal invasion (n = 20, 71%), lymphatic invasion (n = 16, 57%), vascular invasion (n = 1, 3.6%), positive horizontal margins (n = 1, 3.6%), and positive vertical margins (n = 3, 10.7%) in the esophagectomy group and submucosal invasion (n = 28, 90%), lymphatic invasion (n = 11, 35%), vascular invasion (n = 3, 9.7%), positive horizontal margins (n = 2, 6.5%), and positive vertical margins (n = 4, 12.9%) in the CRT group.	('lymphatic', 'Disease', (110, 119))	('vascular invasion', 'CPA', (365, 382))	('lymphatic', 'Disease', (331, 340))	('men', 'Species', '9606', (32, 35))	('submucosal', 'Disease', (75, 85))	('esophagectomy', 'Disease', (272, 285))	('positive', 'Var', (445, 453))
696962	28927031	The association between genetic changes and clinical characteristics can reflect the biological events that promote OSCC invasion and metastasis, and the former may act as molecular tumor markers for diagnosis and prognosis.	('tumor', 'Disease', (182, 187))	('genetic changes', 'Var', (24, 39))	('OSCC', 'Disease', (116, 120))	('metastasis', 'CPA', (134, 144))	('promote', 'PosReg', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('changes', 'Var', (32, 39))
697029	28927031	The survival rate of patients with positive ZEB2 expression was significantly decreased compared with patients with negative expression in univariate and multivariate analysis.	('survival rate', 'CPA', (4, 17))	('ZEB2', 'Gene', (44, 48))	('patients', 'Species', '9606', (102, 110))	('expression', 'MPA', (49, 59))	('positive', 'Var', (35, 43))	('patients', 'Species', '9606', (21, 29))	('decreased', 'NegReg', (78, 87))	('ZEB2', 'Gene', '9839', (44, 48))
697034	28927031	High ZEB2 expression in tumors is significantly and independently associated with poorer overall survival, particularly in patients with lymph node metastasis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('High', 'Var', (0, 4))	('poorer', 'NegReg', (82, 88))	('ZEB2', 'Gene', (5, 9))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('associated', 'Reg', (66, 76))	('expression', 'MPA', (10, 20))	('patients', 'Species', '9606', (123, 131))	('overall survival', 'MPA', (89, 105))	('ZEB2', 'Gene', '9839', (5, 9))
697065	27245876	Among them, GP-HMRG showed a rapid, significant and specific fluorescence increase in tumor-positive samples, while the others did not (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('fluorescence', 'MPA', (61, 73))	('tumor', 'Disease', (86, 91))	('GP-HMRG', 'Var', (12, 19))	('increase', 'PosReg', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
697068	27245876	Next, since there are only a few papers reporting up-regulation of DPP-IV in ESCCs, we performed live-cell imaging of cultured esophageal cancer cells to confirm the reactivity of GP-HMRG and its specificity for DPP-IV.	('DPP-IV', 'Gene', (212, 218))	('esophageal cancer', 'Disease', (127, 144))	('DPP-IV', 'Gene', '1803', (212, 218))	('SCC', 'Gene', '6317', (78, 81))	('GP-HMRG', 'Var', (180, 187))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('DPP-IV', 'Gene', (67, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('reactivity', 'MPA', (166, 176))	('DPP-IV', 'Gene', '1803', (67, 73))	('SCC', 'Gene', (78, 81))
697073	27245876	The penultimate proline is indispensable for the substrate recognition by DPP-IV, so we synthesized a series of candidate probes, EP-HMRG, KP-HMRG, YP-HMRG, LP-HMRG, and PP-HMRG, for further evaluation.	('LP-HMRG', 'Var', (157, 164))	('YP-HMRG', 'Var', (148, 155))	('KP-HMRG', 'Var', (139, 146))	('DPP-IV', 'Gene', (74, 80))	('PP-HMRG', 'Var', (170, 177))	('DPP-IV', 'Gene', '1803', (74, 80))	('EP-HMRG', 'Var', (130, 137))	('proline', 'Chemical', 'MESH:D011392', (16, 23))
697075	27245876	Among these derivatives, EP-HMRG exhibited the lowest Michaelis constant (Km), showing the highest affinity for DPP-IV (Supplementary Table 2).	('lowest', 'NegReg', (47, 53))	('EP-HMRG', 'Var', (25, 32))	('affinity', 'MPA', (99, 107))	('DPP-IV', 'Gene', (112, 118))	('DPP-IV', 'Gene', '1803', (112, 118))	('Michaelis constant', 'MPA', (54, 72))
697079	27245876	We next investigated whether tumor-specific fluorescence imaging could be achieved simply by spraying EP-HMRG onto freshly resected specimens obtained from esophageal cancer patients during endoscopic submucosal dissection (ESD) or at surgical operation.	('EP-HMRG', 'Var', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('esophageal cancer', 'Disease', (156, 173))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Disease', (29, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
697081	27245876	After spraying of EP-HMRG, the tumor could be clearly detected within a few minutes.	('EP-HMRG', 'Var', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
697086	27245876	These results demonstrated that EP-HMRG is cleaved by DPP-IV expressed in the tumor in resected specimens, thereby generating a fluorescence signal.	('generating', 'Reg', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('DPP-IV', 'Gene', '1803', (54, 60))	('EP-HMRG', 'Var', (32, 39))	('tumor', 'Disease', (78, 83))	('fluorescence signal', 'MPA', (128, 147))	('DPP-IV', 'Gene', (54, 60))
697089	27245876	Just 5 min after spraying EP-HMRG onto this resected specimen, the tumor lesion was clearly and specifically visualized (Fig.	('tumor lesion', 'Disease', (67, 79))	('EP-HMRG', 'Var', (26, 33))	('tumor lesion', 'Disease', 'MESH:D051437', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))
697109	27245876	The fluorescence signal obtained with EP-HMRG corresponded well with pathologically cancer-positive lesions, but we have noticed that the fluorescence signal is not uniform within cancer-positive lesions.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('fluorescence', 'MPA', (4, 16))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('EP-HMRG', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
697153	25925371	Multivariate analysis revealed that high JWA (HR 0.22; 95% CI 0.13-0.37; P < 0.001) or XRCC1 (HR 0.36; 95% CI 0.21-0.63; P < 0.001) mRNA expression emerged as the independent prognostic factors for ESCC patients in this cohort.	('JWA', 'Gene', (41, 44))	('ESCC', 'Disease', (198, 202))	('XRCC1', 'Gene', '7515', (87, 92))	('XRCC1', 'Gene', (87, 92))	('patients', 'Species', '9606', (203, 211))	('JWA', 'Gene', '10550', (41, 44))	('high', 'Var', (36, 40))
697155	25925371	Further subgroup analysis showed cisplatin-based treatments could improve mOS of patients with low JWA expression (P < 0.05), especially in those with low BRCA1 expression simultaneously (P < 0.001); while in patients with high JWA expression, high BRCA1 mRNA expression was correlated with increased mOS in docetaxel-based treatments (P = 0.044).	('low JWA', 'Phenotype', 'HP:0002720', (95, 102))	('JWA', 'Gene', '10550', (228, 231))	('BRCA1', 'Gene', '672', (155, 160))	('mOS', 'Gene', (301, 304))	('BRCA1', 'Gene', '672', (249, 254))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('BRCA1', 'Gene', (155, 160))	('increased', 'PosReg', (291, 300))	('BRCA1', 'Gene', (249, 254))	('mOS', 'Gene', '17451', (74, 77))	('JWA', 'Gene', (99, 102))	('docetaxel', 'Chemical', 'MESH:D000077143', (308, 317))	('high', 'Var', (244, 248))	('JWA', 'Gene', '10550', (99, 102))	('mOS', 'Gene', '17451', (301, 304))	('improve', 'PosReg', (66, 73))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (81, 89))	('JWA', 'Gene', (228, 231))	('mOS', 'Gene', (74, 77))
697164	25925371	Single nucleotide polymorphisms (SNPs) of XRCC1 gene acted as a risk factor might be a valuable genetic marker for chemotherapy in various cancers containing esophageal cancer.	('XRCC1', 'Gene', '7515', (42, 47))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('XRCC1', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('esophageal cancer', 'Disease', (158, 175))
697206	25925371	Similarly, patients with high XRCC1 mRNA expression also experienced longer mOS (19.0 vs. 9.0 months, P < 0.001; Figure 1B) in comparison with those with low XRCC1 expression.	('XRCC1', 'Gene', (30, 35))	('mOS', 'Gene', (76, 79))	('mRNA expression', 'Var', (36, 51))	('XRCC1', 'Gene', (158, 163))	('high', 'Var', (25, 29))	('mOS', 'Gene', '17451', (76, 79))	('longer', 'PosReg', (69, 75))	('XRCC1', 'Gene', '7515', (30, 35))	('patients', 'Species', '9606', (11, 19))	('XRCC1', 'Gene', '7515', (158, 163))
697210	25925371	It was shown that patients with both high or JWA high/ XRCC1 low (mOS were 21.0 and 17.0 months) had a better outcome of survival than in the other 2 groups (mOS were 10.0 and 8.0 months), which indicated that JWA mRNA expression mainly affected overall survival of patients in this cohort (Figure 2A, Additional file 1: Table S1).	('mOS', 'Gene', (66, 69))	('patients', 'Species', '9606', (266, 274))	('mOS', 'Gene', '17451', (158, 161))	('high', 'Var', (37, 41))	('JWA', 'Gene', (45, 48))	('low', 'NegReg', (61, 64))	('JWA', 'Gene', (210, 213))	('XRCC1', 'Gene', '7515', (55, 60))	('overall survival', 'MPA', (246, 262))	('mOS', 'Gene', '17451', (66, 69))	('affected', 'Reg', (237, 245))	('patients', 'Species', '9606', (18, 26))	('JWA', 'Gene', '10550', (210, 213))	('mOS', 'Gene', (158, 161))	('XRCC1', 'Gene', (55, 60))	('JWA', 'Gene', '10550', (45, 48))
697224	25925371	Cox proportional hazard analysis revealed that high JWA (HR 0.22; 95% CI 0.13-0.37; P < 0.001) or high XRCC1 mRNA expression (HR 0.36; 95% CI 0.21-0.63; P < 0.001) emerged as independent prognostic factors associated with increased OS, whereas low tumor differentiation grade (HR 1.45; 95% CI 1.06-1.97; P = 0.019) emerged as higher risk for mortality associated with decreased mOS (Table 4).	('mOS', 'Gene', (378, 381))	('low tumor', 'Disease', (244, 253))	('XRCC1', 'Gene', '7515', (103, 108))	('JWA', 'Gene', '10550', (52, 55))	('high', 'Var', (47, 51))	('mOS', 'Gene', '17451', (378, 381))	('high', 'Var', (98, 102))	('decreased', 'NegReg', (368, 377))	('OS', 'Gene', '17451', (379, 381))	('OS', 'Gene', '17451', (232, 234))	('JWA', 'Gene', (52, 55))	('XRCC1', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('low tumor', 'Disease', 'MESH:D009800', (244, 253))
697232	25925371	Though the loss of JWA expression has been discovered to inhibit the cell differentiation and cause more malignant phenotypes, it was still ambiguous whether JWA could be the important regulatory factor in differentiation-related pathways including JAK-STAT, Notch and Wnt signaling pathways.	('cell differentiation', 'CPA', (69, 89))	('loss', 'Var', (11, 15))	('inhibit', 'NegReg', (57, 64))	('JWA', 'Gene', '10550', (19, 22))	('malignant phenotypes', 'CPA', (105, 125))	('JWA', 'Gene', '10550', (158, 161))	('JWA', 'Gene', (19, 22))	('cause', 'Reg', (94, 99))	('JWA', 'Gene', (158, 161))
697237	25925371	Downregulation of JWA was found to be crucial for the invasion and metastasis of human tumor through elevated FAK expression, the induction of RhoA and MMP-2 activation.	('JWA', 'Gene', '10550', (18, 21))	('elevated', 'PosReg', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('invasion', 'CPA', (54, 62))	('JWA', 'Gene', (18, 21))	('tumor', 'Disease', (87, 92))	('Downregulation', 'Var', (0, 14))	('MMP-2', 'Gene', (152, 157))	('RhoA', 'Gene', (143, 147))	('activation', 'PosReg', (158, 168))	('FAK', 'Gene', '5747', (110, 113))	('human', 'Species', '9606', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('RhoA', 'Gene', '387', (143, 147))	('FAK', 'Gene', (110, 113))	('MMP-2', 'Gene', '4313', (152, 157))
697251	25925371	The patients with low JWA/low BRCA1 expressing benefited mostly from cisplatin-based treatment, and those with high JWA/high BRCA1 expression benefited mostly from docetaxel-based treatment.	('BRCA1', 'Gene', (30, 35))	('low JWA', 'Phenotype', 'HP:0002720', (18, 25))	('JWA', 'Gene', (116, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('JWA', 'Gene', '10550', (22, 25))	('benefited', 'PosReg', (47, 56))	('BRCA1', 'Gene', '672', (125, 130))	('BRCA1', 'Gene', (125, 130))	('patients', 'Species', '9606', (4, 12))	('BRCA1', 'Gene', '672', (30, 35))	('JWA', 'Gene', (22, 25))	('JWA', 'Gene', '10550', (116, 119))	('docetaxel', 'Chemical', 'MESH:D000077143', (164, 173))	('low', 'Var', (18, 21))
697252	25925371	From the results, we can separate out the patients with low or high BRCA1 expression who could not benefit from cisplatin- or docetaxel-based treatment.	('expression', 'MPA', (74, 84))	('low', 'Var', (56, 59))	('BRCA1', 'Gene', (68, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (42, 50))	('BRCA1', 'Gene', '672', (68, 73))	('docetaxel', 'Chemical', 'MESH:D000077143', (126, 135))
697259	25350844	 Src Mutation Induces Acquired Lapatinib Resistance in ERBB2-Amplified Human Gastroesophageal Adenocarcinoma Models ERBB2-directed therapy is now a routine component of therapy for ERBB2-amplified metastatic gastroesophageal adenocarcinomas.	('Lapatinib Resistance', 'MPA', (31, 51))	('Src', 'Gene', '6714', (1, 4))	('ERBB2', 'Gene', '2064', (116, 121))	('Gastroesophageal Adenocarcinoma', 'Disease', (77, 108))	('ERBB2', 'Gene', (116, 121))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', (181, 186))	('Lapatinib', 'Chemical', 'MESH:D000077341', (31, 40))	('ERBB2', 'Gene', '2064', (181, 186))	('gastroesophageal adenocarcinomas', 'Disease', (208, 240))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (214, 239))	('Induces', 'Reg', (14, 21))	('gastroesophageal adenocarcinomas', 'Disease', 'MESH:D005764', (208, 240))	('ERBB2', 'Gene', '2064', (55, 60))	('Human', 'Species', '9606', (71, 76))	('Gastroesophageal Adenocarcinoma', 'Disease', 'MESH:D005764', (77, 108))	('Src', 'Gene', (1, 4))	('Mutation', 'Var', (5, 13))
697264	25350844	We identified a novel, acquired Src E527K mutation in a subset of LR OE19 subclones.	('E527K', 'Var', (36, 41))	('Src', 'Gene', '6714', (32, 35))	('E527K', 'Mutation', 'rs879255268', (36, 41))	('Src', 'Gene', (32, 35))
697265	25350844	Cells with this mutant allele harbour increased Src phosphorylation.	('mutant', 'Var', (16, 22))	('increased', 'PosReg', (38, 47))	('Src', 'Gene', '6714', (48, 51))	('Src', 'Gene', (48, 51))
697266	25350844	Genetic and pharmacologic inhibition of Src resensitized these subclones to lapatinib.	('inhibition', 'Var', (26, 36))	('Src', 'Gene', '6714', (40, 43))	('Src', 'Gene', (40, 43))	('lapatinib', 'Chemical', 'MESH:D000077341', (76, 85))
697267	25350844	Biochemically, Src mutations could activate both the phosphatidylinositol 3-kinase and mitogen activated protein kinase pathways in the lapatinib-treated LR OE19 cells.	('mutations', 'Var', (19, 28))	('activate', 'PosReg', (35, 43))	('lapatinib', 'Chemical', 'MESH:D000077341', (136, 145))	('phosphatidylinositol 3-kinase', 'Pathway', (53, 82))	('Src', 'Gene', (15, 18))	('mitogen activated protein kinase pathways', 'Pathway', (87, 128))	('Src', 'Gene', '6714', (15, 18))
697268	25350844	Ectopic expression of Src E527K mutation also was sufficient to induce lapatinib resistance in drug-naive cells.	('Src', 'Gene', '6714', (22, 25))	('induce', 'PosReg', (64, 70))	('E527K', 'Var', (26, 31))	('lapatinib', 'Chemical', 'MESH:D000077341', (71, 80))	('lapatinib resistance', 'MPA', (71, 91))	('Src', 'Gene', (22, 25))	('E527K', 'Mutation', 'rs879255268', (26, 31))
697276	25350844	The etiology of resistance to ERBB2-directed therapies has been widely investigated in breast cancer; the accepted resistance mechanisms included constitutive activation of the PI3-K pathway, truncated p95 isoform of HER2 receptor which cannot bind to trastuzumab, and constitutive Src activation as a common node downstream of multiple pathways.	('activation', 'PosReg', (159, 169))	('ERBB2', 'Gene', '2064', (30, 35))	('truncated', 'Var', (192, 201))	('ERBB2', 'Gene', (30, 35))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('p95', 'Gene', '4683', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('Src', 'Gene', (282, 285))	('p95', 'Gene', (202, 205))	('Src', 'Gene', '6714', (282, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('HER2', 'Gene', (217, 221))	('PI3-K pathway', 'Pathway', (177, 190))	('trastuzumab', 'Chemical', 'MESH:D000068878', (252, 263))	('HER2', 'Gene', '2064', (217, 221))
697277	25350844	In GE cancer, the variant of dopamine and cyclic AMP-regulated phosphoprotein (t-DARPP) has been suggested as a resistance mechanism to ERBB2 inhibitors, and exogenous HGF administration to cell line cultures has been shown to induce in vitro resistance in GE adenocarcinoma.	('adenocarcinoma', 'Disease', (260, 274))	('ERBB2', 'Gene', '2064', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('induce', 'Reg', (227, 233))	('ERBB2', 'Gene', (136, 141))	('GE cancer', 'Disease', 'MESH:D009369', (3, 12))	('GE cancer', 'Disease', (3, 12))	('adenocarcinoma', 'Disease', 'MESH:D000230', (260, 274))	('dopamine', 'Chemical', 'MESH:D004298', (29, 37))	('variant', 'Var', (18, 25))
697285	25350844	Through genomic and functional analyses of this lapatinib-resistant model, we found that an activating mutation of Src was responsible for the acquired lapatinib resistance in OE19 cells.	('acquired lapatinib resistance', 'MPA', (143, 172))	('lapatinib', 'Chemical', 'MESH:D000077341', (48, 57))	('lapatinib', 'Chemical', 'MESH:D000077341', (152, 161))	('Src', 'Gene', '6714', (115, 118))	('mutation', 'Var', (103, 111))	('Src', 'Gene', (115, 118))	('activating', 'PosReg', (92, 102))
697288	25350844	OE19 is ERBB2-amplified gastroesophageal cancer cell line and sensitive to lapatinib, hence OE33 is ERBB2- and MET-amplified gastroesophageal cancer cell line and has intrinsic resistance to lapatinib.	('ERBB2', 'Gene', '2064', (8, 13))	('OE33', 'Var', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (24, 47))	('ERBB2', 'Gene', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('ERBB2', 'Gene', '2064', (100, 105))	('lapatinib', 'Chemical', 'MESH:D000077341', (191, 200))	('ERBB2', 'Gene', (100, 105))	('gastroesophageal cancer', 'Disease', (24, 47))	('gastroesophageal cancer', 'Disease', (125, 148))	('lapatinib', 'Chemical', 'MESH:D000077341', (75, 84))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (125, 148))
697293	25350844	Following six months of culture with drug, we were able to obtain OE19 derivatives that were capable of proliferation in the presence of 3 microM of lapatinib.	('proliferation', 'CPA', (104, 117))	('OE19', 'Var', (66, 70))	('lapatinib', 'Chemical', 'MESH:D000077341', (149, 158))
697295	25350844	OncoPanel_v2 represents a targeted sequencing strategy to simultaneously detect mutations, translocations and copy-number variations in archived clinical tumor specimens.	('mutations', 'Var', (80, 89))	('translocations', 'Var', (91, 105))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('copy-number variations', 'Var', (110, 132))	('tumor', 'Disease', (154, 159))
697297	25350844	The Src E527K mutation (g1579a) was additionally validated by direct sequencing as follows; Src was PCR-amplified from genomic DNA using a 2720 thermal cycler (Applied Biosystems) using OneTaq Quick-Load 2X mix (BioLabs) with each primer (forward: 5'- GGGATGGTGAACCGCGAGGT-3', reverse: 5'-TTCTCCCCGGGCTGGT-3').	('Src', 'Gene', (92, 95))	('E527K', 'Var', (8, 13))	('Src', 'Gene', '6714', (92, 95))	('Src', 'Gene', (4, 7))	('Src', 'Gene', '6714', (4, 7))	('E527K', 'Mutation', 'rs879255268', (8, 13))
697299	25350844	Direct sequencing was using the M13R sequencing primer at Genewiz, Inc. We performed DNA restriction analysis to confirm that the Src E527K mutation is an acquired event owing to the prolonged lapatinib exposure, and it is not already present in the parental OE19 cells.	('E527K', 'Var', (134, 139))	('Src', 'Gene', (130, 133))	('Src', 'Gene', '6714', (130, 133))	('M13R', 'Mutation', 'p.M13R', (32, 36))	('lapatinib', 'Chemical', 'MESH:D000077341', (193, 202))	('E527K', 'Mutation', 'rs879255268', (134, 139))
697300	25350844	Genomic DNA were extracted from the parental OE19 and two LR subclones harbouring Src mutant, and PCR-amplified as described above.	('mutant', 'Var', (86, 92))	('Src', 'Gene', (82, 85))	('Src', 'Gene', '6714', (82, 85))
697308	25350844	Wild-type pDONR223-Src (#23934) was purchased from Addgene Inc. (Cambridge, Massachusetts).	('Src', 'Gene', (19, 22))	('Src', 'Gene', '6714', (19, 22))	('#23934', 'Var', (24, 30))
697311	25350844	pLX301-Src wild-type and PLX301-Src E527K lentiviral vectors were made from pDONR223-Src wild-type and pDONR223-Src E527K, respectively, by performing LR clonase reaction with pLX301 destination vector (Invitrogen).	('E527K', 'Mutation', 'rs879255268', (116, 121))	('Src', 'Gene', (112, 115))	('Src', 'Gene', '6714', (32, 35))	('Src', 'Gene', (85, 88))	('Src', 'Gene', '6714', (85, 88))	('E527K', 'Var', (116, 121))	('E527K', 'Var', (36, 41))	('Src', 'Gene', '6714', (112, 115))	('Src', 'Gene', (7, 10))	('Src', 'Gene', '6714', (7, 10))	('E527K', 'Mutation', 'rs879255268', (36, 41))	('Src', 'Gene', (32, 35))
697317	25350844	Then, the membranes were incubated with primary antibodies overnight at 4 C. Anti-EGFR antibody (#A300-388A) was purchased from Bethyl Laboratories.	('EGFR', 'Gene', '1956', (82, 86))	('EGFR', 'Gene', (82, 86))	('#A300-388A', 'Var', (97, 107))
697318	25350844	All other antibodies including anti-phospho EGFR Y1068 (#3777), anti-phospho ERBB2 Y1221/1222 (#2243), anti-ERBB2 (#2165), anti-phospho SRC Y416 (#6943), anti-SRC (#2109), anti-phospho-ERK 1/2 T202/Y204 (#4370), anti-ERK 1/2 (#4695), anti-phospho AKT S473 (#4060), and anti-AKT (#9272) were purchased from Cell Signaling Technologies.	('#4060', 'Var', (257, 262))	('SRC', 'Gene', '6714', (136, 139))	('AKT', 'Gene', '207', (247, 250))	('SRC', 'Gene', (159, 162))	('#2109', 'Var', (164, 169))	('#6943', 'Var', (146, 151))	('SRC', 'Gene', (136, 139))	('EGFR', 'Gene', '1956', (44, 48))	('AKT', 'Gene', (274, 277))	('ERBB2', 'Gene', (77, 82))	('#4695', 'Var', (226, 231))	('ERBB2', 'Gene', (108, 113))	('AKT', 'Gene', (247, 250))	('ERBB2', 'Gene', '2064', (77, 82))	('AKT', 'Gene', '207', (274, 277))	('EGFR', 'Gene', (44, 48))	('SRC', 'Gene', '6714', (159, 162))	('ERBB2', 'Gene', '2064', (108, 113))	('#2165', 'Var', (115, 120))
697323	25350844	Across these LR subclones, we identified distinct somatic mutations affecting genes Src, KEAP1 and PHOX2B (Figure 1A).	('PHOX2B', 'Gene', '8929', (99, 105))	('mutations', 'Var', (58, 67))	('Src', 'Gene', (84, 87))	('Src', 'Gene', '6714', (84, 87))	('KEAP1', 'Gene', (89, 94))	('PHOX2B', 'Gene', (99, 105))	('KEAP1', 'Gene', '9817', (89, 94))
697325	25350844	Within these data we initially focused upon two distinct clones, both harbouring the same acquired Src E527K mutation (Figure 1B) which was present in ~30% of sequenced alleles in each of these two subclones.	('E527K', 'Mutation', 'rs879255268', (103, 108))	('Src', 'Gene', '6714', (99, 102))	('Src', 'Gene', (99, 102))	('E527K', 'Var', (103, 108))
697328	25350844	Comparing the two clones with the Src mutation, we noted that one of the clones harboured a unique KEAP1 mutation suggesting that these two Src-mutant clones may not be identical.	('mutation', 'Var', (105, 113))	('KEAP1', 'Gene', (99, 104))	('Src', 'Gene', (140, 143))	('Src', 'Gene', '6714', (140, 143))	('Src', 'Gene', '6714', (34, 37))	('Src', 'Gene', (34, 37))	('KEAP1', 'Gene', '9817', (99, 104))
697331	25350844	Src E527K mutation was confirmed by direct sequencing (Figure 1C).	('Src', 'Gene', '6714', (0, 3))	('E527K', 'Var', (4, 9))	('Src', 'Gene', (0, 3))	('E527K', 'Mutation', 'rs879255268', (4, 9))
697332	25350844	Although we did not identify this Src mutation in the parental cell line from our sequencing, we performed additional focused analysis of this locus to detect if low-frequency Src mutant cells were present in the parent cell population.	('mutant', 'Var', (180, 186))	('Src', 'Gene', '6714', (34, 37))	('Src', 'Gene', (34, 37))	('Src', 'Gene', (176, 179))	('Src', 'Gene', '6714', (176, 179))
697334	25350844	The PCR amplicons of 203 bp from two LR subclones harboring Src mutant were not digested, in contrast those from the parental OE19 and Het1A were totally digested and yielded 182 bp products (Figure 1D).	('yielded', 'Reg', (167, 174))	('mutant', 'Var', (64, 70))	('Src', 'Gene', '6714', (60, 63))	('Src', 'Gene', (60, 63))
697335	25350844	From these results, we could identify no evidence of the Src E527K mutant in the parental cell population, suggesting it is an acquired event during the prolonged lapatinib exposure.	('E527K', 'Var', (61, 66))	('Src', 'Gene', (57, 60))	('Src', 'Gene', '6714', (57, 60))	('lapatinib', 'Chemical', 'MESH:D000077341', (163, 172))	('E527K', 'Mutation', 'rs879255268', (61, 66))
697342	25350844	Given the clear association between Src mutation and lapatinib resistance, we asked whether shRNA-mediated silencing of Src might restore lapatinib sensitivity in LR2A and LR2B clones.	('silencing', 'Var', (107, 116))	('Src', 'Gene', (120, 123))	('Src', 'Gene', '6714', (120, 123))	('lapatinib', 'Chemical', 'MESH:D000077341', (138, 147))	('lapatinib sensitivity', 'MPA', (138, 159))	('lapatinib', 'Chemical', 'MESH:D000077341', (53, 62))	('Src', 'Gene', '6714', (36, 39))	('Src', 'Gene', (36, 39))	('restore', 'PosReg', (130, 137))
697343	25350844	Indeed, silencing of Src by two independent small hairpin constructs sensitized both LR2A and LR2B clones to lapatinib treatment to the extent that the sensitivity profile of those two LR subclones became similar to that of parental OE19 (Figure 3A).	('Src', 'Gene', (21, 24))	('LR2B', 'Gene', (94, 98))	('silencing', 'Var', (8, 17))	('sensitized', 'Reg', (69, 79))	('LR2A', 'Gene', (85, 89))	('Src', 'Gene', '6714', (21, 24))	('lapatinib', 'Chemical', 'MESH:D000077341', (109, 118))
697348	25350844	The phosphorylations of AKT and ERK were slightly downregulated in the shLacZ transduced LR subclones, which were not observed dominantly in the mock-treated LR subclones, possibly attributable to the effects from lentiviral infections and puromycin selection.	('ERK', 'Gene', '5594', (32, 35))	('infections', 'Disease', 'MESH:D007239', (225, 235))	('AKT', 'Gene', (24, 27))	('ERK', 'Gene', (32, 35))	('infections', 'Disease', (225, 235))	('AKT', 'Gene', '207', (24, 27))	('shLacZ transduced', 'Var', (71, 88))	('downregulated', 'NegReg', (50, 63))	('phosphorylations', 'MPA', (4, 20))	('puromycin', 'Chemical', 'MESH:D011691', (240, 249))
697354	25350844	While the two Src E527K mutant subclones were not sensitive to either lapatinib or saracatinib alone, their growth was effectively inhibited when the two drugs were combined (Figure 4A & 4B).	('saracatinib', 'Chemical', 'MESH:C515233', (83, 94))	('E527K', 'Mutation', 'rs879255268', (18, 23))	('lapatinib', 'Chemical', 'MESH:D000077341', (70, 79))	('E527K', 'Var', (18, 23))	('Src', 'Gene', (14, 17))	('Src', 'Gene', '6714', (14, 17))	('inhibited', 'NegReg', (131, 140))	('growth', 'MPA', (108, 114))
697356	25350844	HER2 and EGFR phosphorylations were blocked upon lapatinib treatment regardless of the presence of saracatinib in both the parental OE19 cells and the two LR subclones suggesting that the mutant Src-mediated resistance is independent of HER2 or EGFR signalling (Figure 4C).	('HER2', 'Gene', '2064', (237, 241))	('lapatinib', 'Chemical', 'MESH:D000077341', (49, 58))	('blocked', 'NegReg', (36, 43))	('Src', 'Gene', (195, 198))	('EGFR', 'Gene', '1956', (245, 249))	('Src', 'Gene', '6714', (195, 198))	('EGFR', 'Gene', '1956', (9, 13))	('saracatinib', 'Chemical', 'MESH:C515233', (99, 110))	('EGFR', 'Gene', (9, 13))	('HER2', 'Gene', (0, 4))	('EGFR', 'Gene', (245, 249))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (237, 241))	('mutant', 'Var', (188, 194))
697362	25350844	We generated the Src E527K plasmid using site-directed mutagenesis, and transduced either wild-type Src, mutant Src or GFP control into parental OE19 cells.	('Src', 'Gene', (112, 115))	('E527K', 'Mutation', 'rs879255268', (21, 26))	('Src', 'Gene', (17, 20))	('Src', 'Gene', '6714', (17, 20))	('Src', 'Gene', '6714', (112, 115))	('Src', 'Gene', (100, 103))	('Src', 'Gene', '6714', (100, 103))	('E527K', 'Var', (21, 26))	('mutant', 'Var', (105, 111))
697363	25350844	Indeed, Src E527K transduced OE19 developed lapatinib resistance (IC50 to the lapatinib, 1179.0 nM), while GFP or Src wild-type transduced OE19 remained sensitive to lapatinib (IC50 to the lapatinib, 256.6 nM and 313.8 nM, respectively, Figure 5A).	('developed', 'PosReg', (34, 43))	('lapatinib', 'Chemical', 'MESH:D000077341', (189, 198))	('lapatinib', 'Chemical', 'MESH:D000077341', (166, 175))	('E527K transduced', 'Var', (12, 28))	('Src', 'Gene', (8, 11))	('Src', 'Gene', (114, 117))	('lapatinib', 'Chemical', 'MESH:D000077341', (78, 87))	('Src', 'Gene', '6714', (114, 117))	('E527K', 'Mutation', 'rs879255268', (12, 17))	('Src', 'Gene', '6714', (8, 11))	('lapatinib resistance', 'MPA', (44, 64))	('lapatinib', 'Chemical', 'MESH:D000077341', (44, 53))
697364	25350844	Furthermore, the lapatinib resistance conferred by exogenous expression of Src E527K was overcome by the combined treatment of saracatinib (Figure 5B).	('Src', 'Gene', (75, 78))	('Src', 'Gene', '6714', (75, 78))	('lapatinib resistance', 'MPA', (17, 37))	('E527K', 'Mutation', 'rs879255268', (79, 84))	('E527K', 'Var', (79, 84))	('saracatinib', 'Chemical', 'MESH:C515233', (127, 138))	('lapatinib', 'Chemical', 'MESH:D000077341', (17, 26))
697366	25350844	As in the LR subclones harbouring spontaneous Src mutation, expression of p-Src was increased in Src transduced OE19 either with wild-type or E527K mutant compared to the parental or GFP transduced cells (Figure 5C).	('Src', 'Gene', '6714', (46, 49))	('expression', 'MPA', (60, 70))	('Src', 'Gene', '6714', (97, 100))	('E527K', 'Mutation', 'rs879255268', (142, 147))	('increased', 'PosReg', (84, 93))	('Src', 'Gene', (76, 79))	('E527K', 'Var', (142, 147))	('Src', 'Gene', '6714', (76, 79))	('Src', 'Gene', (97, 100))	('Src', 'Gene', (46, 49))
697367	25350844	Src E527K transduced OE19 showed particularly high expression of p-SRC.	('SRC', 'Gene', (67, 70))	('E527K transduced', 'Var', (4, 20))	('Src', 'Gene', '6714', (0, 3))	('Src', 'Gene', (0, 3))	('expression', 'MPA', (51, 61))	('SRC', 'Gene', '6714', (67, 70))	('E527K', 'Mutation', 'rs879255268', (4, 9))
697368	25350844	Although the phosphorylation of Src in the OE19 cells transduced with wild-type Src was not effectively inhibited by saracatinib, Src phosphorylation in Src E527K transduced OE19 was significantly inhibited by saracatinib regardless of the presence of lapatinib.	('Src', 'Gene', '6714', (80, 83))	('Src', 'Gene', (153, 156))	('Src', 'Gene', '6714', (153, 156))	('inhibited', 'NegReg', (197, 206))	('phosphorylation', 'MPA', (134, 149))	('E527K', 'Var', (157, 162))	('Src', 'Gene', '6714', (32, 35))	('saracatinib', 'Chemical', 'MESH:C515233', (210, 221))	('Src', 'Gene', (130, 133))	('Src', 'Gene', '6714', (130, 133))	('lapatinib', 'Chemical', 'MESH:D000077341', (252, 261))	('Src', 'Gene', (80, 83))	('saracatinib', 'Chemical', 'MESH:C515233', (117, 128))	('Src', 'Gene', (32, 35))	('E527K', 'Mutation', 'rs879255268', (157, 162))
697369	25350844	Additionally, the levels of p-AKT and p-ERK 1/2 were not suppressed by lapatinib alone in the Src E527K transduced OE19, consistent with our hypothesis that constitutive Src activation might sustain both downstream signalling pathways.	('E527K', 'Var', (98, 103))	('AKT', 'Gene', '207', (30, 33))	('Src', 'Gene', (94, 97))	('Src', 'Gene', '6714', (94, 97))	('lapatinib', 'Chemical', 'MESH:D000077341', (71, 80))	('Src', 'Gene', '6714', (170, 173))	('AKT', 'Gene', (30, 33))	('Src', 'Gene', (170, 173))	('E527K', 'Mutation', 'rs879255268', (98, 103))
697373	25350844	Through genomic and functional analysis of LR subclones, we found that an activating mutation of Src was responsible for the acquired lapatinib resistance in two of seven isolated subclones in this in vitro model system.	('activating', 'PosReg', (74, 84))	('lapatinib resistance', 'MPA', (134, 154))	('mutation', 'Var', (85, 93))	('Src', 'Gene', '6714', (97, 100))	('lapatinib', 'Chemical', 'MESH:D000077341', (134, 143))	('Src', 'Gene', (97, 100))
697374	25350844	In addition, we further demonstrated that genetic or pharmacologic blockade of Src could restore ERBB2 inhibitor sensitivity in LR subclones with hyperactive Src.	('restore', 'PosReg', (89, 96))	('blockade', 'Var', (67, 75))	('Src', 'Gene', (158, 161))	('Src', 'Gene', '6714', (158, 161))	('hyperactive Src', 'Disease', (146, 161))	('hyperactive Src', 'Disease', 'MESH:D006948', (146, 161))	('Src', 'Gene', (79, 82))	('Src', 'Gene', '6714', (79, 82))	('ERBB2', 'Gene', (97, 102))	('ERBB2', 'Gene', '2064', (97, 102))
697384	25350844	Although the role of increased Src activity in the resistance of ERBB2-amplified breast cancer and GE cancer to ERBB2 inhibition has been documented, we reported here, for the first time, the activation of a spontaneous Src mutation after prolonged exposure to HER2 inhibitor could induce lapatinib resistance in ERBB2-amplified GE adenocarcinoma and present the first evidence of acquired mutation of Src as an etiology of resistance.	('adenocarcinoma', 'Disease', (332, 346))	('GE cancer', 'Disease', (99, 108))	('breast cancer', 'Disease', (81, 94))	('ERBB2', 'Gene', (112, 117))	('Src', 'Gene', (31, 34))	('ERBB2', 'Gene', '2064', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ERBB2', 'Gene', '2064', (112, 117))	('Src', 'Gene', (402, 405))	('adenocarcinoma', 'Disease', 'MESH:D000230', (332, 346))	('Src', 'Gene', (220, 223))	('mutation', 'Var', (224, 232))	('Src', 'Gene', '6714', (31, 34))	('activation', 'PosReg', (192, 202))	('HER2', 'Gene', '2064', (261, 265))	('lapatinib', 'Chemical', 'MESH:D000077341', (289, 298))	('Src', 'Gene', '6714', (220, 223))	('Src', 'Gene', '6714', (402, 405))	('ERBB2', 'Gene', (313, 318))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('induce', 'Reg', (282, 288))	('GE cancer', 'Disease', 'MESH:D009369', (99, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('lapatinib resistance', 'MPA', (289, 309))	('ERBB2', 'Gene', (65, 70))	('ERBB2', 'Gene', '2064', (313, 318))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))	('HER2', 'Gene', (261, 265))
697385	25350844	While these data clearly demonstrate the capacity of activated Src to serve as a mediator of acquired resistance to ERBB2 inhibitor therapy in GE cancers, future studies will be required to query the presence of Src mutation or enhanced activity of this kinase in patient samples upon emergence of resistance.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('ERBB2', 'Gene', '2064', (116, 121))	('activity', 'MPA', (237, 245))	('GE cancer', 'Disease', (143, 152))	('ERBB2', 'Gene', (116, 121))	('GE cancer', 'Disease', 'MESH:D009369', (143, 152))	('mutation', 'Var', (216, 224))	('Src', 'Gene', (212, 215))	('Src', 'Gene', '6714', (212, 215))	('Src', 'Gene', (63, 66))	('Src', 'Gene', '6714', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('patient', 'Species', '9606', (264, 271))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('enhanced', 'PosReg', (228, 236))
697388	25350844	Mechanisms for de novo or acquired trastuzumab resistance included constitutive activation PI3-K pathway owing to PTEN deficiency or PIK3CA gene mutation, the expression of truncated HER2 receptors, and overexpressions of other receptor tyrosine kinases which include EGFR, insulin-like growth factor-1 receptor, and hepatocyte growth factor receptor.	('EGFR', 'Gene', '1956', (268, 272))	('HER2', 'Gene', '2064', (183, 187))	('tyrosine', 'Chemical', 'MESH:D014443', (237, 245))	('PIK3CA', 'Gene', (133, 139))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (274, 311))	('hepatocyte growth factor receptor', 'Gene', '4233', (317, 350))	('PTEN deficiency', 'Disease', (114, 129))	('PIK3CA', 'Gene', '5290', (133, 139))	('EGFR', 'Gene', (268, 272))	('hepatocyte growth factor receptor', 'Gene', (317, 350))	('HER2', 'Gene', (183, 187))	('trastuzumab', 'Chemical', 'MESH:D000068878', (35, 46))	('PTEN deficiency', 'Disease', 'MESH:D006223', (114, 129))	('overexpressions', 'PosReg', (203, 218))	('activation', 'PosReg', (80, 90))	('insulin-like growth factor-1 receptor', 'Gene', (274, 311))	('mutation', 'Var', (145, 153))
697392	25350844	Based upon the results presented in this study, further focused evaluation of Src activation, either due to mutation or other means of activation, should be considered on patient tumors following the acquisition of resistance to ERBB2-directed therapy for evidence.	('ERBB2', 'Gene', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('patient', 'Species', '9606', (171, 178))	('Src', 'Gene', (78, 81))	('Src', 'Gene', '6714', (78, 81))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('activation', 'PosReg', (82, 92))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('mutation', 'Var', (108, 116))	('ERBB2', 'Gene', '2064', (229, 234))
697408	33810377	Since daily rhythm in numerous cellular processes is a crucial part of homeostasis, it is not surprising that perturbation of the clock is associated to pathological conditions such as neurodegeneration, metabolic disorders, and cancer.	('metabolic disorders', 'Disease', (204, 223))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('neurodegeneration', 'Phenotype', 'HP:0002180', (185, 202))	('associated', 'Reg', (139, 149))	('metabolic disorders', 'Disease', 'MESH:D008659', (204, 223))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('perturbation', 'Var', (110, 122))	('neurodegeneration', 'Disease', (185, 202))	('neurodegeneration', 'Disease', 'MESH:D019636', (185, 202))
697412	33810377	Indeed, other pieces of evidence have revealed that dysfunctions in circadian rhythms affect tumorigenesis and clock genes regulate several cancer hallmarks.	('affect', 'Reg', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('regulate', 'Reg', (123, 131))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('circadian', 'MPA', (68, 77))	('dysfunctions', 'Var', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
697438	33810377	The expression of the genetic construction K5CreER:p53fl/fl:RosaYFP was activated through intraperitoneal injection of 2.5 mg of tamoxifen (BOC Science, Shirley, NY, USA, B0084-358326) in sterile sunflower seed oil in 8 weeks-old mice housed under SOPF conditions.	('tamoxifen', 'Chemical', 'MESH:D013629', (129, 138))	('p53', 'Gene', (51, 54))	('K5CreER', 'Var', (43, 50))	('mice', 'Species', '10090', (230, 234))	('RosaYFP', 'Gene', (60, 67))	('seed oil', 'Chemical', '-', (206, 214))	('p53', 'Gene', '22060', (51, 54))	('activated', 'PosReg', (72, 81))	('sunflower', 'Species', '4232', (196, 205))
697489	33810377	However, other mRNAs such as ARNTL (coding for BMAL1 protein) is upregulated in some lines (KYSE-270 and -450), downregulated in another (KYSE-410 and 180) or not modified (KYSE-140) (Figure 2B-F).	('downregulated', 'NegReg', (112, 125))	('BMAL1', 'Gene', (47, 52))	('BMAL1', 'Gene', '406', (47, 52))	('ARNTL', 'Gene', (29, 34))	('ARNTL', 'Gene', '406', (29, 34))	('upregulated', 'PosReg', (65, 76))	('KYSE-270 and -450', 'Var', (92, 109))	('KYSE-410', 'Var', (138, 146))
697490	33810377	To determine whether esophageal cancer cells have somehow conserved a circadian rhythm in spite of these modifications, we then focused our analysis on the KYSE-410 eSCC line.	('esophageal cancer', 'Disease', (21, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (21, 38))	('modifications', 'Var', (105, 118))	('circadian rhythm', 'MPA', (70, 86))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('SCC', 'Phenotype', 'HP:0002860', (166, 169))
697519	33810377	We profiled YFP+ eSCC epithelial cells by RNAseq and compared them to FACS sorted EpCam+ control esophageal epithelial cells (Figure 5D).	('YFP+', 'Var', (12, 16))	('FACS', 'Gene', (70, 74))	('FACS', 'Gene', '14081', (70, 74))	('SCC', 'Phenotype', 'HP:0002860', (18, 21))	('EpCam', 'Gene', (82, 87))	('EpCam', 'Gene', '4072', (82, 87))
697522	33810377	We grew FACS sorted YFP+ tumor epithelial cells in vitro (Figure 6A) and transduced the PER2:Luc construct in these cells using lentiviral particles.	('Luc', 'Gene', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('FACS', 'Gene', (8, 12))	('FACS', 'Gene', '14081', (8, 12))	('transduced', 'Var', (73, 83))	('Luc', 'Gene', '249591', (93, 96))
697532	33810377	It is now clear that the disruption of the circadian rhythm increases the risk of developing cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('circadian', 'MPA', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('disruption', 'Var', (25, 35))
697535	33810377	Mouse models with an invalidation of the clock master genes PER1 and/or PER2 display an increased risk of spontaneous and radiation-induced cancer development.	('PER1', 'Gene', (60, 64))	('PER2', 'Gene', (72, 76))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('invalidation', 'Var', (21, 33))	('Mouse', 'Species', '10090', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('radiation-induced cancer', 'Phenotype', 'HP:0010997', (122, 146))
697665	32884570	The factors related to the difficulty in determining the borders of lesions originating from the muscularis propria in the tunnel during ESTD were as follows: (1) the lesion originated from the muscularis propria, but protruded outward, and there was no visible muscle fiber hyperplasia and hyperemia, so there was no difference between its inner surface of the muscularis propria and that of the normal muscularis propria; (2) using general anesthesia with tracheal intubation and muscle relaxants led to abdominal muscle relaxation; thus, the intraperitoneal pressure was significantly reduced causing the lesions to further protrude outwardly, while the inward protruding was more weakened.	('hyperplasia', 'Disease', 'MESH:D006965', (275, 286))	('abdominal muscle relaxation', 'CPA', (506, 533))	('hyperemia', 'Disease', (291, 300))	('reduced', 'NegReg', (588, 595))	('muscle fiber hyperplasia', 'Phenotype', 'HP:0100293', (262, 286))	('hyperplasia', 'Disease', (275, 286))	('hyperemia', 'Disease', 'MESH:D006940', (291, 300))	('lesions', 'Var', (608, 615))	('muscularis propria', 'Phenotype', 'HP:0030936', (194, 212))	('muscularis propria', 'Phenotype', 'HP:0030936', (362, 380))	('muscularis propria', 'Phenotype', 'HP:0030936', (404, 422))	('muscularis propria', 'Phenotype', 'HP:0030936', (97, 115))	('intraperitoneal pressure', 'MPA', (545, 569))
697674	32487090	CD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively).	('CD4', 'Gene', '920', (5, 8))	('overall survival', 'MPA', (76, 92))	('CD4', 'Gene', '920', (15, 18))	('ICOS', 'Gene', (23, 27))	('CD8', 'Gene', (10, 13))	('CD45', 'Gene', (15, 19))	('CD8', 'Gene', '925', (10, 13))	('CD4', 'Gene', (15, 18))	('better', 'PosReg', (69, 75))	('PD-1', 'Gene', (32, 36))	('CD4', 'Gene', (5, 8))	('CD45', 'Gene', '5788', (15, 19))	('PD-1', 'Gene', '5133', (32, 36))	('CD3', 'Var', (0, 3))
697681	32487090	Response to checkpoint inhibition has been shown to be more effective in tumours with a higher mutational load.	('tumours', 'Disease', (73, 80))	('mutational load', 'Var', (95, 110))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('tumours', 'Disease', 'MESH:D009369', (73, 80))
697683	32487090	EAC is one example of a tumour type with a high mutational frequency with as many as three hundred thousand mutations per tumour.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (108, 117))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (122, 128))	('tumour', 'Disease', (24, 30))	('EAC', 'Disease', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
697687	32487090	There is evidence that PD-L1 expression in EAC tumours is predictive of response in phase 1 trials, NCT01928394, NCT01943461 and NCT01772004 reported in a recent meta-analysis.	('NCT01928394', 'Var', (100, 111))	('PD-L1', 'Gene', (23, 28))	('EAC tumours', 'Disease', (43, 54))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('EAC tumours', 'Disease', 'MESH:C536611', (43, 54))	('PD-L1', 'Gene', '29126', (23, 28))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('NCT01772004', 'Var', (129, 140))
697720	32487090	Kaplan Meier survival analysis showed that high CD3, CD4, CD8 and CD45RO were significantly associated with better OS (Fig.	('CD45', 'Gene', (66, 70))	('CD4', 'Gene', (66, 69))	('CD3', 'Var', (48, 51))	('CD8', 'Gene', (58, 61))	('CD4', 'Gene', '920', (66, 69))	('CD45', 'Gene', '5788', (66, 70))	('CD8', 'Gene', '925', (58, 61))	('high CD3', 'Var', (43, 51))	('better OS', 'Disease', (108, 117))	('CD4', 'Gene', (53, 56))	('associated', 'Reg', (92, 102))	('CD4', 'Gene', '920', (53, 56))
697728	32487090	Unsurprisingly, the highest correlation was CD3:CD8 (r2 = 0.83) while the lowest correlation was seen with CD3:IDO-1 (r2 = 0.16).	('correlation', 'Interaction', (28, 39))	('CD3', 'Var', (44, 47))	('CD8', 'Gene', (48, 51))	('IDO-1', 'Gene', (111, 116))	('IDO-1', 'Gene', '3620', (111, 116))	('CD8', 'Gene', '925', (48, 51))
697733	32487090	Co-expression of high CD45RO and ICOS conferred a significant survival advantage over five-years, 65% (high/high) and 8% (low/low), respectively (Log rank p = < 0.001).	('CD45', 'Gene', '5788', (22, 26))	('ICOS', 'Gene', (33, 37))	('advantage', 'PosReg', (71, 80))	('high', 'Var', (17, 21))	('survival', 'CPA', (62, 70))	('CD45', 'Gene', (22, 26))
697754	32487090	The expression of high CD3, CD4, CD8 and FOXp3 cells in EAC was reported in 128 cases, where all markers achieved significance in univariate analysis, closely mirroring our own data.	('CD8', 'Gene', (33, 36))	('EAC', 'Disease', (56, 59))	('CD8', 'Gene', '925', (33, 36))	('CD4', 'Gene', (28, 31))	('CD4', 'Gene', '920', (28, 31))	('FOXp3', 'Gene', '50943', (41, 46))	('high', 'Var', (18, 22))	('FOXp3', 'Gene', (41, 46))	('CD3', 'Gene', (23, 26))
697806	32454971	The histopathological analysis of the resected specimen revealed squamous cell carcinoma (moderately differentiated) of the esophagus, Ce, 0- IIb, 14x8 mm, pT1b(SM1), INFalpha, ly0(D2-40), v0(EVG), pHM0, pVM0 (Fig.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('SM1', 'Gene', (161, 164))	('squamous cell carcinoma', 'Disease', (65, 88))	('INFalpha', 'Gene', (167, 175))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 88))	('SM1', 'Gene', '7911', (161, 164))	('INFalpha', 'Gene', '3451', (167, 175))	('14x8 mm', 'Var', (147, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('pT1b', 'Var', (156, 160))
697819	32104700	The Kaplan-Meier survival analysis indicated that a three-miRNA signature (miR-1301-3p, miR-431-5p, and miR-769-5p) was significantly associated with the overall survival of ESCA patients.	('miR-769-5p', 'Var', (104, 114))	('associated with', 'Reg', (134, 149))	('miR-1301', 'Gene', '100302246', (75, 83))	('ESCA', 'Phenotype', 'HP:0011459', (174, 178))	('ESCA', 'Disease', (174, 178))	('miR-769-5p', 'Chemical', '-', (104, 114))	('miR-431-5p', 'Var', (88, 98))	('miR-1301', 'Gene', (75, 83))
697832	32104700	have reported that miR-431-5p can inhibit lung carcinoma development, and miR-431-5p is also significantly downregulated in carcinoids that metastasize to the lymph nodes.	('miR-431-5p', 'Var', (74, 84))	('miR-431-5p', 'Var', (19, 29))	('carcinoids', 'Disease', 'MESH:D002276', (124, 134))	('carcinoids', 'Disease', (124, 134))	('carcinoids', 'Phenotype', 'HP:0100570', (124, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('lung carcinoma', 'Disease', 'MESH:D008175', (42, 56))	('downregulated', 'NegReg', (107, 120))	('inhibit', 'NegReg', (34, 41))	('lung carcinoma', 'Disease', (42, 56))
697833	32104700	In addition, miR-769-5p has been involved in the oncogenesis and development of melanoma and can promote the proliferation of this malignancy by suppressing GSK3B.	('involved', 'Reg', (33, 41))	('GSK3B', 'Gene', '2932', (157, 162))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('GSK3B', 'Gene', (157, 162))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('miR-769-5p', 'Var', (13, 23))	('suppressing', 'NegReg', (145, 156))	('proliferation', 'CPA', (109, 122))	('promote', 'PosReg', (97, 104))
697834	32104700	demonstrated that miR-769-5p is significantly downregulated in non-small-cell lung carcinoma.	('miR-769-5p', 'Var', (18, 28))	('non-small-cell lung carcinoma', 'Disease', (63, 92))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (63, 92))	('downregulated', 'NegReg', (46, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
697836	32104700	reported that miR-1301-3p inhibits the migration, invasion, and angiogenesis of hepatocellular carcinoma by targeting BCL9 via Wnt/beta-catenin signaling.	('inhibits', 'NegReg', (26, 34))	('invasion', 'CPA', (50, 58))	('miR-1301-3p', 'Var', (14, 25))	('beta-catenin', 'Gene', (131, 143))	('angiogenesis', 'CPA', (64, 76))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (80, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('BCL9', 'Gene', (118, 122))	('hepatocellular carcinoma', 'Disease', (80, 104))	('migration', 'CPA', (39, 48))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (80, 104))	('beta-catenin', 'Gene', '1499', (131, 143))	('BCL9', 'Gene', '607', (118, 122))	('targeting', 'Reg', (108, 117))
697876	30021250	reported that 47.4% of papilloma lesions were associated with the high-risk HPV serotype 16.	('papilloma lesions', 'Disease', 'MESH:D010212', (23, 40))	('papilloma lesions', 'Disease', (23, 40))	('papilloma', 'Phenotype', 'HP:0012740', (23, 32))	('HPV', 'Species', '10566', (76, 79))	('HPV', 'Gene', (76, 79))	('associated', 'Reg', (46, 56))	('serotype 16', 'Var', (80, 91))
697893	30662463	Many epidemiologic studies have assessed the association between homocysteine and risk of digestive tract cancer, but the results are inconsistent.	('tract cancer', 'Disease', (100, 112))	('homocysteine', 'Var', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (90, 112))	('cancer', 'Disease', (106, 112))	('homocysteine', 'Chemical', 'MESH:D006710', (65, 77))	('tract cancer', 'Disease', 'MESH:D014571', (100, 112))
697898	30662463	Hypermethylation or hypomethylation, in which one-carbon metabolites play an important role, can be observed in a wide variety of malignancies, including gastric, esophageal, and colorectal cancers.	('rectal cancer', 'Phenotype', 'HP:0100743', (183, 196))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('colorectal cancer', 'Phenotype', 'HP:0003003', (179, 196))	('colorectal cancers', 'Disease', (179, 197))	('malignancies', 'Disease', (130, 142))	('Hypermethylation', 'Var', (0, 16))	('hypomethylation', 'Var', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('observed', 'Reg', (100, 108))	('esophageal', 'Disease', (163, 173))	('gastric', 'Disease', (154, 161))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))
697905	30662463	Deficiencies of folate and vitamin B12 can first block the reaction of homocysteine remethylation and, second, block homocysteine catabolism because of the reduced synthesis of SAM.	('synthesis', 'MPA', (164, 173))	('Deficiencies', 'Var', (0, 12))	('block homocysteine catabolism', 'Disease', 'MESH:D006327', (111, 140))	('reaction', 'MPA', (59, 67))	('SAM', 'MPA', (177, 180))	('block homocysteine catabolism', 'Disease', (111, 140))	('block', 'NegReg', (49, 54))	('reduced', 'NegReg', (156, 163))	('homocysteine remethylation', 'MPA', (71, 97))
697906	30662463	Homocysteine has been widely studied in terms of cardiovascular disease and has been recognized as a potential risk factor for stroke, coronary vascular disease, ischemic heart disease, and other vascular occlusive diseases.	('vascular occlusive diseases', 'Disease', (196, 223))	('ischemic heart disease', 'Disease', 'MESH:D003324', (162, 184))	('Homocysteine', 'Var', (0, 12))	('stroke', 'Phenotype', 'HP:0001297', (127, 133))	('stroke', 'Disease', 'MESH:D020521', (127, 133))	('cardiovascular disease', 'Disease', (49, 71))	('stroke', 'Disease', (127, 133))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (49, 71))	('vascular occlusive diseases', 'Disease', 'MESH:D008641', (196, 223))	('cardiovascular disease', 'Disease', 'MESH:D002318', (49, 71))	('ischemic heart disease', 'Disease', (162, 184))	('coronary vascular disease', 'Disease', 'MESH:D003323', (135, 160))	('coronary vascular disease', 'Disease', (135, 160))	('vascular occlusive diseases', 'Phenotype', 'HP:0004950', (196, 223))
697912	30662463	Additionally, studies have demonstrated that hypermethylation could be in the promoter region of mismatch repair gene hMLH1 in patients with sporadic colorectal cancer with microsatellite instability, which can be used as a basis for treatment and prognosis.	('hMLH1', 'Gene', '4292', (118, 123))	('colorectal cancer', 'Disease', (150, 167))	('hypermethylation', 'Var', (45, 61))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('rectal cancer', 'Phenotype', 'HP:0100743', (154, 167))	('microsatellite instability', 'Var', (173, 199))	('hMLH1', 'Gene', (118, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))
697925	29248170	On multivariable analysis, PBT was significantly associated with a reduction in grade 4 lymphopenia risk (odds ratio, 0.29; 95% confidence interval, 0.16 to 0.52; P < 0.0001).	('lymphopenia', 'Disease', (88, 99))	('reduction', 'NegReg', (67, 76))	('grade', 'Disease', (80, 85))	('PBT', 'Var', (27, 30))	('lymphopenia', 'Phenotype', 'HP:0001888', (88, 99))	('lymphopenia', 'Disease', 'MESH:D008231', (88, 99))
697935	29248170	We therefore conducted this propensity matched analysis with the hypothesis that PBT compared to photon RT could result in a lower risk of clinically significant lymphopenia with treatment.	('lymphopenia', 'Phenotype', 'HP:0001888', (162, 173))	('lymphopenia', 'Disease', 'MESH:D008231', (162, 173))	('PBT', 'Var', (81, 84))	('lymphopenia', 'Disease', (162, 173))
697964	29248170	Figure 1 depicts curves that represent the model estimated risk of grade 4 lymphopenia as a function of log PTV for both IMRT and PBT.	('lymphopenia', 'Disease', (75, 86))	('PTV', 'Chemical', '-', (108, 111))	('lymphopenia', 'Phenotype', 'HP:0001888', (75, 86))	('log PTV', 'Var', (104, 111))	('lymphopenia', 'Disease', 'MESH:D008231', (75, 86))
697971	29248170	Adjusting for partial effects of age and PTV, a significant reduction in the risk of grade 4 lymphopenia was seen among patients who received PBT compared to IMRT (OR, 0.290; 95% CI, 0.164 to 0.515; P < 0.0001), which was especially pronounced in patients with stage I-II disease (OR, 0.093; 95% CI, 0.028 to 0.313; P < 0.0001).	('PBT', 'Var', (142, 145))	('lymphopenia', 'Disease', (93, 104))	('grade', 'Disease', (85, 90))	('I-II disease', 'Disease', 'MESH:D056829', (267, 279))	('PTV', 'Chemical', '-', (41, 44))	('lymphopenia', 'Phenotype', 'HP:0001888', (93, 104))	('reduction', 'NegReg', (60, 69))	('lymphopenia', 'Disease', 'MESH:D008231', (93, 104))	('patients', 'Species', '9606', (247, 255))	('patients', 'Species', '9606', (120, 128))	('I-II disease', 'Disease', (267, 279))
697979	29248170	In a propensity-matched patient cohort, PBT compared to IMRT, adjusting for age and PTV, was associated with a clinically meaningful 71% risk reduction in grade 4 lymphopenia.	('reduction', 'NegReg', (142, 151))	('lymphopenia', 'Disease', 'MESH:D008231', (163, 174))	('lymphopenia', 'Phenotype', 'HP:0001888', (163, 174))	('patient', 'Species', '9606', (24, 31))	('PBT', 'Var', (40, 43))	('PTV', 'Chemical', '-', (84, 87))	('lymphopenia', 'Disease', (163, 174))
697983	29248170	This would also suggest that irradiating large pools of blood, such as the heart, would also lead to enhanced risk of lymphopenia.	('lymphopenia', 'Disease', (118, 129))	('lymphopenia', 'Phenotype', 'HP:0001888', (118, 129))	('irradiating', 'Var', (29, 40))	('lymphopenia', 'Disease', 'MESH:D008231', (118, 129))
698161	28243122	As shown in Figure 1, the Kaplan-Meier curves for PFS and OS revealed that, compared to patients in the low LMR group, patients in the high LMR group had a longer PFS (P<0.001, Figure 1A) and OS (P<0.001, Figure 1B).	('LMR', 'Chemical', '-', (140, 143))	('LMR', 'Chemical', '-', (108, 111))	('patients', 'Species', '9606', (119, 127))	('patients', 'Species', '9606', (88, 96))	('high LMR', 'Var', (135, 143))	('PFS', 'MPA', (163, 166))	('longer', 'PosReg', (156, 162))
698179	28243122	Go et al analyzed data from 171 patients with small-cell lung cancer and found that the ratio (98.3%) of the response (CR or PR) was higher in the high LMR group than the low LMR group (P=0.02).	('small-cell lung cancer', 'Disease', (46, 68))	('patients', 'Species', '9606', (32, 40))	('LMR', 'Chemical', '-', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (46, 68))	('higher', 'PosReg', (133, 139))	('LMR', 'Chemical', '-', (152, 155))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (46, 68))	('CR', 'Chemical', '-', (119, 121))	('high LMR', 'Var', (147, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
698184	28243122	The author reported that patients with an LMR <=2.57 had shorter DFS and OS than patients with an LMR >2.57.	('LMR', 'Chemical', '-', (98, 101))	('LMR', 'Chemical', '-', (42, 45))	('patients', 'Species', '9606', (81, 89))	('LMR <=2.57', 'Var', (42, 52))	('patients', 'Species', '9606', (25, 33))	('DFS', 'MPA', (65, 68))	('shorter', 'NegReg', (57, 64))
698196	26785143	Transcriptome profiling in oral cavity and esophagus tissues from (S)-N'-nitrosonornicotine-treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis Recently, we have shown that (S)-N'-Nitrosonornicotine [(S)-NNN], the major form of NNN in tobacco products, is a potent oral cavity and esophageal carcinogen in rats.	('tobacco', 'Species', '4097', (280, 287))	('rats', 'Species', '10116', (100, 104))	("(S)-N'-Nitrosonornicotine", 'Chemical', 'MESH:C008655', (218, 243))	('human', 'Species', '9606', (141, 146))	('(S)-NNN', 'Chemical', 'MESH:C008655', (245, 252))	("S)-N'-Nitrosonornicotine", 'Var', (219, 243))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (163, 188))	('NNN', 'Chemical', 'MESH:C008655', (273, 276))	('esophageal carcinogenesis', 'Disease', (163, 188))	('NNN', 'Chemical', 'MESH:C008655', (249, 252))	('rats', 'Species', '10116', (351, 355))	("(S)-N'-nitrosonornicotine", 'Chemical', 'MESH:C008655', (66, 91))
698204	26785143	NNN causes esophageal, oral cavity, and nasal cavity tumors in rats, nasal cavity tumors in mink, and respiratory tract tumors in mice and hamsters.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', (82, 88))	('respiratory tract tumors', 'Disease', (102, 126))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', (53, 59))	('mice', 'Species', '10090', (130, 134))	('rats', 'Species', '10116', (63, 67))	('esophageal', 'Disease', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('oral cavity', 'Disease', (23, 34))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('NNN', 'Var', (0, 3))	('mink', 'Species', '9666', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('causes', 'Reg', (4, 10))	('respiratory tract tumors', 'Phenotype', 'HP:0100606', (102, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('NNN', 'Chemical', 'MESH:C008655', (0, 3))	('respiratory tract tumors', 'Disease', 'MESH:D012140', (102, 126))
698212	26785143	Indeed, in our recent studies with male F-344 rats treated chronically with 14 ppm (S)-NNN in the drinking water, we showed that (S)-NNN is a strong oral cavity carcinogen, whereas the opposite enantiomer (R)-NNN was inactive, but synergistically enhanced the carcinogenicity of (S)-NNN [2].	('(S)-NNN', 'Chemical', 'MESH:C008655', (279, 286))	('drinking water', 'Chemical', 'MESH:D060766', (98, 112))	('enhanced', 'PosReg', (247, 255))	('(S)-NNN', 'Chemical', 'MESH:C008655', (83, 90))	('carcinogenic', 'Disease', 'MESH:D063646', (260, 272))	('S)-NNN', 'Var', (130, 136))	('(R)-NNN', 'Chemical', '-', (205, 212))	('carcinogenic', 'Disease', (260, 272))	('(S)-NNN', 'Chemical', 'MESH:C008655', (129, 136))	('rats', 'Species', '10116', (46, 50))
698213	26785143	Although (S)-NNN is a potent esophageal and oral cavity carcinogen in rats, the molecular mechanisms responsible for its carcinogenicity and its higher potency as compared to (R)-NNN are not known.	('(S)-NNN', 'Chemical', 'MESH:C008655', (9, 16))	('rats', 'Species', '10116', (70, 74))	('carcinogenic', 'Disease', 'MESH:D063646', (121, 133))	('(R)-NNN', 'Chemical', '-', (175, 182))	('carcinogenic', 'Disease', (121, 133))	('S)-NNN', 'Var', (10, 16))
698240	26785143	The concentration (A260) and purity (A260/A280 and A260/A230) of RNA were determined using NanoDrop 1000 spectrophotometry.	('rat', 'Species', '10116', (11, 14))	('A260/A230', 'Var', (51, 60))	('A260/A280', 'Var', (37, 46))
698266	26785143	The broader list of genes upregulated and downregulated by (S)-NNN in the esophageal mucosa of rats at a less stringent p-value < 0.01 is included in Supplementary Tables 2 and 3, respectively.	('(S)-NNN', 'Chemical', 'MESH:C008655', (59, 66))	('upregulated', 'PosReg', (26, 37))	('rats', 'Species', '10116', (95, 99))	('downregulated', 'NegReg', (42, 55))	('S)-NNN', 'Var', (60, 66))
698272	26785143	At a p-value between 0.005 and < 0.05, five additional genes (ADIPOQ, B3GNT5, EMB, GPR171, and RTP4) showed increased copy numbers in 10 - 21% of esophageal carcinoma cases (Supplementary Figure 1).	('EMB', 'Gene', (78, 81))	('RTP4', 'Gene', '360733', (95, 99))	('ADIPOQ', 'Gene', (62, 68))	('increased', 'PosReg', (108, 117))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (146, 166))	('GPR171', 'Gene', '688737', (83, 89))	('ADIPOQ', 'Gene', '246253', (62, 68))	('esophageal carcinoma', 'Disease', (146, 166))	('B3GNT5', 'Gene', '116740', (70, 76))	('EMB', 'Gene', '114511', (78, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('B3GNT5', 'Gene', (70, 76))	('RTP4', 'Gene', (95, 99))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (146, 166))	('copy numbers', 'Var', (118, 130))	('GPR171', 'Gene', (83, 89))
698273	26785143	In addition to copy number amplifications, ATP13A5, LY6E, NR1D1, B3GNT5, EMB, and RTP4 all showed mRNA upregulation in ESCA in comparison to the adjacent normal tissues (Table 1a).	('ESCA', 'Disease', (119, 123))	('EMB', 'Gene', '114511', (73, 76))	('RTP4', 'Gene', '360733', (82, 86))	('upregulation', 'PosReg', (103, 115))	('EMB', 'Gene', (73, 76))	('NR1D1', 'Gene', (58, 63))	('mRNA', 'MPA', (98, 102))	('B3GNT5', 'Gene', '116740', (65, 71))	('LY6E', 'Var', (52, 56))	('ATP13A5', 'Var', (43, 50))	('B3GNT5', 'Gene', (65, 71))	('NR1D1', 'Gene', '252917', (58, 63))	('RTP4', 'Gene', (82, 86))
698307	26785143	Similarly, Ctla-4 inhibits T cell activation by competing with CD28, a protein that provides co-stimulatory signals required for T cell activation and survival, for binding to leucocyte surface molecules CD80 and CD86, and thereby dampening of T-cell activation and proliferation.	('dampening', 'NegReg', (231, 240))	('T cell activation', 'CPA', (27, 44))	('binding', 'Interaction', (165, 172))	('inhibits', 'NegReg', (18, 26))	('CD86', 'Gene', '56822', (213, 217))	('dampening of T-cell activation', 'Phenotype', 'HP:0005419', (231, 261))	('CD86', 'Gene', (213, 217))	('CD28', 'Gene', (63, 67))	('CD28', 'Gene', '25660', (63, 67))	('CD80', 'Var', (204, 208))	('rat', 'Species', '10116', (273, 276))	('T-cell activation', 'CPA', (244, 261))	('Ctla-4', 'Gene', (11, 17))	('Ctla-4', 'Gene', '63835', (11, 17))
698315	26785143	Overexpression of CDKN2A has been reported in several benign and pre-malignant lesions and this phenomenon is believed to control cell proliferation in response to oncogenic stimuli, thereby protecting cells from malignant transformation.	('reported', 'Reg', (34, 42))	('control', 'Reg', (122, 129))	('Overexpression', 'Var', (0, 14))	('CDKN2A', 'Gene', (18, 24))	('rat', 'Species', '10116', (142, 145))	('cell proliferation', 'CPA', (130, 148))
698318	26785143	Therefore, inhibition of sEH could suppress chronic inflammation-associated cancers.	('inflammation-associated cancers', 'Disease', (52, 83))	('sEH', 'Gene', (25, 28))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('inflammation-associated cancers', 'Disease', 'MESH:D007249', (52, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('inhibition', 'Var', (11, 21))	('sEH', 'Gene', '65030', (25, 28))	('suppress', 'NegReg', (35, 43))
698319	26785143	Indeed, in one recent study, genetic knockout of sEH inhibited dextran sulfate sodium-induced colitis, inflammatory cytokines and chemokines, pre-cancerous dysplastic lesions and colon tumor incidence and tumor size.	('inhibited', 'NegReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('inflammatory cytokines', 'MPA', (103, 125))	('tumor', 'Disease', (185, 190))	('cancerous dysplastic lesions', 'Disease', (146, 174))	('colitis', 'Disease', (94, 101))	('sEH', 'Gene', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('cancerous dysplastic lesions', 'Disease', 'MESH:D009062', (146, 174))	('colitis', 'Disease', 'MESH:D003092', (94, 101))	('dextran sulfate sodium-induced', 'MPA', (63, 93))	('colon tumor', 'Disease', 'MESH:D015179', (179, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('colon tumor', 'Phenotype', 'HP:0100273', (179, 190))	('genetic knockout', 'Var', (29, 45))	('colon tumor', 'Disease', (179, 190))	('tumor', 'Disease', (205, 210))	('colitis', 'Phenotype', 'HP:0002583', (94, 101))	('dextran sulfate sodium', 'Chemical', 'MESH:D016264', (63, 85))	('sEH', 'Gene', '65030', (49, 52))
698323	26785143	Thus, it appears that induction of sEH plays a role in the promotion and progression of inflammation-associated cancers such as oral and esophageal cancer and thus could serve as a biomarker for the early detection of these diseases and as a target for chemopreventive and therapeutic agents.	('induction', 'Var', (22, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('sEH', 'Gene', (35, 38))	('inflammation-associated cancers', 'Disease', (88, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('inflammation-associated cancers', 'Disease', 'MESH:D007249', (88, 119))	('sEH', 'Gene', '65030', (35, 38))	('esophageal cancer', 'Disease', (137, 154))	('promotion', 'PosReg', (59, 68))
698328	26785143	LCK is a member of the Src family nonreceptor protein-tyrosine kinase and aberrant LCK expression and kinase activity have been implicated in the pathogenesis of both lymphoid and nonlymphoid malignancies.	('implicated', 'Reg', (128, 138))	('LCK', 'Gene', (83, 86))	('lymphoid and nonlymphoid malignancies', 'Disease', 'MESH:D008223', (167, 204))	('kinase activity', 'MPA', (102, 117))	('aberrant', 'Var', (74, 82))
698333	26785143	In addition to copy number amplification, both ATP13A5 and LY6E showed mRNA upregulation in human ESCA, suggesting their potential roles in early onset and maintenance of tumorigenesis as a result of increases in genetic activities.	('upregulation', 'PosReg', (76, 88))	('LY6E', 'Var', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mRNA', 'MPA', (71, 75))	('ATP13A5', 'Var', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('human', 'Species', '9606', (92, 97))	('ESCA', 'Disease', (98, 102))
698350	27068172	The presence of BE is associated with a 10-40 fold increased risk for the development of esophageal cancer; however, the rate of progression from BE to EAC is very low at only 0.1-0.3% per year.	('esophageal cancer', 'Disease', (89, 106))	('EAC', 'Gene', '1540', (152, 155))	('BE', 'Phenotype', 'HP:0100580', (146, 148))	('EAC', 'Gene', (152, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BE', 'Phenotype', 'HP:0100580', (16, 18))	('presence', 'Var', (4, 12))	('EAC', 'Phenotype', 'HP:0011459', (152, 155))
698362	27068172	BE and EAC share virtually identical risk factors, so changes in exposure leading to increased EAC likely also increased the risk of BE.	('EAC', 'Phenotype', 'HP:0011459', (95, 98))	('changes', 'Var', (54, 61))	('EAC', 'Gene', '1540', (95, 98))	('EAC', 'Phenotype', 'HP:0011459', (7, 10))	('EAC', 'Gene', (95, 98))	('BE and EAC', 'Gene', '1540', (0, 10))	('BE', 'Phenotype', 'HP:0100580', (133, 135))	('EAC', 'Gene', '1540', (7, 10))	('BE', 'Phenotype', 'HP:0100580', (0, 2))	('EAC', 'Gene', (7, 10))
698377	27068172	Helicobacter pylori dominates the gastric microbiome and causes gastric cancer, but is inversely associated with risk of EAC.	('EAC', 'Gene', '1540', (121, 124))	('Helicobacter pylori', 'Species', '210', (0, 19))	('EAC', 'Gene', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gastric cancer', 'Disease', (64, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('EAC', 'Phenotype', 'HP:0011459', (121, 124))	('Helicobacter pylori', 'Var', (0, 19))	('causes', 'Reg', (57, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))
698381	27068172	Alterations of the gut microbiome have been implicated in many gastrointestinal diseases, including cancers along the GI tract, in particular gastric and colorectal cancer.	('cancers along the GI tract', 'Phenotype', 'HP:0007378', (100, 126))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('colorectal cancer', 'Disease', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Alterations', 'Var', (0, 11))	('implicated', 'Reg', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric', 'Disease', (142, 149))	('gastrointestinal diseases', 'Disease', (63, 88))	('gut microbiome', 'Species', '749906', (19, 33))	('gastrointestinal diseases', 'Disease', 'MESH:D005767', (63, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))	('gastrointestinal diseases', 'Phenotype', 'HP:0011024', (63, 88))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))	('cancers', 'Disease', (100, 107))
698445	27068172	In studies of the fecal microbiome, PPIs have been shown to increase the relative abundance of pharyngeal flora, including Streptococcus species, relative to resident colonic bacteria, likely through removing the barrier of a highly acidic environment.	('removing', 'NegReg', (200, 208))	('PPIs', 'Var', (36, 40))	('increase', 'PosReg', (60, 68))	('Streptococcus', 'Species', '1328', (123, 136))	('colonic bacteria', 'Disease', (167, 183))	('colonic bacteria', 'Disease', 'MESH:D015179', (167, 183))
698446	27068172	PPI treatment increases total bacterial concentrations in the stomach, and significantly alters the gastric microbiome, with statistically significant increases in several genera, including Streptococcus, Staphylococcus, Veilonella.	('increases', 'PosReg', (14, 23))	('increases', 'PosReg', (151, 160))	('alters', 'Reg', (89, 95))	('Veilonella', 'Disease', (221, 231))	('Staphylococcus', 'Disease', (205, 219))	('Streptococcus', 'Species', '1328', (190, 203))	('gastric microbiome', 'MPA', (100, 118))	('PPI', 'Var', (0, 3))	('Streptococcus', 'Disease', (190, 203))
698450	27068172	Although not studied in the esophageal microbiome, dietary choices cause rapid microbiome alterations and likely potentiate cancer risk in other parts of the human gastrointestinal system.	('potentiate', 'PosReg', (113, 123))	('cancer', 'Disease', (124, 130))	('dietary choices', 'Var', (51, 66))	('human', 'Species', '9606', (158, 163))	('microbiome', 'MPA', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('gastrointestinal system', 'Disease', (164, 187))	('gastrointestinal system', 'Disease', 'MESH:D005767', (164, 187))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
698453	27068172	Several theories have been put forward to explain how microbiome alterations could predispose to Barrett's esophagus and EAC.	('EAC', 'Gene', '1540', (121, 124))	('alterations', 'Var', (65, 76))	("Barrett's esophagus", 'Disease', (97, 116))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (97, 116))	('EAC', 'Gene', (121, 124))	('predispose', 'Reg', (83, 93))	('EAC', 'Phenotype', 'HP:0011459', (121, 124))
698455	27068172	Although causation is difficult to determine from observational studies, there are plausible mechanisms through which Gram-negatives could lead to metaplasia.	('metaplasia', 'Disease', 'MESH:D008679', (147, 157))	('metaplasia', 'Disease', (147, 157))	('lead to', 'Reg', (139, 146))	('Gram-negatives', 'Var', (118, 132))
698458	27068172	In animal studies, LPS has been shown to relax the lower esophageal sphincter and delay gastric emptying, both important mechanisms contributing to gastro-esophageal reflux in humans.	('esophageal sphincter', 'Disease', 'MESH:D009122', (57, 77))	('humans', 'Species', '9606', (176, 182))	('gastro-esophageal reflux', 'Disease', 'MESH:D005764', (148, 172))	('relax', 'PosReg', (41, 46))	('gastric', 'MPA', (88, 95))	('delay gastric emptying', 'Phenotype', 'HP:0002578', (82, 104))	('contributing', 'Reg', (132, 144))	('esophageal reflux', 'Phenotype', 'HP:0002020', (155, 172))	('esophageal sphincter', 'Disease', (57, 77))	('LPS', 'Var', (19, 22))	('gastro-esophageal reflux', 'Disease', (148, 172))	('delay', 'NegReg', (82, 87))
698464	27068172	Fusobacterium nucleatum has been shown to directly promote colorectal carcinogenesis through the E-cadherin/beta-catenin pathway.	('beta-catenin', 'Gene', (108, 120))	('Fusobacterium', 'Var', (0, 13))	('E-cadherin', 'Gene', (97, 107))	('E-cadherin', 'Gene', '999', (97, 107))	('beta-catenin', 'Gene', '1499', (108, 120))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (59, 84))	('promote', 'PosReg', (51, 58))	('colorectal carcinogenesis', 'Disease', (59, 84))	('Fusobacterium nucleatum', 'Species', '851', (0, 23))
698510	26515287	CDK2AP1 negatively regulates cell cycle progression and cell proliferation as a target for silencing or downregulation in tumorigenesis.	('regulates', 'Reg', (19, 28))	('CDK2AP1', 'Gene', '8099', (0, 7))	('negatively', 'NegReg', (8, 18))	('cell cycle progression', 'CPA', (29, 51))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cell proliferation', 'CPA', (56, 74))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('silencing', 'Var', (91, 100))	('CDK2AP1', 'Gene', (0, 7))	('downregulation', 'NegReg', (104, 118))	('tumor', 'Disease', (122, 127))
698533	26515287	The results showed that silenced miR-205 decreased the invasion of Hep-2 cells, which was consistent with overexpressed CDK2AP1 (Fig.	('Hep-2', 'CellLine', 'CVCL:1906', (67, 72))	('invasion of Hep-2 cells', 'CPA', (55, 78))	('CDK2AP1', 'Gene', '8099', (120, 127))	('miR-205', 'Gene', (33, 40))	('silenced', 'Var', (24, 32))	('decreased', 'NegReg', (41, 50))	('miR-205', 'Gene', '406988', (33, 40))	('CDK2AP1', 'Gene', (120, 127))
698537	26515287	3c, the activity of MMP2 and MMP9 was significantly downregulated by miR-205 inhibitors and CDK2AP1 compared to control group.	('miR-205', 'Gene', '406988', (69, 76))	('MMP2', 'Gene', (20, 24))	('inhibitors', 'Var', (77, 87))	('CDK2AP1', 'Gene', (92, 99))	('activity', 'MPA', (8, 16))	('downregulated', 'NegReg', (52, 65))	('MMP9', 'Gene', (29, 33))	('MMP2', 'Gene', '4313', (20, 24))	('MMP9', 'Gene', '4318', (29, 33))	('miR-205', 'Gene', (69, 76))	('CDK2AP1', 'Gene', '8099', (92, 99))
698542	26515287	The results revealed that the expression levels of c-Myc and CyclinD1 in miR-205 inhibitors group and overexpressed CDK2AP1 group were significantly lower than that in control group.	('c-Myc', 'Gene', '4609', (51, 56))	('CyclinD1', 'Gene', '595', (61, 69))	('CDK2AP1', 'Gene', '8099', (116, 123))	('inhibitors', 'Var', (81, 91))	('miR-205', 'Gene', '406988', (73, 80))	('c-Myc', 'Gene', (51, 56))	('CyclinD1', 'Gene', (61, 69))	('CDK2AP1', 'Gene', (116, 123))	('lower', 'NegReg', (149, 154))	('expression levels', 'MPA', (30, 47))	('miR-205', 'Gene', (73, 80))
698545	26515287	Dysregulation of miR-205 expression was found in various tumors and implicated in the regulation of cell apoptosis, proliferation and metastasis.	('Dysregulation', 'Var', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('miR-205', 'Gene', (17, 24))	('found', 'Reg', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('metastasis', 'CPA', (134, 144))	('implicated', 'Reg', (68, 78))	('proliferation', 'CPA', (116, 129))	('tumors', 'Disease', (57, 63))	('miR-205', 'Gene', '406988', (17, 24))	('cell apoptosis', 'CPA', (100, 114))
698556	26515287	miR-205 inhibitors suppressed LSCC proliferation and invasion.	('suppressed', 'NegReg', (19, 29))	('invasion', 'CPA', (53, 61))	('miR-205', 'Gene', (0, 7))	('LSCC proliferation', 'CPA', (30, 48))	('miR-205', 'Gene', '406988', (0, 7))	('inhibitors', 'Var', (8, 18))
698564	26515287	Consistent with other tumors, overexpressed CDK2AP1 also suppressed cell proliferation and invasion in LSCC.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('invasion', 'CPA', (91, 99))	('cell proliferation', 'CPA', (68, 86))	('CDK2AP1', 'Gene', (44, 51))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('LSCC', 'Disease', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('overexpressed', 'Var', (30, 43))	('tumors', 'Disease', (22, 28))	('CDK2AP1', 'Gene', '8099', (44, 51))	('suppressed', 'NegReg', (57, 67))
698568	26515287	In this study, attention is also paid to the issues regarding association between the antitumor activity of CDK2AP1 and expression of c-Myc and cyclin D1 gene and our finding shows that miR-205 inhibitors and ectopic CDK2AP1 reduced the expression of c-Myc and cyclin D1 in LSCC cells.	('miR-205', 'Gene', (186, 193))	('CDK2AP1', 'Gene', '8099', (217, 224))	('reduced', 'NegReg', (225, 232))	('CDK2AP1', 'Gene', (217, 224))	('cyclin D1', 'Gene', (144, 153))	('tumor', 'Disease', (90, 95))	('cyclin D1', 'Gene', '595', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('c-Myc', 'Gene', (134, 139))	('cyclin D1', 'Gene', (261, 270))	('miR-205', 'Gene', '406988', (186, 193))	('expression', 'MPA', (237, 247))	('c-Myc', 'Gene', '4609', (134, 139))	('cyclin D1', 'Gene', '595', (261, 270))	('ectopic', 'Var', (209, 216))	('c-Myc', 'Gene', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CDK2AP1', 'Gene', '8099', (108, 115))	('CDK2AP1', 'Gene', (108, 115))	('c-Myc', 'Gene', '4609', (251, 256))
698648	25007268	 TERT-CLPTM1L Rs401681 C>T Polymorphism Was Associated with a Decreased Risk of Esophageal Cancer in a Chinese Population Esophageal cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in China in 2009.	('death', 'Disease', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('Rs401681 C>T', 'Var', (14, 26))	('Esophageal Cancer', 'Disease', (80, 97))	('Esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('CLPTM1L', 'Gene', '81037', (6, 13))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('death', 'Disease', 'MESH:D003643', (232, 237))	('CLPTM1L', 'Gene', (6, 13))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Disease', (133, 139))	('Decreased', 'NegReg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TERT', 'Gene', (1, 5))	('Rs401681', 'Mutation', 'Rs401681', (14, 22))	('TERT', 'Gene', '7015', (1, 5))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', (178, 184))	('Esophageal cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
698651	25007268	We conducted a hospital based case-control study to evaluate functional hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T single nucleotide polymorphisms (SNPs) on the risk of ESCC.	('ESCC', 'Disease', (176, 180))	('rs2736098 G>A', 'Var', (78, 91))	('hTERT', 'Gene', '7015', (72, 77))	('TERT', 'Gene', (96, 100))	('rs401681 C>T', 'Var', (109, 121))	('hTERT', 'Gene', (72, 77))	('TERT', 'Gene', (73, 77))	('rs401681', 'Mutation', 'rs401681', (109, 117))	('TERT', 'Gene', '7015', (96, 100))	('CLPTM1L', 'Gene', '81037', (101, 108))	('TERT', 'Gene', '7015', (73, 77))	('CLPTM1L', 'Gene', (101, 108))	('rs2736098', 'Mutation', 'rs2736098', (78, 87))
698652	25007268	When the TERT-CLPTM1L rs401681 CC homozygote genotype was used as the reference group, the CT genotype was associated with a significantly decreased risk of ESCC (adjusted OR  = 0.74, 95% CI  = 0.58-0.94, p = 0.012); the CT/TT variants were associated with a 26% decreased risk of ESCC (adjusted OR  = 0.74, 95% CI  = 0.59-0.93, P = 0.009).	('ESCC', 'Disease', (281, 285))	('ESCC', 'Disease', (157, 161))	('CLPTM1L', 'Gene', '81037', (14, 21))	('rs401681 CC', 'Var', (22, 33))	('decreased', 'NegReg', (139, 148))	('CLPTM1L', 'Gene', (14, 21))	('decreased', 'NegReg', (263, 272))	('rs401681', 'Mutation', 'rs401681', (22, 30))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
698653	25007268	The significantly decreased risk of ESCC associated with the TERT-CLPTM1L rs401681 C>T polymorphism was associated with male sex, young age (<63 years in our study) and alcohol consumption.	('TERT', 'Gene', (61, 65))	('decreased', 'NegReg', (18, 27))	('TERT', 'Gene', '7015', (61, 65))	('CLPTM1L', 'Gene', '81037', (66, 73))	('CLPTM1L', 'Gene', (66, 73))	('rs401681 C>T', 'Var', (74, 86))	('rs401681', 'Mutation', 'rs401681', (74, 82))	('alcohol', 'Chemical', 'MESH:D000438', (169, 176))	('ESCC', 'Disease', (36, 40))
698654	25007268	No association between the hTERT rs2736098 G>A polymorphism and ESCC risk was observed.	('rs2736098 G>A', 'Var', (33, 46))	('hTERT', 'Gene', '7015', (27, 32))	('ESCC', 'Disease', (64, 68))	('hTERT', 'Gene', (27, 32))	('rs2736098', 'Mutation', 'rs2736098', (33, 42))
698655	25007268	TERT-CLPTM1L rs401681 CT and CT/TT genotypes were associated with decreased risk of ESCC, particularly among men, young patients and those reported to be drinkers.	('CLPTM1L', 'Gene', (5, 12))	('ESCC', 'Disease', (84, 88))	('decreased', 'NegReg', (66, 75))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('patients', 'Species', '9606', (120, 128))	('rs401681', 'Mutation', 'rs401681', (13, 21))	('men', 'Species', '9606', (109, 112))	('rs401681', 'Var', (13, 21))	('CLPTM1L', 'Gene', '81037', (5, 12))
698658	25007268	However, only a subset of individuals exposed to these environmental risk factors develops ESCC, suggesting that genetic factors, such as single nucleotide polymorphisms (SNPs), may also contribute to ESCC carcinogenesis.	('contribute', 'Reg', (187, 197))	('men', 'Species', '9606', (62, 65))	('single nucleotide polymorphisms', 'Var', (138, 169))	('ESCC', 'Disease', (91, 95))	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (201, 220))	('ESCC carcinogenesis', 'Disease', (201, 220))
698659	25007268	Recently, several genome-wide association studies (GWAS) reported that common polymorphisms of Telomerase reverse transcriptase-cleft lip and palate transmembrane 1 like, CLPTM1L (TERT-CLPTM1L), which is located at locus 5p15.33, were associated with the risk of many types of cancer.	('associated with', 'Reg', (235, 250))	('CLPTM1L', 'Gene', '81037', (171, 178))	('cleft lip', 'Phenotype', 'HP:0410030', (128, 137))	('CLPTM1L', 'Gene', (171, 178))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('CLPTM1L', 'Gene', '81037', (185, 192))	('cleft lip and palate', 'Disease', 'MESH:D002971', (128, 148))	('cleft lip and palate', 'Phenotype', 'HP:0000202', (128, 148))	('CLPTM1L', 'Gene', (185, 192))	('TERT', 'Gene', (180, 184))	('TERT', 'Gene', '7015', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('polymorphisms', 'Var', (78, 91))
698662	25007268	Two variants in 5p15 (rs401681 and rs2736098) are significantly associated with bladder cancer in individuals of European ancestry.	('associated', 'Reg', (64, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (80, 94))	('bladder cancer', 'Disease', (80, 94))	('bladder cancer', 'Phenotype', 'HP:0009725', (80, 94))	('rs401681', 'Var', (22, 30))	('rs2736098', 'Var', (35, 44))	('rs2736098', 'Mutation', 'rs2736098', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('rs401681', 'Mutation', 'rs401681', (22, 30))	('5p15', 'Gene', (16, 20))
698663	25007268	These variants are in linkage disequilibrium (LD) with CLPTM1L and TERT, and both variants are also associated with basal cell carcinoma, lung cancer, glioma and other tumors.	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('tumors', 'Disease', (168, 174))	('CLPTM1L', 'Gene', '81037', (55, 62))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (116, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('variants', 'Var', (82, 90))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (116, 136))	('CLPTM1L', 'Gene', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('TERT', 'Gene', (67, 71))	('TERT', 'Gene', '7015', (67, 71))	('associated', 'Reg', (100, 110))	('lung cancer', 'Disease', (138, 149))	('basal cell carcinoma', 'Disease', (116, 136))	('glioma', 'Disease', (151, 157))	('variants', 'Var', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
698664	25007268	The TERT-CLPTM1L rs401681 C allele is also associated with shorter mean telomere length in lymphocytes.	('rs401681', 'Mutation', 'rs401681', (17, 25))	('shorter', 'NegReg', (59, 66))	('TERT', 'Gene', (4, 8))	('rs401681 C', 'Var', (17, 27))	('TERT', 'Gene', '7015', (4, 8))	('CLPTM1L', 'Gene', '81037', (9, 16))	('CLPTM1L', 'Gene', (9, 16))
698666	25007268	Telomeres can become dysfunctional for a variety reasons, such as gradual shortening caused by incomplete replication of chromosomes, oxidative DNA damage or mutations in structural proteins, such as TERT.	('shortening', 'NegReg', (74, 84))	('mutations', 'Var', (158, 167))	('TERT', 'Gene', '7015', (200, 204))	('TERT', 'Gene', (200, 204))
698667	25007268	Mutations in the coding regions of TERT can affect telomerase activity and telomere length, resulting in severe clinical phenotypes, including bone marrow failure syndromes and a substantial increase in cancer frequency.	('telomerase', 'Enzyme', (51, 61))	('activity', 'MPA', (62, 70))	('increase', 'PosReg', (191, 199))	('bone marrow failure syndromes', 'Disease', (143, 172))	('bone marrow failure', 'Phenotype', 'HP:0005528', (143, 162))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('bone marrow failure syndromes', 'Disease', 'MESH:D000080983', (143, 172))	('telomere length', 'CPA', (75, 90))	('affect', 'Reg', (44, 50))	('TERT', 'Gene', (35, 39))	('TERT', 'Gene', '7015', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
698674	25007268	CLPTM1L variants are hypothesized to enhance the metabolic activation of reactive metabolites and/or the formation and persistence of DNA adducts.	('CLPTM1L', 'Gene', '81037', (0, 7))	('CLPTM1L', 'Gene', (0, 7))	('variants', 'Var', (8, 16))	('metabolic activation of reactive metabolites', 'MPA', (49, 93))	('enhance', 'PosReg', (37, 44))
698675	25007268	found that TERT-CLPTM1L rs401681 was a genetic variant associated with the risk of lung cancer.	('rs401681', 'Mutation', 'rs401681', (24, 32))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('rs401681', 'Var', (24, 32))	('associated', 'Reg', (55, 65))	('lung cancer', 'Disease', (83, 94))	('CLPTM1L', 'Gene', '81037', (16, 23))	('TERT', 'Gene', (11, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('TERT', 'Gene', '7015', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CLPTM1L', 'Gene', (16, 23))
698677	25007268	Thus, the objective of this investigation was to evaluate the association between hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T polymorphisms and ESCC susceptibility in a hospital-based case-control study.	('rs2736098', 'Mutation', 'rs2736098', (88, 97))	('association', 'Interaction', (62, 73))	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('ESCC', 'Disease', (150, 154))	('TERT', 'Gene', (83, 87))	('rs401681 C>T', 'Var', (119, 131))	('CLPTM1L', 'Gene', '81037', (111, 118))	('TERT', 'Gene', '7015', (83, 87))	('rs401681', 'Mutation', 'rs401681', (119, 127))	('CLPTM1L', 'Gene', (111, 118))	('hTERT', 'Gene', '7015', (82, 87))	('hTERT', 'Gene', (82, 87))	('rs2736098 G>A', 'Var', (88, 101))
698678	25007268	We performed genotyping analyses of hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T SNPs in 629 ESCC cases and 686 controls in a Chinese population.	('rs401681 C>T', 'Var', (73, 85))	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('TERT', 'Gene', '7015', (60, 64))	('rs401681', 'Mutation', 'rs401681', (73, 81))	('CLPTM1L', 'Gene', '81037', (65, 72))	('ESCC', 'Disease', (98, 102))	('rs2736098 G>A', 'Var', (42, 55))	('CLPTM1L', 'Gene', (65, 72))	('hTERT', 'Gene', '7015', (36, 41))	('rs2736098', 'Mutation', 'rs2736098', (42, 51))	('hTERT', 'Gene', (36, 41))	('TERT', 'Gene', (60, 64))
698681	25007268	We used online predictive tool: http://www.regulomedb.org/and http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm to predict hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T SNPs function.	('TERT', 'Gene', (123, 127))	('rs401681 C>T', 'Var', (159, 171))	('hTERT', 'Gene', (122, 127))	('rs401681', 'Mutation', 'rs401681', (159, 167))	('CLPTM1L', 'Gene', '81037', (151, 158))	('TERT', 'Gene', '7015', (123, 127))	('CLPTM1L', 'Gene', (151, 158))	('hTERT', 'Gene', '7015', (122, 127))	('TERT', 'Gene', (146, 150))	('TERT', 'Gene', '7015', (146, 150))	('rs2736098 G>A', 'Var', (128, 141))	('rs2736098', 'Mutation', 'rs2736098', (128, 137))
698682	25007268	Differences in the distributions of demographic characteristics, selected variables, and genotypes of the hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T variants between the cases and controls were evaluated using the chi 2 test.	('rs2736098 G>A', 'Var', (112, 125))	('TERT', 'Gene', (130, 134))	('rs2736098', 'Mutation', 'rs2736098', (112, 121))	('TERT', 'Gene', '7015', (130, 134))	('hTERT', 'Gene', '7015', (106, 111))	('TERT', 'Gene', (107, 111))	('rs401681 C>T', 'Var', (143, 155))	('CLPTM1L', 'Gene', '81037', (135, 142))	('TERT', 'Gene', '7015', (107, 111))	('rs401681', 'Mutation', 'rs401681', (143, 151))	('CLPTM1L', 'Gene', (135, 142))	('hTERT', 'Gene', (106, 111))
698683	25007268	The associations between hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T genotypes and risk of ESCC were estimated by computing the ORs and their 95% CIs using logistic regression analyses for crude ORs and adjusted ORs when adjusting for age, sex, smoking and drinking status.	('associations', 'Interaction', (4, 16))	('CLPTM1L', 'Gene', (54, 61))	('rs401681 C>T', 'Var', (62, 74))	('TERT', 'Gene', (26, 30))	('hTERT', 'Gene', '7015', (25, 30))	('rs401681', 'Mutation', 'rs401681', (62, 70))	('hTERT', 'Gene', (25, 30))	('TERT', 'Gene', '7015', (26, 30))	('TERT', 'Gene', (49, 53))	('rs2736098', 'Mutation', 'rs2736098', (31, 40))	('TERT', 'Gene', '7015', (49, 53))	('rs2736098 G>A', 'Var', (31, 44))	('ESCC', 'Disease', (97, 101))	('CLPTM1L', 'Gene', '81037', (54, 61))
698685	25007268	For the hTERT rs2736098 G>A, the genotyping was successful in 600 (95.39%) ESCC cases and 651 (94.90%) controls in all 1315 samples, and for TERT-CLPTM1L rs401681 C>T, the genotyping was successful in 604 (96.03%) ESCC cases and 664 (96.78%) controls.	('ESCC', 'Disease', (214, 218))	('TERT', 'Gene', '7015', (141, 145))	('ESCC', 'Disease', (75, 79))	('rs2736098', 'Mutation', 'rs2736098', (14, 23))	('rs2736098 G>A', 'Var', (14, 27))	('hTERT', 'Gene', '7015', (8, 13))	('CLPTM1L', 'Gene', '81037', (146, 153))	('CLPTM1L', 'Gene', (146, 153))	('hTERT', 'Gene', (8, 13))	('TERT', 'Gene', (141, 145))	('rs401681', 'Mutation', 'rs401681', (154, 162))	('TERT', 'Gene', (9, 13))	('rs401681 C>T', 'Var', (154, 166))	('TERT', 'Gene', '7015', (9, 13))
698686	25007268	The genotype distributions of hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T in the cases and the controls are shown in Table 2.	('rs2736098 G>A', 'Var', (36, 49))	('rs2736098', 'Mutation', 'rs2736098', (36, 45))	('TERT', 'Gene', '7015', (54, 58))	('CLPTM1L', 'Gene', '81037', (59, 66))	('CLPTM1L', 'Gene', (59, 66))	('rs401681', 'Mutation', 'rs401681', (67, 75))	('TERT', 'Gene', (31, 35))	('rs401681 C>T', 'Var', (67, 79))	('TERT', 'Gene', '7015', (31, 35))	('hTERT', 'Gene', '7015', (30, 35))	('hTERT', 'Gene', (30, 35))	('TERT', 'Gene', (54, 58))
698687	25007268	In the single locus analyses, the genotype frequencies of TERT-CLPTM1L rs401681 C>T were 47.68% (CC), 41.72% (CT), and 10.60% (TT) in the case patients and 40.06% (CC), 47.74% (CT), and 12.20% (TT) in the control subjects, and the difference was statistically significant (P = 0.024).	('CLPTM1L', 'Gene', '81037', (63, 70))	('patients', 'Species', '9606', (143, 151))	('rs401681 C>T', 'Var', (71, 83))	('TERT', 'Gene', (58, 62))	('rs401681', 'Mutation', 'rs401681', (71, 79))	('TERT', 'Gene', '7015', (58, 62))	('CLPTM1L', 'Gene', (63, 70))
698688	25007268	When the TERT-CLPTM1L rs401681 C allele was used as the reference group, the T allele was associated with a significantly decreased risk for ESCC (T vs C: adjusted OR  = 0.81, 95% CI  = 0.69-0.96, P = 0.014).	('rs401681 C', 'Var', (22, 32))	('CLPTM1L', 'Gene', '81037', (14, 21))	('CLPTM1L', 'Gene', (14, 21))	('rs401681', 'Mutation', 'rs401681', (22, 30))	('ESCC', 'Disease', (141, 145))	('TERT', 'Gene', (9, 13))	('decreased', 'NegReg', (122, 131))	('TERT', 'Gene', '7015', (9, 13))
698689	25007268	When the TERT-CLPTM1L rs401681 CC homozygote genotype was used as the reference group, the CT genotype was associated with a significantly decreased risk for ESCC (CT vs CC: adjusted OR  = 0.74, 95% CI  = 0.58-0.94, P = 0.012).	('ESCC', 'Disease', (158, 162))	('rs401681 CC', 'Var', (22, 33))	('decreased', 'NegReg', (139, 148))	('CLPTM1L', 'Gene', '81037', (14, 21))	('CLPTM1L', 'Gene', (14, 21))	('rs401681', 'Mutation', 'rs401681', (22, 30))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
698690	25007268	When the TERT-CLPTM1L rs401681 CC homozygote genotype was used as the reference group, the TT genotype was not associated with the risk for ESCC (TT vs CC: adjusted OR  = 0.75, 95% CI  = 0.51-1.09, P = 0.126).	('ESCC', 'Disease', (140, 144))	('CLPTM1L', 'Gene', '81037', (14, 21))	('rs401681 CC', 'Var', (22, 33))	('CLPTM1L', 'Gene', (14, 21))	('rs401681', 'Mutation', 'rs401681', (22, 30))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
698691	25007268	In the dominant model, the TERT-CLPTM1L rs401681 CT/TT variants were associated with a 26% decreased risk of ESCC, compared with the TERT-CLPTM1L rs401681 CC genotype (adjusted OR  = 0.74, 95% CI  = 0.59-0.93, P = 0.009).	('ESCC', 'Disease', (109, 113))	('TERT', 'Gene', (133, 137))	('decreased', 'NegReg', (91, 100))	('rs401681', 'Mutation', 'rs401681', (146, 154))	('TERT', 'Gene', '7015', (133, 137))	('TERT', 'Gene', (27, 31))	('TERT', 'Gene', '7015', (27, 31))	('rs401681', 'Var', (40, 48))	('CLPTM1L', 'Gene', '81037', (138, 145))	('rs401681', 'Mutation', 'rs401681', (40, 48))	('CLPTM1L', 'Gene', (138, 145))	('CLPTM1L', 'Gene', '81037', (32, 39))	('CLPTM1L', 'Gene', (32, 39))
698692	25007268	In the recessive model, when the TERT-CLPTM1L rs401681 CC/CT genotypes were used as the reference group, the TT homozygote genotype was not associated with the risk for ESCC (adjusted OR  = 0.87, 95% CI  = 0.61-1.24, P = 0.447) (Table 2).	('TERT', 'Gene', (33, 37))	('ESCC', 'Disease', (169, 173))	('TERT', 'Gene', '7015', (33, 37))	('CLPTM1L', 'Gene', '81037', (38, 45))	('rs401681', 'Mutation', 'rs401681', (46, 54))	('CLPTM1L', 'Gene', (38, 45))	('rs401681 CC/CT', 'Var', (46, 60))
698693	25007268	hTERT rs2736098 G>A was not showed a significant difference in the genotype distributions between cases and controls (P = 0.727).	('rs2736098 G>A', 'Var', (6, 19))	('rs2736098', 'Mutation', 'rs2736098', (6, 15))	('hTERT', 'Gene', (0, 5))	('hTERT', 'Gene', '7015', (0, 5))
698694	25007268	Logistic regression analyses revealed that the hTERT rs2736098 G>A polymorphism was not associated with the risk of ESCC (Table 2).	('rs2736098 G>A', 'Var', (53, 66))	('ESCC', 'Disease', (116, 120))	('hTERT', 'Gene', '7015', (47, 52))	('hTERT', 'Gene', (47, 52))	('rs2736098', 'Mutation', 'rs2736098', (53, 62))
698695	25007268	Using Power and Sample Size Calculation (PS, version 3.0, 2009, http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize) and considering TERT-CLPTM1L rs401681 C>T mutant alleles in the control group, ORs, ESCC samples and control samples, the power of our analysis (alpha = 0.05) was 0.708 in 604 ESCC cases and 664 controls, with an OR of 0.74.	('ESCC', 'Disease', (310, 314))	('rs401681 C>T', 'Var', (163, 175))	('TERT', 'Gene', (150, 154))	('CLPTM1L', 'Gene', '81037', (155, 162))	('rs401681', 'Mutation', 'rs401681', (163, 171))	('CLPTM1L', 'Gene', (155, 162))	('TERT', 'Gene', '7015', (150, 154))
698696	25007268	To evaluate the effects of TERT-CLPTM1L rs401681 C>T genotypes on ESCC risk according to different age, sex, smoking and alcohol drinking status; we performed the stratification analyses (Table 3).	('rs401681 C', 'Var', (40, 50))	('TERT', 'Gene', (27, 31))	('TERT', 'Gene', '7015', (27, 31))	('ESCC', 'Disease', (66, 70))	('rs401681', 'Mutation', 'rs401681', (40, 48))	('alcohol drinking', 'Phenotype', 'HP:0030955', (121, 137))	('CLPTM1L', 'Gene', '81037', (32, 39))	('alcohol', 'Chemical', 'MESH:D000438', (121, 128))	('CLPTM1L', 'Gene', (32, 39))
698697	25007268	A significantly decreased risk of ESCC associated with the TERT-CLPTM1L rs401681 C>T polymorphism was evident among male patients (CT vs CC: P = 0.0003; CT/TT vs CC: P = 0.0002), younger patients (<63 years in our study) (CT/TT vs CC: P = 0.049) and patients who were in drinking status (CT vs CC: P = 0.012; CT/TT vs CC: P = 0.016) (Table 3).	('patients', 'Species', '9606', (187, 195))	('CLPTM1L', 'Gene', '81037', (64, 71))	('CLPTM1L', 'Gene', (64, 71))	('rs401681 C>T', 'Var', (72, 84))	('TERT', 'Gene', (59, 63))	('patients', 'Species', '9606', (250, 258))	('rs401681', 'Mutation', 'rs401681', (72, 80))	('TERT', 'Gene', '7015', (59, 63))	('ESCC', 'Disease', (34, 38))	('patients', 'Species', '9606', (121, 129))	('decreased', 'NegReg', (16, 25))
698698	25007268	In this hospital-based case-control study, we investigated the association of the hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T SNPs with the risk of ESCC in a Chinese population.	('rs2736098', 'Mutation', 'rs2736098', (88, 97))	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('ESCC', 'Disease', (154, 158))	('association', 'Interaction', (63, 74))	('TERT', 'Gene', (83, 87))	('rs401681 C>T', 'Var', (119, 131))	('CLPTM1L', 'Gene', '81037', (111, 118))	('TERT', 'Gene', '7015', (83, 87))	('rs401681', 'Mutation', 'rs401681', (119, 127))	('CLPTM1L', 'Gene', (111, 118))	('hTERT', 'Gene', '7015', (82, 87))	('hTERT', 'Gene', (82, 87))	('rs2736098 G>A', 'Var', (88, 101))
698699	25007268	Multivariate logistic analysis revealed that the TERT-CLPTM1L rs401681 CT and CT/TT genotypes were associated with decreased risk of ESCC, whereas no significant association between the hTERT rs2736098 G>A polymorphism and the risk of ESCC was observed.	('CLPTM1L', 'Gene', (54, 61))	('rs401681', 'Var', (62, 70))	('rs401681', 'Mutation', 'rs401681', (62, 70))	('hTERT', 'Gene', '7015', (186, 191))	('ESCC', 'Disease', (133, 137))	('decreased', 'NegReg', (115, 124))	('TERT', 'Gene', '7015', (187, 191))	('rs2736098', 'Mutation', 'rs2736098', (192, 201))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))	('TERT', 'Gene', (187, 191))	('hTERT', 'Gene', (186, 191))	('CLPTM1L', 'Gene', '81037', (54, 61))
698700	25007268	A significantly decreased risk of ESCC associated with the TERT-CLPTM1L rs401681 C>T polymorphism, particularly among men, young patients and those reported to be drinkers.	('CLPTM1L', 'Gene', '81037', (64, 71))	('CLPTM1L', 'Gene', (64, 71))	('rs401681 C>T', 'Var', (72, 84))	('TERT', 'Gene', (59, 63))	('patients', 'Species', '9606', (129, 137))	('rs401681', 'Mutation', 'rs401681', (72, 80))	('men', 'Species', '9606', (118, 121))	('TERT', 'Gene', '7015', (59, 63))	('ESCC', 'Disease', (34, 38))	('decreased', 'NegReg', (16, 25))
698705	25007268	Variants at this locus are hypothesized to regulate telomere length and be associated with multiple malignancies, including cancers of the lung, prostate, urinary bladder, cervix and pancreas.	('pancreas', 'Disease', 'MESH:D010190', (183, 191))	('Variants', 'Var', (0, 8))	('prostate', 'Disease', (145, 153))	('regulate', 'Reg', (43, 51))	('urinary bladder', 'Disease', (155, 170))	('multiple malignancies', 'Disease', 'MESH:D009369', (91, 112))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('multiple malignancies', 'Disease', (91, 112))	('telomere length', 'MPA', (52, 67))	('cancers of the lung', 'Disease', (124, 143))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('pancreas', 'Disease', (183, 191))	('cancers of the lung', 'Disease', 'MESH:D008175', (124, 143))	('associated', 'Reg', (75, 85))	('cervix', 'Disease', (172, 178))
698706	25007268	Rs401681 is located in intron 13 of CLPTM1L at 5p15.33, and it is one of the most studied SNPs.	('CLPTM1L', 'Gene', (36, 43))	('Rs401681', 'Var', (0, 8))	('CLPTM1L', 'Gene', '81037', (36, 43))	('Rs401681', 'Mutation', 'Rs401681', (0, 8))
698707	25007268	To show that these alterations can indeed contribute to cancer properties, invitro validation studies with specific invitro cell lines of ESCC that harbor these genetic alterations are warrented.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('alterations', 'Var', (19, 30))	('contribute', 'Reg', (42, 52))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('genetic alterations', 'Var', (161, 180))
698708	25007268	Several studies addressing the association between the CLPTM1L rs401681 polymorphism and cancer have been published, with inconsistent results.	('rs401681', 'Var', (63, 71))	('rs401681', 'Mutation', 'rs401681', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('CLPTM1L', 'Gene', '81037', (55, 62))	('CLPTM1L', 'Gene', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
698710	25007268	Nan and collaborators observed a suggestive positive relationship between the rs401681 C allele and shorter relative telomere length.	('relative telomere length', 'MPA', (108, 132))	('rs401681', 'Mutation', 'rs401681', (78, 86))	('rs401681', 'Var', (78, 86))	('shorter', 'NegReg', (100, 107))
698711	25007268	suggested that the rs401681 C allele might be associated with the acceleration of the gradual shortening of telomeres with age.	('rs401681 C', 'Var', (19, 29))	('acceleration', 'PosReg', (66, 78))	('shortening of telomeres', 'Phenotype', 'HP:0031413', (94, 117))	('rs401681', 'Mutation', 'rs401681', (19, 27))	('gradual shortening of telomeres', 'CPA', (86, 117))
698712	25007268	Possible links between shorter telomeres and decreased risk of melanoma have been reported.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('decreased', 'NegReg', (45, 54))	('shorter', 'Var', (23, 30))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
698714	25007268	Rs401681 is also associated with the risk of pancreatic cancer, as shown by the presence of chromosome ends lacking telomeric repeat sequences in this cancer.	('Rs401681', 'Var', (0, 8))	('pancreatic cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('associated', 'Reg', (17, 27))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lacking', 'NegReg', (108, 115))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('Rs401681', 'Mutation', 'Rs401681', (0, 8))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
698715	25007268	found that TERT-CLPTM1L rs401681 T allele was associated with decreased risk of lung cancer.	('rs401681', 'Mutation', 'rs401681', (24, 32))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('decreased', 'NegReg', (62, 71))	('rs401681 T', 'Var', (24, 34))	('lung cancer', 'Disease', (80, 91))	('CLPTM1L', 'Gene', '81037', (16, 23))	('TERT', 'Gene', (11, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('TERT', 'Gene', '7015', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('CLPTM1L', 'Gene', (16, 23))
698716	25007268	And in ESCC cohort, the trend of TERT-CLPTM1L rs401681 T allele is protective but not reach significant (OR  = 0.935, 95% CI  = 0.800-1.093 in additive model), indicating necessary for replications in other cohors.	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('CLPTM1L', 'Gene', '81037', (38, 45))	('rs401681', 'Mutation', 'rs401681', (46, 54))	('CLPTM1L', 'Gene', (38, 45))	('rs401681 T', 'Var', (46, 56))
698717	25007268	In the present Chinese study, the allele frequency of TERT-CLPTM1L rs401681 T was 0.361 in 686 control subjects, which is consistent with the values reported in the SNP database for the Chinese Han (0.305) and Japanese populations (0.343); however, the frequency was lower than that of a Sub-Saharan African (0.642) population (http://www.ncbi.nlm.nih.gov/SNP).	('TERT', 'Gene', '7015', (54, 58))	('CLPTM1L', 'Gene', '81037', (59, 66))	('CLPTM1L', 'Gene', (59, 66))	('rs401681', 'Mutation', 'rs401681', (67, 75))	('rs401681 T', 'Var', (67, 77))	('TERT', 'Gene', (54, 58))
698719	25007268	Second, the polymorphisms investigated in our study were based on functional considerations and may not provide a comprehensive view of the genetic variability of TERT-CLPTM1L, such as rs402710 and rs2736100 et al.	('rs402710', 'Var', (185, 193))	('rs2736100', 'Mutation', 'rs2736100', (198, 207))	('TERT', 'Gene', '7015', (163, 167))	('CLPTM1L', 'Gene', '81037', (168, 175))	('CLPTM1L', 'Gene', (168, 175))	('rs2736100', 'Var', (198, 207))	('TERT', 'Gene', (163, 167))	('rs402710', 'Mutation', 'rs402710', (185, 193))
698720	25007268	Further studies are needed to clarify the genetic mechanism of esophageal carcinogenesis by fine-mapping the susceptibility region of the variants.	('esophageal carcinogenesis', 'Disease', (63, 88))	('variants', 'Var', (138, 146))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (63, 88))
698721	25007268	Finally, we did not obtain detailed information on cancer metastasis and survival, which further restricted the analysis of the roles of the hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T polymorphisms in ESCC progression and prognosis.	('CLPTM1L', 'Gene', (170, 177))	('ESCC', 'Disease', (208, 212))	('rs2736098 G>A', 'Var', (147, 160))	('hTERT', 'Gene', '7015', (141, 146))	('TERT', 'Gene', (165, 169))	('TERT', 'Gene', '7015', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer metastasis', 'Disease', (51, 68))	('hTERT', 'Gene', (141, 146))	('rs2736098', 'Mutation', 'rs2736098', (147, 156))	('cancer metastasis', 'Disease', 'MESH:D009362', (51, 68))	('TERT', 'Gene', (142, 146))	('rs401681 C>T', 'Var', (178, 190))	('TERT', 'Gene', '7015', (142, 146))	('rs401681', 'Mutation', 'rs401681', (178, 186))	('CLPTM1L', 'Gene', '81037', (170, 177))
698722	25007268	In conclusion, our study provides strong evidence that the functional TERT-CLPTM1L rs401681 C>T polymorphism may contribute to the risk of ESCC.	('CLPTM1L', 'Gene', (75, 82))	('rs401681 C>T', 'Var', (83, 95))	('rs401681', 'Mutation', 'rs401681', (83, 91))	('contribute', 'Reg', (113, 123))	('TERT', 'Gene', '7015', (70, 74))	('TERT', 'Gene', (70, 74))	('CLPTM1L', 'Gene', '81037', (75, 82))	('ESCC', 'Disease', (139, 143))	('risk', 'Reg', (131, 135))
698723	25007268	However, the exact functional relevance of the CLPTM1L rs401681 SNP remains unclear.	('rs401681', 'Var', (55, 63))	('CLPTM1L', 'Gene', '81037', (47, 54))	('rs401681', 'Mutation', 'rs401681', (55, 63))	('CLPTM1L', 'Gene', (47, 54))
698732	22778977	ESD was performed using a conventional single-channel endoscope (GIF-H260Z, -Q260J, or -Q260; Olympus, Tokyo, Japan) or a 2-channel endoscope (GIF-2TQ260M, Olympus).	('Q260J', 'Var', (77, 82))	('Q260J', 'SUBSTITUTION', 'None', (77, 82))	('H260Z', 'Var', (69, 74))	('H260Z', 'SUBSTITUTION', 'None', (69, 74))	('or -Q260', 'Var', (84, 92))
698734	22778977	Several spots were marked 3-5 mm outside the margin of each lesion by using argon plasma coagulation or Flush knife (DK2618JB or DK2618JN, FTS, Tokyo, Japan).	('argon', 'Chemical', 'MESH:D001128', (76, 81))	('DK2618JN', 'Var', (129, 137))	('Flush', 'Phenotype', 'HP:0031284', (104, 109))	('FTS', 'Gene', (139, 142))	('FTS', 'Gene', '64400', (139, 142))	('DK2618JB', 'Var', (117, 125))
698789	21694820	Clinical histopathology identified 123 levels (32.6%) as squamous epithelium, 84 levels (22.3%) as columnar epithelium without intestinal metaplasia, 135 levels (35.8%) as columnar epithelium with intestinal metaplasia, 30 levels (8%) as dysplasia (28, low grade dysplasia; 2, high grade dysplasia), and 5 levels (1.3%) as adenocarcinoma.	('intestinal metaplasia', 'Disease', (127, 148))	('adenocarcinoma', 'Disease', 'MESH:D000230', (323, 337))	('Clinical', 'Species', '191496', (0, 8))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (197, 218))	('low', 'Var', (253, 256))	('dysplasia', 'Disease', (238, 247))	('dysplasia', 'Disease', (263, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (127, 148))	('dysplasia', 'Disease', 'MESH:D004476', (263, 272))	('dysplasia', 'Disease', (288, 297))	('dysplasia', 'Disease', 'MESH:D004476', (238, 247))	('intestinal metaplasia', 'Disease', (197, 218))	('adenocarcinoma', 'Disease', (323, 337))	('dysplasia', 'Disease', 'MESH:D004476', (288, 297))
698800	21694820	On the 84 esophageal levels which contained metaplastic columnar epithelium without intestinal metaplasia on clinical histopathology assessment, 59 (70.2%) also had portions of squamous epithelium in at least one of the clinical biopsies.	('intestinal metaplasia', 'Disease', 'MESH:D008679', (84, 105))	('clinical', 'Species', '191496', (109, 117))	('intestinal metaplasia', 'Disease', (84, 105))	('metaplastic', 'Var', (44, 55))	('clinical', 'Species', '191496', (220, 228))
698832	33680941	Importantly, NEAT1 functioned as a competing endogenous RNA for miR-590-3p to regulate MDM2 expression and miR-590-3p acted as a tumor suppressor in ESCC progression and angiogenesis.	('ESCC', 'Disease', (149, 153))	('angiogenesis', 'CPA', (170, 182))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('miR-590-3p', 'Chemical', '-', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('miR-590-3p', 'Chemical', '-', (107, 117))	('MDM2', 'Gene', (87, 91))	('miR-590-3p', 'Var', (107, 117))	('tumor', 'Disease', (129, 134))	('expression', 'MPA', (92, 102))
698845	33680941	Loss of function assays demonstrated that silencing NEAT1 attenuated the progression and angiogenesis of ESCC and rescue experiments revealed that the effects of NEAT1 were dependent on MDM2/p53 axis.	('silencing', 'Var', (42, 51))	('attenuated', 'NegReg', (58, 68))	('ESCC', 'Disease', (105, 109))	('p53', 'Gene', (191, 194))	('NEAT1', 'Gene', (52, 57))	('p53', 'Gene', '7157', (191, 194))	('progression', 'CPA', (73, 84))	('angiogenesis', 'CPA', (89, 101))
698865	33680941	The following primary antibodies were used: anti-beta-actin (Cell Signaling Technology, 3700, 1:1000), anti-p53 (Santa Cruz Biotechnology, sc-126, 1:1,000) and anti-MDM2 (Santa Cruz Biotechnology, sc-965, 1:1,000).	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', (108, 111))	('beta-actin', 'Gene', '728378', (49, 59))	('beta-actin', 'Gene', (49, 59))	('anti-MDM2', 'Var', (160, 169))
698871	33680941	Immunostaining was performed using following antibodies: anti-p53 (Santa Cruz Biotechnology, sc-126, 1:100), anti-MDM2 (Santa Cruz Biotechnology, sc-965, 1:100) and anti-CD31 (Cell Signaling Technology, 3528, 1:100).	('anti-MDM2', 'Var', (109, 118))	('anti-CD31', 'Var', (165, 174))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
698872	33680941	The construct was co-transfected with miR-NC or miR-590-3p mimics into HEK293T cells.	('HEK293T', 'CellLine', 'CVCL:0063', (71, 78))	('miR-NC', 'Disease', 'OMIM:617025', (38, 44))	('miR-NC', 'Disease', (38, 44))	('miR-590-3p', 'Chemical', '-', (48, 58))	('miR-590-3p', 'Var', (48, 58))
698878	33680941	Compared with human esophageal epithelial cell (HET-1A), NEAT1 was at relatively high levels in five ESCC cell lines (ECA109, TE1, TE13, KYSE150, and KYSE140) (Figure 2A).	('human', 'Species', '9606', (14, 19))	('KYSE140', 'Var', (150, 157))	('KYSE150', 'Var', (137, 144))
698879	33680941	Medium from ECA109 or TE13 cells with NEAT1 knockdown dramatically inhibited tube sprout of HUVECs compared with negative control (Figures 2K, L).	('inhibited', 'NegReg', (67, 76))	('NEAT1', 'Gene', (38, 43))	('knockdown', 'Var', (44, 53))	('tube sprout of HUVECs', 'CPA', (77, 98))	('HUVEC', 'CellLine', 'CVCL:2959', (92, 97))
698880	33680941	We performed qRT-PCR in ECA109 cells and results confirmed that knockdown of NEAT1 altered the mRNA expression of several oncogenes (BIRC3, CCND1, GLI1, KRAS, and MDM2) and tumor suppressor genes (TP63 and WWOX) (Figure 3B).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('oncogenes', 'Gene', (122, 131))	('GLI1', 'Gene', '2735', (147, 151))	('BIRC3', 'Gene', '330', (133, 138))	('WWOX', 'Gene', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('KRAS', 'Gene', '3845', (153, 157))	('mRNA expression', 'MPA', (95, 110))	('BIRC3', 'Gene', (133, 138))	('TP63', 'Gene', (197, 201))	('KRAS', 'Gene', (153, 157))	('WWOX', 'Gene', '51741', (206, 210))	('CCND1', 'Gene', '595', (140, 145))	('GLI1', 'Gene', (147, 151))	('NEAT1', 'Gene', (77, 82))	('altered', 'Reg', (83, 90))	('TP63', 'Gene', '8626', (197, 201))	('CCND1', 'Gene', (140, 145))	('tumor', 'Disease', (173, 178))	('knockdown', 'Var', (64, 73))
698883	33680941	And western blotting proved that knockdown of NEAT1 altered the protein level of MDM2 and p53 in ECA109 cells (Figure 3F).	('p53', 'Gene', (90, 93))	('knockdown', 'Var', (33, 42))	('MDM2', 'Protein', (81, 85))	('altered', 'Reg', (52, 59))	('p53', 'Gene', '7157', (90, 93))	('NEAT1', 'Gene', (46, 51))	('protein level', 'MPA', (64, 77))
698886	33680941	ECA109 cells transfected with shRNA-NEAT1 or shRNA-control were injected into axilla subcutaneously of mice and tumor nodules were harvested at 6 weeks after injection (Figure 5A).	('mice', 'Species', '10090', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('shRNA-NEAT1', 'Var', (30, 41))	('tumor', 'Disease', (112, 117))
698888	33680941	IHC staining of harvested tumors implied that knockdown of NEAT1 reduced the expression of MDM2 and CD31 (marker of angiogenesis) and upregulated the expression of p53 in vivo (Figure 5D).	('expression', 'MPA', (77, 87))	('expression', 'MPA', (150, 160))	('reduced', 'NegReg', (65, 72))	('knockdown', 'Var', (46, 55))	('upregulated', 'PosReg', (134, 145))	('MDM2', 'Gene', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('NEAT1', 'Gene', (59, 64))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('CD31', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('p53', 'Gene', (164, 167))	('tumors', 'Disease', (26, 32))	('p53', 'Gene', '7157', (164, 167))
698889	33680941	These results demonstrated that knockdown of NEAT1 inhibited cancer development and angiogenesis of ESCC in vivo.	('angiogenesis', 'CPA', (84, 96))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('knockdown', 'Var', (32, 41))	('NEAT1', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('inhibited', 'NegReg', (51, 60))
698893	33680941	Results showed that miR-590-3p inhibited the luciferase reporter activity of wild-type NEAT1 and MDM2, but not of the mutant type (Figures 6E, F).	('miR-590-3p', 'Chemical', '-', (20, 30))	('miR-590-3p', 'Var', (20, 30))	('luciferase reporter', 'Enzyme', (45, 64))	('MDM2', 'Var', (97, 101))	('inhibited', 'NegReg', (31, 40))
698897	33680941	Validated by CCK8 assay, miR-590-3p inhibited tumor proliferation of ECA109 and TE13 cells (Figures 7A, B).	('inhibited', 'NegReg', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('miR-590-3p', 'Chemical', '-', (25, 35))	('miR-590-3p', 'Var', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
698898	33680941	Transwell and Matrigel assays indicated that miR-590-3p suppressed ESCC cells to migrate and invade (Figures 7C, F).	('suppressed', 'NegReg', (56, 66))	('miR-590-3p', 'Chemical', '-', (45, 55))	('miR-590-3p', 'Var', (45, 55))	('ESCC', 'Gene', (67, 71))
698899	33680941	Likewise, tube formation assays of HUVEC cells were performed and results showed that miR-590-3p reduced angiogenesis of ECA109 and TE13 cells (Figures 7G, H).	('angiogenesis', 'CPA', (105, 117))	('HUVEC', 'CellLine', 'CVCL:2959', (35, 40))	('reduced', 'NegReg', (97, 104))	('miR-590-3p', 'Chemical', '-', (86, 96))	('miR-590-3p', 'Var', (86, 96))
698900	33680941	These findings suggested that miR-590-3p functioned as a suppressor of cancer progression and angiogenesis in ESCC cells.	('angiogenesis', 'CPA', (94, 106))	('suppressor', 'NegReg', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('miR-590-3p', 'Chemical', '-', (30, 40))	('cancer', 'Disease', (71, 77))	('miR-590-3p', 'Var', (30, 40))	('ESCC cells', 'Disease', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
698905	33680941	Furthermore, NEAT1 modulated the expression of MDM2 via functioning as a ceRNA to sponge miR-590-3p and miR-590-3p was validated as a tumor suppressor in ESCC progression and angiogenesis.	('modulated', 'Reg', (19, 28))	('MDM2', 'Gene', (47, 51))	('miR-590-3p', 'Chemical', '-', (89, 99))	('tumor', 'Disease', (134, 139))	('ESCC', 'Disease', (154, 158))	('miR-590-3p', 'Var', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('angiogenesis', 'CPA', (175, 187))	('expression', 'MPA', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('miR-590-3p', 'Chemical', '-', (104, 114))	('miR-590-3p', 'Var', (104, 114))
698918	33680941	Our study firstly demonstrated that NEAT1 promoted angiogenesis in ESCC via modulating MDM2/p53 pathway.	('ESCC', 'Disease', (67, 71))	('NEAT1', 'Var', (36, 41))	('modulating', 'Reg', (76, 86))	('p53', 'Gene', (92, 95))	('angiogenesis', 'CPA', (51, 63))	('promoted', 'PosReg', (42, 50))	('p53', 'Gene', '7157', (92, 95))
698920	33680941	Researches have reported that MDM2 overexpression modulates the angiogenesis-related gene expression profile of prostate cancer cells and MDM2 inhibitors exerted anti- angiogenesis effects in human breast cancer and neuroblastoma.	('angiogenesis-related gene expression profile', 'MPA', (64, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('human', 'Species', '9606', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))	('prostate cancer', 'Disease', (112, 127))	('MDM2', 'Gene', (30, 34))	('anti- angiogenesis effects', 'CPA', (162, 188))	('inhibitors', 'Var', (143, 153))	('neuroblastoma', 'Disease', 'MESH:D009447', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('modulates', 'Reg', (50, 59))	('MDM2', 'Gene', (138, 142))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('neuroblastoma', 'Disease', (216, 229))	('neuroblastoma', 'Phenotype', 'HP:0003006', (216, 229))	('breast cancer', 'Disease', (198, 211))
698922	33680941	As a target of NEAT1, miR-590-3p exerted adverse anti-angiogenic role.	('miR-590-3p', 'Var', (22, 32))	('miR-590-3p', 'Chemical', '-', (22, 32))	('anti-angiogenic', 'CPA', (49, 64))
698925	33680941	Plenty of studies have demonstrated that miR-590-3p was aberrantly expressed in multiple types of cancers and acted as a tumor suppressor, including osteosarcoma, breast cancer, hepatocellular carcinoma, and glioblastoma.	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancers', 'Disease', (98, 105))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (178, 202))	('osteosarcoma', 'Disease', (149, 161))	('osteosarcoma', 'Disease', 'MESH:D012516', (149, 161))	('miR-590-3p', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', (121, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (178, 202))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('glioblastoma', 'Disease', 'MESH:D005909', (208, 220))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('miR-590-3p', 'Chemical', '-', (41, 51))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('osteosarcoma', 'Phenotype', 'HP:0002669', (149, 161))	('hepatocellular carcinoma', 'Disease', (178, 202))	('breast cancer', 'Disease', (163, 176))	('glioblastoma', 'Disease', (208, 220))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('glioblastoma', 'Phenotype', 'HP:0012174', (208, 220))
698926	33680941	In addition, several studies uncovered the role of miR-590-3p in angiogenesis.	('angiogenesis', 'CPA', (65, 77))	('miR-590-3p', 'Chemical', '-', (51, 61))	('miR-590-3p', 'Var', (51, 61))
698927	33680941	Inhibition of miR-590-3p promoted interleukin-18 expression and angiogenesis of endothelial progenitor cells, and NORAD/miR-590-3p axis was a novel regulatory pathway in the angiogenic mechanisms in HUVECs under hypoxia.	('HUVEC', 'CellLine', 'CVCL:2959', (199, 204))	('NORAD', 'Gene', '647979', (114, 119))	('miR-590-3p', 'Chemical', '-', (120, 130))	('miR-590-3p', 'Gene', (14, 24))	('hypoxia', 'Disease', (212, 219))	('expression', 'MPA', (49, 59))	('NORAD', 'Gene', (114, 119))	('promoted', 'PosReg', (25, 33))	('hypoxia', 'Disease', 'MESH:D000860', (212, 219))	('angiogenesis of endothelial progenitor cells', 'CPA', (64, 108))	('interleukin-18', 'Gene', '3606', (34, 48))	('Inhibition', 'Var', (0, 10))	('miR-590-3p', 'Chemical', '-', (14, 24))	('interleukin-18', 'Gene', (34, 48))
698928	33680941	The enhancing effect of miR-590-3p in angiogenesis of ESCC was also validated in this study.	('ESCC', 'Disease', (54, 58))	('enhancing', 'PosReg', (4, 13))	('miR-590-3p', 'Chemical', '-', (24, 34))	('miR-590-3p', 'Var', (24, 34))	('angiogenesis', 'CPA', (38, 50))
698934	33680941	81902354 and 81702444), Natural Science Foundation of Jiangsu Province (BK20181239), National Natural Science Foundation of China (81672869), Jiangsu Provincial Medical Outstanding Talent (Lin Xu), Jiangsu Provincial Medical Youth Talent (BR, QNRC2016657), the Talents Program of Jiangsu Cancer Hospital YC201814 and the "333" Talent Project: BRA2019325.	('81702444', 'Var', (13, 21))	('Cancer', 'Disease', 'MESH:D009369', (288, 294))	('Cancer', 'Phenotype', 'HP:0002664', (288, 294))	('Cancer', 'Disease', (288, 294))
698938	32930509	In addition, siRNA was used to knockdown MMP-14 in ESCC cells, and the proliferation and invasive activity of these cells were then evaluated via MTT and Transwell assays, respectively.	('invasive activity', 'CPA', (89, 106))	('MMP-14', 'Gene', (41, 47))	('MMP-14', 'Gene', '4323', (41, 47))	('MTT', 'Chemical', 'MESH:C070243', (146, 149))	('knockdown', 'Var', (31, 40))
698940	32930509	When MMP-14 was knocked down in ESCC cells, this induced cell cycle arrest, impairing their proliferative and invasive activity.	('MMP-14', 'Gene', (5, 11))	('arrest', 'Disease', (68, 74))	('MMP-14', 'Gene', '4323', (5, 11))	('impairing', 'NegReg', (76, 85))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (57, 74))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('knocked down', 'Var', (16, 28))
698943	32930509	MMP-14 knockdown can additionally compromise the proliferative and invasive activity of these tumor cells, suggesting that MMP-14 may be a viable therapeutic target for the treatment of ESCC, although further research will be needed to validate these findings.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('MMP-14', 'Gene', (123, 129))	('MMP-14', 'Gene', (0, 6))	('tumor', 'Disease', (94, 99))	('compromise', 'NegReg', (34, 44))	('MMP-14', 'Gene', '4323', (123, 129))	('MMP-14', 'Gene', '4323', (0, 6))	('knockdown', 'Var', (7, 16))	('ESCC', 'Disease', (186, 190))
698984	32930509	We knocked down MMP-14 in ESCC cells via an siRNA approach and then evaluated mRNA and protein level expression at 48 and 72 hours post-siRNA transfection.	('knocked', 'Var', (3, 10))	('MMP-14', 'Gene', (16, 22))	('MMP-14', 'Gene', '4323', (16, 22))	('evaluated', 'Reg', (68, 77))
698987	32930509	Relative to mock-transfected cells, those in which MMP-14 had been knocked down markedly exhibited impaired proliferative activity (P < 0.05, Fig 3b).	('MMP-14', 'Gene', '4323', (51, 57))	('knocked down', 'Var', (67, 79))	('impaired', 'NegReg', (99, 107))	('MMP-14', 'Gene', (51, 57))	('proliferative activity', 'CPA', (108, 130))
698988	32930509	We additionally evaluated cell cycle progression in these cells using a flow cytometry-based approach, revealing that MMP-14 knockdown cells were more prone to cell cycle arrest than were ECa-109 cells that had been transfected with a control siRNA construct (Fig 3c).	('ECa-109', 'CellLine', 'CVCL:6898', (188, 195))	('MMP-14', 'Gene', '4323', (118, 124))	('knockdown', 'Var', (125, 134))	('prone', 'Reg', (151, 156))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (160, 177))	('arrest', 'Disease', 'MESH:D006323', (171, 177))	('MMP-14', 'Gene', (118, 124))	('arrest', 'Disease', (171, 177))
698989	32930509	In order to further evaluate the functional importance of MMP-14 in ESCC cells, we utilized a wound healing assay to assess their migratory potential following MMP-14 knockdown or control siRNA transfection.	('migratory potential', 'CPA', (130, 149))	('MMP-14', 'Gene', '4323', (160, 166))	('MMP-14', 'Gene', (58, 64))	('knockdown', 'Var', (167, 176))	('MMP-14', 'Gene', '4323', (58, 64))	('MMP-14', 'Gene', (160, 166))
698990	32930509	This assay revealed that MMP-14 knockdown was associated with significantly impaired ECa-109 cell migration relative to control cells (P < 0.05) (Fig 4a).	('impaired', 'NegReg', (76, 84))	('ECa-109', 'CellLine', 'CVCL:6898', (85, 92))	('knockdown', 'Var', (32, 41))	('MMP-14', 'Gene', (25, 31))	('ECa-109 cell migration', 'CPA', (85, 107))	('MMP-14', 'Gene', '4323', (25, 31))
698992	32930509	This analysis revealed that ESCC cells in which MMP-14 had been knocked down were less capable of penetrating the Matrigel membrane layer than were control cells, thus indicating that this protein serves as a key regulator of ESCC cell invasive activity (P < 0.05) (Fig 4b).	('MMP-14', 'Gene', (48, 54))	('MMP-14', 'Gene', '4323', (48, 54))	('knocked down', 'Var', (64, 76))	('less', 'NegReg', (82, 86))
699001	32930509	In order to more fully explore the functional role of MMP-14 in ESCC, we utilized an siRNA-based approach to knock down the expression of this protein.	('MMP-14', 'Gene', (54, 60))	('ESCC', 'Disease', (64, 68))	('MMP-14', 'Gene', '4323', (54, 60))	('knock', 'Var', (109, 114))	('expression', 'MPA', (124, 134))
699002	32930509	We found that MMP-14 knockdown was associated with reduced proliferative, migratory, and invasive activity, and with increased S phase cell cycle arrest.	('reduced', 'NegReg', (51, 58))	('migratory', 'CPA', (74, 83))	('increased', 'PosReg', (117, 126))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('invasive activity', 'CPA', (89, 106))	('arrest', 'Disease', 'MESH:D006323', (146, 152))	('increased S phase cell cycle', 'Phenotype', 'HP:0003214', (117, 145))	('MMP-14', 'Gene', (14, 20))	('arrest', 'Disease', (146, 152))	('knockdown', 'Var', (21, 30))	('proliferative', 'CPA', (59, 72))	('MMP-14', 'Gene', '4323', (14, 20))
699026	32957442	The protein products of individual CGB genes show amino acid differences at position 117.	('amino acid differences', 'Var', (50, 72))	('CGB', 'Gene', (35, 38))	('CGB', 'Gene', '93659', (35, 38))
699033	32957442	The insertion led to the deletion of a 52-base long segment of the proximal promoter, as well as the entire 5' untranslated region (5'UTR) region of the CGB gene.	(', as', 'Gene', '112935892', (84, 88))	('CGB', 'Gene', (153, 156))	('to', 'Gene', '6999', (18, 20))	('deletion', 'Var', (25, 33))	('CGB', 'Gene', '93659', (153, 156))
699034	32957442	The consequence of this mutation was the creation of a new promoter sequence for CGB1 and CGB2, a new 5'UTR region with an alternative start codon, and a new first exon.	('CGB2', 'Gene', (90, 94))	('CGB1', 'Gene', (81, 85))	('CGB1', 'Gene', '114335', (81, 85))	('mutation', 'Var', (24, 32))	('CGB2', 'Gene', '114336', (90, 94))
699068	32957442	It was also demonstrated that specific targeting of CGB1 and CGB2 with siRNA was much more effective in reducing cancer cell numbers than silencing other CGB genes.	('CGB', 'Gene', '93659', (154, 157))	('CGB', 'Gene', (52, 55))	('targeting', 'Var', (39, 48))	('CGB2', 'Gene', '114336', (61, 65))	('CGB', 'Gene', '93659', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('CGB', 'Gene', (154, 157))	('CGB', 'Gene', (61, 64))	('reducing', 'NegReg', (104, 112))	('cancer', 'Disease', (113, 119))	('CGB', 'Gene', '93659', (52, 55))	('CGB2', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CGB1', 'Gene', (52, 56))	('CGB1', 'Gene', '114335', (52, 56))
699125	32412911	Using qPCR, we determined that either upregulation or downregulation of these two hub DEMs occurred in different ESCC cell lines (KYSE30, KYSE140, KYSE410, KYSE150, KYSE510, Eca109, and TE-1), compared to normal esophageal epithelial (Het1A) cells (Figure 6A and 6D).	('hub', 'Gene', '1993', (82, 85))	('ESCC', 'Disease', (113, 117))	('KYSE30', 'Var', (130, 136))	('downregulation', 'NegReg', (54, 68))	('KYSE140', 'Var', (138, 145))	('KYSE410', 'Var', (147, 154))	('KYSE150', 'Var', (156, 163))	('KYSE510', 'Var', (165, 172))	('hub', 'Gene', (82, 85))	('upregulation', 'PosReg', (38, 50))	('KYSE410', 'CellLine', 'CVCL:1352', (147, 154))
699154	32412911	Analysis of the association between miR-196a-5p and miR-1-3p expression and clinicopathologic features showed a correlation between these miRNAs and ESCC T classification, which suggests that changes in miR-196a-5p and miR-1-3p expression may impact tumor progression.	('miR-1', 'Gene', (219, 224))	('miR-1', 'Gene', (203, 208))	('miR-1', 'Gene', '83856', (219, 224))	('miR-1', 'Gene', '83856', (203, 208))	('miR-1', 'Gene', (52, 57))	('miR-1', 'Gene', '83856', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('changes', 'Var', (192, 199))	('impact', 'Reg', (243, 249))	('ESCC T', 'Disease', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('miR-1', 'Gene', (36, 41))	('miR-1', 'Gene', '83856', (36, 41))	('tumor', 'Disease', (250, 255))
699158	32412911	Recent work also showed that several miRNAs, including miR-200b-3p, miR-31-5p, miR-15b-5p, miR-141-3p, miR-135b-5p, and miR-195-5p, were correlated with overall survival of ESCC patients.	('miR-15b', 'Gene', (79, 86))	('miR-31', 'Gene', (68, 74))	('miR-1', 'Gene', (103, 108))	('miR-1', 'Gene', '83856', (79, 84))	('ESCC', 'Disease', (173, 177))	('correlated with', 'Reg', (137, 152))	('miR-195', 'Gene', '406971', (120, 127))	('miR-1', 'Gene', '83856', (103, 108))	('patients', 'Species', '9606', (178, 186))	('miR-200b-3p', 'Var', (55, 66))	('miR-31', 'Gene', '407035', (68, 74))	('miR-1', 'Gene', (79, 84))	('miR-1', 'Gene', (91, 96))	('miR-1', 'Gene', (120, 125))	('miR-1', 'Gene', '83856', (91, 96))	('miR-15b', 'Gene', '406949', (79, 86))	('miR-1', 'Gene', '83856', (120, 125))	('miR-195', 'Gene', (120, 127))
699172	32412911	Human ESCC KYSE30, KYSE140, KYSE410, KYSE150, KYSE510, Eca109, and TE-1 and normal esophageal epithelial (Het1A) cell lines were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS; BI, Israel), 100 U/mL penicillin, and 100 mug/mL streptomycin at 37 C in an incubator with a humidified atmosphere containing 5% CO2.	('streptomycin', 'Chemical', 'MESH:D013307', (254, 266))	('Human', 'Species', '9606', (0, 5))	('RPMI-1640 medium', 'Chemical', '-', (141, 157))	('KYSE410', 'CellLine', 'CVCL:1352', (28, 35))	('CO2', 'Chemical', 'MESH:D002245', (334, 337))	('KYSE410', 'Var', (28, 35))	('KYSE150', 'Var', (37, 44))	('penicillin', 'Chemical', 'MESH:D010406', (227, 237))	('KYSE140', 'Var', (19, 26))	('KYSE510', 'Var', (46, 53))
699188	31894334	In addition, niclosamide inhibited cell proliferation as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and soft agar colony forming assay, and induced cell apoptosis as determined by Annexin V and PI staining.	('soft agar colony forming assay', 'CPA', (237, 267))	('Annexin V', 'Gene', '308', (313, 322))	('cell apoptosis', 'CPA', (281, 295))	('niclosamide', 'Var', (13, 24))	('Annexin V', 'Gene', (313, 322))	('cell proliferation', 'CPA', (35, 53))	('inhibited', 'NegReg', (25, 34))	('niclosamide', 'Chemical', 'MESH:D009534', (13, 24))
699191	31894334	To confirm the results using an apoptosis assay, the apoptotic enhancement of niclosamide was only demonstrated in CE48T cells co-treated with 5-FU, cisplatin, or paclitaxel, and in BE3 cells co-treated with paclitaxel, but not in CE81T cells.	('5-FU', 'Chemical', 'MESH:D005472', (143, 147))	('enhancement', 'PosReg', (63, 74))	('cisplatin', 'Var', (149, 158))	('paclitaxel', 'Chemical', 'MESH:D017239', (208, 218))	('men', 'Species', '9606', (70, 73))	('paclitaxel', 'Chemical', 'MESH:D017239', (163, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('BE3', 'CellLine', 'CVCL:L992', (182, 185))	('paclitaxel', 'Var', (163, 173))	('niclosamide', 'Chemical', 'MESH:D009534', (78, 89))	('apoptotic', 'CPA', (53, 62))	('5-FU', 'Var', (143, 147))
699210	31894334	The molecular mechanisms underlying the antineoplastic effect of niclosamide have been explored in many human malignant cancers, indicating that niclosamide exhibits anticancer activity by suppressing many oncogenic signaling pathways concurrently.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('oncogenic signaling pathways', 'Pathway', (206, 234))	('niclosamide', 'Chemical', 'MESH:D009534', (145, 156))	('cancer', 'Disease', (170, 176))	('niclosamide', 'Chemical', 'MESH:D009534', (65, 76))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('human', 'Species', '9606', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancers', 'Disease', (120, 127))	('suppressing', 'NegReg', (189, 200))	('niclosamide', 'Var', (145, 156))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
699212	31894334	In ovarian cancer, niclosamide significantly decreased the expression of proteins in the wingless/integrated (Wnt), mammalian target of rapamycin (mTOR) and STAT3 pathways and caused significant inhibition of proliferation of cells.	('niclosamide', 'Var', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('expression of proteins', 'MPA', (59, 81))	('mammalian target of rapamycin', 'Gene', '2475', (116, 145))	('mammalian target of rapamycin', 'Gene', (116, 145))	('decreased', 'NegReg', (45, 54))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('STAT3', 'Gene', '6774', (157, 162))	('inhibition', 'NegReg', (195, 205))	('STAT3', 'Gene', (157, 162))	('ovarian cancer', 'Disease', (3, 17))	('niclosamide', 'Chemical', 'MESH:D009534', (19, 30))	('mTOR', 'Gene', '2475', (147, 151))	('proliferation of cells', 'CPA', (209, 231))	('mTOR', 'Gene', (147, 151))
699213	31894334	In acute myeloid leukemia, niclosamide could induce apoptosis of AML blast cells through inhibition of the nuclear factor-kappaB (NF-kappaB) pathway and increasing the production of reactive oxygen species.	('AML', 'Disease', (65, 68))	('niclosamide', 'Chemical', 'MESH:D009534', (27, 38))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('niclosamide', 'Var', (27, 38))	('inhibition', 'NegReg', (89, 99))	('acute myeloid leukemia', 'Disease', (3, 25))	('apoptosis', 'CPA', (52, 61))	('oxygen', 'Chemical', 'MESH:D010100', (191, 197))	('AML', 'Disease', 'MESH:D015470', (65, 68))	('production of reactive oxygen species', 'MPA', (168, 205))	('increasing', 'PosReg', (153, 163))
699216	31894334	In the present study, the antineoplastic effects of niclosamide on esophageal cancer cells were investigated and it was revealed that niclosamide suppressed the STAT3 signaling pathway and inhibited cell proliferation in esophageal cancer cells.	('niclosamide', 'Var', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('niclosamide', 'Chemical', 'MESH:D009534', (52, 63))	('cell proliferation', 'CPA', (199, 217))	('niclosamide', 'Chemical', 'MESH:D009534', (134, 145))	('esophageal cancer', 'Disease', (221, 238))	('inhibited', 'NegReg', (189, 198))	('STAT3', 'Gene', '6774', (161, 166))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('STAT3', 'Gene', (161, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (221, 238))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('suppressed', 'NegReg', (146, 156))
699222	31894334	F6627), cisplatin (P4394), and paclitaxel (T7402) were purchased from Sigma-Aldrich (Merk KGaA).	('T7402', 'Var', (43, 48))	('F6627', 'Var', (0, 5))	('P4394', 'Var', (19, 24))	('paclitaxel', 'Chemical', 'MESH:D017239', (31, 41))	('P4394', 'Chemical', 'MESH:D010695', (19, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (8, 17))	('F6627', 'Chemical', 'MESH:D005461', (0, 5))	('T7402', 'CellLine', 'CVCL:5492', (43, 48))
699225	31894334	Esophageal cancer cell lines, BE3 (adenocarcinoma), CE48T/VGH and CE81T/VGH (squamous cell carcinoma) were courtesy of Dr Yen and Dr Lee, respectively.	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BE3', 'CellLine', 'CVCL:L992', (30, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('adenocarcinoma', 'Disease', (35, 49))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('CE81T/VGH', 'Var', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))	('Esophageal cancer', 'Disease', (0, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (35, 49))	('CE48T/VGH', 'Var', (52, 61))
699243	31894334	The protein levels of endogenous beta-catenin could only be detected in CE48T and CE81T cells, but not in BE3 cells.	('BE3', 'CellLine', 'CVCL:L992', (106, 109))	('CE81T', 'Var', (82, 87))	('beta-catenin', 'Gene', (33, 45))	('CE48T', 'Var', (72, 77))	('beta-catenin', 'Gene', '1499', (33, 45))
699248	31894334	The IC50 concentrations of niclosamide were 2.8, 11.3, and 5.1 microM for CE48T, CE81T and BE3, respectively.	('CE81T', 'Var', (81, 86))	('CE48T', 'Var', (74, 79))	('niclosamide', 'Chemical', 'MESH:D009534', (27, 38))	('BE3', 'CellLine', 'CVCL:L992', (91, 94))
699256	31894334	The results indicated that the reduction of cell viabilities of CE48T and BE3 cells was mainly caused by niclosamide-induced cell apoptosis, but was partial to that of CE81T cells.	('reduction', 'NegReg', (31, 40))	('BE3', 'CellLine', 'CVCL:L992', (74, 77))	('CE48T', 'Var', (64, 69))	('niclosamide-induced', 'MPA', (105, 124))	('cell viabilities', 'CPA', (44, 60))	('niclosamide', 'Chemical', 'MESH:D009534', (105, 116))
699261	31894334	The proportion of sub-G1 cells was increased in a time-dependent manner in CE48T and BE3 cells after 48 and 72 h treatment.	('CE48T', 'Var', (75, 80))	('increased', 'PosReg', (35, 44))	('BE3', 'CellLine', 'CVCL:L992', (85, 88))	('men', 'Species', '9606', (118, 121))
699266	31894334	The protein levels of various cyclins in CE48T, CE81T and BE3 cells were assessed by western blot assay, and it was revealed that all of the expression levels of cyclin D1, E, A and B1 were almost completely lost in CE81T cells treated with niclosamide for 48 h (Fig.	('niclosamide', 'Chemical', 'MESH:D009534', (241, 252))	('cyclin', 'Gene', (162, 168))	('cyclin', 'Gene', '5111', (30, 36))	('BE3', 'CellLine', 'CVCL:L992', (58, 61))	('cyclin', 'Gene', (30, 36))	('expression', 'MPA', (141, 151))	('cyclin D1, E, A and B1', 'Gene', '595;890;891', (162, 184))	('lost', 'NegReg', (208, 212))	('CE81T', 'Var', (216, 221))	('cyclin', 'Gene', '5111', (162, 168))
699279	31894334	Moreover, the combination of niclosamide and cisplatin (10 microM) resulted in a higher proportion of apoptotic cells than cisplatin treatment alone (56.68+-1.82% vs. 25.57+-8.81%; P<0.05), as well as the combination of niclosamide and paclitaxel (10 nM) which induced a higher proportion of apoptotic cells than paclitaxel treatment alone (28.69+-1.75% vs. 12.54+-1.12%; P<0.005).	('apoptotic cells', 'CPA', (102, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('niclosamide', 'Chemical', 'MESH:D009534', (220, 231))	('paclitaxel', 'Chemical', 'MESH:D017239', (313, 323))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('men', 'Species', '9606', (138, 141))	('paclitaxel', 'Chemical', 'MESH:D017239', (236, 246))	('niclosamide', 'Chemical', 'MESH:D009534', (29, 40))	('men', 'Species', '9606', (329, 332))	('niclosamide', 'Var', (29, 40))
699281	31894334	In BE3 cells, the combination of niclosamide and paclitaxel induced a higher proportion of apoptotic cells than paclitaxel treatment alone (39.88+-6.83% vs. 21.26+-3.26%; P<0.05) (as revealed in Fig.	('niclosamide', 'Var', (33, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (49, 59))	('men', 'Species', '9606', (128, 131))	('BE3', 'CellLine', 'CVCL:L992', (3, 6))	('niclosamide', 'Chemical', 'MESH:D009534', (33, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (112, 122))	('apoptotic cells', 'CPA', (91, 106))
699288	31894334	In addition to its role in STAT3 inhibition, niclosamide has also been revealed to concurrently inhibit multiple intracellular signaling pathways, including the Wnt, Notch 1, mTOR and NF-kappaB signaling cascades.	('Wnt', 'Pathway', (161, 164))	('STAT3', 'Gene', (27, 32))	('Notch 1', 'Gene', '4851', (166, 173))	('Notch 1', 'Gene', (166, 173))	('intracellular signaling pathways', 'Pathway', (113, 145))	('STAT3', 'Gene', '6774', (27, 32))	('niclosamide', 'Var', (45, 56))	('mTOR', 'Gene', '2475', (175, 179))	('inhibit', 'NegReg', (96, 103))	('NF-kappaB signaling cascades', 'Pathway', (184, 212))	('mTOR', 'Gene', (175, 179))	('niclosamide', 'Chemical', 'MESH:D009534', (45, 56))
699293	31894334	Moreover, STAT3 activated HET-1A cells to form tumors in vivo, suggesting that aberrant STAT3 expression plays a crucial role in esophageal carcinogenesis.	('tumors', 'Disease', (47, 53))	('esophageal carcinogenesis', 'Disease', (129, 154))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('STAT3', 'Gene', '6774', (88, 93))	('aberrant', 'Var', (79, 87))	('STAT3', 'Gene', (88, 93))	('STAT3', 'Gene', '6774', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (129, 154))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('STAT3', 'Gene', (10, 15))
699294	31894334	Conversely, STAT3 knockdown significantly reduced cell proliferation of OE21 (ESCC) and OE33 (EAC) cells, and a reduced STAT3 level was revealed to be associated with significant downregulation of cell cycle genes in both cell lines, indicating that STAT3 plays a pivotal role in cell proliferation of esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('STAT3', 'Gene', '6774', (120, 125))	('cell proliferation', 'CPA', (50, 68))	('reduced', 'NegReg', (42, 49))	('downregulation', 'NegReg', (179, 193))	('reduced', 'NegReg', (112, 119))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('knockdown', 'Var', (18, 27))	('EAC', 'Disease', (94, 97))	('EAC', 'Disease', 'MESH:D004941', (94, 97))	('STAT3', 'Gene', (12, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (302, 319))	('STAT3', 'Gene', (250, 255))	('ESCC', 'Disease', (78, 82))	('STAT3', 'Gene', '6774', (12, 17))	('STAT3', 'Gene', '6774', (250, 255))	('esophageal cancer', 'Disease', (302, 319))	('cell cycle genes', 'Gene', (197, 213))	('STAT3', 'Gene', (120, 125))
699296	31894334	In addition, niclosamide treatment did not only markedly suppress the phosphorylation of Y705 of STAT3, but also slightly decreased the total protein levels of STAT3.	('STAT3', 'Gene', (97, 102))	('STAT3', 'Gene', '6774', (160, 165))	('suppress', 'NegReg', (57, 65))	('phosphorylation', 'MPA', (70, 85))	('STAT3', 'Gene', (160, 165))	('men', 'Species', '9606', (30, 33))	('niclosamide', 'Chemical', 'MESH:D009534', (13, 24))	('Y705', 'Var', (89, 93))	('STAT3', 'Gene', '6774', (97, 102))	('decreased', 'NegReg', (122, 131))
699300	31894334	Notably, ESCC CE81T cells were more resistant than ESCC CE48T cells to niclosamide.	('ESCC', 'Disease', (9, 13))	('ESCC', 'Disease', 'MESH:C562729', (51, 55))	('niclosamide', 'Chemical', 'MESH:D009534', (71, 82))	('resistant', 'MPA', (36, 45))	('ESCC', 'Disease', (51, 55))	('ESCC', 'Disease', 'MESH:C562729', (9, 13))	('CE81T', 'Var', (14, 19))
699301	31894334	Similar resistant responses were revealed in a previous study in which CE81T cells were resistant to photofrin-induced inhibition of EGFR as well as to photofrin-mediated dark toxicity, compared with CE48T cells.	('photofrin', 'Chemical', 'MESH:D017323', (101, 110))	('toxicity', 'Disease', 'MESH:D064420', (176, 184))	('EGFR', 'Gene', '1956', (133, 137))	('CE81T', 'Var', (71, 76))	('toxicity', 'Disease', (176, 184))	('photofrin', 'Chemical', 'MESH:D017323', (152, 161))	('EGFR', 'Gene', (133, 137))
699305	31894334	By contrast, in esophageal squamous cell carcinoma cell lines, niclosamide significantly (P<0.05) increased the proportion of early apoptotic cells in both CE48T and CE81T cells, however only significantly increased the proportion of dead cells in CE48T (P<0.005), but not in CE81T cells.	('early apoptotic cells', 'CPA', (126, 147))	('esophageal squamous cell carcinoma', 'Disease', (16, 50))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (16, 50))	('CE48T', 'Var', (156, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('CE81T', 'Var', (166, 171))	('niclosamide', 'Chemical', 'MESH:D009534', (63, 74))	('CE48T', 'Var', (248, 253))	('increased', 'PosReg', (98, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))
699306	31894334	After 48 h of treatment of niclosamide, only a small proportion of Annexin V-positive cells were detected in CE81T, compared with CE48T and BE3 cells.	('niclosamide', 'Chemical', 'MESH:D009534', (27, 38))	('BE3', 'CellLine', 'CVCL:L992', (140, 143))	('Annexin V', 'Gene', '308', (67, 76))	('men', 'Species', '9606', (19, 22))	('CE81T', 'Var', (109, 114))	('Annexin V', 'Gene', (67, 76))
699308	31894334	Previous studies in oral squamous cell carcinoma, adrenocortical carcinoma and head and neck cancer and osteosarcoma revealed that niclosamide could induce G1-phase arrest of the cell cycle.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('head and neck cancer', 'Phenotype', 'HP:0012288', (79, 99))	('adrenocortical carcinoma', 'Disease', (50, 74))	('osteosarcoma', 'Disease', (104, 116))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 48))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('osteosarcoma', 'Phenotype', 'HP:0002669', (104, 116))	('induce', 'Reg', (149, 155))	('niclosamide', 'Chemical', 'MESH:D009534', (131, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (104, 116))	('oral squamous cell carcinoma', 'Disease', (20, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (50, 74))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (50, 74))	('G1-phase arrest of the cell cycle', 'CPA', (156, 189))	('head and neck cancer', 'Disease', 'MESH:D006258', (79, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))	('niclosamide', 'Var', (131, 142))
699309	31894334	Through flow cytometric analysis using DNA dye PI staining, it was revealed that a high proportion of sub-G1 cells were detected in CE48T and BE3 cells after 10 microM niclosamide treatment for 72 h, while only a small proportion of sub-G1 was detected in CE81T cells.	('CE48T', 'Var', (132, 137))	('niclosamide', 'Chemical', 'MESH:D009534', (168, 179))	('men', 'Species', '9606', (185, 188))	('sub-G1', 'Gene', (102, 108))	('detected', 'Reg', (120, 128))	('BE3', 'CellLine', 'CVCL:L992', (142, 145))
699344	31729835	Univariate and multivariate analyses revealed that the expression of SOX6 is significantly associated with patient disease-related survival and is an independent prognostic factor for lung adenocarcinoma.	('patient disease-related survival', 'CPA', (107, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (184, 203))	('SOX6', 'Gene', (69, 73))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (184, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('expression', 'Var', (55, 65))	('lung adenocarcinoma', 'Disease', (184, 203))	('patient', 'Species', '9606', (107, 114))	('associated', 'Reg', (91, 101))
699347	31729835	In this study, SOX6 inhibits the G1/S phase transition of cell cycle by up-regulation of p53 and p21CIPI and down-regulation of cyclin D1 and beta-catenin expression, thereby inhibiting the proliferation, migration and invasion of lung adenocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (231, 250))	('p21', 'Gene', (97, 100))	('p53', 'Gene', (89, 92))	('proliferation', 'CPA', (190, 203))	('up-regulation', 'PosReg', (72, 85))	('beta-catenin', 'Gene', (142, 154))	('cyclin D1', 'Gene', (128, 137))	('down-regulation', 'NegReg', (109, 124))	('beta-catenin', 'Gene', '1499', (142, 154))	('migration', 'CPA', (205, 214))	('inhibiting', 'NegReg', (175, 185))	('cyclin D1', 'Gene', '595', (128, 137))	('p21', 'Gene', '1026', (97, 100))	('inhibits', 'NegReg', (20, 28))	('invasion of lung adenocarcinoma', 'Disease', (219, 250))	('SOX6', 'Var', (15, 19))	('invasion of lung adenocarcinoma', 'Disease', 'MESH:C538231', (219, 250))	('G1/S phase transition', 'CPA', (33, 54))	('p53', 'Gene', '7157', (89, 92))
699348	31729835	MTT 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide NSCLC non-small-cell lung cancer SOX6 Sry-related high-mobility group box6 Lung cancer is the main cause of cancer death worldwide, and its incidence is the second highest among all cancers 1.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('cancer', 'Disease', (96, 102))	('high-mobility group', 'Var', (120, 139))	('3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide', 'Chemical', 'MESH:C000598529', (4, 69))	('death', 'Disease', 'MESH:D003643', (185, 190))	('NSCLC', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('MTT', 'Chemical', 'MESH:C022616', (0, 3))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('lung cancer', 'Disease', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancers', 'Disease', (252, 259))	('cancer', 'Disease', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('death', 'Disease', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('cancer', 'Disease', (178, 184))	('Lung cancer', 'Phenotype', 'HP:0100526', (145, 156))
699376	31729835	According to the pathological diagnostic criteria, the degrees of differentiation of lung adenocarcinoma are defined as follows: well differentiated (>95% gland duct formation), moderately differentiated (50-95% gland duct formation) and poorly differentiated (0-49% gland duct formation).	('50-95', 'Var', (205, 210))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (85, 104))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lung adenocarcinoma', 'Disease', (85, 104))
699381	31729835	Antibodies were diluted as follows: anti-SOX6 (ab30455; Abcam), anti-p53 (1C12; 2524; 1 : 500; Cell Signaling Technology, Danvers, MA, USA); anti-p21CIPI (60214-1-1g, 1 : 1000; Proteintech Group Inc., Wuhan, Hubei, China), anti-catenin (66379-1-1g, 1 : 1000; Proteintech Group Inc.) and anti-cyclin D1 (60186-1-1g, 1 : 1000; Proteintech Group Inc.).	('p53', 'Gene', '7157', (69, 72))	('p53', 'Gene', (69, 72))	('p21', 'Gene', '1026', (146, 149))	('p21', 'Gene', (146, 149))	('cyclin D1', 'Gene', '595', (292, 301))	('60186-1-1g', 'Var', (303, 313))	('cyclin D1', 'Gene', (292, 301))
699407	31729835	The log rank test showed that disease-related survival (date of diagnosis to the date of cancer-related death or last follow-up) of lung adenocarcinoma patients with low SOX6 expression was significantly shorter compared with that of patients with normal levels of SOX6 (median survival, 22.6 versus 36.3 months, respectively; P < 0.001; Fig.	('expression', 'MPA', (175, 185))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (132, 151))	('low', 'Var', (166, 169))	('SOX6', 'Gene', (170, 174))	('lung adenocarcinoma', 'Disease', (132, 151))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('cancer', 'Disease', (89, 95))	('patients', 'Species', '9606', (234, 242))	('death', 'Disease', 'MESH:D003643', (104, 109))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (132, 151))	('death', 'Disease', (104, 109))	('shorter', 'NegReg', (204, 211))	('patients', 'Species', '9606', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
699418	31729835	The levels of p53 and p21CIPI were significantly increased in SOX6 stable cells compared with controls, whereas the levels of cyclin D1 and beta-catenin were significantly decreased (P < 0.001; Fig.	('levels', 'MPA', (4, 10))	('beta-catenin', 'Gene', '1499', (140, 152))	('SOX6', 'Var', (62, 66))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('increased', 'PosReg', (49, 58))	('decreased', 'NegReg', (172, 181))	('p21', 'Gene', '1026', (22, 25))	('p21', 'Gene', (22, 25))	('cyclin D1', 'Gene', '595', (126, 135))	('cyclin D1', 'Gene', (126, 135))	('beta-catenin', 'Gene', (140, 152))
699420	31729835	It has been reported that children with SOX6 mutations experience development of global developmental delay, progressive relapsing-remitting parkinsonism and spinal syrinx 25.	('global developmental delay', 'Phenotype', 'HP:0001263', (81, 107))	('parkinsonism', 'Phenotype', 'HP:0001300', (141, 153))	('mutations', 'Var', (45, 54))	('parkinsonism', 'Disease', 'MESH:D010302', (141, 153))	('global developmental delay', 'Disease', (81, 107))	('SOX6', 'Gene', (40, 44))	('children', 'Species', '9606', (26, 34))	('parkinsonism', 'Disease', (141, 153))	('syrinx', 'Phenotype', 'HP:0003396', (165, 171))	('spinal syrinx 25', 'Disease', (158, 174))
699421	31729835	Some studies have shown that the abnormal expression of Sox6 is related to the occurrence and development of cancer.	('Sox6', 'Gene', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('related', 'Reg', (64, 71))	('expression', 'MPA', (42, 52))	('cancer', 'Disease', (109, 115))	('abnormal', 'Var', (33, 41))	('development', 'CPA', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Sox6', 'Gene', '55553', (56, 60))
699423	31729835	The abnormal expression of SOX6 is also associated with the prognosis of some tumors.	('SOX6', 'Gene', (27, 31))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('associated', 'Reg', (40, 50))
699435	31729835	For example, in prostate cancer, miRNA-671 promotes tumor proliferation by inhibiting the expression of SOX6 14.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('inhibiting', 'NegReg', (75, 85))	('prostate cancer', 'Disease', (16, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('promotes', 'PosReg', (43, 51))	('tumor', 'Disease', (52, 57))	('miRNA-671', 'Var', (33, 42))	('SOX6 14', 'Gene', (104, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (16, 31))	('expression', 'MPA', (90, 100))	('prostate cancer', 'Phenotype', 'HP:0012125', (16, 31))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
699451	31729835	We also found that p53 and p21CIPI levels were significantly increased in lung adenocarcinoma cells transfected with SOX6, whereas the expressions of beta-catenin and cyclin D1 were significantly decreased.	('beta-catenin', 'Gene', '1499', (150, 162))	('p21', 'Gene', (27, 30))	('decreased', 'NegReg', (196, 205))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (74, 93))	('SOX6', 'Var', (117, 121))	('cyclin D1', 'Gene', '595', (167, 176))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('cyclin D1', 'Gene', (167, 176))	('increased', 'PosReg', (61, 70))	('p53', 'Gene', (19, 22))	('lung adenocarcinoma', 'Disease', (74, 93))	('p53', 'Gene', '7157', (19, 22))	('p21', 'Gene', '1026', (27, 30))	('expressions', 'MPA', (135, 146))	('beta-catenin', 'Gene', (150, 162))
699472	30881502	Studies have reported that the detection of high CTCs by the CellSearch  system in metastatic breast cancer is associated with poor overall survival.	('high CTCs', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
699548	30881502	Kaganoi et al used RT-qPCR to detect cancer cells using specific mRNAs; patients who were positive for the mRNA encoding squamous cell carcinoma antigen (SCCA mRNA) had a higher recurrence rate compared with those who were negative for the antigen.	('mRNA', 'Var', (107, 111))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('cancer', 'Disease', (37, 43))	('recurrence rate', 'CPA', (178, 193))	('higher', 'PosReg', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('rat', 'Species', '10116', (189, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('patients', 'Species', '9606', (72, 80))
699553	30881502	Notably, a single patient who accepted the left thoracotomy surgery approach, was CTC positive, with postoperative pathological staging of T1bN0M0, IB, while another patient, who accepted the thoracoscopic and laparoscopic approach with thoracic anastomosis (Ivor-Lewis), was CTM-positive with the same postoperative pathological stage.	('thoracic anastomosis', 'Disease', 'MESH:D013896', (237, 257))	('rat', 'Species', '10116', (108, 111))	('rat', 'Species', '10116', (310, 313))	('patient', 'Species', '9606', (166, 173))	('patient', 'Species', '9606', (18, 25))	('CTM', 'Chemical', '-', (276, 279))	('T1bN0M0', 'Var', (139, 146))	('thoracic anastomosis', 'Disease', (237, 257))
699565	30881502	One study of esophageal cancer illustrated that LODDS predicts survival more accurately compared with the present system of LNMs, and may serve as another indicator of the LNR.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (13, 30))	('rat', 'Species', '10116', (81, 84))	('rat', 'Species', '10116', (37, 40))	('LODDS', 'Var', (48, 53))	('LODDS', 'Chemical', '-', (48, 53))	('survival', 'MPA', (63, 71))	('esophageal cancer', 'Disease', (13, 30))
699638	30578600	The multivariate logistic regression model demonstrated that an ASA score of 3-4 (OR 6.58; P = 0.047), high FFM (OR 21.91; P = 0.003), and VCP (OR 25.83; P=0.017) were independent risk factors leading to long-term SWL after esophagectomy (Table 5).	('ASA', 'Chemical', '-', (64, 67))	('leading to', 'Reg', (193, 203))	('VCP', 'Phenotype', 'HP:0001605', (139, 142))	('SWL', 'Phenotype', 'HP:0001525', (214, 217))	('high', 'Var', (103, 107))	('SWL', 'Disease', (214, 217))
699695	29340113	Though with heterogeneity, subgroup analyses in our study showed that elevated PLR was an effective prognostic factor for poor OS of esophageal cancer patients who had received various types of treatment including surgical resection and mixed treatment.	('poor OS', 'Disease', (122, 129))	('elevated', 'Var', (70, 78))	('patients', 'Species', '9606', (151, 159))	('PLR', 'Gene', (79, 82))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
699724	27777857	The results showed that the incidence of lymph node metastasis was higher in high MALAT1 expression group than that in low MALAT1 expression group (OR = 1.67, 95 % CI 1.30-2.15).	('MALAT1', 'Gene', (123, 129))	('MALAT1', 'Gene', (82, 88))	('higher', 'PosReg', (67, 73))	('high', 'Var', (77, 81))	('MALAT1', 'Gene', '378938', (123, 129))	('lymph node metastasis', 'CPA', (41, 62))	('MALAT1', 'Gene', '378938', (82, 88))
699728	27777857	Recently, long noncoding RNAs (lncRNAs) have caught increasing attention, and might act as potential valuable biomarkers for cancer diagnosis or potential targets for cancer therapy (Esteller; Gibb et al.).	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('long noncoding RNAs', 'Var', (10, 29))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
699729	27777857	Recent studies found that dysregulation of lncRNAs is always associated with cancer development and progression (Zhang et al.	('dysregulation', 'Var', (26, 39))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('lncRNAs', 'Protein', (43, 50))	('progression', 'CPA', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('associated', 'Reg', (61, 71))
699746	27777857	Recent study found that knock-down of MALAT1 expression could inhibit pancreatic cancer cell proliferation, migration, invasion and the process of epithelial-mesenchymal transition, and induce cell apoptosis and G2/M cell cycle arrest in vitro (Jiao et al.).	('G2/M cell cycle arrest', 'CPA', (212, 234))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))	('migration', 'CPA', (108, 117))	('invasion', 'CPA', (119, 127))	('cell apoptosis', 'CPA', (193, 207))	('MALAT1', 'Gene', (38, 44))	('knock-down', 'Var', (24, 34))	('pancreatic cancer', 'Disease', (70, 87))	('induce', 'Reg', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('inhibit', 'NegReg', (62, 69))	('MALAT1', 'Gene', '378938', (38, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (217, 234))	('process of epithelial-mesenchymal transition', 'CPA', (136, 180))
699772	27777857	In high MALAT1 expression group, 393 patients (49.2 %) with cancer had lymph node metastasis, while only 405 patients (50.8 %) in low MALAT1 expression group.	('MALAT1', 'Gene', (134, 140))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (37, 45))	('MALAT1', 'Gene', '378938', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('lymph node metastasis', 'CPA', (71, 92))	('cancer', 'Disease', (60, 66))	('high', 'Var', (3, 7))	('MALAT1', 'Gene', '378938', (134, 140))	('MALAT1', 'Gene', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
699773	27777857	The results found that the incidence of lymph node metastasis was higher in high MALAT1 expression group than that in low MALAT1 expression group (pooled OR = 1.67, 95 % CI 1.30-2.15) (Fig.	('MALAT1', 'Gene', (81, 87))	('lymph node metastasis', 'CPA', (40, 61))	('higher', 'PosReg', (66, 72))	('MALAT1', 'Gene', '378938', (122, 128))	('MALAT1', 'Gene', '378938', (81, 87))	('high', 'Var', (76, 80))	('MALAT1', 'Gene', (122, 128))
699774	27777857	This result demonstrated that the patients with high levels of MALAT1 expression are more prone to lymph node metastasis in different systemic cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('prone', 'Reg', (90, 95))	('systemic cancers', 'Disease', (134, 150))	('MALAT1', 'Gene', '378938', (63, 69))	('high levels', 'Var', (48, 59))	('MALAT1', 'Gene', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('systemic cancers', 'Disease', 'MESH:D009369', (134, 150))	('patients', 'Species', '9606', (34, 42))	('lymph node metastasis', 'CPA', (99, 120))
699775	27777857	In addition, sensitivity analysis indicated that the pooled HR for deregulated MALAT1 associated with OS was not significantly affected by the exclusion of any of the studies (data not shown).	('MALAT1', 'Gene', '378938', (79, 85))	('MALAT1', 'Gene', (79, 85))	('deregulated', 'Var', (67, 78))
699783	27777857	found that MALAT1 knockdown induced a decrease in proliferation-enhanced apoptosis, inhibited invasion, and reduced colony formation and led to cell cycle arrest at the G2/M phase in esophageal squamous cell carcinoma (Yao et al.).	('knockdown', 'Var', (18, 27))	('invasion', 'CPA', (94, 102))	('MALAT1', 'Gene', '378938', (11, 17))	('reduced', 'NegReg', (108, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('MALAT1', 'Gene', (11, 17))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (183, 217))	('colony formation', 'CPA', (116, 132))	('decrease', 'NegReg', (38, 46))	('apoptosis', 'CPA', (73, 82))	('cell cycle arrest at the G2/M phase', 'CPA', (144, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('esophageal squamous cell carcinoma', 'Disease', (183, 217))	('inhibited', 'NegReg', (84, 93))
699798	27777857	Therefore, it is possible that our results might overestimate the prognostic effects of abnormal MALAT1 expression on survival and lymph node metastasis in different types of cancer.	('lymph node metastasis', 'CPA', (131, 152))	('MALAT1', 'Gene', '378938', (97, 103))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('expression', 'MPA', (104, 114))	('abnormal', 'Var', (88, 96))	('MALAT1', 'Gene', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
699813	25266021	Heavy exposure to polycyclic aromatic hydrocarbons (PAHs) can induce risk for esophageal squamous cell cancer and is demonstrated by high levels of urine 1-hydroxypyrene glucuronide (1-OHPG), a stable metabolite that reflects recent exposure to mixed aromatic hydrocarbons.	('1-OHPG', 'Chemical', '-', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('polycyclic', 'Var', (18, 28))	('PAHs', 'Chemical', 'MESH:D011084', (52, 56))	('esophageal squamous cell cancer', 'Disease', (78, 109))	('aromatic hydrocarbons', 'Chemical', 'MESH:D006841', (251, 272))	('aromatic hydrocarbons', 'Chemical', 'MESH:D006841', (29, 50))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (78, 109))	('1-hydroxypyrene glucuronide', 'Chemical', 'MESH:C093851', (154, 181))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (18, 50))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (89, 109))
699846	25266021	In the NIH-AARP study, the association between EAC and dietary fat was generally null once fully adjusted for potential confounders, but there may have been a protective effect against EAC by polyunsaturated fat among subjects with a normal body-mass index (BMI).	('EAC', 'Gene', (185, 188))	('protective', 'NegReg', (159, 169))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('EAC', 'Phenotype', 'HP:0011459', (185, 188))	('EAC', 'Gene', '1540', (47, 50))	('EAC', 'Gene', (47, 50))	('polyunsaturated fat', 'Var', (192, 211))	('saturated', 'Chemical', '-', (198, 207))	('EAC', 'Gene', '1540', (185, 188))
699915	25266021	This stems from the multistep carcinogenesis model characterized by early genetic/epigenetic alterations accompanied by phenotypic and histopathologic changes over a long latency period.	('alterations', 'Var', (93, 104))	('multistep carcinogenesis', 'Disease', (20, 44))	('multistep carcinogenesis', 'Disease', 'MESH:D063646', (20, 44))
700074	25174799	IFIT2 ectopic expression leads to promotion of cell apoptosis, indicating that IFIT2 may function as a suppressor in the development of AGEJ.	('IFIT2', 'Gene', '3433', (79, 84))	('cell apoptosis', 'CPA', (47, 61))	('IFIT2', 'Gene', '3433', (0, 5))	('ectopic expression', 'Var', (6, 24))	('IFIT2', 'Gene', (0, 5))	('IFIT2', 'Gene', (79, 84))	('promotion', 'PosReg', (34, 43))
700075	25174799	Furthermore, inhibition of miR-645 induces up-regulation of IFIT2 and increased caspase-3/7 activity compared with control groups.	('caspase-3/7', 'Gene', (80, 91))	('miR-645', 'Gene', '693230', (27, 34))	('increased', 'PosReg', (70, 79))	('IFIT2', 'Gene', '3433', (60, 65))	('miR-645', 'Gene', (27, 34))	('inhibition', 'Var', (13, 23))	('IFIT2', 'Gene', (60, 65))	('up-regulation', 'PosReg', (43, 56))	('activity', 'MPA', (92, 100))	('caspase-3/7', 'Gene', '836;840', (80, 91))
700080	25174799	In addition, aberrant post-transcriptional regulation of mRNAs by miRNAs is related with tumorigenesis.	('aberrant', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('miR', 'Gene', (66, 69))	('mRNAs', 'Protein', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('miR', 'Gene', '220972', (66, 69))	('post-transcriptional regulation', 'MPA', (22, 53))	('tumor', 'Disease', (89, 94))	('related', 'Reg', (76, 83))
700084	25174799	These studies suggest that dysregulation of miRNAs is frequently involved in carcinogenesis and cancer progression.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinogenesis', 'Disease', (77, 91))	('involved', 'Reg', (65, 73))	('dysregulation', 'Var', (27, 40))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
700102	25174799	The human miR-645 duplex agomir (400 nM), antagomir (400 nM) and negative control were designed and provided by Ribobio (Guangzhou, Guangdong, China).	('human', 'Species', '9606', (4, 9))	('miR-645', 'Gene', (10, 17))	('400 nM', 'Var', (33, 39))	('400 nM', 'Var', (53, 59))	('miR-645', 'Gene', '693230', (10, 17))
700105	25174799	To construct IFIT2-3'UTR plasmid, a wild-type 3'-UTR fragment of human IFIT2 mRNA (1226-1233 nt, Genbank accession no.	('IFIT2', 'Gene', '3433', (13, 18))	('human', 'Species', '9606', (65, 70))	('1226-1233', 'Var', (83, 92))	('IFIT2', 'Gene', (71, 76))	('IFIT2', 'Gene', (13, 18))	('IFIT2', 'Gene', '3433', (71, 76))
700108	25174799	Wild and mutant types of pmirGLO-IFIT2-UTR vectors were validated by DNA sequencing.	('IFIT2', 'Gene', '3433', (33, 38))	('mutant', 'Var', (9, 15))	('IFIT2', 'Gene', (33, 38))
700134	25174799	SGC7901 and BGC-823 cells transfected with miR-645 inhibitors and mimics showed significantly lower and higher levels of cell proliferation, respectively, comparision with the NC or mock groups in the presence of ADR (0.2 mug/mL) as determined by MTT assay (Figure 2B, P < 0.001; Figure 2E, P < 0.001).	('GC', 'Phenotype', 'HP:0012126', (13, 15))	('miR-645', 'Gene', (43, 50))	('miR-645', 'Gene', '693230', (43, 50))	('SGC7901', 'CellLine', 'CVCL:0520', (0, 7))	('MTT', 'Chemical', 'MESH:C070243', (247, 250))	('cell proliferation', 'CPA', (121, 139))	('lower', 'NegReg', (94, 99))	('GC', 'Phenotype', 'HP:0012126', (1, 3))	('higher', 'PosReg', (104, 110))	('BGC-823', 'CellLine', 'CVCL:3360', (12, 19))	('inhibitors', 'Var', (51, 61))
700140	25174799	Wild-type and mutant IFIT2-3'UTR containing the putative binding site of miR-645 were cloned into psiCHECK-2 vector downstream from luciferase gene (Additional file 3: Figure S2).	('miR-645', 'Gene', '693230', (73, 80))	('IFIT2', 'Gene', '3433', (21, 26))	('mutant', 'Var', (14, 20))	('miR-645', 'Gene', (73, 80))	('IFIT2', 'Gene', (21, 26))
700159	25174799	Although accumulating evidence have shown that miRNAs deregulation is involved with tumor carcinogenesis, progression, migration and invasion, metastasis and multidrug resistance.	('tumor carcinogenesis', 'Disease', (84, 104))	('tumor carcinogenesis', 'Disease', 'MESH:D063646', (84, 104))	('invasion', 'CPA', (133, 141))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('progression', 'CPA', (106, 117))	('deregulation', 'Var', (54, 66))	('involved', 'Reg', (70, 78))	('multidrug resistance', 'Disease', (158, 178))	('metastasis', 'CPA', (143, 153))	('migration', 'CPA', (119, 128))
700167	25174799	In this study, we showed that miR-645 impaired cancer cells to serum deprivation-induced apoptosis, whereas the depletion of miR-645 antagonized this effect of miR-645, suggesting that miR-645 may play a crucial role in the adaptation of cancer cells to low nutrition.	('impaired cancer', 'Disease', 'MESH:D009422', (38, 53))	('miR-645', 'Gene', (125, 132))	('cancer', 'Disease', (238, 244))	('miR-645', 'Gene', '693230', (185, 192))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('miR-645', 'Gene', '693230', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('serum deprivation-induced', 'MPA', (63, 88))	('miR-645', 'Gene', (185, 192))	('depletion', 'Var', (112, 121))	('miR-645', 'Gene', '693230', (30, 37))	('impaired cancer', 'Disease', (38, 53))	('miR-645', 'Gene', (160, 167))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('apoptosis', 'CPA', (89, 98))	('miR-645', 'Gene', '693230', (125, 132))	('miR-645', 'Gene', (30, 37))
700169	25174799	On the one hand, microRNAs might function as tumor suppressor via inducing apoptosis, i.e.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('inducing', 'PosReg', (66, 74))	('apoptosis', 'CPA', (75, 84))	('tumor', 'Disease', (45, 50))	('microRNAs', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
700173	25174799	These genes can inhibit viral replication by sacrificing the cell through promoting apoptosis and suppress the cancer progression via inhibiting the malignantly transformed cell survival for the benefit of the host.	('sacrificing', 'NegReg', (45, 56))	('inhibit', 'NegReg', (16, 23))	('inhibiting', 'NegReg', (134, 144))	('apoptosis', 'CPA', (84, 93))	('viral replication', 'CPA', (24, 41))	('malignantly transformed cell survival', 'CPA', (149, 186))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('genes', 'Var', (6, 11))	('suppress', 'NegReg', (98, 106))	('promoting', 'PosReg', (74, 83))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
700187	18840514	Review and pooled analysis of studies on MTHFR C677T polymorphism and esophageal cancer Esophageal cancer has been associated with tobacco and alcohol consumption, gastric reflux, exposure to nitrosamines from food or other environmental sources, and diets lacking folate.	('esophageal cancer', 'Disease', (70, 87))	('Esophageal cancer', 'Disease', (88, 105))	('alcohol', 'Chemical', 'MESH:D000438', (143, 150))	('polymorphism', 'Var', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('MTHFR', 'Gene', (41, 46))	('gastric reflux', 'Disease', 'MESH:D005764', (164, 178))	('C677T', 'Mutation', 'rs1801133', (47, 52))	('folate', 'Chemical', 'MESH:D005492', (265, 271))	('men', 'Species', '9606', (231, 234))	('Esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('tobacco', 'Species', '4097', (131, 138))	('associated', 'Reg', (115, 125))	('C677T polymorphism', 'Var', (47, 65))	('gastric reflux', 'Phenotype', 'HP:0002020', (164, 178))	('nitrosamines', 'Chemical', 'MESH:D009602', (192, 204))	('MTHFR', 'Gene', '4524', (41, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('gastric reflux', 'Disease', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
700189	18840514	The C677T polymorphism is the most common functional variant, leading to a reduction in enzyme activity.	('enzyme activity', 'MPA', (88, 103))	('C677T', 'Mutation', 'rs1801133', (4, 9))	('reduction', 'NegReg', (75, 84))	('C677T', 'Var', (4, 9))
700190	18840514	We report a pooled analysis of 5 studies on the association of MTHFR C677T polymorphism and esophageal cancer, including 725 cases and 1531 controls.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('MTHFR', 'Gene', '4524', (63, 68))	('association', 'Interaction', (48, 59))	('C677T', 'Var', (69, 74))	('MTHFR', 'Gene', (63, 68))	('esophageal cancer', 'Disease', (92, 109))	('C677T', 'Mutation', 'rs1801133', (69, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
700204	18840514	Approximately 60 polymorphisms, as well as 41 rare but deleterious mutations have been described in the MTHFR gene.	('MTHFR', 'Gene', '4524', (104, 109))	('polymorphisms', 'Var', (17, 30))	('MTHFR', 'Gene', (104, 109))
700205	18840514	The most common functional variant and most studied to date is the thermolabile MTHFR C677T polymorphism (rs1801133).	('MTHFR', 'Gene', (80, 85))	('rs1801133', 'Var', (106, 115))	('MTHFR', 'Gene', '4524', (80, 85))	('rs1801133', 'Mutation', 'rs1801133', (106, 115))	('C677T', 'Mutation', 'rs1801133', (86, 91))	('C677T', 'Var', (86, 91))
700206	18840514	The C677T variant is a C to T transition in exon 4 at nucleotide 677, resulting in the conversion of alanine to valine at position 222 of the MTHFR amino acid sequence.	('conversion', 'MPA', (87, 97))	('MTHFR', 'Gene', '4524', (142, 147))	('C677T', 'Mutation', 'rs1801133', (4, 9))	('alanine to valine at position 222', 'Mutation', 'rs1801133', (101, 134))	('C677T', 'Var', (4, 9))	('MTHFR', 'Gene', (142, 147))	('alanine to valine', 'MPA', (101, 118))
700207	18840514	Heterozygotes (CT) and homozygotes (TT) for the C677T variant have respectively 65% and 30% of the MTHFR enzyme activity observed in homozygous wild type subjects (CC).	('MTHFR', 'Gene', '4524', (99, 104))	('MTHFR', 'Gene', (99, 104))	('C677T', 'Mutation', 'rs1801133', (48, 53))	('C677T', 'Var', (48, 53))	('activity', 'MPA', (112, 120))
700209	18840514	The frequency of MTHFR C677T varies by ethnicity.	('C677T', 'Var', (23, 28))	('MTHFR', 'Gene', '4524', (17, 22))	('C677T', 'Mutation', 'rs1801133', (23, 28))	('MTHFR', 'Gene', (17, 22))
700217	18840514	An interaction between folate status and the MTHFR C677T polymorphism has been described.	('interaction', 'Interaction', (3, 14))	('MTHFR', 'Gene', '4524', (45, 50))	('MTHFR', 'Gene', (45, 50))	('C677T', 'Mutation', 'rs1801133', (51, 56))	('C677T', 'Var', (51, 56))	('folate', 'Chemical', 'MESH:D005492', (23, 29))
700218	18840514	Subjects who are homozygous for the MTHFR C677T variant and have a low folate status have been reported to have relative DNA hypomethylation compared with wild-type subjects, while no such effect is observed in subjects with high folate status.	('relative DNA hypomethylation', 'MPA', (112, 140))	('high folate status', 'Phenotype', 'HP:0032164', (225, 243))	('folate', 'Chemical', 'MESH:D005492', (230, 236))	('MTHFR', 'Gene', (36, 41))	('C677T', 'Mutation', 'rs1801133', (42, 47))	('C677T', 'Var', (42, 47))	('folate', 'Chemical', 'MESH:D005492', (71, 77))	('MTHFR', 'Gene', '4524', (36, 41))	('low folate status', 'Phenotype', 'HP:0100507', (67, 84))
700223	18840514	Alcohol acts as a folate antagonist, resulting in malabsorption, increased folate excretion, or abnormalities in folate metabolism through the inhibition of methionine synthase (MTR).	('folate', 'Chemical', 'MESH:D005492', (113, 119))	('increased', 'PosReg', (65, 74))	('folate excretion', 'MPA', (75, 91))	('abnormalities', 'Var', (96, 109))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('malabsorption', 'Disease', (50, 63))	('methionine synthase', 'Gene', (157, 176))	('Alcohol acts', 'Phenotype', 'HP:0030955', (0, 12))	('methionine synthase', 'Gene', '4548', (157, 176))	('abnormalities in folate metabolism', 'Phenotype', 'HP:0012335', (96, 130))	('folate', 'Chemical', 'MESH:D005492', (18, 24))	('malabsorption', 'Disease', 'MESH:D008286', (50, 63))	('increased folate excretion', 'Phenotype', 'HP:0032164', (65, 91))	('inhibition', 'NegReg', (143, 153))	('folate', 'Chemical', 'MESH:D005492', (75, 81))	('malabsorption', 'Phenotype', 'HP:0002024', (50, 63))	('folate metabolism', 'MPA', (113, 130))
700226	18840514	Yang reported a significant inverse trend for esophageal cancer across MTHFR 677 genotypes in heavy drinkers (CC > CT > TT; p = 0.024), while this was not observed in non-heavy drinkers (p = 0.46).	('MTHFR', 'Gene', (71, 76))	('CC > CT > TT', 'Var', (110, 122))	('esophageal cancer', 'Disease', (46, 63))	('inverse', 'NegReg', (28, 35))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('MTHFR', 'Gene', '4524', (71, 76))
700227	18840514	Stolzenberg-Solomon reported no interaction between MTHFR C677T and esophageal cancer and alcohol use during the previous 12 months.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('alcohol use', 'Phenotype', 'HP:0030955', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('C677T', 'Mutation', 'rs1801133', (58, 63))	('MTHFR', 'Gene', '4524', (52, 57))	('C677T', 'Var', (58, 63))	('alcohol', 'Chemical', 'MESH:D000438', (90, 97))	('esophageal cancer', 'Disease', (68, 85))	('MTHFR', 'Gene', (52, 57))
700228	18840514	Yang found no significant interaction between the MTHFR C677T polymorphism and smoking on esophageal cancer risk.	('MTHFR', 'Gene', (50, 55))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('C677T', 'Mutation', 'rs1801133', (56, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('C677T', 'Var', (56, 61))	('MTHFR', 'Gene', '4524', (50, 55))
700229	18840514	Few gene-gene interactions have been reported in the literature regarding MTHFR C677T and esophageal cancer.	('MTHFR', 'Gene', (74, 79))	('esophageal cancer', 'Disease', (90, 107))	('MTHFR', 'Gene', '4524', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('C677T', 'Mutation', 'rs1801133', (80, 85))	('C677T', 'Var', (80, 85))
700230	18840514	The interaction between the MTHFR C677T and A1298C polymorphisms was evaluated in a study on incident and prevalent esophageal cancer cases, and reported a joint effect of 677 CT and 1298 CC genotypes on esophageal cancer risk, although no significant interaction was found.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('677 CT', 'Var', (172, 178))	('MTHFR', 'Gene', '4524', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('C677T', 'Var', (34, 39))	('esophageal cancer', 'Disease', (204, 221))	('C677T', 'Mutation', 'rs1801133', (34, 39))	('A1298C', 'Mutation', 'rs1801131', (44, 50))	('A1298C', 'Var', (44, 50))	('1298 CC', 'Var', (183, 190))	('MTHFR', 'Gene', (28, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('esophageal cancer', 'Disease', (116, 133))
700231	18840514	In a recent case-control study, Wang reported an interaction between MTHFR C677T and SHMT1 C1420T polymorphisms on esophageal squamous cell carcinoma; an increased cancer risk in individuals with wild-type SHMT and variant MTHFR TT genotypes was found.	('polymorphisms', 'Var', (98, 111))	('MTHFR', 'Gene', '4524', (69, 74))	('C1420T polymorphisms', 'Var', (91, 111))	('SHMT', 'Gene', '6470', (206, 210))	('SHMT', 'Gene', (85, 89))	('SHMT1', 'Gene', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('MTHFR', 'Gene', (223, 228))	('C677T', 'Var', (75, 80))	('variant', 'Var', (215, 222))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (115, 149))	('MTHFR', 'Gene', (69, 74))	('SHMT1', 'Gene', '6470', (85, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('SHMT', 'Gene', '6470', (85, 89))	('SHMT', 'Gene', (206, 210))	('cancer', 'Disease', (164, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('C677T', 'Mutation', 'rs1801133', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MTHFR', 'Gene', '4524', (223, 228))	('interaction', 'Interaction', (49, 60))	('esophageal squamous cell carcinoma', 'Disease', (115, 149))	('C1420T', 'Mutation', 'rs1979277', (91, 97))
700232	18840514	There have been mixed reports in the literature regarding the association of MTHFR C677T polymorphism with esophageal cancer (table 1).	('MTHFR', 'Gene', (77, 82))	('association', 'Interaction', (62, 73))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('C677T', 'Var', (83, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('C677T', 'Mutation', 'rs1801133', (83, 88))	('MTHFR', 'Gene', '4524', (77, 82))
700233	18840514	A recent meta--analysis of 7 publications on the association of MTHFR C677T and esophageal cancer observed significant heterogeneity among the studies, and therefore no summary estimate was reported.	('MTHFR', 'Gene', '4524', (64, 69))	('esophageal cancer', 'Disease', (80, 97))	('MTHFR', 'Gene', (64, 69))	('association', 'Interaction', (49, 60))	('C677T', 'Var', (70, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('C677T', 'Mutation', 'rs1801133', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
700234	18840514	We conducted a pooled analysis to assess the overall effect of MTHFR C677T polymorphism on esophageal cancer risk and to test for possible gene-environment interactions with smoking and alcohol consumption.	('men', 'Species', '9606', (151, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MTHFR', 'Gene', '4524', (63, 68))	('C677T', 'Var', (69, 74))	('MTHFR', 'Gene', (63, 68))	('C677T', 'Mutation', 'rs1801133', (69, 74))	('esophageal cancer', 'Disease', (91, 108))	('alcohol', 'Chemical', 'MESH:D000438', (186, 193))
700235	18840514	The pooled-analysis on the association between MTHFR C677T and esophageal cancer was conducted using data available in the GSEC database.	('C677T', 'Mutation', 'rs1801133', (53, 58))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('MTHFR', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('MTHFR', 'Gene', '4524', (47, 52))	('C677T', 'Var', (53, 58))
700237	18840514	A MEDLINE literature search for case-control studies published between 1966 and July 1, 2007 on the association of MTHFR C677T polymorphism and esophageal cancer was conducted using the search term: (mthfr OR methylenetetrahydrofolate reductase) AND (esophagus OR esophageal) AND (cancer OR carcinoma), yielding 24 results.	('carcinoma', 'Disease', 'MESH:D002277', (291, 300))	('mthfr', 'Gene', (200, 205))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (209, 244))	('C677T polymorphism', 'Var', (121, 139))	('MTHFR', 'Gene', '4524', (115, 120))	('methylenetetrahydrofolate reductase', 'Gene', (209, 244))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('mthfr', 'Gene', '4524', (200, 205))	('C677T', 'Mutation', 'rs1801133', (121, 126))	('carcinoma', 'Disease', (291, 300))	('cancer', 'Disease', (155, 161))	('esophageal cancer', 'Disease', (144, 161))	('polymorphism', 'Var', (127, 139))	('MTHFR', 'Gene', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
700241	18840514	Adjusted odds ratios and 95% confidence intervals for MTHFR C677T were estimated using unconditional logistic regression, including study, age, gender, and smoking status as covariates in the model.	('C677T', 'Var', (60, 65))	('MTHFR', 'Gene', (54, 59))	('C677T', 'Mutation', 'rs1801133', (60, 65))	('MTHFR', 'Gene', '4524', (54, 59))
700250	18840514	There were insufficient cases to analyze the association of MTHFR C677T and esophageal adenocarcinoma.	('MTHFR', 'Gene', '4524', (60, 65))	('esophageal adenocarcinoma', 'Disease', (76, 101))	('association', 'Interaction', (45, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('insufficient', 'Disease', 'MESH:D000309', (11, 23))	('MTHFR', 'Gene', (60, 65))	('insufficient', 'Disease', (11, 23))	('C677T', 'Mutation', 'rs1801133', (66, 71))	('C677T', 'Var', (66, 71))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (76, 101))
700259	18840514	A recent meta-analysis by Larsson (2006) also examined the association between MTHFR C677T and esophageal cancer, but did not report a summary estimate due to significant heterogeneity between published studies.	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('MTHFR', 'Gene', '4524', (79, 84))	('C677T', 'Var', (85, 90))	('C677T', 'Mutation', 'rs1801133', (85, 90))	('MTHFR', 'Gene', (79, 84))	('esophageal cancer', 'Disease', (95, 112))	('examined', 'Reg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
700260	18840514	Meta-analyses and/or pooled-analyses examining the role of MTHFR C677T and other cancers have reported significant positive associations with gastric cancer, multiple myeloma, and breast cancer (postmenopausal women); while significant inverse associations have been reported for leukemia (adults) and colorectal cancer.	('multiple myeloma', 'Phenotype', 'HP:0006775', (158, 174))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('positive', 'PosReg', (115, 123))	('multiple myeloma', 'Disease', 'MESH:D009101', (158, 174))	('gastric cancer', 'Disease', (142, 156))	('colorectal cancer', 'Disease', 'MESH:D015179', (302, 319))	('MTHFR', 'Gene', '4524', (59, 64))	('C677T', 'Var', (65, 70))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('colorectal cancer', 'Disease', (302, 319))	('breast cancer', 'Disease', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('men', 'Species', '9606', (199, 202))	('multiple myeloma', 'Disease', (158, 174))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('MTHFR', 'Gene', (59, 64))	('leukemia', 'Phenotype', 'HP:0001909', (280, 288))	('men', 'Species', '9606', (212, 215))	('C677T', 'Mutation', 'rs1801133', (65, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (302, 319))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('leukemia', 'Disease', 'MESH:D007938', (280, 288))	('leukemia', 'Disease', (280, 288))	('women', 'Species', '9606', (210, 215))
700261	18840514	However, a recent meta-analysis reported no significant association for MTHFR C677T and lung cancer.	('C677T', 'Mutation', 'rs1801133', (78, 83))	('lung cancer', 'Disease', (88, 99))	('C677T', 'Var', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('MTHFR', 'Gene', '4524', (72, 77))	('MTHFR', 'Gene', (72, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
700264	18840514	Since low folate status has been shown to interact with MTHFR C677T , it would be expected that TT genotype would be associated with increased risk compared with CC genotype in smokers.	('low folate status', 'Phenotype', 'HP:0100507', (6, 23))	('MTHFR', 'Gene', '4524', (56, 61))	('folate', 'Chemical', 'MESH:D005492', (10, 16))	('C677T', 'Mutation', 'rs1801133', (62, 67))	('C677T', 'Var', (62, 67))	('MTHFR', 'Gene', (56, 61))
700266	18840514	In a previous study, Yang et al observed no interaction between smoking and MTHFR C677T polymorphism on esophageal cancer risk, but reported an interaction between alcohol consumption and genotype, observing an inverse trend across genotypes (CC > CT > TT) in heavy drinkers.	('C677T', 'Var', (82, 87))	('C677T', 'Mutation', 'rs1801133', (82, 87))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('MTHFR', 'Gene', '4524', (76, 81))	('MTHFR', 'Gene', (76, 81))
700268	18840514	It is possible that individual folate levels may play a role in the interaction between alcohol, smoking of the MTHFR C677T polymorphism; unfortunately we did not have sufficient individual folate data for use as a covariate in the pooled analysis.	('C677T', 'Var', (118, 123))	('folate', 'Chemical', 'MESH:D005492', (31, 37))	('MTHFR', 'Gene', (112, 117))	('alcohol', 'Chemical', 'MESH:D000438', (88, 95))	('folate', 'Chemical', 'MESH:D005492', (190, 196))	('MTHFR', 'Gene', '4524', (112, 117))	('play', 'Reg', (49, 53))	('C677T', 'Mutation', 'rs1801133', (118, 123))	('interaction', 'Interaction', (68, 79))
700269	18840514	Currently, there is no literature evaluating the association between the MTHFR C677T polymorphism and esophageal cancer in races other than Asian and Caucasian, such as Latinos, Native Americans, Aboriginals, or people of African decent.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('people', 'Species', '9606', (212, 218))	('C677T', 'Mutation', 'rs1801133', (79, 84))	('C677T', 'Var', (79, 84))	('MTHFR', 'Gene', '4524', (73, 78))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('MTHFR', 'Gene', (73, 78))
700271	18840514	Thus, we were able to adjust for age, gender, race and smoking status; test for interactions between alcohol consumption, smoking, and MTHFR C677T; and stratify our results by smoking habit, which would not be possible with meta-analysis given the aggregate nature of the data available in the published studies.	('MTHFR', 'Gene', (135, 140))	('alcohol', 'Chemical', 'MESH:D000438', (101, 108))	('MTHFR', 'Gene', '4524', (135, 140))	('C677T', 'Var', (141, 146))	('interactions', 'Interaction', (80, 92))	('C677T', 'Mutation', 'rs1801133', (141, 146))	('test', 'Reg', (71, 75))
700274	18840514	Future research on MTHFR C677T and esophageal cancer should be further targeted at the interactive effects of dietary and environmental factors, and gene-gene interactions.	('MTHFR', 'Gene', (19, 24))	('esophageal cancer', 'Disease', (35, 52))	('interactions', 'Interaction', (159, 171))	('men', 'Species', '9606', (129, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('MTHFR', 'Gene', '4524', (19, 24))	('C677T', 'Mutation', 'rs1801133', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('C677T', 'Var', (25, 30))
700275	18840514	Large-scale studies are required to whether an interaction exists between MTHFR C677T and folate levels on esophageal cancer, and if this modifies the risk of esophageal cancer associated with both smoking and alcohol.	('MTHFR', 'Gene', (74, 79))	('interaction', 'Interaction', (47, 58))	('esophageal cancer', 'Disease', (107, 124))	('folate', 'Chemical', 'MESH:D005492', (90, 96))	('esophageal cancer', 'Disease', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('MTHFR', 'Gene', '4524', (74, 79))	('alcohol', 'Chemical', 'MESH:D000438', (210, 217))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('C677T', 'Mutation', 'rs1801133', (80, 85))	('modifies', 'Reg', (138, 146))	('C677T', 'Var', (80, 85))	('folate levels', 'MPA', (90, 103))
700279	22013482	Restricted patterns of type III IFN receptor expression in contrast to ubiquitously expressed IFN-alpha/beta receptors suggest that type III IFNs have limited cytotoxicity to normal cells and can be a possible anticancer agent.	('IFN-alpha', 'Gene', '3439', (94, 103))	('cytotoxicity', 'Disease', 'MESH:D064420', (159, 171))	('IFN-alpha', 'Gene', (94, 103))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cytotoxicity', 'Disease', (159, 171))	('type III', 'Var', (132, 140))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
700375	33941213	This study clarified the prognostic impact of LNM along the left gastric artery in postoperative patients with ESCC.	('patients', 'Species', '9606', (97, 105))	('ESCC', 'Disease', (111, 115))	('LNM', 'Var', (46, 49))
700380	33941213	This study indicated that LNM along the left gastric artery was an important independent prognostic factor for long-term survival among ESCC patients (P = 0.011).	('ESCC', 'Disease', (136, 140))	('patients', 'Species', '9606', (141, 149))	('LNM', 'Var', (26, 29))
700388	33941213	Some previous studies indicated that LNM in specific areas, such as subcarinal, thoracic, and recurrent laryngeal nerve LNs, correlated with poor prognosis in ESCC patients.	('patients', 'Species', '9606', (164, 172))	('LNM', 'Var', (37, 40))	('ESCC', 'Disease', (159, 163))
700390	33941213	This study aimed to perform a retrospective analysis to determine whether LNM presence along the left gastric artery was associated with decreased survival after esophagectomy in ESCC patients.	('patients', 'Species', '9606', (184, 192))	('ESCC', 'Disease', (179, 183))	('survival', 'MPA', (147, 155))	('decreased', 'NegReg', (137, 146))	('LNM', 'Var', (74, 77))
700428	33941213	In this study, we addressed the prognostic role of LNM along the left gastric artery in postoperative patients with ESCC.	('LNM', 'Var', (51, 54))	('ESCC', 'Disease', (116, 120))	('patients', 'Species', '9606', (102, 110))
700433	33941213	Some investigators showed that LNM along the left gastric artery was correlated with prognosis in gastric cancer.	('correlated', 'Reg', (69, 79))	('gastric cancer', 'Disease', (98, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('LNM', 'Var', (31, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
700435	33941213	In this study, we found that sex, smoking history, drinking history, differentiation, vascular tumor thrombus, T stage, N stage, tumor location, and tumor length were significant variables for identifying patients with LNM along the left gastric artery (P <  0.05) (Table 3).	('patients', 'Species', '9606', (205, 213))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('LNM', 'Var', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('vascular tumor thrombus', 'Disease', 'MESH:D013927', (86, 109))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (149, 154))	('vascular tumor thrombus', 'Disease', (86, 109))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('vascular tumor', 'Phenotype', 'HP:0100742', (86, 100))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (95, 100))
700439	33941213	After adjusting for age, tumor length, vascular tumor thrombus, N stage, T stage, and treatment, we found that LNM along the left gastric artery (P = 0.011, HR = 1.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('men', 'Species', '9606', (91, 94))	('vascular tumor thrombus', 'Disease', 'MESH:D013927', (39, 62))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('LNM', 'Var', (111, 114))	('vascular tumor thrombus', 'Disease', (39, 62))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('vascular tumor', 'Phenotype', 'HP:0100742', (39, 53))
700441	33941213	In the present study, we found that patients with LNM along the left gastric artery had poorer survival than those without metastasis, as shown by the CSS curve analysis (P <  0.001, Fig.	('patients', 'Species', '9606', (36, 44))	('poorer', 'NegReg', (88, 94))	('LNM along', 'Var', (50, 59))	('CSS', 'Chemical', '-', (151, 154))	('survival', 'CPA', (95, 103))
700442	33941213	Our results clearly demonstrated that LNM along the left gastric artery could serve as an independent predictor of long-term survival among ESCC patients who have undergone surgery.	('patients', 'Species', '9606', (145, 153))	('LNM', 'Var', (38, 41))	('ESCC', 'Disease', (140, 144))
700454	33941213	In conclusion, LNM along the gastric artery was a predictive factor for long-term survival in patients who underwent esophagectomy for ESCC.	('ESCC', 'Disease', (135, 139))	('LNM', 'Var', (15, 18))	('patients', 'Species', '9606', (94, 102))
700471	33090365	Within the past 10 years, hospital mortality for complex congenital heart disease was as follows (2008, 2013, and 2018): complete atrio-ventricular septal defect (3.5%, 0.6%, and 2.5%, respectively); tetralogy of Fallot (1.8%, 1.4%, and 1.1%, respectively); transposition of the great arteries with intact septum (3.8%, 3.6%, and 2.1%, respectively), ventricular septal defect (5.5%, 5.2%, and 6.9%, respectively), and single ventricle (5.5%, 5.7%, and 5.1%, respectively); and hypoplastic left heart syndrome (12.9%, 9.1%, and 8.8%, respectively).	('transposition', 'Var', (258, 271))	('hypoplastic left heart', 'Phenotype', 'HP:0004383', (478, 500))	('hypoplastic left heart syndrome', 'Disease', 'MESH:D018636', (478, 509))	('transposition of the great arteries', 'Phenotype', 'HP:0001669', (258, 293))	('hypoplastic left heart syndrome', 'Disease', (478, 509))	('ventricular septal defect', 'Phenotype', 'HP:0001629', (351, 376))	('tetralogy of Fallot', 'Phenotype', 'HP:0001636', (200, 219))	('transposition of the great', 'Phenotype', 'HP:0011540', (258, 284))	('atrio-ventricular septal defect', 'Disease', (130, 161))	('ventricular septal defect', 'Phenotype', 'HP:0001629', (136, 161))	('congenital heart disease', 'Disease', 'MESH:D006331', (57, 81))	('complete atrio-ventricular septal defect', 'Phenotype', 'HP:0001674', (121, 161))	('septal defect', 'Phenotype', 'HP:0001671', (363, 376))	('tetralogy of Fallot', 'Disease', (200, 219))	('ventricular septal defect', 'Disease', 'MESH:D018658', (351, 376))	('mortality', 'Disease', (35, 44))	('atrio-ventricular septal defect', 'Disease', 'MESH:D018658', (130, 161))	('ventricular septal defect', 'Disease', (351, 376))	('septal defect', 'Phenotype', 'HP:0001671', (148, 161))	('congenital heart disease', 'Disease', (57, 81))	('ventricular septal defect', 'Disease', 'MESH:D018658', (136, 161))	('congenital heart disease', 'Phenotype', 'HP:0001627', (57, 81))	('atrio-ventricular septal defect', 'Phenotype', 'HP:0006695', (130, 161))	('mortality', 'Disease', 'MESH:D003643', (35, 44))	('single ventricle', 'Phenotype', 'HP:0001750', (419, 435))
700490	33090365	Hospital mortality rates associated with simple TEVAR for type B aortic dissection were 7.0% and 2.0% for acute and chronic cases, respectively.	('aortic dissection', 'Phenotype', 'HP:0002647', (65, 82))	('simple', 'Var', (41, 47))	('mortality', 'Disease', (9, 18))	('TEVAR', 'Phenotype', 'HP:0012727', (48, 53))	('type B aortic dissection', 'Disease', (58, 82))	('type B aortic dissection', 'Phenotype', 'HP:0012499', (58, 82))	('mortality', 'Disease', 'MESH:D003643', (9, 18))
700578	31360303	Additionally, as cancers cells grow and subclonal populations progress and differentiate, they accumulate non-silent point mutations through immune-editing that ultimately leads to loss of tumor immunogenic recognition.	('tumor', 'Disease', (189, 194))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('loss', 'NegReg', (181, 185))	('immune-editing', 'Var', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
700598	31360303	To predict time-to-recurrence, the optimal RQ cut-off points for the individual genes were: CXCL9 (0.2910), IDO1 (2.0180), LAG3 (3.7521), TIM3 (3.0440).	('TIM3', 'Gene', (138, 142))	('TIM3', 'Gene', '84868', (138, 142))	('CXCL9', 'Gene', '4283', (92, 97))	('IDO1', 'Gene', (108, 112))	('0.2910', 'Var', (99, 105))	('CXCL9', 'Gene', (92, 97))	('IDO1', 'Gene', '3620', (108, 112))
700599	31360303	Likewise, to predict OS, the optimal RQ cut-off points were: CXCL9 (0.6506), IDO1 (0.2822), LAG3 (2.9759), TIM3 (3.9181).	('OS', 'Chemical', '-', (21, 23))	('TIM3', 'Gene', (107, 111))	('TIM3', 'Gene', '84868', (107, 111))	('IDO1', 'Gene', '3620', (77, 81))	('0.2822', 'Var', (83, 89))	('CXCL9', 'Gene', '4283', (61, 66))	('0.6506', 'Var', (68, 74))	('IDO1', 'Gene', (77, 81))	('CXCL9', 'Gene', (61, 66))
700652	31360303	RT-PCR was performed according to the manufacturer's guidelines using the following RT2 Primer Assays: TIM3 (Qiagen, Valencia, CA #PPH00583A), IDO1 (Qiagen, Valencia, CA #PPH01328B), LAG3 (Qiagen, Valencia, CA #PPH01035A) CXCL9 (Qiagen, Valencia, CA # PPH00700B).	('IDO1', 'Gene', (143, 147))	('TIM3', 'Gene', (103, 107))	('TIM3', 'Gene', '84868', (103, 107))	('CR', 'Chemical', '-', (4, 6))	('CA #PPH01035A', 'Var', (207, 220))	('CXCL9', 'Gene', '4283', (222, 227))	('IDO1', 'Gene', '3620', (143, 147))	('CXCL9', 'Gene', (222, 227))	('CA # PPH00700B', 'Var', (247, 261))
700691	31182955	Diagnosis is made by a positive family history, characteristic clinical features like focal palmar and plantar hyperkeratosis, oral and esophageal lesions with mutations in RHBDF2.	('RHBDF2', 'Gene', (173, 179))	('mutations', 'Var', (160, 169))	('esophageal lesions', 'Disease', (136, 154))	('plantar hyperkeratosis', 'Disease', 'MESH:C536306', (103, 125))	('RHBDF2', 'Gene', '79651', (173, 179))	('plantar hyperkeratosis', 'Disease', (103, 125))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (111, 125))	('plantar hyperkeratosis', 'Phenotype', 'HP:0007556', (103, 125))	('esophageal lesions', 'Disease', 'MESH:D004935', (136, 154))
700816	29976575	Evaluated by flow cytometry (dilution of the CFDA-SE dye), five out of six ESCC cells lines (TE1, TE6, TE10, TE12, HCE7) had increased proliferation rates when co-cultured with fibroblasts (Fig.	('TE1', 'Var', (93, 96))	('TE12', 'Var', (109, 113))	('increased', 'PosReg', (125, 134))	('CFDA-SE', 'Chemical', 'MESH:C087165', (45, 52))	('proliferation rates', 'CPA', (135, 154))	('TE10', 'Var', (103, 107))
700817	29976575	Furthermore, proliferation of either FEF3 or FEF3303 esophageal CAFs was significantly enhanced by any of the ESCC cells tested (Fig.	('proliferation', 'CPA', (13, 26))	('CAF', 'Gene', (64, 67))	('CAF', 'Gene', '8850', (64, 67))	('FEF3303', 'Var', (45, 52))	('enhanced', 'PosReg', (87, 95))
700818	29976575	In a 3D organotypic culture model of ESCC, addition of FEF3303 CAFs to the epithelial layer (TE11) resulted in a dramatic increase in epithelial layer thickness (hyperplasia), as well as enhanced invasion into the ECM (Fig.	('ECM', 'Gene', (214, 217))	('hyperplasia', 'Disease', (162, 173))	('hyperplasia', 'Disease', 'MESH:D006965', (162, 173))	('enhanced', 'PosReg', (187, 195))	('epithelial layer thickness', 'CPA', (134, 160))	('CAF', 'Gene', (63, 66))	('FEF3303', 'Var', (55, 62))	('CAF', 'Gene', '8850', (63, 66))	('ECM', 'Gene', '22915', (214, 217))	('increase', 'PosReg', (122, 130))
700819	29976575	Importantly, co-injection of TE11 cells with FEF3303, ESCC-CAF-J1 or ESCC-Fb-1 CAFs subcutaneously into flanks of nude mice significantly enhanced tumor growth rate, when compared to TE11 cells alone (Fig.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('ESCC-Fb-1', 'Gene', (69, 78))	('nude mice', 'Species', '10090', (114, 123))	('enhanced', 'PosReg', (138, 146))	('FEF3303', 'Var', (45, 52))	('CAF', 'Gene', (59, 62))	('CAF', 'Gene', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('CAF', 'Gene', '8850', (59, 62))	('CAF', 'Gene', '8850', (79, 82))
700828	29976575	The 3D organotypic cultures formed by TE11 IL-6KO cells were characterized by decreased epithelial hyperplasia and a trend of reduced invasion (Fig.	('epithelial hyperplasia', 'Disease', (88, 110))	('invasion', 'CPA', (134, 142))	('decreased', 'NegReg', (78, 87))	('TE11 IL-6KO', 'Var', (38, 49))	('reduced', 'NegReg', (126, 133))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (88, 110))
700829	29976575	Furthermore, we found that IL-6KO cells formed smaller 3D tumoroids with normalized morphology, compared to IL-6WT TE11 and OE33 cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('smaller', 'NegReg', (47, 54))	('IL-6KO', 'Var', (27, 33))	('3D tumoroid', 'Disease', (55, 66))	('3D tumoroid', 'Disease', 'None', (55, 66))
700831	29976575	Importantly, subcutaneous xenograft tumors formed by the TE11 and OE33 IL-6KO cells were characterized by stalled growth rates (Fig.	('growth rates', 'CPA', (114, 126))	('stalled growth', 'Phenotype', 'HP:0001510', (106, 120))	('xenograft tumors', 'Disease', 'MESH:D009369', (26, 42))	('OE33', 'Var', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('xenograft tumors', 'Disease', (26, 42))
700849	29976575	Remarkably, we found that low IL-6+IL-6Ralpha expression correlated with improved survival not only in esophageal cancer (ESCA), but in the TCGA pan-cancer (PANCAN) dataset as well (Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', (149, 155))	('esophageal cancer', 'Disease', (103, 120))	('low', 'Var', (26, 29))	('improved', 'PosReg', (73, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('survival', 'MPA', (82, 90))	('expression', 'MPA', (46, 56))	('IL-6+IL-6Ralpha', 'Protein', (30, 45))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancer', 'Disease', (114, 120))
700854	29976575	S11A), while the gastric adenocarcinoma xenografts contained a decreased percentage of viable tumor cells, but no changes in necrosis were observed (Fig.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('gastric adenocarcinoma xenografts', 'Disease', (17, 50))	('gastric adenocarcinoma xenografts', 'Disease', 'MESH:D013274', (17, 50))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('S11A', 'Var', (0, 4))	('decreased', 'NegReg', (63, 72))	('necrosis', 'Disease', (125, 133))	('S11A', 'SUBSTITUTION', 'None', (0, 4))	('tumor', 'Disease', (94, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('necrosis', 'Disease', 'MESH:D009336', (125, 133))
700875	29976575	However, there are potential risks associated with targeting the TME as demonstrated by suicide gene-mediated depletion of alphaSMA-expressing cells, which led to invasive tumors and enhanced Treg recruitment in a murine model of pancreatic adenocarcinoma.	('invasive tumors', 'Disease', (163, 178))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (230, 255))	('pancreatic adenocarcinoma', 'Disease', (230, 255))	('murine', 'Species', '10090', (214, 220))	('invasive tumors', 'Disease', 'MESH:D009369', (163, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('Treg recruitment', 'CPA', (192, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (230, 255))	('enhanced', 'PosReg', (183, 191))	('led to', 'Reg', (156, 162))	('depletion', 'Var', (110, 119))
700880	29976575	In support of this, CRISPR/Cas9-mediated knockout of IL-6 in the tumor cells resulted in stalled growth and normalized morphology of the 3D tumoroids, which lack a stromal compartment (Fig.	('tumor', 'Disease', (65, 70))	('IL-6', 'Gene', (53, 57))	('3D tumoroid', 'Disease', (137, 148))	('growth', 'CPA', (97, 103))	('3D tumoroid', 'Disease', 'None', (137, 148))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('knockout', 'Var', (41, 49))	('stalled growth', 'Phenotype', 'HP:0001510', (89, 103))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('normalized morphology', 'CPA', (108, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (140, 145))
700891	29976575	6F, S12B) in gastric adenocarcinoma xenografts).	('gastric adenocarcinoma xenografts', 'Disease', 'MESH:D013274', (13, 46))	('gastric adenocarcinoma xenografts', 'Disease', (13, 46))	('S12B', 'SUBSTITUTION', 'None', (4, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('S12B', 'Var', (4, 8))
700893	29976575	In colon cancer, anti-IL-6Ralpha treatment resulted in decreased tumor growth and 5-fluorouracil resistance.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('decreased tumor', 'Disease', (55, 70))	('anti-IL-6Ralpha', 'Var', (17, 32))	('5-fluorouracil resistance', 'MPA', (82, 107))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (82, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('decreased tumor', 'Disease', 'MESH:D009369', (55, 70))	('colon cancer', 'Disease', (3, 15))
700911	29976575	6F, S12B) raises the possibility of synergy of this agent in combination with immune modulatory therapy such as immune checkpoint inhibitors; in fact, CD274 has been found to be increased in EAC..	('CD274', 'Gene', (151, 156))	('S12B', 'SUBSTITUTION', 'None', (4, 8))	('CD274', 'Gene', '29126', (151, 156))	('EAC..', 'Disease', (191, 196))	('S12B', 'Var', (4, 8))	('EAC', 'Phenotype', 'HP:0011459', (191, 194))	('increased', 'PosReg', (178, 187))
700917	29976575	This strongly indicates that neutralization of IL-6 signaling could have even more potent anti-tumor effects.	('neutralization', 'Var', (29, 43))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (95, 100))
700945	29018482	Meanwhile, there are some reports that an excessively long Roux-limb can cause internal herniation or Roux stasis syndrome.	('excessively long', 'Var', (42, 58))	('internal herniation or Roux stasis syndrome', 'Disease', 'MESH:D054070', (79, 122))	('internal herniation or Roux stasis syndrome', 'Disease', (79, 122))	('hernia', 'Phenotype', 'HP:0100790', (88, 94))	('cause', 'Reg', (73, 78))
700956	29018482	According to Japanese gastric cancer treatment guidelines, PPG is the treatment option for clinically T1N0M0 gastric cancers in the middle third of the stomach at least 4.0 cm away from the pylorus.	('gastric cancers', 'Disease', (109, 124))	('gastric cancers', 'Disease', 'MESH:D013274', (109, 124))	('gastric cancers', 'Phenotype', 'HP:0012126', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (22, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (22, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('PPG', 'Chemical', '-', (59, 62))	('T1N0M0', 'Var', (102, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (22, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
700971	29018482	reported that LPG with DTR for proximal EGC showed excellent postoperative outcomes, particularly with respect to decreased reflux symptoms.	('DTR', 'Chemical', '-', (23, 26))	('EGC', 'Chemical', '-', (40, 43))	('DTR', 'Var', (23, 26))	('LPG', 'Chemical', '-', (14, 17))	('reflux symptoms', 'MPA', (124, 139))	('reflux symptoms', 'Phenotype', 'HP:0002020', (124, 139))	('decreased', 'NegReg', (114, 123))
700981	29018482	Furthermore, a meta-analysis of 5 RCTs and 17 non-RCTs with 3411 patients reported that LADG might result in less blood loss, less consumption of analgesics, and shorter hospital stays, without an increase in total hospitalization costs.	('blood loss', 'Disease', 'MESH:D006473', (114, 124))	('less', 'NegReg', (109, 113))	('blood loss', 'Disease', (114, 124))	('consumption of analgesics', 'MPA', (131, 156))	('LADG', 'Var', (88, 92))	('less', 'NegReg', (126, 130))	('patients', 'Species', '9606', (65, 73))	('LADG', 'Chemical', '-', (88, 92))
700983	29018482	The overall complication rate was significantly lower in the LADG group (LADG versus ODG; 13.0% versus 19.9%, p = 0.001); in particular, the wound complication rate in the LADG group was significantly lower than that in the ODG group (3.1% versus 7.7%, p < 0.001).	('ODG', 'Chemical', '-', (85, 88))	('LADG', 'Var', (172, 176))	('LADG', 'Chemical', '-', (61, 65))	('lower', 'NegReg', (48, 53))	('ODG', 'Chemical', '-', (224, 227))	('wound complication', 'CPA', (141, 159))	('LADG', 'Chemical', '-', (73, 77))	('LADG', 'Chemical', '-', (172, 176))	('lower', 'NegReg', (201, 206))
700993	29018482	In a meta-analysis including five studies with 652 patients, TLDG was associated with less intraoperative blood loss, earlier first flatus, and lower postoperative morbidity than LADG.	('LDG', 'Chemical', '-', (62, 65))	('lower', 'NegReg', (144, 149))	('intraoperative blood loss', 'Disease', (91, 116))	('LADG', 'Chemical', '-', (179, 183))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (91, 116))	('postoperative morbidity', 'CPA', (150, 173))	('patients', 'Species', '9606', (51, 59))	('TLDG', 'Var', (61, 65))	('less', 'NegReg', (86, 90))
701011	29018482	There are several difficulties or limitations in applying laparoscopic surgery to AGC, including total omentectomy, splenic hilar dissection for proximal gastric cancer, bulky positive nodes or large primary tumor, esophageal invasion, and peritoneal lavage.	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('bulky positive', 'Var', (170, 184))	('gastric cancer', 'Disease', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', (208, 213))	('gastric cancer', 'Disease', 'MESH:D013274', (154, 168))	('esophageal', 'Disease', (215, 225))
701022	29018482	Decreased serum albumin and protein levels at one to six months postoperatively and greater abdominal fat volumes at postoperative one year were observed in LADG compared with LAPPG.	('Decreased serum albumin', 'Phenotype', 'HP:0003073', (0, 23))	('PPG', 'Chemical', '-', (178, 181))	('abdominal fat volumes', 'MPA', (92, 113))	('LADG', 'Chemical', '-', (157, 161))	('Decreased', 'NegReg', (0, 9))	('greater', 'PosReg', (84, 91))	('LADG', 'Var', (157, 161))
701025	29018482	They concluded that VPG could improve postoperative QOL compared with conventional gastrectomy.	('improve', 'PosReg', (30, 37))	('VPG', 'Var', (20, 23))	('postoperative', 'MPA', (38, 51))	('PG', 'Chemical', '-', (21, 23))	('QOL', 'MPA', (52, 55))
701048	28852458	Histopathologic analysis revealed Stage II (type 2, T3, ly2, v0, N0, PM0, DM0) esophageal and Stage I (type 0-IIb, T1, ly0, v0, N0) gastric cancer, with positive horizontal margins of dissection of the gastric cancer.	('gastric cancer', 'Disease', (132, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (202, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('esophageal', 'Disease', (79, 89))	('ly2', 'Var', (56, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('gastric cancer', 'Disease', (202, 216))	('gastric cancer', 'Disease', 'MESH:D013274', (202, 216))
701083	27307755	YAP1-knockdown cell lines were constructed using short-hairpin RNA, and MTT, flow cytometry, and transwell chamber assays were used to analyze the effect of YAP1 knockdown on EC cell proliferation, apoptosis, and invasion.	('YAP1', 'Gene', (157, 161))	('apoptosis', 'CPA', (198, 207))	('invasion', 'CPA', (213, 221))	('MTT', 'Chemical', 'MESH:C070243', (72, 75))	('knockdown', 'Var', (162, 171))
701084	27307755	In vivo tumor formation assays were used to investigate the antitumor effect of YAP1 knockdown.	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('YAP1', 'Gene', (80, 84))	('knockdown', 'Var', (85, 94))	('tumor', 'Disease', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
701086	27307755	In addition, animal experiments revealed that YAP1 knockdown suppressed the growth of esophageal tumors in vivo.	('suppressed', 'NegReg', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('growth', 'CPA', (76, 82))	('esophageal tumors', 'Disease', 'MESH:D004938', (86, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('YAP1', 'Gene', (46, 50))	('esophageal tumor', 'Phenotype', 'HP:0100751', (86, 102))	('esophageal tumors', 'Disease', (86, 103))	('esophageal tumors', 'Phenotype', 'HP:0100751', (86, 103))	('knockdown', 'Var', (51, 60))
701101	27307755	In addition, the expression level of YAP1 was significantly downregulated in a subset of breast cancers, and knockdown promotes migration and invasion of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('promotes', 'PosReg', (119, 127))	('breast cancers', 'Disease', 'MESH:D001943', (89, 103))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('breast cancers', 'Disease', (89, 103))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('migration', 'CPA', (128, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('invasion', 'CPA', (142, 150))	('knockdown', 'Var', (109, 118))	('expression level', 'MPA', (17, 33))	('YAP1', 'Gene', (37, 41))	('downregulated', 'NegReg', (60, 73))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))
701139	27307755	The aberrant expression of YAP1 in EC tumor samples and cell lines suggests that it could play an important role in the pathogenesis of EC.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('role', 'Reg', (108, 112))	('play', 'Reg', (90, 94))	('EC tumor', 'Disease', (35, 43))	('YAP1', 'Gene', (27, 31))	('aberrant expression', 'Var', (4, 23))	('EC tumor', 'Disease', 'MESH:D009369', (35, 43))
701143	27307755	The expression level of the antiapoptotic Bcl-2 protein in YAP1-knockdown EC109 and TE10 cells was significantly lower than that in the control group, while that of the proapoptotic Bax protein was increased (Figure 3B and D).	('expression level', 'MPA', (4, 20))	('Bcl-2', 'Gene', (42, 47))	('Bax', 'Gene', '581', (182, 185))	('Bcl-2', 'Gene', '596', (42, 47))	('lower', 'NegReg', (113, 118))	('increased', 'PosReg', (198, 207))	('Bax', 'Gene', (182, 185))	('YAP1-knockdown', 'Gene', (59, 73))	('YAP1-knockdown', 'Var', (59, 73))
701145	27307755	The results showed that the expression levels of both MMP-2 and MMP-9 were significantly lower in EC109 and TE10 YAP1-knockdown cells than those in controls, (Figure 4C and D) further indicating that YAP1 knockdown inhibits the invasion activity of EC cells.	('MMP-2', 'Gene', (54, 59))	('EC109', 'Var', (98, 103))	('lower', 'NegReg', (89, 94))	('YAP1-knockdown', 'Gene', (113, 127))	('expression levels', 'MPA', (28, 45))	('knockdown', 'Var', (205, 214))	('invasion activity of EC cells', 'CPA', (228, 257))	('YAP1', 'Gene', (200, 204))	('MMP-2', 'Gene', '4313', (54, 59))	('inhibits', 'NegReg', (215, 223))	('MMP-9', 'Gene', '4318', (64, 69))	('MMP-9', 'Gene', (64, 69))
701149	27307755	The mean tumor weight in the YAP1-knockdown group was significantly lower than that in the control group (Figure 5B).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('lower', 'NegReg', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('YAP1-knockdown', 'Var', (29, 43))
701152	27307755	These results indicate that YAP1 knockdown suppresses the growth of esophageal tumors in vivo.	('esophageal tumors', 'Disease', 'MESH:D004938', (68, 85))	('suppresses', 'NegReg', (43, 53))	('esophageal tumors', 'Phenotype', 'HP:0100751', (68, 85))	('knockdown', 'Var', (33, 42))	('YAP1', 'Gene', (28, 32))	('esophageal tumors', 'Disease', (68, 85))	('esophageal tumor', 'Phenotype', 'HP:0100751', (68, 84))	('growth', 'MPA', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
701164	27307755	We also performed animal experiments to investigate the effect of YAP1 knockdown on the growth of esophageal tumors in vivo.	('esophageal tumors', 'Disease', 'MESH:D004938', (98, 115))	('YAP1', 'Gene', (66, 70))	('esophageal tumors', 'Disease', (98, 115))	('esophageal tumors', 'Phenotype', 'HP:0100751', (98, 115))	('knockdown', 'Var', (71, 80))	('esophageal tumor', 'Phenotype', 'HP:0100751', (98, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
701166	27307755	Consistent with these findings, our data indicate that YAP1 knockdown suppresses the growth of esophageal tumors in vivo.	('esophageal tumors', 'Disease', 'MESH:D004938', (95, 112))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('growth', 'MPA', (85, 91))	('YAP1', 'Gene', (55, 59))	('esophageal tumors', 'Phenotype', 'HP:0100751', (95, 112))	('esophageal tumor', 'Phenotype', 'HP:0100751', (95, 111))	('esophageal tumors', 'Disease', (95, 112))	('knockdown', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('suppresses', 'NegReg', (70, 80))
701168	27307755	In addition, YAP1 knockdown suppresses the growth of esophageal tumors in vivo in a mouse model.	('knockdown', 'Var', (18, 27))	('growth', 'MPA', (43, 49))	('esophageal tumors', 'Disease', 'MESH:D004938', (53, 70))	('esophageal tumors', 'Phenotype', 'HP:0100751', (53, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('esophageal tumors', 'Disease', (53, 70))	('esophageal tumor', 'Phenotype', 'HP:0100751', (53, 69))	('suppresses', 'NegReg', (28, 38))	('mouse', 'Species', '10090', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('YAP1', 'Gene', (13, 17))
701232	26466785	Of 175 MPM patients, there were only 84 patients who had EGFR mutation status, 25 cases were detected by the methods of direct sequencing while 59 cases were detected by the methods of ARMS, There are only 84 patients subjected to EGFR mutation analysis because EGFR mutation analysis was not becoming the routine clinical practice until 2009, what's more, the quality and quantity of a portion of lung cancer specimens was unqualified or not enough for the EGFR mutation analysis and these patients denied re-biopsy or the performance status(PS) was not suitable for re-biopsy.	('men', 'Species', '9606', (415, 418))	('lung cancer', 'Phenotype', 'HP:0100526', (398, 409))	('patients', 'Species', '9606', (40, 48))	('lung cancer', 'Disease', (398, 409))	('cancer', 'Phenotype', 'HP:0002664', (403, 409))	('mutation', 'Var', (463, 471))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (491, 499))	('lung cancer', 'Disease', 'MESH:D008175', (398, 409))	('patients', 'Species', '9606', (11, 19))	('MPM', 'Chemical', '-', (7, 10))
701244	26466785	It is well established that a high incidence of epidermal growth factor receptor (EGFR) mutations is associated with clinical features, such as adenocarcinoma histology, Asian ethnicity, female sex, and never-smoker status, and MPM patients with nearly 60 % adenocarcinoma histology and nearly 70 % never-smoker status indicate the high possibility of EGFR mutations, which might explain the increased incidence of MPM patients involving lung cancer.	('lung cancer', 'Disease', (438, 449))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('MPM', 'Chemical', '-', (228, 231))	('mutations', 'Var', (88, 97))	('epidermal growth factor receptor', 'Gene', (48, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('patients', 'Species', '9606', (419, 427))	('epidermal growth factor receptor', 'Gene', '1956', (48, 80))	('EGFR', 'Gene', (82, 86))	('adenocarcinoma', 'Disease', (258, 272))	('lung cancer', 'Disease', 'MESH:D008175', (438, 449))	('lung cancer', 'Phenotype', 'HP:0100526', (438, 449))	('cancer', 'Phenotype', 'HP:0002664', (443, 449))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('associated', 'Reg', (101, 111))	('adenocarcinoma', 'Disease', 'MESH:D000230', (258, 272))	('MPM', 'Chemical', '-', (415, 418))	('patients', 'Species', '9606', (232, 240))	('adenocarcinoma', 'Disease', (144, 158))
701247	26466785	This is similar to the common Asian population, which suggests that EGFR mutations are not responsible for the increased incidence of MPM patients involving lung cancer.	('patients', 'Species', '9606', (138, 146))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('lung cancer', 'Disease', (157, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('MPM', 'Disease', (134, 137))	('MPM', 'Chemical', '-', (134, 137))	('EGFR', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
701264	26466785	Such predispositions include Lynch syndrome, an autosomal dominant-inherited disorder of colorectal cancer, and susceptibility to other tumors caused by germline mutations in DNA mismatch repair genes.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('Lynch syndrome', 'Disease', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('dominant-inherited disorder of colorectal cancer', 'Disease', 'MESH:D015179', (58, 106))	('Lynch syndrome', 'Disease', 'MESH:D003123', (29, 43))	('dominant-inherited disorder of colorectal cancer', 'Disease', (58, 106))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('caused by', 'Reg', (143, 152))	('rectal cancer', 'Phenotype', 'HP:0100743', (93, 106))	('germline mutations', 'Var', (153, 171))	('DNA mismatch', 'Gene', (175, 187))
701295	24926347	In addition, high expression levels of TUBB3 have been shown to correlate with low response rates in patients with NSCLC.	('patients', 'Species', '9606', (101, 109))	('expression levels', 'MPA', (18, 35))	('high', 'Var', (13, 17))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('low', 'NegReg', (79, 82))	('TUBB3', 'Gene', (39, 44))	('TUBB3', 'Gene', '10381', (39, 44))	('response', 'MPA', (83, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
701330	24926347	For example, the aberrant regulation of ERCC1, TYMS, TUBB3, RRM1 and TOP2A is associated with the abnormal proliferation of cancer cells, according to the hallmarks of cancer that were proposed previously.	('TUBB3', 'Gene', (53, 58))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('aberrant regulation', 'Var', (17, 36))	('TYMS', 'Gene', '7298', (47, 51))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (155, 174))	('TUBB3', 'Gene', '10381', (53, 58))	('ERCC1', 'Gene', '2067', (40, 45))	('RRM1', 'Gene', (60, 64))	('associated', 'Reg', (78, 88))	('TOP2A', 'Gene', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('abnormal proliferation', 'CPA', (98, 120))	('TYMS', 'Gene', (47, 51))	('ERCC1', 'Gene', (40, 45))	('TOP2A', 'Gene', '7153', (69, 74))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('RRM1', 'Gene', '6240', (60, 64))	('hallmarks of cancer', 'Disease', (155, 174))
701331	24926347	Furthermore, Zhang et al identified that the polymorphism and aberrant expression of TYMS may be associated with a susceptibility to ESCC and gastric cardiac adenocarcinoma.	('gastric cardiac adenocarcinoma', 'Disease', (142, 172))	('expression', 'MPA', (71, 81))	('TYMS', 'Gene', (85, 89))	('polymorphism', 'Var', (45, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('ESCC', 'Disease', (133, 137))	('gastric cardiac adenocarcinoma', 'Disease', 'MESH:D013274', (142, 172))	('aberrant', 'Var', (62, 70))	('TYMS', 'Gene', '7298', (85, 89))	('susceptibility', 'Reg', (115, 129))	('associated', 'Reg', (97, 107))
701369	20086178	The TDCA-induced increase in cell proliferation was significantly reduced by U73122, an inhibiter of PI-PLC.	('U73122', 'Var', (77, 83))	('PI-PLC', 'Gene', (101, 107))	('reduced', 'NegReg', (66, 73))	('PI-PLC', 'Gene', '23236', (101, 107))	('rat', 'Species', '10116', (41, 44))	('cell proliferation', 'CPA', (29, 47))	('U73122', 'Chemical', 'MESH:C060229', (77, 83))	('increase', 'PosReg', (17, 25))
701373	20086178	TDCA significantly increased ERK-2 phosphorylation, an increase which was reduced by U73122 or PI-PLCgamma2 siRNA.	('ERK-2', 'Gene', '5594', (29, 34))	('PLCgamma2', 'Gene', '5336', (98, 107))	('ERK-2', 'Gene', (29, 34))	('increased', 'PosReg', (19, 28))	('phosphorylation', 'MPA', (35, 50))	('U73122', 'Chemical', 'MESH:C060229', (85, 91))	('PLCgamma2', 'Gene', (98, 107))	('U73122', 'Var', (85, 91))
701378	20086178	ROS may cause damage to DNA, RNA, lipids and proteins, which may result in increased mutation and altered functions of enzyme and proteins (e.g.	('ROS', 'Var', (0, 3))	('lipids', 'Chemical', 'MESH:D008055', (34, 40))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('enzyme', 'Enzyme', (119, 125))	('mutation', 'MPA', (85, 93))	('increased', 'PosReg', (75, 84))	('functions', 'MPA', (106, 115))	('altered', 'Reg', (98, 105))
701402	20086178	The primers used were: NOX5-S sense (5'-AAGACTCCATCACGGGGCTGCA-3'), NOX5-S antisense (5'-CCTTCAGCACCTTGGCCAGA -3'), GAPDH sense (5'-CATGACCACAGTC CATGCCATCAC-3'), and GAPDH antisense (5'-AGGTCCACCACCCTGTTGCTGTA-3').	('NOX5', 'Gene', '79400', (68, 72))	("5'-CCTTCAGCACCTTGGCCAGA", 'Var', (86, 109))	("5'-CATGACCACAGTC", 'Chemical', '-', (129, 145))	('NOX5', 'Gene', (23, 27))	('NOX5', 'Gene', (68, 72))	('AAGACTCCATCACGGGGCTGCA', 'Chemical', '-', (40, 62))	('-AGGTCCACCACCCTGTTGCTGTA', 'Chemical', '-', (186, 210))	('GAPDH', 'Gene', '2597', (167, 172))	('GAPDH', 'Gene', '2597', (116, 121))	('GAPDH', 'Gene', (116, 121))	('NOX5', 'Gene', '79400', (23, 27))	('GAPDH', 'Gene', (167, 172))
701422	20086178	We also found that the PI-PLC inhibitor U73122 decreased TDCA-induced NOX5-S protein expression from 395.1+-87.1 to 135.1+-11.3% control (Fig.	('U73122', 'Var', (40, 46))	('NOX5', 'Gene', (70, 74))	('PI-PLC', 'Gene', (23, 29))	('TDCA-induced', 'Gene', (57, 69))	('U73122', 'Chemical', 'MESH:C060229', (40, 46))	('NOX5', 'Gene', '79400', (70, 74))	('PI-PLC', 'Gene', '23236', (23, 29))	('decreased', 'NegReg', (47, 56))
701439	20086178	The MAP kinase kinase inhibitor PD98059 decreased TDCA-induced NOX5-S mRNA expression from 131.4+-3.9 to 59.8+-7.6% control (Fig.	('NOX5', 'Gene', '79400', (63, 67))	('PD98059', 'Var', (32, 39))	('decreased', 'NegReg', (40, 49))	('NOX5', 'Gene', (63, 67))	('PD98059', 'Chemical', 'MESH:C093973', (32, 39))
701443	20086178	We used ERK-1 and ERK-2 siRNA to knock down ERK-1 and ERK-2 expression respectively.	('ERK-2', 'Gene', (18, 23))	('knock', 'Var', (33, 38))	('ERK-1', 'Gene', '5595', (8, 13))	('ERK-1', 'Gene', (44, 49))	('ERK-1', 'Gene', '5595', (44, 49))	('ERK-2', 'Gene', '5594', (54, 59))	('ERK-2', 'Gene', (54, 59))	('ERK-1', 'Gene', (8, 13))	('ERK-2', 'Gene', '5594', (18, 23))
701449	20086178	Conversely, knockdown of ERK-1 protein expression had no statistically significant effect on NOX5-S expression induced by TDCA stimulation (Fig.	('NOX5', 'Gene', (93, 97))	('protein', 'Protein', (31, 38))	('knockdown', 'Var', (12, 21))	('ERK-1', 'Gene', (25, 30))	('NOX5', 'Gene', '79400', (93, 97))	('ERK-1', 'Gene', '5595', (25, 30))
701454	20086178	In addition, TDCA-induced ERK-2 phosphorylation was significantly reduced by U73122 (Fig.	('U73122', 'Var', (77, 83))	('reduced', 'NegReg', (66, 73))	('ERK-2', 'Gene', (26, 31))	('ERK-2', 'Gene', '5594', (26, 31))	('U73122', 'Chemical', 'MESH:C060229', (77, 83))	('phosphorylation', 'MPA', (32, 47))
701468	20086178	In addition, we have previously shown that 10-11M TDCA, but not higher doses, increases cell proliferation.	('increases', 'PosReg', (78, 87))	('TDCA', 'Var', (50, 54))	('rat', 'Species', '10116', (100, 103))	('cell proliferation', 'CPA', (88, 106))
701469	20086178	We found that TDCA increased NOX5-S expression, H2O2 production and cell proliferation.	('H2O2', 'Chemical', 'MESH:D006861', (48, 52))	('NOX5', 'Gene', (29, 33))	('rat', 'Species', '10116', (80, 83))	('cell proliferation', 'CPA', (68, 86))	('TDCA', 'Var', (14, 18))	('increased', 'PosReg', (19, 28))	('NOX5', 'Gene', '79400', (29, 33))	('H2O2 production', 'MPA', (48, 63))
701482	20086178	We found that TDCA-induced increase in NOX5-S expression, H2O2 production and cell proliferation was significantly reduced by the MAP kinase inhibitor PD98059, suggesting that ERK MAP kinase is involved in TDCA-induced NOX5-S expression and H2O2 production.	('H2O2', 'Chemical', 'MESH:D006861', (58, 62))	('rat', 'Species', '10116', (90, 93))	('H2O2', 'Chemical', 'MESH:D006861', (241, 245))	('ERK', 'Gene', (176, 179))	('increase', 'PosReg', (27, 35))	('reduced', 'NegReg', (115, 122))	('PD98059', 'Var', (151, 158))	('NOX5', 'Gene', '79400', (39, 43))	('NOX5', 'Gene', '79400', (219, 223))	('NOX5', 'Gene', (39, 43))	('H2O2 production', 'MPA', (58, 73))	('PD98059', 'Chemical', 'MESH:C093973', (151, 158))	('NOX5', 'Gene', (219, 223))	('ERK', 'Gene', '5594', (176, 179))	('cell proliferation', 'CPA', (78, 96))
701486	20086178	Conversely, knockdown of ERK-1 protein did not have significant effect.	('ERK-1', 'Gene', (25, 30))	('ERK-1', 'Gene', '5595', (25, 30))	('knockdown', 'Var', (12, 21))
701489	20086178	We found that TDCA significantly increased ERK2 phosphorylation, which was significantly reduced by U73122 and by knockdown of PI-PLCgamma2 protein, suggesting that TDCA-induced activation of ERK-2 MAP kinase may depend on activation of PI-PLC gamma2.	('gamma2', 'Gene', '7453', (244, 250))	('PLCgamma2', 'Gene', '5336', (130, 139))	('gamma2', 'Gene', (133, 139))	('ERK2', 'Gene', '5594', (43, 47))	('activation', 'PosReg', (178, 188))	('reduced', 'NegReg', (89, 96))	('PLCgamma2', 'Gene', (130, 139))	('gamma2', 'Gene', (244, 250))	('PI-PLC', 'Gene', '23236', (127, 133))	('ERK2', 'Gene', (43, 47))	('PI-PLC', 'Gene', '23236', (237, 243))	('U73122', 'Chemical', 'MESH:C060229', (100, 106))	('PI-PLC', 'Gene', (127, 133))	('phosphorylation', 'MPA', (48, 63))	('PI-PLC', 'Gene', (237, 243))	('ERK-2', 'Gene', '5594', (192, 197))	('increased', 'PosReg', (33, 42))	('ERK-2', 'Gene', (192, 197))	('U73122', 'Var', (100, 106))	('gamma2', 'Gene', '7453', (133, 139))
701491	20086178	In conclusion, TDCA may induce increase in NOX5-S expression, H2O2 production and cell proliferation in EAcells.	('rat', 'Species', '10116', (94, 97))	('H2O2', 'Chemical', 'MESH:D006861', (62, 66))	('cell proliferation', 'CPA', (82, 100))	('NOX5', 'Gene', (43, 47))	('H2O2 production', 'MPA', (62, 77))	('NOX5', 'Gene', '79400', (43, 47))	('TDCA', 'Var', (15, 19))	('increase', 'PosReg', (31, 39))
701493	20086178	It is possible that bile acid reflux present in patients with Barrett's esophagus may increase ROS production and cell proliferation via activation of PI-PLCgamma2, ERK-2 MAP kinase and NADPH oxidase NOX5-S, thereby causing DNA damage and gene mutation which contribute to the development of EA.	('bile acid', 'Chemical', 'MESH:D001647', (20, 29))	('ROS production', 'MPA', (95, 109))	('PLCgamma2', 'Gene', '5336', (154, 163))	('cell proliferation', 'CPA', (114, 132))	('ROS', 'Chemical', 'MESH:D017382', (95, 98))	('PLCgamma2', 'Gene', (154, 163))	('gene mutation', 'Var', (239, 252))	('increase', 'PosReg', (86, 94))	('NOX5', 'Gene', (200, 204))	('activation', 'PosReg', (137, 147))	('rat', 'Species', '10116', (126, 129))	('DNA damage', 'MPA', (224, 234))	('increase ROS production', 'Phenotype', 'HP:0025464', (86, 109))	('ERK-2', 'Gene', '5594', (165, 170))	('causing', 'Reg', (216, 223))	('acid reflux', 'Phenotype', 'HP:0002020', (25, 36))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (62, 81))	('NOX5', 'Gene', '79400', (200, 204))	('patients', 'Species', '9606', (48, 56))	('ERK-2', 'Gene', (165, 170))
701506	33717270	Studies have reported that with the decrease in pH (acidification), the cells will undergo apoptosis and necrosis, and the acidic extracellular pH accelerates cell metabolism and enhances the abilities of tumor cell migration, invasion and metastasis.	('acidic', 'Var', (123, 129))	('necrosis', 'Disease', 'MESH:D009336', (105, 113))	('cell metabolism', 'CPA', (159, 174))	('pH', 'Gene', '5053', (144, 146))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('rat', 'Species', '10116', (153, 156))	('pH', 'Gene', '5053', (48, 50))	('necrosis', 'Disease', (105, 113))	('enhances', 'PosReg', (179, 187))	('accelerates', 'PosReg', (147, 158))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('rat', 'Species', '10116', (219, 222))	('decrease', 'NegReg', (36, 44))
701519	33717270	Recent research reported that replication of subgroup J avian leukosis virus depends on a functional cellular receptor, the chicken Na+/H+ exchanger type 1, and editing the gene for a virus receptor may confer resistance to this virus and its associated diseases.	('replication', 'MPA', (30, 41))	('avian leukosis virus', 'Species', '11864', (56, 76))	('editing', 'Var', (161, 168))	('Na+/H+ exchanger', 'Gene', (132, 148))	('chicken', 'Species', '9031', (124, 131))	('resistance', 'MPA', (210, 220))	('Na+/H+ exchanger', 'Gene', '285335', (132, 148))
701522	33717270	In MV3 cells, NHE1 overexpression causes rearrangement of F-actin at the cell cortex, which is associated with an increase in cortical stiffness.	('increase', 'PosReg', (114, 122))	('F-actin', 'Protein', (58, 65))	('NHE1', 'Gene', (14, 18))	('cortical stiffness', 'CPA', (126, 144))	('overexpression', 'Var', (19, 33))	('rearrangement', 'MPA', (41, 54))	('MV3', 'CellLine', 'CVCL:W280', (3, 6))
701526	33717270	In addition, activated NHE1 can also increase the expression of MMP-9 and MMP-2 and fuse with pseudopods via lysosomes and vesicles, where it targets the transport of proteases and promotes the hydrolysis of ECM proteins.	('activated', 'Var', (13, 22))	('MMP-2', 'Gene', '4313', (74, 79))	('fuse', 'Gene', '2522', (84, 88))	('fuse', 'Gene', (84, 88))	('transport', 'MPA', (154, 163))	('NHE1', 'Gene', (23, 27))	('promotes', 'PosReg', (181, 189))	('increase', 'PosReg', (37, 45))	('targets', 'MPA', (142, 149))	('hydrolysis of ECM proteins', 'MPA', (194, 220))	('MMP-9', 'Gene', '4318', (64, 69))	('MMP-2', 'Gene', (74, 79))	('expression', 'MPA', (50, 60))	('MMP-9', 'Gene', (64, 69))
701538	33717270	In addition, downregulation of NHE1 gene expression induced by transfected genes led to intracellular acidification and the induction of apoptosis, which enabled the treatment of gastric cancer in experimental studies.	('gastric cancer', 'Phenotype', 'HP:0012126', (179, 193))	('genes', 'Var', (75, 80))	('apoptosis', 'CPA', (137, 146))	('expression', 'MPA', (41, 51))	('downregulation', 'NegReg', (13, 27))	('gastric cancer', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('gastric cancer', 'Disease', 'MESH:D013274', (179, 193))	('NHE1 gene', 'Gene', (31, 40))	('intracellular acidification', 'MPA', (88, 115))	('transfected genes', 'Var', (63, 80))
701548	33717270	In addition, the survival time of patients with high levels of NHE1 expression was significantly shortened.	('NHE1', 'Protein', (63, 67))	('expression', 'MPA', (68, 78))	('survival time', 'CPA', (17, 30))	('high levels', 'Var', (48, 59))	('shortened', 'NegReg', (97, 106))	('patients', 'Species', '9606', (34, 42))
701562	33717270	NHE1 and NHE4 are distributed on the basolateral side of pancreatic acinar cells, and on the basal side of pancreatic ducts, while NHE2 and NHE3 are mainly distributed in the luminal membrane.	('NHE2', 'Gene', (131, 135))	('pancreatic acinar', 'Disease', (57, 74))	('luminal', 'Chemical', 'MESH:D010634', (175, 182))	('NHE3', 'Gene', (140, 144))	('NHE4', 'Gene', (9, 13))	('NHE2', 'Gene', '6549', (131, 135))	('pancreatic acinar', 'Disease', 'MESH:D010190', (57, 74))	('NHE4', 'Gene', '389015', (9, 13))	('NHE1', 'Var', (0, 4))	('NHE3', 'Gene', '6550', (140, 144))
701574	33717270	In the low NHE1 expression group, the 5-year survival rate of patients was significantly better compared with that of the high NHE1 expression group, suggesting that NHE1 may be associated with poor prognosis in patients with ESCC.	('ESCC', 'Disease', (226, 230))	('rat', 'Species', '10116', (54, 57))	('NHE1', 'Var', (166, 170))	('patients', 'Species', '9606', (212, 220))	('patients', 'Species', '9606', (62, 70))
701585	33717270	Among the signaling pathways involved in cancer cell invasion, PRL-mediated activation of AKT and ERK1/2 activates p90RSK, which leads to the phosphorylation of NHE1 Ser703, thereby increasing NHE1 activity, including NHE1-dependent cell migration.	('increasing', 'PosReg', (182, 192))	('cancer', 'Disease', (41, 47))	('ERK1/2', 'Gene', (98, 104))	('ERK1/2', 'Gene', '5595;5594', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('p90RSK', 'Gene', (115, 121))	('NHE1', 'Enzyme', (193, 197))	('activity', 'MPA', (198, 206))	('phosphorylation', 'MPA', (142, 157))	('Ser703', 'Chemical', '-', (166, 172))	('PRL', 'Gene', '5617', (63, 66))	('NHE1', 'Protein', (161, 165))	('Ser703', 'Var', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('rat', 'Species', '10116', (241, 244))	('p90RSK', 'Gene', '6195', (115, 121))	('PRL', 'Gene', (63, 66))	('activates', 'PosReg', (105, 114))	('NHE1-dependent cell migration', 'CPA', (218, 247))	('leads to', 'Reg', (129, 137))
701586	33717270	As a pHi regulatory protein, a previous study examined the role of negatively charged amino acids of extracellular loop 3 (EL3) in the activity of the NHE protein, and demonstrated that amino acids E217 and D226 form part of a negatively charged coordination sphere, which facilitates cation transport in the NHE1 protein.	('NHE', 'Gene', (151, 154))	('NHE', 'Gene', (309, 312))	('amino', 'Var', (186, 191))	('cation transport', 'MPA', (285, 301))	('NHE', 'Gene', '285335', (151, 154))	('rat', 'Species', '10116', (175, 178))	('D226', 'Var', (207, 211))	('NHE', 'Gene', '285335', (309, 312))	('facilitates', 'PosReg', (273, 284))
701591	33717270	Studies have also found that pyrazinoylguanidine-type NHE1 inhibitors potently inhibit the growth and survival of cancer cell spheroids, and this effect is unrelated to NHE1 inhibition.	('inhibit', 'NegReg', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('pyrazinoylguanidine', 'Chemical', '-', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('inhibitors', 'Var', (59, 69))	('NHE1', 'Gene', (54, 58))	('cancer', 'Disease', (114, 120))
701608	33717270	Inhibition of NHE1 during oxygen deprivation contributes to the maintenance of the energy state of glial cells.	('NHE1', 'Gene', (14, 18))	('deprivation', 'Disease', (33, 44))	('deprivation', 'Disease', 'MESH:D012892', (33, 44))	('Inhibition', 'Var', (0, 10))	('maintenance', 'MPA', (64, 75))	('oxygen', 'Chemical', 'MESH:D010100', (26, 32))
701616	33717270	3), inhibition of NHE1 transcription can reduce NaCl and water uptake in the colonic lumen, resulting in diarrhea.	('colonic', 'Disease', (77, 84))	('resulting in', 'Reg', (92, 104))	('water', 'Chemical', 'MESH:D014867', (57, 62))	('NHE1', 'Gene', (18, 22))	('inhibition', 'Var', (4, 14))	('reduce', 'NegReg', (41, 47))	('colonic', 'Disease', 'MESH:D003110', (77, 84))	('NaCl', 'Chemical', 'MESH:D012965', (48, 52))	('diarrhea', 'Phenotype', 'HP:0002014', (105, 113))	('diarrhea', 'Disease', 'MESH:D003967', (105, 113))	('diarrhea', 'Disease', (105, 113))
701623	33717270	Some scholars have suggested that inhibition of NHE1 at the plasma membrane may promote the activation of acid sphingomyelinase and increase membrane fluidity.	('increase', 'PosReg', (132, 140))	('inhibition', 'Var', (34, 44))	('NHE1', 'Gene', (48, 52))	('sphingomyelinase', 'Disease', 'MESH:D052536', (111, 127))	('membrane fluidity', 'MPA', (141, 158))	('activation', 'MPA', (92, 102))	('promote', 'PosReg', (80, 87))	('sphingomyelinase', 'Disease', (111, 127))
701630	33717270	An experiment by Chiang et al demonstrated that EGF is involved in the regulation of NHE1 expression via the PI3K signaling pathway in cervical cancer, and NHE1 can also interact with the actin-related protein ezrin to reconstitute the cytoskeleton and stimulate the migration and invasion of cervical cancer cells.	('cervical cancer', 'Disease', 'MESH:D002583', (293, 308))	('cervical cancer', 'Disease', 'MESH:D002583', (135, 150))	('EGF', 'Gene', '1950', (48, 51))	('NHE1', 'Gene', (85, 89))	('stimulate', 'PosReg', (253, 262))	('cervical cancer', 'Disease', (135, 150))	('NHE1', 'Var', (156, 160))	('rat', 'Species', '10116', (270, 273))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('rat', 'Species', '10116', (37, 40))	('cervical cancer', 'Disease', (293, 308))	('interact', 'Interaction', (170, 178))	('migration', 'CPA', (267, 276))	('EGF', 'Gene', (48, 51))	('ezrin', 'Gene', (210, 215))	('ezrin', 'Gene', '7430', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PI3K signaling pathway', 'Pathway', (109, 131))
701656	32377736	The expression levels of DHX9 affects the formation of splicing products, the deletion of which has been found to increase circRNA biogenesis of.	('increase', 'PosReg', (114, 122))	('formation of splicing products', 'MPA', (42, 72))	('affects', 'Reg', (30, 37))	('deletion', 'Var', (78, 86))	('DHX9', 'Gene', (25, 29))	('DHX9', 'Gene', '1660', (25, 29))	('circRNA biogenesis of', 'MPA', (123, 144))
701657	32377736	Tang et al found that N6-methyladenosine (m6A) modification can promote the generation of circRNA carrying open reading frames in mouse male germ cells.	('generation of circRNA carrying open reading frames', 'MPA', (76, 126))	('promote', 'PosReg', (64, 71))	('N6-methyladenosine', 'Var', (22, 40))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (22, 40))	('modification', 'Var', (47, 59))	('m6A', 'Chemical', '-', (42, 45))	('mouse', 'Species', '10090', (130, 135))
701674	32377736	In addition to proliferation, aberrant circRNA expression has also been reported to influence the ability of cancer cells to invade and migrate, which is a crucial cause of tumor metastasis and subsequent mortality.	('influence', 'Reg', (84, 93))	('aberrant', 'Var', (30, 38))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('mortality', 'Disease', (205, 214))	('cancer', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor metastasis', 'Disease', 'MESH:D009362', (173, 189))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mortality', 'Disease', 'MESH:D003643', (205, 214))	('tumor metastasis', 'Disease', (173, 189))
701675	32377736	Zhong et al found that circ-plasmacytoma variant translocation (circ-PVT1) upregulated the expression of paired box proteins and peroxisome proliferator-activated receptors by sponging miR-4663, resulting in the promotion of esophageal cancer cell proliferation and migration.	('upregulated', 'PosReg', (75, 86))	('expression', 'MPA', (91, 101))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('PVT1', 'Gene', '5820', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('plasmacytoma', 'Phenotype', 'HP:0011857', (28, 40))	('PVT1', 'Gene', (69, 73))	('migration', 'CPA', (266, 275))	('promotion', 'PosReg', (212, 221))	('variant', 'Var', (41, 48))	('miR-4663', 'Gene', (185, 193))	('miR-4663', 'Gene', '100616260', (185, 193))
701676	32377736	The elevated expression levels of circ-tetratricopeptide repeat domain 17, circ-fibronectin type III domain containing 3B (circFNDC3B) and hsa_circ_0000337 have also been revealed to be involved in the proliferation and migration of esophageal cancer cells.	('migration', 'CPA', (220, 229))	('expression levels', 'MPA', (13, 30))	('proliferation', 'CPA', (202, 215))	('hsa_circ_0000337', 'Var', (139, 155))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('elevated', 'PosReg', (4, 12))	('involved', 'Reg', (186, 194))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
701677	32377736	Hsa_circ_0006168, circ-protein kinase Ciota (circ-PRKCI), c-zinc finger protein 292 (cZNF292), circRAD23B, circ-ubiquitin associated protein 2 (circUBAP2) and hsa_circ_0004370 were all found to be upregulated in esophageal cancer cells and tissues, where they have the reported function of promoting proliferation, invasion and migration.	('upregulated', 'PosReg', (197, 208))	('hsa_circ_0004370', 'Gene', (159, 175))	('Hsa_circ_0006168', 'Gene', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cZNF292', 'Chemical', '-', (85, 92))	('invasion', 'CPA', (315, 323))	('circRAD23B', 'Var', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('migration', 'CPA', (328, 337))	('promoting', 'PosReg', (290, 299))	('cancer', 'Disease', (223, 229))
701683	32377736	In 2017, studies discovered that circRNA_100269, circRNA_La ribonucleoprotein 4, hsa_circ_0000705, hsa_circ_0001895, hsa_circ_00001649, hsa_circ_0000745 and hsa_circ_0000190 are all significantly downregulated in gastric cancer, which were found to be closely associated with the increased cell proliferation, differentiation, subcellular localization, stage, Borrmann type and invasion.	('cell proliferation', 'CPA', (290, 308))	('gastric cancer', 'Phenotype', 'HP:0012126', (213, 227))	('hsa_circ_0000190', 'Var', (157, 173))	('increased', 'PosReg', (280, 289))	('differentiation', 'CPA', (310, 325))	('downregulated', 'NegReg', (196, 209))	('gastric cancer', 'Disease', (213, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('gastric cancer', 'Disease', 'MESH:D013274', (213, 227))
701693	32377736	Hsa_circ_0081143 is another circRNA that is highly expressed in gastric cancer, which is positively associated with lymph node metastasis and TNM staging in advanced gastric cancer, the silencing of which can inhibit the development of gastric cancer and enhance the sensitivity of gastric cancer cells to chemotherapeutic agents such as cisplatin.	('sensitivity', 'MPA', (267, 278))	('gastric cancer', 'Disease', (166, 180))	('gastric cancer', 'Phenotype', 'HP:0012126', (282, 296))	('gastric cancer', 'Disease', (64, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('gastric cancer', 'Disease', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('gastric cancer', 'Disease', (282, 296))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('development', 'CPA', (221, 232))	('silencing', 'Var', (186, 195))	('associated', 'Reg', (100, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('inhibit', 'NegReg', (209, 216))	('gastric cancer', 'Disease', 'MESH:D013274', (282, 296))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))	('TNM', 'Gene', '10178', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('enhance', 'PosReg', (255, 262))	('cisplatin', 'Chemical', 'MESH:D002945', (338, 347))	('TNM', 'Gene', (142, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
701704	32377736	Circ_0000977 has been previously found to increase the expression of hypoxia-inducible factor 1 and ADAM10 by competitively binding to miR-153, where circ_0000977 silencing can significantly enhance the cytotoxic effects of natural killer cells on pancreatic cancer.	('increase', 'PosReg', (42, 50))	('circ_0000977', 'Var', (150, 162))	('pancreatic cancer', 'Disease', (248, 265))	('silencing', 'NegReg', (163, 172))	('pancreatic cancer', 'Disease', 'MESH:D010190', (248, 265))	('hypoxia', 'Disease', 'MESH:D000860', (69, 76))	('enhance', 'PosReg', (191, 198))	('miR-153', 'Chemical', '-', (135, 142))	('expression', 'MPA', (55, 65))	('binding', 'Interaction', (124, 131))	('ADAM10', 'Gene', '102', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cytotoxic effects of natural killer cells', 'CPA', (203, 244))	('ADAM10', 'Gene', (100, 106))	('hypoxia', 'Disease', (69, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (248, 265))	('Circ_0000977', 'Var', (0, 12))
701705	32377736	Drug resistance is another important underlying cause of poor prognosis in patients with advanced pancreatic cancer.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('patients', 'Species', '9606', (75, 83))	('Drug resistance', 'Var', (0, 15))	('pancreatic cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('pancreatic cancer', 'Disease', 'MESH:D010190', (98, 115))
701706	32377736	Liu et al previously found that knocking down circ-homeodomain interacting protein kinase 3 expression can effectively improve the sensitivity of pancreatic cancer to gemcitabine.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gemcitabine', 'Chemical', 'MESH:C056507', (167, 178))	('improve', 'PosReg', (119, 126))	('pancreatic cancer', 'Disease', (146, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('knocking down', 'Var', (32, 45))	('sensitivity', 'MPA', (131, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))
701727	32377736	Yang et al previously found that knocking down cZNF292 expression can inhibit angiogenesis, cell proliferation and resistance to radiotherapy in hepatocellular carcinoma, which may be due to the hypoxic environment induced by cZNF292.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('hypoxic', 'Disease', (195, 202))	('hypoxic', 'Disease', 'MESH:D000860', (195, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('hepatocellular carcinoma', 'Disease', (145, 169))	('angiogenesis', 'CPA', (78, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('resistance to radiotherapy', 'CPA', (115, 141))	('expression', 'MPA', (55, 65))	('knocking down', 'Var', (33, 46))	('inhibit', 'NegReg', (70, 77))	('cell proliferation', 'CPA', (92, 110))	('cZNF292', 'Chemical', '-', (47, 54))	('cZNF292', 'Chemical', '-', (226, 233))	('cZNF292', 'Gene', (47, 54))
701728	32377736	Similar to cZNF292, the dysregulation of circRNA_101505, circRNA_104797 and circ_0003418 expression in hepatocellular carcinoma has been demonstrated to increase the resistance of hepatocytes to sorafenib and cisplatin, which is considered to be one of the main underlying causes of poor prognosis in patients with advanced hepatocellular carcinoma.	('sorafenib', 'Chemical', 'MESH:D000077157', (195, 204))	('cZNF292', 'Chemical', '-', (11, 18))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('circ_0003418', 'Var', (76, 88))	('resistance', 'MPA', (166, 176))	('circRNA_101505', 'Var', (41, 55))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (324, 348))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('hepatocellular carcinoma', 'Disease', (324, 348))	('dysregulation', 'Var', (24, 37))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (324, 348))	('patients', 'Species', '9606', (301, 309))	('hepatocellular carcinoma', 'Disease', (103, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('increase', 'PosReg', (153, 161))	('cisplatin', 'Chemical', 'MESH:D002945', (209, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (339, 348))	('circRNA_104797', 'Var', (57, 71))
701738	32377736	In addition, circ-homeodomain interacting protein kinase 3 has been previously found to increase the expression of Rho-associated coiled-coil containing protein kinase 1-CDK6 by sponging miR-124, promoting the proliferation of gallbladder cancer cells.	('gallbladder cancer', 'Disease', (227, 245))	('promoting', 'PosReg', (196, 205))	('gallbladder cancer', 'Disease', 'MESH:D005706', (227, 245))	('proliferation', 'CPA', (210, 223))	('sponging', 'Var', (178, 186))	('Rho-associated coiled-coil containing protein kinase 1', 'Gene', '6093', (115, 169))	('increase', 'PosReg', (88, 96))	('expression', 'MPA', (101, 111))	('CDK6', 'Gene', (170, 174))	('CDK6', 'Gene', '1021', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
701746	32377736	In 2016, circRNA_001569 and hsa_circ_0000069 were found to be highly expressed in patients with colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (82, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('colorectal cancer', 'Disease', (96, 113))	('circRNA_001569', 'Var', (9, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
701758	32377736	In a recent study, Jia et al used a selective binding complementary competitive endogenous RNA array to analyze gastrointestinal stromal tumors, which found circ_0084097, circ_0069765 and circ_0079471 to be aberrantly expressed in gastrointestinal stromal tumors.	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (231, 261))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (231, 262))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (231, 262))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (112, 142))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (112, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('gastrointestinal stromal tumors', 'Disease', (231, 262))	('gastrointestinal stromal tumors', 'Disease', (112, 143))	('circ_0084097', 'Var', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('circ_0069765', 'Var', (171, 183))	('circ_0079471', 'Var', (188, 200))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (112, 143))
701759	32377736	Although further study suggested these circRNAs to serve a regulatory role by sponging mir-144-3p, mir-142-5-p and mir-485-3p, there is no experimental data on the mechanism of circRNA involved in the development of gastrointestinal stromal tumors.	('gastrointestinal stromal tumors', 'Disease', (216, 247))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (216, 246))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (216, 247))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (216, 247))	('mir-144-3p', 'Var', (87, 97))	('mir-485-3p', 'Var', (115, 125))	('mir-142-5-p', 'Var', (99, 110))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
701761	32377736	Supporting this, non-coding RNA dysfunction has been documented to be associated with the occurrence and progression of various chronic diseases and tumors.	('chronic diseases', 'Disease', 'MESH:D002908', (128, 144))	('chronic diseases', 'Disease', (128, 144))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('non-coding RNA', 'Var', (17, 31))	('associated', 'Reg', (70, 80))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))
701766	32377736	Yuan et al found that the lncRNA SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily C member 2 upregulates transmembrane serine protease 2 by binding to miR-551b-3p, promoting the proliferation and invasion of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (244, 258))	('promoting', 'PosReg', (200, 209))	('invasion', 'CPA', (232, 240))	('upregulates', 'PosReg', (129, 140))	('serine', 'Chemical', 'MESH:D012694', (155, 161))	('proliferation', 'CPA', (214, 227))	('SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily C member 2', 'Gene', '6601', (33, 128))	('binding', 'Interaction', (176, 183))	('miR-551b-3p', 'Var', (187, 198))	('transmembrane serine protease 2', 'MPA', (141, 172))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('gastric cancer', 'Disease', (244, 258))	('gastric cancer', 'Disease', 'MESH:D013274', (244, 258))
701768	32377736	The occurrence and procession of digestive system malignancies are closely associated with the aberrant expression of these non-coding RNAs.	('aberrant expression', 'Var', (95, 114))	('malignancies', 'Disease', (50, 62))	('non-coding', 'Protein', (124, 134))	('malignancies', 'Disease', 'MESH:D009369', (50, 62))	('associated', 'Reg', (75, 85))
701776	32377736	ldyyyn2018-54), the Open Fund of State Key Laboratory of Cancer Biology (grant no.	('Cancer', 'Disease', (57, 63))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Cancer', 'Disease', 'MESH:D009369', (57, 63))	('ldyyyn2018-54', 'Var', (0, 13))
701871	32499834	For patients that fail to get off of medical therapy after a 6-month trial of increasing medical care, TIF can restore the angle of HIS and improve the LES function necessary to control reflux symptoms, heal esophagitis, and allow discontinuation of medications.	('esophagitis', 'Phenotype', 'HP:0100633', (208, 219))	('TIF', 'Var', (103, 106))	('improve', 'PosReg', (140, 147))	('esophagitis', 'Disease', 'MESH:D004938', (208, 219))	('reflux symptoms', 'Phenotype', 'HP:0002020', (186, 201))	('angle', 'MPA', (123, 128))	('reflux symptom', 'Phenotype', 'HP:0002020', (186, 200))	('patients', 'Species', '9606', (4, 12))	('LES function', 'MPA', (152, 164))	('reflux symptoms', 'Disease', (186, 201))	('esophagitis', 'Disease', (208, 219))	('restore', 'PosReg', (111, 118))
701873	32499834	The combined laparoscopic and endoscopic approach has fewer and less comprehensive studies to date, but, in available studies, appears to have similar outcomes in symptom control, safety, and normalization of esophageal pH without causing the bloat syndrome side effects that deterred patients from anatomic repair in the past.	('esophageal pH', 'MPA', (209, 222))	('bloat syndrome', 'Phenotype', 'HP:0003270', (243, 257))	('bloat syndrome', 'Disease', (243, 257))	('patients', 'Species', '9606', (285, 293))	('normalization', 'Var', (192, 205))
701938	30871612	suggests that debleaching red blood cells in mice may relieve severe inflammatory reactions and decrease the expression levels of various proinflammatory cytokines, which is the evidence that blood transfusions may lead to elevation of inflammation level.	('mice', 'Species', '10090', (45, 49))	('decrease', 'NegReg', (96, 104))	('elevation', 'PosReg', (223, 232))	('inflammation', 'Disease', 'MESH:D007249', (236, 248))	('elevation of inflammation level', 'Phenotype', 'HP:0012649', (223, 254))	('relieve', 'PosReg', (54, 61))	('inflammation', 'Disease', (236, 248))	('debleaching', 'Var', (14, 25))
701941	30871612	This study suggests that the risk of postoperative AF in the patients with adhesion between lymph nodes and pericardium was 3.954 times the risk of postoperative AF in the patients without adhesion, which seems to be consistent with the reported results above to some extent.	('AF', 'Phenotype', 'HP:0005110', (162, 164))	('postoperative AF', 'Disease', 'MESH:D010149', (37, 53))	('AF', 'Phenotype', 'HP:0005110', (51, 53))	('patients', 'Species', '9606', (61, 69))	('postoperative AF', 'Disease', (148, 164))	('adhesion', 'Var', (75, 83))	('postoperative AF', 'Disease', 'MESH:D010149', (148, 164))	('patients', 'Species', '9606', (172, 180))	('postoperative AF', 'Disease', (37, 53))
702108	29541393	While cancers often accumulate hundreds of mutations and harbor several immunogenic neoantigens, the repertoire of mutation-specific T cells in patients might be restricted.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('accumulate', 'Reg', (20, 30))	('patients', 'Species', '9606', (144, 152))	('mutations', 'Var', (43, 52))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))
702124	29541393	As only neoantigens are non-self peptides derived from somatic non-synonymous mutations in cancer cells, they are potentially more immunogenic.	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('non-synonymous mutations', 'Var', (63, 87))
702139	29541393	Subsequently, using a list of these possible mutations, we predicted the binding affinity of peptides including amino acid substitutions to a HLA-A2402 molecule and identified 81 neoantigen epitopes which showed IC50 of 500 nM or lower.	('HLA-A', 'Gene', (142, 147))	('substitutions', 'Var', (123, 136))	('HLA-A', 'Gene', '3105', (142, 147))	('binding', 'Interaction', (73, 80))
702141	29541393	After priming of CD8+ T cells, we detected neoantigen-specific CD8+ T cells by staining with HLA-dextramers loaded with a neoantigen peptide derived from the missense substitution L143F in dpy-19 like 4 gene (DPY19L4L143F, LYPEFIASI, Figure 2A).	('L143F', 'Mutation', 'rs149228791', (216, 221))	('LYPEFIASI', 'Disease', (223, 232))	('CD8', 'Gene', (17, 20))	('CD8', 'Gene', '925', (17, 20))	('L143F', 'Mutation', 'rs149228791', (180, 185))	('LYPEFIASI', 'Disease', 'None', (223, 232))	('CD8', 'Gene', (63, 66))	('L143F', 'Var', (180, 185))	('CD8', 'Gene', '925', (63, 66))	('dpy-19 like 4', 'Gene', '286148', (189, 202))	('dpy-19 like 4', 'Gene', (189, 202))
702144	29541393	As a second example with higher clinical relevance, we aimed at generating neoantigen-specific CD8+ T cells against a mutation in an ovarian cancer sample.	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('CD8', 'Gene', '925', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ovarian cancer', 'Disease', 'MESH:D010051', (133, 147))	('clinical', 'Species', '191496', (32, 40))	('ovarian cancer', 'Disease', (133, 147))	('mutation', 'Var', (118, 126))	('CD8', 'Gene', (95, 98))
702148	29541393	We successfully identified CD8+ T cells which were primed against a neoantigen peptide derived from RNF19BV372L (V372L mutation in ring finger protein 19B gene, MLIGIPVYV, Figure 2C).	('V372L', 'Mutation', 'p.V372L', (106, 111))	('V372L', 'Mutation', 'p.V372L', (113, 118))	('ring finger protein 19B', 'Gene', (131, 154))	('CD8', 'Gene', (27, 30))	('CD8', 'Gene', '925', (27, 30))	('ring finger protein 19B', 'Gene', '127544', (131, 154))	('RNF19BV372L', 'Gene', (100, 111))	('V372L', 'Var', (113, 118))
702152	29541393	DPY19L4L143F TCR-engineered T cells showed binding of specific dextramers loaded with the mutant but not with the wild-type DPY19L4 peptide (Figure 3A).	('binding', 'Interaction', (43, 50))	('DPY19L4L143F', 'Var', (0, 12))	('mutant', 'Var', (90, 96))	('specific dextramers', 'Protein', (54, 73))	('L143F', 'Mutation', 'rs149228791', (7, 12))
702153	29541393	Furthermore, we confirmed antigen-specific function of DPY19L4L143F TCR-engineered T cells by co-culture with C1R lymphoblastoid cells stably expressing either HLA-A*24:02 or HLA-A*02:01 and loaded with titrated amounts of either mutant or wild-type DPY19L4 peptide.	('HLA-A', 'Gene', '3105', (175, 180))	('C1R', 'Gene', (110, 113))	('HLA-A', 'Gene', (160, 165))	('DPY19L4L143F', 'Var', (55, 67))	('C1R', 'Gene', '715', (110, 113))	('HLA-A', 'Gene', (175, 180))	('HLA-A', 'Gene', '3105', (160, 165))
702155	29541393	The functional characterization substantiated the exquisite specificity of the isolated DPY19L4L143F-TCR because C1R cells were only recognized when (i) expressing HLA-A*24:02 and (ii) loaded with the mutant DPY19L4 peptide.	('L143F', 'Mutation', 'rs149228791', (95, 100))	('HLA-A', 'Gene', '3105', (164, 169))	('DPY19L4L143F-TCR', 'Var', (88, 104))	('mutant', 'Var', (201, 207))	('HLA-A', 'Gene', (164, 169))	('C1R', 'Gene', '715', (113, 116))	('C1R', 'Gene', (113, 116))
702157	29541393	To test whether endogenously processed antigen can be recognized, we incubated DPY19L4L143F TCR-engineered T cells together with TE-8 cancer cells that were reported to express the HLA-A*24:02 allele.	('HLA-A', 'Gene', '3105', (181, 186))	('DPY19L4L143F', 'Var', (79, 91))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('HLA-A', 'Gene', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
702159	29541393	Hence, DPY19L4L143F TCR-engineered T cells secreted IFN-gamma only when incubated with HLA-A*24:02-transfected TE-8 cells, whereas mock-transfected TE-8 cells could not trigger T cell activation (Figure 3C, 3D).	('DPY19L4L143F', 'Var', (7, 19))	('L143F', 'Mutation', 'rs149228791', (14, 19))	('HLA-A', 'Gene', '3105', (87, 92))	('HLA-A', 'Gene', (87, 92))	('secreted', 'MPA', (43, 51))
702160	29541393	In addition, when we pulsed HLA-A*24:02-transfected TE-8 cells with the mutant peptide, IFN-gamma and granzyme B secretion was further enhanced (Figure 3C, 3D).	('mutant', 'Var', (72, 78))	('HLA-A', 'Gene', '3105', (28, 33))	('HLA-A', 'Gene', (28, 33))	('enhanced', 'PosReg', (135, 143))	('granzyme B secretion', 'MPA', (102, 122))
702161	29541393	These results indicate that DPY19L4L143F TCR-engineered T cells recognized the endogenously-expressed mutated peptide in the HLA-A2402-restricted manner and showed cytotoxic activity.	('DPY19L4L143F', 'Var', (28, 40))	('HLA-A', 'Gene', '3105', (125, 130))	('cytotoxic activity', 'CPA', (164, 182))	('HLA-A', 'Gene', (125, 130))
702162	29541393	To further explore the cytotoxic activity of T cells engineered with the DPY19L4L143F-TCR, we made use of HLA-A*24:02-positive TE-11 esophageal cancer cells since we could not establish TE-8 cells that stably express HLA-A*24:02 (Supplementary Figure 3).	('HLA-A', 'Gene', '3105', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('HLA-A', 'Gene', (106, 111))	('HLA-A', 'Gene', '3105', (217, 222))	('HLA-A', 'Gene', (217, 222))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('DPY19L4L143F-TCR', 'Var', (73, 89))
702163	29541393	Direct killing of TE-11 cancer cells was only observed after loading with DPY19L4L143F peptide (cell viability was reduced to 27.5%, Supplementary Movie 1).	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('DPY19L4L143F peptide', 'Var', (74, 94))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))
702165	29541393	In contrast to the analysis of the DPY19L4L143F-TCR, RNF19BV372L TCR-engineered T cells bound dextramers irrespective of whether the HLAs were loaded with mutant or wild-type RNF19BV372L peptide (Figure 4A).	('L143F', 'Mutation', 'rs149228791', (42, 47))	('mutant', 'Var', (155, 161))	('dextramers', 'Protein', (94, 104))	('bound', 'Interaction', (88, 93))	('RNF19BV372L', 'Var', (53, 64))
702166	29541393	IFN-gamma ELISPOT assay also revealed that RNF19BV372L TCR-engineered T cells secreted IFN-gamma at the similar levels when the antigen-presentation cells were pulsed with the wild-type and mutated peptides although the recognition of these peptides by RNF19BV372L TCR-engineered T cells were confirmed to occur on an HLA-A0201-restricted manner (Figure 4B and Supplementary Figure 4).	('RNF19BV372L', 'Var', (43, 54))	('HLA-A', 'Gene', '3105', (318, 323))	('RNF19BV372L', 'Var', (253, 264))	('HLA-A', 'Gene', (318, 323))
702182	29541393	In order to avoid autoimmune side effects when using neoantigen-specific TCRs, the TCRs should not recognize the wild-type analogs of mutated antigens as shown in RNF19BV372L found in the ovarian cancer sample.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ovarian cancer', 'Phenotype', 'HP:0100615', (188, 202))	('ovarian cancer', 'Disease', 'MESH:D010051', (188, 202))	('ovarian cancer', 'Disease', (188, 202))	('RNF19BV372L', 'Var', (163, 174))
702183	29541393	The neoantigens with amino acid changes in the HLA anchor position, usually position 2 and 9 for HLA-A*02:01, relies on significant differences in binding affinity between wild-type and mutant peptides.	('mutant', 'Var', (186, 192))	('binding affinity', 'Interaction', (147, 163))	('HLA-A', 'Gene', '3105', (97, 102))	('amino acid changes', 'Var', (21, 39))	('differences', 'Reg', (132, 143))	('HLA-A', 'Gene', (97, 102))
702184	29541393	However, both wild-type and mutant of the RNF19B peptides (V372L in position 2 of the epitope) are predicted to have similarly high HLA-binding affinity, and each TCR that is raised against the mutant peptide will probably be reactive against its wild-type counterpart.	('mutant', 'Var', (28, 34))	('HLA-binding', 'Protein', (132, 143))	('V372L', 'Mutation', 'p.V372L', (59, 64))	('high', 'PosReg', (127, 131))	('RNF19B', 'Gene', (42, 48))	('RNF19B', 'Gene', '127544', (42, 48))	('V372L', 'Var', (59, 64))
702194	29541393	Finally, somatic variants (single nucleotide variations (SNVs) and indels) were called with the following parameters, (i) base quality of >=15, (ii) sequence depth of >= 10, (iii) variant depth of >=4, (iv) variant frequency in tumor of >=10%, (v) variant frequency in normal of <2%, and (vi) Fisher p value of <0.05.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('variant', 'Var', (207, 214))	('tumor', 'Disease', (228, 233))
702229	28085101	Furthermore, knockdown of Shp2 attenuated cisplatin-sensitivity of ESCC cells.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('attenuated', 'NegReg', (31, 41))	('cisplatin-sensitivity', 'MPA', (42, 63))	('knockdown', 'Var', (13, 22))	('Shp2', 'Gene', (26, 30))
702235	28085101	Intriguingly, activation of Shp2 induced by PTPN11 mutations leads to development of Noonan syndrome and juvenile leukemias.	('activation', 'PosReg', (14, 24))	('leads to', 'Reg', (61, 69))	('Noonan syndrome', 'Disease', (85, 100))	('mutations', 'Var', (51, 60))	('PTPN11', 'Gene', (44, 50))	('leukemias', 'Phenotype', 'HP:0001909', (114, 123))	('Shp2', 'Gene', (28, 32))	('Noonan syndrome', 'Disease', 'MESH:D009634', (85, 100))	('leukemia', 'Phenotype', 'HP:0001909', (114, 122))	('juvenile leukemias', 'Disease', (105, 123))	('juvenile leukemias', 'Disease', 'MESH:D007938', (105, 123))
702236	28085101	In addition, hyperactivation of Shp2 has been confirmed to be involved in the pathogenesis of several solid tumors, identifying that Shp2 acts as an oncogene.	('solid tumors', 'Disease', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('involved', 'Reg', (62, 70))	('Shp2', 'Gene', (32, 36))	('hyperactivation', 'Var', (13, 28))	('solid tumors', 'Disease', 'MESH:D009369', (102, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
702237	28085101	Mutant EGFR activated Shp2 is essential for mutant EGFR driven lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (63, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (63, 82))	('EGFR', 'Gene', (51, 55))	('EGFR', 'Gene', (7, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (63, 82))	('Shp2', 'Gene', (22, 26))	('mutant', 'Var', (44, 50))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', '1956', (7, 11))
702242	28085101	found that hepatocyte-specific Shp2 knockout led to the development of hepatocellular cancer (HCC) in mice via activation of Stat3 (signal transducer and activator of transcription 3), implying a tumor-suppressing role of Shp2.	('activation', 'PosReg', (111, 121))	('knockout', 'Var', (36, 44))	('mice', 'Species', '10090', (102, 106))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (71, 92))	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('hepatocellular cancer', 'Disease', (71, 92))	('tumor', 'Disease', (196, 201))	('Stat3', 'MPA', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Shp2', 'Gene', (31, 35))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (71, 92))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
702246	28085101	Loss of Shp2 promoted proliferation and chemoresistance of the ESCC cell line, suggesting that Shp2 might function as a tumor suppressor in ESCC.	('promoted', 'PosReg', (13, 21))	('chemoresistance', 'CPA', (40, 55))	('ESCC', 'Disease', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Shp2', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('proliferation', 'CPA', (22, 35))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', (120, 125))
702250	28085101	Cyclin D1 and Survivin, downstream molecules of Stat3, were upregulated (1.18 +- 0.01-folds, p < 0.001; 1.49 +- 0.18-folds, p < 0.01) upon Shp2 depletion in ESCC cells, while Cyclin D2 and c-Jun expression were attenuated (0.28 +- 0.14-fold, p < 0.001; 0.29 +- 0.14-fold, p < 0.001; Figure 3E).	('Cyclin D2', 'Gene', '894', (175, 184))	('upregulated', 'PosReg', (60, 71))	('Cyclin D2', 'Gene', (175, 184))	('c-Jun', 'Gene', '3725', (189, 194))	('Cyclin D1', 'Gene', '595', (0, 9))	('depletion', 'Var', (144, 153))	('Survivin', 'Gene', (14, 22))	('Shp2', 'Gene', (139, 143))	('Cyclin D1', 'Gene', (0, 9))	('c-Jun', 'Gene', (189, 194))
702252	28085101	Apparently, p-Stat3-mediated Cyclin D1 and Survivin expressions contribute to the promotion of cell proliferation induced by Shp2 depletion.	('cell proliferation', 'CPA', (95, 113))	('Cyclin D1', 'Gene', '595', (29, 38))	('depletion', 'Var', (130, 139))	('Cyclin D1', 'Gene', (29, 38))	('Survivin', 'Protein', (43, 51))	('Shp2', 'Gene', (125, 129))	('promotion', 'PosReg', (82, 91))
702254	28085101	ESCC cells with Shp2 knockdown displayed enhanced proliferation under cisplatin exposure compared with control cells (Figure 4A).	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('enhanced', 'PosReg', (41, 49))	('proliferation', 'CPA', (50, 63))	('Shp2', 'Gene', (16, 20))	('knockdown', 'Var', (21, 30))
702255	28085101	As described previously, Shp2 depletion led to upregulation of Survivin (Figure 3E), which might contribute to the induction of cisplatin-resistance.	('Shp2', 'Gene', (25, 29))	('cisplatin-resistance', 'MPA', (128, 148))	('depletion', 'Var', (30, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('upregulation', 'PosReg', (47, 59))	('induction', 'Reg', (115, 124))	('Survivin', 'Protein', (63, 71))
702256	28085101	Moreover, Shp2 depletion led to overexpression of ABCG2 and Nanog, responsible for drug-resistance phenotype in ESCC cells (2.05 +- 0.61-folds, p = 0.042; 1.87 +- 0.31-folds, p = 0.041, Figure 4B).	('depletion', 'Var', (15, 24))	('overexpression', 'PosReg', (32, 46))	('Shp2', 'Gene', (10, 14))	('drug-resistance', 'MPA', (83, 98))	('drug-resistance', 'Phenotype', 'HP:0020174', (83, 98))	('Nanog', 'Gene', '79923', (60, 65))	('Nanog', 'Gene', (60, 65))	('ABCG2', 'Gene', (50, 55))	('ABCG2', 'Gene', '9429', (50, 55))
702257	28085101	Thus, Shp2 expression enhanced cisplatin sensitivity of ESCC cells.	('Shp2', 'Gene', (6, 10))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('cisplatin sensitivity', 'MPA', (31, 52))	('expression', 'Var', (11, 21))	('enhanced', 'PosReg', (22, 30))
702261	28085101	Shp2 inhibition suppresses EGFR mutant-induced lung adenocarcinoma by attenuating ERK1/2 and Src activation.	('inhibition suppresses', 'NegReg', (5, 26))	('Shp2', 'Gene', (0, 4))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('EGFR', 'Gene', (27, 31))	('ERK1/2', 'Gene', '5595;5594', (82, 88))	('EGFR', 'Gene', '1956', (27, 31))	('Src', 'Gene', '6714', (93, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('lung adenocarcinoma', 'Disease', (47, 66))	('Src', 'Gene', (93, 96))	('mutant-induced', 'Var', (32, 46))	('ERK1/2', 'Gene', (82, 88))	('attenuating', 'NegReg', (70, 81))
702267	28085101	Ptpn11 gain-of-function mutation D61G induces chromosomal instability, resulting in tumorigenesis of leukemia, lymphoma, Lung adenomas, and skin papillomas in mice.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('chromosomal instability', 'MPA', (46, 69))	('papillomas', 'Phenotype', 'HP:0012740', (145, 155))	('Ptpn11', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('induces', 'Reg', (38, 45))	('skin papillomas', 'Disease', (140, 155))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('chromosomal instability', 'Phenotype', 'HP:0040012', (46, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))	('Lung adenomas', 'Disease', 'MESH:D000236', (121, 134))	('skin papillomas', 'Disease', 'MESH:D010212', (140, 155))	('Ptpn11', 'Gene', '19247', (0, 6))	('Lung adenomas', 'Disease', (121, 134))	('leukemia', 'Disease', (101, 109))	('leukemia', 'Disease', 'MESH:D007938', (101, 109))	('gain-of-function', 'PosReg', (7, 23))	('tumor', 'Disease', (84, 89))	('lymphoma', 'Disease', (111, 119))	('D61G', 'Var', (33, 37))	('mice', 'Species', '10090', (159, 163))	('D61G', 'Mutation', 'rs121918461', (33, 37))	('lymphoma', 'Disease', 'MESH:D008223', (111, 119))
702269	28085101	Deletion of Shp2 in hepatocytes leads to the development of spontaneous hepatocellular tumor and increased incidence of chemical carcinogen-induced HCCs, following hepatic inflammation and necrosis mediated by enhanced IL-6/Stat3 signaling.	('spontaneous', 'CPA', (60, 71))	('hepatic inflammation', 'Disease', (164, 184))	('IL-6', 'Gene', '3569', (219, 223))	('hepatocellular tumor', 'Phenotype', 'HP:0001402', (72, 92))	('increased', 'PosReg', (97, 106))	('necrosis', 'Disease', (189, 197))	('hepatic inflammation', 'Disease', 'MESH:D007249', (164, 184))	('HCC', 'Phenotype', 'HP:0001402', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('chemical carcinogen-induced HCCs', 'Disease', (120, 152))	('hepatocellular tumor', 'Disease', 'MESH:D006528', (72, 92))	('necrosis', 'Disease', 'MESH:D009336', (189, 197))	('hepatocellular tumor', 'Disease', (72, 92))	('Shp2', 'Gene', (12, 16))	('IL-6', 'Gene', (219, 223))	('hepatic inflammation', 'Phenotype', 'HP:0012115', (164, 184))	('Deletion', 'Var', (0, 8))
702271	28085101	Loss-of-function mutations in PTPN11 results in development of metachondromatosis (MC), while Shp2 represses the proliferation of progenitor cell population in cartilage.	('Loss-of-function', 'NegReg', (0, 16))	('PTPN11', 'Gene', (30, 36))	('cartilage', 'Disease', (160, 169))	('cartilage', 'Disease', 'MESH:D002357', (160, 169))	('metachondromatosis', 'Disease', 'MESH:C562938', (63, 81))	('metachondromatosis', 'Disease', (63, 81))	('represses', 'NegReg', (99, 108))	('mutations', 'Var', (17, 26))
702276	28085101	Stat3 was aberrantly suppressed in peripheral blood cells from Noonan syndrome patients with gain-of-function Shp2 mutations, while Stat3 activation was significantly attenuated by activated Shp2 in bone marrow cells.	('mutations', 'Var', (115, 124))	('Shp2', 'Gene', (110, 114))	('suppressed', 'NegReg', (21, 31))	('Noonan syndrome', 'Disease', (63, 78))	('patients', 'Species', '9606', (79, 87))	('Noonan syndrome', 'Disease', 'MESH:D009634', (63, 78))	('gain-of-function', 'PosReg', (93, 109))	('Stat3', 'MPA', (0, 5))
702278	28085101	The inhibitory function of Shp2 on Stat3 activity requires Tyr-759 in the cytoplasmatic domain of gp130, an up-stream signal-transduction component of Stat3.	('Tyr', 'Chemical', 'MESH:D014443', (59, 62))	('Shp2', 'Gene', (27, 31))	('up-stream', 'PosReg', (108, 117))	('Tyr-759', 'Var', (59, 66))	('gp130', 'Gene', (98, 103))	('Stat3 activity', 'MPA', (35, 49))	('inhibitory function', 'NegReg', (4, 23))	('gp130', 'Gene', '3572', (98, 103))
702279	28085101	Shp2 recruitments to gp130 moderate Jak activity and consequently lead to the attenuation of Stat3 signaling.	('Shp2', 'Gene', (0, 4))	('gp130', 'Gene', '3572', (21, 26))	('attenuation', 'NegReg', (78, 89))	('Stat3 signaling', 'MPA', (93, 108))	('recruitments', 'Var', (5, 17))	('gp130', 'Gene', (21, 26))	('Jak activity', 'MPA', (36, 48))
702281	28085101	Cyclin D1 and Survivin, target genes of p-Stat3, were upregulated after Shp2 depletion, indicating the potential functional mechanisms mediated by p-Stat3 in ESCC.	('upregulated', 'PosReg', (54, 65))	('depletion', 'Var', (77, 86))	('Cyclin D1', 'Gene', '595', (0, 9))	('Shp2', 'Gene', (72, 76))	('ESCC', 'Disease', (158, 162))	('Survivin', 'Protein', (14, 22))	('Cyclin D1', 'Gene', (0, 9))
702282	28085101	However, Cyclin D2 and c-Jun expressions were decreased after Shp2 knockdown.	('c-Jun', 'Gene', '3725', (23, 28))	('Shp2', 'Gene', (62, 66))	('knockdown', 'Var', (67, 76))	('c-Jun', 'Gene', (23, 28))	('Cyclin D2', 'Gene', '894', (9, 18))	('decreased', 'NegReg', (46, 55))	('Cyclin D2', 'Gene', (9, 18))
702284	28085101	We suspect that Shp2 depletion in ESCC might decrease p-Erk levels and lead to the downregulation of Cyclin D2 and c-Jun.	('c-Jun', 'Gene', (115, 120))	('Erk', 'Gene', (56, 59))	('Cyclin D2', 'Gene', '894', (101, 110))	('downregulation', 'NegReg', (83, 97))	('depletion', 'Var', (21, 30))	('decrease', 'NegReg', (45, 53))	('Erk', 'Gene', '5594', (56, 59))	('Cyclin D2', 'Gene', (101, 110))	('Shp2', 'Gene', (16, 20))	('c-Jun', 'Gene', '3725', (115, 120))
702288	28085101	In hepatoma cells, Shp2 depletion leads to reduced proliferation and anchor-independent growth under sorafenib exposure.	('anchor-independent growth', 'CPA', (69, 94))	('hepatoma', 'Disease', 'MESH:D006528', (3, 11))	('sorafenib', 'Chemical', 'MESH:D000077157', (101, 110))	('depletion', 'Var', (24, 33))	('proliferation', 'CPA', (51, 64))	('Shp2', 'Gene', (19, 23))	('reduced', 'NegReg', (43, 50))	('hepatoma', 'Disease', (3, 11))
702289	28085101	Surprisingly, the current study revealed that ESCC cells with Shp2 knockdown showed elevated resistance to cisplatin, with upregulation of ABCG2 and Nanog.	('Nanog', 'Gene', '79923', (149, 154))	('elevated', 'PosReg', (84, 92))	('Shp2', 'Gene', (62, 66))	('knockdown', 'Var', (67, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('resistance to cisplatin', 'MPA', (93, 116))	('Nanog', 'Gene', (149, 154))	('ABCG2', 'Gene', (139, 144))	('upregulation', 'PosReg', (123, 135))	('ABCG2', 'Gene', '9429', (139, 144))
702291	28085101	Instead, Shp2 mutants in LEOPARD syndrome patients were catalytically defective and act as dominant negative mutations.	('mutants', 'Var', (14, 21))	('negative', 'NegReg', (100, 108))	('LEOPARD syndrome', 'Disease', 'MESH:D044542', (25, 41))	('Shp2', 'Gene', (9, 13))	('LEOPARD syndrome', 'Disease', (25, 41))	('patients', 'Species', '9606', (42, 50))
702327	28085101	In addition, cisplatin-resistance of Eca109 was significantly enhanced by Shp2 depletion.	('enhanced', 'PosReg', (62, 70))	('depletion', 'Var', (79, 88))	('cisplatin-resistance', 'MPA', (13, 33))	('Shp2', 'Gene', (74, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
702328	28085101	Mechanistically, we found that the knockdown of Shp2 led to overexpression of Cyclin D1 and Survivin.	('knockdown', 'Var', (35, 44))	('Cyclin D1', 'Gene', '595', (78, 87))	('Survivin', 'Protein', (92, 100))	('Shp2', 'Gene', (48, 52))	('overexpression', 'PosReg', (60, 74))	('Cyclin D1', 'Gene', (78, 87))
702329	28085101	Moreover, ABCG2 and Nanog expressions were elevated, elucidating the mechanisms of cisplatin-resistance induced by Shp2 knockdown.	('ABCG2', 'Gene', (10, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('ABCG2', 'Gene', '9429', (10, 15))	('elevated', 'PosReg', (43, 51))	('Shp2', 'Gene', (115, 119))	('knockdown', 'Var', (120, 129))	('Nanog', 'Gene', '79923', (20, 25))	('Nanog', 'Gene', (20, 25))
702422	26806272	The 3-year OS rate for patients with T1-2 and T3-4 lesions was 94.7% (95% CI, 85.2-100%) and 39.6% (95% CI, 24.5-63.9%), respectively, and for patients with stage I/II and stage III disease was 90.9% (95% CI, 79.7-100%) and 37.9% (95% CI, 22.6-63.6%), respectively (Fig.	('OS', 'Chemical', '-', (11, 13))	('patients', 'Species', '9606', (23, 31))	('T1-2', 'Var', (37, 41))	('patients', 'Species', '9606', (143, 151))	('T3-4', 'Var', (46, 50))
702465	26806272	Despite this, our findings indicate that the use of PBT with ACRT, which increases the radiation dose to the tumor while minimizing the exposure to the heart and lungs, can improve the CR rate and long-term prognosis of esophageal cancer patients.	('esophageal cancer', 'Disease', (220, 237))	('PBT', 'Var', (52, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (220, 237))	('CR', 'Chemical', '-', (185, 187))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('improve', 'PosReg', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('CR rate', 'CPA', (185, 192))	('patients', 'Species', '9606', (238, 246))	('CR', 'Chemical', '-', (62, 64))	('tumor', 'Disease', (109, 114))
702488	26355298	This heterogeneity is hypothesized to originate in a number of physiological factors such as tumor metabolism, necrosis, cellularity, and angiogenesis, amongst others, and variability in these factors has been associated with more aggressive cancer behaviour, poorer response to treatment and worse prognosis.	('aggressive cancer', 'Disease', 'MESH:D009369', (231, 248))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('originate', 'Reg', (38, 47))	('variability', 'Var', (172, 183))	('associated', 'Reg', (210, 220))	('more', 'PosReg', (226, 230))	('tumor', 'Disease', (93, 98))	('necrosis', 'Disease', (111, 119))	('aggressive cancer', 'Disease', (231, 248))	('necrosis', 'Disease', 'MESH:D009336', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('angiogenesis', 'CPA', (138, 150))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
702547	26355298	In terms of average accuracy, the 3S-CNN algorithm outperforms all other models, and its performance is followed by a GB algorithm trained on hand-crafted features.	('outperforms', 'PosReg', (51, 62))	('GB', 'Chemical', '-', (118, 120))	('3S-CNN', 'Var', (34, 40))
702559	26355298	This result is consistent with previously reported evidence that high coarseness values are associated with a greater risk of local tumor progression in non-small lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('non-small lung cancer', 'Disease', 'MESH:D002289', (153, 174))	('tumor', 'Disease', (132, 137))	('non-small lung cancer', 'Disease', (153, 174))	('high coarseness values', 'Var', (65, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('small lung', 'Phenotype', 'HP:0002089', (157, 167))
702576	23207070	Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas Esophageal squamous cell carcinoma (ESCC) shows a 5-year survival rate below 10%, demonstrating the urgency in improving its treatment.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (71, 95))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (96, 130))	('Alterations', 'Var', (0, 11))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('Esophageal squamous cell carcinoma', 'Disease', (96, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('epidermal growth factor receptors 1 and 2', 'Gene', '2064', (15, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('esophageal squamous cell carcinomas', 'Disease', (60, 95))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (60, 95))	('men', 'Species', '9606', (226, 229))
702577	23207070	Alterations in epidermal growth factor receptors are closely related to malignancy transformation in a number of tumors and recent successful targeted therapies have been directed to these molecules.	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('Alterations', 'Var', (0, 11))	('malignancy transformation', 'Disease', (72, 97))	('related', 'Reg', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('epidermal growth factor receptors', 'Protein', (15, 48))	('malignancy transformation', 'Disease', 'MESH:D020518', (72, 97))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
702578	23207070	Therefore, in this study, we analyzed the expression of EGFR and HER2 and evaluated EGFR mutation profile as well as the presence of mutations in hotspots of KRAS and BRAF in ESCC patients.	('HER2', 'Gene', '2064', (65, 69))	('KRAS', 'Gene', '3845', (158, 162))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('EGFR', 'Gene', '1956', (56, 60))	('patients', 'Species', '9606', (180, 188))	('EGFR', 'Gene', '1956', (84, 88))	('ESCC', 'Disease', (175, 179))	('analyzed', 'Reg', (29, 37))	('EGFR', 'Gene', (56, 60))	('mutations', 'Var', (133, 142))	('EGFR', 'Gene', (84, 88))	('KRAS', 'Gene', (158, 162))	('HER2', 'Gene', (65, 69))
702585	23207070	Mutation analysis for EGFR (exons 18-21), KRAS (codons 12 and 13) and BRAF (V600E) showed no mutations in any of the hotspots of these genes in almost 100 patients analyzed.	('KRAS', 'Gene', (42, 46))	('V600E', 'Mutation', 'rs113488022', (76, 81))	('KRAS', 'Gene', '3845', (42, 46))	('V600E', 'Var', (76, 81))	('EGFR', 'Gene', '1956', (22, 26))	('patients', 'Species', '9606', (155, 163))	('BRAF', 'Gene', '673', (70, 74))	('EGFR', 'Gene', (22, 26))	('BRAF', 'Gene', (70, 74))
702588	23207070	The absence of mutations of EGFR, KRAS and BRAF as well as the overexpression of EGFR and HER2 in less than 10% of the patients suggest that this signaling pathway is altered in only a small proportion of patients with ESCC.	('KRAS', 'Gene', '3845', (34, 38))	('HER2', 'Gene', (90, 94))	('patients', 'Species', '9606', (205, 213))	('EGFR', 'Gene', '1956', (28, 32))	('BRAF', 'Gene', '673', (43, 47))	('HER2', 'Gene', '2064', (90, 94))	('mutations', 'Var', (15, 24))	('EGFR', 'Gene', (28, 32))	('patients', 'Species', '9606', (119, 127))	('BRAF', 'Gene', (43, 47))	('ESCC', 'Disease', (219, 223))	('altered', 'Reg', (167, 174))	('KRAS', 'Gene', (34, 38))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
702599	23207070	The most common EGFR alterations found in tumors are mRNA and protein overexpression, often associated with gene amplification, followed by mutations in specific hotspots located in the region that encodes the tyrosine-kinase domain of the receptor .	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('EGFR', 'Gene', (16, 20))	('EGFR', 'Gene', '1956', (16, 20))	('mutations', 'Var', (140, 149))	('overexpression', 'PosReg', (70, 84))	('alterations', 'Var', (21, 32))
702601	23207070	Complementary, EGFR mutations were firstly reported in lung cancer patients who had greater response to treatment with EGFR tyrosine kinase inhibitors.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('patients', 'Species', '9606', (67, 75))	('lung cancer', 'Disease', (55, 66))	('EGFR', 'Gene', (119, 123))	('EGFR', 'Gene', (15, 19))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', '1956', (15, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('men', 'Species', '9606', (109, 112))	('reported', 'Reg', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (20, 29))	('men', 'Species', '9606', (6, 9))
702602	23207070	These mutations are generally found in the exons 18-21 of the gene and are more prevalent in Asian non-smoker women with lung adenocarcinoma .	('lung adenocarcinoma', 'Disease', (121, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('prevalent', 'Reg', (80, 89))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (121, 140))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (121, 140))	('mutations', 'Var', (6, 15))	('women', 'Species', '9606', (110, 115))
702603	23207070	The role of HER2 in tumorigenesis is a consequence of abnormally increased protein expression, as a result of gene amplification.	('increased', 'PosReg', (65, 74))	('HER2', 'Gene', (12, 16))	('gene amplification', 'Var', (110, 128))	('HER2', 'Gene', '2064', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('protein expression', 'MPA', (75, 93))
702605	23207070	In addition to the alterations in HER receptors, mutations in genes involved in the signaling pathways activated by these receptors are also correlated with the carcinogenesis process and failure of therapeutic response to HER inhibitors .	('carcinogenesis', 'Disease', (161, 175))	('correlated', 'Reg', (141, 151))	('carcinogenesis', 'Disease', 'MESH:D063646', (161, 175))	('mutations', 'Var', (49, 58))
702606	23207070	For instance, colorectal cancer patients who present mutations in KRAS or BRAF do not respond to panitumumab, a monoclonal antibody against EGFR, recently approved by FDA as a monotherapy against metastatic colorectal carcinoma .	('panitumumab', 'Chemical', 'MESH:D000077544', (97, 108))	('patients', 'Species', '9606', (32, 40))	('colorectal carcinoma', 'Disease', (207, 227))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('EGFR', 'Gene', (140, 144))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('KRAS', 'Gene', '3845', (66, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('mutations', 'Var', (53, 62))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (207, 227))	('colorectal cancer', 'Disease', (14, 31))	('not', 'NegReg', (82, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (14, 31))	('EGFR', 'Gene', '1956', (140, 144))	('KRAS', 'Gene', (66, 70))
702607	23207070	Since EGFR and HER2 alterations may predict a successful response to HER target specific therapy, and ESCC has a very poor prognosis with currently available treatments, it is essential to analyze possible alterations of these receptors in ESCC, to evaluate the potential of use of anti-HER therapy to treat ESCC patients.	('alterations', 'Var', (20, 31))	('EGFR', 'Gene', (6, 10))	('men', 'Species', '9606', (163, 166))	('ESCC', 'Disease', (308, 312))	('HER2', 'Gene', (15, 19))	('HER2', 'Gene', '2064', (15, 19))	('patients', 'Species', '9606', (313, 321))	('EGFR', 'Gene', '1956', (6, 10))
702628	23207070	For antigen retrieval, sections were incubated in a pressure cooker while submerged in a citrate buffer solution, pH 6.0, for 3 min at 121 C. Sections were incubated with the primary antibody against EGFR (Code 4267 - Cell Signaling ; diluted 1:300 in diluent solution)  and HER2 (Code-A048529 1 -  Dako; diluted 1:4000 in diluent solution)  overnight at 4 C. Sections were then washed and covered with biotinylated secondary antibody for 30 min at room temperature followed by incubation in streptavidin-peroxidase solution for 30 min.	('EGFR', 'Gene', '1956', (200, 204))	('EGFR', 'Gene', (200, 204))	('citrate', 'Chemical', 'MESH:D019343', (89, 96))	('Code-A048529', 'Var', (281, 293))	('HER2', 'Gene', (275, 279))	('HER2', 'Gene', '2064', (275, 279))
702645	23207070	Initially we analyzed potential alterations in exons 18 to 21 of EGFR, and found no mutations among the 135 samples studied.	('alterations', 'Var', (32, 43))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))
702648	23207070	Due to the high frequency of the G2607A polymorphism in ESCC patients, we decided to investigate whether this variant confers a risk for esophageal cancer development in a case-control study.	('ESCC', 'Disease', (56, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('G2607A', 'Var', (33, 39))	('men', 'Species', '9606', (162, 165))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('G2607A', 'Mutation', 'rs1023186733', (33, 39))	('esophageal cancer', 'Disease', (137, 154))
702650	23207070	A total of 91 samples were investigated for the presence of potential mutations in KRAS (codons 12 and 13) and BRAF (V600E), with none of them being positive.	('KRAS', 'Gene', (83, 87))	('V600E', 'Var', (117, 122))	('KRAS', 'Gene', '3845', (83, 87))	('BRAF', 'Gene', '673', (111, 115))	('V600E', 'Mutation', 'rs113488022', (117, 122))	('BRAF', 'Gene', (111, 115))
702671	23207070	The present study revealed that ESCC of Brazilian patients, who largelly present typical western characteristics, do not present mutations in hot spots of EGFR (exons 18-21), K-RAS (codons 12 and 13) and BRAF (V600E), and only a minor proportion (4%) present overexpression of EGFR or HER2.	('overexpression', 'PosReg', (259, 273))	('HER2', 'Gene', '2064', (285, 289))	('K-RAS', 'Gene', (175, 180))	('BRAF', 'Gene', (204, 208))	('patients', 'Species', '9606', (50, 58))	('K-RAS', 'Gene', '3845', (175, 180))	('EGFR', 'Gene', '1956', (155, 159))	('V600E', 'Var', (210, 215))	('EGFR', 'Gene', (155, 159))	('EGFR', 'Gene', '1956', (277, 281))	('EGFR', 'Gene', (277, 281))	('V600E', 'Mutation', 'rs113488022', (210, 215))	('HER2', 'Gene', (285, 289))	('BRAF', 'Gene', '673', (204, 208))
702672	23207070	These results indicate that common alterations in EGFR and HER2 receptors and in the Ras-Raf-MAPK signalling pathway, observed in many other epithelial tumors, are rare in ESCC from Brazilian patients.	('epithelial tumors', 'Disease', 'MESH:D002277', (141, 158))	('alterations', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Raf', 'Gene', (89, 92))	('patients', 'Species', '9606', (192, 200))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('EGFR', 'Gene', '1956', (50, 54))	('HER2', 'Gene', (59, 63))	('ESCC', 'Disease', (172, 176))	('EGFR', 'Gene', (50, 54))	('epithelial tumors', 'Disease', (141, 158))	('HER2', 'Gene', '2064', (59, 63))	('Raf', 'Gene', '22882', (89, 92))
702673	23207070	EGFR alterations in cancer can be divided mostly in two categories: mutations in exons 18-21, which encode the tyrosine kinase portion of the receptor, and gene and protein overexpression.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('overexpression', 'PosReg', (173, 187))	('EGFR', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('EGFR', 'Gene', '1956', (0, 4))	('mutations in exons', 'Var', (68, 86))
702674	23207070	EGFR mutations are mostly observed in lung tumors, and curiously they are more prevalent in Asian women diagnosed with adenocarcinoma who never smoked .	('lung tumors', 'Disease', 'MESH:D008175', (38, 49))	('adenocarcinoma', 'Disease', (119, 133))	('EGFR', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('women', 'Species', '9606', (98, 103))	('lung tumors', 'Disease', (38, 49))	('mutations', 'Var', (5, 14))	('adenocarcinoma', 'Disease', 'MESH:D000230', (119, 133))	('observed', 'Reg', (26, 34))	('lung tumors', 'Phenotype', 'HP:0100526', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('EGFR', 'Gene', '1956', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('prevalent', 'Reg', (79, 88))
702675	23207070	The most frequent EGFR mutations are deletions in exon 19 and a point mutation in codon 858 of exon 21, known as L858R (T2573G; ID: rs121434568) .	('T2573G;', 'Var', (120, 127))	('EGFR', 'Gene', '1956', (18, 22))	('L858R', 'Mutation', 'rs121434568', (113, 118))	('EGFR', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('rs121434568', 'Mutation', 'rs121434568', (132, 143))	('deletions in', 'Var', (37, 49))	('T2573G', 'Mutation', 'rs121434568', (120, 126))
702676	23207070	Patients who carry these mutations in EGFR tend to have a better response to gefitinib, an EGFR-TKI, whereas patients with the wild-type genotype show a better response to conventional chemotherapy .	('EGFR', 'Gene', '1956', (38, 42))	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', (91, 95))	('patients', 'Species', '9606', (109, 117))	('better', 'PosReg', (58, 64))	('EGFR', 'Gene', (38, 42))	('Patients', 'Species', '9606', (0, 8))	('gefitinib', 'Chemical', 'MESH:D000077156', (77, 86))	('response to gefitinib', 'MPA', (65, 86))	('EGFR', 'Gene', '1956', (91, 95))
702677	23207070	This could be explained by the fact that the mutated receptor possess a greater affinity to the drug in comparison with ATP, and therefore cannot initiate the phosphorylation cascade downstream through the signaling pathways that lead to proliferation and cell survival.	('cell survival', 'CPA', (256, 269))	('affinity', 'Interaction', (80, 88))	('greater', 'PosReg', (72, 79))	('not', 'NegReg', (142, 145))	('initiate', 'Reg', (146, 154))	('ATP', 'Chemical', 'MESH:D000255', (120, 123))	('proliferation', 'CPA', (238, 251))	('mutated', 'Var', (45, 52))
702678	23207070	However, about 50% of lung cancer patients treated with EGFR-TKI acquire a secondary mutation that confers drug resistance, the T790M (C2369G; ID: rs121434569), located in exon 21 of the gene, which reduces the affinity of the ATP-binding site for the drug .	('lung cancer', 'Disease', (22, 33))	('T790M (C2369G', 'Var', (128, 141))	('confers', 'Reg', (99, 106))	('T790M', 'Mutation', 'rs121434569', (128, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('reduces', 'NegReg', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('rs121434569', 'Mutation', 'rs121434569', (147, 158))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('C2369G', 'Mutation', 'c.2369C>G', (135, 141))	('EGFR', 'Gene', '1956', (56, 60))	('drug resistance', 'Phenotype', 'HP:0020174', (107, 122))	('EGFR', 'Gene', (56, 60))	('patients', 'Species', '9606', (34, 42))	('affinity of', 'MPA', (211, 222))	('ATP', 'Chemical', 'MESH:D000255', (227, 230))	('C2369G;', 'Var', (135, 142))	('drug resistance', 'MPA', (107, 122))
702679	23207070	In addition to lung cancer, other tumors present low frequencies of EGFR mutations, like head and neck cancers, with no more than 7% of the patients carrying these alterations .	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('EGFR', 'Gene', (68, 72))	('neck cancers', 'Disease', 'MESH:D006258', (98, 110))	('head and neck cancers', 'Phenotype', 'HP:0012288', (89, 110))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('EGFR', 'Gene', '1956', (68, 72))	('patients', 'Species', '9606', (140, 148))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('neck cancers', 'Disease', (98, 110))	('lung cancer', 'Disease', (15, 26))	('mutations', 'Var', (73, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
702681	23207070	So far, few studies were published that analyzed mutations in EGFR in ESCCs .	('ESCCs', 'Disease', (70, 75))	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('mutations', 'Var', (49, 58))
702690	23207070	However, several reports showed that mutations in genes involved in the Ras-Raf-MAPK pathway, like KRAS and BRAF, are important biomarkers for colorectal tumor patient response to anti-EGFR mAbs.	('EGFR', 'Gene', (185, 189))	('colorectal tumor', 'Disease', 'MESH:D015179', (143, 159))	('EGFR', 'Gene', '1956', (185, 189))	('colorectal tumor', 'Disease', (143, 159))	('mutations', 'Var', (37, 46))	('Raf', 'Gene', '22882', (76, 79))	('BRAF', 'Gene', '673', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('KRAS', 'Gene', (99, 103))	('patient', 'Species', '9606', (160, 167))	('KRAS', 'Gene', '3845', (99, 103))	('BRAF', 'Gene', (108, 112))	('Raf', 'Gene', (76, 79))
702691	23207070	These mutations turn these proteins constitutively activated, resulting in a receptor-independent activation of the pathway, what culminates in the resistance to treatment with anti-EGFR mAbs .	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('activation', 'PosReg', (98, 108))	('mutations', 'Var', (6, 15))	('men', 'Species', '9606', (167, 170))
702692	23207070	The most frequent mutations observed in colorectal cancer patients are found at codons 12 and 13 of KRAS, in approximately 35% of the patients, and the V600E mutation of BRAF, found in about 15% of the cases .	('KRAS', 'Gene', (100, 104))	('BRAF', 'Gene', (170, 174))	('KRAS', 'Gene', '3845', (100, 104))	('V600E', 'Var', (152, 157))	('colorectal cancer', 'Disease', (40, 57))	('patients', 'Species', '9606', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))	('patients', 'Species', '9606', (58, 66))	('V600E', 'Mutation', 'rs113488022', (152, 157))	('BRAF', 'Gene', '673', (170, 174))
702693	23207070	Head and neck tumors present mutations in KRAS and BRAF, but in very low frequencies, with 6% of the patients carrying a mutation in KRAS and 3% in BRAF.	('KRAS', 'Gene', (42, 46))	('patients', 'Species', '9606', (101, 109))	('neck tumors', 'Disease', 'MESH:D006258', (9, 20))	('KRAS', 'Gene', '3845', (42, 46))	('Head and neck tumors', 'Phenotype', 'HP:0012288', (0, 20))	('mutations', 'Var', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('KRAS', 'Gene', (133, 137))	('mutation', 'Var', (121, 129))	('neck tumors', 'Disease', (9, 20))	('BRAF', 'Gene', '673', (51, 55))	('KRAS', 'Gene', '3845', (133, 137))	('BRAF', 'Gene', '673', (148, 152))	('BRAF', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('BRAF', 'Gene', (148, 152))
702699	23207070	This data is in accordance with the study developed by Hollstein and colleagues, who previously described the absence of mutations in KRAS in ESCC of patients from Normandy (France) and Uruguay , while no study had investigated BRAF mutations in ESCC so far.	('KRAS', 'Gene', '3845', (134, 138))	('BRAF', 'Gene', '673', (228, 232))	('mutations', 'Var', (121, 130))	('BRAF', 'Gene', (228, 232))	('patients', 'Species', '9606', (150, 158))	('ESCC', 'Disease', (142, 146))	('KRAS', 'Gene', (134, 138))
702700	23207070	Therefore, our results both on EGFR hot-spot mutations and expression suggest that the EGFR-Ras-Raf-MAPK pathway is not associated with esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (136, 161))	('associated', 'Reg', (120, 130))	('mutations', 'Var', (45, 54))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', '1956', (31, 35))	('esophageal carcinogenesis', 'Disease', (136, 161))	('Raf', 'Gene', '22882', (96, 99))	('EGFR', 'Gene', (31, 35))	('EGFR', 'Gene', (87, 91))	('Raf', 'Gene', (96, 99))
702701	23207070	HER2 overexpression, as a consequence of gene amplification, was initially seen to be present in around 25% of breast cancer patients, and more recently in a similar percentage of stomach and esophagogastric junction tumors .	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('gene amplification', 'Var', (41, 59))	('junction tumors', 'Disease', 'MESH:D009369', (208, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('overexpression', 'PosReg', (5, 19))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophagogastric junction tumors', 'Phenotype', 'HP:0100751', (192, 223))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('junction tumors', 'Disease', (208, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('HER2', 'Gene', (0, 4))	('breast cancer', 'Disease', (111, 124))	('HER2', 'Gene', '2064', (0, 4))	('patients', 'Species', '9606', (125, 133))
702703	23207070	Breast cancer patients, who present HER2 overexpression and gene amplification, and are treated with trastuzumab present a response rate of 62%, that is substantially higher when compared with 32% achieved with conventional chemotherapy .	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('higher', 'PosReg', (167, 173))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('HER2', 'Gene', (36, 40))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('HER2', 'Gene', '2064', (36, 40))	('response', 'MPA', (123, 131))	('trastuzumab', 'Chemical', 'MESH:D000068878', (101, 112))	('gene amplification', 'Var', (60, 78))	('overexpression', 'PosReg', (41, 55))	('Breast cancer', 'Disease', (0, 13))	('patients', 'Species', '9606', (14, 22))
702705	23207070	Some studies focused on ESCC already described a 3-fold higher frequency of patients with score 2+ for HER2 in comparison with those with score 3+.	('patients', 'Species', '9606', (76, 84))	('HER2', 'Gene', (103, 107))	('score 2+', 'Var', (90, 98))	('HER2', 'Gene', '2064', (103, 107))
702712	23207070	Furthermore, the absence of any EGFR, KRAS and BRAF mutations as well as a frequency of HER overexpression of less than 10% may also suggest that these modifications could be lethal to esophageal cells during transformation.	('mutations', 'Var', (52, 61))	('KRAS', 'Gene', '3845', (38, 42))	('BRAF', 'Gene', (47, 51))	('absence', 'NegReg', (17, 24))	('EGFR', 'Gene', '1956', (32, 36))	('BRAF', 'Gene', '673', (47, 51))	('EGFR', 'Gene', (32, 36))	('KRAS', 'Gene', (38, 42))
702819	33468224	Accumulating evidences show that MetS was related with significant increased colorectal, pancreatic, hepatocellular, breast, prostate cancers risk.	('colorectal', 'Disease', 'MESH:D015179', (77, 87))	('prostate cancers', 'Disease', (125, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('breast', 'Disease', (117, 123))	('colorectal', 'Disease', (77, 87))	('prostate cancers', 'Disease', 'MESH:D011471', (125, 141))	('increased', 'PosReg', (67, 76))	('prostate cancers', 'Phenotype', 'HP:0012125', (125, 141))	('pancreatic', 'Disease', (89, 99))	('hepatocellular', 'Disease', (101, 115))	('MetS', 'Var', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
702855	33468224	The long-term hypoxia environment of the body cells is easy to induce the mutation of normal cells, which will promote the transformation of normal cells into malignant tumor cells.On the other hand, hyperglycemia will also promote the production of a large number of free radicals, further increase the risk of mutation of normal cells.	('malignant tumor', 'Disease', (159, 174))	('hyperglycemia', 'Disease', (200, 213))	('mutation', 'Var', (312, 320))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('hyperglycemia', 'Phenotype', 'HP:0003074', (200, 213))	('ran', 'Gene', (124, 127))	('malignant tumor', 'Disease', 'MESH:D009369', (159, 174))	('ran', 'Gene', '5901', (124, 127))	('increase', 'PosReg', (291, 299))	('promote', 'PosReg', (224, 231))	('hypoxia', 'Disease', (14, 21))	('hypoxia', 'Disease', 'MESH:D000860', (14, 21))	('hyperglycemia', 'Disease', 'MESH:D006943', (200, 213))	('production of', 'MPA', (236, 249))
702878	33376353	The dysregulation of indispensable mRNAs in ceRNA networks also disrupts miRNA-mediated lncRNA/mRNA ceRNA interactions, thereby promoting cancer tumorigenesis and progression.	('miRNA-mediated lncRNA/mRNA', 'MPA', (73, 99))	('disrupts', 'NegReg', (64, 72))	('cancer', 'Disease', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('interactions', 'Interaction', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', (145, 150))	('promoting', 'PosReg', (128, 137))	('progression', 'CPA', (163, 174))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
702954	32707444	For example, our group have previously shown that a methylation panel consisting of four genes (TFPI2, TWIST1, ZNF345, ZNF569) applied to Cytosponge  samples can diagnose Barrett's epithelium (intestinal metaplasia with goblet cells) with an area under the ROC curve (AUC) ranging from 78 7% to 87 7%.	('ZNF569', 'Gene', '148266', (119, 125))	('TWIST1', 'Gene', (103, 109))	('ZNF569', 'Gene', (119, 125))	('TWIST1', 'Gene', '7291', (103, 109))	('diagnose', 'Reg', (162, 170))	("Barrett's epithelium", 'Disease', (171, 191))	('TFPI2', 'Gene', (96, 101))	('methylation', 'Var', (52, 63))	('TFPI2', 'Gene', '7980', (96, 101))	('ZNF345', 'Gene', '25850', (111, 117))	('ZNF345', 'Gene', (111, 117))
702960	32707444	BE is defined as an endoscopically visible segment of columnar epithelium in the distal esophagus; the presence of intestinal metaplasia (IM) in biopsies corroborates the diagnosis and is believed to be related to the associated cancer risk.	('presence', 'Var', (103, 111))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('intestinal metaplasia', 'Disease', (115, 136))	('related', 'Reg', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('BE', 'Phenotype', 'HP:0100580', (0, 2))
702968	32707444	It is increasingly recognized that gene expression silencing by promoter methylation plays an important role in cancer development, including BE progression to EAC.	('EAC', 'Phenotype', 'HP:0011459', (160, 163))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('BE', 'Phenotype', 'HP:0100580', (142, 144))	('EAC', 'Disease', (160, 163))	('promoter methylation', 'Var', (64, 84))	('gene expression', 'MPA', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('silencing', 'NegReg', (51, 60))
703035	32707444	WJ was funded by a Cancer Research UK multidisciplinary award (C47594/A21202).	('Cancer', 'Disease', 'MESH:D009369', (19, 25))	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Cancer', 'Disease', (19, 25))	('C47594/A21202', 'Var', (63, 76))
703092	32391278	Moreover, in the surgery plus radiotherapy/chemotherapy group, the high expression of BAR has a poor prognosis.	('BAR', 'Gene', (86, 89))	('high', 'Var', (67, 71))	('BAR', 'Gene', '9971', (86, 89))
703135	32391278	In addition, there is an interaction between ApoA-1 and the body's inflammatory response, which reduces the rate of liver synthesis and secretion of ApoA-1, and serum low ApoA-1 concentration can indirectly lead to increased cytokine release and strong inflammatory response against tumor cells.	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('ApoA-1', 'Gene', '335', (171, 177))	('secretion', 'MPA', (136, 145))	('ApoA-1', 'Gene', '335', (45, 51))	('cytokine release', 'MPA', (225, 241))	('reduces', 'NegReg', (96, 103))	('serum low', 'Var', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('ApoA-1', 'Gene', (149, 155))	('ApoA-1', 'Gene', (171, 177))	('low ApoA-1 concentration', 'Phenotype', 'HP:0031799', (167, 191))	('ApoA-1', 'Gene', (45, 51))	('liver synthesis', 'MPA', (116, 131))	('lead to', 'Reg', (207, 214))	('increased cytokine', 'Phenotype', 'HP:0031407', (215, 233))	('interaction', 'Interaction', (25, 36))	('rate', 'MPA', (108, 112))	('increased', 'PosReg', (215, 224))	('tumor', 'Disease', (283, 288))	('ApoA-1', 'Gene', '335', (149, 155))
703166	29240008	However, radical LN dissection increases postoperative morbidity and mortality, and is particularly unsuitable for elderly patients and those with cardiopulmonary diseases.	('radical', 'Var', (9, 16))	('increases', 'PosReg', (31, 40))	('patients', 'Species', '9606', (123, 131))	('mortality', 'Disease', 'MESH:D003643', (69, 78))	('postoperative morbidity', 'CPA', (41, 64))	('cardiopulmonary diseases', 'Disease', 'MESH:D006323', (147, 171))	('cardiopulmonary diseases', 'Disease', (147, 171))	('mortality', 'Disease', (69, 78))
703254	28767597	For heart in patients treated with < 50 Gy, the irradiated volumes showed no difference between 2 radiotherapy techniques (mean volume difference: -1.06 [95%CI: -8.47 to 6.35] for V30, P = .78; 4.18 [95%CI: -1.77 to 10.13] for V40, P = .17).	('V40', 'Var', (227, 230))	('patients', 'Species', '9606', (13, 21))	('V30', 'Var', (180, 183))
703263	28767597	For OS, 3 studies were included and the meta-analysis showed IMRT resulted in a better 3-year OS than 3D-CRT did.	('OS', 'Chemical', '-', (94, 96))	('IMRT', 'Var', (61, 65))	('3-year OS', 'CPA', (87, 96))	('OS', 'Chemical', '-', (4, 6))
703306	28230852	A single-channel upper gastrointestinal endoscope (GIF-Q260J; Olympus, Tokyo, Japan) and a standard electrosurgical generator (ICC 200 or VIO300D; ERBE Elektromedizin GmbH, Tubingen, Germany) were used.	('upper gastrointestinal endoscope', 'Disease', (17, 49))	('Q260J', 'SUBSTITUTION', 'None', (55, 60))	('Q260J', 'Var', (55, 60))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (17, 49))
703492	25621687	COX-2 expression, one of the most important inflammation-related factors, could lead to cellular proliferation, angiogenesis, and resistance to apoptosis through the intermediary of prostaglandin E2.	('lead to', 'Reg', (80, 87))	('cellular proliferation', 'CPA', (88, 110))	('angiogenesis', 'CPA', (112, 124))	('inflammation', 'Disease', 'MESH:D007249', (44, 56))	('resistance to apoptosis', 'CPA', (130, 153))	('COX-2', 'Gene', '4513', (0, 5))	('inflammation', 'Disease', (44, 56))	('COX-2', 'Gene', (0, 5))	('expression', 'Var', (6, 16))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (182, 198))
703496	25621687	CDX2 is a highly sensitive marker of intestinal metaplasia; thus, these data indicated that type II CP is significantly associated with dysplasia and intestinal metaplasia in BE as compared with type I (Table 3).	('associated', 'Reg', (120, 130))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (37, 58))	('BE', 'Phenotype', 'HP:0100580', (175, 177))	('type II CP', 'Var', (92, 102))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (150, 171))	('CDX2', 'Gene', (0, 4))	('dysplasia and intestinal metaplasia', 'Disease', 'MESH:D008679', (136, 171))	('intestinal metaplasia', 'Disease', (37, 58))	('intestinal metaplasia', 'Disease', (150, 171))	('CDX2', 'Gene', '1045', (0, 4))
703521	25621687	Multivariate analysis showed that the presence of type II CP was the only statistically significant predictor for the presence of dysplasia, high CD34 expression, and PCNA index.	('PCNA', 'Gene', (167, 171))	('PCNA', 'Gene', '5111', (167, 171))	('dysplasia', 'Disease', (130, 139))	('CD34', 'Gene', '947', (146, 150))	('dysplasia', 'Disease', 'MESH:D004476', (130, 139))	('high', 'Var', (141, 145))	('CD34', 'Gene', (146, 150))
703600	33591377	Among lymphoma patients, identical results were found on MHD data and long-term AMI incidence as in the classic Darby-study; in MHD > 20 Gy cases, 2.5 times higher AMI risk was detected.	('patients', 'Species', '9606', (15, 23))	('MHD', 'Disease', 'None', (128, 131))	('lymphoma', 'Disease', (6, 14))	('> 20 Gy', 'Var', (132, 139))	('MHD', 'Disease', (128, 131))	('lymphoma', 'Disease', 'MESH:D008223', (6, 14))	('lymphoma', 'Phenotype', 'HP:0002665', (6, 14))	('MHD', 'Disease', 'None', (57, 60))	('MHD', 'Disease', (57, 60))
703649	33591377	Accumulated ROS/RNS during and shortly after irradiation may cause macromolecular damage including, lipid peroxidation, protein oxidation/nitration, inactivation of enzymes, DNA damage, interaction with both DNA repair enzymes (e.g., poly-ADP-ribose polymerase 1 [PARP1], p53) and transcription factors (e.g., nuclear factor-kappaB [NF-kappaB]) (Fig.	('macromolecular damage', 'MPA', (67, 88))	('p53', 'Gene', '7157', (272, 275))	('lipid', 'Chemical', 'MESH:D008055', (100, 105))	('nuclear factor-kappaB', 'Gene', (310, 331))	('protein oxidation/nitration', 'MPA', (120, 147))	('poly-ADP-ribose polymerase 1', 'Gene', '142', (234, 262))	('rat', 'Species', '10116', (141, 144))	('PARP1', 'Gene', (264, 269))	('lipid peroxidation', 'MPA', (100, 118))	('p53', 'Gene', (272, 275))	('NF-kappaB', 'Gene', (333, 342))	('poly-ADP-ribose polymerase 1', 'Gene', (234, 262))	('RNS', 'Chemical', 'MESH:D026361', (16, 19))	('cause', 'Reg', (61, 66))	('enzymes', 'Enzyme', (165, 172))	('NF-kappaB', 'Gene', '4790', (333, 342))	('interaction', 'Interaction', (186, 197))	('DNA damage', 'MPA', (174, 184))	('ROS', 'Chemical', 'MESH:D017382', (12, 15))	('PARP1', 'Gene', '142', (264, 269))	('ROS/RNS', 'Var', (12, 19))	('inactivation', 'MPA', (149, 161))	('nuclear factor-kappaB', 'Gene', '4790', (310, 331))
703652	33591377	The oxidation/nitration of proteins involved in excitation-contraction coupling, contractility, Ca2+-handling, elements of the mitochondrial electron transport chain and Krebs cycle, metabolism, and extracellular matrix might result in acute and chronic deleterious events (Fig.	('oxidation/nitration', 'Var', (4, 23))	('Ca2+', 'Chemical', 'MESH:D000069285', (96, 100))	('result in', 'Reg', (226, 235))	('rat', 'Species', '10116', (17, 20))	('Krebs', 'Chemical', '-', (170, 175))	('proteins', 'Protein', (27, 35))
703655	33591377	In the first few hours and days after RT, activated NF-kappaB may induce the secretion of adhesion molecules including, e.g., E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), and cytokines (e.g., IL-6, IL-8) in the damaged endothelial cells thereby activating leukocyte rolling, arrest, and transmigration.	('IL-6', 'Gene', '3569', (316, 320))	('arrest', 'Disease', 'MESH:D006323', (399, 405))	('induce', 'PosReg', (66, 72))	('platelet endothelial cell adhesion molecule-1', 'Gene', '5175', (238, 283))	('E-selectin', 'Gene', (126, 136))	('VCAM-1', 'Gene', '7412', (229, 235))	('platelet endothelial cell adhesion molecule-1', 'Gene', (238, 283))	('intercellular adhesion molecule-1', 'Gene', (150, 183))	('IL-8', 'Gene', '3576', (322, 326))	('IL-6', 'Gene', (316, 320))	('PECAM-1', 'Gene', '5175', (285, 292))	('activated', 'Var', (42, 51))	('R', 'Chemical', '-', (38, 39))	('ICAM-1', 'Gene', (185, 191))	('adhesion', 'MPA', (90, 98))	('rat', 'Species', '10116', (419, 422))	('secretion', 'MPA', (77, 86))	('P-selectin', 'Gene', '6403', (138, 148))	('vascular cell adhesion molecule-1', 'Gene', '7412', (194, 227))	('E-selectin', 'Gene', '6401', (126, 136))	('activating', 'PosReg', (369, 379))	('arrest', 'Disease', (399, 405))	('VCAM-1', 'Gene', (229, 235))	('NF-kappaB', 'Gene', (52, 61))	('PECAM-1', 'Gene', (285, 292))	('transmigration', 'CPA', (411, 425))	('ICAM-1', 'Gene', '3383', (185, 191))	('vascular cell adhesion molecule-1', 'Gene', (194, 227))	('IL-8', 'Gene', (322, 326))	('leukocyte rolling', 'CPA', (380, 397))	('intercellular adhesion molecule-1', 'Gene', '3383', (150, 183))	('NF-kappaB', 'Gene', '4790', (52, 61))	('P-selectin', 'Gene', (138, 148))
703678	33591377	The translocation of Bax from the cytoplasm to the mitochondrial outer membrane induces mitochondrial membrane permeability transition (MPT), leading to mitochondrial swelling, depolarization of the membrane, uncoupled electron transport, and oxidative phosphorylation (Fig.	('mitochondrial membrane permeability transition', 'MPA', (88, 134))	('swelling', 'Disease', (167, 175))	('translocation', 'Var', (4, 17))	('swelling', 'Disease', 'MESH:D004487', (167, 175))	('mitochondrial swelling', 'Phenotype', 'HP:0030774', (153, 175))	('leading to', 'Reg', (142, 152))	('mitochondrial', 'MPA', (153, 166))	('depolarization of the membrane', 'MPA', (177, 207))	('oxidative phosphorylation', 'MPA', (243, 268))	('uncoupled electron transport', 'MPA', (209, 237))	('MPT', 'Chemical', '-', (136, 139))	('induces', 'Reg', (80, 87))
703697	33591377	It is also well-known that aging, cardiovascular risk factors (e.g., hypertension, diabetes mellitus, hypercholesterolemia, and chronic kidney disease), and concomitant anthracycline therapy are also associated with increased oxidative/nitrosative/nitrative stress and low-grade chronic inflammation (Fig.	('diabetes mellitus', 'Disease', 'MESH:D003920', (83, 100))	('hypercholesterolemia', 'Disease', (102, 122))	('hypertension', 'Phenotype', 'HP:0000822', (69, 81))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (83, 100))	('chronic kidney disease', 'Disease', (128, 150))	('anthracycline', 'Var', (169, 182))	('rat', 'Species', '10116', (251, 254))	('increased', 'PosReg', (216, 225))	('low-grade', 'Disease', (269, 278))	('inflammation', 'Disease', 'MESH:D007249', (287, 299))	('chronic kidney disease', 'Disease', 'MESH:D051436', (128, 150))	('anthracycline', 'Chemical', 'MESH:D018943', (169, 182))	('diabetes mellitus', 'Disease', (83, 100))	('kidney disease', 'Phenotype', 'HP:0000112', (136, 150))	('nitrative stress', 'Phenotype', 'HP:0025464', (248, 264))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (128, 150))	('hypertension', 'Disease', 'MESH:D006973', (69, 81))	('inflammation', 'Disease', (287, 299))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (102, 122))	('hypertension', 'Disease', (69, 81))	('oxidative/nitrosative/nitrative stress', 'MPA', (226, 264))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (102, 122))
703793	33591377	The COX-2 inhibitor celecoxib has been reported to act synergistically with RT in cancer cells since it attenuates tumor growth and expression of cell proliferation markers and induces apoptosis in tumor cells.	('celecoxib', 'Chemical', 'MESH:D000068579', (20, 29))	('tumor', 'Disease', (115, 120))	('cancer', 'Disease', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('rat', 'Species', '10116', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('attenuates tumor', 'Disease', 'MESH:C538265', (104, 120))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('apoptosis', 'CPA', (185, 194))	('R', 'Chemical', '-', (76, 77))	('cell proliferation markers', 'CPA', (146, 172))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('celecoxib', 'Var', (20, 29))	('tumor', 'Disease', (198, 203))	('induces', 'Reg', (177, 184))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('attenuates tumor', 'Disease', (104, 120))	('expression', 'MPA', (132, 142))
703799	33591377	Trimetazidine also has anti-oxidant, anti-apoptotic, and inflammatory effects and may improve endothelial function.	('anti-apoptotic', 'CPA', (37, 51))	('inflammatory effects', 'CPA', (57, 77))	('Trimetazidine', 'Chemical', 'MESH:D014292', (0, 13))	('improve', 'PosReg', (86, 93))	('endothelial function', 'MPA', (94, 114))	('Trimetazidine', 'Var', (0, 13))	('anti-oxidant', 'MPA', (23, 35))
703803	33591377	Similarly, two GHRH agonists, JI-34, and MR-356 showed increased viability and reduced ROS levels 48 h after irradiation in neonatal rat cardiomyocytes (Table 2).	('reduced', 'NegReg', (79, 86))	('JI-34', 'Chemical', '-', (30, 35))	('increased', 'PosReg', (55, 64))	('ROS levels', 'MPA', (87, 97))	('R', 'Chemical', '-', (17, 18))	('rat', 'Species', '10116', (133, 136))	('R', 'Chemical', '-', (42, 43))	('ROS', 'Chemical', 'MESH:D017382', (87, 90))	('MR-356', 'Var', (41, 47))	('R', 'Chemical', '-', (87, 88))
703831	33591377	NRG-1beta is critical for cardiac development and repair, and recombinant forms are currently being assessed in clinical trials as possible therapeutic agents for systolic HF even [NCT03388593, NCT04468529].	('systolic HF', 'Disease', (163, 174))	('1beta', 'Chemical', '-', (4, 9))	('NCT04468529]', 'Var', (194, 206))	('systolic HF', 'Disease', 'MESH:D054143', (163, 174))	('NRG-1', 'Gene', '3084', (0, 5))	('NRG-1', 'Gene', (0, 5))	('[NCT03388593', 'Var', (180, 192))
703840	33591377	Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) The endogenous peptide PACAP38 is a member of the secretin/vasoactive intestinal peptide (VIP) family.	('secretin/vasoactive intestinal peptide', 'Gene', '7432', (114, 152))	('secretin/vasoactive intestinal peptide', 'Gene', (114, 152))	('PACAP38', 'Gene', (55, 62))	('PACAP38', 'Var', (87, 94))	('VIP', 'Gene', '7432', (154, 157))	('VIP', 'Gene', (154, 157))
703841	33591377	PACAP38 was radioprotective in H9c2 cardiomyoblasts via anti-apoptotic effects and the overexpression of the nuclear factor erythroid 2-related factor 2 (NRF2), which is a key factor in the expression of antioxidant enzymes.	('PACAP38', 'Var', (0, 7))	('nuclear factor erythroid 2-related factor 2', 'Gene', '4780', (109, 152))	('NRF2', 'Gene', '4780', (154, 158))	('anti-apoptotic effects', 'CPA', (56, 78))	('overexpression', 'PosReg', (87, 101))	('nuclear factor erythroid 2-related factor 2', 'Gene', (109, 152))	('NRF2', 'Gene', (154, 158))
703845	33591377	However, some anti-inflammatory agents, including, e.g., the IL-1 receptor antagonist anakinra (clinical trials NCT03797001, NCT01175018, and NCT02547766) or the IL-6 receptor antagonist tocilizumab (clinical trial NCT01491074), have been already tested against post-infarction remodeling and HF in phase 2 clinical trials.	('IL-6', 'Gene', (162, 166))	('IL-6', 'Gene', '3569', (162, 166))	('infarction remodeling and HF', 'Disease', 'MESH:D007238', (267, 295))	('tocilizumab', 'Chemical', 'MESH:C502936', (187, 198))	('NCT02547766', 'Var', (142, 153))	('NCT01175018', 'Var', (125, 136))	('IL-1', 'Gene', '3552', (61, 65))	('IL-1', 'Gene', (61, 65))
703848	33591377	The TGF-beta receptor-1 antagonist IPW-5371 administered orally 24 h after the radiation exposure and daily after that for 6 or 20 weeks was reported to mitigate the injury of RT (5 Gy total body irradiation plus 6.5 Gy thoracic irradiation) in C57BLJ mice.	('mice', 'Species', '10090', (252, 256))	('TGF-beta', 'Gene', (4, 12))	('TGF-beta', 'Gene', '7039', (4, 12))	('mitigate', 'NegReg', (153, 161))	('R', 'Chemical', '-', (176, 177))	('IPW-5371', 'Var', (35, 43))
703852	33591377	IPW-5371 is not yet in the clinical phase, but another TGF-beta1 receptor inhibitor, the orally bioavailable galunisertib (LY2157299), has already been tested in phase II clinical trials in metastatic breast cancer patients in combination with RT (NCT02538471), hepatocellular carcinoma (NCT02178358), and pancreatic cancer (NCT01373164).	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (262, 286))	('NCT01373164', 'Var', (325, 336))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('NCT02538471', 'Var', (248, 259))	('LY2157299', 'Chemical', 'MESH:C557799', (123, 132))	('hepatocellular carcinoma', 'Disease', (262, 286))	('R', 'Chemical', '-', (244, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('galunisertib', 'Chemical', 'MESH:C557799', (109, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (306, 323))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('NCT02178358', 'Var', (288, 299))	('pancreatic cancer', 'Disease', (306, 323))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Disease', (201, 214))	('NCT01373164', 'Chemical', '-', (325, 336))	('patients', 'Species', '9606', (215, 223))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (262, 286))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (306, 323))
703856	33591377	Several drugs, including VEGF delivered by plasmids or adenoviruses to the heart, have already been tested in HF and AMI in clinical trials (NCT03409627, NCT01002430, NCT04125732, respectively).	('VEGF', 'Gene', '7422', (25, 29))	('NCT01002430', 'Var', (154, 165))	('NCT03409627', 'Var', (141, 152))	('VEGF', 'Gene', (25, 29))
703859	33591377	The ncRNAs are classified as i) longer ncRNAs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), ii) and short ncRNAs (19-22 nucleotides) such as microRNAs (miRs) and small interfering RNAs (siRNAs).	('R', 'Chemical', '-', (98, 99))	('R', 'Chemical', '-', (203, 204))	('19-22', 'Var', (137, 142))	('R', 'Chemical', '-', (6, 7))	('R', 'Chemical', '-', (79, 80))	('R', 'Chemical', '-', (41, 42))	('R', 'Chemical', '-', (177, 178))	('miR', 'Gene', '220972', (175, 178))	('R', 'Chemical', '-', (70, 71))	('miR', 'Gene', (175, 178))	('R', 'Chemical', '-', (131, 132))	('R', 'Chemical', '-', (169, 170))	('R', 'Chemical', '-', (108, 109))	('circular', 'MPA', (89, 97))	('R', 'Chemical', '-', (211, 212))
703862	33591377	Hence, dysregulation of miRs in pathological processes, including RIHD, may alter whole gene networks rather than single genes.	('RIHD', 'Disease', 'None', (66, 70))	('RIHD', 'Disease', (66, 70))	('dysregulation', 'Var', (7, 20))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('whole', 'MPA', (82, 87))	('rat', 'Species', '10116', (102, 105))	('alter', 'Reg', (76, 81))
703887	33591377	MS, RG, MGK, and ZZAK were supported by the New National Excellence Program of the Ministry of Human Capacities (UNKP-20-5-SZTE-166, UNKP-20-4-SZTE-150, UNKP-19-4-I-SZTE-89, and UNKP-19-3-SZTE-159, UNKP-19-3-SZTE-160).	('R', 'Chemical', '-', (4, 5))	('Human', 'Species', '9606', (95, 100))	('UNKP-20-5-SZTE-166', 'Var', (113, 131))	('UNKP-19-3-SZTE-159', 'Var', (178, 196))
703892	33298066	The intraoperative bleeding volume of modified reverse-puncture anastomotic technique group was 157.3 +- 107.4 ml, while it was 191.9 +- 123.6 ml in traditional technique group (P = 0.14).	('intraoperative bleeding', 'Disease', (4, 27))	('modified', 'Var', (38, 46))	('intraoperative bleeding', 'Disease', 'MESH:D016063', (4, 27))
703985	32194853	The analysis identified inter- and intratumor DNA methylation (DNAm) heterogeneity, epigenome-wide DNAm alterations together with the functional regulators involved in the hyper- or hypomethylated regions, and their association with clinical features.	('alterations', 'Var', (104, 115))	('association', 'Interaction', (216, 227))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
703988	32194853	The high intratumor DNAm heterogeneity was associated with lymph node metastasis and worse overall survival.	('tumor', 'Disease', (14, 19))	('high', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('associated', 'Reg', (43, 53))	('lymph node metastasis', 'CPA', (59, 80))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
703989	32194853	Interestingly, hypermethylated regions in ESCC were enriched in promoters of numerous transcription factors, and demethylated noncoding regions related to RXR transcription factor binding appeared to contribute to the development of ESCC.	('hypermethylated', 'Var', (15, 30))	('RXR', 'Gene', (155, 158))	('ESCC', 'Disease', (233, 237))	('ESCC', 'Disease', 'MESH:D000077277', (233, 237))	('RXR', 'Gene', '6256', (155, 158))	('ESCC', 'Disease', (42, 46))	('ESCC', 'Disease', 'MESH:D000077277', (42, 46))	('contribute', 'Reg', (200, 210))
703990	32194853	Furthermore, we identified numerous DNAm alterations associated with carcinogenesis and lymph node metastasis of ESCC.	('ESCC', 'Disease', (113, 117))	('ESCC', 'Disease', 'MESH:D000077277', (113, 117))	('associated', 'Reg', (53, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (69, 83))	('alterations', 'Var', (41, 52))	('carcinogenesis', 'Disease', (69, 83))
703992	32194853	Conclusions: This study presents the first population-level resource for dissecting base-resolution DNAm variation in ESCC and provides novel insights into the ESCC pathogenesis and progression, which might facilitate diagnosis and prognosis for this prevalent malignancy.	('ESCC', 'Disease', 'MESH:D000077277', (118, 122))	('ESCC', 'Disease', (118, 122))	('ESCC', 'Disease', (160, 164))	('variation', 'Var', (105, 114))	('ESCC', 'Disease', 'MESH:D000077277', (160, 164))	('malignancy', 'Disease', 'MESH:D009369', (261, 271))	('malignancy', 'Disease', (261, 271))
703996	32194853	Large-scale exome and genome sequencing have identified numerous genomic alterations in ESCC, including somatic mutations in TP53, PIK3CA, NOTCH1, and copy number alterations (CNAs) in pivotal RTK-MAPK-PI3K pathway genes.	('ESCC', 'Disease', (88, 92))	('ESCC', 'Disease', 'MESH:D000077277', (88, 92))	('copy number alterations', 'Var', (151, 174))	('TP53', 'Gene', '7157', (125, 129))	('mutations', 'Var', (112, 121))	('TP53', 'Gene', (125, 129))	('PIK3CA', 'Gene', (131, 137))	('PIK3CA', 'Gene', '5290', (131, 137))	('NOTCH1', 'Gene', '4851', (139, 145))	('NOTCH1', 'Gene', (139, 145))	('RTK-MAPK-PI3K pathway', 'Pathway', (193, 214))
704000	32194853	Genetic mutations in these epigenetic regulators might disrupt the entire epigenetic regulatory network, highlighting the significance of adjusting our focus beyond genetic alterations in ESCC pathogenesis.	('ESCC', 'Disease', (188, 192))	('ESCC', 'Disease', 'MESH:D000077277', (188, 192))	('Genetic mutations', 'Var', (0, 17))	('disrupt', 'NegReg', (55, 62))
704001	32194853	Some specific DNAm alterations have been established as hallmarks in specific cancers and can be used in the diagnosis of specific cancer types.	('cancer', 'Disease', (131, 137))	('DNAm', 'MPA', (14, 18))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('alterations', 'Var', (19, 30))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
704002	32194853	In particular, abnormal DNAm in oncogenes and tumor-suppressor genes are generally involved in all steps of tumorigenesis.	('abnormal DNAm', 'Var', (15, 28))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (46, 51))	('involved', 'Reg', (83, 91))	('tumor', 'Disease', (108, 113))	('oncogenes', 'Gene', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
704003	32194853	Previous studies have investigated DNAm changes in ESCC based on methylation array data from The Cancer Genome Atlas (TCGA) project, identifying several specific DNAm alterations associated with clinical outcomes in ESCC patients.	('Cancer Genome Atlas', 'Disease', (97, 116))	('patients', 'Species', '9606', (221, 229))	('associated', 'Reg', (179, 189))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (97, 116))	('DNAm', 'MPA', (162, 166))	('ESCC', 'Disease', (216, 220))	('ESCC', 'Disease', 'MESH:D000077277', (216, 220))	('ESCC', 'Disease', (51, 55))	('ESCC', 'Disease', 'MESH:D000077277', (51, 55))	('alterations', 'Var', (167, 178))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))
704010	32194853	Furthermore, we identified epigenome-wide DNAm alterations associated with carcinogenesis and LNM of ESCC.	('epigenome-wide', 'Var', (27, 41))	('carcinogenesis', 'Disease', (75, 89))	('LNM', 'Disease', (94, 97))	('ESCC', 'Disease', 'MESH:D000077277', (101, 105))	('associated', 'Reg', (59, 69))	('ESCC', 'Disease', (101, 105))	('carcinogenesis', 'Disease', 'MESH:D063646', (75, 89))
704020	32194853	After local realignment, somatic single nucleotide variants were identified using MuTect (https://software.broadinstitute.org/cancer/cga/mutect), and annotated using VarCards.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('single nucleotide variants', 'Var', (33, 59))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cga', 'Gene', '1113', (133, 136))	('cga', 'Gene', (133, 136))
704031	32194853	Intratumor DNAm heterogeneity was quantified by PDR, entropy, or epipolymorphism.	('entropy', 'MPA', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('PDR', 'MPA', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('epipolymorphism', 'Var', (65, 80))	('tumor', 'Disease', (5, 10))
704040	32194853	Targeted DNA amplicon sequencing showed 83% of them harbored TP53 mutations (Figure 1A).	('mutations', 'Var', (66, 75))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('harbored', 'Reg', (52, 60))
704054	32194853	As mentioned above, the majority of all identified DMRs were hypomethylated in cancer tissues.	('DMRs', 'Var', (51, 55))	('DMRs', 'Chemical', '-', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hypomethylated', 'Var', (61, 75))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
704059	32194853	As expected, DMRs located within these intergenic regions were enriched for H3K27me3 modification sites (Figure 3B), a mark associated with chromosome inactivation.	('DMRs', 'Chemical', '-', (13, 17))	('H3K27me3 modification sites', 'Var', (76, 103))	('DMRs', 'Var', (13, 17))
704070	32194853	We then compared the methylomes of patients with or without LNM, and identified 490 DMRs associated with LNM features of ESCC (Figure 4C) (Supplementary Table S3).	('DMRs', 'Chemical', '-', (84, 88))	('associated', 'Reg', (89, 99))	('ESCC', 'Disease', 'MESH:D000077277', (121, 125))	('DMRs', 'Var', (84, 88))	('patients', 'Species', '9606', (35, 43))	('ESCC', 'Disease', (121, 125))
704080	32194853	Regions with high epiallele entropy and high epipolymorphism also exhibited higher PDR values, indicating agreement between these methods (Figure 5E, F, G) and supporting the conclusion that intratumor DNAm heterogeneity was higher in patients with LNM than in patients without LNM (Figure 5A, B, C).	('patients', 'Species', '9606', (261, 269))	('higher', 'PosReg', (225, 231))	('tumor', 'Disease', (196, 201))	('PDR values', 'MPA', (83, 93))	('high', 'Var', (13, 17))	('high epipolymorphism', 'Var', (40, 60))	('patients', 'Species', '9606', (235, 243))	('LNM', 'Disease', (249, 252))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('higher', 'PosReg', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
704092	32194853	Also, analysis of ESCC by multiple region whole-exome sequencing to analyze intratumor heterogeneity identified several heterogeneous somatic mutations in tumor-suppressor genes such as TP53, ZNF750, and KMT2D .	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('KMT2D', 'Gene', (204, 209))	('mutations', 'Var', (142, 151))	('KMT2D', 'Gene', '8085', (204, 209))	('ZNF750', 'Gene', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('TP53', 'Gene', '7157', (186, 190))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ESCC', 'Disease', (18, 22))	('TP53', 'Gene', (186, 190))	('ZNF750', 'Gene', '79755', (192, 198))	('ESCC', 'Disease', 'MESH:D000077277', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
704094	32194853	However, when mutant-allele tumor heterogeneity (MATH) based on whole-exome sequencing data of ESCC patients in the TCGA database was analyzed, no significant association was observed between intratumor heterogeneity and clinical outcomes, including overall survival, progression-free survival, and disease-specific survival (Supplementary Figure S1).	('tumor', 'Disease', (28, 33))	('mutant-allele', 'Var', (14, 27))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ESCC', 'Disease', (95, 99))	('ESCC', 'Disease', 'MESH:D000077277', (95, 99))	('progression-free survival', 'CPA', (268, 293))	('disease-specific survival', 'CPA', (299, 324))	('overall survival', 'CPA', (250, 266))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (197, 202))
704096	32194853	Herein, using single-base resolution WGBS, we identified population-level DNAm variations in ESCC, which manifested greater inter-individual DNAm heterogeneity than prostate cancer or chronic lymphocytic leukemia, two well-recognized heterogeneous cancer types.	('chronic lymphocytic leukemia', 'Disease', (184, 212))	('cancer', 'Disease', (248, 254))	('variations', 'Var', (79, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('ESCC', 'Disease', 'MESH:D000077277', (93, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (184, 212))	('prostate cancer', 'Disease', (165, 180))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (184, 212))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('ESCC', 'Disease', (93, 97))	('leukemia', 'Phenotype', 'HP:0001909', (204, 212))
704101	32194853	Together, these data suggest the prognostic value of inter- and intratumor epi-heterogeneity for ESCC patients, although a larger cohort is still needed to validate these findings.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('patients', 'Species', '9606', (102, 110))	('ESCC', 'Disease', 'MESH:D000077277', (97, 101))	('epi-heterogeneity', 'Var', (75, 92))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('ESCC', 'Disease', (97, 101))
704102	32194853	Consistent with the systematically reduced DNAm level in cancers, we observed that the majority of identified DMRs were hypomethylated in ESCC tissues.	('DMRs', 'Chemical', '-', (110, 114))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('hypomethylated', 'Var', (120, 134))	('DNAm level', 'MPA', (43, 53))	('ESCC', 'Disease', 'MESH:D000077277', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('ESCC', 'Disease', (138, 142))
704106	32194853	Interestingly, we observed that more than half of the identified hypomethylated regions in ESCC were located in the distal intergenic regions, which were greatly enriched for binding sites of retinoid X receptor (RXR) that co-occupies active enhancers defined by H3K27ac.	('hypomethylated', 'Var', (65, 79))	('ESCC', 'Disease', (91, 95))	('RXR', 'Gene', '6256', (213, 216))	('ESCC', 'Disease', 'MESH:D000077277', (91, 95))	('retinoid X receptor', 'Gene', (192, 211))	('retinoid X receptor', 'Gene', '6256', (192, 211))	('RXR', 'Gene', (213, 216))
704107	32194853	Regional enrichment of these demethylated regions suggests a correlation between DNA hypomethylation and activation of histone markers in ESCC.	('hypomethylation', 'Var', (85, 100))	('histone markers', 'Protein', (119, 134))	('activation', 'PosReg', (105, 115))	('ESCC', 'Disease', 'MESH:D000077277', (138, 142))	('ESCC', 'Disease', (138, 142))
704108	32194853	This notion is consistent with a previous study showing that DNA hypermethylation in super-enhancers of ESCC reduced active histone markers.	('DNA hypermethylation', 'Var', (61, 81))	('ESCC', 'Disease', 'MESH:D000077277', (104, 108))	('ESCC', 'Disease', (104, 108))	('reduced', 'NegReg', (109, 116))	('active histone markers', 'MPA', (117, 139))
704112	32194853	In summary, we presented high-resolution, population-level DNAm variations in ESCC, provided evidence for widespread intratumor DNAm heterogeneity among ESCC patients, and identified numerous DNAm alterations associated with ESCC carcinogenesis and progression.	('associated with', 'Reg', (209, 224))	('variations', 'Var', (64, 74))	('carcinogenesis', 'Disease', 'MESH:D063646', (230, 244))	('ESCC', 'Disease', (225, 229))	('ESCC', 'Disease', (78, 82))	('ESCC', 'Disease', 'MESH:D000077277', (225, 229))	('ESCC', 'Disease', 'MESH:D000077277', (78, 82))	('alterations', 'Var', (197, 208))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('carcinogenesis', 'Disease', (230, 244))	('ESCC', 'Disease', 'MESH:D000077277', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Disease', (122, 127))	('ESCC', 'Disease', (153, 157))
704119	31118568	RNA-seq was performed to determine the gene expression profiles and overexpressed or knocked down SIVA to validate its role in plumbagin's antitumor activity.	('SIVA', 'Gene', (98, 102))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('knocked down', 'Var', (85, 97))	('SIVA', 'Gene', '10572', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('plumbagin', 'Chemical', 'MESH:C014758', (127, 136))
704185	31118568	The half maximal inhibitory concentration (IC50) for HepG2 was higher than that of LM3, as shown in Figure 1A.	('HepG2', 'Var', (53, 58))	('HepG2', 'CellLine', 'CVCL:0027', (53, 58))	('half maximal inhibitory concentration', 'MPA', (4, 41))	('LM3', 'CellLine', 'CVCL:5998', (83, 86))	('higher', 'PosReg', (63, 69))
704202	31118568	Results showed that the downstream molecules of the mTOR pathway, p-S6K, and p-4EBP1 were suppressed in the SIVA-knockdown group (Figure 5B), which further demonstrated that PL inhibited the mTOR pathway by downregulating the expression of SIVA.	('mTOR', 'Gene', (52, 56))	('inhibited', 'NegReg', (177, 186))	('mTOR', 'Gene', '2475', (52, 56))	('SIVA', 'Gene', (240, 244))	('mTOR', 'Gene', (191, 195))	('mTOR', 'Gene', '2475', (191, 195))	('expression', 'MPA', (226, 236))	('downregulating', 'NegReg', (207, 221))	('SIVA', 'Gene', (108, 112))	('p-S6K', 'Var', (66, 71))	('SIVA', 'Gene', '10572', (240, 244))	('SIVA', 'Gene', '10572', (108, 112))	('suppressed', 'NegReg', (90, 100))	('4EBP1', 'Gene', '1978', (79, 84))	('4EBP1', 'Gene', (79, 84))	('p-S6K', 'Mutation', 'p.S6K', (66, 71))
704259	30717285	Stratification analysis revealed that patients with co-expression of IDO1 and PD-L1 were significantly associated with a lower pCR rate and worse recurrence-free survival than those with one or none positive protein.	('pCR rate', 'CPA', (127, 135))	('IDO1', 'Gene', (69, 73))	('PD-L1', 'Gene', (78, 83))	('lower', 'NegReg', (121, 126))	('co-expression', 'Var', (52, 65))	('lower pCR rate', 'Phenotype', 'HP:0005165', (121, 135))	('patients', 'Species', '9606', (38, 46))	('recurrence-free survival', 'CPA', (146, 170))	('IDO1', 'Gene', '3620', (69, 73))	('worse', 'NegReg', (140, 145))
704260	30717285	In conclusion, IDO1 and PD-L1 co-expression could predict poor pathologic response and high risk of recurrence in ESCC after neoadjuvant CRT, indicating a subset of patients who may benefit from CRT combined with immunotherapy.	('IDO1', 'Gene', '3620', (15, 19))	('ESCC', 'Disease', (114, 118))	('co-expression', 'Var', (30, 43))	('IDO1', 'Gene', (15, 19))	('PD-L1', 'Gene', (24, 29))	('patients', 'Species', '9606', (165, 173))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))
704272	30717285	Accordingly, phase 1/2 trials have indicated that the combination of IDO1 and PD-1 inhibitors may improve patient responses to PD-1 inhibitors alone.	('PD-1', 'Gene', (78, 82))	('improve', 'PosReg', (98, 105))	('PD-1', 'Gene', '5133', (78, 82))	('PD-1', 'Gene', (127, 131))	('PD-1', 'Gene', '5133', (127, 131))	('IDO1', 'Gene', (69, 73))	('patient', 'Species', '9606', (106, 113))	('combination', 'Interaction', (54, 65))	('patient responses', 'CPA', (106, 123))	('IDO1', 'Gene', '3620', (69, 73))	('inhibitors', 'Var', (83, 93))
704287	30717285	Indoleamine 2,3-dioxygenase 1 positivity was significantly associated with alcohol history, longer primary tumor, and advanced tumor stage, whereas PD-L1 positivity was significantly correlated with smoking history.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('positivity', 'Var', (30, 40))	('alcohol history', 'Disease', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (127, 132))	('associated', 'Reg', (59, 69))	('Indoleamine 2,3-dioxygenase 1', 'Gene', '3620', (0, 29))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('alcohol', 'Chemical', 'MESH:D000438', (75, 82))
704296	30717285	Patients with IDO1 positivity demonstrated a significantly higher recurrence rate than those with IDO1 negativity (53.6% vs. 17.6%, P < 0.001), and PD-L1 positivity was also correlated with recurrence risk (41.8% vs. 24.3%, P = 0.022).	('positivity', 'Var', (154, 164))	('recurrence', 'MPA', (66, 76))	('IDO1', 'Gene', (14, 18))	('recurrence', 'Disease', (190, 200))	('IDO1', 'Gene', '3620', (98, 102))	('Patients', 'Species', '9606', (0, 8))	('IDO1', 'Gene', '3620', (14, 18))	('higher', 'PosReg', (59, 65))	('PD-L1', 'Gene', (148, 153))	('IDO1', 'Gene', (98, 102))
704297	30717285	Comparing with IDO1 negativity, IDO1 positivity was significantly associated with worse OS and RFS (Figure 4A,B).	('IDO1', 'Gene', '3620', (15, 19))	('IDO1', 'Gene', '3620', (32, 36))	('IDO1', 'Gene', (15, 19))	('IDO1', 'Gene', (32, 36))	('positivity', 'Var', (37, 47))	('OS', 'Chemical', '-', (88, 90))	('worse OS', 'Disease', (82, 90))	('RFS', 'Disease', (95, 98))
704301	30717285	Considering the positive correlation between IDO1 and PD-L1 expression, we divided patients into 3 immune subtypes: IDO (+)/PD-L1 (+), IDO (+)/PD-L1 (-) or IDO (-)/PD-L1 (+), and IDO (-)/PD-L1 (-), with corresponding pCR rates of 21.4%, 34.5%, and 57.3%, respectively (P = 0.001; Figure 5A).	('IDO1', 'Gene', (45, 49))	('IDO (+)/PD-L1 (+', 'Var', (116, 132))	('IDO (+)/PD-L1 (-', 'Var', (135, 151))	('IDO1', 'Gene', '3620', (45, 49))	('patients', 'Species', '9606', (83, 91))
704304	30717285	In this study, we found that the co-expression of IDO1 and PD-L1 could be not only a predictor for poor pathologic response but also a prognostic factor for high risk of recurrence in ESCC after neoadjuvant CRT.	('co-expression', 'Var', (33, 46))	('IDO1', 'Gene', '3620', (50, 54))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('PD-L1', 'Gene', (59, 64))	('IDO1', 'Gene', (50, 54))	('ESCC', 'Disease', (184, 188))
704305	30717285	Previous investigations have consistently demonstrated that baseline PD-L1 positivity and higher density of TILs are related to better chemotherapy response in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('better', 'PosReg', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('PD-L1', 'Protein', (69, 74))	('breast cancer', 'Disease', (160, 173))	('positivity', 'Var', (75, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('chemotherapy response', 'CPA', (135, 156))
704313	30717285	demonstrated that PD-L1 positivity and CD8+ TIL status were associated with significantly worse OS.	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))	('positivity', 'Var', (24, 34))	('PD-L1', 'Gene', (18, 23))	('OS', 'Chemical', '-', (96, 98))
704324	30717285	Patients with IDO (-)/PD-L1 (+) or IDO (+)/PD-L1 (-) are most likely to benefit from a single anti-PD-1/PD-L1 blockade or anti-IDO1 blockade.	('PD-1/PD-L1 blockade', 'Disease', (99, 118))	('IDO1', 'Gene', (127, 131))	('benefit', 'PosReg', (72, 79))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (99, 118))	('IDO1', 'Gene', '3620', (127, 131))	('Patients', 'Species', '9606', (0, 8))	('IDO (-)/PD-L1 (+', 'Var', (14, 30))
704327	30717285	Through a cytotoxic T cell-dependent mechanism, the combination of anti-PD-L1 therapy and radiotherapy significantly inhibited tumor growth compared with radiotherapy alone or anti-PD-L1 monotherapy in mice.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mice', 'Species', '10090', (202, 206))	('tumor', 'Disease', (127, 132))	('anti-PD-L1', 'Var', (67, 77))	('inhibited', 'NegReg', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
704352	30717285	After deparaffinization, antigen was retrieved by citric acid buffer (pH 6.0) using a steamer autoclave, then incubated with anti-IDO1 antibody (HPA023072, Sigma, Shanghai, China) at 1:1000 dilution, anti-PD-L1 antibody (ab213524, Abcam, Cambridge, MA, USA) at 1:250 dilution, and anti-CD8 antibody (ab108343, Abcam) at 1:500 dilution overnight at 4  C. Subsequently, the sections were incubated with a secondary antibody, stained with diaminobenzidine, and then counterstained with hematoxylin, dehydrated, and coverslipped.	('ab213524', 'Var', (221, 229))	('paraffin', 'Chemical', 'MESH:D010232', (8, 16))	('IDO1', 'Gene', '3620', (130, 134))	('CD8', 'Gene', (286, 289))	('IDO1', 'Gene', (130, 134))	('CD8', 'Gene', '925', (286, 289))
704408	30386117	Intraductal ultrasound (IDUS) has been previously used for diagnosing indeterminate strictures and it has been shown that disruption of normal echo layers, heterogeneity of the internal echo pattern, notching or irregularity of the outer border, papillary surface and hypoechoic mass on IDUS are features suggestive of malignancy.	('malignancy', 'Disease', (319, 329))	('papillary surface', 'CPA', (246, 263))	('internal echo pattern', 'MPA', (177, 198))	('disruption', 'Var', (122, 132))	('hypoechoic mass', 'Disease', 'MESH:C536030', (268, 283))	('hypoechoic mass', 'Disease', (268, 283))	('heterogeneity', 'MPA', (156, 169))	('malignancy', 'Disease', 'MESH:D009369', (319, 329))	('notching', 'Var', (200, 208))
704415	27877079	Amplification of 11q13 resulting in overexpression of CTTN/CCND1 was the most prominent finding, which was observed in 13 of 19 ESCC cases.	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('Amplification', 'Var', (0, 13))	('overexpression', 'PosReg', (36, 50))	('CTTN', 'Gene', (54, 58))	('CCND1', 'Gene', (59, 64))	('CTTN', 'Gene', '2017', (54, 58))	('ESCC', 'Disease', (128, 132))	('CCND1', 'Gene', '595', (59, 64))
704419	27877079	Regions with such high incidence of ESCC (15150/100,000) are referred to as the famous ''Asian Esophageal Cancer Belt,'' which includes the countries of the Caspian littoral region, the central Asian republics, Mongolia and north-western China, which have a 10-100 fold greater chance of being affected by esophageal cancer compared to other countries.	('Esophageal Cancer', 'Disease', (95, 112))	('ESCC', 'Disease', (36, 40))	('15150/100,000', 'Var', (42, 55))	('esophageal cancer', 'Disease', (306, 323))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('esophageal cancer', 'Disease', 'MESH:D004938', (306, 323))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (95, 112))
704422	27877079	Regardless of the ethnic origin of the patients and the etiological factors, genetic instabilities such as microsatellite instability and chromosomal instability are associated with tumorigenesis of ESCC.	('chromosomal', 'MPA', (138, 149))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('microsatellite instability', 'Var', (107, 133))	('tumor', 'Disease', (182, 187))	('patients', 'Species', '9606', (39, 47))	('chromosomal instability', 'Phenotype', 'HP:0040012', (138, 161))	('ESCC', 'Disease', (199, 203))	('associated with', 'Reg', (166, 181))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
704440	27877079	The most frequent genomic imbalances detected in more than 8 out of 19 ESCC cases (> 42%) were gains of 1q21.1-qter, 3q13.11-qter, 5pter-p11, 7pter-p15.3, 7p12.1-p11.2, 7q11-q11.2, 8p12-qter, 11q13.2-q13.3, 12pter-p13.3, 17q24.2, 20q11.21-qter, and 22q11.21-q11.22; and losses of 3pter-p11.1, 4pter-p12, 4q28.3-q31.22, 4q31.3-q32.1, 9pter-p12, 11q22.3-qter, and 13q12.11-q22.1 (Table 2).	('p13', 'Gene', '440926', (214, 217))	('p12', 'Gene', '56655', (339, 342))	('imbalance', 'Phenotype', 'HP:0002172', (26, 35))	('p12', 'Gene', '56655', (299, 302))	('p12', 'Gene', '56655', (156, 159))	('p12', 'Gene', (182, 185))	('p11', 'Gene', '6281', (162, 165))	('4q28.3-q31.22', 'Var', (304, 317))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('p11', 'Gene', '6281', (137, 140))	('p11', 'Gene', (162, 165))	('p12', 'Gene', (339, 342))	('p11', 'Gene', (137, 140))	('p12', 'Gene', (299, 302))	('losses', 'NegReg', (270, 276))	('3q13.11-qter', 'Var', (117, 129))	('p15', 'Gene', (148, 151))	('p12', 'Gene', (156, 159))	('p13', 'Gene', (214, 217))	('imbalances', 'Phenotype', 'HP:0002172', (26, 36))	('p11', 'Gene', '6281', (286, 289))	('ESCC', 'Disease', (71, 75))	('1q21.1-qter', 'Var', (104, 115))	('4q31.3-q32.1', 'Var', (319, 331))	('p12', 'Gene', '56655', (182, 185))	('p11', 'Gene', (286, 289))	('p15', 'Gene', '1030', (148, 151))
704455	27877079	Especially, the isochromosome 3q was visualized in lung cancer, squamous cell carcinomas of the vulva, oral, and the head and neck, as well as in the ESCC cell line KYSE 410-4,, suggesting that isochromosome 3q formation is a mechanism of somatic chromosomal aberrations, resulting in reciprocal loss of 3p and gain of 3q during epithelial cell carcinogenesis.	('loss', 'NegReg', (296, 300))	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('carcinomas of the vulva', 'Phenotype', 'HP:0030416', (78, 101))	('squamous cell carcinomas of the vulva', 'Phenotype', 'HP:0030417', (64, 101))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (64, 88))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (247, 270))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('gain of', 'PosReg', (311, 318))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('squamous cell carcinomas of the vulva', 'Disease', (64, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('squamous cell carcinomas of the vulva', 'Disease', 'MESH:D002294', (64, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('isochromosome', 'Var', (194, 207))
704456	27877079	Amplifications were observed in 41 segmental regions, of which 7p11.2 and 11q13.3 were the most repeatedly involved interesting regions (Table S1).	('p11', 'Gene', '6281', (64, 67))	('Amplifications', 'Var', (0, 14))	('p11', 'Gene', (64, 67))
704459	27877079	In the present study, subsequent examination of CCND1 and CTTN protein expression levels confirmed that genomic amplification status parallels the increased protein level.	('CTTN', 'Gene', '2017', (58, 62))	('CCND1', 'Gene', '595', (48, 53))	('genomic amplification status', 'Var', (104, 132))	('CTTN', 'Gene', (58, 62))	('CCND1', 'Gene', (48, 53))
704465	27877079	Amplification and overexpression of EGFR has been reported in ESCC and was significantly associated with a poor prognosis in ESCC patients indicating that it may play an important role in ESCC progression.	('associated', 'Reg', (89, 99))	('Amplification', 'Var', (0, 13))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('ESCC', 'Disease', (188, 192))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('SCC', 'Phenotype', 'HP:0002860', (189, 192))	('EGFR', 'Gene', '1956', (36, 40))	('patients', 'Species', '9606', (130, 138))	('EGFR', 'Gene', (36, 40))	('ESCC', 'Disease', (62, 66))	('play', 'Reg', (162, 166))	('overexpression', 'PosReg', (18, 32))
704467	27877079	Additional sequencing analysis of CDK2NA revealed a somatic mutation in exon 2 (c.31_32dupCC;p.S12Lfs*15) leading to a stop codon, in one tumor case (TL 0122) of 19 (Fig S2) without the mutation in adjacent normal tissues.	('CDK2', 'Gene', (34, 38))	('c.31_32dupCC;p.S12Lfs*15', 'Var', (80, 104))	('c.31_32dupCC', 'Mutation', 'c.31_32dupCC', (80, 92))	('p.S12Lfs*15', 'Var', (93, 104))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('CDK2', 'Gene', '1017', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('p.S12Lfs*15', 'Mutation', 'p.S12LfsX15', (93, 104))
704468	27877079	FHIT and CDKN2A are virtually known as the most frequently affected genes after TP53 in the context of homozygous deletion, promoter hypermethylation, loss of heterozygosity (LOH), and point mutations in various human cancers including ESCC.	('promoter hypermethylation', 'Var', (124, 149))	('human', 'Species', '9606', (212, 217))	('CDKN2A', 'Gene', '1029', (9, 15))	('SCC', 'Phenotype', 'HP:0002860', (237, 240))	('loss of heterozygosity', 'Var', (151, 173))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('ESCC', 'Disease', (236, 240))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('TP53', 'Gene', '7157', (80, 84))	('cancers', 'Disease', (218, 225))	('TP53', 'Gene', (80, 84))	('point mutations', 'Var', (185, 200))	('FHIT', 'Gene', (0, 4))	('affected', 'Reg', (59, 67))	('FHIT', 'Gene', '2272', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('CDKN2A', 'Gene', (9, 15))
704572	26936768	As our previous work demonstrates, the scan-time correction distinctly improves the prognostic value of the SUR, and it is thus the scan-time corrected value SURtc which should be compared against TLR.	('prognostic value', 'MPA', (84, 100))	('SUR', 'Gene', '6833', (108, 111))	('SUR', 'Gene', (108, 111))	('improves', 'PosReg', (71, 79))	('scan-time', 'Var', (39, 48))	('SUR', 'Gene', '6833', (158, 161))	('SUR', 'Gene', (158, 161))
704630	24959694	In this study, we provide evidence that cisplatin induces necrotic cell death in apoptosis-resistant esophageal cancer cells.	('necrotic cell death', 'Disease', 'MESH:D003643', (58, 77))	('cisplatin', 'Var', (40, 49))	('necrotic cell death', 'Disease', (58, 77))	('esophageal cancer', 'Disease', (101, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
704631	24959694	More importantly, we demonstrate that RIPK3 is necessary for cisplatin-induced killing of esophageal cancer cells because inhibition of RIPK1 activity by necrostatin or knockdown of RIPK3 significantly attenuates necrosis and leads to cisplatin resistance.	('leads to', 'Reg', (226, 234))	('necrosis', 'Disease', (213, 221))	('RIPK1', 'Gene', (136, 141))	('inhibition', 'Var', (122, 132))	('activity', 'MPA', (142, 150))	('knockdown', 'Var', (169, 178))	('attenuates', 'NegReg', (202, 212))	('necrostatin', 'Chemical', '-', (154, 165))	('necrosis', 'Disease', 'MESH:D009336', (213, 221))	('cisplatin', 'Chemical', 'MESH:D002945', (235, 244))	('esophageal cancer', 'Disease', (90, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('cisplatin resistance', 'MPA', (235, 255))	('RIPK3', 'Gene', (182, 187))
704633	24959694	Taken together, our data indicate that RIPK3 and autocrine production of TNFalpha contribute to cisplatin sensitivity by initiating necrosis when the apoptotic pathway is suppressed or absent in esophageal cancer cells.	('esophageal cancer', 'Disease', (195, 212))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('RIPK3', 'Var', (39, 44))	('initiating', 'Reg', (121, 131))	('cisplatin sensitivity', 'MPA', (96, 117))	('necrosis', 'Disease', (132, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('TNFalpha', 'Gene', (73, 81))	('contribute', 'Reg', (82, 92))	('autocrine production', 'MPA', (49, 69))	('necrosis', 'Disease', 'MESH:D009336', (132, 140))	('apoptotic pathway', 'Pathway', (150, 167))
704642	24959694	Recent evidence shows that caspase-8- and FADD-deficient mice die at embryonic stage 10.5; which is rescued by co-deletion of RIPK1 or RIPK3.	('FADD-deficient', 'Disease', (42, 56))	('mice', 'Species', '10090', (57, 61))	('RIPK1', 'Gene', (126, 131))	('RIPK3', 'Gene', (135, 140))	('co-deletion', 'Var', (111, 122))	('FADD-deficient', 'Disease', 'OMIM:613759', (42, 56))
704643	24959694	This indicates that inhibition of the caspase-8-dependent apoptotic pathway triggers RIPK3-dependent necrosis, leading to death during embryonic development.	('leading to', 'Reg', (111, 121))	('RIPK3-dependent', 'Gene', (85, 100))	('inhibition', 'Var', (20, 30))	('caspase-8-dependent apoptotic pathway', 'Pathway', (38, 75))	('death during embryonic development', 'CPA', (122, 156))	('necrosis', 'Disease', (101, 109))	('necrosis', 'Disease', 'MESH:D009336', (101, 109))
704656	24959694	Phosphorylation of both RIPK1 and RIPK3 stabilizes their association within the death-signaling complex and results in the production of reactive oxygen species (ROS) in certain cells by activating enzymes in metabolic pathways.	('results in', 'Reg', (108, 118))	('Phosphorylation', 'Var', (0, 15))	('RIPK1', 'Gene', (24, 29))	('production of reactive oxygen species', 'MPA', (123, 160))	('stabilizes', 'NegReg', (40, 50))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (137, 160))	('ROS', 'Chemical', 'MESH:D017382', (162, 165))	('association', 'Interaction', (57, 68))	('enzymes', 'Enzyme', (198, 205))	('activating', 'PosReg', (187, 197))	('metabolic pathways', 'Pathway', (209, 227))	('RIPK3', 'Gene', (34, 39))
704659	24959694	In this study, we demonstrated that cisplatin selectively induces necrosis in KYSE140, an esophageal squamous carcinoma (ESCC) cell line deficient in SMAC, a pro-apoptotic protein.	('SMAC', 'Gene', (150, 154))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (101, 119))	('ESCC', 'Phenotype', 'HP:0011459', (121, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('KYSE140', 'CellLine', 'CVCL:1347', (78, 85))	('induces', 'Reg', (58, 65))	('necrosis', 'Disease', (66, 74))	('cisplatin', 'Var', (36, 45))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (90, 119))	('SMAC', 'Gene', '56616', (150, 154))	('esophageal squamous carcinoma', 'Disease', (90, 119))	('necrosis', 'Disease', 'MESH:D009336', (66, 74))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (90, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))
704661	24959694	Furthermore, inhibition of RIPK activity by Nec-1 or knockdown of RIPK3 protein with siRNA largely rescued cisplatin-induced necrosis.	('RIPK3', 'Gene', (66, 71))	('protein', 'Protein', (72, 79))	('rescued', 'PosReg', (99, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('knockdown', 'Var', (53, 62))	('necrosis', 'Disease', (125, 133))	('RIPK', 'Enzyme', (27, 31))	('activity', 'MPA', (32, 40))	('inhibition', 'NegReg', (13, 23))	('necrosis', 'Disease', 'MESH:D009336', (125, 133))
704680	24959694	Western blot analysis was performed as described previously, using the following antibodies: anti-caspase-9, anti-caspase-3, anti-Fos, anti-RIPK1, and anti-survivin antibodies from Cell Signaling Technology (Beverly, MA); anti-RIPK3 and anti-SMAC antibodies from Abcam (Cambridge, MA); anti-MLKL, anti-cytochrome C and anti-Bcl-2 antibodies from Santa Cruz Biotechnology.	('caspase-9', 'Gene', '842', (98, 107))	('MLKL', 'Gene', (291, 295))	('SMAC', 'Gene', '56616', (242, 246))	('Fos', 'Gene', (130, 133))	('cytochrome C', 'Gene', '54205', (302, 314))	('Bcl-2', 'Gene', (324, 329))	('caspase-3', 'Gene', (114, 123))	('Bcl-2', 'Gene', '596', (324, 329))	('caspase-9', 'Gene', (98, 107))	('anti-RIPK3', 'Var', (222, 232))	('SMAC', 'Gene', (242, 246))	('caspase-3', 'Gene', '836', (114, 123))	('Fos', 'Gene', '2353', (130, 133))	('MLKL', 'Gene', '197259', (291, 295))	('cytochrome C', 'Gene', (302, 314))
704692	24959694	In this study, we first asked whether the innate SMAC deficiency facilitates cisplatin resistance in ESCC cells.	('deficiency', 'Var', (54, 64))	('cisplatin resistance', 'MPA', (77, 97))	('SMAC', 'Gene', (49, 53))	('ESCC', 'Phenotype', 'HP:0011459', (101, 105))	('facilitates', 'PosReg', (65, 76))	('SMAC', 'Gene', '56616', (49, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))
704698	24959694	Substantial nuclear fragmentation and mitochondrial membrane potential were detected in the positive control EC0156 cells, but not in the KYSE140 cells after cisplatin treatment (Figure 1C and 2A), suggesting that cisplatin induces non-apoptotic cell death in the KYSE140 cells.	('cisplatin', 'Var', (214, 223))	('nuclear fragmentation', 'CPA', (12, 33))	('mitochondrial membrane potential', 'CPA', (38, 70))	('non-apoptotic cell death', 'CPA', (232, 256))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('EC0156', 'CellLine', 'CVCL:K425', (109, 115))	('KYSE140', 'CellLine', 'CVCL:1347', (138, 145))	('KYSE140', 'CellLine', 'CVCL:1347', (264, 271))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))
704706	24959694	Collectively, these data indicates that cisplatin predominately induces non-apoptotic and caspase-independent cell death in KYSE140 cells.	('caspase', 'Gene', '841;12370;842', (90, 97))	('KYSE140', 'CellLine', 'CVCL:1347', (124, 131))	('induces', 'Reg', (64, 71))	('cisplatin', 'Var', (40, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('caspase', 'Gene', (90, 97))
704711	24959694	A higher level of TNFalpha mRNA level was detected in cisplatin-treated KYSE140 cells than in control cells (Figure 3C).	('higher', 'PosReg', (2, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('TNFalpha mRNA level', 'MPA', (18, 37))	('cisplatin-treated', 'Var', (54, 71))	('KYSE140', 'CellLine', 'CVCL:1347', (72, 79))
704732	24959694	We also used siRNA to knock down RIPK1 to test the requirement for necrosis in cisplatin-induced cell death.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('necrosis', 'Disease', 'MESH:D009336', (67, 75))	('knock', 'Var', (22, 27))	('test', 'Reg', (42, 46))	('necrosis', 'Disease', (67, 75))	('RIPK1', 'Gene', (33, 38))
704733	24959694	RIPK1 knockdown profoundly rescued cisplatin-induced cell death (Figure 4H), indicating that RIPK1 is required for cisplatin-induced cell death.	('RIPK1', 'Gene', (0, 5))	('cisplatin-induced', 'MPA', (35, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('rescued', 'PosReg', (27, 34))	('knockdown', 'Var', (6, 15))
704743	24959694	The FOS protein level was markedly increased in the KYSE140 cells after cisplatin treatments for 6, 12 and 24 h. The RIPK3, CYCS and survivin expression levels were also higher in the cisplatin-treated cells.	('higher', 'PosReg', (170, 176))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('FOS', 'Gene', (4, 7))	('RIPK3', 'MPA', (117, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('FOS', 'Gene', '2353', (4, 7))	('cisplatin-treated', 'Var', (184, 201))	('CYCS', 'Gene', '54205', (124, 128))	('CYCS', 'Gene', (124, 128))	('survivin expression levels', 'MPA', (133, 159))	('KYSE140', 'CellLine', 'CVCL:1347', (52, 59))
704746	24959694	In contrast, massive induction of CYCS, APAF1 and CASP9 occured in EC0156 but not in KYSE140 cells (Figure 5D).	('KYSE140', 'CellLine', 'CVCL:1347', (85, 92))	('EC0156', 'Var', (67, 73))	('CYCS', 'Gene', '54205', (34, 38))	('CYCS', 'Gene', (34, 38))	('induction', 'MPA', (21, 30))	('EC0156', 'CellLine', 'CVCL:K425', (67, 73))	('APAF1', 'Gene', (40, 45))	('CASP9', 'Gene', (50, 55))	('APAF1', 'Gene', '317', (40, 45))	('CASP9', 'Gene', '842', (50, 55))
704747	24959694	Together, these data demonstrate that cisplatin triggers necrosis in KYSE140 cells by increasing the expression of necrosis-associated genes as well as anti-apoptotic genes.	('necrosis', 'Disease', (115, 123))	('cisplatin', 'Var', (38, 47))	('necrosis', 'Disease', 'MESH:D009336', (115, 123))	('necrosis', 'Disease', (57, 65))	('increasing', 'PosReg', (86, 96))	('expression', 'MPA', (101, 111))	('KYSE140', 'CellLine', 'CVCL:1347', (69, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
704760	24959694	We therefore propose a summary model to explain how cisplatin induces programmed necrosis in ESCC cells, illustrated in Figure 7: (i) promotion of necrosome assembly via autocrine production of TNFalpha, leading to necrosis, (ii) requirement of RIPK3 for cisplatin-induced necrosis, and (iii) inhibition of endogenous apoptotic pathways.	('ESCC', 'Phenotype', 'HP:0011459', (93, 97))	('necrosis', 'Disease', 'MESH:D009336', (273, 281))	('cisplatin', 'Chemical', 'MESH:D002945', (255, 264))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('inhibition', 'NegReg', (293, 303))	('cisplatin', 'Var', (52, 61))	('necrosis', 'Disease', 'MESH:D009336', (81, 89))	('necrosis', 'Disease', (215, 223))	('endogenous apoptotic pathways', 'Pathway', (307, 336))	('necrosis', 'Disease', (273, 281))	('promotion', 'PosReg', (134, 143))	('necrosome assembly', 'MPA', (147, 165))	('necrosis', 'Disease', (81, 89))	('necrosis', 'Disease', 'MESH:D009336', (215, 223))
704762	24959694	Although apoptosis has been implicated in cisplatin-mediated cytotoxicity, cisplatin has also been shown to induce non-apoptotic cell death.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('non-apoptotic cell death', 'CPA', (115, 139))	('cytotoxicity', 'Disease', (61, 73))	('cisplatin', 'Var', (75, 84))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))
704765	24959694	Our previous data indicated that efficient knockdown of pro-apoptotic SMAC protein significantly attenuates the response of esophageal cancer cells to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('esophageal cancer', 'Disease', (124, 141))	('knockdown', 'Var', (43, 52))	('response', 'MPA', (112, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('SMAC', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('attenuates', 'NegReg', (97, 107))	('SMAC', 'Gene', '56616', (70, 74))
704766	24959694	In the present study, we found that cisplatin selectively induces necrosis in KYSE140 cells, which are endogenously deficient in SMAC expression.	('SMAC', 'Gene', '56616', (129, 133))	('KYSE140', 'CellLine', 'CVCL:1347', (78, 85))	('induces', 'Reg', (58, 65))	('necrosis', 'Disease', (66, 74))	('cisplatin', 'Var', (36, 45))	('necrosis', 'Disease', 'MESH:D009336', (66, 74))	('SMAC', 'Gene', (129, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))
704784	24959694	Thus, using selective knockdown of different individual components of the necrosome, we provide evidence that cisplatin induces necrosis by enhancing the recruiment of the necrosome to excute cell death in ESCC cells.	('necrosis', 'Disease', (128, 136))	('enhancing', 'PosReg', (140, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('recruiment of the necrosome to excute cell death', 'MPA', (154, 202))	('necrosis', 'Disease', 'MESH:D009336', (128, 136))	('ESCC', 'Phenotype', 'HP:0011459', (206, 210))	('cisplatin', 'Var', (110, 119))
704800	24959694	First, we demonstrated a pathway by which cisplatin triggers programmed necrosis, promoting necrosome assembly via autocrine production of TNFalpha and leading to necrosis, during inhibition of endogenous apoptotic pathways.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('necrosome assembly', 'MPA', (92, 110))	('necrosis', 'Disease', (72, 80))	('necrosis', 'Disease', (163, 171))	('cisplatin', 'Var', (42, 51))	('promoting', 'PosReg', (82, 91))	('necrosis', 'Disease', 'MESH:D009336', (72, 80))	('necrosis', 'Disease', 'MESH:D009336', (163, 171))	('TNFalpha', 'Gene', (139, 147))	('autocrine production', 'MPA', (115, 135))
704891	20827430	Genetic polymorphism of p53, but not GSTP1, is association with susceptibility to esophageal cancer risk - A Meta-Analysis A number of studies have evaluated two functional polymorphisms on p53 Arg72Pro and GSTP1 Ile105Val, in relation to esophageal cancer susceptibility.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('GSTP1', 'Gene', (207, 212))	('p53', 'Gene', (24, 27))	('Arg72Pro', 'Var', (194, 202))	('p53', 'Gene', '7157', (24, 27))	('GSTP1', 'Gene', '2950', (37, 42))	('GSTP1', 'Gene', '2950', (207, 212))	('Ile105Val', 'Chemical', '-', (213, 222))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('p53', 'Gene', (190, 193))	('p53', 'Gene', '7157', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('GSTP1', 'Gene', (37, 42))	('esophageal cancer', 'Disease', (239, 256))	('Arg72Pro', 'SUBSTITUTION', 'None', (194, 202))	('esophageal cancer', 'Disease', (82, 99))	('Ile105Val', 'Var', (213, 222))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))
704892	20827430	This meta-analysis on 2919 cases and 4074 controls for p53 Arg72Pro and 1885 cases and 2194 controls for GSTP1 Ile105Val from 13 published case-control studies showed that no significant general main effects for GSTP1 Ile105Val on esophageal cancer risk.	('GSTP1', 'Gene', (105, 110))	('Arg72Pro', 'SUBSTITUTION', 'None', (59, 67))	('p53', 'Gene', (55, 58))	('GSTP1', 'Gene', (212, 217))	('p53', 'Gene', '7157', (55, 58))	('GSTP1', 'Gene', '2950', (105, 110))	('esophageal cancer', 'Disease', (231, 248))	('Ile105Val', 'Chemical', '-', (111, 120))	('GSTP1', 'Gene', '2950', (212, 217))	('esophageal cancer', 'Disease', 'MESH:D004938', (231, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('Arg72Pro', 'Var', (59, 67))	('Ile105Val', 'Chemical', '-', (218, 227))
704893	20827430	However, we found that the p53 Arg72Pro was associated with an increased risk of esophageal cancer ((Pro/Arg +Pro/Pro) versus Arg/Arg: OR=1.20, 95%CI=1.06-1.36) without any between-study heterogeneity.	('Arg', 'Chemical', 'MESH:D001120', (31, 34))	('Pro', 'Chemical', 'MESH:D011392', (36, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('Pro', 'Chemical', 'MESH:D011392', (101, 104))	('Arg72Pro', 'SUBSTITUTION', 'None', (31, 39))	('Arg', 'Chemical', 'MESH:D001120', (126, 129))	('p53', 'Gene', (27, 30))	('Arg', 'Chemical', 'MESH:D001120', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Arg72Pro', 'Var', (31, 39))	('Arg', 'Chemical', 'MESH:D001120', (130, 133))	('Pro', 'Chemical', 'MESH:D011392', (110, 113))	('esophageal cancer', 'Disease', (81, 98))	('Pro', 'Chemical', 'MESH:D011392', (114, 117))	('p53', 'Gene', '7157', (27, 30))
704894	20827430	In the stratified analysis by ethnicity, we found that the increased esophageal cancer risk associated with p53 Arg72Pro polymorphism was more evident in Asian group ((Pro/Arg +Pro/Pro) versus Arg/Arg: OR=1.35, 95%CI=1.14-1.60, P=0.09 for heterogeneity test), although we still failed to find any significant association between GSTP1 Ile105Val polymorphism and esophageal cancer risk in different ethnicity.	('esophageal cancer', 'Disease', (69, 86))	('Arg', 'Chemical', 'MESH:D001120', (193, 196))	('esophageal cancer', 'Disease', (362, 379))	('GSTP1', 'Gene', '2950', (329, 334))	('Asian', 'Disease', (154, 159))	('Pro', 'Chemical', 'MESH:D011392', (181, 184))	('Pro', 'Chemical', 'MESH:D011392', (117, 120))	('Ile105Val', 'Chemical', '-', (335, 344))	('GSTP1', 'Gene', (329, 334))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Arg', 'Chemical', 'MESH:D001120', (112, 115))	('Pro', 'Chemical', 'MESH:D011392', (177, 180))	('p53', 'Gene', '7157', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('Arg', 'Chemical', 'MESH:D001120', (197, 200))	('Arg72Pro', 'Var', (112, 120))	('Pro', 'Chemical', 'MESH:D011392', (168, 171))	('Arg', 'Chemical', 'MESH:D001120', (172, 175))	('p53', 'Gene', (108, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (362, 379))	('Arg72Pro', 'SUBSTITUTION', 'None', (112, 120))
704895	20827430	These results suggest that p53 Arg72Pro polymorphism, but not GSTP1 Ile105Val, may contribute to esophageal cancer development, especially in Asian.	('Arg72Pro', 'SUBSTITUTION', 'None', (31, 39))	('p53', 'Gene', '7157', (27, 30))	('Asian', 'Disease', (142, 147))	('Ile105Val', 'Chemical', '-', (68, 77))	('GSTP1', 'Gene', (62, 67))	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Arg72Pro', 'Var', (31, 39))	('contribute to', 'Reg', (83, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('GSTP1', 'Gene', '2950', (62, 67))	('p53', 'Gene', (27, 30))
704901	20827430	The tumor-suppressor gene p53 is important for cellular growth control once the DNA is subject to damage or mutation and arrests the cell cycle in the G1 phase to allow DNA repair or apoptosis.	('tumor', 'Disease', (4, 9))	('p53', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('p53', 'Gene', '7157', (26, 29))	('mutation', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
704902	20827430	Its mutation is widely detected in all types of cancer, including esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('esophageal cancer', 'Disease', (66, 83))	('mutation', 'Var', (4, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('detected', 'Reg', (23, 31))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
704903	20827430	It is now clear that disruption of p53 pathway, such as through inactivating p53 mutations, is associated with the formation and progression of malignancies.	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('malignancies', 'Disease', 'MESH:D009369', (144, 156))	('inactivating', 'Var', (64, 76))	('p53', 'Gene', (77, 80))	('disruption', 'Var', (21, 31))	('malignancies', 'Disease', (144, 156))	('p53', 'Gene', '7157', (77, 80))	('mutations', 'Var', (81, 90))	('associated', 'Reg', (95, 105))
704904	20827430	For example, it has been shown that >50% of human tumors have inactivating p53 mutations.	('human', 'Species', '9606', (44, 49))	('inactivating', 'Var', (62, 74))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('human', 'Disease', (44, 49))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('mutations', 'Var', (79, 88))
704907	20827430	Because accumulating evidence indicates p53 and GSTP1 play central role in cancer formation and progression, one may reason that functional single nucleotide polymorphisms in these genes might render the carrier susceptible to cancer, including esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', (256, 262))	('GSTP1', 'Gene', (48, 53))	('cancer', 'Disease', (75, 81))	('p53', 'Gene', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('susceptible', 'Reg', (212, 223))	('esophageal cancer', 'Disease', (245, 262))	('cancer', 'Disease', (227, 233))	('p53', 'Gene', '7157', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('single nucleotide polymorphisms', 'Var', (140, 171))	('GSTP1', 'Gene', '2950', (48, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (245, 262))	('render', 'Reg', (193, 199))
704908	20827430	It was reported that the p53 gene is polymorphic and among its single nucleotide polymorphisms, a G>C change at codon 72 (rs1042522) results in Arg>Pro amino acid substitution.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('G>C', 'Var', (98, 101))	('rs1042522', 'Mutation', 'rs1042522', (122, 131))	('Arg', 'MPA', (144, 147))	('Pro amino acid', 'Chemical', '-', (148, 162))	('rs1042522', 'Var', (122, 131))	('Arg', 'Chemical', 'MESH:D001120', (144, 147))
704911	20827430	The GSTP1 gene displays a polymorphism, an A>G change at codon 105, resulting in an Ile-to-Val substitution (rs1695), which alters the enzymatic activity of the protein.	('GSTP1', 'Gene', (4, 9))	('A>G change', 'Var', (43, 53))	('rs1695', 'Mutation', 'rs1695', (109, 115))	('A>G change at codon 105', 'Mutation', 'rs1695', (43, 66))	('Val', 'Chemical', 'MESH:D014633', (91, 94))	('enzymatic activity of', 'MPA', (135, 156))	('Ile-to-Val', 'MPA', (84, 94))	('alters', 'Reg', (124, 130))	('Ile', 'Chemical', 'MESH:D007532', (84, 87))	('GSTP1', 'Gene', '2950', (4, 9))
704913	20827430	Therefore, it's reasonable to hypothesize that the p53 Arg72Pro and GSTP1 Ile105Val polymorphisms may functionally related to the risk of esophageal cancer.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('esophageal cancer', 'Disease', (138, 155))	('GSTP1', 'Gene', (68, 73))	('Arg72Pro', 'SUBSTITUTION', 'None', (55, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('Ile105Val', 'Var', (74, 83))	('Ile105Val', 'Chemical', '-', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('GSTP1', 'Gene', '2950', (68, 73))	('Arg72Pro', 'Var', (55, 63))	('related', 'Reg', (115, 122))
704914	20827430	A number of molecular epidemiology studies have been conducted to examine the association between p53 Arg72Pro, GSTP1 Ile105Val polymorphisms and esophageal cancer susceptibility, but the results remain inconsistent.	('GSTP1', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('esophageal cancer', 'Disease', (146, 163))	('Ile105Val', 'Var', (118, 127))	('GSTP1', 'Gene', '2950', (112, 117))	('Arg72Pro', 'Var', (102, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('p53', 'Gene', (98, 101))	('Arg72Pro', 'SUBSTITUTION', 'None', (102, 110))	('p53', 'Gene', '7157', (98, 101))	('Ile105Val', 'Chemical', '-', (118, 127))
704915	20827430	To estimate the overall risk of p53 Arg72Pro, GSTP1 Ile105Val associated with esophageal cancer risk and to quantify the potential between-study heterogeneity, we conducted a meta-analysis on 13 published case-control studies with 2919 cases and 4074 controls for p53 Arg72Pro and 1885 cases and 2194 controls for GSTP1 Ile105Val.	('GSTP1', 'Gene', '2950', (46, 51))	('p53', 'Gene', (264, 267))	('GSTP1', 'Gene', '2950', (314, 319))	('Arg72Pro', 'Var', (36, 44))	('p53', 'Gene', '7157', (264, 267))	('associated', 'Reg', (62, 72))	('Arg72Pro', 'SUBSTITUTION', 'None', (268, 276))	('Arg72Pro', 'SUBSTITUTION', 'None', (36, 44))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('Ile105Val', 'Chemical', '-', (52, 61))	('Ile105Val', 'Chemical', '-', (320, 329))	('GSTP1', 'Gene', (46, 51))	('GSTP1', 'Gene', (314, 319))	('esophageal cancer', 'Disease', (78, 95))	('Arg72Pro', 'Var', (268, 276))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
704916	20827430	We attempted to include all the case-control studies published to date on the association between p53 Arg72Pro, GSTP1 Ile105Val polymorphisms and esophageal cancer risk.	('GSTP1', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('esophageal cancer', 'Disease', (146, 163))	('Ile105Val', 'Var', (118, 127))	('GSTP1', 'Gene', '2950', (112, 117))	('Arg72Pro', 'Var', (102, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('p53', 'Gene', (98, 101))	('Arg72Pro', 'SUBSTITUTION', 'None', (102, 110))	('p53', 'Gene', '7157', (98, 101))	('Ile105Val', 'Chemical', '-', (118, 127))	('association', 'Interaction', (78, 89))
704918	20827430	The risk of esophageal cancer associated with p53 Arg72Pro, GSTP1 Ile105Val polymorphisms were estimated for each study by odds ratio (OR) with 95% confidence intervals (95%CI).	('GSTP1', 'Gene', (60, 65))	('Ile105Val', 'Var', (66, 75))	('Arg72Pro', 'Var', (50, 58))	('p53', 'Gene', (46, 49))	('p53', 'Gene', '7157', (46, 49))	('GSTP1', 'Gene', '2950', (60, 65))	('Ile105Val', 'Chemical', '-', (66, 75))	('esophageal cancer', 'Disease', (12, 29))	('Arg72Pro', 'SUBSTITUTION', 'None', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (12, 29))
704921	20827430	We also computed the power of the selected studies by using the DSTPLAN4.2 software, in order to assess the probability of detecting an association between RANTES polymorphisms and asthma at the 0.05 level of significance, assuming a genotypic risk of 2.0 and 1.5.	('RANTES', 'Gene', '6352', (156, 162))	('asthma', 'Disease', (181, 187))	('asthma', 'Phenotype', 'HP:0002099', (181, 187))	('RANTES', 'Gene', (156, 162))	('polymorphisms', 'Var', (163, 176))
704922	20827430	All studies indicated that the distributions of two polymorphism's genotypes in the controls were both consistent with Hardy-Weinberg equilibrium except for one study for p53 Arg72Pro, and one studies for GSTP1 Ile105Val.	('Ile105Val', 'Chemical', '-', (211, 220))	('GSTP1', 'Gene', (205, 210))	('GSTP1', 'Gene', '2950', (205, 210))	('Arg72Pro', 'Var', (175, 183))	('Arg72Pro', 'SUBSTITUTION', 'None', (175, 183))	('p53', 'Gene', (171, 174))	('p53', 'Gene', '7157', (171, 174))
704923	20827430	As a result, 6 case-control studies (2919 cases and 4074 controls) for p53 Arg72Pro and 9 studies (1885 cases and 2194 controls) for GSTP1 Ile105Val were available for this meta-analysis.	('GSTP1', 'Gene', '2950', (133, 138))	('Arg72Pro', 'Var', (75, 83))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('Ile105Val', 'Chemical', '-', (139, 148))	('Arg72Pro', 'SUBSTITUTION', 'None', (75, 83))	('GSTP1', 'Gene', (133, 138))
704924	20827430	The minor Pro allele (for p53 Arg72Pro) and Val allele (for GSTP1 Ile105Val) frequency (MAF) were 0.44 and 0.20 for Asian studies, while around 0.60 and 0.32 for Mix and Caucasus populations, respectively.	('GSTP1', 'Gene', (60, 65))	('MAF', 'Gene', (88, 91))	('Mix', 'Gene', (162, 165))	('Val', 'Chemical', 'MESH:D014633', (72, 75))	('p53', 'Gene', (26, 29))	('Val', 'Chemical', 'MESH:D014633', (44, 47))	('GSTP1', 'Gene', '2950', (60, 65))	('Arg72Pro', 'Var', (30, 38))	('Ile105Val', 'Chemical', '-', (66, 75))	('Pro', 'Chemical', 'MESH:D011392', (10, 13))	('p53', 'Gene', '7157', (26, 29))	('MAF', 'Gene', '4094', (88, 91))	('Mix', 'Gene', '83881', (162, 165))	('Pro', 'Chemical', 'MESH:D011392', (35, 38))	('Arg72Pro', 'SUBSTITUTION', 'None', (30, 38))
704925	20827430	As shown in Table 3, the variant homozygote (Pro/Pro) for p53 Arg72Pro was associated with a significantly increased risk of esophageal cancer (Pro/Pro versus Arg/Arg: OR=1.43, 95%CI=1.23-1.68; P = 0.10 for heterogeneity test) compared with wild-type homozygote (Arg/Arg).	('Arg', 'Chemical', 'MESH:D001120', (159, 162))	('Pro', 'Chemical', 'MESH:D011392', (67, 70))	('Arg72Pro', 'SUBSTITUTION', 'None', (62, 70))	('Arg', 'Chemical', 'MESH:D001120', (62, 65))	('Arg', 'Chemical', 'MESH:D001120', (163, 166))	('esophageal cancer', 'Disease', (125, 142))	('Arg', 'Chemical', 'MESH:D001120', (263, 266))	('Arg', 'Chemical', 'MESH:D001120', (267, 270))	('Pro', 'Chemical', 'MESH:D011392', (144, 147))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('Pro', 'Chemical', 'MESH:D011392', (45, 48))	('p53', 'Gene', (58, 61))	('Pro', 'Chemical', 'MESH:D011392', (49, 52))	('Arg72Pro', 'Var', (62, 70))	('Pro', 'Chemical', 'MESH:D011392', (148, 151))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('p53', 'Gene', '7157', (58, 61))
704927	20827430	However, we failed to find any significant main effects for GSTP1 Ile105Val on esophageal cancer risk in different genetic models tested (Table 3 and Figure 2).	('GSTP1', 'Gene', (60, 65))	('Ile105Val', 'Var', (66, 75))	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('GSTP1', 'Gene', '2950', (60, 65))	('Ile105Val', 'Chemical', '-', (66, 75))
704929	20827430	As shown in the Table 4, we found that the increased esophageal cancer risk associated with p53 Arg72Pro polymorphism was more evident in Asian ((Pro/Arg +Pro/Pro) versus Arg/Arg: OR=1.35, 95%CI=1.14-1.60, P=0.09 for heterogeneity test).	('Arg', 'Chemical', 'MESH:D001120', (175, 178))	('Pro', 'Chemical', 'MESH:D011392', (101, 104))	('Arg72Pro', 'SUBSTITUTION', 'None', (96, 104))	('Arg', 'Chemical', 'MESH:D001120', (171, 174))	('p53', 'Gene', '7157', (92, 95))	('Arg', 'Chemical', 'MESH:D001120', (96, 99))	('p53', 'Gene', (92, 95))	('esophageal cancer', 'Disease', (53, 70))	('Arg', 'Chemical', 'MESH:D001120', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('Arg72Pro', 'Var', (96, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('Pro', 'Chemical', 'MESH:D011392', (155, 158))	('Pro', 'Chemical', 'MESH:D011392', (159, 162))	('Asian', 'Disease', (138, 143))	('Pro', 'Chemical', 'MESH:D011392', (146, 149))
704930	20827430	Unfortunately, we still failed to find any significant association between GSTP1 Ile105Val polymorphism and esophageal cancer risk in different ethnicity.	('Ile105Val', 'Chemical', '-', (81, 90))	('esophageal cancer', 'Disease', (108, 125))	('GSTP1', 'Gene', '2950', (75, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('Ile105Val', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('GSTP1', 'Gene', (75, 80))
704931	20827430	3 A, the shape of the funnel plots seemed nonsymmetrical in the dominant genetic model for the p53 Arg72Pro, suggesting that there was significant publication bias.	('Arg72Pro', 'Var', (99, 107))	('Arg72Pro', 'SUBSTITUTION', 'None', (99, 107))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))
704932	20827430	As a result, the publication bias was observed slightly for p53 Arg72Pro (t=4.55, P = 0.01) but was disappeared (t=1.35, P = 0.25) when we excluded the study departure from Hardy-Weinberg equilibrium.	('p53', 'Gene', (60, 63))	('Arg72Pro', 'SUBSTITUTION', 'None', (64, 72))	('Arg72Pro', 'Var', (64, 72))	('p53', 'Gene', '7157', (60, 63))
704933	20827430	No publication bias was observed for GSTP1 Ile105Val (t=1.13, P = 0.29), we also excluded the study departure from Hardy-Weinberg equilibrium and still did not found any publication bias for 28C/G (t=0.90, p=0.39).	('28C/G', 'Var', (191, 196))	('28C/G', 'SUBSTITUTION', 'None', (191, 196))	('GSTP1', 'Gene', '2950', (37, 42))	('Ile105Val', 'Var', (43, 52))	('GSTP1', 'Gene', (37, 42))	('Ile105Val', 'Chemical', '-', (43, 52))
704937	20827430	However, our analysis results showed there was no significant relations between GSTP1 Ile105Val polymorphism and esophageal cancer, but this conclusion was consistent with Hiyama T et al' s review.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('GSTP1', 'Gene', '2950', (80, 85))	('Ile105Val polymorphism', 'Var', (86, 108))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Ile105Val', 'Chemical', '-', (86, 95))	('GSTP1', 'Gene', (80, 85))	('esophageal cancer', 'Disease', (113, 130))
704938	20827430	These findings suggest that the GSTP1 Ile105Val genotype alone does not show any association with the susceptibility to esophageal cancer, even when stratified by subgroup.	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('GSTP1', 'Gene', '2950', (32, 37))	('Ile105Val', 'Chemical', '-', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('esophageal cancer', 'Disease', (120, 137))	('GSTP1', 'Gene', (32, 37))	('Ile105Val', 'Var', (38, 47))
704939	20827430	This finding is perhaps not surprising, because the functional evidence to support the role of GSTP1 Ile105Val as an esophageal cancer risk factor is not strong.	('Ile105Val', 'Var', (101, 110))	('GSTP1', 'Gene', (95, 100))	('esophageal cancer', 'Disease', (117, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('GSTP1', 'Gene', '2950', (95, 100))	('Ile105Val', 'Chemical', '-', (101, 110))
704941	20827430	Therefore, it is reasonable to hypothesize that the GSTP1 Ile105Val polymorphism may be at best a modifier for esophageal cancer by interactive with some lifestyle and dietary habits, but is not a significant independent susceptibility factor.	('esophageal cancer', 'Disease', (111, 128))	('Ile105Val', 'Chemical', '-', (58, 67))	('GSTP1', 'Gene', (52, 57))	('interactive', 'Reg', (132, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Ile105Val', 'Var', (58, 67))	('GSTP1', 'Gene', '2950', (52, 57))
704944	20827430	Both mice and humans harboring germ line inactivating mutations in one p53 allele are highly susceptible to cancer: they develop cancer very early in life and at very high frequencies.	('humans', 'Species', '9606', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('germ', 'Var', (31, 35))	('cancer', 'Disease', (129, 135))	('p53', 'Gene', (71, 74))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('develop', 'PosReg', (121, 128))	('p53', 'Gene', '7157', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mice', 'Species', '10090', (5, 9))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
704945	20827430	The functional impact of this p53 polymorphism has been reported and the Arg/Arg genotype seems to induce apoptosis with faster kinetics and to suppress transformation more efficiently than the Pro/Pro genotype.	('induce', 'PosReg', (99, 105))	('Pro', 'Chemical', 'MESH:D011392', (194, 197))	('Arg', 'Chemical', 'MESH:D001120', (73, 76))	('Pro', 'Chemical', 'MESH:D011392', (198, 201))	('apoptosis', 'CPA', (106, 115))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('Arg/Arg', 'Var', (73, 80))	('Arg', 'Chemical', 'MESH:D001120', (77, 80))	('suppress', 'NegReg', (144, 152))	('transformation', 'MPA', (153, 167))
704948	20827430	Thus, it is reasonable to hypothesize that the Arg72Pro polymorphism with reduced activity of p53 may play more important role in esophageal cancer risk.	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Arg72Pro', 'Var', (47, 55))	('activity', 'MPA', (82, 90))	('reduced', 'NegReg', (74, 81))	('Arg72Pro', 'SUBSTITUTION', 'None', (47, 55))	('esophageal cancer', 'Disease', (130, 147))
704949	20827430	In the present meta-analysis on the association between p53 Arg72Pro, GSTP1 Ile105Val polymorphisms and risk of esophageal cancer, we found that variant 72Pro of alleles p53 Arg72Pro could significantly increase the risk of esophageal cancer, although the association were not significantly evident in most studies individually.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Arg72Pro', 'Var', (60, 68))	('p53', 'Gene', (170, 173))	('Pro', 'Chemical', 'MESH:D011392', (155, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (224, 241))	('p53', 'Gene', '7157', (56, 59))	('Arg72Pro', 'SUBSTITUTION', 'None', (60, 68))	('association', 'Interaction', (36, 47))	('Pro', 'Chemical', 'MESH:D011392', (179, 182))	('increase', 'PosReg', (203, 211))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))	('esophageal cancer', 'Disease', (224, 241))	('p53', 'Gene', (56, 59))	('variant 72Pro', 'Var', (145, 158))	('Arg72Pro', 'Var', (174, 182))	('esophageal cancer', 'Disease', (112, 129))	('Pro', 'Chemical', 'MESH:D011392', (65, 68))	('GSTP1', 'Gene', '2950', (70, 75))	('GSTP1', 'Gene', (70, 75))	('p53', 'Gene', '7157', (170, 173))	('Ile105Val', 'Chemical', '-', (76, 85))	('Arg72Pro', 'SUBSTITUTION', 'None', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
704950	20827430	However, we failed to find any significant association between GSTP1 Ile105Val and esophageal cancer risk.	('esophageal cancer', 'Disease', (83, 100))	('GSTP1', 'Gene', (63, 68))	('Ile105Val', 'Chemical', '-', (69, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('GSTP1', 'Gene', '2950', (63, 68))	('Ile105Val', 'Var', (69, 78))
704951	20827430	In stratified analysis, we further observed that the association between p53 Arg72Pro and risk of esophageal cancer was remained significant in Asian population.	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('Arg72Pro', 'Var', (77, 85))	('esophageal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Arg72Pro', 'SUBSTITUTION', 'None', (77, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
704952	20827430	The different effect of p53 Arg72Pro polymorphism between ethnicity may result from different genetic background and environmental exposures, which may contribute to the frequency of ethnic difference.	('Arg72Pro', 'SUBSTITUTION', 'None', (28, 36))	('p53', 'Gene', '7157', (24, 27))	('p53', 'Gene', (24, 27))	('contribute', 'Reg', (152, 162))	('Arg72Pro', 'Var', (28, 36))
704954	20827430	Several data provided some support for one hypothesis that there may be existed significant interaction between p53 Arg72Pro or GSTP1 Ile105Val polymorphism and smoking, though there were not enough report support us to make meta-analysis in current research.	('Ile105Val', 'Chemical', '-', (134, 143))	('GSTP1', 'Gene', '2950', (128, 133))	('Ile105Val', 'Var', (134, 143))	('Arg72Pro', 'Var', (116, 124))	('p53', 'Gene', (112, 115))	('GSTP1', 'Gene', (128, 133))	('Arg72Pro', 'SUBSTITUTION', 'None', (116, 124))	('p53', 'Gene', '7157', (112, 115))
704955	20827430	Although there have been consistent findings that the p53 codon 72 Pro/Pro genotype was associated with increased esophageal SCC risk, it is worth mentioning that there are 2 main forms of esophageal cancer histologically, squamous cell carcinoma (SCC) and adenocarcinoma, and each has distinct etiologic and pathologic characteristics.	('esophageal cancer', 'Disease', (189, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('SCC', 'Gene', (125, 128))	('SCC', 'Gene', '6317', (125, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (223, 246))	('Pro', 'Chemical', 'MESH:D011392', (67, 70))	('SCC', 'Gene', '6317', (248, 251))	('p53', 'Gene', '7157', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('squamous cell carcinoma', 'Disease', (223, 246))	('SCC', 'Gene', (248, 251))	('adenocarcinoma', 'Disease', (257, 271))	('p53', 'Gene', (54, 57))	('codon 72', 'Var', (58, 66))	('Pro', 'Chemical', 'MESH:D011392', (71, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (189, 206))	('adenocarcinoma', 'Disease', 'MESH:D000230', (257, 271))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))
704960	20827430	More molecular epidemiological studies on adenocarcinoma are needed to further elucidate the real association of the p53 Arg72Pro and GSTP1 Ile105Val polymorphism with esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('GSTP1', 'Gene', (134, 139))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('Ile105Val', 'Chemical', '-', (140, 149))	('Arg72Pro', 'SUBSTITUTION', 'None', (121, 129))	('adenocarcinoma', 'Disease', (42, 56))	('GSTP1', 'Gene', '2950', (134, 139))	('esophageal carcinogenesis', 'Disease', (168, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('adenocarcinoma', 'Disease', 'MESH:D000230', (42, 56))	('Ile105Val', 'Var', (140, 149))	('Arg72Pro', 'Var', (121, 129))
704961	20827430	In conclusion, this meta-analysis of 13 case-control studies provided evidence that the p53 Arg72Pro polymorphism, but not the GSTP1 Ile105Val, was significantly associated with increased risk of esophageal cancer, especially in Asian.	('Ile105Val', 'Chemical', '-', (133, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('GSTP1', 'Gene', (127, 132))	('Arg72Pro', 'Var', (92, 100))	('associated', 'Reg', (162, 172))	('Asian', 'Disease', (229, 234))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('Arg72Pro', 'SUBSTITUTION', 'None', (92, 100))	('GSTP1', 'Gene', '2950', (127, 132))	('esophageal cancer', 'Disease', (196, 213))
705001	18159607	However, about 10% of sporadic colorectal cancers have microsatellite instability.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('colorectal cancers', 'Disease', 'MESH:D015179', (31, 49))	('microsatellite instability', 'Var', (55, 81))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('colorectal cancers', 'Disease', (31, 49))
705002	18159607	We were concerned about the result of microsatellite instability in the sporadic colorectal tumors under mechanical stress and carcinogens.	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('colorectal tumors', 'Disease', 'MESH:D015179', (81, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal tumors', 'Disease', (81, 98))	('microsatellite', 'Var', (38, 52))
705007	29191187	Short surgical outcomes were retrospectively compared between 30 patients at high risk for postoperative pulmonary complications who underwent a PMT (PMT group) and 64 patients at standard risk without a PMT (non-PMT group).	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (91, 128))	('pulmonary complications', 'Phenotype', 'HP:0006532', (105, 128))	('postoperative pulmonary complications', 'Disease', (91, 128))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (168, 176))	('PMT', 'Var', (145, 148))
705009	29191187	Preoperative pulmonary function was lower in the PMT group than in the non-PMT group: FEV1.0 (2.41 vs. 2.68 L, p = 0.035), and the proportion of patients with FEV1.0% <60 (13.3% vs. 0%, p = 0.009).	('lower', 'NegReg', (36, 41))	('pulmonary function', 'CPA', (13, 31))	('patients', 'Species', '9606', (145, 153))	('PMT', 'Var', (49, 52))
705050	29191187	The proportion of patients with FEV1.0% less than 60% was significantly higher in the PMT group than that in the non-PMT group.	('PMT', 'Var', (86, 89))	('patients', 'Species', '9606', (18, 26))	('higher', 'PosReg', (72, 78))
705071	29191187	Among these potential risk factors, multivariate analysis identified FEV1.0% < 70% and vocal cord palsy as independent risk factors.	('vocal cord palsy', 'Disease', 'MESH:D014826', (87, 103))	('FEV1.0% < 70%', 'Var', (69, 82))	('vocal cord palsy', 'Disease', (87, 103))
705084	29191187	A multivariate analysis revealed that FEV1.0% <70% and vocal cord palsy were independent risk factors related to a DMT.	('FEV1.0', 'Var', (38, 44))	('vocal cord palsy', 'Disease', 'MESH:D014826', (55, 71))	('DMT', 'Disease', (115, 118))	('vocal cord palsy', 'Disease', (55, 71))	('DMT', 'Chemical', '-', (115, 118))
705111	28147311	Here we showed that the knockdown of SATB1 in esophageal cancer cell lines diminished the cell proliferation, survival and invasion.	('diminished', 'NegReg', (75, 85))	('invasion', 'CPA', (123, 131))	('cell proliferation', 'CPA', (90, 108))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('knockdown', 'Var', (24, 33))	('SATB1', 'Gene', (37, 42))	('SATB1', 'Gene', '6304', (37, 42))
705125	28147311	[2015] also found esophageal squamous cell carcinoma (ESCC) patients with high SATB1 expression had significantly shorter survival than those with low SATB1 expression, which indicates high SATB1 expression might serve as a predictive biomarker of poor prognosis in ESCC and possibly could be a promising new candidate for targeted therapies.	('ESCC', 'Disease', (266, 270))	('expression', 'Var', (85, 95))	('esophageal squamous cell carcinoma', 'Disease', (18, 52))	('survival', 'MPA', (122, 130))	('expression', 'Species', '29278', (85, 95))	('expression', 'Species', '29278', (157, 167))	('expression', 'Species', '29278', (196, 206))	('SATB1', 'Gene', (79, 84))	('patients', 'Species', '9606', (60, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (29, 52))	('shorter', 'NegReg', (114, 121))	('SATB1', 'Gene', (190, 195))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (18, 52))	('SATB1', 'Gene', '6304', (79, 84))	('SATB1', 'Gene', (151, 156))	('SATB1', 'Gene', '6304', (190, 195))	('high', 'Var', (74, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('SATB1', 'Gene', '6304', (151, 156))
705136	28147311	Aliquots of early log phase 5 x 103/well SATB1 knockdown cells (siSATB1) or control cells (siN) were cultured in 96-well plates for 0, 24, 48, and 72 hrs.	('SATB1', 'Gene', '6304', (66, 71))	('knockdown', 'Var', (47, 56))	('SATB1', 'Gene', (41, 46))	('SATB1', 'Gene', (66, 71))	('SATB1', 'Gene', '6304', (41, 46))
705138	28147311	The knockdown of SATB1 diminished the proliferation and survival of TE-1 cells from 48 h to 96 h (p < 0.001).	('proliferation', 'CPA', (38, 51))	('SATB1', 'Gene', '6304', (17, 22))	('diminished', 'NegReg', (23, 33))	('SATB1', 'Gene', (17, 22))	('survival', 'CPA', (56, 64))	('knockdown', 'Var', (4, 13))	('TE-1', 'CellLine', 'CVCL:1759', (68, 72))
705141	28147311	The SATB1 knockdown indeed caused increased apoptosis in TE-1 cells from 3.87% to 12.07%.	('SATB1', 'Gene', (4, 9))	('SATB1', 'Gene', '6304', (4, 9))	('apoptosis', 'CPA', (44, 53))	('knockdown', 'Var', (10, 19))	('TE-1', 'CellLine', 'CVCL:1759', (57, 61))
705147	28147311	As showed in Figure 1C and Figure 1D, the knockdown of STAB1 by siRNA in these two cell lines was able to induce anti-invasive effects in vitro.	('was', 'Gene', (94, 97))	('STAB1', 'Gene', (55, 60))	('anti-invasive effects', 'CPA', (113, 134))	('was', 'Gene', '101929007', (94, 97))	('STAB1', 'Gene', '23166', (55, 60))	('knockdown', 'Var', (42, 51))
705151	28147311	Therefore, similar analyses were also performed to identify the differentially changed genes in breast cancer cells after knock-down of SATB1.	('SATB1', 'Gene', '6304', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('knock-down', 'Var', (122, 132))	('SATB1', 'Gene', (136, 141))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
705158	28147311	PPI networks were constructed and visualized in Cytoscape for significantly changed genes after knock-down of SATB1 in TE-1 cells and MDA-MB-231 cells under 2D culture condition and 3D culture condition (Figure 2C, 2D and 2E).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (134, 144))	('changed', 'Reg', (76, 83))	('knock-down', 'Var', (96, 106))	('SATB1', 'Gene', (110, 115))	('SATB1', 'Gene', '6304', (110, 115))	('TE-1', 'CellLine', 'CVCL:1759', (119, 123))
705163	28147311	To gain better insight into the gene interactions that caused by SATB1 knockdown in cancer cells, corresponding GO biological process and KEGG pathway analysis were conducted for DEGs of each comparison.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('SATB1', 'Gene', (65, 70))	('SATB1', 'Gene', '6304', (65, 70))	('knockdown', 'Var', (71, 80))	('caused', 'Reg', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
705164	28147311	PPI networks were also constructed for DEGs in "biological regulation" (Figure 3A), and "cellular process" (Figure 3B) and "cell migration" (Figure 3C) in SATB1 knock-down TE-1 cells.	('knock-down', 'Var', (161, 171))	('cell migration', 'CPA', (124, 138))	('TE-1', 'CellLine', 'CVCL:1759', (172, 176))	('SATB1', 'Gene', (155, 160))	('SATB1', 'Gene', '6304', (155, 160))	('cellular process', 'CPA', (89, 105))
705170	28147311	The results showed a significant ~4-fold reduction of FN1 mRNA level and ~3-fold reduction of PDGFRB mRNA level after SATB1 knockdown in TE-1 cells (Figure 3D and 3E, left).	('knockdown', 'Var', (124, 133))	('TE-1', 'CellLine', 'CVCL:1759', (137, 141))	('FN1', 'Gene', (54, 57))	('PDGFRB', 'Gene', '5159', (94, 100))	('PDGFRB', 'Gene', (94, 100))	('reduction', 'NegReg', (81, 90))	('SATB1', 'Gene', '6304', (118, 123))	('FN1', 'Gene', '2335', (54, 57))	('SATB1', 'Gene', (118, 123))	('reduction', 'NegReg', (41, 50))
705171	28147311	While the two target protein level after SATB1 knockdown was also greatly reduced (Figure 3D and 3E, right).	('was', 'Gene', '101929007', (57, 60))	('two target protein level', 'MPA', (10, 34))	('knockdown', 'Var', (47, 56))	('SATB1', 'Gene', (41, 46))	('was', 'Gene', (57, 60))	('SATB1', 'Gene', '6304', (41, 46))	('reduced', 'NegReg', (74, 81))
705172	28147311	Similarly, knockdown of SATB1 in EC-109 cells also caused mRNA and protein expression level reduction for both genes showed by qPCR and western blots (Figure 3F and 3G).	('SATB1', 'Gene', (24, 29))	('SATB1', 'Gene', '6304', (24, 29))	('reduction', 'NegReg', (92, 101))	('EC-109', 'CellLine', 'CVCL:6898', (33, 39))	('expression', 'Species', '29278', (75, 85))	('knockdown', 'Var', (11, 20))
705174	28147311	As showed in the Figure 3H, the luciferase signaling driven by the promoters of FN1 or PDGFRB was significantly increased (~2.5 fold) after SATB1 transfection.	('FN1', 'Gene', (80, 83))	('was', 'Gene', (94, 97))	('SATB1', 'Gene', (140, 145))	('SATB1', 'Gene', '6304', (140, 145))	('PDGFRB', 'Gene', '5159', (87, 93))	('PDGFRB', 'Gene', (87, 93))	('was', 'Gene', '101929007', (94, 97))	('increased', 'PosReg', (112, 121))	('luciferase signaling', 'MPA', (32, 52))	('FN1', 'Gene', '2335', (80, 83))	('transfection', 'Var', (146, 158))
705179	28147311	While knockdown of SATB1 caused the reduced expression of FN1, this reduction was reversed by the overexpression of pcDNA3.1-FN1 (Figure 4B).	('was', 'Gene', '101929007', (78, 81))	('expression', 'Species', '29278', (102, 112))	('expression', 'MPA', (44, 54))	('FN1', 'Gene', '2335', (58, 61))	('FN1', 'Gene', (58, 61))	('was', 'Gene', (78, 81))	('reduced', 'NegReg', (36, 43))	('knockdown', 'Var', (6, 15))	('FN1', 'Gene', '2335', (125, 128))	('SATB1', 'Gene', (19, 24))	('SATB1', 'Gene', '6304', (19, 24))	('FN1', 'Gene', (125, 128))	('expression', 'Species', '29278', (44, 54))
705180	28147311	The MTT readout indicated that the diminished proliferation and survival at 48 h in SATB1 knockdown TE-1 cells was reversed by the overexpression of FN1.	('survival', 'CPA', (64, 72))	('knockdown', 'Var', (90, 99))	('was', 'Gene', (111, 114))	('was', 'Gene', '101929007', (111, 114))	('TE-1', 'CellLine', 'CVCL:1759', (100, 104))	('expression', 'Species', '29278', (135, 145))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('FN1', 'Gene', '2335', (149, 152))	('SATB1', 'Gene', '6304', (84, 89))	('diminished', 'NegReg', (35, 45))	('FN1', 'Gene', (149, 152))	('SATB1', 'Gene', (84, 89))
705195	28147311	Here we showed that the migration of TE-1cells was inhibited by knockdown of STAB1 in in vitro Transwell assay, suggesting STAB1 is one of the contributors for esophageal cancer invasion.	('STAB1', 'Gene', (123, 128))	('was', 'Gene', '101929007', (47, 50))	('STAB1', 'Gene', '23166', (77, 82))	('was', 'Gene', (47, 50))	('STAB1', 'Gene', '23166', (123, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('esophageal cancer', 'Disease', (160, 177))	('STAB1', 'Gene', (77, 82))	('knockdown', 'Var', (64, 73))	('inhibited', 'NegReg', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('TE-1', 'CellLine', 'CVCL:1759', (37, 41))	('migration', 'CPA', (24, 33))
705204	28147311	The "biological regulation", "cellular process" and "cell migration" pathways enriched in SATB1 knockdown TE-1 cells all have two highly connected genes: FN1 and PDGFRB, implying these two hub genes might play essential roles in above mentioned pathways.	('knockdown', 'Var', (96, 105))	('TE-1', 'CellLine', 'CVCL:1759', (106, 110))	('cellular process', 'CPA', (30, 46))	('FN1', 'Gene', '2335', (154, 157))	('FN1', 'Gene', (154, 157))	('SATB1', 'Gene', '6304', (90, 95))	('cell migration', 'CPA', (53, 67))	('hub', 'Gene', '1993', (189, 192))	('hub', 'Gene', (189, 192))	('PDGFRB', 'Gene', '5159', (162, 168))	('men', 'Species', '9606', (235, 238))	('SATB1', 'Gene', (90, 95))	('PDGFRB', 'Gene', (162, 168))
705247	28147311	Cluster Profiler (version 2.4.2) in R package was used to perform GO categories and KEGG pathways enrichment analysis with significant overrepresentation in DEGs comparing with the whole genome.	('men', 'Species', '9606', (104, 107))	('was', 'Gene', (46, 49))	('KEGG pathways', 'Pathway', (84, 97))	('DEGs', 'Var', (157, 161))	('was', 'Gene', '101929007', (46, 49))
705297	25896887	In the present study, reduced uptake (myocardial metabolic disorders) corresponding to RT fields was observed as it was in our previous study.	('myocardial metabolic disorders', 'Disease', (38, 68))	('myocardial metabolic disorders', 'Disease', 'MESH:D009202', (38, 68))	('metabolic disorder', 'Phenotype', 'HP:0001939', (49, 67))	('uptake', 'MPA', (30, 36))	('reduced', 'NegReg', (22, 29))	('RT fields', 'Var', (87, 96))
705298	25896887	Although I-123 BMIPP scintigraphy has not been used routinely compared with myocardial perfusion scintigraphy, some studies showed that I-123 BMIPP is superior to perfusion imaging for evaluating the extent and severity of damage to the myocardium in patients with acute and old myocardial infarctions.	('myocardial infarctions', 'Disease', 'MESH:D009203', (279, 301))	('myocardial infarctions', 'Disease', (279, 301))	('myocardial infarctions', 'Phenotype', 'HP:0001658', (279, 301))	('I-123 BMIPP', 'Chemical', '-', (9, 20))	('I-123 BMIPP', 'Chemical', '-', (136, 147))	('patients', 'Species', '9606', (251, 259))	('I-123', 'Var', (136, 141))	('myocardial infarction', 'Phenotype', 'HP:0001658', (279, 300))
705308	25896887	Because Case 5 in which reduced uptake corresponding to RT fields was distinct had elevation of BNP levels, ECG change and pericardial effusion, we intend to follow up this patient more carefully.	('BNP', 'Gene', (96, 99))	('pericardial effusion', 'Disease', 'MESH:D010490', (123, 143))	('ECG change', 'MPA', (108, 118))	('patient', 'Species', '9606', (173, 180))	('BNP', 'Gene', '4879', (96, 99))	('pericardial effusion', 'Phenotype', 'HP:0001698', (123, 143))	('elevation', 'PosReg', (83, 92))	('pericardial effusion', 'Disease', (123, 143))	('RT fields', 'Var', (56, 65))
705324	25896887	Some studies showed that cisplatin was associated with cardiotoxicity.	('cardiotoxicity', 'Disease', 'MESH:D066126', (55, 69))	('cisplatin', 'Var', (25, 34))	('cardiotoxicity', 'Disease', (55, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (25, 34))
705403	24339953	5) suggested that the patrilineal lineage of haplogroup O3a3c1-M117 individuals was the Taihang Mountain and Fujian high-risk individuals and Chaoshan EC patients, who constituted the central node, and patients of the O3a3c1-M117 individuals from the 2 studied areas were largely from one one-step neighbors containing 1 Chaoshan high-risk individual and 1 Chaoshan GCC patient.	('O3a3c1-M117', 'Var', (218, 229))	('patient', 'Species', '9606', (154, 161))	('patient', 'Species', '9606', (202, 209))	('patients', 'Species', '9606', (154, 162))	('patient', 'Species', '9606', (370, 377))	('GCC', 'Chemical', '-', (366, 369))	('patients', 'Species', '9606', (202, 210))	('O3a3c1-M117', 'Var', (56, 67))
705408	24339953	Recent genome-wide association studies from China high-risk areas showed significant association of a variant at 10q23 in PLCE1 and both esophageal squamous cell carcinoma and gastric cardia adenocarcinoma, which highlights the common genetic mechanisms that may contribute to the etiology of both cancers.	('esophageal squamous cell carcinoma', 'Disease', (137, 171))	('gastric cardia adenocarcinoma', 'Disease', (176, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('cancers', 'Disease', 'MESH:D009369', (298, 305))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('cancers', 'Disease', (298, 305))	('PLCE1', 'Gene', (122, 127))	('PLCE1', 'Gene', '51196', (122, 127))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (137, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (176, 205))	('variant at 10q23', 'Var', (102, 118))	('association', 'Interaction', (85, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
705415	22028801	Epigenetic Subgroups of Esophageal and Gastric Adenocarcinoma with Differential GATA5 DNA Methylation Associated with Clinical and Lifestyle Factors Adenocarcinomas located near the gastroesophageal junction have unclear etiology and are difficult to classify.	('Associated', 'Reg', (102, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Gastric Adenocarcinoma', 'Disease', (39, 61))	('Gastric Adenocarcinoma', 'Disease', 'MESH:D013274', (39, 61))	('Methylation', 'Var', (90, 101))	('gastroesophageal junction', 'Disease', (182, 207))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (182, 207))	('Adenocarcinomas', 'Disease', (149, 164))	('GATA5', 'Gene', (80, 85))	('GATA5', 'Gene', '140628', (80, 85))	('Adenocarcinomas', 'Disease', 'MESH:D000230', (149, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('Esophageal', 'Disease', (24, 34))
705427	22028801	Promoter CpG island hypermethylation is a common occurrence in human cancers, and is generally associated with transcriptional silencing of the associated gene.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('hypermethylation', 'Var', (20, 36))	('human', 'Species', '9606', (63, 68))	('transcriptional', 'MPA', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('associated', 'Reg', (95, 105))	('cancers', 'Disease', (69, 76))
705429	22028801	We and others have shown that targets for transcription repression by the Polycomb group (PcG) proteins in human embryonic stem cells are particularly predisposed to CpG island hypermethylation in cancer.	('predisposed', 'Reg', (151, 162))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('CpG island hypermethylation', 'Var', (166, 193))	('human', 'Species', '9606', (107, 112))	('cancer', 'Disease', (197, 203))	('PcG', 'Gene', (90, 93))	('hypermethylation', 'Var', (177, 193))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
705430	22028801	Irrespective of their role in the oncogenic process, all cancer-specific DNA methylation changes constitute potential biomarkers that might be exploited as clinical tools for diagnosis or early detection of cancer, appraisal of disease progression or response to therapy, or risk assessment in surveillance programs.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (207, 213))	('changes', 'Var', (89, 96))	('cancer', 'Disease', (57, 63))	('men', 'Species', '9606', (286, 289))	('DNA', 'Gene', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('methylation changes', 'Var', (77, 96))
705439	22028801	We have also shown that hypermethylation of the APC gene promoter in the plasma of patients with EAC is associated with reduced patient survival.	('hypermethylation', 'Var', (24, 40))	('EAC', 'Disease', (97, 100))	('patient survival', 'CPA', (128, 144))	('APC', 'Disease', 'MESH:D011125', (48, 51))	('patient', 'Species', '9606', (83, 90))	('patient', 'Species', '9606', (128, 135))	('patients', 'Species', '9606', (83, 91))	('APC', 'Disease', (48, 51))	('reduced', 'NegReg', (120, 127))
705453	22028801	We further excluded 14 samples (13 patients): one sample was from a patient that had previous cancer, eight samples did not have gastric/esophageal tissues, and five samples were omitted because the reported daily caloric intake of these patients was either too low (<=500 calories per day) or too high (>7,000 calories per day).	('<=500', 'Var', (267, 272))	('patient', 'Species', '9606', (68, 75))	('patient', 'Species', '9606', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (35, 43))	('patient', 'Species', '9606', (238, 245))	('patients', 'Species', '9606', (238, 246))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
705467	22028801	We exploited this characteristic in order to investigate the potential associations between specific epigenetic changes in tumors and epidemiological risk factors of exposure.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('epigenetic changes', 'Var', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
705499	22028801	We also did not find any significant associations between the number of methylated genes in the analyzed tumor samples and any of the clinical characteristics or epidemiological risk factors.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (105, 110))	('methylated', 'Var', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
705534	22028801	Our finding is supportive of results of a recent study that showed modest differences in DNA methylation between normal gastric cardiac mucosa and esophageal squamous mucosa, despite considerable differences in histology and expression profiles between these tissues.	('DNA', 'Gene', (89, 92))	('gastric cardiac mucosa', 'Disease', (120, 142))	('esophageal squamous mucosa', 'Disease', (147, 173))	('gastric cardiac mucosa', 'Disease', 'MESH:D006338', (120, 142))	('methylation', 'Var', (93, 104))	('esophageal squamous mucosa', 'Disease', 'MESH:D000077277', (147, 173))
705543	22028801	Abnormal DNA methylation of the GATA5 gene promoter with subsequent loss of function has been previously reported in several cancers including esophageal,, gastric, colorectal, pancreatic, lung, and ovarian cancers.	('loss of function', 'NegReg', (68, 84))	('esophageal', 'Disease', (143, 153))	('colorectal', 'Disease', 'MESH:D015179', (165, 175))	('ovarian cancers', 'Disease', (199, 214))	('reported', 'Reg', (105, 113))	('ovarian cancers', 'Disease', 'MESH:D010051', (199, 214))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('pancreatic', 'Disease', 'MESH:D010195', (177, 187))	('cancers', 'Disease', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('GATA5', 'Gene', (32, 37))	('lung', 'Disease', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic', 'Disease', (177, 187))	('DNA methylation', 'Var', (9, 24))	('ovarian cancers', 'Phenotype', 'HP:0100615', (199, 214))	('GATA5', 'Gene', '140628', (32, 37))	('colorectal', 'Disease', (165, 175))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Disease', (125, 132))	('gastric', 'Disease', (156, 163))
705545	22028801	In our study, GATA5 DNA methylation, was also not significantly associated with any of the three gastroesophageal tumor subtypes.	('gastroesophageal tumor', 'Phenotype', 'HP:0100751', (97, 119))	('associated', 'Reg', (64, 74))	('gastroesophageal tumor', 'Disease', (97, 119))	('GATA5', 'Gene', '140628', (14, 19))	('GATA5', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('methylation', 'Var', (24, 35))	('gastroesophageal tumor', 'Disease', 'MESH:D005764', (97, 119))
705549	22028801	However, our finding showing a lack of association between the GATA5 methylation or GATA5 methylation-based groups and the degree of tumor differentiation does not support this hypothesis.	('GATA5', 'Gene', (63, 68))	('GATA5', 'Gene', '140628', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('GATA5', 'Gene', '140628', (84, 89))	('GATA5', 'Gene', (84, 89))	('tumor', 'Disease', (133, 138))	('methylation', 'Var', (69, 80))
705554	22028801	Moreover, GATA5 promoter DNA methylation was shown to be associated with high levels of DNA damage caused by radiation exposure.	('methylation', 'Var', (29, 40))	('GATA5', 'Gene', (10, 15))	('DNA damage', 'MPA', (88, 98))	('GATA5', 'Gene', '140628', (10, 15))	('associated', 'Reg', (57, 67))
705559	22028801	A positive association between high BMI and methylation levels of a Line region has been recently reported in head and neck squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('neck squamous cell carcinoma', 'Disease', (119, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (119, 147))	('methylation levels', 'MPA', (44, 62))	('high', 'Var', (31, 35))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (110, 147))	('reported', 'Reg', (98, 106))
705571	19002670	Most of the proposed beneficial effects have been attributed to the polyphenolic compounds in tea, but the nature of these activities and the molecular mechanisms of their actions remain unclear.	('tea', 'Gene', '11988', (94, 97))	('beneficial effects', 'PosReg', (21, 39))	('polyphenolic compounds', 'Var', (68, 90))	('polyphenol', 'Chemical', 'MESH:D059808', (68, 78))	('tea', 'Gene', (94, 97))
705594	19002670	Tea catechins are characterized by the di- or tri-hydroxyl groups on the B-ring and the meta-5,7-dihydroxyl groups on the A ring.	('catechins', 'Chemical', 'MESH:D002392', (4, 13))	('Tea', 'Gene', (0, 3))	('5,7-dihydroxyl', 'Chemical', '-', (93, 107))	('Tea', 'Gene', '11988', (0, 3))	('tri-hydroxyl', 'Var', (46, 58))
705595	19002670	The antioxidative activity is further increased by the presence of the trihydroxyl structure in the D-ring (gallate) in EGCG and ECG.	('presence', 'Var', (55, 63))	('ECG', 'Chemical', 'MESH:C062669', (129, 132))	('trihydroxyl structure', 'MPA', (71, 92))	('EGCG', 'Chemical', 'MESH:C045651', (120, 124))	('antioxidative activity', 'MPA', (4, 26))	('increased', 'PosReg', (38, 47))	('trihydroxyl', 'Chemical', '-', (71, 82))
705608	19002670	The hepatic levels of antioxidants (e.g., reduced glutathione) as well as antioxidant enzymes (e.g., superoxide dismutase) were increased by the EGCG treatment.	('men', 'Species', '9606', (155, 158))	('EGCG', 'Var', (145, 149))	('superoxide dismutase', 'Gene', '6647', (101, 121))	('antioxidant enzymes', 'MPA', (74, 93))	('hepatic levels of antioxidants', 'MPA', (4, 34))	('increased', 'PosReg', (128, 137))	('superoxide dismutase', 'Gene', (101, 121))	('glutathione', 'Chemical', 'MESH:D005978', (50, 61))	('EGCG', 'Chemical', 'MESH:C045651', (145, 149))
705640	19002670	We hypothesize that these metabolites form as the result of oxidation of EGCG to a quinone or semi-quinone that then reacts with the sulfhydryl group of cysteine.	('quinone', 'Chemical', 'MESH:C004532', (83, 90))	('quinone', 'Chemical', 'MESH:C004532', (99, 106))	('EGCG', 'Gene', (73, 77))	('oxidation', 'Var', (60, 69))	('cysteine', 'Chemical', 'MESH:D003545', (153, 161))	('reacts', 'MPA', (117, 123))	('sulfhydryl group', 'MPA', (133, 149))	('EGCG', 'Chemical', 'MESH:C045651', (73, 77))
705708	19002670	An interesting recent study suggested that EGCG could prevent photocarcinogenesis via an IL-12 dependent DNA repair pathway.	('IL-12 dependent DNA repair pathway', 'Pathway', (89, 123))	('EGCG', 'Chemical', 'MESH:C045651', (43, 47))	('EGCG', 'Var', (43, 47))	('photocarcinogenesis', 'Disease', (62, 81))	('prevent', 'NegReg', (54, 61))
705711	19002670	heavy smokers and non-smokers were treated with green tea (400-500 mg green tea powder per cup) 5 times per day for 4 weeks.	('tea', 'Gene', (76, 79))	('tea', 'Gene', '11988', (76, 79))	('tea', 'Gene', (54, 57))	('400-500 mg', 'Var', (59, 69))	('tea', 'Gene', '11988', (54, 57))
705726	19002670	Total tumor multiplicity was decreased by both dietary PPE (0.12%) or the corresponding amount of dietary EGCG (0.08%).	('EGCG', 'Chemical', 'MESH:C045651', (106, 110))	('PPE', 'Var', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('decreased', 'NegReg', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('PPE', 'Chemical', 'MESH:C472086', (55, 58))
705727	19002670	Although PPE appeared to be more effective than EGCG at reducing total tumor multiplicity, the difference was not statistically significant.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('PPE', 'Chemical', 'MESH:C472086', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('reducing', 'NegReg', (56, 64))	('PPE', 'Var', (9, 12))	('EGCG', 'Chemical', 'MESH:C045651', (48, 52))	('tumor', 'Disease', (71, 76))
705737	19002670	This decrease in ACF was associated with a 40% decrease in bromodeoxyuridine labeling in the crypt, suggesting that EGCG is inhibiting aberrant cell proliferation.	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (135, 162))	('aberrant cell proliferation', 'CPA', (135, 162))	('rat', 'Species', '10116', (156, 159))	('EGCG', 'Chemical', 'MESH:C045651', (116, 120))	('bromodeoxyuridine', 'Chemical', 'MESH:D001973', (59, 76))	('decrease', 'NegReg', (47, 55))	('ACF', 'MPA', (17, 20))	('EGCG', 'Var', (116, 120))	('inhibiting', 'NegReg', (124, 134))	('bromodeoxyuridine labeling', 'MPA', (59, 85))	('decrease', 'NegReg', (5, 13))
705740	19002670	In our recent study, the oral administration of 0.5% PPE or 0.044% caffeine in the drinking fluid for 32 weeks was found to inhibit the progression of lung adenomas to adenocarcinomas in A/J mice that had been treated with a single dose of NNK 20 weeks earlier.	('progression', 'CPA', (136, 147))	('NNK', 'Chemical', 'MESH:C016583', (240, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('lung adenomas to adenocarcinomas', 'Disease', (151, 183))	('caffeine', 'Chemical', 'MESH:D002110', (67, 75))	('PPE', 'Chemical', 'MESH:C472086', (53, 56))	('rat', 'Species', '10116', (38, 41))	('mice', 'Species', '10090', (191, 195))	('lung adenomas to adenocarcinomas', 'Disease', 'MESH:D000236', (151, 183))	('inhibit', 'NegReg', (124, 131))	('PPE', 'Var', (53, 56))	('0.044%', 'Var', (60, 66))
705772	19002670	Urinary EGC positivity showed a statistically significant inverse association with gastric cancer (OR = 0.52) after adjustment for confounders.	('Urinary EGC', 'Protein', (0, 11))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('inverse', 'NegReg', (58, 65))	('gastric cancer', 'Disease', (83, 97))	('EGC', 'Chemical', 'MESH:C057580', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('positivity', 'Var', (12, 22))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('men', 'Species', '9606', (122, 125))
705779	19002670	The authors concluded that individuals with a low-activity COMT allele have a reduced risk of breast cancer because they metabolize tea polyphenols less efficiently and, therefore, had prolonged exposure to the active parent compound.	('less', 'NegReg', (148, 152))	('low-activity', 'Var', (46, 58))	('tea', 'Gene', (132, 135))	('COMT', 'Gene', '1312', (59, 63))	('polyphenols', 'Chemical', 'MESH:D059808', (136, 147))	('tea', 'Gene', '11988', (132, 135))	('COMT', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('exposure', 'MPA', (195, 203))	('reduced', 'NegReg', (78, 85))	('metabolize', 'MPA', (121, 131))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
705796	19002670	Only 3% of the patients in the catechin treatment group developed prostate cancer, whereas the rate of cancer development on the placebo group was 30%.	('patients', 'Species', '9606', (15, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('catechin', 'Chemical', 'MESH:D002392', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('men', 'Species', '9606', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('rat', 'Species', '10116', (95, 98))	('men', 'Species', '9606', (117, 120))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (103, 109))	('catechin', 'Var', (31, 39))
705813	33408485	LncRNA GIHCG Promotes the Development of Esophageal Cancer by Modulating miR-29b-3p/ANO1 Axis Esophageal cancer is one of the most frequent cancers with a higher mortality worldwide.	('mortality', 'Disease', (162, 171))	('ANO1', 'Gene', '55107', (84, 88))	('Modulating', 'Var', (62, 72))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (140, 146))	('Cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('mortality', 'Disease', 'MESH:D003643', (162, 171))	('cancers', 'Disease', (140, 147))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('ANO1', 'Gene', (84, 88))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
705821	33408485	Downregulation of GIHCG significantly inhibited the growth, colony formation, invasion, migration and induced apoptosis of esophageal cancer cells in vitro.	('esophageal cancer', 'Disease', (123, 140))	('growth', 'CPA', (52, 58))	('invasion', 'CPA', (78, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('GIHCG', 'Chemical', '-', (18, 23))	('induced', 'Reg', (102, 109))	('Downregulation', 'Var', (0, 14))	('inhibited', 'NegReg', (38, 47))	('migration', 'CPA', (88, 97))	('colony formation', 'CPA', (60, 76))	('GIHCG', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('apoptosis', 'CPA', (110, 119))
705822	33408485	Bioinformatic analysis and RIP assay determined that GIHCG was a sponge of miR-29b-3p, and ANO1 was a direct target of miR-29b-3p.	('ANO1', 'Gene', (91, 95))	('miR-29b-3p', 'Chemical', '-', (75, 85))	('miR-29b-3p', 'Chemical', '-', (119, 129))	('ANO1', 'Gene', '55107', (91, 95))	('miR-29b-3p', 'Var', (75, 85))	('GIHCG', 'Chemical', '-', (53, 58))
705824	33408485	Furthermore, in vivo experiment revealed that knockdown of GIHCG significantly inhibited tumor growth in nude mice.	('knockdown', 'Var', (46, 55))	('GIHCG', 'Chemical', '-', (59, 64))	('nude mice', 'Species', '10090', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('GIHCG', 'Gene', (59, 64))	('inhibited', 'NegReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
705832	33408485	For example, GIHCG is highly expressed in ovarian cancer tissues compared with normal tissues, and downregulation of GIHCG can efficiently inhibit the progression of ovarian cancer through stimulating cell cycle and cell proliferation by targeting miR-429.	('downregulation', 'Var', (99, 113))	('GIHCG', 'Chemical', '-', (13, 18))	('ovarian cancer', 'Disease', 'MESH:D010051', (42, 56))	('cell cycle', 'CPA', (201, 211))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('GIHCG', 'Gene', (117, 122))	('progression', 'CPA', (151, 162))	('cell proliferation', 'CPA', (216, 234))	('stimulating', 'PosReg', (189, 200))	('ovarian cancer', 'Disease', (42, 56))	('miR-429', 'Gene', (248, 255))	('ovarian cancer', 'Disease', 'MESH:D010051', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('ovarian cancer', 'Phenotype', 'HP:0100615', (42, 56))	('ovarian cancer', 'Disease', (166, 180))	('inhibit', 'NegReg', (139, 146))	('GIHCG', 'Chemical', '-', (117, 122))	('miR-429', 'Gene', '554210', (248, 255))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))
705835	33408485	In addition, GIHCG has also been found to play crucial oncogenic roles in several other malignancies such as breast cancer, hepatocellular carcinoma, colorectal cancer and renal cell carcinoma.	('GIHCG', 'Chemical', '-', (13, 18))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (124, 148))	('renal cell carcinoma', 'Disease', (172, 192))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (172, 192))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (124, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('malignancies', 'Disease', (88, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (150, 167))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('GIHCG', 'Var', (13, 18))	('colorectal cancer', 'Disease', (150, 167))	('breast cancer', 'Disease', (109, 122))	('hepatocellular carcinoma', 'Disease', (124, 148))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (172, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))
705838	33408485	MiR-29b-3p is shown to be significantly involved in the progression of human tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('involved', 'Reg', (40, 48))	('MiR-29b-3p', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MiR-29b-3p', 'Chemical', '-', (0, 10))	('human', 'Species', '9606', (71, 76))
705839	33408485	For example, upregulation of miR-29b-3p induces chondrocyte apoptosis and promotes the progression of osteoarthritis through targeting PGRN.	('promotes', 'PosReg', (74, 82))	('miR-29b-3p', 'Chemical', '-', (29, 39))	('osteoarthritis', 'Disease', 'MESH:D010003', (102, 116))	('PGRN', 'Gene', '2896', (135, 139))	('miR-29b-3p', 'Var', (29, 39))	('osteoarthritis', 'Disease', (102, 116))	('upregulation', 'PosReg', (13, 25))	('targeting', 'Reg', (125, 134))	('chondrocyte apoptosis', 'CPA', (48, 69))	('induces', 'PosReg', (40, 47))	('osteoarthritis', 'Phenotype', 'HP:0002758', (102, 116))	('PGRN', 'Gene', (135, 139))
705841	33408485	MiR-29b-3p is markedly overexpressed in plasma-derived extracellular vesicles of prostate cancer patients compared with that of healthy subjects, which may be considered as a potential biomarker for prostate cancer.	('prostate cancer', 'Disease', (81, 96))	('prostate cancer', 'Disease', 'MESH:D011471', (199, 214))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (199, 214))	('MiR-29b-3p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('prostate cancer', 'Disease', (199, 214))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('MiR-29b-3p', 'Chemical', '-', (0, 10))	('overexpressed', 'PosReg', (23, 36))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('patients', 'Species', '9606', (97, 105))
705853	33408485	All paired tissue samples were used to compare the expression levels of GIHCG, miR-29b-3p and ANO1.	('miR-29b-3p', 'Chemical', '-', (79, 89))	('ANO1', 'Gene', (94, 98))	('GIHCG', 'Chemical', '-', (72, 77))	('GIHCG', 'Gene', (72, 77))	('ANO1', 'Gene', '55107', (94, 98))	('miR-29b-3p', 'Var', (79, 89))
705880	33408485	Flow cytometric analysis for apoptosis rate was performed by using a FACSCalibur flow cytometer within 1 h. The wild type (WT) and mutant (MUT) of GIHCG or ANO1 containing the putative binding site with miR-29b-3p were amplified by PCR and cloned into pmirGLO luciferase reporter vector (Promega Corporation, Madison, WI, USA).	('ANO1', 'Gene', '55107', (156, 160))	('mutant', 'Var', (131, 137))	('GIHCG', 'Chemical', '-', (147, 152))	('miR-29b-3p', 'Chemical', '-', (203, 213))	('ANO1', 'Gene', (156, 160))	('GIHCG', 'Gene', (147, 152))
705901	33408485	In addition, Kaplan-Meier survival curve indicated that esophageal cancer patients with high GIHCG level had a poorer prognosis compared with that with low GIHCG level (p < 0.01) (Figure 1D).	('GIHCG', 'Chemical', '-', (156, 161))	('esophageal cancer', 'Disease', (56, 73))	('patients', 'Species', '9606', (74, 82))	('GIHCG', 'Var', (93, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('GIHCG', 'Chemical', '-', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('high GIHCG', 'Var', (88, 98))
705903	33408485	To further confirm the oncogenic role in esophageal cancer, si-GIHCG (small interfering RNA targeting GIHCG) or si-NC (negative control) was transfected into Ec-9706 and TE-10 cells, and qRT-PCR indicated that si-GIHCG significantly decreased the expression of GIHCG compared with si-NC in both Ec-9706 (p < 0.001) and TE-10 cells (p < 0.001) (Figure 2A).	('Ec-9706', 'CellLine', 'CVCL:E307', (158, 165))	('Ec-9706', 'CellLine', 'CVCL:E307', (295, 302))	('TE-10', 'CellLine', 'CVCL:1760', (319, 324))	('GIHCG', 'Chemical', '-', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('GIHCG', 'Chemical', '-', (102, 107))	('expression', 'MPA', (247, 257))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('decreased', 'NegReg', (233, 242))	('-GIHCG', 'Chemical', '-', (212, 218))	('GIHCG', 'Chemical', '-', (63, 68))	('-GIHCG', 'Chemical', '-', (62, 68))	('TE-10', 'CellLine', 'CVCL:1760', (170, 175))	('GIHCG', 'Chemical', '-', (261, 266))	('si-GIHCG', 'Var', (210, 218))	('esophageal cancer', 'Disease', (41, 58))
705905	33408485	Si-GIHCG significantly decreased colony number of both Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01) compared with si-NC (Figure 2C).	('TE-10', 'CellLine', 'CVCL:1760', (78, 83))	('Ec-9706', 'CellLine', 'CVCL:E307', (55, 62))	('-GIHCG', 'Chemical', '-', (2, 8))	('Si-GIHCG', 'Var', (0, 8))	('colony number', 'CPA', (33, 46))	('decreased', 'NegReg', (23, 32))
705906	33408485	Meanwhile, si-GIHCG significantly decreased the EdU-positive cells of both Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01) compared with si-NC (Figure 2D).	('si-GIHCG', 'Var', (11, 19))	('TE-10', 'CellLine', 'CVCL:1760', (98, 103))	('-GIHCG', 'Chemical', '-', (13, 19))	('decreased', 'NegReg', (34, 43))	('EdU-positive cells', 'CPA', (48, 66))	('Ec-9706', 'CellLine', 'CVCL:E307', (75, 82))	('EdU', 'Chemical', 'MESH:C031086', (48, 51))
705907	33408485	Transwell assay revealed that si-GIHCG not only inhibited the invasion of both Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01) compared with si-NC (Figure 2E) but also inhibited the migration of both Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01) compared with si-NC (Figure 2F).	('-GIHCG', 'Chemical', '-', (32, 38))	('TE-10', 'CellLine', 'CVCL:1760', (102, 107))	('migration', 'CPA', (180, 189))	('Ec-9706', 'CellLine', 'CVCL:E307', (79, 86))	('si-GIHCG', 'Var', (30, 38))	('inhibited', 'NegReg', (48, 57))	('TE-10', 'CellLine', 'CVCL:1760', (221, 226))	('invasion', 'CPA', (62, 70))	('inhibited', 'NegReg', (166, 175))	('Ec-9706', 'CellLine', 'CVCL:E307', (198, 205))
705910	33408485	To explore the mechanism of GIHCG in esophageal cancer, Starbase was used to predict the potential targets of GIHCH and the results showed that there was a putative binding site between GIHCG and miR-29b-3p (Figure 3A), suggesting that miR-29b-3p might be a potential target of GIHCG.	('miR-29b-3p', 'Var', (196, 206))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('binding', 'Interaction', (165, 172))	('GIHCG', 'Chemical', '-', (28, 33))	('GIHCG', 'Chemical', '-', (278, 283))	('miR-29b-3p', 'Chemical', '-', (196, 206))	('esophageal cancer', 'Disease', (37, 54))	('GIHCG', 'Chemical', '-', (186, 191))	('miR-29b-3p', 'Chemical', '-', (236, 246))	('GIHCG', 'Gene', (186, 191))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
705911	33408485	Then, Ec-9706 and TE-10 cells were transfected with miR-29b-3p mimics or miR-NC, and qRT-PCR revealed that miR-29b-3p mimics significantly increased the expression of miR-29b-3p in both Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01) compared with miR-NC (Figure 3B).	('miR-29b-3p', 'Chemical', '-', (167, 177))	('Ec-9706', 'CellLine', 'CVCL:E307', (6, 13))	('TE-10', 'CellLine', 'CVCL:1760', (209, 214))	('TE-10', 'CellLine', 'CVCL:1760', (18, 23))	('increased', 'PosReg', (139, 148))	('miR-29b-3p', 'Chemical', '-', (107, 117))	('miR-29b-3p mimics', 'Var', (107, 124))	('miR-29b-3p', 'Chemical', '-', (52, 62))	('Ec-9706', 'CellLine', 'CVCL:E307', (186, 193))	('miR-29b-3p', 'Var', (167, 177))	('expression', 'MPA', (153, 163))
705912	33408485	To determine their relationship, luciferase reporter assay was performed and the results indicated that miR-29b-3p mimics significantly decreased the relative luciferase activity of WT GIHCG vector in both Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01), while exhibited no obvious change on MUT GIHCG vector in two cell lines (Figure 3C).	('Ec-9706', 'CellLine', 'CVCL:E307', (206, 213))	('GIHCG', 'Chemical', '-', (294, 299))	('GIHCG', 'Chemical', '-', (185, 190))	('activity', 'MPA', (170, 178))	('miR-29b-3p', 'Chemical', '-', (104, 114))	('miR-29b-3p mimics', 'Var', (104, 121))	('TE-10', 'CellLine', 'CVCL:1760', (229, 234))	('decreased', 'NegReg', (136, 145))	('luciferase', 'Enzyme', (159, 169))
705913	33408485	Meanwhile, si-GIHCG significantly increased the expression of miR-29b-3p in both Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01) compared with si-NC, and overexpression of GIHCG (pc-GIHCG) markedly decreased miR-29b-3p in both Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01) compared with pc-NC (empty vector control) (Figure 3D).	('si-GIHCG', 'Var', (11, 19))	('miR-29b-3p', 'Gene', (62, 72))	('-GIHCG', 'Chemical', '-', (13, 19))	('decreased', 'NegReg', (196, 205))	('miR-29b-3p', 'MPA', (206, 216))	('expression', 'MPA', (48, 58))	('TE-10', 'CellLine', 'CVCL:1760', (248, 253))	('miR-29b-3p', 'Chemical', '-', (206, 216))	('GIHCG', 'Chemical', '-', (14, 19))	('miR-29b-3p', 'Chemical', '-', (62, 72))	('GIHCG', 'Chemical', '-', (180, 185))	('-GIHCG', 'Chemical', '-', (179, 185))	('Ec-9706', 'CellLine', 'CVCL:E307', (225, 232))	('GIHCG', 'Chemical', '-', (170, 175))	('TE-10', 'CellLine', 'CVCL:1760', (104, 109))	('increased', 'PosReg', (34, 43))	('Ec-9706', 'CellLine', 'CVCL:E307', (81, 88))
705915	33408485	Moreover, miR-29b-3p was markedly downregulated in tumor tissues compared with that in adjacent normal tissues (n = 45) (p < 0.01) (Figure 3F).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('downregulated', 'NegReg', (34, 47))	('miR-29b-3p', 'Var', (10, 20))	('tumor', 'Disease', (51, 56))	('miR-29b-3p', 'Chemical', '-', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
705917	33408485	These results revealed that GIHCG was a sponge of miR-29b-3p and the effect of GIHCG in esophageal cancer might be partially mediated by miR-29b-3p.	('miR-29b-3p', 'Chemical', '-', (50, 60))	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('GIHCG', 'Chemical', '-', (28, 33))	('miR-29b-3p', 'Chemical', '-', (137, 147))	('GIHCG', 'Chemical', '-', (79, 84))	('esophageal cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('miR-29b-3p', 'Var', (137, 147))
705918	33408485	To explore whether the effect of GIHCG was mediated by miR-29b-3p, Ec-9706 and TE-10 cells were transfected with si-GIHCG, si-NC, miR-29b-3p inhibitor, or co-transfected with si-GIHCG and miR-29b-3p inhibitor.	('miR-29b-3p', 'Chemical', '-', (130, 140))	('GIHCG', 'Chemical', '-', (116, 121))	('GIHCG', 'Chemical', '-', (178, 183))	('TE-10', 'CellLine', 'CVCL:1760', (79, 84))	('si-NC', 'Var', (123, 128))	('si-GIHCG', 'Var', (113, 121))	('miR-29b-3p', 'Chemical', '-', (188, 198))	('GIHCG', 'Chemical', '-', (33, 38))	('miR-29b-3p', 'Chemical', '-', (55, 65))	('-GIHCG', 'Chemical', '-', (115, 121))	('Ec-9706', 'CellLine', 'CVCL:E307', (67, 74))	('-GIHCG', 'Chemical', '-', (177, 183))
705919	33408485	The results of CCK-8 assay (Figure 4A), colony formation assay (Figure 4B) and EdU staining assay (Figure 4C) revealed that miR-29b-3p inhibitor significantly exacerbated the growth of Ec-9706 and TE-10 cells (p < 0.01), while co-transfection of si-GIHCG and miR-29b-3p inhibitor obviously attenuated the inhibitory effect of si-GIHCG on cell proliferation (p < 0.01).	('exacerbated', 'PosReg', (159, 170))	('miR-29b-3p inhibitor', 'Var', (124, 144))	('Ec-9706', 'CellLine', 'CVCL:E307', (185, 192))	('-GIHCG', 'Chemical', '-', (248, 254))	('-GIHCG', 'Chemical', '-', (328, 334))	('si-GIHCG', 'Var', (326, 334))	('CCK-8', 'Chemical', '-', (15, 20))	('EdU', 'Chemical', 'MESH:C031086', (79, 82))	('cell proliferation', 'CPA', (338, 356))	('miR-29b-3p', 'Chemical', '-', (124, 134))	('attenuated', 'NegReg', (290, 300))	('growth', 'CPA', (175, 181))	('miR-29b-3p', 'Chemical', '-', (259, 269))	('TE-10', 'CellLine', 'CVCL:1760', (197, 202))
705921	33408485	Meanwhile, miR-29b-3p inhibitor significantly decreased apoptosis rate of Ec-9706 and TE-10 cells (p < 0.05), while co-transfection of si-GIHCG and miR-29b-3p inhibitor obviously reversed the effect of si-GIHCG on apoptosis (p < 0.05) (Figure 4F).	('miR-29b-3p', 'Var', (11, 21))	('-GIHCG', 'Chemical', '-', (137, 143))	('miR-29b-3p', 'Chemical', '-', (11, 21))	('TE-10', 'CellLine', 'CVCL:1760', (86, 91))	('decreased', 'NegReg', (46, 55))	('-GIHCG', 'Chemical', '-', (204, 210))	('Ec-9706', 'CellLine', 'CVCL:E307', (74, 81))	('miR-29b-3p', 'Chemical', '-', (148, 158))	('apoptosis rate', 'CPA', (56, 70))
705922	33408485	These results suggested that the effect of GIHCG in esophageal cancer might be partially mediated by miR-29b-3p.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('miR-29b-3p', 'Var', (101, 111))	('miR-29b-3p', 'Chemical', '-', (101, 111))	('GIHCG', 'Chemical', '-', (43, 48))
705923	33408485	Next, TargetScan was used to predict the potential targets of miR-29b-3p, and the results showed that ANO1 might be a target of miR-29b-3p (Figure 5A).	('ANO1', 'Gene', (102, 106))	('miR-29b-3p', 'Var', (128, 138))	('ANO1', 'Gene', '55107', (102, 106))	('miR-29b-3p', 'Chemical', '-', (62, 72))	('miR-29b-3p', 'Chemical', '-', (128, 138))
705924	33408485	Then, luciferase reporter assay was performed and indicated that miR-29b-3p mimics significantly decreased the relative luciferase activity of WT ANO1 vector in both Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01) compared with the miR-NC group, while exhibited no obvious change in MUT ANO1 vector in two cell lines (Figure 5B).	('TE-10', 'CellLine', 'CVCL:1760', (189, 194))	('miR-29b-3p mimics', 'Var', (65, 82))	('ANO1', 'Gene', (285, 289))	('activity', 'MPA', (131, 139))	('luciferase', 'Enzyme', (120, 130))	('ANO1', 'Gene', (146, 150))	('miR-29b-3p', 'Chemical', '-', (65, 75))	('decreased', 'NegReg', (97, 106))	('Ec-9706', 'CellLine', 'CVCL:E307', (166, 173))	('ANO1', 'Gene', '55107', (285, 289))	('ANO1', 'Gene', '55107', (146, 150))
705925	33408485	Meanwhile, miR-29b-3p mimics significantly reduced the expression of ANO1 at both mRNA level and protein level in Ec-9706 and TE-10 cells compared with miR-NC (Figure 5C and D), while miR-29b-3p inhibitor increased the expression of ANO1 at both mRNA level and protein level in two cell lines compared with miR-NC (Figure 5C and D).	('TE-10', 'CellLine', 'CVCL:1760', (126, 131))	('ANO1', 'Gene', (233, 237))	('ANO1', 'Gene', (69, 73))	('expression', 'MPA', (219, 229))	('miR-29b-3p', 'Chemical', '-', (11, 21))	('expression', 'MPA', (55, 65))	('increased', 'PosReg', (205, 214))	('miR-29b-3p inhibitor', 'Var', (184, 204))	('ANO1', 'Gene', '55107', (233, 237))	('ANO1', 'Gene', '55107', (69, 73))	('miR-29b-3p', 'Chemical', '-', (184, 194))	('Ec-9706', 'CellLine', 'CVCL:E307', (114, 121))	('reduced', 'NegReg', (43, 50))
705927	33408485	Pearson's correlation analysis indicated the there was also an obviously negative correlation between miR-29b-3p and ANO1 expression in esophageal cancer tissues (n = 45) (p < 0.01) (Figure 5F).	('esophageal cancer', 'Disease', (136, 153))	('miR-29b-3p', 'Var', (102, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('expression', 'MPA', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('ANO1', 'Gene', (117, 121))	('miR-29b-3p', 'Chemical', '-', (102, 112))	('negative', 'NegReg', (73, 81))	('ANO1', 'Gene', '55107', (117, 121))
705928	33408485	These results suggested that ANO1 was the target of miR-29b-3p and the effect of miR-29b-3p in esophageal cancer might be mediated by ANO1.	('miR-29b-3p', 'Chemical', '-', (81, 91))	('ANO1', 'Gene', '55107', (29, 33))	('ANO1', 'Gene', (134, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('miR-29b-3p', 'Var', (52, 62))	('ANO1', 'Gene', '55107', (134, 138))	('ANO1', 'Gene', (29, 33))	('miR-29b-3p', 'Chemical', '-', (52, 62))	('miR-29b-3p', 'Var', (81, 91))	('esophageal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
705930	33408485	The results of CCK-8 assay (Figure 6A), colony formation assay (Figure 6B) and EdU staining assay (Figure 6C) showed that miR-29b-3p mimics significantly inhibited the proliferation of both Ec-9706 and TE-10 cells compared with miR-NC (p < 0.01), while co-transfection of miR-29b-3p mimics and pcDNA-ANO1 obviously attenuated miR-29b-3p mimics induced inhibitory effect on cell proliferation (p < 0.05).	('miR-29b-3p', 'Chemical', '-', (326, 336))	('proliferation', 'CPA', (168, 181))	('miR-29b-3p', 'Chemical', '-', (122, 132))	('miR-29b-3p mimics', 'Var', (122, 139))	('miR-29b-3p', 'Chemical', '-', (272, 282))	('cell proliferation', 'CPA', (373, 391))	('inhibited', 'NegReg', (154, 163))	('ANO1', 'Gene', (300, 304))	('TE-10', 'CellLine', 'CVCL:1760', (202, 207))	('CCK-8', 'Chemical', '-', (15, 20))	('EdU', 'Chemical', 'MESH:C031086', (79, 82))	('ANO1', 'Gene', '55107', (300, 304))	('Ec-9706', 'CellLine', 'CVCL:E307', (190, 197))	('attenuated', 'NegReg', (315, 325))
705932	33408485	Meanwhile, miR-29b-3p mimics significantly promoted the apoptosis of Ec-9706 (p < 0.01) and TE-10 cells (p < 0.01) compared with miR-NC, while co-transfection of miR-29b-3p mimics and pcDNA-ANO1 obviously reversed the effect of miR-29b-3p mimics on apoptosis (p < 0.05) (Figure 6F).	('miR-29b-3p', 'Chemical', '-', (228, 238))	('miR-29b-3p', 'Var', (11, 21))	('promoted', 'PosReg', (43, 51))	('miR-29b-3p', 'Chemical', '-', (11, 21))	('Ec-9706', 'CellLine', 'CVCL:E307', (69, 76))	('ANO1', 'Gene', (190, 194))	('miR-29b-3p', 'Chemical', '-', (162, 172))	('apoptosis', 'CPA', (56, 65))	('TE-10', 'CellLine', 'CVCL:1760', (92, 97))	('ANO1', 'Gene', '55107', (190, 194))
705933	33408485	These results revealed that overexpression of ANO1 efficiently reversed miR-29b-3p mimics induced inhibitory effect in esophageal cancer progression in vitro.	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('miR-29b-3p', 'Var', (72, 82))	('inhibitory effect', 'MPA', (98, 115))	('ANO1', 'Gene', (46, 50))	('miR-29b-3p', 'Chemical', '-', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ANO1', 'Gene', '55107', (46, 50))	('esophageal cancer', 'Disease', (119, 136))
705934	33408485	Finally, to confirm the role of GIHCG in esophageal cancer, a xenograft tumor model in vivo was established through subcutaneously injected with Ec-9706 cells stably transfected with sh-GIHCG, sh-NC, miR-29b-3p inhibitor, or co-transfected with sh-GIHCG and miR-29b-3p inhibitor.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('tumor', 'Disease', (72, 77))	('Ec-9706', 'CellLine', 'CVCL:E307', (145, 152))	('sh-GIHCG', 'Chemical', '-', (183, 191))	('miR-29b-3p', 'Chemical', '-', (258, 268))	('esophageal cancer', 'Disease', (41, 58))	('miR-29b-3p', 'Var', (200, 210))	('GIHCG', 'Chemical', '-', (248, 253))	('sh-GIHCG', 'Chemical', '-', (245, 253))	('miR-29b-3p', 'Chemical', '-', (200, 210))	('GIHCG', 'Chemical', '-', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('GIHCG', 'Chemical', '-', (32, 37))	('sh-GIHCG', 'Var', (183, 191))
705936	33408485	Compared with the sh-NC group, tumor weight in the sh-GIHCG group was significantly reduced (p < 0.01), and miR-29b-3p inhibitor increased tumor weight (p < 0.01), while co-transfection of sh-GIHCG and miR-29b-3p inhibitor obviously reversed sh-GIHCG induced inhibitory effect (p < 0.05) (Figure 7B).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('sh-GIHCG', 'Chemical', '-', (189, 197))	('miR-29b-3p', 'Var', (108, 118))	('sh-GIHCG', 'Chemical', '-', (51, 59))	('tumor', 'Disease', (31, 36))	('increased', 'PosReg', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('reduced', 'NegReg', (84, 91))	('tumor', 'Disease', (139, 144))	('miR-29b-3p', 'Chemical', '-', (202, 212))	('sh-GIHCG', 'Chemical', '-', (242, 250))	('miR-29b-3p', 'Chemical', '-', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
705937	33408485	Similarly, sh-GIHCG decreased tumor volume compared with sh-NC group (p < 0.01), and miR-29b-3p inhibitor increased the tumor volume (p < 0.01), while co-transfection of sh-GIHCG and miR-29b-3p inhibitor obviously reversed sh-GIHCG induced inhibitory effect (p < 0.05) (Figure 7C).	('miR-29b-3p', 'Chemical', '-', (85, 95))	('sh-GIHCG', 'Chemical', '-', (223, 231))	('decreased', 'NegReg', (20, 29))	('sh-GIHCG', 'Chemical', '-', (11, 19))	('sh-GIHCG', 'Chemical', '-', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('increased', 'PosReg', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('miR-29b-3p', 'Chemical', '-', (183, 193))	('miR-29b-3p', 'Var', (85, 95))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', (120, 125))
705938	33408485	Meanwhile, Ki-67 staining assay in tumor tissues showed that sh-GIHCG obviously decreased the number of Ki-67 positive cells compared with sh-NC, and miR-29b-3p inhibitor increased Ki-67-positive cells, while co-transfection of sh-GIHCG and miR-29b-3p inhibitor obviously reversed sh-GIHCG induced inhibitory effect on proliferation in vivo (Figure 7D).	('Ki-67 positive', 'MPA', (104, 118))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('miR-29b-3p', 'Chemical', '-', (150, 160))	('Ki-67-positive cells', 'CPA', (181, 201))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Ki-67', 'Chemical', '-', (181, 186))	('miR-29b-3p', 'Chemical', '-', (241, 251))	('tumor', 'Disease', (35, 40))	('Ki-67', 'Chemical', '-', (11, 16))	('decreased', 'NegReg', (80, 89))	('miR-29b-3p', 'Var', (150, 160))	('sh-GIHCG', 'Chemical', '-', (228, 236))	('Ki-67', 'Chemical', '-', (104, 109))	('increased', 'PosReg', (171, 180))	('sh-GIHCG', 'Chemical', '-', (281, 289))	('sh-GIHCG', 'Chemical', '-', (61, 69))
705939	33408485	In addition, the expression of ANO1 in tumor tissues was also detected by Western blot, and the results indicated that sh-GIHCG significantly decreased the protein level of ANO1 compared with si-NC (p < 0.01), and miR-29b-3p inhibitor increased ANO1 expression (p < 0.05), while co-transfection of sh-GIHCG and miR-29b-3p inhibitor obviously reversed sh-GIHCG induced inhibitory effect on ANO1 expression (p < 0.05) (Figure 7E).	('ANO1', 'Gene', '55107', (173, 177))	('increased', 'PosReg', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('protein level', 'MPA', (156, 169))	('decreased', 'NegReg', (142, 151))	('ANO1', 'Gene', (389, 393))	('ANO1', 'Gene', (245, 249))	('miR-29b-3p', 'Var', (214, 224))	('sh-GIHCG', 'Chemical', '-', (298, 306))	('miR-29b-3p', 'Chemical', '-', (311, 321))	('ANO1', 'Gene', (31, 35))	('ANO1', 'Gene', (173, 177))	('tumor', 'Disease', (39, 44))	('ANO1', 'Gene', '55107', (389, 393))	('ANO1', 'Gene', '55107', (245, 249))	('miR-29b-3p', 'Chemical', '-', (214, 224))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('sh-GIHCG', 'Chemical', '-', (351, 359))	('sh-GIHCG', 'Chemical', '-', (119, 127))	('ANO1', 'Gene', '55107', (31, 35))	('expression', 'MPA', (250, 260))
705940	33408485	These results revealed that knockdown of GIHCG inhibited tumor growth through modulating miR-29b-3p in vivo.	('miR-29b-3p', 'Protein', (89, 99))	('inhibited', 'NegReg', (47, 56))	('miR-29b-3p', 'Chemical', '-', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('GIHCG', 'Chemical', '-', (41, 46))	('knockdown', 'Var', (28, 37))	('GIHCG', 'Gene', (41, 46))	('tumor', 'Disease', (57, 62))	('modulating', 'Reg', (78, 88))
705944	33408485	Moreover, knockdown of GIHCG markedly inhibited cell proliferation, invasion, migration and induced apoptosis of esophageal cancer cells in vitro, and also inhibited tumor growth in vivo, suggesting an oncogenic role of GIHCG in esophageal cancer.	('GIHCG', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('invasion', 'CPA', (68, 76))	('GIHCG', 'Chemical', '-', (220, 225))	('migration', 'CPA', (78, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cell proliferation', 'CPA', (48, 66))	('esophageal cancer', 'Disease', (113, 130))	('knockdown', 'Var', (10, 19))	('apoptosis', 'CPA', (100, 109))	('tumor', 'Disease', (166, 171))	('esophageal cancer', 'Disease', 'MESH:D004938', (229, 246))	('GIHCG', 'Chemical', '-', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('induced', 'Reg', (92, 99))	('inhibited', 'NegReg', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal cancer', 'Disease', (229, 246))	('inhibited', 'NegReg', (156, 165))
705959	33408485	The results of prediction showed that miR-29b-3p might be a direct target of GIHCG, and luciferase reporter assay determined that miR-29b-3p mimics significantly decreased the relative luciferase activity of WT GIHCG vector in both Ec-9706 and TE-10 cells, while exhibited no obvious change in MUT GIHCG vector in two cell lines.	('GIHCG', 'Chemical', '-', (211, 216))	('miR-29b-3p', 'Chemical', '-', (130, 140))	('miR-29b-3p mimics', 'Var', (130, 147))	('GIHCG', 'Chemical', '-', (298, 303))	('TE-10', 'CellLine', 'CVCL:1760', (244, 249))	('miR-29b-3p', 'Chemical', '-', (38, 48))	('decreased', 'NegReg', (162, 171))	('Ec-9706', 'CellLine', 'CVCL:E307', (232, 239))	('luciferase', 'Enzyme', (185, 195))	('activity', 'MPA', (196, 204))	('GIHCG', 'Chemical', '-', (77, 82))
705962	33408485	These results suggested that the effect of GIHCG in esophageal cancer was partially mediated by miR-29b-3p.	('miR-29b-3p', 'Var', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('miR-29b-3p', 'Chemical', '-', (96, 106))	('GIHCG', 'Chemical', '-', (43, 48))
705964	33408485	ANO1 has been identified to act as direct targets of multiple miRNAs to participate in the biological process involved in cancer progression.	('ANO1', 'Gene', (0, 4))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('ANO1', 'Gene', '55107', (0, 4))	('participate', 'Reg', (72, 83))	('miRNAs', 'Var', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
705966	33408485	Park et al revealed that knockdown of miR-9 promoted the EMT process by targeting ANO1 in colorectal cancer.	('promoted', 'PosReg', (44, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('ANO1', 'Gene', '55107', (82, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('targeting', 'Reg', (72, 81))	('knockdown', 'Var', (25, 34))	('miR-9', 'Gene', (38, 43))	('colorectal cancer', 'Disease', (90, 107))	('EMT process', 'CPA', (57, 68))	('ANO1', 'Gene', (82, 86))
705968	33408485	Here, our results identified that ANO1 was a target of miR-19b-3p, and overexpression of ANO1 significantly reversed miR-29b-3p mimics induced inhibitory effect in esophageal cancer progression in vitro.	('esophageal cancer', 'Disease', (164, 181))	('ANO1', 'Gene', (89, 93))	('ANO1', 'Gene', (34, 38))	('miR-29b-3p', 'Var', (117, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('ANO1', 'Gene', '55107', (89, 93))	('ANO1', 'Gene', '55107', (34, 38))	('miR-29b-3p', 'Chemical', '-', (117, 127))	('inhibitory effect', 'MPA', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
705970	33408485	However, overexpression of ANO1 whether reversed the inhibitory effect of sh-GIHCG and miR-29b-3p mimics in tumor growth in vivo should be determined in the subsequent experiments.	('ANO1', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('miR-29b-3p', 'Var', (87, 97))	('inhibitory effect', 'MPA', (53, 70))	('tumor', 'Disease', (108, 113))	('ANO1', 'Gene', '55107', (27, 31))	('miR-29b-3p', 'Chemical', '-', (87, 97))	('sh-GIHCG', 'Chemical', '-', (74, 82))
705971	33408485	In summary, our study provided a new mechanism of lncRNA GIHCG in esophageal cancer: GIHCG promoted the progression of esophageal cancer through upregulating ANO1 expression by directly sponging miR-29b-3p, suggesting that GIHCG might be a novel therapeutic target for esophageal cancer.	('GIHCG', 'Chemical', '-', (85, 90))	('miR-29b-3p', 'Chemical', '-', (195, 205))	('esophageal cancer', 'Disease', (269, 286))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('upregulating', 'PosReg', (145, 157))	('GIHCG', 'Chemical', '-', (57, 62))	('ANO1', 'Gene', (158, 162))	('promoted', 'PosReg', (91, 99))	('GIHCG', 'Var', (85, 90))	('esophageal cancer', 'Disease', (66, 83))	('GIHCG', 'Chemical', '-', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('progression', 'MPA', (104, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('ANO1', 'Gene', '55107', (158, 162))	('expression', 'MPA', (163, 173))	('esophageal cancer', 'Disease', 'MESH:D004938', (269, 286))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal cancer', 'Disease', (119, 136))
705976	33390848	Mechanistically, overexpression of NETO2 increased the phosphorylation of ERK, PI3k/AKT, and Nuclear factor erythroid-2-related factor 2(Nrf2), whereas silencing NETO2 decreased the phosphorylation of these targets.	('silencing', 'Var', (152, 161))	('increased', 'PosReg', (41, 50))	('NETO2', 'Gene', (162, 167))	('Nrf2', 'Gene', (137, 141))	('decreased', 'NegReg', (168, 177))	('NETO2', 'Gene', (35, 40))	('AKT', 'Gene', '207', (84, 87))	('ERK', 'Gene', '5594', (74, 77))	('phosphorylation', 'MPA', (182, 197))	('Nuclear factor erythroid-2-related factor 2', 'Gene', '4780', (93, 136))	('Nuclear factor erythroid-2-related factor 2', 'Gene', (93, 136))	('ERK', 'Gene', (74, 77))	('AKT', 'Gene', (84, 87))	('phosphorylation', 'MPA', (55, 70))	('Nrf2', 'Gene', '4780', (137, 141))
705993	33390848	Furthermore, NETO2 depletion inhibits cell proliferation, migration and invasion, while enhancing apoptosis in cells via the ERK and PI3K/AKT pathways.	('cell proliferation', 'CPA', (38, 56))	('depletion', 'Var', (19, 28))	('apoptosis', 'CPA', (98, 107))	('AKT', 'Gene', '207', (138, 141))	('ERK', 'Gene', '5594', (125, 128))	('AKT', 'Gene', (138, 141))	('ERK', 'Gene', (125, 128))	('inhibits', 'NegReg', (29, 37))	('invasion', 'CPA', (72, 80))	('NETO2', 'Gene', (13, 18))	('enhancing', 'PosReg', (88, 97))	('migration', 'CPA', (58, 67))
706000	33390848	SCH772948 and LY294002 were purchased from MCE (New Jersey, USA).	('SCH772948', 'Chemical', '-', (0, 9))	('SCH772948', 'Var', (0, 9))	('LY294002', 'Chemical', 'MESH:C085911', (14, 22))	('LY294002', 'Var', (14, 22))
706025	33390848	Kaplan-Meier analysis showed that patients in NETO2-high group have lower OS than low NETO2-expression patients (Figure 1G).	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (34, 42))	('lower', 'NegReg', (68, 73))	('NETO2-high', 'Var', (46, 56))
706035	33390848	We also performed the Hoechst 33342 staining assay to calculate the apoptosis outcomes and found that NETO2 knockdown cells contained more chromatin condensation and apoptotic body formation (Figure 4C,D).	('Hoechst 33342', 'Chemical', 'MESH:C017807', (22, 35))	('knockdown', 'Var', (108, 117))	('apoptotic body formation', 'CPA', (166, 190))	('more', 'PosReg', (134, 138))	('NETO2', 'Gene', (102, 107))	('chromatin condensation', 'CPA', (139, 161))
706036	33390848	Silencing NETO2 dramatically increased activation of caspase3 and activation of PARP, but downregulated Bcl-2 expression (Figure 4E).	('NETO2', 'Gene', (10, 15))	('Bcl-2', 'Gene', (104, 109))	('Bcl-2', 'Gene', '596', (104, 109))	('Silencing', 'Var', (0, 9))	('caspase3', 'Gene', (53, 61))	('PARP', 'Gene', '1302', (80, 84))	('increased activation', 'PosReg', (29, 49))	('downregulated', 'NegReg', (90, 103))	('PARP', 'Gene', (80, 84))	('caspase3', 'Gene', '836', (53, 61))	('activation', 'PosReg', (66, 76))
706042	33390848	Western blot results showed that loss of NETO2 function significantly decreased P-ERK1/2 and P-AKT expression which is consistent with our IHC staining assay in vivo (Figure 3F).	('NETO2', 'Gene', (41, 46))	('ERK1/2', 'Gene', '5595;5594', (82, 88))	('AKT', 'Gene', '207', (95, 98))	('decreased', 'NegReg', (70, 79))	('AKT', 'Gene', (95, 98))	('loss', 'Var', (33, 37))	('ERK1/2', 'Gene', (82, 88))
706043	33390848	To clarify whether NETO2 contributed to malignant progress in ESCC cells through activation of ERK and PI3K/AKT pathways, we treated ESCC cells with an ERK inhibitor SCH772984 or a PI3K inhibitor LY294002.	('AKT', 'Gene', '207', (108, 111))	('ERK', 'Gene', '5594', (152, 155))	('ERK', 'Gene', '5594', (95, 98))	('ERK', 'Gene', (152, 155))	('LY294002', 'Chemical', 'MESH:C085911', (196, 204))	('AKT', 'Gene', (108, 111))	('ERK', 'Gene', (95, 98))	('SCH772984', 'Var', (166, 175))	('LY294002', 'Var', (196, 204))	('malignant progress', 'CPA', (40, 58))	('SCH772984', 'Chemical', 'MESH:C587178', (166, 175))
706047	33390848	Interestingly, our results indicated that Nrf2 was dramatically downregulated by NETO2 knockdown (Figure 6F).	('downregulated', 'NegReg', (64, 77))	('Nrf2', 'Gene', '4780', (42, 46))	('Nrf2', 'Gene', (42, 46))	('NETO2', 'Gene', (81, 86))	('knockdown', 'Var', (87, 96))
706049	33390848	We also investigated EMT biomarkers expression after knockdown Nrf2 (Figure 6I).	('Nrf2', 'Gene', '4780', (63, 67))	('knockdown', 'Var', (53, 62))	('Nrf2', 'Gene', (63, 67))	('investigated', 'Reg', (8, 20))
706050	33390848	Interestingly, in the hypoxic microenvironment, knockdown of Nrf2 led to an obvious effect on cell migration and invasion compared with basal conditions (Figure 6H,J).	('invasion', 'CPA', (113, 121))	('Nrf2', 'Gene', (61, 65))	('effect', 'Reg', (84, 90))	('cell migration', 'CPA', (94, 108))	('Nrf2', 'Gene', '4780', (61, 65))	('knockdown', 'Var', (48, 57))
706052	33390848	Depletion of Nrf2 also downregulated snail and MMP2 protein levels, but upregulated E-cadherin.	('downregulated', 'NegReg', (23, 36))	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('Nrf2', 'Gene', (13, 17))	('snail', 'Gene', (37, 42))	('MMP2', 'Gene', '4313', (47, 51))	('Depletion', 'Var', (0, 9))	('upregulated', 'PosReg', (72, 83))	('MMP2', 'Gene', (47, 51))	('Nrf2', 'Gene', '4780', (13, 17))	('snail', 'Gene', '6615', (37, 42))
706059	33390848	High levels of NETO2 were also a marker of poor survival in ESCC patients.	('NETO2', 'Protein', (15, 20))	('ESCC', 'Disease', (60, 64))	('High levels', 'Var', (0, 11))	('patients', 'Species', '9606', (65, 73))
706060	33390848	NETO2 overexpression or knockdown altered the caspase-dependent apoptosis pathway through regulating the expression of caspase-3, PARP and Bcl-2 protein family members.	('altered', 'Reg', (34, 41))	('PARP', 'Gene', (130, 134))	('caspase-3', 'Gene', '836', (119, 128))	('Bcl-2', 'Gene', (139, 144))	('Bcl-2', 'Gene', '596', (139, 144))	('expression', 'MPA', (105, 115))	('caspase-3', 'Gene', (119, 128))	('regulating', 'Reg', (90, 100))	('NETO2', 'Gene', (0, 5))	('knockdown', 'Var', (24, 33))	('PARP', 'Gene', '1302', (130, 134))	('caspase-dependent apoptosis pathway', 'Pathway', (46, 81))
706065	33390848	In contrast, NETO2 depletion increased expression of E-cadherin and downregulated mesenchymal markers such as vimentin, and N-cadherin.	('N-cadherin', 'Gene', '1000', (124, 134))	('depletion', 'Var', (19, 28))	('vimentin', 'Gene', '7431', (110, 118))	('E-cadherin', 'Gene', (53, 63))	('downregulated', 'NegReg', (68, 81))	('vimentin', 'Gene', (110, 118))	('E-cadherin', 'Gene', '999', (53, 63))	('increased', 'PosReg', (29, 38))	('N-cadherin', 'Gene', (124, 134))	('expression', 'MPA', (39, 49))	('NETO2', 'Gene', (13, 18))	('mesenchymal markers', 'CPA', (82, 101))
706066	33390848	In our work, we also observed that knockdown of NETO2 altered snail, slug and MMP2 protein expression.	('NETO2', 'Gene', (48, 53))	('knockdown', 'Var', (35, 44))	('slug', 'Gene', '6591', (69, 73))	('MMP2', 'Gene', '4313', (78, 82))	('snail', 'Gene', '6615', (62, 67))	('altered', 'Reg', (54, 61))	('slug', 'Gene', (69, 73))	('MMP2', 'Gene', (78, 82))	('snail', 'Gene', (62, 67))
706076	33390848	Interestingly, in the hypoxic microenvironment, knockdown of Nrf2 led to obvious effects on cell migration and invasion compared with basal conditions.	('Nrf2', 'Gene', (61, 65))	('effects', 'Reg', (81, 88))	('cell migration', 'CPA', (92, 106))	('invasion', 'CPA', (111, 119))	('Nrf2', 'Gene', '4780', (61, 65))	('knockdown', 'Var', (48, 57))
706094	32139664	Also, the suppressive impacts of TUG1 silencing on the proliferation and invasion of ESCC cells were mitigated by miR-498 reduction.	('miR-498', 'Gene', '574460', (114, 121))	('proliferation', 'CPA', (55, 68))	('TUG1', 'Gene', '55000', (33, 37))	('ESCC', 'Disease', (85, 89))	('ESCC', 'Disease', 'MESH:D000077277', (85, 89))	('reduction', 'NegReg', (122, 131))	('miR-498', 'Gene', (114, 121))	('invasion', 'CPA', (73, 81))	('TUG1', 'Gene', (33, 37))	('silencing', 'Var', (38, 47))
706096	32139664	Inhibition of TUG1 hampered cell proliferation and invasion by downregulating CDC42 via upregulating miR-498 in ESCC cells.	('TUG1', 'Gene', '55000', (14, 18))	('TUG1', 'Gene', (14, 18))	('miR-498', 'Gene', '574460', (101, 108))	('downregulating', 'NegReg', (63, 77))	('cell proliferation', 'CPA', (28, 46))	('ESCC', 'Disease', (112, 116))	('ESCC', 'Disease', 'MESH:D000077277', (112, 116))	('Inhibition', 'Var', (0, 10))	('miR-498', 'Gene', (101, 108))	('invasion', 'CPA', (51, 59))	('CDC42', 'Gene', '998', (78, 83))	('hampered', 'NegReg', (19, 27))	('upregulating', 'PosReg', (88, 100))	('CDC42', 'Gene', (78, 83))
706113	32139664	reported that abnormal expression of miR-498 might affect the clinicopathological parameters of ESCC and management for ESCC patients.	('patients', 'Species', '9606', (125, 133))	('affect', 'Reg', (51, 57))	('abnormal', 'Var', (14, 22))	('ESCC', 'Disease', (120, 124))	('ESCC', 'Disease', 'MESH:D000077277', (120, 124))	('miR-498', 'Gene', '574460', (37, 44))	('ESCC', 'Disease', (96, 100))	('ESCC', 'Disease', 'MESH:D000077277', (96, 100))	('miR-498', 'Gene', (37, 44))	('expression', 'MPA', (23, 33))
706144	32139664	After blocking for 2 hours, the PVDF membranes were incubated with primary antibodies anti-CDC42 (11A11, 1: 1000) and anti-GAPDH (D16H11, 1: 1000), respectively.	('CDC42', 'Gene', (91, 96))	('GAPDH', 'Gene', (123, 128))	('PVDF', 'Chemical', 'MESH:C024865', (32, 36))	('D16H11', 'Var', (130, 136))	('GAPDH', 'Gene', '2597', (123, 128))	('CDC42', 'Gene', '998', (91, 96))
706154	32139664	The luciferase reporter vectors of wild-type TUG1 (TUG1 WT) and CDC42 3'UTR-WT (CDC42 3'-UTR-WT), as well as mutant TUG1 (TUG1 MUT) and CDC42 3'UTR-MUT (CDC42 3'-UTR-MUT), were established utilizing the pGL3 control luciferase reporter vector (Promega).	('TUG1', 'Gene', (45, 49))	('pGL3', 'Gene', '6391', (203, 207))	('TUG1', 'Gene', (116, 120))	('CDC42', 'Gene', (153, 158))	('CDC42', 'Gene', (136, 141))	('TUG1', 'Gene', (51, 55))	('CDC42', 'Gene', '998', (153, 158))	('CDC42', 'Gene', (80, 85))	('TUG1', 'Gene', '55000', (45, 49))	('TUG1', 'Gene', (122, 126))	('CDC42', 'Gene', '998', (136, 141))	('CDC42', 'Gene', (64, 69))	('CDC42', 'Gene', '998', (80, 85))	('TUG1', 'Gene', '55000', (116, 120))	('mutant', 'Var', (109, 115))	('TUG1', 'Gene', '55000', (51, 55))	('CDC42', 'Gene', '998', (64, 69))	('TUG1', 'Gene', '55000', (122, 126))	('pGL3', 'Gene', (203, 207))
706162	32139664	Furthermore, high TUG1 expression was correlated with tumor size (P= 0.032), TNM stage (P<0.001), and lymph node status (P<0.001) (Table 1).	('lymph node status', 'Disease', (102, 119))	('TNM', 'Gene', (77, 80))	('high', 'Var', (13, 17))	('TUG1', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('TUG1', 'Gene', '55000', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TNM', 'Gene', '10178', (77, 80))	('tumor', 'Disease', (54, 59))	('correlated', 'Reg', (38, 48))	('expression', 'MPA', (23, 33))
706166	32139664	The results of the qRT-PCR exhibited that the expression of TUG1 was drastically declined in KYSE30 and TE-1 cells transfected with 3 specific si-RNAs in comparison to the si-NC group, and the si-TUG1#3 was selected for subsequent studies (Figure 2A, 2B).	('TUG1', 'Gene', (196, 200))	('TUG1', 'Gene', '55000', (60, 64))	('declined', 'NegReg', (81, 89))	('si-RNAs', 'Var', (143, 150))	('TUG1', 'Gene', '55000', (196, 200))	('expression', 'MPA', (46, 56))	('TUG1', 'Gene', (60, 64))
706168	32139664	Next, Transwell assays demonstrated that TUG1 knockdown retarded the invasion of KYSE30 and TE-1 (Figure 2E).	('TUG1', 'Gene', (41, 45))	('invasion of KYSE30', 'CPA', (69, 87))	('knockdown', 'Var', (46, 55))	('retarded', 'Disease', (56, 64))	('retarded', 'Disease', 'MESH:D008607', (56, 64))	('TUG1', 'Gene', '55000', (41, 45))
706169	32139664	Therefore, these results revealed that inhibited TUG1 expression impeded the proliferation and invasion of ESCC cells.	('TUG1', 'Gene', '55000', (49, 53))	('ESCC', 'Disease', 'MESH:D000077277', (107, 111))	('TUG1', 'Gene', (49, 53))	('expression', 'Protein', (54, 64))	('impeded', 'NegReg', (65, 72))	('inhibited', 'Var', (39, 48))	('ESCC', 'Disease', (107, 111))
706180	32139664	To further confirm whether TUG1 worked in ESCC via miR-498, we first assessed the expression of miR-498 in KYSE30 and TE-1 cells transfected with si-TUG1, si-TUG1+in-miR-498, si-NC, or si-TUG1+in-NC.	('TUG1', 'Gene', (158, 162))	('miR-498', 'Gene', '574460', (166, 173))	('miR-498', 'Gene', (96, 103))	('TUG1', 'Gene', (149, 153))	('TUG1', 'Gene', (27, 31))	('in-miR-498', 'Gene', (163, 173))	('miR-498', 'Gene', (166, 173))	('TUG1', 'Gene', '55000', (188, 192))	('ESCC', 'Disease', (42, 46))	('TUG1', 'Gene', '55000', (158, 162))	('miR-498', 'Gene', '574460', (51, 58))	('si-NC', 'Var', (175, 180))	('TUG1', 'Gene', '55000', (149, 153))	('TUG1', 'Gene', '55000', (27, 31))	('in-miR-498', 'Gene', '574460', (163, 173))	('miR-498', 'Gene', '574460', (96, 103))	('miR-498', 'Gene', (51, 58))	('ESCC', 'Disease', 'MESH:D000077277', (42, 46))	('TUG1', 'Gene', (188, 192))
706182	32139664	Next, results from CCK-8 and Transwell assay manifested that transfection of si-TUG1 dramatically impeded the proliferation and invasion in KYSE30 and TE-1 cells, while this inhibition was attenuated by inhibiting of miR-498 (Figures 4B-4D).	('miR-498', 'Gene', (217, 224))	('TUG1', 'Gene', '55000', (80, 84))	('transfection', 'Var', (61, 73))	('impeded', 'NegReg', (98, 105))	('proliferation', 'CPA', (110, 123))	('TUG1', 'Gene', (80, 84))	('miR-498', 'Gene', '574460', (217, 224))	('invasion', 'CPA', (128, 136))
706183	32139664	Conclusively, these results proved that inhibition of miR-498 could attenuate TUG1 downregulation-mediated the repression of proliferation and invasion of ESCC cells.	('inhibition', 'Var', (40, 50))	('attenuate', 'NegReg', (68, 77))	('miR-498', 'Gene', '574460', (54, 61))	('TUG1', 'Gene', '55000', (78, 82))	('downregulation-mediated', 'NegReg', (83, 106))	('miR-498', 'Gene', (54, 61))	('ESCC', 'Disease', 'MESH:D000077277', (155, 159))	('TUG1', 'Gene', (78, 82))	('ESCC', 'Disease', (155, 159))
706190	32139664	Meanwhile, TUG1 knockdown also constrained the CDC42 protein expression in KYSE30 and TE-1 cells (Figure 5G).	('TUG1', 'Gene', '55000', (11, 15))	('constrained', 'Reg', (31, 42))	('CDC42', 'Gene', (47, 52))	('TUG1', 'Gene', (11, 15))	('knockdown', 'Var', (16, 25))	('protein', 'Protein', (53, 60))	('CDC42', 'Gene', '998', (47, 52))	('expression', 'MPA', (61, 71))
706197	32139664	Subsequently, we measured the expression levels of CDC42 protein and mRNA in KYSE30 and TE-1 cells transfected with si-NC, si-TUG1, si-TUG1+in-miR-NC, or si-TUG1+in-miR-498.	('si-NC', 'Var', (116, 121))	('TUG1', 'Gene', (126, 130))	('TUG1', 'Gene', (157, 161))	('in-miR-498', 'Gene', (162, 172))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', (143, 146))	('TUG1', 'Gene', '55000', (135, 139))	('in-miR-498', 'Gene', '574460', (162, 172))	('CDC42', 'Gene', '998', (51, 56))	('miR', 'Gene', '220972', (165, 168))	('miR', 'Gene', (165, 168))	('CDC42', 'Gene', (51, 56))	('TUG1', 'Gene', (135, 139))	('TUG1', 'Gene', '55000', (126, 130))	('TUG1', 'Gene', '55000', (157, 161))	('expression levels', 'MPA', (30, 47))	('mRNA', 'MPA', (69, 73))
706199	32139664	Conclusively, these data showed that knockdown of TUG1 modulated CDC42 expression by sponging miR-498.	('expression', 'MPA', (71, 81))	('miR-498', 'Gene', '574460', (94, 101))	('modulated', 'Reg', (55, 64))	('TUG1', 'Gene', '55000', (50, 54))	('CDC42', 'Gene', '998', (65, 70))	('miR-498', 'Gene', (94, 101))	('knockdown', 'Var', (37, 46))	('CDC42', 'Gene', (65, 70))	('TUG1', 'Gene', (50, 54))
706216	32139664	One report uncovered that circFADS2 silencing curbed invasion and proliferation of lung cancer cells through upregulation miR-498.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('miR-498', 'Gene', (122, 129))	('invasion', 'CPA', (53, 61))	('upregulation', 'PosReg', (109, 121))	('circFADS2', 'Gene', (26, 35))	('lung cancer', 'Disease', (83, 94))	('silencing', 'Var', (36, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('curbed', 'NegReg', (46, 52))	('miR-498', 'Gene', '574460', (122, 129))
706227	32139664	What's more, inhibition of miR-498 attenuated the prohibitive roles of TUG1 knockdown on CDC42 mRNA and protein expression, which was supported that TUG1 bound to miR-498 to regulate CDC42 expression in ESCC cells.	('CDC42', 'Gene', '998', (89, 94))	('miR-498', 'Gene', (27, 34))	('knockdown', 'Var', (76, 85))	('miR-498', 'Gene', '574460', (163, 170))	('attenuated', 'NegReg', (35, 45))	('CDC42', 'Gene', (89, 94))	('regulate', 'Reg', (174, 182))	('TUG1', 'Gene', '55000', (149, 153))	('expression', 'MPA', (189, 199))	('ESCC', 'Disease', (203, 207))	('miR-498', 'Gene', (163, 170))	('CDC42', 'Gene', '998', (183, 188))	('TUG1', 'Gene', '55000', (71, 75))	('ESCC', 'Disease', 'MESH:D000077277', (203, 207))	('TUG1', 'Gene', (149, 153))	('miR-498', 'Gene', '574460', (27, 34))	('TUG1', 'Gene', (71, 75))	('CDC42', 'Gene', (183, 188))
706230	32139664	This study verified that TUG1 knockdown restrained the proliferation and invasion abilities of ESCC cells through downregulating CDC42 by sponging miR-498.	('CDC42', 'Gene', (129, 134))	('miR-498', 'Gene', (147, 154))	('TUG1', 'Gene', (25, 29))	('proliferation', 'CPA', (55, 68))	('ESCC', 'Disease', (95, 99))	('ESCC', 'Disease', 'MESH:D000077277', (95, 99))	('downregulating', 'NegReg', (114, 128))	('invasion abilities', 'CPA', (73, 91))	('restrained', 'NegReg', (40, 50))	('miR-498', 'Gene', '574460', (147, 154))	('CDC42', 'Gene', '998', (129, 134))	('knockdown', 'Var', (30, 39))	('TUG1', 'Gene', '55000', (25, 29))
706252	30285868	For example, high density of Treg cells predicted worse survival in breast cancer whereas favorable survival in colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('high', 'Var', (13, 17))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colon cancer', 'Disease', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('worse', 'NegReg', (50, 55))
706282	30285868	PD-L1 was expressed both on the surface of tumor cells (TCs) and immune cells (ICs), and was regarded as negative or positive if <1% or >= 1% in TCs, respectively, or if <1% or >= 1% in ICs, respectively.	('TCs', 'Chemical', '-', (56, 59))	('TCs', 'Chemical', '-', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('PD-L1', 'Gene', (0, 5))	('negative', 'NegReg', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('<1%', 'Var', (129, 132))	('tumor', 'Disease', (43, 48))
706397	30157793	It has been shown that deregulation of cellular signaling pathways such as WNT, NOTCH, SHH, and BMP is extensively involved in ESCC progression and drug resistance.	('BMP', 'Gene', (96, 99))	('ESCC', 'Disease', (127, 131))	('SHH', 'Gene', (87, 90))	('drug resistance', 'Phenotype', 'HP:0020174', (148, 163))	('BMP', 'Gene', '649', (96, 99))	('cellular signaling pathways', 'Pathway', (39, 66))	('involved', 'Reg', (115, 123))	('deregulation', 'Var', (23, 35))	('SHH', 'Gene', '6469', (87, 90))
706412	30157793	Deregulation of Notch pathway has been reported in a variety of malignancies.	('Notch pathway', 'Pathway', (16, 29))	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('malignancies', 'Disease', (64, 76))	('Deregulation', 'Var', (0, 12))
706415	30157793	It has been shown that tumor progression is related to the epigenetic and genomic changes.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('genomic changes', 'Var', (74, 89))	('epigenetic', 'Var', (59, 69))
706416	30157793	Therefore, it is inevitable that aberrations in chromatin remodelers are correlated with tumor progression.	('correlated', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('aberrations', 'Var', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
706417	30157793	Therefore aberrant expression of HOX family members can be critical for tumorigenesis, indicating the role of such components in tissue homeostasis.	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('aberrant', 'Var', (10, 18))
706433	30157793	The results showed that there was a significant correlation between KCTD12 and MAML1 in which the levels of MAML1 in transfected cells were lower than that in non-transfected cells (- 1.5 fold changes).	('MAML1', 'Gene', (108, 113))	('lower', 'NegReg', (140, 145))	('transfected', 'Var', (117, 128))	('MAML1', 'Gene', '9794', (108, 113))	('KCTD12', 'Gene', (68, 74))	('levels', 'MPA', (98, 104))	('MAML1', 'Gene', (79, 84))	('KCTD12', 'Gene', '115207', (68, 74))	('MAML1', 'Gene', '9794', (79, 84))
706451	30157793	In OCM-1 cell, KCTD12 ectopic expression also suppressed cell growth via down regulation of VEGF-A, VEGF-C, Snail, and Slug.	('KCTD12', 'Gene', (15, 21))	('Slug', 'Gene', (119, 123))	('VEGF-C', 'Gene', (100, 106))	('down regulation', 'NegReg', (73, 88))	('cell growth', 'CPA', (57, 68))	('OCM-1', 'Species', '83984', (3, 8))	('ectopic expression', 'Var', (22, 40))	('suppressed', 'NegReg', (46, 56))	('KCTD12', 'Gene', '115207', (15, 21))	('Snail', 'Gene', '6615', (108, 113))	('Snail', 'Gene', (108, 113))	('Slug', 'Gene', '6591', (119, 123))	('VEGF-A', 'Gene', (92, 98))
706477	28265829	This multicenter study aims to validate the measurement of polysomy (gain of at least two loci) by FISH as a way to discriminate degrees of dysplasia in BE specimens.	('BE', 'Phenotype', 'HP:0100580', (153, 155))	('dysplasia', 'Disease', (140, 149))	('polysomy', 'Var', (59, 67))	('dysplasia', 'Disease', 'MESH:D004476', (140, 149))
706479	28265829	We found that polysomy, as detected by FISH, was the predominant chromosomal abnormality present as dysplasia increased.	('dysplasia', 'Disease', 'MESH:D004476', (100, 109))	('polysomy', 'Var', (14, 22))	('dysplasia', 'Disease', (100, 109))
706480	28265829	Polysomy was also the best predictor for the presence of dysplasia or EA when comparing its area under the curve to that of other FISH abnormalities.	('EA', 'Phenotype', 'HP:0011459', (70, 72))	('dysplasia', 'Disease', (57, 66))	('Polysomy', 'Var', (0, 8))	('dysplasia', 'Disease', 'MESH:D004476', (57, 66))	('FISH abnormalities', 'Disease', 'MESH:D000014', (130, 148))	('FISH abnormalities', 'Disease', (130, 148))
706481	28265829	We observed that if at least 10% of cells had polysomy within a specimen, the FISH probe was able to differentiate between EA/HGD and the remaining pathologies with a sensitivity of 80% and a specificity of 88%.	('EA', 'Phenotype', 'HP:0011459', (123, 125))	('polysomy', 'Var', (46, 54))	('EA/HGD', 'Gene', (123, 129))	('EA/HGD', 'Gene', '3081', (123, 129))
706482	28265829	This study demonstrates that using FISH to determine the percentage of cells with polysomy can accurately and objectively aid in the diagnosis of HGD/EA in BE specimens.	('HGD', 'Gene', '3081', (146, 149))	('BE', 'Phenotype', 'HP:0100580', (156, 158))	('HGD', 'Gene', (146, 149))	('aid', 'Reg', (122, 125))	('polysomy', 'Var', (82, 90))	('EA', 'Phenotype', 'HP:0011459', (150, 152))
706492	28265829	Several studies demonstrate that an increasing number of genetic alterations occur as SIM progresses to EA, and exploration of these markers to diagnose dysplasia is an active area of research.	('SIM', 'Disease', (86, 89))	('dysplasia', 'Disease', (153, 162))	('SIM', 'Disease', 'None', (86, 89))	('genetic alterations', 'Var', (57, 76))	('EA', 'Phenotype', 'HP:0011459', (104, 106))	('dysplasia', 'Disease', 'MESH:D004476', (153, 162))
706493	28265829	In 2006, FISH probes comprising four loci, 8q24 (MYC), 9p21 (CDKN2A), 17q11.2 (ERBB2), and 20q13.2 (ZNF217), showed high sensitivity and specificity for identifying HGD and EA, and this method was shown to be superior to digital image analysis (DIA) and cytology.	('17q11.2', 'Var', (70, 77))	('EA', 'Phenotype', 'HP:0011459', (173, 175))	('HGD', 'Gene', '3081', (165, 168))	('HGD', 'Gene', (165, 168))
706494	28265829	Furthermore, polysomy, as detected by FISH, was the most commonly detected abnormality in areas of dysplasia and EA, and the most likely predictor of progression to HGD/EA.	('dysplasia', 'Disease', 'MESH:D004476', (99, 108))	('dysplasia', 'Disease', (99, 108))	('EA', 'Phenotype', 'HP:0011459', (169, 171))	('polysomy', 'Var', (13, 21))	('EA', 'Phenotype', 'HP:0011459', (113, 115))	('HGD', 'Gene', '3081', (165, 168))	('HGD', 'Gene', (165, 168))
706495	28265829	This multicenter study aims to validate the measurement of polysomy by FISH as a way to objectively discriminate degrees of dysplasia of BE biopsy specimens.	('polysomy', 'Var', (59, 67))	('dysplasia', 'Disease', 'MESH:D004476', (124, 133))	('BE', 'Phenotype', 'HP:0100580', (137, 139))	('dysplasia', 'Disease', (124, 133))
706505	28265829	FISH abnormality types included polysomy (gain of at least two loci), single locus gain (3-9 signals of a single locus and two copies of other loci), amplification of a single locus (>=10 signals of a single locus and two copies of other loci), and 9p21 loss (0-1 signals of 9p21 and two copies of other loci).	('loss', 'NegReg', (254, 258))	('gain', 'PosReg', (42, 46))	('FISH abnormality', 'Disease', 'MESH:D000014', (0, 16))	('gain', 'PosReg', (83, 87))	('9p21', 'Gene', (249, 253))	('polysomy', 'Var', (32, 40))	('FISH abnormality', 'Disease', (0, 16))	('amplification', 'Var', (150, 163))
706510	28265829	Given that prior single-institution data found polysomy to be the most commonly detected abnormality in areas of dysplasia and EA, we focused our analysis on the validation of polysomy as a sensitive and specific marker for detecting varying degrees of dysplasia and EA.	('EA', 'Phenotype', 'HP:0011459', (127, 129))	('polysomy', 'Var', (176, 184))	('dysplasia', 'Disease', (253, 262))	('dysplasia', 'Disease', (113, 122))	('dysplasia', 'Disease', 'MESH:D004476', (253, 262))	('EA', 'Phenotype', 'HP:0011459', (267, 269))	('dysplasia', 'Disease', 'MESH:D004476', (113, 122))	('polysomy', 'Var', (47, 55))
706515	28265829	Table 2 shows the AUC values for both cells with polysomy and cells with 9p21 loss as the predominant FISH abnormality, and the comparative p values.	('FISH abnormality', 'Disease', 'MESH:D000014', (102, 118))	('polysomy', 'Var', (49, 57))	('FISH abnormality', 'Disease', (102, 118))	('loss', 'NegReg', (78, 82))	('9p21', 'Gene', (73, 77))
706516	28265829	In our data, polysomy had the highest discriminatory power for most comparisons, with an AUC of .83 in discriminating EA/HGD from all other diagnoses.	('polysomy', 'Var', (13, 21))	('EA/HGD', 'Gene', (118, 124))	('EA/HGD', 'Gene', '3081', (118, 124))	('EA', 'Phenotype', 'HP:0011459', (118, 120))
706519	28265829	An additional analysis that included any FISH abnormality (polysomy, single gain, amplification, and 9p21 loss) resulted in an AUC of .75 for HGD/EA samples versus rest.	('HGD', 'Gene', '3081', (142, 145))	('9p21', 'Gene', (101, 105))	('polysomy', 'Var', (59, 67))	('HGD', 'Gene', (142, 145))	('FISH abnormality', 'Disease', 'MESH:D000014', (41, 57))	('single gain', 'Var', (69, 80))	('amplification', 'Var', (82, 95))	('FISH abnormality', 'Disease', (41, 57))	('AUC', 'MPA', (127, 130))	('EA', 'Phenotype', 'HP:0011459', (146, 148))	('loss', 'NegReg', (106, 110))
706521	28265829	Furthermore, as SIM progresses to EA, the percent of specimens with polysomy as the most common FISH abnormality also increased from approximately 5 to 80%, respectively.	('EA', 'Phenotype', 'HP:0011459', (34, 36))	('FISH abnormality', 'Disease', 'MESH:D000014', (96, 112))	('FISH abnormality', 'Disease', (96, 112))	('SIM', 'Disease', (16, 19))	('SIM', 'Disease', 'None', (16, 19))	('polysomy', 'Var', (68, 76))
706523	28265829	Since early or subtle mucosal changes in dysplastic tissue may be small and frequently not identifiable by gross examination, we explored whether high-grade lesions elsewhere in the esophagus could lead to a higher number of cells having amplified loci in the surrounding non-HGD/ EA tissue, a so-called field effect.	('amplified loci', 'MPA', (238, 252))	('EA', 'Phenotype', 'HP:0011459', (281, 283))	('dysplastic', 'Disease', (41, 51))	('HGD', 'Gene', '3081', (276, 279))	('dysplastic', 'Disease', 'MESH:D004416', (41, 51))	('HGD', 'Gene', (276, 279))	('lesions', 'Var', (157, 164))	('cells', 'CPA', (225, 230))
706524	28265829	From our analyses, we found 7/7 (100%) of IGD/LGD specimens to have evidence of amplification or polysomy when HGD was present elsewhere in the same esophageal segment (Table 4).	('amplification', 'MPA', (80, 93))	('HGD', 'Gene', (111, 114))	('HGD', 'Gene', '3081', (111, 114))	('polysomy', 'Var', (97, 105))
706530	28265829	In concordance with previous findings, our study demonstrated an increasing number of specimens with polysomy as the predominant chromosomal abnormality detected by FISH as the degree of dysplasia increased (Fig.	('polysomy', 'Var', (101, 109))	('dysplasia', 'Disease', (187, 196))	('dysplasia', 'Disease', 'MESH:D004476', (187, 196))
706536	28265829	We expect this result because 9p21 deletion is an early marker often found in metaplasia, whereas polysomy is more prevalent in dysplasia and EA.	('9p21 deletion', 'Var', (30, 43))	('dysplasia', 'Disease', (128, 137))	('dysplasia', 'Disease', 'MESH:D004476', (128, 137))	('EA', 'Phenotype', 'HP:0011459', (142, 144))	('metaplasia', 'Disease', (78, 88))	('found', 'Reg', (69, 74))
706537	28265829	We found that polysomy by FISH had excellent diagnostic capabilities in discriminating HGD/EA from the remaining histologic diagnoses, a clinically important distinction, as these diagnoses frequently lead to endoscopic treatment and oncologic evaluation.	('HGD', 'Gene', '3081', (87, 90))	('polysomy', 'Var', (14, 22))	('endoscopic', 'Disease', (209, 219))	('HGD', 'Gene', (87, 90))	('EA', 'Phenotype', 'HP:0011459', (91, 93))	('lead to', 'Reg', (201, 208))
706544	28265829	A retrospective analysis of patients with HGD found that if more than 4 of 100 cells had evidence of polysomy, there was a higher likelihood of progression to EA.	('HGD', 'Gene', (42, 45))	('polysomy', 'Var', (101, 109))	('EA', 'Phenotype', 'HP:0011459', (159, 161))	('HGD', 'Gene', '3081', (42, 45))	('patients', 'Species', '9606', (28, 36))
706545	28265829	Although further verification is needed, these findings suggest that genetic changes detected by FISH can both predict HGD lesions elsewhere in the esophageal column as well as progression to EA.	('EA', 'Phenotype', 'HP:0011459', (192, 194))	('genetic changes', 'Var', (69, 84))	('predict', 'Reg', (111, 118))	('esophageal column', 'Disease', 'MESH:C536342', (148, 165))	('HGD', 'Gene', '3081', (119, 122))	('HGD', 'Gene', (119, 122))	('esophageal column', 'Disease', (148, 165))
706547	28265829	In conclusion, this study demonstrated a high detection rate for HGD and EA using a FISH panel with probes to 8q24 (MYC), 9p21 (CDKN2A), 17q12 (ERBB2), and 20q13 (ZNF217).	('HGD', 'Gene', (65, 68))	('EA', 'Phenotype', 'HP:0011459', (73, 75))	('9p21', 'Var', (122, 126))	('HGD', 'Gene', '3081', (65, 68))	('17q12', 'Var', (137, 142))
706554	29254151	KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition.	('epithelial-to-mesenchymal transition', 'CPA', (227, 263))	('expression', 'MPA', (130, 140))	('BMP6', 'Gene', (172, 176))	('miR-301', 'Gene', (105, 112))	('PDCD4', 'Gene', (178, 183))	('inhibition', 'NegReg', (213, 223))	('inhibited', 'NegReg', (21, 30))	('cancer', 'Disease', (49, 55))	('miR-21', 'Gene', '406991', (83, 89))	('maturation', 'CPA', (35, 45))	('BMP6', 'Gene', '654', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('KHSRP', 'Gene', (0, 5))	('induced', 'PosReg', (118, 125))	('PDCD4', 'Gene', '27250', (178, 183))	('miR-21', 'Gene', (83, 89))	('TIMP3', 'Gene', '7078', (189, 194))	('TIMP3', 'Gene', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('miR-130b', 'Gene', '406920', (91, 99))	('miR-301', 'Gene', '407027', (105, 112))	('miR-130b', 'Gene', (91, 99))	('knockdown', 'Var', (6, 15))
706561	29254151	Various miRNAs have been reported to contribute to multiple tumorigenic processes, including cell proliferation, invasion, and metastasis, through changing the expression of oncogenes and tumor suppressor genes.	('tumor', 'Disease', (188, 193))	('contribute', 'Reg', (37, 47))	('expression', 'MPA', (160, 170))	('miRNAs', 'Var', (8, 14))	('invasion', 'CPA', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cell proliferation', 'CPA', (93, 111))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('changing', 'Reg', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (60, 65))	('metastasis', 'CPA', (127, 137))	('oncogenes', 'Protein', (174, 183))
706570	29254151	Similarly, positive cytoplasmic KHSRP immunoreactivity tended to be associated with worse recurrence-free survival probability (P = 0.053), whereas nuclear KHSRP immunoreactivity was not (Supplementary Figure 1B).	('Supplementary Figure 1B', 'Disease', (188, 211))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (188, 211))	('positive', 'Var', (11, 19))	('worse', 'NegReg', (84, 89))	('recurrence-free survival', 'CPA', (90, 114))	('KHSRP', 'Protein', (32, 37))
706571	29254151	In the Cox proportional hazards regression model, cytoplasmic KHSRP immunoreactivity and pT and N stage (pN) categories were statistically significant prognosticators for overall survival by univariate analyses (Table 2).	('Cox', 'Gene', '1351', (7, 10))	('Cox', 'Gene', (7, 10))	('cytoplasmic', 'Var', (50, 61))
706573	29254151	Protein levels of cell cycle inhibitors (p21WAF1/Cip1 and p27Kip1) were increased by knocking down endogenous KHSRP (Figure 2E), although discrepancies between their mRNA and protein levels were observed (Supplementary Figure 3A).	('endogenous', 'MPA', (99, 109))	('p27Kip1', 'Gene', '1027', (58, 65))	('increased', 'PosReg', (72, 81))	('p27Kip1', 'Gene', (58, 65))	('Cip1', 'Gene', '1026', (49, 53))	('cell cycle inhibitors', 'MPA', (18, 39))	('KHSRP', 'Gene', (110, 115))	('knocking down', 'Var', (85, 98))	('Protein levels', 'MPA', (0, 14))	('Cip1', 'Gene', (49, 53))
706574	29254151	Elevated and reduced expression of the epithelial marker (CDH1) and EMT inducer (ZEB1) proteins, respectively, were observed in KHSRP-knockdown cells when compared with control cells by both Western blot analysis (Figure 2H) and fluorescent immunocytochemical staining (Supplementary Figure 3E).	('CDH1', 'Gene', (58, 62))	('expression', 'MPA', (21, 31))	('CDH1', 'Gene', '999', (58, 62))	('KHSRP-knockdown', 'Var', (128, 143))	('ZEB1', 'Gene', '6935', (81, 85))	('ZEB1', 'Gene', (81, 85))	('reduced', 'NegReg', (13, 20))	('KHSRP-knockdown', 'Gene', (128, 143))
706575	29254151	To determine the chronic effects of exogenously overexpressed KHSRP on ESCC cell function in vitro, we established stable transfectants that expressed HA-tagged KHSRP protein using KYSE1190 and KYSE1250 cells with relatively low expression of endogenous KHSRP (Figure 3A and 3B).	('KYSE1250', 'CellLine', 'CVCL:A100', (194, 202))	('protein', 'Protein', (167, 174))	('KHSRP', 'Gene', (161, 166))	('HA-tagged', 'Var', (151, 160))
706579	29254151	Among these miRNAs, the KHSRP knockdown-induced down-regulation was successfully validated with five cancer-associated miRNAs in three ESCC cell lines (Figure 4A).	('down-regulation', 'NegReg', (48, 63))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('KHSRP', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('knockdown-induced', 'Var', (30, 47))
706589	29254151	Conversely, cells that stably overexpressed HA-tagged KHSRP showed higher levels of miR-21, miR-130b, and miR-301a (Figure 4F) and lower levels of BMP6, PDCD4, and TIMP3 mRNAs and proteins compared with control cells (Figure 4G and Supplementary Figure 5E).	('BMP6', 'Gene', (147, 151))	('BMP6', 'Gene', '654', (147, 151))	('higher', 'PosReg', (67, 73))	('KHSRP', 'Gene', (54, 59))	('miR-21', 'Gene', '406991', (84, 90))	('HA-tagged', 'Var', (44, 53))	('miR-21', 'Gene', (84, 90))	('miR-130b', 'Gene', '406920', (92, 100))	('TIMP3', 'Gene', '7078', (164, 169))	('levels', 'MPA', (74, 80))	('TIMP3', 'Gene', (164, 169))	('lower', 'NegReg', (131, 136))	('miR-130b', 'Gene', (92, 100))	('miR-301a', 'Gene', '407027', (106, 114))	('PDCD4', 'Gene', (153, 158))	('miR-301a', 'Gene', (106, 114))	('PDCD4', 'Gene', '27250', (153, 158))
706596	29254151	These results suggested that overexpressed KHSRP promotes ESCC migration and invasion, at least partly, by the up-regulation of a set of cancer-associated miRNAs and by the suppression of their downstream EMT-inhibiting proteins.	('KHSRP', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('up-regulation', 'PosReg', (111, 124))	('ESCC migration', 'CPA', (58, 72))	('invasion', 'CPA', (77, 85))	('suppression', 'NegReg', (173, 184))	('overexpressed', 'Var', (29, 42))	('promotes', 'PosReg', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))
706598	29254151	Overexpression of KHSRP in tumor cells, particularly in the cytoplasm, was an independent prognosticator for overall survival.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('KHSRP', 'Protein', (18, 23))	('tumor', 'Disease', (27, 32))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
706603	29254151	In addition, two independent studies have demonstrated that high KHSRP expression levels were associated with longer overall survival in glioblastoma multiforme.	('expression', 'MPA', (71, 81))	('overall survival', 'MPA', (117, 133))	('KHSRP', 'Protein', (65, 70))	('high', 'Var', (60, 64))	('glioblastoma multiforme', 'Disease', (137, 160))	('glioblastoma', 'Phenotype', 'HP:0012174', (137, 149))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (137, 160))	('longer', 'PosReg', (110, 116))
706606	29254151	Some of these have been reported to exert cancer-associated functions, indicating that deregulation of KHSRP-miRNA interplay may, at least in part, affect the ESCC-specific miRNA expression profile.	('ESCC-specific miRNA expression profile', 'MPA', (159, 197))	('affect', 'Reg', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('deregulation', 'Var', (87, 99))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('KHSRP-miRNA', 'Protein', (103, 114))
706608	29254151	Notably, it has been demonstrated that KHSRP is bound to the precursor of miR-21, and its knockdown reduced the expression levels of mature miR-21 in HeLa and NIH3T3 cells.	('miR-21', 'Gene', (140, 146))	('knockdown', 'Var', (90, 99))	('bound', 'Interaction', (48, 53))	('reduced', 'NegReg', (100, 107))	('miR-21', 'Gene', '406991', (140, 146))	('HeLa', 'CellLine', 'CVCL:0030', (150, 154))	('miR-21', 'Gene', '406991', (74, 80))	('NIH3T3', 'CellLine', 'CVCL:0594', (159, 165))	('expression levels', 'MPA', (112, 129))	('miR-21', 'Gene', (74, 80))	('KHSRP', 'Gene', (39, 44))
706660	24892348	For all patients, compared to IMRT plans, VMAT plans statistically provide: a) significant improvement in CI for PTV; b) significant decrease in delivery time, lung V20, MLD, NT and spinal cord PRV D1cc; c) significant increase in NT V5; and d) no significant reduction in HI for PTV, lung V5, V10, heart V30 and heart MD.	('HI', 'Disease', 'MESH:C538424', (273, 275))	('decrease', 'NegReg', (133, 141))	('heart MD', 'Disease', (313, 321))	('MLD', 'Disease', (170, 173))	('patients', 'Species', '9606', (8, 16))	('MLD', 'Disease', 'MESH:D007966', (170, 173))	('NT V5', 'MPA', (231, 236))	('PTV', 'Chemical', '-', (113, 116))	('improvement', 'PosReg', (91, 102))	('V10', 'Var', (294, 297))	('heart MD', 'Disease', 'MESH:D006331', (313, 321))	('PTV', 'Chemical', '-', (280, 283))	('increase', 'PosReg', (219, 227))	('lung V20', 'MPA', (160, 168))	('delivery time', 'MPA', (145, 158))
706666	24892348	Hall and Wuu (3)  showed that, compared with the three -dimensional (3D) conformal radiation therapy, high-modulated IMRT caused the increase in volume of normal tissue being exposed to a low-dose of radiation, which is estimated to increase the incidence of secondary cancers from 1% to 1.75% at ten years.	('volume of normal tissue', 'MPA', (145, 168))	('high-modulated', 'Var', (102, 116))	('secondary cancers', 'Disease', (259, 276))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('increase', 'PosReg', (133, 141))	('cancers', 'Phenotype', 'HP:0002664', (269, 276))	('secondary cancers', 'Disease', 'MESH:D009369', (259, 276))
706680	24892348	For the PTV, the parameters were D98% (maximum dose), D2% (minimum dose), mean dose, dose standard deviation, CI, and HI.	('D2%', 'Var', (54, 57))	('HI', 'Disease', 'MESH:C538424', (118, 120))	('D98%', 'Var', (33, 37))	('PTV', 'Chemical', '-', (8, 11))
706692	24892348	Although the V5 and V10 in VMAT plans were not significantly higher than those in IMRT plans, obviously they got increased when compared to conformal plans, 26 ,  27  which may lead to increase the risk of radiation pneumonitis.	('pneumonitis', 'Disease', 'MESH:D011014', (216, 227))	('pneumonitis', 'Disease', (216, 227))	('V10', 'Var', (20, 23))
706721	29123947	CpG7909 is of particular interest as a TLR9 agonist used to stimulate plasmacytoid DCs to produce robust CD8+ immunity.	('CD8', 'Gene', (105, 108))	('CD8', 'Gene', '925', (105, 108))	('CpG7909', 'Var', (0, 7))	('TLR9', 'Gene', (39, 43))	('TLR9', 'Gene', '54106', (39, 43))
706722	29123947	AS15 trended toward benefit to overall survival in Phase II and III studies and produced complete responses in 3/36 patients with stage III or IV metastatic melanoma.	('overall', 'MPA', (31, 38))	('benefit', 'PosReg', (20, 27))	('patients', 'Species', '9606', (116, 124))	('AS15', 'Chemical', '-', (0, 4))	('AS15', 'Var', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))
706746	29123947	A current search on ClinicalTrials.gov revealed two terminated studies and one suspended study with this drug for cancer treatment (NCT01341496, NCT02054104, and NCT01258868).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('NCT02054104', 'Var', (145, 156))	('NCT01258868', 'Var', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('NCT01341496', 'Var', (132, 143))	('cancer', 'Disease', (114, 120))
706797	29123947	These include IFA, which increased numbers of antigen-specific and effector memory CCR7-CD45RA- T cells in response to VLPs, GMCSF, which accelerated antibody production after vaccination with CHP-HER2, and CPG7909, which trended toward providing survival benefit when combined with AS15.	('AS15', 'Chemical', '-', (283, 287))	('increased', 'PosReg', (25, 34))	('GMCSF', 'Gene', '1437', (125, 130))	('CCR7', 'Gene', '1236', (83, 87))	('CHP-HER2', 'Disease', 'MESH:D064726', (193, 201))	('CD4', 'Gene', '920', (88, 91))	('CCR7', 'Gene', (83, 87))	('CPG7909', 'Var', (207, 214))	('CHP-HER2', 'Disease', (193, 201))	('CD4', 'Gene', (88, 91))	('GMCSF', 'Gene', (125, 130))	('accelerated', 'PosReg', (138, 149))	('antibody production', 'MPA', (150, 169))
706803	29123947	However, CD8+ T-cell response may be more readily generated with transfection of multiple DC subtypes including those deep within lymph nodes.	('CD8', 'Gene', '925', (9, 12))	('transfection', 'Var', (65, 77))	('CD8', 'Gene', (9, 12))
706832	28834899	Moreover, patients with an LS <16.2 kPa had significantly better OS than those with an LS >=16.2 kPa (P = .028).	('OS', 'Chemical', '-', (65, 67))	('better', 'PosReg', (58, 64))	('LS', 'Chemical', '-', (27, 29))	('LS <16.2 kPa', 'Var', (27, 39))	('patients', 'Species', '9606', (10, 18))	('LS', 'Chemical', '-', (87, 89))
706892	28834899	Since the cut-off value of LS for predicting PLF was 16.2 kPa, we chose this value to divide our patients into 2 groups: group A (LS <16.2 kPa) and group B (LS >=16.2 kPa).	('LS', 'Var', (130, 132))	('LS', 'Chemical', '-', (130, 132))	('PLF', 'Disease', (45, 48))	('LS', 'Chemical', '-', (157, 159))	('LS', 'Chemical', '-', (27, 29))	('patients', 'Species', '9606', (97, 105))
706899	28834899	Furthermore, HCC patients with an LS <16.2 kPa had a better prognosis than did patients with an LS >=16.2 kPa by Kaplan-Meier survival analysis.	('HCC', 'Gene', (13, 16))	('LS', 'Chemical', '-', (34, 36))	('HCC', 'Gene', '619501', (13, 16))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (79, 87))	('LS', 'Chemical', '-', (96, 98))	('HCC', 'Phenotype', 'HP:0001402', (13, 16))	('LS <16.2 kPa', 'Var', (34, 46))
706914	28834899	In the present study, we found HCC patients with a low LS had a longer median OS and a better prognosis than those with a high LS.	('HCC', 'Phenotype', 'HP:0001402', (31, 34))	('HCC', 'Gene', (31, 34))	('low LS', 'Var', (51, 57))	('LS', 'Chemical', '-', (127, 129))	('OS', 'Chemical', '-', (78, 80))	('LS', 'Chemical', '-', (55, 57))	('HCC', 'Gene', '619501', (31, 34))	('patients', 'Species', '9606', (35, 43))
707056	25568668	Interestingly, TE-1 cells highly expressed p21, while p21 levels were virtually undetectable in TE-7 cells, suggesting a p21-dependent mechanism of miR-31-mediated tumor suppression.	('tumor', 'Disease', (164, 169))	('p21', 'Var', (43, 46))	('TE-7', 'CellLine', 'CVCL:9972', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
707057	25568668	Accordingly, knockdown of p21 in TE-1 cells reversed the tumor suppressive actions of miR-31.	('miR-31', 'Gene', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('knockdown', 'Var', (13, 22))
707060	25568668	In addition, we speculate that delivery of miR-31 could provide therapeutic benefit in the personalized management of a subgroup of ESCC patients with p21-deficient tumors.	('p21-deficient tumors', 'Disease', 'MESH:C535365', (151, 171))	('p21-deficient tumors', 'Disease', (151, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('patients', 'Species', '9606', (137, 145))	('miR-31', 'Var', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('ESCC', 'Disease', (132, 136))
707065	25568668	In ESCC, miR-31 has also been reported to be both a promoter and an inhibitor of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('carcinogenesis', 'Disease', (81, 95))	('miR-31', 'Var', (9, 15))
707070	25568668	miR-31 plays an inhibitory role only in tumor cells harboring mutant p53, suggesting miR-31 as a therapeutic target in patients with p53-deficient tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('mutant', 'Var', (62, 68))	('p53', 'Gene', (69, 72))	('p53-deficient tumors', 'Disease', 'MESH:D009369', (133, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('p53-deficient tumors', 'Disease', (133, 153))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
707072	25568668	Surprisingly, we found that while the ESCC cell lines TE-7 and TE-1 harbored deficient p53, miR-31 only exhibited tumor-suppressive activity in the p21-low-expressing cell line TE-7, and not in p21-high-expressing TE-1 cells.	('deficient', 'NegReg', (77, 86))	('TE-7', 'CellLine', 'CVCL:9972', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('TE-7', 'CellLine', 'CVCL:9972', (177, 181))	('p53', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('miR-31', 'Var', (92, 98))	('tumor', 'Disease', (114, 119))
707081	25568668	1D), suggesting that miR-31 may suppress ESCC by downregulating target oncogenes, including E2F2 and STK40.	('STK40', 'Gene', '83931', (101, 106))	('STK40', 'Gene', (101, 106))	('downregulating', 'NegReg', (49, 63))	('E2F2', 'Gene', (92, 96))	('suppress', 'NegReg', (32, 40))	('ESCC', 'Disease', (41, 45))	('E2F2', 'Gene', '1870', (92, 96))	('miR-31', 'Var', (21, 27))
707085	25568668	3), suggesting that p21 could be responsible for inhibition of miR-31-mediated tumor suppression.	('tumor', 'Disease', (79, 84))	('miR-31-mediated', 'Gene', (63, 78))	('p21', 'Var', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('inhibition', 'NegReg', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
707086	25568668	Thus, if p21 inhibited tumor suppressor function of miR-31, one would expect that p21 shRNA treatment would sensitize TE-1 to miR-31.	('p21', 'Var', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('inhibited', 'NegReg', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('p21', 'Var', (82, 85))	('tumor', 'Disease', (23, 28))
707087	25568668	Real-time RT-PCR also showed that miR-31 was able to downregulate the expression of E2F2 and STK40 after p21 shRNA treatment (Fig.	('downregulate', 'NegReg', (53, 65))	('E2F2', 'Gene', (84, 88))	('expression', 'MPA', (70, 80))	('miR-31', 'Var', (34, 40))	('E2F2', 'Gene', '1870', (84, 88))	('STK40', 'Gene', '83931', (93, 98))	('STK40', 'Gene', (93, 98))
707098	25568668	Pearson correlation analysis for the expression profiles of miR-31, two target oncogenes, and p21 suggested that tumor cells with low p21 levels were candidates for future therapeutic delivery of miR-31.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('miR-31', 'Var', (196, 202))	('miR-31', 'Gene', (60, 66))
707103	25568668	Ectopic re-expression of miR-31 re-sensitizes radio-resistant cells to radiation, suggesting that miR-31 exhibits a tumor-suppressing function in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('miR-31', 'Gene', (25, 31))	('esophageal cancer', 'Disease', (146, 163))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('miR-31', 'Var', (98, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
707107	25568668	p21 is known to function as a double-edged sword in cancers.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('p21', 'Var', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
707111	25568668	One explanation of this phenomenon is the possibility that p53 mutation led to low p21 expression and changed susceptibility to cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('p53', 'Gene', (59, 62))	('p21', 'Protein', (83, 86))	('susceptibility', 'MPA', (110, 124))	('mutation', 'Var', (63, 71))	('low', 'NegReg', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('changed', 'Reg', (102, 109))	('cancer', 'Disease', (128, 134))
707112	25568668	Our Pearson correlation analysis of the expression levels of miR-31, its target oncogenes, and p21 in 27 ESCC tissues suggested that miR-31 can regulate its target genes only in p21-low patients.	('patients', 'Species', '9606', (186, 194))	('regulate', 'Reg', (144, 152))	('miR-31', 'Var', (133, 139))
707137	25568668	Blots were probed with antibodies against p53 (1:500, Santa Cruz, Dallas, TX), p21 (1:1000, Cell Signaling, Danvers, MA), beta-actin (1:5000, Sigma, St. Louis, MO).	('beta-actin', 'Gene', (122, 132))	('beta-actin', 'Gene', '728378', (122, 132))	('1:500', 'Var', (47, 52))
707143	25452806	Serine/threonine kinase 15 gene polymorphism and risk of digestive system cancers: A meta-analysis Previous studies have reported an association between the two coding polymorphisms (91T>A and 169G>A) of the serine/threonine kinase 15 (STK15) gene and the risk of digestive system cancers; however, the results are inconsistent.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('Serine/threonine kinase 15', 'Gene', '6790', (0, 26))	('system cancers', 'Disease', 'MESH:D009369', (274, 288))	('91T>A', 'Mutation', 'rs2273535', (183, 188))	('STK15', 'Gene', (236, 241))	('STK15', 'Gene', '6790', (236, 241))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('system cancers', 'Disease', (67, 81))	('169G>A', 'Var', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('169G>A', 'Mutation', 'rs1047972', (193, 199))	('system cancers', 'Disease', 'MESH:D009369', (67, 81))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('system cancers', 'Disease', (274, 288))	('91T>A', 'Var', (183, 188))	('serine/threonine kinase 15', 'Gene', '6790', (208, 234))	('serine/threonine kinase 15', 'Gene', (208, 234))	('Serine/threonine kinase 15', 'Gene', (0, 26))
707144	25452806	In the present study, a meta-analysis was carried out to assess the association between the two STK15 polymorphisms and the risk of digestive system cancers.	('association', 'Interaction', (68, 79))	('polymorphisms', 'Var', (102, 115))	('system cancers', 'Disease', (142, 156))	('system cancers', 'Disease', 'MESH:D009369', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('STK15', 'Gene', (96, 101))	('STK15', 'Gene', '6790', (96, 101))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
707146	25452806	Of these, 15 studies concerned the 91T>A polymorphism and included 7,619 cases and 7,196 controls and four studies concerned the 161G>A polymorphism and included 826 cases and 713 controls.	('91T>A', 'Var', (35, 40))	('161G>A', 'Mutation', 'c.161G>A', (129, 135))	('91T>A', 'Mutation', 'rs2273535', (35, 40))	('161G>A', 'Var', (129, 135))
707147	25452806	A significantly increased risk of digestive system cancers was observed for the 91T>A polymorphism (recessive model: OR, 1.19; 95% CI, 1.07-1.31).	('system cancers', 'Disease', 'MESH:D009369', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('system cancers', 'Disease', (44, 58))	('91T>A', 'Var', (80, 85))	('91T>A', 'Mutation', 'rs2273535', (80, 85))
707148	25452806	Stratification by tumor type indicated that the 91T>A polymorphism was associated with an increased risk of esophageal and colorectal cancers under the recessive model (OR, 1.19; 95% CI, 1.03-1.38; and OR, 1.24; 95% CI, 1.04-1.46; respectively); however, no significant association was observed between the 169G>A polymorphism and the risk of digestive system cancers in any of the genetic models.	('esophageal', 'Disease', 'MESH:D004941', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('colorectal cancers', 'Disease', 'MESH:D015179', (123, 141))	('169G>A', 'Var', (307, 313))	('tumor', 'Disease', (18, 23))	('169G>A', 'Mutation', 'rs1047972', (307, 313))	('colorectal cancers', 'Disease', (123, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('91T>A', 'Var', (48, 53))	('esophageal', 'Disease', (108, 118))	('91T>A', 'Mutation', 'rs2273535', (48, 53))	('cancers', 'Phenotype', 'HP:0002664', (360, 367))	('system cancers', 'Disease', (353, 367))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('system cancers', 'Disease', 'MESH:D009369', (353, 367))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
707149	25452806	The present meta-analysis demonstrated that the STK15 gene 91T>A polymorphism, but not the 169G>A polymorphism, may be a risk factor for digestive system cancers, particularly for esophageal and colorectal cancers.	('risk factor', 'Reg', (121, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (195, 212))	('colorectal cancers', 'Disease', 'MESH:D015179', (195, 213))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('colorectal cancers', 'Disease', (195, 213))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('STK15', 'Gene', (48, 53))	('STK15', 'Gene', '6790', (48, 53))	('esophageal', 'Disease', (180, 190))	('169G>A', 'Mutation', 'rs1047972', (91, 97))	('91T>A', 'Mutation', 'rs2273535', (59, 64))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('system cancers', 'Disease', 'MESH:D009369', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('system cancers', 'Disease', (147, 161))	('91T>A polymorphism', 'Var', (59, 77))	('esophageal', 'Disease', 'MESH:D004941', (180, 190))
707156	25452806	Two non-synonymous polymorphisms, 91T>A (rs2273535) and 169G>A (rs1047972), have been identified in the STK15 gene.	('STK15', 'Gene', '6790', (104, 109))	('169G>A', 'Mutation', 'rs1047972', (56, 62))	('rs2273535', 'Var', (41, 50))	('rs1047972', 'Var', (64, 73))	('91T>A', 'Mutation', 'rs2273535', (34, 39))	('STK15', 'Gene', (104, 109))	('rs2273535', 'Mutation', 'rs2273535', (41, 50))	('rs1047972', 'Mutation', 'rs1047972', (64, 73))	('169G>A (rs1047972', 'Var', (56, 73))
707157	25452806	A thymine (T)/adenine (A) polymorphism located at nucleotide position 91 encodes a phenylalanine (Phe)-to-isoleucine (Ile) substitution at amino acid position 31.	('thymine', 'Chemical', 'MESH:D013941', (2, 9))	('phenylalanine', 'Chemical', 'MESH:D010649', (83, 96))	('adenine', 'Chemical', 'MESH:D000225', (14, 21))	('substitution', 'Var', (123, 135))	('Ile', 'Chemical', '-', (118, 121))	('polymorphism', 'Var', (26, 38))	('Phe', 'Chemical', 'MESH:D010649', (98, 101))
707158	25452806	A guanine (G)/A polymorphism at nucleotide 169 encodes a valine (Val)-to-Ile substitution at amino acid position 57.	('Val', 'Chemical', 'MESH:D014633', (65, 68))	('guanine', 'Var', (2, 9))	('valine', 'Chemical', 'MESH:D014633', (57, 63))	('guanine', 'Chemical', 'MESH:D006147', (2, 9))	('encodes', 'Reg', (47, 54))	('Ile', 'Chemical', '-', (73, 76))
707160	25452806	It has been revealed that the A allele of the 91T>A (31Ile>Phe) polymorphism is preferentially amplified and more potent than the T allele in leading to aneuploidy and transformation.	('91T>A', 'Mutation', 'rs2273535', (46, 51))	('transformation', 'CPA', (168, 182))	('leading to', 'Reg', (142, 152))	('91T>A (31Ile>Phe', 'Var', (46, 62))	('aneuploidy', 'Disease', (153, 163))	('31Ile>Phe', 'Mutation', 'rs2273535', (53, 62))	('aneuploidy', 'Disease', 'MESH:D000782', (153, 163))
707163	25452806	The aim of the present study was therefore to conduct a meta-analysis to evaluate the association between the two STK15 polymorphisms and susceptibility to digestive system cancers.	('system cancers', 'Disease', (166, 180))	('system cancers', 'Disease', 'MESH:D009369', (166, 180))	('STK15', 'Gene', (114, 119))	('polymorphisms', 'Var', (120, 133))	('association', 'Interaction', (86, 97))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('STK15', 'Gene', '6790', (114, 119))
707167	25452806	Studies included in this meta-analysis were selected according to the following criteria: i) Studies that evaluated the association between the STK15 polymorphisms (91T>A or 169G>A) and digestive system cancers; ii) studies that had a case-control design; and iii) studies that had a detailed genotype frequency of cases and controls or that had presented sufficient data for this to be calculated from the article text.	('system cancers', 'Disease', 'MESH:D009369', (196, 210))	('association', 'Interaction', (120, 131))	('91T>A', 'Var', (165, 170))	('STK15', 'Gene', (144, 149))	('STK15', 'Gene', '6790', (144, 149))	('91T>A', 'Mutation', 'rs2273535', (165, 170))	('169G>A', 'Mutation', 'rs1047972', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('system cancers', 'Disease', (196, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
707169	25452806	The risk of digestive system cancers associated with the STK15 polymorphisms was estimated for each study by the odds ratio (OR) and 95% confidence interval (CI).	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('STK15', 'Gene', '6790', (57, 62))	('STK15', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('polymorphisms', 'Var', (63, 76))	('system cancers', 'Disease', (22, 36))	('system cancers', 'Disease', 'MESH:D009369', (22, 36))
707171	25452806	Since the study by Ewart-Toland et al included two populations, these populations were treated separately in the current meta-analysis (Tables I and II); as such, there were 15 case-control studies from 14 publications with 7,619 cases and 7,196 controls concerning the 91T>A polymorphism and four studies with 826 cases and 713 controls concerning the 169G>A polymorphism.	('91T>A', 'Var', (270, 275))	('169G>A', 'Mutation', 'rs1047972', (353, 359))	('91T>A', 'Mutation', 'rs2273535', (270, 275))	('169G>A', 'Var', (353, 359))
707173	25452806	Fifteen studies reported an association between the 91T>A polymorphism and susceptibility to digestive system cancers.	('system cancers', 'Disease', 'MESH:D009369', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('91T>A', 'Var', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('91T>A', 'Mutation', 'rs2273535', (52, 57))	('system cancers', 'Disease', (103, 117))
707174	25452806	Stratification by tumor type indicated that the 91T>A polymorphism was associated with an increased risk of esophageal and colorectal cancers under the recessive model (OR, 1.19; 95% CI, 1.03-1.38; and OR, 1.24; 95% CI, 1.04-1.46; respectively); however, no significant association was detected for gastric cancer.	('esophageal', 'Disease', 'MESH:D004941', (108, 118))	('gastric cancer', 'Disease', 'MESH:D013274', (299, 313))	('colorectal cancers', 'Disease', 'MESH:D015179', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('tumor', 'Disease', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('colorectal cancers', 'Disease', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('gastric cancer', 'Phenotype', 'HP:0012126', (299, 313))	('91T>A', 'Var', (48, 53))	('esophageal', 'Disease', (108, 118))	('91T>A', 'Mutation', 'rs2273535', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('gastric cancer', 'Disease', (299, 313))
707176	25452806	Four studies reported an association between the 169G>A polymorphism and the risk of digestive system cancers.	('169G>A', 'Var', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('169G>A', 'Mutation', 'rs1047972', (49, 55))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('system cancers', 'Disease', (95, 109))	('system cancers', 'Disease', 'MESH:D009369', (95, 109))
707177	25452806	Substantial heterogeneities were observed among the studies for the association between the risk of digestive system cancers and the 91T>A (dominant model: I2=68%, P<0.0001; TA versus TT: I2=63%, P=0.0005; AA versus TT: I2=58%, P=0.002) and 169G>A (recessive model: I2=58%, P=0.07; AA versus TT: I2=56%, P=0.08) STK19 polymorphisms.	('169G>A', 'Var', (241, 247))	('STK19', 'Gene', '8859', (312, 317))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('STK19', 'Gene', (312, 317))	('system cancers', 'Disease', (110, 124))	('91T>A', 'Mutation', 'rs2273535', (133, 138))	('system cancers', 'Disease', 'MESH:D009369', (110, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('169G>A', 'Mutation', 'rs1047972', (241, 247))	('91T>A', 'Var', (133, 138))
707179	25452806	For the 91T>A polymorphism, the heterogeneity was partially decreased or removed in colorectal and gastric cancers and Caucasian populations; however, significant heterogeneity remained for esophageal cancer and Asian populations.	('91T>A', 'Var', (8, 13))	('decreased', 'NegReg', (60, 69))	('91T>A', 'Mutation', 'rs2273535', (8, 13))	('gastric cancers', 'Phenotype', 'HP:0012126', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('esophageal cancer', 'Disease', 'MESH:D004938', (190, 207))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (84, 114))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('removed', 'NegReg', (73, 80))
707180	25452806	For the 169G>A polymorphism, the heterogeneity significantly decreased when the study by Kimura et al was excluded from the analysis.	('decreased', 'NegReg', (61, 70))	('heterogeneity', 'MPA', (33, 46))	('169G>A', 'Var', (8, 14))	('169G>A', 'Mutation', 'rs1047972', (8, 14))
707183	25452806	Although the mechanism remains unclear, it is believed that the polymorphism may partially affect STK15 expression and therefore modify its function.	('STK15', 'Gene', (98, 103))	('STK15', 'Gene', '6790', (98, 103))	('function', 'MPA', (140, 148))	('modify', 'Reg', (129, 135))	('affect', 'Reg', (91, 97))	('expression', 'MPA', (104, 114))	('polymorphism', 'Var', (64, 76))
707186	25452806	To date, a number of studies have investigated the association between STK15 polymorphisms and the risk of cancers, particularly cancers of the digestive system; however, the results have been inconsistent.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', (107, 114))	('investigated', 'Reg', (34, 46))	('STK15', 'Gene', (71, 76))	('STK15', 'Gene', '6790', (71, 76))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('polymorphisms', 'Var', (77, 90))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('association', 'Interaction', (51, 62))	('cancers', 'Disease', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
707191	25452806	Furthermore, the association between the 169G>A polymorphism and the risk of digestive system cancers was explored.	('system cancers', 'Disease', (87, 101))	('system cancers', 'Disease', 'MESH:D009369', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('169G>A', 'Var', (41, 47))	('169G>A', 'Mutation', 'rs1047972', (41, 47))
707192	25452806	In the current meta-analysis, 15 studies were pooled to examine the association between the two STK15 polymorphisms and risk of digestive system cancers.	('system cancers', 'Disease', (138, 152))	('polymorphisms', 'Var', (102, 115))	('system cancers', 'Disease', 'MESH:D009369', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('STK15', 'Gene', (96, 101))	('STK15', 'Gene', '6790', (96, 101))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
707194	25452806	When stratified by tumor type, the 91T>A polymorphism was associated with an increased risk of esophageal and colorectal cancers, but not gastric cancer.	('gastric cancer', 'Disease', (138, 152))	('esophageal', 'Disease', (95, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('esophageal', 'Disease', 'MESH:D004941', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('91T>A', 'Var', (35, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('colorectal cancers', 'Disease', 'MESH:D015179', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Disease', (19, 24))	('colorectal cancers', 'Disease', (110, 128))	('91T>A', 'Mutation', 'rs2273535', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
707196	25452806	No significant association was found between the 169G>A polymorphism and the risk of digestive system cancers in any of the genetic models.	('169G>A', 'Var', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('169G>A', 'Mutation', 'rs1047972', (49, 55))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('system cancers', 'Disease', (95, 109))	('system cancers', 'Disease', 'MESH:D009369', (95, 109))
707199	25452806	For the 169G>A polymorphism, the heterogeneity significantly decreased when the study by Kimura et al was excluded from analysis.	('decreased', 'NegReg', (61, 70))	('heterogeneity', 'MPA', (33, 46))	('169G>A', 'Var', (8, 14))	('169G>A', 'Mutation', 'rs1047972', (8, 14))
707202	25452806	In conclusion, the present meta-analysis suggests that the STK15 gene 91T>A polymorphism, but not the 169G>A polymorphism, may be a risk factor for digestive system cancers, particularly for esophageal and colorectal cancers.	('system cancers', 'Disease', 'MESH:D009369', (158, 172))	('169G>A', 'Mutation', 'rs1047972', (102, 108))	('risk factor', 'Reg', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('colorectal cancer', 'Phenotype', 'HP:0003003', (206, 223))	('colorectal cancers', 'Disease', 'MESH:D015179', (206, 224))	('esophageal', 'Disease', 'MESH:D004941', (191, 201))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('STK15', 'Gene', (59, 64))	('polymorphism', 'Var', (76, 88))	('STK15', 'Gene', '6790', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('colorectal cancers', 'Disease', (206, 224))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('system cancers', 'Disease', (158, 172))	('91T>A', 'Mutation', 'rs2273535', (70, 75))	('91T>A polymorphism', 'Var', (70, 88))	('esophageal', 'Disease', (191, 201))
707207	20680162	H. pylori eradication in patients with peptic ulcer disease may be associated with increased risk of development of GERD compared with untreated patients.	('patients', 'Species', '9606', (145, 153))	('GERD', 'Disease', 'MESH:D005764', (116, 120))	('H. pylori', 'Protein', (0, 9))	('GERD', 'Disease', (116, 120))	('H. pylori', 'Species', '210', (0, 9))	('eradication', 'Var', (10, 21))	('patients', 'Species', '9606', (25, 33))	('peptic ulcer', 'Phenotype', 'HP:0004398', (39, 51))	('peptic ulcer disease', 'Disease', (39, 59))	('peptic ulcer disease', 'Disease', 'MESH:D010437', (39, 59))
707219	20680162	Most studies suggest that H. pylori may protect against development of GERD or may reduce its severity, however, a few studies do suggest that it may aggravate GERD.	('GERD', 'Disease', 'MESH:D005764', (71, 75))	('H. pylori', 'Species', '210', (26, 35))	('H. pylori', 'Var', (26, 35))	('severity', 'MPA', (94, 102))	('GERD', 'Disease', (160, 164))	('reduce', 'NegReg', (83, 89))	('GERD', 'Disease', 'MESH:D005764', (160, 164))	('GERD', 'Disease', (71, 75))	('aggravate', 'PosReg', (150, 159))
707231	20680162	It is well-established that eradication of H. pylori heals peptic ulcer and prevents its recurrence.	('peptic ulcer', 'Phenotype', 'HP:0004398', (59, 71))	('H. pylori', 'Species', '210', (43, 52))	('eradication', 'Var', (28, 39))	('peptic ulcer', 'Disease', 'MESH:D010437', (59, 71))	('H. pylori', 'Gene', (43, 52))	('peptic ulcer', 'Disease', (59, 71))
707232	20680162	Increased severity of GERD and its complications such as BE after successful eradication of H. pylori in patients with or without peptic ulcer has been documented in several studies.	('GERD', 'Disease', (22, 26))	('H. pylori', 'Species', '210', (92, 101))	('GERD', 'Disease', 'MESH:D005764', (22, 26))	('patients', 'Species', '9606', (105, 113))	('peptic ulcer', 'Disease', 'MESH:D010437', (130, 142))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('peptic ulcer', 'Disease', (130, 142))	('H. pylori', 'Gene', (92, 101))	('peptic ulcer', 'Phenotype', 'HP:0004398', (130, 142))	('eradication', 'Var', (77, 88))
707234	20680162	Development of GERD following eradication of H. pylori may reflect an increase in the acidity of the refluxate superimposed on pre-existing abnormalities in gastroesophageal motility.	('eradication', 'Var', (30, 41))	('increase', 'PosReg', (70, 78))	('H. pylori', 'Species', '210', (45, 54))	('abnormalities in gastroesophageal motility', 'Phenotype', 'HP:0030895', (140, 182))	('GERD', 'Disease', 'MESH:D005764', (15, 19))	('gastroesophageal motility', 'Disease', 'MESH:D005764', (157, 182))	('acidity of the refluxate', 'MPA', (86, 110))	('GERD', 'Disease', (15, 19))	('gastroesophageal motility', 'Disease', (157, 182))
707235	20680162	Conversely, some studies did show beneficial effect of H. pylori eradication on symptoms of GERD.	('GERD', 'Disease', (92, 96))	('eradication', 'Var', (65, 76))	('H. pylori', 'Protein', (55, 64))	('H. pylori', 'Species', '210', (55, 64))	('GERD', 'Disease', 'MESH:D005764', (92, 96))
707254	20680162	Another multi-ethnic study from Malaysia suggested that cagA-positive strains of H. pylori was associated with reduced severity of GERD among Indians.	('Malaysia', 'Disease', 'None', (32, 40))	('Malaysia', 'Disease', (32, 40))	('H. pylori', 'Species', '210', (81, 90))	('severity', 'MPA', (119, 127))	('reduced', 'NegReg', (111, 118))	('strains', 'Var', (70, 77))	('GERD', 'Disease', 'MESH:D005764', (131, 135))	('GERD', 'Disease', (131, 135))	('H. pylori', 'Gene', (81, 90))
707263	20680162	Limited studies have shown that IL-1B-511C allele, IL-1B-31T allele, G protein beta 3 subunit 825T allele, IL-1RN + 2018 2/2 genotype, 2/2 genotype of IL-10-1082, homozygous extensive of CYP2C19, b allele (val105) of glutathione S-transferase P1, A/A genotype of cyclin D1 (CCND1) G870A and homozygous variant of Xeroderma pigmentosum complementary group C poly (AT) insertion/deletion polymorphism gene are the potential risk factors for either GERD or its complications such as BE and EAC.	('insertion/deletion polymorphism', 'Var', (367, 398))	('Xeroderma pigmentosum complementary', 'Disease', (313, 348))	('EAC', 'Phenotype', 'HP:0011459', (487, 490))	('G870A', 'Var', (281, 286))	('GERD', 'Disease', (446, 450))	('GERD', 'Disease', 'MESH:D005764', (446, 450))	('BE', 'Phenotype', 'HP:0100580', (480, 482))	('IL-1B', 'Gene', (32, 37))	('IL-1B', 'Gene', '3553', (51, 56))	('IL-1RN', 'Gene', '3557', (107, 113))	('CCND1', 'Gene', (274, 279))	('EAC', 'Disease', (487, 490))	('IL-1B', 'Gene', '3553', (32, 37))	('Xeroderma pigmentosum complementary', 'Disease', 'MESH:D014983', (313, 348))	('IL-1RN', 'Gene', (107, 113))	('G870A', 'Mutation', 'rs1295685', (281, 286))	('IL-1B', 'Gene', (51, 56))
707271	20680162	Limited studies have shown that host genetic factors that may influence development of GERD include genes, which may alter gastric acid secretion (pro and anti-inflammatory factors and those involved in acid secretory pathway), DNA repair pathway (for BE and EAC), carcinogen detoxification pathway (for EAC), cell cycle regulatory pathway and visceral hypersensitivity to the refluxed acid in esophagus (Fig.	('EAC', 'Phenotype', 'HP:0011459', (304, 307))	('DNA repair pathway', 'Pathway', (228, 246))	('refluxed acid', 'Phenotype', 'HP:0002020', (377, 390))	('gastric acid secretion', 'MPA', (123, 145))	('influence', 'Reg', (62, 71))	('BE', 'Phenotype', 'HP:0100580', (252, 254))	('GERD', 'Disease', (87, 91))	('GERD', 'Disease', 'MESH:D005764', (87, 91))	('cell cycle regulatory pathway', 'Pathway', (310, 339))	('alter', 'Reg', (117, 122))	('hypersensitivity to the', 'Disease', (353, 376))	('genes', 'Var', (100, 105))	('carcinogen detoxification pathway', 'Pathway', (265, 298))	('hypersensitivity to the', 'Disease', 'MESH:D004342', (353, 376))	('EAC', 'Phenotype', 'HP:0011459', (259, 262))
707280	20680162	Some of these cytokine polymorphisms have been shown to affect the degree of gastritis.	('polymorphisms', 'Var', (23, 36))	('gastritis', 'Disease', 'MESH:D005756', (77, 86))	('affect', 'Reg', (56, 62))	('gastritis', 'Disease', (77, 86))	('gastritis', 'Phenotype', 'HP:0005263', (77, 86))
707292	20680162	Latest studies targeting the role of inflammatory markers (IL-1B and IL-1RN) suggest that presence of the pro-inflammatory genotypes are associated with less severe GERD.	('GERD', 'Disease', 'MESH:D005764', (165, 169))	('presence', 'Var', (90, 98))	('IL-1B', 'Gene', '3553', (59, 64))	('GERD', 'Disease', (165, 169))	('IL-1B', 'Gene', (59, 64))	('IL-1RN', 'Gene', (69, 75))	('IL-1RN', 'Gene', '3557', (69, 75))
707314	32476689	Incidence trends of the 12 most relevant sites in Uruguay are described in this article, corresponding to codes C50 (female breast cancer),C61(prostate), C33-C34 (lung), C18-C21 (colon, rectum and annus), C64-C65 (kidney and renal pelvis), C66-C68 (bladder, urethra and ureter), C16 (stomach), C15 (esophagus), C53 (cervix uteri), C73 (thyroid), C62 (testis) and all cancer sites excluding non-melanoma skin cancer.	('cancer', 'Phenotype', 'HP:0002664', (408, 414))	('C16', 'Var', (279, 282))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('C53', 'Gene', (311, 314))	('C73', 'Var', (331, 334))	('C33', 'Gene', (154, 157))	('C64-C65', 'Var', (205, 212))	('kidney and renal pelvis', 'Disease', 'MESH:D007680', (214, 237))	('C66-C68', 'Var', (240, 247))	('C62', 'Var', (346, 349))	('C50', 'Var', (112, 115))	('C61', 'Var', (139, 142))	('renal pelvis', 'Phenotype', 'HP:0000125', (225, 237))	('C33', 'Gene', '3732', (154, 157))	('melanoma', 'Phenotype', 'HP:0002861', (394, 402))	('C15', 'Var', (294, 297))	('cervix uteri', 'Phenotype', 'HP:0000139', (316, 328))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('C53', 'Gene', '80279', (311, 314))	('skin cancer', 'Phenotype', 'HP:0008069', (403, 414))	('C18-C21', 'Var', (170, 177))
707416	26581671	Patients with no residual, viable tumor cells in the surgical specimen (ypT0N0M0) were classified as having a pathologic complete response (pCR), all other patients were considered to have residual disease.	('patients', 'Species', '9606', (156, 164))	('tumor', 'Disease', (34, 39))	('ypT0N0M0', 'Var', (72, 80))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('N0', 'Chemical', 'MESH:C491690', (76, 78))
707447	26581671	On multivariate analysis, patients with pCR (OR 0.19, 95% CI 0.05-0.68, p = 0.011) were less likely to experience distant recurrence.	('distant recurrence', 'CPA', (114, 132))	('less', 'NegReg', (88, 92))	('pCR', 'Var', (40, 43))	('patients', 'Species', '9606', (26, 34))
707455	26581671	In the presented analysis, patients obtaining a pCR were less likely to experience a distant relapse and had an improved OS versus patients with residual disease.	('patients', 'Species', '9606', (131, 139))	('less', 'NegReg', (57, 61))	('patients', 'Species', '9606', (27, 35))	('pCR', 'Var', (48, 51))	('distant relapse', 'CPA', (85, 100))	('improved', 'PosReg', (112, 120))
707496	31496055	Additionally, our in vitro experiments further demonstrated that knockdown of UTP14a inhibits cell proliferation and invasion in ECA109 cells.	('UTP14a', 'Gene', (78, 84))	('inhibits', 'NegReg', (85, 93))	('UTP14a', 'Gene', '10813', (78, 84))	('EC', 'Disease', 'MESH:D004938', (129, 131))	('knockdown', 'Var', (65, 74))
707541	31496055	In Fig 2e,f, compared with UTP14a negative group, UTP14a positive group was significantly higher in DFS and DSS (P = 0.012 and P = 0.003, respectively), and high UTP14a expression may indicate poor prognosis.	('UTP14a', 'Gene', '10813', (162, 168))	('UTP14a', 'Gene', '10813', (50, 56))	('high', 'Var', (157, 161))	('UTP14a', 'Gene', (27, 33))	('UTP14a', 'Gene', '10813', (27, 33))	('DSS', 'Disease', (108, 111))	('DFS', 'Disease', (100, 103))	('expression', 'MPA', (169, 179))	('UTP14a', 'Gene', (162, 168))	('higher', 'PosReg', (90, 96))	('UTP14a', 'Gene', (50, 56))
707548	31496055	Knockdown of WIG-1 can increase cell death and reduce cell cycle arrest upon DNA damage.	('WIG-1', 'Gene', (13, 18))	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('death', 'Disease', (37, 42))	('Knockdown', 'Var', (0, 9))	('reduce', 'NegReg', (47, 53))	('WIG-1', 'Gene', '64393', (13, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('arrest', 'Disease', (65, 71))	('increase', 'PosReg', (23, 31))	('death', 'Disease', 'MESH:D003643', (37, 42))
707555	31496055	They demonstrated that UTP14a forms a complex with USP36/Fbw7gamma, stabilizes c-Myc in the nucleolus, and inhibits c-Myc degradation; knockdown of UTP14a leads to a decrease in c-Myc levels and inhibits tumor growth.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('c-Myc', 'Gene', (178, 183))	('c-Myc', 'Gene', '4609', (178, 183))	('USP36', 'Gene', (51, 56))	('c-Myc', 'Gene', (79, 84))	('stabilizes', 'MPA', (68, 78))	('UTP14a', 'Gene', '10813', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('c-Myc', 'Gene', '4609', (79, 84))	('UTP14a', 'Gene', '10813', (148, 154))	('inhibits', 'NegReg', (195, 203))	('USP36', 'Gene', '57602', (51, 56))	('inhibits', 'NegReg', (107, 115))	('c-Myc', 'Gene', (116, 121))	('UTP14a', 'Gene', (23, 29))	('knockdown', 'Var', (135, 144))	('tumor', 'Disease', (204, 209))	('c-Myc', 'Gene', '4609', (116, 121))	('UTP14a', 'Gene', (148, 154))	('decrease', 'NegReg', (166, 174))
707560	31496055	Meanwhile, from the Kaplan-Meier survival curves and the log-rank test, we found that high UTP14a expression predicts poor DFS and DSS.	('UTP14a', 'Gene', (91, 97))	('UTP14a', 'Gene', '10813', (91, 97))	('DFS', 'Disease', (123, 126))	('poor', 'NegReg', (118, 122))	('DSS', 'Disease', (131, 134))	('high', 'Var', (86, 90))	('expression', 'MPA', (98, 108))
707562	31496055	Furthermore, our in vitro experiments showed that upon knockdown of UTP14a, cell proliferation and cell invasion were decreased significantly.	('knockdown', 'Var', (55, 64))	('cell invasion', 'CPA', (99, 112))	('UTP14a', 'Gene', (68, 74))	('cell proliferation', 'CPA', (76, 94))	('UTP14a', 'Gene', '10813', (68, 74))	('decreased', 'NegReg', (118, 127))
707636	29977357	The results demonstrated that the number of Ki67+ NK cells was significantly higher following propofol stimulation compared with control cells (Fig.	('higher', 'PosReg', (77, 83))	('Ki67+', 'Var', (44, 49))	('propofol', 'Chemical', 'MESH:D015742', (94, 102))
707674	28947981	In patients, high Lin28B expression was significantly correlated with high levels of lymphatic metastasis, distant metastasis and a poor prognosis.	('high', 'Var', (13, 17))	('Lin28B', 'Gene', '389421', (18, 24))	('expression', 'MPA', (25, 35))	('correlated', 'Reg', (54, 64))	('patients', 'Species', '9606', (3, 11))	('Lin28B', 'Gene', (18, 24))	('distant metastasis', 'CPA', (107, 125))
707679	28947981	In human PDAC samples, high Lin28B expression was associated with decreased let-7 expression and increased c-MYC, HMGA2 and KRAS expression.	('PDAC', 'Phenotype', 'HP:0006725', (9, 13))	('c-MYC', 'Gene', (107, 112))	('KRAS', 'Gene', (124, 128))	('high', 'Var', (23, 27))	('expression', 'MPA', (82, 92))	('HMGA2', 'Gene', (114, 119))	('increased', 'PosReg', (97, 106))	('decreased', 'NegReg', (66, 75))	('KRAS', 'Gene', '3845', (124, 128))	('human', 'Species', '9606', (3, 8))	('Lin28B', 'Gene', (28, 34))	('expression', 'MPA', (35, 45))	('PDAC', 'Chemical', '-', (9, 13))	('c-MYC', 'Gene', '4609', (107, 112))	('let-7', 'Gene', '266952', (76, 81))	('HMGA2', 'Gene', '8091', (114, 119))	('let-7', 'Gene', (76, 81))	('Lin28B', 'Gene', '389421', (28, 34))
707714	28947981	According to the results of the cell counting kit-8 (CCK-8) assay, Lin28B knockdown with a specific siRNA markedly decreased the rates of AsPC-1 and Hs766t cell proliferation compared with that of the vector-transfected cells (Figure 2B and 2C).	('Lin28B', 'Gene', (67, 73))	('AsPC-1', 'CellLine', 'CVCL:0152', (138, 144))	('decreased', 'NegReg', (115, 124))	('knockdown', 'Var', (74, 83))	('Hs766t cell proliferation', 'CPA', (149, 174))	('Lin28B', 'Gene', '389421', (67, 73))	('Hs766', 'CellLine', 'CVCL:0334', (149, 154))
707715	28947981	We found that Lin28B knockdown significantly decreased the numbers of Hs766t cells colony formation (Figure 2D).	('Lin28B', 'Gene', '389421', (14, 20))	('Hs766', 'CellLine', 'CVCL:0334', (70, 75))	('decreased', 'NegReg', (45, 54))	('Lin28B', 'Gene', (14, 20))	('knockdown', 'Var', (21, 30))
707717	28947981	Compared with the control, Lin28B knockdown significantly decreased the fraction of AsPC-1 and Hs766t cells in S phase and increased the fraction of cells in G0/G1 phase (Figure 2E and 2F).	('increased', 'PosReg', (123, 132))	('Lin28B', 'Gene', '389421', (27, 33))	('AsPC-1', 'CellLine', 'CVCL:0152', (84, 90))	('decreased', 'NegReg', (58, 67))	('Lin28B', 'Gene', (27, 33))	('knockdown', 'Var', (34, 43))	('Hs766', 'CellLine', 'CVCL:0334', (95, 100))
707720	28947981	The Transwell migration assay yielded similar results, with a smaller number of cells penetrating the membrane in the Lin28B knockdown group than in the control group (Figure 3B and 3C).	('knockdown', 'Var', (125, 134))	('smaller', 'NegReg', (62, 69))	('cells penetrating the membrane', 'CPA', (80, 110))	('Lin28B', 'Gene', '389421', (118, 124))	('Transwell migration', 'CPA', (4, 23))	('Lin28B', 'Gene', (118, 124))
707727	28947981	The subtype with high Lin28B expression exhibited an average increase in the levels of genes involved in the EMT pathway and the expression of the targets of miR-200 (Figure 5A), an important EMT inhibitor.	('miR-200', 'Chemical', '-', (158, 165))	('EMT pathway', 'Pathway', (109, 120))	('high', 'Var', (17, 21))	('Lin28B', 'Gene', (22, 28))	('Lin28B', 'Gene', '389421', (22, 28))	('levels of genes involved', 'MPA', (77, 101))	('increase', 'PosReg', (61, 69))	('expression of', 'MPA', (129, 142))	('miR-200', 'Gene', (158, 165))
707735	28947981	The expression of let-7 targets was substantially increased in the subtype with high Lin28B expression, which exhibited increased levels of KRAS signaling intermediates and c-MYC targets (Figure 6A).	('c-MYC', 'Gene', '4609', (173, 178))	('KRAS', 'Gene', '3845', (140, 144))	('Lin28B', 'Gene', (85, 91))	('increased', 'PosReg', (50, 59))	('c-MYC', 'Gene', (173, 178))	('expression', 'MPA', (4, 14))	('let-7', 'Gene', (18, 23))	('let-7', 'Gene', '266952', (18, 23))	('Lin28B', 'Gene', '389421', (85, 91))	('increased', 'PosReg', (120, 129))	('high', 'Var', (80, 84))	('KRAS', 'Gene', (140, 144))
707745	28947981	Aberrant regulation of the Lin28B and let-7 loop in human malignancies is reportedly involved in cancer development, contributing to cell transformation, metastasis, resistance to cell death, metabolic reprogramming, and tumor-associated inflammation.	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('malignancies', 'Disease', 'MESH:D009369', (58, 70))	('let-7', 'Gene', '266952', (38, 43))	('malignancies', 'Disease', (58, 70))	('Lin28B', 'Gene', '389421', (27, 33))	('cancer', 'Disease', (97, 103))	('Aberrant', 'Var', (0, 8))	('metabolic reprogramming', 'CPA', (192, 215))	('resistance to cell death', 'CPA', (166, 190))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('inflammation', 'Disease', 'MESH:D007249', (238, 250))	('tumor', 'Disease', (221, 226))	('let-7', 'Gene', (38, 43))	('metastasis', 'CPA', (154, 164))	('cell transformation', 'CPA', (133, 152))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('inflammation', 'Disease', (238, 250))	('involved', 'Reg', (85, 93))	('human', 'Species', '9606', (52, 57))	('contributing', 'Reg', (117, 129))	('Lin28B', 'Gene', (27, 33))
707747	28947981	In addition, Lin28B silencing in PDAC cells inhibited cell proliferation, cell cycle transition, migration and the EMT and increased the expression of the c-MYC, HMGA2 and KRAS genes, which are targeted by the cancer suppressor miRNA let-7.	('KRAS', 'Gene', '3845', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('c-MYC', 'Gene', (155, 160))	('KRAS', 'Gene', (172, 176))	('expression', 'MPA', (137, 147))	('inhibited', 'NegReg', (44, 53))	('let-7', 'Gene', '266952', (234, 239))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('silencing', 'Var', (20, 29))	('cell cycle transition', 'CPA', (74, 95))	('HMGA2', 'Gene', (162, 167))	('increased', 'PosReg', (123, 132))	('Lin28B', 'Gene', '389421', (13, 19))	('Lin28B', 'Gene', (13, 19))	('EMT', 'CPA', (115, 118))	('PDAC', 'Chemical', '-', (33, 37))	('cell proliferation', 'CPA', (54, 72))	('PDAC', 'Phenotype', 'HP:0006725', (33, 37))	('migration', 'CPA', (97, 106))	('let-7', 'Gene', (234, 239))	('HMGA2', 'Gene', '8091', (162, 167))	('c-MYC', 'Gene', '4609', (155, 160))	('cancer', 'Disease', (210, 216))
707751	28947981	The effects of Lin28 and Lin28B, which seem similar to the effects of an oncogene, are largely due to their abilities to inhibit the let-7 miRNA family.	('inhibit', 'NegReg', (121, 128))	('Lin28', 'Var', (15, 20))	('let-7', 'Gene', '266952', (133, 138))	('let-7', 'Gene', (133, 138))	('Lin28B', 'Gene', (25, 31))	('Lin28B', 'Gene', '389421', (25, 31))
707770	28947981	The correlation between high Lin28B expression and a poor prognosis in patients with PDAC in this study is comparable with the results of the studies described above.	('PDAC', 'Chemical', '-', (85, 89))	('patients', 'Species', '9606', (71, 79))	('PDAC', 'Disease', (85, 89))	('Lin28B', 'Gene', '389421', (29, 35))	('PDAC', 'Phenotype', 'HP:0006725', (85, 89))	('high', 'Var', (24, 28))	('Lin28B', 'Gene', (29, 35))	('expression', 'MPA', (36, 46))
707773	28947981	One of the best characterized examples is the negative feedback loop between the let-7 miRNA family and Lin28, in which Lin28 represses let-7 family biogenesis.	('let-7', 'Gene', '266952', (81, 86))	('let-7', 'Gene', (81, 86))	('let-7', 'Gene', '266952', (136, 141))	('let-7', 'Gene', (136, 141))	('Lin28', 'Var', (120, 125))	('represses', 'NegReg', (126, 135))
707779	28947981	High Lin28B expression was associated with decreased let-7 expression and increased HMGA2, c-MYC and KRAS expression in human PDAC samples.	('let-7', 'Gene', (53, 58))	('human', 'Species', '9606', (120, 125))	('c-MYC', 'Gene', '4609', (91, 96))	('Lin28B', 'Gene', (5, 11))	('HMGA2', 'Gene', (84, 89))	('High', 'Var', (0, 4))	('Lin28B', 'Gene', '389421', (5, 11))	('PDAC', 'Chemical', '-', (126, 130))	('KRAS', 'Gene', (101, 105))	('KRAS', 'Gene', '3845', (101, 105))	('increased', 'PosReg', (74, 83))	('expression', 'MPA', (59, 69))	('PDAC', 'Phenotype', 'HP:0006725', (126, 130))	('c-MYC', 'Gene', (91, 96))	('expression', 'MPA', (12, 22))	('decreased', 'NegReg', (43, 52))	('HMGA2', 'Gene', '8091', (84, 89))	('let-7', 'Gene', '266952', (53, 58))
707789	28947981	NF-kB directly activates Lin28B transcription, leading to the inhibition of let-7 and expression of IL-6 (a let-7 target).	('let-7', 'Gene', (108, 113))	('Lin28B', 'Gene', '389421', (25, 31))	('let-7', 'Gene', '266952', (76, 81))	('activates', 'PosReg', (15, 24))	('Lin28B', 'Gene', (25, 31))	('NF-kB', 'Var', (0, 5))	('expression', 'MPA', (86, 96))	('inhibition', 'NegReg', (62, 72))	('IL-6', 'Gene', (100, 104))	('transcription', 'MPA', (32, 45))	('IL-6', 'Gene', '3569', (100, 104))	('let-7', 'Gene', '266952', (108, 113))	('let-7', 'Gene', (76, 81))
707812	28947981	Human whole genome microarray datasets GSE15471/16515/32676/32688/42952/9599/71989 for pancreatic cancer and normal adjacent tissues were downloaded from the Gene Expression Omnibus (GEO).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Human', 'Species', '9606', (0, 5))	('pancreatic cancer', 'Disease', (87, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('GSE15471/16515/32676/32688/42952/9599/71989', 'Var', (39, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))
707877	28877681	reported that some patients with FN1 mutation were asymptomatic, and suggested that this genetic abnormality did not necessarily cause a phenotypic abnormality.	('FN1', 'Gene', (33, 36))	('FN1', 'Gene', '2335', (33, 36))	('patients', 'Species', '9606', (19, 27))	('mutation', 'Var', (37, 45))
707879	28877681	In the current case, there might have been asymptomatic patients with FN1 mutations in her family, or the mutation might have arisen de novo.	('FN1', 'Gene', '2335', (70, 73))	('patients', 'Species', '9606', (56, 64))	('mutations', 'Var', (74, 83))	('FN1', 'Gene', (70, 73))
707880	28877681	Mutations at the FN1 gene locus at 2q32 were first confirmed by Castelletti et al.	('FN1', 'Gene', (17, 20))	('Mutations', 'Var', (0, 9))	('FN1', 'Gene', '2335', (17, 20))
707881	28877681	They identified three heterozygous missense mutations, Y973C, W1925R, and L1974R, but reported that these mutations only accounted for 40% of cases of fibronectin glomerulopathy.	('fibronectin', 'Gene', (151, 162))	('Y973C', 'Mutation', 'rs137854488', (55, 60))	('Y973C', 'Var', (55, 60))	('fibronectin', 'Gene', '2335', (151, 162))	('W1925R', 'Mutation', 'rs137854486', (62, 68))	('L1974R', 'Var', (74, 80))	('W1925R', 'Var', (62, 68))	('glomerulopathy', 'Phenotype', 'HP:0100820', (163, 177))	('L1974R', 'Mutation', 'rs137854487', (74, 80))	('glomerulopathy', 'Disease', 'MESH:D007674', (163, 177))	('glomerulopathy', 'Disease', (163, 177))
707882	28877681	subsequently identified six FN1 mutations in 12 families with fibronectin glomerulopathy, including five novel FN1 mutations (p.Pro969Leu, p.Pro1472del, p.Trp1925Cys, p.Lys1953_Ile1961del, and p.Leu1974Pro).	('p.Lys1953_Ile1961del', 'Var', (167, 187))	('p.Pro969Leu', 'Mutation', 'p.P969L', (126, 137))	('p.Lys1953_Ile1961del', 'Mutation', 'p.1953_,1961delI', (167, 187))	('glomerulopathy', 'Disease', (74, 88))	('FN1', 'Gene', '2335', (111, 114))	('p.Trp1925Cys', 'SUBSTITUTION', 'None', (153, 165))	('fibronectin', 'Gene', (62, 73))	('glomerulopathy', 'Phenotype', 'HP:0100820', (74, 88))	('p.Pro1472del', 'Var', (139, 151))	('p.Pro1472del', 'Mutation', 'p.1472del', (139, 151))	('glomerulopathy', 'Disease', 'MESH:D007674', (74, 88))	('FN1', 'Gene', (111, 114))	('p.Pro969Leu', 'Var', (126, 137))	('fibronectin', 'Gene', '2335', (62, 73))	('FN1', 'Gene', '2335', (28, 31))	('p.Leu1974Pro', 'Mutation', 'rs137854487', (193, 205))	('p.Leu1974Pro', 'Var', (193, 205))	('p.Trp1925Cys', 'Var', (153, 165))	('FN1', 'Gene', (28, 31))
707884	28877681	This finding was in line with a previous report suggesting that some patients with fibronectin glomerulopathy showed no causative gene mutations in FN1.	('fibronectin', 'Gene', (83, 94))	('glomerulopathy', 'Phenotype', 'HP:0100820', (95, 109))	('glomerulopathy', 'Disease', (95, 109))	('mutations', 'Var', (135, 144))	('glomerulopathy', 'Disease', 'MESH:D007674', (95, 109))	('FN1', 'Gene', '2335', (148, 151))	('fibronectin', 'Gene', '2335', (83, 94))	('patients', 'Species', '9606', (69, 77))	('FN1', 'Gene', (148, 151))
707919	28560390	As a transcription factor expressed in the tooth mesenchyme during tooth morphogenesis, heterozygous mutations in PAX9 have been associated with non-syndromic tooth agenesis, predominantly in the molars.	('non-syndromic tooth agenesis', 'Disease', 'MESH:D000848', (145, 173))	('associated', 'Reg', (129, 139))	('heterozygous mutations', 'Var', (88, 110))	('PAX9', 'Gene', (114, 118))	('non-syndromic tooth agenesis', 'Disease', (145, 173))	('tooth agenesis', 'Phenotype', 'HP:0009804', (159, 173))	('syndromic tooth agenesis', 'Phenotype', 'HP:0001592', (149, 173))
707990	28560390	The present study demonstrated that adjuvant radiotherapy may benefit patients with PAX9-positive tumors and suggests that PAX9 may be a predictor of radiation sensitivity in ESCC patients.	('patients', 'Species', '9606', (70, 78))	('benefit', 'PosReg', (62, 69))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('PAX9', 'Var', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ESCC', 'Disease', (175, 179))	('PAX9-positive tumors', 'Disease', (84, 104))	('rat', 'Species', '10116', (25, 28))	('PAX9-positive tumors', 'Disease', 'MESH:D009369', (84, 104))	('patients', 'Species', '9606', (180, 188))
708002	28560390	In addition, cells transfected with PAX9 siRNA and cells infected with adenovirus-mediated expression of dominant-negative c-myb have been reported to display cell cycle arrest at the G0 phase.	('cell cycle arrest at the G0 phase', 'CPA', (159, 192))	('dominant-negative', 'Var', (105, 122))	('c-myb', 'Gene', (123, 128))	('c-myb', 'Gene', '4602', (123, 128))
708007	28560390	In a study conducted by Kendall et al, PAX9 was identified as a lung cell lineage addiction oncogene, representing a fundamental tumor survival mechanism with important therapeutic implications; in addition to thyroid transcription factor 1 (TTF1) and NK2 homeobox 8 (NKX2-8), PAX9 serves a role in the maintenance of squamous cell carcinoma tumor cells that exhibit the 14q13.3 amplification, which is a recurrent amplicon in lung cancer.	('PAX9', 'Gene', (277, 281))	('NKX2-8', 'Gene', '26257;4824', (268, 274))	('squamous cell carcinoma tumor', 'Disease', 'MESH:D002294', (318, 347))	('cancer', 'Phenotype', 'HP:0002664', (432, 438))	('NK2 homeobox 8', 'Gene', (252, 266))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (318, 341))	('tumor', 'Disease', (129, 134))	('squamous cell carcinoma tumor', 'Disease', (318, 347))	('lung cancer', 'Disease', (427, 438))	('14q13.3 amplification', 'Var', (371, 392))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('NK2 homeobox 8', 'Gene', '26257', (252, 266))	('TTF1', 'Gene', '7080', (242, 246))	('tumor', 'Disease', (342, 347))	('TTF1', 'Gene', (242, 246))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('lung cancer', 'Disease', 'MESH:D008175', (427, 438))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (427, 438))	('thyroid transcription factor 1', 'Gene', (210, 240))	('NKX2-8', 'Gene', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('thyroid transcription factor 1', 'Gene', '7080', (210, 240))
708008	28560390	The amplification of these genes frequently results in the promotion of lung cancer and cell proliferation.	('results in', 'Reg', (44, 54))	('lung cancer', 'Disease', (72, 83))	('amplification', 'Var', (4, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cell proliferation', 'CPA', (88, 106))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('rat', 'Species', '10116', (100, 103))	('promotion', 'PosReg', (59, 68))
708009	28560390	Hsu et al demonstrated that this three-gene signature is associated with genes and pathways involved in embryonal tissue development (JAK/STAT, Wnt, BMP and Hedgehog) and lung development (mitogen activated protein kinase, PI3 K and JAK/STAT).	('PI3', 'Var', (223, 226))	('lung development', 'CPA', (171, 187))	('BMP', 'Gene', (149, 152))	('embryonal tissue development', 'CPA', (104, 132))	('rat', 'Species', '10116', (17, 20))	('BMP', 'Gene', '649', (149, 152))
708016	28560390	Driven by heritable and somatic alterations in DNA, ESCC displays genetic and epigenetic alterations, including DNA methylation, histone deacetylation, chromatin remodeling, gene imprinting and noncoding RNA regulation, which underpin carcinogenesis, progression and metastasis.	('carcinogenesis', 'Disease', 'MESH:D063646', (235, 249))	('carcinogenesis', 'Disease', (235, 249))	('rat', 'Species', '10116', (36, 39))	('alterations', 'Var', (32, 43))	('histone deacetylation', 'MPA', (129, 150))	('rat', 'Species', '10116', (93, 96))
708020	28560390	PAX9 may be an independent prognostic factor for ESCC patient survival.	('patient', 'Species', '9606', (54, 61))	('PAX9', 'Var', (0, 4))	('ESCC', 'Disease', (49, 53))
708021	28560390	Additionally, PAX9 may serve as a possible predictor of radiation sensitivity, which may assist clinicians in developing a rational approach to personalized treatment for ESCC patients.	('rat', 'Species', '10116', (123, 126))	('PAX9', 'Var', (14, 18))	('ESCC', 'Disease', (171, 175))	('patients', 'Species', '9606', (176, 184))
708027	27938406	Notch is also one of the most commonly activated signaling pathways in tumors and its aberrant activation plays a key role in cancer advancement.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer advancement', 'Disease', (126, 144))	('Notch', 'Gene', (0, 5))	('activated', 'PosReg', (39, 48))	('activation', 'PosReg', (95, 105))	('Notch', 'Gene', '31293', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer advancement', 'Disease', 'MESH:D006223', (126, 144))	('aberrant', 'Var', (86, 94))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
708033	27938406	The potential risk factors include Helicobacter pylori (H. pylori) or Ebstein-Barr virus (EBV) infection, high-salt and low-vegetable diet, smoking, chronic gastritis with glandular atrophy and intestinal metaplasia, and host genetic susceptible single nucleotide polymorphisms (SNPs).	('gastritis', 'Phenotype', 'HP:0005263', (157, 166))	('Helicobacter pylori', 'Species', '210', (35, 54))	('glandular atrophy', 'Disease', (172, 189))	('chronic gastritis', 'Phenotype', 'HP:0005231', (149, 166))	('H. pylori', 'Species', '210', (56, 65))	('gastritis', 'Disease', (157, 166))	('Ebstein-Barr virus (EBV) infection', 'Disease', 'MESH:D020031', (70, 104))	('Helicobacter pylori', 'Disease', (35, 54))	('salt', 'Chemical', 'MESH:D012492', (111, 115))	('chronic gastritis with glandular atrophy', 'Phenotype', 'HP:0002582', (149, 189))	('glandular atrophy', 'Disease', 'MESH:D002277', (172, 189))	('single nucleotide polymorphisms', 'Var', (246, 277))	('intestinal metaplasia', 'Disease', (194, 215))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (194, 215))	('gastritis', 'Disease', 'MESH:D005756', (157, 166))
708036	27938406	GC can be attributed to deregulation of signaling pathways, which are often followed by precancerous lesions.	('GC', 'Phenotype', 'HP:0012126', (0, 2))	('signaling pathways', 'Pathway', (40, 58))	('precancerous lesions', 'Disease', 'MESH:D011230', (88, 108))	('deregulation', 'Var', (24, 36))	('precancerous lesions', 'Disease', (88, 108))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
708041	27938406	Aberrant Notch signaling activation has been implicated in a variety of cancers.	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('implicated', 'Reg', (45, 55))	('Notch', 'Gene', (9, 14))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('activation', 'PosReg', (25, 35))	('Notch', 'Gene', '31293', (9, 14))
708062	27938406	The ligand-receptor interactions are modulated by post-translational modification of NOTCH receptors.	('modulated', 'Reg', (37, 46))	('NOTCH', 'Gene', '31293', (85, 90))	('ligand-receptor interactions', 'Interaction', (4, 32))	('NOTCH', 'Gene', (85, 90))	('post-translational modification', 'Var', (50, 81))
708067	27938406	Phosphorylation of NICDs on serine residues promotes the formation of NICD/CSL complex and is responsible for the intracellular localization of NICDs.	('promotes', 'PosReg', (44, 52))	('formation', 'MPA', (57, 66))	('serine', 'Chemical', 'MESH:D012694', (28, 34))	('Phosphorylation', 'Var', (0, 15))	('CSL', 'Gene', (75, 78))	('CSL', 'Gene', '3516', (75, 78))
708081	27938406	In mouse esophagus, expressions of NOTCH1, NOTCH2, JAG1 and JAG2 is highly detected in the basal layer.	('mouse', 'Species', '10090', (3, 8))	('JAG1', 'Gene', (51, 55))	('JAG2', 'Gene', (60, 64))	('NOTCH2', 'Var', (43, 49))	('NOTCH1', 'Var', (35, 41))
708085	27938406	In NOTCH2 and JAG1 heterozygous mice, bile duct paucity is found in mutant mice.	('mice', 'Species', '10090', (75, 79))	('bile', 'Disease', (38, 42))	('bile duct paucity', 'Phenotype', 'HP:0005248', (38, 55))	('mice', 'Species', '10090', (32, 36))	('mutant', 'Var', (68, 74))
708088	27938406	DLL1 is the most important ligand for the NOTCH1 receptor in intestinal crypt epithelium and the absence of DLL1 causes an increase of goblet cells.	('absence', 'Var', (97, 104))	('DLL1', 'Gene', '28514', (108, 112))	('DLL1', 'Gene', (108, 112))	('increase', 'PosReg', (123, 131))	('goblet cells', 'CPA', (135, 147))	('DLL1', 'Gene', '28514', (0, 4))	('DLL1', 'Gene', (0, 4))
708094	27938406	Deregulated Notch cascade was first identified in T-cell acute lymphoblastic leukemia (T-ALL).	('leukemia', 'Phenotype', 'HP:0001909', (77, 85))	('Deregulated', 'Var', (0, 11))	('Notch', 'Gene', '31293', (12, 17))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (50, 85))	('T-cell acute lymphoblastic leukemia', 'Disease', (50, 85))	('T-ALL', 'Phenotype', 'HP:0006727', (87, 92))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (50, 85))	('Notch', 'Gene', (12, 17))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (57, 85))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (63, 85))
708099	27938406	The abnormal richness of NOTCH1-4 mRNA was found to be associated with unfavorable overall survival for 876 GC patients for 20 years.	('overall survival', 'MPA', (83, 99))	('NOTCH1-4', 'Var', (25, 33))	('associated', 'Reg', (55, 65))	('GC', 'Phenotype', 'HP:0012126', (108, 110))	('abnormal richness', 'Var', (4, 21))	('patients', 'Species', '9606', (111, 119))
708100	27938406	In GC, activated NOTCH1 was a poor prognostic factor for patients.	('NOTCH1', 'Gene', (17, 23))	('activated', 'Var', (7, 16))	('patients', 'Species', '9606', (57, 65))	('GC', 'Phenotype', 'HP:0012126', (3, 5))
708103	27938406	Aberrant DLL1 promoter hypermethylation has been showed in 52% primary tumors in at least one region but not in healthy controls.	('Aberrant', 'Var', (0, 8))	('DLL1', 'Gene', '28514', (9, 13))	('tumors', 'Disease', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('DLL1', 'Gene', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('hypermethylation', 'Var', (23, 39))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
708104	27938406	Therefore, epigenetic regulation of the NOTCH ligand DLL1 only partly explained the activated NOTCH1 signaling in GC.	('epigenetic regulation', 'Var', (11, 32))	('NOTCH', 'Gene', (94, 99))	('activated', 'PosReg', (84, 93))	('GC', 'Phenotype', 'HP:0012126', (114, 116))	('NOTCH', 'Gene', (40, 45))	('NOTCH', 'Gene', '31293', (40, 45))	('DLL1', 'Gene', '28514', (53, 57))	('DLL1', 'Gene', (53, 57))	('NOTCH', 'Gene', '31293', (94, 99))
708107	27938406	Over-activated NOTCH1 was considered to prevent gastric carcinoma BGC-823 cells from TNFalpha-induced apoptosis.	('TNFalpha', 'Gene', (85, 93))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (48, 65))	('NOTCH1', 'Gene', (15, 21))	('gastric carcinoma', 'Disease', 'MESH:D013274', (48, 65))	('TNFalpha', 'Gene', '7124', (85, 93))	('BGC-823', 'CellLine', 'CVCL:3360', (66, 73))	('gastric carcinoma', 'Disease', (48, 65))	('GC', 'Phenotype', 'HP:0012126', (67, 69))	('Over-activated', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
708119	27938406	These findings implied that NOTCH1 and NOTCH2 boosted GC carcinogenesis through up-regulating COX-2.	('up-regulating', 'PosReg', (80, 93))	('COX-2', 'Gene', (94, 99))	('carcinogenesis', 'Disease', 'MESH:D063646', (57, 71))	('carcinogenesis', 'Disease', (57, 71))	('COX-2', 'Gene', '5743', (94, 99))	('NOTCH2', 'Var', (39, 45))	('boosted', 'PosReg', (46, 53))	('GC', 'Phenotype', 'HP:0012126', (54, 56))	('NOTCH1', 'Var', (28, 34))
708120	27938406	High NOTCH2 expression was identified as a prognostic parameter, as it was correlated with poor survival in GC patients.	('High', 'Var', (0, 4))	('GC', 'Phenotype', 'HP:0012126', (108, 110))	('poor', 'NegReg', (91, 95))	('NOTCH2', 'Gene', (5, 11))	('expression', 'MPA', (12, 22))	('patients', 'Species', '9606', (111, 119))
708132	27938406	To further address the Notch signaling cascade in GC with more updated information, we summarized the genetic alteration rates including copy number changes (amplification and deep deletion), somatic mutations and mRNA upregulation of NOTCH1-4 in the TCGA cohort (Fig.	('deep deletion', 'Var', (176, 189))	('rat', 'Species', '10116', (114, 117))	('Notch', 'Gene', '31293', (23, 28))	('mutations', 'Var', (200, 209))	('NOTCH1-4', 'Gene', (235, 243))	('copy number changes', 'Var', (137, 156))	('GC', 'Phenotype', 'HP:0012126', (50, 52))	('Notch', 'Gene', (23, 28))	('upregulation', 'PosReg', (219, 231))	('rat', 'Species', '10116', (121, 124))
708133	27938406	From the TCGA cohort analyzed by cBioPortal, NOTCH2 and NOTCH3 have the highest mutation rate (7% respectively) and mutations include truncating mutation, missense driver mutation and missense passenger mutation.	('mutation', 'MPA', (80, 88))	('missense', 'Var', (155, 163))	('truncating', 'MPA', (134, 144))	('rat', 'Species', '10116', (89, 92))	('NOTCH3', 'Gene', (56, 62))	('missense passenger mutation', 'Var', (184, 211))	('NOTCH3', 'Gene', '4854', (56, 62))
708136	27938406	In addition to GC, aberrant Notch pathway has been linked to liver malignancies.	('liver malignancies', 'Disease', 'MESH:D009369', (61, 79))	('linked', 'Reg', (51, 57))	('Notch', 'Gene', (28, 33))	('GC', 'Phenotype', 'HP:0012126', (15, 17))	('liver malignancies', 'Disease', (61, 79))	('liver malignancies', 'Phenotype', 'HP:0002896', (61, 79))	('Notch', 'Gene', '31293', (28, 33))	('aberrant', 'Var', (19, 27))
708140	27938406	They found that different NOTCH receptors had drastically different functions during HCC development and inhibition of NOTCH2 represented the most significant therapeutic option in the treatment.	('inhibition', 'Var', (105, 115))	('HCC', 'Gene', '619501', (85, 88))	('NOTCH', 'Gene', (26, 31))	('NOTCH', 'Gene', '31293', (26, 31))	('NOTCH', 'Gene', (119, 124))	('NOTCH', 'Gene', '31293', (119, 124))	('functions', 'MPA', (68, 77))	('HCC', 'Gene', (85, 88))
708148	27938406	Both NOTCH1 and NOTCH4 were immunohistochemical biomarkers predicting HCC patients with short disease specific survival.	('NOTCH1', 'Var', (5, 11))	('short disease', 'Disease', 'MESH:C537327', (88, 101))	('NOTCH4', 'Gene', (16, 22))	('NOTCH4', 'Gene', '4855', (16, 22))	('patients', 'Species', '9606', (74, 82))	('HCC', 'Gene', (70, 73))	('short disease', 'Disease', (88, 101))	('HCC', 'Gene', '619501', (70, 73))
708153	27938406	Defective NOTCH signaling led to impaired ability of repairing liver damage.	('impaired', 'NegReg', (33, 41))	('liver damage', 'Disease', (63, 75))	('liver damage', 'Disease', 'MESH:D056486', (63, 75))	('Defective', 'Var', (0, 9))	('NOTCH', 'Gene', (10, 15))	('NOTCH', 'Gene', '31293', (10, 15))
708160	27938406	Again, self-renewal deficiency and cell growth reduction after NOTCH2 depletion indicated its oncogenic role in HCC.	('deficiency and cell growth reduction', 'Disease', 'MESH:D006130', (20, 56))	('HCC', 'Gene', (112, 115))	('NOTCH2', 'Gene', (63, 69))	('HCC', 'Gene', '619501', (112, 115))	('depletion', 'Var', (70, 79))
708170	27938406	In colorectal carcinoma cells, NOTCH1-deppendent activation of cell cycle and proliferation were mediated by repression of cyclin-dependent kinase inhibitor p27.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('p27', 'Gene', '3429', (157, 160))	('repression', 'NegReg', (109, 119))	('cell cycle', 'CPA', (63, 73))	('p27', 'Gene', (157, 160))	('cyclin', 'Gene', '5111', (123, 129))	('rat', 'Species', '10116', (85, 88))	('colorectal carcinoma', 'Disease', (3, 23))	('NOTCH1-deppendent', 'Var', (31, 48))	('proliferation', 'CPA', (78, 91))	('cyclin', 'Gene', (123, 129))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (3, 23))	('activation', 'PosReg', (49, 59))
708173	27938406	Activation of NOTCH1 converted high-grade adenoma into low-grade adenoma in an APC min mouse colon cancer model.	('colon cancer', 'Disease', (93, 105))	('converted', 'Reg', (21, 30))	('mouse', 'Species', '10090', (87, 92))	('adenoma', 'Disease', 'MESH:D000236', (65, 72))	('adenoma', 'Disease', 'MESH:D000236', (42, 49))	('adenoma', 'Disease', (42, 49))	('Activation', 'Var', (0, 10))	('adenoma', 'Disease', (65, 72))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colon cancer', 'Disease', 'MESH:D015179', (93, 105))	('NOTCH1', 'Gene', (14, 20))
708185	27938406	Moreover, inhibition of NOTCH activity by GSIs decreased tumor growth using patient derived xenograft models.	('NOTCH', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('GS', 'Disease', 'MESH:D011125', (42, 44))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('NOTCH', 'Gene', '31293', (24, 29))	('inhibition', 'Var', (10, 20))	('patient', 'Species', '9606', (76, 83))	('tumor', 'Disease', (57, 62))	('decreased', 'NegReg', (47, 56))
708192	27938406	Mutation in NOTCH1 was related to well-differentiated, early-stage malignancy and less metastasis to regional lymph nodes.	('related', 'Reg', (23, 30))	('NOTCH1', 'Gene', (12, 18))	('Mutation', 'Var', (0, 8))	('malignancy', 'Disease', 'MESH:D009369', (67, 77))	('less metastasis to regional lymph nodes', 'CPA', (82, 121))	('well-differentiated', 'CPA', (34, 53))	('malignancy', 'Disease', (67, 77))
708193	27938406	NOTCH3 contributed to esophageal cell fate decisions by promoting squamous cell differentiation while preventing dedifferentiation to mesenchymal cell lineages expressing ZEBs, through which inhibition of NOTCH pathway promoted TGF-beta-mediated EMT.	('inhibition', 'Var', (191, 201))	('promoting', 'PosReg', (56, 65))	('NOTCH3', 'Gene', '4854', (0, 6))	('NOTCH3', 'Gene', (0, 6))	('NOTCH', 'Gene', (205, 210))	('NOTCH', 'Gene', '31293', (205, 210))	('esophageal cell fate decisions', 'CPA', (22, 52))	('TGF-beta-mediated EMT', 'CPA', (228, 249))	('NOTCH', 'Gene', (0, 5))	('promoted', 'PosReg', (219, 227))	('preventing', 'NegReg', (102, 112))	('squamous cell differentiation', 'CPA', (66, 95))	('NOTCH', 'Gene', '31293', (0, 5))	('dedifferentiation to mesenchymal cell lineages', 'CPA', (113, 159))
708196	27938406	Ectopic NOTCH activation induced accumulation of nestin-positive precursor cells and expansion of metaplastic ductal epithelium, which was identified as precursor lesion for PC.	('nestin-positive', 'Protein', (49, 64))	('NOTCH', 'Gene', '31293', (8, 13))	('NOTCH', 'Gene', (8, 13))	('Ectopic', 'Var', (0, 7))	('expansion', 'CPA', (85, 94))	('accumulation', 'PosReg', (33, 45))
708201	27938406	Downregulation of NOTCH1 inhibited proliferation, increased apoptosis, reduced cell migration and invasion of PC cells.	('NOTCH1', 'Gene', (18, 24))	('cell migration', 'CPA', (79, 93))	('increased', 'PosReg', (50, 59))	('Downregulation', 'Var', (0, 14))	('apoptosis', 'CPA', (60, 69))	('reduced', 'NegReg', (71, 78))	('invasion of PC cells', 'CPA', (98, 118))	('inhibited', 'NegReg', (25, 34))	('rat', 'Species', '10116', (42, 45))	('rat', 'Species', '10116', (87, 90))
708216	27938406	NOTCH2 signaling increased apoptosis, whereas NICD4 promoted cell proliferation and growth in MDA-MB-231 cells.	('NOTCH2', 'Var', (0, 6))	('NICD4', 'Var', (46, 51))	('growth', 'CPA', (84, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (94, 104))	('apoptosis', 'CPA', (27, 36))	('promoted', 'PosReg', (52, 60))	('rat', 'Species', '10116', (73, 76))	('cell proliferation', 'CPA', (61, 79))
708217	27938406	The first evidence of Notch oncogenic role in lung cancer was identified in a tumor-associated translocation between chromosome 15 and 19.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Notch', 'Gene', '31293', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Notch', 'Gene', (22, 27))	('tumor', 'Disease', (78, 83))	('translocation', 'Var', (95, 108))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
708219	27938406	Deregulation of Notch pathway was a relatively frequent event in none-small cell lung carcinoma (NSCLC).	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (76, 95))	('Deregulation', 'Var', (0, 12))	('NSCLC', 'Disease', (97, 102))	('Notch', 'Gene', '31293', (16, 21))	('cell lung carcinoma', 'Disease', (76, 95))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (70, 95))	('Notch', 'Gene', (16, 21))
708224	27938406	High NOTCH1 expression was significantly correlated with poor outcome in lung adenocarcinomas.	('lung adenocarcinomas', 'Disease', (73, 93))	('High', 'Var', (0, 4))	('NOTCH1', 'Gene', (5, 11))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (73, 93))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (73, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('expression', 'MPA', (12, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
708228	27938406	By meta-analysis, NOTCH1 and NOTCH3 were correlated with tumor progression and poor prognosis in NSCLC.	('NOTCH3', 'Gene', '4854', (29, 35))	('NOTCH1', 'Var', (18, 24))	('NSCLC', 'Disease', (97, 102))	('correlated with', 'Reg', (41, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('NOTCH3', 'Gene', (29, 35))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('tumor', 'Disease', (57, 62))
708447	31583502	The patient-level risk factors considered included age at surgery (<= 59, 60-64, 65-69, 70-74, 75-79, and >= 80 years), sex (female vs male), body mass index (BMI; <= 25 vs. > 25 kg/m2), weight loss (< 10% vs. >= 10%), smoking within 1 year (yes vs. no), habitual alcohol use (yes vs. no), any respiratory distress (yes vs. no), preoperative activities of daily living (ADL) with any assistance (yes vs. no), American Society of Anesthesiologists physical status (ASAPS; 1-2 vs. >=3), diabetes mellitus (DM) with insulin use (yes vs. no), chronic obstructive pulmonary disease (COPD; yes vs. no), hypertension (yes vs. no), congestive heart failure (yes vs. no), previous cardiovascular surgery (yes vs. no), previous cerebrovascular accident (yes vs. no), need for preoperative dialysis (yes vs. no), chronic steroid use (yes vs. no), serum albumin (< 2.5 vs. >= 2.5 g/dL), serum creatinine (<= 1.2 vs>1.2 mg/dL), clinical T stage (T0-Tis-T1, T2-T3), clinical N stage (N0, N1, N2, N3), and use of thoracoscopic surgery (yes vs no).	('alcohol', 'Chemical', 'MESH:D000431', (264, 271))	('congestive heart failure', 'Phenotype', 'HP:0001635', (624, 648))	('DM', 'Disease', 'MESH:D003920', (504, 506))	('congestive heart failure', 'Disease', 'MESH:D006333', (624, 648))	('alcohol use', 'Phenotype', 'HP:0030955', (264, 275))	('cerebrovascular accident', 'Disease', (718, 742))	('<=', 'Var', (893, 895))	('cerebrovascular accident', 'Disease', 'MESH:D020521', (718, 742))	('COPD', 'Phenotype', 'HP:0006510', (578, 582))	('weight loss', 'Disease', (187, 198))	('cerebrovascular accident', 'Phenotype', 'HP:0001297', (718, 742))	('insulin', 'Gene', (513, 520))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (539, 576))	('COPD', 'Disease', 'MESH:D029424', (578, 582))	('COPD', 'Disease', (578, 582))	('hypertension', 'Disease', 'MESH:D006973', (597, 609))	('diabetes mellitus', 'Disease', (485, 502))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (539, 576))	('steroid', 'Chemical', 'MESH:D013256', (810, 817))	('hypertension', 'Disease', (597, 609))	('activities of daily living', 'Phenotype', 'HP:0031058', (342, 368))	('DM', 'Phenotype', 'HP:0000819', (504, 506))	('chronic obstructive pulmonary disease', 'Disease', (539, 576))	('hypertension', 'Phenotype', 'HP:0000822', (597, 609))	('diabetes mellitus', 'Disease', 'MESH:D003920', (485, 502))	('congestive heart failure', 'Disease', (624, 648))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (547, 576))	('N0', 'Var', (970, 972))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (485, 502))	('insulin', 'Gene', '3630', (513, 520))	('patient', 'Species', '9606', (4, 11))	('weight loss', 'Disease', 'MESH:D015431', (187, 198))	('ADL', 'Phenotype', 'HP:0031058', (370, 373))	('serum albumin', 'MPA', (836, 849))	('respiratory distress', 'Phenotype', 'HP:0002098', (294, 314))	('respiratory distress', 'Disease', 'MESH:D012128', (294, 314))	('respiratory distress', 'Disease', (294, 314))	('creatinine', 'Chemical', 'MESH:D003404', (881, 891))	('weight loss', 'Phenotype', 'HP:0001824', (187, 198))	('serum creatinine', 'MPA', (875, 891))
708580	29939306	reported that NCRT was significantly associated with an increased risk of pneumonia, pleural effusion, and cardiac arrhythmia, but this did not increase the mortality risk.	('NCRT', 'Var', (14, 18))	('pleural effusion', 'Disease', 'MESH:D010996', (85, 101))	('cardiac arrhythmia', 'Disease', (107, 125))	('pleural effusion', 'Phenotype', 'HP:0002202', (85, 101))	('pleural effusion', 'Disease', (85, 101))	('pneumonia', 'Phenotype', 'HP:0002090', (74, 83))	('pneumonia', 'Disease', (74, 83))	('pneumonia', 'Disease', 'MESH:D011014', (74, 83))	('cardiac arrhythmia', 'Disease', 'MESH:D001145', (107, 125))	('cardiac arrhythmia', 'Phenotype', 'HP:0011675', (107, 125))	('arrhythmia', 'Phenotype', 'HP:0011675', (115, 125))
708616	29290915	HRM showed that the maximum DCI was 8099.9 mmHg-s-cm and the integrated relaxation pressure (IRP) was 21.5 mmHg (Figure 1C).	('8099.9', 'Var', (36, 42))	('DCI', 'MPA', (28, 31))	('DCI', 'Chemical', '-', (28, 31))
708619	29290915	HRM showed typical hypercontractile contractions (6 swallows with DCI > 8000 mmHg-s-cm in 10 liquid swallows) and IRP 14.7 mmHg (Figure 2A), whereas impedance-pH monitoring was negative (Figure 2B).	('liquid swallows', 'Phenotype', 'HP:0002015', (93, 108))	('hypercontractile contractions', 'Disease', (19, 48))	('DCI', 'Chemical', '-', (66, 69))	('DCI > 8000 mmHg-s-cm', 'Var', (66, 86))	('hypercontractile contractions', 'Disease', 'MESH:D001261', (19, 48))
708658	28275685	The Clinical Evidence Linking Helicobacter pylori to Gastric Cancer Gastric cancer has long been recognized to be accompanied and preceded by chronic gastritis, lasting decades.	('gastritis', 'Disease', 'MESH:D005756', (150, 159))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Gastric cancer', 'Disease', (68, 82))	('chronic gastritis', 'Phenotype', 'HP:0005231', (142, 159))	('gastritis', 'Phenotype', 'HP:0005263', (150, 159))	('Gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('Helicobacter', 'Var', (30, 42))	('gastritis', 'Disease', (150, 159))	('Helicobacter pylori', 'Species', '210', (30, 49))
708662	28275685	Based largely on randomized studies in high gastric cancer prevalence regions in East Asia, it appears that primary and tertiary intervention to eradicate H pylori can halve the risk of gastric cancer.	('gastric cancer', 'Disease', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('eradicate', 'Var', (145, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('H pylori', 'Gene', (155, 163))	('high gastric cancer', 'Phenotype', 'HP:0006753', (39, 58))	('H pylori', 'Species', '210', (155, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('high gastric cancer prevalence', 'Phenotype', 'HP:0006753', (39, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('high gastric cancer', 'Disease', 'MESH:D013274', (39, 58))	('high gastric cancer', 'Disease', (39, 58))	('halve', 'NegReg', (168, 173))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))
708667	28275685	In some regions of the world with especially high gastric cancer prevalence, intervention programs have been established to eradicate H pylori with the expectation that this will significantly decrease mortality from this disease.	('eradicate', 'Var', (124, 133))	('high gastric cancer', 'Disease', 'MESH:D013274', (45, 64))	('high gastric cancer', 'Disease', (45, 64))	('H pylori', 'Disease', (134, 142))	('H pylori', 'Species', '210', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('high gastric cancer', 'Phenotype', 'HP:0006753', (45, 64))	('mortality', 'MPA', (202, 211))	('decrease', 'NegReg', (193, 201))	('high gastric cancer prevalence', 'Phenotype', 'HP:0006753', (45, 75))
708696	28275685	A positive correlation between H pylori seroprevalence and gastric cancer in cross-sectional sampling was reported in a study conducted among 13 European nations.	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('H pylori', 'Gene', (31, 39))	('H pylori', 'Species', '210', (31, 39))	('seroprevalence', 'Var', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gastric cancer', 'Disease', (59, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))
708710	28275685	In noncardia gastric cancers, CagA-positive H pylori strains (which are the more common strains worldwide) increase the risk of gastric cancer to a greater extent than do infections by the more rare CagA-negative strains.	('infection', 'Disease', (171, 180))	('gastric cancer', 'Phenotype', 'HP:0012126', (13, 27))	('gastric cancer', 'Disease', (128, 142))	('strains', 'Var', (53, 60))	('infection', 'Disease', 'MESH:D007239', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('increase', 'PosReg', (107, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('increase the risk of gastric cancer', 'Phenotype', 'HP:0006753', (107, 142))	('gastric cancers', 'Phenotype', 'HP:0012126', (13, 28))	('noncardia gastric cancers', 'Disease', (3, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('gastric cancer', 'Disease', 'MESH:D013274', (13, 27))	('H pylori', 'Species', '210', (44, 52))	('noncardia gastric cancers', 'Disease', 'MESH:D013274', (3, 28))	('H pylori', 'Gene', (44, 52))
708711	28275685	H pylori eradication can reduce the risk of developing gastric cancer (see later).	('gastric cancer', 'Disease', (55, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('H pylori', 'Species', '210', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('eradication', 'Var', (9, 20))
708716	28275685	Nevertheless, recent meta-analyses of the many underpowered studies that were conducted are conclusive, indicating that H pylori eradication decreases the risk of gastric cancer development by approximately 40% in studies of primary prevention (asymptomatic individuals), and by 54% as a tertiary prevention strategy (preventing the occurrence of a second gastric malignancy after endoscopic resection of an early gastric cancer).	('gastric cancer', 'Disease', (163, 177))	('gastric cancer', 'Disease', (414, 428))	('men', 'Species', '9606', (185, 188))	('H pylori', 'Species', '210', (120, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (414, 428))	('H pylori', 'Gene', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('decreases', 'NegReg', (141, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (414, 428))	('gastric malignancy', 'Phenotype', 'HP:0006753', (356, 374))	('decreases the risk of gastric cancer', 'Phenotype', 'HP:0006753', (141, 177))	('gastric malignancy', 'Disease', 'MESH:D013274', (356, 374))	('gastric malignancy', 'Disease', (356, 374))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('eradication', 'Var', (129, 140))
708725	28275685	The eradication of H pylori from a community should help prevent much gastric cancer, as well as greatly diminish the morbidity of peptic ulcers too.	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('ulcers', 'Disease', (138, 144))	('prevent', 'NegReg', (57, 64))	('ulcers', 'Disease', 'MESH:D014456', (138, 144))	('diminish', 'NegReg', (105, 113))	('eradication', 'Var', (4, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('peptic ulcer', 'Phenotype', 'HP:0004398', (131, 143))	('H pylori', 'Gene', (19, 27))	('morbidity', 'MPA', (118, 127))	('peptic ulcers', 'Phenotype', 'HP:0004398', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('H pylori', 'Species', '210', (19, 27))	('gastric cancer', 'Disease', (70, 84))
708731	28275685	This places H pylori in a unique position among the World Health Organization's list of biological agents that cause cancer, in that its presence is associated positively with certain cancers (gastric noncardia adenocarcinoma, gastric marginal zone B-cell lymphoma) although related inversely to another cancer type (esophageal adenocarcinoma).	('cancer', 'Disease', (184, 190))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (317, 342))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (304, 310))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('gastric noncardia adenocarcinoma', 'Disease', (193, 225))	('esophageal adenocarcinoma', 'Disease', (317, 342))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancers', 'Disease', (184, 191))	('gastric noncardia adenocarcinoma', 'Disease', 'MESH:D013274', (193, 225))	('lymphoma', 'Phenotype', 'HP:0002665', (256, 264))	('positively', 'PosReg', (160, 170))	('associated', 'Reg', (149, 159))	('H pylori', 'Species', '210', (12, 20))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (249, 264))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('presence', 'Var', (137, 145))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (317, 342))
708733	28275685	The absence of H pylori may promote more severe esophageal mucosal damage, Barrett's metaplasia, and the consequent development of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (131, 156))	('esophageal mucosal damage', 'Disease', 'MESH:D004935', (48, 73))	('H pylori', 'Species', '210', (15, 23))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (131, 156))	('men', 'Species', '9606', (123, 126))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (131, 156))	('promote', 'PosReg', (28, 35))	("Barrett's metaplasia", 'Disease', (75, 95))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (75, 95))	('H pylori', 'Protein', (15, 23))	('absence', 'Var', (4, 11))	('esophageal mucosal damage', 'Disease', (48, 73))
708852	28077159	However, a large retrospective analysis showed that, for esophageal squamous cell carcinoma (ESCC) patients with malignant fistulae, radiotherapy significantly extended overall survival (OS) compared with supportive care.	('esophageal squamous cell carcinoma', 'Disease', (57, 91))	('malignant fistulae', 'Disease', (113, 131))	('overall survival', 'MPA', (169, 185))	('extended', 'PosReg', (160, 168))	('malignant fistulae', 'Disease', 'MESH:D005402', (113, 131))	('radiotherapy', 'Var', (133, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('patients', 'Species', '9606', (99, 107))	('OS', 'Chemical', '-', (187, 189))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (57, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))
708881	28077159	The criteria for GTV of positive lymph nodes (GTV-ln) based on CT scans were as follows: short axis size >=10 mm, a lymph node with an infiltrative margin, or central necrosis.	('necrosis', 'Disease', 'MESH:D009336', (167, 175))	('GTV', 'Chemical', '-', (17, 20))	('necrosis', 'Disease', (167, 175))	('>=10', 'Var', (105, 109))	('GTV', 'Chemical', '-', (46, 49))
708933	28077159	Although clinical CR after CCRT may not be significantly associated with pathologic CR, maximizing the CR rate is likely to increase the proportion of patients with the most favorable outcome, potentially increasing the survival rate of the whole group.	('CR', 'Chemical', '-', (103, 105))	('increasing', 'PosReg', (205, 215))	('CR', 'Chemical', '-', (28, 30))	('CR', 'Chemical', '-', (18, 20))	('patients', 'Species', '9606', (151, 159))	('CR', 'Chemical', '-', (84, 86))	('maximizing', 'Var', (88, 98))
709044	24885430	In non-responders, a valuable therapeutic window may have been lost, the patient may have unnecessarily experienced severe CRT toxicity, and may even have lost the opportunity to have potentially curative surgery.	('toxicity', 'Disease', 'MESH:D064420', (127, 135))	('toxicity', 'Disease', (127, 135))	('patient', 'Species', '9606', (73, 80))	('lost', 'NegReg', (155, 159))	('non-responders', 'Var', (3, 17))	('CRT', 'Gene', '799', (123, 126))	('CRT', 'Gene', (123, 126))
709089	23377668	The clinical trial under which these patients were treated is listed on-line Cancer Treatment With Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes (www.clinicaltrials.gov) as protocol NCT01273181, title MAGE-A3/12 Metastatic.	('clinical', 'Species', '191496', (4, 12))	('Cancer', 'Disease', (77, 83))	('Cancer', 'Disease', 'MESH:D009369', (77, 83))	('clinical', 'Species', '191496', (152, 160))	('patients', 'Species', '9606', (37, 45))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Anti-MAGE-A3/12', 'Var', (99, 114))
709157	23377668	Ex vivo cell expansion resulted in slightly more CD8+ than CD4 + T cells on average (43% CD4+ and 50% CD8+).	('CD8', 'Gene', (102, 105))	('CD8', 'Gene', '925', (102, 105))	('CD4+', 'Var', (89, 93))	('CD8', 'Gene', (49, 52))	('CD8', 'Gene', '925', (49, 52))
709161	23377668	At one-month post-treatment peripheral blood samples were obtained to determine the presence and biological activity of the TCR gene-modified T cells (it should be noted that samples from patients 7 and 8 were obtained after the administration of high-dose steroids, see below).	('patients', 'Species', '9606', (188, 196))	('steroids', 'Chemical', 'MESH:D013256', (257, 265))	('TCR', 'Gene', (124, 127))	('gene-modified', 'Var', (128, 141))
709168	23377668	Every patient analyzed was reactive with both peptide pulsed cells and the tumor cell line targets (patients7 and 8 had low levels of antigen reactive cells in the circulation, e.g., for patient 7; 127 IFN-gamma spots/1 x 10  PBMC with peptide MAGE-A3 peptide pulsed cells, compared to control peptide <10).	('patient', 'Species', '9606', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('patient', 'Species', '9606', (100, 107))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('peptide MAGE-A3', 'Var', (236, 251))	('patient', 'Species', '9606', (187, 194))	('tumor', 'Disease', (75, 80))
709169	23377668	Five of 9 patients demonstrated cancer regression using RECIST criteria following infusion of anti-MAGE-A3 TCR gene-engineered T cells (Table 1, Fig.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('patients', 'Species', '9606', (10, 18))	('anti-MAGE-A3', 'Var', (94, 106))
709224	23377668	Following ex vivo cell expansion of the CSF cells, the introduced TCR genes were found expressed in a higher percentage of CD4+ than CD8+ T cells (Fig.	('TCR genes', 'Gene', (66, 75))	('CD8', 'Gene', '925', (133, 136))	('CD8', 'Gene', (133, 136))	('CD4+', 'Var', (123, 127))
709236	23377668	Transfection of this gene into HLA-A2*0201 positive cells did not cause release of IFN-gamma in co -culture assays (not shown), suggesting lack of protein processing and/or HLA presentation.	('protein', 'Protein', (147, 154))	('HLA-A', 'Gene', '3105', (31, 36))	('Transfection', 'Var', (0, 12))	('lack', 'NegReg', (139, 143))	('HLA-A', 'Gene', (31, 36))
709266	23377668	In the trial reported herein, two of the five melanoma patients treated with MAGE-A3 TCR transduced T cells are on-going responders to this therapy, with patient 1 being a complete responder (15+ months) and patient 7 having a residual PET+ lymph node (12+ months).	('patient', 'Species', '9606', (208, 215))	('patient', 'Species', '9606', (154, 161))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('MAGE-A3', 'Var', (77, 84))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (55, 63))
709271	23377668	In the trials targeting the melanocyte differentiation antigens MART-1 and gp100, we reported that TCR gene-modified T cell infusions were associated with skin rash, uveitis, and auditory/vestibular dysfunction while the targeting of CEA resulted in the transient induction of colitis.	('uveitis', 'Disease', (166, 173))	('gene-modified', 'Var', (103, 116))	('colitis', 'Phenotype', 'HP:0002583', (277, 284))	('vestibular dysfunction', 'Phenotype', 'HP:0001751', (188, 210))	('skin rash', 'Disease', 'MESH:D005076', (155, 164))	('skin rash', 'Disease', (155, 164))	('auditory/vestibular dysfunction', 'Disease', 'MESH:D006311', (179, 210))	('uveitis', 'Phenotype', 'HP:0000554', (166, 173))	('TCR', 'Gene', (99, 102))	('MART-1', 'Gene', (64, 70))	('MART-1', 'Gene', '2315', (64, 70))	('associated', 'Reg', (139, 149))	('uveitis', 'Disease', 'MESH:D014605', (166, 173))	('colitis', 'Disease', 'MESH:D003092', (277, 284))	('auditory/vestibular dysfunction', 'Disease', (179, 210))	('skin rash', 'Phenotype', 'HP:0000988', (155, 164))	('colitis', 'Disease', (277, 284))
709276	23377668	We have used three murine-derived TCR in previous trials (targeting gp100, p53, and CEA) and did not observe off-target toxicities.	('p53', 'Var', (75, 78))	('toxicities', 'Disease', 'MESH:D064420', (120, 130))	('murine', 'Species', '10090', (19, 25))	('gp100', 'Var', (68, 73))	('toxicities', 'Disease', (120, 130))
709277	23377668	The specific modifications of the CDR3 region of this TCR were designed to increase MAGE-A3 reactivity and CD8-independence and similar modifications were made in the NY-ESO-1 TCR used in our first CTA targeted TCR gene therapy trial without issue.	('modifications', 'Var', (136, 149))	('MAGE-A3 reactivity', 'MPA', (84, 102))	('increase', 'PosReg', (75, 83))	('CD8', 'Gene', (107, 110))	('CD8', 'Gene', '925', (107, 110))	('NY-ESO-1', 'Gene', (167, 175))	('modifications', 'Var', (13, 26))	('NY-ESO-1', 'Gene', '246100', (167, 175))
709280	23377668	We observed an enrichment of CD4+ MAGE -A3 TCR+ T cells in CSF samples derived from patients 5, 7, and 8 and cells from the CSF of patient 5 recognized MAGE-A3/A12 expressing tumors (Fig.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('patients', 'Species', '9606', (84, 92))	('A12', 'Gene', (160, 163))	('A12', 'Gene', '28887', (160, 163))	('patient', 'Species', '9606', (131, 138))	('CD4+', 'Var', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patient', 'Species', '9606', (84, 91))
709288	23377668	Thus, although the number of patients in the trial was small, these data suggest a potential dose-related toxicity was associated with the administration of MAGE-A3 TCR gene engineered T cells.	('patients', 'Species', '9606', (29, 37))	('MAGE-A3', 'Var', (157, 164))	('toxicity', 'Disease', 'MESH:D064420', (106, 114))	('toxicity', 'Disease', (106, 114))
709290	23377668	Furthermore, in an early melanoma immunotherapy trial using the administration of an anti-GD2 mAb, neurological toxicity including sensory and motor neuropathy and mental status changes were reported.	('anti-GD2', 'Var', (85, 93))	('neurological toxicity', 'Disease', 'MESH:D020258', (99, 120))	('sensory and', 'Disease', (131, 142))	('neurological toxicity', 'Disease', (99, 120))	('motor neuropathy', 'Disease', (143, 159))	('neuropathy', 'Phenotype', 'HP:0009830', (149, 159))	('motor neuropathy', 'Phenotype', 'HP:0007178', (143, 159))	('motor neuropathy', 'Disease', 'MESH:D016472', (143, 159))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('mental status changes', 'CPA', (164, 185))
709310	23377668	Modifying the affinity of an anti-myelin-specific class II-restricted TCR, has been reported to alter pathogenicity in the murine EAE model.	('pathogenicity', 'MPA', (102, 115))	('TCR', 'Gene', (70, 73))	('murine', 'Species', '10090', (123, 129))	('anti-myelin-specific class II-restricted', 'Protein', (29, 69))	('alter', 'Reg', (96, 101))	('affinity', 'Interaction', (14, 22))	('Modifying', 'Var', (0, 9))
709463	33204160	miR-105 Promotes the Progression and Predicts the Prognosis for Oral Squamous Cell Carcinoma (OSCC) miRNA-105 has been reported in a vast number of malignancies, including hepatocellular carcinoma and colorectal, esophageal, breast and non-small lung cancers.	('colorectal', 'Disease', (201, 211))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (64, 92))	('Oral Squamous Cell Carcinoma', 'Disease', (64, 92))	('lung cancers', 'Disease', 'MESH:D008175', (246, 258))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (172, 196))	('lung cancers', 'Disease', (246, 258))	('Carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('reported', 'Reg', (119, 127))	('non-small lung cancer', 'Phenotype', 'HP:0030358', (236, 257))	('lung cancer', 'Phenotype', 'HP:0100526', (246, 257))	('miRNA-105', 'Var', (100, 109))	('lung cancers', 'Phenotype', 'HP:0100526', (246, 258))	('age', 'Gene', (218, 221))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (172, 196))	('malignancies', 'Disease', 'MESH:D009369', (148, 160))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('breast', 'Disease', (225, 231))	('miR-105', 'Chemical', '-', (0, 7))	('malignancies', 'Disease', (148, 160))	('small lung', 'Phenotype', 'HP:0002089', (240, 250))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('hepatocellular carcinoma', 'Disease', (172, 196))	('Promotes', 'PosReg', (8, 16))	('age', 'Gene', '5973', (218, 221))
709481	33204160	In recent years, numerous studies have shown that miRNAs participate in a wide range of biological processes, including cell proliferation, migration, invasion, and apoptosis, eventually providing roles as oncogenes or tumor suppressor genes in multiple types of cancer.	('cell proliferation', 'CPA', (120, 138))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Disease', (219, 224))	('cancer', 'Disease', (263, 269))	('miRNAs', 'Var', (50, 56))	('apoptosis', 'CPA', (165, 174))	('participate', 'Reg', (57, 68))	('invasion', 'CPA', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('migration', 'CPA', (140, 149))
709519	33204160	According to the median value of miR-105 expression in tumor tissues, OSCC patients were divided into two groups: miR-105 low (below the median, n=45) and miR-105 high (above the median, n=45).	('OSCC', 'Disease', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miR-105', 'Chemical', '-', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('miR-105', 'Gene', (114, 121))	('patients', 'Species', '9606', (75, 83))	('low', 'NegReg', (122, 125))	('tumor', 'Disease', (55, 60))	('miR-105', 'Chemical', '-', (33, 40))	('miR-105', 'Var', (155, 162))	('miR-105', 'Chemical', '-', (155, 162))
709521	33204160	As shown in Table 1, patients with high miR-105 expression presented a higher proportion of T3-T4 tumors than those with low expression of miR-105 (P = 0.020).	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('miR-105', 'Chemical', '-', (139, 146))	('miR-105', 'Chemical', '-', (40, 47))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('miR-105', 'Gene', (40, 47))	('T3-T4', 'Disease', (92, 97))	('high', 'Var', (35, 39))
709531	33204160	Based on qRT-PCR analysis, we were able to confirm that miR-105 mimics can significantly increase miR-105 expression in these selected cell lines (P < 0.001, Figure 3A and B).	('mimics', 'Var', (64, 70))	('miR-105', 'Chemical', '-', (56, 63))	('expression', 'MPA', (106, 116))	('miR-105', 'Gene', (56, 63))	('miR-105', 'Chemical', '-', (98, 105))	('miR-105', 'Gene', (98, 105))	('increase', 'PosReg', (89, 97))
709540	33204160	Chen and colleagues have reported that miR-1254 may restrain the progression of OSCC by downregulating CD36, which may also represent an effective treatment strategy for affected patients.	('OSCC', 'Disease', (80, 84))	('miR-1254', 'Var', (39, 47))	('restrain', 'NegReg', (52, 60))	('CD36', 'Species', '42374', (103, 107))	('downregulating', 'NegReg', (88, 102))	('patients', 'Species', '9606', (179, 187))	('progression', 'CPA', (65, 76))	('CD36', 'Protein', (103, 107))	('miR-1254', 'Chemical', '-', (39, 47))
709750	31885581	In another study, the deletion of Liver Kinase B1 (Lkb1) gene in stromal fibroblasts resulted in penetrant polyposis in mice, underscoring the involvement of these cells in the tumorigenesis of GI Peutz-Jeghers syndrome.	('GI Peutz-Jeghers syndrome', 'Disease', (194, 219))	('mice', 'Species', '10090', (120, 124))	('polyposis', 'Disease', 'MESH:D044483', (107, 116))	('resulted in', 'Reg', (85, 96))	('deletion', 'Var', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('Lkb1', 'Gene', (51, 55))	('Liver Kinase B1', 'Gene', '20869', (34, 49))	('polyposis', 'Disease', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('Liver Kinase B1', 'Gene', (34, 49))	('GI Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (194, 219))	('tumor', 'Disease', (177, 182))
709753	31885581	The stromal PGE2 silenced miR-149 through hypermethylation, removing the suppression of its target genes, IL6 and PGE2 receptor 2.	('hypermethylation', 'Var', (42, 58))	('miR-149', 'Gene', (26, 33))	('miR-149', 'Gene', '406941', (26, 33))	('IL6', 'Gene', '3569', (106, 109))	('IL6', 'Gene', (106, 109))	('removing', 'NegReg', (60, 68))	('PGE2', 'Chemical', 'MESH:D015232', (114, 118))	('suppression', 'MPA', (73, 84))	('silenced', 'NegReg', (17, 25))	('PGE2', 'Chemical', 'MESH:D015232', (12, 16))
709759	31885581	The miRNA 320a can also affect EMT by decreasing PBX Homebox 3 (PBX3), Extracellular Signal-Regulated Kinase 1 and 2 (ERK1/2) signaling, and N-cadherin expression, and simultaneously increase E-cadherin.	('EMT', 'CPA', (31, 34))	('PBX Homebox 3', 'Gene', '5090', (49, 62))	('Extracellular Signal-Regulated Kinase 1 and 2', 'Gene', '5595', (71, 116))	('increase', 'PosReg', (183, 191))	('PBX Homebox 3', 'Gene', (49, 62))	('N-cadherin', 'Gene', (141, 151))	('ERK1/2', 'Gene', (118, 124))	('ERK1/2', 'Gene', '5595;5594', (118, 124))	('decreasing', 'NegReg', (38, 48))	('E-cadherin', 'Gene', (192, 202))	('E-cadherin', 'Gene', '999', (192, 202))	('PBX3', 'Gene', (64, 68))	('PBX3', 'Gene', '5090', (64, 68))	('miRNA 320a', 'Var', (4, 14))	('expression', 'MPA', (152, 162))	('N-cadherin', 'Gene', '1000', (141, 151))
709797	31885581	Coculturing GC cells with both LECs and CD4+ T cells resulted in the upregulation of Programmed Death-Ligand 1 (PD-L1) and Indoleamine 2,3-Dioxygenase (IDO) mRNA expression.	('IDO', 'Gene', (152, 155))	('CD4+ T', 'Var', (40, 46))	('upregulation', 'PosReg', (69, 81))	('PD-L1', 'Gene', (112, 117))	('LEC', 'Gene', (31, 34))	('LEC', 'Gene', '6360', (31, 34))	('C', 'Chemical', 'MESH:D002244', (33, 34))	('C', 'Chemical', 'MESH:D002244', (40, 41))	('Indoleamine 2,3-Dioxygenase', 'Gene', '3620', (123, 150))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('IDO', 'Gene', '3620', (152, 155))	('C', 'Chemical', 'MESH:D002244', (13, 14))
709808	31885581	In vivo, exosomal miR-25-3p elicited vascular leakiness and promoted CRC metastasis.	('vascular leakiness', 'Disease', 'MESH:C535298', (37, 55))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('miR-25-3p', 'Chemical', '-', (18, 27))	('promoted', 'PosReg', (60, 68))	('elicited', 'Reg', (28, 36))	('CRC metastasis', 'CPA', (69, 83))	('miR-25-3p', 'Var', (18, 27))	('vascular leakiness', 'Disease', (37, 55))	('C', 'Chemical', 'MESH:D002244', (71, 72))
709816	31885581	Additionally, mice coinjected with squamous cell carcinoma cells and EC-Bcl-2 displayed significantly higher lung metastasis.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('EC-Bcl-2', 'Var', (69, 77))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 58))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('lung metastasis', 'CPA', (109, 124))	('squamous cell carcinoma', 'Disease', (35, 58))	('mice', 'Species', '10090', (14, 18))	('higher', 'PosReg', (102, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))
709841	31885581	In fact, Stat-3 inhibition enhanced the antitumor function of T and NK cells, DCs, and innate immunity against tumors.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('DCs', 'CPA', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('enhanced', 'PosReg', (27, 35))	('tumors', 'Disease', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (111, 116))	('Stat-3', 'Gene', '6774', (9, 15))	('Stat-3', 'Gene', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('tumor', 'Disease', (44, 49))	('inhibition', 'Var', (16, 26))
709853	31885581	MDSCs were also increased in HCC patients and could induce the formation of TReg populations, suggesting this as one of the mechanisms responsible for immunosuppression in HCC.	('C', 'Chemical', 'MESH:D002244', (3, 4))	('C', 'Chemical', 'MESH:D002244', (31, 32))	('induce', 'Reg', (52, 58))	('MDSCs', 'Var', (0, 5))	('patients', 'Species', '9606', (33, 41))	('HCC', 'Disease', (29, 32))	('TReg populations', 'CPA', (76, 92))	('formation', 'CPA', (63, 72))	('C', 'Chemical', 'MESH:D002244', (173, 174))	('increased', 'PosReg', (16, 25))	('C', 'Chemical', 'MESH:D002244', (30, 31))	('C', 'Chemical', 'MESH:D002244', (174, 175))
709866	31885581	In a mouse model of esophageal cancer, recruitment of MDSC was correlated with IL-6 levels and tumor invasiveness, IL-6 being shown to induce the MDSCs.	('IL-6', 'Var', (115, 119))	('IL-6 levels', 'MPA', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('C', 'Chemical', 'MESH:D002244', (149, 150))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('tumor invasiveness', 'Disease', (95, 113))	('tumor invasiveness', 'Disease', 'MESH:D009361', (95, 113))	('mouse', 'Species', '10090', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', (31, 37))
709882	31885581	On the other hand, microsatellite unstable GC patients with high CD163+ (M2) macrophages, FOXP3+, and CD8+ TILs where those with the highest survival advantage.	('CD163', 'Gene', '9332', (65, 70))	('FOXP3+', 'Var', (90, 96))	('patients', 'Species', '9606', (46, 54))	('CD8', 'Gene', (102, 105))	('C', 'Chemical', 'MESH:D002244', (65, 66))	('CD8', 'Gene', '925', (102, 105))	('CD163', 'Gene', (65, 70))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('microsatellite unstable', 'Var', (19, 42))
709883	31885581	In CRC, as opposite to other cancer types, FOXP3+ TRegs were associated with good prognosis.	('C', 'Chemical', 'MESH:D002244', (3, 4))	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('FOXP3+', 'Var', (43, 49))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('CRC', 'Disease', (3, 6))	('TRegs', 'Chemical', '-', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
709905	31885581	However, genetic inhibition of the Shh pathway results in more aggressive tumors in a PDAC model and accelerates progression of KRAS-driven PDAC.	('KRAS', 'Gene', (128, 132))	('aggressive tumors', 'Disease', (63, 80))	('PDAC', 'Chemical', '-', (140, 144))	('KRAS', 'Gene', '3845', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Shh pathway', 'Pathway', (35, 46))	('PDAC', 'Chemical', '-', (86, 90))	('genetic inhibition', 'Var', (9, 27))	('more', 'PosReg', (58, 62))	('aggressive tumors', 'Disease', 'MESH:D001523', (63, 80))	('accelerates', 'PosReg', (101, 112))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
709906	31885581	Inhibiting VEGF receptor (VEGFR) in Shh-deficient mice increased survival and impaired tumor progression, suggesting that combinatory approaches could be more effective to overcome tumor resistance.	('impaired tumor', 'Disease', 'MESH:D060825', (78, 92))	('tumor', 'Disease', (181, 186))	('Inhibiting', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('increased', 'PosReg', (55, 64))	('tumor', 'Disease', (87, 92))	('VEGFR', 'Gene', (26, 31))	('survival', 'CPA', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('impaired tumor', 'Disease', (78, 92))	('mice', 'Species', '10090', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
709909	31885581	Intriguingly, depletion of CAFs based on their alpha-SMA expression can induce immunodepression and accelerate pancreas cancer progression, leading to resistance to chemotherapies.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('immunodepression', 'Disease', 'None', (79, 95))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('CAFs', 'Gene', (27, 31))	('pancreas cancer', 'Disease', (111, 126))	('pancreas cancer', 'Disease', 'MESH:D010190', (111, 126))	('alpha-SMA', 'Gene', '58', (47, 56))	('induce', 'Reg', (72, 78))	('accelerate', 'PosReg', (100, 110))	('alpha-SMA', 'Gene', (47, 56))	('leading to', 'Reg', (140, 150))	('pancreas cancer', 'Phenotype', 'HP:0002894', (111, 126))	('depletion', 'Var', (14, 23))	('immunodepression', 'Disease', (79, 95))
709914	31885581	A recent study showed that drugs targeting mutated K-Ras force cancer cells to get energy thought autophagy in PDAC.	('PDAC', 'Disease', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('PDAC', 'Chemical', '-', (111, 115))	('get', 'PosReg', (79, 82))	('autophagy', 'CPA', (98, 107))	('K-Ras', 'Gene', '3845', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('mutated', 'Var', (43, 50))	('cancer', 'Disease', (63, 69))	('K-Ras', 'Gene', (51, 56))
709922	31885581	In fact, ESC patients with high expression of CXCR7 and IL-6 presented worse overall survival upon receiving cisplatin after surgery.	('IL-6', 'Gene', (56, 60))	('C', 'Chemical', 'MESH:D002244', (48, 49))	('patients', 'Species', '9606', (13, 21))	('CXCR7', 'Gene', '57007', (46, 51))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('high expression', 'Var', (27, 42))	('overall survival', 'MPA', (77, 93))	('worse', 'NegReg', (71, 76))	('ESC', 'Disease', (9, 12))	('CXCR7', 'Gene', (46, 51))	('C', 'Chemical', 'MESH:D002244', (11, 12))
709928	31885581	Moreover, crosstalk between TAM and tumor infiltrating cells through STAT3 can improve chemotherapeutic efficacy by repressing antitumoral CD8+ T-lymphocyte activity.	('chemotherapeutic efficacy', 'CPA', (87, 112))	('CD8', 'Gene', (139, 142))	('tumoral', 'Disease', 'MESH:D009369', (131, 138))	('STAT3', 'Gene', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('CD8', 'Gene', '925', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('STAT3', 'Gene', '6774', (69, 74))	('TAM', 'Chemical', '-', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (131, 136))	('improve', 'PosReg', (79, 86))	('repressing', 'NegReg', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumoral', 'Disease', (131, 138))	('tumor', 'Disease', (36, 41))	('crosstalk', 'Var', (10, 19))
709942	31885581	As we pointed out above, depletion of alpha-SMA-expressing CAFs can accelerate pancreas cancer progression.	('CAFs', 'Protein', (59, 63))	('accelerate', 'PosReg', (68, 78))	('pancreas cancer', 'Phenotype', 'HP:0002894', (79, 94))	('alpha-SMA', 'Gene', '58', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('depletion', 'Var', (25, 34))	('alpha-SMA', 'Gene', (38, 47))	('C', 'Chemical', 'MESH:D002244', (59, 60))	('pancreas cancer', 'Disease', (79, 94))	('pancreas cancer', 'Disease', 'MESH:D010190', (79, 94))
709954	31885581	Indeed, some patients receiving IPI-926 had a shorter median survival time compared with the placebo group.	('median survival', 'MPA', (54, 69))	('patients', 'Species', '9606', (13, 21))	('IPI-926', 'Var', (32, 39))	('IPI-926', 'Chemical', 'MESH:C541444', (32, 39))	('shorter', 'NegReg', (46, 53))
709958	31885581	In fact, a phase II clinical trial using PEGPH20 in association with gemcitabine and nab-paclitaxel showed improvement in the progression-free survival of PDAC patients and it is now being evaluated in a phase III trial (Table 3).	('progression-free survival', 'CPA', (126, 151))	('patients', 'Species', '9606', (160, 168))	('improvement', 'PosReg', (107, 118))	('nab', 'Chemical', '-', (85, 88))	('PDAC', 'Chemical', '-', (155, 159))	('gemcitabine', 'Chemical', 'MESH:C056507', (69, 80))	('PEGPH20', 'Var', (41, 48))	('paclitaxel', 'Chemical', 'MESH:D017239', (89, 99))	('PDAC', 'Disease', (155, 159))
709959	31885581	However, PEGPH20 in association with a modified FOLFIRINOX regimen presented high toxicity when compared with FOLFIRINOX alone.	('toxicity', 'Disease', (82, 90))	('PEGPH20', 'Var', (9, 16))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (48, 58))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (110, 120))	('toxicity', 'Disease', 'MESH:D064420', (82, 90))
709970	31885581	CTL4-A (cytotoxic T-lymphocyte antigen 4) signaling diminishes immune response against tumor cells and the use of antibodies against CTL4-A was effective in treating tumors as melanomas.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('diminishes immune response', 'Phenotype', 'HP:0002721', (52, 78))	('CTL4', 'Gene', '80736', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('antibodies', 'Var', (114, 124))	('melanomas', 'Disease', 'MESH:D008545', (176, 185))	('diminishes', 'NegReg', (52, 62))	('CTL4', 'Gene', (0, 4))	('melanomas', 'Disease', (176, 185))	('tumors', 'Disease', (166, 172))	('CTL4', 'Gene', (133, 137))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('CTL4', 'Gene', '80736', (0, 4))
709971	31885581	However, clinical trials in PDAC using monotherapies with CTLA-4 or PD-1 inhibitors presented low response rates, with the exception of the PDAC patient subpopulation with microsatelite instability.	('microsatelite instability', 'Var', (172, 197))	('PDAC', 'Chemical', '-', (140, 144))	('PDAC', 'Chemical', '-', (28, 32))	('patient', 'Species', '9606', (145, 152))	('CTLA-4', 'Gene', (58, 64))	('CTLA-4', 'Gene', '1493', (58, 64))	('PDAC', 'Disease', (28, 32))	('PD-1', 'Gene', (68, 72))
709977	31885581	Another study showed that a therapy targeting FAP+ cells that express CXCL12 synergized with anti-PD-L1 immunotherapy in PDAC, and inhibition of its receptor, CXCR4, in sorafenib-treated HCC facilitates anti-PDL-1 immunotherapy.	('CXCL12', 'Gene', (70, 76))	('PDL-1', 'Gene', (208, 213))	('CXCR4', 'Gene', (159, 164))	('PDAC', 'Chemical', '-', (121, 125))	('sorafenib', 'Chemical', 'MESH:D000077157', (169, 178))	('CXCL12', 'Gene', '6387', (70, 76))	('CXCR4', 'Gene', '7852', (159, 164))	('PDAC', 'Disease', (121, 125))	('inhibition', 'Var', (131, 141))	('PDL-1', 'Gene', '29126', (208, 213))
710029	30936596	In a similar way to 2DG, metformin affects cell metabolism and barricades the signaling pathways of mTOR that are sensitive to energy.	('cell metabolism', 'MPA', (43, 58))	('signaling pathways', 'Pathway', (78, 96))	('barricades', 'NegReg', (63, 73))	('metformin', 'Var', (25, 34))	('affects', 'Reg', (35, 42))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
710031	30936596	Metformin prevents the respiratory chain complex 1 in hepatocytes and it destroys the consumption of oxygen in colon cancer cells, which is incompatible with the prevention of oxidative phosphorylation.	('colon cancer', 'Disease', 'MESH:D015179', (111, 123))	('respiratory chain complex 1', 'Enzyme', (23, 50))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('destroys', 'NegReg', (73, 81))	('colon cancer', 'Disease', (111, 123))	('Metformin', 'Var', (0, 9))	('prevents', 'NegReg', (10, 18))	('colon cancer', 'Phenotype', 'HP:0003003', (111, 123))	('oxygen', 'Chemical', 'MESH:D010100', (101, 107))	('consumption of oxygen', 'MPA', (86, 107))
710032	30936596	Changes in the p53 and p16 pathways and mutations of p53 are involved in the outreach of ESCC.	('p16', 'Gene', (23, 26))	('involved', 'Reg', (61, 69))	('mutations', 'Var', (40, 49))	('ESCC', 'Disease', (89, 93))	('p53', 'Gene', (53, 56))	('p16', 'Gene', '1029', (23, 26))	('Changes', 'Reg', (0, 7))
710066	30936596	However, metformin may slightly lead to lactic acidosis.	('lead to', 'Reg', (32, 39))	('lactic acidosis', 'Disease', (40, 55))	('lactic acidosis', 'Disease', 'MESH:D000140', (40, 55))	('acidosis', 'Phenotype', 'HP:0001941', (47, 55))	('metformin', 'Var', (9, 18))	('lactic acidosis', 'Phenotype', 'HP:0003128', (40, 55))
710273	26528489	A highly significant statistical correlation between WGA fluorescence and degree of dysplasia was found (P = 0.0002), with areas of high grade dysplasia and cancer showing lower fluorescence intensity and WGA binding relative to areas of nondysplastic Barrett's esophagus and normal esophageal mucosa.	('binding', 'Interaction', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('dysplasia', 'Disease', 'MESH:D004476', (143, 152))	("nondysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (238, 271))	('fluorescence intensity', 'MPA', (178, 200))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (252, 271))	('dysplasia', 'Disease', (84, 93))	('lower', 'NegReg', (172, 177))	('WGA', 'MPA', (205, 208))	("nondysplastic Barrett's esophagus", 'Disease', (238, 271))	('dysplasia', 'Disease', 'MESH:D004476', (84, 93))	('dysplasia', 'Disease', (143, 152))	('high grade', 'Var', (132, 142))	('dysplasia and cancer', 'Disease', 'MESH:D009369', (143, 163))
710323	25062038	Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365-0.905, P = 0.017).	('rat', 'Species', '10116', (94, 97))	('overall survival', 'MPA', (69, 85))	('longer', 'PosReg', (62, 68))	('ATX levels', 'MPA', (4, 14))	('Low', 'Var', (0, 3))
710408	25062038	The variables CRP (<=0.5 mg/dl vs. >0.5 mg/dl), MELD score (<=18 vs. >18) and serum ATX level (<=1.103 mg/l vs. >1.103 mg/l) were also included in the multivariate analysis.	('<=1.103', 'Var', (95, 102))	('MELD', 'MPA', (48, 52))	('CRP', 'Gene', '1401', (14, 17))	('CRP', 'Gene', (14, 17))
710409	25062038	The analysis showed that lower age (P = 0.034), lower MELD score (P = 0.011), normal CRP (P<0.001) and low ATX levels (P = 0.008) were independently associated with OS in this cohort of cirrhotic patients (Table 3).	('normal', 'Var', (78, 84))	('low ATX levels', 'MPA', (103, 117))	('lower', 'NegReg', (48, 53))	('CRP', 'Gene', (85, 88))	('lower', 'NegReg', (25, 30))	('patients', 'Species', '9606', (196, 204))	('MELD score', 'MPA', (54, 64))	('CRP', 'Gene', '1401', (85, 88))
710464	24742107	During these events, a series of genetic and epigenetic aberrations contributes to the carcinogenesis, which will be potential biomarkers for early screening, surveillance and treatment of the dysplasia and adenocarcinoma.	('genetic', 'Var', (33, 40))	('dysplasia and adenocarcinoma', 'Disease', 'MESH:D000230', (193, 221))	('contributes', 'Reg', (68, 79))	('rat', 'Species', '10116', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('carcinogenesis', 'Disease', (87, 101))	('epigenetic aberrations', 'Var', (45, 67))
710471	24742107	In addition, the amplification and overexpression of cyclin E have been reported in a variety of cancers including breast, lung, ovarian, stomach, colorectal, bladder, endometrial carcinoma and thyroid.	('endometrial carcinoma', 'Disease', 'MESH:D016889', (168, 189))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('stomach', 'Disease', (138, 145))	('cancers', 'Disease', (97, 104))	('breast', 'Disease', (115, 121))	('cyclin E', 'Gene', (53, 61))	('cyclin E', 'Gene', '25729', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('overexpression', 'PosReg', (35, 49))	('ovarian', 'Disease', (129, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('endometrial carcinoma', 'Disease', (168, 189))	('reported', 'Reg', (72, 80))	('amplification', 'Var', (17, 30))	('bladder', 'Disease', (159, 166))	('lung', 'Disease', (123, 127))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (168, 189))	('colorectal', 'Disease', (147, 157))	('thyroid', 'Disease', (194, 201))
710474	24742107	Cyclin E gene amplification in esophageal adenocarcinoma was also confirmed in 13.8% (9/65) and 12.6% (11 of 87) in esophageal adenocarcinoma by quantitative PCR molecular analysis.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (31, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('esophageal adenocarcinoma ', 'Gene', '1540', (116, 142))	('esophageal adenocarcinoma ', 'Gene', (116, 142))	('Cyclin E', 'Gene', '25729', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('esophageal adenocarcinoma ', 'Gene', (31, 57))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (116, 141))	('Cyclin E', 'Gene', (0, 8))	('esophageal adenocarcinoma ', 'Gene', '1540', (31, 57))	('amplification', 'Var', (14, 27))
710496	24742107	Analysis of 116 EAC specimens using high density copy number microarrays revealed amplification of CCNE1 in 19.0% (22/116) (Figure 2).	('EAC', 'Gene', '1540', (16, 19))	('EAC', 'Gene', (16, 19))	('CCNE1', 'Gene', (99, 104))	('CCNE1', 'Gene', '898', (99, 104))	('amplification', 'Var', (82, 95))	('EAC', 'Phenotype', 'HP:0011459', (16, 19))
710497	24742107	In this cohort, the median overall survival of patients with CCNE1 amplification was approximately 20 months compared with 25 months for those without amplification (p = 0.22).	('amplification', 'Var', (67, 80))	('patients', 'Species', '9606', (47, 55))	('CCNE1', 'Gene', '898', (61, 66))	('CCNE1', 'Gene', (61, 66))
710508	24742107	The mean overall survival in the cyclin E high expression group was 42 months, while that in the group without high cyclin E expression was 38 months.	('cyclin E', 'Gene', (33, 41))	('high expression', 'Var', (42, 57))	('cyclin E', 'Gene', '25729', (33, 41))	('cyclin E', 'Gene', (116, 124))	('cyclin E', 'Gene', '25729', (116, 124))
710514	24742107	With SNP DNA microarray study, the amplification of cyclin E was also present in esophageal adenocarcinoma, but was not identified in Barrett's esophagus and columnar cell metaplasia.	('amplification', 'Var', (35, 48))	('cyclin E', 'Gene', '25729', (52, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cyclin E', 'Gene', (52, 60))	('columnar cell metaplasia', 'Disease', (158, 182))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (134, 153))	('esophageal adenocarcinoma', 'Disease', (81, 106))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (81, 106))	('columnar cell metaplasia', 'Disease', 'MESH:D008679', (158, 182))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (81, 106))
710515	24742107	In addition, we found that high expression of cyclin E may be associated with better prognosis although this did not reach statistical significance.	('cyclin E', 'Gene', (46, 54))	('cyclin E', 'Gene', '25729', (46, 54))	('high', 'Var', (27, 31))
710532	24742107	The median of cyclin E expression significantly increased in normal through hyperplastic and adenomatous tissues and slightly decreased in adenocarcinoma of colon samples, which confirmed the finding in the rat model and proved that the expression of cyclin E promoted abnormal proliferation of cells during colorectal carcinogenesis.	('rat', 'Species', '10116', (207, 210))	('adenocarcinoma of colon', 'Disease', (139, 162))	('abnormal proliferation of cells', 'Phenotype', 'HP:0031377', (269, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('cyclin E', 'Gene', '25729', (251, 259))	('cyclin E', 'Gene', (251, 259))	('cyclin E', 'Gene', '25729', (14, 22))	('cells', 'CPA', (295, 300))	('rat', 'Species', '10116', (285, 288))	('cyclin E', 'Gene', (14, 22))	('colorectal carcinogenesis', 'Disease', (308, 333))	('adenocarcinoma of colon', 'Disease', 'MESH:D003110', (139, 162))	('adenocarcinoma of colon', 'Phenotype', 'HP:0040276', (139, 162))	('decreased', 'NegReg', (126, 135))	('promoted', 'PosReg', (260, 268))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (308, 333))	('expression', 'MPA', (23, 33))	('increased', 'PosReg', (48, 57))	('adenomatous', 'Disease', (93, 104))	('adenomatous', 'Disease', 'MESH:D011125', (93, 104))	('expression', 'Var', (237, 247))
710535	24742107	High expression of cyclin E may play an important role in early stage of carcinogenesis in esophagus and could be a potential targeted marker to early interfere with cancer progress and stratify high risk patients with precancerous lesion for close surveillance.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('patients', 'Species', '9606', (205, 213))	('High', 'Var', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (222, 228))	('cyclin E', 'Gene', '25729', (19, 27))	('cyclin E', 'Gene', (19, 27))	('rat', 'Species', '10116', (188, 191))	('interfere', 'NegReg', (151, 160))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('precancerous lesion', 'Disease', 'MESH:D011230', (219, 238))	('precancerous lesion', 'Disease', (219, 238))	('esophagus', 'Disease', (91, 100))
710537	24742107	siRNA treatment significantly reduced CCNE1 or cyclin E-CDK-2 complex expression and significantly inhibited cell growth in CCNE1-expressing cells, suggesting that CCNE1-targeted therapy may benefit ovarian, breast and lung cancer patients with CCNE1 amplification.	('CCNE1', 'Gene', (245, 250))	('CCNE1', 'Gene', (38, 43))	('cyclin E', 'Gene', (47, 55))	('breast and lung cancer', 'Disease', 'MESH:D001943', (208, 230))	('cyclin E', 'Gene', '25729', (47, 55))	('amplification', 'Var', (251, 264))	('CCNE1', 'Gene', '898', (245, 250))	('inhibited', 'NegReg', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('CCNE1', 'Gene', (164, 169))	('CCNE1', 'Gene', '898', (38, 43))	('benefit', 'PosReg', (191, 198))	('CCNE1', 'Gene', (124, 129))	('CCNE1', 'Gene', '898', (164, 169))	('cell growth', 'CPA', (109, 120))	('expression', 'MPA', (70, 80))	('reduced', 'NegReg', (30, 37))	('CCNE1', 'Gene', '898', (124, 129))	('ovarian', 'Disease', (199, 206))	('patients', 'Species', '9606', (231, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (219, 230))
710541	24742107	Amplification and high expression of cyclin E were reported to relate with poor prognosis in many different tumors.	('Amplification', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cyclin E', 'Gene', '25729', (37, 45))	('cyclin E', 'Gene', (37, 45))	('tumors', 'Disease', (108, 114))	('high', 'Var', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('expression', 'MPA', (23, 33))
710543	24742107	In ovarian cancer, the amplification was identified in 18 (20%) of 88 ovarian carcinoma, which was significantly correlated with shorter disease-free survival and overall survival.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (70, 87))	('ovarian carcinoma', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('disease-free survival', 'CPA', (137, 158))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('amplification', 'Var', (23, 36))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Disease', (3, 17))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (70, 87))	('shorter', 'NegReg', (129, 136))
710546	24742107	In the esophagus, similar to the cyclin E study, we recently found that HER2 amplification and expression were associated with better but not significantly better prognoses, which is confirmed by a Mayo clinical study.	('HER2', 'Gene', (72, 76))	('HER2', 'Gene', '2064', (72, 76))	('cyclin E', 'Gene', (33, 41))	('amplification', 'Var', (77, 90))	('cyclin E', 'Gene', '25729', (33, 41))	('Mayo', 'Species', '162683', (198, 202))	('expression', 'MPA', (95, 105))
710547	24742107	They further proved that HER2 positivity was significantly associated with a better survival.	('better', 'PosReg', (77, 83))	('positivity', 'Var', (30, 40))	('HER2', 'Gene', (25, 29))	('HER2', 'Gene', '2064', (25, 29))
710552	24742107	In addition, the amplification and high expression of cyclin E are associated with a better prognosis, but not statistically significant.	('cyclin E', 'Gene', (54, 62))	('high expression', 'MPA', (35, 50))	('cyclin E', 'Gene', '25729', (54, 62))	('amplification', 'Var', (17, 30))
710564	23703970	While smoking, alcohol consumption and HPV16 infection constitute the major risk factors, other factors such as diet, environmental and occupational exposures, dentition and oral hygiene, gastroesophageal reflux and inherited cancer syndromes have also been associated with the disease.	('alcohol', 'Chemical', 'MESH:D000438', (15, 22))	('HPV16', 'Gene', (39, 44))	('HPV16', 'Species', '333760', (39, 44))	('associated', 'Reg', (258, 268))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (188, 211))	('inherited cancer syndromes', 'Disease', 'MESH:D009386', (216, 242))	('infection', 'Var', (45, 54))	('inherited cancer syndromes', 'Disease', (216, 242))	('gastroesophageal reflux', 'Disease', (188, 211))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (188, 211))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
710585	23703970	BMI was modeled categorically according World Health Organization guidelines for adult BMI classification: underweight (BMI < 18.5), normal (18.5 <= BMI < 25), overweight (25 <= BMI < 30), and obese (BMI >= 30).	('overweight', 'Phenotype', 'HP:0025502', (160, 170))	('18.5 <=', 'Var', (141, 148))	('25 <= BMI', 'Var', (172, 181))	('obese', 'Disease', (193, 198))	('underweight', 'Disease', (107, 118))	('obese', 'Disease', 'MESH:D009765', (193, 198))
710663	23033453	We included incident primary SCC of the oral cavity including the tongue (C01-C06), oropharynx (C09-C10) and hypopharynx (C13-C14), esophagus (C15) and larynx (C32) in our study.	('C13-C14', 'Var', (122, 129))	('C09-C10', 'Var', (96, 103))	('C32', 'Gene', (160, 163))	('SCC', 'Gene', '6317', (29, 32))	('C32', 'Gene', '51192', (160, 163))	('esophagus', 'Disease', (132, 141))	('C01-C06', 'Var', (74, 81))	('C15', 'Gene', '51316', (143, 146))	('SCC', 'Gene', (29, 32))	('SCC', 'Phenotype', 'HP:0002860', (29, 32))	('C15', 'Gene', (143, 146))
710669	23033453	Meat intake was also analyzed as continuous variable with increments of 20g/1000 kcals for total meat, 10g/1000 kcals for red and processed meat, 5g/1000 kcals for poultry, 10g/1000kcals for fish, and 200mug/1000kcals for dietary heme iron, corresponding approximately to one standard deviation in intake of the respective intake variable.	('men', 'Species', '9606', (63, 66))	('5g/1000 kcals', 'Var', (146, 159))	('iron', 'Chemical', 'MESH:D007501', (235, 239))	('heme', 'Chemical', 'MESH:D006418', (230, 234))	('10g/1000kcals', 'Var', (173, 186))
710754	21152431	The cleavage of the EpCAM ectodomain, EpEx, by the protease tumor necrosis factor alpha converting enzyme (TACE) and its shedding has been shown to release its intracellular domain (Ep-ICD) which then translocates to the nucleus resulting in activation of oncogenic signalling.	('cleavage', 'Var', (4, 12))	('tumor necrosis factor alpha converting enzyme', 'Gene', (60, 105))	('activation', 'PosReg', (242, 252))	('translocates', 'MPA', (201, 213))	('EpCAM', 'Gene', '4072', (20, 25))	('TACE', 'Gene', '6868', (107, 111))	('ICD', 'Gene', (185, 188))	('ICD', 'Gene', '79158', (185, 188))	('oncogenic signalling', 'CPA', (256, 276))	('TACE', 'Gene', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor necrosis factor alpha converting enzyme', 'Gene', '6868', (60, 105))	('EpCAM', 'Gene', (20, 25))	('intracellular domain', 'MPA', (160, 180))
710839	21152431	The AUC values were found to be 0.905 for breast cancer, 0.867 for prostate cancer, 0.822 for HNSCC, and 0.630 for ESCC.	('ESCC', 'Disease', (115, 119))	('prostate cancer', 'Disease', (67, 82))	('HNSCC', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (67, 82))	('breast cancer', 'Disease', (42, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('0.630', 'Var', (105, 110))
710842	21152431	The AUC values for cytoplasmic Ep-ICD were 0.928 in breast cancer, 0.880 in prostate cancer, 0.864 in HNSCC, and 0.758 in ESCC.	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('ICD', 'Gene', (34, 37))	('ICD', 'Gene', '79158', (34, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('0.758', 'Var', (113, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('HNSCC', 'Disease', (102, 107))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('0.864', 'Var', (93, 98))
710869	21152431	The survival rates of patients with high EpCAM expression in tumors and in the peripheral vein were significantly higher than those for patients having low EpCAM expression.	('survival rates', 'CPA', (4, 18))	('tumors', 'Disease', (61, 67))	('high', 'Var', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('EpCAM', 'Gene', (41, 46))	('patients', 'Species', '9606', (22, 30))	('EpCAM', 'Gene', '4072', (41, 46))	('patients', 'Species', '9606', (136, 144))	('EpCAM', 'Gene', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('higher', 'PosReg', (114, 120))	('EpCAM', 'Gene', '4072', (156, 161))
710876	21152431	Previous strategies for EpCAM-based targeted therapies focused on monoclonal antibodies to EpEx including the humanized antibodies that are in phase III trials.	('EpCAM', 'Gene', (24, 29))	('human', 'Species', '9606', (110, 115))	('EpCAM', 'Gene', '4072', (24, 29))	('monoclonal antibodies', 'Var', (66, 87))
710908	19111726	GERD comparison group members were randomly selected from among all members with the following characteristics prior to their index date: a GERD-related diagnosis code (ICD-9 codes 530.11 [reflux esophagitis] or 530.81 [gastroesophageal reflux]); a prescription for at least a 90 days supply of a histamine-2 receptor antagonist or a proton pump inhibitor (medications used for treating GERD symptoms) in the previous year (from electronic pharmacy records); no prior diagnosis of Barrett's esophagus; and an esophagogastroduodenoscopy close to the index date that did not demonstrate esophageal columnar metaplasia of any type.	('ICD', 'Disease', 'OMIM:252500', (169, 172))	('esophagitis', 'Phenotype', 'HP:0100633', (196, 207))	('esophagitis', 'Disease', (196, 207))	('ICD', 'Disease', (169, 172))	('esophagitis', 'Disease', 'MESH:D004941', (196, 207))	('530.81', 'Var', (212, 218))	('esophageal columnar metaplasia', 'Disease', 'MESH:D008679', (585, 615))	("Barrett's esophagus", 'Disease', (481, 500))	('esophageal columnar metaplasia', 'Disease', (585, 615))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (481, 500))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (220, 243))
710972	19111726	The presence of GERD may partially mediate the association between socioeconomic status and the risk of Barrett's esophagus, though there are likely other pathways through which alcohol and socioeconomic status affect the risk of Barrett's esophagus.	('alcohol', 'Chemical', 'MESH:D000438', (178, 185))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (104, 123))	('affect', 'Reg', (211, 217))	("Barrett's esophagus", 'Disease', (230, 249))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (230, 249))	("Barrett's esophagus", 'Disease', (104, 123))	('presence', 'Var', (4, 12))
710991	33680929	We further confirmed the oncogenic roles of circ_0087378 in ESCC cells through a series of biological function assays.	('circ_0087378', 'Var', (44, 56))	('ESCC', 'Disease', (60, 64))	('circ_0087378', 'Chemical', '-', (44, 56))
710992	33680929	Then, we used an RNA pull-down assay and luciferase reporter assay to identify miR-140-3p that directly interacts with circ_0087378.	('interacts', 'Interaction', (104, 113))	('miR-140-3p', 'Chemical', '-', (79, 89))	('circ_0087378', 'Chemical', '-', (119, 131))	('miR-140-3p', 'Var', (79, 89))
710993	33680929	Subsequent studies were performed to demonstrate that the circ_0087378/miR-140-3p/E2F3 axis promotes ESCC development.	('promotes', 'PosReg', (92, 100))	('circ_0087378', 'Chemical', '-', (58, 70))	('miR-140-3p', 'Chemical', '-', (71, 81))	('ESCC', 'Disease', (101, 105))	('circ_0087378/miR-140-3p/E2F3', 'Var', (58, 86))
710995	33680929	Our results further revealed that knockdown of circ_0087378 suppressed the proliferation, migration, and invasion of ESCC cells and reduced tumor growth in vivo.	('invasion', 'CPA', (105, 113))	('circ_0087378', 'Chemical', '-', (47, 59))	('suppressed', 'NegReg', (60, 70))	('circ_0087378', 'Var', (47, 59))	('migration', 'CPA', (90, 99))	('reduced', 'NegReg', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('proliferation', 'CPA', (75, 88))	('tumor', 'Disease', (140, 145))
710996	33680929	Mechanistically, we showed that circ_0087378 could directly bind to miR-miR-140-3p and relieve the suppression for target E2F3, which accelerated cell proliferation, migration, and invasion.	('suppression', 'MPA', (99, 110))	('migration', 'CPA', (166, 175))	('accelerated', 'PosReg', (134, 145))	('relieve', 'NegReg', (87, 94))	('bind', 'Interaction', (60, 64))	('miR-miR-140-3p', 'Chemical', '-', (68, 82))	('E2F3', 'Protein', (122, 126))	('invasion', 'CPA', (181, 189))	('circ_0087378', 'Var', (32, 44))	('circ_0087378', 'Chemical', '-', (32, 44))	('cell proliferation', 'CPA', (146, 164))
710997	33680929	Correlation analysis in ESCC specimens supported the involvement of the circ_0087378/miR-140-3p/E2F3 axis in ESCC progression.	('involvement', 'Reg', (53, 64))	('ESCC', 'Disease', (109, 113))	('circ_0087378/miR-140-3p/E2F3', 'Var', (72, 100))	('circ_0087378', 'Chemical', '-', (72, 84))	('miR-140-3p', 'Chemical', '-', (85, 95))
710998	33680929	This study demonstrated that circ_0087378 might act as a competing endogenous RNA for miR-140-3p, which could inhibit the tumorigenesis and progression of ESCC through upregulating E2F3 expression.	('miR-140-3p', 'Var', (86, 96))	('miR-140-3p', 'Chemical', '-', (86, 96))	('progression', 'CPA', (140, 151))	('upregulating', 'PosReg', (168, 180))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('E2F3', 'Protein', (181, 185))	('expression', 'MPA', (186, 196))	('inhibit', 'NegReg', (110, 117))	('ESCC', 'Disease', (155, 159))	('tumor', 'Disease', (122, 127))	('circ_0087378', 'Var', (29, 41))	('circ_0087378', 'Chemical', '-', (29, 41))
711008	33680929	Circ_0087378 is a newly identified circRNA in breast cancer.	('Circ_0087378', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))
711009	33680929	To date, however, the functions and mechanisms of circ_0087378 in ESCC remain largely unknown.	('circ_0087378', 'Var', (50, 62))	('circ_0087378', 'Chemical', '-', (50, 62))	('ESCC', 'Disease', (66, 70))
711010	33680929	MiR-140-3p was reported to suppress the malignant properties in colorectal cancer, breast cancer, and lung cancer.	('colorectal cancer', 'Disease', (64, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('malignant properties', 'CPA', (40, 60))	('lung cancer', 'Disease', (102, 113))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('MiR-140-3p', 'Chemical', '-', (0, 10))	('breast cancer', 'Disease', (83, 96))	('MiR-140-3p', 'Var', (0, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('suppress', 'NegReg', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))
711011	33680929	However, the role and potential target genes of miR-140-3p in ESCC is still poorly understood.	('ESCC', 'Disease', (62, 66))	('miR-140-3p', 'Var', (48, 58))	('miR-140-3p', 'Chemical', '-', (48, 58))
711015	33680929	In this study, we have proved that circ_0087378, as a newly discovered circRNA in ESCC, could sponge miR-140-3p to upregulate the expression of E2F3 and eventually serve as a tumor promotor in ESCC.	('E2F3', 'Gene', (144, 148))	('ESCC', 'Disease', (193, 197))	('expression', 'MPA', (130, 140))	('tumor', 'Disease', (175, 180))	('circ_0087378', 'Var', (35, 47))	('circ_0087378', 'Chemical', '-', (35, 47))	('miR-140-3p', 'Chemical', '-', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('upregulate', 'PosReg', (115, 125))
711020	33680929	The ESCC cell lines (KYSE41, EC109, EC9706, KYSE150, and KYSE30) and the immortalized human esophageal epithelial cell line SHEE were obtained from the Cell Bank of Type Culture Collection of Chinese Academy of Sciences (Shanghai, China).	('KYSE41', 'CellLine', 'CVCL:0151', (21, 27))	('EC', 'Disease', 'MESH:D005955', (29, 31))	('human', 'Species', '9606', (86, 91))	('KYSE150', 'Var', (44, 51))	('KYSE41', 'Var', (21, 27))	('EC', 'Disease', 'MESH:D005955', (36, 38))	('EC9706', 'CellLine', 'CVCL:E307', (36, 42))	('KYSE30', 'Var', (57, 63))	('KYSE150', 'CellLine', 'CVCL:1348', (44, 51))
711039	33680929	Briefly, the luciferase reporter plasmids containing circ_0087378-wild type (WT), circ_0087378-muatnt (MUT), E2F3-WT or E2F3-MUT were produced from the pmirGLO vectors (Promega, Madison, WI, USA).	('circ_0087378', 'Chemical', '-', (82, 94))	('E2F3-WT', 'Var', (109, 116))	('E2F3-MUT', 'Var', (120, 128))	('circ_0087378', 'Chemical', '-', (53, 65))	('circ_0087378-muatnt', 'Var', (82, 101))
711041	33680929	EC109 or KYSE150 cells were co-transfected with the above reporter plasmids, with miR-140-3p mimic or miR-NC, respectively.	('miR-NC', 'Var', (102, 108))	('EC', 'Disease', 'MESH:D005955', (0, 2))	('KYSE150', 'CellLine', 'CVCL:1348', (9, 16))	('miR-140-3p mimic', 'Var', (82, 98))	('miR-140-3p', 'Chemical', '-', (82, 92))
711051	33680929	Consistent with these results, we found that higher circ_0087378 expression was positively correlated with tumor size, histological grade, tumor stage, and the presence of metastasis in patients with ESCC ( Table 4 ).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('patients', 'Species', '9606', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('circ_0087378', 'Var', (52, 64))	('expression', 'MPA', (65, 75))	('circ_0087378', 'Chemical', '-', (52, 64))	('higher', 'PosReg', (45, 51))	('ESCC', 'Disease', (200, 204))	('metastasis', 'CPA', (172, 182))
711053	33680929	Kaplan-Meier survival analysis showed that patients with higher circ_0087378 levels displayed lower overall survival rates ( Figure 1C ).	('circ_0087378', 'Chemical', '-', (64, 76))	('patients', 'Species', '9606', (43, 51))	('circ_0087378 levels', 'Var', (64, 83))	('lower', 'NegReg', (94, 99))	('overall', 'CPA', (100, 107))
711055	33680929	Circ_0087378 expression was significantly higher in human ESCC cell lines than that in human esophageal epithelial cell line SHEE ( Figure 1D ).	('Circ_0087378', 'Var', (0, 12))	('expression', 'MPA', (13, 23))	('human', 'Species', '9606', (87, 92))	('human', 'Species', '9606', (52, 57))	('higher', 'PosReg', (42, 48))
711059	33680929	Taken together, our data supported that circ_0087378 was highly expressed in ESCC, and higher circ_0087378 was correlated with poorer outcomes in ESCC patients.	('ESCC', 'Disease', (77, 81))	('patients', 'Species', '9606', (151, 159))	('circ_0087378', 'Var', (94, 106))	('circ_0087378', 'Chemical', '-', (94, 106))	('circ_0087378', 'Var', (40, 52))	('circ_0087378', 'Chemical', '-', (40, 52))
711063	33680929	The results demonstrated that depletion of circ_0087378 with shRNAs could significantly inhibit the proliferation, migration, and invasion of ESCC cell lines ( Figures 2B-E ).	('circ_0087378', 'Var', (43, 55))	('circ_0087378', 'Chemical', '-', (43, 55))	('migration', 'CPA', (115, 124))	('proliferation', 'CPA', (100, 113))	('invasion', 'CPA', (130, 138))	('inhibit', 'NegReg', (88, 95))	('depletion', 'MPA', (30, 39))	('ESCC', 'Disease', (142, 146))
711064	33680929	Flow cytometry analysis showed that knockdown of circ_0087378 in ESCC cells significantly induced cell apoptosis ( Figure 2F ).	('induced', 'Reg', (90, 97))	('circ_0087378', 'Var', (49, 61))	('circ_0087378', 'Chemical', '-', (49, 61))	('cell apoptosis', 'CPA', (98, 112))
711066	33680929	We found that the downregulation of circ_0087378 resulted in a significantly lower tumor size and weight compared with controls ( Figures 2G, H ).	('lower', 'NegReg', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('downregulation', 'NegReg', (18, 32))	('circ_0087378', 'Chemical', '-', (36, 48))	('circ_0087378', 'Var', (36, 48))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
711067	33680929	These data suggested that silencing of circ_0087378 significantly inhibited the progression of xenograft tumors possibly through inducing apoptosis in vivo.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('circ_0087378', 'Chemical', '-', (39, 51))	('circ_0087378', 'Gene', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('apoptosis', 'CPA', (138, 147))	('silencing', 'Var', (26, 35))	('inhibited', 'NegReg', (66, 75))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('inducing', 'NegReg', (129, 137))
711070	33680929	We then selected the top three miRNAs (including miR-140-3p, miR-431-5p, and miR-432-5p) based on conjugation scores ( Figure 3A ).	('miR-432', 'Gene', (77, 84))	('miR-140-3p', 'Chemical', '-', (49, 59))	('miR-431', 'Gene', '574038', (61, 68))	('miR-431', 'Gene', (61, 68))	('miR-432', 'Gene', '574451', (77, 84))	('miR-140-3p', 'Var', (49, 59))
711071	33680929	Our qRT-PCR assays determined that knocking down circ_0087378 in ESCC cells significantly upregulated the expression of miR-140-3p (but not the remaining two miRNAs) ( Figure 3B ).	('knocking down circ_0087378', 'Var', (35, 61))	('expression', 'MPA', (106, 116))	('circ_0087378', 'Var', (49, 61))	('circ_0087378', 'Chemical', '-', (49, 61))	('miR-140-3p', 'Var', (120, 130))	('upregulated', 'PosReg', (90, 101))	('miR-140-3p', 'Chemical', '-', (120, 130))
711072	33680929	Subsequently, we confirmed the downregulation of miR-140-3p in ESCC tissues compared with adjacent normal tissues ( Figure 3C ).	('downregulation', 'NegReg', (31, 45))	('miR-140-3p', 'Chemical', '-', (49, 59))	('ESCC', 'Disease', (63, 67))	('miR-140-3p', 'Var', (49, 59))
711073	33680929	Furthermore, we detected the negative correlation between the expression of circ_0087378 and miR-140-3p in ESCC tissues by performing the qRT-PCR analysis ( Figure 3D ).	('miR-140-3p', 'Var', (93, 103))	('miR-140-3p', 'Chemical', '-', (93, 103))	('circ_0087378', 'Var', (76, 88))	('negative', 'NegReg', (29, 37))	('ESCC', 'Disease', (107, 111))	('circ_0087378', 'Chemical', '-', (76, 88))
711075	33680929	Next, we utilized a luciferase reporter assay to verify the binding of miR-140-3p to circ_0087378 in ESCC cells ( Figure 3F ).	('circ_0087378', 'Chemical', '-', (85, 97))	('circ_0087378', 'Gene', (85, 97))	('miR-140-3p', 'Var', (71, 81))	('miR-140-3p', 'Chemical', '-', (71, 81))	('binding', 'Interaction', (60, 67))
711076	33680929	Overexpression of miR-140-3p inhibited the luciferase activity of circ_0087378-WT, but did not impact the luciferase activity of the circ_0087378-MUT ( Figure 3G ).	('inhibited', 'NegReg', (29, 38))	('circ_0087378', 'Chemical', '-', (133, 145))	('miR-140-3p', 'Var', (18, 28))	('luciferase', 'Enzyme', (43, 53))	('miR-140-3p', 'Chemical', '-', (18, 28))	('circ_0087378', 'Chemical', '-', (66, 78))	('activity', 'MPA', (54, 62))
711078	33680929	After that, we performed the RIP assay to pull down circ_0087378 and miR-140-3p in ESCC cells using anti-Ago2 antibodies or control IgG, following by qRT-PCR analysis.	('miR-140-3p', 'Var', (69, 79))	('miR-140-3p', 'Chemical', '-', (69, 79))	('Ago2', 'Gene', '27161', (105, 109))	('circ_0087378', 'Chemical', '-', (52, 64))	('Ago2', 'Gene', (105, 109))
711079	33680929	The results showed that circ_0087378 and miR-140-3p were significantly enriched in the Ago2 IP fraction in comparison to the IgG control fractions ( Figure 3I ).	('miR-140-3p', 'Var', (41, 51))	('miR-140-3p', 'Chemical', '-', (41, 51))	('circ_0087378', 'Var', (24, 36))	('circ_0087378', 'Chemical', '-', (24, 36))	('Ago2', 'Gene', (87, 91))	('Ago2', 'Gene', '27161', (87, 91))
711080	33680929	Collectively, these results supported a direct interaction between circ_0087378 and miR-140-3p in ESCC cells.	('interaction', 'Interaction', (47, 58))	('circ_0087378', 'Var', (67, 79))	('circ_0087378', 'Chemical', '-', (67, 79))	('miR-140-3p', 'Var', (84, 94))	('miR-140-3p', 'Chemical', '-', (84, 94))
711081	33680929	We questioned whether circ_0087378 exerts its tumor-promoting effects via sponging miR-140-3p by performing rescue experiments.	('circ_0087378', 'Chemical', '-', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('circ_0087378', 'Var', (22, 34))	('miR-140-3p', 'Chemical', '-', (83, 93))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
711083	33680929	Subsequent cell functional assays demonstrated that the inhibition of miR-140-3p restored the proliferative and invasive properties of ESCC cells that were produced by circ_0087378 knockdown ( Figures 4B-F ).	('inhibition', 'NegReg', (56, 66))	('ESCC', 'Disease', (135, 139))	('miR-140-3p', 'Var', (70, 80))	('proliferative', 'CPA', (94, 107))	('restored', 'PosReg', (81, 89))	('miR-140-3p', 'Chemical', '-', (70, 80))	('circ_0087378', 'Chemical', '-', (168, 180))	('invasive properties', 'CPA', (112, 131))
711084	33680929	The flow cytometry analysis indicated that the knockdown of circ_0087378 increased cell apoptosis, while co-transfection with anti-miR-1403p significantly reduced cell apoptosis compared with the control ( Figure 4F ).	('circ_0087378', 'Chemical', '-', (60, 72))	('increased', 'PosReg', (73, 82))	('reduced', 'NegReg', (155, 162))	('cell apoptosis', 'CPA', (83, 97))	('circ_0087378', 'Var', (60, 72))
711085	33680929	The downregulation of miR-140-3p was more likely to occur in patients with high tumor grade, late-stage, and a high risk of lymph node metastasis ( Table 4 ).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (61, 69))	('miR-140-3p', 'Var', (22, 32))	('tumor', 'Disease', (80, 85))	('miR-140-3p', 'Chemical', '-', (22, 32))	('downregulation', 'NegReg', (4, 18))	('lymph node metastasis', 'CPA', (124, 145))
711086	33680929	These results suggested that circ_0087378 promotes the proliferation and invasiveness of ESCC cells by sponging miR-140-3p.	('miR-140-3p', 'MPA', (112, 122))	('sponging', 'NegReg', (103, 111))	('invasiveness', 'CPA', (73, 85))	('proliferation', 'CPA', (55, 68))	('promotes', 'PosReg', (42, 50))	('ESCC', 'Disease', (89, 93))	('miR-140-3p', 'Chemical', '-', (112, 122))	('circ_0087378', 'Var', (29, 41))	('circ_0087378', 'Chemical', '-', (29, 41))
711087	33680929	Since these data indicated that circ_0087378 enhances the aggressive features of ESCC cells via miR-140-3p sequestration, we sought to determine whether circ_0087378 could increase the expression of miR-140-3p target genes.	('miR-140-3p sequestration', 'MPA', (96, 120))	('increase', 'PosReg', (172, 180))	('miR-140-3p', 'Chemical', '-', (96, 106))	('expression', 'MPA', (185, 195))	('circ_0087378', 'Var', (32, 44))	('enhances', 'PosReg', (45, 53))	('circ_0087378', 'Chemical', '-', (32, 44))	('circ_0087378', 'Var', (153, 165))	('circ_0087378', 'Chemical', '-', (153, 165))	('miR-140-3p', 'Chemical', '-', (199, 209))	('aggressive features of ESCC cells', 'CPA', (58, 91))
711089	33680929	To validate whether E2F3 is a miR-140-3p target gene, ESCC cells were co-transfected with E2F3 3'-UTR-WT or E2F3 3'-UTR-MUT, along with (or without) miR-140-3p mimic.	('miR-140-3p', 'Chemical', '-', (30, 40))	('E2F3', 'Gene', (90, 94))	('miR-140-3p', 'Chemical', '-', (149, 159))	('E2F3', 'Var', (108, 112))
711090	33680929	As a result, miR-140-3p mimic significantly decreased the luciferase activities of E2F3 3'-UTR-WT ( Figure 5B ).	('miR-140-3p', 'Chemical', '-', (13, 23))	('activities', 'MPA', (69, 79))	('luciferase', 'Enzyme', (58, 68))	('E2F3', 'Var', (83, 87))	('miR-140-3p mimic', 'Var', (13, 29))	('decreased', 'NegReg', (44, 53))
711091	33680929	However, the transfection with miR-140-3p mimic did not significantly impact the luciferase signal of E2F3 3'-UTR-MUT ( Figure 5B ).	('miR-140-3p', 'Chemical', '-', (31, 41))	('luciferase', 'Enzyme', (81, 91))	('E2F3', 'Var', (102, 106))
711092	33680929	Moreover, ESCC cells transfected with miR-140-3p mimic expressed lower E2F3 protein levels ( Figure 5C ).	('miR-140-3p mimic', 'Var', (38, 54))	('lower', 'NegReg', (65, 70))	('E2F3 protein levels', 'MPA', (71, 90))	('miR-140-3p', 'Chemical', '-', (38, 48))
711093	33680929	Our further studies showed that silencing of circ_0087378 could lead to an apparent downregulation of E2F3 ( Figure 5D ).	('circ_0087378', 'Chemical', '-', (45, 57))	('silencing', 'Var', (32, 41))	('E2F3 ( Figure 5D', 'Gene', '1871', (102, 118))	('circ_0087378', 'Gene', (45, 57))	('downregulation', 'NegReg', (84, 98))
711097	33680929	In agreement with these findings, the levels of circ_0087378 were positively correlated to the expression of E2F3 expression in ESCC tissue (n = 50) ( Figure 5G ).	('E2F3', 'Gene', (109, 113))	('circ_0087378', 'Chemical', '-', (48, 60))	('circ_0087378', 'Var', (48, 60))	('ESCC', 'Disease', (128, 132))	('expression', 'MPA', (95, 105))
711100	33680929	Furthermore, overexpression of miR-140-3p led to decreased cell growth, cell migration and invasion, as well as increased cell apoptosis ( Figures 6A-F ).	('miR-140-3p', 'Var', (31, 41))	('invasion', 'CPA', (91, 99))	('miR-140-3p', 'Chemical', '-', (31, 41))	('cell migration', 'CPA', (72, 86))	('cell apoptosis', 'CPA', (122, 136))	('decreased', 'NegReg', (49, 58))	('overexpression', 'PosReg', (13, 27))	('increased', 'PosReg', (112, 121))	('cell growth', 'CPA', (59, 70))
711102	33680929	For example, circ_0000337 could sponge miR-670-5p to regulate the migration and invasion of ESCC cells.	('invasion', 'CPA', (80, 88))	('circ_0000337', 'Var', (13, 25))	('regulate', 'Reg', (53, 61))	('migration', 'CPA', (66, 75))	('miR-670', 'Gene', '100313777', (39, 46))	('miR-670', 'Gene', (39, 46))
711103	33680929	In addition, circ_0000337 promotes ESCC metastasis by augmenting beta-catenin signaling.	('circ_0000337', 'Var', (13, 25))	('promotes', 'PosReg', (26, 34))	('beta-catenin', 'Gene', '1499', (65, 77))	('augmenting', 'NegReg', (54, 64))	('ESCC', 'Disease', (35, 39))	('beta-catenin', 'Gene', (65, 77))
711105	33680929	In this study, we found that circ_0087378 was highly expressed in ESCC tumor tissues relative to adjacent normal tissues.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('circ_0087378', 'Var', (29, 41))	('circ_0087378', 'Chemical', '-', (29, 41))
711106	33680929	Our in vitro and in vivo results demonstrated that circ_0087378 performed pro-oncogenic functions in ESCC.	('pro-oncogenic functions', 'CPA', (74, 97))	('circ_0087378', 'Var', (51, 63))	('ESCC', 'Disease', (101, 105))	('circ_0087378', 'Chemical', '-', (51, 63))
711108	33680929	Several previous studies have shown that miR-140-3p is a critical miRNA that acts as a tumor suppressor in various cancers.	('miR-140-3p', 'Var', (41, 51))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('miR-140-3p', 'Chemical', '-', (41, 51))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('tumor', 'Disease', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
711109	33680929	Furthermore, miR-140-3p was shown to be down-regulated in ESCC tissues.	('miR-140-3p', 'Var', (13, 23))	('ESCC', 'Disease', (58, 62))	('miR-140-3p', 'Chemical', '-', (13, 23))	('down-regulated', 'NegReg', (40, 54))
711110	33680929	MiR-140-3p could interact with NRIP1 to inhibit the tumorigenesis of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('inhibit', 'NegReg', (40, 47))	('tumor', 'Disease', (52, 57))	('NRIP1', 'Gene', (31, 36))	('MiR-140-3p', 'Chemical', '-', (0, 10))	('MiR-140-3p', 'Var', (0, 10))	('ESCC', 'Disease', (69, 73))	('NRIP1', 'Gene', '8204', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('interact', 'Interaction', (17, 25))
711111	33680929	Consistent with these results, we demonstrated that circ_0000337 promoted the proliferation and invasion of ESCC cells via sponging miR-140-3p.	('circ_0000337', 'Var', (52, 64))	('miR-140-3p', 'Chemical', '-', (132, 142))	('invasion', 'CPA', (96, 104))	('promoted', 'PosReg', (65, 73))	('proliferation', 'CPA', (78, 91))	('ESCC', 'Disease', (108, 112))
711112	33680929	As an important member of the E2F family, E2F3 affects tumorigenesis and progression in lung cancer and osteosarcoma.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('lung cancer', 'Disease', (88, 99))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('affects', 'Reg', (47, 54))	('osteosarcoma', 'Disease', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (55, 60))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('osteosarcoma', 'Phenotype', 'HP:0002669', (104, 116))	('osteosarcoma', 'Disease', 'MESH:D012516', (104, 116))	('progression', 'CPA', (73, 84))	('E2F3', 'Var', (42, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
711113	33680929	Here, our results verified that miR-140-3p directly binds to E2F3 and inhibits its expression in ESCC cells.	('binds', 'Interaction', (52, 57))	('miR-140-3p', 'Var', (32, 42))	('inhibits', 'NegReg', (70, 78))	('miR-140-3p', 'Chemical', '-', (32, 42))	('expression', 'MPA', (83, 93))	('E2F3', 'Gene', (61, 65))
711114	33680929	E2F3 enhances the malignant properties of ESCC cells, and overexpression of E2F3 could reverse the tumor-suppressing functions of miR-140-3p.	('tumor', 'Disease', (99, 104))	('enhances', 'PosReg', (5, 13))	('E2F3', 'Gene', (76, 80))	('malignant properties of ESCC cells', 'CPA', (18, 52))	('miR-140-3p', 'Var', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('E2F3', 'Var', (0, 4))	('miR-140-3p', 'Chemical', '-', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
711115	33680929	Moreover, the expression of E2F3 was significantly positively correlated with the levels of circ_0087378, while E2F3 expression was negatively correlated with the levels of miR-140-3p in ESCC tumor tissues.	('circ_0087378', 'Var', (92, 104))	('tumor', 'Disease', (192, 197))	('positively', 'PosReg', (51, 61))	('circ_0087378', 'Chemical', '-', (92, 104))	('correlated', 'Interaction', (62, 72))	('negatively', 'NegReg', (132, 142))	('miR-140-3p', 'Chemical', '-', (173, 183))	('expression', 'MPA', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('E2F3', 'Var', (28, 32))
711116	33680929	Taken together, our findings demonstrated that circ_0087378 promoted the tumorigenesis and progression of ESCC via regulating the miR-140-3p/E2F3 axis.	('circ_0087378', 'Chemical', '-', (47, 59))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('progression', 'CPA', (91, 102))	('circ_0087378', 'Var', (47, 59))	('promoted', 'PosReg', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ESCC', 'Disease', (106, 110))	('miR-140-3p/E2F3 axis', 'Pathway', (130, 150))	('tumor', 'Disease', (73, 78))	('regulating', 'Reg', (115, 125))	('miR-140-3p', 'Chemical', '-', (130, 140))
711117	33680929	We only tested the effects of circ_0087378 knockdown, but not the influence of circ_0087378 overexpression on ESCC cells.	('tested', 'Reg', (8, 14))	('circ_0087378 knockdown', 'Var', (30, 52))	('circ_0087378', 'Chemical', '-', (30, 42))	('circ_0087378', 'Chemical', '-', (79, 91))	('knockdown', 'Var', (43, 52))
711118	33680929	In addition, our results showed that circ_0087378 inhibits the function of miR-140-3p, while inhibiting miR-140-3p expression failed to completely eliminate the effects of circ_0087378 knockdown on ESCC cells.	('miR-140-3p', 'Chemical', '-', (104, 114))	('function', 'MPA', (63, 71))	('miR-140-3p', 'Chemical', '-', (75, 85))	('circ_0087378', 'Chemical', '-', (172, 184))	('inhibits', 'NegReg', (50, 58))	('circ_0087378', 'Var', (37, 49))	('circ_0087378', 'Chemical', '-', (37, 49))
711123	33680929	In conclusion, our results provide new evidence showing that circ_0087378 is a novel oncogenic circRNA that exerts its tumor-promoting activities in ESCC through mediating the miR-140-3p/E2F3 axis.	('circ_0087378', 'Var', (61, 73))	('tumor', 'Disease', (119, 124))	('ESCC', 'Disease', (149, 153))	('circ_0087378', 'Chemical', '-', (61, 73))	('miR-140-3p', 'Chemical', '-', (176, 186))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mediating', 'Reg', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
711149	32312948	For example, autoantibodies against mutated TP53 are widely observed in various cancer patient's serum and are clinically used as cancer diagnostic biomarkers.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('observed', 'Reg', (60, 68))	('mutated', 'Var', (36, 43))	('patient', 'Species', '9606', (87, 94))	('TP53', 'Gene', '7157', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('TP53', 'Gene', (44, 48))	('cancer', 'Disease', (80, 86))
711205	30598708	Besides, aberrant expression of specific lncRNAs as molecular biomarkers was associated closely with prognosis of GIC patients and involved in targeted therapy, which might promote the development of novel prevention strategies and advanced therapies.	('expression', 'MPA', (18, 28))	('aberrant', 'Var', (9, 17))	('promote', 'PosReg', (173, 180))	('patients', 'Species', '9606', (118, 126))	('associated', 'Reg', (77, 87))
711208	30598708	lncRNA FEZF1-AS1 recruits and bounds to LSD1 to epigenetically repress downstream gene p21, thereby promoting proliferation, and lncRNA GHET1 promotes gastric carcinoma cell proliferation by increasing c-Myc mRNA stability.	('increasing', 'PosReg', (191, 201))	('gastric carcinoma', 'Disease', 'MESH:D013274', (151, 168))	('c-Myc', 'Gene', (202, 207))	('epigenetically', 'Var', (48, 62))	('gastric carcinoma', 'Disease', (151, 168))	('AS1', 'Gene', (13, 16))	('c-Myc', 'Gene', '4609', (202, 207))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (151, 168))	('lncRNA GHET1', 'Gene', '102723099', (129, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('promoting', 'PosReg', (100, 109))	('p21', 'Gene', (87, 90))	('lncRNA GHET1', 'Gene', (129, 141))	('proliferation', 'CPA', (110, 123))	('p21', 'Gene', '644914', (87, 90))	('FEZF1', 'Gene', '389549', (7, 12))	('AS1', 'Gene', '5729', (13, 16))	('FEZF1', 'Gene', (7, 12))	('LSD1', 'Gene', '23028', (40, 44))	('LSD1', 'Gene', (40, 44))	('promotes', 'PosReg', (142, 150))
711212	30598708	Recently, mounting evidences have indicated that various lncRNAs can function as oncogenes or tumor suppressor genes and the dysregulation of lncRNA expression as molecular biomarkers presented promising huge prognostic values in GIC patients.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('patients', 'Species', '9606', (234, 242))	('GIC', 'Disease', (230, 233))	('dysregulation', 'Var', (125, 138))
711230	30598708	The results from this meta-analysis showed that the pooled HR values (95% CI) of OS and DFS related to different lncRNA expressions in GIC patients were 2.00 (1.87-2.13) and 1.92 (1.73-2.14), respectively, which implied that aberrantly expressed lncRNAs may serve as cancer biomarkers in GIC patients.	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('patients', 'Species', '9606', (139, 147))	('aberrantly', 'Var', (225, 235))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('patients', 'Species', '9606', (292, 300))
711248	30223861	Recent evidence has demonstrated that the dysregulation of lncRNAs plays important roles in the proliferation, metastasis, invasion, angiogenesis, apoptosis, chemoradiotherapy resistance, and stemness of EC, which suggests potential clinical implications.	('metastasis', 'CPA', (111, 121))	('stemness', 'Disease', 'MESH:D020295', (192, 200))	('stemness', 'Disease', (192, 200))	('proliferation', 'CPA', (96, 109))	('ncRNA', 'Gene', (60, 65))	('invasion', 'CPA', (123, 131))	('dysregulation', 'Var', (42, 55))	('angiogenesis', 'CPA', (133, 145))	('ncRNA', 'Gene', '220202', (60, 65))	('apoptosis', 'CPA', (147, 156))	('EC', 'Phenotype', 'HP:0011459', (204, 206))
711263	30223861	Accumulating evidence suggests that the aberrant lncRNA expression is associated with oncogenesis and the development of various cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('ncRNA', 'Gene', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('associated', 'Reg', (70, 80))	('ncRNA', 'Gene', '220202', (50, 55))	('aberrant', 'Var', (40, 48))	('oncogenesis', 'Disease', (86, 97))
711290	30223861	Thus, LincRNA-uc002yug.2 may modulate cell proliferation and the tumor growth of ESCC through the alternative splicing of RUNX1.	('cell proliferation', 'CPA', (38, 56))	('tumor', 'Disease', (65, 70))	('LincRNA-uc002yug.2', 'Gene', (6, 24))	('modulate', 'Reg', (29, 37))	('ESCC', 'Disease', (81, 85))	('alternative splicing', 'Var', (98, 118))	('RUNX1', 'Gene', (122, 127))	('LincRNA-uc002yug.2', 'Gene', '100506385', (6, 24))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('RUNX1', 'Gene', '861', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
711297	30223861	Hence, the dysregulation of the lnc-ATB/miR-200b/kindlin-2 axis is involved in the development of ESCC.	('involved', 'Reg', (67, 75))	('miR-200b', 'Gene', (40, 48))	('ESCC', 'Disease', (98, 102))	('ATB', 'Chemical', 'MESH:C042207', (36, 39))	('dysregulation', 'Var', (11, 24))	('kindlin-2', 'Gene', (49, 58))	('miR-200b', 'Gene', '406984', (40, 48))	('kindlin-2', 'Gene', '10979', (49, 58))
711321	30223861	Further analysis revealed that both basal and EGF- and IGF-induced phosphorylation of ERK1/2, Akt, p70S6K, and mTOR were significantly decreased following the knockdown of LINC01503.	('LINC01503', 'Gene', '100506119', (172, 181))	('knockdown', 'Var', (159, 168))	('ERK1/2', 'Gene', (86, 92))	('mTOR', 'Gene', '2475', (111, 115))	('Akt', 'Gene', (94, 97))	('p70S6K', 'Gene', (99, 105))	('EGF', 'Gene', '1950', (46, 49))	('mTOR', 'Gene', (111, 115))	('p70S6K', 'Gene', '6198', (99, 105))	('ERK1/2', 'Gene', '5595;5594', (86, 92))	('LINC01503', 'Gene', (172, 181))	('decreased', 'NegReg', (135, 144))	('Akt', 'Gene', '207', (94, 97))	('EGF', 'Gene', (46, 49))	('phosphorylation', 'MPA', (67, 82))
711322	30223861	In addition, silencing LINC01503 expression increased the binding of EBP-1 to the PI3K subunit p85, suggesting that LINC01503 inhibits PI3K deubiquitination to activate the PI3K/Akt signaling pathway.	('inhibits', 'NegReg', (126, 134))	('LINC01503', 'Gene', (23, 32))	('EBP-1', 'Gene', (69, 74))	('binding', 'Interaction', (58, 65))	('PI3K deubiquitination', 'MPA', (135, 156))	('activate', 'PosReg', (160, 168))	('LINC01503', 'Gene', (116, 125))	('p85', 'Gene', (95, 98))	('Akt', 'Gene', '207', (178, 181))	('EBP-1', 'Gene', '4790', (69, 74))	('LINC01503', 'Gene', '100506119', (23, 32))	('LINC01503', 'Gene', '100506119', (116, 125))	('p85', 'Gene', '5296', (95, 98))	('increased', 'PosReg', (44, 53))	('Akt', 'Gene', (178, 181))	('silencing', 'Var', (13, 22))
711357	30223861	Thus, the knockdown of CDKN2B-AS1 rescued the slow proliferation of EC109 cells induced by beta-elemene, an anticancer drug.	('slow proliferation', 'CPA', (46, 64))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('beta-elemene', 'Chemical', 'MESH:C445979', (91, 103))	('CDKN2B-AS1', 'Gene', '100048912', (23, 33))	('EC109', 'CellLine', 'CVCL:6898', (68, 73))	('EC', 'Phenotype', 'HP:0011459', (68, 70))	('rescued', 'PosReg', (34, 41))	('CDKN2B-AS1', 'Gene', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('knockdown', 'Var', (10, 19))
711358	30223861	BC032469, another lncRNA that is overexpressed in ESCC tissues, was positively associated with a larger tumor size and shorter OS.	('associated', 'Reg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ncRNA', 'Gene', (19, 24))	('ncRNA', 'Gene', '220202', (19, 24))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('shorter OS', 'CPA', (119, 129))	('BC032469', 'Var', (0, 8))	('OS', 'Chemical', '-', (127, 129))	('BC032469', 'Chemical', '-', (0, 8))
711359	30223861	Silencing BC032469 expression in ESCC cells resulted in the inhibition of cell proliferation.	('cell proliferation', 'CPA', (74, 92))	('inhibition', 'NegReg', (60, 70))	('BC032469', 'Gene', (10, 18))	('Silencing', 'Var', (0, 9))	('BC032469', 'Chemical', '-', (10, 18))
711360	30223861	Mechanical assays revealed that BC032469 induced cell cycle arrest in the G0/G1 phase by regulating the expression of hTERT.	('regulating', 'Reg', (89, 99))	('BC032469', 'Var', (32, 40))	('hTERT', 'Gene', '7015', (118, 123))	('BC032469', 'Chemical', '-', (32, 40))	('expression', 'MPA', (104, 114))	('hTERT', 'Gene', (118, 123))	('arrest', 'Disease', 'MESH:D006323', (60, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))	('arrest', 'Disease', (60, 66))
711364	30223861	PVT1 has been identified as an oncogene, and high PVT1 expression was shown to be associated with the development of EC.	('associated with', 'Reg', (82, 97))	('PVT1', 'Gene', '5820', (50, 54))	('PVT1', 'Gene', (0, 4))	('expression', 'MPA', (55, 65))	('high', 'Var', (45, 49))	('EC', 'Phenotype', 'HP:0011459', (117, 119))	('PVT1', 'Gene', '5820', (0, 4))	('PVT1', 'Gene', (50, 54))
711370	30223861	Silencing the expression of SNHG1 in ESCC cells was demonstrated to inhibit cell proliferation and cell invasion capacity, as well as the EMT phenomenon, through suppressing the Notch signaling pathway.	('Notch', 'Gene', '4851', (178, 183))	('cell invasion capacity', 'CPA', (99, 121))	('SNHG1', 'Gene', (28, 33))	('Notch', 'Gene', (178, 183))	('inhibit', 'NegReg', (68, 75))	('EMT phenomenon', 'CPA', (138, 152))	('cell proliferation', 'CPA', (76, 94))	('suppressing', 'NegReg', (162, 173))	('SNHG1', 'Gene', '23642', (28, 33))	('Silencing', 'Var', (0, 9))
711376	30223861	Recently, Wang reported that the knockdown of HAS1 suppressed the expression of VEGF in ESCC cells.	('HAS1', 'Gene', '3036', (46, 50))	('VEGF', 'Gene', (80, 84))	('knockdown', 'Var', (33, 42))	('HAS1', 'Gene', (46, 50))	('expression', 'MPA', (66, 76))	('suppressed', 'NegReg', (51, 61))	('VEGF', 'Gene', '7422', (80, 84))
711384	30223861	POU6F2-AS2 knockdown induced prolonged DNA tails in ESCC cells following ionizing radiation (IR) and caused sensitivity to IR, indicating that POU6F2-AS2 is involved in the DNA damage response.	('POU6F2-AS2', 'Gene', '100689074;11281', (0, 10))	('POU6F2-AS2', 'Gene', '100689074;11281', (143, 153))	('POU6F2-AS2', 'Gene', (0, 10))	('POU6F2-AS2', 'Gene', (143, 153))	('prolonged', 'PosReg', (29, 38))	('DNA tails', 'MPA', (39, 48))	('knockdown', 'Var', (11, 20))
711386	30223861	Finally, the dysregulation of POU6F2-AS2 expression in ESCC cell lines regulates cell survival after IR.	('regulates', 'Reg', (71, 80))	('dysregulation', 'Var', (13, 26))	('POU6F2-AS2', 'Gene', '100689074;11281', (30, 40))	('POU6F2-AS2', 'Gene', (30, 40))	('cell survival after IR', 'CPA', (81, 103))
711391	30223861	The authors detected that three lncRNAs (AFAP1-AS1, UCA1, and HOTAIR) were dysregulated in cisplatin-resistant cells compared with the parent cell line.	('UCA1', 'Gene', '652995', (52, 56))	('UCA1', 'Gene', (52, 56))	('HOTAIR', 'Gene', '100124700', (62, 68))	('cisplatin-resistant', 'Var', (91, 110))	('ncRNA', 'Gene', '220202', (33, 38))	('dysregulated', 'Reg', (75, 87))	('AS1', 'Gene', '5729', (47, 50))	('AS1', 'Gene', (47, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))	('AFAP1', 'Gene', (41, 46))	('HOTAIR', 'Gene', (62, 68))	('AFAP1', 'Gene', '60312', (41, 46))	('ncRNA', 'Gene', (33, 38))
711395	30223861	Another lncRNA, LOC285194, also known as LSAMP antisense RNA 3, has been reported to be downregulated in several cancers, including EC and was found to be closely associated with a poor patient prognosis.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ncRNA', 'Gene', '220202', (9, 14))	('LSAMP', 'Gene', '4045', (41, 46))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('associated', 'Reg', (163, 173))	('downregulated', 'NegReg', (88, 101))	('LSAMP', 'Gene', (41, 46))	('patient', 'Species', '9606', (186, 193))	('ncRNA', 'Gene', (9, 14))	('LOC285194', 'Var', (16, 25))	('EC', 'Phenotype', 'HP:0011459', (132, 134))
711399	30223861	Zhang and colleagues reported that ESCC patients with high WISP1 expression had a significantly poorer prognosis compared with those with low WISP1 levels after radiotherapy.	('WISP1', 'Gene', '8840', (59, 64))	('ESCC', 'Disease', (35, 39))	('high', 'Var', (54, 58))	('patients', 'Species', '9606', (40, 48))	('WISP1', 'Gene', '8840', (142, 147))	('WISP1', 'Gene', (59, 64))	('WISP1', 'Gene', (142, 147))
711428	30223861	The aberrant expression of several lncRNAs has been significantly associated with EC prognosis and may serve as potential prognostic predictors.	('ncRNA', 'Gene', (36, 41))	('EC', 'Phenotype', 'HP:0011459', (82, 84))	('associated', 'Reg', (66, 76))	('aberrant expression', 'Var', (4, 23))	('ncRNA', 'Gene', '220202', (36, 41))
711431	30223861	Kaplan-Meier analysis has revealed that patients in the high PCAT-1 group (n = 65) had shorter survival times compared with those in the low PCAT-1 group (n = 39).	('PCAT-1', 'Gene', '100750225', (61, 67))	('patients', 'Species', '9606', (40, 48))	('PCAT-1', 'Gene', (141, 147))	('shorter', 'NegReg', (87, 94))	('PCAT-1', 'Gene', '100750225', (141, 147))	('PCAT-1', 'Gene', (61, 67))	('survival times', 'CPA', (95, 109))	('high', 'Var', (56, 60))
711433	30223861	In addition, from the Kaplan-Meier survival curves, it was observed that the 5-year overall survival (OS) and disease-free survival (DFS) of ESCC patients with high levels of ZEB1-AS1 were shorter compared with those with low levels of ZEB1-AS1.	('high', 'Var', (160, 164))	('OS', 'Chemical', '-', (102, 104))	('ZEB1-AS1', 'Gene', (236, 244))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (236, 244))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (175, 183))	('shorter', 'NegReg', (189, 196))	('overall survival', 'CPA', (84, 100))	('disease-free survival', 'CPA', (110, 131))	('patients', 'Species', '9606', (146, 154))	('ZEB1-AS1', 'Gene', (175, 183))	('ESCC', 'Disease', (141, 145))
711434	30223861	Additionally, the dysregulation of lncRNAs ATB, XIST, AK001796, MALAT1, nuclear transcription factor NF-kappaB interacting lncRNA (NKILA), SPRY4-IT1, and zinc finger antisense 1 (ZFAS1) has also been demonstrated to be markedly associated with advanced lymph node metastasis, aggressive TNM stage, and shorter survival time.	('ZFAS1', 'Gene', '441951', (179, 184))	('SPRY4-IT1', 'Gene', '81848;79441', (139, 148))	('XIST', 'Gene', '7503', (48, 52))	('ATB', 'Chemical', 'MESH:C042207', (43, 46))	('advanced lymph node metastasis', 'CPA', (244, 274))	('ncRNA', 'Gene', (124, 129))	('SPRY4-IT1', 'Gene', (139, 148))	('MALAT1', 'Gene', (64, 70))	('NF-kappaB interacting lncRNA', 'Gene', (101, 129))	('ncRNA', 'Gene', (36, 41))	('ncRNA', 'Gene', '220202', (124, 129))	('NF-kappaB interacting lncRNA', 'Gene', '105416157', (101, 129))	('NKILA', 'Gene', '105416157', (131, 136))	('AK001796', 'Gene', (54, 62))	('dysregulation', 'Var', (18, 31))	('ncRNA', 'Gene', '220202', (36, 41))	('MALAT1', 'Gene', '378938', (64, 70))	('associated', 'Reg', (228, 238))	('NKILA', 'Gene', (131, 136))	('AK001796', 'Gene', '541471', (54, 62))	('zinc finger antisense 1', 'Gene', (154, 177))	('TNM', 'Gene', '10178', (287, 290))	('TNM', 'Gene', (287, 290))	('ZFAS1', 'Gene', (179, 184))	('XIST', 'Gene', (48, 52))	('zinc finger antisense 1', 'Gene', '441951', (154, 177))
711440	30223861	It is now recognized that aberrant expression of lncRNAs is a crucial determinant for human cancer.	('aberrant', 'Var', (26, 34))	('cancer', 'Disease', (92, 98))	('ncRNA', 'Gene', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('human', 'Species', '9606', (86, 91))	('ncRNA', 'Gene', '220202', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
711486	28807841	Among Asians, variants in genes involved in alcohol metabolism confer increased risk of SCC.	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('variants', 'Var', (14, 22))	('SCC', 'Gene', (88, 91))	('risk', 'Reg', (80, 84))	('SCC', 'Gene', '6317', (88, 91))
711489	28807841	A number of genome-wide association studies (GWAS) of esophageal SCC have been performed in Asian populations and identified functional variants in alcohol metabolizing genes, ALDH2 and ADH1B, that, when combined with lifestyle factors, significantly increase risk of SCC.	('ADH1B', 'Gene', (186, 191))	('variants', 'Var', (136, 144))	('SCC', 'Gene', (65, 68))	('ADH1B', 'Gene', '125', (186, 191))	('alcohol', 'Chemical', 'MESH:D000438', (148, 155))	('SCC', 'Gene', (268, 271))	('ALDH2', 'Gene', '217', (176, 181))	('SCC', 'Gene', '6317', (65, 68))	('esophageal SCC', 'Disease', (54, 68))	('SCC', 'Gene', '6317', (268, 271))	('increase', 'PosReg', (251, 259))	('esophageal SCC', 'Disease', 'MESH:D004941', (54, 68))	('ALDH2', 'Gene', (176, 181))
711490	28807841	Moreover, variants in PLCE1 were associated with SCC in 2 GWAS evaluations, and the allele frequencies of these variants are similar across populations, but have not been studied as risk factors in non-Asian populations.	('variants', 'Var', (10, 18))	('SCC', 'Gene', (49, 52))	('PLCE1', 'Gene', (22, 27))	('PLCE1', 'Gene', '51196', (22, 27))	('SCC', 'Gene', '6317', (49, 52))	('associated', 'Reg', (33, 43))
711495	28807841	GWAS for Barrett's esophagus and esophageal adenocarcinoma in individuals of European descent have identified a number of genetic variants in CRTC1, BARX1, FOXP1, GDF7, TBX5 and HLA.	('variants', 'Var', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('TBX5', 'Gene', (169, 173))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (9, 28))	('esophageal adenocarcinoma', 'Disease', (33, 58))	('TBX5', 'Gene', '6910', (169, 173))	('FOXP1', 'Gene', (156, 161))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (33, 58))	('BARX1', 'Gene', (149, 154))	('GDF7', 'Gene', (163, 167))	('CRTC1', 'Gene', (142, 147))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (33, 58))	('GDF7', 'Gene', '151449', (163, 167))	('CRTC1', 'Gene', '23373', (142, 147))	('BARX1', 'Gene', '56033', (149, 154))	('FOXP1', 'Gene', '27086', (156, 161))
711496	28807841	The risk variant in CRTC1 has 30% higher allele frequency in European Americans compared with Blacks; however, the other GWAS variants do not have large allele frequency differences or have higher frequency of the risk allele in Blacks and would not explain differences in risk between populations.	('variant', 'Var', (9, 16))	('CRTC1', 'Gene', (20, 25))	('allele', 'MPA', (41, 47))	('higher', 'PosReg', (34, 40))	('CRTC1', 'Gene', '23373', (20, 25))
711497	28807841	Additional work is needed to understand the contribution of genetic variants in addition to known environmental risk factors for adenocarcinoma in Whites compared with other US populations.	('variants', 'Var', (68, 76))	('adenocarcinoma', 'Disease', (129, 143))	('adenocarcinoma', 'Disease', 'MESH:D000230', (129, 143))	('men', 'Species', '9606', (105, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))
711511	28807841	While many studies have advocated eradication of H. pylori to reduce non-cardia gastric cancer incidence, strong evidence for this approach is still lacking.	('eradication', 'Var', (34, 45))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (69, 94))	('H. pylori', 'Gene', (49, 58))	('reduce', 'NegReg', (62, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('H. pylori', 'Species', '210', (49, 58))	('non-cardia gastric cancer', 'Disease', (69, 94))
711515	28807841	Among Asians, low penetrance genetic variants in PSCA, PLCE1, PRKAA1 and MUC1 increase risk for gastric cancer and among Europeans, loss of function of ATM increases gastric cancer risk.	('gastric cancer', 'Disease', (166, 180))	('PRKAA1', 'Gene', (62, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('increase', 'Reg', (78, 86))	('PLCE1', 'Gene', (55, 60))	('ATM', 'Gene', (152, 155))	('PLCE1', 'Gene', '51196', (55, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('loss', 'Var', (132, 136))	('PSCA', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('PSCA', 'Gene', '8000', (49, 53))	('PRKAA1', 'Gene', '5562', (62, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('increase risk for gastric cancer', 'Phenotype', 'HP:0006753', (78, 110))	('increases gastric cancer', 'Phenotype', 'HP:0006753', (156, 180))	('MUC1', 'Gene', (73, 77))	('MUC1', 'Gene', '4582', (73, 77))	('ATM', 'Gene', '472', (152, 155))	('increases', 'PosReg', (156, 165))	('variants', 'Var', (37, 45))	('gastric cancer', 'Disease', (96, 110))
711516	28807841	Inactivating mutations in the E-Cadherin gene (CDH1) leads to hereditary diffuse gastric cancer syndrome in a small fraction of individuals.	('CDH1', 'Gene', '999', (47, 51))	('E-Cadherin', 'Gene', (30, 40))	('Inactivating mutations', 'Var', (0, 22))	('hereditary diffuse gastric cancer syndrome', 'Disease', (62, 104))	('E-Cadherin', 'Gene', '999', (30, 40))	('hereditary diffuse gastric cancer syndrome', 'Disease', 'MESH:D013274', (62, 104))	('CDH1', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('leads to', 'Reg', (53, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
711517	28807841	This same gene is the target of inactivation through methylation in the presence of H. pylori infection.	('H. pylori infection', 'Phenotype', 'HP:0005202', (84, 103))	('infection', 'Disease', (94, 103))	('infection', 'Disease', 'MESH:D007239', (94, 103))	('H. pylori', 'Species', '210', (84, 93))	('H. pylori', 'Disease', (84, 93))	('methylation', 'Var', (53, 64))
711530	28807841	Hereditary syndromes (such as those due to germline mutations in STK11, BRCA1/2, PALB2, CDKN2A, and DNA repair genes) significantly increase pancreatic cancer risk, especially with family history of pancreatic cancer in a first-degree relative.	('pancreatic cancer', 'Disease', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PALB2', 'Gene', '79728', (81, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (141, 158))	('CDKN2A', 'Gene', (88, 94))	('BRCA1/2', 'Gene', (72, 79))	('increase', 'PosReg', (132, 140))	('STK11', 'Gene', (65, 70))	('pancreatic cancer', 'Disease', (141, 158))	('increase pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('germline mutations', 'Var', (43, 61))	('CDKN2A', 'Gene', '1029', (88, 94))	('BRCA1/2', 'Gene', '672;675', (72, 79))	('STK11', 'Gene', '6794', (65, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (141, 158))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('PALB2', 'Gene', (81, 86))
711551	28807841	For small bowel neuroendocrine tumors, GWAS evaluations have identified risk variants upstream of ELK3, though the impact of these variants by race is not known.	('variants', 'Var', (77, 85))	('small bowel neuroendocrine tumors', 'Disease', 'MESH:D018358', (4, 37))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (16, 37))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('small bowel neuroendocrine tumors', 'Disease', (4, 37))	('ELK3', 'Gene', (98, 102))	('ELK3', 'Gene', '2004', (98, 102))
711574	28807841	With Lynch syndrome, the cumulative risk for CRC in Blacks and NHWs with a germline mismatch repair mutation was nearly identical; however, the mutational spectrum of the mismatch repair genes was different, likely reflecting the genetic diversity of the Black population.	('CRC', 'Disease', (45, 48))	('Lynch syndrome', 'Disease', 'MESH:D003123', (5, 19))	('Lynch syndrome', 'Disease', (5, 19))	('mutation', 'Var', (100, 108))
711584	28807841	Black patients display a higher frequency of KRAS mutations in tumors, increasing the aggressiveness of the CRC.	('KRAS', 'Gene', '3845', (45, 49))	('aggressiveness', 'Phenotype', 'HP:0000718', (86, 100))	('increasing', 'PosReg', (71, 81))	('mutations', 'Var', (50, 59))	('aggressiveness', 'Disease', 'MESH:D001523', (86, 100))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('aggressiveness', 'Disease', (86, 100))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('KRAS', 'Gene', (45, 49))
711585	28807841	Mutations in the driver genes EPHA6 and FLCN were found exclusively in Black CRCs, suggesting a unique behavior modifying role for these CRCs.	('EPHA6', 'Gene', (30, 35))	('FLCN', 'Gene', '201163', (40, 44))	('EPHA6', 'Gene', '285220', (30, 35))	('Mutations', 'Var', (0, 9))	('FLCN', 'Gene', (40, 44))
711586	28807841	Another study identified novel somatic alterations in well-known CRC genes (APC, BRAF, KRAS, and PIK3CA) among Blacks.	('KRAS', 'Gene', (87, 91))	('PIK3CA', 'Gene', (97, 103))	('KRAS', 'Gene', '3845', (87, 91))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('alterations', 'Var', (39, 50))	('CRC genes', 'Gene', (65, 74))	('APC', 'Disease', 'MESH:D011125', (76, 79))	('APC', 'Disease', (76, 79))	('PIK3CA', 'Gene', '5290', (97, 103))
711587	28807841	Microsatellite instability (MSI), a good prognostic biomarker caused by the hypermethylation of the DNA mismatch repair gene MLH1, shows a lower frequency among Blacks, although a meta-analysis did not reach statistical significance to show a difference.	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('MSI', 'Disease', 'None', (28, 31))	('hypermethylation', 'Var', (76, 92))	('Microsatellite instability', 'Disease', (0, 26))	('MSI', 'Disease', (28, 31))	('caused by', 'Reg', (62, 71))	('MLH1', 'Gene', '4292', (125, 129))	('MLH1', 'Gene', (125, 129))
711590	28807841	Somatic epigenetic differences have not been adequately studied between races; insulin and TGFbeta pathway genes (GAS7, BMP3, GPR75) were observed epigenetically inactivated among Blacks, but without comparison with their NHW counterparts.	('GAS7', 'Gene', (114, 118))	('GPR75', 'Gene', '10936', (126, 131))	('BMP3', 'Gene', (120, 124))	('epigenetically', 'Var', (147, 161))	('insulin', 'Gene', (79, 86))	('BMP3', 'Gene', '651', (120, 124))	('insulin', 'Gene', '3630', (79, 86))	('GPR75', 'Gene', (126, 131))	('GAS7', 'Gene', '8522', (114, 118))
711617	28807841	Variants for NAFLD risk exist in single nucleotide polymorphisms in or near PNPLA3 and PPP1R3B genes in Hispanic Americans and PNPLA3, NCAN, GCKR, and PPP1R3B genes in Blacks.	('PNPLA3', 'Gene', (76, 82))	('GCKR', 'Gene', (141, 145))	('Variants', 'Var', (0, 8))	('PNPLA3', 'Gene', '80339', (127, 133))	('NCAN', 'Gene', (135, 139))	('PPP1R3B', 'Gene', '79660', (87, 94))	('PNPLA3', 'Gene', '80339', (76, 82))	('PPP1R3B', 'Gene', '79660', (151, 158))	('NAFLD', 'Gene', (13, 18))	('PPP1R3B', 'Gene', (151, 158))	('GCKR', 'Gene', '2646', (141, 145))	('NCAN', 'Gene', '1463', (135, 139))	('PPP1R3B', 'Gene', (87, 94))	('PNPLA3', 'Gene', (127, 133))
711649	28074552	Validation of microRNA pathway polymorphisms in esophageal adenocarcinoma survival Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (48, 73))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (221, 246))	('cancer', 'Disease', (167, 173))	('miR', 'Gene', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('esophageal adenocarcinoma', 'Disease', (48, 73))	('esophageal adenocarcinoma', 'Disease', (221, 246))	('associated', 'Reg', (151, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('polymorphisms', 'Var', (31, 44))	('miR', 'Gene', '220972', (110, 113))	('microRNA', 'Gene', (14, 22))	('miR', 'Gene', '220972', (100, 103))	('Polymorphisms', 'Var', (83, 96))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (48, 73))	('miR', 'Gene', (110, 113))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (221, 246))
711650	28074552	Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (152, 177))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (59, 84))	('esophageal adenocarcinoma', 'Disease', (152, 177))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (152, 177))	('patients', 'Species', '9606', (178, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('polymorphisms', 'Var', (42, 55))	('esophageal adenocarcinoma', 'Disease', (59, 84))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (59, 84))
711655	28074552	GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04-1.80]; P = 0.02), hsa-mir-124-1 rs531564 (aHR = 0.60, 95% CI: [0.53-0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28-0.96]; P = 0.04) were found associated with OS.	('GEMIN3', 'Gene', '11218', (0, 6))	('associated', 'Reg', (206, 216))	('hsa-mir-124-1', 'Gene', '406907', (60, 73))	('rs531564', 'Var', (74, 82))	('KIAA0423', 'Gene', (132, 140))	('rs531564', 'Mutation', 'rs531564', (74, 82))	('hsa-mir-124-1', 'Gene', (60, 73))	('GEMIN3', 'Gene', (0, 6))	('rs1053667', 'Mutation', 'rs1053667', (141, 150))	('OS', 'Chemical', '-', (222, 224))	('KIAA0423', 'Gene', '23116', (132, 140))	('rs197412', 'Var', (7, 15))	('rs197412', 'Mutation', 'rs197412', (7, 15))
711656	28074552	Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03-1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01-1.64]; P = 0.04) were found associated with PFS.	('GEMIN3', 'Gene', '11218', (13, 19))	('rs3660', 'Var', (83, 89))	('KRT81', 'Gene', '3887', (77, 82))	('associated', 'Reg', (145, 155))	('GEMIN3', 'Gene', (13, 19))	('rs197412', 'Var', (20, 28))	('rs197412', 'Mutation', 'rs197412', (20, 28))	('KRT81', 'Gene', (77, 82))	('PFS', 'Disease', (161, 164))	('rs3660', 'Mutation', 'rs3660', (83, 89))
711657	28074552	Although none of these polymorphisms were significant in the second cohort, hsa-mir-124-1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa-mir-124-1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS.	('rs531564', 'Var', (229, 237))	('rs1053667', 'Mutation', 'rs1053667', (112, 121))	('hsa-mir-124-1', 'Gene', (76, 89))	('GEMIN3', 'Gene', '11218', (198, 204))	('KIAA0423', 'Gene', '23116', (243, 251))	('hsa-mir-124-1', 'Gene', '406907', (215, 228))	('rs531564', 'Mutation', 'rs531564', (90, 98))	('KIAA0423', 'Gene', (103, 111))	('rs197412', 'Mutation', 'rs197412', (205, 213))	('OS', 'Chemical', '-', (301, 303))	('rs197412', 'Var', (205, 213))	('rs1053667', 'Mutation', 'rs1053667', (252, 261))	('GEMIN3', 'Gene', (198, 204))	('rs531564', 'Mutation', 'rs531564', (229, 237))	('associated with', 'Reg', (285, 300))	('hsa-mir-124-1', 'Gene', '406907', (76, 89))	('hsa-mir-124-1', 'Gene', (215, 228))	('KIAA0423', 'Gene', (243, 251))	('KIAA0423', 'Gene', '23116', (103, 111))
711658	28074552	We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort.	('polymorphisms', 'Var', (57, 70))	('esophageal adenocarcinoma', 'Disease', (76, 101))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('patients', 'Species', '9606', (137, 145))	('association', 'Interaction', (19, 30))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (76, 101))
711668	28074552	Although rare, single-nucleotide polymorphisms (SNPs) in miRNA and miRNA-processing pathway genes, which may alter the expression, transcription, and processing of miRNA have also been linked with cancer-related risk and outcomes in a variety of tumor subtypes including esophageal adenocarcinoma risk 5.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('miR', 'Gene', (164, 167))	('single-nucleotide polymorphisms', 'Var', (15, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('linked with', 'Reg', (185, 196))	('miR', 'Gene', (67, 70))	('expression', 'MPA', (119, 129))	('miR', 'Gene', '220972', (57, 60))	('processing', 'MPA', (150, 160))	('cancer', 'Disease', (197, 203))	('transcription', 'MPA', (131, 144))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (271, 296))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', (246, 251))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (271, 296))	('miR', 'Gene', (57, 60))	('miR', 'Gene', '220972', (164, 167))	('alter', 'Reg', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('esophageal adenocarcinoma', 'Disease', (271, 296))	('miR', 'Gene', '220972', (67, 70))
711672	28074552	Our aims of the study are: (1) to identify miRNA and miRNA pathways polymorphisms associated with cancer risk that can serve as prognostic markers of esophageal adenocarcinoma; and (2) to evaluate any previously identified polymorphic prognostic relationships in cancer in a cohort of esophageal adenocarcinoma patients.	('miR', 'Gene', '220972', (53, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (285, 310))	('associated', 'Reg', (82, 92))	('cancer', 'Disease', (263, 269))	('polymorphisms', 'Var', (68, 81))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (150, 175))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('esophageal adenocarcinoma', 'Disease', (285, 310))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (150, 175))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('miR', 'Gene', (53, 56))	('miR', 'Gene', '220972', (43, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('esophageal adenocarcinoma', 'Disease', (150, 175))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('miR', 'Gene', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('patients', 'Species', '9606', (311, 319))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (285, 310))
711675	28074552	Two separate cohorts of patients:(1) a discovery cohort and (2) a validation cohort:were created for this study from a molecular epidemiology study evaluating the association between germline SNPs, esophageal cancer risk, and prognosis.	('germline SNPs', 'Var', (183, 196))	('esophageal cancer', 'Disease', (198, 215))	('patients', 'Species', '9606', (24, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (198, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
711690	28074552	We specifically selected variants that had been assessed in types of esophageal cancer, and further included other variants where there was a putative association with cancer incidence and survival of any cancer type.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('variants', 'Var', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('variants', 'Var', (115, 123))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
711710	28074552	Two SNPs (GOLGA7 rs11337, MIR30C1 rs16827546) were excluded due to MAF <5%, two SNPs (USP9X rs10463, hsa-let-7f-2 rs17276588) were excluded as they are located on the X chromosome where time-to-event methodologic approaches have not been developed to take into account X inactivation, and five SNPs (DGCR8 rs3757, DROSHA rs10719, hsa-mir-100 rs1834306, hsa-mir-219-1 rs213210, hsa-mir-26a-1 rs7372209) were excluded for not being in Hardy-Weinberg Equilibrium (P < 0.05).	('DGCR8', 'Gene', '54487', (300, 305))	('rs10719', 'Mutation', 'rs10719', (321, 328))	('rs7372209', 'Mutation', 'rs7372209', (391, 400))	('DROSHA', 'Gene', '29102', (314, 320))	('rs1834306', 'Mutation', 'rs1834306', (342, 351))	('USP9X', 'Gene', '8239', (86, 91))	('DROSHA', 'Gene', (314, 320))	('let-7f-2', 'Gene', '406889', (105, 113))	('rs11337', 'Mutation', 'rs11337', (17, 24))	('rs10463', 'Mutation', 'rs10463', (92, 99))	('rs16827546', 'Mutation', 'rs16827546', (34, 44))	('rs16827546', 'Var', (34, 44))	('USP9X', 'Gene', (86, 91))	('GOLGA7', 'Gene', '51125', (10, 16))	('mir-26a-1', 'Gene', '407015', (381, 390))	('mir-26a-1', 'Gene', (381, 390))	('MAF', 'Gene', (67, 70))	('rs3757', 'Var', (306, 312))	('rs1834306', 'Var', (342, 351))	('mir-100', 'Gene', '406892', (334, 341))	('GOLGA7', 'Gene', (10, 16))	('rs17276588', 'Mutation', 'rs17276588', (114, 124))	('mir-100', 'Gene', (334, 341))	('rs213210', 'Mutation', 'rs213210', (367, 375))	('MIR30C1', 'Gene', (26, 33))	('mir-219-1', 'Gene', (357, 366))	('MIR30C1', 'Gene', '407031', (26, 33))	('MAF', 'Gene', '4094', (67, 70))	('rs3757', 'Mutation', 'rs3757', (306, 312))	('rs213210', 'Var', (367, 375))	('mir-219-1', 'Gene', '407002', (357, 366))	('let-7f-2', 'Gene', (105, 113))	('DGCR8', 'Gene', (300, 305))
711714	28074552	Univariable analysis identified five polymorphisms that were significantly associated with OS, namely biogenesis pathway gene polymorphisms GEMIN3 rs197412 and GEMIN4 rs3744741, miRNA target gene polymorphisms CD86 rs17281995 and KIAA0423 rs1053667, and pre-miRNA polymorphism hsa-mir-492 rs2289030.	('miR', 'Gene', '220972', (178, 181))	('rs2289030', 'Var', (289, 298))	('rs17281995', 'Var', (215, 225))	('rs3744741', 'Mutation', 'rs3744741', (167, 176))	('miR', 'Gene', '220972', (258, 261))	('biogenesis pathway gene', 'Gene', (102, 125))	('KIAA0423', 'Gene', (230, 238))	('mir-492', 'Gene', (281, 288))	('miR', 'Gene', (178, 181))	('miR', 'Gene', (258, 261))	('rs1053667', 'Var', (239, 248))	('GEMIN3', 'Gene', '11218', (140, 146))	('mir-492', 'Gene', '574449', (281, 288))	('GEMIN4', 'Gene', (160, 166))	('rs2289030', 'Mutation', 'rs2289030', (289, 298))	('rs197412', 'Mutation', 'rs197412', (147, 155))	('associated', 'Reg', (75, 85))	('rs3744741', 'Var', (167, 176))	('GEMIN3', 'Gene', (140, 146))	('CD86', 'Gene', '942', (210, 214))	('KIAA0423', 'Gene', '23116', (230, 238))	('CD86', 'Gene', (210, 214))	('rs197412', 'Var', (147, 155))	('OS', 'Chemical', '-', (91, 93))	('GEMIN4', 'Gene', '50628', (160, 166))	('rs17281995', 'Mutation', 'rs17281995', (215, 225))	('rs1053667', 'Mutation', 'rs1053667', (239, 248))
711715	28074552	In multivariable analysis, GEMIN3 rs197412 and KIAA0423 rs1053667 remained significantly associated with OS (aHR = 1.37, 95% CI: (1.04-1.80); P = 0.02 and aHR = 0.51, 95% CI: (0.28-0.96); P = 0.04, respectively).	('associated', 'Reg', (89, 99))	('GEMIN3', 'Gene', '11218', (27, 33))	('KIAA0423', 'Gene', '23116', (47, 55))	('rs1053667', 'Var', (56, 65))	('rs197412', 'Var', (34, 42))	('GEMIN3', 'Gene', (27, 33))	('rs1053667', 'Mutation', 'rs1053667', (56, 65))	('OS', 'Chemical', '-', (105, 107))	('rs197412', 'Mutation', 'rs197412', (34, 42))	('KIAA0423', 'Gene', (47, 55))
711716	28074552	In addition, one pri-miRNA polymorphisms was found to be significantly associated with OS in multivariable analysis that was originally not found associated with OS in univariable analysis:hsa-mir-124-1 rs531564 (aHR = 0.60, 95% CI: (0.37-0.99); P = 0.05).	('hsa-mir-124-1', 'Gene', (189, 202))	('hsa-mir-124-1', 'Gene', '406907', (189, 202))	('OS', 'Chemical', '-', (162, 164))	('OS', 'Chemical', '-', (87, 89))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('rs531564', 'Var', (203, 211))	('rs531564', 'Mutation', 'rs531564', (203, 211))	('associated', 'Reg', (71, 81))
711717	28074552	GEMIN3 rs197412 was found also to be associated with PFS in both univariable analysis and multivariable analysis (aHR = 1.33, 95% CI: (1.03-1.74); P = 0.03).	('GEMIN3', 'Gene', '11218', (0, 6))	('PFS', 'Disease', (53, 56))	('GEMIN3', 'Gene', (0, 6))	('associated', 'Reg', (37, 47))	('rs197412', 'Var', (7, 15))	('rs197412', 'Mutation', 'rs197412', (7, 15))
711718	28074552	One additional polymorphism was also significantly associated with PFS in multivariable analysis, but not in univariable analysis: KRT81 rs3660 (aHR = 1.29, 95% CI: (1.01-1.64); P = 0.04).	('KRT81', 'Gene', '3887', (131, 136))	('KRT81', 'Gene', (131, 136))	('PFS', 'Disease', (67, 70))	('rs3660', 'Mutation', 'rs3660', (137, 143))	('associated', 'Reg', (51, 61))	('rs3660', 'Var', (137, 143))
711719	28074552	KRT81 rs3660 was significantly associated with PFS, but showed opposite directionality (aHR = 0.62, 95% CI: (0.42-0.91); P = 0.02).	('rs3660', 'Var', (6, 12))	('associated', 'Reg', (31, 41))	('KRT81', 'Gene', '3887', (0, 5))	('PFS', 'Disease', (47, 50))	('rs3660', 'Mutation', 'rs3660', (6, 12))	('KRT81', 'Gene', (0, 5))
711720	28074552	The strongest identified nonsignificant trend that was consistent in directionality was hsa-mir-124-1 rs531564 with OS (aHR = 0.72, 95% CI: (0.47-1.11); P = 0.13) (Table 3).	('rs531564', 'Var', (102, 110))	('hsa-mir-124-1', 'Gene', (88, 101))	('rs531564', 'Mutation', 'rs531564', (102, 110))	('OS', 'Chemical', '-', (116, 118))	('hsa-mir-124-1', 'Gene', '406907', (88, 101))
711721	28074552	Upon combining both the discovery and validation cohorts, hsa-mir-124-1 rs531564 (aHR = 0.72, 95% CI: (0.52-0.99); P = 0.05) remained significantly associated with OS using the discovery cohort model (Table 4).	('rs531564', 'Mutation', 'rs531564', (72, 80))	('hsa-mir-124-1', 'Gene', (58, 71))	('hsa-mir-124-1', 'Gene', '406907', (58, 71))	('associated with', 'Reg', (148, 163))	('OS', 'Chemical', '-', (164, 166))	('rs531564', 'Var', (72, 80))
711722	28074552	The Kaplan-Meier curves for hsa-mir-124-1 rs531564 in the discovery, validation, and combined cohorts can be found in Figure 1.	('hsa-mir-124-1', 'Gene', (28, 41))	('rs531564', 'Var', (42, 50))	('hsa-mir-124-1', 'Gene', '406907', (28, 41))	('rs531564', 'Mutation', 'rs531564', (42, 50))
711723	28074552	In addition, KIAA0423 rs1053667 was found significantly associated with OS in both the discovery cohort (aHR = 0.56, 95% CI: (0.32-0.97); P = 0.04) and sensitivity analysis model (aHR = 0.64, 95% CI: (0.41-0.99); P = 0.04) (Table 4, Table S4).	('OS', 'Chemical', '-', (72, 74))	('rs1053667', 'Mutation', 'rs1053667', (22, 31))	('KIAA0423', 'Gene', '23116', (13, 21))	('associated', 'Reg', (56, 66))	('KIAA0423', 'Gene', (13, 21))	('rs1053667', 'Var', (22, 31))
711724	28074552	GEMIN3 rs197412 was only found significantly associated with OS (aHR = 1.26, 95% CI: (1.03-1.55); P = 0.02) in the sensitivity analysis model (Table 4, Table S4).	('GEMIN3', 'Gene', '11218', (0, 6))	('associated', 'Reg', (45, 55))	('GEMIN3', 'Gene', (0, 6))	('OS', 'Chemical', '-', (61, 63))	('rs197412', 'Var', (7, 15))	('rs197412', 'Mutation', 'rs197412', (7, 15))
711725	28074552	As an exploratory analysis, we evaluated the combined effects of our two most consistently associated SNPs with overall survival (hsa-mir-124-1 rs531564 and KIAA0423 rs1053667) in our combined patient (discovery and validation) cohort.	('KIAA0423', 'Gene', '23116', (157, 165))	('rs531564', 'Mutation', 'rs531564', (144, 152))	('rs531564', 'Var', (144, 152))	('rs1053667', 'Mutation', 'rs1053667', (166, 175))	('hsa-mir-124-1', 'Gene', (130, 143))	('patient', 'Species', '9606', (193, 200))	('hsa-mir-124-1', 'Gene', '406907', (130, 143))	('overall', 'MPA', (112, 119))	('KIAA0423', 'Gene', (157, 165))
711727	28074552	Patients carrying at least one variant allele were found to have reduced risk of OS (aHR = 0.59, 95% CI: (0.42-0.83); P = 0.002) and reduced risk of PFS (aHR1 = 0.71, 95% CI: (0.51-0.99); P = 0.043).	('reduced', 'NegReg', (65, 72))	('PFS', 'Disease', (149, 152))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (81, 83))	('reduced', 'NegReg', (133, 140))	('variant', 'Var', (31, 38))
711729	28074552	Given the diversity of pathways that are regulated by miRNA, polymorphisms in both miRNA and miRNA-processing pathway genes may help to identify potential new targets for esophageal adenocarcinoma treatment.	('polymorphisms', 'Var', (61, 74))	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('esophageal adenocarcinoma', 'Disease', (171, 196))	('miR', 'Gene', '220972', (83, 86))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (171, 196))	('miR', 'Gene', (83, 86))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (171, 196))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (93, 96))	('help', 'Reg', (128, 132))
711730	28074552	Here, by evaluating SNPs in miRNA and miRNA pathway genes previously associated with risk of development of cancer in esophageal adenocarcinoma prognosis, we have identified hsa-mir-124-1 rs531564 as a relatively consistent predictor of overall survival whereby each variant allele contributed to a 30-40% decrease in mortality.	('esophageal adenocarcinoma', 'Disease', (118, 143))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (118, 143))	('mortality', 'MPA', (318, 327))	('associated', 'Reg', (69, 79))	('rs531564', 'Var', (188, 196))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (118, 143))	('rs531564', 'Mutation', 'rs531564', (188, 196))	('miR', 'Gene', '220972', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('miR', 'Gene', (38, 41))	('miR', 'Gene', '220972', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('miR', 'Gene', (28, 31))	('decrease', 'NegReg', (306, 314))	('hsa-mir-124-1', 'Gene', '406907', (174, 187))	('hsa-mir-124-1', 'Gene', (174, 187))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
711731	28074552	Two additional polymorphisms were identified that may potentially be associated with OS in esophageal adenocarcinoma; namely KIAA0423 rs1053667 and GEMIN3 rs197412.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('OS', 'Chemical', '-', (85, 87))	('rs1053667', 'Mutation', 'rs1053667', (134, 143))	('GEMIN3', 'Gene', '11218', (148, 154))	('associated', 'Reg', (69, 79))	('KIAA0423', 'Gene', (125, 133))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (91, 116))	('esophageal adenocarcinoma', 'Disease', (91, 116))	('KIAA0423', 'Gene', '23116', (125, 133))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (91, 116))	('rs197412', 'Var', (155, 163))	('rs197412', 'Mutation', 'rs197412', (155, 163))	('GEMIN3', 'Gene', (148, 154))	('rs1053667', 'Var', (134, 143))
711733	28074552	This is the first study known to date, evaluating the potential for polymorphisms in miRNA pathways as prognostic markers in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (125, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('miR', 'Gene', '220972', (85, 88))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (125, 150))	('miR', 'Gene', (85, 88))	('polymorphisms', 'Var', (68, 81))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (125, 150))
711734	28074552	Pri-mRNA hsa-mir-124-1 rs531564 is a SNP that has previously been found associated with risk of development of cervical, colorectal, and esophageal squamous cell cancers 28, 29.	('esophageal squamous cell cancers', 'Disease', (137, 169))	('rs531564', 'Var', (23, 31))	('associated with', 'Reg', (72, 87))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (148, 169))	('hsa-mir-124-1', 'Gene', (9, 22))	('cervical', 'Disease', (111, 119))	('hsa-mir-124-1', 'Gene', '406907', (9, 22))	('rs531564', 'Mutation', 'rs531564', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal', 'Disease', (121, 131))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('esophageal squamous cell cancers', 'Disease', 'MESH:D002294', (137, 169))
711735	28074552	Bioinformatics analyses have suggested that rs531564 may modulate the secondary structure of hsa-mir124-1 and alter the efficiency of the processing of pri-miRNA-124-1, which can explain the association of different expression levels of mature miRNA-124 with different alleles of this polymorphism 30.	('processing', 'MPA', (138, 148))	('rs531564', 'Var', (44, 52))	('secondary structure', 'MPA', (70, 89))	('hsa-mir124-1', 'Gene', (93, 105))	('modulate', 'Reg', (57, 65))	('rs531564', 'Mutation', 'rs531564', (44, 52))	('miR', 'Gene', '220972', (244, 247))	('miR', 'Gene', (244, 247))	('hsa-mir124-1', 'Gene', '406907', (93, 105))	('alter', 'Reg', (110, 115))	('efficiency', 'MPA', (120, 130))	('miR', 'Gene', '220972', (156, 159))	('miR', 'Gene', (156, 159))
711737	28074552	In noncancer studies, mi-RNA 124 has been suggested to have an immune modulatory role, as it has been found associated with experimental autoimmune encephalomyelitis (EAE), inflammatory bowel disease and hence may modulate the microenvironment by playing an immunosuppressive role to enhance tumorigenesis 36, 37, 38.	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Disease', (292, 297))	('modulate', 'Reg', (214, 222))	('autoimmune encephalomyelitis', 'Disease', (137, 165))	('autoimmune encephalomyelitis', 'Disease', 'MESH:D004681', (137, 165))	('mi-RNA 124', 'Var', (22, 32))	('associated', 'Reg', (108, 118))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (173, 199))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (173, 199))	('cancer', 'Disease', (6, 12))	('enhance', 'PosReg', (284, 291))	('inflammatory bowel disease', 'Disease', (173, 199))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
711739	28074552	Since the previously demonstrated effects of miRNA-124 appears to be potentially pro-tumorigenic in the tumor microenvironment but inhibitory to tumorigenesis in the cancer cell, further studies on the functional effects of the rs531564 in esophageal adenocarcinoma are necessary.	('tumor', 'Disease', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('miR', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('rs531564', 'Var', (228, 236))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (240, 265))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (240, 265))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('rs531564', 'Mutation', 'rs531564', (228, 236))	('miR', 'Gene', '220972', (45, 48))	('esophageal adenocarcinoma', 'Disease', (240, 265))
711742	28074552	Among cancer studies, KIAA0423 rs1053667, a 3' UTR polymorphism was found not associated with risk or OS in non-Hodgkin's lymphoma or hepatocellular carcinoma and also not associated with prognosis in multiple myeloma patients undergoing autologous stem cell transplant 19, 42, 43, 44, 45.	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (134, 158))	('KIAA0423', 'Gene', '23116', (22, 30))	('multiple myeloma', 'Phenotype', 'HP:0006775', (201, 217))	('rs1053667', 'Mutation', 'rs1053667', (31, 40))	('hepatocellular carcinoma', 'Disease', (134, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('patients', 'Species', '9606', (218, 226))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (108, 130))	('multiple myeloma', 'Disease', 'MESH:D009101', (201, 217))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (112, 130))	('KIAA0423', 'Gene', (22, 30))	("non-Hodgkin's lymphoma", 'Disease', (108, 130))	('cancer', 'Disease', (6, 12))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (108, 130))	('OS', 'Chemical', '-', (102, 104))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('rs1053667', 'Var', (31, 40))	('multiple myeloma', 'Disease', (201, 217))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (134, 158))
711743	28074552	In addition, in a study evaluating SNP regulation of miRNA expression and colon cancer risk, rs1053667 was found associated with differential expression of its targeting miRNA, hsa-miR-19b-3p in nontumor colonic tissues, but when comparing tumor versus nontumor tissue, the miRNA showed differential expression while rs1053667 was found not associated with risk of colon cancer 46.	('miR', 'Gene', '220972', (53, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (74, 86))	('miR', 'Gene', '220972', (274, 277))	('colon cancer', 'Disease', (365, 377))	('miR', 'Gene', (181, 184))	('rs1053667', 'Mutation', 'rs1053667', (317, 326))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('miR', 'Gene', '220972', (170, 173))	('miR', 'Gene', (53, 56))	('tumor', 'Disease', (240, 245))	('miR', 'Gene', (274, 277))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colon cancer', 'Disease', 'MESH:D015179', (74, 86))	('rs1053667', 'Mutation', 'rs1053667', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', (256, 261))	('miR', 'Gene', (170, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (365, 377))	('colon cancer', 'Disease', (74, 86))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Disease', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('colon cancer', 'Disease', 'MESH:D015179', (365, 377))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('rs1053667', 'Var', (93, 102))	('miR', 'Gene', '220972', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('associated', 'Reg', (113, 123))
711745	28074552	GEMIN3 rs197412 was also found consistently associated with OS in both the discovery and combined cohorts.	('associated', 'Reg', (44, 54))	('GEMIN3', 'Gene', '11218', (0, 6))	('GEMIN3', 'Gene', (0, 6))	('rs197412', 'Var', (7, 15))	('OS', 'Chemical', '-', (60, 62))	('rs197412', 'Mutation', 'rs197412', (7, 15))
711746	28074552	GEMIN3 rs197412 was previously found to be associated with recurrence-free survival in bladder cancer and overall survival in non-Hodgkin's lymphoma 47, 48.	('rs197412', 'Var', (7, 15))	('GEMIN3', 'Gene', '11218', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (126, 148))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (126, 148))	("non-Hodgkin's lymphoma", 'Disease', (126, 148))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('recurrence-free survival', 'CPA', (59, 83))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (130, 148))	('lymphoma', 'Phenotype', 'HP:0002665', (140, 148))	('GEMIN3', 'Gene', (0, 6))	('associated', 'Reg', (43, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('bladder cancer', 'Disease', (87, 101))	('rs197412', 'Mutation', 'rs197412', (7, 15))
711747	28074552	GEMIN3 rs197412 was not associated with outcome in hepatocellular carcinoma and studies in colorectal cancer have yielded inconclusive results 49, 50, 51, 52.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('colorectal cancer', 'Disease', (91, 108))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (51, 75))	('GEMIN3', 'Gene', '11218', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('hepatocellular carcinoma', 'Disease', (51, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('GEMIN3', 'Gene', (0, 6))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('rs197412', 'Var', (7, 15))	('rs197412', 'Mutation', 'rs197412', (7, 15))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (51, 75))
711751	28074552	Polymorphisms in miRNA can potentially modulate miRNA-mRNA interaction and potentially create or destroy miRNA binding sites; while those in processing genes can influence the miRNA transcript either through altering transcription, processing, or maturation 5.	('miR', 'Gene', (105, 108))	('miR', 'Gene', '220972', (17, 20))	('transcription', 'MPA', (217, 230))	('destroy', 'NegReg', (97, 104))	('miR', 'Gene', (17, 20))	('Polymorphisms', 'Var', (0, 13))	('modulate', 'Reg', (39, 47))	('miR', 'Gene', '220972', (48, 51))	('influence', 'Reg', (162, 171))	('miR', 'Gene', (48, 51))	('altering', 'Reg', (208, 216))	('miR', 'Gene', '220972', (176, 179))	('miR', 'Gene', (176, 179))	('miR', 'Gene', '220972', (105, 108))
711758	28074552	In summary, this is the first study to evaluate the prognostic effects of miRNA pathways polymorphisms in a cohort of esophageal adenocarcinoma patients.	('miR', 'Gene', (74, 77))	('esophageal adenocarcinoma', 'Disease', (118, 143))	('miR', 'Gene', '220972', (74, 77))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (118, 143))	('polymorphisms', 'Var', (89, 102))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (118, 143))	('patients', 'Species', '9606', (144, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))
711759	28074552	We have identified multiple polymorphisms in miRNA pathway genes that were found associated with esophageal adenocarcinoma prognosis which was not validated in an independent cohort of esophageal adenocarcinoma patients but was found to have consistent relationships when both cohorts were combined.	('esophageal adenocarcinoma', 'Disease', (97, 122))	('patients', 'Species', '9606', (211, 219))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (97, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('polymorphisms', 'Var', (28, 41))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (185, 210))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (185, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('esophageal adenocarcinoma', 'Disease', (185, 210))	('associated', 'Reg', (81, 91))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (97, 122))
711760	28074552	They were namely: hsa-mir-124-1 rs531564, KIAA0423 rs1053667, and GEMIN3 rs197412.	('rs531564', 'Var', (32, 40))	('KIAA0423', 'Gene', (42, 50))	('hsa-mir-124-1', 'Gene', (18, 31))	('rs531564', 'Mutation', 'rs531564', (32, 40))	('hsa-mir-124-1', 'Gene', '406907', (18, 31))	('GEMIN3', 'Gene', '11218', (66, 72))	('rs1053667', 'Var', (51, 60))	('KIAA0423', 'Gene', '23116', (42, 50))	('rs1053667', 'Mutation', 'rs1053667', (51, 60))	('GEMIN3', 'Gene', (66, 72))	('rs197412', 'Var', (73, 81))	('rs197412', 'Mutation', 'rs197412', (73, 81))
711781	16483364	If this hypothesis is correct, H. pylori eradication should worsen the condition.	('eradication', 'Var', (41, 52))	('H. pylori', 'Species', '210', (31, 40))	('H. pylori', 'Disease', (31, 40))
711782	16483364	However to add more confusion to this scenario, two recent studies have shown that H. pylori eradication does not influence relapse rates in GERD and it may be even beneficial on symptomatic relapse in mild GERD.	('H. pylori', 'Gene', (83, 92))	('symptomatic relapse', 'MPA', (179, 198))	('H. pylori', 'Species', '210', (83, 92))	('confusion', 'Phenotype', 'HP:0001289', (20, 29))	('GERD', 'Disease', (141, 145))	('eradication', 'Var', (93, 104))	('GERD', 'Disease', 'MESH:D005764', (141, 145))	('GERD', 'Disease', (207, 211))	('GERD', 'Disease', 'MESH:D005764', (207, 211))	('beneficial', 'PosReg', (165, 175))
711841	16483364	Moreover, the presence of H. pylori is also likely to increase the efficacy of PPIs and conversely, the eradication of the bacteria decreases the drug effect.	('H. pylori', 'Species', '210', (26, 35))	('presence', 'Var', (14, 22))	('PPIs', 'Disease', (79, 83))	('efficacy', 'MPA', (67, 75))	('drug effect', 'MPA', (146, 157))	('increase', 'PosReg', (54, 62))	('H. pylori', 'Var', (26, 35))	('decreases', 'NegReg', (132, 141))
711859	16483364	Although we did not perform endoscopic procedures in this population, it must be outlined that there is a high predictive value of the presence of GERD when heartburn is the dominant or exclusive symptom.	('GERD', 'Disease', (147, 151))	('GERD', 'Disease', 'MESH:D005764', (147, 151))	('presence', 'Var', (135, 143))	('heartburn', 'Phenotype', 'HP:0002020', (157, 166))	('heartburn', 'Disease', (157, 166))
711870	16483364	Alcohol can decrease LES pressure and in moderate amounts impairs the normal acid clearance in supine position.	('normal acid clearance in supine position', 'MPA', (70, 110))	('Alcohol', 'Var', (0, 7))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('impairs', 'NegReg', (58, 65))	('LES pressure', 'MPA', (21, 33))	('decrease', 'NegReg', (12, 20))
711905	33688489	On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.	('venous tumor thrombus', 'Disease', 'MESH:D013927', (90, 111))	('lymphopenia', 'Phenotype', 'HP:0001888', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('venous tumor thrombus', 'Disease', (90, 111))	('venous tumor', 'Phenotype', 'HP:0012721', (90, 102))	('increased', 'PosReg', (174, 183))	('Grade 3', 'Var', (31, 38))	('death', 'Disease', 'MESH:D003643', (240, 245))	('lymphopenia', 'Disease', 'MESH:D008231', (49, 60))	('death', 'Disease', (240, 245))	('higher', 'PosReg', (42, 48))	('portal venous tumor thrombus', 'Phenotype', 'HP:0030242', (83, 111))	('CP score', 'MPA', (184, 192))	('Child', 'Species', '9606', (145, 150))	('venous tumor thrombus', 'Phenotype', 'HP:0004936', (90, 111))	('increased CP', 'Phenotype', 'HP:0003236', (174, 186))	('lymphopenia', 'Disease', (49, 60))
711907	33688489	Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.	('lymphopenia', 'Disease', 'MESH:D008231', (21, 32))	('lymphopenia', 'Phenotype', 'HP:0001888', (21, 32))	('Protons', 'Var', (0, 7))	('mitigate', 'NegReg', (12, 20))	('lymphopenia', 'Disease', (21, 32))	('lymphopoiesis', 'Disease', (109, 122))	('lymphopoiesis', 'Disease', 'None', (109, 122))
711922	33688489	For each patient, body dose-volume indices Vx (the volume receiving a dose of X or higher, eg, V1Gy, V5Gy, V10Gy) were extracted from treatment planning software.	('V5Gy', 'Var', (101, 105))	('V1Gy', 'Var', (95, 99))	('patient', 'Species', '9606', (9, 16))	('V10Gy', 'Var', (107, 112))
711932	33688489	The mean pre-treatment Child-Pugh score was 5.8 (range, 5-9) for patients receiving photon RT and 5.8 (range, 5-8) for those receiving proton RT.	('patients', 'Species', '9606', (65, 73))	('photon RT', 'Var', (84, 93))	('Child', 'Species', '9606', (23, 28))	('Child-Pugh score', 'Disease', (23, 39))
711948	33688489	Factors on univariable analysis significantly associated with worse overall survival (Table 2) included the presence of portal venous tumor thrombus, increasing pre-RT Child-Pugh score, pre-RT ALC <= 0.5, post-RT ALC <= 0.5, G3 or higher lymphopenia during treatment, use of IMRT/VMAT, increasing volume of planning target volume (PTV), and increase in Child-Pugh score after RT.	('lymphopenia', 'Disease', (238, 249))	('portal venous tumor thrombus', 'Phenotype', 'HP:0030242', (120, 148))	('venous tumor thrombus', 'Disease', 'MESH:D013927', (127, 148))	('increase', 'PosReg', (341, 349))	('Child', 'Species', '9606', (168, 173))	('venous tumor thrombus', 'Phenotype', 'HP:0004936', (127, 148))	('increasing', 'PosReg', (150, 160))	('Child', 'Species', '9606', (353, 358))	('lymphopenia', 'Phenotype', 'HP:0001888', (238, 249))	('Child-Pugh score', 'MPA', (353, 369))	('lymphopenia', 'Disease', 'MESH:D008231', (238, 249))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('increasing', 'PosReg', (286, 296))	('venous tumor', 'Phenotype', 'HP:0012721', (127, 139))	('pre-RT', 'Var', (186, 192))	('venous tumor thrombus', 'Disease', (127, 148))
711951	33688489	Patients with pre-RT ALC <= 0.5 had significantly shorter OS (median 7 vs 20 months, p=0.03) and DFS (median 7 vs 28 months) but not DMFS (11 vs 30 months, p=0.71).	('ALC <= 0.5', 'Var', (21, 31))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (50, 57))	('DFS', 'CPA', (97, 100))
711964	33688489	A combined cohort of various newly diagnosed solid tumors demonstrated that high-grade lymphopenia was associated with an increased risk of death in all pathology types studied (hazard ratio [HR] 2.1, 95% CI, 1.54-2.78; p<0.0001).	('lymphopenia', 'Disease', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('high-grade', 'Var', (76, 86))	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('lymphopenia', 'Phenotype', 'HP:0001888', (87, 98))	('lymphopenia', 'Disease', 'MESH:D008231', (87, 98))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
711974	33688489	An esophageal cancer study found that 40.4% of patients treated with photons developed grade 4 lymphopenia compared to 17.6% in the proton group (p<0.0001).	('cancer', 'Disease', (14, 20))	('patients', 'Species', '9606', (47, 55))	('lymphopenia', 'Disease', (95, 106))	('photons', 'Var', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lymphopenia', 'Phenotype', 'HP:0001888', (95, 106))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('lymphopenia', 'Disease', 'MESH:D008231', (95, 106))
711975	33688489	Similarly, a propensity-matched cohort analysis conducted at the Mayo Clinic found that photon RT was associated with higher rates of G4 lymphopenia than proton RT in patients with esophageal cancer (56% vs 22%; p<0.01).	('lymphopenia', 'Disease', 'MESH:D008231', (137, 148))	('Mayo', 'Species', '162683', (65, 69))	('patients', 'Species', '9606', (167, 175))	('lymphopenia', 'Disease', (137, 148))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('photon RT', 'Var', (88, 97))	('lymphopenia', 'Phenotype', 'HP:0001888', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
711976	33688489	Additionally, a propensity-matched analysis of 144 patients treated with proton RT or photon RT for esophageal cancer demonstrated that photon RT resulted in higher rates of high-grade lymphopenia as compared to proton RT (56% vs 22%; p < 0.01).	('lymphopenia', 'Phenotype', 'HP:0001888', (185, 196))	('lymphopenia', 'Disease', 'MESH:D008231', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('lymphopenia', 'Disease', (185, 196))	('photon RT', 'Var', (136, 145))
711981	33688489	Similarly, an analysis of Phase I/II lung cancer trials showed that SBRT was associated with an attenuated decrease in ALC in patients receiving combined immunotherapy with RT.	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('SBRT', 'Var', (68, 72))	('ALC', 'MPA', (119, 122))	('II lung cancer', 'Disease', (34, 48))	('patients', 'Species', '9606', (126, 134))	('decrease', 'NegReg', (107, 115))	('II lung cancer', 'Disease', 'MESH:D008175', (34, 48))
712003	33488710	Conversely, knockdown of survivin increases Bad mRNA and protein expression and induces cell cycle arrest and apoptosis.	('survivin', 'Gene', (25, 33))	('knockdown', 'Var', (12, 21))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (88, 105))	('arrest', 'Disease', 'MESH:D006323', (99, 105))	('apoptosis', 'CPA', (110, 119))	('arrest', 'Disease', (99, 105))	('induces', 'Reg', (80, 87))	('increases', 'PosReg', (34, 43))
712020	33488710	Phosphorylation of Bad at Ser112, Ser136, and Ser155 inhibits its proapoptotic activity in response to growth and survival signal.	('Ser155', 'Var', (46, 52))	('Ser136', 'Chemical', '-', (34, 40))	('Ser155', 'Chemical', '-', (46, 52))	('Ser112', 'Chemical', '-', (26, 32))	('Phosphorylation', 'MPA', (0, 15))	('Ser136', 'Var', (34, 40))	('proapoptotic activity', 'MPA', (66, 87))	('inhibits', 'NegReg', (53, 61))	('Ser112', 'Var', (26, 32))
712032	33488710	The resulting PCR products were inserted into the GV142 vector between HindIII and XhoI sites, yielding GV142-survivin overexpression and GV142-control plasmids.	('GV142', 'Chemical', '-', (50, 55))	('GV142', 'Chemical', '-', (138, 143))	('overexpression', 'PosReg', (119, 133))	('GV142-survivin', 'Var', (104, 118))	('GV142', 'Chemical', '-', (104, 109))
712038	33488710	Groups in survivin knockdown are the KD group, NC group, and BC group.	('knockdown', 'Var', (19, 28))	('survivin', 'Protein', (10, 18))	('KD', 'Disease', 'MESH:C537017', (37, 39))
712076	33488710	These results suggested that survivin knockdown induces cell cycle arrest and apoptosis in esophageal carcinoma cell.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (91, 111))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('apoptosis', 'CPA', (78, 87))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('survivin', 'Protein', (29, 37))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (91, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('esophageal carcinoma', 'Disease', (91, 111))	('arrest', 'Disease', (67, 73))	('knockdown', 'Var', (38, 47))
712085	33488710	Cytometry showed that survivin overexpression promotes transformation of cell cycle to S phase and knockdown induces cell cycle arrest and apoptosis.	('arrest', 'Disease', 'MESH:D006323', (128, 134))	('transformation', 'CPA', (55, 69))	('arrest', 'Disease', (128, 134))	('knockdown', 'Var', (99, 108))	('cell cycle', 'CPA', (73, 83))	('survivin', 'Protein', (22, 30))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (117, 134))	('overexpression', 'PosReg', (31, 45))	('apoptosis', 'CPA', (139, 148))	('induces', 'Reg', (109, 116))
712087	33488710	Survivin overexpression promotes transformation of cell cycle to S phase, and knockdown induces cell cycle arrest and apoptosis.	('apoptosis', 'CPA', (118, 127))	('arrest', 'Disease', 'MESH:D006323', (107, 113))	('induces', 'Reg', (88, 95))	('arrest', 'Disease', (107, 113))	('knockdown', 'Var', (78, 87))	('transformation', 'CPA', (33, 47))	('cell cycle', 'CPA', (51, 61))	('Survivin', 'Protein', (0, 8))	('overexpression promotes', 'PosReg', (9, 32))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))
712096	31426805	The mean number of lymph nodes removed was significantly higher in the EOX group (EOX 29 +- 15.5 vs. CROSS 22 +- 8.8; p < 0.05).	('OS', 'Chemical', '-', (103, 105))	('EOX', 'Var', (71, 74))	('higher', 'PosReg', (57, 63))
712155	31426805	OS was significantly better in the EOX group (p < 0.000) (Fig.	('EOX', 'Var', (35, 38))	('OS', 'Chemical', '-', (0, 2))	('better', 'PosReg', (21, 27))
712160	31426805	A significant difference was found in pCR rate in patients who underwent radiochemotherapy compared to perioperative chemotherapy (12 vs. 5 patients, 23% vs. 10% respectively, p = 0.000).	('pCR', 'Disease', (38, 41))	('patients', 'Species', '9606', (140, 148))	('patients', 'Species', '9606', (50, 58))	('radiochemotherapy', 'Var', (73, 90))
712221	30909623	Furthermore, the anatomical abnormalities in the structure of the lower esophageal sphincter or its dysfunction can result in more frequent or sometimes prolonged exposure of the esophageal mucosa to gastric acid, resulting in esophageal damage due to reflux esophagitis.	('anatomical', 'Var', (17, 27))	('abnormalities', 'Var', (28, 41))	('reflux esophagitis', 'Disease', 'MESH:D005764', (252, 270))	('esophageal damage', 'Disease', 'MESH:D004935', (227, 244))	('reflux esophagitis', 'Disease', (252, 270))	('result in', 'Reg', (116, 125))	('esophageal sphincter', 'Disease', (72, 92))	('due to reflux esophagitis', 'Phenotype', 'HP:0002020', (245, 270))	('esophageal sphincter', 'Disease', 'MESH:D009122', (72, 92))	('esophagitis', 'Phenotype', 'HP:0100633', (259, 270))	('esophageal damage', 'Disease', (227, 244))	('exposure', 'MPA', (163, 171))
712231	30909623	Curcumin was equally potent as SN-50 (an NF-kappaB inhibitor), chelerythrine (a PKC inhibitor), and PD-098059 (a p44/42 MAPK inhibitor), yet all of them efficiently abolished the acid-induced mucosal expression of IL-6 and IL-8.	('abolished', 'NegReg', (165, 174))	('Curcumin', 'Chemical', 'MESH:D003474', (0, 8))	('IL-8', 'Gene', '3576', (223, 227))	('NF-kappaB', 'Gene', '4790', (41, 50))	('PKC', 'Gene', '5578;5581', (80, 83))	('PKC', 'Gene', (80, 83))	('acid-induced mucosal expression', 'MPA', (179, 210))	('IL-8', 'Gene', (223, 227))	('NF-kappaB', 'Gene', (41, 50))	('PD-098059', 'Var', (100, 109))	('chelerythrine', 'Chemical', 'MESH:C016299', (63, 76))	('PD-098059', 'Chemical', 'MESH:C093973', (100, 109))	('SN-50', 'Chemical', '-', (31, 36))
712261	30909623	It is well-known that the ingestion of NSAIDs is associated with the risk of GI adverse effects including gastric micro bleeding, damage to the epithelial structure, cessation of GI blood flow, decline in gastric mucus and alkaline secretion, and alteration in GI motility.	('GI motility', 'Disease', (261, 272))	('GI motility', 'Disease', 'MESH:D015835', (261, 272))	('cessation', 'NegReg', (166, 175))	('ingestion', 'Var', (26, 35))	('bleeding', 'Disease', 'MESH:D006470', (120, 128))	('decline', 'NegReg', (194, 201))	('bleeding', 'Disease', (120, 128))	('rat', 'Species', '10116', (251, 254))	('alteration', 'Reg', (247, 257))
712281	30909623	In addition, the suppression of MMP-2 activity by H2O2 in a dose- and time-dependent manner in vitro was blocked by antioxidants including curcumin.	('curcumin', 'Chemical', 'MESH:D003474', (139, 147))	('MMP-2', 'Gene', '4313', (32, 37))	('H2O2', 'Chemical', 'MESH:D006861', (50, 54))	('H2O2', 'Var', (50, 54))	('suppression', 'NegReg', (17, 28))	('MMP-2', 'Gene', (32, 37))
712298	30909623	This observation was in keeping with the earlier study by Mathattanadul et al., who have also indicated that both curcumin and bisdemethoxycurcumin can inhibit the basal gastric acid secretion in pylorus-ligated rat model and that this antisecretory effect can contribute to an acceleration of the healing of chronic gastric ulcerations of the mucosa.	('inhibit', 'NegReg', (152, 159))	('gastric ulcerations', 'Disease', 'MESH:D013276', (317, 336))	('curcumin', 'Chemical', 'MESH:D003474', (139, 147))	('rat', 'Species', '10116', (284, 287))	('acceleration', 'PosReg', (278, 290))	('healing', 'CPA', (298, 305))	('basal gastric acid secretion', 'MPA', (164, 192))	('gastric ulcerations', 'Disease', (317, 336))	('bisdemethoxycurcumin', 'Chemical', 'MESH:C034786', (127, 147))	('rat', 'Species', '10116', (329, 332))	('gastric ulcer', 'Phenotype', 'HP:0002592', (317, 330))	('rat', 'Species', '10116', (212, 215))	('curcumin', 'Chemical', 'MESH:D003474', (114, 122))	('bisdemethoxycurcumin', 'Var', (127, 147))
712336	30909623	The functional ablation of sensory afferent nerves with capsaicin or pretreatment with capsazepine blunted the curcumin-induced decrease in the lesion index and the increase in GBF evoked by cold stress.	('increase', 'PosReg', (165, 173))	('GBF', 'Gene', (177, 180))	('curcumin-induced', 'MPA', (111, 127))	('capsaicin', 'Chemical', 'MESH:D002211', (56, 65))	('ablation', 'Var', (15, 23))	('blunted', 'NegReg', (99, 106))	('GBF', 'Gene', '1316', (177, 180))	('lesion index', 'MPA', (144, 156))	('capsazepine', 'Chemical', 'MESH:C071423', (87, 98))	('decrease', 'NegReg', (128, 136))	('curcumin', 'Chemical', 'MESH:D003474', (111, 119))
712359	30909623	They concluded that demethoxycurcumin and bisdemethoxycurcumin showed more pronounced spasmolytic effects in guinea pig ileum as well as vasodilation and negative inotropic activity in guinea pig arteries and atria, respectively, than those exhibited by a parent curcumin.	('guinea pig', 'Species', '10141', (109, 119))	('guinea pig', 'Species', '10141', (185, 195))	('negative', 'NegReg', (154, 162))	('bisdemethoxycurcumin', 'Var', (42, 62))	('demethoxycurcumin', 'Chemical', 'MESH:C050229', (45, 62))	('curcumin', 'Chemical', 'MESH:D003474', (29, 37))	('demethoxycurcumin', 'Var', (20, 37))	('curcumin', 'Chemical', 'MESH:D003474', (54, 62))	('curcumin', 'Chemical', 'MESH:D003474', (263, 271))	('vasodilation', 'CPA', (137, 149))	('bisdemethoxycurcumin', 'Chemical', 'MESH:C034786', (42, 62))	('spasmolytic effects', 'MPA', (86, 105))	('demethoxycurcumin', 'Chemical', 'MESH:C050229', (20, 37))
712361	30909623	Thus, future studies are required to prove if the enrichment of extracts of C. longa with curcumin metabolites demethoxycurcumin and bisdemethoxycurcumin could potently enhance the therapeutic efficacy of curcumin.	('curcumin', 'Chemical', 'MESH:D003474', (145, 153))	('bisdemethoxycurcumin', 'Chemical', 'MESH:C034786', (133, 153))	('therapeutic efficacy', 'CPA', (181, 201))	('demethoxycurcumin', 'Chemical', 'MESH:C050229', (111, 128))	('curcumin', 'Chemical', 'MESH:D003474', (120, 128))	('enhance', 'PosReg', (169, 176))	('demethoxycurcumin', 'Var', (111, 128))	('bisdemethoxycurcumin', 'Var', (133, 153))	('C. longa', 'Species', '136217', (76, 84))	('demethoxycurcumin', 'Chemical', 'MESH:C050229', (136, 153))	('curcumin', 'Chemical', 'MESH:D003474', (90, 98))	('curcumin', 'Chemical', 'MESH:D003474', (205, 213))
712375	27696537	We report for the first time, loss of Beclin-1, a key mediator of autophagy, was significantly linked to prognostic factors in EAC.	('Beclin-1', 'Protein', (38, 46))	('EAC', 'Phenotype', 'HP:0011459', (127, 130))	('EAC', 'Gene', '1540', (127, 130))	('linked', 'Reg', (95, 101))	('loss', 'Var', (30, 34))	('EAC', 'Gene', (127, 130))
712379	27696537	C-PAC induced Beclin-1-independent autophagy in EAC cells characterized by reduced phosphorylation at serine 15 and 93, and significant cell death induction.	('cell death', 'CPA', (136, 146))	('serine', 'Chemical', 'MESH:D012694', (102, 108))	('EAC', 'Gene', (48, 51))	('phosphorylation', 'CPA', (83, 98))	('reduced', 'NegReg', (75, 82))	('C-PAC', 'Var', (0, 5))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('EAC', 'Phenotype', 'HP:0011459', (48, 51))	('Beclin-1-independent', 'Protein', (14, 34))	('EAC', 'Gene', '1540', (48, 51))
712402	27696537	C-PAC induced autophagy in EAC cells, but surprisingly was accompanied by slight reductions in total Beclin-1 levels and larger magnitude reductions in phospho-specific forms, raising the question of Beclin-1 independent autophagy induction.	('autophagy', 'CPA', (14, 23))	('reductions', 'NegReg', (138, 148))	('reductions', 'NegReg', (81, 91))	('phospho-specific forms', 'MPA', (152, 174))	('C-PAC', 'Var', (0, 5))	('Beclin-1 levels', 'MPA', (101, 116))	('EAC', 'Phenotype', 'HP:0011459', (27, 30))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('EAC', 'Gene', '1540', (27, 30))	('EAC', 'Gene', (27, 30))
712407	27696537	Specifically, TMAs BS02051, ES208, and ES804 were purchased from US Biomax, Inc. (Rockville, MD).	('ES804', 'Var', (39, 44))	('ES208', 'Var', (28, 33))	('TMAs', 'Chemical', '-', (14, 18))
712420	27696537	C-PAC contains three types of linkages, two common B-type linkages (C4 C6 and C4 C8) and at least one unique A-type ether linkage (C2 O C7) found in cranberry, chokeberry, plums, and avocado.	('C4 C8', 'Var', (78, 83))	('C4 C6', 'Var', (68, 73))	('avocado', 'Species', '3435', (183, 190))	('plums', 'Species', '3758', (172, 177))	('C-PAC', 'Chemical', '-', (0, 5))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))
712432	27696537	Immunoblotting was performed using commercially available antibodies from Cell Signaling: Beclin-1 (#3738; 1:750), LC3AB (#4108; 1:1000), Rab7 (#9367; 1:1000), phospho-Beclin-1 at Ser15 (#13825; 1:750), and Ser93 (#14717; 1:750).	('Rab7', 'Gene', (138, 142))	('#3738; 1:750', 'Var', (100, 112))	('#9367; 1:1000', 'Var', (144, 157))	('Rab7', 'Gene', '338382', (138, 142))	('#13825; 1:750', 'Var', (187, 200))	('#4108; 1:1000', 'Var', (122, 135))	('LC3', 'Gene', '84557', (115, 118))	('Ser15', 'Chemical', '-', (180, 185))	('#14717;', 'Var', (214, 221))	('Ser93', 'Chemical', '-', (207, 212))	('LC3', 'Gene', (115, 118))
712433	27696537	Phospho-Beclin-1 antibodies at Ser234 (#p117-234; 1:250) and Ser295 (#p117-295; 1:250) were from Phospho-Solutions (Aurora, CO).	('Ser295', 'Chemical', '-', (61, 67))	('#p117-295; 1:250', 'Var', (69, 85))	('Ser234', 'Chemical', '-', (31, 37))	('#p117-234;', 'Var', (39, 49))
712453	27696537	Furthermore, OE19 cells are resistant to caspase-dependent cell death and we have found OE19 cells more readily form tumor xenografts in nude mice, supporting they are phenotypically aggressive compared to OE33 and JHAD1 cells.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('nude mice', 'Species', '10090', (137, 146))	('JHAD1', 'Chemical', '-', (215, 220))	('OE19', 'Var', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
712465	27696537	In addition, we recently published results showing that C-PAC induces autophagic vacuole formation early (6 h) followed by increased formation of degradative autophagic vacuoles (24 h), a late event, in esophageal adenocarcinoma JHAD1 cells as measured by transmission electron microscopy.	('PAC', 'Phenotype', 'HP:0006699', (58, 61))	('increased', 'PosReg', (123, 132))	('autophagic vacuole', 'Phenotype', 'HP:0003736', (70, 88))	('JHAD1', 'Chemical', '-', (229, 234))	('autophagic vacuole', 'Phenotype', 'HP:0003736', (158, 176))	('autophagic vacuoles', 'Phenotype', 'HP:0003736', (158, 177))	('induces', 'Reg', (62, 69))	('autophagic vacuole formation', 'CPA', (70, 98))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (203, 228))	('C-PAC', 'Var', (56, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('esophageal adenocarcinoma', 'Disease', (203, 228))	('C-PAC', 'Chemical', '-', (56, 61))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (203, 228))
712466	27696537	Next, siRNA was utilized to knockdown Beclin-1 in EAC cells, followed by a 48 h treatment with C-PAC or rapamycin to further investigate the role of Beclin-1 alterations in relation to LC3 expression.	('rapamycin', 'Chemical', 'MESH:D020123', (104, 113))	('LC3', 'Gene', '84557', (185, 188))	('Beclin-1', 'Gene', (38, 46))	('LC3', 'Gene', (185, 188))	('EAC', 'Gene', '1540', (50, 53))	('PAC', 'Phenotype', 'HP:0006699', (97, 100))	('EAC', 'Gene', (50, 53))	('C-PAC', 'Chemical', '-', (95, 100))	('knockdown', 'Var', (28, 37))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))
712467	27696537	Beclin-1 knockdown efficiency was 84% and 72% in JHAD1 and OE19 cells, respectively based on densitometry.	('Beclin-1', 'Gene', (0, 8))	('JHAD1', 'Chemical', '-', (49, 54))	('knockdown', 'Var', (9, 18))
712470	27696537	Conversely, rapamycin treatment of JHAD1 cells increased Beclin-1 levels (1.4-fold) and with Beclin-1 knockdown levels of LC3-I and LC3-II remained in nearly equal proportions (48.5% vs. 51.5%, respectively).	('JHAD1', 'Chemical', '-', (35, 40))	('rapamycin', 'Chemical', 'MESH:D020123', (12, 21))	('LC3', 'Gene', (122, 125))	('knockdown', 'Var', (102, 111))	('Beclin-1 levels', 'MPA', (57, 72))	('LC3', 'Gene', '84557', (132, 135))	('increased', 'PosReg', (47, 56))	('LC3', 'Gene', (132, 135))	('LC3', 'Gene', '84557', (122, 125))
712471	27696537	C-PAC treatment of OE19 cells with Beclin-1 knockdown resulted in LC3-II levels which increased in magnitude (1.9% or 55.9% vs. 2.1% or 55.2%) following C-PAC treatment, although interestingly, the proportion of LC3-1 to LC3-II remained unchanged in OE19 cells compared to JHAD1 cells.	('LC3', 'Gene', '84557', (212, 215))	('LC3', 'Gene', (212, 215))	('increased', 'PosReg', (86, 95))	('LC3', 'Gene', '84557', (66, 69))	('C-PAC', 'Chemical', '-', (153, 158))	('LC3', 'Gene', (66, 69))	('JHAD1', 'Chemical', '-', (273, 278))	('Beclin-1', 'Gene', (35, 43))	('PAC', 'Phenotype', 'HP:0006699', (155, 158))	('LC3', 'Gene', '84557', (221, 224))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('knockdown', 'Var', (44, 53))	('LC3', 'Gene', (221, 224))
712473	27696537	Results support that C-PAC induces an alternative autophagic pathway which is not dependent on Beclin-1 as a molecular regulator.	('autophagic pathway', 'CPA', (50, 68))	('induces', 'Reg', (27, 34))	('C-PAC', 'Var', (21, 26))	('C-PAC', 'Chemical', '-', (21, 26))	('PAC', 'Phenotype', 'HP:0006699', (23, 26))
712477	27696537	Furthermore, these data show for the first time that C-PAC induces autophagy without inducing Beclin-1 or increasing phosphorylation specific forms of Beclin-1 in EAC cells.	('C-PAC', 'Var', (53, 58))	('EAC', 'Gene', '1540', (163, 166))	('C-PAC', 'Chemical', '-', (53, 58))	('EAC', 'Gene', (163, 166))	('induces', 'Reg', (59, 66))	('PAC', 'Phenotype', 'HP:0006699', (55, 58))	('autophagy', 'CPA', (67, 76))	('EAC', 'Phenotype', 'HP:0011459', (163, 166))
712483	27696537	In parallel, levels of Beclin-1 phosphorylated at Ser15 increased 1.5-fold in OE19 cells following rapamycin treatment, but significantly decreased in JHAD1 cells (P <0.031; 24 h and 48 h), potentially due to cell line specific sensitivity to rapamycin induced mitigation of AMPK and ULK signaling pathways.	('increased', 'PosReg', (56, 65))	('rapamycin', 'Var', (99, 108))	('decreased', 'NegReg', (138, 147))	('Beclin-1', 'MPA', (23, 31))	('rapamycin', 'Chemical', 'MESH:D020123', (243, 252))	('rapamycin', 'Chemical', 'MESH:D020123', (99, 108))	('AMPK', 'Gene', '5562', (275, 279))	('AMPK', 'Gene', (275, 279))	('levels', 'MPA', (13, 19))	('Ser15', 'Chemical', '-', (50, 55))	('JHAD1', 'Chemical', '-', (151, 156))
712486	27696537	Cell line specific effects were also noted for Ser234 and Ser295, whose phosphorylation has been linked to autophagy inhibition and tumorigenesis.	('Ser295', 'Var', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Ser295', 'Chemical', '-', (58, 64))	('Ser234', 'Var', (47, 53))	('tumor', 'Disease', (132, 137))	('Ser234', 'Chemical', '-', (47, 53))	('autophagy inhibition', 'CPA', (107, 127))
712487	27696537	Levels of Ser234 and Ser295, important for AKT-mediated autophagy, increased in OE19 cells; whereas, Ser234 decreased in JHAD1 cells and Ser295 was not detectable supporting constitutive loss.	('Ser234', 'Var', (10, 16))	('JHAD1', 'Chemical', '-', (121, 126))	('Ser234', 'Chemical', '-', (10, 16))	('Ser295', 'Var', (21, 27))	('AKT', 'Gene', '207', (43, 46))	('Ser295', 'Chemical', '-', (21, 27))	('Ser295', 'Chemical', '-', (137, 143))	('Ser234', 'Chemical', '-', (101, 107))	('increased', 'PosReg', (67, 76))	('AKT', 'Gene', (43, 46))
712493	27696537	Finally, only OE19 cells constitutively express phosphorylated Beclin-1 at Ser295, likely linked to differential AKT activation and levels decreased post-treatment.	('Ser295', 'Chemical', '-', (75, 81))	('levels', 'MPA', (132, 138))	('AKT', 'Gene', '207', (113, 116))	('Beclin-1', 'Gene', (63, 71))	('decreased', 'NegReg', (139, 148))	('AKT', 'Gene', (113, 116))	('Ser295', 'Var', (75, 81))	('activation', 'PosReg', (117, 127))
712499	27696537	The lowest concentration of rapamycin resulted in the greatest reduction in viability of JHAD1 (13%, P <0.001) and OE19 (9%, P <0.02) cells at 48 h. Moreover, when JHAD1 cells treated for 48 h were replenished with fresh media and followed for an additional 72 h to evaluate cell fate (Figure 4A and C), all rapamycin treated JHAD1 cells exhibited significantly increased viability compared to vehicle treated cells (P <0.009).	('JHAD1', 'Chemical', '-', (326, 331))	('rapamycin', 'Chemical', 'MESH:D020123', (308, 317))	('increased', 'PosReg', (362, 371))	('viability', 'CPA', (372, 381))	('JHAD1', 'Chemical', '-', (89, 94))	('rapamycin treated', 'Var', (308, 325))	('JHAD1', 'Chemical', '-', (164, 169))	('rapamycin', 'Chemical', 'MESH:D020123', (28, 37))
712501	27696537	Conversely, C-PAC treated (48 h) EAC cells replenished with media continued to die in large numbers when assessed for viability 72 h later and effects were in a dose responsive manner, supporting that C-PAC alterations in autophagic machinery is linked to EAC cell death; whereas, rapamycin induced alterations in autophagic markers supports cancer cell survival, particularly in JHAD1 cells.	('alterations', 'Reg', (299, 310))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('EAC', 'Phenotype', 'HP:0011459', (33, 36))	('PAC', 'Phenotype', 'HP:0006699', (203, 206))	('C-PAC', 'Chemical', '-', (201, 206))	('C-PAC', 'Chemical', '-', (12, 17))	('PAC', 'Phenotype', 'HP:0006699', (14, 17))	('cancer', 'Disease', (342, 348))	('EAC', 'Gene', '1540', (256, 259))	('EAC', 'Gene', '1540', (33, 36))	('alterations', 'Var', (207, 218))	('EAC', 'Gene', (33, 36))	('EAC', 'Gene', (256, 259))	('rapamycin', 'Chemical', 'MESH:D020123', (281, 290))	('autophagic machinery', 'CPA', (222, 242))	('JHAD1', 'Chemical', '-', (380, 385))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('EAC', 'Phenotype', 'HP:0011459', (256, 259))
712504	27696537	The images parallel the graphic data clearly illustrating that C-PAC [75 mug/ml] induced potent EAC cell death with little recovery of viability after the removal of C-PAC.	('EAC', 'Gene', (96, 99))	('PAC', 'Phenotype', 'HP:0006699', (168, 171))	('PAC', 'Phenotype', 'HP:0006699', (65, 68))	('EAC', 'Phenotype', 'HP:0011459', (96, 99))	('C-PAC [75', 'Var', (63, 72))	('C-PAC', 'Chemical', '-', (63, 68))	('EAC', 'Gene', '1540', (96, 99))	('C-PAC', 'Chemical', '-', (166, 171))
712509	27696537	In addition, we have treated Barrett's cells with C-PAC and noted greater resistance to cell death compared to EAC cells (data not shown) supporting that C-PAC is not highly toxic, but selectively induces cell death in premalignant and cancer cell lines.	('cell death', 'CPA', (205, 215))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('EAC', 'Gene', '1540', (111, 114))	('EAC', 'Gene', (111, 114))	('C-PAC', 'Var', (154, 159))	('cancer', 'Disease', (236, 242))	('C-PAC', 'Chemical', '-', (50, 55))	('C-PAC', 'Chemical', '-', (154, 159))	('PAC', 'Phenotype', 'HP:0006699', (52, 55))	('PAC', 'Phenotype', 'HP:0006699', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('induces', 'Reg', (197, 204))	('EAC', 'Phenotype', 'HP:0011459', (111, 114))
712513	27696537	Specifically, our results show that LC3 lipidation can be induced in the presence of Beclin-1 repression or knock down supporting potential alternative pathways of autophagy induction.	('induced', 'PosReg', (58, 65))	('knock down', 'Var', (108, 118))	('Beclin-1', 'Gene', (85, 93))	('LC3', 'Gene', '84557', (36, 39))	('LC3', 'Gene', (36, 39))
712516	29073155	Genetic variability in LMP2 and LMP7 is associated with the risk of esophageal squamous cell carcinoma in the Kazakh population but is not associated with HPV infection The Kazakh population in Xinjiang Province in northwestern China exhibits a high incidence of esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', (263, 297))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 102))	('LMP7', 'Gene', '5696', (32, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('Genetic variability', 'Var', (0, 19))	('LMP2', 'Gene', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('LMP2', 'Gene', '5698', (23, 27))	('HPV infection', 'Disease', 'MESH:D030361', (155, 168))	('esophageal squamous cell carcinoma', 'Disease', (68, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (263, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('LMP7', 'Gene', (32, 36))	('HPV infection', 'Disease', (155, 168))	('associated', 'Reg', (40, 50))
712520	29073155	Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect LMP2/LMP7 gene single-nucleotide polymorphisms (SNPs).	('LMP7', 'Gene', (116, 120))	('LMP7', 'Gene', '5696', (116, 120))	('LMP2', 'Gene', (111, 115))	('single-nucleotide polymorphisms', 'Var', (126, 157))	('LMP2', 'Gene', '5698', (111, 115))
712521	29073155	We found a clear increased risk of ESCC in the Kazakh population for the heterozygous LMP2 R/C genotype and the homozygous C/C genotype (OR = 1.470, 95%CI = 1.076-2.008, p = 0.015 forLMP2R/C; OR = 2.048, 95% CI = 1.168-3.591, p = 0.011 for LMP2 C/C).	('R/C', 'Var', (91, 94))	('LMP2', 'Gene', (240, 244))	('LMP2', 'Gene', (183, 187))	('LMP2', 'Gene', '5698', (240, 244))	('LMP2', 'Gene', '5698', (183, 187))	('LMP2', 'Gene', (86, 90))	('ESCC', 'Disease', (35, 39))	('LMP2', 'Gene', '5698', (86, 90))
712522	29073155	Conversely, the heterozygous LMP7 Q/K polymorphism was found to decrease the risk of ESCC in this population (OR = 0.421, 95% CI = 0.286-0.621, p = 8.83x10-6).	('LMP7', 'Gene', (29, 33))	('LMP7', 'Gene', '5696', (29, 33))	('Q/K polymorphism', 'Var', (34, 50))	('decrease', 'NegReg', (64, 72))	('ESCC', 'Disease', (85, 89))
712523	29073155	Moreover, LMP2 R/C+C/C genotype was associated with increased tumor invasion depth (p = 0.041).	('increased', 'PosReg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('R/C+C/C', 'Var', (15, 22))	('LMP2', 'Gene', (10, 14))	('tumor', 'Disease', (62, 67))	('LMP2', 'Gene', '5698', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
712524	29073155	Haplotype analysis showed that haplotype A, which includes wild-type homozygous LMP2/TAP1 and mutant LMP7, decreases susceptibility to ESCC in the Kazakh population; in contrast, haplotype E, which includes wild-type homozygous LMP2/LMP7/TAP1, acts as a risk factor for increased susceptibility to ESCC.	('LMP2', 'Gene', (228, 232))	('susceptibility', 'MPA', (117, 131))	('ESCC', 'Disease', (135, 139))	('LMP2', 'Gene', '5698', (228, 232))	('TAP1', 'Gene', (85, 89))	('TAP1', 'Gene', '6890', (85, 89))	('decreases', 'NegReg', (107, 116))	('ESCC', 'Disease', (298, 302))	('LMP7', 'Gene', (233, 237))	('haplotype', 'Var', (179, 188))	('mutant', 'Var', (94, 100))	('LMP7', 'Gene', '5696', (233, 237))	('TAP1', 'Gene', (238, 242))	('LMP7', 'Gene', (101, 105))	('LMP2', 'Gene', (80, 84))	('TAP1', 'Gene', '6890', (238, 242))	('LMP2', 'Gene', '5698', (80, 84))	('LMP7', 'Gene', '5696', (101, 105))
712525	29073155	This is the first study to report that the heterozygous LMP2 R/C and homozygous C/C genotypes increase susceptibility to ESCC in the Kazakh population and that the heterozygous LMP7 Q/K genotype decreases susceptibility to ESCC in this population.	('LMP7', 'Gene', (177, 181))	('susceptibility', 'MPA', (103, 117))	('C/C', 'Var', (80, 83))	('LMP7', 'Gene', '5696', (177, 181))	('increase', 'PosReg', (94, 102))	('ESCC', 'Disease', (223, 227))	('susceptibility', 'MPA', (205, 219))	('R/C', 'Var', (61, 64))	('LMP2', 'Gene', (56, 60))	('LMP2', 'Gene', '5698', (56, 60))	('ESCC', 'Disease', (121, 125))	('decreases', 'NegReg', (195, 204))
712527	29073155	Understanding LMP2/LMP7 genetic variability will provide a new therapeutic perspective for Kazakh patients with ESCC.	('LMP7', 'Gene', '5696', (19, 23))	('ESCC', 'Disease', (112, 116))	('patients', 'Species', '9606', (98, 106))	('LMP2', 'Gene', (14, 18))	('LMP2', 'Gene', '5698', (14, 18))	('genetic variability', 'Var', (24, 43))	('LMP7', 'Gene', (19, 23))
712531	29073155	Moreover, many genetic variations, especially polymorphisms, are prevalent in the Kazakh population, some of which are associated with an increased risk of cancer.	('genetic variations', 'Var', (15, 33))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('polymorphisms', 'Var', (46, 59))	('associated', 'Reg', (119, 129))
712537	29073155	A series of previous studies found that polymorphisms in LMP2 codon 60 (LMP2-60) (Arg-Cys) and LMP7 codon 145 (LMP7-145) (Gln-Lys) are responsible for functional evolution and thus reduce the ability of these molecules to function in antigen processing.	('function', 'MPA', (222, 230))	('LMP2', 'Gene', (57, 61))	('Gln-Lys', 'Var', (122, 129))	('polymorphisms', 'Var', (40, 53))	('ability', 'MPA', (192, 199))	('LMP2', 'Gene', '5698', (57, 61))	('antigen processing', 'MPA', (234, 252))	('LMP7', 'Gene', (95, 99))	('LMP7', 'Gene', '5696', (111, 115))	('Cys', 'Chemical', 'MESH:D003545', (86, 89))	('LMP7', 'Gene', '5696', (95, 99))	('reduce', 'NegReg', (181, 187))	('LMP7', 'Gene', (111, 115))	('Arg', 'Chemical', 'MESH:D001120', (82, 85))	('Lys', 'Chemical', 'MESH:D008239', (126, 129))	('LMP2', 'Gene', (72, 76))	('Gln', 'Chemical', 'MESH:D005973', (122, 125))	('LMP2', 'Gene', '5698', (72, 76))
712538	29073155	Accordingly, these genetic variants in LMP2/LMP7 have been linked to the occurrence, development, and prognosis of many diseases, including viral infection, autoimmune disease, and malignant tumors.	('LMP2', 'Gene', (39, 43))	('LMP7', 'Gene', (44, 48))	('viral infection', 'Disease', (140, 155))	('LMP2', 'Gene', '5698', (39, 43))	('LMP7', 'Gene', '5696', (44, 48))	('malignant tumors', 'Disease', (181, 197))	('autoimmune disease', 'Disease', (157, 175))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('malignant tumors', 'Disease', 'MESH:D018198', (181, 197))	('viral infection', 'Disease', 'MESH:D001102', (140, 155))	('linked to', 'Reg', (59, 68))	('autoimmune disease', 'Disease', 'MESH:D001327', (157, 175))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('autoimmune disease', 'Phenotype', 'HP:0002960', (157, 175))	('genetic variants', 'Var', (19, 35))
712539	29073155	Many studies to date have found that LMP2/LMP7 polymorphism affects susceptibility to numerous cancers.	('LMP2', 'Gene', (37, 41))	('affects', 'Reg', (60, 67))	('LMP2', 'Gene', '5698', (37, 41))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('LMP7', 'Gene', '5696', (42, 46))	('LMP7', 'Gene', (42, 46))	('numerous cancers', 'Disease', 'MESH:D009369', (86, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('polymorphism', 'Var', (47, 59))	('numerous cancers', 'Disease', (86, 102))	('susceptibility', 'MPA', (68, 82))
712540	29073155	For instance, the LMP7-145 gene polymorphism contributes to increased susceptibility to gastric cancer and ovarian cancer.	('increased susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (60, 102))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('polymorphism', 'Var', (32, 44))	('susceptibility', 'Reg', (70, 84))	('LMP7', 'Gene', (18, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (107, 121))	('LMP7', 'Gene', '5696', (18, 22))	('ovarian cancer', 'Disease', (107, 121))
712542	29073155	In contrast, no statistical correlation has yet been found between LMP2-60 polymorphic genotypes and the risk of ovarian or lung cancers.	('ovarian or lung cancers', 'Disease', (113, 136))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('LMP2', 'Gene', (67, 71))	('LMP2', 'Gene', '5698', (67, 71))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('polymorphic genotypes', 'Var', (75, 96))	('ovarian or lung cancers', 'Disease', 'MESH:D010051', (113, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (124, 136))
712543	29073155	However, the relationship between LMP2/LMP7 polymorphism and the risk of ESCC in the Kazakh population remains unclear.	('LMP7', 'Gene', (39, 43))	('LMP7', 'Gene', '5696', (39, 43))	('LMP2', 'Gene', (34, 38))	('LMP2', 'Gene', '5698', (34, 38))	('polymorphism', 'Var', (44, 56))	('ESCC', 'Disease', (73, 77))
712556	29073155	The wild-type genotype of the LMP2-60 polymorphism yielded bands of 79 and 251 bp, and the heterozygous genotype yielded bands of 79, 251 and 330 bp (S1 Fig).	('LMP2', 'Gene', '5698', (30, 34))	('polymorphism', 'Var', (38, 50))	('LMP2', 'Gene', (30, 34))
712566	29073155	The relationship between single-nucleotide polymorphisms (SNPs) in LMP2/LMP7 and the risk of ESCC was estimated by determining the odds ratios (ORs) at 95% confidence intervals (CIs) using logistic regression analyses for crude ORs and adjusted ORs when adjusting for age and sex.	('single-nucleotide polymorphisms', 'Var', (25, 56))	('LMP2', 'Gene', (67, 71))	('LMP2', 'Gene', '5698', (67, 71))	('LMP7', 'Gene', (72, 76))	('ESCC', 'Disease', (93, 97))	('LMP7', 'Gene', '5696', (72, 76))
712569	29073155	The genotype frequencies of LMP2/LMP7 gene polymorphisms are presented in Table 2.	('polymorphisms', 'Var', (43, 56))	('LMP7', 'Gene', '5696', (33, 37))	('LMP2', 'Gene', (28, 32))	('LMP2', 'Gene', '5698', (28, 32))	('LMP7', 'Gene', (33, 37))
712572	29073155	In contrast, the KK genotype was not associated with the risk of ESCC in the Kazakh population in the recessive model (QQ+QK versus KK (OR = 1.684, 95% CI = 0.675-4.201, p = 0.259), Table 2).	('QQ+', 'Chemical', '-', (119, 122))	('ESCC', 'Disease', (65, 69))	('QQ+QK', 'Var', (119, 124))
712573	29073155	We used the expression of quantitative trait loci (eQTL) data which have been reported (https://gtexportal.org/home/) to study the effects of SNP locus of LMP2/LMP7 gene on gene expression, the results showed that SNP locus of LMP2 in esophageal tissues affected the expression of LMP2 (p = 1.30x10-7, S3 Fig).	('LMP7', 'Gene', '5696', (160, 164))	('LMP2', 'Gene', (281, 285))	('LMP2', 'Gene', '5698', (281, 285))	('LMP2', 'Gene', (227, 231))	('affected', 'Reg', (254, 262))	('LMP2', 'Gene', '5698', (227, 231))	('SNP', 'Var', (214, 217))	('LMP2', 'Gene', (155, 159))	('LMP7', 'Gene', (160, 164))	('LMP2', 'Gene', '5698', (155, 159))	('expression', 'MPA', (267, 277))
712575	29073155	To evaluate the contribution of confounding factors, including gender /age/ smoking and drinking to the risk of ESCC in the Kazakh population, stratification analyses were performed to investigate the potential effect of genetic variants of LMP2/LMP7 with ESCC risk in population subgroups (Table 3 and Table 4).	('LMP7', 'Gene', (246, 250))	('ESCC', 'Disease', (256, 260))	('LMP7', 'Gene', '5696', (246, 250))	('ESCC', 'Disease', (112, 116))	('LMP2', 'Gene', (241, 245))	('LMP2', 'Gene', '5698', (241, 245))	('variants', 'Var', (229, 237))	('genetic variants', 'Var', (221, 237))
712576	29073155	This analysis showed that the LMP2-60 R/C and R/C+C/C genotypes were associated with an increased risk of ESCC in Kazakh patients aged >=57 years but not in those aged <57 years.	('R/C+C/C', 'Var', (46, 53))	('LMP2', 'Gene', (30, 34))	('LMP2', 'Gene', '5698', (30, 34))	('ESCC', 'Disease', (106, 110))	('patients', 'Species', '9606', (121, 129))
712577	29073155	In contrast, the LMP7-145 Q/K and QK+KK genotypes were associated with a decreased risk of ESCC in male patients aged >=57 years but not in male patients aged <57 years.	('patients', 'Species', '9606', (145, 153))	('decreased', 'NegReg', (73, 82))	('ESCC', 'Disease', (91, 95))	('LMP7', 'Gene', '5696', (17, 21))	('LMP7', 'Gene', (17, 21))	('QK+KK', 'Var', (34, 39))	('patients', 'Species', '9606', (104, 112))
712578	29073155	This analysis explained that the LMP2-60 R/C and R/C+C/C genotypes were associated with an increased risk of ESCC in Kazakh patients with smoking but not in those without smoking(p<0.05).	('LMP2', 'Gene', (33, 37))	('LMP2', 'Gene', '5698', (33, 37))	('ESCC', 'Disease', (109, 113))	('R/C+C/C', 'Var', (49, 56))	('patients', 'Species', '9606', (124, 132))
712579	29073155	Equally contrary, the LMP7-145 Q/K and QK+KK genotypes were associated with a decreased risk of ESCC with smoking people but not in those without smoking(p<0.05).	('LMP7', 'Gene', (22, 26))	('LMP7', 'Gene', '5696', (22, 26))	('QK+KK', 'Var', (39, 44))	('people', 'Species', '9606', (114, 120))	('ESCC', 'Disease', (96, 100))	('decreased', 'NegReg', (78, 87))
712580	29073155	Nevertheless, the result indicated that LMP7-145 Q/K and QK+KK genotypes were associated with a decreased risk of ESCC who don't drink but not in those with drinking(p<0.05).	('LMP7', 'Gene', (40, 44))	('ESCC', 'Disease', (114, 118))	('LMP7', 'Gene', '5696', (40, 44))	('decreased', 'NegReg', (96, 105))	('QK+KK', 'Var', (57, 62))
712581	29073155	When Kazakh ESCC patients were divided into two subgroups, T1/T2 and T3/T4, according to the AJCC TNM classification of EC, the RC+CC genotype was significantly associated with ESCC tumor depth (OR = 1.679, 95% CI = 1.023-2.756, p = 0.041).	('associated with', 'Reg', (161, 176))	('EC', 'Phenotype', 'HP:0011459', (120, 122))	('ESCC tumor depth', 'Disease', 'MESH:D004938', (177, 193))	('patients', 'Species', '9606', (17, 25))	('ESCC tumor depth', 'Disease', (177, 193))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('RC+CC', 'Var', (128, 133))
712582	29073155	However, there was no significant association between LMP2/LMP7 polymorphism and ESCC in the Kazakh population with respect to clinical pathological parameters (p>0.05).	('LMP2', 'Gene', '5698', (54, 58))	('LMP7', 'Gene', (59, 63))	('ESCC', 'Disease', (81, 85))	('LMP7', 'Gene', '5696', (59, 63))	('polymorphism', 'Var', (64, 76))	('LMP2', 'Gene', (54, 58))
712583	29073155	The association between TAP1 polymorphisms and ESCC in the Kazakh population was shown in a previous study (40).	('TAP1', 'Gene', '6890', (24, 28))	('polymorphisms', 'Var', (29, 42))	('ESCC', 'Disease', (47, 51))	('TAP1', 'Gene', (24, 28))
712584	29073155	Thus, haplotype analysis was performed to further evaluate the combined effects of LMP2/LMP7 and TAP1 polymorphisms on the risk of ESCC in this population.	('LMP7', 'Gene', (88, 92))	('LMP7', 'Gene', '5696', (88, 92))	('polymorphisms', 'Var', (102, 115))	('LMP2', 'Gene', (83, 87))	('TAP1', 'Gene', (97, 101))	('LMP2', 'Gene', '5698', (83, 87))	('TAP1', 'Gene', '6890', (97, 101))	('ESCC', 'Disease', (131, 135))
712586	29073155	The results showed that haplotype A, which includes wild-type homozygous LMP2/TAP1 and mutant LMP7, decreases susceptibility to ESCC in the Kazakh population (OR = 0.37, 95%CI = 0.23-0.59, p<0.001), whereas haplotype E, which includes wild-type homozygous LMP2/LMP7/TAP1, acts as a risk factor to increase susceptibility to ESCC in the Kazakh population (OR = 3.67, 95% CI = 1.85-7.28, p<0.001).	('ESCC', 'Disease', (324, 328))	('LMP7', 'Gene', '5696', (94, 98))	('LMP2', 'Gene', (256, 260))	('LMP2', 'Gene', '5698', (256, 260))	('susceptibility', 'MPA', (110, 124))	('decreases', 'NegReg', (100, 109))	('LMP2', 'Gene', (73, 77))	('mutant', 'Var', (87, 93))	('LMP2', 'Gene', '5698', (73, 77))	('LMP7', 'Gene', (261, 265))	('TAP1', 'Gene', '6890', (266, 270))	('ESCC', 'Disease', (128, 132))	('TAP1', 'Gene', (266, 270))	('LMP7', 'Gene', '5696', (261, 265))	('LMP7', 'Gene', (94, 98))	('TAP1', 'Gene', (78, 82))	('TAP1', 'Gene', '6890', (78, 82))
712587	29073155	The results of genotype frequency analysis for LMP2/LMP7 gene polymorphisms in HPV-positive and HPV-negative patients are summarized in Table 3 and Table 4.	('HPV', 'Species', '10566', (96, 99))	('LMP2', 'Gene', (47, 51))	('LMP2', 'Gene', '5698', (47, 51))	('HPV', 'Species', '10566', (79, 82))	('patients', 'Species', '9606', (109, 117))	('polymorphisms', 'Var', (62, 75))	('LMP7', 'Gene', (52, 56))	('LMP7', 'Gene', '5696', (52, 56))
712590	29073155	In our study, the association between LMP2 and LMP7 polymorphisms and the risk of ESCC in the Kazakh population was investigated.	('LMP7', 'Gene', (47, 51))	('ESCC', 'Disease', (82, 86))	('LMP7', 'Gene', '5696', (47, 51))	('LMP2', 'Gene', (38, 42))	('polymorphisms', 'Var', (52, 65))	('association', 'Interaction', (18, 29))	('LMP2', 'Gene', '5698', (38, 42))
712591	29073155	According to our results, heterozygous LMP2 R/C and homozygous LMP2 C/C genotypes are risk factors for ESCC in the Kazakh population.	('LMP2', 'Gene', (39, 43))	('LMP2', 'Gene', '5698', (39, 43))	('R/C', 'Var', (44, 47))	('C/C', 'Var', (68, 71))	('LMP2', 'Gene', (63, 67))	('LMP2', 'Gene', '5698', (63, 67))	('ESCC', 'Disease', (103, 107))	('risk factors', 'Reg', (86, 98))
712592	29073155	This finding differed from that of Xiang Ma and Bangwei Cao's, which revealed no statistical correlation between LMP2-60 polymorphism and ovarian and gastric cancers.	('LMP2', 'Gene', '5698', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('ovarian and gastric cancers', 'Disease', 'MESH:D013274', (138, 165))	('gastric cancers', 'Phenotype', 'HP:0012126', (150, 165))	('polymorphism', 'Var', (121, 133))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('LMP2', 'Gene', (113, 117))
712594	29073155	Nevertheless, in our study, the heterozygous LMP7 Q/K genotype was associated with significantly decreased risk of ESCC in the Kazakh population.	('ESCC', 'Disease', (115, 119))	('LMP7', 'Gene', (45, 49))	('Q/K', 'Var', (50, 53))	('LMP7', 'Gene', '5696', (45, 49))	('decreased', 'NegReg', (97, 106))
712596	29073155	The discrepancy between these results and our findings may be attributed to the fact that the same polymorphism may have diverse genetic effects on different types of cancer, ethnicities and races.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('polymorphism', 'Var', (99, 111))	('effects', 'Reg', (137, 144))
712597	29073155	When considered together, Kazakh patients possessing both the LMP2 R/C+C/C genotype and the wild-type homozygous LMP7 Q/Q genotype exhibited a higher risk of developing ESCC, further illustrating the existence of linkage disequilibrium in LMP polymorphisms.	('LMP7', 'Gene', (113, 117))	('ESCC', 'Disease', (169, 173))	('LMP', 'Chemical', '-', (113, 116))	('R/C+C/C', 'Var', (67, 74))	('patients', 'Species', '9606', (33, 41))	('LMP', 'Chemical', '-', (62, 65))	('LMP7', 'Gene', '5696', (113, 117))	('LMP2', 'Gene', (62, 66))	('LMP2', 'Gene', '5698', (62, 66))	('LMP', 'Chemical', '-', (239, 242))
712598	29073155	In subgroup analysis, the LMP2 R/C genotype was associated with increased tumor invasion depth in ESCC, suggesting that genetic variation in immune response genes may play a role in ESCC progression.	('LMP2', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('LMP2', 'Gene', '5698', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('play', 'Reg', (167, 171))	('ESCC', 'Disease', (98, 102))	('tumor', 'Disease', (74, 79))	('ESCC', 'Disease', (182, 186))	('increased', 'PosReg', (64, 73))	('R/C', 'Var', (31, 34))
712599	29073155	Additionally, no association between LMP7-145 polymorphism genotypes and ESCC clinicopathological characteristics of the Kazakh population was observed in our study.	('polymorphism', 'Var', (46, 58))	('ESCC', 'Disease', (73, 77))	('LMP7', 'Gene', '5696', (37, 41))	('LMP7', 'Gene', (37, 41))
712600	29073155	Song revealed that LMP7 polymorphism increases the risk of lymph node and tumor distant metastasis in ovarian cancer.	('metastasis in ovarian cancer', 'Disease', (88, 116))	('LMP7', 'Gene', '5696', (19, 23))	('metastasis in ovarian cancer', 'Disease', 'MESH:D009362', (88, 116))	('polymorphism', 'Var', (24, 36))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('increases', 'PosReg', (37, 46))	('tumor', 'Disease', (74, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))	('LMP7', 'Gene', (19, 23))
712601	29073155	The LMP2-60 C/C and R/C+C/C genotypes were associated with an increased risk of ESCC in Kazakh patients aged >=57 years but not in those aged <57 years.	('patients', 'Species', '9606', (95, 103))	('LMP2', 'Gene', (4, 8))	('LMP2', 'Gene', '5698', (4, 8))	('R/C+C/C', 'Var', (20, 27))	('ESCC', 'Disease', (80, 84))
712605	29073155	Nonetheless, the LMP7-145 Q/K and QK+KK genotypes were associated with a decreased risk of ESCC in male patients aged >=57 years but not in male patients aged <57 years.	('patients', 'Species', '9606', (145, 153))	('decreased', 'NegReg', (73, 82))	('ESCC', 'Disease', (91, 95))	('LMP7', 'Gene', '5696', (17, 21))	('LMP7', 'Gene', (17, 21))	('QK+KK', 'Var', (34, 39))	('patients', 'Species', '9606', (104, 112))
712606	29073155	Our previous studies found that TAP1 polymorphisms could increase susceptibility to ESCC in the Kazakh population.	('polymorphisms', 'Var', (37, 50))	('ESCC', 'Disease', (84, 88))	('susceptibility', 'MPA', (66, 80))	('increase', 'PosReg', (57, 65))	('TAP1', 'Gene', (32, 36))	('TAP1', 'Gene', '6890', (32, 36))
712608	29073155	In our study, eight haplotypes were constructed to analyze linkage disequilibrium for LMP2, LMP7 and TAP1, and our results indicated that haplotypes A and E were more common in both the patients and control individuals.	('LMP7', 'Gene', (92, 96))	('LMP2', 'Gene', '5698', (86, 90))	('LMP7', 'Gene', '5696', (92, 96))	('TAP1', 'Gene', (101, 105))	('common', 'Reg', (167, 173))	('TAP1', 'Gene', '6890', (101, 105))	('LMP2', 'Gene', (86, 90))	('patients', 'Species', '9606', (186, 194))	('haplotypes A', 'Var', (138, 150))
712609	29073155	Haplotype A, including wild-type homozygous LMP2/TAP1 and mutant LMP7, decreased the risk of ESCC in the Kazakh population.	('mutant', 'Var', (58, 64))	('LMP2', 'Gene', (44, 48))	('LMP2', 'Gene', '5698', (44, 48))	('TAP1', 'Gene', (49, 53))	('TAP1', 'Gene', '6890', (49, 53))	('LMP7', 'Gene', (65, 69))	('LMP7', 'Gene', '5696', (65, 69))	('ESCC', 'Disease', (93, 97))	('decreased', 'NegReg', (71, 80))
712610	29073155	Moreover, haplotype E, including wild-type homozygous LMP2/LMP7/TAP1, increased the risk of ESCC in this population.	('LMP2', 'Gene', '5698', (54, 58))	('ESCC', 'Disease', (92, 96))	('increased', 'PosReg', (70, 79))	('LMP7', 'Gene', (59, 63))	('haplotype E', 'Var', (10, 21))	('LMP7', 'Gene', '5696', (59, 63))	('TAP1', 'Gene', (64, 68))	('LMP2', 'Gene', (54, 58))	('TAP1', 'Gene', '6890', (64, 68))
712611	29073155	These results indicate that the LMP7-145 (Gln-Lys) gene variation may weaken the susceptibility of the haplotype to ESCC in the Kazakh population.	('LMP7', 'Gene', '5696', (32, 36))	('Gln', 'Chemical', 'MESH:D005973', (42, 45))	('ESCC', 'Disease', (116, 120))	('Gln-Lys', 'Var', (42, 49))	('Lys', 'Chemical', 'MESH:D008239', (46, 49))	('weaken', 'NegReg', (70, 76))	('LMP7', 'Gene', (32, 36))	('susceptibility', 'MPA', (81, 95))
712616	29073155	Our study sought to assess a connection between LMP2/LMP7 polymorphism and HPV infection, though we found no association between these variables.	('LMP7', 'Gene', (53, 57))	('HPV infection', 'Disease', (75, 88))	('polymorphism', 'Var', (58, 70))	('LMP7', 'Gene', '5696', (53, 57))	('LMP2', 'Gene', (48, 52))	('LMP2', 'Gene', '5698', (48, 52))	('HPV infection', 'Disease', 'MESH:D030361', (75, 88))
712617	29073155	Our results indicate that HPV infection and LMP2/LMP7 polymorphisms may function independently to influence the risk of ESCC in the Kazakh population, a conclusion that supports the research of Cao in Anyang, China.	('polymorphisms', 'Var', (54, 67))	('LMP2', 'Gene', (44, 48))	('influence', 'Reg', (98, 107))	('LMP2', 'Gene', '5698', (44, 48))	('HPV infection', 'Disease', (26, 39))	('ESCC', 'Disease', (120, 124))	('LMP7', 'Gene', '5696', (49, 53))	('LMP7', 'Gene', (49, 53))	('HPV infection', 'Disease', 'MESH:D030361', (26, 39))
712618	29073155	In conclusion, to the best of our knowledge, the present study is the first to demonstrate that LMP2/LMP7 polymorphisms are associated with the risk of ESCC in the Kazakh population, a Chinese ethnic minority.	('polymorphisms', 'Var', (106, 119))	('associated', 'Reg', (124, 134))	('LMP2', 'Gene', (96, 100))	('LMP2', 'Gene', '5698', (96, 100))	('LMP7', 'Gene', (101, 105))	('ESCC', 'Disease', (152, 156))	('LMP7', 'Gene', '5696', (101, 105))
712639	28977940	Furthermore, emerging evidence indicates that LNR showed better prognostic value than metastatic LN number for esophageal cancer.	('LNR', 'Var', (46, 49))	('esophageal cancer', 'Disease', (111, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
712643	28977940	A previous meta-analysis also indicated that LNR was a prognostic factor with regard to overall survival for breast cancer and colorectal cancer.	('breast cancer', 'Disease', (109, 122))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('LNR', 'Var', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
712816	23195204	It is plausible that deficiencies in the dynamics of physician-patient communication, the understanding of patient preferences, and overall patient trust are common to high and low volume hospitals, and may contribute to racial disparities in the use of cancer-directed surgery among elderly patients.	('deficiencies', 'Var', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('contribute', 'Reg', (207, 217))	('patient', 'Species', '9606', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('patient', 'Species', '9606', (292, 299))	('cancer', 'Disease', (254, 260))	('patient', 'Species', '9606', (63, 70))	('patients', 'Species', '9606', (292, 300))	('patient', 'Species', '9606', (107, 114))
712894	26099633	The apparent permeability coefficient (P) was determined by the equation  where dQ/dt is the drug permeation rate (mumol/s), A is the surface area of the epithelium (cm2), and Co is the initial concentration in the donor compartment at time 0 (mM).	('mum', 'Gene', '56925', (115, 118))	('donor', 'Species', '9606', (215, 220))	('mum', 'Gene', (115, 118))	('dQ/dt', 'Var', (80, 85))	('drug permeation rate', 'MPA', (93, 113))
712897	26099633	Guided by MTT assay against oral carcinoma cell line (SCC2095), ZSP powder was extracted by water and alcohol to generated extracts, which were further fractionated by liquid-liquid partition with ethyl acetate, n-butanol, and water to afford a fraction GS409 with 5.2 % in yield (extraction and isolation section).	('GS409', 'Chemical', '-', (254, 259))	('water', 'Chemical', 'MESH:D014867', (92, 97))	('oral carcinoma', 'Disease', 'MESH:D020820', (28, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('oral carcinoma', 'Disease', (28, 42))	('MTT', 'Chemical', 'MESH:C070243', (10, 13))	('n-butanol', 'Chemical', 'MESH:D020001', (212, 221))	('water', 'Chemical', 'MESH:D014867', (227, 232))	('ethyl acetate', 'Chemical', 'MESH:C007650', (197, 210))	('alcohol', 'Chemical', 'MESH:D000438', (102, 109))	('ZSP', 'Chemical', '-', (64, 67))	('GS409', 'Var', (254, 259))	('SCC2095', 'CellLine', 'CVCL:Y038', (54, 61))
712898	26099633	The MTT results showed that the IC50 of GS409 (295.7 mug/ml) was significantly lower than that of ZSP (>500 mug/ml) (Table 2) indicating that GS409 is more potential against oral carcinoma.	('oral carcinoma', 'Disease', 'MESH:D020820', (174, 188))	('GS409', 'Chemical', '-', (142, 147))	('lower', 'NegReg', (79, 84))	('oral carcinoma', 'Disease', (174, 188))	('GS409', 'Var', (40, 45))	('IC50', 'MPA', (32, 36))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('ZSP', 'Chemical', '-', (98, 101))	('GS409', 'Chemical', '-', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('GS409', 'Var', (142, 147))
712927	26099633	The MTT results showed that the activity of GS409 is significantly higher than that of ZSP (Table 2).	('higher', 'PosReg', (67, 73))	('ZSP', 'Chemical', '-', (87, 90))	('activity', 'MPA', (32, 40))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('GS409', 'Var', (44, 49))	('GS409', 'Chemical', '-', (44, 49))
712928	26099633	In addition, the contents of the active compounds were increased in GS409 comparing with those in ZSP (Table 3).	('contents of the active compounds', 'MPA', (17, 49))	('increased', 'PosReg', (55, 64))	('ZSP', 'Chemical', '-', (98, 101))	('GS409', 'Var', (68, 73))	('GS409', 'Chemical', '-', (68, 73))
712929	26099633	The content of fraxinellone, dictamnine, and maackiain were 23, 26, and 350-folds higher in GS409 than those in ZSP respectively suggesting the active compounds were concentrated in GS409.	('GS409', 'Chemical', '-', (182, 187))	('GS409', 'Var', (92, 97))	('higher', 'PosReg', (82, 88))	('ZSP', 'Chemical', '-', (112, 115))	('dictamnine', 'Chemical', 'MESH:C026398', (29, 39))	('GS409', 'Chemical', '-', (92, 97))	('content', 'MPA', (4, 11))	('maackiain', 'Chemical', 'MESH:C001449', (45, 54))	('fraxinellone', 'Chemical', 'MESH:C075391', (15, 27))
712963	23442983	For breast carcinomas, it was reported that high fascin-1 mRNA levels were associated with a lung metastasis signature and decreased overall and metastasis- free survival.	('high', 'Var', (44, 48))	('breast carcinoma', 'Phenotype', 'HP:0003002', (4, 20))	('breast carcinomas', 'Disease', 'MESH:D001943', (4, 21))	('breast carcinomas', 'Disease', (4, 21))	('decreased', 'NegReg', (123, 132))	('lung metastasis signature', 'CPA', (93, 118))	('fascin-1', 'Gene', '14086', (49, 57))	('breast carcinomas', 'Phenotype', 'HP:0003002', (4, 21))	('fascin-1', 'Gene', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('mRNA levels', 'MPA', (58, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
712978	23442983	For dichotomous outcomes (that is, lymph node metastasis and distant metastasis), the number of patients with the event of interest and total number of patients in each category group (that is, high, low, positive or negative expression) were extracted and the data used to compute risk ratios.	('low', 'NegReg', (200, 203))	('lymph node metastasis', 'CPA', (35, 56))	('positive', 'Var', (205, 213))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (152, 160))
712992	23442983	Based on studies examining fascin-1 positivity, the pooled fixed effects HR estimate was 2.48 (1.38 to 4.46; P = 0.002) for mortality, recurrence or metastasis outcomes (Figure 3).	('metastasis', 'CPA', (149, 159))	('fascin-1', 'Gene', '14086', (27, 35))	('fascin-1', 'Gene', (27, 35))	('recurrence', 'CPA', (135, 145))	('positivity', 'Var', (36, 46))
712999	23442983	Two studies examined the association of fascin-1 positivity of carcinomas with time-to-disease progression, with a total of 354 colorectal carcinoma cases.	('colorectal carcinoma', 'Disease', (128, 148))	('fascin-1', 'Gene', '14086', (40, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('carcinomas', 'Disease', 'MESH:D002277', (63, 73))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (128, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('association', 'Interaction', (25, 36))	('carcinomas', 'Disease', (63, 73))	('positivity', 'Var', (49, 59))	('fascin-1', 'Gene', (40, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
713000	23442983	Based on studies examining fascin-1 positivity, the pooled random effects HR estimate was 2.12 (1.00 to 4.47; P = 0.05) for mortality, recurrence or metastasis outcomes (Figure 3).	('metastasis', 'CPA', (149, 159))	('fascin-1', 'Gene', '14086', (27, 35))	('fascin-1', 'Gene', (27, 35))	('recurrence', 'CPA', (135, 145))	('positivity', 'Var', (36, 46))
713028	23442983	Eleven studies examined the association of fascin-1 positivity of carcinomas with mortality and seven studies examined the association of high fascin-1 with mortality, with a total of 3,645 carcinoma cases.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('fascin-1', 'Gene', '14086', (43, 51))	('carcinoma', 'Disease', 'MESH:D002277', (190, 199))	('carcinomas', 'Disease', (66, 76))	('carcinomas', 'Disease', 'MESH:D002277', (66, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('carcinoma', 'Disease', (66, 75))	('fascin-1', 'Gene', '14086', (143, 151))	('association', 'Interaction', (28, 39))	('fascin-1', 'Gene', (43, 51))	('positivity', 'Var', (52, 62))	('fascin-1', 'Gene', (143, 151))	('carcinoma', 'Disease', (190, 199))	('carcinoma', 'Disease', 'MESH:D002277', (66, 75))	('examined', 'Reg', (15, 23))
713034	23442983	Six studies examined the association of fascin-1 positivity with time-to-disease progression, with a total of 928 carcinoma cases.	('fascin-1', 'Gene', '14086', (40, 48))	('carcinoma', 'Disease', 'MESH:D002277', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('association', 'Interaction', (25, 36))	('positivity', 'Var', (49, 59))	('fascin-1', 'Gene', (40, 48))	('carcinoma', 'Disease', (114, 123))	('examined', 'Reg', (12, 20))
713036	23442983	Ten studies examined the association of fascin-1 positivity of carcinomas with lymph node metastasis and seven studies examined the association of high fascin-1 with lymph node metastasis, with a total of 2,906 carcinoma cases.	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('fascin-1', 'Gene', '14086', (40, 48))	('carcinomas', 'Disease', 'MESH:D002277', (63, 73))	('fascin-1', 'Gene', (152, 160))	('carcinoma', 'Disease', (63, 72))	('carcinomas', 'Disease', (63, 73))	('fascin-1', 'Gene', (40, 48))	('association', 'Interaction', (25, 36))	('carcinoma', 'Disease', 'MESH:D002277', (211, 220))	('high', 'Var', (147, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('carcinoma', 'Disease', (211, 220))	('fascin-1', 'Gene', '14086', (152, 160))	('carcinoma', 'Disease', 'MESH:D002277', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('lymph node metastasis', 'CPA', (79, 100))
713149	21694870	The triggering event that leads to ganglion cell degeneration in achalasia is still unclear, but loss of nitric oxide-secreting neurons leads to an imbalance between the excitatory and inhibitory neurons of the myenteric plexus, producing irreversible manometric changes in such patients.	('leads to', 'Reg', (136, 144))	('loss', 'Var', (97, 101))	('nitric oxide', 'Chemical', 'MESH:D009569', (105, 117))	('nitric', 'Protein', (105, 111))	('achalasia', 'Phenotype', 'HP:0002571', (65, 74))	('imbalance', 'Phenotype', 'HP:0002172', (148, 157))	('manometric changes', 'MPA', (252, 270))	('patients', 'Species', '9606', (279, 287))	('achalasia', 'Disease', (65, 74))	('achalasia', 'Disease', 'MESH:D004931', (65, 74))
713207	21694870	Furthermore, a systematic review and meta-analysis of 105 papers that reported on 761 patients with achalasia who underwent endoscopic treatment with esophageal dilation or botulinum toxin A showed that symptom relief was better for dilation, and the necessity for further treatment was significantly reduced.	('esophageal dilation', 'Disease', 'MESH:D002311', (150, 169))	('achalasia', 'Disease', 'MESH:D004931', (100, 109))	('dilation', 'Var', (233, 241))	('achalasia', 'Phenotype', 'HP:0002571', (100, 109))	('esophageal dilation', 'Disease', (150, 169))	('achalasia', 'Disease', (100, 109))	('patients', 'Species', '9606', (86, 94))
713214	21694870	The dysphagia rate attributed to fundoplication ranges from 0% to 8%.	('dysphagia', 'Disease', (4, 13))	('fundoplication', 'Var', (33, 47))	('dysphagia', 'Phenotype', 'HP:0002015', (4, 13))	('dysphagia', 'Disease', 'MESH:D003680', (4, 13))
713292	33614703	In terms of the described effects of CKAP4 on the architecture of the ER and microtubule networks, there are predicted phosphorylation sites of serine 3, 17, and 19 on CKAP4 (Figure 1), which have shown negatively regulated microtubule and induced collapse of the ER around the nucleus.	('ER', 'Gene', '2069', (264, 266))	('serine', 'Chemical', 'MESH:D012694', (144, 150))	('CKAP4', 'Var', (168, 173))	('collapse', 'MPA', (248, 256))	('regulated microtubule', 'MPA', (214, 235))	('ER', 'Gene', '2069', (70, 72))	('negatively', 'NegReg', (203, 213))
713298	33614703	Palmitoyl acyltransferase DHHC2, which is a putative tumor suppressor, modifies Cys100 of CKAP4 and contributes to the localization of CKAP4 on the plasma membrane.	('Cys100', 'Chemical', '-', (80, 86))	('DHHC2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('modifies', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('contributes', 'Reg', (100, 111))	('Cys100', 'MPA', (80, 86))	('tumor', 'Disease', (53, 58))	('localization', 'MPA', (119, 131))	('DHHC2', 'Gene', '51201', (26, 31))	('CKAP4', 'Gene', (90, 95))
713299	33614703	In the extracellular region, CKAP4 contains three coiled-coil regions, two shorter regions (AA 130-214 and AA 533-602) and one longer one (AA 256-460), and a leucine zipper (LZ) domain (AA 468-503) (Figure 1).	('leucine', 'Chemical', 'MESH:D007930', (158, 165))	('CKAP4', 'Gene', (29, 34))	('AA 533-602', 'Var', (107, 117))	('coiled-coil regions', 'MPA', (50, 69))	('AA 130-214', 'Var', (92, 102))
713302	33614703	Furthermore, these coiled-coil domains are also required for its multimerization and intermolecular interactions, which associate with tyrosine sulfation of CKAP4.	('tyrosine', 'Var', (135, 143))	('CKAP4', 'Gene', (157, 162))	('tyrosine', 'Chemical', 'MESH:D014443', (135, 143))
713314	33614703	Transfection of the mutant's COS-1 cells led to an increase in tPA-catalyzed plasminogen activation, which confirmed the role of cell surface CKAP4 in tPA binding.	('increase', 'PosReg', (51, 59))	('tPA', 'Gene', (63, 66))	('mutant', 'Var', (20, 26))	('tPA', 'Gene', '100128998', (63, 66))	('tPA', 'Gene', (151, 154))	('tPA', 'Gene', '100128998', (151, 154))	('COS-1', 'CellLine', 'CVCL:0223', (29, 34))
713340	33614703	CKAP4 knockdown or CRD-1 deletion mutants of DKKs inhibited MDCK cellular proliferation (14).	('MDCK cellular proliferation', 'CPA', (60, 87))	('MDCK', 'CellLine', 'CVCL:0422', (60, 64))	('DKK', 'Gene', (45, 48))	('deletion mutants', 'Var', (25, 41))	('CRD-1', 'Gene', '1319', (19, 24))	('CRD-1', 'Gene', (19, 24))	('DKK', 'Gene', '22943', (45, 48))	('inhibited', 'NegReg', (50, 59))
713347	33614703	Following CKAP4 knockdown, the inhibition effect of APF on T24 cell proliferation was eliminated, indicating the important role of the receptor in mediating the antiproliferation activity of APF in bladder cancer cells.	('APF', 'Chemical', '-', (191, 194))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('T24 cell proliferation', 'CPA', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('bladder cancer', 'Disease', (198, 212))	('knockdown', 'Var', (16, 25))	('eliminated', 'NegReg', (86, 96))	('CKAP4', 'Gene', (10, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('APF', 'Chemical', '-', (52, 55))
713351	33614703	When CKAP4 was reduced with siRNA or anti-CKAP4 antibody, the upregulation of CCN2 during APF treatment was inhibited.	('upregulation', 'MPA', (62, 74))	('CCN2', 'Gene', '1490', (78, 82))	('reduced', 'NegReg', (15, 22))	('APF', 'Chemical', '-', (90, 93))	('anti-CKAP4 antibody', 'Var', (37, 56))	('CCN2', 'Gene', (78, 82))	('inhibited', 'NegReg', (108, 117))
713357	33614703	Further research demonstrated that CKAP4 phosphorylation of N-terminal serine residues (S3, S17, and S19) is necessary for translocation from the plasma membrane to the nucleus in Hela cell (Figure 2).	('S19', 'Var', (101, 104))	('translocation', 'MPA', (123, 136))	('S17', 'Gene', '6218', (92, 95))	('S3', 'Var', (88, 90))	('Hela cell', 'CellLine', 'CVCL:0030', (180, 189))	('serine', 'Chemical', 'MESH:D012694', (71, 77))	('S17', 'Gene', (92, 95))
713359	33614703	CKAP4 of palmitoylation site mutant (C100S) or phosphorylation site mutant does not cause relocalization and has APF-like activity inhibiting cell proliferation.	('APF', 'Chemical', '-', (113, 116))	('APF-like activity', 'MPA', (113, 130))	('cell proliferation', 'CPA', (142, 160))	('inhibiting', 'NegReg', (131, 141))	('C100S', 'Mutation', 'p.C100S', (37, 42))	('CKAP4', 'Protein', (0, 5))	('C100S', 'Var', (37, 42))
713360	33614703	It suggests that the mutation of CKAP4 could be used to treat excessive proliferation diseases such as tumor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CKAP4', 'Gene', (33, 38))	('proliferation diseases', 'Disease', (72, 94))	('tumor', 'Disease', (103, 108))	('proliferation diseases', 'Disease', 'MESH:C565054', (72, 94))	('mutation', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
713362	33614703	Moreover, high expression of CKAP4 inhibited the growth of xenograft tumor and the metastatic potential of HCC in nude mice.	('HCC', 'Phenotype', 'HP:0001402', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CKAP4', 'Gene', (29, 34))	('tumor', 'Disease', (69, 74))	('nude mice', 'Species', '10090', (114, 123))	('metastatic potential of HCC', 'CPA', (83, 110))	('high expression', 'Var', (10, 25))	('inhibited', 'NegReg', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
713371	33614703	Furthermore, in vivo experiments also showed that the low CKAP4 expression cells formed much smaller xenograft tumors than the control group.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('low', 'Var', (54, 57))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('smaller', 'NegReg', (93, 100))	('CKAP4', 'Gene', (58, 63))
713373	33614703	It is worth noting that knockdown of CKAP4 did not influence cell proliferation in cells with insufficient DKK1 and/or DKK3.	('CKAP4', 'Gene', (37, 42))	('DKK1', 'Var', (107, 111))	('DKK3', 'Gene', '27122', (119, 123))	('knockdown', 'Var', (24, 33))	('DKK3', 'Gene', (119, 123))	('cell proliferation', 'CPA', (61, 79))
713381	33614703	It was noted that CKAP4 was not directly involved in alpha5beta1 integrin endocytosis but inhibited its recycling.	('beta1 integrin', 'Gene', '3688', (59, 73))	('beta1 integrin', 'Gene', (59, 73))	('CKAP4', 'Var', (18, 23))	('inhibited', 'NegReg', (90, 99))	('recycling', 'MPA', (104, 113))
713397	33614703	Prognosis was favorable in patients with high CKAP4 or high DHHC2 expression compared with those with low CKAP4 or low DHHC2 expression.	('DHHC2', 'Gene', '51201', (119, 124))	('DHHC2', 'Gene', (60, 65))	('high CKAP4', 'Var', (41, 51))	('DHHC2', 'Gene', (119, 124))	('expression', 'MPA', (66, 76))	('patients', 'Species', '9606', (27, 35))	('high', 'Var', (55, 59))	('DHHC2', 'Gene', '51201', (60, 65))
713402	33614703	Prognostic values of CKAP4 expression showed that the high-CKAP4 patients had a much longer overall survival and lower recurrence rate than the low-CKAP4 patients, and CKAP4 is an independent predictor for overall survival in ICC patients.	('longer', 'PosReg', (85, 91))	('lower', 'NegReg', (113, 118))	('recurrence rate', 'CPA', (119, 134))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (230, 238))	('IC', 'Disease', 'MESH:C566126', (226, 228))	('patients', 'Species', '9606', (65, 73))	('overall survival', 'CPA', (92, 108))	('high-CKAP4', 'Var', (54, 64))
713407	33614703	The positive rates of CKAP4 and DKK1in lung adenocarcinoma were 74.6 and 79.1%, respectively, and in squamous cell carcinoma were 74.6 and 73.8%, respectively (Table 2).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('CKAP4', 'Var', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('DKK1in', 'Var', (32, 38))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('squamous cell carcinoma', 'Disease', (101, 124))	('lung adenocarcinoma', 'Disease', (39, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))
713408	33614703	Patients positive for both CKAP4 and DKK1 showed a more shorter relapse-free survival than patients positive for either CKAP4 or DKK1 or negative for both (Table 2).	('DKK1', 'Var', (37, 41))	('patients', 'Species', '9606', (91, 99))	('relapse-free survival', 'CPA', (64, 85))	('CKAP4', 'Var', (27, 32))	('shorter', 'NegReg', (56, 63))	('Patients', 'Species', '9606', (0, 8))
713413	33614703	analyzed 119 cases and 72 cases of esophageal squamous cell carcinoma (ESCC) and showed that expression of CKAP4, along with DKK1 and/or DKK3, in ESCC was associated with poor prognosis (Table 2).	('DKK3', 'Gene', (137, 141))	('expression', 'Var', (93, 103))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('associated', 'Reg', (155, 165))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('CKAP4', 'Gene', (107, 112))	('DKK3', 'Gene', '27122', (137, 141))
713420	33614703	Patients positive for both CKAP4 and ligands (DKK1 and/or DKK3) showed unfavorable prognosis and shortened relapse-free survival than do patients positive for either CKAP4 or DKK1/DKK3 or negative for CKAP4 and DKK1/DKK3 (Table 2).	('relapse-free survival', 'CPA', (107, 128))	('DKK3', 'Gene', (216, 220))	('DKK3', 'Gene', '27122', (58, 62))	('DKK3', 'Gene', (58, 62))	('CKAP4', 'Var', (27, 32))	('patients', 'Species', '9606', (137, 145))	('Patients', 'Species', '9606', (0, 8))	('shortened', 'NegReg', (97, 106))	('DKK3', 'Gene', '27122', (180, 184))	('DKK3', 'Gene', (180, 184))	('DKK3', 'Gene', '27122', (216, 220))	('DKK1', 'Var', (46, 50))
713423	33614703	However, patients with high CKAP4 protein levels had unfavorable overall survival and relapse-free survival, and overexpression of CKAP4 was significantly associated with TNM stages and Fuhrman grades (Table 2).	('patients', 'Species', '9606', (9, 17))	('relapse-free survival', 'CPA', (86, 107))	('high', 'Var', (23, 27))	('overall survival', 'CPA', (65, 81))	('overexpression', 'PosReg', (113, 127))	('TNM', 'Gene', (171, 174))	('associated', 'Reg', (155, 165))	('CKAP4 protein', 'Protein', (28, 41))	('Fuhrman', 'Disease', (186, 193))	('CKAP4', 'Gene', (131, 136))	('TNM', 'Gene', '10178', (171, 174))
713427	33614703	In the cells with high CKAP4 but with little ligands, DKKs, CKAP4 did not affect cellular proliferation.	('DKK', 'Gene', '22943', (54, 57))	('DKK', 'Gene', (54, 57))	('high CKAP4', 'Var', (18, 28))	('CKAP4', 'Var', (23, 28))
713428	33614703	On the other hand, patients positive for both CKAP4 and DKKs show unfavorable prognosis and shorter relapse-free survival in pancreatic, lung, and esophageal tumors.	('DKK', 'Gene', '22943', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('pancreatic', 'Disease', (125, 135))	('relapse-free survival', 'CPA', (100, 121))	('patients', 'Species', '9606', (19, 27))	('esophageal tumors', 'Disease', 'MESH:D004938', (147, 164))	('DKK', 'Gene', (56, 59))	('esophageal tumors', 'Disease', (147, 164))	('esophageal tumors', 'Phenotype', 'HP:0100751', (147, 164))	('CKAP4', 'Var', (46, 51))	('pancreatic', 'Disease', 'MESH:D010195', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('shorter', 'NegReg', (92, 99))	('lung', 'Disease', (137, 141))
713429	33614703	However, high expression of CKAP4 showed a favorable overall survival and longer disease-free survival in HCC and ICC.	('high expression', 'Var', (9, 24))	('HCC', 'Disease', (106, 109))	('CKAP4', 'Gene', (28, 33))	('HCC', 'Phenotype', 'HP:0001402', (106, 109))	('IC', 'Disease', 'MESH:C566126', (114, 116))
713432	33614703	Palmitoylated CKAP4 translocates to the nucleus and then binds to CCN2 gene, which inhibits cell proliferation, adhesion, migration, differentiation, and survival.	('inhibits', 'NegReg', (83, 91))	('survival', 'CPA', (154, 162))	('CCN2', 'Gene', (66, 70))	('Palmitoylated', 'Var', (0, 13))	('differentiation', 'CPA', (133, 148))	('adhesion', 'CPA', (112, 120))	('migration', 'CPA', (122, 131))	('cell proliferation', 'CPA', (92, 110))	('CCN2', 'Gene', '1490', (66, 70))	('binds', 'Interaction', (57, 62))
713448	33614703	The results showed that the sensitivity of the serum CKAP4 is 70% and the specificity is 67.5%, and detection of serum CKAP4 increased the diagnostic efficacy especially in HCC patients with low or negative alpha-fetoprotein (AFP).	('low', 'NegReg', (191, 194))	('HCC', 'Disease', (173, 176))	('serum CKAP4', 'Var', (113, 124))	('increased', 'PosReg', (125, 134))	('HCC', 'Phenotype', 'HP:0001402', (173, 176))	('patients', 'Species', '9606', (177, 185))	('alpha-fetoprotein', 'Gene', '174', (207, 224))	('AFP', 'Gene', (226, 229))	('AFP', 'Gene', '174', (226, 229))	('alpha-fetoprotein', 'Gene', (207, 224))	('negative', 'NegReg', (198, 206))
713450	33614703	The sensitivity and specificity for HCC diagnosis of CKAP4 alone had no advantage compared with AFP, but combined CKAP4 and AFP showed a better diagnostic accuracy (sensitivity = 0.8, specificity = 0.963), even in early HCC (sensitivity = 0.762, specificity = 0.963), which was similar to our results (Table 3).	('AFP', 'Gene', '174', (124, 127))	('AFP', 'Gene', '174', (96, 99))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('AFP', 'Gene', (96, 99))	('CKAP4', 'Var', (114, 119))	('HCC', 'Phenotype', 'HP:0001402', (220, 223))	('AFP', 'Gene', (124, 127))	('early HCC', 'Disease', (214, 223))
713469	33614703	Furthermore, an anti-CKAP4 polyclonal antibody (pAb) can significantly reduce xenograft tumor volume and weight caused by these cancer cell lines, suggesting that CAKP4 represents a novel molecular target for cancer therapy.	('anti-CKAP4', 'Var', (16, 26))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('reduce', 'NegReg', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('anti-CKAP4', 'Gene', (16, 26))	('tumor', 'Disease', (88, 93))	('cancer', 'Disease', (128, 134))
713482	33614703	Mechanistically, TGF-beta was revealed to induce CKAP4 expression, and inhibition of CKAP4 increased the expression of markers for activated fibroblasts under TGF-beta treatment.	('TGF-beta', 'Gene', (17, 25))	('CKAP4', 'Gene', (49, 54))	('inhibition', 'Var', (71, 81))	('TGF-beta', 'Gene', (159, 167))	('TGF-beta', 'Gene', '7039', (17, 25))	('induce', 'PosReg', (42, 48))	('expression', 'MPA', (55, 65))	('CKAP4', 'Gene', (85, 90))	('TGF-beta', 'Gene', '7039', (159, 167))	('increased', 'PosReg', (91, 100))	('expression of', 'MPA', (105, 118))
713484	33614703	Another research showed that it is possible to establish a noninvasion diagnostic method for IC/PBS because the special domains of CKAP4 (AA127-360, AA361-524) could enhance the binding activity to APF, increasing detection efficiency to APF concentrations in urine.	('APF concentrations', 'MPA', (238, 256))	('APF', 'Protein', (198, 201))	('IC', 'Disease', 'MESH:C566126', (93, 95))	('AA127-360', 'Var', (138, 147))	('APF', 'Chemical', '-', (198, 201))	('detection efficiency', 'MPA', (214, 234))	('PBS', 'Chemical', 'MESH:D007854', (96, 99))	('enhance', 'PosReg', (166, 173))	('increasing', 'PosReg', (203, 213))	('AA361-524', 'Var', (149, 158))	('APF', 'Chemical', '-', (238, 241))	('CKAP4', 'Gene', (131, 136))	('binding', 'Interaction', (178, 185))
713500	33614703	81600593, 81770763, and 81500583), the State Key Project for Liver Cancer (2017ZX10203,2017ZX10203206), and the National Key Research and Development Program (2017YFC0906900).	('81770763', 'Var', (10, 18))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Liver Cancer', 'Disease', 'MESH:D006528', (61, 73))	('Liver Cancer', 'Phenotype', 'HP:0002896', (61, 73))	('2017ZX10203,2017ZX10203206', 'Var', (75, 101))	('Liver Cancer', 'Disease', (61, 73))	('81500583', 'Var', (24, 32))	('81600593', 'Var', (0, 8))
713659	33200076	PCI has been shown to improve survival, as well as local control, in small cell carcinomas of the lung.	('improve', 'PosReg', (22, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('small cell carcinomas of the lung', 'Phenotype', 'HP:0030357', (69, 102))	('PCI', 'Var', (0, 3))	('small cell carcinomas', 'Disease', (69, 90))	('local control', 'CPA', (51, 64))	('survival', 'CPA', (30, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('small cell carcinomas', 'Disease', 'MESH:D018288', (69, 90))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (69, 89))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (80, 102))
713715	31346548	A total of 1.5 x 105 cells transfected with pcDNA3.1-PTTG3P or pcDNA3.1 in 100 mul of serum-free medium were added to each well.	('pcDNA3.1', 'Var', (63, 71))	('PTTG3P', 'Gene', '26255', (53, 59))	('PTTG3P', 'Gene', (53, 59))
713737	31346548	Cell Transwell assays showed that PTTG1 and PTTG2 knockdown partially attenuated the effects of PTTG3P-overexpressing on ESCC cell migration and invasioncompared with that of the controls (Figure 6B).	('attenuated', 'NegReg', (70, 80))	('knockdown', 'Var', (50, 59))	('PTTG1', 'Gene', (34, 39))	('PTTG2', 'Gene', (44, 49))	('PTTG3P', 'Gene', (96, 102))	('PTTG1', 'Gene', '9232', (34, 39))	('invasioncompared', 'CPA', (145, 161))	('Tran', 'Gene', '7154', (5, 9))	('PTTG2', 'Gene', '10744', (44, 49))	('Tran', 'Gene', (5, 9))	('ESCC', 'Disease', (121, 125))	('PTTG3P', 'Gene', '26255', (96, 102))
713739	31346548	In the past ten years, pseudogenes have gained more and more attentions because of their important roles in human malignancies.	('malignancies', 'Disease', (114, 126))	('pseudogenes', 'Var', (23, 34))	('human', 'Species', '9606', (108, 113))	('malignancies', 'Disease', 'MESH:D009369', (114, 126))
713744	31346548	Obviously, pseudogenes play important roles in the development of esophageal cancer and have great research prospects.	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('esophageal cancer', 'Disease', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('pseudogenes', 'Var', (11, 22))
713759	30979011	Here, we established a method to identify and isolate CSCs in ESCC using fluorescence-activated cell sorting with combined surface biomarkers including CD71, CD271, and CD338.	('CD271', 'Gene', '4804', (158, 163))	('CD338', 'Gene', (169, 174))	('CD271', 'Gene', (158, 163))	('CD71', 'Var', (152, 156))	('CD338', 'Gene', '9429', (169, 174))	('ESCC', 'Disease', (62, 66))
713776	30979011	In this study, various combinations of CD71, CD338, CD271, and CD49f have been considered and tested in ECa9706, ECa109, KYSE50, and CAES17.	('tested', 'Reg', (94, 100))	('CD49f', 'Gene', '3655', (63, 68))	('CD338', 'Gene', (45, 50))	('CD271', 'Gene', '4804', (52, 57))	('CD49f', 'Gene', (63, 68))	('CD338', 'Gene', '9429', (45, 50))	('ECa9706', 'CellLine', 'CVCL:E307', (104, 111))	('CD71', 'Var', (39, 43))	('CD271', 'Gene', (52, 57))
713782	30979011	Through a literature review, four candidate stem surface markers (CD49f, CD71, CD338, and CD271) were selected for CSC sorting in ECa9706, ECa109, CAES17, and KYSE150.	('CD71', 'Gene', (73, 77))	('ECa9706', 'CellLine', 'CVCL:E307', (130, 137))	('ECa109', 'Var', (139, 145))	('CD49f', 'Gene', '3655', (66, 71))	('CD338', 'Gene', '9429', (79, 84))	('CD271', 'Gene', '4804', (90, 95))	('CD49f', 'Gene', (66, 71))	('CD338', 'Gene', (79, 84))	('CD271', 'Gene', (90, 95))	('ECa9706', 'Var', (130, 137))
713783	30979011	We firstly detected CD49f, CD71, CD338, and CD271 when stained individually; CD49f and CD71 were detected with high positive rates, and CD338 and CD271 were expressed with low positive rates (Figure 1A).	('CD338', 'Gene', '9429', (33, 38))	('CD71', 'Var', (87, 91))	('CD338', 'Gene', '9429', (136, 141))	('CD271', 'Gene', (44, 49))	('CD338', 'Gene', (33, 38))	('CD49f', 'Gene', (77, 82))	('CD271', 'Gene', '4804', (146, 151))	('CD49f', 'Gene', (20, 25))	('CD338', 'Gene', (136, 141))	('CD271', 'Gene', (146, 151))	('CD49f', 'Gene', '3655', (77, 82))	('CD49f', 'Gene', '3655', (20, 25))	('CD271', 'Gene', '4804', (44, 49))
713788	30979011	In EC9706, the rates for positive (CD71-/CD271+/CD338+) and negative (CD71+/CD271-/CD338-) subpopulations were 0.86% and 90.0%, respectively.	('CD338', 'Gene', (83, 88))	('EC9706', 'CellLine', 'CVCL:E307', (3, 9))	('CD271', 'Gene', '4804', (41, 46))	('CD338', 'Gene', '9429', (48, 53))	('CD338', 'Gene', '9429', (83, 88))	('CD271', 'Gene', '4804', (76, 81))	('CD271', 'Gene', (41, 46))	('EC9706', 'Var', (3, 9))	('CD338', 'Gene', (48, 53))	('CD271', 'Gene', (76, 81))
713800	30979011	We detected growth inhibition in SSM with 1 microg/mL of DDP.	('DDP', 'Var', (57, 60))	('growth', 'MPA', (12, 18))	('DDP', 'Chemical', 'MESH:D002945', (57, 60))
713802	30979011	When cultured with 0.1 microg/mL, 0.5 microg/mL, and 1.0 microg/mL DDP for 120 h, both positive and negative cells were inhibited, and the inhibitory effect gradually increased with increasing concentrations, where the negative subpopulation cells were more sensitive to DPP treatment (Figure 3K).	('DPP', 'Chemical', 'MESH:C038694', (271, 274))	('inhibited', 'NegReg', (120, 129))	('DDP', 'Chemical', 'MESH:D002945', (67, 70))	('DDP', 'Var', (67, 70))
713811	30979011	Thirty-nine up-regulated miRNAs, including hsa-miR-18a-5p, hsa-miR-18b-5p, hsa-miR-29b-3p, hsa-miR-29c-3p, and hsa-let-7b were identified (Figure 4C).	('miRNAs', 'MPA', (25, 31))	('hsa-miR-18a', 'Gene', (43, 54))	('hsa-let-7b', 'Gene', '406884', (111, 121))	('hsa-miR-18a', 'Gene', '406953', (43, 54))	('up-regulated', 'PosReg', (12, 24))	('hsa-miR-18b', 'Gene', (59, 70))	('hsa-miR-29b-3p', 'Var', (75, 89))	('hsa-miR-18b', 'Gene', '574033', (59, 70))	('hsa-miR-29c', 'Gene', (91, 102))	('hsa-miR-29c', 'Gene', '407026', (91, 102))	('hsa-let-7b', 'Gene', (111, 121))
713828	30979011	The relative luciferase activity was significantly reduced (nearly 80.0%) by hsa-miR-21-3p when the reporter plasmid carried the wild type TRAF4 3'UTR, but no significant suppression was observed in the negative control plasmid; for cells transfected with mutant plasmid, only 25.6% of the relative luciferase activity was reduced (Figure 6G), which suggested miR-21-3p bound directly to the predicted TRAF4 3'UTR and negatively regulated TRAF4 expression.	('activity', 'MPA', (24, 32))	('reduced', 'NegReg', (51, 58))	('TRAF4', 'Gene', (439, 444))	('activity', 'MPA', (310, 318))	('miR-21-3p', 'Gene', (81, 90))	('miR-21-3p', 'Gene', '406995', (81, 90))	('miR-21-3p', 'Gene', '406995', (360, 369))	('TRAF4', 'Gene', (402, 407))	('hsa-miR-21-3p', 'Gene', '406995', (77, 90))	('mutant', 'Var', (256, 262))	('miR-21-3p', 'Gene', (360, 369))	('negatively regulated', 'NegReg', (418, 438))	('expression', 'MPA', (445, 455))	('hsa-miR-21-3p', 'Gene', (77, 90))	('bound', 'Interaction', (370, 375))
713829	30979011	We further confirmed that down-regulation of TRAF4 could partly rescue the functional changes in proliferation, cell cycle, and apoptosis in EC9706 (Figure 6B-D).	('EC9706', 'CellLine', 'CVCL:E307', (141, 147))	('down-regulation', 'NegReg', (26, 41))	('TRAF4', 'Gene', (45, 50))	('cell cycle', 'CPA', (112, 122))	('apoptosis', 'CPA', (128, 137))	('EC9706', 'Var', (141, 147))
713847	30979011	In ESCC, CD71 is reported to be correlated with tumorigenic properties.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('CD71', 'Var', (9, 13))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
713851	30979011	miR-135a can inhibit the development of Cancer Stem Cell-Driven Medulloblastoma by repressing Arhgef6 Expression.	('miR-135a', 'Var', (0, 8))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Expression', 'MPA', (102, 112))	('repressing', 'NegReg', (83, 93))	('miR-135a', 'Chemical', '-', (0, 8))	('Medulloblastoma', 'Phenotype', 'HP:0002885', (64, 79))	('Cancer Stem Cell-Driven Medulloblastoma', 'Disease', 'MESH:D008527', (40, 79))	('Arhgef6', 'Gene', '9459', (94, 101))	('Arhgef6', 'Gene', (94, 101))	('inhibit', 'NegReg', (13, 20))	('Cancer Stem Cell-Driven Medulloblastoma', 'Disease', (40, 79))
713853	30979011	discovered that miRNA-148b suppressed CSCs by targeting neuropilin-1 in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('suppressed', 'NegReg', (27, 37))	('hepatocellular carcinoma', 'Disease', (72, 96))	('neuropilin-1', 'Gene', (56, 68))	('miRNA-148b', 'Var', (16, 26))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('neuropilin-1', 'Gene', '8829', (56, 68))	('targeting', 'Reg', (46, 55))	('CSCs', 'MPA', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
714033	30221470	If the esophageal stent is placed first, the stent may compromise the airway, aggravate airway stenosis and dyspnea, and even threaten life.	('airway stenosis', 'Phenotype', 'HP:0002777', (88, 103))	('dyspnea', 'Disease', 'MESH:D004417', (108, 115))	('aggravate', 'PosReg', (78, 87))	('airway stenosis', 'Disease', (88, 103))	('life', 'CPA', (135, 139))	('dyspnea', 'Phenotype', 'HP:0002094', (108, 115))	('airway', 'CPA', (70, 76))	('compromise', 'NegReg', (55, 65))	('threaten', 'Reg', (126, 134))	('stent', 'Var', (45, 50))	('dyspnea', 'Disease', (108, 115))
714105	29897944	Defective autophagy has been implicated in cancer biology and therapy resistance.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('implicated', 'Reg', (29, 39))	('Defective', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('autophagy', 'CPA', (10, 19))
714190	29897944	WIPI1 and LC3B mRNA were assessed via qPCR in OE19 and OE33 upon two concentrations of paclitaxel.	('LC3B', 'Gene', (10, 14))	('WIPI1', 'Gene', (0, 5))	('WIPI1', 'Gene', '55062', (0, 5))	('paclitaxel', 'Chemical', 'MESH:D017239', (87, 97))	('OE33', 'Var', (55, 59))	('LC3B', 'Gene', '81631', (10, 14))
714209	29897944	It is also of note that the cell counts for CD3+ TILs in the tumor center was significantly higher in non-responders than responders (p = 0.041, data not shown).	('higher', 'PosReg', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CD3+ TILs', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
714221	29897944	Low LC3B dot-like staining and combined high p62 dot-like and cytoplasmic staining or low p62 nuclear staining was associated only in trend with a worse overall survival in the neo-adjuvant treated EAC cohort respectively (Fig 5, data not shown for p62 nuclear staining).	('p62', 'Gene', (249, 252))	('LC3B', 'Gene', (4, 8))	('p62', 'Gene', '8878', (45, 48))	('p62', 'Gene', (45, 48))	('p62', 'Gene', (90, 93))	('p62', 'Gene', '8878', (90, 93))	('EAC', 'Disease', (198, 201))	('LC3B', 'Gene', '81631', (4, 8))	('p62', 'Gene', '8878', (249, 252))	('Low', 'Var', (0, 3))
714231	29897944	Additionally, the combination of low LC3B dot-like/high p62 dot-like-cytoplasmic expression correlated with nonresponse.	('LC3B', 'Gene', '81631', (37, 41))	('low', 'Var', (33, 36))	('p62', 'Gene', '8878', (56, 59))	('nonresponse', 'Disease', (108, 119))	('p62', 'Gene', (56, 59))	('LC3B', 'Gene', (37, 41))
714253	29897944	The observation that the number of cases with high nuclear p62 in the primary resected cohort superseded that of the number of cases in the neo-adjuvant chemotherapy treated cohort could potentially speak to nuclear p62's role as a mediator of an alternative nuclear proteolytic degradation pathway.	('p62', 'Gene', '8878', (216, 219))	('p62', 'Gene', '8878', (59, 62))	('p62', 'Gene', (216, 219))	('nuclear', 'Var', (208, 215))	('p62', 'Gene', (59, 62))
714256	29897944	Some studies show that high expression of p62 in gastrointenstinal cancers in a treatment naive setting is associated with a more aggressive or advanced phenotype as well as with a worse overall survival.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('gastrointenstinal cancers', 'Disease', 'MESH:D009369', (49, 74))	('high expression', 'Var', (23, 38))	('associated', 'Reg', (107, 117))	('p62', 'Gene', (42, 45))	('p62', 'Gene', '8878', (42, 45))	('gastrointenstinal cancers', 'Disease', (49, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
714288	29764483	The occurrence rate of anastomotic leakage was significantly higher in patients with T2DM than in those without T2DM (P < 0.001).	('T2DM', 'Var', (85, 89))	('anastomotic leakage', 'CPA', (23, 42))	('higher', 'PosReg', (61, 67))	('patients', 'Species', '9606', (71, 79))
714289	29764483	In the subgroup with weight loss rate <= 5.05%, ESCC patients with T2DM had a significant longer overall survival than did those without T2DM (P = 0.003), whereas in the subgroup with weight loss rate > 5.05%, the patients without T2DM showed a longer survival (P = 0.001).	('patients', 'Species', '9606', (214, 222))	('patients', 'Species', '9606', (53, 61))	('T2DM', 'Var', (67, 71))	('weight loss', 'Disease', (21, 32))	('overall survival', 'MPA', (97, 113))	('weight loss', 'Disease', 'MESH:D015431', (184, 195))	('longer', 'PosReg', (90, 96))	('weight loss', 'Phenotype', 'HP:0001824', (21, 32))	('weight loss', 'Disease', (184, 195))	('ESCC', 'Disease', (48, 52))	('weight loss', 'Phenotype', 'HP:0001824', (184, 195))	('weight loss', 'Disease', 'MESH:D015431', (21, 32))
714297	29764483	T2DM patients have shown an increased incidence of several cancers, including pancreatic cancer, liver cancer, colorectal cancer, gastric cancer, and renal cancer.	('renal cancer', 'Disease', (150, 162))	('renal cancer', 'Phenotype', 'HP:0009726', (150, 162))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Disease', (78, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('patients', 'Species', '9606', (5, 13))	('renal cancer', 'Disease', 'MESH:D007680', (150, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('liver cancer', 'Disease', 'MESH:D006528', (97, 109))	('colorectal cancer', 'Disease', (111, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('liver cancer', 'Phenotype', 'HP:0002896', (97, 109))	('gastric cancer', 'Disease', (130, 144))	('T2DM', 'Var', (0, 4))	('liver cancer', 'Disease', (97, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (59, 66))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))
714329	29764483	However, the patients with T2DM were significantly older (P = 0.012), had higher percentage of smoking (P < 0.001), had a significantly higher percentage of female (P = 0.024), had a significantly higher BMI (P = 0.006), had significantly higher probability of no complications (P = 0.018), and had higher rates of postoperative anastomotic leakage (P = 0.001) than the patients without T2DM.	('higher', 'PosReg', (74, 80))	('higher', 'PosReg', (136, 142))	('higher', 'PosReg', (197, 203))	('postoperative anastomotic leak', 'Disease', (315, 345))	('patients', 'Species', '9606', (13, 21))	('BMI', 'MPA', (204, 207))	('T2DM', 'Var', (27, 31))	('patients', 'Species', '9606', (370, 378))	('higher', 'PosReg', (299, 305))	('postoperative anastomotic leak', 'Disease', 'MESH:D057868', (315, 345))
714333	29764483	Log-rank test showed that the OS rate tended to be higher in ESCC patients with T2DM than in those without T2DM, but the difference between them was not significant (P = 0.563, Fig.	('OS rate', 'MPA', (30, 37))	('ESCC', 'Disease', (61, 65))	('OS', 'Chemical', '-', (30, 32))	('higher', 'PosReg', (51, 57))	('patients', 'Species', '9606', (66, 74))	('T2DM', 'Var', (80, 84))
714336	29764483	Subgroup analysis of patients with low weight loss rate (<= 5.05%) showed that survival was significantly longer in patients with T2DM than in those without T2DM (P = 0.003, Fig.	('low weight', 'Phenotype', 'HP:0004325', (35, 45))	('low weight loss', 'Disease', 'MESH:D015431', (35, 50))	('weight loss', 'Phenotype', 'HP:0001824', (39, 50))	('patients', 'Species', '9606', (116, 124))	('longer', 'PosReg', (106, 112))	('T2DM', 'Var', (130, 134))	('patients', 'Species', '9606', (21, 29))	('low weight loss', 'Disease', (35, 50))	('survival', 'MPA', (79, 87))
714337	29764483	In contrast, analysis of patients with high weight loss rate (> 5.05%) showed that survival was significantly shorter in patient with T2DM than in those without T2DM (P = 0.001, Fig.	('weight loss', 'Disease', (44, 55))	('weight loss', 'Phenotype', 'HP:0001824', (44, 55))	('shorter', 'NegReg', (110, 117))	('T2DM', 'Var', (134, 138))	('patient', 'Species', '9606', (25, 32))	('patients', 'Species', '9606', (25, 33))	('weight loss', 'Disease', 'MESH:D015431', (44, 55))	('patient', 'Species', '9606', (121, 128))	('survival', 'MPA', (83, 91))
714342	29764483	Analysis of the subgroup of patients with weight loss rate <= 5.05% showed that OS was significantly longer in patients with T2DM than in those without T2DM, whereas analysis of the subgroup with weight loss rate > 5.05% showed that OS was significantly shorter in patients with T2DM than in those without T2DM.	('T2DM', 'Var', (125, 129))	('longer', 'PosReg', (101, 107))	('OS', 'Chemical', '-', (233, 235))	('weight loss', 'Disease', (196, 207))	('OS', 'Chemical', '-', (80, 82))	('weight loss', 'Disease', 'MESH:D015431', (42, 53))	('shorter', 'NegReg', (254, 261))	('weight loss', 'Phenotype', 'HP:0001824', (196, 207))	('weight loss', 'Disease', (42, 53))	('patients', 'Species', '9606', (265, 273))	('weight loss', 'Phenotype', 'HP:0001824', (42, 53))	('patients', 'Species', '9606', (28, 36))	('weight loss', 'Disease', 'MESH:D015431', (196, 207))	('patients', 'Species', '9606', (111, 119))
714350	29764483	Our findings also demonstrated that the rate of anastomotic leakage was almost threefold higher in patients with T2DM than in those without T2DM.	('patients', 'Species', '9606', (99, 107))	('anastomotic leakage', 'MPA', (48, 67))	('higher', 'PosReg', (89, 95))	('T2DM', 'Var', (113, 117))
714372	29506341	The rate of p16 expression was also significantly higher in the RE+ group than in the other two groups (p=0.003).	('RE+', 'Var', (64, 67))	('higher', 'PosReg', (50, 56))	('p16', 'Gene', '1029', (12, 15))	('p16', 'Gene', (12, 15))	('expression', 'MPA', (16, 26))
714412	29506341	The incidence of positive p16 expression was significantly higher in the RE+ group than in the other two groups (Table 4).	('p16', 'Gene', (26, 29))	('expression', 'MPA', (30, 40))	('RE+', 'Var', (73, 76))	('p16', 'Gene', '1029', (26, 29))	('higher', 'PosReg', (59, 65))
714425	29506341	Additionally, p16 was found to be a key regulator at the G1-S checkpoint in the cell cycle, and functional alterations in its expression may be important in carcinogenesis.	('important', 'Reg', (144, 153))	('p16', 'Gene', '1029', (14, 17))	('expression', 'MPA', (126, 136))	('carcinogenesis', 'Disease', 'MESH:D063646', (157, 171))	('alterations', 'Var', (107, 118))	('p16', 'Gene', (14, 17))	('carcinogenesis', 'Disease', (157, 171))
714437	28927085	The Kaplan-Meier method and Cox multi-factor analysis indicated that high GRObeta expression, lymph node metastasis and histopathological grade were significantly associated with poor survival of patients with LSCC.	('lymph node metastasis', 'CPA', (94, 115))	('expression', 'MPA', (82, 92))	('LSCC', 'Disease', (210, 214))	('patients', 'Species', '9606', (196, 204))	('Cox', 'Gene', (28, 31))	('Cox', 'Gene', '1351', (28, 31))	('LSCC', 'Phenotype', 'HP:0012118', (210, 214))	('poor', 'NegReg', (179, 183))	('high', 'Var', (69, 73))	('GRObeta', 'Gene', (74, 81))	('GRObeta', 'Gene', '2920', (74, 81))
714489	28927085	A previous study also confirmed that high GROalpha expression is associated with an aggressive malignant phenotype of LSCC, and GROalpha may be a valuable prognostic biomarker for patients with LSCC.	('LSCC', 'Phenotype', 'HP:0012118', (118, 122))	('high', 'Var', (37, 41))	('LSCC', 'Phenotype', 'HP:0012118', (194, 198))	('GROalpha', 'Gene', (42, 50))	('GROalpha', 'Gene', '2919', (128, 136))	('associated', 'Reg', (65, 75))	('GROalpha', 'Gene', '2919', (42, 50))	('GROalpha', 'Gene', (128, 136))	('expression', 'MPA', (51, 61))	('patients', 'Species', '9606', (180, 188))	('LSCC', 'Disease', (118, 122))
714506	28927085	In the present study, high GRObeta expression in LSCC was associated with three clinical pathological characteristics, namely TNM stage, lymph node metastasis and histopathological grade.	('TNM stage', 'Disease', (126, 135))	('associated', 'Reg', (58, 68))	('GRObeta', 'Gene', '2920', (27, 34))	('GRObeta', 'Gene', (27, 34))	('high', 'Var', (22, 26))	('expression', 'MPA', (35, 45))	('clinical', 'Species', '191496', (80, 88))	('LSCC', 'Phenotype', 'HP:0012118', (49, 53))	('lymph', 'Disease', (137, 142))
714507	28927085	In addition, univariate and multivariate analysis revealed the prognostic value of GRObeta overexpression, indicating that patients with LSCC with high GRObeta expression may have poor prognoses.	('expression', 'MPA', (160, 170))	('LSCC', 'Disease', (137, 141))	('LSCC', 'Phenotype', 'HP:0012118', (137, 141))	('GRObeta', 'Gene', (83, 90))	('GRObeta', 'Gene', '2920', (83, 90))	('patients', 'Species', '9606', (123, 131))	('GRObeta', 'Gene', (152, 159))	('high', 'Var', (147, 151))	('GRObeta', 'Gene', '2920', (152, 159))
714508	28927085	The Kaplan-Meier curve also implied that high GRObeta expression in patients with LSCC indicated unfavorable overall survival.	('LSCC', 'Disease', (82, 86))	('LSCC', 'Phenotype', 'HP:0012118', (82, 86))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (68, 76))	('GRObeta', 'Gene', (46, 53))	('GRObeta', 'Gene', '2920', (46, 53))
714509	28927085	The obtained data were consistent with the results of a previous study, which illustrated that high GRObeta expression was associated with poor prognosis and contributed to ovarian cancer tumorigenesis and metastasis.	('tumor', 'Disease', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('ovarian cancer', 'Disease', (173, 187))	('GRObeta', 'Gene', (100, 107))	('high', 'Var', (95, 99))	('GRObeta', 'Gene', '2920', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('ovarian cancer', 'Phenotype', 'HP:0100615', (173, 187))	('expression', 'MPA', (108, 118))	('contributed to', 'Reg', (158, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (173, 187))	('metastasis', 'CPA', (206, 216))
714511	28927085	The results revealed that high GRObeta expression may be associated with the development and progression of LSCC.	('GRObeta', 'Gene', (31, 38))	('high', 'Var', (26, 30))	('GRObeta', 'Gene', '2920', (31, 38))	('LSCC', 'Disease', (108, 112))	('expression', 'MPA', (39, 49))	('LSCC', 'Phenotype', 'HP:0012118', (108, 112))	('associated', 'Reg', (57, 67))
714541	24913395	Both an increased NO synthesis and a reduction in PP were observed after eNOS and neuronal NOS (nNOS) isoforms of NOS were transfected.	('nNOS', 'Gene', '4842', (96, 100))	('neuronal NOS', 'Gene', '4842', (82, 94))	('reduction', 'NegReg', (37, 46))	('NO synthesis', 'MPA', (18, 30))	('neuronal NOS', 'Gene', (82, 94))	('nNOS', 'Gene', (96, 100))	('transfected', 'Var', (123, 134))
714542	24913395	Accordingly, both superoxide dismutase (SOD) gene transfer and reduction of superoxide activity have been shown to reduce PP in CCl4 cirrhotic rats.	('rats', 'Species', '10116', (143, 147))	('superoxide', 'Chemical', 'MESH:D013481', (76, 86))	('superoxide', 'Chemical', 'MESH:D013481', (18, 28))	('CCl4', 'Chemical', 'MESH:D002251', (128, 132))	('gene transfer', 'Var', (45, 58))	('superoxide activity', 'MPA', (76, 95))	('reduction', 'NegReg', (63, 72))	('reduce', 'NegReg', (115, 121))
714545	24913395	Specifically, experimental supplementation of BH4 improved endothelial dysfunction.	('endothelial dysfunction', 'MPA', (59, 82))	('supplementation', 'Var', (27, 42))	('improved', 'PosReg', (50, 58))	('BH4', 'Gene', (46, 49))	('BH4', 'Chemical', 'MESH:C003402', (46, 49))
714572	24913395	Cumulative risk of variceal growth at 2, 3, 4 and 5 years were significantly lower for nadolol than for placebo (p<0.001).	('lower', 'NegReg', (77, 82))	('nadolol', 'Var', (87, 94))	('nadolol', 'Chemical', 'MESH:D009248', (87, 94))	('variceal growth', 'Disease', (19, 34))
714597	24913395	Finally, within a group of compensated, patients, the presence of CSPH showed a 6-fold increase in the incidence of HCC.	('CSPH', 'Gene', (66, 70))	('CSPH', 'Chemical', '-', (66, 70))	('increase', 'PosReg', (87, 95))	('patients', 'Species', '9606', (40, 48))	('presence', 'Var', (54, 62))	('HCC', 'Disease', (116, 119))
714605	24913395	However, when the hemodynamic response was analyzed according to the presence/absence of CSPH, it was observed that patients with CSPH had a significant drop in HVPG, while those without CSPH did not Responsiveness at this stage may depend on an already developed hyperdynamic circulation and collateralization of the portal venous system.	('CSPH', 'Var', (130, 134))	('CSPH', 'Chemical', '-', (187, 191))	('patients', 'Species', '9606', (116, 124))	('drop', 'NegReg', (153, 157))	('CSPH', 'Chemical', '-', (130, 134))	('CSPH', 'Chemical', '-', (89, 93))	('HVPG', 'MPA', (161, 165))
714627	24913395	There is evidence that SVR in patients with advanced fibrosis is associated with a significant decreased of clinical decompensation and HCC.	('decreased', 'NegReg', (95, 104))	('fibrosis', 'Disease', 'MESH:D005355', (53, 61))	('clinical decompensation', 'CPA', (108, 131))	('SVR', 'Var', (23, 26))	('patients', 'Species', '9606', (30, 38))	('HCC', 'Disease', (136, 139))	('fibrosis', 'Disease', (53, 61))
714662	24891992	Moreover, the presence of H pylori infection lowers the risk of esophageal cancer.	('presence', 'Var', (14, 22))	('lowers', 'NegReg', (45, 51))	('H pylori infection', 'Disease', 'MESH:D016481', (26, 44))	('H pylori infection', 'Phenotype', 'HP:0005202', (26, 44))	('H pylori infection', 'Disease', (26, 44))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
714713	24891992	Inhibition of FXR (by guggulsterone) induced apoptosis in vitro and reduced tumor formation and growth in nude mouse xenografts.	('mouse', 'Species', '10090', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('FXR', 'Gene', (14, 17))	('guggulsterone', 'Chemical', 'MESH:C023617', (22, 35))	('Inhibition', 'Var', (0, 10))	('apoptosis', 'CPA', (45, 54))	('reduced', 'NegReg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
714723	24891992	Additionally, in breast cancer cell lines MCF-7 and MDA-MB-468, the FXR CDCA-like ligand GW4064 induced SHP, the atypical nuclear receptor that down-regulates genes by interacting with other nuclear receptors including the estrogen receptor to prevent gene transcription.	('SHP', 'Gene', (104, 107))	('GW4064', 'Chemical', 'MESH:C412815', (89, 95))	('SHP', 'Gene', '8431', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('MCF-7', 'CellLine', 'CVCL:0031', (42, 47))	('down-regulates', 'NegReg', (144, 158))	('breast cancer', 'Disease', (17, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('genes', 'MPA', (159, 164))	('interacting', 'Interaction', (168, 179))	('prevent', 'NegReg', (244, 251))	('CDCA', 'Chemical', 'MESH:D002635', (72, 76))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (52, 62))	('gene transcription', 'MPA', (252, 270))	('GW4064', 'Var', (89, 95))
714763	24891992	SN-38 is then metabolized into the inactive metabolite SN38G by the liver via glucuronidation and excreted in the bile.	('SN38G', 'Var', (55, 60))	('SN-38', 'Chemical', 'MESH:D000077146', (0, 5))	('glucuronidation', 'MPA', (78, 93))
714769	24891992	Inhibitors of bacterial beta-glucuronidases protect mice from diarrhea without altering the microbiome or harming mammalian cells.	('beta-glucuronidase', 'Gene', '2990', (24, 42))	('diarrhea', 'Phenotype', 'HP:0002014', (62, 70))	('mammalian', 'Species', '9606', (114, 123))	('Inhibitors', 'Var', (0, 10))	('diarrhea', 'Disease', (62, 70))	('mice', 'Species', '10090', (52, 56))	('beta-glucuronidase', 'Gene', (24, 42))	('diarrhea', 'Disease', 'MESH:D003967', (62, 70))
714772	24891992	For example, in the digestive lumen in one animal model, the presence of beta-glucuronidase increased the genotoxicity of heterocyclic amines by 300%.	('beta-glucuronidase', 'Gene', '2990', (73, 91))	('genotoxicity of heterocyclic amines', 'MPA', (106, 141))	('increased', 'PosReg', (92, 101))	('presence', 'Var', (61, 69))	('heterocyclic amines', 'Chemical', '-', (122, 141))	('beta-glucuronidase', 'Gene', (73, 91))
714782	24891992	Of note, heterocyclic amines are less genotoxic and carcinogenic in individuals who consume mainly plant-derived foods.	('carcinogenic', 'Disease', 'MESH:D063646', (52, 64))	('heterocyclic', 'Var', (9, 21))	('heterocyclic amines', 'Chemical', '-', (9, 28))	('carcinogenic', 'Disease', (52, 64))
714817	24891992	Digestion results in glucose that can undergo anaerobic glycolysis to acetyl-CoA, the terminal oxidation product of glycolysis.	('Digestion', 'Var', (0, 9))	('glucose', 'Chemical', 'MESH:D005947', (21, 28))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (70, 80))	('anaerobic glycolysis to acetyl-CoA', 'MPA', (46, 80))
714824	24891992	Numerous studies in multiple colorectal cell lines have demonstrated that butyrate inhibits cell proliferation and stimulates apoptosis.	('inhibits', 'NegReg', (83, 91))	('apoptosis', 'CPA', (126, 135))	('butyrate', 'Chemical', 'MESH:D002087', (74, 82))	('butyrate', 'Var', (74, 82))	('stimulates', 'PosReg', (115, 125))	('cell proliferation', 'CPA', (92, 110))
714838	24891992	Evidence supports GPR109A as a tumor suppressor in breast tissue.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('breast tissue', 'Disease', (51, 64))	('GPR109A', 'Var', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
714839	24891992	As with colon cancer, its re-expression and butyrate binding may induce apoptosis.	('colon cancer', 'Disease', 'MESH:D015179', (8, 20))	('butyrate', 'Protein', (44, 52))	('colon cancer', 'Disease', (8, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('re-expression', 'Var', (26, 39))	('induce', 'PosReg', (65, 71))	('butyrate', 'Chemical', 'MESH:D002087', (44, 52))	('apoptosis', 'CPA', (72, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (8, 20))	('binding', 'Interaction', (53, 60))
714840	24891992	In the MMTV/neu mouse model of spontaneous breast cancer, deletion of GPR109A increased tumor incidence, triggered early onset of tumorigenesis, and increased lung metastasis.	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('MMTV', 'Species', '11757', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('increased', 'PosReg', (149, 158))	('GPR109A', 'Gene', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('increased', 'PosReg', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (88, 93))	('mouse', 'Species', '10090', (16, 21))	('deletion', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (130, 135))	('lung metastasis', 'CPA', (159, 174))
714865	24891992	In all three microbial transformations discussed here, a low-animal fat/high-vegetable diet is associated with beneficial ecological profiles including decreased production of toxic bile acids, decreased de-glucuronidation, and increased butyrate production.	('bile acids', 'Chemical', 'MESH:D001647', (182, 192))	('butyrate', 'Chemical', 'MESH:D002087', (238, 246))	('de-glucuronidation', 'MPA', (204, 222))	('decreased', 'NegReg', (152, 161))	('butyrate production', 'MPA', (238, 257))	('increased', 'PosReg', (228, 237))	('low-animal', 'Var', (57, 67))	('decreased', 'NegReg', (194, 203))	('production of toxic bile acids', 'MPA', (162, 192))
714895	22375181	Postoperative findings demonstrated a squamous cell carcinoma of the stomach, pT4N2M0 with serosa invasion, 4 out of 41 local lymph nodes metastasis with perineurovascular invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('squamous cell carcinoma of the stomach', 'Disease', 'MESH:D002294', (38, 76))	('squamous cell carcinoma of the stomach', 'Disease', (38, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('pT4N2M0', 'Var', (78, 85))
714930	22178570	Multivariable mixed models adjusting for familial correlations showed that multiplex kindreds were associated with a younger age of cancer diagnosis (p = 0.0186).	('multiplex', 'Var', (75, 84))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
714962	22178570	Multiplex kindreds had a statistically significant greater chance of lung (p=0.0021), bone (p=0.0027) and liver (p=0.0234) cancer as compared to the other family types.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('liver', 'Disease', (106, 111))	('lung', 'Disease', (69, 73))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('bone', 'Disease', (86, 90))	('Multiplex', 'Var', (0, 9))
714964	22178570	Other risk factors such as high BMI and smoking, which have been positively associated with BE and EAC in previous studies, were inversely associated with multiplex FBE kindreds, suggesting that familial aggregation of BE and its associated cancers is not related to a common exposure to these environmental factors in family members.	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('BE', 'Phenotype', 'HP:0100580', (166, 168))	('EAC', 'Disease', (99, 102))	('high BMI', 'Var', (27, 35))	('BE', 'Phenotype', 'HP:0100580', (92, 94))	('cancers', 'Disease', 'MESH:D009369', (241, 248))	('BE', 'Phenotype', 'HP:0100580', (219, 221))	('cancers', 'Disease', (241, 248))
714977	22178570	However, we speculate that another reason could be that FBE is caused specifically by genetic variants that predispose to an injury to the esophagus or the development of intestinal metaplasia rather than a more general cancer susceptibility gene.	('caused', 'Reg', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('injury to the esophagus', 'Disease', (125, 148))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (171, 192))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('injury to the esophagus', 'Disease', 'MESH:D004938', (125, 148))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('variants', 'Var', (94, 102))	('cancer', 'Disease', (220, 226))	('intestinal metaplasia', 'Disease', (171, 192))	('FBE', 'Disease', (56, 59))
714985	22178570	However, this bias seems less likely given that multiplex families with an EAC proband did not have a lower mean age of diagnosis than multiplex families with a BE proband, as might be expected if cancer fear precipitated earlier diagnosis.	('EAC', 'Var', (75, 78))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('BE', 'Phenotype', 'HP:0100580', (161, 163))	('EAC', 'Phenotype', 'HP:0011459', (75, 78))
715003	18940647	Patients with resection of the tongue base may experience severe impairment of swallow function.	('resection', 'Var', (14, 23))	('Patients', 'Species', '9606', (0, 8))	('swallow function', 'MPA', (79, 95))	('impairment of swallow', 'Phenotype', 'HP:0002015', (65, 86))
715004	18940647	Resection of greater than 25% of the tongue base is associated with inability to trigger a pharyngeal swallow, difficulty clearing the bolus from the pharynx, and severe postsurgical aspiration.	('aspiration', 'Phenotype', 'HP:0002835', (183, 193))	('inability', 'Disease', 'MESH:D016388', (68, 77))	('Resection', 'Var', (0, 9))	('inability', 'Disease', (68, 77))	('trigger a pharyngeal swallow', 'MPA', (81, 109))	('clearing the bolus from the pharynx', 'MPA', (122, 157))
715048	18940647	Patients who receive hemilaryngectomy usually have fewer incidents of aspiration and achieve oral intake and return to a normal diet sooner than those who have had any type of supraglottic laryngectomy.	('aspiration', 'Disease', (70, 80))	('achieve', 'PosReg', (85, 92))	('fewer', 'NegReg', (51, 56))	('oral intake', 'MPA', (93, 104))	('Patients', 'Species', '9606', (0, 8))	('hemilaryngectomy', 'Var', (21, 37))	('aspiration', 'Phenotype', 'HP:0002835', (70, 80))
715053	18940647	Manometric studies of patients with total laryngectomy have indicated that the post-laryngectomy swallow is characterized by significantly lower resting pressures in the pharyngoesophageal (PE) segment, lower peak pressures after swallow, greater numbers of swallows with discoordination between contraction of the pharyngeal constrictors and relaxation of the PE segment, a loss of the normal negative pressure preceding the bolus, reduced pharyngeal clearing force, and loss of asymmetrical contractile forces when compared to subjects with normal anatomy.	('post-laryngectomy', 'Var', (79, 96))	('reduced', 'NegReg', (433, 440))	('peak pressures', 'MPA', (209, 223))	('lower', 'NegReg', (203, 208))	('asymmetrical contractile forces', 'MPA', (480, 511))	('loss', 'NegReg', (375, 379))	('swallow', 'Disease', (97, 104))	('resting pressures', 'MPA', (145, 162))	('swallows', 'MPA', (258, 266))	('loss', 'NegReg', (472, 476))	('patients', 'Species', '9606', (22, 30))	('lower', 'NegReg', (139, 144))	('pharyngeal clearing force', 'MPA', (441, 466))
715061	18940647	Although radiotherapy provides important curative benefits, it also induces damage in normal tissues and may result in mucositis, xerostomia, fibrosis, soft-tissue necrosis, and osteoradionecrosis of the mandible.	('radiotherapy', 'Var', (9, 21))	('induces', 'Reg', (68, 75))	('mucositis', 'Disease', 'MESH:D052016', (119, 128))	('necrosis', 'Disease', (164, 172))	('necrosis', 'Disease', 'MESH:D009336', (188, 196))	('osteoradionecrosis of the mandible', 'Phenotype', 'HP:0007626', (178, 212))	('xerostomia', 'Disease', (130, 140))	('fibrosis', 'Disease', (142, 150))	('result in', 'Reg', (109, 118))	('necrosis', 'Disease', 'MESH:D009336', (164, 172))	('fibrosis', 'Disease', 'MESH:D005355', (142, 150))	('tissue necrosis', 'Phenotype', 'HP:0010885', (157, 172))	('xerostomia', 'Phenotype', 'HP:0000217', (130, 140))	('mucositis', 'Disease', (119, 128))	('xerostomia', 'Disease', 'MESH:D014987', (130, 140))	('necrosis', 'Disease', (188, 196))
715063	18940647	Many investigators have found that oropharyngeal functioning is worse in patients receiving postoperative radiotherapy when compared with those with surgical excision only.	('patients', 'Species', '9606', (73, 81))	('radiotherapy', 'Var', (106, 118))	('oropharyngeal functioning', 'CPA', (35, 60))
715074	18940647	Patients with resections involving the oral tongue will experience difficulty with bolus formation, slowed oral transit, and increased oral residue.	('oral transit', 'MPA', (107, 119))	('increased', 'PosReg', (125, 134))	('slowed', 'NegReg', (100, 106))	('Patients', 'Species', '9606', (0, 8))	('bolus formation', 'MPA', (83, 98))	('oral residue', 'MPA', (135, 147))	('resections', 'Var', (14, 24))	('difficulty with bolus formation', 'Phenotype', 'HP:0031146', (67, 98))
715076	18940647	When resection involves the tongue base or arytenoid cartilage, the risk of aspiration increases.	('aspiration', 'Disease', (76, 86))	('arytenoid cartilage', 'Disease', 'MESH:D002357', (43, 62))	('arytenoid cartilage', 'Disease', (43, 62))	('resection', 'Var', (5, 14))	('aspiration', 'Phenotype', 'HP:0002835', (76, 86))
715107	18940647	It is reported that 100% of patients who receive altered fractionation (twice daily treatments) have mucositis, with more than half experiencing the highest grades (worst level) of this toxicity.	('mucositis', 'Disease', (101, 110))	('altered', 'Var', (49, 56))	('mucositis', 'Disease', 'MESH:D052016', (101, 110))	('toxicity', 'Disease', 'MESH:D064420', (186, 194))	('toxicity', 'Disease', (186, 194))	('patients', 'Species', '9606', (28, 36))
715146	18940647	Changes in head or body position have been shown to eliminate aspiration of at least one liquid bolus volume in 77% of patients with various medical diagnoses and in 81% of postsurgical head and neck cancer patients.	('eliminate', 'NegReg', (52, 61))	('head and neck cancer', 'Disease', 'MESH:D006258', (186, 206))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('patients', 'Species', '9606', (119, 127))	('aspiration of at least one liquid bolus volume', 'MPA', (62, 108))	('Changes', 'Var', (0, 7))	('head and neck cancer', 'Phenotype', 'HP:0012288', (186, 206))	('aspiration', 'Phenotype', 'HP:0002835', (62, 72))
715157	18940647	Head rotation to the weaker side causes the bolus to lateralize away from the direction of rotation, and also increases upper esophageal sphincter (UES) opening diameter while causing a significant reduction in UES pressure.	('reduction', 'NegReg', (198, 207))	('lateralize', 'MPA', (53, 63))	('bolus', 'MPA', (44, 49))	('Head rotation', 'Var', (0, 13))	('increases', 'PosReg', (110, 119))	('upper esophageal sphincter', 'Disease', 'MESH:D009122', (120, 146))	('UES pressure', 'MPA', (211, 223))	('upper esophageal sphincter', 'Disease', (120, 146))
715244	18940647	Given the potential for surface NMES to actually depress the hyoid and larynx, the clinician should proceed with caution when considering use of this technique with treated head and neck cancer patients.	('patients', 'Species', '9606', (194, 202))	('surface NMES', 'Var', (24, 36))	('actually depress the hyoid', 'Disease', 'MESH:D000275', (40, 66))	('head and neck cancer', 'Phenotype', 'HP:0012288', (173, 193))	('actually depress the hyoid', 'Disease', (40, 66))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('NMES', 'Var', (32, 36))	('head and neck cancer', 'Disease', 'MESH:D006258', (173, 193))
715311	32924793	Mutational signatures that cause somatic mutations in ESCC were described and driver genes contributing to tumorigenesis of ESCC were identified.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('ESCC', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
715312	32924793	Our previous study demonstrated that ZNF750 mutations encoding truncated or disrupted proteins might contribute to ESCC tumorigenesis.	('contribute', 'Reg', (101, 111))	('proteins', 'Protein', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('ZNF750', 'Gene', (37, 43))	('disrupted proteins', 'Protein', (76, 94))	('tumor', 'Disease', (120, 125))
715318	32924793	The present study revealed that inhibiting KDR might be a therapy option for patients with ESCC, especially harboring the ZNF750 inactivating variation.	('ESCC', 'Disease', (91, 95))	('patients', 'Species', '9606', (77, 85))	('KDR', 'Protein', (43, 46))	('inhibiting', 'Var', (32, 42))	('ZNF750', 'Gene', (122, 128))
715328	32924793	The target ESCC cells (KYSE150 and KYSE140 with stable ZNF750 knockdown) were infected with lentiviral particles and incubated at 37 C for 24 h and then the viral supernatant was replaced with fresh media.	('ZNF750', 'Gene', (55, 61))	('infected', 'Disease', 'MESH:D007239', (78, 86))	('infected', 'Disease', (78, 86))	('knockdown', 'Var', (62, 71))
715330	32924793	The wild-type ZNF750 gene was cloned into the lentivirus expression vector to produce pLV[Exp]-mCherry/Neo-EF1A>HA/hZNF750, with multiplicity of infection values of 150.	('hZNF750', 'Gene', (115, 122))	('pLV', 'Var', (86, 89))	('infection', 'Disease', (145, 154))	('ZNF750', 'Gene', (14, 20))	('infection', 'Disease', 'MESH:D007239', (145, 154))	('EF1A', 'Gene', (107, 111))	('EF1A', 'Gene', '1917', (107, 111))	('hZNF750', 'Gene', '79755', (115, 122))
715354	32924793	In addition, only 5 out of 196 genes whose mutation frequency was 2.5-5% had known drug-gene interactions, including patched 1 (4.3%), erb-b2 receptor tyrosine kinase 4 (3.2%), NOTCH2 (2.8%), ATP binding cassette subfamily B member 1 (3.0%) and BRCA2 (2.6%); the first 3 genes were previously identified to be significantly mutated genes in ESCC (Figure 1A).	('erb-b2', 'Gene', (135, 141))	('NOTCH2', 'Gene', '4853', (177, 183))	('BRCA2', 'Gene', (245, 250))	('mutation', 'Var', (43, 51))	('receptor tyrosine kinase', 'Gene', (142, 166))	('ATP binding cassette subfamily B member 1', 'Gene', '5243', (192, 233))	('NOTCH2', 'Gene', (177, 183))	('receptor tyrosine kinase', 'Gene', '5979', (142, 166))	('BRCA2', 'Gene', '675', (245, 250))	('erb-b2', 'Gene', '2064', (135, 141))	('ESCC', 'Disease', (341, 345))	('ATP binding cassette subfamily B member 1', 'Gene', (192, 233))
715357	32924793	Although the mutation frequency was lower, KDR and EGFR harbored frequent and marked copy number amplification in ESCC.	('ESCC', 'Disease', (114, 118))	('EGFR', 'Gene', (51, 55))	('KDR', 'Gene', (43, 46))	('copy number amplification', 'Var', (85, 110))	('EGFR', 'Gene', '1956', (51, 55))
715368	32924793	In the process of studying the role of ZNF750 in ESCC, it was identified that ZNF750 knockdown resulted in a fold change >2 in the expression of 10 genes, including upregulated KDR using the human Cancer Pathway Finder RT Profiler PCR array (Figure 4B).	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Cancer', 'Disease', (197, 203))	('Cancer', 'Disease', 'MESH:D009369', (197, 203))	('KDR', 'Gene', (177, 180))	('upregulated', 'PosReg', (165, 176))	('expression', 'MPA', (131, 141))	('knockdown', 'Var', (85, 94))	('human', 'Species', '9606', (191, 196))	('ZNF750', 'Gene', (78, 84))
715373	32924793	Although most genetic alterations are passenger mutations that are not able to give cancer cells a selective growth advantage, an individual cell can gain a greater malignant phenotype if it acquires a sufficient series of genetic driving mutations.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('genetic alterations', 'Var', (14, 33))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('gain', 'PosReg', (150, 154))
715383	32924793	This result is consistent with the previous results that inhibition of the proteasome can induce autophagy in human ESCC cells and also increase cell death.	('inhibition', 'Var', (57, 67))	('autophagy', 'CPA', (97, 106))	('human', 'Species', '9606', (110, 115))	('proteasome', 'Protein', (75, 85))	('induce', 'PosReg', (90, 96))	('increase', 'PosReg', (136, 144))	('cell death', 'CPA', (145, 155))
715388	32924793	In ESCC, Xu et al indicated that the usage of species-specific neutralizing antibodies for KDR could suppress ESCC tumor growth, metastasis and angiogenesis in preclinical models, providing strong evidence of the importance of tumor micro-environments in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (227, 232))	('suppress', 'NegReg', (101, 109))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('tumor', 'Disease', (115, 120))	('neutralizing', 'Var', (63, 75))	('KDR', 'Gene', (91, 94))	('metastasis', 'CPA', (129, 139))	('angiogenesis', 'CPA', (144, 156))	('cancer', 'Disease', (255, 261))	('ESCC', 'Disease', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
715389	32924793	ZNF750 has been empirically proved to harbor frequently inactivating mutations in different types of human squamous cell carcinomas by previous independent studies.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('ZNF750', 'Gene', (0, 6))	('inactivating mutations', 'Var', (56, 78))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (107, 131))	('squamous cell carcinomas', 'Disease', (107, 131))	('human', 'Species', '9606', (101, 106))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (107, 131))
715390	32924793	In our previous study, mutations of ZNF750 were identified in 6% of ESCC tumors and ZNF750 deletions were observed in 21% of ESCC tumors.	('identified', 'Reg', (48, 58))	('ESCC tumors', 'Disease', (68, 79))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('ESCC tumors', 'Disease', 'MESH:D004938', (68, 79))	('deletions', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ESCC tumors', 'Disease', (125, 136))	('ZNF750', 'Gene', (84, 90))	('ESCC tumors', 'Disease', 'MESH:D004938', (125, 136))	('ZNF750', 'Gene', (36, 42))	('observed', 'Reg', (106, 114))
715398	31981293	A total of 86 endoscopic biopsy samples from EC patients who received neoadjuvant chemotherapy (NAC) prior to surgery were evaluated for the number of intratumoral CD4+ lymphocytes (with/without Foxp3 expression), CD8+ lymphocytes (with/without PD-1 expression), monocytes (CD14+) and macrophages (CD86+, CD163+ and CD206+) by multiplex immunohistochemistry (IHC).	('CD8', 'Gene', (214, 217))	('Foxp3', 'Gene', (195, 200))	('CD206', 'Gene', '4360', (316, 321))	('NAC', 'Chemical', '-', (96, 99))	('CD8', 'Gene', (298, 301))	('CD206', 'Gene', (316, 321))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('CD8', 'Gene', '925', (214, 217))	('CD8', 'Gene', '925', (298, 301))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('patients', 'Species', '9606', (48, 56))	('CD163+', 'Var', (305, 311))
715400	31981293	The high infiltration of CD163+ or CD206+ macrophages was significantly associated with poor pathological response to NAC (P = 0.0057 and 0.0196, respectively).	('CD163+', 'Var', (25, 31))	('CD206', 'Gene', (35, 40))	('NAC', 'Chemical', '-', (118, 121))	('CD206', 'Gene', '4360', (35, 40))
715422	31981293	The median cell counts in the 670 mum x 500 mum field were as follows: 189 for CD4+ lymphocytes, 73 for Foxp3+CD4+ lymphocytes, 204 for CD8+ lymphocytes, 15 for PD-1+CD8+ lymphocytes, 557 for CD14+ cells, 18.5 for CD86+ macrophages, 322 for CD163+ macrophages and 142 for CD206+ macrophages.	('CD8', 'Gene', (214, 217))	('CD206', 'Gene', '4360', (272, 277))	('CD206', 'Gene', (272, 277))	('CD8', 'Gene', (136, 139))	('CD8', 'Gene', '925', (214, 217))	('Foxp3+CD4+', 'Var', (104, 114))	('CD8', 'Gene', '925', (136, 139))	('CD8', 'Gene', (166, 169))	('CD8', 'Gene', '925', (166, 169))
715432	31981293	The number of tumor-infiltrating CD163+ (P = 0.0057) and CD206+ (P = 0.0196) macrophages was significantly higher in non-responders (histological grade 0-1b, n = 39) compared to responders (histological grade 2-3, n = 47), whereas the number of CD14+, CD4+, CD8+ and CD86+ cells did not correlate with the NAC response (P = 0.91, P = 0.34, P = 0.86 and P = 0.54, respectively; Figure 2A).	('CD8', 'Gene', (267, 270))	('tumor', 'Disease', (14, 19))	('CD8', 'Gene', '925', (267, 270))	('NAC', 'Chemical', '-', (306, 309))	('CD8', 'Gene', (258, 261))	('CD206', 'Gene', '4360', (57, 62))	('CD206', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('CD8', 'Gene', '925', (258, 261))	('higher', 'PosReg', (107, 113))	('CD163+', 'Var', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
715437	31981293	However, no significant correlation was identified between CD163+ or CD206+ macrophages and Foxp3+CD4+ lymphocytes (Figure S1; P = 0.36 and P = 0.94, respectively).	('CD163+', 'Var', (59, 65))	('CD206', 'Gene', '4360', (69, 74))	('CD206', 'Gene', (69, 74))
715439	31981293	The positivity of arginase-1 in CD163+ macrophages and CD206+ macrophages is 23.6% and 14.7%, respectively.	('CD206', 'Gene', '4360', (55, 60))	('CD206', 'Gene', (55, 60))	('arginase-1', 'Protein', (18, 28))	('positivity', 'Var', (4, 14))
715455	31981293	In contrast to the immune-suppressive function of Tregs, the ratio of Foxp3+ CD4+ lymphocytes was higher in responders than non-responders in the present analysis.	('higher', 'PosReg', (98, 104))	('Foxp3+', 'Var', (70, 76))	('Tregs', 'Chemical', '-', (50, 55))
715499	31836455	HPV impacts host function via protein interactions, or via integration into the host genome, which may additionally affect host gene expression.	('host gene expression', 'MPA', (123, 143))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Var', (0, 3))	('affect', 'Reg', (116, 122))	('host function', 'MPA', (12, 25))	('impacts', 'Reg', (4, 11))	('protein', 'Protein', (30, 37))
715502	31836455	In most SCCs HPV infections and TP53 mutations are mutually exclusive.	('TP53', 'Gene', '7157', (32, 36))	('SCCs HPV infections', 'Disease', (8, 27))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', (32, 36))	('SCCs HPV infections', 'Disease', 'MESH:D030361', (8, 27))	('SCCs', 'Phenotype', 'HP:0002860', (8, 12))
715503	31836455	Unlike HPV- HNSCCs, HPV+ ones preserve wild type alleles of TP53 and CDKN2A, and lack EGFR mutations.	('HPV', 'Species', '10566', (7, 10))	('CDKN2A', 'Gene', '1029', (69, 75))	('HPV', 'Species', '10566', (20, 23))	('EGFR', 'Gene', '1956', (86, 90))	('SCCs', 'Phenotype', 'HP:0002860', (14, 18))	('EGFR', 'Gene', (86, 90))	('TP53', 'Gene', '7157', (60, 64))	('mutations', 'Var', (91, 100))	('TP53', 'Gene', (60, 64))	('CDKN2A', 'Gene', (69, 75))	('lack', 'NegReg', (81, 85))
715505	31836455	Of importance, HPV+ HNSCCs typically exhibit better prognosis compared to the HPV- group, potentially associated with the preponderant wild type status of TP53 in the former group.	('SCCs', 'Phenotype', 'HP:0002860', (22, 26))	('TP53', 'Gene', '7157', (155, 159))	('better', 'PosReg', (45, 51))	('TP53', 'Gene', (155, 159))	('HPV', 'Species', '10566', (15, 18))	('HPV', 'Species', '10566', (78, 81))	('prognosis', 'CPA', (52, 61))	('HPV+ HNSCCs', 'Var', (15, 26))
715512	31836455	These HRAS-CASP8 mutated tumors, however, differ from their HPV+ counterparts in their methylation patterns, and each belongs to a hypermethylated cluster "C4" and "C2", respectively, when comparing across Pan-SCCs, resulting in suppressed candidate drivers e.g., TET1, FANCF and PAPRG.	('differ', 'Reg', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('TET1', 'Gene', (264, 268))	('PAPRG', 'Disease', (280, 285))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('FANCF', 'Gene', (270, 275))	('CASP8', 'Gene', '841', (11, 16))	('SCCs', 'Phenotype', 'HP:0002860', (210, 214))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('TET1', 'Gene', '80312', (264, 268))	('methylation', 'MPA', (87, 98))	('CASP8', 'Gene', (11, 16))	('HPV', 'Species', '10566', (60, 63))	('FANCF', 'Gene', '2188', (270, 275))	('mutated', 'Var', (17, 24))
715513	31836455	Unlike HPV+ group, "basal" group diverges considerably at the genomic level, encompassing tumors with HRAS/CASP8 mutations, NOTCH1 mutations, and those with 11q amplification.	('NOTCH1', 'Gene', (124, 130))	('mutations', 'Var', (131, 140))	('HPV', 'Species', '10566', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CASP8', 'Gene', (107, 112))	('CASP8', 'Gene', '841', (107, 112))	('tumors', 'Disease', (90, 96))	('mutations', 'Var', (113, 122))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('NOTCH1', 'Gene', '4851', (124, 130))
715515	31836455	The atypical subgroup of HPV- HNSCCs, unlike HPV+ counterparts, have a plethora of common HNSCC mutations including the universal loss of TP53 and CDKN2A.	('HNSCC', 'Gene', (90, 95))	('HPV', 'Species', '10566', (25, 28))	('TP53', 'Gene', '7157', (138, 142))	('HPV', 'Species', '10566', (45, 48))	('TP53', 'Gene', (138, 142))	('plethora', 'Phenotype', 'HP:0001050', (71, 79))	('loss', 'NegReg', (130, 134))	('CDKN2A', 'Gene', (147, 153))	('SCCs', 'Phenotype', 'HP:0002860', (32, 36))	('CDKN2A', 'Gene', '1029', (147, 153))	('mutations', 'Var', (96, 105))
715517	31836455	These two groups contain the most NFE2L2/KEAP1 mutations resulting in aberrant NRF2 signaling, harbor the majority of NSD1 mutations, and maintain NOTCH wild type status.	('NFE2L2', 'Gene', '4780', (34, 40))	('mutations', 'Var', (123, 132))	('NRF2', 'Gene', (79, 83))	('KEAP1', 'Gene', '9817', (41, 46))	('NSD1', 'Gene', '64324', (118, 122))	('mutations', 'Var', (47, 56))	('NFE2L2', 'Gene', (34, 40))	('KEAP1', 'Gene', (41, 46))	('NOTCH', 'Gene', '31293', (147, 152))	('NSD1', 'Gene', (118, 122))	('NOTCH', 'Gene', (147, 152))	('NRF2', 'Gene', '4780', (79, 83))	('resulting in', 'Reg', (57, 69))
715518	31836455	NFE2L2/KEAP1 mutated and NSD1 mutated tumors however exhibit minimal overlap with each other, and each belong to a methylation cluster "C1" and "C5", respectively.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('NSD1', 'Gene', (25, 29))	('tumors', 'Disease', (38, 44))	('KEAP1', 'Gene', '9817', (7, 12))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('NFE2L2', 'Gene', '4780', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mutated', 'Var', (30, 37))	('KEAP1', 'Gene', (7, 12))	('NFE2L2', 'Gene', (0, 6))	('NSD1', 'Gene', '64324', (25, 29))
715519	31836455	In particular, methylation C5 cluster exhibits a strong association with NSD1 mutations, and presents a unique hypomethylation pattern with activation of putative drivers, e.g., LCK, suggesting, suggesting a potential functional interaction between NSD1 and hypomethylation landscape within this group of HNSCCs.	('methylation', 'Var', (15, 26))	('LCK', 'Gene', (178, 181))	('LCK', 'Gene', '3932', (178, 181))	('NSD1', 'Gene', (73, 77))	('NSD1', 'Gene', '64324', (249, 253))	('mutations', 'Var', (78, 87))	('SCCs', 'Phenotype', 'HP:0002860', (307, 311))	('association', 'Interaction', (56, 67))	('NSD1', 'Gene', (249, 253))	('NSD1', 'Gene', '64324', (73, 77))	('hypomethylation', 'MPA', (111, 126))
715520	31836455	In addition, "classical" HPV- group tends to be enriched with HNSCCs harboring 3q26-3q28 amplification, the genomic region containing SOX2/PIK3CA/TP63 genes, even though it occurs universally in all groups.	('PIK3CA', 'Gene', '5290', (139, 145))	('HPV', 'Species', '10566', (25, 28))	('SCCs', 'Phenotype', 'HP:0002860', (64, 68))	('PIK3CA', 'Gene', (139, 145))	('3q26-3q28 amplification', 'Var', (79, 102))	('SOX2', 'Gene', '6657', (134, 138))	('HNSCCs', 'Disease', (62, 68))	('SOX2', 'Gene', (134, 138))
715521	31836455	In contrast, activating mutations in PIK3CA is prevalent in the "atypical" HPV- group.	('PIK3CA', 'Gene', '5290', (37, 43))	('prevalent', 'Reg', (47, 56))	('activating mutations', 'Var', (13, 33))	('HPV', 'Species', '10566', (75, 78))	('PIK3CA', 'Gene', (37, 43))
715534	31836455	ESCCs are strongly enriched for amplifications of CCND1, 3q26-3q28, FGFR1, and mutations of NOTCH1, ZNF750, KDM6A (UTX), whereas EACs are specifically enriched for amplifications of ERBB2, VEGFA, GATA4, GATA6, and mutations in SMAD4 and ARID1A.	('GATA4', 'Gene', (196, 201))	('CCND1', 'Gene', '595', (50, 55))	('ZNF750', 'Gene', '79755', (100, 106))	('mutations', 'Var', (79, 88))	('NOTCH1', 'Gene', (92, 98))	('CCND1', 'Gene', (50, 55))	('mutations', 'Var', (214, 223))	('ZNF750', 'Gene', (100, 106))	('FGFR1', 'Gene', '2260', (68, 73))	('ERBB2', 'Gene', (182, 187))	('GATA6', 'Gene', '2627', (203, 208))	('SMAD4', 'Gene', (227, 232))	('GATA4', 'Gene', '2626', (196, 201))	('3q26-3q28', 'Gene', (57, 66))	('KDM6A', 'Gene', '7403', (108, 113))	('VEGFA', 'Gene', (189, 194))	('NOTCH1', 'Gene', '4851', (92, 98))	('UTX', 'Gene', (115, 118))	('ARID1A', 'Gene', (237, 243))	('UTX', 'Gene', '7403', (115, 118))	('ERBB2', 'Gene', '2064', (182, 187))	('SMAD4', 'Gene', '4089', (227, 232))	('FGFR1', 'Gene', (68, 73))	('ARID1A', 'Gene', '8289', (237, 243))	('VEGFA', 'Gene', '7422', (189, 194))	('KDM6A', 'Gene', (108, 113))	('GATA6', 'Gene', (203, 208))	('SCCs', 'Phenotype', 'HP:0002860', (1, 5))
715535	31836455	CDKN2A is inactivated in both, yet it is mainly through deletion in ESCCs and epigenetic silencing in EACs.	('deletion', 'Var', (56, 64))	('SCCs', 'Phenotype', 'HP:0002860', (69, 73))	('CDKN2A', 'Gene', (0, 6))	('epigenetic silencing', 'Var', (78, 98))	('CDKN2A', 'Gene', '1029', (0, 6))
715537	31836455	ESCC1 is prevalent in Asian patients, exhibits highly aberrant NRF2 signaling due to NFE2L2/KEAP1/CUL3 mutations, accompanied with characteristic 3q amplification.	('KEAP1', 'Gene', (92, 97))	('mutations', 'Var', (103, 112))	('ESCC1', 'Gene', (0, 5))	('NRF2', 'Gene', (63, 67))	('CUL3', 'Gene', '8452', (98, 102))	('CUL3', 'Gene', (98, 102))	('NFE2L2', 'Gene', '4780', (85, 91))	('NFE2L2', 'Gene', (85, 91))	('aberrant', 'PosReg', (54, 62))	('KEAP1', 'Gene', '9817', (92, 97))	('patients', 'Species', '9606', (28, 36))	('NRF2', 'Gene', '4780', (63, 67))
715539	31836455	A second ESCC subgroup, ESCC2 appears more common in East European and South American populations, exhibiting frequent NOTCH1 and ZNF750 mutations, features shared with the HNSCCs "basal" subgroup (Figure 1).	('SCCs', 'Phenotype', 'HP:0002860', (175, 179))	('NOTCH1', 'Gene', '4851', (119, 125))	('ZNF750', 'Gene', '79755', (130, 136))	('mutations', 'Var', (137, 146))	('NOTCH1', 'Gene', (119, 125))	('ZNF750', 'Gene', (130, 136))
715540	31836455	APOBEC mutational signature is stronger in ESCCs compared to EACs, and appears to be further enriched in this particular ESCC2 group, especially patients from Ukraine and Russia.	('patients', 'Species', '9606', (145, 153))	('ESCCs', 'Disease', (43, 48))	('stronger', 'PosReg', (31, 39))	('APOBEC', 'Gene', (0, 6))	('SCCs', 'Phenotype', 'HP:0002860', (44, 48))	('mutational', 'Var', (7, 17))
715541	31836455	A third ESCC subgroup, ESCC3 has only very few cases and are found in North America populations, characterized by mutations in ATG7, KMT2D (MLL2), PTEN, PIK3CA (activating), with lower TP53 mutation rates compared to other ESCCs.	('PIK3CA', 'Gene', '5290', (153, 159))	('ATG7', 'Gene', '10533', (127, 131))	('lower', 'NegReg', (179, 184))	('TP53', 'Gene', (185, 189))	('mutations', 'Var', (114, 123))	('MLL2', 'Gene', '8085', (140, 144))	('mutation rates', 'MPA', (190, 204))	('KMT2D', 'Gene', (133, 138))	('KMT2D', 'Gene', '8085', (133, 138))	('SCCs', 'Phenotype', 'HP:0002860', (224, 228))	('PTEN', 'Gene', '5728', (147, 151))	('ATG7', 'Gene', (127, 131))	('PTEN', 'Gene', (147, 151))	('MLL2', 'Gene', (140, 144))	('PIK3CA', 'Gene', (153, 159))	('TP53', 'Gene', '7157', (185, 189))
715542	31836455	All four ESCC3 cases under study uniquely harbor SMARCA4 mutations not shared with any other SCCs.	('SMARCA4', 'Gene', (49, 56))	('ESCC3', 'Gene', (9, 14))	('SMARCA4', 'Gene', '6597', (49, 56))	('mutations', 'Var', (57, 66))	('SCCs', 'Phenotype', 'HP:0002860', (93, 97))	('harbor', 'Reg', (42, 48))
715550	31836455	The "classical" group strongly resembles those of "classical" HNSCCs and ESCC1 tumors (Figure 1), exhibiting high level of NRF2 signaling deregulation due to NFE2L2/KEAP1/CUL3 mutations.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mutations', 'Var', (176, 185))	('NFE2L2', 'Gene', '4780', (158, 164))	('CUL3', 'Gene', '8452', (171, 175))	('KEAP1', 'Gene', (165, 170))	('CUL3', 'Gene', (171, 175))	('NFE2L2', 'Gene', (158, 164))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('NRF2', 'Gene', '4780', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('KEAP1', 'Gene', '9817', (165, 170))	('SCCs', 'Phenotype', 'HP:0002860', (64, 68))	('NRF2', 'Gene', (123, 127))
715551	31836455	Largely absent in this group are NOTCH mutations, along with newly discovered ASCL4 and FOXP1 mutations.	('FOXP1', 'Gene', (88, 93))	('NOTCH', 'Gene', '31293', (33, 38))	('mutations', 'Var', (94, 103))	('NOTCH', 'Gene', (33, 38))	('ASCL4', 'Gene', (78, 83))	('FOXP1', 'Gene', '27086', (88, 93))	('ASCL4', 'Gene', '121549', (78, 83))
715553	31836455	Interestingly, LSCC "basal" group exhibits NF1 mutations that are uncommon in other SCCs.	('LSCC', 'Phenotype', 'HP:0030359', (15, 19))	('NF1', 'Gene', (43, 46))	('mutations', 'Var', (47, 56))	('NF1', 'Gene', '4763', (43, 46))	('SCCs', 'Phenotype', 'HP:0002860', (84, 88))
715555	31836455	In contrast, NKX2-1 amplification, KRAS activation and STK11 inactivation are frequent in LAC but are rare in LSCCs.	('inactivation', 'Var', (61, 73))	('STK11', 'Gene', '6794', (55, 60))	('LAC', 'Phenotype', 'HP:0030078', (90, 93))	('KRAS', 'Gene', (35, 39))	('NKX2-1', 'Gene', '7080', (13, 19))	('KRAS', 'Gene', '3845', (35, 39))	('LSCC', 'Phenotype', 'HP:0030359', (110, 114))	('STK11', 'Gene', (55, 60))	('SCCs', 'Phenotype', 'HP:0002860', (111, 115))	('LAC', 'Disease', (90, 93))	('NKX2-1', 'Gene', (13, 19))
715556	31836455	EGFR alterations have been found in both, although their frequencies and types of mutations differ.	('alterations', 'Var', (5, 16))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
715558	31836455	In this regard, efforts have been made to seek targetable oncogenic events enriched in LSCCs, e,g., DDR2 and FGFR mutations.	('mutations', 'Var', (114, 123))	('DDR2', 'Gene', '4921', (100, 104))	('LSCCs', 'Disease', (87, 92))	('LSCC', 'Phenotype', 'HP:0030359', (87, 91))	('DDR2', 'Gene', (100, 104))	('SCCs', 'Phenotype', 'HP:0002860', (88, 92))	('FGFR', 'Gene', (109, 113))
715565	31836455	Cervical adenocarcinomas belong to the "adeno" subgroup based on integrative molecular analysis, and diverge from CxSCCs with frequent amplifications of 17q12 (ERBB2), BCAR4 long non-coding RNA, 13q22 (KLF5), significant activation of hormonal signaling and ERalpha, FOXA1, FOXA2, FGFR1 pathways, and expression of KRT18 (non-stratified simple epithelial keratin).	('KLF5', 'Gene', '688', (202, 206))	('KRT18', 'Gene', '3875', (315, 320))	('17q12', 'Gene', (153, 158))	('KRT18', 'Gene', (315, 320))	('ERalpha', 'Gene', '2099', (258, 265))	('amplifications', 'Var', (135, 149))	('BCAR4', 'Gene', '400500', (168, 173))	('KLF5', 'Gene', (202, 206))	('FOXA1', 'Gene', '3169', (267, 272))	('ERBB2', 'Gene', (160, 165))	('FGFR1', 'Gene', '2260', (281, 286))	('FOXA1', 'Gene', (267, 272))	('FOXA2', 'Gene', (274, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('SCCs', 'Phenotype', 'HP:0002860', (116, 120))	('ERBB2', 'Gene', '2064', (160, 165))	('hormonal signaling', 'Pathway', (235, 253))	('FOXA2', 'Gene', '3170', (274, 279))	('adenocarcinomas', 'Disease', 'MESH:D000230', (9, 24))	('adenocarcinomas', 'Disease', (9, 24))	('FGFR1', 'Gene', (281, 286))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('activation', 'PosReg', (221, 231))	('BCAR4', 'Gene', (168, 173))	('ERalpha', 'Gene', (258, 265))
715567	31836455	APOBEC mutagenesis signature is pronounced in cervical cancers across all groups, but is infrequent in the minority HPV- group, which is more closely related to endometrial carcinomas.	('HPV', 'Species', '10566', (116, 119))	('cervical cancers', 'Disease', 'MESH:D002583', (46, 62))	('mutagenesis', 'Var', (7, 18))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (161, 183))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('endometrial carcinomas', 'Disease', (161, 183))	('APOBEC', 'Gene', (0, 6))	('pronounced', 'Reg', (32, 42))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cervical cancers', 'Disease', (46, 62))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (161, 183))
715569	31836455	Keratin-high group is also enriched with PIK3CA, MAPK1, NFE2L2 and TGFBR2 mutations.	('TGFBR2', 'Gene', '7048', (67, 73))	('MAPK1', 'Gene', '5594', (49, 54))	('mutations', 'Var', (74, 83))	('PIK3CA', 'Gene', (41, 47))	('NFE2L2', 'Gene', '4780', (56, 62))	('MAPK1', 'Gene', (49, 54))	('TGFBR2', 'Gene', (67, 73))	('NFE2L2', 'Gene', (56, 62))	('PIK3CA', 'Gene', '5290', (41, 47))
715592	31836455	Interestingly, NOTCH mutation rate appears to be much higher in cSCCs compared to other SCCs, and HRAS/CASP8 mutations are also prevalent in cSCC, similar to the basal groups of other SCCs (Figure 1).	('NOTCH', 'Gene', '31293', (15, 20))	('cSCC', 'Disease', (141, 145))	('NOTCH', 'Gene', (15, 20))	('SCCs', 'Phenotype', 'HP:0002860', (65, 69))	('prevalent', 'Reg', (128, 137))	('CASP8', 'Gene', (103, 108))	('higher', 'Reg', (54, 60))	('CASP8', 'Gene', '841', (103, 108))	('cSCCs', 'Phenotype', 'HP:0006739', (64, 69))	('mutations', 'Var', (109, 118))	('SCCs', 'Phenotype', 'HP:0002860', (184, 188))	('cSCCs', 'Disease', (64, 69))	('SCCs', 'Phenotype', 'HP:0002860', (88, 92))
715593	31836455	On the other hand, it remains unclear whether a group of 3q amplification, NRF2 de-regulation, or NSD1 mutation has an equivalent counterpart in cSCC, given UV damage rather than smoking is top risk factors for skin cancer.	('skin cancer', 'Disease', 'MESH:D012878', (211, 222))	('cSCC', 'Disease', (145, 149))	('NRF2', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('NSD1', 'Gene', '64324', (98, 102))	('NRF2', 'Gene', '4780', (75, 79))	('skin cancer', 'Phenotype', 'HP:0008069', (211, 222))	('mutation', 'Var', (103, 111))	('de-regulation', 'NegReg', (80, 93))	('NSD1', 'Gene', (98, 102))	('skin cancer', 'Disease', (211, 222))
715594	31836455	Mutations in cancer drivers such as TP53, NOTCH and HRAS are all frequent events in cSCC.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('HRAS', 'Disease', (52, 56))	('TP53', 'Gene', '7157', (36, 40))	('cSCC', 'Disease', (84, 88))	('cancer', 'Disease', (13, 19))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('NOTCH', 'Gene', '31293', (42, 47))	('TP53', 'Gene', (36, 40))	('NOTCH', 'Gene', (42, 47))
715596	31836455	Field cancerization was initially described in HNSCCs, where it has been frequently observed that local secondary tumours could occur at the site of surgically removed primary tumours (sporadic non-familial cases), suggesting a cancerous 'field' of pre-malignant tissues or mutations in the peritumoral epithelia.	('tumours', 'Disease', (114, 121))	('cancerous', 'Disease', (228, 237))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumours', 'Disease', (176, 183))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('tumor', 'Disease', (295, 300))	('tumours', 'Disease', 'MESH:D009369', (176, 183))	('cancer', 'Disease', (228, 234))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', (6, 12))	('cancerous', 'Disease', 'MESH:D009369', (228, 237))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('SCCs', 'Phenotype', 'HP:0002860', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('mutations', 'Var', (274, 283))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
715599	31836455	TP53 mutations are also known to occur in a patchy fashion (Garcia et al., 1999)(Tabor et al., 2002; Tabor et al., 2001; van Houten et al., 2002), involving the otherwise normal epithelial mucosa of these abovementioned tissues, and most notably in the skin epidermis.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('Garcia', 'Disease', 'MESH:C536767', (60, 66))	('Garcia', 'Disease', (60, 66))
715602	31836455	In the case of esophagus, the frequencies of cancer driver mutations could be even higher in normal than cancer, and may occur as early as infancy.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('esophagus', 'Disease', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (45, 51))	('higher', 'PosReg', (83, 89))
715617	31836455	Interestingly, HRAS mutations are relatively infrequent in primary tumors, but become highly enriched in BRAF inhibitor treated tumors, pointing to a predominant role for HRAS in driving secondary cSCCs.	('BRAF', 'Gene', '673', (105, 109))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('BRAF', 'Gene', (105, 109))	('cSCCs', 'Phenotype', 'HP:0006739', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('HRAS', 'Gene', (15, 19))	('tumors', 'Disease', (67, 73))	('mutations', 'Var', (20, 29))	('SCCs', 'Phenotype', 'HP:0002860', (198, 202))
715635	31836455	Many pathways have been repeatedly revealed to be essential for SCCs across various sites, including cell cycle, squamous differentiation and developmental genes, oxidative stress regulators, and epigenetic factors.	('squamous differentiation', 'CPA', (113, 137))	('stress', 'Disease', 'MESH:D000079225', (173, 179))	('oxidative stress', 'Phenotype', 'HP:0025464', (163, 179))	('cell cycle', 'CPA', (101, 111))	('stress', 'Disease', (173, 179))	('epigenetic', 'Var', (196, 206))	('SCCs', 'Phenotype', 'HP:0002860', (64, 68))
715640	31836455	TP63 mutation is the most common genetic basis for the congenital ectrodactyly, ectodermal dysplasia, and facial clefts (EEC) syndrome.	('ectodermal dysplasia', 'Disease', 'MESH:D004476', (80, 100))	('congenital ectrodactyly', 'Disease', (55, 78))	('facial clefts (EEC) syndrome', 'Disease', 'MESH:C536189', (106, 134))	('ectodermal dysplasia', 'Disease', (80, 100))	('common', 'Reg', (26, 32))	('ectrodactyly', 'Phenotype', 'HP:0100257', (66, 78))	('ectodermal dysplasia', 'Phenotype', 'HP:0000968', (80, 100))	('facial clefts', 'Phenotype', 'HP:0002006', (106, 119))	('TP63', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
715646	31836455	Given its key role in squamous lineage specification and stratification of epithelial tissues, it is not surprising that TP63 is one of the most well-established oncogenic drivers for squamous cancers and basal subtype carcinomas from stratified epithelia.	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))	('TP63', 'Var', (121, 125))	('squamous cancer', 'Phenotype', 'HP:0002860', (184, 199))	('basal subtype carcinomas', 'Phenotype', 'HP:0002671', (205, 229))	('basal', 'Disease', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carcinomas', 'Disease', 'MESH:D009369', (219, 229))	('squamous cancers', 'Disease', (184, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('squamous cancers', 'Disease', 'MESH:D002294', (184, 200))	('carcinomas', 'Disease', (219, 229))
715647	31836455	Its molecular mechanisms have been linked to interaction with TP53, P21 and YAP  Adding to its complexity, TP63 has multiple isoforms due to both N- and C-terminal alternative splicing.	('TP53', 'Gene', '7157', (62, 66))	('TP63', 'Var', (107, 111))	('P21', 'Gene', '644914', (68, 71))	('YAP', 'Gene', (76, 79))	('TP53', 'Gene', (62, 66))	('P21', 'Gene', (68, 71))	('YAP', 'Gene', '55249', (76, 79))
715651	31836455	Knocking out or overexpressing SOX2 in cultured SCC cancer cells suggests it is indeed a lineage survival oncogene.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('SOX2', 'Gene', (31, 35))	('SOX2', 'Gene', '6657', (31, 35))	('overexpressing', 'PosReg', (16, 30))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('Knocking out', 'Var', (0, 12))
715653	31836455	However, in SCLCs the SOX2 amplification may reflect the importance of its function in neuronal lineages rather than a squamous lineage.	('SCLC', 'Gene', '7864', (12, 16))	('SCLC', 'Gene', (12, 16))	('SOX2', 'Gene', '6657', (22, 26))	('SOX2', 'Gene', (22, 26))	('SCLC', 'Phenotype', 'HP:0030357', (12, 16))	('amplification', 'Var', (27, 40))
715659	31836455	Even though PIK3CA is frequently mutated across many cancers, its mutational identity in SCCs is unique: PIK3CA E542K and E545K is enriched in CxSCC, HNSCC, and bladder cancer, and is very different from breast cancer and others, raising an intriguing possibility that a subset of PI3K pathway genes genetically or biochemically interact with these particular mutant PI3Ks in SCCs compared to other cancer types.	('cancer', 'Disease', (399, 405))	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('SCCs', 'Phenotype', 'HP:0002860', (89, 93))	('PIK3CA', 'Gene', '5290', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (399, 405))	('bladder cancer', 'Disease', 'MESH:D001749', (161, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))	('bladder cancer', 'Disease', (161, 175))	('PIK3CA', 'Gene', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('bladder cancer', 'Phenotype', 'HP:0009725', (161, 175))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('HNSCC', 'Disease', (150, 155))	('breast cancer', 'Disease', (204, 217))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('PIK3CA', 'Gene', (105, 111))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('CxSCC', 'Disease', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (399, 405))	('E545K', 'Mutation', 'rs104886003', (122, 127))	('cancer', 'Disease', (53, 59))	('cancers', 'Disease', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('SCCs', 'Phenotype', 'HP:0002860', (376, 380))	('E542K', 'Mutation', 'rs121913273', (112, 117))	('PIK3CA', 'Gene', '5290', (12, 18))	('E545K', 'Var', (122, 127))	('E542K', 'Var', (112, 117))	('cancer', 'Disease', (211, 217))	('interact', 'Reg', (329, 337))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('mutant', 'Var', (360, 366))
715662	31836455	NOTCH1 mutations in SCCs are loss-of-function type, implicating Notch1 as a tumor suppressor therein.	('SCCs', 'Phenotype', 'HP:0002860', (20, 24))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('loss-of-function', 'NegReg', (29, 45))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('mutations', 'Var', (7, 16))
715665	31836455	Skin epidermis-specific deletion of Notch1 leads to accelerated carcinogenesis in mice, possibly due to cell non-autonomous effect from the tumor microenvironment.	('mice', 'Species', '10090', (82, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('carcinogenesis', 'Disease', (64, 78))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Notch1', 'Gene', (36, 42))	('deletion', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('accelerated', 'PosReg', (52, 63))	('tumor', 'Disease', (140, 145))
715669	31836455	NOTCH pathway mutations are also common in NSCLCs and SCLCs.	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('common', 'Reg', (33, 39))	('NSCLCs', 'Disease', (43, 49))	('SCLC', 'Gene', (54, 58))	('SCLC', 'Gene', '7864', (44, 48))	('NOTCH', 'Gene', (0, 5))	('SCLC', 'Gene', (44, 48))	('NOTCH', 'Gene', '31293', (0, 5))	('SCLC', 'Gene', '7864', (54, 58))	('SCLC', 'Phenotype', 'HP:0030357', (54, 58))	('SCLC', 'Phenotype', 'HP:0030357', (44, 48))	('NSCLCs', 'Disease', 'MESH:D002289', (43, 49))	('mutations', 'Var', (14, 23))
715675	31836455	In this regard, it is intriguing to notice that TP63 amplified and NOTCH1 mutated LSCCs exhibit minimal overlap, raising the possibility of direct genetic interaction between these two SCC drivers.	('NOTCH1', 'Gene', '4851', (67, 73))	('NOTCH1', 'Gene', (67, 73))	('LSCC', 'Phenotype', 'HP:0030359', (82, 86))	('SCCs', 'Phenotype', 'HP:0002860', (83, 87))	('TP63 amplified', 'Var', (48, 62))
715681	31836455	MYC also appears to be important for SCC resistance to combined miR-21 antagonism and PI3K/mTOR inhibition.	('MYC', 'Gene', (0, 3))	('antagonism', 'Var', (71, 81))	('miR-21', 'Gene', '406991', (64, 70))	('mTOR', 'Gene', (91, 95))	('MYC', 'Gene', '4609', (0, 3))	('mTOR', 'Gene', '2475', (91, 95))	('miR-21', 'Gene', (64, 70))
715688	31836455	Interestingly, KLF5 is also frequently amplified or mutated in other cancers, including HNSCC, ESCC and LSCC, salivary gland tumors, uterine cervical adenocarcinomas, gastric cancers, and bladder cancers.	('bladder cancers', 'Disease', 'MESH:D001749', (188, 203))	('HNSCC', 'Disease', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('bladder cancers', 'Disease', (188, 203))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('LSCC', 'Disease', (104, 108))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('gastric cancers', 'Disease', 'MESH:D013274', (167, 182))	('mutated', 'Var', (52, 59))	('gastric cancers', 'Disease', (167, 182))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('gastric cancers', 'Phenotype', 'HP:0012126', (167, 182))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('KLF5', 'Gene', '688', (15, 19))	('cancers', 'Disease', (196, 203))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('adenocarcinomas', 'Disease', 'MESH:D000230', (150, 165))	('cancers', 'Disease', (69, 76))	('bladder cancers', 'Phenotype', 'HP:0009725', (188, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('adenocarcinomas', 'Disease', (150, 165))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (110, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ESCC', 'Disease', (95, 99))	('KLF5', 'Gene', (15, 19))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('LSCC', 'Phenotype', 'HP:0030359', (104, 108))
715740	29853858	Pollution was positively linked to high cancer incidents in a number of cancer village across Henan province, Jiangsu province, and Anhui province by Chinese Center for Disease Control and Prevention.	('linked', 'Reg', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('high cancer', 'Disease', 'MESH:D009369', (35, 46))	('Pollution', 'Var', (0, 9))	('high cancer', 'Disease', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
715751	29207103	Additionally, the methylation levels of the Igf2 promoter region were 31.82 and 54.55% in cancer tissues and adjacent non-cancerous tissues, respectively, suggesting that low methylation of the Igf2 gene promoter region may promote the expression of Igf2 and miR-483-5p; this, in turn, induces the degradation of miR-483-5p target genes, and leads to the upregulation of oncogenes and the downregulation of tumor suppressors, which promotes the development of ESCC.	('Igf2', 'Gene', (194, 198))	('miR-483', 'Gene', (313, 320))	('Igf2', 'Gene', '3481', (194, 198))	('miR-483', 'Gene', '619552', (259, 266))	('Igf2', 'Gene', '3481', (250, 254))	('Igf2', 'Gene', (250, 254))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('methylation', 'Var', (175, 186))	('promote', 'PosReg', (224, 231))	('oncogenes', 'Protein', (371, 380))	('induces', 'Reg', (286, 293))	('miR-483', 'Gene', '619552', (313, 320))	('promotes', 'PosReg', (432, 440))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', (407, 412))	('degradation', 'MPA', (298, 309))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('upregulation', 'PosReg', (355, 367))	('tumor', 'Disease', 'MESH:D009369', (407, 412))	('ESCC', 'Disease', (460, 464))	('expression', 'MPA', (236, 246))	('Igf2', 'Gene', (44, 48))	('Igf2', 'Gene', '3481', (44, 48))	('low methylation', 'Var', (171, 186))	('cancer', 'Disease', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (407, 412))	('miR-483', 'Gene', (259, 266))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (90, 96))	('downregulation', 'NegReg', (389, 403))
715760	29207103	A polymorphism at the miR-483-5p binding site in the 3'-untranslated region of the basigin gene has been demonstrated to be associated with increased susceptibility to esophageal cancer in a Chinese population.	('esophageal cancer', 'Disease', (168, 185))	('susceptibility', 'Reg', (150, 164))	('basigin', 'Gene', '682', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('miR-483', 'Gene', '619552', (22, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('associated', 'Reg', (124, 134))	('miR-483', 'Gene', (22, 29))	('basigin', 'Gene', (83, 90))	('polymorphism', 'Var', (2, 14))
715762	29207103	Epigenetic alterations have been a subject of research, due to their involvement in malignant transformation and tumor progression.	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('malignant transformation', 'CPA', (84, 108))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('involvement', 'Reg', (69, 80))
715764	29207103	The aim of the present study was to clarify the association between miR-483-5p expression in serum and tissues from patient with esophageal cancer, with epigenetic alterations in the Igf2 promoter, in addition to the effect of imiR-483-5p on target gene expression.	('miR-483', 'Gene', '619552', (228, 235))	('epigenetic alterations', 'Var', (153, 175))	('patient', 'Species', '9606', (116, 123))	('miR-483', 'Gene', (228, 235))	('miR-483', 'Gene', '619552', (68, 75))	('miR-483', 'Gene', (68, 75))	('esophageal cancer', 'Disease', (129, 146))	('Igf2', 'Gene', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Igf2', 'Gene', '3481', (183, 187))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
715808	29207103	The results of the present study demonstrated that the differences in Igf2 promoter methylation resulted in the differential expression of Igf2 between cancer tissues and paracancerous tissues in patients with ESCC.	('Igf2', 'Gene', '3481', (139, 143))	('differential', 'Reg', (112, 124))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('differences', 'Var', (55, 66))	('patients', 'Species', '9606', (196, 204))	('expression', 'MPA', (125, 135))	('paracancerous tissues', 'Disease', (171, 192))	('ESCC', 'Disease', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Igf2', 'Gene', (70, 74))	('Igf2', 'Gene', '3481', (70, 74))	('paracancerous tissues', 'Disease', 'MESH:D009380', (171, 192))	('Igf2', 'Gene', (139, 143))
715812	29207103	Therefore, the extent of methylation in the host gene promoter region influences miRNA expression, indicating that epigenetic modification serves an important role in the regulation of miRNA expression.	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (81, 84))	('influences', 'Reg', (70, 80))	('miR', 'Gene', '220972', (185, 188))	('methylation', 'Var', (25, 36))	('miR', 'Gene', (185, 188))
715813	29207103	It has been demonstrated that miRNAs are able to bind to their complementary mRNA sites through base-pairing to regulate gene expression.	('bind', 'Interaction', (49, 53))	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('base-pairing', 'Var', (96, 108))	('regulate', 'Reg', (112, 120))	('gene expression', 'MPA', (121, 136))
715887	24179541	A total of 11 patients with tracheal stenosis due to LNM compressing and infiltrating the trachea were selected between November 2009 and January 2013.	('LNM', 'Var', (53, 56))	('patients', 'Species', '9606', (14, 22))	('tracheal stenosis', 'Disease', (28, 45))	('tracheal stenosis', 'Phenotype', 'HP:0002777', (28, 45))
715971	21453483	Artemin siRNA expression vectors were constructed to knockdown of artemin expression mitigated migration and invasiveness in KYSE150 cells.	('artemin', 'Gene', (66, 73))	('knockdown', 'Var', (53, 62))	('expression', 'Species', '29278', (14, 24))	('artemin', 'Gene', '9048', (66, 73))	('KYSE150', 'CellLine', 'CVCL:1348', (125, 132))	('rat', 'Species', '10116', (98, 101))	('Artemin', 'Gene', '9048', (0, 7))	('expression vectors', 'Species', '29278', (14, 32))	('expression', 'Species', '29278', (74, 84))	('mitigated', 'NegReg', (85, 94))	('Artemin', 'Gene', (0, 7))
715977	21453483	Overexpression of miR-223 decreased expression of ARTN in KYSE150 cells while silencing miR-223 increased expression of ARTN in EC9706 cells.	('miR-223', 'Gene', (88, 95))	('increased', 'PosReg', (96, 105))	('ARTN', 'Gene', (50, 54))	('expression', 'Species', '29278', (106, 116))	('KYSE150', 'CellLine', 'CVCL:1348', (58, 65))	('expression', 'Species', '29278', (4, 14))	('miR-223', 'Gene', '407008', (88, 95))	('expression', 'MPA', (106, 116))	('miR-223', 'Gene', (18, 25))	('ARTN', 'Gene', '9048', (50, 54))	('ARTN', 'Gene', (120, 124))	('silencing', 'Var', (78, 87))	('ARTN', 'Gene', '9048', (120, 124))	('EC9706', 'CellLine', 'CVCL:E307', (128, 134))	('miR-223', 'Gene', '407008', (18, 25))	('expression', 'Species', '29278', (36, 46))	('decreased', 'NegReg', (26, 35))	('expression', 'MPA', (36, 46))
715979	21453483	Silencing of miR-223 in EC9706 cells increased cell migration and invasiveness.	('miR-223', 'Gene', (13, 20))	('EC9706', 'CellLine', 'CVCL:E307', (24, 30))	('invasiveness', 'CPA', (66, 78))	('miR-223', 'Gene', '407008', (13, 20))	('increased', 'PosReg', (37, 46))	('cell migration', 'CPA', (47, 61))	('Silencing', 'Var', (0, 9))	('rat', 'Species', '10116', (55, 58))
715983	21453483	Increasing evidence had demonstrated a connection between high expression of ARTN and tumor relapse, metastasis and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('expression', 'Species', '29278', (63, 73))	('tumor', 'Disease', (86, 91))	('high expression', 'Var', (58, 73))	('metastasis', 'CPA', (101, 111))	('ARTN', 'Gene', (77, 81))	('ARTN', 'Gene', '9048', (77, 81))	('poor prognosis', 'CPA', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('rat', 'Species', '10116', (31, 34))
715985	21453483	It has been confirmed that miRNA abnormalities play an important role in gene regulation, apoptosis, the maintenance of cell differentiation and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('abnormalities', 'Var', (33, 46))	('miRNA', 'MPA', (27, 32))	('tumor', 'Disease', (145, 150))	('gene regulation', 'MPA', (73, 88))	('apoptosis', 'CPA', (90, 99))
716033	21453483	Following incubation of physically-wounded cells for 48 h, KYSE150/RNAi cells had traveled a significantly shorter distance than control cells [Figure 2(D)].	('shorter', 'NegReg', (107, 114))	('KYSE150/RNAi', 'Var', (59, 71))	('KYSE150', 'CellLine', 'CVCL:1348', (59, 66))
716034	21453483	KYSE150 and KYSE150/NC cells had strong invasive abilities while inhibition of artemin resulted in a massive reduction in invasion (Figure 2E and 2F).	('inhibition', 'NegReg', (65, 75))	('artemin', 'Gene', (79, 86))	('KYSE150', 'CellLine', 'CVCL:1348', (0, 7))	('invasive abilities', 'CPA', (40, 58))	('invasion', 'CPA', (122, 130))	('reduction', 'NegReg', (109, 118))	('KYSE150/NC', 'Var', (12, 22))	('artemin', 'Gene', '9048', (79, 86))	('KYSE150', 'CellLine', 'CVCL:1348', (12, 19))	('KYSE150', 'Var', (0, 7))
716045	21453483	Mutation of the binding site abolished the ability of miR-223 to inhibit the expression of the luciferase reporter (Figure 3B).	('expression', 'MPA', (77, 87))	('inhibit', 'NegReg', (65, 72))	('miR-223', 'Gene', '407008', (54, 61))	('luciferase', 'Enzyme', (95, 105))	('Mutation', 'Var', (0, 8))	('abolished', 'NegReg', (29, 38))	('miR-223', 'Gene', (54, 61))	('expression', 'Species', '29278', (77, 87))
716050	21453483	Interestingly, ARTN expression levels were higher in KYSE150 and KYSE510 than in EC9706 and TE13 cell lines, suggesting that expression of miR-223 was inversely related to ARTN protein level in esophageal carcinoma.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (194, 214))	('EC9706', 'CellLine', 'CVCL:E307', (81, 87))	('ARTN', 'Gene', (15, 19))	('expression', 'Species', '29278', (125, 135))	('KYSE150', 'CellLine', 'CVCL:1348', (53, 60))	('expression', 'Species', '29278', (20, 30))	('miR-223', 'Gene', '407008', (139, 146))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (194, 214))	('ARTN', 'Gene', (172, 176))	('higher', 'PosReg', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('KYSE150', 'Var', (53, 60))	('expression', 'MPA', (125, 135))	('ARTN', 'Gene', '9048', (15, 19))	('related', 'Reg', (161, 168))	('esophageal carcinoma', 'Disease', (194, 214))	('KYSE510', 'Var', (65, 72))	('miR-223', 'Gene', (139, 146))	('ARTN', 'Gene', '9048', (172, 176))
716051	21453483	KYSE150 and EC9706 were used as models to further investigate the function of miR-223 in esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (89, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('miR-223', 'Gene', (78, 85))	('KYSE150', 'CellLine', 'CVCL:1348', (0, 7))	('esophageal squamous cell carcinoma', 'Disease', (89, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('miR-223', 'Gene', '407008', (78, 85))	('EC9706', 'Var', (12, 18))	('EC9706', 'CellLine', 'CVCL:E307', (12, 18))
716053	21453483	Consistent with this result, silencing of miR-223 using an miR-223 inhibitor resulted in an increase of ARTN protein level in EC9706 cells (Figure 3F).	('EC9706', 'CellLine', 'CVCL:E307', (126, 132))	('silencing', 'Var', (29, 38))	('miR-223', 'Gene', (42, 49))	('miR-223', 'Gene', (59, 66))	('miR-223', 'Gene', '407008', (42, 49))	('increase', 'PosReg', (92, 100))	('ARTN', 'Gene', (104, 108))	('miR-223', 'Gene', '407008', (59, 66))	('ARTN', 'Gene', '9048', (104, 108))
716058	21453483	The morphology of KYSE150 cells transfected with either pcDNA3.1 (+) or pcDNA3.1 (+)-miR-223 did not change compared to the untreated group, and no difference in cell viability between the three groups was observed (Additional file 2, Figure S2A).	('pcDNA3.1', 'Var', (72, 80))	('miR-223', 'Gene', (85, 92))	('miR-223', 'Gene', '407008', (85, 92))	('KYSE150', 'CellLine', 'CVCL:1348', (18, 25))
716063	21453483	KYSE150 cells transfected with pcDNA3.1 (+)-miR-223 closed the scratch-wounds more slowly than cells that were untreated or transfected with pcDNA3.1 (+) (Figure 4A, B).	('slowly', 'NegReg', (83, 89))	('KYSE150', 'CellLine', 'CVCL:1348', (0, 7))	('miR-223', 'Gene', '407008', (44, 51))	('pcDNA3.1', 'Var', (31, 39))	('closed', 'NegReg', (52, 58))	('miR-223', 'Gene', (44, 51))	('scratch-wounds', 'CPA', (63, 77))	('rat', 'Species', '10116', (65, 68))
716065	21453483	To examine invasion, KYSE150 cells were transfected with either pcDNA3.1 (+)-miR-223 or pcDNA3.1 (+) and reseeded on top of the insert.	('miR-223', 'Gene', '407008', (77, 84))	('KYSE150', 'CellLine', 'CVCL:1348', (21, 28))	('miR-223', 'Gene', (77, 84))	('pcDNA3.1 (+', 'Var', (88, 99))
716082	21453483	To verify whether ARTN expression is regulated by miRNAs, miR-105, miR-223 and miR-760 were chosen for further study according to the results of a bioinformatic search.	('ARTN', 'Gene', '9048', (18, 22))	('regulated', 'Reg', (37, 46))	('miR-223', 'Gene', '407008', (67, 74))	('miR-760', 'Gene', (79, 86))	('miR-105', 'Var', (58, 65))	('miR-760', 'Gene', '100126348', (79, 86))	('miR-223', 'Gene', (67, 74))	('expression', 'Species', '29278', (23, 33))	('ARTN', 'Gene', (18, 22))
716087	21453483	On the contrary, silencing of miR-223 increases ARTN expression and promotes cellular migration and invasion in EC9706 cells.	('increases', 'PosReg', (38, 47))	('ARTN', 'Gene', '9048', (48, 52))	('promotes', 'PosReg', (68, 76))	('EC9706', 'CellLine', 'CVCL:E307', (112, 118))	('cellular migration', 'CPA', (77, 95))	('miR-223', 'Gene', '407008', (30, 37))	('rat', 'Species', '10116', (89, 92))	('expression', 'Species', '29278', (53, 63))	('invasion', 'CPA', (100, 108))	('ARTN', 'Gene', (48, 52))	('silencing', 'Var', (17, 26))	('miR-223', 'Gene', (30, 37))
716094	21453483	This work was partly supported by the grants from the Key Project from National Natural Science Foundation of China(No.30430300), National Natural Science Foundation of China (No.81000950), National 973 Program (No.2010CB529405), Tianjin Scientific Innovation System Program (No.07SYSYSF05000, 07SYSYJC27900), China-Sweden Cooperative Foundation (No.09ZCZDSF04100), and Major Project of Tianjin Sci-Tech Support Program (06YFSZSF05300).	('No.81000950', 'Var', (176, 187))	('No.30430300', 'Var', (116, 127))	('No.07SYSYSF05000', 'Var', (276, 292))	('No.2010CB529405', 'Var', (212, 227))	('07SYSYJC27900', 'Var', (294, 307))	('rat', 'Species', '10116', (328, 331))	('No.09ZCZDSF04100', 'Var', (347, 363))
716154	31356800	Surgery is Associated with Survival Benefit in T4a Esophageal Adenocarcinoma: A National Analysis The National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of surgery for clinical T4a esophageal adenocarcinoma.	('T4a', 'Var', (206, 209))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (51, 76))	('Adenocarcinoma', 'Disease', (62, 76))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (210, 235))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('Cancer', 'Disease', (125, 131))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal adenocarcinoma', 'Disease', (210, 235))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (210, 235))
716156	31356800	The National Cancer Database (NCDB) was used to identify patients from 2010-2015 with clinical T4aN0-3M0 esophageal adenocarcinoma, and grouped by receipt of surgery (with or without perioperative therapy) or definitive, concurrent chemoradiation.	('esophageal adenocarcinoma', 'Disease', (105, 130))	('Cancer', 'Disease', (13, 19))	('patients', 'Species', '9606', (57, 65))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (105, 130))	('T4aN0-3M0', 'Var', (95, 104))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (105, 130))
716161	31356800	In this national analysis, surgery for cT4a esophageal adenocarcinoma was associated with improved outcomes when compared to definitive chemoradiation.	('esophageal adenocarcinoma', 'Disease', (44, 69))	('outcomes', 'MPA', (99, 107))	('improved', 'PosReg', (90, 98))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (44, 69))	('cT4a', 'Var', (39, 43))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (44, 69))
716162	31356800	Surgery should be considered for medically fit patients with cT4aN0-3M0 esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (72, 97))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (72, 97))	('patients', 'Species', '9606', (47, 55))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (72, 97))	('cT4aN0-3M0', 'Var', (61, 71))
716198	31356800	Fujita and colleagues described a prospective trial of 53 patients with T4N0-1M0 squamous cell cancer who underwent either definitive chemoradiation or surgery with both pre- and postoperative chemoradiation .	('T4N0-1M0', 'Var', (72, 80))	('squamous cell cancer', 'Disease', 'MESH:D002294', (81, 101))	('squamous cell cancer', 'Disease', (81, 101))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (81, 101))
716200	31356800	Stahl and colleagues reported a prospective, randomized controlled trial (RCT) of 172 patients with T3-4N0M0 squamous cell cancer treated with either chemoradiation followed by surgery or extended, definitive chemoradiation .	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('squamous cell cancer', 'Disease', (109, 129))	('squamous cell cancer', 'Disease', 'MESH:D002294', (109, 129))	('T3-4N0M0', 'Var', (100, 108))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (109, 129))	('patients', 'Species', '9606', (86, 94))
716201	31356800	performed an RCT of 259 patients with T3N0-1M0 squamous cell cancer, who were treated with either chemoradiation alone or chemoradiation followed by surgery .	('squamous cell cancer', 'Phenotype', 'HP:0002860', (47, 67))	('squamous cell cancer', 'Disease', 'MESH:D002294', (47, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('squamous cell cancer', 'Disease', (47, 67))	('patients', 'Species', '9606', (24, 32))	('T3N0-1M0', 'Var', (38, 46))
716245	31839955	The HNSPT detection rate is significantly higher using NBI (sensitivity 100%, specificity 97.5%) compared with only white-light endoscopy (WL).	('higher', 'PosReg', (42, 48))	('WL', 'Chemical', '-', (139, 141))	('NBI', 'Var', (55, 58))	('HNSPT', 'Disease', (4, 9))
716274	31839955	The HNSPT prevalence in the study by Nonaka and colleagues was 3.3% (14/424) with a median detection period of 27.6 months (range, 7.1-143.5) in patients screened with NBI and 101.0 months (range, 11.0-134.5) in patients screened with WL.	('patients', 'Species', '9606', (145, 153))	('HNSPT', 'Disease', (4, 9))	('patients', 'Species', '9606', (212, 220))	('WL', 'Chemical', '-', (235, 237))	('NBI', 'Var', (168, 171))
716346	31043582	Our previous study identified OV6 as a novel esophageal TIC marker, because the OV6+ ESCC cells exhibit the ability to form tumours and possesses a stronger resistance to chemotherapy.	('esophageal TIC', 'Disease', 'MESH:D004941', (45, 59))	('resistance', 'CPA', (157, 167))	('OV6+', 'Var', (80, 84))	('TIC', 'Phenotype', 'HP:0100033', (56, 59))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('stronger', 'PosReg', (148, 156))	('esophageal TIC', 'Disease', (45, 59))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
716351	31043582	Importantly, proteins that contain arginine-glycine-rich motifs (RG) are often targets for PRMT-mediated methylation.	('glycine', 'Chemical', 'MESH:D005998', (44, 51))	('proteins', 'Protein', (13, 21))	('arginine-glycine-rich', 'Var', (35, 56))	('arginine', 'Chemical', 'MESH:D001120', (35, 43))
716353	31043582	A growing amount of evidence indicates that arginine methylation might be a driver for the initiation and progression of cancer.	('arginine', 'Chemical', 'MESH:D001120', (44, 52))	('arginine methylation', 'Var', (44, 64))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
716354	31043582	Dysregulation of PRMT1 has been observed in several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('observed', 'Reg', (32, 40))	('Dysregulation', 'Var', (0, 13))	('PRMT1', 'Gene', (17, 22))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
716368	31043582	The lentiviral vectors were transfected into the HCC cells with a multiplicity of infection (MOI) 5 in the presence of polybrene (5 mug/ml) for 6 h. Stable Eca109 and TE-1 cells knockdown of PRMT1 were generated using lentiviral constructs expressing shPRMT1(shPRMT11# GGACATGACATCCAAAGATTA; shPRMT12# GCAACTCCATGTTTCATAACC; shPRMT13# GCAACTCCATGTTTCATAACC) and negative control (HeYuan Bio-technology Co., Shanghai, China), and incubated with 2 mug/ml puromycin (Sigma, St Louis, USA).	('HCC', 'CellLine', 'CVCL:0C54', (49, 52))	('rat', 'Species', '10116', (206, 209))	('shPRMT13# GCAACTCCATGTTTCATAACC', 'Var', (325, 356))	('shPRMT12# GCAACTCCATGTTTCATAACC', 'Var', (292, 323))	('infection', 'Disease', (82, 91))	('infection', 'Disease', 'MESH:D007239', (82, 91))
716371	31043582	Protein extracts were subjected to SDS-PAGE and analysed using the following primary antibodies: PRMT1 (Abcam, ab73246), H4R3me2a (Active Motif,), H4R3me2s (Active Motif), histone H3 (CST) and GADPH (Abcam, ab8245).	('CST', 'Gene', '106478911', (184, 187))	('H4R3me2a', 'Var', (121, 129))	('H4R3me2s', 'Var', (147, 155))	('histone H3', 'Protein', (172, 182))	('PRMT1', 'Gene', (97, 102))	('SDS', 'Chemical', 'MESH:D012967', (35, 38))	('CST', 'Gene', (184, 187))
716391	31043582	Moreover, the positive staining of PRMT1 in ESCC was significantly correlated with aberrant clinicopathological characteristics and poor prognosis of ESCC patients (Table 3, Fig.	('correlated', 'Reg', (67, 77))	('ESCC', 'Disease', (150, 154))	('PRMT1', 'Gene', (35, 40))	('positive', 'Var', (14, 22))	('patients', 'Species', '9606', (155, 163))
716395	31043582	In the PRMT1 high-expression groups, the percentage of patients with high OV6 expression was 71.8%, higher than that in the OV6 low-expression groups (45.8%), showing an association between OV6 and PRMT1 expression (Fig.	('patients', 'Species', '9606', (55, 63))	('PRMT1', 'Gene', (7, 12))	('PRMT1', 'Gene', (198, 203))	('high', 'Var', (69, 73))
716396	31043582	Moreover, patients with high expression of both OV6 and PRMT1 possessed aggressive clinicopathological features, including high T grades and TNM stage (Table 4).	('OV6', 'Gene', (48, 51))	('TNM', 'Gene', '10178', (141, 144))	('PRMT1', 'Gene', (56, 61))	('high expression', 'Var', (24, 39))	('TNM', 'Gene', (141, 144))	('high T grades', 'CPA', (123, 136))	('patients', 'Species', '9606', (10, 18))
716409	31043582	As anticipated, cis-platinum enriched more chemo-resistant OV6+ ESCC cells in the LV-PRMT1 groups than the LV-GFP groups (Fig.	('cis-platinum', 'Chemical', 'MESH:D002945', (16, 28))	('cis-platinum', 'Var', (16, 28))	('LV-PRMT1', 'Gene', '3276', (82, 90))	('LV-PRMT1', 'Gene', (82, 90))	('more', 'PosReg', (38, 42))	('chemo-resistant OV6+ ESCC cells', 'CPA', (43, 74))
716411	31043582	Our previous data suggested that OV6+ ESCC cells, compared with their OV6- counterparts, exhibited an increased capacity to form tumours in vivo.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('OV6+ ESCC', 'Var', (33, 42))	('tumours', 'Disease', (129, 136))
716422	31043582	Since the decreased histone methylarginine levels were observed, we applied RNA-seq to profile the transcriptome in PRMT1 overexpression ECA109 cells versus control ECA109 cells.	('PRMT1', 'Gene', (116, 121))	('decreased', 'NegReg', (10, 19))	('histone methylarginine levels', 'MPA', (20, 49))	('methylarginine', 'Chemical', '-', (28, 42))	('overexpression', 'Var', (122, 136))
716423	31043582	The GO analysis revealed that Notch binding correlated genes were upregulated by PRMT1 overexpression, including DLL3 and EGFL7 (Fig.	('EGFL7', 'Gene', '51162', (122, 127))	('PRMT1', 'Gene', (81, 86))	('overexpression', 'Var', (87, 101))	('DLL3', 'Gene', (113, 117))	('upregulated', 'PosReg', (66, 77))	('DLL3', 'Gene', '10683', (113, 117))	('EGFL7', 'Gene', (122, 127))
716426	31043582	We then conducted gene set enrichment analysis (GSEA) of RNA-Seq data using stemness-related gene signatures and showed that TIC related genes were positively correlated with the PRMT1 overexpression ECA109 cells, indicating that overexpression of PRMT1 upregulated TIC related genes (Fig.	('PRMT1', 'Gene', (179, 184))	('GSEA', 'Chemical', '-', (48, 52))	('TIC', 'Disease', (266, 269))	('PRMT1', 'Gene', (248, 253))	('upregulated', 'PosReg', (254, 265))	('TIC', 'Phenotype', 'HP:0100033', (125, 128))	('TIC', 'Phenotype', 'HP:0100033', (266, 269))	('overexpression', 'Var', (230, 244))
716430	31043582	The Notch downstream genes were also showed to be up-regulated by qRT-PCR in LV-PRMT1 ECA109 and TE1 cells (Fig.	('Notch downstream genes', 'Gene', (4, 26))	('up-regulated', 'PosReg', (50, 62))	('LV-PRMT1', 'Gene', '3276', (77, 85))	('LV-PRMT1', 'Gene', (77, 85))	('qRT-PCR', 'Var', (66, 73))
716440	31043582	Some recent data also suggested that PRMT1 and its binding partner AE9a could promote transcription activation of AE9a-associated genes through enrichment of H4R3 methylation and H3 Lys9/14 acetylation, facilitating the development and self-renewal capacity of leukemia.	('acetylation', 'MPA', (190, 201))	('promote', 'PosReg', (78, 85))	('leukemia', 'Disease', (261, 269))	('leukemia', 'Phenotype', 'HP:0001909', (261, 269))	('leukemia', 'Disease', 'MESH:D007938', (261, 269))	('development', 'CPA', (220, 231))	('H3 Lys9/14', 'Protein', (179, 189))	('H4R3', 'Protein', (158, 162))	('methylation', 'Var', (163, 174))	('self-renewal capacity', 'CPA', (236, 257))	('facilitating', 'PosReg', (203, 215))	('AE9a-associated genes', 'Gene', (114, 135))	('PRMT1', 'Gene', (37, 42))	('transcription activation', 'MPA', (86, 110))
716481	30940189	Patients were excluded if they had (i) previous treatments with irinotecan, fluorouracil, or any targeted or immunotherapy agents in a palliative setting, (ii) fluorouracil-based adjuvant chemotherapy within 6 months before the randomization, and (iii) cerebral or meningeal metastases.	('fluorouracil', 'Chemical', 'MESH:D005472', (76, 88))	('fluorouracil', 'Chemical', 'MESH:D005472', (160, 172))	('irinotecan', 'Chemical', 'MESH:D000077146', (64, 74))	('meningeal metastases', 'Disease', 'MESH:D009362', (265, 285))	('Patients', 'Species', '9606', (0, 8))	('meningeal metastases', 'Disease', (265, 285))	('fluorouracil-based', 'Var', (160, 178))
716537	30940189	The proportion of patients receiving anti-PD-1 antibodies in later lines of treatment were almost identical (4/62 [6.4%] in the S-1 monotherapy group vs. 4/61 [6.6%] in the irinotecan plus S-1 group).	('S-1', 'Gene', '5707', (189, 192))	('S-1', 'Gene', '5707', (128, 131))	('patients', 'Species', '9606', (18, 26))	('S-1', 'Gene', (128, 131))	('anti-PD-1', 'Var', (37, 46))	('S-1', 'Gene', (189, 192))	('irinotecan', 'Chemical', 'MESH:D000077146', (173, 183))
716590	30444080	The antibodies used were as follows: anti-Capn4 (1:1000), anti-beta-catenin (Abcam, Cambridge, MA, USA); anti-ZEB1 (1:1000, Cell Signaling Technology, Danvers, MA, USA); and anti-GAPDH (1:1000, Santa Cruz, Biotechnology Inc., Santa Cruz, CA, USA).	('beta-catenin', 'Gene', (63, 75))	('GAPDH', 'Gene', (179, 184))	('beta-catenin', 'Gene', '1499', (63, 75))	('anti-ZEB1', 'Var', (105, 114))	('anti-Capn4', 'Var', (37, 47))	('GAPDH', 'Gene', '2597', (179, 184))
716594	30444080	Esophageal squamous cell carcinoma cells overexpressing or silencing Capn4 were transplanted into SCID beige mice via tail vein injection.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('Esophageal squamous cell carcinoma', 'Disease', (0, 34))	('SCID', 'Disease', 'MESH:D053632', (98, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('SCID', 'Disease', (98, 102))	('Capn4', 'Gene', (69, 74))	('mice', 'Species', '10090', (109, 113))	('silencing', 'Var', (59, 68))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (0, 34))
716601	30444080	qRT-PCR and Western blotting results showed that knockdown of Capn4 reduced ZEB1 mRNA and protein levels in the ECA109 and TE7 cells (Fig 2b-d).	('knockdown', 'Var', (49, 58))	('Capn4', 'Gene', (62, 67))	('TE7', 'CellLine', 'CVCL:9972', (123, 126))	('reduced', 'NegReg', (68, 75))
716608	30444080	Meanwhile, in a TOP-Flash reporter luciferase assay, silencing of Capn4 in ECA109 cells decreased the transcriptional activity of TCF4 compared to the control groups (Fig 4b).	('transcriptional activity', 'MPA', (102, 126))	('silencing', 'Var', (53, 62))	('Capn4', 'Gene', (66, 71))	('decreased', 'NegReg', (88, 97))	('TCF4', 'Gene', (130, 134))	('TCF4', 'Gene', '6925', (130, 134))
716609	30444080	In addition, we found that upregulation of beta-catenin reversed the effects of decreased ZEB1 expression and cell migration and invasion induced by Capn4 knockdown (Fig.	('expression', 'MPA', (95, 105))	('Capn4', 'Gene', (149, 154))	('knockdown', 'Var', (155, 164))	('beta-catenin', 'Gene', '1499', (43, 55))	('cell migration', 'CPA', (110, 124))	('decreased', 'NegReg', (80, 89))	('upregulation', 'PosReg', (27, 39))	('beta-catenin', 'Gene', (43, 55))	('ZEB1', 'Protein', (90, 94))
716621	30444080	Second, Capn4 knockdown led to the recovery of ZEB1 protein levels in cells overexpressing beta-catenin.	('Capn4', 'Gene', (8, 13))	('ZEB1', 'Protein', (47, 51))	('beta-catenin', 'Gene', (91, 103))	('recovery', 'MPA', (35, 43))	('knockdown', 'Var', (14, 23))	('beta-catenin', 'Gene', '1499', (91, 103))
716622	30444080	Third, Capn4 upregulation decreased ZEB1 in cells silencing beta-catenin.	('silencing', 'Var', (50, 59))	('ZEB1', 'MPA', (36, 40))	('Capn4', 'Gene', (7, 12))	('beta-catenin', 'Gene', (60, 72))	('upregulation', 'PosReg', (13, 25))	('beta-catenin', 'Gene', '1499', (60, 72))	('decreased', 'NegReg', (26, 35))
716625	30479563	miR-144/451 cluster plays an oncogenic role in esophageal cancer by inhibiting cell invasion miRNA clusters are widely expressed across species, accumulating evidence has illustrated that miRNA cluster functioned more efficiently than single miRNA in cancer oncogenesis.	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('inhibiting', 'NegReg', (68, 78))	('esophageal cancer', 'Disease', (47, 64))	('cell invasion', 'CPA', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('miR-144', 'Gene', (0, 7))	('miR-144', 'Gene', '406936', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (251, 257))	('miRNA', 'Var', (188, 193))
716644	30479563	miR-144/451 cluster is highly conversed in different species, miRbase database (http://www.mirbase.org/) shows miR-144/451 cluster is constituted by miR-144-3p, miR-144-5p, miR-451a, miR-4732-3p and miR-4732-5p (Table 1).	('144-3p', 'Chemical', '-', (153, 159))	('miR-144', 'Gene', (161, 168))	('miR-144', 'Gene', (0, 7))	('miR-144', 'Gene', '406936', (0, 7))	('miR-4732-3p', 'Var', (183, 194))	('miR-144', 'Gene', '406936', (161, 168))	('miR-144', 'Gene', (149, 156))	('miR-4732-5p', 'Var', (199, 210))	('miR-144', 'Gene', (111, 118))	('miR-144', 'Gene', '406936', (149, 156))	('miR-451a', 'Gene', '574411', (173, 181))	('miR-451a', 'Gene', (173, 181))	('miR-144', 'Gene', '406936', (111, 118))
716677	30479563	We detected the expression of miR-144/451 in ECa9706, ECa109, H5E46 and Het-1A.	('miR-144', 'Gene', '406936', (30, 37))	('H5E46', 'CellLine', 'CVCL:U874', (62, 67))	('ECa9706', 'Var', (45, 52))	('ECa9706', 'CellLine', 'CVCL:E307', (45, 52))	('miR-144', 'Gene', (30, 37))
716678	30479563	miR-144-3p, miR-144-5p, miR-451a and miR-4732-3p were low expressed (Fig.	('miR-144', 'Gene', (0, 7))	('miR-451a', 'Gene', (24, 32))	('miR-144', 'Gene', '406936', (0, 7))	('miR-451a', 'Gene', '574411', (24, 32))	('miR-144', 'Gene', (12, 19))	('miR-4732-3p', 'Var', (37, 48))	('144-3p', 'Chemical', '-', (4, 10))	('miR-144', 'Gene', '406936', (12, 19))
716680	30479563	In ECa9706, miRNA mimics significantly up-regulated expression of miR-144-3p, miR-144-5p, miR-451a, miR-4732-3p and miR-4732-5p.	('miR-144', 'Gene', (78, 85))	('miR-144', 'Gene', '406936', (78, 85))	('miR-4732-3p', 'Var', (100, 111))	('miR-4732-5p', 'Var', (116, 127))	('ECa9706', 'CellLine', 'CVCL:E307', (3, 10))	('miR-144', 'Gene', (66, 73))	('expression', 'MPA', (52, 62))	('miR-144', 'Gene', '406936', (66, 73))	('up-regulated', 'PosReg', (39, 51))	('miR-451a', 'Gene', (90, 98))	('miR-451a', 'Gene', '574411', (90, 98))	('144-3p', 'Chemical', '-', (70, 76))
716684	30479563	Proliferation rate of cells overexpressing miR-144-3p, miR-144-5p, miR-451a and miR-4732-3p were (34.18 +- 5.83)%, (33.56 +- 3.94)%, (34.15 +- 2.94)% and (31.50 +- 2.01)% respectively, in control the proliferation rate was (41.16 +- 2.13)% (Fig.	('miR-4732-3p', 'Var', (80, 91))	('miR-144', 'Gene', (43, 50))	('miR-144', 'Gene', '406936', (43, 50))	('miR-144', 'Gene', (55, 62))	('144-3p', 'Chemical', '-', (47, 53))	('miR-144', 'Gene', '406936', (55, 62))	('miR-451a', 'Gene', '574411', (67, 75))	('miR-451a', 'Gene', (67, 75))
716685	30479563	For cell migration, compared with the number of migrated cells of 36.67 +- 3.58 in control, miR-144-3p, miR-451a, miR-4732-3p and miR-4732-5p inhibited cell migration, the number of cells passed through the membrane were 15.63 +- 1.00, 21.27 +- 1.70, 26.97 +- 3.47 and 24.87 +- 1.36 respectively.	('miR-144', 'Gene', (92, 99))	('miR-4732-5p', 'Var', (130, 141))	('miR-144', 'Gene', '406936', (92, 99))	('cell migration', 'CPA', (4, 18))	('miR-4732-3p', 'Var', (114, 125))	('miR-451a', 'Gene', (104, 112))	('miR-451a', 'Gene', '574411', (104, 112))	('cell migration', 'CPA', (152, 166))	('inhibited', 'NegReg', (142, 151))	('144-3p', 'Chemical', '-', (96, 102))
716687	30479563	For cell invasion, miR-144-3p obviously inhibited invasive ability, only 12.07 +- 1.10 cells passed through reconstituted basement membrane in cells overexpressing miR-133-3p, while the number was 25.90 +- 2.26 in control.	('miR-144', 'Gene', '406936', (19, 26))	('invasive ability', 'CPA', (50, 66))	('inhibited', 'NegReg', (40, 49))	('cell invasion', 'CPA', (4, 17))	('144-3p', 'Chemical', '-', (23, 29))	('miR-133-3p', 'Var', (164, 174))	('miR-144', 'Gene', (19, 26))
716688	30479563	For cell proliferation, miR-144-3p, miR-144-5p, miR-451a and miR-4732-3p significantly inhibited proliferation of ECa9706 (Fig.	('ECa9706', 'CellLine', 'CVCL:E307', (114, 121))	('proliferation', 'CPA', (97, 110))	('miR-144', 'Gene', (24, 31))	('miR-451a', 'Gene', (48, 56))	('miR-144', 'Gene', '406936', (24, 31))	('miR-451a', 'Gene', '574411', (48, 56))	('inhibited', 'NegReg', (87, 96))	('miR-4732-3p', 'Var', (61, 72))	('144-3p', 'Chemical', '-', (28, 34))	('miR-144', 'Gene', (36, 43))	('miR-144', 'Gene', '406936', (36, 43))
716690	30479563	No significant difference of the expression of miR-4732-3p and miR-4732-5p were found between pri-miR-144/451 and the control.	('miR-144', 'Gene', '406936', (98, 105))	('miR-4732-3p', 'Var', (47, 58))	('miR-144', 'Gene', (98, 105))	('miR-4732-5p', 'Var', (63, 74))
716691	30479563	miR-4732-3p and miR-4732-5p seems not to be the member of miR-144/451 cluster (Table 2).	('miR-144', 'Gene', (58, 65))	('miR-4732-3p', 'Var', (0, 11))	('miR-144', 'Gene', '406936', (58, 65))	('miR-4732-5p', 'Var', (16, 27))
716699	30479563	miR-144-3p, miR-144-5p, miR-451a, miR-4732-3p and miR-4732-5p slightly increased the expression of phosphorylated beta-catenin with the IOD of 1.01, 1.00, 1.00, 0.99 and 0.99 respectively, while the IOD for control was 0.92.	('expression', 'MPA', (85, 95))	('beta-catenin', 'Gene', (114, 126))	('miR-144', 'Gene', (0, 7))	('miR-451a', 'Gene', (24, 32))	('miR-144', 'Gene', '406936', (0, 7))	('miR-451a', 'Gene', '574411', (24, 32))	('beta-catenin', 'Gene', '1499', (114, 126))	('increased', 'PosReg', (71, 80))	('phosphorylated', 'MPA', (99, 113))	('miR-144', 'Gene', (12, 19))	('144-3p', 'Chemical', '-', (4, 10))	('miR-4732-3p', 'Var', (34, 45))	('miR-144', 'Gene', '406936', (12, 19))	('miR-4732-5p', 'Var', (50, 61))
716703	30479563	Expression of p53 was increased in cells over-expressing miR-4732-5p and pri-miR-144/451, miR-144-3p decreased the expression of non-activated Caspase3 (Fig.	('144-3p', 'Chemical', '-', (94, 100))	('miR-4732-5p', 'Var', (57, 68))	('miR-144', 'Gene', '406936', (77, 84))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('Expression', 'MPA', (0, 10))	('decreased', 'NegReg', (101, 110))	('increased', 'PosReg', (22, 31))	('miR-144', 'Gene', (90, 97))	('expression', 'MPA', (115, 125))	('miR-144', 'Gene', '406936', (90, 97))	('non-activated', 'Protein', (129, 142))	('miR-144', 'Gene', (77, 84))	('Caspase3', 'Gene', (143, 151))	('Caspase3', 'Gene', '836', (143, 151))
716704	30479563	No difference of expression of PTEN and ERK1/2 were observed among cells overexpressing miRNA and miR-144/451 cluster and the control cells.	('PTEN', 'Gene', (31, 35))	('PTEN', 'Gene', '5728', (31, 35))	('miR-144', 'Gene', (98, 105))	('miR-144', 'Gene', '406936', (98, 105))	('miRNA', 'Var', (88, 93))	('ERK1/2', 'Gene', (40, 46))	('ERK1/2', 'Gene', '5595;5594', (40, 46))
716705	30479563	miR-144-3p, miR-451a, miR-4732-3p and miR-144/451 cluster decreased the expression of phosphorylated ERK1/2 (Fig.	('miR-144', 'Gene', (0, 7))	('decreased', 'NegReg', (58, 67))	('miR-144', 'Gene', '406936', (0, 7))	('phosphorylated', 'MPA', (86, 100))	('miR-144', 'Gene', (38, 45))	('expression', 'MPA', (72, 82))	('miR-144', 'Gene', '406936', (38, 45))	('ERK1/2', 'Gene', (101, 107))	('miR-451a', 'Gene', (12, 20))	('miR-4732-3p', 'Var', (22, 33))	('ERK1/2', 'Gene', '5595;5594', (101, 107))	('144-3p', 'Chemical', '-', (4, 10))	('miR-451a', 'Gene', '574411', (12, 20))
716706	30479563	miR-144-3p, miR-4732-5p and miR-144/451 decreased the expression of MMP9 (Fig.	('expression', 'MPA', (54, 64))	('miR-144', 'Gene', (0, 7))	('miR-144', 'Gene', '406936', (0, 7))	('miR-4732-5p', 'Var', (12, 23))	('miR-144', 'Gene', (28, 35))	('miR-144', 'Gene', '406936', (28, 35))	('MMP9', 'Gene', '4318', (68, 72))	('MMP9', 'Gene', (68, 72))	('144-3p', 'Chemical', '-', (4, 10))	('decreased', 'NegReg', (40, 49))
716713	30479563	miR-144-3p, miR-451a, miR-4732-3p and miR-4732-5p inhibited cell migration, miR-144-3p, miR-144-5p, miR-451a and miR-4732-3p inhibited cell proliferation, however, no change of cell migration and proliferation were observed in cells over-expressing miR-144/451.	('miR-144', 'Gene', '406936', (249, 256))	('inhibited', 'NegReg', (50, 59))	('cell migration', 'CPA', (60, 74))	('miR-144', 'Gene', '406936', (88, 95))	('miR-451a', 'Gene', '574411', (100, 108))	('miR-144', 'Gene', '406936', (0, 7))	('miR-451a', 'Gene', '574411', (12, 20))	('cell proliferation', 'CPA', (135, 153))	('miR-4732-3p', 'Var', (113, 124))	('miR-144', 'Gene', (76, 83))	('144-3p', 'Chemical', '-', (4, 10))	('miR-144', 'Gene', (249, 256))	('miR-4732-5p', 'Var', (38, 49))	('miR-144', 'Gene', (88, 95))	('144-3p', 'Chemical', '-', (80, 86))	('miR-144', 'Gene', (0, 7))	('miR-451a', 'Gene', (100, 108))	('miR-4732-3p', 'Var', (22, 33))	('miR-451a', 'Gene', (12, 20))	('inhibited', 'NegReg', (125, 134))	('miR-144', 'Gene', '406936', (76, 83))
716718	30479563	Phosphorylation of Thr41, Ser37 and Ser33 is the main degradation pathway.	('Ser33', 'Chemical', '-', (36, 41))	('Thr41', 'Chemical', '-', (19, 24))	('Ser33', 'Var', (36, 41))	('Ser37', 'Var', (26, 31))	('Phosphorylation', 'MPA', (0, 15))	('Thr41', 'Var', (19, 24))	('Ser37', 'Chemical', '-', (26, 31))
716721	30479563	Phosphorylation of the Ser62 Strengthened stability of c-Myc, therefore prolonged the half-life of c-Myc.	('Ser62', 'Gene', (23, 28))	('c-Myc', 'Gene', '4609', (55, 60))	('Phosphorylation', 'Var', (0, 15))	('c-Myc', 'Gene', (55, 60))	('stability', 'MPA', (42, 51))	('half-life', 'MPA', (86, 95))	('Ser62', 'Chemical', '-', (23, 28))	('prolonged', 'PosReg', (72, 81))	('Strengthened', 'PosReg', (29, 41))	('c-Myc', 'Gene', '4609', (99, 104))	('c-Myc', 'Gene', (99, 104))
716726	30479563	The inhibition of MAPK/ERK signaling pathway may mainly caused by posttranscriptional modification of ERK1/2, miR-144-3p and miR-451a played a synergistic role in the inhibition of MAPK/ERK signaling pathway.	('posttranscriptional modification', 'Var', (66, 98))	('ERK', 'Gene', '5594', (186, 189))	('144-3p', 'Chemical', '-', (114, 120))	('ERK1/2', 'Gene', '5595;5594', (102, 108))	('ERK', 'Gene', (186, 189))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'Gene', (23, 26))	('ERK', 'Gene', '5594', (102, 105))	('miR-451a', 'Gene', '574411', (125, 133))	('miR-451a', 'Gene', (125, 133))	('miR-144', 'Gene', (110, 117))	('miR-144', 'Gene', '406936', (110, 117))	('ERK', 'Gene', (102, 105))	('inhibition', 'NegReg', (4, 14))	('ERK1/2', 'Gene', (102, 108))
716734	30479563	In this study, miR-144-3p decreased the expression of 34KD Caspase3, no change in the expression of Caspase3 were observed in stable cell over-expressing miR-144/451, which were consistent with results of cell apoptosis.	('expression', 'MPA', (40, 50))	('miR-144', 'Gene', (15, 22))	('Caspase3', 'Gene', '836', (100, 108))	('miR-144', 'Gene', '406936', (15, 22))	('Caspase3', 'Gene', '836', (59, 67))	('Caspase3', 'Gene', (100, 108))	('miR-144', 'Gene', (154, 161))	('Caspase3', 'Gene', (59, 67))	('miR-144', 'Gene', '406936', (154, 161))	('34KD', 'Var', (54, 58))	('144-3p', 'Chemical', '-', (19, 25))	('decreased', 'NegReg', (26, 35))
716736	30479563	miR-144-3p prometed the apoptosis of EC9706, miR-451a can lead to the arrest of G2 phase, miR-144-3, miR-451a,miR-4732-3p inhibited the migration of cell, miR-144-3p inhibited the invasion of cell, the proliferation can be inhibited by miR-144-3p, miR-144-5p, miR-451a and miR-4732-3p.	('miR-451a', 'Gene', (260, 268))	('miR-144', 'Gene', (155, 162))	('miR-144', 'Gene', '406936', (248, 255))	('migration of cell', 'CPA', (136, 153))	('inhibited', 'NegReg', (122, 131))	('miR-144', 'Gene', '406936', (0, 7))	('miR-451a', 'Gene', '574411', (45, 53))	('miR-144', 'Gene', (90, 97))	('miR-451a', 'Gene', '574411', (101, 109))	('144-3p', 'Chemical', '-', (4, 10))	('miR-4732-3p', 'Var', (273, 284))	('EC9706', 'CellLine', 'CVCL:E307', (37, 43))	('miR-144', 'Gene', '406936', (236, 243))	('miR-451a', 'Gene', '574411', (260, 268))	('miR-144', 'Gene', '406936', (155, 162))	('miR-144', 'Gene', (248, 255))	('inhibited', 'NegReg', (223, 232))	('inhibited', 'NegReg', (166, 175))	('144-3p', 'Chemical', '-', (159, 165))	('144-3p', 'Chemical', '-', (240, 246))	('proliferation', 'CPA', (202, 215))	('miR-4732-3p', 'Var', (110, 121))	('miR-451a', 'Gene', (45, 53))	('EC9706', 'Var', (37, 43))	('miR-144', 'Gene', (0, 7))	('G2 phase', 'CPA', (80, 88))	('miR-144', 'Gene', '406936', (90, 97))	('miR-451a', 'Gene', (101, 109))	('arrest', 'MPA', (70, 76))	('miR-144', 'Gene', (236, 243))
716773	29147256	There were 4 patients with non-T4 M1 LYM, 4 patients with T4 M0, and 1 patient with T4 M1 LYM.	('T4 M0', 'Var', (58, 63))	('patient', 'Species', '9606', (44, 51))	('non-T4', 'Disease', (27, 33))	('patients', 'Species', '9606', (44, 52))	('patient', 'Species', '9606', (13, 20))	('patients', 'Species', '9606', (13, 21))	('patient', 'Species', '9606', (71, 78))
716844	25158929	In addition, we also observed an inverse association with high levels of E1S.	('E1S', 'Protein', (73, 76))	('E1S', 'Chemical', 'MESH:D004970', (73, 76))	('inverse', 'NegReg', (33, 40))	('high', 'Var', (58, 62))
716850	25158929	There is other evidence that may support our observations, particularly for the effect of free testosterone and free DHT.	('free DHT', 'Var', (112, 120))	('DHT', 'Chemical', 'MESH:D013196', (117, 120))	('free testosterone', 'MPA', (90, 107))	('free testosterone', 'Chemical', '-', (90, 107))
716858	25158929	In theory, testosterone could also undergo intra-esophageal conversion to estradiol via aromatase with subsequent pro-inflammatory effects , although there is scant evidence that CYP19A1 is expressed in normal esophagus (GDS1321, GDS3838).	('GDS3838', 'Var', (230, 237))	('intra-esophageal', 'Disease', (43, 59))	('estradiol', 'Chemical', 'MESH:D004958', (74, 83))	('GDS1321', 'Var', (221, 228))	('testosterone', 'Chemical', 'MESH:D013739', (11, 23))	('CYP19A1', 'Gene', '1588', (179, 186))	('intra-esophageal', 'Disease', 'MESH:D004941', (43, 59))	('CYP19A1', 'Gene', (179, 186))
716862	25158929	In addition, AR gene transcription has been observed in both normal squamous epithelium (GEO accession: GDS3838 ) and:to a weaker extent:in BE (GDS3472 , GDS1321 ).	('AR', 'Gene', '367', (13, 15))	('GDS3472', 'Var', (144, 151))	('GDS1321 ', 'Var', (154, 162))	('BE', 'Phenotype', 'HP:0100580', (140, 142))
716866	25158929	Gene expression data support the presence of both ER beta and ER alpha receptors in stratified squamous epithelium and in BE (GDS4350 , GDS1321 , GDS3838 , GDS3472 ).	('GDS3472 ', 'Var', (156, 164))	('GDS4350', 'Var', (126, 133))	('ER beta', 'Gene', '2100', (50, 57))	('ER alpha', 'Gene', '2099', (62, 70))	('ER beta', 'Gene', (50, 57))	('BE', 'Phenotype', 'HP:0100580', (122, 124))	('GDS3838', 'Var', (146, 153))	('GDS1321', 'Var', (136, 143))	('ER alpha', 'Gene', (62, 70))
716868	25158929	Prior animal and in vitro studies of esophageal adenocarcinoma have shown that E2  and 2-methoxyestradiol  exhibit anti-carcinogenic properties, and the normal esophagus is known to express certain 17-beta-hydroxysteroid dehydrogenases:such as HSD17B-1, 4, 5, 7, 8, 10 and 11 (GDS4350 GDS1321 GDS3472 GDS3838):which indicates that local conversion between estrone and estradiol is possible.	('steroid', 'Chemical', 'MESH:D013256', (213, 220))	('estradiol', 'Chemical', 'MESH:D004958', (96, 105))	('GDS4350 GDS1321 GDS3472 GDS3838):', 'Var', (277, 310))	('carcinogenic', 'Disease', 'MESH:D063646', (120, 132))	('esophageal adenocarcinoma', 'Disease', (37, 62))	('estradiol', 'Chemical', 'MESH:D004958', (368, 377))	('HSD17B-1, 4, 5, 7, 8, 10 and 11', 'Gene', '3292;3295;8644;51478;7923;3028;51170', (244, 275))	('carcinogenic', 'Disease', (120, 132))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (37, 62))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (37, 62))	('estrone', 'Chemical', 'MESH:D004970', (356, 363))	('2-methoxyestradiol', 'Chemical', 'MESH:D000077584', (87, 105))
716877	24121790	The first is on 19p13 (rs10419226, P=3.6x10-10) in CRTC1 (CREB-regulated transcription co-activator), whose aberrant activation has been associated with oncogenic activity.	('associated', 'Reg', (137, 147))	('oncogenic activity', 'CPA', (153, 171))	('rs10419226', 'Mutation', 'rs10419226', (23, 33))	('CREB', 'Gene', (58, 62))	('CRTC1', 'Gene', (51, 56))	('CREB', 'Gene', '1385', (58, 62))	('activation', 'PosReg', (117, 127))	('rs10419226', 'Var', (23, 33))
716878	24121790	A second is on 9q22 (rs11789015, P=1.0x10-9) in BARX1, which encodes a transcription factor important in esophageal specification.	('rs11789015', 'Var', (21, 31))	('rs11789015', 'Mutation', 'rs11789015', (21, 31))	('BARX1', 'Gene', (48, 53))
716879	24121790	A third is on 3p14 (rs2687201, P=5.5x10-9) near the transcription factor, FOXP1, which regulates esophageal development.	('rs2687201', 'Var', (20, 29))	('FOXP1', 'Gene', (74, 79))	('esophageal development', 'CPA', (97, 119))	('regulates', 'Reg', (87, 96))	('FOXP1', 'Gene', '27086', (74, 79))	('rs2687201', 'Mutation', 'rs2687201', (20, 29))
716893	24121790	A second significant locus was at 9q22.32 (Figure 2b) for rs11789015 PMETA(BE+EA)= 1.02 x 10-9, OR(CI) = 0.83 (0.79-0.88).	('rs11789015', 'Var', (58, 68))	('PMETA', 'Gene', (69, 74))	('rs11789015', 'Mutation', 'rs11789015', (58, 68))
716894	24121790	The third genome-wide significant locus was at 3p13 (rs2687201) near FOXP1 (Figure 2c) with PMETA(BE+EA)= 5.47 x 10-9, OR(CI) = 1.18 (1.12 - 1.25) A previous study of Barrett's esophagus identified the SNP rs9936833, near the putative tumor suppressor gene FOXF1.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('FOXP1', 'Gene', '27086', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('rs9936833', 'Var', (206, 215))	('FOXF1', 'Gene', '2294', (257, 262))	("Barrett's esophagus", 'Disease', (167, 186))	('rs9936833', 'Mutation', 'rs9936833', (206, 215))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (167, 186))	('tumor', 'Disease', (235, 240))	('rs2687201', 'Mutation', 'rs2687201', (53, 62))	('FOXF1', 'Gene', (257, 262))	('FOXP1', 'Gene', (69, 74))	('rs2687201', 'Var', (53, 62))
716898	24121790	The previous study of Barrett's esophagus also identified rs9257809 in the major histocompatibility complex (HLA) as being associated with increased risk of Barrett's esophagus.	('associated', 'Reg', (123, 133))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (22, 41))	("Barrett's esophagus", 'Disease', (157, 176))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (157, 176))	('rs9257809', 'Mutation', 'rs9257809', (58, 67))	('rs9257809', 'Var', (58, 67))
716900	24121790	A previous report using BEACON data showed that Barrett's esophagus and esophageal adenocarcinoma risk is influenced by a large number of common genetic variants, and that a large proportion of the genes affecting risk of these two conditions are shared between them.	('esophageal adenocarcinoma', 'Disease', (72, 97))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (72, 97))	("Barrett's esophagus", 'Disease', (48, 67))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (48, 67))	('variants', 'Var', (153, 161))	('influenced by', 'Reg', (106, 119))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (72, 97))
716903	24121790	The SNPs in 19p13.11, rs10419226 and rs10423674, are intronic CRTC1 (CREB-regulated transcription co-activator) variants associated with oncogenic activity.	('rs10419226', 'Mutation', 'rs10419226', (22, 32))	('associated with', 'Reg', (121, 136))	('CREB', 'Gene', (69, 73))	('CRTC1', 'Gene', (62, 67))	('rs10419226', 'Var', (22, 32))	('rs10423674', 'Var', (37, 47))	('rs10423674', 'Mutation', 'rs10423674', (37, 47))	('oncogenic activity', 'CPA', (137, 155))	('CREB', 'Gene', '1385', (69, 73))
716906	24121790	rs10419226 has been shown to be an expression quantitative trait loci (eQTL) for PIK3R2 in lymphoblastoid cell lines.	('PIK3R2', 'Gene', (81, 87))	('rs10419226', 'Mutation', 'rs10419226', (0, 10))	('PIK3R2', 'Gene', '5296', (81, 87))	('rs10419226', 'Var', (0, 10))
716913	24121790	Three of these, rs200331191, rs139340769 and rs8102046, lie in a region of probable promoter and enhancer activities across multiple cell lines.	('rs139340769', 'Var', (29, 40))	('rs8102046', 'Var', (45, 54))	('rs200331191', 'Mutation', 'rs200331191', (16, 27))	('enhancer', 'PosReg', (97, 105))	('rs139340769', 'Mutation', 'rs139340769', (29, 40))	('rs200331191', 'Var', (16, 27))	('rs8102046', 'Mutation', 'rs8102046', (45, 54))
716914	24121790	The intronic CRTC1 SNP rs10423674 influences age at menarche.	('rs10423674', 'Mutation', 'rs10423674', (23, 33))	('rs10423674', 'Var', (23, 33))	('influences', 'Reg', (34, 44))
716916	24121790	rs10423674 is an eQTL for PBX4 in lymphoblastoid cell lines.	('PBX4', 'Gene', '80720', (26, 30))	('PBX4', 'Gene', (26, 30))	('rs10423674', 'Mutation', 'rs10423674', (0, 10))	('rs10423674', 'Var', (0, 10))
716917	24121790	The nearest gene to the peak SNP on chromosome 3 (rs2687201) is FOXP1.	('FOXP1', 'Gene', '27086', (64, 69))	('rs2687201', 'Var', (50, 59))	('FOXP1', 'Gene', (64, 69))	('rs2687201', 'Mutation', 'rs2687201', (50, 59))
716921	24121790	One of them, rs7626449, is at a site where there is also evidence from DNase-seq for transcription factor binding in esophageal epithelial cells.	('rs7626449', 'Mutation', 'rs7626449', (13, 22))	('binding', 'Interaction', (106, 113))	('rs7626449', 'Var', (13, 22))
716922	24121790	The SNP rs11789015 lies in an intron of BARX1, a homeobox transcription factor known to be involved in esophageal and trachea differentiation in developing mouse embryos and associated with down-regulation of Wnt pathway activity in stomach morphogenesis and specification.	('involved', 'Reg', (91, 99))	('Wnt pathway', 'Pathway', (209, 220))	('down-regulation', 'NegReg', (190, 205))	('activity', 'MPA', (221, 229))	('rs11789015', 'Var', (8, 18))	('rs11789015', 'Mutation', 'rs11789015', (8, 18))	('mouse', 'Species', '10090', (156, 161))	('BARX1', 'Gene', (40, 45))
716924	24121790	rs11789015 lies in a region where histone marks denote likely promoter activity.	('rs11789015', 'Mutation', 'rs11789015', (0, 10))	('rs11789015', 'Var', (0, 10))	('histone marks', 'Protein', (34, 47))
716925	24121790	rs11789015 also alters a known regulatory motif for the transcription factor FOXP1.	('rs11789015', 'Var', (0, 10))	('rs11789015', 'Mutation', 'rs11789015', (0, 10))	('FOXP1', 'Gene', (77, 82))	('regulatory motif', 'MPA', (31, 47))	('FOXP1', 'Gene', '27086', (77, 82))	('alters', 'Reg', (16, 22))
716926	24121790	A correlated SNP, rs62574346 (r2=0.97 with rs11789015), resides where there is also evidence from DNase-seq for transcription factor binding in esophageal epithelial cells.	('rs62574346', 'Var', (18, 28))	('rs11789015', 'Mutation', 'rs11789015', (43, 53))	('rs11789015', 'Var', (43, 53))	('rs62574346', 'Mutation', 'rs62574346', (18, 28))	('binding', 'Interaction', (133, 140))
716929	24121790	Two other SNPs near rs9936833, rs2178146 and rs3111601, have stronger and more significant associations in esophageal adenocarcinoma cases (Table 2 and Supplementary Figure 3b).	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (107, 132))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (107, 132))	('rs2178146', 'Mutation', 'rs2178146', (31, 40))	('rs2178146', 'Var', (31, 40))	('rs3111601', 'Mutation', 'rs3111601', (45, 54))	('rs3111601', 'Var', (45, 54))	('rs9936833', 'Mutation', 'rs9936833', (20, 29))	('associations', 'Interaction', (91, 103))	('esophageal adenocarcinoma', 'Disease', (107, 132))
716930	24121790	Since the size and direction of effect of the Barrett's esophagus-associated SNPs at 16q24 were similar in esophageal adenocarcinoma, we used the combined Barrett's esophagus and cancer data to identify other SNPs which are more significantly associated in 16q24 than rs9936833 (Table 2).	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (107, 132))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (46, 65))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (107, 132))	('associated', 'Reg', (243, 253))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (155, 174))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('rs9936833', 'Var', (268, 277))	('rs9936833', 'Mutation', 'rs9936833', (268, 277))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('16q24', 'Var', (257, 262))	('cancer', 'Disease', (179, 185))	('esophageal adenocarcinoma', 'Disease', (107, 132))
716931	24121790	One of these is rs3111601, which is in high LD (r2 = 0.75) with rs9936833.	('rs3111601', 'Mutation', 'rs3111601', (16, 25))	('rs9936833', 'Mutation', 'rs9936833', (64, 73))	('rs3111601', 'Var', (16, 25))	('rs9936833', 'Var', (64, 73))
716932	24121790	All of the SNPs in high LD with rs3111601 are intergenic, although rs1979654 (r2=0.64 with rs3111601) stands out as having excellent regulatory potential across a wide range of cell types and is likely to affect protein binding, chromatin structure and histone modification.	('protein', 'Protein', (212, 219))	('regulatory potential', 'MPA', (133, 153))	('binding', 'Interaction', (220, 227))	('affect', 'Reg', (205, 211))	('histone', 'MPA', (253, 260))	('rs3111601', 'Mutation', 'rs3111601', (32, 41))	('rs3111601', 'Mutation', 'rs3111601', (91, 100))	('rs3111601', 'Var', (32, 41))	('rs3111601', 'Var', (91, 100))	('rs1979654', 'Mutation', 'rs1979654', (67, 76))	('chromatin', 'MPA', (229, 238))
716933	24121790	There was evidence for additional independent signals in the region at rs3950627 (38kb nearer to FOXF1) and rs2178146 (64kb nearer to FOXF1), where both had similar P-values to rs3111601 (Table 2 and Figure 2d), but were in only modest LD (r2 < 0.2) with rs3111601.	('FOXF1', 'Gene', (97, 102))	('rs2178146', 'Var', (108, 117))	('rs3111601', 'Mutation', 'rs3111601', (255, 264))	('FOXF1', 'Gene', '2294', (134, 139))	('rs2178146', 'Mutation', 'rs2178146', (108, 117))	('rs3950627', 'Mutation', 'rs3950627', (71, 80))	('FOXF1', 'Gene', '2294', (97, 102))	('FOXF1', 'Gene', (134, 139))	('rs3111601', 'Mutation', 'rs3111601', (177, 186))	('rs3111601', 'Var', (177, 186))	('rs3950627', 'Var', (71, 80))
716934	24121790	Neither are good regulatory candidates, although rs8045253 (imputation association PDISCOVERY(BE+EA) = 8.04 x 10-5), in r2=0.63 with rs3950627, changes a motif for the transcription factor FOXP1.	('FOXP1', 'Gene', '27086', (189, 194))	('rs8045253', 'Mutation', 'rs8045253', (49, 58))	('rs3950627', 'Mutation', 'rs3950627', (133, 142))	('motif', 'MPA', (154, 159))	('FOXP1', 'Gene', (189, 194))	('changes', 'Reg', (144, 151))	('rs3950627', 'Var', (133, 142))	('rs8045253', 'Var', (49, 58))
716961	24121790	We used the same logistic regression model and covariates as in our primary analysis, and also fitted rs3950627 as a covariate since it was the most significant SNP 100kb up or downstream of rs9936833.	('rs9936833', 'Mutation', 'rs9936833', (191, 200))	('rs3950627', 'Mutation', 'rs3950627', (102, 111))	('rs3950627', 'Var', (102, 111))	('rs9936833', 'Var', (191, 200))
716962	24121790	This conditional analysis identified rs2178146 as the most significant SNP 100kb up or downstream of rs9936833.	('rs9936833', 'Mutation', 'rs9936833', (101, 110))	('rs2178146', 'Mutation', 'rs2178146', (37, 46))	('rs2178146', 'Var', (37, 46))	('rs9936833', 'Var', (101, 110))
716963	24121790	We repeated this analysis four more times identifying and adding to each successive model rs2178146, rs3111601, rs1490865, and rs13332095, respectively, stopping when the p-value of the most significant remaining SNP had P > 0.01 (Table 3).	('rs1490865', 'Mutation', 'rs1490865', (112, 121))	('rs2178146', 'Mutation', 'rs2178146', (90, 99))	('rs2178146', 'Var', (90, 99))	('rs3111601', 'Mutation', 'rs3111601', (101, 110))	('rs13332095', 'Var', (127, 137))	('rs3111601', 'Var', (101, 110))	('rs13332095', 'Mutation', 'rs13332095', (127, 137))	('rs1490865', 'Var', (112, 121))
716979	21658856	The most significant single parameters for predicting acute esophagitis (RTOG Grade 2 or greater) were MOH85, mean esophagus dose (MED), and V30.	('acute esophagitis', 'Disease', (54, 71))	('MOH85', 'Gene', (103, 108))	('V30', 'Var', (141, 144))	('acute esophagitis', 'Disease', 'MESH:D004941', (54, 71))	('esophagitis', 'Phenotype', 'HP:0100633', (60, 71))
716985	21658856	Five dosimetric parameters were identified as predictive of AE with or without chemotherapy: mean esophageal dose (MED), maximal esophageal dose, V20 (percentage of esophagus volume receiving >20 Gy), V35, and V60.	('V35', 'Gene', (201, 204))	('V35', 'Gene', '28474', (201, 204))	('V20', 'Var', (146, 149))	('V60', 'Var', (210, 213))
717062	31966919	Minimisation, a type of dynamic allocation, is gaining popularity especially in clinical cancer trials.	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Minimisation', 'Var', (0, 12))
717138	26402816	As for the depth of tumor invasion, 6 (9.8%), 4 (6.6%), 27 (44.3%), and 24 (39.3%) cases were Tis-T1, T2, T3, and T4 respectively.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Tis-T1', 'Var', (94, 100))
717157	26402816	However, there was a statistically significant difference in platelet count in patients who had CTCs/CTM in their peripheral blood as compared with those who did not (254.7 vs 213.1, P < 0.05) (Table 3).	('platelet count', 'MPA', (61, 75))	('CTCs/CTM', 'Var', (96, 104))	('patients', 'Species', '9606', (79, 87))	('CTM', 'Chemical', '-', (101, 104))	('significant', 'Reg', (35, 46))
717177	26402816	Thus, CTM appear to be a promising potential biomarker for cancer metastasis.	('CTM', 'Var', (6, 9))	('cancer metastasis', 'Disease', (59, 76))	('CTM', 'Chemical', '-', (6, 9))	('cancer metastasis', 'Disease', 'MESH:D009362', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
717197	26402816	In this study, there was a significant difference (P < 0.05) in baseline platelet levels between patients with positive CTCs and patients with negative CTCs using ISET assay (Table 3).	('ISET', 'Chemical', '-', (163, 167))	('patients', 'Species', '9606', (129, 137))	('platelet levels', 'MPA', (73, 88))	('positive', 'Var', (111, 119))	('patients', 'Species', '9606', (97, 105))
717223	25844602	In colon cancer, inappropriate permanent activation of the Wnt cascade always due to the loss of APC allele, Axin mutation or activating beta-catenin point mutation.	('beta-catenin', 'Gene', '1499', (137, 149))	('Wnt cascade', 'Pathway', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('loss', 'NegReg', (89, 93))	('Axin', 'Gene', '8312', (109, 113))	('APC', 'Gene', '324', (97, 100))	('activation', 'PosReg', (41, 51))	('APC', 'Gene', (97, 100))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('APC', 'Phenotype', 'HP:0005227', (97, 100))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('beta-catenin', 'Gene', (137, 149))	('mutation', 'Var', (114, 122))	('point mutation', 'Var', (150, 164))	('Axin', 'Gene', (109, 113))	('colon cancer', 'Disease', (3, 15))	('activating', 'PosReg', (126, 136))
717225	25844602	On the other hand, dysregulation of negative regulators could also contribute to constitutive activation of the Wnt/beta-catenin signalling in cancer.	('dysregulation', 'Var', (19, 32))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('beta-catenin', 'Gene', '1499', (116, 128))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('beta-catenin', 'Gene', (116, 128))	('activation', 'PosReg', (94, 104))
717247	25844602	Similarly, CD90 population was dramatically decreased in antagomir-942 cells compared with control cells (Fig.	('CD90', 'Gene', '7070', (11, 15))	('antagomir-942', 'Var', (57, 70))	('antagomir-942', 'Chemical', '-', (57, 70))	('CD90', 'Gene', (11, 15))	('decreased', 'NegReg', (44, 53))
717249	25844602	However, inhibition of miR-942 is only slightly suppressed in Eca109 and Kyse510 compare to the control cells (Fig.	('miR-942', 'Gene', (23, 30))	('inhibition', 'MPA', (9, 19))	('miR-942', 'Gene', '100126331', (23, 30))	('suppressed', 'NegReg', (48, 58))	('Kyse510', 'Var', (73, 80))	('Eca109', 'Var', (62, 68))
717250	25844602	Thus, our experiments indicated that endogenous miR-942 might act as a cancer stem cell inducer which promotes ESCC stem cell-like traits.	('endogenous', 'Var', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('promotes', 'PosReg', (102, 110))	('cancer', 'Disease', (71, 77))	('miR-942', 'Gene', '100126331', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-942', 'Gene', (48, 55))	('ESCC', 'Disease', (111, 115))
717254	25844602	In contrast, when endogenous expression of miR-942 was inhibited using antagomir-942, the tumours were obviously smaller and lighter than those formed by control cells.	('endogenous expression', 'MPA', (18, 39))	('smaller', 'NegReg', (113, 120))	('antagomir-942', 'Var', (71, 84))	('antagomir-942', 'Chemical', '-', (71, 84))	('miR-942', 'Gene', (43, 50))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('miR-942', 'Gene', '100126331', (43, 50))	('lighter', 'NegReg', (125, 132))	('inhibited', 'NegReg', (55, 64))	('tumours', 'Disease', (90, 97))
717260	25844602	Conversely, transfection of antagomir-942 reduced the luciferase activity, and mutant miR-942 had no effect (Fig.	('miR-942', 'Gene', '100126331', (86, 93))	('activity', 'MPA', (65, 73))	('reduced', 'NegReg', (42, 49))	('mutant', 'Var', (79, 85))	('luciferase', 'Enzyme', (54, 64))	('miR-942', 'Gene', (86, 93))	('antagomir-942', 'Chemical', '-', (28, 41))
717264	25844602	In addition, results of the luciferase reporter activities, which linked to the 3'UTRs of sFRP4, GSK3beta, and TLE1, indicated that miR-942 overexpression significantly repressed, whereas inhibition of endogenous miR-942 increased, the luciferase activity of 3'UTRs, and ectopically expressing mutant miR-942 had no inhibitory effect on the 3'UTRs luciferase activity (Fig.	('miR-942', 'Gene', (301, 308))	('TLE1', 'Gene', (111, 115))	('sFRP4', 'Gene', (90, 95))	('increased', 'PosReg', (221, 230))	('luciferase', 'Enzyme', (236, 246))	('GSK3beta', 'Gene', '2932', (97, 105))	('miR-942', 'Gene', '100126331', (132, 139))	('miR-942', 'Gene', '100126331', (301, 308))	('miR-942', 'Gene', (213, 220))	('miR-942', 'Gene', (132, 139))	('sFRP4', 'Gene', '6424', (90, 95))	('miR-942', 'Gene', '100126331', (213, 220))	('TLE1', 'Gene', '7088', (111, 115))	('mutant', 'Var', (294, 300))	('activity', 'MPA', (247, 255))	('GSK3beta', 'Gene', (97, 105))
717270	25844602	5F and 5G, individually silencing sFRP4, GSK3beta, or TLE1 increased the tumour sphere formation and enhanced the TOP flash/FOP flash activity of antagomir-942 cells.	('sFRP4', 'Gene', (34, 39))	('TLE1', 'Gene', '7088', (54, 58))	('tumour', 'Disease', (73, 79))	('GSK3beta', 'Gene', '2932', (41, 49))	('sFRP4', 'Gene', '6424', (34, 39))	('TLE1', 'Gene', (54, 58))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('enhanced', 'PosReg', (101, 109))	('TOP flash/FOP flash activity', 'MPA', (114, 142))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('GSK3beta', 'Gene', (41, 49))	('antagomir-942', 'Chemical', '-', (146, 159))	('increased', 'PosReg', (59, 68))	('silencing', 'Var', (24, 33))
717307	25844602	The esophageal cancer cell lines, including Kyse140, Kyse180, Kyse30, Kyse410, Kyse510, Kyse520, Eca109, TE-1, EC18, EC9706, HKESC1 and 108CA were grown in the DMEM medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum (HyClone, Logan, UT).	('EC9706', 'Var', (117, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('HKESC1', 'CellLine', 'CVCL:D568', (125, 131))	('bovine', 'Species', '9913', (227, 233))	('EC9706', 'CellLine', 'CVCL:E307', (117, 123))	('Kyse520', 'Var', (88, 95))	('Kyse30', 'Var', (62, 68))	('DMEM medium', 'Chemical', '-', (160, 171))	('Kyse510', 'Var', (79, 86))	('Kyse410', 'Var', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal cancer', 'Disease', (4, 21))	('Kyse180', 'Var', (53, 60))
717326	25844602	Western blot analysis was performed using anti- sFRP4 (1:2000, Abcam, Cambridge, MA, USA); anti-GSK3beta (1:5000, Abcam, Cambridge, MA, USA), anti-TLE1 (1:3000, Abcam, Cambridge, MA, USA); anti-beta-catenin (1:5000, Abcam, Cambridge, MA, USA); anti-c-myc (1:1000, Abcam, Cambridge, MA, USA).	('GSK3beta', 'Gene', '2932', (96, 104))	('c-myc', 'Gene', (249, 254))	('TLE1', 'Gene', '7088', (147, 151))	('1:5000', 'Var', (106, 112))	('beta-catenin', 'Gene', (194, 206))	('sFRP4', 'Gene', '6424', (48, 53))	('c-myc', 'Gene', '4609', (249, 254))	('beta-catenin', 'Gene', '1499', (194, 206))	('TLE1', 'Gene', (147, 151))	('sFRP4', 'Gene', (48, 53))	('GSK3beta', 'Gene', (96, 104))
717331	25844602	The BALB/c nude mice were randomly divided into two groups (n=6/group) and was inoculated subcutaneously with Eca109/Vector cells (1 x 106) in the left dorsal flank and with Eca109/miR-942 cells (1 x 106) in the right dorsal flank per mouse.	('miR-942', 'Gene', '100126331', (181, 188))	('miR-942', 'Gene', (181, 188))	('mouse', 'Species', '10090', (235, 240))	('Eca109/Vector', 'Var', (110, 123))	('nude mice', 'Species', '10090', (11, 20))
717363	19483069	As such, major adjustments in the process of swallowing, eating and dining can lead to distressing responses such as shame, anxiety, depression, and isolation.	('adjustments', 'Var', (15, 26))	('depression', 'Disease', (133, 143))	('anxiety', 'Disease', (124, 131))	('anxiety', 'Phenotype', 'HP:0000739', (124, 131))	('shame', 'Disease', (117, 122))	('depression', 'Phenotype', 'HP:0000716', (133, 143))	('lead to', 'Reg', (79, 86))	('men', 'Species', '9606', (21, 24))	('anxiety', 'Disease', 'MESH:D001008', (124, 131))	('depression', 'Disease', 'MESH:D000275', (133, 143))	('isolation', 'Disease', (149, 158))
717383	19483069	Moderate sucrose, high salt, and high citric acid levels elicit higher lingual swallowing pressures.	('elicit', 'Reg', (57, 63))	('high', 'Var', (33, 37))	('higher', 'PosReg', (64, 70))	('citric acid', 'Chemical', 'MESH:D019343', (38, 49))	('sucrose', 'Chemical', 'MESH:D013395', (9, 16))	('salt', 'Chemical', 'MESH:D012492', (23, 27))	('lingual swallowing pressures', 'MPA', (71, 99))
717394	19483069	Angiotensin-Converting Enzyme (ACE) inhibitors have been considered for elderly dysphagic patients even when they do not have hypertension, secondary to studies showing lower rates of pneumonia in patients treated with ACE inhibitors; however, ACE inhibitors also are associated with symptoms such as chronic cough that may mimic, mask or exacerbate dysphagia symptoms and therefore should be prescribed judiciously in the older adult at risk for dysphagia.	('chronic cough', 'Disease', (301, 314))	('patients', 'Species', '9606', (197, 205))	('dysphagia', 'Disease', 'MESH:D003680', (447, 456))	('hypertension', 'Phenotype', 'HP:0000822', (126, 138))	('ACE', 'Gene', '1636', (31, 34))	('cough', 'Phenotype', 'HP:0012735', (309, 314))	('inhibitors', 'Var', (248, 258))	('ACE', 'Gene', (31, 34))	('dysphagia', 'Disease', (447, 456))	('pneumonia', 'Phenotype', 'HP:0002090', (184, 193))	('dysphagia symptoms', 'Disease', 'MESH:D003680', (350, 368))	('Angiotensin-Converting Enzyme', 'Gene', '1636', (0, 29))	('associated', 'Reg', (268, 278))	('dysphagia', 'Disease', 'MESH:D003680', (350, 359))	('pneumonia', 'Disease', 'MESH:D011014', (184, 193))	('ACE', 'Gene', '1636', (244, 247))	('dysphagia', 'Disease', (350, 359))	('ACE', 'Gene', (244, 247))	('dysphagia', 'Phenotype', 'HP:0002015', (447, 456))	('pneumonia', 'Disease', (184, 193))	('ACE', 'Gene', '1636', (219, 222))	('ACE', 'Gene', (219, 222))	('dysphagia symptoms', 'Disease', (350, 368))	('patients', 'Species', '9606', (90, 98))	('dysphagia', 'Phenotype', 'HP:0002015', (350, 359))	('hypertension', 'Disease', 'MESH:D006973', (126, 138))	('Angiotensin-Converting Enzyme', 'Gene', (0, 29))	('mask', 'Disease', (331, 335))	('hypertension', 'Disease', (126, 138))	('exacerbate', 'PosReg', (339, 349))
717411	19483069	Head and neck cancer surgeries, some spinal cord surgeries, thyroid surgeries, and any intervention that can jeopardize the recurrent laryngeal nerve may result in dysphagia.	('dysphagia', 'Phenotype', 'HP:0002015', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('neck cancer', 'Disease', 'MESH:D006258', (9, 20))	('neck cancer', 'Disease', (9, 20))	('dysphagia', 'Disease', 'MESH:D003680', (164, 173))	('result in', 'Reg', (154, 163))	('Head and neck cancer', 'Phenotype', 'HP:0012288', (0, 20))	('surgeries', 'Var', (21, 30))	('dysphagia', 'Disease', (164, 173))
717451	19483069	However, current data suggest that healthy adults approaching 70 years of age will more likely be faced with problems of excessive energy intake leading to overweight and obesity, as well as deficiencies in vitamins and minerals due to consumption of low nutrient density foods.	('obesity', 'Phenotype', 'HP:0001513', (171, 178))	('overweight', 'Phenotype', 'HP:0025502', (156, 166))	('overweight', 'Disease', (156, 166))	('obesity', 'Disease', 'MESH:D009765', (171, 178))	('vitamins', 'Protein', (207, 215))	('deficiencies', 'Var', (191, 203))	('obesity', 'Disease', (171, 178))
717471	19483069	Risk for vitamin B-12 deficiency is increased in the elderly due to a high prevalence of atrophic gastritis which limits the absorption of protein-bound vitamin B-12 from foods and affects 10-30% of individuals greater than 60 years of age.	('gastritis', 'Phenotype', 'HP:0005263', (98, 107))	('limits', 'NegReg', (114, 120))	('atrophic gastritis', 'Disease', (89, 107))	('vitamin B-12', 'Gene', (9, 21))	('absorption of protein-bound', 'MPA', (125, 152))	('vitamin B-12', 'Chemical', 'MESH:D014805', (9, 21))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (89, 107))	('vitamin B-12', 'Chemical', 'MESH:D014805', (153, 165))	('atrophic gastritis', 'Disease', 'MESH:D005757', (89, 107))	('vitamin B-12 deficiency', 'Phenotype', 'HP:0100502', (9, 32))	('deficiency', 'Var', (22, 32))
717472	19483069	Vitamin B-12 deficiency leads to irreversible neurological damage, walking and balance disturbances, and cognitive impairment including confusion and mood changes.	('neurological damage', 'Disease', (46, 65))	('mood', 'Disease', (150, 154))	('mood changes', 'Phenotype', 'HP:0001575', (150, 162))	('cognitive impairment', 'Disease', 'MESH:D003072', (105, 125))	('deficiency', 'Var', (13, 23))	('confusion', 'Phenotype', 'HP:0001289', (136, 145))	('neurological damage', 'Disease', 'MESH:D009422', (46, 65))	('balance disturbances', 'Phenotype', 'HP:0002172', (79, 99))	('confusion', 'Disease', (136, 145))	('Vitamin B-12 deficiency', 'Phenotype', 'HP:0100502', (0, 23))	('cognitive impairment', 'Phenotype', 'HP:0100543', (105, 125))	('cognitive impairment', 'Disease', (105, 125))	('Vitamin B-12', 'Gene', (0, 12))	('Vitamin B-12', 'Chemical', 'MESH:D014805', (0, 12))
717580	19483069	It was designed as two sequential RCTs to compare the efficacy of two of the most commonly prescribed dysphagia interventions: chin-down posture and thickened liquids of either nectar-thick (300cps) and honey-thick (3000cps) viscosity1 for patients with Parkinson's disease (PD) and/or dementia in the short term and over a longer period of time.	("Parkinson's disease", 'Disease', 'MESH:D010300', (254, 273))	('dysphagia', 'Phenotype', 'HP:0002015', (102, 111))	('dementia', 'Disease', 'MESH:D003704', (286, 294))	('dysphagia', 'Disease', 'MESH:D003680', (102, 111))	('PD', 'Disease', 'MESH:D010300', (275, 277))	('dysphagia', 'Disease', (102, 111))	('patients', 'Species', '9606', (240, 248))	('dementia', 'Phenotype', 'HP:0000726', (286, 294))	("Parkinson's disease", 'Disease', (254, 273))	('dementia', 'Disease', (286, 294))	('3000cps', 'Var', (216, 223))
717583	19483069	The primary outcome of Part I showed that aspiration was significantly reduced with honey-thick liquids as compared with both nectar-thick and chin-down posture interventions.	('honey-thick liquids', 'Chemical', '-', (84, 103))	('aspiration', 'CPA', (42, 52))	('honey-thick liquids', 'Var', (84, 103))	('reduced', 'NegReg', (71, 78))	('aspiration', 'Phenotype', 'HP:0002835', (42, 52))
717613	19483069	Poor oral hygiene is a risk factor for pneumonia, and aspiration of saliva, whether or not it is combined with food or fluid, can increase the likelihood of infection.	('infection', 'Disease', (157, 166))	('aspiration of saliva', 'Phenotype', 'HP:0003781', (54, 74))	('infection', 'Disease', 'MESH:D007239', (157, 166))	('pneumonia', 'Phenotype', 'HP:0002090', (39, 48))	('Poor oral', 'Phenotype', 'HP:0000160', (0, 9))	('pneumonia', 'Disease', (39, 48))	('pneumonia', 'Disease', 'MESH:D011014', (39, 48))	('aspiration', 'Phenotype', 'HP:0002835', (54, 64))	('aspiration', 'Var', (54, 64))
717620	19047905	In this study, we examined the contribution of aberrant methylation of promoter regions in methylation-prone tumor suppressors to the pathogenesis of vulvar cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('vulvar cancer', 'Disease', (150, 163))	('aberrant methylation', 'Var', (47, 67))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('vulvar cancer', 'Disease', 'MESH:D014846', (150, 163))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('vulvar cancer', 'Phenotype', 'HP:0030416', (150, 163))
717622	19047905	Of the 22 tumor suppressor genes examined, aberrant methylation was observed for 9 genes: TP73, FHIT, VHL, APC, ESR1, CDKN2B, DAPK1, GSTP1 andI GSF4.	('TP73', 'Gene', (90, 94))	('VHL', 'Gene', (102, 105))	('DAPK1', 'Gene', (126, 131))	('andI GSF4', 'Gene', (139, 148))	('CDKN2B', 'Gene', (118, 124))	('tumor', 'Disease', (10, 15))	('methylation', 'MPA', (52, 63))	('VHL', 'Gene', '7428', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('DAPK1', 'Gene', '1612', (126, 131))	('CDKN2B', 'Gene', '1030', (118, 124))	('observed', 'Reg', (68, 76))	('GSTP1', 'Gene', '2950', (133, 138))	('FHIT', 'Gene', (96, 100))	('ESR1', 'Gene', '2099', (112, 116))	('APC', 'Disease', 'MESH:D011125', (107, 110))	('APC', 'Disease', (107, 110))	('GSTP1', 'Gene', (133, 138))	('ESR1', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('TP73', 'Gene', '7161', (90, 94))	('FHIT', 'Gene', '2272', (96, 100))	('aberrant', 'Var', (43, 51))
717623	19047905	The most frequently methylated genes included TP73 in 9 of 13 cell lines, and IGSF4, DAPK1 and FHIT in 3 of 13 cell lines.	('methylated', 'Var', (20, 30))	('IGSF4', 'Gene', (78, 83))	('IGSF4', 'Gene', '23705', (78, 83))	('DAPK1', 'Gene', '1612', (85, 90))	('FHIT', 'Gene', (95, 99))	('FHIT', 'Gene', '2272', (95, 99))	('TP73', 'Gene', '7161', (46, 50))	('TP73', 'Gene', (46, 50))	('DAPK1', 'Gene', (85, 90))
717625	19047905	In the context of gene copy number and methylation status, both copies of the TP73 gene were hypermethylated.	('TP73', 'Gene', '7161', (78, 82))	('TP73', 'Gene', (78, 82))	('hypermethylated', 'Var', (93, 108))
717627	19047905	Frequent genetic alterations of loss and gain ofgene copy number included gain of GSTP1 and MEN1, and loss of MFHAS1 and IGSF4 in over 50% of the SCV cell lines.	('GSTP1', 'Gene', (82, 87))	('gain', 'PosReg', (41, 45))	('copy number', 'Var', (53, 64))	('IGSF4', 'Gene', (121, 126))	('loss', 'NegReg', (32, 36))	('GSTP1', 'Gene', '2950', (82, 87))	('IGSF4', 'Gene', '23705', (121, 126))	('gain', 'PosReg', (74, 78))	('loss', 'NegReg', (102, 106))	('MEN1', 'Gene', '4221', (92, 96))	('SCV', 'Phenotype', 'HP:0030417', (146, 149))	('MEN1', 'Gene', (92, 96))	('MFHAS1', 'Gene', '9258', (110, 116))	('MFHAS1', 'Gene', (110, 116))
717628	19047905	These findings underscore the contribution of both genetic and epigenetic events to the underlying pathogenesis of squamous cell carcinoma of the vulva.	('epigenetic', 'Var', (63, 73))	('squamous cell carcinoma of the vulva', 'Disease', (115, 151))	('squamous cell carcinoma of the vulva', 'Phenotype', 'HP:0030417', (115, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('squamous cell carcinoma of the vulva', 'Disease', 'MESH:D002294', (115, 151))
717631	19047905	Aberrant methylation of CpG islands is a hallmark of human cancers and is found early during carcinogenesis.	('carcinogenesis', 'Disease', (93, 107))	('CpG', 'Protein', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Aberrant methylation', 'Var', (0, 20))	('human', 'Species', '9606', (53, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (93, 107))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))
717633	19047905	In this study, we focus on aberrant methylation of promoter regions in methylation-prone tumor suppressors in the pathogenesis of vulvar cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('vulvar cancer', 'Disease', 'MESH:D014846', (130, 143))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('aberrant methylation', 'Var', (27, 47))	('vulvar cancer', 'Disease', (130, 143))	('tumor', 'Disease', (89, 94))	('vulvar cancer', 'Phenotype', 'HP:0030416', (130, 143))
717645	19047905	The number of passages for the cell lines were as follows: UM-SCV-1A - passage(P) 22, UM-SCV-1B - P8, UM-SCV-2 - P22, UM-SCV- 3 - P26, UM-SCV- 4 - P19, UM-SCV-6 - P17, UM-SCV-7 - P13, UT-SCV-1 - P26, UT-SCV-2 and -3 - P27, UT-SCV-4 - P12, UT-SCV-5 - P9, and UT-SCV-6 - P12.	('P22', 'Gene', (113, 116))	('P27', 'Gene', (218, 221))	('P19', 'Gene', (147, 150))	('SCV', 'Phenotype', 'HP:0030417', (138, 141))	('P12', 'Gene', (234, 237))	('UM-SCV-1A', 'Var', (59, 68))	('SCV', 'Phenotype', 'HP:0030417', (105, 108))	('SCV', 'Phenotype', 'HP:0030417', (89, 92))	('P17', 'Gene', '653820', (163, 166))	('P22', 'Gene', '11261', (113, 116))	('P26', 'Gene', (195, 198))	('P13', 'Gene', (179, 182))	('P13', 'Gene', '440926', (179, 182))	('SCV', 'Phenotype', 'HP:0030417', (121, 124))	('P19', 'Gene', '1029', (147, 150))	('P12', 'Gene', '56655', (269, 272))	('P26', 'Gene', (130, 133))	('SCV', 'Phenotype', 'HP:0030417', (62, 65))	('P12', 'Gene', (269, 272))	('UM-SCV-1B - P8', 'Var', (86, 100))	('P26', 'Gene', '23423', (195, 198))	('P27', 'Gene', '3429', (218, 221))	('P12', 'Gene', '56655', (234, 237))	('P17', 'Gene', (163, 166))	('P26', 'Gene', '23423', (130, 133))
717664	19047905	To detect both aberrant methylation and changes in copy number, each sample requires 2 MLPA reactions.	('aberrant methylation', 'Var', (15, 35))	('changes', 'Reg', (40, 47))	('methylation', 'Var', (24, 35))	('copy number', 'MPA', (51, 62))	('MLPA', 'Chemical', '-', (87, 91))
717666	19047905	The modified DNA served as a template using primers specific for either the methylated or modified unmethylated TP73 and FHIT sequences.	('TP73', 'Gene', (112, 116))	('TP73', 'Gene', '7161', (112, 116))	('FHIT', 'Gene', (121, 125))	('FHIT', 'Gene', '2272', (121, 125))	('modified', 'Var', (90, 98))
717673	19047905	The most frequently methylated genes were TP73 in 9 of 13 cell lines, detected by MS-MLPA in 6/13 and MSP in 3/13, followed by IGSF4, DAPK1 and FHIT in 3 of 13 cell lines (Table 5).	('methylated', 'Var', (20, 30))	('DAPK1', 'Gene', '1612', (134, 139))	('TP73', 'Gene', '7161', (42, 46))	('TP73', 'Gene', (42, 46))	('IGSF4', 'Gene', (127, 132))	('IGSF4', 'Gene', '23705', (127, 132))	('FHIT', 'Gene', (144, 148))	('DAPK1', 'Gene', (134, 139))	('FHIT', 'Gene', '2272', (144, 148))	('MS-MLPA', 'Chemical', '-', (82, 89))
717682	19047905	Aberrant methylation of GSTP1, observed in only UT- SCV-2 indicated hypermethylation of 1 of 3 copies.	('Aberrant', 'Var', (0, 8))	('SCV', 'Phenotype', 'HP:0030417', (52, 55))	('GSTP1', 'Gene', (24, 29))	('hypermethylation', 'MPA', (68, 84))	('methylation', 'MPA', (9, 20))	('GSTP1', 'Gene', '2950', (24, 29))
717684	19047905	Homozygous loss of CDKN2B was noted in UM-SCV-4, loss of one copy in UT-SCV-6, gain of copies in UM-SCV-7 and UT-SCV-4, and methylation of 1 of 3 copies in UT-SCV-2.	('loss', 'NegReg', (49, 53))	('SCV', 'Phenotype', 'HP:0030417', (113, 116))	('loss', 'NegReg', (11, 15))	('gain', 'PosReg', (79, 83))	('SCV', 'Phenotype', 'HP:0030417', (100, 103))	('SCV', 'Phenotype', 'HP:0030417', (42, 45))	('CDKN2B', 'Gene', (19, 25))	('SCV', 'Phenotype', 'HP:0030417', (159, 162))	('CDKN2B', 'Gene', '1030', (19, 25))	('copies', 'MPA', (87, 93))	('SCV', 'Phenotype', 'HP:0030417', (72, 75))	('methylation', 'Var', (124, 135))
717695	19047905	MSP of TP73 confirmed aberrant methylation detected by MS-MLPA for UM-SCV-2, UM-SCV-3, UT-SCV-3, -4 and -6.	('aberrant', 'Var', (22, 30))	('methylation', 'MPA', (31, 42))	('TP73', 'Gene', '7161', (7, 11))	('TP73', 'Gene', (7, 11))	('MS-MLPA', 'Chemical', '-', (55, 62))	('SCV', 'Phenotype', 'HP:0030417', (90, 93))	('SCV', 'Phenotype', 'HP:0030417', (70, 73))	('SCV', 'Phenotype', 'HP:0030417', (80, 83))
717699	19047905	Promoter region hypermethylation is known to be an early event in carcinogenesis.	('carcinogenesis', 'Disease', (66, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('hypermethylation', 'Var', (16, 32))
717700	19047905	The consequence of CpG island hypermethylation, especially for those islands associated with tumor suppressor gene (TSG) promoters is the loss of TSG function, which contributes to tumorigenesis.	('loss', 'NegReg', (138, 142))	('function', 'MPA', (150, 158))	('tumor', 'Disease', (181, 186))	('TSG', 'Gene', '57045', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TSG', 'Gene', (146, 149))	('tumor', 'Disease', (93, 98))	('TSG', 'Gene', '57045', (146, 149))	('TSG', 'Gene', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('hypermethylation', 'Var', (30, 46))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
717701	19047905	The Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) assay is a high throughput quantitative assay permitting the dual detection of genomic alterations of losses and gains and epigenetic events of promoter hypermethylation.	('epigenetic events', 'Var', (207, 224))	('MS-MLPA', 'Chemical', '-', (75, 82))	('losses', 'Var', (186, 192))	('gains', 'PosReg', (197, 202))
717702	19047905	In our study using MS-MLPA, a candidate multi-gene approach, we identified, concomitantly, genetic and epigenetic alterations in SCV.	('SCV', 'Phenotype', 'HP:0030417', (129, 132))	('MS-MLPA', 'Chemical', '-', (19, 26))	('epigenetic alterations', 'Var', (103, 125))	('SCV', 'Gene', (129, 132))
717703	19047905	The most frequently methylated gene was TP73 (9 of 13 cell lines).	('TP73', 'Gene', (40, 44))	('methylated', 'Var', (20, 30))	('TP73', 'Gene', '7161', (40, 44))
717709	19047905	Hypermethylation of TP73 in nasopharyngeal carcinomas has been reported with a frequency of 20%.	('TP73', 'Gene', '7161', (20, 24))	('TP73', 'Gene', (20, 24))	('nasopharyngeal carcinomas', 'Disease', (28, 53))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (28, 52))	('Hypermethylation', 'Var', (0, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('nasopharyngeal carcinomas', 'Disease', 'MESH:D000077274', (28, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('nasopharyngeal carcinomas', 'Phenotype', 'HP:0100630', (28, 53))
717710	19047905	In head and neck squamous cell carcinoma (HNSCC) cell lines, hypermethylation of TP73 occurred as a primary as well as a disease progression event.	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('occurred', 'Reg', (86, 94))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('hypermethylation', 'Var', (61, 77))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (12, 40))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('TP73', 'Gene', '7161', (81, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('TP73', 'Gene', (81, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
717712	19047905	Reduced mRNA expression has been reported in methylated lymphomas where TP73 abnormalities were mainly found in aggressive tumors with bad response to conventional polychemotherapy suggesting a relation between TP73 inactivation and the aggressiveness of these tumors.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('TP73', 'Gene', '7161', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('abnormalities', 'Var', (77, 90))	('lymphomas', 'Disease', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('TP73', 'Gene', (72, 76))	('TP73', 'Gene', '7161', (211, 215))	('found', 'Reg', (103, 108))	('mRNA expression', 'MPA', (8, 23))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('Reduced', 'NegReg', (0, 7))	('aggressiveness', 'Disease', (237, 251))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('aggressive tumors', 'Disease', (112, 129))	('TP73', 'Gene', (211, 215))	('aggressiveness', 'Phenotype', 'HP:0000718', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('aggressiveness', 'Disease', 'MESH:D001523', (237, 251))	('tumors', 'Disease', (123, 129))	('lymphomas', 'Disease', 'MESH:D008223', (56, 65))	('aggressive tumors', 'Disease', 'MESH:D001523', (112, 129))	('lymphomas', 'Phenotype', 'HP:0002665', (56, 65))
717714	19047905	IGSF4 is a novel immunoglobulin-like intercellular adhesion molecule first characterized as a tumor suppressor of non-small cell lung cancer and termed TSLC1, where silencing was primarily achieved by allelic loss and promoter methylation.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('non-small cell lung cancer', 'Disease', (114, 140))	('TSLC1', 'Gene', '23705', (152, 157))	('TSLC1', 'Gene', (152, 157))	('IGSF4', 'Gene', (0, 5))	('IGSF4', 'Gene', '23705', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (118, 140))	('tumor', 'Disease', (94, 99))	('promoter methylation', 'Var', (218, 238))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (114, 140))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (114, 140))	('allelic', 'Var', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
717715	19047905	TSLC1 (IGSF4) silencing through promoter hypermethylation has been suggested as the major mechanism of epigenetic control in several cancers including non-small cell lung cancer, pancreatic cancer and hepatocellular carcinoma.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (151, 177))	('promoter hypermethylation', 'Var', (32, 57))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('TSLC1', 'Gene', '23705', (0, 5))	('pancreatic cancer', 'Disease', 'MESH:D010190', (179, 196))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (201, 225))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (151, 177))	('pancreatic cancer', 'Disease', (179, 196))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (201, 225))	('cancers', 'Disease', (133, 140))	('IGSF4', 'Gene', (7, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('non-small cell lung cancer', 'Disease', (151, 177))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TSLC1', 'Gene', (0, 5))	('IGSF4', 'Gene', '23705', (7, 12))	('hepatocellular carcinoma', 'Disease', (201, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (179, 196))	('silencing', 'NegReg', (14, 23))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (155, 177))
717716	19047905	In esophageal squamous cell carcinoma (ESCC), loss of TSLC1 protein expression as a consequence of promoter hypermethylation, a late stage event in ESCC carcinogenesis, has been implicated in invasion and metastasis and aggressive tumor behavior through the disruption of cell-cell interactions.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('expression', 'MPA', (68, 78))	('loss', 'NegReg', (46, 50))	('aggressive tumor', 'Disease', 'MESH:D001523', (220, 236))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (148, 167))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('aggressive tumor', 'Disease', (220, 236))	('invasion', 'CPA', (192, 200))	('implicated', 'Reg', (178, 188))	('interactions', 'Interaction', (282, 294))	('promoter hypermethylation', 'Var', (99, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('protein', 'Protein', (60, 67))	('TSLC1', 'Gene', '23705', (54, 59))	('TSLC1', 'Gene', (54, 59))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))	('ESCC carcinogenesis', 'Disease', (148, 167))
717718	19047905	Promoter hypermethylation of the tumor suppressor gene, TSLC1, is also a highly frequent event in cervical cancers where epigenetic silencing of TSLC1 has been implicated in the progression from high-risk HPV-containing, high-grade CIN lesions to invasive cervical cancer.	('cancers', 'Disease', (107, 114))	('TSLC1', 'Gene', '23705', (56, 61))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('TSLC1', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('implicated', 'Reg', (160, 170))	('TSLC1', 'Gene', '23705', (145, 150))	('epigenetic silencing', 'Var', (121, 141))	('TSLC1', 'Gene', (145, 150))	('CIN lesions to invasive cervical cancer', 'Disease', (232, 271))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('CIN lesions to invasive cervical cancer', 'Disease', 'MESH:D002583', (232, 271))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('Promoter hypermethylation', 'Var', (0, 25))
717722	19047905	DAPK1 expression is commonly lost in urinary bladder, breast, B-cell neoplasms and renal cell carcinoma cell lines due to promoter hypermethylation.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('DAPK1', 'Gene', '1612', (0, 5))	('B-cell neoplasms', 'Phenotype', 'HP:0012191', (62, 78))	('expression', 'MPA', (6, 16))	('promoter hypermethylation', 'Var', (122, 147))	('neoplasms', 'Phenotype', 'HP:0002664', (69, 78))	('DAPK1', 'Gene', (0, 5))	('lost', 'NegReg', (29, 33))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (83, 103))	('neoplasms and renal cell carcinoma', 'Disease', 'MESH:C538614', (69, 103))
717723	19047905	Aberrant promoter methylation of DAPK1 has been shown to frequently occur in human head and neck cancers, non-small cell lung carcinomas, gastric and colorectal carcinomas, and uterine cervical carcinomas.	('occur', 'Reg', (68, 73))	('gastric', 'Disease', (138, 145))	('colorectal carcinomas', 'Disease', (150, 171))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (150, 171))	('DAPK1', 'Gene', '1612', (33, 38))	('neck cancers', 'Disease', (92, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('neck cancers', 'Disease', 'MESH:D006258', (92, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('Aberrant', 'Var', (0, 8))	('cervical carcinomas', 'Disease', 'MESH:D002575', (185, 204))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (106, 136))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (110, 136))	('human', 'Species', '9606', (77, 82))	('cervical carcinomas', 'Disease', (185, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('DAPK1', 'Gene', (33, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (106, 136))	('non-small cell lung carcinomas', 'Disease', (106, 136))	('promoter', 'MPA', (9, 17))	('head and neck cancers', 'Phenotype', 'HP:0012288', (83, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
717724	19047905	In HNSCC, DAPK1 promoter hypermethylation has been associated with metastasis to lymph nodes as well as advanced disease stage.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('DAPK1', 'Gene', '1612', (10, 15))	('associated', 'Reg', (51, 61))	('promoter hypermethylation', 'Var', (16, 41))	('metastasis to lymph nodes', 'CPA', (67, 92))	('DAPK1', 'Gene', (10, 15))
717725	19047905	A study of DAPK1 expression in uterine and ovarian carcinomas showed that aberrant promoter methylation of DAPK1, which occurred frequently in gynecological carcinomas, led to decreased DAPK protein expression suggesting that DAPK1 gene silencing is involved in carcinogenesis of female reproductive organs.	('ovarian carcinomas', 'Disease', 'MESH:D010051', (43, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('DAPK', 'Gene', (226, 230))	('carcinomas', 'Disease', 'MESH:D002277', (51, 61))	('decreased', 'NegReg', (176, 185))	('DAPK1', 'Gene', '1612', (11, 16))	('ovarian carcinomas', 'Disease', (43, 61))	('DAPK', 'Gene', (107, 111))	('DAPK', 'Gene', (186, 190))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (43, 61))	('carcinomas', 'Disease', (157, 167))	('expression', 'MPA', (199, 209))	('DAPK', 'Gene', '1612', (226, 230))	('DAPK1', 'Gene', (226, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('DAPK', 'Gene', (11, 15))	('DAPK', 'Gene', '1612', (107, 111))	('DAPK', 'Gene', '1612', (186, 190))	('DAPK1', 'Gene', (107, 112))	('promoter', 'MPA', (83, 91))	('carcinomas', 'Disease', (51, 61))	('DAPK', 'Gene', '1612', (11, 15))	('carcinogenesis', 'Disease', (262, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('DAPK1', 'Gene', (11, 16))	('carcinomas', 'Disease', 'MESH:D002277', (157, 167))	('DAPK1', 'Gene', '1612', (226, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('carcinogenesis', 'Disease', 'MESH:D063646', (262, 276))	('DAPK1', 'Gene', '1612', (107, 112))	('aberrant', 'Var', (74, 82))
717726	19047905	In bladder cancer, the methylation status of DAPK1 is an important prognostic factor for recurrence.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('DAPK1', 'Gene', '1612', (45, 50))	('methylation status', 'Var', (23, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('DAPK1', 'Gene', (45, 50))
717728	19047905	Loss of heterozygosity of FHIT has been associated with esophageal, stomach, colon carcinomas, lung cancers as well as HNSCC.	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('Loss of heterozygosity', 'Var', (0, 22))	('lung cancers', 'Disease', 'MESH:D008175', (95, 107))	('lung cancers', 'Phenotype', 'HP:0100526', (95, 107))	('FHIT', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('esophageal', 'Disease', (56, 66))	('colon carcinomas', 'Disease', (77, 93))	('FHIT', 'Gene', '2272', (26, 30))	('stomach', 'Disease', (68, 75))	('lung cancers', 'Disease', (95, 107))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('colon carcinomas', 'Disease', 'MESH:D015179', (77, 93))	('HNSCC', 'Disease', (119, 124))	('associated', 'Reg', (40, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
717729	19047905	Promoter hypermethylation of FHIT in squamous cell carcinomas of the esophagus has been reported to be associated with transcriptional inactivation.	('squamous cell carcinomas of the esophagus', 'Disease', 'MESH:D002294', (37, 78))	('FHIT', 'Gene', (29, 33))	('FHIT', 'Gene', '2272', (29, 33))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (37, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('squamous cell carcinomas of the esophagus', 'Disease', (37, 78))	('transcriptional', 'MPA', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('Promoter hypermethylation', 'Var', (0, 25))
717730	19047905	One study of esophageal squamous cell carcinomas detected hypermethylation of FHIT in 50% of tumor cell lines and 45% of primary tumors.	('esophageal squamous cell carcinomas', 'Disease', (13, 48))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (13, 48))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('FHIT', 'Gene', (78, 82))	('FHIT', 'Gene', '2272', (78, 82))	('primary tumors', 'Disease', (121, 135))	('hypermethylation', 'Var', (58, 74))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (93, 98))	('primary tumors', 'Disease', 'MESH:D009369', (121, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (24, 48))	('tumor', 'Disease', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (24, 47))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
717731	19047905	This same study found that hypermethylation of FHIT occurred frequently in clinical stages I and II of esophageal squamous cell carcinomas suggesting that FHIT hypermethylation may play a role in early carcinogenesis.	('hypermethylation', 'Var', (27, 43))	('esophageal squamous cell carcinomas', 'Disease', (103, 138))	('FHIT', 'Gene', (47, 51))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (103, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('FHIT', 'Gene', '2272', (47, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (202, 216))	('play', 'Reg', (181, 185))	('carcinogenesis', 'Disease', (202, 216))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (114, 138))	('FHIT', 'Gene', (155, 159))	('FHIT', 'Gene', '2272', (155, 159))
717733	19047905	Genetic and epigenetic alterations in APC (adenomatosis polyposis coli), a tumor suppressor gene originally implicated in colon cancer have been reported in other malignancies including oral squamous cell carcinomas, gastric cancers and esophageal adenocarcinomas.	('oral squamous cell carcinoma', 'Disease', (186, 214))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (191, 214))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('gastric cancers', 'Disease', (217, 232))	('gastric cancers', 'Disease', 'MESH:D013274', (217, 232))	('gastric cancers', 'Phenotype', 'HP:0012126', (217, 232))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('squamous cell carcinomas', 'Disease', (191, 215))	('tumor', 'Disease', (75, 80))	('epigenetic alterations', 'Var', (12, 34))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('APC', 'Disease', 'MESH:D011125', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (237, 263))	('reported', 'Reg', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('APC', 'Disease', (38, 41))	('esophageal adenocarcinomas', 'Disease', (237, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('malignancies', 'Disease', 'MESH:D009369', (163, 175))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('colon cancer', 'Disease', (122, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (253, 263))	('adenomatosis polyposis coli', 'Phenotype', 'HP:0005227', (43, 70))	('malignancies', 'Disease', (163, 175))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (191, 215))	('adenomatosis polyposis coli', 'Disease', 'MESH:D011125', (43, 70))	('Genetic', 'Var', (0, 7))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (186, 214))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (191, 215))	('adenomatosis polyposis coli', 'Disease', (43, 70))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
717734	19047905	Uesugi et al previously reported APC as being mutated and/or deleted in primary oral squamous cell carcinoma (OSCC) tissues and suggested that loss of APC function contributes to carcinogenesis in the oral region.	('APC', 'Disease', 'MESH:D011125', (33, 36))	('oral squamous cell carcinoma', 'Disease', (80, 108))	('APC', 'Disease', (33, 36))	('contributes', 'Reg', (164, 175))	('carcinogenesis', 'Disease', 'MESH:D063646', (179, 193))	('carcinogenesis in the oral region', 'Phenotype', 'HP:0100649', (179, 212))	('APC', 'Disease', 'MESH:D011125', (151, 154))	('APC', 'Disease', (151, 154))	('carcinogenesis', 'Disease', (179, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('loss of APC function', 'Disease', 'MESH:D011125', (143, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 108))	('deleted', 'Var', (61, 68))	('loss of APC function', 'Disease', (143, 163))
717735	19047905	Promoter hypermethylation is also an important mechanism of APC inactivation in oral cancers occurring in 25% of OSCC cell.	('APC', 'Disease', 'MESH:D011125', (60, 63))	('APC', 'Disease', (60, 63))	('oral cancers', 'Disease', 'MESH:D009062', (80, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('oral cancers', 'Disease', (80, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('inactivation', 'NegReg', (64, 76))	('Promoter hypermethylation', 'Var', (0, 25))
717737	19047905	The presence of aberrant methylation of p15 and p16 in precancerous oral tissues and lesions of the head and neck implicates methylation of p15 and p16 as early events in the pathogenesis of these lesions.	('aberrant', 'Var', (16, 24))	('p16', 'Gene', '1029', (48, 51))	('methylation', 'MPA', (25, 36))	('p15', 'Gene', '1030', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('p16', 'Gene', '1029', (148, 151))	('lesions of the head and neck', 'Phenotype', 'HP:0012288', (85, 113))	('p15', 'Gene', (140, 143))	('cancer', 'Disease', (58, 64))	('p15', 'Gene', '1030', (140, 143))	('p16', 'Gene', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('p16', 'Gene', (148, 151))	('p15', 'Gene', (40, 43))
717740	19047905	Hypermethylation of VHL promoter region in clear-cell renal carcinomas is associated with absence of transcript expression.	('Hypermethylation', 'Var', (0, 16))	('clear-cell renal carcinomas', 'Disease', (43, 70))	('renal carcinomas', 'Phenotype', 'HP:0005584', (54, 70))	('transcript expression', 'MPA', (101, 122))	('VHL', 'Gene', (20, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('clear-cell renal carcinomas', 'Phenotype', 'HP:0006770', (43, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('VHL', 'Gene', '7428', (20, 23))	('clear-cell renal carcinomas', 'Disease', 'MESH:C538614', (43, 70))
717744	19047905	In esophageal adenocarcinomas (EAC) abnormal methylation patterns were found in premalignant Barrett's tissue in addition to adenocarcinoma tissue suggesting that DNA hypermethylation is an early epigenetic event in the progression of EAC.	('esophageal adenocarcinomas', 'Disease', (3, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (3, 29))	('adenocarcinoma', 'Disease', (125, 139))	('adenocarcinoma', 'Disease', (14, 28))	('DNA hypermethylation', 'Var', (163, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('adenocarcinoma', 'Disease', 'MESH:D000230', (125, 139))	('adenocarcinoma', 'Disease', 'MESH:D000230', (14, 28))
717746	19047905	The pi-class of glutathione S-transferase enzymes has been associated with preneoplastic and neoplastic changes.	('preneoplastic', 'CPA', (75, 88))	('glutathione S-transferase enzymes', 'Enzyme', (16, 49))	('neoplastic changes', 'Phenotype', 'HP:0002664', (93, 111))	('associated', 'Reg', (59, 69))	('glutathione', 'Chemical', 'MESH:D005978', (16, 27))	('pi-class', 'Var', (4, 12))
717747	19047905	Inactivation of GSTP1 by promoter hypermethylation is characteristic of steroid related neoplasms such as breast, liver, and prostate cancers.	('prostate cancers', 'Disease', (125, 141))	('breast', 'Disease', (106, 112))	('neoplasms', 'Phenotype', 'HP:0002664', (88, 97))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('GSTP1', 'Gene', '2950', (16, 21))	('steroid', 'Chemical', 'MESH:D013256', (72, 79))	('prostate cancers', 'Disease', 'MESH:D011471', (125, 141))	('GSTP1', 'Gene', (16, 21))	('neoplasms', 'Disease', 'MESH:D009369', (88, 97))	('prostate cancers', 'Phenotype', 'HP:0012125', (125, 141))	('neoplasms', 'Disease', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('liver', 'Disease', (114, 119))	('Inactivation', 'Var', (0, 12))	('promoter hypermethylation', 'Var', (25, 50))
717757	19047905	Lack of confirmation by MSP of TP73 methylation in UM-SCV-4, detected by MS-MLPA may be primarily due to insufficient amounts of DNA for bisulfite conversion.	('TP73', 'Gene', '7161', (31, 35))	('TP73', 'Gene', (31, 35))	('bisulfite', 'Chemical', 'MESH:C042345', (137, 146))	('MS-MLPA', 'Chemical', '-', (73, 80))	('SCV', 'Phenotype', 'HP:0030417', (54, 57))	('methylation', 'Var', (36, 47))
717768	19047905	These findings suggest that epigenetic events of DNA hypermethylation may contribute to the underlying pathogenesis of squamous cell carcinoma of the vulva.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('contribute', 'Reg', (74, 84))	('DNA', 'Gene', (49, 52))	('squamous cell carcinoma of the vulva', 'Disease', (119, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('squamous cell carcinoma of the vulva', 'Phenotype', 'HP:0030417', (119, 155))	('hypermethylation', 'Var', (53, 69))	('epigenetic events', 'Var', (28, 45))	('squamous cell carcinoma of the vulva', 'Disease', 'MESH:D002294', (119, 155))
717769	19047905	As a frequent and consistent target of aberrant promoter hypermethylation, TP73 may serve as a therapeutic biomarker for gene reactivation studies in SCV.	('TP73', 'Gene', '7161', (75, 79))	('TP73', 'Gene', (75, 79))	('aberrant', 'Var', (39, 47))	('SCV', 'Phenotype', 'HP:0030417', (150, 153))
717773	19047905	Consistent and SCV-specific epigenetic alterations would signify important biomarkers relevant to the diagnosis, prognosis, and treatment of squamous cell carcinoma of the vulva.	('squamous cell carcinoma of the vulva', 'Phenotype', 'HP:0030417', (141, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('squamous cell carcinoma of the vulva', 'Disease', 'MESH:D002294', (141, 177))	('squamous cell carcinoma of the vulva', 'Disease', (141, 177))	('SCV', 'Phenotype', 'HP:0030417', (15, 18))	('epigenetic alterations', 'Var', (28, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))
717795	33639396	Moreover, the rs12255372 variant of TCF7L2 was also associated with obesity in Cameroonians.	('obesity', 'Phenotype', 'HP:0001513', (68, 75))	('rs12255372', 'Var', (14, 24))	('TCF7L2', 'Gene', (36, 42))	('obesity', 'Disease', 'MESH:D009765', (68, 75))	('TCF7L2', 'Gene', '6934', (36, 42))	('associated', 'Reg', (52, 62))	('obesity', 'Disease', (68, 75))	('rs12255372', 'Mutation', 'rs12255372', (14, 24))
717796	33639396	The majority of these early studies used genetic variants associated with NCDs in European and Asian populations that were limited by the differences in allele frequencies and LD pattern in Africans.	('NCDs', 'Disease', (74, 78))	('NCDs', 'Disease', 'None', (74, 78))	('variants', 'Var', (49, 57))
717798	33639396	For instance, the association of the rs1121980 and rs7204609 variants of the FTO gene with BMI in West Africans were replicated in African Americans.	('rs1121980', 'Mutation', 'rs1121980', (37, 46))	('FTO', 'Gene', (77, 80))	('BMI', 'Disease', (91, 94))	('rs1121980', 'Var', (37, 46))	('rs7204609', 'Mutation', 'rs7204609', (51, 60))	('FTO', 'Gene', '79068', (77, 80))	('rs7204609', 'Var', (51, 60))
717800	33639396	With the gradual advancement of GWAS in Africa, the utilization of genotyping arrays, such as the Metabochip, enabled the evaluation of the associations of about 200,000 genetic variants with NCDs.	('men', 'Species', '9606', (24, 27))	('variants', 'Var', (178, 186))	('NCDs', 'Disease', 'None', (192, 196))	('NCDs', 'Disease', (192, 196))	('associations', 'Interaction', (140, 152))
717802	33639396	Some of these include the association of SEC16B variants with BMI in black South Africans which had not been identified in previous candidate gene studies (Table 1).	('SEC16B', 'Gene', '89866', (41, 47))	('variants', 'Var', (48, 56))	('SEC16B', 'Gene', (41, 47))	('BMI', 'Disease', (62, 65))	('association', 'Interaction', (26, 37))
717806	33639396	However, most GWAS genotyping arrays were designed based on the genetic variation of European populations and therefore, might have missed the population-specific variants associated with NCDs in African populations.	('NCDs', 'Disease', (188, 192))	('variants', 'Var', (163, 171))	('NCDs', 'Disease', 'None', (188, 192))	('missed', 'NegReg', (132, 138))
717807	33639396	Despite the improved efficacy to discover more genetic variants associated with NCDs through GWAS in African populations, most studies were underpowered to adequately detect significant associations.	('variants', 'Var', (55, 63))	('NCDs', 'Disease', 'None', (80, 84))	('NCDs', 'Disease', (80, 84))
717813	33639396	Another small scale GWAS of 474 prostate cancer cases and 458 healthy controls in Ghana identified rs34575154, rs985081 and rs2185710 to be associated with high Gleason score prostate cancer.	('prostate cancer', 'Disease', (32, 47))	('rs2185710', 'Mutation', 'rs2185710', (124, 133))	('associated', 'Reg', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('rs985081', 'Mutation', 'rs985081', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('rs34575154', 'Var', (99, 109))	('prostate cancer', 'Disease', (175, 190))	('rs985081', 'Var', (111, 119))	('rs2185710', 'Var', (124, 133))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('rs34575154', 'Mutation', 'rs34575154', (99, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (175, 190))
717815	33639396	There are currently ongoing GWASs across Africa aiming to identify genetic variants associated with cancer through various research groups and consortia including Evolving Risk Factors for Cancers in African Populations (ERICA), African Female Breast Cancer Epidemiology (AFBRECANE), and Africa Esophageal Cancer Consortium (AfrECC).	('Breast Cancer', 'Phenotype', 'HP:0003002', (244, 257))	('Cancer', 'Disease', (251, 257))	('Cancer', 'Disease', (306, 312))	('Cancer', 'Disease', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('variants', 'Var', (75, 83))	('Cancers', 'Phenotype', 'HP:0002664', (189, 196))	('Cancers', 'Disease', (189, 196))	('Cancer', 'Disease', 'MESH:D009369', (189, 195))	('Cancer', 'Disease', 'MESH:D009369', (251, 257))	('Cancer', 'Disease', 'MESH:D009369', (306, 312))	('cancer', 'Disease', (100, 106))	('Breast Cancer', 'Disease', 'MESH:D001943', (244, 257))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Cancer', 'Phenotype', 'HP:0002664', (251, 257))	('Breast Cancer', 'Disease', (244, 257))	('Cancer', 'Phenotype', 'HP:0002664', (189, 195))	('Cancer', 'Phenotype', 'HP:0002664', (306, 312))	('Cancers', 'Disease', 'MESH:D009369', (189, 196))
717825	33639396	Over and above the H3Africa array, this network has designed a genotyping array to aid the identification of Afrocentric variants for cancer and to explore polygenic risk scores.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('variants', 'Var', (121, 129))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
717826	33639396	An earlier study of a genetic risk score containing 100 European derived genetic variants found that the top 10% of Ugandan men had a 4.86-fold (95%CI:2.70, 8.76) increase in prostate cancer risk.	('increase', 'PosReg', (163, 171))	('men', 'Species', '9606', (124, 127))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('prostate cancer', 'Disease', (175, 190))	('prostate cancer', 'Disease', 'MESH:D011471', (175, 190))	('variants', 'Var', (81, 89))
717831	33639396	Notably, the blockbuster PCSK9 inhibitors were developed to mimic the effects of the cholesterol lowering PCSK9 variants that are more prevalent in individuals of African ancestry.	('cholesterol', 'Chemical', 'MESH:D002784', (85, 96))	('PCSK9', 'Gene', (106, 111))	('cholesterol lowering', 'Phenotype', 'HP:0003146', (85, 105))	('PCSK9', 'Gene', '255738', (106, 111))	('PCSK9', 'Gene', (25, 30))	('PCSK9', 'Gene', '255738', (25, 30))	('variants', 'Var', (112, 120))
717835	33639396	However since African Americans are admixed and greater genetic diversity exists in continental Africans, there is a need to include/create an Afrocentric database such as the African Functional Genomics Resource (AFGR) of variants which might not be in these databases but are significantly associated with NCDs in continental Africans.	('NCDs', 'Disease', (308, 312))	('variants', 'Var', (223, 231))	('associated', 'Reg', (292, 302))	('NCDs', 'Disease', 'None', (308, 312))
717872	32927716	The authors attribute the SERS peaks of discrimination to phenylalanine, tyrosine, tryptophan, proline, certain proteins, collagen, phospholipids, and Amide I (Table 2).	('tryptophan', 'MPA', (83, 93))	('proline', 'Chemical', 'MESH:D011392', (95, 102))	('phenylalanine', 'Chemical', 'MESH:D010649', (58, 71))	('Amide', 'Chemical', 'MESH:D000577', (151, 156))	('tyrosine', 'Chemical', 'MESH:D014443', (73, 81))	('tryptophan', 'Chemical', 'MESH:D014364', (83, 93))	('phospholipids', 'Chemical', 'MESH:D010743', (132, 145))	('SERS', 'Chemical', '-', (26, 30))	('proline', 'MPA', (95, 102))	('proteins', 'Protein', (112, 120))	('tyrosine', 'MPA', (73, 81))	('phenylalanine', 'Var', (58, 71))	('collagen', 'MPA', (122, 130))
717878	32927716	Specific SERS peaks were also identified between cancer and control groups, particularly corresponding to phenylalanine, proline, valine, proteins, and collagens (see Table 2).	('proteins', 'Protein', (138, 146))	('proline', 'MPA', (121, 128))	('valine', 'MPA', (130, 136))	('SERS', 'Chemical', '-', (9, 13))	('valine', 'Chemical', 'MESH:D014633', (130, 136))	('phenylalanine', 'Var', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('proline', 'Chemical', 'MESH:D011392', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('phenylalanine', 'Chemical', 'MESH:D010649', (106, 119))	('cancer', 'Disease', (49, 55))
718051	32662828	There are three overlapped miRNAs including hsa-miR-409-3p (1 up-regulated, Figure 2A), hsa-miR-133b and hsa-miR-139-5p (2 down-regulated, Figure 2B) in both microarrays.	('hsa-miR-139-5p', 'Var', (105, 119))	('hsa-miR-133b', 'Gene', (88, 100))	('hsa-miR-409', 'Gene', '574413', (44, 55))	('hsa-miR-133b', 'Gene', '442890', (88, 100))	('up-regulated', 'PosReg', (62, 74))	('miR-139-5p', 'Chemical', '-', (109, 119))	('hsa-miR-409', 'Gene', (44, 55))
718088	32662828	reported that overexpression of miR-125b-5p inhibited cell proliferation, migration, and invasion partially by down-regulating HMGA2 in ESCC.	('cell proliferation', 'CPA', (54, 72))	('miR-125b-5p', 'Chemical', '-', (32, 43))	('inhibited', 'NegReg', (44, 53))	('down-regulating', 'NegReg', (111, 126))	('ESCC', 'Disease', (136, 140))	('HMGA2', 'Gene', '8091', (127, 132))	('invasion', 'CPA', (89, 97))	('migration', 'CPA', (74, 83))	('HMGA2', 'Gene', (127, 132))	('miR-125b-5p', 'Var', (32, 43))
718090	32662828	Long non-coding RNA DANCR was up-regulated, similar to an oncogene, and knocked down the expression of DANCR significantly suppressed cell migration, proliferation, and invasion in human ESCC tissues.	('human', 'Species', '9606', (181, 186))	('DANCR', 'Gene', (103, 108))	('expression', 'MPA', (89, 99))	('DANCR', 'Gene', '57291', (20, 25))	('DANCR', 'Gene', '57291', (103, 108))	('suppressed', 'NegReg', (123, 133))	('DANCR', 'Gene', (20, 25))	('knocked', 'Var', (72, 79))	('up-regulated', 'PosReg', (30, 42))	('cell migration', 'CPA', (134, 148))	('invasion in human ESCC tissues', 'CPA', (169, 199))
718098	32662828	A study found that miR-139-5p has the tumor-suppressive features, invasiveness, and growth suppressing characteristic in human ESCC by targeting the 3' UTR of oncogenic NR5A2.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('invasiveness', 'CPA', (66, 78))	('NR5A2', 'Gene', (169, 174))	('ESCC', 'Disease', (127, 131))	('miR-139-5p', 'Var', (19, 29))	('miR-139-5p', 'Chemical', '-', (19, 29))	('human', 'Species', '9606', (121, 126))	('growth suppressing', 'CPA', (84, 102))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('targeting', 'Reg', (135, 144))	('NR5A2', 'Gene', '2494', (169, 174))
718101	32662828	Consistent with the results from previous studies, in the present study, we also found that miR-409-3p was up-regulated, miR-133b and miR-139-5p were down-regulated in both GSE97051and GSE59973 dataset.	('down-regulated', 'NegReg', (150, 164))	('up-regulated', 'PosReg', (107, 119))	('miR-133b', 'Gene', '442890', (121, 129))	('miR-139-5p', 'Var', (134, 144))	('miR-139-5p', 'Chemical', '-', (134, 144))	('miR-133b', 'Gene', (121, 129))	('miR-409', 'Gene', (92, 99))	('miR-409', 'Gene', '574413', (92, 99))
718103	32662828	In addition, high mRNA expression of miR-409 and miR-139-5p were associated with worse OS for EC patients, yet have no statistical difference, including hsa-miR-133b (Table _8_SuppInfo.xls).	('miR-409', 'Gene', '574413', (37, 44))	('hsa-miR-133b', 'Gene', (153, 165))	('hsa-miR-133b', 'Gene', '442890', (153, 165))	('mRNA expression', 'MPA', (18, 33))	('miR-409', 'Gene', (37, 44))	('miR-139-5p', 'Var', (49, 59))	('miR-139-5p', 'Chemical', '-', (49, 59))	('patients', 'Species', '9606', (97, 105))
718104	32662828	Therefore, the results are in accordance with these previous studies, which suggests that hsa-miR-133b and hsa-miR-139-5p probably indirectly or directly play important roles in ESCC development.	('hsa-miR-133b', 'Gene', '442890', (90, 102))	('roles', 'Reg', (169, 174))	('hsa-miR-139-5p', 'Var', (107, 121))	('play', 'Reg', (154, 158))	('ESCC', 'Disease', (178, 182))	('hsa-miR-133b', 'Gene', (90, 102))	('miR-139-5p', 'Chemical', '-', (111, 121))
718107	32662828	In the present study, significant lncRNA MAST4-IT1 (ENST00000514241) up-regulation and lncRNA RP11-1437A8.4 (ENST00000565847) down-regulation were also observed in ESCC tissue compared with control tissue in GSE89102.	('up-regulation', 'PosReg', (69, 82))	('RP11', 'Gene', (94, 98))	('MAST4-IT1', 'Gene', (41, 50))	('RP11', 'Gene', '26121', (94, 98))	('ENST00000514241', 'Var', (52, 67))	('ESCC', 'Disease', (164, 168))	('ENST00000565847', 'Var', (109, 124))	('down-regulation', 'NegReg', (126, 141))	('MAST4-IT1', 'Gene', '100874310;375449;79441', (41, 50))
718114	32662828	Aberrant activation of the Cyclin D1-CDK4/6-Rb signaling pathway is common in ESCC, suggesting that CDK6 amplification promoting the progress of aggressive type of esophageal cancer.	('activation', 'PosReg', (9, 19))	('Cyclin D1', 'Gene', (27, 36))	('ESCC', 'Disease', (78, 82))	('CDK4/6', 'Gene', '1019;1021', (37, 43))	('amplification', 'Var', (105, 118))	('CDK4/6', 'Gene', (37, 43))	('aggressive type of esophageal cancer', 'Disease', 'MESH:D004938', (145, 181))	('aggressive type of esophageal cancer', 'Disease', (145, 181))	('CDK6', 'Gene', (100, 104))	('Cyclin D1', 'Gene', '595', (27, 36))	('CDK6', 'Gene', '1021', (100, 104))	('promoting', 'PosReg', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
718126	32662828	Heat shock protein 90 alpha family class A member 1 (HSP90AA1), also known as HSP90alpha, localized in the cytoplasm and played an important role in the proper folding, assembly and localization of many cellular proteins, which required for tumor progression and highly expressed in many cancer cells, inhibition of HSP90AA1 is a promising strategy for cancer therapy.	('HSP90AA1', 'Gene', (316, 324))	('HSP90alpha', 'Gene', (78, 88))	('HSP90AA1', 'Gene', '3320', (316, 324))	('tumor', 'Disease', (241, 246))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('shock', 'Phenotype', 'HP:0031273', (5, 10))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('HSP90AA1', 'Gene', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('cancer', 'Disease', (288, 294))	('cancer', 'Disease', (353, 359))	('HSP90AA1', 'Gene', '3320', (53, 61))	('inhibition', 'Var', (302, 312))	('HSP90alpha', 'Gene', '3320', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('Heat shock protein 90 alpha family class A member 1', 'Gene', '3320', (0, 51))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
718129	32662828	Moreover, some studies found that suppressing MYC is associated with radiosensitizes and attenuates malignant growth in ESCC.	('malignant growth', 'CPA', (100, 116))	('ESCC', 'Disease', (120, 124))	('suppressing', 'Var', (34, 45))	('radiosensitizes', 'CPA', (69, 84))	('MYC', 'Gene', (46, 49))	('MYC', 'Gene', '4609', (46, 49))	('attenuates', 'NegReg', (89, 99))
718131	32662828	A study found that the silencing of EGR1 reduced cisplatin-induced apoptosis in WHCO1 cells.	('reduced', 'NegReg', (41, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('silencing', 'Var', (23, 32))	('EGR1', 'Gene', (36, 40))	('EGR1', 'Gene', '1958', (36, 40))	('cisplatin-induced', 'MPA', (49, 66))
718172	31460704	The dose constraints for the OARs were as follows: lung, the mean dose (Dmean) < 13 Gy, V5Gy <= 55% (i.e., the percentage volume of the lung receiving >=5 Gy), V20Gy <= 28%, and V30Gy <= 20%; spinal cord PRV, D1% (the minimal dose received by the hottest 1% volume) <= 45 Gy; heart, V30Gy <= 40%.	('OAR', 'Gene', '4936', (29, 32))	('V30Gy <=', 'Var', (178, 186))	('V20Gy <=', 'Var', (160, 168))	('V5Gy <= 55%', 'Var', (88, 99))	('OAR', 'Gene', (29, 32))
718177	31460704	To evaluate OAR sparing, DVH parameters for the lung (Dmean, V5Gy, V10Gy, V13Gy, V20Gy, V30Gy, and V40Gy), spinal cord PRV (D1%), heart (Dmean, V30Gy, and V40Gy), body-PTV50.4 (Dmean, V5Gy, V10Gy, V20Gy, V30Gy, V40Gy, and V50Gy) were calculated and compared.	('OAR', 'Gene', '4936', (12, 15))	('V30Gy', 'Var', (204, 209))	('V10Gy', 'Var', (190, 195))	('OAR', 'Gene', (12, 15))	('V40Gy', 'Var', (211, 216))	('V20Gy', 'Var', (197, 202))
718188	31460704	Regarding the other OARs, the D1% to the spinal cord PRV, and the Dmean, V30Gy, and V40Gy of the heart in the FJT plans were lower than those in the SFT plans, but only the difference in the heart Dmean reached statistical significance (P < 0.05).	('V30Gy', 'Var', (73, 78))	('FJT', 'Var', (110, 113))	('OAR', 'Gene', (20, 23))	('lower', 'NegReg', (125, 130))	('V40Gy', 'Var', (84, 89))	('OAR', 'Gene', '4936', (20, 23))
718190	31460704	Owing to the complexity of the target and surrounding anatomy, radiotherapy planning for cervical and upper thoracic EC is very challenging.4 IMRT has a much greater potential for dose sculpting and normal tissue sparing than 3D-CRT and has been widely adopted for EC treatment in clinical practice.2, 5 However, IMRT generally produces widely distributed low-dose levels in the normal tissues surrounding the PTV, especially for the treatment of large and complex targets.	('upper thoracic EC', 'Disease', (102, 119))	('IMRT', 'Var', (313, 317))	('men', 'Species', '9606', (439, 442))	('men', 'Species', '9606', (273, 276))	('upper thoracic EC', 'Disease', 'MESH:D004938', (102, 119))	('low-dose levels', 'MPA', (356, 371))	('EC', 'Disease', 'MESH:D004938', (117, 119))	('EC', 'Disease', 'MESH:D004938', (265, 267))
718192	31460704	Our data showed that the volumes of the body-PTV50.4 and lung receiving low and intermediate doses were significantly reduced with the FJT, and the other OARs, including the heart and spinal cord PRV, were also better spared compared to the SFT.	('volumes', 'MPA', (25, 32))	('reduced', 'NegReg', (118, 125))	('FJT', 'Var', (135, 138))	('OAR', 'Gene', '4936', (154, 157))	('OAR', 'Gene', (154, 157))
718199	31460704	performed a retrospective study of 86 EC patients undergoing definitive chemoradiotherapy, and found that the V5Gy and V10Gy values were the only factors significantly correlated with grade 2 or higher RP.8 Similarly, Shaikh et al.	('V10Gy', 'Var', (119, 124))	('V5Gy', 'Var', (110, 114))	('patients', 'Species', '9606', (41, 49))	('correlated', 'Reg', (168, 178))	('EC', 'Disease', 'MESH:D004938', (38, 40))	('RP', 'Disease', 'MESH:D017564', (202, 204))
718315	30187702	A previous study demonstrated that DIS is well correlated with AET of the distal esophagus in NERD and that patients with abnormal AET are more likely to show DIS than those with normal AET.	('DIS', 'Disease', (35, 38))	('DIS', 'Disease', (159, 162))	('DIS', 'Chemical', '-', (159, 162))	('DIS', 'Chemical', '-', (35, 38))	('patients', 'Species', '9606', (108, 116))	('abnormal AET', 'Var', (122, 134))
718392	25157956	A significant association was observed between high HOTAIR expression and poor overall survival (OS) in patients with cancer (pooled HR 2.22, 95% CI: 1.68-2.93).	('poor', 'NegReg', (74, 78))	('high', 'Var', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('OS', 'Chemical', '-', (97, 99))	('HOTAIR', 'Protein', (52, 58))	('overall survival', 'MPA', (79, 95))
718394	25157956	Subgroup analysis showed that HOTAIR abundance was an independent prognostic factor for cancer metastasis (HR 3.90, 95% CI: 2.25-6.74).	('cancer metastasis', 'Disease', 'MESH:D009362', (88, 105))	('HOTAIR abundance', 'Var', (30, 46))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer metastasis', 'Disease', (88, 105))
718395	25157956	For esophageal carcinoma, high HOTAIR expression was significantly associated with TNM stage (III/IV vs. I/II: OR 6.90, 95% CI: 2.81-16.9) without heterogeneity.	('esophageal carcinoma', 'Disease', (4, 24))	('carcinoma', 'Disease', 'MESH:D002277', (15, 24))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (4, 24))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (4, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('TNM', 'Gene', '10178', (83, 86))	('associated', 'Reg', (67, 77))	('carcinoma', 'Disease', (15, 24))	('high HOTAIR expression', 'Var', (26, 48))	('TNM', 'Gene', (83, 86))
718396	25157956	In gastric cancer, HOTAIR expression was found to be significantly associated with lymph node metastases (present vs. absent: OR 4.47, 95% CI: 1.88-10.63) and vessel invasion (positive vs. negative: OR 2.88, 95% CI: 1.38-6.04) without obvious heterogeneity.	('HOTAIR', 'Var', (19, 25))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('vessel invasion', 'CPA', (159, 174))	('associated', 'Reg', (67, 77))	('gastric cancer', 'Disease', (3, 17))	('lymph node metastases', 'Disease', 'MESH:D009362', (83, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('lymph node metastases', 'Disease', (83, 104))
718408	25157956	Subgroup analysis showed that HOTAIR was an independent prognostic factor for digestive system cancer patients without preoperative treatment in Asian countries, and sample size and paper quality did not change the overall result.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('system cancer', 'Disease', (88, 101))	('HOTAIR', 'Var', (30, 36))	('system cancer', 'Disease', 'MESH:D009369', (88, 101))
718410	25157956	In esophageal carcinoma, high HOTAIR expression was significantly associated with TNM stage (III/IV vs. I/II: OR 6.90, 95%CI: 2.81-16.9) and N status (N2/3 vs. N0/1: OR 3.29, 95% CI:1.18-9.16) whereas no significant correlation was found with T classification (T3/4 vs. T1/2: OR 2.15, 95% CI: 0.24-19.5) or grade of differentiation (G3/4 vs. G1/2: OR 1.14, 95% CI: 0.10-13.0).	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('esophageal carcinoma', 'Disease', (3, 23))	('N status', 'Disease', (141, 149))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (3, 23))	('G1/2: OR 1.14', 'Gene', '10820;5544;7916', (342, 355))	('associated', 'Reg', (66, 76))	('high', 'Var', (25, 29))	('TNM stage', 'Disease', (82, 91))	('T1/2: OR 2', 'Gene', '923;9173;292', (270, 280))	('T1/2: OR 2', 'Gene', (270, 280))	('G1/2: OR 1.14', 'Gene', (342, 355))
718430	24255701	Tight control of Wnt signaling is crucial for the correct orchestration of development and aberrant constitutive activation of the Wnt signaling pathway will lead to uncontrolled cell proliferation, growth and survival, therefore promoting the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('lead to', 'Reg', (158, 165))	('uncontrolled', 'MPA', (166, 178))	('survival', 'CPA', (210, 218))	('activation', 'PosReg', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('Wnt signaling pathway', 'Pathway', (131, 152))	('aberrant', 'Var', (91, 99))	('promoting', 'PosReg', (230, 239))	('growth', 'CPA', (199, 205))	('cancer', 'Disease', (259, 265))
718462	24255701	However, our experience showed that ICC staining using diaminobenzidine as chromogen would produce a thickened membranous staining which was similar to cytoplasmic staining.	('thickened membranous staining', 'MPA', (101, 130))	('diaminobenzidine', 'Chemical', '-', (55, 71))	('diaminobenzidine', 'Var', (55, 71))
718484	24255701	Using this median number as the cut-off point, 27 patients with FZD3 ICC score > 321.5 and 8 patients with FZD3 ICC score <= 321.5 had recurrent or metastatic CRC after follow-up for 42 months and the association between FZD3 ICC scores and recurrent or metastatic CRC was highly significant (Chi-square test: chi2 = 13.34; P < 0.001).	('FZD3', 'Gene', (107, 111))	('patients', 'Species', '9606', (50, 58))	('> 321.5', 'Var', (79, 86))	('FZD3', 'Gene', (221, 225))	('recurrent', 'Disease', (241, 250))	('FZD3', 'Gene', (64, 68))	('FZD3', 'Gene', '7976', (107, 111))	('recurrent', 'CPA', (135, 144))	('FZD3', 'Gene', '7976', (221, 225))	('patients', 'Species', '9606', (93, 101))	('FZD3', 'Gene', '7976', (64, 68))
718785	21237573	Amino acids 54-73 (Cationic region 1) have been shown to inhibit the proliferation of sub-confluent endothelial cells, while amino acids 113-130 (cationic region 2) stimulates DNA synthesis (Fig.1).	('DNA synthesis', 'MPA', (176, 189))	('N', 'Chemical', 'MESH:D009584', (177, 178))	('amino acids 113-130', 'Var', (125, 144))	('proliferation of sub-confluent endothelial cells', 'CPA', (69, 117))	('inhibit', 'NegReg', (57, 64))	('stimulates', 'PosReg', (165, 175))	('Amino acids', 'Var', (0, 11))
718787	21237573	Matrix metalloproteinases (MMP-2, -3, -7 and -13, plasmin and trypsin, have been shown to cleave SPARC in vitro, producing KGHK-containing fragment.	('plasmin', 'Gene', (50, 57))	('MMP-2, -3, -7 and -13', 'Gene', '4313;4314;4316;4322', (27, 48))	('KGHK-containing fragment', 'MPA', (123, 147))	('producing', 'Reg', (113, 122))	('plasmin', 'Gene', '5340', (50, 57))	('SPARC', 'Protein', (97, 102))	('cleave', 'Var', (90, 96))
718788	21237573	The presence of truncated form of SPARC protein has been recently reported in hepatocellular carcinoma (HCC) samples and esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('carcinoma', 'Disease', 'MESH:D002277', (132, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('truncated form', 'Var', (16, 30))	('reported', 'Reg', (66, 74))	('HCC', 'Gene', (104, 107))	('carcinoma', 'Disease', (93, 102))	('carcinoma', 'Disease', (132, 141))	('SPARC protein', 'Protein', (34, 47))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (78, 102))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (121, 141))	('HCC', 'Gene', '619501', (104, 107))	('carcinoma', 'Disease', 'MESH:D002277', (93, 102))
718792	21237573	Truncated SPARC in the tumor sinusoidal area has been correlated to the tumor microvessel density (MVD), suggesting that truncated SPARC may play a significant pro-angiogenic role in HCC.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('HCC', 'Gene', '619501', (183, 186))	('truncated SPARC', 'Var', (121, 136))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('HCC', 'Gene', (183, 186))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
718793	21237573	Over-expression of SPARC leads to a decrease in MVD, at least in part, resulting in delayed tumor formation and reduction of tumor size.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('MVD', 'MPA', (48, 51))	('tumor', 'Disease', (92, 97))	('reduction', 'NegReg', (112, 121))	('tumor', 'Disease', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Over-expression', 'Var', (0, 15))	('SPARC', 'Gene', (19, 24))	('decrease', 'NegReg', (36, 44))
718796	21237573	Likewise, high expression of truncated-SPARC protein in tumor sinusoidal areas has been associated with increased tumor MVD while over-expression of full-length SPARC correlates with a decrease in tumor MVD, accompanied by a delay in tumor formation and a decrease in tumor size.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('delay', 'NegReg', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (114, 119))	('expression', 'MPA', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('truncated-SPARC', 'Var', (29, 44))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('protein', 'Protein', (45, 52))	('tumor', 'Disease', (56, 61))	('decrease', 'NegReg', (185, 193))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('increased', 'PosReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('decrease', 'NegReg', (256, 264))	('tumor', 'Disease', (268, 273))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
718797	21237573	Importance of exact sequence and the angiogenic properties of truncated- and intact-SPARC proteins observed in human liver cancer will be the subject of many future studies.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('human', 'Species', '9606', (111, 116))	('liver cancer', 'Disease', 'MESH:D006528', (117, 129))	('liver cancer', 'Disease', (117, 129))	('truncated-', 'Var', (62, 72))
718802	21237573	SiRNA knockdown of Stabilin-1 reduces SPARC expression, while elevated SPARC level is observed in Stabilin-1 over-expressing cells.	('SPARC', 'MPA', (71, 76))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('knockdown', 'Var', (6, 15))	('reduces', 'NegReg', (30, 37))	('SPARC expression', 'MPA', (38, 54))
718805	21237573	ShRNA of SOX-5 in nasopharyngeal carcinoma (NPC) cells causes a significant increase in SPARC.	('SOX-5', 'Gene', (9, 14))	('increase', 'PosReg', (76, 84))	('carcinoma', 'Disease', 'MESH:D002277', (33, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (18, 42))	('SPARC', 'MPA', (88, 93))	('ShRNA', 'Var', (0, 5))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('SOX-5', 'Gene', '6660', (9, 14))	('NPC', 'Disease', 'MESH:D052556', (44, 47))	('carcinoma', 'Disease', (33, 42))	('NPC', 'Disease', (44, 47))
718807	21237573	Exogenous TGF-beta induces over-expression of both collagen and SPARC, while this response is significantly attenuated in fibroblasts, pre-transfected with SPARC small interfering RNA.	('Exogenous', 'Var', (0, 9))	('TGF-beta', 'Gene', (10, 18))	('over-expression', 'MPA', (27, 42))	('SPARC', 'Gene', (64, 69))	('N', 'Chemical', 'MESH:D009584', (181, 182))	('collagen', 'Protein', (51, 59))	('TGF-beta', 'Gene', '7040', (10, 18))
718811	21237573	In general, alteration in DNA methylation involves DNA methyltransferases (1, 3a and 3b) leading to inactivation of many tumor suppressor genes during tumor growth.	('alteration', 'Var', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (121, 126))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('inactivation', 'MPA', (100, 112))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
718853	21237573	SPARC also alters glioma growth by changing the tumor microenvironment and by repressing tumor vascularity through inhibition of VEGF expression.	('inhibition', 'NegReg', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('VEGF', 'Gene', '7422', (129, 133))	('glioma', 'Disease', (18, 24))	('tumor', 'Disease', (48, 53))	('expression', 'MPA', (134, 144))	('glioma', 'Disease', 'MESH:D005910', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('VEGF', 'Gene', (129, 133))	('alters', 'Reg', (11, 17))	('repressing', 'NegReg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('changing', 'Reg', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('SPARC', 'Var', (0, 5))
718869	21237573	Over-expression of SPARC in gliomas induces brain tumor invasion and migration in vitro and in vivo, whereas administration of SPARC siRNA into glioma cells results in down-regulation of SPARC expression, and considerable suppression in glioma cell migration in vitro and lower tumor cell survival and invasion.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('brain tumor', 'Disease', (44, 55))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('brain tumor', 'Disease', 'MESH:D001932', (44, 55))	('Over-expression', 'Var', (0, 15))	('expression', 'MPA', (193, 203))	('migration', 'CPA', (69, 78))	('gliomas', 'Disease', (28, 35))	('lower', 'NegReg', (272, 277))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('glioma', 'Disease', (144, 150))	('suppression', 'NegReg', (222, 233))	('tumor', 'Disease', (50, 55))	('induces', 'Reg', (36, 43))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('tumor', 'Disease', (278, 283))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('glioma', 'Disease', (237, 243))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('invasion', 'CPA', (302, 310))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('glioma', 'Disease', 'MESH:D005910', (237, 243))	('brain tumor', 'Phenotype', 'HP:0030692', (44, 55))	('down-regulation', 'NegReg', (168, 183))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('glioma', 'Disease', (28, 34))	('SPARC', 'Gene', (19, 24))	('SPARC', 'Gene', (187, 192))
718872	21237573	Inhibition of HSP27, mRNA reverse SPARC-stimulated changes in morphology, migration and invasion in vitro.	('N', 'Chemical', 'MESH:D009584', (23, 24))	('HSP27', 'Gene', '3315', (14, 19))	('invasion', 'CPA', (88, 96))	('migration', 'CPA', (74, 83))	('changes', 'Reg', (51, 58))	('Inhibition', 'Var', (0, 10))	('morphology', 'CPA', (62, 72))	('HSP27', 'Gene', (14, 19))
718875	21237573	Abrogation of general cell adhesion function plays a vital role in the development of cancer.	('Abrogation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('general cell adhesion', 'Protein', (14, 35))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
718901	21237573	In colorectal cancer cell lines, over-expression of SPARC reduces cell viability and enhances apoptosis in cells exposed to various chemotherapeutic agents.	('reduces', 'NegReg', (58, 65))	('over-expression', 'Var', (33, 48))	('cell viability', 'CPA', (66, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('enhances', 'PosReg', (85, 93))	('rectal cancer', 'Phenotype', 'HP:0100743', (7, 20))	('SPARC', 'Gene', (52, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('apoptosis', 'CPA', (94, 103))
718944	33898321	Human EC cell lines HEEC, ECA109, EC9706, KYSE30, TE-1, and KYSE140 were preserved at Renji Hospital, Shanghai Jiao Tong University School of Medicine.	('Human', 'Species', '9606', (0, 5))	('EC9706', 'CellLine', 'CVCL:E307', (34, 40))	('KYSE140', 'Chemical', '-', (60, 67))	('EC9706', 'Var', (34, 40))	('KYSE140', 'Var', (60, 67))
718957	33898321	For subcutaneous xenograft models, KYSE140CTRL and KYSE140sh DRD5 suspended in DMEM at a concentration of 2 x 107 cells/ml were injected; the injecting volume was 200 mul, respectively.	('DMEM', 'Chemical', '-', (79, 83))	('KYSE140CTRL', 'Var', (35, 46))	('KYSE140', 'Chemical', '-', (35, 42))	('KYSE140', 'Chemical', '-', (51, 58))	('KYSE140sh', 'Var', (51, 60))
718961	33898321	The inhibition of protein degeneration and dephosphorylation was blocked via using protease and phosphatase inhibitor (HY-K0010 and HY-K0023, MCE, China).	('protein degeneration', 'Disease', 'MESH:D012162', (18, 38))	('HY-K0010', 'Var', (119, 127))	('HY-K0023', 'Var', (132, 140))	('protein degeneration', 'Disease', (18, 38))	('dephosphorylation', 'MPA', (43, 60))
718966	33898321	Antibodies involved were as follows: HIF-1alpha (D1S7W) Rabbit mAb (#36169), c-Myc (D84C12) Rabbit mAb (#5605), Phospho-Akt (Thr308) (244F9) Rabbit mAb (#4056), Phospho-Akt (Ser473) (587F11) Mouse mAb (#4051), Akt (pan) (11E7) Rabbit mAb (#4685), p70 S6 Kinase (49D7) Rabbit mAb (#2708), Phospho-p70 S6 Kinase (Thr421/Ser424) Antibody (#9204), Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (D13.14.4E) Rabbit mAb (HRP Conjugate) (#8544), p44/42 MAPK (Erk1/2) (137F5) Rabbit mAb (#4695), Rb (4H1) Mouse mAb (#9309), Phospho-Rb (Ser807/811) (D20B12) XP  Rabbit mAb (#8516), PRAS40 Antibody (#2610), Phospho-PRAS40 (Thr246) (D4D2)Rabbit mAb (#13175), p-mTOR (#2971), and mTOR (#2983) and were purchased from Cell Signaling Technology (USA).	('Akt', 'Gene', (120, 123))	('#2610', 'Var', (588, 593))	('Rb', 'Gene', '19645', (522, 524))	('Mouse', 'Species', '10090', (191, 196))	('Akt', 'Gene', '11651', (120, 123))	('PRAS40', 'Gene', '67605', (604, 610))	('Erk1/2', 'Gene', (365, 371))	('PRAS40', 'Gene', '67605', (571, 577))	('#13175', 'Var', (638, 644))	('Akt', 'Gene', (210, 213))	('Akt', 'Gene', (169, 172))	('Erk1/2', 'Gene', '26417;26413', (365, 371))	('Erk1/2', 'Gene', (450, 456))	('Rb', 'Gene', '19645', (486, 488))	('#8516', 'Var', (563, 568))	('Akt', 'Gene', '11651', (210, 213))	('c-Myc', 'Gene', (77, 82))	('Akt', 'Gene', '11651', (169, 172))	('Mouse', 'Species', '10090', (495, 500))	('PRAS40', 'Gene', (604, 610))	('c-Myc', 'Gene', '4609', (77, 82))	('PRAS40', 'Gene', (571, 577))	('Erk1/2', 'Gene', '26417;26413', (450, 456))
718995	33898321	To consolidate, we analyzed the results of IHC-P through scoring and calculated the relationship of DRD2 or DRD5 and TH, which illustrated that DRD5 was co-expressed with TH ( Figures 2D, E ).	('TH', 'Gene', '7054', (171, 173))	('TH', 'Gene', '7054', (117, 119))	('DRD2', 'Gene', (100, 104))	('DRD2', 'Gene', '1813', (100, 104))	('DRD5', 'Var', (144, 148))
718996	33898321	We also performed IF to observe the colocation of DRD2 or DRD5 and TH; the results further displayed that DRD5 was vital in the dopamine pathway in EC ( Figures 2F, G ).	('dopamine', 'Chemical', 'MESH:D004298', (128, 136))	('dopamine pathway', 'Pathway', (128, 144))	('DRD5', 'Var', (106, 110))	('TH', 'Gene', '7054', (67, 69))	('DRD2', 'Gene', (50, 54))	('DRD2', 'Gene', '1813', (50, 54))
718999	33898321	It has been shown that the knockdown of TH significantly hampered cell viability through inhibiting the synthesis of dopamine which could be demonstrated by the fact that administration of dopamine could rescue this effect ( Figure 3B  and  Supplemental Figure 1B ).	('dopamine', 'Chemical', 'MESH:D004298', (189, 197))	('knockdown', 'Var', (27, 36))	('dopamine', 'Chemical', 'MESH:D004298', (117, 125))	('cell viability', 'CPA', (66, 80))	('inhibiting', 'NegReg', (89, 99))	('synthesis of dopamine', 'MPA', (104, 125))	('hampered', 'NegReg', (57, 65))	('TH', 'Gene', '7054', (40, 42))
719000	33898321	We then proceeded to explore and found that knockdown of either TH or DRD5 would prohibit the proliferation of tumor cells, emphasizing the importance of dopamine pathway in EC ( Figure 3C ).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('TH', 'Gene', '7054', (64, 66))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('knockdown', 'Var', (44, 53))	('prohibit', 'NegReg', (81, 89))	('dopamine', 'Chemical', 'MESH:D004298', (154, 162))	('DRD5', 'Gene', (70, 74))
719020	33898321	We have discovered that the knockdown of DRD5 in KYSE140 significantly decreased the metastatic ability to the lymphatic node ( Figures 5A, B ).	('metastatic ability to the lymphatic node', 'CPA', (85, 125))	('KYSE140', 'Gene', (49, 56))	('KYSE140', 'Chemical', '-', (49, 56))	('DRD5', 'Gene', (41, 45))	('knockdown', 'Var', (28, 37))	('decreased', 'NegReg', (71, 80))
719021	33898321	The knockdown of DRD5 significantly attenuated tumor burden of model mice both in tumor weight and tumor growth value ( Figures 5C-E ).	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mice', 'Species', '10090', (69, 73))	('attenuated tumor', 'Disease', (36, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('DRD5', 'Gene', (17, 21))	('attenuated tumor', 'Disease', 'MESH:C538265', (36, 52))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (47, 52))
719023	33898321	In accordance with our formed results, more Ki67 staining could be observed in the control group, while the inference of DRD5 would lead to significant severe apoptosis in vivo ( Figures 5F, G ).	('DRD5', 'Var', (121, 125))	('Ki67', 'Gene', (44, 48))	('Ki67', 'Gene', '17345', (44, 48))	('lead', 'Reg', (132, 136))	('apoptosis', 'CPA', (159, 168))
719024	33898321	In summary, these data illustrated that the knockdown of DRD5 could inhibit the metastasis and growth of tumor cell of EC in vivo.	('metastasis', 'CPA', (80, 90))	('inhibit', 'NegReg', (68, 75))	('DRD5', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('knockdown', 'Var', (44, 53))	('tumor', 'Disease', (105, 110))
719071	33030640	In CAS, the division of the GDA during pancreaticoduodenectomy can cause an ischemic threat, not only to the liver, stomach, and remnant pancreas, but also to the gastrojejunal, hepaticojejunal, and pancreaticojejunal anastomoses.	('cause', 'Reg', (67, 72))	('ischemic', 'Disease', 'MESH:D007511', (76, 84))	('CAS', 'Phenotype', 'HP:0012327', (3, 6))	('ischemic', 'Disease', (76, 84))	('CAS', 'Chemical', '-', (3, 6))	('GDA', 'Chemical', '-', (28, 31))	('division', 'Var', (12, 20))
719138	31490704	PTK7 knockdown not only reduced ligand-free and fibroblast growth factor (FGF)-induced phosphorylation of FGFR1 but also the interaction of signaling adaptor proteins with FGFR1 and activation of downstream signaling proteins in TE-10 cells.	('FGFR1', 'Gene', (106, 111))	('PTK7', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('reduced', 'NegReg', (24, 31))	('FGFR1', 'Gene', '2260', (172, 177))	('interaction', 'Interaction', (125, 136))	('ligand-free', 'MPA', (32, 43))	('FGFR1', 'Gene', '2260', (106, 111))	('FGFR1', 'Gene', (172, 177))	('activation', 'PosReg', (182, 192))	('phosphorylation', 'MPA', (87, 102))	('TE', 'Chemical', 'MESH:D013691', (229, 231))
719153	31490704	However, at higher molar ratios, PTK7 encloses KDR molecules and prevents activation of KDR.	('encloses', 'Reg', (38, 46))	('KDR', 'Gene', '3791', (88, 91))	('PTK7', 'Var', (33, 37))	('KDR', 'Gene', '3791', (47, 50))	('prevents', 'NegReg', (65, 73))	('KDR', 'Gene', (88, 91))	('KDR', 'Gene', (47, 50))	('activation', 'MPA', (74, 84))
719155	31490704	In ESCC cells, PTK7 transactivates matrix metallopeptidase 9 (MMP-9) expression via activation of activator protein 1 (AP-1) and NF-kappaB.	('AP-1', 'Gene', '3726', (119, 123))	('AP-1', 'Gene', (119, 123))	('MMP-9', 'Gene', (62, 67))	('NF-kappaB', 'Gene', (129, 138))	('activation', 'PosReg', (84, 94))	('MMP-9', 'Gene', '4318', (62, 67))	('expression', 'Species', '29278', (69, 79))	('expression', 'MPA', (69, 79))	('PTK7', 'Var', (15, 19))	('NF-kappaB', 'Gene', '4790', (129, 138))
719172	31490704	The pcDNA3-PTK7-Ext-TM-FLAG encoding the human PTK7 extracellular domain and TM domain (residues 34-725) with a C-terminal FLAG-tag was constructed by deleting nucleotides encoding residues 726-1070 of PTK7 (GenBank U40271) from pcDNA3-hPTK7-FLAG.	('hPTK7', 'Gene', '5754', (236, 241))	('PTK7', 'Gene', (202, 206))	('human', 'Species', '9606', (41, 46))	('deleting', 'Var', (151, 159))	('hPTK7', 'Gene', (236, 241))
719177	31490704	The pLKO.1-shRNA-PTK7-6433 and -6434 constructs for human PTK7 knockdown and the pLKO.1-control (MilliporeSigma) were previously described by Shin et al..	('knockdown', 'Var', (63, 72))	('PTK7', 'Gene', (58, 62))	('human', 'Species', '9606', (52, 57))
719219	31490704	Specific binding of PTK7 to the FGFR1 extracellular domain was further supported by the finding that knockout of FGFR1 abolished the interaction of sPTK7-His with FGFR1 in TE-10 cells (Supplemental Fig.	('interaction', 'Interaction', (133, 144))	('FGFR1', 'Gene', (32, 37))	('abolished', 'NegReg', (119, 128))	('knockout', 'Var', (101, 109))	('FGFR1', 'Gene', '2260', (163, 168))	('sPTK7-His', 'Protein', (148, 157))	('TE', 'Chemical', 'MESH:D013691', (172, 174))	('FGFR1', 'Gene', (113, 118))	('FGFR1', 'Gene', '2260', (32, 37))	('FGFR1', 'Gene', '2260', (113, 118))	('FGFR1', 'Gene', (163, 168))
719220	31490704	To observe whether PTK7 colocalizes with FGFR1 on the cell surface, we analyzed the subcellular localization of PTK7 and FGFR1 in HEK293 cells coexpressing PTK7-FLAG and FGFR1-HA using confocal microscopy.	('FGFR1', 'Gene', '2260', (170, 175))	('HEK293', 'CellLine', 'CVCL:0045', (130, 136))	('PTK7-FLAG', 'Var', (156, 165))	('FGFR1', 'Gene', (121, 126))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))	('FGFR1', 'Gene', (170, 175))	('FGFR1', 'Gene', '2260', (121, 126))
719228	31490704	The presence of full-length PTK7 significantly increased FGFR1 phosphorylation under both ligand-free and aFGF-stimulated conditions in HEK293 cells (Fig.	('FGFR1', 'Gene', (57, 62))	('HEK293', 'CellLine', 'CVCL:0045', (136, 142))	('aFGF', 'Gene', '2246', (106, 110))	('FGFR1', 'Gene', '2260', (57, 62))	('PTK7', 'Gene', (28, 32))	('increased FGFR1', 'Phenotype', 'HP:0030269', (47, 62))	('increased', 'PosReg', (47, 56))	('phosphorylation', 'MPA', (63, 78))	('presence', 'Var', (4, 12))	('aFGF', 'Gene', (106, 110))
719231	31490704	Consistently, PTK7 knockdown in TE-10 cells reduced tyrosine phosphorylation of FGFR1 and cellular proteins independent of aFGF stimulation (Fig.	('FGFR1', 'Gene', '2260', (80, 85))	('PTK7', 'Gene', (14, 18))	('knockdown', 'Var', (19, 28))	('tyrosine', 'Chemical', 'MESH:D014443', (52, 60))	('aFGF', 'Gene', '2246', (123, 127))	('tyrosine phosphorylation', 'MPA', (52, 76))	('FGFR1', 'Gene', (80, 85))	('reduced', 'NegReg', (44, 51))	('TE', 'Chemical', 'MESH:D013691', (32, 34))	('cellular', 'Protein', (90, 98))	('aFGF', 'Gene', (123, 127))
719233	31490704	Thus, PTK7 enhances FGFR1 activation by interaction of their extracellular domains independent of the presence of a cognate ligand but is not phosphorylated by activated FGFR1.	('FGFR1', 'Gene', '2260', (170, 175))	('activation', 'MPA', (26, 36))	('FGFR1', 'Gene', (20, 25))	('FGFR1', 'Gene', '2260', (20, 25))	('interaction', 'Interaction', (40, 51))	('FGFR1', 'Gene', (170, 175))	('PTK7', 'Var', (6, 10))	('enhances', 'PosReg', (11, 19))
719236	31490704	PTK7 knockdown also decreased aFGF-induced association of FGFR1 with FGFR1-interacting proteins such as FRS2, Src, Grb2, p85 PI3-kinase, and Shc (Fig.	('aFGF', 'Gene', (30, 34))	('FRS2', 'Gene', (104, 108))	('association', 'Interaction', (43, 54))	('decreased', 'NegReg', (20, 29))	('PTK7', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('Shc', 'Gene', '6464', (141, 144))	('aFGF', 'Gene', '2246', (30, 34))	('FGFR1', 'Gene', (58, 63))	('FGFR1', 'Gene', (69, 74))	('Grb2', 'Gene', (115, 119))	('FGFR1', 'Gene', '2260', (58, 63))	('FRS2', 'Gene', '10818', (104, 108))	('Shc', 'Gene', (141, 144))	('FGFR1', 'Gene', '2260', (69, 74))	('Grb2', 'Gene', '2885', (115, 119))
719237	31490704	Decreased FGFR1 binding with interacting proteins by PTK7 knockdown was also detected in the absence of aFGF stimulation but to a much weaker extent (Fig.	('knockdown', 'Var', (58, 67))	('aFGF', 'Gene', (104, 108))	('Decreased', 'NegReg', (0, 9))	('FGFR1', 'Gene', (10, 15))	('aFGF', 'Gene', '2246', (104, 108))	('binding', 'Interaction', (16, 23))	('FGFR1', 'Gene', '2260', (10, 15))	('PTK7', 'Gene', (53, 57))	('proteins', 'Protein', (41, 49))
719246	31490704	In these cells, PTK7 knockdown decreased fibroblast growth factor (FGF)-induced proliferation to the same extent as FGFR1 knockout (Fig.	('FGFR1', 'Gene', (116, 121))	('FGFR1', 'Gene', '2260', (116, 121))	('decreased', 'NegReg', (31, 40))	('knockdown', 'Var', (21, 30))	('PTK7', 'Gene', (16, 20))
719248	31490704	In ESCC TE-6, TE-9, TE-10, and TE-11 cells, knockdown of PTK7 reduced phosphorylation of FGFR1 independent of aFGF and decreased binding to FGFR1 (Fig.	('TE', 'Chemical', 'MESH:D013691', (20, 22))	('decreased', 'NegReg', (119, 128))	('TE', 'Chemical', 'MESH:D013691', (31, 33))	('FGFR1', 'Gene', (140, 145))	('aFGF', 'Gene', (110, 114))	('TE', 'Chemical', 'MESH:D013691', (14, 16))	('FGFR1', 'Gene', (89, 94))	('FGFR1', 'Gene', '2260', (89, 94))	('FGFR1', 'Gene', '2260', (140, 145))	('phosphorylation', 'MPA', (70, 85))	('TE', 'Chemical', 'MESH:D013691', (8, 10))	('aFGF', 'Gene', '2246', (110, 114))	('knockdown', 'Var', (44, 53))	('binding', 'Interaction', (129, 136))	('PTK7', 'Gene', (57, 61))	('reduced', 'NegReg', (62, 69))
719249	31490704	PTK7 knockdown also inhibited aFGF- and bFGF-induced proliferation in the ESCC cells (Fig.	('aFGF', 'Gene', (30, 34))	('bFGF', 'Gene', (40, 44))	('PTK7', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('aFGF', 'Gene', '2246', (30, 34))	('inhibited', 'NegReg', (20, 29))	('proliferation', 'CPA', (53, 66))	('bFGF', 'Gene', '2247', (40, 44))
719253	31490704	FGFR1 is associated with poor survival of patients with ESCC, and inhibition of FGFR1 activity reduces ESCC tumor growth in vivo.	('ESCC', 'Disease', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('FGFR1', 'Gene', '2260', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('tumor', 'Disease', (108, 113))	('FGFR1', 'Gene', (80, 85))	('inhibition', 'Var', (66, 76))	('ESCC', 'Disease', (103, 107))	('patients', 'Species', '9606', (42, 50))	('reduces', 'NegReg', (95, 102))
719262	31490704	Similarly, PTK7 might promote ligand-independent oligomerization of FGFR1 and increase phosphorylation of FGFR1.	('promote', 'PosReg', (22, 29))	('FGFR1', 'Gene', (106, 111))	('PTK7', 'Var', (11, 15))	('FGFR1', 'Gene', (68, 73))	('FGFR1', 'Gene', '2260', (106, 111))	('increase', 'PosReg', (78, 86))	('FGFR1', 'Gene', '2260', (68, 73))	('ligand-independent oligomerization', 'MPA', (30, 64))	('phosphorylation', 'MPA', (87, 102))
719264	31490704	Similarly, the PTK7 extracellular domain or a truncated PTK7 mutant lacking the Cyt domain is sufficient to bind to and activate KDR or tyrosine-protein kinase transmembrane receptor 2 (ROR2) as much as the intact PTK7 does.	('bind', 'Interaction', (108, 112))	('activate', 'PosReg', (120, 128))	('KDR', 'Gene', '3791', (129, 132))	('mutant', 'Var', (61, 67))	('PTK7', 'Gene', (56, 60))	('KDR', 'Gene', (129, 132))	('ROR2', 'Gene', '4920', (186, 190))	('ROR2', 'Gene', (186, 190))	('tyrosine', 'Chemical', 'MESH:D014443', (136, 144))
719270	31490704	Ligand-independent activation of FGFR1 often occurs in the presence of FGFR1 mutations within the TM domain, such as Y373C, which induce dimerization of FGFR1.	('FGFR1', 'Gene', (153, 158))	('FGFR1', 'Gene', '2260', (153, 158))	('FGFR1', 'Gene', (71, 76))	('Y373C', 'Var', (117, 122))	('FGFR1', 'Gene', '2260', (33, 38))	('FGFR1', 'Gene', '2260', (71, 76))	('activation', 'PosReg', (19, 29))	('dimerization', 'MPA', (137, 149))	('Y373C', 'SUBSTITUTION', 'None', (117, 122))	('FGFR1', 'Gene', (33, 38))
719273	31490704	Here, we have shown that PTK7 activates FGFR1 in the absence of FGF and enhances FGFR1 activity in the presence of FGF.	('FGFR1', 'Gene', (81, 86))	('activity', 'MPA', (87, 95))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('FGFR1', 'Gene', '2260', (81, 86))	('activates', 'PosReg', (30, 39))	('PTK7', 'Var', (25, 29))	('enhances', 'PosReg', (72, 80))
719277	31490704	Overexpression of PTK7 increases proliferation, migration, and invasion in PTK7-low (TE-5 and TE-14) cells but decreases them in PTK7-high (TE-6 and TE-10) cells.	('migration', 'CPA', (48, 57))	('TE', 'Chemical', 'MESH:D013691', (140, 142))	('PTK7-low', 'Var', (75, 83))	('expression', 'Species', '29278', (4, 14))	('TE', 'Chemical', 'MESH:D013691', (94, 96))	('decreases', 'NegReg', (111, 120))	('TE', 'Chemical', 'MESH:D013691', (149, 151))	('PTK7', 'Gene', (18, 22))	('proliferation', 'CPA', (33, 46))	('invasion', 'CPA', (63, 71))	('increases', 'PosReg', (23, 32))	('TE', 'Chemical', 'MESH:D013691', (85, 87))
719279	31490704	Previously, we showed that low expression of PTK7 oligomerizes and activates KDR molecules, but high levels of PTK7 surround and inhibit KDR molecules in endothelial cells.	('oligomerizes', 'MPA', (50, 62))	('KDR', 'Gene', '3791', (77, 80))	('PTK7', 'Var', (111, 115))	('PTK7', 'Gene', (45, 49))	('inhibit', 'NegReg', (129, 136))	('expression', 'Species', '29278', (31, 41))	('activates', 'PosReg', (67, 76))	('KDR', 'Gene', '3791', (137, 140))	('KDR', 'Gene', (77, 80))	('KDR', 'Gene', (137, 140))
719308	29439724	7b) and c-kit, alpha-smooth muscle actin, desmin, and CD34 negativity, establishing the diagnosis of esophageal schwannoma.	('alpha-smooth muscle actin', 'Protein', (15, 40))	('CD34', 'Gene', (54, 58))	('desmin', 'Gene', (42, 48))	('CD34', 'Gene', '947', (54, 58))	('schwannoma', 'Phenotype', 'HP:0100008', (112, 122))	('esophageal schwannoma', 'Disease', (101, 122))	('desmin', 'Gene', '1674', (42, 48))	('negativity', 'Var', (59, 69))	('c-kit', 'Gene', '3815', (8, 13))	('c-kit', 'Gene', (8, 13))	('esophageal schwannoma', 'Disease', 'MESH:D009442', (101, 122))
719371	28415685	The original AUCs of miR-4746 were 0.849 (GSE43732) and 0.687 (GSE61047), respectively (Figure 6).	('miR-4746', 'Gene', '100616371', (21, 29))	('miR-4746', 'Gene', (21, 29))	('0.849 (GSE43732', 'Var', (35, 50))	('GSE61047', 'Var', (63, 71))	('GSE43732', 'Var', (42, 50))	('0.687 (GSE61047', 'Var', (56, 71))
719427	28415685	reported that DNA methylation of ADCY5 was correlated with recurrence of lung adenocarcinoma.	('DNA', 'Var', (14, 17))	('lung adenocarcinoma', 'Disease', (73, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('correlated', 'Reg', (43, 53))	('ADCY5', 'Gene', '111', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('ADCY5', 'Gene', (33, 38))
719441	28415685	The number of miRNA and mRNA expression values were 1881 and 60483.	('60483', 'Var', (61, 66))	('mRNA', 'MPA', (24, 28))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))
719443	28415685	The miRNAs and genes were deemed to be DEMs and DEGs if  log2FoldChange  > 1 and  log2FoldChange  >1.5, respectively, both with p-value < 0.05 and false discovery rate (FDR) < 0.05.	('miR', 'Gene', '220972', (4, 7))	('log2FoldChange  > 1', 'Var', (57, 76))	('miR', 'Gene', (4, 7))	('log2FoldChange  >1.5', 'Var', (82, 102))
719466	27626688	In our present study, we found that DADA could modulate oxidative phosphorylation as well as increase the intracellular levels of reactive oxygen species (ROS).	('DADA', 'Chemical', 'MESH:C001002', (36, 40))	('DADA', 'Var', (36, 40))	('oxidative phosphorylation', 'MPA', (56, 81))	('increase', 'PosReg', (93, 101))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (130, 153))	('ROS', 'Chemical', 'MESH:D017382', (155, 158))	('increase the intracellular levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (93, 153))	('modulate', 'Reg', (47, 55))	('intracellular levels of reactive oxygen species', 'MPA', (106, 153))
719478	27626688	Preclinical trials on DCA have shown that DCA could enhance the radiosensitivity of several tumor types when combined with RT.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('DCA', 'Var', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('DCA', 'Chemical', 'MESH:D003999', (42, 45))	('enhance', 'PosReg', (52, 59))	('tumor', 'Disease', (92, 97))	('DCA', 'Chemical', 'MESH:D003999', (22, 25))
719485	27626688	Increasing levels of mitochondria-derived reactive oxygen species (ROS) could be the potential mechanism through which DADA enhances the radiotherapy sensitivity of ESCC cell lines.	('DADA', 'Chemical', 'MESH:C001002', (119, 123))	('DADA', 'Var', (119, 123))	('ROS', 'Chemical', 'MESH:D017382', (67, 70))	('mitochondria-derived reactive oxygen species', 'MPA', (21, 65))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (42, 65))	('enhances', 'PosReg', (124, 132))	('radiotherapy sensitivity', 'CPA', (137, 161))	('levels', 'MPA', (11, 17))
719500	27626688	These data indicated that DADA significantly increased cell death in irradiated ESCC cells.	('DADA', 'Chemical', 'MESH:C001002', (26, 30))	('DADA', 'Var', (26, 30))	('cell death', 'CPA', (55, 65))
719530	27626688	In the present study, we have shown that DADA inhibited the growth of esophageal cancer cells in vitro.	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('DADA', 'Chemical', 'MESH:C001002', (41, 45))	('DADA', 'Var', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('inhibited', 'NegReg', (46, 55))	('growth of', 'CPA', (60, 69))
719546	27626688	Therefore, modulating glycolysis in cells to sensitize them to RT could be an effective approach in treating cancer.	('glycolysis', 'MPA', (22, 32))	('treating cancer', 'Disease', (100, 115))	('treating cancer', 'Disease', 'MESH:D009369', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('modulating', 'Var', (11, 21))
719547	27626688	Meng and his colleagues demonstrated that knockdown of PKM2 expression using pshRNA-PKM2 effectively enhanced the radiosensitivity of NSCLC cell lines and xenografts.	('PKM2', 'Gene', '5315', (84, 88))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('radiosensitivity', 'CPA', (114, 130))	('PKM2', 'Gene', (55, 59))	('NSCLC', 'Disease', (134, 139))	('PKM2', 'Gene', '5315', (55, 59))	('enhanced', 'PosReg', (101, 109))	('PKM2', 'Gene', (84, 88))	('knockdown', 'Var', (42, 51))
719625	27326249	The eligibility criteria were as follows: (1) histologically or cytologically confirmed ESCC; (2) clinical stages of T3-4N0M0, T1-4N1M0 or T1-4N0-1M1 (lymph node metastasis) were included; (3) unresectable or inoperable to receive surgical treatment; (3) two-drug chemotherapy, including taxane-based and fluorouracil-based regimens, was delivered in the first-line setting.	('ESCC', 'Disease', (88, 92))	('T1-4N1M0', 'Var', (127, 135))	('fluorouracil', 'Chemical', 'MESH:D005472', (305, 317))	('T1-4N0-1M1', 'Var', (139, 149))	('taxane', 'Chemical', 'MESH:C080625', (288, 294))	('T3-4N0M0', 'Var', (117, 125))
719715	27326249	An explanation for why we observed a higher incidence of perforation or fistula in the fluorouracil group might be that fluorouracil increased the risk of mucositis, leading to a higher probability of perforation.	('mucositis', 'Disease', (155, 164))	('fistula', 'Disease', 'MESH:D005402', (72, 79))	('fistula', 'Disease', (72, 79))	('perforation', 'MPA', (201, 212))	('mucositis', 'Disease', 'MESH:D052016', (155, 164))	('fluorouracil', 'Chemical', 'MESH:D005472', (120, 132))	('fluorouracil', 'Var', (120, 132))	('fluorouracil', 'Chemical', 'MESH:D005472', (87, 99))
719732	26896735	IKKbetaca mice developed esophagitis and had increased numbers of blood vessels in the esophageal stroma, compared with controls.	('esophageal stroma', 'Disease', 'MESH:D004941', (87, 104))	('esophagitis', 'Phenotype', 'HP:0100633', (25, 36))	('increased', 'PosReg', (45, 54))	('esophagitis', 'Disease', (25, 36))	('esophageal stroma', 'Disease', (87, 104))	('mice', 'Species', '10090', (10, 14))	('esophagitis', 'Disease', 'MESH:D004941', (25, 36))	('developed', 'PosReg', (15, 24))	('IKKbetaca', 'Var', (0, 9))
719736	26896735	Injections of anti-GMCSF reduced angiogenesis and numbers of CD31+ blood vessels in esophageal tissues of IKKbetaca mice but did not alter the esophageal vasculature of control mice and did not alter recruitment of intraepithelial leukocytes to esophageal tissues of IKKbetaca mice.	('mice', 'Species', '10090', (277, 281))	('mice', 'Species', '10090', (116, 120))	('anti-GMCSF', 'Var', (14, 24))	('reduced', 'NegReg', (25, 32))	('angiogenesis', 'CPA', (33, 45))	('CD31', 'Gene', '18613', (61, 65))	('CD31', 'Gene', (61, 65))	('mice', 'Species', '10090', (177, 181))
719740	26896735	Defective esophageal epithelial homeostasis has been linked to inflammation and injury and is implicated in the pathogenesis of esophageal diseases, resulting in significant morbidity, mortality, and health care expenditures.	('inflammation and injury', 'Disease', 'MESH:D007249', (63, 86))	('resulting', 'Reg', (149, 158))	('esophageal diseases', 'Disease', (128, 147))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (10, 30))	('linked', 'Reg', (53, 59))	('esophageal epithelial homeostasis', 'Disease', 'MESH:D002277', (10, 43))	('Defective', 'Var', (0, 9))	('esophageal diseases', 'Disease', 'MESH:D004935', (128, 147))	('esophageal epithelial homeostasis', 'Disease', (10, 43))	('implicated', 'Reg', (94, 104))
719744	26896735	Dysregulation of signaling by the NFkappaB transcription factor family is associated with numerous inflammatory diseases and cancers, including reflux esophagitis, and members of the NFkappaB family are pivotal for the maintenance of homeostasis by controlling diverse biological processes, such as inflammation, cell survival, and cell growth.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('esophagitis', 'Phenotype', 'HP:0100633', (151, 162))	('inflammation', 'Disease', (299, 311))	('Dysregulation', 'Var', (0, 13))	('signaling', 'MPA', (17, 26))	('reflux esophagitis', 'Disease', 'MESH:D005764', (144, 162))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('NFkappaB', 'Gene', (34, 42))	('reflux esophagitis', 'Disease', (144, 162))	('numerous inflammatory diseases and cancers', 'Disease', 'MESH:D058922', (90, 132))	('inflammation', 'Disease', 'MESH:D007249', (299, 311))	('associated', 'Reg', (74, 84))
719752	26896735	Mutant mice were hemizygous for Rosa26-Stop-Floxed-Constitutively active IKK2 (Rosa26-IKK2caSFL, Jackson Laboratories, Bar Harbor, ME) and for the Cre transgene.	('Rosa26-IKK2caSFL', 'Gene', '16150;14910', (79, 95))	('Rosa26', 'Gene', '14910', (32, 38))	('IKK2', 'Gene', (73, 77))	('Rosa26', 'Gene', (79, 85))	('IKK2', 'Gene', (86, 90))	('IKK2', 'Gene', '16150', (73, 77))	('IKK2', 'Gene', '16150', (86, 90))	('mice', 'Species', '10090', (7, 11))	('Rosa26', 'Gene', (32, 38))	('Mutant', 'Var', (0, 6))	('Rosa26', 'Gene', '14910', (79, 85))	('Rosa26-IKK2caSFL', 'Gene', (79, 95))
719765	26896735	The following numbers of matched littermate control and mutant mice were injected with neutralizing antibody or control: IgG2a, three pairs; MP1-22E9, three pairs.	('IgG2a', 'Gene', '668478', (121, 126))	('MP1', 'Gene', '56692', (141, 144))	('IgG2a', 'Gene', (121, 126))	('mutant', 'Var', (56, 62))	('mice', 'Species', '10090', (63, 67))	('MP1', 'Gene', (141, 144))
719766	26896735	The following numbers of mutant mice were injected with neutralizing antibody or control: IgG1, four mice; and XT3.11, 4 mice.	('mutant', 'Var', (25, 31))	('XT3', 'Gene', (111, 114))	('IgG1', 'Gene', (90, 94))	('mice', 'Species', '10090', (101, 105))	('mice', 'Species', '10090', (121, 125))	('mice', 'Species', '10090', (32, 36))	('XT3', 'Gene', '22599', (111, 114))	('IgG1', 'Gene', '16017', (90, 94))
719780	26896735	Infiltrating leukocytes were observed in the epithelia and lamina propria of L2/IKKbetaca mice (Figure 2B/D), compared to controls (Figure 2A/C), at 6 weeks (Figure 2A-B) and 3 months (Figure 2C-D) of age.	('L2/IKKbetaca', 'Gene', (77, 89))	('2B/D', 'SUBSTITUTION', 'None', (103, 107))	('2B/D', 'Var', (103, 107))	('mice', 'Species', '10090', (90, 94))	('2A/C', 'SUBSTITUTION', 'None', (139, 143))	('2A/C', 'Var', (139, 143))	('L2/IKKbetaca', 'Gene', '23960', (77, 89))
719797	26896735	In addition, conditioned media from cultured primary human esophageal keratinocytes expressing IKKbetaca revealed increased secretion of GM-CSF, compared to controls (Figure 4C).	('IKKbetaca', 'Var', (95, 104))	('increased', 'PosReg', (114, 123))	('GM-CSF', 'MPA', (137, 143))	('human', 'Species', '9606', (53, 58))	('secretion', 'MPA', (124, 133))
719799	26896735	Treatment of HUVECs with conditioned media from primary human esophageal keratinocytes expressing IKKbetaca increased capillary tube formation (Figure 5C/E), compared to controls (Figure 5A/E).	('increased capillary', 'Phenotype', 'HP:0030005', (108, 127))	('IKKbetaca', 'Gene', (98, 107))	('increased', 'PosReg', (108, 117))	('5C/E', 'SUBSTITUTION', 'None', (151, 155))	('human', 'Species', '9606', (56, 61))	('5A/E', 'SUBSTITUTION', 'None', (187, 191))	('5C/E', 'Var', (151, 155))	('capillary tube formation', 'CPA', (118, 142))	('5A/E', 'Var', (187, 191))
719800	26896735	This increase in tube formation was abolished by treatment with GM-CSF blocking antibody (Figure 5D/E).	('tube formation', 'CPA', (17, 31))	('5D/E', 'SUBSTITUTION', 'None', (97, 101))	('5D/E', 'Var', (97, 101))
719804	26896735	In contrast, compared to L2/IKKbetaca mice treated with IgG2a (Figure 6A/D), L2/IKKbetaca mice with GM-CSF neutralization (Figure 6B/E) had a significant reduction in the number of CD31+ blood vessels (Figure 6C) and VWF positive endothelial cells.	('IgG2a', 'Gene', '668478', (56, 61))	('6A/D', 'Var', (70, 74))	('6A/D', 'SUBSTITUTION', 'None', (70, 74))	('mice', 'Species', '10090', (38, 42))	('L2/IKKbetaca', 'Gene', '23960', (25, 37))	('L2/IKKbetaca', 'Gene', (77, 89))	('6B/E', 'SUBSTITUTION', 'None', (130, 134))	('CD31', 'Gene', '18613', (181, 185))	('IgG2a', 'Gene', (56, 61))	('VWF', 'Gene', '22371', (217, 220))	('VWF', 'Gene', (217, 220))	('CD31', 'Gene', (181, 185))	('L2/IKKbetaca', 'Gene', (25, 37))	('mice', 'Species', '10090', (90, 94))	('reduction', 'NegReg', (154, 163))	('6B/E', 'Var', (130, 134))	('L2/IKKbetaca', 'Gene', '23960', (77, 89))
719811	26896735	Staining for the leukocyte marker CD45 showed decreased immune cell infiltration in the esophageal mucosa of L2/IKKbetaca mice treated with XT3.11 (Figure 7D-E) compared to L2/IKKbetaca mice treated with IgG1 (Figure 7C/E).	('immune cell infiltration', 'CPA', (56, 80))	('IgG1', 'Gene', '16017', (204, 208))	('mice', 'Species', '10090', (122, 126))	('decreased immune cell', 'Phenotype', 'HP:0002721', (46, 67))	('7C/E', 'SUBSTITUTION', 'None', (217, 221))	('L2/IKKbetaca', 'Gene', (109, 121))	('L2/IKKbetaca', 'Gene', (173, 185))	('XT3', 'Gene', '22599', (140, 143))	('L2/IKKbetaca', 'Gene', '23960', (109, 121))	('IgG1', 'Gene', (204, 208))	('7C/E', 'Var', (217, 221))	('XT3', 'Gene', (140, 143))	('decreased', 'NegReg', (46, 55))	('mice', 'Species', '10090', (186, 190))	('L2/IKKbetaca', 'Gene', '23960', (173, 185))
719843	26896735	Of note, GM-CSF improves esophageal mucosal healing and enhances blood vessel formation in patients with severe radiation esophagitis.	('radiation esophagitis', 'Disease', (112, 133))	('patients', 'Species', '9606', (91, 99))	('improves', 'PosReg', (16, 24))	('blood vessel formation', 'CPA', (65, 87))	('radiation esophagitis', 'Disease', 'MESH:D004194', (112, 133))	('esophageal mucosal healing', 'Disease', (25, 51))	('esophageal mucosal healing', 'Disease', 'MESH:D052016', (25, 51))	('esophagitis', 'Phenotype', 'HP:0100633', (122, 133))	('GM-CSF', 'Var', (9, 15))	('enhances', 'PosReg', (56, 64))
719923	19953331	Multiple studies have demonstrated that patients with lymph node metastasis have more aggressive tumor biology, higher rates of locoregional and distant recurrence, and hence, worse survival.	('lymph node metastasis', 'Var', (54, 75))	('aggressive tumor', 'Disease', 'MESH:D001523', (86, 102))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('worse', 'NegReg', (176, 181))	('aggressive tumor', 'Disease', (86, 102))
719963	33725812	Here, we describe 2 cases of renal metastases with chromosome duplications in urine exfoliated cells.	('renal metastases', 'Disease', 'MESH:D009362', (29, 45))	('renal metastases', 'Disease', (29, 45))	('chromosome duplications', 'Var', (51, 74))
720046	33725812	Chromosomal aberrations are a prominent feature of human malignancies.	('Chromosomal aberrations', 'Var', (0, 23))	('malignancies', 'Disease', (57, 69))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('human', 'Species', '9606', (51, 56))	('malignancies', 'Disease', 'MESH:D009369', (57, 69))
720051	33725812	The main chromosomal structural aberrations that occurred were 1q+, 1p+, 6q-, 8q+, 14q+, 18p+, 18q+, and 2p21-p23.	('18p+', 'Var', (89, 93))	('p23', 'Gene', (110, 113))	('1q+', 'Var', (63, 66))	('8q+', 'Var', (78, 81))	('14q+', 'Var', (83, 87))	('p23', 'Gene', '8851', (110, 113))	('18q+', 'Var', (95, 99))	('1p+', 'Var', (68, 71))	('6q-', 'Var', (73, 76))
720055	33725812	The immunohistochemistry results of patient 2 indicated positivity for BCL-2 and BCL-6, which implied that the prognosis was poor.	('BCL-2', 'Gene', (71, 76))	('BCL', 'Phenotype', 'HP:0012191', (71, 74))	('BCL-6', 'Gene', (81, 86))	('positivity', 'Var', (56, 66))	('BCL', 'Phenotype', 'HP:0012191', (81, 84))	('BCL-6', 'Gene', '604', (81, 86))	('BCL-2', 'Gene', '596', (71, 76))	('patient', 'Species', '9606', (36, 43))
720056	33725812	The data from these studies indicate that tumor cells of esophageal squamous cell carcinoma and NHL have possible chromosome 3, 7, and 17 aberrations and/or deletion or amplification of the p16 gene locus on chromosome 9.	('esophageal squamous cell carcinoma', 'Disease', (57, 91))	('tumor', 'Disease', (42, 47))	('amplification', 'Var', (169, 182))	('aberrations', 'Var', (138, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('deletion', 'Var', (157, 165))	('p16', 'Gene', '1029', (190, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (57, 91))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('NHL', 'Phenotype', 'HP:0012539', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('p16', 'Gene', (190, 193))
720068	33725812	The FISH test results of the primary esophageal cancer tissue and the renal metastatic tumor tissue in patient 1 showed aberrations in chromosome 3, 7, and 17, which were consistent with the urine FISH results.	('renal metastatic tumor', 'Disease', (70, 92))	('renal metastatic tumor', 'Disease', 'MESH:C538445', (70, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('esophageal cancer', 'Disease', (37, 54))	('patient', 'Species', '9606', (103, 110))	('aberrations', 'Var', (120, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
720076	33718190	The high expression of PEDF is an independent unfavorable prognostic factor for ESCC patients' overall survival (OS).	('PEDF', 'Gene', '5176', (23, 27))	('patients', 'Species', '9606', (85, 93))	('high', 'Var', (4, 8))	('overall', 'MPA', (95, 102))	('PEDF', 'Gene', (23, 27))	('ESCC', 'Disease', (80, 84))
720078	33718190	Overexpression of PEDF significantly promoted the migration and invasion of ESCC cells in vitro, while silencing PEDF yielded the opposite effects.	('silencing', 'Var', (103, 112))	('PEDF', 'Gene', '5176', (113, 117))	('promoted', 'PosReg', (37, 45))	('invasion', 'CPA', (64, 72))	('PEDF', 'Gene', (18, 22))	('migration', 'CPA', (50, 59))	('PEDF', 'Gene', '5176', (18, 22))	('PEDF', 'Gene', (113, 117))
720105	33718190	Moreover, we demonstrated for the first time the relationship between the abnormal expression of PEDF and the progression of ESCC and reported that PEDF augments ESCC cell migration, invasion, and EMT.	('PEDF', 'Gene', (148, 152))	('augments', 'PosReg', (153, 161))	('PEDF', 'Gene', (97, 101))	('EMT', 'CPA', (197, 200))	('invasion', 'CPA', (183, 191))	('PEDF', 'Gene', '5176', (148, 152))	('ESCC', 'Disease', (162, 166))	('abnormal', 'Var', (74, 82))	('PEDF', 'Gene', '5176', (97, 101))	('ESCC', 'Disease', (125, 129))
720109	33718190	All ESCC cells including KYSE140 and KYSE510, were cultured using RPIM 1640 medium (Gibco, Beijing, China) supplemented with 10% fetal bovine serum (FBS) (Gibco, Montevideo, Uruguay), 100 U ml-1 penicillin, and 100 mg ml-1 streptomycin.	('ml-1', 'Gene', (190, 194))	('KYSE510', 'Var', (37, 44))	('ml-1', 'Gene', '112744', (190, 194))	('ml-1', 'Gene', (218, 222))	('ml-1', 'Gene', '112744', (218, 222))	('RPIM 1640 medium', 'Chemical', '-', (66, 82))	('penicillin', 'Chemical', 'MESH:D010406', (195, 205))	('streptomycin', 'Chemical', 'MESH:D013307', (223, 235))
720111	33718190	For transient knockdown or overexpression of PEDF, ESCC cells were plated at 6 x 105 cells in 6-well plates (Corning, Michigan, USA) with 2 ml medium.	('PEDF', 'Gene', '5176', (45, 49))	('overexpression', 'PosReg', (27, 41))	('PEDF', 'Gene', (45, 49))	('knockdown', 'Var', (14, 23))
720122	33718190	The primarily used antibodies included anti-E-cadherin (610181), anti-alpha-catenin(610193) and anti-N-cadherin (610921) from BD Pharmingen (San Diego, CA, USA); anti-p-ERK1/2(#9102), anti-ERK1/2(#4370), anti-ATK(#4691S), anti-pAKT(#4060S) and anti-GAPDH(2118S) from Cell Signaling Technology (Danvers, MA, USA); anti-PEDF(MAB1059) from Millipore (Millipore, MA, USA).	('N-cadherin', 'Gene', '1000', (101, 111))	('ERK1/2', 'Gene', (189, 195))	('PEDF', 'Gene', '5176', (318, 322))	('AKT', 'Gene', '207', (228, 231))	('610193', 'Var', (84, 90))	('610181', 'Var', (56, 62))	('ERK1/2', 'Gene', '5595;5594', (189, 195))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('ERK1/2', 'Gene', (169, 175))	('ERK1/2', 'Gene', '5595;5594', (169, 175))	('AKT', 'Gene', (228, 231))	('GAPDH', 'Gene', '2597', (249, 254))	('PEDF', 'Gene', (318, 322))	('GAPDH', 'Gene', (249, 254))	('610921', 'Var', (113, 119))	('#4691S', 'Var', (213, 219))	('N-cadherin', 'Gene', (101, 111))
720132	33718190	Endogenous peroxidase activity and non-specific binding of antibodies were blocked by 3% H2O2 and 1% goat serum albumin, respectively.	('activity', 'MPA', (22, 30))	('blocked', 'NegReg', (75, 82))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('serum albumin', 'Gene', '213', (106, 119))	('serum albumin', 'Gene', (106, 119))	('H2O2', 'Chemical', 'MESH:D006861', (89, 93))	('H2O2', 'Var', (89, 93))	('non-specific binding', 'Interaction', (35, 55))
720145	33718190	These observations suggest that high PEDF expression may play a key role in ESCC metastasis and may be a novel prognostic factor for ESCC patients.	('high', 'Var', (32, 36))	('PEDF', 'Gene', '5176', (37, 41))	('ESCC', 'Disease', (133, 137))	('expression', 'MPA', (42, 52))	('PEDF', 'Gene', (37, 41))	('ESCC', 'Disease', (76, 80))	('patients', 'Species', '9606', (138, 146))
720151	33718190	Kaplan-Meier survival curves showed that female patients (p = 0.0034), patients with low expression of PEDF (cut-off score <6) (p < 0.001), patients with N0-1 stage disease (p < 0.001) and patients with TNM stage I/II disease (p < 0.001) had significantly longer survival times than male patients, patients with overexpression of PEDF, patients with N2-3 stage disease and patients with TNM stage III/IV disease, respectively ( Figure 2D ).	('PEDF', 'Gene', (103, 107))	('patients', 'Species', '9606', (71, 79))	('survival times', 'CPA', (263, 277))	('PEDF', 'Gene', '5176', (103, 107))	('patients', 'Species', '9606', (189, 197))	('PEDF', 'Gene', (330, 334))	('patients', 'Species', '9606', (298, 306))	('stage disease', 'Disease', 'MESH:D058625', (159, 172))	('PEDF', 'Gene', '5176', (330, 334))	('patients', 'Species', '9606', (140, 148))	('N0-1', 'Var', (154, 158))	('longer', 'PosReg', (256, 262))	('stage disease', 'Disease', (159, 172))	('patients', 'Species', '9606', (288, 296))	('stage disease', 'Disease', 'MESH:D058625', (355, 368))	('patients', 'Species', '9606', (336, 344))	('stage disease', 'Disease', (355, 368))	('patients', 'Species', '9606', (373, 381))	('patients', 'Species', '9606', (48, 56))
720152	33718190	Cox proportional hazard regression analyses revealed that high PEDF expression was an independent predictor of unfavorable prognosis in ESCC patients (hazard ratio [HR] = 3.173, p < 0.001) ( Table 2 ).	('PEDF', 'Gene', (63, 67))	('ESCC', 'Disease', (136, 140))	('PEDF', 'Gene', '5176', (63, 67))	('high', 'Var', (58, 62))	('patients', 'Species', '9606', (141, 149))
720162	33718190	In contrast, the migration and invasion capabilities of KYSE140-siPEDF and KYSE510-siPEDF knockdown cells were decreased compared with those of the negative control siRNA (si-NC)-transfected cells ( Figures 4A, B ).	('KYSE140-siPEDF and KYSE510-siPEDF', 'Disease', 'None', (56, 89))	('decreased', 'NegReg', (111, 120))	('knockdown', 'Var', (90, 99))
720165	33718190	Thus, we measured the expression of EMT-related markers by Western blotting, and the results demonstrated that PEDF-overexpressing KYSE140 and KYSE510 cells exhibited a striking decrease in the expression of epithelial markers (E-cadherin and alpha-catenin) and an increase in the mesenchymal marker (N-cadherin) in comparison with that in the corresponding control cells.	('N-cadherin', 'Gene', '1000', (301, 311))	('E-cadherin', 'Gene', (228, 238))	('E-cadherin', 'Gene', '999', (228, 238))	('KYSE510', 'Var', (143, 150))	('alpha-catenin', 'Protein', (243, 256))	('decrease', 'NegReg', (178, 186))	('PEDF', 'Gene', (111, 115))	('epithelial', 'CPA', (208, 218))	('expression', 'MPA', (194, 204))	('increase', 'PosReg', (265, 273))	('KYSE140', 'Var', (131, 138))	('PEDF', 'Gene', '5176', (111, 115))	('mesenchymal', 'CPA', (281, 292))	('N-cadherin', 'Gene', (301, 311))
720166	33718190	Consistent with the results in PEDF-overexpressing cells, we observed that silencing PEDF with siRNA increased E-cadherin and alpha-catenin expression but decreased N-cadherin expression in both KYSE140-siPEDF and KYSE510-siPEDF cells compared with si-NC cells ( Figure 4C ).	('increased', 'PosReg', (101, 110))	('PEDF', 'Gene', (205, 209))	('siRNA', 'Gene', (95, 100))	('N-cadherin', 'Gene', (165, 175))	('expression', 'MPA', (176, 186))	('N-cadherin', 'Gene', '1000', (165, 175))	('PEDF', 'Gene', '5176', (205, 209))	('PEDF', 'Gene', (31, 35))	('PEDF', 'Gene', '5176', (31, 35))	('KYSE140-siPEDF and KYSE510-siPEDF', 'Disease', 'None', (195, 228))	('PEDF', 'Gene', (85, 89))	('PEDF', 'Gene', '5176', (85, 89))	('silencing', 'Var', (75, 84))	('E-cadherin', 'Gene', (111, 121))	('E-cadherin', 'Gene', '999', (111, 121))	('PEDF', 'Gene', (224, 228))	('expression', 'MPA', (140, 150))	('decreased', 'NegReg', (155, 164))	('PEDF', 'Gene', '5176', (224, 228))	('alpha-catenin', 'Protein', (126, 139))
720172	33718190	To validate our experimental results, we used the ERK inhibitors PD98059 and U0126 to block ERK1/2 phosphorylation in PEDF-overexpressing cells.	('PEDF', 'Gene', '5176', (118, 122))	('U0126', 'Var', (77, 82))	('phosphorylation', 'MPA', (99, 114))	('block', 'NegReg', (86, 91))	('ERK', 'Gene', '5594', (50, 53))	('ERK', 'Gene', '5594', (92, 95))	('PD98059', 'Var', (65, 72))	('ERK', 'Gene', (50, 53))	('PEDF', 'Gene', (118, 122))	('ERK', 'Gene', (92, 95))	('ERK1/2', 'Gene', (92, 98))	('PD98059', 'Chemical', 'MESH:C093973', (65, 72))	('U0126', 'Chemical', 'MESH:C113580', (77, 82))	('ERK1/2', 'Gene', '5595;5594', (92, 98))
720173	33718190	The results showed that ERK1/2 inhibition by PD98059 and U0126 impaired the PEDF-induced migration, invasion, and EMT of KYSE140 and KYSE510 cells ( Figures 5B, C ).	('inhibition', 'NegReg', (31, 41))	('U0126', 'Var', (57, 62))	('PD98059', 'Var', (45, 52))	('PEDF', 'Gene', (76, 80))	('PEDF', 'Gene', '5176', (76, 80))	('invasion', 'CPA', (100, 108))	('PD98059', 'Chemical', 'MESH:C093973', (45, 52))	('U0126', 'Chemical', 'MESH:C113580', (57, 62))	('EMT of KYSE140', 'CPA', (114, 128))	('ERK1/2', 'Gene', '5595;5594', (24, 30))	('impaired', 'NegReg', (63, 71))	('ERK1/2', 'Gene', (24, 30))
720218	33718190	Moreover, PD98059 and U0126, inhibitors of ERK1/2 phosphorylation, blocked the overexpression of PEDF, thus regulating EMT.	('blocked', 'NegReg', (67, 74))	('PD98059', 'Chemical', 'MESH:C093973', (10, 17))	('U0126', 'Var', (22, 27))	('PEDF', 'Gene', (97, 101))	('PD98059', 'Var', (10, 17))	('ERK1/2', 'Gene', (43, 49))	('U0126', 'Chemical', 'MESH:C113580', (22, 27))	('ERK1/2', 'Gene', '5595;5594', (43, 49))	('EMT', 'CPA', (119, 122))	('regulating', 'Reg', (108, 118))	('overexpression', 'MPA', (79, 93))	('PEDF', 'Gene', '5176', (97, 101))
720223	33718190	P53 mutation is the most dominant feature of ESCC.	('P53', 'Gene', '7157', (0, 3))	('P53', 'Gene', (0, 3))	('ESCC', 'Disease', (45, 49))	('mutation', 'Var', (4, 12))
720249	32047546	Studies have found that polymorphisms in aldehyde dehydrogenase 2 (ALDH2) gene also lead to the development of ESCC especially in Asian populations.	('lead to', 'Reg', (84, 91))	('ALDH2', 'Gene', (67, 72))	('ESCC', 'Disease', 'MESH:C562729', (111, 115))	('aldehyde dehydrogenase 2', 'Gene', '217', (41, 65))	('polymorphisms', 'Var', (24, 37))	('aldehyde dehydrogenase 2', 'Gene', (41, 65))	('ALDH2', 'Gene', '217', (67, 72))	('ESCC', 'Disease', (111, 115))
720251	32047546	In addition, epigenetic alterations including DNA methylation of such as APC, RB1 and CDKN2A, histone modification, and loss of genome imprinting also contribute to ESCC.	('RB1', 'Gene', '5925', (78, 81))	('ESCC', 'Disease', 'MESH:C562729', (165, 169))	('CDKN2A', 'Gene', '1029', (86, 92))	('histone', 'MPA', (94, 101))	('DNA methylation', 'Var', (46, 61))	('ESCC', 'Disease', (165, 169))	('APC', 'Disease', 'MESH:D011125', (73, 76))	('contribute', 'Reg', (151, 161))	('RB1', 'Gene', (78, 81))	('CDKN2A', 'Gene', (86, 92))	('APC', 'Disease', (73, 76))	('loss', 'Var', (120, 124))
720258	32047546	In order to validate our findings, microarray dataset of GSE53625 from Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) in NCBI (The National Center for Biotechnology Information) containing 179 esophageal squamous cell carcinoma patients with prognosis information were used to confirm our results.	('esophageal squamous cell carcinoma', 'Disease', (211, 245))	('GSE53625', 'Var', (57, 65))	('patients', 'Species', '9606', (246, 254))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (211, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))
720285	32047546	As for key pathways of KEGG enrichment, aberrant base excision repair capacity and altered p53 signaling pathways have been found to be associated with ESCC development by a number of studies.	('associated', 'Reg', (136, 146))	('altered', 'Reg', (83, 90))	('ESCC', 'Disease', 'MESH:C562729', (152, 156))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('base excision repair capacity', 'MPA', (49, 78))	('ESCC', 'Disease', (152, 156))	('aberrant', 'Var', (40, 48))
720289	32047546	Aberrant TCP1 gene status has been detected in hepatocellular carcinoma, breast cancer and colorectal cancer, but no study has been performed for its effect in ESCC.	('ESCC', 'Disease', (160, 164))	('detected', 'Reg', (35, 43))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('ESCC', 'Disease', 'MESH:C562729', (160, 164))	('TCP1', 'Gene', (9, 13))	('breast cancer', 'Disease', (73, 86))	('TCP1', 'Gene', '6950', (9, 13))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (47, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('hepatocellular carcinoma', 'Disease', (47, 71))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (47, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
720296	32047546	According to our findings, aberrant metabolism of carbohydrate, fat and protein might be closely related to the progression of ESCC.	('related', 'Reg', (97, 104))	('aberrant', 'Var', (27, 35))	('ESCC', 'Disease', (127, 131))	('metabolism', 'MPA', (36, 46))	('carbohydrate', 'Chemical', 'MESH:D002241', (50, 62))	('ESCC', 'Disease', 'MESH:C562729', (127, 131))
720297	32047546	In addition, alternations in functions of ribosome, RNA transport might also be promising research directions for ESCC.	('ESCC', 'Disease', (114, 118))	('ribosome', 'Protein', (42, 50))	('functions', 'MPA', (29, 38))	('ESCC', 'Disease', 'MESH:C562729', (114, 118))	('alternations', 'Var', (13, 25))	('RNA transport', 'MPA', (52, 65))
720308	31921980	ESD procedures were performed using video endoscopy (GIF-Q260 J or GIF-H260Z; Olympus Co, Tokyo, Japan).	('H260Z', 'Var', (71, 76))	('H260Z', 'SUBSTITUTION', 'None', (71, 76))	('GIF-Q260 J', 'Var', (53, 63))
720327	31316750	Knockout of TP53 in mice leads to the development of different tumors, including lymphomas, sarcomas adenocarcinoma and benign tumors such as hemangioma, before they reach 6 month of age .	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('hemangioma', 'Disease', (142, 152))	('leads to', 'Reg', (25, 33))	('sarcomas adenocarcinoma', 'Disease', (92, 115))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('lymphomas', 'Disease', (81, 90))	('sarcomas adenocarcinoma', 'Disease', 'MESH:D012509', (92, 115))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('mice', 'Species', '10090', (20, 24))	('benign tumors', 'Disease', 'MESH:D009369', (120, 133))	('tumors', 'Disease', (63, 69))	('TP53', 'Gene', (12, 16))	('hemangioma', 'Phenotype', 'HP:0001028', (142, 152))	('hemangioma', 'Disease', 'MESH:D006391', (142, 152))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('Knockout', 'Var', (0, 8))	('lymphomas', 'Disease', 'MESH:D008223', (81, 90))	('benign tumors', 'Disease', (120, 133))	('lymphomas', 'Phenotype', 'HP:0002665', (81, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
720337	31316750	Mutation analysis results demonstrate a higher TP53 mutation rate in esophageal adenocarcinoma compared to squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('higher', 'PosReg', (40, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('mutation', 'Var', (52, 60))	('esophageal adenocarcinoma', 'Disease', (69, 94))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (69, 94))	('TP53', 'Gene', (47, 51))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (69, 94))
720339	31316750	The percentage of deleterious nsSNPs predicted by SIFT and PolyPhen was 66.7% ( Figure 2), those SNPs were A161D, K164E, R175P and S215N according to SIFT and PolyPhen ( Table 3- Table 4).	('S215N', 'Var', (131, 136))	('A161D', 'Mutation', 'rs1064795691', (107, 112))	('K164E', 'Var', (114, 119))	('A161D', 'Var', (107, 112))	('R175P', 'Var', (121, 126))	('R175P', 'Mutation', 'p.R175P', (121, 126))	('S215N', 'Mutation', 'rs587782177', (131, 136))	('K164E', 'Mutation', 'rs879254249', (114, 119))
720340	31316750	I-Mutant suite also give the same percentage for deleterious nsSNPs which is 66.7% ( Table 5) but in case of using I-Mutant suite the predicted SNPs to be deleterious were, A161D, R175P, S215N and M160V ( Table 6).	('R175P', 'SUBSTITUTION', 'None', (180, 185))	('M160V', 'Mutation', 'rs377274728', (197, 202))	('S215N', 'Var', (187, 192))	('S215N', 'SUBSTITUTION', 'None', (187, 192))	('R175P', 'Var', (180, 185))	('M160V', 'Var', (197, 202))	('A161D', 'SUBSTITUTION', 'None', (173, 178))	('A161D', 'Var', (173, 178))
720342	31316750	All other SNPs M160V, A161D, A161A, Y163Y, K164E, R175P, S215N, P222P, and K305K representing 90% of all SNPs were predicted to be disease related according to MutationTaster software ( Table 8).	('A161D', 'Var', (22, 27))	('P222P', 'Var', (64, 69))	('R175P', 'Var', (50, 55))	('Y163Y', 'Mutation', 'p.Y163Y', (36, 41))	('P222P', 'Mutation', 'rs72661118', (64, 69))	('M160V', 'SUBSTITUTION', 'None', (15, 20))	('K305K', 'Var', (75, 80))	('A161A', 'Var', (29, 34))	('K164E', 'SUBSTITUTION', 'None', (43, 48))	('R175P', 'SUBSTITUTION', 'None', (50, 55))	('Y163Y', 'Var', (36, 41))	('M160V', 'Var', (15, 20))	('K305K', 'Mutation', 'p.K305K', (75, 80))	('K164E', 'Var', (43, 48))	('S215N', 'Var', (57, 62))	('S215N', 'SUBSTITUTION', 'None', (57, 62))	('A161D', 'SUBSTITUTION', 'None', (22, 27))
720343	31316750	TP53 mutations were found in 22.9% of esophageal SCCs and 14.3% of esophageal ACs in a study done by Zheng et al.	('TP53', 'Gene', (0, 4))	('esophageal SCCs', 'Disease', 'MESH:D004941', (38, 53))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('mutations', 'Var', (5, 14))	('found', 'Reg', (20, 25))	('esophageal ACs', 'Disease', (67, 81))	('esophageal SCCs', 'Disease', (38, 53))
720344	31316750	Genomic results have identified a high TP53 mutation rate in esophageal Adenocarcinoma compared to squamous cell carcinoma.	('mutation', 'Var', (44, 52))	('TP53', 'Gene', (39, 43))	('esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (61, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (61, 86))	('esophageal Adenocarcinoma', 'Disease', (61, 86))
720346	31316750	The authors evaluated single nucleotide polymorphisms (SNPs) in TP53 gene exon 5-8, and found that 37.2% of esophageal squamous cell carcinoma (SCC) samples harbored mutation, whereas 57.1% of esophageal adenocarcinoma (AC) samples harbored mutation.	('harbored', 'Reg', (157, 165))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (193, 218))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (108, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('single nucleotide polymorphisms', 'Var', (22, 53))	('TP53', 'Gene', (64, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('esophageal squamous cell carcinoma', 'Disease', (108, 142))
720350	31316750	The authors should also describe in Table 2 the mutations identified using the international nomenclature to show exactly the position in which the substitution occurred and the type of mutation (example: c.595 G> T, GGA / TGA.)	('c.595 G> T', 'Mutation', 'c.595G>T', (205, 215))	('TGA', 'Gene', '6899', (223, 226))	('c.595 G> T', 'Var', (205, 215))	('TGA', 'Gene', (223, 226))
720364	30774483	Such a shunt is, in the true sense, a prototype that can lead to PS syndrome.	('shunt', 'Var', (7, 12))	('PS syndrome', 'Disease', (65, 76))	('lead to', 'Reg', (57, 64))	('PS syndrome', 'Disease', 'MESH:C562429', (65, 76))
720390	30774483	The presence of PS had a significantly higher risk of ascites and variceal bleeding with lower transplant-free survival.	('ascites', 'Disease', 'MESH:D001201', (54, 61))	('ascites', 'Disease', (54, 61))	('lower', 'NegReg', (89, 94))	('ascites', 'Phenotype', 'HP:0001541', (54, 61))	('variceal bleeding', 'Disease', (66, 83))	('transplant-free survival', 'CPA', (95, 119))	('presence', 'Var', (4, 12))
720674	29991874	Microsatellite instability (MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatment-refractory solid tumors with MSI status and the third-line or greater treatment of PD-L1 positive advanced gastric/GEJ cancers.	('PD-L1', 'Gene', '29126', (268, 273))	('PD-L1', 'Gene', (37, 42))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('gastric/GEJ cancers', 'Disease', 'MESH:D013274', (292, 311))	('cancers', 'Phenotype', 'HP:0002664', (304, 311))	('solid tumors', 'Disease', (196, 208))	('response', 'MPA', (88, 96))	('higher', 'PosReg', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('PD-L1', 'Gene', '29126', (37, 42))	('Microsatellite instability', 'Disease', (0, 26))	('gastric/GEJ cancers', 'Disease', (292, 311))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('PD-L1', 'Gene', (268, 273))	('solid tumors', 'Disease', 'MESH:D009369', (196, 208))	('pembrolizumab', 'Chemical', 'MESH:C582435', (158, 171))	('MSI status', 'Var', (214, 224))
720681	29991874	Deficiency of PD-1 leads to impaired tolerance, as demonstrated by the development of pathologies resembling lupus and graft-versus-host disease in mice with PD-1 gene disruption, and in transgenic mice with the PD-1 null mutation, respectively.	('graft-versus-host disease', 'Disease', 'MESH:D006086', (119, 144))	('transgenic mice', 'Species', '10090', (187, 202))	('gene disruption', 'Var', (163, 178))	('tolerance', 'MPA', (37, 46))	('PD-1', 'Gene', (158, 162))	('mice', 'Species', '10090', (148, 152))	('graft-versus-host disease', 'Disease', (119, 144))	('mice', 'Species', '10090', (198, 202))	('Deficiency of PD-1', 'Disease', (0, 18))	('lupus', 'Disease', (109, 114))	('Deficiency of PD-1', 'Disease', 'MESH:D010300', (0, 18))	('impaired', 'NegReg', (28, 36))
720698	29991874	Of particular interest were findings suggestive that a relevant proportion of gastric cancer cases may be inherently receptive to immune checkpoint blockade, given that EBV-positive subtypes representing 9% of cases were characterized by genomic amplification of chromosomal region 9p24.1, the locus of genes encoding PD-L1 and PD-L2, and 21.7% of cases demonstrated MSI.	('PD-L1', 'Gene', (318, 323))	('EBV', 'Species', '10376', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('PD-L2', 'Gene', (328, 333))	('gastric cancer', 'Disease', (78, 92))	('PD-L1', 'Gene', '29126', (318, 323))	('PD-L2', 'Gene', '80380', (328, 333))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('genomic amplification', 'Var', (238, 259))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
720706	29991874	In another study, presence of TILs and PD-L2 in esophageal cancers were inversely correlated, in contrast to PD-L1 expression, which had no significant correlation with TILs.	('presence', 'Var', (18, 26))	('TIL', 'Gene', (30, 33))	('esophageal cancers', 'Disease', (48, 66))	('PD-L2', 'Gene', (39, 44))	('PD-L2', 'Gene', '80380', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('TIL', 'Gene', '7096', (169, 172))	('PD-L1', 'Gene', (109, 114))	('esophageal cancers', 'Disease', 'MESH:D004938', (48, 66))	('PD-L1', 'Gene', '29126', (109, 114))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('TIL', 'Gene', '7096', (30, 33))	('TIL', 'Gene', (169, 172))
720707	29991874	PD-L1 positivity, however, was associated with significantly poorer prognosis - especially in more advanced stages - and found to be an independent prognostic factor upon multivariate analysis.	('positivity', 'Var', (6, 16))	('PD-L1', 'Gene', (0, 5))	('prognosis', 'CPA', (68, 77))	('PD-L1', 'Gene', '29126', (0, 5))	('poorer', 'NegReg', (61, 67))
720714	29991874	Interestingly, findings of tumor-infiltrating PD-L1+ inflammatory cells occurred only in cancers with EBV positivity or MSI, and among gastric cancers in another study, these were noted to have upregulated immune escape pathway genes.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', (89, 96))	('EBV', 'Species', '10376', (102, 105))	('MSI', 'Gene', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('PD-L1', 'Gene', (46, 51))	('immune escape pathway', 'Pathway', (206, 227))	('tumor', 'Disease', (27, 32))	('PD-L1', 'Gene', '29126', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('upregulated', 'PosReg', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('gastric cancers', 'Disease', (135, 150))	('gastric cancers', 'Phenotype', 'HP:0012126', (135, 150))	('gastric cancers', 'Disease', 'MESH:D013274', (135, 150))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('EBV', 'Gene', (102, 105))	('positivity', 'Var', (106, 116))	('cancers', 'Disease', 'MESH:D009369', (143, 150))
720715	29991874	Mismatch repair (MMR) deficiency has also been associated with PD-L1 expression in other series.	('MMR', 'Gene', (17, 20))	('expression', 'MPA', (69, 79))	('PD-L1', 'Gene', (63, 68))	('PD-L1', 'Gene', '29126', (63, 68))	('associated', 'Reg', (47, 57))	('deficiency', 'Var', (22, 32))
720726	29991874	PD-L1+ gastric cancers tended to have stromal immune cells expressing PD-1 and PD-L1, and those with PD-L1+ immune cells had increased depth of invasion, although PD-L1+ tumor cells had greater prognostic impact than did PD-L1+ immune cells.	('increased', 'PosReg', (125, 134))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Disease', (170, 175))	('PD-L1', 'Gene', (79, 84))	('PD-L1', 'Gene', '29126', (0, 5))	('PD-L1', 'Gene', '29126', (79, 84))	('PD-L1', 'Gene', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('PD-L1', 'Gene', '29126', (221, 226))	('PD-L1', 'Gene', (101, 106))	('stromal immune cells', 'CPA', (38, 58))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PD-L1', 'Gene', '29126', (101, 106))	('gastric cancers', 'Disease', 'MESH:D013274', (7, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('depth of invasion', 'CPA', (135, 152))	('gastric cancers', 'Disease', (7, 22))	('gastric cancers', 'Phenotype', 'HP:0012126', (7, 22))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('PD-L1', 'Gene', (163, 168))	('gastric cancer', 'Phenotype', 'HP:0012126', (7, 21))	('PD-L1', 'Gene', '29126', (163, 168))	('PD-1', 'Var', (70, 74))
720727	29991874	Although both PD-L1 expression and increased CD3+ TIL density in the TME of gastric cancers were significantly associated with improved 5-year disease-free survival (DFS) and OS, there was no significant correlation between PD-L1 expression and CD3+ TIL density, leading to the hypothesis that tumor production of immunosuppressive proteins may be a mechanism intrinsic to the tumor.	('gastric cancers', 'Phenotype', 'HP:0012126', (76, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('expression', 'Var', (20, 30))	('TIL', 'Gene', '7096', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('improved', 'PosReg', (127, 135))	('PD-L1', 'Gene', (224, 229))	('PD-L1', 'Gene', '29126', (224, 229))	('TIL', 'Gene', (250, 253))	('tumor', 'Disease', (377, 382))	('CD3', 'Gene', '397455', (245, 248))	('PD-L1', 'Gene', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (377, 382))	('CD3', 'Gene', '397455', (45, 48))	('PD-L1', 'Gene', '29126', (14, 19))	('increased', 'PosReg', (35, 44))	('disease-free', 'Disease', (143, 155))	('TIL', 'Gene', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('CD3', 'Gene', (245, 248))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('tumor', 'Disease', (294, 299))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('CD3', 'Gene', (45, 48))	('gastric cancers', 'Disease', 'MESH:D013274', (76, 91))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('gastric cancers', 'Disease', (76, 91))	('TIL', 'Gene', '7096', (250, 253))
720734	29991874	Response was significantly associated with the presence of PD-L1 positivity in tumor-infiltrating immune cells (P = 0.007), but not tumor cells (P = 0.079), with better response among patients with greater IHC scores.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (79, 84))	('patients', 'Species', '9606', (184, 192))	('positivity', 'Var', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('PD-L1', 'Gene', (59, 64))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('PD-L1', 'Gene', '29126', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
720738	29991874	Patients receiving avelumab exhibited increased ORR if harboring PD-L1 positivity of at least 1% tumor cell staining by an IHC assay (Dako, clone 73-10).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', (65, 70))	('positivity', 'Var', (71, 81))	('PD-L1', 'Gene', '29126', (65, 70))
720753	29991874	Grade 3-4 TRAEs including diarrhea and elevated transaminases were reported more often in the N1+I3 group, which also achieved greater ORR regardless of PD-L1 status.	('PD-L1', 'Gene', (153, 158))	('diarrhea', 'Phenotype', 'HP:0002014', (26, 34))	('diarrhea', 'Disease', 'MESH:D003967', (26, 34))	('diarrhea', 'Disease', (26, 34))	('N1+I3', 'Var', (94, 99))	('PD-L1', 'Gene', '29126', (153, 158))	('elevated transaminases', 'Phenotype', 'HP:0002910', (39, 61))	('elevated transaminases', 'MPA', (39, 61))
720757	29991874	PD-L1 >= 1% tumors appeared to demonstrate more favorable rates of 12-month OS in the N1+I3 (50%) vs nivolumab alone (34%) and N3+I1 (23%) groups.	('nivolumab', 'Chemical', 'MESH:D000077594', (101, 110))	('N1+I3', 'Var', (86, 91))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('PD-L1', 'Gene', '29126', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
720781	29991874	Tumor testing was able to be retrospectively conducted on 192 patient samples, with 26 patients (14%) harboring tumors with PD-L1 positivity in >= 1% of tumor cells.	('PD-L1', 'Gene', (124, 129))	('positivity', 'Var', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('PD-L1', 'Gene', '29126', (124, 129))	('patient', 'Species', '9606', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('patient', 'Species', '9606', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (87, 95))	('tumors', 'Disease', (112, 118))
720804	29991874	Among non-MSI-H tumors, the ORR was 11% with nivolumab alone, 19% with N1+I3, and 5% with N3+I1.	('MSI-H tumors', 'Disease', (10, 22))	('MSI-H tumors', 'Disease', 'MESH:D009369', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('nivolumab', 'Chemical', 'MESH:D000077594', (45, 54))	('N1+I3', 'Var', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
720811	29991874	In-situ hybridization demonstrated a correlation between EBV positivity and PD-L1 expression as well as higher TIL infiltration.	('EBV', 'Gene', (57, 60))	('PD-L1', 'Gene', (76, 81))	('expression', 'MPA', (82, 92))	('PD-L1', 'Gene', '29126', (76, 81))	('TIL', 'Gene', '7096', (111, 114))	('EBV', 'Species', '10376', (57, 60))	('positivity', 'Var', (61, 71))	('TIL', 'Gene', (111, 114))
720813	29991874	MSI-H tumors with defective dMMR certainly exemplify high TMB with analyses by Llosa et al reporting on average 1782 mutations per tumor by whole-exome sequencing in cases of MMR deficiency, compared to 73 in cases with MMR proficiency (P = 0.007).	('TMB', 'Chemical', '-', (58, 61))	('mutations', 'Var', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('MMR deficiency', 'Disease', (175, 189))	('MMR deficiency', 'Disease', 'MESH:C536143', (175, 189))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', (131, 136))	('MSI-H tumors', 'Disease', 'MESH:D009369', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('MSI-H tumors', 'Disease', (0, 12))
720820	29991874	A follow-up report of gastroesophageal cancers sequenced by the IMPACT panel appeared to suggest that a cutoff of > 9.7 mutations/Mb, representing the top quartile of 40 patients treated with immune checkpoint inhibitors, correlated to greater benefit (median OS 16.8 mo vs 6.62 mo, P = 0.058).	('patients', 'Species', '9606', (170, 178))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('benefit', 'PosReg', (244, 251))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (22, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('gastroesophageal cancers', 'Disease', (22, 46))	('mutations/Mb', 'Var', (120, 132))
720823	29991874	A recent phase I trial in on the anti-PD-1 antibody SHR-1210 in ESCC supported somatic nonsynonymous mutational load (by WES) as a biomarker of predictive benefit with higher TMB associated with benefit (P = 0.048).	('TMB', 'Chemical', '-', (175, 178))	('SCC', 'Gene', (65, 68))	('nonsynonymous mutational load', 'Var', (87, 116))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('higher', 'PosReg', (168, 174))	('TMB', 'MPA', (175, 178))
720864	28965871	On the other hand, haploinsufficiency of FOXO1 protects against insulin resistance caused by defective insulin signaling.	('haploinsufficiency', 'Disease', (19, 37))	('insulin', 'Gene', (64, 71))	('defective', 'Var', (93, 102))	('insulin resistance', 'Phenotype', 'HP:0000855', (64, 82))	('FOXO1', 'Gene', (41, 46))	('insulin', 'Gene', '3630', (64, 71))	('haploinsufficiency', 'Disease', 'MESH:D058495', (19, 37))	('insulin', 'Gene', (103, 110))	('insulin', 'Gene', '3630', (103, 110))
720865	28965871	In addition, loss or reactivation of FOXO1 in humans, as a result of chromosomal deletion (13q14), may promote androgen- and androgen receptor-independent prostate tumorigenesis.	('tumor', 'Disease', (164, 169))	('FOXO1', 'Gene', (37, 42))	('humans', 'Species', '9606', (46, 52))	('androgen-', 'Disease', (111, 120))	('reactivation', 'Var', (21, 33))	('loss', 'NegReg', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('promote', 'PosReg', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
720882	28965871	Mutation of FOXO1 where three Akt sites were replaced by alanines in the NLS displays a reduction in ubiquitination.	('Akt', 'Gene', '207', (30, 33))	('FOXO1', 'Gene', (12, 17))	('alanines', 'Var', (57, 65))	('reduction', 'NegReg', (88, 97))	('Mutation', 'Var', (0, 8))	('alanines', 'Chemical', 'MESH:D000409', (57, 65))	('Akt', 'Gene', (30, 33))	('ubiquitination', 'MPA', (101, 115))
720885	28965871	Consistently, disruption of FOXO1 levels/activity promotes carcinogenesis.	('FOXO1', 'Gene', (28, 33))	('carcinogenesis', 'Disease', 'MESH:D063646', (59, 73))	('disruption', 'Var', (14, 24))	('levels/activity', 'MPA', (34, 49))	('carcinogenesis', 'Disease', (59, 73))	('promotes', 'PosReg', (50, 58))
720886	28965871	Several major signaling pathways, such as PI3K, mitogen-activated protein kinase (MAPK), and IkappaB kinase (IKK), promote carcinogenesis through FOXO family members.	('promote', 'PosReg', (115, 122))	('carcinogenesis', 'Disease', 'MESH:D063646', (123, 137))	('PI3K', 'Var', (42, 46))	('FOXO', 'Gene', (146, 150))	('carcinogenesis', 'Disease', (123, 137))
720887	28965871	Previous studies have reported that low levels of FOXO1 are closely associated with digestive malignancy.	('low levels', 'Var', (36, 46))	('associated', 'Reg', (68, 78))	('FOXO1', 'Gene', (50, 55))	('malignancy', 'Disease', 'MESH:D009369', (94, 104))	('malignancy', 'Disease', (94, 104))
720901	28965871	In addition, AQP9 overexpression also increases apoptotic cells as evidenced by caspase-3 immunostaining.	('caspase-3', 'Gene', (80, 89))	('increases', 'PosReg', (38, 47))	('apoptotic cells', 'CPA', (48, 63))	('AQP9', 'Gene', '366', (13, 17))	('overexpression', 'Var', (18, 32))	('caspase-3', 'Gene', '836', (80, 89))	('AQP9', 'Gene', (13, 17))
720904	28965871	Consistently, inhibition of miR1269 decreases the proliferation of HCC as shown by increased the percentage of cells at G1/G0 phase.	('miR1269', 'Gene', (28, 35))	('increased', 'PosReg', (83, 92))	('HCC', 'Gene', '619501', (67, 70))	('proliferation', 'CPA', (50, 63))	('HCC', 'Gene', (67, 70))	('inhibition', 'Var', (14, 24))	('decreases', 'NegReg', (36, 45))	('miR1269', 'Gene', '100302177', (28, 35))
720915	28965871	Depletion of thep85 subunit of PI3K sensitizes colorectal cancer cells to 5-fluorouracil (5-FU)-induced apoptosis through activating FOXO1.	('FOXO1', 'Gene', (133, 138))	('activating', 'PosReg', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('sensitizes', 'Reg', (36, 46))	('Depletion', 'Var', (0, 9))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (74, 88))	('5-FU', 'Chemical', 'MESH:D005472', (90, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('PI3K', 'Gene', (31, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))
720923	28965871	In addition, FOXO1 expression negatively regulates the migration and invasion of several gastric cancer cell lines (SNU-638, MKN45, SNU-216 and NCI-N87) by downregulating human estrogen receptor 2 (HER2) accompanied by increased expression of E-cadherin.	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('estrogen receptor 2', 'Gene', (177, 196))	('increased', 'PosReg', (219, 228))	('migration', 'CPA', (55, 64))	('HER2', 'Gene', '2064', (198, 202))	('E-cadherin', 'Gene', (243, 253))	('E-cadherin', 'Gene', '999', (243, 253))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('downregulating', 'NegReg', (156, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))	('expression', 'Var', (19, 29))	('FOXO1', 'Gene', (13, 18))	('regulates', 'Reg', (41, 50))	('NCI-N87', 'CellLine', 'CVCL:1603', (144, 151))	('human', 'Species', '9606', (171, 176))	('expression', 'MPA', (229, 239))	('HER2', 'Gene', (198, 202))	('gastric cancer', 'Disease', (89, 103))	('invasion', 'CPA', (69, 77))	('negatively', 'NegReg', (30, 40))	('estrogen receptor 2', 'Gene', '2100', (177, 196))
720924	28965871	Consistently, FOXO1 knockdown promotes migration and invasion of gastric cancer cells, concomitant with increased expression of HER2.	('HER2', 'Gene', (128, 132))	('HER2', 'Gene', '2064', (128, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('promotes', 'PosReg', (30, 38))	('invasion', 'CPA', (53, 61))	('increased', 'PosReg', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('FOXO1', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('migration', 'CPA', (39, 48))	('expression', 'MPA', (114, 124))	('gastric cancer', 'Disease', (65, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))
720925	28965871	It was found that FOXO1 silencing enhances angiogenesis of gastric cancer by upregulating HIF-1alpha and VEGF.	('upregulating', 'PosReg', (77, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('HIF-1alpha', 'Gene', (90, 100))	('angiogenesis', 'CPA', (43, 55))	('VEGF', 'Gene', (105, 109))	('enhances', 'PosReg', (34, 42))	('FOXO1', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gastric cancer', 'Disease', (59, 73))	('HIF-1alpha', 'Gene', '3091', (90, 100))	('VEGF', 'Gene', '7422', (105, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))	('silencing', 'Var', (24, 33))
720929	28965871	MK-801, a glutamate antagonist, dephosphorylates Thr24 of FOXO1 and induces its nuclear import, thus increasing transcription of thioredoxin-interactingprotein (TXNIP) gene, which is concomitant with increased cyclin D1 and G1/S cell cycle arrest.	('increasing', 'PosReg', (101, 111))	('cyclin D1', 'Gene', (210, 219))	('nuclear import', 'MPA', (80, 94))	('G1/S cell cycle arrest', 'CPA', (224, 246))	('glutamate', 'Chemical', 'MESH:D018698', (10, 19))	('increased', 'PosReg', (200, 209))	('thioredoxin-interactingprotein', 'Gene', '10628', (129, 159))	('Thr24', 'Chemical', '-', (49, 54))	('TXNIP', 'Gene', '10628', (161, 166))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (229, 246))	('MK-801', 'Var', (0, 6))	('FOXO1', 'Gene', (58, 63))	('TXNIP', 'Gene', (161, 166))	('MK-801', 'Chemical', 'MESH:D016291', (0, 6))	('thioredoxin-interactingprotein', 'Gene', (129, 159))	('cyclin D1', 'Gene', '595', (210, 219))	('induces', 'PosReg', (68, 75))	('transcription', 'MPA', (112, 125))
720938	28965871	In addition, Galpha12 gep oncogene inhibits FOXO1 following dysregulation of miR135b and miR194, thereby promoting the development of HCC.	('Galpha12', 'Gene', (13, 21))	('FOXO1', 'Gene', (44, 49))	('miR194', 'Var', (89, 95))	('HCC', 'Gene', (134, 137))	('inhibits', 'NegReg', (35, 43))	('Galpha12', 'Gene', '2768', (13, 21))	('miR135b', 'Gene', '442891', (77, 84))	('HCC', 'Gene', '619501', (134, 137))	('promoting', 'PosReg', (105, 114))	('miR135b', 'Gene', (77, 84))	('dysregulation', 'Var', (60, 73))
720940	28965871	Inhibition of miR96 significantly represses HCC proliferation and colony formation accompanied by upregulation of FOXO1.	('HCC', 'Gene', (44, 47))	('miR96', 'Gene', (14, 19))	('miR96', 'Gene', '407053', (14, 19))	('HCC', 'Gene', '619501', (44, 47))	('upregulation', 'PosReg', (98, 110))	('Inhibition', 'Var', (0, 10))	('FOXO1', 'Gene', (114, 119))	('colony formation', 'CPA', (66, 82))	('represses', 'NegReg', (34, 43))
720941	28965871	These results again indicate that increase in the levelsFOXO1may provide beneficial effects for treating HCC.	('HCC', 'Gene', (105, 108))	('levelsFOXO1may', 'Var', (50, 64))	('HCC', 'Gene', '619501', (105, 108))
720944	28965871	Silencing of miR96 results in inhibiting the proliferation of colorectal cancer cells via activating FOXO1.	('inhibiting', 'NegReg', (30, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('miR96', 'Gene', '407053', (13, 18))	('proliferation', 'CPA', (45, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('activating', 'PosReg', (90, 100))	('colorectal cancer', 'Disease', (62, 79))	('FOXO1', 'Gene', (101, 106))	('Silencing', 'Var', (0, 9))	('miR96', 'Gene', (13, 18))
720962	28965871	Moreover, administration of miR21 antisense significantly upregulates FOXO1 levels in implanted PDAC, resulting in significant reduction in PDAC growth.	('levels', 'MPA', (76, 82))	('PDAC', 'Chemical', '-', (140, 144))	('PDAC', 'Chemical', '-', (96, 100))	('miR21', 'Gene', (28, 33))	('upregulates', 'PosReg', (58, 69))	('FOXO1', 'Gene', (70, 75))	('antisense', 'Var', (34, 43))	('reduction', 'NegReg', (127, 136))	('PDAC growth', 'CPA', (140, 151))	('miR21', 'Gene', '406991', (28, 33))
720966	28965871	Similarly, Benzyl Isothiocyante also induces apoptosis and suppress pancreatic cancer growth by activating FOXO1 signaling through inhibiting PI3K/AKT, which is correlated with the increased expression of Bim, p27, and p21 in BxPC-3 cells.	('Bim', 'Gene', '10018', (205, 208))	('activating', 'PosReg', (96, 106))	('FOXO1 signaling', 'MPA', (107, 122))	('inhibiting', 'NegReg', (131, 141))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))	('Bim', 'Gene', (205, 208))	('apoptosis', 'CPA', (45, 54))	('pancreatic cancer', 'Disease', (68, 85))	('AKT', 'Gene', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('p27', 'Gene', '3429', (210, 213))	('p27', 'Gene', (210, 213))	('Benzyl Isothiocyante', 'Var', (11, 31))	('Benzyl Isothiocyante', 'Chemical', '-', (11, 31))	('BxPC-3', 'CellLine', 'CVCL:0186', (226, 232))	('induces', 'PosReg', (37, 44))	('p21', 'Gene', (219, 222))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('p21', 'Gene', '644914', (219, 222))	('AKT', 'Gene', '207', (147, 150))	('suppress', 'NegReg', (59, 67))
720970	28965871	The squamous cell carcinomas of head and neck (SCCHN) with aberrant epidermal growth factor receptor (EGFR) signaling are often associated with poor prognosis and a low survival rate.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('epidermal growth factor receptor', 'Gene', (68, 100))	('aberrant', 'Var', (59, 67))	('squamous cell carcinomas', 'Disease', (4, 28))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (4, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('carcinomas of head and neck', 'Phenotype', 'HP:0012288', (18, 45))	('epidermal growth factor receptor', 'Gene', '1956', (68, 100))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (4, 28))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (4, 27))
720973	28965871	Specifically, Quercetin inhibits EGFR/Akt pathway with concomitant FOXO1 activation while FOXO1 knockdown attenuates quercetin-induced antineoplastic effects.	('knockdown', 'Var', (96, 105))	('antineoplastic effects', 'CPA', (135, 157))	('FOXO1', 'Gene', (67, 72))	('activation', 'PosReg', (73, 83))	('attenuates', 'NegReg', (106, 116))	('inhibits', 'NegReg', (24, 32))	('EGFR', 'Gene', '1956', (33, 37))	('Akt', 'Gene', '207', (38, 41))	('Quercetin', 'Chemical', 'MESH:D011794', (14, 23))	('EGFR', 'Gene', (33, 37))	('quercetin', 'Chemical', 'MESH:D011794', (117, 126))	('FOXO1', 'Gene', (90, 95))	('Akt', 'Gene', (38, 41))
720983	28965871	Cdk5 inhibition induces apoptosis of urinary tumor-initiating cells by stabilizing the transcription factor FOXO1, thereby suppressing its chemoresistance.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('inhibition', 'Var', (5, 15))	('suppressing', 'NegReg', (123, 134))	('tumor', 'Disease', (45, 50))	('Cdk5', 'Gene', (0, 4))	('urinary tumor', 'Phenotype', 'HP:0010786', (37, 50))	('stabilizing', 'MPA', (71, 82))	('chemoresistance', 'CPA', (139, 154))	('Cdk5', 'Gene', '1020', (0, 4))	('FOXO1', 'Gene', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
720986	28965871	Furthermore, knockdown of FOXO1 inhibits TNF-alpha-induced apoptosis and expression of caspase-3, 8, and 9.	('caspase-3, 8, and 9', 'Gene', '836;841;842', (87, 106))	('TNF-alpha', 'Gene', '7124', (41, 50))	('FOXO1', 'Gene', (26, 31))	('TNF-alpha', 'Gene', (41, 50))	('apoptosis', 'CPA', (59, 68))	('expression', 'MPA', (73, 83))	('inhibits', 'NegReg', (32, 40))	('knockdown', 'Var', (13, 22))
720997	28965871	They conclude that inhibition of FoxO1 might lead to insulin resistance (IR) and metabolic dysregulation.	('insulin', 'Gene', (53, 60))	('inhibition', 'Var', (19, 29))	('FoxO1', 'Gene', (33, 38))	('insulin', 'Gene', '3630', (53, 60))	('metabolic dysregulation', 'CPA', (81, 104))	('insulin resistance', 'Phenotype', 'HP:0000855', (53, 71))	('lead to', 'Reg', (45, 52))
721004	28965871	They examined whether polymorphism of miR-targeting sites in FOXO1 is correlated with HCC susceptibility.	('FOXO1', 'Gene', (61, 66))	('HCC', 'Gene', (86, 89))	('HCC', 'Gene', '619501', (86, 89))	('polymorphism', 'Var', (22, 34))	('correlated', 'Reg', (70, 80))
721005	28965871	Intriguingly, three miR-targeted UTR sites of FOXO1 (rs17592236), FOXO3 (rs4946936), and FOXO4 (rs4503258) were identified.	('rs17592236', 'Mutation', 'rs17592236', (53, 63))	('rs4946936', 'Var', (73, 82))	('rs4946936', 'Mutation', 'rs4946936', (73, 82))	('rs4503258', 'Mutation', 'rs4503258', (96, 105))	('FOXO3', 'Gene', (66, 71))	('FOXO4', 'Gene', (89, 94))	('rs17592236', 'Var', (53, 63))	('rs4503258', 'Var', (96, 105))	('FOXO1', 'Gene', (46, 51))	('FOXO3', 'Gene', '2309', (66, 71))	('FOXO4', 'Gene', '4303', (89, 94))
721006	28965871	Multivariate logistic regression analysis (MLRA) showed that the CT/TT genotype in rs17592236 and the rs17592236 polymorphism are associated with decreased HCC hereditary susceptibility.	('rs17592236', 'Var', (83, 93))	('rs17592236', 'Mutation', 'rs17592236', (102, 112))	('decreased HCC hereditary', 'Disease', (146, 170))	('rs17592236', 'Var', (102, 112))	('rs17592236', 'Mutation', 'rs17592236', (83, 93))	('decreased HCC hereditary', 'Disease', 'MESH:D006528', (146, 170))
721012	28965871	They further reported that decreased levels of FOXO1 and high levels of ZBTB20 are associated with a poor 5-year survival rate.	('poor', 'NegReg', (101, 105))	('high', 'Var', (57, 61))	('decreased', 'NegReg', (27, 36))	('ZBTB20', 'Gene', (72, 78))	('FOXO1', 'Protein', (47, 52))	('5-year survival rate', 'CPA', (106, 126))	('ZBTB20', 'Gene', '26137', (72, 78))
721015	28965871	Conversely, FOXO1 silencing enhances Cisplatin cytotoxicity and Cisplatin-induced apoptosis via activating the PI3K/Akt pathway.	('cytotoxicity', 'Disease', 'MESH:D064420', (47, 59))	('FOXO1', 'Gene', (12, 17))	('silencing', 'Var', (18, 27))	('Cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('cytotoxicity', 'Disease', (47, 59))	('activating', 'PosReg', (96, 106))	('Akt', 'Gene', '207', (116, 119))	('Cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('enhances', 'PosReg', (28, 36))	('Akt', 'Gene', (116, 119))
721016	28965871	Moreover, Kim et al reported that expression of pFOXO1a is correlated with reduced tumor growth and a longer survival rate.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('longer', 'PosReg', (102, 108))	('reduced tumor', 'Disease', 'MESH:D015354', (75, 88))	('expression', 'Var', (34, 44))	('FOXO1a', 'Gene', (49, 55))	('reduced tumor', 'Disease', (75, 88))	('FOXO1a', 'Gene', '2308', (49, 55))
721019	28965871	Nuclear export or FOXO1 phosphorylation leads to FOXO1 inactivation and cell growth, which is correlated with the development of malignancy in the digestive system.	('cell growth', 'CPA', (72, 83))	('malignancy', 'Disease', (129, 139))	('inactivation', 'NegReg', (55, 67))	('Nuclear', 'Var', (0, 7))	('FOXO1', 'Gene', (18, 23))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))	('FOXO1', 'Gene', (49, 54))	('phosphorylation', 'Var', (24, 39))
721020	28965871	Experimental and clinical evidence further suggests that decreased expression of FOXO1 has a close correlation with incidence of digestive malignancy; high levels of FOXO1 predict an optimal outcome in digestive malignancy patients.	('high levels', 'Var', (151, 162))	('malignancy', 'Disease', 'MESH:D009369', (212, 222))	('FOXO1', 'Gene', (81, 86))	('malignancy', 'Disease', (212, 222))	('malignancy', 'Disease', 'MESH:D009369', (139, 149))	('malignancy', 'Disease', (139, 149))	('expression', 'MPA', (67, 77))	('FOXO1', 'Gene', (166, 171))	('patients', 'Species', '9606', (223, 231))
721035	29179502	A recent systematic review evaluated 27 studies comprising a total of 1972 patients who received >= 60 Gy CCRT and found that >= 60 Gy CCRT improved clinical outcomes as compared to the 50~54 Gy CCRT arm.	('improved', 'PosReg', (140, 148))	('>= 60 Gy CCRT', 'Var', (126, 139))	('clinical outcomes', 'CPA', (149, 166))	('patients', 'Species', '9606', (75, 83))
721050	29179502	As shown in Figure 3A, patients received >= circa 50 Gy radiation had significantly better outcomes (pooled HR = 0.75, 95% CI: 0.57-0.98, P = 0.03), and patients who received 70 Gy radiation had no survival benefit (Figure 2B).	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (23, 31))	('better', 'PosReg', (84, 90))	('>= circa 50 Gy radiation', 'Var', (41, 65))	('outcomes', 'MPA', (91, 99))
721054	29179502	There were 4 studies comparing odds ratios (ORs) between radiation dose > 50.4/51 Gy with <= 50.4/51 Gy, and the results showed that the HD group (> 50.4/51 Gy) had a nearly significant association with higher locoregional control (pooled OR = 0.71, 95% CI = 0.49-1.02, P = 0.06, Figure 5A).	('higher', 'PosReg', (203, 209))	('> 50.4/51 Gy', 'Var', (147, 159))	('HD', 'Disease', 'MESH:D006816', (137, 139))
721073	29179502	In 2015, Song and colleagues conducted a systematic review in a large group of patients worldwide and found that >= 60 Gy CCRT (cisplatin-based) improved clinical outcomes (response rate, local regional recurrence rate distant failure rate and overall survival) relative to the conventional dose (50~54 Gy) group, especially for esophageal squamous cell carcinoma.	('overall survival', 'CPA', (244, 260))	('response rate', 'CPA', (173, 186))	('esophageal squamous cell carcinoma', 'Disease', (329, 363))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (354, 363))	('distant failure', 'CPA', (219, 234))	('local regional recurrence', 'CPA', (188, 213))	('improved', 'PosReg', (145, 153))	('patients', 'Species', '9606', (79, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (340, 363))	('>= 60 Gy', 'Var', (113, 121))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (329, 363))
721074	29179502	In addition to the prolonged treatment time of HD arm in the INT-0123 trial, another possible explanation might be that there was a significantly higher rate of salvage surgery after progression in 50.4 Gy CCRT group compared with the >= 60 Gy group in Hirano's retrospective study, which might have also led to a prolongation in OS in the 50.4 Gy group.	('higher', 'PosReg', (146, 152))	('OS', 'Chemical', '-', (330, 332))	('prolongation', 'Disease', 'MESH:D011273', (314, 326))	('50.4 Gy CCRT', 'Var', (198, 210))	('HD', 'Disease', 'MESH:D006816', (47, 49))	('prolongation', 'Disease', (314, 326))	('salvage surgery', 'CPA', (161, 176))
721076	29179502	From the subgroup analysis according to geographic area, we found that >= 60 Gy radiation would be an optimal dose for Asian EC patients, while the optimal radiation dose for Western EC patients is still unclear.	('patients', 'Species', '9606', (186, 194))	('patients', 'Species', '9606', (128, 136))	('>= 60 Gy', 'Var', (71, 79))	('Asian EC', 'Disease', (119, 127))
721078	29179502	Certainly, our results reflect the rationale behind the three currently ongoing clinical trials evaluating HD and LD treatment options; NCT01348217: 50 Gy vs 66 Gy (since 2011, France); NCT01937208: 50 Gy vs 60 Gy (since 2013, China) and NCT02556762: 50 Gy vs 66 Gy (since 2015, China).	('NCT01937208', 'Var', (186, 197))	('NCT01348217', 'Var', (136, 147))	('HD', 'Disease', 'MESH:D006816', (107, 109))	('NCT02556762', 'Var', (238, 249))
721160	21576902	The best characterized include aneuploidy/tetraploidy and 17p loss of heterozygosity (LOH).	('loss of', 'NegReg', (62, 69))	('17p', 'Var', (58, 61))	('aneuploidy/tetraploidy', 'Disease', 'MESH:D057891', (31, 53))	('aneuploidy/tetraploidy', 'Disease', (31, 53))
721168	21576902	Gene amplification plays an important role in promoting neoplastic progression in many tumor types (25.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('promoting', 'PosReg', (46, 55))	('Gene amplification', 'Var', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('neoplastic progression', 'CPA', (56, 78))
721171	21576902	This result suggests that amplification is involved early in cancer progression rather than late.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('amplification', 'Var', (26, 39))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
721174	21576902	For example, amplification and over-expression of EGFR and the structurally related ERBB2 have been established as indicators of poor prognosis in several human cancers, such as breast and ovarian cancer.	('ERBB2', 'Gene', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ovarian cancer', 'Phenotype', 'HP:0100615', (189, 203))	('over-expression', 'PosReg', (31, 46))	('human', 'Species', '9606', (155, 160))	('cancers', 'Disease', (161, 168))	('EGFR', 'Gene', '1956', (50, 54))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('amplification', 'Var', (13, 26))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('EGFR', 'Gene', (50, 54))	('ERBB2', 'Gene', '2064', (84, 89))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (178, 203))
721179	21576902	High compared to low MET expression has also been found to be associated with significantly reduced overall and disease specific 5-year survival rates as well as an increased risk of developing distant metastases.	('metastases', 'Disease', 'MESH:D009362', (202, 212))	('disease specific 5-year survival rates', 'CPA', (112, 150))	('High', 'Var', (0, 4))	('reduced', 'NegReg', (92, 99))	('metastases', 'Disease', (202, 212))
721180	21576902	Mutations of receptor tyrosine kinases often lead to developmental abnormalities, metabolic defects, or oncogenesis.	('developmental abnormalities', 'Disease', (53, 80))	('developmental abnormalities', 'Disease', 'MESH:D006130', (53, 80))	('lead to', 'Reg', (45, 52))	('Mutations', 'Var', (0, 9))	('oncogenesis', 'CPA', (104, 115))	('metabolic defects', 'Disease', (82, 99))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (53, 80))	('metabolic defects', 'Disease', 'MESH:D008659', (82, 99))
721191	21576902	The main disadvantage for in vivo use, however, is the low penetration depth of light through tissues and concerns about toxicity.. Small molecules have also been developed as a class of molecular probe.	('toxicity', 'Disease', 'MESH:D064420', (121, 129))	('Small', 'Var', (132, 137))	('toxicity', 'Disease', (121, 129))
721214	21576902	HER-2/neu oncogene amplification on FISH has been shown to correlate with reduced patient survival and appears to independently predict poor outcome in patients with Barrett's associated adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('adenocarcinoma', 'Disease', 'MESH:D000230', (187, 201))	('patient', 'Species', '9606', (82, 89))	('amplification', 'Var', (19, 32))	('reduced', 'NegReg', (74, 81))	('oncogene', 'Protein', (10, 18))	('HER-2', 'Gene', (0, 5))	('HER-2', 'Gene', '2064', (0, 5))	('neu', 'Gene', '2064', (6, 9))	('adenocarcinoma', 'Disease', (187, 201))	('patient', 'Species', '9606', (152, 159))	('neu', 'Gene', (6, 9))	('patients', 'Species', '9606', (152, 160))	('patient survival', 'CPA', (82, 98))
721230	21483804	Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia.	('Barrett neoplasia', 'Disease', 'MESH:D001471', (158, 175))	('chr4q21 chemokine cluster', 'Gene', (103, 128))	('neoplasia', 'Phenotype', 'HP:0002664', (166, 175))	('Promoter hypomethylation', 'Var', (0, 24))	('transcripts', 'MPA', (139, 150))	('upregulation', 'PosReg', (85, 97))	('Barrett neoplasia', 'Disease', (158, 175))
721231	21483804	We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined "CpG islands," but may also occur through a mechanism of differential methylation outside of these regions.	('epigenetic regulation', 'Var', (21, 42))	('epithelial carcinogenesis', 'Disease', 'MESH:D063646', (50, 75))	('epithelial carcinogenesis', 'Disease', (50, 75))
721237	21483804	Finally we uncovered proteins that upregulated by loss of methylation or gene amplification (CXCL1 and 3, GATA6, and DMBT1) and show their relevance by validating their levels in larger independent panel of samples, thus confirming the utility of integrative analysis in cancer biomarker discovery.	('gene', 'MPA', (73, 77))	('DMBT1', 'Gene', '1755', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('loss', 'NegReg', (50, 54))	('GATA6', 'Gene', (106, 111))	('GATA6', 'Gene', '2627', (106, 111))	('methylation', 'Var', (58, 69))	('upregulated', 'PosReg', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('CXCL1 and 3', 'Gene', '2919;2921', (93, 104))	('DMBT1', 'Gene', (117, 122))	('cancer', 'Disease', (271, 277))
721247	21483804	Our studies have identified striking epigenomic alterations, and in specific, widespread hypomethylation, which occurs at the earliest stages of epithelial carcinogenesis.	('epithelial carcinogenesis', 'Disease', (145, 170))	('epigenomic alterations', 'Var', (37, 59))	('epithelial carcinogenesis', 'Disease', 'MESH:D063646', (145, 170))	('hypomethylation', 'Var', (89, 104))
721248	21483804	This approach is in direct contrast to most single- or limited-locus studies that have focused on epigenetic silencing of candidate tumor suppressor genes by hypermethylation of the promoter.	('hypermethylation', 'Var', (158, 174))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('epigenetic silencing', 'Var', (98, 118))
721249	21483804	In addition, we have identified clustered transcripts, such as the chemokine ligands CXCL1 and 3, that are markedly upregulated via simultaneous biallelic alteration by hypomethylation and gene amplification, respectively, and whose protein products have the potential to serve as serum biomarkers of neoplastic progression in BE.	('biallelic', 'Var', (145, 154))	('gene amplification', 'Var', (189, 207))	('CXCL1 and 3', 'Gene', '2919;2921', (85, 96))	('upregulated', 'PosReg', (116, 127))	('hypomethylation', 'Var', (169, 184))
721264	21483804	These results suggest an epigenetic regulatory function for CG dinucleotide elements in the genome that do not meet the threshold for canonical CpG islands, which are strictly defined on base compositional criteria.	('epigenetic regulatory function', 'MPA', (25, 55))	('CG dinucleotide', 'Chemical', 'MESH:C015772', (60, 75))	('dinucleotide elements', 'Var', (63, 84))
721272	21483804	This finding suggests the importance of methylation of the remaining allele in regulating expression, and provides direct experimental evidence for genetic and epigenetic hits acting concurrently and synergistically to downregulate tumor suppressor genes during oncogenesis through bi-allelic inactivation (Figure S3).	('bi-allelic inactivation', 'Var', (282, 305))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('expression', 'MPA', (90, 100))	('downregulate', 'NegReg', (219, 231))	('tumor', 'Disease', (232, 237))
721273	21483804	In particular, we focused on genes that were significantly overexpressed in pair-wise comparisons, by hypomethylation and / or genomic amplification, and validated selected examples of patient-specific aberrations in larger sample sets.	('hypomethylation', 'Var', (102, 117))	('patient', 'Species', '9606', (185, 192))	('overexpressed', 'PosReg', (59, 72))
721283	21483804	Assessment of the aCGH data and FISH on primary tissues readily validated the copy number alterations at the GATA6 locus during esophageal carcinogenesis (Figure 6A, 6B).	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (128, 153))	('GATA6', 'Gene', (109, 114))	('GATA6', 'Gene', '2627', (109, 114))	('esophageal carcinogenesis', 'Disease', (128, 153))	('CG', 'Chemical', 'MESH:C028505', (19, 21))	('copy number alterations', 'Var', (78, 101))
721287	21483804	Loss of Gata6 function did not affect proliferation, (Figure 6L) but resulted in significantly decreased anchorage independent growth of OE33 cells and also led to decrease in invasion and migration (Figure 6M-6P), thus providing a putative functional association between GATA6 amplification and disease progression in BE.	('Gata6', 'Gene', (8, 13))	('decreased', 'NegReg', (95, 104))	('Gata6', 'Gene', '2627', (8, 13))	('function', 'Var', (14, 22))	('Loss', 'NegReg', (0, 4))	('decrease', 'NegReg', (164, 172))	('GATA6', 'Gene', '2627', (272, 277))	('GATA6', 'Gene', (272, 277))	('anchorage independent growth', 'CPA', (105, 133))
721292	21483804	Hypomethylation has been hypothesized to lead to carcinogenesis by encouraging genomic instability as well as by aberrant activation of oncogenes.	('genomic instability', 'CPA', (79, 98))	('Hypomethylation', 'Var', (0, 15))	('carcinogenesis', 'Disease', 'MESH:D063646', (49, 63))	('oncogenes', 'Protein', (136, 145))	('activation', 'PosReg', (122, 132))	('lead to', 'Reg', (41, 48))	('encouraging', 'PosReg', (67, 78))	('carcinogenesis', 'Disease', (49, 63))
721293	21483804	Additionally, as illustrated in the example of DMBT1, hypomethylation alone can lead to transcriptional upregulation during multistep progression to high-grade dysplasia and cancer.	('upregulation', 'PosReg', (104, 116))	('dysplasia', 'Disease', (160, 169))	('DMBT1', 'Gene', (47, 52))	('dysplasia', 'Disease', 'MESH:D004476', (160, 169))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('transcriptional', 'MPA', (88, 103))	('DMBT1', 'Gene', '1755', (47, 52))	('hypomethylation', 'Var', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
721295	21483804	Importantly, these CG alterations are not merely stochastic in nature, but appear to have bona fide regulatory influence on transcript expression.	('CG', 'Chemical', 'MESH:C028505', (19, 21))	('alterations', 'Var', (22, 33))	('transcript expression', 'MPA', (124, 145))
721298	21483804	Our study provides direct experimental evidence of deletions and promoter methylation acting in concert to silence tumor suppressors in a bi-allelic manner, as first postulated by Knudson's two-hit paradigm.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('deletions', 'Var', (51, 60))	('silence', 'NegReg', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
721306	21483804	It has been suggested that these chemokines potentiate tumor progression especially with cells with p53 inactivation, an event seen commonly in esophageal neoplasms.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('potentiate', 'PosReg', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('inactivation', 'Var', (104, 116))	('p53', 'Gene', '7157', (100, 103))	('esophageal neoplasms', 'Phenotype', 'HP:0100751', (144, 164))	('esophageal neoplasms', 'Disease', (144, 164))	('neoplasms', 'Phenotype', 'HP:0002664', (155, 164))	('esophageal neoplasms', 'Disease', 'MESH:D004938', (144, 164))	('p53', 'Gene', (100, 103))
721416	18392848	Improper selection of representative tumor areas on the donor block's H&E slide by the pathologist or incorrect punching of these representative areas out of the donor block can cause tissue cores that contain too little tumor.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('donor', 'Species', '9606', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('H&E', 'Chemical', '-', (70, 73))	('can', 'Reg', (174, 177))	('donor', 'Species', '9606', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('Improper', 'Var', (0, 8))
721451	33194681	NGS examination of this patient demonstrated that PIK3CA mutation and a RICTOR amplification might participate in primary and acquired resistance to nimotuzumab, respectively, via the PI3K/AKT/mTOR signaling pathway.	('RICTOR', 'Gene', (72, 78))	('mutation', 'Var', (57, 65))	('RICTOR', 'Gene', '253260', (72, 78))	('AKT', 'Gene', (189, 192))	('PIK3CA', 'Gene', '5290', (50, 56))	('mTOR', 'Gene', '2475', (193, 197))	('participate', 'Reg', (99, 110))	('mTOR', 'Gene', (193, 197))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('patient', 'Species', '9606', (24, 31))	('AKT', 'Gene', '207', (189, 192))	('PIK3CA', 'Gene', (50, 56))	('nimotuzumab', 'Chemical', 'MESH:C501466', (149, 160))
721456	33194681	Protein overexpression of epidermal growth factor receptor (EGFR) and EGFR amplification has been observed in many ESCC patients and is related to a poor prognosis in both progression-free survival (PFS) and overall survival (OS).	('overexpression', 'PosReg', (8, 22))	('ESCC', 'Disease', (115, 119))	('epidermal growth factor receptor', 'Gene', '1956', (26, 58))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('amplification', 'Var', (75, 88))	('EGFR', 'Gene', (70, 74))	('patients', 'Species', '9606', (120, 128))	('epidermal growth factor receptor', 'Gene', (26, 58))	('EGFR', 'Gene', (60, 64))
721462	33194681	Regrettably, not all patients harboring EGFR amplification or EGFR protein overexpression respond well to nimotuzumab, while primary and acquired resistance to nimotuzumab from monotherapy or combined regimens can be observed in multiple studies on ESCC.	('nimotuzumab', 'Chemical', 'MESH:C501466', (160, 171))	('overexpression', 'PosReg', (75, 89))	('EGFR', 'Gene', (62, 66))	('patients', 'Species', '9606', (21, 29))	('nimotuzumab', 'Chemical', 'MESH:C501466', (106, 117))	('EGFR', 'Gene', (40, 44))	('protein', 'Protein', (67, 74))	('SCC', 'Phenotype', 'HP:0002860', (250, 253))	('amplification', 'Var', (45, 58))
721484	33194681	NGS assays of this patient revealed that EGFR amplification and the p.E545K mutation of PIK3CA were present in his peripheral blood before nimotuzumab treatment.	('patient', 'Species', '9606', (19, 26))	('PIK3CA', 'Gene', '5290', (88, 94))	('p.E545K', 'Mutation', 'rs104886003', (68, 75))	('nimotuzumab', 'Chemical', 'MESH:C501466', (139, 150))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('PIK3CA', 'Gene', (88, 94))	('p.E545K', 'Var', (68, 75))
721489	33194681	PIK3CA mutations result in the persistent phosphorylation of Akt1 and overactivate the EGFR signaling pathway, which is related to primary resistance to cetuximab.	('Akt1', 'Gene', (61, 65))	('Akt1', 'Gene', '207', (61, 65))	('cetuximab', 'Chemical', 'MESH:D000068818', (153, 162))	('phosphorylation', 'MPA', (42, 57))	('PIK3CA', 'Gene', (0, 6))	('overactivate', 'PosReg', (70, 82))	('EGFR signaling pathway', 'Pathway', (87, 109))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (7, 16))
721490	33194681	Recently, studies have verified the relationship between PIK3CA mutation and primary cetuximab resistance.	('PIK3CA', 'Gene', '5290', (57, 63))	('mutation', 'Var', (64, 72))	('primary cetuximab resistance', 'MPA', (77, 105))	('cetuximab', 'Chemical', 'MESH:D000068818', (85, 94))	('PIK3CA', 'Gene', (57, 63))
721491	33194681	After phosphorylation of Akt1 and activation of the EGFR signaling pathway, PIK3CA mutations can lead to cetuximab resistance via activation of the downstream mTOR signaling pathway.	('Akt1', 'Gene', (25, 29))	('mutations', 'Var', (83, 92))	('PIK3CA', 'Gene', '5290', (76, 82))	('activation', 'PosReg', (130, 140))	('mTOR', 'Gene', (159, 163))	('cetuximab resistance', 'MPA', (105, 125))	('mTOR', 'Gene', '2475', (159, 163))	('Akt1', 'Gene', '207', (25, 29))	('PIK3CA', 'Gene', (76, 82))	('EGFR signaling pathway', 'Pathway', (52, 74))	('cetuximab', 'Chemical', 'MESH:D000068818', (105, 114))	('lead to', 'Reg', (97, 104))
721492	33194681	Extraordinarily, the p.E545K mutation of PIK3CA enhances the binding ability to EGFR and significantly activates the downstream Akt signaling pathway.	('activates', 'PosReg', (103, 112))	('p.E545K', 'Var', (21, 28))	('PIK3CA', 'Gene', '5290', (41, 47))	('Akt', 'Gene', (128, 131))	('EGFR', 'Protein', (80, 84))	('binding ability', 'Interaction', (61, 76))	('p.E545K', 'Mutation', 'rs104886003', (21, 28))	('PIK3CA', 'Gene', (41, 47))	('Akt', 'Gene', '207', (128, 131))	('enhances', 'PosReg', (48, 56))
721499	33194681	Given that nimotuzumab is a mAb for EGFR, the p.E545K mutation of PIK3CA in this patient might have led to constitutive Akt phosphorylation, and activation of the EGFR signaling pathway is strongly associated with primary resistance to nimotuzumab and a short time to treatment failure (TTF).	('activation', 'PosReg', (145, 155))	('led to', 'Reg', (100, 106))	('nimotuzumab', 'Chemical', 'MESH:C501466', (236, 247))	('patient', 'Species', '9606', (81, 88))	('Akt', 'Gene', '207', (120, 123))	('PIK3CA', 'Gene', (66, 72))	('constitutive', 'MPA', (107, 119))	('nimotuzumab', 'Chemical', 'MESH:C501466', (11, 22))	('associated', 'Reg', (198, 208))	('p.E545K', 'Var', (46, 53))	('EGFR signaling pathway', 'Pathway', (163, 185))	('PIK3CA', 'Gene', '5290', (66, 72))	('Akt', 'Gene', (120, 123))	('p.E545K', 'Mutation', 'rs104886003', (46, 53))
721502	33194681	PIK3CA mutation and RICTOR amplification may participate in primary and acquired resistance to nimotuzumab, respectively, via the PI3K/AKT/mTOR signaling pathway.	('AKT', 'Gene', '207', (135, 138))	('nimotuzumab', 'Chemical', 'MESH:C501466', (95, 106))	('mTOR', 'Gene', (139, 143))	('mTOR', 'Gene', '2475', (139, 143))	('PIK3CA', 'Gene', (0, 6))	('AKT', 'Gene', (135, 138))	('PIK3CA', 'Gene', '5290', (0, 6))	('RICTOR', 'Gene', (20, 26))	('mutation', 'Var', (7, 15))	('RICTOR', 'Gene', '253260', (20, 26))	('participate', 'Reg', (45, 56))
721503	33194681	Further treatment with alpelisib (BYL719) or rapalagos, which target the mTOR pathway, might benefit ESCC patients harboring mutations or genetic alterations that increase the activation of the PI3K-AKT/mTOR signaling pathway.	('genetic alterations', 'Var', (138, 157))	('mutations', 'Var', (125, 134))	('mTOR', 'Gene', '2475', (73, 77))	('AKT', 'Gene', (199, 202))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('mTOR', 'Gene', (73, 77))	('patients', 'Species', '9606', (106, 114))	('AKT', 'Gene', '207', (199, 202))	('ESCC', 'Disease', (101, 105))	('mTOR', 'Gene', (203, 207))	('mTOR', 'Gene', '2475', (203, 207))
721512	30664196	Quantitative polymerase chain reaction was used to measure the transcript levels of the TF variants in 11 human cell lines, including cervical cancer, breast cancer, hepatoblastoma, colorectal cancer and umbilical vein cells, and five types of tissue specimen, including placenta, esophageal cancer, breast cancer, cervical cancer (alongside normal cervical tissues) and non-small cell lung cancer (alongside adjacent and normal tissues).	('human', 'Species', '9606', (106, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('cervical cancer', 'Disease', (134, 149))	('cervical cancer', 'Disease', 'MESH:D002583', (134, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (166, 180))	('men', 'Species', '9606', (256, 259))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (300, 313))	('esophageal cancer', 'Disease', 'MESH:D004938', (281, 298))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (375, 397))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (371, 397))	('cervical cancer', 'Disease', (315, 330))	('cervical cancer', 'Disease', 'MESH:D002583', (315, 330))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Disease', 'MESH:D001943', (300, 313))	('breast cancer', 'Disease', (151, 164))	('breast cancer', 'Disease', (300, 313))	('esophageal cancer', 'Disease', (281, 298))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('TF', 'Gene', '2152', (88, 90))	('colorectal cancer', 'Disease', (182, 199))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (371, 397))	('hepatoblastoma', 'Disease', (166, 180))	('hepatoblastoma', 'Disease', 'MESH:D018197', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('variants', 'Var', (91, 99))	('non-small cell lung cancer', 'Disease', (371, 397))	('lung cancer', 'Phenotype', 'HP:0100526', (386, 397))
721523	30664196	Alternative splicing of TF results in three naturally occurring protein isoforms: Full-length (fl)TF, alternatively spliced (as)TF and TF-A.	('TF-A', 'Gene', '2152', (135, 139))	('TF', 'Gene', '2152', (98, 100))	('TF', 'Gene', '2152', (24, 26))	('TF', 'Gene', '2152', (135, 137))	('Alternative splicing', 'Var', (0, 20))	('TF-A', 'Gene', (135, 139))	('results in', 'Reg', (27, 37))	('TF', 'Gene', '2152', (128, 130))
721532	30664196	In order to investigate the association between TF variants and CDCA/apoM, the difference in the expression of TF variants in various cell strains and tissues was examined in the present study.	('variants', 'Var', (51, 59))	('TF', 'Gene', '2152', (48, 50))	('CDCA/apoM', 'Gene', '55937', (64, 73))	('TF', 'Gene', '2152', (111, 113))	('CDCA/apoM', 'Gene', (64, 73))
721560	30664196	There was a significant increase in the expression levels of flTF in the HepG2 and EA.hy926 cells treated with CDCA (Fig.	('increase', 'PosReg', (24, 32))	('HepG2', 'CellLine', 'CVCL:0027', (73, 78))	('flTF', 'Gene', (61, 65))	('flTF', 'Chemical', '-', (61, 65))	('EA.hy926', 'CellLine', 'CVCL:3901', (83, 91))	('CDCA', 'Chemical', 'MESH:D002635', (111, 115))	('expression levels', 'MPA', (40, 57))	('CDCA', 'Var', (111, 115))
721562	30664196	Compared with in the NC (empty vector control) group, apoM lentivirus transduction increased apoM expression by 9.95-fold (P<0.0001) in Caco-2 cells (Fig.	('increased', 'PosReg', (83, 92))	('apoM', 'Gene', (93, 97))	('apoM', 'Gene', '55937', (93, 97))	('transduction', 'Var', (70, 82))	('Caco-2', 'CellLine', 'CVCL:0025', (136, 142))	('apoM', 'Gene', (54, 58))	('apoM', 'Gene', '55937', (54, 58))	('expression', 'MPA', (98, 108))
721585	30664196	The present study revealed that the expression levels of asTF were increased in Caco-2 cells that overexpressed apoM compared with the control cells.	('Caco-2', 'CellLine', 'CVCL:0025', (80, 86))	('asTF', 'Chemical', '-', (57, 61))	('increased', 'PosReg', (67, 76))	('overexpressed', 'Var', (98, 111))	('asTF', 'Gene', (57, 61))	('expression levels', 'MPA', (36, 53))	('apoM', 'Gene', (112, 116))	('apoM', 'Gene', '55937', (112, 116))
721590	30664196	The results of the present study demonstrated that as one of the bile acids, CDCA increased the expression levels of the two TF variants in the EA.hy926 cells and apoM increased as TF expression in Caco-2 cells.	('CDCA', 'Chemical', 'MESH:D002635', (77, 81))	('increased', 'PosReg', (168, 177))	('EA.hy926', 'CellLine', 'CVCL:3901', (144, 152))	('expression levels', 'MPA', (96, 113))	('Caco-2', 'CellLine', 'CVCL:0025', (198, 204))	('bile acids', 'Chemical', 'MESH:D001647', (65, 75))	('TF', 'Gene', '2152', (181, 183))	('variants', 'Var', (128, 136))	('CDCA', 'Gene', (77, 81))	('apoM', 'Gene', (163, 167))	('TF', 'Gene', '2152', (125, 127))	('increased', 'PosReg', (82, 91))	('apoM', 'Gene', '55937', (163, 167))
721594	30664196	The present study demonstrated that the measurement of asTF mRNA may be associated with cervical cancer risk.	('cervical cancer', 'Disease', (88, 103))	('asTF mRNA', 'MPA', (55, 64))	('cervical cancer', 'Disease', 'MESH:D002583', (88, 103))	('associated', 'Reg', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('asTF', 'Chemical', '-', (55, 59))	('measurement', 'Var', (40, 51))	('men', 'Species', '9606', (47, 50))
721630	29451177	However, the prevalence of PVT was higher in patients with CTP class B and C, hepatocellular carcinoma, and previous upper gastrointestinal bleeding.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('upper gastrointestinal bleeding', 'Disease', 'MESH:D006471', (117, 148))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (123, 148))	('hepatocellular carcinoma', 'Disease', (78, 102))	('CTP class B', 'Var', (59, 70))	('patients', 'Species', '9606', (45, 53))	('CTP', 'Chemical', '-', (59, 62))	('PVT', 'Phenotype', 'HP:0030242', (27, 30))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (78, 102))	('PVT', 'Disease', (27, 30))	('previous upper gastrointestinal bleeding', 'Phenotype', 'HP:0002788', (108, 148))	('upper gastrointestinal bleeding', 'Disease', (117, 148))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (78, 102))	('higher', 'PosReg', (35, 41))
721640	28870211	The median calculated biological effective dose using the LQ model with alpha/beta = 10 Gy (BED10) in patients in whom re-irradiation was performed was significantly lower than the median BED10 in others.	('LQ', 'Chemical', '-', (58, 60))	('alpha/beta = 10 Gy', 'Var', (72, 90))	('patients', 'Species', '9606', (102, 110))	('BED', 'Disease', (92, 95))	('BED', 'Disease', (188, 191))	('lower', 'NegReg', (166, 171))	('biological effective dose', 'MPA', (22, 47))	('BED', 'Disease', 'MESH:C564092', (92, 95))	('BED', 'Disease', 'MESH:C564092', (188, 191))
721715	27544058	Patients excluded from analysis included: clinical M1, M1A, or M1B metastatic disease, tumors located in the cervical esophagus, and those that did not receive an esophagectomy.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('M1A', 'Var', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('Patients', 'Species', '9606', (0, 8))	('M1B', 'Var', (63, 66))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('metastatic disease', 'CPA', (67, 85))
721748	27544058	While the NCDB does not record cancer recurrence or disease free survival, a previous pooled analysis of pCR patients (after neoadjuvant chemoradiation and esophagectomy) documented cancer recurrence in approximately 30% of ypT0N0M0 patients, with a median time to recurrence of 12 months, and median disease-free survival of 48 months.	('ypT0N0M0', 'Var', (224, 232))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('patients', 'Species', '9606', (109, 117))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (182, 188))	('patients', 'Species', '9606', (233, 241))	('cancer', 'Disease', (31, 37))
721761	27544058	If the rates of neoadjuvant therapy completion are actually lower among chemoradiation patients compared to chemotherapy patients, this could potentially influence long-term survival.	('chemoradiation', 'Var', (72, 86))	('influence', 'Reg', (154, 163))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (121, 129))	('lower', 'NegReg', (60, 65))
721850	24759662	The key rationale of endoscopic treatment is to resect and/or ablate the dysplastic mucosa, followed by acid suppression to permit re-epithelialization with neosquamous mucosa.	('dysplastic mucosa', 'Disease', 'MESH:D004416', (73, 90))	('dysplastic mucosa', 'Disease', (73, 90))	('ablate', 'Var', (62, 68))
721852	24759662	By eradicating dysplasia and intestinal metaplasia (IM), the cancer rate may decrease, leading to improved survival.	('eradicating', 'Var', (3, 14))	('survival', 'MPA', (107, 115))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('decrease', 'NegReg', (77, 85))	('cancer', 'Disease', (61, 67))	('dysplasia and intestinal metaplasia', 'Disease', 'MESH:D008679', (15, 50))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('improved', 'PosReg', (98, 106))
721867	24759662	Young age at diagnosis, presence of multifocal LGD and LGD on several biopsy sessions may pose a higher risk of progression and, hence, are candidates for ablation.	('multifocal', 'Var', (36, 46))	('LGD', 'Disease', 'None', (55, 58))	('LGD', 'Disease', (55, 58))	('progression', 'MPA', (112, 123))	('LGD', 'Disease', 'None', (47, 50))	('LGD', 'Disease', (47, 50))
721890	24759662	There are two commercially available devices to perform RFA in the esophagus: the HALO360 and HALO90 (BARRX Medical, Inc, Sunnyvale, CA, USA).	('HALO90', 'CellLine', 'CVCL:1B47', (94, 100))	('HALO360', 'Var', (82, 89))	('HALO90', 'Var', (94, 100))
721899	24759662	Increased reduction of BE surface area and complete eradication of BE were noted in patients with normal-mild-, compared to moderate-severe, EAE (99 vs 95%).	('patients', 'Species', '9606', (84, 92))	('BE', 'Phenotype', 'HP:0100580', (67, 69))	('EAE', 'Disease', (141, 144))	('BE', 'Phenotype', 'HP:0100580', (23, 25))	('BE surface area', 'CPA', (23, 38))	('reduction', 'NegReg', (10, 19))	('normal-mild-', 'Var', (98, 110))
721905	24759662	In a retrospective study of 79 subjects with T1-T4 cancer and a mean tumor burden of 4 cm, complete response of intraluminal disease was seen in 61% (75% with mucosal cancer), with 13% developing benign strictures.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mucosal cancer', 'Disease', (159, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Disease', (69, 74))	('T1-T4', 'Var', (45, 50))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('intraluminal disease', 'Disease', (112, 132))	('intraluminal disease', 'Disease', 'MESH:D004194', (112, 132))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mucosal cancer', 'Disease', 'MESH:D009062', (159, 173))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
722008	33669692	However, the most exploited is the second one, thanks to which the DeltaT occurring within the tissue subjected to heating can be determined as described in the following equation: where phi(T) and phi(T0) are the phases of the image in the current and initial instants at the corresponding temperatures T and T0, respectively.	('phi(T', 'Var', (187, 192))	('phi(T0', 'Var', (198, 204))	('DeltaT', 'Mutation', 'c.delT', (67, 73))
722031	33669692	The time delay, t, of a reflected wave at temperature T0 depends on the position (z) and the speed of sound in a given material at T0 temperature (c0 (T0)), as shown in the following equation:  The DeltaT experienced by material causes two main phenomena: thermal expansion and change in the speed of sound.	('DeltaT', 'Mutation', 'c.delT', (198, 204))	('DeltaT', 'Var', (198, 204))	('speed of sound', 'MPA', (292, 306))	('thermal expansion', 'CPA', (256, 273))
722065	33669692	The main drawbacks are represented by: single point measurements (unless additional probes are inserted, however, making the working area very crowded); and measurement errors due to the interaction between the RF electromagnetic field and the metallic components from which thermocouples and thermistors' connecting wires are made.	('errors', 'Var', (169, 175))	('metal', 'Chemical', 'MESH:D008670', (244, 249))	('due', 'Reg', (176, 179))	('interaction', 'Interaction', (187, 198))
722104	31989830	The DGR region recognizes ETGE and DLG motifs in the Neh2 domain of NRF2 protein.	('Neh2', 'Gene', '252969', (53, 57))	('ETGE', 'Var', (26, 30))	('DLG motifs', 'Var', (35, 45))	('Neh2', 'Gene', (53, 57))	('NRF2', 'Gene', (68, 72))
722107	31989830	The highly reactive cysteine residues, Cys151, Cys171, Cys273, and Cys288, are located in the BTB-IVR domains of KEAP1 protein.	('Cys288', 'Chemical', '-', (67, 73))	('KEAP1', 'Gene', (113, 118))	('Cys273', 'Var', (55, 61))	('Cys171', 'Var', (47, 53))	('Cys151', 'Var', (39, 45))	('Cys171', 'Chemical', '-', (47, 53))	('cysteine', 'Chemical', 'MESH:D003545', (20, 28))	('BTB', 'Chemical', '-', (94, 97))	('Cys273', 'Chemical', '-', (55, 61))	('KEAP1', 'Gene', '9817', (113, 118))	('Cys151', 'Chemical', '-', (39, 45))	('Cys288', 'Var', (67, 73))
722109	31989830	Cys151 of KEAP1 was found to facilitate NRF2 activity, whereas Cys288 was shown to diminish NRF2 activity.	('activity', 'MPA', (45, 53))	('NRF2', 'Enzyme', (40, 44))	('KEAP1', 'Gene', '9817', (10, 15))	('KEAP1', 'Gene', (10, 15))	('Cys151', 'Chemical', '-', (0, 6))	('NRF2 activity', 'MPA', (92, 105))	('facilitate', 'PosReg', (29, 39))	('Cys288', 'Var', (63, 69))	('Cys288', 'Chemical', '-', (63, 69))	('diminish', 'NegReg', (83, 91))	('Cys151', 'Var', (0, 6))
722110	31989830	Modification of redox-sensitive cysteines (Cys119, Cys235) of NRF2 prevents KEAP1 recognition and binding.	('binding', 'Interaction', (98, 105))	('prevents', 'NegReg', (67, 75))	('Cys235', 'Chemical', '-', (51, 57))	('NRF2', 'Gene', (62, 66))	('KEAP1', 'Gene', '9817', (76, 81))	('cysteines', 'Chemical', 'MESH:D003545', (32, 41))	('Cys119', 'Chemical', '-', (43, 49))	('Cys119', 'Var', (43, 49))	('Cys235', 'Var', (51, 57))	('KEAP1', 'Gene', (76, 81))
722111	31989830	Modification of those residues alters the conformation of KEAP1, causing detachment of the DLG motif (low-affinity binding site) from the KEAP1-NRF2 complex.	('conformation', 'MPA', (42, 54))	('KEAP1', 'Gene', '9817', (58, 63))	('KEAP1', 'Gene', '9817', (138, 143))	('detachment', 'MPA', (73, 83))	('Modification', 'Var', (0, 12))	('KEAP1', 'Gene', (58, 63))	('KEAP1', 'Gene', (138, 143))	('alters', 'Reg', (31, 37))
722130	31989830	For instance, the mutation of fumarate hydratase in papillary renal cell carcinoma leads to fumarate accumulation, which induces KEAP1 succination and NRF2 stabilization.	('fumarate', 'Chemical', 'MESH:D005650', (92, 100))	('fumarate hydratase', 'Gene', '2271', (30, 48))	('fumarate', 'Chemical', 'MESH:D005650', (30, 38))	('fumarate accumulation', 'MPA', (92, 113))	('fumarate hydratase', 'Gene', (30, 48))	('leads to', 'Reg', (83, 91))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (52, 82))	('KEAP1', 'Gene', '9817', (129, 134))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (52, 82))	('NRF2 stabilization', 'MPA', (151, 169))	('induces', 'Reg', (121, 128))	('mutation', 'Var', (18, 26))	('papillary renal cell carcinoma', 'Disease', (52, 82))	('KEAP1', 'Gene', (129, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
722133	31989830	Finally, glycation destabilizes NRF2 via increased proteasomal degradation in hepatocellular carcinoma (HCC).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('HCC', 'Phenotype', 'HP:0001402', (104, 107))	('increased', 'PosReg', (41, 50))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (78, 102))	('proteasomal degradation', 'MPA', (51, 74))	('destabilizes', 'NegReg', (19, 31))	('HCC', 'Gene', (104, 107))	('glycation', 'Var', (9, 18))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (78, 102))	('HCC', 'Gene', '619501', (104, 107))	('hepatocellular carcinoma', 'Disease', (78, 102))	('NRF2', 'Protein', (32, 36))
722142	31989830	Although this study did not elucidate a mechanism of action, Cordycepin may induce caveolin-1 (Cav-1) expression.	('caveolin-1', 'Gene', (83, 93))	('expression', 'MPA', (102, 112))	('Cav-1', 'Gene', (95, 100))	('Cordycepin', 'Var', (61, 71))	('caveolin-1', 'Gene', '857', (83, 93))	('induce', 'PosReg', (76, 82))	('Cav-1', 'Gene', '857', (95, 100))
722147	31989830	In breast cancer cells, NRF2 translocation to the nucleus is induced by 15d-PGJ2, resulting in enhanced interaction between NRF2 with ARE to drive the expression of a variety of phase 2 detoxifying and antioxidant enzymes.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('NRF2', 'Gene', (24, 28))	('15d-PGJ2', 'Var', (72, 80))	('interaction', 'Interaction', (104, 115))	('breast cancer', 'Disease', (3, 16))	('expression', 'MPA', (151, 161))	('NRF2', 'Gene', (124, 128))	('15d-PGJ2', 'Chemical', 'MESH:C477819', (72, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('drive', 'PosReg', (141, 146))	('translocation', 'MPA', (29, 42))	('enhanced', 'PosReg', (95, 103))
722166	31989830	DPP3 expression and copy number were increased in NFE2L2 wild-type and KEAP1 mutant tumors as compared with NFE2L2 mutant or KEAP1 wild-type tumors.	('expression', 'MPA', (5, 15))	('DPP3', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('NFE2L2', 'Gene', '4780', (108, 114))	('increased', 'PosReg', (37, 46))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (141, 147))	('KEAP1', 'Gene', '9817', (71, 76))	('tumors', 'Disease', (84, 90))	('NFE2L2', 'Gene', '4780', (50, 56))	('copy number', 'MPA', (20, 31))	('NFE2L2', 'Gene', (108, 114))	('KEAP1', 'Gene', (71, 76))	('KEAP1', 'Gene', '9817', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('KEAP1', 'Gene', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('mutant', 'Var', (77, 83))	('NFE2L2', 'Gene', (50, 56))	('DPP3', 'Gene', '10072', (0, 4))
722175	31989830	Hence, the expression of antioxidant genes, such as HMOX1 an NQO1, in response to H2O2 treatment is enhanced.	('HMOX1', 'Gene', '3162', (52, 57))	('expression', 'MPA', (11, 21))	('enhanced', 'PosReg', (100, 108))	('NQO1', 'Gene', (61, 65))	('NQO1', 'Gene', '1728', (61, 65))	('H2O2', 'Chemical', 'MESH:D006861', (82, 86))	('H2O2', 'Var', (82, 86))	('HMOX1', 'Gene', (52, 57))	('antioxidant genes', 'Gene', (25, 42))
722177	31989830	During the initiation of the autophagy cascade, p62 binds to KEAP1 and initiates NRF2 transactivation of target genes.	('KEAP1', 'Gene', (61, 66))	('transactivation', 'MPA', (86, 101))	('binds', 'Interaction', (52, 57))	('initiates', 'Reg', (71, 80))	('p62', 'Var', (48, 51))	('KEAP1', 'Gene', '9817', (61, 66))	('NRF2', 'Gene', (81, 85))
722178	31989830	As an autophagy substrate, p62 can also interfere with NRF2-KEAP1 interaction through binding to the DLG/ETGE motif and activating NRF2.	('KEAP1', 'Gene', (60, 65))	('interaction', 'Interaction', (66, 77))	('interfere', 'NegReg', (40, 49))	('p62', 'Var', (27, 30))	('binding', 'Interaction', (86, 93))	('NRF2', 'Gene', (131, 135))	('KEAP1', 'Gene', '9817', (60, 65))	('activating', 'PosReg', (120, 130))
722179	31989830	The role of p62 in NRF2 transactivation was confirmed in hepatic adenoma, HCC, breast and ovarian cancers, and in glioma.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('glioma', 'Disease', (114, 120))	('HCC', 'Gene', '619501', (74, 77))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('hepatic adenoma', 'Disease', (57, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('hepatic adenoma', 'Disease', 'MESH:D000236', (57, 72))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('transactivation', 'PosReg', (24, 39))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('NRF2', 'Gene', (19, 23))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (79, 105))	('ovarian cancers', 'Phenotype', 'HP:0100615', (90, 105))	('hepatic adenoma', 'Phenotype', 'HP:0012028', (57, 72))	('p62', 'Var', (12, 15))	('HCC', 'Gene', (74, 77))
722180	31989830	The expression of p62 and oligomerization in the cytosol is also a negative prognostic factor in HCC recurrence.	('HCC', 'Phenotype', 'HP:0001402', (97, 100))	('p62', 'Var', (18, 21))	('HCC', 'Gene', (97, 100))	('oligomerization', 'Var', (26, 41))	('HCC', 'Gene', '619501', (97, 100))
722190	31989830	Studies assessing statistics of genetic alterations in lung cancer demonstrate frequent loss-of-function (LOF) mutations in KEAP1 and loss-of-heterozygosity at the genetic locus of KEAP1.	('mutations', 'Var', (111, 120))	('KEAP1', 'Gene', '9817', (181, 186))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('KEAP1', 'Gene', (181, 186))	('KEAP1', 'Gene', '9817', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('KEAP1', 'Gene', (124, 129))	('loss-of-function', 'NegReg', (88, 104))	('loss-of-heterozygosity', 'NegReg', (134, 156))
722191	31989830	KEAP1 missense or nonsense mutations have been also identified in malignant melanoma, thyroid cancer, HCC, endometrial carcinoma, and breast and ovarian cancers.	('malignant melanoma', 'Phenotype', 'HP:0002861', (66, 84))	('thyroid cancer', 'Disease', 'MESH:D013964', (86, 100))	('malignant melanoma', 'Disease', 'MESH:D008545', (66, 84))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('endometrial carcinoma', 'Disease', (107, 128))	('ovarian cancers', 'Phenotype', 'HP:0100615', (145, 160))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (134, 160))	('KEAP1', 'Gene', '9817', (0, 5))	('thyroid cancer', 'Phenotype', 'HP:0002890', (86, 100))	('KEAP1', 'Gene', (0, 5))	('HCC', 'Gene', '619501', (102, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (107, 128))	('HCC', 'Gene', (102, 105))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (107, 128))	('nonsense mutations', 'Var', (18, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (145, 159))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('malignant melanoma', 'Disease', (66, 84))	('thyroid cancer', 'Disease', (86, 100))	('identified', 'Reg', (52, 62))	('missense', 'Var', (6, 14))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
722192	31989830	In summary, mutations of KEAP1 that confer loss of function or hypomorphic function induce NRF2 activity.	('activity', 'MPA', (96, 104))	('NRF2', 'Protein', (91, 95))	('KEAP1', 'Gene', '9817', (25, 30))	('mutations', 'Var', (12, 21))	('induce', 'Reg', (84, 90))	('KEAP1', 'Gene', (25, 30))
722193	31989830	The genetic mutation of NFE2L2 affecting the DLG/ETGE motif of the Neh2 domain was shown in a lung cancer cell line, renal cell carcinoma, HCC, skin cancer, and esophageal carcinoma.	('renal cell carcinoma', 'Disease', (117, 137))	('DLG/ETGE motif', 'MPA', (45, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (117, 137))	('Neh2', 'Gene', '252969', (67, 71))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (161, 181))	('affecting', 'Reg', (31, 40))	('lung cancer', 'Disease', (94, 105))	('skin cancer', 'Disease', (144, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('HCC', 'Gene', (139, 142))	('NFE2L2', 'Gene', '4780', (24, 30))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('skin cancer', 'Phenotype', 'HP:0008069', (144, 155))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (161, 181))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (117, 137))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('esophageal carcinoma', 'Disease', (161, 181))	('HCC', 'Gene', '619501', (139, 142))	('HCC', 'Phenotype', 'HP:0001402', (139, 142))	('NFE2L2', 'Gene', (24, 30))	('skin cancer', 'Disease', 'MESH:D012878', (144, 155))	('Neh2', 'Gene', (67, 71))	('mutation', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
722194	31989830	A unique genetic mutation, deletion of the NFE2L2 exon 2, was found to stabilize NRF2 and enhance its activity in nonsmall-cell lung carcinoma (NSCLC) and head-neck cancer.	('NSCLC', 'Disease', (144, 149))	('NFE2L2', 'Gene', (43, 49))	('NRF2', 'Protein', (81, 85))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('enhance', 'PosReg', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('deletion', 'Var', (27, 35))	('nonsmall-cell lung carcinoma', 'Disease', 'MESH:D002289', (114, 142))	('activity', 'MPA', (102, 110))	('stabilize', 'MPA', (71, 80))	('head-neck cancer', 'Disease', 'MESH:D006258', (155, 171))	('neck cancer', 'Phenotype', 'HP:0012288', (160, 171))	('NFE2L2', 'Gene', '4780', (43, 49))	('head-neck cancer', 'Disease', (155, 171))	('nonsmall-cell lung carcinoma', 'Disease', (114, 142))
722195	31989830	Moreover, copy number loss of Cul3 or inactivating mutation of RBx1, which controls NRF2 degradation, was shown in esophageal and ovarian cancer, as well as in thyroid and renal cell carcinoma.	('Cul3', 'Gene', '8452', (30, 34))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (172, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (130, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('inactivating mutation', 'Var', (38, 59))	('thyroid and renal cell carcinoma', 'Disease', 'MESH:C538614', (160, 192))	('ovarian cancer', 'Disease', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('RBx1', 'Gene', '9978', (63, 67))	('ovarian cancer', 'Phenotype', 'HP:0100615', (130, 144))	('esophageal', 'Disease', (115, 125))	('RBx1', 'Gene', (63, 67))	('copy number loss', 'Var', (10, 26))	('Cul3', 'Gene', (30, 34))
722196	31989830	A recent study identified two single nucleotide polymorphisms of KEAP1 associated with shorter relapse-free survival in breast carcinoma.	('breast carcinoma', 'Disease', (120, 136))	('KEAP1', 'Gene', '9817', (65, 70))	('breast carcinoma', 'Disease', 'MESH:D001943', (120, 136))	('KEAP1', 'Gene', (65, 70))	('shorter', 'NegReg', (87, 94))	('relapse-free survival', 'CPA', (95, 116))	('breast carcinoma', 'Phenotype', 'HP:0003002', (120, 136))	('single nucleotide polymorphisms', 'Var', (30, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('associated', 'Reg', (71, 81))
722198	31989830	Our search in the TCGA-BRCA dataset revealed prominent amplification of DPP3 and p62 genes, which suggests amplification of NRF2 activity in breast cancer by noncanonical mechanisms (Fig.	('amplification', 'Var', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('NRF2', 'Gene', (124, 128))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('DPP3', 'Gene', '10072', (72, 76))	('p62 genes', 'Gene', (81, 90))	('activity', 'MPA', (129, 137))	('breast cancer', 'Disease', (141, 154))	('DPP3', 'Gene', (72, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))
722199	31989830	Epigenetic modification in KEAP1 or NFE2L2 promoter regions can also contribute to NRF2 stabilization in many cancers.	('KEAP1', 'Gene', '9817', (27, 32))	('stabilization', 'MPA', (88, 101))	('NFE2L2', 'Gene', (36, 42))	('cancers', 'Disease', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('NRF2', 'Protein', (83, 87))	('KEAP1', 'Gene', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('contribute', 'Reg', (69, 79))	('NFE2L2', 'Gene', '4780', (36, 42))	('Epigenetic modification', 'Var', (0, 23))
722201	31989830	Hypomethylation, due to the reduced expression of EZH2 methyltransferase, is associated with NRF2 overexpression in colon cancer.	('reduced', 'NegReg', (28, 35))	('expression', 'MPA', (36, 46))	('overexpression', 'PosReg', (98, 112))	('Hypomethylation', 'Var', (0, 15))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('NRF2', 'Gene', (93, 97))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('colon cancer', 'Disease', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('EZH2', 'Gene', (50, 54))
722202	31989830	Hypermethylation of the NFE2L2 promoter is associated with prostate cancer and leads to reduced NRF2 activity, a rare example among malignant diseases.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('NFE2L2', 'Gene', '4780', (24, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('malignant diseases', 'Disease', (132, 150))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('Hypermethylation', 'Var', (0, 16))	('NFE2L2', 'Gene', (24, 30))	('activity', 'MPA', (101, 109))	('NRF2', 'Protein', (96, 100))	('associated', 'Reg', (43, 53))	('prostate cancer', 'Disease', (59, 74))	('reduced', 'NegReg', (88, 95))	('malignant diseases', 'Disease', 'MESH:D009369', (132, 150))
722206	31989830	KEAP1 hypermethylation is associated with lung, colorectal, breast, prostate, thyroid, and renal cancers, as well as malignant glioma.	('malignant glioma', 'Disease', (117, 133))	('thyroid', 'Disease', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('malignant glioma', 'Disease', 'MESH:D005910', (117, 133))	('hypermethylation', 'Var', (6, 22))	('colorectal', 'Disease', (48, 58))	('KEAP1', 'Gene', (0, 5))	('lung', 'Disease', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('prostate', 'Disease', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('renal cancers', 'Disease', 'MESH:D007680', (91, 104))	('renal cancers', 'Disease', (91, 104))	('breast', 'Disease', (60, 66))	('KEAP1', 'Gene', '9817', (0, 5))	('associated', 'Reg', (26, 36))
722209	31989830	The miRNAs, miR-507, miR-634, miR450a, miR129-5p miR-340, miR-146b, and miR144, were reported to directly suppress NRF2 activation in different cancer types, including acute myeloid leukemia (AML), breast cancer, and esophageal cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (174, 190))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('miR-634', 'Gene', '693219', (21, 28))	('AML', 'Disease', 'MESH:D015470', (192, 195))	('miR-507', 'Gene', '574512', (12, 19))	('cancer', 'Disease', (144, 150))	('miR129-5p miR-340', 'Var', (39, 56))	('AML', 'Disease', (192, 195))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('suppress', 'NegReg', (106, 114))	('AML', 'Phenotype', 'HP:0004808', (192, 195))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Disease', (198, 211))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (168, 190))	('leukemia', 'Phenotype', 'HP:0001909', (182, 190))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (168, 190))	('esophageal cancer', 'Disease', 'MESH:D004938', (217, 234))	('miR-340', 'Var', (49, 56))	('miR144', 'Gene', '406936', (72, 78))	('miR-146b', 'Gene', (58, 66))	('cancer', 'Disease', (228, 234))	('esophageal cancer', 'Disease', (217, 234))	('miR144', 'Gene', (72, 78))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('miR-634', 'Gene', (21, 28))	('activation', 'MPA', (120, 130))	('miR-507', 'Gene', (12, 19))	('acute myeloid leukemia', 'Disease', (168, 190))	('miR-146b', 'Gene', '574447', (58, 66))	('miR450a', 'Var', (30, 37))	('NRF2', 'Protein', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
722212	31989830	For example, miR-155 promotes lung cancer and miR93a and miR153 drive the malignant transformation of the breast.	('miR153', 'Chemical', '-', (57, 63))	('malignant transformation of the breast', 'CPA', (74, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('miR153', 'Gene', (57, 63))	('lung cancer', 'Disease', (30, 41))	('drive', 'Reg', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('miR-155', 'Gene', (13, 20))	('promotes', 'PosReg', (21, 29))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('miR93a', 'Var', (46, 52))	('miR-155', 'Gene', '406947', (13, 20))
722223	31989830	The importance of Ras signaling is highlighted by the findings that H-Ras-activated HO-1 overexpression is abolished by ERK inhibitors or NFE2L2 knockdown.	('NFE2L2', 'Gene', (138, 144))	('knockdown', 'Var', (145, 154))	('overexpression', 'PosReg', (89, 103))	('abolished', 'NegReg', (107, 116))	('NFE2L2', 'Gene', '4780', (138, 144))	('HO-1', 'Gene', (84, 88))	('ERK', 'Gene', '5594', (120, 123))	('H-Ras', 'Gene', '3265', (68, 73))	('H-Ras', 'Gene', (68, 73))	('ERK', 'Gene', (120, 123))	('HO-1', 'Gene', '3162', (84, 88))
722224	31989830	In K-Ras-associated malignancies, the elevated expression of antioxidant genes (HMOX1 and NQO1) is associated with an aggressive phenotype, whereas the elimination of NRF2 disrupts malignant progression and restores sensitivity to cancer therapy.	('K-Ras', 'Gene', (3, 8))	('sensitivity', 'MPA', (216, 227))	('elevate', 'Disease', 'MESH:D006973', (38, 45))	('HMOX1', 'Gene', '3162', (80, 85))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('expression', 'MPA', (47, 57))	('restores', 'PosReg', (207, 215))	('NQO1', 'Gene', '1728', (90, 94))	('disrupts', 'NegReg', (172, 180))	('K-Ras', 'Gene', '3845', (3, 8))	('malignant progression', 'CPA', (181, 202))	('elimination', 'Var', (152, 163))	('NRF2', 'Gene', (167, 171))	('associated', 'Reg', (99, 109))	('HMOX1', 'Gene', (80, 85))	('NQO1', 'Gene', (90, 94))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('malignancies', 'Disease', 'MESH:D009369', (20, 32))	('malignancies', 'Disease', (20, 32))	('elevate', 'Disease', (38, 45))
722226	31989830	Interestingly, NFE2L2 knockdown in normal organoids was tolerated, whereas NRF2 knockdown was detrimental in tumor-derived organoids.	('NFE2L2', 'Gene', (15, 21))	('knockdown', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('NFE2L2', 'Gene', '4780', (15, 21))	('NRF2', 'Gene', (75, 79))	('tumor', 'Disease', (109, 114))
722230	31989830	Further, in Keap1-deficient mice, PI3K-AKT activation leads to NRF2 nuclear accumulation and NRF2-driven cell proliferation of hepatocytes.	('NRF2', 'Gene', (63, 67))	('mice', 'Species', '10090', (28, 32))	('Keap1', 'Gene', '50868', (12, 17))	('nuclear accumulation', 'MPA', (68, 88))	('Keap1', 'Gene', (12, 17))	('PI3K-AKT', 'Var', (34, 42))	('cell proliferation of', 'CPA', (105, 126))
722242	31989830	The p62-dependent NRF2 activation also occurs in a carfilzomib- (proteasome inhibitor) resistant model of multiple myeloma.	('multiple myeloma', 'Disease', (106, 122))	('NRF2', 'Gene', (18, 22))	('multiple myeloma', 'Phenotype', 'HP:0006775', (106, 122))	('activation', 'PosReg', (23, 33))	('carfilzomib', 'Chemical', 'MESH:C524865', (51, 62))	('multiple myeloma', 'Disease', 'MESH:D009101', (106, 122))	('p62-dependent', 'Var', (4, 17))
722250	31989830	These changes collectively lead to NRF2-mediated gene expression and contribute to the development of HCC in xenograft animals.	('HCC', 'Gene', (102, 105))	('HCC', 'Gene', '619501', (102, 105))	('changes', 'Var', (6, 13))	('NRF2-mediated gene', 'Gene', (35, 53))	('lead to', 'Reg', (27, 34))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('contribute', 'Reg', (69, 79))
722254	31989830	The S349 residue of p62 can be phosphorylated by class III PtdIns3 lipid kinase (VPS34), whereas VPS34 induces NRF2-dependent expression of p62 and induces the noncanonical activation of NRF2.	('lipid', 'Chemical', 'MESH:D008055', (67, 72))	('S349', 'Var', (4, 8))	('VPS34', 'Gene', '5289', (81, 86))	('NRF2', 'Pathway', (187, 191))	('induces', 'Reg', (148, 155))	('VPS34', 'Gene', (81, 86))	('expression', 'MPA', (126, 136))	('p62', 'Gene', (140, 143))	('induces', 'Reg', (103, 110))	('VPS34', 'Gene', '5289', (97, 102))	('VPS34', 'Gene', (97, 102))	('noncanonical activation', 'MPA', (160, 183))
722255	31989830	Moreover, VPS34 promotes PKCdelta-dependent phosphorylation of p62, also on S349, that not only strengthens the interaction between NRF2 and p62 in response to caspase inhibitor treatment but also activates downstream signaling pathways leading to tumor formation, including the MEK/ERK pathway.	('phosphorylation', 'MPA', (44, 59))	('tumor', 'Disease', (248, 253))	('response to caspase inhibitor treatment', 'MPA', (148, 187))	('ERK', 'Gene', '5594', (283, 286))	('MEK', 'Gene', (279, 282))	('VPS34', 'Gene', '5289', (10, 15))	('MEK', 'Gene', '5609', (279, 282))	('activates', 'PosReg', (197, 206))	('VPS34', 'Gene', (10, 15))	('S349', 'Var', (76, 80))	('ERK', 'Gene', (283, 286))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('NRF2', 'Protein', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('strengthens', 'PosReg', (96, 107))	('PKCdelta', 'Gene', '5580', (25, 33))	('PKCdelta', 'Gene', (25, 33))	('interaction', 'Interaction', (112, 123))
722256	31989830	In terms of generic carbon rewiring for energy metabolism, HCC expressing pS349-p62, reprogram both glucose and glutamine metabolism, marked by the induction of the glucuronate pathway and glutamine-derived glutathione synthesis in an NRF2-dependent manner.	('HCC', 'Phenotype', 'HP:0001402', (59, 62))	('carbon', 'Chemical', 'MESH:D002244', (20, 26))	('glucose', 'Chemical', 'MESH:D005947', (100, 107))	('pS349-p62', 'Var', (74, 83))	('glutamine-derived glutathione synthesis', 'MPA', (189, 228))	('glucuronate', 'Chemical', 'MESH:D020723', (165, 176))	('glucuronate pathway', 'Pathway', (165, 184))	('HCC', 'Gene', (59, 62))	('glutamine', 'Chemical', 'MESH:D005973', (112, 121))	('induction', 'PosReg', (148, 157))	('glutathione', 'Chemical', 'MESH:D005978', (207, 218))	('HCC', 'Gene', '619501', (59, 62))	('glutamine', 'Chemical', 'MESH:D005973', (189, 198))	('reprogram', 'Reg', (85, 94))
722261	31989830	In accordance with this suggestion, reduced ATP induces NRF2 activity, causing an alteration in redox balance, as recently described in lung carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('alteration', 'Reg', (82, 92))	('NRF2', 'Gene', (56, 60))	('lung carcinoma', 'Disease', 'MESH:D008175', (136, 150))	('lung carcinoma', 'Disease', (136, 150))	('causing', 'Reg', (71, 78))	('induces', 'Reg', (48, 55))	('redox balance', 'MPA', (96, 109))	('activity', 'MPA', (61, 69))	('reduced', 'Var', (36, 43))	('ATP', 'Chemical', 'MESH:D000255', (44, 47))
722265	31989830	In principle, inhibition of SLC7A11, depletion of intracellular cysteine and glutathione, and lipid peroxidation suppress GPX4 activity and initiate ferroptosis.	('lipid peroxidation', 'MPA', (94, 112))	('GPX4', 'Gene', (122, 126))	('GPX4', 'Gene', '2879', (122, 126))	('ferroptosis', 'CPA', (149, 160))	('glutathione', 'MPA', (77, 88))	('suppress', 'NegReg', (113, 121))	('SLC7A11', 'Gene', (28, 35))	('initiate', 'PosReg', (140, 148))	('cysteine', 'Chemical', 'MESH:D003545', (64, 72))	('lipid', 'Chemical', 'MESH:D008055', (94, 99))	('inhibition', 'Var', (14, 24))	('glutathione', 'Chemical', 'MESH:D005978', (77, 88))
722271	31989830	Also, in KrasG12D, TP53-/- lung adenocarcinoma cells, the expression of the KEAP1 LOF mutant induces SLC7A11, which boosts GSH and reduces ROS levels.	('GSH', 'MPA', (123, 126))	('reduces', 'NegReg', (131, 138))	('lung adenocarcinoma', 'Disease', (27, 46))	('Kras', 'Gene', (9, 13))	('LOF', 'NegReg', (82, 85))	('induces', 'Reg', (93, 100))	('TP53', 'Gene', (19, 23))	('GSH', 'Chemical', '-', (123, 126))	('SLC7A11', 'Gene', (101, 108))	('boosts', 'PosReg', (116, 122))	('Kras', 'Gene', '16653', (9, 13))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (27, 46))	('mutant', 'Var', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('ROS levels', 'MPA', (139, 149))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (27, 46))	('KEAP1', 'Gene', '9817', (76, 81))	('TP53', 'Gene', '7157', (19, 23))	('KEAP1', 'Gene', (76, 81))	('ROS', 'Chemical', 'MESH:D017382', (139, 142))
722272	31989830	Moreover, the repression of xCT impairs colony formation in Ras-transformed cell models.	('repression', 'Var', (14, 24))	('colony formation', 'CPA', (40, 56))	('xCT', 'Gene', (28, 31))	('xCT', 'Gene', '23657', (28, 31))	('impairs', 'NegReg', (32, 39))
722275	31989830	Recent evidence also indicates that depletion of ovarian tumor family member deubiquitinase (OTUB1) or the inactivation of breast cancer type 1 susceptibility protein (BRCA1) associated protein 1 (BAP1) tumor suppressor in breast cancer leads to induction of xCT in an NRF2/hypoxia-inducible factor 1alpha (HIF1alpha)-dependent fashion, which protects cancer cells from ferroptosis.	('ovarian tumor', 'Phenotype', 'HP:0100615', (49, 62))	('tumor', 'Disease', (203, 208))	('OTUB1', 'Gene', '55611', (93, 98))	('cancer', 'Disease', (352, 358))	('NRF2/hypoxia-inducible factor 1alpha', 'Gene', '4780;3091', (269, 305))	('depletion', 'MPA', (36, 45))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('breast cancer type 1 susceptibility protein', 'Gene', (123, 166))	('breast cancer', 'Disease', (223, 236))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('xCT', 'Gene', '23657', (259, 262))	('NRF2/hypoxia-inducible factor 1alpha', 'Gene', (269, 305))	('inactivation', 'Var', (107, 119))	('BAP1', 'Gene', '8314', (197, 201))	('cancer', 'Disease', (230, 236))	('induction', 'Reg', (246, 255))	('OTUB1', 'Gene', (93, 98))	('ovarian tumor', 'Disease', (49, 62))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('ovarian tumor', 'Disease', 'MESH:D010051', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('breast cancer type 1 susceptibility protein', 'Gene', '672', (123, 166))	('xCT', 'Gene', (259, 262))	('HIF1alpha', 'Gene', '3091', (307, 316))	('BAP1', 'Gene', (197, 201))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('BRCA1) associated protein 1', 'Gene', '8314;672', (168, 195))	('cancer', 'Disease', (130, 136))	('HIF1alpha', 'Gene', (307, 316))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
722276	31989830	It should be noted that a high level of NRF2 accumulation, which is achieved by the functional impairment of KEAP1 or NRF2 hyperactivation, combined with sustained oncogenic signaling, allows NRF2 to modulate metabolism under pathological conditions.	('modulate', 'Reg', (200, 208))	('KEAP1', 'Gene', (109, 114))	('accumulation', 'PosReg', (45, 57))	('NRF2', 'Gene', (118, 122))	('hyperactivation', 'Var', (123, 138))	('metabolism', 'MPA', (209, 219))	('KEAP1', 'Gene', '9817', (109, 114))
722280	31989830	The knockdown of SLC7A11 rescues viability in glucose-free conditions.	('viability', 'MPA', (33, 42))	('rescues', 'PosReg', (25, 32))	('SLC7A11', 'Gene', (17, 24))	('glucose', 'Chemical', 'MESH:D005947', (46, 53))	('knockdown', 'Var', (4, 13))
722281	31989830	Inhibition of xCT in nonsmall lung cancer cells improves survival in glucose-free medium, when bioenergetics rely primarily on mitochondrial OXPHOS through glutamine oxidation.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('glucose', 'Chemical', 'MESH:D005947', (69, 76))	('nonsmall lung cancer', 'Disease', 'MESH:D002289', (21, 41))	('glutamine', 'Chemical', 'MESH:D005973', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('xCT', 'Gene', (14, 17))	('nonsmall lung cancer', 'Disease', (21, 41))	('xCT', 'Gene', '23657', (14, 17))	('glutamine oxidation', 'MPA', (156, 175))	('Inhibition', 'Var', (0, 10))	('improves', 'PosReg', (48, 56))	('mitochondrial OXPHOS', 'MPA', (127, 147))	('survival', 'CPA', (57, 65))
722283	31989830	Thus, the export glutamate via the Xc- system due to the expression of SLC7A11 maintains glucose addiction for survival.	('SLC7A11', 'Gene', (71, 78))	('glutamate', 'Chemical', 'MESH:D018698', (17, 26))	('glucose addiction', 'MPA', (89, 106))	('export glutamate via the Xc- system', 'MPA', (10, 45))	('expression', 'Var', (57, 67))	('glucose', 'Chemical', 'MESH:D005947', (89, 96))	('maintains', 'PosReg', (79, 88))
722292	31989830	Thus, a combination of KI696, a compound inhibiting KEAP1-NRF2 interaction, with CB-839 is another plausible strategy to target NRF2 overexpressing cancers.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('KEAP1', 'Gene', '9817', (52, 57))	('NRF2', 'Gene', (128, 132))	('interaction', 'Interaction', (63, 74))	('KI696', 'Var', (23, 28))	('inhibiting', 'NegReg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('KEAP1', 'Gene', (52, 57))	('overexpressing', 'PosReg', (133, 147))	('CB-839', 'Chemical', 'MESH:C000593334', (81, 87))	('KI696', 'Chemical', '-', (23, 28))
722306	31989830	Strikingly, NRF2 silencing suppresses HIF1alpha accumulation in breast cancer cells under hypoxic conditions.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('HIF1alpha', 'Gene', (38, 47))	('HIF1alpha', 'Gene', '3091', (38, 47))	('suppresses', 'NegReg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('NRF2', 'Gene', (12, 16))	('silencing', 'Var', (17, 26))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
722308	31989830	Inhibition of metabolic adaptations eventually impairs the viability of NRF2-silenced cancer cells in a hypoxic environment.	('viability', 'CPA', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('metabolic adaptations', 'CPA', (14, 35))	('impairs', 'NegReg', (47, 54))	('iron', 'Chemical', 'MESH:D007501', (115, 119))	('Inhibition', 'Var', (0, 10))	('NRF2-silenced', 'Gene', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
722315	31989830	Moreover, loss of NRF2 inhibited HIF1alpha accumulation and VEGF induction, resulting in reduced angiogenesis in colorectal carcinoma cells; this effect was mediated by the induction of HIF1alpha hydroxylation in hypoxia.	('loss', 'Var', (10, 14))	('VEGF', 'Gene', '7422', (60, 64))	('angiogenesis', 'CPA', (97, 109))	('HIF1alpha', 'Gene', '3091', (33, 42))	('NRF2', 'Gene', (18, 22))	('inhibited', 'NegReg', (23, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('hypoxia', 'Disease', 'MESH:D000860', (213, 220))	('VEGF', 'Gene', (60, 64))	('colorectal carcinoma', 'Disease', (113, 133))	('hypoxia', 'Disease', (213, 220))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (113, 133))	('reduced', 'NegReg', (89, 96))	('HIF1alpha', 'Gene', (33, 42))	('HIF1alpha', 'Gene', '3091', (186, 195))	('HIF1alpha', 'Gene', (186, 195))
722319	31989830	Oxidative PPP converts G6P, a glycolytic intermediate, into ribulose-5-phosphate and generates NADPH, which is used for GSH regeneration, detoxification, and biosynthesis of lipids.	('NADPH', 'Gene', (95, 100))	('PPP', 'Var', (10, 13))	('NADPH', 'Gene', '1666', (95, 100))	('G6P', 'Chemical', '-', (23, 26))	('ribulose-5-phosphate', 'Chemical', 'MESH:C031524', (60, 80))	('lipids', 'Chemical', 'MESH:D008055', (174, 180))	('GSH', 'Chemical', '-', (120, 123))
722328	31989830	Polyamines, such as putrescine, spermine, and spermidine, have unknown biological function and accumulate in cancer cells, resulting in increased proliferation.	('Polyamines', 'Chemical', 'MESH:D011073', (0, 10))	('spermidine', 'Var', (46, 56))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('putrescine', 'Chemical', 'MESH:D011700', (20, 30))	('proliferation', 'CPA', (146, 159))	('spermidine', 'Chemical', 'MESH:D013095', (46, 56))	('spermine', 'Var', (32, 40))	('cancer', 'Disease', (109, 115))	('spermine', 'Chemical', 'MESH:D013096', (32, 40))	('increased', 'PosReg', (136, 145))	('accumulate', 'PosReg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
722332	31989830	MAT2A expression is upregulated in TAMR-MCF-7 cells compared with control MCF-7 cells.	('MCF-7', 'CellLine', 'CVCL:0031', (40, 45))	('MAT2A', 'Gene', '4144', (0, 5))	('expression', 'MPA', (6, 16))	('TAMR-MCF-7', 'Var', (35, 45))	('MAT2A', 'Gene', (0, 5))	('upregulated', 'PosReg', (20, 31))	('TAMR', 'Chemical', '-', (35, 39))	('MCF-7', 'CellLine', 'CVCL:0031', (74, 79))
722348	31989830	Inhibition of NRF2 and the antioxidant system (Txns and GSH) inhibits sphere formation and cancer growth in vivo.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('NRF2', 'Protein', (14, 18))	('GSH', 'Chemical', '-', (56, 59))	('Inhibition', 'Var', (0, 10))	('inhibits', 'NegReg', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('sphere formation', 'CPA', (70, 86))
722350	31989830	The induction of NRF2 in CD44+ cells is dependent on the noncanonical activation of NRF2 through p62, and NRF2 induction facilitates spheroid formation and induces chemoresistance to 5-fluorouracil and doxorubicin.	('5-fluorouracil', 'Chemical', 'MESH:D005472', (183, 197))	('CD44', 'Gene', '960', (25, 29))	('induction', 'Var', (111, 120))	('facilitates', 'PosReg', (121, 132))	('doxorubicin', 'Chemical', 'MESH:D004317', (202, 213))	('CD44', 'Gene', (25, 29))	('chemoresistance', 'CPA', (164, 179))	('induces', 'Reg', (156, 163))	('spheroid formation', 'CPA', (133, 151))	('NRF2', 'Gene', (106, 110))
722351	31989830	Formation of spheroids and xenografts is suppressed after NRF2 silencing in CD44high cells in the same studies.	('CD44', 'Gene', (76, 80))	('NRF2', 'Gene', (58, 62))	('suppressed', 'NegReg', (41, 51))	('CD44', 'Gene', '960', (76, 80))	('silencing', 'Var', (63, 72))
722354	31989830	NRF2 expression in TCGA datasets also corresponds with the expression of E/M markers (high ZEB1, high miR-200) and elevated NRF2 expression correlates with a worse prognosis of breast cancer.	('high', 'Var', (97, 101))	('breast cancer', 'Disease', (177, 190))	('NRF2', 'Gene', (0, 4))	('expression', 'MPA', (129, 139))	('elevate', 'Disease', 'MESH:D006973', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('NRF2', 'Gene', (124, 128))	('ZEB1', 'Gene', '6935', (91, 95))	('ZEB1', 'Gene', (91, 95))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('elevate', 'Disease', (115, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))
722355	31989830	In cell models of breast cancer, NRF2 overexpression or KEAP1 knockdown promotes cell migration (assessed by wound healing assay) and invasion (transwell invasion assay) through G6pd and possibly Notch1 induction.	('Notch1', 'Gene', (196, 202))	('Notch1', 'Gene', '4851', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('KEAP1', 'Gene', '9817', (56, 61))	('breast cancer', 'Disease', (18, 31))	('G6pd', 'Gene', '2539', (178, 182))	('invasion', 'CPA', (134, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('overexpression', 'PosReg', (38, 52))	('G6pd', 'Gene', (178, 182))	('NRF2', 'Gene', (33, 37))	('KEAP1', 'Gene', (56, 61))	('promotes', 'PosReg', (72, 80))	('cell migration', 'CPA', (81, 95))	('knockdown', 'Var', (62, 71))
722367	31989830	In Drosophila, NRF2 expression extends the lifespan and induces tolerance to paraquat treatment.	('extends', 'PosReg', (31, 38))	('paraquat', 'Chemical', 'MESH:D010269', (77, 85))	('tolerance to paraquat treatment', 'MPA', (64, 95))	('expression', 'Var', (20, 30))	('lifespan', 'CPA', (43, 51))	('induces', 'Reg', (56, 63))	('NRF2', 'Gene', (15, 19))	('Drosophila', 'Species', '7227', (3, 13))
722385	31989830	Further, NRF2 activity modulates the function of antigen-presenting dendritic cells and T cells, implying a modality to improve anticancer immune response.	('function', 'MPA', (37, 45))	('cancer', 'Disease', (132, 138))	('improve', 'PosReg', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('activity', 'Var', (14, 22))	('NRF2', 'Gene', (9, 13))	('dendritic', 'Disease', 'MESH:D007635', (68, 77))	('dendritic', 'Disease', (68, 77))	('modulates', 'Reg', (23, 32))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
722388	31989830	The modulation of NRF2 tone will likely impact the sensitivity of tumors to chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('modulation', 'Var', (4, 14))	('impact', 'Reg', (40, 46))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('NRF2', 'Protein', (18, 22))	('sensitivity', 'MPA', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))
722392	31989830	beta-TrCP beta-transducin repeat-containing protein 4-OHE2 4-Hydroxyestradiol 15d-PGJ2 15-deoxy-prostaglandin J2 AKT protein kinase B ALDH1 aldehyde-dehydrogenase 1 AMER1 Wilms tumor gene on the X chromosome AML acute myeloid leukemia AMPK AMP-activated protein kinase ARE antioxidant response element ATF4 activating transcription factor 4 Bach1 BTB and CNC homology 1 BAP1 BRCA1 associated protein 1 BRCA1 breast cancer type 1 susceptibility protein BRCA2 breast cancer type 2 susceptibility protein BRD4 bromodomain protein 4 BTB Broad complex/Tramtrack/Bric-a-brac bZIP basic leucine zipper domain Cav-1 caveolin-1 CDK20 cyclin-dependent kinase 20 CDO1 cysteine dioxygenase 1 CHD6 chromodomain helicase DNA binding protein 6 COX-2 cyclooxygenase-2 CSC cancer stem cell CTCs circulating tumor cells CTR carboxy-terminal Cul3 cullin 3 DGR double glycine repeats DPP3 dipeptidyl peptidase 3 E/M epithelial/mesenchymal EMT epithelial-mesenchymal transition EpRE electrophilic response element ERK extracellular signal-regulated kinase FAM129B family with sequence similarity 129, member B FH fumarate hydratase G6pd glucose-6-phosphate dehydrogenase GCL glutamate-cysteine ligase GCLC glutamate-cysteine ligase catalytic GCLM glutamate-cysteine ligase modifier Gpx2 glutathione peroxidase 2 GRP78 heat shock 70 kDa protein 5 GSH reduced glutathione GSK3 glycogen synthase kinase 3 GSK3beta glycogen synthase kinase 3beta Gsr1 glutathione reductase 1 GSSG oxidized glutathione GST glutathione S-transferase HCC hepatocellular carcinoma HER2 human epidermal growth receptor 2, HER2/neu, cErbb2 HIF1alpha hypoxia-inducible factor 1alpha HMOX1 heme oxygenase (decycling) 1 Idh1 isocitrate dehydrogenase 1 IVR intervening region KEAP1 Kelch-like ECH-associated protein 1 KHK-A ketohexokinase-A LCA lithocholic acid LOF loss-of-function MAT methionine adenosyltransferase MAT2A methionine adenosyltransferase 2A Me1 malic enzyme 1 MEK mitogen activated protein kinase kinase MET mesenchymal-epithelial transition MICA not defined as abbreviation miRNA microRNA MnSOD manganese-dependent superoxide dismutase Mrps multidrug-resistance-associated transporters Mrp1 multidrug resistance-associated protein 1 MSLP maximum species lifespan potential mTORC1 mechanistic (or mammalian) target of rapamycin complex 1 N/A not applicable NFE2 nuclear factor erythroid 2 Neh NRF2-ECH homology NQO1 NAD(P)H quinone dehydrogenase 1 NRF2 NFE2-related factor 2 (Nfe2l2, commonly called NRF2) NSCLC nonsmall-cell lung carcinoma OGG1 8-Oxoguanine glycosylase OTUB1 ovarian tumor family member deubiquitinase p62 sequestosome 1 PALB2 partner and localizer of BRCA2 PDAC pancreatic ductal adenocarcinoma PERK protein kinase R-like endoplasmic reticulum kinase Pgd 6-phosphogluconate dehydrogenase PI3K phosphoinositide 3-kinases PPP pentose-phosphate pathway PUFA polyunsaturated fatty acid RARalpha retinoic acid receptor X receptor alpha ROS oxygen-centered reactive species RXRalpha retinoid X receptor alpha SLC7A11 solute carrier family 7 member 11 Srxn1 sulfiredoxin 1 TAMR tamoxifen-resistant TCA tricarboxylic acid cycle TKT transketolase TP53 gene encoding for tumor protein P53 Txn1 thioredoxin 1 Txnrd1 thioredoxin reductase 1 UHRF1 ubiquitin-like, containing PHD and RING finger domains-1 UPR unfolded protein response VEGF vascular endothelial growth factor WTX Wilms tumor gene on the X chromosome xCT protein encoded by SLC7A11	('methionine adenosyltransferase 2A', 'Gene', (1872, 1905))	('6-phosphogluconate dehydrogenase', 'Gene', '26227', (2739, 2771))	('GSK3beta', 'Gene', '2931', (1381, 1389))	('glucose-6-phosphate dehydrogenase', 'Gene', (1116, 1149))	('transketolase', 'Gene', '7086', (3108, 3121))	('PDAC', 'Chemical', '-', (2641, 2645))	('protein kinase B', 'Gene', '2185', (117, 133))	('GCLC', 'Gene', (1180, 1184))	('glutamate-cysteine ligase catalytic', 'Gene', '2729', (1185, 1220))	('UHRF1', 'Gene', (3213, 3218))	('activating transcription factor 4', 'Gene', (307, 340))	('GCL', 'Gene', (1221, 1224))	('glutathione', 'Chemical', 'MESH:D005978', (1464, 1475))	('fumarate hydratase', 'Gene', (1092, 1110))	('cyclooxygenase-2', 'Gene', '5743', (735, 751))	('caveolin-1', 'Gene', (608, 618))	('NAD(P)H quinone dehydrogenase 1', 'Gene', '1728', (2381, 2412))	('AMER1', 'Gene', (165, 170))	('CDO1', 'Gene', (652, 656))	('TCA', 'Chemical', 'MESH:D014238', (3075, 3078))	('hypoxia-inducible factor 1', 'Gene', '3091', (1602, 1628))	('beta-TrCP', 'Gene', '8945', (0, 9))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (3079, 3097))	('cancer', 'Phenotype', 'HP:0002664', (415, 421))	('BRCA2', 'Gene', (452, 457))	('Wilms tumor', 'Disease', (171, 182))	('glutamate-cysteine ligase', 'Gene', '2729', (1154, 1179))	('acute myeloid leukemia', 'Disease', (212, 234))	('WTX', 'Gene', (3346, 3349))	('cancer', 'Disease', 'MESH:D009369', (756, 762))	('15d-PGJ2', 'Chemical', 'MESH:C477819', (78, 86))	('HMOX1', 'Gene', '3162', (1634, 1639))	('glycine', 'Chemical', 'MESH:D005998', (848, 855))	('MAT2A', 'Gene', (1866, 1871))	('ketohexokinase', 'Gene', '3795', (1772, 1786))	('thioredoxin reductase 1', 'Gene', '7296', (3189, 3212))	('PUFA', 'Gene', (2834, 2838))	('GSK3beta', 'Gene', (1381, 1389))	('AMP-activated protein kinase', 'Gene', '5564', (240, 268))	('BAP1', 'Gene', '8314', (370, 374))	('GCL', 'Gene', '2729', (1150, 1153))	('malic enzyme 1', 'Gene', '4199', (1910, 1924))	('LCA', 'Chemical', 'MESH:D008095', (1789, 1792))	('GCLM', 'Gene', (1221, 1225))	('GCLC', 'Gene', '2729', (1180, 1184))	('breast cancer', 'Phenotype', 'HP:0003002', (408, 421))	('pentose-phosphate', 'Chemical', 'MESH:D010428', (2808, 2825))	('Cul3', 'Gene', (823, 827))	('BRCA2', 'Gene', '675', (452, 457))	('isocitrate dehydrogenase 1', 'Gene', (1674, 1700))	('ATF4', 'Gene', (302, 306))	('isocitrate dehydrogenase 1', 'Gene', '3417', (1674, 1700))	('ketohexokinase', 'Gene', (1772, 1786))	('BAP1', 'Gene', (370, 374))	('Bach1', 'Gene', (341, 346))	('ATF4', 'Gene', '468', (302, 306))	('Srxn1', 'Gene', (3029, 3034))	('Nfe2l2', 'Gene', '4780', (2441, 2447))	('OGG1', 'Gene', (2506, 2510))	('UHRF1', 'Gene', '29128', (3213, 3218))	('Wilms tumor', 'Disease', 'MESH:D009396', (171, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cysteine dioxygenase 1', 'Gene', '1036', (657, 679))	('xCT', 'Gene', '23657', (3387, 3390))	('GCL', 'Gene', (1150, 1153))	('superoxide', 'Chemical', 'MESH:D013481', (2081, 2091))	('KEAP1', 'Gene', '9817', (1724, 1729))	('hepatocellular carcinoma', 'Disease', (1510, 1534))	('VEGF', 'Gene', '7422', (3306, 3310))	('HER2', 'Gene', (1575, 1579))	('NFE2-related factor 2', 'Gene', (2418, 2439))	('AMPK', 'Gene', (235, 239))	('Txnrd1', 'Gene', '7296', (3182, 3188))	('leucine', 'Chemical', 'MESH:D007930', (580, 587))	('glutathione', 'Chemical', 'MESH:D005978', (1480, 1491))	('GCL', 'Gene', (1180, 1183))	('tumor', 'Disease', (790, 795))	('aldehyde-dehydrogenase 1', 'Gene', (140, 164))	('3 E/M', 'Var', (890, 895))	('Kelch-like ECH-associated protein 1', 'Gene', (1730, 1765))	('Wilms tumor', 'Phenotype', 'HP:0002667', (171, 182))	('HER2', 'Gene', (1535, 1539))	('MICA', 'Gene', (2007, 2011))	('tumor', 'Disease', (3145, 3150))	('GSSG', 'Chemical', 'MESH:D019803', (1450, 1454))	('MEK', 'Gene', '5609', (1925, 1928))	('ALDH1', 'Gene', '216', (134, 139))	('BRD4', 'Gene', (502, 506))	('shock', 'Phenotype', 'HP:0031273', (1302, 1307))	('PDAC', 'Phenotype', 'HP:0006725', (2641, 2645))	('protein kinase B', 'Gene', (117, 133))	('ovarian tumor', 'Disease', (2542, 2555))	('tumor', 'Disease', 'MESH:D009369', (790, 795))	('COX-2', 'Gene', (729, 734))	('tamoxifen', 'Chemical', 'MESH:D013629', (3055, 3064))	('cancer', 'Disease', 'MESH:D009369', (465, 471))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (2646, 2678))	('tumor', 'Disease', 'MESH:D009369', (3145, 3150))	('malic enzyme 1', 'Gene', (1910, 1924))	('glutamate-cysteine ligase', 'Gene', '2729', (1226, 1251))	('NQO1', 'Gene', (2376, 2380))	('MAT', 'Gene', (1866, 1869))	('AML', 'Disease', (208, 211))	('Cul3', 'Gene', '8452', (823, 827))	('mTORC1', 'Gene', (2239, 2245))	('Cav-1', 'Gene', (602, 607))	('4-Hydroxyestradiol', 'Chemical', 'MESH:C014036', (59, 77))	('KHK', 'Gene', '3795', (1766, 1769))	('NSCLC', 'Disease', 'MESH:D002289', (2471, 2476))	('Gpx2', 'Gene', '2877', (1261, 1265))	('4-OHE2', 'Chemical', 'MESH:C014036', (52, 58))	('Bach1', 'Gene', '571', (341, 346))	('Cav-1', 'Gene', '857', (602, 607))	('glutathione reductase', 'Gene', '2936', (1426, 1447))	('mTORC1', 'Gene', '382056', (2239, 2245))	('HER2', 'Gene', '2064', (1575, 1579))	('6-phosphogluconate dehydrogenase', 'Gene', (2739, 2771))	('15-deoxy-prostaglandin J2', 'Chemical', 'MESH:C477819', (87, 112))	('MAT', 'Gene', '4143', (1866, 1869))	('nonsmall-cell lung carcinoma', 'Disease', 'MESH:D002289', (2477, 2505))	('methionine adenosyltransferase 2A', 'Gene', '4144', (1872, 1905))	('COX-2', 'Gene', '5743', (729, 734))	('glutamate-cysteine ligase catalytic', 'Gene', (1185, 1220))	('ALDH1', 'Gene', (134, 139))	('vascular endothelial growth factor', 'Gene', '7422', (3311, 3345))	('oxygen', 'Chemical', 'MESH:D010100', (668, 674))	('HER2', 'Gene', '2064', (1535, 1539))	('nonsmall-cell lung carcinoma', 'Disease', (2477, 2505))	('cancer', 'Disease', 'MESH:D009369', (415, 421))	('glutamate-cysteine ligase', 'Gene', '2729', (1185, 1210))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (212, 234))	('BRCA1 associated protein', 'Gene', '8315', (375, 399))	('TKT', 'Gene', '7086', (3104, 3107))	('aldehyde-dehydrogenase 1', 'Gene', '216', (140, 164))	('1 N/A', 'SUBSTITUTION', 'None', (2301, 2306))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (212, 234))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (2646, 2678))	('breast cancer', 'Disease', 'MESH:D001943', (408, 421))	('TKT', 'Gene', (3104, 3107))	('MAT', 'Gene', (1831, 1834))	('ovarian tumor', 'Phenotype', 'HP:0100615', (2542, 2555))	('rapamycin', 'Chemical', 'MESH:D020123', (2283, 2292))	('TAMR', 'Chemical', '-', (3050, 3054))	('OGG1', 'Gene', '4968', (2506, 2510))	('HMOX1', 'Gene', (1634, 1639))	('mammalian', 'Species', '9606', (2262, 2271))	('DPP3', 'Gene', '10072', (864, 868))	('tumor', 'Phenotype', 'HP:0002664', (2550, 2555))	('cancer', 'Disease', (756, 762))	('carcinoma', 'Phenotype', 'HP:0030731', (2669, 2678))	('BRCA2', 'Gene', (2635, 2640))	('FAM129B', 'Gene', '64855', (1035, 1042))	('protein kinase R-like endoplasmic reticulum kinase', 'Gene', '9451', (2684, 2734))	('GSH', 'Chemical', '-', (1325, 1328))	('tumor', 'Phenotype', 'HP:0002664', (3356, 3361))	('1 N/A', 'Var', (2301, 2306))	('protein kinase R-like endoplasmic reticulum kinase', 'Gene', (2684, 2734))	('MAT', 'Gene', '4143', (1831, 1834))	('KHK', 'Gene', (1766, 1769))	('breast cancer type 1 susceptibility protein', 'Gene', (408, 451))	('3 E/M', 'SUBSTITUTION', 'None', (890, 895))	('AMPK', 'Gene', '5564', (235, 239))	('Me1', 'Gene', '4199', (1906, 1909))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (218, 234))	('glutamate-cysteine ligase', 'Gene', (1154, 1179))	('oxygen', 'Chemical', 'MESH:D010100', (2919, 2925))	('cullin', 'Gene', '143384', (828, 834))	('NQO1', 'Gene', '1728', (2376, 2380))	('FAM129B', 'Gene', (1035, 1042))	('cancer', 'Disease', (415, 421))	('BTB', 'Chemical', '-', (529, 532))	('MnSOD', 'Gene', '6648', (2055, 2060))	('Txnrd1', 'Gene', (3182, 3188))	('glutathione reductase', 'Gene', (1426, 1447))	('BTB', 'Chemical', '-', (347, 350))	('carcinoma', 'Phenotype', 'HP:0030731', (1525, 1534))	('breast cancer', 'Phenotype', 'HP:0003002', (458, 471))	('TP53', 'Gene', (3122, 3126))	('ovarian tumor', 'Disease', 'MESH:D010051', (2542, 2555))	('CHD6', 'Gene', '84181', (680, 684))	('BRCA2', 'Gene', '675', (2635, 2640))	('PERK', 'Gene', (2679, 2683))	('xCT', 'Gene', (3387, 3390))	('HCC', 'Phenotype', 'HP:0001402', (1506, 1509))	('OTUB1', 'Gene', '55611', (2536, 2541))	('human', 'Species', '9606', (1540, 1545))	('tumor', 'Disease', (177, 182))	('G6pd', 'Gene', '2539', (1111, 1115))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (1510, 1534))	('cyclooxygenase-2', 'Gene', (735, 751))	('breast cancer', 'Disease', (458, 471))	('ERK', 'Gene', (993, 996))	('sequestosome 1', 'Gene', (2589, 2603))	('hypoxia-inducible factor 1', 'Gene', (1602, 1628))	('transketolase', 'Gene', (3108, 3121))	('leukemia', 'Phenotype', 'HP:0001909', (226, 234))	('NFE2-related factor 2', 'Gene', '4780', (2418, 2439))	('FH', 'Disease', 'MESH:D006938', (1089, 1091))	('AMP-activated protein kinase', 'Gene', (240, 268))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('fumarate hydratase', 'Gene', '2271', (1092, 1110))	('Wilms tumor', 'Phenotype', 'HP:0002667', (3350, 3361))	('oxygen', 'Chemical', 'MESH:D010100', (1645, 1651))	('heme', 'Chemical', 'MESH:D006418', (1640, 1644))	('NSCLC', 'Disease', (2471, 2476))	('activating transcription factor 4', 'Gene', '468', (307, 340))	('glucose-6-phosphate dehydrogenase', 'Gene', '2539', (1116, 1149))	('GCL', 'Gene', '2729', (1221, 1224))	('glutathione peroxidase 2', 'Gene', '2877', (1266, 1290))	('WTX', 'Gene', '139285', (3346, 3349))	('PALB2', 'Gene', (2604, 2609))	('Pgd', 'Gene', '26227', (2735, 2738))	('lithocholic acid', 'Chemical', 'MESH:D008095', (1793, 1809))	('Nfe2l2', 'Gene', (2441, 2447))	('Gpx2', 'Gene', (1261, 1265))	('cancer', 'Disease', (465, 471))	('ERK', 'Gene', (2680, 2683))	('cullin', 'Gene', (828, 834))	('Wilms tumor', 'Disease', (3350, 3361))	('BRCA1 associated protein', 'Gene', (375, 399))	('GCLM', 'Gene', '2730', (1221, 1225))	('MAT2A', 'Gene', '4144', (1866, 1871))	('glutathione', 'Chemical', 'MESH:D005978', (1337, 1348))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (1730, 1765))	('Srxn1', 'Gene', '140809', (3029, 3034))	('HIF1alpha', 'Gene', (1592, 1601))	('PALB2', 'Gene', '79728', (2604, 2609))	('reduced', 'NegReg', (1329, 1336))	('CHD6', 'Gene', (680, 684))	('pancreatic ductal adenocarcinoma', 'Disease', (2646, 2678))	('KEAP1', 'Gene', (1724, 1729))	('Pgd', 'Gene', (2735, 2738))	('ROS', 'Chemical', 'MESH:D017382', (2915, 2918))	('glutathione', 'Chemical', 'MESH:D005978', (1266, 1277))	('sequestosome 1', 'Gene', '8878', (2589, 2603))	('glutamate-cysteine ligase', 'Gene', (1226, 1251))	('cancer', 'Phenotype', 'HP:0002664', (756, 762))	('VEGF', 'Gene', (3306, 3310))	('DPP3', 'Gene', (864, 868))	('ERK', 'Gene', '5594', (993, 996))	('neu', 'Gene', '2064', (1580, 1583))	('beta-TrCP', 'Gene', (0, 9))	('MET', 'Gene', (1969, 1972))	('caveolin-1', 'Gene', '857', (608, 618))	('GRP78', 'Gene', '3309', (1291, 1296))	('HCC', 'Gene', '619501', (1506, 1509))	('GRP78', 'Gene', (1291, 1296))	('AML', 'Disease', 'MESH:D015470', (208, 211))	('AML', 'Phenotype', 'HP:0004808', (208, 211))	('MnSOD', 'Gene', (2055, 2060))	('Idh1', 'Gene', '3417', (1669, 1673))	('MEK', 'Gene', (1925, 1928))	('Wilms tumor', 'Disease', 'MESH:D009396', (3350, 3361))	('HCC', 'Gene', (1506, 1509))	('tumor', 'Disease', (2550, 2555))	('breast cancer', 'Disease', 'MESH:D001943', (458, 471))	('CDO1', 'Gene', '1036', (652, 656))	('AMER1', 'Gene', '139285', (165, 170))	('ERK', 'Gene', '5594', (2680, 2683))	('CDK20', 'Gene', '23552', (619, 624))	('tumor', 'Phenotype', 'HP:0002664', (790, 795))	('tumor', 'Disease', (3356, 3361))	('tumor', 'Disease', 'MESH:D009369', (2550, 2555))	('GCL', 'Gene', '2729', (1180, 1183))	('BRD4', 'Gene', '23476', (502, 506))	('carcinoma', 'Phenotype', 'HP:0030731', (2496, 2505))	('PERK', 'Gene', '9451', (2679, 2683))	('breast cancer type 1 susceptibility protein', 'Gene', '672', (408, 451))	('BTB and CNC homology 1', 'Gene', '571', (347, 369))	('tumor', 'Phenotype', 'HP:0002664', (3145, 3150))	('G6pd', 'Gene', (1111, 1115))	('MICA', 'Gene', '100507436', (2007, 2011))	('MET', 'Gene', '79811', (1969, 1972))	('tumor', 'Disease', 'MESH:D009369', (3356, 3361))	('Idh1', 'Gene', (1669, 1673))	('neu', 'Gene', (1580, 1583))	('OTUB1', 'Gene', (2536, 2541))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (1510, 1534))	('cysteine dioxygenase 1', 'Gene', (657, 679))	('CDK20', 'Gene', (619, 624))	('thioredoxin reductase 1', 'Gene', (3189, 3212))	('TP53', 'Gene', '7157', (3122, 3126))	('HIF1alpha', 'Gene', '3091', (1592, 1601))	('polyunsaturated fatty acid', 'Chemical', 'MESH:D005231', (2839, 2865))	('oxygen', 'Chemical', 'MESH:D010100', (740, 746))	('Me1', 'Gene', (1906, 1909))	('vascular endothelial growth factor', 'Gene', (3311, 3345))	('ubiquitin-like, containing PHD and RING finger domains-1', 'Gene', '29128', (3219, 3275))	('glutathione', 'Chemical', 'MESH:D005978', (1426, 1437))	('cancer', 'Phenotype', 'HP:0002664', (465, 471))	('PUFA', 'Gene', '9933', (2834, 2838))	('glutathione peroxidase 2', 'Gene', (1266, 1290))
722398	30275518	We also found that telomere shortening and smoking have a significantly synergistic effect in intensifying risk of GCA (OR = 7.03, 95% CI = 4.55-10.86, P = 1.43 x 10-18).	('telomere shortening', 'Phenotype', 'HP:0031413', (19, 38))	('GCA', 'Gene', '25801', (115, 118))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('GCA', 'Gene', (115, 118))	('telomere shortening', 'Var', (19, 38))
722403	30275518	found a U-shaped association between telomere length and risk of gastric adenocarcinoma in the Singapore Chinese Health Study.	('telomere length', 'Var', (37, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (65, 87))	('gastric adenocarcinoma', 'Disease', (65, 87))	('S', 'Chemical', 'MESH:D013455', (120, 121))	('S', 'Chemical', 'MESH:D013455', (95, 96))
722407	30275518	However, GCA and esophageal cancer may have similar patterns of age and sex distribution and morphology and share common environmental risk factors such as cigarette smoking, heavy alcohol consumption, dietary carcinogen exposure, low-intake of fruits and vegetables and gastroesophageal reflux disease.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('esophageal cancer', 'Disease', (17, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (17, 34))	('men', 'Species', '9606', (128, 131))	('GCA', 'Gene', (9, 12))	('alcohol', 'Chemical', 'MESH:D000438', (181, 188))	('GC', 'Phenotype', 'HP:0012126', (9, 11))	('GCA', 'Gene', '25801', (9, 12))	('low-intake', 'Var', (231, 241))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (271, 294))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (271, 302))	('gastroesophageal reflux disease', 'Disease', (271, 302))	('heavy alcohol consumption', 'Phenotype', 'HP:0030955', (175, 200))
722433	30275518	With an adjustment for age, sex, smoking status and drinking status, we found a significantly elevated GCA risk (OR = 1.71; 95% CI = 1.31-2.24; P = 9.05 x 10-5) among patients with short RTL.	('men', 'Species', '9606', (14, 17))	('elevated', 'PosReg', (94, 102))	('GC', 'Phenotype', 'HP:0012126', (103, 105))	('patients', 'Species', '9606', (167, 175))	('GCA', 'Gene', '25801', (103, 106))	('GCA', 'Gene', (103, 106))	('short RTL', 'Var', (181, 190))
722434	30275518	Quartiles analyses of RTL showed that individuals with the first quartile of the shortest RTL (RTL < 0.898) had a doubled GCA risk (OR = 2.18; 95% CI = 1.47-3.22; P = 9.90 x 10-5) when compared with those in the fourth quartile of the longest RTL (RTL >= 1.448).	('GCA', 'Gene', '25801', (122, 125))	('GC', 'Phenotype', 'HP:0012126', (122, 124))	('GCA', 'Gene', (122, 125))	('RTL < 0.898', 'Var', (95, 106))
722435	30275518	In addition, when compared with the lowest risk individuals in the fourth quartile, the adjusted OR (95% CI) of RTL among cases in the second (RTL = 0.898-1.179) and third (RTL = 1.180-1.447) quartiles were 1.49 (95% CI = 1.00-2.22) and 2.07 (95% CI = 1.40-3.04) respectively, indicating a significant dose-response relationship between telomere length shortening and increased GCA risk.	('GC', 'Phenotype', 'HP:0012126', (378, 380))	('GCA', 'Gene', '25801', (378, 381))	('increased', 'PosReg', (368, 377))	('GCA', 'Gene', (378, 381))	('telomere length shortening', 'Var', (337, 363))	('telomere length shortening', 'Phenotype', 'HP:0031413', (337, 363))
722436	30275518	When stratified by host characteristics, the similar association between short telomere length and elevated GCA risk were observed in each stratum (Table 3).	('short telomere length', 'Phenotype', 'HP:0031413', (73, 94))	('GCA', 'Gene', '25801', (108, 111))	('short telomere length', 'Var', (73, 94))	('GCA', 'Gene', (108, 111))	('elevated', 'PosReg', (99, 107))	('GC', 'Phenotype', 'HP:0012126', (108, 110))	('short telomere', 'Phenotype', 'HP:0031413', (73, 87))
722437	30275518	Interestingly, short RTL was associated with a higher risk of GCA among men (OR = 1.43, 95% CI = 1.07-1.92), but not in females (OR = 1.17, 95% CI = 0.59-2.36).	('GC', 'Phenotype', 'HP:0012126', (62, 64))	('GCA', 'Gene', '25801', (62, 65))	('GCA', 'Gene', (62, 65))	('short RTL', 'Var', (15, 24))	('men', 'Species', '9606', (72, 75))
722438	30275518	Moreover, short telomere length tended to be more pronouncedly associated with increased risk of GCA among persons with high-risk profile such as cigarette smoking (OR = 2.21; 95% CI = 1.35-3.64) and alcohol drinking (OR = 2.18; 95% CI = 1.33-3.60).	('short telomere length', 'Phenotype', 'HP:0031413', (10, 31))	('short telomere length', 'Var', (10, 31))	('associated', 'Reg', (63, 73))	('GCA', 'Gene', '25801', (97, 100))	('GCA', 'Gene', (97, 100))	('short telomere', 'Phenotype', 'HP:0031413', (10, 24))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('persons', 'Species', '9606', (107, 114))	('alcohol', 'Chemical', 'MESH:D000438', (200, 207))	('alcohol drinking', 'Phenotype', 'HP:0030955', (200, 216))
722439	30275518	In contrast, the ORs for GCA risk in individuals with short RTL were 1.59 (95% CI = 1.14-2.22) among current nonsmokers and 1.58 (95% CI = 1.14-2.20) for nondrinkers, respectively.	('short RTL', 'Var', (54, 63))	('GCA', 'Gene', '25801', (25, 28))	('GCA', 'Gene', (25, 28))	('GC', 'Phenotype', 'HP:0012126', (25, 27))
722441	30275518	As shown in Table 4, although nonsmokers with short RTL had an increased risk of GCA (adjusted OR = 1.65; 95% CI = 1.19-2.28) than nonsmokers having long RTL, the group of smokers with short RTL had highest GCA risk, with the OR being 7.03 (95% CI = 4.55-10.86, P = 1.43 x 10-18), even higher than the product of the OR for smokers with long RTL (adjusted OR = 3.79; 95% CI = 2.36-6.09) and the OR for nonsmokers with short RTL (i.e., 1.65 x 3.79 = 6.25).	('GC', 'Phenotype', 'HP:0012126', (207, 209))	('GCA', 'Gene', (207, 210))	('GCA', 'Gene', '25801', (81, 84))	('short RTL', 'Var', (185, 194))	('GCA', 'Gene', (81, 84))	('GCA', 'Gene', '25801', (207, 210))	('GC', 'Phenotype', 'HP:0012126', (81, 83))
722442	30275518	These results showed that smoking and short RTL in peripheral blood leukocytes had a synergistic effect on risk of GCA (Table 4).	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('GCA', 'Gene', '25801', (115, 118))	('GCA', 'Gene', (115, 118))	('short RTL', 'Var', (38, 47))
722445	30275518	In addition, a cumulative effect between short telomeres and cigarette smoking on GCA risk was also found.	('GCA', 'Gene', (82, 85))	('short telomeres', 'Var', (41, 56))	('short telomere', 'Phenotype', 'HP:0031413', (41, 55))	('GC', 'Phenotype', 'HP:0012126', (82, 84))	('short telomeres', 'Phenotype', 'HP:0031413', (41, 56))	('GCA', 'Gene', '25801', (82, 85))
722448	30275518	found that short telomeres were associated with an increased risk to developing several cancers, such as esophageal cancer, GC, bladder cancer, and renal cancer.	('renal cancer', 'Disease', (148, 160))	('renal cancer', 'Phenotype', 'HP:0009726', (148, 160))	('associated', 'Reg', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('short telomeres', 'Phenotype', 'HP:0031413', (11, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('short telomeres', 'Var', (11, 26))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('esophageal cancer', 'Disease', (105, 122))	('renal cancer', 'Disease', 'MESH:D007680', (148, 160))	('short telomere', 'Phenotype', 'HP:0031413', (11, 25))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('GC', 'Phenotype', 'HP:0012126', (124, 126))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
722453	30275518	Our findings that short telomere length was associated with an elevated GCA risk were consistent with its role in the risk to developing esophageal cancer and GC.	('short telomere length', 'Phenotype', 'HP:0031413', (18, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('GC', 'Phenotype', 'HP:0012126', (72, 74))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('GCA', 'Gene', '25801', (72, 75))	('short telomere length', 'Var', (18, 39))	('GCA', 'Gene', (72, 75))	('GC', 'Phenotype', 'HP:0012126', (159, 161))	('short telomere', 'Phenotype', 'HP:0031413', (18, 32))	('esophageal cancer', 'Disease', (137, 154))
722455	30275518	found that longer telomere length was significantly associated with an increased risk of breast cancer by analyzing telomere length among 256 patients and 446 matched health controls.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('longer', 'Var', (11, 17))	('associated', 'Reg', (52, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('patients', 'Species', '9606', (142, 150))
722464	30275518	Consistent with these epidemiology data, we observed a significantly synergistic effect between short telomeres and smoking in elevating GCA risk.	('GCA', 'Gene', '25801', (137, 140))	('elevating', 'PosReg', (127, 136))	('short telomeres', 'Var', (96, 111))	('short telomere', 'Phenotype', 'HP:0031413', (96, 110))	('short telomeres', 'Phenotype', 'HP:0031413', (96, 111))	('GC', 'Phenotype', 'HP:0012126', (137, 139))	('GCA', 'Gene', (137, 140))
722465	30275518	Individuals in our study who had two risk factors, short telomere length and smoking, exhibited a 7.03-fold elevated risk to develop GCA (P = 1.43 x 10-18), although short RTL is an independent risk factor for GCA.	('short telomere length', 'Phenotype', 'HP:0031413', (51, 72))	('GC', 'Phenotype', 'HP:0012126', (133, 135))	('GCA', 'Gene', '25801', (210, 213))	('GCA', 'Gene', (210, 213))	('short', 'Var', (166, 171))	('short telomere length', 'Var', (51, 72))	('GC', 'Phenotype', 'HP:0012126', (210, 212))	('short telomere', 'Phenotype', 'HP:0031413', (51, 65))	('GCA', 'Gene', '25801', (133, 136))	('GCA', 'Gene', (133, 136))
722466	30275518	These results elucidated the hypothesis that short telomere length can serve as a molecular marker to predict and evaluate GCA risk.	('short telomere length', 'Phenotype', 'HP:0031413', (45, 66))	('GC', 'Phenotype', 'HP:0012126', (123, 125))	('short telomere length', 'Var', (45, 66))	('short telomere', 'Phenotype', 'HP:0031413', (45, 59))	('GCA', 'Gene', '25801', (123, 126))	('GCA', 'Gene', (123, 126))
722467	30275518	In all, this is the first study demonstrating that subjects with short telomeres may have an increased risk of GCA in Chinese population, which provided precious clues for better interpretation the underlying contribution of telomeres to GCA development and implied the potential of short telomeres as a biomarker for assessing individuals with high GCA risk.	('GCA', 'Gene', '25801', (350, 353))	('GCA', 'Gene', (350, 353))	('short telomeres', 'Phenotype', 'HP:0031413', (65, 80))	('short telomeres', 'Phenotype', 'HP:0031413', (283, 298))	('GCA', 'Gene', (238, 241))	('GCA', 'Gene', (111, 114))	('GCA', 'Gene', '25801', (238, 241))	('short telomeres', 'Var', (65, 80))	('men', 'Species', '9606', (249, 252))	('GCA', 'Gene', '25801', (111, 114))	('GC', 'Phenotype', 'HP:0012126', (238, 240))	('short telomere', 'Phenotype', 'HP:0031413', (65, 79))	('GC', 'Phenotype', 'HP:0012126', (111, 113))	('GC', 'Phenotype', 'HP:0012126', (350, 352))	('short telomere', 'Phenotype', 'HP:0031413', (283, 297))
722482	29566278	On the other side, POTEG inhibited epithelial-mesenchymal transition and suppressed tumor cell metastasis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('epithelial-mesenchymal transition', 'CPA', (35, 68))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('POTEG', 'Var', (19, 24))	('tumor', 'Disease', (84, 89))	('suppressed', 'NegReg', (73, 83))	('inhibited', 'NegReg', (25, 34))
722492	29566278	The in vitro and in vivo assays indicated that POTEG could inhibit tumor cell growth and motility.	('motility', 'CPA', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('inhibit', 'NegReg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('POTEG', 'Var', (47, 52))
722525	29566278	Cells with POTEG overexpression (510-POTEG) and vector control were injected subcutaneously into nude mice, respectively.	('nude mice', 'Species', '10090', (97, 106))	('overexpression', 'PosReg', (17, 31))	('510-POTEG', 'Var', (33, 42))
722532	29566278	Although no significant changes were observed in total Rb (retinoblastoma), the phosphorylation of Rb (Ser807/811 and Ser795) decreased significantly in both 109-POTEG and 510-POTEG cells (Figure 4A and Supplementary Figure S1A).	('decreased', 'NegReg', (126, 135))	('retinoblastoma', 'Disease', (59, 73))	('Ser795', 'Chemical', '-', (118, 124))	('retinoblastoma', 'Disease', 'MESH:D012175', (59, 73))	('Rb', 'Gene', '5925', (99, 101))	('retinoblastoma', 'Phenotype', 'HP:0009919', (59, 73))	('phosphorylation', 'MPA', (80, 95))	('Ser795', 'Var', (118, 124))	('Ser807/811', 'Var', (103, 113))	('Ser807', 'Chemical', '-', (103, 109))	('Rb', 'Gene', '5925', (55, 57))
722538	29566278	in vitro assays revealed that cells' ability of migration and invasion decreased significantly in POTEG overexpressed EC109 and KYSE510 cells (P < 0.01, Student's t-test, Figures 5B and 5C).	('KYSE510', 'Var', (128, 135))	('decreased', 'NegReg', (71, 80))	('EC109', 'CellLine', 'CVCL:6898', (118, 123))	('invasion', 'CPA', (62, 70))
722549	29566278	Our results revealed that POTEG enhanced expression could suppress ESCC tumor cell growth significantly in vitro and in vivo.	('POTEG enhanced', 'Gene', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('expression', 'Var', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('suppress', 'NegReg', (58, 66))
722559	29566278	In aggregate, our results suggested that POTEG inhibited EMT, thereby inhibited ESCC tumor cell metastasis.	('tumor', 'Disease', (85, 90))	('inhibited', 'NegReg', (47, 56))	('POTEG', 'Var', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('EMT', 'CPA', (57, 60))	('inhibited', 'NegReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ESCC', 'Disease', (80, 84))
722581	29394925	Non-coding RNAs have recently emerged as key players in cancer initiation and progression, therefore their clinical value is under intense investigation.	('Non-coding', 'Var', (0, 10))	('cancer initiation', 'Disease', (56, 73))	('clinical', 'Species', '191496', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer initiation', 'Disease', 'MESH:D009369', (56, 73))
722582	29394925	The large collection of non-coding RNAs (ncRNAs) of the human genome is broadly grouped per size and function in two main types: a group of < 40 nt long RNAs known as "small RNAs" (including microRNAs, piwiRNAs, snoRNAs) and a group of > 200 nt long RNA named "long non-coding RNAs".	('ncRNA', 'Gene', (41, 46))	('human', 'Species', '9606', (56, 61))	('ncRNA', 'Gene', '54719', (41, 46))	('< 40', 'Var', (140, 144))
722590	29394925	Different lines of evidence have revealed that the epigenetic control of nc886 is complex and may own clinical relevance.	('epigenetic', 'Var', (51, 61))	('nc886', 'Gene', '100126299', (73, 78))	('nc886', 'Gene', (73, 78))	('clinical', 'Species', '191496', (102, 110))
722635	29394925	Several public methylomes available at the Gene Expression Omnibus (GEO) repository were also analyzed: matched normal and tissue PrCa GSE76938, PrCa metastasis GSE38240, PrCa cell lines GSE34340, GSE62053 and GSE54758 and HCT166 cell lines GSE51810.	('PrCa', 'Phenotype', 'HP:0012125', (145, 149))	('HCT166', 'CellLine', 'CVCL:V754', (223, 229))	('PrCa', 'Phenotype', 'HP:0012125', (130, 134))	('PrCa', 'Phenotype', 'HP:0012125', (171, 175))	('GSE38240', 'Var', (161, 169))	('GSE76938', 'Var', (135, 143))	('GSE62053', 'Var', (197, 205))	('GSE34340', 'Var', (187, 195))
722636	29394925	The average of the normalized beta-values for the 6 CpGs sites located at the nc886 TSS200 promoter (cg18678645, cg06536614, cg26328633, cg25340688, cg26896946, cg00124993) were calculated.	('cg18678645', 'Var', (101, 111))	('nc886', 'Gene', (78, 83))	('cg26328633', 'Var', (125, 135))	('nc886', 'Gene', '100126299', (78, 83))	('cg25340688', 'Var', (137, 147))	('cg06536614', 'Var', (113, 123))	('cg00124993', 'Var', (161, 171))	('cg26896946', 'Var', (149, 159))
722641	29394925	The analysis of the available 50 paired tissue samples showed a statistically significant increase of the methylation average in tumor (0.6615 +- 0.08215) relative to normal tissue (0.5734 +- 0.08049) (p-value < 0.001) (Fig.	('methylation', 'MPA', (106, 117))	('increase', 'PosReg', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('0.6615 +- 0.08215', 'Var', (136, 153))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
722642	29394925	An identical analysis was performed using a recently published PrCa cohort comprising 52 matched cancer and benign-adjacent tissue of radical prostatectomies from Stanford University Medical Center, yielding very similar results (0.5437 +- 0.06445 normal vs 0.6092 +- 0.06278 tumor) (Fig.	('0.6092 +- 0.06278', 'Var', (258, 275))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('cancer', 'Disease', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('0.5437 +- 0.06445 normal', 'Var', (230, 254))	('tumor', 'Disease', (276, 281))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('PrCa', 'Phenotype', 'HP:0012125', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
722650	29394925	We also found that the nc886 methylation status in the normal prostatic tissue dissected from prostatectomies, calculated with the 10 selected CpG sites (Additional file 2: Figure S2), is associated with the clinical T-value of the matched patient tissue (Additional file 2: Figure S2D) (p-value < 0.05).	('methylation', 'Var', (29, 40))	('nc886', 'Gene', (23, 28))	('associated', 'Reg', (188, 198))	('nc886', 'Gene', '100126299', (23, 28))	('clinical', 'Species', '191496', (208, 216))	('patient', 'Species', '9606', (240, 247))
722665	29394925	Therefore, DU145 and LNCaP/PC-3 PrCa cell lines represent suitable models for the spectrum of nc886 variability observed in the clinical set.	('PrCa', 'Phenotype', 'HP:0012125', (32, 36))	('clinical', 'Species', '191496', (128, 136))	('nc886', 'Gene', (94, 99))	('variability', 'Var', (100, 111))	('DU145', 'CellLine', 'CVCL:0105', (11, 16))	('LNCaP/PC-3 PrCa', 'CellLine', 'CVCL:6E93', (21, 36))	('nc886', 'Gene', '100126299', (94, 99))
722671	29394925	Further support for the specific role of DNMT3B in nc886 promoter methylation is provided by the analysis of a GEO dataset, which uncovered a drastic reduction in its methylation upon the deletion of DNMT3B in the HCT116 cell line (Fig.	('deletion', 'Var', (188, 196))	('HCT116', 'CellLine', 'CVCL:0291', (214, 220))	('reduction', 'NegReg', (150, 159))	('nc886', 'Gene', (51, 56))	('nc886', 'Gene', '100126299', (51, 56))	('methylation', 'MPA', (167, 178))	('DNMT3B', 'Gene', (200, 206))
722691	29394925	Initially, we studied the expression of differentially expressed genes identified in a knock down of nc886 in esophageal, gastric and thyroid cell lines.	('knock down', 'Var', (87, 97))	('nc886', 'Gene', '100126299', (101, 106))	('nc886', 'Gene', (101, 106))
722695	29394925	When we analyzed all the tumors of the TCGA-PRAD dataset, 6 out of 28 genes of the signature show a concordant significantly positive correlation with the TSS200 nc886 methylation (p-value < 0.0001) and none of them show a negative correlation with TSS 200 nc886 methylation (Additional file 5: Table S3).	('nc886', 'Gene', '100126299', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('methylation', 'Var', (168, 179))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('nc886', 'Gene', (257, 262))	('nc886', 'Gene', '100126299', (257, 262))	('nc886', 'Gene', (162, 167))	('positive', 'PosReg', (125, 133))
722697	29394925	5a); tumors at the 10th percentile (average beta-value 0.542 +- 0.003) were classified as low TSS200 methylation and consequently high nc886 expression, while tumors at the 90th percentile (average beta-value 0.780 +- 0.003) were classified as high TSS200 methylation and consequently low nc886 expression.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('high', 'PosReg', (130, 134))	('tumors', 'Disease', (159, 165))	('expression', 'MPA', (295, 305))	('nc886', 'Gene', '100126299', (289, 294))	('TSS200', 'Gene', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('low', 'NegReg', (285, 288))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('methylation', 'Var', (101, 112))	('nc886', 'Gene', '100126299', (135, 140))	('nc886', 'Gene', (289, 294))	('expression', 'MPA', (141, 151))	('nc886', 'Gene', (135, 140))	('tumors', 'Disease', (5, 11))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('low', 'NegReg', (90, 93))
722698	29394925	5b, low and high TSS200 nc886 methylation tumors tend to cluster based on the expression of the CCP signature.	('methylation', 'Var', (30, 41))	('high', 'Var', (12, 16))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('nc886', 'Gene', '100126299', (24, 29))	('nc886', 'Gene', (24, 29))	('low', 'Var', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
722700	29394925	The etiology of its downregulation in cancer has been linked to the methylation of its promoter in leukemia, colon, lung, gastric, bladder, breast and esophageal tumors.	('colon', 'Disease', (109, 114))	('bladder', 'Disease', (131, 138))	('leukemia', 'Disease', 'MESH:D007938', (99, 107))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('gastric', 'Disease', (122, 129))	('methylation', 'Var', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('leukemia', 'Disease', (99, 107))	('breast and esophageal tumors', 'Disease', 'MESH:D001943', (140, 168))	('downregulation', 'NegReg', (20, 34))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('esophageal tumors', 'Phenotype', 'HP:0100751', (151, 168))	('colon', 'Disease', 'MESH:D015179', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', (38, 44))	('lung', 'Disease', (116, 120))
722707	29394925	Furthermore, the predominant medium and high nc886 methylation groups tissues, in both normal and tumor TCGA-PRAD samples, positively correlate with the clinical outcome of the disease.	('high', 'Var', (40, 44))	('correlate with', 'Reg', (134, 148))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('clinical', 'Species', '191496', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('nc886', 'Gene', (45, 50))	('methylation', 'Var', (51, 62))	('tumor', 'Disease', (98, 103))	('nc886', 'Gene', '100126299', (45, 50))
722719	29394925	In addition, we show that nc886 promoter methylation negatively regulates its transcript abundance in PrCa cell lines, as was shown previously in leukemia, gastric and esophageal tumors.	('transcript abundance', 'MPA', (78, 98))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('nc886', 'Gene', (26, 31))	('nc886', 'Gene', '100126299', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('regulates', 'Reg', (64, 73))	('PrCa', 'Phenotype', 'HP:0012125', (102, 106))	('methylation', 'Var', (41, 52))	('esophageal tumors', 'Disease', 'MESH:D004938', (168, 185))	('negatively', 'NegReg', (53, 63))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('gastric', 'Disease', (156, 163))	('leukemia', 'Disease', (146, 154))	('esophageal tumors', 'Phenotype', 'HP:0100751', (168, 185))	('esophageal tumors', 'Disease', (168, 185))
722720	29394925	Although aberrant DNA hypermethylation in PrCa is a fundamental driver of tumor progression and overexpression of the DNMTs is a signature of disease origin and evolution, the mechanism responsible for the epigenetic silencing of nc886 in cancer has not been addressed so far.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('PrCa', 'Gene', (42, 46))	('DNMT', 'Gene', '1786', (118, 122))	('nc886', 'Gene', (230, 235))	('epigenetic silencing', 'Var', (206, 226))	('DNMT', 'Gene', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('nc886', 'Gene', '100126299', (230, 235))	('cancer', 'Disease', (239, 245))	('tumor', 'Disease', (74, 79))	('aberrant', 'Var', (9, 17))	('PrCa', 'Phenotype', 'HP:0012125', (42, 46))	('men', 'Species', '9606', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
722722	29394925	Functional studies in siRNA cell lines, cadmium-transformed prostate epithelial cells and TRAMP mouse models, together with the association between PrCa risk and a polymorphism in DNMT3B leading to increased enzyme expression, have provided further support to this hypothesis.	('polymorphism', 'Var', (164, 176))	('mouse', 'Species', '10090', (96, 101))	('TRAMP', 'Gene', (90, 95))	('increased', 'PosReg', (198, 207))	('PrCa', 'Gene', (148, 152))	('association', 'Interaction', (128, 139))	('cadmium', 'Chemical', 'MESH:D002104', (40, 47))	('TRAMP', 'Gene', '8718', (90, 95))	('DNMT3B', 'Gene', (180, 186))	('PrCa', 'Phenotype', 'HP:0012125', (148, 152))	('enzyme expression', 'MPA', (208, 225))
722726	29394925	Seeking the effect of nc886 deregulation in prostate tissue, we analyzed several PrCa cell lines finding support for the correlation between nc886 expression and methylation seen in the clinical samples.	('deregulation', 'Var', (28, 40))	('nc886', 'Gene', (22, 27))	('nc886', 'Gene', '100126299', (22, 27))	('expression', 'MPA', (147, 157))	('clinical samples', 'Species', '191496', (186, 202))	('methylation', 'MPA', (162, 173))	('PrCa', 'Phenotype', 'HP:0012125', (81, 85))	('nc886', 'Gene', (141, 146))	('nc886', 'Gene', '100126299', (141, 146))
722731	29394925	In this context, we chose two cell lines with different levels of nc886 methylation and concomitant expression to cover the spectrum of nc886 variation in prostate tissue.	('nc886', 'Gene', (136, 141))	('nc886', 'Gene', '100126299', (136, 141))	('variation', 'Var', (142, 151))	('nc886', 'Gene', '100126299', (66, 71))	('nc886', 'Gene', (66, 71))
722733	29394925	We found that nc886 overexpression produces a significant decrease of the in vitro proliferation, possibly by a retention of the cells in the G2/M stage of the cell cycle.	('overexpression', 'Var', (20, 34))	('decrease', 'NegReg', (58, 66))	('nc886', 'Gene', '100126299', (14, 19))	('nc886', 'Gene', (14, 19))	('in vitro proliferation', 'CPA', (74, 96))
722739	29394925	We observed that most of the expression of genes previously shown to be upregulated upon nc886 knock-down in cell lines models of esophageal, gastric and thyroid cancer, do not correlate with nc886 expression in prostate tumor tissues.	('knock-down', 'Var', (95, 105))	('thyroid cancer', 'Disease', 'MESH:D013964', (154, 168))	('prostate tumor', 'Disease', 'MESH:D011471', (212, 226))	('nc886', 'Gene', (192, 197))	('nc886', 'Gene', (89, 94))	('nc886', 'Gene', '100126299', (89, 94))	('gastric', 'Disease', (142, 149))	('prostate tumor', 'Phenotype', 'HP:0100787', (212, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('nc886', 'Gene', '100126299', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('upregulated', 'PosReg', (72, 83))	('prostate tumor', 'Disease', (212, 226))	('thyroid cancer', 'Phenotype', 'HP:0002890', (154, 168))	('thyroid cancer', 'Disease', (154, 168))	('expression', 'MPA', (29, 39))	('esophageal', 'Disease', (130, 140))
722740	29394925	This finding suggests that the molecular changes induced by nc886 deregulation in esophageal, gastric and thyroid cancer are different that those in the prostate, thus favoring a tissue specific model of nc886 action in cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('nc886', 'Gene', '100126299', (204, 209))	('esophageal', 'Disease', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('nc886', 'Gene', (60, 65))	('deregulation', 'Var', (66, 78))	('nc886', 'Gene', '100126299', (60, 65))	('gastric', 'Disease', (94, 101))	('thyroid cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('thyroid cancer', 'Phenotype', 'HP:0002890', (106, 120))	('cancer', 'Disease', (220, 226))	('nc886', 'Gene', (204, 209))	('thyroid cancer', 'Disease', 'MESH:D013964', (106, 120))	('cancer', 'Disease', (114, 120))
722750	29394925	The relevance of the proliferative effect in the clinical set is supported by the positive correlation between TSS200 nc886 methylation and the PrCa proliferation gene signature (CCP) in the TCGA-PRAD.	('clinical', 'Species', '191496', (49, 57))	('nc886', 'Gene', (118, 123))	('nc886', 'Gene', '100126299', (118, 123))	('PrCa', 'Phenotype', 'HP:0012125', (144, 148))	('methylation', 'Var', (124, 135))
722819	29147071	Univariate analysis revealed that clinical stage IV, tumor length, weight loss, and all dosiological factors (such as MLD, V20, V15, V10, or V5) were important factors for the development of SRP.	('MLD', 'Disease', 'MESH:D007966', (118, 121))	('MLD', 'Disease', (118, 121))	('SRP', 'Disease', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('V20', 'Var', (123, 126))	('weight loss', 'Disease', 'MESH:D015431', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('V15', 'Gene', '28814', (128, 131))	('V10', 'Var', (133, 136))	('tumor', 'Disease', (53, 58))	('weight loss', 'Disease', (67, 78))	('weight loss', 'Phenotype', 'HP:0001824', (67, 78))	('V15', 'Gene', (128, 131))
722832	29147071	At the same time, many drugs can also affect the determination of eNO; certain studies have found that inhaling or orally administrating cortisol hormones can reduce eNO while L-arginine can increase the level of eNO.	('reduce', 'NegReg', (159, 165))	('eNO', 'MPA', (166, 169))	('L-arginine', 'Var', (176, 186))	('L-arginine', 'Chemical', 'MESH:D001120', (176, 186))
722834	29147071	Patients with the postradiotherapy eNO value greater than 19.5 ppb or the eNO -changing ratio greater than 1.305 may have higher risk of SRP, so that such patients should be intervened and treated in advance so as to control and reduce the occurrence of SRP.	('Patients', 'Species', '9606', (0, 8))	('greater', 'Var', (45, 52))	('patients', 'Species', '9606', (155, 163))	('greater than', 'Var', (94, 106))	('SRP', 'Disease', (137, 140))
722835	28977926	Redox-dependent modulation of metformin contributes to enhanced sensitivity of esophageal squamous cell carcinoma to cisplatin Glutathione is the major intracellular anti-oxidant against reactive oxygen species and serves as a detoxification essential.	('sensitivity', 'MPA', (64, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (187, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('enhanced', 'PosReg', (55, 63))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('metformin', 'Chemical', 'MESH:D008687', (30, 39))	('modulation', 'Var', (16, 26))	('Glutathione', 'Chemical', 'MESH:D005978', (127, 138))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))
722837	28977926	In this study, we provided evidence that metformin inhibits proliferation and induces apoptosis of esophageal squamous cancer cells.	('induces', 'Reg', (78, 85))	('inhibits', 'NegReg', (51, 59))	('metformin', 'Var', (41, 50))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (99, 125))	('esophageal squamous cancer', 'Disease', (99, 125))	('proliferation', 'CPA', (60, 73))	('metformin', 'Chemical', 'MESH:D008687', (41, 50))	('squamous cancer', 'Phenotype', 'HP:0002860', (110, 125))	('apoptosis', 'CPA', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
722863	28977926	Figure 1B, 1C and 1D showed that metformin decreased cell viability in Eca109, KYSE30 and KYSE150 cells in a time-dependent manner.	('cell viability', 'CPA', (53, 67))	('metformin', 'Var', (33, 42))	('metformin', 'Chemical', 'MESH:D008687', (33, 42))	('decreased', 'NegReg', (43, 52))
722865	28977926	Consistently, metformin at 5mM significantly decreased the colony formation in Eca109, KYSE30, KYSE150 and KYSE510 cells, while 10mM metformin even completely eliminated colonies of Eca109cells (Figure 1E and Supplementary Figure 1C).	('KYSE510', 'CellLine', 'CVCL:1354', (107, 114))	('metformin', 'Chemical', 'MESH:D008687', (133, 142))	('decreased', 'NegReg', (45, 54))	('KYSE150', 'Var', (95, 102))	('eliminated', 'NegReg', (159, 169))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('KYSE510', 'Var', (107, 114))	('colony formation', 'CPA', (59, 75))	('KYSE30', 'Var', (87, 93))
722874	28977926	Moreover, metformin significantly increased the enzymic activity of PARP and caspases (Figure 2C, Supplementary Figure 2D and 2E).	('Supplementary Figure 2D', 'Disease', (98, 121))	('PARP', 'Gene', (68, 72))	('metformin', 'Var', (10, 19))	('caspases', 'Gene', (77, 85))	('Supplementary Figure 2D', 'Disease', 'MESH:D017034', (98, 121))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('caspases', 'Gene', '842', (77, 85))	('increased', 'PosReg', (34, 43))	('PARP', 'Gene', '1302', (68, 72))	('enzymic activity', 'MPA', (48, 64))
722883	28977926	In accordance with the abovementioned data, we found that the ROS level was significantly increased by cisplatin (Figure 3D).	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('increased', 'PosReg', (90, 99))	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('ROS level', 'MPA', (62, 71))	('cisplatin', 'Var', (103, 112))
722884	28977926	Importantly, the intracellular glutathione level was also elevated after cisplatin treatment (Figure 3E), which may be due to a feedback regulation of ROS induced activation of anti-oxidant system and was further corroborated by a previous report.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('activation', 'PosReg', (163, 173))	('glutathione', 'Chemical', 'MESH:D005978', (31, 42))	('ROS', 'Chemical', 'MESH:D017382', (151, 154))	('cisplatin', 'Var', (73, 82))	('elevated', 'PosReg', (58, 66))	('intracellular glutathione level', 'MPA', (17, 48))
722886	28977926	Modulation of intracellular glutathione level has been reported to impact the cytotoxic efficiency of platinum compounds.	('Modulation', 'Var', (0, 10))	('impact', 'NegReg', (67, 73))	('intracellular glutathione level', 'MPA', (14, 45))	('glutathione', 'Chemical', 'MESH:D005978', (28, 39))	('cytotoxic efficiency', 'CPA', (78, 98))	('platinum', 'Chemical', 'MESH:D010984', (102, 110))
722889	28977926	Expression of NOX1 was synergistically upregulated by combination of metformin and cisplatin (Supplementary Figure 3B).	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('Expression', 'MPA', (0, 10))	('upregulated', 'PosReg', (39, 50))	('metformin', 'Chemical', 'MESH:D008687', (69, 78))	('cisplatin', 'Var', (83, 92))	('NOX1', 'Gene', '27035', (14, 18))	('NOX1', 'Gene', (14, 18))
722900	28977926	Consistent with the in vitro results that metformin decreased the growth of ESCC cells and synergized with cisplatin to induce cytotoxicity, administration of metformin significantly suppressed the tumor growth in nude mice and combination of metformin and cisplatin resulted in more effective inhibition of tumor growth than either agent alone (Figure 6A and 6B).	('cisplatin', 'Chemical', 'MESH:D002945', (257, 266))	('metformin', 'Chemical', 'MESH:D008687', (243, 252))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('inhibition', 'NegReg', (294, 304))	('suppressed', 'NegReg', (183, 193))	('nude mice', 'Species', '10090', (214, 223))	('cytotoxicity', 'Disease', (127, 139))	('metformin', 'Var', (42, 51))	('metformin', 'Chemical', 'MESH:D008687', (42, 51))	('growth', 'MPA', (66, 72))	('cytotoxicity', 'Disease', 'MESH:D064420', (127, 139))	('tumor', 'Disease', (198, 203))	('metformin', 'Chemical', 'MESH:D008687', (159, 168))	('tumor', 'Disease', (308, 313))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('decreased', 'NegReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (308, 313))
722903	28977926	Immunohistochemistry analysis with an antibody against Ki-67, a marker of cell proliferation, showed that Ki-67-positive cells were significantly decreased in the combination group compared with that in the metformin- or cisplatin-treated group (Figure 6E).	('metformin', 'Chemical', 'MESH:D008687', (207, 216))	('cisplatin', 'Chemical', 'MESH:D002945', (221, 230))	('combination', 'Var', (163, 174))	('decreased', 'NegReg', (146, 155))	('Ki-67-positive', 'Gene', (106, 120))
722905	28977926	Taken together, our data suggest that metformin enhance sensitivity of ESCC cells to cisplatin in vitro and in vivo.	('metformin', 'Var', (38, 47))	('enhance', 'PosReg', (48, 55))	('metformin', 'Chemical', 'MESH:D008687', (38, 47))	('sensitivity', 'MPA', (56, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
722913	28977926	However, acquired resistance often leads to therapy failure and disease relapse.	('disease', 'Disease', (64, 71))	('failure', 'Disease', 'MESH:D017093', (52, 59))	('acquired resistance', 'Var', (9, 28))	('failure', 'Disease', (52, 59))
722918	28977926	This discrepancy was understandable as metformin activates glutathione production in WHCO1, WHCO5, SNO cells while accelerates glutathione consumption in Eca109 and KYSE30 cells leading to apposite sensitivity to cisplatin.	('WHCO5', 'Chemical', '-', (92, 97))	('accelerates', 'PosReg', (115, 126))	('SNO', 'Gene', '22904', (99, 102))	('activates', 'PosReg', (49, 58))	('SNO', 'Gene', (99, 102))	('glutathione', 'Chemical', 'MESH:D005978', (127, 138))	('glutathione', 'Chemical', 'MESH:D005978', (59, 70))	('metformin', 'Chemical', 'MESH:D008687', (39, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (213, 222))	('glutathione consumption', 'MPA', (127, 150))	('WHCO1', 'Chemical', '-', (85, 90))	('apposite sensitivity to cisplatin', 'MPA', (189, 222))	('metformin', 'Var', (39, 48))	('glutathione production', 'MPA', (59, 81))
722924	28977926	Moreover, in the nude mice model, we and others observed metformin significantly suppressed tumor development and enhanced sensitivity to cisplatin treatment.	('metformin', 'Var', (57, 66))	('sensitivity to cisplatin treatment', 'MPA', (123, 157))	('suppressed', 'NegReg', (81, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('metformin', 'Chemical', 'MESH:D008687', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('enhanced', 'PosReg', (114, 122))	('nude mice', 'Species', '10090', (17, 26))	('tumor', 'Disease', (92, 97))
722926	28977926	Moreover, metformin enhanced sensitivity of ESCC cells to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('enhanced', 'PosReg', (20, 28))	('metformin', 'Var', (10, 19))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('sensitivity', 'MPA', (29, 40))
722934	28977926	Human ESCC cell lines KYSE520, KYSE140, KYSE410, KYSE30, KYSE150 and KYSE510 were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), the German Resource Centre for Biological Material.	('Human', 'Species', '9606', (0, 5))	('KYSE410', 'Var', (40, 47))	('von', 'Disease', 'MESH:D014842', (114, 117))	('KYSE140', 'Var', (31, 38))	('von', 'Disease', (114, 117))	('KYSE510', 'Var', (69, 76))	('KYSE150', 'Var', (57, 64))	('KYSE30', 'Var', (49, 55))	('KYSE510', 'CellLine', 'CVCL:1354', (69, 76))
723077	33690683	At the molecular level, recent studies have revealed that approximately 59-93% of patients with ESCC harbor mutations in tumor protein p53.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mutations', 'Var', (108, 117))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Disease', (121, 126))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('ESCC', 'Disease', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
723107	33690683	The AUC was 0.912 (sensitivity 91.7%, specificity 76.0%) for serum miR-1246, 0.823 (sensitivity 90.3%, specificity 62.0%) for urine miR-1246, and 0.802 (sensitivity 83.3%, specificity 66.0%) for saliva miR-1246.	('miR-1246', 'Gene', '100302142', (67, 75))	('miR-1246', 'Gene', (132, 140))	('0.802', 'Var', (146, 151))	('miR-1246', 'Gene', '100302142', (202, 210))	('miR-1246', 'Gene', (67, 75))	('0.823', 'Var', (77, 82))	('urine', 'MPA', (126, 131))	('miR-1246', 'Gene', (202, 210))	('miR-1246', 'Gene', '100302142', (132, 140))
723118	33690683	The prognosis of the group with high serum miR-1246 expression was significantly worse than that of the group with low serum miR-1246 expression (p = 0.035), consistent with our previous report.	('high', 'Var', (32, 36))	('miR-1246', 'Gene', '100302142', (43, 51))	('miR-1246', 'Gene', (43, 51))	('miR-1246', 'Gene', '100302142', (125, 133))	('worse', 'NegReg', (81, 86))	('miR-1246', 'Gene', (125, 133))
723136	33690683	Mechanistically, inhibition of miR-1246 expression reduces stemness and epithelial-mesenchymal transition in non-small cell lung cancer, in addition to suppressing proliferation, sphere formation, colony formation, and invasion of tumor cells.	('colony formation', 'CPA', (197, 213))	('reduces', 'NegReg', (51, 58))	('miR-1246', 'Gene', '100302142', (31, 39))	('stemness', 'Disease', 'MESH:D020295', (59, 67))	('stemness', 'Disease', (59, 67))	('sphere formation', 'CPA', (179, 195))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (109, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('inhibition', 'Var', (17, 27))	('tumor', 'Disease', (231, 236))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (113, 135))	('lung cancer', 'Disease', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('proliferation', 'CPA', (164, 177))	('miR-1246', 'Gene', (31, 39))	('suppressing', 'NegReg', (152, 163))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
723140	33690683	To date, 18 salivary miRs (miR-1246, miR-4644, miR-21, miR-34a, mir-155, miR-200b, miR-376a, miR-23a, miR-23b, miR-29c, miR-210, miR-216, miR -940, miR-3679-5p, miR-17, miR-18b, miR-18a, and miR-196a) have been studied in gastrointestinal cancers and pancreatic cancer, regardless of tumor progression.	('miR-376a', 'Var', (83, 91))	('miR-29c', 'Gene', '407026', (111, 118))	('miR-17', 'Gene', '406952', (161, 167))	('miR -940', 'Gene', '100126328', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('miR-18b', 'Gene', (169, 176))	('miR-1246', 'Gene', (27, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (251, 268))	('miR-18a', 'Gene', (178, 185))	('miR-29c', 'Gene', (111, 118))	('miR-18b', 'Gene', '574033', (169, 176))	('miR-23b', 'Gene', '407011', (102, 109))	('miR -940', 'Gene', (138, 146))	('mir-155', 'Gene', (64, 71))	('miR-4644', 'Gene', '100616430', (37, 45))	('pancreatic cancer', 'Disease', 'MESH:D010190', (251, 268))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('miR-21', 'Gene', '406991', (120, 126))	('miR-21', 'Gene', '406991', (129, 135))	('mir-155', 'Gene', '406947', (64, 71))	('miR-200b', 'Gene', '406984', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('miR-4644', 'Gene', (37, 45))	('miR-17', 'Gene', (161, 167))	('miR-3679', 'Gene', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('pancreatic cancer', 'Disease', (251, 268))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (222, 246))	('miR-18a', 'Gene', '406953', (178, 185))	('miR-23b', 'Gene', (102, 109))	('miR-1246', 'Gene', '100302142', (27, 35))	('miR-21', 'Gene', '406991', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('miR-216', 'Gene', (129, 136))	('miR-210', 'Gene', '406992', (120, 127))	('miR-23a', 'Gene', '407010', (93, 100))	('miR-216', 'Gene', '406998', (129, 136))	('miR-23a', 'Gene', (93, 100))	('miR-21', 'Gene', (120, 126))	('miR-21', 'Gene', (129, 135))	('miR-3679', 'Gene', '100500878', (148, 156))	('miR-34a', 'Gene', (55, 62))	('gastrointestinal cancers', 'Disease', (222, 246))	('miR-210', 'Gene', (120, 127))	('miR-200b', 'Gene', (73, 81))	('tumor', 'Disease', (284, 289))	('miR-34a', 'Gene', '407040', (55, 62))	('miR-21', 'Gene', (47, 53))
723150	33058523	When interplay effect was considered, plans in Group S-I performed statistically better for heart Dmean and V30Gy[RBE], lung Dmean and V5Gy[RBE], and liver Dmean, with slightly increased but clinically acceptable spinal cord Dmax.	('heart Dmean', 'Disease', (92, 103))	('spinal cord Dmax', 'CPA', (213, 229))	('better', 'PosReg', (81, 87))	('Dmean', 'Chemical', '-', (98, 103))	('Dmean', 'Chemical', '-', (156, 161))	('increased', 'PosReg', (177, 186))	('V5Gy[RBE', 'Var', (135, 143))	('Dmean', 'Chemical', '-', (125, 130))	('V30Gy[', 'Var', (108, 114))
723168	33058523	In this study, we compared the IMPT plan quality and robustness for distal esophageal carcinoma between R-L oblique posterior beams (Group R-L) and S-I oblique posterior beams (Group S-I).	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (75, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('beam', 'Chemical', 'MESH:C041191', (170, 174))	('R-L', 'Var', (104, 107))	('esophageal carcinoma', 'Disease', (75, 95))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (75, 95))	('beam', 'Chemical', 'MESH:C041191', (126, 130))
723194	33058523	In addition, we also calculated relative volumes V5Gy[RBE] and V20Gy[RBE] for lung, V30Gy[RBE] and V40Gy[RBE] for heart, V30Gy[RBE] for liver, V18Gy[RBE] for kidney, and V45Gy[RBE]cc for stomach, with VXGy[RBE] and VXGy[RBE]cc defined as the normalized and absolute (cc) volume of a structure receiving at least X Gy[RBE] dose, respectively.	('V20Gy[RBE', 'Var', (63, 72))	('V45Gy[RBE]cc', 'Var', (170, 182))	('VXGy', 'Disease', 'None', (201, 205))	('VXGy', 'Disease', (201, 205))	('V30Gy[RBE', 'Var', (84, 93))	('V5Gy[', 'Var', (49, 54))	('V18Gy[RBE', 'Var', (143, 152))	('VXGy', 'Disease', (215, 219))	('V30Gy[RBE]', 'Var', (121, 131))	('V40Gy[RBE]', 'Var', (99, 109))	('VXGy', 'Disease', 'None', (215, 219))
723217	33058523	Generally speaking, on one hand, the R-L oblique posterior beams have more potential to penetrate the nearby OARs, such as kidneys, lungs, liver etc., while the S-I oblique posterior beams would have less beam paths through the diaphragm radially.	('R-L', 'Var', (37, 40))	('beam', 'Chemical', 'MESH:C041191', (205, 209))	('beam', 'Chemical', 'MESH:C041191', (183, 187))	('OAR', 'Gene', '4936', (109, 112))	('OAR', 'Gene', (109, 112))	('beam', 'Chemical', 'MESH:C041191', (59, 63))
723240	33058523	This study supports our choice of clinically using the S-I posterior oblique beams, instead of R-L posterior oblique beams, as our preferred method for the IMPT treatment of patients with distal esophageal carcinoma requiring chemoradiation.	('S-I', 'Var', (55, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('esophageal carcinoma', 'Disease', (195, 215))	('beam', 'Chemical', 'MESH:C041191', (117, 121))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (195, 215))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (195, 215))	('patients', 'Species', '9606', (174, 182))	('beam', 'Chemical', 'MESH:C041191', (77, 81))
723243	32793456	Strictures adversely impact patients' quality of life.	('Strictures', 'Var', (0, 10))	('patients', 'Species', '9606', (28, 36))	('quality of life', 'CPA', (38, 53))	('impact', 'Reg', (21, 27))
723274	32793456	Benign anastomotic strictures developed in 5 of 39 patients (13%) in the PPI group and in 18 of 40 patients (45%) in the control group (risk ratio, 5.6; 95% confidence interval, 2.0-15.9; p= 0.001).	('patients', 'Species', '9606', (99, 107))	('Benign', 'Disease', (0, 6))	('PPI', 'Var', (73, 76))	('patients', 'Species', '9606', (51, 59))
723358	29434851	Mechanistic studies revealed that bufotalin effectively induced ESCC cell apoptosis, as characterized by DNA fragmentation and nuclear condensation, which was primarily mediated through activation of caspase family members.	('nuclear condensation', 'CPA', (127, 147))	('ESCC', 'Disease', (64, 68))	('bufotalin', 'Chemical', 'MESH:C004600', (34, 43))	('DNA fragmentation', 'CPA', (105, 122))	('bufotalin', 'Var', (34, 43))
723361	29434851	Furthermore, bufotalin demonstrated in vivo anticancer efficacy in a tumor-bearing nude mice model, where bufotalin effectively inhibited Eca-109 xenograft tumor growth in a time- and dose-dependent manner, through activation of the p53 signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('nude mice', 'Species', '10090', (83, 92))	('p53 signaling pathway', 'Pathway', (233, 254))	('bufotalin', 'Var', (106, 115))	('activation', 'PosReg', (215, 225))	('tumor', 'Disease', (69, 74))	('bufotalin', 'Chemical', 'MESH:C004600', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('bufotalin', 'Chemical', 'MESH:C004600', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('inhibited', 'NegReg', (128, 137))
723379	29434851	The results suggested that bufotalin and bufalin effectively impeded the viability of a panel of five ESCC cell lines by inducing cell apoptosis through activation of the tumor protein p53 (p53) signaling pathway.	('bufalin', 'Chemical', 'MESH:C022777', (41, 48))	('inducing', 'NegReg', (121, 129))	('activation', 'PosReg', (153, 163))	('cell apoptosis', 'CPA', (130, 144))	('impeded', 'NegReg', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('viability', 'CPA', (73, 82))	('bufotalin', 'Chemical', 'MESH:C004600', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('bufalin', 'Var', (41, 48))
723380	29434851	Furthermore, bufotalin exhibited in vivo anticancer efficacy in a nude mouse model, where bufotalin inhibited the growth of tumors through activation of the p53 signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('activation', 'PosReg', (139, 149))	('bufotalin', 'Chemical', 'MESH:C004600', (13, 22))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('bufotalin', 'Var', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('inhibited', 'NegReg', (100, 109))	('bufotalin', 'Chemical', 'MESH:C004600', (90, 99))	('cancer', 'Disease', (45, 51))	('mouse', 'Species', '10090', (71, 76))	('p53 signaling pathway', 'Pathway', (157, 178))
723425	29434851	Dysregulation of cell apoptosis (also known as programmed cell death) has been demonstrated to be associated with a number of human chronic diseases, including cancer.	('chronic diseases', 'Disease', 'MESH:D002908', (132, 148))	('chronic diseases', 'Disease', (132, 148))	('human', 'Species', '9606', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (160, 166))	('cell apoptosis', 'CPA', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('associated', 'Reg', (98, 108))
723436	29434851	These results revealed that bufotalin induces ESCC cell apoptosis through the activation of caspase-mediated apoptosis, with the involvement of mitochondria and death receptors.	('ESCC', 'Disease', (46, 50))	('bufotalin', 'Var', (28, 37))	('induces', 'Reg', (38, 45))	('bufotalin', 'Chemical', 'MESH:C004600', (28, 37))	('caspase-mediated', 'CPA', (92, 108))	('activation', 'PosReg', (78, 88))
723441	29434851	Bufotalin markedly increased the expression of p53 total protein and p-p53 (Ser15) in Eca-109 cells compared with the control (Fig.	('p-p53', 'Var', (69, 74))	('increased', 'PosReg', (19, 28))	('Ser15', 'Chemical', '-', (76, 81))	('expression', 'MPA', (33, 43))	('Bufotalin', 'Chemical', 'MESH:C004600', (0, 9))	('p53 total protein', 'Protein', (47, 64))
723446	29434851	These results suggested that bufotalin activates ESCC cell apoptosis through activation of the p53-dependent signaling pathway.	('activates', 'PosReg', (39, 48))	('p53-dependent signaling pathway', 'Pathway', (95, 126))	('ESCC', 'Disease', (49, 53))	('bufotalin', 'Var', (29, 38))	('bufotalin', 'Chemical', 'MESH:C004600', (29, 38))
723458	29434851	In addition, bufotalin demonstrated in vivo anticancer efficacy in a nude mouse model, where bufotalin markedly suppressed tumor growth through activation of the p53 signaling pathway.	('suppressed', 'NegReg', (112, 122))	('tumor', 'Disease', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('bufotalin', 'Chemical', 'MESH:C004600', (13, 22))	('p53 signaling pathway', 'Pathway', (162, 183))	('activation', 'PosReg', (144, 154))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('bufotalin', 'Var', (93, 102))	('mouse', 'Species', '10090', (74, 79))	('bufotalin', 'Chemical', 'MESH:C004600', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
723478	29240732	The majority (65%) of the patients had T1b superficial esophageal squamous cell carcinoma and 55% of the tumors had lymphovascular invasion.	('T1b', 'Var', (39, 42))	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (55, 89))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('esophageal squamous cell carcinoma', 'Disease', (55, 89))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
723482	29240732	In a similar prior study that compared combined ER+ CRT vs. CRT alone for early stage SCC, a trend toward higher overall 3 year survival in ER+ CRT group (90% in ER+CRT vs. 63.2% in CRT alone group) was observed.	('SCC', 'Gene', (86, 89))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('SCC', 'Gene', '6317', (86, 89))	('higher', 'PosReg', (106, 112))	('ER+ CRT', 'Var', (140, 147))
723526	28186990	Over 300 substrates for ISG15 modification have been reported.	('ISG15', 'Gene', (24, 29))	('modification', 'Var', (30, 42))	('ISG15', 'Gene', '9636', (24, 29))
723558	28186990	Analysis of cellular morphology showed vesicle accumulation in cells treated with 5-FU (Figure 3D upper right panel, arrowheads).	('5-FU', 'Var', (82, 86))	('5-FU', 'Chemical', 'MESH:D005472', (82, 86))	('vesicle accumulation', 'MPA', (39, 59))
723573	28186990	Depletion of ISG15 also enhanced the recovery of FLO-1 cells, relative to scrambled controls (Supplementary Figure 3D).	('ISG15', 'Gene', '9636', (13, 18))	('recovery', 'MPA', (37, 45))	('ISG15', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('enhanced', 'PosReg', (24, 32))	('FLO-1 cells', 'CPA', (49, 60))
723593	28186990	The combination of chloroquine and 5-FU (green overlay) resulted in autophagosome accumulation in excess of either chloroquine or drug alone, which was further enhanced by UBE2L6 siRNA (red overlay) relative to scrambled controls (blue overlay) (***p < 0.0001).	('chloroquine', 'Var', (19, 30))	('5-FU', 'Var', (35, 39))	('autophagosome accumulation', 'CPA', (68, 94))	('UBE2L6', 'Gene', (172, 178))	('UBE2L6', 'Gene', '9246', (172, 178))	('5-FU', 'Chemical', 'MESH:D005472', (35, 39))	('chloroquine', 'Chemical', 'MESH:D002738', (115, 126))	('enhanced', 'PosReg', (160, 168))	('chloroquine', 'Chemical', 'MESH:D002738', (19, 30))
723600	28186990	The Cyto-ID assay also demonstrates a significant difference in autophagosome accumulation in FLO-1 cells with depleted UBE2L6 (orange overlay) when compared to scrambled controls (green overlay) (Supplementary Figure 5D) (**p = 0.0013).	('UBE2L6', 'Gene', '9246', (120, 126))	('UBE2L6', 'Gene', (120, 126))	('autophagosome accumulation', 'CPA', (64, 90))	('depleted', 'Var', (111, 119))
723629	28186990	ISGylation at Lys-349 and Lys 369 was reported to enhance Parkins E3 ligase activity.	('Lys 369', 'Var', (26, 33))	('Lys', 'Chemical', 'MESH:D008239', (14, 17))	('activity', 'MPA', (76, 84))	('ISGylation', 'Var', (0, 10))	('Parkins E3 ligase', 'Enzyme', (58, 75))	('Lys', 'Chemical', 'MESH:D008239', (26, 29))	('enhance', 'PosReg', (50, 57))
723630	28186990	Aberrant expression of UBE2L6 or other members of the ISGylation system have been reported in various cancers.	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('UBE2L6', 'Gene', (23, 29))	('UBE2L6', 'Gene', '9246', (23, 29))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('reported', 'Reg', (82, 90))
723633	28186990	In nasopharyngeal cancer, high ISG15 correlated with frequent local cancer recurrence and shorter overall survival.	('cancer', 'Disease', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('high', 'Var', (26, 30))	('shorter', 'NegReg', (90, 97))	('ISG15', 'Gene', '9636', (31, 36))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (3, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('ISG15', 'Gene', (31, 36))	('cancer', 'Disease', (68, 74))	('overall', 'MPA', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
723638	28186990	A previous study evaluated the effects of silencing either ISG15 or UBE2L6 on drug sensitivity in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('silencing', 'Var', (42, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('ISG15', 'Gene', (59, 64))	('drug sensitivity', 'Phenotype', 'HP:0020174', (78, 94))	('drug sensitivity', 'MPA', (78, 94))	('UBE2L6', 'Gene', (68, 74))	('UBE2L6', 'Gene', '9246', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ISG15', 'Gene', '9636', (59, 64))
723639	28186990	They reported a significant decrease in sensitivity to camptothecin (CPT) when either ISG15 or UBE2L6 were silenced.	('sensitivity to camptothecin', 'MPA', (40, 67))	('UBE2L6', 'Gene', (95, 101))	('camptothecin', 'Chemical', 'MESH:D002166', (55, 67))	('ISG15', 'Gene', '9636', (86, 91))	('silenced', 'Var', (107, 115))	('UBE2L6', 'Gene', '9246', (95, 101))	('ISG15', 'Gene', (86, 91))	('decrease', 'NegReg', (28, 36))
723641	28186990	In our study we found that while depletion of both IGS15 and UBE2L6 elevates autophagy, only those esophageal cancer cells with ISG15 knockdown showed a decrease in sensitivity to 5-FU, consistent with the effects of ISG15 silencing reported by Desai et al.	('ISG15', 'Gene', '9636', (217, 222))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('UBE2L6', 'Gene', (61, 67))	('IGS15', 'Gene', (51, 56))	('ISG15', 'Gene', (217, 222))	('depletion', 'MPA', (33, 42))	('UBE2L6', 'Gene', '9246', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('knockdown', 'Var', (134, 143))	('ISG15', 'Gene', '9636', (128, 133))	('sensitivity to 5-FU', 'MPA', (165, 184))	('elevates', 'Reg', (68, 76))	('autophagy', 'CPA', (77, 86))	('5-FU', 'Chemical', 'MESH:D005472', (180, 184))	('ISG15', 'Gene', (128, 133))	('esophageal cancer', 'Disease', (99, 116))	('decrease', 'NegReg', (153, 161))
723642	28186990	In contrast, sensitivity of esophageal cells to 5-FU was unaffected by UBE2L6 knockdown.	('UBE2L6', 'Gene', (71, 77))	('knockdown', 'Var', (78, 87))	('5-FU', 'Chemical', 'MESH:D005472', (48, 52))	('UBE2L6', 'Gene', '9246', (71, 77))
723647	28186990	However, if expression of the ISG15 pathway was directly required for autophagy induction, we would have expected silencing of either UBE2L6 or ISG15 to inhibit autophagy in our cells rather than inducing it.	('ISG15', 'Gene', '9636', (144, 149))	('inhibit', 'NegReg', (153, 160))	('ISG15', 'Gene', (30, 35))	('ISG15', 'Gene', (144, 149))	('UBE2L6', 'Gene', (134, 140))	('silencing', 'Var', (114, 123))	('UBE2L6', 'Gene', '9246', (134, 140))	('ISG15', 'Gene', '9636', (30, 35))	('autophagy', 'CPA', (161, 170))
723655	28186990	Silencing of UBE2L6 or ISG15 by siRNA may therefore lead to increased poly-ubiquitination and degradation of a negative regulator(s) of autophagy.	('degradation', 'MPA', (94, 105))	('poly-ubiquitination', 'MPA', (70, 89))	('UBE2L6', 'Gene', (13, 19))	('UBE2L6', 'Gene', '9246', (13, 19))	('ISG15', 'Gene', '9636', (23, 28))	('Silencing', 'Var', (0, 9))	('ISG15', 'Gene', (23, 28))	('increased', 'PosReg', (60, 69))
723736	25998788	The non-essential amino acid LP and its role in cancer metabolism has been recently highlighted  whereas alterations in ketone bodies (BHBA) have been shown to promote tumor growth and metastasis and altered carbohydrate (DM) levels have been related to cancer development and progression .	('altered', 'Reg', (200, 207))	('LP', 'Chemical', 'MESH:D011392', (29, 31))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', (254, 260))	('ketone bodies', 'Phenotype', 'HP:0001946', (120, 133))	('carbohydrate', 'Chemical', 'MESH:D002241', (208, 220))	('DM', 'Disease', 'MESH:D009223', (222, 224))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('promote', 'PosReg', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('related', 'Reg', (243, 250))	('alterations', 'Var', (105, 116))	('ketone', 'Chemical', 'MESH:D007659', (120, 126))	('tumor', 'Disease', (168, 173))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('BHBA', 'Chemical', '-', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
723737	25998788	Similar to our findings, altered LP levels have been found in other cancer types such as renal cell carcinoma , and changes in LP levels have been associated with early detection of recurrence in breast cancer.	('altered', 'Reg', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('LP', 'Chemical', 'MESH:D011392', (127, 129))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('LP levels', 'MPA', (127, 136))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (89, 109))	('changes', 'Var', (116, 123))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (196, 209))	('cancer', 'Disease', (203, 209))	('LP', 'Chemical', 'MESH:D011392', (33, 35))	('renal cell carcinoma', 'Disease', (89, 109))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('associated', 'Reg', (147, 157))	('found', 'Reg', (53, 58))	('LP levels', 'MPA', (33, 42))	('cancer', 'Disease', (68, 74))
723765	26107665	After matching, both the pre-OP CRT+S and S+post-OP CRT groups were significantly associated with a better survival compared with the S group (pre-OP CRT+S vs. S: P < 0.001; S+post-OP CRT vs. S: P = 0.005).	('CRT', 'Gene', '799', (52, 55))	('CRT', 'Gene', (52, 55))	('better', 'PosReg', (100, 106))	('CRT', 'Gene', '799', (32, 35))	('survival', 'CPA', (107, 115))	('CRT', 'Gene', '799', (184, 187))	('CRT', 'Gene', (32, 35))	('S+post-OP', 'Var', (42, 51))	('CRT', 'Gene', (184, 187))	('CRT', 'Gene', '799', (150, 153))	('CRT', 'Gene', (150, 153))
723773	26107665	In the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) that compared surgery alone and chemotherapy concurrent with radiotherapy followed by surgery for T1N1 or T2-3N0-1 esophageal cancer, the median overall survival was 49.4 months in the pre-OP CRT plus surgery group vs. 24.0 months in the surgery alone group.	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('CRT', 'Gene', '799', (274, 277))	('Oesophageal Cancer', 'Disease', 'MESH:D009369', (29, 47))	('esophageal cancer', 'Disease', (197, 214))	('CRT', 'Gene', (274, 277))	('Oesophageal Cancer', 'Disease', (29, 47))	('T2-3N0-1', 'Var', (188, 196))
723787	26107665	Specifically, we identified 6140 patients who were diagnosed with ESCC between 2008 and 2011, with the appropriate International Classification of Diseases for Oncology (ICD-O-3) site codes (C15.0, C15.1, C15.2, C15.3, C15.4, C15.5, C15.8, and C15.9) and morphology codes (8052, 8070, 8071, 8072, 8073, 8074, 8076, 8077, 8083, and 8084).	('patients', 'Species', '9606', (33, 41))	('8077', 'Var', (315, 319))	('Oncology', 'Phenotype', 'HP:0002664', (160, 168))	('8076', 'Var', (309, 313))	('8072', 'Var', (291, 295))	('C15.4', 'Var', (219, 224))	('ESCC', 'Disease', (66, 70))	('8071', 'Var', (285, 289))	('C15.0', 'Var', (191, 196))	('8073', 'Var', (297, 301))	('8052', 'Var', (273, 277))
723793	26107665	For matching patients who received S+post-OP CRT and those who underwent surgery alone, a propensity score was calculated using the variables of age, sex, clinical stages, tumor location, differentiation grade, pathological stages, tumor size, and margin status.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('CRT', 'Gene', '799', (45, 48))	('tumor', 'Disease', (172, 177))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('CRT', 'Gene', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('S+post-OP', 'Var', (35, 44))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
723809	26107665	A survival analysis with a Cox proportional hazards regression model identified significant prognostic factors for poor outcome including clinical and pathological stages, a tumor length of more than 5 cm, tumors located in the upper third of the esophagus, and R1/2 resection, whereas female sex was associated with a better outcome (Table 2).	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('Cox', 'Gene', '1351', (27, 30))	('R1/2', 'Var', (262, 266))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Disease', (206, 211))	('Cox', 'Gene', (27, 30))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
723811	26107665	Clinical T3/4 stage, pT3/4 stage, pN+, a tumor length of more than 5 cm, tumors located in the upper third of the esophagus, and R1/2 resection remained significant independent prognostic factors for poor outcome in patients who received primary esophagectomy, whereas female sex and post-OP CRT were favorable prognostic factors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('CRT', 'Gene', '799', (292, 295))	('tumor', 'Disease', (41, 46))	('CRT', 'Gene', (292, 295))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('patients', 'Species', '9606', (216, 224))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('pN+', 'Var', (34, 37))
723815	26107665	Kaplan-Meier curves showed that both pre-OP CRT+S and S+post-OP CRT were significantly associated with a better overall survival than surgery alone (Figure 2B.	('better', 'PosReg', (105, 111))	('overall', 'CPA', (112, 119))	('S+post-OP', 'Var', (54, 63))	('CRT', 'Gene', '799', (44, 47))	('CRT', 'Gene', '799', (64, 67))	('CRT', 'Gene', (44, 47))	('CRT', 'Gene', (64, 67))
723844	26107665	The 1-year and 3-year overall survival rates in the S+post-OP CRT group and the surgery alone group were 86.0% versus 44.0% and 48.6% versus 16.8%, respectively (P = 0.003).	('CRT', 'Gene', '799', (62, 65))	('S+post-OP', 'Var', (52, 61))	('CRT', 'Gene', (62, 65))
723872	26107665	Some surgeons may suggest post-OP CRT for patients with N+, T4 diseases and tumor infiltration close to the surgical margins, while they may suggest observation only for patients with less advanced tumors.	('patients', 'Species', '9606', (170, 178))	('CRT', 'Gene', '799', (34, 37))	('T4 diseases', 'Var', (60, 71))	('CRT', 'Gene', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('patients', 'Species', '9606', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
723873	26107665	Even so, the survival in S+post-OP CRT group was still better than surgery alone.	('CRT', 'Gene', (35, 38))	('CRT', 'Gene', '799', (35, 38))	('S+post-OP', 'Var', (25, 34))
723900	25355583	The hospital mortality rates associated with TEVAR for type B aortic dissection were 7.3 % in acute cases and 2.6 % for chronic cases, respectively.	('aortic dissection', 'Phenotype', 'HP:0002647', (62, 79))	('TEVAR', 'Phenotype', 'HP:0012727', (45, 50))	('type B aortic dissection', 'Disease', (55, 79))	('TEVAR', 'Var', (45, 50))	('type B aortic dissection', 'Phenotype', 'HP:0012499', (55, 79))	('TEVAR', 'Chemical', '-', (45, 50))
723963	25098614	Evidence that alterations in the expression of certain miRNAs (e.g., hsa-miR-21, hsa-miR-223 and hsa-miR-75) might be associated with the development, prognosis and survival rates of esophageal cancer is increasing .	('alterations', 'Var', (14, 25))	('hsa-miR-223', 'Gene', (81, 92))	('hsa-miR-223', 'Gene', '407008', (81, 92))	('hsa-miR-21', 'Gene', '406991', (69, 79))	('hsa-miR-75', 'Gene', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('esophageal cancer', 'Disease', (183, 200))	('expression', 'MPA', (33, 43))	('associated', 'Reg', (118, 128))	('hsa-miR-21', 'Gene', (69, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (183, 200))
723967	25098614	The profile included four collections: GSE42363 (14 EAC tissue samples), GSE17351 (5 ESCC cases and 5 adjacent normal esophageal tissues), GSE26886 (21 EAC tissues, 9 ESCC tissues, and 19 normal tissues from healthy subjects), and GSE3701 (40 ESCC tissue samples).	('GSE42363', 'Var', (39, 47))	('GSE3701', 'Chemical', '-', (231, 238))	('GSE26886', 'Var', (139, 147))	('GSE3701', 'Var', (231, 238))	('GSE17351', 'Var', (73, 81))
723977	25098614	Five of the remaining pathways, microRNAs in cancer (hsa05206), pancreatic cancer (hsa05212), pathways in cancer (hsa05200), basal cell carcinoma (hsa05217) and colorectal cancer (hsa05210), were reported as correlated with cancer.	('colorectal cancer', 'Disease', (161, 178))	('hsa05212', 'Var', (83, 91))	('hsa05200', 'Var', (114, 122))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (125, 145))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (125, 145))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('basal cell carcinoma', 'Disease', (125, 145))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (45, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', (75, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
723978	25098614	Two cancer-related pathways, proteoglycans in cancer (hsa05205) and transcriptional misregulation in cancers (hsa05202), were also indicated.	('proteoglycans', 'Protein', (29, 42))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('transcriptional', 'MPA', (68, 83))	('cancer', 'Disease', (4, 10))	('hsa05202', 'Var', (110, 118))
723993	25098614	Five of the 11 pathways enriched for EAC are known to be cancer-related, and two, the Hippo signaling pathway (hsa04390) and the transforming growth factor (TGF)-beta-signaling pathway (hsa04350), are signal-transduction pathways.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('transforming growth factor (TGF)-beta', 'Gene', '7040', (129, 166))	('cancer', 'Disease', (57, 63))	('EAC', 'Disease', (37, 40))	('hsa04350', 'Var', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Hippo signaling pathway', 'Pathway', (86, 109))	('hsa04390', 'Var', (111, 119))
723996	25098614	The most significantly target gene-enriched ESCC pathways were also signal transduction pathways: the Jak-STAT signaling pathway (hsa04630), TGF-beta signaling pathway (hsa04350), and PI3K-Akt signaling pathway (hsa04151).	('Jak-STAT signaling pathway', 'Pathway', (102, 128))	('TGF-beta', 'Gene', '7040', (141, 149))	('PI3K-Akt signaling pathway', 'Pathway', (184, 210))	('TGF-beta', 'Gene', (141, 149))	('hsa04151', 'Var', (212, 220))	('hsa04630', 'Var', (130, 138))	('hsa04350', 'Var', (169, 177))
724011	23226753	RsaI/PstI polymorphisms in the promoter gene region are believed to affect the transcriptional activity of the gene, and occur as a wild-type homozygous genotype (c1/c1), a heterozygous genotype (c1/c2) and a variant homozygous rare genotype (c2/c2), and the frequency of the variant c1 allele was observed to be much higher in patients with esophageal diseases than that of healthy individuals.	('c1/c2', 'Gene', (196, 201))	('esophageal diseases', 'Disease', (342, 361))	('PstI', 'Gene', (5, 9))	('transcriptional activity', 'MPA', (79, 103))	('patients', 'Species', '9606', (328, 336))	('polymorphisms', 'Var', (10, 23))	('c1/c2', 'Gene', '6966', (196, 201))	('PstI', 'Gene', '6690', (5, 9))	('esophageal diseases', 'Disease', 'MESH:D004935', (342, 361))	('affect', 'Reg', (68, 74))	('higher', 'PosReg', (318, 324))
724016	23226753	Therefore, we conducted a meta-analysis of case-control studies in order to review and summarize the epidemiological evidence, and aimed to precisely detect the correlation between the CYP2E1 RsaI/PstI polymorphism and the risk of EC among Chinese individuals.	('PstI', 'Gene', (197, 201))	('CYP2E1', 'Gene', (185, 191))	('PstI', 'Gene', '6690', (197, 201))	('CYP2E1', 'Gene', '1571', (185, 191))	('polymorphism', 'Var', (202, 214))
724018	23226753	Terms used in the search were as follows: i) esophag* and oesophag*; ii) cancer, carcinoma, adenocarcinoma, neoplasm, neoplasia and neoplastic; iii) cytochrome p450 2E1, cytochrome p450II1, CYP2E1, CYPIIE1; iv) polymorphism; v) China and Chinese, without restrictions.	('CYPIIE1', 'Gene', (198, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('neoplasm', 'Phenotype', 'HP:0002664', (108, 116))	('polymorphism', 'Var', (211, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinoma', 'Disease', (97, 106))	('cytochrome p450 2E1', 'Gene', (149, 168))	('adenocarcinoma', 'Disease', (92, 106))	('cancer', 'Disease', (73, 79))	('carcinoma', 'Disease', (81, 90))	('oesophag', 'Disease', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('neoplasia', 'Disease', 'MESH:D009369', (118, 127))	('carcinoma', 'Disease', 'MESH:D002277', (97, 106))	('CYP2E1', 'Gene', '1571', (190, 196))	('adenocarcinoma', 'Disease', 'MESH:D000230', (92, 106))	('neoplasia', 'Disease', (118, 127))	('CYPIIE1', 'Gene', '1571', (198, 205))	('carcinoma', 'Disease', 'MESH:D002277', (81, 90))	('neoplasm', 'Disease', 'MESH:D009369', (108, 116))	('esophag', 'Disease', (45, 52))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('neoplasm', 'Disease', (108, 116))	('cytochrome p450 2E1', 'Gene', '1571', (149, 168))	('CYP2E1', 'Gene', (190, 196))	('neoplasia', 'Phenotype', 'HP:0002664', (118, 127))
724021	23226753	Of the 108 records retrieved initially, 17 studies including 18 trails were identified for the association between the CYP2E1 RsaI/PstI polymorphism and risk of EC, including a total of 1,663 cases and 2,603 controls.	('association', 'Interaction', (95, 106))	('polymorphism', 'Var', (136, 148))	('CYP2E1', 'Gene', (119, 125))	('PstI', 'Gene', (131, 135))	('CYP2E1', 'Gene', '1571', (119, 125))	('PstI', 'Gene', '6690', (131, 135))
724024	23226753	3); for c2/c2 vs. c1/c1+c1/c2: OR=0.76; 95% CI, 0.60-0.96; P=0.02 (Fig.	('c1/c1+c1/c2', 'Gene', (18, 29))	('c2/c2', 'Var', (8, 13))	('c1/c1+c1/c2', 'Gene', '6966', (18, 29))
724027	23226753	When studies were stratified for control source, an association was detected for all genetic models, with the exception of PB in c2/c2 vs. c1/c1 and c2/c2 vs. c1/c1+c1/c2 (both P>0.05).	('c1/c1+c1/c2', 'Gene', '6966', (159, 170))	('c2/c2 vs.', 'Var', (129, 138))	('c1/c1+c1/c2', 'Gene', (159, 170))
724028	23226753	In the stratified analysis by tumor type, the results were similar to the control source; the ESCC type showed no association in c2/c2 vs. c1/c1 and c2/c2 vs. c1/c1+c1/c2 (both P>0.05).	('c1/c1+c1/c2', 'Gene', '6966', (159, 170))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('c2/c2 vs.', 'Var', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('c1/c1+c1/c2', 'Gene', (159, 170))	('tumor', 'Disease', (30, 35))
724035	23226753	The RsaI/PstI polymorphisms in the promoter gene region are reported to affect the transcriptional activity of the gene.	('affect', 'Reg', (72, 78))	('PstI', 'Gene', (9, 13))	('transcriptional activity', 'MPA', (83, 107))	('polymorphisms', 'Var', (14, 27))	('PstI', 'Gene', '6690', (9, 13))
724036	23226753	Numerous large-sample and unbiased epidemiological studies of CYP2E1 RsaI/PstI polymorphisms could confirm it as a predisposition gene for EC risk, particularly in China.	('CYP2E1', 'Gene', (62, 68))	('PstI', 'Gene', (74, 78))	('polymorphisms', 'Var', (79, 92))	('CYP2E1', 'Gene', '1571', (62, 68))	('PstI', 'Gene', '6690', (74, 78))
724037	23226753	Molecular biological studies have also demonstrated that the rare allele of the RsaI/PstI polymorphism in the CYP2E1 gene is associated with increased transcriptional activity, which may play an important role in EC development.	('PstI', 'Gene', '6690', (85, 89))	('transcriptional activity', 'MPA', (151, 175))	('CYP2E1', 'Gene', '1571', (110, 116))	('increased', 'PosReg', (141, 150))	('CYP2E1', 'Gene', (110, 116))	('polymorphism', 'Var', (90, 102))	('PstI', 'Gene', (85, 89))
724042	23226753	However, the meta-analysis of ESCC subgroup failed to identify any significant association in c2/c2 vs. c1/c1 (OR=0.94; 95% CI, 0.61-1.46; P=0.80) and c2/c2 vs. c1/c1+c1/c2 (OR=0.96; 95% CI, 0.62-1.49, P=0.87) genetic models.	('c1/c1+c1/c2', 'Gene', '6966', (161, 172))	('c2/c2', 'Var', (94, 99))	('c1/c1+c1/c2', 'Gene', (161, 172))
724046	23226753	Hence, the heterogeneity of the studies did not substantially lower the statistical validity of the study and the CYP2E1 RsaI/PstI polymorphism is clearly associated with EC risk in Chinese individuals.	('CYP2E1', 'Gene', '1571', (114, 120))	('PstI', 'Gene', '6690', (126, 130))	('polymorphism', 'Var', (131, 143))	('CYP2E1', 'Gene', (114, 120))	('associated with', 'Reg', (155, 170))	('PstI', 'Gene', (126, 130))
724145	22655277	FOLOFOX4 was found to have a higher response rate (45 vs. 29%), which translated to a longer overall survival (22.7 vs. 15.1 months).	('longer', 'PosReg', (86, 92))	('FOLOFOX4', 'Var', (0, 8))	('FOLOFOX4', 'Chemical', '-', (0, 8))	('overall survival', 'MPA', (93, 109))
724151	22655277	Moreover, the incidence of KRAS mutations in junctional or gastric adenocarcinoma (6-21%) and in esophageal squamous cancer (16% in one report) appears to be less than in colon cancer where these mutations are predictive of resistance to cetuximab (Sommerer et al.,; Lyronis et al.,).	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (97, 123))	('junctional', 'Disease', (45, 55))	('esophageal squamous cancer', 'Disease', (97, 123))	('KRAS', 'Gene', '3845', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (171, 183))	('cetuximab', 'Chemical', 'MESH:D000068818', (238, 247))	('colon cancer', 'Disease', 'MESH:D015179', (171, 183))	('mutations', 'Var', (32, 41))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (59, 81))	('colon cancer', 'Disease', (171, 183))	('gastric adenocarcinoma', 'Disease', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('KRAS', 'Gene', (27, 31))	('squamous cancer', 'Phenotype', 'HP:0002860', (108, 123))
724164	22655277	Although the addition of Bevacizumab to chemotherapy with capecitabine or 5-FU and cisplatin in the AVAGAST trial (N = 774) resulted in a significant improvement in overall response rate (37.4-46%) and PFS (5.3-6.7 months) in patients with advanced gastric or GEJ adenocarcinoma, this trial failed to meet its primary endpoint of prolonging OS (12.1 vs. 10.1 months, HR 0.87; P = 0.1002; Ohtsu et al.,).	('prolonging OS', 'Disease', (330, 343))	('gastric or GEJ adenocarcinoma', 'Disease', 'MESH:D013274', (249, 278))	('overall response', 'MPA', (165, 181))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('capecitabine', 'Chemical', 'MESH:D000069287', (58, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('gastric or GEJ adenocarcinoma', 'Disease', (249, 278))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (25, 36))	('PFS', 'MPA', (202, 205))	('patients', 'Species', '9606', (226, 234))	('improvement', 'PosReg', (150, 161))	('prolonging OS', 'Disease', 'MESH:C567932', (330, 343))	('cisplatin', 'Var', (83, 92))	('5-FU', 'Var', (74, 78))	('5-FU', 'Chemical', 'MESH:D005472', (74, 78))
724172	22655277	In correlative studies as part of the ECOG 1201 study mentioned above, analysis of single nucleotide polymorphisms in DNA repair pathways to seek predictors of response identified an allele associated with a lower likelihood of pCR.	('lower', 'NegReg', (208, 213))	('pCR', 'Disease', (228, 231))	('single nucleotide polymorphisms', 'Var', (83, 114))	('CR', 'Chemical', 'MESH:D002857', (229, 231))
724182	33898327	Our previous studies indicated that inactivation of neddylation by the NAE inhibitor induced apoptosis and autophagy in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('NAE', 'Chemical', '-', (71, 74))	('autophagy', 'CPA', (107, 116))	('cancer', 'Disease', (120, 126))	('induced', 'Reg', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('inactivation', 'Var', (36, 48))	('apoptosis', 'CPA', (93, 102))	('neddylation', 'Protein', (52, 63))	('NAE', 'Gene', (71, 74))
724189	33898327	Post-translational modification of proteins plays crucial roles in the regulation of tumorigenesis and tumor progression.	('tumor', 'Disease', (85, 90))	('proteins', 'Protein', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Post-translational', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
724207	33898327	Targeting the neddylation pathway to inactivate CRL E3 ligases has been shown to induce autophagy.	('induce', 'PosReg', (81, 87))	('CRL', 'Gene', (48, 51))	('autophagy', 'CPA', (88, 97))	('inactivate', 'Var', (37, 47))	('CRL', 'Gene', '133396', (48, 51))	('neddylation pathway', 'Pathway', (14, 33))
724218	33898327	Cell lysates were prepared for immunoblotting analysis using antibodies against LC3, p62, NEDD8, AMPK, p-AMPKalpha (Thr172), ULK1, p-ULK1 (Ser317), p-H2AX, WEE1, p21, ORC1, Beclin1, ATG5, p-p70S6K (Thr389), p70S6K, 4EBP1, p-4EBP1 (Thr37/46), cleaved PARP, cleaved Caspase-3, IkappaBalpha, p-IkappaBalpha, p65, LaminA/C and Tublin (Cell Signaling Technology), Cullin1 (Abcam).	('p65', 'Gene', (305, 308))	('Caspase-3', 'Gene', (264, 273))	('ULK1', 'Gene', '8408', (125, 129))	('WEE1', 'Gene', (156, 160))	('ULK1', 'Gene', (133, 137))	('AMPK', 'Gene', '5563', (97, 101))	('LC3', 'Gene', (80, 83))	('p62', 'Gene', '23636', (85, 88))	('PARP', 'Gene', '1302', (250, 254))	('p70S6K', 'Gene', (207, 213))	('p70S6K', 'Gene', (190, 196))	('4EBP1', 'Gene', '1978', (224, 229))	('ULK1', 'Gene', (125, 129))	('p62', 'Gene', (85, 88))	('IkappaBalpha', 'Gene', (275, 287))	('Beclin1', 'Gene', '8678', (173, 180))	('AMPK', 'Gene', (105, 109))	('4EBP1', 'Gene', '1978', (215, 220))	('p65', 'Gene', '5970', (305, 308))	('IkappaBalpha', 'Gene', (291, 303))	('IkappaBalpha', 'Gene', '4792', (275, 287))	('AMPK', 'Gene', (97, 101))	('ATG5', 'Gene', '9474', (182, 186))	('Cullin1', 'Gene', '8454', (359, 366))	('PARP', 'Gene', (250, 254))	('WEE1', 'Gene', '7465', (156, 160))	('LaminA/C', 'Gene', (310, 318))	('Caspase-3', 'Gene', '836', (264, 273))	('IkappaBalpha', 'Gene', '4792', (291, 303))	('ORC1', 'Gene', '4998', (167, 171))	('LC3', 'Gene', '84557', (80, 83))	('NEDD8', 'Gene', '4738', (90, 95))	('Beclin1', 'Gene', (173, 180))	('H2AX', 'Gene', (150, 154))	('p70S6K', 'Gene', '6198', (190, 196))	('p70S6K', 'Gene', '6198', (207, 213))	('LaminA/C', 'Gene', '4000', (310, 318))	('ORC1', 'Gene', (167, 171))	('cleaved', 'Var', (242, 249))	('4EBP1', 'Gene', (224, 229))	('ATG5', 'Gene', (182, 186))	('Cullin1', 'Gene', (359, 366))	('p21', 'Gene', (162, 165))	('4EBP1', 'Gene', (215, 220))	('NEDD8', 'Gene', (90, 95))	('p21', 'Gene', '644914', (162, 165))	('H2AX', 'Gene', '3014', (150, 154))	('ULK1', 'Gene', '8408', (133, 137))	('AMPK', 'Gene', '5563', (105, 109))
724229	33898327	Firstly, we determined the conversion of LC3-I to LC3-II, a classical marker of autophagy, and found that CPT dramatically induced the conversion of LC3-I to LC3-II and inhibited the expression of p62 in EC1 and EC109 cells ( Figure 1A ).	('LC3', 'Gene', (158, 161))	('EC1', 'Gene', '4819', (212, 215))	('LC3', 'Gene', (149, 152))	('LC3', 'Gene', '84557', (50, 53))	('p62', 'Gene', '23636', (197, 200))	('EC1', 'Gene', '4819', (204, 207))	('p62', 'Gene', (197, 200))	('LC3', 'Gene', '84557', (41, 44))	('expression', 'MPA', (183, 193))	('EC109', 'CellLine', 'CVCL:6898', (212, 217))	('inhibited', 'NegReg', (169, 178))	('LC3', 'Gene', '84557', (158, 161))	('conversion', 'MPA', (135, 145))	('LC3', 'Gene', '84557', (149, 152))	('CPT', 'Var', (106, 109))	('LC3', 'Gene', (50, 53))	('CPT', 'Chemical', 'MESH:D002166', (106, 109))	('EC1', 'Gene', (212, 215))	('LC3', 'Gene', (41, 44))	('EC1', 'Gene', (204, 207))
724235	33898327	Next we found that CPT significantly induced apoptosis ( Figures 1E, F  ), as best evidenced by the increase of Annexin V-positive cell populations and the accumulation of cleaved-PARP and cleaved-Caspase-3, two classical markers of apoptosis.	('CPT', 'Var', (19, 22))	('Caspase-3', 'Gene', (197, 206))	('PARP', 'Gene', '1302', (180, 184))	('accumulation', 'PosReg', (156, 168))	('CPT', 'Chemical', 'MESH:D002166', (19, 22))	('Annexin V', 'Gene', '308', (112, 121))	('apoptosis', 'CPA', (45, 54))	('PARP', 'Gene', (180, 184))	('increase', 'PosReg', (100, 108))	('Caspase-3', 'Gene', '836', (197, 206))	('Annexin V', 'Gene', (112, 121))
724239	33898327	CPT-treated tumors progressed slowly, whereas control tumors grew rapidly over time, as shown by tumor growth curve ( Figure 1G ) and tumor weight analysis ( Figure 1H ).	('slowly', 'NegReg', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('progressed', 'CPA', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CPT-treated', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (54, 59))	('CPT', 'Chemical', 'MESH:D002166', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
724248	33898327	Previous studies indicated that the activation of AMPK/ULK1 pathway induced autophagy, and inactivation of the mTOR pathway could promote autophagy in multiple human cancers.	('ULK1', 'Gene', (55, 59))	('cancers', 'Disease', (166, 173))	('AMPK', 'Gene', (50, 54))	('autophagy', 'CPA', (138, 147))	('promote', 'PosReg', (130, 137))	('mTOR', 'Gene', '2475', (111, 115))	('autophagy', 'CPA', (76, 85))	('ULK1', 'Gene', '8408', (55, 59))	('mTOR', 'Gene', (111, 115))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('activation', 'PosReg', (36, 46))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('AMPK', 'Gene', '5563', (50, 54))	('inactivation', 'Var', (91, 103))	('human', 'Species', '9606', (160, 165))
724252	33898327	In order to determine the role of AMPK in CPT-induced expression of p-ULK1 and inhibition of p-p70S6K in EC1 and EC109 cells, we used Compound C (an AMPK inhibitor) to inactivate the AMPK pathway and found that inactivation of AMPK significantly reversed CPT-induced expression of p-ULK1 in ESCC cells.	('AMPK', 'Gene', (149, 153))	('AMPK', 'Gene', '5563', (34, 38))	('ULK1', 'Gene', '8408', (70, 74))	('AMPK', 'Gene', '5563', (183, 187))	('ULK1', 'Gene', '8408', (283, 287))	('inactivation', 'Var', (211, 223))	('EC1', 'Gene', (105, 108))	('AMPK', 'Gene', (227, 231))	('EC109', 'CellLine', 'CVCL:6898', (113, 118))	('EC1', 'Gene', (113, 116))	('p70S6K', 'Gene', (95, 101))	('ULK1', 'Gene', (70, 74))	('ULK1', 'Gene', (283, 287))	('AMPK', 'Gene', (34, 38))	('EC1', 'Gene', '4819', (105, 108))	('AMPK', 'Gene', (183, 187))	('EC1', 'Gene', '4819', (113, 116))	('AMPK', 'Gene', '5563', (149, 153))	('CPT', 'Chemical', 'MESH:D002166', (255, 258))	('expression', 'MPA', (267, 277))	('CPT', 'Chemical', 'MESH:D002166', (42, 45))	('p70S6K', 'Gene', '6198', (95, 101))	('AMPK', 'Gene', '5563', (227, 231))
724253	33898327	Consistently, inactivation of AMPK significantly reversed CPT-inhibited expression of p-p70S6K.	('p70S6K', 'Gene', (88, 94))	('AMPK', 'Gene', '5563', (30, 34))	('inactivation', 'Var', (14, 26))	('AMPK', 'Gene', (30, 34))	('expression', 'MPA', (72, 82))	('CPT', 'Chemical', 'MESH:D002166', (58, 61))	('p70S6K', 'Gene', '6198', (88, 94))
724254	33898327	Moreover, inactivation of AMPK via Compound C treatment significantly increased CPT-induced proliferation inhibition ( Figure 3B ).	('AMPK', 'Gene', '5563', (26, 30))	('CPT-induced proliferation inhibition', 'CPA', (80, 116))	('increased', 'PosReg', (70, 79))	('inactivation', 'Var', (10, 22))	('AMPK', 'Gene', (26, 30))	('CPT', 'Chemical', 'MESH:D002166', (80, 83))
724256	33898327	In order to determine the role of ULK1 in CPT-induced autophagy in EC1 and EC109 cells, we knockdown ULK1 and found that ULK1 knockdown markedly attenuated the conversion of LC3 I to LC3 II in ESCC cell ( Figures 3E, F  ).	('ULK1', 'Gene', '8408', (101, 105))	('attenuated', 'NegReg', (145, 155))	('EC1', 'Gene', '4819', (67, 70))	('EC1', 'Gene', '4819', (75, 78))	('ULK1', 'Gene', (101, 105))	('ULK1', 'Gene', '8408', (34, 38))	('LC3 II', 'Chemical', '-', (183, 189))	('LC3', 'Protein', (174, 177))	('ULK1', 'Gene', '8408', (121, 125))	('conversion', 'MPA', (160, 170))	('ULK1', 'Gene', (34, 38))	('CPT', 'Chemical', 'MESH:D002166', (42, 45))	('ULK1', 'Gene', (121, 125))	('LC3 I', 'Chemical', '-', (183, 188))	('EC1', 'Gene', (67, 70))	('EC109', 'CellLine', 'CVCL:6898', (75, 80))	('knockdown', 'Var', (126, 135))	('EC1', 'Gene', (75, 78))	('LC3 I', 'Chemical', '-', (174, 179))
724263	33898327	Since the inactivation of NF-kappaB could induce ROS generation, we next determined whether ROS/AMPK/mTOR/ULK1 axis-induced autophagy is mediated by the NF-kappaB pathway.	('ROS', 'Chemical', 'MESH:D017382', (92, 95))	('NF-kappaB', 'Gene', '4790', (26, 35))	('mTOR', 'Gene', (101, 105))	('induce', 'Reg', (42, 48))	('NF-kappaB', 'Gene', (26, 35))	('mTOR', 'Gene', '2475', (101, 105))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('inactivation', 'Var', (10, 22))	('AMPK', 'Gene', '5563', (96, 100))	('ROS generation', 'MPA', (49, 63))	('AMPK', 'Gene', (96, 100))	('ULK1', 'Gene', (106, 110))	('NF-kappaB', 'Gene', '4790', (153, 162))	('ULK1', 'Gene', '8408', (106, 110))	('NF-kappaB', 'Gene', (153, 162))
724269	33898327	Interestingly, we found that CPT indeed suppressed the global protein neddylation and the neddylation levels of Cullin1 ( Figure 5D ).	('Cullin1', 'Gene', '8454', (112, 119))	('suppressed', 'NegReg', (40, 50))	('CPT', 'Var', (29, 32))	('global protein neddylation', 'MPA', (55, 81))	('CPT', 'Chemical', 'MESH:D002166', (29, 32))	('neddylation levels', 'MPA', (90, 108))	('Cullin1', 'Gene', (112, 119))
724271	33898327	The key neddylation enzymes, NAE1, UBA3 and UBC12, were obviously suppressed upon CPT treatment in EC1 cells ( Figure 5E ).	('neddylation enzymes', 'Enzyme', (8, 27))	('UBC12', 'Gene', '9040', (44, 49))	('UBA3', 'Gene', '9039', (35, 39))	('NAE1', 'Gene', '8883', (29, 33))	('UBC12', 'Gene', (44, 49))	('NAE1', 'Gene', (29, 33))	('suppressed', 'NegReg', (66, 76))	('UBA3', 'Gene', (35, 39))	('CPT', 'Chemical', 'MESH:D002166', (82, 85))	('treatment', 'Var', (86, 95))	('EC1', 'Gene', '4819', (99, 102))	('EC1', 'Gene', (99, 102))
724274	33898327	As shown in  Figure 5F , CPT indeed suppressed the global protein neddylation, cullin1 neddylation, and the expression of the neddylation enzyme UBC12.	('suppressed', 'NegReg', (36, 46))	('CPT', 'Chemical', 'MESH:D002166', (25, 28))	('global protein neddylation', 'MPA', (51, 77))	('neddylation', 'MPA', (87, 98))	('UBC12', 'Gene', '9040', (145, 150))	('cullin1', 'Gene', '8454', (79, 86))	('expression', 'MPA', (108, 118))	('CPT', 'Var', (25, 28))	('cullin1', 'Gene', (79, 86))	('UBC12', 'Gene', (145, 150))
724277	33898327	We found that IkappaBalpha knockdown markedly attenuated CPT-induced expression of p-AMPK, p-ULK1 ( Figure 5G ) and the generation of ROS ( Figures 5H, I  ).	('AMPK', 'Gene', '5563', (85, 89))	('knockdown', 'Var', (27, 36))	('ULK1', 'Gene', (93, 97))	('IkappaBalpha', 'Gene', (14, 26))	('ROS', 'Chemical', 'MESH:D017382', (134, 137))	('IkappaBalpha', 'Gene', '4792', (14, 26))	('ULK1', 'Gene', '8408', (93, 97))	('AMPK', 'Gene', (85, 89))	('expression', 'MPA', (69, 79))	('attenuated', 'NegReg', (46, 56))	('generation', 'MPA', (120, 130))	('CPT', 'Chemical', 'MESH:D002166', (57, 60))	('ROS', 'MPA', (134, 137))	('CPT-induced', 'Gene', (57, 68))
724278	33898327	Furthermore, we found that IkappaBalpha knockdown significantly enhanced CPT-induced proliferation inhibition ( Figure 5J ).	('CPT', 'Chemical', 'MESH:D002166', (73, 76))	('CPT-induced proliferation inhibition', 'CPA', (73, 109))	('knockdown', 'Var', (40, 49))	('IkappaBalpha', 'Gene', '4792', (27, 39))	('IkappaBalpha', 'Gene', (27, 39))	('enhanced', 'PosReg', (64, 72))
724279	33898327	In addition, IkappaBalpha knockdown significantly enhanced CPT-induced apoptosis, as evidenced by the accumulation of cleaved PARP ( Figure 5G ) and the increase of Annexin V-positive cell populations ( Figure 5K ).	('PARP', 'Gene', '1302', (126, 130))	('accumulation', 'PosReg', (102, 114))	('Annexin V', 'Gene', '308', (165, 174))	('Annexin V', 'Gene', (165, 174))	('apoptosis', 'CPA', (71, 80))	('PARP', 'Gene', (126, 130))	('enhanced', 'PosReg', (50, 58))	('increase', 'PosReg', (153, 161))	('IkappaBalpha', 'Gene', '4792', (13, 25))	('knockdown', 'Var', (26, 35))	('CPT-induced', 'Disease', (59, 70))	('CPT', 'Chemical', 'MESH:D002166', (59, 62))	('IkappaBalpha', 'Gene', (13, 25))
724298	33898327	Mechanistically, CPT inactivates neddylation pathway, which induce the expression of p-IkappaBalpha to modulate AMPK/mTOR/ULK1 pathway to trigger pro-survival autophagy, whereas targeting this pathway blocks the autophagic response and thus sensitizes cancer cells to CPT-induced apoptosis.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('mTOR', 'Gene', '2475', (117, 121))	('IkappaBalpha', 'Gene', (87, 99))	('targeting', 'Var', (178, 187))	('IkappaBalpha', 'Gene', '4792', (87, 99))	('inactivates', 'NegReg', (21, 32))	('AMPK', 'Gene', '5563', (112, 116))	('CPT', 'Chemical', 'MESH:D002166', (268, 271))	('trigger', 'PosReg', (138, 145))	('pro-survival autophagy', 'CPA', (146, 168))	('neddylation pathway', 'Pathway', (33, 52))	('ULK1', 'Gene', '8408', (122, 126))	('blocks', 'NegReg', (201, 207))	('expression', 'MPA', (71, 81))	('cancer', 'Disease', (252, 258))	('AMPK', 'Gene', (112, 116))	('autophagic response', 'CPA', (212, 231))	('ULK1', 'Gene', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('CPT', 'Chemical', 'MESH:D002166', (17, 20))	('modulate', 'Reg', (103, 111))	('mTOR', 'Gene', (117, 121))	('sensitizes', 'Reg', (241, 251))
724325	32199464	Significantly more perioperative mortality was seen (30 or 90 days) in the NACRT group (OR = 1.79 CI 1.15-2.80, p = .01) (Fig.	('perioperative mortality', 'CPA', (19, 42))	('NACRT', 'Var', (75, 80))	('NACRT', 'Chemical', '-', (75, 80))
724338	32199464	The meta-analysis also showed 48% lower recurrences (systemic and locoregional) in the NACRT arm.	('NACRT', 'Var', (87, 92))	('lower', 'NegReg', (34, 39))	('recurrences', 'CPA', (40, 51))	('NACRT', 'Chemical', '-', (87, 92))
724343	32199464	Third, there is also a possibility of increased non-cancer-related deaths in the long term in the NACRT group.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('NACRT', 'Chemical', '-', (98, 103))	('NACRT', 'Var', (98, 103))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('increased', 'PosReg', (38, 47))
724358	32199464	also showed a trend towards survival benefit with NACT, but this did not reach statistical significance.	('survival benefit', 'CPA', (28, 44))	('NACT', 'Chemical', '-', (50, 54))	('NACT', 'Var', (50, 54))
724380	30408943	Rupture of esophageal/gastric varices may lead to life-threatening and massive bleeding.	('gastric varices', 'Phenotype', 'HP:0030169', (22, 37))	('esophageal/gastric varices', 'Phenotype', 'HP:0002040', (11, 37))	('esophageal', 'Disease', (11, 21))	('Rupture', 'Var', (0, 7))	('bleeding', 'Disease', 'MESH:D006470', (79, 87))	('lead to', 'Reg', (42, 49))	('esophageal', 'Disease', 'MESH:D004941', (11, 21))	('bleeding', 'Disease', (79, 87))
724433	30408943	Complications of EIS or BRTO can easily lead to hepatic failure, therefore continuous efforts are necessary to perform procedures skillfully and to establish a safe and effective standard treatment.	('lead to', 'Reg', (40, 47))	('hepatic failure', 'Disease', 'MESH:D017093', (48, 63))	('Complications', 'Var', (0, 13))	('men', 'Species', '9606', (193, 196))	('hepatic failure', 'Disease', (48, 63))	('hepatic failure', 'Phenotype', 'HP:0001399', (48, 63))
724436	30408943	The findings of this study suggested that, among patients with CP-C end-stage LC, those with lower CPS (10 or lower) and lower serum total bilirubin levels (4.0 mg/dL or lower) did not have a worse prognosis after invasive treatment.	('LC', 'Phenotype', 'HP:0001394', (78, 80))	('CP-C', 'Var', (63, 67))	('bilirubin', 'Chemical', 'MESH:D001663', (139, 148))	('men', 'Species', '9606', (228, 231))	('lower', 'NegReg', (121, 126))	('CPS', 'MPA', (99, 102))	('patients', 'Species', '9606', (49, 57))	('CPS', 'Chemical', '-', (99, 102))	('CP-C', 'Chemical', '-', (63, 67))	('serum total bilirubin levels', 'MPA', (127, 155))
724451	29390385	A blood test showed leukocytosis (10390 mm3/muL) and anemia (hemoglobin: 7.6 mg/dL).	('anemia', 'Disease', (53, 59))	('anemia', 'Disease', 'MESH:D000740', (53, 59))	('leukocytosis', 'Phenotype', 'HP:0001974', (20, 32))	('10390', 'Var', (34, 39))	('leukocytosis', 'Disease', 'MESH:D007964', (20, 32))	('anemia', 'Phenotype', 'HP:0001903', (53, 59))	('leukocytosis', 'Disease', (20, 32))
724493	27080237	One notable finding was that miRNA expression profiles of colon adenocarcinoma with high microsatellite instability (MSI-H) were visibly different from those of low MSI (MSI-L) and microsatellite-stable (MSS) samples as shown in hierarchical clustering (Fig.	('different', 'Reg', (137, 146))	('miRNA expression profiles', 'MPA', (29, 54))	('colon adenocarcinoma', 'Disease', (58, 78))	('high', 'Var', (84, 88))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (58, 78))	('microsatellite instability', 'MPA', (89, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
724501	27080237	On the basis of this analysis, we developed a miRNA-based formula to predict disease progression in untreated colon adenocarcinoma:  s = 22.22 *log2(TPM of let-7f-2) + (-13.93)*log2(TPM of miR-106a).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('let-7f-2', 'Gene', '406889', (156, 164))	('colon adenocarcinoma', 'Disease', (110, 130))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (110, 130))	('let-7f-2', 'Gene', (156, 164))	('miR-106a', 'Gene', '406899', (189, 197))	('miR-106a', 'Gene', (189, 197))	('s =', 'Var', (133, 136))
724551	27080237	Stratification of Digestive Cancers with Different Pathological Features and Survival Outcomes by MicroRNA Expression.	('MicroRNA', 'Var', (98, 106))	('Cancers', 'Disease', (28, 35))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Cancers', 'Phenotype', 'HP:0002664', (28, 35))	('Cancers', 'Disease', 'MESH:D009369', (28, 35))
724637	33658929	Dihydroartemisinin Inhibits the Proliferation of Esophageal Squamous Cell Carcinoma Partially by Targeting AKT1 and p70S6K Dihydroartemisinin (DHA), a sesquiterpene lactone with endoperoxide bridge, is one of the derivatives of artemisinin.	('Carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('Dihydroartemisinin', 'Chemical', 'MESH:C039060', (123, 141))	('artemisinin', 'Chemical', 'MESH:C031327', (7, 18))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('AKT1', 'Gene', '207', (107, 111))	('Inhibits', 'NegReg', (19, 27))	('Proliferation', 'CPA', (32, 45))	('endoperoxide', 'Chemical', '-', (178, 190))	('Squamous Cell Carcinoma', 'Disease', (60, 83))	('artemisinin', 'Chemical', 'MESH:C031327', (228, 239))	('DHA', 'Chemical', 'MESH:C039060', (143, 146))	('AKT1', 'Gene', (107, 111))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('artemisinin', 'Chemical', 'MESH:C031327', (130, 141))	('Dihydroartemisinin', 'Chemical', 'MESH:C039060', (0, 18))	('p70S6K', 'Var', (116, 122))	('sesquiterpene lactone', 'Chemical', '-', (151, 172))
724640	33658929	In this study, DHA was found to inhibit the proliferation of ESCC, and the underlying molecular mechanisms were explored.	('DHA', 'Chemical', 'MESH:C039060', (15, 18))	('inhibit', 'NegReg', (32, 39))	('ESCC', 'CPA', (61, 65))	('DHA', 'Var', (15, 18))	('proliferation', 'CPA', (44, 57))
724644	33658929	Furthermore, the levels of mTORS2448, p70S6KT389, p70S6KT421/S424 and RPS6S235/S236 were decreased after DHA treatment in KYSE30 and KYSE150 cells.	('p70S6K', 'Gene', '6198', (50, 56))	('p70S6K', 'Gene', (50, 56))	('DHA', 'Chemical', 'MESH:C039060', (105, 108))	('p70S6K', 'Gene', (38, 44))	('RPS6', 'Gene', (70, 74))	('mTORS2448', 'Chemical', '-', (27, 36))	('p70S6K', 'Gene', '6198', (38, 44))	('RPS6', 'Gene', '6194', (70, 74))	('levels', 'MPA', (17, 23))	('mTORS2448', 'Var', (27, 36))	('KYSE150', 'CellLine', 'CVCL:1348', (133, 140))	('decreased', 'NegReg', (89, 98))
724647	33658929	In vivo, DHA inhibited the tumor growth of ESCC patient-derived xenografts and weakened p-mTOR, p-p70S6K, and p-RPS6 expression in tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('RPS6', 'Gene', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('DHA', 'Chemical', 'MESH:C039060', (9, 12))	('mTOR', 'Gene', (90, 94))	('tumor', 'Disease', (27, 32))	('mTOR', 'Gene', '2475', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('p70S6K', 'Gene', (98, 104))	('inhibited', 'NegReg', (13, 22))	('RPS6', 'Gene', '6194', (112, 116))	('tumor', 'Disease', (131, 136))	('DHA', 'Var', (9, 12))	('patient', 'Species', '9606', (48, 55))	('p70S6K', 'Gene', '6198', (98, 104))	('weakened', 'NegReg', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
724659	33658929	As the modification of the carboxy group to a hydroxy group improves their efficacy, dihydroartemisinin (DHA) is introduced as a new antimalarial drug.	('improves', 'PosReg', (60, 68))	('DHA', 'Chemical', 'MESH:C039060', (105, 108))	('efficacy', 'MPA', (75, 83))	('dihydroartemisinin', 'Chemical', 'MESH:C039060', (85, 103))	('modification', 'Var', (7, 19))
724666	33658929	DHA inhibits the growth of ESCC cells Eca109 and Ec9706 and enhances the therapeutic effect of photodynamic therapy.	('growth', 'CPA', (17, 23))	('Ec9706', 'Var', (49, 55))	('inhibits', 'NegReg', (4, 12))	('enhances', 'PosReg', (60, 68))	('ESCC', 'Disease', (27, 31))	('therapeutic effect of photodynamic therapy', 'CPA', (73, 115))	('DHA', 'Chemical', 'MESH:C039060', (0, 3))	('Ec9706', 'CellLine', 'CVCL:E307', (49, 55))
724672	33658929	LY2584702 (p70S6K inhibitor, Cat #1082949-68-5) was purchased from Med Chem Express.	('p70S6K', 'Gene', (11, 17))	('LY2584702', 'Chemical', 'MESH:C588151', (0, 9))	('LY2584702', 'Var', (0, 9))	('p70S6K', 'Gene', '6198', (11, 17))
724692	33658929	A16-10G) or p70S6K (Signalchem, Catalog No.	('A16-10G', 'Var', (0, 7))	('A16-10G', 'SUBSTITUTION', 'None', (0, 7))	('p70S6K', 'Gene', '6198', (12, 18))	('p70S6K', 'Gene', (12, 18))
724709	33658929	The colony size and colony number of KYSE30 and KYSE150 cells in those treated with DHA were lower than with controls (Figure 1C).	('colony number', 'CPA', (20, 33))	('KYSE150', 'Var', (48, 55))	('DHA', 'Chemical', 'MESH:C039060', (84, 87))	('KYSE150', 'CellLine', 'CVCL:1348', (48, 55))	('lower', 'NegReg', (93, 98))	('colony size', 'CPA', (4, 15))	('DHA', 'Var', (84, 87))
724712	33658929	With the increase of DHA concentration, the cell cycles of KYSE30 (Figures 2A,C) and KYSE150 (Figures 2B,D) were significantly blocked in G 0/G 1 phase.	('cell cycles', 'CPA', (44, 55))	('G 0/G 1 phase', 'CPA', (138, 151))	('increase', 'PosReg', (9, 17))	('KYSE150', 'Var', (85, 92))	('KYSE30', 'Var', (59, 65))	('blocked', 'NegReg', (127, 134))	('DHA', 'Chemical', 'MESH:C039060', (21, 24))	('KYSE150', 'CellLine', 'CVCL:1348', (85, 92))
724715	33658929	Protein p21 was upregulated by DHA in KYSE30 (Figure 2E) and KYSE150 cells (Figure 2F).	('upregulated', 'PosReg', (16, 27))	('DHA', 'Var', (31, 34))	('p21', 'Gene', (8, 11))	('p21', 'Gene', '644914', (8, 11))	('DHA', 'Chemical', 'MESH:C039060', (31, 34))	('KYSE150', 'CellLine', 'CVCL:1348', (61, 68))
724718	33658929	KYSE30 and KYSE150 cells were treated with DHA (10 muM) for 12 h. The results indicated that DHA inhibited the phosphorylation of p38alpha, p70S6K, eNOS, Fgr, STAT5b, PLC-gamma1 and PYK2 (Figure 3A).	('Fgr', 'Gene', (154, 157))	('p70S6K', 'Gene', '6198', (140, 146))	('Fgr', 'Gene', '2268', (154, 157))	('eNOS', 'Gene', (148, 152))	('DHA', 'Chemical', 'MESH:C039060', (93, 96))	('eNOS', 'Gene', '4846', (148, 152))	('inhibited', 'NegReg', (97, 106))	('STAT5b', 'Gene', (159, 165))	('phosphorylation', 'MPA', (111, 126))	('PYK2', 'Gene', '2185', (182, 186))	('PLC-gamma1', 'Gene', '5335', (167, 177))	('KYSE150', 'CellLine', 'CVCL:1348', (11, 18))	('p70S6K', 'Gene', (140, 146))	('DHA', 'Chemical', 'MESH:C039060', (43, 46))	('DHA', 'Var', (93, 96))	('p38alpha', 'Gene', (130, 138))	('PLC-gamma1', 'Gene', (167, 177))	('PYK2', 'Gene', (182, 186))	('STAT5b', 'Gene', '6777', (159, 165))	('p38alpha', 'Gene', '1432', (130, 138))
724722	33658929	Treatment with DHA at 0, 5, 10, or 15 muM for 24 h downregulated the levels of p-mTORS2448, p-p70S6KT389, p-p70S6KT421/S424 and p-RPS6S235/S236 in KYSE30 cells (Figure 3B).	('p-mTORS2448', 'Var', (79, 90))	('mTORS2448', 'Chemical', '-', (81, 90))	('DHA', 'Chemical', 'MESH:C039060', (15, 18))	('RPS6', 'Gene', '6194', (130, 134))	('downregulated', 'NegReg', (51, 64))	('p70S6K', 'Gene', '6198', (94, 100))	('p70S6K', 'Gene', '6198', (108, 114))	('p70S6K', 'Gene', (108, 114))	('p70S6K', 'Gene', (94, 100))	('RPS6', 'Gene', (130, 134))
724729	33658929	We once again confirmed that AKT1 and p70S6K directly phosphorylated S2448 site of mTOR through an in vitro kinase assay, and DHA significantly attenuated the phosphorylation level of mTOR through AKT1 and p70S6K (Figures 4C,D).	('S2448 site', 'Var', (69, 79))	('attenuated', 'NegReg', (144, 154))	('mTOR', 'Gene', (83, 87))	('DHA', 'Var', (126, 129))	('mTOR', 'Gene', '2475', (184, 188))	('mTOR', 'Gene', (184, 188))	('p70S6K', 'Gene', (38, 44))	('p70S6K', 'Gene', (206, 212))	('AKT1', 'Gene', '207', (29, 33))	('DHA', 'Chemical', 'MESH:C039060', (126, 129))	('p70S6K', 'Gene', '6198', (38, 44))	('p70S6K', 'Gene', '6198', (206, 212))	('phosphorylation level', 'MPA', (159, 180))	('AKT1', 'Gene', '207', (197, 201))	('AKT1', 'Gene', (29, 33))	('AKT1', 'Gene', (197, 201))	('mTOR', 'Gene', '2475', (83, 87))
724730	33658929	What's more, MK2206 (an AKT inhibitor) and LY-2584702 (a p70S6K inhibitor) reduced the phosphorylation of mTOR in the in vitro kinase assays and in ESCC cells, respectively (Figures 4C,D; Supplementary Figure S1).	('p70S6K', 'Gene', (57, 63))	('MK2206', 'Chemical', 'MESH:C548887', (13, 19))	('AKT', 'Gene', (24, 27))	('p70S6K', 'Gene', '6198', (57, 63))	('reduced', 'NegReg', (75, 82))	('MK2206', 'Var', (13, 19))	('phosphorylation', 'MPA', (87, 102))	('AKT', 'Gene', '207', (24, 27))	('LY-2584702', 'Var', (43, 53))	('mTOR', 'Gene', (106, 110))	('mTOR', 'Gene', '2475', (106, 110))	('LY-2584702', 'Chemical', 'MESH:C588151', (43, 53))
724734	33658929	The results showed that DHA significantly inhibited tumor growth compared with the control group (Figure 5C).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('DHA', 'Var', (24, 27))	('inhibited', 'NegReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('DHA', 'Chemical', 'MESH:C039060', (24, 27))
724737	33658929	The weights of the tumor tissues treated with DHA (Figure 5D) were lower than those of the control group.	('DHA', 'Chemical', 'MESH:C039060', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('weights', 'CPA', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('DHA', 'Var', (46, 49))	('tumor', 'Disease', (19, 24))	('lower', 'NegReg', (67, 72))
724739	33658929	In these two cases, DHA significantly inhibited tumor growth without loss in body weight with reference to the control group (Figure 5A).	('DHA', 'Var', (20, 23))	('tumor', 'Disease', (48, 53))	('inhibited', 'NegReg', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('DHA', 'Chemical', 'MESH:C039060', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
724741	33658929	We investigated the effect of DHA on p-mTORS2448, p-p70S6KT389, p-p70S6KT421/S424 and p-RPS6S235/S236 by immunohistochemical (IHC) analysis of PDX LEG20 and LEG24 tumor samples.	('RPS6', 'Gene', '6194', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('DHA', 'Chemical', 'MESH:C039060', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('p70S6K', 'Gene', (52, 58))	('p-mTORS2448', 'Var', (37, 48))	('p70S6K', 'Gene', '6198', (52, 58))	('tumor', 'Disease', (163, 168))	('p70S6K', 'Gene', (66, 72))	('RPS6', 'Gene', (88, 92))	('p70S6K', 'Gene', '6198', (66, 72))	('mTORS2448', 'Chemical', '-', (39, 48))
724742	33658929	The phosphorylation of mTOR, p70S6K, RPS6 were strongly inhibited in the DHA-treated group (Figure 6; Supplementary Figure S3), which also proved by western blot analysis (Supplementary Figure S2).	('RPS6', 'Gene', '6194', (37, 41))	('phosphorylation', 'MPA', (4, 19))	('DHA-treated', 'Var', (73, 84))	('inhibited', 'NegReg', (56, 65))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (23, 27))	('p70S6K', 'Gene', (29, 35))	('RPS6', 'Gene', (37, 41))	('p70S6K', 'Gene', '6198', (29, 35))	('DHA', 'Chemical', 'MESH:C039060', (73, 76))
724748	33658929	Previous studies showed that DHA inhibited cell proliferation and induced apoptosis in human hepatocellular carcinoma cells by upregulating TNF expression via JNK/NF-kappaB pathways.	('JNK', 'Gene', (159, 162))	('NF-kappaB', 'Gene', (163, 172))	('upregulating', 'PosReg', (127, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (93, 117))	('induced', 'PosReg', (66, 73))	('expression', 'MPA', (144, 154))	('hepatocellular carcinoma', 'Disease', (93, 117))	('TNF', 'Gene', '7124', (140, 143))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (93, 117))	('human', 'Species', '9606', (87, 92))	('DHA', 'Chemical', 'MESH:C039060', (29, 32))	('JNK', 'Gene', '5599', (159, 162))	('NF-kappaB', 'Gene', '4790', (163, 172))	('DHA', 'Var', (29, 32))	('cell proliferation', 'CPA', (43, 61))	('inhibited', 'NegReg', (33, 42))	('TNF', 'Gene', (140, 143))
724753	33658929	Furthermore, DHA induced cell cycle arrest in G1 phase, and the related regulatory proteins CDK2 and p21 changed correspondingly (Figure 2).	('DHA', 'Var', (13, 16))	('CDK2', 'Gene', '1017', (92, 96))	('DHA', 'Chemical', 'MESH:C039060', (13, 16))	('arrest', 'Disease', 'MESH:D006323', (36, 42))	('p21', 'Gene', (101, 104))	('changed', 'Reg', (105, 112))	('p21', 'Gene', '644914', (101, 104))	('arrest', 'Disease', (36, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (25, 42))	('CDK2', 'Gene', (92, 96))
724757	33658929	Multiple studies have suggested that inhibiting the activity of mTOR blocks the cycle of cancer cells and further inhibits proliferation.	('proliferation', 'CPA', (123, 136))	('activity', 'MPA', (52, 60))	('inhibits', 'NegReg', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('mTOR', 'Gene', (64, 68))	('cancer', 'Disease', (89, 95))	('inhibiting', 'Var', (37, 47))	('mTOR', 'Gene', '2475', (64, 68))	('blocks', 'NegReg', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
724760	33658929	Evidence suggests that DHA can affect the AKT and/or mTOR pathway in different diseases.	('affect', 'Reg', (31, 37))	('AKT', 'Gene', (42, 45))	('DHA', 'Chemical', 'MESH:C039060', (23, 26))	('mTOR', 'Gene', (53, 57))	('mTOR', 'Gene', '2475', (53, 57))	('AKT', 'Gene', '207', (42, 45))	('DHA', 'Var', (23, 26))
724762	33658929	In the autoimmune thyroiditis (AIT), DHA inhibits the CXCR3/PI3K/AKT/NF-kappaB signaling pathway which executes important roles in AIT.	('CXCR3', 'Gene', (54, 59))	('inhibits', 'NegReg', (41, 49))	('AKT', 'Gene', (65, 68))	('NF-kappaB', 'Gene', '4790', (69, 78))	('DHA', 'Chemical', 'MESH:C039060', (37, 40))	('autoimmune thyroiditis', 'Disease', (7, 29))	('CXCR3', 'Gene', '2833', (54, 59))	('AKT', 'Gene', '207', (65, 68))	('NF-kappaB', 'Gene', (69, 78))	('thyroiditis', 'Phenotype', 'HP:0100646', (18, 29))	('autoimmune thyroiditis', 'Disease', 'MESH:D013967', (7, 29))	('DHA', 'Var', (37, 40))
724764	33658929	Recent studies indicate that DHA induces cell autophagy via mTOR/p70S6k signaling pathway.	('p70S6k', 'Gene', '6198', (65, 71))	('cell autophagy', 'CPA', (41, 55))	('DHA', 'Chemical', 'MESH:C039060', (29, 32))	('mTOR', 'Gene', '2475', (60, 64))	('mTOR', 'Gene', (60, 64))	('DHA', 'Var', (29, 32))	('p70S6k', 'Gene', (65, 71))
724766	33658929	In our study, DHA did not significantly reduce the phosphorylation of AKT in ESCC cells, but significantly inhibited the phosphorylation of mTOR (Figures 3B,D).	('AKT', 'Gene', '207', (70, 73))	('DHA', 'Var', (14, 17))	('phosphorylation', 'MPA', (121, 136))	('AKT', 'Gene', (70, 73))	('mTOR', 'Gene', '2475', (140, 144))	('mTOR', 'Gene', (140, 144))	('inhibited', 'NegReg', (107, 116))	('DHA', 'Chemical', 'MESH:C039060', (14, 17))
724770	33658929	Studies have shown that AKT and p70S6K phosphorylate the S2448 site of mTOR protein to activate the mTOR pathway.	('p70S6K', 'Gene', (32, 38))	('AKT', 'Gene', (24, 27))	('p70S6K', 'Gene', '6198', (32, 38))	('mTOR', 'Gene', '2475', (71, 75))	('activate', 'PosReg', (87, 95))	('mTOR', 'Gene', (71, 75))	('AKT', 'Gene', '207', (24, 27))	('S2448', 'Var', (57, 62))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
724771	33658929	Chiang and Abraham also proved that p70S6 kinase phosphorylates mTOR at Ser-2448 in vitro, and that ectopic expression of p70S6 kinase restores Ser-2448 phosphorylation in rapamycin-treated cells.	('restores', 'PosReg', (135, 143))	('p70S6', 'Var', (36, 41))	('Ser', 'Chemical', 'MESH:D012694', (144, 147))	('Ser', 'Chemical', 'MESH:D012694', (72, 75))	('mTOR', 'Gene', (64, 68))	('mTOR', 'Gene', '2475', (64, 68))	('rapamycin', 'Chemical', 'MESH:D020123', (172, 181))	('Ser-2448 phosphorylation', 'MPA', (144, 168))	('p70S6 kinase', 'Var', (122, 134))
724773	33658929	Next, our results demonstrated that active AKT1 (S473) and p70S6K (T389) phosphorylated S2448 site of mTOR in an in vitro kinase assay.	('AKT1', 'Gene', (43, 47))	('S2448 site', 'Var', (88, 98))	('mTOR', 'Gene', (102, 106))	('p70S6K', 'Gene', '6198', (59, 65))	('mTOR', 'Gene', '2475', (102, 106))	('p70S6K', 'Gene', (59, 65))	('AKT1', 'Gene', '207', (43, 47))	('S473', 'Var', (49, 53))
724775	33658929	To further confirm these phenomena, we measured the mTOR phosphorylation levels in kinase inhibitor (MK2206 and LY-2584702)-treated ESCC cells.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('LY-2584702', 'Var', (112, 122))	('MK2206', 'Chemical', 'MESH:C548887', (101, 107))	('LY-2584702', 'Chemical', 'MESH:C588151', (112, 122))
724777	33658929	Likewise, MK2206 and LY-2584702 decreased the phosphorylation level of mTOR via AKT-S473 and p70S6K-T389 in the in vitro kinase assay.	('AKT', 'Gene', '207', (80, 83))	('LY-2584702', 'Var', (21, 31))	('MK2206', 'Chemical', 'MESH:C548887', (10, 16))	('LY-2584702', 'Chemical', 'MESH:C588151', (21, 31))	('decreased', 'NegReg', (32, 41))	('mTOR', 'Gene', '2475', (71, 75))	('AKT', 'Gene', (80, 83))	('mTOR', 'Gene', (71, 75))	('p70S6K', 'Gene', (93, 99))	('phosphorylation level', 'MPA', (46, 67))	('MK2206', 'Var', (10, 16))	('p70S6K', 'Gene', '6198', (93, 99))
724785	30716477	Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables.	('25(OH)D', 'Chemical', '-', (163, 170))	('rs17216707', 'Mutation', 'rs17216707', (105, 115))	('rs10741657', 'Mutation', 'rs10741657', (54, 64))	('rs12785878', 'Mutation', 'rs12785878', (66, 76))	('rs3755967', 'Var', (43, 52))	('rs10745742', 'Mutation', 'rs10745742', (78, 88))	('rs8018720', 'Mutation', 'rs8018720', (90, 99))	('rs17216707', 'Var', (105, 115))	('rs10741657', 'Var', (54, 64))	('rs10745742', 'Var', (78, 88))	('rs12785878', 'Var', (66, 76))	('rs3755967', 'Mutation', 'rs3755967', (43, 52))	('rs8018720', 'Var', (90, 99))
724795	30716477	This approach uses instrumental variables (e.g., genetic variants as proxy markers of directly measured risk factors) to make inferences about the relation between an exposure (e.g., low 25(OH)D concentration) and outcome (e.g., BE and EAC).	('25(OH)D', 'Chemical', '-', (187, 194))	('BE', 'Phenotype', 'HP:0100580', (229, 231))	('variants', 'Var', (57, 65))	('EAC', 'Phenotype', 'HP:0011459', (236, 239))	('low', 'Var', (183, 186))
724803	30716477	These six SNPs are uncorrelated and are located in or close to the following genes: GC (rs3755967), CYP2R1 (rs10741657), DHCR7 (rs12785878), AMDHD1 (rs10745742), SEC23A (rs8018720) and CYP24A1 (rs17216707).	('rs10745742', 'Var', (149, 159))	('CYP2R1', 'Gene', '120227', (100, 106))	('AMDHD1', 'Gene', (141, 147))	('rs10741657', 'Mutation', 'rs10741657', (108, 118))	('rs8018720', 'Var', (170, 179))	('CYP2R1', 'Gene', (100, 106))	('CYP24A1', 'Gene', '1591', (185, 192))	('DHCR7', 'Gene', (121, 126))	('rs17216707', 'Mutation', 'rs17216707', (194, 204))	('rs12785878', 'Var', (128, 138))	('rs3755967', 'Var', (88, 97))	('rs10741657', 'Var', (108, 118))	('DHCR7', 'Gene', '1717', (121, 126))	('rs10745742', 'Mutation', 'rs10745742', (149, 159))	('AMDHD1', 'Gene', '144193', (141, 147))	('rs12785878', 'Mutation', 'rs12785878', (128, 138))	('rs17216707', 'Var', (194, 204))	('rs8018720', 'Mutation', 'rs8018720', (170, 179))	('SEC23A', 'Gene', (162, 168))	('SEC23A', 'Gene', '10484', (162, 168))	('rs3755967', 'Mutation', 'rs3755967', (88, 97))	('CYP24A1', 'Gene', (185, 192))
724819	30716477	Only the SNP rs12785878 was nominally associated with the risk of BE (per copy of the T allele, summary OR, 1.07; 95% CI, 1.02-1.13; P = 0.008) and none were associated with the risk of EAC (all P values > 0.1).	('rs12785878', 'Var', (13, 23))	('EAC', 'Disease', (186, 189))	('SNP', 'Var', (9, 12))	('rs12785878', 'Mutation', 'rs12785878', (13, 23))	('BE', 'Phenotype', 'HP:0100580', (66, 68))	('EAC', 'Phenotype', 'HP:0011459', (186, 189))
724824	30716477	As shown in Supplementary Table 2, we did not find any associations at genome-wide significance (P < 5 x10-8), other than rs17216707 with eGFR creatinine (P = 6 x10-13).	('eGFR', 'Gene', '1956', (138, 142))	('rs17216707', 'Mutation', 'rs17216707', (122, 132))	('creatinine', 'Chemical', 'MESH:D003404', (143, 153))	('eGFR', 'Gene', (138, 142))	('rs17216707', 'Var', (122, 132))
724825	30716477	In this Mendelian randomization study, we used genetic variants as instrumental variables for 25(OH)D and examined associations between 25(OH)D and risks of BE and EAC.	('25(OH)D', 'Chemical', '-', (94, 101))	('variants', 'Var', (55, 63))	('EAC', 'Phenotype', 'HP:0011459', (164, 167))	('associations', 'Interaction', (115, 127))	('25(OH)D', 'Chemical', '-', (136, 143))	('EAC', 'Disease', (164, 167))	('BE', 'Phenotype', 'HP:0100580', (157, 159))
724826	30716477	We found no evidence that 25(OH)D concentration, as predicted by genotype, was associated with risks of BE or EAC.	('BE or EAC', 'Disease', (104, 113))	('BE', 'Phenotype', 'HP:0100580', (104, 106))	('25(OH)D', 'Chemical', '-', (26, 33))	('25(OH)D concentration', 'Var', (26, 47))	('EAC', 'Phenotype', 'HP:0011459', (110, 113))
724827	30716477	Thus, the study provides little evidence that 25(OH)D concentration is associated with risk of BE or EAC.	('25(OH)D concentration', 'Var', (46, 67))	('BE or EAC', 'Disease', (95, 104))	('BE', 'Phenotype', 'HP:0100580', (95, 97))	('25(OH)D', 'Chemical', '-', (46, 53))	('EAC', 'Phenotype', 'HP:0011459', (101, 104))
724828	30716477	Observational studies have examined the association between 25(OH)D concentration and the risk of various cancers.	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('25(OH)D', 'Chemical', '-', (60, 67))	('25(OH)D concentration', 'Var', (60, 81))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
724839	30716477	The findings from the present Mendelian randomization study provide further evidence that 25(OH)D concentration is not associated with the risk of BE or EAC.	('25(OH)D', 'Chemical', '-', (90, 97))	('25(OH)D concentration', 'Var', (90, 111))	('BE or EAC', 'Disease', (147, 156))	('BE', 'Phenotype', 'HP:0100580', (147, 149))	('EAC', 'Phenotype', 'HP:0011459', (153, 156))
724844	30716477	It is possible that in populations with low 25(OH)D due to limited sun exposure, genetically determined variation in 25(OH)D may be associated with BE or EAC.	('EAC', 'Phenotype', 'HP:0011459', (154, 157))	('25(OH)D', 'Chemical', '-', (117, 124))	('BE', 'Phenotype', 'HP:0100580', (148, 150))	('EAC', 'Disease', (154, 157))	('25(OH)D', 'Chemical', '-', (44, 51))	('variation', 'Var', (104, 113))	('25(OH)D', 'Gene', (117, 124))	('associated', 'Reg', (132, 142))	('BE or EAC', 'Disease', (148, 157))
724847	30716477	We conducted a Mendelian randomization study to evaluate the association between 25(OH)D and risks of BE and EAC.	('EAC', 'Phenotype', 'HP:0011459', (109, 112))	('EAC', 'Disease', (109, 112))	('25(OH)D', 'Chemical', '-', (81, 88))	('BE', 'Phenotype', 'HP:0100580', (102, 104))	('25(OH)D', 'Var', (81, 88))
724850	30361291	Association between Cyclin D1 G870A (rs9344) polymorphism and cancer risk in Indian population: meta-analysis and trial sequential analysis Introduction: Association between Cyclin D1 (CCND1) single nucleotide polymorphism (SNP) rs9344 and cancer risk is paradoxical.	('CCND1', 'Gene', '595', (185, 190))	('rs9344', 'Mutation', 'rs9344', (37, 43))	('rs9344', 'Var', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('single nucleotide polymorphism', 'Var', (192, 222))	('Cyclin D1', 'Gene', (20, 29))	('rs9344', 'Mutation', 'rs9344', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Cyclin D1', 'Gene', '595', (174, 183))	('Cyclin D1', 'Gene', '595', (20, 29))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('CCND1', 'Gene', (185, 190))	('cancer', 'Disease', (240, 246))	('Cyclin D1', 'Gene', (174, 183))	('G870A', 'Mutation', 'rs9344', (30, 35))
724851	30361291	Thus, we performed a meta-analysis to explore the association between CCND1 variant and overall cancer risk in Indian population.	('variant', 'Var', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CCND1', 'Gene', '595', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('CCND1', 'Gene', (70, 75))	('cancer', 'Disease', (96, 102))
724853	30361291	Subgroup analysis according to cancer types presented significant association of CCND1 polymorphism and increased breast cancer risk in dominant model (GG vs GA+AA: OR = 2.75, 95%CI = 1.54-4.90, P=0.0006) and allelic model (G vs A: OR = 1.63, 95%CI = 1.22-2.19, P=0.001).	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('increased', 'PosReg', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('polymorphism', 'Var', (87, 99))	('CCND1', 'Gene', '595', (81, 86))	('CCND1', 'Gene', (81, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', (121, 127))	('breast cancer', 'Disease', (114, 127))
724856	30361291	However, in case of cervical cancer risk a non-significant association was reported under the recessive model (GG+GA vs AA: OR = 1.52, 95%CI = 0.60-3.90, P=0.38) with reference to CCND1 polymorphism (rs9344).	('CCND1', 'Gene', '595', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cervical cancer', 'Disease', 'MESH:D002583', (20, 35))	('rs9344', 'Var', (200, 206))	('cervical cancer', 'Disease', (20, 35))	('CCND1', 'Gene', (180, 185))	('rs9344', 'Mutation', 'rs9344', (200, 206))
724858	30361291	Conclusion: CCND1 polymorphism rs9344 may not have a role in overall cancer susceptibility in Indian population.	('CCND1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs9344', 'Var', (31, 37))	('CCND1', 'Gene', '595', (12, 17))	('rs9344', 'Mutation', 'rs9344', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
724859	30361291	However, this polymorphism acts as a crucial risk factor for breast, esophageal, and colorectal cancer but not for cervical cancer.	('cervical cancer', 'Disease', 'MESH:D002583', (115, 130))	('cervical cancer', 'Disease', (115, 130))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('polymorphism', 'Var', (14, 26))	('colorectal cancer', 'Disease', (85, 102))	('risk', 'Reg', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal', 'Disease', (69, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('breast', 'Disease', (61, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
724871	30361291	The clinical importance of CCND1 gene lies in the fact that 5-20% of breast cancer cases present with either amplified or deleted version of the gene.	('deleted', 'Var', (122, 129))	('CCND1', 'Gene', '595', (27, 32))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('CCND1', 'Gene', (27, 32))	('present', 'Reg', (89, 96))
724874	30361291	An important functional single nucleotide polymorphism (SNP) in CCND1 gene (rs9344) G870A, may influence the breast cancer development.	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('influence', 'Reg', (95, 104))	('rs9344', 'Mutation', 'rs9344', (76, 82))	('CCND1', 'Gene', (64, 69))	('G870A', 'Mutation', 'rs9344', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rs9344) G870A', 'Var', (76, 89))	('men', 'Species', '9606', (130, 133))	('CCND1', 'Gene', '595', (64, 69))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
724884	30361291	This SNP rs9344 is located at codon 242 in the exon-4/intron boundary of CCND1 and responsible for alternate splicing of transcripts with different half-lives.	('rs9344', 'Var', (9, 15))	('CCND1', 'Gene', (73, 78))	('CCND1', 'Gene', '595', (73, 78))	('rs9344', 'Mutation', 'rs9344', (9, 15))
724885	30361291	Since then many case-control studies have been conducted to explore the potential association between CCND1 SNP (rs9344) and cancer susceptibility.	('rs9344', 'Var', (113, 119))	('rs9344', 'Mutation', 'rs9344', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('CCND1', 'Gene', (102, 107))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('CCND1', 'Gene', '595', (102, 107))
724886	30361291	Occurrence of this nucleotide variation has been found to be coupled with the risk of various cancers including cervical, breast, oral, esophageal, lung, urinary bladder, prostate, and colorectal.	('esophageal', 'Disease', (136, 146))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('lung', 'Disease', (148, 152))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('prostate', 'Disease', (171, 179))	('colorectal', 'Disease', 'MESH:D015179', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('colorectal', 'Disease', (185, 195))	('oral', 'Disease', (130, 134))	('nucleotide variation', 'Var', (19, 39))	('urinary bladder', 'Disease', (154, 169))	('breast', 'Disease', (122, 128))	('cancers', 'Disease', (94, 101))	('cervical', 'Disease', (112, 120))
724887	30361291	To overcome this conflict, several meta-analyses have been performed worldwide to see the effect of CCND1 polymorphism and risk for different types of cancer.	('CCND1', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('CCND1', 'Gene', '595', (100, 105))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('polymorphism', 'Var', (106, 118))
724888	30361291	To the best of our knowledge, no report is available from India addressing the impact of CCND1 SNP and overall cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('SNP', 'Var', (95, 98))	('CCND1', 'Gene', (89, 94))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('CCND1', 'Gene', '595', (89, 94))
724889	30361291	Hence, we aimed to investigate the role of CCND1 polymorphism G870A (rs9344) in overall cancer susceptibility amongst Indian population by conducting this meta-analysis.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('G870A', 'Mutation', 'rs9344', (62, 67))	('G870A', 'Var', (62, 67))	('CCND1', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('rs9344', 'Mutation', 'rs9344', (69, 75))	('CCND1', 'Gene', '595', (43, 48))
724890	30361291	The present data could be helpful in enriching the existing knowledge with respect to involvement of CCND1 polymorphism and cancer susceptibility in Indian population.	('CCND1', 'Gene', (101, 106))	('cancer', 'Disease', (124, 130))	('men', 'Species', '9606', (93, 96))	('polymorphism', 'Var', (107, 119))	('CCND1', 'Gene', '595', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
724892	30361291	(i) Prospective or case-control studies involving association analysis between CCND1 SNP G870A (rs9344) and cancer susceptibility, (ii) studies included Indian population, (iii) genotypic and allelic details are provided for both the cases and control groups, (iv) full text available, and (v) articles published in English language.	('G870A', 'Mutation', 'rs9344', (89, 94))	('CCND1', 'Gene', '595', (79, 84))	('G870A', 'Var', (89, 94))	('SNP G870A', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CCND1', 'Gene', (79, 84))	('rs9344', 'Mutation', 'rs9344', (96, 102))	('association', 'Interaction', (50, 61))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
724895	30361291	Meta-analysis of CCND1 gene G870A polymorphism (rs9344) was performed by RevMan 5.3 .	('CCND1', 'Gene', '595', (17, 22))	('G870A', 'Mutation', 'rs9344', (28, 33))	('rs9344', 'Mutation', 'rs9344', (48, 54))	('CCND1', 'Gene', (17, 22))	('G870A polymorphism', 'Var', (28, 46))
724896	30361291	Odds ratios (ORs) with 95% confidence intervals (95%CIs) were used to assess the strength of association between the CCND1-G870A polymorphisms and cancer risk.	('polymorphisms', 'Var', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('G870A', 'Mutation', 'rs9344', (123, 128))	('CCND1', 'Gene', '595', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('CCND1', 'Gene', (117, 122))
724906	30361291	Details of genotypic and allelic frequencies of CCND1 polymorphism is shown in Table 2.	('polymorphism', 'Var', (54, 66))	('CCND1', 'Gene', (48, 53))	('CCND1', 'Gene', '595', (48, 53))
724907	30361291	A total of 12 studies were included in the analysis to evaluate the association between CCND1 polymorphism and cancer risk in Indian population.	('CCND1', 'Gene', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('polymorphism', 'Var', (94, 106))	('CCND1', 'Gene', '595', (88, 93))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
724908	30361291	The results from meta-analysis of the association between CCND1 polymorphism (rs9344) and cancer risk in 12 case-control studies are shown in Figure 2 and Table 3.	('CCND1', 'Gene', '595', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs9344', 'Var', (78, 84))	('rs9344', 'Mutation', 'rs9344', (78, 84))	('CCND1', 'Gene', (58, 63))	('polymorphism (rs9344', 'Var', (64, 84))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
724909	30361291	Here, we demonstrate that CCND1 polymorphism G870A (rs9344) is not associated with the risk for overall cancers in Indian population.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('G870A', 'Mutation', 'rs9344', (45, 50))	('CCND1', 'Gene', (26, 31))	('polymorphism', 'Var', (32, 44))	('G870A', 'Var', (45, 50))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('rs9344', 'Mutation', 'rs9344', (52, 58))	('CCND1', 'Gene', '595', (26, 31))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
724910	30361291	On subgroup analysis stratified according to cancer types showed significant association of CCND1 polymorphism and increased breast cancer risk in dominant model (GG vs GA+AA: OR = 2.75, 95%CI = 1.54-4.90, P=0.0006), allelic model (G vs A: OR = 1.63, 95%CI = 1.22-2.19, P=0.001).	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('CCND1', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('polymorphism', 'Var', (98, 110))	('breast cancer', 'Disease', (125, 138))	('CCND1', 'Gene', '595', (92, 97))	('cancer', 'Disease', (45, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
724914	30361291	Although a non-significant association was observed in recessive model (GG+GA vs AA: OR = 1.52, 95%CI = 0.60-3.90, P=0.38) and co-dominant model (GG vs AA: OR = 1.45, 95%CI = 0.55-3.85, P=0.46) with reference to CCND1 polymorphism (rs9344) (Figures 3-6 and Table 4).	('rs9344', 'Var', (232, 238))	('rs9344', 'Mutation', 'rs9344', (232, 238))	('CCND1', 'Gene', (212, 217))	('CCND1', 'Gene', '595', (212, 217))
724915	30361291	The TSA for association between CCND1 polymorphism (rs9344) and overall cancer risk showed that only conventional boundary was crossed by Z-curve, however, it neither crossed the TSA boundary nor the futility area.	('CCND1', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('TSA', 'Chemical', '-', (179, 182))	('TSA', 'Chemical', '-', (4, 7))	('association', 'Interaction', (12, 23))	('CCND1', 'Gene', '595', (32, 37))	('rs9344', 'Var', (52, 58))	('rs9344', 'Mutation', 'rs9344', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
724916	30361291	CCND1 is key driver of normal cell cycle regulation and genetic variation in this gene has been reported in many types of cancers.	('genetic variation', 'Var', (56, 73))	('reported', 'Reg', (96, 104))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('CCND1', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('CCND1', 'Gene', '595', (0, 5))
724917	30361291	A SNP G870A (rs9344) located on exon-4-intron boundary of CCND1 has been studied extensively in several cancer types.	('G870A', 'Mutation', 'rs9344', (6, 11))	('CCND1', 'Gene', '595', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs9344', 'Var', (13, 19))	('rs9344', 'Mutation', 'rs9344', (13, 19))	('CCND1', 'Gene', (58, 63))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
724919	30361291	However, these reports are conflicting thus we performed meta-analysis on the literature available in order to provide more accurate information on the role of CCND1 G870A (rs9344) polymorphism and overall cancer risk in Indian population.	('rs9344', 'Mutation', 'rs9344', (173, 179))	('polymorphism', 'Var', (181, 193))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('CCND1', 'Gene', (160, 165))	('G870A', 'Mutation', 'rs9344', (166, 171))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('CCND1', 'Gene', '595', (160, 165))	('rs9344', 'Var', (173, 179))
724921	30361291	(2008), performed a meta-analysis on role of CCND1 polymorphism in different types of cancers and populations.	('CCND1', 'Gene', (45, 50))	('polymorphism', 'Var', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CCND1', 'Gene', '595', (45, 50))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
724923	30361291	The present meta-analysis, contained a total of 12 studies comprising 1791 cancer cases and 1948 controls showed the lack of significant association between CCND1 G870A polymorphism (rs9344) and overall cancer risk in all the genetic models.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('CCND1', 'Gene', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('G870A', 'Mutation', 'rs9344', (163, 168))	('G870A', 'Var', (163, 168))	('CCND1', 'Gene', '595', (157, 162))	('rs9344', 'Mutation', 'rs9344', (183, 189))
724924	30361291	(2016), which ruled out the involvement of CCND1 polymorphism (G870A) with the risk of hepatocellular carcinoma.	('men', 'Species', '9606', (35, 38))	('G870A', 'Mutation', 'rs9344', (63, 68))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (87, 111))	('hepatocellular carcinoma', 'Disease', (87, 111))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (87, 111))	('G870A', 'Var', (63, 68))	('CCND1', 'Gene', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('CCND1', 'Gene', '595', (43, 48))
724925	30361291	(2015) suggested that CCND1 polymorphism may not be associated with the risk of prostate cancer.	('polymorphism', 'Var', (28, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('CCND1', 'Gene', (22, 27))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('CCND1', 'Gene', '595', (22, 27))	('prostate cancer', 'Disease', (80, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
724926	30361291	(2018) also found no significant association between the let-7i rs10877887 and let-7a-1/let-7f-1/let-7d rs13293512 polymorphisms and overall cancer risk.	('let-7a-1', 'Gene', '406881', (79, 87))	('rs10877887', 'Var', (64, 74))	('let-7d', 'Gene', '406886', (97, 103))	('let-7f-1', 'Gene', (88, 96))	('let-7i', 'Gene', (57, 63))	('let-7d', 'Gene', (97, 103))	('let-7f-1', 'Gene', '406888', (88, 96))	('rs10877887', 'Mutation', 'rs10877887', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('let-7a-1', 'Gene', (79, 87))	('let-7i', 'Gene', '406891', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('rs13293512', 'Mutation', 'rs13293512', (104, 114))	('rs13293512', 'Var', (104, 114))	('cancer', 'Disease', (141, 147))
724930	30361291	(2014) also indicated that CCND1 polymorphism may increase the risk of non-Hodgkin lymphoma but it was not true in case of leukemia.	('leukemia', 'Disease', (123, 131))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('leukemia', 'Disease', 'MESH:D007938', (123, 131))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (71, 91))	('CCND1', 'Gene', '595', (27, 32))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (75, 91))	('increase', 'PosReg', (50, 58))	('non-Hodgkin lymphoma', 'Disease', (71, 91))	('polymorphism', 'Var', (33, 45))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (71, 91))	('lymphoma', 'Phenotype', 'HP:0002665', (83, 91))	('CCND1', 'Gene', (27, 32))
724931	30361291	(2014) too observed the lack of association between CCND1 polymorphism (G870A) and head and neck cancer, however; they found that smokers carrying 'A' allele or 'AA' genotype for rs9344 SNP located on CCND1 may be at higher risk to head and neck cancer development.	('rs9344 SNP', 'Var', (179, 189))	('CCND1', 'Gene', (201, 206))	('CCND1', 'Gene', '595', (52, 57))	('head and neck cancer', 'Phenotype', 'HP:0012288', (83, 103))	('G870A', 'Mutation', 'rs9344', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('neck cancer', 'Disease', 'MESH:D006258', (92, 103))	('neck cancer', 'Disease', (92, 103))	('rs9344', 'Mutation', 'rs9344', (179, 185))	('men', 'Species', '9606', (260, 263))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('head and neck cancer', 'Phenotype', 'HP:0012288', (232, 252))	('CCND1', 'Gene', '595', (201, 206))	('neck cancer', 'Disease', 'MESH:D006258', (241, 252))	('neck cancer', 'Disease', (241, 252))	('CCND1', 'Gene', (52, 57))
724934	30361291	In another study, no significant association was reported between the CCND1 SNP (rs9344) and overall risk for cervical cancer in the Asian population but on stratification analysis by race, individuals carrying the AA or AA/AG genotypes showed a significant higher risk in comparison with GG carriers.	('cervical cancer', 'Disease', (110, 125))	('rs9344', 'Var', (81, 87))	('rs9344', 'Mutation', 'rs9344', (81, 87))	('CCND1', 'Gene', '595', (70, 75))	('higher', 'PosReg', (258, 264))	('CCND1', 'Gene', (70, 75))	('cervical cancer', 'Disease', 'MESH:D002583', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
724935	30361291	(2014), also did not find the association of CCND1 G870A polymorphism and cervical cancer risk amongst different ethnic groups including Asian, Caucasian, and mixed in a cumulative meta-analysis.	('CCND1', 'Gene', (45, 50))	('cervical cancer', 'Disease', (74, 89))	('cervical cancer', 'Disease', 'MESH:D002583', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CCND1', 'Gene', '595', (45, 50))	('G870A', 'Mutation', 'rs9344', (51, 56))	('G870A', 'Var', (51, 56))
724936	30361291	Additionally, a significant association between CCND1 polymorphism and increased risk for breast and esophageal cancer has been established.	('CCND1', 'Gene', '595', (48, 53))	('polymorphism', 'Var', (54, 66))	('breast and esophageal cancer', 'Disease', 'MESH:D004938', (90, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CCND1', 'Gene', (48, 53))
724937	30361291	Similar to our results, Sergentanis and Economopoulos (2011) found that the 'A' allele of the CCND1 G870A polymorphism is associated with higher risk for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CCND1', 'Gene', (94, 99))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('G870A', 'Mutation', 'rs9344', (100, 105))	('CCND1', 'Gene', '595', (94, 99))	('G870A', 'Var', (100, 105))
724938	30361291	(2012) that showed the association of AA genotype of CCND1 G870A polymorphism with breast cancer susceptibility.	('association', 'Interaction', (23, 34))	('CCND1', 'Gene', (53, 58))	('G870A', 'Mutation', 'rs9344', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('G870A', 'Var', (59, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('CCND1', 'Gene', '595', (53, 58))
724939	30361291	(2016) showed a significant association between CCND1 G870A polymorphism and breast cancer risk but in Caucasians.	('breast cancer', 'Disease', (77, 90))	('G870A', 'Var', (54, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('CCND1', 'Gene', '595', (48, 53))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('CCND1', 'Gene', (48, 53))	('G870A', 'Mutation', 'rs9344', (54, 59))
724940	30361291	(2014) supported our data that CCND1 G870A polymorphism is a potential risk factor in the development of esophageal cancer.	('risk', 'Reg', (71, 75))	('CCND1', 'Gene', (31, 36))	('men', 'Species', '9606', (97, 100))	('CCND1', 'Gene', '595', (31, 36))	('esophageal cancer', 'Disease', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('G870A', 'Mutation', 'rs9344', (37, 42))	('G870A', 'Var', (37, 42))
724941	30361291	(2013) is not in agreement with our findings and showed lack of potential association between CCND1 G870A polymorphism and esophageal cancer risk.	('esophageal cancer', 'Disease', (123, 140))	('CCND1', 'Gene', (94, 99))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('G870A', 'Mutation', 'rs9344', (100, 105))	('CCND1', 'Gene', '595', (94, 99))	('men', 'Species', '9606', (22, 25))	('G870A', 'Var', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
724942	30361291	(2015), also observed similar results describing that CCND1 SNP rs9344 is not having role in esophageal squamous cell carcinoma.The present study suggests that there is a significant correlation between this polymorphism and increased risk of colorectal cancer amongst Indian population.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('colorectal cancer', 'Disease', (243, 260))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('rs9344', 'Mutation', 'rs9344', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('CCND1', 'Gene', (54, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (243, 260))	('esophageal squamous cell carcinoma', 'Disease', (93, 127))	('polymorphism', 'Var', (208, 220))	('colorectal cancer', 'Phenotype', 'HP:0003003', (243, 260))	('CCND1', 'Gene', '595', (54, 59))
724944	30361291	(2006) suggested that the CCND1 G870 AA genotype may increase the colorectal cancer risk compared with the GG+AG genotype (OR = 1.56, 95%CI = 1.10-2.21) in an Indian population.	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('CCND1', 'Gene', (26, 31))	('increase', 'PosReg', (53, 61))	('G870 AA', 'Mutation', 'c.870G>AA', (32, 39))	('G870 AA', 'Var', (32, 39))	('colorectal cancer', 'Disease', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CCND1', 'Gene', '595', (26, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
724945	30361291	(2016), suggested that CCND1 polymorphism is a risk factor for gastric cancer in Caucasians.	('gastric cancer', 'Disease', (63, 77))	('risk', 'Reg', (47, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('CCND1', 'Gene', (23, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('polymorphism', 'Var', (29, 41))	('CCND1', 'Gene', '595', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
724946	30361291	(2016) also tried to establish the association between CCND1 polymorphism (rs678653) located on the 3'-UTR and susceptibility to cancer, but they have not studied the polymorphism under investigation G870A (rs9344).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('rs9344', 'Mutation', 'rs9344', (207, 213))	('CCND1', 'Gene', '595', (55, 60))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('association', 'Interaction', (35, 46))	('rs678653', 'Mutation', 'rs678653', (75, 83))	('G870A', 'Mutation', 'rs9344', (200, 205))	('rs678653', 'Var', (75, 83))	('CCND1', 'Gene', (55, 60))
724948	30361291	In conclusion, present meta-analysis showed that CCND1 SNP (rs9344) may not serve as a risk factor for overall cancer susceptibility in Indian population.	('rs9344', 'Var', (60, 66))	('CCND1', 'Gene', '595', (49, 54))	('rs9344', 'Mutation', 'rs9344', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('CCND1', 'Gene', (49, 54))
724950	30361291	Moreover, a non-significant increased risk for cervical cancer in relation to CCND1 polymorphism was observed in Indian population.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('CCND1', 'Gene', (78, 83))	('cervical cancer', 'Disease', (47, 62))	('cervical cancer', 'Disease', 'MESH:D002583', (47, 62))	('polymorphism', 'Var', (84, 96))	('CCND1', 'Gene', '595', (78, 83))
724951	30361291	Thus, CCND1 G870A (rs9344) polymorphism has a potential to be served as a prognostic biomarker for breast, esophageal, and colorectal cancer in Indian population.	('G870A (rs9344', 'Var', (12, 25))	('rs9344', 'Var', (19, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('rs9344', 'Mutation', 'rs9344', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colorectal cancer', 'Disease', (123, 140))	('esophageal', 'Disease', (107, 117))	('CCND1', 'Gene', (6, 11))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))	('breast', 'Disease', (99, 105))	('G870A', 'Mutation', 'rs9344', (12, 17))	('CCND1', 'Gene', '595', (6, 11))
724952	30361291	CCND1 cyclin D1 OR odds ratio PMID PubMed IDentifier RevMan Review Manager RIS required information size SNP single nucleotide polymorphism TSA trial sequential analysis 95%CI 95% confidence interval	('TSA', 'Chemical', '-', (140, 143))	('CCND1', 'Gene', (0, 5))	('single nucleotide', 'Var', (109, 126))	('CCND1', 'Gene', '595', (0, 5))
552308	25668428	A randomized, sham-controlled trial showed that RFA resulted in a high rate of complete eradication of neoplasia and a reduction in the rate of neoplastic progression.	('rate', 'MPA', (136, 140))	('RFA', 'Var', (48, 51))	('neoplastic progression', 'MPA', (144, 166))	('reduction', 'NegReg', (119, 128))	('neoplasia', 'Phenotype', 'HP:0002664', (103, 112))	('neoplasia', 'Disease', 'MESH:D009369', (103, 112))	('neoplasia', 'Disease', (103, 112))
724980	25668428	Exclusion criteria included: 1) esophageal stricture preventing endoscope passage; 2) prior endoscopic resection (ER) or ablation; 3) any non-flat esophageal mucosa; 4) any history of esophageal non-squamous cell cancer, or history of ESCC (any stage) prior to 3 months before primary RFA; 5) ESCC with T1m3 or worse invasion, G3 or worse differentiation, or lymphatic or vascular invasion; 6) N or M positive status in ESCC patients.	('ESCC', 'Disease', (235, 239))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (199, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('esophageal non-squamous cell cancer', 'Disease', (184, 219))	('T1m3', 'Var', (303, 307))	('esophageal stricture', 'Disease', (32, 52))	('lymphatic or vascular invasion', 'CPA', (359, 389))	('patients', 'Species', '9606', (425, 433))	('esophageal non-squamous cell cancer', 'Disease', 'MESH:D002294', (184, 219))	('esophageal stricture', 'Phenotype', 'HP:0002043', (32, 52))	('ESCC', 'Disease', (293, 297))
552317	25668428	Endoscopy procedures were performed with Olympus GIF-H260, GIF-H260Z, or GIF-H260J (Olympus, Tokyo, Japan) high-resolution endoscopes (Lucera systems).	('H260Z', 'SUBSTITUTION', 'None', (63, 68))	('H260J', 'SUBSTITUTION', 'None', (77, 82))	('H260Z', 'Var', (63, 68))	('H260J', 'Var', (77, 82))
725086	28871164	Inclusion criteria of the meta-analysis were: studies included must have (1) been published as original articles; (2) evaluated human subjects; (3) CD45RO+ T cells in tumor specimens were evaluated by IHC; (4) provided Kaplan - Meier curves of high and low CD45RO+ T cell density with overall survival (OS), and/or disease-free survival (DFS), or relapse-free survival (RFS); (5) published in English.	('relapse-free survival', 'CPA', (347, 368))	('disease-free survival', 'CPA', (315, 336))	('CD45', 'Gene', (148, 152))	('overall survival', 'CPA', (285, 301))	('OS', 'Chemical', '-', (303, 305))	('CD45', 'Gene', '5788', (257, 261))	('low', 'Var', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('CD45', 'Gene', '5788', (148, 152))	('human', 'Species', '9606', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('CD45', 'Gene', (257, 261))	('tumor', 'Disease', (167, 172))
725130	26972059	Patients with EUS non-traversable EC demonstrated a significantly lower 5-year overall survival than patients with EUS traversable EC (30.8% vs. 49.3%, p = 0.023).	('patients', 'Species', '9606', (101, 109))	('lower', 'NegReg', (66, 71))	('Patients', 'Species', '9606', (0, 8))	('non-traversable', 'Var', (18, 33))	('overall survival', 'MPA', (79, 95))
725141	26972059	A retrospective review of the consecutive patients identified 104 patients with advanced locoregional EC (stage II or III; T2-3N0M0 or T1-3N1M0).	('patients', 'Species', '9606', (42, 50))	('T2-3N0M0', 'Var', (123, 131))	('T1-3N1M0', 'Var', (135, 143))	('patients', 'Species', '9606', (66, 74))
725163	26972059	These patients with EUS non-traversable EC showed a higher rate of dysphagia (88.5% vs. 52.4%, p = 0.001) and need for insertion of self-expanding esophageal stent (30.8% vs. 1.6%, p < 0.001) than patients with EUS traversable EC.	('dysphagia', 'Disease', 'MESH:D003680', (67, 76))	('patients', 'Species', '9606', (197, 205))	('dysphagia', 'Disease', (67, 76))	('patients', 'Species', '9606', (6, 14))	('dysphagia', 'Phenotype', 'HP:0002015', (67, 76))	('non-traversable', 'Var', (24, 39))
725173	26972059	Patients with EUS non-traversable EC showed a significantly lower 5-year overall survival than patients with EUS traversable EC (30.8% vs. 49.3%, p = 0.023) (Fig.	('patients', 'Species', '9606', (95, 103))	('Patients', 'Species', '9606', (0, 8))	('non-traversable', 'Var', (18, 33))	('overall survival', 'MPA', (73, 89))	('lower', 'NegReg', (60, 65))
725175	26972059	Weight loss >= 10% (p = 0.033), EUS non-traversability (p = 0.003), non-response to preoperative CRT (p = 0.002), and incompletion of esophagectomy (p = 0.002) remained significant negative factors of survival in multivariate analysis (Table 2, Fig.	('incompletion', 'Var', (118, 130))	('Weight loss', 'Phenotype', 'HP:0001824', (0, 11))	('negative', 'NegReg', (181, 189))	('Weight loss', 'Disease', (0, 11))	('Weight loss', 'Disease', 'MESH:D015431', (0, 11))
725176	26972059	Five-year survival rate was 50.0% when 16 patients with EUS non-traversable EC achieved a clinical response to preoperative CRT and also underwent esophagectomy (vs. 64.5% of 34 patients with EUS traversable EC; p = 0.153) (Fig.	('non-traversable', 'Var', (60, 75))	('patients', 'Species', '9606', (178, 186))	('esophagectomy', 'Disease', (147, 160))	('clinical response to preoperative CRT', 'MPA', (90, 127))	('patients', 'Species', '9606', (42, 50))
725196	26972059	Although the pathologic stage was not evaluable in our patients due to the effect of preoperative CRT, these evidences suggest that preoperative CRT followed by esophagectomy for some of our patients with non-traversable EC may have been a stage-inappropriate treatment and thus adversely affected survival outcome.	('patients', 'Species', '9606', (191, 199))	('patients', 'Species', '9606', (55, 63))	('survival', 'MPA', (298, 306))	('affected', 'Reg', (289, 297))	('CRT', 'Disease', (145, 148))	('preoperative', 'Var', (132, 144))
725222	25351873	ADAM17 mRNA expression in esophageal squamous cell carcinoma was correlated with lymph node metastasis (P<0.01) and tumor, node and metastasis (TNM) staging (P<0.05), however, it was not correlated with gender, age or histological grade (P>0.05).	('esophageal squamous cell carcinoma', 'Disease', (26, 60))	('mRNA', 'Var', (7, 11))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('lymph node metastasis', 'CPA', (81, 102))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (26, 60))	('tumor', 'Disease', (116, 121))	('ADAM17', 'Gene', (0, 6))	('correlated', 'Reg', (65, 75))
725266	25351873	Statistical analysis showed that the EGFR positive expression rate in the ADAM17 positive expression group was significantly higher than the of the ADAM17 negative expression group (P<0.01).	('positive expression', 'Var', (81, 100))	('EGFR', 'Gene', '1956', (37, 41))	('ADAM17', 'Gene', (74, 80))	('higher', 'PosReg', (125, 131))	('EGFR', 'Gene', (37, 41))
725288	25351873	It proved that the ADAM17 mRNA was involved in breast carcinogenesis and progression, the high expression of ADAM17 will increase the invasiveness and spreading ability of MCF-7 breast cancer cells in vitro.	('spreading ability', 'CPA', (151, 168))	('breast carcinogenesis', 'Disease', (47, 68))	('increase', 'PosReg', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (47, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('ADAM17', 'Gene', (109, 115))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (172, 191))	('MCF-7 breast cancer', 'Disease', (172, 191))	('invasiveness', 'CPA', (134, 146))	('high expression', 'Var', (90, 105))
725289	25351873	ADAM17 can shed amphiregulin, transforming growth factor alpha and other EGFR ligands, it can also activate the EGFR to thereby improve the lung cancer cell proliferation and cell motility capacity.	('EGFR', 'Gene', (112, 116))	('cell motility capacity', 'CPA', (175, 197))	('lung cancer', 'Disease', (140, 151))	('transforming growth factor alpha', 'Gene', (30, 62))	('EGFR', 'Gene', '1956', (73, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('activate', 'PosReg', (99, 107))	('transforming growth factor alpha', 'Gene', '7124', (30, 62))	('amphiregulin', 'Gene', (16, 28))	('shed', 'MPA', (11, 15))	('EGFR', 'Gene', (73, 77))	('ADAM17', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('improve', 'PosReg', (128, 135))	('EGFR', 'Gene', '1956', (112, 116))	('amphiregulin', 'Gene', '374', (16, 28))
725293	25351873	Kornfeld et al reported that ADAM17 can activate the EGFR through the release of regulatory proteins in two ways to thereby enhance the proliferation and invasion of head and neck squamous cell carcinoma.	('neck squamous cell carcinoma', 'Disease', (175, 203))	('ADAM17', 'Var', (29, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('enhance', 'PosReg', (124, 131))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (175, 203))	('invasion', 'CPA', (154, 162))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('release of', 'MPA', (70, 80))	('activate', 'PosReg', (40, 48))	('proliferation', 'CPA', (136, 149))
725301	25351873	ADAMl7 mRNA and protein overexpression suggested gene mutation occurs in the process of esophageal carcinoma.	('mutation', 'Var', (54, 62))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (88, 108))	('occurs', 'Reg', (63, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('esophageal carcinoma', 'Disease', (88, 108))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (88, 108))
725308	25351873	This indicated that high ADAMl7 mRNA and protein expression may become an marker for metastasis and prognosis in esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('ADAMl7', 'Gene', (25, 31))	('high', 'Var', (20, 24))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))
725324	24847386	Treatment of FLO-1 and SKGT4 EAC cells with 5-Aza-deoxytidine led to a significant reduction in the promoter DNA methylation levels with restoration of the DSC3 expression, suggesting that promoter DNA methylation is a key epigenetic mechanism regulating DSC3 expression.	('SKGT4', 'CellLine', 'CVCL:2195', (23, 28))	('DSC3', 'Gene', (255, 259))	('5-Aza-deoxytidine', 'Chemical', '-', (44, 61))	('EAC', 'Gene', '1540', (29, 32))	('expression', 'MPA', (161, 171))	('promoter DNA methylation levels', 'MPA', (100, 131))	('DSC3', 'Gene', '1825', (156, 160))	('DSC3', 'Gene', (156, 160))	('EAC', 'Gene', (29, 32))	('5-Aza-deoxytidine', 'Var', (44, 61))	('reduction', 'NegReg', (83, 92))	('DSC3', 'Gene', '1825', (255, 259))
725326	24847386	CONCLUSION: Taken together, our results demonstrate that epigenetic silencing of DSC3 is a frequent finding in EAC that is possibly associated with advanced stages.	('DSC3', 'Gene', (81, 85))	('EAC', 'Gene', '1540', (111, 114))	('EAC', 'Gene', (111, 114))	('DSC3', 'Gene', '1825', (81, 85))	('associated', 'Reg', (132, 142))	('epigenetic silencing', 'Var', (57, 77))
725331	24847386	Recent evidences demonstrated that hypermethylation of the gene promoter CpG island, alone or in coordination with other genetic or epigenetic mechanisms, is one of the major mechanisms in silencing tumor suppressor genes as well as others which are associated with key oncogenic functions such as angiogenesis, invasion, metastasis, and progression.	('tumor', 'Disease', (199, 204))	('hypermethylation', 'Var', (35, 51))	('metastasis', 'CPA', (322, 332))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('silencing', 'NegReg', (189, 198))
725340	24847386	Our results indicated that epigenetic silencing of DSC3 is a molecular event in esophageal adenocarcinomas that is progressive with advanced stages of the disease.	('DSC3', 'Gene', (51, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('epigenetic silencing', 'Var', (27, 47))	('esophageal adenocarcinomas', 'Disease', (80, 106))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (80, 106))	('DSC3', 'Gene', '1825', (51, 55))
725365	24847386	To study DSC3 gene expression and DNA methylation in esophageal adenocarcinoma, we have collected a panel of 10 cell lines originated from esophagus, including normal esophageal squamous epithelium (HET1A and HEEC), Barrett's esophagus (BART, CPA, and CPB) and adenocarcinomas (OE33, FLO-1, OE19, SKGT4, and JHU-Eso-Ad1).	('OE19', 'Var', (291, 295))	('SKGT4', 'CellLine', 'CVCL:2195', (297, 302))	('esophageal adenocarcinoma', 'Disease', (53, 78))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (53, 78))	('DSC3', 'Gene', '1825', (9, 13))	('adenocarcinomas', 'Disease', 'MESH:D000230', (261, 276))	('adenocarcinomas', 'Disease', (261, 276))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (53, 78))	('DSC3', 'Gene', (9, 13))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (216, 235))	('carcinomas', 'Phenotype', 'HP:0030731', (266, 276))	('esophageal squamous', 'Disease', 'MESH:D000077277', (167, 186))	('esophageal squamous', 'Disease', (167, 186))
725372	24847386	Spearman's rank correlation analysis demonstrated a significant inverse correlation between DSC3 promoter DNA methylation and mRNA expression fold (coefficient r=-0.685, P<.0001; Figure 3C).	('inverse', 'NegReg', (64, 71))	('DSC3', 'Gene', '1825', (92, 96))	('mRNA expression fold', 'MPA', (126, 146))	('methylation', 'Var', (110, 121))	('DSC3', 'Gene', (92, 96))
725375	24847386	These results suggest that the DSC3 promoter hypermethylation is a key molecular factor involved in suppression of its mRNA expression in EACs.	('EAC', 'Gene', (138, 141))	('DSC3', 'Gene', '1825', (31, 35))	('hypermethylation', 'Var', (45, 61))	('suppression', 'NegReg', (100, 111))	('mRNA expression', 'MPA', (119, 134))	('DSC3', 'Gene', (31, 35))	('EAC', 'Gene', '1540', (138, 141))
725377	24847386	To confirm the epigenetic silencing of DSC3 gene expression, FLO-1 and SKGT4, which have DSC3 promoter hypermethylation and loss of DSC3 mRNA expression, were treated with 5-Aza-2' alone or in combination with TSA.	('loss', 'NegReg', (124, 128))	('SKGT4', 'CellLine', 'CVCL:2195', (71, 76))	('DSC3', 'Gene', '1825', (132, 136))	('DSC3', 'Gene', (89, 93))	('DSC3', 'Gene', (132, 136))	('TSA', 'Chemical', 'MESH:C012589', (210, 213))	('DSC3', 'Gene', '1825', (39, 43))	("5-Aza-2'", 'Chemical', '-', (172, 180))	('mRNA expression', 'MPA', (137, 152))	('epigenetic silencing', 'Var', (15, 35))	('DSC3', 'Gene', (39, 43))	('DSC3', 'Gene', '1825', (89, 93))
725378	24847386	The results show that treatment with 5-Aza-2' alone, and not TSA alone, led to significant restoration of DSC3 mRNA expression in both FLO-1 and SKGT4 cell lines (P<.001; Figure 5A and 5C).	('DSC3', 'Gene', (106, 110))	('SKGT4', 'CellLine', 'CVCL:2195', (145, 150))	('TSA', 'Chemical', 'MESH:C012589', (61, 64))	('DSC3', 'Gene', '1825', (106, 110))	("5-Aza-2'", 'Var', (37, 45))	('restoration', 'PosReg', (91, 102))	("5-Aza-2'", 'Chemical', '-', (37, 45))
725379	24847386	The expression of DSC3 was enhanced upon combination of 5-Aza-2' with TSA (P<.001; Figure 5A and 5C).	('DSC3', 'Gene', (18, 22))	('enhanced', 'PosReg', (27, 35))	('expression', 'MPA', (4, 14))	("5-Aza-2'", 'Var', (56, 64))	('combination', 'Interaction', (41, 52))	('TSA', 'Chemical', 'MESH:C012589', (70, 73))	("5-Aza-2'", 'Chemical', '-', (56, 64))	('DSC3', 'Gene', '1825', (18, 22))
725383	24847386	As shown in Figure 6, DSC3 DNA hypermethylation was significantly correlated with advanced tumor stage (P<.001) and lymph node metastasis (P<.001).	('correlated', 'Reg', (66, 76))	('hypermethylation', 'Var', (31, 47))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('lymph node metastasis', 'CPA', (116, 137))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('DSC3', 'Gene', '1825', (22, 26))	('DSC3', 'Gene', (22, 26))	('tumor', 'Disease', (91, 96))
725394	24847386	The results demonstrated hypermethylation of DSC3 in almost all EAC samples with a strong inverse correlation between the DNA methylation and gene expression levels (r=-0.685).	('DSC3', 'Gene', (45, 49))	('hypermethylation', 'Var', (25, 41))	('EAC', 'Gene', '1540', (64, 67))	('EAC', 'Gene', (64, 67))	('DSC3', 'Gene', '1825', (45, 49))
725395	24847386	These data suggest that epigenetic promoter methylation is a possible regulatory mechanism of DSC3 gene expression in EAC.	('EAC', 'Gene', '1540', (118, 121))	('DSC3', 'Gene', '1825', (94, 98))	('EAC', 'Gene', (118, 121))	('DSC3', 'Gene', (94, 98))	('epigenetic', 'Var', (24, 34))
725397	24847386	These results add to previous findings of DSC3 methylation in colorectal and lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('DSC3', 'Gene', '1825', (42, 46))	('DSC3', 'Gene', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('methylation', 'Var', (47, 58))	('lung cancers', 'Phenotype', 'HP:0100526', (77, 89))	('colorectal and lung cancers', 'Disease', 'MESH:D015179', (62, 89))
725398	24847386	Of note, in our assay, we detected DSC3 hypermethylation (> 10%) in all EACs except one (97.5%, 39/40) whereas none of the 22 (0%) normal esophageal epithelial samples showed DSC3 hypermethylation.	('EAC', 'Gene', '1540', (72, 75))	('DSC3', 'Gene', '1825', (35, 39))	('EAC', 'Gene', (72, 75))	('DSC3', 'Gene', (35, 39))	('hypermethylation', 'Var', (40, 56))	('DSC3', 'Gene', '1825', (175, 179))	('DSC3', 'Gene', (175, 179))
725405	24847386	In conclusion, this is the first study reporting DNA hypermethylation and silencing of DSC3 in EACs.	('DSC3', 'Gene', (87, 91))	('EAC', 'Gene', '1540', (95, 98))	('EAC', 'Gene', (95, 98))	('hypermethylation', 'Var', (53, 69))	('silencing', 'MPA', (74, 83))	('DSC3', 'Gene', '1825', (87, 91))
725470	33540531	To create esophageal cell lines, immortalized cell lines were derived from human esophageal mucosal biopsies transformed with human papilloma virus E6E7.	('human', 'Species', '9606', (126, 131))	('papilloma', 'Phenotype', 'HP:0012740', (132, 141))	('human', 'Species', '9606', (75, 80))	('human papilloma virus', 'Species', '10566', (126, 147))	('age', 'Gene', '5973', (15, 18))	('age', 'Gene', (86, 89))	('E6E7', 'Var', (148, 152))	('age', 'Gene', '5973', (86, 89))	('age', 'Gene', (15, 18))
725493	33540531	In an effort to elucidate details of the complex role of the microbiome in esophageal disease, we aimed to associate variations in the microbial community with esophageal disease.	('associate', 'Reg', (107, 116))	('esophageal disease', 'Disease', 'MESH:D004935', (160, 178))	('esophageal disease', 'Disease', 'MESH:D004935', (75, 93))	('variations', 'Var', (117, 127))	('esophageal disease', 'Disease', (160, 178))	('esophageal disease', 'Disease', (75, 93))
725531	33061972	Associated with RAP1B and circ_0052867, two miRNAs (miR-133b and miR-139-5p) were identified as being differentially expressed and downregulated across the two datasets.	('RAP1B', 'Gene', '5908', (16, 21))	('miR-133b', 'Gene', '442890', (52, 60))	('miR-133b', 'Gene', (52, 60))	('RAP1B', 'Gene', (16, 21))	('miR-139-5p', 'Var', (65, 75))	('downregulated', 'NegReg', (131, 144))
725534	33061972	The occurrence and progression of ESCC are related to genetic factors such as genomic amplifications, mutations, insertions, and deletions, as well as tumor epigenetics.	('deletions', 'Var', (129, 138))	('insertions', 'Var', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('ESCC', 'Disease', (34, 38))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
725535	33061972	Several studies have assessed the possible role of miRNA in identifying the potential for hepatocellular carcinoma metastasis and tumor recurrence, and it has also been shown that miRNAs can act on different pathways associated with chemotherapeutic drug sensitivity or resistance in several tumors.	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('hepatocellular carcinoma metastasis', 'Disease', (90, 125))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('tumor recurrence', 'CPA', (130, 146))	('tumors', 'Disease', (292, 298))	('drug sensitivity', 'Phenotype', 'HP:0020174', (250, 266))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('act', 'Reg', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('hepatocellular carcinoma metastasis', 'Disease', 'MESH:D009362', (90, 125))	('miRNAs', 'Var', (180, 186))
725536	33061972	Similarly, miR-455-3p was found to play an antioncogenic role by downregulating FAM83F and could be an independent clinical biomarker for predicting the outcome of ESCC patients.	('downregulating', 'NegReg', (65, 79))	('FAM83F', 'Gene', (80, 86))	('FAM83F', 'Gene', '113828', (80, 86))	('miR-455-3p', 'Chemical', '-', (11, 21))	('ESCC', 'Disease', (164, 168))	('miR-455-3p', 'Var', (11, 21))
725544	33061972	While it has been found that the expression level of miR-139-5P in 11 cases of esophageal cancer is significantly higher than that of adjacent paracarcinoma tissue.	('paracarcinoma', 'Disease', 'None', (143, 156))	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('expression level', 'MPA', (33, 49))	('miR-139-5P', 'Var', (53, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('higher', 'PosReg', (114, 120))	('paracarcinoma', 'Disease', (143, 156))
725546	31383722	Abemaciclib is effective against pancreatic cancer cells and synergizes with HuR and YAP1 inhibition Mutation or promoter hypermethylation of CDKN2A is found in over 90% of pancreatic ductal adenocarcinomas (PDAC) and leads to loss of function of cell cycle inhibitors p16 (INK4A) and p14 (ARF) resulting in unchecked proliferation.	('ARF', 'Disease', 'MESH:D058186', (290, 293))	('INK4A', 'Gene', '1029', (274, 279))	('loss of function', 'NegReg', (227, 243))	('Mutation', 'Var', (101, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (33, 50))	('INK4A', 'Gene', (274, 279))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (173, 206))	('YAP1', 'Gene', '10413', (85, 89))	('pancreatic ductal adenocarcinomas', 'Disease', (173, 206))	('ARF', 'Disease', (290, 293))	('p14', 'Gene', '1029', (285, 288))	('PDAC', 'Chemical', '-', (208, 212))	('p16', 'Gene', (269, 272))	('HuR', 'Gene', (77, 80))	('pancreatic cancer', 'Disease', 'MESH:D010190', (33, 50))	('CDKN2A', 'Gene', (142, 148))	('YAP1', 'Gene', (85, 89))	('p16', 'Gene', '1029', (269, 272))	('PDAC', 'Phenotype', 'HP:0006725', (208, 212))	('p14', 'Gene', (285, 288))	('HuR', 'Gene', '1994', (77, 80))	('pancreatic cancer', 'Disease', (33, 50))	('unchecked proliferation', 'CPA', (308, 331))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
725553	31383722	PDAC cells chronically cultured with abemaciclib displayed a reduction in cellular growth rates (GR) and co-resistance to gemcitabine and 5-FU, but not to HuR or YAP1 inhibitors as compared to no treatment controls.	('gemcitabine', 'Chemical', 'MESH:C056507', (122, 133))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('co-resistance', 'MPA', (105, 118))	('HuR', 'Gene', '1994', (155, 158))	('PDAC', 'Chemical', '-', (0, 4))	('HuR', 'Gene', (155, 158))	('reduction', 'NegReg', (61, 70))	('YAP1', 'Gene', (162, 166))	('5-FU', 'Chemical', 'MESH:D005472', (138, 142))	('YAP1', 'Gene', '10413', (162, 166))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('abemaciclib', 'Var', (37, 48))	('cellular growth rates', 'CPA', (74, 95))	('abemaciclib', 'Chemical', 'MESH:C000590451', (37, 48))
725562	31383722	Loss of CDKN2A due to the gene mutation or promoter hyper-methylation can be found in 90-98% of PDAC cells.	('CDKN2A', 'Gene', (8, 14))	('PDAC', 'Chemical', '-', (96, 100))	('gene mutation', 'Var', (26, 39))	('Loss', 'NegReg', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (96, 100))	('promoter', 'MPA', (43, 51))
725567	31383722	Inactivation of Rb leads to the release of the E2F 1-3 transcription factors, and upon release, there is a transcriptional up-regulation of target cell cycle genes such as cyclin E and cyclin A, allowing for progression of the cell cycle into S phase.	('release', 'MPA', (32, 39))	('Rb', 'Chemical', 'MESH:D012413', (16, 18))	('E2F', 'Protein', (47, 50))	('si', 'Chemical', 'MESH:D012825', (215, 217))	('cyclin A', 'Gene', (185, 193))	('cyclin', 'MPA', (172, 178))	('cyclin A', 'Gene', '890', (185, 193))	('Inactivation', 'Var', (0, 12))	('up-regulation', 'PosReg', (123, 136))
725568	31383722	As described above, in PDAC, loss of p16 leads to unchecked cellular division and disruption of the G1/S checkpoints.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('unchecked cellular division', 'CPA', (50, 77))	('G1/S checkpoints', 'CPA', (100, 116))	('leads to', 'Reg', (41, 49))	('PDAC', 'Phenotype', 'HP:0006725', (23, 27))	('loss', 'Var', (29, 33))	('p16', 'Gene', '1029', (37, 40))	('PDAC', 'Chemical', '-', (23, 27))	('disruption', 'Reg', (82, 92))	('p16', 'Gene', (37, 40))
725569	31383722	When p16 is silenced, Rb remains non-functional as a regulator allowing for unchecked proliferation.	('p16', 'Gene', (5, 8))	('Rb', 'Chemical', 'MESH:D012413', (22, 24))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('p16', 'Gene', '1029', (5, 8))	('silenced', 'Var', (12, 20))
725570	31383722	While the p16 pathway is frequently disrupted in PDAC, Rb is commonly preserved in PDAC and the presence of pRb is an important predictor of response for CDK4/6 inhibitors.	('presence', 'Var', (96, 104))	('disrupted', 'Reg', (36, 45))	('pRb', 'Gene', (108, 111))	('CDK4/6', 'Gene', '1019;1021', (154, 160))	('Rb', 'Chemical', 'MESH:D012413', (109, 111))	('PDAC', 'Chemical', '-', (49, 53))	('PDAC', 'Chemical', '-', (83, 87))	('p16', 'Gene', (10, 13))	('CDK4/6', 'Gene', (154, 160))	('PDAC', 'Phenotype', 'HP:0006725', (49, 53))	('Rb', 'Chemical', 'MESH:D012413', (55, 57))	('PDAC', 'Phenotype', 'HP:0006725', (83, 87))	('p16', 'Gene', '1029', (10, 13))
725573	31383722	Additionally, the CDK4/6 inhibitor abemaciclib (LY2835219) is currently being investigated in a phase 2 trial, as a solo agent, and in combination with a PI3K inhibitor in metastatic pancreatic cancer patients .	('patients', 'Species', '9606', (201, 209))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (183, 200))	('abemaciclib', 'Chemical', 'MESH:C000590451', (35, 46))	('LY2835219', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('CDK4/6', 'Gene', '1019;1021', (18, 24))	('LY2835219', 'Chemical', 'MESH:C000590451', (48, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (183, 200))	('pancreatic cancer', 'Disease', (183, 200))	('CDK4/6', 'Gene', (18, 24))
725639	31383722	We also tested standard PDAC chemotherapeutics gemcitabine and oxaliplatin on PDAC cell lines and found abemaciclib was less effective at inhibiting cell survival as compared to gemcitabine, but more potent than oxaliplatin (Figure 1C, HPNE comparison shown in Supplemental 1D).	('abemaciclib', 'Var', (104, 115))	('gemcitabine', 'Chemical', 'MESH:C056507', (178, 189))	('gemcitabine', 'Chemical', 'MESH:C056507', (47, 58))	('PDAC', 'Phenotype', 'HP:0006725', (78, 82))	('abemaciclib', 'Chemical', 'MESH:C000590451', (104, 115))	('PDAC', 'Chemical', '-', (24, 28))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (63, 74))	('cell survival', 'CPA', (149, 162))	('inhibiting', 'NegReg', (138, 148))	('PDAC', 'Chemical', '-', (78, 82))	('PDAC', 'Phenotype', 'HP:0006725', (24, 28))	('HPNE', 'Chemical', '-', (236, 240))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (212, 223))
725643	31383722	The PDX lines were found to have a deletion of CDKN2A and abemaciclib also had similar effects on cell viability (Supplemental 1B).	('si', 'Chemical', 'MESH:D012825', (79, 81))	('abemaciclib', 'Chemical', 'MESH:C000590451', (58, 69))	('CDKN2A', 'Gene', (47, 53))	('deletion', 'Var', (35, 43))	('cell viability', 'CPA', (98, 112))
725649	31383722	We sought to assess whether abemaciclib causes cell death, senescence, or both in our PDAC cells (Figure 2A).	('senescence', 'CPA', (59, 69))	('abemaciclib', 'Var', (28, 39))	('abemaciclib', 'Chemical', 'MESH:C000590451', (28, 39))	('PDAC', 'Chemical', '-', (86, 90))	('death', 'Disease', 'MESH:D003643', (52, 57))	('death', 'Disease', (52, 57))	('PDAC', 'Phenotype', 'HP:0006725', (86, 90))
725651	31383722	We detected an increase in cleaved caspase 3 levels in Mia PaCa2 cells treated with abemaciclib compared to no treatment on days 1-3 of treatment, compared to staurosporine-treated cells which served as our positive control (Figure 2B).	('Mia PaCa2', 'CellLine', 'CVCL:0428', (55, 64))	('caspase 3', 'Gene', (35, 44))	('caspase 3', 'Gene', '836', (35, 44))	('increase', 'PosReg', (15, 23))	('abemaciclib', 'Var', (84, 95))	('si', 'Chemical', 'MESH:D012825', (209, 211))	('abemaciclib', 'Chemical', 'MESH:C000590451', (84, 95))	('staurosporine', 'Chemical', 'MESH:D019311', (159, 172))
725679	31383722	We found that H2O2 increased DCFDA florescence (positive control) 24 hours after treatment, but abemaciclib did not cause any significant increase in DCFDA florescence even at day 7 (Supplemental 3B).	('DCFDA', 'Chemical', 'MESH:C029569', (29, 34))	('abemaciclib', 'Chemical', 'MESH:C000590451', (96, 107))	('DCFDA', 'Chemical', 'MESH:C029569', (150, 155))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('DCFDA florescence', 'MPA', (29, 46))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('increased', 'PosReg', (19, 28))	('H2O2', 'Chemical', 'MESH:D006861', (14, 18))	('H2O2', 'Var', (14, 18))
725694	31383722	Importantly, HuR is a critical regulator of cyclin D1, with loss of HuR leading to a dramatic decrease in cyclin D1 expression at the mRNA and protein level.	('expression', 'MPA', (116, 126))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('cyclin D1', 'Gene', '595', (106, 115))	('cyclin D1', 'Gene', '595', (44, 53))	('cyclin D1', 'Gene', (106, 115))	('loss', 'Var', (60, 64))	('HuR', 'Gene', '1994', (13, 16))	('cyclin D1', 'Gene', (44, 53))	('HuR', 'Gene', (68, 71))	('HuR', 'Gene', (13, 16))	('HuR', 'Gene', '1994', (68, 71))	('decrease', 'NegReg', (94, 102))
725700	31383722	To assess for synergistic combinations in a long-term assay, we performed colony formation assays with abemaciclib and the HuR and YAP1 inhibitors that were found to be synergistic in long term drug sensitivity assay as well (Figure 6C-D).	('drug sensitivity', 'Phenotype', 'HP:0020174', (194, 210))	('inhibitors', 'Var', (136, 146))	('abemaciclib', 'Chemical', 'MESH:C000590451', (103, 114))	('YAP1', 'Gene', (131, 135))	('YAP1', 'Gene', '10413', (131, 135))	('si', 'Chemical', 'MESH:D012825', (202, 204))	('HuR', 'Gene', '1994', (123, 126))	('HuR', 'Gene', (123, 126))	('colony formation assays', 'CPA', (74, 97))
725704	31383722	As a secondary method to confirm that inhibition of HuR or YAP1 increased abemaciclib's sensitivity in PDAC cells, we transfected cells with either siHuR or siYAP1 oligonucleotides.	('YAP1', 'Gene', (59, 63))	('YAP1', 'Gene', '10413', (59, 63))	('PDAC', 'Chemical', '-', (103, 107))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('HuR', 'Gene', '1994', (150, 153))	('HuR', 'Gene', '1994', (52, 55))	('HuR', 'Gene', (52, 55))	('inhibition', 'Var', (38, 48))	('YAP1', 'Gene', (159, 163))	('oligonucleotides', 'Chemical', 'MESH:D009841', (164, 180))	('si', 'Chemical', 'MESH:D012825', (157, 159))	('YAP1', 'Gene', '10413', (159, 163))	('HuR', 'Gene', (150, 153))	('PDAC', 'Phenotype', 'HP:0006725', (103, 107))	('increased', 'PosReg', (64, 73))	('abemaciclib', 'Chemical', 'MESH:C000590451', (74, 85))	('sensitivity', 'MPA', (88, 99))
725706	31383722	We validated target knockdown by western blot analysis and found there was a 67% knockdown of HuR and 90% knockdown of YAP1, as compared to control cells, three days after transfection had taken place (Supplemental 6E).	('YAP1', 'Gene', '10413', (119, 123))	('HuR', 'Gene', (94, 97))	('HuR', 'Gene', '1994', (94, 97))	('knockdown', 'Var', (106, 115))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('knockdown', 'NegReg', (81, 90))	('YAP1', 'Gene', (119, 123))
725708	31383722	Increased expression of cyclin D1 after CDK4/6 inhibition has been seen in other models and has been linked to a possible mode of CDK4/6 resistance, but interestingly, after HuR or YAP1 knockdown there is no increase in cyclin D1 protein levels in the abemaciclib treated samples (Supplemental 6E).	('knockdown', 'Var', (186, 195))	('YAP1', 'Gene', (181, 185))	('YAP1', 'Gene', '10413', (181, 185))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('CDK4/6', 'Gene', (130, 136))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('CDK4/6', 'Gene', '1019;1021', (40, 46))	('CDK4/6', 'Gene', (40, 46))	('cyclin D1', 'Gene', '595', (220, 229))	('abemaciclib', 'Chemical', 'MESH:C000590451', (252, 263))	('cyclin D1', 'Gene', '595', (24, 33))	('cyclin D1', 'Gene', (220, 229))	('HuR', 'Gene', (174, 177))	('cyclin D1', 'Gene', (24, 33))	('HuR', 'Gene', '1994', (174, 177))	('CDK4/6', 'Gene', '1019;1021', (130, 136))
725739	31383722	Along with validating that cyclin D1 pulls down with HuR via RIP (Supplemental 6F), we have observed that by targeting cyclin D1 we were able to sensitize cells to abemaciclib treatment (Supplemental 6G).	('sensitize', 'Reg', (145, 154))	('cyclin D1', 'Gene', (27, 36))	('abemaciclib', 'Chemical', 'MESH:C000590451', (164, 175))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('targeting', 'Var', (109, 118))	('cyclin D1', 'Gene', '595', (119, 128))	('HuR', 'Gene', (53, 56))	('HuR', 'Gene', '1994', (53, 56))	('cyclin D1', 'Gene', (119, 128))	('cyclin D1', 'Gene', '595', (27, 36))
725766	30582155	Here, the authors found that moderate/severe fluorosis is associated with a ten-fold increased cancer risk in Eastern Africa, particularly if tooth loss or decay is co-present.	('tooth loss', 'Disease', 'MESH:D016388', (142, 152))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('fluorosis', 'Var', (45, 54))	('tooth loss', 'Disease', (142, 152))	('cancer', 'Disease', (95, 101))	('tooth loss', 'Phenotype', 'HP:0006480', (142, 152))	('tooth loss or decay', 'Phenotype', 'HP:0000670', (142, 161))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('moderate/severe fluorosis', 'Var', (29, 54))
725798	30582155	The DMFT OR was strongly attenuated upon adjustment for, separately, leukoplakia (OR 3.7, model 4) or dental fluorosis (OR 3.0, model 5), but remained a significant independent risk factor.	('attenuated', 'NegReg', (25, 35))	('DMFT', 'Chemical', '-', (4, 8))	('leukoplakia', 'Disease', 'MESH:D007971', (69, 80))	('DMFT', 'Var', (4, 8))	('men', 'Species', '9606', (47, 50))	('leukoplakia', 'Disease', (69, 80))	('dental fluorosis', 'Disease', (102, 118))
725886	29904400	EP3622; Neomarkers, Inc., Portsmouth, NH, USA) and CD83 (1:100; cat.	('CD83', 'Gene', '9308', (51, 55))	('a', 'Gene', '65057', (65, 66))	('A', 'Gene', '65057', (44, 45))	('a', 'Gene', '65057', (12, 13))	('a', 'Gene', '65057', (47, 48))	('EP3622', 'Var', (0, 6))	('CD83', 'Gene', (51, 55))
725918	29904400	The number of CD83+DCs was significantly higher in nITM tissues compared with NP tissues.	('CD83+', 'Gene', (14, 19))	('a', 'Gene', '65057', (35, 36))	('CD83+', 'Gene', '9308', (14, 19))	('nITM', 'Var', (51, 55))	('higher', 'PosReg', (41, 47))	('a', 'Gene', '65057', (68, 69))	('a', 'Gene', '65057', (24, 25))
725923	29904400	The results of the present study indicate that the number of DCs in nITM tissue is significantly lower compared with NP tissues, which is consistent with previous reports and suggests that DCs may serve an important role in the onset and development of NP.	('a', 'Gene', '65057', (107, 108))	('nITM', 'Var', (68, 72))	('a', 'Gene', '65057', (194, 195))	('a', 'Gene', '65057', (186, 187))	('a', 'Gene', '65057', (171, 172))	('lower', 'NegReg', (97, 102))	('a', 'Gene', '65057', (91, 92))	('a', 'Gene', '65057', (44, 45))	('a', 'Gene', '65057', (234, 235))	('a', 'Gene', '65057', (38, 39))	('a', 'Gene', '65057', (203, 204))	('a', 'Gene', '65057', (212, 213))
725924	29904400	CD40+ staining suggests that DCs may be associated with the pathogenesis of NP, mainly via impacting the differentiation of T cells.	('a', 'Gene', '65057', (115, 116))	('a', 'Gene', '65057', (94, 95))	('a', 'Gene', '65057', (8, 9))	('a', 'Gene', '65057', (46, 47))	('CD40+', 'Gene', (0, 5))	('DCs', 'Var', (29, 32))	('a', 'Gene', '65057', (61, 62))	('a', 'Gene', '65057', (81, 82))	('a', 'Gene', '65057', (26, 27))	('a', 'Gene', '65057', (40, 41))	('a', 'Gene', '65057', (89, 90))	('a', 'Gene', '65057', (34, 35))	('CD40+', 'Gene', '958', (0, 5))
726007	29312644	High CXCR2 expression was significantly associated with poor RFS (pooled HR = 1.40; 95% CI = 1.21-1.62; P < 0.001) (Figure 5).	('poor', 'NegReg', (56, 60))	('High', 'Var', (0, 4))	('CXCR2', 'Gene', '3579', (5, 10))	('RFS', 'MPA', (61, 64))	('CXCR2', 'Gene', (5, 10))
726009	29312644	High CXCR2 expression was significantly associated with poor DFS (pooled HR = 1.89; 95% CI = 1.05-3.40; P = 0.033) (Figure 6).	('CXCR2', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('CXCR2', 'Gene', '3579', (5, 10))
726022	29312644	The subgroup analyses revealed that high CXCR2 expression was associated with poor prognosis of most digestive system cancers, including hepatocellular carcinoma, gastric cancer, and esophageal cancer.	('gastric cancer', 'Disease', (163, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('system cancers', 'Disease', (111, 125))	('system cancers', 'Disease', 'MESH:D009369', (111, 125))	('CXCR2', 'Gene', '3579', (41, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (137, 161))	('esophageal cancer', 'Disease', (183, 200))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (137, 161))	('CXCR2', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (183, 200))	('hepatocellular carcinoma', 'Disease', (137, 161))	('high', 'Var', (36, 40))
726026	29312644	This was the first meta-analysis to demonstrate that high CXCR2 expression was significantly associated with poor prognosis of most solid tumors.	('CXCR2', 'Gene', '3579', (58, 63))	('high', 'Var', (53, 57))	('solid tumors', 'Disease', 'MESH:D009369', (132, 144))	('CXCR2', 'Gene', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('solid tumors', 'Disease', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
726040	27489353	HPV16 E6-E7 induces cancer stem-like cells phenotypes in esophageal squamous cell carcinoma through the activation of PI3K/Akt signaling pathway in vitro and in vivo High-risk human papillomavirus (HPV), especially HPV16, correlates with cancerogenesis of human esophageal squamous cell carcinoma (ESCC) and we have reported that HPV16 related with a poor prognosis of ESCC patients in China.	('HPV', 'Species', '10566', (330, 333))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('human', 'Species', '9606', (176, 181))	('HPV16', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('HPV16', 'Species', '333760', (330, 335))	('esophageal squamous cell carcinoma', 'Disease', (57, 91))	('human', 'Species', '9606', (256, 261))	('cancer', 'Disease', (238, 244))	('ESCC', 'Disease', (369, 373))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('esophageal squamous cell carcinoma', 'Disease', (262, 296))	('Akt', 'Gene', (123, 126))	('E6-E7', 'Var', (6, 11))	('HPV16', 'Species', '333760', (0, 5))	('Akt', 'Gene', '207', (123, 126))	('induces', 'PosReg', (12, 19))	('HPV', 'Species', '10566', (215, 218))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (57, 91))	('cancer', 'Disease', (20, 26))	('human papillomavirus', 'Species', '10566', (176, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('HPV16', 'Gene', (330, 335))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('HPV16', 'Species', '333760', (215, 220))	('HPV', 'Species', '10566', (0, 3))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (262, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (273, 296))	('patients', 'Species', '9606', (374, 382))	('HPV', 'Species', '10566', (198, 201))
726043	27489353	HPV16 E6-E7 induced PI3K/Akt signaling pathway activation and this affect could be effectively inhibited by LY294002, a specific PI3K inhibitor.	('HPV16', 'Species', '333760', (0, 5))	('activation', 'PosReg', (47, 57))	('HPV16', 'Gene', (0, 5))	('Akt', 'Gene', '207', (25, 28))	('LY294002', 'Chemical', 'MESH:C085911', (108, 116))	('Akt', 'Gene', (25, 28))	('E6-E7', 'Var', (6, 11))
726044	27489353	It was also indicated that the inhibition of PI3K/Akt signaling pathway by PI3K and Akt siRNA reverse the effect which induced by HPV16 E6-E7 in ESCC cells.	('inhibition', 'NegReg', (31, 41))	('PI3K', 'Var', (75, 79))	('Akt', 'Gene', '207', (50, 53))	('Akt', 'Gene', '207', (84, 87))	('HPV16', 'Species', '333760', (130, 135))	('Akt', 'Gene', (50, 53))	('Akt', 'Gene', (84, 87))	('HPV16', 'Gene', (130, 135))	('E6-E7', 'Var', (136, 141))
726045	27489353	Taken together, the present study demonstrates that HPV16 E6-E7 promotes CSCs phenotype in ESCC cells through the activation of PI3K/Akt signaling pathway.	('activation', 'PosReg', (114, 124))	('E6-E7', 'Var', (58, 63))	('promotes', 'PosReg', (64, 72))	('Akt', 'Gene', '207', (133, 136))	('CSCs phenotype', 'Disease', (73, 87))	('Akt', 'Gene', (133, 136))	('HPV16', 'Species', '333760', (52, 57))	('HPV16', 'Gene', (52, 57))
726060	27489353	It was also found that targeting PI3K benefits for prostate cancer by eliminate prostate CSCs.	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('prostate cancer', 'Disease', (51, 66))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('PI3K', 'Var', (33, 37))	('prostate CSCs', 'Disease', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
726061	27489353	Up-regulation of hypoxia-inducible factor 1alpha inhibits proliferation and promotes survival of prostate cancer stem cells through the PI3K.	('PI3K', 'Var', (136, 140))	('proliferation', 'CPA', (58, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('inhibits', 'NegReg', (49, 57))	('survival', 'CPA', (85, 93))	('hypoxia', 'Disease', (17, 24))	('hypoxia', 'Disease', 'MESH:D000860', (17, 24))	('Up-regulation', 'PosReg', (0, 13))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('promotes', 'PosReg', (76, 84))	('prostate cancer', 'Disease', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
726065	27489353	In the present study, we first detected the influence and the potential mechanism of HPV16 E6-E7 expression in ESCC cells in vitro and in vivo.	('E6-E7', 'Var', (91, 96))	('HPV16', 'Gene', (85, 90))	('HPV16', 'Species', '333760', (85, 90))
726066	27489353	LY294002, a specific PI3K inhibitor suppressing PI3K/Akt pathways which plays a vital role in carcinogenesis, was selected due to its small size and ease of use in vitro and in vivo systems.	('LY294002', 'Var', (0, 8))	('suppressing', 'NegReg', (36, 47))	('Akt', 'Gene', '207', (53, 56))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('Akt', 'Gene', (53, 56))	('carcinogenesis', 'Disease', 'MESH:D063646', (94, 108))	('carcinogenesis', 'Disease', (94, 108))
726067	27489353	The results demonstrated that HPV16 E6-E7 expression promoted CSCs phenotypes in ESCC cells via activating PI3K/Akt signaling pathway in vitro and in vivo.	('promoted', 'PosReg', (53, 61))	('HPV16', 'Species', '333760', (30, 35))	('Akt', 'Gene', '207', (112, 115))	('activating', 'PosReg', (96, 106))	('HPV16', 'Gene', (30, 35))	('Akt', 'Gene', (112, 115))	('E6-E7 expression', 'Var', (36, 52))	('CSCs', 'Disease', (62, 66))
726068	27489353	HPV16 E6-E7 protein was stably expressed in HPV16 E6-E7 lentiviral vector transfected ESCC cells, which were labeled as Eca109-psb and TE-1-psb cells, while no expression of HPV16 E6-E7 protein was observed in control vector transfected ESCC cells, which were labeled as Eca109-control and TE-1-control cells.	('Eca109-psb', 'Chemical', '-', (120, 130))	('HPV16', 'Species', '333760', (44, 49))	('HPV16', 'Species', '333760', (0, 5))	('HPV16', 'Species', '333760', (174, 179))	('protein', 'Protein', (12, 19))	('HPV16', 'Gene', (0, 5))	('TE-1-psb', 'Chemical', '-', (135, 143))	('HPV16 E6-E7', 'Var', (44, 55))	('E6-E7', 'Var', (50, 55))	('E6-E7', 'Var', (6, 11))
726069	27489353	The transfection outcome of HPV16 E6-E7 lentiviral vector was observed using a fluorescence microscope 72 h after experimental treatment of Eca109 and TE-1 cells (Figure 1B).	('E6-E7', 'Var', (34, 39))	('men', 'Species', '9606', (132, 135))	('HPV16', 'Species', '333760', (28, 33))	('HPV16', 'Gene', (28, 33))	('men', 'Species', '9606', (120, 123))
726071	27489353	It could be concluded that HPV16 E6-E7 increases migration and invasion potential in ESCC cells in vitro.	('migration', 'CPA', (49, 58))	('invasion potential', 'CPA', (63, 81))	('ESCC', 'Disease', (85, 89))	('HPV16', 'Gene', (27, 32))	('E6-E7', 'Var', (33, 38))	('HPV16', 'Species', '333760', (27, 32))	('increases', 'PosReg', (39, 48))
726072	27489353	The studies above demonstrated that HPV16 E6-E7 behaved as a tumor-promoting factor in ESCC cells.	('E6-E7', 'Var', (42, 47))	('HPV16', 'Gene', (36, 41))	('HPV16', 'Species', '333760', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('ESCC', 'Disease', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
726073	27489353	We next examined the effect of HPV16 E6-E7 on the spherogenesis ability of ESCC cells which was considered to be an important characteristic of CSCs in vitro.	('examined', 'Reg', (8, 16))	('HPV16', 'Species', '333760', (31, 36))	('E6-E7', 'Var', (37, 42))	('spherogenesis ability', 'CPA', (50, 71))	('HPV16', 'Gene', (31, 36))
726074	27489353	It was observed obviously (P<0.001) increased in the number of spheres in Eca109-psb and TE-1-psb cells compared to control cells on day 14(Figure 2A and 2B).	('TE-1-psb', 'Chemical', '-', (89, 97))	('increased', 'PosReg', (36, 45))	('Eca109-psb', 'Var', (74, 84))	('Eca109-psb', 'Chemical', '-', (74, 84))
726075	27489353	It shows that HPV16 E6-E7 enhances the spherogenesis of ESCC cells in vitro.	('spherogenesis of ESCC cells', 'CPA', (39, 66))	('HPV16', 'Species', '333760', (14, 19))	('enhances', 'PosReg', (26, 34))	('HPV16', 'Gene', (14, 19))	('E6-E7', 'Var', (20, 25))
726077	27489353	In this study, flow cytometry was applied to investigate whether HPV16 E6-E7 increased p75NTR positive cells in ESCC cells, as it increased sphereogenesis as demonstrated above.	('p75NTR', 'Gene', (87, 93))	('p75NTR', 'Gene', '4804', (87, 93))	('HPV16', 'Gene', (65, 70))	('HPV16', 'Species', '333760', (65, 70))	('increased', 'PosReg', (77, 86))	('E6-E7', 'Var', (71, 76))	('increased', 'PosReg', (130, 139))	('sphereogenesis', 'CPA', (140, 154))
726078	27489353	As shown in Figure 2C-2F, significant (P<0.05-0.001) improvement of p75NTR positive cells were detected in Eca109-psb and TE-1-psb cells than control cells.	('p75NTR', 'Gene', '4804', (68, 74))	('improvement', 'PosReg', (53, 64))	('Eca109-psb', 'Var', (107, 117))	('men', 'Species', '9606', (60, 63))	('Eca109-psb', 'Chemical', '-', (107, 117))	('p75NTR', 'Gene', (68, 74))	('TE-1-psb', 'Chemical', '-', (122, 130))
726079	27489353	Similarly, it was also found that the p75NTR positive cells significantly (P<0.01-0.001) increased in Eca109-psb and TE-1-psb cell spheres compared to control cell spheres.	('TE-1-psb cell spheres', 'CPA', (117, 138))	('p75NTR', 'Gene', '4804', (38, 44))	('Eca109-psb', 'Chemical', '-', (102, 112))	('Eca109-psb', 'Var', (102, 112))	('TE-1-psb', 'Chemical', '-', (117, 125))	('increased', 'PosReg', (89, 98))	('p75NTR', 'Gene', (38, 44))
726080	27489353	This suggests that HPV16 E6-E7 increases the ratio of p75NTR positive cells in ESCC cells in vitro.	('HPV16', 'Gene', (19, 24))	('HPV16', 'Species', '333760', (19, 24))	('E6-E7', 'Var', (25, 30))	('increases', 'PosReg', (31, 40))	('p75NTR', 'Gene', (54, 60))	('p75NTR', 'Gene', '4804', (54, 60))
726081	27489353	Flow cytometry was performed to investigate the effect of HPV16 E6-E7 on ESCC cells cycle progression.	('ESCC', 'Disease', (73, 77))	('E6-E7', 'Var', (64, 69))	('HPV16', 'Gene', (58, 63))	('HPV16', 'Species', '333760', (58, 63))
726082	27489353	As shown in Figure 2G and 2H, compared to control cells, HPV16 E6-E7 significantly (P<0.05-0.01) decreased cells that were arrested at the G0/G1 transition evidenced by a less accumulated cells in the G0/G1 peak.	('E6-E7', 'Var', (63, 68))	('HPV16', 'Species', '333760', (57, 62))	('2H', 'Chemical', 'MESH:D003903', (26, 28))	('cells that', 'CPA', (107, 117))	('HPV16 E6-E7', 'Var', (57, 68))	('decreased', 'NegReg', (97, 106))
726083	27489353	This indicates that HPV16 E6-E7 leads to the accumulation of cells in G2/M and extensively decreases the percentage of cells in G0/G1 phase in ESCC cells in vitro.	('HPV16', 'Species', '333760', (20, 25))	('accumulation', 'PosReg', (45, 57))	('HPV16', 'Gene', (20, 25))	('decreases', 'NegReg', (91, 100))	('E6-E7', 'Var', (26, 31))
726084	27489353	CCK-8 assay was performed to determine whether HPV16 E6-E7 had an effect on ESCC cell proliferation after cisplatinum (CDDP), one of the representative cytotoxic drugs, treatment.	('effect', 'Reg', (66, 72))	('HPV16', 'Gene', (47, 52))	('HPV16', 'Species', '333760', (47, 52))	('ESCC cell proliferation', 'CPA', (76, 99))	('E6-E7', 'Var', (53, 58))	('CDDP', 'Chemical', 'MESH:D002945', (119, 123))	('men', 'Species', '9606', (174, 177))	('cisplatinum', 'Chemical', 'MESH:D002945', (106, 117))
726087	27489353	It could be obviously concluded that all of the IC50 value of Eca109-psb and TE-1-psb cells at 48 and 72h are significantly (P<0.001) higher than control cells.	('IC50', 'MPA', (48, 52))	('higher', 'PosReg', (134, 140))	('Eca109-psb', 'Var', (62, 72))	('Eca109-psb', 'Chemical', '-', (62, 72))	('2h', 'Chemical', 'MESH:D003903', (103, 105))	('TE-1-psb', 'Chemical', '-', (77, 85))
726088	27489353	These results above indicate that HPV16 E6-E7 increases chemoresistance in ESCC cells in vitro.	('chemoresistance', 'CPA', (56, 71))	('increases', 'PosReg', (46, 55))	('HPV16', 'Gene', (34, 39))	('HPV16', 'Species', '333760', (34, 39))	('E6-E7', 'Var', (40, 45))
726089	27489353	The colony formation assay was performed to determine the influence of HPV16 E6-E7 on radioresistance in ESCC cells.	('E6-E7', 'Var', (77, 82))	('radioresistance', 'CPA', (86, 101))	('HPV16', 'Gene', (71, 76))	('HPV16', 'Species', '333760', (71, 76))
726091	27489353	It was found that the value of D0, k and SF2 significantly (P<0.001-0.05) increased in Eca109-psb and TE-1-psb cells compared to control cells (Supplementary Table S1) while no significant differences were observed in the value of N, Dq.	('SF2', 'Gene', '6426', (41, 44))	('increased', 'PosReg', (74, 83))	('SF2', 'Gene', (41, 44))	('men', 'Species', '9606', (150, 153))	('Eca109-psb', 'Chemical', '-', (87, 97))	('Eca109-psb', 'Var', (87, 97))	('TE-1-psb', 'Chemical', '-', (102, 110))
726092	27489353	This indicates that HPV16 E6-E7 also increases radioresistance of ESCC cells in vitro.	('radioresistance', 'CPA', (47, 62))	('HPV16', 'Species', '333760', (20, 25))	('HPV16', 'Gene', (20, 25))	('increases', 'PosReg', (37, 46))	('E6-E7', 'Var', (26, 31))
726093	27489353	Annexin V-APC/PI flow cytometry was applied to assess the effect of HPV16 E6-E7 on ESCC cells apoptosis after ionizing radiation.	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('HPV16', 'Species', '333760', (68, 73))	('HPV16', 'Gene', (68, 73))	('E6-E7', 'Var', (74, 79))
726095	27489353	Meanwhile, the ratio of apoptosis cells was significantly (P<0.05-0.001) lower in Eca109-psb and TE-1-psb cells than control cells when treated by 4, 6 and 8Gy (Figure 3E), with no significant differences by 2Gy (P=0.065, 0.087, respectively) or untreated (P=0.118, 0.069, respectively).	('Eca109-psb', 'Chemical', '-', (82, 92))	('Eca109-psb', 'Var', (82, 92))	('TE-1-psb', 'Chemical', '-', (97, 105))	('lower', 'NegReg', (73, 78))
726096	27489353	This means that HPV16 E6-E7 inhibits the apoptosis in ESCC cells when treated by ionizing radiation, especially accumulating and highly dose of ionizing radiation in vitro.	('HPV16', 'Species', '333760', (16, 21))	('inhibits', 'NegReg', (28, 36))	('HPV16', 'Gene', (16, 21))	('E6-E7', 'Var', (22, 27))	('apoptosis', 'CPA', (41, 50))
726098	27489353	So, we speculate that HPV16 E6-E7 may increase the CSCs properties of ESCC cells through up-regulation of PI3K/Akt signaling.	('increase', 'PosReg', (38, 46))	('E6-E7', 'Var', (28, 33))	('HPV16', 'Species', '333760', (22, 27))	('Akt', 'Gene', (111, 114))	('HPV16', 'Gene', (22, 27))	('Akt', 'Gene', '207', (111, 114))	('CSCs properties of', 'CPA', (51, 69))	('up-regulation', 'PosReg', (89, 102))
726099	27489353	The expression of PI3K, phosphorylation-Akt (ser473), also named as p-Akt (ser473), and p75NTR in the Eca109-psb and TE-1-psb cells significantly (P<0.001) increased compared to control cells.	('Akt', 'Gene', '207', (40, 43))	('ser473', 'Chemical', '-', (45, 51))	('Akt', 'Gene', (70, 73))	('Eca109-psb', 'Chemical', '-', (102, 112))	('p75NTR', 'Gene', (88, 94))	('PI3K', 'Var', (18, 22))	('expression', 'MPA', (4, 14))	('increased', 'PosReg', (156, 165))	('p75NTR', 'Gene', '4804', (88, 94))	('Akt', 'Gene', (40, 43))	('TE-1-psb', 'Chemical', '-', (117, 125))	('Akt', 'Gene', '207', (70, 73))	('ser473', 'Chemical', '-', (75, 81))
726100	27489353	Whereas, no significant alterations could be observed in the expression of total Akt in Eca109-psb and TE-1-psb cells compared to control cells (Figure 4A and 4B).	('Akt', 'Gene', '207', (81, 84))	('TE-1-psb', 'Chemical', '-', (103, 111))	('Akt', 'Gene', (81, 84))	('Eca109-psb', 'Chemical', '-', (88, 98))	('Eca109-psb', 'Var', (88, 98))
726101	27489353	Immunofluorescence of ESCC cells (Figure 4C) demonstrated that PI3K, p-Akt (ser473) and p75NTR expressions were markedly increased in Eca109-psb and TE-1-psb cells compared to control cells.	('Akt', 'Gene', '207', (71, 74))	('Eca109-psb', 'Chemical', '-', (134, 144))	('Eca109-psb', 'Var', (134, 144))	('increased', 'PosReg', (121, 130))	('Akt', 'Gene', (71, 74))	('p75NTR', 'Gene', (88, 94))	('p75NTR', 'Gene', '4804', (88, 94))	('PI3K', 'Protein', (63, 67))	('ser473', 'Chemical', '-', (76, 82))	('TE-1-psb', 'Chemical', '-', (149, 157))
726102	27489353	Meanwhile, immunofluorescence of spheres (Figure 4D) also demonstrated that PI3K, p-Akt (ser473) and p75NTR expression are obviously stronger in spheres derived from Eca109-psb and TE-1-psb cells than spheres derived from control cells.	('TE-1-psb', 'Chemical', '-', (181, 189))	('ser473', 'Chemical', '-', (89, 95))	('Akt', 'Gene', '207', (84, 87))	('stronger', 'PosReg', (133, 141))	('Eca109-psb', 'Var', (166, 176))	('Akt', 'Gene', (84, 87))	('p75NTR', 'Gene', (101, 107))	('p75NTR', 'Gene', '4804', (101, 107))	('Eca109-psb', 'Chemical', '-', (166, 176))	('PI3K', 'Gene', (76, 80))
726103	27489353	It suggests that HPV16 E6-E7 activates the PI3K/Akt signaling pathway in ESCC cells and spheres derived from ESCC cells.	('Akt', 'Gene', (48, 51))	('activates', 'PosReg', (29, 38))	('HPV16', 'Species', '333760', (17, 22))	('HPV16', 'Gene', (17, 22))	('E6-E7', 'Var', (23, 28))	('Akt', 'Gene', '207', (48, 51))
726104	27489353	To investigate whether inhibiting the PI3K/Akt signaling pathway can reverse CSCs phenotypes caused by HPV16 E6-E7.	('Akt', 'Gene', '207', (43, 46))	('Akt', 'Gene', (43, 46))	('CSCs', 'Disease', (77, 81))	('HPV16', 'Gene', (103, 108))	('HPV16', 'Species', '333760', (103, 108))	('E6-E7', 'Var', (109, 114))
726106	27489353	Consequently, there were no significant difference in the expression of PI3K, p-Akt (ser473) and p75NTR as they all decreased (P<0.001) in ESCC cells after LY294002 treatment (Figure 4A and 4B).	('LY294002', 'Chemical', 'MESH:C085911', (156, 164))	('Akt', 'Gene', '207', (80, 83))	('LY294002', 'Var', (156, 164))	('Akt', 'Gene', (80, 83))	('p75NTR', 'Gene', (97, 103))	('p75NTR', 'Gene', '4804', (97, 103))	('men', 'Species', '9606', (170, 173))	('decreased', 'NegReg', (116, 125))	('ser473', 'Chemical', '-', (85, 91))
726107	27489353	However, there were still no alternations in the expression of total Akt in the ESCC cells after being treated with LY294002 (Figure 4A and 4B).	('Akt', 'Gene', (69, 72))	('LY294002', 'Chemical', 'MESH:C085911', (116, 124))	('Akt', 'Gene', '207', (69, 72))	('LY294002', 'Var', (116, 124))
726108	27489353	Based on the results above, LY294002 treatment reverse the expression of PI3K, p-Akt (ser473) and p75NTR in Eca109-psb and TE-1-psb cells, and this further demonstrated that the activation of PI3K/Akt signaling pathway, induced by HPV16 E6-E7, plays a vital role in maintaining CSCs phenotypes in ESCC cells.	('CSCs', 'Disease', (278, 282))	('HPV16', 'Gene', (231, 236))	('E6-E7', 'Var', (237, 242))	('Akt', 'Gene', '207', (197, 200))	('men', 'Species', '9606', (42, 45))	('LY294002', 'Var', (28, 36))	('Akt', 'Gene', '207', (81, 84))	('ESCC', 'Disease', (297, 301))	('Eca109-psb', 'Chemical', '-', (108, 118))	('HPV16', 'Species', '333760', (231, 236))	('Akt', 'Gene', (197, 200))	('ser473', 'Chemical', '-', (86, 92))	('Akt', 'Gene', (81, 84))	('LY294002', 'Chemical', 'MESH:C085911', (28, 36))	('PI3K', 'Gene', (73, 77))	('TE-1-psb', 'Chemical', '-', (123, 131))	('p75NTR', 'Gene', (98, 104))	('p75NTR', 'Gene', '4804', (98, 104))
726111	27489353	Treated with the PI3K siRNA 1178, 619 and 856, the expression of PI3K, p-Akt (ser473) and p75NTR in ESCC cells were all significantly (P<0.01-0.001) decreased in siRNA group, compared to control siRNA group, (Figure 5A, 5C and Figure 6A, 6C), but no significant alternations were observed in total Akt expressions (Figure 5A, 5C and Figure 6A, 6C).	('ser473', 'Chemical', '-', (78, 84))	('Akt', 'Gene', (73, 76))	('p75NTR', 'Gene', (90, 96))	('p75NTR', 'Gene', '4804', (90, 96))	('Akt', 'Gene', '207', (298, 301))	('PI3K', 'Gene', (65, 69))	('expression', 'MPA', (51, 61))	('856', 'Var', (42, 45))	('Akt', 'Gene', (298, 301))	('decreased', 'NegReg', (149, 158))	('Akt', 'Gene', '207', (73, 76))	('PI3K', 'Var', (17, 21))
726112	27489353	Consistently, the PI3K, p-Akt (ser473) and p75NTR expressions were significantly higher (P<0.05-0.001) in Eca109-psb and TE-1-psb cells than control cells in control siRNA groups (Figure 5A, 5C and Figure 6A, 6C) with no significant difference of that in the PI3K siRNA groups (Figure 5A, 5C and Figure 6A, 6C).	('Akt', 'Gene', '207', (26, 29))	('ser473', 'Chemical', '-', (31, 37))	('TE-1-psb', 'Chemical', '-', (121, 129))	('higher', 'PosReg', (81, 87))	('Eca109-psb', 'Var', (106, 116))	('p75NTR', 'Gene', (43, 49))	('Akt', 'Gene', (26, 29))	('p75NTR', 'Gene', '4804', (43, 49))	('Eca109-psb', 'Chemical', '-', (106, 116))	('PI3K', 'Gene', (18, 22))
726118	27489353	Interestingly, the PI3K expressions were significantly (P<0.05-0.001) higher in Eca109-psb and TE-1-psb, compared to control cells in control siRNA group and Akt siRNA group (Figure 5B, 5D and Figure 6B, 6D).	('Akt', 'Gene', (158, 161))	('Akt', 'Gene', '207', (158, 161))	('Eca109-psb', 'Chemical', '-', (80, 90))	('TE-1-psb', 'Var', (95, 103))	('TE-1-psb', 'Chemical', '-', (95, 103))	('higher', 'PosReg', (70, 76))	('Eca109-psb', 'Var', (80, 90))	('PI3K', 'Protein', (19, 23))
726119	27489353	p-Akt (ser473) and p75NTR expressions were significantly (P<0.05-0.001) higher in Eca109-psb and TE-1-psb cells, compared to control cells, in control siRNA group with no significant difference of that in the Akt siRNA group.	('Eca109-psb', 'Chemical', '-', (82, 92))	('Eca109-psb', 'Var', (82, 92))	('ser473', 'Chemical', '-', (7, 13))	('Akt', 'Gene', (2, 5))	('TE-1-psb', 'Chemical', '-', (97, 105))	('Akt', 'Gene', '207', (209, 212))	('p75NTR', 'Gene', (19, 25))	('Akt', 'Gene', (209, 212))	('higher', 'PosReg', (72, 78))	('p75NTR', 'Gene', '4804', (19, 25))	('Akt', 'Gene', '207', (2, 5))
726120	27489353	GAPDH was used for positive control to make sure siRNA knock-down efficiency and beta-actin was used as the endogenous reference.	('beta-actin', 'Gene', '728378', (81, 91))	('beta-actin', 'Gene', (81, 91))	('knock-down', 'Var', (55, 65))	('GAPDH', 'Gene', '2597', (0, 5))	('GAPDH', 'Gene', (0, 5))
726121	27489353	The xenograft nude mouse model was established to verify the effects of HPV16 E6-E7 on tumorigenesis in ESCC cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mouse', 'Species', '10090', (19, 24))	('tumor', 'Disease', (87, 92))	('ESCC', 'Disease', (104, 108))	('HPV16', 'Species', '333760', (72, 77))	('E6-E7', 'Var', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('HPV16', 'Gene', (72, 77))
726122	27489353	The mice were randomly distributed into four groups (N=6): Control, Radiation, LY294002 and LY294002+Radiation group.	('LY294002', 'Var', (79, 87))	('mice', 'Species', '10090', (4, 8))	('Rad', 'Gene', '6236', (101, 104))	('LY294002', 'Chemical', 'MESH:C085911', (92, 100))	('Rad', 'Gene', (101, 104))	('Rad', 'Gene', '6236', (68, 71))	('LY294002', 'Chemical', 'MESH:C085911', (79, 87))	('Rad', 'Gene', (68, 71))
726123	27489353	The xenograft tumour growth markedly (P<0.05) increased in mice bearing Eca109-psb cells, compared to the Eca109-control cells, both in Control group and Radiation group (Figure 7A, 7B).	('tumour', 'Disease', (14, 20))	('mice', 'Species', '10090', (59, 63))	('increased', 'PosReg', (46, 55))	('Rad', 'Gene', '6236', (154, 157))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('Rad', 'Gene', (154, 157))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('Eca109-psb', 'Chemical', '-', (72, 82))	('Eca109-psb cells', 'Var', (72, 88))
726124	27489353	However, there was no significant difference in the tumor volumes between LY294002 group and the LY294002+radiation group.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('LY294002', 'Chemical', 'MESH:C085911', (74, 82))	('tumor', 'Disease', (52, 57))	('LY294002', 'Var', (74, 82))	('LY294002', 'Chemical', 'MESH:C085911', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
726125	27489353	Moreover, no marked changes in body weight were found in the four groups while the growth of body weight in LY294002+radiation group is the slowest in four groups (Figure 7D).	('LY294002', 'Chemical', 'MESH:C085911', (108, 116))	('slowest', 'NegReg', (140, 147))	('LY294002+radiation', 'Var', (108, 126))
726126	27489353	This indicates that tumors derived from Eca109-psb cells grow markedly and significantly (P<0.05) faster than tumors derived from control cells in Control group and Radiation group.	('Rad', 'Gene', (165, 168))	('tumors', 'Disease', (20, 26))	('Eca109-psb', 'Var', (40, 50))	('grow', 'CPA', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('Eca109-psb', 'Chemical', '-', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Rad', 'Gene', '6236', (165, 168))	('faster', 'PosReg', (98, 104))
726130	27489353	However, in the LY294002 and LY294002+radiation groups, no significant difference could be observed in the expression of PI3K, p-Akt (ser473) and p75NTR between the tumors derived from Eca109-psb cells and tumors derived from Eca109-control cells in vivo (Figure 7E).	('LY294002', 'Chemical', 'MESH:C085911', (16, 24))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('p75NTR', 'Gene', '4804', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('ser473', 'Chemical', '-', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('LY294002', 'Chemical', 'MESH:C085911', (29, 37))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('PI3K', 'Var', (121, 125))	('tumors', 'Disease', (206, 212))	('LY294002+radiation', 'Var', (29, 47))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('Eca109-psb', 'Chemical', '-', (185, 195))	('Akt', 'Gene', (129, 132))	('LY294002', 'Var', (16, 24))	('Akt', 'Gene', '207', (129, 132))	('p75NTR', 'Gene', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (165, 171))
726131	27489353	What's more, the expressions of PI3K, p-Akt (ser473) and p75NTR are all inhibited by LY294002 (Figure 7E).	('Akt', 'Gene', '207', (40, 43))	('ser473', 'Chemical', '-', (45, 51))	('ser473', 'Var', (45, 51))	('Akt', 'Gene', (40, 43))	('p75NTR', 'Gene', (57, 63))	('p75NTR', 'Gene', '4804', (57, 63))	('LY294002', 'Chemical', 'MESH:C085911', (85, 93))	('inhibited', 'NegReg', (72, 81))	('PI3K', 'Protein', (32, 36))	('LY294002', 'Var', (85, 93))
726132	27489353	Taken together, it could be easily concluded that HPV16 E6-E7 promotes the tumorigenesis and radioresistance in ESCC cells in vivo.	('HPV16', 'Gene', (50, 55))	('E6-E7', 'Var', (56, 61))	('HPV16', 'Species', '333760', (50, 55))	('ESCC', 'Disease', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('promotes', 'PosReg', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('radioresistance', 'CPA', (93, 108))	('tumor', 'Disease', (75, 80))
726134	27489353	IHC results suggest that the activation of PI3K/Akt signaling pathway induced by HPV16 E6-E7 could be inhibited by LY294002 in vivo.	('activation', 'PosReg', (29, 39))	('Akt', 'Gene', (48, 51))	('inhibited', 'NegReg', (102, 111))	('HPV16', 'Gene', (81, 86))	('E6-E7', 'Var', (87, 92))	('HPV16', 'Species', '333760', (81, 86))	('Akt', 'Gene', '207', (48, 51))	('LY294002', 'Chemical', 'MESH:C085911', (115, 123))
726137	27489353	The present study firstly aims at finding the influence on cell behavior and potential mechanism after HPV16 E6-E7 infecting the ESCC cells.	('E6-E7', 'Var', (109, 114))	('HPV16', 'Gene', (103, 108))	('HPV16', 'Species', '333760', (103, 108))
726140	27489353	Our previous study also demonstrated that p75NTR positive cells significantly increased in Eca109R-50Gy cells (Eca109 cells achieved by accumulated 50 Gy ionizing radiation with high radioresistance and characteristics of CSCs), compared to Eca109 cells.	('Eca109R-50Gy', 'Var', (91, 103))	('p75NTR', 'Gene', (42, 48))	('increased', 'PosReg', (78, 87))	('p75NTR', 'Gene', '4804', (42, 48))
726141	27489353	Basing on this, we sent out to investigate the role of HPV16 E6-E7 in the biological behavior of ESCC cells.	('HPV16', 'Gene', (55, 60))	('E6-E7', 'Var', (61, 66))	('HPV16', 'Species', '333760', (55, 60))
726142	27489353	Transwell assay in this study found that HPV16 E6-E7 promoted the migration and invasion ability significantly (Figure 1C-1F).	('promoted', 'PosReg', (53, 61))	('migration', 'CPA', (66, 75))	('HPV16', 'Species', '333760', (41, 46))	('invasion ability', 'CPA', (80, 96))	('HPV16', 'Gene', (41, 46))	('E6-E7', 'Var', (47, 52))
726143	27489353	The spherogenesis assay performed in this study found that HPV16 E6-E7 also induced spherogenesis in ESCC cells (Figure 2A, 2B).	('E6-E7', 'Var', (65, 70))	('HPV16', 'Gene', (59, 64))	('spherogenesis', 'CPA', (84, 97))	('HPV16', 'Species', '333760', (59, 64))	('ESCC', 'Disease', (101, 105))	('induced', 'Reg', (76, 83))
726144	27489353	Next, flow cytometry was applied to analysis of p75NTR positive cells, and the results showed that HPV16 E6-E7 induced the stemness in ESCC cells because of the increased ratio of p75NTR positive cells in Eca109-psb, TE-1-psb cells and spheres derived from them (Figure 2C-2F).	('ESCC', 'Disease', (135, 139))	('Eca109-psb', 'Chemical', '-', (205, 215))	('p75NTR', 'Gene', (180, 186))	('TE-1-psb', 'Chemical', '-', (217, 225))	('p75NTR', 'Gene', '4804', (48, 54))	('p75NTR', 'Gene', '4804', (180, 186))	('stemness', 'Disease', 'MESH:D020295', (123, 131))	('stemness', 'Disease', (123, 131))	('HPV16', 'Species', '333760', (99, 104))	('induced', 'PosReg', (111, 118))	('HPV16 E6-E7', 'Var', (99, 110))	('increased', 'PosReg', (161, 170))	('E6-E7', 'Var', (105, 110))	('p75NTR', 'Gene', (48, 54))
726145	27489353	All of the results above indicate that HPV16 E6-E7 induces CSCs phenotypes in ESCC cells.	('HPV16', 'Gene', (39, 44))	('HPV16', 'Species', '333760', (39, 44))	('ESCC', 'Disease', (78, 82))	('E6-E7', 'Var', (45, 50))	('induces', 'Reg', (51, 58))	('CSCs', 'Disease', (59, 63))
726146	27489353	Cell cycle analysis showed that HPV16 E6-E7 caused an accumulation of cells in G2/M phase with significantly reduction in G0/G1 phase (Figure 2G, 2H).	('G0/G1 phase', 'CPA', (122, 133))	('HPV16', 'Gene', (32, 37))	('E6-E7', 'Var', (38, 43))	('HPV16', 'Species', '333760', (32, 37))	('reduction', 'NegReg', (109, 118))	('2H', 'Chemical', 'MESH:D003903', (146, 148))	('cells in G2/M phase', 'CPA', (70, 89))	('accumulation', 'PosReg', (54, 66))
726147	27489353	In the cell proliferation analysis, CCK8 cell viability assay (Figure 3A) and colony formation assay (Figure 3B, 3C, Supplementary Table S1) suggested HPV16 E6-E7 promoted chemoresistance and radioresistance in ESCC cells, respectively.	('HPV16', 'Species', '333760', (151, 156))	('promoted', 'PosReg', (163, 171))	('radioresistance', 'CPA', (192, 207))	('HPV16', 'Gene', (151, 156))	('men', 'Species', '9606', (123, 126))	('chemoresistance', 'CPA', (172, 187))	('E6-E7', 'Var', (157, 162))
726148	27489353	Then the cell apoptosis assay performed by flow cytometry analysis revealed that HPV16 E6-E7 increased the anti-apoptotic ability of ESCC cells when treated by ionizing radiation (Figure 3D, 3E).	('increased', 'PosReg', (93, 102))	('HPV16', 'Gene', (81, 86))	('E6-E7', 'Var', (87, 92))	('HPV16', 'Species', '333760', (81, 86))	('anti-apoptotic ability', 'CPA', (107, 129))
726149	27489353	All in all, HPV16 E6-E7 increases the chemoresistance, radioresistance and plays an anti-apoptotic effect in ESCC cells.	('increases', 'PosReg', (24, 33))	('HPV16', 'Gene', (12, 17))	('E6-E7', 'Var', (18, 23))	('HPV16', 'Species', '333760', (12, 17))	('radioresistance', 'CPA', (55, 70))	('chemoresistance', 'CPA', (38, 53))	('anti-apoptotic effect', 'CPA', (84, 105))
726150	27489353	As the results described above, the potential mechanism that HPV16 E6-E7 induces CSCs phenotypes in ESCC should be detected.	('HPV16', 'Gene', (61, 66))	('HPV16', 'Species', '333760', (61, 66))	('ESCC', 'Disease', (100, 104))	('induces', 'Reg', (73, 80))	('E6-E7', 'Var', (67, 72))	('CSCs phenotypes', 'Disease', (81, 96))
726154	27489353	Akt is the major effector kinases in the downstream of PI3K/Akt pathway, inhibition of PI3K/Akt activity attenuate CSCs metabolism and is critical for CSCs quiescence.	('attenuate', 'NegReg', (105, 114))	('activity', 'MPA', (96, 104))	('Akt', 'Gene', '207', (60, 63))	('Akt', 'Gene', '207', (92, 95))	('Akt', 'Gene', '207', (0, 3))	('Akt', 'Gene', (60, 63))	('Akt', 'Gene', (92, 95))	('Akt', 'Gene', (0, 3))	('inhibition', 'Var', (73, 83))	('CSCs metabolism', 'MPA', (115, 130))
726155	27489353	So we investigated the PI3K/Akt signaling pathway in ESCC cells with LY294002, PI3K siRNA and Akt siRNA.	('Akt', 'Gene', (28, 31))	('investigated', 'Reg', (6, 18))	('LY294002', 'Var', (69, 77))	('Akt', 'Gene', (94, 97))	('LY294002', 'Chemical', 'MESH:C085911', (69, 77))	('Akt', 'Gene', '207', (94, 97))	('Akt', 'Gene', '207', (28, 31))
726156	27489353	Western blotting indicated that HPV16 E6-E7 increased PI3K, p-Akt (ser473) and p75NTR expression in ESCC cells (Figure 4A, 4B, Figure 5 and Figure 6).	('p75NTR', 'Gene', (79, 85))	('p75NTR', 'Gene', '4804', (79, 85))	('HPV16', 'Gene', (32, 37))	('E6-E7', 'Var', (38, 43))	('HPV16', 'Species', '333760', (32, 37))	('PI3K', 'Pathway', (54, 58))	('Akt', 'Gene', '207', (62, 65))	('ser473', 'Chemical', '-', (67, 73))	('increased', 'PosReg', (44, 53))	('Akt', 'Gene', (62, 65))
726158	27489353	Immunofluorescence also demonstrated that HPV16 E6-E7 improved PI3K, p-Akt (ser473) and p75NTR expression in ESCC cells and spheres from ESCC cells (Figure 4C and 4D).	('Akt', 'Gene', '207', (71, 74))	('HPV16 E6-E7', 'Var', (42, 53))	('p75NTR', 'Gene', (88, 94))	('Akt', 'Gene', (71, 74))	('p75NTR', 'Gene', '4804', (88, 94))	('HPV16', 'Species', '333760', (42, 47))	('ser473', 'Chemical', '-', (76, 82))	('improved', 'PosReg', (54, 62))	('PI3K', 'Pathway', (63, 67))
726162	27489353	The xenograft study found that the proliferation effect significantly promoted by HPV16 E6-E7 in Eca109 cells could be inhibited by LY294002 in vivo (Figure 7A, 7B).	('HPV16', 'Gene', (82, 87))	('HPV16', 'Species', '333760', (82, 87))	('promoted', 'PosReg', (70, 78))	('E6-E7', 'Var', (88, 93))	('LY294002', 'Chemical', 'MESH:C085911', (132, 140))	('proliferation effect', 'CPA', (35, 55))
726163	27489353	Furthermore, the IHC found the expression of PI3K, p-Akt (473) and p75NTR in the Eca109-psb cells tissues is definitely higher than control cells tissues in the Control group and Radiation group while no difference could be seen in LY294002 group and LY294002+Radiation group (Figure 7E).	('Rad', 'Gene', (179, 182))	('PI3K', 'Var', (45, 49))	('Akt', 'Gene', '207', (53, 56))	('Eca109-psb', 'Chemical', '-', (81, 91))	('LY294002', 'Chemical', 'MESH:C085911', (232, 240))	('higher', 'PosReg', (120, 126))	('p75NTR', 'Gene', (67, 73))	('LY294002', 'Chemical', 'MESH:C085911', (251, 259))	('p75NTR', 'Gene', '4804', (67, 73))	('Rad', 'Gene', '6236', (260, 263))	('expression', 'MPA', (31, 41))	('Rad', 'Gene', (260, 263))	('Akt', 'Gene', (53, 56))	('Rad', 'Gene', '6236', (179, 182))
726164	27489353	This further confirms our hypothesis that HPV16 E6-E7 promotes CSCs phenotypes of ESCC cells which can be partly inhibited by the blocking of PI3K/Akt signaling pathway in vivo.	('E6-E7', 'Var', (48, 53))	('CSCs phenotypes', 'Disease', (63, 78))	('HPV16', 'Species', '333760', (42, 47))	('Akt', 'Gene', '207', (147, 150))	('HPV16', 'Gene', (42, 47))	('Akt', 'Gene', (147, 150))	('ESCC cells', 'Disease', (82, 92))	('promotes', 'PosReg', (54, 62))
726165	27489353	In summary, although many previous studies declare the important role of HPV16 infection in the incidence of ESCC, the present study is firstly investigate the potential role and mechanism of HPV16 E6-E7 in the development of ESCC.	('ESCC', 'Disease', (109, 113))	('infection', 'Disease', (79, 88))	('HPV16', 'Species', '333760', (192, 197))	('infection', 'Disease', 'MESH:D007239', (79, 88))	('HPV16', 'Species', '333760', (73, 78))	('E6-E7', 'Var', (198, 203))	('men', 'Species', '9606', (218, 221))	('HPV16', 'Gene', (73, 78))
726166	27489353	It is supposed that HPV16 E6-E7 function as a CSCs phenotypes promoter in ESCC cells through activation of PI3K/Akt signaling pathway with the up-regulate of p75NTR, a CSCs marker in ESCC cells.	('up-regulate', 'PosReg', (143, 154))	('activation', 'PosReg', (93, 103))	('HPV16', 'Species', '333760', (20, 25))	('Akt', 'Gene', '207', (112, 115))	('HPV16', 'Gene', (20, 25))	('Akt', 'Gene', (112, 115))	('p75NTR', 'Gene', (158, 164))	('p75NTR', 'Gene', '4804', (158, 164))	('E6-E7', 'Var', (26, 31))
726167	27489353	However, it is also indicated that the inhibition of PI3K/Akt signaling pathway reverses the effect which induced by HPV16 E6-E7 in ESCC cells, in vitro and in vivo.	('E6-E7', 'Var', (123, 128))	('inhibition', 'NegReg', (39, 49))	('Akt', 'Gene', '207', (58, 61))	('HPV16', 'Gene', (117, 122))	('HPV16', 'Species', '333760', (117, 122))	('Akt', 'Gene', (58, 61))	('ESCC', 'Disease', (132, 136))
726170	27489353	The authenticity of cancer cell lines was tested by short tandem repeat profiling.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('short tandem repeat', 'Var', (52, 71))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))
726174	27489353	It was constructed by ligating the HPV16 E6-E7 precursor (789bp) into the EcoR I and Xba I sites of the pLVX-EGFP-T2A-Puro lentivector (8934bp).	('HPV16', 'Species', '333760', (35, 40))	('HPV16', 'Gene', (35, 40))	('T2A', 'Mutation', 'rs1225055065', (114, 117))	('789bp', 'Var', (58, 63))
726179	27489353	The expression of HPV16 E6-E7 was confirmed by Western blotting.	('HPV16', 'Gene', (18, 23))	('HPV16', 'Species', '333760', (18, 23))	('E6-E7', 'Var', (24, 29))
726203	27489353	Secondary antibodies used were horseradish peroxidase (HRP) - conjugated anti-rabbit (#4414, CST, USA) and anti-mouse (#4410, CST, USA).	('CST', 'Gene', '106478911', (93, 96))	('#4414', 'Var', (86, 91))	('CST', 'Gene', (126, 129))	('CST', 'Gene', (93, 96))	('rabbit', 'Species', '9986', (78, 84))	('mouse', 'Species', '10090', (112, 117))	('CST', 'Gene', '106478911', (126, 129))	('horseradish', 'Species', '3704', (31, 42))	('#4410', 'Var', (119, 124))
726209	27489353	The mice were randomly distributed into four groups (N=6):Control, Radiation, LY294002 and LY294002 +Radiation group.	('mice', 'Species', '10090', (4, 8))	('LY294002', 'Chemical', 'MESH:C085911', (91, 99))	('Rad', 'Gene', '6236', (101, 104))	('LY294002', 'Chemical', 'MESH:C085911', (78, 86))	('Rad', 'Gene', '6236', (67, 70))	('Rad', 'Gene', (67, 70))	('Rad', 'Gene', (101, 104))	('LY294002', 'Var', (78, 86))
726214	27489353	The mice in the group treated with the combined LY294002 and radiation were irradiated after the injection of LY294002 every time.	('mice', 'Species', '10090', (4, 8))	('LY294002', 'Var', (48, 56))	('LY294002', 'Var', (110, 118))	('LY294002', 'Chemical', 'MESH:C085911', (48, 56))	('LY294002', 'Chemical', 'MESH:C085911', (110, 118))
726258	26134767	Abnormality of vital signs was defined as just one occurrence among SpO2 < 90 %, BP < 90 mmHg and bradycardia (PR < 50 bpm) during the procedure.	('bradycardia', 'Phenotype', 'HP:0001662', (98, 109))	('bradycardia', 'Disease', (98, 109))	('bradycardia', 'Disease', 'MESH:D001919', (98, 109))	('< 90 %', 'Var', (73, 79))
726261	28470144	DKK3 Overexpression Increases the Malignant Properties of Head and Neck Squamous Cell Carcinoma Cells DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells.	('DKK3', 'Gene', '27122', (0, 4))	('DKK3', 'Gene', (102, 106))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (58, 95))	('expression', 'MPA', (233, 243))	('reduced', 'NegReg', (225, 232))	('dickkopf', 'Gene', (124, 132))	('cancer', 'Disease', (247, 253))	('dickkopf', 'Gene', '22943', (124, 132))	('Carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('DKK3', 'Gene', '27122', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('Malignant Properties', 'CPA', (34, 54))	('tumor', 'Disease', (193, 198))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (67, 95))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('Increases', 'PosReg', (20, 29))	('DKK3', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Overexpression', 'Var', (5, 19))	('Neck Squamous Cell Carcinoma', 'Disease', (67, 95))
726263	28470144	Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion.	('cellular migration', 'CPA', (202, 220))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('reduced', 'NegReg', (194, 201))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('expression', 'Var', (45, 55))	('invasion', 'CPA', (225, 233))	('SCC', 'Gene', '6317', (17, 20))	('survival', 'CPA', (100, 108))	('SCC', 'Gene', '6317', (152, 155))	('metastasis', 'CPA', (78, 88))	('SCC', 'Phenotype', 'HP:0002860', (22, 25))	('SCC', 'Gene', (17, 20))	('SCC', 'Gene', (152, 155))	('HNSCC', 'Phenotype', 'HP:0012288', (15, 20))	('cancer', 'Disease', (164, 170))	('DKK3', 'Gene', (40, 44))	('HNSCC', 'Phenotype', 'HP:0012288', (150, 155))	('SCC', 'Gene', '6317', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('patients', 'Species', '9606', (26, 34))	('SCC', 'Gene', (22, 25))	('DKK3', 'Gene', (142, 146))
726268	28470144	DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc.	('DKK3', 'Gene', (0, 4))	('increased', 'PosReg', (103, 112))	('mRNA expression', 'MPA', (113, 128))	('cyclin D1', 'Gene', '595', (132, 141))	('c-myc', 'Gene', '4609', (146, 151))	('cellular proliferation', 'CPA', (43, 65))	('invasion', 'CPA', (82, 90))	('c-myc', 'Gene', (146, 151))	('cyclin D1', 'Gene', (132, 141))	('migration', 'CPA', (67, 76))	('elevated', 'PosReg', (34, 42))	('overexpression', 'Var', (5, 19))
726270	28470144	For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated.	('S473', 'Var', (138, 142))	('c-Jun', 'Gene', (148, 153))	('Akt', 'Gene', '207', (133, 136))	('Akt', 'Gene', (133, 136))	('phosphorylation', 'MPA', (114, 129))	('c-Jun', 'Gene', '3725', (148, 153))	('Ser63', 'Chemical', '-', (155, 160))	('elevated', 'PosReg', (166, 174))
726271	28470144	The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion.	('invasion', 'CPA', (139, 147))	('HSC-3', 'Gene', (57, 62))	('LY294002', 'Chemical', 'MESH:C085911', (44, 52))	('migration', 'CPA', (124, 133))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('LY294002', 'Var', (44, 52))	('HSC-3', 'Gene', '150353', (57, 62))	('decreased', 'NegReg', (88, 97))	('tumor', 'Disease', (98, 103))
726272	28470144	From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K-Akt signaling.	('cellular proliferation', 'CPA', (66, 88))	('Akt', 'Gene', '207', (252, 255))	('HNSCC', 'Phenotype', 'HP:0012288', (138, 143))	('migration', 'CPA', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('SCC', 'Phenotype', 'HP:0002860', (140, 143))	('SCC', 'Gene', '6317', (140, 143))	('Akt', 'Gene', (252, 255))	('tumor', 'Disease', (115, 120))	('DKK3', 'Var', (41, 45))	('contribute', 'Reg', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('invasion', 'CPA', (90, 98))	('SCC', 'Gene', (140, 143))
726277	28470144	DKKs will interfere with LRP5/6 and Kremen coreceptors and antagonize Wnt signaling by mediating internalization of LRP.	('LRP5/6', 'Gene', (25, 31))	('Kremen', 'Gene', '83999', (36, 42))	('LRP', 'Gene', '4035', (116, 119))	('LRP', 'Gene', (116, 119))	('LRP5/6', 'Gene', '4041;4040', (25, 31))	('LRP', 'Gene', (25, 28))	('interfere', 'NegReg', (10, 19))	('Kremen', 'Gene', (36, 42))	('Wnt signaling', 'Pathway', (70, 83))	('internalization', 'MPA', (97, 112))	('LRP', 'Gene', '4035', (25, 28))	('mediating', 'Reg', (87, 96))	('antagonize', 'NegReg', (59, 69))	('DKKs', 'Var', (0, 4))
726281	28470144	Thus, DKK3 is believed to be a tumor suppressor that may affect a wide range of malignancies.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('DKK3', 'Var', (6, 10))	('tumor', 'Disease', (31, 36))	('affect', 'Reg', (57, 63))	('malignancies', 'Disease', 'MESH:D009369', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('malignancies', 'Disease', (80, 92))
726282	28470144	Interestingly, our previous report demonstrated that DKK3 protein expression was widely observed in head and neck squamous cell carcinoma (HNSCC) and its precursor lesions and that patients with DKK3 expression showed shorter disease-free and metastasis-free survival.	('protein', 'Protein', (58, 65))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (109, 137))	('observed', 'Reg', (88, 96))	('DKK3', 'Var', (195, 199))	('SCC', 'Gene', (141, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (139, 144))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('SCC', 'Gene', '6317', (141, 144))	('patients', 'Species', '9606', (181, 189))	('neck squamous cell carcinoma', 'Disease', (109, 137))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (100, 137))	('shorter', 'NegReg', (218, 225))	('DKK3', 'Gene', (53, 57))
726283	28470144	In addition, knockdown of DKK3 in HNSCC-derived cell lines resulted in reduced cellular migration and invasion.	('cellular migration', 'CPA', (79, 97))	('DKK3', 'Gene', (26, 30))	('invasion', 'CPA', (102, 110))	('SCC', 'Gene', (36, 39))	('reduced', 'NegReg', (71, 78))	('SCC', 'Phenotype', 'HP:0002860', (36, 39))	('HNSCC', 'Phenotype', 'HP:0012288', (34, 39))	('SCC', 'Gene', '6317', (36, 39))	('knockdown', 'Var', (13, 22))
726287	28470144	Moreover, DKK3-overexpressing HNSCC cells formed a larger tumor mass when subcutaneously injected into nude mice.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('larger', 'PosReg', (51, 57))	('SCC', 'Gene', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (30, 35))	('nude mice', 'Species', '10090', (103, 112))	('DKK3-overexpressing', 'Var', (10, 29))	('SCC', 'Gene', '6317', (32, 35))
726292	28470144	A PI3K kinase inhibitor, LY294002 (Cell Signaling Technology, Danvers, MA, USA), was added in 50 muM in order to assess the involvement of PI3K-Akt signaling in DKK3 transfectants.	('Akt', 'Gene', (144, 147))	('DKK3', 'Gene', (161, 165))	('LY294002', 'Chemical', 'MESH:C085911', (25, 33))	('transfectants', 'Var', (166, 179))	('Akt', 'Gene', '207', (144, 147))
726324	28470144	In order to confirm TCF activity change by DKK3 transfection, a TOP/FOP Flash assay was performed as previously described.	('transfection', 'Var', (48, 60))	('TCF', 'Gene', (20, 23))	('DKK3', 'Gene', (43, 47))	('TCF', 'Gene', '3172', (20, 23))
726333	28470144	Because previous reports demonstrated that adenovirus-mediated DKK3 overexpression caused cellular apoptosis, we performed an apoptosis assay to confirm whether DKK3 expression plasmid would cause apoptosis.	('DKK3', 'Var', (161, 165))	('DKK3', 'Gene', (63, 67))	('adenovirus', 'Species', '10508', (43, 53))	('overexpression', 'PosReg', (68, 82))	('cellular apoptosis', 'CPA', (90, 108))
726345	28470144	To examine whether the Wnt signaling pathway mediates increased malignancy by DKK3 overexpression, RT-qPCRs for Wnt target genes and TCF/LEF reporter assay were performed.	('malignancy', 'Disease', (64, 74))	('overexpression', 'Var', (83, 97))	('TCF/LEF', 'Gene', '3172', (133, 140))	('increased', 'PosReg', (54, 63))	('TCF/LEF', 'Gene', (133, 140))	('malignancy', 'Disease', 'MESH:D009369', (64, 74))	('DKK3', 'Gene', (78, 82))
726351	28470144	Phosphorylation of Akt (Ser473) seemed to be slightly elevated, and notably c-Jun expression was decreased in HSC-3 DKK3, and consequently phosphorylation of c-Jun (Ser63) was increased (Fig.	('HSC-3', 'Gene', (110, 115))	('phosphorylation', 'MPA', (139, 154))	('Akt', 'Gene', '207', (19, 22))	('increased', 'PosReg', (176, 185))	('c-Jun', 'Gene', (76, 81))	('c-Jun', 'Gene', '3725', (158, 163))	('elevated', 'PosReg', (54, 62))	('HSC-3', 'Gene', '150353', (110, 115))	('Ser63', 'Chemical', '-', (165, 170))	('Phosphorylation', 'MPA', (0, 15))	('Ser473', 'Var', (24, 30))	('decreased', 'NegReg', (97, 106))	('Akt', 'Gene', (19, 22))	('Ser473', 'Chemical', '-', (24, 30))	('c-Jun', 'Gene', '3725', (76, 81))	('c-Jun', 'Gene', (158, 163))
726352	28470144	This implied that increased malignancy of HSC-3 cells by DKK3 overexpression might be driven by a certain signaling pathway separate from the Wnt/beta-catenin signaling pathway.	('HSC-3', 'Gene', '150353', (42, 47))	('increased', 'PosReg', (18, 27))	('malignancy', 'Disease', (28, 38))	('overexpression', 'Var', (62, 76))	('beta-catenin', 'Gene', (146, 158))	('HSC-3', 'Gene', (42, 47))	('beta-catenin', 'Gene', '1499', (146, 158))	('DKK3', 'Gene', (57, 61))	('malignancy', 'Disease', 'MESH:D009369', (28, 38))
726354	28470144	A PI3K kinase inhibitor, LY294002, was applied at 50 muM into HSC-3 DKK3 cells, which resulted in reduced phospho-Akt (S473), without affecting DKK3 overexpression (Fig.	('LY294002', 'Var', (25, 33))	('HSC-3', 'Gene', '150353', (62, 67))	('Akt', 'Gene', (114, 117))	('LY294002', 'Chemical', 'MESH:C085911', (25, 33))	('Akt', 'Gene', '207', (114, 117))	('reduced', 'NegReg', (98, 105))	('HSC-3', 'Gene', (62, 67))
726355	28470144	The MTT assay revealed that HSC-3 DKK3 + LY294002 showed significantly reduced cellular proliferation (p < 0.01) compared with HSC-3, HSC-3 GFP, and HSC-3DKK3 (Fig.	('HSC-3', 'Gene', (149, 154))	('HSC-3', 'Gene', '150353', (28, 33))	('HSC-3', 'Gene', (28, 33))	('HSC-3', 'Gene', (134, 139))	('DKK3 + LY294002', 'Var', (34, 49))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('HSC-3', 'Gene', '150353', (149, 154))	('reduced', 'NegReg', (71, 78))	('HSC-3', 'Gene', (127, 132))	('LY294002', 'Chemical', 'MESH:C085911', (41, 49))	('cellular proliferation', 'CPA', (79, 101))	('HSC-3', 'Gene', '150353', (134, 139))	('HSC-3', 'Gene', '150353', (127, 132))
726371	28470144	We have shown that DKK3 is mostly expressed in HNSCC tissue samples and that patients with DKK3 expression showed significantly shorter disease-free and metastasis-free survival.	('SCC', 'Gene', (49, 52))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('shorter', 'NegReg', (128, 135))	('patients', 'Species', '9606', (77, 85))	('SCC', 'Gene', '6317', (49, 52))	('HNSCC', 'Phenotype', 'HP:0012288', (47, 52))	('DKK3 expression', 'Var', (91, 106))	('expression', 'Var', (96, 106))
726372	28470144	In addition, DKK3 knockdown by siRNA in HNSCC-derived cell lines resulted in reduced cellular migration and invasion.	('knockdown', 'Var', (18, 27))	('DKK3', 'Gene', (13, 17))	('SCC', 'Gene', (42, 45))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('cellular migration', 'CPA', (85, 103))	('reduced', 'NegReg', (77, 84))	('SCC', 'Gene', '6317', (42, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('invasion', 'CPA', (108, 116))
726375	28470144	The key findings in the present study are as follows: (1) DKK3 expression was exclusively seen in HNSCC and ESCC; (2) DKK3 overexpression did not induce apoptosis in HSC-3 cells but increased cellular proliferation, invasion, migration, and in vivo tumor growth; and (3) DKK3 overexpression resulted in elevated cyclin D1 and c-myc mRNA expression, which was not driven by Wnt/beta-catenin signaling, and the malignant properties of DKK3-transfected HNSCC-derived cells were increased by augmentation of c-Jun phosphorylation and/or expression changes of the genes lured by DKK3 overexpression.	('increased', 'PosReg', (182, 191))	('SCC', 'Gene', (100, 103))	('increased', 'PosReg', (475, 484))	('HNSCC', 'Phenotype', 'HP:0012288', (450, 455))	('HSC-3', 'Gene', '150353', (166, 171))	('cyclin D1', 'Gene', '595', (312, 321))	('tumor', 'Disease', (249, 254))	('HNSCC', 'Phenotype', 'HP:0012288', (98, 103))	('SCC', 'Gene', (452, 455))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('augmentation', 'PosReg', (488, 500))	('invasion', 'CPA', (216, 224))	('expression', 'MPA', (533, 543))	('c-myc', 'Gene', '4609', (326, 331))	('HSC-3', 'Gene', (166, 171))	('migration', 'CPA', (226, 235))	('malignant properties', 'CPA', (409, 429))	('elevated', 'PosReg', (303, 311))	('SCC', 'Phenotype', 'HP:0002860', (452, 455))	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('DKK3', 'Var', (271, 275))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('beta-catenin', 'Gene', (377, 389))	('SCC', 'Gene', '6317', (109, 112))	('SCC', 'Gene', '6317', (452, 455))	('beta-catenin', 'Gene', '1499', (377, 389))	('c-Jun', 'Gene', '3725', (504, 509))	('SCC', 'Gene', '6317', (100, 103))	('cyclin D1', 'Gene', (312, 321))	('cellular proliferation', 'CPA', (192, 214))	('SCC', 'Gene', (109, 112))	('c-Jun', 'Gene', (504, 509))	('c-myc', 'Gene', (326, 331))
726382	28470144	Interestingly, another study reported that PANC-1 cells express DKK3 protein to maintain the cells in dedifferentiation and proliferative states and that DKK3 knockdown resulted in the induction of p15INK4b, p21CIP1, and p27KIP1 .	('p21CIP1', 'Gene', (208, 215))	('knockdown', 'Var', (159, 168))	('induction', 'Reg', (185, 194))	('DKK3', 'Gene', (154, 158))	('p15INK4b', 'Gene', (198, 206))	('p21CIP1', 'Gene', '1026', (208, 215))	('p27KIP1', 'Gene', '1027', (221, 228))	('PANC-1', 'CellLine', 'CVCL:0480', (43, 49))	('p15INK4b', 'Gene', '1030', (198, 206))	('p27KIP1', 'Gene', (221, 228))
726394	28470144	However, DKK3 did not seem to have an effect on the metabolism of beta-catenin.	('DKK3', 'Var', (9, 13))	('beta-catenin', 'Gene', '1499', (66, 78))	('beta-catenin', 'Gene', (66, 78))
726397	28470144	For instance, phosphorylation of Akt (S473) correlates to local recurrence and a poorer prognosis and an increase in the incidence of lymph node metastasis.	('Akt', 'Gene', '207', (33, 36))	('increase', 'PosReg', (105, 113))	('phosphorylation', 'MPA', (14, 29))	('local recurrence', 'CPA', (58, 74))	('Akt', 'Gene', (33, 36))	('lymph node metastasis', 'CPA', (134, 155))	('S473', 'Var', (38, 42))
726398	28470144	We then hypothesized that the increment of tumor aggressiveness in DKK3-transfectant HNSCC cells might be driven by Akt signaling.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (43, 63))	('SCC', 'Gene', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('Akt', 'Gene', '207', (116, 119))	('DKK3-transfectant', 'Var', (67, 84))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('SCC', 'Gene', '6317', (87, 90))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('Akt', 'Gene', (116, 119))	('tumor aggressiveness', 'Disease', (43, 63))	('aggressiveness', 'Phenotype', 'HP:0000718', (49, 63))
726399	28470144	Application of LY294002, an inhibitor for Akt signaling to HSC-3 DKK3 cells, resulted in reduced phosphorylation of Akt (S473) and cancellation of the effects of DKK3 overexpression on cell proliferation, migration, and invasion.	('Akt', 'Gene', (42, 45))	('HSC-3', 'Gene', '150353', (59, 64))	('LY294002', 'Chemical', 'MESH:C085911', (15, 23))	('cell proliferation', 'CPA', (185, 203))	('invasion', 'CPA', (220, 228))	('migration', 'CPA', (205, 214))	('HSC-3', 'Gene', (59, 64))	('LY294002', 'Var', (15, 23))	('Akt', 'Gene', '207', (116, 119))	('phosphorylation', 'MPA', (97, 112))	('reduced', 'NegReg', (89, 96))	('Akt', 'Gene', '207', (42, 45))	('Akt', 'Gene', (116, 119))
726409	28470144	Upregulation of miR-25-3p in OSCC cell results in attenuated cellular proliferation with upregulated p21 (cip1) and p27 (kip1) expression.	('cip1', 'Gene', (106, 110))	('Upregulation', 'PosReg', (0, 12))	('SCC', 'Gene', '6317', (30, 33))	('kip1', 'Gene', '1027', (121, 125))	('expression', 'MPA', (127, 137))	('upregulated', 'PosReg', (89, 100))	('p21', 'Gene', '1026', (101, 104))	('p27', 'Gene', (116, 119))	('cellular proliferation', 'CPA', (61, 83))	('cip1', 'Gene', '1026', (106, 110))	('p21', 'Gene', (101, 104))	('SCC', 'Gene', (30, 33))	('attenuated', 'NegReg', (50, 60))	('miR-25-3p', 'Chemical', '-', (16, 25))	('miR-25-3p', 'Var', (16, 25))	('p27', 'Gene', '10671', (116, 119))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))	('kip1', 'Gene', (121, 125))
726410	28470144	Moreover, cyclin D1, Akt, and FOXO1 expression was decreased, and phosphorylation of Akt and FOXO1 was inactivated in the miR-25-3p-transferred cells.	('FOXO1', 'Gene', (30, 35))	('Akt', 'Gene', '207', (85, 88))	('FOXO1', 'Gene', '2308', (30, 35))	('phosphorylation', 'MPA', (66, 81))	('decreased', 'NegReg', (51, 60))	('inactivated', 'NegReg', (103, 114))	('Akt', 'Gene', (21, 24))	('Akt', 'Gene', (85, 88))	('FOXO1', 'Gene', '2308', (93, 98))	('Akt', 'Gene', '207', (21, 24))	('cyclin D1', 'Gene', '595', (10, 19))	('FOXO1', 'Gene', (93, 98))	('miR-25-3p-transferred', 'Var', (122, 143))	('miR-25-3p', 'Chemical', '-', (122, 131))	('cyclin D1', 'Gene', (10, 19))	('expression', 'MPA', (36, 46))
726442	32607876	The diagnosis was T3N0M0 esophageal squamous cell cancer.	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (25, 56))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (36, 56))	('esophageal squamous cell cancer', 'Disease', (25, 56))	('T3N0M0', 'Var', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
726507	31970867	Correlation between MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility: An updated meta-analysis The aim of this study was to investigate the correlation between MDM2 T309G single nucleotide polymorphism (SNP) and esophageal cancer susceptibility through pooling the open published data.	('MDM2', 'Gene', '4193', (190, 194))	('MDM2', 'Gene', (190, 194))	('T309G', 'Var', (195, 200))	('esophageal cancer', 'Disease', (66, 83))	('MDM2', 'Gene', '4193', (20, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('T309G', 'Mutation', 'rs2279744', (195, 200))	('esophageal cancer', 'Disease', (242, 259))	('MDM2', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('T309G', 'Mutation', 'rs2279744', (25, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (242, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
726508	31970867	By systematic searching the databases of Medline, EMBASE, CBM and CNKI, the case-control or cohort studies related to MDM2 T309G single nucleotide polymorphism and esophageal cancer risk were screened.	('esophageal cancer', 'Disease', (164, 181))	('T309G single nucleotide', 'Var', (123, 146))	('MDM2', 'Gene', (118, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('T309G', 'Mutation', 'rs2279744', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
726510	31970867	The correlation between MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility was demonstrated by the odds ratio (OR) and its corresponding 95% confidence interval (95% CI).	('T309G', 'Mutation', 'rs2279744', (29, 34))	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('MDM2', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('T309G single nucleotide polymorphism', 'Var', (29, 65))
726512	31970867	Based on the present data, there was a significant correlation between MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility.	('T309G single nucleotide polymorphism', 'Var', (76, 112))	('esophageal cancer', 'Disease', (117, 134))	('MDM2', 'Gene', (71, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('T309G', 'Mutation', 'rs2279744', (76, 81))
726513	31970867	Individuals with G genotype may have an increased risk of developing esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('G genotype', 'Var', (17, 27))	('esophageal cancer', 'Disease', (69, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))
726516	31970867	In year 2018, there were approximately 307 000 new cases of esophageal cancer and 283 000 deaths in China, ranking fifth in the incidence of malignant tumors and fourth in the mortality rate.2 As is already known, the development of esophageal cancer is the result of the interaction of genes and environmental factors, but the specific pathogenesis of both have not as yet been fully elucidated, and need further exploration.3 In recent years, studies have confirmed that gene single nucleotide polymorphism (SNP) was closely correlated with the cancer susceptibility.4  Murine double minute 2 (MDM2) locating in chromosome 12q15 encodes a nuclear-localized E3 ubiquitin ligase.	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('esophageal cancer', 'Disease', (60, 77))	('Murine double minute 2', 'Gene', (572, 594))	('malignant tumors', 'Disease', (141, 157))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Disease', (71, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('malignant tumors', 'Disease', 'MESH:D018198', (141, 157))	('cancer', 'Disease', (547, 553))	('MDM2', 'Gene', (596, 600))	('esophageal cancer', 'Disease', (233, 250))	('000 deaths', 'Disease', 'MESH:D003643', (86, 96))	('locating', 'Var', (602, 610))	('cancer', 'Phenotype', 'HP:0002664', (547, 553))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('000 deaths', 'Disease', (86, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('cancer', 'Disease', 'MESH:D009369', (547, 553))	('Murine double minute 2', 'Gene', '4193', (572, 594))
726518	31970867	309 T > G of MDM2 gene is a common SNP site for human beings and considered to correlate with cancer susceptibility.	('human', 'Species', '9606', (48, 53))	('MDM2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('309 T > G', 'Var', (0, 9))	('correlate', 'Reg', (79, 88))	('309 T > G', 'Mutation', 'rs2279744', (0, 9))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
726519	31970867	Chen and colleagues5 discussed the 309 T > G SNP and esophageal cancer risk and published their meta-analysis in 2015.	('309 T > G', 'Mutation', 'rs2279744', (35, 44))	('esophageal cancer', 'Disease', (53, 70))	('309 T > G', 'Var', (35, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
726520	31970867	Since five years have now past, several new studies have been published which are relevant to MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility.	('MDM2', 'Gene', (94, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('esophageal cancer', 'Disease', (140, 157))	('T309G', 'Mutation', 'rs2279744', (99, 104))	('T309G single nucleotide polymorphism', 'Var', (99, 135))
726521	31970867	Here, we provide an updated meta-analysis relevant to MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility by adding new publications.	('MDM2', 'Gene', (54, 58))	('esophageal cancer', 'Disease', (100, 117))	('T309G single nucleotide polymorphism', 'Var', (59, 95))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('T309G', 'Mutation', 'rs2279744', (59, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))
726522	31970867	A systematic search of the electronic databases of Medline, EMBASE, CBM and CNKI was performed using the following subject terms: MDM2, murine double minute 2, esophageal, esophagus, carcinoma or cancer or malignancy or neoplasm or tumor or tumor, all related names to the specified SNP: rs2279744 or SNP309, or T309G by two reviewers (L.L.	('T309G', 'Var', (312, 317))	('neoplasm', 'Phenotype', 'HP:0002664', (220, 228))	('murine double minute 2', 'Gene', '4193', (136, 158))	('SNP309', 'Var', (301, 307))	('carcinoma or cancer', 'Disease', 'MESH:D009369', (183, 202))	('T309G', 'Mutation', 'rs2279744', (312, 317))	('tumor', 'Disease', (241, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Disease', (232, 237))	('malignancy or neoplasm or tumor', 'Disease', (206, 237))	('rs2279744', 'Var', (288, 297))	('carcinoma or cancer', 'Disease', (183, 202))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('malignancy or neoplasm or tumor', 'Disease', 'MESH:D009369', (206, 237))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('murine double minute 2', 'Gene', (136, 158))	('rs2279744', 'Mutation', 'rs2279744', (288, 297))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))
726524	31970867	Publication exclusion criteria was as follows: (i) Case report or literature review publications relevant to MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility; (ii) studies published in other languages; (iii) duplicated publishing data; (iv) esophageal cancer not confirmed by pathology or cytology; and (v) the genotype of GG, TG and TT could not be directly extracted or calculated from the original studies.	('single', 'Var', (120, 126))	('MDM2', 'Gene', (109, 113))	('esophageal cancer', 'Disease', (271, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('esophageal cancer', 'Disease', (155, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (271, 288))	('T309G', 'Var', (114, 119))	('esophageal cancer', 'Disease', 'MESH:D004938', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('TG', 'Chemical', '-', (357, 359))	('T309G', 'Mutation', 'rs2279744', (114, 119))
726525	31970867	The genotype of MDM2 T309G distribution were also extracted and cross checked.	('T309G', 'Var', (21, 26))	('T309G', 'Mutation', 'rs2279744', (21, 26))	('MDM2', 'Gene', (16, 20))
726526	31970867	The correlation between MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility was expressed by the odds ratio (OR) and 95% CI.	('T309G', 'Mutation', 'rs2279744', (29, 34))	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('MDM2', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('T309G single nucleotide polymorphism', 'Var', (29, 65))
726527	31970867	Nine studies6, 7, 8, 9, 10, 11, 12, 13, 14 relevant to MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility fulfilled the inclusion criteria and were included in the meta-analysis (Fig 1).	('T309G', 'Mutation', 'rs2279744', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('MDM2', 'Gene', (55, 59))	('T309G single nucleotide polymorphism', 'Var', (60, 96))
726530	31970867	The median TG and GG genotype frequency were 0.4843 and 0.2566 in the esophageal cancer group.	('TG', 'Chemical', '-', (11, 13))	('esophageal cancer', 'Disease', (70, 87))	('0.2566', 'Var', (56, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('0.4843', 'Var', (45, 51))
726531	31970867	For the control group, the median TG and GG genotype frequency were 0.5007 and 0.1762 (Fig 2).	('TG', 'Chemical', '-', (34, 36))	('0.1762', 'Var', (79, 85))	('0.5007', 'Var', (68, 74))
726533	31970867	Without statistical heterogeneity, the odds ratio for MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility was pooled by the fixed effect model.	('MDM2', 'Gene', (54, 58))	('esophageal cancer', 'Disease', (100, 117))	('T309G single nucleotide polymorphism', 'Var', (59, 95))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('T309G', 'Mutation', 'rs2279744', (59, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))
726537	31970867	In the present updated meta-analysis, nine case-control studies relevant to MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility were included.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('T309G single nucleotide', 'Var', (81, 104))	('T309G', 'Mutation', 'rs2279744', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('MDM2', 'Gene', (76, 80))
726539	31970867	The pooled data showed there was a significant correlation between MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('MDM2', 'Gene', (67, 71))	('T309G single nucleotide polymorphism', 'Var', (72, 108))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('T309G', 'Mutation', 'rs2279744', (72, 77))	('esophageal cancer', 'Disease', (113, 130))
726541	31970867	Chen and colleagues discussed the 309 T > G SNP and esophageal cancer risk by meta-analysis in year 2015 and found that MDM2 T309G SNP was correlated with esophageal cancer susceptibility.	('309 T > G', 'Mutation', 'rs2279744', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (155, 172))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('MDM2', 'Gene', (120, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('T309G', 'Mutation', 'rs2279744', (125, 130))	('T309G SNP', 'Var', (125, 134))	('correlated with', 'Reg', (139, 154))
726542	31970867	MDM2 is itself transcriptionally-regulated by p53.15 Overexpression or amplification of this gene has been detected in a variety of malignant carcinomas.16, 17 Studies have also determined that MDM2 309 T > G SNP were also correlated with an increased risk of solid tumors.	('solid tumors', 'Disease', (260, 272))	('309 T > G', 'Mutation', 'rs2279744', (199, 208))	('malignant carcinomas', 'Disease', 'MESH:D009369', (132, 152))	('p53', 'Gene', (46, 49))	('correlated with', 'Reg', (223, 238))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('malignant carcinomas', 'Disease', (132, 152))	('p53', 'Gene', '7157', (46, 49))	('solid tumors', 'Disease', 'MESH:D009369', (260, 272))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('MDM2 309 T > G SNP', 'Var', (194, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
726543	31970867	reported that MDM2 T309 G polymorphism may contribute to NSCLC susceptibility, especially in the Asian population and women.18 Li et al.	('contribute', 'Reg', (43, 53))	('T309 G', 'Mutation', 'rs2279744', (19, 25))	('women', 'Species', '9606', (118, 123))	('T309 G polymorphism', 'Var', (19, 38))	('MDM2', 'Gene', (14, 18))	('NSCLC', 'Disease', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
726544	31970867	found that the GG genotype of MDM2 SNP309 was significantly associated with an increased endometrial cancer risk by the meta-analysis.19 In our meta-analysis, we also confirmed the G allele could increase the esophageal cancer susceptibility, which was in accordance with previous publications.	('esophageal cancer', 'Disease', (209, 226))	('endometrial cancer', 'Disease', 'MESH:D016889', (89, 107))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('endometrial cancer', 'Phenotype', 'HP:0012114', (89, 107))	('G allele', 'Var', (181, 189))	('esophageal cancer', 'Disease', 'MESH:D004938', (209, 226))	('increase', 'PosReg', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('endometrial cancer', 'Disease', (89, 107))
726545	31970867	However, the exact mechanism of how MDM2 T309 G SNP affects cancer susceptibility has not yet been fully elucidated.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('T309 G', 'Mutation', 'rs2279744', (41, 47))	('MDM2 T309 G', 'Var', (36, 47))	('cancer', 'Disease', (60, 66))	('affects', 'Reg', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
726546	31970867	Knappskog and colleagues found that MDM2 T309 G SNP affected cancer risk through modulation of Sp1 transcription factor binding.20 Other researchers reported that key SNP changes of MDM2 may have a large impact on the activity of p53-dependent tumor suppression.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('impact', 'Reg', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (244, 249))	('cancer', 'Disease', (61, 67))	('p53', 'Gene', '7157', (230, 233))	('T309 G', 'Mutation', 'rs2279744', (41, 47))	('changes', 'Var', (171, 178))	('activity', 'MPA', (218, 226))	('MDM2', 'Gene', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('p53', 'Gene', (230, 233))
726547	31970867	Although the exact pathogenesis of how SNP changes MDM2 and cancer susceptibility are not fully understood, a significant correlation between MDM2 T309 G SNP and esophageal cancer has been confirmed by our present meta-analysis.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('esophageal cancer', 'Disease', (162, 179))	('T309 G SNP', 'Var', (147, 157))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('T309 G', 'Mutation', 'rs2279744', (147, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('MDM2', 'Gene', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
726557	31897228	Inhibition of ILK kinase activity suppresses proliferation and blocks invasion and migration of ESCC cells.	('ESCC', 'Disease', 'MESH:C562729', (96, 100))	('ILK', 'Gene', '3611', (14, 17))	('suppresses', 'NegReg', (34, 44))	('Inhibition', 'Var', (0, 10))	('blocks', 'NegReg', (63, 69))	('ESCC', 'Disease', (96, 100))	('ILK', 'Gene', (14, 17))
726558	31897228	Signaling pathway analysis revealed that ILK regulates AKT phosphorylation on Ser473 but not GSK-3beta on Ser9 to promote proliferation and motility of ESCC cells.	('motility', 'CPA', (140, 148))	('Ser', 'Chemical', 'MESH:C530429', (78, 81))	('Ser', 'Chemical', 'MESH:C530429', (106, 109))	('AKT', 'Gene', (55, 58))	('GSK-3beta', 'Gene', '2932', (93, 102))	('GSK-3beta', 'Gene', (93, 102))	('Ser473', 'Var', (78, 84))	('ESCC', 'Disease', 'MESH:C562729', (152, 156))	('phosphorylation', 'MPA', (59, 74))	('ILK', 'Gene', (41, 44))	('ILK', 'Gene', '3611', (41, 44))	('proliferation', 'CPA', (122, 135))	('AKT', 'Gene', '207', (55, 58))	('phospho', 'Chemical', 'MESH:C033601', (59, 66))	('ESCC', 'Disease', (152, 156))	('promote', 'PosReg', (114, 121))
726598	31897228	Fresh serum-free medium containing cpd22 at the concentration of 3 muM, 1.5 muM and 1 muM for ECA-109, KYSE-150 and HEEC-1 were added, and photos were taken at an appropriate time to assess cell migration using a light microscope (Leica Corporation).	('muM', 'Gene', '56925', (86, 89))	('HEEC-1', 'CellLine', 'CVCL:B526', (116, 122))	('muM', 'Gene', '56925', (67, 70))	('muM', 'Gene', '56925', (76, 79))	('muM', 'Gene', (86, 89))	('cell migration', 'CPA', (190, 204))	('cpd22', 'Var', (35, 40))	('muM', 'Gene', (67, 70))	('muM', 'Gene', (76, 79))	('KYSE-150', 'CellLine', 'CVCL:1348', (103, 111))
726601	31897228	After blocking with 5% nonfat milk (BioRad, Hercules, CA, USA), the membranes were incubated with primary antibodies against beta-actin, AKT, phospho-AKT (S473), phospho-AKT (T308), GSK-3beta, phospho-GSK-3beta (S9) (Multi Science) and ILK (Abcam).	('GSK-3beta', 'Gene', (182, 191))	('S473', 'Var', (155, 159))	('GSK-3beta', 'Gene', '2932', (201, 210))	('AKT', 'Gene', '207', (170, 173))	('AKT', 'Gene', '207', (137, 140))	('S473', 'Chemical', 'MESH:C015765', (155, 159))	('phospho', 'Chemical', 'MESH:C033601', (142, 149))	('GSK-3beta', 'Gene', (201, 210))	('AKT', 'Gene', '207', (150, 153))	('beta-actin', 'Gene', '728378', (125, 135))	('AKT', 'Gene', (170, 173))	('AKT', 'Gene', (137, 140))	('phospho', 'Chemical', 'MESH:C033601', (162, 169))	('phospho', 'Chemical', 'MESH:C033601', (193, 200))	('GSK-3beta', 'Gene', '2932', (182, 191))	('ILK', 'Gene', (236, 239))	('ILK', 'Gene', '3611', (236, 239))	('AKT', 'Gene', (150, 153))	('beta-actin', 'Gene', (125, 135))
726632	31897228	Cell viability assay indicated that cpd22 significantly inhibited proliferation of ESCC cells in a concentration-dependent manner (Fig.5B).	('ESCC', 'Disease', 'MESH:C562729', (83, 87))	('cpd22', 'Var', (36, 41))	('proliferation', 'CPA', (66, 79))	('ESCC', 'Disease', (83, 87))	('inhibited', 'NegReg', (56, 65))
726636	31897228	As expected, both ECA-109 and KYSE-150 cells treated with cpd22 failed to invade through matrigel-coated upper chamber, comparing to DMSO treated control cells (Fig.5C).	('cpd22', 'Var', (58, 63))	('failed', 'NegReg', (64, 70))	('KYSE-150', 'CellLine', 'CVCL:1348', (30, 38))	('DMSO', 'Chemical', 'MESH:D004121', (133, 137))
726637	31897228	Furthermore wound-healing assay indicated that the open wound area remains unchanged in cpd22 treated cells but is diminished to approximately half of the initial area in DMSO treated group (Fig.5D).	('cpd22', 'Var', (88, 93))	('DMSO', 'Chemical', 'MESH:D004121', (171, 175))	('open wound area', 'CPA', (51, 66))	('diminished', 'NegReg', (115, 125))
726645	31897228	6, the phosphorylation level of AKT on Ser473 decreased in a concentration-dependent manner, while phosphorylation on Thr308 remained unchanged.	('AKT', 'Gene', '207', (32, 35))	('Ser473', 'Var', (39, 45))	('Thr', 'Chemical', 'MESH:C055175', (118, 121))	('phospho', 'Chemical', 'MESH:C033601', (99, 106))	('phosphorylation level', 'MPA', (7, 28))	('AKT', 'Gene', (32, 35))	('decreased', 'NegReg', (46, 55))	('phospho', 'Chemical', 'MESH:C033601', (7, 14))	('Ser', 'Chemical', 'MESH:C530429', (39, 42))
726647	31897228	These results indicated that ILK facilitates ESCC cell proliferation and migration through the AKT signaling pathway by phosphorylation on Ser473 of AKT, rather than the GSK-3beta pathway in our model systems.	('ESCC', 'Disease', 'MESH:C562729', (45, 49))	('migration', 'CPA', (73, 82))	('AKT', 'Gene', '207', (95, 98))	('AKT', 'Gene', (149, 152))	('ILK', 'Gene', (29, 32))	('ILK', 'Gene', '3611', (29, 32))	('GSK-3beta', 'Gene', '2932', (170, 179))	('GSK-3beta', 'Gene', (170, 179))	('ESCC', 'Disease', (45, 49))	('AKT', 'Gene', (95, 98))	('phospho', 'Chemical', 'MESH:C033601', (120, 127))	('phosphorylation on Ser473', 'Var', (120, 145))	('Ser', 'Chemical', 'MESH:C530429', (139, 142))	('facilitates', 'PosReg', (33, 44))	('AKT', 'Gene', '207', (149, 152))
726661	31897228	On the one hand, ILK was reported to regulate AKT and GSK-3beta signaling pathway by phosphorylating AKT on Ser473 and GSK-3beta on Ser9, respectively.	('AKT', 'Gene', '207', (101, 104))	('AKT', 'Gene', '207', (46, 49))	('regulate', 'Reg', (37, 45))	('phospho', 'Chemical', 'MESH:C033601', (85, 92))	('Ser473', 'Var', (108, 114))	('Ser', 'Chemical', 'MESH:C530429', (108, 111))	('AKT', 'Gene', (101, 104))	('GSK-3beta', 'Gene', (54, 63))	('AKT', 'Gene', (46, 49))	('Ser', 'Chemical', 'MESH:C530429', (132, 135))	('GSK-3beta', 'Gene', '2932', (54, 63))	('ILK', 'Gene', (17, 20))	('ILK', 'Gene', '3611', (17, 20))	('GSK-3beta', 'Gene', '2932', (119, 128))	('GSK-3beta', 'Gene', (119, 128))
726674	31533461	Aberrant Cyclin E and Hepatocyte Growth Factor Expression, Microvascular Density, and Micro-Lymphatic Vessel Density in Esophageal Squamous Cell Carcinoma Cyclin E and hepatocyte growth factor (HGF) have been observed as a multifaceted factor in many cancers, and the assessment of microvascular density (MVD) and micro-lymphatic vessel density (MLVD) has been used to quantify tumor angiogenesis and lymphangiogenesis.	('hepatocyte growth factor', 'Gene', (168, 192))	('HGF', 'Gene', (194, 197))	('tumor', 'Disease', (378, 383))	('Aberrant', 'Var', (0, 8))	('HGF', 'Gene', '3082', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('Esophageal Squamous Cell Carcinoma', 'Disease', (120, 154))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('hepatocyte growth factor', 'Gene', '3082', (168, 192))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:C562729', (120, 154))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('cancers', 'Disease', (251, 258))	('tumor', 'Disease', 'MESH:D009369', (378, 383))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('Hepatocyte Growth Factor', 'Gene', '3082', (22, 46))	('Carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('Hepatocyte Growth Factor', 'Gene', (22, 46))
726680	31533461	Furthermore, the expression of MVD and MLVD in both the high cyclin E and high HGF expression groups was significantly higher compared to the low cyclin E and HGF expression groups (P < .001).	('high', 'Var', (74, 78))	('expression', 'MPA', (17, 27))	('higher', 'PosReg', (119, 125))	('HGF', 'Gene', (159, 162))	('HGF', 'Gene', (79, 82))	('HGF', 'Gene', '3082', (159, 162))	('HGF', 'Gene', '3082', (79, 82))	('high', 'Var', (56, 60))
726722	31533461	Moreover, MVD and MLVD levels in the high HGF expression group were also significantly higher compared to the low HGF expression group (P < .001; Table 5).	('high', 'Var', (37, 41))	('HGF', 'Gene', (42, 45))	('HGF', 'Gene', (114, 117))	('HGF', 'Gene', '3082', (42, 45))	('HGF', 'Gene', '3082', (114, 117))	('higher', 'PosReg', (87, 93))
726733	31533461	It has been reported that patients with high cyclin E expression tend to be at more advanced TNM stages than those with low cyclin E expression, suggesting that high cyclin E expression is significantly associated with high tumor proliferation and may be involved in ESCC progression.	('expression', 'MPA', (175, 185))	('ESCC', 'Disease', (267, 271))	('high tumor proliferation', 'Disease', 'MESH:C565054', (219, 243))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('low cyclin E expression', 'Phenotype', 'HP:0500152', (120, 143))	('associated with', 'Reg', (203, 218))	('involved', 'Reg', (255, 263))	('patients', 'Species', '9606', (26, 34))	('high', 'Var', (161, 165))	('high tumor proliferation', 'Disease', (219, 243))	('ESCC', 'Disease', 'MESH:C562729', (267, 271))
726889	30464635	Imbalances and deficiencies among crucial one-carbon metabolism nutrients may interfere with DNA replication, DNA repair, and regulation of gene expression, any of which could promote carcinogenesis.	('promote', 'PosReg', (176, 183))	('interfere', 'NegReg', (78, 87))	('Imbalances', 'Phenotype', 'HP:0002172', (0, 10))	('Imbalances', 'Var', (0, 10))	('DNA replication', 'CPA', (93, 108))	('DNA repair', 'CPA', (110, 120))	('regulation', 'MPA', (126, 136))	('carbon', 'Chemical', 'MESH:D002244', (46, 52))	('deficiencies', 'Var', (15, 27))	('carcinogenesis', 'CPA', (184, 198))
726891	30464635	Deficiency of one or more of the three vitamins required for DNA maintenance is known to cause abnormal pairing of the four bases, which can then result in mutations and the development of cancer.	('cause', 'Reg', (89, 94))	('mutations', 'Var', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('Deficiency', 'Disease', 'MESH:D007153', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('abnormal', 'Var', (95, 103))	('Deficiency', 'Disease', (0, 10))	('result in', 'Reg', (146, 155))	('cancer', 'Disease', (189, 195))
726987	19401529	Constitutive short telomere length of chromosome 17p and 12q but not 11q and 2p are associated with an increased risk for esophageal cancer Short telomere may cause chromosomal instability in Barrett's esophagus and thus promote tumorigenesis.	('esophageal cancer', 'Disease', (122, 139))	('Short telomere', 'Var', (140, 154))	('promote', 'PosReg', (221, 228))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('chromosomal instability', 'Phenotype', 'HP:0040012', (165, 188))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (192, 211))	('tumor', 'Disease', (229, 234))	('cause', 'Reg', (159, 164))	('associated', 'Reg', (84, 94))	('chromosomal instability', 'MPA', (165, 188))	('short telomere length', 'Phenotype', 'HP:0031413', (13, 34))	('Short telomere', 'Phenotype', 'HP:0031413', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
726988	19401529	However, whether short telomere length in all chromosomes or just some of them is associated with increased esophageal cancer (EC) risk is largely unknown.	('associated', 'Reg', (82, 92))	('short telomere length', 'Var', (17, 38))	('increased esophageal cancer', 'Disease', (98, 125))	('increased esophageal cancer', 'Disease', 'MESH:D004938', (98, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('short telomere length', 'Phenotype', 'HP:0031413', (17, 38))
726990	19401529	Our study provides the first epidemiological evidence that short telomere length of 17p and 12q play an important role in esophageal carcinogenesis, suggesting that short telomere length of specific chromosomes is associated with the etiology of different cancer types.	('short telomere length', 'Phenotype', 'HP:0031413', (59, 80))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (122, 147))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('esophageal carcinogenesis', 'Disease', (122, 147))	('short telomere length', 'Var', (165, 186))	('cancer', 'Disease', (256, 262))	('short telomere length', 'Phenotype', 'HP:0031413', (165, 186))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('associated', 'Reg', (214, 224))
726992	19401529	Short telomere length may induce cells to undergo cell cycle arrest and apoptosis.	('arrest', 'Disease', (61, 67))	('Short telomere length', 'Var', (0, 21))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('Short telomere length', 'Phenotype', 'HP:0031413', (0, 21))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('apoptosis', 'CPA', (72, 81))	('Short telomere', 'Phenotype', 'HP:0031413', (0, 14))	('induce', 'Reg', (26, 32))
726993	19401529	In the setting of abrogated DNA damage checkpoints, critically short telomeres may cause chromosome instability and drives early carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('chromosome instability', 'Phenotype', 'HP:0040012', (89, 111))	('carcinogenesis', 'Disease', (129, 143))	('critically short telomeres', 'Var', (52, 78))	('cause', 'Reg', (83, 88))	('chromosome instability', 'CPA', (89, 111))	('short telomeres', 'Phenotype', 'HP:0031413', (63, 78))
726994	19401529	Previous studies have reported that short overall telomeres are associated with the initiation and progression of malignancies in mouse models and epidemiologic studies.	('associated', 'Reg', (64, 74))	('malignancies', 'Disease', 'MESH:D009369', (114, 126))	('short', 'Var', (36, 41))	('malignancies', 'Disease', (114, 126))	('mouse', 'Species', '10090', (130, 135))
726997	19401529	Meeker et al demonstrated that telomere shortening occurs early in the etiology of esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (83, 108))	('telomere shortening', 'Phenotype', 'HP:0031413', (31, 50))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (83, 108))	('telomere shortening', 'Var', (31, 50))
727018	19401529	demonstrating that overall telomere length of blood leukocyte is associated with EC risk in patients with Barrett's esophagus.	('patients', 'Species', '9606', (92, 100))	('associated', 'Reg', (65, 75))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (106, 125))	("Barrett's esophagus", 'Disease', (106, 125))	('telomere', 'Var', (27, 35))
727021	19401529	Although it is increasingly clear that short overall telomere length contributes to tumorigenesis, no epidemiologic reports have addressed whether all telomeres or only a few specific telomeres contribute to tumorigenesis in a specific cancer type.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('short', 'Var', (39, 44))	('contributes', 'Reg', (69, 80))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('contribute', 'Reg', (194, 204))
727027	19401529	Accordingly, high frequencies of LOH on chromosome 17p have been reported in many types of cancer, including EC.	('LOH', 'Var', (33, 36))	('reported', 'Reg', (65, 73))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
727073	31850330	For example, IF Peptide 1<=0.7 AND Peptide 2>=1.02, THEN type = "Brain cancer."	('Peptide 1<=0.7', 'Var', (16, 30))	('Brain cancer', 'Phenotype', 'HP:0030692', (65, 77))	('Brain cancer', 'Disease', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Brain cancer', 'Disease', 'MESH:D001932', (65, 77))	('Peptide 2>=1.02', 'Var', (35, 50))
727119	31850330	The third identified peptide has a specific sequence of AQNADELEEYSASKHDGGSC, which can be realigned to multiple tumor-associated proteins, such as mediator of RNA polymerase II transcription subunit 1, protein FAM45A, and protein SETSIP (Altschul et al.,; Mount,; Pruitt et al.,).	('tumor', 'Disease', (113, 118))	('protein FAM45A', 'Gene', '404636', (203, 217))	('protein SETSIP', 'Gene', '646817', (223, 237))	('AQNADELEEYSASKHDGGSC', 'Var', (56, 76))	('protein FAM45A', 'Gene', (203, 217))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('protein SETSIP', 'Gene', (223, 237))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mediator of RNA polymerase II transcription subunit 1', 'Gene', '5469', (148, 201))
727157	30867685	The results indicated that patients with ESCC with high miR-375 expression had a better survival rate compared with patients with ESCC with low miR-375 expression.	('miR-375', 'Gene', (144, 151))	('better', 'PosReg', (81, 87))	('miR-375', 'Gene', (56, 63))	('patients', 'Species', '9606', (116, 124))	('ESCC', 'Disease', (41, 45))	('patients', 'Species', '9606', (27, 35))	('high', 'Var', (51, 55))	('miR-375', 'Gene', '494324', (144, 151))	('miR-375', 'Gene', '494324', (56, 63))	('survival rate', 'CPA', (88, 101))
727169	30867685	High SP1 expression was identified in several types of cancer and was associated with poor prognosis.	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('SP1', 'Gene', (5, 8))	('expression', 'MPA', (9, 19))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
727172	30867685	The present study revealed that knockdown of miR-375 significantly increased ESCC cell proliferation and colony formation.	('miR-375', 'Gene', (45, 52))	('colony formation', 'CPA', (105, 121))	('knockdown', 'Var', (32, 41))	('miR-375', 'Gene', '494324', (45, 52))	('increased', 'PosReg', (67, 76))	('increased ESCC', 'Phenotype', 'HP:0003565', (67, 81))	('ESCC cell proliferation', 'CPA', (77, 100))
727198	30867685	Similarly, the expression level of miR-375 was significantly decreased in ESCC cell lines KYSE450 and KYSE150, compared with normal esophageal endothelial cell line Het-1A (Fig.	('miR-375', 'Gene', (35, 42))	('ESCC', 'Disease', (74, 78))	('expression level', 'MPA', (15, 31))	('miR-375', 'Gene', '494324', (35, 42))	('decreased', 'NegReg', (61, 70))	('KYSE150', 'Var', (102, 109))
727203	30867685	Similar results were obtained in the colony formation assays, miR-375 overexpression inhibited colony formation in ESCC cells, whilst downregulation of miR-375 expression induced the opposite effect (Fig.	('miR-375', 'Gene', (62, 69))	('downregulation', 'NegReg', (134, 148))	('inhibited', 'NegReg', (85, 94))	('overexpression', 'Var', (70, 84))	('miR-375', 'Gene', (152, 159))	('colony formation in', 'CPA', (95, 114))	('miR-375', 'Gene', '494324', (62, 69))	('miR-375', 'Gene', '494324', (152, 159))
727220	30867685	Furthermore, the overall survival analysis demonstrated that patients with ESCC with high miR-375 expression had a better 5-year survival rate compared with patients with ESCC with low miR-375 expression (Fig.	('miR-375', 'Gene', (90, 97))	('patients', 'Species', '9606', (61, 69))	('high', 'Var', (85, 89))	('patients', 'Species', '9606', (157, 165))	('better', 'PosReg', (115, 121))	('miR-375', 'Gene', '494324', (185, 192))	('miR-375', 'Gene', '494324', (90, 97))	('miR-375', 'Gene', (185, 192))
727251	29977156	Here, we systematically studied the expression of PAR1, 2, and 4 in clinical esophageal carcinoma patients and determined their role in esophageal carcinoma in vivo and in vitro through the overexpression or knockdown of PAR1, 2, and 4.	('PAR1, 2, and 4', 'Gene', '2149;2150;9002', (221, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('esophageal carcinoma', 'Disease', (136, 156))	('PAR1, 2, and 4', 'Gene', '2149;2150;9002', (50, 64))	('knockdown', 'Var', (208, 217))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (77, 97))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (136, 156))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (77, 97))	('patients', 'Species', '9606', (98, 106))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (136, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('overexpression', 'PosReg', (190, 204))	('esophageal carcinoma', 'Disease', (77, 97))
727254	29977156	In contrast, the expression of PAR4 expressed decreased in esophageal carcinoma, and its expression induced apoptosis in vivo and vitro.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('esophageal carcinoma', 'Disease', (59, 79))	('expression', 'MPA', (17, 27))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (59, 79))	('expression', 'Var', (89, 99))	('PAR4', 'Gene', (31, 35))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (59, 79))	('induced', 'Reg', (100, 107))	('decreased', 'NegReg', (46, 55))	('apoptosis', 'CPA', (108, 117))
727259	29977156	The presence of PAR1, 2, and 4 promote cell proliferation and migration or apoptosis of types of cancer cells.	('migration', 'CPA', (62, 71))	('cancer', 'Disease', (97, 103))	('apoptosis', 'CPA', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('promote', 'PosReg', (31, 38))	('presence', 'Var', (4, 12))	('cell proliferation', 'CPA', (39, 57))	('PAR1, 2, and 4', 'Gene', '2149;2150;9002', (16, 30))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
727261	29977156	Furthermore, the expression of PAR1 is involved in the promotion of tumor cell proliferation and migration.	('tumor', 'Disease', (68, 73))	('migration', 'CPA', (97, 106))	('promotion', 'PosReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('expression', 'Var', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PAR1', 'Gene', (31, 35))
727283	29977156	To generate stable high-efficiency PAR interference constructs, the following CRISPR-Cas9 gene knockdown system (Inovogen, Beijing, China) was used to knockdown the PAR1, PAR2, and PAR4 genes.	('PAR', 'Gene', '8856', (171, 174))	('PAR', 'Gene', (35, 38))	('PAR', 'Gene', '8856', (181, 184))	('PAR2', 'Gene', (171, 175))	('PAR', 'Gene', '8856', (165, 168))	('PAR', 'Gene', '8856', (35, 38))	('PAR', 'Gene', (165, 168))	('PAR', 'Gene', (171, 174))	('PAR2', 'Gene', '2150', (171, 175))	('PAR', 'Gene', (181, 184))	('knockdown', 'Var', (151, 160))
727290	29977156	Antibodies for actin (1:1500 dilution), PAR1 (1:1000 dilution), PAR2 (1:1000 dilution) and PAR4 (1:1000 dilution) obtained from Santa Cruz (Santa Cruz, Shanghai, China).	('actin', 'Gene', (15, 20))	('1:1000', 'Var', (70, 76))	('PAR2', 'Gene', '2150', (64, 68))	('PAR2', 'Gene', (64, 68))	('PAR4', 'Gene', (91, 95))
727291	29977156	To measure cell viability, six TE-1 cells containing PARs expression-regulating plasmids and an equal number of vehicle control cells were equally plated in 96-well plates.	('PAR', 'Gene', (53, 56))	('plasmids', 'Var', (80, 88))	('PAR', 'Gene', '8856', (53, 56))
727310	29977156	2, the mRNA and protein expression of PARs decreased significantly (P < 0.05) in the PAR knockdown group (CRISPR group) and increased (P < 0.05) in the PAR overexpression group (pIRES2 group).	('PAR', 'Gene', (38, 41))	('PAR', 'Gene', (152, 155))	('PAR', 'Gene', '8856', (38, 41))	('increased', 'PosReg', (124, 133))	('PAR', 'Gene', (85, 88))	('PAR', 'Gene', '8856', (152, 155))	('knockdown', 'Var', (89, 98))	('PAR', 'Gene', '8856', (85, 88))	('decreased', 'NegReg', (43, 52))
727323	29977156	5, we found that the tumors in the nude mice injected with TE-1 cells containing PAR1 and 2 overexpression plasmids were larger than those in the nude mice injected with control TE-1 cells.	('nude mice', 'Species', '10090', (35, 44))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('overexpression plasmids', 'Var', (92, 115))	('tumors', 'Disease', (21, 27))	('PAR1', 'Gene', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('nude mice', 'Species', '10090', (146, 155))	('larger', 'PosReg', (121, 127))
727325	29977156	Similarly, the tumor volume in the nude mice injected with the TE-1 cells containing PAR2 overexpression plasmids was significantly bigger (1632 +- 184 mm3) than in the control group.	('nude mice', 'Species', '10090', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('PAR2', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('overexpression plasmids', 'Var', (90, 113))	('PAR2', 'Gene', '2150', (85, 89))	('bigger', 'PosReg', (132, 138))
727342	29977156	It is possible that the expressions of PAR1 and 2 are highly associated with more aggressive esophageal carcinoma in nude mice.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('PAR1', 'Gene', (39, 43))	('aggressive esophageal carcinoma', 'Disease', 'MESH:D004938', (82, 113))	('expressions', 'Var', (24, 35))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (93, 113))	('aggressive esophageal carcinoma', 'Disease', (82, 113))	('associated', 'Reg', (61, 71))	('nude mice', 'Species', '10090', (117, 126))
727388	27110939	EDA also reduced the incidence of acute respiratory distress syndrome (ARDS), although it didn't reach statistical significance (P = 0.082).	('acute respiratory distress syndrome', 'Disease', 'MESH:D012128', (34, 69))	('acute respiratory distress syndrome', 'Disease', (34, 69))	('acute respiratory distress syndrome', 'Phenotype', 'HP:0011948', (34, 69))	('EDA', 'Var', (0, 3))	('reduced', 'NegReg', (9, 16))	('respiratory distress', 'Phenotype', 'HP:0002098', (40, 60))	('ARDS', 'Phenotype', 'HP:0011948', (71, 75))
727389	27110939	The incidence of anastomotic leakage in EDA group was 14.0%, and was significantly lower than that of IVA group (23.0%, P = 0.029).	('IVA', 'Disease', (102, 105))	('lower', 'NegReg', (83, 88))	('IVA', 'Disease', 'MESH:C538167', (102, 105))	('EDA', 'Var', (40, 43))	('anastomotic leakage', 'CPA', (17, 36))
727393	27110939	The change in CRP of EDA group was significantly lower than that of IVA group (preoperative, 6.2 vs. 6.2; POD 1, 108.1 vs. 121.3; POD 3, 131.5 vs. 137.8; POD 7, 69.3 vs. 82.1 mg/L; P = 0.044, Fig 2A).	('IVA', 'Disease', (68, 71))	('CRP', 'Gene', '1401', (14, 17))	('EDA', 'Var', (21, 24))	('IVA', 'Disease', 'MESH:C538167', (68, 71))	('lower', 'NegReg', (49, 54))	('CRP', 'Gene', (14, 17))
727416	25139395	Small-molecule survivin inhibitor YM155 enhances radiosensitization in esophageal squamous cell carcinoma by the abrogation of G2 checkpoint and suppression of homologous recombination repair Survivin is overexpressed in cancer cells and plays a crucial role in apoptosis evasion.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('survivin', 'Gene', '11799', (15, 23))	('Survivin', 'Gene', '11799', (192, 200))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('enhances', 'PosReg', (40, 48))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('cancer', 'Disease', (221, 227))	('suppression', 'NegReg', (145, 156))	('Survivin', 'Gene', (192, 200))	('YM155', 'Chemical', 'MESH:C523798', (34, 39))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('YM155', 'Var', (34, 39))	('survivin', 'Gene', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('abrogation', 'NegReg', (113, 123))	('radiosensitization', 'MPA', (49, 67))
727417	25139395	YM155, a small-molecule inhibitor of survivin, could enhance the cytotoxicity of various DNA-damaging agents.	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('survivin', 'Gene', '11799', (37, 45))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('YM155', 'Var', (0, 5))	('enhance', 'PosReg', (53, 60))	('cytotoxicity', 'Disease', (65, 77))	('survivin', 'Gene', (37, 45))
727418	25139395	Here, we evaluated the radiosensitizaion potential of YM155 in human esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (69, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('human', 'Species', '9606', (63, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('YM155', 'Chemical', 'MESH:C523798', (54, 59))	('YM155', 'Var', (54, 59))	('esophageal squamous cell carcinoma', 'Disease', (69, 103))	('radiosensitizaion potential', 'MPA', (23, 50))
727422	25139395	YM155 induced radiosensitization in ESCC cell lines Eca109 and TE13, associated with the abrogation of radiation induced G2/M checkpoint, impaired Rad51 focus formation, and the prolongation of gamma-H2AX signaling.	('H2AX', 'Gene', '3014', (200, 204))	('G2/M checkpoint', 'MPA', (121, 136))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('H2AX', 'Gene', (200, 204))	('prolongation', 'PosReg', (178, 190))	('YM155', 'Var', (0, 5))	('radiosensitization', 'CPA', (14, 32))	('impaired', 'NegReg', (138, 146))	('Rad51', 'Gene', (147, 152))	('abrogation', 'NegReg', (89, 99))	('Rad51', 'Gene', '5888', (147, 152))
727423	25139395	G2/M transition markers, including the activation of cyclinB1/Cdc2 kinase and the suppression of Cdc2 Thr14/Tyr15 phosphorylation were induced by YM155 in irradiated cells.	('Cdc2', 'Gene', '983', (97, 101))	('activation', 'PosReg', (39, 49))	('Tyr15', 'Chemical', '-', (108, 113))	('Cdc2', 'Gene', (62, 66))	('cyclinB1', 'Gene', (53, 61))	('Cdc2', 'Gene', '983', (62, 66))	('Cdc2', 'Gene', (97, 101))	('Thr14', 'Chemical', '-', (102, 107))	('YM155', 'Chemical', 'MESH:C523798', (146, 151))	('cyclinB1', 'Gene', '891', (53, 61))	('YM155', 'Var', (146, 151))	('suppression', 'NegReg', (82, 93))
727424	25139395	The combination of YM155 plus irradiation delayed the growth of ESCC tumor xenografts to a greater extent compared with either treatment modality alone.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('YM155', 'Var', (19, 24))	('ESCC tumor', 'Disease', (64, 74))	('YM155', 'Chemical', 'MESH:C523798', (19, 24))	('delayed', 'NegReg', (42, 49))	('ESCC tumor', 'Disease', 'MESH:D004938', (64, 74))	('growth', 'CPA', (54, 60))
727425	25139395	Our findings suggest that the abrogation of G2 checkpoint and the inhibition of HRR contribute to radiosensitization by YM155 in ESCC cells.	('HRR', 'Protein', (80, 83))	('ESCC', 'Disease', (129, 133))	('radiosensitization', 'CPA', (98, 116))	('YM155', 'Chemical', 'MESH:C523798', (120, 125))	('G2 checkpoint', 'Protein', (44, 57))	('YM155', 'Var', (120, 125))	('abrogation', 'NegReg', (30, 40))	('inhibition', 'NegReg', (66, 76))
727431	25139395	Accordingly, the suppression of survivin expression with the use of antisense oligonucleotides or ribozymes effectively overcame apoptosis resistance in different types of cancer cells and sensitized cancer cells to radiation and chemotherapeutic agents in vitro and in vivo -.	('overcame', 'NegReg', (120, 128))	('survivin', 'Gene', '11799', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('oligonucleotides', 'Chemical', 'MESH:D009841', (78, 94))	('apoptosis resistance', 'CPA', (129, 149))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('antisense', 'Var', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('survivin', 'Gene', (32, 40))	('cancer', 'Disease', (172, 178))	('suppression', 'NegReg', (17, 28))	('cancer', 'Disease', (200, 206))
727439	25139395	YM155 was identified as a first-in-class small molecule inhibitor of survivin.	('survivin', 'Gene', (69, 77))	('YM155', 'Var', (0, 5))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('survivin', 'Gene', '11799', (69, 77))
727440	25139395	YM155 selectively inhibited survivin expression at both mRNA and protein levels at subnanomolar range and exhibited anticancer activity in preclinical models of several types of cancers -.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('survivin', 'Gene', (28, 36))	('cancer', 'Disease', (120, 126))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('YM155', 'Var', (0, 5))	('cancer', 'Disease', (178, 184))	('inhibited', 'NegReg', (18, 27))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('expression', 'MPA', (37, 47))	('survivin', 'Gene', '11799', (28, 36))
727442	25139395	In the present study, we employed two ESCC cell lines Eca109 and TE-13 to evaluate the radiosensitizing effects of YM155 on ESCC, with a special emphasis on its interference with cell cycle checkpoint.	('cell cycle', 'CPA', (179, 189))	('YM155', 'Var', (115, 120))	('YM155', 'Chemical', 'MESH:C523798', (115, 120))
727444	25139395	Western blot analysis showed that YM155 inhibited survivin expression in a dose dependent manner, but had no significant effect on the abundance of other IAP family members such as XIAP and c-IAP1 (Figure 1).	('XIAP', 'Gene', '331', (181, 185))	('survivin', 'Gene', '11799', (50, 58))	('inhibited', 'NegReg', (40, 49))	('c-IAP1', 'Gene', (190, 196))	('survivin', 'Gene', (50, 58))	('c-IAP1', 'Gene', '329', (190, 196))	('YM155', 'Chemical', 'MESH:C523798', (34, 39))	('IAP', 'Gene', (154, 157))	('expression', 'MPA', (59, 69))	('IAP', 'Gene', '961', (182, 185))	('YM155', 'Var', (34, 39))	('IAP', 'Gene', (192, 195))	('IAP', 'Gene', '961', (154, 157))	('IAP', 'Gene', '961', (192, 195))	('IAP', 'Gene', (182, 185))	('XIAP', 'Gene', (181, 185))
727445	25139395	These results suggest that YM155 specifically suppresses survivin at low nanomolar concentrations in ESCC cells.	('suppresses', 'NegReg', (46, 56))	('survivin', 'Gene', '11799', (57, 65))	('YM155', 'Var', (27, 32))	('YM155', 'Chemical', 'MESH:C523798', (27, 32))	('survivin', 'Gene', (57, 65))
727450	25139395	Colony-forming assay with ESCC cells showed that YM155 promoted radiation-induced clonogenic cell death in a dose dependent manner.	('YM155', 'Chemical', 'MESH:C523798', (49, 54))	('YM155', 'Var', (49, 54))	('promoted', 'PosReg', (55, 63))	('radiation-induced clonogenic cell death', 'CPA', (64, 103))
727451	25139395	When the concentration of YM155 reached 10 nM, the SER (sensitization enhancement ratio) of Eca109 and TE13 cells was 1.51 and 1.73, respectively.	('YM155', 'Chemical', 'MESH:C523798', (26, 31))	('SER', 'Chemical', '-', (51, 54))	('SER', 'MPA', (51, 54))	('YM155', 'Var', (26, 31))
727452	25139395	These data indicate that YM155 remarkably enhanced cell death in irradiated ESCC cells.	('YM155', 'Var', (25, 30))	('YM155', 'Chemical', 'MESH:C523798', (25, 30))	('enhanced', 'PosReg', (42, 50))	('cell death', 'CPA', (51, 61))
727454	25139395	Radiation-induced G2/M arrest was abrogated by 10 nM YM155 (34.7% for Eca109 and 36.4% for TE13), with a concomitant rise in G1 and S phases (Figure 3A and B).	('YM155', 'Chemical', 'MESH:C523798', (53, 58))	('YM155', 'Var', (53, 58))	('rise', 'PosReg', (117, 121))	('G2/M arrest', 'CPA', (18, 29))	('10 nM YM155', 'Var', (47, 58))	('Eca109', 'Var', (70, 76))	('abrogated', 'NegReg', (34, 43))
727455	25139395	Exposure of the cells to YM155 alone caused small decrease in G2/M fraction and slight accumulation of G1 population (Figure 3A).	('YM155', 'Var', (25, 30))	('G2/M fraction', 'MPA', (62, 75))	('accumulation', 'PosReg', (87, 99))	('G1 population', 'CPA', (103, 116))	('YM155', 'Chemical', 'MESH:C523798', (25, 30))	('decrease', 'NegReg', (50, 58))
727456	25139395	In order to confirm that YM155 abrogated G2 arrest, rather than induced a G1/S- phase block, mitotic inhibitor nocodazole was used.	('YM155', 'Var', (25, 30))	('abrogated', 'NegReg', (31, 40))	('nocodazole', 'Chemical', 'MESH:D015739', (111, 121))	('G2 arrest', 'CPA', (41, 50))	('YM155', 'Chemical', 'MESH:C523798', (25, 30))
727458	25139395	Therefore, YM155 seems to impact the progression of cells from G2 to M phase.	('progression', 'CPA', (37, 48))	('impact', 'Reg', (26, 32))	('YM155', 'Chemical', 'MESH:C523798', (11, 16))	('YM155', 'Var', (11, 16))
727460	25139395	However, YM155 resulted in significant activation of Cdc2 kinase in irradiated cells, and this effect was most evident when nocodazole was administered post-irradiation to prevent cells from existing M phase (Figure 4A).	('YM155', 'Var', (9, 14))	('Cdc2', 'Gene', (53, 57))	('activation', 'PosReg', (39, 49))	('Cdc2', 'Gene', '983', (53, 57))	('nocodazole', 'Chemical', 'MESH:D015739', (124, 134))	('YM155', 'Chemical', 'MESH:C523798', (9, 14))
727462	25139395	DNA damage induced G2 phase arrest is linked to the accumulation of relatively inactive, hyperphosphorylated Cdc2/cyclin B1 complexes which have inhibitory phosphates on two residues (Thr14/Tyr15) of Cdc2.	('Cdc2', 'Gene', '983', (200, 204))	('G2 phase arrest', 'CPA', (19, 34))	('Cdc2', 'Gene', '983', (109, 113))	('Thr14', 'Chemical', '-', (184, 189))	('phosphates', 'Chemical', 'MESH:D010710', (156, 166))	('accumulation', 'PosReg', (52, 64))	('cyclin B1', 'Gene', '891', (114, 123))	('cyclin B1', 'Gene', (114, 123))	('Tyr15', 'Chemical', '-', (190, 195))	('Thr14/Tyr15', 'Var', (184, 195))	('Cdc2', 'Gene', (200, 204))	('Cdc2', 'Gene', (109, 113))	('inhibitory', 'MPA', (145, 155))
727463	25139395	To determine whether YM155 induced abrogation of G2 checkpoint is mediated by the suppression of Cdc2 inhibitory phosphorylation, we monitored the phosphorylation level of Cdc2 as well as cyclin B1 expression in Eca109 and TE13 cells.	('cyclin B1', 'Gene', '891', (188, 197))	('cyclin B1', 'Gene', (188, 197))	('Cdc2', 'Gene', '983', (97, 101))	('inhibitory phosphorylation', 'MPA', (102, 128))	('Cdc2', 'Gene', (172, 176))	('Cdc2', 'Gene', (97, 101))	('YM155', 'Var', (21, 26))	('YM155', 'Chemical', 'MESH:C523798', (21, 26))	('Cdc2', 'Gene', '983', (172, 176))	('suppression', 'NegReg', (82, 93))
727464	25139395	Western blot analysis showed that treatment with YM155 alone slightly suppressed basal level of phospho-Cdc2 and cyclin B1.	('Cdc2', 'Gene', (104, 108))	('suppressed', 'NegReg', (70, 80))	('YM155', 'Chemical', 'MESH:C523798', (49, 54))	('cyclin B1', 'Gene', '891', (113, 122))	('cyclin B1', 'Gene', (113, 122))	('YM155', 'Var', (49, 54))	('Cdc2', 'Gene', '983', (104, 108))
727467	25139395	To further explore the mechanisms of YM155 induced abrogation of G2 arrest, we detected gamma-H2AX and RAD51 foci in Eca109 cells.	('RAD51', 'Gene', (103, 108))	('YM155', 'Chemical', 'MESH:C523798', (37, 42))	('H2AX', 'Gene', '3014', (94, 98))	('H2AX', 'Gene', (94, 98))	('YM155', 'Var', (37, 42))	('RAD51', 'Gene', '5888', (103, 108))	('G2 arrest', 'CPA', (65, 74))
727469	25139395	However, YM155 treatment resulted in a significant prolongation of gamma-H2AX signal at least 24 h post irradiation (47.7 +- 3.0%) compared with radiation alone (7 +- 2.8%; P < 0.001) (Figure 5A).	('H2AX', 'Gene', '3014', (73, 77))	('YM155 treatment', 'Var', (9, 24))	('H2AX', 'Gene', (73, 77))	('prolongation', 'PosReg', (51, 63))	('YM155', 'Chemical', 'MESH:C523798', (9, 14))
727470	25139395	These results suggest that YM155 significantly inhibited the repair of DSBs manifested as the persistence of gamma-H2AX foci at 4 to 24 h after radiation.	('inhibited', 'NegReg', (47, 56))	('H2AX', 'Gene', '3014', (115, 119))	('DSBs', 'Disease', (71, 75))	('H2AX', 'Gene', (115, 119))	('repair', 'MPA', (61, 67))	('YM155', 'Var', (27, 32))	('YM155', 'Chemical', 'MESH:C523798', (27, 32))
727473	25139395	However, in the presence of YM155, the assembly of Rad51 foci in response to radiation was significantly suppressed, which was in contrast with kinetics of gamma-H2AX (Figure 5B).	('suppressed', 'NegReg', (105, 115))	('assembly', 'MPA', (39, 47))	('H2AX', 'Gene', '3014', (162, 166))	('H2AX', 'Gene', (162, 166))	('Rad51', 'Gene', (51, 56))	('Rad51', 'Gene', '5888', (51, 56))	('response to radiation', 'MPA', (65, 86))	('YM155', 'Chemical', 'MESH:C523798', (28, 33))	('YM155', 'Var', (28, 33))
727474	25139395	Taken together, these findings support the conclusion that YM155 inhibits HRR, likely through the inhibition of Rad51 focus formation in response to radiation.	('HRR', 'CPA', (74, 77))	('inhibits', 'NegReg', (65, 73))	('inhibition', 'NegReg', (98, 108))	('YM155', 'Chemical', 'MESH:C523798', (59, 64))	('Rad51', 'Gene', (112, 117))	('Rad51', 'Gene', '5888', (112, 117))	('YM155', 'Var', (59, 64))
727475	25139395	To analyze the possible enhancement of radiation-induced apoptosis in ECSS cells after YM155 exposure, we first performed Annexin V/FITC and propidium iodide dual staining to quantify apoptotic cells after treatment with YM155 (10 nM) and radiation (8 Gy), alone and in combination for 48 h. As shown in Figure 6A, the induction of early apoptotic events (Annexin V positive) was most evident when cells were treated with 8 Gy plus YM155.	('Annexin V', 'Gene', '308', (356, 365))	('FITC', 'Chemical', '-', (132, 136))	('Annexin V', 'Gene', (122, 131))	('propidium iodide', 'Chemical', 'MESH:D011419', (141, 157))	('Annexin V', 'Gene', '308', (122, 131))	('Annexin V', 'Gene', (356, 365))	('YM155', 'Chemical', 'MESH:C523798', (432, 437))	('YM155', 'Chemical', 'MESH:C523798', (87, 92))	('YM155', 'Var', (432, 437))	('YM155', 'Chemical', 'MESH:C523798', (221, 226))
727477	25139395	As shown in Figure 6B, higher levels of cleaved PARP and caspase-3 were observed in Eca109 cells treated with 8 Gy radiation plus 10 nM YM155, compared with the cells treated with YM155 or radiation alone.	('higher', 'PosReg', (23, 29))	('caspase-3', 'Gene', (57, 66))	('PARP', 'Gene', '1302', (48, 52))	('YM155', 'Chemical', 'MESH:C523798', (136, 141))	('PARP', 'Gene', (48, 52))	('YM155', 'Var', (136, 141))	('caspase-3', 'Gene', '836', (57, 66))	('YM155', 'Chemical', 'MESH:C523798', (180, 185))
727478	25139395	To determine the in vivo radiosensitizing activity of YM155 for ESCC, mice bearing Eca109 cells xenograft tumor were utilized.	('YM155', 'Chemical', 'MESH:C523798', (54, 59))	('YM155', 'Var', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
727479	25139395	As shown in Figure 7A, YM155 or irradiation alone produced significant tumor volume regression on day 20 (P = 0.006 for irradiation, P = 0.001 for YM155) compared to control group.	('YM155', 'Chemical', 'MESH:C523798', (23, 28))	('regression', 'NegReg', (84, 94))	('YM155', 'Var', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('YM155', 'Chemical', 'MESH:C523798', (147, 152))	('tumor', 'Disease', (71, 76))
727480	25139395	However, the combination of YM155 and radiation produced more tumor volume regression (P < 0.05 for YM155 plus IR versus single treatment).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('YM155', 'Var', (28, 33))	('YM155', 'Chemical', 'MESH:C523798', (28, 33))	('YM155', 'Chemical', 'MESH:C523798', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
727484	25139395	Immunohistochemical analysis demonstrated that YM155 significantly inhibited survivin expression in either IR treated or untreated tumors (Figure 7C, upper panel).	('inhibited', 'NegReg', (67, 76))	('YM155', 'Chemical', 'MESH:C523798', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('untreated tumors', 'Disease', (121, 137))	('YM155', 'Var', (47, 52))	('untreated tumors', 'Disease', 'MESH:D009369', (121, 137))	('expression', 'MPA', (86, 96))	('survivin', 'Gene', '11799', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('survivin', 'Gene', (77, 85))
727485	25139395	The mean density of survivin staining in tumors from YM155 treated groups (YM155: 0.021 +- 0.0087; IR plus YM155: 0.008 +- 0.0036) was significantly lower than that in YM155 untreated groups (Control, 0.061 +- 0.0025; IR: 0.050 +- 0.0044) (P < 0.01).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('YM155', 'Chemical', 'MESH:C523798', (53, 58))	('density', 'MPA', (9, 16))	('survivin', 'Gene', (20, 28))	('YM155', 'Var', (53, 58))	('YM155', 'Chemical', 'MESH:C523798', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('YM155', 'Chemical', 'MESH:C523798', (168, 173))	('survivin', 'Gene', '11799', (20, 28))	('YM155', 'Chemical', 'MESH:C523798', (107, 112))	('lower', 'NegReg', (149, 154))
727487	25139395	As shown in Figure 7C (middle panel), the mean apoptotic index was 2.8% in the control group, 30.6% in the YM155 group, and 22.2% in the IR group; while the combined treatment group had an apoptotic index of 61.2%, significantly higher than either treatment alone (P < 0.01).	('apoptotic index', 'CPA', (47, 62))	('YM155', 'Var', (107, 112))	('YM155', 'Chemical', 'MESH:C523798', (107, 112))
727490	25139395	These data indicated that YM155 radiosensitized ESCC in vivo.	('ESCC', 'Disease', (48, 52))	('YM155', 'Chemical', 'MESH:C523798', (26, 31))	('YM155', 'Var', (26, 31))
727491	25139395	In the present study, we have shown that survivin inhibition by YM155 enhanced radiation-induced inhibition of growth of esophageal cancer cells and xenografts.	('survivin', 'Gene', (41, 49))	('growth', 'CPA', (111, 117))	('esophageal cancer', 'Disease', (121, 138))	('inhibition', 'NegReg', (97, 107))	('inhibition', 'NegReg', (50, 60))	('YM155', 'Chemical', 'MESH:C523798', (64, 69))	('radiation-induced', 'CPA', (79, 96))	('survivin', 'Gene', '11799', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('YM155', 'Var', (64, 69))	('enhanced', 'PosReg', (70, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))
727492	25139395	Radiosensitization by YM155 in ESCC is associated with the abrogation of radiation-induced G2 checkpoint as well as the attenuation of homologous-recombination-mediated DNA damage repair.	('abrogation', 'NegReg', (59, 69))	('YM155', 'Chemical', 'MESH:C523798', (22, 27))	('YM155', 'Var', (22, 27))	('attenuation', 'NegReg', (120, 131))	('radiation-induced G2', 'CPA', (73, 93))	('ESCC', 'Gene', (31, 35))	('homologous-recombination-mediated DNA', 'Enzyme', (135, 172))
727493	25139395	indicated that radiosensitization of NSCLC cells by YM155 was associated with increased activity of caspase-3, suggesting that YM155 sensitized tumor cells to radiation partly by enhancing radiation-induced apoptosis.	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('tumor', 'Disease', (144, 149))	('caspase-3', 'Gene', (100, 109))	('radiation-induced apoptosis', 'CPA', (189, 216))	('enhancing', 'PosReg', (179, 188))	('caspase-3', 'Gene', '836', (100, 109))	('activity', 'MPA', (88, 96))	('NSCLC', 'Disease', (37, 42))	('YM155', 'Chemical', 'MESH:C523798', (127, 132))	('increased', 'PosReg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('YM155', 'Var', (127, 132))	('YM155', 'Chemical', 'MESH:C523798', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('YM155', 'Var', (52, 57))
727495	25139395	We found that YM155 at nanomolar concentration was sufficient to abrogate G2 arrest.	('abrogate', 'NegReg', (65, 73))	('YM155', 'Var', (14, 19))	('YM155', 'Chemical', 'MESH:C523798', (14, 19))	('G2 arrest', 'CPA', (74, 83))
727496	25139395	In support of this possibility, we found that YM155 significantly increased persistent gamma-H2AX expression and suppressed RAD51 recruitment in the nuclei of irradiated ESCC cells.	('H2AX', 'Gene', '3014', (93, 97))	('YM155', 'Var', (46, 51))	('increased', 'PosReg', (66, 75))	('H2AX', 'Gene', (93, 97))	('suppressed', 'NegReg', (113, 123))	('RAD51', 'Gene', (124, 129))	('RAD51', 'Gene', '5888', (124, 129))	('YM155', 'Chemical', 'MESH:C523798', (46, 51))	('expression', 'MPA', (98, 108))
727497	25139395	Consistently, we demonstrated that YM155 enhanced the apoptosis and promoted the cleavage of caspase-3 and PARP in irradiated ESCC cells.	('caspase-3', 'Gene', (93, 102))	('apoptosis', 'CPA', (54, 63))	('promoted', 'PosReg', (68, 76))	('cleavage', 'MPA', (81, 89))	('YM155', 'Chemical', 'MESH:C523798', (35, 40))	('enhanced', 'PosReg', (41, 49))	('PARP', 'Gene', '1302', (107, 111))	('caspase-3', 'Gene', '836', (93, 102))	('PARP', 'Gene', (107, 111))	('YM155', 'Var', (35, 40))
727504	25139395	Therefore, the cells harboring mutations in p53 are deficient in G1 checkpoint and depend on p53-independent G2 checkpoint for DNA damage repair, rendering them more sensitive to G2 checkpoint abrogation.	('mutations', 'Var', (31, 40))	('p53', 'Gene', (93, 96))	('more', 'PosReg', (161, 165))	('p53', 'Gene', '7157', (93, 96))	('G1 checkpoint', 'MPA', (65, 78))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('deficient', 'NegReg', (52, 61))	('sensitive', 'MPA', (166, 175))
727510	25139395	reported that the concomitant treatment of YM155 relieved docetaxel-induced cell cycle arrest at the G2/M phase and synergistically enhanced the cytotoxic activity of docetaxel.	('relieved', 'NegReg', (49, 57))	('docetaxel', 'Chemical', 'MESH:D000077143', (58, 67))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('YM155', 'Chemical', 'MESH:C523798', (43, 48))	('YM155', 'Var', (43, 48))	('enhanced', 'PosReg', (132, 140))	('cytotoxic activity', 'CPA', (145, 163))	('docetaxel', 'Chemical', 'MESH:D000077143', (167, 176))	('cell cycle arrest at the G2/M phase', 'CPA', (76, 111))
727511	25139395	Accordingly, our present findings demonstrate that YM155 abrogates the G2 arrest induced by ionizing radiation, thus resulting in preferential cancer cell death.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('YM155', 'Var', (51, 56))	('G2 arrest', 'MPA', (71, 80))	('abrogates', 'NegReg', (57, 66))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('preferential', 'PosReg', (130, 142))	('YM155', 'Chemical', 'MESH:C523798', (51, 56))
727512	25139395	YM155 probably abrogates G2 checkpoint by inhibiting the Wee1/Mik1 kinases that suppress Cdc2 activation or by activating the Cdc25C phosphatase that, in turn, activates Cdc2.	('Cdc2', 'Gene', '983', (126, 130))	('Cdc2', 'Gene', '983', (170, 174))	('activates', 'PosReg', (160, 169))	('Cdc2', 'Gene', (89, 93))	('abrogates', 'NegReg', (15, 24))	('Cdc2', 'Gene', (126, 130))	('inhibiting', 'NegReg', (42, 52))	('suppress', 'NegReg', (80, 88))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('Cdc25C', 'Gene', (126, 132))	('activating', 'PosReg', (111, 121))	('activation', 'MPA', (94, 104))	('YM155', 'Var', (0, 5))	('Cdc2', 'Gene', (170, 174))	('Wee1', 'Gene', (57, 61))	('Cdc2', 'Gene', '983', (89, 93))	('Cdc25C', 'Gene', '995', (126, 132))	('Wee1', 'Gene', '7465', (57, 61))
727513	25139395	Targeting survivin with potent inhibitor YM155 modulates G2/M cell cycle checkpoint and mediates radiosensitization of esophageal cancer cells both in vitro and in vivo.	('survivin', 'Gene', (10, 18))	('radiosensitization', 'CPA', (97, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('mediates', 'Reg', (88, 96))	('G2/M cell', 'Pathway', (57, 66))	('survivin', 'Gene', '11799', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('YM155', 'Chemical', 'MESH:C523798', (41, 46))	('modulates', 'Reg', (47, 56))	('YM155', 'Var', (41, 46))	('esophageal cancer', 'Disease', (119, 136))
727514	25139395	Our preclinical results identify survivin inhibitor YM155 as a novel cell-cycle checkpoint abrogator which provides a rationale for future clinical investigation of therapeutic efficacy of YM155 in combination with DNA-damaging agents.	('survivin', 'Gene', '11799', (33, 41))	('YM155', 'Chemical', 'MESH:C523798', (189, 194))	('survivin', 'Gene', (33, 41))	('YM155', 'Chemical', 'MESH:C523798', (52, 57))	('YM155', 'Var', (52, 57))
727525	25139395	Western blot analysis was performed as previously described, using rabbit polyclonal antibodies to human survivin and c-IAP1 (R&D systems, MN), XIAP and Cyclin B1 (Cell signaling, MA), phosphor-Cdc25C, Cdc2, phospho-Cdc2, cleaved PARP and cleaved caspase-3 (Santa Cruz, CA).	('survivin', 'Gene', '11799', (105, 113))	('Cdc2', 'Gene', (216, 220))	('caspase-3', 'Gene', '836', (247, 256))	('rabbit', 'Species', '9986', (67, 73))	('c-IAP1', 'Gene', '329', (118, 124))	('Cyclin B1', 'Gene', (153, 162))	('caspase-3', 'Gene', (247, 256))	('cleaved', 'Protein', (222, 229))	('cleaved', 'Gene', (239, 246))	('XIAP', 'Gene', '331', (144, 148))	('c-IAP1', 'Gene', (118, 124))	('Cyclin B1', 'Gene', '891', (153, 162))	('Cdc2', 'Gene', '983', (202, 206))	('PARP', 'Gene', '1302', (230, 234))	('and', 'Var', (235, 238))	('Cdc2', 'Gene', '983', (194, 198))	('Cdc25C', 'Gene', '995', (194, 200))	('MN', 'CellLine', 'CVCL:U508', (139, 141))	('Cdc2', 'Gene', '983', (216, 220))	('XIAP', 'Gene', (144, 148))	('Cdc25C', 'Gene', (194, 200))	('Cdc2', 'Gene', (202, 206))	('PARP', 'Gene', (230, 234))	('survivin', 'Gene', (105, 113))	('Cdc2', 'Gene', (194, 198))	('human', 'Species', '9606', (99, 104))
727551	25139395	The sections were then incubated overnight at 4 C with polyclonal antibody to survivin (1:50; Abcam, Ltd., Cambridge, United Kingdom) or cleaved caspase-3 (1:100; Cell Signaling, Beverly, MA, USA).	('caspase-3', 'Gene', (145, 154))	('survivin', 'Gene', '11799', (78, 86))	('caspase-3', 'Gene', '836', (145, 154))	('cleaved', 'Var', (137, 144))	('survivin', 'Gene', (78, 86))
727562	24151445	The TNF-alpha -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated.	('-308G>A', 'Mutation', 'rs1800629', (78, 85))	('-238G>A', 'Mutation', 'rs361525', (99, 106))	('rs361525', 'Var', (108, 116))	('36A>G', 'Mutation', 'rs767455', (153, 158))	('TNFRSF1A', 'Gene', '7132', (119, 127))	('rs1800630', 'Mutation', 'rs1800630', (45, 54))	('rs4149570', 'Mutation', 'rs4149570', (137, 146))	('TNFRSF1A', 'Gene', (119, 127))	('TNF-alpha', 'Gene', '7124', (4, 13))	('rs1799964', 'Var', (24, 33))	('TNF-alpha', 'Gene', (4, 13))	('-857C>T', 'Mutation', 'rs1799724', (57, 64))	('rs1799724', 'Var', (66, 75))	('rs1799724', 'Mutation', 'rs1799724', (66, 75))	('-1031T>C', 'Mutation', 'rs1799964', (14, 22))	('rs1800629', 'Var', (87, 96))	('-609G>T', 'Mutation', 'rs4149570', (128, 135))	('rs1800630', 'Var', (45, 54))	('rs767455', 'Mutation', 'rs767455', (160, 168))	('rs1800629', 'Mutation', 'rs1800629', (87, 96))	('rs1799964', 'Mutation', 'rs1799964', (24, 33))	('-863C>A', 'Mutation', 'rs1800630', (36, 43))	('rs361525', 'Mutation', 'rs361525', (108, 116))
727566	24151445	Tumor necrosis factor alpha (TNF-alpha), an important proinflammatory cytokine, is produced by activated macrophages and exerts its effects by binding to its two cognate cell surface receptors, TNFRSF1A/TNFR1 (p55/60) and TNFRSF1B/TNFR2 (p75/80).	('binding', 'Interaction', (143, 150))	('TNFRSF1B', 'Gene', (222, 230))	('p75', 'Gene', (238, 241))	('TNFR1', 'Gene', (203, 208))	('TNFRSF1A', 'Gene', '7132', (194, 202))	('TNFR2', 'Gene', '7133', (231, 236))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TNF-alpha', 'Gene', '7124', (29, 38))	('Tumor necrosis factor alpha', 'Gene', '7124', (0, 27))	('p75', 'Gene', '7133', (238, 241))	('p55/60', 'Var', (210, 216))	('TNFR2', 'Gene', (231, 236))	('TNF-alpha', 'Gene', (29, 38))	('TNFR1', 'Gene', '7132', (203, 208))	('TNFRSF1A', 'Gene', (194, 202))	('TNFRSF1B', 'Gene', '7133', (222, 230))	('Tumor necrosis factor alpha', 'Gene', (0, 27))
727571	24151445	TNF-alpha and TNFRSF1A may play important roles in esophageal squamous cell carcinoma (ESCC), TNFRSF1A was found to be strongly expressed in an esophageal carcinoma cell line, and silencing the expression of TNFRSF1A promoted cell proliferation and downregulated the apoptotic rate.	('downregulated', 'NegReg', (249, 262))	('TNFRSF1A', 'Gene', '7132', (208, 216))	('esophageal carcinoma', 'Disease', (144, 164))	('esophageal squamous cell carcinoma', 'Disease', (51, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('TNFRSF1A', 'Gene', (208, 216))	('silencing', 'Var', (180, 189))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (144, 164))	('TNFRSF1A', 'Gene', '7132', (14, 22))	('TNFRSF1A', 'Gene', '7132', (94, 102))	('TNFRSF1A', 'Gene', (14, 22))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (51, 85))	('TNFRSF1A', 'Gene', (94, 102))	('TNF-alpha', 'Gene', '7124', (0, 9))	('cell proliferation', 'CPA', (226, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('TNF-alpha', 'Gene', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (144, 164))	('apoptotic rate', 'CPA', (267, 281))	('promoted', 'PosReg', (217, 225))
727574	24151445	Some of these polymorphisms were recently shown to be related to tumor progression, metastasis, prognosis, and survival.	('tumor', 'Disease', (65, 70))	('related', 'Reg', (54, 61))	('metastasis', 'CPA', (84, 94))	('polymorphisms', 'Var', (14, 27))	('survival', 'CPA', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('prognosis', 'CPA', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
727575	24151445	However, these studies included patients treated with surgery or neoadjuvant chemoradiotherapy (CRT); therefore, the association between these TNF-alpha and TNFRSF1A polymorphisms and the prediction of clinical outcome with definitive CRT in ESCC remains unknown.	('TNFRSF1A', 'Gene', (157, 165))	('CR', 'Chemical', 'MESH:D002857', (96, 98))	('patients', 'Species', '9606', (32, 40))	('TNF-alpha', 'Gene', (143, 152))	('ESCC', 'Disease', (242, 246))	('TNFRSF1A', 'Gene', '7132', (157, 165))	('polymorphisms', 'Var', (166, 179))	('CR', 'Chemical', 'MESH:D002857', (235, 237))	('TNF-alpha', 'Gene', '7124', (143, 152))
727576	24151445	Predicting therapeutic responses is important in definitive CRT prior to the initiation of treatment; we previously reported a significant correlation between clinical response and survival, and showed that the TNFRSF1B 1466A/G (rs1061624) genotype could predict clinical response with definitive 5-FU/cisplatin (CDDP)-based CRT in 46 male Japanese patients with ESCC.	('ESCC', 'Disease', (363, 367))	('patients', 'Species', '9606', (349, 357))	('1466A/G', 'Var', (220, 227))	('CDDP', 'Chemical', 'MESH:D002945', (313, 317))	('cisplatin', 'Chemical', 'MESH:D002945', (302, 311))	('rs1061624', 'Mutation', 'rs1061624', (229, 238))	('CR', 'Chemical', 'MESH:D002857', (60, 62))	('TNFRSF1B', 'Gene', '7133', (211, 219))	('rs1061624', 'Var', (229, 238))	('5-FU', 'Chemical', 'MESH:D005472', (297, 301))	('1466A/G', 'Mutation', 'rs1061624', (220, 227))	('TNFRSF1B', 'Gene', (211, 219))	('CR', 'Chemical', 'MESH:D002857', (325, 327))	('predict', 'Reg', (255, 262))
727577	24151445	Although these findings suggest that TNF-alpha and its receptors may play a critical role in clinical response and survival, to the best of our knowledge, no published study has investigated associations between the polymorphisms of TNF-alpha and TNFRSF1A genes and the prediction of clinical outcome in ESCC patients treated with definitive CRT.	('TNFRSF1A', 'Gene', (247, 255))	('TNF-alpha', 'Gene', (233, 242))	('ESCC', 'Disease', (304, 308))	('associations', 'Interaction', (191, 203))	('polymorphisms', 'Var', (216, 229))	('TNF-alpha', 'Gene', '7124', (37, 46))	('TNFRSF1A', 'Gene', '7132', (247, 255))	('TNF-alpha', 'Gene', (37, 46))	('CR', 'Chemical', 'MESH:D002857', (342, 344))	('patients', 'Species', '9606', (309, 317))	('TNF-alpha', 'Gene', '7124', (233, 242))
727578	24151445	The TNF-alpha -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were selected for genotyping because they affect expression or transcription and have been associated with tumor progression, metastasis, prognosis, or survival in cancer.	('-308G>A', 'Mutation', 'rs1800629', (78, 85))	('cancer', 'Disease', (344, 350))	('-238G>A', 'Mutation', 'rs361525', (99, 106))	('rs361525', 'Var', (108, 116))	('36A>G', 'Mutation', 'rs767455', (153, 158))	('TNFRSF1A', 'Gene', '7132', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('rs1800630', 'Mutation', 'rs1800630', (45, 54))	('rs4149570', 'Mutation', 'rs4149570', (137, 146))	('TNFRSF1A', 'Gene', (119, 127))	('TNF-alpha', 'Gene', '7124', (4, 13))	('TNF-alpha', 'Gene', (4, 13))	('-857C>T', 'Mutation', 'rs1799724', (57, 64))	('associated with', 'Reg', (271, 286))	('rs1799724', 'Mutation', 'rs1799724', (66, 75))	('-1031T>C', 'Mutation', 'rs1799964', (14, 22))	('tumor', 'Disease', (287, 292))	('cancer', 'Disease', 'MESH:D009369', (344, 350))	('transcription', 'MPA', (243, 256))	('metastasis', 'CPA', (306, 316))	('-609G>T', 'Mutation', 'rs4149570', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('rs767455', 'Mutation', 'rs767455', (160, 168))	('rs1800629', 'Mutation', 'rs1800629', (87, 96))	('expression', 'MPA', (229, 239))	('affect', 'Reg', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('rs1799964', 'Mutation', 'rs1799964', (24, 33))	('-863C>A', 'Mutation', 'rs1800630', (36, 43))	('rs361525', 'Mutation', 'rs361525', (108, 116))
727596	24151445	Table 2 shows the association between the TNF-alpha and TNFRSF1A genotypes, and TNF-alpha -1031T>C, -863C>A, -857C>T, -308G>A, -238G>A, TNFRSF1A -609G>T, and 36A>G genotypes and clinical response in ESCC patients.	('TNFRSF1A', 'Gene', '7132', (136, 144))	('TNFRSF1A', 'Gene', '7132', (56, 64))	('-609G>T', 'Mutation', 'rs4149570', (145, 152))	('36A>G', 'Var', (158, 163))	('patients', 'Species', '9606', (204, 212))	('TNFRSF1A', 'Gene', (136, 144))	('36A>G', 'Mutation', 'rs767455', (158, 163))	('TNFRSF1A', 'Gene', (56, 64))	('TNF-alpha', 'Gene', '7124', (42, 51))	('-857C>T', 'Mutation', 'rs1799724', (109, 116))	('TNF-alpha', 'Gene', (42, 51))	('-238G>A', 'Mutation', 'rs361525', (127, 134))	('ESCC', 'Disease', (199, 203))	('TNF-alpha', 'Gene', '7124', (80, 89))	('association', 'Interaction', (18, 29))	('-863C>A', 'Mutation', 'rs1800630', (100, 107))	('TNF-alpha', 'Gene', (80, 89))	('-308G>A', 'Mutation', 'rs1800629', (118, 125))	('-1031T>C', 'Mutation', 'rs1799964', (90, 98))
727599	24151445	The 5-year survival rates were 55.6 % (15/27) and 26.3 % (5/19) in patients with CC-857 and CT-857 + TT-857, respectively, and the TNF-alpha -857C>T genotype had no significant effect on 5-year survival (CC-857 vs. CT-857 + TT-857, P = 0.072, Fisher's exact test).	('patients', 'Species', '9606', (67, 75))	('TNF-alpha', 'Gene', '7124', (131, 140))	('-857C>T', 'Mutation', 'rs1799724', (141, 148))	('TNF-alpha', 'Gene', (131, 140))	('CT-857 + TT-857', 'Var', (92, 107))	('CC-857', 'Var', (81, 87))
727601	24151445	The median overall survival time (+-SE) was more than 60 months and 22.4 +- 8.0 months for patients with CC-857 and CT-857 + TT-857, respectively; however, the genotype could not predict survival (P = 0.070, Log-rank test).	('CT-857 + TT-857', 'Var', (116, 131))	('CC-857', 'Var', (105, 111))	('patients', 'Species', '9606', (91, 99))
727605	24151445	We identified the TNF-alpha -857C>T genotype as a new predictive genetic marker of clinical response to treatment; patients with the T-allele at position -857 in the TNF-alpha promoter had a poorer response, whereas no such association was found for TNF-alpha -1031T>C, -863C>A, -308G>A, -238G>A, TNFRSF1A -609G>T, or 36A>G (Table 2).	('-238G>A', 'Mutation', 'rs361525', (288, 295))	('patients', 'Species', '9606', (115, 123))	('TNF-alpha', 'Gene', '7124', (18, 27))	('36A>G', 'Mutation', 'rs767455', (318, 323))	('TNFRSF1A', 'Gene', '7132', (297, 305))	('-1031T>C', 'Mutation', 'rs1799964', (260, 268))	('TNF-alpha', 'Gene', (18, 27))	('TNF-alpha', 'Gene', '7124', (166, 175))	('-609G>T', 'Mutation', 'rs4149570', (306, 313))	('-857C>T', 'Mutation', 'rs1799724', (28, 35))	('T-allele', 'Var', (133, 141))	('-308G>A', 'Mutation', 'rs1800629', (279, 286))	('-863C>A', 'Mutation', 'rs1800630', (270, 277))	('TNF-alpha', 'Gene', (166, 175))	('TNF-alpha', 'Gene', '7124', (250, 259))	('36A>G', 'Var', (318, 323))	('TNF-alpha', 'Gene', (250, 259))	('TNFRSF1A', 'Gene', (297, 305))
727608	24151445	None of the other polymorphisms of TNF-alpha and TNFRSF1A had any effect on clinical response, long-term survival, or severe acute leucopenia, stomatitis, and cheilitis.	('stomatitis', 'Disease', 'MESH:D013280', (143, 153))	('stomatitis', 'Disease', (143, 153))	('TNF-alpha', 'Gene', '7124', (35, 44))	('TNFRSF1A', 'Gene', (49, 57))	('TNF-alpha', 'Gene', (35, 44))	('leucopenia', 'Disease', 'MESH:C536227', (131, 141))	('stomatitis', 'Phenotype', 'HP:0010280', (143, 153))	('polymorphisms', 'Var', (18, 31))	('TNFRSF1A', 'Gene', '7132', (49, 57))	('cheilitis', 'Disease', 'MESH:D002613', (159, 168))	('cheilitis', 'Phenotype', 'HP:0100825', (159, 168))	('cheilitis', 'Disease', (159, 168))	('leucopenia', 'Disease', (131, 141))
727612	24151445	Several polymorphisms have been identified in the TNF-alpha gene, which may contribute to differences in gene expression levels.	('gene expression levels', 'MPA', (105, 127))	('TNF-alpha', 'Gene', '7124', (50, 59))	('differences', 'Reg', (90, 101))	('TNF-alpha', 'Gene', (50, 59))	('contribute', 'Reg', (76, 86))	('polymorphisms', 'Var', (8, 21))
727613	24151445	These results suggest the possibility that if polymorphisms in the promoter region of TNF-alpha increase TNF-alpha production, tolerance to 5-FU may increase via the activation of NF-kappaB.	('TNF-alpha', 'Gene', (105, 114))	('5-FU', 'Chemical', 'MESH:D005472', (140, 144))	('increase', 'PosReg', (149, 157))	('TNF-alpha', 'Gene', '7124', (86, 95))	('TNF-alpha', 'Gene', (86, 95))	('polymorphisms in', 'Var', (46, 62))	('tolerance', 'MPA', (127, 136))	('NF-kappaB', 'Gene', '4790', (180, 189))	('TNF-alpha', 'Gene', '7124', (105, 114))	('increase', 'PosReg', (96, 104))	('NF-kappaB', 'Gene', (180, 189))
727618	24151445	This may have been because the effect of activation with TNF-alpha polymorphisms differed depending on the cell lines used and ethnicity, and a combination of these polymorphisms.	('TNF-alpha', 'Gene', (57, 66))	('TNF-alpha', 'Gene', '7124', (57, 66))	('activation', 'PosReg', (41, 51))	('polymorphisms', 'Var', (67, 80))
727632	24151445	The TNFRSF1A -609G/T and 36A/G genotypes were also not associated with clinical response or long-term survival.	('36A/G', 'SUBSTITUTION', 'None', (25, 30))	('TNFRSF1A', 'Gene', (4, 12))	('36A/G', 'Var', (25, 30))	('-609G/T', 'Mutation', 'rs4149570', (13, 20))	('TNFRSF1A', 'Gene', '7132', (4, 12))
727642	24151445	This is the first study to identify the association between TNF-alpha polymorphisms and clinical response with definitive CRT in Japanese ESCC patients.	('patients', 'Species', '9606', (143, 151))	('CR', 'Chemical', 'MESH:D002857', (122, 124))	('polymorphisms', 'Var', (70, 83))	('association', 'Interaction', (40, 51))	('TNF-alpha', 'Gene', '7124', (60, 69))	('TNF-alpha', 'Gene', (60, 69))
727648	23448401	We analyzed tissue specimens by immunohistochemical staining for CD133, p53, p16, p27, murine double minute 2 (MDM2), Ki-67, and epidermal growth factor receptor (EGFR).	('epidermal growth factor receptor', 'Gene', (129, 161))	('epidermal growth factor receptor', 'Gene', '13649', (129, 161))	('men', 'Species', '9606', (24, 27))	('p27', 'Var', (82, 85))	('Ki-67', 'Gene', '17345', (118, 123))	('murine double minute 2', 'Gene', '17246', (87, 109))	('p16', 'Var', (77, 80))	('murine double minute 2', 'Gene', (87, 109))	('Ki-67', 'Gene', (118, 123))	('CD133', 'Gene', (65, 70))	('p53', 'Var', (72, 75))
727652	23448401	In addition, CD133 may play a role in the regulation of tumor cell cycle through p27 and p16 in ESCC.	('p27', 'Var', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('play', 'Reg', (23, 27))	('tumor', 'Disease', (56, 61))	('ESCC', 'Disease', (96, 100))	('CD133', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('p16', 'Var', (89, 92))
727676	23448401	The proportion of positive nuclei in more than 1,000 tumor cells of more than three fields under a x400 magnification microscope (Leica DM LB2) at the deepest area of each tumor was calculated for p53, p27, MDM2, and Ki-67.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('p53', 'Var', (197, 200))	('Ki-67', 'Gene', (217, 222))	('tumor', 'Disease', (172, 177))	('000 tumor', 'Disease', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('p27', 'Var', (202, 205))	('000 tumor', 'Disease', 'MESH:D009369', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('Ki-67', 'Gene', '17345', (217, 222))	('MDM2', 'Var', (207, 211))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
727679	23448401	The cut-off values for abnormal expression were as follows: p53, >=10%  ; p16, <=5%  ; p27, >=10%  ; MDM2, >=20%  ; and Ki-67, >=30%  .	('p53', 'Var', (60, 63))	('MDM2', 'Var', (101, 105))	('Ki-67', 'Gene', '17345', (120, 125))	('p16', 'Var', (74, 77))	('p27', 'Var', (87, 90))	('Ki-67', 'Gene', (120, 125))
727686	23448401	pT and pStage were significantly more advanced among CD133-negative patients compared with CD133-positive patients (Table  1).	('pStage', 'CPA', (7, 13))	('advanced', 'PosReg', (38, 46))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (106, 114))	('CD133-negative', 'Var', (53, 67))
727690	23448401	Overall survival was significantly correlated with pT, pN, pStage, and CD133 status, and was significantly longer in CD133-positive patients than in CD133-negative patients (P = 0.049) (Figure  2).	('CD133-positive', 'Var', (117, 131))	('correlated', 'Reg', (35, 45))	('longer', 'PosReg', (107, 113))	('CD133', 'Gene', (71, 76))	('Overall', 'MPA', (0, 7))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (132, 140))
727710	23448401	Moreover, CD133-negative expression in cholangiocarcinomas was correlated with poor prognosis  , which is similar to that revealed in our study.	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (39, 58))	('expression', 'MPA', (25, 35))	('CD133-negative', 'Var', (10, 24))	('cholangiocarcinomas', 'Disease', (39, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
727728	17634755	All patients participating in surveillance experience the pain and discomfort of biennial upper GI endoscopy, whereas progression to adenocarcinoma occurs only in a minority of BE patients and undisputable evidence that surveillance prolongs survival is still lacking.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('pain', 'Disease', 'MESH:D010146', (58, 62))	('adenocarcinoma', 'Disease', (133, 147))	('pain', 'Disease', (58, 62))	('biennial', 'Var', (81, 89))	('BE', 'Phenotype', 'HP:0100580', (177, 179))	('adenocarcinoma', 'Disease', 'MESH:D000230', (133, 147))	('patients', 'Species', '9606', (4, 12))	('pain', 'Phenotype', 'HP:0012531', (58, 62))	('patients', 'Species', '9606', (180, 188))
727860	33632211	A lung cancer cohort study (GSE31210) showed that high SLC7A7 expression was associated with poor overall survival (OS) and relapse-free survival (RFS).	('lung cancer', 'Phenotype', 'HP:0100526', (2, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('SLC7A7', 'Gene', '9056', (55, 61))	('SLC7A7', 'Gene', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (2, 13))	('expression', 'MPA', (62, 72))	('overall survival', 'CPA', (98, 114))	('relapse-free survival', 'CPA', (124, 145))	('poor', 'NegReg', (93, 97))	('high', 'Var', (50, 54))	('lung cancer', 'Disease', (2, 13))
727875	33632211	In addition, mutations in SLC7A7 causing cation transporter dysfunction are associated with a variety of clinical symptoms.	('associated', 'Reg', (76, 86))	('SLC7A7', 'Gene', '9056', (26, 32))	('SLC7A7', 'Gene', (26, 32))	('causing', 'Reg', (33, 40))	('mutations', 'Var', (13, 22))	('cation transporter dysfunction', 'MPA', (41, 71))
727876	33632211	Overexpression of SLC7A7 is correlated with poor RFS and OS in patients with glioblastoma.	('SLC7A7', 'Gene', '9056', (18, 24))	('RFS', 'MPA', (49, 52))	('glioblastoma', 'Disease', (77, 89))	('SLC7A7', 'Gene', (18, 24))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('poor', 'NegReg', (44, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (63, 71))
727935	33632211	Interestingly, one cohort (GSE19615) including 115 samples showed that high SLC7A7 expression was associated with a better prognosis in breast cancer (distant metastasis-free survival [DMFS]; HR = 0.19, 95% CI 0.06-0.68, P = 0.0103).	('better', 'PosReg', (116, 122))	('distant metastasis-free', 'CPA', (151, 174))	('SLC7A7', 'Gene', '9056', (76, 82))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('SLC7A7', 'Gene', (76, 82))	('high', 'Var', (71, 75))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('expression', 'MPA', (83, 93))
727964	33632211	DCs can promote tumor metastasis by increasing Treg cells and attenuating CD8 + T cell cytotoxicity.	('DCs', 'Var', (0, 3))	('CD8', 'Gene', '925', (74, 77))	('increasing', 'PosReg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Treg cells', 'CPA', (47, 57))	('tumor', 'Disease', (16, 21))	('attenuating', 'NegReg', (62, 73))	('promote', 'PosReg', (8, 15))	('CD8', 'Gene', (74, 77))
727977	33632211	Herein, variations in SLC7A7 expression levels were found to be correlated with prognosis in different types of cancer.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SLC7A7', 'Gene', '9056', (22, 28))	('expression levels', 'MPA', (29, 46))	('variations', 'Var', (8, 18))	('SLC7A7', 'Gene', (22, 28))	('correlated', 'Reg', (64, 74))
727989	33632211	Multiple myeloma and breast cancer were exceptions where high SLC7A7 expression showed a better prognosis.	('Multiple myeloma', 'Phenotype', 'HP:0006775', (0, 16))	('Multiple myeloma and breast cancer', 'Disease', 'MESH:D001943', (0, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('high', 'Var', (57, 61))	('expression', 'MPA', (69, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('SLC7A7', 'Gene', '9056', (62, 68))	('SLC7A7', 'Gene', (62, 68))
727990	33632211	In one dataset of PrognoScan, high SLC7A7 expression could be used as an independent risk factor for poor prognosis in NSCLC (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('SLC7A7', 'Gene', '9056', (35, 41))	('SLC7A7', 'Gene', (35, 41))	('expression', 'MPA', (42, 52))	('high', 'Var', (30, 34))	('NSCLC', 'Disease', (119, 124))
728010	33632211	The microenvironment deprivation of L-arginine in turn leads to the suppression of T-cell activation, proliferation, differentiation and function.	('differentiation', 'CPA', (117, 132))	('L-arginine', 'Chemical', 'MESH:D001120', (36, 46))	('suppression', 'NegReg', (68, 79))	('L-arginine', 'Var', (36, 46))	('T-cell activation', 'CPA', (83, 100))	('function', 'CPA', (137, 145))
728023	33468140	RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between circSDHC, miR-127-3p and its target genes.	('interactions', 'Interaction', (111, 123))	('SDHC', 'Gene', (136, 140))	('miR-127-3p', 'Var', (142, 152))	('SDHC', 'Gene', '6391', (136, 140))
728027	33468140	Furthermore, knockdown of circSDHC caused decreased CDKN3 expression and E2F1 pathway inhibition, which could be rescued by treatment with an miR-127-3p inhibitor.	('SDHC', 'Gene', (30, 34))	('decreased', 'NegReg', (42, 51))	('expression', 'MPA', (58, 68))	('E2F1 pathway', 'Pathway', (73, 85))	('SDHC', 'Gene', '6391', (30, 34))	('CDKN3', 'Pathway', (52, 57))	('knockdown', 'Var', (13, 22))	('inhibition', 'NegReg', (86, 96))
728037	33468140	This process can mediate cancer progression; for example, circMAPK4 acts as a sponge for miR-125a-3p, which participates glioma progression via the MAPK signaling pathway.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('miR-125a-3p', 'Var', (89, 100))	('cancer', 'Disease', (25, 31))	('participates', 'Reg', (108, 120))	('glioma', 'Disease', (121, 127))
728038	33468140	Further, circZNF609 can interact with and downregulate miR-138-5p, promoting RCC progression; however, the biological functions and clinical significance of circRNAs in RCC remain largely unknown, and require elucidation.	('circZNF609', 'Var', (9, 19))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('miR-138-5p', 'Gene', (55, 65))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('promoting', 'PosReg', (67, 76))	('downregulate', 'NegReg', (42, 54))
728040	33468140	By performing in vitro and in vivo experiments, we demonstrate that circSDHC serves as a sponge for miRNA-127-3p, thereby regulating the CDKN3/E2F1 axis.	('regulating', 'Reg', (122, 132))	('miRNA-127-3p', 'Var', (100, 112))	('CDKN3/E2F1 axis', 'Pathway', (137, 152))	('SDHC', 'Gene', (72, 76))	('SDHC', 'Gene', '6391', (72, 76))
728053	33468140	Two datasets were retrieved: GSE100186, consisting of 4 tumors and matched adjacent normal tissue; and GSE137836, consisting of 3 primary tumors and 3 metastatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Disease', (138, 144))	('GSE100186', 'Var', (29, 38))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
728091	33468140	Two GEO datasets (GSE137836 and GSE100186) from circRNA microarray chips analyzing human tissue samples were used to investigate the role of circRNA in RCC development and progression.	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('human', 'Species', '9606', (83, 88))	('GSE137836', 'Var', (18, 27))	('GSE100186', 'Var', (32, 41))
728092	33468140	The GSE137836 dataset was from three primary and three metastatic tumors, while GSE100186 includes data from four tumors and matched adjacent normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (66, 72))	('GSE137836', 'Var', (4, 13))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
728112	33468140	Further, proliferation of these cells was also suppressed on knockdown of circSDHC (Fig.	('knockdown', 'Var', (61, 70))	('suppressed', 'NegReg', (47, 57))	('SDHC', 'Gene', (78, 82))	('SDHC', 'Gene', '6391', (78, 82))
728119	33468140	Four miRNAs, including miR-3612, miR-650, miR-519a-3p, and miR-127-3p, were identified as potential targets of circSDHC in both databases (Fig.	('miR-3612', 'Gene', (23, 31))	('miR-3612', 'Gene', '100500817', (23, 31))	('miR-519a-3p', 'Var', (42, 53))	('miR-127-3p', 'Var', (59, 69))	('miR-650', 'Gene', (33, 40))	('SDHC', 'Gene', (115, 119))	('SDHC', 'Gene', '6391', (115, 119))	('miR-650', 'Gene', '723778', (33, 40))
728122	33468140	Subsequent qRT-PCR confirmed that miR-127-3p could bind to circSDHC in both 786-O and A498 cells (Fig.	('miR-127-3p', 'Var', (34, 44))	('SDHC', 'Gene', '6391', (63, 67))	('SDHC', 'Gene', (63, 67))	('bind', 'Interaction', (51, 55))
728123	33468140	Further, biotin-labeled miR-127-3p captured more circSDHC than a negative control probe (Fig.	('biotin', 'Chemical', 'MESH:D001710', (9, 15))	('SDHC', 'Gene', (53, 57))	('miR-127-3p', 'Var', (24, 34))	('SDHC', 'Gene', '6391', (53, 57))
728124	33468140	3f) and FISH analysis in 786-O cells showed that circSDHC and miR-127-3p were co-localized in the cytoplasm (Fig.	('miR-127-3p', 'Var', (62, 72))	('SDHC', 'Gene', '6391', (53, 57))	('SDHC', 'Gene', (53, 57))
728125	33468140	Furthermore, analysis of our ccRCC patient data showed a negative correlation between miR-127-3p and circSDHC (Fig.	('SDHC', 'Gene', '6391', (105, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('patient', 'Species', '9606', (35, 42))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	('miR-127-3p', 'Var', (86, 96))	('SDHC', 'Gene', (105, 109))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('negative', 'NegReg', (57, 65))
728126	33468140	These results demonstrate that circSDHC can bind to miR-127-3p and act as a sponge for miR-127-3p.	('bind', 'Interaction', (44, 48))	('SDHC', 'Gene', (35, 39))	('miR-127-3p', 'Protein', (52, 62))	('miR-127-3p', 'Var', (87, 97))	('SDHC', 'Gene', '6391', (35, 39))
728127	33468140	According to TCGA ccRCC database, miR-127-3p expression is lower in tumor tissues of ccRCC, compared to normal tissue (Additional file 5: Fig.	('tumor', 'Disease', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('lower', 'NegReg', (59, 64))	('miR-127-3p', 'Var', (34, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
728128	33468140	Moreover, it has previously been reported that lower expression of miR-127-3p correlates with early relapse in patients with RCC following nephrectomy.	('lower', 'NegReg', (47, 52))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('early relapse', 'CPA', (94, 107))	('expression', 'MPA', (53, 63))	('miR-127-3p', 'Var', (67, 77))	('patients', 'Species', '9606', (111, 119))
728129	33468140	These data suggested that miR-127-3p may have an inhibitory role in RCC development and progression.	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('miR-127-3p', 'Var', (26, 36))
728130	33468140	We also had similar observations in our patient cohort, where lower miR-127-3p expression was detected in tumor tissues than in adjacent normal adjacent tissues (Additional file 5: Fig.	('patient', 'Species', '9606', (40, 47))	('miR-127-3p', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('lower', 'NegReg', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
728132	33468140	Consistent with these findings, overexpression of miR-127-3p in 786-O and A498 cells resulted in decreases in both aggression and proliferation (Fig.	('miR-127-3p', 'Var', (50, 60))	('overexpression', 'PosReg', (32, 46))	('aggression', 'Disease', 'MESH:D001523', (115, 125))	('aggression', 'Disease', (115, 125))	('decreases', 'NegReg', (97, 106))	('proliferation', 'CPA', (130, 143))	('aggression', 'Phenotype', 'HP:0000718', (115, 125))
728133	33468140	Cyclin dependent kinase inhibitor 3 (CDKN3) was identified as a potential candidate gene regulated by miR-127-3p, with the binding classified as 7mer-m8 (Fig.	('miR-127-3p', 'Var', (102, 112))	('Cyclin dependent kinase inhibitor 3', 'Gene', (0, 35))	('regulated', 'Reg', (89, 98))	('CDKN3', 'Gene', (37, 42))	('Cyclin dependent kinase inhibitor 3', 'Gene', '1033', (0, 35))
728134	33468140	Moreover, in our patient cohort, we detected a negative relationship between miR-127-3p and CDKN3 expression levels (Additional file 6: Fig.	('miR-127-3p', 'Var', (77, 87))	('negative', 'NegReg', (47, 55))	('patient', 'Species', '9606', (17, 24))	('CDKN3 expression levels', 'MPA', (92, 115))
728135	33468140	These results indicate that miR-127-3p can inhibit RCC progression through downregulation of CDKN3.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('downregulation', 'NegReg', (75, 89))	('CDKN3', 'Gene', (93, 98))	('miR-127-3p', 'Var', (28, 38))	('inhibit', 'NegReg', (43, 50))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
728137	33468140	CDKN3 knockdown in RCC cells led to a lower proliferation rate and diminished migration and invasion abilities (Fig.	('diminished', 'NegReg', (67, 77))	('lower', 'NegReg', (38, 43))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('knockdown', 'Var', (6, 15))	('proliferation rate', 'CPA', (44, 62))	('CDKN3', 'Gene', (0, 5))
728139	33468140	E2F1 is a potent transcription regulator that participates in the development of many different types of cancer, and a previous paper reported that E2F1 is also involved in ccRCC progression.	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('involved', 'Reg', (161, 169))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('E2F1', 'Var', (148, 152))
728144	33468140	In contrast, the CDKN3/E2F1 pathway could be activated by transfection with the circSDHC overexpression vector and this effect was diminished by introduction of miR-127-3p mimic into 769P cells (Fig.	('SDHC', 'Gene', '6391', (84, 88))	('transfection', 'Var', (58, 70))	('CDKN3/E2F1 pathway', 'Pathway', (17, 35))	('activated', 'PosReg', (45, 54))	('SDHC', 'Gene', (84, 88))
728146	33468140	Our result proved that knockdown of circSDHC caused downregulation of CDKN3 and further decreased the expression of CDK1 and CDK2 (Additional file 6: Fig.	('CDKN3', 'Gene', (70, 75))	('expression', 'MPA', (102, 112))	('knockdown', 'Var', (23, 32))	('CDK1', 'Gene', (116, 120))	('CDK2', 'Gene', (125, 129))	('decreased', 'NegReg', (88, 97))	('downregulation', 'NegReg', (52, 66))	('SDHC', 'Gene', (40, 44))	('SDHC', 'Gene', '6391', (40, 44))
728150	33468140	On both gross and microscope examination, lungs from mice injected with circSDHC knockdown cancer cells had less metastatic foci than controls (Fig.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('knockdown', 'Var', (81, 90))	('SDHC', 'Gene', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SDHC', 'Gene', '6391', (76, 80))	('mice', 'Species', '10090', (53, 57))	('less', 'NegReg', (108, 112))	('metastatic foci', 'CPA', (113, 128))
728151	33468140	Further, evaluation of subcutaneous tumor formation demonstrated that the circSDHC knockdown group had significantly lower overall mean tumor volume (Fig.	('SDHC', 'Gene', '6391', (78, 82))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (23, 41))	('knockdown', 'Var', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('lower', 'NegReg', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (136, 141))	('SDHC', 'Gene', (78, 82))	('tumor', 'Disease', (36, 41))
728154	33468140	These results demonstrate that knockdown of circSDHC inhibits RCC tumor progression in vivo.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('circSDHC inhibits RCC tumor', 'Disease', 'MESH:C538614', (44, 71))	('circSDHC inhibits RCC tumor', 'Disease', (44, 71))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('knockdown', 'Var', (31, 40))
728165	33468140	Subsequently, we used a biotin-labeled probe targeting circSDHC and luciferase reporter assays to confirm that miR-127-3p is a target of circSDHC.	('SDHC', 'Gene', (59, 63))	('biotin', 'Chemical', 'MESH:D001710', (24, 30))	('SDHC', 'Gene', '6391', (59, 63))	('SDHC', 'Gene', (141, 145))	('miR-127-3p', 'Var', (111, 121))	('SDHC', 'Gene', '6391', (141, 145))
728166	33468140	Further, analysis of TCGA dataset and data from our own patient cohort showed lower expression of miR-127-3p in tumor, compared with normal tissues.	('tumor', 'Disease', (112, 117))	('patient', 'Species', '9606', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('expression', 'MPA', (84, 94))	('lower', 'NegReg', (78, 83))	('miR-127-3p', 'Var', (98, 108))
728167	33468140	Our findings are consistent with previous studies, which proved that miR-127-3p functions as a tumor suppressor in several different cancers, including osteosarcoma, oral squamous cell carcinoma, and prostate cancer.	('tumor suppressor', 'Gene', (95, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('osteosarcoma', 'Phenotype', 'HP:0002669', (152, 164))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('miR-127-3p', 'Var', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('prostate cancer', 'Disease', (200, 215))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (166, 194))	('tumor suppressor', 'Gene', '7248', (95, 111))	('oral squamous cell carcinoma', 'Disease', (166, 194))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('osteosarcoma', 'Disease', (152, 164))	('osteosarcoma', 'Disease', 'MESH:D012516', (152, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
728168	33468140	Despite the negative regulatory effects of CDKN3 on CDK1 and CDK2, an oncogenic role for aberrant overexpression of CDKN3 has been implicated in numerous types of human cancer, including prostate cancer, gastric cancer, nasopharyngeal carcinoma, and esophageal cancer.	('implicated', 'Reg', (131, 141))	('CDK2', 'Gene', (61, 65))	('carcinoma', 'Disease', 'MESH:D009369', (235, 244))	('cancer', 'Disease', (169, 175))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (220, 244))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('negative', 'NegReg', (12, 20))	('CDKN3', 'Gene', (116, 121))	('CDK1', 'Gene', (52, 56))	('gastric cancer', 'Disease', (204, 218))	('esophageal cancer', 'Disease', 'MESH:D004938', (250, 267))	('aberrant', 'Var', (89, 97))	('overexpression', 'PosReg', (98, 112))	('cancer', 'Disease', (261, 267))	('esophageal cancer', 'Disease', (250, 267))	('CDKN3', 'Gene', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('gastric cancer', 'Disease', 'MESH:D013274', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('cancer', 'Disease', (212, 218))	('carcinoma', 'Disease', (235, 244))	('regulatory', 'MPA', (21, 31))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('prostate cancer', 'Disease', 'MESH:D011471', (187, 202))	('gastric cancer', 'Phenotype', 'HP:0012126', (204, 218))	('human', 'Species', '9606', (163, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (187, 202))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('prostate cancer', 'Disease', (187, 202))
728172	33468140	Specifically, E2F1 promotes tumor malignancy and correlates with TNM stage in ccRCC.	('tumor malignancy', 'Disease', (28, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('promotes', 'PosReg', (19, 27))	('TNM', 'Gene', '10178', (65, 68))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('tumor malignancy', 'Disease', 'MESH:D009369', (28, 44))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('E2F1', 'Var', (14, 18))	('TNM', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
728173	33468140	Therefore, we predicted that the CDKN3/E2F1 pathway may be a target of circSDHC and miR-127-3p.	('CDKN3/E2F1 pathway', 'Pathway', (33, 51))	('SDHC', 'Gene', '6391', (75, 79))	('SDHC', 'Gene', (75, 79))	('miR-127-3p', 'Var', (84, 94))
728176	33468140	Further, circSDHC promotes ccRCC progression and metastasis by acting as a sponge for miR-127-3p, which is a tumor suppressor that downregulates the activity of CDKN3/E2F1 axis.	('SDHC', 'Gene', (13, 17))	('metastasis', 'CPA', (49, 59))	('SDHC', 'Gene', '6391', (13, 17))	('tumor suppressor', 'Gene', (109, 125))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('activity', 'MPA', (149, 157))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('CDKN3/E2F1 axis', 'Pathway', (161, 176))	('promotes', 'PosReg', (18, 26))	('miR-127-3p', 'Var', (86, 96))	('tumor suppressor', 'Gene', '7248', (109, 125))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('downregulates', 'NegReg', (131, 144))
728184	32824841	Twenty-seven of 76 patients (36.5%) showed CK20 positivity in the blood, 19 of 61 patients (31.1%) in bone marrow, and 40 (51.9%) of 77 patients were positive in either blood or bone marrow or both.	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (82, 90))	('positivity', 'Var', (48, 58))	('patients', 'Species', '9606', (136, 144))	('CK20', 'Gene', '54474', (43, 47))	('CK20', 'Gene', (43, 47))
728244	32824841	If the 485 bp CK20 amplicon was detected in at least one PCR run, the sample was judged as positive.	('485 bp', 'Var', (7, 13))	('CK20', 'Gene', (14, 18))	('CK20', 'Gene', '54474', (14, 18))
728247	32824841	In bone marrow and venous blood samples of this clinical control group, we observed CK20 positivity in 3 patients, all with premalignant diseases.	('positivity', 'Var', (89, 99))	('patients', 'Species', '9606', (105, 113))	('premalignant diseases', 'Disease', (124, 145))	('CK20', 'Gene', (84, 88))	('CK20', 'Gene', '54474', (84, 88))	('premalignant diseases', 'Disease', 'MESH:D003141', (124, 145))
728264	32824841	As shown in Figure 2, no significant correlation between CK20 positivity in blood samples and overall survival (p = 0.936) (Figure 2A) or tumor-specific survival (p = 0.69) (Figure 2B) could be determined.	('tumor', 'Disease', (138, 143))	('positivity', 'Var', (62, 72))	('CK20', 'Gene', '54474', (57, 61))	('CK20', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
728265	32824841	However, there was a significant correlation between bone marrow CK20 positivity and overall survival (p = 0.029), as well as tumor-specific survival (p = 0.048).	('CK20', 'Gene', (65, 69))	('CK20', 'Gene', '54474', (65, 69))	('positivity', 'Var', (70, 80))	('bone', 'Protein', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('overall survival', 'CPA', (85, 101))	('tumor', 'Disease', (126, 131))
728273	32824841	While no significant correlation between CK20 mRNA detection in blood samples and overall survival (p = 0.261) or tumor-specific survival (p = 0.196) could be determined (Figure 3A), a significant correlation between bone marrow CK20 positivity and overall survival for EC patients with UICC stages I and II (p = 0.023) could be observed (Figure 3B,C).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('patients', 'Species', '9606', (273, 281))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('positivity', 'Var', (234, 244))	('tumor', 'Disease', (114, 119))	('CK20', 'Gene', (229, 233))	('overall survival', 'CPA', (249, 265))	('CK20', 'Gene', '54474', (229, 233))	('CK20', 'Gene', '54474', (41, 45))	('CK20', 'Gene', (41, 45))
728281	32824841	There was no significant correlation between bone marrow CK20 positivity and overall survival (p = 0.217) and tumor-specific survival (p = 0.169) (Figure 4B,C).	('positivity', 'Var', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('CK20', 'Gene', '54474', (57, 61))	('CK20', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
728289	32824841	Furthermore, there was a significant association between bone marrow CK20 positivity and overall survival (p = 0.013), as well as bone marrow CK20 positivity and tumor-specific survival (p = 0.041) in this patient cohort (Figure 5).	('positivity', 'Var', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('CK20', 'Gene', (69, 73))	('CK20', 'Gene', (142, 146))	('CK20', 'Gene', '54474', (69, 73))	('patient', 'Species', '9606', (206, 213))	('tumor', 'Disease', (162, 167))	('CK20', 'Gene', '54474', (142, 146))	('bone', 'Protein', (57, 61))	('bone marrow', 'CPA', (130, 141))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('overall survival', 'CPA', (89, 105))
728299	32824841	Examination of bone marrow samples revealed no correlation between CK20 positivity and any of the clinical parameters tested.	('CK20', 'Gene', (67, 71))	('CK20', 'Gene', '54474', (67, 71))	('positivity', 'Var', (72, 82))
728302	32824841	The following correlations between CK20 positivity and clinical parameters could be shown in the patient collective consisting of blood and/or bone marrow.	('CK20', 'Gene', (35, 39))	('CK20', 'Gene', '54474', (35, 39))	('patient', 'Species', '9606', (97, 104))	('positivity', 'Var', (40, 50))
728305	32824841	Here, 8 of 10 patients (80%) showed CK20 positivity in blood and/or bone marrow.	('CK20', 'Gene', (36, 40))	('patients', 'Species', '9606', (14, 22))	('CK20', 'Gene', '54474', (36, 40))	('positivity', 'Var', (41, 51))
728312	32824841	Thus, CK20 positivity in bone marrow was included in the calculations for overall and tumor-specific survival, whereas CK20 mRNA detection in blood samples was not.	('CK20', 'Gene', (6, 10))	('CK20', 'Gene', '54474', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CK20', 'Gene', '54474', (119, 123))	('positivity', 'Var', (11, 21))	('tumor', 'Disease', (86, 91))	('included', 'Reg', (41, 49))	('CK20', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
728330	32824841	Similarly, no significant relation could be shown between CK20 positivity in bone marrow and the UICC stage, TNM category, gender, histological tumor type, recurrence rate or frequency of neo-adjuvant chemotherapy, which is in line with other studies demonstrating no correlation of DTC presence in bone marrow and clinical parameters in EC patients.	('tumor', 'Disease', (144, 149))	('patients', 'Species', '9606', (341, 349))	('CK20', 'Gene', (58, 62))	('CK20', 'Gene', '54474', (58, 62))	('TNM', 'Gene', (109, 112))	('positivity', 'Var', (63, 73))	('DTC', 'Chemical', '-', (283, 286))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('TNM', 'Gene', '10178', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
728331	32824841	In contrast, a significant correlation between CK20 positivity in the bone marrow of EC patients and their survival could be shown.	('patients', 'Species', '9606', (88, 96))	('positivity', 'Var', (52, 62))	('bone marrow of EC', 'Disease', 'MESH:D001855', (70, 87))	('CK20', 'Gene', (47, 51))	('bone marrow of EC', 'Disease', (70, 87))	('CK20', 'Gene', '54474', (47, 51))
728333	32824841	Moreover, there was also a correlation by trend between the presence of DTC in bone marrow and recurrence-free survival.	('DTC', 'Chemical', '-', (72, 75))	('recurrence-free survival', 'CPA', (95, 119))	('presence', 'Var', (60, 68))
728335	32824841	Furthermore, the multivariate Cox regression analysis revealed that the presence of CK20 mRNA expression in the bone marrow is an independent prognostic factor for overall survival and tumor-specific survival of EC patients.	('tumor', 'Disease', (185, 190))	('patients', 'Species', '9606', (215, 223))	('presence', 'Var', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('CK20', 'Gene', (84, 88))	('CK20', 'Gene', '54474', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
728337	32824841	Analysis of a sub-collective of 34 patients without lymph node metastases revealed a significant correlation between bone marrow CK20 positivity and overall survival, as well as tumor-specific survival, which was similar to the overall collective.	('tumor', 'Disease', (178, 183))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('overall survival', 'CPA', (149, 165))	('CK20', 'Gene', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('CK20', 'Gene', '54474', (129, 133))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('positivity', 'Var', (134, 144))	('metastases', 'Disease', (63, 73))
728341	32824841	In our patient collective exhibiting CK20 positivity in the bone marrow, only 11 (39.29%) of the 28 stage II patients were treated with neo-adjuvant therapy, while nine (47.37%) of the 19 stage III patients had received neo-adjuvant chemotherapy.	('patient', 'Species', '9606', (109, 116))	('patient', 'Species', '9606', (198, 205))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (198, 206))	('patient', 'Species', '9606', (7, 14))	('positivity', 'Var', (42, 52))	('CK20', 'Gene', (37, 41))	('CK20', 'Gene', '54474', (37, 41))
728347	32824841	These findings coincide with our data, which demonstrate a significant correlation between CK20 positivity in the bone marrow and neo-adjuvant therapy.	('positivity', 'Var', (96, 106))	('CK20', 'Gene', (91, 95))	('CK20', 'Gene', '54474', (91, 95))
728371	32489320	CSEC216 was an uncontaminated cell line, exhibited epithelial cell features with polygonal morphology and adherent growth as monolayer.	('CSEC216', 'CellLine', 'CVCL:E309', (0, 7))	('adherent growth', 'CPA', (106, 121))	('CSEC216', 'Var', (0, 7))
728404	32489320	In this step, cleans data (clean reads) were obtained by removing reads containing adapter, reads containing poly-N and low quality reads from raw data.	('adapter', 'Var', (83, 90))	('poly-N', 'Var', (109, 115))	('poly-N', 'Chemical', '-', (109, 115))
728407	32489320	A significant CNA region was defined as having amplification or deletion with a G-score > 0.1, corresponding to a p-value threshold of 0.05 from the permutation-derived null distribution.	('amplification', 'Var', (47, 60))	('str', 'Gene', '6779', (176, 179))	('str', 'Gene', (176, 179))	('deletion', 'Var', (64, 72))
728429	32489320	AMEL, D5S818, D13S17, D7S820, D16S539, vWA, TH01, TP0X, CSF1PO STR loci were matched with the STR database of ATCC and DSMZ.	('STR', 'Gene', '6779', (63, 66))	('STR', 'Gene', '6779', (94, 97))	('D7S820', 'Var', (22, 28))	('D16S539', 'Var', (30, 37))	('D13S17', 'Var', (14, 20))	('D5S818', 'Var', (6, 12))	('STR', 'Gene', (63, 66))	('STR', 'Gene', (94, 97))	('CSF1', 'Gene', (56, 60))	('CSF1', 'Gene', '1435', (56, 60))
728438	32489320	der (13) t(?8;13)(?;p11)t(?8;?10)(?;?)t(?10;?13)(?;?)t(?8;?13)(?;?).	('p11', 'Gene', '6281', (20, 23))	('p11', 'Gene', (20, 23))	('?;?)t(?8;?13', 'Var', (49, 61))
728453	32489320	Globally, high rate of C > T transition at TpCpX, CpCpX, ApCpG and C > G transversion at TpCpA/C/T trinucleotide were commonly found among cell lines.	('C > G transversion', 'Var', (67, 85))	('C > T', 'Var', (23, 28))	('trinucleotide', 'Chemical', '-', (99, 112))	('TpCpA', 'Chemical', '-', (89, 94))
728465	32489320	39 genes were identified in SNA/INDEL data, TP53 undoubtedly was the most prevalent one, every cell line possessed 1 or 2 mutations in TP53, followed by LRP1B (42.9%), CSMD3 (39.3%), NOTCH1 (35.7%), ZFHX4 (32.143%), NFE2L2 (28.6%) (Fig.	('NOTCH1', 'Gene', '4851', (183, 189))	('NOTCH1', 'Gene', (183, 189))	('ZFHX4', 'Gene', '79776', (199, 204))	('LRP1B', 'Gene', '53353', (153, 158))	('NFE2L2', 'Gene', '4780', (216, 222))	('TP53', 'Gene', '7157', (135, 139))	('NFE2L2', 'Gene', (216, 222))	('TP53', 'Gene', (135, 139))	('mutations', 'Var', (122, 131))	('ZFHX4', 'Gene', (199, 204))	('TP53', 'Gene', '7157', (44, 48))	('LRP1B', 'Gene', (153, 158))	('TP53', 'Gene', (44, 48))	('CSMD3', 'Gene', (168, 173))	('CSMD3', 'Gene', '114788', (168, 173))
728470	32489320	Short tandem repeat profiling is the standard method for authenticating cell lines by using at least eight STR loci and the application of match criteria.	('STR', 'Gene', (107, 110))	('Short tandem repeat', 'Var', (0, 19))	('STR', 'Gene', '6779', (107, 110))
728475	32489320	Previous studies and DSMZ online resources demonstrated that cell lines derived from ESCC harbored frequent chromosome number variation.	('chromosome number variation', 'Var', (108, 135))	('str', 'Gene', '6779', (48, 51))	('str', 'Gene', (48, 51))
728484	32489320	Normal human cells are diploid, but in tumor cells, there are copy number amplified or deleted regions in the genome.	('copy number amplified', 'Var', (62, 83))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('human', 'Species', '9606', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
728485	32489320	Deletions of genome in some cancers could lead to inactivation of cancer suppressor genes like RB1, P16, PTEN, etc.	('cancers', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('inactivation', 'MPA', (50, 62))	('PTEN', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('RB1', 'Gene', (95, 98))	('PTEN', 'Gene', '5728', (105, 109))	('P16', 'Gene', (100, 103))	('RB1', 'Gene', '5925', (95, 98))	('P16', 'Gene', '1029', (100, 103))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('lead', 'Reg', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (28, 34))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('Deletions', 'Var', (0, 9))	('cancer', 'Disease', (66, 72))
728487	32489320	Copy number gain at 3q, 5p, 8q, 12p, 20p, 20q and loss 3p, 4q, 4q, 5q, 9p, 10p, 13q, 18q, 19p, 21q in ESCC cancer cells have been reported in ESCC.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ESCC', 'Disease', (102, 106))	('loss', 'NegReg', (50, 54))	('gain', 'PosReg', (12, 16))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ESCC', 'Disease', (142, 146))	('Copy number', 'Var', (0, 11))	('cancer', 'Disease', (107, 113))
728495	32489320	CSEC216 exhibited hypotriploidy karyotype with complicated chromosomal aberrations.	('hypotriploidy', 'Disease', (18, 31))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (59, 82))	('exhibited', 'Reg', (8, 17))	('hypotriploidy', 'Disease', 'None', (18, 31))	('CSEC216', 'Var', (0, 7))	('CSEC216', 'CellLine', 'CVCL:E309', (0, 7))
728500	32489320	EC Esophageal cancer ESCC Esophageal squamous cell carcinoma PDT Population doubling time IF Immunofluorescence SKY Spectral karyotyping STR Short tandem repeats WGS Whole genome sequencing SNA Single nucleotide alteration INDEL Insertion and deletion CNA Copy number alteration Supplementary information accompanies this paper at 10.1186/s12935-020-01268-x.	('cancer', 'Disease', (14, 20))	('EC', 'Disease', 'MESH:D005955', (0, 2))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('deletion', 'Var', (243, 251))	('DT', 'Chemical', 'MESH:D013936', (62, 64))	('STR', 'Gene', (137, 140))	('squamous cell carcinoma', 'Disease', (37, 60))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 60))	('STR', 'Gene', '6779', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
728506	30744098	In the airway epithelium, increased pendrin expression during inflammatory diseases leads to imbalances in airway surface liquid thickness and mucin release, while, in the esophageal epithelium, dysregulated pendrin expression is supposed to impact the intracellular pH regulation system.	('mucin', 'Gene', '100508689', (143, 148))	('impact', 'Reg', (242, 248))	('mucin', 'Gene', (143, 148))	('pendrin', 'Protein', (208, 215))	('increased', 'PosReg', (26, 35))	('pendrin', 'Protein', (36, 43))	('imbalances', 'Phenotype', 'HP:0002172', (93, 103))	('leads to', 'Reg', (84, 92))	('dysregulated', 'Var', (195, 207))
728522	30744098	Several studies aiming to define the role of STAT6 in allergic asthma highlighted its importance in this pathological condition, since mouse models constitutively expressing STAT6 are prone to allergic phenotypes, while, in contrast, in vivo models lacking this transcription factor are protected from allergy.	('allergic asthma', 'Disease', (54, 69))	('allergic', 'Disease', (193, 201))	('allergy', 'Disease', 'MESH:D004342', (302, 309))	('allergic', 'Disease', 'MESH:D004342', (54, 62))	('prone', 'Reg', (184, 189))	('allergic', 'Disease', (54, 62))	('mouse', 'Species', '10090', (135, 140))	('asthma', 'Phenotype', 'HP:0002099', (63, 69))	('STAT6', 'Var', (174, 179))	('allergy', 'Disease', (302, 309))	('allergic asthma', 'Disease', 'MESH:D004342', (54, 69))	('allergy', 'Phenotype', 'HP:0012393', (302, 309))	('allergic', 'Disease', 'MESH:D004342', (193, 201))
728567	30744098	demonstrated that the ASL layer was thicker in HNE cells from patients with a mutated SLC26A4 compared to controls.	('SLC26A4', 'Gene', (86, 93))	('thicker', 'PosReg', (36, 43))	('SLC26A4', 'Gene', '5172', (86, 93))	('mutated', 'Var', (78, 85))	('patients', 'Species', '9606', (62, 70))
728568	30744098	These results are particularly intriguing, considering that the ion transporter expression pattern in airway epithelia showed no difference between patients carrying the SLC26A4 mutation with respect to controls, except for a decreased CFTR expression.	('decreased', 'NegReg', (226, 235))	('patients', 'Species', '9606', (148, 156))	('SLC26A4', 'Gene', (170, 177))	('mutation', 'Var', (178, 186))	('CFTR expression', 'MPA', (236, 251))	('SLC26A4', 'Gene', '5172', (170, 177))
728572	30744098	This compensatory mechanism regulates the ASL thickness but is lost in patients with mutated pendrin, resulting in an increased accumulation of ASL.	('patients', 'Species', '9606', (71, 79))	('ASL thickness', 'MPA', (42, 55))	('ASL', 'MPA', (144, 147))	('increased accumulation', 'PosReg', (118, 140))	('mutated', 'Var', (85, 92))
728579	30744098	Another study in the same year demonstrated low expression levels of MUC5AC in the nasal epithelium of patients carrying a non-functional pendrin, and no significant changes in mucin expression were seen even following IL-13 stimulation of the nasal epithelial cells coming from the same patients.	('low', 'NegReg', (44, 47))	('mucin', 'Gene', (177, 182))	('expression levels', 'MPA', (48, 65))	('non-functional', 'Var', (123, 137))	('MUC5AC', 'Gene', (69, 75))	('patients', 'Species', '9606', (288, 296))	('MUC5AC', 'Gene', '4586', (69, 75))	('mucin', 'Gene', '100508689', (177, 182))	('patients', 'Species', '9606', (103, 111))
728580	30744098	The same study also revealed that mutations on the pendrin gene leading to a non-functional transporter did not result in IL-13-driven goblet cell hyperplasia in the nasal epithelia, probably a consequence of the lower number of goblet cells in the epithelia of patients carrying a mutation with respect to the controls.	('goblet cell hyperplasia in the nasal epithelia', 'Disease', 'MESH:D002276', (135, 181))	('hyperplasia in the nasal', 'Phenotype', 'HP:0000448', (147, 171))	('goblet cell hyperplasia in the nasal epithelia', 'Disease', (135, 181))	('patients', 'Species', '9606', (262, 270))	('pendrin', 'Gene', (51, 58))	('mutations', 'Var', (34, 43))	('non-functional transporter', 'MPA', (77, 103))
728591	30744098	Here, SCN- reacts with H2O2 produced by dual oxidase 1 (DUOX1) and 2 (DUOX2) leading to OSCN- production.	('DUOX1', 'Gene', (56, 61))	('dual oxidase 1', 'Gene', '53905', (40, 54))	('OSCN', 'Chemical', 'MESH:C014607', (88, 92))	('H2O2', 'Chemical', 'MESH:D006861', (23, 27))	('H2O2', 'Var', (23, 27))	('DUOX2', 'Gene', '50506', (70, 75))	('dual oxidase 1', 'Gene', (40, 54))	('DUOX2', 'Gene', (70, 75))	('OSCN- production', 'MPA', (88, 104))	('DUOX1', 'Gene', '53905', (56, 61))
728617	30744098	In recent years, there was an increased understanding that asthma and COPD, as well as rhinosinusitis and EE, are not simply inflammatory, but also epithelial diseases, since defects in barrier function may increase allergens or pathogens penetration and wall remodeling.	('increase', 'PosReg', (207, 215))	('wall remodeling', 'CPA', (255, 270))	('asthma', 'Disease', (59, 65))	('rhinosinusitis', 'Disease', (87, 101))	('rhinosinusitis', 'Disease', 'None', (87, 101))	('asthma', 'Disease', 'MESH:D001249', (59, 65))	('pathogens penetration', 'CPA', (229, 250))	('sinusitis', 'Phenotype', 'HP:0000246', (92, 101))	('asthma', 'Phenotype', 'HP:0002099', (59, 65))	('COPD', 'Disease', 'MESH:D029424', (70, 74))	('allergens', 'CPA', (216, 225))	('defects', 'Var', (175, 182))	('COPD', 'Disease', (70, 74))
728620	30744098	The fact that overexpression of pendrin alone drives higher mucus formation, AHR, and respiratory neutrophilic infiltration in human airway epithelial cells may support the idea that increased pendrin expression is causing epithelial remodeling even prior to cytokine release, identifying pendrin as a possible primary therapeutic target.	('mucus formation', 'MPA', (60, 75))	('higher', 'PosReg', (53, 59))	('human', 'Species', '9606', (127, 132))	('pendrin', 'Gene', (193, 200))	('respiratory neutrophilic infiltration', 'Disease', 'MESH:D012131', (86, 123))	('epithelial remodeling', 'Disease', (223, 244))	('AHR', 'CPA', (77, 80))	('respiratory neutrophilic infiltration', 'Disease', (86, 123))	('causing', 'Reg', (215, 222))	('increased', 'Var', (183, 192))
728631	30744098	In the airways, increased pendrin expression is linked to diseases such as asthma, COPD, rhinitis, chronic rhinosinusitis, and pertussis, where it dysregulates the ASL thickness, induces mucus production, and initiates the inflammatory process via OSCN-.	('expression', 'MPA', (34, 44))	('pertussis', 'Disease', (127, 136))	('asthma', 'Disease', 'MESH:D001249', (75, 81))	('rhinitis', 'Disease', 'MESH:D012220', (89, 97))	('rhinitis', 'Phenotype', 'HP:0012384', (89, 97))	('linked', 'Reg', (48, 54))	('asthma', 'Phenotype', 'HP:0002099', (75, 81))	('inflammatory process', 'CPA', (223, 243))	('COPD', 'Disease', 'MESH:D029424', (83, 87))	('COPD', 'Disease', (83, 87))	('sinusitis', 'Phenotype', 'HP:0000246', (112, 121))	('asthma', 'Disease', (75, 81))	('dysregulates', 'Var', (147, 159))	('rhinitis', 'Disease', (89, 97))	('mucus production', 'MPA', (187, 203))	('chronic rhinosinusitis', 'Disease', (99, 121))	('induces', 'PosReg', (179, 186))	('OSCN', 'Chemical', 'MESH:C014607', (248, 252))	('increased', 'PosReg', (16, 25))	('initiates', 'Reg', (209, 218))	('chronic rhinosinusitis', 'Disease', 'MESH:D006505', (99, 121))	('pendrin', 'Protein', (26, 33))
728636	30615636	The post-CRT FDG PET of 114 patients with esophageal squamous cell carcinoma (ESCC) were independently interpreted using a qualitative 4-point scale (Qual4PS) that identified focal esophageal FDG uptake greater than liver uptake as residual tumor.	('Qual4PS', 'Chemical', '-', (150, 157))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (42, 76))	('tumor', 'Disease', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('esophageal squamous cell carcinoma', 'Disease', (42, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('FDG', 'Chemical', 'MESH:D019788', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('FDG', 'Chemical', 'MESH:D019788', (192, 195))	('patients', 'Species', '9606', (28, 36))	('focal', 'Var', (175, 180))
728643	30615636	The 2-year OS rates of Qual4PS(-) patients undergoing CRT alone (68.4%) and patients undergoing trimodality therapy (62.5%) were not significant different, but the 2-year OS rates of Qual4PS(+) patients undergoing CRT alone (10.0%) were significantly lower than in patients undergoing trimodality therapy (42.1%).	('patients', 'Species', '9606', (76, 84))	('OS', 'Chemical', '-', (11, 13))	('patients', 'Species', '9606', (194, 202))	('Qual4PS', 'Chemical', '-', (23, 30))	('lower', 'NegReg', (251, 256))	('trimodality', 'Chemical', '-', (96, 107))	('patients', 'Species', '9606', (265, 273))	('patients', 'Species', '9606', (34, 42))	('trimodality', 'Chemical', '-', (285, 296))	('Qual4PS(+', 'Var', (183, 192))	('Qual4PS', 'Chemical', '-', (183, 190))	('OS', 'Chemical', '-', (171, 173))
728678	30615636	DeltaSUVmax71.6% and DeltaSUVmax50% used relative reduction of SUVmax cut-off values in the primary tumor between pre- and post-CRT FDG PET scans.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('DeltaSUVmax50', 'Var', (21, 34))	('reduction', 'NegReg', (50, 59))	('tumor', 'Disease', (100, 105))	('FDG', 'Chemical', 'MESH:D019788', (132, 135))	('SUVmax cut-off values', 'MPA', (63, 84))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
728680	30615636	The cut-off value of DeltaSUVmax 71.6%, SUVmean 2.4, MV 2.2, and TLG 4.99 was the median data of the primary tumor in our patients.	('DeltaSUVmax', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('patients', 'Species', '9606', (122, 130))	('TLG', 'Chemical', '-', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
728704	30615636	Univariable Cox regression analysis identified AJCC stage, and post-CRT FDG PET using the Qual4PS, SUVmax3.4, DeltaSUVmax71.6%, DeltaSUVmax50%, SUVmean2.4, and MV2.2, cut-offs as significant predictors of OS (Table 3).	('DeltaSUVmax50', 'Var', (128, 141))	('DeltaSUVmax71.6', 'Var', (110, 125))	('OS', 'Chemical', '-', (205, 207))	('FDG', 'Chemical', 'MESH:D019788', (72, 75))	('Qual4PS', 'Chemical', '-', (90, 97))	('Cox', 'Gene', '1351', (12, 15))	('Cox', 'Gene', (12, 15))
728707	30615636	The 2-year OS rates were 68.4% for the Qual4PS(-)/dCRT group, 62.5% for the Qual4PS(-)/trimodality group, 42.1% for the Qual4PS(+)/trimodality group, and 10.0% for the Qual4PS(+)/dCRT group.	('trimodality', 'Chemical', '-', (131, 142))	('Qual4PS', 'Chemical', '-', (39, 46))	('Qual4PS', 'Var', (39, 46))	('OS', 'Chemical', '-', (11, 13))	('Qual4PS', 'Chemical', '-', (120, 127))	('Qual4PS', 'Chemical', '-', (168, 175))	('dCRT', 'Chemical', '-', (50, 54))	('dCRT', 'Chemical', '-', (179, 183))	('trimodality', 'Chemical', '-', (87, 98))	('Qual4PS', 'Chemical', '-', (76, 83))	('Qual4PS', 'Var', (76, 83))
728709	30615636	The Qual4PS(-)/trimodality group had a nonsignificantly higher survival rate than did the Qual4PS(+)/trimodality group.	('trimodality', 'Chemical', '-', (15, 26))	('survival', 'CPA', (63, 71))	('Qual4PS', 'Chemical', '-', (90, 97))	('Qual4PS', 'Chemical', '-', (4, 11))	('Qual4PS(-)/trimodality', 'Var', (4, 26))	('higher', 'PosReg', (56, 62))	('trimodality', 'Chemical', '-', (101, 112))
728710	30615636	The Qual4PS(+)/dCRT group had a significantly lower survival rate than did the other three groups (Fig 5a).	('survival rate', 'CPA', (52, 65))	('lower', 'NegReg', (46, 51))	('dCRT', 'Chemical', '-', (15, 19))	('Qual4PS', 'Chemical', '-', (4, 11))	('Qual4PS(+)/dCRT', 'Var', (4, 19))
728721	30615636	qualitatively defined PET-CR as a decreased FDG uptake to a level indistinguishable from that of the surrounding normal tissue.	('FDG uptake', 'MPA', (44, 54))	('PET-CR', 'Var', (22, 28))	('FDG', 'Chemical', 'MESH:D019788', (44, 47))	('decreased', 'NegReg', (34, 43))
728723	30615636	In this study, we also tested (a) the adjusted cut-off of SUVmax3.4, because of its optimal ability to detect post-CRT viable residual tumors in our institution, and (b) the adjusted cut-off of DeltaSUVmax 71.6%, which was the median reduction value in this cohort.	('SUVmax3.4', 'Gene', (58, 67))	('DeltaSUVmax', 'Var', (194, 205))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
728750	29514673	In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth.	('hypoxic tumor', 'Disease', (194, 207))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('Ki67', 'Chemical', '-', (215, 219))	('tumor', 'Disease', (202, 207))	('nimorazole', 'Chemical', 'MESH:D009554', (29, 39))	('tumor', 'Disease', (264, 269))	('decreased hypoxic', 'Disease', (54, 71))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('decreased hypoxic', 'Disease', 'MESH:D000860', (54, 71))	('cancer', 'Disease', (165, 171))	('enhanced', 'PosReg', (125, 133))	('nimorazole', 'Chemical', 'MESH:D009554', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('nimorazole', 'Var', (114, 124))	('suppress', 'NegReg', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('hypoxic tumor', 'Disease', 'MESH:D009369', (194, 207))
728762	29514673	The tracer entrapment is based on a reduction of the NO2-group followed by continued reduction under hypoxic conditions and eventually covalent binding to intracellular macromolecules.	('binding', 'Interaction', (144, 151))	('NO2', 'Chemical', 'MESH:D009585', (53, 56))	('reduction', 'NegReg', (36, 45))	('hypoxic conditions', 'Disease', 'MESH:D009135', (101, 119))	('reduction', 'NegReg', (85, 94))	('hypoxic conditions', 'Disease', (101, 119))	('NO2-group', 'Var', (53, 62))
728829	29514673	As it is known that fractionation causes tumor cell reoxygenation, the RT regimen itself could have radiosensitizing effects, minimizing the effect of nimorazole.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('oxygen', 'Chemical', 'MESH:D010100', (54, 60))	('causes', 'Reg', (34, 40))	('tumor', 'Disease', (41, 46))	('radiosensitizing effects', 'MPA', (100, 124))	('minimizing', 'NegReg', (126, 136))	('nimorazole', 'Chemical', 'MESH:D009554', (151, 161))	('fractionation', 'Var', (20, 33))	('nimorazole', 'MPA', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
728969	22221634	We used the International Classification of Diseases 9th edition (ICD-9) to categorize cancer types as follows: head and neck (140-149, 160, 161), esophagus (150), colorectal (153, 154), non-small cell lung cancer (162), malignant melanoma (172) and lymphoma (200-202).	('esophagus', 'Disease', (147, 156))	('non-small cell lung cancer', 'Disease', (187, 213))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('lymphoma', 'Phenotype', 'HP:0002665', (250, 258))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('colorectal', 'Disease', 'MESH:D015179', (164, 174))	('malignant melanoma', 'Disease', (221, 239))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (187, 213))	('lymphoma', 'Disease', (250, 258))	('cancer', 'Disease', (87, 93))	('153', 'Var', (176, 179))	('lymphoma', 'Disease', 'MESH:D008223', (250, 258))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (191, 213))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('malignant melanoma', 'Phenotype', 'HP:0002861', (221, 239))	('colorectal', 'Disease', (164, 174))	('malignant melanoma', 'Disease', 'MESH:D008545', (221, 239))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (187, 213))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('140-149', 'Var', (127, 134))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
729044	22221634	Whether PET is associated with superior patient outcomes and impacts overall costs will require either studies that measure changes in major decision points along a cancer's natural history or studies that directly measure outcomes.	('patient', 'Species', '9606', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('costs', 'MPA', (77, 82))	('PET', 'Var', (8, 11))	('superior', 'PosReg', (31, 39))
729113	33649858	The present study revealed that MLT significantly inhibited cell activity in a dose-dependent manner and MLT significantly enhanced 5-FU-mediated inhibition of cell proliferation in esophageal cancer cells.	('enhanced', 'PosReg', (123, 131))	('MLT', 'Gene', (105, 108))	('5-FU-mediated inhibition', 'MPA', (132, 156))	('MLT', 'Chemical', 'MESH:D008550', (32, 35))	('MLT', 'Chemical', 'MESH:D008550', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('5-FU', 'Chemical', 'MESH:D005472', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cell activity', 'CPA', (60, 73))	('MLT', 'Var', (32, 35))	('inhibited', 'NegReg', (50, 59))
729115	33649858	The present study also revealed that MLT and 5-FU synergistically promoted apoptosis via activation of the caspase-dependent apoptosis pathway.	('MLT', 'Var', (37, 40))	('MLT', 'Chemical', 'MESH:D008550', (37, 40))	('apoptosis', 'CPA', (75, 84))	('5-FU', 'Chemical', 'MESH:D005472', (45, 49))	('caspase-dependent apoptosis pathway', 'Pathway', (107, 142))	('activation', 'PosReg', (89, 99))	('promoted', 'PosReg', (66, 74))
729163	33649858	Samples were incubated at 4 C overnight with the following primary antibodies: Anti-Bcl-2 (1:500; product code ab32124), anti-Mcl-1 (1:500; product code ab32087), and anti-caspase-3 (1:500; product code ab32351; all from Abcam).	('caspase-3', 'Gene', '836', (172, 181))	('Mcl-1', 'Gene', (126, 131))	('Bcl-2', 'Gene', (84, 89))	('Bcl-2', 'Gene', '596', (84, 89))	('Mcl-1', 'Gene', '4170', (126, 131))	('caspase-3', 'Gene', (172, 181))	('1:500;', 'Var', (133, 139))
729187	33649858	To further investigate the roles of EZH2 in EC, two EZH2 siRNAs were designed to knockdown EZH2.	('EZH2', 'Gene', (91, 95))	('EZH2', 'Gene', '2146', (91, 95))	('EZH2', 'Gene', (52, 56))	('EZH2', 'Gene', '2146', (52, 56))	('knockdown', 'Var', (81, 90))	('EZH2', 'Gene', '2146', (36, 40))	('EZH2', 'Gene', (36, 40))
729189	33649858	Next, the present study further investigated the effects of silencing EZH2 expression on the biological function in EC.	('EZH2', 'Gene', (70, 74))	('EZH2', 'Gene', '2146', (70, 74))	('silencing', 'Var', (60, 69))
729190	33649858	CCK-8 assays revealed that EZH2 knockdown significantly inhibited cell proliferation of EC-9706 and EC-109 cells (Fig.	('EZH2', 'Gene', (27, 31))	('EZH2', 'Gene', '2146', (27, 31))	('cell proliferation', 'CPA', (66, 84))	('EC-109', 'CellLine', 'CVCL:6898', (100, 106))	('knockdown', 'Var', (32, 41))	('EC-9706', 'CellLine', 'CVCL:E307', (88, 95))	('inhibited', 'NegReg', (56, 65))	('CCK-8', 'Chemical', '-', (0, 5))
729191	33649858	Transwell assays revealed that EZH2 knockdown significantly inhibited cell invasion and migration of EC-9706 and EC-109 cells (Fig.	('EC-9706', 'CellLine', 'CVCL:E307', (101, 108))	('EZH2', 'Gene', '2146', (31, 35))	('cell invasion', 'CPA', (70, 83))	('inhibited', 'NegReg', (60, 69))	('knockdown', 'Var', (36, 45))	('EZH2', 'Gene', (31, 35))	('migration', 'CPA', (88, 97))	('EC-109', 'CellLine', 'CVCL:6898', (113, 119))
729192	33649858	However, silencing of EZH2 expression significantly promoted apoptosis in EC-9706 and EC-109 cells (Fig.	('apoptosis', 'CPA', (61, 70))	('EZH2', 'Gene', (22, 26))	('silencing', 'Var', (9, 18))	('EC-109', 'CellLine', 'CVCL:6898', (86, 92))	('EC-9706', 'CellLine', 'CVCL:E307', (74, 81))	('promoted', 'PosReg', (52, 60))	('EZH2', 'Gene', '2146', (22, 26))
729218	33649858	Although no study has demonstrated that MLT increases 5-FU sensitivity in EC cells, a study has revealed that MLT enhanced 5-FU sensitivity and inhibited tumor cell growth in colorectal cancer cells.	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('5-FU', 'Chemical', 'MESH:D005472', (123, 127))	('MLT', 'Chemical', 'MESH:D008550', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('5-FU sensitivity', 'MPA', (123, 139))	('colorectal cancer', 'Disease', (175, 192))	('inhibited', 'NegReg', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('enhanced', 'PosReg', (114, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('MLT', 'Var', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('5-FU', 'Chemical', 'MESH:D005472', (54, 58))	('MLT', 'Chemical', 'MESH:D008550', (110, 113))	('tumor', 'Disease', (154, 159))
729224	33649858	Wang et al revealed that EZH2 contributed to 5-FU resistance in gastric cancer by epigenetically suppressing F-box protein 32 expression.	('EZH2', 'Gene', '2146', (25, 29))	('expression', 'MPA', (126, 136))	('EZH2', 'Gene', (25, 29))	('epigenetically', 'Var', (82, 96))	('5-FU', 'Chemical', 'MESH:D005472', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gastric cancer', 'Disease', (64, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('5-FU resistance', 'MPA', (45, 60))	('suppressing', 'NegReg', (97, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))	('F-box protein', 'Protein', (109, 122))
729275	32252671	When comparing the highest with the lowest categories, dietary folate intake was associated with a reduced risk of esophageal cancer-specific mortality in patients with esophageal squamous cell carcinoma (HR: 0.41, 95% CI: 0.25-0.69), with low heterogeneity (I2 = 0%, P = 0.788).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('dietary', 'Var', (55, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('folate', 'Chemical', 'MESH:D005492', (63, 69))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (169, 203))	('esophageal cancer', 'Disease', (115, 132))	('mortality', 'Disease', 'MESH:D003643', (142, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('patients', 'Species', '9606', (155, 163))	('reduced', 'NegReg', (99, 106))	('esophageal squamous cell carcinoma', 'Disease', (169, 203))	('mortality', 'Disease', (142, 151))
729276	32252671	When comparing the highest with the lowest categories of alcohol consumption, alcohol consumption was associated with an increased risk of all-cause mortality in patients with esophageal squamous cell carcinoma (HR: 1.29, 95% CI: 1.07-1.55; heterogeneity: I2 = 53%, P = 0.030), but this increased risk was not significant in patients with esophageal adenocarcinoma (HR = 1.05, 95% CI: 0.84-1.32).	('carcinoma', 'Phenotype', 'HP:0030731', (355, 364))	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (325, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('alcohol', 'Chemical', 'MESH:D000438', (78, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('mortality', 'Disease', (149, 158))	('alcohol', 'Chemical', 'MESH:D000438', (57, 64))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (339, 364))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (176, 210))	('alcohol consumption', 'Var', (78, 97))	('esophageal adenocarcinoma', 'Disease', (339, 364))	('esophageal squamous cell carcinoma', 'Disease', (176, 210))	('mortality', 'Disease', 'MESH:D003643', (149, 158))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (339, 364))
729277	32252671	This review with pre-diagnostic dietary exposure showed that dietary folate intake was associated with a reduced risk of mortality of esophageal squamous cell carcinoma, whereas alcohol consumption was associated with an increased risk.	('mortality', 'Disease', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('esophageal squamous cell carcinoma', 'Disease', (134, 168))	('alcohol', 'Chemical', 'MESH:D000438', (178, 185))	('folate', 'Chemical', 'MESH:D005492', (69, 75))	('reduced', 'NegReg', (105, 112))	('mortality', 'Disease', 'MESH:D003643', (121, 130))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (134, 168))	('dietary', 'Var', (61, 68))
729316	32252671	The pooled results in our study showed that pre-diagnostic alcohol consumption could increase risk of mortality among EC and ESCC patients by 48 and 29% respectively; however, this effect was not found in EAC patients.	('mortality', 'Disease', 'MESH:D003643', (102, 111))	('mortality', 'Disease', (102, 111))	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (209, 217))	('alcohol', 'Chemical', 'MESH:D000438', (59, 66))	('pre-diagnostic', 'Var', (44, 58))	('EAC', 'Phenotype', 'HP:0011459', (205, 208))	('ESCC', 'Disease', (125, 129))
729336	32252671	In summary, this review with limited evidence suggested that folate intake was associated with a reduced risk of esophageal cancer-specific mortality for ESCC, whereas alcohol consumption was associated with increased risk of mortality for ESCC.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('mortality', 'Disease', 'MESH:D003643', (226, 235))	('mortality', 'Disease', 'MESH:D003643', (140, 149))	('ESCC', 'Disease', (154, 158))	('reduced', 'NegReg', (97, 104))	('alcohol', 'Chemical', 'MESH:D000438', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mortality', 'Disease', (226, 235))	('mortality', 'Disease', (140, 149))	('folate', 'Var', (61, 67))	('esophageal cancer', 'Disease', (113, 130))	('folate', 'Chemical', 'MESH:D005492', (61, 67))
729752	11394425	As a matter of fact, symptoms are caused either by pathological refluxes or by abnormal sensitivity of esophageal mucosa, or by both.	('refluxes', 'MPA', (64, 72))	('abnormal', 'Var', (79, 87))	('esophageal mucosa', 'Disease', (103, 120))	('symptoms', 'Disease', (21, 29))	('esophageal mucosa', 'Disease', 'MESH:D004941', (103, 120))	('caused', 'Reg', (34, 40))	('sensitivity', 'MPA', (88, 99))
729809	11394425	Transient dysphagia is common after fundoplications, especially after a total one.	('fundoplications', 'Var', (36, 51))	('dysphagia', 'Disease', (10, 19))	('dysphagia', 'Phenotype', 'HP:0002015', (10, 19))	('dysphagia', 'Disease', 'MESH:D003680', (10, 19))
730063	31466948	Several taxa were increased in the HGD/EAC subjects, notably in Enterobacteriaceae and Verrucomicrobiaceae, specifically Akkermansia muciniphila.	('Verrucomicrobiaceae', 'Disease', (87, 106))	('increased', 'PosReg', (18, 27))	('EAC', 'Phenotype', 'HP:0011459', (39, 42))	('Enterobacteriaceae', 'Disease', (64, 82))	('Akkermansia muciniphila', 'Species', '239935', (121, 144))	('HGD/EAC', 'Var', (35, 42))	('Akkermansia muciniphila', 'Disease', (121, 144))
730090	31466948	In this fashion, the presence of A. muciniphila could conceivably lead to increased Barrett's tissue inflammation and promote progression to EAC.	('EAC', 'Disease', (141, 144))	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('A. muciniphila', 'Species', '239935', (33, 47))	('inflammation', 'Disease', (101, 113))	('increased', 'PosReg', (74, 83))	('EAC', 'Phenotype', 'HP:0011459', (141, 144))	('presence', 'Var', (21, 29))	('promote', 'PosReg', (118, 125))
730109	30314310	On the other hand, the genetic and epigenetic alterations underlying the cancerogenesis process inevitably modify the tissue homeostasis and may induce a chronic inflammatory response.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('rat', 'Species', '10116', (50, 53))	('tissue homeostasis', 'MPA', (118, 136))	('induce', 'Reg', (145, 151))	('chronic inflammatory response', 'CPA', (154, 183))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('modify', 'Reg', (107, 113))	('epigenetic alterations', 'Var', (35, 57))
730124	30314310	Tumor cells are often characterized by COX-2 aberrant expression, resulting from transcriptional and/or post-transcriptional alterations and contributing to tumor diseases, such as in colorectal cancer.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor diseases', 'Disease', (157, 171))	('colorectal cancer', 'Disease', 'MESH:D015179', (184, 201))	('COX-2', 'Gene', (39, 44))	('alterations', 'Var', (125, 136))	('rat', 'Species', '10116', (129, 132))	('aberrant expression', 'Var', (45, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (184, 201))	('transcriptional', 'MPA', (81, 96))	('tumor diseases', 'Disease', 'MESH:D009369', (157, 171))	('COX-2', 'Gene', '5743', (39, 44))	('contributing to', 'Reg', (141, 156))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('colorectal cancer', 'Disease', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('resulting', 'Reg', (66, 75))
730125	30314310	Importantly, the tumor-associated aberrant expression of COX-2 is often related to epigenetic alterations affecting COX-2 gene (PTGS2) as well as other genes involved into biosynthesis and signaling of its main prostaglandin products.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('epigenetic alterations', 'Var', (83, 105))	('tumor', 'Disease', (17, 22))	('aberrant', 'Var', (34, 42))	('COX-2', 'Gene', (57, 62))	('rat', 'Species', '10116', (98, 101))	('related', 'Reg', (72, 79))	('PTGS2', 'Gene', (128, 133))	('COX-2', 'Gene', (116, 121))	('PTGS2', 'Gene', '5743', (128, 133))	('expression', 'MPA', (43, 53))	('COX-2', 'Gene', '5743', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('prostaglandin', 'Chemical', 'MESH:D011453', (211, 224))	('COX-2', 'Gene', '5743', (116, 121))
730131	30314310	However, increased levels of COX-1 expression have been occasionally reported in several cancers, and it has been shown that the genetic disruption of COX-1 is as effective as COX-2 disruption in reducing intestinal and skin tumorigenesis in mouse models, thus suggesting that both COX isoforms could cooperate in the cancerogenesis process.	('cancer', 'Disease', (318, 324))	('COX-2', 'Gene', '5743', (176, 181))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumor', 'Disease', (225, 230))	('cancer', 'Disease', (89, 95))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('reducing', 'NegReg', (196, 204))	('COX-1', 'Gene', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('mouse', 'Species', '10090', (242, 247))	('COX-2', 'Gene', (176, 181))	('rat', 'Species', '10116', (306, 309))	('genetic disruption', 'Var', (129, 147))
730135	30314310	The pathophysiological relevance of COX-2 in renal cell carcinoma (RCC) is generally acknowledged, and recently, it has been shown that COX-2 inhibition enhances the efficacy of immunotherapy and tyrosine kinase inhibitor-based treatment.	('enhances', 'PosReg', (153, 161))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (45, 65))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (45, 65))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('COX-2', 'Gene', (36, 41))	('efficacy', 'CPA', (166, 174))	('immunotherapy', 'CPA', (178, 191))	('COX-2', 'Gene', (136, 141))	('COX-2', 'Gene', '5743', (136, 141))	('COX-2', 'Gene', '5743', (36, 41))	('inhibition', 'Var', (142, 152))	('renal cell carcinoma', 'Disease', (45, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
730159	30314310	Interestingly, experimental mouse studies using genetic disruption of COX-1 or COX-2 plus Apc genes already 15 years ago suggested that both isoforms were involved in intestinal polyp formation.	('COX-2', 'Gene', '5743', (79, 84))	('mouse', 'Species', '10090', (28, 33))	('COX-1', 'Gene', (70, 75))	('intestinal polyp', 'Phenotype', 'HP:0005266', (167, 183))	('intestinal polyp', 'Disease', (167, 183))	('involved', 'Reg', (155, 163))	('Apc genes', 'Gene', (90, 99))	('COX-2', 'Gene', (79, 84))	('genetic disruption', 'Var', (48, 66))
730170	30314310	Moreover, induction of cell growth arrest and apoptosis are induced in MCF-7 human breast cell line in vitro by the COX-1 inhibitor FR122047, and additive effects on tumor cell growth by COX-1 and COX-2 inhibitors are induced in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('apoptosis', 'CPA', (46, 55))	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('growth arrest', 'Phenotype', 'HP:0001510', (28, 41))	('induced', 'Reg', (60, 67))	('FR122047', 'Var', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('COX-2', 'Gene', (197, 202))	('arrest', 'Disease', (35, 41))	('COX-2', 'Gene', '5743', (197, 202))	('FR122047', 'Chemical', 'MESH:C085131', (132, 140))	('MCF-7', 'CellLine', 'CVCL:0031', (71, 76))	('human', 'Species', '9606', (77, 82))
730190	30314310	Accordingly, the expression of COX-1 is higher in ovarian cancer patients with low CD8+ (cytotoxic T cells) and high CD1a+ (dendritic cells) cell density than in those with high CD8+ cell density, and COX-1 overexpression is the characterizing element in a cluster of ovarian cancer patients in which the poor prognosis is associated with an immunosuppressive status.	('CD1a', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('higher', 'PosReg', (40, 46))	('CD8', 'Gene', (178, 181))	('high', 'Var', (112, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (268, 282))	('CD8', 'Gene', (83, 86))	('ovarian cancer', 'Disease', 'MESH:D010051', (50, 64))	('cluster of ovarian cancer', 'Disease', (257, 282))	('patients', 'Species', '9606', (283, 291))	('expression', 'MPA', (17, 27))	('CD8', 'Gene', '925', (178, 181))	('CD1a', 'Gene', '909', (117, 121))	('COX-1', 'Gene', (31, 36))	('ovarian cancer', 'Disease', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('patients', 'Species', '9606', (65, 73))	('ovarian cancer', 'Disease', 'MESH:D010051', (268, 282))	('CD8', 'Gene', '925', (83, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (50, 64))	('cluster of ovarian cancer', 'Disease', 'MESH:D010051', (257, 282))
730195	30314310	Importantly, genetic knockdown of COX-1 in ovarian cancer cell lines resulted in down-regulation of both PG signaling and multiple pro-tumorigenic pathways, thus strongly encouraging further development of methods to selectively target COX-1 in the management of HGSOC tumors.	('COX-1', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('ovarian cancer', 'Disease', 'MESH:D010051', (43, 57))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('ovarian cancer', 'Disease', (43, 57))	('PG signaling', 'Pathway', (105, 117))	('tumor', 'Disease', (135, 140))	('down-regulation', 'NegReg', (81, 96))	('tumor', 'Disease', (269, 274))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', (269, 275))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('knockdown', 'Var', (21, 30))	('ovarian cancer', 'Phenotype', 'HP:0100615', (43, 57))	('PG', 'Chemical', 'MESH:D011453', (105, 107))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
730215	30314310	Interestingly, the central enzymes involved in the synthesis of MSC-derived chemoprotective factors are COX-1 and thromboxane synthase, thus suggesting that enzyme inhibition could restore cancer cell sensitivity.	('thromboxane', 'Chemical', 'MESH:D013931', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('inhibition', 'Var', (164, 174))	('restore', 'PosReg', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
730227	30314310	Based upon a peculiar histopathological pattern showing elevated levels of COX-1 (not COX-2) in the epithelial compartment of ovarian tumor tissue undergoing extensive angiogenesis, the pharmacological action of SC-560 in ovarian cancer models was first investigated by Gupta R.A. et al.. On ovarian cancer cell lines characterized for COX isoforms expression and activity, SC-560 showed in vitro antiproliferative effects similar to those of indomethacin and celecoxib (non-COX isoform selective and COX-2-selective, respectively), and only at doses 50-100 times greater than those achieved in in vivo systems.	('antiproliferative effects', 'CPA', (397, 422))	('SC-560', 'Chemical', 'MESH:C115461', (212, 218))	('COX-2', 'Gene', (501, 506))	('ovarian cancer', 'Phenotype', 'HP:0100615', (292, 306))	('ovarian tumor', 'Phenotype', 'HP:0100615', (126, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('COX-2', 'Gene', (86, 91))	('COX-2', 'Gene', '5743', (501, 506))	('indomethacin', 'Chemical', 'MESH:D007213', (443, 455))	('SC-560', 'Chemical', 'MESH:C115461', (374, 380))	('SC-560', 'Var', (374, 380))	('COX-2', 'Gene', '5743', (86, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (222, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('ovarian tumor', 'Disease', (126, 139))	('celecoxib', 'Chemical', 'MESH:D000068579', (460, 469))	('ovarian cancer', 'Disease', 'MESH:D010051', (292, 306))	('rat', 'Species', '10116', (408, 411))	('ovarian tumor', 'Disease', 'MESH:D010051', (126, 139))	('ovarian cancer', 'Disease', (222, 236))	('ovarian cancer', 'Disease', (292, 306))	('ovarian cancer', 'Phenotype', 'HP:0100615', (222, 236))
730238	30314310	Moreover, it cannot be excluded that in in vivo systems SC-560 could inhibit also COX-2, and that COX-independent effects could contribute to antitumor activity.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('COX-2', 'Gene', (82, 87))	('SC-560', 'Chemical', 'MESH:C115461', (56, 62))	('SC-560', 'Var', (56, 62))	('COX-2', 'Gene', '5743', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('inhibit', 'NegReg', (69, 76))	('contribute', 'Reg', (128, 138))
730240	30314310	Interestingly, SC-560 increases also paclitaxel sensitivity of taxane-resistant ovarian cancer cell lines characterized by MDR1/P-glycoprotein upregulation.	('ovarian cancer', 'Disease', (80, 94))	('taxane', 'Chemical', 'MESH:C080625', (63, 69))	('MDR1', 'Gene', (123, 127))	('P-glycoprotein', 'Gene', '5243', (128, 142))	('P-glycoprotein', 'Gene', (128, 142))	('paclitaxel', 'Chemical', 'MESH:D017239', (37, 47))	('paclitaxel sensitivity', 'MPA', (37, 59))	('MDR1', 'Gene', '5243', (123, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('upregulation', 'PosReg', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('increases', 'PosReg', (22, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('SC-560', 'Chemical', 'MESH:C115461', (15, 21))	('SC-560', 'Var', (15, 21))
730241	30314310	A similar effect was produced by the COX-2 selective inhibitor NS398, not modified by PGE2 addition, thus suggesting a prostaglandin- and COX-independent mechanism.	('NS398', 'Var', (63, 68))	('prostaglandin', 'Chemical', 'MESH:D011453', (119, 132))	('COX-2', 'Gene', (37, 42))	('COX-2', 'Gene', '5743', (37, 42))	('PGE2', 'Chemical', 'MESH:D015232', (86, 90))	('NS398', 'Chemical', 'MESH:C080955', (63, 68))
730245	30314310	Independently from COX status, both SC-560 and celecoxib affected in vitro cell survival and induced a G0/G1 block, whereas only celecoxib induced apoptosis.	('affected', 'Reg', (57, 65))	('celecoxib', 'Chemical', 'MESH:D000068579', (47, 56))	('G0/G1 block', 'CPA', (103, 114))	('celecoxib', 'Chemical', 'MESH:D000068579', (129, 138))	('SC-560', 'Chemical', 'MESH:C115461', (36, 42))	('SC-560', 'Var', (36, 42))	('induced', 'Reg', (93, 100))
730252	30314310	Interestingly, two cancer-related genes, NAG-1 (officially known as GDF15), and thymosin beta-4 (TMSB4X), were induced by SC-560, thus suggesting potentially contrasting effects on its antitumor activity.	('tumor', 'Disease', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('NAG-1', 'Gene', '9518', (41, 46))	('thymosin beta-4', 'Gene', '7114', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('GDF15', 'Gene', (68, 73))	('cancer', 'Disease', (19, 25))	('thymosin beta-4', 'Gene', (80, 95))	('TMSB4X', 'Gene', '7114', (97, 103))	('induced', 'PosReg', (111, 118))	('GDF15', 'Gene', '9518', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('TMSB4X', 'Gene', (97, 103))	('SC-560', 'Var', (122, 128))	('NAG-1', 'Gene', (41, 46))	('SC-560', 'Chemical', 'MESH:C115461', (122, 128))
730258	30314310	Interestingly, the growth suppression induced by SC-560, but not celecoxib treatment, was associated with reactive oxygen species production.	('reactive oxygen species production', 'MPA', (106, 140))	('SC-560', 'Var', (49, 55))	('celecoxib', 'Chemical', 'MESH:D000068579', (65, 74))	('suppression', 'NegReg', (26, 37))	('SC-560', 'Chemical', 'MESH:C115461', (49, 55))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (106, 129))	('growth', 'CPA', (19, 25))
730261	30314310	From a mechanistic point of view, treatment of tumor cells with SC-560, as well as with the coxib CAY10404, was associated with activation of ERK1/2 signaling pathway.	('activation', 'PosReg', (128, 138))	('SC-560', 'Chemical', 'MESH:C115461', (64, 70))	('SC-560', 'Var', (64, 70))	('CAY10404', 'Chemical', 'MESH:C501048', (98, 106))	('ERK1/2', 'Gene', (142, 148))	('ERK1/2', 'Gene', '5595;5594', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
730268	30314310	Besides inhibiting preneoplastic lesions, mofezolac significantly reduces the incidence, multiplicity and volume of azoxymethane-induced rat colon carcinomas, thus confirming the COX-1 pathophysiological role in the AOM-induced intestinal carcinogenesis.	('incidence', 'CPA', (78, 87))	('colon carcinomas', 'Disease', (141, 157))	('AOM', 'Chemical', 'MESH:D001397', (216, 219))	('carcinogenesis', 'Disease', 'MESH:D063646', (239, 253))	('reduces', 'NegReg', (66, 73))	('azoxymethane', 'Chemical', 'MESH:D001397', (116, 128))	('carcinogenesis', 'Disease', (239, 253))	('colon carcinomas', 'Disease', 'MESH:D015179', (141, 157))	('rat', 'Species', '10116', (137, 140))	('mofezolac', 'Chemical', 'MESH:C054999', (42, 51))	('mofezolac', 'Var', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
730272	30314310	The antitumor activity of FR122047 has been investigated in vitro on MCF-7 breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('FR122047', 'Chemical', 'MESH:C085131', (26, 34))	('MCF-7', 'CellLine', 'CVCL:0031', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('FR122047', 'Var', (26, 34))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
730273	30314310	FR122047 treatment inhibits in vitro cell growth of MCF-7 cells, and induces apoptotic cell death that is mechanistically independent from treatment-associated ROS production, as well as from PGE2 production inhibition.	('PGE2', 'Chemical', 'MESH:D015232', (192, 196))	('FR122047', 'Chemical', 'MESH:C085131', (0, 8))	('apoptotic cell death', 'CPA', (77, 97))	('induces', 'Reg', (69, 76))	('MCF-7', 'CellLine', 'CVCL:0031', (52, 57))	('ROS', 'Chemical', 'MESH:D017382', (160, 163))	('inhibits', 'NegReg', (19, 27))	('FR122047', 'Var', (0, 8))
730274	30314310	Mechanisms of MCF-7 cell death induced by FR12207 were further investigated by the same group, showing that FR122047 treatment induces caspase-mediated apoptosis and at the same time stimulates a defensive autophagic response of MCF-7 cells.	('stimulates', 'PosReg', (183, 193))	('FR122047', 'Var', (108, 116))	('MCF-7', 'CellLine', 'CVCL:0031', (14, 19))	('caspase-mediated apoptosis', 'CPA', (135, 161))	('induces', 'Reg', (127, 134))	('FR122047', 'Chemical', 'MESH:C085131', (108, 116))	('MCF-7', 'CellLine', 'CVCL:0031', (229, 234))	('defensive autophagic response', 'CPA', (196, 225))
730275	30314310	Interestingly, the inhibition of caspase-9 blocks the cytoprotective autophagic process, thus increasing the susceptibility of MCF-7 cells to FR-122047-induced cell death.	('blocks', 'NegReg', (43, 49))	('inhibition', 'Var', (19, 29))	('caspase-9', 'Gene', (33, 42))	('MCF-7', 'CellLine', 'CVCL:0031', (127, 132))	('cytoprotective autophagic process', 'CPA', (54, 87))	('caspase-9', 'Gene', '842', (33, 42))	('susceptibility', 'MPA', (109, 123))	('increasing', 'PosReg', (94, 104))
730276	30314310	In general, in vitro and in vivo antitumor properties of COX-1-selective inhibitors resemble those of other NSAIDs and coxibs; in some cases, COX-dependent, and in others, COX-independent mechanisms having been reported.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('COX-1-selective', 'Gene', (57, 72))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('inhibitors', 'Var', (73, 83))
730278	30314310	COX-1-selective inhibitors, not different from other NSAIDs or coxibs, impair cell growth and proliferation, this biological end-point being most often associated with cell cycle G1-phase arrest and cell death.	('arrest', 'Disease', 'MESH:D006323', (188, 194))	('arrest', 'Disease', (188, 194))	('inhibitors', 'Var', (16, 26))	('rat', 'Species', '10116', (101, 104))	('cell', 'CPA', (199, 203))	('COX-1-selective', 'Gene', (0, 15))	('associated', 'Reg', (152, 162))	('impair', 'NegReg', (71, 77))
730281	30314310	However, whilst considering the protein interaction caveat, it is not surprising that COX-1 inhibitors (as well as traditional NSAIDs and coxibs) have weak antiproliferative effects related to enzymatic inhibition.	('antiproliferative effects', 'CPA', (156, 181))	('COX-1', 'Gene', (86, 91))	('rat', 'Species', '10116', (167, 170))	('inhibitors', 'Var', (92, 102))
730396	28983231	We found that the absence of ICG fluorescein imaging was an independent risk factor for AL following EC surgery [HR 9.0740, 95% confidence interval (CI) 1.5923-171.2574, p = 0.0098].	('fluorescein', 'Chemical', 'MESH:D019793', (33, 44))	('AL following EC surgery', 'Disease', (88, 111))	('ICG', 'Chemical', 'MESH:D007208', (29, 32))	('absence', 'Var', (18, 25))
730397	28983231	In the current study, we, for the first time, demonstrated that the absence of ICG fluorescein imaging is an independent predictor of postoperative AL.	('ICG', 'Chemical', 'MESH:D007208', (79, 82))	('ICG', 'MPA', (79, 82))	('absence', 'Var', (68, 75))	('fluorescein', 'Chemical', 'MESH:D019793', (83, 94))
730420	28983231	Recently, we reported that high NLR was one of several independent variables associated with the development of postoperative infectious complications, including AL, following gastrectomy for gastric cancer.	('postoperative infectious complications', 'Disease', 'MESH:D011183', (112, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (192, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('postoperative infectious complications', 'Disease', (112, 150))	('high', 'Var', (27, 31))	('gastric cancer', 'Disease', (192, 206))	('gastric cancer', 'Disease', 'MESH:D013274', (192, 206))	('associated with', 'Reg', (77, 92))
730482	27698910	We provide evidence that there is an increased prevalence of esophageal cancer in areas with high nickel levels in farm soils, compared with areas with low levels.	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('esophageal cancer', 'Disease', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('high', 'Var', (93, 97))	('nickel', 'Chemical', 'MESH:D009532', (98, 104))
730520	26920496	CTL activity to at least one peptide at the time of the third and sixth vaccination increased in 2 and 3 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 2 and 1 of 6 (30 mg) patients, respectively.	('10', 'Var', (111, 113))	('CTL activity to at least one peptide', 'MPA', (0, 36))	('increased', 'PosReg', (84, 93))	('patients', 'Species', '9606', (170, 178))
730521	26920496	IgG levels, at the third and sixth vaccination, were also increased in 1 and 1 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 1 and 3 of 6 (30 mg) patients, respectively.	('patients', 'Species', '9606', (144, 152))	('10', 'Var', (85, 87))	('increased', 'PosReg', (58, 67))	('IgG levels', 'MPA', (0, 10))
730527	26920496	Patients were required to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, the ability to eat, and adequate organ function as assessed by a platelet (>=75 000/mm3) count, an absolute lymphocyte (>=1000/mm3) count, serum total bilirubin (<=2.0 mg/dL), serum creatinine (<=1.5 mg/dL) and alanine aminotransferase and aspartate aminotransferase (<=100 IU/L, or <=200 IU/L in patients with hepatic metastasis) levels.	('aspartate aminotransferase', 'MPA', (376, 402))	('Oncology', 'Phenotype', 'HP:0002664', (94, 102))	('<=200 IU/L', 'Var', (419, 429))	('Patients', 'Species', '9606', (0, 8))	('alanine aminotransferase', 'Gene', (347, 371))	('hepatic metastasis', 'Disease', (447, 465))	('bilirubin', 'Chemical', 'MESH:D001663', (287, 296))	('serum creatinine', 'MPA', (312, 328))	('hepatic metastasis', 'Disease', 'MESH:D009362', (447, 465))	('patients', 'Species', '9606', (433, 441))	('alanine aminotransferase', 'Gene', '2875', (347, 371))
730555	26920496	HLA-class IA types determined by genotyping were A24 (n = 10), A2 (9), A31 (6), A26 (4), A33 (3), A11 (2) and A3 (1).	('A33', 'Gene', '10223', (89, 92))	('A24', 'Gene', (49, 52))	('A24', 'Gene', '28924', (49, 52))	('A26', 'Gene', (80, 83))	('A33', 'Gene', (89, 92))	('A11', 'Gene', (98, 101))	('A31', 'Var', (71, 74))	('A11', 'Gene', '8248', (98, 101))	('A26', 'Gene', '28906', (80, 83))
730562	26920496	However, CTL activity to at least one peptide at the third and sixth vaccination increased in 2 and 3 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 2 and 1 of 6 (30 mg) patients, respectively.	('10', 'Var', (108, 110))	('increased', 'PosReg', (81, 90))	('patients', 'Species', '9606', (167, 175))	('CTL activity to at least one peptide', 'MPA', (9, 45))
730578	26920496	However, of note, the 10-mg group was dominated by advanced esophageal cancer patients, whereas the other groups were dominated by colorectal cancer patients.	('10-mg', 'Var', (22, 27))	('patients', 'Species', '9606', (149, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (78, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colorectal cancer', 'Disease', (131, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
730606	14558708	GERD has been shown to significantly affect patients' quality of life and is a potential risk factor for adeno-carcinoma of the esophagus.	('adeno-carcinoma of the esophagus', 'Disease', (105, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('patients', 'Species', '9606', (44, 52))	('adeno-carcinoma of the esophagus', 'Disease', 'MESH:D004938', (105, 137))	('quality of life', 'CPA', (54, 69))	('affect', 'Reg', (37, 43))	('GERD', 'Var', (0, 4))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (111, 137))
730698	20163722	Mean copy number of CDKN2A and CEP9 and frequency of nuclei with loss of PIK3CA were significantly different in the CM group compared with normal mucosa and marginal levels of deletions in TP63, FHIT, PIK3CA, EGFR, CDKN2A, YES and gains at PIK3CA, TP63, FGFR1, MYC, CDNK2A and NCOA3 were detected in few CM cases, mainly with dilation grades III and IV.	('TP63', 'Gene', (248, 252))	('PIK3CA', 'Gene', '5290', (201, 207))	('FGFR1', 'Gene', (254, 259))	('PIK3CA', 'Gene', '5290', (240, 246))	('CEP9', 'Gene', (31, 35))	('CDKN2A', 'Gene', '1029', (20, 26))	('dilation grades III', 'Disease', (326, 345))	('TP63', 'Gene', '8626', (248, 252))	('PIK3CA', 'Gene', '5290', (73, 79))	('EGFR', 'Gene', (209, 213))	('NCOA3', 'Gene', (277, 282))	('FHIT', 'Gene', (195, 199))	('deletions', 'Var', (176, 185))	('PIK3CA', 'Gene', (201, 207))	('TP63', 'Gene', (189, 193))	('loss', 'NegReg', (65, 69))	('different', 'Reg', (99, 108))	('CDKN2A', 'Gene', (215, 221))	('MYC', 'Gene', (261, 264))	('PIK3CA', 'Gene', (240, 246))	('FHIT', 'Gene', '2272', (195, 199))	('FGFR1', 'Gene', '2260', (254, 259))	('PIK3CA', 'Gene', (73, 79))	('TP63', 'Gene', '8626', (189, 193))	('EGFR', 'Gene', '1956', (209, 213))	('CDKN2A', 'Gene', '1029', (215, 221))	('CDKN2A', 'Gene', (20, 26))	('MYC', 'Gene', '4609', (261, 264))	('NCOA3', 'Gene', '8202', (277, 282))
730713	20163722	In ESCC, molecular cytogenetic techniques have shown common occurrence of unbalanced genomic regions involved in amplification of oncogenes and deletion of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('amplification', 'MPA', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('deletion', 'Var', (144, 152))	('oncogenes', 'Gene', (130, 139))	('ESCC', 'Disease', (3, 7))	('tumor', 'Disease', (156, 161))
730731	20163722	# 32-190006, MYC mapped at 8q24)/homebrew FGFR1 (RP11-350N15, mapped at 8p12), and the homebrew probes FHIT (CTD-2196D15, mapped at 3p14.2)/centromere 3 (palpha 3.5), TP63 (RP11-373I6, mapped at 3q28)/PIK3CA (RP11-245C23, mapped at 3q26) and YES1 (RP11-769O8, mapped at 18q11.31)/NCOA3 (RP11-456N23, mapped at 20q12).	('RP11', 'Gene', '26121', (209, 213))	('PIK3CA', 'Gene', '5290', (201, 207))	('RP11', 'Gene', '26121', (49, 53))	('RP11', 'Gene', '26121', (248, 252))	('NCOA3', 'Gene', (280, 285))	('MYC', 'Gene', '4609', (13, 16))	('RP11', 'Gene', (173, 177))	('TP63', 'Gene', (167, 171))	('FHIT', 'Gene', '2272', (103, 107))	('RP11', 'Gene', '26121', (287, 291))	('TP63', 'Gene', '8626', (167, 171))	('RP11', 'Gene', (209, 213))	('PIK3CA', 'Gene', (201, 207))	('FGFR1', 'Gene', '2260', (42, 47))	('YES1', 'Gene', '7525', (242, 246))	('RP11', 'Gene', (49, 53))	('RP11', 'Gene', (248, 252))	('RP11', 'Gene', (287, 291))	('RP11', 'Gene', '26121', (173, 177))	('NCOA3', 'Gene', '8202', (280, 285))	('MYC', 'Gene', (13, 16))	('CTD-2196D15', 'Var', (109, 120))	('FGFR1', 'Gene', (42, 47))	('YES1', 'Gene', (242, 246))	('FHIT', 'Gene', (103, 107))
730734	20163722	Fluorescence signals were scored in epifluorescence microscope using single band filters for DAPI, FITC (fluorescein), and Texas red, double-band pass filter (FITC and Texas red) and triple-band pass filter (DAPI, FITC, and Texas Red).	('FITC', 'Chemical', 'MESH:D016650', (159, 163))	('Texas Red', 'Chemical', 'MESH:C034657', (224, 233))	('FITC', 'Chemical', 'MESH:D016650', (214, 218))	('DAPI', 'Chemical', 'MESH:C007293', (93, 97))	('FITC', 'Chemical', 'MESH:D016650', (99, 103))	('Texas red', 'Chemical', 'MESH:C034657', (123, 132))	('double-band', 'Var', (134, 145))	('fluorescein', 'Chemical', 'MESH:D019793', (105, 116))	('DAPI', 'Chemical', 'MESH:C007293', (208, 212))	('Texas red', 'Chemical', 'MESH:C034657', (168, 177))	('triple-band', 'Var', (183, 194))
730743	20163722	In another investigative approach, frequencies of nuclei with normal (2 copies) or loss (<2 copies) and gain (>2 copies) for each gene were compared (Table 2), and only for PIK3CA there were higher frequencies of cells with copy number loss in the CM group compared to NM (36.4% vs. 28.5%).	('PIK3CA', 'Gene', '5290', (173, 179))	('loss', 'NegReg', (236, 240))	('copy number', 'Var', (224, 235))	('PIK3CA', 'Gene', (173, 179))	('loss', 'NegReg', (83, 87))
730746	20163722	Several cases were identified harboring deletions on specifics targets: CM7 (YES1), CM12 (CDKN2A), CM13 (PIK3CA; TP63), CM19 (PIK3CA), CM30 (EGFR), CM36 (FHIT; CEP9), CM16 and CM34 (CEP9).	('CM7', 'Var', (72, 75))	('CM30', 'Var', (135, 139))	('PIK3CA', 'Gene', '5290', (105, 111))	('TP63', 'Gene', '8626', (113, 117))	('CDKN2A', 'Gene', (90, 96))	('YES1', 'Gene', '7525', (77, 81))	('EGFR', 'Gene', '1956', (141, 145))	('PIK3CA', 'Gene', '5290', (126, 132))	('CM36', 'Var', (148, 152))	('PIK3CA', 'Gene', (105, 111))	('CDKN2A', 'Gene', '1029', (90, 96))	('CM13', 'Var', (99, 103))	('FHIT', 'Gene', (154, 158))	('YES1', 'Gene', (77, 81))	('PIK3CA', 'Gene', (126, 132))	('deletions', 'Var', (40, 49))	('TP63', 'Gene', (113, 117))	('CM12', 'Var', (84, 88))	('CM34', 'Var', (176, 180))	('EGFR', 'Gene', (141, 145))	('CM16', 'Gene', (167, 171))	('FHIT', 'Gene', '2272', (154, 158))	('CM19', 'Var', (120, 124))
730747	20163722	Other cases showed genomic gain for specific targets: CM3 (MYC), CM6 (TP63; MYC), CM7 (TP63), CM11 (PIK3CA; CDKN2A), CM16 (CDKN2A), CM28 (PIK3CA), CM30 (MYC; FGFR1), CM36 (NCOA3), and CM11 and CM21 (CEP9).	('MYC', 'Gene', (59, 62))	('gain', 'PosReg', (27, 31))	('PIK3CA', 'Gene', (100, 106))	('MYC', 'Gene', (76, 79))	('CDKN2A', 'Gene', (123, 129))	('TP63', 'Gene', (87, 91))	('NCOA3', 'Gene', '8202', (172, 177))	('CM36', 'Var', (166, 170))	('CDKN2A', 'Gene', '1029', (108, 114))	('CM16', 'Var', (117, 121))	('CM11', 'Var', (184, 188))	('FGFR1', 'Gene', (158, 163))	('CM28', 'Var', (132, 136))	('PIK3CA', 'Gene', (138, 144))	('MYC', 'Gene', (153, 156))	('MYC', 'Gene', '4609', (59, 62))	('CDKN2A', 'Gene', '1029', (123, 129))	('CM30', 'Var', (147, 151))	('TP63', 'Gene', '8626', (87, 91))	('MYC', 'Gene', '4609', (76, 79))	('TP63', 'Gene', (70, 74))	('CM21', 'Var', (193, 197))	('PIK3CA', 'Gene', '5290', (100, 106))	('CM7', 'Var', (82, 85))	('NCOA3', 'Gene', (172, 177))	('TP63', 'Gene', '8626', (70, 74))	('CM11', 'Var', (94, 98))	('CM3', 'Var', (54, 57))	('MYC', 'Gene', '4609', (153, 156))	('CM6', 'Var', (65, 68))	('FGFR1', 'Gene', '2260', (158, 163))	('CDKN2A', 'Gene', (108, 114))	('PIK3CA', 'Gene', '5290', (138, 144))
730750	20163722	Several genetic alterations are also associated with ESCC, such as chromosomal changes, allelic deletions, activation of oncogenes and inactivation of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('ESCC', 'Disease', (53, 57))	('tumor', 'Disease', (151, 156))	('allelic deletions', 'Var', (88, 105))	('chromosomal changes', 'Var', (67, 86))	('inactivation', 'Var', (135, 147))	('oncogenes', 'Gene', (121, 130))	('activation', 'PosReg', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
730756	20163722	Genetic and epigenetic alterations in CDKN2A have been reported in early stages of esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (83, 108))	('reported', 'Reg', (55, 63))	('epigenetic alterations', 'Var', (12, 34))	('esophageal carcinogenesis', 'Disease', (83, 108))	('Genetic', 'Var', (0, 7))	('CDKN2A', 'Gene', (38, 44))	('CDKN2A', 'Gene', '1029', (38, 44))
730757	20163722	In primary esophageal carcinomas and cell lines, deletions and point mutations in CDKN2A gene have been reported in 16% to 82% of cases, and hypermethylation of promoter region in 20% to 88% of ESCC and precancerous lesions.	('ESCC', 'Disease', (194, 198))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('hypermethylation', 'Var', (141, 157))	('CDKN2A', 'Gene', (82, 88))	('reported', 'Reg', (104, 112))	('esophageal carcinomas', 'Disease', (11, 32))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (11, 31))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (11, 32))	('point mutations', 'Var', (63, 78))	('CDKN2A', 'Gene', '1029', (82, 88))	('deletions', 'Var', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('precancerous lesions', 'Disease', 'MESH:D011230', (203, 223))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('precancerous lesions', 'Disease', (203, 223))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (11, 32))
730758	20163722	The current study detected deletion of CDKN2A and CEP 9 sequences in CM compared with NM group.	('deletion', 'Var', (27, 35))	('CEP 9', 'Gene', (50, 55))	('CDKN2A', 'Gene', '1029', (39, 45))	('CDKN2A', 'Gene', (39, 45))
730761	20163722	Additionally, recent subset analyses by our group did not find mutations in CDKN2A (exons 1 and 2) and FHIT (exons 5 and 7) genes, suggesting these events are uncommon in CM, and have detected copy number changes of chromosomes 7, 11 and 17 and TP53 deletion by FISH.	('CDKN2A', 'Gene', '1029', (76, 82))	('deletion', 'Var', (250, 258))	('TP53', 'Gene', (245, 249))	('CDKN2A', 'Gene', (76, 82))	('FHIT', 'Gene', '2272', (103, 107))	('FHIT', 'Gene', (103, 107))
730763	20163722	Deletion in both FHIT alleles results in failure in the transcript and consequent absence or reduction of Fhit protein, which act in the cell cycle regulation and apoptosis.	('reduction', 'NegReg', (93, 102))	('cell cycle', 'CPA', (137, 147))	('absence', 'NegReg', (82, 89))	('FHIT', 'Gene', (17, 21))	('protein', 'Protein', (111, 118))	('Fhit', 'Gene', (106, 110))	('FHIT', 'Gene', '2272', (17, 21))	('transcript', 'MPA', (56, 66))	('Fhit', 'Gene', '2272', (106, 110))	('failure', 'NegReg', (41, 48))	('Deletion', 'Var', (0, 8))
730764	20163722	Genetic and epigenetic alterations of FHIT are associated with development of several cancer types.	('associated with', 'Reg', (47, 62))	('epigenetic alterations', 'Var', (12, 34))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Genetic', 'Var', (0, 7))	('FHIT', 'Gene', (38, 42))	('FHIT', 'Gene', '2272', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
730766	20163722	While hypermethylation of FHIT gene has been described in 33% to 69.4% of ESCC cases, it is also known that deletion and loss of protein expression are frequent in esophageal carcinoma.	('hypermethylation', 'Var', (6, 22))	('esophageal carcinoma', 'Disease', (164, 184))	('FHIT', 'Gene', (26, 30))	('ESCC', 'Disease', (74, 78))	('loss of', 'NegReg', (121, 128))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (164, 184))	('FHIT', 'Gene', '2272', (26, 30))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (164, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('protein', 'Protein', (129, 136))	('deletion', 'Var', (108, 116))
730767	20163722	Deletion of FHIT observed in a single megaesophagus specimen in the present study may associate with early onset of genetic chances in these lesions, but it is worth to note that no significant decrease in the level of Fhit protein expression have been detected in chagasic megaesophagus.	('FHIT', 'Gene', (12, 16))	('Fhit', 'Gene', '2272', (219, 223))	('single megaesophagus', 'Phenotype', 'HP:0100580', (31, 51))	('FHIT', 'Gene', '2272', (12, 16))	('Fhit', 'Gene', (219, 223))	('Deletion', 'Var', (0, 8))
730770	20163722	showed that PIK3CA gene amplification was highly correlated with protein overexpression, supporting amplification as a major mechanism for overexpression.	('correlated', 'Reg', (49, 59))	('PIK3CA', 'Gene', '5290', (12, 18))	('protein overexpression', 'MPA', (65, 87))	('amplification', 'Var', (24, 37))	('PIK3CA', 'Gene', (12, 18))
730772	20163722	Gene amplification was one of the basic mechanisms leading to overexpression of the TP63 in ESCC.	('ESCC', 'Disease', (92, 96))	('TP63', 'Gene', '8626', (84, 88))	('TP63', 'Gene', (84, 88))	('Gene amplification', 'Var', (0, 18))	('overexpression', 'PosReg', (62, 76))
730773	20163722	The amplification of TP63, whose protein plays in the development and maintenance of stratified epithelial tissues has been described in early stage of ESCC carcinogenesis but down-regulated in advanced.	('down-regulated', 'NegReg', (176, 190))	('TP63', 'Gene', '8626', (21, 25))	('amplification', 'Var', (4, 17))	('TP63', 'Gene', (21, 25))	('ESCC', 'Disease', (152, 156))
730774	20163722	Amplification of the membrane receptor genes EGFR and FGFR1 has been reported in various cancers including ESCC, and this phenomenon has been suggested to be a poor prognostic factor in solid tumors.	('Amplification', 'Var', (0, 13))	('EGFR', 'Gene', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('solid tumors', 'Disease', 'MESH:D009369', (186, 198))	('reported', 'Reg', (69, 77))	('FGFR1', 'Gene', (54, 59))	('FGFR1', 'Gene', '2260', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('solid tumors', 'Disease', (186, 198))	('ESCC', 'Disease', (107, 111))	('EGFR', 'Gene', '1956', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
730775	20163722	In ESCC, co-expression of both aFGF and FGFR1 was associated with larger tumor area and worse prognosis which suggests that the membrane receptor may promote proliferation of esophageal cancer cells in an angiogenesis-independent and autocrine manner and may contribute to rapid recurrence after esophageal resection.	('esophageal cancer', 'Disease', (175, 192))	('promote', 'PosReg', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('FGFR1', 'Gene', (40, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('FGFR1', 'Gene', '2260', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('aFGF', 'Gene', (31, 35))	('tumor', 'Disease', (73, 78))	('ESCC', 'Disease', (3, 7))	('aFGF', 'Gene', '2246', (31, 35))	('co-expression', 'Var', (9, 22))	('proliferation', 'CPA', (158, 171))	('contribute', 'Reg', (259, 269))
730777	20163722	MYC is regulated in part through mitogenic stimuli and is activated constitutively in cancer cells through gene amplification, chromosomal translocation, point mutation and mitogenic stimulation.	('MYC', 'Gene', (0, 3))	('chromosomal translocation', 'Var', (127, 152))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('MYC', 'Gene', '4609', (0, 3))	('activated', 'PosReg', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('point mutation', 'Var', (154, 168))	('cancer', 'Disease', (86, 92))
730785	20163722	In conclusion, among 40 chagasic megaesophagus comprehensively investigated with a panel of FISH probes, copy number gain was only displayed by three specimens for MYC, by one specimen for FGFR1 and one specimen for NCOA3.	('MYC', 'Gene', (164, 167))	('copy number', 'Var', (105, 116))	('gain', 'PosReg', (117, 121))	('FGFR1', 'Gene', (189, 194))	('MYC', 'Gene', '4609', (164, 167))	('NCOA3', 'Gene', (216, 221))	('FGFR1', 'Gene', '2260', (189, 194))	('NCOA3', 'Gene', '8202', (216, 221))
730791	20163722	We also thank the Brazilian Agency CAPES and the NCI grants U01CA85070, P30-CA46934 and P50 CA58187 for financial and technical support.	('P50', 'Gene', '4790', (88, 91))	('P30', 'Gene', (72, 75))	('U01CA85070', 'Var', (60, 70))	('P50', 'Gene', (88, 91))	('P30', 'Gene', '201161', (72, 75))
730847	28109079	Silencing of Ribosomal Protein L34 (RPL34) Inhibits the Proliferation and Invasion of Esophageal Cancer Cells Ribosomal protein L34 (RPL34) belongs to the L34E family of ribosomal proteins and contains a zinc finger motif.	('Cancer', 'Disease', 'MESH:D009369', (97, 103))	('Ribosomal protein L34', 'Gene', '6164', (110, 131))	('Inhibits', 'NegReg', (43, 51))	('Ribosomal Protein L34', 'Gene', (13, 34))	('Ribosomal protein L34', 'Gene', (110, 131))	('RPL34', 'Gene', (133, 138))	('RPL34', 'Gene', (36, 41))	('Ribosomal Protein L34', 'Gene', '6164', (13, 34))	('RPL34', 'Gene', '6164', (133, 138))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('RPL34', 'Gene', '6164', (36, 41))	('Silencing', 'Var', (0, 9))	('L34E', 'Mutation', 'p.L34E', (155, 159))	('Cancer', 'Disease', (97, 103))
730848	28109079	Aberrant expression of RPL34 has been reported in several human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('human', 'Species', '9606', (58, 63))	('malignancies', 'Disease', (64, 76))	('reported', 'Reg', (38, 46))	('Aberrant', 'Var', (0, 8))	('RPL34', 'Gene', (23, 28))
730854	28109079	Finally, knockdown of RPL34 attenuated tumor growth in nude mice.	('nude mice', 'Species', '10090', (55, 64))	('attenuated tumor', 'Disease', (28, 44))	('knockdown', 'Var', (9, 18))	('attenuated tumor', 'Disease', 'MESH:C538265', (28, 44))	('RPL34', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))
730855	28109079	In conclusion, our study revealed that RPL34 functions as an oncogene that modulates the proliferation and metastasis of esophageal cancer cells, in part, by the inactivation of the PI3K/Akt signaling pathway.	('proliferation', 'CPA', (89, 102))	('RPL34', 'Var', (39, 44))	('metastasis', 'CPA', (107, 117))	('Akt', 'Gene', (187, 190))	('esophageal cancer', 'Disease', (121, 138))	('inactivation', 'NegReg', (162, 174))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('Akt', 'Gene', '207', (187, 190))	('modulates', 'Reg', (75, 84))
730862	28109079	Aberrant expression of RPL34 has been reported in several human malignancies, including non-small cell lung cancer (NSCLC), gastric cancer, and osteosarcoma.	('human', 'Species', '9606', (58, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('lung cancer', 'Disease', (103, 114))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('malignancies', 'Disease', (64, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (144, 156))	('NSCLC', 'Disease', (116, 121))	('gastric cancer', 'Disease', (124, 138))	('Aberrant expression', 'Var', (0, 19))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (88, 114))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('osteosarcoma', 'Disease', (144, 156))	('reported', 'Reg', (38, 46))	('RPL34', 'Gene', (23, 28))	('osteosarcoma', 'Disease', 'MESH:D012516', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (92, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))
730863	28109079	confirmed that the expression of RPL34 was upregulated in human pancreatic cancer (PC) tissues and cell lines, and knockdown of RPL34 substantially inhibited the proliferation, colony formation, migration, and drug resistance of PC cells.	('human', 'Species', '9606', (58, 63))	('PC', 'CellLine', 'CVCL:0152', (83, 85))	('knockdown', 'Var', (115, 124))	('expression', 'MPA', (19, 29))	('drug resistance', 'Phenotype', 'HP:0020174', (210, 225))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('migration', 'CPA', (195, 204))	('upregulated', 'PosReg', (43, 54))	('RPL34', 'Gene', (33, 38))	('PC', 'Phenotype', 'HP:0002894', (229, 231))	('proliferation', 'CPA', (162, 175))	('PC', 'CellLine', 'CVCL:0152', (229, 231))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))	('drug resistance', 'CPA', (210, 225))	('RPL34', 'Gene', (128, 133))	('colony formation', 'CPA', (177, 193))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('inhibited', 'NegReg', (148, 157))	('PC', 'Phenotype', 'HP:0002894', (83, 85))
730867	28109079	ECA109 cells were transfected with sh-RPL34 or sh-NC using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) and were used 48 h posttransfection.	('sh-RPL34', 'Var', (35, 43))	('sh-NC', 'Gene', (47, 52))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (59, 77))
730870	28109079	The primers used were as follows: RPL34, 5'-GTTTGACATACCGACGTAGGC-3' (forward) and 5'-GCACACATGGAACCACCATAG-3' (reverse); GAPDH, 5'-TGACTTCAACAGCGACACCCA-3' (forward) and 5'-CACCCTGTTGCTGTAGCCAAA-3' (reverse).	('RPL34', 'Var', (34, 39))	('GAPDH', 'Gene', '2597', (122, 127))	('GAPDH', 'Gene', (122, 127))
730873	28109079	The membranes were blocked with 5% nonfat dry milk in Tris-buffered saline (TBS) for 1 h followed by incubation in the primary antibodies (anti-RPL34, anti-E-cadherin, anti-N-cadherin, anti-PI3K, anti-p-PI3K, anti-Akt, anti-p-Akt, and anti-GAPDH; Santa Cruz Biotechnology, Santa Cruz, CA, USA) at 4 C overnight.	('N-cadherin', 'Gene', '1000', (173, 183))	('anti-RPL34', 'Var', (139, 149))	('dry milk', 'Disease', (42, 50))	('GAPDH', 'Gene', '2597', (240, 245))	('TBS', 'Chemical', '-', (76, 79))	('GAPDH', 'Gene', (240, 245))	('E-cadherin', 'Gene', (156, 166))	('E-cadherin', 'Gene', '999', (156, 166))	('dry milk', 'Disease', 'MESH:D016269', (42, 50))	('Akt', 'Gene', '207', (214, 217))	('Akt', 'Gene', '207', (226, 229))	('Akt', 'Gene', (214, 217))	('N-cadherin', 'Gene', (173, 183))	('Tris-buffered saline', 'Chemical', '-', (54, 74))	('Akt', 'Gene', (226, 229))
730885	28109079	To examine the biological role of RPL34 in esophageal cancer progression, we employed shRNA against RPL34 to stably knock down RPL34 in ECA109 cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('esophageal cancer', 'Disease', (43, 60))	('knock down', 'Var', (116, 126))	('RPL34', 'Gene', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
730889	28109079	To determine the mechanism by which sh-RPL34 inhibited esophageal cancer cell proliferation and invasion, we examined the effect of RPL34 deregulation on the protein expression of p-PI3K and p-Akt by Western blot.	('Akt', 'Gene', '207', (193, 196))	('deregulation', 'Var', (138, 150))	('Akt', 'Gene', (193, 196))	('RPL34', 'Gene', (132, 137))	('esophageal cancer', 'Disease', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('sh-RPL34', 'Var', (36, 44))	('invasion', 'CPA', (96, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('inhibited', 'NegReg', (45, 54))
730890	28109079	Compared with the sh-NC group, knockdown of RPL34 significantly downregulated the protein expression levels of p-PI3K and p-Akt in ECA109 cells (Fig.	('p-PI3K', 'Protein', (111, 117))	('Akt', 'Gene', (124, 127))	('protein expression levels', 'MPA', (82, 107))	('RPL34', 'Gene', (44, 49))	('Akt', 'Gene', '207', (124, 127))	('knockdown', 'Var', (31, 40))	('downregulated', 'NegReg', (64, 77))
730892	28109079	We observed that treatment of 15 muM LY294002 markedly decreased cell viability; thus, 10 muM LY294002 was chosen for additional experiments (Fig.	('LY294002', 'Chemical', 'MESH:C085911', (94, 102))	('LY294002', 'Chemical', 'MESH:C085911', (37, 45))	('cell viability', 'CPA', (65, 79))	('decreased', 'NegReg', (55, 64))	('LY294002', 'Var', (37, 45))
730893	28109079	4e) of ECA109 cells were significantly suppressed by LY294002 treatment.	('LY294002', 'Chemical', 'MESH:C085911', (53, 61))	('LY294002', 'Var', (53, 61))	('suppressed', 'NegReg', (39, 49))
730895	28109079	Tumors formed by RPL34-silenced ECA109 cells were smaller in size than the tumors formed by control cells (Fig.	('RPL34-silenced', 'Var', (17, 31))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('ECA109', 'Gene', (32, 38))	('tumors', 'Disease', (75, 81))	('smaller', 'NegReg', (50, 57))
730899	28109079	Mounting evidence suggests that deregulation of RPL34 is associated with various types of human cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('deregulation', 'Var', (32, 44))	('human', 'Species', '9606', (90, 95))	('RPL34', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('associated', 'Reg', (57, 67))
730908	28109079	In the current study, we observed that knockdown of RPL34 efficiently inhibited esophageal cancer cell migration and invasion in vitro.	('RPL34', 'Gene', (52, 57))	('knockdown', 'Var', (39, 48))	('esophageal cancer', 'Disease', (80, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('inhibited', 'NegReg', (70, 79))
730910	28109079	These results are in line with that from PC cells and partly support our data from esophageal cancer cell lines showing that depletion of RPL34 is sufficient to suppress the EMT phenotype, resulting in the inhibition of migration and invasion of esophageal cancer cells.	('migration', 'CPA', (220, 229))	('PC', 'CellLine', 'CVCL:0152', (41, 43))	('esophageal cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('RPL34', 'Gene', (138, 143))	('invasion', 'CPA', (234, 242))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (246, 263))	('PC', 'Phenotype', 'HP:0002894', (41, 43))	('depletion', 'Var', (125, 134))	('esophageal cancer', 'Disease', (246, 263))	('suppress', 'NegReg', (161, 169))	('EMT phenotype', 'CPA', (174, 187))	('inhibition', 'NegReg', (206, 216))
730916	28109079	These data suggest that knockdown of RPL34 suppressed the proliferation and metastasis of esophageal cancer cells, likely through inactivation of the PI3K/Akt signaling pathway.	('inactivation', 'NegReg', (130, 142))	('metastasis', 'CPA', (76, 86))	('proliferation', 'CPA', (58, 71))	('RPL34', 'Gene', (37, 42))	('esophageal cancer', 'Disease', (90, 107))	('Akt', 'Gene', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Akt', 'Gene', '207', (155, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('knockdown', 'Var', (24, 33))	('suppressed', 'NegReg', (43, 53))
730917	28109079	In conclusion, our study revealed that RPL34 functions as an oncogene that modulates the proliferation and metastasis of esophageal cancer cells in part through the inactivation of the PI3K/Akt signaling pathway.	('proliferation', 'CPA', (89, 102))	('RPL34', 'Var', (39, 44))	('metastasis', 'CPA', (107, 117))	('inactivation', 'NegReg', (165, 177))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Akt', 'Gene', (190, 193))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('modulates', 'Reg', (75, 84))	('Akt', 'Gene', '207', (190, 193))
730918	32449803	Downregulation of lncRNA-HEIH curbs esophageal squamous cell carcinoma progression by modulating miR-4458/PBX3 Long non-coding RNAs (lncRNAs) have been found to play a specific part in the development of esophageal squamous cell carcinoma (ESCC), except for lncRNA HEIH.	('esophageal squamous cell carcinoma', 'Disease', (36, 70))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (204, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('miR-4458', 'Gene', '100616142', (97, 105))	('PBX3', 'Gene', (106, 110))	('PBX3', 'Gene', '5090', (106, 110))	('lncRNA HEIH', 'Gene', '100859930', (258, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (36, 70))	('lncRNA HEIH', 'Gene', (258, 269))	('HEIH', 'Gene', '100859930', (25, 29))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (215, 238))	('miR', 'Gene', '220972', (97, 100))	('lncRNA-HEIH', 'Gene', (18, 29))	('HEIH', 'Gene', '100859930', (265, 269))	('modulating', 'Var', (86, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('lncRNA-HEIH', 'Gene', '100859930', (18, 29))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 70))	('miR', 'Gene', (97, 100))	('esophageal squamous cell carcinoma', 'Disease', (204, 238))	('HEIH', 'Gene', (25, 29))	('miR-4458', 'Gene', (97, 105))	('HEIH', 'Gene', (265, 269))
730922	32449803	Recent studies have found that multiple LncRNAs can participate in a variety of molecular and cellular processes, such as chromosome dosage compensation, imprinting, intracellular transport, cell cycle regulation, reprogramming, epigenetic regulation, stem cell differentiation, and regulate a variety of developmental processes of human diseases.	('intracellular transport', 'MPA', (166, 189))	('cell cycle regulation', 'CPA', (191, 212))	('regulate', 'Reg', (283, 291))	('stem cell differentiation', 'CPA', (252, 277))	('developmental processes', 'CPA', (305, 328))	('epigenetic', 'Var', (229, 239))	('reprogramming', 'CPA', (214, 227))	('human', 'Species', '9606', (332, 337))	('participate', 'Reg', (52, 63))
730936	32449803	Furthermore, high HEIH expression was closely related to tumor grading and TNM stage (Table 2).	('TNM', 'Gene', (75, 78))	('related', 'Reg', (46, 53))	('high', 'Var', (13, 17))	('tumor grading', 'CPA', (57, 70))	('HEIH', 'Protein', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('TNM', 'Gene', '10178', (75, 78))
730937	32449803	The results showed that the luciferase activity of HEIH-WT was decreased by miR-4458 mimics, while there was no change in HEIH-MUT (Fig 3b).	('mimics', 'Var', (85, 91))	('HEIH-MUT', 'Disease', (122, 130))	('decreased', 'NegReg', (63, 72))	('luciferase', 'Enzyme', (28, 38))	('activity', 'MPA', (39, 47))	('miR-4458', 'Gene', (76, 84))	('HEIH-MUT', 'Disease', 'MESH:C565390', (122, 130))
730938	32449803	EGFR-AS1,15 MNX1-AS116 and FER1L417 have been found to have influences on tumorigenesis and development in ESCC.	('influences', 'Reg', (60, 70))	('development', 'CPA', (92, 103))	('MNX1', 'Gene', (12, 16))	('tumorigenesis', 'CPA', (74, 87))	('FER1L417', 'Var', (27, 35))	('MNX1', 'Gene', '3110', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('EGFR-AS1', 'Gene', '100507500', (0, 8))	('ESCC', 'Disease', (107, 111))	('EGFR-AS1', 'Gene', (0, 8))
730943	32449803	Consistent with previous results, PBX was revealed to enhance cell proliferation, migration and invasion in gastric cancer.27 Moreover, our findings indicated that HEIH regulated ESCC cell progression by modulating the miR-4458/PBX3 axis.	('ESCC cell', 'Disease', (179, 188))	('regulated', 'Reg', (169, 178))	('miR-4458/PBX3 axis', 'Pathway', (219, 237))	('HEIH', 'Var', (164, 168))	('modulating', 'Reg', (204, 214))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('gastric cancer', 'Disease', (108, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (108, 122))
730949	31332625	Although EVSL affects esophageal motility by relatively decreasing LES pressure, it does not induce substantial motor abnormalities nor increase risk of abnormal gastroesophageal reflux disease in cirrhosis patients.	('abnormal gastroesophageal reflux disease', 'Disease', (153, 193))	('EVSL', 'Var', (9, 13))	('patients', 'Species', '9606', (207, 215))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (162, 185))	('cirrhosis', 'Disease', 'MESH:D005355', (197, 206))	('motor abnormalities', 'Phenotype', 'HP:0001270', (112, 131))	('LES pressure', 'MPA', (67, 79))	('cirrhosis', 'Disease', (197, 206))	('abnormal gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (153, 193))	('decreasing', 'NegReg', (56, 66))	('esophageal', 'Disease', (22, 32))	('cirrhosis', 'Phenotype', 'HP:0001394', (197, 206))
730958	31332625	The aim of our study was to investigate whether EVSL affects esophageal motility and causes abnormal gastroesophageal reflux.	('causes', 'Reg', (85, 91))	('affects', 'Reg', (53, 60))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (101, 124))	('EVSL', 'Var', (48, 52))	('esophageal motility', 'CPA', (61, 80))	('abnormal gastroesophageal reflux', 'Disease', (92, 124))	('abnormal gastroesophageal reflux', 'Disease', 'MESH:D005764', (92, 124))
730998	31332625	Hence, we conclude that EVSL normalizes LES pressure, has little adverse impact on esophageal motility, and does not increase risk of gastroesophageal reflux.	('LES pressure', 'MPA', (40, 52))	('EVSL', 'Var', (24, 28))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (134, 157))	('esophageal', 'Disease', (83, 93))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (134, 157))	('gastroesophageal reflux', 'Disease', (134, 157))	('normalizes', 'NegReg', (29, 39))
731010	30854784	FAM175B promotes apoptosis by inhibiting ATF4 ubiquitination in esophageal squamous cell carcinoma FAM175B is a reported regulator of p53 and suppresses tumorigenesis in numerous types of cancer, but very little is known about its function in esophageal squamous cell carcinomas (ESCCs), almost 70% of which exhibit mutations in p53.	('inhibiting', 'NegReg', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (243, 277))	('FAM175B', 'Gene', '23172', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal squamous cell carcinomas', 'Disease', (243, 278))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (243, 278))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (254, 277))	('tumor', 'Disease', (153, 158))	('ATF4', 'Gene', (41, 45))	('p53', 'Gene', '7157', (134, 137))	('ATF4', 'Gene', '468', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('mutations', 'Var', (316, 325))	('FAM175B', 'Gene', (0, 7))	('carcinomas', 'Phenotype', 'HP:0030731', (268, 278))	('esophageal squamous cell carcinoma', 'Disease', (64, 98))	('FAM175B', 'Gene', '23172', (99, 106))	('p53', 'Gene', '7157', (329, 332))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('cancer', 'Disease', (188, 194))	('p53', 'Gene', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('suppresses', 'NegReg', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('p53', 'Gene', (329, 332))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (254, 278))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (64, 98))	('FAM175B', 'Gene', (99, 106))
731025	30854784	Hypermethylation of CDKN2A and MGMT, which is associated with the loss of expression of these proteins and advanced histological grade of cancer, is relatively commonly reported in ESCC (Guo et al., 2006; Hibi et al., 2001; Kaz and Grady, 2014; Salam et al., 2009; Taghavi et al., 2010; Tokugawa et al., 2002; Xing et al., 1999; Zhang et al., 2003).	('expression', 'MPA', (74, 84))	('loss', 'NegReg', (66, 70))	('cancer', 'Disease', (138, 144))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('CDKN2A', 'Gene', (20, 26))	('ESCC', 'Disease', (181, 185))	('Salam', 'Species', '883761', (245, 250))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
731033	30854784	However, to date, no study has revealed the p53-independent carcinogenic activity of FAM175B in ESCC patients, among which almost 70% exhibit p53 mutation (Abedi-Ardekani, 2014; Kawano et al., 2014; Makino et al., 2010).	('carcinogenic', 'Disease', (60, 72))	('patients', 'Species', '9606', (101, 109))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('FAM175B', 'Gene', '23172', (85, 92))	('carcinogenic', 'Disease', 'MESH:D063646', (60, 72))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('ESCC', 'Disease', (96, 100))	('mutation', 'Var', (146, 154))	('FAM175B', 'Gene', (85, 92))
731046	30854784	The following antibodies were used in this study: anti-FAM175B mouse polyclonal antibody (ab68801; Abcam, Cambridge, MA, USA); anti-FAM175B rabbit polyclonal antibody (HPA037591; Atlas Antibodies); anti-ATF4 rabbit monoclonal antibody (D4B8, CST); anti-ATF4 mouse monoclonal antibody (60035-1-Ig; Proteintech, Wuhan, China); anti-ubiquitin (P4D1) mouse monoclonal antibody (#3936, CST); anti-HA tag mouse monoclonal antibody (66006-2-Ig; Proteintech); anti-CHOP rabbit polyclonal antibody (15204-1-AP; Proteintech); and anti-GAPDH mouse monoclonal antibody (60004-1-Ig; Proteintech).	('mouse', 'Species', '10090', (63, 68))	('15204-1-AP', 'Var', (490, 500))	('ATF4', 'Gene', (203, 207))	('GAPDH', 'Gene', '2597', (525, 530))	('FAM175B', 'Gene', '23172', (55, 62))	('mouse', 'Species', '10090', (531, 536))	('rabbit', 'Species', '9986', (208, 214))	('ATF4', 'Gene', '468', (203, 207))	('mouse', 'Species', '10090', (347, 352))	('rabbit', 'Species', '9986', (462, 468))	('60004-1-Ig', 'Var', (558, 568))	('FAM175B', 'Gene', '23172', (132, 139))	('mouse', 'Species', '10090', (258, 263))	('GAPDH', 'Gene', (525, 530))	('66006-2-Ig', 'Var', (426, 436))	('CHOP', 'Gene', '1649', (457, 461))	('FAM175B', 'Gene', (55, 62))	('ATF4', 'Gene', (253, 257))	('mouse', 'Species', '10090', (399, 404))	('rabbit', 'Species', '9986', (140, 146))	('FAM175B', 'Gene', (132, 139))	('ATF4', 'Gene', '468', (253, 257))	('CHOP', 'Gene', (457, 461))
731066	30854784	EC9706 and KYSE30 cells were transfected with pCMV-HA or pCMV-FAM175B.	('FAM175B', 'Gene', '23172', (62, 69))	('FAM175B', 'Gene', (62, 69))	('pCMV-HA', 'Var', (46, 53))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))
731091	30854784	To determine the effects of FAM175B on cell proliferation, FAM175B was separately overexpressed and knocked down in both KYSE30 and EC9706 cells.	('FAM175B', 'Gene', (59, 66))	('knocked down', 'Var', (100, 112))	('EC9706', 'CellLine', 'CVCL:E307', (132, 138))	('FAM175B', 'Gene', (28, 35))	('FAM175B', 'Gene', '23172', (59, 66))	('FAM175B', 'Gene', '23172', (28, 35))
731092	30854784	With increased expression of FAM175B, the proliferation rate decreased and colony formation was inhibited in both cell lines.	('proliferation rate', 'CPA', (42, 60))	('expression', 'Var', (15, 25))	('FAM175B', 'Gene', '23172', (29, 36))	('colony formation', 'CPA', (75, 91))	('increased', 'PosReg', (5, 14))	('inhibited', 'NegReg', (96, 105))	('decreased', 'NegReg', (61, 70))	('FAM175B', 'Gene', (29, 36))
731105	30854784	Moreover, FAM175B knockdown attenuated H2O2-induced upregulation of proapoptotic proteins (such as Bax, active caspase-3, and gamma-H2AX, Fig.	('knockdown', 'Var', (18, 27))	('upregulation', 'PosReg', (52, 64))	('caspase-3', 'Gene', (111, 120))	('attenuated', 'NegReg', (28, 38))	('gamma-H2AX', 'MPA', (126, 136))	('Bax', 'Gene', (99, 102))	('FAM175B', 'Gene', (10, 17))	('caspase-3', 'Gene', '836', (111, 120))	('proapoptotic proteins', 'MPA', (68, 89))	('H2O2-induced', 'Gene', (39, 51))	('H2O2', 'Chemical', 'MESH:D006861', (39, 43))	('FAM175B', 'Gene', '23172', (10, 17))	('Bax', 'Gene', '581', (99, 102))
731124	30854784	Moreover, consistent with the results of the western blot analysis, the q-PCR analysis results showed that ATF4 knockdown downregulated CHOP mRNA expression and FAM175B overexpression upregulated CHOP mRNA expression (Fig.	('downregulated', 'NegReg', (122, 135))	('CHOP', 'Gene', '1649', (196, 200))	('FAM175B', 'Gene', (161, 168))	('ATF4', 'Gene', '468', (107, 111))	('CHOP', 'Gene', '1649', (136, 140))	('overexpression upregulated', 'PosReg', (169, 195))	('CHOP', 'Gene', (196, 200))	('knockdown', 'Var', (112, 121))	('CHOP', 'Gene', (136, 140))	('FAM175B', 'Gene', '23172', (161, 168))	('ATF4', 'Gene', (107, 111))
731135	30854784	Due to the high mutation rate of p53 in ESCC, this tumor suppressor effect may be p53-independent.	('ESCC', 'Disease', (40, 44))	('mutation', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
731136	30854784	The ESCC cell lines EC9706 and KYSE30, both of which carry p53 mutations, were selected for further assays.	('mutations', 'Var', (63, 72))	('p53', 'Gene', (59, 62))	('EC9706', 'CellLine', 'CVCL:E307', (20, 26))	('p53', 'Gene', '7157', (59, 62))	('carry', 'Reg', (53, 58))
731138	30854784	Nearly half of all cancers are p53-mutated (Liu et al., 2013; Stoklosa and Golab, 2005; Szymanska and Hainaut, 2003), suggesting that the p53-independent tumor-suppressive effect of FAM175B in ESCC also exists in other cancer types with p53 mutations.	('p53', 'Gene', (138, 141))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('FAM175B', 'Gene', '23172', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Disease', (154, 159))	('ESCC', 'Disease', (193, 197))	('p53', 'Gene', '7157', (237, 240))	('p53', 'Gene', '7157', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('p53', 'Gene', (237, 240))	('p53', 'Gene', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('FAM175B', 'Gene', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('cancer', 'Disease', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('p53', 'Gene', '7157', (138, 141))	('mutations', 'Var', (241, 250))
731154	30854784	The results of our study suggest that the lack of FAM175B-ATF-4-CHOP pathway activity may facilitate the development of apoptosis resistance in cancer cells in a hypoxic environment.	('development', 'CPA', (105, 116))	('CHOP', 'Gene', '1649', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('FAM175B', 'Gene', '23172', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('facilitate', 'PosReg', (90, 100))	('apoptosis resistance', 'CPA', (120, 140))	('CHOP', 'Gene', (64, 68))	('cancer', 'Disease', (144, 150))	('ATF-4', 'Gene', '468', (58, 63))	('activity', 'MPA', (77, 85))	('lack', 'Var', (42, 46))	('FAM175B', 'Gene', (50, 57))	('ATF-4', 'Gene', (58, 63))
731171	30537965	HLPMDA achieved AUCs of 0.9232, 0.8437 and 0.9218 +- 0.0004 based on global and local leave-one-out cross validation and 5-fold cross validation, respectively.	('HL', 'CellLine', 'CVCL:2492', (0, 2))	('0.9218 +- 0.0004', 'Var', (43, 59))	('0.8437', 'Var', (32, 38))
731234	30537965	HLPMDA achieved AUCs of 0.9232, 0.8437 and 0.9218 +- 0.0004 based on global/local LOOCV and 5-fold cross validation, respectively.	('HL', 'CellLine', 'CVCL:2492', (0, 2))	('0.9218 +- 0.0004', 'Var', (43, 59))	('0.8437', 'Var', (32, 38))
731285	30537965	3, HLPMDA achieved AUCs of 0.9232, 0.8437 and 0.9218 +- 0.0004 in the global LOOCV, local LOOCV and 5-fold CV, respectively, which shows a better predictive capability than other ten methods: PBMDA, MCMDA, MaxFlow, HGIMDA, RLSMDA, HDMP WBSMDA, MirAI, MIDP and RWRMDA.	('0.8437', 'Var', (35, 41))	('HL', 'CellLine', 'CVCL:2492', (3, 5))	('0.9218', 'Var', (46, 52))	('PBMDA', 'Chemical', '-', (192, 197))
731305	30537965	Furthermore, in human breast cancer cells miRNA-200 family alterations relates to mesenchymal and drug-resistant phenotypes.	('alterations', 'Var', (59, 70))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('relates', 'Reg', (71, 78))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('human', 'Species', '9606', (16, 21))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
731336	30537965	AUCs of HLPMDA are 0.9232 (global LOOCV), 0.8437 (local LOOCV) and 0.9218 +- 0.0004 (5-fold CV).	('0.9218 +- 0.0004', 'Var', (67, 83))	('HL', 'CellLine', 'CVCL:2492', (8, 10))	('0.8437', 'Var', (42, 48))
731346	29106393	Moreover, we demonstrated that DHRS2 could reduce reactive oxygen species and decrease nicotinamide adenine dinucleotide phosphate (oxidized/reduced), increase p53 stability and decrease Rb phosphorylation; it also decreased p38 mitogen-activated protein kinase phosphorylation and matrix metalloproteinase 2.	('p38', 'Gene', '5594', (225, 228))	('nicotinamide adenine dinucleotide phosphate', 'MPA', (87, 130))	('Rb', 'Chemical', 'MESH:D012413', (187, 189))	('reduce', 'NegReg', (43, 49))	('stability', 'MPA', (164, 173))	('decrease', 'NegReg', (78, 86))	('Rb phosphorylation', 'MPA', (187, 205))	('p53', 'Protein', (160, 163))	('DHRS2', 'Var', (31, 36))	('decrease', 'NegReg', (178, 186))	('p38', 'Gene', (225, 228))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (50, 73))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (87, 130))	('matrix metalloproteinase 2', 'Gene', '4313', (282, 308))	('matrix metalloproteinase 2', 'Gene', (282, 308))	('increase', 'PosReg', (151, 159))	('decreased', 'NegReg', (215, 224))	('reactive oxygen species', 'MPA', (50, 73))
731349	29106393	Like most solid tumors, chromosomal alteration is frequently observed in ESCC.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('chromosomal alteration', 'Var', (24, 46))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('solid tumors', 'Disease', 'MESH:D009369', (10, 22))	('observed', 'Reg', (61, 69))	('solid tumors', 'Disease', (10, 22))	('ESCC', 'Disease', (73, 77))
731350	29106393	For example, loss of 14q11.2 is one of the most common chromosomal changes identified by comparative genomic hybridization and high-resolution deletion mapping in many cancers, including ESCC, gastrointestinal tumors, nasopharyngeal carcinoma, mesothelioma, suggesting that tumor-suppressor genes might exist in frequently deleted regions.	('ESCC', 'Disease', (187, 191))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (218, 242))	('cancers', 'Disease', (168, 175))	('loss', 'Var', (13, 17))	('gastrointestinal tumors', 'Disease', (193, 216))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (193, 216))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (218, 242))	('tumor-suppressor', 'Gene', '7248', (274, 290))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (193, 216))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('mesothelioma', 'Disease', (244, 256))	('tumor-suppressor', 'Gene', (274, 290))	('mesothelioma', 'Disease', 'MESH:D008654', (244, 256))	('nasopharyngeal carcinoma', 'Disease', (218, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
731357	29106393	It was reported that DHRS2 expression correlated with estrogen receptor status in breast cancer, and introduction of adenovirus harboring DHRS2 could suppress renal cancer cell growth.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('DHRS2', 'Gene', (21, 26))	('DHRS2', 'Var', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('renal cancer', 'Disease', (159, 171))	('expression', 'MPA', (27, 37))	('renal cancer', 'Phenotype', 'HP:0009726', (159, 171))	('estrogen receptor status', 'MPA', (54, 78))	('renal cancer', 'Disease', 'MESH:D007680', (159, 171))	('suppress', 'NegReg', (150, 158))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('correlated', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
731370	29106393	As deletion of 14q11.2 was often reported in many cancers, fluorescence in situ hybridization (FISH) was used to examine the DNA copy number alteration of DHRS2 in ESCC cell lines and tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('DHRS2', 'Gene', (155, 160))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancers', 'Disease', (50, 57))	('tumor', 'Disease', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('deletion', 'Var', (3, 11))
731371	29106393	The results revealed that copy number loss of DHRS2 existed in ESCC cell lines and ESCC tumor tissues (Supplementary Figures 1B and C).	('ESCC tumor', 'Disease', 'MESH:D004938', (83, 93))	('Supplementary Figures 1B', 'Disease', (103, 127))	('DHRS2', 'Gene', (46, 51))	('copy number loss', 'Var', (26, 42))	('ESCC tumor', 'Disease', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ESCC', 'Disease', (63, 67))	('Supplementary Figures 1B', 'Disease', 'MESH:D017034', (103, 127))
731372	29106393	To further explore whether DHRS2 affects tumor cell growth, DHRS2-V1 or DHRS2-V2 was stabled overexpressed into KYSE30 and KYSE510 cells, respectively.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('KYSE510', 'CellLine', 'CVCL:1354', (123, 130))	('DHRS2-V2', 'Gene', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('DHRS2-V1', 'Var', (60, 68))
731373	29106393	Both DHRS2-V1 and DHRS2-V2 reduced significantly foci formation rate (P<0.01, Figure 2b) and colony formation rate in soft agar (P<0.01, Figure 2c) in both KYSE30 and KYSE510 cells.	('reduced', 'NegReg', (27, 34))	('DHRS2-V1', 'Var', (5, 13))	('agar', 'Chemical', 'MESH:D000362', (123, 127))	('DHRS2-V2', 'Var', (18, 26))	('colony formation rate in soft agar', 'CPA', (93, 127))	('KYSE510', 'CellLine', 'CVCL:1354', (167, 174))	('foci formation rate', 'CPA', (49, 68))
731375	29106393	Cell growth assay and foci formation results showed that DHRS2 knock-down could increase the tumorgenecity in KYSE180 and HKESC1 cells (Figures 2e and f).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('increase', 'PosReg', (80, 88))	('tumor', 'Disease', (93, 98))	('knock-down', 'Var', (63, 73))	('HKESC1', 'CellLine', 'CVCL:D568', (122, 128))	('DHRS2', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
731379	29106393	The tumor volume and tumor weight of the xenografts induced by DHRS2-V1 or V2 significantly decreased compared with the xenografts induced by vector control cells (P<0.01, Figure 2g).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('DHRS2-V1', 'Var', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('decreased', 'NegReg', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
731382	29106393	When DHRS2 was silenced in KYSE180 and HKESC1 cells, the number of cells migrated increased in DHRS2 knock-down cells (P<0.01, Figure 3c).	('HKESC1', 'CellLine', 'CVCL:D568', (39, 45))	('DHRS2', 'Gene', (5, 10))	('increased', 'PosReg', (82, 91))	('number of cells migrated', 'CPA', (57, 81))	('knock-down', 'Var', (101, 111))	('DHRS2', 'Gene', (95, 100))
731386	29106393	The in situ terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick and labeling assays showed that the number of apoptotic cells increased in DHRS2-V1 and DHRS2-V2-transfected KYSE30 and KYSE510 cells compared with 30-Vec and 510-Vec, respectively (P<0.05, Figure 4b).	('KYSE510', 'CellLine', 'CVCL:1354', (205, 212))	('increased', 'PosReg', (147, 156))	('DHRS2-V2-transfected', 'Var', (173, 193))	('dUTP', 'Chemical', 'MESH:C027078', (63, 67))	('digoxigenin', 'Chemical', 'MESH:D004076', (68, 79))	('DHRS2-V1', 'Var', (160, 168))
731391	29106393	When DHRS2 was knocked-down in KYSE180 and HKESC1 cells, ROS increased compared with control cells (Figure 5c and d).	('knocked-down', 'Var', (15, 27))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('HKESC1', 'CellLine', 'CVCL:D568', (43, 49))	('increased', 'PosReg', (61, 70))	('DHRS2', 'Gene', (5, 10))	('ROS', 'MPA', (57, 60))
731395	29106393	Our results showed that both DHRS2-V1 and V2 could stabilize P53 through phosphorylation at Ser15 and decrease the phosphorylation of Rb at ser795 (Figure 6a and Supplementary Figure 2A).	('Rb', 'Chemical', 'MESH:D012413', (134, 136))	('stabilize', 'MPA', (51, 60))	('decrease', 'NegReg', (102, 110))	('P53', 'Gene', (61, 64))	('P53', 'Gene', '7157', (61, 64))	('phosphorylation at Ser15', 'MPA', (73, 97))	('phosphorylation', 'MPA', (115, 130))	('Ser15', 'Chemical', '-', (92, 97))	('ser795', 'Chemical', '-', (140, 146))	('DHRS2-V1', 'Var', (29, 37))
731397	29106393	As DHRS2 could downregulate ROS and ROS is known to actively participate in the cell migration process, we examined the activation of MAPK family of proteins.	('MAPK', 'Gene', (134, 138))	('DHRS2', 'Var', (3, 8))	('downregulate', 'NegReg', (15, 27))	('MAPK', 'Gene', '5595;5594;5595', (134, 138))	('ROS', 'Chemical', 'MESH:D017382', (28, 31))	('ROS', 'Protein', (28, 31))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('ROS', 'Protein', (36, 39))
731398	29106393	As shown by Figure 6c, phosphorylation of p38MAPK at Thr180/Tyr182 decreased in DHRS2-V1 and DHRS2-V2-overexpressed cells (Figure 6c and Supplementary Figure 2D).	('Thr180', 'Chemical', '-', (53, 59))	('phosphorylation', 'MPA', (23, 38))	('Thr180/Tyr182', 'Var', (53, 66))	('Tyr182', 'Chemical', '-', (60, 66))	('decreased', 'NegReg', (67, 76))
731399	29106393	The phosphorylation of p38MAPK increased when DHRS2 was knocked-down in KYSE180 and HKESC1 cells (Figure 6d and Supplementary Figure 2E).	('increased', 'PosReg', (31, 40))	('DHRS2', 'Gene', (46, 51))	('phosphorylation', 'MPA', (4, 19))	('p38MAPK', 'Protein', (23, 30))	('HKESC1', 'CellLine', 'CVCL:D568', (84, 90))	('knocked-down', 'Var', (56, 68))
731401	29106393	Matrix metalloproteinase 2 (MMP2) decreased in DHRS2-V1 and V2-transfected cells and increased when DHRS2 was knocked-down (Figures 6c and d and Supplementary Figures 2D and E).	('Matrix metalloproteinase 2', 'Gene', (0, 26))	('decreased', 'NegReg', (34, 43))	('DHRS2', 'Gene', (100, 105))	('MMP2', 'Gene', (28, 32))	('Matrix metalloproteinase 2', 'Gene', '4313', (0, 26))	('knocked-down', 'Var', (110, 122))	('increased', 'PosReg', (85, 94))	('MMP2', 'Gene', '4313', (28, 32))
731403	29106393	Deletion of 14q11.2 region is frequently detected in many tumors, including ESCC.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('ESCC', 'Disease', (76, 80))	('detected', 'Reg', (41, 49))	('Deletion', 'Var', (0, 8))
731414	29106393	The phosphorylation of Rb induces Rb to dissociate from E2F, permitting the transcription of cell proliferation promoting genes.	('permitting', 'PosReg', (61, 71))	('Rb', 'Chemical', 'MESH:D012413', (23, 25))	('Rb', 'Chemical', 'MESH:D012413', (34, 36))	('cell proliferation', 'CPA', (93, 111))	('transcription', 'MPA', (76, 89))	('phosphorylation', 'Var', (4, 19))
731422	29106393	The variant degrees of oxidative stress exhibit to bring diverse outcomes in tumor cells: while high oxidative stress can lead to cell death, mild oxidative stress initiates cell signaling activation, including increased cell growth, migration and invasion.	('oxidative stress', 'Phenotype', 'HP:0025464', (23, 39))	('cell signaling', 'MPA', (174, 188))	('cell growth', 'CPA', (221, 232))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('oxidative stress', 'Phenotype', 'HP:0025464', (147, 163))	('increased', 'PosReg', (211, 220))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('invasion', 'CPA', (248, 256))	('oxidative stress', 'Phenotype', 'HP:0025464', (101, 117))	('variant', 'Var', (4, 11))	('migration', 'CPA', (234, 243))	('mild oxidative stress', 'Var', (142, 163))	('tumor', 'Disease', (77, 82))
731428	29106393	Both DHRS2 variants (V1 and V2) could suppress tumor cell growth and cell motility.	('tumor', 'Disease', (47, 52))	('variants', 'Var', (11, 19))	('V1 and V2', 'Gene', '28299', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cell motility', 'CPA', (69, 82))	('DHRS2', 'Gene', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('suppress', 'NegReg', (38, 46))
731430	29106393	KYSE30, KYSE140, KYSE180, KYSE410, KYSE510 and KYSE520 were acquired from the German Resource Center for Biological Material (DSMZ) (Braunschweig, Germany).	('KYSE410', 'Var', (26, 33))	('KYSE520', 'Var', (47, 54))	('KYSE510', 'Var', (35, 42))	('KYSE140', 'Var', (8, 15))	('KYSE510', 'CellLine', 'CVCL:1354', (35, 42))	('KYSE180', 'Var', (17, 24))
731431	29106393	HKESC1, EC109 and EC9706, were supplied by Dr G Srivastava (Department of Pathology, The University of Hong Kong, Hong Kong, China) and Dr G Tsao (Department of Anatomy, The University of Hong Kong), respectively.	('HKESC1', 'CellLine', 'CVCL:D568', (0, 6))	('EC9706', 'CellLine', 'CVCL:E307', (18, 24))	('EC9706', 'Var', (18, 24))	('EC109', 'Var', (8, 13))
731443	29106393	For the scratch assay, DHRS2-V1, DHRS2-V2 or empty vector-transfected cells were cultured in a 100 mm dish until 95% confluence and then wounded with a pipette tip.	('pipette tip', 'Disease', (152, 163))	('pipette tip', 'Disease', 'MESH:D060725', (152, 163))	('DHRS2-V1', 'Var', (23, 31))	('DHRS2-V2', 'Var', (33, 41))
731462	29434854	Activation of the phosphatidylinositol 3-kinase/protein kinase-B/mechanistic target of rapamycin (mTOR) pathway was also suppressed by COE.	('suppressed', 'NegReg', (121, 131))	('rapamycin', 'Chemical', 'MESH:D020123', (87, 96))	('COE', 'Var', (135, 138))
731515	29434854	6A), and PI3K, Akt, p-Akt, mTOR and p-mTOR protein expression levels (Fig.	('Akt', 'Gene', '207', (15, 18))	('p-mTOR protein expression levels', 'MPA', (36, 68))	('mTOR', 'MPA', (27, 31))	('Akt', 'Gene', (22, 25))	('Akt', 'Gene', (15, 18))	('PI3K', 'Var', (9, 13))	('Akt', 'Gene', '207', (22, 25))
731532	29434854	It was demonstrated that the levels of PI3K, p-AKT, mTOR and p-mTOR decreased significantly, while the expression of AKT did not change following COE treatment.	('AKT', 'Gene', (47, 50))	('AKT', 'Gene', '207', (117, 120))	('decreased', 'NegReg', (68, 77))	('mTOR', 'MPA', (52, 56))	('AKT', 'Gene', (117, 120))	('AKT', 'Gene', '207', (47, 50))	('p-mTOR', 'MPA', (61, 67))	('PI3K', 'Var', (39, 43))
731638	26943418	The clinical diagnosis was esophageal cancer (T3N0M1 stage IV according to the 7th edition of the Union for International Cancer Control classification) and synchronous right breast cancer (T1cN0M0 stage I).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Cancer', 'Disease', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('synchronous right breast cancer', 'Disease', (157, 188))	('esophageal cancer', 'Disease', (27, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('Cancer', 'Disease', 'MESH:D009369', (122, 128))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))	('T1cN0M0', 'Var', (190, 197))	('synchronous right breast cancer', 'Disease', 'MESH:D001943', (157, 188))
731737	25810707	In a large retrospective study of 1,304 patients from several European countries, 1 x 8 Gy was similarly effective as 5 x 4 Gy in one week, 10 x 3 Gy in two weeks, 15 x 2.5 Gy in three weeks and 20 x 2 Gy in four weeks with respect to improvement of motor function.	('patients', 'Species', '9606', (40, 48))	('motor function', 'MPA', (250, 264))	('improvement', 'PosReg', (235, 246))	('1 x 8 Gy', 'Var', (82, 90))
731741	25810707	One has to be aware that in-field recurrences of MESCC occur more frequently after 5 x 4 Gy than after 10 x 3 Gy.	('MESCC', 'Disease', (49, 54))	('5 x 4 Gy', 'Var', (83, 91))	('MESCC', 'Chemical', '-', (49, 54))
731815	24315827	Subsequent studies showed modest success in patients with non-small cell lung cancers that express IGF1.	('patients', 'Species', '9606', (44, 52))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (58, 85))	('IGF1', 'Gene', (99, 103))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (58, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (62, 85))	('non-small cell lung cancers', 'Disease', (58, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('lung cancers', 'Phenotype', 'HP:0100526', (73, 85))	('express', 'Var', (91, 98))
731853	24315827	Gene polymorphisms that affect insulin signaling have been associated with body size.	('associated', 'Reg', (59, 69))	('insulin', 'Gene', (31, 38))	('body size', 'Disease', (75, 84))	('al', 'Chemical', 'MESH:D000535', (43, 45))	('insulin', 'Gene', '3630', (31, 38))	('polymorphisms', 'Var', (5, 18))
731857	24315827	The most powerfully associated single-nucleotide polymorphism associated with increased body mass is the fat mass and obesity-related (FTO) gene, which may function through nutrient sensing but with no relation to GI cancers.	('obesity', 'Disease', (118, 125))	('single-nucleotide polymorphism', 'Var', (31, 61))	('FTO', 'Gene', (135, 138))	('body mass', 'Disease', (88, 97))	('GI cancers', 'Disease', (214, 224))	('increased body mass', 'Phenotype', 'HP:0004324', (78, 97))	('GI cancer', 'Phenotype', 'HP:0007378', (214, 223))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('GI cancers', 'Disease', 'MESH:D009369', (214, 224))	('FTO', 'Gene', '79068', (135, 138))	('increased', 'PosReg', (78, 87))	('obesity', 'Phenotype', 'HP:0001513', (118, 125))	('obesity', 'Disease', 'MESH:D009765', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
731871	24315827	The altered activity of Treg cells might increase inflammation in the adipose tissue to promote carcinogenesis.	('adipose', 'Gene', '230796', (70, 77))	('inflammation', 'Disease', 'MESH:D007249', (50, 62))	('adipose', 'Gene', (70, 77))	('altered', 'Var', (4, 11))	('promote', 'PosReg', (88, 95))	('al', 'Chemical', 'MESH:D000535', (4, 6))	('increase inflammation in the adipose tissue', 'Phenotype', 'HP:0012490', (41, 84))	('inflammation', 'Disease', (50, 62))	('activity', 'MPA', (12, 20))	('carcinogenesis', 'Disease', 'MESH:D063646', (96, 110))	('carcinogenesis', 'Disease', (96, 110))	('increase', 'PosReg', (41, 49))
731901	24315827	In men, BMI > 35 increases the risk of dying from hepato-digestive cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('BMI > 35', 'Var', (8, 16))	('dying', 'Disease', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('men', 'Species', '9606', (3, 6))
731930	24315827	Adiponectin polymorphisms have not clearly been related to colorectal neoplasia.	('polymorphisms', 'Var', (12, 25))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (59, 79))	('neoplasia', 'Phenotype', 'HP:0002664', (70, 79))	('colorectal neoplasia', 'Disease', (59, 79))	('related', 'Reg', (48, 55))
731934	24315827	Furthermore, in the same model, a weekly dose of a neutralizing antibody against the IL6 receptor reduced average tumor numbers and size compared to control mice.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('IL6', 'Gene', (85, 88))	('mice', 'Species', '10090', (157, 161))	('neutralizing antibody', 'Var', (51, 72))	('al', 'Chemical', 'MESH:D000535', (56, 58))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('reduced', 'NegReg', (98, 105))
731937	24315827	Interestingly, sTNFR2 is associated with increased insulin resistance, and in this study it was also related to increased BMI.	('insulin resistance', 'Phenotype', 'HP:0000855', (51, 69))	('increased', 'PosReg', (41, 50))	('sTNFR2', 'Var', (15, 21))	('al', 'Chemical', 'MESH:D000535', (96, 98))	('increased', 'PosReg', (112, 121))	('insulin', 'Gene', (51, 58))	('BMI', 'MPA', (122, 125))	('increased BMI', 'Phenotype', 'HP:0031418', (112, 125))	('insulin', 'Gene', '3630', (51, 58))
731940	24315827	LTD4 stimulates proliferation and reduces apoptosis in several non-transformed intestinal epithelial cell lines.	('LTD4', 'Var', (0, 4))	('stimulates', 'PosReg', (5, 15))	('reduces', 'NegReg', (34, 41))	('al', 'Chemical', 'MESH:D000535', (87, 89))	('apoptosis', 'CPA', (42, 51))	('proliferation', 'CPA', (16, 29))	('al', 'Chemical', 'MESH:D000535', (98, 100))	('al', 'Chemical', 'MESH:D000535', (60, 62))
731942	24315827	Type II diabetes and obesity are influenced by genetic and functional variations in the WNT signaling pathway, important for energy metabolism.	('obesity', 'Phenotype', 'HP:0001513', (21, 28))	('influenced', 'Reg', (33, 43))	('al', 'Chemical', 'MESH:D000535', (96, 98))	('Type II diabetes', 'Disease', 'MESH:D003924', (0, 16))	('variations', 'Var', (70, 80))	('obesity', 'Disease', 'MESH:D009765', (21, 28))	('al', 'Chemical', 'MESH:D000535', (67, 69))	('Type II diabetes', 'Phenotype', 'HP:0005978', (0, 16))	('obesity', 'Disease', (21, 28))	('WNT signaling pathway', 'Pathway', (88, 109))	('Type II diabetes', 'Disease', (0, 16))
731943	24315827	Altered WNT signaling, mutations in RAS and RAF, DNA epigenetic changes and loss of function of p53 are all involved in development of CRC.	('epigenetic changes', 'Var', (53, 71))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('RAF', 'Gene', (44, 47))	('CRC', 'Disease', (135, 138))	('al', 'Chemical', 'MESH:D000535', (104, 106))	('mutations', 'Var', (23, 32))	('RAF', 'Gene', '22882', (44, 47))	('involved', 'Reg', (108, 116))	('loss of function', 'NegReg', (76, 92))	('CRC', 'Phenotype', 'HP:0003003', (135, 138))	('RAS', 'Gene', (36, 39))	('al', 'Chemical', 'MESH:D000535', (16, 18))	('men', 'Species', '9606', (127, 130))
731951	24315827	Loss of 18q frequently occurs during late stages colorectal carcinogenesis; it is inversely associated with MSI and CpG island methylation.	('MSI', 'Gene', '5928', (108, 111))	('MSI', 'Gene', (108, 111))	('18q', 'Protein', (8, 11))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (49, 74))	('colorectal carcinogenesis', 'Disease', (49, 74))	('Loss', 'Var', (0, 4))
731958	24315827	It is important to note that obesity-associated molecular changes in the colon could determine outcomes of patients with cancer, and be used to direct therapy.	('molecular changes', 'Var', (48, 65))	('obesity', 'Disease', 'MESH:D009765', (29, 36))	('determine', 'Reg', (85, 94))	('obesity', 'Disease', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('obesity', 'Phenotype', 'HP:0001513', (29, 36))	('patients', 'Species', '9606', (107, 115))
731959	24315827	Finally, a recent increase in BMI (by 5 kg/m2 increments) was associated with microsatellite stable and MSI-low, but not with MSI-high tumors.	('MSI-high tumors', 'Disease', (126, 141))	('increase', 'PosReg', (18, 26))	('al', 'Chemical', 'MESH:D000535', (3, 5))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('men', 'Species', '9606', (51, 54))	('MSI-high tumors', 'Disease', 'MESH:D009369', (126, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('MSI-low', 'Disease', 'MESH:D009800', (104, 111))	('BMI', 'Disease', (30, 33))	('increase in BMI', 'Phenotype', 'HP:0031418', (18, 33))	('microsatellite', 'Var', (78, 92))	('MSI-low', 'Disease', (104, 111))
731978	24315827	A meta-analysis showed significant and dose-dependent associations between obesity and gastroesophgeal reflux disease, with RRs increasing from 1.43 to 1.94 for BMIs 25-30 kg/m2.	('obesity', 'Disease', (75, 82))	('gastroesophgeal reflux disease', 'Phenotype', 'HP:0002020', (87, 117))	('BMIs 25-30 kg/m2', 'Var', (161, 177))	('al', 'Chemical', 'MESH:D000535', (100, 102))	('gastroesophgeal reflux disease', 'Disease', (87, 117))	('obesity', 'Phenotype', 'HP:0001513', (75, 82))	('gastroesophgeal reflux disease', 'Disease', 'MESH:D005764', (87, 117))	('al', 'Chemical', 'MESH:D000535', (9, 11))	('obesity', 'Disease', 'MESH:D009765', (75, 82))
731987	24315827	There are few data on the contribution of epigenetic alterations to the metaplasia-dysplasia-EAC pathway.	('metaplasia-dysplasia', 'Disease', 'MESH:D008679', (72, 92))	('EAC', 'Gene', '1540', (93, 96))	('EAC', 'Gene', (93, 96))	('metaplasia-dysplasia', 'Disease', (72, 92))	('al', 'Chemical', 'MESH:D000535', (53, 55))	('epigenetic alterations', 'Var', (42, 64))
731988	24315827	The biologic and diagnostic implications of epigenetic changes and altered metabolism remain to be explored and may provide novel targets for the prevention and treatment of BE and EAC.	('epigenetic changes', 'Var', (44, 62))	('men', 'Species', '9606', (166, 169))	('metabolism', 'MPA', (75, 85))	('altered', 'Reg', (67, 74))	('al', 'Chemical', 'MESH:D000535', (67, 69))	('BE', 'Phenotype', 'HP:0100580', (174, 176))	('EAC', 'Gene', '1540', (181, 184))	('EAC', 'Gene', (181, 184))
732004	24315827	Variants at the CDX2 binding site of VDR, which encodes the human vitamin D receptor, have been associated with obesity and fat mass.	('Variants', 'Var', (0, 8))	('obesity', 'Disease', 'MESH:D009765', (112, 119))	('associated', 'Reg', (96, 106))	('VDR', 'Gene', (37, 40))	('CDX2', 'Gene', (16, 20))	('obesity', 'Disease', (112, 119))	('CDX2', 'Gene', '1045', (16, 20))	('vitamin D receptor', 'Gene', '7421', (66, 84))	('VDR', 'Gene', '7421', (37, 40))	('fat mass', 'Disease', (124, 132))	('vitamin D receptor', 'Gene', (66, 84))	('human', 'Species', '9606', (60, 65))	('obesity', 'Phenotype', 'HP:0001513', (112, 119))
732028	24315827	Low levels of IGF1R mRNA were associated with increased rate of overall survival in patients with GCA.	('al', 'Chemical', 'MESH:D000535', (78, 80))	('patients', 'Species', '9606', (84, 92))	('increased', 'PosReg', (46, 55))	('overall survival', 'MPA', (64, 80))	('GCA', 'Disease', (98, 101))	('IGF1R', 'Gene', (14, 19))	('al', 'Chemical', 'MESH:D000535', (68, 70))	('mRNA', 'MPA', (20, 24))	('IGF1R', 'Gene', '3480', (14, 19))	('Low levels', 'Var', (0, 10))
732042	24315827	A large meta-analysis found RRs of 1.07 and 1.12 for PAC per 5 kg/m2 increase in BMI in men and women, respectively.	('increase in BMI', 'Phenotype', 'HP:0031418', (69, 84))	('BMI', 'MPA', (81, 84))	('PAC', 'Chemical', '-', (53, 56))	('men', 'Species', '9606', (88, 91))	('PAC', 'Phenotype', 'HP:0006725', (53, 56))	('women', 'Species', '9606', (96, 101))	('men', 'Species', '9606', (98, 101))	('PAC', 'Var', (53, 56))	('PAC', 'Phenotype', 'HP:0006699', (53, 56))	('al', 'Chemical', 'MESH:D000535', (15, 17))
732049	24315827	A case-control study found that subjects in the lowest quartile of plasma IGFBP1 level had an odds ratio for PAC of 2.07, compared to the 3 highest quartiles; the effects of low plasma IGFBP1 became progressively stronger with time.	('PAC', 'Phenotype', 'HP:0006699', (109, 112))	('IGFBP1', 'Gene', (185, 191))	('PAC', 'Disease', (109, 112))	('IGFBP1', 'Gene', '3484', (74, 80))	('low', 'Var', (174, 177))	('PAC', 'Chemical', '-', (109, 112))	('PAC', 'Phenotype', 'HP:0006725', (109, 112))	('IGFBP1', 'Gene', '3484', (185, 191))	('IGFBP1', 'Gene', (74, 80))
732058	24315827	In a case-control study, carries of a specific NR5A2 variant had a lower risk of PAC compared to carries of a common allele, regardless of BMI or diabetes.	('NR5A2', 'Gene', '2494', (47, 52))	('al', 'Chemical', 'MESH:D000535', (117, 119))	('PAC', 'Disease', (81, 84))	('variant', 'Var', (53, 60))	('PAC', 'Chemical', '-', (81, 84))	('PAC', 'Phenotype', 'HP:0006725', (81, 84))	('NR5A2', 'Gene', (47, 52))	('diabetes', 'Disease', (146, 154))	('diabetes', 'Disease', 'MESH:D003920', (146, 154))	('PAC', 'Phenotype', 'HP:0006699', (81, 84))	('lower', 'NegReg', (67, 72))
732059	24315827	The association between PAC and polymorphisms in PPARG is controversial.	('polymorphisms', 'Var', (32, 45))	('PPARG', 'Gene', (49, 54))	('PAC', 'Phenotype', 'HP:0006725', (24, 27))	('al', 'Chemical', 'MESH:D000535', (69, 71))	('PAC', 'Phenotype', 'HP:0006699', (24, 27))	('PAC', 'Chemical', '-', (24, 27))	('PPARG', 'Gene', '5468', (49, 54))	('PAC', 'Disease', (24, 27))
732351	31040888	Improvement in GER symptoms was seen with 140 mm stent compared to 70 mm stent.	('GER', 'Gene', '59330', (15, 18))	('140 mm', 'Var', (42, 48))	('GER', 'Gene', (15, 18))	('Improvement', 'PosReg', (0, 11))	('men', 'Species', '9606', (7, 10))	('GER', 'Phenotype', 'HP:0002020', (15, 18))
732368	31040888	The complications such as bleeding, stent migration, and stent occlusion were also similar between anti reflux and standard stent.	('bleeding', 'Disease', (26, 34))	('anti reflux', 'Var', (99, 110))	('bleeding', 'Disease', 'MESH:D006470', (26, 34))	('anti reflux', 'Phenotype', 'HP:0002020', (99, 110))
732372	31040888	The risk of adverse outcomes of bleeding related to stent, stent migration and stent occlusion was also comparable between anti reflux and standard stent.	('bleeding', 'Disease', 'MESH:D006470', (32, 40))	('anti reflux', 'Phenotype', 'HP:0002020', (123, 134))	('anti reflux', 'Var', (123, 134))	('bleeding', 'Disease', (32, 40))
732461	29139215	Indeed, we observed a higher percentage of 30- and 90-day mortality in the >=80 age group, though the absolute number of deaths is smaller than the 70-79-year-old group and the rates in the >=80 group may be overestimated due to the relatively small number of patients in that age group (~6% of the trimodality cohort).	('>=80', 'Var', (75, 79))	('higher', 'PosReg', (22, 28))	('patients', 'Species', '9606', (260, 268))
732508	29147443	Our study first reported that 4-NQO induced esophageal cancer in mice.	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mice', 'Species', '10090', (65, 69))	('4-NQO', 'Var', (30, 35))	('esophageal cancer', 'Disease', (44, 61))	('4-NQO', 'Chemical', 'MESH:D015112', (30, 35))
732513	29147443	Massive obesity mice, C57BL/6J-Lee (ob/ob) mice lack leptin and show mild hyperglycemia and hyperinsulinemia.	('mice', 'Species', '10090', (43, 47))	('hyperinsulinemia', 'Disease', (92, 108))	('obesity', 'Disease', (8, 15))	('hyperglycemia', 'Disease', (74, 87))	('lack', 'NegReg', (48, 52))	('Massive obesity', 'Phenotype', 'HP:0012743', (0, 15))	('obesity', 'Phenotype', 'HP:0001513', (8, 15))	('leptin', 'MPA', (53, 59))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (92, 108))	('hyperglycemia', 'Phenotype', 'HP:0003074', (74, 87))	('C57BL/6J-Lee', 'Var', (22, 34))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (92, 108))	('mice', 'Species', '10090', (16, 20))	('hyperglycemia', 'Disease', 'MESH:D006943', (74, 87))	('obesity', 'Disease', 'MESH:D009765', (8, 15))
732515	29147443	C57BL6/KsJ + Leprdb (db/db) mice with mutations impairing leptin receptor signaling have severe hyperglycemia, hyperinsulinemia and obesity as early as 10 days of age.	('hyperglycemia', 'Disease', (96, 109))	('obesity', 'Disease', (132, 139))	('impairing', 'NegReg', (48, 57))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (111, 127))	('mice', 'Species', '10090', (28, 32))	('hyperglycemia', 'Phenotype', 'HP:0003074', (96, 109))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (111, 127))	('obesity', 'Phenotype', 'HP:0001513', (132, 139))	('hyperinsulinemia', 'Disease', (111, 127))	('hyperglycemia', 'Disease', 'MESH:D006943', (96, 109))	('leptin receptor signaling', 'MPA', (58, 83))	('mutations', 'Var', (38, 47))	('obesity', 'Disease', 'MESH:D009765', (132, 139))
732563	29147443	3a) was significantly up-regulated in the TSOD mice that received 4-NQO (P < 0.01).	('mice', 'Species', '10090', (47, 51))	('up-regulated', 'PosReg', (22, 34))	('4-NQO', 'Var', (66, 71))	('4-NQO', 'Chemical', 'MESH:D015112', (66, 71))
732573	29147443	However, the numbers of oral and esophageal tumors per animal in the TSOD mice that received 4-NQO were higher than those of TSNO mice given 4-NQO.	('4-NQO', 'Var', (93, 98))	('esophageal tumors', 'Disease', 'MESH:D004938', (33, 50))	('mice', 'Species', '10090', (130, 134))	('esophageal tumors', 'Phenotype', 'HP:0100751', (33, 50))	('4-NQO', 'Chemical', 'MESH:D015112', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('esophageal tumors', 'Disease', (33, 50))	('4-NQO', 'Chemical', 'MESH:D015112', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('TSNO', 'Chemical', '-', (125, 129))	('higher', 'PosReg', (104, 110))	('mice', 'Species', '10090', (74, 78))
732575	29147443	The exact mechanism(s) for the findings are not known, but our analysis indicated that several pro-inflammatory cytokines and chemokines in the esophagus of the TSOD mice that received 4-NQO were highly expressed when compared with the TSNO mice.	('TSNO', 'Chemical', '-', (236, 240))	('mice', 'Species', '10090', (241, 245))	('pro-inflammatory cytokines', 'MPA', (95, 121))	('mice', 'Species', '10090', (166, 170))	('4-NQO', 'Var', (185, 190))	('4-NQO', 'Chemical', 'MESH:D015112', (185, 190))
732645	27812512	Increased body weight gain was observed in colon cancer patients after 12 weeks of nutritional intervention with ONS containing eicosapentaenoic acid (EPA) compared to that of the control patients (4.94 vs. -1.17; p = 0.045).	('patients', 'Species', '9606', (56, 64))	('eicosapentaenoic', 'Var', (128, 144))	('EPA', 'Chemical', 'MESH:D015118', (151, 154))	('ONS', 'Chemical', '-', (113, 116))	('colon cancer', 'Disease', 'MESH:D015179', (43, 55))	('colon cancer', 'Phenotype', 'HP:0003003', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('body weight', 'CPA', (10, 21))	('patients', 'Species', '9606', (188, 196))	('Increased', 'PosReg', (0, 9))	('colon cancer', 'Disease', (43, 55))	('eicosapentaenoic acid', 'Chemical', 'MESH:D015118', (128, 149))	('Increased body weight', 'Phenotype', 'HP:0004324', (0, 21))	('gain', 'PosReg', (22, 26))
732652	27812512	Patients who received EN containing arginine, n-3 fatty acid, ribonucleic acid, and MCT showed lower serum IL-8 concentration compared to that in the control patients.	('lower', 'NegReg', (95, 100))	('n-3 fatty acid', 'Chemical', 'MESH:D015525', (46, 60))	('Patients', 'Species', '9606', (0, 8))	('arginine', 'Var', (36, 44))	('n-3 fatty acid', 'Var', (46, 60))	('IL-8', 'Gene', '3576', (107, 111))	('patients', 'Species', '9606', (158, 166))	('arginine', 'Chemical', 'MESH:D001120', (36, 44))	('IL-8', 'Gene', (107, 111))	('MCT', 'Chemical', '-', (84, 87))
732653	27812512	ONS containing leucine, and fish oil resulted in decreased serum prostaglandin E2 (PGE2) concentrations.	('decreased serum prostaglandin E2', 'Phenotype', 'HP:0003566', (49, 81))	('PGE2', 'Chemical', 'MESH:D015232', (83, 87))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (65, 81))	('leucine', 'Var', (15, 22))	('decreased', 'NegReg', (49, 58))	('ONS', 'Chemical', '-', (0, 3))	('leucine', 'Chemical', 'MESH:D007930', (15, 22))
732713	27812512	A recent mechanistic study showed that dendritic cells exposed to arachidonic acid and DHA reduced T helper cell, which may explain their anti-inflammatory activities.	('arachidonic acid', 'Chemical', 'MESH:D016718', (66, 82))	('DHA', 'Chemical', 'MESH:D004281', (87, 90))	('DHA', 'Var', (87, 90))	('arachidonic acid', 'Var', (66, 82))	('reduced', 'NegReg', (91, 98))	('T helper cell', 'CPA', (99, 112))	('DHA reduced T helper cell', 'Phenotype', 'HP:0008165', (87, 112))
732721	27812512	Among selected studies, 2 studies involving liver cancer patients used branched-chain amino acid (BCAA) including leucine, isoleucine, and valine.	('liver cancer', 'Disease', (44, 56))	('valine', 'Chemical', 'MESH:D014633', (139, 145))	('leucine', 'Var', (114, 121))	('leucine', 'Chemical', 'MESH:D007930', (126, 133))	('valine', 'Var', (139, 145))	('liver cancer', 'Disease', 'MESH:D006528', (44, 56))	('patients', 'Species', '9606', (57, 65))	('isoleucine', 'Var', (123, 133))	('liver cancer', 'Phenotype', 'HP:0002896', (44, 56))	('leucine', 'Chemical', 'MESH:D007930', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('isoleucine', 'Chemical', 'MESH:D007532', (123, 133))	('branched-chain amino acid', 'MPA', (71, 96))	('BCAA', 'Chemical', 'MESH:D000597', (98, 102))	('branched-chain amino acid', 'Chemical', 'MESH:D000597', (71, 96))
732727	27812512	Glutamine supplementation also alleviates cancer treatment-induced mucositis by stimulating rapid epithelial cell production.	('Glutamine', 'Chemical', 'MESH:D005973', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mucositis', 'Disease', (67, 76))	('rapid epithelial cell production', 'MPA', (92, 124))	('Glutamine', 'Protein', (0, 9))	('stimulating', 'PosReg', (80, 91))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('mucositis', 'Disease', 'MESH:D052016', (67, 76))	('supplementation', 'Var', (10, 25))	('alleviates', 'NegReg', (31, 41))
732839	26264462	According to this study, miR-210 stable expression mimics hypoxia-induced metabolic changes associated with a slight but significant stabilization of HIF-1alpha, and this information, combined with a strong reduction of radioresistance following HIF-1 silencing, reinforces the central role of HIF-1 in the resistance to radiotherapy.	('HIF-1alpha', 'Gene', '3091', (150, 160))	('stabilization', 'MPA', (133, 146))	('reduction', 'NegReg', (207, 216))	('hypoxia', 'Disease', (58, 65))	('HIF-1', 'Gene', '3091', (246, 251))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('radioresistance', 'CPA', (220, 235))	('silencing', 'Var', (252, 261))	('HIF-1', 'Gene', '3091', (150, 155))	('HIF-1', 'Gene', '3091', (294, 299))	('miR-210', 'Gene', (25, 32))	('miR-210', 'Gene', '406992', (25, 32))	('HIF-1', 'Gene', (246, 251))	('HIF-1alpha', 'Gene', (150, 160))	('HIF-1', 'Gene', (150, 155))	('HIF-1', 'Gene', (294, 299))
732845	26264462	Furthermore, these authors also demonstrated that esophageal tumors with high expression of miR-296-5p had a worse prognosis compared with those with low expression.	('esophageal tumors', 'Disease', (50, 67))	('esophageal tumors', 'Phenotype', 'HP:0100751', (50, 67))	('miR-296', 'Gene', '407022', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('high expression', 'Var', (73, 88))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal tumors', 'Disease', 'MESH:D004938', (50, 67))	('miR-296', 'Gene', (92, 99))
732931	24957772	Decades of research have demonstrated that aberrant glycosylation can lead to malignant degeneration.	('glycosylation', 'Protein', (52, 65))	('malignant degeneration', 'Disease', 'MESH:D009369', (78, 100))	('malignant degeneration', 'Disease', (78, 100))	('lead to', 'Reg', (70, 77))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (43, 65))	('aberrant', 'Var', (43, 51))
732937	24957772	It has been known for decades that specific alterations in PTMs can lead to pathology including tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lead to', 'Reg', (68, 75))	('metastasis', 'CPA', (115, 125))	('tumor', 'Disease', (96, 101))	('alterations', 'Var', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
732944	24957772	From the standpoint of cancer, aberrantly glycosylated proteins present an interesting opportunity for biomarker identification.	('aberrantly glycosylated', 'Var', (31, 54))	('proteins', 'Protein', (55, 63))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
732950	24957772	Within the last several years, a number of authors have described techniques using novel technologies, such as mass spectroscopy, that have shown promise in using these known alterations in glycosylation to isolate both specific glycoprotein profiles and individual glycans in breast, colorectal, hepatocellular, pancreatic, prostate, ovarian, and esophageal cancer.	('pancreatic', 'Disease', (313, 323))	('alterations', 'Var', (175, 186))	('prostate', 'Disease', (325, 333))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('glycans', 'Chemical', 'MESH:D011134', (266, 273))	('esophageal cancer', 'Disease', (348, 365))	('esophageal cancer', 'Disease', 'MESH:D004938', (348, 365))	('hepatocellular', 'Disease', (297, 311))	('ovarian', 'Disease', (335, 342))	('pancreatic', 'Disease', 'MESH:D010195', (313, 323))	('breast', 'Disease', (277, 283))	('colorectal', 'Disease', (285, 295))
733056	23103824	A higher percentage of patients with incomplete EIM were female (40%) than those with CEIM (20%, P=.045); patients with incomplete EIM also had a longer segment of BE (5.5 vs 4.0 cm, P=.03), incomplete healing between treatment sessions (45% vs 15%, P=0.004), and underwent more treatment sessions (4 vs 3, P=.007).	('men', 'Species', '9606', (223, 226))	('incomplete', 'NegReg', (191, 201))	('patients', 'Species', '9606', (23, 31))	('CEIM', 'Chemical', '-', (86, 90))	('men', 'Species', '9606', (156, 159))	('men', 'Species', '9606', (284, 287))	('patients', 'Species', '9606', (106, 114))	('incomplete EIM', 'Var', (120, 134))	('longer', 'PosReg', (146, 152))
733136	23103824	After performing multivariate analysis, incomplete healing between treatment sessions (OR 3.7; 95% CI 1.3-9.9) was an independent predictor of incomplete EIM after controlling for length of BE and total number of treatment sessions to complete therapy.	('men', 'Species', '9606', (72, 75))	('incomplete EIM', 'Disease', (143, 157))	('men', 'Species', '9606', (218, 221))	('incomplete', 'Var', (40, 50))
733163	23103824	Stricture was not statistically associated with pre-treatment histology, although patients with stricture were numerically more likely to have IMC before treatment (25%) compared to those without stricture (15%).	('stricture', 'Var', (96, 105))	('men', 'Species', '9606', (159, 162))	('IMC', 'Chemical', '-', (143, 146))	('patients', 'Species', '9606', (82, 90))	('IMC', 'Disease', (143, 146))	('men', 'Species', '9606', (57, 60))
733228	23573078	Additionally, molecular alterations are associated with epigenetic changes such as the methylation and acetylation status as known for APC and p16.	('APC', 'Disease', (135, 138))	('acetylation status', 'MPA', (103, 121))	('APC', 'Disease', 'MESH:D011125', (135, 138))	('methylation', 'MPA', (87, 98))	('molecular alterations', 'Var', (14, 35))	('epigenetic changes', 'MPA', (56, 74))
733248	23573078	The expression pattern of P53 as well as the hypermethylation of p16 and APC suggests high potency, followed by the cell-cycle-associated proteins Cyclin A and D1.	('potency', 'MPA', (91, 98))	('P53', 'Gene', (26, 29))	('hypermethylation', 'Var', (45, 61))	('Cyclin A', 'Gene', '890', (147, 155))	('P53', 'Gene', '7157', (26, 29))	('APC', 'Disease', 'MESH:D011125', (73, 76))	('p16', 'Gene', (65, 68))	('Cyclin A', 'Gene', (147, 155))	('APC', 'Disease', (73, 76))
733254	23573078	From the set of molecular markers, "only" p53, p16, and p21 currently represent applicable biomarkers, especially for progression.	('p21', 'Gene', (56, 59))	('p16', 'Var', (47, 50))	('p21', 'Gene', '644914', (56, 59))
733258	23573078	comprehensively reviewed the role of inflammation on genetic and epigenetic changes in BE and EAC focusing on oxidative stress and the NF-kappaB-pathway.	('NF-kappaB', 'Gene', (135, 144))	('BE', 'Phenotype', 'HP:0100580', (87, 89))	('inflammation', 'Disease', 'MESH:D007249', (37, 49))	('inflammation', 'Disease', (37, 49))	('oxidative stress', 'Phenotype', 'HP:0025464', (110, 126))	('epigenetic changes', 'Var', (65, 83))	('NF-kappaB', 'Gene', '4790', (135, 144))	('EAC', 'Phenotype', 'HP:0011459', (94, 97))
733364	19479888	Fhit-deficient mice are more susceptible to carcinogen induction of tumors than wild type mice, and Fhit gene therapy inhibits tumor induction and progression.	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (127, 132))	('inhibits', 'NegReg', (118, 126))	('Fhit-deficient', 'Var', (0, 14))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('Fhit', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('gene therapy', 'Var', (105, 117))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
733369	19479888	Nit1 knockout in mouse tissues/cells results in increased cell proliferation, enhanced survival of cells exposed to DNA-damaging agents and an increased incidence of NMBA-induced tumors.	('increased', 'PosReg', (48, 57))	('NMBA', 'Chemical', 'MESH:C014707', (166, 170))	('mouse', 'Species', '10090', (17, 22))	('knockout', 'Var', (5, 13))	('tumors', 'Disease', (179, 185))	('cell proliferation', 'CPA', (58, 76))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('survival', 'CPA', (87, 95))	('Nit1', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('enhanced', 'PosReg', (78, 86))
733373	19479888	alphaKGM and alphaKSM are generated in vivo by transamination of glutamine and asparagine, respectively.	('asparagine', 'Chemical', 'MESH:D001216', (79, 89))	('transamination', 'Var', (47, 61))	('glutamine', 'Chemical', 'MESH:D005973', (65, 74))	('glutamine', 'Protein', (65, 74))
733410	19479888	Antisera for IHC were used to detect Ki67 (M7240, Dako North America, Inc., Carpinteria, CA), cyclin D1 (RM-9104, Thermo Fisher Scientific, Fremont, CA), pChk2 (AB38461, Abcam), and gammaH2AX (IHC-00059, Bethyl Lab).	('cyclin D1', 'Gene', (94, 103))	('gammaH2AX', 'Gene', (182, 191))	('Ki67', 'Gene', (37, 41))	('pChk2', 'Gene', (154, 159))	('gammaH2AX', 'Gene', '15270', (182, 191))	('cyclin D1', 'Gene', '12443', (94, 103))	('RM-9104', 'Var', (105, 112))	('Ki67', 'Gene', '17345', (37, 41))
733436	19479888	As reported previously, Fhit-/- and Nit1-/- mice are healthy, fertile and long-lived as are DKO mice.	('Nit1-/-', 'Var', (36, 43))	('Fhit-/-', 'Var', (24, 31))	('mice', 'Species', '10090', (44, 48))	('mice', 'Species', '10090', (96, 100))
733448	19479888	The average tumors per mouse were 1.75 for Fhit-/- versus 2.25 for DKO.	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Fhit-/-', 'Var', (43, 50))	('mouse', 'Species', '10090', (23, 28))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
733457	19479888	The incidence of dysplasia in untreated DKO mice was significantly higher than in untreated Fhit-/- mice.	('dysplasia', 'Disease', 'MESH:D004476', (17, 26))	('higher', 'PosReg', (67, 73))	('DKO', 'Var', (40, 43))	('mice', 'Species', '10090', (100, 104))	('mice', 'Species', '10090', (44, 48))	('dysplasia', 'Disease', (17, 26))
733469	19479888	Immunofluorescence results of this staining are shown in Figure 5C, left panel, which illustrates that wt cells show the highest level of 8-OHdG and DKO cells the lowest, with quantification of 8-OHdG levels shown in Figure 5C, right panel; >95% (P<0.01) of wt cells were positive for 8-OHdG, while only 14% of DKO cells and ~55% of Fhit-/- cells were positive.	('8-OHdG', 'Var', (285, 291))	('positive', 'Reg', (272, 280))	('8-OHdG', 'Chemical', 'MESH:C067134', (285, 291))	('8-OHdG', 'Chemical', 'MESH:C067134', (138, 144))	('8-OHdG', 'Chemical', 'MESH:C067134', (194, 200))
733479	19479888	Fhit tumor suppressor function, which does not require that the protein be catalytically active, is an example, and Nit1 tumor suppressor function is likely another, since over-expression of a recombinant Nit1 catalytic mutant showed tumor suppressor activity.	('tumor', 'Disease', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('over-expression', 'PosReg', (172, 187))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('mutant', 'Var', (220, 226))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('Nit1', 'Gene', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
733481	19479888	In this study we find that DKO mice were more susceptible to NMBA induction of such tumors and developed more spontaneous tumors than Fhit-/- mice, suggesting that loss of Nit1 and Fhit in gastrointestinal tissue leads to increased susceptibility to tumor development than the singly deficient mice.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('mice', 'Species', '10090', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('NMBA', 'Chemical', 'MESH:C014707', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumors', 'Disease', (84, 90))	('Nit1', 'Gene', (172, 176))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('loss', 'Var', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Fhit', 'Gene', (181, 185))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('mice', 'Species', '10090', (294, 298))	('tumors', 'Disease', (122, 128))	('mice', 'Species', '10090', (142, 146))	('susceptibility', 'MPA', (232, 246))	('tumor', 'Disease', (84, 89))
733482	19479888	The results shown in Table 1, concerning visible tumors during necropsy, suggests that the average tumor burden per mouse is not quite 2-fold higher in the DKO mice in comparison to Fhit-/- tumor burden for each comparable group.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (190, 195))	('tumors', 'Disease', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('mice', 'Species', '10090', (160, 164))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mouse', 'Species', '10090', (116, 121))	('DKO', 'Var', (156, 159))
733484	19479888	Thus, the DKO mice were much more likely to develop malignant tumors of the forestomach.	('malignant tumors of the forestomach', 'Disease', (52, 87))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mice', 'Species', '10090', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('develop', 'PosReg', (44, 51))	('DKO', 'Var', (10, 13))	('malignant tumors of the forestomach', 'Disease', 'MESH:D013274', (52, 87))
733496	19479888	Fhit and Nit1 are not coordinately lost in these tumors, as Fhit and Wwox protein are in tumors; Fhit and Wwox are both encoded at fragile sites and thus are highly susceptible to similar intrinsic and extrinsic DNA damaging agents, while Nit1 is not encoded at a fragile site.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Wwox', 'Gene', (106, 110))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('Wwox', 'Gene', '80707', (106, 110))	('tumors', 'Disease', (49, 55))	('Fhit', 'Var', (97, 101))	('Wwox', 'Gene', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('Wwox', 'Gene', '80707', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('encoded', 'Reg', (120, 127))
733500	19479888	Nit1 knockout in mouse tissues/cells results in increased cell proliferation, enhanced survival of cells exposed to DNA-damaging agents and increased incidence of NMBA-induced tumors.	('increased', 'PosReg', (48, 57))	('NMBA', 'Chemical', 'MESH:C014707', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mouse', 'Species', '10090', (17, 22))	('knockout', 'Var', (5, 13))	('cell proliferation', 'CPA', (58, 76))	('tumors', 'Disease', (176, 182))	('survival', 'CPA', (87, 95))	('Nit1', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('increased', 'PosReg', (140, 149))	('enhanced', 'PosReg', (78, 86))
733501	19479888	Nit1 over-expression leads to decreased cancer cell viability and increased apoptosis, even after over-expression of a Nit1 protein with the Cys residue of the catalytic site mutated to Ala.	('Cys', 'Chemical', 'MESH:D003545', (141, 144))	('increased', 'PosReg', (66, 75))	('Nit1', 'Gene', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('Ala', 'Chemical', 'MESH:D000409', (186, 189))	('over-expression', 'Var', (5, 20))	('cancer', 'Disease', (40, 46))	('Nit1', 'Gene', (0, 4))	('apoptosis', 'CPA', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('decreased', 'NegReg', (30, 39))
733503	19479888	Evidence was presented recently that Nit2 protein can also act as a tumor suppressor, even when its catalytic site is mutated.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('Nit2', 'Var', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
733603	30813135	Surgery has been therefore recommended for the patients with Stage I SCLC, especially cT1N0M0 in the Japanese guideline for treatment of carcinoma of the lung, and a relatively high incidence of the operable SCLCs patients was also reported by other Japanese groups.	('carcinoma of the lung', 'Disease', 'MESH:D008175', (137, 158))	('patients', 'Species', '9606', (214, 222))	('SCLC', 'Phenotype', 'HP:0030357', (69, 73))	('SCLC', 'Disease', (208, 212))	('SCLC', 'Disease', 'MESH:D018288', (208, 212))	('patients', 'Species', '9606', (47, 55))	('cT1N0M0', 'Var', (86, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('SCLC', 'Phenotype', 'HP:0030357', (208, 212))	('carcinoma of the lung', 'Disease', (137, 158))	('SCLC', 'Disease', (69, 73))	('SCLC', 'Disease', 'MESH:D018288', (69, 73))
733622	26839961	Additionally, the biological function assays demonstrated that CRABP2 acted as a tumor suppressor in esophageal squamous carcinogenesis by significantly inhibiting cell growth, inducing cell apoptosis and blocking cell metastasis both in vitro and in vivo.	('inhibiting', 'NegReg', (153, 163))	('esophageal squamous carcinogenesis', 'Disease', (101, 135))	('cell metastasis', 'CPA', (214, 229))	('blocking', 'NegReg', (205, 213))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cell growth', 'CPA', (164, 175))	('CRABP2', 'Var', (63, 69))	('inducing', 'NegReg', (177, 185))	('esophageal squamous carcinogenesis', 'Disease', 'MESH:D063646', (101, 135))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cell apoptosis', 'CPA', (186, 200))	('tumor', 'Disease', (81, 86))
733649	26839961	The next day, the membranes were incubated with appropriate secondary antibodies conjugated with fluorescence [Licor, 926-32210 (Mouse) or 926-32211(Rabbit)].	('Rabbit', 'Species', '9986', (149, 155))	('Mouse', 'Species', '10090', (129, 134))	('926-32211', 'Var', (139, 148))	('926-32210', 'Var', (118, 127))
733673	26839961	As shown in Fig 3, the G1 phase of CRABP2 OE transfected stable EC109 cells was significantly less than that of Vector transfectedEC109 cells, whereas the S phase of CRABP2 OE transfected EC109 cells was much more than that of Vector transfected EC109 cells at both 24 h and 48 h, suggesting that CRABP2 might promote the G1/S checkpoint progression in esophageal tumor cells.	('promote', 'PosReg', (310, 317))	('less', 'NegReg', (94, 98))	('G1/S checkpoint progression', 'CPA', (322, 349))	('esophageal tumor', 'Disease', 'MESH:D004938', (353, 369))	('EC', 'Phenotype', 'HP:0011459', (130, 132))	('EC', 'Phenotype', 'HP:0011459', (64, 66))	('esophageal tumor', 'Disease', (353, 369))	('EC', 'Phenotype', 'HP:0011459', (246, 248))	('EC', 'Phenotype', 'HP:0011459', (188, 190))	('esophageal tumor', 'Phenotype', 'HP:0100751', (353, 369))	('CRABP2', 'Gene', (35, 41))	('EC109', 'CellLine', 'CVCL:6898', (246, 251))	('EC109', 'CellLine', 'CVCL:6898', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('CRABP2', 'Var', (297, 303))	('EC109', 'CellLine', 'CVCL:6898', (188, 193))	('EC109', 'CellLine', 'CVCL:6898', (64, 69))
733683	26839961	Remarkably, the weight of CRABP2 OE tumors was less than that of Vector tumors (Fig 5B, *p = 0.019).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('weight', 'MPA', (16, 22))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('less', 'NegReg', (47, 51))	('Vector tumors', 'Disease', 'MESH:D000079426', (65, 78))	('tumors', 'Disease', (72, 78))	('Vector tumors', 'Disease', (65, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('CRABP2 OE', 'Var', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
733687	26839961	Previous studies have demonstrated that CRABP2 is epigenetically downregulated in a large number of carcinomas, such as prostate cancer, human head and neck tumors, astrocytic gliomas.	('epigenetically', 'Var', (50, 64))	('gliomas', 'Phenotype', 'HP:0009733', (176, 183))	('downregulated', 'NegReg', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (165, 183))	('neck tumors', 'Disease', 'MESH:D006258', (152, 163))	('human', 'Species', '9606', (137, 142))	('astrocytic gliomas', 'Disease', (165, 183))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('carcinomas', 'Disease', (100, 110))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('head and neck tumors', 'Phenotype', 'HP:0012288', (143, 163))	('prostate cancer', 'Disease', (120, 135))	('CRABP2', 'Gene', (40, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('carcinomas', 'Disease', 'MESH:D002277', (100, 110))	('neck tumors', 'Disease', (152, 163))
733698	26839961	has detected extensive CpG methylation upstream of the CRABP2 gene locus in a study sample comprising 100 astrocytic gliomas of WHO Grade II to IV, which is negatively correlated with CRABP2 mRNA expression.	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('CRABP2', 'Gene', (55, 61))	('astrocytic gliomas', 'Disease', (106, 124))	('CpG methylation', 'Var', (23, 38))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (106, 124))
733700	26839961	It has been reported to be epigenetically modulated by the trascription factors MyoD and Sp1 to promote myoblast differentiation in C2C12 cells.	('epigenetically modulated', 'Var', (27, 51))	('MyoD', 'Gene', '17927', (80, 84))	('Sp1', 'Gene', (89, 92))	('promote', 'PosReg', (96, 103))	('C2C12', 'CellLine', 'CVCL:0188', (132, 137))	('myoblast differentiation', 'CPA', (104, 128))	('MyoD', 'Gene', (80, 84))
733704	26839961	Additionally, further tumor-bearing nude mice experiments confirmed that CRABP2 in esophageal tumor cells could significantly suppress the cell proliferation in vivo.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cell proliferation in vivo', 'CPA', (139, 165))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (94, 99))	('nude mice', 'Species', '10090', (36, 45))	('esophageal tumor', 'Disease', 'MESH:D004938', (83, 99))	('esophageal tumor', 'Disease', (83, 99))	('tumor', 'Disease', (22, 27))	('CRABP2', 'Var', (73, 79))	('suppress', 'NegReg', (126, 134))	('esophageal tumor', 'Phenotype', 'HP:0100751', (83, 99))
733710	26839961	Taken together, CRABP2 in esophageal tumorigenesis acted as a tumor suppressor not only by inhibiting cell proliferation, but also by blocking cell metastasis via EMT process.	('esophageal tumor', 'Disease', (26, 42))	('inhibiting', 'NegReg', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('esophageal tumor', 'Phenotype', 'HP:0100751', (26, 42))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('esophageal tumor', 'Disease', 'MESH:D004938', (26, 42))	('CRABP2', 'Var', (16, 22))	('cell proliferation', 'CPA', (102, 120))	('cell metastasis via EMT process', 'CPA', (143, 174))	('blocking', 'NegReg', (134, 142))
733785	21703447	We show here that p63 null embryos rapidly develop intestine-like metaplasia with gene expression profiles similar to Barrett's metaplasia.	('metaplasia', 'Disease', 'MESH:D008679', (128, 138))	('metaplasia', 'Disease', (66, 76))	('metaplasia', 'Disease', (128, 138))	('p63 null', 'Var', (18, 26))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (118, 138))	("Barrett's metaplasia", 'Disease', (118, 138))	('metaplasia', 'Disease', 'MESH:D008679', (66, 76))	('develop', 'PosReg', (43, 50))
733797	21703447	Indeed the p63 null embryos have been reported to have idiopathic metaplastic changes both the esophagus and proximal stomach, two normally squamous tissues in the mouse.	('p63 null', 'Var', (11, 19))	('metaplastic changes', 'CPA', (66, 85))	('mouse', 'Species', '10090', (164, 169))
733798	21703447	The p63 null mouse therefore offers a unique opportunity to probe the link between tissue damage and metaplasia.	('mouse', 'Species', '10090', (13, 18))	('metaplasia', 'Disease', (101, 111))	('metaplasia', 'Disease', 'MESH:D008679', (101, 111))	('p63', 'Var', (4, 7))
733804	21703447	Barrett's esophagus in humans also lacks p63 staining unlike adjacent squamous tissues where p63 strongly decorates basal nuclei (; Fig.	('p63', 'Var', (93, 96))	('decorates', 'NegReg', (106, 115))	('basal nuclei', 'CPA', (116, 128))	('humans', 'Species', '9606', (23, 29))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (0, 19))	('p63', 'Protein', (41, 44))	('lacks', 'NegReg', (35, 40))
733805	21703447	Antibodies to keratin 8 stain human Barrett's esophagus as well as the metaplasia in the p63 null mouse (Fig.	('human', 'Species', '9606', (30, 35))	("Barrett's esophagus", 'Disease', (36, 55))	('Antibodies', 'Var', (0, 10))	('stain', 'Reg', (24, 29))	('metaplasia', 'Disease', 'MESH:D008679', (71, 81))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (36, 55))	('metaplasia', 'Disease', (71, 81))	('mouse', 'Species', '10090', (98, 103))	('keratin', 'Protein', (14, 21))
733807	21703447	We probed the metaplasia and control tissues for known markers of Barrett's esophagus using antibodies against villin (Vil1) and anterior gradient 2 (Agr2) in addition to keratin 8 (Krt8), all of which showed specific and robust staining of the metaplasia in the p63 null embryos (Figure S1).	('metaplasia', 'Disease', 'MESH:D008679', (245, 255))	('metaplasia', 'Disease', (245, 255))	('metaplasia', 'Disease', (14, 24))	('Agr2', 'Gene', (150, 154))	('Krt8', 'Gene', '16691', (182, 186))	('Vil1', 'Gene', (119, 123))	('Krt8', 'Gene', (182, 186))	('p63', 'Var', (263, 266))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (66, 85))	('metaplasia', 'Disease', 'MESH:D008679', (14, 24))
733809	21703447	We compared the gene expression profile of the metaplastic epithelia with those of specific regions of the gastrointestinal tract in mutant and wild type animals, comparing RNA from microdissected tissues on expression microarray chips.	('gastrointestinal tract', 'Disease', (107, 129))	('mutant', 'Var', (133, 139))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (107, 129))
733816	21703447	Significantly, ectopic expression of Cdx2 in parietal cells resulted in an intestinal metaplasia of transgenic mice, suggesting a dominant role for this transcription factor in the transcommitment to intestinal programs.	('Cdx2', 'Gene', '12591', (37, 41))	('metaplasia', 'Disease', (86, 96))	('ectopic expression', 'Var', (15, 33))	('Cdx2', 'Gene', (37, 41))	('metaplasia', 'Disease', 'MESH:D008679', (86, 96))	('transgenic mice', 'Species', '10090', (100, 115))
733820	21703447	Together, these data argue that both Barrett's esophagus and the p63 null metaplasia are different entities from other regions of the gastrointestinal tract.	('p63', 'Var', (65, 68))	("Barrett's esophagus", 'Disease', (37, 56))	('gastrointestinal tract', 'Disease', (134, 156))	('metaplasia', 'Disease', 'MESH:D008679', (74, 84))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (37, 56))	('metaplasia', 'Disease', (74, 84))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (134, 156))
733821	21703447	We next asked how the gene expression differences between wild type and p63 null proximal stomach compared with two available, independent datasets of human Barrett's metaplasia and normal esophagus (Fig.	("Barrett's metaplasia", 'Disease', (157, 177))	('human', 'Species', '9606', (151, 156))	('p63 null', 'Var', (72, 80))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (157, 177))
733827	21703447	In fact, the fold-change in these genes in the p63 null metaplasia (mucin 4 (Muc4, 73x), keratin 20 (Krt20, 61x), trefoil factor 2 (TFF2, 49x), claudin 3 (Cldn3, 46x), Agr2 (120x), and Vil1 (27x); p< 10-5 for all) greatly exceeded those in the Barrett's datasets (Table S2).	('fold-change', 'MPA', (13, 24))	('claudin 3', 'Gene', '12739', (144, 153))	('Krt20', 'Gene', '66809', (101, 106))	('mucin 4', 'Gene', (68, 75))	('TFF2', 'Gene', (132, 136))	('trefoil factor 2', 'Gene', (114, 130))	('TFF2', 'Gene', '21785', (132, 136))	('keratin 20', 'Gene', (89, 99))	('mucin 4', 'Gene', '140474', (68, 75))	('claudin 3', 'Gene', (144, 153))	('Krt20', 'Gene', (101, 106))	('trefoil factor 2', 'Gene', '21785', (114, 130))	('p63', 'Var', (47, 50))	('metaplasia', 'Disease', 'MESH:D008679', (56, 66))	('keratin 20', 'Gene', '66809', (89, 99))	('metaplasia', 'Disease', (56, 66))
733831	21703447	These findings, while broadly based, suggest similar processes are occurring in the cells of the p63 null metaplasia and those of Barrett's esophagus.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (130, 149))	('p63 null', 'Var', (97, 105))	('metaplasia', 'Disease', 'MESH:D008679', (106, 116))	('metaplasia', 'Disease', (106, 116))
733836	21703447	When we compared the Car4 staining pattern on the p63 null and wild type proximal stomach at E13, both yielded a similarly appearing, Car4-expressing columnar epithelium (Fig.	('Car4', 'Gene', '12351', (134, 138))	('E13', 'Gene', '114727', (93, 96))	('Car4', 'Gene', '12351', (21, 25))	('E13', 'Gene', (93, 96))	('p63 null', 'Var', (50, 58))	('Car4', 'Gene', (134, 138))	('Car4', 'Gene', (21, 25))
733838	21703447	Why do the p63 null embryos go on to develop a Barrett's-like metaplasia while the wild type embryos do not?	('p63 null', 'Var', (11, 19))	('develop', 'PosReg', (37, 44))	('metaplasia', 'Disease', (62, 72))	('metaplasia', 'Disease', 'MESH:D008679', (62, 72))
733843	21703447	Car4 cells with direct access to the basement membrane at E14 had a proliferation index greater than 65%, while those undermined by p63-expressing cells showed a proliferation index of approximately 10%, suggesting a mechanism by which the p63 cells prevent the Car4 cells from evolving into a proliferative metaplasia (Fig.	('Car4', 'Gene', (0, 4))	('p63', 'Var', (240, 243))	('Car4', 'Gene', '12351', (262, 266))	('Car4', 'Gene', (262, 266))	('metaplasia', 'Disease', 'MESH:D008679', (308, 318))	('metaplasia', 'Disease', (308, 318))	('E14', 'Gene', (58, 61))	('E14', 'Gene', '114729', (58, 61))	('Car4', 'Gene', '12351', (0, 4))
733851	21703447	Therefore in the p63 null embryo this Car4 epithelium evolves to yield a Barrett's-like metaplasia independent of a "transcommitment" mechanism.	('Car4', 'Gene', '12351', (38, 42))	('metaplasia', 'Disease', 'MESH:D008679', (88, 98))	('metaplasia', 'Disease', (88, 98))	('yield', 'Reg', (65, 70))	('p63', 'Var', (17, 20))	('Car4', 'Gene', (38, 42))
733853	21703447	Car4 cells persist in the E18 and E19 metaplasia, though as a discrete population of small cells that do not express Krt7 and appear strongly associated with the basement membrane (not shown).	('Car4', 'Gene', (0, 4))	('E19 metaplasia', 'Disease', (34, 48))	('E18', 'Var', (26, 29))	('associated', 'Reg', (142, 152))	('E19 metaplasia', 'Disease', 'MESH:D008679', (34, 48))	('Car4', 'Gene', '12351', (0, 4))
733862	21703447	We confirmed that two of these, Muc4 and chorioembryonic antigen cell adhesion molecule (CEACAM), were present in the squamocolumnar junction of wild type adult mice and in the metaplasia of E18 p63 null mice (Figure S5).	('mice', 'Species', '10090', (161, 165))	('metaplasia', 'Disease', 'MESH:D008679', (177, 187))	('metaplasia', 'Disease', (177, 187))	('E18 p63', 'Var', (191, 198))	('mice', 'Species', '10090', (204, 208))
733863	21703447	A separate comparison between genes significantly (p<0.05) high in the junction versus p63 null metaplasia versus those high in Barrett's esophagus revealed a consensus overlap of 87 genes represented as heatmaps (Fig.	('p63', 'Var', (87, 90))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (128, 147))	('metaplasia', 'Disease', 'MESH:D008679', (96, 106))	('metaplasia', 'Disease', (96, 106))
733887	21703447	Once established, it is clear that Barrett's metaplasia evolves along complex pathways in which inflammation drives proliferation-induced mutations and epigenetic changes that become the basis of the observed clonal selection.	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (35, 55))	("Barrett's metaplasia", 'Disease', (35, 55))	('inflammation', 'Disease', (96, 108))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('epigenetic changes', 'Var', (152, 170))	('mutations', 'Var', (138, 147))
733899	21703447	Indeed p63 null squamous tissues such as the epidermis and thymus still undergo normal differentiation as evidenced by loricrin and involucrin in the epidermis and the acquisition of functionally mature antigen presentation cells and normal T cell maturation in the thymus.	('loricrin', 'Gene', (119, 127))	('T cell maturation', 'CPA', (241, 258))	('acquisition', 'PosReg', (168, 179))	('loricrin', 'Gene', '16939', (119, 127))	('involucrin', 'MPA', (132, 142))	('p63', 'Var', (7, 10))
733900	21703447	A similar effect of the loss of p63 in the squamous stem cells present in the esophagus at E13 would explain the absence of squamous progenitors that normally undermine and suppress the uncontrolled growth of the Car4 cells in the proximal stomach.	('loss', 'Var', (24, 28))	('Car4', 'Gene', '12351', (213, 217))	('Car4', 'Gene', (213, 217))	('absence', 'NegReg', (113, 120))	('E13', 'Gene', '114727', (91, 94))	('suppress', 'NegReg', (173, 181))	('uncontrolled', 'MPA', (186, 198))	('E13', 'Gene', (91, 94))	('p63', 'Gene', (32, 35))	('undermine', 'NegReg', (159, 168))
734013	31601040	Such interventions can thus also be expected to prevent the progression of sarcopenia that would have resulted from exacerbated dysphagia.	('sarcopenia', 'Disease', 'MESH:D055948', (75, 85))	('interventions', 'Var', (5, 18))	('sarcopenia', 'Disease', (75, 85))	('dysphagia', 'Disease', (128, 137))	('dysphagia', 'Phenotype', 'HP:0002015', (128, 137))	('dysphagia', 'Disease', 'MESH:D003680', (128, 137))
734026	31601040	On the other hand, it was reported that low visceral fat content was associated with poor prognosis in patients with upper gastrointestinal cancers, including in esophageal cancer.	('fat', 'Gene', (53, 56))	('esophageal cancer', 'Disease', (162, 179))	('fat', 'Gene', '2195', (53, 56))	('low', 'Var', (40, 43))	('upper gastrointestinal cancers', 'Disease', (117, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (123, 146))	('patients', 'Species', '9606', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('upper gastrointestinal cancers', 'Disease', 'MESH:D005770', (117, 147))
734047	31059058	Further bioinformatics analyses identified a nine-lncRNA signature, including AC098973, AL133493, RP11-51M24, RP11-317N8, RP11-834C11, RP11-69C17, LINC00471, LINC01193 and RP1-124C.	('RP11', 'Gene', '26121', (122, 126))	('RP1', 'Gene', '6101', (110, 113))	('RP1', 'Gene', (172, 175))	('LINC01193', 'Gene', '348120', (158, 167))	('RP1', 'Gene', '6101', (135, 138))	('AC098973', 'Var', (78, 86))	('RP1', 'Gene', '6101', (172, 175))	('RP11', 'Gene', '26121', (110, 114))	('RP11', 'Gene', '26121', (135, 139))	('RP11', 'Gene', (122, 126))	('RP11', 'Gene', (98, 102))	('RP1', 'Gene', (98, 101))	('RP1', 'Gene', (122, 125))	('LINC01193', 'Gene', (158, 167))	('RP1', 'Gene', '6101', (98, 101))	('LINC00471', 'Gene', '151477', (147, 156))	('AL133493', 'Var', (88, 96))	('RP1', 'Gene', '6101', (122, 125))	('RP11', 'Gene', (110, 114))	('RP11', 'Gene', (135, 139))	('RP1', 'Gene', (110, 113))	('RP1', 'Gene', (135, 138))	('LINC00471', 'Gene', (147, 156))	('RP11', 'Gene', '26121', (98, 102))
734058	31059058	The development and progression of cancer involve various types of genomic alterations, including DNA mutations, epigenetic modifications, changes in gene expression and the complex interplay of these processes.	('epigenetic modifications', 'Var', (113, 137))	('changes', 'Reg', (139, 146))	('DNA', 'Disease', (98, 101))	('gene expression', 'MPA', (150, 165))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
734061	31059058	Aberrantly expressed lncRNAs have been reported to serve as potential biomarkers for cancer diagnosis and prognosis.	('Aberrantly expressed', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('lncRNAs', 'Protein', (21, 28))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
734086	31059058	A total of nine optimal lncRNA biomarkers of ESCC were identified, including AC098973, AL133493, RP11-51M24, RP11-317N8, RP11-834C11, RP11-69C17, LINC00471, LINC01193 and RP1-124C.	('RP1', 'Gene', (134, 137))	('LINC01193', 'Gene', '348120', (157, 166))	('RP11', 'Gene', '26121', (121, 125))	('RP11', 'Gene', '26121', (97, 101))	('RP1', 'Gene', '6101', (109, 112))	('RP1', 'Gene', '6101', (134, 137))	('RP1', 'Gene', (171, 174))	('AC098973', 'Var', (77, 85))	('RP11', 'Gene', '26121', (109, 113))	('LINC00471', 'Gene', '151477', (146, 155))	('RP1', 'Gene', '6101', (171, 174))	('LINC01193', 'Gene', (157, 166))	('RP11', 'Gene', '26121', (134, 138))	('RP11', 'Gene', (121, 125))	('RP11', 'Gene', (97, 101))	('RP1', 'Gene', (121, 124))	('RP1', 'Gene', (97, 100))	('LINC00471', 'Gene', (146, 155))	('RP1', 'Gene', '6101', (97, 100))	('RP1', 'Gene', '6101', (121, 124))	('RP11', 'Gene', (109, 113))	('AL133493', 'Var', (87, 95))	('ESCC', 'Disease', (45, 49))	('RP11', 'Gene', (134, 138))	('RP1', 'Gene', (109, 112))
734087	31059058	The expression levels of AC098973, AL133493, RP11-51M24 and RP11-317N8 were significantly increased in early-stage tumors compared with advanced-stage tumors, whereas the expression levels of the remaining five lncRNAs were significantly decreased in early-stage tumors (Table II).	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('RP11', 'Gene', (60, 64))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('AL133493', 'Var', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('expression levels', 'MPA', (4, 21))	('RP11', 'Gene', '26121', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('increased', 'PosReg', (90, 99))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (115, 121))	('AC098973', 'Var', (25, 33))	('RP11', 'Gene', '26121', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('expression', 'MPA', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', (263, 269))	('RP11', 'Gene', (45, 49))
734108	31059058	According to the present results, the tumor progression stage predicted by the constructed SVM classifier was significantly correlated with the patient survival rate in the following subgroups: Male patients, patients <60 years old, alcohol consumers, smokers, patients with tumors at TNM stages of N0+N1 or T3+T4 and patients who did not receive adjuvant therapy.	('tumor', 'Disease', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('patient', 'Species', '9606', (318, 325))	('T3+T4', 'Var', (308, 313))	('patient', 'Species', '9606', (199, 206))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('patient', 'Species', '9606', (261, 268))	('patient', 'Species', '9606', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Disease', (275, 281))	('alcohol', 'Chemical', 'MESH:D000438', (233, 240))	('patients', 'Species', '9606', (209, 217))	('tumor', 'Disease', (38, 43))	('patient', 'Species', '9606', (209, 216))	('patients', 'Species', '9606', (318, 326))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (261, 269))
734112	31059058	Using a random forest algorithm, a total of nine lncRNA biomarkers associated with ESCC were identified, including AC098973, AL133493, RP11-51M24, RP11-317N8, RP11-834C11, RP11-69C17, LINC00471, LINC01193 and RP1-124C.	('LINC00471', 'Gene', (184, 193))	('RP1', 'Gene', (172, 175))	('RP1', 'Gene', '6101', (135, 138))	('AL133493', 'Var', (125, 133))	('ESCC', 'Disease', (83, 87))	('RP11', 'Gene', (147, 151))	('RP1', 'Gene', (209, 212))	('RP1', 'Gene', '6101', (172, 175))	('RP11', 'Gene', (172, 176))	('RP1', 'Gene', (147, 150))	('LINC01193', 'Gene', '348120', (195, 204))	('RP11', 'Gene', '26121', (159, 163))	('RP11', 'Gene', '26121', (135, 139))	('RP1', 'Gene', '6101', (209, 212))	('RP1', 'Gene', '6101', (147, 150))	('RP1', 'Gene', (159, 162))	('AC098973', 'Var', (115, 123))	('LINC00471', 'Gene', '151477', (184, 193))	('RP11', 'Gene', '26121', (147, 151))	('LINC01193', 'Gene', (195, 204))	('RP1', 'Gene', '6101', (159, 162))	('RP11', 'Gene', '26121', (172, 176))	('RP11', 'Gene', (159, 163))	('RP11', 'Gene', (135, 139))	('RP1', 'Gene', (135, 138))
734115	31059058	The association between the dysregulation of certain lncRNAs and the prognosis of patients with cancer has been reported for several malignancies, such as hepatocellular carcinoma, breast cancer and colorectal cancer.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('dysregulation', 'Var', (28, 41))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (199, 216))	('cancer', 'Disease', (96, 102))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (181, 194))	('colorectal cancer', 'Disease', (199, 216))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('malignancies', 'Disease', 'MESH:D009369', (133, 145))	('hepatocellular carcinoma', 'Disease', (155, 179))	('association', 'Interaction', (4, 15))	('patients', 'Species', '9606', (82, 90))	('malignancies', 'Disease', (133, 145))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (199, 216))	('cancer', 'Disease', (210, 216))
734116	31059058	Li et al compared the expression levels of lncRNAs in ESCC tissues with paired adjacent normal tissues and identified a three-lncRNA signature, consisting of ENST00000435885.1, XLOC_013014 and ENST00000547963.1, which was identified to be associated with the prognosis of patients with ESCC (GEO accession no.	('associated', 'Reg', (239, 249))	('ENST00000547963.1', 'Var', (193, 210))	('XLOC_013014', 'Var', (177, 188))	('patients', 'Species', '9606', (272, 280))	('ENST00000435885.1', 'Var', (158, 175))	('ESCC', 'Disease', (286, 290))
734119	31059058	To the best of our knowledge, the lncRNAs identified in the present study, including AC098973, AL133493, RP11-51M24, RP11-317N8, RP11-834C11, RP11-69C17, LINC00471, LINC01193 and RP1-124C have not been functionally annotated.	('RP11', 'Gene', (117, 121))	('RP1', 'Gene', '6101', (142, 145))	('LINC01193', 'Gene', '348120', (165, 174))	('RP1', 'Gene', (117, 120))	('RP1', 'Gene', '6101', (117, 120))	('RP1', 'Gene', (179, 182))	('RP11', 'Gene', (105, 109))	('RP11', 'Gene', '26121', (142, 146))	('RP11', 'Gene', (129, 133))	('RP1', 'Gene', (105, 108))	('AC098973', 'Var', (85, 93))	('RP1', 'Gene', (129, 132))	('RP1', 'Gene', '6101', (179, 182))	('LINC01193', 'Gene', (165, 174))	('LINC00471', 'Gene', '151477', (154, 163))	('RP11', 'Gene', '26121', (117, 121))	('RP1', 'Gene', '6101', (105, 108))	('RP1', 'Gene', '6101', (129, 132))	('AL133493', 'Var', (95, 103))	('RP11', 'Gene', (142, 146))	('RP1', 'Gene', (142, 145))	('LINC00471', 'Gene', (154, 163))	('RP11', 'Gene', '26121', (129, 133))	('RP11', 'Gene', '26121', (105, 109))
734129	30172884	The endogenous expression of PD-L1 was reduced by treatment with an EGFR inhibitor (erlotinib) or by the knockdown of EGFR.	('PD-L1', 'Gene', (29, 34))	('erlotinib', 'Chemical', 'MESH:D000069347', (84, 93))	('knockdown', 'Var', (105, 114))	('EGFR', 'Gene', (118, 122))	('reduced', 'NegReg', (39, 46))	('endogenous expression', 'MPA', (4, 25))
734142	30172884	MPDL3280A, which is a human anti-PD-L1 monoclonal antibody, has now been approved by the FDA for treating PD-L1-positive urothelial bladder cancer and non-small cell lung cancer.	('PD-L1-positive urothelial bladder cancer', 'Disease', (106, 146))	('MPDL3280A', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (151, 177))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (132, 146))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (151, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('human', 'Species', '9606', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('non-small cell lung cancer', 'Disease', (151, 177))	('PD-L1-positive urothelial bladder cancer', 'Disease', 'MESH:D010300', (106, 146))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (155, 177))
734173	30172884	Furthermore, positive PD-L1 staining were associated with advanced disease state (stages III and IV; P value = .0379) and lymph node metastasis (P value = .0466) as determined by chi-square analysis (Table 1).	('positive', 'Var', (13, 21))	('advanced disease', 'Disease', (58, 74))	('PD-L1', 'Protein', (22, 27))	('lymph node metastasis', 'CPA', (122, 143))	('advanced disease', 'Disease', 'MESH:D020178', (58, 74))
734175	30172884	After exposing to the chemotherapeutic agents, the expression level of PD-L1 in both cell lines increased drastically for both carboplatin plus paclitaxel and 5-FU plus cisplatin treatment (Figure 3A).	('increased', 'PosReg', (96, 105))	('carboplatin', 'Chemical', 'MESH:D016190', (127, 138))	('PD-L1', 'Gene', (71, 76))	('5-FU', 'Var', (159, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('5-FU', 'Chemical', 'MESH:D005472', (159, 163))	('paclitaxel', 'Chemical', 'MESH:D017239', (144, 154))	('expression level', 'MPA', (51, 67))
734182	30172884	The finding that PD-L1 is upregulated by an activating mutation in EGFR in non-small cell lung cancer (NSCLC) links the association of PD-L1 expression with the EGFR pathway and prompted us to study the regulation of PD-L1 by EGFR signaling pathway in ESCC.	('PD-L1', 'Gene', (135, 140))	('activating', 'PosReg', (44, 54))	('upregulated', 'PosReg', (26, 37))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (75, 101))	('NSCLC', 'Disease', (103, 108))	('EGFR pathway', 'Pathway', (161, 173))	('non-small cell lung cancer', 'Disease', (75, 101))	('PD-L1', 'Gene', (17, 22))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (79, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (75, 101))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
734202	30172884	Previous studies demonstrate that high PD-L1 expression is associated with advanced disease and lymph node metastasis in various cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('advanced disease', 'Disease', (75, 91))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('PD-L1', 'Protein', (39, 44))	('advanced disease', 'Disease', 'MESH:D020178', (75, 91))	('associated with', 'Reg', (59, 74))	('cancers', 'Disease', (129, 136))	('expression', 'MPA', (45, 55))	('high', 'Var', (34, 38))	('lymph node metastasis', 'CPA', (96, 117))
734203	30172884	Interestingly, there is another ESCC study reporting the opposite correlation, as patients with PD-L1 expression had a longer disease-free survival than the patients without PD-1 expression.	('disease-free survival', 'CPA', (126, 147))	('longer', 'PosReg', (119, 125))	('PD-1', 'Gene', (174, 178))	('patients', 'Species', '9606', (82, 90))	('PD-1', 'Gene', '5133', (174, 178))	('patients', 'Species', '9606', (157, 165))	('expression', 'Var', (102, 112))	('PD-L1', 'Gene', (96, 101))
734210	30172884	Consistent with the in vitro study, the in vivo study also shows that the treatment of carboplatin plus paclitaxel and 5-FU plus cisplatin caused an induction of PD-L1 level in the ESCC orthotopic tumors, as demonstrated by the Western blotting and IHC staining results.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('PD-L1 level', 'MPA', (162, 173))	('tumors', 'Disease', (197, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('carboplatin', 'Chemical', 'MESH:D016190', (87, 98))	('5-FU', 'Var', (119, 123))
734214	30172884	Studies demonstrate that the EGFR activation, by EGF stimulation or mutation, upregulates PD-L1 in lung cancer.	('EGF', 'Gene', (29, 32))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutation', 'Var', (68, 76))	('upregulates', 'PosReg', (78, 89))	('EGF', 'Gene', '1950', (29, 32))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))	('activation', 'PosReg', (34, 44))	('EGF', 'Gene', (49, 52))	('EGF', 'Gene', '1950', (49, 52))	('PD-L1', 'Gene', (90, 95))
734219	30172884	In concordance with this, our results illustrate an increase in the ERK phosphorylation along with the induction of PD-L1, after chemotherapy treatment, and its inhibition by AZD6244 attenuated the upregulation of PD-L1 in ESCC cells, indicating the regulation of PD-L1 expression by the MAPK/ERK pathway, likely as a downstream effector of EGFR activation.	('ERK', 'Gene', (293, 296))	('increase', 'PosReg', (52, 60))	('MAPK', 'Gene', '5594', (288, 292))	('PD-L1', 'Gene', (116, 121))	('phosphorylation', 'MPA', (72, 87))	('attenuated', 'NegReg', (183, 193))	('ERK', 'Gene', '5594', (68, 71))	('ERK', 'Gene', '5594', (293, 296))	('AZD6244', 'Var', (175, 182))	('upregulation', 'MPA', (198, 210))	('inhibition', 'NegReg', (161, 171))	('ERK', 'Gene', (68, 71))	('AZD6244', 'Chemical', 'MESH:C517975', (175, 182))	('MAPK', 'Gene', (288, 292))
734221	30172884	For instance, whether the increase in PD-L1 induced by chemotherapy affects the tumor behavior, such as metastasis, or the sensitivity to chemotherapy is of interest, as there are reports showing that PD-L1 affects tumor metastasis and chemosensitivity.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor metastasis', 'Disease', (215, 231))	('PD-L1', 'Var', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('metastasis', 'CPA', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('affects', 'Reg', (68, 75))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('PD-L1', 'Gene', (38, 43))	('tumor', 'Disease', (215, 220))	('tumor metastasis', 'Disease', 'MESH:D009362', (215, 231))	('chemosensitivity', 'CPA', (236, 252))	('affects', 'Reg', (207, 214))
734231	24089344	Nineteen percent of patients had ypT0N0 disease, 27% ypT1-2N0, 21% ypT3-4N0, and 33% N+.	('N', 'Chemical', 'MESH:D009584', (37, 38))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('ypT0N0 disease', 'Disease', (33, 47))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('ypT1', 'Gene', (53, 57))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('ypT3-4N0', 'Var', (67, 75))	('ypT1', 'Gene', '5861', (53, 57))	('patients', 'Species', '9606', (20, 28))
734232	24089344	The 5-year RFS rates for patients with ypT3-4 or N+ disease were better for those with a near complete response (94%) than for those with a major (64%) or minor (61%) response (P < 0.02).	('RFS', 'MPA', (11, 14))	('N+ disease', 'Var', (49, 59))	('ypT3-4', 'Var', (39, 45))	('better', 'PosReg', (65, 71))	('patients', 'Species', '9606', (25, 33))	('N', 'Chemical', 'MESH:D009584', (49, 50))
734294	24089344	Pathologic classification was ypT0N0 in 47 patients (18.7%), ypT1-2N0 in 68 patients (27.1%), ypT3-4N0 in 53 patients (21.1%), and any ypT with pN+ in 83 patients (33.1%).	('N', 'Chemical', 'MESH:D009584', (67, 68))	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (109, 117))	('ypT3-4N0', 'Var', (94, 102))	('patients', 'Species', '9606', (43, 51))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('patients', 'Species', '9606', (154, 162))	('ypT1', 'Gene', (61, 65))	('ypT1', 'Gene', '5861', (61, 65))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('pN+', 'Chemical', 'MESH:C070006', (144, 147))
734413	29113302	Most (90%) patients in the present study completed chemoradiotherapy with a total radiation dose of at least 50 Gy, with only five patients discontinuing radiotherapy after a dose of < 50 Gy as a result of early disease progression, cisplatin-induced acute renal failure, withdrawal of agreement, or delirium, a neuropsychiatric complication in cancer patients.	('patients', 'Species', '9606', (131, 139))	('acute renal failure', 'Disease', (251, 270))	('neuropsychiatric complication', 'Disease', 'MESH:D020945', (312, 341))	('renal failure', 'Phenotype', 'HP:0000083', (257, 270))	('patients', 'Species', '9606', (352, 360))	('cisplatin', 'Chemical', 'MESH:D002945', (233, 242))	('withdrawal', 'Var', (272, 282))	('acute renal failure', 'Disease', 'MESH:D058186', (251, 270))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('delirium', 'Phenotype', 'HP:0031258', (300, 308))	('patients', 'Species', '9606', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('acute renal failure', 'Phenotype', 'HP:0001919', (251, 270))	('neuropsychiatric complication', 'Disease', (312, 341))	('delirium', 'Disease', 'MESH:D003693', (300, 308))	('delirium', 'Disease', (300, 308))	('cancer', 'Disease', (345, 351))
734459	28693228	A variety of genetic and epigenetic alterations are associated with esophageal carcinoma, including mutation of the p53 gene.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (68, 88))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (68, 88))	('associated', 'Reg', (52, 62))	('mutation', 'Var', (100, 108))	('p53', 'Gene', '7157', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('epigenetic alterations', 'Var', (25, 47))	('esophageal carcinoma', 'Disease', (68, 88))	('p53', 'Gene', (116, 119))
734461	28693228	The role of epigenetic changes, including aberrant DNA methylation, is particularly significant in human cancer development.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('aberrant', 'Var', (42, 50))	('DNA methylation', 'MPA', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (99, 104))
734462	28693228	An increasing number of tumor-related genes (TRGs) that are inactivated by the hypermethylation of CpG islands have been reported in esophageal cancer, including ESCC.	('TRG', 'Gene', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('hypermethylation', 'Var', (79, 95))	('TRG', 'Gene', '6965', (45, 48))	('tumor', 'Disease', (24, 29))	('reported', 'Reg', (121, 129))	('esophageal cancer', 'Disease', (133, 150))	('ESCC', 'Disease', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
734464	28693228	In esophageal carcinomas, FHIT, E-cadherin and MLH1/MSH2 have been previously demonstrated to be inactivated through hypermethylation of their promoters.	('E-cadherin', 'Gene', (32, 42))	('MLH1', 'Gene', '4292', (47, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('FHIT', 'Gene', (26, 30))	('esophageal carcinomas', 'Disease', (3, 24))	('MLH1', 'Gene', (47, 51))	('hypermethylation', 'Var', (117, 133))	('E-cadherin', 'Gene', '999', (32, 42))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (3, 23))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (3, 24))	('FHIT', 'Gene', '2272', (26, 30))	('MSH2', 'Gene', (52, 56))	('inactivated', 'NegReg', (97, 108))	('MSH2', 'Gene', '4436', (52, 56))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (3, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
734465	28693228	However, epigenetic change is likely to be the predominant mechanism associated with the loss of FHIT, E-cadherin and MLH1/MSH2 function in sporadic esophageal carcinomas.	('FHIT', 'Gene', '2272', (97, 101))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (149, 170))	('MSH2', 'Gene', (123, 127))	('MSH2', 'Gene', '4436', (123, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('esophageal carcinomas', 'Disease', (149, 170))	('E-cadherin', 'Gene', '999', (103, 113))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (149, 169))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('FHIT', 'Gene', (97, 101))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (149, 170))	('E-cadherin', 'Gene', (103, 113))	('MLH1', 'Gene', (118, 122))	('epigenetic change', 'Var', (9, 26))	('MLH1', 'Gene', '4292', (118, 122))	('loss', 'NegReg', (89, 93))
734467	28693228	Increasing evidence indicates that smoking and alcohol induce epigenetic alterations, particularly aberrant patterns of DNA methylation.	('aberrant', 'Var', (99, 107))	('alcohol', 'Chemical', 'MESH:D000438', (47, 54))	('patterns', 'MPA', (108, 116))	('DNA methylation', 'MPA', (120, 135))	('epigenetic alterations', 'MPA', (62, 84))
734499	28693228	Cases with staining (E-cadherin, membrane; MLH1/MSH2, nucleus; COX-2, cytoplasm) in <30% of the tumor cells or with a complete absence of staining were categorized as decreased, respectively.	('MLH1', 'Gene', '4292', (43, 47))	('staining', 'Var', (11, 19))	('MLH1', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('MSH2', 'Gene', (48, 52))	('MSH2', 'Gene', '4436', (48, 52))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('COX-2', 'Gene', (63, 68))	('COX-2', 'Gene', '5743', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
734511	28693228	Epigenetic changes, including hypermethylation of the CpG island associated with a TRG, may result in the transcriptional silencing of a gene, with the subsequent loss of protein expression that may contribute to tumorigenesis.	('tumor', 'Disease', (213, 218))	('protein expression', 'MPA', (171, 189))	('loss', 'NegReg', (163, 167))	('result in', 'Reg', (92, 101))	('TRG', 'Gene', '6965', (83, 86))	('contribute', 'Reg', (199, 209))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('silencing', 'NegReg', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('hypermethylation', 'Var', (30, 46))	('TRG', 'Gene', (83, 86))	('transcriptional', 'MPA', (106, 121))
734514	28693228	Additionally, ESN progression was indicated to be associated with the accumulation of methylation-modulated absence or reduced expression of the TRGs.	('ESN', 'Disease', (14, 17))	('TRG', 'Gene', '6965', (145, 148))	('expression', 'MPA', (127, 137))	('ESN', 'Chemical', '-', (14, 17))	('methylation-modulated', 'Var', (86, 107))	('absence', 'NegReg', (108, 115))	('reduced', 'NegReg', (119, 126))	('TRG', 'Gene', (145, 148))
734523	28693228	In the present study, lost or reduced MLH1/MSH2 expression was detected in 0% (0/19) of LGIN cases, 7.1% (5/70) of HGIN/CIS cases, and 11.5% (6/52) of invasive cancer cases, indicating that loss of MLH1/MSH2 gene expression is involved in the carcinogenesis of some cases of ESCC.	('MLH1', 'Gene', (198, 202))	('MSH2', 'Gene', '4436', (43, 47))	('loss', 'Var', (190, 194))	('MLH1', 'Gene', (38, 42))	('MLH1', 'Gene', '4292', (198, 202))	('LGIN', 'Disease', (88, 92))	('expression', 'MPA', (48, 58))	('carcinogenesis', 'Disease', (243, 257))	('MLH1', 'Gene', '4292', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lost', 'NegReg', (22, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (243, 257))	('invasive cancer', 'Disease', (151, 166))	('MSH2', 'Gene', (203, 207))	('invasive cancer', 'Disease', 'MESH:D009362', (151, 166))	('reduced', 'NegReg', (30, 37))	('MSH2', 'Gene', (43, 47))	('ESCC', 'Disease', (275, 279))	('MSH2', 'Gene', '4436', (203, 207))	('involved', 'Reg', (227, 235))
734526	28693228	Additionally, it has been reported that COX-2 expression is regulated by promoter methylation in human esophageal cancer cell lines.	('promoter methylation', 'Var', (73, 93))	('esophageal cancer', 'Disease', (103, 120))	('human', 'Species', '9606', (97, 102))	('regulated', 'Reg', (60, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('COX-2', 'Gene', (40, 45))	('COX-2', 'Gene', '5743', (40, 45))	('expression', 'MPA', (46, 56))
734531	28693228	There is also evidence to support the association of alcohol use with aberrant DNA methylation patterns in several types of cancer.	('alcohol', 'Chemical', 'MESH:D000438', (53, 60))	('cancer', 'Disease', (124, 130))	('association', 'Interaction', (38, 49))	('aberrant', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DNA methylation', 'MPA', (79, 94))	('alcohol use', 'Phenotype', 'HP:0030955', (53, 64))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
734533	28693228	In general, chronic inflammation induced by alcohol/tobacco use is considered an inducer of aberrant DNA methylation.	('aberrant', 'Var', (92, 100))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('inflammation', 'Disease', 'MESH:D007249', (20, 32))	('tobacco', 'Species', '4097', (52, 59))	('inflammation', 'Disease', (20, 32))
734536	28693228	Tobacco and alcohol consumption may cause p53 mutation, one of the most frequent events in esophageal carcinogenesis.	('p53', 'Gene', (42, 45))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (91, 116))	('esophageal carcinogenesis', 'Disease', (91, 116))	('cause', 'Reg', (36, 41))	('p53', 'Gene', '7157', (42, 45))	('Tobacco', 'Species', '4097', (0, 7))	('alcohol', 'Chemical', 'MESH:D000438', (12, 19))	('mutation', 'Var', (46, 54))
734537	28693228	Point mutations in the p53 gene typically occur at an early stage of ESCC and correlate with tumor progression, therefore suggesting an important role of this genetic alteration in ESCC development.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('occur', 'Reg', (42, 47))	('tumor', 'Disease', (93, 98))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('ESCC', 'Disease', (69, 73))	('Point mutations', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
734538	28693228	However, in the present study as well as a previous study, altered p53 expression was not significantly associated with the early stage of ESCC progression.	('altered', 'Var', (59, 66))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('associated', 'Reg', (104, 114))	('ESCC', 'Disease', (139, 143))
734540	28693228	Alterations in the p53 gene and its expression have been reported in a variety of types of epithelial tumor and premalignant lesion, including HNC and esophageal cancer.	('HNC', 'Disease', (143, 146))	('esophageal cancer', 'Disease', (151, 168))	('epithelial tumor', 'Phenotype', 'HP:0031492', (91, 107))	('Alterations', 'Var', (0, 11))	('epithelial tumor', 'Disease', 'MESH:D002277', (91, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('reported', 'Reg', (57, 65))	('expression', 'MPA', (36, 46))	('epithelial tumor', 'Disease', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
734549	27510297	High GPBAR1 gene expression was found to be an indicator of worse prognosis in gastric and breast cancer patients, and an indication of better prognosis in ovarian cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ovarian cancer', 'Disease', 'MESH:D010051', (156, 170))	('breast cancer', 'Disease', (91, 104))	('patients', 'Species', '9606', (105, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ovarian cancer', 'Disease', (156, 170))	('gastric', 'Disease', (79, 86))	('patients', 'Species', '9606', (171, 179))	('GPBAR1', 'Gene', '151306', (5, 11))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('GPBAR1', 'Gene', (5, 11))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
734551	27510297	Negative, weak or mild expression of TGR5 was correlated with younger age, higher plasma level of total/direct bilirubin, higher plasma concentration of CA-125, advanced tumor stage and advanced AJCC TNM stage.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('higher plasma level of total/direct bilirubin', 'Phenotype', 'HP:0003573', (75, 120))	('higher', 'PosReg', (122, 128))	('higher', 'PosReg', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('plasma level of total/direct bilirubin', 'MPA', (82, 120))	('CA-125', 'Gene', '94025', (153, 159))	('bilirubin', 'Chemical', 'MESH:D001663', (111, 120))	('TGR5', 'Gene', (37, 41))	('tumor', 'Disease', (170, 175))	('CA-125', 'Gene', (153, 159))	('Negative', 'NegReg', (0, 8))	('mild', 'Var', (18, 22))	('weak', 'NegReg', (10, 14))
734552	27510297	The disease-specific survival rate was highest in ampullary adenocarcinoma patients with high TGR5 expression and high total bilirubin level.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('expression', 'MPA', (99, 109))	('highest', 'Reg', (39, 46))	('high total bilirubin level', 'Phenotype', 'HP:0002904', (114, 140))	('TGR5', 'Gene', (94, 98))	('patients', 'Species', '9606', (75, 83))	('bilirubin', 'Chemical', 'MESH:D001663', (125, 134))	('total bilirubin level', 'MPA', (119, 140))	('high', 'Var', (89, 93))	('ampullary adenocarcinoma', 'Disease', 'MESH:D000230', (50, 74))	('high total bilirubin', 'Phenotype', 'HP:0003573', (114, 134))	('ampullary adenocarcinoma', 'Disease', (50, 74))
734562	27510297	The accumulation of ROS/RNS was found to cause oxidative DNA damage and further mutation in colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('RNS', 'Gene', '56975', (24, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('accumulation', 'PosReg', (4, 16))	('ROS', 'Chemical', 'MESH:D017382', (20, 23))	('colon cancer', 'Disease', (92, 104))	('cause', 'Reg', (41, 46))	('oxidative DNA damage', 'MPA', (47, 67))	('mutation', 'Var', (80, 88))	('RNS', 'Gene', (24, 27))
734576	27510297	Mild to strong TGR5 staining is associated with poor patient survival, and TCDA increased proliferation of a gastric adenocarcinoma cell line through the TGR5-dependent pathway.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (109, 131))	('gastric adenocarcinoma', 'Disease', (109, 131))	('proliferation', 'CPA', (90, 103))	('increased', 'PosReg', (80, 89))	('TCDA', 'Var', (75, 79))	('TGR5-dependent pathway', 'Pathway', (154, 176))	('TCDA', 'Chemical', 'MESH:D013655', (75, 79))	('Mild to', 'Var', (0, 7))	('TGR5', 'Protein', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('patient', 'Species', '9606', (53, 60))
734607	27510297	1) revealed that prognosis was poorer in gastric cancer and breast cancer patients with high GPBAR1 gene expression than in those with low expression (Fig.	('high', 'Var', (88, 92))	('breast cancer', 'Disease', (60, 73))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('GPBAR1', 'Gene', '151306', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('GPBAR1', 'Gene', (93, 99))	('gastric cancer', 'Disease', (41, 55))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
734609	27510297	Ovarian cancer patients with high GPBAR1 gene expression tended to have a better prognosis than those with low expression (Fig.	('high', 'Var', (29, 33))	('patients', 'Species', '9606', (15, 23))	('GPBAR1', 'Gene', (34, 40))	('Ovarian cancer', 'Disease', 'MESH:D010051', (0, 14))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Ovarian cancer', 'Disease', (0, 14))	('GPBAR1', 'Gene', '151306', (34, 40))
734611	27510297	High GPBAR1 gene expression predicted a trend toward poor prognosis in 12 datasets (Table I) and good prognosis in 15 datasets (Table II).	('GPBAR1', 'Gene', (5, 11))	('GPBAR1', 'Gene', '151306', (5, 11))	('High', 'Var', (0, 4))
734612	27510297	In most datasets, the GPBAR1 gene expression was not significantly correlated with survival and only one dataset in each group displayed predictive power (GSE13507 and GSE8894).	('GSE8894', 'Var', (168, 175))	('GSE8894', 'Chemical', '-', (168, 175))	('GPBAR1', 'Gene', '151306', (22, 28))	('GPBAR1', 'Gene', (22, 28))	('GSE13507', 'Var', (155, 163))
734628	27510297	Negative, weak or mild expression of TGR5 was correlated with younger age (P=0.043) and higher level of direct bilirubin (P=0.023, separately) and tended to be correlated with higher level of total bilirubin (P=0.059), higher plasma level of cancer antigen-125 (CA-125) (P=0.099), advanced tumor stage and AJCC TNM stage (P=0.063 and 0.062, separately) (Table III).	('CA-125', 'Gene', '94025', (262, 268))	('bilirubin', 'Chemical', 'MESH:D001663', (111, 120))	('TGR5', 'Gene', (37, 41))	('plasma level', 'MPA', (226, 238))	('bilirubin', 'Chemical', 'MESH:D001663', (198, 207))	('cancer antigen-125', 'Gene', (242, 260))	('tumor', 'Disease', (290, 295))	('weak', 'NegReg', (10, 14))	('higher', 'PosReg', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('AJCC TNM', 'Disease', (306, 314))	('CA-125', 'Gene', (262, 268))	('Negative', 'NegReg', (0, 8))	('cancer antigen-125', 'Gene', '94025', (242, 260))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('mild', 'Var', (18, 22))	('higher', 'PosReg', (176, 182))	('higher', 'PosReg', (88, 94))	('level', 'MPA', (95, 100))	('total bilirubin', 'MPA', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
734630	27510297	The recurrences in patients with negative, weak or mild TGR5 expression tended to be earlier (within postoperative 12 months) (P=0.089), although the level of TGR5 expression was not associated with recurrence patterns (Table IV).	('TGR5', 'Gene', (56, 60))	('patients', 'Species', '9606', (19, 27))	('mild', 'Var', (51, 55))	('weak', 'NegReg', (43, 47))	('negative', 'NegReg', (33, 41))	('expression', 'MPA', (61, 71))
734641	27510297	Negative, weak or mild TGR5 expression was correlated with elevation of plasma bilirubin.	('bilirubin', 'Chemical', 'MESH:D001663', (79, 88))	('TGR5', 'Gene', (23, 27))	('elevation', 'PosReg', (59, 68))	('plasma bilirubin', 'MPA', (72, 88))	('mild', 'Var', (18, 22))
734645	27510297	Nuclear accumulation of beta-catenin promotes WNT activation and cancer progression; however, loss of the beta-catenin protein in ampullary cancer is correlated with poor prognosis.	('beta-catenin', 'Gene', (24, 36))	('beta-catenin', 'Gene', '1499', (106, 118))	('WNT activation', 'CPA', (46, 60))	('ampullary cancer', 'Disease', (130, 146))	('beta-catenin', 'Gene', '1499', (24, 36))	('cancer', 'Disease', (140, 146))	('loss', 'Var', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('beta-catenin', 'Gene', (106, 118))	('ampullary cancer', 'Disease', 'MESH:D009369', (130, 146))
734648	27510297	However, loss of EpCAM is linked to a more aggressive phenotype of ampullary cancer, suggesting that EpCAM may play a different role in ampullary cancer than in other cancers.	('ampullary cancer', 'Disease', (136, 152))	('EpCAM', 'Gene', (101, 106))	('EpCAM', 'Gene', '4072', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('loss', 'Var', (9, 13))	('cancers', 'Disease', (167, 174))	('linked', 'Reg', (26, 32))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('ampullary cancer', 'Disease', 'MESH:D009369', (67, 83))	('EpCAM', 'Gene', '4072', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('EpCAM', 'Gene', (17, 22))	('ampullary cancer', 'Disease', (67, 83))	('ampullary cancer', 'Disease', 'MESH:D009369', (136, 152))
734662	27510297	We analyzed multiple microarray datasets and found that high GPBAR1 gene expression predicted poor prognosis in some datasets, but good prognosis in others (Tables I and II; Fig.	('GPBAR1', 'Gene', '151306', (61, 67))	('GPBAR1', 'Gene', (61, 67))	('high', 'Var', (56, 60))
734671	27510297	Moreover, TGR5 expression is associated with the poor prognosis of patients, suppresses STAT3 signaling and inhibits cell cycle progression, angiogenesis, metastasis and evasion of the immune system in gastric cancer.	('angiogenesis', 'CPA', (141, 153))	('expression', 'Var', (15, 25))	('metastasis', 'CPA', (155, 165))	('cell cycle progression', 'CPA', (117, 139))	('patients', 'Species', '9606', (67, 75))	('suppresses', 'NegReg', (77, 87))	('evasion', 'MPA', (170, 177))	('STAT3', 'Gene', '6774', (88, 93))	('inhibits', 'NegReg', (108, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (202, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('STAT3', 'Gene', (88, 93))	('TGR5', 'Gene', (10, 14))	('gastric cancer', 'Disease', (202, 216))	('gastric cancer', 'Disease', 'MESH:D013274', (202, 216))
734678	27510297	The patients with strong TGR5 expression tended to have a lower plasma level of CA-125, earlier tumor stage, and earlier AJCC TNM stage and also a better disease-specific survival rate, particularly those patients with total bilirubin concentration higher than 2.45 mg/dl.	('bilirubin concentration higher', 'Phenotype', 'HP:0002904', (225, 255))	('patients', 'Species', '9606', (205, 213))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lower', 'NegReg', (58, 63))	('better', 'PosReg', (147, 153))	('total bilirubin concentration', 'MPA', (219, 248))	('CA-125', 'Gene', '94025', (80, 86))	('CA-125', 'Gene', (80, 86))	('expression', 'Var', (30, 40))	('tumor', 'Disease', (96, 101))	('disease-specific survival rate', 'CPA', (154, 184))	('bilirubin', 'Chemical', 'MESH:D001663', (225, 234))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('TGR5', 'Gene', (25, 29))
734680	27510297	In summary, high TGR5 expression was correlated with lower plasma concentration of total/direct bilirubin, lower plasma level of CA-125, early tumor stage and AJCC TNM stage.	('bilirubin', 'Chemical', 'MESH:D001663', (96, 105))	('high', 'Var', (12, 16))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('plasma concentration of total/direct bilirubin', 'MPA', (59, 105))	('lower', 'NegReg', (107, 112))	('AJCC', 'Disease', (159, 163))	('TGR5', 'Gene', (17, 21))	('lower plasma concentration', 'Phenotype', 'HP:0020171', (53, 79))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('CA-125', 'Gene', (129, 135))	('lower', 'NegReg', (53, 58))	('expression', 'MPA', (22, 32))	('CA-125', 'Gene', '94025', (129, 135))
734681	27510297	High TGR5 expression also predicted a good survival in patients with total bilirubin levelss higher than 2.45 mg/dl.	('total bilirubin levelss', 'MPA', (69, 92))	('High', 'Var', (0, 4))	('TGR5', 'Gene', (5, 9))	('patients', 'Species', '9606', (55, 63))	('bilirubin', 'Chemical', 'MESH:D001663', (75, 84))	('predicted', 'Reg', (26, 35))
734689	24509200	In one subject, FISH confirmed loss of CDKN2A and amplification of chromosome 8 in IM but not in a nearby NGM biopsy.	('amplification', 'Var', (50, 63))	('CDKN2A', 'Gene', (39, 45))	('loss', 'NegReg', (31, 35))	('CDKN2A', 'Gene', '1029', (39, 45))
734690	24509200	Our results show that IM has a much higher frequency of cancer-associated mutations than NGM.	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
734699	24509200	One thing that is known however, is that EAC arises through accumulation of multiple DNA alterations (mutation, DNA copy number abnormality, methylation), many of which are also observed in early dysplastic lesions.	('dysplastic lesions', 'Disease', 'MESH:D021782', (196, 214))	('mutation', 'Var', (102, 110))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('dysplastic lesions', 'Disease', (196, 214))	('methylation', 'Var', (141, 152))	('EAC', 'Disease', (41, 44))
734701	24509200	Thus, the goal of this study was to determine and compare the spectrum and frequency of DNA copy number alterations and cancer-associated point mutations in NGM and IM.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('NGM', 'Gene', (157, 160))	('copy number alterations', 'Var', (92, 115))
734728	24509200	These include deletions at 3p14 (FHIT; 54% of samples), 9p21.3 (CDKN2A; 35%) and 16q23.1 (WWOX; 15%) and amplifications at 8q24 (c-MYC; 4%) and 18q11.2 (GATA6; 8%).	('WWOX', 'Gene', '51741', (90, 94))	('amplifications', 'Var', (105, 119))	('WWOX', 'Gene', (90, 94))	('and 1', 'Gene', (140, 145))	('GATA6', 'Gene', '2627', (153, 158))	('GATA6', 'Gene', (153, 158))	('FHIT', 'Gene', (33, 37))	('FHIT', 'Gene', '2272', (33, 37))	('and 1', 'Gene', '11169', (77, 82))	('p14', 'Gene', (28, 31))	('CDKN2A', 'Gene', (64, 70))	('and 1', 'Gene', '11169', (140, 145))	('c-MYC', 'Gene', '4609', (129, 134))	('CDKN2A', 'Gene', '1029', (64, 70))	('deletions', 'Var', (14, 23))	('p14', 'Gene', '1029', (28, 31))	('c-MYC', 'Gene', (129, 134))	('and 1', 'Gene', (77, 82))
734729	24509200	These include regional deletions on 4p and 4q, amplification on 5q and deletion on 5p, deletion on 9q and amplifications on both 10p and 10q (Figure 1).	('deletions', 'Var', (23, 32))	('and 1', 'Gene', (133, 138))	('amplifications', 'Var', (106, 120))	('and 1', 'Gene', '11169', (133, 138))	('deletion', 'Var', (71, 79))	('amplification', 'Var', (47, 60))	('deletion', 'Var', (87, 95))
734730	24509200	This included 5 subjects (PID's: 50, 92, 124, 169,188) with both IM and NGM, 1 subject (PID: 89) with both composite and IM and 3 subjects (PID's: 55, 68 and 104) with composite, IM and NGM.	('and 1', 'Gene', (154, 159))	('PID', 'Gene', (26, 29))	('NGM', 'Var', (72, 75))	('PID', 'Gene', (88, 91))	('and 1', 'Gene', '11169', (154, 159))	('PID', 'Gene', '9219', (26, 29))	('PID', 'Gene', '9219', (88, 91))	('PID', 'Gene', (140, 143))	('PID', 'Gene', '9219', (140, 143))
734740	24509200	In order to identify cancer-associated point mutations in NGM and IM, we used a highly multiplexed PCR amplification approach to re-sequence 20 genes that are frequently mutated in EAC based upon an interim analysis of an emerging study of the spectrum of mutations in this disease.	('point mutations', 'Var', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('EAC', 'Phenotype', 'HP:0011459', (181, 184))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('NGM', 'Gene', (58, 61))	('EAC', 'Disease', (181, 184))
734743	24509200	Finally, three non-synonymous mutations were identified in the composite samples including a mutation in APC in one sample and mutations in ERBB2 and LRPB1 in another sample (sample UR286 from subject 89) (Figure 3).	('LRPB1', 'Gene', (150, 155))	('APC', 'Disease', (105, 108))	('ERBB2', 'Gene', '2064', (140, 145))	('ERBB2', 'Gene', (140, 145))	('APC', 'Disease', 'MESH:D011125', (105, 108))	('mutations', 'Var', (127, 136))	('mutation', 'Var', (93, 101))	('UR286', 'Chemical', '-', (182, 187))
734744	24509200	Interestingly, the IM sample (UR289) from the same subject had identical ERBB2 and LRPB1 mutations indicating clonality.	('UR289', 'Chemical', '-', (30, 35))	('LRPB1', 'Gene', (83, 88))	('mutations', 'Var', (89, 98))	('ERBB2', 'Gene', (73, 78))	('ERBB2', 'Gene', '2064', (73, 78))
734746	24509200	These data report the largest and most comprehensive comparison of cancer-associated genetic changes in NGM and IM.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('NGM', 'Gene', (104, 107))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('genetic changes', 'Var', (85, 100))
734748	24509200	These findings are in agreement with previous studies and reveal that the changes frequently target well known cancer-associated genes and regions which are similarly altered in early stage EAC.	('EAC', 'Phenotype', 'HP:0011459', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('changes', 'Var', (74, 81))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
734751	24509200	Eleven non-synonymous mutations in 16 IM samples were identified including mutations in the TP53 and CDKN2A genes as previously reported.	('CDKN2A', 'Gene', (101, 107))	('CDKN2A', 'Gene', '1029', (101, 107))	('TP53', 'Gene', '7157', (92, 96))	('mutations', 'Var', (75, 84))	('TP53', 'Gene', (92, 96))
734752	24509200	We also identified non-synonymous mutations in other cancer-associated genes not previously reported, including ERBB2, SMARCA4 and LRP1B.	('LRP1B', 'Gene', '53353', (131, 136))	('SMARCA4', 'Gene', '6597', (119, 126))	('ERBB2', 'Gene', '2064', (112, 117))	('cancer', 'Disease', (53, 59))	('ERBB2', 'Gene', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('LRP1B', 'Gene', (131, 136))	('SMARCA4', 'Gene', (119, 126))	('non-synonymous mutations', 'Var', (19, 43))
734753	24509200	Many of the observed mutations in IM tissues are present in the COSMIC database, indicating that they may be drivers of cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mutations', 'Var', (21, 30))
734754	24509200	Interestingly one of these mutations was in the CDKN2A gene and this specific mutation is also in the COSMIC database.	('mutations', 'Var', (27, 36))	('CDKN2A', 'Gene', '1029', (48, 54))	('CDKN2A', 'Gene', (48, 54))
734763	24509200	Many of these changes have also been associated with a markedly increased risk of progression to dysplasia or EAC.	('dysplasia', 'Disease', (97, 106))	('dysplasia', 'Disease', 'MESH:D004476', (97, 106))	('EAC', 'Phenotype', 'HP:0011459', (110, 113))	('changes', 'Var', (14, 21))	('EAC', 'Disease', (110, 113))
734764	24509200	Specifically, loss or mutation of TP53 and CDKN2A, aneuploidy and the extent of clonal diversity observed in IM are all generally accepted biomarkers for increased risk of progression.	('mutation', 'Var', (22, 30))	('TP53', 'Gene', (34, 38))	('CDKN2A', 'Gene', (43, 49))	('aneuploidy', 'Disease', (51, 61))	('CDKN2A', 'Gene', '1029', (43, 49))	('aneuploidy', 'Disease', 'MESH:D000782', (51, 61))	('TP53', 'Gene', '7157', (34, 38))	('loss', 'NegReg', (14, 18))
734793	24348397	A total of 95% of GISTs express KIT or DOG 1 and have mutations in KIT or platelet-derived growth factor receptor, alpha polypeptide.	('GISTs', 'Phenotype', 'HP:0100723', (18, 23))	('KIT', 'Gene', (67, 70))	('DOG 1', 'Gene', (39, 44))	('KIT', 'Gene', (32, 35))	('mutations', 'Var', (54, 63))	('DOG', 'Species', '9615', (39, 42))
734803	24348397	The PDGFRA mutation D842V, sporadic wild-type GISTs, mutations with succinate dehydrogenase or BRAF-mutated GISTs are unlikely to respond to imatinib.	('D842V', 'Var', (20, 25))	('PDGFRA', 'Gene', '5156', (4, 10))	('PDGFRA', 'Gene', (4, 10))	('BRAF', 'Gene', '673', (95, 99))	('imatinib', 'Chemical', 'MESH:D000068877', (141, 149))	('mutations', 'Var', (53, 62))	('GISTs', 'Phenotype', 'HP:0100723', (108, 113))	('BRAF', 'Gene', (95, 99))	('respond', 'MPA', (130, 137))	('GISTs', 'Phenotype', 'HP:0100723', (46, 51))	('mutation D842V', 'Var', (11, 25))	('D842V', 'Mutation', 'rs121908585', (20, 25))
734816	32709007	One of the biggest clinical issues is that most patients receiving chemotherapy, particularly cisplatin, suffer from adverse effects, including anorexia, vomiting, gastrointestinal damage, muscle loss, myelosuppression, nephrotoxicity, and ototoxicity, which can limit the effective dosage of chemotherapy drugs.	('nephrotoxicity', 'Disease', (220, 234))	('anorexia', 'Disease', (144, 152))	('myelosuppression', 'Disease', 'MESH:D001855', (202, 218))	('muscle loss', 'Phenotype', 'HP:0003202', (189, 200))	('gastrointestinal damage', 'Disease', 'MESH:D005767', (164, 187))	('nephrotoxicity', 'Disease', 'MESH:D007674', (220, 234))	('gastrointestinal damage', 'Disease', (164, 187))	('anorexia', 'Disease', 'MESH:D000855', (144, 152))	('muscle loss', 'Disease', (189, 200))	('cisplatin', 'Var', (94, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('vomiting', 'Disease', 'MESH:D014839', (154, 162))	('ototoxicity', 'Disease', 'MESH:D006311', (240, 251))	('myelosuppression', 'Disease', (202, 218))	('anorexia', 'Phenotype', 'HP:0002039', (144, 152))	('vomiting', 'Phenotype', 'HP:0002013', (154, 162))	('muscle loss', 'Disease', 'MESH:D009135', (189, 200))	('vomiting', 'Disease', (154, 162))	('ototoxicity', 'Disease', (240, 251))	('patients', 'Species', '9606', (48, 56))
734829	32709007	Based on preclinical evidence, several prospective trials are ongoing to evaluate the potential clinical effects of oral 5-ALA phosphate with sodium ferrous citrate in unresectable gastric cancer (trial ID: UMIN000024642), localized prostate cancer (jRCTs051190077), mitochondrial disease (JMA-IIA00358), Alzheimer's disease (jRCTs041180135), and autism spectrum disorder (jRCTs051190017).	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (347, 371))	('prostate cancer', 'Phenotype', 'HP:0012125', (233, 248))	('5-ALA phosphate', 'Chemical', '-', (121, 136))	('mitochondrial disease', 'Disease', (267, 288))	('gastric cancer', 'Disease', (181, 195))	('jRCTs051190017', 'Var', (373, 387))	('autism', 'Phenotype', 'HP:0000717', (347, 353))	('jRCTs041180135', 'Var', (326, 340))	('localized prostate cancer', 'Disease', (223, 248))	('gastric cancer', 'Disease', 'MESH:D013274', (181, 195))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (305, 324))	("Alzheimer's disease", 'Disease', (305, 324))	('jRCTs051190077', 'Var', (250, 264))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (305, 324))	('autism spectrum disorder', 'Disease', 'MESH:D000067877', (347, 371))	('gastric cancer', 'Phenotype', 'HP:0012126', (181, 195))	('sodium ferrous citrate', 'Chemical', '-', (142, 164))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('mitochondrial disease', 'Disease', 'MESH:D028361', (267, 288))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('autism spectrum disorder', 'Disease', (347, 371))	('localized prostate cancer', 'Disease', 'MESH:D011471', (223, 248))
734838	32709007	Significant atrophic changes in PMM were observed at days 7 and 14, between the non-treated control (0.024 and 0.025 cm2, respectively) and the GC chemotherapy (0.018 and 0.018 cm2, respectively).	('atrophic changes', 'CPA', (12, 28))	('0.018 cm2', 'Var', (171, 180))	('0.024', 'Var', (101, 106))	('0.018', 'Var', (161, 166))	('0.025 cm2', 'Var', (111, 120))	('GC', 'Chemical', '-', (144, 146))
734839	32709007	This negative effect induced by the chemotherapy was ameliorated by supplementary anamorelin (0.022 and 0.023 cm2, respectively), but not by 5-ALA (0.019 and 0.019 cm2, respectively).	('0.022', 'Var', (94, 99))	('0.023 cm2', 'Var', (104, 113))	('anamorelin', 'Chemical', 'MESH:C000593861', (82, 92))	('5-ALA', 'Chemical', 'MESH:C000614854', (141, 146))	('rat', 'Species', '10116', (59, 62))
734845	32709007	Quantitative analysis by densitometry (Figure 3 and Figure S1) revealed that the phosphorylation level of FOXO1 in skeletal muscles was decreased by GC chemotherapy (p = 0.03; non-treated control [1.0 +- 0.09] vs. GC chemotherapy [0.55 +- 0.09] in PMM and p = 0.03; non-treated control [1.0 +- 0.13] vs. GC chemotherapy [0.65 +- 0.11] in quadriceps muscle).	('FOXO1', 'Gene', (106, 111))	('FOXO1', 'Gene', '56458', (106, 111))	('phosphorylation level', 'MPA', (81, 102))	('GC', 'Chemical', '-', (149, 151))	('GC', 'Chemical', '-', (214, 216))	('GC', 'Chemical', '-', (304, 306))	('GC chemotherapy', 'Var', (149, 164))	('decreased', 'NegReg', (136, 145))
734859	32709007	GC chemotherapy induced a significantly high gastric damage (53 +- 16%), which was suppressed by oral anamorelin (26 +- 14%), but not by 5-ALA (50 +- 8%).	('5-ALA', 'Chemical', 'MESH:C000614854', (137, 142))	('chemotherapy', 'Var', (3, 15))	('high gastric damage', 'Disease', 'MESH:D013272', (40, 59))	('anamorelin', 'Chemical', 'MESH:C000593861', (102, 112))	('high gastric damage', 'Disease', (40, 59))	('GC', 'Chemical', '-', (0, 2))
734866	32709007	Of these proteins, deacyl ghrelin, IL-6, albumin, and creatinine were not affected by the GC chemotherapy (Table 4), whereas significant decrease was observed in active ghrelin (p = 0.042, vs. non-treated control).	('IL-6', 'Gene', (35, 39))	('IL-6', 'Gene', '16193', (35, 39))	('GC', 'Chemical', '-', (90, 92))	('decrease', 'NegReg', (137, 145))	('chemotherapy', 'Var', (93, 105))	('albumin', 'Gene', (41, 48))	('ghrelin', 'Gene', '58991', (169, 176))	('active', 'MPA', (162, 168))	('ghrelin', 'Gene', (169, 176))	('albumin', 'Gene', '11657', (41, 48))	('creatinine', 'MPA', (54, 64))	('creatinine', 'Chemical', 'MESH:D003404', (54, 64))	('ghrelin', 'Gene', '58991', (26, 33))	('ghrelin', 'Gene', (26, 33))
734872	32709007	First, GC chemotherapy induced anorexia and skeletal muscle atrophy, which might be associated with decreased ghrelin and the phosphorylation of FOXO1 or atrogin-1.	('skeletal muscle atrophy', 'Disease', 'MESH:D009133', (44, 67))	('GC', 'Chemical', '-', (7, 9))	('atrogin-1', 'Gene', '67731', (154, 163))	('anorexia', 'Disease', (31, 39))	('atrogin-1', 'Gene', (154, 163))	('chemotherapy', 'Var', (10, 22))	('ghrelin', 'Gene', '58991', (110, 117))	('phosphorylation', 'MPA', (126, 141))	('skeletal muscle atrophy', 'Phenotype', 'HP:0003202', (44, 67))	('anorexia', 'Disease', 'MESH:D000855', (31, 39))	('decreased', 'NegReg', (100, 109))	('ghrelin', 'Gene', (110, 117))	('skeletal muscle atrophy', 'Disease', (44, 67))	('muscle atrophy', 'Phenotype', 'HP:0003202', (53, 67))	('FOXO1', 'Gene', (145, 150))	('FOXO1', 'Gene', '56458', (145, 150))	('anorexia', 'Phenotype', 'HP:0002039', (31, 39))
734913	32709007	As a result of phosphorylation of FOXO1, its downstream target gene, atrogin-1, could be upregulated and could stimulate proteolysis and degradation of the skeletal muscle.	('phosphorylation', 'Var', (15, 30))	('upregulated', 'PosReg', (89, 100))	('atrogin-1', 'Gene', '67731', (69, 78))	('FOXO1', 'Gene', (34, 39))	('FOXO1', 'Gene', '56458', (34, 39))	('degradation', 'MPA', (137, 148))	('stimulate', 'PosReg', (111, 120))	('proteolysis', 'MPA', (121, 132))	('atrogin-1', 'Gene', (69, 78))
734973	32709007	We found anamorelin was able to mitigate anorexia, gastric mucositis, and skeletal muscle atrophy.	('anorexia', 'Disease', (41, 49))	('gastric mucositis', 'Disease', (51, 68))	('anorexia', 'Phenotype', 'HP:0002039', (41, 49))	('muscle atrophy', 'Phenotype', 'HP:0003202', (83, 97))	('anamorelin', 'Var', (9, 19))	('skeletal muscle atrophy', 'Phenotype', 'HP:0003202', (74, 97))	('mitigate', 'NegReg', (32, 40))	('skeletal muscle atrophy', 'Disease', (74, 97))	('gastric mucositis', 'Phenotype', 'HP:0005263', (51, 68))	('anorexia', 'Disease', 'MESH:D000855', (41, 49))	('anamorelin', 'Chemical', 'MESH:C000593861', (9, 19))	('gastric mucositis', 'Disease', 'MESH:D013272', (51, 68))	('skeletal muscle atrophy', 'Disease', 'MESH:D009133', (74, 97))
734979	32709007	; Data curation, Y.O., T.O, S.O., and S.A.; Formal analysis, Y.O., T.F., and S.O.	('Y.O.', 'Var', (61, 65))	('T.F.', 'Var', (67, 71))	('rat', 'Species', '10116', (9, 12))	('S.O', 'Var', (77, 80))
734987	31886273	High expression of MYC was associated with advanced pTNM-stage (P=0.011), and PDIA3 and ITGA5B1 were correlated with both lymph node metastasis (PDIA3: P < 0.001; ITGA5B1: P=0.001) and pTNM-stage (PDIA3: P=0.001; ITGA5B1: P=0.009).	('TNM', 'Gene', (186, 189))	('advanced', 'CPA', (43, 51))	('PDIA3', 'Gene', (78, 83))	('ITGA5', 'Gene', '3678', (213, 218))	('High', 'Var', (0, 4))	('MYC', 'Gene', '4609', (19, 22))	('ITGA5', 'Gene', (163, 168))	('TNM', 'Gene', (53, 56))	('correlated', 'Reg', (101, 111))	('associated', 'Reg', (27, 37))	('ITGA5', 'Gene', (88, 93))	('lymph node metastasis', 'CPA', (122, 143))	('TNM', 'Gene', '10178', (186, 189))	('TNM', 'Gene', '10178', (53, 56))	('ITGA5', 'Gene', '3678', (163, 168))	('MYC', 'Gene', (19, 22))	('ITGA5', 'Gene', (213, 218))	('ITGA5', 'Gene', '3678', (88, 93))
735001	31886273	MYC amplification is a recurrent event in many tumors and contributes to tumor development and progression.	('MYC', 'Gene', (0, 3))	('progression', 'CPA', (95, 106))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('contributes', 'Reg', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (73, 78))	('amplification', 'Var', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MYC', 'Gene', '4609', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))
735014	31886273	An independent validation set (GSE53622 and GSE5364) was obtained from the publicly available GEO database (https://www.ncbi.nlm.nih.gov/).	('GSE53622', 'Var', (31, 39))	('GSE5364', 'Chemical', '-', (44, 51))	('GSE5364', 'Var', (44, 51))
735028	31886273	Nonetheless, low-expression of PDIA3 or high expression of ITGA5B1 significantly correlated with lymph node (LN) metastasis, whereas no correlation was found between MYC and LN metastasis (Table 2).	('high', 'Var', (40, 44))	('MYC', 'Gene', '4609', (166, 169))	('ITGA5', 'Gene', '3678', (59, 64))	('correlated', 'Reg', (81, 91))	('MYC', 'Gene', (166, 169))	('low-expression', 'NegReg', (13, 27))	('PDIA3', 'Gene', (31, 36))	('ITGA5', 'Gene', (59, 64))
735057	31886273	Our results are in line with other clinical studies, which have shown that high expression and rearrangement of MYC are associated with better response to chemoradiotherapy compared with patients without these abnormalities.	('high expression', 'Var', (75, 90))	('patients', 'Species', '9606', (187, 195))	('MYC', 'Gene', '4609', (112, 115))	('MYC', 'Gene', (112, 115))	('rearrangement', 'Var', (95, 108))
735062	31886273	Antisense oligonucleotides (ASOs) targeting MYC have been shown to block cell proliferation and induce apoptosis in solid and hematologic tumors.	('MYC', 'Gene', '4609', (44, 47))	('hematologic tumors', 'Disease', 'MESH:D019337', (126, 144))	('induce', 'PosReg', (96, 102))	('oligonucleotides', 'Chemical', 'MESH:D009841', (10, 26))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('hematologic tumors', 'Disease', (126, 144))	('cell proliferation', 'CPA', (73, 91))	('block', 'NegReg', (67, 72))	('apoptosis', 'CPA', (103, 112))	('Antisense', 'Var', (0, 9))	('MYC', 'Gene', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
735069	31886273	PDIA3 expression level is correlated with the clinical outcome of patients with ovarian carcinoma who receive chemoradiotherapy, and the sensitivity to paclitaxel can be enhanced by PDIA3 silencing.	('ovarian carcinoma', 'Disease', 'MESH:D010051', (80, 97))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (80, 97))	('ovarian carcinoma', 'Disease', (80, 97))	('sensitivity to paclitaxel', 'MPA', (137, 162))	('PDIA3', 'Gene', (0, 5))	('paclitaxel', 'Chemical', 'MESH:D017239', (152, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('patients', 'Species', '9606', (66, 74))	('enhanced', 'PosReg', (170, 178))	('PDIA3 silencing', 'Var', (182, 197))	('expression level', 'MPA', (6, 22))
735073	31886273	Taken together, these data suggest that MYC, PDIA3, and ITGA5B1 may serve as potential therapeutic targets for ESCC treatment, and cotargeting of these biomarkers might be more effective than targeting a single biomarker alone.	('ITGA5', 'Gene', (56, 61))	('MYC', 'Gene', '4609', (40, 43))	('ITGA5', 'Gene', '3678', (56, 61))	('MYC', 'Gene', (40, 43))	('PDIA3', 'Gene', (45, 50))	('cotargeting', 'Var', (131, 142))	('ESCC', 'Disease', (111, 115))
735112	31258738	In univariate analysis, pT1b, pN+ and lymphovascular invasion were adverse risk factors for OS and DFS, while subcarinal node dissection procedure as well as other factors, including age and surgery, was not associated with survival.	('DFS', 'Disease', (99, 102))	('pT1', 'Gene', (24, 27))	('pN+', 'Var', (30, 33))	('OS', 'Chemical', '-', (92, 94))	('pT1', 'Gene', '58492', (24, 27))
735122	31258738	It was reported subcarinal node dissection not only increased blood loss, operation time and postoperative pleural drainage volume, but also increased the incidence of postoperative complications significantly, especially pulmonary complications.	('pulmonary complications', 'Phenotype', 'HP:0006532', (222, 245))	('increased', 'PosReg', (52, 61))	('blood loss', 'Disease', (62, 72))	('pulmonary complications', 'Disease', (222, 245))	('blood loss', 'Disease', 'MESH:D006473', (62, 72))	('increased', 'PosReg', (141, 150))	('pulmonary complications', 'Disease', 'MESH:D008171', (222, 245))	('subcarinal node', 'Disease', (16, 31))	('postoperative pleural drainage volume', 'Disease', (93, 130))	('dissection', 'Var', (32, 42))	('postoperative pleural drainage volume', 'Disease', 'MESH:D010149', (93, 130))
735153	30143675	It consists of 3475 genes associated to molecular signatures such as, altered transcription (2600), altered translation (560), contain copy number variation/structural variations (233), SNPs (102), altered DNA methylation (82), Histone modifications (16) and miRNA based regulation (261).	('altered', 'Reg', (70, 77))	('SNPs', 'Disease', (186, 190))	('miRNA based regulation', 'MPA', (259, 281))	('altered', 'Reg', (100, 107))	('copy number variation/structural variations', 'Var', (135, 178))	('altered', 'Var', (198, 205))	('His', 'Chemical', 'MESH:D006639', (228, 231))	('translation', 'MPA', (108, 119))	('Histone modifications', 'MPA', (228, 249))
735163	30143675	Apart from the lifestyles, genetic variations in the diverse population such as single nucleotide polymorphism (SNP), and structural variation, along with epigenetic modifications such as DNA Methylation, and Histone modification (HM), are also known to play a major role in ESCC.	('His', 'Chemical', 'MESH:D006639', (209, 212))	('DNA Methylation', 'Var', (188, 203))	('Histone', 'MPA', (209, 216))	('ESCC', 'Disease', (275, 279))	('single nucleotide polymorphism', 'Var', (80, 110))
735176	30143675	As an outcome of promoter hypermethylation, GPX3 was down regulated in gastric cancer.	('GPX3', 'Gene', (44, 48))	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('hypermethylation', 'Var', (26, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('down regulated', 'NegReg', (53, 67))	('GPX3', 'Gene', '2878', (44, 48))
735177	30143675	Furthermore, an in vitro study an association between GPX3 and lymph node metastasis was found in gastric cancer upon downregulation of GPX3 expression and promoter hypermethylation.	('downregulation', 'NegReg', (118, 132))	('GPX3', 'Gene', (136, 140))	('GPX3', 'Gene', '2878', (136, 140))	('promoter hypermethylation', 'Var', (156, 181))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gastric cancer', 'Disease', (98, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('expression', 'MPA', (141, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('GPX3', 'Gene', '2878', (54, 58))	('lymph node metastasis', 'CPA', (63, 84))	('GPX3', 'Gene', (54, 58))
735178	30143675	In a previous study, GPX3 was methylated in prostate cancer and an in vitro overexpression of GPX3 in prostate cancer cell lines could suppress formation of colonies as well as growth of cells in an anchorage-independent manner, and reduce the invasiness of the prostate cancer cells indicates the tumor suppressor activity of GPX3.	('GPX3', 'Gene', (21, 25))	('prostate cancer', 'Disease', (44, 59))	('invasiness of the prostate cancer', 'Disease', (244, 277))	('growth', 'CPA', (177, 183))	('GPX3', 'Gene', (94, 98))	('invasiness of the prostate cancer', 'Disease', 'MESH:D011471', (244, 277))	('overexpression', 'PosReg', (76, 90))	('tumor', 'Disease', (298, 303))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('GPX3', 'Gene', '2878', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('GPX3', 'Gene', '2878', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('methylated', 'Var', (30, 40))	('suppress', 'NegReg', (135, 143))	('prostate cancer', 'Disease', 'MESH:D011471', (262, 277))	('prostate cancer', 'Phenotype', 'HP:0012125', (262, 277))	('reduce', 'NegReg', (233, 239))	('GPX3', 'Gene', (327, 331))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))	('prostate cancer', 'Disease', (102, 117))	('GPX3', 'Gene', '2878', (327, 331))	('formation of colonies', 'CPA', (144, 165))	('prostate cancer', 'Disease', 'MESH:D011471', (44, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))
735180	30143675	Hypermethylation of GPX3 promoter was observed in breast cancer, but not in normal tissues.	('Hypermethylation', 'Var', (0, 16))	('GPX3', 'Gene', (20, 24))	('GPX3', 'Gene', '2878', (20, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('observed', 'Reg', (38, 46))
735189	30143675	The knockdown inhibition of EZR led to decrease in growth, adhesion, and invasiveness of the ESCC cells in vitro and ability to induce tumorigenesis in in vivo conditions.	('invasiveness of the ESCC cells', 'CPA', (73, 103))	('adhesion', 'CPA', (59, 67))	('EZR', 'Gene', (28, 31))	('decrease', 'NegReg', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('growth', 'CPA', (51, 57))	('EZR', 'Gene', '7430', (28, 31))	('tumor', 'Disease', (135, 140))	('induce', 'Reg', (128, 134))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
735196	30143675	An overexpression of MMP2 has been reported in ESCC tissues as compared to adjacent normal epithelia, and MMP3 SNP (MMP3 -1612 5A/6A) polymorphism was significantly associated with susceptibility to ESCC means ESCC subjects bearing 5A allele were more prone of getting ESCC as compared with 6A allele.	('MMP2', 'Gene', (21, 25))	('associated', 'Reg', (165, 175))	('MMP3', 'Gene', (116, 120))	('MMP3', 'Gene', (106, 110))	('ESCC', 'Disease', (269, 273))	('MMP2', 'Gene', '4313', (21, 25))	('MMP3', 'Gene', '4314', (116, 120))	('ESCC', 'Disease', (199, 203))	('MMP3', 'Gene', '4314', (106, 110))	('polymorphism', 'Var', (134, 146))
735202	30143675	In SNPs based study on PADI4, rs2240337 G > A SNP was found to be significantly associated with decreased risk of ESCC.	('decreased', 'NegReg', (96, 105))	('rs2240337 G > A', 'Var', (30, 45))	('PADI4', 'Gene', '23569', (23, 28))	('PADI4', 'Gene', (23, 28))	('rs2240337', 'Mutation', 'rs2240337', (30, 39))
735203	30143675	Earlier findings in SNPs study on PADI4 in EC reported rs10437048 and rs41265997 were significantly associated with decreased and increased risk of EC, respectively.	('rs41265997', 'Var', (70, 80))	('rs10437048', 'Var', (55, 65))	('PADI4', 'Gene', '23569', (34, 39))	('PADI4', 'Gene', (34, 39))	('rs41265997', 'Mutation', 'rs41265997', (70, 80))	('rs10437048', 'Mutation', 'rs10437048', (55, 65))
735205	30143675	We could find 6 genes with altered histone modifications for Chinese (Acetylation 1; phosphorylation 6, deacetylation 1, gene PTK6 has both Deacetylation, Phosphorylation evidence), 4 for Japanese (Acetylation 3; phosphorylation 1, deacetylation 0), 1 for Korean (Acetylation 0; phosphorylation 1, deacetylation 0), and none for Indian and Iranian populations (no HM studies in these two).	('Deacetylation', 'MPA', (140, 153))	('altered', 'Reg', (27, 34))	('deacetylation 1', 'Var', (104, 119))	('PTK6', 'Gene', '5753', (126, 130))	('PTK6', 'Gene', (126, 130))
735222	30143675	Indeed, oncogenic FGFR amplification is seen as a requirement that results in ectopic activation of the STAT3 transcriptional response.	('STAT3', 'Gene', '6774', (104, 109))	('STAT3', 'Gene', (104, 109))	('amplification', 'Var', (23, 36))	('FGFR', 'Gene', (18, 22))	('activation', 'PosReg', (86, 96))	('ectopic', 'MPA', (78, 85))
735231	30143675	Variant rs4647602 (CC genotype) significantly reduced the transcriptional activity of caspase-3 and it was associated with an increased risk of ESCC in the Chinese population.	('transcriptional activity', 'MPA', (58, 82))	('caspase-3', 'Gene', (86, 95))	('rs4647602', 'Mutation', 'rs4647602', (8, 17))	('caspase-3', 'Gene', '836', (86, 95))	('ESCC', 'Disease', (144, 148))	('reduced', 'NegReg', (46, 53))	('rs4647602', 'Var', (8, 17))
735235	30143675	Curated SNP data shows that the polymorphisms found in the genes XRCC1, POLQ, FANCG, FEN1, SMUG1 were directly associated with risk of ESCC in the Chinese population.	('polymorphisms', 'Var', (32, 45))	('ESCC', 'Disease', (135, 139))	('SMUG1', 'Gene', (91, 96))	('FEN1', 'Gene', (85, 89))	('XRCC1', 'Gene', '7515', (65, 70))	('POLQ', 'Gene', (72, 76))	('SMUG1', 'Gene', '23583', (91, 96))	('associated', 'Reg', (111, 121))	('POLQ', 'Gene', '10721', (72, 76))	('FANCG', 'Gene', (78, 83))	('XRCC1', 'Gene', (65, 70))	('FANCG', 'Gene', '2189', (78, 83))	('FEN1', 'Gene', '2237', (85, 89))
735239	30143675	Polymorphisms found in CYP2E1 and CYP1A1 are risk factors for development of ESCC.	('CYP1A1', 'Gene', '1543', (34, 40))	('ESCC', 'Disease', (77, 81))	('Polymorphisms', 'Var', (0, 13))	('CYP2E1', 'Gene', '1571', (23, 29))	('risk factors', 'Reg', (45, 57))	('CYP1A1', 'Gene', (34, 40))	('CYP2E1', 'Gene', (23, 29))
735250	30143675	The second step is catalyzed by aldehyde dehydrogenase (ALDH2), it is found that variants of these genes affect the catalytic rate of the reaction in both steps.	('ALDH2', 'Gene', '217', (56, 61))	('catalytic rate', 'MPA', (116, 130))	('affect', 'Reg', (105, 111))	('ALDH2', 'Gene', (56, 61))	('variants', 'Var', (81, 89))
735251	30143675	An SNP found in the ADH1B gene (rs1229984) that replaces arginine with Histidine at the 48th position makes the enzyme catalytically faster.	('arginine', 'Chemical', 'MESH:D001120', (57, 65))	('Histidine', 'Chemical', 'MESH:D006639', (71, 80))	('catalytically', 'MPA', (119, 132))	('arginine', 'MPA', (57, 65))	('ADH1B', 'Gene', (20, 25))	('rs1229984', 'Mutation', 'rs1229984', (32, 41))	('ADH1B', 'Gene', '125', (20, 25))	('faster', 'PosReg', (133, 139))	('rs1229984', 'Var', (32, 41))
735252	30143675	The heterozygous (ADH1B Arg/His) and homozygous (ADH1B His/His) variants of the gene possess higher catalytic activity and are faster in converting ethanol to acetaldehyde compared to the wild type (ADH1B Arg/Arg) allele.	('converting ethanol to acetaldehyde', 'MPA', (137, 171))	('ADH1B', 'Gene', (18, 23))	('ADH1B', 'Gene', '125', (199, 204))	('faster', 'PosReg', (127, 133))	('ADH1B', 'Gene', '125', (49, 54))	('His', 'Chemical', 'MESH:D006639', (28, 31))	('His', 'Chemical', 'MESH:D006639', (59, 62))	('ADH1B', 'Gene', (199, 204))	('ADH1B', 'Gene', (49, 54))	('variants', 'Var', (64, 72))	('higher', 'PosReg', (93, 99))	('ethanol', 'Chemical', 'MESH:D000431', (148, 155))	('Arg', 'Chemical', 'MESH:D001120', (24, 27))	('Arg', 'Chemical', 'MESH:D001120', (205, 208))	('catalytic activity', 'MPA', (100, 118))	('acetaldehyde', 'Chemical', 'MESH:D000079', (159, 171))	('His', 'Chemical', 'MESH:D006639', (55, 58))	('Arg', 'Chemical', 'MESH:D001120', (209, 212))	('ADH1B', 'Gene', '125', (18, 23))
735254	30143675	It's accumulation in the body due to its rapid production by the variant versions of the ADH1B enzyme leads to acetaldehyde carcinogenesis.	('acetaldehyde carcinogenesis', 'Disease', (111, 138))	('ADH1B', 'Gene', (89, 94))	('ADH1B', 'Gene', '125', (89, 94))	('variant', 'Var', (65, 72))	('acetaldehyde carcinogenesis', 'Disease', 'MESH:D063646', (111, 138))	('leads to', 'Reg', (102, 110))
735256	30143675	The variant alleles of ALDH2 render it inactive, thereby promoting acetaldehyde accumulation and carcinogenesis in ESCC.	('acetaldehyde accumulation', 'Phenotype', 'HP:0003533', (67, 92))	('ALDH2', 'Gene', (23, 28))	('carcinogenesis', 'Disease', (97, 111))	('acetaldehyde', 'Chemical', 'MESH:D000079', (67, 79))	('variant', 'Var', (4, 11))	('promoting', 'PosReg', (57, 66))	('acetaldehyde accumulation', 'MPA', (67, 92))	('ALDH2', 'Gene', '217', (23, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (97, 111))
735262	30143675	Three SNPs in NER pathway particularly the variant alleles of the XPD Lys751Gln, ERCC1 8092C/A and ERCC1 118C/T were associated with an increased risk of EAC.	('ERCC1', 'Gene', '2067', (81, 86))	('NER pathway', 'Pathway', (14, 25))	('EAC', 'Phenotype', 'HP:0011459', (154, 157))	('ERCC1', 'Gene', '2067', (99, 104))	('XPD', 'Gene', (66, 69))	('118C/T', 'Mutation', 'rs11615', (105, 111))	('associated with', 'Reg', (117, 132))	('XPD', 'Gene', '2068', (66, 69))	('EAC', 'Disease', (154, 157))	('Lys751Gln', 'SUBSTITUTION', 'None', (70, 79))	('Lys751Gln', 'Var', (70, 79))	('ERCC1', 'Gene', (81, 86))	('8092C/A', 'Mutation', 'rs3212986', (87, 94))	('ERCC1', 'Gene', (99, 104))
735410	27876891	Genetic variations in the PI3K-PTEN-AKT-mTOR pathway are associated with distant metastasis in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy Distant metastasis is the primary failure pattern of nasopharyngeal carcinoma(NPC) in intensity-modulated radiation therapy(IMRT) era.	('PTEN', 'Gene', (31, 35))	('NPC', 'Disease', 'MESH:D052556', (258, 261))	('nasopharyngeal carcinoma', 'Disease', (95, 119))	('NPC', 'Phenotype', 'HP:0100630', (258, 261))	('distant metastasis', 'CPA', (73, 91))	('PTEN', 'Gene', '5728', (31, 35))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (233, 257))	('NPC', 'Disease', (258, 261))	('mTOR', 'Gene', (40, 44))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (95, 119))	('AKT', 'Gene', (36, 39))	('Genetic variations', 'Var', (0, 18))	('associated', 'Reg', (57, 67))	('Distant metastasis', 'CPA', (180, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('mTOR', 'Gene', '2475', (40, 44))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (95, 119))	('nasopharyngeal carcinoma', 'Disease', (233, 257))	('AKT', 'Gene', '207', (36, 39))	('patients', 'Species', '9606', (120, 128))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (233, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
735411	27876891	This study was conducted to find the impact of genetic variations in the phosphatidylinositol 3-kinase(PI3K)/phosphatase and tensin homologue(PTEN)/v-akt murine thymoma viral oncogene homologue(AKT)/mammalian target of rapamycin(mTOR) pathway on the risk of distant metastasis in NPC.	('akt', 'Gene', (150, 153))	('thymoma viral', 'Disease', (161, 174))	('akt', 'Gene', '207', (150, 153))	('mammalian target of rapamycin(mTOR)', 'Gene', '2475', (199, 234))	('NPC', 'Phenotype', 'HP:0100630', (280, 283))	('thymoma', 'Phenotype', 'HP:0100522', (161, 168))	('variations', 'Var', (55, 65))	('murine', 'Species', '10090', (154, 160))	('NPC', 'Disease', 'MESH:D052556', (280, 283))	('thymoma viral', 'Disease', 'MESH:D013945', (161, 174))	('distant metastasis', 'CPA', (258, 276))	('mammalian target of rapamycin(mTOR', 'Gene', (199, 233))	('NPC', 'Disease', (280, 283))
735413	27876891	We observed that two loci in the AKT1 gene(rs3803300 and rs2494738 alone or combined) were associated with prognosis, with patients carrying at least one variant allele had significantly reduced risk of distant failure, especially in N2-3 group.	('rs2494738', 'Var', (57, 66))	('rs2494738', 'Mutation', 'rs2494738', (57, 66))	('patients', 'Species', '9606', (123, 131))	('reduced', 'NegReg', (187, 194))	('rs3803300', 'Var', (43, 52))	('AKT1', 'Gene', '207', (33, 37))	('rs3803300', 'Mutation', 'rs3803300', (43, 52))	('AKT1', 'Gene', (33, 37))	('distant failure', 'CPA', (203, 218))	('associated', 'Reg', (91, 101))
735414	27876891	In addition, we found that genetic variation may had some joint effect with N classification in recursive-partitioning analysis(RPA) analysis, with which patients were stratified into four different risk subgroups (RPA model): RPA1(low risk), RPA2(moderate risk), RPA3(high risk) and RPA4(highest risk).	('genetic variation', 'Var', (27, 44))	('RPA', 'Gene', '6117', (215, 218))	('RPA2', 'Gene', '6118', (243, 247))	('RPA', 'Gene', (243, 246))	('RPA3', 'Gene', (264, 268))	('RPA', 'Gene', '6117', (284, 287))	('RPA', 'Gene', (227, 230))	('RPA4', 'Gene', '29935', (284, 288))	('RPA3', 'Gene', '6119', (264, 268))	('RPA2', 'Gene', (243, 247))	('RPA', 'Gene', (128, 131))	('RPA', 'Gene', (264, 267))	('RPA', 'Gene', '6117', (243, 246))	('patients', 'Species', '9606', (154, 162))	('RPA', 'Gene', (215, 218))	('RPA4', 'Gene', (284, 288))	('RPA1', 'Gene', '6117', (227, 231))	('RPA', 'Gene', '6117', (227, 230))	('RPA1', 'Gene', (227, 231))	('RPA', 'Gene', (284, 287))	('RPA', 'Gene', '6117', (264, 267))	('effect', 'Reg', (64, 70))	('RPA', 'Gene', '6117', (128, 131))
735415	27876891	Our findings suggested that genetic variations within the PI3K signaling pathway modulate the development and invasion of NPC patients.	('NPC', 'Disease', 'MESH:D052556', (122, 125))	('PI3K signaling pathway', 'Pathway', (58, 80))	('NPC', 'Disease', (122, 125))	('NPC', 'Phenotype', 'HP:0100630', (122, 125))	('modulate', 'Reg', (81, 89))	('development', 'CPA', (94, 105))	('patients', 'Species', '9606', (126, 134))	('invasion', 'CPA', (110, 118))	('genetic variations', 'Var', (28, 46))
735421	27876891	Several literatures have been reported that genetic variations in this pathway are associated with clinical outcomes, invasion property, drug resistance to chemotherapy and treatment complications, including head and neck squamous cell carcinoma, esophageal cancer, cervical cancer, gastric cancer, colorectal carcinoma, lung cancer and bladder cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (321, 332))	('neck squamous cell carcinoma', 'Disease', (217, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (217, 245))	('colorectal carcinoma', 'Disease', (299, 319))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (299, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('gastric cancer', 'Disease', (283, 297))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('drug resistance', 'Phenotype', 'HP:0020174', (137, 152))	('cervical cancer', 'Disease', 'MESH:D002583', (266, 281))	('lung cancer', 'Disease', (321, 332))	('cervical cancer', 'Disease', (266, 281))	('gastric cancer', 'Disease', 'MESH:D013274', (283, 297))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (208, 245))	('esophageal cancer', 'Disease', 'MESH:D004938', (247, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('bladder cancer', 'Disease', 'MESH:D001749', (337, 351))	('bladder cancer', 'Disease', (337, 351))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('esophageal cancer', 'Disease', (247, 264))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('lung cancer', 'Disease', 'MESH:D008175', (321, 332))	('genetic variations', 'Var', (44, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (337, 351))	('associated', 'Reg', (83, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (283, 297))
735423	27876891	Herein, we performed this study, which enrolled 496 NPC patients treated by IMRT with or without chemotherapy, aimed to identify the potential associations between genetic variations in PI3K/PTEN/AKT/mTOR pathway and the occurrence of distant metastasis in patients with NPC.	('patients', 'Species', '9606', (56, 64))	('NPC', 'Phenotype', 'HP:0100630', (52, 55))	('NPC', 'Disease', (271, 274))	('PI3K/PTEN/AKT/mTOR pathway', 'Pathway', (186, 212))	('NPC', 'Disease', 'MESH:D052556', (52, 55))	('distant metastasis', 'CPA', (235, 253))	('NPC', 'Disease', (52, 55))	('NPC', 'Phenotype', 'HP:0100630', (271, 274))	('patients', 'Species', '9606', (257, 265))	('genetic variations', 'Var', (164, 182))	('NPC', 'Disease', 'MESH:D052556', (271, 274))
735433	27876891	Most of the SNPs had a call rate of at least 95%, except two SNPs, with rs2494738 and rs892119 shown to be 93.1% and 94.0%, respectively.	('rs892119', 'Var', (86, 94))	('rs892119', 'Mutation', 'rs892119', (86, 94))	('rs2494738', 'Var', (72, 81))	('rs2494738', 'Mutation', 'rs2494738', (72, 81))	('call rate', 'CPA', (23, 32))
735434	27876891	Another two SNPs(rs2494732 and rs3803300) were genotyped by TaqMan assay.	('rs2494732', 'Mutation', 'rs2494732', (17, 26))	('rs2494732', 'Var', (17, 26))	('rs3803300', 'Var', (31, 40))	('rs3803300', 'Mutation', 'rs3803300', (31, 40))
735449	27876891	Variant genotypes of each of the 16 individual SNP were evaluated for association with DMFS after definitive chemo-radiotherapy, by using univariate and multivariate analysis.	('DMFS', 'Chemical', '-', (87, 91))	('DMFS', 'Disease', (87, 91))	('association', 'Interaction', (70, 81))	('Variant', 'Var', (0, 7))
735450	27876891	Of the 16 SNPs, only two SNPs- AKT1: rs3803300 and AKT1:rs2494738-were found to be significantly associated with DMFS after MVA (Table 4).	('AKT1', 'Gene', '207', (51, 55))	('AKT1', 'Gene', (51, 55))	('AKT1', 'Gene', '207', (31, 35))	('DMFS', 'Chemical', '-', (113, 117))	('rs3803300', 'Var', (37, 46))	('associated with', 'Reg', (97, 112))	('AKT1', 'Gene', (31, 35))	('rs3803300', 'Mutation', 'rs3803300', (37, 46))	('DMFS', 'Disease', (113, 117))	('rs2494738', 'Mutation', 'rs2494738', (56, 65))
735451	27876891	AKT1: rs3803300, as detailed in Table 4, resulted in significantly inferior DMFS for patients with wild-type genotype compared with those with one or two variant alleles (Fig.	('AKT1', 'Gene', '207', (0, 4))	('inferior', 'NegReg', (67, 75))	('AKT1', 'Gene', (0, 4))	('DMFS', 'MPA', (76, 80))	('patients', 'Species', '9606', (85, 93))	('DMFS', 'Chemical', '-', (76, 80))	('rs3803300', 'Mutation', 'rs3803300', (6, 15))	('rs3803300', 'Var', (6, 15))
735453	27876891	Patients carrying at least one variant allele for AKT1: rs2494738 had a better DMFS than those with wile-type genotype (86.9% vs. 80.5%, P = 0.106) (Fig.	('DMFS', 'Chemical', '-', (79, 83))	('better', 'PosReg', (72, 78))	('rs2494738', 'Var', (56, 65))	('Patients', 'Species', '9606', (0, 8))	('AKT1', 'Gene', '207', (50, 54))	('AKT1', 'Gene', (50, 54))	('DMFS', 'MPA', (79, 83))	('rs2494738', 'Mutation', 'rs2494738', (56, 65))
735454	27876891	As showed in MVA, another two SNPs-AKT1:rs1130214, and mTOR:rs11121704 showed an obvious trend toward inferior DMFS in patients with one or two variant alleles (AKT1:rs1130214 HR = 1.566, 95% CI = 0.956-2.567, P = 0.075; mTOR:rs11121704 HR = 1.655, 95% CI = 0.933-2.935, P = 0.085).	('rs1130214', 'Var', (40, 49))	('AKT1', 'Gene', '207', (161, 165))	('AKT1', 'Gene', (161, 165))	('DMFS', 'MPA', (111, 115))	('inferior', 'NegReg', (102, 110))	('patients', 'Species', '9606', (119, 127))	('rs11121704', 'Mutation', 'rs11121704', (226, 236))	('rs11121704', 'Mutation', 'rs11121704', (60, 70))	('AKT1', 'Gene', '207', (35, 39))	('DMFS', 'Chemical', '-', (111, 115))	('rs1130214', 'Mutation', 'rs1130214', (166, 175))	('rs1130214', 'Var', (166, 175))	('AKT1', 'Gene', (35, 39))	('rs11121704', 'Var', (60, 70))	('rs1130214', 'Mutation', 'rs1130214', (40, 49))
735455	27876891	While AKT2: rs892119 indicated a clear trend to have reduced risk of distant failure when patients carried at least one variant allele (HR = 0.579, 95% CI = 0.317-1.057, P = 0.075).	('rs892119', 'Var', (12, 20))	('rs892119', 'Mutation', 'rs892119', (12, 20))	('reduced', 'NegReg', (53, 60))	('distant failure', 'CPA', (69, 84))	('AKT2', 'Gene', (6, 10))	('AKT2', 'Gene', '208', (6, 10))	('patients', 'Species', '9606', (90, 98))
735470	27876891	There is a growing realization that genetic polymorphisms not only influence the development of cancer, but also the progression of cancer and prognosis.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('influence', 'Reg', (67, 76))	('genetic polymorphisms', 'Var', (36, 57))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('development of', 'CPA', (81, 95))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
735471	27876891	Better understanding of the influence of genetic variations on the clinical outcome of patients may in fact provide additional biomarkers for individualized treatment for NPC.	('NPC', 'Disease', (171, 174))	('NPC', 'Phenotype', 'HP:0100630', (171, 174))	('genetic variations', 'Var', (41, 59))	('patients', 'Species', '9606', (87, 95))	('NPC', 'Disease', 'MESH:D052556', (171, 174))
735472	27876891	In this study, we determined whether genetic variations in the PI3K/PTEN/AKT/mTOR pathway were associated with risk of distant failure in NPC patients.	('NPC', 'Phenotype', 'HP:0100630', (138, 141))	('NPC', 'Disease', 'MESH:D052556', (138, 141))	('distant failure', 'CPA', (119, 134))	('genetic variations', 'Var', (37, 55))	('NPC', 'Disease', (138, 141))	('patients', 'Species', '9606', (142, 150))	('associated', 'Reg', (95, 105))	('PI3K/PTEN/AKT/mTOR pathway', 'Pathway', (63, 89))
735474	27876891	We found that SNPs in AKT1: rs3803300 and AKT1: rs2494738 were strongly correlated to risk of distant failure.	('rs3803300', 'Mutation', 'rs3803300', (28, 37))	('correlated', 'Reg', (72, 82))	('AKT1', 'Gene', '207', (42, 46))	('AKT1', 'Gene', (42, 46))	('rs2494738', 'Var', (48, 57))	('rs2494738', 'Mutation', 'rs2494738', (48, 57))	('AKT1', 'Gene', '207', (22, 26))	('rs3803300', 'Var', (28, 37))	('distant failure', 'CPA', (94, 109))	('AKT1', 'Gene', (22, 26))
735480	27876891	Recent studies have identified that SNPs and their haplotypes of AKT1 were linked with AKT1 protein expression level and with apoptotic capacity.	('AKT1', 'Gene', '207', (65, 69))	('SNPs', 'Disease', (36, 40))	('AKT1', 'Gene', '207', (87, 91))	('apoptotic capacity', 'CPA', (126, 144))	('AKT1', 'Gene', (87, 91))	('AKT1', 'Gene', (65, 69))	('linked', 'Reg', (75, 81))	('haplotypes', 'Var', (51, 61))
735481	27876891	The most interesting finding of current series was that two SNPs in this gene, AKT1:rs3803300 and AKT: rs2494738 alone or combined, were significantly associated with DMFS in NPC patients.	('NPC', 'Disease', 'MESH:D052556', (175, 178))	('NPC', 'Disease', (175, 178))	('AKT1', 'Gene', '207', (79, 83))	('associated', 'Reg', (151, 161))	('rs3803300', 'Mutation', 'rs3803300', (84, 93))	('AKT1', 'Gene', (79, 83))	('rs3803300', 'Var', (84, 93))	('rs2494738', 'Mutation', 'rs2494738', (103, 112))	('patients', 'Species', '9606', (179, 187))	('NPC', 'Phenotype', 'HP:0100630', (175, 178))	('DMFS', 'Disease', (167, 171))	('DMFS', 'Chemical', '-', (167, 171))
735482	27876891	The first SNP AKT1:rs3803300 is located in the 3' untranslated region of AKT1 and may affect gene expression through changes in transcription factor-binding sites (i.e.	('AKT1', 'Gene', '207', (14, 18))	('affect', 'Reg', (86, 92))	('AKT1', 'Gene', '207', (73, 77))	('rs3803300', 'Mutation', 'rs3803300', (19, 28))	('AKT1', 'Gene', (14, 18))	('AKT1', 'Gene', (73, 77))	('rs3803300', 'Var', (19, 28))	('transcription factor-binding sites', 'MPA', (128, 162))	('changes', 'Reg', (117, 124))	('gene expression', 'MPA', (93, 108))
735484	27876891	miR-4270 predicted in http://www.bioguo.org/miRNASNP/), and/or splicing variants.	('splicing variants', 'Var', (63, 80))	('miR-4270', 'Gene', (0, 8))	('miR-4270', 'Gene', '100422868', (0, 8))
735485	27876891	Similar results for AKT1: rs3803300 have been observed in other cancers.	('AKT1', 'Gene', '207', (20, 24))	('AKT1', 'Gene', (20, 24))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('rs3803300', 'Var', (26, 35))	('cancers', 'Disease', (64, 71))	('rs3803300', 'Mutation', 'rs3803300', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
735488	27876891	from China also indicated that variant genotypes AG and GG of AKT1:rs3803300, especially the GG genotype, showed a strong association with higher Oral squamous cell carcinoma (OSCC) susceptibility than the wild-type genotype AA, but they did not find any association between OSCC progression and genotype distribution of this SNP.	('AKT1', 'Gene', '207', (62, 66))	('AKT1', 'Gene', (62, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('rs3803300', 'Var', (67, 76))	('rs3803300', 'Mutation', 'rs3803300', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('Oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (146, 174))	('Oral squamous cell carcinoma', 'Disease', (146, 174))	('higher', 'PosReg', (139, 145))
735489	27876891	As for AKT1: rs2494738, individuals who carrying at least one variant allele of this SNP had a better DMFS in our analysis.	('DMFS', 'Chemical', '-', (102, 106))	('AKT1', 'Gene', '207', (7, 11))	('rs2494738', 'Var', (13, 22))	('AKT1', 'Gene', (7, 11))	('rs2494738', 'Mutation', 'rs2494738', (13, 22))	('DMFS', 'MPA', (102, 106))	('better', 'PosReg', (95, 101))
735491	27876891	However, it is important to note that the AKT1: rs2494738 polymorphism was not found to be associated with prognosis in Caucasian patients with NSCLC and esophageal cancer.	('NSCLC', 'Disease', (144, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('AKT1', 'Gene', '207', (42, 46))	('AKT1', 'Gene', (42, 46))	('patients', 'Species', '9606', (130, 138))	('rs2494738', 'Var', (48, 57))	('rs2494738', 'Mutation', 'rs2494738', (48, 57))	('esophageal cancer', 'Disease', (154, 171))
735496	27876891	This observation highlighted the important role of genetic variation in modulating distant metastasis in NPC patients, which may provide additional biomarkers for individualized treatment.	('genetic variation', 'Var', (51, 68))	('patients', 'Species', '9606', (109, 117))	('modulating', 'Reg', (72, 82))	('NPC', 'Phenotype', 'HP:0100630', (105, 108))	('NPC', 'Disease', 'MESH:D052556', (105, 108))	('NPC', 'Disease', (105, 108))	('distant metastasis', 'CPA', (83, 101))
735497	27876891	Our results suggest that another SNP rs1130214 in AKT1 may modulate the invasion activity, as patients carrying at least one variant allele of rs1130214 in AKT1 had a clear trend toward higher risk of distant metastasis.	('rs1130214', 'Var', (37, 46))	('patients', 'Species', '9606', (94, 102))	('rs1130214', 'Mutation', 'rs1130214', (143, 152))	('distant metastasis', 'CPA', (201, 219))	('rs1130214', 'Var', (143, 152))	('AKT1', 'Gene', '207', (156, 160))	('AKT1', 'Gene', '207', (50, 54))	('rs1130214', 'Mutation', 'rs1130214', (37, 46))	('AKT1', 'Gene', (50, 54))	('AKT1', 'Gene', (156, 160))	('modulate', 'Reg', (59, 67))	('invasion activity', 'CPA', (72, 89))
735501	27876891	from USA observed a conflicting result in non-Hispanic Caucasian patients, they found that AKT1: rs1121304 resulting in significantly decreased risks of distant progression in patients carrying at least one variant allele.	('decreased', 'NegReg', (134, 143))	('AKT1', 'Gene', '207', (91, 95))	('patients', 'Species', '9606', (176, 184))	('AKT1', 'Gene', (91, 95))	('rs1121304', 'Var', (97, 106))	('patients', 'Species', '9606', (65, 73))	('distant progression', 'CPA', (153, 172))	('rs1121304', 'Mutation', 'rs1121304', (97, 106))
735504	27876891	The current series found that rs892119 in AKT2 exhibited significant associations with the hazard of distant metastasis, patients who had at least one variant allele had significant reduction of distant failure.	('reduction of distant failure', 'Disease', (182, 210))	('AKT2', 'Gene', (42, 46))	('AKT2', 'Gene', '208', (42, 46))	('distant metastasis', 'CPA', (101, 119))	('associations', 'Reg', (69, 81))	('reduction of distant failure', 'Disease', 'MESH:D051437', (182, 210))	('patients', 'Species', '9606', (121, 129))	('rs892119', 'Var', (30, 38))	('rs892119', 'Mutation', 'rs892119', (30, 38))
735505	27876891	indicated that the rs892119 A allele was significantly associated with reduced risk of both recurrence and death, and was also found to be associated with a poorer response to therapy.	('rs892119 A', 'Var', (19, 29))	('recurrence', 'CPA', (92, 102))	('death', 'Disease', 'MESH:D003643', (107, 112))	('reduced', 'NegReg', (71, 78))	('death', 'Disease', (107, 112))	('rs892119', 'Mutation', 'rs892119', (19, 27))
735508	27876891	The current study found that patients with the CT/CC genotype of mTOR: rs11121704 tended to have higher risk of distant failure than those with TT genotype.	('mTOR', 'Gene', (65, 69))	('patients', 'Species', '9606', (29, 37))	('rs11121704', 'Mutation', 'rs11121704', (71, 81))	('distant failure', 'CPA', (112, 127))	('rs11121704', 'Var', (71, 81))
735509	27876891	However, an American study conducted in Caucasians indicated that the TT genotype of rs11121704 was associated with poor survival and resistance to chemotherapy.	('poor', 'NegReg', (116, 120))	('rs11121704', 'Var', (85, 95))	('rs11121704', 'Mutation', 'rs11121704', (85, 95))	('resistance to chemotherapy', 'CPA', (134, 160))
735512	27876891	In conclusion, polymorphisms in the PI3K/PTEN/AKT/mTOR pathway were found to be independent prognostic markers for NPC patients, especially in N2-3 patients.	('patients', 'Species', '9606', (148, 156))	('N2-3', 'Disease', (143, 147))	('NPC', 'Phenotype', 'HP:0100630', (115, 118))	('patients', 'Species', '9606', (119, 127))	('NPC', 'Disease', 'MESH:D052556', (115, 118))	('NPC', 'Disease', (115, 118))	('PI3K/PTEN/AKT/mTOR pathway', 'Pathway', (36, 62))	('polymorphisms', 'Var', (15, 28))
735515	27876891	Genetic variations in the PI3K-PTEN-AKT-mTOR pathway are associated with distant metastasis in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy.	('distant metastasis', 'CPA', (73, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('PI3K-PTEN-AKT-mTOR pathway', 'Pathway', (26, 52))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (95, 119))	('patients', 'Species', '9606', (120, 128))	('nasopharyngeal carcinoma', 'Disease', (95, 119))	('Genetic variations', 'Var', (0, 18))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (95, 119))	('associated', 'Reg', (57, 67))
735595	25020203	Consistent with previous results, we found that a poor PS was associated with an increased risk for cisplatin nephrotoxicity.	('poor PS', 'Var', (50, 57))	('nephrotoxicity', 'Disease', (110, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('nephrotoxicity', 'Disease', 'MESH:D007674', (110, 124))	('cisplatin', 'MPA', (100, 109))
735596	25020203	This finding underscores the notion that patients with a PS of 2, which is characterized by an increased risk for severe toxicity in general, need special attention with regard to the potential development of nephrotoxicity during high-dose cisplatin chemotherapy, especially given that such treatment in these patients is controversial.	('cisplatin', 'Chemical', 'MESH:D002945', (241, 250))	('PS of 2', 'Var', (57, 64))	('patients', 'Species', '9606', (41, 49))	('patients', 'Species', '9606', (311, 319))	('nephrotoxicity', 'Disease', (209, 223))	('toxicity', 'Disease', (121, 129))	('toxicity', 'Disease', 'MESH:D064420', (121, 129))	('nephrotoxicity', 'Disease', 'MESH:D007674', (209, 223))	('toxicity', 'Disease', 'MESH:D064420', (215, 223))	('toxicity', 'Disease', (215, 223))
735627	20309934	The utility of extensively mutated malignantly transformed cells or cancer cells as models for understanding the development of Barrett's esophagus and the metaplasia dysplasia carcinoma sequence is limited as they have already acquired mutations and other changes that may not accurately reflect the process in vivo.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('metaplasia dysplasia carcinoma', 'Disease', (156, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('mutations', 'Var', (237, 246))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (128, 147))	('metaplasia dysplasia carcinoma', 'Disease', 'MESH:D008679', (156, 186))
735635	20309934	We developed a monoclonal antibody (mAb) 7E12H12, also known as mAb Das-1, that specifically reacts with human colon epithelial cells (both goblet and non-goblet cells), but not with any other parts of the gastrointestinal tract, including small intestine, gastric and esophageal mucosa.	('gastrointestinal tract', 'Disease', 'MESH:D004067', (206, 228))	('7E12H12', 'CellLine', 'CVCL:G696', (41, 48))	('esophageal mucosa', 'Disease', (269, 286))	('7E12H12', 'Var', (41, 48))	('esophageal mucosa', 'Disease', 'MESH:D004941', (269, 286))	('gastrointestinal tract', 'Disease', (206, 228))	('human', 'Species', '9606', (105, 110))
735662	20309934	Gene expression assays that included primer and probe sets for Taqman assays for p21 (Hs00355782_m1), MDM2 (Hs00242813_m1) and PERP (Hs00751717_s1) genes were obtained from Applied Biosystems.	('PERP', 'Gene', '64065', (127, 131))	('Hs00242813_m1', 'Var', (108, 121))	('MDM2', 'Gene', '4193', (102, 106))	('MDM2', 'Gene', (102, 106))	('Hs00355782_m1', 'Var', (86, 99))	('Hs00751717_s1', 'Var', (133, 146))	('p21', 'Gene', (81, 84))	('p21', 'Gene', '644914', (81, 84))	('PERP', 'Gene', (127, 131))
735688	20309934	In general, at 18 weeks and 48 weeks, p53 expression in A+B treated BAR-T cells was higher than in that of control cells.	('p53', 'Gene', '7157', (38, 41))	('p53', 'Gene', (38, 41))	('expression', 'MPA', (42, 52))	('A+B treated', 'Var', (56, 67))	('higher', 'PosReg', (84, 90))
735697	20309934	Anchorage independent behavior was observed as foci formation and growth on soft agar in the A+B treated cells.	('foci formation', 'CPA', (47, 61))	('A+B', 'Var', (93, 96))	('growth on soft agar', 'CPA', (66, 85))	('agar', 'Chemical', 'MESH:D000362', (81, 85))
735702	20309934	Early studies described the presence of p53 mutations in esophageal adenocarcinoma and increased frequency of p53 mutations during the progression of metaplasia dysplasia carcinoma sequence.	('p53', 'Gene', (110, 113))	('mutations', 'Var', (114, 123))	('esophageal adenocarcinoma', 'Disease', (57, 82))	('p53', 'Gene', '7157', (110, 113))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (57, 82))	('p53', 'Gene', (40, 43))	('metaplasia dysplasia carcinoma', 'Disease', 'MESH:D008679', (150, 180))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (57, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('mutations', 'Var', (44, 53))	('metaplasia dysplasia carcinoma', 'Disease', (150, 180))	('p53', 'Gene', '7157', (40, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
735704	20309934	Combined p53 mutation and LOH of 17p (the p53 locus) results in loss of p53 tumor suppressor function, propensity to develop genomic instability, emergence of aneuploid subclones, and disabled G1 checkpoint leading to clonal expansion of abnormal cells.	('p53', 'Gene', (42, 45))	('G1 checkpoint', 'Pathway', (193, 206))	('p53', 'Gene', '7157', (42, 45))	('develop', 'PosReg', (117, 124))	('mutation', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('p53', 'Gene', (72, 75))	('tumor', 'Disease', (76, 81))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', '7157', (9, 12))	('loss', 'NegReg', (64, 68))	('genomic', 'MPA', (125, 132))	('LOH', 'Var', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
735706	20309934	Evidence supports the association between 17p LOH and p53 mutations with increased risk of dysplasia and/or esophageal adenocarcinoma.	('mutations', 'Var', (58, 67))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (108, 133))	('esophageal adenocarcinoma', 'Disease', (108, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (108, 133))	('p53', 'Gene', (54, 57))	('dysplasia', 'Disease', (91, 100))	('p53', 'Gene', '7157', (54, 57))	('association', 'Interaction', (22, 33))	('dysplasia', 'Disease', 'MESH:D004476', (91, 100))
735713	20309934	This may be explained by either acquired mutation in p53 and/or loss of heterozygosity at 17p that either leads to reduced stabilization of p53 or increased degradation.	('loss of heterozygosity', 'Var', (64, 86))	('increased', 'PosReg', (147, 156))	('reduced', 'NegReg', (115, 122))	('mutation', 'Var', (41, 49))	('stabilization', 'MPA', (123, 136))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('p53', 'Gene', (140, 143))	('degradation', 'MPA', (157, 168))	('p53', 'Gene', '7157', (140, 143))
735718	20309934	We hypothesize that dysregulation of the p53 pathway contributes to the transformed phenotype.	('p53', 'Gene', '7157', (41, 44))	('p53', 'Gene', (41, 44))	('dysregulation', 'Var', (20, 33))
735723	20309934	One might conclude that loss of p16 itself is not sufficient to recapitulate transformation.	('loss', 'Var', (24, 28))	('p16', 'Gene', '1029', (32, 35))	('p16', 'Gene', (32, 35))
735726	20309934	It is likely that additional molecular alterations such as dysregulation of the p53 pathway have led to the phenotypic change particularly growth in soft agar, a hallmark of transformation observed in BAR-T treated cells after prolonged A+B treatment.	('led', 'Reg', (97, 100))	('agar', 'Chemical', 'MESH:D000362', (154, 158))	('p53', 'Gene', (80, 83))	('dysregulation', 'Var', (59, 72))	('p53', 'Gene', '7157', (80, 83))	('growth', 'MPA', (139, 145))
735731	32239639	Furthermore, SNHG12 sequestered miR-6835-3p and induced the proto-oncogene, polycomb ring finger (BMI1).	('SNHG12', 'Var', (13, 19))	('BMI1', 'Gene', (98, 102))	('induced', 'PosReg', (48, 55))	('polycomb ring finger', 'Disease', (76, 96))	('polycomb ring finger', 'Phenotype', 'HP:0009971', (76, 96))	('miR-6835-3p', 'Chemical', '-', (32, 43))	('miR-6835-3p', 'Protein', (32, 43))	('BMI1', 'Gene', '648', (98, 102))
735732	32239639	SNHG12 also enhanced the stability of CTNNB1, the mRNA encoding beta-catenin, via recruiting insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in ESCC.	('IGF2BP2', 'Gene', (146, 153))	('stability', 'MPA', (25, 34))	('CTNNB1', 'Gene', (38, 44))	('recruiting', 'PosReg', (82, 92))	('insulin-like growth factor 2 mRNA-binding protein 2', 'Gene', '10644', (93, 144))	('enhanced', 'PosReg', (12, 20))	('beta-catenin', 'Gene', (64, 76))	('SNHG12', 'Var', (0, 6))	('IGF2BP2', 'Gene', '10644', (146, 153))	('beta-catenin', 'Gene', '1499', (64, 76))	('CTNNB1', 'Gene', '1499', (38, 44))
735735	32239639	Finally, in vivo data showed SNHG12 knockdown retarded tumorigenesis and metastasis in ESCC.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('as', 'Gene', '112935892', (76, 78))	('as', 'Gene', '112935892', (79, 81))	('SNHG12', 'Gene', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('retarded', 'NegReg', (46, 54))	('tumor', 'Disease', (55, 60))	('knockdown', 'Var', (36, 45))	('ESCC', 'Disease', (87, 91))
735737	32239639	In esophageal squamous cell carcinoma, SNHG12 regulates BMI1 expression via sponging miR-6835-3p and enhances CTNNB1 stability via recruiting IGF2BP2.	('IGF2BP2', 'Gene', (142, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('SNHG12', 'Var', (39, 45))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('stability', 'MPA', (117, 126))	('CTNNB1', 'Gene', '1499', (110, 116))	('sponging', 'MPA', (76, 84))	('BMI1', 'Gene', '648', (56, 60))	('recruiting', 'PosReg', (131, 141))	('IGF2BP2', 'Gene', '10644', (142, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('CTNNB1', 'Gene', (110, 116))	('miR-6835-3p', 'Chemical', '-', (85, 96))	('BMI1', 'Gene', (56, 60))	('expression', 'MPA', (61, 71))	('regulates', 'Reg', (46, 55))	('enhances', 'PosReg', (101, 109))
735738	32239639	Thus, SNHG12 activates Wnt/beta-catenin signaling and facilitates proliferation, metastasis, and stemness.	('SNHG12', 'Var', (6, 12))	('beta-catenin', 'Gene', '1499', (27, 39))	('as', 'Gene', '112935892', (87, 89))	('proliferation', 'CPA', (66, 79))	('as', 'Gene', '112935892', (84, 86))	('stemness', 'CPA', (97, 105))	('activates', 'PosReg', (13, 22))	('facilitates', 'PosReg', (54, 65))	('beta-catenin', 'Gene', (27, 39))
735746	32239639	Additionally, aberrant expression of lncRNAs has been associated with the occurrence and progression of multiple tumors, including ESCC (Hao et al., 2015; Li et al., 2013).	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('as', 'Gene', '112935892', (54, 56))	('as', 'Gene', '112935892', (46, 48))	('aberrant expression', 'Var', (14, 33))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('As', 'Gene', '112935892', (42, 44))	('ESCC', 'Disease', (131, 135))
735749	32239639	LncRNA SNHG12 is related to the poor prognosis of prostate cancer patients and facilitates tumorigenesis through sponging miR-133b (Cheng et al., 2019).	('miR-133b', 'Gene', (122, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('prostate cancer', 'Disease', (50, 65))	('facilitates', 'PosReg', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('sponging', 'Var', (113, 121))	('tumor', 'Disease', (91, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))	('patients', 'Species', '9606', (66, 74))	('miR-133b', 'Gene', '442890', (122, 130))
735759	32239639	Human ESCC cell lines including EC9706, EC109, KYSE410, KYSE150, and KYSE450 were all available from the ATCC (Manassas, VA, USA) for cell culture with 5% CO2 at 37  C. RPMI-1640 medium (Gibco, Carlsbad, CA, USA) was acquired commercially, with 1% Pen/Strep mixture and 10% FBS as supplements.	('Human', 'Species', '9606', (0, 5))	('as', 'Gene', '112935892', (278, 280))	('as', 'Gene', '112935892', (117, 119))	('as', 'Gene', '112935892', (114, 116))	('EC109', 'Var', (40, 45))	('Pen', 'Gene', '27344', (248, 251))	('as', 'Gene', '112935892', (214, 216))	('KYSE410', 'Var', (47, 54))	('CO2', 'Chemical', 'MESH:D002245', (155, 158))	('EC9706', 'Var', (32, 38))	('RPMI-1640 medium', 'Chemical', '-', (169, 185))	('Pen', 'Gene', (248, 251))	('EC9706', 'CellLine', 'CVCL:E307', (32, 38))
735768	32239639	Using PARIS  Kit (Ambion, Austin, TX, USA), the nucleus or cytoplasm of CD133-EC109/KYSE410 and CD133+EC109/KYSE410 cell samples was severally separated as per instruction.	('as', 'Gene', '112935892', (65, 67))	('as', 'Gene', '112935892', (153, 155))	('as', 'Gene', '112935892', (130, 132))	('CD133+EC109/KYSE410', 'Var', (96, 115))	('CD133-EC109/KYSE410', 'Var', (72, 91))
735794	32239639	SNHG12 or BMI1 fragments covering miR-6835-3p wild-type and mutant binding sequences were used to construct reporter vectors with luciferase reporter pmirGLO (Promega, Madison, WI, USA).	('BMI1', 'Gene', '648', (10, 14))	('BMI1', 'Gene', (10, 14))	('mutant', 'Var', (60, 66))	('as', 'Gene', '112935892', (137, 139))	('miR-6835-3p', 'Chemical', '-', (34, 45))
735795	32239639	The acquired SNHG12-WT/Mut and BMI1-WT/Mut were cotransfected with indicated transfection plasmids in HEK 293T cells.	('SNHG12-WT/Mut', 'Var', (13, 26))	('BMI1', 'Gene', '648', (31, 35))	('HEK 293T', 'CellLine', 'CVCL:0063', (102, 110))	('as', 'Gene', '112935892', (92, 94))	('BMI1', 'Gene', (31, 35))
735796	32239639	Besides, the wild-type or mutant SOX4 binding sites to SNHG12 promoter were cloned to pGL3 vector (Promega) and then transfected into CD133+EC109 or CD133-EC109 cells.	('mutant', 'Var', (26, 32))	('SNHG12', 'Gene', (55, 61))	('SOX4', 'Gene', '6659', (33, 37))	('SOX4', 'Gene', (33, 37))
735818	32239639	According to Kaplan-Meier analysis, high SNHG12 level was linked to unsatisfactory survival in ESCC patients (Fig.	('as', 'Gene', '112935892', (55, 57))	('ESCC', 'Disease', (95, 99))	('patients', 'Species', '9606', (100, 108))	('SNHG12', 'Gene', (41, 47))	('high', 'Var', (36, 40))
735828	32239639	Additionally, we could see that the FISH intensity of SNHG12 was stronger in CD133+ ESCC cells than in CD133- ESCC cells (Fig.	('CD133+ ESCC', 'Var', (77, 88))	('stronger', 'PosReg', (65, 73))	('SNHG12', 'Gene', (54, 60))	('FISH', 'MPA', (36, 40))	('as', 'Gene', '112935892', (62, 64))
735840	32239639	Transwell and western blot demonstrated that cell migration, invasion, and EMT process were hindered by silencing SNHG12 (Fig.	('EMT process', 'CPA', (75, 86))	('silencing', 'Var', (104, 113))	('SNHG12', 'Gene', (114, 120))	('cell migration', 'CPA', (45, 59))	('as', 'Gene', '112935892', (64, 66))	('hindered', 'NegReg', (92, 100))
735841	32239639	Moreover, sphere formation efficiency declined and levels of stem cell markers (SOX2, SOX4, OCT4, and Nanog) were reduced in sh-SNHG12#1/#2-transfected ESCC cells (Fig.	('SOX4', 'Gene', (86, 90))	('SOX2', 'Gene', (80, 84))	('reduced', 'NegReg', (114, 121))	('sphere formation efficiency', 'CPA', (10, 37))	('SOX2', 'Gene', '6657', (80, 84))	('SOX4', 'Gene', '6659', (86, 90))	('sh-SNHG12', 'Var', (125, 134))	('OCT4', 'Gene', '5460', (92, 96))	('OCT4', 'Gene', (92, 96))	('Nanog', 'Gene', '79923', (102, 107))	('Nanog', 'Gene', (102, 107))	('declined', 'NegReg', (38, 46))
735844	32239639	Since lncRNAs were extensively supported to participate in post-transcriptional regulation through ceRNA mechanism, we screened out a cluster of microRNA (miRNAs) possibly bind with SNHG12 from starBase.	('bind', 'Interaction', (172, 176))	('As', 'Gene', '112935892', (159, 161))	('SNHG12', 'Var', (182, 188))	('As', 'Gene', '112935892', (11, 13))	('as', 'Gene', '112935892', (199, 201))
735845	32239639	Then, qRT-PCR identified the top five miRNAs (miR-330-5p, miR-3605-3p, miR-1908-5p, miR-326, and miR-6835-3p) with the lowest expression in ESCC cells, and miR-6835-3p exhibited the lowest expression among the 5 miRNAs (Fig.	('miR-326', 'Gene', '442900', (84, 91))	('miR-3605-3p', 'Var', (58, 69))	('expression', 'MPA', (126, 136))	('miR-1908', 'Gene', '100302263', (71, 79))	('lowest', 'NegReg', (119, 125))	('As', 'Gene', '112935892', (216, 218))	('miR-1908', 'Gene', (71, 79))	('miR-6835-3p', 'Chemical', '-', (97, 108))	('miR-330', 'Gene', '442902', (46, 53))	('miR-326', 'Gene', (84, 91))	('miR-330', 'Gene', (46, 53))	('miR-6835-3p', 'Chemical', '-', (156, 167))	('miR-6835-3p', 'Var', (97, 108))	('miR-6835-3p', 'Var', (156, 167))	('As', 'Gene', '112935892', (42, 44))
735846	32239639	RNA pull-down data supported that only miR-6835-3p was enriched in SNHG12 biotin probe but not SNHG12 no-biotin probe group among above miRNAs (Fig.	('as', 'Gene', '112935892', (52, 54))	('biotin', 'Chemical', 'MESH:D001710', (74, 80))	('biotin', 'Chemical', 'MESH:D001710', (105, 111))	('SNHG12', 'Var', (67, 73))	('miR-6835-3p', 'Var', (39, 50))	('As', 'Gene', '112935892', (140, 142))	('miR-6835-3p', 'Chemical', '-', (39, 50))
735847	32239639	Further, the predicted miR-6835-3p sites in SNHG12 were obtained from starBase and were mutated to generate SNHG12-Mut (Fig.	('miR-6835-3p', 'Chemical', '-', (23, 34))	('miR-6835-3p', 'Var', (23, 34))	('SNHG12', 'Gene', (44, 50))	('as', 'Gene', '112935892', (75, 77))
735848	32239639	Besides, the satisfying overexpression efficiency of miR-6835-3p was obtained by miR-6835-3p mimics in HEK 293T cells (Fig.	('as', 'Gene', '112935892', (66, 68))	('HEK 293T', 'CellLine', 'CVCL:0063', (103, 111))	('overexpression', 'MPA', (24, 38))	('miR-6835-3p', 'Chemical', '-', (53, 64))	('miR-6835-3p mimics', 'Var', (81, 99))	('miR-6835-3p', 'Chemical', '-', (81, 92))
735849	32239639	Overexpressing miR-6835-3p inhibited the luciferase activity of SNHG12-WT and failed to alter SNHG12-Mut activity (Fig.	('as', 'Gene', '112935892', (48, 50))	('activity', 'MPA', (52, 60))	('inhibited', 'NegReg', (27, 36))	('miR-6835-3p', 'Chemical', '-', (15, 26))	('miR-6835-3p', 'Var', (15, 26))
735851	32239639	Data from qRT-PCR demonstrated BMI1 expression was downregulated most significantly by miR-6835-3p mimics and upregulated most significantly by miR-6835-3p inhibitors (Fig.	('miR-6835-3p', 'Chemical', '-', (144, 155))	('as', 'Gene', '112935892', (48, 50))	('miR-6835-3p', 'Var', (144, 155))	('miR-6835-3p mimics', 'Var', (87, 105))	('BMI1', 'Gene', '648', (31, 35))	('upregulated', 'PosReg', (110, 121))	('miR-6835-3p', 'Chemical', '-', (87, 98))	('downregulated', 'NegReg', (51, 64))	('BMI1', 'Gene', (31, 35))	('expression', 'MPA', (36, 46))
735853	32239639	RIP assay showed the obvious enrichment of SNHG12, miR-6835-3p, and BMI1 in the Ago2 group (Fig.	('SNHG12', 'Var', (43, 49))	('as', 'Gene', '112935892', (4, 6))	('Ago2', 'Gene', '27161', (80, 84))	('BMI1', 'Gene', (68, 72))	('miR-6835-3p', 'Chemical', '-', (51, 62))	('Ago2', 'Gene', (80, 84))	('miR-6835-3p', 'Var', (51, 62))	('BMI1', 'Gene', '648', (68, 72))
735854	32239639	Additionally, starBase was utilized to predict the binding sites between miR-6835-3p and BMI1 (Fig.	('BMI1', 'Gene', '648', (89, 93))	('as', 'Gene', '112935892', (24, 26))	('binding', 'Interaction', (51, 58))	('miR-6835-3p', 'Chemical', '-', (73, 84))	('as', 'Gene', '112935892', (19, 21))	('miR-6835-3p', 'Var', (73, 84))	('BMI1', 'Gene', (89, 93))
735856	32239639	Overexpressing miR-6835-3p suppressed BMI1-WT luciferase activity, and this inhibitory impact was offset by SNHG12 overexpression, with the luciferase activity of BMI1-Mut unaffected (Fig.	('as', 'Gene', '112935892', (147, 149))	('BMI1', 'Gene', '648', (38, 42))	('suppressed', 'NegReg', (27, 37))	('as', 'Gene', '112935892', (53, 55))	('BMI1', 'Gene', (38, 42))	('BMI1', 'Gene', '648', (163, 167))	('activity', 'MPA', (57, 65))	('as', 'Gene', '112935892', (95, 97))	('miR-6835-3p', 'Chemical', '-', (15, 26))	('miR-6835-3p', 'Var', (15, 26))	('BMI1', 'Gene', (163, 167))
735858	32239639	To sum up, SNHG12 upregulated BMI1 expression via sequestering miR-6835-3p in ESCC.	('BMI1', 'Gene', '648', (30, 34))	('BMI1', 'Gene', (30, 34))	('expression', 'MPA', (35, 45))	('miR-6835-3p', 'Chemical', '-', (63, 74))	('sequestering miR-6835-3p', 'MPA', (50, 74))	('SNHG12', 'Var', (11, 17))	('upregulated', 'PosReg', (18, 29))
735862	32239639	Besides, overexpression of BMI1 partly restored cell migration and invasion that was repressed by sh-SNHG12#1, and silence of BMI1 partly abrogates migration and invasion encouraged by pcDNA3.1/SNHG12 (Figs 5D and S5A).	('BMI1', 'Gene', '648', (27, 31))	('as', 'Gene', '112935892', (70, 72))	('cell migration', 'CPA', (48, 62))	('BMI1', 'Gene', '648', (126, 130))	('silence', 'Var', (115, 122))	('BMI1', 'Gene', (126, 130))	('BMI1', 'Gene', (27, 31))	('as', 'Gene', '112935892', (82, 84))	('as', 'Gene', '112935892', (165, 167))	('abrogates', 'NegReg', (138, 147))
735863	32239639	Moreover, upregulation of E-cadherin and decline of N-cadherin and vimentin caused by pcDNA3.1/SNHG12 were partially rescued by BMI1 deficiency.	('decline', 'NegReg', (41, 48))	('deficiency', 'Var', (133, 143))	('pcDNA3.1/SNHG12', 'Var', (86, 101))	('E-cadherin', 'Gene', (26, 36))	('BMI1', 'Gene', '648', (128, 132))	('vimentin', 'Gene', '7431', (67, 75))	('BMI1', 'Gene', (128, 132))	('N-cadherin', 'Gene', (52, 62))	('E-cadherin', 'Gene', '999', (26, 36))	('vimentin', 'Gene', (67, 75))	('N-cadherin', 'Gene', '1000', (52, 62))	('upregulation', 'PosReg', (10, 22))
735864	32239639	In the meantime, BMI1 overexpression partially reversed the decline of E-cadherin and upregulation of N-cadherin and vimentin caused by sh-SNHG12#1 (Fig.	('vimentin', 'Gene', '7431', (117, 125))	('upregulation', 'PosReg', (86, 98))	('vimentin', 'Gene', (117, 125))	('N-cadherin', 'Gene', (102, 112))	('E-cadherin', 'Gene', (71, 81))	('E-cadherin', 'Gene', '999', (71, 81))	('sh-SNHG12#1', 'Var', (136, 147))	('BMI1', 'Gene', (17, 21))	('N-cadherin', 'Gene', '1000', (102, 112))	('decline', 'NegReg', (60, 67))	('BMI1', 'Gene', '648', (17, 21))
735870	32239639	Interestingly, we found that sh-SNHG12#1 reduced Wnt-associated genes (beta-catenin, SOX2, SOX4, C-myc, and MMP7), and such effect was partly reversed by overexpressing BMI1.	('reduced', 'NegReg', (41, 48))	('BMI1', 'Gene', (169, 173))	('MMP7', 'Gene', '4316', (108, 112))	('as', 'Gene', '112935892', (132, 134))	('sh-SNHG12#1', 'Var', (29, 40))	('as', 'Gene', '112935892', (53, 55))	('SOX4', 'Gene', (91, 95))	('SOX4', 'Gene', '6659', (91, 95))	('BMI1', 'Gene', '648', (169, 173))	('MMP7', 'Gene', (108, 112))	('SOX2', 'Gene', '6657', (85, 89))	('beta-catenin', 'Gene', '1499', (71, 83))	('beta-catenin', 'Gene', (71, 83))	('SOX2', 'Gene', (85, 89))	('C-myc', 'Gene', '4609', (97, 102))	('C-myc', 'Gene', (97, 102))
735871	32239639	Overexpressing SNHG12 increased the Wnt-related proteins, and such effect was partly counteracted by BMI1 knockdown (Fig.	('as', 'Gene', '112935892', (27, 29))	('SNHG12', 'Var', (15, 21))	('BMI1', 'Gene', '648', (101, 105))	('as', 'Gene', '112935892', (75, 77))	('Wnt-related proteins', 'MPA', (36, 56))	('BMI1', 'Gene', (101, 105))
735873	32239639	Data of qRT-PCR revealed that SNHG12 depletion decreased CTNNB1 expression (Fig.	('as', 'Gene', '112935892', (52, 54))	('expression', 'MPA', (64, 74))	('depletion', 'Var', (37, 46))	('CTNNB1', 'Gene', '1499', (57, 63))	('CTNNB1', 'Gene', (57, 63))
735881	32239639	Additionally, RIP assay confirmed that the enrichment of CTNNB1 in the anti-IGF2BP2 group was decreased when knocking down SNHG12 (Fig.	('IGF2BP2', 'Gene', (76, 83))	('SNHG12', 'Gene', (123, 129))	('as', 'Gene', '112935892', (18, 20))	('CTNNB1', 'Gene', '1499', (57, 63))	('as', 'Gene', '112935892', (91, 93))	('knocking down', 'Var', (109, 122))	('as', 'Gene', '112935892', (99, 101))	('enrichment', 'MPA', (43, 53))	('CTNNB1', 'Gene', (57, 63))	('IGF2BP2', 'Gene', '10644', (76, 83))
735882	32239639	Finally, after actinomycin D treatment, qRT-PCR showed that silencing SNHG12 or IGF2BP2 accelerated the degradation of CTNNB1 (Fig.	('degradation', 'MPA', (104, 115))	('SNHG12', 'Gene', (70, 76))	('CTNNB1', 'Gene', (119, 125))	('IGF2BP2', 'Gene', (80, 87))	('accelerated', 'PosReg', (88, 99))	('actinomycin D', 'Chemical', 'MESH:D003609', (15, 28))	('silencing', 'Var', (60, 69))	('CTNNB1', 'Gene', '1499', (119, 125))	('IGF2BP2', 'Gene', '10644', (80, 87))
735888	32239639	Sh-CTNNB1 impaired ESCC cell migration, invasion, and EMT process that was facilitated by pcDNA3.1/SNHG12, and such impairment was strengthened by jointly knocking down CTNNB1 and BMI1.	('as', 'Gene', '112935892', (72, 74))	('EMT process', 'CPA', (54, 65))	('ESCC cell migration', 'CPA', (19, 38))	('CTNNB1', 'Gene', (3, 9))	('as', 'Gene', '112935892', (128, 130))	('CTNNB1', 'Gene', '1499', (169, 175))	('facilitated', 'PosReg', (75, 86))	('BMI1', 'Gene', '648', (180, 184))	('knocking down', 'Var', (155, 168))	('as', 'Gene', '112935892', (43, 45))	('CTNNB1', 'Gene', (169, 175))	('CTNNB1', 'Gene', '1499', (3, 9))	('impaired', 'NegReg', (10, 18))	('BMI1', 'Gene', (180, 184))
735892	32239639	CD133 + ratio increased by SNHG12 overexpression was partly reversed by CTNNB1 knockdown and was fully reversed by the knockdown of CTNNB1 and BMI1.	('BMI1', 'Gene', '648', (143, 147))	('SNHG12', 'Gene', (27, 33))	('as', 'Gene', '112935892', (94, 96))	('CTNNB1', 'Gene', '1499', (132, 138))	('BMI1', 'Gene', (143, 147))	('overexpression', 'PosReg', (34, 48))	('CTNNB1', 'Gene', (72, 78))	('as', 'Gene', '112935892', (19, 21))	('as', 'Gene', '112935892', (50, 52))	('CTNNB1', 'Gene', (132, 138))	('knockdown', 'Var', (79, 88))	('CD133 + ratio', 'MPA', (0, 13))	('CTNNB1', 'Gene', '1499', (72, 78))
735893	32239639	The effect of SNHG12 knockdown on reducing CD133 + ratio was partly counteracted by CTNNB1 overexpression and was fully counteracted by co-overexpression of CTNNB1 and BMI1 (Fig.	('as', 'Gene', '112935892', (58, 60))	('SNHG12', 'Gene', (14, 20))	('overexpression', 'PosReg', (91, 105))	('BMI1', 'Gene', '648', (168, 172))	('CTNNB1', 'Gene', '1499', (157, 163))	('reducing', 'NegReg', (34, 42))	('CTNNB1', 'Gene', '1499', (84, 90))	('CTNNB1', 'Gene', (157, 163))	('as', 'Gene', '112935892', (111, 113))	('CD133 + ratio', 'MPA', (43, 56))	('BMI1', 'Gene', (168, 172))	('knockdown', 'Var', (21, 30))	('CTNNB1', 'Gene', (84, 90))
735896	32239639	Among the key downstream genes, we found that SOX2 or SOX4 expression changes could influence the expression of SNHG12.	('influence', 'Reg', (84, 93))	('SOX2', 'Gene', '6657', (46, 50))	('SOX4', 'Gene', (54, 58))	('SOX2', 'Gene', (46, 50))	('SNHG12', 'Gene', (112, 118))	('SOX4', 'Gene', '6659', (54, 58))	('changes', 'Var', (70, 77))	('expression', 'MPA', (98, 108))
735901	32239639	Further, DNA pull-down-western blot assay revealed the obvious enrichment of SOX4 in the bio-SNHG12 promoter group rather than the non-bio-SNHG12 promoter group (Fig.	('SOX4', 'Gene', '6659', (77, 81))	('bio-SNHG12', 'Var', (89, 99))	('SOX4', 'Gene', (77, 81))	('as', 'Gene', '112935892', (36, 38))
735905	32239639	To monitor tumorigenesis, CD133+ EC109 cells transfected with sh-NC or sh-SNHG12#1 were subcutaneously inoculated into mice to generate xenografts.	('mice', 'Species', '10090', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('sh-SNHG12', 'Var', (71, 80))
735906	32239639	As observed, growth of tumors in mice was slower in the sh-SNHG12#1 group than in the sh-NC group (Fig.	('tumors', 'Disease', (23, 29))	('sh-SNHG12#1', 'Var', (56, 67))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('slower', 'NegReg', (42, 48))	('as', 'Gene', '112935892', (39, 41))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mice', 'Species', '10090', (33, 37))	('As', 'Gene', '112935892', (0, 2))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
735908	32239639	qRT-PCR results validated that levels of SNHG12, BMI1, and CTNNB1 were lower in xenografts with SNHG12 knockdown than control (Fig.	('SNHG12', 'Gene', (96, 102))	('levels', 'MPA', (31, 37))	('CTNNB1', 'Gene', '1499', (59, 65))	('BMI1', 'Gene', '648', (49, 53))	('CTNNB1', 'Gene', (59, 65))	('BMI1', 'Gene', (49, 53))	('knockdown', 'Var', (103, 112))	('lower', 'NegReg', (71, 76))
735909	32239639	Besides, the protein levels of BMI1, beta-catenin, the downstream factors c-Myc and MMP7, and EMT-related N-cadherin and vimentin were reduced but level of E-cadherin was increased in xenografts with sh-SNHG12#1 (Fig.	('c-Myc', 'Gene', '4609', (74, 79))	('sh-SNHG12#', 'Var', (200, 210))	('vimentin', 'Gene', '7431', (121, 129))	('as', 'Gene', '112935892', (176, 178))	('MMP7', 'Gene', '4316', (84, 88))	('E-cadherin', 'Gene', (156, 166))	('vimentin', 'Gene', (121, 129))	('E-cadherin', 'Gene', '999', (156, 166))	('protein levels', 'MPA', (13, 27))	('BMI1', 'Gene', (31, 35))	('as', 'Gene', '112935892', (168, 170))	('N-cadherin', 'Gene', (106, 116))	('beta-catenin', 'Gene', (37, 49))	('reduced', 'NegReg', (135, 142))	('N-cadherin', 'Gene', '1000', (106, 116))	('beta-catenin', 'Gene', '1499', (37, 49))	('MMP7', 'Gene', (84, 88))	('BMI1', 'Gene', '648', (31, 35))	('c-Myc', 'Gene', (74, 79))
735910	32239639	Stemness-specific proteins including SOX2, SOX4, OCT4, and Nanog were lessened under SNHG12 knockdown in vivo (Fig.	('lessened', 'NegReg', (70, 78))	('OCT4', 'Gene', (49, 53))	('knockdown', 'Var', (92, 101))	('SOX4', 'Gene', (43, 47))	('SOX2', 'Gene', (37, 41))	('SNHG12', 'Gene', (85, 91))	('Nanog', 'Gene', '79923', (59, 64))	('SOX2', 'Gene', '6657', (37, 41))	('SOX4', 'Gene', '6659', (43, 47))	('Nanog', 'Gene', (59, 64))	('Stemness-specific', 'CPA', (0, 17))	('OCT4', 'Gene', '5460', (49, 53))
735911	32239639	Through IHC staining, we discovered that proliferation indexes including Ki-67 and PCNA declined in xenografts with SNHG12 knockdown (Fig.	('PCNA', 'Gene', '5111', (83, 87))	('declined', 'NegReg', (88, 96))	('proliferation indexes', 'CPA', (41, 62))	('SNHG12', 'Gene', (116, 122))	('PCNA', 'Gene', (83, 87))	('Ki-67', 'CPA', (73, 78))	('knockdown', 'Var', (123, 132))
735913	32239639	Consequently, sh-SNHG12#1 led to less metastasis nodules in mice (Fig.	('as', 'Gene', '112935892', (41, 43))	('less', 'NegReg', (33, 37))	('as', 'Gene', '112935892', (44, 46))	('mice', 'Species', '10090', (60, 64))	('sh-SNHG12#1', 'Var', (14, 25))
735914	32239639	Together, SNHG12 knockdown retards tumorigenesis and reduces metastasis in ESCC in vivo.	('SNHG12', 'Gene', (10, 16))	('retards tumorigenesis', 'Disease', 'MESH:D063646', (27, 48))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ESCC', 'Disease', (75, 79))	('as', 'Gene', '112935892', (67, 69))	('retards tumorigenesis', 'Disease', (27, 48))	('as', 'Gene', '112935892', (64, 66))	('reduces', 'NegReg', (53, 60))	('knockdown', 'Var', (17, 26))
735932	32239639	Here, among a group of predicted mRNAs, BMI1 was found to be the most significantly affected under miR-6835-3p overexpression or knockdown in ESCC cells.	('BMI1', 'Gene', (40, 44))	('miR-6835-3p', 'Var', (99, 110))	('knockdown', 'Var', (129, 138))	('As', 'Gene', '112935892', (36, 38))	('as', 'Gene', '112935892', (46, 48))	('BMI1', 'Gene', '648', (40, 44))	('overexpression', 'PosReg', (111, 125))	('miR-6835-3p', 'Chemical', '-', (99, 110))	('affected', 'Reg', (84, 92))
735953	32239639	Mechanistically, SNHG12 sequesters miR-6835-3p to induce BMI1 and interacted with IGF2BP2 to stabilize CTNNB1 and activated Wnt/beta-catenin pathway (Fig.	('CTNNB1', 'Gene', '1499', (103, 109))	('activated', 'PosReg', (114, 123))	('IGF2BP2', 'Gene', '10644', (82, 89))	('beta-catenin', 'Gene', (128, 140))	('BMI1', 'Gene', (57, 61))	('CTNNB1', 'Gene', (103, 109))	('miR-6835-3p', 'Chemical', '-', (35, 46))	('beta-catenin', 'Gene', '1499', (128, 140))	('IGF2BP2', 'Gene', (82, 89))	('SNHG12', 'Var', (17, 23))	('BMI1', 'Gene', '648', (57, 61))	('induce', 'PosReg', (50, 56))
736092	32591522	The MFI was based on a Region of Interest (ROI) which was carefully determined on the H/E 4-mum slides by a board-certified pathologist blinded for the fluorescent imaging data and subsequently overlayed precisely on the corresponding tumor and normal tissue slices.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('H/E 4', 'SUBSTITUTION', 'None', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('H/E 4', 'Var', (86, 91))	('tumor', 'Disease', (235, 240))
736437	26735287	Multifocal signal abnormalities were seen in seven limbs on T1-GRE sequences but not on T2-FSE images.	('T1-GRE', 'Var', (60, 66))	('Multifocal signal abnormalities', 'Disease', (0, 31))	('Multifocal signal abnormalities', 'Disease', 'None', (0, 31))
736464	26735287	Methods: Contrast-enhanced CT studies of PPID free horses, divided in three different age groups:young (<5 years), adult (5-15 years), and aged (>15 years); three different size groups:small (<250 kg), average (250-550 kg), and large (>550 kg); and two gender groups:male, female, were reviewed.	('horses', 'Species', '9796', (51, 57))	('250-550 kg', 'Var', (211, 221))	('<250 kg', 'Var', (192, 199))	('>550 kg', 'Var', (235, 242))
736466	26735287	Findings: Twenty-one horses and ponies were included in the study: 10 young (<5 years), five adults (5-15 years), and six aged (>15 years)/three small (<250 kg), 11 average (250-550 kg), and seven large (>550 kg)/eight male and 13 female.	('horses', 'Species', '9796', (21, 27))	('<250 kg', 'Var', (152, 159))	('>550 kg', 'Var', (204, 211))	('250-550 kg', 'Var', (174, 184))
736655	26735287	Importantly, high ICCR was significantly (rs = 0.1986, P = 0.006) correlated to cerebellar herniation.	('correlated', 'Reg', (66, 76))	('high', 'Var', (13, 17))	('cerebellar herniation', 'Disease', (80, 101))	('cerebellar herniation', 'Disease', 'MESH:D004677', (80, 101))	('hernia', 'Phenotype', 'HP:0100790', (91, 97))
736715	26735287	Right ventricle/LVCT in T, SA, and 4C views were significantly increased in group A (T: 0.873 +- 0.101; SA: 0.866 +- 0.065; 4C: 0.881 +- 0.065) compared to group C (T: 0.657 +- 0.114, P < 0.05; SA: 0.669 +- 0.068, P < 0.05; 4C: 0.710 +- 0.075, P < 0.05).	('LV', 'Disease', 'MESH:C535509', (16, 18))	('increased', 'PosReg', (63, 72))	('T: 0.873 +- 0.101;', 'Var', (85, 103))
736735	26735287	Evaluated CT parameters are: type and morphology of the aberrant subclavian arteries, presence of concurrent vascular abnormalities, reason, and degree of esophageal constriction.	('vascular abnormalities', 'Disease', (109, 131))	('vascular abnormalities', 'Disease', 'MESH:D000783', (109, 131))	('vascular abnormalities', 'Phenotype', 'HP:0002597', (109, 131))	('aberrant', 'Var', (56, 64))
736737	26735287	Aberrant left subclavian artery (LSA) was diagnosed in 4/13 cases (all of them scanned because of a suspected vascular ring anomaly) concurrently with persistent right aortic arch (PRAA) with left ligamentum arteriosum that was considered the only cause of esophageal constriction in 3/4 cases.	('Aberrant', 'Var', (0, 8))	('vascular ring anomaly', 'Disease', (110, 131))	('vascular ring', 'Phenotype', 'HP:0010775', (110, 123))	('vascular ring anomaly', 'Disease', 'MESH:D000073872', (110, 131))	('right aortic arch', 'Phenotype', 'HP:0012020', (162, 179))
736912	26735287	Presence of LTV is a predisposition for early disc degeneration in some young dogs.	('disc degeneration', 'Phenotype', 'HP:0008419', (46, 63))	('disc degeneration', 'Disease', (46, 63))	('disc degeneration', 'Disease', 'MESH:D055959', (46, 63))	('LTV', 'Gene', (12, 15))	('dogs', 'Species', '9615', (78, 82))	('early', 'Disease', (40, 45))	('Presence', 'Var', (0, 8))
737077	30741466	Survival analysis indicated that patients with high CD47 or CD133 expression exhibited poor overall survival and progression-free survival (PFS).	('patients', 'Species', '9606', (33, 41))	('CD47', 'Gene', (52, 56))	('high', 'Var', (47, 51))	('CD133', 'Gene', (60, 65))	('overall survival', 'CPA', (92, 108))	('poor', 'NegReg', (87, 91))	('progression-free survival', 'CPA', (113, 138))
737083	30741466	Knockdown of CD47 suppressed certain stem-like properties of cancer cells, such as self-renewal and chemoresistance,14, 15, 16, 17 suggesting that targeting CD47 could not only active the phagocytosis of macrophages, but also be refined into a potent supplement in treatment against CSCs.	('CD47', 'Gene', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('active', 'PosReg', (177, 183))	('cancer', 'Disease', (61, 67))	('CSCs', 'Disease', (283, 287))	('phagocytosis of macrophages', 'CPA', (188, 215))	('targeting', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('suppressed', 'NegReg', (18, 28))	('CD47', 'Gene', (13, 17))
737111	30741466	Kaplan-Meier survival curves and a log-rank test were conducted, certifying that patients with high CD47 expression had shorter OS (P = 0.0006, Figure 3A) and PFS (P = 0.001, Figure 3B).Similarly, high CD133 indicated worse OS (P = 0.012, Figure 3C) and PFS (P = 0.011, Figure 3D) than patients with low expression.	('patients', 'Species', '9606', (81, 89))	('PFS', 'MPA', (254, 257))	('CD133', 'Var', (202, 207))	('high CD133', 'Var', (197, 207))	('patients', 'Species', '9606', (286, 294))
737113	30741466	To assess whether CD47 or CD133 could be utilized as an independent indicator of OS/PFS, we performed a multivariate Cox proportional hazards analysis.	('CD47', 'Var', (18, 22))	('OS/PFS', 'Disease', (81, 87))	('Cox', 'Gene', '1351', (117, 120))	('CD133', 'Gene', (26, 31))	('Cox', 'Gene', (117, 120))
737114	30741466	As illustrated in Table 3, CD47/CD133 expression was associated with an increased risk of tumor progression in ESCC patients.	('CD47/CD133 expression', 'Var', (27, 48))	('ESCC', 'Disease', (111, 115))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('associated', 'Reg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
737118	30741466	We FACSorted primary ESCC cells from 6 patients for CD47 or CD133 and surveyed their self-renewal capacity by sphere formation assay.	('CD47', 'Var', (52, 56))	('CD133', 'Gene', (60, 65))	('patients', 'Species', '9606', (39, 47))
737131	30741466	[33] The Data from Shigemasa S et.al shows that CD47 is regulated by miR-133a which probably function as a tumor suppressor.7 Our study provides preliminary proof that CD47 blockade may improve CSC eradicating strategy, while whether other novel and effective mechanisms exist merits further investigation.	('blockade', 'Var', (173, 181))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CD47', 'Gene', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('improve', 'PosReg', (186, 193))	('CSC eradicating', 'Disease', (194, 209))
737133	30741466	Inhibiting CD47 was an effective method of suppressing tumor stemness even at high levels in CD133+ cells.	('Inhibiting', 'Var', (0, 10))	('suppressing', 'NegReg', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CD47', 'Gene', (11, 15))	('tumor stemness', 'Disease', 'MESH:D020295', (55, 69))	('tumor stemness', 'Disease', (55, 69))
737174	30881012	Anti-MLL3 (PLA0028, 1:1,000) and Anti-GST (SAB4200692, 1:1,000) were obtained from Sigma; anti-GAPDH (#5174, 1:1,000), anti-Flag (#14793, 1:1,000), anti-Myc (#2276, 1:1,000), anti-P16 (#80772, 1:1,000), anti-P21 (#2947, 1:1,000), anti-P27 (#3686, 1:1,000), and anti-P53 (#2524, 1:1,000) were obtained from Cell Signaling Technology.	('GAPDH', 'Gene', (95, 100))	('MLL3', 'Gene', (5, 9))	('P53', 'Gene', (266, 269))	('P27', 'Gene', (235, 238))	('P16', 'Gene', '1029', (180, 183))	('P27', 'Gene', '3429', (235, 238))	('P53', 'Gene', '7157', (266, 269))	('P21', 'Gene', (208, 211))	('MLL3', 'Gene', '58508', (5, 9))	('#2524', 'Var', (271, 276))	('P16', 'Gene', (180, 183))	('Myc', 'Gene', '4609', (153, 156))	('Myc', 'Gene', (153, 156))	('GAPDH', 'Gene', '2597', (95, 100))	('P21', 'Gene', '644914', (208, 211))
737202	30881012	Downregulation of MLL3 promoted ESCC cell growth as revealed by MTT assay (Figure 3B).	('ESCC', 'Disease', (32, 36))	('promoted', 'PosReg', (23, 31))	('MTT', 'Chemical', 'MESH:C070243', (64, 67))	('MLL3', 'Gene', '58508', (18, 22))	('Downregulation', 'Var', (0, 14))	('MLL3', 'Gene', (18, 22))
737207	30881012	As shown in Figure 4A, knocking down MLL3 expression reduced P21, P27, and P53 mRNA levels.	('MLL3', 'Gene', (37, 41))	('P21', 'Gene', '644914', (61, 64))	('P53', 'Gene', '7157', (75, 78))	('P27', 'Gene', (66, 69))	('reduced', 'NegReg', (53, 60))	('P27', 'Gene', '3429', (66, 69))	('MLL3', 'Gene', '58508', (37, 41))	('knocking down', 'Var', (23, 36))	('P21', 'Gene', (61, 64))	('P53', 'Gene', (75, 78))
737209	30881012	In the functional study, knocking down the expression of P16 abolished the senescence-promoting effects of MLL3 (Figure 4C and D).	('knocking down', 'Var', (25, 38))	('MLL3', 'Gene', '58508', (107, 111))	('P16', 'Gene', (57, 60))	('P16', 'Gene', '1029', (57, 60))	('abolished', 'NegReg', (61, 70))	('MLL3', 'Gene', (107, 111))	('senescence-promoting effects', 'CPA', (75, 103))
737220	30881012	Our findings suggest that MLL3 is a tumor suppressor in ESCC, define it as an upstream protector of p16, and thereby reveal that alteration in MLL3 represents a point of vulnerability in cancer.	('ESCC', 'Disease', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('alteration', 'Var', (129, 139))	('MLL3', 'Gene', (26, 30))	('MLL3', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('p16', 'Gene', (100, 103))	('MLL3', 'Gene', '58508', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('MLL3', 'Gene', '58508', (26, 30))	('tumor', 'Disease', (36, 41))	('p16', 'Gene', '1029', (100, 103))
737222	30881012	In addition, knocking down MLL3 expression reduced senescence.	('senescence', 'CPA', (51, 61))	('MLL3', 'Gene', '58508', (27, 31))	('knocking down', 'Var', (13, 26))	('MLL3', 'Gene', (27, 31))	('reduced', 'NegReg', (43, 50))
737225	30881012	This finding is consistent with previous findings demonstrating that loss of p16 expression was associated with poor differentiation of ESCC.	('p16', 'Gene', (77, 80))	('loss', 'Var', (69, 73))	('ESCC', 'Disease', (136, 140))	('associated', 'Reg', (96, 106))	('p16', 'Gene', '1029', (77, 80))	('poor differentiation', 'CPA', (112, 132))
737316	30218087	When DeltaUDE + DeltaUEF + DeltaUDF = DeltaDEF is satisfied, the patient belongs to the cancerous lesion stage.	('cancerous lesion', 'Disease', (88, 104))	('cancerous lesion', 'Phenotype', 'HP:0002664', (88, 104))	('DeltaUDE + DeltaUEF + DeltaUDF', 'Var', (5, 35))	('patient', 'Species', '9606', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancerous lesion', 'Disease', 'MESH:D009062', (88, 104))
737318	30218087	When DeltaUDE + DeltaUEF + DeltaUDF = DeltaDEF is satisfied, the patient belongs to this cancerous lesion stage.	('cancerous lesion', 'Disease', 'MESH:D009062', (89, 105))	('DeltaUDE + DeltaUEF + DeltaUDF', 'Var', (5, 35))	('cancerous lesion', 'Disease', (89, 105))	('cancerous lesion', 'Phenotype', 'HP:0002664', (89, 105))	('patient', 'Species', '9606', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
737386	29342161	As the measured hormone levels could be affected by cachexia:or weight loss due to underlying EA:we categorized the cases into three groups: 1) individuals without weight loss between BMI reported 5-years prior to interview and the BMI measured at interview (i.e., BMI change >= 0 kg/m2); among individuals with weight loss, we dichotomized BMI change at the mean into 2) BMI change <-3.8 kg/m2 and 3) BMI change -3.8 to <0 kg/m2.	('cachexia', 'Disease', 'MESH:D002100', (52, 60))	('change -3.8', 'Var', (406, 417))	('weight loss', 'Disease', (164, 175))	('weight loss', 'Disease', (312, 323))	('weight loss', 'Disease', (64, 75))	('cachexia', 'Disease', (52, 60))	('weight loss', 'Phenotype', 'HP:0001824', (164, 175))	('weight loss', 'Phenotype', 'HP:0001824', (312, 323))	('weight loss', 'Phenotype', 'HP:0001824', (64, 75))	('cachexia', 'Phenotype', 'HP:0004326', (52, 60))	('weight loss', 'Disease', 'MESH:D015431', (64, 75))	('weight loss', 'Disease', 'MESH:D015431', (164, 175))	('weight loss', 'Disease', 'MESH:D015431', (312, 323))
737387	29342161	Significant differences were noted for GERD symptoms (20% controls v. 48% EA cases), H. pylori positivity (63% v. 52%), manual occupation (51% v. 63%), ever-smoking (64% v. 84%), and education (11.7 v. 10.6 years).	('GERD', 'Disease', (39, 43))	('H. pylori', 'Species', '210', (85, 94))	('H. pylori', 'Disease', (85, 94))	('GERD', 'Disease', 'MESH:D005764', (39, 43))	('positivity', 'Var', (95, 105))	('pylori positivity', 'Phenotype', 'HP:0005202', (88, 105))
737391	29342161	Individual sex steroid hormones, and calculated free estradiol, free testosterone, and free DHT, were associated with significantly decreased EA odds (Table 2).	('free', 'Var', (87, 91))	('steroid hormones', 'Chemical', 'MESH:D013256', (15, 31))	('free estradiol', 'MPA', (48, 62))	('testosterone', 'Chemical', 'MESH:D013739', (69, 81))	('DHT', 'Chemical', 'MESH:D013196', (92, 95))	('decreased', 'NegReg', (132, 141))	('estradiol', 'Chemical', 'MESH:D004958', (53, 62))	('free testosterone', 'MPA', (64, 81))
737418	29342161	One of these studies further examined the effects of estradiol and DHT administration on EA tumors in mice and reported that estradiol injections resulted in a high estradiol:DHT ratio and significant inhibition of tumor growth.	('mice', 'Species', '10090', (102, 106))	('EA tumors', 'Disease', (89, 98))	('estradiol', 'Chemical', 'MESH:D004958', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('estradiol injections', 'Var', (125, 145))	('high estradiol', 'Phenotype', 'HP:0025134', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('estradiol:DHT ratio', 'MPA', (165, 184))	('estradiol', 'Chemical', 'MESH:D004958', (53, 62))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('EA tumors', 'Disease', 'MESH:D009369', (89, 98))	('DHT', 'Chemical', 'MESH:D013196', (175, 178))	('tumor', 'Disease', (215, 220))	('inhibition', 'NegReg', (201, 211))	('DHT', 'Chemical', 'MESH:D013196', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('injections', 'Var', (135, 145))	('tumor', 'Disease', (92, 97))	('estradiol', 'Chemical', 'MESH:D004958', (165, 174))
737460	28288195	All cancer cases identified as codes C15 (esophageal cancer) or C16 (gastric cancer) from the 10th revision of the International Classification of Disease (ICD-10) were included in the analysis.	('C15', 'Gene', '51316', (37, 40))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('C15', 'Gene', (37, 40))	('C16', 'Var', (64, 67))	('ICD', 'Disease', (156, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('esophageal cancer', 'Disease', (42, 59))	('gastric cancer', 'Disease', (69, 83))	('ICD', 'Disease', 'OMIM:252500', (156, 159))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('cancer', 'Disease', (4, 10))
737571	26112428	A meta-analysis exploring association of pCR with overall survival, suggested 3- and 5-year survival of 75 and 50 % with pCR vs 29 and 22.6 % without, including patients with adenocarcinoma and squamous cell carcinoma.	('adenocarcinoma', 'Disease', (175, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('adenocarcinoma', 'Disease', 'MESH:D000230', (175, 189))	('patients', 'Species', '9606', (161, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('pCR', 'Var', (121, 124))	('squamous cell carcinoma', 'Disease', (194, 217))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (194, 217))
737598	26112428	Perioperative morbidity was substantially less (57 vs 27 %, p<0.001) with transhiatal resection, especially pulmonary complications, but in-hospital mortality was similar.	('transhiatal resection', 'Var', (74, 95))	('pulmonary complications', 'Disease', (108, 131))	('pulmonary complications', 'Disease', 'MESH:D008171', (108, 131))	('less', 'NegReg', (42, 46))	('pulmonary complications', 'Phenotype', 'HP:0006532', (108, 131))
737619	26112428	Randomized trials have now robustly demonstrated the preoperative therapy with chemoradiotherapy and chemotherapy alone improves survival outcome for the bulk of curable patients, those with locally advanced T1N1M0 and T2-3 N0-1 M0 disease.	('patients', 'Species', '9606', (170, 178))	('survival outcome', 'MPA', (129, 145))	('T2-3 N0-1 M0', 'Var', (219, 231))	('improves', 'PosReg', (120, 128))	('T1N1M0', 'Var', (208, 214))
737621	24930674	Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including esophageal squamous cell cancer (ESCC).	('ORAOV1', 'Gene', '220064', (26, 32))	('cancer', 'Disease', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ORAOV1', 'Gene', (26, 32))	('human', 'Species', '9606', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (255, 286))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (41, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (237, 243))	('ROS', 'Chemical', 'MESH:D017382', (133, 136))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('amplification', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('aggressive phenotype', 'MPA', (85, 105))	('proline metabolism', 'MPA', (110, 128))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (266, 286))	('esophageal squamous cell cancer', 'Disease', (255, 286))	('esophageal squamous cell cancer', 'Disease', (41, 72))	('promotes', 'PosReg', (73, 81))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (52, 72))	('proline', 'Chemical', 'MESH:D011392', (110, 117))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (66, 72))
737624	24930674	ORAOV1 amplification was significantly associated with a poorly differentiated histology and tumors located in the upper or middle esophagus.	('poorly differentiated histology', 'CPA', (57, 88))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('associated', 'Reg', (39, 49))	('ORAOV1', 'Gene', '220064', (0, 6))	('tumors', 'Disease', (93, 99))	('amplification', 'Var', (7, 20))	('ORAOV1', 'Gene', (0, 6))
737638	24930674	Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including esophageal squamous cell cancer (ESCC), and can be associated with an advanced stage and poor prognosis.	('cancer', 'Disease', (132, 138))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (107, 138))	('associated', 'Reg', (158, 168))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (118, 138))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (89, 95))	('esophageal squamous cell cancer', 'Disease', (107, 138))	('Chromosomal band 11q13', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
737650	24930674	To develop a high-throughput method for detecting ORAOV1 amplification in a clinical setting, we verified a real-time PCR-based detection method, the TaqMan Copy Number Assay.	('ORAOV1', 'Gene', (50, 56))	('ORAOV1', 'Gene', '220064', (50, 56))	('clinical', 'Species', '191496', (76, 84))	('amplification', 'Var', (57, 70))
737651	24930674	Using a cut off of 4 copies, the number was 0.98-3.3 copies in the non-amplified cell lines; however, the number in the ORAOV1-amplified cell lines was 4.2-14.4 copies (KYSE140, KYSE180, KYSE220, and T.T).	('T.T', 'Var', (200, 203))	('ORAOV1', 'Gene', '220064', (120, 126))	('KYSE180', 'Var', (178, 185))	('ORAOV1', 'Gene', (120, 126))	('KYSE220', 'Var', (187, 194))
737653	24930674	Next, ORAOV1 amplification was evaluated using Hs03772057_cn (intron 2) in 94 FFPE samples of stage III ESCC specimens.	('ORAOV1', 'Gene', '220064', (6, 12))	('ORAOV1', 'Gene', (6, 12))	('Hs03772057_cn', 'Var', (47, 60))
737657	24930674	Specifically, patients with ORAOV1 amplification tended to have poorly differentiated tumors in the upper or middle region of the esophagus.	('amplification', 'Var', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('ORAOV1', 'Gene', '220064', (28, 34))	('ORAOV1', 'Gene', (28, 34))	('patients', 'Species', '9606', (14, 22))
737659	24930674	Patients with ORAOV1 amplification tended to have a shorter disease-free survival (DFS) and overall survival (OS) after surgery, compared with patients without amplification, although the differences were not significant (median DFS, 11.6 vs. 12.6 months, P = 0.50, and median OS, 21.6 vs. 33.7 months, P = 0.16, respectively) (Figure 3A and B).	('disease-free survival', 'CPA', (60, 81))	('ORAOV1', 'Gene', (14, 20))	('shorter', 'NegReg', (52, 59))	('patients', 'Species', '9606', (143, 151))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'CPA', (92, 108))	('amplification', 'Var', (21, 34))	('ORAOV1', 'Gene', '220064', (14, 20))
737678	24930674	Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including ESCC, and is associated with an advanced disease stage and a poor prognosis.	('associated with', 'Reg', (120, 135))	('human', 'Species', '9606', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('Chromosomal band 11q13', 'Var', (0, 22))	('ESCC', 'Disease', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
737691	24930674	Therefore, as was seen in our study, the ORAOV1 gene enhances tumorigenicity and tumor growth.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('enhances', 'PosReg', (53, 61))	('gene', 'Var', (48, 52))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ORAOV1', 'Gene', '220064', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ORAOV1', 'Gene', (41, 47))	('tumor', 'Disease', (81, 86))
737692	24930674	In our cohort, the ORAOV1 gene was amplified in approximately half of the stage III ESCC, and patients with ORAOV1 amplification tended to have a shorter OS than patients without amplification, although the difference was not significant.	('ORAOV1', 'Gene', (108, 114))	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (94, 102))	('amplification', 'Var', (115, 128))	('ORAOV1', 'Gene', '220064', (19, 25))	('ORAOV1', 'Gene', (19, 25))	('stage III ESCC', 'Disease', (74, 88))	('ORAOV1', 'Gene', '220064', (108, 114))
737696	24930674	Therefore, patients with ORAOV1 amplification may exhibit the amplification of other cancer-related genes, which might also be related to a poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('amplification', 'Var', (32, 45))	('related', 'Reg', (127, 134))	('amplification', 'MPA', (62, 75))	('cancer', 'Disease', (85, 91))	('exhibit', 'Reg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('ORAOV1', 'Gene', '220064', (25, 31))	('patients', 'Species', '9606', (11, 19))	('ORAOV1', 'Gene', (25, 31))
737697	24930674	ORAOV1 amplification was significantly associated with a poorly differentiated histology and, in our xenograft study, ORAOV1-overexpressed cells produced poorly differentiated tumors.	('ORAOV1', 'Gene', '220064', (118, 124))	('poorly differentiated histology', 'CPA', (57, 88))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ORAOV1', 'Gene', (118, 124))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('associated', 'Reg', (39, 49))	('ORAOV1', 'Gene', '220064', (0, 6))	('amplification', 'Var', (7, 20))	('ORAOV1', 'Gene', (0, 6))
737716	24930674	The primer IDs used for the ORAOV1 gene were Hs03772057_cn (intron 2) and Hs03793932_cn (intron 3).	('ORAOV1', 'Gene', '220064', (28, 34))	('Hs03793932_cn', 'Var', (74, 87))	('Hs03772057_cn', 'Var', (45, 58))	('ORAOV1', 'Gene', (28, 34))
737800	21126707	A more definitive trial, comparing PPI therapy to PPI and aspirin in Barrett's using adenocarcinoma as the outcome is ongoing.	('adenocarcinoma', 'Disease', (85, 99))	('aspirin', 'Chemical', 'MESH:D001241', (58, 65))	('Barrett', 'Disease', (69, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))	('PPI', 'Var', (35, 38))
737845	21126707	A recent controlled study showed that ablation of the inlet patch improved the symptom of globus in these patients.	('globus', 'Disease', (90, 96))	('improved', 'PosReg', (66, 74))	('patients', 'Species', '9606', (106, 114))	('ablation', 'Var', (38, 46))	('symptom', 'MPA', (79, 86))
737855	21126707	PPI therapy has been very effective in managing the problem of peptic stricture but has not significantly impacted on the problem of adenocarcinoma or its precursor lesion, Barrett's esophagus.	('adenocarcinoma', 'Disease', (133, 147))	('peptic stricture', 'MPA', (63, 79))	('adenocarcinoma', 'Disease', 'MESH:D000230', (133, 147))	('PPI', 'Var', (0, 3))	("Barrett's esophagus", 'Disease', (173, 192))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (173, 192))
737860	18980994	Cell proliferation, cell cycle abnormalities, and cancer outcome in patients with Barrett's esophagus: A long-term prospective study Elevated cellular proliferation and cell cycle abnormalities, which have been associated with premalignant lesions, may be caused by inactivation of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Elevated', 'PosReg', (133, 141))	('tumor', 'Disease', (282, 287))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (82, 101))	('patients', 'Species', '9606', (68, 76))	('cell cycle abnormalities', 'Phenotype', 'HP:0011018', (169, 193))	('cell cycle abnormalities', 'Phenotype', 'HP:0011018', (20, 44))	('inactivation', 'Var', (266, 278))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cellular proliferation', 'CPA', (142, 164))	('cell cycle abnormalities', 'CPA', (169, 193))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
737865	18980994	Diploid S and 4N (G2/tetraploid) fractions were significantly higher in biopsies with TP53 mutation and LOH.	('mutation', 'Var', (91, 99))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', (86, 90))	('LOH', 'Var', (104, 107))	('higher', 'PosReg', (62, 68))
737866	18980994	CDKN2A inactivation was not associated with higher Ki67-positive, diploid S, G1, or 4N fractions.	('Ki67', 'Chemical', '-', (51, 55))	('inactivation', 'Var', (7, 19))	('Ki67-positive', 'Var', (51, 64))	('CDKN2A', 'Gene', (0, 6))	('diploid S', 'CPA', (66, 75))	('CDKN2A', 'Gene', '1029', (0, 6))
737868	18980994	High Ki67-positive proliferative fractions were not associated with inactivation of CDKN2A and TP53 or future development of cancer in our cohort of patients with Barrett's esophagus.	('patients', 'Species', '9606', (149, 157))	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (125, 131))	('Ki67', 'Chemical', '-', (5, 9))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (163, 182))	('TP53', 'Gene', '7157', (95, 99))	('inactivation', 'Var', (68, 80))	('TP53', 'Gene', (95, 99))
737869	18980994	Bi-allelic inactivation of TP53 was associated with elevated 4N fractions, which have been associated with the future development of esophageal adenocarcinoma.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('Bi-allelic inactivation', 'Var', (0, 23))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (133, 158))	('esophageal adenocarcinoma', 'Disease', (133, 158))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (133, 158))	('associated', 'Reg', (91, 101))	('4N fractions', 'MPA', (61, 73))	('elevated', 'PosReg', (52, 60))
737873	18980994	These tumor suppressors could be inactivated by a two hit mechanism involving loss of heterozygosity (LOH) of one allele and mutation or methylation of the second.	('methylation', 'Var', (137, 148))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('loss of', 'NegReg', (78, 85))	('tumor', 'Disease', (6, 11))	('mutation', 'Var', (125, 133))
737874	18980994	Abnormalities involving CDKN2A and TP53 are among the most commonly reported in human cancers and premalignant neoplasms.	('Abnormalities', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TP53', 'Gene', '7157', (35, 39))	('CDKN2A', 'Gene', (24, 30))	('TP53', 'Gene', (35, 39))	('premalignant neoplasms', 'Disease', 'MESH:D009369', (98, 120))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('CDKN2A', 'Gene', '1029', (24, 30))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('premalignant neoplasms', 'Disease', (98, 120))	('neoplasms', 'Phenotype', 'HP:0002664', (111, 120))
737877	18980994	Several, but not all, cross-sectional studies using DNA content flow cytometry, multiparameter flow cytometry and immunohistochemistry have reported associations between abnormal proliferation/cell cycle fractions and advancing grades of dysplasia.	('abnormal', 'Var', (170, 178))	('associations', 'Interaction', (149, 161))	('dysplasia', 'Disease', 'MESH:D004476', (238, 247))	('dysplasia', 'Disease', (238, 247))
737892	18980994	Biopsies from 214 of the participants were evaluated for CDKN2A mutation, 192 for TP53 mutation, 245 for 9p LOH, 241 for 17p LOH, and 96 for CDKN2A methylation.	('TP53', 'Gene', (82, 86))	('CDKN2A', 'Gene', '1029', (141, 147))	('mutation', 'Var', (64, 72))	('CDKN2A', 'Gene', (57, 63))	('participants', 'Species', '9606', (25, 37))	('CDKN2A', 'Gene', '1029', (57, 63))	('TP53', 'Gene', '7157', (82, 86))	('mutation', 'Var', (87, 95))	('CDKN2A', 'Gene', (141, 147))
737911	18980994	Evaluation of mutation of exons 5-9 of the TP53 gene was performed on 382 flow-purified fractions from 192 participants as described previously.	('TP53', 'Gene', '7157', (43, 47))	('mutation', 'Var', (14, 22))	('TP53', 'Gene', (43, 47))	('participants', 'Species', '9606', (107, 119))
737920	18980994	Receiver operating characteristic (ROC) curves were used to plot the sensitivity and specificity of using various thresholds of S phase or 4N fractions to discriminate between biopsies with and without TP53 inactivation.	('TP53', 'Gene', (202, 206))	('inactivation', 'Var', (207, 219))	('TP53', 'Gene', '7157', (202, 206))
737921	18980994	However, because we hypothesize that inactivation of TP53 increases S and 4N fractions, all specificities and sensitivities are computed in terms of the number of TP53-inactivated samples with S or 4N fractions above a threshold.	('increases', 'PosReg', (58, 67))	('TP53', 'Gene', '7157', (163, 167))	('TP53', 'Gene', (163, 167))	('TP53', 'Gene', '7157', (53, 57))	('inactivation', 'Var', (37, 49))	('TP53', 'Gene', (53, 57))
737922	18980994	In all analyses, neutral TP53 mutations were considered equivalent to TP53 wild type.	('TP53', 'Gene', (25, 29))	('TP53', 'Gene', '7157', (70, 74))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', '7157', (25, 29))
737927	18980994	This allowed us to directly test the hypotheses that proliferative and cell cycle abnormalities are predictors of progression from BE to EA that develop as early events due to inactivation of the tumor suppressors CDKN2A and TP53.	('cell cycle abnormalities', 'Phenotype', 'HP:0011018', (71, 95))	('CDKN2A', 'Gene', (214, 220))	('tumor', 'Disease', (196, 201))	('CDKN2A', 'Gene', '1029', (214, 220))	('TP53', 'Gene', '7157', (225, 229))	('inactivation', 'Var', (176, 188))	('TP53', 'Gene', (225, 229))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
737929	18980994	We tested the associations between CDKN2A inactivation and cell proliferative and cell cycle fractions.	('CDKN2A', 'Gene', '1029', (35, 41))	('tested', 'Reg', (3, 9))	('inactivation', 'Var', (42, 54))	('cell proliferative', 'CPA', (59, 77))	('CDKN2A', 'Gene', (35, 41))
737930	18980994	Ki67-positive, S phase, and 4N fractions were measured in diploid BE biopsies at the same time as the Ki67-positive G1 cells were sorted for subsequent examination of the mutation and LOH statuses of CDKN2A and TP53 and the CpG island methylation status of CDKN2A.	('CDKN2A', 'Gene', '1029', (200, 206))	('Ki67', 'Chemical', '-', (102, 106))	('mutation', 'Var', (171, 179))	('Ki67', 'Chemical', '-', (0, 4))	('TP53', 'Gene', '7157', (211, 215))	('CDKN2A', 'Gene', '1029', (257, 263))	('TP53', 'Gene', (211, 215))	('CDKN2A', 'Gene', (257, 263))	('CDKN2A', 'Gene', (200, 206))
737934	18980994	CDKN2A methylation and 9p LOH co-occurred in biopsies less frequently than expected by chance (p = 0.0001, chi-square test).	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))	('methylation', 'Var', (7, 18))
737935	18980994	S phase and 4N fractions were significantly higher in diploid biopsies with both TP53 mutation and 17p LOH than those with no detectable TP53 alterations (+/+) (p = 0.007 and p < 0.0001, respectively), while they were not significantly different between TP53 +/+ samples and those with only one form of TP53 abnormality (Figure 2).	('TP53', 'Gene', '7157', (254, 258))	('TP53', 'Gene', (254, 258))	('TP53', 'Gene', '7157', (303, 307))	('S phase', 'MPA', (0, 7))	('TP53', 'Gene', (303, 307))	('higher', 'PosReg', (44, 50))	('TP53', 'Gene', '7157', (137, 141))	('mutation', 'Var', (86, 94))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('TP53', 'Gene', (137, 141))
737936	18980994	TP53 mutation and 17p LOH co-occurred in biopsies more frequently than expected by chance (p = 0.0005, chi-square test).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
737937	18980994	Analyses of the effects of CDKN2A inactivation excluded biopsies with detectable TP53 alterations in order to determine the effects of CDKN2A inactivation in isolation.	('CDKN2A', 'Gene', (135, 141))	('CDKN2A', 'Gene', '1029', (135, 141))	('inactivation', 'Var', (34, 46))	('CDKN2A', 'Gene', (27, 33))	('CDKN2A', 'Gene', '1029', (27, 33))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
737939	18980994	Because TP53 abnormalities were significantly associated with high S phase and 4N fractions, we estimated the sensitivity and specificity of these fractions for detecting biopsies with TP53 mutation and LOH (Figure 3).	('mutation', 'Var', (190, 198))	('TP53', 'Gene', (185, 189))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('associated', 'Reg', (46, 56))	('TP53', 'Gene', '7157', (185, 189))
737941	18980994	4N fraction was a good discriminator of biopsies with both TP53 mutation and LOH (AUC=0.92, 95% CI=0.87-0.97), but diploid S phase fraction was not (AUC=0.70, 95% CI=0.60-0.79).	('TP53', 'Gene', '7157', (59, 63))	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (59, 63))
737950	18980994	In another study, the unusual distribution of Ki67-stained cells in colonic crypts, but not the total fraction of Ki67-positive epithelial cells, was associated with an increased risk of development of secondary tumors in participants who had early colorectal tumors.	('participants', 'Species', '9606', (222, 234))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('secondary tumors', 'Disease', (202, 218))	('secondary tumors', 'Disease', 'MESH:D060085', (202, 218))	('colorectal tumors', 'Disease', (249, 266))	('colorectal tumors', 'Disease', 'MESH:D015179', (249, 266))	('Ki67-stained', 'Var', (46, 58))	('Ki67', 'Chemical', '-', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('Ki67', 'Chemical', '-', (114, 118))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('associated with', 'Reg', (150, 165))
737953	18980994	TP53 is involved in the G1/S checkpoint, thus, inactivation of this tumor suppressor would be expected to increase the numbers of cells in S and G2/M phases of the cell cycle.	('tumor', 'Disease', (68, 73))	('inactivation', 'Var', (47, 59))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('increase', 'PosReg', (106, 114))	('G2/M phases of the cell cycle', 'CPA', (145, 174))
737956	18980994	TP53 mutation and LOH were found in the same biopsies more frequently than expected by chance, suggesting that bi-allelic inactivation of TP53 is selected, which is consistent with Knudson's two hit hypothesis for inactivating tumor suppressor genes and previous studies of our cohort.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (138, 142))	('tumor', 'Disease', (227, 232))	('bi-allelic inactivation', 'Var', (111, 134))	('TP53', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
737957	18980994	We found that high 4N fractions were a sensitive and specific indicator of bi-allelic TP53 inactivation (Figure 3).	('TP53', 'Gene', (86, 90))	('high', 'Var', (14, 18))	('inactivation', 'NegReg', (91, 103))	('TP53', 'Gene', '7157', (86, 90))
737963	18980994	Since TP53 abnormalities can be pleiotropic and could be selected for loss of proliferative control, decreased apoptosis or gain of function, it will be difficult to determine the exact mechanism in human biopsies in vivo, given heterogeneity in both constitutive and neoplastic genetic backgrounds and uncontrolled environment exposures.	('abnormalities', 'Var', (11, 24))	('proliferative control', 'CPA', (78, 99))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('loss', 'NegReg', (70, 74))	('human', 'Species', '9606', (199, 204))	('decreased', 'NegReg', (101, 110))	('gain of function', 'PosReg', (124, 140))	('apoptosis', 'CPA', (111, 120))
737964	18980994	CDKN2A negatively regulates the transition from G1 to S phase, so we had expected to observe higher S phase and 4N fractions in samples with CDKN2A inactivation.	('higher', 'PosReg', (93, 99))	('CDKN2A', 'Gene', '1029', (141, 147))	('S phase', 'MPA', (100, 107))	('regulates', 'Reg', (18, 27))	('inactivation', 'Var', (148, 160))	('CDKN2A', 'Gene', (0, 6))	('transition', 'MPA', (32, 42))	('CDKN2A', 'Gene', (141, 147))	('4N fractions', 'MPA', (112, 124))	('CDKN2A', 'Gene', '1029', (0, 6))
737965	18980994	However, since at least one allele of CDKN2A was inactivated in most of our samples, it was difficult to evaluate the effects of CDKN2A inactivation on proliferation and cell cycle in the absence of sufficient wild-type samples with BE to use as a comparison group.	('inactivation', 'Var', (136, 148))	('CDKN2A', 'Gene', (129, 135))	('CDKN2A', 'Gene', '1029', (129, 135))	('CDKN2A', 'Gene', (38, 44))	('cell cycle', 'CPA', (170, 180))	('CDKN2A', 'Gene', '1029', (38, 44))
737967	18980994	We did not find an association between inactivation of CDKN2A or TP53 and increased Ki67-positive or G1 fractions, a result consistent with their known biological properties in studies in model systems.	('CDKN2A', 'Gene', '1029', (55, 61))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('G1 fractions', 'CPA', (101, 113))	('Ki67-positive', 'CPA', (84, 97))	('inactivation', 'Var', (39, 51))	('Ki67', 'Chemical', '-', (84, 88))	('CDKN2A', 'Gene', (55, 61))
737973	18980994	PPI use can alleviate the symptoms of gastroesophageal reflux, but its effects on the development of cancer are not known, although dose can be studied in a randomized trial such as AspECT.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('symptoms', 'MPA', (26, 34))	('PPI', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (38, 61))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (38, 61))	('gastroesophageal reflux', 'Disease', (38, 61))	('alleviate', 'NegReg', (12, 21))
737974	18980994	In a recent study of the same cohort, the best predictor of cancer outcome was a combination of chromosomal instability biomarkers that included early (9p LOH), intermediate (17p LOH), and late events (tetraploidy, aneuploidy) in neoplastic progression.	('9p LOH', 'Var', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('chromosomal instability', 'Phenotype', 'HP:0040012', (96, 119))	('cancer', 'Disease', (60, 66))	('tetraploidy', 'Disease', 'MESH:D057891', (202, 213))	('aneuploidy', 'Disease', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('aneuploidy', 'Disease', 'MESH:D000782', (215, 225))	('tetraploidy', 'Disease', (202, 213))
738067	33659206	Furthermore, the rate of death is 62% lower among patients who were treated using radiotherapy than those who did not.	('patients', 'Species', '9606', (50, 58))	('lower', 'NegReg', (38, 43))	('radiotherapy', 'Var', (82, 94))	('death', 'Disease', 'MESH:D003643', (25, 30))	('death', 'Disease', (25, 30))
738141	31278574	On multivariate binary logistic regression, both the presence of avid nodes at restaging (mN stage 2) and lack of mTR (% reduction in primary tumor SUVmax) were associated with coexistent metastatic disease (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('associated', 'Reg', (161, 171))	('mTR', 'Gene', '21748', (114, 117))	('tumor', 'Disease', (142, 147))	('lack', 'Var', (106, 110))	('metastatic disease', 'Disease', (188, 206))	('mTR', 'Gene', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('reduction', 'NegReg', (121, 130))
738157	31278574	Interestingly, the small number with ypN-mN+ disease (i.e., presumed false avid positive) demonstrated a trend towards worse prognosis for DFS (p = 0.085) with significantly worse recurrence, suggesting the possibility of pathologically missed micro-metastases.	('DFS', 'Disease', (139, 142))	('metastases', 'Disease', (250, 260))	('metastases', 'Disease', 'MESH:D009362', (250, 260))	('ypN-mN+', 'Var', (37, 44))
738159	31278574	On multivariate regression, lack of complete mNR was associated with recurrence and death at both time points: OR 4.18 (1.56-11.2; p = 0.004) and 3.63 (1.26-10.5; p = 0.017) respectively.	('recurrence', 'Disease', (69, 79))	('mNR', 'Gene', '74477', (45, 48))	('lack', 'Var', (28, 32))	('death', 'Disease', 'MESH:D003643', (84, 89))	('death', 'Disease', (84, 89))	('mNR', 'Gene', (45, 48))
738176	31278574	This suggests persistent nodal avidity to be a surrogate of a worse cancer phenotype.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('nodal avidity', 'Var', (25, 38))	('cancer', 'Disease', (68, 74))
738177	31278574	While the reasons for nodal avidity are complex and incompletely understood (perhaps reflecting mutational burden disrupting glucose utilization, in conjunction with tumor micro-environment, perfusion, and hypoxia), at a simplistic level, it may be possible to infer chemo(in)sensitivity.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('mutational', 'Var', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('glucose utilization', 'MPA', (125, 144))	('glucose', 'Chemical', 'MESH:D005947', (125, 132))	('hypoxia', 'Disease', 'MESH:D000860', (206, 213))	('tumor', 'Disease', (166, 171))	('hypoxia', 'Disease', (206, 213))	('disrupting', 'NegReg', (114, 124))
738182	31278574	Lack of mNR may therefore be an indicator of chemo-resistant clones within resectable lymph nodes, and therefore by extrapolation, a surrogate for the occult distant nodal or hematogenous micrometastases that are responsible for recurrence.	('mNR', 'Gene', (8, 11))	('metastases', 'Disease', (193, 203))	('Lack', 'Var', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (193, 203))	('mNR', 'Gene', '74477', (8, 11))
738204	30276974	pN0 esophageal cancer refers to tumors histologically proven to be free of lymph node involvement after resection and account for nearly half of all completely resected squamous cell carcinomas located in the thoracic esophagus.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (169, 193))	('squamous cell carcinomas', 'Disease', (169, 193))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('pN0 esophageal cancer', 'Phenotype', 'HP:0011459', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (169, 193))	('esophageal cancer', 'Disease', (4, 21))	('pN0', 'Var', (0, 3))
738206	30276974	The five-year survival rate of pT2N0M0 and pT3N0M0 ESCC patients is < 50%.8 Postoperative recurrence is the main cause of treatment failure.	('patients', 'Species', '9606', (56, 64))	('pT2N0M0', 'Var', (31, 38))	('pT3N0M0', 'Var', (43, 50))
738212	30276974	Only patients determined by pathological examination with pT1b-T4aN0M0 disease after radical resection, without nodal involvement, will be enrolled in the study.	('nodal', 'Gene', (112, 117))	('pT1b-T4aN0M0', 'Var', (58, 70))	('patients', 'Species', '9606', (5, 13))	('nodal', 'Gene', '4838', (112, 117))
738247	30276974	In conclusion, patients with pN0 ESCC remain at risk of recurrence even after radical esophagectomy and systemic lymph node dissection.	('patients', 'Species', '9606', (15, 23))	('ESCC', 'Disease', (33, 37))	('pN0', 'Var', (29, 32))
738268	29551902	Overexpression of TPX2 could cause DNA aneuploidy and polyploidy.	('TPX2', 'Gene', (18, 22))	('cause', 'Reg', (29, 34))	('Overexpression', 'Var', (0, 14))	('aneuploidy and polyploidy', 'Disease', 'MESH:D011123', (39, 64))
738269	29551902	The aberrant expression of TPX2 could inhibit normal mitosis and lead to carcinogenesis.	('carcinogenesis', 'Disease', (73, 87))	('mitosis', 'Disease', (53, 60))	('aberrant expression', 'Var', (4, 23))	('mitosis', 'Disease', 'None', (53, 60))	('lead to', 'Reg', (65, 72))	('carcinogenesis', 'Disease', 'MESH:D063646', (73, 87))	('TPX2', 'Gene', (27, 31))	('inhibit', 'NegReg', (38, 45))
738272	29551902	A recently published work by Liu et al revealed a significant relationship of positive TPX2 to cancer stage III/IV and cancer grade of differentiation.	('positive', 'Var', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', (119, 125))	('TPX2', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
738292	29551902	There was a significant association of increased TPX2 expression with DFS of patients in studies with a quality score of >85% (HR =2.54, 95% CI: 1.81-3.57) and <85% (HR =2.42, 95% CI: 1.76-3.33).	('expression', 'MPA', (54, 64))	('<85%', 'Var', (160, 164))	('patients', 'Species', '9606', (77, 85))	('increased', 'PosReg', (39, 48))	('TPX2', 'Gene', (49, 53))
738298	29551902	The pooled results showed that TPX2 expression was an independent prognostic factor for OS of patients with digestive system cancers (pooled HR =2.31, 95% CI: 1.78-3.01), and there was no heterogeneity among the studies (I2=0.0%, p=0.660) (Figure 6).	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('patients', 'Species', '9606', (94, 102))	('system cancers', 'Disease', (118, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('expression', 'Var', (36, 46))	('system cancers', 'Disease', 'MESH:D009369', (118, 132))	('TPX2', 'Gene', (31, 35))
738314	29551902	Furthermore, in vivo and in vitro, silencing of TPX2 gene could reduce the tumorigenicity of cancer cells.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('silencing', 'Var', (35, 44))	('reduce', 'NegReg', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('TPX2', 'Gene', (48, 52))	('tumor', 'Disease', (75, 80))
738318	29551902	Depletion of TPX2 can lead to the upregulation of E-cadherin proteins that inhibit tumor metastasis and the downregulation of N-cadherin, beta-catenin, Slug, MMP-9 and MMP-2 proteins that promote tumor metastasis.	('MMP-9', 'Gene', (158, 163))	('tumor', 'Disease', (196, 201))	('MMP-2', 'Gene', (168, 173))	('tumor', 'Disease', (83, 88))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('E-cadherin proteins', 'Protein', (50, 69))	('Slug', 'Gene', '6591', (152, 156))	('downregulation', 'NegReg', (108, 122))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('promote', 'PosReg', (188, 195))	('inhibit', 'NegReg', (75, 82))	('TPX2', 'Gene', (13, 17))	('MMP-2', 'Gene', '4313', (168, 173))	('N-cadherin', 'Gene', (126, 136))	('beta-catenin', 'Gene', (138, 150))	('beta-catenin', 'Gene', '1499', (138, 150))	('N-cadherin', 'Gene', '1000', (126, 136))	('Slug', 'Gene', (152, 156))	('MMP-9', 'Gene', '4318', (158, 163))	('upregulation', 'PosReg', (34, 46))
738446	23514407	High WDR66 expression was significantly associated with poor overall survival (P = 0.031) of patients suffering from esophageal squamous carcinomas.	('poor', 'NegReg', (56, 60))	('esophageal squamous carcinomas', 'Disease', (117, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (117, 146))	('WDR66', 'Gene', '144406', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('overall survival', 'MPA', (61, 77))	('WDR66', 'Gene', (5, 10))	('patients', 'Species', '9606', (93, 101))	('esophageal squamous carcinomas', 'Disease', 'MESH:D000077277', (117, 147))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (128, 146))
738448	23514407	WDR66 knockdown by RNA interference resulted particularly in changes of the expression of membrane components.	('changes', 'Reg', (61, 68))	('RNA interference', 'MPA', (19, 35))	('expression of membrane components', 'MPA', (76, 109))	('WDR66', 'Gene', '144406', (0, 5))	('knockdown', 'Var', (6, 15))	('WDR66', 'Gene', (0, 5))
738449	23514407	Expression of vimentin was down regulated in WDR66 knockdown cells while that of the tight junction protein occludin was markedly up regulated.	('vimentin', 'Gene', '7431', (14, 22))	('WDR66', 'Gene', '144406', (45, 50))	('vimentin', 'Gene', (14, 22))	('Expression', 'MPA', (0, 10))	('up regulated', 'PosReg', (130, 142))	('occludin', 'Gene', (108, 116))	('WDR66', 'Gene', (45, 50))	('down regulated', 'NegReg', (27, 41))	('occludin', 'Gene', '100506658', (108, 116))	('knockdown', 'Var', (51, 60))
738450	23514407	Furthermore, siRNA-mediated knockdown of WDR66 resulted in suppression of cell growth and reduced cell motility.	('cell motility', 'CPA', (98, 111))	('suppression', 'NegReg', (59, 70))	('WDR66', 'Gene', '144406', (41, 46))	('reduced', 'NegReg', (90, 97))	('WDR66', 'Gene', (41, 46))	('cell growth', 'CPA', (74, 85))	('knockdown', 'Var', (28, 37))
738463	23514407	A genome-wide association study identified a single-nucleotide polymorphism located within intron 3 of WDR66 associated with mean platelet volume.	('associated', 'Reg', (109, 119))	('WDR66', 'Gene', '144406', (103, 108))	('single-nucleotide polymorphism located', 'Var', (45, 83))	('WDR66', 'Gene', (103, 108))	('mean platelet volume', 'MPA', (125, 145))
738484	23514407	For quantification of mRNA-expression, qRT-PCR was performed for 3 genes plus one control, using pre-designed gene-specific TaqMan  probes and primer sets purchased from Applied Biosystems (Hs01566237_m1 for WDR66, Hs00958116_m1 for VIM, Hs00170162_m1 for OCLD, and 4326317E for GAPDH).	('Hs01566237_m1', 'Var', (190, 203))	('OCLD', 'Gene', '100506658', (256, 260))	('Hs00958116_m1', 'Var', (215, 228))	('GAPDH', 'Gene', '2597', (279, 284))	('VIM', 'Gene', '7431', (233, 236))	('GAPDH', 'Gene', (279, 284))	('WDR66', 'Gene', '144406', (208, 213))	('WDR66', 'Gene', (208, 213))	('VIM', 'Gene', (233, 236))	('OCLD', 'Gene', (256, 260))	('Hs00170162_m1', 'Var', (238, 251))	('4326317E', 'Var', (266, 274))
738485	23514407	KYSE520, OE33, SW480, Caco2, HCT116, HT29, HL60, LS174T, Daudi, HEK293, MCF7, MDA-MB-231, MDA-MB-435 and Capan-I were obtained from the American Type Culture Collection (ATCC, Manassas, VA) and cultured according to the supplier's instructions.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (78, 88))	('HEK293', 'CellLine', 'CVCL:0045', (64, 70))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (90, 100))	('MCF7', 'CellLine', 'CVCL:0031', (72, 76))	('LS174T', 'Var', (49, 55))	('HT29', 'CellLine', 'CVCL:0320', (37, 41))	('SW480', 'Var', (15, 20))	('HCT116', 'CellLine', 'CVCL:0291', (29, 35))	('SW480', 'CellLine', 'CVCL:0546', (15, 20))	('HL60', 'CellLine', 'CVCL:0002', (43, 47))
738486	23514407	For siRNA-mediated knockdown of WDR66, cells were seeded in 6-well plates on the day before transfection.	('knockdown', 'Var', (19, 28))	('WDR66', 'Gene', (32, 37))	('WDR66', 'Gene', '144406', (32, 37))
738507	23514407	High expression of WDR66 RNA was found to be a significant prognostic factor with regard to cancer-related survival (P = 0.031; Figure 2).	('High expression', 'Var', (0, 15))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('WDR66', 'Gene', '144406', (19, 24))	('WDR66', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
738510	23514407	Subsequently, a microarray expression analysis was performed in order to identify the genes affected by WDR66 knockdown.	('knockdown', 'Var', (110, 119))	('WDR66', 'Gene', (104, 109))	('WDR66', 'Gene', '144406', (104, 109))
738511	23514407	Functional enrichment analysis identified 10 GO terms to be significantly associated with the WDR66 knockdown (Additional file 2: Table S2).	('WDR66', 'Gene', (94, 99))	('WDR66', 'Gene', '144406', (94, 99))	('knockdown', 'Var', (100, 109))
738513	23514407	Microarray data were validated by qRT-PCR and Western blotting providing independent evidence of the changes of vimentin (VIM) and occludin (OCLD) expression associated with the WDR66 knockdown (Figure 3B, 3C).	('knockdown', 'Var', (184, 193))	('WDR66', 'Gene', (178, 183))	('occludin', 'Gene', '100506658', (131, 139))	('expression', 'MPA', (147, 157))	('OCLD', 'Gene', (141, 145))	('VIM', 'Gene', '7431', (122, 125))	('occludin', 'Gene', (131, 139))	('vimentin', 'Gene', '7431', (112, 120))	('OCLD', 'Gene', '100506658', (141, 145))	('VIM', 'Gene', (122, 125))	('vimentin', 'Gene', (112, 120))	('WDR66', 'Gene', '144406', (178, 183))
738517	23514407	Moreover, we found that introduction of siWDR66 remarkably suppressed growth of KYSE520 in comparison to control cells (Figure 4B).	('introduction', 'Var', (24, 36))	('WDR66', 'Gene', (42, 47))	('suppressed', 'NegReg', (59, 69))	('growth', 'MPA', (70, 76))	('WDR66', 'Gene', '144406', (42, 47))
738539	23514407	This is also in agreement with the results of our microarray study, which showed that claudin-4 was significantly less expressed in ESCC and also remarkably over expressed after WDR66 knockdown (data not shown).	('knockdown', 'Var', (184, 193))	('less', 'NegReg', (114, 118))	('WDR66', 'Gene', (178, 183))	('claudin-4', 'Gene', (86, 95))	('over expressed', 'PosReg', (157, 171))	('expressed', 'MPA', (119, 128))	('ESCC', 'Disease', (132, 136))	('WDR66', 'Gene', '144406', (178, 183))	('claudin-4', 'Gene', '1364', (86, 95))
738541	23514407	This result is based on our observations that (1) WDR66 is specifically highly expressed in esophageal squamous cell carcinoma and high WDR66 expression correlates with poor overall survival, (2) WDR66 regulates vimentin and occludin expression and plays a crucial role for EMT, and (3) knockdown of WDR66 suppresses cell growth and motility and decreases cell viability of ESCC cells.	('expression', 'MPA', (234, 244))	('WDR66', 'Gene', '144406', (136, 141))	('WDR66', 'Gene', '144406', (50, 55))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (92, 126))	('decreases', 'NegReg', (346, 355))	('occludin', 'Gene', '100506658', (225, 233))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('WDR66', 'Gene', (300, 305))	('regulates', 'Reg', (202, 211))	('WDR66', 'Gene', (136, 141))	('WDR66', 'Gene', '144406', (300, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('WDR66', 'Gene', (196, 201))	('knockdown', 'Var', (287, 296))	('occludin', 'Gene', (225, 233))	('cell viability of ESCC cells', 'CPA', (356, 384))	('vimentin', 'Gene', '7431', (212, 220))	('vimentin', 'Gene', (212, 220))	('WDR66', 'Gene', '144406', (196, 201))	('esophageal squamous cell carcinoma', 'Disease', (92, 126))	('suppresses', 'NegReg', (306, 316))	('WDR66', 'Gene', (50, 55))
738556	19568547	There is definite genetic predisposition to the development of BE, as it has been demonstrated that there is an increase in the risk of EAC in patients with GERD or BE carrying the genotypes for epidermal growth factor (EGF) A61G G/G, cyclooxygenase 2 (COX2) 8473 C. Also an animal study suggested that multipotential progenitor cells of bone marrow origin may play a role in metaplasia in BE.	('COX2', 'Gene', (253, 257))	('cyclooxygenase 2', 'Gene', (235, 251))	('GERD', 'Disease', (157, 161))	('metaplasia', 'Disease', (376, 386))	('EAC', 'Phenotype', 'HP:0011459', (136, 139))	('GERD', 'Disease', 'MESH:D005764', (157, 161))	('EGF', 'Gene', (220, 223))	('8473 C.', 'Var', (259, 266))	('EAC', 'Disease', (136, 139))	('A61G', 'Mutation', 'rs4444903', (225, 229))	('A61G G/G', 'Var', (225, 233))	('metaplasia', 'Disease', 'MESH:D008679', (376, 386))	('men', 'Species', '9606', (55, 58))	('COX2', 'Gene', '5743', (253, 257))	('BE', 'Phenotype', 'HP:0100580', (390, 392))	('epidermal growth factor', 'Gene', (195, 218))	('cyclooxygenase 2', 'Gene', '5743', (235, 251))	('BE', 'Phenotype', 'HP:0100580', (63, 65))	('epidermal growth factor', 'Gene', '1950', (195, 218))	('patients', 'Species', '9606', (143, 151))	('EGF', 'Gene', '1950', (220, 223))	('BE', 'Phenotype', 'HP:0100580', (165, 167))
738557	19568547	Multiple inflammatory mediators have become a target for researchers in the hope of decreasing the progression to adenocarcinoma, especially after studies demonstrated that superoxide dismutase and COX2 inhibitors decreased the progression of BE and adenocarcinoma in animal models of BE.	('BE', 'Phenotype', 'HP:0100580', (285, 287))	('adenocarcinoma', 'Disease', 'MESH:D000230', (114, 128))	('COX2', 'Gene', (198, 202))	('COX2', 'Gene', '5743', (198, 202))	('adenocarcinoma', 'Disease', 'MESH:D000230', (250, 264))	('inhibitors', 'Var', (203, 213))	('BE', 'Phenotype', 'HP:0100580', (243, 245))	('decreased', 'NegReg', (214, 223))	('adenocarcinoma', 'Disease', (114, 128))	('adenocarcinoma', 'Disease', (250, 264))
738559	19568547	Also, aspirin in combination with a PPI was demonstrated to decrease the concentration of prostaglandin E2.	('PPI', 'Var', (36, 39))	('decrease', 'NegReg', (60, 68))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (90, 106))	('concentration of prostaglandin E2', 'MPA', (73, 106))	('aspirin', 'Chemical', 'MESH:D001241', (6, 13))	('decrease the concentration of prostaglandin E2', 'Phenotype', 'HP:0003566', (60, 106))
738616	19568547	A large multicenter RCT demonstrated that PDT decreases the likelihood of high-grade dysplasia (HGD) [absolute risk reduction (ARR) of 38%], cancer (ARR 14%), and a longer time to progression to cancer in patients with BE.	('BE', 'Phenotype', 'HP:0100580', (219, 221))	('patients', 'Species', '9606', (205, 213))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (195, 201))	('longer', 'PosReg', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('PDT', 'Var', (42, 45))	('decreases', 'NegReg', (46, 55))	('dysplasia', 'Disease', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('dysplasia', 'Disease', 'MESH:D004476', (85, 94))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
738627	19568547	When compared with surgery, endoprevention is associated with a higher risk of progression of adenocarcinoma, whereas surgery has a higher cost and results in more frequent minor complications but is curative.	('adenocarcinoma', 'Disease', (94, 108))	('adenocarcinoma', 'Disease', 'MESH:D000230', (94, 108))	('endoprevention', 'Var', (28, 42))
738629	19568547	A large prospective German study conducted in two phases to establish the criteria for the diagnosis of neoplasia in cases of normal macroscopic appearing mucosa in patients with BE showed that compared with standard high resolution endoscopy (HRE), CLM had a higher negative predictive value (98.8%) for neoplasia in BE but had a poor positive predictive value (44%), these results need further validation on a larger scale.	('neoplasia', 'Disease', (104, 113))	('neoplasia', 'Phenotype', 'HP:0002664', (305, 314))	('CLM', 'Var', (250, 253))	('neoplasia', 'Disease', 'MESH:D009369', (305, 314))	('neoplasia', 'Disease', 'MESH:D009369', (104, 113))	('neoplasia', 'Disease', (305, 314))	('neoplasia', 'Phenotype', 'HP:0002664', (104, 113))	('BE', 'Phenotype', 'HP:0100580', (318, 320))	('patients', 'Species', '9606', (165, 173))	('negative', 'NegReg', (267, 275))	('BE', 'Phenotype', 'HP:0100580', (179, 181))
738644	33249700	Multiple logistic regression analyses showed that an older age, larger number of pack-years, smaller body mass index, larger MCV, presence of a slow-metabolizing alcohol dehydrogenase-1B genotype (rs1229984), presence of an inactive heterozygous ALDH2 genotype, and more advanced degree of CAG increased the odds ratios (ORs) for DIULs, while the 2008-2013 and 2014-2018 screening periods had lower ORs for DIULs than the 2003-2007 screening period.	('DIULs', 'Chemical', '-', (330, 335))	('C', 'Chemical', '-', (126, 127))	('presence', 'Var', (209, 217))	('ALDH2', 'Gene', (246, 251))	('DIULs', 'Chemical', '-', (407, 412))	('rs1229984', 'Mutation', 'rs1229984', (197, 206))	('alcohol dehydrogenase-1B', 'Gene', (162, 186))	('alcohol dehydrogenase-1B', 'Gene', '125', (162, 186))	('CAG', 'Phenotype', 'HP:0002582', (290, 293))	('C', 'Chemical', '-', (290, 291))	('ALDH2', 'Gene', '217', (246, 251))	('rs1229984', 'Var', (197, 206))	('presence', 'Var', (130, 138))	('smaller body mass index', 'Phenotype', 'HP:0045082', (93, 116))	('increased', 'PosReg', (294, 303))	('DIULs', 'Disease', (330, 335))
738645	33249700	The presence of HH/CLE decreased the OR for multiple DIULs and was associated with a more proximal location of ESCC.	('decreased', 'NegReg', (23, 32))	('DIULs', 'Chemical', '-', (53, 58))	('HH/CLE', 'Gene', '51637', (16, 22))	('presence', 'Var', (4, 12))	('HH/CLE', 'Gene', (16, 22))	('ESCC', 'Disease', (111, 115))
738655	33249700	Inactive aldehyde dehydrogenase-2 encoded by the ALDH2*1/*2 genotype (rs671) and slow-metabolizing alcohol dehydrogenase-1B encoded by the ADH1B*1/*1 genotype (rs1229984) are strong risk factors for ESCC, 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  10 ,  11 ,  12  DIULs >= 5 mm, 3 ,  13  and multiple DIULs 3 ,  6 ,  13 ,  14  among East Asian drinkers.	('alcohol dehydrogenase-1B', 'Gene', '125', (99, 123))	('ADH1B', 'Gene', (139, 144))	('aldehyde dehydrogenase-2', 'Gene', '217', (9, 33))	('rs671', 'Var', (70, 75))	('ADH1B', 'Gene', '125', (139, 144))	('aldehyde dehydrogenase-2', 'Gene', (9, 33))	('rs1229984', 'Mutation', 'rs1229984', (160, 169))	('ALDH2', 'Gene', '217', (49, 54))	('rs671', 'Mutation', 'rs671', (70, 75))	('risk', 'Reg', (182, 186))	('ESCC', 'Disease', (199, 203))	('DIULs', 'Chemical', '-', (288, 293))	('rs1229984', 'Var', (160, 169))	('DIULs', 'Chemical', '-', (251, 256))	('ALDH2', 'Gene', (49, 54))	('alcohol dehydrogenase-1B', 'Gene', (99, 123))
738667	33249700	The examinations were performed using Olympus endoscopes (models XQ230, Q240, Q240Z, Q260, and Q260Z in chronological order of use; Olympus Optical Co. Ltd.).	('Q240Z', 'Var', (78, 83))	('Q260Z', 'Var', (95, 100))	('C', 'Chemical', '-', (148, 149))	('Q260Z', 'SUBSTITUTION', 'None', (95, 100))	('Q240Z', 'SUBSTITUTION', 'None', (78, 83))	('Q260', 'Var', (85, 89))	('Q240', 'Var', (72, 76))
738672	33249700	When the axial length between the diaphragmatic pinch and the border between the white squamous epithelium and the red epithelium was >=10 mm for the entire circumference (Figure 1C), the subject was diagnosed as having an HH/CLE >= 10 mm, which was regarded as evidence of long-term gastroesophageal reflux.	('>=10', 'Var', (134, 138))	('HH/CLE', 'Gene', '51637', (223, 229))	('C', 'Chemical', '-', (180, 181))	('HH/CLE', 'Gene', (223, 229))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (284, 307))	('C', 'Chemical', '-', (226, 227))	('gastroesophageal reflux', 'Disease', (284, 307))
738692	33249700	For the 2003-2007 period, the 2008-2012 period, and the 2013-2018 period, the respective detection rates of DIULs >= 5 mm (all: 20.6%, 12.4%, and 8.6%; dysplasia: 11.7%, 7.9%, and 4.8%; SCC: 4.4%, 3.1%, and 2.4%) and multiple DIULs (20.0%, 14.9%, and 14.9%) decreased (Table 2).	('DIULs', 'Disease', (108, 113))	('dysplasia', 'Disease', (152, 161))	('>= 5 mm', 'Var', (114, 121))	('DIULs', 'Chemical', '-', (108, 113))	('decreased', 'NegReg', (258, 267))	('DIULs', 'Chemical', '-', (226, 231))	('dysplasia', 'Disease', 'MESH:C536170', (152, 161))	('SCC', 'Disease', (186, 189))	('multiple', 'Disease', (217, 225))
738702	33249700	A high rate of H. pylori-negative results was observed with the C0-C1 classification, while a low rate was observed with the C2-O1 classification.	('H. pylori-negative', 'Disease', (15, 33))	('C', 'Chemical', '-', (125, 126))	('C', 'Chemical', '-', (67, 68))	('C', 'Chemical', '-', (64, 65))	('C0-C1', 'Var', (64, 69))	('H. pylori', 'Species', '210', (15, 24))
738704	33249700	Multiple logistic regression analyses showed that the C3-O1 category and the O2-O3 category of CAG increased the ORs (95% CI) for DIULs >= 5 mm (all: 1.52 [1.18-1.90] and 1.76 [1.27-2.44], respectively; dysplasia: 1.57 [1.15-2.15] and 1.72 [1.15-2.58], respectively; SCC: 1.56 [0.96-2.54] and 2.27 [1.29-3.99]) and multiple DIULs (1.40 [1.10-1.79] and 1.67 [1.22-2.30], respectively), compared with the C0-C2 category (Table 5).	('ORs', 'MPA', (113, 116))	('C', 'Chemical', '-', (268, 269))	('C', 'Chemical', '-', (269, 270))	('DIULs', 'Chemical', '-', (324, 329))	('C', 'Chemical', '-', (403, 404))	('C', 'Chemical', '-', (406, 407))	('DIULs', 'Chemical', '-', (130, 135))	('CAG', 'Phenotype', 'HP:0002582', (95, 98))	('dysplasia', 'Disease', 'MESH:C536170', (203, 212))	('C', 'Chemical', '-', (95, 96))	('C', 'Chemical', '-', (54, 55))	('C', 'Chemical', '-', (122, 123))	('dysplasia', 'Disease', (203, 212))	('C3-O1', 'Var', (54, 59))
738713	33249700	The detection rates of DIULs >= 5 mm (all), DIULs >= 5 mm (dysplasia), and multiple DIULs, which are regarded as high-ESCC-risk lesions, and of ESCC were relatively high during the chromoendoscopic screening of alcohol-dependent men.	('DIULs', 'Disease', (23, 28))	('DIULs', 'Chemical', '-', (84, 89))	('>= 5 mm', 'Var', (50, 57))	('>= 5 mm', 'Var', (29, 36))	('DIULs', 'Chemical', '-', (23, 28))	('dysplasia', 'Disease', 'MESH:C536170', (59, 68))	('DIULs', 'Chemical', '-', (44, 49))	('men', 'Species', '9606', (229, 232))	('dysplasia', 'Disease', (59, 68))	('DIULs', 'Var', (44, 49))	('alcohol', 'Chemical', 'MESH:D000438', (211, 218))
738719	33249700	Other factors associated with the DIULs were an older age, a larger number of pack-years, a smaller BMI, a larger MCV, the presence of a slow-metabolizing ADH1B genotype, and the presence of an inactive heterozygous ALDH2 genotype.	('ADH1B', 'Gene', '125', (155, 160))	('ALDH2', 'Gene', '217', (216, 221))	('C', 'Chemical', '-', (115, 116))	('ALDH2', 'Gene', (216, 221))	('presence', 'Var', (123, 131))	('ADH1B', 'Gene', (155, 160))	('DIULs', 'Chemical', '-', (34, 39))
738729	33249700	An increment in BMI has been reported to reduce the risk of ESCC, 4 ,  5 ,  47  and we observed a lower risk of the DIULs with an increment in the BMI.	('ESCC', 'Disease', (60, 64))	('men', 'Species', '9606', (8, 11))	('men', 'Species', '9606', (135, 138))	('increment', 'Var', (130, 139))	('DIULs', 'Chemical', '-', (116, 121))	('reduce', 'NegReg', (41, 47))	('BMI', 'Gene', (16, 19))	('increment', 'Var', (3, 12))
738779	33173314	Epigenetic changes play an important role in the occurrence and development of cancers.	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('Epigenetic changes', 'Var', (0, 18))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
738783	33173314	Mechanistically, LOC441178 may epigenetically inhibit miR-182 expression through DNA methylation.	('DNA methylation', 'MPA', (81, 96))	('miR-182', 'Gene', (54, 61))	('inhibit', 'NegReg', (46, 53))	('expression', 'MPA', (62, 72))	('miR-182', 'Gene', '406958', (54, 61))	('LOC441178', 'Gene', (17, 26))	('epigenetically', 'Var', (31, 45))	('LOC441178', 'Gene', '441178', (17, 26))
738838	33173314	These data indicated that LOC441178 may epigenetically reduce miR-182 expression via DNA methylation.	('epigenetically', 'Var', (40, 54))	('LOC441178', 'Gene', (26, 35))	('miR-182', 'Gene', (62, 69))	('DNA', 'Reg', (85, 88))	('expression', 'MPA', (70, 80))	('reduce', 'NegReg', (55, 61))	('LOC441178', 'Gene', '441178', (26, 35))	('miR-182', 'Gene', '406958', (62, 69))
738882	33173314	LOC441178 epigenetically suppressed miR-182 expression via DNA methylation.	('miR-182', 'Gene', (36, 43))	('expression', 'MPA', (44, 54))	('LOC441178', 'Gene', (0, 9))	('miR-182', 'Gene', '406958', (36, 43))	('epigenetically', 'Var', (10, 24))	('LOC441178', 'Gene', '441178', (0, 9))
738885	32500232	Exploratory open-label clinical study to determine the S-588410 cancer peptide vaccine-induced tumor-infiltrating lymphocytes and changes in the tumor microenvironment in esophageal cancer patients Cancer vaccines induce cancer-specific T-cells capable of eradicating cancer cells.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('Cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('S-588410', 'Var', (55, 63))	('cancer', 'Disease', (64, 70))	('tumor', 'Disease', (145, 150))	('induce', 'PosReg', (214, 220))	('cancer', 'Disease', (182, 188))	('Cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Disease', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', (95, 100))	('Cancer', 'Disease', (198, 204))	('cancer', 'Disease', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('eradicating', 'CPA', (256, 267))
738891	32500232	The same sequences of peptide-specific TCRs were identified in post-vaccination T-lymphocytes derived from both tumor tissue and blood, suggesting that functional peptide-specific CTLs infiltrate tumor tissue after vaccination.	('peptide-specific', 'Var', (163, 179))	('TCR', 'Gene', '6962', (39, 42))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TCR', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
738893	32500232	In conclusion, S-588410 induces a tumor immune response in esophageal cancer.	('tumor', 'Disease', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('S-588410', 'Chemical', '-', (15, 23))	('S-588410', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
738894	32500232	Induction of CD8+ PD-1+ tumor-infiltrating lymphocytes and PD-L1 expression in the TME by vaccination suggests S-588410 in combination with anti-PD-(L)1 antibodies may offer a clinically useful therapy.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('CD8', 'Gene', (13, 16))	('tumor', 'Disease', (24, 29))	('CD8', 'Gene', '925', (13, 16))	('S-588410', 'Var', (111, 119))	('S-588410', 'Chemical', '-', (111, 119))	('PD-L1', 'Gene', (59, 64))	('PD-(L)1', 'Gene', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('PD-(L)1', 'Gene', '29126', (145, 152))
738909	32500232	For example, the presence of TILs and immune-related molecules, such as PD-L1, in the tumor microenvironment (TME) among patients with esophageal cancer was associated with better survival.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', (146, 152))	('better', 'PosReg', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('men', 'Species', '9606', (104, 107))	('tumor', 'Disease', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('presence', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('PD-L1', 'Gene', (72, 77))	('patients', 'Species', '9606', (121, 129))
738915	32500232	This exploratory study aims to determine the tumor immune response of S-588410 in the TME.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('S-588410', 'Chemical', '-', (70, 78))	('tumor', 'Disease', (45, 50))	('S-588410', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
738920	32500232	Blood and tumor tissue samples were obtained before and after S-588410 administration.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('S-588410', 'Var', (62, 70))	('tumor', 'Disease', (10, 15))	('S-588410', 'Chemical', '-', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
738922	32500232	Secondary endpoints included the safety of S-588410 administration and the presence or absence of CTL induction in blood samples.	('CTL', 'Gene', (98, 101))	('S-588410', 'Var', (43, 51))	('S-588410', 'Chemical', '-', (43, 51))
738941	32500232	CD8+ T-cells in cryopreserved PBMCs were assessed using flow cytometry to detect molecular markers for CD3 and CD8 positivity and CD14, CD19 and CD54 negativity.	('CD14', 'Gene', (130, 134))	('CD14', 'Gene', '929', (130, 134))	('CD8', 'Gene', (0, 3))	('CD19', 'Gene', (136, 140))	('negativity', 'NegReg', (150, 160))	('positivity', 'Var', (115, 125))	('CD3', 'Gene', (103, 106))	('CD8', 'Gene', '925', (0, 3))	('CD54', 'Gene', '3383', (145, 149))	('CD19', 'Gene', '930', (136, 140))	('CD8', 'Gene', '925', (111, 114))	('CD8', 'Gene', (111, 114))	('CD54', 'Gene', (145, 149))
738968	32500232	The median (range) percent change from baseline in CD8+ lymphocyte density following S-588410 administration was 149.37% (95% confidence interval, - 75.0%, 615.9%).	('CD8', 'Gene', (51, 54))	('S-588410', 'Var', (85, 93))	('CD8', 'Gene', '925', (51, 54))	('S-588410', 'Chemical', '-', (85, 93))
738985	32500232	In this exploratory study, we demonstrate that the five-peptide CPV S-588410 induces an immune response in tumor tissue from participants with esophageal cancer.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('CPV S-588410', 'Var', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('immune response', 'MPA', (88, 103))	('CPV', 'Chemical', '-', (64, 67))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('S-588410', 'Chemical', '-', (68, 76))	('participants', 'Species', '9606', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('induces', 'Reg', (77, 84))
738986	32500232	Peptide-specific CTLs for all peptides were induced after a median five injections of S-588410, with at least one peptide being observed in all participants.	('CTLs', 'MPA', (17, 21))	('peptides', 'Chemical', 'MESH:D010455', (30, 38))	('induced', 'Reg', (44, 51))	('S-588410', 'Chemical', '-', (86, 94))	('S-588410', 'Var', (86, 94))	('participants', 'Species', '9606', (144, 156))
738995	32500232	Assuming CD8+ T-cells infiltrate tumor tissue, it can be hypothesized that PD-L1 expression may be increased by IFN-gamma produced by TILs induced by S-588410 administration.	('CD8', 'Gene', '925', (9, 12))	('S-588410', 'Chemical', '-', (150, 158))	('S-588410', 'Var', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('PD-L1', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('IFN-gamma', 'Gene', (112, 121))	('tumor', 'Disease', (33, 38))	('increased', 'PosReg', (99, 108))	('IFN-gamma', 'Gene', '3458', (112, 121))	('CD8', 'Gene', (9, 12))	('expression', 'MPA', (81, 91))
738998	32500232	S-588410 administration could also contribute to changes in the TME from an immune desert to an inflamed tumor.	('S-588410', 'Chemical', '-', (0, 8))	('S-588410', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('changes', 'Reg', (49, 56))	('TME', 'MPA', (64, 67))	('tumor', 'Disease', (105, 110))
738999	32500232	Accordingly, transformation of cancer-immune phenotypes by S-588410 may have therapeutic potential when combined with anti-PD-(L)1 antibodies in patients.	('patients', 'Species', '9606', (145, 153))	('S-588410', 'Chemical', '-', (59, 67))	('S-588410', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('PD-(L)1', 'Gene', (123, 130))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('PD-(L)1', 'Gene', '29126', (123, 130))	('cancer', 'Disease', (31, 37))
739001	32500232	previously described the equivalence of the PD-L1 antibodies 22C3 (indicated in combination with pembrolizumab) and SP263 (used in our study).	('SP263', 'Chemical', '-', (116, 121))	('SP263', 'Var', (116, 121))	('pembrolizumab', 'Chemical', 'MESH:C582435', (97, 110))	('PD-L1', 'Gene', (44, 49))
739002	32500232	If the efficacy of pembrolizumab is confirmed in patients with >= 5% PD-L1+ tumor cells characterized by 22C3 in KEYNOTE-181, PD-L1 induction by S-588410 may support combination therapy with a PD-(L)1 antibody.	('PD-(L)1', 'Gene', '29126', (193, 200))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('S-588410', 'Chemical', '-', (145, 153))	('S-588410', 'Var', (145, 153))	('pembrolizumab', 'Chemical', 'MESH:C582435', (19, 32))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('PD-(L)1', 'Gene', (193, 200))
739003	32500232	S-588410 also induced PD-1-expressing CD4+ cells in the TME.	('induced', 'PosReg', (14, 21))	('PD-1-expressing', 'Gene', (22, 37))	('S-588410', 'Var', (0, 8))	('S-588410', 'Chemical', '-', (0, 8))
739006	32500232	S-588410 may have indirect effects on CD4+ cells, but there are currently no data to show S-588410 has the ability to directly bind to HLA class II.	('S-588410', 'Chemical', '-', (0, 8))	('S-588410', 'Chemical', '-', (90, 98))	('S-588410', 'Var', (90, 98))	('HLA class II', 'Protein', (135, 147))	('bind', 'Interaction', (127, 131))
739023	32500232	In conclusion, vaccination with the CPV S-588410 induces functional CD8+ and CD4+ TILs and PD-L1 expression in esophageal cancer.	('induces', 'PosReg', (49, 56))	('CD8', 'Gene', (68, 71))	('PD-L1', 'Gene', (91, 96))	('CPV S-588410', 'Var', (36, 48))	('CD8', 'Gene', '925', (68, 71))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('S-588410', 'Var', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('S-588410', 'Chemical', '-', (40, 48))	('CD4+ TILs', 'MPA', (77, 86))	('expression', 'MPA', (97, 107))	('CPV', 'Chemical', '-', (36, 39))
739026	32500232	Therefore, a combination of S-588410 with anti-PD-(L)1 antibodies may be expected to have a synergistic effect.	('S-588410', 'Var', (28, 36))	('PD-(L)1', 'Gene', (47, 54))	('S-588410', 'Chemical', '-', (28, 36))	('combination', 'Interaction', (13, 24))	('PD-(L)1', 'Gene', '29126', (47, 54))
739037	32009096	After SPDPS, there were no obvious complications, and the patient's ammonia level significantly decreased.	('SPDPS', 'Var', (6, 11))	('decreased', 'NegReg', (96, 105))	('patient', 'Species', '9606', (58, 65))	('ammonia level', 'MPA', (68, 81))	('ammonia', 'Chemical', 'MESH:D000641', (68, 75))	('SPDPS', 'Chemical', 'MESH:C018151', (6, 11))
739054	32009096	During the periods of hospitalization, the patient received lactulose, branched-chain amino acids, and protein restriction.	('branched-chain', 'Var', (71, 85))	('patient', 'Species', '9606', (43, 50))	('protein', 'Protein', (103, 110))	('lactulose', 'Chemical', 'MESH:D007792', (60, 69))	('branched-chain amino acids', 'Chemical', 'MESH:D000597', (71, 97))
739075	32009096	In this case, it was considered that B-RTO would likely worsen the portal hypertension and cause the deterioration of the patient's general condition because only the left lateral segment of the liver remained after surgery.	('cause', 'Reg', (91, 96))	('patient', 'Species', '9606', (122, 129))	('hypertension', 'Disease', (74, 86))	('portal hypertension', 'Phenotype', 'HP:0001409', (67, 86))	('hypertension', 'Phenotype', 'HP:0000822', (74, 86))	('worsen', 'NegReg', (56, 62))	('hypertension', 'Disease', 'MESH:D006973', (74, 86))	('B-RTO', 'Var', (37, 42))
739096	31132995	MIILE was associated with a longer duration, less blood loss and more lymph node dissected than Sweet esophagectomy.	('blood loss', 'Disease', 'MESH:D006473', (50, 60))	('MIILE', 'Chemical', '-', (0, 5))	('MIILE', 'Var', (0, 5))	('blood loss', 'Disease', (50, 60))
739111	31132995	For patients with a cTisN0M0 or cT1aN0M0 classification, endoscopic mucosal resection or endoscopic submucosal dissection was implemented.	('cTisN0M0', 'Var', (20, 28))	('patients', 'Species', '9606', (4, 12))	('cT1aN0M0', 'Var', (32, 40))
739142	31132995	More complications, especially pneumonia, occurred in the Sweet group.	('Sweet', 'Var', (58, 63))	('pneumonia', 'Phenotype', 'HP:0002090', (31, 40))	('pneumonia', 'Disease', (31, 40))	('pneumonia', 'Disease', 'MESH:D011014', (31, 40))
739159	31132995	RLN lymph node metastasis was associated with poor OS and DFS in the whole cohort and in the MIILE group but had no influence on survival in the Sweet group (Fig.	('OS', 'Chemical', '-', (51, 53))	('DFS', 'MPA', (58, 61))	('MIILE', 'Chemical', '-', (93, 98))	('RLN', 'Var', (0, 3))	('poor OS', 'Disease', (46, 53))
739160	31132995	MIILE group scored significantly higher in the postoperative global health and physical component and lower in symptom categories than the Sweet group.	('lower', 'NegReg', (102, 107))	('higher', 'PosReg', (33, 39))	('MIILE', 'Chemical', '-', (0, 5))	('MIILE', 'Var', (0, 5))	('global health', 'MPA', (61, 74))	('symptom categories', 'MPA', (111, 129))	('physical component', 'MPA', (79, 97))
739161	31132995	Furthermore, the scores for global health, physical function, role function, emotional function, cognitive function, social function, fatigue, and pain improved faster in the MIILE group.	('MIILE', 'Chemical', '-', (175, 180))	('global', 'CPA', (28, 34))	('fatigue', 'Disease', 'MESH:D005221', (134, 141))	('improved', 'PosReg', (152, 160))	('role', 'CPA', (62, 66))	('cognitive function', 'CPA', (97, 115))	('physical', 'CPA', (43, 51))	('MIILE', 'Var', (175, 180))	('fatigue', 'Disease', (134, 141))	('pain', 'Phenotype', 'HP:0012531', (147, 151))	('fatigue', 'Phenotype', 'HP:0012378', (134, 141))	('emotional function', 'CPA', (77, 95))	('pain', 'Disease', 'MESH:D010146', (147, 151))	('social function', 'CPA', (117, 132))	('pain', 'Disease', (147, 151))
739169	31132995	Compared with the Sweet approach, MIILE approach accelerated the recovery phase, as MIILE patients had decreased ICU stays, accelerated oral intake and shortened postoperative hospital stays.	('oral intake', 'CPA', (136, 147))	('MIILE', 'Chemical', '-', (34, 39))	('MIILE', 'Var', (84, 89))	('patients', 'Species', '9606', (90, 98))	('decreased', 'NegReg', (103, 112))	('shortened', 'NegReg', (152, 161))	('MIILE', 'Chemical', '-', (84, 89))	('accelerated', 'PosReg', (124, 135))	('ICU stays', 'MPA', (113, 122))
739175	31132995	Among factors affecting survival, the influence of a longer tumor diameter may be ascribed to a more advanced TNM stage, and the impact of high BMI may be due to its relationship to a lower pathological stage.	('TNM stage', 'CPA', (110, 119))	('high BMI', 'Var', (139, 147))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
739177	31132995	A significant difference favoring MIILE was found in the global health, physical component summary, and symptom categories in postoperative patients at three to six months, which is in line with observations made in previous studies.	('MIILE', 'Chemical', '-', (34, 39))	('physical component summary', 'MPA', (72, 98))	('global health', 'MPA', (57, 70))	('patients', 'Species', '9606', (140, 148))	('MIILE', 'Var', (34, 39))
739178	31132995	The advantage of MIILE in QOL may be ascribed to decreased surgical trauma and reduced pain.	('reduced', 'NegReg', (79, 86))	('pain', 'Disease', 'MESH:D010146', (87, 91))	('pain', 'Disease', (87, 91))	('MIILE', 'Chemical', '-', (17, 22))	('decreased', 'NegReg', (49, 58))	('trauma', 'Disease', 'MESH:D014947', (68, 74))	('reduced pain', 'Phenotype', 'HP:0007328', (79, 91))	('trauma', 'Disease', (68, 74))	('MIILE', 'Var', (17, 22))	('pain', 'Phenotype', 'HP:0012531', (87, 91))
739210	31014381	Substantial evidence from preclinical models indicates that blocking PD-1/PD-L1 interactions can enhance immune normalization and reinforce anticancer responses.	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PD-1', 'Gene', (69, 73))	('PD-1', 'Gene', '5133', (69, 73))	('cancer', 'Disease', (144, 150))	('reinforce', 'PosReg', (130, 139))	('enhance', 'PosReg', (97, 104))	('interactions', 'Interaction', (80, 92))	('blocking', 'Var', (60, 68))	('immune normalization', 'CPA', (105, 125))
739216	31014381	Nevertheless, this study suggests that PD-1 blockading may prolong therapeutic durability.	('therapeutic durability', 'CPA', (67, 89))	('PD-1', 'Gene', (39, 43))	('prolong', 'PosReg', (59, 66))	('PD-1', 'Gene', '5133', (39, 43))	('blockading', 'Var', (44, 54))
739221	31014381	The exception to this can be observed in tumors with specific genetic changes, such as MSI-H, deficient mismatch repair (dMMR), and high tumor mutational burden (TMB).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MSI-H', 'Disease', 'MESH:D000848', (87, 92))	('tumor', 'Disease', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('TMB', 'Chemical', '-', (162, 165))	('MSI-H', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('deficient', 'Var', (94, 103))	('dMMR', 'Chemical', '-', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mismatch repair', 'MPA', (104, 119))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
739224	31014381	This may be due to genetic alterations within DNA encoding immunogenic signaling pathway proteins, a lack of sufficient mutation-associated neoantigens (MANAs) in the presence of an immunosuppressive tumor microenvironment, and/or the unmasking of immunogenicity by immune checkpoint inhibitors (ICPIs) to induce an enhanced antitumor response.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('immunosuppressive tumor', 'Disease', (182, 205))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (182, 205))	('enhanced', 'PosReg', (316, 324))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('DNA', 'Gene', (46, 49))	('tumor', 'Disease', (329, 334))	('alterations', 'Var', (27, 38))
739231	31014381	The efficacy of PD-1/PD-L1 blockades can be lasting for some patients, although tumor development remains a constant threat even under continuous therapy.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('PD-1', 'Gene', '5133', (16, 20))	('blockades', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (61, 69))	('tumor', 'Disease', (80, 85))	('PD-1', 'Gene', (16, 20))
739234	31014381	At present, the possible mechanisms of acquired immunotherapy resistance appear to include loss-of-function mutations in beta-2-microglobulin (B2M) and Janus kinases (JAK1 and JAK2).	('JAK2', 'Gene', (176, 180))	('beta-2-microglobulin', 'Gene', (121, 141))	('mutations', 'Var', (108, 117))	('B2M', 'Gene', (143, 146))	('B2M', 'Gene', '567', (143, 146))	('JAK1', 'Gene', (167, 171))	('JAK1', 'Gene', '3716', (167, 171))	('JAK2', 'Gene', '3717', (176, 180))	('beta-2-microglobulin', 'Gene', '567', (121, 141))	('loss-of-function', 'NegReg', (91, 107))
739239	31014381	Adding to the aforementioned side effects and drug resistance after immunotherapy, studies indicate that a small number of patients on PD-1 blockades will experience hyper-progression.	('patients', 'Species', '9606', (123, 131))	('hyper-progression', 'MPA', (166, 183))	('drug resistance', 'Phenotype', 'HP:0020174', (46, 61))	('PD-1', 'Gene', (135, 139))	('PD-1', 'Gene', '5133', (135, 139))	('blockades', 'Var', (140, 149))
739242	31014381	conducted an analysis of somatic alterations looking into the biomarkers for hyper-progression and found that copy number alterations in murine double minute 2/4 (MDM2/MDM4), the epidermal growth factor receptor (EGFR), and several genes located on 11q13 are associated with hyper-progression.	('MDM4', 'Gene', '17248', (168, 172))	('epidermal growth factor receptor', 'Gene', (179, 211))	('EGFR', 'Gene', (213, 217))	('epidermal growth factor receptor', 'Gene', '13649', (179, 211))	('MDM4', 'Gene', (168, 172))	('copy number alterations', 'Var', (110, 133))	('murine', 'Species', '10090', (137, 143))	('associated', 'Reg', (259, 269))	('hyper-progression', 'Disease', (275, 292))
739254	31014381	Any abnormality in processing T cell immune clearance can lead to a decrease or even the disappearance of antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('decrease', 'NegReg', (68, 76))	('abnormality', 'Var', (4, 15))	('disappearance', 'NegReg', (89, 102))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('T cell immune clearance', 'CPA', (30, 53))
739257	31014381	Tumors can also escape variant selection and tumor-associated antigen expression loss, as well as co-stimulatory molecule downregulation and immunosuppressive factor secretion.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('downregulation', 'NegReg', (122, 136))	('tumor', 'Disease', (45, 50))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('variant selection', 'Var', (23, 40))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('loss', 'NegReg', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
739276	31014381	Targeted therapies focusing on tumor-specific gene mutation show promise and therefore are likely candidates for further investigation.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('mutation', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
739277	31014381	In addition, evidence suggests PD-1/PD-L1 blockades can be combined directly with other immune checkpoint inhibitors (ICPIs), including some immunosuppressive small molecule blockades, having compatible, and theoretically complementary modalities.	('PD-1', 'Gene', '5133', (31, 35))	('blockades', 'Var', (42, 51))	('PD-1', 'Gene', (31, 35))
739290	31014381	On the other hand, CTLA-4 blockades also inhibit the B7-CTLA-4 pathway, which can initiate CD8+ T cell proliferation in lymph nodes and increase the infiltration of CTLs into tumor tissues.	('CD8', 'Gene', (91, 94))	('tumor', 'Disease', (175, 180))	('CTLA-4', 'Gene', '1493', (19, 25))	('CD8', 'Gene', '925', (91, 94))	('CTLA-4', 'Gene', (56, 62))	('infiltration', 'CPA', (149, 161))	('initiate', 'PosReg', (82, 90))	('CTLs into', 'CPA', (165, 174))	('inhibit', 'NegReg', (41, 48))	('blockades', 'Var', (26, 35))	('CTLA-4', 'Gene', (19, 25))	('increase', 'PosReg', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('CTLA-4', 'Gene', '1493', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
739291	31014381	Additionally, CTLA-4 antagonists may impede tumor inhibition capabilities of Treg cells.	('CTLA-4', 'Gene', (14, 20))	('impede', 'NegReg', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('antagonists', 'Var', (21, 32))	('CTLA-4', 'Gene', '1493', (14, 20))	('tumor', 'Disease', (44, 49))
739298	31014381	Interestingly, the CheckMate-227 study which compared chemotherapy alone with double immunotherapy found that double immunotherapy can improve mPFS as well as ORR in patients suffering lung cancer, irrespective of PD-L1 expression.	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('double immunotherapy', 'Var', (110, 130))	('mPFS', 'CPA', (143, 147))	('lung cancer', 'Disease', (185, 196))	('patients', 'Species', '9606', (166, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('ORR', 'Disease', (159, 162))	('improve', 'PosReg', (135, 142))
739302	31014381	The use of small molecular bioeffectors, such as histone deacetylase (HDAC) inhibitors which enhance the expression of T cell chemokines, may augment response rates to PD-1 blocking immunotherapy.	('HDAC', 'Gene', (70, 74))	('histone deacetylase', 'Gene', '9734', (49, 68))	('HDAC', 'Gene', '9734', (70, 74))	('PD-1', 'Gene', (168, 172))	('enhance', 'PosReg', (93, 100))	('histone deacetylase', 'Gene', (49, 68))	('augment', 'PosReg', (142, 149))	('inhibitors', 'Var', (76, 86))	('PD-1', 'Gene', '5133', (168, 172))	('expression', 'MPA', (105, 115))	('response rates', 'CPA', (150, 164))
739304	31014381	The guiding principle of the synergistic effect for combining small molecule drugs with ICPIs is that this may enhance tumor immunogenicity, which may in turn may enhance the efficacy of immuno-oncological (IO) treatments.	('tumor', 'Disease', (119, 124))	('small', 'Var', (62, 67))	('immuno-oncological', 'CPA', (187, 205))	('enhance', 'PosReg', (163, 170))	('enhance', 'PosReg', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
739310	31014381	Increasing attention is being given to targeted therapies because the identification of actionable oncogenic driver alterations has improved and we are gaining a deeper understanding of the microenvironments in which tumor develop.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('alterations', 'Var', (116, 127))
739311	31014381	Monoclonal antibodies (McAbs) which target tumors mainly include drugs that target tumor-driving genes, inhibit protein kinase complexes by targeting the fusion mutation of EGFR, ALK, etc., or drugs which target angiogenesis (e.g., axitinib or sorafenib).	('sorafenib', 'Chemical', 'MESH:D000077157', (244, 253))	('tumor', 'Disease', (83, 88))	('targeting', 'Reg', (140, 149))	('fusion mutation', 'Var', (154, 169))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('protein', 'Protein', (112, 119))	('ALK', 'Gene', '238', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ALK', 'Gene', (179, 182))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('EGFR', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('angiogenesis', 'CPA', (212, 224))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('axitinib', 'Chemical', 'MESH:D000077784', (232, 240))	('inhibit', 'NegReg', (104, 111))	('McAbs', 'Chemical', 'MESH:D000911', (23, 28))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
739314	31014381	In a melanoma mouse model, dabrafenib significantly increased the infiltration of CD8+ T cells, and trametinib in BRAF wild-type tumor cells appears to upregulate human leukocyte antigen (HLA) molecule expression while downregulating certain immunosuppressive factors such as PD-L1, IL1, IL8, CD73, and vascular endothelial growth factor A (VEGFA).	('IL1', 'Gene', (283, 286))	('upregulate', 'PosReg', (152, 162))	('IL8', 'Gene', (288, 291))	('expression', 'MPA', (202, 212))	('VEGFA', 'Gene', '22339', (341, 346))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('CD73', 'Gene', '23959', (293, 297))	('CD73', 'Gene', (293, 297))	('tumor', 'Disease', (129, 134))	('trametinib', 'Var', (100, 110))	('infiltration', 'CPA', (66, 78))	('downregulating', 'NegReg', (219, 233))	('vascular endothelial growth factor A', 'Gene', '22339', (303, 339))	('increased', 'PosReg', (52, 61))	('CD8', 'Gene', (82, 85))	('VEGFA', 'Gene', (341, 346))	('IL1', 'Gene', '111343', (283, 286))	('mouse', 'Species', '10090', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('trametinib', 'Chemical', 'MESH:C560077', (100, 110))	('vascular endothelial growth factor A', 'Gene', (303, 339))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('IL8', 'Gene', '20309', (288, 291))	('CD8', 'Gene', '925', (82, 85))	('human', 'Species', '9606', (163, 168))	('dabrafenib', 'Chemical', 'MESH:C561627', (27, 37))
739329	31014381	PD-1 blockades amplify these abscopal effects, and radiotherapy increases the expression of PD-L1 in tumor cells which suggests intervention compatibility.	('expression', 'MPA', (78, 88))	('PD-1', 'Gene', (0, 4))	('PD-L1', 'Gene', (92, 97))	('PD-1', 'Gene', '5133', (0, 4))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('blockades', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('increases', 'PosReg', (64, 73))
739350	31014381	Similar results have been found in patients with previously untreated metastatic non-squamous NSCLC without EGFR or ALK mutations.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('EGFR', 'Gene', (108, 112))	('NSCLC', 'Disease', (94, 99))	('ALK', 'Gene', (116, 119))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (35, 43))	('ALK', 'Gene', '238', (116, 119))
739372	31014381	ICPIs in esophageal cancer encourage optimism and combined with an immunotherapy may bring further benefit for those suffering esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('esophageal cancer', 'Disease', (127, 144))	('ICPIs', 'Var', (0, 5))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('esophageal cancer', 'Disease', (9, 26))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (9, 26))
739382	31014381	The results of the ATTRACTION-02 phase III study focusing on heavily pretreated patients with advanced gastric or gastroesophageal junction cancer found OS rates in nivolumab compared with placebo were 27.3% and 11.6% at 12 months, and then 10.6% and 3.2% at 24 months, respectively.	('gastric or gastroesophageal junction cancer', 'Disease', 'MESH:D013274', (103, 146))	('patients', 'Species', '9606', (80, 88))	('OS', 'Gene', '17451', (153, 155))	('nivolumab', 'Chemical', 'MESH:D000077594', (165, 174))	('gastric or gastroesophageal junction cancer', 'Disease', (103, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('nivolumab', 'Var', (165, 174))
739384	31014381	Comparatively, the KEYNOTE-061 trial which focused on pembrolizumab with paclitaxel in patients with advanced gastric cancer whom had developed resistance after platinum and fluoropyrimidine treatment found that pembrolizumab did not significantly improve OS compared to paclitaxel, with an 9.1 month mOS versus 8.3 months.	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('paclitaxel', 'Chemical', 'MESH:D017239', (73, 83))	('paclitaxel', 'Chemical', 'MESH:D017239', (271, 281))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('mOS', 'Gene', (301, 304))	('pembrolizumab', 'Chemical', 'MESH:C582435', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('fluoropyrimidine', 'Chemical', '-', (174, 190))	('mOS', 'Gene', '17451', (301, 304))	('pembrolizumab', 'Chemical', 'MESH:C582435', (212, 225))	('OS', 'Gene', '17451', (256, 258))	('platinum', 'Chemical', 'MESH:D010984', (161, 169))	('pembrolizumab', 'Var', (212, 225))	('patients', 'Species', '9606', (87, 95))	('OS', 'Gene', '17451', (302, 304))
739396	31014381	Recent results have indicated the potential of PD-1/PD-L1 blockades for the treatment of advanced HCC.	('PD-1', 'Gene', (47, 51))	('HCC', 'Gene', (98, 101))	('PD-1', 'Gene', '5133', (47, 51))	('blockades', 'Var', (58, 67))	('HCC', 'Gene', '619501', (98, 101))	('HCC', 'Phenotype', 'HP:0001402', (98, 101))
739400	31014381	In addition, liver toxicity of PD-1/PD-L1 blockades was lower than that of conventional drugs.	('blockades', 'Var', (42, 51))	('lower', 'NegReg', (56, 61))	('PD-1', 'Gene', (31, 35))	('PD-1', 'Gene', '5133', (31, 35))	('toxicity', 'Disease', 'MESH:D064420', (19, 27))	('toxicity', 'Disease', (19, 27))
739412	31014381	In addition, several clinical trials of PD-1/PD-L1 blockades combined with other types of antitumor therapy are also under way.	('PD-1', 'Gene', '5133', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('blockades', 'Var', (51, 60))	('tumor', 'Disease', (94, 99))	('PD-1', 'Gene', (40, 44))
739414	31014381	In addition, emerging data suggests MMR or MSI-H mutation tumors have a much higher response rate to PD-1/L1 inhibitors, and in cholangiocarcinoma, MSI-H accounting for 5% of gallbladder cancers (GBC), 5-13% of extrahepatic cholangiocarcinoma (ECC), and 10% of intrahepatic cholangiocarcinoma (ICC).	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (274, 292))	('gallbladder cancers', 'Disease', 'MESH:D005706', (175, 194))	('extrahepatic cholangiocarcinoma', 'Disease', (211, 242))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('MSI-H', 'Disease', (148, 153))	('cholangiocarcinoma', 'Disease', (274, 292))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (274, 292))	('higher', 'PosReg', (77, 83))	('mutation', 'Var', (49, 57))	('PD-1/L1', 'Gene', (101, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (224, 242))	('extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (211, 242))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (128, 146))	('MSI-H', 'Disease', (43, 48))	('MSI-H', 'Disease', 'MESH:D000848', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('cholangiocarcinoma', 'Disease', (224, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('cholangiocarcinoma', 'Disease', (128, 146))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (224, 242))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (128, 146))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('tumors', 'Disease', (58, 64))	('response', 'MPA', (84, 92))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (261, 292))	('intrahepatic cholangiocarcinoma', 'Disease', (261, 292))	('MSI-H', 'Disease', 'MESH:D000848', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('PD-1/L1', 'Gene', '5133;3897', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('gallbladder cancers', 'Disease', (175, 194))
739417	31014381	One small sample study found after treatment with PD-1 blockades combined with lenvatinib, 3:14 patients had a 21.4% ORR and a 93% DCR.	('DCR', 'Gene', (131, 134))	('blockades', 'Var', (55, 64))	('lenvatinib', 'Chemical', 'MESH:C531958', (79, 89))	('ORR', 'MPA', (117, 120))	('patients', 'Species', '9606', (96, 104))	('PD-1', 'Gene', (50, 54))	('PD-1', 'Gene', '5133', (50, 54))	('DCR', 'Gene', '1637', (131, 134))
739420	31014381	PD-1/L1 blockades combined with a standard chemotherapy is frequently administered as a second-line therapy, although there appears to be an element of trial and error adjustment.	('PD-1/L1', 'Gene', (0, 7))	('PD-1/L1', 'Gene', '5133;3897', (0, 7))	('blockades', 'Var', (8, 17))
739439	31014381	The potential benefit of PD-1/PD-L1 blockades combined with other therapeutic approaches has resulted in a number of trials focusing on resectable pancreatic cancer, broad line resectable pancreatic cancer, and advanced pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('PD-1', 'Gene', (25, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('PD-1', 'Gene', '5133', (25, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('blockades', 'Var', (36, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('pancreatic cancer', 'Disease', (188, 205))	('pancreatic cancer', 'Disease', (147, 164))	('pancreatic cancer', 'Disease', (220, 237))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))
739444	31014381	Nevertheless, the colorectal cancer group of phase II clinical trials evaluating the clinical activity of pembrolizumab in patients with progressive metastatic carcinoma has shown that the ORR and DCR of patients with mismatch repair-deficient (dMMR) within 20 weeks were 40 and 90%, respectively.	('patients', 'Species', '9606', (204, 212))	('dMMR', 'Chemical', '-', (245, 249))	('DCR', 'Gene', '1637', (197, 200))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('carcinoma', 'Disease', 'MESH:D002277', (160, 169))	('DCR', 'Gene', (197, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('mismatch repair-deficient', 'Var', (218, 243))	('patients', 'Species', '9606', (123, 131))	('colorectal cancer', 'Disease', (18, 35))	('carcinoma', 'Disease', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('pembrolizumab', 'Chemical', 'MESH:C582435', (106, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))
739445	31014381	For the mismatch repair-proficient (pMMR) group, these values were 0 and 11%, respectively which suggests that mismatch repair status may be used as efficient indicators of PD-1 antibodies, although further research is needed for clarification.	('mismatch', 'Var', (111, 119))	('PD-1', 'Gene', (173, 177))	('PD-1', 'Gene', '5133', (173, 177))
739450	31014381	As mentioned previously, PD-1 inhibitor monotherapy has little effect in patients with microsatellite stable colorectal cancer.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('microsatellite', 'Var', (87, 101))	('PD-1', 'Gene', (25, 29))	('PD-1', 'Gene', '5133', (25, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('patients', 'Species', '9606', (73, 81))
739454	31014381	MEK inhibition upregulates tumor major histocompatibility complex-I expression, promoting intra-tumoral T cell accumulation while improving anti-PD-L1 responses.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('upregulates', 'PosReg', (15, 26))	('MEK', 'Gene', (0, 3))	('tumor', 'Disease', (27, 32))	('promoting', 'PosReg', (80, 89))	('MEK', 'Gene', '5609', (0, 3))	('tumor', 'Disease', (96, 101))	('improving', 'PosReg', (130, 139))	('inhibition', 'Var', (4, 14))	('intra-tumoral T', 'Disease', 'MESH:D009369', (90, 105))	('anti-PD-L1 responses', 'MPA', (140, 160))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('intra-tumoral T', 'Disease', (90, 105))
739558	30444046	Simultaneously, tumor suppressor genes (TSGs) can be inactivated by promoter hypermethylation (Llinas-Arias and Esteller, 2017).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('promoter hypermethylation', 'Var', (68, 93))	('Llinas-Arias', 'Disease', (95, 107))	('tumor', 'Disease', (16, 21))	('Llinas-Arias', 'Disease', 'MESH:D005878', (95, 107))
739559	30444046	CpG island hypermethylation in cancer cells is associated with a decrease in histone active marks: histone H3 and H4 acetylation, H3K4 trimethylation, and gain of repressive marks: H3K9me3 and H3K27me3 (Llinas-Arias and Esteller, 2017).	('H3K27me3', 'Var', (193, 201))	('H3K4', 'Protein', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('histone H3', 'Protein', (99, 109))	('H3K9me3', 'Protein', (181, 188))	('hypermethylation', 'Var', (11, 27))	('Llinas-Arias', 'Disease', 'MESH:D005878', (203, 215))	('gain', 'PosReg', (155, 159))	('histone', 'MPA', (77, 84))	('decrease', 'NegReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('repressive', 'MPA', (163, 173))	('cancer', 'Disease', (31, 37))	('Llinas-Arias', 'Disease', (203, 215))
739574	30444046	This KRAB-ZNF is upregulated in bladder cancer, while its knockdown induces apoptosis and reduces the viability of cancer cells in in vitro and in vivo experiments (Kawahara et al., 2016).	('induces', 'Reg', (68, 75))	('cancer', 'Disease', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('upregulated', 'PosReg', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('reduces', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ZNF', 'Gene', (10, 13))	('apoptosis', 'CPA', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('knockdown', 'Var', (58, 67))	('ZNF', 'Gene', '284390', (10, 13))
739604	30444046	For breast cancer, we used nine different cell lines representing distinct molecular subtypes: luminal A (MCF7, T47D), luminal B (BT474), basal (BT20, BT549, HS578T, MDA-MB231, MDA-MB468), and HER2 positive (SKBR3).	('T47D', 'CellLine', 'CVCL:0553', (112, 116))	('HER2', 'Gene', (193, 197))	('MDA-MB231', 'CellLine', 'CVCL:0062', (166, 175))	('MDA-MB231', 'Var', (166, 175))	('BT549', 'CellLine', 'CVCL:1092', (151, 156))	('MDA-MB468', 'Var', (177, 186))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('HER2', 'Gene', '2064', (193, 197))	('HS578T', 'CellLine', 'CVCL:0332', (158, 164))	('MDA-MB468', 'CellLine', 'CVCL:0419', (177, 186))	('SKBR3', 'CellLine', 'CVCL:0033', (208, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MCF7', 'CellLine', 'CVCL:0031', (106, 110))	('BT20', 'Var', (145, 149))	('HS578T', 'Var', (158, 164))
739626	30444046	Interestingly, the majority of the KRAB-ZNFs with an altered mRNA level exhibited reduced expression, while only a small but distinct cluster of 16 KRAB-ZNFs showed upregulation in multiple cancer types (Fig.	('ZNFs', 'Chemical', '-', (40, 44))	('multiple cancer', 'Disease', (181, 196))	('altered', 'Var', (53, 60))	('expression', 'MPA', (90, 100))	('reduced', 'NegReg', (82, 89))	('ZNFs', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('upregulation', 'PosReg', (165, 177))	('mRNA level', 'MPA', (61, 71))	('multiple cancer', 'Disease', 'MESH:D009369', (181, 196))
739660	30444046	As aberrant splicing is a frequent event in carcinogenesis, we wanted to explore the isoform signature for cancer-associated KRAB-ZNFs in TCGA datasets.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinogenesis', 'Disease', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ZNFs', 'Chemical', '-', (130, 134))	('aberrant splicing', 'Var', (3, 20))	('cancer', 'Disease', (107, 113))
739663	30444046	As expected, we found that a majority of splicing variants (84.5%) were overexpressed in cancer tissues compared to their normal counterparts (Fig.	('splicing variants', 'Var', (41, 58))	('overexpressed', 'PosReg', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
739664	30444046	Out of 490 significant isoforms, 21 variants (4.3%) showed expression only in cancer tissues, 220 variants (44.9%) were strongly overexpressed in cancer compared to normal (>= 2-fold overexpression, with the highest level reaching 652-fold change), and 173 variants (35.3%) showed mild overexpression (FC < 2 and >= 1.2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (286, 300))	('overexpressed', 'PosReg', (129, 142))	('variants', 'Var', (98, 106))
739665	30444046	It is of note that 21 isoforms that fell below the detection threshold in normal samples included mainly truncated and nonsense variants of ZNF695.	('ZNF695', 'Gene', '57116', (140, 146))	('nonsense', 'Var', (119, 127))	('ZNF695', 'Gene', (140, 146))
739670	30444046	ZNF273, the isoform with a 5' partial deletion of the KRAB domain, was switched to three other isoforms, which could be translated to a full-length protein, a variant with a C-terminal partial deletion of the KRAB domain, and a protein devoid of the zinc finger domain.	('ZNF273', 'Gene', (0, 6))	('partial deletion', 'Var', (30, 46))	('ZNF273', 'Gene', '10793', (0, 6))
739675	30444046	Four out of five ZNF273 variants (Fig.	('ZNF273', 'Gene', '10793', (17, 23))	('ZNF273', 'Gene', (17, 23))	('variants', 'Var', (24, 32))
739733	30444046	Finally, our survival analysis indicated that the expression of KRAB-ZNFs may act as a risk factor.	('KRAB-ZNFs', 'Gene', (64, 73))	('ZNFs', 'Chemical', '-', (69, 73))	('expression', 'Var', (50, 60))
739734	30444046	Patients with high expression of five out of 10 analyzed KRAB-ZNFs presented significantly shorter overall survival than those with low expression (Fig.	('ZNFs', 'Chemical', '-', (62, 66))	('overall survival', 'MPA', (99, 115))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('KRAB-ZNFs', 'Gene', (57, 66))	('shorter', 'NegReg', (91, 98))
739736	30444046	In contrast, high expression was associated with better prognosis in the case of ZNF205 (P < 0.001, hazard ratio = 0.5), ZNF707 (P = 0.001, hazard ratio = 0.5), and ZNF789 (P = 0.017, hazard ratio = 0.5) (Fig.	('ZNF205', 'Gene', (81, 87))	('high', 'Var', (13, 17))	('ZNF707', 'Gene', '286075', (121, 127))	('ZNF789', 'Gene', (165, 171))	('ZNF789', 'Gene', '285989', (165, 171))	('better', 'PosReg', (49, 55))	('ZNF205', 'Gene', '7755', (81, 87))	('ZNF707', 'Gene', (121, 127))
739751	30444046	We observed that the majority of variants was detected both in normal and cancer tissues, but as expected, they had a higher level in tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('variants', 'Var', (33, 41))
739752	30444046	The differential expression of KRAB-ZNF splicing isoforms in cancer was reported only by Juarez-Mendez and colleagues (Juarez-Mendez et al., 2013), who demonstrated a specific increase of ZNF695 variants in ovarian cancer compared to normal cells.	('ZNF', 'Gene', (36, 39))	('variants', 'Var', (195, 203))	('increase', 'PosReg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ovarian cancer', 'Disease', (207, 221))	('cancer', 'Disease', (61, 67))	('ZNF', 'Gene', (188, 191))	('ZNF', 'Gene', '284390', (36, 39))	('ZNF695', 'Gene', '57116', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF', 'Gene', '284390', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))	('ZNF695', 'Gene', (188, 194))
739763	30444046	Furthermore, we have previously shown that ZNF695 was upregulated in pluripotent stem cells compared to more specialized cell types, whereas its knockdown resulted in the loss of self-renewal properties and differentiation of pluripotent stem cells (Oleksiewicz et al., 2017).	('ZNF695', 'Gene', '57116', (43, 49))	('knockdown', 'Var', (145, 154))	('upregulated', 'PosReg', (54, 65))	('self-renewal properties', 'CPA', (179, 202))	('differentiation', 'CPA', (207, 222))	('ZNF695', 'Gene', (43, 49))	('loss', 'NegReg', (171, 175))
739877	29581759	Furthermore, due to the majority stage T1N0 patients with ESCC owning long-term survival, only length and depth of tumor invasion, microscopic tumor budding, poor differentiation and lymphovascular invasion had been found as independent prognostic indicators for postoperative OS reported by limited literatures.	('postoperative OS', 'Disease', 'MESH:C567932', (263, 279))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (115, 120))	('postoperative OS', 'Disease', (263, 279))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('T1N0', 'Var', (39, 43))
739904	29581759	In univariate analysis, the PI 0, GPS 0, and low CRP (<= 1.090 mg/l), NLR (<= 1.976), PLR (<= 103.200), CAR (<= 0.023) were significantly correlated with longer DFS and OS (all p<0.050, Table 1).	('CRP', 'Gene', '1401', (49, 52))	('GPS 0', 'Var', (34, 39))	('OS', 'Chemical', '-', (169, 171))	('PI 0', 'Var', (28, 32))	('low', 'NegReg', (45, 48))	('PLR', 'MPA', (86, 89))	('CRP', 'Gene', (49, 52))	('CAR', 'Disease', (104, 107))
739906	29581759	The best cut point of the resected lymph nodes count (RLNs) was determined as 13 in our study based on ROC curve and we had found that the 10-year DFS was significantly longer for RLNs >13 than for RLNs <=13 (79.2% vs. 65.3%, p=0.048), but not in OS (p=0.061).	('RLNs >13', 'Var', (180, 188))	('DFS', 'MPA', (147, 150))	('longer', 'PosReg', (169, 175))	('OS', 'Chemical', '-', (247, 249))
739907	29581759	2) were predictive of better long-term survival in patients with pathological T1N0 ESCC.	('better', 'PosReg', (22, 28))	('patients', 'Species', '9606', (51, 59))	('T1N0', 'Var', (78, 82))
739923	29581759	In 2007, the first study in colon and rectal cancer from McMillan DC et al indicated that the modified GPS (mGPS) was significantly associated with overall survival.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('modified GPS', 'Var', (94, 106))	('overall', 'MPA', (148, 155))	('colon', 'Disease', (28, 33))	('colon', 'Disease', 'MESH:D015179', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('rectal cancer', 'Phenotype', 'HP:0100743', (38, 51))	('associated with', 'Reg', (132, 147))	('cancer', 'Disease', (45, 51))
739935	29581759	For instance, the best cut-off values of NLR (1.976) and PLR (103.2) in our stage T1N0 ESCC patients were smaller than the previous EC cohort with non-selected stages (range of NLR cut-off: 2.0-5.0, range of PLR cut-off: 103.0-163.8).	('T1N0', 'Var', (82, 86))	('ESCC', 'Disease', (87, 91))	('patients', 'Species', '9606', (92, 100))
739943	29581759	To these patients with high GPS or elevated CAR, endoscopic resection (ER) may not suitable and postoperative adjuvant chemotherapy may be considered.	('high GPS', 'Var', (23, 31))	('patients', 'Species', '9606', (9, 17))	('CAR', 'MPA', (44, 47))
740051	25538945	Experimental studies showed that downregulation or targeting of ErbB4 suppresses the tumor progression to a great extent.	('tumor', 'Disease', (85, 90))	('ErbB4', 'Gene', '2066', (64, 69))	('targeting', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('suppresses', 'NegReg', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('downregulation', 'NegReg', (33, 47))	('ErbB4', 'Gene', (64, 69))
740053	25538945	showed that ErbB4 knockdown resulted in inhibition of ESCC migration and invasion activities.	('knockdown', 'Var', (18, 27))	('invasion activities', 'CPA', (73, 92))	('inhibition', 'NegReg', (40, 50))	('ErbB4', 'Gene', (12, 17))	('ErbB4', 'Gene', '2066', (12, 17))	('ESCC migration', 'CPA', (54, 68))
740054	25538945	In addition, in xenografts model, ErbB4 mediated apoptosis was shown to be essential for the antitumor effect of tamoxifen and cancer patients with ErbB4 expression responded very well with tamoxifen therapy.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ErbB4', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tamoxifen', 'Chemical', 'MESH:D013629', (113, 122))	('ErbB4', 'Gene', '2066', (34, 39))	('ErbB4', 'Gene', (148, 153))	('patients', 'Species', '9606', (134, 142))	('expression', 'Var', (154, 164))	('tumor', 'Disease', (97, 102))	('ErbB4', 'Gene', '2066', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('tamoxifen', 'Chemical', 'MESH:D013629', (190, 199))
740113	25538945	As can be seen (Figure 2(f)), miR-140-5P significantly inhibited the reporter with wild type ErbB4 3'UTR compared to that miR-NC which did not show any inhibitory effect while, on the other hand, analogous reporter with mutant ErbB4 3'UTR was relatively insensitive to miR-140-5P transfection.	('miR-140', 'Gene', '406932', (269, 276))	('inhibited', 'NegReg', (55, 64))	('miR', 'Gene', (30, 33))	('miR', 'Gene', '220972', (30, 33))	('miR-140', 'Gene', '406932', (30, 37))	('ErbB4', 'Gene', (93, 98))	('ErbB4', 'Gene', (227, 232))	('mutant', 'Var', (220, 226))	('ErbB4', 'Gene', '2066', (227, 232))	('miR', 'Gene', '220972', (122, 125))	('miR-140', 'Gene', (269, 276))	('miR', 'Gene', (122, 125))	('miR', 'Gene', '220972', (269, 272))	('ErbB4', 'Gene', '2066', (93, 98))	('miR', 'Gene', (269, 272))	('miR-140', 'Gene', (30, 37))
740115	25538945	The transfection showed that wild type ErbB4 3'UTR was prone to the inhibition of luciferase gene upon miR-140-5p exposure while that of mutation blocks the potential binding site in cells resulting in no inhibition of luciferase expression.	('mutation', 'Var', (137, 145))	('expression', 'MPA', (230, 240))	('luciferase', 'Enzyme', (219, 229))	('miR-140', 'Gene', (103, 110))	('luciferase gene', 'Gene', (82, 97))	('inhibition', 'NegReg', (68, 78))	('ErbB4', 'Gene', (39, 44))	('miR-140', 'Gene', '406932', (103, 110))	('ErbB4', 'Gene', '2066', (39, 44))	('binding', 'Interaction', (167, 174))
740184	24188482	Secondly, both in vitro and in vivo studies have further demonstrated that down-regulation of XIAP expression, either by RNA interference (RNAi) or antisense oligonucleotides, results in stimulation of sensitization to gamma-irradiation and chemotherapeutic-induced apoptosis in tumor cells.	('RNA interference', 'MPA', (121, 137))	('chemotherapeutic-induced', 'CPA', (241, 265))	('expression', 'MPA', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('antisense oligonucleotides', 'Var', (148, 174))	('tumor', 'Disease', (279, 284))	('down-regulation', 'NegReg', (75, 90))	('XIAP', 'Gene', (94, 98))	('XIAP', 'Gene', '331', (94, 98))	('oligonucleotides', 'Chemical', 'MESH:D009841', (158, 174))	('stimulation', 'PosReg', (187, 198))	('sensitization', 'CPA', (202, 215))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
740188	24188482	Moreover, aberrant nuclear factor-kappaB (NF-kappaB) expression has been detected in many human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('detected', 'Reg', (73, 81))	('aberrant', 'Var', (10, 18))	('NF-kappaB', 'Gene', '4790', (42, 51))	('malignancies', 'Disease', (96, 108))	('human', 'Species', '9606', (90, 95))	('expression', 'MPA', (53, 63))	('NF-kappaB', 'Gene', (42, 51))	('nuclear factor-kappaB', 'Gene', (19, 40))	('nuclear factor-kappaB', 'Gene', '4790', (19, 40))
740222	24188482	Differentiation and high expression of XIAP and NF-kappaB were associated with decreased survival (P < 0.05), whereas other clinicopathological variables were not significant.	('decreased', 'NegReg', (79, 88))	('survival', 'MPA', (89, 97))	('NF-kappaB', 'Gene', '4790', (48, 57))	('high', 'Var', (20, 24))	('XIAP', 'Gene', (39, 43))	('NF-kappaB', 'Gene', (48, 57))	('XIAP', 'Gene', '331', (39, 43))
740231	24188482	Recently, increasingly more research studies have found that small-molecule XIAP inhibitors could enhance irradiation-induced apoptosis in most cancer cells.	('enhance', 'PosReg', (98, 105))	('small-molecule', 'Var', (61, 75))	('XIAP', 'Gene', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('XIAP', 'Gene', '331', (76, 80))	('irradiation-induced apoptosis', 'CPA', (106, 135))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
740329	22022340	Numerous studies suggest that a number of nutritional compounds have epigenetic targets in cancer cells.	('epigenetic targets', 'Var', (69, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
740333	22022340	Compounds found in dietary phytochemical preparations such as teas, garlic, soy products, herbs, grapes and cruciferous vegetables are now generally accepted to defend against the development of many different types of tumors as well as acting as epigenetic modulators that impact not only the initiation, but also the progression of oncogenesis.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('impact', 'Reg', (274, 280))	('oncogenesis', 'CPA', (334, 345))	('tea', 'Gene', (62, 65))	('tea', 'Gene', '11988', (62, 65))	('epigenetic', 'Var', (247, 257))	('garlic', 'Species', '4682', (68, 74))
740334	22022340	Epigenetic modifications typically occur by changes in DNA methylation, histone covalent modifications or by RNAi.	('changes', 'Reg', (44, 51))	('covalent modifications', 'MPA', (80, 102))	('methyl', 'Chemical', 'MESH:C051224', (59, 65))	('occur', 'Reg', (35, 40))	('Epigenetic', 'Var', (0, 10))	('DNA methylation', 'MPA', (55, 70))	('histone', 'Protein', (72, 79))
740337	22022340	DNA methylation has many roles in various cellular processes and may impact the transcription of genes by preventing the binding of key transcriptional factors.	('methyl', 'Chemical', 'MESH:C051224', (4, 10))	('transcription of', 'MPA', (80, 96))	('methylation', 'Var', (4, 15))	('binding', 'Interaction', (121, 128))	('impact', 'Reg', (69, 75))	('preventing', 'NegReg', (106, 116))	('key', 'Protein', (132, 135))
740338	22022340	Transcriptional silencing due to DNA methylation is thought to occur by the recruitment of methyl CpG-binding transcriptional repressors and by interfering with the DNA binding of transcriptional activators, which in turn results in a condensed chromatin state.	('Transcriptional', 'MPA', (0, 15))	('results in', 'Reg', (222, 232))	('methylation', 'Var', (37, 48))	('methyl', 'Chemical', 'MESH:C051224', (37, 43))	('condensed chromatin state', 'MPA', (235, 260))	('binding', 'Interaction', (169, 176))	('methyl', 'Chemical', 'MESH:C051224', (91, 97))	('interfering', 'NegReg', (144, 155))
740340	22022340	DNA methylation is catalyzed by enzymes known as DNA methyltransferases (DNMTs) and hypermethylation of CpG dinucleotides or CpG islands by DNMTs usually results in transcriptional gene silencing and gene inactivation.	('methyl', 'Chemical', 'MESH:C051224', (4, 10))	('DNMT', 'Gene', (73, 77))	('results in', 'Reg', (154, 164))	('methyl', 'Chemical', 'MESH:C051224', (53, 59))	('DNMT', 'Gene', '1786', (140, 144))	('methyl', 'Chemical', 'MESH:C051224', (89, 95))	('DNMT', 'Gene', (140, 144))	('DNMT', 'Gene', '1786', (73, 77))	('hypermethylation', 'Var', (84, 100))	('gene', 'CPA', (200, 204))	('transcriptional', 'MPA', (165, 180))
740343	22022340	In addition, global hypomethylation is associated with nearly all human cancers.	('global hypomethylation', 'Var', (13, 35))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('associated', 'Reg', (39, 49))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('methyl', 'Chemical', 'MESH:C051224', (24, 30))
740348	22022340	Lysine methylation can cause either activation or repression of transcription, while arginine methylation typically activates transcription.	('methyl', 'Chemical', 'MESH:C051224', (7, 13))	('transcription', 'MPA', (126, 139))	('Lysine methylation', 'Var', (0, 18))	('repression', 'NegReg', (50, 60))	('methyl', 'Chemical', 'MESH:C051224', (94, 100))	('activation', 'PosReg', (36, 46))	('arginine', 'Chemical', 'MESH:D001120', (85, 93))	('activates', 'PosReg', (116, 125))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('cause', 'Reg', (23, 28))	('arginine', 'Var', (85, 93))	('transcription', 'MPA', (64, 77))
740349	22022340	This is apparent in carcinogenesis where aberrant activity of HATs and HDACs are thought to trigger carcinogenic processes.	('carcinogenesis', 'Disease', 'MESH:D063646', (20, 34))	('trigger', 'Reg', (92, 99))	('carcinogenic', 'Disease', 'MESH:D063646', (100, 112))	('aberrant activity', 'Var', (41, 58))	('carcinogenic', 'Disease', (100, 112))	('carcinogenesis', 'Disease', (20, 34))	('HDAC', 'Gene', (71, 75))	('HDAC', 'Gene', '9734', (71, 75))
740350	22022340	For example, in the yeast Schizosaccharomyces pombe, the deletion of different components of the RNAi machinery results in the loss of H3K9 methylation, as well as impairment of centromere function.	('methylation', 'MPA', (140, 151))	('deletion', 'Var', (57, 65))	('yeast', 'Species', '4932', (20, 25))	('Schizosaccharomyces pombe', 'Species', '4896', (26, 51))	('loss', 'NegReg', (127, 131))	('methyl', 'Chemical', 'MESH:C051224', (140, 146))	('impairment', 'NegReg', (164, 174))	('H3K9', 'Protein', (135, 139))	('centromere function', 'CPA', (178, 197))
740351	22022340	Similarly, DNA methylation and H3K9 methylation have been demonstrated in Arabidopsis thaliana and in alpha-thalassaemia.	('methylation', 'Var', (15, 26))	('methyl', 'Chemical', 'MESH:C051224', (36, 42))	('methyl', 'Chemical', 'MESH:C051224', (15, 21))	('alpha-thalassaemia', 'Disease', (102, 120))	('H3K9', 'Protein', (31, 35))	('Arabidopsis thaliana', 'Species', '3702', (74, 94))
740354	22022340	Exciting developments have indicated that RNAi-directed silencing of heterochromatic regions might trigger direct histone modifications and DNA methylation to specific loci, causing gene silencing.	('histone', 'Protein', (114, 121))	('silencing', 'Var', (56, 65))	('DNA methylation', 'MPA', (140, 155))	('trigger', 'Reg', (99, 106))	('methyl', 'Chemical', 'MESH:C051224', (144, 150))	('gene', 'MPA', (182, 186))
740355	22022340	Epigenetic modifications are of particular interest in the field of cancer research since their impact on the epigenome is involved in cell proliferation, differentiation and survival.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('involved', 'Reg', (123, 131))	('Epigenetic modifications', 'Var', (0, 24))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('impact', 'Reg', (96, 102))	('cancer', 'Disease', (68, 74))
740356	22022340	Furthermore, epigenetic modifications are often involved in transcriptional regulation and have been implicated both in tumor development and progression.	('epigenetic modifications', 'Var', (13, 37))	('implicated', 'Reg', (101, 111))	('transcriptional regulation', 'MPA', (60, 86))	('involved', 'Reg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
740357	22022340	Epigenetic modifications causing transcriptional deregulation may result in the inappropriate expression or activation of transcription factors associated with oncogenes and/or the failure to express genes responsible for tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('result', 'Reg', (66, 72))	('transcription', 'Protein', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('transcriptional', 'MPA', (33, 48))	('Epigenetic modifications', 'Var', (0, 24))	('expression', 'MPA', (94, 104))	('activation', 'PosReg', (108, 118))
740359	22022340	In addition, the impact of epigenomic processes in cancer is apparent by the finding that at least half of all tumor suppressor genes are inactivated through epigenetic mechanisms in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', (111, 116))	('inactivated', 'NegReg', (138, 149))	('tumor', 'Disease', (183, 188))	('epigenetic', 'Var', (158, 168))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
740364	22022340	This is especially illustrated by an early investigation conducted in an animal model, which demonstrated that dietary methyl deficiency of folate, choline and methionine altered DNA methylation patterns in the liver and induced hepatocarcinoma.	('DNA methylation patterns', 'MPA', (179, 203))	('methionine', 'Chemical', 'MESH:D008715', (160, 170))	('hepatocarcinoma', 'Disease', (229, 244))	('hepatocarcinoma', 'Disease', 'None', (229, 244))	('methyl deficiency', 'Var', (119, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('methyl', 'Chemical', 'MESH:C051224', (183, 189))	('deficiency of folate', 'Phenotype', 'HP:0100507', (126, 146))	('folate', 'Chemical', 'MESH:D005492', (140, 146))	('methyl', 'Chemical', 'MESH:C051224', (119, 125))	('choline', 'Chemical', 'MESH:D002794', (148, 155))	('altered', 'Reg', (171, 178))	('induced', 'Reg', (221, 228))
740383	22022340	As previously stated, polyphenolic compounds in tea may actively reduce the risk of diseases such as cancer.	('tea', 'Gene', (48, 51))	('polyphenolic compounds', 'Var', (22, 44))	('tea', 'Gene', '11988', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('polyphenolic compounds', 'Chemical', '-', (22, 44))	('reduce', 'NegReg', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
740404	22022340	Interestingly, studies conducted using EGCG and a prodrug of EGCG (pEGCG and EGCG octa-acetate) to enhance the bioavailability and stability of EGCG display inhibition of hTERT, the catalytic subunit of telomerase, through epigenetic mechanisms affecting the hTERT gene regulatory region in breast cancer cells.	('EGCG', 'Chemical', 'MESH:C045651', (144, 148))	('stability', 'MPA', (131, 140))	('pEGCG', 'Chemical', '-', (67, 72))	('bioavailability', 'MPA', (111, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (291, 304))	('hTERT', 'Gene', '7015', (259, 264))	('EGCG', 'Chemical', 'MESH:C045651', (39, 43))	('hTERT', 'Gene', '7015', (171, 176))	('inhibition', 'NegReg', (157, 167))	('epigenetic', 'Var', (223, 233))	('enhance', 'PosReg', (99, 106))	('breast cancer', 'Disease', 'MESH:D001943', (291, 304))	('EGCG', 'Chemical', 'MESH:C045651', (68, 72))	('breast cancer', 'Disease', (291, 304))	('EGCG', 'Chemical', 'MESH:C045651', (77, 81))	('EGCG', 'Chemical', 'MESH:C045651', (61, 65))	('hTERT', 'Gene', (259, 264))	('EGCG', 'Gene', (144, 148))	('hTERT', 'Gene', (171, 176))	('octa-acetate', 'Chemical', '-', (82, 94))	('affecting', 'Reg', (245, 254))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
740430	22022340	This evidence suggests that sirturins can affect normal gene expression through chromatin regulation and may provide a link between epigenetic changes associated with aging and obesity as well as epigenetic modifications in tumors.	('affect', 'Reg', (42, 48))	('sirturins', 'Chemical', '-', (28, 37))	('obesity', 'Disease', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('epigenetic modifications', 'Var', (196, 220))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('link', 'Reg', (119, 123))	('obesity', 'Phenotype', 'HP:0001513', (177, 184))	('chromatin regulation', 'MPA', (80, 100))	('normal gene expression', 'MPA', (49, 71))	('obesity', 'Disease', 'MESH:D009765', (177, 184))
740439	22022340	These data provide evidence of a link between inflammation and epigenetic alterations that are also seen in cancer.	('inflammation', 'Disease', 'MESH:D007249', (46, 58))	('inflammation', 'Disease', (46, 58))	('epigenetic alterations', 'Var', (63, 85))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
740444	22022340	While the inhibition of both HATs and HDACs may seem contradictory, recent investigations provide evidence that HAT inhibitors have a potential role in cancer therapies and that inhibition of both HATs and HDACs together may provide a potent strategy for cancer treatment.	('HDAC', 'Gene', (206, 210))	('HDAC', 'Gene', '9734', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('HDAC', 'Gene', '9734', (206, 210))	('inhibition', 'Var', (178, 188))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('HDAC', 'Gene', (38, 42))
740466	22022340	Furthermore, investigations have demonstrated that genistein-mediated hypomethylation and hyperacetylation reactivate the expression of tumor suppressor genes in prostate cancer cells.	('hyperacetylation', 'Var', (90, 106))	('expression', 'MPA', (122, 132))	('hypomethylation', 'Var', (70, 85))	('prostate cancer', 'Disease', 'MESH:D011471', (162, 177))	('genistein', 'Chemical', 'MESH:D019833', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('methyl', 'Chemical', 'MESH:C051224', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('prostate cancer', 'Phenotype', 'HP:0012125', (162, 177))	('reactivate', 'PosReg', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('tumor', 'Disease', (136, 141))	('prostate cancer', 'Disease', (162, 177))
740479	22022340	In fact, allyl-isothiocyanate, found in broccoli, has been reported to increase histone acetylation in mouse erythroleukemia cells.	('histone acetylation', 'MPA', (80, 99))	('allyl-isothiocyanate', 'Var', (9, 29))	('mouse', 'Species', '10090', (103, 108))	('erythroleukemia', 'Disease', (109, 124))	('allyl-isothiocyanate', 'Chemical', 'MESH:C004471', (9, 29))	('increase', 'PosReg', (71, 79))	('erythroleukemia', 'Disease', 'MESH:D004915', (109, 124))	('leukemia', 'Phenotype', 'HP:0001909', (116, 124))
740481	22022340	PHI has also been reported to inhibit HDAC activity and plays a role in remodeling chromatin to activate p21 and induce cell cycle arrest in prostate cancer and leukemia cells.	('HDAC', 'Gene', '9734', (38, 42))	('PHI', 'Var', (0, 3))	('leukemia', 'Disease', (161, 169))	('leukemia', 'Phenotype', 'HP:0001909', (161, 169))	('induce', 'PosReg', (113, 119))	('activate', 'PosReg', (96, 104))	('inhibit', 'NegReg', (30, 37))	('arrest in prostate cancer', 'Disease', (131, 156))	('PHI', 'Chemical', 'MESH:C073279', (0, 3))	('p21', 'Gene', '1026', (105, 108))	('arrest in prostate cancer', 'Disease', 'MESH:D011471', (131, 156))	('leukemia', 'Disease', 'MESH:D007938', (161, 169))	('prostate cancer', 'Phenotype', 'HP:0012125', (141, 156))	('p21', 'Gene', (105, 108))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (120, 137))	('HDAC', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
740512	22022340	revealed that garlic organosulfur compound, allyl mercaptan, inhibits histone deacetylase (Figure 3 & Table 1) and enhances Sp3 binding on the P21/WAF1 promoter, which results in elevated p21 protein expression and cell cycle arrest.	('and cell cycle', 'CPA', (211, 225))	('allyl mercaptan', 'Chemical', '-', (44, 59))	('enhances', 'Protein', (115, 123))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (215, 232))	('allyl mercaptan', 'Var', (44, 59))	('Sp3', 'Interaction', (124, 127))	('garlic', 'Species', '4682', (14, 20))	('P21', 'Gene', '1026', (143, 146))	('and', 'PosReg', (111, 114))	('histone', 'Protein', (70, 77))	('sulfur', 'Chemical', 'MESH:D013455', (27, 33))	('p21', 'Gene', '1026', (188, 191))	('p21', 'Gene', (188, 191))	('P21', 'Gene', (143, 146))	('inhibits', 'NegReg', (61, 69))
740517	22022340	While folate has been studied extensively for its developmental effects, folate deficiencies lead to hypomethylated genomic DNA, which is associated with tumorigenesis.	('hypomethylated genomic', 'Var', (101, 123))	('lead to', 'Reg', (93, 100))	('folate', 'Chemical', 'MESH:D005492', (6, 12))	('associated', 'Reg', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('folate', 'Chemical', 'MESH:D005492', (73, 79))	('folate deficiencies', 'Phenotype', 'HP:0100507', (73, 92))	('deficiencies', 'Var', (80, 92))	('methyl', 'Chemical', 'MESH:C051224', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('folate', 'Gene', (73, 79))	('tumor', 'Disease', (154, 159))
740519	22022340	Folate regulates the biosynthesis, repair and methylation of DNA, whereas deficiencies in folate can induce carcinogenesis by augmenting these processes.	('repair', 'MPA', (35, 41))	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('DNA', 'Protein', (61, 64))	('folate', 'Chemical', 'MESH:D005492', (90, 96))	('biosynthesis', 'MPA', (21, 33))	('methyl', 'Chemical', 'MESH:C051224', (46, 52))	('regulates', 'Reg', (7, 16))	('methylation', 'MPA', (46, 57))	('folate', 'Gene', (90, 96))	('induce', 'PosReg', (101, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('augmenting', 'PosReg', (126, 136))	('deficiencies', 'Var', (74, 86))	('carcinogenesis', 'Disease', (108, 122))
740520	22022340	In addition, studies involving colorectal cancer indicated that folate deficiency can alter cytosine methylation in DNA leading to the activation of c-Myc, a known oncogene.	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('deficiency', 'Var', (71, 81))	('activation', 'PosReg', (135, 145))	('DNA', 'Gene', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('c-Myc', 'Gene', '4609', (149, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('cytosine', 'Chemical', 'MESH:D003596', (92, 100))	('colorectal cancer', 'Disease', (31, 48))	('methyl', 'Chemical', 'MESH:C051224', (101, 107))	('alter', 'Reg', (86, 91))	('c-Myc', 'Gene', (149, 154))	('folate deficiency', 'Phenotype', 'HP:0100507', (64, 81))	('cytosine methylation', 'MPA', (92, 112))	('folate', 'Chemical', 'MESH:D005492', (64, 70))
740529	22022340	Furthermore, future studies focusing on the clinical relevance and mechanism of epigenetic modification of bio-active dietary factors are needed to further assess the applicability of dietary factors as cancer preventive and chemopreventive agents.	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('epigenetic modification', 'Var', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
740530	22022340	Papers of special note have been highlighted as:   of interest    of considerable interest Epigenetic modifications typically occur by changes in DNA methylation, histone modifications, or by RNAi and can be influenced by dietary factors.	('changes', 'Reg', (135, 142))	('occur', 'Reg', (126, 131))	('Epigenetic modifications', 'Var', (91, 115))	('DNA', 'Protein', (146, 149))	('methyl', 'Chemical', 'MESH:C051224', (150, 156))	('histone', 'Protein', (163, 170))
740531	22022340	At least a half of all tumor suppressor genes are inactivated through epigenetic mechanisms in tumorigenesis.	('epigenetic mechanisms', 'Var', (70, 91))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('inactivated', 'NegReg', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (95, 100))
740532	22022340	Dietary polyphenols such as tea polyphenols (i.e., epicatechin, epicatechin-3-gallate, epigallocatechin and epigallocatechin-3-gallate), resveratrol and curcumin can inhibit DNA methyltransferases and act as histone modifiers and demonstrate potential as anticancer therapeutic as well as chemopreventive agents.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('tea', 'Gene', '11988', (28, 31))	('DNA methyltransferases', 'Enzyme', (174, 196))	('resveratrol', 'Chemical', 'MESH:D000077185', (137, 148))	('inhibit', 'NegReg', (166, 173))	('epicatechin-3-gallate', 'Chemical', 'MESH:C062669', (64, 85))	('cancer', 'Disease', (259, 265))	('tea', 'Gene', (28, 31))	('curcumin', 'Chemical', 'MESH:D003474', (153, 161))	('epicatechin', 'Chemical', 'MESH:D002392', (51, 62))	('epigallocatechin-3-gallate', 'Var', (108, 134))	('epigallocatechin', 'Chemical', 'MESH:C057580', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('polyphenols', 'Chemical', 'MESH:D059808', (8, 19))	('epicatechin', 'Chemical', 'MESH:D002392', (64, 75))	('polyphenols', 'Chemical', 'MESH:D059808', (32, 43))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (108, 134))	('epigallocatechin', 'Chemical', 'MESH:C057580', (108, 124))	('methyl', 'Chemical', 'MESH:C051224', (178, 184))
740535	22022340	Other dietary factors including those found in Brazilian nuts, chicken, cereals, coffee, cashews, garlic, parsley, milk thistle and rosemary, have also been reported to have epigenetic targets in cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('rosemary', 'Species', '39367', (132, 140))	('parsley', 'Species', '4043', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('milk thistle', 'Species', '92921', (115, 127))	('cashews', 'Species', '171929', (89, 96))	('epigenetic', 'Var', (174, 184))	('cancer', 'Disease', (196, 202))	('chicken', 'Species', '9031', (63, 70))	('garlic', 'Species', '4682', (98, 104))
740661	31849530	MiRNAs participate in several significant biological processes, including cell differentiation, proliferation, apoptosis, and host response against viral infections.	('host response', 'CPA', (126, 139))	('MiRNAs', 'Var', (0, 6))	('proliferation', 'CPA', (96, 109))	('cell differentiation', 'CPA', (74, 94))	('participate', 'Reg', (7, 18))	('viral infections', 'Disease', (148, 164))	('apoptosis', 'CPA', (111, 120))	('viral infections', 'Disease', 'MESH:D001102', (148, 164))
740671	31849530	Studies found that miR-326 can inhibit NSCLC cell invasion, possibly by downregulating Adam17 expression level.	('Adam17', 'Gene', (87, 93))	('downregulating', 'NegReg', (72, 86))	('miR-326', 'Var', (19, 26))	('Adam17', 'Gene', '6868', (87, 93))	('NSCLC', 'Disease', (39, 44))	('inhibit', 'NegReg', (31, 38))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('miR-326', 'Chemical', '-', (19, 26))
740674	31849530	Li et al reported that miR-326 hampered NSCLC cell invasion via inhibiting the protein level of NSBP1.	('hampered', 'NegReg', (31, 39))	('miR-326', 'Chemical', '-', (23, 30))	('protein level', 'MPA', (79, 92))	('inhibiting', 'NegReg', (64, 74))	('miR-326', 'Var', (23, 30))	('NSCLC', 'Disease', (40, 45))	('NSBP1', 'Gene', (96, 101))	('NSBP1', 'Gene', '79366', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
740676	31849530	Wang et al found that miR-326 slowed NSCLC metastasis by targeting Phox2a.	('miR-326', 'Chemical', '-', (22, 29))	('slowed', 'NegReg', (30, 36))	('targeting', 'Reg', (57, 66))	('Phox2a', 'Gene', '401', (67, 73))	('NSCLC', 'Disease', (37, 42))	('miR-326', 'Var', (22, 29))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('Phox2a', 'Gene', (67, 73))
740678	31849530	Survival analysis indicated that low expression of miR-326 was a prognostic factor for poor outcome for gastric cancer patients.	('miR-326', 'Var', (51, 58))	('low', 'NegReg', (33, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('patients', 'Species', '9606', (119, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('miR-326', 'Chemical', '-', (51, 58))	('expression', 'MPA', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gastric cancer', 'Disease', (104, 118))
740680	31849530	As an actin-binding protein, FSCN1 is often upregulated in different cancers, and overexpression of FSCN1 promotes tumor invasion and metastasis.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('upregulated', 'PosReg', (44, 55))	('overexpression', 'Var', (82, 96))	('promotes', 'PosReg', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (115, 120))	('FSCN1', 'Gene', (100, 105))	('FSCN1', 'Gene', '6624', (100, 105))	('metastasis', 'CPA', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('FSCN1', 'Gene', (29, 34))	('FSCN1', 'Gene', '6624', (29, 34))	('cancers', 'Disease', (69, 76))
740681	31849530	In BC, miR-326 was reported to repress cell metastasis by targeting B7-H3, an immunomodulin belonging to the B7 family.	('repress', 'NegReg', (31, 38))	('miR-326', 'Chemical', '-', (7, 14))	('targeting', 'Reg', (58, 67))	('BC', 'Phenotype', 'HP:0003002', (3, 5))	('B7-H3', 'Gene', (68, 73))	('cell metastasis', 'CPA', (39, 54))	('B7-H3', 'Gene', '80381', (68, 73))	('miR-326', 'Var', (7, 14))
740683	31849530	In cervical cancer, restoration of ETS domain-containing protein (ELK1) was reported to eliminate cell invasion due to miR-326 mimics, indicating that miR-326 suppressed cell invasion and metastasis by targeting ELK1.	('cell invasion', 'CPA', (98, 111))	('miR-326', 'Var', (151, 158))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('restoration', 'Var', (20, 31))	('miR-326', 'Chemical', '-', (119, 126))	('cancer', 'Disease', (12, 18))	('ELK1', 'Gene', '2002', (66, 70))	('eliminate', 'NegReg', (88, 97))	('miR-326', 'Chemical', '-', (151, 158))	('cell invasion', 'CPA', (170, 183))	('ELK1', 'Gene', (212, 216))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('suppressed', 'NegReg', (159, 169))	('ELK1', 'Gene', '2002', (212, 216))	('ELK1', 'Gene', (66, 70))
740686	31849530	In osteosarcoma, glioma and colorectal cancer, miR-326 can target NOB1 to inhibit metastasis.	('NOB1', 'Gene', (66, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('miR-326', 'Chemical', '-', (47, 54))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('osteosarcoma', 'Disease', (3, 15))	('colorectal cancer', 'Disease', (28, 45))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('inhibit', 'NegReg', (74, 81))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('metastasis', 'CPA', (82, 92))	('glioma', 'Disease', (17, 23))	('miR-326', 'Var', (47, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('NOB1', 'Gene', '28987', (66, 70))
740688	31849530	Analysis from data in TargetScan and MicroRNA.org identified TWIST1 as a potential target of miR-326, and luciferase reporter assays were consistent with the targeting of TWIST1 by miR-326.	('miR-326', 'Var', (93, 100))	('miR-326', 'Chemical', '-', (181, 188))	('miR-326', 'Chemical', '-', (93, 100))	('TWIST1', 'Gene', (61, 67))	('TWIST1', 'Gene', '7291', (61, 67))	('TWIST1', 'Gene', (171, 177))	('TWIST1', 'Gene', '7291', (171, 177))	('miR-326', 'Var', (181, 188))
740690	31849530	In endometrial cancer, in vitro assays revealed that knockdown of TWIST1 inhibited tumor cell invasion.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('endometrial cancer', 'Phenotype', 'HP:0012114', (3, 21))	('tumor', 'Disease', (83, 88))	('knockdown', 'Var', (53, 62))	('TWIST1', 'Gene', (66, 72))	('endometrial cancer', 'Disease', 'MESH:D016889', (3, 21))	('TWIST1', 'Gene', '7291', (66, 72))	('inhibited', 'NegReg', (73, 82))	('endometrial cancer', 'Disease', (3, 21))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
740691	31849530	In prostatic carcinoma, miR-326 functioned as a tumor suppressor by negatively regulating Mucin1 (MUC1).	('Mucin1', 'Gene', (90, 96))	('miR-326', 'Var', (24, 31))	('tumor', 'Disease', (48, 53))	('prostatic carcinoma', 'Disease', 'MESH:D011471', (3, 22))	('prostatic carcinoma', 'Disease', (3, 22))	('negatively regulating', 'NegReg', (68, 89))	('prostatic carcinoma', 'Phenotype', 'HP:0012125', (3, 22))	('miR-326', 'Chemical', '-', (24, 31))	('MUC1', 'Gene', (98, 102))	('MUC1', 'Gene', '4582', (98, 102))	('Mucin1', 'Gene', '4582', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
740695	31849530	Additionally, the expression of miR-326 was correlated with poor prognosis in esophageal squamous cell carcinoma patients.	('esophageal squamous cell carcinoma', 'Disease', (78, 112))	('patients', 'Species', '9606', (113, 121))	('miR-326', 'Var', (32, 39))	('expression', 'MPA', (18, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('miR-326', 'Chemical', '-', (32, 39))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (78, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
740696	31849530	Thus, several studies have shown that miR-326 plays a role in inhibiting invasion and metastasis in a variety of tumor cells, but the specific mechanism has not been elucidated.	('tumor', 'Disease', (113, 118))	('miR-326', 'Var', (38, 45))	('miR-326', 'Chemical', '-', (38, 45))	('inhibiting', 'NegReg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
740698	31849530	Numerous genes may be involved in the regulation by miR-326 on cell apoptosis and proliferation, such as CyclinD1 (CCND1), fibroblast growth factor 1 (FGF1), son of sevenless homolog 1 (SOS1), and neuroblastoma RAS viral oncogene homolog (NRAS).	('CCND1', 'Gene', (115, 120))	('CyclinD1', 'Gene', '595', (105, 113))	('SOS1', 'Gene', (186, 190))	('son of sevenless homolog 1', 'Gene', (158, 184))	('CyclinD1', 'Gene', (105, 113))	('NRAS', 'Gene', (239, 243))	('neuroblastoma', 'Disease', (197, 210))	('proliferation', 'CPA', (82, 95))	('neuroblastoma', 'Phenotype', 'HP:0003006', (197, 210))	('FGF1', 'Gene', (151, 155))	('fibroblast growth factor 1', 'Gene', (123, 149))	('son of sevenless homolog 1', 'Gene', '6654', (158, 184))	('neuroblastoma', 'Disease', 'MESH:D009447', (197, 210))	('miR-326', 'Var', (52, 59))	('SOS1', 'Gene', '6654', (186, 190))	('CCND1', 'Gene', '595', (115, 120))	('FGF1', 'Gene', '2246', (151, 155))	('cell', 'CPA', (63, 67))	('fibroblast growth factor 1', 'Gene', '2246', (123, 149))	('NRAS', 'Gene', '4893', (239, 243))	('miR-326', 'Chemical', '-', (52, 59))
740700	31849530	Consequently, changes in CCND1 gene amplification, posttranscriptional or posttranslational modifications, rearrangements, and variant polymorphisms can give rise to abnormal protein expression and increase risk of tumorigenesis.	('CCND1', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('increase', 'PosReg', (198, 206))	('give rise to abnormal', 'Reg', (153, 174))	('variant polymorphisms', 'Var', (127, 148))	('CCND1', 'Gene', '595', (25, 30))	('rearrangements', 'Var', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('changes', 'Var', (14, 21))	('tumor', 'Disease', (215, 220))	('protein expression', 'MPA', (175, 193))
740701	31849530	In NSCLC, miR-326 may inhibit tumor proliferation by targeting CCND1.	('CCND1', 'Gene', '595', (63, 68))	('miR-326', 'Var', (10, 17))	('targeting', 'Reg', (53, 62))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('inhibit', 'NegReg', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('miR-326', 'Chemical', '-', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('CCND1', 'Gene', (63, 68))	('tumor', 'Disease', (30, 35))
740702	31849530	Sun et al found that miR-326 could suppress cyclin D1, thus facilitating the expression level of p57 and p21, which might explain the proliferation-inhibition property of miR-326.	('miR-326', 'Chemical', '-', (171, 178))	('miR-326', 'Chemical', '-', (21, 28))	('facilitating', 'PosReg', (60, 72))	('p57', 'Gene', '1028', (97, 100))	('cyclin D1', 'Gene', '595', (44, 53))	('expression level', 'MPA', (77, 93))	('p21', 'Gene', (105, 108))	('p57', 'Gene', (97, 100))	('cyclin D1', 'Gene', (44, 53))	('p21', 'Gene', '644914', (105, 108))	('miR-326', 'Var', (21, 28))	('suppress', 'NegReg', (35, 43))
740707	31849530	Studies have shown that miR-326 restrained FGF1 expression to modulate cell proliferation and apoptosis.	('modulate', 'Reg', (62, 70))	('FGF1', 'Gene', '2246', (43, 47))	('expression', 'MPA', (48, 58))	('cell proliferation', 'CPA', (71, 89))	('miR-326 restrained', 'Var', (24, 42))	('miR-326', 'Chemical', '-', (24, 31))	('FGF1', 'Gene', (43, 47))	('apoptosis', 'CPA', (94, 103))
740723	31849530	Additionally, focal deletions, mutations, or gene amplifications that encode pathway components like Gli2, Smoothened, and Patched 1 have been shown to be involved in crucial oncogenic events in SHH-driven medulloblastoma (SHH-MB).	('mutations', 'Var', (31, 40))	('SHH', 'Gene', (195, 198))	('SHH', 'Gene', '6469', (195, 198))	('SHH', 'Gene', (223, 226))	('medulloblastoma', 'Disease', 'MESH:D008527', (206, 221))	('Gli2', 'Gene', '2736', (101, 105))	('medulloblastoma', 'Phenotype', 'HP:0002885', (206, 221))	('involved', 'Reg', (155, 163))	('Patched 1', 'Gene', (123, 132))	('SHH', 'Gene', '6469', (223, 226))	('Gli2', 'Gene', (101, 105))	('Patched 1', 'Gene', '5727', (123, 132))	('medulloblastoma', 'Disease', (206, 221))
740724	31849530	Other mechanisms of activation of non-canonical Hh/Gli pathways include p53/17p gene deletion, aberrant PI3K/Akt/S6 activation, histone methylation, and post-transcriptional modification of Gli1.	('p53/17p gene', 'Gene', (72, 84))	('Akt', 'Gene', '207', (109, 112))	('Gli', 'Gene', (51, 54))	('Gli1', 'Gene', (190, 194))	('Gli', 'Gene', '2735', (51, 54))	('histone', 'MPA', (128, 135))	('post-transcriptional modification', 'Var', (153, 186))	('activation', 'PosReg', (116, 126))	('Gli', 'Gene', (190, 193))	('activation', 'PosReg', (20, 30))	('Akt', 'Gene', (109, 112))	('Gli1', 'Gene', '2735', (190, 194))	('Gli', 'Gene', '2735', (190, 193))
740733	31849530	Phosphorylation of T308 by phosphoinositide-dependent kinase 1 initiates excitation, which is then completed by phosphorylation on the S473 residue, possibly due to the action of diverse proteins, such as mTOR.	('T308', 'Chemical', '-', (19, 23))	('mTOR', 'Gene', (205, 209))	('mTOR', 'Gene', '2475', (205, 209))	('excitation', 'MPA', (73, 83))	('T308', 'Var', (19, 23))
740734	31849530	Phosphorylated Akt then can induce downstream pathways that control cell proliferation and survival, including the phosphorylation and activation of MDM2 E3 ubiquitin ligase transcription factor, NF-kB, and mTOR kinase, and the inactivation of pro-apoptotic protein BAD and FOXO1 transcription factor to promote tumorigenesis.	('promote', 'PosReg', (304, 311))	('cell proliferation', 'CPA', (68, 86))	('Akt', 'Gene', (15, 18))	('tumor', 'Disease', (312, 317))	('inactivation', 'Var', (228, 240))	('MDM2', 'Gene', '4193', (149, 153))	('Akt', 'Gene', '207', (15, 18))	('mTOR', 'Gene', (207, 211))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('Phosphorylated', 'Var', (0, 14))	('activation', 'PosReg', (135, 145))	('FOXO1', 'Gene', '2308', (274, 279))	('mTOR', 'Gene', '2475', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('NF-kB', 'Protein', (196, 201))	('induce', 'Reg', (28, 34))	('FOXO1', 'Gene', (274, 279))	('E3 ubiquitin', 'Protein', (154, 166))	('MDM2', 'Gene', (149, 153))
740735	31849530	For example, miR-326 expression level is restrained by abnormal PI3 kinase signaling, resulting in downregulation in glioblastoma.	('miR-326', 'Chemical', '-', (13, 20))	('downregulation', 'NegReg', (99, 113))	('glioblastoma', 'Disease', (117, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (117, 129))	('expression level', 'MPA', (21, 37))	('miR-326', 'Var', (13, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))
740741	31849530	Dimerization was proposed as essential for ERK's nuclear translocation because mutations that alter dimerization of ERK2 reduced nuclear access.	('ERK', 'Gene', (116, 119))	('ERK2', 'Gene', (116, 120))	('reduced', 'NegReg', (121, 128))	('dimerization', 'MPA', (100, 112))	('ERK', 'Gene', '5594', (116, 119))	('ERK', 'Gene', (43, 46))	('ERK', 'Gene', '5594', (43, 46))	('nuclear access', 'MPA', (129, 143))	('ERK2', 'Gene', '5594', (116, 120))	('mutations', 'Var', (79, 88))
740745	31849530	Kang et al showed that miR-326 plays tumor-suppressive roles in melanoma by directly regulating KRAS and indirectly regulating the ERK signaling pathway.	('KRAS', 'Gene', '3845', (96, 100))	('miR-326', 'Chemical', '-', (23, 30))	('ERK', 'Gene', '5594', (131, 134))	('regulating', 'Reg', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('regulating', 'Reg', (85, 95))	('melanoma', 'Disease', (64, 72))	('ERK', 'Gene', (131, 134))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('miR-326', 'Var', (23, 30))	('KRAS', 'Gene', (96, 100))
740748	31849530	Studies have reported that miR-326 is involved in the MDR mechanism of hepatocellular carcinoma and BC, with two genes reported to be involved, ABCC1 and Bcl-xL.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('miR-326', 'Var', (27, 34))	('ABCC1', 'Gene', (144, 149))	('Bcl-xL', 'Gene', (154, 160))	('miR-326', 'Chemical', '-', (27, 34))	('involved', 'Reg', (38, 46))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 95))	('hepatocellular carcinoma', 'Disease', (71, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (71, 95))	('ABCC1', 'Gene', '4363', (144, 149))	('BC', 'Phenotype', 'HP:0003002', (100, 102))	('BC', 'Phenotype', 'HP:0003002', (145, 147))	('Bcl-xL', 'Gene', '598', (154, 160))
740756	31849530	Liang et al found that miR-326 could attenuate the expression of ABCC1 and sensitize BC cells to ADM and VP-16.	('miR-326', 'Chemical', '-', (23, 30))	('BC', 'Phenotype', 'HP:0003002', (85, 87))	('VP-16', 'Gene', (105, 110))	('ABCC1', 'Gene', (65, 70))	('sensitize', 'Reg', (75, 84))	('expression', 'MPA', (51, 61))	('miR-326', 'Var', (23, 30))	('ABCC1', 'Gene', '4363', (65, 70))	('BC', 'Phenotype', 'HP:0003002', (66, 68))	('VP-16', 'Gene', '3054', (105, 110))	('attenuate', 'NegReg', (37, 46))	('ADM', 'Chemical', 'MESH:D004317', (97, 100))
740760	31849530	Transfection of MCF-7/VP with miR-326 also resulted in decreased resistance to ADM.	('decreased', 'NegReg', (55, 64))	('miR-326', 'Var', (30, 37))	('resistance to ADM', 'MPA', (65, 82))	('ADM', 'Chemical', 'MESH:D004317', (79, 82))	('MCF-7/VP', 'CellLine', 'CVCL:5I65', (16, 24))	('miR-326', 'Chemical', '-', (30, 37))
740761	31849530	The resistance of MCF-7/VP prior to transfection of miR-326 to ADM was 20 times higher than the MCF-7 parental cells.	('MCF-7/VP', 'CellLine', 'CVCL:5I65', (18, 26))	('MCF-7', 'CellLine', 'CVCL:0031', (18, 23))	('miR-326', 'Var', (52, 59))	('MCF-7', 'CellLine', 'CVCL:0031', (96, 101))	('resistance', 'MPA', (4, 14))	('ADM', 'Chemical', 'MESH:D004317', (63, 66))	('miR-326', 'Chemical', '-', (52, 59))	('higher', 'PosReg', (80, 86))
740762	31849530	After MCF-7/VP cells were transfected with miR-326, their IC50 to ADM was 10 times lower than that of MCF-7/VP cells transfected with control oligonucleotide and only 1.9 times higher than the MCF-7 parental cells.	('miR-326', 'Chemical', '-', (43, 50))	('MCF-7', 'CellLine', 'CVCL:0031', (102, 107))	('MCF-7/VP', 'CellLine', 'CVCL:5I65', (6, 14))	('MCF-7', 'CellLine', 'CVCL:0031', (6, 11))	('IC50 to ADM', 'MPA', (58, 69))	('lower', 'NegReg', (83, 88))	('oligonucleotide', 'Chemical', 'MESH:D009841', (142, 157))	('miR-326', 'Var', (43, 50))	('ADM', 'Chemical', 'MESH:D004317', (66, 69))	('MCF-7/VP', 'CellLine', 'CVCL:5I65', (102, 110))	('MCF-7', 'CellLine', 'CVCL:0031', (193, 198))
740764	31849530	They found that miR-326 altered the protein expression of Bcl-xl by luciferase assay, suggesting that miR-326 might sensitize hepatocellular carcinoma cells to 5-Fluorouracil by targeting Bcl-xL, though the detailed mechanism remains unclear.	('Bcl-xL', 'Gene', '598', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('hepatocellular carcinoma', 'Disease', (126, 150))	('Bcl-xl', 'Gene', '598', (58, 64))	('Bcl-xL', 'Gene', (188, 194))	('miR-326', 'Chemical', '-', (102, 109))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (126, 150))	('targeting', 'Reg', (178, 187))	('sensitize', 'Reg', (116, 125))	('Bcl-xl', 'Gene', (58, 64))	('miR-326', 'Chemical', '-', (16, 23))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (160, 174))	('miR-326', 'Var', (102, 109))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (126, 150))
740770	31849530	We may be able to artificially inhibit tumor growth and metastasis using miR-326 mimics or synthetic agents, or to predict the prognosis of tumor patients by detecting the expression level of miR-326.	('miR-326', 'Var', (192, 199))	('miR-326', 'Chemical', '-', (192, 199))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('expression', 'MPA', (172, 182))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('miR-326', 'Chemical', '-', (73, 80))	('tumor', 'Disease', (39, 44))	('inhibit', 'NegReg', (31, 38))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Disease', (140, 145))
740771	31849530	Overall, we need to further explore the mechanisms by which miR-326 affects tumor suppression and study the molecules and pathways that interact with miR-326 to understand the roles of this RNA in cancer and to develop gene therapy strategies for clinical treatment.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('tumor', 'Disease', (76, 81))	('affects', 'Reg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('miR-326', 'Var', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('miR-326', 'Chemical', '-', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('miR-326', 'Chemical', '-', (150, 157))
740795	31719796	Importantly, some single nucleotide polymorphisms (SNPs) of TRIM27 is associated with human ESCC.	('ESCC', 'Disease', (92, 96))	('single nucleotide polymorphisms', 'Var', (18, 49))	('human', 'Species', '9606', (86, 91))	('associated', 'Reg', (70, 80))	('TRIM27', 'Gene', '5987', (60, 66))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))	('TRIM27', 'Gene', (60, 66))
740823	31719796	KYSE150 cells were transfected with siNC or siTRIM27, the cells were lysed in 1% SDS-containing radio immunoprecipitation assay (RIPA) buffer by sonication on ice.	('KYSE150', 'CellLine', 'CVCL:1348', (0, 7))	('siNC', 'Var', (36, 40))	('SDS', 'Chemical', 'MESH:C032259', (81, 84))	('TRIM27', 'Gene', '5987', (46, 52))	('transfected', 'Var', (19, 30))	('TRIM27', 'Gene', (46, 52))
740832	31719796	Therefore, knockdown of TRIM27 was induced in TE-11 and KYSE150 cells respectively.	('TRIM27', 'Gene', (24, 30))	('KYSE150', 'CellLine', 'CVCL:1348', (56, 63))	('TE-1', 'CellLine', 'CVCL:1759', (46, 50))	('knockdown', 'Var', (11, 20))	('TRIM27', 'Gene', '5987', (24, 30))
740844	31719796	Obviously, the apoptosis profile of siTRIM27-1 or siTRIM27-2 transfected cells was much higher than that of siNC transfected cells (Fig.	('higher', 'PosReg', (88, 94))	('TRIM27', 'Gene', '5987', (38, 44))	('TRIM27', 'Gene', (38, 44))	('TRIM27', 'Gene', (52, 58))	('transfected', 'Var', (61, 72))	('apoptosis profile', 'CPA', (15, 32))	('TRIM27', 'Gene', '5987', (52, 58))
740853	31719796	Moreover, the protein level of cleaved caspased-3 was remarkably upregulated in siTRIM27-1 or siTRIM27-2 transfected cells.	('TRIM27', 'Gene', '5987', (96, 102))	('TRIM27', 'Gene', (82, 88))	('TRIM27', 'Gene', (96, 102))	('transfected', 'Var', (105, 116))	('protein level of cleaved caspased-3', 'MPA', (14, 49))	('upregulated', 'PosReg', (65, 76))	('TRIM27', 'Gene', '5987', (82, 88))
740857	31719796	The cell proliferation rate was significantly promoted in oeTRIM27 transfected cells (Fig.	('promoted', 'PosReg', (46, 54))	('cell proliferation rate', 'CPA', (4, 27))	('transfected', 'Var', (67, 78))	('TRIM27', 'Gene', '5987', (60, 66))	('TRIM27', 'Gene', (60, 66))
740858	31719796	However, the AKT inhibitor LY294002 deeply suppressed the cell proliferation rate of oeNC and oeTRIM27 transfected cells.	('LY294002', 'Var', (27, 35))	('TRIM27', 'Gene', '5987', (96, 102))	('cell proliferation rate', 'CPA', (58, 81))	('TRIM27', 'Gene', (96, 102))	('AKT', 'Gene', '207', (13, 16))	('LY294002', 'Chemical', 'MESH:C085911', (27, 35))	('AKT', 'Gene', (13, 16))	('suppressed', 'NegReg', (43, 53))
740859	31719796	Moreover, the apoptosis rate was deeply inhibited in oeTRIM27 transfected cells.	('TRIM27', 'Gene', '5987', (55, 61))	('transfected', 'Var', (62, 73))	('inhibited', 'NegReg', (40, 49))	('TRIM27', 'Gene', (55, 61))	('apoptosis rate', 'CPA', (14, 28))
740860	31719796	Interestingly, the inhibitor LY294002 and 3-BrPA remarkably promoted the cell apoptosis rate in oeNC or oeTRIM27 transfected cells (Fig.	('TRIM27', 'Gene', (106, 112))	('LY294002', 'Chemical', 'MESH:C085911', (29, 37))	('promoted', 'PosReg', (60, 68))	('LY294002', 'Var', (29, 37))	('cell apoptosis rate', 'CPA', (73, 92))	('TRIM27', 'Gene', '5987', (106, 112))	('3-BrPA', 'Var', (42, 48))
740863	31719796	Moreover, the inhibitor LY294002 and 3-BrPA deeply inhibited the glucose transportation in oeTRIM27 transfected cells (Fig.	('LY294002', 'Var', (24, 32))	('TRIM27', 'Gene', '5987', (93, 99))	('glucose transportation', 'CPA', (65, 87))	('TRIM27', 'Gene', (93, 99))	('LY294002', 'Chemical', 'MESH:C085911', (24, 32))	('inhibited', 'NegReg', (51, 60))	('glucose', 'Chemical', 'MESH:D005947', (65, 72))
740864	31719796	4d, the protein content of GLUT1 and HKII were significantly increased in oeTRIM27 transfected cells.	('transfected', 'Var', (83, 94))	('TRIM27', 'Gene', '5987', (76, 82))	('GLUT1', 'Gene', (27, 32))	('TRIM27', 'Gene', (76, 82))	('increased', 'PosReg', (61, 70))	('HKII', 'Gene', (37, 41))	('GLUT1', 'Gene', '6513', (27, 32))	('protein content', 'MPA', (8, 23))	('HKII', 'Gene', '3099', (37, 41))
740865	31719796	However, the AKT inhibitor LY294002 deeply inhibited the expression of GLUT1 and HKII in oeNC or oeTRIM27 transfected cells.	('GLUT1', 'Gene', (71, 76))	('expression', 'MPA', (57, 67))	('LY294002', 'Var', (27, 35))	('HKII', 'Gene', '3099', (81, 85))	('GLUT1', 'Gene', '6513', (71, 76))	('inhibited', 'NegReg', (43, 52))	('AKT', 'Gene', '207', (13, 16))	('LY294002', 'Chemical', 'MESH:C085911', (27, 35))	('TRIM27', 'Gene', '5987', (99, 105))	('HKII', 'Gene', (81, 85))	('AKT', 'Gene', (13, 16))	('TRIM27', 'Gene', (99, 105))
740868	31719796	Taken together, all these results demonstrated that the effect of TRIM27 was deeply abolished by the AKT inhibitor LY294002 and 3-BrPA on ESCC cells.	('AKT', 'Gene', '207', (101, 104))	('TRIM27', 'Gene', '5987', (66, 72))	('ESCC', 'Disease', 'MESH:C562729', (138, 142))	('TRIM27', 'Gene', (66, 72))	('LY294002', 'Var', (115, 123))	('AKT', 'Gene', (101, 104))	('abolished', 'NegReg', (84, 93))	('ESCC', 'Disease', (138, 142))	('LY294002', 'Chemical', 'MESH:C085911', (115, 123))
740877	31719796	5b, knockdown of TRIM27 deeply reduced the level of PTEN poly-ubiquitination in ESCC cells.	('TRIM27', 'Gene', (17, 23))	('reduced', 'NegReg', (31, 38))	('PTEN', 'Gene', (52, 56))	('PTEN', 'Gene', '5728', (52, 56))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('TRIM27', 'Gene', '5987', (17, 23))	('knockdown', 'Var', (4, 13))	('ESCC', 'Disease', (80, 84))
740889	31719796	Growing evidences have indicated that the dysfunction of PI3/AKT signaling pathway is one of the hallmarks for human cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PI3', 'Gene', '5266', (57, 60))	('AKT', 'Gene', '207', (61, 64))	('human', 'Species', '9606', (111, 116))	('dysfunction', 'Var', (42, 53))	('PI3', 'Gene', (57, 60))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('AKT', 'Gene', (61, 64))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
740890	31719796	In the present study, our results demonstrated that the AKT inhibitor LY294002 disrupted the function of TRIM27 in ESCC cells.	('ESCC', 'Disease', (115, 119))	('AKT', 'Gene', '207', (56, 59))	('AKT', 'Gene', (56, 59))	('LY294002', 'Var', (70, 78))	('TRIM27', 'Gene', '5987', (105, 111))	('ESCC', 'Disease', 'MESH:C562729', (115, 119))	('disrupted', 'NegReg', (79, 88))	('function', 'MPA', (93, 101))	('TRIM27', 'Gene', (105, 111))	('LY294002', 'Chemical', 'MESH:C085911', (70, 78))
740906	31719796	In this study, we induced knockdown and overexpression of TRIM27 in ESCC cells.	('TRIM27', 'Gene', (58, 64))	('ESCC', 'Disease', (68, 72))	('overexpression', 'PosReg', (40, 54))	('knockdown', 'Var', (26, 35))	('ESCC', 'Disease', 'MESH:C562729', (68, 72))	('TRIM27', 'Gene', '5987', (58, 64))
740911	30854468	Accumulation of genetic and epigenetic alterations in normal cells and cancer risk Cancers develop due to the accumulation of genetic and epigenetic alterations.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('genetic', 'Var', (126, 133))	('cancer', 'Disease', (71, 77))	('Cancers', 'Disease', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Cancers', 'Disease', 'MESH:D009369', (83, 90))	('Cancers', 'Phenotype', 'HP:0002664', (83, 90))	('epigenetic alterations', 'Var', (138, 160))	('epigenetic alterations', 'Var', (28, 50))
740912	30854468	Genetic alterations are induced by aging, mutagenic chemicals, ultraviolet light, and other factors; whereas, epigenetic alterations are mainly by aging and chronic inflammation.	('mutagenic chemicals', 'Var', (42, 61))	('inflammation', 'Disease', 'MESH:D007249', (165, 177))	('Genetic alterations', 'MPA', (0, 19))	('induced', 'Reg', (24, 31))	('inflammation', 'Disease', (165, 177))
740913	30854468	Most accumulated alterations are considered as passengers, but their accumulation is correlated with cancer drivers.	('cancer', 'Disease', (101, 107))	('alterations', 'Var', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
740915	30854468	When high levels of alterations accumulate, the tissue has a high risk of developing cancer or even multiple cancers and is considered as a "cancerization field", with or without expansion of physiological patches of clonal cells.	('alterations', 'Var', (20, 31))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Disease', (109, 116))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (141, 147))
740917	30854468	Human cancers develop due to the accumulation of genetic and epigenetic alterations.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('epigenetic alterations', 'Var', (61, 83))	('genetic', 'Var', (49, 56))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))
740920	30854468	Tissue with accumulated alterations is known as a "field for cancerization (cancerization field)", with or without expansion of physiological patches of clonal cells.	('alterations', 'Var', (24, 35))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
740922	30854468	In this review, we describe the mechanisms by which genetic and epigenetic cancerization fields are induced, its characteristics, and how we can apply the field in precision cancer risk diagnosis.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('epigenetic', 'Var', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
740928	30854468	Most recently, approximately 85,000,000 mutations in more than 23,829 cancers were classified into single base substitutions (SBS) in 96 trinucleotide contexts, doublet base substitutions (DBS), and small insertion and deletions (ID).	('SBS', 'Disease', (126, 129))	('trinucleotide', 'Chemical', '-', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SBS', 'Disease', 'MESH:C536611', (126, 129))	('mutations', 'Var', (40, 49))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
740930	30854468	Signature 1, characterized by C>T transitions at NpCpG trinucleotides, is associated with aging; signature 7, reflecting a large number of CC>TT dinucleotide mutations at dipyrimidines, with UV light; signature 4, characterized by C>A transversions with strand bias, with cigarette smoking; signature 2, characterized by C>T and C>G mutations at TpCpN trinucleotides, with excessive activity of cytidine deaminases (AID/APOBEC), which is observed in chronic inflammation.	('AID', 'Gene', (416, 419))	('dipyrimidines', 'Chemical', '-', (171, 184))	('TT dinucleotide', 'Chemical', '-', (142, 157))	('TpCpN', 'Gene', (346, 351))	('C>G mutations', 'Var', (329, 342))	('inflammation', 'Disease', 'MESH:D007249', (458, 470))	('activity', 'MPA', (383, 391))	('inflammation', 'Disease', (458, 470))	('trinucleotides', 'Chemical', '-', (55, 69))	('trinucleotides', 'Chemical', '-', (352, 366))	('cytidine deaminases', 'Enzyme', (395, 414))	('C>T', 'Var', (321, 324))	('AID', 'Gene', '57379', (416, 419))
740932	30854468	Specific patterns of copy number alterations can be also present in cancer tissues, referred to as a "copy number signature".	('copy number alterations', 'Var', (21, 44))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))
740933	30854468	For example, copy number signatures in high-grade serous ovarian cancers can predict overall patient survival and the probability of platinum-resistant relapse.	('serous ovarian cancers', 'Disease', (50, 72))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (50, 72))	('platinum-resistant relapse', 'CPA', (133, 159))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('platinum', 'Chemical', 'MESH:D010984', (133, 141))	('predict', 'Reg', (77, 84))	('patient', 'Species', '9606', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('copy number signatures', 'Var', (13, 35))	('ovarian cancers', 'Phenotype', 'HP:0100615', (57, 72))
740934	30854468	C>T transitions at GpCpN trinucleotides were detected in normal gastric mucosae exposed to gastritis triggered by Helicobacter pylori (H. pylori) infection, which induces up-regulation of AID.	('GpCpN', 'Gene', (19, 24))	('gastritis', 'Disease', 'MESH:D005756', (91, 100))	('gastritis', 'Phenotype', 'HP:0005263', (91, 100))	('Helicobacter pylori', 'Species', '210', (114, 133))	('trinucleotides', 'Chemical', '-', (25, 39))	('infection', 'Disease', (146, 155))	('AID', 'Gene', '57379', (188, 191))	('infection', 'Disease', 'MESH:D007239', (146, 155))	('gastritis', 'Disease', (91, 100))	('H. pylori', 'Species', '210', (135, 144))	('up-regulation', 'PosReg', (171, 184))	('AID', 'Gene', (188, 191))	('C>T transitions', 'Var', (0, 15))
740935	30854468	Signature 1 and signature 5, T>C transitions at ApTpN trinucleotides, were predominant in normal esophageal tissues, and C>A transversions were frequently detected in those of individuals with a severe smoking history.	('detected', 'Reg', (155, 163))	('T>C transitions', 'Var', (29, 44))	('ApTpN', 'Gene', (48, 53))	('C>A transversions', 'Var', (121, 138))	('trinucleotides', 'Chemical', '-', (54, 68))
740942	30854468	Phenotypically, carcinogen-specific induction of aberrant DNA methylation has been demonstrated in hepatocellular carcinomas (HCCs) and cirrhotic liver tissues associated with HBV infection, HCV infection, or alcohol.	('DNA', 'Protein', (58, 61))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (99, 124))	('hepatocellular carcinomas', 'Disease', (99, 124))	('alcohol', 'Chemical', 'MESH:D000438', (209, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('HCV infection', 'Disease', (191, 204))	('aberrant', 'Var', (49, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('HCV infection', 'Disease', 'MESH:D006526', (191, 204))	('HCCs', 'Phenotype', 'HP:0001402', (126, 130))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (136, 151))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (99, 124))	('HBV infection', 'Disease', (176, 189))	('HBV infection', 'Disease', 'MESH:D006509', (176, 189))
740946	30854468	Taken together, analyzing genetic and epigenetic alterations accumulated in normal cells can provide information on an individual's life-time exposure to environmental factors that induce genetic and epigenetic alterations that may eventually lead to cancer.	('induce', 'Reg', (181, 187))	('epigenetic alterations', 'Var', (200, 222))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('genetic', 'MPA', (188, 195))	('lead to', 'Reg', (243, 250))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (251, 257))
740950	30854468	The finding was further advanced by detecting TP53 mutations in clonally expanded patches of cells, which may or may not be detected by routine microscopic examination, in multiple types of cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('mutations', 'Var', (51, 60))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
740951	30854468	In contrast, even without the expansion of clonal patches of cells, the cancerization field can be formed by accumulating mutations and/or aberrant DNA methylation.	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (122, 131))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('aberrant', 'Var', (139, 147))	('DNA', 'MPA', (148, 151))
740956	30854468	Epithelial organoids expanded from a single stem cell were used to measure mutations accumulated in normal adult tissue stem cells of the small intestine, colon, and liver.	('colon', 'Disease', (155, 160))	('colon', 'Disease', 'MESH:D015179', (155, 160))	('mutations', 'Var', (75, 84))
740957	30854468	However, because of the high sequencing cost of analyzing a large number of human clinical samples, the association of these mutations with cancer risk could not be robustly established.	('mutations', 'Var', (125, 134))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('human', 'Species', '9606', (76, 81))	('clinical samples', 'Species', '191496', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
740958	30854468	The impact of accumulation of point mutations in normal tissues on cancer risk was demonstrated using the 100 copy-based method.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('point mutations', 'Var', (30, 45))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
740960	30854468	The mutation frequency in esophageal tissues (non-cancerous tissues) of ESCC patients (high-risk group) was 1.4-fold higher than that in esophageal tissues of healthy people without any exposure to ESCC risk factors (low-risk group).	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutation', 'Var', (4, 12))	('patients', 'Species', '9606', (77, 85))	('people', 'Species', '9606', (167, 173))	('higher', 'PosReg', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ESCC', 'Disease', (72, 76))
740961	30854468	Even among people exposed to the risk factors, the mutation frequency in the high-risk group was higher than that in the intermediate-risk group (healthy people with exposure to the risk factors).	('people', 'Species', '9606', (11, 17))	('higher', 'PosReg', (97, 103))	('mutation', 'Var', (51, 59))	('people', 'Species', '9606', (154, 160))
740962	30854468	Therefore, the mutations detected were likely to be derived from independent patches, and to be involved in cancerization field type-I.	('mutations', 'Var', (15, 24))	('involved', 'Reg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
740964	30854468	Most accumulated genetic alterations are considered as passengers, but their accumulation is correlated with cancer drivers.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('genetic alterations', 'Var', (17, 36))
740965	30854468	In normal skin tissues, NOTCH1 and NOTCH2 mutations showed a significant excess of non-synonymous mutations, and clustered in the extracellular epidermal growth factor-like domain.	('excess', 'PosReg', (73, 79))	('NOTCH2', 'Gene', (35, 41))	('NOTCH1', 'Gene', '4851', (24, 30))	('NOTCH1', 'Gene', (24, 30))	('NOTCH2', 'Gene', '4853', (35, 41))	('non-synonymous mutations', 'MPA', (83, 107))	('mutations', 'Var', (42, 51))
740966	30854468	In normal esophageal tissues, NOTCH1 mutations were present in 25-42% of the cells, and were considered to be associated with clonal expansion.	('NOTCH1', 'Gene', (30, 36))	('associated', 'Reg', (110, 120))	('mutations', 'Var', (37, 46))	('NOTCH1', 'Gene', '4851', (30, 36))
740967	30854468	In benign lesions of melanoma patients, which are clearly with clonal expansion, BRAF V600E mutation was detected.	('V600E', 'Var', (86, 91))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('patients', 'Species', '9606', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('V600E', 'Mutation', 'rs113488022', (86, 91))
740968	30854468	In normal blood cells, specific chromosomal alterations were detected in expanded clonal cells, and were associated with increased risk of hematological malignancies.	('hematological malignancies', 'Phenotype', 'HP:0004377', (139, 165))	('chromosomal alterations', 'Var', (32, 55))	('associated', 'Reg', (105, 115))	('hematological malignancies', 'Disease', (139, 165))	('hematological malignancies', 'Disease', 'MESH:D019337', (139, 165))
740969	30854468	These mutations are considered to be involved in the formation of cancerization field type-II, which is associated with the expansion of clonal patches.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('involved', 'Reg', (37, 45))	('cancer', 'Disease', (66, 72))	('mutations', 'Var', (6, 15))
740971	30854468	The impact of accumulation of aberrant DNA methylation on cancer risk was shown much more easily because its accumulation levels in normal tissues are high and can be readily measured.	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('aberrant', 'Var', (30, 38))
740975	30854468	Most epigenetic alterations accumulated in normal tissues are considered to be passengers, which are involved in cancerization field type-I.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('epigenetic alterations', 'Var', (5, 27))	('involved', 'Reg', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
740979	30854468	Taken all together, accumulation of genetic and epigenetic alterations in normal tissues can be associated with cancer risk.	('genetic', 'Var', (36, 43))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('associated', 'Reg', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('epigenetic alterations', 'Var', (48, 70))
740980	30854468	Both genetic and epigenetic alterations are involved in forming a field for cancerization, but their contributions differ depending on the cancer type.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('involved', 'Reg', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('epigenetic alterations', 'Var', (17, 39))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (139, 145))
740981	30854468	3a), indicating that the impact of genetic and epigenetic alterations on cancer risk is similar for ESCCs (Fig.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('epigenetic alterations', 'Var', (47, 69))	('ESCCs', 'Disease', (100, 105))
740982	30854468	The different impacts of genetic and epigenetic alterations on cancer risk are considered to depend on the major carcinogens involved and their carcinogenic mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('epigenetic alterations', 'Var', (37, 59))	('carcinogenic', 'Disease', 'MESH:D063646', (144, 156))	('carcinogenic', 'Disease', (144, 156))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
740986	30854468	This showed that the combined measurement of both genetic and epigenetic alterations can achieve precise cancer risk estimation, and provide cancer risk information that cannot be obtained from life history of exposure to traditional risk factors.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('epigenetic alterations', 'Var', (62, 84))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (141, 147))
740989	30854468	It has been considered and is now shown that aberrant DNA methylation (methylation burden) has a much larger impact on gastric cancer risk than mutations.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('gastric cancer', 'Disease', (119, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('aberrant DNA methylation', 'Var', (45, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))
740991	30854468	After a median follow-up period of 5.46 years, patients who had the highest methylation burden (highest quartile) had a 3-fold higher risk of developing a metachronous gastric cancer than those who had the lowest burden (Fig.	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gastric cancer', 'Disease', (168, 182))	('gastric cancer', 'Disease', 'MESH:D013274', (168, 182))	('methylation burden', 'Var', (76, 94))
740992	30854468	Determining an individual's future cancer risk by measuring genetic and epigenetic alterations is a promising approach for precision cancer risk diagnosis.	('epigenetic alterations', 'Var', (72, 94))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', (35, 41))	('genetic', 'Var', (60, 67))
740994	30854468	Additionally, the causal involvement of epigenetic alterations is now suggested for various human chronic disorders, such as neurodegenerative and metabolic disorders.	('neurodegenerative', 'Disease', (125, 142))	('chronic disorders', 'Disease', (98, 115))	('metabolic disorders', 'Disease', 'MESH:D008659', (147, 166))	('epigenetic alterations', 'Var', (40, 62))	('neurodegenerative', 'Disease', 'MESH:D019636', (125, 142))	('metabolic disorders', 'Disease', (147, 166))	('human', 'Species', '9606', (92, 97))	('chronic disorders', 'Disease', 'MESH:D002908', (98, 115))
740995	30854468	Therefore, risk diagnosis by measuring epigenetic alterations has the potential to be expanded to various human disorders other than cancer.	('human', 'Species', '9606', (106, 111))	('epigenetic alterations', 'Var', (39, 61))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
741008	30587227	Among them, advanced non-small cell lung cancer (NSCLC) has become a major indication for the use of inhibitors of programmed cell death 1 (PD-1) and its ligand (PD-L1).	('inhibitors', 'Var', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('NSCLC', 'Disease', (49, 54))	('PD-1', 'Gene', (140, 144))	('PD-L1', 'Gene', '29126', (162, 167))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (21, 47))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('PD-1', 'Gene', '5133', (140, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (25, 47))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (21, 47))	('non-small cell lung cancer', 'Disease', (21, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('PD-L1', 'Gene', (162, 167))
741012	30587227	Lower gastrointestinal (GI) tract irAEs, such as diarrhea and colitis, are described in up to one-third of patients treated with inhibitors of cytotoxic lymphocyte associated protein 4 (CTLA-4), with almost 10% of events classified as grade >= 3; however, these irAEs are less frequent and severe with anti-PD1 therapies.	('colitis', 'Disease', (62, 69))	('inhibitors', 'Var', (129, 139))	('Lower gastrointestinal (GI) tract irAEs', 'Disease', 'MESH:D004067', (0, 39))	('CTLA-4', 'Gene', (186, 192))	('diarrhea', 'Phenotype', 'HP:0002014', (49, 57))	('diarrhea', 'Disease', 'MESH:D003967', (49, 57))	('colitis', 'Phenotype', 'HP:0002583', (62, 69))	('diarrhea', 'Disease', (49, 57))	('cytotoxic lymphocyte associated protein 4', 'Gene', '1493', (143, 184))	('CTLA-4', 'Gene', '1493', (186, 192))	('patients', 'Species', '9606', (107, 115))	('cytotoxic lymphocyte associated protein 4', 'Gene', (143, 184))	('colitis', 'Disease', 'MESH:D003092', (62, 69))
741013	30587227	In contrast, upper GI tract involvement has been more frequently reported with PD-1 inhibitors, although it is far less common and still poorly characterized.	('inhibitors', 'Var', (84, 94))	('upper GI tract involvement', 'Disease', (13, 39))	('PD-1', 'Gene', (79, 83))	('PD-1', 'Gene', '5133', (79, 83))	('upper GI tract involvement', 'Disease', 'MESH:D012141', (13, 39))
741072	30587227	Interestingly, upper GI tract irAEs are mostly described with PD-1 inhibitors in contrast to lower GI tract irAEs, which are more prevalent with CTLA-4 inhibitors.	('inhibitors', 'Var', (67, 77))	('CTLA-4', 'Gene', (145, 151))	('GI tract irAEs', 'Disease', 'MESH:D004067', (99, 113))	('PD-1', 'Gene', (62, 66))	('GI tract irAEs', 'Disease', (99, 113))	('GI tract irAEs', 'Disease', 'MESH:D004067', (21, 35))	('PD-1', 'Gene', '5133', (62, 66))	('GI tract irAEs', 'Disease', (21, 35))	('CTLA-4', 'Gene', '1493', (145, 151))
741082	30587227	Several agents have been proposed for the management of steroid-refractory or steroid-dependent irAEs, including antibodies blocking tumor necrosis factor alpha (TNFalpha) or mycophenolate mofetil, but the two molecules have not been approved by the patient's insurance.	('steroid', 'Chemical', 'MESH:D013256', (78, 85))	('antibodies', 'Var', (113, 123))	('blocking', 'NegReg', (124, 132))	('mycophenolate mofetil', 'Chemical', 'MESH:D009173', (175, 196))	('tumor necrosis factor alpha', 'Gene', '7124', (133, 160))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('TNFalpha', 'Gene', (162, 170))	('tumor necrosis factor alpha', 'Gene', (133, 160))	('steroid', 'Chemical', 'MESH:D013256', (56, 63))	('TNFalpha', 'Gene', '7124', (162, 170))	('patient', 'Species', '9606', (250, 257))	('irAEs', 'Disease', (96, 101))
741085	30587227	Very interestingly, the combined blockade of IL-6 and PD-1/PD-L1 axe provides the synergistic effects not only on CD4+ Th1 response but also on the recruitment and function of CD8+ T cells in the tumor and its microenvironment.	('PD-1', 'Gene', '5133', (54, 58))	('CD8', 'Gene', '925', (176, 179))	('blockade', 'Var', (33, 41))	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('function', 'MPA', (164, 172))	('Th1', 'Gene', '51497', (119, 122))	('CD4', 'Gene', (114, 117))	('CD4', 'Gene', '920', (114, 117))	('PD-L1', 'Gene', (59, 64))	('IL-6', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('CD8', 'Gene', (176, 179))	('recruitment', 'CPA', (148, 159))	('IL-6', 'Gene', '3569', (45, 49))	('PD-L1', 'Gene', '29126', (59, 64))	('PD-1', 'Gene', (54, 58))	('Th1', 'Gene', (119, 122))
741086	30587227	Moreover, the lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy.	('interleukin-6', 'Gene', (22, 35))	('interleukin-6', 'Gene', '3569', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('type-1 immunity', 'MPA', (75, 90))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('lack', 'Var', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Disease', (43, 48))	('augments', 'PosReg', (66, 74))	('cancer', 'Disease', (121, 127))	('increases', 'PosReg', (95, 104))
741106	29844307	Here we show that the novel miR-550a-3-5p acts as a tumor suppressor and reverses BRAF inhibitor resistance through the direct targeting of YAP.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BRAF', 'Gene', '673', (82, 86))	('tumor', 'Disease', (52, 57))	('miR-550a-3-5p', 'Var', (28, 41))	('reverses', 'NegReg', (73, 81))	('BRAF', 'Gene', (82, 86))	('YAP', 'Gene', '10413', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('3-5p', 'Chemical', '-', (37, 41))	('YAP', 'Gene', (140, 143))
741107	29844307	Our data showed that the miR-550a-3-5p suppressed cell proliferation, metastasis, and tumor sphere formation through the direct inhibition of YAP and its oncogenic pathway in various cancer cell types.	('metastasis', 'CPA', (70, 80))	('YAP', 'Gene', '10413', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', (183, 189))	('inhibition', 'NegReg', (128, 138))	('3-5p', 'Chemical', '-', (34, 38))	('miR-550a-3-5p', 'Var', (25, 38))	('YAP', 'Gene', (142, 145))	('tumor', 'Disease', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('oncogenic pathway', 'Pathway', (154, 171))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('suppressed', 'NegReg', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cell proliferation', 'CPA', (50, 68))
741108	29844307	In addition, we showed that the YAP signature was associated with poor survival of colon cancer and identified an inverse correlation between miR-550a-3-5p and YAP in colon cancer tissues.	('colon cancer', 'Disease', (83, 95))	('YAP', 'Gene', '10413', (32, 35))	('colon cancer', 'Phenotype', 'HP:0003003', (167, 179))	('miR-550a-3-5p', 'Var', (142, 155))	('3-5p', 'Chemical', '-', (151, 155))	('colon cancer', 'Disease', 'MESH:D015179', (83, 95))	('YAP', 'Gene', '10413', (160, 163))	('colon cancer', 'Disease', 'MESH:D015179', (167, 179))	('colon cancer', 'Phenotype', 'HP:0003003', (83, 95))	('YAP', 'Gene', (32, 35))	('YAP', 'Gene', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('colon cancer', 'Disease', (167, 179))	('inverse', 'NegReg', (114, 121))	('associated', 'Reg', (50, 60))	('poor', 'NegReg', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
741109	29844307	Furthermore, high levels of miR-550a-3-5p were associated with a good prognosis of esophageal cancer, which was suggestive of the clinical relevance of miR-550a-3-5p-mediated YAP regulation in multiple cancers.	('YAP', 'Gene', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('3-5p', 'Chemical', '-', (161, 165))	('esophageal cancer', 'Disease', (83, 100))	('multiple cancers', 'Disease', (193, 209))	('miR-550a-3-5p', 'Var', (28, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('miR-550a-3-5p-mediated', 'Var', (152, 174))	('multiple cancers', 'Disease', 'MESH:D009369', (193, 209))	('YAP', 'Gene', '10413', (175, 178))	('3-5p', 'Chemical', '-', (37, 41))
741110	29844307	Importantly, we demonstrated that miR-550a-3-5p treatment sensitized vemurafenib-resistant colon and melanoma cells through YAP inhibition with reduced AKT activity.	('colon', 'Disease', (91, 96))	('reduced', 'NegReg', (144, 151))	('miR-550a-3-5p', 'Var', (34, 47))	('3-5p', 'Chemical', '-', (43, 47))	('inhibition', 'NegReg', (128, 138))	('AKT', 'Gene', '207', (152, 155))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('vemurafenib', 'Chemical', 'MESH:D000077484', (69, 80))	('activity', 'MPA', (156, 164))	('YAP', 'Gene', (124, 127))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('AKT', 'Gene', (152, 155))	('YAP', 'Gene', '10413', (124, 127))
741111	29844307	Moreover, the tumor-suppressive activity of miR-550a-3-5p and its sensitization effect for vemurafenib resistance were also observed in tumor xenograft models.	('3-5p', 'Chemical', '-', (53, 57))	('miR-550a-3-5p', 'Var', (44, 57))	('tumor', 'Disease', (14, 19))	('vemurafenib', 'Chemical', 'MESH:D000077484', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('vemurafenib', 'MPA', (91, 102))	('tumor', 'Disease', (136, 141))
741112	29844307	Collectively, our data suggest that miR-550a-3-5p acts as a tumor suppressor through the targeting of oncogenic YAP and may be a new therapeutic tool for YAP-mediated BRAF inhibitor resistance in BRAF-mutant cancer cells.	('cancer', 'Disease', (208, 214))	('3-5p', 'Chemical', '-', (45, 49))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('BRAF', 'Gene', '673', (196, 200))	('YAP', 'Gene', '10413', (112, 115))	('YAP', 'Gene', '10413', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('BRAF', 'Gene', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('YAP', 'Gene', (154, 157))	('tumor', 'Disease', (60, 65))	('miR-550a-3-5p', 'Var', (36, 49))	('YAP', 'Gene', (112, 115))
741115	29844307	The phosphorylation of YAP leads to its ubiquitination, degradation, and cytoplasmic retention, whereas de-phosphorylated YAP, by the inactivation of the Hippo pathway, is translocated into the nucleus and activates various target genes, such as connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61).	('inactivation', 'Var', (134, 146))	('degradation', 'MPA', (56, 67))	('CYR61', 'Gene', (326, 331))	('YAP', 'Gene', '10413', (122, 125))	('YAP', 'Gene', (23, 26))	('cysteine-rich angiogenic inducer 61', 'Gene', '3491', (289, 324))	('phosphorylation', 'Var', (4, 19))	('activates', 'PosReg', (206, 215))	('CTGF', 'Gene', '1490', (279, 283))	('cysteine-rich angiogenic inducer 61', 'Gene', (289, 324))	('Hippo pathway', 'Pathway', (154, 167))	('cytoplasmic', 'MPA', (73, 84))	('ubiquitination', 'MPA', (40, 54))	('CTGF', 'Gene', (279, 283))	('YAP', 'Gene', '10413', (23, 26))	('connective tissue growth factor', 'Gene', '1490', (246, 277))	('CYR61', 'Gene', '3491', (326, 331))	('connective tissue growth factor', 'Gene', (246, 277))	('YAP', 'Gene', (122, 125))
741123	29844307	Dysregulated miRNAs play critical roles in tumor progression by acting as an oncogene or tumor suppressor in human cancers.	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('miRNAs', 'Protein', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Dysregulated', 'Var', (0, 12))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
741128	29844307	In the present study, we showed that novel miR-550a-3-5p directly suppressed oncogenic YAP and exerted tumor-suppressive activity in various cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', (103, 108))	('YAP', 'Gene', (87, 90))	('3-5p', 'Chemical', '-', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('suppressed', 'NegReg', (66, 76))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('miR-550a-3-5p', 'Var', (43, 56))	('YAP', 'Gene', '10413', (87, 90))	('cancer', 'Disease', (141, 147))
741129	29844307	In addition, we demonstrated that miR-550a-3-5p treatment could sensitize BRAF inhibitor-resistant colon cancer and melanoma cells.	('miR-550a-3-5p', 'Var', (34, 47))	('3-5p', 'Chemical', '-', (43, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('colon cancer', 'Disease', (99, 111))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('sensitize', 'Reg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
741130	29844307	Therefore, our data provided evidence that miR-550a-3-5p acts as a tumor suppressor via YAP inhibition in multiple cancer cells and a novel therapeutic tool for BRAF inhibitor resistance in BRAF-mutant colon and melanoma cells.	('cancer', 'Disease', (115, 121))	('BRAF', 'Gene', (190, 194))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('YAP', 'Gene', '10413', (88, 91))	('inhibition', 'NegReg', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('BRAF', 'Gene', (161, 165))	('3-5p', 'Chemical', '-', (52, 56))	('BRAF', 'Gene', '673', (161, 165))	('YAP', 'Gene', (88, 91))	('melanoma', 'Disease', (212, 220))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('tumor', 'Disease', (67, 72))	('miR-550a-3-5p', 'Var', (43, 56))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('BRAF', 'Gene', '673', (190, 194))
741131	29844307	As miR-550a-3-5p, a novel miRNA, was screened as one of the possible growth-inhibitory miRNAs in HCT116 colon cancer cells, the role of miR-550a-3-5p was examined in multiple human cancer cell lines to determine any possible tumor-suppressive activity.	('human', 'Species', '9606', (175, 180))	('colon cancer', 'Disease', (104, 116))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('3-5p', 'Chemical', '-', (12, 16))	('miR-550a-3-5p', 'Var', (3, 16))	('tumor', 'Disease', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('colon cancer', 'Phenotype', 'HP:0003003', (104, 116))	('colon cancer', 'Disease', 'MESH:D015179', (104, 116))	('cancer', 'Disease', (181, 187))	('3-5p', 'Chemical', '-', (145, 149))	('HCT116', 'CellLine', 'CVCL:0291', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
741132	29844307	We found that miR-550a-3-5p overexpression significantly reduced cell proliferation (Fig.	('3-5p', 'Chemical', '-', (23, 27))	('miR-550a-3-5p', 'Var', (14, 27))	('cell proliferation', 'CPA', (65, 83))	('overexpression', 'PosReg', (28, 42))	('reduced', 'NegReg', (57, 64))
741134	29844307	In addition, miR-550a-3-5p overexpression increased levels of cleaved-PARP and annexin V, markers of apoptosis (Fig.	('increased', 'PosReg', (42, 51))	('annexin V', 'Gene', '308', (79, 88))	('annexin V', 'Gene', (79, 88))	('miR-550a-3-5p', 'Var', (13, 26))	('PARP', 'Gene', '1302', (70, 74))	('PARP', 'Gene', (70, 74))	('3-5p', 'Chemical', '-', (22, 26))
741136	29844307	Moreover, we found that miR-550a-3-5p overexpression reduced tumor growth in the HCT116 xenograft model (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (81, 87))	('miR-550a-3-5p', 'Var', (24, 37))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('reduced', 'NegReg', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('3-5p', 'Chemical', '-', (33, 37))	('tumor', 'Disease', (61, 66))
741137	29844307	1g), which suggested that miR-550a-3-5p inhibited cancer cell proliferation.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('inhibited', 'NegReg', (40, 49))	('3-5p', 'Chemical', '-', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('miR-550a-3-5p', 'Var', (26, 39))
741138	29844307	Next, we further examined the role of miR-550a-3-5p in tumor migration, invasion, and tumor sphere formation.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR-550a-3-5p', 'Var', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (86, 91))	('examined', 'Reg', (17, 25))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('3-5p', 'Chemical', '-', (47, 51))
741139	29844307	Interestingly, we found that miR-550a-3-5p overexpression also reduced migration (Fig.	('miR-550a-3-5p', 'Var', (29, 42))	('reduced', 'NegReg', (63, 70))	('3-5p', 'Chemical', '-', (38, 42))	('migration', 'CPA', (71, 80))
741141	29844307	In addition, miR-550a-3-5p overexpression inhibited tumor sphere formation in H460 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('3-5p', 'Chemical', '-', (22, 26))	('miR-550a-3-5p', 'Var', (13, 26))	('tumor', 'Disease', (52, 57))	('inhibited', 'NegReg', (42, 51))	('overexpression', 'PosReg', (27, 41))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('H460', 'CellLine', 'CVCL:0459', (78, 82))
741144	29844307	Therefore, our data indicated that the novel miR-550a-3-5p has an antitumor activity in various cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('3-5p', 'Chemical', '-', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('miR-550a-3-5p', 'Var', (45, 58))	('tumor', 'Disease', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
741146	29844307	Among the putative targets and genes downregulated by miR-550a-3-5p, four candidate genes (YAP, MBN1, DCAF7, and ZAK) were commonly regulated (Fig.	('downregulated', 'NegReg', (37, 50))	('ZAK', 'Gene', '51776', (113, 116))	('DCAF7', 'Gene', '10238', (102, 107))	('DCAF7', 'Gene', (102, 107))	('regulated', 'Reg', (132, 141))	('3-5p', 'Chemical', '-', (63, 67))	('YAP', 'Gene', '10413', (91, 94))	('ZAK', 'Gene', (113, 116))	('YAP', 'Gene', (91, 94))	('miR-550a-3-5p', 'Var', (54, 67))	('MBN1', 'Gene', (96, 100))
741149	29844307	To confirm whether YAP was a direct target of miR-550a-3-5p, wild-type (YAP 3' UTR-WT) and mutant (YAP 3' UTR-MUT) 3' UTR regions of the YAP gene were separately cloned into the pGL3 vector downstream of the luciferase-coding region (Fig.	('YAP', 'Gene', '10413', (72, 75))	('YAP', 'Gene', (99, 102))	('YAP', 'Gene', '10413', (99, 102))	('3-5p', 'Chemical', '-', (55, 59))	('YAP', 'Gene', '10413', (19, 22))	('pGL3', 'Gene', '6391', (178, 182))	('YAP', 'Gene', (72, 75))	('YAP', 'Gene', '10413', (137, 140))	('YAP', 'Gene', (19, 22))	('mutant', 'Var', (91, 97))	('YAP', 'Gene', (137, 140))	('pGL3', 'Gene', (178, 182))
741150	29844307	The luciferase reporter assay indicated that miR-550a-3-5p reduced the luciferase activity of the WT 3' UTR reporter in HCT116 cells, but had no effect on the MUT 3' UTR reporter (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (120, 126))	('reduced', 'NegReg', (59, 66))	('luciferase', 'Enzyme', (71, 81))	('miR-550a-3-5p', 'Var', (45, 58))	('activity', 'MPA', (82, 90))	('3-5p', 'Chemical', '-', (54, 58))
741151	29844307	3c); this suggested that YAP was directly regulated by miR-550a-3-5p.	('3-5p', 'Chemical', '-', (64, 68))	('YAP', 'Gene', (25, 28))	('miR-550a-3-5p', 'Var', (55, 68))	('YAP', 'Gene', '10413', (25, 28))	('regulated', 'Reg', (42, 51))
741152	29844307	Next, we further examined whether miR-550a-3-5p downregulated endogenous YAP expression and found that miR-550a-3-5p overexpression was able to downregulate YAP mRNA and protein levels after a relatively short time (24 h) in HCT116 cells (Fig.	('3-5p', 'Chemical', '-', (112, 116))	('expression', 'MPA', (77, 87))	('3-5p', 'Chemical', '-', (43, 47))	('HCT116', 'CellLine', 'CVCL:0291', (225, 231))	('YAP', 'Gene', '10413', (73, 76))	('YAP', 'Gene', (73, 76))	('downregulated', 'NegReg', (48, 61))	('miR-550a-3-5p', 'Var', (103, 116))	('YAP', 'Gene', '10413', (157, 160))	('downregulate', 'NegReg', (144, 156))	('YAP', 'Gene', (157, 160))
741154	29844307	In addition, antago-miR-550a-3-5p treatment rescued the miR-550a-3-5p-induced cellular phenotype, such as decreased YAP expression and reduced cell proliferation (Fig.	('decreased', 'NegReg', (106, 115))	('YAP', 'Gene', (116, 119))	('cell proliferation', 'CPA', (143, 161))	('miR-550a-3-5p-induced', 'Var', (56, 77))	('3-5p', 'Chemical', '-', (65, 69))	('YAP', 'Gene', '10413', (116, 119))	('reduced', 'NegReg', (135, 142))	('3-5p', 'Chemical', '-', (29, 33))
741155	29844307	Furthermore, the cytotoxic effect of miR-550a-3-5p was similar to the effect of YAP siRNA in various cancer cells (Fig.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('YAP', 'Gene', '10413', (80, 83))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('YAP', 'Gene', (80, 83))	('3-5p', 'Chemical', '-', (46, 50))	('miR-550a-3-5p', 'Var', (37, 50))
741157	29844307	Notably, miR-550a-3-5p was able to efficiently downregulate YAP after a relatively short time (24 h) in comparison with other miRNAs in HCT116 and RKO cells (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (136, 142))	('downregulate', 'NegReg', (47, 59))	('RKO', 'CellLine', 'CVCL:0504', (147, 150))	('YAP', 'Gene', '10413', (60, 63))	('miR-550a-3-5p', 'Var', (9, 22))	('3-5p', 'Chemical', '-', (18, 22))	('YAP', 'Gene', (60, 63))
741158	29844307	3i), which indicated the supremacy of miR-550a-3-5p-mediated YAP targeting.	('3-5p', 'Chemical', '-', (47, 51))	('YAP', 'Gene', (61, 64))	('YAP', 'Gene', '10413', (61, 64))	('miR-550a-3-5p-mediated', 'Var', (38, 60))
741159	29844307	Collectively, our data suggested that miR-550a-3-5p exerted tumor-suppressive activity through YAP inhibition in multiple cancer cell lines.	('miR-550a-3-5p', 'Var', (38, 51))	('YAP', 'Gene', '10413', (95, 98))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('inhibition', 'NegReg', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('YAP', 'Gene', (95, 98))	('tumor', 'Disease', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('3-5p', 'Chemical', '-', (47, 51))
741160	29844307	To further understand the role of miR-550a-3-5p in the regulation of the oncogenic YAP pathway, we next examined whether miR-550a-3-5p modulated the YAP pathway.	('YAP', 'Gene', '10413', (83, 86))	('3-5p', 'Chemical', '-', (43, 47))	('modulated', 'Reg', (135, 144))	('3-5p', 'Chemical', '-', (130, 134))	('YAP', 'Gene', (149, 152))	('YAP', 'Gene', (83, 86))	('miR-550a-3-5p', 'Var', (121, 134))	('YAP', 'Gene', '10413', (149, 152))
741162	29844307	The reporter activity showed that miR-550a-3-5p overexpression suppressed YAP/TAZ transcriptional activity in HCT119 cells (Fig.	('TAZ', 'Gene', '6901', (78, 81))	('miR-550a-3-5p', 'Var', (34, 47))	('3-5p', 'Chemical', '-', (43, 47))	('TAZ', 'Gene', (78, 81))	('YAP', 'Gene', '10413', (74, 77))	('suppressed', 'NegReg', (63, 73))	('HCT119', 'CellLine', 'CVCL:V750', (110, 116))	('YAP', 'Gene', (74, 77))
741163	29844307	In addition, miR-550a-3-5p overexpression decreased the mRNA and protein levels of CTGF and CYR61, direct target genes of YAP, in HCT116 and HEp2 cells (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (130, 136))	('YAP', 'Gene', (122, 125))	('3-5p', 'Chemical', '-', (22, 26))	('miR-550a-3-5p', 'Var', (13, 26))	('decreased', 'NegReg', (42, 51))	('CTGF', 'Gene', (83, 87))	('CYR61', 'Gene', (92, 97))	('CYR61', 'Gene', '3491', (92, 97))	('YAP', 'Gene', '10413', (122, 125))	('HEp2', 'CellLine', 'CVCL:1906', (141, 145))	('CTGF', 'Gene', '1490', (83, 87))
741164	29844307	4b, c), which indicated that miR-550a-3-5p inhibited the YAP pathway.	('inhibited', 'NegReg', (43, 52))	('3-5p', 'Chemical', '-', (38, 42))	('miR-550a-3-5p', 'Var', (29, 42))	('YAP', 'Gene', '10413', (57, 60))	('YAP', 'Gene', (57, 60))
741165	29844307	Next, to check whether miR-550a-3-5p modulated YAP/TAZ nuclear translocation activity in addition to the regulation of YAP expression, immunofluorescence staining for YAP was performed in high density culture and low density culture of HEp-2 cells treated with control miRNA or miR-550a-3-5p.	('3-5p', 'Chemical', '-', (287, 291))	('HEp-2', 'CellLine', 'CVCL:1906', (236, 241))	('YAP', 'Gene', (167, 170))	('miR-550a-3-5p', 'Var', (278, 291))	('modulated', 'Reg', (37, 46))	('YAP', 'Gene', '10413', (119, 122))	('TAZ', 'Gene', '6901', (51, 54))	('YAP', 'Gene', '10413', (47, 50))	('miR-550a-3-5p', 'Var', (23, 36))	('YAP', 'Gene', '10413', (167, 170))	('TAZ', 'Gene', (51, 54))	('3-5p', 'Chemical', '-', (32, 36))	('YAP', 'Gene', (119, 122))	('YAP', 'Gene', (47, 50))
741167	29844307	miR-550a-3-5p overexpression completely suppressed cytoplasmic YAP, but not nuclear YAP (Fig.	('miR-550a-3-5p', 'Var', (0, 13))	('suppressed', 'NegReg', (40, 50))	('YAP', 'Gene', (63, 66))	('YAP', 'Gene', '10413', (84, 87))	('cytoplasmic', 'MPA', (51, 62))	('YAP', 'Gene', (84, 87))	('YAP', 'Gene', '10413', (63, 66))	('3-5p', 'Chemical', '-', (9, 13))
741168	29844307	4d, miR-550a-3-5p-treated panel), which indicated that miR-550a-3-5p suppressed cellular YAP.	('3-5p', 'Chemical', '-', (64, 68))	('3-5p', 'Chemical', '-', (13, 17))	('YAP', 'Gene', '10413', (89, 92))	('suppressed', 'NegReg', (69, 79))	('miR-550a-3-5p', 'Var', (55, 68))	('YAP', 'Gene', (89, 92))
741170	29844307	The GSEA using MSigDB (C6 oncogenic signature) revealed a decrease of the YAP signature in miR-550a-3-5p-treated HCT116 cells (nominal P-value < 0.05) (Fig.	('miR-550a-3-5p-treated', 'Var', (91, 112))	('HCT116', 'CellLine', 'CVCL:0291', (113, 119))	('YAP', 'Gene', '10413', (74, 77))	('3-5p', 'Chemical', '-', (100, 104))	('decrease', 'NegReg', (58, 66))	('YAP', 'Gene', (74, 77))	('GSEA', 'Chemical', '-', (4, 8))
741171	29844307	Therefore, our data indicated that miR-550a-3-5p inhibited the oncogenic YAP pathway through the suppression of cellular YAP.	('YAP', 'Gene', '10413', (73, 76))	('YAP', 'Gene', (73, 76))	('suppression', 'NegReg', (97, 108))	('YAP', 'Gene', (121, 124))	('miR-550a-3-5p', 'Var', (35, 48))	('inhibited', 'NegReg', (49, 58))	('YAP', 'Gene', '10413', (121, 124))	('3-5p', 'Chemical', '-', (44, 48))
741172	29844307	To address whether the YAP pathway was associated with miR-550a-3-5p in tumor patients, we first evaluated the clinical significance of the YAP pathway by using a colon cancer public database and tumor specimens.	('3-5p', 'Chemical', '-', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (72, 77))	('YAP', 'Gene', '10413', (23, 26))	('patients', 'Species', '9606', (78, 86))	('colon cancer public', 'Disease', 'MESH:D015179', (163, 182))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('miR-550a-3-5p', 'Var', (55, 68))	('associated', 'Reg', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('YAP', 'Gene', '10413', (140, 143))	('YAP', 'Gene', (23, 26))	('colon cancer', 'Phenotype', 'HP:0003003', (163, 175))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('YAP', 'Gene', (140, 143))	('colon cancer public', 'Disease', (163, 182))
741176	29844307	With regard to the prognostic value of miR-550a-3-5p, we were able to determine that the high levels of miR-550a-3-5p were associated with good prognosis in esophageal cancer (Fig.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('esophageal cancer', 'Disease', (157, 174))	('3-5p', 'Chemical', '-', (48, 52))	('miR-550a-3-5p', 'Var', (104, 117))	('3-5p', 'Chemical', '-', (113, 117))
741177	29844307	5b) and supported the tumor suppressive role of miR-550a-3-5p in multiple cancers.	('multiple cancers', 'Disease', (65, 81))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('miR-550a-3-5p', 'Var', (48, 61))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('multiple cancers', 'Disease', 'MESH:D009369', (65, 81))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('3-5p', 'Chemical', '-', (57, 61))
741178	29844307	Next, we further examined the correlation between YAP and miR-550a-3-5p expression in 47 colon cancer specimens and their paired adjacent noncancerous specimens.	('3-5p', 'Chemical', '-', (67, 71))	('miR-550a-3-5p', 'Var', (58, 71))	('YAP', 'Gene', '10413', (50, 53))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('examined', 'Reg', (17, 25))	('cancer', 'Disease', (95, 101))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('YAP', 'Gene', (50, 53))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('colon cancer', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (141, 147))
741179	29844307	YAP mRNA levels were upregulated in colon cancer tissues in comparison with their respective adjacent noncancerous specimens, whereas miR-550a-3-5p levels were downregulated (Fig.	('3-5p', 'Chemical', '-', (143, 147))	('YAP', 'Gene', (0, 3))	('miR-550a-3-5p', 'Var', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colon cancer', 'Disease', 'MESH:D015179', (36, 48))	('cancer', 'Disease', (105, 111))	('colon cancer', 'Disease', (36, 48))	('upregulated', 'PosReg', (21, 32))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('YAP', 'Gene', '10413', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('downregulated', 'NegReg', (160, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (36, 48))
741184	29844307	As it has been reported that many tumor suppressive miRNAs are epigenetically inactivated in tumor tissues and that YAP regulated miRNA biogenesis in a cell density-dependent manner, we further examined whether the decreased miR-550a-3-5p in cancer cells was controlled by epigenetic modification or density-dependent regulation.	('YAP', 'Gene', (116, 119))	('cancer', 'Disease', (242, 248))	('tumor', 'Disease', (34, 39))	('miRNA biogenesis', 'MPA', (130, 146))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('3-5p', 'Chemical', '-', (234, 238))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('YAP', 'Gene', '10413', (116, 119))	('miR-550a-3-5p', 'Var', (225, 238))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('decreased', 'NegReg', (215, 224))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
741185	29844307	We found that treatment with 5-aza-2-deoxycytidine, a demethylating agent, did not modulate the expression of miR-550a-3-5p in HCT116 and HEp-2 cells (Supplementary Fig.	('HEp-2', 'CellLine', 'CVCL:1906', (138, 143))	('5-aza-2-deoxycytidine', 'Chemical', 'MESH:D000077209', (29, 50))	('HCT116', 'CellLine', 'CVCL:0291', (127, 133))	('miR-550a-3-5p', 'Var', (110, 123))	('modulate', 'Reg', (83, 91))	('3-5p', 'Chemical', '-', (119, 123))
741186	29844307	Instead, miR-550a-3-5p was increased in the high-density HEp-2 culture, whereas YAP was decreased in the same conditions (Fig.	('increased', 'PosReg', (27, 36))	('YAP', 'Gene', '10413', (80, 83))	('miR-550a-3-5p', 'Var', (9, 22))	('3-5p', 'Chemical', '-', (18, 22))	('YAP', 'Gene', (80, 83))	('HEp-2', 'CellLine', 'CVCL:1906', (57, 62))
741187	29844307	5f), which suggested that the decrease of miR-550a-3-5p in cancer cells could be regulated by a density-dependent manner.	('3-5p', 'Chemical', '-', (51, 55))	('miR-550a-3-5p', 'Var', (42, 55))	('decrease', 'NegReg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
741194	29844307	Notably, we found that miR-550a-3-5p treatment sensitized the vemurafenib resistance of RKO cells through the reduced phosphorylation of AKT, but did not modulate phosphorylated ERK in RKO cells (Fig.	('RKO', 'CellLine', 'CVCL:0504', (88, 91))	('sensitized', 'NegReg', (47, 57))	('reduced', 'NegReg', (110, 117))	('vemurafenib', 'Chemical', 'MESH:D000077484', (62, 73))	('AKT', 'Gene', '207', (137, 140))	('ERK', 'Gene', '5594', (178, 181))	('vemurafenib resistance', 'MPA', (62, 84))	('phosphorylation', 'MPA', (118, 133))	('RKO', 'CellLine', 'CVCL:0504', (185, 188))	('3-5p', 'Chemical', '-', (32, 36))	('miR-550a-3-5p', 'Var', (23, 36))	('ERK', 'Gene', (178, 181))	('AKT', 'Gene', (137, 140))
741196	29844307	As BRAF mutation is commonly observed in patients with melanoma and its resistance mechanism is associated with YAP activation, vemurafenib-resistant WM3248 melanoma cells, which are cells with acquired resistance, were utilized to further examine the role of miR-550a-3-5p in BRAF inhibitor resistance.	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('WM3248', 'CellLine', 'CVCL:6798', (150, 156))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('BRAF', 'Gene', '673', (277, 281))	('BRAF', 'Gene', (277, 281))	('YAP', 'Gene', '10413', (112, 115))	('3-5p', 'Chemical', '-', (269, 273))	('vemurafenib', 'Chemical', 'MESH:D000077484', (128, 139))	('BRAF', 'Gene', '673', (3, 7))	('patients', 'Species', '9606', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('mutation', 'Var', (8, 16))	('BRAF', 'Gene', (3, 7))	('melanoma', 'Disease', (55, 63))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('YAP', 'Gene', (112, 115))
741198	29844307	Importantly, we found that miR-550a-3-5p treatment increased vemurafenib sensitivity through the reduced phosphorylation of AKT, but marginally modulated phosphorylated ERK in the resistant WM3248 cells (Fig.	('phosphorylation', 'MPA', (105, 120))	('ERK', 'Gene', '5594', (169, 172))	('ERK', 'Gene', (169, 172))	('increased', 'PosReg', (51, 60))	('3-5p', 'Chemical', '-', (36, 40))	('AKT', 'Gene', (124, 127))	('miR-550a-3-5p', 'Var', (27, 40))	('reduced', 'NegReg', (97, 104))	('vemurafenib sensitivity', 'MPA', (61, 84))	('vemurafenib', 'Chemical', 'MESH:D000077484', (61, 72))	('modulated', 'Reg', (144, 153))	('WM3248', 'CellLine', 'CVCL:6798', (190, 196))	('AKT', 'Gene', '207', (124, 127))
741201	29844307	Moreover, we further validated the inhibitory effect of miR-550a-3-5p on BRAF inhibitor resistance by using an RKO xenograft model.	('BRAF', 'Gene', '673', (73, 77))	('3-5p', 'Chemical', '-', (65, 69))	('miR-550a-3-5p', 'Var', (56, 69))	('BRAF', 'Gene', (73, 77))	('RKO', 'CellLine', 'CVCL:0504', (111, 114))
741203	29844307	6g), whereas the combination treatment of miR-550a-3-5p and vemurafenib sensitized the vemurafenib resistance of the RKO xenograft model through YAP inhibition (Fig.	('vemurafenib', 'Chemical', 'MESH:D000077484', (60, 71))	('3-5p', 'Chemical', '-', (51, 55))	('miR-550a-3-5p', 'Var', (42, 55))	('YAP', 'Gene', (145, 148))	('vemurafenib resistance', 'MPA', (87, 109))	('vemurafenib', 'Chemical', 'MESH:D000077484', (87, 98))	('RKO', 'CellLine', 'CVCL:0504', (117, 120))	('sensitized', 'PosReg', (72, 82))	('YAP', 'Gene', '10413', (145, 148))
741205	29844307	Our data showed that the novel miR-550a-3-5p suppressed cell proliferation, metastasis, and tumor sphere formation through the direct inhibition of oncogenic YAP in various cancer cell types.	('metastasis', 'CPA', (76, 86))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('miR-550a-3-5p', 'Var', (31, 44))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('suppressed', 'NegReg', (45, 55))	('inhibition', 'NegReg', (134, 144))	('cell proliferation', 'CPA', (56, 74))	('YAP', 'Gene', '10413', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', (92, 97))	('YAP', 'Gene', (158, 161))	('3-5p', 'Chemical', '-', (40, 44))
741206	29844307	In addition, we demonstrated the clinical relevance of miR-550a-3-5p-mediated YAP regulation in multiple cancers, including an inverse correlation between miR-550a-3-5p and YAP signature in colon cancers and its prognostic value in esophageal cancer.	('multiple cancers', 'Disease', 'MESH:D009369', (96, 112))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('3-5p', 'Chemical', '-', (164, 168))	('miR-550a-3-5p-mediated', 'Var', (55, 77))	('YAP', 'Gene', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('YAP', 'Gene', (78, 81))	('colon cancers', 'Phenotype', 'HP:0003003', (190, 203))	('multiple cancers', 'Disease', (96, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (232, 249))	('3-5p', 'Chemical', '-', (64, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (190, 202))	('YAP', 'Gene', '10413', (173, 176))	('YAP', 'Gene', '10413', (78, 81))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('colon cancers', 'Disease', 'MESH:D015179', (190, 203))	('esophageal cancer', 'Disease', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('colon cancers', 'Disease', (190, 203))	('inverse', 'NegReg', (127, 134))	('miR-550a-3-5p', 'Var', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
741207	29844307	Importantly, we found that miR-550a-3-5p treatment sensitized vemurafenib resistance through YAP inhibition with reduced AKT activity in vemurafenib-resistant colon cancer and melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('inhibition', 'NegReg', (97, 107))	('sensitized', 'Reg', (51, 61))	('miR-550a-3-5p', 'Var', (27, 40))	('colon cancer', 'Phenotype', 'HP:0003003', (159, 171))	('reduced', 'NegReg', (113, 120))	('AKT', 'Gene', '207', (121, 124))	('vemurafenib', 'Chemical', 'MESH:D000077484', (137, 148))	('YAP', 'Gene', (93, 96))	('colon cancer', 'Disease', 'MESH:D015179', (159, 171))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('vemurafenib', 'Chemical', 'MESH:D000077484', (62, 73))	('activity', 'MPA', (125, 133))	('YAP', 'Gene', '10413', (93, 96))	('colon cancer', 'Disease', (159, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('AKT', 'Gene', (121, 124))	('3-5p', 'Chemical', '-', (36, 40))	('vemurafenib', 'Gene', (62, 73))
741208	29844307	Therefore, our data provide the first evidence for the potential role of the novel miR-550a-3-5p in YAP-mediated tumorigenesis and BRAF inhibitor resistance.	('3-5p', 'Chemical', '-', (92, 96))	('tumor', 'Disease', (113, 118))	('YAP', 'Gene', (100, 103))	('BRAF', 'Gene', (131, 135))	('miR-550a-3-5p', 'Var', (83, 96))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('YAP', 'Gene', '10413', (100, 103))	('BRAF', 'Gene', '673', (131, 135))
741210	29844307	Our results revealed that the novel miR-550a-3-5p exerted its tumor suppressive role through the targeting of YAP in various cancer cells.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('3-5p', 'Chemical', '-', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (62, 67))	('YAP', 'Gene', (110, 113))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('miR-550a-3-5p', 'Var', (36, 49))	('YAP', 'Gene', '10413', (110, 113))
741211	29844307	We showed that miR-550a-3-5p overexpression inhibited various oncogenic properties, including cell proliferation, anti-apoptosis, migration, invasion, and cancer stemness, which was consistent with the effects of YAP inhibition in various cancer cells (Figs.	('invasion', 'CPA', (141, 149))	('miR-550a-3-5p overexpression', 'Var', (15, 43))	('cancer stemness', 'Disease', (155, 170))	('oncogenic properties', 'CPA', (62, 82))	('inhibited', 'NegReg', (44, 53))	('3-5p', 'Chemical', '-', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('anti-apoptosis', 'CPA', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('YAP', 'Gene', '10413', (213, 216))	('cancer', 'Disease', (239, 245))	('cancer stemness', 'Disease', 'MESH:D009369', (155, 170))	('migration', 'CPA', (130, 139))	('cell proliferation', 'CPA', (94, 112))	('YAP', 'Gene', (213, 216))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
741215	29844307	Several pieces of evidences from our data, including luciferase activity assay, western blot analysis, YAP reporter assay, target gene expression analysis, and GSEA, clearly indicated that YAP was a bona fide target of miR-550a-3-5p.	('YAP', 'Gene', '10413', (103, 106))	('luciferase', 'Enzyme', (53, 63))	('miR-550a-3-5p', 'Var', (219, 232))	('YAP', 'Gene', (189, 192))	('YAP', 'Gene', (103, 106))	('GSEA', 'Chemical', '-', (160, 164))	('activity', 'MPA', (64, 72))	('YAP', 'Gene', '10413', (189, 192))	('3-5p', 'Chemical', '-', (228, 232))
741217	29844307	However, we showed that miR-550a-3-5p downregulated YAP in various types of cancer cells, including colon, head and neck, lung, and breast cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('miR-550a-3-5p', 'Var', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('YAP', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('downregulated', 'NegReg', (38, 51))	('YAP', 'Gene', '10413', (52, 55))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('lung', 'Disease', (122, 126))	('colon', 'Disease', (100, 105))	('3-5p', 'Chemical', '-', (33, 37))	('breast cancer', 'Disease', (132, 145))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('cancer', 'Disease', (139, 145))
741218	29844307	In addition, miR-550a-3-5p was able to inhibit YAP in a relatively short time (24 h) compared with other miRNAs (Fig.	('miR-550a-3-5p', 'Var', (13, 26))	('inhibit', 'NegReg', (39, 46))	('YAP', 'Gene', '10413', (47, 50))	('YAP', 'Gene', (47, 50))	('3-5p', 'Chemical', '-', (22, 26))
741219	29844307	3i), which supported the miR-550a-3-5p targeting of YAP and exerts its tumor-suppressive role in multiple cancers.	('multiple cancers', 'Disease', (97, 113))	('3-5p', 'Chemical', '-', (34, 38))	('miR-550a-3-5p', 'Var', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('YAP', 'Gene', (52, 55))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('multiple cancers', 'Disease', 'MESH:D009369', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('YAP', 'Gene', '10413', (52, 55))
741224	29844307	Furthermore, we showed that decreased miR-550a-3-5p was not mediated by hypermethylation in HCT116 and HEp-2 cells.	('HCT116', 'CellLine', 'CVCL:0291', (92, 98))	('HEp-2', 'CellLine', 'CVCL:1906', (103, 108))	('decreased', 'NegReg', (28, 37))	('miR-550a-3-5p', 'Var', (38, 51))	('3-5p', 'Chemical', '-', (47, 51))
741225	29844307	Therefore, it was possible that the reduction of miR-550a-3-5p might be associated with YAP overexpression as a positive feedback mechanism in multiple cancers.	('multiple cancers', 'Disease', 'MESH:D009369', (143, 159))	('YAP', 'Gene', '10413', (88, 91))	('miR-550a-3-5p', 'Var', (49, 62))	('reduction', 'NegReg', (36, 45))	('3-5p', 'Chemical', '-', (58, 62))	('YAP', 'Gene', (88, 91))	('multiple cancers', 'Disease', (143, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
741226	29844307	Constitutive activation mutations in BRAF promote malignant tumorigenesis through the activation of downstream signaling via MEK and ERK.	('activation', 'PosReg', (86, 96))	('BRAF', 'Gene', '673', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('BRAF', 'Gene', (37, 41))	('ERK', 'Gene', '5594', (133, 136))	('downstream signaling', 'Pathway', (100, 120))	('activation', 'PosReg', (13, 23))	('promote', 'PosReg', (42, 49))	('ERK', 'Gene', (133, 136))	('MEK', 'Gene', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MEK', 'Gene', '5609', (125, 128))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', (60, 65))
741228	29844307	Although selective BRAF mutant inhibitors have been developed, such as vemurafenib and dabrafenib, acquired or intrinsic drug resistance is a major problem for the treatment of BRAF-mutant cancer patients.	('mutant', 'Var', (24, 30))	('BRAF', 'Gene', '673', (19, 23))	('dabrafenib', 'Chemical', 'MESH:C561627', (87, 97))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('BRAF', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('drug resistance', 'Phenotype', 'HP:0020174', (121, 136))	('patients', 'Species', '9606', (196, 204))	('vemurafenib', 'Chemical', 'MESH:D000077484', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
741230	29844307	Notably, we demonstrated that miR-550a-3-5p treatment sensitized BRAF inhibitor-resistant colon and melanoma cancer cells through YAP inhibition with reduced AKT activity, which suggested that miR-550a-3-5p treatment could be useful for the treatment of acquired and intrinsic vemurafenib resistance.	('3-5p', 'Chemical', '-', (39, 43))	('YAP', 'Gene', (130, 133))	('miR-550a-3-5p', 'Var', (30, 43))	('vemurafenib', 'Chemical', 'MESH:D000077484', (277, 288))	('3-5p', 'Chemical', '-', (202, 206))	('activity', 'MPA', (162, 170))	('melanoma cancer', 'Disease', 'MESH:C563985', (100, 115))	('YAP', 'Gene', '10413', (130, 133))	('inhibition', 'NegReg', (134, 144))	('AKT', 'Gene', '207', (158, 161))	('reduced', 'NegReg', (150, 157))	('melanoma cancer', 'Disease', (100, 115))	('BRAF', 'Gene', '673', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('BRAF', 'Gene', (65, 69))	('AKT', 'Gene', (158, 161))
741233	29844307	S5) suggested that miR-550a-3-5p could largely modulate the PI3K/AKT pathway.	('AKT', 'Gene', (65, 68))	('3-5p', 'Chemical', '-', (28, 32))	('modulate', 'Reg', (47, 55))	('AKT', 'Gene', '207', (65, 68))	('miR-550a-3-5p', 'Var', (19, 32))
741235	29844307	Therefore, it is possible that miR-550a-3-5p exerts direct inhibition of oncogenic YAP and subsequently perturbs the PI3K/AKT pathway in BRAF mutant cancer cells.	('inhibition', 'NegReg', (59, 69))	('YAP', 'Gene', '10413', (83, 86))	('cancer', 'Disease', (149, 155))	('YAP', 'Gene', (83, 86))	('miR-550a-3-5p', 'Var', (31, 44))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('perturbs', 'NegReg', (104, 112))	('mutant', 'Var', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('AKT', 'Gene', '207', (122, 125))	('3-5p', 'Chemical', '-', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('AKT', 'Gene', (122, 125))
741236	29844307	In conclusion, our results suggested that the novel miR-550a-3-5p acts as a tumor suppressor and reverses BRAF inhibitor resistance through the direct regulation of YAP in multiple cancer cells.	('YAP', 'Gene', (165, 168))	('regulation', 'Reg', (151, 161))	('3-5p', 'Chemical', '-', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('BRAF', 'Gene', '673', (106, 110))	('tumor', 'Disease', (76, 81))	('miR-550a-3-5p', 'Var', (52, 65))	('reverses', 'NegReg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('BRAF', 'Gene', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('YAP', 'Gene', '10413', (165, 168))	('cancer', 'Disease', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
741284	29844307	The miR-550a-3-5p or control miRNA with in vivo-jetPEI (Polyplus Transfection, NY) complex in a volume of 50 mul (15 mug/site) were injected intratumorally three times per week, between day 14 and 33 after inoculation, in accordance with the manufacturer's protocol.	('3-5p', 'Chemical', '-', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('miR-550a-3-5p', 'Var', (4, 17))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
741300	24145676	In humans, long-term use of opiates, particularly morphine, can commonly cause constipation, which results from opium's disruption of neurotransmission in the enteric nervous system, leading to decreased motility and decreased secretion of water, electrolytes and bile in the GI tract.	('constipation', 'Disease', 'MESH:D003248', (79, 91))	('secretion of water', 'MPA', (227, 245))	('decreased', 'NegReg', (217, 226))	('opiates', 'Chemical', 'MESH:D053610', (28, 35))	('constipation', 'Disease', (79, 91))	('morphine', 'Chemical', 'MESH:D009020', (50, 58))	('water', 'Chemical', 'MESH:D014867', (240, 245))	('humans', 'Species', '9606', (3, 9))	('morphine', 'Var', (50, 58))	('motility', 'CPA', (204, 212))	('decreased', 'NegReg', (194, 203))	('cause', 'Reg', (73, 78))	('constipation', 'Phenotype', 'HP:0002019', (79, 91))
741346	24145676	Of these, the risk of esophageal cancer and cirrhosis were statistically significantly increased by opium use, whereas the risk of gastric cancer was not.	('increased', 'PosReg', (87, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('cirrhosis', 'Phenotype', 'HP:0001394', (44, 53))	('esophageal cancer', 'Disease', (22, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cirrhosis', 'Disease', 'MESH:D005355', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('opium', 'Var', (100, 105))	('cirrhosis', 'Disease', (44, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))	('gastric cancer', 'Disease', (131, 145))
741382	24145676	Similar to other substances metabolized by the liver, morphine exposure may result in some levels of hepatotoxicity.	('hepatotoxicity', 'Disease', (101, 115))	('morphine', 'Var', (54, 62))	('result', 'Reg', (76, 82))	('morphine', 'Chemical', 'MESH:D009020', (54, 62))	('hepatotoxicity', 'Disease', 'MESH:D056486', (101, 115))
741386	24145676	Since opium has been shown to decrease the secretion of water, electrolytes and bile acids into the GI tract, and to significantly reduce GI motility, it could cause considerable changes in GI microbiota, which could make opium users prone to both inflammatory and malignant diseases of the GI tract, as well as other chronic diseases.	('water', 'Chemical', 'MESH:D014867', (56, 61))	('cause', 'Reg', (160, 165))	('GI motility', 'Disease', (138, 149))	('opium', 'Var', (6, 11))	('inflammatory', 'Disease', (248, 260))	('decrease', 'NegReg', (30, 38))	('malignant', 'CPA', (265, 274))	('prone', 'PosReg', (234, 239))	('chronic disease', 'Disease', (318, 333))	('GI motility', 'Disease', 'MESH:D015835', (138, 149))	('bile acids into the', 'MPA', (80, 99))	('changes', 'Reg', (179, 186))	('chronic disease', 'Disease', 'MESH:D002908', (318, 333))	('bile acids', 'Chemical', 'MESH:D001647', (80, 90))	('secretion of water', 'MPA', (43, 61))	('reduce', 'NegReg', (131, 137))	('inflammatory and malignant diseases of the GI tract', 'Phenotype', 'HP:0007378', (248, 299))
741393	24145676	There is now ample evidence in the literature that many patients in the United States, Canada, Australia and Europe who use long term prescribed opioids such as morphine, hydromorphone, codeine, and oxycodone for chronic non-cancer pain are also at increased risk of dying from digestive disease, cardiovascular disease, and cancer, like the opium users in Golestan.	('patients', 'Species', '9606', (56, 64))	('non-cancer pain', 'Disease', 'MESH:D000072716', (221, 236))	('cancer', 'Disease', (225, 231))	('digestive disease', 'Phenotype', 'HP:0011024', (278, 295))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('hydromorphone', 'Var', (171, 184))	('digestive disease', 'Disease', (278, 295))	('cancer', 'Disease', (325, 331))	('oxycodone', 'Chemical', 'MESH:D010098', (199, 208))	('codeine', 'Chemical', 'MESH:D003061', (186, 193))	('pain', 'Phenotype', 'HP:0012531', (232, 236))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('dying', 'Disease', (267, 272))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (297, 319))	('cardiovascular disease', 'Disease', 'MESH:D002318', (297, 319))	('morphine', 'Chemical', 'MESH:D009020', (161, 169))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('cardiovascular disease', 'Disease', (297, 319))	('hydromorphone', 'Chemical', 'MESH:D004091', (171, 184))	('non-cancer pain', 'Disease', (221, 236))
741414	28556501	In conclusion, our data reveal that the tumor-promoting role of LOXL2 in ESCC is mediated by perturbing the architecture of actin cytoskeleton through its PPIs.	('architecture of actin cytoskeleton', 'MPA', (108, 142))	('PPIs', 'MPA', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('ESCC', 'Disease', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('perturbing', 'NegReg', (93, 103))	('LOXL2', 'Var', (64, 69))
741424	28556501	Moreover, aberrant expression of actin-related proteins plays an important role in tumor progression as the actin cytoskeletal architecture impacts many cancer-related cellular processes 12, 13.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', (153, 159))	('tumor', 'Disease', (83, 88))	('aberrant', 'Var', (10, 18))	('actin cytoskeletal', 'MPA', (108, 126))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('impacts', 'Reg', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
741463	28556501	Due to its absence in microarray expression profiles in our study (GSE53624 and GSE53622), the core protein PFN1 was left out at first.	('GSE53624', 'Var', (67, 75))	('GSE53622', 'Var', (80, 88))	('PFN1', 'Gene', '5216', (108, 112))	('PFN1', 'Gene', (108, 112))
741486	28556501	Whereas, LOXL2 knockdown markedly reduces stress fiber and focal adhesion formation in human clear cell renal cell carcinoma cells 8.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (93, 124))	('clear cell renal cell carcinoma', 'Disease', (93, 124))	('knockdown', 'Var', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('human', 'Species', '9606', (87, 92))	('reduces', 'NegReg', (34, 41))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (93, 124))	('focal adhesion formation', 'CPA', (59, 83))	('stress fiber', 'CPA', (42, 54))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (104, 124))
741490	28556501	Therefore, we suggest that the intracellular (cytoplasmic) distribution of LOXL2 in ESCC probably has a novel biological function, independent of its classical secreted role as extracellular LOXL2, whereby LOXL2 indirectly causes perturbation of actin cytoskeleton through its PPIs in ESCC, and contributes to hyperactivation or loss-of-function of some key proteins in carcinogenic pathways to enhance oncogenicity.	('loss-of-function', 'NegReg', (329, 345))	('perturbation', 'MPA', (230, 242))	('carcinogenic', 'Disease', 'MESH:D063646', (370, 382))	('enhance', 'PosReg', (395, 402))	('proteins', 'Protein', (358, 366))	('LOXL2', 'Var', (206, 211))	('hyperactivation', 'PosReg', (310, 325))	('carcinogenic', 'Disease', (370, 382))	('oncogenicity', 'CPA', (403, 415))	('actin', 'MPA', (246, 251))
741504	28556501	The derivation of these three genes predictive of clinical outcome in patients with ESCC may reveal PPI anticancer targets for the development of therapy for esophageal cancer.	('patients', 'Species', '9606', (70, 78))	('cancer', 'Disease', (169, 175))	('ESCC', 'Disease', (84, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('derivation', 'Var', (4, 14))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', (108, 114))	('esophageal cancer', 'Disease', (158, 175))
741509	28556501	For the first time, our data reveal that the tumor-promoting role of LOXL2 in ESCC probably perturbs the architecture of the actin cytoskeleton through its PPIs and induces additional oncogenic effects by hyperactivation or loss-of-function of key proteins.	('key proteins', 'Protein', (244, 256))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('proteins', 'Protein', (248, 256))	('ESCC', 'Disease', (78, 82))	('LOXL2', 'Var', (69, 74))	('architecture of the actin cytoskeleton', 'MPA', (105, 143))	('tumor', 'Disease', (45, 50))	('loss-of-function', 'NegReg', (224, 240))	('hyperactivation', 'PosReg', (205, 220))	('perturbs', 'NegReg', (92, 100))	('PPIs', 'MPA', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('oncogenic effects', 'CPA', (184, 201))
741568	28322515	<=60 Gy vs. >60 Gy), there were proportionally more N2, stage IIIB, and tumor length >8 cm in the <=60 Gy group.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('more', 'PosReg', (47, 51))	('tumor', 'Disease', (72, 77))	('stage', 'Disease', (56, 61))	('<=60', 'Var', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
741626	28322515	In the two patients who suffered from grade 4 respiratory failure, one received an RT dose of 64 Gy, lung V20 = 32%, lung V10 = 59%, and mean lung dose of 16 Gy, while the other received an RT dose of 60 Gy, lung V20 = 13%, lung V10 = 50%, and mean lung dose of 12 Gy.	('lung V20 = 13%', 'Var', (208, 222))	('respiratory failure', 'Disease', (46, 65))	('lung V10 =', 'Var', (117, 127))	('lung V10 =', 'Var', (224, 234))	('respiratory failure', 'Disease', 'MESH:D012131', (46, 65))	('lung V20 =', 'Var', (101, 111))	('patients', 'Species', '9606', (11, 19))	('respiratory failure', 'Phenotype', 'HP:0002878', (46, 65))
741638	27594930	BRB treatment resulted in: histologic regression of oral intraepithelial neoplasia associated with improved histologic grade and significantly reduced loss of heterozygosity at tumor suppressor gene loci, modulated genes linked to RNA processing and growth factor recycling; in the colon, BRB inhibited FAP-associated polyp progression, demethylated tumor suppressor genes and improved plasma cytokine profiles; in Barrett's patients, BRB consumption increased tissue levels of GST-pi and decreased 8-isoprostane, a marker of lipid peroxidation/oxidative stress.	('inhibited', 'NegReg', (293, 302))	('FAP', 'Disease', (303, 306))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (57, 82))	('FAP', 'Disease', 'MESH:C567782', (303, 306))	('plasma cytokine profiles', 'MPA', (386, 410))	('neoplasia', 'Phenotype', 'HP:0002664', (73, 82))	('lipid', 'Chemical', 'MESH:D008055', (526, 531))	('men', 'Species', '9606', (9, 12))	('patients', 'Species', '9606', (425, 433))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', (350, 355))	('tissue levels of GST-pi', 'MPA', (461, 484))	('oxidative stress', 'Phenotype', 'HP:0025464', (545, 561))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('oral intraepithelial neoplasia', 'Disease', 'MESH:D019048', (52, 82))	('decreased', 'NegReg', (489, 498))	('decreased 8-isoprostane', 'Phenotype', 'HP:0020199', (489, 512))	('improved', 'PosReg', (377, 385))	('8-isoprostane', 'MPA', (499, 512))	('increased', 'PosReg', (451, 460))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('demethylated', 'Var', (337, 349))	('oral intraepithelial neoplasia', 'Disease', (52, 82))
741646	27594930	In turn, the metabolites reportedly modify cellular adhesion and inflammatory signaling cascades, both important cancer associated processes.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('modify', 'Reg', (36, 42))	('inflammatory signaling cascades', 'Pathway', (65, 96))	('cancer', 'Disease', (113, 119))	('metabolites', 'Var', (13, 24))	('cellular adhesion', 'CPA', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
741651	27594930	Among never smokers, high fruit consumption is strongly protective against head and neck cancers.	('neck cancers', 'Disease', 'MESH:D006258', (84, 96))	('head and neck cancers', 'Phenotype', 'HP:0012288', (75, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('high', 'Var', (21, 25))	('neck cancers', 'Disease', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
741731	27594930	Immunohistochemical staining results showed that BRB modulated beta-catenin, Ki-67, TUNEL, CD105, and DNMT1 in colorectal tissue and CD105 and DNMT1 in normal tissues.	('beta-catenin', 'Gene', (63, 75))	('CD105', 'Gene', (91, 96))	('colorectal', 'Disease', (111, 121))	('TUNEL', 'Gene', (84, 89))	('C', 'Chemical', 'MESH:D002244', (133, 134))	('DNMT1', 'Gene', (143, 148))	('beta-catenin', 'Gene', '1499', (63, 75))	('modulated', 'Reg', (53, 62))	('DNMT1', 'Gene', (102, 107))	('DNMT1', 'Gene', '1786', (102, 107))	('CD105', 'Var', (133, 138))	('BRB', 'Gene', (49, 52))	('Ki-67', 'Gene', (77, 82))	('C', 'Chemical', 'MESH:D002244', (91, 92))	('DNMT1', 'Gene', '1786', (143, 148))
741732	27594930	The fact that BRB significantly altered a number of markers in key molecular pathways known to be altered in colon cancer is encouraging and it is notable that the effect occurred in a relatively short period of time.	('colon cancer', 'Phenotype', 'HP:0003003', (109, 121))	('colon cancer', 'Disease', 'MESH:D015179', (109, 121))	('BRB', 'Var', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('altered', 'Reg', (32, 39))	('colon cancer', 'Disease', (109, 121))	('altered', 'Reg', (98, 105))
741740	27594930	FAP is due to germline mutations in the APC gene and requires patients to be closely monitored via endoscopic surveillance for early detection of polyps.	('APC', 'Disease', 'MESH:D011125', (40, 43))	('polyps', 'Disease', 'MESH:D011127', (146, 152))	('FAP', 'Disease', 'MESH:C567782', (0, 3))	('APC', 'Disease', (40, 43))	('due to', 'Reg', (7, 13))	('patients', 'Species', '9606', (62, 70))	('polyps', 'Disease', (146, 152))	('FAP', 'Disease', (0, 3))	('germline mutations', 'Var', (14, 32))
741759	27594930	Still, this study did detect that miRNAs regulating Wnt pathways were demethylated by BRB in adenomas from responders.	('adenomas', 'Disease', (93, 101))	('demethylated', 'Var', (70, 82))	('Wnt pathways', 'Pathway', (52, 64))	('BRB', 'Gene', (86, 89))	('adenomas', 'Disease', 'MESH:D000236', (93, 101))
741804	22108196	Experimental studies have also shown that treatment with COX-2 inhibitors can inhibit the growth in vitro of Barrett's esophagus cells, an effect potentially mediated by suppression of basic fibroblast growth factor .	('growth', 'CPA', (90, 96))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (109, 128))	('suppression', 'NegReg', (170, 181))	('COX-2', 'Gene', (57, 62))	('inhibit', 'NegReg', (78, 85))	('COX-2', 'Gene', '5743', (57, 62))	('inhibitors', 'Var', (63, 73))
741806	22108196	Although several studies have observed that COX-2 inhibitors slow the growth of gastric tumor cells and induce apoptosis, they have also suggested that this may be mediated through pathways other than suppressing COX-2.	('inhibitors', 'Var', (50, 60))	('gastric tumor', 'Disease', 'MESH:D013274', (80, 93))	('growth', 'CPA', (70, 76))	('gastric tumor', 'Phenotype', 'HP:0006753', (80, 93))	('slow', 'NegReg', (61, 65))	('induce', 'Reg', (104, 110))	('COX-2', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('COX-2', 'Gene', '5743', (44, 49))	('COX-2', 'Gene', (213, 218))	('COX-2', 'Gene', '5743', (213, 218))	('gastric tumor', 'Disease', (80, 93))	('apoptosis', 'CPA', (111, 120))
741979	33787085	Downregulation of TAB182 sensitized cancer cells to ionizing radiation, particularly in radioresistant TE-1R cells that spontaneously overexpress TAB182.	('overexpress', 'PosReg', (134, 145))	('TAB182', 'Chemical', '-', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('TE', 'Chemical', 'MESH:D013691', (103, 105))	('sensitized', 'Reg', (25, 35))	('cancer', 'Disease', (36, 42))	('Downregulation', 'Var', (0, 14))	('TAB182', 'Gene', (18, 24))	('TAB182', 'Chemical', '-', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('TAB182', 'Gene', (146, 152))
741982	33787085	TAB182 potentiates the radioresistance of ESCC cells by modulating the G2-M checkpoint through its interaction with FHL2.	('radioresistance', 'CPA', (23, 38))	('FHL2', 'Gene', '2274', (116, 120))	('TAB182', 'Chemical', '-', (0, 6))	('modulating', 'Reg', (56, 66))	('TAB182', 'Var', (0, 6))	('interaction', 'Interaction', (99, 110))	('FHL2', 'Gene', (116, 120))	('G2-M', 'MPA', (71, 75))	('potentiates', 'PosReg', (7, 18))
741995	33787085	15  In the cytoplasm, TAB182 interacted with the multi-subunit CCR4 (carbon catabolite repressor 4)-NOT (Negative on TATA) complex (CCR4-NOT complex, CNOT) to affect the outcome of target mRNA by modulating helicase recruitment to the complex.	('affect', 'Reg', (159, 165))	('modulating', 'Reg', (196, 206))	('helicase', 'Gene', '164045', (207, 215))	('helicase', 'Gene', (207, 215))	('carbon', 'Chemical', 'MESH:D002244', (69, 75))	('outcome', 'MPA', (170, 177))	('recruitment', 'MPA', (216, 227))	('TAB182', 'Chemical', '-', (22, 28))	('TAB182', 'Var', (22, 28))
742049	33787085	As seen in Figure 1A, the median count of TAB182 in 88 ESCC samples was 20357, higher than that of 12445 in 11 normal samples, p = 0.01.	('20357', 'Var', (72, 77))	('TAB182', 'Chemical', '-', (42, 48))	('TAB182', 'Gene', (42, 48))	('ESCC', 'Disease', (55, 59))	('higher', 'PosReg', (79, 85))
742075	33787085	In contrast, D q and D 0 were decreased in TAB182 knockdown TE-1R cells.	('knockdown', 'Var', (50, 59))	('D q', 'MPA', (13, 16))	('D 0', 'MPA', (21, 24))	('D q', 'Chemical', '-', (13, 16))	('TE', 'Chemical', 'MESH:D013691', (60, 62))	('TAB182', 'Gene', (43, 49))	('TAB182', 'Chemical', '-', (43, 49))	('decreased', 'NegReg', (30, 39))
742090	33787085	As expected, TAB182 expression was significantly lower and failed to increase in TE-1 and TE-1R cells with TAB182 knockdown.	('TAB182', 'Chemical', '-', (13, 19))	('expression', 'MPA', (20, 30))	('TAB182', 'Gene', (13, 19))	('knockdown', 'Var', (114, 123))	('TAB182', 'Gene', (107, 113))	('TE', 'Chemical', 'MESH:D013691', (90, 92))	('TAB182', 'Chemical', '-', (107, 113))	('lower', 'NegReg', (49, 54))	('TE', 'Chemical', 'MESH:D013691', (81, 83))
742097	33787085	To further corroborate the role of TAB182 in radioresistance, rescue experiments were applied by upregulating TAB182 in TAB182 knockdown TE-1 cells.	('TE', 'Chemical', 'MESH:D013691', (137, 139))	('TAB182', 'Gene', (120, 126))	('TAB182', 'Chemical', '-', (35, 41))	('TAB182', 'Gene', (110, 116))	('TAB182', 'Chemical', '-', (110, 116))	('upregulating', 'PosReg', (97, 109))	('knockdown', 'Var', (127, 136))	('TAB182', 'Chemical', '-', (120, 126))
742100	33787085	As seen in Figure 5B, the survival fraction was higher in TE-1 shTAB182 sm.	('TE', 'Chemical', 'MESH:D013691', (58, 60))	('survival fraction', 'CPA', (26, 43))	('TAB182', 'Chemical', '-', (65, 71))	('higher', 'PosReg', (48, 54))	('TE-1 shTAB182 sm', 'Var', (58, 74))
742105	33787085	Furthermore, both elevated phospho-CDC25C and phospho-CDC2 were observed in the TE-1 shTAB182 sm group.	('TE-1 shTAB182 sm', 'Var', (80, 96))	('TE', 'Chemical', 'MESH:D013691', (80, 82))	('CDC25C', 'Gene', (35, 41))	('CDC2', 'Gene', '983', (35, 39))	('TAB182', 'Chemical', '-', (87, 93))	('CDC2', 'Gene', (35, 39))	('CDC2', 'Gene', (54, 58))	('CDC2', 'Gene', '983', (54, 58))	('CDC25C', 'Gene', '995', (35, 41))	('elevated', 'PosReg', (18, 26))
742118	33787085	On the one hand, TAB182 mediates the autophosphorylation of DNA-PKcs, thus enhancing DNA damage repair activity, 19  consistent with our observation showing that more gamma-H2A.X foci are detected after IR when TAB182 was downregulated in TE-1 and TE-10 cells.	('downregulated', 'NegReg', (222, 235))	('TAB182', 'Chemical', '-', (17, 23))	('enhancing', 'PosReg', (75, 84))	('DNA-PKcs', 'Gene', '5591', (60, 68))	('gamma-H2A', 'Chemical', '-', (167, 176))	('autophosphorylation', 'MPA', (37, 56))	('TAB182', 'Var', (17, 23))	('TE', 'Chemical', 'MESH:D013691', (248, 250))	('TAB182', 'Chemical', '-', (211, 217))	('DNA damage repair activity', 'MPA', (85, 111))	('DNA-PKcs', 'Gene', (60, 68))	('TAB182', 'Gene', (211, 217))	('TE', 'Chemical', 'MESH:D013691', (239, 241))
742123	33787085	On the other hand, we found that TAB182 wires the IR-induced FHL2/CHK2/CDC25C/CDC2 signaling pathway through its interaction with FHL2, a key regulator of radioresistance.	('CHK2', 'Gene', '11200', (66, 70))	('FHL2', 'Gene', '2274', (130, 134))	('CDC25C', 'Gene', '995', (71, 77))	('FHL2', 'Gene', '2274', (61, 65))	('CDC2', 'Gene', (71, 75))	('CDC2', 'Gene', '983', (71, 75))	('wires', 'PosReg', (40, 45))	('CHK2', 'Gene', (66, 70))	('TAB182', 'Chemical', '-', (33, 39))	('CDC2', 'Gene', '983', (78, 82))	('CDC25C', 'Gene', (71, 77))	('FHL2', 'Gene', (130, 134))	('CDC2', 'Gene', (78, 82))	('FHL2', 'Gene', (61, 65))	('TAB182', 'Var', (33, 39))	('interaction', 'Interaction', (113, 124))
742126	33787085	In addition, the phosphorylation of CHK2 was higher in the TAB182 knockdown group, consistent with increased gamma-H2A.X foci.	('CHK2', 'Gene', (36, 40))	('CHK2', 'Gene', '11200', (36, 40))	('phosphorylation', 'MPA', (17, 32))	('gamma-H2A', 'Chemical', '-', (109, 118))	('TAB182', 'Chemical', '-', (59, 65))	('TAB182', 'Gene', (59, 65))	('increased', 'PosReg', (99, 108))	('higher', 'PosReg', (45, 51))	('knockdown', 'Var', (66, 75))
742127	33787085	Subsequent phosphorylation of CDC25C was failed due to TAB182 downregulation, indicating that TAB182 acts the downstream of CHK2 and functions with FHL2 to inactivate CDC25C.	('inactivate', 'NegReg', (156, 166))	('CHK2', 'Gene', '11200', (124, 128))	('CDC25C', 'Gene', (30, 36))	('FHL2', 'Gene', (148, 152))	('CDC25C', 'Gene', '995', (167, 173))	('TAB182', 'Chemical', '-', (55, 61))	('CDC25C', 'Gene', '995', (30, 36))	('downregulation', 'NegReg', (62, 76))	('TAB182', 'Chemical', '-', (94, 100))	('TAB182', 'Var', (94, 100))	('FHL2', 'Gene', '2274', (148, 152))	('CHK2', 'Gene', (124, 128))	('CDC25C', 'Gene', (167, 173))
742138	33491650	Cancer is the end result of a process of accumulation of genetic and epigenetic alterations.	('epigenetic alterations', 'Var', (69, 91))	('genetic', 'Var', (57, 64))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
742140	33491650	Carcinogens such as tobacco smoking, aflatoxin, and aristolochic acid are also known to induce characteristic mutations at specific motifs.	('mutations', 'Var', (110, 119))	('aristolochic acid', 'Chemical', 'MESH:C000228', (52, 69))	('aristolochic acid', 'Var', (52, 69))	('induce', 'Reg', (88, 94))	('tobacco', 'Species', '4097', (20, 27))	('aflatoxin', 'Chemical', 'MESH:D000348', (37, 46))
742165	33491650	It has long been known that certain types of mutations, such as C>T transitions resulting from cytosine deamination, accumulate with age.	('C>T transitions', 'Var', (64, 79))	('accumulate', 'PosReg', (117, 127))	('resulting', 'Reg', (80, 89))	('cytosine', 'Chemical', 'MESH:D003596', (95, 103))
742169	33491650	Not surprisingly, we found C>T transitions to be present in large fractions in many cancer types.	('C>T', 'Var', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
742170	33491650	However, others, such as C>A transversions in stomach and prostate adenocarcinomas, and adrenocortical carcinomas, T>C transitions in liver hepatocellular carcinomas, C>G transversions in colorectal adenocarcinomas, head and neck squamous cell carcinomas, prostate adenocarcinomas, renal clear cell carcinomas, testicular germ cell tumors, and uterine corpus carcinoma, and any mutations of the T pyrimidine in prostate and kidney cancers, and testicular tumors, had not been previously described as major age-associated mutations (Figure 4a, and Figure 4:figure supplements 1-30).	('prostate adenocarcinomas', 'Disease', (256, 280))	('cancers', 'Phenotype', 'HP:0002664', (431, 438))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (188, 214))	('corpus carcinoma', 'Disease', 'MESH:D009369', (352, 368))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (88, 113))	('kidney cancer', 'Phenotype', 'HP:0009726', (424, 437))	('corpus carcinoma', 'Disease', (352, 368))	('adrenocortical carcinomas', 'Disease', (88, 113))	('kidney cancers', 'Phenotype', 'HP:0009726', (424, 438))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumors', 'Disease', 'MESH:D009369', (455, 461))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('testicular tumors', 'Disease', 'MESH:D013736', (444, 461))	('neck squamous cell carcinomas', 'Disease', (225, 254))	('testicular tumors', 'Phenotype', 'HP:0010788', (444, 461))	('renal clear cell carcinomas', 'Disease', 'MESH:C538614', (282, 309))	('testicular', 'Disease', (311, 321))	('prostate adenocarcinomas', 'Disease', 'MESH:D011471', (58, 82))	('colorectal adenocarcinomas', 'Disease', (188, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (88, 113))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (225, 254))	('tumors', 'Disease', (332, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (455, 460))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('prostate adenocarcinomas', 'Disease', 'MESH:D011471', (256, 280))	('tumors', 'Phenotype', 'HP:0002664', (455, 461))	('liver hepatocellular carcinomas', 'Disease', 'MESH:D006528', (134, 165))	('germ cell tumors', 'Phenotype', 'HP:0100728', (322, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('prostate adenocarcinomas', 'Disease', (58, 82))	('tumors', 'Disease', 'MESH:D009369', (332, 338))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('C>G transversions', 'Var', (167, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (244, 254))	('prostate and kidney cancers', 'Disease', 'MESH:D011471', (411, 438))	('stomach', 'Disease', (46, 53))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (230, 254))	('liver hepatocellular carcinomas', 'Disease', (134, 165))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (140, 165))	('testicular tumors', 'Disease', (444, 461))	('renal clear cell carcinomas', 'Disease', (282, 309))	('tumors', 'Disease', (455, 461))
742172	33491650	We were thus able to obtain tissue-specific SuperSigs for mismatch repair deficiency, mutations in DNA polymerase delta or epsilon genes, mutations in the breast cancer susceptibility genes BRCA1 or BRCA2, methylation of the MGMT and IDH1 genes, and APOBEC (Figure 4b, Figure 4:figure supplements 31-67, Supplementary file 2, and Materials and methods).	('epsilon genes', 'Gene', (123, 136))	('methylation', 'Var', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('BRCA2', 'Gene', (199, 204))	('MGMT', 'Gene', (225, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('mutations', 'Var', (86, 95))	('BRCA2', 'Gene', '675', (199, 204))	('BRCA1', 'Gene', '672', (190, 195))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('DNA polymerase delta', 'Gene', (99, 119))	('breast cancer', 'Disease', (155, 168))	('BRCA1', 'Gene', (190, 195))	('IDH1', 'Gene', (234, 238))	('mutations', 'Var', (138, 147))	('deficiency', 'Var', (74, 84))	('mismatch', 'Gene', (58, 66))	('DNA polymerase delta', 'Gene', '5424', (99, 119))	('MGMT', 'Gene', '4255', (225, 229))	('APOBEC', 'Gene', (250, 256))	('IDH1', 'Gene', '3417', (234, 238))
742174	33491650	And the SuperSigs associated with BRCA gene mutations were considerably different between breast and ovarian cancers (Figure 4:figure supplements 36-37).	('BRCA', 'Gene', '672', (34, 38))	('ovarian cancers', 'Phenotype', 'HP:0100615', (101, 116))	('BRCA', 'Gene', (34, 38))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (90, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('mutations', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))
742181	33491650	For example, obesity could lead to cancer by inducing mutations or by stimulating the growth of neoplastic cells that have already acquired mutations.	('obesity', 'Phenotype', 'HP:0001513', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('obesity', 'Disease', 'MESH:D009765', (13, 20))	('inducing', 'Reg', (45, 53))	('mutations', 'Var', (54, 63))	('obesity', 'Disease', (13, 20))	('stimulating', 'PosReg', (70, 81))	('growth of neoplastic cells', 'CPA', (86, 112))	('lead to', 'Reg', (27, 34))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
742182	33491650	If the former explanation were valid, there might be a mutational signature associated with obesity, but no such signature has been previously identified.	('mutational', 'Var', (55, 65))	('obesity', 'Disease', 'MESH:D009765', (92, 99))	('obesity', 'Disease', (92, 99))	('associated', 'Reg', (76, 86))	('obesity', 'Phenotype', 'HP:0001513', (92, 99))
742187	33491650	The finding of a negative difference in the rate of T[C>G]T mutations in obese patients with uterine cancer (Figure 6) suggests an explanation for the observation that often the total number of somatic mutations found in cancers of obese patients is not significantly different from that of non-obese patients, when controlling for age.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('obese', 'Disease', (232, 237))	('patients', 'Species', '9606', (301, 309))	('obese', 'Disease', (295, 300))	('non-obese', 'Disease', (291, 300))	('obese', 'Disease', 'MESH:D009765', (232, 237))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('obese', 'Disease', (73, 78))	('obese', 'Disease', 'MESH:D009765', (295, 300))	('non-obese', 'Disease', 'MESH:D009765', (291, 300))	('obese', 'Disease', 'MESH:D009765', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancers', 'Disease', (221, 228))	('cancer', 'Disease', (221, 227))	('T[C>G]T mutations', 'Var', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('patients', 'Species', '9606', (238, 246))	('uterine cancer', 'Phenotype', 'HP:0010784', (93, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (79, 87))
742197	33491650	For example, inherited mutations in the fundamental genes involved in DNA repair or recombination, such as BRCA2, might be expected to result in predispositions to cancers of all types, but they only increase cancer risk in a limited subset of tissues.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('result in predispositions', 'Reg', (135, 160))	('BRCA2', 'Gene', '675', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('mutations', 'Var', (23, 32))	('cancer', 'Disease', (164, 170))	('cancers', 'Disease', (164, 171))	('cancer', 'Disease', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('BRCA2', 'Gene', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
742215	33491650	The discovery of SuperSigs for obesity in the four tissues analyzed - with two of them relatively robust in cross-validation - suggests that, at least in those tissues, part of the risk from obesity may be attributable to mutagenesis.	('obesity', 'Disease', (191, 198))	('obesity', 'Phenotype', 'HP:0001513', (31, 38))	('obesity', 'Disease', 'MESH:D009765', (31, 38))	('obesity', 'Phenotype', 'HP:0001513', (191, 198))	('mutagenesis', 'Var', (222, 233))	('obesity', 'Disease', (31, 38))	('obesity', 'Disease', 'MESH:D009765', (191, 198))
742224	33491650	We removed samples with microsatellite instability (MSI) or with a mutation in POLE/POLE2/POLE3/POLE4 or POLD1/POLD2/POLD3/POLD4 genes - except for when the signature for the specific effects of those mutations was the objective of the analysis - because of the known large increase in the number of mutations they induce.	('POLD2', 'Gene', '5425', (111, 116))	('POLE4', 'Gene', '56655', (96, 101))	('POLE4', 'Gene', (96, 101))	('POLD4', 'Gene', '57804', (123, 128))	('mutation', 'Var', (67, 75))	('POLE2', 'Gene', (84, 89))	('POLD3', 'Gene', (117, 122))	('POLD2', 'Gene', (111, 116))	('POLD1', 'Gene', (105, 110))	('POLD3', 'Gene', '10714', (117, 122))	('POLD1', 'Gene', '5424', (105, 110))	('POLE3', 'Gene', (90, 95))	('POLE3', 'Gene', '54107', (90, 95))	('POLE2', 'Gene', '5427', (84, 89))	('POLD4', 'Gene', (123, 128))	('microsatellite instability', 'MPA', (24, 50))
742228	33491650	In addition to six single base substitutions: C>A, C>G, C>T, T>A, T>C, and T>G, named according to the pyrimidine of the mutated Watson-Crick base pair, there are 48 dinucleotides, in which the substitution is paired with a specific base as a prefix or as a suffix but not both (e.g.	('T>C', 'Var', (66, 69))	('T>A', 'Var', (61, 64))	('C>T', 'Var', (56, 59))	('dinucleotide', 'Chemical', 'MESH:D015226', (166, 178))	('C>G', 'Var', (51, 54))	('T>G', 'Var', (75, 78))	('C>A', 'Var', (46, 49))
742230	33491650	The simple substitution C>T spawns dinucleotide children, such as A[C>T], and trinucleotide grandchildren like A[C>T]G. Frequent, exposure-driven A[C>T] substitutions would increase the observed rates of both the C>T parent and the trinucleotide children, making it difficult to assign ownership to the correct generation.	('children', 'Species', '9606', (48, 56))	('children', 'Species', '9606', (97, 105))	('dinucleotide', 'Chemical', 'MESH:D015226', (35, 47))	('C>T', 'Var', (24, 27))	('children', 'Species', '9606', (246, 254))	('trinucleotide', 'Chemical', '-', (78, 91))	('spawns', 'Chemical', '-', (28, 34))	('increase', 'PosReg', (173, 181))	('substitutions', 'Var', (153, 166))	('A[C>T', 'Var', (146, 151))	('trinucleotide', 'Chemical', '-', (232, 245))
742234	33491650	Moving down a generation, [C>T]A, as the child of the C>T substitution, and the grandchild of the total number of mutations (Total Mutations), would be tested twice to see if it significantly exceeded its expected number based on the total number of mutations as well as the number of C>T.	('child', 'Species', '9606', (41, 46))	('child', 'Species', '9606', (85, 90))	('substitution', 'Var', (58, 70))	('C>T substitution', 'Var', (54, 70))
742237	33491650	And, for each sample, its mutation count will be updated by removing the mutations of the second-phase candidate feature children.	('removing', 'NegReg', (60, 68))	('children', 'Species', '9606', (121, 129))	('mutations', 'Var', (73, 82))
742244	33491650	In step two, we randomly break down the obtained proportion of each of the six main mutation types into the 16 fundamental trinucleotide mutations (16 for C>A, 16 for C>T, and so on).	('break down', 'Phenotype', 'HP:0001061', (25, 35))	('C>A', 'Var', (155, 158))	('C>T', 'Var', (167, 170))	('trinucleotide', 'Chemical', '-', (123, 136))
742256	33491650	Pretend we had no annotation for the presence of defects in the gene POL-epsilon among patients with endometrial cancer in the UCEC-TCGA dataset and that we did not know the POL-epsilon signature.	('endometrial cancer', 'Disease', (101, 119))	('endometrial cancer', 'Phenotype', 'HP:0012114', (101, 119))	('POL-epsilon', 'Gene', (69, 80))	('endometrial cancer', 'Disease', 'MESH:D016889', (101, 119))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('defects', 'Var', (49, 56))
742262	33491650	A repository for the R package containing the SuperSigs algorithm can be found at https://github.com/TomasettiLab/superSigs (; copy archived at swh:1:rev:7d6aac85a1b3930cb93e0810039db4d65a242cca).	('TomasettiLab', 'Disease', 'None', (101, 113))	('TomasettiLab', 'Disease', (101, 113))	('rev:7d6aac85a1b3930cb93e0810039db4d65a242cca', 'Var', (150, 194))
742267	33491650	A repository for the R package containing the SuperSigs algorithm is found at https://github.com/TomasettiLab/superSigs (copy archived at https://archive.softwareheritage.org/swh:1:rev:7d6aac85a1b3930cb93e0810039db4d65a242cca/).	('TomasettiLab', 'Disease', (97, 109))	('rev:7d6aac85a1b3930cb93e0810039db4d65a242cca/', 'Var', (181, 226))	('TomasettiLab', 'Disease', 'None', (97, 109))
742286	33491650	Summary: In this manuscript, the authors describe a new approach to identify patterns of genetic alterations in tumors that reflect biological processes that affect DNA.	('tumors', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('genetic alterations', 'Var', (89, 108))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
742296	33491650	For example, breast cancers are well characterized into different subtypes, especially with respect to underlying factors such as BRCA1/2 mutation status (germline) that associate with the different subtypes (e.g.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('breast cancers', 'Phenotype', 'HP:0003002', (13, 27))	('breast cancers', 'Disease', 'MESH:D001943', (13, 27))	('associate', 'Reg', (170, 179))	('breast cancers', 'Disease', (13, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('BRCA1/2', 'Gene', (130, 137))	('mutation', 'Var', (138, 146))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('BRCA1/2', 'Gene', '672;675', (130, 137))
742297	33491650	However, as a general method, SuperSigs provides a new and well-tested method for deriving mutational signatures from cancer genomic data that likely will have a significant impact on the field of cancer research and, ultimately in areas of cancer prevention as well as revealing new cancer etiologies.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('impact', 'Reg', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutational', 'Var', (91, 101))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
742317	33491650	Our current approach is indeed offering higher flexibility as the fundamental unit of analysis is not forced to be the trinucleotide, but it is found to be of length 1, 2 or 3 nucleotides depending on our statistically guided approach of feature engineering/selection (as depicted for example in Figure 4 of the main text, with signatures containing nucleotides, binucleotides and trinucleotides as features, which is different from Alexandrov's).	('trinucleotide', 'Chemical', '-', (119, 132))	('trinucleotides', 'Var', (381, 395))	('trinucleotide', 'Chemical', '-', (381, 394))	('binucleotides', 'Var', (363, 376))	('trinucleotides', 'Chemical', '-', (381, 395))
742335	33029538	In several malignancies, IDO expression in either tumor cells or tumor-associated cells has been linked to adverse outcome, as demonstrated by Jia et al.	('linked to', 'Reg', (97, 106))	('IDO expression', 'Var', (25, 39))	('malignancies', 'Disease', 'MESH:D009369', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('malignancies', 'Disease', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
742343	33029538	The immunohistochemical and RNA BaseScope data were statistically correlated with survival and molecular data like TP53 mutational status and HER2/neu status.	('HER2', 'Gene', (142, 146))	('HER2', 'Gene', '2064', (142, 146))	('TP53', 'Gene', '7157', (115, 119))	('neu', 'Gene', '2064', (147, 150))	('TP53', 'Gene', (115, 119))	('mutational', 'Var', (120, 130))	('neu', 'Gene', (147, 150))
742354	33029538	The resulting metabolites (l-kynurenine, l-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were initially considered to protect the host from infections but have recently been recognized to provide regulatory effects on the inflammatory microenvironment.	('l-kynurenine', 'Chemical', 'MESH:D007737', (27, 39))	('infections', 'Disease', 'MESH:D007239', (177, 187))	('quinolinic acid', 'Chemical', 'MESH:D017378', (89, 104))	('infections', 'Disease', (177, 187))	('3-hydroxyanthranilic acid', 'Chemical', 'MESH:D015095', (62, 87))	('l-hydroxykynurenine', 'Chemical', '-', (41, 60))	('picolinic acid', 'Chemical', 'MESH:C030614', (110, 124))	('l-kynurenine', 'Var', (27, 39))	('l-hydroxykynurenine', 'Var', (41, 60))
742519	29928485	Up until now, only two targeted therapies have been incorporated in daily practice for patients with metastatic esophagogastric cancer; (i) anti-erbb2 (HER2) targeted therapy with trastuzumab in first line treatment of HER2 overexpressing tumors, and (ii) second line anti-VEGFR2 therapy.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('overexpressing', 'PosReg', (224, 238))	('HER2', 'Gene', '2064', (152, 156))	('VEGFR2', 'Gene', '3791', (273, 279))	('HER2', 'Gene', (219, 223))	('targeted therapy', 'Var', (158, 174))	('cancer', 'Disease', (128, 134))	('tumors', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('trastuzumab', 'Chemical', 'MESH:D000068878', (180, 191))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('HER2', 'Gene', (152, 156))	('erbb2', 'Gene', '2064', (145, 150))	('HER2', 'Gene', '2064', (219, 223))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('erbb2', 'Gene', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('patients', 'Species', '9606', (87, 95))	('VEGFR2', 'Gene', (273, 279))
742573	29928485	We identify HER2 status discordance in 2.1% of the resectable cases, of which 1.4% positive and 0.7% negative discordances were observed.	('HER2', 'Gene', (12, 16))	('status discordance', 'Var', (17, 35))	('HER2', 'Gene', '2064', (12, 16))
742574	29928485	Importantly, positive discordance could be clinically relevant, as in principle these patients are eligible for HER2 targeting therapy, either in the context of clinical studies in the adjuvant setting, or as standard of care if they were to develop metastatic disease.	('metastatic disease', 'CPA', (250, 268))	('develop', 'PosReg', (242, 249))	('HER2', 'Gene', (112, 116))	('HER2', 'Gene', '2064', (112, 116))	('targeting therapy', 'Var', (117, 134))	('patients', 'Species', '9606', (86, 94))
742583	29928485	Of note, however, in breast cancer patients with a positive discordant HER2 status treated with HER2 targeted therapy, a reduced survival was observed compared to patients with concordant HER2 positive status.	('patients', 'Species', '9606', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('HER2', 'Gene', (188, 192))	('HER2', 'Gene', (71, 75))	('reduced', 'NegReg', (121, 128))	('positive discordant', 'Var', (51, 70))	('breast cancer', 'Disease', (21, 34))	('survival', 'MPA', (129, 137))	('HER2', 'Gene', '2064', (71, 75))	('HER2', 'Gene', '2064', (188, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('HER2', 'Gene', (96, 100))	('patients', 'Species', '9606', (35, 43))	('HER2', 'Gene', '2064', (96, 100))
742598	29928485	Subgroup analyses in the ToGA trial demonstrated that HER2 protein expression negative (IHC 0 or 1+) tumors with amplification of the HER2 gene assessed by ISH, had no survival benefit of the addition of trastuzumab to the standard chemotherapy regimen.	('negative', 'NegReg', (78, 86))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('HER2', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('HER2', 'Gene', '2064', (54, 58))	('amplification', 'Var', (113, 126))	('HER2', 'Gene', (134, 138))	('trastuzumab', 'Chemical', 'MESH:D000068878', (204, 215))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('HER2', 'Gene', '2064', (134, 138))	('tumors', 'Disease', (101, 107))
742603	29928485	Loss of HER2 was demonstrated to result in a more mesenchymal phenotype, in which cells obtain an enhanced migratory capacity, resulting in a more aggressive tumor cell behavior, and the development of metastatic disease, contributing to a poor patient survival.	('enhanced', 'PosReg', (98, 106))	('aggressive tumor', 'Disease', 'MESH:D001523', (147, 163))	('HER2', 'Gene', (8, 12))	('more', 'PosReg', (142, 146))	('mesenchymal phenotype', 'CPA', (50, 71))	('HER2', 'Gene', '2064', (8, 12))	('more', 'PosReg', (45, 49))	('aggressive tumor', 'Disease', (147, 163))	('metastatic disease', 'CPA', (202, 220))	('migratory capacity', 'CPA', (107, 125))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Loss', 'Var', (0, 4))	('patient', 'Species', '9606', (245, 252))
742617	29928485	Those IHC2+ scoring tumors with an amplification of the HER2 gene were also defined to have a HER2-positive status.	('amplification', 'Var', (35, 48))	('HER2', 'Gene', (56, 60))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('HER2', 'Gene', '2064', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('HER2', 'Gene', '2064', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('HER2', 'Gene', (94, 98))
742754	27941828	They classified the patients into three groups according to the LNR (<=0.2, 0.21~0.5, and >0.5), and found that LNR can stratify survival better than the AJCC/UICC N stage.	('patients', 'Species', '9606', (20, 28))	('stratify', 'Reg', (120, 128))	('LNR', 'Var', (112, 115))
742789	27025161	On MVA, the lung V5 (OR 1.101 95% CI 1.1014-1.195) and V20 (OR 1.149 95% CI 1.1015-1.301) remained associated with grade 2+ RP.	('V20', 'Var', (55, 58))	('MVA', 'Disease', 'MESH:C536987', (3, 6))	('grade 2+ RP', 'Disease', (115, 126))	('MVA', 'Disease', (3, 6))	('associated', 'Reg', (99, 109))
742797	27025161	The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) study recommended a lung V20 <= 30-35% and MLD <= 20-23 Gray (Gy) to limit the risk of RP to <= 20% in definitive radiation for non-small cell lung cancer with conventional fractionation .	('MLD', 'Disease', 'MESH:D007966', (118, 121))	('MLD', 'Disease', (118, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (203, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (207, 229))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (203, 229))	('non-small cell lung cancer', 'Disease', (203, 229))	('<= 30-35%', 'Var', (104, 113))
742809	27025161	Extracted data included the V5, V10, V20, V30, V40, V50 and the MLD.	('V40', 'Var', (47, 50))	('MLD', 'Disease', (64, 67))	('V30', 'Var', (42, 45))	('MLD', 'Disease', 'MESH:D007966', (64, 67))
742826	27025161	The MLD, V5, V10, V20, and V30 were associated with an increased risk of symptomatic RP as continuous variables.	('V30', 'Var', (27, 30))	('MLD', 'Disease', 'MESH:D007966', (4, 7))	('MLD', 'Disease', (4, 7))	('V10', 'Var', (13, 16))	('V20', 'Var', (18, 21))
742828	27025161	On multivariable analysis, after controlling for dosimetric variables, tumor location, and radiation dose, the lung V5 (OR 1.101 95% CI 1.1014-1.195) and V20 (OR 1.149 95% CI 1.1015-1.301) remained significantly associated with symptomatic RP.	('associated with', 'Reg', (212, 227))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('V20', 'Var', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
742832	27025161	In our analysis, dosimetric factors (MLD, V5, V10, V20, and V30) and clinical factors (upper/middle location, radiation dose) were associated with an increased risk for symptomatic RP in patients completing tri-modality therapy.	('patients', 'Species', '9606', (187, 195))	('MLD', 'Disease', 'MESH:D007966', (37, 40))	('associated', 'Reg', (131, 141))	('MLD', 'Disease', (37, 40))	('V10', 'Var', (46, 49))	('V30', 'Var', (60, 63))	('V20', 'Var', (51, 54))
742834	27025161	In particular, MLD, V5, V10, V20, and V30 were associated with an increased risk of symptomatic RP.	('V10', 'Var', (24, 27))	('MLD', 'Disease', 'MESH:D007966', (15, 18))	('MLD', 'Disease', (15, 18))	('V30', 'Var', (38, 41))	('V20', 'Var', (29, 32))
742836	27025161	Minimizing low dose radiation appears to decrease the risk of RP in patients with localized esophageal cancer undergoing concurrent chemoradiation.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Minimizing', 'Var', (0, 10))	('decrease', 'NegReg', (41, 49))	('patients', 'Species', '9606', (68, 76))	('localized esophageal cancer', 'Disease', (82, 109))	('localized esophageal cancer', 'Disease', 'MESH:D004938', (82, 109))
742859	27025161	Minimizing low dose spread to the lung can decrease the potential risk for RP in patients undergoing tri-modality therapy for locally advanced esophageal cancer and should be considered as a quality metric in patients receiving tri-modality therapy.	('decrease', 'NegReg', (43, 51))	('Minimizing', 'Var', (0, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (209, 217))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('esophageal cancer', 'Disease', (143, 160))
742866	26150152	It is down-regulated, frequently due to hypermethylation, in esophageal, prostate, breast and colon cancers, together with glioma (oncosuppressor function), although it is up-regulated in papillary thyroid cancer (oncogenic role).	('esophageal', 'Disease', (61, 71))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('papillary thyroid cancer', 'Disease', (188, 212))	('up-regulated', 'PosReg', (172, 184))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (188, 212))	('down-regulated', 'NegReg', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('thyroid cancer', 'Phenotype', 'HP:0002890', (198, 212))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (188, 212))	('colon cancers', 'Phenotype', 'HP:0003003', (94, 107))	('hypermethylation', 'Var', (40, 56))	('breast and colon cancers', 'Disease', 'MESH:D001943', (83, 107))	('glioma', 'Disease', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('prostate', 'Disease', (73, 81))
742872	26150152	Apart from the full-length protein, the cleavage of a leader peptide yields the shorter protein called augurin, and further cleavage of the last carboxyl terminal 16 amino acids produces the so-called CDelta16 augurin.	('cleavage', 'Var', (124, 132))	('CDelta16', 'Chemical', '-', (201, 209))	('augurin', 'Gene', '84417', (210, 217))	('augurin', 'Gene', '84417', (103, 110))	('augurin', 'Gene', (210, 217))	('augurin', 'Gene', (103, 110))
742955	26150152	No somatic mutations have been found in the ECRG4 gene in esophageal cancer tissues, although hypermethylation of a 5' CpG island in its promoter region is one of the main silencing mechanisms in esophageal cancer cell lines.	('esophageal cancer', 'Disease', (58, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('hypermethylation', 'Var', (94, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('esophageal cancer', 'Disease', (196, 213))	('ECRG4', 'Gene', (44, 49))
742957	26150152	They are also associated with significantly shorter survival, ECRG4 expression being an independent prognostic factor for ESCC patients.	('ECRG4', 'Var', (62, 67))	('survival', 'MPA', (52, 60))	('ESCC', 'Disease', (122, 126))	('patients', 'Species', '9606', (127, 135))	('shorter', 'NegReg', (44, 51))
742969	26150152	CpG site hypermethylation is considered to be the main mechanism of down-regulation in these neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (93, 102))	('neoplasms', 'Disease', (93, 102))	('hypermethylation', 'Var', (9, 25))	('down-regulation', 'NegReg', (68, 83))	('neoplasms', 'Phenotype', 'HP:0002664', (93, 102))
742971	26150152	ECRG4 hypermethylation has been reported for cell lines from colorectal, hepatocellular and breast carcinoma.	('breast carcinoma', 'Disease', 'MESH:D001943', (92, 108))	('breast carcinoma', 'Disease', (92, 108))	('hypermethylation', 'Var', (6, 22))	('breast carcinoma', 'Phenotype', 'HP:0003002', (92, 108))	('colorectal', 'Disease', (61, 71))	('hepatocellular', 'Disease', (73, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))
742974	26150152	Jurkat and 293T cells transfected with ECRG4 have been reported to show a significantly slower growth rate.	('Jurkat', 'CellLine', 'CVCL:0065', (0, 6))	('293T', 'CellLine', 'CVCL:0063', (11, 15))	('rat', 'Species', '10116', (102, 105))	('transfected', 'Var', (22, 33))	('ECRG4', 'Gene', (39, 44))	('growth rate', 'CPA', (95, 106))	('slower', 'NegReg', (88, 94))
742975	26150152	Over-expression of ECRG4 into squamous cell carcinoma of the head and neck M2 cell line inhibits cell proliferation and promotes cell cycle arrest and apoptosis, together with Bax upregulation and Bcl-2 and Cyclin A down-regulation.	('M2', 'CellLine', 'CVCL:U035', (75, 77))	('Bcl-2', 'Gene', (197, 202))	('Over-expression', 'Var', (0, 15))	('apoptosis', 'CPA', (151, 160))	('Bax', 'Gene', (176, 179))	('arrest', 'Disease', (140, 146))	('Cyclin A', 'Gene', (207, 215))	('rat', 'Species', '10116', (109, 112))	('Bax', 'Gene', '581', (176, 179))	('Bcl-2', 'Gene', '596', (197, 202))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('cell proliferation', 'CPA', (97, 115))	('upregulation', 'PosReg', (180, 192))	('arrest', 'Disease', 'MESH:D006323', (140, 146))	('Cyclin A', 'Gene', '890', (207, 215))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 53))	('promotes', 'PosReg', (120, 128))	('inhibits', 'NegReg', (88, 96))	('down-regulation', 'NegReg', (216, 231))	('ECRG4', 'Gene', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('squamous cell carcinoma', 'Disease', (30, 53))
742979	26150152	Decreased cell proliferation has been reported in human lung epithelial cells in response to ECRG4 over-expression.	('rat', 'Species', '10116', (22, 25))	('cell proliferation', 'CPA', (10, 28))	('Decreased', 'NegReg', (0, 9))	('over-expression', 'Var', (99, 114))	('ECRG4', 'Gene', (93, 98))	('human', 'Species', '9606', (50, 55))
742988	26150152	ECRG4 is down-regulated and hypermethylated in glioma.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('ECRG4', 'Gene', (0, 5))	('glioma', 'Disease', (47, 53))	('down-regulated', 'NegReg', (9, 23))	('hypermethylated', 'Var', (28, 43))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
742994	26150152	Functional ECRG4 knock-down in developing zebrafish increases cell proliferation of GFAP-positive cells at the ventricular surface and produces severe defects, including a ventricular hydrocephalus-like edema phenotype.	('hydrocephalus', 'Phenotype', 'HP:0000238', (184, 197))	('defects', 'MPA', (151, 158))	('zebrafish', 'Species', '7955', (42, 51))	('edema', 'Disease', (203, 208))	('increases', 'PosReg', (52, 61))	('ECRG4', 'Gene', (11, 16))	('rat', 'Species', '10116', (74, 77))	('cell proliferation', 'CPA', (62, 80))	('knock-down', 'Var', (17, 27))	('ventricular hydrocephalus', 'Disease', (172, 197))	('ventricular hydrocephalus', 'Disease', 'MESH:D006849', (172, 197))	('edema', 'Disease', 'MESH:D004487', (203, 208))	('edema', 'Phenotype', 'HP:0000969', (203, 208))
742996	26150152	The secreted form of ECRG4 is present in the culture medium of senescent oligodendrocyte precursor cells, and the addition of recombinant mouse ECRG4 induces senescence of mouse oligodendrocyte precursor cells and neural progenitor cells of the dentate gyrus.	('ECRG4', 'Gene', (144, 149))	('addition', 'Var', (114, 122))	('mouse', 'Species', '10090', (138, 143))	('mouse', 'Species', '10090', (172, 177))	('senescence', 'CPA', (158, 168))
743026	26150152	In addition, the C-terminal domain of ECRG4 (ECRG4133-148) may be processed and shed in a thrombin-like consensus sequence or internalised by cells through binding to the TLR4 innate immunity receptor complex.	('TLR4', 'Gene', (171, 175))	('thrombin', 'Gene', (90, 98))	('ECRG4133-148', 'Var', (45, 57))	('ECRG4', 'Gene', (38, 43))	('thrombin', 'Gene', '2147', (90, 98))	('TLR4', 'Gene', '7099', (171, 175))	('binding', 'Interaction', (156, 163))
743029	26150152	Thus, during injury and inflammatory responses, cell surface processing of ECRG4 by proteases may generate peptides (such as ECRG4133-148) which in turn activate other cells.	('ECRG4133-148', 'Var', (125, 137))	('peptides', 'MPA', (107, 115))	('rat', 'Species', '10116', (102, 105))	('activate', 'PosReg', (153, 161))	('ECRG4', 'Protein', (75, 80))
743030	26150152	It has recently been suggested that ECRG4 inhibition of tumour growth is exerted more by immunosurveillance than classic tumour suppression.	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour growth', 'Disease', (56, 69))	('ECRG4', 'Var', (36, 41))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour growth', 'Disease', 'MESH:D006130', (56, 69))	('tumour', 'Disease', (121, 127))	('tumour', 'Disease', (56, 62))
743033	26150152	Conversely, ECRG4 transfection in intracranially injected glioma cells has been reported to increase survival and decrease tumour burden.	('tumour burden', 'Disease', (123, 136))	('tumour burden', 'Disease', 'MESH:D009369', (123, 136))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('ECRG4 transfection', 'Var', (12, 30))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('increase', 'PosReg', (92, 100))	('survival', 'CPA', (101, 109))	('decrease', 'NegReg', (114, 122))	('glioma', 'Disease', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
743036	26150152	The intact thrombin cleavage site in ECRG4 was found to be necessary for microglia activation and chemo-attraction of myeloid cells, ECRG4133-148 being the main peptide involved.	('thrombin', 'Gene', (11, 19))	('microglia', 'CPA', (73, 82))	('thrombin', 'Gene', '2147', (11, 19))	('ECRG4', 'Gene', (37, 42))	('ECRG4133-148', 'Var', (133, 145))
743037	26150152	In conclusion, membrane-bound ECRG4 may be considered as a sentinel factor processed by proteases (thrombin) to give soluble pro-inflammatory ECRG4 forms (ECRG4133-148) which then exert anti-tumoral activity through recruitment and activation of immune cells.	('thrombin', 'Gene', '2147', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('ECRG4133-148', 'Var', (155, 167))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('thrombin', 'Gene', (99, 107))
743041	26150152	Instead, knock-down of endogenous ECRG4 mRNA with siRNA in Jurkat FasR cells causes decreased survival rates and increased sensitivity to alterations in mitochondrial membrane depolarisation after Fas stimulation.	('survival rates', 'CPA', (94, 108))	('Fas', 'Chemical', 'MESH:C038178', (197, 200))	('rat', 'Species', '10116', (103, 106))	('Jurkat', 'CellLine', 'CVCL:0065', (59, 65))	('ECRG4', 'Gene', (34, 39))	('knock-down', 'Var', (9, 19))	('increased', 'PosReg', (113, 122))	('Fas', 'Chemical', 'MESH:C038178', (66, 69))	('decreased', 'NegReg', (84, 93))	('rat', 'Species', '10116', (142, 145))
743044	26150152	ECRG4 transduction of fibroblasts in vitro produces a significant decrease in the rate of directional migration, in the absence of changes in proliferation.	('rat', 'Species', '10116', (149, 152))	('ECRG4 transduction', 'Var', (0, 18))	('rat', 'Species', '10116', (105, 108))	('rat', 'Species', '10116', (82, 85))	('decrease', 'NegReg', (66, 74))
743052	26150152	It is down-regulated, frequently due to hypermethylation, in various tumours, including esophageal, prostate, breast and colon cancers, together with glioma (oncosuppressor function).	('tumours', 'Disease', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colon cancers', 'Phenotype', 'HP:0003003', (121, 134))	('down-regulated', 'NegReg', (6, 20))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('hypermethylation', 'Var', (40, 56))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('glioma', 'Disease', (150, 156))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('prostate', 'Disease', (100, 108))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('esophageal', 'Disease', (88, 98))	('breast and colon cancers', 'Disease', 'MESH:D001943', (110, 134))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
743058	25693567	Instead, different genomic regions vary by up to 5-fold in the local density of somatic mutations, posing a fundamental problem for statistical methods of cancer genomics.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
743060	25693567	We investigated the distribution of mutations in multiple samples of diverse cancer types and compared them to cell-type-specific epigenomic features.	('cancer type', 'Disease', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (36, 45))	('cancer type', 'Disease', 'MESH:D009369', (77, 88))
743061	25693567	Here, we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutation', 'Var', (132, 140))	('chromatin accessibility', 'MPA', (19, 42))	('modification', 'MPA', (47, 59))
743064	25693567	We show further that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))
743073	25693567	We compared the genomic distribution of mutations in these cancer genomes to 424 epigenetic features that were measured by the Epigenome Roadmap consortium [EC00].	('mutations', 'Var', (40, 49))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
743080	25693567	As another example, even though H3K4me1 marks in melanocytes and hepatocytes are highly correlated (r=0.8), the distribution of mutations in liver cancer followed the levels of H3K4me1 in hepatocytes, but not in melanocytes, while melanoma mutations correlated with the levels of H3K4me1 in melanocytes but not in hepatocytes (Figure 1c).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutations', 'Var', (128, 137))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('liver cancer', 'Phenotype', 'HP:0002896', (141, 153))	('liver cancer', 'Disease', 'MESH:D006528', (141, 153))	('liver cancer', 'Disease', (141, 153))
743081	25693567	Remarkably epigenetic marks, together with replication timing measured in ENCODE cell lines , collectively explained 74-86% of the variance in mutation density in seven cancer types (Figure 2a).	('mutation', 'Var', (143, 151))	('cancer type', 'Disease', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('explained', 'Reg', (107, 116))	('cancer type', 'Disease', 'MESH:D009369', (169, 180))	('epigenetic marks', 'Var', (11, 27))
743083	25693567	This is substantially higher than in earlier studies and indicates that, at least for these cancer types, we have identified a set of epigenetic variables and cell types that almost fully predict the mutational variability along the genome.	('cancer type', 'Disease', 'MESH:D009369', (92, 103))	('mutational variability', 'Var', (200, 222))	('predict', 'Reg', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer type', 'Disease', (92, 103))
743085	25693567	As a point of direct comparison with an earlier study that did not use cell type specific chromatin marks, our model explained 50% of the variance in mutation density in the melanoma cell line COLO829, for which the earlier study explained 29% of the variance.	('COLO829', 'CellLine', 'CVCL:1137', (193, 200))	('mutation', 'Var', (150, 158))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))
743089	25693567	There was a sweeping association between cancer mutations and chromatin marks measured in the cell type of origin of each cancer (Figures 3a).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('mutations', 'Var', (48, 57))
743094	25693567	Lung adenocarcinoma and lung squamous cell carcinoma were the only exceptions in that the top predictors were scattered among different tissue groups; the lack of tissue specificity in these cases likely results from the absence of epigenetic marks from normal lung epithelial cells in our dataset.	('absence', 'NegReg', (221, 228))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (24, 52))	('adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (29, 52))	('epigenetic marks', 'Var', (232, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
743095	25693567	The results of the Random Forest regression were confirmed using backward feature selection to identify the minimal set of epigenetic predictors of mutations in each cancer type (Methods).	('cancer type', 'Disease', 'MESH:D009369', (166, 177))	('mutations', 'Var', (148, 157))	('cancer type', 'Disease', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
743097	25693567	The above results pose a key question on whether epigenomic features derived from the cell type of origin are the strongest determinants of cancer mutations, or whether they simply serve as the best available proxies to the chromatin organization of the corresponding malignant cells.	('mutations', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
743099	25693567	Surprisingly, in both cases, epigenomic features from the cell type of origin resulted in a higher prediction accuracy than those from the cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('prediction', 'MPA', (99, 109))	('higher', 'PosReg', (92, 98))	('epigenomic features', 'Var', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (139, 145))
743103	25693567	First, most of the mutations observed in cancers may arise prior to the epigenetic changes linked to neoplastic progression.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (19, 28))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
743108	25693567	Thus, mutational patterns contain sufficient information for identifying the cell type of origin of a tumor.	('mutational', 'Var', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))
743124	25693567	We also determined the mutation densities for all possible types of mutations in each cancer types by counting different types of mutations in 1 Mb windows and normalizing for the sequence composition of each window.	('cancer type', 'Disease', (86, 97))	('mutations', 'Var', (130, 139))	('cancer type', 'Disease', 'MESH:D009369', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))
743145	25157773	Predictors of therapy selection for patients with cT2N0 esophageal cancer in the NCDB from 1998-2011 were identified with multivariable logistic regression.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('patients', 'Species', '9606', (36, 44))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('esophageal cancer', 'Disease', (56, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cT2N0', 'Var', (50, 55))
743153	25157773	Induction therapy for patients with cT2N0 esophageal cancer in the NCDB is not associated with improved survival.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('esophageal cancer', 'Disease', (42, 59))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cT2N0', 'Var', (36, 41))
743159	25157773	The purpose of this study was to use one of the largest nationwide cancer databases to test the hypothesis that induction therapy followed by surgical resection is associated with improved survival compared to initial treatment with surgical resection for patients with cT2N0 esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (287, 293))	('N', 'Chemical', 'MESH:D009584', (273, 274))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('patients', 'Species', '9606', (256, 264))	('esophageal cancer', 'Disease', (276, 293))	('improved', 'PosReg', (180, 188))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('esophageal cancer', 'Disease', 'MESH:D004938', (276, 293))	('cT2N0', 'Var', (270, 275))
743208	25157773	In addition, the T2N0M0 esophageal cancer substage was included in a randomized trial that demonstrated a survival benefit to induction chemoradiotherapy followed by surgery compared to surgery alone for esophageal or esophagogastric junction cancer.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('esophageal cancer', 'Disease', (24, 41))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('esophageal or esophagogastric junction cancer', 'Disease', 'MESH:D004938', (204, 249))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('esophageal or esophagogastric junction cancer', 'Disease', (204, 249))	('T2N0M0', 'Var', (17, 23))
743215	25157773	On the other hand, while considering that 69.8% of cT2N0 patients are correctly staged as node negative, a strategy of induction therapy for cT2N0 disease may lead to administration of chemoradiation that may not have been necessary in over two-thirds of cases.	('patients', 'Species', '9606', (57, 65))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('N', 'Chemical', 'MESH:D009584', (144, 145))	('cT2N0', 'Var', (141, 146))	('lead to', 'Reg', (159, 166))
743221	25157773	The benefit of induction therapy for patients who truly have N0 disease prior to therapy is likely to be minimal given their better prognosis, and may needlessly subject these patients to the risks associated with chemotherapy and radiotherapy.	('patients', 'Species', '9606', (176, 184))	('subject', 'Reg', (162, 169))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('patients', 'Species', '9606', (37, 45))	('N0 disease', 'Var', (61, 71))
743238	25157773	As many as 55% of patients with clinically staged T2N0 esophageal cancers have previously been reported as having nodal disease after resection.	('nodal disease', 'Disease', 'MESH:D013611', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('nodal disease', 'Disease', (114, 127))	('T2N0', 'Var', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('esophageal cancers', 'Disease', (55, 73))	('esophageal cancers', 'Disease', 'MESH:D004938', (55, 73))	('patients', 'Species', '9606', (18, 26))	('N', 'Chemical', 'MESH:D009584', (52, 53))
743239	25157773	The specificity and the sensitivity for identifying lymph node disease is better for EUS-FNA compared to EUS alone.	('lymph node disease', 'Disease', (52, 70))	('EUS-FNA', 'Var', (85, 92))	('lymph node disease', 'Phenotype', 'HP:0002733', (52, 70))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('lymph node disease', 'Disease', 'MESH:D000072717', (52, 70))
743241	25157773	In conclusion, treatment of cT2N0 esophageal cancer is variable.	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cT2N0', 'Var', (28, 33))	('N', 'Chemical', 'MESH:D009584', (31, 32))
743246	25157773	Although prospective studies in the form of either a randomized trial or via creation of a prospective registry would be ideal to more definitively establish optimal treatment, this current study suggests that the most efficient treatment strategy for cT2N0 esophageal cancer is initial surgery.	('esophageal cancer', 'Disease', (258, 275))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('esophageal cancer', 'Disease', 'MESH:D004938', (258, 275))	('N', 'Chemical', 'MESH:D009584', (255, 256))	('cT2N0', 'Var', (252, 257))
743268	21603589	A variety of approaches has been employed to isolate CSCs, often based on markers characteristic of normal stem cells such as CD44, CD133, CD15, CXCR4, etc.	('CD15', 'Gene', (139, 143))	('CD133', 'Var', (132, 137))	('CXCR4', 'Gene', (145, 150))	('CD15', 'Gene', '2526', (139, 143))	('CD44', 'Gene', '960', (126, 130))	('CXCR4', 'Gene', '7852', (145, 150))	('CD44', 'Gene', (126, 130))
743274	21603589	Cells isolated from primary lung tumors that are CD133+ show increased tumorigenicity and expression of stemness, adhesion, and drug efflux genes compared with the corresponding CD133- tumor cells.	('increased', 'PosReg', (61, 70))	('expression', 'MPA', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('primary lung tumors', 'Disease', (20, 39))	('tumor', 'Disease', (185, 190))	('adhesion', 'Gene', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('stemness', 'Gene', (104, 112))	('CD133+', 'Var', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (71, 76))	('primary lung tumors', 'Disease', 'MESH:D008175', (20, 39))	('lung tumor', 'Phenotype', 'HP:0100526', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('lung tumors', 'Phenotype', 'HP:0100526', (28, 39))
743282	21603589	Its expression was first identified in breast CSCs as these cells seem to express CD44 variant isoforms, rather than a CD133+ population.	('CD44', 'Gene', '960', (82, 86))	('CD44', 'Gene', (82, 86))	('variant', 'Var', (87, 94))
743297	21603589	In esophageal cancer, patients with deficient ALDH showed high risk for developing cancer, although there is no report to date about the existence of ALDH1 in esophageal CSC.	('cancer', 'Disease', (14, 20))	('deficient', 'Var', (36, 45))	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('ALDH1', 'Gene', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('ALDH1', 'Gene', '216', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', (83, 89))	('ALDH', 'Gene', (46, 50))
743304	21603589	For example, aberrant Wnt pathway has been shown to play a role in NSCLC such as Wnt2 is overexpressed in NSCLC and inhibition of Wnt2-mediated signaling leads to apoptosis in NSCLC cell lines.	('Wnt pathway', 'Pathway', (22, 33))	('Wnt2', 'Gene', (130, 134))	('SCLC', 'Phenotype', 'HP:0030357', (68, 72))	('SCLC', 'Phenotype', 'HP:0030357', (107, 111))	('Wnt2', 'Gene', (81, 85))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('overexpressed', 'PosReg', (89, 102))	('apoptosis', 'CPA', (163, 172))	('Wnt2', 'Gene', '7472', (130, 134))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('NSCLC', 'Disease', (67, 72))	('SCLC', 'Phenotype', 'HP:0030357', (177, 181))	('NSCLC', 'Disease', (106, 111))	('Wnt2', 'Gene', '7472', (81, 85))	('inhibition', 'Var', (116, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('NSCLC', 'Disease', (176, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (176, 181))
743307	21603589	Interestingly, the Wnt inhibitor Dickkopf-1 (Dkk-1) is expressed in distal pulmonary epithelium and studies have shown that knocking out Dkk-1 inhibits branching morphogenesis.	('Dkk-1', 'Gene', (45, 50))	('inhibits', 'NegReg', (143, 151))	('Dkk-1', 'Gene', '22943', (137, 142))	('Dickkopf-1', 'Gene', '22943', (33, 43))	('Dkk-1', 'Gene', (137, 142))	('Dkk-1', 'Gene', '22943', (45, 50))	('branching morphogenesis', 'CPA', (152, 175))	('Dickkopf-1', 'Gene', (33, 43))	('knocking out', 'Var', (124, 136))
743318	21603589	Although it is not yet clear if both lung and esophageal CSCs require Hedgehog signaling for self-renewal, several studies have suggested that specific inhibitors targeting the Hedgehog pathway could hamper tumor growth, some of which are currently in clinical trails for lung SCLC.	('inhibitors', 'Var', (152, 162))	('hamper', 'NegReg', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('lung SCLC', 'Disease', (272, 281))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('lung SCLC', 'Disease', 'MESH:D018288', (272, 281))	('SCLC', 'Phenotype', 'HP:0030357', (277, 281))	('tumor', 'Disease', (207, 212))	('Hedgehog pathway', 'Pathway', (177, 193))
743334	21603589	Also, in glioma, radiation induced DNA damage to a similar degree in CD133+ and CD133- cells, but CD133+ cells repaired DNA damage more efficiently and rapidly than CD133- cells.	('CD133+', 'Var', (98, 104))	('glioma', 'Disease', (9, 15))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('glioma', 'Disease', 'MESH:D005910', (9, 15))
743336	21603589	Inhibition of this response radiosensitized CD133+ glioma cells.	('glioma', 'Disease', (51, 57))	('Inhibition', 'Var', (0, 10))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (51, 57))
743340	21603589	Interestingly, beta-catenin expression spiked immediately with increasing irradiation doses and when the expression of beta-catenin was suppressed by Wnt antagonist Dkk1, Eca109R50Gy cells displayed an enhancement of radiosensitivity.	('beta-catenin', 'Gene', '1499', (119, 131))	('radiosensitivity', 'CPA', (217, 233))	('suppressed', 'NegReg', (136, 146))	('expression', 'MPA', (28, 38))	('Eca109R50Gy', 'Var', (171, 182))	('Dkk1', 'Gene', (165, 169))	('beta-catenin', 'Gene', (15, 27))	('beta-catenin', 'Gene', (119, 131))	('enhancement', 'PosReg', (202, 213))	('beta-catenin', 'Gene', '1499', (15, 27))	('men', 'Species', '9606', (209, 212))	('expression', 'MPA', (105, 115))	('Dkk1', 'Gene', '22943', (165, 169))
743347	21603589	Reoxygenation between dose fractions is generally believed to improve the efficacy of radiation treatment by increasing tumor radiosensitivity.	('tumor radiosensitivity', 'Phenotype', 'HP:0010997', (120, 142))	('increasing', 'PosReg', (109, 119))	('improve', 'PosReg', (62, 69))	('men', 'Species', '9606', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Reoxygenation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
743351	21603589	Activation of HIF2alpha induces the expression of Oct-4, which is a central player in CSC self-renewal.	('Oct-4', 'Gene', (50, 55))	('HIF2alpha', 'Gene', '2034', (14, 23))	('Oct-4', 'Gene', '5460', (50, 55))	('Activation', 'Var', (0, 10))	('HIF2alpha', 'Gene', (14, 23))	('expression', 'MPA', (36, 46))
743359	21603589	The human radioresistant esophageal cancer cell line, Eca109R50Gy had increased G0/G1 phase proportion, decreased G2/M phase proportion, and lower apoptosis rate compared with its parental cells, indicating they are relatively quiescent.	('human', 'Species', '9606', (4, 9))	('esophageal cancer', 'Disease', (25, 42))	('increased', 'PosReg', (70, 79))	('decreased', 'NegReg', (104, 113))	('G2/M phase proportion', 'CPA', (114, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (25, 42))	('G0/G1 phase proportion', 'CPA', (80, 102))	('apoptosis rate', 'CPA', (147, 161))	('lower', 'NegReg', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Eca109R50Gy', 'Var', (54, 65))
743467	33609251	This study was performed to identify if the short-term oncological and perioperative outcomes following RALE were better than that following TLE.	('RALE', 'Phenotype', 'HP:0030830', (104, 108))	('RALE', 'Var', (104, 108))	('TLE', 'Disease', 'MESH:D004833', (141, 144))	('TLE', 'Disease', (141, 144))
743503	33609251	This can help identify if RALE can contribute to better lymph node yield without increasing the risk of RLN injury and possibly contribute to better survival.	('RALE', 'Phenotype', 'HP:0030830', (26, 30))	('RLN injury', 'Disease', (104, 114))	('RLN injury', 'Disease', 'MESH:D014947', (104, 114))	('RALE', 'Var', (26, 30))	('better', 'PosReg', (49, 55))	('lymph node yield', 'CPA', (56, 72))	('contribute', 'Reg', (128, 138))
743542	32408886	The change in CRP also showed a similar change to WBC count, which was statistically different from the value before treatment (P = 0.014), as shown in Table 1.	('change', 'Reg', (40, 46))	('CRP', 'Gene', '1401', (14, 17))	('change', 'Var', (4, 10))	('WBC count', 'MPA', (50, 59))	('CRP', 'Gene', (14, 17))
743548	32408886	Improper treatment will induce other serious postoperative complications including thoracic infection, empyema, MODS, and septic shock, and can even be life-threatening in severe cases.	('infection', 'Disease', 'MESH:D007239', (92, 101))	('empyema', 'Disease', 'MESH:D004653', (103, 110))	('empyema', 'Disease', (103, 110))	('induce', 'Reg', (24, 30))	('Improper treatment', 'Var', (0, 18))	('septic shock', 'Disease', 'MESH:D012772', (122, 134))	('postoperative complications', 'Disease', (45, 72))	('postoperative complications', 'Disease', 'MESH:D011183', (45, 72))	('shock', 'Phenotype', 'HP:0031273', (129, 134))	('septic shock', 'Disease', (122, 134))	('septic shock', 'Phenotype', 'HP:0100806', (122, 134))	('infection', 'Disease', (92, 101))	('MODS', 'Disease', (112, 116))
743597	32219034	The mRNA expression levels in the NFI family were significantly downregulated in most cancers compared with normal tissues and DNA hypermethylation might downregulate the NFI family expression.	('expression', 'MPA', (182, 192))	('NFI family', 'Gene', (34, 44))	('hypermethylation', 'Var', (131, 147))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mRNA expression levels', 'MPA', (4, 26))	('downregulate', 'NegReg', (154, 166))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('NFI', 'Protein', (171, 174))	('downregulated', 'NegReg', (64, 77))
743600	32219034	Further survival analyses based on the KM plotter and SurvExpress databases showed dysregulations of the NFI genes were significantly correlated with survival outcomes in breast, lung, and head and neck cancers.	('NFI genes', 'Gene', (105, 114))	('head and neck cancer', 'Phenotype', 'HP:0012288', (189, 209))	('head and neck cancers', 'Phenotype', 'HP:0012288', (189, 210))	('head and neck cancers', 'Disease', 'MESH:D006258', (189, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('dysregulations', 'Var', (83, 97))	('breast', 'Disease', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('lung', 'Disease', (179, 183))	('correlated with', 'Reg', (134, 149))
743648	32219034	Breast invasive carcinoma patients with a NFIX gene alteration showed significantly poor overall survival (OS) and disease-free survival (DFS) compared with breast invasive carcinoma patients without NFIX gene alteration.	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (157, 182))	('OS', 'Chemical', '-', (107, 109))	('poor', 'NegReg', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('Breast invasive carcinoma', 'Disease', (0, 25))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (0, 25))	('alteration', 'Var', (52, 62))	('disease-free survival', 'CPA', (115, 136))	('NFIX', 'Gene', (42, 46))	('Breast invasive carcinoma', 'Disease', 'MESH:D018270', (0, 25))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (157, 182))	('overall survival', 'CPA', (89, 105))	('breast invasive carcinoma', 'Disease', (157, 182))
743653	32219034	Decreased NFIA expression showed better RFS, OS and DMFS in the HER2-enriched subtype.	('OS', 'Chemical', '-', (45, 47))	('NFIA', 'Protein', (10, 14))	('Decreased', 'NegReg', (0, 9))	('DMFS', 'Var', (52, 56))	('RFS', 'MPA', (40, 43))	('expression', 'MPA', (15, 25))	('better', 'PosReg', (33, 39))
743667	32219034	The NFI genes in lung cancer were analyzed and depicted as oncoprints representing mutation, amplification, deep deletion, mRNA high, mRNA low, and multiple alterations (Figs.	('amplification', 'Var', (93, 106))	('deep deletion', 'Var', (108, 121))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('NFI', 'Gene', (4, 7))
743668	32219034	Lung adenocarcinoma patients with NFIB gene alteration showed better DFS compared with lung adenocarcinoma patients without NFIB gene alteration (Fig.	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('better', 'PosReg', (62, 68))	('DFS', 'MPA', (69, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('NFIB', 'Gene', (34, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('gene alteration', 'Var', (39, 54))
743669	32219034	Lung squamous cell carcinoma patients with NFIA gene alteration showed worse OS compared with lung squamous cell carcinoma patients without NFIA gene alterations (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (94, 122))	('gene alteration', 'Var', (48, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('lung squamous cell carcinoma', 'Disease', (94, 122))	('OS', 'Chemical', '-', (77, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('squamous cell carcinoma', 'Disease', (5, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))
743686	32219034	Bladder urothelial carcinoma patients with NFIB gene alteration showed significantly better OS compared with bladder urothelial patients without NFIB gene alteration.	('better', 'PosReg', (85, 91))	('urothelial carcinoma', 'Disease', (8, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('gene alteration', 'Var', (48, 63))	('NFIB', 'Gene', (43, 47))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (8, 28))	('OS', 'Chemical', '-', (92, 94))	('bladder urothelial', 'Disease', 'MESH:D001745', (109, 127))	('bladder urothelial', 'Disease', (109, 127))
743701	32219034	Head and neck cancer patients with NFIA gene alteration showed better OS compared with head and neck cancer patients without NFIA gene alteration.	('OS', 'Chemical', '-', (70, 72))	('neck cancer', 'Disease', 'MESH:D006258', (96, 107))	('NFIA', 'Gene', (35, 39))	('head and neck cancer', 'Phenotype', 'HP:0012288', (87, 107))	('neck cancer', 'Disease', 'MESH:D006258', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('neck cancer', 'Disease', (9, 20))	('Head and neck cancer', 'Phenotype', 'HP:0012288', (0, 20))	('better', 'PosReg', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gene alteration', 'Var', (40, 55))	('neck cancer', 'Disease', (96, 107))
743730	32219034	The NFI genes in kidney cancer were analyzed and depicted as oncoprints representing mutation, amplification, deep deletion, mRNA high, mRNA low and multiple alterations (Figs.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('kidney cancer', 'Phenotype', 'HP:0009726', (17, 30))	('kidney cancer', 'Disease', 'MESH:D007680', (17, 30))	('deep deletion', 'Var', (110, 123))	('kidney cancer', 'Disease', (17, 30))	('amplification', 'Var', (95, 108))	('NFI', 'Gene', (4, 7))
743732	32219034	Kidney renal papillary cell carcinoma patients with NFIX gene alteration showed worse OS compared with kidney renal papillary cell carcinoma patients without NFIX gene alteration (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('kidney renal papillary cell carcinoma', 'Disease', (103, 140))	('OS', 'Chemical', '-', (86, 88))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (103, 140))	('Kidney renal papillary cell carcinoma', 'Disease', (0, 37))	('gene alteration', 'Var', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (0, 37))	('NFIX', 'Gene', (52, 56))
743769	32219034	In the KM plotter database, high NFIA and NFIX expression predicted better OS and disease-specific survival (DSS) in liver cancer patients.	('DSS', 'Chemical', '-', (109, 112))	('NFIX', 'Protein', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('disease-specific survival', 'CPA', (82, 107))	('better', 'PosReg', (68, 74))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('OS', 'Chemical', '-', (75, 77))	('liver cancer', 'Disease', 'MESH:D006528', (117, 129))	('liver cancer', 'Disease', (117, 129))	('NFIA', 'Protein', (33, 37))	('high', 'Var', (28, 32))
743787	32219034	Survival analysis indicated that almost none of the NFI genes with gene alterations were associated with OS or DFS.	('associated', 'Reg', (89, 99))	('gene alterations', 'Var', (67, 83))	('NFI genes', 'Gene', (52, 61))	('OS', 'Chemical', '-', (105, 107))	('DFS', 'Disease', (111, 114))
743788	32219034	These findings indicate that NFI gene alterations might not independently influence its transcription in various tumors.	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('alterations', 'Var', (38, 49))	('NFI gene', 'Gene', (29, 37))	('transcription', 'MPA', (88, 101))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
743792	32219034	Glioblastoma multiforme (GBM) patients with higher NFIB expression survived significantly longer than patients with lower NFIB expression.	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('Glioblastoma multiforme', 'Disease', (0, 23))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('expression', 'Var', (56, 66))	('NFIB', 'Gene', (51, 55))
743793	32219034	In another study, NFIX DNA hypermethylation was reportedly associated with significantly decreased NFIX expression and was related to shorter OS and RFS in patients with lung adenocarcinoma.	('hypermethylation', 'Var', (27, 43))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('RFS', 'MPA', (149, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('OS', 'Chemical', '-', (142, 144))	('lung adenocarcinoma', 'Disease', (170, 189))	('shorter OS', 'Disease', (134, 144))	('expression', 'MPA', (104, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('NFIX', 'Protein', (99, 103))	('NFIX', 'Gene', (18, 22))	('decreased', 'NegReg', (89, 98))
743795	32219034	In a previous study, high NFIA expression was shown an independent predictor of poor prognosis in esophageal squamous carcinoma, and high NFIB expression was a negative prognostic value in esophagogastric junction adenocarcinoma.	('high', 'Var', (133, 137))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (189, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('high', 'Var', (21, 25))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (109, 127))	('esophagogastric junction adenocarcinoma', 'Disease', (189, 228))	('esophagogastric junction adenocarcinoma', 'Disease', 'MESH:C537006', (189, 228))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (98, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (98, 127))	('esophageal squamous carcinoma', 'Disease', (98, 127))
743797	32219034	In the present study, high expression of NFIA, NFIB and NFIX was significantly associated with improved prognosis in breast cancer.	('high expression', 'Var', (22, 37))	('NFIX', 'Gene', (56, 60))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('NFIB', 'Gene', (47, 51))	('improved', 'PosReg', (95, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('NFIA', 'Gene', (41, 45))
743803	32219034	In gastric cancer, high NFIX expression was significantly correlated with better overall prognosis in gastric cancer and HER2+ gastric cancer, and marginally correlated with PPS in HER2-gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HER2-gastric cancer', 'Disease', 'MESH:D013274', (181, 200))	('gastric cancer', 'Disease', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('gastric cancer', 'Disease', (127, 141))	('NFIX', 'Protein', (24, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (127, 141))	('better', 'PosReg', (74, 80))	('HER2-gastric cancer', 'Disease', (181, 200))	('PPS', 'Chemical', '-', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', (3, 17))	('expression', 'MPA', (29, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('high', 'Var', (19, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
743809	32219034	The breast cancer cell line, MCF7, treated with NFIC siRNA, enhanced EMT, motility, migration and invasion.	('EMT', 'CPA', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('NFIC', 'Var', (48, 52))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('MCF7', 'CellLine', 'CVCL:0031;0.06756287128990074', (29, 33))	('invasion', 'CPA', (98, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('motility', 'CPA', (74, 82))	('enhanced', 'PosReg', (60, 68))
743812	32219034	Genomic analysis showed the alterations in each NFI family gene were less frequent in various tumors and had little influence on survival outcomes.	('NFI family gene', 'Gene', (48, 63))	('alterations', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('less', 'NegReg', (69, 73))
743814	32219034	A certain negative correlation was observed, indicating that epigenetic alteration is an important mechanism of dysregulated NFI expression in human cancers.	('cancers', 'Disease', (149, 156))	('NFI', 'Gene', (125, 128))	('cancers', 'Disease', 'MESH:D009369', (149, 156))	('epigenetic alteration', 'Var', (61, 82))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
744134	28744162	The inclusion of the full set (C1-C10) of ICD-9 variable clusters in the initial multivariate logistic LASSO regression model resulted in five retained clusters (C1, C2, C6, C8, and C10).	('C10', 'Gene', (34, 37))	('C10', 'Gene', '3226', (182, 185))	('C10', 'Gene', '3226', (34, 37))	('ICD-9', 'Gene', (42, 47))	('C1', 'Var', (162, 164))	('C10', 'Gene', (182, 185))
744137	28744162	CART analysis generated a recursive tree with three cluster indicator variables (C2, C6, C8) and four terminal nodes (TN) (Figure 1).	('C8', 'Var', (89, 91))	('CART', 'Gene', (0, 4))	('CART', 'Gene', '9607', (0, 4))	('C2', 'Var', (81, 83))
744157	28744162	The classification model using a hybrid LASSO/CART approach with a cutoff of Z1>=2 (Table 3D) retained similar identification accuracy (AUROC=86%; PPV=82%).	('Z1>=2', 'Var', (77, 82))	('CART', 'Gene', (46, 50))	('CART', 'Gene', '9607', (46, 50))
744161	28744162	The agreement between the hybrid five-cluster variable model with Z1>=2 as the cutoff and the CART three-cluster models was "outstanding" (kappa=0.93; 95% CI: 0.88-0.97).	('CART', 'Gene', '9607', (94, 98))	('CART', 'Gene', (94, 98))	('Z1>=2', 'Var', (66, 71))
744172	26528858	Mutually exclusive mutations in NOTCH1 and PIK3CA associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China Recurrent genetic abnormalities that correlate with clinical features could be used to determine patients' prognosis, select treatments and predict responses to therapy.	('genetic abnormalities', 'Disease', (169, 190))	('PIK3CA', 'Gene', '5290', (43, 49))	('NOTCH1', 'Gene', '4851', (32, 38))	('NOTCH1', 'Gene', (32, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (115, 149))	('patients', 'Species', '9606', (256, 264))	('mutations', 'Var', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('genetic abnormalities', 'Disease', 'MESH:D030342', (169, 190))	('esophageal squamous cell carcinoma', 'Disease', (115, 149))	('associated', 'Reg', (50, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('PIK3CA', 'Gene', (43, 49))
744174	26528858	Univariate and multivariate analyses with Cox proportional hazards model were used to examine the association between mutations and overall survival and response to chemotherapy.	('Cox', 'Gene', (42, 45))	('overall', 'CPA', (132, 139))	('mutations', 'Var', (118, 127))	('Cox', 'Gene', '1351', (42, 45))
744176	26528858	We identified statistically significant mutual exclusivity between mutations in NOTCH1 and PIK3CA in ESCC samples.	('PIK3CA', 'Gene', (91, 97))	('PIK3CA', 'Gene', '5290', (91, 97))	('mutations', 'Var', (67, 76))	('ESCC', 'Disease', (101, 105))	('NOTCH1', 'Gene', (80, 86))
744177	26528858	Mutations in NOTCH1 were associated with well-differentiated, early-stage malignancy and less metastasis to regional lymph nodes.	('malignancy', 'Disease', (74, 84))	('well-differentiated', 'CPA', (41, 60))	('associated', 'Reg', (25, 35))	('NOTCH1', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('less metastasis to regional lymph nodes', 'CPA', (89, 128))	('malignancy', 'Disease', 'MESH:D009369', (74, 84))
744178	26528858	Nonetheless, patients with NOTCH1 mutations had shorter survival times than patients without NOTCH1 mutations, and failed to respond to chemotherapy.	('patients', 'Species', '9606', (76, 84))	('survival times', 'CPA', (56, 70))	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (48, 55))	('NOTCH1', 'Gene', (27, 33))	('mutations', 'Var', (34, 43))
744179	26528858	In contrast, patients with mutations in PIK3CA had better responses to chemotherapy and longer survival times than patients without PIK3CA mutations.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (115, 123))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('patients', 'Species', '9606', (13, 21))	('PIK3CA', 'Gene', '5290', (132, 138))	('responses to chemotherapy', 'MPA', (58, 83))	('better', 'PosReg', (51, 57))	('PIK3CA', 'Gene', (132, 138))	('longer', 'PosReg', (88, 94))	('survival times', 'CPA', (95, 109))
744180	26528858	In a genetic analysis of ESCCs from patients in China, we identified mutually exclusive mutations in NOTCH1 and PIK3CA.	('NOTCH1', 'Gene', (101, 107))	('patients', 'Species', '9606', (36, 44))	('PIK3CA', 'Gene', '5290', (112, 118))	('mutations', 'Var', (88, 97))	('PIK3CA', 'Gene', (112, 118))
744196	26528858	In this study, we describe the identification and validation of mutually exclusive mutational patterns of NOTCH1 and PIK3CA, two significantly mutated genes (SMGs) identified in ESCC via genomic analyses, and their associations with clinical variables.	('mutational', 'Var', (83, 93))	('PIK3CA', 'Gene', (117, 123))	('NOTCH1', 'Gene', (106, 112))	('PIK3CA', 'Gene', '5290', (117, 123))	('associations', 'Interaction', (215, 227))	('ESCC', 'Disease', (178, 182))
744198	26528858	Mutations of SMGs are likely to be 'drivers' in pathogenesis and these genes may affect the biology of a given tumor.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('SMGs', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (81, 87))
744201	26528858	Although one patient was found, and further validated via PCR-Sanger sequencing, with concomitant mutations of NOTCH1 and PIK3CA, the frequency of double mutations was 0.0096, which is not significantly different from 0.0 by chi-squared analysis.	('PIK3CA', 'Gene', (122, 128))	('patient', 'Species', '9606', (13, 20))	('PIK3CA', 'Gene', '5290', (122, 128))	('mutations', 'Var', (98, 107))	('NOTCH1', 'Gene', (111, 117))
744204	26528858	When the tumors from cohorts #1 and #2 (n=193), that recruited patients from Taihang Mountains and exhibited similar pattern of NOTCH1 and PIK3CA mutations, were combined, this mutually exclusive pattern between NOTCH1 and PIK3CA mutations was highly significant (Figure 1F).	('PIK3CA', 'Gene', '5290', (139, 145))	('mutations', 'Var', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PIK3CA', 'Gene', (223, 229))	('NOTCH1', 'Gene', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('patients', 'Species', '9606', (63, 71))	('PIK3CA', 'Gene', '5290', (223, 229))	('PIK3CA', 'Gene', (139, 145))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('NOTCH1', 'Gene', (128, 134))
744205	26528858	Together, these data suggest that there is a strong inverse relationship between the NOTCH1 and PIK3CA mutations in ESCC that was previously undiscovered.	('mutations', 'Var', (103, 112))	('ESCC', 'Gene', (116, 120))	('NOTCH1', 'Gene', (85, 91))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('inverse', 'NegReg', (52, 59))
744206	26528858	The overall frequency of tumor samples with NOTCH1 or PIK3CA mutations in cohort #1 or #2 was statistically higher than that of cohort #3 or #4 (Supplementary Figure 1B).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('PIK3CA', 'Gene', '5290', (54, 60))	('tumor', 'Disease', (25, 30))	('mutations', 'Var', (61, 70))	('NOTCH1', 'Gene', (44, 50))	('higher', 'PosReg', (108, 114))	('PIK3CA', 'Gene', (54, 60))
744207	26528858	Moreover, the frequencies of the most common tumor-associated PIK3CA mutations, involving either the helical domain (exon 9: c.1624G>A:p.Glu542Lys and c.1633G>A:p.Glu545Lys) or kinase domain (exon 20: c.3140A>G:p.His1047Arg), were significantly different among these cohorts, with 77.8% (14/18) in cohort #1, 85.7% (12/14) in cohort #2, 75% (3/4) in cohort #3, and 25% (2/8) in cohort #5 (Supplementary Figure 1C).	('p.His1047Arg', 'Mutation', 'rs121913279', (211, 223))	('p.His1047Arg', 'Var', (211, 223))	('c.1624G>A', 'Mutation', 'rs121913273', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('c.1633G>A', 'Var', (151, 160))	('c.3140A>G:p.His1047Arg', 'Var', (201, 223))	('tumor', 'Disease', (45, 50))	('PIK3CA', 'Gene', (62, 68))	('c.3140A>G', 'Mutation', 'rs121913279', (201, 210))	('p.Glu545Lys', 'Mutation', 'rs104886003', (161, 172))	('PIK3CA', 'Gene', '5290', (62, 68))	('c.1633G>A', 'Mutation', 'rs104886003', (151, 160))	('c.1624G>A', 'Var', (125, 134))	('p.Glu542Lys', 'Mutation', 'rs121913273', (135, 146))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
744214	26528858	In cohort #1, NOTCH1 mutations were significantly associated with well-differentiation (P = 0.001) and an absence of regional lymph node metastases (N0, P = 0.002), and were dramatically enriched in stage I tumors (P = 0.011, Table 1).	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('absence', 'NegReg', (106, 113))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('I tumors', 'Disease', (205, 213))	('metastases', 'Disease', (137, 147))	('well-differentiation', 'CPA', (66, 86))	('I tumors', 'Disease', 'MESH:D009369', (205, 213))	('NOTCH1', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
744215	26528858	The association of NOTCH1 mutations with tumor stage and lymph node metastasis also held true in this cohort (P < 0.0001, Supplementary Table 2).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('NOTCH1', 'Gene', (19, 25))	('lymph node metastasis', 'CPA', (57, 78))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
744216	26528858	Collectively, our results strongly suggest that the NOTCH1 mutations were associated with ESCC metastasis; ESCC patients who harbor NOTCH1 mutations show less risk of metastasis.	('NOTCH1', 'Gene', (132, 138))	('mutations', 'Var', (139, 148))	('patients', 'Species', '9606', (112, 120))	('NOTCH1', 'Gene', (52, 58))	('mutations', 'Var', (59, 68))	('ESCC', 'Disease', (90, 94))	('associated', 'Reg', (74, 84))
744217	26528858	However, PIK3CA mutations were not correlated with clinicopathological characteristics, including tumor differentiation, pathologic stage, and lymph node metastasis.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PIK3CA', 'Gene', (9, 15))	('tumor', 'Disease', (98, 103))	('PIK3CA', 'Gene', '5290', (9, 15))
744218	26528858	Next, we used Kaplan-Meier analysis to assess the impact of NOTCH1 or PIK3CA mutations on OS in cohort #1 and validated it in cohort #2.	('PIK3CA', 'Gene', (70, 76))	('PIK3CA', 'Gene', '5290', (70, 76))	('mutations', 'Var', (77, 86))	('NOTCH1', 'Gene', (60, 66))
744219	26528858	The patients showed a median OS of 60 months and 80 months for the NOTCH1-mutated and NOTCH1-wild type (WT) groups, respectively, in cohort #1 (Table 1).	('NOTCH1-mutated', 'Var', (67, 81))	('NOTCH1-wild', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
744220	26528858	Surprisingly, although ESCC patients with NOTCH1 mutations showed less risk of metastasis, the association of NOTCH1 mutations with OS was not statistically significant (Log-rank (Mantel-Cox), P = 0.310, Figure 2A; Cox regression analysis, P = 0.318, Figure 2B).	('NOTCH1', 'Gene', (110, 116))	('mutations', 'Var', (117, 126))	('mutations', 'Var', (49, 58))	('Cox', 'Gene', '1351', (215, 218))	('Cox', 'Gene', (187, 190))	('NOTCH1', 'Gene', (42, 48))	('Cox', 'Gene', '1351', (187, 190))	('patients', 'Species', '9606', (28, 36))	('metastasis', 'CPA', (79, 89))	('Cox', 'Gene', (215, 218))
744222	26528858	We did, however, find a significant effect on OS for the PIK3CA mutations.	('PIK3CA', 'Gene', '5290', (57, 63))	('effect', 'Reg', (36, 42))	('mutations', 'Var', (64, 73))	('PIK3CA', 'Gene', (57, 63))
744223	26528858	The PIK3CA mutations showed a positive correlation with OS (log-rank P = 0.048) in cohort #1 (Figure 3A).	('correlation', 'Interaction', (39, 50))	('mutations', 'Var', (11, 20))	('PIK3CA', 'Gene', (4, 10))	('PIK3CA', 'Gene', '5290', (4, 10))
744225	26528858	These data indicate that the PIK3CA mutation may be a marker of favorable prognosis for ESCC patients from the population in Taihang Mountains, Northern China.	('ESCC', 'Disease', (88, 92))	('patients', 'Species', '9606', (93, 101))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('mutation', 'Var', (36, 44))
744226	26528858	Based on the mutually exclusivity of NOTCH1 and PIK3CA, ESCC patients could be divided into three groups: patients with NOTCH1 mutations, patients with PIK3CA mutations, and patients without mutations of either gene (Supplementary Table 4).	('ESCC', 'Disease', (56, 60))	('PIK3CA', 'Gene', '5290', (152, 158))	('PIK3CA', 'Gene', (152, 158))	('mutations', 'Var', (159, 168))	('PIK3CA', 'Gene', (48, 54))	('NOTCH1', 'Gene', (120, 126))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (106, 114))	('PIK3CA', 'Gene', '5290', (48, 54))	('mutations', 'Var', (127, 136))	('patients', 'Species', '9606', (138, 146))
744227	26528858	We extended our survival analysis in these groups and found that patients with PIK3CA mutations had a significantly longer OS (median OS of 80.9 months) than patients without mutations in either gene (median OS 40 months) (log-rank P = 0.026, Figure 4A; Cox regression analysis, P = 0.037, Figure 4B).	('mutations', 'Var', (86, 95))	('longer', 'PosReg', (116, 122))	('Cox', 'Gene', '1351', (254, 257))	('Cox', 'Gene', (254, 257))	('PIK3CA', 'Gene', (79, 85))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (158, 166))	('PIK3CA', 'Gene', '5290', (79, 85))
744228	26528858	Notably, although NOTCH1 mutations were significantly associated with tumor well-differentiation, early pathologic stage, and low lymph node metastasis, patients with NOTCH1 mutations tended to have an even shorter OS than patients with PIK3CA mutations; the OS of patients with NOTCH1 mutations was not different from that of patients without mutations in these two genes (Cox regression analysis, P = 0.144, Figure 4B).	('NOTCH1', 'Gene', (18, 24))	('Cox', 'Gene', (374, 377))	('low lymph node metastasis', 'Disease', 'MESH:D009362', (126, 151))	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('patients', 'Species', '9606', (265, 273))	('PIK3CA', 'Gene', '5290', (237, 243))	('mutations', 'Var', (174, 183))	('low lymph node metastasis', 'Disease', (126, 151))	('low lymph node', 'Phenotype', 'HP:0002732', (126, 140))	('associated', 'Reg', (54, 64))	('patients', 'Species', '9606', (327, 335))	('patients', 'Species', '9606', (153, 161))	('NOTCH1', 'Gene', (167, 173))	('tumor', 'Disease', (70, 75))	('Cox', 'Gene', '1351', (374, 377))	('PIK3CA', 'Gene', (237, 243))	('patients', 'Species', '9606', (223, 231))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
744229	26528858	PIK3CA mutations correlate with OS (Cox regression analysis, P < 0.001, HR=0.002, 95% CI: 0.0-0.038, Figure 4D), whereas NOTCH1 mutations show no correlation with OS (Cox regression analysis, P = 0.561, Figure 4D).	('Cox', 'Gene', '1351', (167, 170))	('Cox', 'Gene', (167, 170))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('Cox', 'Gene', '1351', (36, 39))	('Cox', 'Gene', (36, 39))	('mutations', 'Var', (7, 16))
744232	26528858	In cohort #1, 70 patients received standard chemotherapy, including 16 patients with NOTCH1 mutations, 12 patients with PIK3CA mutations, 1 patient with both the NOTCH1 and PIK3CA mutations, and 41 patients with neither NOTCH1 nor PIK3CA mutations (Supplementary Table 5).	('PIK3CA', 'Gene', '5290', (173, 179))	('PIK3CA', 'Gene', (231, 237))	('PIK3CA', 'Gene', (120, 126))	('patient', 'Species', '9606', (198, 205))	('PIK3CA', 'Gene', '5290', (231, 237))	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (71, 79))	('patient', 'Species', '9606', (106, 113))	('patient', 'Species', '9606', (17, 24))	('patient', 'Species', '9606', (140, 147))	('NOTCH1', 'Gene', (85, 91))	('mutations', 'Var', (92, 101))	('PIK3CA', 'Gene', '5290', (120, 126))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (106, 114))	('mutations', 'Var', (127, 136))	('patient', 'Species', '9606', (71, 78))	('PIK3CA', 'Gene', (173, 179))
744235	26528858	Patients with NOTCH1 mutations showed a median OS of 27.09 months, whereas those with PIK3CA mutations showed a median OS of 80 months.	('PIK3CA', 'Gene', (86, 92))	('Patients', 'Species', '9606', (0, 8))	('PIK3CA', 'Gene', '5290', (86, 92))	('NOTCH1', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
744237	26528858	Of 17 patients who had NOTCH1 mutations and received standard chemotherapy, 70.6% (12 out of 17) exhibited failure of chemotherapy.	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (30, 39))	('NOTCH1', 'Gene', (23, 29))
744238	26528858	Surprisingly, we found no benefit of standard chemotherapy for patients with NOTCH1 mutations compared to those with mutations in neither gene (P = 0.389, Fisher's exact test).	('mutations', 'Var', (84, 93))	('NOTCH1', 'Gene', (77, 83))	('patients', 'Species', '9606', (63, 71))
744239	26528858	Conversely, having a PIK3CA mutation was associated with a better response than having mutations in neither gene (P = 0.026, Fisher's exact test).	('mutation', 'Var', (28, 36))	('PIK3CA', 'Gene', (21, 27))	('response', 'MPA', (66, 74))	('PIK3CA', 'Gene', '5290', (21, 27))
744240	26528858	Of 13 patients with PIK3CA mutations who received standard chemotherapy, only 23% (3 out of 13) showed failure of chemotherapy.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (20, 26))	('patients', 'Species', '9606', (6, 14))	('PIK3CA', 'Gene', '5290', (20, 26))
744241	26528858	Moreover, patients with PIK3CA mutations showed significantly better responses than those with NOTCH1 mutations (P = 0.01, Fisher's exact test, Figure 5A, right panel).	('mutations', 'Var', (31, 40))	('responses', 'MPA', (69, 78))	('PIK3CA', 'Gene', (24, 30))	('better', 'PosReg', (62, 68))	('PIK3CA', 'Gene', '5290', (24, 30))	('patients', 'Species', '9606', (10, 18))
744242	26528858	This cohort included 18 patients with NOTCH1 mutations, 14 patients with PIK3CA mutations, and 57 patients mutations in neither gene.	('PIK3CA', 'Gene', '5290', (73, 79))	('mutations', 'Var', (45, 54))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (59, 67))	('NOTCH1', 'Gene', (38, 44))	('PIK3CA', 'Gene', (73, 79))
744243	26528858	Patients in cohort #2 had a median OS of 44.6 months, with a median OS of 32.78 months for patients with NOTCH1 mutations and 60 months for those with PIK3CA mutations.	('patients', 'Species', '9606', (91, 99))	('NOTCH1', 'Gene', (105, 111))	('PIK3CA', 'Gene', (151, 157))	('mutations', 'Var', (112, 121))	('Patients', 'Species', '9606', (0, 8))	('PIK3CA', 'Gene', '5290', (151, 157))
744244	26528858	A total of 13 out of 18 patients with NOTCH1 mutations failed to respond to chemotherapy, whereas 12 out of 14 patients with PIK3CA mutations responded to chemotherapy (P = 0.001, Fisher's exact test, Supplementary Figure 4A and Supplementary Table 5), consistent with the trend seen in cohort #1.	('mutations', 'Var', (45, 54))	('responded', 'MPA', (142, 151))	('PIK3CA', 'Gene', (125, 131))	('NOTCH1', 'Gene', (38, 44))	('patients', 'Species', '9606', (24, 32))	('PIK3CA', 'Gene', '5290', (125, 131))	('patients', 'Species', '9606', (111, 119))
744245	26528858	Next, we examined the effects of NOTCH1 and PIK3CA mutations on the progression-free survival (PFS) of patients in cohorts #1 and #2 who received standard chemotherapy.	('PIK3CA', 'Gene', (44, 50))	('NOTCH1', 'Gene', (33, 39))	('mutations', 'Var', (51, 60))	('PIK3CA', 'Gene', '5290', (44, 50))	('patients', 'Species', '9606', (103, 111))
744246	26528858	As expected, patients in cohort #1 with PIK3CA mutations showed significantly longer PFS than those with NOTCH1 mutations by Log-rank (Mantel-Cox) (P = 0.018, Figure 5B) and univariate analyses (P = 0.03, HR = 4.124, 95% CI: 1.145-14.86, Figure 5C).	('PFS', 'MPA', (85, 88))	('longer', 'PosReg', (78, 84))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (47, 56))	('Cox', 'Gene', '1351', (142, 145))	('Cox', 'Gene', (142, 145))
744247	26528858	Our data suggest that patients with NOTCH1 mutations, who are likely to exhibit a better outcome without chemotherapy, might suffer unnecessarily from side effects of chemotherapy.	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (22, 30))	('NOTCH1', 'Gene', (36, 42))
744248	26528858	However, patients with PIK3CA mutations could benefit from standard chemotherapy, and could thus survive longer.	('patients', 'Species', '9606', (9, 17))	('PIK3CA', 'Gene', (23, 29))	('PIK3CA', 'Gene', '5290', (23, 29))	('mutations', 'Var', (30, 39))	('benefit', 'PosReg', (46, 53))
744249	26528858	Therefore, PIK3CA mutational status may have a potential role as a biomarker for standard chemotherapy and prognosis in ESCC patients from Taihang Mountains, Northern China.	('mutational', 'Var', (18, 28))	('ESCC', 'Disease', (120, 124))	('PIK3CA', 'Gene', (11, 17))	('PIK3CA', 'Gene', '5290', (11, 17))	('patients', 'Species', '9606', (125, 133))
744251	26528858	However, in our study, we found frequent NOTCH1 mutations in early-stage malignancy and less metastasis to regional lymph nodes, but with poor prognosis in ESCC patients.	('less', 'NegReg', (88, 92))	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('malignancy', 'Disease', (73, 83))	('metastasis to regional lymph nodes', 'CPA', (93, 127))	('patients', 'Species', '9606', (161, 169))	('NOTCH1', 'Gene', (41, 47))	('mutations', 'Var', (48, 57))	('ESCC', 'Disease', (156, 160))
744253	26528858	Therefore, we had very rare relapsed tumors to analyze NOTCH1 mutation status.	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutation', 'Var', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('NOTCH1', 'Gene', (55, 61))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
744254	26528858	Alternatively, we performed mutation analysis of NOTCH1 in regional metastatic lymph nodes from 37 of stage III ESCC patients in cohort #1 and 19 of stage III ESCC patients in cohort #2.	('stage III ESCC', 'Disease', (102, 116))	('patients', 'Species', '9606', (164, 172))	('mutation analysis', 'Var', (28, 45))	('patients', 'Species', '9606', (117, 125))	('NOTCH1', 'Gene', (49, 55))
744259	26528858	However, we observed no correlation of NOTCH1 gene with cell migration and invasion as monitored by the iCELLigence RTCA DP system (Figure 6C-6D), indicating that NOTCH1 may involve cell proliferation but not migration and invasion in ESCC cells.	('NOTCH1', 'Var', (163, 169))	('cell proliferation', 'CPA', (182, 200))	('involve', 'Reg', (174, 181))	('DP', 'Chemical', '-', (121, 123))	('RTCA', 'Gene', (116, 120))	('RTCA', 'Gene', '8634', (116, 120))
744261	26528858	A striking finding of this study is the previously unreported, significant mutually exclusive mutational pattern between NOTCH1 and PIK3CA in ESCC.	('mutational', 'Var', (94, 104))	('ESCC', 'Disease', (142, 146))	('NOTCH1', 'Gene', (121, 127))	('PIK3CA', 'Gene', '5290', (132, 138))	('PIK3CA', 'Gene', (132, 138))
744262	26528858	Moreover, our results suggest that patients who harbor NOTCH1 mutations have a statistically significant association with well differentiation, an early stage of malignancy, and less regional lymph node metastasis; however, they exhibited a poor outcome and failure to respond to standard chemotherapy treatment.	('malignancy', 'Disease', 'MESH:D009369', (162, 172))	('less', 'NegReg', (178, 182))	('malignancy', 'Disease', (162, 172))	('patients', 'Species', '9606', (35, 43))	('well differentiation', 'CPA', (122, 142))	('NOTCH1', 'Gene', (55, 61))	('mutations', 'Var', (62, 71))
744263	26528858	In contrast, patients who harbor PIK3CA mutations showed a better response to standard chemotherapy and exhibited favorable survival.	('PIK3CA', 'Gene', '5290', (33, 39))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (40, 49))	('better', 'PosReg', (59, 65))	('PIK3CA', 'Gene', (33, 39))	('response', 'MPA', (66, 74))
744267	26528858	The frequencies of PIK3CA and NOTCH1 mutations in cohorts #1 and #2 (from Taihang Mountain, Northern China) were higher than those of cohorts #3 (from Chaoshan District, Southern China) and cohorts #4 and #5 (recruited from CICAMS, where patients came from all over the country and did not have a limited geographic distribution pattern).	('PIK3CA', 'Gene', (19, 25))	('PIK3CA', 'Gene', '5290', (19, 25))	('higher', 'PosReg', (113, 119))	('NOTCH1', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (238, 246))
744270	26528858	NOTCH1 was mutated in around 20% out of ESCC patients, and correlated with well differentiation, early TNM stage, and absence of regional lymph node metastases.	('ESCC', 'Disease', (40, 44))	('metastases', 'Disease', (149, 159))	('TNM', 'Gene', '10178', (103, 106))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('well differentiation', 'CPA', (75, 95))	('TNM', 'Gene', (103, 106))	('patients', 'Species', '9606', (45, 53))	('NOTCH1', 'Gene', (0, 6))	('mutated', 'Var', (11, 18))
744271	26528858	The close link between NOTCH1 mutation types and clinicopathological features leads us to speculate that ESCC patients with NOTCH1 mutations may have a better prognosis.	('NOTCH1', 'Gene', (124, 130))	('mutations', 'Var', (131, 140))	('ESCC', 'Disease', (105, 109))	('patients', 'Species', '9606', (110, 118))
744273	26528858	Meanwhile, a worse response to standard chemotherapy was observed on patients with NOTCH1 mutations compared to those with PIK3CA mutations.	('mutations', 'Var', (90, 99))	('PIK3CA', 'Gene', (123, 129))	('PIK3CA', 'Gene', '5290', (123, 129))	('patients', 'Species', '9606', (69, 77))	('NOTCH1', 'Gene', (83, 89))
744276	26528858	Considering that NOTCH1 mutations associated with early stage and non-lymph node metastasis that was supporting by both genetics alterations and functional study, however, no statistically significant differences in patient outcome and standard chemotherapy benefit were observed in patients contained NOTCH1 mutations, we speculate that there is a possibility that patients harbor NNOTCH1 mutations who should exhibit a better outcome may suffer side-effect of chemotherapy or receive extra treatment.	('patient', 'Species', '9606', (366, 373))	('NOTCH1', 'Gene', (302, 308))	('associated', 'Reg', (34, 44))	('mutations', 'Var', (390, 399))	('patients', 'Species', '9606', (283, 291))	('NNOTCH1', 'Gene', (382, 389))	('patient', 'Species', '9606', (216, 223))	('patients', 'Species', '9606', (366, 374))	('NOTCH1', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))	('suffer', 'Reg', (440, 446))	('patient', 'Species', '9606', (283, 290))
744279	26528858	In our and others' cohorts of ESCC patients, many of the missense mutations in the NOTCH1 gene occurred at or near identified important domains, such as the ligand-binding domain (EGF repeats) and the majority of the mutations were predicted to alter the protein N-terminal to the transmembrane region.	('missense mutations', 'Var', (57, 75))	('alter', 'Reg', (245, 250))	('protein', 'Protein', (255, 262))	('patients', 'Species', '9606', (35, 43))	('mutations', 'Var', (217, 226))	('NOTCH1', 'Gene', (83, 89))
744280	26528858	c.2234G>A:p.Trp745*) observed in NOTCH1 gene generate a premature stop codon, which results in a truncated NOTCH1 protein that lacks the C-terminal domain, which contains a proline-glutamate-serine-threonine (PEST) sequence and is important for transcription activation.	('results in', 'Reg', (84, 94))	('NOTCH1', 'Gene', (33, 39))	('glutamate', 'Chemical', 'MESH:D018698', (181, 190))	('protein', 'Protein', (114, 121))	('threonine', 'Chemical', 'MESH:D013912', (198, 207))	('p.Trp745*', 'Mutation', 'p.W745*', (10, 19))	('proline', 'Chemical', 'MESH:D011392', (173, 180))	('truncated', 'MPA', (97, 106))	('serine', 'Chemical', 'MESH:D012694', (191, 197))	('c.2234G>A', 'Mutation', 'c.2234G>A', (0, 9))	('NOTCH1', 'Gene', (107, 113))	('c.2234G>A', 'Var', (0, 9))
744281	26528858	Thus, although the activating mutations in NOTCH1 were identified in T-cell acute lymphoblastic leukemia, chronic lymphoblastic leukemia, and breast cancer, the pattern of the mutations in genes that involve the NOTCH pathway suggests its potential tumor suppressing roles in ESCC, as has been reported for head and neck squamous cell carcinoma, chronic myelomonocytic leukemia, and lung squamous cell carcinoma.	('mutations', 'Var', (176, 185))	('activating', 'PosReg', (19, 29))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (307, 344))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (383, 411))	('breast cancer', 'Disease', (142, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('tumor', 'Disease', (249, 254))	('NOTCH', 'Gene', (212, 217))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (388, 411))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (346, 377))	('lung squamous cell carcinoma', 'Disease', (383, 411))	('squamous cell carcinoma', 'Disease', (321, 344))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (114, 136))	('chronic lymphoblastic leukemia', 'Disease', 'MESH:D015451', (106, 136))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (82, 104))	('NOTCH', 'Gene', '4851;18128', (212, 217))	('chronic lymphoblastic leukemia', 'Phenotype', 'HP:0005550', (106, 136))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (388, 411))	('lymphoblastic leukemia', 'Disease', (82, 104))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (69, 104))	('chronic myelomonocytic leukemia', 'Disease', (346, 377))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (321, 344))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('NOTCH', 'Gene', (43, 48))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (76, 104))	('mutations', 'Var', (30, 39))	('chronic lymphoblastic leukemia', 'Disease', (106, 136))	('leukemia', 'Phenotype', 'HP:0001909', (369, 377))	('ESCC', 'Disease', (276, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (402, 411))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (114, 136))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (383, 411))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('leukemia', 'Phenotype', 'HP:0001909', (128, 136))	('NOTCH', 'Gene', '4851;18128', (43, 48))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (346, 377))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (82, 104))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (321, 344))
744282	26528858	This interpretation is consistent with the functional studies of the role of NOTCH1 in ESCC cells, as NOTCH1 depletion promotes tumor cell proliferation in tissue culture.	('promotes', 'PosReg', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('depletion', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('NOTCH1', 'Gene', (102, 108))	('tumor', 'Disease', (128, 133))
744283	26528858	Inhibition of NOTCH1 pathway has been shown to sensitize cancer cells to chemotherapy in prostate cancer, ovarian cancer, colon cancer, and glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('cancer', 'Disease', (57, 63))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (89, 104))	('cancer', 'Disease', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('NOTCH1 pathway', 'Pathway', (14, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('prostate cancer', 'Disease', (89, 104))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('ovarian cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('sensitize', 'Reg', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Inhibition', 'Var', (0, 10))	('colon cancer', 'Disease', (122, 134))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('glioma', 'Disease', (140, 146))	('cancer', 'Disease', (114, 120))
744284	26528858	Recent studies have aimed to develop antibodies against specific NOTCH receptors and ligands with the hope of limiting side effects while providing the same therapeutic benefit as gamma secretase inhibitors (drugs that inhibit NOTCH signaling); these studies were carried out in human cancers with commonly overactivated mutations in NOTCH1 that confer a survival advantage on the tumors, leading to poorer outcomes for the patients.	('NOTCH', 'Gene', (334, 339))	('tumors', 'Phenotype', 'HP:0002664', (381, 387))	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('NOTCH', 'Gene', '4851;18128', (334, 339))	('tumors', 'Disease', (381, 387))	('human', 'Species', '9606', (279, 284))	('survival', 'CPA', (355, 363))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('NOTCH', 'Gene', (227, 232))	('cancers', 'Disease', (285, 292))	('patients', 'Species', '9606', (424, 432))	('tumors', 'Disease', 'MESH:D009369', (381, 387))	('advantage', 'PosReg', (364, 373))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('NOTCH', 'Gene', (65, 70))	('NOTCH', 'Gene', '4851;18128', (227, 232))	('mutations', 'Var', (321, 330))	('overactivated', 'PosReg', (307, 320))	('NOTCH', 'Gene', '4851;18128', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (285, 292))
744286	26528858	In accordance with the previous literature, the PIK3CA mutation could serve as a favorable predictive biomarker in ESCC patients from Taihang Mountains, Northern China.	('ESCC', 'Disease', (115, 119))	('PIK3CA', 'Gene', (48, 54))	('patients', 'Species', '9606', (120, 128))	('PIK3CA', 'Gene', '5290', (48, 54))	('mutation', 'Var', (55, 63))
744287	26528858	However, PIK3CA mutations were not associated with patient outcomes in ESCC patients from the Chaoshan population, Southern China (cohort #3) and from CICAMS, which does not have any geographic distribution limitations (cohort #5).	('patients', 'Species', '9606', (76, 84))	('ESCC', 'Disease', (71, 75))	('mutations', 'Var', (16, 25))	('patient', 'Species', '9606', (51, 58))	('PIK3CA', 'Gene', (9, 15))	('patient', 'Species', '9606', (76, 83))	('PIK3CA', 'Gene', '5290', (9, 15))
744289	26528858	In addition to the different mutation frequencies of PIK3CA among the cohorts, the most common tumor-associated PIK3CA mutations (those involving the helical domain (exon 9: c.1624G>A:p.Glu542Lys and c.1633G>A:p.Glu545Lys) or the kinase domain (exon 20: c.3140A>G:p.His1047Arg)) had significantly different frequencies among these cohorts.	('p.Glu545Lys', 'Mutation', 'rs104886003', (210, 221))	('c.3140A>G', 'Mutation', 'rs121913279', (254, 263))	('PIK3CA', 'Gene', '5290', (53, 59))	('p.Glu542Lys', 'Mutation', 'rs121913273', (184, 195))	('PIK3CA', 'Gene', '5290', (112, 118))	('c.1624G>A', 'Var', (174, 183))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('p.His1047Arg', 'Mutation', 'rs121913279', (264, 276))	('p.His1047Arg', 'Var', (264, 276))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('c.1633G>A:p.Glu545Lys', 'Var', (200, 221))	('c.1624G>A', 'Mutation', 'rs121913273', (174, 183))	('c.1633G>A', 'Mutation', 'rs104886003', (200, 209))	('PIK3CA', 'Gene', (53, 59))	('PIK3CA', 'Gene', (112, 118))	('tumor', 'Disease', (95, 100))
744290	26528858	In previous studies, the c.1633G>A:p.Glu545Lys and c.3140A>G:p.His1047Arg mutations have been implicated in favorable overall survival in the ESCC patients.	('p.Glu545Lys', 'Mutation', 'rs104886003', (35, 46))	('favorable', 'PosReg', (108, 117))	('c.3140A>G:p.His1047Arg', 'Var', (51, 73))	('p.His1047Arg', 'Mutation', 'rs121913279', (61, 73))	('p.His1047Arg', 'Var', (61, 73))	('c.1633G>A:p.Glu545Lys', 'Var', (25, 46))	('c.3140A>G', 'Mutation', 'rs121913279', (51, 60))	('patients', 'Species', '9606', (147, 155))	('c.1633G>A', 'Mutation', 'rs104886003', (25, 34))	('ESCC', 'Disease', (142, 146))	('p.Glu545Lys', 'Var', (35, 46))
744291	26528858	PIK3CA has been named as the key oncogenic effector and could be a potential driver mutation in tumorigenesis of ESCC and these mutants have previously shown oncogenic effects in vivo and may act as a p otential target site of treatment as in other cancer types.	('ESCC', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutants', 'Var', (128, 135))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Disease', (96, 101))	('cancer', 'Disease', (249, 255))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('oncogenic effects', 'CPA', (158, 175))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
744292	26528858	We speculate that the lower frequency of mutations in PIK3CA hotspots in cohort #5 results in a negative association between PIK3CA mutations and survival.	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', '5290', (54, 60))	('survival', 'MPA', (146, 154))	('mutations', 'Var', (132, 141))	('negative', 'NegReg', (96, 104))	('PIK3CA', 'Gene', (125, 131))	('PIK3CA', 'Gene', '5290', (125, 131))	('PIK3CA', 'Gene', (54, 60))
744293	26528858	Moreover, our previous mutational signature analysis showed that hotspot mutations (c.1624G>A:p.Glu542Lys, c.1633G>A:p.Glu545Lys) of PIK3CA were significantly enriched in ESCC tumors that had an apolipoprotein B mRNA-editing enzyme catalytic (APOBEC) signature in both cohort #1 and cohort #3, which implicates APOBEC activity as a common key driver of PIK3CA mutagenesis in ESCC patients from Northern or Southern populations in China.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PIK3CA', 'Gene', (353, 359))	('apolipoprotein B', 'Gene', (195, 211))	('ESCC tumors', 'Disease', (171, 182))	('c.1624G>A:', 'Var', (84, 94))	('c.1633G>A', 'Var', (107, 116))	('PIK3CA', 'Gene', (133, 139))	('PIK3CA', 'Gene', '5290', (133, 139))	('apolipoprotein B', 'Gene', '338', (195, 211))	('PIK3CA', 'Gene', '5290', (353, 359))	('patients', 'Species', '9606', (380, 388))	('c.1624G>A', 'Mutation', 'rs121913273', (84, 93))	('p.Glu542Lys', 'Mutation', 'rs121913273', (94, 105))	('ESCC tumors', 'Disease', 'MESH:D004938', (171, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('c.1633G>A', 'Mutation', 'rs104886003', (107, 116))	('p.Glu545Lys', 'Mutation', 'rs104886003', (117, 128))
744294	26528858	Therefore, the effect of PIK3CA mutations on survival prognosis might be observed when cohort #3 is extended to increase the sample size.	('mutations', 'Var', (32, 41))	('PIK3CA', 'Gene', '5290', (25, 31))	('effect', 'Reg', (15, 21))	('PIK3CA', 'Gene', (25, 31))
744295	26528858	Together with previously reported NGS data, our results document for the first time that NOTCH1 and PIK3CA mutations are mutually exclusive alterations in ESCC.	('mutations', 'Var', (107, 116))	('PIK3CA', 'Gene', (100, 106))	('NOTCH1', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (100, 106))	('ESCC', 'Disease', (155, 159))
744296	26528858	Although NOTCH1 mutations had a statistically significant association with well-differentiation, early stage of malignancy and less regional lymph node metastasis in ESCC, patients who harbor NOTCH1 mutations would not benefit from standard chemotherapy, and alternative therapeutic strategy must be developed for these patients.	('mutations', 'Var', (16, 25))	('less regional lymph node metastasis', 'CPA', (127, 162))	('NOTCH1', 'Gene', (192, 198))	('patients', 'Species', '9606', (320, 328))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('patients', 'Species', '9606', (172, 180))	('mutations', 'Var', (199, 208))	('NOTCH1', 'Gene', (9, 15))	('ESCC', 'Disease', (166, 170))	('malignancy', 'Disease', (112, 122))	('well-differentiation', 'CPA', (75, 95))
744297	26528858	Conversely, patients who harbor PIK3CA mutations could benefit from standard chemotherapy, and thus PIK3CA mutational status may have a potential role as a biomarker for standard chemotherapy and prognosis.	('patients', 'Species', '9606', (12, 20))	('PIK3CA', 'Gene', '5290', (32, 38))	('benefit', 'PosReg', (55, 62))	('PIK3CA', 'Gene', (100, 106))	('mutations', 'Var', (39, 48))	('PIK3CA', 'Gene', '5290', (100, 106))	('PIK3CA', 'Gene', (32, 38))
744298	26528858	These results raise the possibility for the categorization of ESCC using the mutations of NOTCH1 and PIK3CA.	('PIK3CA', 'Gene', '5290', (101, 107))	('mutations', 'Var', (77, 86))	('NOTCH1', 'Gene', (90, 96))	('ESCC', 'Disease', (62, 66))	('PIK3CA', 'Gene', (101, 107))
744299	26528858	However, the NOTCH1 and PIK3CA mutated samples represented a small proportion of ESCC, and the majority of samples had wild-type NOTCH1 and PIK3CA.	('PIK3CA', 'Gene', (140, 146))	('PIK3CA', 'Gene', (24, 30))	('ESCC', 'Disease', (81, 85))	('NOTCH1', 'Gene', (13, 19))	('PIK3CA', 'Gene', '5290', (140, 146))	('PIK3CA', 'Gene', '5290', (24, 30))	('mutated', 'Var', (31, 38))
744306	26528858	Additionally, to provide high-confidence mutations, 96 pairs of tumors and matched normal tissue were selected for deep target capture-based validation (TCS, at least 365x).	('mutations', 'Var', (41, 50))	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
744318	26528858	Briefly, n columns correspond to NOTCH1 and PIK3CA mutations and m rows correspond to patients whose tumor samples were collected (with m n).	('PIK3CA', 'Gene', (44, 50))	('NOTCH1', 'Gene', (33, 39))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PIK3CA', 'Gene', '5290', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('patients', 'Species', '9606', (86, 94))
744321	26528858	Fisher's exact test was used to analyze categorical features such as the association of NOTCH1 or PIK3CA mutations with clinical and pathological features, the distribution of gene mutations in different clusters or different cohorts, and the response rate to chemotherapy among the subgroups.	('NOTCH1', 'Gene', (88, 94))	('PIK3CA', 'Gene', (98, 104))	('association', 'Interaction', (73, 84))	('PIK3CA', 'Gene', '5290', (98, 104))	('mutations', 'Var', (105, 114))
744328	26528858	Univariate and multivariate analyses with the Cox proportional hazards model were used to examine the association between mutations and overall survival and response to chemotherapy.	('Cox', 'Gene', '1351', (46, 49))	('Cox', 'Gene', (46, 49))	('overall', 'MPA', (136, 143))	('mutations', 'Var', (122, 131))
744331	26528858	For overexpression experiments, NOTCH1 wild-type and NOTCH1-W745X mutant were cloned into pLV-EGFP(2A)-puro-GFP-vector and validated by sequencing.	('NOTCH1', 'Gene', (32, 38))	('W745X', 'Mutation', 'p.W745X', (60, 65))	('NOTCH1-W745X', 'Var', (53, 65))
744344	23063200	Because there is not a consensus on how to manage T2N0 disease, we examined survival after resection of T2N0 esophageal cancer with or without radiation therapy.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))	('esophageal cancer', 'Disease', (109, 126))	('T2N0', 'Var', (104, 108))
744345	23063200	Patients who underwent resection for T2N0 squamous cell carcinoma or adenocarcinoma of the mid or distal esophagus with or without radiation were identified using the Surveillance, Epidemiology and End Results cancer registry from 1998-2008.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (42, 65))	('squamous cell carcinoma', 'Disease', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('adenocarcinoma of the mid', 'Disease', 'MESH:D000230', (69, 94))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('T2N0', 'Var', (37, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('cancer', 'Disease', (210, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('adenocarcinoma of the mid', 'Disease', (69, 94))
744353	23063200	Combining radiation with esophagectomy did not result in improved outcomes compared to esophagectomy alone for patients with T2N0 esophageal cancer in the Surveillance, Epidemiology and End Results database.	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('T2N0', 'Var', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('esophageal cancer', 'Disease', (130, 147))	('patients', 'Species', '9606', (111, 119))
744357	23063200	In particular, the optimal treatment strategy of T2N0 esophageal cancer is still subject of debate.	('T2N0', 'Var', (49, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('esophageal cancer', 'Disease', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
744360	23063200	Considering this lack of consensus, we aimed to analyze outcomes of a larger patient cohort with T2N0 esophageal cancer using the Surveillance Epidemiology and End Results (SEER) cancer registry and advanced statistical analyses including landmark studies and competing-risks regression in order to provide important additional evidence for guiding future therapy.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('T2N0', 'Var', (97, 101))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('patient', 'Species', '9606', (77, 84))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Disease', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
744364	23063200	The variable "Histologic Type ICD-O-3" (International classifications of Diseases for Oncology, 3rd edition) was used to restrict the study cohort to patients with either squamous cell cancer (codes 8050-8089) or adenocarcinomas (codes 8140-8389).	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('adenocarcinomas', 'Disease', (213, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('squamous cell cancer', 'Disease', 'MESH:D002294', (171, 191))	('patients', 'Species', '9606', (150, 158))	('codes 8140-8389', 'Var', (230, 245))	('Oncology', 'Phenotype', 'HP:0002664', (86, 94))	('squamous cell cancer', 'Disease', (171, 191))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (171, 191))	('codes 8050-8089', 'Var', (193, 208))	('adenocarcinomas', 'Disease', 'MESH:D000230', (213, 228))
744383	23063200	A total of 490 patients with T2N0 esophageal cancer of the mid and lower esophagus were identified in the SEER cancer registry during the study period from 1998 to 2008: 267 (54%) were treated with surgery only and 223 (46%) had both esophagectomy and radiation therapy.	('esophageal cancer', 'Disease', (34, 51))	('patients', 'Species', '9606', (15, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('T2N0', 'Var', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (45, 51))
744392	23063200	In this study using the SEER database, which is the largest United States population based cancer registry, we demonstrate that approximately half of the patients treated with surgery for T2N0M0 esophageal cancer from 1998-2008 also were treated with radiation therapy.	('T2N0M0', 'Var', (188, 194))	('esophageal cancer', 'Disease', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('patients', 'Species', '9606', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
744396	23063200	The treatment of patients with T2N0 esophageal cancer has previously been the subject of debate.	('esophageal cancer', 'Disease', 'MESH:D004938', (36, 53))	('T2N0', 'Var', (31, 35))	('patients', 'Species', '9606', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal cancer', 'Disease', (36, 53))
744398	23063200	Given it's uncommon incidence, the population of patients with T2N0 esophageal cancer is typically underrepresented in studies of multimodality therapy in which T2N0 is included.	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('T2N0', 'Var', (63, 67))	('esophageal cancer', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (49, 57))
744403	23063200	As many as 55% of patients with clinically staged T2N0 esophageal cancers have been reported as having nodal disease after resection.	('nodal disease', 'Disease', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('T2N0', 'Var', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('esophageal cancers', 'Disease', (55, 73))	('esophageal cancers', 'Disease', 'MESH:D004938', (55, 73))	('patients', 'Species', '9606', (18, 26))	('nodal disease', 'Disease', 'MESH:D013611', (103, 116))
744408	23063200	N0 status is associated with decreased likelihood of systemic disease.	('decreased likelihood of systemic disease', 'Disease', 'MESH:D034721', (29, 69))	('decreased likelihood of systemic disease', 'Disease', (29, 69))	('N0 status', 'Var', (0, 9))
744411	23063200	This strategy is supported by others based on gastroesophageal adenocarcinomas, while others advocate for neoadjuvant treatment in cT2N0 esophageal cancer patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cT2N0', 'Var', (131, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('gastroesophageal adenocarcinomas', 'Disease', (46, 78))	('patients', 'Species', '9606', (155, 163))	('esophageal cancer', 'Disease', (137, 154))	('gastroesophageal adenocarcinomas', 'Disease', 'MESH:D005764', (46, 78))
744421	23063200	In conclusion, treatment of T2N0 esophageal cancer is highly variable, as approximately half of patients in the SEER database who were treated with surgery also received radiation therapy.	('T2N0', 'Var', (28, 32))	('esophageal cancer', 'Disease', (33, 50))	('patients', 'Species', '9606', (96, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
744424	23063200	Given the relatively uncommon nature of T2N0 esophageal cancer, clinicians should strongly consider including patients with this stage of disease in multi-institutional registries to allow further evaluation of different treatment strategies and outcomes.	('esophageal cancer', 'Disease', (45, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('T2N0', 'Var', (40, 44))	('patients', 'Species', '9606', (110, 118))
744499	23341788	The high prevalence of comorbidities and poor performance status among the elderly population may reduce treatment tolerance and increase occurrence of adverse events, and may therefore offset the survival gain associated with CRT, with variable results for each elderly patient.	('men', 'Species', '9606', (110, 113))	('comorbidities', 'Disease', (23, 36))	('survival', 'MPA', (197, 205))	('poor', 'Var', (41, 45))	('reduce', 'NegReg', (98, 104))	('patient', 'Species', '9606', (271, 278))	('increase', 'PosReg', (129, 137))	('offset', 'NegReg', (186, 192))	('treatment tolerance', 'CPA', (105, 124))
744518	23341788	In addition, in the fit elderly subgroup with a SCS of <10, hypertension was significantly more common in patients who received CRT than in those who received RT alone, and the distribution of age did not differ between the RT and CRT groups.	('common', 'Reg', (96, 102))	('hypertension', 'Disease', (60, 72))	('CRT', 'Var', (128, 131))	('hypertension', 'Phenotype', 'HP:0000822', (60, 72))	('patients', 'Species', '9606', (106, 114))	('hypertension', 'Disease', 'MESH:D006973', (60, 72))
744570	23300854	The risk of cancer associated with different dosage levels of ALNs shows that, compared to the non-ALN cohort, the adjusted HRs of cancer were increased with an increased dosage in the ALN cohort.	('dosage', 'Var', (171, 177))	('cancer', 'Disease', (131, 137))	('increased', 'PosReg', (143, 152))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('ALN', 'Chemical', 'MESH:D019386', (62, 65))	('cancer', 'Disease', (12, 18))	('ALN', 'Chemical', 'MESH:D019386', (185, 188))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('ALN', 'Chemical', 'MESH:D019386', (99, 102))
744614	23300854	Figure 1 demonstrates that the cancer-free proportions among patients treated with ALN >=1.0 g/year, <1.0 g/year, and in the control group were significantly different over time.	('>=1.0', 'Var', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ALN', 'Chemical', 'MESH:D019386', (83, 86))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('ALN', 'Gene', (83, 86))
744639	21888637	Conventional single agents active in esophageal cancer include cisplatin, 5-FU, etoposide, and mitomycin, with response rates ranging from 15% to 25%.	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('etoposide', 'Chemical', 'MESH:D005047', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mitomycin', 'Chemical', 'MESH:D016685', (95, 104))	('esophageal cancer', 'Disease', (37, 54))	('cisplatin', 'Var', (63, 72))	('5-FU', 'Chemical', 'MESH:D005472', (74, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
744840	20300187	Recent studies indicate the possible roles of HSP72 and gp96 in the development and progression of gastrointestinal carcinomas but detailed information is still ambiguous.	('carcinomas', 'Disease', (116, 126))	('gastrointestinal carcinomas', 'Disease', 'MESH:D004067', (99, 126))	('HSP72', 'Protein', (46, 51))	('carcinoma', 'Disease', 'MESH:D002277', (116, 125))	('gastrointestinal carcinomas', 'Disease', (99, 126))	('gp96', 'Var', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('carcinomas', 'Disease', 'MESH:D002277', (116, 126))	('carcinoma', 'Disease', (116, 125))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (99, 126))
744870	20300187	likely, we analyzed the patients' serum prior to initial treatment, the results indicated that the diagnostic sensitivity of CYFRA 21-1, SCC and CEA were only 45.8%, 24.2%, and 11.7%, and there were no significant correlation between CYFRA 21-1, SCC, CEA and the differentiation of esophageal squamous cell carcinomas, while the expressions of HSP72 and gp96 in esophagheal carcinoma were 93.9% and 85.0%, respectively.	('esophagheal carcinoma', 'Phenotype', 'HP:0011459', (362, 383))	('esophagheal carcinoma', 'Disease', 'MESH:D002277', (362, 383))	('esophageal squamous cell carcinomas', 'Disease', (282, 317))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (293, 316))	('HSP72', 'Protein', (344, 349))	('gp96', 'Var', (354, 358))	('carcinomas', 'Phenotype', 'HP:0030731', (307, 317))	('esophagheal carcinoma', 'Disease', (362, 383))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (293, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (374, 383))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))
744871	20300187	The expression of both HSP72 and gp96 in esophageal squamous cell carcinoma was related to the differentiated tissue type of esophageal squamous cell cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('related', 'Reg', (80, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (125, 156))	('expression', 'MPA', (4, 14))	('esophageal squamous cell carcinoma', 'Disease', (41, 75))	('HSP72', 'Protein', (23, 28))	('gp96', 'Var', (33, 37))	('esophageal squamous cell cancer', 'Disease', (125, 156))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (136, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))
744874	20300187	Our data shows high-level expression of HSP72 and gp96 in esophageal squamous cell carcinomas, and there was a significant correlation between their expression and progression, metastasis of tumors.	('expression', 'MPA', (26, 36))	('metastasis of tumors', 'Disease', (177, 197))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('esophageal squamous cell carcinomas', 'Disease', (58, 93))	('progression', 'CPA', (164, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('gp96', 'Var', (50, 54))	('correlation', 'Reg', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('HSP72', 'Protein', (40, 45))	('metastasis of tumors', 'Disease', 'MESH:D009362', (177, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (69, 93))
744877	33463006	Then, a risk model involving three miRNAs (miR-4521, miR-3682-3p, and miR-1269a) was designed to predict prognosis in EC patients.	('miR-4521', 'Gene', '100616406', (43, 51))	('miR-1269a', 'Gene', (70, 79))	('miR-1269a', 'Gene', '100302177', (70, 79))	('patients', 'Species', '9606', (121, 129))	('miR-3682-3p', 'Var', (53, 64))	('miR-4521', 'Gene', (43, 51))
744888	33463006	MiRNAs have been implicated in a variety of biological processes (BP), thus promote tumor progression, including EC [4].	('promote', 'PosReg', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('MiRNAs', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('EC [4]', 'Disease', (113, 119))
744889	33463006	For example, in our previous study, we found that miR-34a-5p could directly target LEF1 and promote epithelial-mesenchymal transition and progression in esophageal squamous cell carcinoma [5].	('promote', 'PosReg', (92, 99))	('miR-34a-5p', 'Var', (50, 60))	('epithelial-mesenchymal transition', 'CPA', (100, 133))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (153, 187))	('LEF1', 'Gene', '51176', (83, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('LEF1', 'Gene', (83, 87))	('esophageal squamous cell carcinoma', 'Disease', (153, 187))
744891	33463006	The above findings indicate that miRNAs may serve as a promising biomarker for diagnosis, prediction of survival, and precision treatment in cancers.	('miRNAs', 'Var', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
744905	33463006	Moreover, miRNAs could correlate with cancer stem-like properties in various tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('correlate', 'Reg', (23, 32))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Disease', (38, 44))	('miRNAs', 'Var', (10, 16))
744906	33463006	Specifically, miR-181b directly binds to STAT3 and activates downstream CYLD pathways regulating the proliferation of CSCs in esophageal squamous cell carcinoma [16].	('activates', 'PosReg', (51, 60))	('STAT3', 'Gene', (41, 46))	('esophageal squamous cell carcinoma', 'Disease', (126, 160))	('miR-181b', 'Chemical', '-', (14, 22))	('binds', 'Interaction', (32, 37))	('miR-181b', 'Var', (14, 22))	('CYLD', 'Gene', (72, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (126, 160))	('CYLD', 'Gene', '1540', (72, 76))	('STAT3', 'Gene', '6774', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
744943	33463006	Subsequently, multivariate Cox regression analysis followed by LASSO analysis selected three miRNAs (miR-4521, miR-3682-3p, and miR-1269a) to construct prediction model with their coefficient as follows: miRNA risk score = (0.26 x expression of miR-4521) + (0.34 x expression of miR-3682-3p) + (0.07 x expression of miR-1269a).	('miR-1269a', 'Gene', '100302177', (128, 137))	('miR-4521', 'Gene', '100616406', (101, 109))	('miR-4521', 'Gene', '100616406', (245, 253))	('miR-1269a', 'Gene', '100302177', (316, 325))	('miR-3682-3p) + (', 'Var', (279, 295))	('miR-4521', 'Gene', (245, 253))	('miR-4521', 'Gene', (101, 109))	('miR-1269a', 'Gene', (316, 325))	('miR-1269a', 'Gene', (128, 137))
744944	33463006	The Kaplan-Meier curve pointed out that the high expressions of miR-4521, miR-3682-3p, and miR-1269a were associated with poor prognosis of EC patients (Fig.	('miR-3682-3p', 'Var', (74, 85))	('miR-1269a', 'Gene', (91, 100))	('miR-1269a', 'Gene', '100302177', (91, 100))	('miR-4521', 'Gene', '100616406', (64, 72))	('patients', 'Species', '9606', (143, 151))	('miR-4521', 'Gene', (64, 72))
744945	33463006	The survival status in three groups showed that the high-risk score patients had higher mortality rates than the low-risk group (Fig.	('high-risk score', 'Var', (52, 67))	('mortality', 'Disease', (88, 97))	('higher', 'PosReg', (81, 87))	('patients', 'Species', '9606', (68, 76))	('mortality', 'Disease', 'MESH:D003643', (88, 97))
744948	33463006	The overlapping target genes in the Venn diagram implicated 110, 113, and 119 genes presented in three databases as potential target genes for miR-4521, miR-3682-3p, and miR-1269a, respectively (Fig.	('miR-4521', 'Gene', (143, 151))	('miR-4521', 'Gene', '100616406', (143, 151))	('miR-3682-3p', 'Var', (153, 164))	('miR-1269a', 'Gene', '100302177', (170, 179))	('miR-1269a', 'Gene', (170, 179))
745008	33463006	In our study, we found that miR-34a-5p directly targeted LEF1 and inactivated the Hippo signaling pathway, which inhibited invasion and migration of ESCC [5].	('LEF1', 'Gene', '51176', (57, 61))	('inactivated', 'NegReg', (66, 77))	('targeted', 'Reg', (48, 56))	('inhibited', 'NegReg', (113, 122))	('LEF1', 'Gene', (57, 61))	('Hippo signaling pathway', 'Pathway', (82, 105))	('miR-34a-5p', 'Var', (28, 38))
745014	33463006	A three miRNA-based prediction signature including miR-4521, miR-3682-3p, and miR-1269a was obtained in the training group by univariate Cox and multivariate Cox analysis.	('miR-3682-3p', 'Var', (61, 72))	('miR-1269a', 'Gene', (78, 87))	('miR-1269a', 'Gene', '100302177', (78, 87))	('miR-4521', 'Gene', (51, 59))	('miR-4521', 'Gene', '100616406', (51, 59))
745028	33463006	High expression of CBX3 was found to be strongly associated with a more aggressive subtype of C1, C2, and C6, implicating CBX3 as a potential tumor promoter in EC.	('CBX3', 'Gene', '11335', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('High', 'Var', (0, 4))	('tumor', 'Disease', (142, 147))	('associated', 'Reg', (49, 59))	('CBX3', 'Gene', (19, 23))	('CBX3', 'Gene', (122, 126))	('CBX3', 'Gene', '11335', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
745039	33463006	More specifically, as LIFR is down-regulated by miR-3682-3p and less M1 macrophages infiltrate into TME, the ability of EC progression was enhanced, suggesting the role of LIFR in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('down-regulated', 'NegReg', (30, 44))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('enhanced', 'PosReg', (139, 147))	('tumor', 'Disease', (180, 185))	('LIFR', 'Gene', (22, 26))	('LIFR', 'Gene', '3977', (22, 26))	('miR-3682-3p', 'Var', (48, 59))	('LIFR', 'Gene', '3977', (172, 176))	('LIFR', 'Gene', (172, 176))	('EC progression', 'CPA', (120, 134))
745054	33463006	More specifically, taking LIFR as an example, we revealed that miR-3682-3p was up-regulated in EC and associated with poor patient prognosis.	('up-regulated', 'PosReg', (79, 91))	('patient', 'Species', '9606', (123, 130))	('associated', 'Reg', (102, 112))	('LIFR', 'Gene', '3977', (26, 30))	('LIFR', 'Gene', (26, 30))	('miR-3682-3p', 'Var', (63, 74))
745055	33463006	Additionally, high expression of miR-3682-3p contributed to low LIFR expression and was correlated with various immune cell infiltration and stromal components in the TME as well as enhancing stem-like properties in EC.	('miR-3682-3p', 'Var', (33, 44))	('low', 'NegReg', (60, 63))	('LIFR', 'Gene', '3977', (64, 68))	('LIFR', 'Gene', (64, 68))	('expression', 'MPA', (69, 79))	('enhancing', 'PosReg', (182, 191))	('stem-like properties', 'CPA', (192, 212))
745079	33534860	In multivariate Poisson regression, under-reporting of HNSCC in cause-of-death records significantly increased in 2012 compared to 2010 (+7%) and was independently associated with a primary HNSCC site other than the larynx, a former primary or second synchronous cancer other than HNSCC, distant metastasis, palliative care, and death in hospitals other than comprehensive cancer care centers.	('under-reporting', 'Var', (36, 51))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('associated with', 'Reg', (164, 179))	('palliative care', 'Disease', (308, 323))	('increased', 'PosReg', (101, 110))	('cancer', 'Disease', (263, 269))	('death', 'Disease', (329, 334))	('death', 'Disease', (73, 78))	('death', 'Disease', 'MESH:D003643', (73, 78))	('synchronous cancer', 'Disease', 'MESH:D009369', (251, 269))	('death', 'Disease', 'MESH:D003643', (329, 334))	('synchronous cancer', 'Disease', (251, 269))	('cancer', 'Disease', 'MESH:D009369', (373, 379))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Disease', (373, 379))	('distant metastasis', 'Disease', (288, 306))	('HNSCC', 'Gene', (55, 60))
745154	33534860	Under-reporting was significantly higher in 2012 compared to 2010 (+7%) and was independently associated with intermediate ages (45-74 years), a primary HNSCC site other than the larynx, a former primary or second synchronous cancer other than HNSCC, any record of distant metastasis after HNSCC diagnosis, HIV/AIDS, depression, palliative care, and death in hospitals other than a comprehensive cancer care center (Table 3).	('distant metastasis', 'CPA', (265, 283))	('cancer', 'Disease', 'MESH:D009369', (396, 402))	('death', 'Disease', (350, 355))	('AIDS', 'Disease', (311, 315))	('synchronous cancer', 'Disease', 'MESH:D009369', (214, 232))	('HIV', 'Disease', 'MESH:D015658', (307, 310))	('depression', 'Disease', 'MESH:D000275', (317, 327))	('associated', 'Reg', (94, 104))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('HIV', 'Disease', (307, 310))	('death', 'Disease', 'MESH:D003643', (350, 355))	('cancer', 'Disease', (396, 402))	('depression', 'Phenotype', 'HP:0000716', (317, 327))	('higher', 'PosReg', (34, 40))	('AIDS', 'Disease', 'MESH:D000163', (311, 315))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('synchronous cancer', 'Disease', (214, 232))	('depression', 'Disease', (317, 327))	('cancer', 'Disease', (226, 232))	('Under-reporting', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
745159	33534860	In addition, under-reporting was independently associated with dying at home, which, together with public local hospitals, was the place of death associated with the highest rate of under-reporting.	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('dying at home', 'Disease', (63, 76))	('under-reporting', 'Var', (13, 28))
745266	33534860	One additional comment to consider is to add to the discussion that some of the head and neck SCC deaths may be hidden/included in the group of ICD 10 codes C76-C80 Malignant neoplasms of ill-defined, secondary and unspecified site.	('neck SCC deaths', 'Disease', 'MESH:D003643', (89, 104))	('men', 'Species', '9606', (18, 21))	('C76-C80', 'Var', (157, 164))	('neck SCC deaths', 'Disease', (89, 104))	('neoplasms', 'Phenotype', 'HP:0002664', (175, 184))	('Malignant neoplasms', 'Disease', 'MESH:D009369', (165, 184))	('Malignant neoplasms', 'Disease', (165, 184))	('unspecified', 'Species', '32644', (215, 226))
745363	33489925	Therefore, we hypothesized that the risk of AL might be minimized if anastomosis was created in the area that was enhanced within 60 s; subsequently, we found that anastomosis in an area of the conduit where ICG perfusion was detected by FA within 60 s resulted in a lower leak rate.	('leak rate', 'MPA', (273, 282))	('lower', 'NegReg', (267, 272))	('anastomosis', 'Var', (164, 175))	('ICG', 'Chemical', 'MESH:D007208', (208, 211))
745368	33489925	In conclusion, for the assessment of esophageal conduits, ICG-FA has the potential to reduce the rate of AL in McKeown MIE.	('reduce', 'NegReg', (86, 92))	('ICG-FA', 'Var', (58, 64))	('esophageal conduits', 'Phenotype', 'HP:0100628', (37, 56))	('ICG-FA', 'Chemical', '-', (58, 64))
745527	26287423	The majority of chemotherapy treatments consisted of 5-fluorouracyl and cisplatin regimens, and the majority of chemoradiotherapy treatments consisted of concomitant regimens based on 5-fluorouracyl-cisplatin and 40 Gy of radiation based on the previous studies.	('5-fluorouracyl-cisplatin', 'Chemical', '-', (184, 208))	('cisplatin', 'Chemical', 'MESH:D002945', (199, 208))	('5-fluorouracyl', 'Chemical', '-', (184, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('5-fluorouracyl', 'Chemical', '-', (53, 67))	('5-fluorouracyl-cisplatin', 'Var', (184, 208))	('5-fluorouracyl', 'MPA', (53, 67))
745654	25884226	Logistic regression analysis showed that mean dose, V20-V40, age, co-morbidity, method of anastomosis, operating time and interval between last radiotherapy treatment and surgery were not predictors of anastomotic leakage and stenosis.	('V20-V40', 'Var', (52, 59))	('anastomotic leak', 'Disease', (202, 218))	('anastomotic leak', 'Disease', 'MESH:D057868', (202, 218))
745682	25884226	From this future anastomotic region we calculated the following parameters: volume, mean dose, V20, V25, V30, V35 and V40 (percentage irradiated volume receiving more than respectively 20, 25, 30, 35 and 40 Gy).	('V25', 'Var', (100, 103))	('V35', 'Gene', '28474', (110, 113))	('V30', 'Var', (105, 108))	('V40', 'Var', (118, 121))	('V35', 'Gene', (110, 113))
745702	25884226	In addition univariable analysis also showed that patients with a high V20 percentage were less likely to develop anastomotic leakage.	('develop', 'PosReg', (106, 113))	('patients', 'Species', '9606', (50, 58))	('high V20', 'Var', (66, 74))	('less', 'NegReg', (91, 95))	('anastomotic leak', 'Disease', 'MESH:D057868', (114, 130))	('anastomotic leak', 'Disease', (114, 130))
745707	25884226	All other factors like BMI, cardiovascular and pulmonary co-morbidity, histology, ASA classification, type of operation, operating time, method of anastomosis, mean dose, and V20-V40 were not significant predictors for anastomotic stenosis in our univariable analysis and were therefore not analysed in the multivariable analysis (Table 4).	('anastomotic stenosis', 'Disease', (219, 239))	('ASA', 'Chemical', 'MESH:D001241', (82, 85))	('anastomotic stenosis', 'Disease', 'MESH:D057868', (219, 239))	('V20-V40', 'Var', (175, 182))
745715	25884226	In our study, variations in mean dose and V20-V40 showed no significant influence on developing anastomotic stenosis.	('anastomotic stenosis', 'Disease', (96, 116))	('anastomotic stenosis', 'Disease', 'MESH:D057868', (96, 116))	('V20-V40', 'Var', (42, 49))
745739	25884226	Recent study in lung cancer patients showed association between higher V50 and esophagitis.	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('esophagitis', 'Phenotype', 'HP:0100633', (79, 90))	('esophagitis', 'Disease', (79, 90))	('higher V50', 'Var', (64, 74))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('esophagitis', 'Disease', 'MESH:D004941', (79, 90))	('patients', 'Species', '9606', (28, 36))	('association', 'Interaction', (44, 55))	('lung cancer', 'Disease', (16, 27))
745775	25004461	GERD was defined by the presence of an ICD-CM-9 code (530.10, 530.11, 530.12, or 530.81; esophagitis, reflux esophagitis, acute esophagitis or esophageal reflux, respectively) in at least 2 outpatient records that were 30 days to 18 months apart.	('esophagitis', 'Disease', 'MESH:D004941', (109, 120))	('esophageal reflux', 'Disease', (143, 160))	('esophagitis', 'Disease', (89, 100))	('esophagitis', 'Phenotype', 'HP:0100633', (89, 100))	('esophagitis', 'Disease', 'MESH:D004941', (89, 100))	('GERD', 'Disease', (0, 4))	('530.10', 'Var', (54, 60))	('GERD', 'Disease', 'MESH:D005764', (0, 4))	('esophageal reflux', 'Disease', 'MESH:D005764', (143, 160))	('reflux esophagitis', 'Disease', (102, 120))	('reflux esophagitis', 'Disease', 'MESH:D005764', (102, 120))	('esophageal reflux', 'Phenotype', 'HP:0002020', (143, 160))	('esophagitis', 'Disease', (128, 139))	('esophagitis', 'Phenotype', 'HP:0100633', (128, 139))	('esophagitis', 'Disease', 'MESH:D004941', (128, 139))	('esophagitis', 'Phenotype', 'HP:0100633', (109, 120))	('esophagitis', 'Disease', (109, 120))	('outpatient', 'Species', '9606', (190, 200))
745780	25004461	The screening EGD was identified by CPT codes (43200 - 43259, excluding 43246) or ICD-9 procedure codes (422.3, 422.4, 441.3, 441.4, 451.3, 451.4, or 451.6) in the one year after the GERD index date.	('GERD', 'Disease', 'MESH:D005764', (183, 187))	('GERD', 'Disease', (183, 187))	('43200 - 43259', 'Var', (47, 60))	('422.3', 'Var', (105, 110))
745898	32976380	In the patient described in this report, kyphotic posture and reduction in the elasticity of supporting structures, such as the hepatoduodenal and hepatogastric ligaments, and relaxation of the esophageal hiatus due to aging, may have caused esophageal hiatus hernia, and stiffening of the stomach wall caused by scirrhous gastric cancer could be an advanced feature of hernia.	('kyphotic', 'Var', (41, 49))	('hernia', 'Disease', 'MESH:D006547', (370, 376))	('hernia', 'Phenotype', 'HP:0100790', (260, 266))	('esophageal hiatus hernia', 'Disease', 'MESH:D006551', (242, 266))	('esophageal hiatus hernia', 'Disease', (242, 266))	('hernia', 'Disease', 'MESH:D006547', (260, 266))	('patient', 'Species', '9606', (7, 14))	('hernia', 'Phenotype', 'HP:0100790', (370, 376))	('gastric cancer', 'Phenotype', 'HP:0012126', (323, 337))	('caused', 'Reg', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('hernia', 'Disease', (260, 266))	('hiatus hernia', 'Phenotype', 'HP:0002036', (253, 266))	('elasticity', 'MPA', (79, 89))	('hernia', 'Disease', (370, 376))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (313, 337))	('reduction', 'NegReg', (62, 71))	('scirrhous gastric cancer', 'Disease', (313, 337))
745923	32280762	All lesions were generally examined using a magnifying endoscope with NBI (GIF-Q240Z, GIF-H260Z or GIF-H290Z; Olympus Medical Systems, Tokyo, Japan) before ESD.	('Q240Z', 'Var', (79, 84))	('H290Z', 'SUBSTITUTION', 'None', (103, 108))	('H260Z', 'Var', (90, 95))	('H260Z', 'SUBSTITUTION', 'None', (90, 95))	('H290Z', 'Var', (103, 108))	('Q240Z', 'SUBSTITUTION', 'None', (79, 84))
745930	32280762	Therefore, we developed a 0-6 numerical depth estimation scale in an attempt to express both conclusive and inconclusive estimation: 0 = Depth of tumor can be certainly distinguished as EP/LPM (EP/LPM).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('EP/LPM', 'Disease', (186, 192))	('0 = Depth', 'Var', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
745938	32280762	high confident estimation), whereas scores of 1 (EP/LPM > MM/SM1), 2 (MM/SM1 > EP/LPM), 4 (MM/SM1 > SM2), and 5 (SM2 > MM/SM1) indicated inconclusive estimation (i.e.	('MM/SM1', 'Gene', '7911', (70, 76))	('EP/LPM', 'Var', (49, 55))	('MM/SM1', 'Gene', (70, 76))	('MM/SM1', 'Gene', (119, 125))	('SM2', 'Gene', (100, 103))	('MM/SM1', 'Gene', '7911', (91, 97))	('MM/SM1', 'Gene', '7911', (58, 64))	('SM2', 'Gene', '53366', (113, 116))	('MM/SM1', 'Gene', '7911', (119, 125))	('MM/SM1', 'Gene', (91, 97))	('SM2', 'Gene', '53366', (100, 103))	('SM2', 'Gene', (113, 116))	('MM/SM1', 'Gene', (58, 64))
745948	32280762	Histologically, the depth of invasion was EP/LPM (pathological score = 0) in 171 lesions, MM/SM1 (pathological score = 3) in 31 lesions, and SM2 (pathological score = 6) in 9 lesions.	('MM/SM1', 'Gene', '7911', (90, 96))	('SM2', 'Gene', (141, 144))	('MM/SM1', 'Gene', (90, 96))	('EP/LPM', 'Var', (42, 48))	('SM2', 'Gene', '53366', (141, 144))
745950	32280762	In a subgroup analysis, M-NBI significantly reduced the average (+-SE) of discordance scores between steps 1 and 2 in all three subgroups of tumor depth (EP/LPM, 0.47 +- 0.04 to 0.27 +- 0.03, P < 0.001; MM/SM1, 1.72 +- 0.11 to 1.36 +- 0.15, P = 0.0009; SM2, 3.62 +- 0.55 to 2.51 +- 0.63, P = 0.0067).	('MM/SM1', 'Gene', (203, 209))	('M-NBI', 'Chemical', '-', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor depth', 'Disease', (141, 152))	('M-NBI', 'Var', (24, 29))	('SE', 'Disease', 'None', (67, 69))	('tumor depth', 'Disease', 'MESH:D007222', (141, 152))	('SM2', 'Gene', '53366', (253, 256))	('discordance scores', 'MPA', (74, 92))	('reduced', 'NegReg', (44, 51))	('MM/SM1', 'Gene', '7911', (203, 209))	('SM2', 'Gene', (253, 256))
745975	32280762	Using this scale, we could show the additional benefit of M-NBI of not only improving the accuracy of depth estimation but also increasing its conclusiveness, which we emphasize as a unique point of this study.	('improving', 'PosReg', (76, 85))	('M-NBI', 'Chemical', '-', (58, 63))	('M-NBI', 'Var', (58, 63))	('conclusiveness', 'MPA', (143, 157))	('increasing', 'PosReg', (128, 138))	('accuracy', 'MPA', (90, 98))
746199	28882179	CanSPUC Cancer Screening Program in Urban China CAMS Chinese Academy of Medical Sciences EMR electronic medical record CNY Chinese Yuan GDP gross domestic product CPI consumer price index ESCC esophageal squamous cell carcinoma	('Cancer', 'Disease', 'MESH:D009369', (8, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('CAMS', 'Chemical', '-', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (193, 227))	('Cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Cancer', 'Disease', (8, 14))	('ESCC', 'Var', (188, 192))	('esophageal squamous cell carcinoma', 'Disease', (193, 227))
746351	27036032	The DAB2 expression levels of five human ESCC cell lines (KYSE-50, KYSE-70, KYSE-150, KYSE-170, KYSE-510) and a human normal esophageal squamous epithelial cell line (Het-1A) were assessed by western blot (Figure 2A).	('KYSE-510', 'Var', (96, 104))	('KYSE-150', 'Var', (76, 84))	('human', 'Species', '9606', (35, 40))	('KYSE-170', 'Var', (86, 94))	('DAB2', 'Gene', '1601', (4, 8))	('human', 'Species', '9606', (112, 117))	('DAB2', 'Gene', (4, 8))
746371	27036032	The study further validate whether aberrant hypermethylation of the promoter in DAB2 gene may correlate to low DAB-2 expression in ESCC.	('aberrant hypermethylation', 'Var', (35, 60))	('DAB-2', 'Gene', (111, 116))	('DAB2', 'Gene', (80, 84))	('expression', 'MPA', (117, 127))	('DAB2', 'Gene', '1601', (80, 84))	('DAB-2', 'Gene', '1601', (111, 116))	('low', 'NegReg', (107, 110))	('ESCC', 'Disease', (131, 135))
746375	27036032	Some high-DAB2 cell lines (KYSE-50, KYSE-70) even were demonstrated with DAB2 promoter hypermethylation.	('DAB2', 'Gene', '1601', (73, 77))	('DAB2', 'Gene', (73, 77))	('DAB2', 'Gene', '1601', (10, 14))	('hypermethylation', 'Var', (87, 103))	('DAB2', 'Gene', (10, 14))
746403	27036032	The silencing of DAB2 gene expression can be modified by epigenetic changes.	('epigenetic changes', 'Var', (57, 75))	('silencing', 'MPA', (4, 13))	('expression', 'MPA', (27, 37))	('DAB2', 'Gene', (17, 21))	('DAB2', 'Gene', '1601', (17, 21))
746404	27036032	The aberrant DAB2 promoter methylation was detected in 13 of 45 (29%) patients with low-DAB2 ESCC in our study.	('patients', 'Species', '9606', (70, 78))	('aberrant', 'Var', (4, 12))	('DAB2', 'Gene', '1601', (88, 92))	('methylation', 'Var', (27, 38))	('DAB2', 'Gene', (88, 92))	('detected', 'Reg', (43, 51))	('DAB2', 'Gene', '1601', (13, 17))	('DAB2', 'Gene', (13, 17))
746405	27036032	This data suggested DAB2 promoter hypermethylation just decreased DAB2 expression in a subset of ESCC.	('DAB2', 'Gene', '1601', (20, 24))	('expression', 'MPA', (71, 81))	('DAB2', 'Gene', '1601', (66, 70))	('hypermethylation', 'Var', (34, 50))	('DAB2', 'Gene', (66, 70))	('decreased', 'NegReg', (56, 65))	('DAB2', 'Gene', (20, 24))	('ESCC', 'Disease', (97, 101))
746410	27036032	Our data illustrated the Erk inhibitors suppressed cell migration in the low-DAB2 cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('inhibitors', 'Var', (29, 39))	('suppressed', 'NegReg', (40, 50))	('Erk', 'Gene', '5594', (25, 28))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('DAB2', 'Gene', (77, 81))	('DAB2', 'Gene', '1601', (77, 81))	('Erk', 'Gene', (25, 28))
746434	27036032	Grade 0 is defined as the complete absence or weak phospho-ERK immunostaining in <5% of the tumor cells; grade 1+ is focal positivity in 5-25% of the tumor cells; grade 2+ is frequency staining in 25-50% of the tumor cells; and grade 3+ is frequency staining in >50% of the tumor cells.	('grade 2+', 'Var', (163, 171))	('ERK', 'Gene', (59, 62))	('grade 1+', 'Var', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('weak', 'NegReg', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (211, 216))	('absence', 'NegReg', (35, 42))	('tumor', 'Disease', (92, 97))	('ERK', 'Gene', '5594', (59, 62))	('tumor', 'Disease', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (150, 155))
746461	27689325	PTK7 knockdown reduced gelatin degradation and MMP-9 secretion in cultures of ESCC TE-10 cells, and showed reduced levels of MMP9 mRNA using real-time RT-PCR and luciferase reporter assays.	('MMP-9', 'Gene', '4318', (47, 52))	('PTK7', 'Gene', (0, 4))	('levels', 'MPA', (115, 121))	('knockdown', 'Var', (5, 14))	('TE-10', 'CellLine', 'CVCL:1760', (83, 88))	('reduced', 'NegReg', (107, 114))	('MMP9', 'Gene', '4318', (125, 129))	('MMP9', 'Gene', (125, 129))	('reduced', 'NegReg', (15, 22))	('MMP-9', 'Gene', (47, 52))	('gelatin degradation', 'MPA', (23, 42))
746462	27689325	PTK7 knockdown decreased not only phosphorylation of NF-kappaB, IkappaB, ERK, and JNK, but also nuclear localization of NF-kappaB and AP-1 consisting of c-Fos and c-Jun.	('nuclear localization', 'MPA', (96, 116))	('phosphorylation', 'MPA', (34, 49))	('PTK7', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('ERK', 'Protein', (73, 76))	('c-Jun', 'Gene', (163, 168))	('c-Fos', 'Gene', '2353', (153, 158))	('NF-kappaB', 'Protein', (53, 62))	('AP-1', 'Gene', '3725', (134, 138))	('AP-1', 'Gene', (134, 138))	('IkappaB', 'Protein', (64, 71))	('decreased', 'NegReg', (15, 24))	('NF-kappaB', 'Protein', (120, 129))	('JNK', 'MPA', (82, 85))	('c-Jun', 'Gene', '3725', (163, 168))	('c-Fos', 'Gene', (153, 158))
746469	27689325	Homozygosity for a truncated PTK7 gene was perinatally lethal in mice and associated with severe developmental defects, including defective neural tube closure.	('Homozygosity', 'Var', (0, 12))	('defective', 'NegReg', (130, 139))	('developmental defects', 'Disease', (97, 118))	('mice', 'Species', '10090', (65, 69))	('developmental defects', 'Disease', 'MESH:D003147', (97, 118))	('truncated', 'Var', (19, 28))	('PTK7', 'Gene', (29, 33))	('defective neural tube closure', 'Phenotype', 'HP:0045005', (130, 159))	('associated with', 'Reg', (74, 89))
746470	27689325	PTK7 mutant mice phenotypically overlap with known planar cell polarity (PCP) mutant mice and frogs, and PTK7 is genetically linked to Vangl2, a core PCP gene.	('PCP', 'Chemical', '-', (150, 153))	('Vangl2', 'Gene', (135, 141))	('mice', 'Species', '10090', (85, 89))	('PTK7', 'Gene', (0, 4))	('Vangl2', 'Gene', '93840', (135, 141))	('mice', 'Species', '10090', (12, 16))	('PCP', 'Chemical', '-', (73, 76))	('mutant', 'Var', (5, 11))	('PTK7', 'Gene', (105, 109))
746472	27689325	Moreover, PTK7 interacts with Wnt5A, non-canonical Wnt/PCP ligand, and induces JNK activation during morphogenetic movements in Xenopus.	('Xenopus', 'Species', '8355', (128, 135))	('Wnt5A', 'Gene', (30, 35))	('interacts', 'Interaction', (15, 24))	('PCP', 'Chemical', '-', (55, 58))	('Wnt5A', 'Gene', '378689', (30, 35))	('induces', 'Reg', (71, 78))	('JNK activation', 'MPA', (79, 93))	('PTK7', 'Var', (10, 14))
746486	27689325	Two lines of PTK7 knockdown cells, PTK7-KD-6433 and PTK7-KD-6434, showed significantly decreased degradation of FITC-labeled gelatin compared to control vector-transfected cells (Figure 1).	('decreased', 'NegReg', (87, 96))	('FITC-labeled gelatin', 'MPA', (112, 132))	('PTK7-KD-6434', 'Var', (52, 64))	('degradation', 'MPA', (97, 108))	('FITC', 'Chemical', 'MESH:D016650', (112, 116))	('PTK7', 'Gene', (13, 17))
746488	27689325	TIMP-1 expression significantly reduced gelatin degradation to the similar extent as PTK7 knockdown in TE-10 cells.	('TIMP-1', 'Gene', (0, 6))	('TIMP-1', 'Gene', '7076', (0, 6))	('expression', 'Species', '29278', (7, 17))	('reduced', 'NegReg', (32, 39))	('TE-10', 'CellLine', 'CVCL:1760', (103, 108))	('expression', 'Var', (7, 17))	('gelatin degradation', 'MPA', (40, 59))
746492	27689325	MMP-9 secretion was significantly decreased in PTK7 knockdown cells compared to control cells.	('PTK7', 'Gene', (47, 51))	('decreased', 'NegReg', (34, 43))	('secretion', 'MPA', (6, 15))	('MMP-9', 'Gene', '4318', (0, 5))	('knockdown', 'Var', (52, 61))	('MMP-9', 'Gene', (0, 5))
746495	27689325	PTK7 knockout almost completely abolished MMP-9 secretion (Figure 2B, right panel).	('MMP-9', 'Gene', (42, 47))	('knockout', 'Var', (5, 13))	('PTK7', 'Gene', (0, 4))	('abolished', 'NegReg', (32, 41))	('MMP-9', 'Gene', '4318', (42, 47))
746500	27689325	Incubation with GW280264X (ADAM 17/10 inhibitor) and/or DAPT (gamma-secretase inhibitor) to inhibit generation of PTK7-CTF2, did not change the secreted MMP-9 level in TE-10 cells (Supplementary Figure S1A).	('generation', 'MPA', (100, 110))	('GW280264X', 'Chemical', 'MESH:C492546', (16, 25))	('PTK7-CTF2', 'MPA', (114, 123))	('GW280264X', 'Var', (16, 25))	('TE-10', 'CellLine', 'CVCL:1760', (168, 173))	('MMP-9', 'Gene', '4318', (153, 158))	('inhibit', 'NegReg', (92, 99))	('MMP-9', 'Gene', (153, 158))	('DAPT', 'Chemical', '-', (56, 60))
746503	27689325	Therefore, we conclude that PTK7-CTF2 does not affect induction of MMP-9 expression in TE-10 cells.	('PTK7-CTF2', 'Var', (28, 37))	('expression', 'Species', '29278', (73, 83))	('TE-10', 'CellLine', 'CVCL:1760', (87, 92))	('MMP-9', 'Gene', '4318', (67, 72))	('MMP-9', 'Gene', (67, 72))
746505	27689325	In PTK7-KD-6433 and PTK7-KD-6434 cells, MMP9 mRNA levels were reduced to 20% and 15% and PTK7 mRNA levels were reduced to 26% and 12%, respectively, compared to control cells (Figure 3B).	('PTK7-KD-6434', 'Var', (20, 32))	('PTK7 mRNA levels', 'MPA', (89, 105))	('reduced', 'NegReg', (111, 118))	('MMP9', 'Gene', (40, 44))	('PTK7-KD-6433', 'Var', (3, 15))	('MMP9', 'Gene', '4318', (40, 44))	('reduced', 'NegReg', (62, 69))
746511	27689325	Phosphorylation of IkappaB, NF-kappaB, ERK, and JNK was reduced in the PTK7 knockdown cells, and nuclear levels of AP-1 consisting of c-Fos and c-Jun, and NF-kappaB were decreased in the PTK7 knockdown cells compared to control cells (Figure 4B).	('JNK', 'Gene', (48, 51))	('knockdown', 'Var', (76, 85))	('PTK7', 'Var', (187, 191))	('reduced', 'NegReg', (56, 63))	('IkappaB', 'Protein', (19, 26))	('AP-1', 'Gene', (115, 119))	('c-Fos', 'Gene', (134, 139))	('Phosphorylation', 'MPA', (0, 15))	('PTK7', 'Var', (71, 75))	('c-Jun', 'Gene', '3725', (144, 149))	('decreased', 'NegReg', (170, 179))	('c-Fos', 'Gene', '2353', (134, 139))	('NF-kappaB', 'MPA', (155, 164))	('NF-kappaB', 'Protein', (28, 37))	('ERK', 'Protein', (39, 42))	('knockdown', 'Var', (192, 201))	('c-Jun', 'Gene', (144, 149))	('AP-1', 'Gene', '3725', (115, 119))
746515	27689325	Incubation of control vector-transfected TE-10 cells with a pan-PTK inhibitor (genistein), a multi-target RPTK inhibitor (TKI-258), and Src family kinase inhibitors (PP1 and PP2) decreased not only tyrosine phosphorylation of total cellular proteins and Src, but also phosphorylation of IkappaB, NF-kappaB, ERK, and JNK, to the same extent as seen in PTK7 knockdown cells treated with vehicle control dimethyl sulfoxide (DMSO) (Figure 5C).	('tyrosine', 'Chemical', 'MESH:D014443', (198, 206))	('PTK', 'Gene', '2185', (351, 354))	('PTK', 'Gene', '2185', (64, 67))	('TE-10', 'CellLine', 'CVCL:1760', (41, 46))	('PTK', 'Gene', (107, 110))	('NF-kappaB', 'Protein', (296, 305))	('PP2', 'Gene', '4888', (174, 177))	('genistein', 'Chemical', 'MESH:D019833', (79, 88))	('ERK', 'Protein', (307, 310))	('tyrosine phosphorylation', 'MPA', (198, 222))	('PTK', 'Gene', (351, 354))	('phosphorylation', 'MPA', (268, 283))	('decreased', 'NegReg', (179, 188))	('PP1', 'Var', (166, 169))	('PP2', 'Gene', (174, 177))	('PTK', 'Gene', (64, 67))	('IkappaB', 'Protein', (287, 294))	('JNK', 'Protein', (316, 319))	('Src', 'MPA', (254, 257))	('PTK', 'Gene', '2185', (107, 110))
746519	27689325	In TE-10 cells, PTK7 knockdown decreased phosphorylation of Akt, IkappaB, and NF-kappaB (Figure 6A).	('Akt', 'Gene', '207', (60, 63))	('decreased', 'NegReg', (31, 40))	('phosphorylation', 'MPA', (41, 56))	('NF-kappaB', 'Protein', (78, 87))	('TE-10', 'CellLine', 'CVCL:1760', (3, 8))	('Akt', 'Gene', (60, 63))	('knockdown', 'Var', (21, 30))	('IkappaB', 'Protein', (65, 72))	('PTK7', 'Gene', (16, 20))
746520	27689325	As expected, PI3K inhibitor LY294002 decreased phosphorylation of IkappaB and NF-kappaB in control vector-transfected cells, whereas MEK inhibitor PD98059 and JNK inhibitor SP600125 did not inhibit phosphorylation of either protein.	('IkappaB', 'Protein', (66, 73))	('MEK', 'Gene', (133, 136))	('MEK', 'Gene', '5609', (133, 136))	('LY294002', 'Var', (28, 36))	('phosphorylation', 'MPA', (47, 62))	('SP600125', 'Chemical', 'MESH:C432165', (173, 181))	('PD98059', 'Chemical', 'MESH:C093973', (147, 154))	('NF-kappaB', 'Protein', (78, 87))	('LY294002', 'Chemical', 'MESH:C085911', (28, 36))	('decreased', 'NegReg', (37, 46))
746524	27689325	In 2D culture, treatment of cells with all tested inhibitors, as well as PTK7 knockdown, significantly decreased the level of secreted MMP-9 (Figure 7A).	('MMP-9', 'Gene', '4318', (135, 140))	('knockdown', 'Var', (78, 87))	('decreased', 'NegReg', (103, 112))	('MMP-9', 'Gene', (135, 140))	('PTK7', 'Gene', (73, 77))
746531	27689325	PTK7 knockdown in TE-6, TE-9, and TE-10 cells reduced levels of secreted MMP-9 (Figure 8B).	('TE', 'Chemical', 'MESH:D013691', (34, 36))	('PTK7', 'Gene', (0, 4))	('TE-10', 'CellLine', 'CVCL:1760', (34, 39))	('knockdown', 'Var', (5, 14))	('TE', 'Chemical', 'MESH:D013691', (24, 26))	('MMP-9', 'Gene', '4318', (73, 78))	('TE', 'Chemical', 'MESH:D013691', (18, 20))	('reduced', 'NegReg', (46, 53))	('MMP-9', 'Gene', (73, 78))
746532	27689325	In PTK7 knockdown TE-6, TE-9, and TE-10 cells, PTK7 mRNA levels were decreased to 34%, 27%, and 12% respectively, of control values, and in these cells MMP9 mRNA levels were decreased to 20%, 30%, and 14%, respectively, of control (Figure 8C and 8D).	('TE', 'Chemical', 'MESH:D013691', (34, 36))	('decreased', 'NegReg', (174, 183))	('PTK7', 'Gene', (3, 7))	('TE-10', 'CellLine', 'CVCL:1760', (34, 39))	('knockdown', 'Var', (8, 17))	('TE', 'Chemical', 'MESH:D013691', (24, 26))	('decreased', 'NegReg', (69, 78))	('MMP9', 'Gene', (152, 156))	('TE', 'Chemical', 'MESH:D013691', (18, 20))	('MMP9', 'Gene', '4318', (152, 156))	('PTK7 mRNA levels', 'MPA', (47, 63))
746533	27689325	Thus, we are confident that PTK7 enhances MMP9 expression at the transcriptional level in other ESCC cells as well as in TE-10 cells.	('PTK7', 'Var', (28, 32))	('MMP9', 'Gene', '4318', (42, 46))	('MMP9', 'Gene', (42, 46))	('enhances', 'PosReg', (33, 41))	('TE-10', 'CellLine', 'CVCL:1760', (121, 126))	('expression', 'Species', '29278', (47, 57))	('expression', 'MPA', (47, 57))
746539	27689325	In this study, we found that PTK7 knockdown reduced focal degradation of underlying gelatin in TE-10 cell cultures.	('TE-10', 'CellLine', 'CVCL:1760', (95, 100))	('reduced', 'NegReg', (44, 51))	('PTK7', 'Gene', (29, 33))	('knockdown', 'Var', (34, 43))	('focal degradation of underlying gelatin', 'MPA', (52, 91))
746542	27689325	We found that PTK7 increased nuclear levels of c-Fos and c-Jun through activation of ERK and JNK and increased the level of activated NF-kappaB by phosphorylation and degradation of IkappaB and phosphorylation of RelA/p65.	('phosphorylation', 'MPA', (194, 209))	('c-Jun', 'Gene', '3725', (57, 62))	('increased', 'PosReg', (101, 110))	('JNK', 'Pathway', (93, 96))	('RelA', 'Gene', '5970', (213, 217))	('c-Jun', 'Gene', (57, 62))	('level of activated', 'MPA', (115, 133))	('p65', 'Gene', (218, 221))	('increased', 'PosReg', (19, 28))	('ERK', 'Protein', (85, 88))	('PTK7', 'Var', (14, 18))	('activation', 'PosReg', (71, 81))	('p65', 'Gene', '5970', (218, 221))	('c-Fos', 'Gene', (47, 52))	('phosphorylation', 'MPA', (147, 162))	('RelA', 'Gene', (213, 217))	('c-Fos', 'Gene', '2353', (47, 52))	('NF-kappaB', 'Protein', (134, 143))	('degradation', 'MPA', (167, 178))	('IkappaB', 'Protein', (182, 189))
746543	27689325	It is interesting to understand how PTK7 activates MAPKs and IKK to activate AP-1 and NF-kappaB.	('activate', 'PosReg', (68, 76))	('AP-1', 'Gene', '3725', (77, 81))	('AP-1', 'Gene', (77, 81))	('NF-kappaB', 'Protein', (86, 95))	('PTK7', 'Var', (36, 40))	('MAPKs', 'Protein', (51, 56))
746551	27689325	We also found that PTK7 knockdown decreases phosphorylation of Src and Src substrate CAS.	('phosphorylation', 'MPA', (44, 59))	('decreases', 'NegReg', (34, 43))	('CAS', 'Gene', (85, 88))	('CAS', 'Gene', '9564', (85, 88))	('PTK7', 'Gene', (19, 23))	('knockdown', 'Var', (24, 33))
746552	27689325	Indeed, treatment of Src family kinase inhibitors PP1 and PP2 and expression of dominant-negative Src decreased activation of ERK, JNK, IkappaB, and NF-kappaB to the same extent as PTK7 knockdown.	('JNK', 'Protein', (131, 134))	('ERK', 'Protein', (126, 129))	('PP2', 'Gene', (58, 61))	('PP2', 'Gene', '4888', (58, 61))	('Src', 'Gene', (98, 101))	('PP1', 'Var', (50, 53))	('NF-kappaB', 'Protein', (149, 158))	('expression', 'Species', '29278', (66, 76))	('IkappaB', 'Protein', (136, 143))	('activation', 'MPA', (112, 122))	('decreased', 'NegReg', (102, 111))
746555	27689325	Interestingly, we found that PTK7-mediated phosphorylation of IkappaB and NF-kappaB was inhibited by a PI3K inhibitor, LY294002.	('inhibited', 'NegReg', (88, 97))	('phosphorylation', 'MPA', (43, 58))	('LY294002', 'Chemical', 'MESH:C085911', (119, 127))	('NF-kappaB', 'Protein', (74, 83))	('LY294002', 'Var', (119, 127))	('IkappaB', 'Protein', (62, 69))
746557	27689325	In our study, phosphorylation of IKKalpha at Thr23 and of IKKalpha/beta at Ser176/180 was decreased by LY294002 treatment and overexpression of dominant-negative Akt.	('Akt', 'Gene', (162, 165))	('IKKalpha', 'Gene', (33, 41))	('overexpression', 'PosReg', (126, 140))	('IKKalpha/beta', 'Gene', (58, 71))	('LY294002', 'Var', (103, 111))	('decreased', 'NegReg', (90, 99))	('IKKalpha', 'Gene', '1147', (33, 41))	('phosphorylation', 'MPA', (14, 29))	('IKKalpha/beta', 'Gene', '1147;3551', (58, 71))	('Thr23', 'Chemical', '-', (45, 50))	('Ser176', 'Chemical', '-', (75, 81))	('IKKalpha', 'Gene', '1147', (58, 66))	('LY294002', 'Chemical', 'MESH:C085911', (103, 111))	('expression', 'Species', '29278', (130, 140))	('IKKalpha', 'Gene', (58, 66))	('Akt', 'Gene', '207', (162, 165))
746561	27689325	Use of a 3D culture system that incorporates Matrigel and DQ-gelatin to mimic in vivo conditions, we demonstrated that PTK7 knockdown, as well as inhibition of MEK, JNK, PI3K, and NF-kappaB activation, significantly inhibited degradation of ECM components.	('knockdown', 'Var', (124, 133))	('activation', 'PosReg', (190, 200))	('NF-kappaB', 'Protein', (180, 189))	('PI3K', 'CPA', (170, 174))	('inhibited', 'NegReg', (216, 225))	('inhibition', 'NegReg', (146, 156))	('MEK', 'Gene', '5609', (160, 163))	('JNK', 'Protein', (165, 168))	('MEK', 'Gene', (160, 163))	('degradation', 'MPA', (226, 237))	('PTK7', 'Gene', (119, 123))
746567	27689325	Chemoresistant cancer cells often show NF-kappaB activation, and NF-kappaB knockdown strengthens the effect of chemotherapeutic agent 5-FU on cell death in cancer cells.	('effect', 'MPA', (101, 107))	('cancer', 'Disease', (156, 162))	('5-FU', 'Chemical', 'MESH:D005472', (134, 138))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('strengthens', 'PosReg', (85, 96))	('death', 'Disease', 'MESH:D003643', (147, 152))	('NF-kappaB', 'Protein', (39, 48))	('knockdown', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('death', 'Disease', (147, 152))	('NF-kappaB', 'Gene', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('activation', 'PosReg', (49, 59))
746568	27689325	Consistently, we have shown that PTK7 knockdown sensitizes cells to 5-FU-induced death.	('death', 'Disease', 'MESH:D003643', (81, 86))	('5-FU', 'Chemical', 'MESH:D005472', (68, 72))	('death', 'Disease', (81, 86))	('sensitizes', 'Reg', (48, 58))	('PTK7', 'Gene', (33, 37))	('knockdown', 'Var', (38, 47))
746569	27689325	These data suggest the possibility that inhibition of PTK7 function reduces NF-kappaB activation and enhances the effect of 5-FU in chemoresistant cancer cells.	('NF-kappaB', 'Protein', (76, 85))	('inhibition', 'Var', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('reduces', 'NegReg', (68, 75))	('effect of 5-FU', 'MPA', (114, 128))	('activation', 'MPA', (86, 96))	('5-FU', 'Chemical', 'MESH:D005472', (124, 128))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('PTK7', 'Gene', (54, 58))	('enhances', 'PosReg', (101, 109))
746571	27689325	Thus, attenuation of PTK7 function would be a valuable therapeutic means to control ESCC and other cancers that express PTK7.	('PTK7', 'Gene', (120, 124))	('PTK7', 'Gene', (21, 25))	('ESCC', 'Disease', (84, 88))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('attenuation', 'Var', (6, 17))
746574	27689325	Genistein, PP1, PP2, and LY294002 were purchased from AG Scientific (San Diego, CA, USA).	('LY294002', 'Var', (25, 33))	('LY294002', 'Chemical', 'MESH:C085911', (25, 33))	('PP2', 'Gene', (16, 19))	('PP2', 'Gene', '4888', (16, 19))	('Genistein', 'Chemical', 'MESH:D019833', (0, 9))
746575	27689325	PD98059 and SP600125 were purchased from Tocris Bioscience (Bristol, UK).	('SP600125', 'Chemical', 'MESH:C432165', (12, 20))	('SP600125', 'Var', (12, 20))	('PD98059', 'Var', (0, 7))	('Tocris Bioscience', 'Disease', (41, 58))	('Tocris Bioscience', 'Disease', 'None', (41, 58))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))
746587	27689325	Expression vector encoding K297R/Y529F dominant-negative mouse Src (pLNCX-mSrc [K297R/Y529F]) was generated by site-directed mutagenesis using pLNCX-mSrc, which was a generous gift from Professor E.-S. Oh (Ewha Womans University, Korea), as a template and primer pairs listed in Supplementary Table S1.	('K297R', 'Var', (27, 32))	('K297R', 'SUBSTITUTION', 'None', (27, 32))	('Y529F', 'Mutation', 'p.Y529F', (33, 38))	('K297R', 'Var', (80, 85))	('Expression', 'Species', '29278', (0, 10))	('K297R', 'SUBSTITUTION', 'None', (80, 85))	('mouse', 'Species', '10090', (57, 62))	('Y529F', 'Mutation', 'p.Y529F', (86, 91))
746591	27689325	Puromycin-resistant cells were enriched by incubation of the cultures with 2.5 mug/ml puromycin for 14 d. A mixed culture of PTK7 knockdown cells and individual clones of PTK7 knockout cells were maintained in the presence of 1 mug/ml puromycin.	('puromycin', 'Chemical', 'MESH:D011691', (86, 95))	('puromycin', 'Chemical', 'MESH:D011691', (235, 244))	('Puromycin', 'Chemical', 'MESH:D011691', (0, 9))	('knockdown', 'Var', (130, 139))	('PTK7', 'Gene', (125, 129))
746634	26749521	The SEER database was queried for all cases of EC using tumor site codes (C15.0-C15.9) and ICD-9 codes diagnosed between 1973 and 2009.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('C15.0-C15.9', 'Var', (74, 85))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
746635	26749521	Only histologic codes for adenocarcinoma (8140-8573) and squamous cell cancers (8050-8082) were included in the search.	('8050-8082', 'Var', (80, 89))	('adenocarcinoma', 'Disease', (26, 40))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('adenocarcinoma', 'Disease', 'MESH:D000230', (26, 40))	('8140-8573', 'Var', (42, 51))	('squamous cell cancers', 'Disease', (57, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (57, 78))	('squamous cell cancers', 'Disease', 'MESH:D002294', (57, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
746663	26749521	Specifically, receipt of surgery (HR= 0.52; 95% CI: 0.49-0.79; p < 0.001), adjuvant radiotherapy (HR = 0.70; 95% CI: 0.67-0.73; p < 0.001) and diagnoses of disease in the 2000's (HR = 0.94; 95% CI: 0.90-0.98; p < 0.04) were associated with a decreased risk of death.	('decreased', 'NegReg', (242, 251))	('adjuvant', 'Var', (75, 83))	('death', 'Disease', (260, 265))	('death', 'Disease', 'MESH:D003643', (260, 265))
746695	26893670	The IL-6 silencing vector significantly reduced invasion and proliferation of the two cell lines and attenuated tumor growth in xenograft mouse models (P<0.05).	('silencing vector', 'Var', (9, 25))	('mouse', 'Species', '10090', (138, 143))	('attenuated tumor', 'Disease', (101, 117))	('attenuated tumor', 'Disease', 'MESH:C538265', (101, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('reduced', 'NegReg', (40, 47))	('rat', 'Species', '10116', (68, 71))	('IL-6', 'Gene', (4, 8))
746696	26893670	The IL-6 silencing vector markedly reduced the presence of Ki-67 (a typical proliferation marker) and microvessel density, indicating that downregulation of IL-6 levels may greatly affect tumor growth and inhibition.	('tumor', 'Disease', (188, 193))	('microvessel density', 'CPA', (102, 121))	('rat', 'Species', '10116', (83, 86))	('inhibition', 'CPA', (205, 215))	('silencing vector', 'Var', (9, 25))	('reduced', 'NegReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('IL-6', 'Gene', (4, 8))	('vector', 'Var', (19, 25))	('Ki-67', 'Protein', (59, 64))	('downregulation', 'NegReg', (139, 153))	('affect', 'Reg', (181, 187))
746697	26893670	The IL-6 silencing vector increased E-cadherin and matrix metalloproteinase (MMP)-9 expression levels in the two esophageal carcinoma cell lines.	('E-cadherin', 'MPA', (36, 46))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (113, 133))	('matrix metalloproteinase (MMP)-9', 'Gene', '4318', (51, 83))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (113, 133))	('silencing vector', 'Var', (9, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('expression levels', 'MPA', (84, 101))	('expression', 'Species', '29278', (84, 94))	('increased', 'PosReg', (26, 35))	('IL-6', 'Gene', (4, 8))	('esophageal carcinoma', 'Disease', (113, 133))
746699	26893670	The secretion of vascular endothelial growth factor and cluster of differentiation 31 (a nuclear protein) immunoreactive molecules were also reduced by the IL-6 silencing vector.	('reduced', 'NegReg', (141, 148))	('vascular endothelial growth factor', 'Gene', (17, 51))	('silencing vector', 'Var', (161, 177))	('vascular endothelial growth factor', 'Gene', '7422', (17, 51))	('cluster', 'Protein', (56, 63))	('IL-6', 'Gene', (156, 160))
746700	26893670	Therefore, IL-6 may be an important trigger in the progression of angiogenesis and endothelial tube formation within the tumor, and targeting IL-6 may be a promising strategy for the treatment of esophageal cancer.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('targeting', 'Var', (132, 141))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('rat', 'Species', '10116', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('angiogenesis', 'CPA', (66, 78))	('esophageal cancer', 'Disease', (196, 213))	('endothelial tube formation', 'CPA', (83, 109))	('IL-6', 'Gene', (142, 146))
746737	26893670	IL-6 expression was measured using a fluorescence microscope (FM200BA; AmScope, Irvine, CA, USA), as GFP expression vectors were used for the transfection.	('expression', 'MPA', (5, 15))	('expression vectors', 'Species', '29278', (105, 123))	('FM200BA', 'Var', (62, 69))	('IL-6', 'Gene', (0, 4))	('expression', 'Species', '29278', (105, 115))	('expression', 'Species', '29278', (5, 15))
746742	26893670	For the four experimental groups (KYSE170, KYSE170-IL6 silencing vector, TE13, TE13-IL6 silencing vector; 12 mice per group), an intraperitoneal injection of IL-6 (75 ng/mouse, 3 times/week) was initiated 1 day prior to tumor implantation.	('KYSE170', 'Var', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('mouse', 'Species', '10090', (170, 175))	('TE13-IL6', 'Gene', '16193', (79, 87))	('mice', 'Species', '10090', (109, 113))	('KYSE170-IL6', 'Var', (43, 54))	('TE13-IL6', 'Gene', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
746779	26893670	2A, the IL-6-GFP silencing vector markedly decreased the expression of IL-6 in the two cell lines, as demonstrated by a clear reduction in the intensity of red fluorescence (indicating IL-6 expression) compared with that of control-vector-transfected cells.	('expression', 'MPA', (57, 67))	('vector', 'Var', (27, 33))	('IL-6', 'Gene', (71, 75))	('IL-6-GFP', 'Gene', (8, 16))	('rat', 'Species', '10116', (109, 112))	('intensity of red fluorescence', 'MPA', (143, 172))	('silencing vector', 'Var', (17, 33))	('expression', 'Species', '29278', (190, 200))	('reduction', 'NegReg', (126, 135))	('expression', 'MPA', (190, 200))	('expression', 'Species', '29278', (57, 67))	('decreased', 'NegReg', (43, 52))
746780	26893670	This was accompanied by differences in the viable cell count over 8 days: The IL-6 silencing vector significantly reduced the proliferation of the two cell lines compared with the control-vector-transfected cells throughout the study period (P=0.0013; Fig.	('proliferation', 'CPA', (126, 139))	('reduced', 'NegReg', (114, 121))	('IL-6', 'Gene', (78, 82))	('rat', 'Species', '10116', (133, 136))	('silencing vector', 'Var', (83, 99))
746781	26893670	In addition, the silencing vector significantly attenuated the growth of tumors in the xenograft mouse models (P=0.0031).	('attenuated', 'NegReg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('mouse', 'Species', '10090', (97, 102))	('silencing vector', 'Var', (17, 33))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
746782	26893670	The tumor volume in mice bearing KYSE170 and TE13 tumors increased significantly more rapidly (up to ~1,000 mm3) (P=0.002), while the IL-6 vector was found to inhibit growth by ~300 mm3 by controlling the vascular endothelial cells (Fig.	('tumor', 'Disease', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mice', 'Species', '10090', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('KYSE170', 'Var', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('increased', 'PosReg', (57, 66))	('TE13', 'Var', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (50, 55))
746790	26893670	It has been previously reported that B-cell lymphoma-2 is upregulated in tumor-associated endothelial cells and that its regulation accelerates tumor growth.	('rat', 'Species', '10116', (138, 141))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('upregulated', 'PosReg', (58, 69))	('tumor', 'Disease', (73, 78))	('regulation', 'Var', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('accelerates', 'PosReg', (132, 143))	('B-cell lymphoma-2', 'Gene', (37, 54))
746792	26893670	Migration scratch assays clearly demonstrated the ability of the IL-6 silencing vector to inhibit the invasion capacity of the two esophageal cancer cell lines.	('silencing vector', 'Var', (70, 86))	('inhibit', 'NegReg', (90, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('rat', 'Species', '10116', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rat', 'Species', '10116', (40, 43))	('esophageal cancer', 'Disease', (131, 148))	('invasion capacity of the two', 'CPA', (102, 130))	('rat', 'Species', '10116', (3, 6))	('IL-6', 'Gene', (65, 69))
746797	26893670	Subsequently, the tumors developed in each of the 4 groups (KYSE; KYSE+IL-6 vector; TE13; and TE13+IL-6 vector) were evaluated.	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('TE13+IL-6', 'Var', (94, 103))	('KYSE+IL-6', 'Gene', (66, 75))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('KYSE+IL-6', 'Gene', '3569', (66, 75))
746800	26893670	5, the IL-6 silencing vector significantly regulated the release of IL-6 in the cell supernatant compared with that of controls in KYSE170 tumor-bearing mice (P=0.019).	('silencing vector', 'Var', (12, 28))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('regulated', 'Reg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('release of IL-6 in the cell supernatant', 'MPA', (57, 96))	('tumor', 'Disease', (139, 144))	('IL-6', 'Gene', (7, 11))	('mice', 'Species', '10090', (153, 157))
746806	26893670	The IL-6 silencing vector markedly reduced the secretion of VEGF and CD31 (a nuclear protein) compared with that of control tumors, which showed dark staining for these immunoreactive molecules (Fig.	('VEGF', 'Gene', '7422', (60, 64))	('CD31', 'Gene', '5175', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('reduced', 'NegReg', (35, 42))	('silencing vector', 'Var', (9, 25))	('VEGF', 'Gene', (60, 64))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('secretion of', 'MPA', (47, 59))	('IL-6', 'Gene', (4, 8))	('CD31', 'Gene', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))
746812	26893670	Therefore, in the present study, IL-6 expression or release was suppressed with IL-6 silencing vector in two types of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('expression', 'Species', '29278', (38, 48))	('IL-6', 'Gene', (33, 37))	('IL-6', 'Gene', (80, 84))	('expression', 'MPA', (38, 48))	('suppressed', 'NegReg', (64, 74))	('silencing vector', 'Var', (85, 101))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('release', 'MPA', (52, 59))
746816	26893670	Silencing of IL-6 also resulted in the significant attenuation of tumor growth and invasive ability in specific cell lines (P<0.05).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('IL-6', 'Gene', (13, 17))	('invasive ability in specific cell lines', 'CPA', (83, 122))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('Silencing', 'Var', (0, 9))	('attenuation', 'NegReg', (51, 62))
746828	26893670	Mian et al reported that inhibition of IL-8 markedly suppressed the expression levels of MMP-2 and MMP-9 in cancer cells, leading to a decrease in invasion and an increase in the progression of disease symptoms.	('expression', 'Species', '29278', (68, 78))	('IL-8', 'Gene', '3576', (39, 43))	('MMP-9', 'Gene', (99, 104))	('MMP-2', 'Gene', (89, 94))	('increase', 'PosReg', (163, 171))	('IL-8', 'Gene', (39, 43))	('invasion', 'CPA', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('MMP-9', 'Gene', '4318', (99, 104))	('inhibition', 'Var', (25, 35))	('progression of disease symptoms', 'CPA', (179, 210))	('decrease', 'NegReg', (135, 143))	('expression levels', 'MPA', (68, 85))	('suppressed', 'NegReg', (53, 63))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
746872	33364140	Deep Q waves on ECG are usually associated with myocardial scarring, commonly from a myocardial infarction (MI).	('myocardial infarction', 'Disease', (85, 106))	('MI', 'Phenotype', 'HP:0001658', (108, 110))	('myocardial scarring', 'Disease', (48, 67))	('myocardial infarction', 'Disease', 'MESH:D009203', (85, 106))	('Deep', 'Var', (0, 4))	('scarring', 'Phenotype', 'HP:0100699', (59, 67))	('myocardial infarction', 'Phenotype', 'HP:0001658', (85, 106))	('associated with', 'Reg', (32, 47))
746941	30185893	Interestingly, the hallmark of cancer feature 'immune' presented itself as most significant associated with worse OS, and therefore may harbor potential to apply targeted therapies.	('worse OS', 'Disease', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('hallmark of cancer', 'Disease', (19, 37))	('hallmark of cancer', 'Disease', 'MESH:D009369', (19, 37))	("'immune'", 'Var', (46, 54))	('associated', 'Reg', (92, 102))
746949	30185893	Likewise, the inhibition of CDK4/6 in p14ARF mutant patients by small molecules or pan-CDK inhibitors is being invested as add-on to standard chemotherapy backbones, potentially enabling blockage of unrestricted cell division caused by p14ARF mutations.	('mutant', 'Var', (45, 51))	('blockage', 'NegReg', (187, 195))	('CDK4/6', 'Gene', '1019;1021', (28, 34))	('p14ARF', 'Gene', '1029', (236, 242))	('p14ARF', 'Gene', (38, 44))	('CDK4/6', 'Gene', (28, 34))	('unrestricted cell division', 'CPA', (199, 225))	('p14ARF', 'Gene', '1029', (38, 44))	('p14ARF', 'Gene', (236, 242))	('patients', 'Species', '9606', (52, 60))	('enabling', 'PosReg', (178, 186))
746951	30185893	Hence, inhibition of COX-2, an important regulator of cell growth, differentiation and apoptosis, may be a valuable contribution in the treatment of EAC.	('COX-2', 'Gene', '5743', (21, 26))	('inhibition', 'Var', (7, 17))	('EAC', 'Phenotype', 'HP:0011459', (149, 152))	('COX-2', 'Gene', (21, 26))	('EAC', 'Disease', (149, 152))
747000	29552190	Previous studies have reported that alcohol dehydrogenase (ADH) genes are associated with upper aerodigestive types of cancer, and the genetic variation of the ADH cluster increases the risk of cancer for alcohol drinkers.	('ADH', 'Gene', (160, 163))	('ADH', 'Gene', '10327', (160, 163))	('increases', 'PosReg', (172, 181))	('cancer', 'Disease', (194, 200))	('alcohol dehydrogenase', 'Gene', '10327', (36, 57))	('alcohol', 'Chemical', 'MESH:D000438', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('genetic variation', 'Var', (135, 152))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (205, 221))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('ADH', 'Gene', (59, 62))	('cancer', 'Disease', (119, 125))	('ADH', 'Gene', '10327', (59, 62))	('alcohol dehydrogenase', 'Gene', (36, 57))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('alcohol', 'Chemical', 'MESH:D000438', (205, 212))	('associated', 'Reg', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
747026	29552190	The valid gene Affymetrix ID of ADH genes in the KM-plotter tool were 207820_at (ADH1A; Fig.	('ADH', 'Gene', (32, 35))	('ADH', 'Gene', '10327', (32, 35))	('ADH', 'Gene', (81, 84))	('ADH', 'Gene', '10327', (81, 84))	('207820_at', 'Var', (70, 79))	('ADH1A', 'Gene', '124', (81, 86))	('ADH1A', 'Gene', (81, 86))
747032	29552190	9A-C) and 21055_at (ADH7; Fig.	('ADH7', 'Gene', '131', (20, 24))	('ADH7', 'Gene', (20, 24))	('21055_at', 'Var', (10, 18))
747051	29552190	In contrast, high ADH6 expression significantly increased the risk of mortality for patients with GC receiving 5-FU-based adjuvant chemotherapy compared with patients with low expression of these genes (P=0.043; Table I).	('increased', 'PosReg', (48, 57))	('ADH6', 'Gene', '130', (18, 22))	('patients', 'Species', '9606', (84, 92))	('high', 'Var', (13, 17))	('5-FU', 'Chemical', 'MESH:D005472', (111, 115))	('ADH6', 'Gene', (18, 22))	('patients', 'Species', '9606', (158, 166))	('GC', 'Phenotype', 'HP:0012126', (98, 100))	('expression', 'MPA', (23, 33))
747052	29552190	The strata of patients with GC receiving surgery alone revealed that the high expression of ADH1B significantly decreased the risk of mortality for patients with GC compared with low expression (P=0.0082), whereas no significant associations between any of the other ADH genes expression and GC prognosis were identified in the present study following surgery alone.	('patients', 'Species', '9606', (148, 156))	('ADH1B', 'Gene', (92, 97))	('GC', 'Phenotype', 'HP:0012126', (292, 294))	('ADH', 'Gene', (267, 270))	('ADH', 'Gene', (92, 95))	('ADH1B', 'Gene', '125', (92, 97))	('ADH', 'Gene', '10327', (267, 270))	('ADH', 'Gene', '10327', (92, 95))	('GC', 'Phenotype', 'HP:0012126', (28, 30))	('mortality', 'CPA', (134, 143))	('GC', 'Phenotype', 'HP:0012126', (162, 164))	('high expression', 'Var', (73, 88))	('decreased', 'NegReg', (112, 121))	('patients', 'Species', '9606', (14, 22))
747054	29552190	Similar results may also be observed with high expression of ADH1A (P=0.032) and ADH1B (P=0.0033) being significantly associated with a favorable prognosis in patients with GC with a positive HER2 status (Table II).	('ADH1B', 'Gene', (81, 86))	('ADH1A', 'Gene', '124', (61, 66))	('ADH1B', 'Gene', '125', (81, 86))	('HER2', 'Gene', (192, 196))	('ADH1A', 'Gene', (61, 66))	('GC', 'Phenotype', 'HP:0012126', (173, 175))	('associated', 'Reg', (118, 128))	('high', 'Var', (42, 46))	('HER2', 'Gene', '2064', (192, 196))	('patients', 'Species', '9606', (159, 167))
747055	29552190	Stratified analysis by pathological grade, presented in Table III, indicate that the high expression of ADH1C was significantly associated with the decreased risk of mortality for patients with GC with well-differentiated tumors (P=0.046) compared with low expression, whereas high ADH5 expression was significantly associated with an increased risk of mortality compared with low expression (P=0.028).	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('ADH1C', 'Gene', '126', (104, 109))	('high expression', 'Var', (85, 100))	('ADH5', 'Gene', '128', (282, 286))	('mortality', 'MPA', (166, 175))	('GC', 'Phenotype', 'HP:0012126', (194, 196))	('ADH1C', 'Gene', (104, 109))	('decreased', 'NegReg', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('patients', 'Species', '9606', (180, 188))	('ADH5', 'Gene', (282, 286))
747056	29552190	The stratified analysis in GC clinical stages suggests that high expression of ADH1A (P=0.025), ADH4 (P=0.035), ADH5 (P=0.0059) and ADH6 (P=0.022) in stage 2 patients, and high expression of ADH5 (P=0.033) in stage 3 patients demonstrated a significantly increased risk of mortality compared with low expression (Table IV).	('ADH5', 'Gene', (191, 195))	('ADH6', 'Gene', '130', (132, 136))	('ADH4', 'Gene', '127', (96, 100))	('ADH5', 'Gene', '128', (191, 195))	('patients', 'Species', '9606', (217, 225))	('GC', 'Phenotype', 'HP:0012126', (27, 29))	('ADH5', 'Gene', (112, 116))	('high expression', 'Var', (172, 187))	('ADH4', 'Gene', (96, 100))	('ADH6', 'Gene', (132, 136))	('ADH1A', 'Gene', '124', (79, 84))	('ADH5', 'Gene', '128', (112, 116))	('patients', 'Species', '9606', (158, 166))	('ADH1A', 'Gene', (79, 84))
747057	29552190	In contrast, high expression of ADH7 was significantly associated with a decreased risk of mortality in patients with stage 1 GC (P=0.028; Table IV).	('decreased', 'NegReg', (73, 82))	('ADH7', 'Gene', (32, 36))	('high expression', 'Var', (13, 28))	('mortality', 'MPA', (91, 100))	('ADH7', 'Gene', '131', (32, 36))	('patients', 'Species', '9606', (104, 112))	('GC', 'Phenotype', 'HP:0012126', (126, 128))
747080	29552190	These results suggest that disturbances of ADH isoenzyme activity serve a notable function in alcohol-associated neoplasms, and may be potential diagnostic biomarkers.	('ADH', 'Gene', (43, 46))	('ADH', 'Gene', '10327', (43, 46))	('neoplasms', 'Phenotype', 'HP:0002664', (113, 122))	('disturbances', 'Var', (27, 39))	('alcohol', 'Chemical', 'MESH:D000438', (94, 101))	('neoplasms', 'Disease', 'MESH:D009369', (113, 122))	('neoplasms', 'Disease', (113, 122))
747082	29552190	The comparison of tumor and adjacent non-tumor tissues suggests that the dysregulation of ADH1A, ADH1B, ADH1C, ADH5 and ADH7 were associated with tumorigenesis in GC.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('ADH1B', 'Gene', '125', (97, 102))	('ADH5', 'Gene', (111, 115))	('ADH7', 'Gene', '131', (120, 124))	('ADH5', 'Gene', '128', (111, 115))	('ADH1C', 'Gene', (104, 109))	('tumor', 'Disease', (146, 151))	('ADH1B', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('ADH1C', 'Gene', '126', (104, 109))	('tumor', 'Disease', (18, 23))	('non-tumor', 'Disease', (37, 46))	('dysregulation', 'Var', (73, 86))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('non-tumor', 'Disease', 'MESH:D009369', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (41, 46))	('ADH1A', 'Gene', (90, 95))	('GC', 'Phenotype', 'HP:0012126', (163, 165))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('associated', 'Reg', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('ADH1A', 'Gene', '124', (90, 95))	('ADH7', 'Gene', (120, 124))
747086	29552190	High ADH4 expression was significantly associated with a favorable prognosis and may be a potential prognostic marker for patients with HCC.	('ADH4', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('expression', 'MPA', (10, 20))	('patients', 'Species', '9606', (122, 130))	('HCC', 'Disease', (136, 139))	('ADH4', 'Gene', '127', (5, 9))
747088	29552190	The genetic variation of ADH genes has additionally been reported to be involved in the association between ADH polymorphisms and cancer survival.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('polymorphisms', 'Var', (112, 125))	('cancer', 'Disease', (130, 136))	('ADH', 'Gene', (25, 28))	('ADH', 'Gene', '10327', (25, 28))	('involved', 'Reg', (72, 80))	('ADH', 'Gene', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('genetic variation', 'Var', (4, 21))	('association', 'Interaction', (88, 99))	('ADH', 'Gene', '10327', (108, 111))
747089	29552190	A study by Li et al demonstrated that the genetic variation of ADH1B-rs1229984 was associated with laryngeal cancer overall survival (OS), and that the genetic algorithm genotype of rs1229984 decreased the risk of mortality in patients with laryngeal cancer and may be a prognostic indicator.	('rs1229984', 'Mutation', 'rs1229984', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('laryngeal cancer', 'Disease', (241, 257))	('decreased', 'NegReg', (192, 201))	('laryngeal cancer', 'Disease', 'MESH:D007822', (99, 115))	('rs1229984', 'Mutation', 'rs1229984', (69, 78))	('rs1229984', 'Var', (182, 191))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (241, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('laryngeal cancer', 'Disease', (99, 115))	('ADH1B', 'Gene', (63, 68))	('associated', 'Reg', (83, 93))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (99, 115))	('laryngeal cancer', 'Disease', 'MESH:D007822', (241, 257))	('ADH1B', 'Gene', '125', (63, 68))	('patients', 'Species', '9606', (227, 235))
747090	29552190	The survival analysis performed in the present study demonstrated that the high expression of ADH1A, ADH1B and ADH5 were associated with a significantly decreased risk of mortality in all patients with GC.	('high expression', 'Var', (75, 90))	('ADH5', 'Gene', (111, 115))	('ADH1A', 'Gene', '124', (94, 99))	('ADH1B', 'Gene', '125', (101, 106))	('ADH1A', 'Gene', (94, 99))	('GC', 'Phenotype', 'HP:0012126', (202, 204))	('ADH5', 'Gene', '128', (111, 115))	('patients', 'Species', '9606', (188, 196))	('decreased', 'NegReg', (153, 162))	('mortality', 'MPA', (171, 180))	('ADH1B', 'Gene', (101, 106))
747098	29552190	Overexpression of HER2 is associated with poor GC prognosis and associated with Lauren classification, tumor size, lymph node and World Health Organization classification.	('associated', 'Reg', (64, 74))	('GC', 'Phenotype', 'HP:0012126', (47, 49))	('Lauren classification', 'Disease', (80, 101))	('HER2', 'Gene', '2064', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('HER2', 'Gene', (18, 22))
747100	29552190	The results of the present study revealed that high expression of ADH1A and ADH1B were associated with a significantly decreased risk of mortality in patients with HER2-positive GC, in addition to high ADH1B and ADH5 for patients with HER2-negative GC.	('patients', 'Species', '9606', (221, 229))	('HER2', 'Gene', (235, 239))	('ADH5', 'Gene', (212, 216))	('ADH1B', 'Gene', (202, 207))	('HER2', 'Gene', (164, 168))	('patients', 'Species', '9606', (150, 158))	('ADH5', 'Gene', '128', (212, 216))	('high', 'Var', (47, 51))	('mortality', 'MPA', (137, 146))	('decreased', 'NegReg', (119, 128))	('ADH1A', 'Gene', (66, 71))	('HER2', 'Gene', '2064', (235, 239))	('HER2', 'Gene', '2064', (164, 168))	('ADH1A', 'Gene', '124', (66, 71))	('GC', 'Phenotype', 'HP:0012126', (178, 180))	('ADH1B', 'Gene', '125', (76, 81))	('GC', 'Phenotype', 'HP:0012126', (249, 251))	('ADH1B', 'Gene', '125', (202, 207))	('ADH1B', 'Gene', (76, 81))
747126	29483923	Researchers has found that after being activated by ligand, PPARgamma can induce tumor cell differentiation, repress their proliferation, promote their apoptosis, and concomitantly reduce neoplastic angiogenesis, which eventually halts the tumor growth, proliferation, infiltration, and metastasis.	('induce', 'PosReg', (74, 80))	('PPARgamma', 'Var', (60, 69))	('tumor', 'Disease', (240, 245))	('repress', 'NegReg', (109, 116))	('halts', 'NegReg', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('reduce', 'NegReg', (181, 187))	('promote', 'PosReg', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', (81, 86))	('neoplastic angiogenesis', 'CPA', (188, 211))	('apoptosis', 'CPA', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('infiltration', 'CPA', (269, 281))
747135	29483923	Taken together, the gene expression of PPARgamma is associated with the development and prognosis of esophageal cancer.	('PPARgamma', 'Gene', (39, 48))	('esophageal cancer', 'Disease', (101, 118))	('associated with', 'Reg', (52, 67))	('gene expression', 'Var', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))
747141	29483923	Helicobacter pylori infection is one of the most common carcinogenic factors, and elimination of Helicobacter pylori has also reduced the expression of PPARgamma in the gastric mucosa, suggesting that PPARgamma has been involved in the carcinogenic process of Helicobacter pylori.	('elimination', 'Var', (82, 93))	('Helicobacter pylori', 'Species', '210', (0, 19))	('carcinogenic', 'Disease', 'MESH:D063646', (236, 248))	('carcinogenic', 'Disease', (236, 248))	('Helicobacter pylori', 'Disease', (0, 19))	('Helicobacter pylori', 'Species', '210', (97, 116))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (0, 29))	('expression', 'MPA', (138, 148))	('carcinogenic', 'Disease', 'MESH:D063646', (56, 68))	('Helicobacter pylori', 'Species', '210', (260, 279))	('carcinogenic', 'Disease', (56, 68))	('PPARgamma', 'Gene', (152, 161))	('reduced', 'NegReg', (126, 133))
747142	29483923	Several papers have reported an antitumor effect of PPARgamma agonists (such as thiazolidinedione, prostaglandin, and their metabolic derivatives) in gastric cancer tissues, where PPARgamma agonists disturb the growth cycle of tumor cells, induce tumor cell differentiation, promote tumor cell apoptosis, repress tumor cell proliferation and metastasis, and reduce tumor angiogenesis, and these effects are dose-dependent.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Disease', (313, 318))	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('gastric cancer', 'Disease', (150, 164))	('disturb', 'Reg', (199, 206))	('repress tumor', 'Disease', 'MESH:D009369', (305, 318))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', (36, 41))	('prostaglandin', 'Chemical', 'MESH:D011453', (99, 112))	('thiazolidinedione', 'Chemical', 'MESH:C089946', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('induce', 'PosReg', (240, 246))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Disease', (247, 252))	('promote', 'PosReg', (275, 282))	('tumor', 'Disease', (365, 370))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('growth cycle', 'CPA', (211, 223))	('tumor', 'Disease', (283, 288))	('PPARgamma', 'Var', (180, 189))	('reduce', 'NegReg', (358, 364))	('repress tumor', 'Disease', (305, 318))
747145	29483923	After being activated by ligands, PPARgamma can not only inhibit the proliferation of gastric cancer growth, but also prevent the development and growth of gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('development', 'CPA', (130, 141))	('proliferation', 'CPA', (69, 82))	('PPARgamma', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('gastric cancer', 'Disease', (156, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('inhibit', 'NegReg', (57, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (156, 170))	('growth', 'CPA', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (156, 170))	('prevent', 'NegReg', (118, 125))	('gastric cancer', 'Disease', (86, 100))
747161	29483923	An experimentation on animals indicate that, in PPARgamma-expressing and PPARgamma-deficient mouse models of hepatic carcinogenesis, PPARgamma deletion in hepatocytes of did not modify hepatic carcinogenesis but increased the thiazolidinedione antitumorigenic effect in part by inhibition of nucleophosmin expression and p53 activation.	('thiazolidinedione', 'Chemical', 'MESH:C089946', (226, 243))	('tumor', 'Disease', (248, 253))	('hepatic carcinogenesis', 'Disease', 'MESH:D063646', (185, 207))	('mouse', 'Species', '10090', (93, 98))	('nucleophosmin', 'Gene', (292, 305))	('PPARgamma', 'Gene', (133, 142))	('p53', 'Gene', (321, 324))	('deletion', 'Var', (143, 151))	('hepatic carcinogenesis', 'Disease', (185, 207))	('activation', 'PosReg', (325, 335))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('inhibition', 'NegReg', (278, 288))	('hepatic carcinogenesis', 'Disease', (109, 131))	('nucleophosmin', 'Gene', '18148', (292, 305))	('increased', 'PosReg', (212, 221))	('p53', 'Gene', '22060', (321, 324))	('hepatic carcinogenesis', 'Disease', 'MESH:D063646', (109, 131))
747168	29483923	By means of increasing the uptake of glucose in the skeletal and adipose tissue by regulation of glucose transporters, also promoting catabolic events to produce ATP by increasing insulin signaling modulating AMP-activated protein kinase (AMPK), PPARgamma increases the insulin sensitivity in the peripheral tissues.	('increasing', 'PosReg', (169, 179))	('PPARgamma', 'Var', (246, 255))	('increasing', 'PosReg', (12, 22))	('insulin', 'Gene', (180, 187))	('insulin', 'Gene', (270, 277))	('AMPK', 'Gene', '5562', (239, 243))	('promoting', 'PosReg', (124, 133))	('uptake of glucose', 'MPA', (27, 44))	('AMPK', 'Gene', (239, 243))	('insulin', 'Gene', '3630', (180, 187))	('insulin', 'Gene', '3630', (270, 277))	('glucose', 'Chemical', 'MESH:D005947', (97, 104))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('increases', 'PosReg', (256, 265))	('ATP', 'Chemical', 'MESH:D000255', (162, 165))	('catabolic events', 'MPA', (134, 150))	('AMP-activated protein kinase', 'Gene', '5562', (209, 237))	('AMP-activated protein kinase', 'Gene', (209, 237))
747170	29483923	Moreover, in the new adipose tissue, PPARgamma reduces leptin expression indirectly by antagonism on leptin promoter with CCAAT/enhancer binding protein (C/EBP), whereas the nuclear receptor transcription factors control adiponectin directly which also induces the secretion of HMW adiponectin from adipocytes.	('reduces', 'NegReg', (47, 54))	('HMW', 'Gene', (278, 281))	('C/EBP', 'Gene', (154, 159))	('CCAAT/enhancer binding protein', 'Gene', (122, 152))	('C/EBP', 'Gene', '1050', (154, 159))	('leptin expression', 'MPA', (55, 72))	('HMW', 'Gene', '57587', (278, 281))	('secretion', 'MPA', (265, 274))	('PPARgamma', 'Var', (37, 46))	('CCAAT/enhancer binding protein', 'Gene', '1050', (122, 152))	('antagonism', 'Var', (87, 97))	('induces', 'Reg', (253, 260))
747172	29483923	PPARgamma inhibits resistin synthesis, which is an adipokine associated with inflammation and diabetes type 2, which is the main source of macrophages.	('resistin', 'Gene', (19, 27))	('inhibits', 'NegReg', (10, 18))	('resistin', 'Gene', '56729', (19, 27))	('PPARgamma', 'Var', (0, 9))	('inflammation', 'Disease', 'MESH:D007249', (77, 89))	('inflammation', 'Disease', (77, 89))	('diabetes type 2', 'Disease', (94, 109))	('diabetes type 2', 'Disease', 'MESH:D003924', (94, 109))
747174	29483923	PPARgamma primes primary human monocytes into M2 differentiation and keeps M2 marker expression in resting state or M1 macrophages.	('human', 'Species', '9606', (25, 30))	('expression', 'MPA', (85, 95))	('PPARgamma', 'Var', (0, 9))	('M2 differentiation', 'CPA', (46, 64))
747175	29483923	In adipose tissue, PPARgamma reduces the production of the proinflammatory cytokines tumor necrosis factor- (TNF-) alpha, interleukin- (IL-) 6, and plasminogen activator inhibitor- (PAI-) 1.	('production of', 'MPA', (41, 54))	('tumor necrosis factor- (TNF-) alpha', 'Gene', '7124', (85, 120))	('PPARgamma', 'Var', (19, 28))	('reduces', 'NegReg', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
747196	29449669	GERD was also predicted by C-peptide >= 360 pg/mL, while BE was predicted by fractalkine >= 250 pg/mL and IP-10 >= 290 pg/mL.	('C-peptide', 'MPA', (27, 36))	('IP-10', 'Gene', (106, 111))	('fractalkine', 'Gene', '6376', (77, 88))	('fractalkine', 'Gene', (77, 88))	('GERD', 'Disease', (0, 4))	('GERD', 'Disease', 'MESH:D005764', (0, 4))	('IP-10', 'Gene', '3627', (106, 111))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('>= 360 pg/mL', 'Var', (37, 49))
747232	29449669	Crude Model: Tumor necrosis factor-alpha (TNF-alpha) >= 6 pg/mL and C-peptide >= 360 pg/mL significantly predicted GERD in the univariate model.	('TNF-alpha', 'Gene', '7124', (42, 51))	('>= 360', 'Var', (78, 84))	('TNF-alpha', 'Gene', (42, 51))	('Tumor necrosis factor-alpha', 'Gene', (13, 40))	('Tumor necrosis factor-alpha', 'Gene', '7124', (13, 40))	('GERD', 'Disease', (115, 119))	('GERD', 'Disease', 'MESH:D005764', (115, 119))	('C-peptide', 'MPA', (68, 77))	('predicted', 'Reg', (105, 114))	('Tumor', 'Phenotype', 'HP:0002664', (13, 18))
747239	29449669	TNF-alpha >= 6 pg/mL, fractalkine >= 250 pg/mL and IP-10 >= 290 pg/mL continued to predict BE with ORs (95%CI) of 3.84(1.23-12.03), 3.42(1.18-9.96) and 4.47(1.45-13.84), respectively (Table 1).	('TNF-alpha', 'Gene', (0, 9))	('TNF-alpha', 'Gene', '7124', (0, 9))	('BE', 'Phenotype', 'HP:0100580', (91, 93))	('IP-10', 'Gene', (51, 56))	('>= 250', 'Var', (34, 40))	('IP-10', 'Gene', '3627', (51, 56))	('fractalkine', 'Gene', '6376', (22, 33))	('fractalkine', 'Gene', (22, 33))
747301	29416375	Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies.	('SLC', 'Gene', '6366', (28, 31))	('SLC', 'Gene', (28, 31))	('system neoplasms', 'Disease', 'MESH:D009369', (138, 154))	('digestive system neoplasms', 'Phenotype', 'HP:0007378', (128, 154))	('dysregulation', 'Var', (94, 107))	('system neoplasms', 'Disease', (138, 154))	('neoplasms', 'Phenotype', 'HP:0002664', (145, 154))
747337	29416375	Inhibition of luminal iron can suppress murine intestinal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('murine', 'Species', '10090', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Inhibition', 'Var', (0, 10))	('iron', 'Chemical', 'MESH:D007501', (22, 26))	('suppress', 'NegReg', (31, 39))	('luminal', 'Protein', (14, 21))
747353	29416375	Twelve out of 57 (21%) squamous cell carcinoma patients gained response for anti-SLC2A1 antibodies, when a mean+2x standard deviation of healthy donors was used as a cut-off level.	('patients', 'Species', '9606', (47, 55))	('gained', 'PosReg', (56, 62))	('anti-SLC2A1', 'Var', (76, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('response', 'MPA', (63, 71))	('squamous cell carcinoma', 'Disease', (23, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))
747354	29416375	Teng et al found that hepatitis B virus pre-S2 mutant can induce the expression of SLC2A1 via EIF4EBP1, YY1, and MYC dependent manner, which contributed to aberrant glucose uptake and lactate production, thereby promoting tumorigenesis in the liver.	('glucose', 'CPA', (165, 172))	('lactate', 'Chemical', 'MESH:D019344', (184, 191))	('lactate production', 'MPA', (184, 202))	('SLC2A1', 'Gene', (83, 89))	('induce', 'PosReg', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('MYC', 'Gene', '4609', (113, 116))	('expression', 'MPA', (69, 79))	('pre-S2', 'Gene', (40, 46))	('hepatitis B virus', 'Species', '10407', (22, 39))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('hepatitis', 'Phenotype', 'HP:0012115', (22, 31))	('MYC', 'Gene', (113, 116))	('promoting', 'PosReg', (212, 221))	('mutant', 'Var', (47, 53))	('glucose', 'Chemical', 'MESH:D005947', (165, 172))
747357	29416375	In gastric cancer, expression of SLC5A8 was epigenetically inactivated, as indicated by the aberrant methylation of SLC5A8 promoter region in 23 of 71 (30%) primary gastric cancer cases.	('aberrant', 'Var', (92, 100))	('expression', 'MPA', (19, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('inactivated', 'NegReg', (59, 70))	('SLC5A8', 'Gene', (33, 39))	('methylation', 'MPA', (101, 112))	('SLC5A8', 'Gene', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', (165, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (165, 179))
747366	29416375	Deletion of CAGA elements located within the -273/-222 region of SLC5A8 promoter abolishes its transcription activation by Activin A, and Smad signaling seems to be responsible for Activin A-induced transcription activation of SLC5A8.	('SLC5A8', 'Gene', (65, 71))	('CAGA', 'Gene', (12, 16))	('abolishes', 'NegReg', (81, 90))	('transcription activation', 'MPA', (95, 119))	('CAGA', 'Gene', '6279', (12, 16))	('Deletion', 'Var', (0, 8))
747367	29416375	Using transcriptome sequencing analysis, Palanisamy et al identified that a gene fusions including SLC45A3 can induce neoplastic transformation of prostate cells.	('gene fusions', 'Var', (76, 88))	('induce', 'PosReg', (111, 117))	('SLC45A3', 'Gene', '85414', (99, 106))	('neoplastic transformation of prostate cells', 'CPA', (118, 161))	('SLC45A3', 'Gene', (99, 106))
747372	29416375	Another study by Zhu et al also showed that the genetic variant rs7758229 in SLC22A3 has no correlation with the risk of cancer in Chinese population.	('rs7758229', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('rs7758229', 'Mutation', 'rs7758229', (64, 73))	('SLC22A3', 'Gene', '6581', (77, 84))	('SLC22A3', 'Gene', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
747381	29416375	This was probably mediated by the methylation of SLC22A1 promoter region.	('mediated by', 'Reg', (18, 29))	('SLC22A1', 'Gene', '6580', (49, 56))	('SLC22A1', 'Gene', (49, 56))	('methylation', 'Var', (34, 45))
747390	29416375	Overexpression of SL22A18 induced G2/M cell cycle arrest as well as reduced colony formation of colon cancer cells, and this may inhibit KRAS(G12D)-mediated anchorage-independent growth of cancer cells.	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('arrest', 'Disease', 'MESH:D006323', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('SL22A18', 'Gene', (18, 25))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('KRAS', 'Gene', '3845', (137, 141))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('KRAS', 'Gene', (137, 141))	('G12D', 'Mutation', 'rs121913529', (142, 146))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (39, 56))	('cancer', 'Disease', (102, 108))	('arrest', 'Disease', (50, 56))	('colon cancer', 'Disease', (96, 108))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('inhibit', 'NegReg', (129, 136))	('reduced', 'NegReg', (68, 75))
747391	29416375	Knockdown of Kras promotes SLC22A18, further proving their mutual interaction.	('SLC22A18', 'Gene', (27, 35))	('Knockdown', 'Var', (0, 9))	('Kras', 'Gene', (13, 17))	('Kras', 'Gene', '3845', (13, 17))	('promotes', 'PosReg', (18, 26))	('SLC22A18', 'Gene', '5002', (27, 35))
747392	29416375	By developing an antibody-drug conjugate ASG-5ME, it was found that pancreatic cancer cell viability, as well as xenografted growth of tumor cells, can be prominently reduced by targeting SLC44A4 in pancreatic cancer cells.	('pancreatic cancer', 'Disease', (199, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('tumor', 'Disease', (135, 140))	('targeting', 'Var', (178, 187))	('SLC44A4', 'Gene', (188, 195))	('SLC44A4', 'Gene', '80736', (188, 195))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('ASG-5ME', 'Chemical', 'MESH:C583373', (41, 48))	('pancreatic cancer', 'Disease', (68, 85))	('reduced', 'NegReg', (167, 174))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
747393	29416375	In colon cancer, single nucleotide polymorphisms (SNPs) of SLC12A2 were found and showed correlation with a 34% reduced adenoma risk.	('single nucleotide polymorphisms', 'Var', (17, 48))	('SLC12A2', 'Gene', (59, 66))	('adenoma', 'Disease', 'MESH:D000236', (120, 127))	('SLC12A2', 'Gene', '6558', (59, 66))	('adenoma', 'Disease', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('reduced', 'NegReg', (112, 119))	('colon cancer', 'Disease', (3, 15))
747395	29416375	However, expression of SLC12A2 was induced by hyperosmolarity, and induced expression of SLC12A1 in hepatic stellate cells can promote its activation toward myofibroblast-like phenotype.	('activation', 'CPA', (139, 149))	('promote', 'PosReg', (127, 134))	('SLC12A1', 'Gene', (89, 96))	('expression', 'Var', (75, 85))	('SLC12A2', 'Gene', (23, 30))	('SLC12A2', 'Gene', '6558', (23, 30))	('SLC12A1', 'Gene', '6557', (89, 96))
747397	29416375	NKCC1, which was encoded by SLC12A2, was primarily located in the cytoplasm of esophageal carcinoma cells, and depletion of NKCC1 suppressed cell proliferation and rendered G2/M cell cycle arrest.	('SLC12A2', 'Gene', (28, 35))	('SLC12A2', 'Gene', '6558', (28, 35))	('arrest', 'Disease', 'MESH:D006323', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('suppressed', 'NegReg', (130, 140))	('esophageal carcinoma', 'Disease', (79, 99))	('arrest', 'Disease', (189, 195))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (79, 99))	('NKCC1', 'Gene', (0, 5))	('NKCC1', 'Gene', '6558', (0, 5))	('cell proliferation', 'CPA', (141, 159))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (79, 99))	('rendered', 'Reg', (164, 172))	('NKCC1', 'Gene', (124, 129))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (178, 195))	('depletion', 'Var', (111, 120))	('NKCC1', 'Gene', '6558', (124, 129))
747398	29416375	Microarray analysis revealed that knockdown of SLC12A2 initiates G2/M DNA damage pathway-related proteins including MAD2L1, DTL, BLM, CDC20, BRCA1, and E2F5.	('BLM', 'Gene', '641', (129, 132))	('MAD2L1', 'Gene', (116, 122))	('BRCA1', 'Gene', '672', (141, 146))	('initiates', 'PosReg', (55, 64))	('CDC20', 'Gene', (134, 139))	('CDC20', 'Gene', '991', (134, 139))	('BLM', 'Gene', (129, 132))	('BRCA1', 'Gene', (141, 146))	('MAD2L1', 'Gene', '4085', (116, 122))	('E2F5', 'Gene', '1875', (152, 156))	('knockdown', 'Var', (34, 43))	('SLC12A2', 'Gene', (47, 54))	('G2/M DNA damage pathway-related proteins', 'Pathway', (65, 105))	('E2F5', 'Gene', (152, 156))	('SLC12A2', 'Gene', '6558', (47, 54))
747403	29416375	This leads to shorter survival in colon cancer patients with high SLC12A5 expression.	('colon cancer', 'Disease', (34, 46))	('shorter', 'NegReg', (14, 21))	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (47, 55))	('SLC12A5', 'Gene', (66, 73))	('survival', 'MPA', (22, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (34, 46))	('colon cancer', 'Disease', 'MESH:D015179', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('SLC12A5', 'Gene', '57468', (66, 73))
747418	29416375	Chang et al found that expression of SLC7A11 can be suppressed by 15-keto-PGE2, which in turn reduced intracellular glutathione due to the lack of cysteine and halted cell proliferation and survival of pancreatic cancer cells, suggesting silencing of SLC7A11 as a potential strategy to inhibit pancreatic cells under oxidative stress.	('glutathione', 'Chemical', 'MESH:D005978', (116, 127))	('silencing', 'Var', (238, 247))	('oxidative stress', 'Phenotype', 'HP:0025464', (317, 333))	('lack', 'NegReg', (139, 143))	('pancreatic', 'Disease', 'MESH:D010195', (202, 212))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (202, 219))	('survival', 'CPA', (190, 198))	('cell proliferation', 'CPA', (167, 185))	('intracellular glutathione', 'MPA', (102, 127))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (66, 78))	('SLC7A11', 'Gene', (251, 258))	('SLC7A11', 'Gene', '23657', (251, 258))	('pancreatic', 'Disease', (202, 212))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('SLC7A11', 'Gene', (37, 44))	('reduced', 'NegReg', (94, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (202, 219))	('SLC7A11', 'Gene', '23657', (37, 44))	('pancreatic', 'Disease', 'MESH:D010195', (294, 304))	('suppressed', 'NegReg', (52, 62))	('cysteine', 'MPA', (147, 155))	('cysteine', 'Chemical', 'MESH:D003545', (147, 155))	('halted', 'NegReg', (160, 166))	('pancreatic cancer', 'Disease', (202, 219))	('pancreatic', 'Disease', (294, 304))
747428	29416375	The mechanism underlying induction of cell proliferation by SLC29A2 overexpression may involve activation of STAT3 signaling pathway.	('cell proliferation', 'CPA', (38, 56))	('SLC29A2', 'Gene', (60, 67))	('STAT3', 'Gene', '6774', (109, 114))	('STAT3', 'Gene', (109, 114))	('overexpression', 'Var', (68, 82))
747434	29416375	Vasuri et al found that two organic anion transporters OATP-1B1 and OATP-1B3, which were encoded by SLCO1B1 and SLCO1B3, respectively, were inversely correlated with the expression of the biliary type keratins K7 and K19, which indicated poor prognosis after liver transplantation in HCC patients.	('OATP-1B3', 'Gene', '28234', (68, 76))	('SLCO1B1', 'Gene', (100, 107))	('OATP-1B1', 'Gene', (55, 63))	('patients', 'Species', '9606', (288, 296))	('HCC', 'Gene', '619501', (284, 287))	('inversely', 'NegReg', (140, 149))	('biliary type keratins', 'Protein', (188, 209))	('SLCO1B3', 'Gene', (112, 119))	('OATP-1B1', 'Gene', '10599', (55, 63))	('HCC', 'Phenotype', 'HP:0001402', (284, 287))	('SLCO1B1', 'Gene', '10599', (100, 107))	('K19', 'Var', (217, 220))	('correlated', 'Reg', (150, 160))	('OATP-1B3', 'Gene', (68, 76))	('SLCO1B3', 'Gene', '28234', (112, 119))	('HCC', 'Gene', (284, 287))	('organic anion transporters', 'MPA', (28, 54))	('expression', 'MPA', (170, 180))
747436	29416375	However, Teft et al found that polymorphism of SLCO1B1 at 388G/G may predict longer progression-free survival (PFS), while SLCO1B3 expression was associated with reduced PFS.	('longer', 'PosReg', (77, 83))	('polymorphism', 'Var', (31, 43))	('SLCO1B1', 'Gene', '10599', (47, 54))	('SLCO1B3', 'Gene', (123, 130))	('SLCO1B1', 'Gene', (47, 54))	('SLCO1B3', 'Gene', '28234', (123, 130))	('progression-free survival', 'CPA', (84, 109))
747443	29416375	Exploratory analysis showed that polymorphisms of SLCO1B1 can affect the pharmacokinetics and pharmacodynamics of irinotecan, as evidenced by more variability of irinotecan and its active metabolite AUC in patients with SLCO1B1 polymorphisms.	('irinotecan', 'Chemical', 'MESH:D000077146', (162, 172))	('affect', 'Reg', (62, 68))	('irinotecan', 'MPA', (162, 172))	('SLCO1B1', 'Gene', '10599', (50, 57))	('SLCO1B1', 'Gene', (220, 227))	('polymorphisms', 'Var', (33, 46))	('pharmacodynamics', 'MPA', (94, 110))	('pharmacokinetics', 'MPA', (73, 89))	('SLCO1B1', 'Gene', '10599', (220, 227))	('SLCO1B1', 'Gene', (50, 57))	('active metabolite AUC', 'MPA', (181, 202))	('variability', 'MPA', (147, 158))	('patients', 'Species', '9606', (206, 214))	('more', 'PosReg', (142, 146))	('irinotecan', 'Chemical', 'MESH:D000077146', (114, 124))
747444	29416375	Huang et al found that genotype GA/AA of SNP rs2306283 of SLCO1B1 and genotype GG of SNP rs1051266 of SLC19A1 were associated with a higher rapid response rate of colorectal cancer to irinotecan plus fluoropyrimidine treatment, while SLCO1B1 SNP also predicted longer PFS.	('SLCO1B1', 'Gene', (234, 241))	('SLCO1B1', 'Gene', '10599', (58, 65))	('rs1051266', 'Mutation', 'rs1051266', (89, 98))	('fluoropyrimidine', 'Chemical', '-', (200, 216))	('SLCO1B1', 'Gene', '10599', (234, 241))	('irinotecan', 'Chemical', 'MESH:D000077146', (184, 194))	('SNP', 'Var', (41, 44))	('rapid response', 'MPA', (140, 154))	('higher', 'PosReg', (133, 139))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('SLC19A1', 'Gene', (102, 109))	('rs2306283', 'Var', (45, 54))	('SNP', 'Var', (85, 88))	('SLC19A1', 'Gene', '6573', (102, 109))	('colorectal cancer', 'Disease', (163, 180))	('colorectal cancer', 'Disease', 'MESH:D015179', (163, 180))	('rs2306283', 'Mutation', 'rs2306283', (45, 54))	('SLCO1B1', 'Gene', (58, 65))
747445	29416375	Experimental observation showed that pancreatic cells with high expression of SLCO1B1 and SLCO1B3 were more sensitive to gemcitabine treatment than those with lower expression.	('SLCO1B1', 'Gene', '10599', (78, 85))	('pancreatic', 'Disease', 'MESH:D010195', (37, 47))	('SLCO1B3', 'Gene', '28234', (90, 97))	('pancreatic', 'Disease', (37, 47))	('gemcitabine', 'Chemical', 'MESH:C056507', (121, 132))	('sensitive to gemcitabine treatment', 'MPA', (108, 142))	('high expression', 'Var', (59, 74))	('SLCO1B1', 'Gene', (78, 85))	('SLCO1B3', 'Gene', (90, 97))
747448	29416375	Hypermethylation of SLC19A3 was found in gastric cancer cell lines (57%, 4/7), primary gastric carcinoma tissues (51%, 52/101), and precancerous lesion (intestinal metaplasia) tissues (32%, 8/25).	('intestinal metaplasia', 'Disease', 'MESH:D008679', (153, 174))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (87, 104))	('precancerous lesion', 'Disease', (132, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('Hypermethylation', 'Var', (0, 16))	('found', 'Reg', (32, 37))	('gastric carcinoma', 'Disease', 'MESH:D013274', (87, 104))	('precancerous lesion', 'Disease', 'MESH:D011230', (132, 151))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('SLC19A3', 'Gene', '80704', (20, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('intestinal metaplasia', 'Disease', (153, 174))	('gastric carcinoma', 'Disease', (87, 104))	('gastric cancer', 'Disease', (41, 55))	('SLC19A3', 'Gene', (20, 27))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
747484	29416375	Depletion of intracellular zinc can reduce the migratory and invasive ability of cancer cells.	('reduce', 'NegReg', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('Depletion', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
747497	29416375	Although there is still no direct scientific evidence to show that knockdown of SLC22 can cause CHOL, it is postulated that abnormal bile acid secretion and formation caused by SLC22 loss may be associated with bile duct carcinogenesis by mutated cells.	('associated', 'Reg', (195, 205))	('formation', 'MPA', (157, 166))	('loss', 'NegReg', (183, 187))	('SLC', 'Gene', '6366', (177, 180))	('carcinogenesis', 'Disease', (221, 235))	('knockdown', 'Var', (67, 76))	('CHOL', 'Phenotype', 'HP:0030153', (96, 100))	('CHOL', 'Disease', (96, 100))	('SLC', 'Gene', '6366', (80, 83))	('SLC', 'Gene', (177, 180))	('SLC', 'Gene', (80, 83))	('cause', 'Reg', (90, 95))	('bile acid', 'Chemical', 'MESH:D001647', (133, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (221, 235))	('abnormal bile acid secretion', 'MPA', (124, 152))
747498	29416375	Regarding the critical role of SLC proteins in mediating the initiation, progression, and metastasis of different cancers, which has been critically reviewed elsewhere and in our present review, pharmacologic modulations on the expressions and activities of SLC proteins might deliver potential therapeutic activities on cancers.	('SLC', 'Gene', '6366', (258, 261))	('modulations', 'Var', (209, 220))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('SLC', 'Gene', (258, 261))	('cancers', 'Phenotype', 'HP:0002664', (321, 328))	('cancers', 'Disease', (114, 121))	('cancers', 'Disease', (321, 328))	('SLC', 'Gene', (31, 34))	('cancers', 'Disease', 'MESH:D009369', (321, 328))	('metastasis of different cancers', 'Disease', (90, 121))	('activities', 'MPA', (244, 254))	('metastasis of different cancers', 'Disease', 'MESH:D009362', (90, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('SLC', 'Gene', '6366', (31, 34))
747499	29416375	A series of small molecule modulators of SLC proteins have been discovered with high-throughput screening of large compound libraries, most of which were found to be inhibitors of transporters function.	('modulators', 'Var', (27, 37))	('transporters function', 'MPA', (180, 201))	('SLC', 'Gene', '6366', (41, 44))	('SLC', 'Gene', (41, 44))
747515	29416375	These findings suggest that particular modulators (Figure 2) of SLC family proteins may be potential next-generation therapeutic agents for digestive system neoplasms.	('system neoplasms', 'Disease', 'MESH:D009369', (150, 166))	('digestive system neoplasms', 'Phenotype', 'HP:0007378', (140, 166))	('system neoplasms', 'Disease', (150, 166))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('SLC', 'Gene', '6366', (64, 67))	('SLC', 'Gene', (64, 67))	('modulators', 'Var', (39, 49))
747518	29416375	Mutation or dysfunction of SLC proteins is, therefore, a risk factor for the occurrence of gastrointestinal malignancies, or it mediates the progression of cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('gastrointestinal malignancies', 'Disease', (91, 120))	('dysfunction of SLC proteins', 'Disease', (12, 39))	('mediates', 'Reg', (128, 136))	('cancers', 'Disease', (156, 163))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (91, 120))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('Mutation', 'Var', (0, 8))	('dysfunction of SLC proteins', 'Disease', 'MESH:D011488', (12, 39))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
747531	29416375	Changes in expression and regulation of SLC family proteins (as summarized in Figure 3) were observed in neoplasms of digestive system and their dysregulation may be associated with increased carcinogenesis, tumor progression, and metastasis, as well as with resistance of cancer cells to chemotherapeutic agents.	('increased', 'PosReg', (182, 191))	('expression', 'MPA', (11, 21))	('metastasis', 'CPA', (231, 241))	('neoplasms', 'Disease', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('regulation', 'MPA', (26, 36))	('SLC', 'Gene', '6366', (40, 43))	('tumor', 'Disease', (208, 213))	('Changes', 'Reg', (0, 7))	('associated', 'Reg', (166, 176))	('dysregulation', 'Var', (145, 158))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('neoplasms', 'Phenotype', 'HP:0002664', (105, 114))	('carcinogenesis', 'Disease', (192, 206))	('neoplasms of digestive system', 'Phenotype', 'HP:0007378', (105, 134))	('cancer', 'Disease', (273, 279))	('carcinogenesis', 'Disease', 'MESH:D063646', (192, 206))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('SLC', 'Gene', (40, 43))	('neoplasms', 'Disease', 'MESH:D009369', (105, 114))
747679	28970723	B-Actin (Qiagen, Valencia, CA, United States; #PPR0650C-200) and RPLP1 (Qiagen, Valencia, CA, United States; #PPR42363C-200) were selected as endogenous controls.	('; #PPR42363C-200', 'Var', (107, 123))	('RPLP1', 'Gene', '140661', (65, 70))	('RPLP1', 'Gene', (65, 70))
747723	28970723	The present study assessed the expression levels of MUC2, MUC5AC, CK19, and CK20 at each esophageal disease level harvested from surgically induced rat reflux model.	('CK19', 'Gene', (66, 70))	('rat', 'Species', '10116', (148, 151))	('esophageal disease', 'Disease', 'MESH:D004935', (89, 107))	('expression', 'MPA', (31, 41))	('CK20', 'Var', (76, 80))	('esophageal disease', 'Disease', (89, 107))
747741	28970723	Using this model, authors determine respective rates of carcinogenic development and gene expression levels of MUC2, CK19, and CK20.	('CK20', 'Var', (127, 131))	('rat', 'Species', '10116', (47, 50))	('carcinogenic development', 'CPA', (56, 80))	('MUC2', 'Gene', (111, 115))	('CK19', 'Var', (117, 121))
747765	27193097	DLT was defined as any of the following adverse events occurring within 28 days after completion of the protocol treatment: (1) febrile neutropenia lasting >4 days; (2) grade 4 thrombocytopenia (<0.25 x 109/l); (3) grade 3 or 4 non-hematologic toxic effects, except grade 3 alopecia, anorexia, nausea, vomiting, constipation, stomatitis, esophagitis or infection due to stomatitis; (4) discontinuation of treatment due to an adverse event; or (5) treatment-related death.	('stomatitis', 'Phenotype', 'HP:0010280', (326, 336))	('thrombocytopenia', 'Disease', (177, 193))	('febrile neutropenia', 'Disease', 'MESH:D009503', (128, 147))	('esophagitis or infection', 'Disease', 'MESH:D004941', (338, 362))	('anorexia', 'Disease', (284, 292))	('vomiting', 'Phenotype', 'HP:0002013', (302, 310))	('esophagitis or infection', 'Disease', (338, 362))	('stomatitis', 'Disease', 'MESH:D013280', (370, 380))	('vomiting', 'Disease', (302, 310))	('stomatitis', 'Disease', (370, 380))	('nausea', 'Phenotype', 'HP:0002018', (294, 300))	('<0.25 x 109/l', 'Var', (195, 208))	('constipation', 'Phenotype', 'HP:0002019', (312, 324))	('thrombocytopenia', 'Disease', 'MESH:D013921', (177, 193))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (177, 193))	('alopecia', 'Phenotype', 'HP:0001596', (274, 282))	('nausea', 'Disease', (294, 300))	('stomatitis', 'Phenotype', 'HP:0010280', (370, 380))	('constipation', 'Disease', 'MESH:D003248', (312, 324))	('febrile neutropenia', 'Disease', (128, 147))	('stomatitis', 'Disease', 'MESH:D013280', (326, 336))	('stomatitis', 'Disease', (326, 336))	('neutropenia', 'Phenotype', 'HP:0001875', (136, 147))	('nausea', 'Disease', 'MESH:D009325', (294, 300))	('constipation', 'Disease', (312, 324))	('esophagitis', 'Phenotype', 'HP:0100633', (338, 349))	('anorexia', 'Phenotype', 'HP:0002039', (284, 292))	('vomiting', 'Disease', 'MESH:D014839', (302, 310))
747766	27193097	Adjacent organs were considered to be involved if the tumor extended into the lumen or caused a deformity of the airway in the trachea or tracheobronchial tree, and if the tumor was attached to the organ at a contact angle >=90  in the thoracic aorta as observed on the CT scan.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('deformity of the airway', 'Phenotype', 'HP:0002086', (96, 119))	('deformity', 'Disease', (96, 105))	('thoracic aorta', 'Phenotype', 'HP:0012727', (236, 250))	('caused', 'Reg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('deformity of the airway in the trachea', 'Phenotype', 'HP:0002778', (96, 134))	('tumor', 'Var', (54, 59))	('deformity', 'Disease', 'MESH:D009140', (96, 105))
747780	27193097	Although these survival data were equivalent to those of our present study, DCF-R was associated with a relatively high incidence of FN (grade 3 or more, 38.1 %) and late toxic effects, namely grade 3 or more pericardial effusion (2.6 %), esophagus-related toxicities (7.7 %) and cardiovascular toxicities (2.6 %).	('cardiovascular toxicities', 'Disease', (280, 305))	('pericardial effusion', 'Disease', 'MESH:D010490', (209, 229))	('cardiovascular toxicities', 'Disease', 'MESH:D002318', (280, 305))	('pericardial effusion', 'Phenotype', 'HP:0001698', (209, 229))	('esophagus-related toxicities', 'Disease', (239, 267))	('pericardial effusion', 'Disease', (209, 229))	('DCF-R', 'Var', (76, 81))
747812	26831229	For PTV, D98% and D2% (dose received by the 98% and 2% of the volume, respectively) were defined as the minimum and maximum doses, respectively.	('D98%', 'Var', (9, 13))	('PTV', 'Chemical', '-', (4, 7))	('D2%', 'Var', (18, 21))
747824	26831229	This is not possible during VMAT treatments and a malfunction of the gantry readout can lead to a wrong position of the gantry.	('VMAT', 'Disease', 'None', (28, 32))	('lead to', 'Reg', (88, 95))	('VMAT', 'Disease', (28, 32))	('malfunction', 'Var', (50, 61))
747887	26506988	The 5-year overall survival rates for patients with PS0, PS1 and PS2 were 48.7 % (95 % CI, 33.1-64.6), 44.3 % (95 % CI, 36.7-52.1) and 22.3 % (95 % CI, 9.5-44.1), respectively.	('PS2', 'Gene', (65, 68))	('PS0', 'Var', (52, 55))	('PS1', 'Gene', '338399', (57, 60))	('PS2', 'Gene', '338412', (65, 68))	('PS1', 'Gene', (57, 60))	('patients', 'Species', '9606', (38, 46))
748066	33104915	In a recent study of 271 patients in each group, the number of dissected lymph nodes along RLN was significantly higher using RAME than VAME.	('RAME', 'Var', (126, 130))	('RAME', 'Chemical', '-', (126, 130))	('higher', 'PosReg', (113, 119))	('VAME', 'Chemical', '-', (136, 140))	('patients', 'Species', '9606', (25, 33))
748084	30233644	In conclusion, our data demonstrate the methylation panel of ADHFE1, EOMES, SALL1 and TFPI2 could be an effective methylation-based diagnostic assay for ESCC.	('methylation', 'Var', (40, 51))	('EOMES', 'Gene', (69, 74))	('ADHFE1', 'Gene', (61, 67))	('SALL1', 'Gene', (76, 81))	('ADHFE1', 'Gene', '137872', (61, 67))	('SALL1', 'Gene', '6299', (76, 81))	('EOMES', 'Gene', '8320', (69, 74))	('TFPI2', 'Gene', '7980', (86, 91))	('TFPI2', 'Gene', (86, 91))	('ESCC', 'Disease', (153, 157))
748092	30233644	DNA methylation, which usually occurs in CpG dinucleotides, functioning as an epigenetic modification in mammalian genome and is involved in regulating gene and microRNA expression and alternative splicing.	('involved', 'Reg', (129, 137))	('gene', 'MPA', (152, 156))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (41, 58))	('methylation', 'Var', (4, 15))	('mammalian', 'Species', '9606', (105, 114))	('regulating', 'Reg', (141, 151))
748093	30233644	Global hypo-methylation as well as the hyper-methylation of CpG islands in the tumor suppressor genes have been widely identified in the process of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (79, 84))	('Global hypo-methylation', 'Var', (0, 23))	('tumor', 'Disease', (148, 153))	('hyper-methylation', 'Var', (39, 56))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('identified', 'Reg', (119, 129))
748094	30233644	DNA methylation was the first epigenetic alteration to be identified in cancer and multiple lines of studies have found that DNA methylation alterations could serve as biomarkers for cancer diagnosis including ESCC.	('alterations', 'Var', (141, 152))	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('methylation alterations', 'Var', (129, 152))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('DNA', 'Gene', (125, 128))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Disease', (72, 78))
748115	30233644	Based on the CpG sites selection criteria which was described in Patients and Methods, six significant CpG sites (cg20295442, cg20912169, cg22383888, cg04550052, cg04698114, cg12973591) located at the four candidate genes were selected for validation (Table 1).	('cg20912169', 'Var', (126, 136))	('cg04698114', 'Var', (162, 172))	('cg04550052', 'Var', (150, 160))	('cg20295442', 'Var', (114, 124))	('Patients', 'Species', '9606', (65, 73))	('cg12973591', 'Var', (174, 184))	('cg22383888', 'Var', (138, 148))
748124	30233644	However, when concentrating on the effect of alcohol use, we found that the non-alcohol use subgroup showed obviously higher AUC than that of the alcohol use subgroup (0.84 vs. 0.77 respectively, Supplementary Table 9).	('higher', 'PosReg', (118, 124))	('non-alcohol use', 'Var', (76, 91))	('alcohol use', 'Phenotype', 'HP:0030955', (45, 56))	('AUC', 'MPA', (125, 128))	('alcohol use', 'Phenotype', 'HP:0030955', (80, 91))	('alcohol use', 'Phenotype', 'HP:0030955', (146, 157))	('alcohol', 'Chemical', 'MESH:D000438', (45, 52))	('alcohol', 'Chemical', 'MESH:D000438', (146, 153))	('alcohol', 'Chemical', 'MESH:D000438', (80, 87))
748126	30233644	To assess the associations between gene expression and methylation of these four candidates, we conducted the study to demethylase the human esophageal squamous carcinoma cell line (CaES-17) with 5-aza-2'-deoxycytidine and quantified the gene expression of these candidate genes.	('squamous carcinoma', 'Phenotype', 'HP:0002860', (152, 170))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (141, 170))	('esophageal squamous carcinoma', 'Disease', (141, 170))	('demethylase', 'Var', (119, 130))	('human', 'Species', '9606', (135, 140))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (141, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('CaES-17', 'CellLine', 'CVCL:X556', (182, 189))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (196, 218))
748131	30233644	ADHFE1 promoter hyper-methylation was found in colorectal cancer (CRC) and the alcohol could down-regulate the expression of ADHFE1 through hyper-methylation and further induce the proliferation of CRC cells.	('proliferation', 'CPA', (181, 194))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('CRC', 'Phenotype', 'HP:0003003', (66, 69))	('CRC', 'Disease', (198, 201))	('down-regulate', 'NegReg', (93, 106))	('expression', 'MPA', (111, 121))	('ADHFE1', 'Gene', (125, 131))	('hyper-methylation', 'Var', (140, 157))	('ADHFE1', 'Gene', (0, 6))	('alcohol', 'Chemical', 'MESH:D000438', (79, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('ADHFE1', 'Gene', '137872', (125, 131))	('ADHFE1', 'Gene', '137872', (0, 6))	('induce', 'PosReg', (170, 176))	('CRC', 'Phenotype', 'HP:0003003', (198, 201))
748132	30233644	also identified that ADHFE1 was one of the target genes of differentially expressed miRNAs in esophageal adenocarcinomas.	('miRNAs', 'Var', (84, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('esophageal adenocarcinomas', 'Disease', (94, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (94, 119))	('ADHFE1', 'Gene', (21, 27))	('ADHFE1', 'Gene', '137872', (21, 27))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (94, 120))
748137	30233644	In addition, SALL1 hyper-methylation has already been confirmed as the diagnostic biomarker for breast cancer and other epithelial cancers, especially for the colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('epithelial cancers', 'Disease', 'MESH:D000077216', (120, 138))	('SALL1', 'Gene', '6299', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hyper-methylation', 'Var', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('epithelial cancers', 'Disease', (120, 138))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('colorectal cancer', 'Disease', (159, 176))	('SALL1', 'Gene', (13, 18))
748139	30233644	Moreover, have found that the TFPI2 is frequently methylated in esophageal cancer with a progression tendency, and the restoration of TFPI2 expression could inhibit the invasion, migration, colony formation and proliferation in KYSE70 cell line.	('TFPI2', 'Gene', (134, 139))	('expression', 'MPA', (140, 150))	('invasion', 'CPA', (169, 177))	('colony formation', 'CPA', (190, 206))	('TFPI2', 'Gene', '7980', (30, 35))	('TFPI2', 'Gene', (30, 35))	('esophageal cancer', 'Disease', (64, 81))	('TFPI2', 'Gene', '7980', (134, 139))	('inhibit', 'NegReg', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('restoration', 'Var', (119, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('KYSE70', 'CellLine', 'CVCL:1356', (228, 234))
748141	30233644	Similarly, also showed that the methylation status of TFPI2 promoter could detect Barrett's esophagus when applied to Cytosponge samples.	('TFPI2', 'Gene', '7980', (54, 59))	('TFPI2', 'Gene', (54, 59))	("Barrett's esophagus", 'Disease', (82, 101))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (82, 101))	('methylation status', 'Var', (32, 50))	('detect', 'Reg', (75, 81))
748142	30233644	also revealed that celecoxib, which was reported to induce promoter demethylation and reactivate expression of some metastasis-suppressor genes in lung cancer cells, could demethylate the methylation status of TFPI2 in vivo and up-regulate the gene expression as well as inducing the apoptosis of cancer cells.	('inducing', 'Reg', (271, 279))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('celecoxib', 'Chemical', 'MESH:D000068579', (19, 28))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('TFPI2', 'Gene', (210, 215))	('gene expression', 'MPA', (244, 259))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('promoter', 'MPA', (59, 67))	('demethylate', 'Var', (172, 183))	('reactivate expression', 'MPA', (86, 107))	('lung cancer', 'Disease', (147, 158))	('up-regulate', 'PosReg', (228, 239))	('cancer', 'Disease', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('TFPI2', 'Gene', '7980', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('methylation status', 'MPA', (188, 206))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
748152	30233644	Methylation profiles of ADHFE1, EOMES, SALL1, TFPI2 could be an effective methylation-based assay (Sensitivity = 0.66, Specificity = 0.87, AUC = 0.81) for the ESCC diagnosis with high specificity.	('SALL1', 'Gene', '6299', (39, 44))	('EOMES', 'Gene', '8320', (32, 37))	('EOMES', 'Gene', (32, 37))	('Methylation', 'Var', (0, 11))	('ADHFE1', 'Gene', (24, 30))	('SALL1', 'Gene', (39, 44))	('ADHFE1', 'Gene', '137872', (24, 30))	('TFPI2', 'Gene', '7980', (46, 51))	('TFPI2', 'Gene', (46, 51))	('ESCC', 'Disease', (159, 163))
748180	29877046	Membranes were incubated overnight at 4 C with primary antibodies anti-FOXM1 (1:500) and anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (1: 5000; Abcam, Cambridge, MA, USA).	('GAPDH', 'Gene', '2597', (136, 141))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (94, 134))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (94, 134))	('anti-FOXM1', 'Var', (66, 76))	('GAPDH', 'Gene', (136, 141))
748405	24742531	However, ectopic NGAL expression did alter the sensitivity of breast cancer cells to targeted therapy.	('sensitivity', 'MPA', (47, 58))	('ectopic', 'Var', (9, 16))	('alter', 'Reg', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('NGAL', 'Gene', '3934', (17, 21))	('NGAL', 'Gene', (17, 21))
748418	24742531	Ectopic expression of NGAL suppressed, in vivo, the liver metastasis of metastatic human colon cancer cell lines in experimentally-driven metastasis assays.	('NGAL', 'Gene', '3934', (22, 26))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('suppressed', 'NegReg', (27, 37))	('human', 'Species', '9606', (83, 88))	('Ectopic expression', 'Var', (0, 18))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('colon cancer', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('men', 'Species', '9606', (122, 125))	('NGAL', 'Gene', (22, 26))
748439	24742531	identified a new NGALR isoform designated as NGALR-3, that results from alternative splicing.	('NGALR', 'Gene', (45, 50))	('NGALR-3', 'Gene', (45, 52))	('NGALR-3', 'Gene', '51310', (45, 52))	('NGALR', 'Gene', '51310', (45, 50))	('NGALR', 'Gene', '51310', (17, 22))	('NGALR', 'Gene', (17, 22))	('alternative splicing', 'Var', (72, 92))
748441	24742531	These findings suggest that the new NGALR-3 variant could play a more important role in esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (88, 108))	('NGALR-3', 'Gene', '51310', (36, 43))	('variant', 'Var', (44, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('NGALR-3', 'Gene', (36, 43))	('esophageal carcinoma', 'Disease', (88, 108))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (88, 108))
748445	24742531	Their results demonstrated that the antisense blocking of NGAL transcription not only decreased effectively the activity of MMP-9 and MMP-2 secreted by SHEEC cells, but also suppressed significantly the invasion of these cells in nude mice.	('antisense blocking', 'Var', (36, 54))	('MMP-2', 'Gene', '17390', (134, 139))	('NGAL', 'Gene', '3934', (58, 62))	('NGAL', 'Gene', (58, 62))	('suppressed', 'NegReg', (174, 184))	('invasion of these cells in nude', 'CPA', (203, 234))	('decreased', 'NegReg', (86, 95))	('nude mice', 'Species', '10090', (230, 239))	('MMP-9', 'Protein', (124, 129))	('activity', 'MPA', (112, 120))	('MMP-2', 'Gene', (134, 139))
748509	24742531	We can gather from this study that modulation of NGAL activity could control PaCa angiogenesis and metastasis.	('PaCa', 'Phenotype', 'HP:0002894', (77, 81))	('modulation', 'Var', (35, 45))	('NGAL', 'Gene', '3934', (49, 53))	('NGAL', 'Gene', (49, 53))	('PaCa', 'Disease', (77, 81))	('PaCa', 'CellLine', 'CVCL:1U09', (77, 81))	('control', 'PosReg', (69, 76))	('metastasis', 'CPA', (99, 109))
748568	19654874	Increasing evidence is emerging that a large percentage of human tumors have elevated expression of DNA polymerase beta (Pol beta) and in many cases, mutations within the Pol beta coding region results in over-expression of dysfunctional Pol beta proteins.	('results in', 'Reg', (194, 204))	('human', 'Species', '9606', (59, 64))	('DNA polymerase beta', 'Gene', (100, 119))	('Pol beta', 'Gene', (121, 129))	('expression', 'MPA', (86, 96))	('tumors', 'Disease', (65, 71))	('over-expression', 'PosReg', (205, 220))	('elevated', 'PosReg', (77, 85))	('mutations', 'Var', (150, 159))	('DNA polymerase beta', 'Gene', '5423', (100, 119))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('Pol', 'Protein', (238, 241))	('Pol beta', 'Gene', (171, 179))	('dysfunctional', 'MPA', (224, 237))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
748571	19654874	Ectopic Pol beta expression in human cancer cells is associated with aneuploidy, abnormal localization of centrosome-associated gamma tubulin protein expression during mitosis, increased microsatellite instability and is found to promote tumorigenesis in immunodeficient nude mice.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('aneuploidy', 'Disease', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('Ectopic', 'Var', (0, 7))	('nude mice', 'Species', '10090', (271, 280))	('promote', 'PosReg', (230, 237))	('associated', 'Reg', (53, 63))	('centrosome-associated gamma tubulin protein', 'Protein', (106, 149))	('cancer', 'Disease', (37, 43))	('human', 'Species', '9606', (31, 36))	('increased', 'PosReg', (177, 186))	('tumor', 'Disease', (238, 243))	('aneuploidy', 'Disease', 'MESH:D000782', (69, 79))	('mitosis', 'Disease', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('Pol beta', 'Gene', (8, 16))	('immunodeficient', 'Disease', 'MESH:D007153', (255, 270))	('immunodeficient', 'Disease', (255, 270))	('localization', 'MPA', (90, 102))	('microsatellite instability', 'MPA', (187, 213))	('mitosis', 'Disease', 'None', (168, 175))
748573	19654874	Furthermore, approximately 30% of human cancers express mutant or aberrant forms of Pol beta proteins, leading to genomic instability and possibly conferring a mutator phenotype to cells.	('human', 'Species', '9606', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('Pol', 'Gene', (84, 87))	('mutant', 'Var', (56, 62))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('aberrant', 'Var', (66, 74))	('genomic instability', 'MPA', (114, 133))	('leading to', 'Reg', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
748574	19654874	Taken together, current evidence indicates an imbalance in Pol beta expression, either increased or decreased, leads to functional deficiency of the base excision repair pathway and promotes genomic instability.	('Pol beta', 'Protein', (59, 67))	('imbalance', 'Var', (46, 55))	('expression', 'MPA', (68, 78))	('imbalance', 'Phenotype', 'HP:0002172', (46, 55))	('deficiency', 'Disease', (131, 141))	('genomic instability', 'CPA', (191, 210))	('decreased', 'NegReg', (100, 109))	('promotes', 'PosReg', (182, 190))	('deficiency', 'Disease', 'MESH:D007153', (131, 141))	('base excision repair pathway', 'Pathway', (149, 177))
748587	19654874	It is our hypothesis that altered expression of Pol beta and the resulting imbalance in BER can predispose to tumor formation.	('predispose', 'Reg', (96, 106))	('expression', 'MPA', (34, 44))	('imbalance in BER', 'MPA', (75, 91))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('Pol', 'Enzyme', (48, 51))	('imbalance', 'Phenotype', 'HP:0002172', (75, 84))	('altered', 'Var', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
748633	19654874	Altered expression or mutations in BER proteins such as Pol beta that impact function or protein-protein interactions can predispose to sensitivity to genotoxins, an increase in genome alterations, mutations and tumor formation.	('protein-protein', 'Protein', (89, 104))	('function', 'MPA', (77, 85))	('increase', 'PosReg', (166, 174))	('Pol beta', 'Gene', (56, 64))	('genome alterations', 'MPA', (178, 196))	('mutations', 'CPA', (198, 207))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('mutations', 'Var', (22, 31))	('interactions', 'Interaction', (105, 117))	('predispose', 'Reg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('sensitivity to genotoxins', 'MPA', (136, 161))	('impact', 'Reg', (70, 76))	('tumor', 'Disease', (212, 217))
748634	19654874	In total, cellular, epidemiological and pathological analyses suggested a correlation between several human cancers and Pol beta mutations and/or expression changes.	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('mutations', 'Var', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Pol beta', 'Gene', (120, 128))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('expression', 'MPA', (146, 156))	('cancers', 'Disease', (108, 115))	('human', 'Species', '9606', (102, 107))
748635	19654874	In cell-based studies, alteration in expression of Pol beta impacts BER capacity and manifests as a genome destabilizing phenotype, consistent with the observation that greater than 30% of human tumors have elevated expression of Pol beta and in a separate study it was revealed that greater than 30% of human tumors express mutant forms of Pol beta.	('tumors', 'Disease', (195, 201))	('elevated', 'PosReg', (207, 215))	('BER capacity', 'CPA', (68, 80))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('human', 'Species', '9606', (189, 194))	('impacts', 'Reg', (60, 67))	('alteration', 'Var', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('expression', 'MPA', (216, 226))	('tumors', 'Disease', (310, 316))	('tumors', 'Phenotype', 'HP:0002664', (310, 316))	('tumors', 'Disease', 'MESH:D009369', (310, 316))	('expression', 'MPA', (37, 47))	('mutant', 'Var', (325, 331))	('human', 'Species', '9606', (304, 309))	('Pol beta', 'Gene', (51, 59))
748636	19654874	Only a few animal models with altered Pol beta expression have been characterized to study how alterations in Pol beta expression might impact tumor formation in the whole animal.	('tumor', 'Disease', (143, 148))	('Pol beta', 'Gene', (110, 118))	('impact', 'Reg', (136, 142))	('alterations', 'Var', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
748637	19654874	Mice with a partial deficiency in Pol beta expression (Pol beta heterozygote mice) have an elevated mutant frequency in male germ cells and a small increase in the incidence of lymphoid hyperplasia and adenocarcinoma.	('deficiency', 'Disease', 'MESH:D007153', (20, 30))	('mice', 'Species', '10090', (77, 81))	('increase', 'PosReg', (148, 156))	('Pol beta', 'Protein', (34, 42))	('lymphoid hyperplasia', 'Phenotype', 'HP:0002716', (177, 197))	('mutant', 'Var', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('Mice', 'Species', '10090', (0, 4))	('deficiency', 'Disease', (20, 30))	('lymphoid hyperplasia and adenocarcinoma', 'Disease', 'MESH:D006965', (177, 216))
748643	19654874	The majority of non-neoplastic and neoplastic lesions observed in the Pol beta Tg mice were considered spontaneous and age-related as previously reported in C57BL and other mouse strains.	('mice', 'Species', '10090', (82, 86))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (35, 52))	('Pol beta Tg', 'Var', (70, 81))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (35, 53))	('neoplastic lesion', 'Disease', (35, 52))	('mouse', 'Species', '10090', (173, 178))	('neoplastic lesion', 'Disease', 'MESH:D051437', (35, 52))
748644	19654874	The more commonly occurring spontaneous lesions in C57BL/6 (e.g., lymphoma and histiocytic sarcoma) were not increased in the Pol beta Tg mice.	('Pol beta Tg', 'Var', (126, 137))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('mice', 'Species', '10090', (138, 142))	('lymphoma', 'Disease', (66, 74))	('sarcoma', 'Disease', (91, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('lymphoma', 'Disease', 'MESH:D008223', (66, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (66, 74))
748647	19654874	The 39% incidence of proliferative duodenal lesions in the Pol beta Tg mice is considerably higher than previously reported incidences of 4% and 21% in aged C57BL mice.	('Pol beta Tg', 'Var', (59, 70))	('mice', 'Species', '10090', (71, 75))	('higher', 'PosReg', (92, 98))	('mice', 'Species', '10090', (163, 167))	('proliferative', 'CPA', (21, 34))
748648	19654874	Other spontaneous plaquelike lesions or polyposis in the pyloric area of the glandular stomach have been observed in C57BL/Ncrx129/SvTer (B6,129) mice, 129/SvTer mice, Ahr-null mice, TGF b-1 heterozygous mice, Smad4 heterozygous mice, CYP1A2-null mice, and B6C3F1 mice.	('Ahr', 'Gene', (168, 171))	('Smad4', 'Gene', '17128', (210, 215))	('mice', 'Species', '10090', (204, 208))	('C57BL/Ncrx129/SvTer', 'Var', (117, 136))	('mice', 'Species', '10090', (162, 166))	('mice', 'Species', '10090', (146, 150))	('CYP1A2', 'Gene', '13077', (235, 241))	('TGF b-1', 'Gene', '21803', (183, 190))	('polyposis', 'Disease', (40, 49))	('mice', 'Species', '10090', (247, 251))	('Ahr', 'Gene', '11622', (168, 171))	('TGF b-1', 'Gene', (183, 190))	('Smad4', 'Gene', (210, 215))	('polyposis', 'Disease', 'MESH:D011125', (40, 49))	('mice', 'Species', '10090', (264, 268))	('mice', 'Species', '10090', (177, 181))	('CYP1A2', 'Gene', (235, 241))	('plaquelike lesions', 'Disease', 'MESH:D051437', (18, 36))	('plaquelike lesions', 'Disease', (18, 36))	('mice', 'Species', '10090', (229, 233))
748649	19654874	Moreover, C57BL mice have been reported to be very susceptible to duodenal neoplasia following some carcinogen treatments.	('neoplasia', 'Disease', (75, 84))	('C57BL', 'Var', (10, 15))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('susceptible', 'Reg', (51, 62))	('mice', 'Species', '10090', (16, 20))	('neoplasia', 'Disease', 'MESH:D009369', (75, 84))	('duodenal neoplasia', 'Phenotype', 'HP:0006771', (66, 84))
748655	19654874	Molecular alterations in these duodenal lesions are similar to those of colorectal tumors and include K-ras mutation and the overexpression of p53, p21/Waf1, p16, and/or APC.	('p21', 'Gene', '12575', (148, 151))	('p16', 'Gene', '12578', (158, 161))	('Waf1', 'Gene', (152, 156))	('colorectal tumors', 'Disease', 'MESH:D015179', (72, 89))	('Waf1', 'Gene', '12575', (152, 156))	('p53', 'Gene', (143, 146))	('duodenal', 'Disease', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('p16', 'Gene', (158, 161))	('p53', 'Gene', '22060', (143, 146))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('p21', 'Gene', (148, 151))	('APC', 'Disease', 'MESH:D011125', (170, 173))	('APC', 'Disease', (170, 173))	('colorectal tumors', 'Disease', (72, 89))	('K-ras', 'Gene', '16653', (102, 107))	('K-ras', 'Gene', (102, 107))	('mutation', 'Var', (108, 116))	('overexpression', 'PosReg', (125, 139))
748656	19654874	Mice which carry a mutation in the Apc gene have multiple neoplastic lesions in duodenum (42%), jejunum (38%), stomach (25%), ileum (15%), and colon (8%).	('Apc', 'Gene', '11789', (35, 38))	('mutation', 'Var', (19, 27))	('neoplastic lesion', 'Disease', (58, 75))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (58, 76))	('duodenum', 'Disease', (80, 88))	('colon', 'Disease', (143, 148))	('neoplastic lesion', 'Disease', 'MESH:D051437', (58, 75))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (58, 75))	('Mice', 'Species', '10090', (0, 4))	('Apc', 'Gene', (35, 38))	('colon', 'Disease', 'MESH:D015179', (143, 148))
748657	19654874	It is not known if altered expression of the above-mentioned genes might be related to the pathogenesis of duodenal lesions in Pol beta Tg mice.	('duodenal lesions', 'Disease', (107, 123))	('Pol', 'Var', (127, 130))	('mice', 'Species', '10090', (139, 143))
748661	19654874	Therefore, the incidence of osteogenic tumors in Pol beta Tg mice is considerably higher than incidences cited in the literature.	('osteogenic tumors', 'Disease', 'MESH:D012516', (28, 45))	('Pol beta Tg', 'Var', (49, 60))	('mice', 'Species', '10090', (61, 65))	('higher', 'PosReg', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('osteogenic tumors', 'Disease', (28, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
748672	19654874	This mouse model might be a useful tool for cancer chemotherapy as well as evaluating the environmental and genetic factors that cooperate with Pol beta expression variation to impact hyperplasia and tumor formation.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('impact', 'Reg', (177, 183))	('hyperplasia', 'Disease', (184, 195))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('variation', 'Var', (164, 173))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Disease', (200, 205))	('hyperplasia', 'Disease', 'MESH:D006965', (184, 195))	('mouse', 'Species', '10090', (5, 10))	('Pol beta', 'Gene', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
748693	19654874	Analysis of mRNA expression was conducted as per the manufacturer (DeltaDeltaCT method) using Applied Biosystems TaqMan  Gene Expression Assays (human POL beta: part #4331182, Hs01099715_m1; mouse Pol beta: part #4331182, Mm00448234_m1) and normalized to the expression of mouse beta-actin (part #4352933E).	('beta-actin', 'Gene', '11461', (279, 289))	('POL beta', 'Gene', '5423', (151, 159))	('POL beta', 'Gene', (151, 159))	('Mm00448234_m1', 'Var', (222, 235))	('human', 'Species', '9606', (145, 150))	('Hs01099715_m1', 'Var', (176, 189))	('mouse', 'Species', '10090', (191, 196))	('mouse', 'Species', '10090', (273, 278))	('beta-actin', 'Gene', (279, 289))
748695	19654874	The pre-amplified cDNA was next analyzed using the Applied Biosystems TaqMan  Gene Expression Assays (human POL beta: part #4331182, Hs01099715_m1; mouse Pol beta: part #4331182, Mm00448234_m1) and normalized to the expression of mouse beta-actin.	('mouse', 'Species', '10090', (230, 235))	('beta-actin', 'Gene', (236, 246))	('mouse', 'Species', '10090', (148, 153))	('POL beta', 'Gene', '5423', (108, 116))	('POL beta', 'Gene', (108, 116))	('beta-actin', 'Gene', '11461', (236, 246))	('Mm00448234_m1', 'Var', (179, 192))	('human', 'Species', '9606', (102, 107))
748775	33912737	In a large, single-center, randomized controlled comparison of electronic patient-reported systematic symptom monitoring versus usual care in patients receiving chemotherapy for metastatic solid tumors, Basch et al found that systematic symptom monitoring was associated with increased survival.	('systematic symptom', 'Var', (226, 244))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('patient', 'Species', '9606', (74, 81))	('survival', 'MPA', (286, 294))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('increased', 'PosReg', (276, 285))	('patient', 'Species', '9606', (142, 149))	('patients', 'Species', '9606', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
748783	33157916	Whether for thoracic or for intra-abdominal segments, there were no significant differences between R3DCT and R50, but significant differences between R3DCT and RMIP, R3DCT and RCBCT.	('RCBCT', 'Chemical', '-', (177, 182))	('R3DCT', 'Var', (151, 156))	('R3DCT', 'Var', (167, 172))	('RMIP', 'Chemical', '-', (161, 165))
748822	33157916	There was a significant difference between R3DCT and RCBCT for the thoracic and intra-abdominal oesophagus, and similar results were found between R3DCT and RMIP (P = .000-.004; Table 4).	('thoracic', 'CPA', (67, 75))	('R3DCT', 'Var', (43, 48))	('RMIP', 'Chemical', '-', (157, 161))	('RCBCT', 'Chemical', '-', (53, 58))
748868	32643039	Luminal narrowing of the airway can lead to atelectasis, bronchiectasis, and mucous plugging (Fig.	('lead to', 'Reg', (36, 43))	('mucous plugging', 'Disease', (77, 92))	('Luminal', 'Chemical', 'MESH:D010634', (0, 7))	('bronchiectasis', 'Phenotype', 'HP:0002110', (57, 71))	('Luminal', 'Var', (0, 7))	('atelectasis', 'Disease', (44, 55))	('bronchiectasis', 'Disease', (57, 71))	('atelectasis', 'Phenotype', 'HP:0100750', (44, 55))
748967	32643039	While typically asymptomatic, if the lesion is large, patients can present with dysphagia, obstruction, cough, and chest pain.	('pain', 'Phenotype', 'HP:0012531', (121, 125))	('cough', 'Disease', (104, 109))	('dysphagia', 'Disease', (80, 89))	('patients', 'Species', '9606', (54, 62))	('obstruction', 'Disease', 'MESH:D000402', (91, 102))	('chest pain', 'Phenotype', 'HP:0100749', (115, 125))	('dysphagia', 'Phenotype', 'HP:0002015', (80, 89))	('obstruction', 'Disease', (91, 102))	('cough', 'Disease', 'MESH:D003371', (104, 109))	('chest pain', 'Disease', 'MESH:D002637', (115, 125))	('lesion', 'Var', (37, 43))	('dysphagia', 'Disease', 'MESH:D003680', (80, 89))	('cough', 'Phenotype', 'HP:0012735', (104, 109))	('chest pain', 'Disease', (115, 125))
749080	32391091	Previous clinical trials have revealed improved anti-tumor activity in patients treated with an anti-claudin antibody by investigating the expression of claudin 18.2 in tumor cells.	('claudin 18', 'Gene', '51208', (153, 163))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('patients', 'Species', '9606', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('claudin 18', 'Gene', (153, 163))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', (53, 58))	('improved', 'PosReg', (39, 47))	('anti-claudin', 'Var', (96, 108))
749091	32391091	The accumulation of various mutations, copy-number variations and chromothripsis causing genetic instability finally result in carcinogenesis.	('copy-number variations', 'Var', (39, 61))	('chromothripsis', 'Disease', (66, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('chromothripsis', 'Disease', 'MESH:D000072837', (66, 80))	('carcinogenesis', 'Disease', (127, 141))	('result in', 'Reg', (117, 126))	('mutations', 'Var', (28, 37))
749105	32391091	Additionally, in combination with chemotherapy, IMAB362 enhances T-cell infiltration and induces the release of pro-inflammatory cytokines.	('induces', 'Reg', (89, 96))	('release of pro-inflammatory cytokines', 'MPA', (101, 138))	('IMAB362', 'Var', (48, 55))	('T-cell infiltration', 'CPA', (65, 84))	('IMAB362', 'Chemical', 'MESH:C585662', (48, 55))	('enhances', 'PosReg', (56, 64))
749106	32391091	IMAB362 is currently undergoing a number of phase I and IIb trials, which have revealed that IMAB362 is well-tolerated, exhibits anti-tumor activity and improves the disease control rate and progression-free survival time when administered as a monotherapy or in combination with chemotherapy.	('improves', 'PosReg', (153, 161))	('disease control rate', 'CPA', (166, 186))	('progression-free survival time', 'CPA', (191, 221))	('IMAB362', 'Chemical', 'MESH:C585662', (0, 7))	('IMAB362', 'Var', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('IMAB362', 'Chemical', 'MESH:C585662', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
749139	32391091	However, none of the analyzed co-variables (including T-cell inflammation, mutations in TP53 and ARID1A and HER2 expression) affected the OS time in relation to claudin 18.2 expression (data not shown).	('HER2', 'Gene', (108, 112))	('claudin 18', 'Gene', (161, 171))	('HER2', 'Gene', '2064', (108, 112))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('ARID1A', 'Gene', '8289', (97, 103))	('mutations', 'Var', (75, 84))	('TP53', 'Gene', '7157', (88, 92))	('ARID1A', 'Gene', (97, 103))	('claudin 18', 'Gene', '51208', (161, 171))	('TP53', 'Gene', (88, 92))	('affected', 'Reg', (125, 133))
749141	32391091	Comparative molecular analyses of gastric adenocarcinomas have revealed important differences between gastric and esophageal adenocarcinomas, including the absence of the Epstein-Barr virus and microsatellite instability in EAC.	('Epstein-Barr', 'Protein', (171, 183))	('esophageal adenocarcinomas', 'Disease', (114, 140))	('gastric', 'Disease', (102, 109))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (34, 57))	('microsatellite instability', 'Var', (194, 220))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (114, 139))	('gastric adenocarcinomas', 'Disease', (34, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('esophageal adenocarcinomas', 'Disease', 'MESH:D000230', (114, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('Epstein-Barr virus', 'Species', '10376', (171, 189))
749167	31920397	Silencing of Peroxiredoxin 1 Inhibits the Proliferation of Esophageal Cancer Cells and Promotes Apoptosis by Inhibiting the Activity of the PI3K/AKT Pathway To study the effect of peroxiredoxin 1 (PRDX1) on esophageal squamous carcinoma cells and determine whether it plays a role in regulating the PI3K/AKT signaling pathway.	('squamous carcinoma', 'Disease', (218, 236))	('AKT', 'Gene', '207', (304, 307))	('Promotes', 'PosReg', (87, 95))	('Peroxiredoxin 1', 'Gene', '5052', (13, 28))	('PRDX1', 'Gene', (197, 202))	('Silencing', 'Var', (0, 9))	('PRDX1', 'Gene', '5052', (197, 202))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (218, 236))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (207, 236))	('Peroxiredoxin 1', 'Gene', (13, 28))	('squamous carcinoma', 'Disease', 'MESH:D002294', (218, 236))	('AKT', 'Gene', (145, 148))	('peroxiredoxin 1', 'Gene', '5052', (180, 195))	('AKT', 'Gene', (304, 307))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Proliferation', 'CPA', (42, 55))	('Apoptosis', 'CPA', (96, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('Inhibits', 'NegReg', (29, 37))	('Inhibiting', 'NegReg', (109, 119))	('peroxiredoxin 1', 'Gene', (180, 195))	('Activity', 'MPA', (124, 132))	('AKT', 'Gene', '207', (145, 148))
749171	31920397	Subsequently, cells were treated with a PI3K/AKT pathway inhibitor and activator, alone or in combination with silencing of PRDX1, and the above indicators were re-tested.	('silencing', 'Var', (111, 120))	('AKT', 'Gene', (45, 48))	('PRDX1', 'Gene', (124, 129))	('AKT', 'Gene', '207', (45, 48))	('PRDX1', 'Gene', '5052', (124, 129))
749175	31920397	In contrast to the control group, the proliferation and clonality of cells in the silencing PRDX1 group was decreased, the proportion of apoptotic cells was increased, and the phosphorylation levels of PI3K and AKT were decreased (p<0.05).	('PRDX1', 'Gene', '5052', (92, 97))	('decreased', 'NegReg', (220, 229))	('AKT', 'Gene', '207', (211, 214))	('silencing', 'Var', (82, 91))	('decreased', 'NegReg', (108, 117))	('AKT', 'Gene', (211, 214))	('PI3K', 'Pathway', (202, 206))	('increased', 'PosReg', (157, 166))	('clonality of cells', 'CPA', (56, 74))	('PRDX1', 'Gene', (92, 97))	('phosphorylation levels', 'MPA', (176, 198))
749176	31920397	Compared with the control group, treatment with the inhibitor LY294002 alone significantly inhibited cell proliferation and promoted apoptosis (p<0.05); this effect was similar to that observed in the silencing PRDX1 group.	('PRDX1', 'Gene', '5052', (211, 216))	('LY294002', 'Var', (62, 70))	('inhibited', 'NegReg', (91, 100))	('apoptosis', 'CPA', (133, 142))	('promoted', 'PosReg', (124, 132))	('LY294002', 'Chemical', 'MESH:C085911', (62, 70))	('PRDX1', 'Gene', (211, 216))	('cell proliferation', 'CPA', (101, 119))
749178	31920397	Silencing of PRDX1 can inhibit the proliferation of esophageal cancer cells and promote apoptosis.	('apoptosis', 'CPA', (88, 97))	('PRDX1', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('proliferation', 'CPA', (35, 48))	('PRDX1', 'Gene', '5052', (13, 18))	('inhibit', 'NegReg', (23, 30))	('esophageal cancer', 'Disease', (52, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('Silencing', 'Var', (0, 9))	('promote', 'PosReg', (80, 87))
749184	31920397	The accumulation of multiple genetic/epigenetic changes is often associated with the development of ESCC, including the stimulation of oncogenes or inactivation of tumor suppressor genes.	('tumor', 'Disease', (164, 169))	('ESCC', 'Disease', 'MESH:C562729', (100, 104))	('stimulation', 'PosReg', (120, 131))	('oncogenes', 'Protein', (135, 144))	('associated', 'Reg', (65, 75))	('ESCC', 'Disease', (100, 104))	('inactivation', 'Var', (148, 160))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
749193	31920397	The relationship between PRDX1 and the P13K/AKT signaling pathway was rarely investigated in previous studies.	('P13K', 'SUBSTITUTION', 'None', (39, 43))	('AKT', 'Gene', '207', (44, 47))	('PRDX1', 'Gene', (25, 30))	('PRDX1', 'Gene', '5052', (25, 30))	('AKT', 'Gene', (44, 47))	('P13K', 'Var', (39, 43))
749196	31920397	The experiment was divided into the following five groups: blank control group (control), negative control group (lv-NC), silencing PRDX1 group (lv-PRDX1), PI3K/AKT pathway inhibitor group (LY294002), and PRDX1 silencing plus activator group (lv-PRDX1+740 Y-P).	('PRDX1', 'Gene', '5052', (246, 251))	('LY294002', 'Chemical', 'MESH:C085911', (190, 198))	('PRDX1', 'Gene', '5052', (205, 210))	('PRDX1', 'Gene', '5052', (132, 137))	('PRDX1', 'Gene', (148, 153))	('AKT', 'Gene', '207', (161, 164))	('PRDX1', 'Gene', (132, 137))	('PRDX1', 'Gene', (205, 210))	('silencing', 'Var', (122, 131))	('PRDX1', 'Gene', '5052', (148, 153))	('PRDX1', 'Gene', (246, 251))	('AKT', 'Gene', (161, 164))
749212	31920397	Western blotting was used to detect the expression levels of PRDX1, p-PI3K, PI3K, AKT, and p-AKT in each cell line.	('PRDX1', 'Gene', (61, 66))	('PRDX1', 'Gene', '5052', (61, 66))	('AKT', 'Gene', '207', (93, 96))	('AKT', 'Gene', (93, 96))	('AKT', 'Gene', '207', (82, 85))	('PI3K', 'Var', (76, 80))	('p-PI3K', 'Var', (68, 74))	('AKT', 'Gene', (82, 85))
749216	31920397	The primary antibodies were rabbit anti-p-PI3K (1:500, orb338965; Biorbyt, Cambridge, UK), anti-PI3K (1:500, orb137259; Biorbyt), anti-AKT (1:2000, ab235958; Abcam, Cambridge, UK), anti-p-AKT (1:1000, ab8932; Abcam), anti-PRDX1 (1:500, orb335510; Biorbyt), and polyclonal beta-actin (1:1000, ab8227; Abcam).	('AKT', 'Gene', '207', (135, 138))	('PRDX1', 'Gene', '5052', (222, 227))	('AKT', 'Gene', (135, 138))	('orb335510', 'Chemical', 'None', (236, 245))	('beta-actin', 'Gene', '728378', (272, 282))	('AKT', 'Gene', '207', (188, 191))	('beta-actin', 'Gene', (272, 282))	('rabbit', 'Species', '9986', (28, 34))	('PRDX1', 'Gene', (222, 227))	('1:500', 'Var', (229, 234))	('orb137259', 'Chemical', 'None', (109, 118))	('AKT', 'Gene', (188, 191))
749225	31920397	Western blotting was used to detect changes in the activity of the PI3K/AKT pathway after silencing PRDX1.	('AKT', 'Gene', '207', (72, 75))	('activity', 'MPA', (51, 59))	('silencing', 'Var', (90, 99))	('PRDX1', 'Gene', (100, 105))	('AKT', 'Gene', (72, 75))	('PRDX1', 'Gene', '5052', (100, 105))
749228	31920397	Cells were treated with the inhibitor LY294002 to inhibit the signaling pathway, and in combination with the activator 740 Y-P on the basis of silencing PRDX1.	('PRDX1', 'Gene', '5052', (153, 158))	('LY294002', 'Var', (38, 46))	('signaling pathway', 'Pathway', (62, 79))	('inhibit', 'NegReg', (50, 57))	('PRDX1', 'Gene', (153, 158))	('LY294002', 'Chemical', 'MESH:C085911', (38, 46))	('silencing', 'Var', (143, 152))
749229	31920397	The proliferation and clonality of cells treated with LY294002 were significantly decreased, the proportion of apoptotic was increased, and the protein expression levels of p-AKT and p-PI3K were decreased (p<0.05) compared with those of the control group.	('proliferation', 'CPA', (4, 17))	('LY294002', 'Chemical', 'MESH:C085911', (54, 62))	('increased', 'PosReg', (125, 134))	('clonality', 'CPA', (22, 31))	('decreased', 'NegReg', (195, 204))	('AKT', 'Gene', '207', (175, 178))	('protein expression levels', 'MPA', (144, 169))	('LY294002', 'Var', (54, 62))	('decreased', 'NegReg', (82, 91))	('AKT', 'Gene', (175, 178))
749231	31920397	In comparison with the lv-PRDX1 group, the cells were treated with the activator 740 Y-P on the basis of silencing PRDX1.	('PRDX1', 'Gene', '5052', (26, 31))	('PRDX1', 'Gene', (115, 120))	('PRDX1', 'Gene', (26, 31))	('silencing', 'Var', (105, 114))	('PRDX1', 'Gene', '5052', (115, 120))
749242	31920397	It has been shown that the P13K/AKT pathway is related to the proliferation, migration and invasion of ESCC.	('AKT', 'Gene', '207', (32, 35))	('ESCC', 'Disease', 'MESH:C562729', (103, 107))	('invasion', 'CPA', (91, 99))	('P13K', 'Var', (27, 31))	('migration', 'CPA', (77, 86))	('AKT', 'Gene', (32, 35))	('related', 'Reg', (47, 54))	('P13K', 'SUBSTITUTION', 'None', (27, 31))	('ESCC', 'Disease', (103, 107))
749243	31920397	In the P13K/AKT pathway, following the activation of PI3K, 3,4,5-phosphatidylinositol trisphosphate phosphorylation is catalyzed and the protein kinase AKT is activated to promote the growth and proliferation of cells.	('AKT', 'Gene', '207', (12, 15))	('AKT', 'Gene', '207', (152, 155))	('P13K', 'Var', (7, 11))	('growth', 'CPA', (184, 190))	('3,4,5-phosphatidylinositol trisphosphate', 'Chemical', 'MESH:C060974', (59, 99))	('AKT', 'Gene', (12, 15))	('promote', 'PosReg', (172, 179))	('AKT', 'Gene', (152, 155))	('P13K', 'SUBSTITUTION', 'None', (7, 11))	('PI3K', 'Var', (53, 57))
749244	31920397	Our investigation of the specific mechanism of PRDX in EC cells showed that the effects of silencing PRDX1 alone and adding the P13K/AKT pathway inhibitor alone were similar.	('EC', 'Disease', 'MESH:D004938', (55, 57))	('AKT', 'Gene', '207', (133, 136))	('PRDX1', 'Gene', (101, 106))	('P13K', 'Var', (128, 132))	('silencing', 'Var', (91, 100))	('AKT', 'Gene', (133, 136))	('P13K', 'SUBSTITUTION', 'None', (128, 132))	('PRDX1', 'Gene', '5052', (101, 106))
749246	31920397	However, in combination with an activator of the P13K/AKT pathway on the basis of silencing PRDX1, the inhibitory effect on tumor development is offset.	('PRDX1', 'Gene', '5052', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('P13K', 'Var', (49, 53))	('AKT', 'Gene', '207', (54, 57))	('tumor', 'Disease', (124, 129))	('silencing', 'Var', (82, 91))	('P13K', 'SUBSTITUTION', 'None', (49, 53))	('AKT', 'Gene', (54, 57))	('PRDX1', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
749247	31920397	The results of the present study showed that silencing of PRDX1 inhibited the activity of the P13K/AKT pathway, thereby inhibiting the proliferation of ESCC cells and promoting apoptosis.	('P13K', 'SUBSTITUTION', 'None', (94, 98))	('silencing', 'Var', (45, 54))	('apoptosis', 'CPA', (177, 186))	('inhibiting', 'NegReg', (120, 130))	('PRDX1', 'Gene', (58, 63))	('inhibited', 'NegReg', (64, 73))	('AKT', 'Gene', '207', (99, 102))	('P13K', 'Var', (94, 98))	('proliferation', 'CPA', (135, 148))	('ESCC', 'Disease', 'MESH:C562729', (152, 156))	('PRDX1', 'Gene', '5052', (58, 63))	('AKT', 'Gene', (99, 102))	('promoting', 'PosReg', (167, 176))	('activity', 'MPA', (78, 86))	('ESCC', 'Disease', (152, 156))
749311	31312573	In the present study, patients with lower CRP level (<=10.0 mg/L) had better survival rates than patients with CRP >10.0 mg/L (74.2% vs. 6.7%, p<0.001).	('lower', 'NegReg', (36, 41))	('CRP', 'Gene', (111, 114))	('CRP', 'Gene', '1401', (42, 45))	('CRP', 'Gene', '1401', (111, 114))	('<=10.0 mg/L', 'Var', (53, 64))	('patients', 'Species', '9606', (22, 30))	('survival rates', 'CPA', (77, 91))	('better', 'PosReg', (70, 76))	('CRP', 'Gene', (42, 45))	('patients', 'Species', '9606', (97, 105))
749321	31312573	A single indicator may be affected by many factors; the ratio of CRP and PNI may reduce this effect.	('PNI', 'Gene', (73, 76))	('CRP', 'Gene', '1401', (65, 68))	('ratio', 'Var', (56, 61))	('reduce', 'NegReg', (81, 87))	('CRP', 'Gene', (65, 68))	('PNI', 'Gene', '30833', (73, 76))
749339	28789382	The antitumor effect of small interfering RNA against PARP1 (siPARP1) was examined in a proliferation assay, and the mechanisms of this effect were investigated using western blot analysis and cell cycle assays.	('PARP1', 'Gene', (63, 68))	('small', 'Var', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('PARP1', 'Gene', '142', (54, 59))	('tumor', 'Disease', (8, 13))	('PARP1', 'Gene', (54, 59))	('PARP1', 'Gene', '142', (63, 68))
749340	28789382	Cox multivariate analysis revealed that high expression of PARP1 in IHC staining was a statistically significant independent prognostic factor of poor overall survival (OS).	('high expression', 'Var', (40, 55))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('OS', 'Chemical', '-', (169, 171))	('PARP1', 'Gene', '142', (59, 64))	('overall survival', 'MPA', (151, 167))	('poor', 'NegReg', (146, 150))	('PARP1', 'Gene', (59, 64))
749341	28789382	The adjusted hazard ratio for OS in the group with high expression of PARP1 was 2.39 (95% confidence interval, 1.29-4.44; P=0.0051).	('PARP1', 'Gene', (70, 75))	('OS', 'Chemical', '-', (30, 32))	('PARP1', 'Gene', '142', (70, 75))	('high expression', 'Var', (51, 66))
749347	28789382	Poly (ADP-ribose) polymerase-1 (PARP1) is a 113-kDa nuclear polymerase that modifies substrates by poly ADP-ribosylation, and can conjugate ADP from NAD+ to target proteins, such as histones.	('modifies', 'Reg', (76, 84))	('substrates', 'MPA', (85, 95))	('ADP', 'Chemical', 'MESH:D000244', (104, 107))	('ADP', 'Var', (140, 143))	('Poly (ADP-ribose) polymerase-1', 'Gene', '142', (0, 30))	('conjugate', 'Interaction', (130, 139))	('PARP1', 'Gene', '142', (32, 37))	('PARP1', 'Gene', (32, 37))	('Poly (ADP-ribose) polymerase-1', 'Gene', (0, 30))	('NAD+', 'Chemical', 'MESH:D009243', (149, 153))	('histones', 'Protein', (182, 190))	('ADP', 'Chemical', 'MESH:D000244', (6, 9))	('ADP', 'Chemical', 'MESH:D000244', (140, 143))	('poly ADP-ribosylation', 'MPA', (99, 120))
749348	28789382	At present, it has been shown that PARP1 plays a role in the repair of DNA damage and is activated by DNA strand breaks, particularly those of single-stranded DNA.	('PARP1', 'Gene', '142', (35, 40))	('single-stranded DNA', 'Var', (143, 162))	('PARP1', 'Gene', (35, 40))	('repair', 'MPA', (61, 67))	('activated', 'PosReg', (89, 98))
749379	28789382	The sequence of siPARP1 was designed as follows: sc-29437A sense, 5'-GAGUCAAGAGUGAAGGAAATT-3' and antisense, 5'-UUUCCUUCACUCUUGACUCTT-3'; sc-29437B sense, 5'-GGUAUCAACAAAUCUGAAATT-3' and antisense, 5'-UUUCAGAUUUGUUGAUACCTT-3'; sc-29437C sense, 5'-GCAACAAACUGGAACAGAUTT-3' and antisense, 5'-AUCUGUUCCAGUUUGUUGCTT-3'.	('PARP1', 'Gene', '142', (18, 23))	('sc-29437C', 'Var', (227, 236))	('PARP1', 'Gene', (18, 23))
749387	28789382	Cells were seeded into 96-well plates at a density of 5x103 cells/100 microl/well (Costar; Corning Inc., Corning, NY, USA) for 24 h, and then transfected with siPARP (catalog nos.	('transfected', 'Var', (142, 153))	('PARP', 'Gene', '142', (161, 165))	('PARP', 'Gene', (161, 165))
749400	28789382	The group with high PARP1 expression had a significantly worse OS compared with patients with low expression [HR 2.25; 95% confidence interval (CI), 1.23-4.11; P=0.0092; Fig.	('high', 'Var', (15, 19))	('patients', 'Species', '9606', (80, 88))	('OS', 'Chemical', '-', (63, 65))	('expression', 'Var', (26, 36))	('PARP1', 'Gene', '142', (20, 25))	('PARP1', 'Gene', (20, 25))
749402	28789382	Multivariate Cox regression analysis revealed that high expression of PARP1 was a statistically significant independent prognostic factor of poor OS, along with pT3 and 4 and pN1-3 disease (Table II).	('PARP1', 'Gene', '142', (70, 75))	('Cox', 'Gene', (13, 16))	('poor OS', 'Disease', (141, 148))	('pN1', 'Gene', '5270', (175, 178))	('PARP1', 'Gene', (70, 75))	('OS', 'Chemical', '-', (146, 148))	('pN1', 'Gene', (175, 178))	('high expression', 'Var', (51, 66))	('Cox', 'Gene', '1351', (13, 16))
749403	28789382	The adjusted HR for OS in the group with high PARP1 expression was 2.39 (95% CI, 1.29-4.44; P=0.0051).	('PARP1', 'Gene', '142', (46, 51))	('PARP1', 'Gene', (46, 51))	('expression', 'MPA', (52, 62))	('high', 'Var', (41, 45))	('OS', 'Chemical', '-', (20, 22))
749416	28789382	Furthermore, it was demonstrated that inhibition of PARP1 with siPARP1 reduced the proliferative activity of ESCC cells, and the effect of PARP1 inhibition induced cell cycle arrest at the G2/M phase.	('PARP1', 'Gene', '142', (52, 57))	('PARP1', 'Gene', (52, 57))	('PARP1', 'Gene', '142', (139, 144))	('PARP1', 'Gene', (139, 144))	('inhibition', 'Var', (38, 48))	('reduced', 'NegReg', (71, 78))	('cell cycle arrest at the G2/M phase', 'CPA', (164, 199))	('PARP1', 'Gene', '142', (65, 70))	('proliferative activity of ESCC cells', 'CPA', (83, 119))	('PARP1', 'Gene', (65, 70))	('inhibition', 'NegReg', (145, 155))
749422	28789382	Jelinic and Levine reported that PARP inhibitors did not affect homology-directed DNA damage, but did affect cell cycle arrest at the G2 phase in a human osteosarcoma cell line.	('osteosarcoma', 'Disease', (154, 166))	('osteosarcoma', 'Phenotype', 'HP:0002669', (154, 166))	('osteosarcoma', 'Disease', 'MESH:D012516', (154, 166))	('PARP', 'Gene', '142', (33, 37))	('human', 'Species', '9606', (148, 153))	('cell cycle arrest at the G2 phase', 'CPA', (109, 142))	('inhibitors', 'Var', (38, 48))	('PARP', 'Gene', (33, 37))	('affect', 'Reg', (102, 108))
749424	28789382	Overall, it was hypothesized that PARP1 inhibition suppressed proliferation and regulated the cell cycle at the G2/M checkpoint in ESCC.	('inhibition', 'Var', (40, 50))	('PARP1', 'Gene', (34, 39))	('proliferation', 'CPA', (62, 75))	('suppressed', 'NegReg', (51, 61))	('cell cycle at the G2/M checkpoint', 'CPA', (94, 127))	('regulated', 'Reg', (80, 89))	('PARP1', 'Gene', '142', (34, 39))	('ESCC', 'Disease', (131, 135))
749427	28789382	In addition, western blotting was used to examine the detailed mechanisms of G2/M arrest induced by PARP1 inhibition.	('PARP1', 'Gene', (100, 105))	('G2/M arrest', 'CPA', (77, 88))	('PARP1', 'Gene', '142', (100, 105))	('inhibition', 'Var', (106, 116))
749428	28789382	This analysis showed that PARP1 inhibition inhibited the phosphorylation of Chk2 and cdc25c, the latter of which is responsible for removal of phosphates at Thr14 and Tyr15 and the subsequent activation of cdc2.	('Tyr15', 'Var', (167, 172))	('Chk2', 'Gene', (76, 80))	('cdc2', 'Gene', (85, 89))	('cdc25c', 'Gene', (85, 91))	('Thr14', 'Chemical', '-', (157, 162))	('inhibition inhibited', 'NegReg', (32, 52))	('phosphates', 'Chemical', 'MESH:D010710', (143, 153))	('cdc2', 'Gene', '983', (85, 89))	('cdc2', 'Gene', (206, 210))	('cdc25c', 'Gene', '995', (85, 91))	('activation', 'PosReg', (192, 202))	('PARP1', 'Gene', '142', (26, 31))	('PARP1', 'Gene', (26, 31))	('phosphorylation', 'MPA', (57, 72))	('cdc2', 'Gene', '983', (206, 210))	('Tyr15', 'Chemical', '-', (167, 172))	('Chk2', 'Gene', '11200', (76, 80))
749480	28735527	In this group, all individuals had tumors diagnosed as pT2 or pT3, N0-N2 and M0 according to the TNM classification, and the second group had tumors diagnosed as pT2 or pT3, N0-N3 and M0 according to the pTNM classification (applied according to the guidelines from the American Joint Committee on Cancer staging manual) and received neoadjuvant chemoradiotherapy before surgery.	('TNM', 'Gene', (205, 208))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('pT3', 'Gene', '7694', (62, 65))	('Cancer', 'Phenotype', 'HP:0002664', (298, 304))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('pT3', 'Gene', (169, 172))	('tumors', 'Disease', (142, 148))	('N0-N2', 'Var', (67, 72))	('pT3', 'Gene', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('TNM', 'Gene', '10178', (97, 100))	('pT3', 'Gene', '7694', (169, 172))	('pT2', 'Var', (55, 58))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('TNM', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Disease', (35, 41))	('TNM', 'Gene', '10178', (205, 208))
749552	27547696	This paper summarizes the methodologies for estimating, challenges in the analysis of, and utility of, population attributable and preventable fractions for cancers caused by major risk factors such as tobacco smoking, dietary factors, high body fat, physical inactivity, alcohol consumption, infectious agents, occupational exposure, air pollution, sun exposure, and insufficient breastfeeding.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('alcohol consumption', 'Disease', (272, 291))	('physical', 'Disease', (251, 259))	('tobacco', 'Species', '4097', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('high body fat', 'Var', (236, 249))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('alcohol', 'Chemical', 'MESH:D000438', (272, 279))
749591	27547696	There also may be differences in RRs among people with genetic variations (e.g., people with the ALDH 2 genotype have a much greater risk of cancer due to alcohol consumption), with the size of the effect of these genetic variations dependent upon the size of the effect modification and the prevalence of the genetic variation in the population.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('variations', 'Var', (63, 73))	('ALDH 2', 'Gene', (97, 103))	('people', 'Species', '9606', (43, 49))	('alcohol', 'Chemical', 'MESH:D000438', (155, 162))	('RRs', 'MPA', (33, 36))	('people', 'Species', '9606', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('ALDH 2', 'Gene', '217', (97, 103))	('cancer', 'Disease', (141, 147))
749640	27547696	Furthermore, changes in risk factors that are taxable products (such as tobacco and alcohol) to preventable targets may result in decreases in state revenues; however, decreases in health care expenditures and increases in productivity achieved through the reduction of these risk factors are likely to far outweigh losses in state revenues.	('alcohol', 'Chemical', 'MESH:D000438', (84, 91))	('decreases', 'NegReg', (168, 177))	('increases', 'PosReg', (210, 219))	('health care expenditures', 'MPA', (181, 205))	('changes', 'Var', (13, 20))	('state revenues', 'MPA', (143, 157))	('tobacco', 'Species', '4097', (72, 79))	('productivity', 'MPA', (223, 235))	('decreases', 'NegReg', (130, 139))	('reduction', 'NegReg', (257, 266))
749759	26019801	CD44 variants are expressed in both normal and tumor cells.	('CD44', 'Gene', '960', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('variants', 'Var', (5, 13))	('CD44', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
749801	26019801	Several studies have shown the overexpression of CD44 and its variants in variety of malignancies.	('malignancies', 'Disease', 'MESH:D009369', (85, 97))	('variants', 'Var', (62, 70))	('malignancies', 'Disease', (85, 97))	('CD44', 'Gene', '960', (49, 53))	('CD44', 'Gene', (49, 53))	('overexpression', 'PosReg', (31, 45))
749805	26019801	Many studies have shown the correlation between CD44 variants gene expression and depth of tumor cells invasion and metastasis in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('variants', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CD44', 'Gene', '960', (48, 52))	('tumor', 'Disease', (91, 96))	('CD44', 'Gene', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('human', 'Species', '9606', (130, 135))
749819	33931649	Among these abnormalities, cancer-specific DNA hypermethylation at CpG-Island (CGI) promoters is perhaps the most well-established epigenetic deregulation.	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('DNA hypermethylation', 'Var', (43, 63))
749820	33931649	DNA hypermethylation results in transcriptional repression of a large number of genes in cancer.	('transcriptional repression', 'MPA', (32, 58))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('hypermethylation', 'Var', (4, 20))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
749821	33931649	While some are known tumor suppressors, such as BRCA1, MLH1, and VHL, the majority of such hypermethylated genes are "passengers" (little or no functional contribution to cancer biology).	('BRCA1', 'Gene', '672', (48, 53))	('VHL', 'Gene', '7428', (65, 68))	('hypermethylated', 'Var', (91, 106))	('tumor', 'Disease', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('BRCA1', 'Gene', (48, 53))	('cancer', 'Disease', (171, 177))	('MLH1', 'Gene', '4292', (55, 59))	('MLH1', 'Gene', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('VHL', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
749822	33931649	In virtually every cancer type, hundreds of CGI promoters are DNA hypermethylated.	('cancer', 'Disease', (19, 25))	('DNA', 'Var', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
749823	33931649	CGI promoters make up a large class of promoters in vertebrate genomes (55-75% of all transcription start sites (TSSs)), and only a small fraction are targeted by DNA hypermethylation in cancer.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('hypermethylation', 'Var', (167, 183))	('cancer', 'Disease', (187, 193))
749833	33931649	Among them, H3K27me3 is considered as a hallmark of PcG-dependent transcriptional repression.	('PcG', 'Gene', '40358', (52, 55))	('H3K27me3', 'Var', (12, 20))	('PcG', 'Gene', (52, 55))
749836	33931649	While numerous studies have focused on the hypermethylation and epigenetic silencing of PRC2-associated genes, very few have looked systematically at how the entire class of PRC2-occupied CGI promoters are dysregulated in cancer.	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (222, 228))	('dysregulated', 'Reg', (206, 218))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('epigenetic', 'Var', (64, 74))	('PRC2-associated genes', 'Gene', (88, 109))
749848	33931649	Using ESC chromatin marks to define PRC2+ and PRC2- gene classes has been a common practice in the definition of CpG Island Methylator Phenotype (CIMP) and other cancer methylation signatures, due to the more diffuse distribution of H3K27me3 ChIP-Seq in differentiated cell types and the fact that PRC2 ChIP-Seq has been attempted in very few differentiated cell types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('PRC2+', 'Chemical', '-', (36, 41))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('H3K27me3', 'Var', (233, 241))
749852	33931649	PRC2+-CGI genes with an FPKM greater than 4 showed a marked increase in H3K27ac in most cell types (Supplementary Fig.	('PRC2+', 'Chemical', '-', (0, 5))	('H3K27ac', 'Protein', (72, 79))	('increase', 'PosReg', (60, 68))	('PRC2+-CGI genes', 'Var', (0, 15))
749853	33931649	2a), and the H3K27me3 mark, a hallmark of PRC2-occupancy, was only positive in PRC2+-CGI genes with FPKM < 4 (Supplementary Fig.	('PRC2+-CGI', 'Gene', (79, 88))	('H3K27me3', 'Var', (13, 21))	('PRC2+', 'Chemical', '-', (79, 84))
749857	33931649	As described below, we independently analyzed each of these 16 TCGA cancer types, using transcriptome and DNA methylation profiles to define three distinct gene groups: hypermethylated PRC2+-CGI, upregulated PRC2+-CGI, and upregulated PRC2--CGI (Fig.	('hypermethylated', 'Var', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PRC2+', 'Chemical', '-', (185, 190))	('upregulated', 'PosReg', (223, 234))	('upregulated', 'PosReg', (196, 207))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('PRC2+-CGI', 'CPA', (208, 217))	('PRC2', 'Gene', (235, 239))	('cancer', 'Disease', (68, 74))	('PRC2+', 'Chemical', '-', (208, 213))	('PRC2+-CGI', 'Gene', (185, 194))
749859	33931649	Consistent with well-established findings, almost 52% of PRC2+-CGI genes (2,274 of 4,378) became hypermethylated in at least one cancer type, corresponding to 4,260 promoters (56% of all PRC2+-CGI promoters).	('hypermethylated', 'Var', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('PRC2+-CGI genes', 'Gene', (57, 72))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('PRC2+', 'Chemical', '-', (187, 192))	('PRC2+', 'Chemical', '-', (57, 62))
749860	33931649	Most cancer types (12/16) had > 400 hypermethylated PRC2+-CGI genes (Fig.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('PRC2+-CGI genes', 'Gene', (52, 67))	('hypermethylated', 'Var', (36, 51))	('cancer', 'Disease', (5, 11))	('PRC2+', 'Chemical', '-', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
749861	33931649	1b), confirming the pervasiveness of this type of epigenetic silencing across human cancers.	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('epigenetic silencing', 'Var', (50, 70))	('human', 'Species', '9606', (78, 83))
749867	33931649	Shown as an example, the LEF1 gene is marked with both H3K27me3 and H3K4me3 and devoid of H3K27ac in normal colon tissue.	('H3K27me3', 'Var', (55, 63))	('H3K4me3', 'Var', (68, 75))	('LEF1', 'Gene', '51176', (25, 29))	('LEF1', 'Gene', (25, 29))
749871	33931649	For example, CEP72, the gene encoding a centrosomal protein associated with regulation of cell cycle, harbors an active promoter marked with H3K27ac and ATAC-Seq chromatin accessibility in normal colon tissue, and becomes transcriptionally upregulated in colon cancer with an increase in both H3K27ac and ATAC-Seq accessibility (Fig.	('CEP72', 'Gene', '55722', (13, 18))	('CEP72', 'Gene', (13, 18))	('increase', 'PosReg', (276, 284))	('H3K27ac', 'Var', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('H3K27ac', 'Var', (293, 300))	('upregulated', 'PosReg', (240, 251))	('ATAC-Seq accessibility', 'MPA', (305, 327))	('colon cancer', 'Disease', 'MESH:D015179', (255, 267))	('colon cancer', 'Phenotype', 'HP:0003003', (255, 267))	('colon cancer', 'Disease', (255, 267))
749872	33931649	As anticipated, H3K27me3 levels were similarly high in both PRC2+-CGI hypermethylated and PRC2+-CGI upregulated promoters, but undetectable in PRC2--CGI promoters.	('H3K27me3', 'Protein', (16, 24))	('high', 'PosReg', (47, 51))	('PRC2+-CGI', 'Var', (60, 69))	('PRC2+', 'Chemical', '-', (90, 95))	('upregulated', 'PosReg', (100, 111))	('PRC2+-CGI', 'Var', (90, 99))	('PRC2+', 'Chemical', '-', (60, 65))
749876	33931649	Interestingly, despite high H3K27me3 signal in both PRC2+-CGI classes, hypermethylated PRC2+ promoters showed much stronger enrichment in LADs than upregulated PRC2+ promoters (Fig.	('hypermethylated', 'Var', (71, 86))	('LADs', 'Disease', 'None', (138, 142))	('LADs', 'Disease', (138, 142))	('PRC2+', 'Chemical', '-', (52, 57))	('PRC2+', 'Chemical', '-', (87, 92))	('H3K27me3', 'Protein', (28, 36))	('PRC2+', 'Chemical', '-', (160, 165))
749878	33931649	Extending the LAD analysis to pan-cancer samples, we found that the hypermethylated PRC2+-CGI class had an average of 2.4X more genes (37.8% vs 15.7%) within LADs than the upregulated PRC2+-CGI class.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('LADs', 'Disease', (158, 162))	('more', 'PosReg', (123, 127))	('LAD', 'Disease', (14, 17))	('LAD', 'Disease', 'MESH:C535887', (158, 161))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('hypermethylated', 'Var', (68, 83))	('cancer', 'Disease', (34, 40))	('LAD', 'Disease', 'MESH:C535887', (14, 17))	('PRC2+', 'Chemical', '-', (184, 189))	('genes', 'MPA', (128, 133))	('LAD', 'Disease', (158, 161))	('PRC2+', 'Chemical', '-', (84, 89))	('LADs', 'Disease', 'None', (158, 162))
749881	33931649	Similarly, expression in normal tissue was (negatively) correlated with hypermethylated PRC2+-CGI promoters but not upregulated PRC2+-CGI promoters.	('PRC2+', 'Chemical', '-', (88, 93))	('expression', 'MPA', (11, 21))	('PRC2+-CGI', 'Gene', (88, 97))	('hypermethylated', 'Var', (72, 87))	('PRC2+', 'Chemical', '-', (128, 133))
749884	33931649	Looking specifically at DMVs, we found that they were associated both with hypermethylation and upregulation of PRC2+-CGI genes in similar ratios (Supplementary Fig.	('hypermethylation', 'MPA', (75, 91))	('PRC2+-CGI genes', 'Gene', (112, 127))	('upregulation', 'PosReg', (96, 108))	('PRC2+', 'Chemical', '-', (112, 117))	('DMVs', 'Var', (24, 28))
749898	33931649	Consistent with earlier reports, hypermethylated PRC2+-CGI genes were slightly downregulated in TCGA tumors relative to adjacent nonmalignant tissues (Fig.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('downregulated', 'NegReg', (79, 92))	('hypermethylated', 'Var', (33, 48))	('PRC2+', 'Chemical', '-', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('PRC2+-CGI genes', 'Gene', (49, 64))
749905	33931649	While hypermethylated genes are known to have some cancer-type specificity, this class had the lowest percentage of cancer-type-restricted genes in all but 2 cancer types (Fig.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (158, 164))	('hypermethylated', 'Var', (6, 21))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
749908	33931649	Indeed, in every cancer type, the fraction of these "plastic genes" was much higher in PRC2+- than PRC2--CGI class (Fig.	('higher', 'PosReg', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('PRC2+', 'Chemical', '-', (87, 92))	('cancer', 'Disease', (17, 23))	('fraction', 'MPA', (34, 42))	('PRC2+-', 'Var', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
749953	33931649	Interestingly, the TFBSs of PRC2--CGI promoters had higher CpG densities than the TFBSs of PRC2+-CGI promoters (Supplementary Fig.	('PRC2+', 'Chemical', '-', (91, 96))	('PRC2--CGI promoters', 'Var', (28, 47))	('TF', 'Gene', '2152', (19, 21))	('CpG densities', 'CPA', (59, 72))	('TF', 'Gene', '2152', (82, 84))	('higher', 'PosReg', (52, 58))
749954	33931649	Enhancer regions showed the opposite pattern of promoter regions, with the PRC2+-CGI class being more enriched for enhancer motifs than the PRC2--CGI class in almost all cancer types (an average of 11 motifs for PRC2+-CGI vs. 4 motifs for PRC2--CGI, Fig.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('PRC2+', 'Chemical', '-', (75, 80))	('PRC2+', 'Chemical', '-', (212, 217))	('cancer', 'Disease', (170, 176))	('PRC2+-CGI', 'Var', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
749961	33931649	As predicted, in both HCT116 (COAD) and A549 (LUAD) cells, SP1-binding events were considerably more enriched in PRC2-- (53.2%-76.1%) than PRC2+-CGI promoters (15.8%-28.4%, Fig.	('PRC2--', 'Var', (113, 119))	('COAD', 'Disease', (30, 34))	('HCT116', 'CellLine', 'CVCL:0291', (22, 28))	('SP1-binding', 'Protein', (59, 70))	('COAD', 'Disease', 'MESH:D029424', (30, 34))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('PRC2+', 'Chemical', '-', (139, 144))
749990	33931649	Additionally, this regulation appeared to be PRC2+-CGI-specific:only 1 out of 17 PRC2--CGI genes (5.9%) overlapping with HNF4A ChIP-Seq was downregulated in the knockdown (Fig.	('HNF4A', 'Gene', '3172', (121, 126))	('downregulated', 'NegReg', (140, 153))	('HNF4A', 'Gene', (121, 126))	('PRC2+', 'Chemical', '-', (45, 50))	('knockdown', 'Var', (161, 170))	('PRC2--CGI', 'Gene', (81, 90))
749991	33931649	As H3K27me3 data was unavailable for any of these cell types other than normal esophagus, we performed promoter H3K27me3 ChIP-qPCR in OE19 HNF4A-wildtype and HNF4A-knockdown cells.	('HNF4A', 'Gene', (158, 163))	('HNF4A', 'Gene', '3172', (139, 144))	('H3K27me3', 'Var', (112, 120))	('HNF4A', 'Gene', (139, 144))	('HNF4A', 'Gene', '3172', (158, 163))
749993	33931649	All gene promoters showed gain of H3K27me3 signal in the knockdown of HNF4A (Fig.	('HNF4A', 'Gene', '3172', (70, 75))	('HNF4A', 'Gene', (70, 75))	('knockdown', 'Var', (57, 66))	('H3K27me3', 'Protein', (34, 42))	('gain', 'PosReg', (26, 30))
749997	33931649	Consistent with prior findings, we showed that many PRC2+-CGI genes were commonly hypermethylated and downregulated in most cancers, affecting 2,274 of 4,378 genes across in one or more of 16 cancer types.	('affecting', 'Reg', (133, 142))	('cancer', 'Disease', (124, 130))	('downregulated', 'NegReg', (102, 115))	('PRC2+-CGI genes', 'Gene', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('PRC2+', 'Chemical', '-', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('hypermethylated', 'Var', (82, 97))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
750001	33931649	In tumors, our analysis showed that unlike hypermethylated PRC2+-CGI promoters, upregulated PRC2+-CGI promoters gain accessibility and the H3K27ac mark (illustrated in Fig.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('H3K27ac mark', 'Var', (139, 151))	('PRC2+-CGI', 'Var', (92, 101))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('PRC2+', 'Chemical', '-', (59, 64))	('upregulated', 'PosReg', (80, 91))	('accessibility', 'MPA', (117, 130))	('gain', 'PosReg', (112, 116))	('PRC2+', 'Chemical', '-', (92, 97))
750004	33931649	This property allowed for better clustering of cancer types and subtypes using the upregulated PRC2+-CGI class than either of the other two classes, although hypermethylated PRC2+-CGI also showed good clustering.	('PRC2+', 'Chemical', '-', (95, 100))	('PRC2+', 'Chemical', '-', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('PRC2+-CGI', 'Var', (95, 104))	('cancer', 'Disease', (47, 53))	('upregulated', 'PosReg', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
750005	33931649	Interestingly, nearly half (762/1,543) of upregulated PRC2+-CGI genes were also hypermethylated in other cancer types, including some known tumor suppressors, such as DKK1, NFGR, PRICKLE1.	('hypermethylated', 'Var', (80, 95))	('DKK1', 'Gene', '22943', (167, 171))	('DKK1', 'Gene', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Disease', (105, 111))	('PRICKLE1', 'Gene', (179, 187))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('PRC2+-CGI genes', 'Gene', (54, 69))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('upregulated', 'PosReg', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('PRICKLE1', 'Gene', '144165', (179, 187))	('PRC2+', 'Chemical', '-', (54, 59))	('tumor', 'Disease', (140, 145))
750012	33931649	Functionally, upregulated PRC2+- and PRC2--CGI genes controlled distinct sets of pathways in cancer.	('PRC2+-', 'Gene', (26, 32))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('PRC2+', 'Chemical', '-', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('upregulated', 'PosReg', (14, 25))	('PRC2--', 'Var', (37, 43))
750018	33931649	Indeed, consistent with this notion, recent studies have shown that EZH2 inhibition leads to heightened anti-cancer immunity and synergizes with immune-checkpoint blockade therapy in different cancer types.	('EZH2', 'Gene', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (109, 115))	('heightened', 'PosReg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('EZH2', 'Gene', '2146', (68, 72))	('inhibition', 'Var', (73, 83))
750026	33931649	While this mode of activation appears to be prevalent in cancer based on our analysis, additional layers of deregulation of these genes may be caused by genetic disruption of PRC2 proteins themselves, given the discovery of both loss-of-function and gain-of-function mutations of PRC2 complex (particularly EZH2) in cancer.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('PRC2 complex', 'Gene', (280, 292))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', (57, 63))	('activation', 'PosReg', (19, 29))	('mutations', 'Var', (267, 276))	('EZH2', 'Gene', (307, 311))	('EZH2', 'Gene', '2146', (307, 311))	('genetic', 'Var', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('disruption', 'NegReg', (161, 171))	('loss-of-function', 'NegReg', (229, 245))	('cancer', 'Disease', (316, 322))	('PRC2', 'Gene', (175, 179))	('gain-of-function', 'PosReg', (250, 266))
750037	33931649	The following additional datasets were collected: H3K27ac ChIP-Seq in nonmalignant colonic crypts and primary colon cancer cells (GSE77737), H3K27ac ChIP-Seq in nonmalignant and tumor samples of kidney renal clear cell carcinoma (KIRC) from GSE86095, HNF4A ChIP-Seq in OE19 (E-MTAB-6858) and Caco-2 (GSE23436) cell lines, TP63 ChIP-Seq in HCC95 cell line (GSE46837), SP1 and JUND ChIP-Seq in HCT116 and A549 cell lines (ENCODE), H3K27ac ChIP-Seq in OE19 (GSE132686), HCC95 (GSE66992), HCT116 (ENCODE), Caco-2 (GSE96069) and A549 (ENCODE) cell lines.	('kidney renal clear cell carcinoma', 'Disease', (195, 228))	('nonmalignant colonic crypts and primary colon cancer', 'Disease', 'MESH:D015179', (70, 122))	('JUND', 'Gene', (375, 379))	('A549', 'CellLine', 'CVCL:0023', (524, 528))	('HCT116', 'CellLine', 'CVCL:0291', (392, 398))	('tumor', 'Disease', (178, 183))	('JUND', 'Gene', '3727', (375, 379))	('Caco-2', 'CellLine', 'CVCL:0025', (502, 508))	('HCT116', 'CellLine', 'CVCL:0291', (485, 491))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('HCC95', 'CellLine', 'CVCL:5137', (467, 472))	('Caco-2', 'CellLine', 'CVCL:0025', (292, 298))	('HNF4A', 'Gene', '3172', (251, 256))	('HNF4A', 'Gene', (251, 256))	('TP63', 'Gene', (322, 326))	('HCC95', 'CellLine', 'CVCL:5137', (339, 344))	('A549', 'CellLine', 'CVCL:0023', (403, 407))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (195, 228))	('TP63', 'Gene', '8626', (322, 326))	('H3K27ac ChIP-Seq', 'Var', (429, 445))
750039	33931649	RNA-Seq of HNF4A knockdown, ATAC-Seq of nonmalignant esophageal epithelium, EAC tissues, normal esophageal cells (HET1A) and OE19 tumor cells were downloaded from E-MTAB-6756, E-MTAB-5169 and E-MTAB-6931.	('HNF4A', 'Gene', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('knockdown', 'Var', (17, 26))	('tumor', 'Disease', (130, 135))	('HNF4A', 'Gene', '3172', (11, 16))
750044	33931649	H3K27me3 and H3K27ac ChIP-Seq profiles in both ESCs (H1) and normal tissues (colonic mucosa, lung, breast epithelium, rectum, esophagus, uterus and liver) were obtained from the combined NIH RoadMap/ENCODE data repository.	('colonic mucosa', 'Disease', 'MESH:D003110', (77, 91))	('H1', 'CellLine', 'CVCL:Z499', (53, 55))	('H3K27me3', 'Var', (0, 8))	('colonic mucosa', 'Disease', (77, 91))	('ESCs', 'Disease', (47, 51))	('H3K27ac', 'Var', (13, 20))
750047	33931649	An FPKM value of 4 in TCGA normal tissues readily separated PRC2+-CGI genes with divergent H3K27ac levels: PRC2+-CGI genes with FPKM < 4 had considerably lower H3K27ac signals than those with FPKM >= 4 (Supplementary Fig.	('lower', 'NegReg', (154, 159))	('H3K27ac signals', 'MPA', (160, 175))	('FPKM < 4', 'Var', (128, 136))	('PRC2+', 'Chemical', '-', (107, 112))	('PRC2+', 'Chemical', '-', (60, 65))
750048	33931649	Furthermore, we confirmed that PRC2+-CGI genes with FPKM < 4 had much higher H3K27me3 levels than those with FPKM >= 4 (Supplementary Fig.	('PRC2+-CGI genes', 'Gene', (31, 46))	('FPKM < 4', 'Var', (52, 60))	('H3K27me3 levels', 'MPA', (77, 92))	('PRC2+', 'Chemical', '-', (31, 36))	('higher', 'PosReg', (70, 76))
750061	33931649	Considering that TFs from the same TF family can recognize identical binding sequences (such as GATA and SOX families), we retained only those  motifs corresponding to TFs with FPKM > 10 and p-value < 0.01 in the corresponding cancer types.	('FPKM > 10', 'Var', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('TF', 'Gene', '2152', (17, 19))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('TF', 'Gene', '2152', (168, 170))	('TF', 'Gene', '2152', (35, 37))	('cancer', 'Disease', (227, 233))	('GATA', 'Gene', (96, 100))	('GATA', 'Gene', '55278', (96, 100))
750062	33931649	Breast cancer cell lines HS578T (#HTB-126) and MDAMB436 (#HTB-130) were obtained from ATCC, and EAC cells OE19 were obtained from Sigma-Aldrich, and were authenticated by the STR-PCR analysis.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('HS578T', 'CellLine', 'CVCL:0332', (25, 31))	('#HTB-130', 'Var', (57, 65))	('Breast cancer', 'Disease', (0, 13))
750072	33931649	The ATAC-Seq data used in this study are available in ArrayExpress database under accession code E-MTAB-5169 and E-MTAB-6931; ENCODE project [https://www.encodeproject.org/] and NSCLC ATAC Project [https://pms.cd120.com/index.html].	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('NSCLC', 'Disease', (178, 183))	('E-MTAB-6931', 'Var', (113, 124))
750081	29780831	Esophagectomy counts as a type of invasive surgery, and obstructions of the food passageway and the overgrowth of tissue postoperatively may cause malnutrition.	('Esophagectomy', 'Disease', (0, 13))	('malnutrition', 'Disease', (147, 159))	('malnutrition', 'Disease', 'MESH:D044342', (147, 159))	('overgrowth', 'CPA', (100, 110))	('overgrowth', 'Phenotype', 'HP:0001548', (100, 110))	('obstructions', 'Var', (56, 68))	('malnutrition', 'Phenotype', 'HP:0004395', (147, 159))	('cause', 'Reg', (141, 146))
750108	26373456	Although GERD is reported to induce inflammation and oxidative stress in the esophageal epithelium, and this stress is thought to contribute to the pathogenesis of BE, there is only a single study on autophagy in BE, and it is focused on the Beclin gene.	('GERD', 'Var', (9, 13))	('oxidative stress', 'Phenotype', 'HP:0025464', (53, 69))	('inflammation', 'Disease', 'MESH:D007249', (36, 48))	('contribute', 'Reg', (130, 140))	('inflammation', 'Disease', (36, 48))	('induce', 'Reg', (29, 35))	('oxidative stress', 'MPA', (53, 69))	('BE', 'Phenotype', 'HP:0100580', (164, 166))	('BE', 'Phenotype', 'HP:0100580', (213, 215))
750153	26373456	CPA and CPD are human BE cell lines isolated from non-dysplastic (CPA) and dysplastic (CPD) BE, both are also immortalized with telomerase and have allelic losses and mutations.	('CPA', 'Gene', (66, 69))	('CPD', 'Disease', (87, 90))	('CPD', 'Disease', 'MESH:C565865', (87, 90))	('CPA', 'Gene', '1357', (0, 3))	('CPD', 'Disease', (8, 11))	('CPD', 'Disease', 'MESH:C565865', (8, 11))	('CPA', 'Gene', '1357', (66, 69))	('mutations', 'Var', (167, 176))	('BE', 'Phenotype', 'HP:0100580', (22, 24))	('non-dysplastic', 'Disease', (50, 64))	('non-dysplastic', 'Disease', 'MESH:D004416', (50, 64))	('dysplastic', 'Disease', 'MESH:D004416', (54, 64))	('CPA', 'Gene', (0, 3))	('BE', 'Phenotype', 'HP:0100580', (92, 94))	('human', 'Species', '9606', (16, 21))	('dysplastic', 'Disease', (75, 85))	('dysplastic', 'Disease', (54, 64))	('dysplastic', 'Disease', 'MESH:D004416', (75, 85))
750154	26373456	CPA cells have mutant p16 but wild-type p53, and CPD cells are mutant in both genes.	('CPD', 'Disease', 'MESH:C565865', (49, 52))	('CPA', 'Gene', '1357', (0, 3))	('p16', 'Gene', '1029', (22, 25))	('p53', 'Gene', (40, 43))	('CPA', 'Gene', (0, 3))	('p53', 'Gene', '7157', (40, 43))	('mutant', 'Var', (15, 21))	('p16', 'Gene', (22, 25))	('CPD', 'Disease', (49, 52))
750155	26373456	OE19 and OE33 cells were isolated from human EAC and have mutations in their p53 genes.	('mutations', 'Var', (58, 67))	('p53', 'Gene', '7157', (77, 80))	('p53', 'Gene', (77, 80))	('EAC', 'Phenotype', 'HP:0011459', (45, 48))	('human', 'Species', '9606', (39, 44))
591926	26373456	These L2-IL-1beta mice develop a chronic inflammatory esophagitis by 3 months (Figure 1A) that is followed subsequently by the development of a columnar metaplasia with intestinal features that later progresses to dysplasia and cancer.	('columnar metaplasia', 'Disease', (144, 163))	('inflammatory esophagitis', 'Disease', 'MESH:D004941', (41, 65))	('columnar metaplasia', 'Disease', 'MESH:D008679', (144, 163))	('mice', 'Species', '10090', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('inflammatory esophagitis', 'Disease', (41, 65))	('dysplasia and cancer', 'Disease', 'MESH:D009369', (214, 234))	('esophagitis', 'Phenotype', 'HP:0100633', (54, 65))	('L2-IL-1beta', 'Var', (6, 17))
750181	26373456	IHC staining for the autophagy-activated cleaved form of LC3 was increased in the esophageal epithelium of L2-IL-1beta mice compared to controls (Figure 4A).	('LC3', 'Gene', (57, 60))	('mice', 'Species', '10090', (119, 123))	('increased', 'PosReg', (65, 74))	('L2-IL-1beta', 'Var', (107, 118))	('autophagy-activated', 'CPA', (21, 40))
750182	26373456	Esophageal cells from L2-IL-1beta mice demonstrated relative 2-fold increase in fluorescent intensity (Figure 4B and 4C), compared to esophageal cells derived from littermate controls.	('mice', 'Species', '10090', (34, 38))	('increase', 'PosReg', (68, 76))	('fluorescent intensity', 'MPA', (80, 101))	('L2-IL-1beta', 'Var', (22, 33))
750184	26373456	The Oxyblot analysis revealed a significant increase in carbonyl adducts in L2-IL-1beta mice compared to controls, suggesting elevated ROS and oxidative stress in these cells.	('oxidative stress', 'Phenotype', 'HP:0025464', (143, 159))	('carbonyl adducts', 'MPA', (56, 72))	('ROS', 'MPA', (135, 138))	('increase', 'PosReg', (44, 52))	('oxidative stress', 'MPA', (143, 159))	('elevated', 'PosReg', (126, 134))	('ROS', 'Chemical', 'MESH:D017382', (135, 138))	('mice', 'Species', '10090', (88, 92))	('L2-IL-1beta', 'Var', (76, 87))
750189	26373456	In terms of viability after acid exposure, the cancer cell line OE19 was the most tolerant and the normal human esophageal cells (STR) the least, with the following pattern emerging with regard to the panel: OE19> CPD> CPA> STR (Figure 5A and 5B).	('CPA', 'Gene', '1357', (219, 222))	('human', 'Species', '9606', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('CPD', 'Disease', (214, 217))	('CPD', 'Disease', 'MESH:C565865', (214, 217))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CPA', 'Gene', (219, 222))	('OE19', 'Var', (208, 212))
750231	26373456	As an example, loss of Autophagy-related protein 7 (Atg7), which is required for fusion of peroxisomal and vacuolar membranes and is critical for normal autophagy responses, leads to increased oxidative stress and elevated ROS in cells.	('ROS', 'MPA', (223, 226))	('Atg7', 'Gene', (52, 56))	('elevated', 'PosReg', (214, 222))	('oxidative stress', 'MPA', (193, 209))	('increased', 'PosReg', (183, 192))	('Autophagy-related protein 7', 'Gene', '10533', (23, 50))	('Atg7', 'Gene', '10533', (52, 56))	('ROS', 'Chemical', 'MESH:D017382', (223, 226))	('loss', 'Var', (15, 19))	('oxidative stress', 'Phenotype', 'HP:0025464', (193, 209))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (183, 209))	('Autophagy-related protein 7', 'Gene', (23, 50))
750235	26373456	Several studies have established that excessive ROS can damage DNA leading to mutations and epigenetic changes in gene expression, fostering neoplastic transformation.	('epigenetic changes', 'Var', (92, 110))	('mutations', 'MPA', (78, 87))	('neoplastic transformation', 'CPA', (141, 166))	('fostering', 'PosReg', (131, 140))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))
750248	26373456	Similarly, hyperactivation of receptor tyrosine kinases (RTKs) either by activating mutations or gene amplifications, can inhibit autophagy through their downstream effects on mTOR1 and Akt signaling.	('hyperactivation', 'PosReg', (11, 26))	('Akt', 'Gene', '207', (186, 189))	('mTOR', 'Gene', '2475', (176, 180))	('gene amplifications', 'Var', (97, 116))	('mTOR', 'Gene', (176, 180))	('Akt', 'Gene', (186, 189))	('mutations', 'Var', (84, 93))	('inhibit', 'NegReg', (122, 129))	('autophagy', 'CPA', (130, 139))
750255	26373456	However excessive ROS can damage mitochondria as well as other organelles.	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('ROS', 'Var', (18, 21))	('damage', 'Reg', (26, 32))	('mitochondria', 'MPA', (33, 45))
750324	26770036	The difference in the AUC between TLG and MTV, TLG, and SUVmean, and MTV and SUVmean were 0.017 (P=0.559), 0.086 (P=0.266), and 0.069 (P=0.460), respectively.	('MTV', 'Chemical', '-', (69, 72))	('MTV', 'Chemical', '-', (42, 45))	('0.086', 'Var', (107, 112))	('AUC', 'MPA', (22, 25))	('TLG', 'Chemical', '-', (47, 50))	('TLG', 'Chemical', '-', (34, 37))
750343	26770036	However, high TLG was significantly associated with reduced OS in patients who received both the combination (P=0.037) and single regimens (P=0.014).	('reduced', 'NegReg', (52, 59))	('TLG', 'Gene', (14, 17))	('TLG', 'Chemical', '-', (14, 17))	('OS', 'Chemical', '-', (60, 62))	('patients', 'Species', '9606', (66, 74))	('high', 'Var', (9, 13))
750344	26770036	In the univariate analyses, high TLG was associated with poor OS (HR, 4.69; 95% CI, 1.540-14.281; P=0.007) (Table 2).	('poor OS', 'Disease', (57, 64))	('OS', 'Chemical', '-', (62, 64))	('TLG', 'Chemical', '-', (33, 36))	('high', 'Var', (28, 32))	('TLG', 'MPA', (33, 36))
750612	23731608	Recognizing T2N0 as a threshold for induction therapy in esophageal cancer, many surgeons have opted to treat T2N0 disease with induction therapy, despite the fact that one quarter of these patients will be pathological T1N0.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('T2N0', 'Var', (110, 114))	('patients', 'Species', '9606', (190, 198))	('esophageal cancer', 'Disease', (57, 74))
750624	23731608	Using the database, we investigated the accuracy of clinical staging of T2N0 esophageal cancer, examined current practice patterns in terms of treatment regimens, and examined the impact of induction therapy on peri-operative morbidity and mortality in this subset of clinically staged T2N0 patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('T2N0', 'Var', (72, 76))	('patients', 'Species', '9606', (291, 299))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))
750672	23731608	While the techniques of clinical staging cannot be confirmed within the current versions of the GTSD, this study confirms the findings presented in previous single center studies regarding the inaccuracy of clinical staging of T2N0 esophageal cancer.	('GTSD', 'Disease', (96, 100))	('T2N0', 'Var', (227, 231))	('esophageal cancer', 'Disease', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('GTSD', 'Disease', 'None', (96, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (232, 249))
750691	23731608	While our data confirms the inaccuracy of clinical staging, this broad approach of offering induction therapy to all of these patients would mean that over 50% of those treated in this manner would have limited disease, 26% with T1N0, and 27.4% with T2N0 disease.	('limited', 'Disease', (203, 210))	('T1N0', 'Var', (229, 233))	('T2N0', 'Var', (250, 254))	('patients', 'Species', '9606', (126, 134))
750728	23731608	So if you look at your group that were overstaged, those less than T2 N0, add to those the true T2 N0, and then add any T3 N0 patients, who also have a very good survival rate because they are node negative, the subgroup that really might benefit from neoadjuvant therapy, the group at risk for systemic disease, ie those with nodal disease, becomes very small.	('nodal disease', 'Disease', 'MESH:D013611', (327, 340))	('systemic disease', 'Disease', 'MESH:D034721', (295, 311))	('nodal disease', 'Disease', (327, 340))	('T3 N0', 'Var', (120, 125))	('T2 N0', 'Var', (67, 72))	('systemic disease', 'Disease', (295, 311))	('patients', 'Species', '9606', (126, 134))
750837	32190317	A 65-year-old man was diagnosed as having hypopharyngeal squamous cell carcinoma of cT4aN0M0 cStage IVA (AJCC Cancer Staging Manual 8th edition) and upper thoracic esophageal squamous cell carcinoma of cT3N1M0 cStage IIIA (UICC 8th edition).	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (42, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('cStage IVA', 'Disease', (93, 103))	('cT4aN0M0', 'Var', (84, 92))	('upper thoracic esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (149, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('hypopharyngeal squamous cell carcinoma', 'Disease', (42, 80))	('man', 'Species', '9606', (14, 17))	('cStage IVA', 'Disease', 'MESH:C538167', (93, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (175, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('upper thoracic esophageal squamous cell carcinoma', 'Disease', (149, 198))
750923	31002369	Notably, the patients with EAC who expressed a high level of these cell cycle-associated genes exhibited poorer prognosis with regard to disease/progression-free survival compared with patients without altered expression of these genes (median months disease-free: 15.67 vs. 24.06; Fig.	('patients', 'Species', '9606', (13, 21))	('high', 'Var', (47, 51))	('EAC', 'Phenotype', 'HP:0011459', (27, 30))	('patients', 'Species', '9606', (185, 193))	('EAC', 'Disease', (27, 30))
750933	31002369	Immunohistochemical scoring for the cancer tissues from these patients indicated that high PARP4 expression was associated with poorer survival (Fig.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('survival', 'MPA', (135, 143))	('PARP4', 'Gene', (91, 96))	('cancer', 'Disease', (36, 42))	('poorer', 'NegReg', (128, 134))	('PARP4', 'Gene', '143', (91, 96))	('high', 'Var', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('patients', 'Species', '9606', (62, 70))	('expression', 'MPA', (97, 107))
750947	31002369	This finding holds considerable promise, as in the clinic numerous compounds are already utilized that can target components of cell cycle signaling, including cyclin-dependent kinase (CDK)4/CDK6 (palbociclib, ribociclib and abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib) and tubulin (taxanes and vinca alkaloids).	('vinca alkaloids', 'Chemical', 'MESH:D014748', (340, 355))	('MLN8237', 'Var', (266, 273))	('AT9283', 'Var', (255, 261))	('tubulin', 'Protein', (319, 326))	('CDK)4', 'Gene', '1019', (185, 190))	('Wee1', 'Gene', (276, 280))	('Wee1', 'Gene', '7465', (276, 280))	('KSP', 'Protein', (299, 302))	('taxanes', 'Chemical', 'MESH:D043823', (328, 335))	('CDK6', 'Gene', '1021', (191, 195))	('CDK6', 'Gene', (191, 195))
750972	30088538	Furthermore, the cytotoxicity of icariin was decreased after p53 knockdown or by using caspase inhibitors.	('knockdown', 'Var', (65, 74))	('icariin', 'Chemical', 'MESH:C056599', (33, 40))	('cytotoxicity', 'Disease', (17, 29))	('decreased', 'NegReg', (45, 54))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('p53', 'Gene', '7157', (61, 64))	('caspase', 'Gene', (87, 94))	('p53', 'Gene', (61, 64))	('cytotoxicity', 'Disease', 'MESH:D064420', (17, 29))	('caspase', 'Gene', '842', (87, 94))
750987	30088538	Blocking the mdm2-p53 interaction and reactivating p53 function is a promising therapeutic strategy for the treatment of cancers.	('cancers', 'Disease', (121, 128))	('p53', 'Gene', (18, 21))	('p53', 'Gene', (51, 54))	('mdm2', 'Gene', (13, 17))	('p53', 'Gene', '7157', (51, 54))	('p53', 'Gene', '7157', (18, 21))	('mdm2', 'Gene', '4193', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('reactivating', 'Var', (38, 50))	('function', 'MPA', (55, 63))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('interaction', 'Interaction', (22, 33))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
751017	30088538	After a blocking incubation with 5% milk-TBST, the membranes were incubated with primary antibodies at a dilution of 1:1000 for the specific detection of caspase-3 (ab4051), cleaved caspase-3 (ab32042), caspase-9 (ab32539), cleaved caspase-9 (ab32539), PARP (ab32138), cleaved PARP (ab32138), p53 (ab131442), mdm2 (ab38618), p-p53(ab1431), p21 (ab109520), Bcl-2 (ab32124), Bax (ab32503), gamma-H2AX (ab11174), and beta-actin (ab8227, Abcam, USA) at 4 C overnight.	('PARP', 'Gene', (253, 257))	('PARP', 'Gene', (277, 281))	('mdm2', 'Gene', (309, 313))	('caspase-9', 'Gene', '842', (203, 212))	('p53', 'Gene', '7157', (327, 330))	('Bcl-2', 'Gene', '596', (356, 361))	('p53', 'Gene', '7157', (293, 296))	('p53', 'Gene', (327, 330))	('caspase-3', 'Gene', '836', (182, 191))	('Bax', 'Gene', (373, 376))	('caspase-9', 'Gene', (203, 212))	('caspase-3', 'Gene', (182, 191))	('Bax', 'Gene', '581', (373, 376))	('beta-actin', 'Gene', (414, 424))	('caspase-9', 'Gene', '842', (232, 241))	('p21', 'Gene', (340, 343))	('p53', 'Gene', (293, 296))	('ab11174', 'Var', (400, 407))	('p21', 'Gene', '644914', (340, 343))	('mdm2', 'Gene', '4193', (309, 313))	('PARP', 'Gene', '1302', (253, 257))	('PARP', 'Gene', '1302', (277, 281))	('caspase-3', 'Gene', '836', (154, 163))	('caspase-9', 'Gene', (232, 241))	('caspase-3', 'Gene', (154, 163))	('Bcl-2', 'Gene', (356, 361))	('beta-actin', 'Gene', '728378', (414, 424))
751032	30088538	Some apoptosis-promoting proteins were activated by icariin, including cleaved caspase-9 and -3 and cleaved PARP.	('icariin', 'Chemical', 'MESH:C056599', (52, 59))	('cleaved', 'Var', (100, 107))	('cleaved', 'MPA', (71, 78))	('activated', 'PosReg', (39, 48))	('PARP', 'Gene', '1302', (108, 112))	('apoptosis-promoting proteins', 'Protein', (5, 33))	('PARP', 'Gene', (108, 112))	('si', 'Chemical', 'MESH:D012825', (11, 13))	('caspase-9 and -3', 'Gene', '842;836', (79, 95))
751058	30088538	This indicated that p53 knockdown inhibited icariin-induced DNA damage and DNA damage was an outcome of p53-induced apoptosis (Figure 6B).	('p53', 'Gene', (20, 23))	('p53', 'Gene', (104, 107))	('p53', 'Gene', '7157', (20, 23))	('icariin-induced DNA damage', 'MPA', (44, 70))	('p53', 'Gene', '7157', (104, 107))	('icariin', 'Chemical', 'MESH:C056599', (44, 51))	('inhibited', 'NegReg', (34, 43))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('knockdown', 'Var', (24, 33))
751064	30088538	As shown in Figure 7D, caspase-9 and -3 were not activated by icariin after p53 knockdown.	('knockdown', 'Var', (80, 89))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('caspase-9 and -3', 'Gene', '842;836', (23, 39))	('icariin', 'Chemical', 'MESH:C056599', (62, 69))
751087	30088538	Hence, apoptosis is suppressed if the p53 gene is mutated or its function is damaged.	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('suppressed', 'NegReg', (20, 30))	('mutated', 'Var', (50, 57))	('apoptosis', 'CPA', (7, 16))	('si', 'Chemical', 'MESH:D012825', (13, 15))
751095	30088538	It might be possible that p53 knockdown inhibited the cytotoxicity of icariin and impaired the harmful effect on HCT116 cells, including DNA damage.	('cytotoxicity', 'Disease', (54, 66))	('HCT116', 'CellLine', 'CVCL:0291', (113, 119))	('inhibited', 'NegReg', (40, 49))	('icariin', 'Chemical', 'MESH:C056599', (70, 77))	('impaired', 'NegReg', (82, 90))	('p53', 'Gene', (26, 29))	('cytotoxicity', 'Disease', 'MESH:D064420', (54, 66))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('harmful effect', 'MPA', (95, 109))	('knockdown', 'Var', (30, 39))	('p53', 'Gene', '7157', (26, 29))	('DNA damage', 'MPA', (137, 147))
751125	29107016	Cloning the TCR sequence in viral vectors and transducing T lymphocytes isolated from peripheral blood can generate large numbers of tumor-specific T cells without the cumbersome process of isolation and expansion of TILs.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('TCR', 'Gene', (12, 15))	('Cloning', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('TCR', 'Gene', '6962', (12, 15))
751127	29107016	High-throughput analysis of TILs, in combination with deep sequencing of the autologous tumor, has led to T-cell therapy that targets tumor neoantigens arising from mutations.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('led to', 'Reg', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mutations', 'Var', (165, 174))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (134, 139))
751156	29107016	A subsequent dose-escalation Phase I/II study established feasibility and safety of administering HER2-targeted CAR T cells (104/m2-108/m2) to patients with recurrent or refractory HER2-positive tumors; however, the clinical benefit was limited as only 4 of 17 evaluable patients had stable disease.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('stable disease', 'Disease', (284, 298))	('104/m2-108/m2', 'Var', (125, 138))	('stable disease', 'Disease', 'MESH:D060050', (284, 298))	('HER2', 'Gene', (98, 102))	('patients', 'Species', '9606', (143, 151))	('HER2', 'Gene', (181, 185))	('HER2', 'Gene', '2064', (98, 102))	('patients', 'Species', '9606', (271, 279))	('HER2', 'Gene', '2064', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
751164	29107016	Overexpression of MSLN is correlated with tumor aggressiveness, KRAS mutation positivity, and decreased survival in lung ADC.	('positivity', 'Var', (78, 88))	('lung ADC', 'Disease', (116, 124))	('mutation', 'Reg', (69, 77))	('expression', 'Species', '29278', (4, 14))	('aggressiveness', 'Phenotype', 'HP:0000718', (48, 62))	('tumor aggressiveness', 'Disease', (42, 62))	('KRAS', 'Gene', (64, 68))	('decreased', 'NegReg', (94, 103))	('survival', 'CPA', (104, 112))	('MSLN', 'Var', (18, 22))	('KRAS', 'Gene', '3845', (64, 68))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (42, 62))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
751167	29107016	A case from a clinical trial (NCT01355965) conducted by the University of Pennsylvania that tested the safety and feasibility of repetitive intravenous or intratumoral administration of mRNA engineered T cells that transiently expressed an anti-MSLN CAR did not reveal evidence of off-tumor toxicities; however, epitope spreading was observed as a result of the antitumor efficacy.	('tumor', 'Disease', (366, 371))	('CAR', 'Gene', (250, 253))	('tumor toxicities', 'Disease', (285, 301))	('anti-MSLN', 'Var', (240, 249))	('CAR', 'Gene', '9970', (250, 253))	('tumor toxicities', 'Disease', 'MESH:D009369', (285, 301))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('tumor', 'Disease', (285, 290))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
751168	29107016	An anaphylactic event caused by immunogenicity against the scFv of murine origin occurred after repeated infusions.	('scFv', 'Gene', '652070', (59, 63))	('murine', 'Species', '10090', (67, 73))	('scFv', 'Gene', (59, 63))	('immunogenicity', 'Var', (32, 46))	('anaphylactic event', 'Phenotype', 'HP:0100845', (3, 21))	('anaphylactic', 'Disease', (3, 15))
751170	29107016	Based on our preclinical data of enhanced antitumor efficacy following regional, rather than systemic, administration of CAR T cells, we are conducting a Phase I clinical trial to evaluate the safety of regionally administered MSLN-targeted CAR T cells in patients with primary or secondary pleural malignancies (NCT02414269).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('pleural malignancies', 'Disease', (291, 311))	('patients', 'Species', '9606', (256, 264))	('tumor', 'Disease', (46, 51))	('MSLN-targeted', 'Var', (227, 240))	('pleural malignancies', 'Disease', 'MESH:D016066', (291, 311))	('enhanced', 'PosReg', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
751187	29107016	Recent research has shown that FAP-targeting CAR T cells disrupt stromagenesis, diminish tumor angiogenesis, and may increase immune cell infiltration in highly desmoplastic tumors.	('tumor', 'Disease', (174, 179))	('disrupt', 'NegReg', (57, 64))	('stromagenesis', 'CPA', (65, 78))	('increase', 'PosReg', (117, 125))	('FAP-targeting', 'Var', (31, 44))	('diminish', 'NegReg', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('desmoplastic tumors', 'Disease', 'MESH:D058405', (161, 180))	('desmoplastic tumors', 'Disease', (161, 180))	('immune cell infiltration', 'CPA', (126, 150))	('desmoplastic tumors', 'Phenotype', 'HP:0100245', (161, 180))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
751203	29107016	Our published observations that intrapleural administration of anti-MSLN CAR T cells yields long-term antitumor activity, even at a 30-fold lower doses to achieve complete response in a preclinical model, provides a clinically significant opportunity to treat pleural malignancies; the current annual incidence in the U.S. alone is 150 000 patients.	('pleural', 'Disease', (260, 267))	('pleural malignancies', 'Disease', (260, 280))	('anti-MSLN', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('patients', 'Species', '9606', (340, 348))	('pleural', 'Disease', 'MESH:D010995', (260, 267))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('pleural', 'Disease', 'MESH:D010995', (37, 44))	('pleural malignancies', 'Disease', 'MESH:D016066', (260, 280))	('tumor', 'Disease', (106, 111))	('pleural', 'Disease', (37, 44))
751274	28418870	In analyzing OS, we found statistically significant differences in HR when comparing multivariate and univariate analyses (P = 0.001), presence of C-index to select NLR cutoff (P = 0.002), and NLR < 3 compared to > 3 (P = 0.026).	('OS', 'Chemical', '-', (13, 15))	('significant', 'Reg', (40, 51))	('presence', 'Var', (135, 143))	('NLR', 'Var', (193, 196))
751275	28418870	The meta-regression scatter plot showed minor but statistically significant association between NLR cutoff and the hazard ratio for OS (beta = 0.224; P = 0.019) (Supplementary Figure 1).	('NLR', 'Gene', (96, 99))	('cutoff', 'Var', (100, 106))	('OS', 'Chemical', '-', (132, 134))
751285	28418870	In this systematic review and meta-analysis, we identified over a decade and a half of data from 45,905 GI cancer patients that underwent neutrophil-to-lymphocyte ratio testing to determine OS as well as DFS, PFS, or CSS.	('CSS', 'Chemical', '-', (217, 220))	('GI cancer', 'Phenotype', 'HP:0007378', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('DFS', 'Var', (204, 207))	('OS', 'Chemical', '-', (190, 192))	('GI cancer', 'Disease', (104, 113))	('PFS', 'Disease', (209, 212))	('patients', 'Species', '9606', (114, 122))	('GI cancer', 'Disease', 'MESH:D009369', (104, 113))
751440	27370310	p53 shows nuclear staining because of accumulation of mutant p53, which often has an increased stability and is resistant to degradation, making it detectable by IHC.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('accumulation', 'PosReg', (38, 50))	('p53', 'Gene', '7157', (61, 64))	('increased', 'PosReg', (85, 94))	('mutant', 'Var', (54, 60))	('p53', 'Gene', (61, 64))	('stability', 'MPA', (95, 104))
751472	27370310	However, if p53 is mutated, the mutant p53 protein can accumulate in the cell nucleus, although in some cases, nonsense mutations or a quickly degraded mutant protein can cause lack of expression.	('nonsense mutations', 'Var', (111, 129))	('accumulate', 'PosReg', (55, 65))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('mutant', 'Var', (32, 38))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('protein', 'Protein', (43, 50))
751473	27370310	Therefore, p53 over-expression is generally associated with the inactivation of p53.	('p53', 'Gene', (11, 14))	('inactivation', 'Var', (64, 76))	('p53', 'Gene', '7157', (11, 14))	('p53', 'Gene', (80, 83))	('p53', 'Gene', '7157', (80, 83))	('over-expression', 'PosReg', (15, 30))
751474	27370310	Based on its functions, positive p53 expression in cancer cells may promote cell migration, invasion, and metastasis, finally leading to poor prognosis.	('promote', 'PosReg', (68, 75))	('invasion', 'CPA', (92, 100))	('cell migration', 'CPA', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('positive', 'Var', (24, 32))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('metastasis', 'CPA', (106, 116))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
751476	27370310	The results of the overall pooled analysis in the present study on the association of p53 expression with survival in EC patients suggested that positive p53 expression was significantly related to poorer OS (RR = 1.30, 95 % CI: 1.11-1.51).	('related', 'Reg', (187, 194))	('p53', 'Gene', '7157', (86, 89))	('expression', 'MPA', (158, 168))	('poorer OS', 'Disease', (198, 207))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('positive', 'Var', (145, 153))	('patients', 'Species', '9606', (121, 129))	('p53', 'Gene', (86, 89))
751477	27370310	These findings demonstrated the significance of p53 expression in the prognosis of patients with EC and agreed with the theoretical inference that patients with positive p53 expression, which is often cause by mutation, could have poorer clinical prognosis than those with negative p53 expression.	('p53', 'Gene', (48, 51))	('cause', 'Reg', (201, 206))	('expression', 'MPA', (174, 184))	('p53', 'Gene', (282, 285))	('p53', 'Gene', '7157', (48, 51))	('p53', 'Gene', '7157', (282, 285))	('positive', 'Var', (161, 169))	('p53', 'Gene', (170, 173))	('patients', 'Species', '9606', (147, 155))	('p53', 'Gene', '7157', (170, 173))	('patients', 'Species', '9606', (83, 91))
751479	27370310	We also analyzed the relationship between p53 and clinicopathological parameters; the results showed that p53 expression was significantly associated with more advanced TNM stages (I/II vs. III/IV, OR = 0.74, 95 % CI: 0.55-0.99), lymph node metastasis (OR = 0.77, 95 % CI: 0.66-0.90), and distant metastasis (OR = 0.46, 95 % CI: 0.26-0.80).	('p53', 'Gene', (42, 45))	('p53', 'Gene', '7157', (106, 109))	('p53', 'Gene', '7157', (42, 45))	('TNM', 'Gene', '10178', (169, 172))	('associated', 'Reg', (139, 149))	('lymph node metastasis', 'CPA', (230, 251))	('p53', 'Gene', (106, 109))	('TNM', 'Gene', (169, 172))	('expression', 'Var', (110, 120))	('distant metastasis', 'CPA', (289, 307))
751480	27370310	Given that a more advanced TNM stage, positive lymph node metastasis, and distant metastasis are adverse prognostic features, the present results may explain why positive p53 expression is associated with poor 5-year survival in patients with EC.	('patients', 'Species', '9606', (229, 237))	('TNM', 'Gene', '10178', (27, 30))	('expression', 'MPA', (175, 185))	('poor', 'NegReg', (205, 209))	('TNM', 'Gene', (27, 30))	('positive', 'Var', (162, 170))	('p53', 'Gene', (171, 174))	('p53', 'Gene', '7157', (171, 174))
751483	27370310	Nevertheless, the sensitivity of IHC to assess p53 mutations through protein accumulation is generally poor; some mutations, such as truncated mutant, can lead to complete loss of p53 staining and be missed by IHC.	('loss', 'NegReg', (172, 176))	('mutations', 'Var', (114, 123))	('p53', 'Gene', (180, 183))	('p53', 'Gene', '7157', (180, 183))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
751486	27370310	In conclusion, our findings indicate that positive p53 expression is independently and significantly associated with poorer 5-year survival, more advanced TNM stages, lymph node metastasis, and distant metastasis in patients with EC.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('distant metastasis', 'CPA', (194, 212))	('TNM', 'Gene', '10178', (155, 158))	('poorer', 'NegReg', (117, 123))	('positive', 'Var', (42, 50))	('patients', 'Species', '9606', (216, 224))	('lymph node metastasis', 'CPA', (167, 188))	('TNM', 'Gene', (155, 158))	('5-year survival', 'CPA', (124, 139))
751492	25928665	Accumulating studies reported the important role of microRNAs (miRNAs) in the regulation of gene expression, among of which, the miR-124/STAT3 interaction has been widely reported in various cancers, while its role in EC has not been investigated yet.	('reported', 'Reg', (171, 179))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('regulation of gene expression', 'MPA', (78, 107))	('miR-124/STAT3', 'Var', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('interaction', 'Interaction', (143, 154))
751495	25928665	Next, we detected the effects of ectopic miR-124 expression on the proliferation, cell cycle distribution, apoptosis, migration and invasion of EC cells in vitro, and the tumor growth in vivo.	('ectopic', 'Var', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('miR-124', 'Gene', (41, 48))	('migration', 'CPA', (118, 127))	('cell cycle distribution', 'CPA', (82, 105))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('apoptosis', 'CPA', (107, 116))	('invasion', 'CPA', (132, 140))
751498	25928665	Next, functional experiments showed that ectopic expression of miR-124 in EC cells induced a complex phenotype, namely an inhibition of cell proliferation, block of G1/S phase transition, induction of cell apoptosis, and suppression of cell invasion in vitro, as well as inhibition of tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('G1/S phase transition', 'CPA', (165, 186))	('tumor', 'Disease', (285, 290))	('suppression', 'NegReg', (221, 232))	('cell invasion in vitro', 'CPA', (236, 258))	('inhibition', 'NegReg', (122, 132))	('miR-124', 'Gene', (63, 70))	('block', 'NegReg', (156, 161))	('ectopic expression', 'Var', (41, 59))	('inhibition', 'NegReg', (271, 281))	('cell proliferation', 'CPA', (136, 154))	('cell apoptosis', 'CPA', (201, 215))
751499	25928665	Moreover, restored the expression of STAT3 in esophageal cancer cells transfected with miR-124 before, could partially abolished the suppressive effects of miR-124 on the proliferation and invasion of Eca109 cells.	('abolished', 'NegReg', (119, 128))	('proliferation', 'CPA', (171, 184))	('STAT3', 'Gene', (37, 42))	('miR-124', 'Gene', (87, 94))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('invasion', 'CPA', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('miR-124', 'Var', (156, 163))	('expression', 'MPA', (23, 33))
751504	25928665	A key concept of the cancer-related inflammation pathway is that some genetic events endow cancer cells with growth advantages, among of which, an important one is the signal transducer and activator of transcription-3 (STAT3) signaling pathway.	('growth advantages', 'CPA', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('inflammation', 'Disease', 'MESH:D007249', (36, 48))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('inflammation', 'Disease', (36, 48))	('genetic', 'Var', (70, 77))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('endow', 'Reg', (85, 90))	('signal transducer and activator of transcription-3', 'Gene', '6774', (168, 218))
751505	25928665	Activation by tyrosine phosphorylation leads to its dimer formation, translocation to the nucleus, recognition of STAT3-specific DNA-binding elements, and transcriptional activation of the target genes.	('transcriptional', 'MPA', (155, 170))	('dimer formation', 'MPA', (52, 67))	('tyrosine phosphorylation', 'Var', (14, 38))	('translocation', 'MPA', (69, 82))	('activation', 'PosReg', (171, 181))	('tyrosine', 'Chemical', 'MESH:D014443', (14, 22))
751506	25928665	For esophageal cancer, STAT3 was constitutively activated in cancer tissues, and overexpression of STAT3 could activate esophageal epithelium cells to form tumors in vivo by up-regulating Oct-1.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', (156, 162))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('cancer', 'Disease', (61, 67))	('Oct-1', 'Gene', (188, 193))	('Oct-1', 'Gene', '5451', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('activate', 'PosReg', (111, 119))	('up-regulating', 'PosReg', (174, 187))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('STAT3', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('overexpression', 'Var', (81, 95))	('esophageal cancer', 'Disease', (4, 21))
751511	25928665	STAT3 has been reported to be the target gene of miR-124 in endometrial cancer cells, and be involved in the miR-124-mediated suppressive effects on endometrial cancer cells.	('endometrial cancer', 'Disease', 'MESH:D016889', (60, 78))	('endometrial cancer', 'Phenotype', 'HP:0012114', (60, 78))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('endometrial cancer', 'Disease', (149, 167))	('miR-124', 'Gene', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('endometrial cancer', 'Phenotype', 'HP:0012114', (149, 167))	('endometrial cancer', 'Disease', 'MESH:D016889', (149, 167))	('endometrial cancer', 'Disease', (60, 78))	('miR-124-mediated', 'Var', (109, 125))
751512	25928665	Strikingly, rs531564 GG polymorphism of primary gene of miR-124, pri-miR-124-1 which may promote the expression of miR-124, has been observed to show significant effects on decreasing the risks of esophageal squamous cell carcinoma in subgroups of elderly persons, females, no drinking and no smoking Chinese people.	('persons', 'Species', '9606', (256, 263))	('esophageal squamous cell carcinoma', 'Disease', (197, 231))	('decreasing', 'NegReg', (173, 183))	('miR-124-1', 'Gene', (69, 78))	('promote', 'PosReg', (89, 96))	('people', 'Species', '9606', (309, 315))	('rs531564', 'Mutation', 'rs531564', (12, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('miR-124', 'Gene', (56, 63))	('expression', 'MPA', (101, 111))	('miR-124', 'Gene', (115, 122))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (197, 231))	('rs531564 GG', 'Var', (12, 23))	('miR-124-1', 'Gene', '406907', (69, 78))
751519	25928665	These cells were maintained in Dualbecco's modified Eagle's medium (DMEM, Invitrogen, CA, USA) supplemented with 10% fetal bovine serum (FBS; PAA, Pasching, Austria) and streptomycin (100 mug/mL), penicillin (100 U/mL).	('penicillin', 'Chemical', 'MESH:D010406', (197, 207))	('bovine', 'Species', '9913', (123, 129))	('100', 'Var', (184, 187))	('FBS', 'Disease', 'MESH:D005198', (137, 140))	('streptomycin', 'Chemical', 'MESH:D013307', (170, 182))	('DMEM', 'Chemical', '-', (68, 72))	('FBS', 'Disease', (137, 140))	("'s modified Eagle's medium", 'Chemical', '-', (40, 66))
751542	25928665	Co-transfection with miR-124 and constructs containing the 3'UTR of miR-124 putative binding site led to significant suppression of luciferase activity in both esophageal cancer cell lines (Figure 1A), suggesting that miR-124 suppressed the transcription activity of STAT3 gene in esophageal cancer cells by targeting the putative 3'UTR of STAT3 mRNA independently.	('suppression', 'NegReg', (117, 128))	('luciferase', 'Enzyme', (132, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (281, 298))	('miR-124', 'Var', (218, 225))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('STAT3 gene', 'Gene', (267, 277))	('esophageal cancer', 'Disease', (160, 177))	('suppressed', 'NegReg', (226, 236))	('transcription activity', 'MPA', (241, 263))	('esophageal cancer', 'Disease', (281, 298))	('activity', 'MPA', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
751545	25928665	Collectively, these findings identified that miR-124 regulates the expression of STAT3 post-transcriptionally in esophageal cancer cells.	('regulates', 'Reg', (53, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('miR-124', 'Var', (45, 52))	('STAT3', 'Gene', (81, 86))	('expression', 'MPA', (67, 77))	('esophageal cancer', 'Disease', (113, 130))
751552	25928665	These data suggested that alteration of miR-124 might be a frequent event in human esophageal cancer and has a pivotal role in the tumorigenesis of esophageal cancer.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('esophageal cancer', 'Disease', (83, 100))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('alteration', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', (148, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('tumor', 'Disease', (131, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('role', 'Reg', (119, 123))	('miR-124', 'Gene', (40, 47))	('human', 'Species', '9606', (77, 82))
751556	25928665	As shown in Figure 3D, ectopic miR-124 expression increased proportions of annexin V -positive only cells compared to scramble control group (P < 0.05) (Figure 3D), suggesting miR-124 can efficiently induce apoptosis of esophageal cancer cells.	('esophageal cancer', 'Disease', (220, 237))	('apoptosis', 'CPA', (207, 216))	('ectopic', 'Var', (23, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (220, 237))	('increased', 'PosReg', (50, 59))	('miR-124', 'Gene', (31, 38))	('induce', 'PosReg', (200, 206))	('miR-124', 'Var', (176, 183))	('annexin V', 'Gene', '308', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('annexin V', 'Gene', (75, 84))
751570	25928665	These data indicated that introduction of miR-124 remarkably inhibited the tumorigenicity of Eca-109 cells in the nude mouse xenograft model, providing a novel method for esophageal cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mouse', 'Species', '10090', (119, 124))	('inhibited', 'NegReg', (61, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('esophageal cancer', 'Disease', (171, 188))	('miR-124', 'Gene', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('introduction', 'Var', (26, 38))	('tumor', 'Disease', (75, 80))
751579	25928665	This is consistent with Chen et al., whose work suggested that dysregulation of miR-124 presents borderline longer overall survival and relapse-free survival in acute myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (175, 183))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (161, 183))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (167, 183))	('acute myeloid leukemia', 'Disease', (161, 183))	('overall survival', 'CPA', (115, 131))	('relapse-free survival', 'CPA', (136, 157))	('dysregulation', 'Var', (63, 76))	('longer', 'PosReg', (108, 114))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (161, 183))	('miR-124', 'Gene', (80, 87))
751584	25928665	These results shown here demonstrate that miR-124 could suppress the carcinogenesis of esophageal in vitro.	('carcinogenesis of esophageal', 'Disease', 'MESH:D063646', (69, 97))	('carcinogenesis of esophageal', 'Disease', (69, 97))	('suppress', 'NegReg', (56, 64))	('miR-124', 'Var', (42, 49))
751586	25928665	In our in vivo study, treatment of miR-124 also reduced tumor burden in nude mice, suggesting that miR-124 inhibits the tumor growth of esophageal cancer in vivo.	('esophageal cancer', 'Disease', (136, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('reduced', 'NegReg', (48, 55))	('tumor', 'Disease', (56, 61))	('inhibits', 'NegReg', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('nude mice', 'Species', '10090', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (120, 125))	('miR-124', 'Var', (99, 106))
751591	25928665	reported that STAT3 knockdown reduced cell proliferation and migration of esophageal cancer cells OE33.	('STAT3', 'Gene', (14, 19))	('cell proliferation', 'CPA', (38, 56))	('esophageal cancer', 'Disease', (74, 91))	('reduced', 'NegReg', (30, 37))	('knockdown', 'Var', (20, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
751737	22844446	TGFbetaRI inhibition can efficiently block this process, perhaps providing a guide for future therapeutic strategies in the treatment of tumors and metastasis.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('TGFbetaRI', 'Protein', (0, 9))	('inhibition', 'Var', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
751765	22328939	Moreover, a case-control study in this population observed that the presence of HPV DNA in cancer specimens and the presence of HPV-16 E7 antibody in sera were associated with an increased risk of ESCC (Unpublished manuscript).	('HPV-16', 'Species', '333760', (128, 134))	('HPV DNA', 'Gene', (80, 87))	('cancer', 'Disease', (91, 97))	('ESCC', 'Disease', (197, 201))	('men', 'Species', '9606', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('HPV', 'Species', '10566', (128, 131))	('HPV', 'Species', '10566', (80, 83))	('presence', 'Var', (68, 76))	('HPV-16', 'Gene', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (160, 170))
751913	21112495	In these same cells, expression of Hes1, a downstream target of Notch, is down-regulated by CDX2 overexpression, suggesting that inhibition of Notch signaling by CDX2 may play a role in metaplasia formation.	('Hes1', 'Gene', '3280', (35, 39))	('CDX2', 'Gene', (92, 96))	('down-regulated', 'NegReg', (74, 88))	('metaplasia', 'Disease', (186, 196))	('CDX2', 'Gene', '1045', (162, 166))	('expression', 'MPA', (21, 31))	('CDX2', 'Gene', '1045', (92, 96))	('overexpression', 'Var', (97, 111))	('CDX2', 'Gene', (162, 166))	('Hes1', 'Gene', (35, 39))	('metaplasia', 'Disease', 'MESH:D008679', (186, 196))
751915	21112495	Recently, in an animal model of reflux and Barrett's esophagus, inhibitors of Notch signaling caused the proliferative Barrett's cells to differentiate into goblet cells.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (43, 62))	('rat', 'Species', '10116', (112, 115))	('inhibitors', 'Var', (64, 74))	('Notch signaling', 'Gene', (78, 93))
751927	21112495	Surprisingly, studies have shown that these cancer hallmarks can be acquired by normal cells through disruptions in only a few key growth regulatory pathways including the p16/Retinoblastoma (Rb) and p53 pathways, the Ras signaling pathway, and the telomerase-dependent senescence pathway (Table 1).	('Retinoblastoma', 'Disease', (176, 190))	('disruptions', 'Var', (101, 112))	('telomerase-dependent senescence pathway', 'Pathway', (249, 288))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('p53', 'Gene', (200, 203))	('Ras signaling pathway', 'Pathway', (218, 239))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (176, 190))	('p16', 'Gene', (172, 175))	('p53', 'Gene', '7157', (200, 203))	('growth regulatory pathways', 'Pathway', (131, 157))	('Retinoblastoma', 'Disease', 'MESH:D012175', (176, 190))	('Rb', 'Chemical', '-', (192, 194))	('p16', 'Gene', '1029', (172, 175))
751932	21112495	Although the data are inconclusive, it appears that Rb itself is targeted for inactivation in the latter stages of Barrett's carcinogenesis (i.e.	('inactivation', 'Var', (78, 90))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (115, 139))	('Rb', 'Chemical', '-', (52, 54))	("Barrett's carcinogenesis", 'Disease', (115, 139))
751937	21112495	Thus, inactivation of p16 would allow cells to pass unhindered from G1 into S phase and is, in fact, the earliest and most common genetic alteration found in non-dysplastic Barrett's metplasia.	("non-dysplastic Barrett's metplasia", 'Disease', 'MESH:D001471', (158, 192))	('inactivation', 'Var', (6, 18))	('p16', 'Gene', '1029', (22, 25))	("non-dysplastic Barrett's metplasia", 'Disease', (158, 192))	('rat', 'Species', '10116', (142, 145))	('p16', 'Gene', (22, 25))	('allow', 'Reg', (32, 37))
751942	21112495	Therefore, disruption of the p53 pathway gives cells the ability to avoid growth inhibitory signals, to replicate without limit, and to resist apoptosis.	('p53', 'Gene', (29, 32))	('apoptosis', 'CPA', (143, 152))	('disruption', 'Var', (11, 21))	('p53', 'Gene', '7157', (29, 32))	('growth inhibitory signals', 'MPA', (74, 99))
751943	21112495	Using immunohistochemical staining, mutant p53 expression has been detected in non-dysplastic Barrett's metaplasia and the frequency of mutant p53 detection increases as dysplasia and adenocarcinoma ensue.	('p53', 'Gene', '7157', (143, 146))	('dysplasia and adenocarcinoma', 'Disease', 'MESH:D000230', (170, 198))	("non-dysplastic Barrett's metaplasia", 'Disease', 'MESH:D001471', (79, 114))	('detected', 'Reg', (67, 75))	("non-dysplastic Barrett's metaplasia", 'Disease', (79, 114))	('mutant', 'Var', (36, 42))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('mutant', 'Var', (136, 142))	('p53', 'Gene', (143, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
751944	21112495	The majority of human tumors demonstrate mutations in Ras (i.e.	('mutations', 'Var', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('rat', 'Species', '10116', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Ras', 'Gene', (54, 57))	('human', 'Species', '9606', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
751977	33519815	Since inhibition of the immune response by IC can be used by cancer to avoid recognition and destruction by immune system, blocking them enhances the anti-tumor response.	('blocking', 'Var', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('enhances', 'PosReg', (137, 145))	('cancer', 'Disease', (61, 67))	('tumor', 'Disease', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
751978	33519815	Since genetic variants may affect both expression and structure of ICs, they are considered as risk factors of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('genetic variants', 'Var', (6, 22))	('ICs', 'Protein', (67, 70))	('expression', 'MPA', (39, 49))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('structure', 'MPA', (54, 63))	('affect', 'Reg', (27, 33))
751980	33519815	In this review, we have comprehensively summarized the current understanding of the relationship between inherited variations of CTLA-4, PDCD1, PD-L1, BTLA, TIM-3, and LAG-3 genes in order to select SNPs which can be used as predictive biomarkers in personalized evaluation of cancer risk development and outcomes as well as possible response to immunotherapy.	('TIM-3', 'Gene', '84868', (157, 162))	('PDCD1', 'Gene', (137, 142))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('PDCD1', 'Gene', '5133', (137, 142))	('BTLA', 'Gene', (151, 155))	('variations', 'Var', (115, 125))	('LAG-3', 'Gene', (168, 173))	('PD-L1', 'Gene', (144, 149))	('LAG-3', 'Gene', '3902', (168, 173))	('CTLA-4', 'Gene', (129, 135))	('TIM-3', 'Gene', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
751982	33519815	A discovery made by prof. Allison and prof. Honjo (Nobel Prize in 2018), indicating that blocking these molecules elicits an anti-cancer response, has opened up new perspectives for cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('molecules', 'Protein', (104, 113))	('cancer', 'Disease', (130, 136))	('blocking', 'Var', (89, 97))	('elicits', 'Reg', (114, 121))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
751988	33519815	The immune status of cancer is modulated by many factors including patients' immune reactivity which may be affected by single nucleotide polymorphisms (SNPs) of immune related genes.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('patients', 'Species', '9606', (67, 75))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('affected', 'Reg', (108, 116))	('single nucleotide polymorphisms', 'Var', (120, 151))
751990	33519815	Hence, genetic polymorphism may impair function of molecules important for effective activity of anti-tumor response, such as CTLA-4; the SNPs of CTLA-4 and other immune checkpoints molecules have been studied in the context of variety types of cancers.	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('cancers', 'Disease', (245, 252))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('impair', 'NegReg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('genetic polymorphism', 'Var', (7, 27))	('CTLA-4', 'Gene', (126, 132))	('tumor', 'Disease', (102, 107))	('function', 'MPA', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
751991	33519815	This review will summarize current knowledge about the impact of the genetic variants of CTLA-4, PDCD1, PD-L1, BTLA, TIM-3, and LAG-3 on cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('variants', 'Var', (77, 85))	('TIM-3', 'Gene', (117, 122))	('LAG-3', 'Gene', (128, 133))	('LAG-3', 'Gene', '3902', (128, 133))	('TIM-3', 'Gene', '84868', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('PDCD1', 'Gene', (97, 102))	('cancer', 'Disease', (137, 143))	('PDCD1', 'Gene', '5133', (97, 102))	('CTLA-4', 'Gene', (89, 95))	('BTLA', 'Gene', (111, 115))	('PD-L1', 'Gene', (104, 109))
752000	33519815	The discovery made by Prof. Allison's group showing in murine model of tumor that the blocking of CTLA-4 caused an enhanced antitumor immunity, gave a new perspective on therapeutic approaches to cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('enhanced', 'PosReg', (115, 123))	('cancer', 'Disease', (196, 202))	('tumor', 'Disease', (128, 133))	('blocking', 'Var', (86, 94))	('CTLA-4', 'Gene', (98, 104))	('tumor', 'Disease', (71, 76))	('murine', 'Species', '10090', (55, 61))
752010	33519815	Below we described the most intensively examined genetic variants of CTLA-4 in human tumors together with their functional relevance, if such data were available in literature.	('human', 'Species', '9606', (79, 84))	('tumors', 'Disease', (85, 91))	('CTLA-4', 'Gene', (69, 75))	('variants', 'Var', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
752011	33519815	rs4553808 (CTLA-4c.-1661A>G) and rs733618 (CTLA-4c.-1722T>C) are located in the upstream regulatory region and may impact the transcription-associated binding activity of CCAAT-enhancer binding protein C/EBPbeta and nuclear factor 1 (NF-1) TFs, respectively.	('NF-1', 'Gene', '4763', (234, 238))	('C/EBPbeta', 'Gene', '1050', (202, 211))	('transcription-associated binding', 'Interaction', (126, 158))	('c.-1722T>C', 'Var', (49, 59))	('rs4553808', 'Mutation', 'rs4553808', (0, 9))	('CCAAT-enhancer', 'Enzyme', (171, 185))	('C/EBPbeta', 'Gene', (202, 211))	('NF-1', 'Gene', (234, 238))	('nuclear factor 1', 'Gene', (216, 232))	('c.-1722T>C', 'SUBSTITUTION', 'None', (49, 59))	('rs733618', 'Mutation', 'rs733618', (33, 41))	('c.-1661A>G', 'SUBSTITUTION', 'None', (17, 27))	('nuclear factor 1', 'Gene', '4763', (216, 232))	('impact', 'NegReg', (115, 121))	('c.-1661A>G', 'Var', (17, 27))	('rs4553808', 'Var', (0, 9))
752012	33519815	The in silico analysis suggested that the change of adenine to guanine at -1661 position may lead to creation of a new binding site for a C/EBPbeta TF.	('C/EBPbeta', 'Gene', '1050', (138, 147))	('guanine', 'Chemical', 'MESH:D006147', (63, 70))	('adenine', 'Chemical', 'MESH:D000225', (52, 59))	('C/EBPbeta', 'Gene', (138, 147))	('change', 'Var', (42, 48))	('lead to', 'Reg', (93, 100))	('binding', 'Interaction', (119, 126))
752014	33519815	Therefore, it can be anticipated that an extra C/EBPbeta binding motif created by CTLA-4c.-1661A>G may increase the transcriptional activity and lead to higher expression of CTLA-4.	('transcriptional activity', 'MPA', (116, 140))	('expression', 'MPA', (160, 170))	('c.-1661A>G', 'SUBSTITUTION', 'None', (88, 98))	('higher', 'PosReg', (153, 159))	('increase', 'PosReg', (103, 111))	('c.-1661A>G', 'Var', (88, 98))	('C/EBPbeta', 'Gene', '1050', (47, 56))	('CTLA-4', 'Gene', (174, 180))	('C/EBPbeta', 'Gene', (47, 56))
752015	33519815	Such a phenomenon was recently described for the rs975484C>G located in a protein arginine methyltransferase 1 gene (PRMTI).	('protein arginine methyltransferase 1', 'Gene', '3276', (74, 110))	('rs975484C>G', 'Var', (49, 60))	('rs975484C>G', 'DBSNP_MENTION', 'None', (49, 60))	('protein arginine methyltransferase 1', 'Gene', (74, 110))	('PRMTI', 'Gene', (117, 122))
752017	33519815	In contrast, the substitution of thymine to cytosine at position -1722 was predicted to destroy a binding site for a NF-1 TF.	('thymine', 'Chemical', 'MESH:D013941', (33, 40))	('NF-1', 'Gene', '4763', (117, 121))	('cytosine', 'Chemical', 'MESH:D003596', (44, 52))	('binding site', 'Interaction', (98, 110))	('substitution', 'Var', (17, 29))	('NF-1', 'Gene', (117, 121))	('destroy', 'NegReg', (88, 95))
752020	33519815	rs11571317C>T (CTLA-4c.-658C>T) is located in 5' UTR region.	('rs11571317C>T', 'DBSNP_MENTION', 'None', (0, 13))	('c.-658C>T', 'Var', (21, 30))	('c.-658C>T', 'SUBSTITUTION', 'None', (21, 30))	('rs11571317C>T', 'Var', (0, 13))
752021	33519815	In silico analysis revealed that this polymorphism is located in potential binding site for a SP1 TF (C allele), and that presence of thymine at this site may lead to disruption of the SP1 binding motif.	('SP1', 'Protein', (185, 188))	('thymine', 'Chemical', 'MESH:D013941', (134, 141))	('lead to', 'Reg', (159, 166))	('binding', 'Interaction', (75, 82))	('presence', 'Var', (122, 130))	('disruption', 'MPA', (167, 177))
752022	33519815	Hence, in the context of cancer, CTLA-4c.-658*C allele (higher expression of CTLA-4 molecule) may confer increased risk of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('expression', 'MPA', (63, 73))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (123, 129))	('CTLA-4c.-658', 'Var', (33, 45))	('higher', 'PosReg', (56, 62))	('cancer', 'Disease', (25, 31))
752023	33519815	rs5742909C>T (CTLA-4c.-319C>T) is located in the promoter region.	('rs5742909C>T', 'DBSNP_MENTION', 'None', (0, 12))	('c.-319C>T', 'Var', (20, 29))	('c.-319C>T', 'SUBSTITUTION', 'None', (20, 29))	('rs5742909C>T', 'Var', (0, 12))
752027	33519815	The CTLA-4c.-319*T allele has also been associated with significantly increased expression of CTLA-4 mRNA and surface CTLA-4 expression on unstimulated peripheral blood mononuclear cells (PMBC) and CD4+ T cells, but not on CD8+ T cells.	('mRNA', 'MPA', (101, 105))	('CTLA-4c.-319', 'Var', (4, 16))	('increased', 'PosReg', (70, 79))	('CTLA-4', 'Gene', (94, 100))	('CTLA-4', 'Gene', (118, 124))	('expression', 'MPA', (125, 135))	('expression', 'MPA', (80, 90))	('CD8', 'Gene', (223, 226))	('CD8', 'Gene', '925', (223, 226))
752028	33519815	Based on that, it may be assumed that CTLA-4c.-319*T allele is associated with higher expression of CTLA-4, and therefore, may increase a risk of cancer development and progression.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('CTLA-4', 'Gene', (100, 106))	('CTLA-4c.-319', 'Var', (38, 50))	('expression', 'MPA', (86, 96))	('increase', 'PosReg', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('progression', 'CPA', (169, 180))	('higher', 'PosReg', (79, 85))
752029	33519815	Xiong and colleagues investigated functional relevance of CTLA-4c.-319C>T and found that upon stimulation PBMCs derived from subjects with CTLA-4c.-319 T/T genotype had significantly lower proliferation ability, produced lower levels of IL-2 and IL-4, but on the contrary higher levels of TGF-beta compared with PBMCs derived from subjects with CTLA-4c.-319 C/T or CTLA-4c.-319 C/C genotypes.	('IL-4', 'Gene', (246, 250))	('proliferation ability', 'CPA', (189, 210))	('IL-2', 'Gene', '3558', (237, 241))	('levels', 'MPA', (279, 285))	('CTLA-4c.-319 T/T', 'Var', (139, 155))	('TGF-beta', 'Gene', (289, 297))	('IL-2', 'Gene', (237, 241))	('IL-4', 'Gene', '3565', (246, 250))	('c.-319C>T', 'Var', (64, 73))	('lower', 'NegReg', (221, 226))	('T/T', 'Var', (152, 155))	('TGF-beta', 'Gene', '7039', (289, 297))	('higher', 'PosReg', (272, 278))	('c.-319C>T', 'SUBSTITUTION', 'None', (64, 73))	('lower', 'NegReg', (183, 188))	('levels', 'MPA', (227, 233))
752030	33519815	Furthermore, the authors demonstrated, that stimulated PBMCs with CTLA-4c.-319 T/T genotype were significantly less cytotoxic towards CaSki cell line cells (HPV 16-positive cervical cancer cell line) than PBMCs from individuals with CTLA-4c.-319 C/T or C/C genotypes.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CaSki', 'CellLine', 'CVCL:1100', (134, 139))	('T/T', 'Var', (79, 82))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('HPV 16', 'Species', '333760', (157, 163))	('cytotoxic', 'CPA', (116, 125))	('less', 'NegReg', (111, 115))	('CTLA-4c.-319 T/T', 'Var', (66, 82))
752032	33519815	rs231775A>G (CTLA-4c.49A>G) is a non-synonymous SNP which leads to an amino acid change from threonine to alanine in position 17 of CTLA-4 leader peptide (Thr17Ala).	('change', 'Reg', (81, 87))	('c.49A>G', 'SUBSTITUTION', 'None', (19, 26))	('threonine to alanine in position 17', 'Mutation', 'rs231775', (93, 128))	('c.49A>G', 'Var', (19, 26))	('Thr17Ala', 'Var', (155, 163))	('rs231775A>G', 'DBSNP_MENTION', 'None', (0, 11))	('amino', 'MPA', (70, 75))	('Thr17Ala', 'SUBSTITUTION', 'None', (155, 163))	('rs231775A>G', 'Var', (0, 11))
752033	33519815	The presence of the CTLA-4c.49 A/A (Thr17) genotype, as opposed to the G/G genotype (Ala17), was associated with significantly lower levels of T cells activation and lower proliferation of these cells.	('proliferation', 'CPA', (172, 185))	('lower', 'NegReg', (127, 132))	('Thr17', 'Chemical', '-', (36, 41))	('T cells', 'CPA', (143, 150))	('lower', 'NegReg', (166, 171))	('Ala17', 'Chemical', '-', (85, 90))	('CTLA-4c.49 A/A', 'Var', (20, 34))	('activation', 'PosReg', (151, 161))	('lower levels of T cells', 'Phenotype', 'HP:0005403', (127, 150))
752036	33519815	It was also postulated that the CTLA-4c.49A>G in the leader sequence alters the inhibitory function of CTLA-4 by influencing the rate of endocytosis or surface trafficking.	('rate of endocytosis', 'MPA', (129, 148))	('CTLA-4', 'Gene', (103, 109))	('c.49A>G', 'SUBSTITUTION', 'None', (38, 45))	('inhibitory function', 'MPA', (80, 99))	('surface trafficking', 'MPA', (152, 171))	('alters', 'Reg', (69, 75))	('influencing', 'Reg', (113, 124))	('c.49A>G', 'Var', (38, 45))
752037	33519815	Taking into consideration the aforementioned observation it is reasonable to consider the CTLA-4c.49*A allele as a risk factor of cancer development.	('CTLA-4c.49*A', 'Var', (90, 102))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
752041	33519815	Five out of the aforementioned polymorphisms mainly focused researchers' attention: CTLA-4c.-1722T>C, CTLA-4c.-1661A>G, CTLA-4c.-319C>T, CTLA-4c.49A>G, and CTLA-4CT60G>A.	('c.-1661A>G', 'Var', (108, 118))	('c.49A>G', 'SUBSTITUTION', 'None', (143, 150))	('c.-1722T>C', 'Var', (90, 100))	('c.-319C>T', 'Var', (126, 135))	('c.-1722T>C', 'SUBSTITUTION', 'None', (90, 100))	('c.49A>G', 'Var', (143, 150))	('c.-319C>T', 'SUBSTITUTION', 'None', (126, 135))	('c.-1661A>G', 'SUBSTITUTION', 'None', (108, 118))	('CTLA-4CT60G', 'Gene', (156, 167))
752042	33519815	The association of these polymorphisms with susceptibility to various types of cancers were investigated in many case-control studies and their results were analyzed in several meta-analyses.	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('polymorphisms', 'Var', (25, 38))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
752043	33519815	In the next paragraphs the reported relationships between genetic variants of the CTLA-4 gene and particular cancers were described.	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('relationships', 'Interaction', (36, 49))	('cancers', 'Disease', (109, 116))	('genetic variants', 'Var', (58, 74))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CTLA-4', 'Gene', (82, 88))
752044	33519815	included 67 different studies analyzing CTLA-4c.49A>G (23,617 cases, 27,261 controls), CTLA-4c.-319C>T (7,741 cases, 9,611), CTLA-4CT60G>A (9,675 cases, 9,623 controls), CTLA-4c.-1661A>G (3,635 cases, 4,104 controls), and CTLA-4c.-1722T>C (in 14 studies).	('c.-1661A>G', 'Var', (176, 186))	('c.-319C>T', 'Var', (93, 102))	('c.-319C>T', 'SUBSTITUTION', 'None', (93, 102))	('c.49A>G', 'SUBSTITUTION', 'None', (46, 53))	('c.49A>G', 'Var', (46, 53))	('CTLA-4CT60G', 'Var', (125, 136))	('c.-1722T>C', 'Var', (228, 238))	('c.-1722T>C', 'SUBSTITUTION', 'None', (228, 238))	('c.-1661A>G', 'SUBSTITUTION', 'None', (176, 186))
752045	33519815	According to this analysis, three SNPs were significantly associated with overall cancer risk: CTLA-4c.-1661A>G (G/G vs. A+, OR = 1.38; G+ vs. A/A OR = 1.48); CTLA-4c.-319C>T (T+ vs. C/C OR = 1.33); CTLA-4c.49A>G (A/A vs. G+, OR = 1.1; A+ vs. G/G OR = 1.16), while CTLA-4CT60G>A and CTLA-4c.-1722T>C were not associated with overall cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('c.49A>G', 'Var', (205, 212))	('associated', 'Reg', (58, 68))	('c.-1661A>G', 'SUBSTITUTION', 'None', (101, 111))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('c.-1722T>C', 'Var', (289, 299))	('c.-1661A>G', 'Var', (101, 111))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (333, 339))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('c.-319C>T', 'Var', (165, 174))	('c.-1722T>C', 'SUBSTITUTION', 'None', (289, 299))	('c.-319C>T', 'SUBSTITUTION', 'None', (165, 174))	('c.49A>G', 'SUBSTITUTION', 'None', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))
752046	33519815	In analyses stratified by ethnicity, both CTLA-4c.49A>G and CTLA-4c.-1661A>G were significant susceptibility polymorphisms in Asians, but not in Caucasians, while CTLA-4c.-319C>T was associated with overall cancer susceptibility in Caucasians (T+ vs. C/C, OR = 1.63).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('c.49A>G', 'Var', (48, 55))	('cancer', 'Disease', (207, 213))	('c.-319C>T', 'Var', (169, 178))	('c.-319C>T', 'SUBSTITUTION', 'None', (169, 178))	('c.49A>G', 'SUBSTITUTION', 'None', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('c.-1661A>G', 'SUBSTITUTION', 'None', (66, 76))	('c.-1661A>G', 'Var', (66, 76))
752047	33519815	When stratify by cancer type, the strong associations between the CTLA-4c.49A>G and bone, liver and pancreatic cancers (A/A vs. G+, OR = 2.04, OR = 1.41 and OR = 1.67, respectively) as well as breast and head and neck cancers (A+ vs. G/G, OR = 1.27 and OR = 1.33, respectively) were observed.	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('cancer', 'Disease', (17, 23))	('liver and pancreatic cancers', 'Disease', 'MESH:D006528', (90, 118))	('cancer', 'Disease', (111, 117))	('bone', 'Disease', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (100, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('head and neck cancers', 'Disease', 'MESH:D006258', (204, 225))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('c.49A>G', 'SUBSTITUTION', 'None', (72, 79))	('breast', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('head and neck cancers', 'Phenotype', 'HP:0012288', (204, 225))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (100, 117))	('c.49A>G', 'Var', (72, 79))
752048	33519815	Additionally, CTLA-4c.-1661A>G was associated with significantly increased susceptibility to breast and head and neck cancers (G+ vs. A/A, OR = 1.44 and OR = 1.99, respectively).	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('c.-1661A>G', 'SUBSTITUTION', 'None', (20, 30))	('breast', 'Disease', (93, 99))	('c.-1661A>G', 'Var', (20, 30))	('head and neck cancers', 'Disease', 'MESH:D006258', (104, 125))	('head and neck cancers', 'Phenotype', 'HP:0012288', (104, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
752051	33519815	On the contarary, the presence of CTLA-4c.-319*T allele was associated with an increased overall cancer risk exclusively in Europeans.	('cancer', 'Disease', (97, 103))	('CTLA-4c.-319', 'Gene', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('presence', 'Var', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
752054	33519815	The presence of CTLA-4CT60 A/A genotype increased the risk of skin cancer, while presence of CTLA-4CT60*G allele the risk of breast and cervical cancers.	('breast and cervical cancers', 'Disease', 'MESH:D001943', (125, 152))	('skin cancer', 'Phenotype', 'HP:0008069', (62, 73))	('skin cancer', 'Disease', 'MESH:D012878', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('skin cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('increased', 'PosReg', (40, 49))	('presence', 'Var', (81, 89))	('CTLA-4CT60', 'Gene', (93, 103))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('CTLA-4CT60', 'Gene', (16, 26))
752056	33519815	The results of latest meta-analysis confirmed previous reports about lack of associations between CTLA-4c.-1722T>C and overall cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('c.-1722T>C', 'Var', (104, 114))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('c.-1722T>C', 'SUBSTITUTION', 'None', (104, 114))	('cancer', 'Disease', (127, 133))	('associations', 'Interaction', (77, 89))
752057	33519815	The most recent meta-analysis summarizing the results of 11 studies (3,899 cases, 4,608 controls) indicated significant association between CTLA-4c.-319*T allele and T/T genotype and cervical cancer risk (T/T vs. C+, 1.96; T+ vs. C/C OR = 1.47, respectively).	('CTLA-4c.-319', 'Gene', (140, 152))	('cancer', 'Disease', (192, 198))	('T/T', 'Var', (166, 169))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
752060	33519815	It has been conclusively established that CTLA-4c.49A>G is associated with the risk of cervical cancer.	('c.49A>G', 'Var', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('associated', 'Reg', (59, 69))	('c.49A>G', 'SUBSTITUTION', 'None', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
752061	33519815	Several meta-analyses, including, proved that the A/A genotype of CTLA-4c.49A>G and the possession of CTLA-4c.49*A allele confer the increased susceptibility to this cancer type of about 20% (OR = 1.20).	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('susceptibility', 'Reg', (143, 157))	('CTLA-4c.49', 'Gene', (102, 112))	('c.49A>G', 'SUBSTITUTION', 'None', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('c.49A>G', 'Var', (72, 79))
752062	33519815	(365 women - cases and controls) the carriage of CTLA-4CT60*G allele was associated with increased cervical cancer risk (OR = 1.92), and with more advanced stages of this disease, whereas the other studies did not demonstrate such association.	('increased cervical cancer', 'Phenotype', 'HP:0030159', (89, 114))	('carriage', 'Var', (37, 45))	('women', 'Species', '9606', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CTLA-4CT60', 'Gene', (49, 59))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
752064	33519815	Collectively, the findings of presented studies suggest that women possessing CTLA-4c.49* A allele and CTLA-4c.-319*T allele are more prone to develop cervical cancer.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('women', 'Species', '9606', (61, 66))	('CTLA-4c.-319', 'Var', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CTLA-4c.49', 'Var', (78, 88))	('develop', 'PosReg', (143, 150))
752065	33519815	The association between CTLA-4c.49A>G and breast cancer (BC) was evaluated in two meta-analyses including the data from 5 studies.	('c.49A>G', 'SUBSTITUTION', 'None', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('c.49A>G', 'Var', (30, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))
752069	33519815	Additionally, this group explored pooled effect of CTLA-4c.49A>G in BC based on 9 studies, and found that the carriage of CTLA-4c.49*G allele decreased 1.3 times risk of BC, whereas the CTLA-4c.49*A allele conferred an increased risk of BC developing, what was in agreement with previous analyses.	('c.49A>G', 'SUBSTITUTION', 'None', (57, 64))	('CTLA-4c.49', 'Gene', (122, 132))	('decreased', 'NegReg', (142, 151))	('c.49A>G', 'Var', (57, 64))	('BC developing', 'Disease', (237, 250))
752072	33519815	The G/G genotype was associated with restricted tumor growth, while G/A and A/A genotypes promote tumor growth.	('G/A', 'Var', (68, 71))	('tumor', 'Disease', (48, 53))	('G/G', 'Var', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('A/A', 'Var', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('promote', 'PosReg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
752073	33519815	This group also investigated relationship between CTLA-4c.-658C>T and BC and demonstrated that C/C genotype significantly increased the risk of BC development in comparison to C/T genotype.	('c.-658C>T', 'SUBSTITUTION', 'None', (56, 65))	('C/C', 'Var', (95, 98))	('c.-658C>T', 'Var', (56, 65))	('increased', 'PosReg', (122, 131))	('BC development', 'CPA', (144, 158))
752074	33519815	revealed association between the CTLA-4c.-1661*G allele and susceptibility to BC development, while CTLA-4c.-1772T>C was not associated with BC risk in these studies.	('susceptibility', 'Reg', (60, 74))	('association', 'Reg', (9, 20))	('c.-1772T>C', 'Var', (106, 116))	('c.-1772T>C', 'SUBSTITUTION', 'None', (106, 116))	('CTLA-4c.-1661', 'Gene', (33, 46))	('BC development', 'CPA', (78, 92))
752075	33519815	The most recent meta-analysis published in 2020 which relates to digestive system malignancies (among them gastric cancers) summarizes the results from available studies concerning the following CTLA-4 SNPs: CTLA-4c.-1772T>C, CTLA-4c.-1661A>G, CTLA-4c.-319C>T, CTLA-4c.49A>G, CTLA-4CT60G>A and gastric cancer (GC) risk.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('c.-1661A>G', 'SUBSTITUTION', 'None', (232, 242))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('malignancies', 'Disease', (82, 94))	('gastric cancer', 'Disease', (294, 308))	('gastric cancers', 'Disease', (107, 122))	('gastric cancers', 'Disease', 'MESH:D013274', (107, 122))	('gastric cancers', 'Phenotype', 'HP:0012126', (107, 122))	('c.49A>G', 'SUBSTITUTION', 'None', (267, 274))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('c.-319C>T', 'SUBSTITUTION', 'None', (250, 259))	('gastric cancer', 'Disease', 'MESH:D013274', (294, 308))	('c.-1772T>C', 'SUBSTITUTION', 'None', (214, 224))	('CTLA-4CT60G', 'Var', (276, 287))	('c.-1661A>G', 'Var', (232, 242))	('c.49A>G', 'Var', (267, 274))	('c.-1772T>C', 'Var', (214, 224))	('gastric cancer', 'Phenotype', 'HP:0012126', (294, 308))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('c.-319C>T', 'Var', (250, 259))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
752077	33519815	In contrast, examination of CTLA-4c.-319C>T revealed significant association between the possession of CTLA-4c.-319 C/C genotype and increased risk of GC (OR = 1.58).	('c.-319C>T', 'SUBSTITUTION', 'None', (34, 43))	('c.-319C>T', 'Var', (34, 43))	('CTLA-4c.-319', 'Gene', (103, 115))
752079	33519815	There is only a limited number of studies investigating CTLA-4 gene polymorphisms and risk of hepatocellular cancer (HCC) available in the literature.	('hepatocellular cancer', 'Disease', (94, 115))	('CTLA-4', 'Gene', (56, 62))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (94, 115))	('polymorphisms', 'Var', (68, 81))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
752080	33519815	[analyzing data included in work by Wang et al., except one study published in Chinese language, and data from two additional studies ], did not confirm previous observations and suggested a lack of association between the CTLA-4c.49A>G and HCC risk.	('c.49A>G', 'Var', (229, 236))	('HCC', 'Disease', (241, 244))	('c.49A>G', 'SUBSTITUTION', 'None', (229, 236))
752081	33519815	investigated association between CTLA-4c.49A>G, CTLA-4CT60G>A, CTLA-4c.-1722T>C, CTLA-4 rs16840252C>T, and HCC risk in a group of 584 patients and 923 control subjects of an Eastern Chinese Han population.	('rs16840252C>T', 'DBSNP_MENTION', 'None', (88, 101))	('c.49A>G', 'SUBSTITUTION', 'None', (39, 46))	('c.-1722T>C', 'Var', (69, 79))	('rs16840252C>T', 'Var', (88, 101))	('c.49A>G', 'Var', (39, 46))	('patients', 'Species', '9606', (134, 142))	('c.-1722T>C', 'SUBSTITUTION', 'None', (69, 79))	('CTLA-4', 'Gene', (81, 87))	('HCC', 'Disease', (107, 110))
752083	33519815	The authors observed about 1.5 increased risk of HCC cancer for individuals with CTLA-4CT60 G/G genotype as compared to carriers of CTLA-4CT60*A allele.	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('HCC cancer', 'Disease', (49, 59))	('CTLA-4CT60 G/G', 'Var', (81, 95))	('HCC cancer', 'Disease', 'MESH:D006528', (49, 59))
752084	33519815	Similarly, to results obtained by Xiong and colleagues, these authors observed that the CTLA-4c.-319 C/T and T/T genotypes were associated with lower production of interleukins IL-2 and IL-4, an increased production of TGF-beta and lower cell proliferation, what was demonstrated for PBMCs with these genotypes stimulated with PHA.	('TGF-beta', 'Gene', (219, 227))	('IL-4', 'Gene', '3565', (186, 190))	('lower', 'NegReg', (144, 149))	('C/T', 'Var', (101, 104))	('IL-4', 'Gene', (186, 190))	('TGF-beta', 'Gene', '7039', (219, 227))	('cell proliferation', 'CPA', (238, 256))	('IL-2', 'Gene', '3558', (177, 181))	('increased', 'PosReg', (195, 204))	('IL-2', 'Gene', (177, 181))	('production', 'MPA', (205, 215))	('T/T', 'Var', (109, 112))	('lower', 'NegReg', (232, 237))	('CTLA-4c.-319', 'Gene', (88, 100))
752086	33519815	The evaluation of association between CTLA-4 polymorphisms and colorectal cancer (CRC) risk was the subject of several studies.	('rectal cancer', 'Phenotype', 'HP:0100743', (67, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('association', 'Interaction', (18, 29))	('colorectal cancer', 'Disease', (63, 80))	('polymorphisms', 'Var', (45, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('CTLA-4', 'Gene', (38, 44))
752087	33519815	(2013) [based on data from ] did not show association between the CTLA-4c.49A>G and CRC risk.	('c.49A>G', 'SUBSTITUTION', 'None', (72, 79))	('c.49A>G', 'Var', (72, 79))	('CRC', 'Disease', (84, 87))
752089	33519815	For CTLA-4c.-1722T>C, CTLA-4c.-1661A>G, CTLA-4c.-319C>T, and CTLA-4CT60G>A, there was no evidence of associations with CRC risk.	('c.-319C>T', 'SUBSTITUTION', 'None', (46, 55))	('c.-319C>T', 'Var', (46, 55))	('c.-1722T>C', 'Var', (10, 20))	('CRC', 'Disease', (119, 122))	('CTLA-4CT60G>A', 'Var', (61, 74))	('c.-1722T>C', 'SUBSTITUTION', 'None', (10, 20))	('c.-1661A>G', 'SUBSTITUTION', 'None', (28, 38))	('c.-1661A>G', 'Var', (28, 38))
752090	33519815	published results of meta-analysis exploring association between CTLA-4c.-1661A>G, CTLA-4c.49A>G, CTLA-4CT60G>A, and the risk of bone sarcoma based on data from four case-control studies performed on Asians.	('CTLA-4CT60G', 'Gene', (98, 109))	('c.49A>G', 'SUBSTITUTION', 'None', (89, 96))	('c.-1661A>G', 'SUBSTITUTION', 'None', (71, 81))	('bone sarcoma', 'Disease', 'MESH:D012509', (129, 141))	('bone sarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('c.49A>G', 'Var', (89, 96))	('c.-1661A>G', 'Var', (71, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('bone sarcoma', 'Disease', (129, 141))
752093	33519815	The relationship between CTLA-4c.-319C>T and CTLA-4c.49A>G and susceptibility to osteosarcoma was examined most recently in a meta-analysis by Wang et al.	('osteosarcoma', 'Disease', (81, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (81, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('c.49A>G', 'SUBSTITUTION', 'None', (51, 58))	('c.49A>G', 'Var', (51, 58))	('c.-319C>T', 'SUBSTITUTION', 'None', (31, 40))	('c.-319C>T', 'Var', (31, 40))
752095	33519815	Bilbaoilbao-Aldaiturriaga and colleagues investigated association between CTLA-4c.49A>G and osteosarcoma (99 patients, 125 controls) and concluded that carriers of CTLA-4c.49*G allele had 2-fold lower risk of osteosarcoma in comparison to homozygotes A/A in Spanish population.	('osteosarcoma', 'Disease', 'MESH:D012516', (92, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (209, 221))	('c.49A>G', 'Var', (80, 87))	('patients', 'Species', '9606', (109, 117))	('osteosarcoma', 'Disease', (209, 221))	('lower', 'NegReg', (195, 200))	('osteosarcoma', 'Disease', 'MESH:D012516', (209, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('CTLA-4c.49*G', 'Var', (164, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('osteosarcoma', 'Disease', (92, 104))	('c.49A>G', 'SUBSTITUTION', 'None', (80, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (92, 104))
752098	33519815	Dai and colleagues performed a meta-analysis [based on data from 9 case-control studies performed on Caucasians (7 reports) and Asians (2 reports) ] aimed at evaluation of association between CTLA-4c.-319C>T, CTLA-4c.49A>G, CTLA-4CT60G>A, and susceptibility to lymphoid malignancies.	('association', 'Interaction', (172, 183))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (261, 282))	('CTLA-4CT60G', 'Gene', (224, 235))	('c.-319C>T', 'SUBSTITUTION', 'None', (198, 207))	('c.-319C>T', 'Var', (198, 207))	('c.49A>G', 'Var', (215, 222))	('c.49A>G', 'SUBSTITUTION', 'None', (215, 222))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (261, 282))	('lymphoid malignancies', 'Disease', (261, 282))
752100	33519815	Furthermore, a stratified analysis by ethnicity (Asian or Caucasian) and histopathological subtype (non-Hodgkin lymphoma) also failed to detect an association between the studied polymorphisms and risk of lymphoid malignancy.	('non-Hodgkin lymphoma', 'Disease', (100, 120))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (100, 120))	('lymphoid malignancy', 'Disease', (205, 224))	('polymorphisms', 'Var', (179, 192))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('lymphoid malignancy', 'Phenotype', 'HP:0002665', (205, 224))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (104, 120))	('lymphoid malignancy', 'Disease', 'MESH:D008223', (205, 224))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (100, 120))
752101	33519815	examined CTLA-4c.-319C>T, CTLA-4c.49A>G, and CTLA-4CT60G>A SNPs in childhood acute lymphoblastic leukemia (ALL) and demonstrated that the presence of CTLA-4c.-319*T allele conferred susceptibility to this disease.	('c.-319C>T', 'Var', (15, 24))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (77, 105))	('c.49A>G', 'Var', (32, 39))	('c.-319C>T', 'SUBSTITUTION', 'None', (15, 24))	('susceptibility', 'Reg', (182, 196))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('CTLA-4c.-319*T', 'Var', (150, 164))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (77, 105))	('c.49A>G', 'SUBSTITUTION', 'None', (32, 39))	('acute lymphoblastic leukemia', 'Disease', (77, 105))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (83, 105))
752103	33519815	There are a very limited number of studies on the association between the CTLA-4 polymorphisms and lung cancer risk.	('lung cancer', 'Disease', (99, 110))	('polymorphisms', 'Var', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('CTLA-4', 'Gene', (74, 80))	('association', 'Interaction', (50, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
752105	33519815	Two other investigated SNPs of CTLA-4, namely CTLA-4c.-1722T>C and CTLA-4c.-1661A>G were not associated with lung cancer risk.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('c.-1722T>C', 'Var', (52, 62))	('c.-1661A>G', 'Var', (73, 83))	('c.-1722T>C', 'SUBSTITUTION', 'None', (52, 62))	('associated', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('c.-1661A>G', 'SUBSTITUTION', 'None', (73, 83))
752107	33519815	The CTLA-4c.-319C>T and CTLA-4CT60G>A were not associated with the risk of lung cancer development.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('c.-319C>T', 'Var', (10, 19))	('c.-319C>T', 'SUBSTITUTION', 'None', (10, 19))
752109	33519815	There is only one study considering associations between CTLA-4c.49A>G and CTLA-4CT60G>A and bladder cancer risk in North Indian population (200 cases, 200 controls).	('CTLA-4CT60G', 'Gene', (75, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))	('bladder cancer', 'Disease', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('c.49A>G', 'SUBSTITUTION', 'None', (63, 70))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('c.49A>G', 'Var', (63, 70))
752110	33519815	The authors found that the G/G genotype of CTLA-4c.49A>G was associated with almost 4-fold higher risk of bladder cancer in comparison to A/G and A/A genotypes.	('G/G', 'Var', (27, 30))	('higher', 'PosReg', (91, 97))	('c.49A>G', 'SUBSTITUTION', 'None', (49, 56))	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))	('c.49A>G', 'Var', (49, 56))
752112	33519815	The relationship between CTLA-4c.-319C>T, CTLA-4CT60G>A and prostate cancer (PC) (301 cases, 301 controls) was investigated by Karabon et al.	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))	('prostate cancer', 'Disease', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CTLA-4CT60G', 'Gene', (42, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('c.-319C>T', 'SUBSTITUTION', 'None', (31, 40))	('c.-319C>T', 'Var', (31, 40))
752117	33519815	In Polish case-control study (323 patients, 518 controls) the following SNPs: CTLA-4c.49A>G, CTLA-4c.-319C>T, CTLA-4CT60G>A were investigated.	('c.49A>G', 'Var', (84, 91))	('c.-319C>T', 'SUBSTITUTION', 'None', (99, 108))	('patients', 'Species', '9606', (34, 42))	('c.-319C>T', 'Var', (99, 108))	('c.49A>G', 'SUBSTITUTION', 'None', (84, 91))
752118	33519815	The authors reported that the presence CTLA-4CT60*G allele increased 1.5 times risk of clear cell renal cancer.	('renal cancer', 'Phenotype', 'HP:0009726', (98, 110))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (87, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CTLA-4CT60*G', 'Var', (39, 51))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (87, 110))	('clear cell renal cancer', 'Disease', (87, 110))	('CTLA-4CT60', 'Gene', (39, 49))
752119	33519815	Furthermore, the presence of CTLA-4CT60*G allele was significantly associated with necrosis and advanced stages of a clear cell renal cell cancer.	('necrosis', 'Disease', (83, 91))	('associated with', 'Reg', (67, 82))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('necrosis', 'Disease', 'MESH:D009336', (83, 91))	('cell renal cell cancer', 'Disease', 'MESH:C538614', (123, 145))	('renal cell cancer', 'Phenotype', 'HP:0005584', (128, 145))	('presence', 'Var', (17, 25))	('CTLA-4CT60', 'Gene', (29, 39))	('cell renal cell cancer', 'Disease', (123, 145))
752120	33519815	Only two studies evaluated the potential association between CTLA-4 polymorphisms and pancreatic cancer (PC) risk.	('pancreatic cancer', 'Disease', (86, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('polymorphisms', 'Var', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CTLA-4', 'Gene', (61, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
752121	33519815	examined association between CTLA-4c.49A>G and PC and reported that CTLA-4c.49*A allele conferred the risk of PC and that the homozygotes A/A were 2.2 times more prone to develop PC in comparison to homozygotes G/G and heterozygotes A/G.	('conferred', 'Reg', (88, 97))	('c.49A>G', 'SUBSTITUTION', 'None', (35, 42))	('c.49A>G', 'Var', (35, 42))	('CTLA-4c.49*A', 'Var', (68, 80))
752123	33519815	The summary of above presented associations between CTLA-4 polymorphisms and cancer risk is shown in  Supplementary Table 1 .	('CTLA-4', 'Gene', (52, 58))	('associations', 'Interaction', (31, 43))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('polymorphisms', 'Var', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
752138	33519815	Two additional regulatory elements (-3.7 and +17.1kb form the TSS) contain STAT binding sites and contribute to the enhanced transcriptional activity after TCR and IL-6 or IL-12 cytokine stimulation.	('enhanced', 'PosReg', (116, 124))	('-3.7', 'Var', (36, 40))	('STAT', 'Protein', (75, 79))	('transcriptional activity', 'MPA', (125, 149))	('IL-6', 'Gene', (164, 168))	('IL-6', 'Gene', '3569', (164, 168))
752140	33519815	Table 1  includes the frequency of PDCD1 polymorphisms described below in different populations.	('PDCD1', 'Gene', (35, 40))	('polymorphisms', 'Var', (41, 54))	('PDCD1', 'Gene', '5133', (35, 40))
752142	33519815	Given the above, one can assume that carriers of PD-1.1*G allele could have a higher expression of PD-1 and in consequence inhibited activation and proliferation of T cells, which in turn can lead to poor ability to fight/remove cancer cells.	('PD-1.1*G', 'Var', (49, 57))	('expression', 'MPA', (85, 95))	('PD-1', 'Gene', (99, 103))	('poor', 'NegReg', (200, 204))	('cancer', 'Disease', (229, 235))	('lead', 'Reg', (192, 196))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('higher', 'PosReg', (78, 84))	('inhibited', 'NegReg', (123, 132))	('T cells', 'CPA', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
752143	33519815	However, some literature data [among others: ] described the PD-1.1*G allele as associated with a decreased risk of cancers (detailed description below) and therefore further functional studies are necessary.	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('PD-1.1*G', 'Var', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('decreased', 'NegReg', (98, 107))
752146	33519815	the presence of PD-1.3*A allele disrupted the binding site for RUNX1 TF in the first repeat, which in consequence may lead to aberrant PD-1 expression and deregulated lymphocyte activity.	('lead to', 'Reg', (118, 125))	('binding site', 'Interaction', (46, 58))	('RUNX1', 'Gene', '861', (63, 68))	('PD-1.3', 'Var', (16, 22))	('expression', 'MPA', (140, 150))	('disrupted', 'NegReg', (32, 41))	('PD-1', 'Gene', (135, 139))	('RUNX1', 'Gene', (63, 68))	('deregulated', 'PosReg', (155, 166))	('lymphocyte activity', 'CPA', (167, 186))
752149	33519815	It was shown that PD-1 expression (% PD-1+CD4+ T cells) was significantly lower in individuals with PD-1.5 C/C genotype than those with the PD-1.5 C/T and PD-1.5 T/T genotypes.	('PD-1.5 T', 'Disease', (155, 163))	('PD-1.5 T', 'Disease', 'MESH:C566017', (155, 163))	('PD-1', 'Gene', (18, 22))	('PD-1.5 C/C', 'Var', (100, 110))	('lower', 'NegReg', (74, 79))	('expression', 'MPA', (23, 33))
752150	33519815	From the aforementioned observation it may be concluded that subjects with PD-1.5 C/C genotype could have lower risk of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lower', 'NegReg', (106, 111))	('PD-1.5 C/C', 'Var', (75, 85))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
752151	33519815	rs10204525C>T (PD-1.6, G>A REV) is located in the 3'UTR region, in a putative miRNA binding site.	('rs10204525C>T', 'DBSNP_MENTION', 'None', (0, 13))	('miR', 'Gene', (78, 81))	('miR', 'Gene', '220972', (78, 81))	('rs10204525C>T', 'Var', (0, 13))
752153	33519815	In lymphocytes from chronic HBV patients with PD-1.6 G/G genotype (but not in lymphocytes from patients with PD-1.6 A/A) miR-4717 mimic significantly decreased PD-1 expression and increased TNF-alpha and IFN-gamma production, whereas miR-4717 inhibitor acted in opposite way.	('miR-4717', 'Gene', '100616241', (121, 129))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (95, 103))	('TNF-alpha', 'Gene', '7124', (190, 199))	('increased', 'PosReg', (180, 189))	('IFN-gamma', 'Gene', (204, 213))	('expression', 'MPA', (165, 175))	('chronic HBV', 'Disease', (20, 31))	('PD-1.6', 'Var', (46, 52))	('IFN-gamma', 'Gene', '3458', (204, 213))	('TNF-alpha', 'Gene', (190, 199))	('PD-1', 'Protein', (160, 164))	('decreased PD', 'Phenotype', 'HP:0032198', (150, 162))	('miR-4717', 'Gene', (234, 242))	('miR-4717', 'Gene', '100616241', (234, 242))	('miR-4717', 'Gene', (121, 129))	('decreased', 'NegReg', (150, 159))
752154	33519815	showed that PD-1 mRNA levels were the highest in individuals with PD-1.6 A/A genotype and decreased as the number of G allele increased; in HBV patients PD-1 expression in individuals with PD-1.6 G/G genotype was significantly lower in comparison to subjects with PD-1.6 A/A genotype.	('PD-1.6', 'Var', (66, 72))	('PD-1', 'MPA', (12, 16))	('expression', 'MPA', (158, 168))	('lower', 'NegReg', (227, 232))	('patients', 'Species', '9606', (144, 152))	('PD-1.6 G/G', 'Var', (189, 199))	('PD-1', 'Gene', (153, 157))	('HBV', 'Disease', (140, 143))
752155	33519815	Since inhibition of PD-1 promotes an effective immune response against cancer cells, PD-1.6*G could be considered as protective allele in cancer development.	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('PD-1', 'Gene', (20, 24))	('cancer', 'Disease', (71, 77))	('promotes', 'PosReg', (25, 33))	('immune response', 'CPA', (47, 62))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('inhibition', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
752156	33519815	rs2227982G>A (PD-1.9, C>T REV) is a nonsynonymous SNP, located in exon 5, causing an amino acid substitution from alanine to valine in the extracellular domain of PD-1 leading to a different structure and possibly altering the function of PD-1.	('valine', 'Chemical', 'MESH:D014633', (125, 131))	('different', 'Reg', (181, 190))	('alanine', 'Chemical', 'MESH:D000409', (114, 121))	('function', 'MPA', (227, 235))	('rs2227982G>A', 'Var', (0, 12))	('rs2227982G>A', 'DBSNP_MENTION', 'None', (0, 12))	('PD-1', 'Gene', (163, 167))	('amino acid substitution', 'Var', (85, 108))	('causing', 'Reg', (74, 81))	('altering', 'Reg', (214, 222))	('structure', 'MPA', (191, 200))
752158	33519815	Due to the disruption of the splice site or alteration of the mRNA secondary structure, PD-1 rs7421861T>C may induce aberrant splicing, and lead to translational suppression.	('mRNA secondary structure', 'MPA', (62, 86))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (93, 105))	('splicing', 'MPA', (126, 134))	('induce', 'Reg', (110, 116))	('rs7421861T>C', 'Var', (93, 105))	('alteration', 'Reg', (44, 54))	('aberrant', 'MPA', (117, 125))	('translational', 'MPA', (148, 161))	('disruption', 'Reg', (11, 21))	('PD-1', 'Gene', (88, 92))
752160	33519815	Rs41386349*T allele created a negative cis-element for transcription and had lower PD-1 transcriptional activity in human T cells than rs41386349*C allele.	('lower', 'NegReg', (77, 82))	('negative', 'NegReg', (30, 38))	('rs41386349*C', 'Var', (135, 147))	('PD-1', 'Gene', (83, 87))	('Rs41386349*T', 'Var', (0, 12))	('rs41386349', 'Mutation', 'rs41386349', (135, 145))	('cis-element for transcription', 'MPA', (39, 68))	('human', 'Species', '9606', (116, 121))
752161	33519815	Therefore, it can be concluded that rs41386349*T allele conferring higher risk for autoimmune diseases could be considered as protective factor against cancer development.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('autoimmune diseases', 'Disease', 'MESH:D001327', (83, 102))	('autoimmune diseases', 'Disease', (83, 102))	('rs41386349*T', 'Var', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (83, 102))	('rs41386349', 'Mutation', 'rs41386349', (36, 46))
752163	33519815	Recent comprehensive meta-analysis regarding the association of PDCD1 polymorphisms with overall cancer risk was performed by Hashemi et al.	('PDCD1', 'Gene', '5133', (64, 69))	('cancer', 'Disease', (97, 103))	('PDCD1', 'Gene', (64, 69))	('association', 'Interaction', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('polymorphisms', 'Var', (70, 83))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
752166	33519815	revealed that in addition to PD-1.5, also PD-1.3 was associated with overall cancer risk.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('PD-1.3', 'Var', (42, 48))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
752169	33519815	Furthermore, the results of the latest meta-analysis (3,576 patients, 5,277 controls) revealed that the carriers of T/C genotype of rs7421861T>C had an increased risk of cancer (OR = 1.16).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (132, 144))	('cancer', 'Disease', (170, 176))	('patients', 'Species', '9606', (60, 68))	('rs7421861T>C', 'Var', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
752170	33519815	Given the results of this study, it can be assumed that higher risk of cancer concerned carriers of rs7421861*C allele (OR = 1.14).	('rs7421861*C', 'Var', (100, 111))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs7421861', 'Mutation', 'rs7421861', (100, 109))
752173	33519815	However, analysis stratified by ethnicity (performed as part of the meta-analysis by Da et al., 4,445 cases, 5,126 controls), revealed an increased risk of cancer for individuals with PD-1.1 A/A genotype in the Asian population (OR = 1.15).	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('PD-1.1 A/A', 'Var', (184, 194))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))
752179	33519815	The association with increased risk was observed only for a combination of genotypes CD28(rs3116496TT)/IFNG (rs2430561AA)/PDCD1(rs2227981CT), although a major contribution to the observed association was suggested for CD28 and IFNG SNPs.	('IFNG', 'Gene', (227, 231))	('CD28', 'Gene', (218, 222))	('PDCD1', 'Gene', '5133', (122, 127))	('rs2227981', 'Mutation', 'rs2227981', (128, 137))	('PDCD1', 'Gene', (122, 127))	('IFNG', 'Gene', '3458', (103, 107))	('CD28', 'Gene', (85, 89))	('rs3116496', 'Mutation', 'rs3116496', (90, 99))	('rs2430561', 'Mutation', 'rs2430561', (109, 118))	('CD28', 'Gene', '940', (218, 222))	('CD28', 'Gene', '940', (85, 89))	('IFNG', 'Gene', '3458', (227, 231))	('IFNG', 'Gene', (103, 107))	('rs2430561AA', 'Var', (109, 120))
752180	33519815	Polymorphisms of the PDCD1 have been studied also in breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('PDCD1', 'Gene', (21, 26))	('Polymorphisms', 'Var', (0, 13))	('PDCD1', 'Gene', '5133', (21, 26))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
752181	33519815	Two meta-analyses investigating the association between PDCD1 SNPs and overall cancer risk, in a subgroup analysis by cancer type (951 patients, 806 controls), indicated an association between PD-1.5 and susceptibility to BC.	('cancer', 'Disease', (118, 124))	('patients', 'Species', '9606', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PDCD1', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('PDCD1', 'Gene', '5133', (56, 61))	('association', 'Interaction', (173, 184))	('susceptibility', 'Reg', (204, 218))	('PD-1.5', 'Gene', (193, 199))	('SNPs', 'Var', (62, 66))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
752186	33519815	However, Ren and colleagues in the study conducted on 560 patients and 583 individuals observed a decreased risk for BC in individuals carrying the PD-1.9*T allele (OR = 0.69).	('PD-1.9*T', 'Var', (148, 156))	('Ren', 'Gene', (9, 12))	('patients', 'Species', '9606', (58, 66))	('decreased', 'NegReg', (98, 107))	('Ren', 'Gene', '5972', (9, 12))
752188	33519815	Increased risk of BC was identified for PD-1.1*A allele carriers (decreased for PD-1.1 G/G genotype, OR = 0.71), which is in accordance with the results obtained for overall cancer risk in Asians.	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('PD-1.1*A', 'Var', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))
752189	33519815	No association with breast cancer risk was suggested for rs7421861T>C, PD-1.6, and PD-1.3.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('rs7421861T>C', 'Var', (57, 69))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (57, 69))
752190	33519815	According to our best knowledge, only two studies have assessed the potential association between PDCD1 polymorphisms and ovarian cancer.	('PDCD1', 'Gene', (98, 103))	('ovarian cancer', 'Disease', 'MESH:D010051', (122, 136))	('ovarian cancer', 'Disease', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('polymorphisms', 'Var', (104, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))	('PDCD1', 'Gene', '5133', (98, 103))
752192	33519815	demonstrated that possession of PD-1.9*T allele was associated with increased risk of ovarian cancer (OR = 1.67).	('ovarian cancer', 'Disease', (86, 100))	('PD-1.9*T', 'Var', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))
752194	33519815	it can be concluded that the PD-1.5*T allele was associated with a reduced risk of ovarian cancer (OR = 0.82).	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('PD-1.5*T', 'Var', (29, 37))	('reduced', 'NegReg', (67, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ovarian cancer', 'Disease', (83, 97))
752195	33519815	mentioned above was aimed inter alia at evaluation of association between PDCD1 polymorphisms and the risk of gastrointestinal cancer (a cancer group that affects the digestive system which contains inter alia esophageal cancer, esophagogastric junction adenocarcinoma, gastric cancer, hepatocellular carcinoma and colorectal cancer, which are separately described below).	('junction adenocarcinoma', 'Disease', (245, 268))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('gastric cancer', 'Disease', (270, 284))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (286, 310))	('rectal cancer', 'Phenotype', 'HP:0100743', (319, 332))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (278, 284))	('association', 'Interaction', (54, 65))	('junction adenocarcinoma', 'Disease', 'MESH:D000230', (245, 268))	('colorectal cancer', 'Phenotype', 'HP:0003003', (315, 332))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('hepatocellular carcinoma', 'Disease', (286, 310))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (110, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (270, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('cancer', 'Disease', (326, 332))	('polymorphisms', 'Var', (80, 93))	('cancer', 'Disease', (127, 133))	('PDCD1', 'Gene', (74, 79))	('PDCD1', 'Gene', '5133', (74, 79))	('gastrointestinal cancer', 'Disease', (110, 133))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (110, 133))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (229, 268))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (221, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('colorectal cancer', 'Disease', 'MESH:D015179', (315, 332))	('gastric cancer', 'Phenotype', 'HP:0012126', (270, 284))	('alia esophageal cancer', 'Disease', (205, 227))	('alia esophageal cancer', 'Disease', 'MESH:D004938', (205, 227))	('colorectal cancer', 'Disease', (315, 332))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (286, 310))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('cancer', 'Disease', 'MESH:D009369', (127, 133))
752196	33519815	Just as in the case of overall cancer risk, decreased risk of gastrointestinal cancer was observed for individuals with the PD-1.5 T/T genotype (OR = 0.60), whereas increased risk was noted for subjects with rs7421861 T/C genotype (OR = 1.19).	('rs7421861', 'Mutation', 'rs7421861', (208, 217))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (62, 85))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (62, 85))	('PD-1.5 T', 'Disease', (124, 132))	('PD-1.5 T', 'Disease', 'MESH:C566017', (124, 132))	('gastrointestinal cancer', 'Disease', (62, 85))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('rs7421861 T/C', 'Var', (208, 221))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('decreased', 'NegReg', (44, 53))
752200	33519815	In all three studies the PD-1.6 was suggested to be associated with susceptibility to esophageal cancer.	('associated', 'Reg', (52, 62))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('PD-1.6', 'Var', (25, 31))
752201	33519815	reported the opposite effect:carriage of PD-1.6*G allele was associated with increased risk of esophageal cancer (OR = 1.26).	('esophageal cancer', 'Disease', (95, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('PD-1.6*G', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
752204	33519815	Some evidence suggests increased risk of esophageal cancer (OR = 1.24) and higher TNM stage (OR = 1.37) for rs7421861*T allele carriers (decreased for individuals with rs7421861 C/C genotype) while another shows no association of this SNP with ESCC at al.. As was described above, analysis conducted for gastrointestinal cancers pointed to association between rs7421861*C allele with increased risk.	('cancers', 'Phenotype', 'HP:0002664', (321, 328))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('association', 'Interaction', (340, 351))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('gastrointestinal cancers', 'Disease', (304, 328))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (304, 328))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (304, 327))	('rs7421861', 'Mutation', 'rs7421861', (360, 369))	('rs7421861', 'Mutation', 'rs7421861', (168, 177))	('rs7421861', 'Mutation', 'rs7421861', (108, 117))	('rs7421861*C', 'Var', (360, 371))	('esophageal cancer', 'Disease', (41, 58))
752206	33519815	made an attempt to find a potential association between PDCD1 polymorphisms (PD-1.1, PD-1.6, PD-1.9, and rs7421861T>C) and risk of esophagogastric junction adenocarcinoma (EGJA) (however it is worth mentioning that 1,063 patients and 1,677 controls were enrolled in this study).	('patients', 'Species', '9606', (221, 229))	('junction adenocarcinoma', 'Disease', 'MESH:D000230', (147, 170))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (105, 117))	('PDCD1', 'Gene', (56, 61))	('PDCD1', 'Gene', '5133', (56, 61))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (131, 170))	('junction adenocarcinoma', 'Disease', (147, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('rs7421861T>C', 'Var', (105, 117))
752207	33519815	Increased risk of EGJA (similarly as in the case of overall cancer risk) was noted for carriers of rs7421861*C allele (OR = 1.43).	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('rs7421861', 'Mutation', 'rs7421861', (99, 108))	('cancer', 'Disease', (60, 66))	('rs7421861*C', 'Var', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('EGJA', 'Disease', (18, 22))
752209	33519815	in their study aimed at determining the potential association between PD-1.5 and gastric cancer indicated that the presence of PD-1.5 C/T genotype may be a risk factor for GC (OR = 1.77).	('PD-1.5', 'Gene', (127, 133))	('presence', 'Var', (115, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('C/T', 'Var', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('risk', 'Reg', (156, 160))
752212	33519815	The PD-1.9, PD-1.6, and rs7421861T>C were studied in gastric cardia adenocarcinoma (GCA), however, for none of them the difference in genotype distribution between 330 GCA patients and 608 controls were found.	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (53, 82))	('rs7421861T>C', 'Var', (24, 36))	('gastric cardia adenocarcinoma', 'Disease', (53, 82))	('patients', 'Species', '9606', (172, 180))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (24, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
752217	33519815	However, after patients subdivision for cancer location, it was observed that PD-1.5 C/T genotype was significantly more frequent in colon cancer patients as compared with healthy controls (OR = 1.74).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patients', 'Species', '9606', (15, 23))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PD-1.5 C/T', 'Var', (78, 88))	('cancer', 'Disease', (40, 46))	('colon cancer', 'Disease', (133, 145))	('cancer', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('patients', 'Species', '9606', (146, 154))	('frequent', 'Reg', (121, 129))
752218	33519815	Moreover, decreased risk of colon cancer was observed for PD-1.1*A allele carriers (OR = 0.09).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('decreased', 'NegReg', (10, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (28, 40))	('colon cancer', 'Disease', 'MESH:D015179', (28, 40))	('PD-1.1*A', 'Var', (58, 66))	('colon cancer', 'Disease', (28, 40))
752220	33519815	Of the four SNPs (rs6710479, rs7421861T>C, PD-1.9, PD-1.6) examined by Ge et al.	('rs7421861T>C', 'DBSNP_MENTION', 'None', (29, 41))	('rs6710479', 'Var', (18, 27))	('rs6710479', 'Mutation', 'rs6710479', (18, 27))	('rs7421861T>C', 'Var', (29, 41))
752221	33519815	(601 patients, 627 controls), only rs7421861T>C was shown to be associated with susceptibility to CRC, with the rs7421861 T/C genotype increasing risk of CRC development (OR = 1.31).	('patients', 'Species', '9606', (5, 13))	('rs7421861 T/C', 'Var', (112, 125))	('rs7421861T>C', 'Var', (35, 47))	('rs7421861', 'Mutation', 'rs7421861', (112, 121))	('CRC', 'Disease', (154, 157))	('CRC', 'Disease', (98, 101))	('rs7421861', 'Mutation', 'rs7421861', (35, 44))	('increasing', 'PosReg', (135, 145))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (35, 47))
752222	33519815	it can be concluded that the PD-1.3*A allele was associated with increased CRC risk (OR = 2.18), however, it should be stated that only a small number of patients and controls (80 and 110, respectively) were enrolled in this study and further investigations will be needed.	('patients', 'Species', '9606', (154, 162))	('CRC', 'Disease', (75, 78))	('PD-1.3*A', 'Var', (29, 37))
752223	33519815	Furthermore, it is also noteworthy to mention that in the group of Korean patients (N = 688), individuals with PD-1.6 A/A genotype had shorter overall survival as compared to PD-1.6*G allele carriers (HR = 1.47).	('shorter', 'NegReg', (135, 142))	('overall survival', 'MPA', (143, 159))	('PD-1.6 A/A', 'Var', (111, 121))	('patients', 'Species', '9606', (74, 82))
752224	33519815	The potential association of PDCD1 polymorphisms with hematological malignancies was evaluated in several studies including multiple myeloma and leukemia.	('hematological malignancies', 'Disease', (54, 80))	('myeloma and leukemia', 'Disease', 'MESH:D009101', (133, 153))	('hematological malignancies', 'Disease', 'MESH:D019337', (54, 80))	('multiple myeloma', 'Phenotype', 'HP:0006775', (124, 140))	('multiple myeloma', 'Disease', 'MESH:D009101', (124, 140))	('multiple myeloma', 'Disease', (124, 140))	('association', 'Interaction', (14, 25))	('hematological malignancies', 'Phenotype', 'HP:0004377', (54, 80))	('leukemia', 'Phenotype', 'HP:0001909', (145, 153))	('polymorphisms', 'Var', (35, 48))	('PDCD1', 'Gene', '5133', (29, 34))	('PDCD1', 'Gene', (29, 34))
752225	33519815	According to Kasamatsu et al., none of the three investigated SNPs (PD-1.1, rs41386349, PD-1.9) individually were associated with multiple myeloma (MM).	('rs41386349', 'Mutation', 'rs41386349', (76, 86))	('multiple myeloma', 'Phenotype', 'HP:0006775', (130, 146))	('associated', 'Reg', (114, 124))	('MM', 'Disease', 'MESH:D009101', (148, 150))	('multiple myeloma', 'Disease', 'MESH:D009101', (130, 146))	('multiple myeloma', 'Disease', (130, 146))	('rs41386349', 'Var', (76, 86))
752226	33519815	However, the authors observed higher frequency of the haplotype combination (PD-1.1 rs41386349 PD-1.9/PD-1.1 rs41386349 PD-1.9) G C C/G C C in the group of MM patients (N = 124) as compared with controls (N = 211).	('rs41386349', 'Mutation', 'rs41386349', (109, 119))	('rs41386349', 'Var', (84, 94))	('higher', 'PosReg', (30, 36))	('rs41386349', 'Var', (109, 119))	('rs41386349', 'Mutation', 'rs41386349', (84, 94))	('patients', 'Species', '9606', (159, 167))	('MM', 'Disease', 'MESH:D009101', (156, 158))
752227	33519815	In the study by Grzywnowicz et al., no associations between five SNPs of PDCD1 (PD-1.1, PD-1.3, PD-1.5, PD-1.9, and rs41386349C>T) and susceptibility to chronic lymphocytic leukemia (CLL) were found in the group of 114 patients and 150 controls.	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (161, 181))	('patients', 'Species', '9606', (219, 227))	('rs41386349C>T', 'DBSNP_MENTION', 'None', (116, 129))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (153, 181))	('PDCD1', 'Gene', (73, 78))	('susceptibility', 'Reg', (135, 149))	('rs41386349C>T', 'Var', (116, 129))	('PDCD1', 'Gene', '5133', (73, 78))	('lymphocytic leukemia', 'Disease', (161, 181))	('leukemia', 'Phenotype', 'HP:0001909', (173, 181))
752228	33519815	reported the PD-1.9 C/T genotype as associated with a decreased risk of leukemia (OR = 0.43), however, taking into consideration the fact that only 59 leukemia patients (28 acute myeloid leukemia, 20 acute lymphocytic leukemia, 11 chronic myelogenous leukemia) and 46 controls were enrolled in this study, these results should be interpreted warily.	('leukemia', 'Disease', (218, 226))	('lymphocytic leukemia', 'Disease', (206, 226))	('leukemia', 'Phenotype', 'HP:0001909', (151, 159))	('myelogenous leukemia', 'Disease', (239, 259))	('leukemia', 'Phenotype', 'HP:0001909', (72, 80))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (231, 259))	('leukemia', 'Disease', 'MESH:D007938', (151, 159))	('myeloid leukemia', 'Disease', (179, 195))	('leukemia', 'Phenotype', 'HP:0001909', (251, 259))	('leukemia', 'Disease', (151, 159))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (200, 226))	('leukemia', 'Disease', (72, 80))	('leukemia', 'Disease', 'MESH:D007938', (72, 80))	('decreased', 'NegReg', (54, 63))	('leukemia', 'Phenotype', 'HP:0001909', (187, 195))	('C/T', 'Var', (20, 23))	('chronic', 'Disease', (231, 238))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (239, 259))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (206, 226))	('leukemia', 'Disease', (251, 259))	('leukemia', 'Disease', 'MESH:D007938', (251, 259))	('myeloid leukemia', 'Disease', 'MESH:D007951', (179, 195))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (179, 195))	('leukemia', 'Disease', (187, 195))	('leukemia', 'Disease', 'MESH:D007938', (187, 195))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (173, 195))	('leukemia', 'Phenotype', 'HP:0001909', (218, 226))	('patients', 'Species', '9606', (160, 168))	('PD-1.9', 'Var', (13, 19))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (239, 259))	('leukemia', 'Disease', 'MESH:D007938', (218, 226))
752231	33519815	carriage of PD-1.5*T allele was associated with decreased risk of lung cancer (OR = 0.84).	('PD-1.5*T', 'Var', (12, 20))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('decreased', 'NegReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
752235	33519815	According to our best knowledge, there are only individual articles regarding PDCD1 polymorphisms in relation to thyroid cancer, head and neck squamous cell carcinomas, brain tumor, cutaneous melanoma and basal cell carcinoma.	('PDCD1', 'Gene', (78, 83))	('brain tumor', 'Phenotype', 'HP:0030692', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (205, 225))	('brain tumor', 'Disease', (169, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('brain tumor', 'Disease', 'MESH:D001932', (169, 180))	('cutaneous melanoma', 'Disease', (182, 200))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (182, 200))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (182, 200))	('basal cell carcinoma', 'Disease', (205, 225))	('thyroid cancer', 'Disease', (113, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('head and neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (129, 167))	('thyroid cancer', 'Disease', 'MESH:D013964', (113, 127))	('polymorphisms', 'Var', (84, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (143, 167))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (205, 225))	('thyroid cancer', 'Phenotype', 'HP:0002890', (113, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('PDCD1', 'Gene', '5133', (78, 83))
752236	33519815	It was found that PD-1.5*T allele was associated with increased risk of thyroid and brain cancers, while PD-1.3*A allele with decrease risk of basal cell carcinoma.	('PD-1.5*T', 'Var', (18, 26))	('thyroid', 'Disease', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('brain cancers', 'Disease', 'MESH:D001932', (84, 97))	('brain cancers', 'Disease', (84, 97))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('PD-1.3*A', 'Var', (105, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (143, 163))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (143, 163))	('basal cell carcinoma', 'Disease', (143, 163))
752249	33519815	In silico analysis predicted that rs4143815G>C is situated in putative binding site for miR-7-1*, miR-495, miR-298 and miR-570.	('miR-570', 'Gene', (119, 126))	('miR-495', 'Gene', (98, 105))	('miR-495', 'Gene', '574453', (98, 105))	('miR-298', 'Gene', '100126296', (107, 114))	('rs4143815G>C', 'Var', (34, 46))	('miR-570', 'Gene', '693155', (119, 126))	('binding', 'Interaction', (71, 78))	('miR-298', 'Gene', (107, 114))	('miR-7-1', 'Gene', (88, 95))	('rs4143815G>C', 'DBSNP_MENTION', 'None', (34, 46))	('miR-7-1', 'Gene', '407043', (88, 95))
752250	33519815	in luciferase reporter assay rs4143815*G allele was associated with a higher expression of PD-L1 due to disruption of the miR-570 binding site, hence this allele may be considered as potential cancer risk factor.	('disruption', 'NegReg', (104, 114))	('expression', 'MPA', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('PD-L1', 'Gene', (91, 96))	('cancer', 'Disease', (193, 199))	('miR-570', 'Gene', (122, 129))	('binding site', 'Interaction', (130, 142))	('rs4143815', 'Mutation', 'rs4143815', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('higher', 'PosReg', (70, 76))	('rs4143815*G', 'Var', (29, 40))	('miR-570', 'Gene', '693155', (122, 129))
752251	33519815	rs2297136A>G is located in 3'UTR, in potential binding site for miR-296-5p and miR-324-5p.	('miR-324', 'Gene', '442898', (79, 86))	('miR-296', 'Gene', '407022', (64, 71))	('miR-324', 'Gene', (79, 86))	('rs2297136A>G', 'Var', (0, 12))	('rs2297136A>G', 'DBSNP_MENTION', 'None', (0, 12))	('miR-296', 'Gene', (64, 71))	('binding', 'Interaction', (47, 54))
752252	33519815	showed that the expression in constructs containing rs2297136*G allele was significantly inhibited by miR-296-5p.	('miR-296', 'Gene', (102, 109))	('inhibited', 'NegReg', (89, 98))	('miR-296', 'Gene', '407022', (102, 109))	('rs2297136*G', 'Var', (52, 63))	('rs2297136', 'Mutation', 'rs2297136', (52, 61))	('expression', 'MPA', (16, 26))
752253	33519815	From these data it can be concluded that rs2297136*G can be considered as protective allele in the context of cancer development, due to its association with decreased PD-L1 expression.	('cancer', 'Disease', (110, 116))	('decreased', 'NegReg', (158, 167))	('expression', 'MPA', (174, 184))	('rs2297136*G', 'Var', (41, 52))	('decreased PD', 'Phenotype', 'HP:0032198', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rs2297136', 'Mutation', 'rs2297136', (41, 50))	('PD-L1', 'Protein', (168, 173))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
752256	33519815	Moreover, PD-L1 mRNA expression was higher in rs10815225 G/G homozygous gastric cancer patients in comparison to patients with the rs10815225 G/C genotype.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('rs10815225 G/G', 'Var', (46, 60))	('higher', 'PosReg', (36, 42))	('patients', 'Species', '9606', (113, 121))	('rs10815225', 'Mutation', 'rs10815225', (131, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PD-L1', 'Gene', (10, 15))	('rs10815225', 'Mutation', 'rs10815225', (46, 56))	('patients', 'Species', '9606', (87, 95))	('gastric cancer', 'Disease', (72, 86))
752257	33519815	Based on that, it can be inferred that rs10815225*C may be associated with lower cancer risk, due to the lower PD-L1 expression.	('lower', 'NegReg', (105, 110))	('lower', 'NegReg', (75, 80))	('PD-L1', 'Protein', (111, 116))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('expression', 'MPA', (117, 127))	('cancer', 'Disease', (81, 87))	('rs10815225*C', 'Var', (39, 51))	('rs10815225', 'Mutation', 'rs10815225', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
752258	33519815	rs4742098A>G is located in 3'UTR, in the miR binding site.	('rs4742098A>G', 'Var', (0, 12))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (0, 12))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))
752259	33519815	According to literature data, the expression in constructs containing rs4742098*A allele was significantly suppressed by miR-138.	('expression', 'MPA', (34, 44))	('rs4742098*A', 'Var', (70, 81))	('suppressed', 'NegReg', (107, 117))	('rs4742098', 'Mutation', 'rs4742098', (70, 79))	('miR-138', 'Chemical', '-', (121, 128))	('miR-138', 'Var', (121, 128))
752260	33519815	The rs4742098*A allele may be considered as protective in cancers overexpressing miR-138, due to promotion of lower PD-L1 expression.	('miR-138', 'Gene', (81, 88))	('expression', 'MPA', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('miR-138', 'Chemical', '-', (81, 88))	('rs4742098*A', 'Var', (4, 15))	('promotion', 'PosReg', (97, 106))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('rs4742098', 'Mutation', 'rs4742098', (4, 13))	('lower', 'NegReg', (110, 115))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('PD-L1', 'Protein', (116, 121))	('cancers', 'Disease', (58, 65))
752263	33519815	A meta-analysis by Zou et al., including 11 articles (3,711 cases, 3,704 controls), revealed association between the rs4143815C>G and overall susceptibility to cancer, with increased risk for rs4143815*G allele carriers (OR = 1.28).	('association', 'Reg', (93, 104))	('rs4143815*G', 'Var', (192, 203))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('rs4143815', 'Mutation', 'rs4143815', (117, 126))	('cancer', 'Disease', (160, 166))	('rs4143815C>G', 'Var', (117, 129))	('rs4143815', 'Mutation', 'rs4143815', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rs4143815C>G', 'DBSNP_MENTION', 'None', (117, 129))	('susceptibility', 'Reg', (142, 156))
752264	33519815	investigated the rs2890658C>A, however no evidence of association between this polymorphism and overall cancer risk was found.	('rs2890658C>A', 'DBSNP_MENTION', 'None', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs2890658C>A', 'Var', (17, 29))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
752266	33519815	Similarly, as in the case of overall cancer risk, increased susceptibility to ovarian cancer was observed for carriers of rs4143815*G allele (OR = 2.00) in the study performed on 164 patients and 170 control subjects.	('rs4143815*G', 'Var', (122, 133))	('susceptibility', 'Reg', (60, 74))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('ovarian cancer', 'Disease', 'MESH:D010051', (78, 92))	('cancer', 'Disease', (37, 43))	('rs4143815', 'Mutation', 'rs4143815', (122, 131))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ovarian cancer', 'Disease', (78, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('patients', 'Species', '9606', (183, 191))	('cancer', 'Disease', (86, 92))
752267	33519815	The carriers of rs4143815*G allele showed also higher differentiation grade.	('rs4143815', 'Mutation', 'rs4143815', (16, 25))	('higher', 'PosReg', (47, 53))	('differentiation grade', 'CPA', (54, 75))	('rs4143815*G', 'Var', (16, 27))
752268	33519815	(pooling gastrointestinal cancers together) revealed lower risk of gastrointestinal cancer for rs4143815*C allele carriers (OR = 0.64) (higher for rs4143815 G/G genotype), while no evidence of association was found for rs2890658A>C.	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (9, 33))	('rs2890658A>C', 'DBSNP_MENTION', 'None', (219, 231))	('rs2890658A>C', 'Var', (219, 231))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('gastrointestinal cancers', 'Disease', (9, 33))	('rs4143815 G/G', 'Var', (147, 160))	('gastrointestinal cancer', 'Disease', (67, 90))	('rs4143815', 'Mutation', 'rs4143815', (95, 104))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (67, 90))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (9, 32))	('rs4143815', 'Mutation', 'rs4143815', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (67, 90))	('rs4143815*C', 'Var', (95, 106))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (9, 32))	('lower', 'NegReg', (53, 58))
752270	33519815	examined two polymorphisms of PD-L1: rs2890658A>C and rs4143815C>G (575 patients, 577 controls) and found association only for rs2890658A>C in smokers.	('rs4143815C>G', 'DBSNP_MENTION', 'None', (54, 66))	('rs2890658A>C', 'Var', (37, 49))	('PD-L1', 'Gene', (30, 35))	('association', 'Reg', (106, 117))	('rs2890658A>C', 'DBSNP_MENTION', 'None', (37, 49))	('rs4143815C>G', 'Var', (54, 66))	('rs2890658A>C', 'Var', (127, 139))	('rs2890658A>C', 'DBSNP_MENTION', 'None', (127, 139))	('patients', 'Species', '9606', (72, 80))
752271	33519815	In this subgroup the rs2890658 A/C genotype seemed to increase the risk of ESCC (OR = 1.51).	('rs2890658 A/C', 'Var', (21, 34))	('ESCC', 'Disease', (75, 79))	('rs2890658', 'Mutation', 'rs2890658', (21, 30))
752273	33519815	Both of them were included in the above mentioned subgroup analysis performed by Hashemi et al.. Of the two polymorphisms (rs2297136A>G and rs4143815C>G) examined by Wang et al.	('rs4143815C>G', 'DBSNP_MENTION', 'None', (140, 152))	('rs2297136A>G', 'Var', (123, 135))	('rs2297136A>G', 'DBSNP_MENTION', 'None', (123, 135))	('rs4143815C>G', 'Var', (140, 152))
752274	33519815	on the group of 205 patients and 393 controls, only rs4143815C>G was reported as associated with susceptibility to GC, with the rs4143815 G/G genotype increasing risk (over 3.5-fold, OR = 3.73).	('rs4143815C>G', 'Var', (52, 64))	('increasing', 'PosReg', (151, 161))	('patients', 'Species', '9606', (20, 28))	('rs4143815', 'Mutation', 'rs4143815', (52, 61))	('rs4143815 G/G', 'Var', (128, 141))	('rs4143815C>G', 'DBSNP_MENTION', 'None', (52, 64))	('rs4143815', 'Mutation', 'rs4143815', (128, 137))
752275	33519815	In an extended study carried out by the same research team (350 patients, 500 subjects) the association of rs4143815C>G was confirmed, however this study revealed that the presence of one rs4143815*G allele was sufficient to cause an increased risk of gastric cancer (OR = 1.86).	('rs4143815*G', 'Var', (188, 199))	('rs4143815C>G', 'Var', (107, 119))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('gastric cancer', 'Disease', (252, 266))	('rs4143815', 'Mutation', 'rs4143815', (188, 197))	('gastric cancer', 'Disease', 'MESH:D013274', (252, 266))	('rs4143815', 'Mutation', 'rs4143815', (107, 116))	('rs4143815C>G', 'DBSNP_MENTION', 'None', (107, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (252, 266))
752276	33519815	the association between rs10815225G>C and GC was observed.	('rs10815225G>C', 'DBSNP_MENTION', 'None', (24, 37))	('association', 'Reg', (4, 15))	('rs10815225G>C', 'Var', (24, 37))
752277	33519815	The presence of rs10815225*C allele decreased the risk of GC (OR = 0.60).	('rs10815225*C', 'Var', (16, 28))	('rs10815225', 'Mutation', 'rs10815225', (16, 26))	('decreased', 'NegReg', (36, 45))
752278	33519815	It is worth noting that in this study was stated that both rs4143815C>G and rs10815225G>C were in HWE, however it can be calculated that for both of SNPs deviations from HWE exist in controls.	('rs10815225G>C', 'Var', (76, 89))	('rs4143815C>G', 'Var', (59, 71))	('rs4143815C>G', 'DBSNP_MENTION', 'None', (59, 71))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (76, 89))
752279	33519815	Also, in the case of HCC, the evaluation of potential associations between polymorphisms of PD-L1 (rs2297136A>G, rs4143815C>G, rs2890658A>C, rs17718883C>G) and risk of developing this type of cancer was conducted (225 patients, 200 controls).	('rs4143815C>G', 'DBSNP_MENTION', 'None', (113, 125))	('patients', 'Species', '9606', (218, 226))	('PD-L1', 'Gene', (92, 97))	('rs2297136A>G', 'Var', (99, 111))	('rs17718883C>G', 'DBSNP_MENTION', 'None', (141, 154))	('rs17718883C>G', 'Var', (141, 154))	('cancer', 'Disease', (192, 198))	('rs4143815C>G', 'Var', (113, 125))	('rs2890658A>C', 'Var', (127, 139))	('rs2297136A>G', 'DBSNP_MENTION', 'None', (99, 111))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('rs2890658A>C', 'DBSNP_MENTION', 'None', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
752280	33519815	The results of this study indicated an association between rs2297136 A/A as well as rs4143815 G/G genotypes and increased risk of HCC (OR = 1.44 and OR = 1.62, respectively), while a decreased risk of HCC was observed for carriers of minor rs17718883*G allele (OR = 0.15).	('rs4143815', 'Mutation', 'rs4143815', (84, 93))	('rs2297136 A/A', 'Var', (59, 72))	('HCC', 'Disease', (130, 133))	('rs2297136', 'Mutation', 'rs2297136', (59, 68))	('rs4143815 G/G', 'Var', (84, 97))	('rs17718883', 'Mutation', 'rs17718883', (240, 250))
752281	33519815	Since the frequency of alleles at rs2297136A>G polymorphic site in databases (Ensembl and dbSNP) for all populations (including Asian) is opposite to that presented in the article i.e., the minor allele at rs2297136 is the G allele (not A), the results described by Xie et al.	('rs2297136A>G', 'Var', (34, 46))	('rs2297136A>G', 'DBSNP_MENTION', 'None', (34, 46))	('rs2297136', 'Var', (206, 215))	('rs2297136', 'Mutation', 'rs2297136', (34, 43))	('rs2297136', 'Mutation', 'rs2297136', (206, 215))
752282	33519815	An attempt to find evidence on a potential association between PD-L1 genetic variations (rs2890657G>C, rs822338T>C, rs10815225G>C, rs4143815C>G, rs866066C>T) and another type of gastrointestinal cancer:colorectal cancer, was made by Catalano et al.	('rs822338T>C', 'Var', (103, 114))	('colorectal cancer', 'Disease', (202, 219))	('rs4143815C>G', 'Var', (131, 143))	('PD-L1', 'Gene', (63, 68))	('rs4143815C>G', 'DBSNP_MENTION', 'None', (131, 143))	('rectal cancer', 'Phenotype', 'HP:0100743', (206, 219))	('rs2890657G>C', 'Var', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('rs2890657G>C', 'DBSNP_MENTION', 'None', (89, 101))	('rs10815225G>C', 'Var', (116, 129))	('rs866066C>T', 'DBSNP_MENTION', 'None', (145, 156))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (178, 201))	('rs866066C>T', 'Var', (145, 156))	('gastrointestinal cancer', 'Disease', (178, 201))	('rs822338T>C', 'DBSNP_MENTION', 'None', (103, 114))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (116, 129))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (178, 201))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))
752287	33519815	], including 3 articles, (1,109 cases and 1,193 controls), the association between rs2890658A>C and NSCLC was revealed.	('rs2890658A>C', 'Var', (83, 95))	('NSCLC', 'Disease', (100, 105))	('rs2890658A>C', 'DBSNP_MENTION', 'None', (83, 95))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('association', 'Reg', (63, 74))
752288	33519815	According to this analysis, carriers of the rs2890658*C allele possessed more than 1.5-fold higher susceptibility to NSCLC (OR = 1.77) in comparison to individuals with the rs2890658 A/A genotype.	('NSCLC', 'Disease', (117, 122))	('higher', 'PosReg', (92, 98))	('rs2890658', 'Mutation', 'rs2890658', (173, 182))	('rs2890658', 'Mutation', 'rs2890658', (44, 53))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('rs2890658*C', 'Var', (44, 55))
752289	33519815	that NSCLC patients carrying rs2890658*C allele had increased risk of regional LN metastasis as compared to individuals with rs2890658 A/A genotype (OR = 5.65).	('rs2890658', 'Mutation', 'rs2890658', (29, 38))	('rs2890658*C', 'Var', (29, 40))	('NSCLC', 'Disease', (5, 10))	('regional LN metastasis', 'CPA', (70, 92))	('patients', 'Species', '9606', (11, 19))	('rs2890658', 'Mutation', 'rs2890658', (125, 134))	('NSCLC', 'Disease', 'MESH:D002289', (5, 10))
752290	33519815	However, all the aforementioned results concerning NSCLC should be treated cautiously since the frequency of alleles at rs2890658 in databases (Ensembl and dbSNP) for all populations (including Asian) as well as in the study by Zhou et al.	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('rs2890658', 'Mutation', 'rs2890658', (120, 129))	('NSCLC', 'Disease', (51, 56))	('rs2890658', 'Var', (120, 129))
752292	33519815	Additionally, three SNPs in 3'UTR of PD-L1 (rs4143815C>G, rs2297136A>G, and rs4742098A>G) were examined in NSCLC in the study performed on 320 patients and 199 control individuals by Du et al..	('rs4742098A>G', 'Var', (76, 88))	('rs2297136A>G', 'DBSNP_MENTION', 'None', (58, 70))	('rs4143815C>G', 'DBSNP_MENTION', 'None', (44, 56))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (76, 88))	('PD-L1', 'Gene', (37, 42))	('NSCLC', 'Disease', (107, 112))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('patients', 'Species', '9606', (143, 151))	('rs4143815C>G', 'Var', (44, 56))	('rs2297136A>G', 'Var', (58, 70))
752293	33519815	In the case of 2297136A>G and rs4742098A>G, significant differences in genotype distribution between cases and controls were found.	('2297136A>G', 'Var', (15, 25))	('2297136A>G', 'Mutation', 'g.2297136A>G', (15, 25))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (30, 42))	('rs4742098A>G', 'Var', (30, 42))	('differences', 'Reg', (56, 67))
752294	33519815	Increased risk of NSCLC was noted for rs2297136 A/G (OR = 2.29) as well as for rs4742098 A/G heterozygotes (OR = 1.60).	('NSCLC', 'Disease', (18, 23))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('rs2297136', 'Mutation', 'rs2297136', (38, 47))	('rs4742098 A/G', 'Var', (79, 92))	('rs4742098', 'Mutation', 'rs4742098', (79, 88))	('rs2297136 A/G', 'Var', (38, 51))
752295	33519815	Furthermore, from this study it can be concluded that individuals with rs2297136 G/G genotype were less likely to exhibit LN metastasis (OR = 0.27) and more likely to exhibit distant metastasis (OR = 3.83) in comparison to subject with the rs2297136 A/A genotype.	('LN metastasis', 'CPA', (122, 135))	('rs2297136 G/G', 'Var', (71, 84))	('rs2297136', 'Mutation', 'rs2297136', (71, 80))	('less', 'NegReg', (99, 103))	('distant metastasis', 'CPA', (175, 193))	('rs2297136', 'Mutation', 'rs2297136', (240, 249))	('exhibit', 'Reg', (167, 174))	('more', 'PosReg', (152, 156))
752296	33519815	In case of rs4742098A>G, carriers of rs4742098*G allele had greater depth of tumor infiltration as compared to individuals with rs4742098 A/A (OR = 2.30).	('rs4742098A>G', 'DBSNP_MENTION', 'None', (11, 23))	('rs4742098', 'Mutation', 'rs4742098', (11, 20))	('rs4742098', 'Mutation', 'rs4742098', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('rs4742098A>G', 'Var', (11, 23))	('greater', 'PosReg', (60, 67))	('tumor', 'Disease', (77, 82))	('rs4742098*G', 'Var', (37, 48))	('rs4742098', 'Mutation', 'rs4742098', (128, 137))
752297	33519815	Taking into consideration the fact that this is the only study considering 3'UTR polymorphisms and NSCLC, further investigations are needed (especially since in this study deviations from HWE in control group existed for rs2297136A>G and rs4143815C>G, although in the manuscript is stated otherwise).	('rs4143815C>G', 'DBSNP_MENTION', 'None', (238, 250))	('rs2297136A>G', 'Var', (221, 233))	('rs2297136A>G', 'DBSNP_MENTION', 'None', (221, 233))	('rs4143815C>G', 'Var', (238, 250))	('NSCLC', 'Disease', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
752298	33519815	Although rs4143815G>C did not show the association with NSCLC risk and progression in the aforementioned study by Du et al.	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('NSCLC', 'Disease', (56, 61))	('rs4143815G>C', 'DBSNP_MENTION', 'None', (9, 21))	('rs4143815G>C', 'Var', (9, 21))
752299	33519815	(on 354 NSCLC patients) that individuals with rs4143815 G/G genotype (G allele is a minor allele in Korean population) had shorter overall survival as compared to rs4143815*C allele carriers.	('shorter', 'NegReg', (123, 130))	('overall survival', 'MPA', (131, 147))	('NSCLC', 'Disease', (8, 13))	('rs4143815', 'Mutation', 'rs4143815', (46, 55))	('rs4143815 G/G', 'Var', (46, 59))	('patients', 'Species', '9606', (14, 22))	('NSCLC', 'Disease', 'MESH:D002289', (8, 13))	('rs4143815', 'Mutation', 'rs4143815', (163, 172))
752300	33519815	Similar effect was also observed for two promoter polymorphisms of PD-L1 gene:rs822336G>C and rs822337T>A.	('rs822336G>C', 'Var', (78, 89))	('rs822337T>A', 'Var', (94, 105))	('rs822336G>C', 'SUBSTITUTION', 'None', (78, 89))	('PD-L1', 'Gene', (67, 72))	('rs822337T>A', 'DBSNP_MENTION', 'None', (94, 105))
752301	33519815	In details, subjects with rs822336 C/C as well as subjects with rs822337 A/A genotypes showed shorter overall survival as compared to rs822336*G and rs822337*T allele carriers, respectively.	('rs822337', 'Mutation', 'rs822337', (64, 72))	('rs822336', 'Mutation', 'rs822336', (26, 34))	('rs822336', 'Mutation', 'rs822336', (134, 142))	('shorter', 'NegReg', (94, 101))	('rs822336 C/C', 'Var', (26, 38))	('rs822337 A/A', 'Var', (64, 76))	('overall survival', 'MPA', (102, 118))	('rs822337', 'Mutation', 'rs822337', (149, 157))
752302	33519815	The above described associations between PD-L1 polymorphisms and cancer risk are summarized in  Supplementary Table 3 .	('polymorphisms', 'Var', (47, 60))	('PD-L1', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
752315	33519815	Similarly, to T and B lymphocytes, BTLA is expressed by NKT cells, and its expression inhibits cytokine (IL-2, IL4, and IFN-gamma) secretion.	('inhibits', 'NegReg', (86, 94))	('expression', 'Var', (75, 85))	('IL4', 'Gene', '3565', (111, 114))	('IL4', 'Gene', (111, 114))	('IFN-gamma', 'Gene', (120, 129))	('IFN-gamma', 'Gene', '3458', (120, 129))	('IL-2', 'Gene', '3558', (105, 109))	('IL-2', 'Gene', (105, 109))	('BTLA', 'Gene', (35, 39))
752316	33519815	Moreover, it was shown on mice models of breast cancer that blocking of BTLA pathway promotes the anticancer activity of NKT cells, which infiltrate tumors and inhibit tumor growth.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('inhibit', 'NegReg', (160, 167))	('infiltrate', 'PosReg', (138, 148))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('promotes', 'PosReg', (85, 93))	('tumors', 'Disease', (149, 155))	('BTLA', 'Gene', (72, 76))	('blocking', 'Var', (60, 68))	('tumor', 'Disease', (168, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('cancer', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mice', 'Species', '10090', (26, 30))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (41, 54))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
752318	33519815	At the beginning in literature, there were only a few studies that addressed BTLA gene polymorphisms, and majority of them have investigated its role in susceptibility to autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes mellitus.	('SLE', 'Disease', (257, 260))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (227, 255))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (266, 281))	('diabetes mellitus', 'Disease', 'MESH:D003920', (273, 290))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (227, 255))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (200, 220))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (273, 290))	('RA', 'Disease', 'MESH:D001172', (222, 224))	('polymorphisms', 'Var', (87, 100))	('arthritis', 'Phenotype', 'HP:0001369', (211, 220))	('rheumatoid arthritis', 'Disease', (200, 220))	('autoimmune diseases', 'Disease', 'MESH:D001327', (171, 190))	('BTLA', 'Gene', (77, 81))	('systemic lupus erythematosus', 'Disease', (227, 255))	('autoimmune diseases', 'Disease', (171, 190))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (171, 190))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (200, 220))	('diabetes mellitus', 'Disease', (273, 290))	('SLE', 'Disease', 'MESH:D008180', (257, 260))
752319	33519815	Below we described the most intensively examined genetic variants of BTLA in human diseases together with their functional relevance, if such data were available in literature.	('variants', 'Var', (57, 65))	('BTLA', 'Gene', (69, 73))	('human', 'Species', '9606', (77, 82))
752320	33519815	rs1844089C>T (G>A REV) and rs2705535C>T (G>A REV) are located in first intron, the exact functional role of these SNPs was not established yet, however Ge at al.	('rs1844089C>T', 'DBSNP_MENTION', 'None', (0, 12))	('rs1844089C>T', 'Var', (0, 12))	('rs2705535C>T', 'DBSNP_MENTION', 'None', (27, 39))	('rs2705535C>T', 'Var', (27, 39))
752321	33519815	postulated that rs2705535 may affect splicing of BTLA gene.	('splicing', 'MPA', (37, 45))	('rs2705535', 'Var', (16, 25))	('affect', 'Reg', (30, 36))	('rs2705535', 'Mutation', 'rs2705535', (16, 25))	('BTLA gene', 'Gene', (49, 58))
752323	33519815	postulate based on the human splicing finder software analysis, that rs9288953*T allele may potentially activate six new splice sites in splicing enhancer motifs and break one splicing sites in the silencer motif and in this way may perhaps promote higher BTLA expression.	('splice sites', 'MPA', (121, 133))	('silencer motif', 'Disease', 'None', (198, 212))	('silencer motif', 'Disease', (198, 212))	('break one', 'NegReg', (166, 175))	('activate', 'PosReg', (104, 112))	('promote', 'PosReg', (241, 248))	('rs9288953*T', 'Var', (69, 80))	('human', 'Species', '9606', (23, 28))	('rs9288953', 'Mutation', 'rs9288953', (69, 78))	('higher BTLA expression', 'MPA', (249, 271))
752324	33519815	rs76844316T>G (BTLAc.590A>C REV) is located in exon 4, and leads to the exchange of asparagine to threonine at position 197 in the intracellular domain.	('asparagine to threonine at position 197', 'Mutation', 'rs76844316', (84, 123))	('leads to', 'Reg', (59, 67))	('c.590A>C', 'SUBSTITUTION', 'None', (19, 27))	('asparagine to threonine', 'MPA', (84, 107))	('rs76844316T>G', 'Var', (0, 13))	('rs76844316T>G', 'DBSNP_MENTION', 'None', (0, 13))	('exchange', 'Var', (72, 80))	('c.590A>C', 'Var', (19, 27))
752325	33519815	Oki and colleagues performed in vitro study in order to evaluate functional relevance of BTLAc.590A>C in Jurkat T cells transfected with construct with BTLAc.590*A or BTLAc.590*C allele.	('BTLAc.590*C', 'Var', (167, 178))	('Jurkat T', 'CellLine', 'CVCL:0065', (105, 113))	('BTLAc.590*A', 'Var', (152, 163))	('c.590A>C', 'SUBSTITUTION', 'None', (93, 101))	('c.590A>C', 'Var', (93, 101))
752326	33519815	Stimulation of infected Jurkat cells with concanavalin A (ConA) indicated that IL-2 production was strongly inhibited in cells expressing BTLA with BTLAc.590*A, whereas in cells with BTLAc.590*C the IL-2 production was enhanced.	('IL-2', 'Gene', '3558', (199, 203))	('infected', 'Disease', (15, 23))	('IL-2', 'Gene', (199, 203))	('IL-2', 'Gene', '3558', (79, 83))	('enhanced', 'PosReg', (219, 227))	('IL-2', 'Gene', (79, 83))	('BTLAc.590*A', 'Var', (148, 159))	('infected', 'Disease', 'MESH:D007239', (15, 23))	('Jurkat', 'CellLine', 'CVCL:0065', (24, 30))	('inhibited', 'NegReg', (108, 117))
752328	33519815	The authors suggest that BTLAc.590*C had not ability to inhibit IL-2 production by Jurkat cells.	('BTLAc.590', 'Var', (25, 34))	('Jurkat', 'CellLine', 'CVCL:0065', (83, 89))	('IL-2', 'Gene', (64, 68))	('IL-2', 'Gene', '3558', (64, 68))	('inhibit', 'NegReg', (56, 63))
752329	33519815	Even though the amino acid exchange is not within the ITIM motifs of BTLA, it is hypothesized that this substitution may alter the posttranslational modifications of BTLA, such as glycosylation of asparagine, or phosphorylation of threonine by serine/threonine kinase, which may influence the strength of BTLA signaling by SHP1/SHP2.	('posttranslational modifications', 'MPA', (131, 162))	('phosphorylation of threonine', 'MPA', (212, 240))	('threonine', 'Chemical', 'MESH:D013912', (251, 260))	('BTLA signaling', 'MPA', (305, 319))	('SHP2', 'Gene', (328, 332))	('SHP1', 'Gene', (323, 327))	('SHP1', 'Gene', '8431', (323, 327))	('threonine', 'Chemical', 'MESH:D013912', (231, 240))	('strength', 'MPA', (293, 301))	('serine', 'Chemical', 'MESH:D012694', (244, 250))	('asparagine', 'Chemical', 'MESH:D001216', (197, 207))	('SHP2', 'Gene', '5781', (328, 332))	('substitution', 'Var', (104, 116))	('influence', 'Reg', (279, 288))	('glycosylation of asparagine', 'MPA', (180, 207))	('alter', 'Reg', (121, 126))
752330	33519815	Hence, BTLAc.590*A allele was associated with decreased inhibitory activity of BTLA in Jurkat cells it may potentially constitute cancer risk factor.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('BTLAc.590*A', 'Var', (7, 18))	('cancer', 'Disease', (130, 136))	('Jurkat', 'CellLine', 'CVCL:0065', (87, 93))	('inhibitory activity', 'MPA', (56, 75))	('decreased', 'NegReg', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
752331	33519815	rs9288952T>C (BTLAc.800G>A REV) is a non-synonymous SNP causing an amino acid substitution from proline to leucine at position 267 in exon 5, which was initially described as associated with susceptibility to RA.	('c.800G>A', 'SUBSTITUTION', 'None', (18, 26))	('rs9288952T>C', 'DBSNP_MENTION', 'None', (0, 12))	('c.800G>A', 'Var', (18, 26))	('rs9288952T>C', 'Var', (0, 12))	('RA', 'Disease', 'MESH:D001172', (209, 211))	('proline to leucine at position 267', 'Mutation', 'rs9288952', (96, 130))
752334	33519815	However, it was shown that the presence of rs1982809*C allele was associated with lower mRNA expression level of BTLA in the subset of T cells of the CLL patients.	('mRNA expression level of BTLA', 'MPA', (88, 117))	('patients', 'Species', '9606', (154, 162))	('rs1982809', 'Mutation', 'rs1982809', (43, 52))	('rs1982809*C', 'Var', (43, 54))	('lower', 'NegReg', (82, 87))
752335	33519815	Although, it can be postulated that BTLA rs1982809*T allele may confer increased susceptibility to cancer development, the published already data indicated that C allele confers susceptibility to several cancers (CLL, renal and lung cancer).	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('rs1982809', 'Mutation', 'rs1982809', (41, 50))	('CLL', 'Disease', (213, 216))	('rs1982809*T', 'Var', (41, 52))	('susceptibility', 'Reg', (178, 192))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Disease', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))	('renal and lung cancer', 'Disease', 'MESH:D008175', (218, 239))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('susceptibility', 'MPA', (81, 95))
752336	33519815	rs2705511A>C is located in the intragenic region between genes encoding CD200 and BTLA (-97820bp  -3334bp).	('rs2705511A>C', 'DBSNP_MENTION', 'None', (0, 12))	('-97820bp  -3334bp', 'Var', (88, 105))	('CD200', 'Gene', '4345', (72, 77))	('rs2705511A>C', 'Var', (0, 12))	('CD200', 'Gene', (72, 77))
752337	33519815	Rs2705511 and rs1982809 are in moderate linkage disequilibrium with each other.	('Rs2705511', 'Var', (0, 9))	('rs1982809', 'Var', (14, 23))	('rs1982809', 'Mutation', 'rs1982809', (14, 23))
752339	33519815	Five SNPs of BTLA gene: rs1844089C>T, rs2705535C>T, rs2633562T>C, rs2931761T>G, and rs9288952A>G were investigated in Chinese women (592 patients, 506 controls) in relation to malignant BC risk.	('rs2705535C>T', 'Var', (38, 50))	('rs2931761T>G', 'Var', (66, 78))	('rs2633562T>C', 'Var', (52, 64))	('BTLA', 'Gene', (13, 17))	('rs1844089C>T', 'DBSNP_MENTION', 'None', (24, 36))	('rs2705535C>T', 'DBSNP_MENTION', 'None', (38, 50))	('patients', 'Species', '9606', (137, 145))	('rs9288952A>G', 'Var', (84, 96))	('women', 'Species', '9606', (126, 131))	('rs2931761T>G', 'DBSNP_MENTION', 'None', (66, 78))	('rs1844089C>T', 'Var', (24, 36))	('rs2633562T>C', 'DBSNP_MENTION', 'None', (52, 64))	('rs9288952A>G', 'DBSNP_MENTION', 'None', (84, 96))
752340	33519815	It was found that rs1844089 C/T and rs2705535 C/T genotypes increased the risk of BC 1.3 and 1.5 times respectively, while rs1844089 C/C genotype rs2705535 C/C genotype and rs9288952 G/G genotypes conferred 1.3, 1.4, and 1.7 times lower risk of BC, respectively.	('rs1844089 C/C', 'Var', (123, 136))	('rs9288952 G/G', 'Var', (173, 186))	('rs2705535 C/C', 'Var', (146, 159))	('rs1844089 C/T', 'Var', (18, 31))	('rs2705535', 'Mutation', 'rs2705535', (146, 155))	('rs1844089', 'Mutation', 'rs1844089', (123, 132))	('rs1844089', 'Mutation', 'rs1844089', (18, 27))	('rs9288952', 'Mutation', 'rs9288952', (173, 182))	('rs2705535 C/T', 'Var', (36, 49))	('rs2705535', 'Mutation', 'rs2705535', (36, 45))	('increased', 'PosReg', (60, 69))
752341	33519815	Moreover, the haplotype (rs9288952, rs2931761, rs2633562, rs2705535, rs1844089) GTTTT was associated with the three times increased risk of BC in this population.	('GTTTT', 'Gene', (80, 85))	('rs9288952', 'Mutation', 'rs9288952', (25, 34))	('rs2705535', 'Mutation', 'rs2705535', (58, 67))	('rs2633562', 'Mutation', 'rs2633562', (47, 56))	('rs2931761', 'Var', (36, 45))	('rs1844089', 'Mutation', 'rs1844089', (69, 78))	('rs2705535', 'Var', (58, 67))	('rs9288952', 'Var', (25, 34))	('rs2931761', 'Mutation', 'rs2931761', (36, 45))	('rs1844089', 'Var', (69, 78))	('rs2633562', 'Var', (47, 56))
752342	33519815	The frequency of rs1844089 C/T genotype was higher in patients with tumor size over 5 cm, while (rs9288952, rs2931761, rs2633562, rs2705535, rs1844089) GTCTC haplotype was significantly more frequent in patients with metastasis to LNs.	('rs2705535', 'Var', (130, 139))	('patients', 'Species', '9606', (54, 62))	('rs1844089', 'Mutation', 'rs1844089', (17, 26))	('rs2633562', 'Mutation', 'rs2633562', (119, 128))	('rs9288952', 'Var', (97, 106))	('rs1844089', 'Var', (141, 150))	('frequent', 'Reg', (191, 199))	('tumor', 'Disease', (68, 73))	('rs2633562', 'Var', (119, 128))	('rs9288952', 'Mutation', 'rs9288952', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('patients', 'Species', '9606', (203, 211))	('rs2931761', 'Var', (108, 117))	('rs1844089', 'Mutation', 'rs1844089', (141, 150))	('rs2705535', 'Mutation', 'rs2705535', (130, 139))	('rs1844089 C/T', 'Var', (17, 30))	('higher', 'PosReg', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('metastasis', 'CPA', (217, 227))	('rs2931761', 'Mutation', 'rs2931761', (108, 117))
752343	33519815	Association between four BTLA SNPs (rs16859629T>C, rs1982809A>G, rs2171513G>A, and rs3112270T>C) and esophageal squamous cell carcinoma was investigated by Cao et al.	('rs3112270T>C', 'DBSNP_MENTION', 'None', (83, 95))	('rs2171513G>A', 'DBSNP_MENTION', 'None', (65, 77))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (101, 135))	('rs2171513G>A', 'Var', (65, 77))	('rs3112270T>C', 'Var', (83, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('rs16859629T>C', 'DBSNP_MENTION', 'None', (36, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('rs16859629T>C', 'Var', (36, 49))	('rs1982809A>G', 'DBSNP_MENTION', 'None', (51, 63))	('esophageal squamous cell carcinoma', 'Disease', (101, 135))	('rs1982809A>G', 'Var', (51, 63))
752345	33519815	However, it was shown that T/C genotype of rs3112270T>C slightly lowered (1.2 times) risk of ESCC development in males.	('ESCC development', 'Disease', (93, 109))	('lowered', 'NegReg', (65, 72))	('rs3112270T>C', 'Var', (43, 55))	('rs3112270T>C', 'DBSNP_MENTION', 'None', (43, 55))
752346	33519815	In a stratified analysis by age, BMI, smoking status, and alcohol consumption it was noticed that rs3112270 T/C genotype may protect lean individuals with BMI<24 from ESCC (T/C vs. T/T; OR = 0.72).	('rs3112270 T/C', 'Var', (98, 111))	('ESCC', 'Disease', (167, 171))	('protect', 'Reg', (125, 132))	('alcohol', 'Chemical', 'MESH:D000438', (58, 65))	('rs3112270', 'Mutation', 'rs3112270', (98, 107))
752348	33519815	Additionally, the G/A genotype of rs2171513G>A (G/A vs. A/A) was associated with lower risk of ESCC (OR = 0.61) in individuals', who overused alcohol.	('rs2171513G>A', 'DBSNP_MENTION', 'None', (34, 46))	('lower', 'NegReg', (81, 86))	('ESCC', 'Disease', (95, 99))	('rs2171513G>A', 'Var', (34, 46))	('alcohol', 'Chemical', 'MESH:D000438', (142, 149))
752349	33519815	examined relationship between BTLA SNPs (rs16859629T>C, rs1982809A>G, rs2171513G>A, and rs3112270T>C) and EGJA risk in 1,234 patients and 1,540 control subjects.	('rs16859629T>C', 'Var', (41, 54))	('rs2171513G>A', 'DBSNP_MENTION', 'None', (70, 82))	('rs1982809A>G', 'Var', (56, 68))	('BTLA SNPs', 'Gene', (30, 39))	('rs2171513G>A', 'Var', (70, 82))	('rs3112270T>C', 'DBSNP_MENTION', 'None', (88, 100))	('EGJA', 'Disease', (106, 110))	('rs3112270T>C', 'Var', (88, 100))	('rs1982809A>G', 'DBSNP_MENTION', 'None', (56, 68))	('rs16859629T>C', 'DBSNP_MENTION', 'None', (41, 54))	('patients', 'Species', '9606', (125, 133))
752350	33519815	However, haplotype analysis revealed that haplotype (rs16859629, rs1982809, rs2171513, rs31122708) TAAG increased three times risk of EGJA development.	('rs16859629', 'Mutation', 'rs16859629', (53, 63))	('rs1982809', 'Mutation', 'rs1982809', (65, 74))	('rs2171513', 'Var', (76, 85))	('rs31122708', 'Var', (87, 97))	('rs31122708', 'Mutation', 'rs31122708', (87, 97))	('rs16859629', 'Var', (53, 63))	('rs1982809', 'Var', (65, 74))	('rs2171513', 'Mutation', 'rs2171513', (76, 85))	('EGJA development', 'CPA', (134, 150))	('TAAG', 'Chemical', '-', (99, 103))
752351	33519815	Moreover, after adjustment for gender, age, alcohol consumption and smoking, the A/A genotype of rs1982809A>G was associated with two times higher risk of EGJA in heavy smokers.	('rs1982809A>G', 'Var', (97, 109))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('EGJA', 'Disease', (155, 159))	('rs1982809A>G', 'DBSNP_MENTION', 'None', (97, 109))
752352	33519815	As mentioned previously Ge and coworkers analyzed association between SNPs of genes encoding co-inhibitory molecules such as CTLA-4, PD-1 and BTLA and CRC risk (601 patients, 627 controls).	('CTLA-4', 'Gene', (125, 131))	('BTLA', 'Gene', (142, 146))	('patients', 'Species', '9606', (165, 173))	('association', 'Interaction', (50, 61))	('SNPs', 'Var', (70, 74))	('PD-1', 'Gene', (133, 137))
752353	33519815	Three SNPs within the BTLA gene were investigated: rs1844089G>A, rs2705535C>T, and 9288953C>T.	('BTLA', 'Gene', (22, 26))	('9288953C>T', 'Var', (83, 93))	('rs2705535C>T', 'DBSNP_MENTION', 'None', (65, 77))	('rs2705535C>T', 'Var', (65, 77))	('9288953C>T', 'Mutation', 'g.9288953C>T', (83, 93))	('rs1844089G>A', 'Var', (51, 63))	('rs1844089G>A', 'DBSNP_MENTION', 'None', (51, 63))
752354	33519815	The T/T genotype of rs2705535C>T was associated with 2 times increased risk of rectal cancer development (in comparison to C/T+C/C), while the presence of rs9288953 T/T genotype decreased 1.4 times the risk of rectal cancer (in comparison to C/T+C/C).	('rs2705535C>T', 'Var', (20, 32))	('rs2705535C>T', 'DBSNP_MENTION', 'None', (20, 32))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('rs9288953', 'Mutation', 'rs9288953', (155, 164))	('rectal cancer', 'Phenotype', 'HP:0100743', (79, 92))	('rs9288953', 'Var', (155, 164))	('rectal cancer', 'Phenotype', 'HP:0100743', (210, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Disease', (86, 92))
752355	33519815	As far as potential association between BTLA polymorphisms and hematological malignancies is concerned, such evaluation was performed only for CLL.	('hematological malignancies', 'Disease', (63, 89))	('polymorphisms', 'Var', (45, 58))	('hematological malignancies', 'Disease', 'MESH:D019337', (63, 89))	('BTLA', 'Gene', (40, 44))	('hematological malignancies', 'Phenotype', 'HP:0004377', (63, 89))
752357	33519815	Among the investigated BTLA SNPs were: rs2705511A>C, rs1982809A>G, rs9288952A>G, rs76844316T>G, rs16859633T>C, rs9288953C>T, rs2705535A>C, rs1844089G>A, rs2705565C>T, and rs2633580C>G.	('rs76844316T>G', 'DBSNP_MENTION', 'None', (81, 94))	('rs2705511A>C', 'DBSNP_MENTION', 'None', (39, 51))	('rs2705535A>C', 'Var', (125, 137))	('rs2705511A>C', 'Var', (39, 51))	('rs76844316T>G', 'Var', (81, 94))	('rs2633580C>G', 'Var', (171, 183))	('rs16859633T>C', 'DBSNP_MENTION', 'None', (96, 109))	('rs9288952A>G', 'DBSNP_MENTION', 'None', (67, 79))	('rs1982809A>G', 'DBSNP_MENTION', 'None', (53, 65))	('rs1844089G>A', 'DBSNP_MENTION', 'None', (139, 151))	('rs1982809A>G', 'Var', (53, 65))	('rs2705535A>C', 'DBSNP_MENTION', 'None', (125, 137))	('rs2633580C>G', 'DBSNP_MENTION', 'None', (171, 183))	('rs9288953C>T', 'Var', (111, 123))	('rs9288953C>T', 'DBSNP_MENTION', 'None', (111, 123))	('rs2705565C>T', 'Var', (153, 165))	('rs1844089G>A', 'Var', (139, 151))	('rs2705565C>T', 'DBSNP_MENTION', 'None', (153, 165))	('rs9288952A>G', 'Var', (67, 79))	('rs16859633T>C', 'Var', (96, 109))
752358	33519815	The carriers of rs1982809*G allele and rs2705511*C allele were more prone to CLL development (OR = 1.5 and OR = 1.6, respectively).	('rs2705511', 'Mutation', 'rs2705511', (39, 48))	('prone', 'PosReg', (68, 73))	('rs2705511*C', 'Var', (39, 50))	('rs1982809*G', 'Var', (16, 27))	('CLL development', 'CPA', (77, 92))	('rs1982809', 'Mutation', 'rs1982809', (16, 25))
752359	33519815	Additionally, the T/T genotype of rs9288953C>T was associated with 1.7 times higher risk of CLL.	('rs9288953C>T', 'DBSNP_MENTION', 'None', (34, 46))	('rs9288953C>T', 'Var', (34, 46))	('CLL', 'Disease', (92, 95))
752360	33519815	carried out a case-control study on the group of 282 patients and 480 control subjects in order to evaluate association between the following BTLA SNPs rs1844089G>A, rs2705535A>C, rs9288953C>T, rs9288952A>G, rs16859633T>C, rs1982809A>G, rs2705511A>C, and renal cell carcinoma (RCC).	('renal cell carcinoma', 'Disease', 'MESH:C538614', (255, 275))	('rs1982809A>G', 'DBSNP_MENTION', 'None', (223, 235))	('RCC', 'Disease', 'MESH:C538614', (277, 280))	('rs16859633T>C', 'DBSNP_MENTION', 'None', (208, 221))	('rs1982809A>G', 'Var', (223, 235))	('patients', 'Species', '9606', (53, 61))	('rs2705511A>C', 'DBSNP_MENTION', 'None', (237, 249))	('rs2705511A>C', 'Var', (237, 249))	('rs2705535A>C', 'DBSNP_MENTION', 'None', (166, 178))	('renal cell carcinoma', 'Disease', (255, 275))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (255, 275))	('rs9288952A>G', 'DBSNP_MENTION', 'None', (194, 206))	('rs1844089G>A', 'DBSNP_MENTION', 'None', (152, 164))	('rs16859633T>C', 'Var', (208, 221))	('rs9288952A>G', 'Var', (194, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('RCC', 'Disease', (277, 280))	('rs2705535A>C', 'Var', (166, 178))	('rs9288953C>T', 'DBSNP_MENTION', 'None', (180, 192))	('rs9288953C>T', 'Var', (180, 192))	('rs1844089G>A', 'Var', (152, 164))
752361	33519815	The presence of rs1982809*G allele (G/G + A/G) was associated with 1.4 times higher risk of RCC, while G/G genotype was associated with higher risk (OR = 2.75) of the clear cell RCC (ccRCC) high grade tumors.	('RCC', 'Disease', (185, 188))	('rs1982809*G', 'Var', (16, 27))	('RCC', 'Disease', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('RCC', 'Disease', (178, 181))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('rs1982809', 'Mutation', 'rs1982809', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
752362	33519815	The association of the following genetic variants of BTLA rs1982809A>G, rs9288952A>G and rs9288953C>T with lung cancer risk was studied recently in the Tunisian population (196 patients, 300 controls).	('rs1982809A>G', 'Var', (58, 70))	('rs9288952A>G', 'Var', (72, 84))	('BTLA', 'Gene', (53, 57))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('patients', 'Species', '9606', (177, 185))	('rs9288953C>T', 'Var', (89, 101))	('rs9288953C>T', 'DBSNP_MENTION', 'None', (89, 101))	('rs1982809A>G', 'DBSNP_MENTION', 'None', (58, 70))	('lung cancer', 'Disease', (107, 118))	('rs9288952A>G', 'DBSNP_MENTION', 'None', (72, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
752363	33519815	The possession of rs1982809*G allele was associated with 1.5 increased risk of lung cancer development.	('rs1982809*G', 'Var', (18, 29))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('rs1982809', 'Mutation', 'rs1982809', (18, 27))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
752364	33519815	The rs1982809*G allele was also associated with T4 tumor size (OR = 1.8), metastasis to LNs (OR = 3.71), and development of adenocarcinoma subtype of lung cancer (OR = 2.8).	('rs1982809', 'Mutation', 'rs1982809', (4, 13))	('rs1982809*G', 'Var', (4, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('adenocarcinoma subtype of lung cancer', 'Disease', (124, 161))	('tumor', 'Disease', (51, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('adenocarcinoma subtype of lung cancer', 'Disease', 'MESH:D008175', (124, 161))	('associated', 'Reg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('metastasis to LNs', 'CPA', (74, 91))
752365	33519815	The summary of above-described associations between BTLA polymorphisms and cancer risk is shown in  Supplementary Table 4 .	('polymorphisms', 'Var', (57, 70))	('associations', 'Interaction', (31, 43))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('BTLA', 'Gene', (52, 56))
752384	33519815	rs891246256G>A (-1541C>T REV) and rs10053538C>A (-1516G>T REV) are the 2 kb upstream SNPs.	('rs10053538C>A', 'DBSNP_MENTION', 'None', (34, 47))	('rs10053538C>A', 'Var', (34, 47))	('rs891246256G>A', 'DBSNP_MENTION', 'None', (0, 14))	('-1516G>T', 'Mutation', 'rs10053538', (49, 57))	('rs891246256G>A', 'Var', (0, 14))	('-1541C>T', 'Mutation', 'rs891246256', (16, 24))
752386	33519815	The rs10053538 is situated at the putative binding site of p300 TF.	('p300', 'Gene', (59, 63))	('rs10053538', 'Mutation', 'rs10053538', (4, 14))	('p300', 'Gene', '2033', (59, 63))	('rs10053538', 'Var', (4, 14))
752387	33519815	The presence of -1516*T allele (G/T+T/T) of this SNP has been shown to be associated with higher expression of TIM-3 on liver infiltrating lymphocytes in tumor tissue of HCC patients in comparison to -1516 G/G genotype as determined by immunohistochemistry   rs1036199A>C (+4259T>G REV) is located in exon 3.	('tumor', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('HCC', 'Disease', (170, 173))	('TIM-3', 'Gene', (111, 116))	('TIM-3', 'Gene', '84868', (111, 116))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('rs1036199A>C', 'Var', (259, 271))	('T+T', 'Disease', 'MESH:D001260', (34, 37))	('+4259T>G', 'Mutation', 'rs1036199', (273, 281))	('rs1036199A>C', 'DBSNP_MENTION', 'None', (259, 271))	('higher', 'PosReg', (90, 96))	('expression', 'MPA', (97, 107))	('T+T', 'Disease', (34, 37))
752389	33519815	The functional consequence of this change has not been reported so far but it can be postulated that this variant may affect the mucin domain.	('affect', 'Reg', (118, 124))	('mucin', 'Gene', (129, 134))	('mucin', 'Gene', '100508689', (129, 134))	('variant', 'Var', (106, 113))
752390	33519815	A meta-analysis aimed at evaluation of association between the rs1036199 and autoimmune diseases (ADs) mainly in Asian populations pointed to the rs1036199*G allele as a risk factor increasing susceptibility to ADs.	('ADs', 'Disease', (211, 214))	('rs1036199', 'Mutation', 'rs1036199', (63, 72))	('rs1036199', 'Var', (63, 72))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (77, 96))	('rs1036199', 'Mutation', 'rs1036199', (146, 155))	('autoimmune diseases', 'Disease', 'MESH:D001327', (77, 96))	('rs1036199*G', 'Var', (146, 157))	('autoimmune diseases', 'Disease', (77, 96))
752391	33519815	The -1516G>T, -574G>T, and +4259T>G of the HAVCR2 gene are the most studied polymorphisms in terms of association with overall cancer risks.	('-574G>T', 'Mutation', 'rs10515746', (14, 21))	('+4259T>G', 'Mutation', 'rs1036199', (27, 35))	('association', 'Interaction', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('HAVCR2', 'Gene', (43, 49))	('HAVCR2', 'Gene', '84868', (43, 49))	('+4259T>G', 'Var', (27, 35))	('-1516G>T', 'Mutation', 'rs10053538', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
752392	33519815	based on six published studies (2,039 cases, 2,372 controls) evaluating the association between -1516G>T, -574T>G, and +4259T>G and cancer risk in the Chinese Han population.	('cancer', 'Disease', (132, 138))	('+4259T>G', 'Var', (119, 127))	('-1516G>T', 'Mutation', 'rs10053538', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('+4259T>G', 'Mutation', 'rs1036199', (119, 127))	('-574T>G', 'Mutation', 'rs10515746', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('-574T>G', 'Var', (106, 113))
752393	33519815	This analysis revealed that the minor alleles in investigated SNPs: -1516*T (OR = 1.40), -574*T (OR = 1.99), and +4259*G (OR = 2.21) were associated with a higher overall cancer risk.	('+4259*G', 'Var', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('-574*T', 'Var', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
752394	33519815	The authors also analyzed association between those variants and cancer risk based on human systems.	('human', 'Species', '9606', (86, 91))	('variants', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('analyzed', 'Reg', (17, 25))
752396	33519815	The authors postulated that minor alleles of investigated variants may potentially cause higher individual risk of cancer by increasing TIM-3 expression or enhancing its function.	('cancer', 'Disease', (115, 121))	('TIM-3', 'Gene', '84868', (136, 141))	('function', 'MPA', (170, 178))	('variants', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cause', 'Reg', (83, 88))	('expression', 'MPA', (142, 152))	('increasing', 'PosReg', (125, 135))	('enhancing', 'PosReg', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('TIM-3', 'Gene', (136, 141))
752397	33519815	This meta-analysis took into consideration the following SNPs: -1516G>T, -822C>T, -574G>T, and +4259 T>G.	('+4259 T>G', 'Mutation', 'rs1036199', (95, 104))	('-1516G>T', 'Var', (63, 71))	('-1516G>T', 'Mutation', 'rs10053538', (63, 71))	('-574G>T', 'Var', (82, 89))	('+4259 T>G', 'Var', (95, 104))	('-822C>T', 'Mutation', 'rs886692404', (73, 80))	('-574G>T', 'Mutation', 'rs10515746', (82, 89))
752405	33519815	The authors concluded that their study clearly demonstrated involvement of HAVCR2 gene polymorphisms (minor alleles of examined SNPs) in conferring higher risk for development of different human cancers.	('human', 'Species', '9606', (189, 194))	('HAVCR2', 'Gene', (75, 81))	('HAVCR2', 'Gene', '84868', (75, 81))	('polymorphisms', 'Var', (87, 100))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
752407	33519815	The authors investigated five SNPs: -1541C>T, -1516 G>T, -822C>T, -574G>T, and +4259T>G in 212 patients and 252 control subjects of the Chinese Han population.	('-1516 G>T', 'Var', (46, 55))	('-1541C>T', 'Var', (36, 44))	('-1516 G>T', 'Mutation', 'rs10053538', (46, 55))	('-822C>T', 'Mutation', 'rs886692404', (57, 64))	('+4259T>G', 'Mutation', 'rs1036199', (79, 87))	('patients', 'Species', '9606', (95, 103))	('-1541C>T', 'Mutation', 'rs891246256', (36, 44))	('+4259T>G', 'Var', (79, 87))	('-574G>T', 'Var', (66, 73))	('-574G>T', 'Mutation', 'rs10515746', (66, 73))
752410	33519815	conducted a case-control study on 306 patients with pancreatic cancer (PC) and 422 control subjects of Han Chinese ethnicity in order to examine any possible association between -1516G>T, -574G>T, and +4259T>G and susceptibility to PC.	('-1516G>T', 'Mutation', 'rs10053538', (178, 186))	('pancreatic cancer', 'Disease', (52, 69))	('+4259T>G', 'Mutation', 'rs1036199', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (52, 69))	('patients', 'Species', '9606', (38, 46))	('-574G>T', 'Var', (188, 195))	('-574G>T', 'Mutation', 'rs10515746', (188, 195))	('+4259T>G', 'Var', (201, 209))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 69))
752411	33519815	The association was found only for +4259T>G, namely the carriers of the +4259 T/G genotype had almost three times higher risk (OR = 2.82) of PC development in comparison to subjects with the G/G genotype.	('+4259T>G', 'Mutation', 'rs1036199', (35, 43))	('+4259 T/G', 'Var', (72, 81))	('+4259T>G', 'Var', (35, 43))	('+4259 T/G', 'SUBSTITUTION', 'None', (72, 81))	('higher', 'PosReg', (114, 120))
752412	33519815	To the best of our knowledge, so far only one study investigating an association between predisposition to colorectal cancer (CRC) development and SNPs of HAVCR2 has been published.	('HAVCR2', 'Gene', '84868', (155, 161))	('rectal cancer', 'Phenotype', 'HP:0100743', (111, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('HAVCR2', 'Gene', (155, 161))	('SNPs', 'Var', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colorectal cancer', 'Disease', (107, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))
752414	33519815	The first study attempting to examine relations between the HAVCR2 gene polymorphisms and susceptibility to breast cancer were carried out on 560 BC patients and 583 control subjects of Northwest China descent.	('patients', 'Species', '9606', (149, 157))	('HAVCR2', 'Gene', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('HAVCR2', 'Gene', '84868', (60, 66))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('polymorphisms', 'Var', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))
752415	33519815	The authors investigated the following HAVCR2 SNPs: -1516G>T, +4259T>G, and rs4704846A>G and found that the carriers of the -1516*T allele had higher risk of BC development (OR = 1.37) in comparison to the G/G genotype.	('+4259T>G', 'Mutation', 'rs1036199', (62, 70))	('HAVCR2', 'Gene', (39, 45))	('HAVCR2', 'Gene', '84868', (39, 45))	('rs4704846A>G', 'Var', (76, 88))	('rs4704846A>G', 'DBSNP_MENTION', 'None', (76, 88))	('-1516G>T', 'Mutation', 'rs10053538', (52, 60))	('BC development', 'CPA', (158, 172))
752417	33519815	Additionally, immunohistochemical analysis demonstrated that -1516 G/T and T/T genotypes were associated with increased TIM-3 protein expression as compared to G/G genotype.	('expression', 'MPA', (134, 144))	('increased', 'PosReg', (110, 119))	('-1516 G/T', 'Mutation', 'rs10053538', (61, 70))	('T/T', 'Var', (75, 78))	('-1516 G/T', 'Var', (61, 70))	('TIM-3', 'Gene', '84868', (120, 125))	('TIM-3', 'Gene', (120, 125))
752418	33519815	assessed association between-1516G>T, -574G>T, +4259T>G, and risk of invasive BC in a group of 301 patients with invasive BC and 151 control individuals of Chinese Han ethnicity.	('invasive BC', 'Disease', (113, 124))	('+4259T>G', 'Var', (47, 55))	('invasive BC', 'Disease', (69, 80))	('patients', 'Species', '9606', (99, 107))	('-1516G>T', 'Mutation', 'rs10053538', (28, 36))	('+4259T>G', 'Mutation', 'rs1036199', (47, 55))	('-574G>T', 'Var', (38, 45))	('-574G>T', 'Mutation', 'rs10515746', (38, 45))
752420	33519815	As for hematological malignancies, the -1516G>T, -574G>T, and +4259T>G polymorphisms were investigated in non-Hodgkin lymphoma (NHL).	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (106, 126))	('+4259T>G', 'Mutation', 'rs1036199', (62, 70))	('-1516G>T', 'Mutation', 'rs10053538', (39, 47))	('hematological malignancies', 'Disease', (7, 33))	('hematological malignancies', 'Disease', 'MESH:D019337', (7, 33))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (110, 126))	('+4259T>G', 'Var', (62, 70))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (106, 126))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('-574G>T', 'Var', (49, 56))	('non-Hodgkin lymphoma', 'Disease', (106, 126))	('hematological malignancies', 'Phenotype', 'HP:0004377', (7, 33))	('-574G>T', 'Mutation', 'rs10515746', (49, 56))
752422	33519815	The study demonstrated that subjects with the -574 G/T or +4259 T/G genotypes had more than two times higher risk for NHL development (OR = 2.72 and OR = 2.59, respectively) in comparison to subjects possessing wild type genotypes -574 G/G and +4259 T/T.	('-574 G/T', 'SUBSTITUTION', 'None', (46, 54))	('+4259 T/G', 'Var', (58, 67))	('NHL', 'Disease', (118, 121))	('+4259 T/G', 'SUBSTITUTION', 'None', (58, 67))	('-574 G/T', 'Var', (46, 54))
752424	33519815	Bai and colleagues examined -1516G>T, -574G>T, and +4259T>G in 432 NSCLC patients and 466 control subjects from the Han Chinese population.	('+4259T>G', 'Mutation', 'rs1036199', (51, 59))	('-1516G>T', 'Mutation', 'rs10053538', (28, 36))	('+4259T>G', 'Var', (51, 59))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('NSCLC', 'Disease', (67, 72))	('patients', 'Species', '9606', (73, 81))	('-574G>T', 'Var', (38, 45))	('-574G>T', 'Mutation', 'rs10515746', (38, 45))
752425	33519815	The study revealed that +4259 T/G (G/G genotype was not determined neither in patients nor in the control group) genotype was associated with increased risk of NSCLC (OR = 2.81).	('+4259 T/G', 'Var', (24, 33))	('patients', 'Species', '9606', (78, 86))	('+4259 T/G', 'SUBSTITUTION', 'None', (24, 33))	('NSCLC', 'Disease', (160, 165))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
752426	33519815	Moreover, patients carrying the +4259 T/G genotype had shorter survival in comparison to those with T/T genotype (15.2 vs. 27.7 months, respectively).	('+4259 T/G', 'Var', (32, 41))	('+4259 T/G', 'SUBSTITUTION', 'None', (32, 41))	('shorter', 'NegReg', (55, 62))	('patients', 'Species', '9606', (10, 18))	('survival', 'MPA', (63, 71))
752427	33519815	Cai and colleagues investigated -1516G>T, -574G>T, and +4259T>G polymorphisms in 322 RRC patients and 402 control subjects of Chinese descent.	('-574G>T', 'Mutation', 'rs10515746', (42, 49))	('+4259T>G', 'Mutation', 'rs1036199', (55, 63))	('Cai', 'Gene', '759', (0, 3))	('Cai', 'Gene', (0, 3))	('RRC', 'Disease', (85, 88))	('patients', 'Species', '9606', (89, 97))	('+4259T>G', 'Var', (55, 63))	('-1516G>T', 'Mutation', 'rs10053538', (32, 40))	('-574G>T', 'Var', (42, 49))
752428	33519815	Of the examined SNPs, association with increased RCC cancer risk was found for the -574 G/T (OR = 2.85) genotype and +4259 T/G genotype (OR = 3.34) (the -574G>T T/T and the +4259 G/G genotypes, were not determined in the investigated groups).	('-574G>T', 'Mutation', 'rs10515746', (153, 160))	('-574 G/T', 'SUBSTITUTION', 'None', (83, 91))	('-574 G/T', 'Var', (83, 91))	('RCC cancer', 'Disease', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('increased', 'PosReg', (39, 48))	('+4259 T/G', 'Var', (117, 126))	('+4259 T/G', 'SUBSTITUTION', 'None', (117, 126))	('RCC cancer', 'Disease', 'MESH:C538614', (49, 59))
752430	33519815	The summary of above presented associations between HAVCR2 genetic variants and cancer risk is shown in  Supplementary Table 5 .	('associations', 'Interaction', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('HAVCR2', 'Gene', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('HAVCR2', 'Gene', '84868', (52, 58))	('variants', 'Var', (67, 75))	('cancer', 'Disease', (80, 86))
752443	33519815	Lee and colleagues performed a case-control study aimed at investigation of association between common SNPs in immunoregulatory genes and a risk of multiple myeloma in women.	('multiple myeloma', 'Phenotype', 'HP:0006775', (148, 164))	('multiple myeloma', 'Disease', 'MESH:D009101', (148, 164))	('association', 'Interaction', (76, 87))	('multiple myeloma', 'Disease', (148, 164))	('common SNPs', 'Var', (96, 107))	('women', 'Species', '9606', (168, 173))
752445	33519815	For two intronic variants of LAG-3 gene rs2365094G>C and rs3782735A>G the potential association with MM risk was found.	('LAG-3', 'Gene', '3902', (29, 34))	('rs3782735A>G', 'DBSNP_MENTION', 'None', (57, 69))	('LAG-3', 'Gene', (29, 34))	('association', 'Reg', (84, 95))	('rs3782735A>G', 'Var', (57, 69))	('rs2365094G>C', 'Var', (40, 52))	('rs2365094G>C', 'DBSNP_MENTION', 'None', (40, 52))	('MM', 'Disease', 'MESH:D009101', (101, 103))
752446	33519815	The carriers of rs2365094*C allele were more likely to develop (OR = 1.57) MM, whereas carriers of rs3782735*A allele were less likely to develop MM (OR = 0.69).	('rs3782735', 'Mutation', 'rs3782735', (99, 108))	('develop', 'CPA', (55, 62))	('rs2365094', 'Mutation', 'rs2365094', (16, 25))	('MM', 'Disease', 'MESH:D009101', (146, 148))	('rs2365094*C', 'Var', (16, 27))	('MM', 'Disease', 'MESH:D009101', (75, 77))
752447	33519815	The frequency of the LAG-3 genetic variants (described below) in different populations is presented in  Table 1 .	('LAG-3', 'Gene', (21, 26))	('LAG-3', 'Gene', '3902', (21, 26))	('variants', 'Var', (35, 43))
752448	33519815	As was mentioned in the Introduction, the association between inherited variants in genes for ICs and cancer risk has been extensively investigated for CTLA-4 and broadly for PD-1/PD-L1 in a wide spectrum of cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (208, 214))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancers', 'Disease', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('CTLA-4', 'Gene', (152, 158))	('variants', 'Var', (72, 80))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('PD-1/PD-L1', 'Gene', (175, 185))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('ICs', 'Disease', (94, 97))
752451	33519815	From numerous studies it might be concluded that the CTLA-4c.49*A allele is associated with higher overall cancer risk alongside the risk of developing particular types of cancers, including breast, bone, and cervical cancers.	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('cervical cancers', 'Disease', (209, 225))	('cervical cancers', 'Disease', 'MESH:D002583', (209, 225))	('cancers', 'Disease', (218, 225))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('higher', 'PosReg', (92, 98))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('CTLA-4c.49*A', 'Var', (53, 65))	('cancers', 'Disease', (172, 179))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bone', 'Disease', (199, 203))	('breast', 'Disease', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
752452	33519815	Similarly, the CTLA-4c.-319*T increased an overall cancer risk in Caucasians, and predisposed to breast, cervical and hepatocellular cancers and bone cancer in Asian.	('hepatocellular cancers', 'Disease', 'MESH:D006528', (118, 140))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('increased', 'PosReg', (30, 39))	('bone cancer', 'Disease', 'MESH:D001859', (145, 156))	('cervical', 'Disease', (105, 113))	('bone cancer', 'Disease', (145, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('hepatocellular cancers', 'Disease', (118, 140))	('CTLA-4c.-319*T', 'Var', (15, 29))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (118, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('breast', 'Disease', (97, 103))	('cancer', 'Disease', (51, 57))
752453	33519815	The CTLA-4CT60*G allele was associated with higher risk of breast and hepatocellular cancers, while the CTLA-4c.-1661*G allele with overall, breast and gastric cancer risk.	('gastric cancer', 'Disease', 'MESH:D013274', (152, 166))	('breast', 'Disease', (141, 147))	('gastric cancer', 'Disease', (152, 166))	('breast and hepatocellular cancers', 'Disease', 'MESH:D001943', (59, 92))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (70, 91))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('CTLA-4CT60*G', 'Var', (4, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
752455	33519815	The available data suggest that the PD-1.5*T allele may protect from cancer development in general, and specifically against ovarian and breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (137, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('protect', 'PosReg', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PD-1.5*T', 'Var', (36, 44))	('cancer', 'Disease', (144, 150))	('ovarian and breast cancers', 'Disease', 'MESH:D001943', (125, 151))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (69, 75))
752456	33519815	The rs7421861*C allele increased overall cancer risk as well as the development of colorectal and EGJA cancers.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Disease', (103, 109))	('rs7421861', 'Mutation', 'rs7421861', (4, 13))	('increased', 'PosReg', (23, 32))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('colorectal and EGJA cancers', 'Disease', 'MESH:D015179', (83, 110))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('rs7421861*C', 'Var', (4, 15))
752458	33519815	Only one polymorphism in the PD-L1 gene, namely rs4143815G>C has been shown to be associated with cancer risk, in particular the rs4143815*G allele increased risk of overall, hepatocellular, ovarian, and gastric cancers.	('associated', 'Reg', (82, 92))	('increased', 'PosReg', (148, 157))	('ovarian', 'Disease', 'MESH:D010049', (191, 198))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('rs4143815*G', 'Var', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs4143815', 'Mutation', 'rs4143815', (129, 138))	('hepatocellular', 'Disease', (175, 189))	('rs4143815G>C', 'DBSNP_MENTION', 'None', (48, 60))	('PD-L1', 'Gene', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('ovarian', 'Disease', (191, 198))	('cancer', 'Disease', (212, 218))	('rs4143815', 'Mutation', 'rs4143815', (48, 57))	('gastric cancers', 'Disease', 'MESH:D013274', (204, 219))	('rs4143815G>C', 'Var', (48, 60))	('gastric cancers', 'Disease', (204, 219))	('gastric cancers', 'Phenotype', 'HP:0012126', (204, 219))	('overall', 'Disease', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('gastric cancer', 'Phenotype', 'HP:0012126', (204, 218))
752460	33519815	On the basis of available literature, it can be however postulated, that rs1982809*G confer higher risk of lung cancer, CLL and renal cancer.	('rs1982809', 'Mutation', 'rs1982809', (73, 82))	('rs1982809*G', 'Var', (73, 84))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('renal cancer', 'Disease', (128, 140))	('renal cancer', 'Phenotype', 'HP:0009726', (128, 140))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('renal cancer', 'Disease', 'MESH:D007680', (128, 140))	('CLL', 'Disease', (120, 123))
752461	33519815	The rs9288953 G/G genotype can be considered as a factor increasing risk of CLL and colorectal cancer, whereas rs1844089*T allele as a risk factor of breast cancer.	('colorectal cancer', 'Disease', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('rectal cancer', 'Phenotype', 'HP:0100743', (88, 101))	('rs1844089*T', 'Var', (111, 122))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('breast cancer', 'Disease', (150, 163))	('CLL', 'Disease', (76, 79))	('rs9288953', 'Mutation', 'rs9288953', (4, 13))	('rs1844089', 'Mutation', 'rs1844089', (111, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('rs9288953 G/G', 'Var', (4, 17))
752462	33519815	Finally, rs2705535*A allele seems to be associated with higher risk of breast cancer and rs2705511*C with higher susceptibility to colorectal cancer and CLL.	('breast cancer', 'Disease', (71, 84))	('rectal cancer', 'Phenotype', 'HP:0100743', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rs2705511*C', 'Var', (89, 100))	('rs2705511', 'Mutation', 'rs2705511', (89, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('CLL', 'Disease', (153, 156))	('rs2705535', 'Mutation', 'rs2705535', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', (131, 148))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('rs2705535*A', 'Var', (9, 20))
752464	33519815	According to them, the minor alleles of -1516G>T, -822C>T, -574G>T, and +4259T>G can be considered as overall cancer risk factors.	('-822C>T', 'Mutation', 'rs886692404', (50, 57))	('-1516G>T', 'Mutation', 'rs10053538', (40, 48))	('-574G>T', 'Mutation', 'rs10515746', (59, 66))	('cancer', 'Disease', (110, 116))	('+4259T>G', 'Mutation', 'rs1036199', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('+4259T>G', 'Var', (72, 80))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
752466	33519815	The associations between variants of genes encoding LAG-3 and TIGIT and cancer risk has not been evaluated yet and this area is almost unexplored.	('variants', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('LAG-3', 'Gene', '3902', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('LAG-3', 'Gene', (52, 57))	('associations', 'Interaction', (4, 16))	('cancer', 'Disease', (72, 78))
752469	33519815	The analysis of constellation of SNPs will allow to evaluate the phenotypic effect of particular haplotypes on immune cells which may allow evaluate if particular haplotype is associated with higher, lower or neutral risk of cancer development.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (225, 231))	('haplotype', 'Var', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))
752470	33519815	It is also worth to analyze the impact of variation within genes encoding IC in context of tumor progression (among others impact on metastasis and overall survival).	('variation', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('impact', 'Reg', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('metastasis', 'CPA', (133, 143))	('tumor', 'Disease', (91, 96))
752472	33519815	In conclusion, the variants in genes encoding the molecules which regulate the immune surveillance might be considered as low-risk variants (OR<2) for cancer development, which has been well documented by numerous reports for CTLA-4, PDCD1, PD-L1 genes, while more studies are needed for BTLA, TIM3, LAG3, and TIGIT.	('PDCD1', 'Gene', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('PDCD1', 'Gene', '5133', (234, 239))	('TIM3', 'Gene', (294, 298))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('TIM3', 'Gene', '84868', (294, 298))	('LAG3', 'Gene', (300, 304))	('variants', 'Var', (19, 27))	('LAG3', 'Gene', '3902', (300, 304))	('CTLA-4', 'Gene', (226, 232))
752512	31727671	In comparison to the TCGA classification, where underlying somatic genomic processes were central to development of the classifier, ACRG developed a classification into four groups based on array-based gene expression profiling of 300 gastric adenocarcinomas: MSI (22.7%), microsatellite stable with epithelial-to-mesenchymal transition (MSS/EMT) (15.3%), MSS/TP53+ (26.3%), and MSS/TP53- (35.7%).	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (235, 258))	('TP53', 'Gene', (360, 364))	('carcinomas', 'Phenotype', 'HP:0030731', (248, 258))	('gastric adenocarcinomas', 'Disease', (235, 258))	('TP53', 'Gene', '7157', (383, 387))	('TP53', 'Gene', (383, 387))	('microsatellite', 'Var', (273, 287))	('TP53', 'Gene', '7157', (360, 364))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
752516	31727671	While no survival associations were seen in the TCGA study, potentially owing to the therapeutic heterogeneity of the internationally diverse sample set, subsequent studies applying the TCGA classes to two large independent cohorts demonstrated that EBV+ tumors have superior and GS tumors have inferior survival.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('tumors', 'Disease', (255, 261))	('inferior', 'NegReg', (295, 303))	('superior', 'CPA', (267, 275))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('EBV', 'Species', '10376', (250, 253))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('EBV+', 'Var', (250, 254))	('GS tumors', 'Disease', 'MESH:D011125', (280, 289))	('tumors', 'Disease', (283, 289))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('GS tumors', 'Disease', (280, 289))
752522	31727671	Although specific methylation patterns were enriched in EACs relative to distal gastric cancers, multiple analyses attempting to differentiate the molecular features of CIN tumors of the stomach and esophagus failed to dichotomize these cancers.	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('CIN tumors', 'Disease', 'MESH:D009369', (169, 179))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancers', 'Disease', (237, 244))	('gastric cancers', 'Disease', 'MESH:D013274', (80, 95))	('gastric cancers', 'Disease', (80, 95))	('gastric cancers', 'Phenotype', 'HP:0012126', (80, 95))	('EACs', 'Disease', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('CIN tumors', 'Disease', (169, 179))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('tumors of the stomach', 'Phenotype', 'HP:0006753', (173, 194))	('CIN', 'Phenotype', 'HP:0040012', (169, 172))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('methylation', 'Var', (18, 29))	('cancers', 'Disease', 'MESH:D009369', (237, 244))
752523	31727671	EACs have fewer APC mutations, suggesting less WNT dependence or alternate means of activating WNT signaling, and higher frequency of RUNX1 deletion and VEGFA and MYC amplifications.	('MYC', 'Gene', '4609', (163, 166))	('VEGFA', 'Gene', '7422', (153, 158))	('MYC', 'Gene', (163, 166))	('WNT dependence', 'Disease', (47, 61))	('WNT dependence', 'Disease', 'MESH:D019966', (47, 61))	('RUNX1', 'Gene', (134, 139))	('VEGFA', 'Gene', (153, 158))	('deletion', 'Var', (140, 148))	('activating WNT signaling', 'MPA', (84, 108))	('RUNX1', 'Gene', '861', (134, 139))	('APC', 'Disease', 'MESH:D011125', (16, 19))	('APC', 'Disease', (16, 19))
752529	31727671	While the anatomic gradients of molecular subtypes and molecular features could be used to argue firmer separation of cancers in the anatomic esophagus or stomach, it is notable that such gradients are present within analogous diseases such as CRC, where methylation and MSI are more prevalent in the ascending colon and CIN more common in the distal colon and rectum.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('CRC', 'Phenotype', 'HP:0003003', (244, 247))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('methylation', 'Var', (255, 266))	('colon and CIN', 'Disease', 'MESH:D003110', (311, 324))	('CIN', 'Phenotype', 'HP:0040012', (321, 324))	('CRC', 'Disease', (244, 247))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
752538	31727671	These data correspond to the discrepant patterns of oncogene activation in these tumors, with amplifications predominant in GEA, and mutations, chiefly RAS, prevalent in CRC.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('CRC', 'Disease', (170, 173))	('activation', 'PosReg', (61, 71))	('RAS', 'Gene', (152, 155))	('amplifications', 'Var', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CRC', 'Phenotype', 'HP:0003003', (170, 173))	('GEA', 'Chemical', '-', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
752540	31727671	CIN-F GEAs frequently harbor amplifications of RTKs, RAS, and cell cycle genes.	('cell cycle genes', 'Gene', (62, 78))	('CIN-F GEAs', 'Disease', (0, 10))	('CIN-F GEAs', 'Disease', 'OMIM:102510', (0, 10))	('RAS', 'Gene', (53, 56))	('amplifications', 'Var', (29, 43))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))	('RTKs', 'Gene', (47, 51))
752541	31727671	TP53 mutations are more common in CIN-F tumors (76% as compared to 54% of CIN-B tumors), as is whole genome doubling (68% vs. 42%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CIN-F tumors', 'Disease', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (5, 14))	('CIN-B tumors', 'Disease', (74, 86))	('CIN', 'Phenotype', 'HP:0040012', (74, 77))	('CIN-B tumors', 'Disease', 'MESH:D006509', (74, 86))	('CIN-F tumors', 'Disease', 'OMIM:102510', (34, 46))	('common', 'Reg', (24, 30))	('CIN', 'Phenotype', 'HP:0040012', (34, 37))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
752545	31727671	A specific mutational signature of A>C transversions at AA dinucleotides has been observed in GEAs and is associated with the CIN-F phenotype.	('A>C transversions', 'Var', (35, 52))	('associated', 'Reg', (106, 116))	('CIN-F', 'Disease', 'OMIM:102510', (126, 131))	('CIN-F', 'Disease', (126, 131))	('GEA', 'Chemical', '-', (94, 97))	('CIN', 'Phenotype', 'HP:0040012', (126, 129))
752547	31727671	As IBD-associated CRCs also resemble CIN GEA in relative paucity of APC mutations and greater prevalence of oncogene activation via amplification, these data raise the hypothesis that inflammation may contribute to the patterns of genomic evolution in GEA.	('IBD', 'Disease', (3, 6))	('mutations', 'Var', (72, 81))	('GEA', 'Chemical', '-', (252, 255))	('inflammation', 'Disease', 'MESH:D007249', (184, 196))	('APC', 'Disease', 'MESH:D011125', (68, 71))	('IBD', 'Disease', 'MESH:D015212', (3, 6))	('APC', 'Disease', (68, 71))	('CRC', 'Phenotype', 'HP:0003003', (18, 21))	('inflammation', 'Disease', (184, 196))	('CIN GEA', 'Disease', 'MESH:D007674', (37, 44))	('CIN', 'Phenotype', 'HP:0040012', (37, 40))	('IBD', 'Phenotype', 'HP:0002037', (3, 6))	('GEA', 'Chemical', '-', (41, 44))	('CIN GEA', 'Disease', (37, 44))
752550	31727671	These features include both transformation leading to cancer cells with multiple driving mitogenic oncogenes (e.g., cancer cells with co-amplification of ERBB2 and MET) as well as heterogeneous tumors where distinct driving amplified oncogenes are present in distinct subclones of tumors (Figure 2).	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('ERBB2', 'Gene', '2064', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('co-amplification', 'Var', (134, 150))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('MET', 'Gene', (164, 167))	('cancer', 'Disease', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Disease', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (281, 287))	('ERBB2', 'Gene', (154, 159))	('leading to', 'Reg', (43, 53))	('tumors', 'Disease', 'MESH:D009369', (194, 200))
752553	31727671	The origin of the GS nomenclature in TCGA followed their lack of CIN, MSI/hypermutation, and the hypermethylation found in EBV+ tumors.	('GS', 'Disease', 'MESH:D011125', (18, 20))	('CIN', 'Phenotype', 'HP:0040012', (65, 68))	('hypermethylation', 'Var', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CIN', 'Disease', (65, 68))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('EBV', 'Species', '10376', (123, 126))	('CIN', 'Disease', 'MESH:D007674', (65, 68))	('lack', 'NegReg', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
752556	31727671	The most characteristic somatic features of GS tumors are CDH1 (E-cadherin) loss-of-function mutations in 30%, notably the gene also responsible for hereditary diffuse gastric cancer when altered in the germline.	('CDH1', 'Gene', (58, 62))	('GS tumors', 'Disease', 'MESH:D011125', (44, 53))	('mutations', 'Var', (93, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (149, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('E-cadherin', 'Gene', (64, 74))	('GS tumors', 'Disease', (44, 53))	('hereditary diffuse gastric cancer', 'Disease', (149, 182))	('CDH1', 'Gene', '999', (58, 62))	('loss-of-function', 'NegReg', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('E-cadherin', 'Gene', '999', (64, 74))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
752557	31727671	In families without altered CDH1, mutations have been described in CTNNA1, which functions in the same complex as E-cadherin; in DNA repair genes such as PALB2, BRCA1, BRCA2, RAD51C, and ATM; and in MSR1 and STK11.	('MSR1', 'Gene', (199, 203))	('MSR1', 'Gene', '4481', (199, 203))	('RAD51C', 'Gene', (175, 181))	('BRCA2', 'Gene', (168, 173))	('BRCA1', 'Gene', '672', (161, 166))	('BRCA1', 'Gene', (161, 166))	('ATM', 'Gene', '472', (187, 190))	('CDH1', 'Gene', '999', (28, 32))	('CTNNA1', 'Gene', (67, 73))	('CTNNA1', 'Gene', '1495', (67, 73))	('STK11', 'Gene', (208, 213))	('DNA repair', 'Gene', (129, 139))	('E-cadherin', 'Gene', (114, 124))	('BRCA2', 'Gene', '675', (168, 173))	('E-cadherin', 'Gene', '999', (114, 124))	('CDH1', 'Gene', (28, 32))	('PALB2', 'Gene', (154, 159))	('ATM', 'Gene', (187, 190))	('STK11', 'Gene', '6794', (208, 213))	('PALB2', 'Gene', '79728', (154, 159))	('RAD51C', 'Gene', '5889', (175, 181))	('mutations', 'Var', (34, 43))
752560	31727671	Highly recurrent missense mutations in the RHOA GTPase were identified contemporaneously by three groups in 2014.	('GTP', 'Chemical', 'MESH:D006160', (48, 51))	('missense mutations', 'Var', (17, 35))	('RHOA', 'Gene', '387', (43, 47))	('RHOA', 'Gene', (43, 47))
752561	31727671	While missense mutations cluster in the amino-terminal GTPase domain, studies on the activity of these mutations are mixed, with data supporting both a mechanistic gain-of-function but also attenuation of the GTP loading of RHOA, a proxy for its activation.	('attenuation', 'NegReg', (190, 201))	('mutations', 'Var', (103, 112))	('GTP', 'Chemical', 'MESH:D006160', (209, 212))	('missense mutations', 'Var', (6, 24))	('GTP loading', 'MPA', (209, 220))	('GTP', 'Chemical', 'MESH:D006160', (55, 58))	('gain-of-function', 'PosReg', (164, 180))	('RHOA', 'Gene', '387', (224, 228))	('RHOA', 'Gene', (224, 228))
752562	31727671	Intriguingly, the most recurrent RHOA mutation is in the highly conserved core effector region at codon Y42.	('RHOA', 'Gene', '387', (33, 37))	('RHOA', 'Gene', (33, 37))	('mutation', 'Var', (38, 46))
752563	31727671	This residue is analogous to HRAS Y40, where mutations selectively modulate specific downstream effects of HRAS.	('mutations', 'Var', (45, 54))	('HRAS', 'Gene', '3265', (107, 111))	('HRAS', 'Gene', '3265', (29, 33))	('modulate', 'Reg', (67, 75))	('HRAS', 'Gene', (107, 111))	('HRAS', 'Gene', (29, 33))
752565	31727671	Intriguingly, the CLDN18-RHOGAP fusions are mutually exclusive with both CDH1 and RHOA alterations, suggesting this fusion may modulate both cellular adhesion and the RHO pathway in gastric cancer pathogenesis.	('fusion', 'Var', (116, 122))	('CDH1', 'Gene', (73, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('CDH1', 'Gene', '999', (73, 77))	('cellular adhesion', 'CPA', (141, 158))	('RHOA', 'Gene', '387', (82, 86))	('CLDN18', 'Gene', (18, 24))	('modulate', 'Reg', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('CLDN18', 'Gene', '51208', (18, 24))	('RHO pathway', 'Pathway', (167, 178))	('RHOA', 'Gene', (82, 86))	('gastric cancer', 'Disease', (182, 196))	('RHOGAP', 'Gene', (25, 31))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))	('RHOGAP', 'Gene', '392', (25, 31))
752572	31727671	Clinically, MSI is a favorable prognostic factor in resectable primary gastric cancer.	('MSI', 'Var', (12, 15))	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))
752575	31727671	Like in CRC, MSI gastric adenocarcinomas typically occur following MLH1 silencing in the presence of a DNA hypermethylation phenotype, or less commonly MLH1 or MSH2 mutations, leading to defective DNA mismatch repair resulting in insertion/deletion events and single-nucleotide variants.	('defective', 'NegReg', (187, 196))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (17, 40))	('occur', 'Reg', (51, 56))	('MSH2', 'Gene', '4436', (160, 164))	('insertion/deletion', 'MPA', (230, 248))	('single-nucleotide variants', 'Var', (260, 286))	('mutations', 'Var', (165, 174))	('MLH1', 'Gene', (67, 71))	('CRC', 'Disease', (8, 11))	('CRC', 'Phenotype', 'HP:0003003', (8, 11))	('DNA mismatch repair', 'MPA', (197, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('silencing', 'NegReg', (72, 81))	('MLH1', 'Gene', '4292', (67, 71))	('MLH1', 'Gene', (152, 156))	('gastric adenocarcinomas', 'Disease', (17, 40))	('MSH2', 'Gene', (160, 164))	('MLH1', 'Gene', '4292', (152, 156))
752580	31727671	Beyond MSI, there are also rare tumors with hypermutation not due to mismatch repair but secondary to POLE mutations.	('hypermutation', 'Var', (44, 57))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
752585	31727671	EBV+ gastric tumors epigenetically silence CDKN2A, similar to many CIN GEAs, but infrequently harbor TP53 mutation or CIN.	('CDKN2A', 'Gene', (43, 49))	('TP53', 'Gene', (101, 105))	('CIN', 'Disease', (67, 70))	('gastric tumors', 'Disease', (5, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('CIN', 'Phenotype', 'HP:0040012', (118, 121))	('CDKN2A', 'Gene', '1029', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('CIN', 'Disease', 'MESH:D007674', (118, 121))	('CIN', 'Phenotype', 'HP:0040012', (67, 70))	('TP53', 'Gene', '7157', (101, 105))	('epigenetically', 'Var', (20, 34))	('CIN GEAs', 'Disease', (67, 75))	('CIN GEAs', 'Disease', 'MESH:D007674', (67, 75))	('gastric tumors', 'Disease', 'MESH:D013274', (5, 19))	('CIN', 'Disease', 'MESH:D007674', (67, 70))	('silence', 'NegReg', (35, 42))	('gastric tumors', 'Phenotype', 'HP:0006753', (5, 19))	('CIN', 'Disease', (118, 121))	('EBV', 'Species', '10376', (0, 3))
752586	31727671	EBV+ gastric cancers have long been recognized to have strong lymphoid infiltration, leading to the term 'lymphoepithelioma-like carcinoma' on histologic analysis.	('lymphoepithelioma-like carcinoma', 'Disease', (106, 138))	('gastric cancers', 'Disease', 'MESH:D013274', (5, 20))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('gastric cancers', 'Disease', (5, 20))	('gastric cancers', 'Phenotype', 'HP:0012126', (5, 20))	('lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D009369', (106, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('EBV', 'Species', '10376', (0, 3))	('EBV+', 'Var', (0, 4))	('gastric cancer', 'Phenotype', 'HP:0012126', (5, 19))
752591	31727671	This confluence of immune features imparts sensitivity to immune checkpoint blockade, as observed by the impressive response rates in lymphomas with 9p24.1 amplification and in EBV+ lymphomas, and more recently, in EBV+ gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('9p24.1', 'Gene', (149, 155))	('amplification', 'Var', (156, 169))	('lymphomas', 'Disease', 'MESH:D008223', (182, 191))	('EBV', 'Species', '10376', (177, 180))	('EBV', 'Species', '10376', (215, 218))	('gastric cancer', 'Phenotype', 'HP:0012126', (220, 234))	('lymphomas', 'Phenotype', 'HP:0002665', (182, 191))	('gastric cancers', 'Disease', 'MESH:D013274', (220, 235))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('lymphoma', 'Phenotype', 'HP:0002665', (134, 142))	('gastric cancers', 'Disease', (220, 235))	('gastric cancers', 'Phenotype', 'HP:0012126', (220, 235))	('lymphomas', 'Disease', (134, 143))	('lymphomas', 'Disease', 'MESH:D008223', (134, 143))	('lymphoma', 'Phenotype', 'HP:0002665', (182, 190))	('lymphomas', 'Phenotype', 'HP:0002665', (134, 143))	('lymphomas', 'Disease', (182, 191))
752592	31727671	Beyond immunotherapy, somatic analysis has also revealed highly recurrent PIK3CA activating mutations and mutations in ARID1A and BCOR.	('ARID1A', 'Gene', '8289', (119, 125))	('ARID1A', 'Gene', (119, 125))	('PIK3CA', 'Gene', '5290', (74, 80))	('mutations', 'Var', (92, 101))	('BCOR', 'Gene', (130, 134))	('mutations', 'Var', (106, 115))	('BCOR', 'Gene', '54880', (130, 134))	('PIK3CA', 'Gene', (74, 80))
752596	31727671	The poster child for this paradigm shift to precision medicine in GEA was amplification of ERBB2, which occurs in 15-20% of GEA.	('ERBB2', 'Gene', '2064', (91, 96))	('amplification', 'Var', (74, 87))	('ERBB2', 'Gene', (91, 96))	('GEA', 'Chemical', '-', (66, 69))	('GEA', 'Chemical', '-', (124, 127))	('child', 'Species', '9606', (11, 16))
752621	31727671	Genomic analysis has demonstrated that over half of ERBB2-amplified GEA tumors have concomitant baseline genomic alterations that may contribute to intrinsic trastuzumab resistance, including activating mutations in the PI3K pathway, and amplifications of CCNE1, CDK6, EGFR, and MET, in line with the focal CIN pattern characteristic of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (343, 349))	('activating', 'PosReg', (192, 202))	('trastuzumab', 'Chemical', 'MESH:D000068878', (158, 169))	('CDK6', 'Gene', '1021', (263, 267))	('CCNE1', 'Gene', '898', (256, 261))	('MET', 'Gene', (279, 282))	('tumors', 'Disease', (72, 78))	('CIN', 'Disease', (307, 310))	('amplifications', 'Var', (238, 252))	('PI3K pathway', 'Pathway', (220, 232))	('CDK6', 'Gene', (263, 267))	('tumors', 'Disease', 'MESH:D009369', (343, 349))	('EGFR', 'Gene', '1956', (269, 273))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('GEA tumors', 'Disease', (68, 78))	('CIN', 'Phenotype', 'HP:0040012', (307, 310))	('intrinsic trastuzumab resistance', 'MPA', (148, 180))	('ERBB2', 'Gene', (52, 57))	('CIN', 'Disease', 'MESH:D007674', (307, 310))	('tumors', 'Phenotype', 'HP:0002664', (343, 349))	('GEA tumors', 'Disease', 'MESH:D009369', (68, 78))	('CCNE1', 'Gene', (256, 261))	('contribute', 'Reg', (134, 144))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('EGFR', 'Gene', (269, 273))	('ERBB2', 'Gene', '2064', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))
752624	31727671	Moreover, genomic analysis demonstrated that GEA patients with ERBB2 amplification and co-occurring lesions had inferior survival, especially when compared to those with the highest level of ERBB2 amplification by NGS.	('ERBB2', 'Gene', (191, 196))	('ERBB2', 'Gene', '2064', (191, 196))	('inferior', 'NegReg', (112, 120))	('ERBB2', 'Gene', '2064', (63, 68))	('GS', 'Disease', 'MESH:D011125', (215, 217))	('ERBB2', 'Gene', (63, 68))	('survival', 'CPA', (121, 129))	('patients', 'Species', '9606', (49, 57))	('GEA', 'Chemical', '-', (45, 48))	('amplification', 'Var', (69, 82))
752628	31727671	While it is difficult to argue at this time that the presence of heterogeneous ERBB2 is sufficient rationale to deprive a patient of trastuzumab therapy, research may ultimately show that therapy against a target clearly present in metastatic disease could be superior to targeting ERBB2 that is detectable only in the primary lesion.	('trastuzumab', 'Chemical', 'MESH:D000068878', (133, 144))	('patient', 'Species', '9606', (122, 129))	('ERBB2', 'Gene', (79, 84))	('deprive', 'NegReg', (112, 119))	('presence', 'Var', (53, 61))	('heterogeneous', 'Var', (65, 78))	('ERBB2', 'Gene', '2064', (79, 84))	('ERBB2', 'Gene', (282, 287))	('ERBB2', 'Gene', '2064', (282, 287))
752629	31727671	A telling example stems from a basket trial evaluating the ERBB2 kinase inhibitor neratinib in patients with ERBB2 somatic mutations.	('neratinib', 'Chemical', 'MESH:C487932', (82, 91))	('patients', 'Species', '9606', (95, 103))	('ERBB2', 'Gene', '2064', (109, 114))	('ERBB2', 'Gene', (109, 114))	('ERBB2', 'Gene', (59, 64))	('ERBB2', 'Gene', '2064', (59, 64))	('mutations', 'Var', (123, 132))
752631	31727671	These results evoke memories of the failure to reproduce the stunning albeit transient effects of BRAF inhibition from V600E mutant melanoma in CRCs also harboring the identical mutation.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('CRC', 'Phenotype', 'HP:0003003', (144, 147))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('V600E', 'Mutation', 'rs113488022', (119, 124))	('V600E mutant', 'Var', (119, 131))	('inhibition', 'NegReg', (103, 113))
752653	31727671	Moreover, in one study, 10 of 21 MET-amplified GEAs harbored co-amplification of ERBB2 and/or EGFR with MET in the same tumor cells, conferring de novo resistance to MET inhibition.	('ERBB2', 'Gene', (81, 86))	('EGFR', 'Gene', '1956', (94, 98))	('MET', 'Var', (104, 107))	('ERBB2', 'Gene', '2064', (81, 86))	('co-amplification', 'Var', (61, 77))	('EGFR', 'Gene', (94, 98))	('resistance to MET inhibition', 'MPA', (152, 180))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('GEA', 'Chemical', '-', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
752655	31727671	The PI3K-AKT-mTOR pathway is frequently activated in GEA, particularly in the EBV+ subtype, through PIK3CA activating mutations and amplifications, and PTEN truncating mutations and deletions.	('AKT', 'Gene', '207', (9, 12))	('activated', 'PosReg', (40, 49))	('GEA', 'Chemical', '-', (53, 56))	('PTEN', 'Gene', (152, 156))	('mutations', 'Var', (118, 127))	('activating', 'PosReg', (107, 117))	('PIK3CA', 'Gene', (100, 106))	('deletions', 'Var', (182, 191))	('truncating mutations', 'Var', (157, 177))	('PTEN', 'Gene', '5728', (152, 156))	('mTOR', 'Gene', '2475', (13, 17))	('AKT', 'Gene', (9, 12))	('mTOR', 'Gene', (13, 17))	('EBV', 'Species', '10376', (78, 81))	('PIK3CA', 'Gene', '5290', (100, 106))
752657	31727671	Biomarker analysis for this trial has not been published; however, an earlier phase 2 study identified phosphorylated S6, a downstream effector of mTOR, as a potential predictive factor that remains to be validated.	('mTOR', 'Gene', '2475', (147, 151))	('mTOR', 'Gene', (147, 151))	('phosphorylated', 'Var', (103, 117))
752658	31727671	FGFR2 amplifications occur in 5% of GEA, with enrichment in the CIN and GS subtypes.	('CIN', 'Disease', (64, 67))	('GEA', 'Chemical', '-', (36, 39))	('amplifications', 'Var', (6, 20))	('CIN', 'Disease', 'MESH:D007674', (64, 67))	('CIN', 'Phenotype', 'HP:0040012', (64, 67))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))	('GS', 'Disease', 'MESH:D011125', (72, 74))
752659	31727671	As with MET, cell line studies in GEAs with FGFR2 amplification show robust responses to kinase inhibition.	('amplification', 'Var', (50, 63))	('responses', 'MPA', (76, 85))	('GEA', 'Chemical', '-', (34, 37))	('kinase inhibition', 'MPA', (89, 106))	('FGFR2', 'Gene', '2263', (44, 49))	('FGFR2', 'Gene', (44, 49))
752661	31727671	However, no differences in PFS were observed in the randomized phase 2 SHINE study comparing the FGFR1/2/3 TKI AZD4547 to paclitaxel for the second-line treatment of gastric cancers with FGFR2 polysomy or amplification as determined by FISH on archival tumor specimens.	('archival tumor', 'Disease', (244, 258))	('FGFR1/2/3', 'Gene', '2260;2263;2261', (97, 106))	('amplification', 'Var', (205, 218))	('polysomy', 'Var', (193, 201))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('FGFR2', 'Gene', (187, 192))	('FGFR2', 'Gene', '2263', (187, 192))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('AZD4547', 'Chemical', 'MESH:C572463', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('archival tumor', 'Disease', 'MESH:D009369', (244, 258))	('paclitaxel', 'Chemical', 'MESH:D017239', (122, 132))	('gastric cancers', 'Disease', 'MESH:D013274', (166, 181))	('FGFR1/2/3', 'Gene', (97, 106))	('gastric cancers', 'Disease', (166, 181))	('gastric cancers', 'Phenotype', 'HP:0012126', (166, 181))
752663	31727671	Indeed, another translational clinical trial demonstrated that response to AZD4547 can be predicted by high-level homogeneous FGFR2 amplification as opposed to subclonal amplification, again highlighting the critical importance of identifying an effective biomarker threshold and considering heterogeneity.	('AZD4547', 'Var', (75, 82))	('response', 'MPA', (63, 71))	('AZD4547', 'Chemical', 'MESH:C572463', (75, 82))	('FGFR2', 'Gene', '2263', (126, 131))	('FGFR2', 'Gene', (126, 131))
752669	31727671	Future correlative studies will be integral to maximizing the efficacy of anti-angiogenic therapy, especially given that VEGFA amplifications occur in 28% of EACs and 7% of gastric adenocarcinomas.	('gastric adenocarcinomas', 'Disease', (173, 196))	('VEGFA', 'Gene', (121, 126))	('amplifications', 'Var', (127, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('occur', 'Reg', (142, 147))	('EACs', 'Disease', (158, 162))	('VEGFA', 'Gene', '7422', (121, 126))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (173, 196))
752672	31727671	Recent work has demonstrated clear enrichment of responses in patients with MSI and EBV+ gastric cancer, again emphasizing the importance of molecular stratification in the application of immunotherapy for GEA.	('gastric cancer', 'Disease', (89, 103))	('EBV+', 'Var', (84, 88))	('EBV', 'Species', '10376', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('GEA', 'Chemical', '-', (206, 209))	('MSI', 'Disease', (76, 79))	('patients', 'Species', '9606', (62, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))
752690	31727671	Although systematic validation of the accuracy, reliability, and reproducibility of ctDNA assays is a work in progress, clinical utility has been demonstrated in several studies on GEA with amplifications of ERBB2, EGFR, MET, and FGFR2.	('ERBB2', 'Gene', (208, 213))	('FGFR2', 'Gene', '2263', (230, 235))	('EGFR', 'Gene', '1956', (215, 219))	('EGFR', 'Gene', (215, 219))	('GEA', 'Chemical', '-', (181, 184))	('amplifications', 'Var', (190, 204))	('MET', 'Gene', (221, 224))	('FGFR2', 'Gene', (230, 235))	('ERBB2', 'Gene', '2064', (208, 213))
752691	31727671	In an umbrella trial of targeted therapy in GEA, approximately one-third of patients had discordant oncogene amplification between synchronous primary tumor and metastatic biopsies, leading to treatment reassignment.	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('GEA', 'Chemical', '-', (44, 47))	('tumor', 'Disease', (151, 156))	('amplification', 'Var', (109, 122))	('oncogene', 'Gene', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
752693	31727671	Biomarker detection and validation might also improve with ctDNA analysis; for example, higher EGFR copy number in ctDNA correlated with response to anti-EGFR therapy, and a similar finding was reported for FGFR2 amplification and response to an FGFR TKI.	('EGFR', 'Gene', (154, 158))	('higher', 'PosReg', (88, 94))	('response', 'MPA', (137, 145))	('FGFR2', 'Gene', (207, 212))	('EGFR', 'Gene', '1956', (95, 99))	('copy number', 'Var', (100, 111))	('FGFR2', 'Gene', '2263', (207, 212))	('EGFR', 'Gene', '1956', (154, 158))	('EGFR', 'Gene', (95, 99))
752694	31727671	Additionally, ctDNA mutational load predicted response to pembrolizumab in MSI-high metastatic gastric cancer, and lower ctDNA levels at six weeks post-treatment predicted improved outcomes.	('ctDNA levels', 'MPA', (121, 133))	('mutational load', 'Var', (20, 35))	('response', 'MPA', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('lower', 'NegReg', (115, 120))	('gastric cancer', 'Disease', (95, 109))	('ctDNA', 'Gene', (14, 19))	('predicted', 'Reg', (36, 45))	('pembrolizumab', 'Chemical', 'MESH:C582435', (58, 71))
752696	31727671	PANGEA (NCT02213289) and VIKTORY (NCT02299648) are both biomarker-based umbrella trials for metastatic GEA or gastric cancer, respectively, that prospectively use tumor genomic profiling to assign patients to targeted therapy treatment arms spanning key RTK pathway amplifications and mutations.	('gastric cancer', 'Disease', (110, 124))	('NCT02213289', 'Var', (8, 19))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('patients', 'Species', '9606', (197, 205))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('NCT02299648', 'Var', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('metastatic GEA', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('GEA', 'Chemical', '-', (3, 6))	('tumor', 'Disease', (163, 168))	('GEA', 'Chemical', '-', (103, 106))
752702	31727671	The diversity of oncogenic amplifications in the CIN subtype of GEA have made it challenging to identify a unifying vulnerability of these tumors.	('CIN', 'Phenotype', 'HP:0040012', (49, 52))	('GEA', 'Chemical', '-', (64, 67))	('CIN', 'Disease', (49, 52))	('amplifications', 'Var', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('CIN', 'Disease', 'MESH:D007674', (49, 52))
752706	31727671	One example followed the recognition that CIN GEAs frequently activate the KRAS oncogene not via canonical mutations seen in many other cancers but through focal high-level genomic amplification comprising 14% of CIN GEA and causing as much as several hundred-fold overexpression of wild type KRAS protein.	('KRAS', 'Gene', (293, 297))	('CIN GEAs', 'Disease', 'MESH:D007674', (42, 50))	('CIN', 'Phenotype', 'HP:0040012', (42, 45))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('CIN GEAs', 'Disease', (42, 50))	('cancers', 'Disease', (136, 143))	('activate', 'PosReg', (62, 70))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('KRAS', 'Gene', '3845', (293, 297))	('CIN GEA', 'Disease', 'MESH:D007674', (213, 220))	('KRAS', 'Gene', (75, 79))	('CIN GEA', 'Disease', (213, 220))	('CIN', 'Phenotype', 'HP:0040012', (213, 216))	('CIN GEA', 'Disease', 'MESH:D007674', (42, 49))	('overexpression', 'PosReg', (265, 279))	('genomic', 'Var', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('KRAS', 'Gene', '3845', (75, 79))
752709	31727671	Phase 1 trials are underway to evaluate the safety and tolerability of the SHP2 inhibitors TNO155 (NCT03114319) and RMC-4630 (NCT03634982) in advanced solid tumors.	('NCT03634982', 'Var', (126, 137))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('RMC-4630', 'Chemical', '-', (116, 124))	('TNO155', 'Chemical', '-', (91, 97))	('tumors', 'Disease', (157, 163))	('NCT03114319', 'Var', (99, 110))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('SHP2', 'Gene', '5781', (75, 79))	('SHP2', 'Gene', (75, 79))
752711	31727671	Epigenetic silencing or deletion of CDKN2A is common, particularly in EAC and EBV+ gastric cancer, as are amplifications of cyclin-CDK proteins that coordinate the G1/S transition, specifically CCNE1, CCND1, and CDK6.	('CDKN2A', 'Gene', (36, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('CDK', 'Gene', (131, 134))	('deletion', 'Var', (24, 32))	('EBV', 'Species', '10376', (78, 81))	('CDK', 'Gene', 'None', (212, 215))	('CCND1', 'Gene', '595', (201, 206))	('CCND1', 'Gene', (201, 206))	('CDK', 'Gene', 'None', (36, 39))	('CDK6', 'Gene', '1021', (212, 216))	('CDKN2A', 'Gene', '1029', (36, 42))	('gastric cancer', 'Disease', (83, 97))	('cyclin', 'Gene', '5111', (124, 130))	('CCNE1', 'Gene', (194, 199))	('CDK6', 'Gene', (212, 216))	('CDK', 'Gene', 'None', (131, 134))	('Epigenetic silencing', 'Var', (0, 20))	('CDK', 'Gene', (212, 215))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('CCNE1', 'Gene', '898', (194, 199))	('cyclin', 'Gene', (124, 130))	('EAC', 'Disease', (70, 73))	('CDK', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
752712	31727671	On the surface, these alterations seemingly converge on a final common pathway to phosphorylate and disable the RB1 tumor suppressor.	('RB1', 'Gene', '5925', (112, 115))	('phosphorylate', 'MPA', (82, 95))	('disable', 'NegReg', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('alterations', 'Var', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('RB1', 'Gene', (112, 115))	('tumor', 'Disease', (116, 121))	('converge', 'Reg', (44, 52))
752713	31727671	Interestingly, however, primary RB1 deletion rarely occurs in CIN GEA, raising the possibility that cyclin-CDK amplifications may also promote distinct oncogenic functions and confer specific genetic dependencies independent of RB1 inhibition.	('promote', 'PosReg', (135, 142))	('deletion', 'Var', (36, 44))	('CDK', 'Gene', 'None', (107, 110))	('RB1', 'Gene', (32, 35))	('dependencies', 'Disease', (200, 212))	('oncogenic functions', 'CPA', (152, 171))	('RB1', 'Gene', (228, 231))	('cyclin', 'Gene', '5111', (100, 106))	('RB1', 'Gene', '5925', (32, 35))	('CIN GEA', 'Disease', 'MESH:D007674', (62, 69))	('RB1', 'Gene', '5925', (228, 231))	('dependencies', 'Disease', 'MESH:D019966', (200, 212))	('CIN GEA', 'Disease', (62, 69))	('CDK', 'Gene', (107, 110))	('CIN', 'Phenotype', 'HP:0040012', (62, 65))	('cyclin', 'Gene', (100, 106))
752714	31727671	CDK4/6 inhibition is a candidate therapeutic strategy for GEA with amplifications of CCND1 or CDK6, or silencing/deletion of CDKN2A.	('CCND1', 'Gene', '595', (85, 90))	('silencing/deletion', 'Var', (103, 121))	('CDKN2A', 'Gene', '1029', (125, 131))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('GEA', 'Chemical', '-', (58, 61))	('CCND1', 'Gene', (85, 90))	('CDKN2A', 'Gene', (125, 131))	('CDK6', 'Gene', (94, 98))	('CDK4/6', 'Gene', (0, 6))	('CDK6', 'Gene', '1021', (94, 98))	('inhibition', 'NegReg', (7, 17))	('amplifications', 'Var', (67, 81))
752729	31727671	More broadly, there is a widening spectrum of therapeutic agents in the DNA damage sphere, for example, inhibitors of CHEK1, ATR, and WEE1, which may be combined with PARP inhibition to attack cancer cells with high basal replication stress, even when HR remains intact.	('PARP', 'Gene', (167, 171))	('ATR', 'Gene', (125, 128))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('CHEK1', 'Gene', '1111', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('WEE1', 'Gene', '7465', (134, 138))	('ATR', 'Gene', '545', (125, 128))	('WEE1', 'Gene', (134, 138))	('CHEK1', 'Gene', (118, 123))	('inhibitors', 'Var', (104, 114))	('PARP', 'Gene', '1302', (167, 171))
752734	31727671	The phase 2 FAST trial randomized advanced/recurrent gastric and GEJ cancer patients, including 45% with diffuse type histology, to first-line chemotherapy with or without IMAB362 (also known as claudiximab or zolbetuximab), a chimeric monoclonal antibody against CLDN18.2 that functions not via inhibition of CLDN18.2 but instead by using CLDN18.2 as a specific marker for antibody binding to elicit immune activation (NCT01630083).	('patients', 'Species', '9606', (76, 84))	('CLDN18', 'Gene', (340, 346))	('claudiximab', 'Chemical', 'MESH:C585662', (195, 206))	('CLDN18', 'Gene', (264, 270))	('zolbetuximab', 'Chemical', 'MESH:C585662', (210, 222))	('CLDN18', 'Gene', '51208', (340, 346))	('IMAB362', 'Chemical', 'MESH:C585662', (172, 179))	('CLDN18', 'Gene', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CLDN18', 'Gene', '51208', (310, 316))	('CLDN18', 'Gene', '51208', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('NCT01630083', 'Var', (420, 431))	('cancer', 'Disease', (69, 75))
752736	31727671	The addition of IMAB362 improved ORR (39% vs. 25%, p=0.022), the primary endpoint of PFS (7.5 vs. 5.3 months, p<0.0005), and OS (13.0 vs. 8.4 months, p=0.0008), with even greater benefit in the subgroup with CLDN18.2 IHC >=2+ in at least 70% of cells.	('improved', 'PosReg', (24, 32))	('IMAB362', 'Chemical', 'MESH:C585662', (16, 23))	('CLDN18', 'Gene', (208, 214))	('CLDN18', 'Gene', '51208', (208, 214))	('IHC >=2+', 'Var', (217, 225))	('IMAB362', 'Gene', (16, 23))	('ORR', 'MPA', (33, 36))
752826	31191025	Proliferation, apoptosis, cell cycle, migration and invasion were examined in ESCC cells knocked down for LINC00152 knockdown by siRNA.	('LINC00152', 'Gene', '112597', (106, 115))	('LINC00152', 'Gene', (106, 115))	('knockdown', 'Var', (116, 125))
752827	31191025	Furthermore, an mRNA microarray was performed in ESCC cells with LINC00152 knockdown.	('knockdown', 'Var', (75, 84))	('LINC00152', 'Gene', '112597', (65, 74))	('LINC00152', 'Gene', (65, 74))
752829	31191025	Furthermore, ESCC patients with LINC00152 overexpression had significantly shorter overall survival (P=0.007), and LINC00152 overexpression was an independent risk factor for overall survival of ESCC patients.	('LINC00152', 'Gene', (32, 41))	('overall survival', 'MPA', (83, 99))	('overexpression', 'Var', (42, 56))	('LINC00152', 'Gene', '112597', (115, 124))	('patients', 'Species', '9606', (200, 208))	('ESCC', 'Disease', (13, 17))	('LINC00152', 'Gene', '112597', (32, 41))	('LINC00152', 'Gene', (115, 124))	('shorter', 'NegReg', (75, 82))	('patients', 'Species', '9606', (18, 26))
752830	31191025	LINC00152 knockdown inhibited the proliferation, migration and invasion of ESCC cells in vitro.	('proliferation', 'CPA', (34, 47))	('LINC00152', 'Gene', (0, 9))	('migration', 'CPA', (49, 58))	('ESCC', 'Disease', (75, 79))	('invasion of', 'CPA', (63, 74))	('LINC00152', 'Gene', '112597', (0, 9))	('inhibited', 'NegReg', (20, 29))	('knockdown', 'Var', (10, 19))
752881	31191025	Furthermore, Kaplan-Meier analysis demonstrated that ESCC patients in the high LINC00152 expression group had a significantly shorter OS compared with patients in the low LINC00152 expression group (P=0.007, Figure 2E).	('LINC00152', 'Gene', (171, 180))	('shorter', 'NegReg', (126, 133))	('ESCC', 'Disease', (53, 57))	('high', 'Var', (74, 78))	('LINC00152', 'Gene', (79, 88))	('patients', 'Species', '9606', (151, 159))	('LINC00152', 'Gene', '112597', (171, 180))	('patients', 'Species', '9606', (58, 66))	('LINC00152', 'Gene', '112597', (79, 88))
752890	31191025	We also evaluated cell cycle distribution in ESCC cells downregulated for LINC00152 and found that both TE1 and TE13 cells with LINC00152 knockdown showed an S phase arrest (Figure 4A).	('knockdown', 'Var', (138, 147))	('S phase arrest', 'CPA', (158, 172))	('LINC00152', 'Gene', '112597', (128, 137))	('LINC00152', 'Gene', '112597', (74, 83))	('downregulated', 'NegReg', (56, 69))	('cell', 'CPA', (18, 22))	('LINC00152', 'Gene', (128, 137))	('LINC00152', 'Gene', (74, 83))
752891	31191025	However, silencing LINC00152 had no impact on the apoptosis of ESCC cells (Figure 4B).	('silencing', 'Var', (9, 18))	('LINC00152', 'Gene', '112597', (19, 28))	('apoptosis', 'CPA', (50, 59))	('LINC00152', 'Gene', (19, 28))
752894	31191025	In addition, Matrigel assay revealed that the invasion of ESCC cells was inhibited by LINC00152 knockdown compared with NC cells (Figure 5B).	('knockdown', 'Var', (96, 105))	('LINC00152', 'Gene', '112597', (86, 95))	('LINC00152', 'Gene', (86, 95))	('inhibited', 'NegReg', (73, 82))	('invasion of', 'CPA', (46, 57))
752897	31191025	To uncover the potential oncogenic mechanism of LINC00152, we performed mRNA array analysis in LINC00152 knockdown ESCC cells compared with controls and analyzed the results by Gene Set Enrichment Analysis (GSEA).	('LINC00152', 'Gene', '112597', (48, 57))	('LINC00152', 'Gene', (95, 104))	('GSEA', 'Chemical', '-', (207, 211))	('LINC00152', 'Gene', (48, 57))	('knockdown', 'Var', (105, 114))	('LINC00152', 'Gene', '112597', (95, 104))	('men', 'Species', '9606', (192, 195))
752898	31191025	The differentially expressed genes in ESCC cells with LINC00152 knockdown were enriched in the cell cycle pathway and the SNARE interactions in vesicular transport pathway (Figure 6A).	('vesicular transport pathway', 'Pathway', (144, 171))	('cell cycle pathway', 'Pathway', (95, 113))	('LINC00152', 'Gene', '112597', (54, 63))	('differentially', 'Reg', (4, 18))	('knockdown', 'Var', (64, 73))	('LINC00152', 'Gene', (54, 63))
752900	31191025	Western blot analysis indicated that LINC00152 knockdown significantly increased protein levels of MAD2L1, CDK6 and STX3, while STX12 level was decreased compared with negative controls (Figure 6B).	('LINC00152', 'Gene', (37, 46))	('STX12', 'Gene', '23673', (128, 133))	('MAD2L1', 'Gene', (99, 105))	('STX3', 'Gene', (116, 120))	('STX12', 'Gene', (128, 133))	('STX3', 'Gene', '6809', (116, 120))	('LINC00152', 'Gene', '112597', (37, 46))	('knockdown', 'Var', (47, 56))	('MAD2L1', 'Gene', '4085', (99, 105))	('protein levels', 'MPA', (81, 95))	('CDK6', 'Gene', (107, 111))	('increased', 'PosReg', (71, 80))	('CDK6', 'Gene', '1021', (107, 111))
752905	31191025	The dysregulation of LINC00152 has been found in various cancers including lung cancer, gastric cancer, hepatocellular cancer, pancreatic ductal adenocarcinoma, gallbladder cancer, renal cell cancer, glioma and tongue squamous cell cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('dysregulation', 'Var', (4, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('tongue squamous cell cancer', 'Phenotype', 'HP:0030413', (211, 238))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('LINC00152', 'Gene', '112597', (21, 30))	('hepatocellular cancer', 'Disease', (104, 125))	('glioma', 'Disease', (200, 206))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (104, 125))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (57, 64))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('tongue squamous cell cancer', 'Disease', 'MESH:D002294', (211, 238))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (127, 159))	('renal cell cancer', 'Disease', (181, 198))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (104, 125))	('gallbladder cancer', 'Disease', (161, 179))	('renal cell cancer', 'Disease', 'MESH:C538614', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('lung cancer', 'Disease', (75, 86))	('renal cell cancer', 'Phenotype', 'HP:0005584', (181, 198))	('found', 'Reg', (40, 45))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('pancreatic ductal adenocarcinoma', 'Disease', (127, 159))	('LINC00152', 'Gene', (21, 30))	('gastric cancer', 'Disease', (88, 102))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (127, 159))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (218, 238))	('gallbladder cancer', 'Disease', 'MESH:D005706', (161, 179))	('tongue squamous cell cancer', 'Disease', (211, 238))
752906	31191025	LINC00152 has been shown to exhibit oncogenic functions and regulate other genes by epigenetic modifications and interactions with proteins and miRNAs.	('LINC00152', 'Gene', (0, 9))	('regulate', 'Reg', (60, 68))	('proteins', 'Protein', (131, 139))	('oncogenic functions', 'CPA', (36, 55))	('LINC00152', 'Gene', '112597', (0, 9))	('interactions', 'Interaction', (113, 125))	('epigenetic modifications', 'Var', (84, 108))
752919	31191025	Notably, our flow cytometric analysis showed that ESCC cells knocked down for LINC00152 showed an S phase arrest, indicating LINC00152 might promote the proliferation of ECSS cells via regulating the cell cycle, which was consistent with the GSEA results.	('S phase arrest', 'CPA', (98, 112))	('knocked down', 'Var', (61, 73))	('LINC00152', 'Gene', '112597', (125, 134))	('regulating', 'Reg', (185, 195))	('LINC00152', 'Gene', '112597', (78, 87))	('GSEA', 'Chemical', '-', (242, 246))	('LINC00152', 'Gene', (125, 134))	('cell cycle', 'CPA', (200, 210))	('proliferation', 'CPA', (153, 166))	('promote', 'PosReg', (141, 148))	('LINC00152', 'Gene', (78, 87))
752923	31191025	Breast cancer patients with STX3 overexpression had advanced TNM stage and shorter overall and disease-free survival compared with patients with low STX3 expression.	('patients', 'Species', '9606', (131, 139))	('STX3', 'Gene', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('STX3', 'Gene', '6809', (149, 153))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('TNM', 'Gene', (61, 64))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('advanced', 'PosReg', (52, 60))	('overexpression', 'Var', (33, 47))	('shorter', 'NegReg', (75, 82))	('STX3', 'Gene', (28, 32))	('Breast cancer', 'Disease', (0, 13))	('TNM', 'Gene', '10178', (61, 64))	('STX3', 'Gene', '6809', (28, 32))	('patients', 'Species', '9606', (14, 22))
752941	30719206	Inhibition of receptor expression by siRNA selectively reduced CMKLR1 or GPR1 and inhibited the action of chemerin indicating that both receptors contributed to the functional response.	('reduced', 'NegReg', (55, 62))	('inhibited', 'NegReg', (82, 91))	('chemerin', 'Gene', (106, 114))	('CMKLR1', 'MPA', (63, 69))	('GPR1', 'Gene', (73, 77))	('chemerin', 'Gene', '5919', (106, 114))	('Inhibition', 'Var', (0, 10))
752948	30719206	It is well established that infection with Helicobacter pylori carries an increased risk of gastric cancer but progression occurs over many decades following a well document sequence of chronic inflammation, atrophy, metaplasia and dysplasia.	('Helicobacter pylori', 'Species', '210', (43, 62))	('metaplasia and dysplasia', 'Disease', 'MESH:D008679', (217, 241))	('atrophy', 'Disease', 'MESH:D001284', (208, 215))	('gastric cancer', 'Disease', (92, 106))	('inflammation', 'Disease', (194, 206))	('infection', 'Disease', (28, 37))	('inflammation', 'Disease', 'MESH:D007249', (194, 206))	('atrophy', 'Disease', (208, 215))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('infection', 'Disease', 'MESH:D007239', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Helicobacter pylori', 'Var', (43, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (74, 106))
752970	30719206	There is a similar transformation, which has been characterised as epithelial-mesenchymal transition (EMT), in response to gastrin which is protein kinase C (PKC) mediated; in the present study inhibition of PKC using Ro-320432 also abolished the transformation in response to chemerin (Figure 3D).	('PKC', 'Gene', '112476', (158, 161))	('gastrin', 'Gene', '2520', (123, 130))	('Ro-320432', 'Chemical', '-', (218, 227))	('protein kinase C', 'Gene', (140, 156))	('chemerin', 'Gene', (277, 285))	('chemerin', 'Gene', '5919', (277, 285))	('gastrin', 'Gene', (123, 130))	('PKC', 'Gene', (208, 211))	('protein kinase C', 'Gene', '112476', (140, 156))	('PKC', 'Gene', (158, 161))	('PKC', 'Gene', '112476', (208, 211))	('inhibition', 'Var', (194, 204))
752972	30719206	These showed increased migration in response to both chemerin and phorbol 12-myristate 13-acetate (PMA) (Figure 4B); the effect of chemerin was inhibited by 1 muM CCX832 (Figure 4C), 5 muM alpha-NETA (Figure 4D) and 1 muM Ro-320432 (Figure 4E).	('chemerin', 'Gene', '5919', (53, 61))	('PMA', 'Chemical', 'MESH:D013755', (99, 102))	('migration', 'CPA', (23, 32))	('muM', 'Gene', '56925', (218, 221))	('increased', 'PosReg', (13, 22))	('muM', 'Gene', '56925', (185, 188))	('chemerin', 'Gene', '5919', (131, 139))	('muM', 'Gene', (218, 221))	('muM', 'Gene', '56925', (159, 162))	('muM', 'Gene', (185, 188))	('muM', 'Gene', (159, 162))	('phorbol 12-myristate 13-acetate', 'Chemical', 'MESH:D013755', (66, 97))	('CCX832', 'Chemical', '-', (163, 169))	('alpha-NETA', 'Chemical', '-', (189, 199))	('chemerin', 'Gene', (53, 61))	('inhibited', 'NegReg', (144, 153))	('chemerin', 'Gene', (131, 139))	('Ro-320432', 'Chemical', '-', (222, 231))	('CCX832', 'Var', (163, 169))	('Ro-320432', 'Var', (222, 231))
752975	30719206	In Boyden chamber migration assays, selective knockdown of CMKLR1 and GPR1 significantly inhibited the response to chemerin, although in each case it was not completely suppressed (Figure 5B).	('chemerin', 'Gene', '5919', (115, 123))	('CMKLR1', 'Gene', (59, 65))	('knockdown', 'Var', (46, 55))	('inhibited', 'NegReg', (89, 98))	('GPR1', 'Gene', (70, 74))	('chemerin', 'Gene', (115, 123))
752977	30719206	Similarly, in invasion assays, siRNA knockdown of both receptors inhibited but did not abolish the response to chemerin, while that to PMA was unaffected (Figure 5C).	('PMA', 'Chemical', 'MESH:D013755', (135, 138))	('abolish', 'NegReg', (87, 94))	('knockdown', 'Var', (37, 46))	('inhibited', 'NegReg', (65, 74))	('chemerin', 'Gene', (111, 119))	('chemerin', 'Gene', '5919', (111, 119))
752982	30719206	In keeping with the observation that the effects of chemerin are mediated by PKC, the addition of Ro-320432 reversed the decrease in TIMP-1 and TIMP-2 abundance in response to chemerin (Figure 7A, right).	('TIMP-1', 'Gene', '7076', (133, 139))	('TIMP-2', 'Gene', (144, 150))	('Ro-320432', 'Var', (98, 107))	('Ro-320432', 'Chemical', '-', (98, 107))	('chemerin', 'Gene', (52, 60))	('chemerin', 'Gene', '5919', (52, 60))	('PKC', 'Gene', (77, 80))	('TIMP-2', 'Gene', '7077', (144, 150))	('decrease', 'NegReg', (121, 129))	('TIMP-1', 'Gene', (133, 139))	('PKC', 'Gene', '112476', (77, 80))	('chemerin', 'Gene', (176, 184))	('chemerin', 'Gene', '5919', (176, 184))
752994	30719206	Previously, primary esophageal squamous cancers were shown to express CMKLR1; neuroblastoma cells also express both receptors and there is evidence that chemerin acts via CMKLR1 in an alpha-NETA sensitive mechanism to increase MMP-2 to promote tumor growth.	('chemerin', 'Gene', (153, 161))	('MMP-2', 'Gene', '4313', (227, 232))	('squamous cancer', 'Phenotype', 'HP:0002860', (31, 46))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('neuroblastoma', 'Disease', (78, 91))	('neuroblastoma', 'Phenotype', 'HP:0003006', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('neuroblastoma', 'Disease', 'MESH:D009447', (78, 91))	('promote', 'PosReg', (236, 243))	('chemerin', 'Gene', '5919', (153, 161))	('MMP-2', 'Gene', (227, 232))	('increase', 'PosReg', (218, 226))	('esophageal squamous cancers', 'Disease', (20, 47))	('alpha-NETA', 'Chemical', '-', (184, 194))	('tumor', 'Disease', (244, 249))	('CMKLR1', 'Var', (171, 177))	('esophageal squamous cancers', 'Disease', 'MESH:D004938', (20, 47))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
753029	30719206	The efficiency of knockdown for CMKLR1 and GPR-1 was verified by immunocytochemistry.	('GPR-1', 'Gene', (43, 48))	('knockdown', 'Var', (18, 27))	('GPR-1', 'Gene', '2825', (43, 48))	('CMKLR1', 'Gene', (32, 38))
753031	30719206	Briefly, AGS cells (106 cells, 10cm dishes, approximately 70% confluency) were incubated with chemerin (10 nM), or not, for 24 h; for the last 6 h the medium was changed to one containing either 13C6 lysine and 13C6 arginine (heavy label; chemerin), or 12C6 lysine and 12C6 arginine (control, light label), to dynamically label secreted proteins.	('chemerin', 'Gene', (94, 102))	('12C6 lysine', 'Chemical', '-', (253, 264))	('chemerin', 'Gene', '5919', (94, 102))	('13C6 arginine', 'Chemical', '-', (211, 224))	('chemerin', 'Gene', (239, 247))	('chemerin', 'Gene', '5919', (239, 247))	('12C6 arginine', 'Chemical', '-', (269, 282))	('13C6', 'Var', (195, 199))	('13C6 lysine', 'Chemical', '-', (195, 206))
753045	30579354	Lipophilic simvastatin, but not hydrophilic pravastatin, had significant inhibitory effects on the proliferation of Eca-109 and OE-19 cells.	('simvastatin', 'Chemical', 'MESH:D019821', (11, 22))	('Lipophilic', 'Var', (0, 10))	('Eca-109', 'CPA', (116, 123))	('inhibitory', 'NegReg', (73, 83))	('proliferation', 'CPA', (99, 112))	('pravastatin', 'Chemical', 'MESH:D017035', (44, 55))
753052	30579354	Ogunwobo has found that lipophilic simvastatin, but not hydrophilic pravastatin, can inhibit proliferation of EAC FLO-1 cells in a dose-dependent manner.	('proliferation', 'CPA', (93, 106))	('inhibit', 'NegReg', (85, 92))	('lipophilic', 'Var', (24, 34))	('simvastatin', 'Chemical', 'MESH:D019821', (35, 46))	('EAC', 'Phenotype', 'HP:0011459', (110, 113))	('EAC FLO-1 cells', 'CPA', (110, 125))	('pravastatin', 'Chemical', 'MESH:D017035', (68, 79))
753092	30579354	In the present study, lipophilic simvastatin at the concentration of 30 muM significantly inhibited the proliferation of both Eca-109 and OE-19 cells in a time-dependent manner, while similar effect was not observed with hydrophilic pravastatin.	('simvastatin', 'Chemical', 'MESH:D019821', (33, 44))	('proliferation', 'CPA', (104, 117))	('muM', 'Gene', '56925', (72, 75))	('Eca-109', 'CPA', (126, 133))	('muM', 'Gene', (72, 75))	('inhibited', 'NegReg', (90, 99))	('pravastatin', 'Chemical', 'MESH:D017035', (233, 244))	('lipophilic', 'Var', (22, 32))
753093	30579354	Similarly, lipophilic, but bot hydrophilic stains, have been shown to reduce proliferation in colorectal cancer, breast cancer, thyroid cancer cells in vitro.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('breast cancer', 'Disease', (113, 126))	('thyroid cancer', 'Phenotype', 'HP:0002890', (128, 142))	('thyroid cancer', 'Disease', (128, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('lipophilic', 'Var', (11, 21))	('reduce', 'NegReg', (70, 76))	('thyroid cancer', 'Disease', 'MESH:D013964', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('proliferation', 'CPA', (77, 90))
753095	30579354	found that all the lipophilic simvastatin, lovastatin, and hydrophilic pravastatin inhibited Ras farnesylation and proliferation of OE33 and BIC-1 cells.	('lipophilic', 'Var', (19, 29))	('simvastatin', 'Chemical', 'MESH:D019821', (30, 41))	('BIC-1', 'CellLine', 'CVCL:8092', (141, 146))	('proliferation', 'CPA', (115, 128))	('inhibited', 'NegReg', (83, 92))	('pravastatin', 'Chemical', 'MESH:D017035', (71, 82))	('lovastatin', 'Chemical', 'MESH:D008148', (43, 53))	('Ras farnesylation', 'MPA', (93, 110))
753129	30579354	Our study suggested that lipophilic simvastatin but not hydrophilic pravastatin have a significant inhibition effect on the proliferation of Eca-109 and OE-19 cells, accompanying with the down-regulation of COX-2 and PGE2, which was independent of lipid-lowering effects.	('lipophilic simvastatin', 'Var', (25, 47))	('simvastatin', 'Chemical', 'MESH:D019821', (36, 47))	('proliferation', 'CPA', (124, 137))	('PGE2', 'Chemical', 'MESH:D015232', (217, 221))	('COX-2', 'Gene', (207, 212))	('lipid', 'Chemical', 'MESH:D008055', (248, 253))	('inhibition', 'NegReg', (99, 109))	('PGE2', 'Gene', (217, 221))	('down-regulation', 'NegReg', (188, 203))	('COX-2', 'Gene', '5743', (207, 212))	('pravastatin', 'Chemical', 'MESH:D017035', (68, 79))
753144	30546455	The etiology and pathogenesis of malignant tumor remain unclear, yet most of them have been related with accumulation of relative gene mutation or aberrant expression of gene.	('malignant tumor', 'Disease', 'MESH:D018198', (33, 48))	('aberrant expression', 'Var', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('relative gene mutation', 'Var', (121, 143))	('malignant tumor', 'Disease', (33, 48))	('accumulation', 'PosReg', (105, 117))
753152	30546455	In 2007, study by Seymour et al found that the genetic foundation of cpdm phenotype derived from spontaneous mutation in the mouse Sharpin gene, suggesting that Sharpin may participate in cell proliferation, apoptosis, organ development, immune and inflammatory reaction.	('apoptosis', 'CPA', (208, 217))	('cell proliferation', 'CPA', (188, 206))	('Sharpin', 'Gene', (131, 138))	('Sharpin', 'Gene', '106025', (131, 138))	('organ development', 'CPA', (219, 236))	('rat', 'Species', '10116', (200, 203))	('participate', 'Reg', (173, 184))	('mouse', 'Species', '10090', (125, 130))	('men', 'Species', '9606', (232, 235))	('Sharpin', 'Gene', (161, 168))	('inflammatory reaction', 'CPA', (249, 270))	('Sharpin', 'Gene', '106025', (161, 168))	('mutation', 'Var', (109, 117))
753154	30546455	Our study widely explored the feature of SHARPIN expression in multiple malignant tumors originated from different germ layers by immunohistochemistry and immunofluorescence, confirmed the previous findings about SHARPIN's upregulation in entodermal and mesodermal cancers, and identified SHARPIN's downregulation, loss of function and translocation in ectodermal cancers, offering its complicated characters as oncogene or anti-oncogene.	('loss of function', 'NegReg', (315, 331))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('SHARPIN', 'Gene', (213, 220))	('cancers', 'Disease', 'MESH:D009369', (364, 371))	('ectodermal cancers', 'Disease', (353, 371))	('upregulation', 'PosReg', (223, 235))	('downregulation', 'NegReg', (299, 313))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('translocation', 'Var', (336, 349))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancers', 'Phenotype', 'HP:0002664', (364, 371))	('SHARPIN', 'Gene', (289, 296))	('cancers', 'Disease', (364, 371))	('malignant tumors', 'Disease', 'MESH:D018198', (72, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('ectodermal cancers', 'Disease', 'MESH:D009369', (353, 371))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('SHARPIN', 'Gene', (41, 48))	('cancers', 'Disease', (265, 272))	('malignant tumors', 'Disease', (72, 88))
753203	30546455	After analysis of expression and function between SHARPIN and PTEN in 2010, He et al considered that SHARPIN affects tumorigenesis via inhibition of PTEN function.	('SHARPIN', 'Var', (101, 108))	('PTEN', 'Gene', (62, 66))	('inhibition', 'NegReg', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PTEN', 'Gene', '5728', (62, 66))	('function', 'MPA', (154, 162))	('PTEN', 'Gene', (149, 153))	('tumor', 'Disease', (117, 122))	('PTEN', 'Gene', '5728', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
753245	27595477	Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing due to a lack of robust stratification methods.	('Mutational', 'Var', (0, 10))	('Esophageal adenocarcinoma', 'Disease', (118, 143))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (118, 143))	('esophageal adenocarcinoma', 'Disease', (25, 50))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (25, 50))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (118, 143))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (25, 50))
753246	27595477	Whole-genome sequencing (WGS) analysis of 129 cases demonstrates that this is a heterogeneous cancer dominated by copy number alterations with frequent large scale rearrangements.	('copy number alterations', 'Var', (114, 137))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
753247	27595477	However, mutational signatures reveal three distinct molecular subtypes with potential therapeutic relevance, which we verify in an independent cohort (n=87): i) enriched for BRCA signature with prevalent defects in the homologous recombination pathway; ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; iii) C>A/T mutational pattern with evidence of an ageing imprint.	('BRCA', 'Gene', (175, 179))	('homologous recombination pathway', 'Pathway', (220, 252))	('dominant T>G', 'Var', (258, 270))	('C>A/T', 'Var', (357, 362))	('associated', 'Reg', (290, 300))	('BRCA', 'Gene', '672', (175, 179))
753255	27595477	The emerging genomic biomarkers are based on single nucleotide mutations, structural rearrangements and mutational signatures, and in some instances these have led to the development of stratified trials with the promise of improved patient outcomes.	('patient', 'Species', '9606', (233, 240))	('mutational', 'Var', (104, 114))	('led to', 'Reg', (160, 166))	('single nucleotide mutations', 'Var', (45, 72))
753256	27595477	However, as many of the mutations occur in tumor suppressor genes (TP53, SMAD4, ARID1A), actionable oncogenic mutations have remained elusive.	('SMAD4', 'Gene', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ARID1A', 'Gene', '8289', (80, 86))	('SMAD4', 'Gene', '4089', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ARID1A', 'Gene', (80, 86))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', (43, 48))
753262	27595477	As previously noted, point mutations are abundant in this cancer.	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('point mutations', 'Var', (21, 36))
753265	27595477	Mobile element insertions were found in signalling, cell cycle and cell adhesion regulators: ERBB4 - 6/129, - 5/129, CTNNA2 - 4/129, CDH18 - 3/129, SOX5 - 2/129.	('CDH18', 'Gene', '1016', (133, 138))	('CTNNA2', 'Gene', '1496', (117, 123))	('SOX5', 'Gene', '6660', (148, 152))	('CDH18', 'Gene', (133, 138))	('ERBB4', 'Gene', '2066', (93, 98))	('CTNNA2', 'Gene', (117, 123))	('insertions', 'Var', (15, 25))	('ERBB4', 'Gene', (93, 98))	('SOX5', 'Gene', (148, 152))
753266	27595477	comprised genes like ERBB2, EFGR, RB1, GATA4/6, CCND1, MDM2 among others, while the top significantly deleted loci in the cohort (9p21, 21p11, 3p14, etc.)	('CCND1', 'Gene', '595', (48, 53))	('RB1', 'Gene', '5925', (34, 37))	('GATA4/6', 'Gene', (39, 46))	('EFGR', 'Gene', (28, 32))	('ERBB2', 'Gene', '2064', (21, 26))	('9p21', 'Var', (130, 134))	('GATA4/6', 'Gene', '2626;2627', (39, 46))	('ERBB2', 'Gene', (21, 26))	('MDM2', 'Gene', '4193', (55, 59))	('MDM2', 'Gene', (55, 59))	('RB1', 'Gene', (34, 37))	('CCND1', 'Gene', (48, 53))
753269	27595477	In addition SYNE1 was mutated in 23% of cases, but did not reach significance by MutSigCV.	('mutated', 'Var', (22, 29))	('SYNE1', 'Gene', '23345', (12, 17))	('SYNE1', 'Gene', (12, 17))
753273	27595477	Hence, this is a heterogeneous cancer dominated by copy number alterations and large scale rearrangements.	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('copy number alterations', 'Var', (51, 74))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))
753277	27595477	Since copy number gain events were seen most commonly in ERBB2, EGFR, MET and FGFRs, a panel of small molecular inhibitors was selected to target these RTKs.	('ERBB2', 'Gene', '2064', (57, 62))	('ERBB2', 'Gene', (57, 62))	('copy number', 'Var', (6, 17))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('FGFRs', 'Gene', (78, 83))
753278	27595477	In cell lines with an ERBB2 and a MET amplification, a significant reduction in cell proliferation was observed when both RTKs were inhibited with a GI50 down in the nanomolar range, for example OE33 (Fig.	('ERBB2', 'Gene', '2064', (22, 27))	('inhibited', 'NegReg', (132, 141))	('ERBB2', 'Gene', (22, 27))	('down', 'NegReg', (154, 158))	('MET amplification', 'Var', (34, 51))	('reduction', 'NegReg', (67, 76))	('OE33', 'Var', (195, 199))	('cell proliferation', 'CPA', (80, 98))	('amplification', 'Var', (38, 51))
753282	27595477	Six signatures were prominent (Supplementary Figures 13-14): S17, the hallmark signature of EAC dominated by T>G substitutions in a CTT context and possibly associated with gastric acid reflux - here renamed S17A; a previously uncharacterized variant of this signature combining a relatively higher frequency of T>C substitutions with the classical T>G pattern found in S17, which we call S17B; S3, a complex pattern caused by defects in the BRCA1/2-led homologous recombination pathway; S2, C>T mutations in a TCA/TCT context, an APOBEC-driven hypermutated phenotype; S1, C>T in a *CG context, associated with aging processes; and an S18-like signature, C>A/T dominant in a GCA/TCT context, formerly described in neuroblastoma, breast and stomach cancers (Fig.	('neuroblastoma', 'Phenotype', 'HP:0003006', (714, 727))	('breast and stomach cancers', 'Disease', 'MESH:D013274', (729, 755))	('C>A/T', 'Var', (655, 660))	('S17B', 'Var', (389, 393))	('cancers', 'Phenotype', 'HP:0002664', (748, 755))	('S17B', 'SUBSTITUTION', 'None', (389, 393))	('BRCA1', 'Gene', (442, 447))	('gastric acid reflux', 'Phenotype', 'HP:0002020', (173, 192))	('BRCA1', 'Gene', '672', (442, 447))	('neuroblastoma', 'Disease', 'MESH:D009447', (714, 727))	('cancer', 'Phenotype', 'HP:0002664', (748, 754))	('neuroblastoma', 'Disease', (714, 727))	('S17A', 'Mutation', 'rs1402064476', (208, 212))	('stomach cancers', 'Phenotype', 'HP:0012126', (740, 755))
753284	27595477	When considering the dominant mutation signatures on a per-patient basis, three subgroups of patients became apparent: C>A/T dominant (age, S18-like), DNA Damage Repair (DDR) impaired (BRCA), and mutagenic (predominantly S17A or S17B) (Fig.	('BRCA', 'Gene', '672', (185, 189))	('S17A', 'Var', (221, 225))	('mutagenic', 'Var', (196, 205))	('BRCA', 'Gene', (185, 189))	('patient', 'Species', '9606', (59, 66))	('DNA', 'MPA', (151, 154))	('S17B', 'Var', (229, 233))	('S17A', 'Mutation', 'rs1402064476', (221, 225))	('patient', 'Species', '9606', (93, 100))	('S17B', 'SUBSTITUTION', 'None', (229, 233))	('impaired', 'NegReg', (175, 183))	('patients', 'Species', '9606', (93, 101))
753287	27595477	Of note, the C>A/T dominant subgroup had a two-fold higher frequency of ERBB2/MET co-amplifications, but this did not reach statistical significance.	('co-amplifications', 'Var', (82, 99))	('ERBB2', 'Gene', '2064', (72, 77))	('C>A/T', 'Var', (13, 18))	('higher', 'PosReg', (52, 58))	('ERBB2', 'Gene', (72, 77))
753292	27595477	It is therefore likely that a pathway-level disruption of HR contributes to the BRCA-like mutational signature rather than mutations of BRCA genes.	('disruption', 'Var', (44, 54))	('BRCA', 'Gene', '672', (80, 84))	('BRCA', 'Gene', (136, 140))	('BRCA', 'Gene', (80, 84))	('BRCA', 'Gene', '672', (136, 140))
753296	27595477	Defects in ARID1A impair this process and may sensitise cells in vitro and in vivo to PARP inhibition (PARPi).	('ARID1A', 'Gene', '8289', (11, 17))	('ARID1A', 'Gene', (11, 17))	('Defects', 'Var', (0, 7))	('PARP', 'Gene', '1302', (103, 107))	('PARP', 'Gene', (103, 107))	('sensitise', 'Reg', (46, 55))	('PARP', 'Gene', '1302', (86, 90))	('PARP', 'Gene', (86, 90))	('impair', 'NegReg', (18, 24))
753300	27595477	We found a higher density of CD8+ T cells in a subset of available samples from the mutagenic signature subgroup compared with samples from the other subgroups (Fig.	('mutagenic signature', 'Var', (84, 103))	('CD8', 'Gene', '925', (29, 32))	('CD8', 'Gene', (29, 32))	('higher', 'PosReg', (11, 17))
753302	27595477	To start to test this hypothesis, we used newly derived cell line models from patients in the OCCAMS consortium with an available germline reference sequence from which we could derive the signatures: OES127, DDR impaired profile; MFD, mutagenic profile; CAM02 C>A/T dominant profile (Fig.	('patients', 'Species', '9606', (78, 86))	('OES127', 'Var', (201, 207))	('CAM02 C>A/T', 'Var', (255, 266))	('DDR', 'MPA', (209, 212))
753306	27595477	Next we tested the efficacy of Wee1/Chk1 inhibitors given the high frequency of TP53 mutation in this disease.	('tested', 'Reg', (8, 14))	('Chk1', 'Gene', (36, 40))	('Wee1', 'Gene', (31, 35))	('Chk1', 'Gene', '1111', (36, 40))	('TP53', 'Gene', '7157', (80, 84))	('Wee1', 'Gene', '7465', (31, 35))	('mutation', 'Var', (85, 93))	('TP53', 'Gene', (80, 84))
753307	27595477	Several recent studies revealed that pharmacological inhibition of G2/M-phase checkpoint regulators Wee1 and Chk1/2 resulted in an antitumorigenic effect in some highly mutated cancers.	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('Wee1', 'Gene', (100, 104))	('Chk1/2', 'Gene', (109, 115))	('Wee1', 'Gene', '7465', (100, 104))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('Chk1/2', 'Gene', '1111;11200', (109, 115))	('highly', 'Var', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
753310	27595477	In the MFD cells with a mutagenic signature, there was a 25-fold and 10-fold increased sensitivity in response to the Wee1 and Chk1/2 inhibitor, respectively, compared with the CAM02 cells from the C>A/T dominant subgroup.	('mutagenic', 'Var', (24, 33))	('sensitivity', 'MPA', (87, 98))	('Wee1', 'Gene', (118, 122))	('response', 'MPA', (102, 110))	('Chk1/2', 'Gene', (127, 133))	('Wee1', 'Gene', '7465', (118, 122))	('increased', 'PosReg', (77, 86))	('Chk1/2', 'Gene', '1111;11200', (127, 133))
753312	27595477	Whole-genome sequencing of 129 EAC patients has unveiled a high prevalence of large-scale alterations that may play an important role in the development of this cancer.	('alterations', 'Var', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('patients', 'Species', '9606', (35, 43))	('cancer', 'Disease', (161, 167))	('EAC', 'Disease', (31, 34))
753313	27595477	Similarly to ovarian, breast and lung cancers which have been described as 'copy number driven', relatively few genes were recurrently point-mutated (except TP53), but there were frequent recurrent amplifications in sites harbouring oncogenes, deletions of important cell cycle components (CDKN2A, CDKN2B) and rearrangements of genes like RUNX1, frequently translocated in leukemias.	('TP53', 'Gene', (157, 161))	('leukemias', 'Disease', 'MESH:D007938', (373, 382))	('CDKN2A', 'Gene', (290, 296))	('rearrangements', 'Var', (310, 324))	('oncogenes', 'Gene', (233, 242))	('leukemias', 'Phenotype', 'HP:0001909', (373, 382))	('RUNX1', 'Gene', (339, 344))	('RUNX1', 'Gene', '861', (339, 344))	('amplifications', 'Reg', (198, 212))	('CDKN2A', 'Gene', '1029', (290, 296))	('leukemias', 'Disease', (373, 382))	('TP53', 'Gene', '7157', (157, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancers', 'Phenotype', 'HP:0100526', (33, 45))	('CDKN2B', 'Gene', (298, 304))	('breast and lung cancers', 'Disease', 'MESH:D001943', (22, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('deletions', 'Var', (244, 253))	('CDKN2B', 'Gene', '1030', (298, 304))
753314	27595477	Although all six mutational signatures are seen to some extent in most patient tumors, three distinct dominant subtypes, namely DDR impaired, C>A/T dominant, and mutagenic, point to specific etiological factors or genetic instabilities dominating the development of any individual's EAC.	('DDR impaired', 'Disease', (128, 140))	('C>A/T', 'Var', (142, 147))	('EAC', 'Disease', (283, 286))	('mutagenic', 'Var', (162, 171))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('patient', 'Species', '9606', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
753321	27595477	Both the nonsynonymous mutation burden and the neoantigen level, as well as CD8+ cell infiltration, have been shown to be good biomarkers in predicting response to immunotherapy in both smoking-related non-small cell lung cancer and melanoma.	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (202, 228))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (202, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (206, 228))	('CD8', 'Gene', '925', (76, 79))	('CD8', 'Gene', (76, 79))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('melanoma', 'Disease', (233, 241))	('non-small cell lung cancer', 'Disease', (202, 228))	('nonsynonymous mutation', 'Var', (9, 31))
753326	27595477	with synthetic lethality approaches combined with radiotherapy or mutant TP53 reactivating drugs.	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('mutant', 'Var', (66, 72))
753350	27595477	The signature which we termed S17A had a higher cosine similarity distance compared to S17B (0.98 versus 0.92), and we hence considered it to be more reflective of the signature reported in the literature.	('S17A', 'Mutation', 'rs1402064476', (30, 34))	('S17B', 'SUBSTITUTION', 'None', (87, 91))	('S17B', 'Var', (87, 91))	('cosine similarity distance', 'MPA', (48, 74))	('higher', 'PosReg', (41, 47))
753358	27595477	The probability of a gene being affected by M nonsynonymous mutations in the cohort follows a poisson binomial distribution and is calculated relative to a basal probability depending on the number of nonsynonymous (nns) and synonymous (ns) mutations, gene size (L), local mutational density for the locus (d) and total length of coding regions in the genome (E) as follows:  Subsequently, we catalogued those that harboured nonsynonymous somatic mutations/indels with possible deleterious effect (as predicted by SIFT /PolyPhen) or copy number alterations (amplifications and deletions using the defined GISTIC cut-offs) in our cohort.	('copy number alterations', 'Var', (533, 556))	('mutations/indels', 'Var', (447, 463))	('SIFT', 'Disease', (514, 518))	('mutations', 'Var', (60, 69))	('SIFT', 'Disease', 'None', (514, 518))
753369	27595477	Small molecular inhibitors used for treatment were: Lapatinib, AZD-4547, Olaparib, MK-1775 and AZD-7762 (BioVision), Crizotinib (LKT Labs) and Topotecan (Cayman Chemical).	('MK-1775', 'Chemical', 'MESH:C549567', (83, 90))	('AZD-4547', 'Chemical', 'MESH:C572463', (63, 71))	('Lapatinib', 'Chemical', 'MESH:D000077341', (52, 61))	('Crizotinib', 'Chemical', 'MESH:D000077547', (117, 127))	('Topotecan', 'Chemical', 'MESH:D019772', (143, 152))	('AZD-7762', 'Chemical', 'MESH:C532363', (95, 103))	('AZD-4547', 'Var', (63, 71))	('Olaparib', 'Chemical', 'MESH:C531550', (73, 81))	('AZD-7762', 'Var', (95, 103))	('MK-1775', 'Var', (83, 90))
753453	27524911	Li et al reported that the 1-year and 3-year OS rates were 81% and 36.5%, respectively, for nonsurgical ESCC patients treated with chemoradiation therapy, including docetaxel and cisplatin, and a radiation dose of 60-64 Gy, whereas the 1-year and 3-year OS rates were 84.4% and 45.6%, respectively, for advanced esophageal cancer treated with 5-FU, cisplatin, and a radiation dose of 60 Gy.	('nonsurgical', 'Disease', (92, 103))	('patients', 'Species', '9606', (109, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (349, 358))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('cisplatin', 'Var', (349, 358))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('5-FU', 'Chemical', 'MESH:D005472', (343, 347))	('esophageal cancer', 'Disease', (312, 329))	('esophageal cancer', 'Disease', 'MESH:D004938', (312, 329))	('docetaxel', 'Chemical', 'MESH:D000077143', (165, 174))
753462	27524911	Patients with a high ERCC1 expression had a poor prognosis than those with low expression.	('ERCC1', 'Gene', (21, 26))	('high', 'Var', (16, 20))	('ERCC1', 'Gene', '2067', (21, 26))	('expression', 'MPA', (27, 37))	('Patients', 'Species', '9606', (0, 8))
753466	27524911	In another study including 175 cases of esophageal carcinoma, ERCC1-negative patients benefited from cisplatin before surgery, but high ERCC1 expression was correlated with better long-term prognosis.	('ERCC1', 'Gene', (136, 141))	('cisplatin', 'MPA', (101, 110))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (40, 60))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (40, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('ERCC1', 'Gene', (62, 67))	('ERCC1', 'Gene', '2067', (62, 67))	('patients', 'Species', '9606', (77, 85))	('esophageal carcinoma', 'Disease', (40, 60))	('expression', 'MPA', (142, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('high', 'Var', (131, 135))	('ERCC1', 'Gene', '2067', (136, 141))
753467	27524911	This study showed a poor prognosis in high ERCC1 expression patients, two cases out of the three patients were cT4N1M0 IIIc stage, and another one case was cT3N1M0 IIIa stage.	('patients', 'Species', '9606', (60, 68))	('high', 'Var', (38, 42))	('ERCC1', 'Gene', '2067', (43, 48))	('ERCC1', 'Gene', (43, 48))	('patients', 'Species', '9606', (97, 105))
753472	27524911	First, the genome and tumor heterogeneity will affect an individual's response to drugs.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('heterogeneity', 'Var', (28, 41))	('affect', 'Reg', (47, 53))	('tumor', 'Disease', (22, 27))	('response to drugs', 'MPA', (70, 87))
753475	24787743	Single nucleotide polymorphisms (SNP) located in its functional region may alter DNA repair capacity phenotype and cancer risk.	('cancer', 'Disease', (115, 121))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('alter', 'Reg', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('DNA repair capacity phenotype', 'MPA', (81, 110))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
753477	24787743	We conducted a comprehensive meta-analysis to assess the association between XPD Lys751Gln polymorphism and digestive tract cancers risk.	('Lys751Gln', 'SUBSTITUTION', 'None', (81, 90))	('XPD', 'Gene', '2068', (77, 80))	('Lys751Gln', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tract cancers', 'Disease', (118, 131))	('tract cancers', 'Disease', 'MESH:D014571', (118, 131))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('XPD', 'Gene', (77, 80))
753479	24787743	The results showed that XPD Lys751Gln polymorphism was associated with the increased risk of digestive tract cancers (homozygote comparison (GlnGln vs. LysLys): OR = 1.12, 95% CI = 1.01-1.24, P = 0.029, P heterogeneity = 0.133).	('Lys751Gln', 'SUBSTITUTION', 'None', (28, 37))	('tract cancers', 'Disease', (103, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('tract cancers', 'Disease', 'MESH:D014571', (103, 116))	('XPD', 'Gene', (24, 27))	('XPD', 'Gene', '2068', (24, 27))	('Lys751Gln', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('GlnGln', 'Chemical', '-', (141, 147))	('increased risk of digestive tract', 'Phenotype', 'HP:0011024', (75, 108))	('LysLys', 'Chemical', 'MESH:C024575', (152, 158))
753493	24787743	Mutations on different sites in XPD gene can give rise to repair and transcription defects, and altered DNA repair capacity can render a higher risk of developing different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('altered', 'Reg', (96, 103))	('transcription', 'MPA', (69, 82))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('Mutations', 'Var', (0, 9))	('DNA repair', 'MPA', (104, 114))	('cancer', 'Disease', (182, 188))	('XPD', 'Gene', (32, 35))	('XPD', 'Gene', '2068', (32, 35))	('repair', 'MPA', (58, 64))
753494	24787743	Several polymorphisms of XPD were identified, like Asp312Asn, Lys751Gln, Arg194Trp and Arg399Gln.	('XPD', 'Gene', (25, 28))	('Arg194Trp', 'Var', (73, 82))	('Arg399Gln', 'Var', (87, 96))	('XPD', 'Gene', '2068', (25, 28))	('Arg399Gln', 'SUBSTITUTION', 'None', (87, 96))	('Asp312Asn', 'Var', (51, 60))	('Lys751Gln', 'SUBSTITUTION', 'None', (62, 71))	('Asp312Asn', 'SUBSTITUTION', 'None', (51, 60))	('Lys751Gln', 'Var', (62, 71))	('Arg194Trp', 'SUBSTITUTION', 'None', (73, 82))
753495	24787743	The XPD polymorphic loci that has been of particular interest in molecular epidemiology studies is the Lys751Gln polymorphism (rs13181) in exon 23.	('XPD', 'Gene', (4, 7))	('Lys751Gln', 'SUBSTITUTION', 'None', (103, 112))	('XPD', 'Gene', '2068', (4, 7))	('rs13181', 'Var', (127, 134))	('Lys751Gln', 'Var', (103, 112))	('rs13181', 'Mutation', 'rs13181', (127, 134))
753496	24787743	The lysine to glutamine transition at position 751 in exon 23 may affect different protein interactions, diminish the activity of TFIIH complexes, and alter the genetic susceptibility to cancer.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('affect', 'Reg', (66, 72))	('TFIIH', 'Gene', (130, 135))	('cancer', 'Disease', (187, 193))	('activity', 'MPA', (118, 126))	('lysine', 'Var', (4, 10))	('diminish', 'NegReg', (105, 113))	('protein', 'Protein', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('alter', 'Reg', (151, 156))	('lysine to glutamine transition at position 751', 'Mutation', 'rs13181', (4, 50))	('TFIIH', 'Gene', '2068', (130, 135))
753497	24787743	Genetic variant in XPD Lys751Gln had been demonstrated to be associated with some cancers risk in different meta-analysis, such as esophageal cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, lung cancer and bladder cancer.	('Lys751Gln', 'Var', (23, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('bladder cancer', 'Phenotype', 'HP:0009725', (233, 247))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('cancers', 'Disease', (82, 89))	('gastric cancer', 'Disease', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('prostate cancer', 'Disease', (200, 215))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('XPD', 'Gene', '2068', (19, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (166, 183))	('esophageal cancer', 'Disease', (131, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('colorectal cancer', 'Disease', (166, 183))	('associated', 'Reg', (61, 71))	('Lys751Gln', 'SUBSTITUTION', 'None', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', (217, 228))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('XPD', 'Gene', (19, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (166, 183))	('breast cancer', 'Disease', (185, 198))	('bladder cancer', 'Disease', 'MESH:D001749', (233, 247))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('bladder cancer', 'Disease', (233, 247))
753499	24787743	In consideration of the extensive role of XPD in digestive tract cancers, we performed a meta-analysis of all 37 eligible case-control studies: oral cancer, esophageal cancer, gastric cancer http://www.sciencedirect.com/science/article/pii/S0188440911000853 - bib10and colorectal cancer, to derive a more precise association of XPD Lys751Gln polymorphism and different types of digestive tract cancers risk.	('tract cancers', 'Disease', 'MESH:D014571', (388, 401))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('colorectal cancer', 'Phenotype', 'HP:0003003', (269, 286))	('Lys751Gln', 'Var', (332, 341))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('XPD', 'Gene', '2068', (328, 331))	('tract cancers', 'Disease', (388, 401))	('tract cancers', 'Disease', 'MESH:D014571', (59, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('XPD', 'Gene', '2068', (42, 45))	('Lys751Gln', 'SUBSTITUTION', 'None', (332, 341))	('tract cancers', 'Disease', (59, 72))	('oral cancer', 'Disease', 'MESH:D009062', (144, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (269, 286))	('oral cancer', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('colorectal cancer', 'Disease', (269, 286))	('polymorphism', 'Var', (342, 354))	('gastric cancer', 'Disease', (176, 190))	('XPD', 'Gene', (328, 331))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('XPD', 'Gene', (42, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('esophageal cancer', 'Disease', (157, 174))
753500	24787743	Using PubMed, we identified all published case-control studies which investigated the association between the XPD Lys751Gln polymorphism and digestive tract cancers risk using a retrieving query formulation "(XPD or ERCC2) polymorphisms AND (colorectal cancer OR gastric cancer OR esophageal cancer OR oral cancer)".The digestive tract cancers in this article refer to oral cancer, esophageal cancer, gastric cancer and colorectal cancer.	('ERCC2', 'Gene', (216, 221))	('XPD', 'Gene', '2068', (209, 212))	('XPD', 'Gene', (110, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (263, 277))	('tract cancers', 'Disease', 'MESH:D014571', (151, 164))	('cancers', 'Phenotype', 'HP:0002664', (336, 343))	('ERCC2', 'Gene', '2068', (216, 221))	('Lys751Gln', 'SUBSTITUTION', 'None', (114, 123))	('tract cancers', 'Disease', (151, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (281, 298))	('colorectal cancer', 'Disease', 'MESH:D015179', (420, 437))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('tract cancers', 'Disease', 'MESH:D014571', (330, 343))	('gastric cancer', 'Disease', (401, 415))	('esophageal cancer', 'Disease', 'MESH:D004938', (382, 399))	('gastric cancer', 'Phenotype', 'HP:0012126', (263, 277))	('colorectal cancer', 'Phenotype', 'HP:0003003', (242, 259))	('oral cancer', 'Disease', 'MESH:D009062', (369, 380))	('esophageal cancer', 'Disease', (281, 298))	('colorectal cancer', 'Disease', (420, 437))	('XPD', 'Gene', (209, 212))	('oral cancer', 'Disease', (369, 380))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('tract cancers', 'Disease', (330, 343))	('oral cancer', 'Disease', 'MESH:D009062', (302, 313))	('esophageal cancer', 'Disease', (382, 399))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('oral cancer', 'Disease', (302, 313))	('XPD', 'Gene', '2068', (110, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (401, 415))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('Lys751Gln', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gastric cancer', 'Disease', (263, 277))	('gastric cancer', 'Phenotype', 'HP:0012126', (401, 415))	('colorectal cancer', 'Disease', 'MESH:D015179', (242, 259))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('colorectal cancer', 'Phenotype', 'HP:0003003', (420, 437))	('colorectal cancer', 'Disease', (242, 259))
753501	24787743	Eligible studies had to meet the following criteria: (a) only case-control designs were considered, (b) The study explored the correlation between different types of digestive tract cancers and XPD Lys751Gln polymorphism.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('XPD', 'Gene', '2068', (194, 197))	('Lys751Gln', 'Var', (198, 207))	('tract cancers', 'Disease', (176, 189))	('tract cancers', 'Disease', 'MESH:D014571', (176, 189))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('XPD', 'Gene', (194, 197))	('Lys751Gln', 'SUBSTITUTION', 'None', (198, 207))
753502	24787743	The risks ORs of digestive tract cancers associated with the XPD Lys751Gln polymorphism were estimated for each study.	('XPD', 'Gene', (61, 64))	('tract cancers', 'Disease', (27, 40))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('tract cancers', 'Disease', 'MESH:D014571', (27, 40))	('Lys751Gln', 'SUBSTITUTION', 'None', (65, 74))	('XPD', 'Gene', '2068', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Lys751Gln', 'Var', (65, 74))
753503	24787743	The pooled ORs were evaluated on co-dominant model (Lys/Gln vs.Lys/Lys, Gln/Gln vs. Lys/Lys), dominant model (Gln/Gln + Lys/Gln vs. Lys/Lys), recessive model (Gln/Gln vs. Lys/Gln+Lys/Lys), respectively.	('Lys', 'Chemical', 'MESH:D008239', (179, 182))	('Gln/Gln', 'Var', (159, 166))	('Gln', 'Chemical', 'MESH:D005973', (159, 162))	('Lys', 'Chemical', 'MESH:D008239', (52, 55))	('Gln', 'Chemical', 'MESH:D005973', (175, 178))	('Gln', 'Chemical', 'MESH:D005973', (110, 113))	('Gln', 'Chemical', 'MESH:D005973', (72, 75))	('Lys', 'Chemical', 'MESH:D008239', (183, 186))	('Gln', 'Chemical', 'MESH:D005973', (56, 59))	('Lys', 'Chemical', 'MESH:D008239', (88, 91))	('Lys', 'Chemical', 'MESH:D008239', (120, 123))	('Lys', 'Chemical', 'MESH:D008239', (136, 139))	('Lys', 'Chemical', 'MESH:D008239', (63, 66))	('Gln', 'Chemical', 'MESH:D005973', (124, 127))	('Gln', 'Chemical', 'MESH:D005973', (163, 166))	('Lys/Gln', 'Var', (52, 59))	('Gln', 'Chemical', 'MESH:D005973', (114, 117))	('Lys', 'Chemical', 'MESH:D008239', (132, 135))	('Gln', 'Chemical', 'MESH:D005973', (76, 79))	('Lys', 'Chemical', 'MESH:D008239', (67, 70))	('Lys', 'Chemical', 'MESH:D008239', (84, 87))	('Lys', 'Chemical', 'MESH:D008239', (171, 174))	('Gln/Gln + Lys/Gln vs.', 'Var', (110, 131))
753506	24787743	After carefully reviewing, 40 eligible case-control studies (3 studies not consistent with HWE were also shown) on the relationship between XPD Lys715Gln polymorphism and digestive cancers risk were involved in this meta-analysis, including 4 oral cancer studies, 13 esophageal cancer studies, 12 gastric cancer studies and 11 colorectal cancer studies.	('colorectal cancer', 'Disease', 'MESH:D015179', (327, 344))	('XPD', 'Gene', '2068', (140, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (267, 284))	('esophageal cancer', 'Disease', (267, 284))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('colorectal cancer', 'Disease', (327, 344))	('gastric cancer', 'Phenotype', 'HP:0012126', (297, 311))	('oral cancer', 'Disease', 'MESH:D009062', (243, 254))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('oral cancer', 'Disease', (243, 254))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('XPD', 'Gene', (140, 143))	('gastric cancer', 'Disease', (297, 311))	('colorectal cancer', 'Phenotype', 'HP:0003003', (327, 344))	('Lys715Gln', 'SUBSTITUTION', 'None', (144, 153))	('Lys715Gln', 'Var', (144, 153))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('gastric cancer', 'Disease', 'MESH:D013274', (297, 311))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
753507	24787743	Table2 lists the main results of the meta-analysis for XPD Lys751Gln: having the Gln/Gln genotype is a risk factor for digestive tract cancers: GlnGln vs. LysLys: OR = 1.12, 95% CI = 1.01-1.24, P = 0.029, P heterogeneity = 0.133.	('Gln', 'Chemical', 'MESH:D005973', (144, 147))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('Lys751Gln', 'SUBSTITUTION', 'None', (59, 68))	('XPD', 'Gene', (55, 58))	('Lys751Gln', 'Var', (59, 68))	('GlnGln', 'Chemical', '-', (144, 150))	('XPD', 'Gene', '2068', (55, 58))	('Gln/Gln', 'Var', (81, 88))	('Gln', 'Chemical', 'MESH:D005973', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('LysLys', 'Chemical', 'MESH:C024575', (155, 161))	('Gln', 'Chemical', 'MESH:D005973', (85, 88))	('tract cancers', 'Disease', (129, 142))	('tract cancers', 'Disease', 'MESH:D014571', (129, 142))	('Gln', 'Chemical', 'MESH:D005973', (147, 150))	('GlnGln', 'Var', (144, 150))	('Gln', 'Chemical', 'MESH:D005973', (65, 68))
753510	24787743	The Gln/Gln vs. Lys/Lys genotype had an elevated risk in Asian population (OR = 1.28, 95% CI = 1.01-1.63, P = 0.045, P heterogeneity = 0.287, I 2 = 14.2%; Figure 3).	('Gln', 'Chemical', 'MESH:D005973', (4, 7))	('Lys', 'Chemical', 'MESH:D008239', (20, 23))	('Gln', 'Chemical', 'MESH:D005973', (8, 11))	('Lys', 'Chemical', 'MESH:D008239', (16, 19))	('Lys/Lys', 'Var', (16, 23))	('Asian population', 'Disease', (57, 73))	('Gln/Gln', 'Var', (4, 11))
753512	24787743	In addition, the results did not suggest any association between XPD Lys751Gln polymorphism and digestive cancers susceptibility for all genetic models in European individuals or in population-based studies overall.	('XPD', 'Gene', (65, 68))	('Lys751Gln', 'SUBSTITUTION', 'None', (69, 78))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('XPD', 'Gene', '2068', (65, 68))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('Lys751Gln', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
753514	24787743	There was moderate heterogeneity among these studies in GlnGln+GlnLys vs.LysLys comparisons and Gln/Gln vs. Lys/Lys comparisons, but not in the other genetic models.	('Gln', 'Chemical', 'MESH:D005973', (96, 99))	('GlnGln+GlnLys', 'Var', (56, 69))	('Gln', 'Chemical', 'MESH:D005973', (63, 66))	('Gln', 'Chemical', 'MESH:D005973', (100, 103))	('Lys', 'Chemical', 'MESH:D008239', (108, 111))	('Lys', 'Chemical', 'MESH:D008239', (76, 79))	('Lys', 'Chemical', 'MESH:D008239', (73, 76))	('Gln', 'Chemical', 'MESH:D005973', (56, 59))	('Gln', 'Chemical', 'MESH:D005973', (59, 62))	('Lys', 'Chemical', 'MESH:D008239', (112, 115))	('GlnGln', 'Chemical', '-', (56, 62))	('Gln/Gln', 'Var', (96, 103))	('LysLys', 'Chemical', 'MESH:C024575', (73, 79))	('Lys', 'Chemical', 'MESH:D008239', (66, 69))	('GlnLys', 'Chemical', '-', (63, 69))
753517	24787743	There was no evidence of publication bias in XPD Lys751Gln (Begg's test P = 0.284, Egger's test P = 0.324, t = 1.00, 95% CI = 0.41-1.21).	('XPD', 'Gene', (45, 48))	('Lys751Gln', 'SUBSTITUTION', 'None', (49, 58))	('XPD', 'Gene', '2068', (45, 48))	('Lys751Gln', 'Var', (49, 58))
753518	24787743	We present funnel plot for ORs of Gln/Gln versus Lys/Lys (Figure 5).	('Gln', 'Chemical', 'MESH:D005973', (38, 41))	('Lys', 'Chemical', 'MESH:D008239', (49, 52))	('Lys', 'Chemical', 'MESH:D008239', (53, 56))	('Lys/Lys', 'Var', (49, 56))	('Gln/Gln', 'Var', (34, 41))	('Gln', 'Chemical', 'MESH:D005973', (34, 37))
753521	24787743	Genetic variation in XPD may contribute to impaired DNA repair capacity and increased cancer risk.	('Genetic variation', 'Var', (0, 17))	('XPD', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('impaired', 'NegReg', (43, 51))	('XPD', 'Gene', '2068', (21, 24))	('DNA repair', 'MPA', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
753522	24787743	The Lys to Gln change at position 751 of XPD results in complete changes about the charge configuration of the amino acid, which affects the interactions of XPD protein and its helicase activator.	('XPD', 'Gene', (157, 160))	('XPD', 'Gene', (41, 44))	('affects', 'Reg', (129, 136))	('XPD', 'Gene', '2068', (157, 160))	('XPD', 'Gene', '2068', (41, 44))	('charge configuration of the amino acid', 'MPA', (83, 121))	('Lys to Gln change at position 751', 'Mutation', 'rs13181', (4, 37))	('changes', 'Reg', (65, 72))	('interactions', 'Interaction', (141, 153))	('Lys to Gln', 'Var', (4, 14))	('helicase', 'Protein', (177, 185))
753523	24787743	To date, a number of epidemiological studies have been conducted to evaluate the role of Lys751Gln polymorphism on several cancer risks, but the results remain controversial.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Lys751Gln', 'Var', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('Lys751Gln', 'SUBSTITUTION', 'None', (89, 98))
753524	24787743	As far as we know, several previous meta-analyses on XPD Lys751Gln polymorphism and cancers risk have been performed, such as gastric cancer, colorectal cancer, esophageal cancer, breast cancer and bladder cancer.	('XPD', 'Gene', '2068', (53, 56))	('gastric cancer', 'Disease', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('Lys751Gln', 'SUBSTITUTION', 'None', (57, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('bladder cancer', 'Disease', (198, 212))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('colorectal cancer', 'Disease', (142, 159))	('breast cancer', 'Disease', (180, 193))	('esophageal cancer', 'Disease', (161, 178))	('XPD', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('Lys751Gln', 'Var', (57, 66))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
753525	24787743	But to date, there is no meta-analysis on the association between digestive tract cancers risk and XPD Lys751Gln polymorphism.	('XPD', 'Gene', '2068', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tract cancers', 'Disease', (76, 89))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('tract cancers', 'Disease', 'MESH:D014571', (76, 89))	('Lys751Gln', 'SUBSTITUTION', 'None', (103, 112))	('Lys751Gln', 'Var', (103, 112))	('XPD', 'Gene', (99, 102))
753526	24787743	Through analyzing genotypes from the 37 eligible studies, we found the Gln/Gln genotype carries might be at potential risk to digestive tract cancers.	('risk', 'Reg', (118, 122))	('tract cancers', 'Disease', 'MESH:D014571', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Gln/Gln', 'Var', (71, 78))	('Gln', 'Chemical', 'MESH:D005973', (71, 74))	('Gln', 'Chemical', 'MESH:D005973', (75, 78))	('tract cancers', 'Disease', (136, 149))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
753527	24787743	The Lys to Gln variation on position 751 of XPD resulted in complete changes about the electronic configuration of the amino acid, which affected the interactions of XPD protein and its helicase activator.	('XPD', 'Gene', '2068', (44, 47))	('interactions', 'Interaction', (150, 162))	('affected', 'Reg', (137, 145))	('Lys', 'Chemical', 'MESH:D008239', (4, 7))	('XPD', 'Gene', (166, 169))	('Lys to Gln', 'Var', (4, 14))	('helicase', 'Protein', (186, 194))	('electronic configuration of the amino acid', 'MPA', (87, 129))	('XPD', 'Gene', (44, 47))	('XPD', 'Gene', '2068', (166, 169))	('changes', 'Reg', (69, 76))	('Gln', 'Chemical', 'MESH:D005973', (11, 14))
753533	24787743	The functional XPD Lys751Gln polymorphism resulting in decreased activity of XPD protein may increase risk of digestive tract cancers on the basis of damage tissue.	('XPD', 'Gene', '2068', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('XPD', 'Gene', '2068', (77, 80))	('Lys751Gln', 'Var', (19, 28))	('Lys751Gln', 'SUBSTITUTION', 'None', (19, 28))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('activity of', 'MPA', (65, 76))	('decreased', 'NegReg', (55, 64))	('XPD', 'Gene', (15, 18))	('XPD', 'Gene', (77, 80))	('increase risk of digestive tract', 'Phenotype', 'HP:0011024', (93, 125))	('tract cancers', 'Disease', (120, 133))	('tract cancers', 'Disease', 'MESH:D014571', (120, 133))
753536	24787743	detected that Gln/Gln genotype carriers might have an increased risk of gastric cancer in the Helico-bacter pylori (H.pylori)-positive population, but not in the Helico-bacter pylori (H. pylori)-negative population.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('pylori', 'Species', '210', (108, 114))	('pylori', 'Species', '210', (187, 193))	('gastric cancer', 'Disease', (72, 86))	('pylori', 'Species', '210', (118, 124))	('Gln', 'Chemical', 'MESH:D005973', (14, 17))	('Gln', 'Chemical', 'MESH:D005973', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('Helico-bacter pylori', 'Disease', (94, 114))	('H. pylori', 'Species', '210', (184, 193))	('H.pylori', 'Species', '210', (116, 124))	('Gln/Gln', 'Var', (14, 21))	('pylori', 'Species', '210', (176, 182))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (54, 86))
753537	24787743	One possible explanation is that the modulation of digestive tract cancers risk may depend not only on a single gene/single nucleotide polymorphism, but also on a joint effect of multiple polymorphisms within different genes or pathways, or on close interaction between polymorphisms and environmental factor.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gene/single nucleotide polymorphism', 'Var', (112, 147))	('depend', 'Reg', (84, 90))	('tract cancers', 'Disease', (61, 74))	('tract cancers', 'Disease', 'MESH:D014571', (61, 74))
753541	24787743	In summary, this meta-analysis indicated that XPD Lys751Gln polymorphism, individuals carrying the variant homozygote Gln/Gln may increase the susceptibility of digestive tract cancers.	('tract cancers', 'Disease', 'MESH:D014571', (171, 184))	('Gln/Gln', 'Var', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('Gln', 'Chemical', 'MESH:D005973', (56, 59))	('Gln', 'Chemical', 'MESH:D005973', (118, 121))	('XPD', 'Gene', (46, 49))	('Lys751Gln', 'SUBSTITUTION', 'None', (50, 59))	('increase', 'PosReg', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('XPD', 'Gene', '2068', (46, 49))	('Gln', 'Chemical', 'MESH:D005973', (122, 125))	('tract cancers', 'Disease', (171, 184))	('Lys751Gln', 'Var', (50, 59))
753542	24787743	It should be noted explicitly: first, the effective sample size is much smaller for the Gln/Gln vs. Lys/Lys analyses than the other genetic models and therefore it is more prone to random error and false positive results; second, the results for GlnGln vs. GlyLys+LysLys, while not statistically significant (OR 1.09, 95% CI = 0.99-1.20, P = 0.072, P heterogeneity = 0.385), strengthen our conclusion about which genetic model is most appropriate.	('Lys', 'Chemical', 'MESH:D008239', (104, 107))	('Lys', 'Chemical', 'MESH:D008239', (264, 267))	('GlnGln', 'Chemical', '-', (246, 252))	('error', 'Disease', (188, 193))	('GlyLys', 'Chemical', 'MESH:C035809', (257, 263))	('Gln', 'Chemical', 'MESH:D005973', (246, 249))	('Lys', 'Chemical', 'MESH:D008239', (267, 270))	('error', 'Disease', 'MESH:D012030', (188, 193))	('Gln', 'Chemical', 'MESH:D005973', (249, 252))	('Gln', 'Chemical', 'MESH:D005973', (88, 91))	('LysLys', 'Chemical', 'MESH:C024575', (264, 270))	('Lys', 'Chemical', 'MESH:D008239', (260, 263))	('Gln', 'Chemical', 'MESH:D005973', (92, 95))	('GlnGln', 'Var', (246, 252))	('Lys', 'Chemical', 'MESH:D008239', (100, 103))
753545	24614244	Five-year cancer-specific and overall survival of patients with T1N0M0 squamous cell or adenocarcinoma of the mid or distal esophagus treated with either surgery or local therapy with ablative and/or excision techniques in the SEER cancer registry from 1998-2008 were compared using the Kaplan-Meier approach and multivariable and propensity score adjusted Cox proportional-hazard and competing risk models.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('Cox', 'Gene', '1351', (357, 360))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Disease', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('squamous cell', 'Disease', (71, 84))	('Cox', 'Gene', (357, 360))	('adenocarcinoma of the mid', 'Disease', (88, 113))	('T1N0M0', 'Var', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('adenocarcinoma of the mid', 'Disease', 'MESH:D000230', (88, 113))	('cancer', 'Disease', (10, 16))
753546	24614244	Of 1458 patients with T1N0 esophageal cancer, 1204 (83%) had surgery and 254 (17%) had local therapy only.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('T1N0', 'Var', (22, 26))	('esophageal cancer', 'Disease', (27, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))	('patients', 'Species', '9606', (8, 16))
753556	24614244	The variable "Histologic Type ICD-O-3'' (International classifications of Diseases for Oncology, 3rd edition) was used to restrict the study cohort to patients with either squamous cell cancer (codes 8050-8089) or adenocarcinomas (codes 8140-8389).	('codes 8050-8089', 'Var', (194, 209))	('squamous cell cancer', 'Disease', (172, 192))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (172, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('codes 8140-8389', 'Var', (231, 246))	('patients', 'Species', '9606', (151, 159))	('adenocarcinomas', 'Disease', 'MESH:D000230', (214, 229))	('Oncology', 'Phenotype', 'HP:0002664', (87, 95))	('adenocarcinomas', 'Disease', (214, 229))	('squamous cell cancer', 'Disease', 'MESH:D002294', (172, 192))
753557	24614244	To restrict the cohort to patients with T1N0M0 tumors, the tumor-node-metastasis (TNM) stage was either directly extracted from the SEER database or manually recoded using available SEER variables.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('patients', 'Species', '9606', (26, 34))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (59, 80))	('tumor-node-metastasis', 'Disease', (59, 80))	('T1N0M0', 'Var', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
753573	24614244	A total of 1458 patients with T1N0M0 esophageal cancer of the mid and lower esophagus were identified in the SEER cancer registry during the study period from 1998 to 2008: Of these, 1204 (83%) were treated with surgery and 254 (17%) had local therapy only.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (16, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))	('T1N0M0', 'Var', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('esophageal cancer', 'Disease', (37, 54))	('cancer', 'Disease', (114, 120))
753589	24614244	In this study using the SEER database, which is the largest United States population based cancer registry, we found that local therapy was increasingly utilized for the treatment of T1N0M0 esophageal cancer over the time period 1998-2008, with a concomitant decrease in the use of esophagectomy.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('T1N0M0', 'Var', (183, 189))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('esophageal cancer', 'Disease', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (190, 207))	('decrease', 'NegReg', (259, 267))
753621	32244169	Tumor-Derived EV-Encapsulated miR-181b-5p Induces Angiogenesis to Foster Tumorigenesis and Metastasis of ESCC Pathological angiogenesis is necessary for tumor development and metastasis.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Foster', 'PosReg', (66, 72))	('Metastasis', 'CPA', (91, 101))	('miR-181b-5p', 'Var', (30, 41))	('miR-181b-5p', 'Chemical', '-', (30, 41))	('tumor', 'Disease', (153, 158))	('Tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('Induces', 'Reg', (42, 49))	('Angiogenesis', 'CPA', (50, 62))
753625	32244169	In addition, ESCC-derived EVs-miR-181b-5p dramatically induced angiogenesis by targeting PTEN and PHLPP2, and thereby facilitated tumor growth and metastasis.	('facilitated', 'PosReg', (118, 129))	('angiogenesis', 'CPA', (63, 75))	('PHLPP2', 'Gene', (98, 104))	('targeting', 'NegReg', (79, 88))	('induced', 'PosReg', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('EVs-miR-181b-5p', 'Var', (26, 41))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('PHLPP2', 'Gene', '23035', (98, 104))	('PTEN', 'Gene', (89, 93))	('tumor', 'Disease', (130, 135))	('EVs-miR-181b-5p', 'Chemical', '-', (26, 41))	('PTEN', 'Gene', '5728', (89, 93))
753626	32244169	Moreover, miR-181b-5p was highly expressed in ESCC tissues and serum EVs.	('miR-181b-5p', 'Var', (10, 21))	('ESCC', 'Disease', (46, 50))	('miR-181b-5p', 'Chemical', '-', (10, 21))
753629	32244169	miR-181b-5p-enriched EVs secreted from ESCC cells are involved in angiogenesis that control metastasis of ESCC, providing a potential diagnostic biomarker or drug target for ESCC patients.	('miR-181b-5p-enriched', 'Var', (0, 20))	('ESCC', 'Disease', (106, 110))	('metastasis', 'CPA', (92, 102))	('patients', 'Species', '9606', (179, 187))	('control', 'MPA', (84, 91))	('miR-181b-5p', 'Chemical', '-', (0, 11))
753645	32244169	In this study, we identified that miR-181b-5p was highly expressed in ESCC tissues and EVs.	('miR-181b-5p', 'Var', (34, 45))	('ESCC', 'Disease', (70, 74))	('miR-181b-5p', 'Chemical', '-', (34, 45))
753646	32244169	We found that ESCC-derived EVs-miR-181b-5p can be transferred to vascular endothelial cells and targeted phosphatase and tensin homolog (PTEN) and PH domain and Leucine rich repeat Protein Phosphatases 2 (PHLPP2), thereby activating Akt signaling to promote angiogenesis.	('EVs-miR-181b-5p', 'Var', (27, 42))	('promote', 'PosReg', (250, 257))	('EVs-miR-181b-5p', 'Chemical', '-', (27, 42))	('PHLPP2', 'Gene', '23035', (205, 211))	('Akt', 'Gene', '207', (233, 236))	('PTEN', 'Gene', (137, 141))	('PTEN', 'Gene', '5728', (137, 141))	('Akt', 'Gene', (233, 236))	('angiogenesis', 'CPA', (258, 270))	('PHLPP2', 'Gene', (205, 211))	('activating', 'PosReg', (222, 232))	('phosphatase and tensin homolog', 'Gene', '5728', (105, 135))
753647	32244169	In addition, we demonstrated that EVs-miR-181b-5p promoted the ESCC tumor growth and consequently metastasis in nude mice by inducing angiogenesis.	('tumor', 'Disease', (68, 73))	('EVs-miR-181b-5p', 'Chemical', '-', (34, 49))	('promoted', 'PosReg', (50, 58))	('inducing', 'PosReg', (125, 133))	('metastasis', 'CPA', (98, 108))	('angiogenesis', 'CPA', (134, 146))	('nude mice', 'Species', '10090', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('ESCC', 'Disease', (63, 67))	('EVs-miR-181b-5p', 'Var', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
753649	32244169	These findings suggest that miRNAs in tumor-derived EVs play an important role in intercellular communication during angiogenesis and implicate that antagonism of EVs-miR-181b-5p represents a potential therapeutic strategy for cancer therapy.	('antagonism', 'Var', (149, 159))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('miR', 'Gene', '220972', (167, 170))	('miR', 'Gene', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('EVs-miR-181b-5p', 'Chemical', '-', (163, 178))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('intercellular communication', 'MPA', (82, 109))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('miR', 'Gene', '220972', (28, 31))	('cancer', 'Disease', (227, 233))	('miR', 'Gene', (28, 31))
753667	32244169	miR-181b-5p was the most highly expressed in 58 pairs of ESCC tissues compared with adjacent nonmalignant tissues (Figures 2C and S2A).	('ESCC', 'Disease', (57, 61))	('miR-181b-5p', 'Chemical', '-', (0, 11))	('miR-181b-5p', 'Var', (0, 11))
753668	32244169	More importantly, miR-181b-5p expression was also validated to be elevated in 10 ESCC cell lines and ESCC cell EVs, compared with HEECs (Figures 2D and 2E), and exhibited a high correlation score (Figure 2F).	('expression', 'MPA', (30, 40))	('miR-181b-5p', 'Var', (18, 29))	('ESCC', 'Disease', (81, 85))	('HEEC', 'Chemical', '-', (130, 134))	('elevated', 'PosReg', (66, 74))	('miR-181b-5p', 'Chemical', '-', (18, 29))
753670	32244169	Surprisingly, we found that the expression of EVs-miR-181b-5p was positively correlated with the metastasis in the different ESCC cell lines (Figures S2C-S2E).	('EVs-miR-181b-5p', 'Chemical', '-', (46, 61))	('metastasis', 'CPA', (97, 107))	('EVs-miR-181b-5p', 'Var', (46, 61))	('correlated', 'Reg', (77, 87))
753672	32244169	We found that high miR-181b-5p expression was notably correlated with high advanced TNM stage (N stage, p = 0.008; clinical stage, p = 0.003; Table S2).	('TNM', 'Gene', (84, 87))	('miR-181b-5p', 'Var', (19, 30))	('miR-181b-5p', 'Chemical', '-', (19, 30))	('expression', 'MPA', (31, 41))	('correlated', 'Reg', (54, 64))	('TNM', 'Gene', '10178', (84, 87))
753673	32244169	These data indicated that overexpression of miR-181b-5p was strongly associated with poor clinicopathological characteristics of ESCC patients.	('ESCC', 'Disease', (129, 133))	('overexpression', 'PosReg', (26, 40))	('patients', 'Species', '9606', (134, 142))	('miR-181b-5p', 'Chemical', '-', (44, 55))	('miR-181b-5p', 'Var', (44, 55))
753674	32244169	To further validate whether the role of miR-181b-5p was associated with angiogenesis, we transiently transfected HUVECs with miR-181b-5p mimic, inhibitor, and negative control, respectively (Figure S3A).	('miR-181b-5p mimic', 'Var', (125, 142))	('miR-181b-5p', 'Chemical', '-', (125, 136))	('miR-181b-5p', 'Chemical', '-', (40, 51))	('associated', 'Reg', (56, 66))	('angiogenesis', 'CPA', (72, 84))
753675	32244169	In vitro assay illustrated that miR-181b-5p induced HUVEC migration and proliferation, and promoted cell-cycle progression and tube formation (Figures 2G-2O).	('HUVEC migration', 'CPA', (52, 67))	('promoted', 'PosReg', (91, 99))	('tube formation', 'CPA', (127, 141))	('miR-181b-5p', 'Var', (32, 43))	('miR-181b-5p', 'Chemical', '-', (32, 43))	('proliferation', 'CPA', (72, 85))	('cell-cycle progression', 'CPA', (100, 122))	('induced', 'PosReg', (44, 51))
753677	32244169	EVs from Eca-109/miR-181b-5p cells enhanced cell growth and migration, and facilitated the progress of cell-cycle and tube formation of HUVECs, whereas inhibiting miR-181b-5p expression attenuated these functions (Figures S3C-S3G).	('Eca-109/miR-181b-5p', 'Gene', (9, 28))	('facilitated', 'PosReg', (75, 86))	('tube formation', 'CPA', (118, 132))	('enhanced', 'PosReg', (35, 43))	('attenuated', 'NegReg', (186, 196))	('Eca', 'Chemical', '-', (9, 12))	('cell growth', 'CPA', (44, 55))	('miR-181b-5p', 'Chemical', '-', (163, 174))	('inhibiting', 'Var', (152, 162))	('migration', 'CPA', (60, 69))	('miR-181b-5p', 'Chemical', '-', (17, 28))	('miR-181b-5p', 'Gene', (163, 174))	('progress', 'CPA', (91, 99))
753680	32244169	However, these phenotypes were blocked by prior addition of the EV secretion inhibitor GW4869 to Eca-109 cells, showing that ESCC cells regulate angiogenesis via EVs-miR-181b-5p.	('angiogenesis', 'CPA', (145, 157))	('EVs-miR-181b-5p', 'Var', (162, 177))	('GW4869', 'Chemical', 'MESH:C468773', (87, 93))	('Eca', 'Chemical', '-', (97, 100))	('regulate', 'Reg', (136, 144))	('EVs-miR-181b-5p', 'Chemical', '-', (162, 177))
753683	32244169	First, we confirmed that PTEN and PHLPP2 expression could be downregulated in HUVECs by miR-181b-5p or Eca-109/miR-181b-5p EVs at protein levels.	('Eca-109/miR-181b-5p', 'Var', (103, 122))	('miR-181b-5p', 'Chemical', '-', (111, 122))	('PHLPP2', 'Gene', (34, 40))	('downregulated', 'NegReg', (61, 74))	('HUVECs', 'Disease', (78, 84))	('expression', 'MPA', (41, 51))	('miR-181b-5p', 'Var', (88, 99))	('miR-181b-5p', 'Chemical', '-', (88, 99))	('PHLPP2', 'Gene', '23035', (34, 40))	('Eca', 'Chemical', '-', (103, 106))	('PTEN', 'Gene', (25, 29))	('PTEN', 'Gene', '5728', (25, 29))
753684	32244169	However, the levels of PTEN and PHLPP2 mRNA were essentially unchanged regardless of whether the cells were transfected with miR-181b-5p or treated with Eca-109/miR-181b-5p EVs (Figures 3B, S6A, and S6B).	('miR-181b-5p', 'Var', (125, 136))	('miR-181b-5p', 'Chemical', '-', (125, 136))	('S6A', 'Mutation', 'p.S6A', (190, 193))	('PHLPP2', 'Gene', '23035', (32, 38))	('PTEN', 'Gene', (23, 27))	('PTEN', 'Gene', '5728', (23, 27))	('miR-181b-5p', 'Chemical', '-', (161, 172))	('levels', 'MPA', (13, 19))	('Eca', 'Chemical', '-', (153, 156))	('PHLPP2', 'Gene', (32, 38))
753685	32244169	Then the alignment between miR-181b-5p sequence and the full length of PTEN or PHLPP2 sequence was determined to show that 3' UTRs of PTEN and PHLPP2 were potential targets of miR-181b-5p (Figure 3C).	('miR-181b-5p', 'Var', (176, 187))	('miR-181b-5p', 'Chemical', '-', (176, 187))	('PHLPP2', 'Gene', (143, 149))	('PTEN', 'Gene', (71, 75))	('PHLPP2', 'Gene', (79, 85))	('PTEN', 'Gene', '5728', (71, 75))	('PHLPP2', 'Gene', '23035', (143, 149))	('miR-181b-5p', 'Chemical', '-', (27, 38))	('PTEN', 'Gene', (134, 138))	('PHLPP2', 'Gene', '23035', (79, 85))	('PTEN', 'Gene', '5728', (134, 138))
753686	32244169	Subsequently, the wild-type and mutated miR-181b-5p binding site were cloned into the luciferase vectors.	('miR-181b-5p', 'Gene', (40, 51))	('miR-181b-5p', 'Chemical', '-', (40, 51))	('mutated', 'Var', (32, 39))
753687	32244169	It was obvious that luciferase activity decreased markedly in HUVECs co-transfected with the wild-type binding site vector in the presence of miR-181b-5p.	('activity', 'MPA', (31, 39))	('miR-181b-5p', 'Var', (142, 153))	('miR-181b-5p', 'Chemical', '-', (142, 153))	('luciferase', 'Enzyme', (20, 30))	('decreased', 'NegReg', (40, 49))
753689	32244169	These results reveal that PTEN and PHLPP2 are direct targets of miR-181b-5p in HUVECs.	('PHLPP2', 'Gene', (35, 41))	('miR-181b-5p', 'Var', (64, 75))	('miR-181b-5p', 'Chemical', '-', (64, 75))	('HUVECs', 'Disease', (79, 85))	('PTEN', 'Gene', (26, 30))	('PTEN', 'Gene', '5728', (26, 30))	('PHLPP2', 'Gene', '23035', (35, 41))
753690	32244169	Furthermore, to confirm that PTEN and PHLPP2 acted as downstream target genes of miR-181b-5p in ESCC, we performed migration assays and tube formation assays.	('PHLPP2', 'Gene', (38, 44))	('miR-181b-5p', 'Var', (81, 92))	('PTEN', 'Gene', (29, 33))	('PTEN', 'Gene', '5728', (29, 33))	('miR-181b-5p', 'Chemical', '-', (81, 92))	('ESCC', 'Disease', (96, 100))	('PHLPP2', 'Gene', '23035', (38, 44))
753691	32244169	As shown in Figures 3E and 3F, miR-181b-5p exhibited a promotion on motility and tubulogenesis of HUVECs.	('promotion', 'PosReg', (55, 64))	('motility', 'CPA', (68, 76))	('tubulogenesis of', 'CPA', (81, 97))	('miR-181b-5p', 'Var', (31, 42))	('miR-181b-5p', 'Chemical', '-', (31, 42))
753692	32244169	However, overexpression of full-length PTEN or PHLPP2 (Figures S6E and S6F) could neutralize the effect of miR-181b-5p on angiogenesis.	('overexpression', 'PosReg', (9, 23))	('miR-181b-5p', 'Var', (107, 118))	('miR-181b-5p', 'Chemical', '-', (107, 118))	('PHLPP2', 'Gene', '23035', (47, 53))	('PTEN', 'Gene', (39, 43))	('angiogenesis', 'CPA', (122, 134))	('PTEN', 'Gene', '5728', (39, 43))	('PHLPP2', 'Gene', (47, 53))	('neutralize', 'NegReg', (82, 92))
753694	32244169	Overall, these results suggest that ESCC-derived EVs-miR-181b-5p induces angiogenesis by directly targeting PTEN and PHLPP2.	('EVs-miR-181b-5p', 'Var', (49, 64))	('targeting', 'Reg', (98, 107))	('PTEN', 'Gene', (108, 112))	('induces', 'PosReg', (65, 72))	('PHLPP2', 'Gene', (117, 123))	('PTEN', 'Gene', '5728', (108, 112))	('EVs-miR-181b-5p', 'Chemical', '-', (49, 64))	('PHLPP2', 'Gene', '23035', (117, 123))	('angiogenesis', 'CPA', (73, 85))
753695	32244169	Results above showed that ESCC-derived EVs-miR-181b-5p enhanced motility and tubulogenesis of HUVECs by downregulating the expression of PTEN and PHLPP2, which function as tumor suppressors by negatively regulating the Akt signaling pathway.	('EVs-miR-181b-5p', 'Chemical', '-', (39, 54))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('PHLPP2', 'Gene', '23035', (146, 152))	('expression', 'MPA', (123, 133))	('tumor', 'Disease', (172, 177))	('enhanced', 'PosReg', (55, 63))	('downregulating', 'NegReg', (104, 118))	('negatively regulating', 'NegReg', (193, 214))	('PTEN', 'Gene', (137, 141))	('EVs-miR-181b-5p', 'Var', (39, 54))	('Akt', 'Gene', '207', (219, 222))	('PTEN', 'Gene', '5728', (137, 141))	('PHLPP2', 'Gene', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('Akt', 'Gene', (219, 222))
753699	32244169	Furthermore, miR-181b-5p expression or PTEN/PHLPP2 suppression also promoted Akt phosphorylation (Figure 4C), whereas overexpression of PTEN/PHLPP2 suppressed Akt phosphorylation (Figure 4C).	('Akt', 'Gene', (159, 162))	('PHLPP2', 'Gene', (44, 50))	('Akt', 'Gene', '207', (77, 80))	('promoted', 'PosReg', (68, 76))	('suppression', 'NegReg', (51, 62))	('Akt', 'Gene', (77, 80))	('PHLPP2', 'Gene', '23035', (44, 50))	('PHLPP2', 'Gene', (141, 147))	('miR-181b-5p', 'Var', (13, 24))	('PTEN', 'Gene', (39, 43))	('miR-181b-5p', 'Chemical', '-', (13, 24))	('PTEN', 'Gene', '5728', (39, 43))	('Akt', 'Gene', '207', (159, 162))	('PTEN', 'Gene', (136, 140))	('PTEN', 'Gene', '5728', (136, 140))	('PHLPP2', 'Gene', '23035', (141, 147))
753700	32244169	All of these data indicate that miR-181b-5p induces angiogenesis by mediating Akt signaling activation.	('angiogenesis', 'CPA', (52, 64))	('miR-181b-5p', 'Var', (32, 43))	('miR-181b-5p', 'Chemical', '-', (32, 43))	('activation', 'PosReg', (92, 102))	('Akt', 'Gene', '207', (78, 81))	('Akt', 'Gene', (78, 81))	('induces', 'PosReg', (44, 51))
753701	32244169	Among them, the role of Akt signaling in the mediation of angiopoitin 1 (Ang1), Ang2, and endothelial nitric oxide synthase (eNOS) induced by miR-181b-5p is worthy of investigating.	('miR-181b-5p', 'Var', (142, 153))	('miR-181b-5p', 'Chemical', '-', (142, 153))	('eNOS', 'Gene', (125, 129))	('endothelial nitric oxide synthase', 'Gene', '4846', (90, 123))	('Ang', 'Gene', '283', (73, 76))	('Ang2', 'Gene', '285', (80, 84))	('Ang2', 'Gene', (80, 84))	('Ang', 'Gene', '283', (80, 83))	('eNOS', 'Gene', '4846', (125, 129))	('endothelial nitric oxide synthase', 'Gene', (90, 123))	('Akt', 'Gene', '207', (24, 27))	('Ang', 'Gene', (73, 76))	('Ang', 'Gene', (80, 83))	('Akt', 'Gene', (24, 27))
753702	32244169	Immunoblotting analyses showed that p-Akt, Ang1, and eNOS expression were promoted, whereas Ang2 expression was depressed by miR-181b-5p mimic or PTEN/PHLPP2 knockdown; however, it was reversed by overexpression of PTEN/PHLPP2 (Figure 4C).	('miR-181b-5p mimic', 'Var', (125, 142))	('miR-181b-5p', 'Chemical', '-', (125, 136))	('expression', 'MPA', (58, 68))	('PHLPP2', 'Gene', (151, 157))	('Ang', 'Gene', '283', (92, 95))	('PHLPP2', 'Gene', '23035', (151, 157))	('Akt', 'Gene', (38, 41))	('PTEN', 'Gene', (146, 150))	('PHLPP2', 'Gene', (220, 226))	('eNOS', 'Gene', (53, 57))	('Ang2', 'Gene', '285', (92, 96))	('Akt', 'Gene', '207', (38, 41))	('Ang', 'Gene', '283', (43, 46))	('PHLPP2', 'Gene', '23035', (220, 226))	('expression', 'MPA', (97, 107))	('eNOS', 'Gene', '4846', (53, 57))	('Ang', 'Gene', (92, 95))	('PTEN', 'Gene', '5728', (146, 150))	('PTEN', 'Gene', (215, 219))	('Ang', 'Gene', (43, 46))	('promoted', 'PosReg', (74, 82))	('PTEN', 'Gene', '5728', (215, 219))	('Ang2', 'Gene', (92, 96))	('knockdown', 'Var', (158, 167))	('depressed', 'NegReg', (112, 121))
753706	32244169	Collectively, these results suggest that ESCC-derived EVs-miR-181b-5p suppresses the expression of PTEN and PHLPP2, and thereby activates Akt signaling in vascular endothelial cells.	('PHLPP2', 'Gene', '23035', (108, 114))	('expression', 'MPA', (85, 95))	('Akt', 'Gene', (138, 141))	('activates', 'PosReg', (128, 137))	('EVs-miR-181b-5p', 'Var', (54, 69))	('Akt', 'Gene', '207', (138, 141))	('PHLPP2', 'Gene', (108, 114))	('PTEN', 'Gene', (99, 103))	('suppresses', 'NegReg', (70, 80))	('PTEN', 'Gene', '5728', (99, 103))	('EVs-miR-181b-5p', 'Chemical', '-', (54, 69))
753708	32244169	Mice injected with Eca-109/miR-181b-5p EVs showed a high rate of tumor growth and a slow rate of weight gain.	('weight gain', 'Phenotype', 'HP:0004324', (97, 108))	('tumor', 'Disease', (65, 70))	('weight gain', 'Disease', (97, 108))	('Eca-109/miR-181b-5p', 'Var', (19, 38))	('Mice', 'Species', '10090', (0, 4))	('miR-181b-5p', 'Chemical', '-', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('weight gain', 'Disease', 'MESH:D015430', (97, 108))	('Eca', 'Chemical', '-', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
753709	32244169	On the contrary, tumor growth was significantly slower in mice implanted with the Eca-109/inh-181b-5p EVs than in the control group (Figures 5A, 5B, and S7C-S7E).	('Eca', 'Chemical', '-', (82, 85))	('tumor', 'Disease', (17, 22))	('slower', 'NegReg', (48, 54))	('mice', 'Species', '10090', (58, 62))	('-181b-5p', 'Chemical', '-', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('Eca-109/inh-181b-5p', 'Var', (82, 101))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
753710	32244169	These results illustrated that EVs-miR-181b-5p promoted tumorigenicity and proliferation of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EVs-miR-181b-5p', 'Var', (31, 46))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('promoted', 'PosReg', (47, 55))	('tumor', 'Disease', (56, 61))	('EVs-miR-181b-5p', 'Chemical', '-', (31, 46))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
753711	32244169	Additionally, the levels of miR-181b-5p, PTEN, and PHLPP2 were validated in tumor tissues from each group.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('miR-181b-5p', 'Chemical', '-', (28, 39))	('PHLPP2', 'Gene', (51, 57))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '5728', (41, 45))	('miR-181b-5p', 'Var', (28, 39))	('PHLPP2', 'Gene', '23035', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
753712	32244169	As expected, the Eca-109/miR-181b-5p group had a higher miR-181b-5p expression compared with the control group (Figure 5C).	('miR-181b-5p', 'Chemical', '-', (56, 67))	('Eca', 'Chemical', '-', (17, 20))	('miR-181b-5p expression', 'MPA', (56, 78))	('Eca-109/miR-181b-5p', 'Var', (17, 36))	('miR-181b-5p', 'Chemical', '-', (25, 36))	('higher', 'PosReg', (49, 55))
753715	32244169	Furthermore, the level of EVs-miR-181b-5p isolated from the serum of mice injected with Eca-109/miR-181b-5p EVs was significantly higher than the corresponding control group (Figure 5E).	('higher', 'PosReg', (130, 136))	('Eca-109/miR-181b-5p', 'Var', (88, 107))	('miR-181b-5p', 'Chemical', '-', (30, 41))	('mice', 'Species', '10090', (69, 73))	('miR-181b-5p', 'Chemical', '-', (96, 107))	('Eca', 'Chemical', '-', (88, 91))	('EVs-miR-181b-5p', 'Chemical', '-', (26, 41))
753716	32244169	Most importantly, a lower intratumoral microvessel density was observed in tumor tissues from the Eca-109/inh-181b-5p group (Figure 5F), indicating that EVs-miR-181b-5p modulated tumor-induced angiogenesis.	('-181b-5p', 'Chemical', '-', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('lower', 'NegReg', (20, 25))	('-181b-5p', 'Chemical', '-', (160, 168))	('modulated', 'Reg', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('EVs-miR-181b-5p', 'Var', (153, 168))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('EVs-miR-181b-5p', 'Chemical', '-', (153, 168))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('Eca-109/inh-181b-5p', 'Gene', (98, 117))	('tumor', 'Disease', (75, 80))	('Eca', 'Chemical', '-', (98, 101))	('tumor', 'Disease', (179, 184))
753717	32244169	Inspiringly, more hepatic and pulmonary metastases were observed in mice implanted with Eca-109/miR-181b-5p EVs (Figure 5G), suggesting that EVs-miR-181b-5p contributed to ESCC metastasis.	('mice', 'Species', '10090', (68, 72))	('miR-181b-5p', 'Chemical', '-', (145, 156))	('EVs-miR-181b-5p', 'Var', (141, 156))	('more', 'PosReg', (13, 17))	('pulmonary metastases', 'Disease', (30, 50))	('Eca-109/miR-181b-5p', 'Var', (88, 107))	('pulmonary metastases', 'Disease', 'MESH:D009362', (30, 50))	('EVs-miR-181b-5p', 'Chemical', '-', (141, 156))	('ESCC', 'Disease', (172, 176))	('miR-181b-5p', 'Chemical', '-', (96, 107))	('Eca', 'Chemical', '-', (88, 91))	('contributed', 'Reg', (157, 168))
753718	32244169	To further confirm whether tumor-derived EVs-miR-181b-5p promotes ESCC metastasis via miR-181b-5p-induced angiogenesis, GFP-labeled KYSE30 cells were intravenously injected into nude mice, which were subsequently treated with EVs derived from the different transfected Eca-109 cells mentioned above (Figure 6A).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('miR-181b-5p-induced', 'Var', (86, 105))	('Eca', 'Chemical', '-', (269, 272))	('tumor', 'Disease', (27, 32))	('EVs-miR-181b-5p', 'Chemical', '-', (41, 56))	('nude mice', 'Species', '10090', (178, 187))	('ESCC', 'Disease', (66, 70))	('miR-181b-5p', 'Chemical', '-', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('miR-181b-5p', 'Chemical', '-', (86, 97))	('promotes', 'PosReg', (57, 65))
753719	32244169	As expected, Eca-109/miR-181b-5p EVs dramatically induced ESCC metastasis (Figure 6B).	('Eca', 'Chemical', '-', (13, 16))	('Eca-109/miR-181b-5p', 'Var', (13, 32))	('induced', 'PosReg', (50, 57))	('ESCC', 'Disease', (58, 62))	('miR-181b-5p', 'Chemical', '-', (21, 32))
753721	32244169	On the contrary, Eca-109/inh-181b-5p EVs dramatically inhibited ESCC metastasis compared with the control group (Figures 6C, 6D, S7F, and S7G).	('inhibited', 'NegReg', (54, 63))	('Eca', 'Chemical', '-', (17, 20))	('ESCC', 'Disease', (64, 68))	('S7G', 'Mutation', 'rs115235376', (138, 141))	('S7F', 'Mutation', 'p.S7F', (129, 132))	('-181b-5p', 'Chemical', '-', (28, 36))	('Eca-109/inh-181b-5p', 'Var', (17, 36))
753723	32244169	Taken together, the above results suggest that ESCC-derived EVs-miR-181b-5p regulates angiogenesis to foster tumor growth and metastasis.	('foster', 'PosReg', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('EVs-miR-181b-5p', 'Var', (60, 75))	('regulates', 'Reg', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('angiogenesis', 'CPA', (86, 98))	('EVs-miR-181b-5p', 'Chemical', '-', (60, 75))	('tumor', 'Disease', (109, 114))
753729	32244169	To further determine the correlation of miR-181b-5p expression with clinicopathological features, we performed in situ hybridization (ISH) of 87 human ESCC tissue samples and confirmed that miR-181b-5p expression was elevated in ESCC tissues compared with normal tissues (Figure 7D).	('ESCC', 'Disease', (229, 233))	('miR-181b-5p', 'Var', (190, 201))	('miR-181b-5p', 'Chemical', '-', (40, 51))	('miR-181b-5p', 'Chemical', '-', (190, 201))	('expression', 'MPA', (202, 212))	('human', 'Species', '9606', (145, 150))	('elevated', 'PosReg', (217, 225))
753731	32244169	As shown in Figure 7E, high miR-181b-5p expression was well predicted for poor overall survival (OS).	('overall', 'MPA', (79, 86))	('poor', 'NegReg', (74, 78))	('miR-181b-5p expression', 'Var', (28, 50))	('miR-181b-5p', 'Chemical', '-', (28, 39))
753732	32244169	In addition, it was detected that high miR-181b-5p expression was correlated with high advanced N stage and clinical stage (N stage, p = 0.000; clinical stage, p = 0.000; Table S3).	('miR-181b-5p', 'Chemical', '-', (39, 50))	('clinical stage', 'CPA', (108, 122))	('miR-181b-5p', 'Var', (39, 50))
753733	32244169	In addition, multivariate analysis indicated that miR-181b-5p expression (hazard ratio [HR], 0.423; 95% confidence interval [CI], 0.215-0.831; p = 0.012) was an independent prognostic factor for OS in ESCC patients (Table S4).	('miR-181b-5p', 'Var', (50, 61))	('ESCC', 'Disease', (201, 205))	('patients', 'Species', '9606', (206, 214))	('miR-181b-5p', 'Chemical', '-', (50, 61))
753734	32244169	Taken together, these data showed that miR-181b-5p is highly expressed in ESCC tissues and serum EVs.	('ESCC', 'Disease', (74, 78))	('miR-181b-5p', 'Chemical', '-', (39, 50))	('miR-181b-5p', 'Var', (39, 50))
753736	32244169	To further confirm the correlation between miR-181b-5p expression and microvessel density in ESCC, we performed ISH of miR-181b-5p in combination with IHC staining of vascular endothelial cell markers (CD31) on serial sections of human ESCC tissues and adjacent normal tissues.	('CD31', 'Gene', (202, 206))	('miR-181b-5p', 'Chemical', '-', (43, 54))	('miR-181b-5p', 'Var', (119, 130))	('miR-181b-5p', 'Chemical', '-', (119, 130))	('CD31', 'Gene', '5175', (202, 206))	('human', 'Species', '9606', (230, 235))
753737	32244169	As shown in Figures 7F and 7G, miR-181b-5p signals were present in both tumor cells and vascular endothelial cells around the tumor, and CD31 was strongly positively correlated with miR-181b-5p, indicating that miR-181b-5p correlates with angiogenesis in ESCC patients.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('miR-181b-5p', 'Chemical', '-', (211, 222))	('angiogenesis', 'CPA', (239, 251))	('tumor', 'Disease', (72, 77))	('CD31', 'Gene', (137, 141))	('ESCC', 'Disease', (255, 259))	('patients', 'Species', '9606', (260, 268))	('miR-181b-5p', 'Var', (182, 193))	('correlated', 'Interaction', (166, 176))	('CD31', 'Gene', '5175', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('miR-181b-5p', 'Chemical', '-', (182, 193))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('miR-181b-5p', 'Chemical', '-', (31, 42))	('tumor', 'Disease', (126, 131))
753740	32244169	In our study, we provide a novel insight on the mechanism that ESCC-derived EVs-miR-181b-5p reprograms endothelial cells in the tumor microenvironment, primarily inducing angiogenesis by decreasing its targets PTEN and PHLPP2 expression to activate the Akt signaling pathway.	('PTEN', 'Gene', '5728', (210, 214))	('decreasing', 'NegReg', (187, 197))	('Akt', 'Gene', '207', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('EVs-miR-181b-5p', 'Var', (76, 91))	('inducing', 'PosReg', (162, 170))	('PHLPP2', 'Gene', (219, 225))	('expression', 'MPA', (226, 236))	('activate', 'PosReg', (240, 248))	('EVs-miR-181b-5p', 'Chemical', '-', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('angiogenesis', 'CPA', (171, 183))	('PHLPP2', 'Gene', '23035', (219, 225))	('Akt', 'Gene', (253, 256))	('tumor', 'Disease', (128, 133))	('PTEN', 'Gene', (210, 214))
753741	32244169	Subsequently, rich vascular anastomoses further facilitate ESCC tumorigenesis by supplying oxygen and nutrients, and foster tumor metastasis by serving as a conduit (Figure 7H), which is one of the reasons that tumor-derived EVs-miR-181b-5p facilitates ESCC tumorigenesis and metastasis.	('tumor', 'Disease', (258, 263))	('tumor', 'Disease', (124, 129))	('foster', 'PosReg', (117, 123))	('ESCC', 'Disease', (59, 63))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('facilitates', 'PosReg', (241, 252))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('oxygen', 'Chemical', 'MESH:D010100', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('facilitate', 'PosReg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (64, 69))	('ESCC', 'Disease', (253, 257))	('EVs-miR-181b-5p', 'Var', (225, 240))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('EVs-miR-181b-5p', 'Chemical', '-', (225, 240))
753743	32244169	Moreover, miR-181b was reported to promote cell autophagy and restrain cell apoptosis by regulating the CREBRF/CREB3 pathway in gallbladder carcinoma.	('CREB3', 'Gene', (111, 116))	('CREB3', 'Gene', '10488', (111, 116))	('regulating', 'Reg', (89, 99))	('cell apoptosis', 'CPA', (71, 85))	('restrain', 'NegReg', (62, 70))	('miR-181b', 'Chemical', '-', (10, 18))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (128, 149))	('miR-181b', 'Var', (10, 18))	('CREBRF', 'Gene', (104, 110))	('CREBRF', 'Gene', '153222', (104, 110))	('promote', 'PosReg', (35, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('gallbladder carcinoma', 'Disease', (128, 149))	('cell autophagy', 'CPA', (43, 57))
753744	32244169	In addition, miR-181b-5p could regulate the expression of proteins associated with cell migration, including TIMP-3 and annexin A2.	('proteins', 'Protein', (58, 66))	('expression of', 'MPA', (44, 57))	('cell migration', 'CPA', (83, 97))	('TIMP-3', 'Gene', '7078', (109, 115))	('regulate', 'Reg', (31, 39))	('miR-181b-5p', 'Var', (13, 24))	('miR-181b-5p', 'Chemical', '-', (13, 24))	('annexin A2', 'Gene', '302', (120, 130))	('TIMP-3', 'Gene', (109, 115))	('annexin A2', 'Gene', (120, 130))
753745	32244169	Previous studies have reported that miR-181b-5p is expressed aberrantly in several cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('miR-181b-5p', 'Var', (36, 47))	('miR-181b-5p', 'Chemical', '-', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
753746	32244169	For example, astrocytoma shows high expression of miR-181b-5p, which is significantly associated with poor patient survival.	('astrocytoma', 'Disease', (13, 24))	('astrocytoma', 'Phenotype', 'HP:0009592', (13, 24))	('miR-181b-5p', 'Var', (50, 61))	('miR-181b-5p', 'Chemical', '-', (50, 61))	('associated', 'Reg', (86, 96))	('patient', 'Species', '9606', (107, 114))	('astrocytoma', 'Disease', 'MESH:D001254', (13, 24))
753747	32244169	It is also determined that miR-181b-5p is upregulated in serum of acute myeloid leukemia (AML) patients compared with healthy controls.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (72, 88))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (66, 88))	('AML', 'Phenotype', 'HP:0004808', (90, 93))	('AML', 'Disease', (90, 93))	('patients', 'Species', '9606', (95, 103))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (66, 88))	('upregulated', 'PosReg', (42, 53))	('AML', 'Disease', 'MESH:D015470', (90, 93))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('acute myeloid leukemia', 'Disease', (66, 88))	('miR-181b-5p', 'Var', (27, 38))	('miR-181b-5p', 'Chemical', '-', (27, 38))
753748	32244169	To the contrary, miR-181b-5p is significantly downregulated and acts as a tumor suppressor in astrocytoma.	('astrocytoma', 'Disease', 'MESH:D001254', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('astrocytoma', 'Disease', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('tumor', 'Disease', (74, 79))	('downregulated', 'NegReg', (46, 59))	('miR-181b-5p', 'Var', (17, 28))	('miR-181b-5p', 'Chemical', '-', (17, 28))
753749	32244169	However, few studies have reported the biological functions of miR-181b-5p in tumor progression.	('miR-181b-5p', 'Chemical', '-', (63, 74))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('miR-181b-5p', 'Var', (63, 74))
753750	32244169	Our data demonstrate that ESCC-derived EVs-miR-181b-5p modulates vascular endothelial cells to secrete Ang1 and eNOS, which contributes to tumor angiogenesis.	('EVs-miR-181b-5p', 'Chemical', '-', (39, 54))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Ang', 'Gene', '283', (103, 106))	('modulates', 'Reg', (55, 64))	('secrete', 'MPA', (95, 102))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('eNOS', 'Gene', (112, 116))	('Ang', 'Gene', (103, 106))	('EVs-miR-181b-5p', 'Var', (39, 54))	('contributes', 'Reg', (124, 135))	('eNOS', 'Gene', '4846', (112, 116))
753751	32244169	Moreover, EVs-miR-181b-5p facilitates tumor growth and has a positive correlation with ESCC metastasis.	('EVs-miR-181b-5p', 'Var', (10, 25))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('EVs-miR-181b-5p', 'Chemical', '-', (10, 25))	('ESCC', 'Disease', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('facilitates', 'PosReg', (26, 37))
753752	32244169	In addition, miR-181b-5p is highly expressed in ESCC tissues and serum EVs, and high miR-181b-5p expression in ESCC patients predicts a poor outcome, which holds important implications for efficient prevention and therapeutic strategies.	('predicts', 'Reg', (125, 133))	('patients', 'Species', '9606', (116, 124))	('miR-181b-5p', 'Gene', (85, 96))	('miR-181b-5p', 'Chemical', '-', (85, 96))	('miR-181b-5p', 'Var', (13, 24))	('miR-181b-5p', 'Chemical', '-', (13, 24))	('ESCC', 'Disease', (48, 52))	('high', 'Var', (80, 84))	('expression', 'MPA', (97, 107))	('ESCC', 'Disease', (111, 115))
753756	32244169	Bioinformatics data predict that PTEN and PHLPP2 are the direct targets of miR-181b-5p, which are well-known tumor suppressors due to their ability to block the Akt signaling pathway in several cancer cells.	('cancer', 'Disease', (194, 200))	('miR-181b-5p', 'Var', (75, 86))	('block', 'NegReg', (151, 156))	('PHLPP2', 'Gene', (42, 48))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (33, 37))	('Akt', 'Gene', '207', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('miR-181b-5p', 'Chemical', '-', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('PHLPP2', 'Gene', '23035', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('Akt', 'Gene', (161, 164))	('tumor', 'Disease', (109, 114))
753765	32244169	Therefore, the role of Akt signaling in the activation of Ang2 and eNOS signaling induced by EVs-miR-181b-5p seems worthy of investigating.	('Ang2', 'Gene', '285', (58, 62))	('Akt', 'Gene', '207', (23, 26))	('eNOS', 'Gene', (67, 71))	('activation', 'PosReg', (44, 54))	('EVs-miR-181b-5p', 'Var', (93, 108))	('Akt', 'Gene', (23, 26))	('EVs-miR-181b-5p', 'Chemical', '-', (93, 108))	('eNOS', 'Gene', '4846', (67, 71))	('Ang2', 'Gene', (58, 62))
753766	32244169	Our results show that ESCC-derived EVs-miR-181b-5p suppresses the expression level of Ang2 but increases the expression levels of Ang1 and eNOS in vascular endothelial cells to promote cancer-induced angiogenesis via Akt signaling and downstream signaling activation.	('expression level', 'MPA', (66, 82))	('promote', 'PosReg', (177, 184))	('Ang', 'Gene', (86, 89))	('expression levels', 'MPA', (109, 126))	('suppresses', 'NegReg', (51, 61))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Ang2', 'Gene', '285', (86, 90))	('Ang', 'Gene', '283', (130, 133))	('eNOS', 'Gene', (139, 143))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('eNOS', 'Gene', '4846', (139, 143))	('Ang', 'Gene', '283', (86, 89))	('increases', 'PosReg', (95, 104))	('Akt', 'Gene', (217, 220))	('Ang2', 'Gene', (86, 90))	('Ang', 'Gene', (130, 133))	('EVs-miR-181b-5p', 'Var', (35, 50))	('EVs-miR-181b-5p', 'Chemical', '-', (35, 50))	('Akt', 'Gene', '207', (217, 220))
753767	32244169	In conclusion, our results indicate that ESCC-derived EVs-miR-181b-5p modulates vascular endothelial cells by decreasing PTEN and PHLPP2, which activates the Akt signaling pathway to promote intratumoral microvessel formation.	('PTEN', 'Gene', (121, 125))	('tumor', 'Disease', (196, 201))	('PTEN', 'Gene', '5728', (121, 125))	('Akt', 'Gene', '207', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('PHLPP2', 'Gene', '23035', (130, 136))	('EVs-miR-181b-5p', 'Var', (54, 69))	('modulates', 'Reg', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('activates', 'PosReg', (144, 153))	('Akt', 'Gene', (158, 161))	('PHLPP2', 'Gene', (130, 136))	('EVs-miR-181b-5p', 'Chemical', '-', (54, 69))	('promote', 'PosReg', (183, 190))	('decreasing', 'NegReg', (110, 120))
753768	32244169	More importantly, high miR-181b-5p expression in tissues and serum EVs shows a positive correlation with poor prognosis in ESCC patients.	('ESCC', 'Disease', (123, 127))	('expression', 'MPA', (35, 45))	('miR-181b-5p', 'Var', (23, 34))	('miR-181b-5p', 'Chemical', '-', (23, 34))	('patients', 'Species', '9606', (128, 136))	('high miR-181b-5p', 'Var', (18, 34))
753781	32244169	The human ESCC cell lines (TE-10, TE-12, TE-13, Eca-109, KYSE-30, KYSE-150, KYSE-180, KYSE-410, KYSE-450, KYSE-510) and normal HEEC lines were kindly supplied by Prof. Yifeng Zhou, Suzhou University, in 2015.	('KYSE-150', 'Var', (66, 74))	('human', 'Species', '9606', (4, 9))	('KYSE-410', 'Var', (86, 94))	('Eca', 'Chemical', '-', (48, 51))	('HEEC', 'Chemical', '-', (127, 131))
753784	32244169	Antibodies for TSG101 (14497-1-AP, 1:1,000), HSP70 (10995-1-AP, 1:1,000), Angiopoietin 1 (23302-1-AP, 1:1,000), Angiopoietin 2 (24613-1-AP, 1:000), PHLPP2 (25244-1-AP, 1:1,000), and p-Akt (66444-1-Ig, 1:3,000) were purchased from Sanying (China).	('PHLPP2', 'Gene', '23035', (148, 154))	('Angiopoietin 2', 'Gene', '285', (112, 126))	('14497-1-AP', 'Var', (23, 33))	('23302-1-AP', 'Var', (90, 100))	('10995-1-AP', 'Var', (52, 62))	('Angiopoietin 2', 'Gene', (112, 126))	('HSP70', 'Gene', (45, 50))	('TSG101', 'Gene', '7251', (15, 21))	('Akt', 'Gene', (184, 187))	('TSG101', 'Gene', (15, 21))	('Angiopoietin 1', 'Gene', '284', (74, 88))	('PHLPP2', 'Gene', (148, 154))	('Angiopoietin 1', 'Gene', (74, 88))	('HSP70', 'Gene', '3308', (45, 50))	('Akt', 'Gene', '207', (184, 187))
753786	32244169	Antibodies for GRP94 (D120724, 1:1,000) were purchased from BBI (China).	('GRP94', 'Gene', '7184', (15, 20))	('GRP94', 'Gene', (15, 20))	('D120724', 'Var', (22, 29))
753828	32244169	Quantitative relative real-time PCR was used to detect miR-181b-5p expression in tumor tissues or EVs from mice serum.	('miR-181b-5p', 'Var', (55, 66))	('miR-181b-5p', 'Chemical', '-', (55, 66))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mice', 'Species', '10090', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
753834	32244169	To identify the binding site between miR-181b-5p and PTEN/PHLPP2, HUVECs were transfected with a luciferase construct containing PTEN and PHLPP2 with the wild-type or a mutated version of the binding site, and co-transfected with a miR-181b-5p mimic or an empty vector.	('mutated', 'Var', (169, 176))	('PHLPP2', 'Gene', (58, 64))	('miR-181b-5p', 'Chemical', '-', (232, 243))	('PTEN', 'Gene', (129, 133))	('miR-181b-5p', 'Chemical', '-', (37, 48))	('PTEN', 'Gene', '5728', (129, 133))	('PTEN', 'Gene', (53, 57))	('PHLPP2', 'Gene', (138, 144))	('PTEN', 'Gene', '5728', (53, 57))	('PHLPP2', 'Gene', '23035', (58, 64))	('PHLPP2', 'Gene', '23035', (138, 144))
753835	32244169	For evaluating the luciferase activities of PTEN and PHLPP2, HUVECs were pre-treated with tumor-derived EVs for 24 h and then transfected with a luciferase vector containing PTEN and PHLPP2 with the wild-type or a mutated version of the binding site.	('PTEN', 'Gene', '5728', (174, 178))	('PHLPP2', 'Gene', '23035', (183, 189))	('PHLPP2', 'Gene', '23035', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('PTEN', 'Gene', (44, 48))	('PHLPP2', 'Gene', (183, 189))	('mutated', 'Var', (214, 221))	('PHLPP2', 'Gene', (53, 59))	('PTEN', 'Gene', '5728', (44, 48))	('PTEN', 'Gene', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
753849	32244169	The paired t test was performed to detect the differential expression of miR-181b-5p in cancer tissues compared with adjacent nonmalignant tissues.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('miR-181b-5p', 'Chemical', '-', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('miR-181b-5p', 'Var', (73, 84))
753873	31996261	The Montreal definition has been adopted by clinicians and researchers, and defines GERD as "a condition which develops when the reflux of stomach contents causes troublesome symptoms (e.g., retrosternal burning (heartburn), regurgitation) and/or complications (e.g., esophagitis, esophageal stricture)".	('esophageal stricture', 'Phenotype', 'HP:0002043', (281, 301))	('reflux', 'Var', (129, 135))	('reflux of stomach', 'Phenotype', 'HP:0002020', (129, 146))	('esophagitis', 'Phenotype', 'HP:0100633', (268, 279))	('retrosternal burning', 'Disease', (191, 211))	('esophagitis', 'Disease', (268, 279))	('esophagitis', 'Disease', 'MESH:D004941', (268, 279))	('heartburn', 'Phenotype', 'HP:0002020', (213, 222))	('GERD', 'Disease', (84, 88))	('GERD', 'Disease', 'MESH:D005764', (84, 88))
753884	31996261	The goal of treatment for BE and/or low- or high-grade dysplasia is to slow or halt GERD symptoms, reduce mucosal inflammation, control dysplasia and prevent progression to adenocarcinoma.	('halt', 'NegReg', (79, 83))	('dysplasia', 'Disease', (55, 64))	('reduce', 'NegReg', (99, 105))	('dysplasia', 'Disease', 'MESH:D015792', (136, 145))	('low- or high-grade', 'Var', (36, 54))	('adenocarcinoma', 'Disease', 'MESH:D000230', (173, 187))	('mucosal inflammation', 'Disease', 'MESH:D007249', (106, 126))	('dysplasia', 'Disease', 'MESH:D015792', (55, 64))	('BE', 'Phenotype', 'HP:0100580', (26, 28))	('dysplasia', 'Disease', (136, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('adenocarcinoma', 'Disease', (173, 187))	('GERD', 'Disease', (84, 88))	('mucosal inflammation', 'Disease', (106, 126))	('GERD', 'Disease', 'MESH:D005764', (84, 88))	('men', 'Species', '9606', (17, 20))
754044	31996261	Those diagnosed at earlier stages (T1 and T2) can be treated with potentially curable therapies, for example, esophagectomy in patients with high-grade dysplasia and stage T1a cancer has been associated with a greater survival; 89% at 1 year, 77% at five years and 68% at 10 years.	('dysplasia', 'Disease', (152, 161))	('stage T1a', 'Var', (166, 175))	('esophagectomy', 'Disease', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('dysplasia', 'Disease', 'MESH:D015792', (152, 161))
754142	31684983	There were 9 patients who had interrupted re-RT and received doses <=40 Gy due to major bleeding (1 patient), esophageal fistula (1 patient), rapid progression (3 patient) and cost of treatment concerns (4 patient).	('esophageal fistula', 'Disease', 'MESH:D004937', (110, 128))	('esophageal fistula', 'Disease', (110, 128))	('bleeding', 'Disease', 'MESH:D006470', (88, 96))	('patient', 'Species', '9606', (13, 20))	('patients', 'Species', '9606', (13, 21))	('patient', 'Species', '9606', (206, 213))	('bleeding', 'Disease', (88, 96))	('patient', 'Species', '9606', (100, 107))	('patient', 'Species', '9606', (163, 170))	('patient', 'Species', '9606', (132, 139))	('<=40 Gy', 'Var', (67, 74))
754214	30867781	CI in IMRT group was significantly higher than that in 3D-CRT group (P<0.001).	('CRT', 'Gene', '799', (58, 61))	('CRT', 'Gene', (58, 61))	('IMRT', 'Var', (6, 10))	('higher', 'PosReg', (35, 41))
754218	30867781	The incidence rates of radiation esophagitis and radiation pneumonitis in IMRT group were remarkably lower than those in 3D-CRT group (P<0.05).	('IMRT', 'Var', (74, 78))	('pneumonitis', 'Disease', 'MESH:D011014', (59, 70))	('radiation esophagitis', 'Disease', 'MESH:D004194', (23, 44))	('CRT', 'Gene', '799', (124, 127))	('CRT', 'Gene', (124, 127))	('lower', 'NegReg', (101, 106))	('esophagitis', 'Phenotype', 'HP:0100633', (33, 44))	('pneumonitis', 'Disease', (59, 70))	('radiation esophagitis', 'Disease', (23, 44))
754232	30867781	In terms of tumor-node-metastasis (TNM) stage, there were 22 cases in T1N0M0, 23 cases in T2N0M0, 8 cases in T3N0M0 and 7 cases in T4N0M0.	('T1N0M0', 'Var', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (12, 33))	('tumor-node-metastasis', 'Disease', (12, 33))
754246	30867781	The PTV Dmax, PTV Dmin, PTV Dmean and CI were 6813.41+-225.74 cGy, 5054.31+-193.52 cGy, 6257.35+-216.25 cGy and 0.605+-0.063 in 3D-CRT group, and 6737.07+-267.36 cGy, 5107.48+-173.52 cGy, 6199.07+-195.26 cGy and 0.719+-0.072 in IMRT group.	('6257.35+-216.25 cGy', 'Var', (88, 107))	('5054.31+-193.52', 'Var', (67, 82))	('6737.07+-267.36 cGy', 'Var', (146, 165))	('PTV Dmin', 'Chemical', '-', (14, 22))	('CRT', 'Gene', '799', (131, 134))	('PTV Dmean', 'Chemical', '-', (24, 33))	('6813.41+-225.74', 'Var', (46, 61))	('CRT', 'Gene', (131, 134))	('PTV Dmax', 'Chemical', '-', (4, 12))	('0.605+-0.063', 'Var', (112, 124))
754249	30867781	The organ-at-risk dose parameters V5, V20, V30 and spinal cord Dmax were 40.63+-7.63%, 25.63+-2.57%, 18.52+-1.93% and 4520.74+-273.52 cGy in 3D-CRT group, and 42.47+-7.07%, 23.42+-2.93%, 17.87+-2.17% and 4481.63+-237.12 cGy in IMRT group.	('CRT', 'Gene', (144, 147))	('CRT', 'Gene', '799', (144, 147))	('4481.63+-237.12', 'Var', (204, 219))	('4520.74+-273.52', 'Var', (118, 133))
754261	30867781	The incidence rates of radiation esophagitis and radiation pneumonitis in IMRT group were remarkably lower than those in 3D-CRT group (chi2=16.205, P<0.001; chi2=5.714, P=0.028) (Table II).	('IMRT', 'Var', (74, 78))	('pneumonitis', 'Disease', 'MESH:D011014', (59, 70))	('radiation esophagitis', 'Disease', 'MESH:D004194', (23, 44))	('CRT', 'Gene', '799', (124, 127))	('CRT', 'Gene', (124, 127))	('lower', 'NegReg', (101, 106))	('esophagitis', 'Phenotype', 'HP:0100633', (33, 44))	('pneumonitis', 'Disease', (59, 70))	('radiation esophagitis', 'Disease', (23, 44))
754276	30867781	The higher the double-lung V20 is, the more severe the radiation-induced pulmonary injury will be.	('double-lung V20', 'Var', (15, 30))	('pulmonary injury', 'Disease', 'MESH:D055370', (73, 89))	('pulmonary injury', 'Disease', (73, 89))
754278	30867781	According to the study of Yom et al, in advanced NSCLC patients with chemoradiotherapy, the risk of >= grade 3 treatment-related pneumonia caused by IMRT is significantly lower than that caused by 3D-CRT, which is similar to the conclusion in this study.	('pneumonia', 'Phenotype', 'HP:0002090', (129, 138))	('IMRT', 'Var', (149, 153))	('NSCLC', 'Disease', (49, 54))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('CRT', 'Gene', '799', (200, 203))	('pneumonia', 'Disease', (129, 138))	('pneumonia', 'Disease', 'MESH:D011014', (129, 138))	('CRT', 'Gene', (200, 203))	('patients', 'Species', '9606', (55, 63))	('lower', 'NegReg', (171, 176))
754295	30538559	A multivariate Cox regression analysis identified cases suffering from higher overall mortalities with RV>=0.218 compared to RV<0.218 (HR=1.45; 95% CI, 1.21-2.02; P=0.015); similar results were also found for DFS (HR=1.38; 95% CI, 1.03-1.86; P=0.033).	('higher', 'PosReg', (71, 77))	('mortalities', 'CPA', (86, 97))	('RV>=0.218', 'Var', (103, 112))	('Cox', 'Gene', '1351', (15, 18))	('Cox', 'Gene', (15, 18))
754296	30538559	Kaplan-Meier survival curves showed that cases with RV<0.218 had better OS and DFS than cases with RV>=0.218 (log rank = 75.80, P<0.001; log rank = 24.78, P<0.001).	('OS', 'Chemical', '-', (72, 74))	('RV<0.218', 'Var', (52, 60))	('better', 'PosReg', (65, 71))	('DFS', 'CPA', (79, 82))
754334	30538559	In addition, the area under the curve was 0.688 for OS (95% CI 0.653-0.723; P<0.001; Figure 3) and 0.645 for DFS (95% CI 0.582-0.708; P<0.001; Figure 4).	('OS', 'Chemical', '-', (52, 54))	('DFS', 'Disease', (109, 112))	('0.645', 'Var', (99, 104))
754347	30538559	After incorporating significant covariates, multivariate Cox regression analysis identified cases suffering from higher overall mortalities with RV>=0.218 compared to RV <0.218 (HR =1.45; 95% CI 1.21-2.02; P=0.015).	('Cox', 'Gene', (57, 60))	('Cox', 'Gene', '1351', (57, 60))	('higher', 'PosReg', (113, 119))	('RV>=0.218', 'Var', (145, 154))
754350	30538559	According to the Kaplan-Meier survival curves, cases with RV<0.218 had better OS and DFS than cases with RV>=0.218 (log rank =75.80, P<0.001; log rank =24.78, P<0.001; Figures 5 and 6).	('better', 'PosReg', (71, 77))	('DFS', 'CPA', (85, 88))	('RV<0.218', 'Var', (58, 66))	('OS', 'Chemical', '-', (78, 80))
754352	30538559	In TNM stages 2, 3, and 4, patients with RV>=0.218 had a worse prognosis than those with RV<0.218.	('TNM', 'Gene', (3, 6))	('patients', 'Species', '9606', (27, 35))	('TNM', 'Gene', '10178', (3, 6))	('RV>=0.218', 'Var', (41, 50))
754356	30538559	The AUC was 0.544 for OS (95% CI 0.506-0.582; P=0.025) and 0.532 for DFS (95% CI 0.458-0.605; P=0.405) in TNM classification (Figure 7).	('0.544', 'Var', (12, 17))	('TNM', 'Gene', '10178', (106, 109))	('TNM', 'Gene', (106, 109))	('OS', 'Chemical', '-', (22, 24))	('0.532', 'Var', (59, 64))
754435	29491399	Previously published primer pairs were used for Streptococcus, Enterobacteriaceae und Eubacteria and newly designed for Lautropia (Laut_16s_F: 5'-GTCCTTTTCGTTCCCGCC-3', Laut_16s_R: 5'-CAAGGCGACGATCTGTAGCTGG-3').	('Laut_16s_R', 'Var', (169, 179))	('Lautropia', 'Disease', (120, 129))	('Lautropia', 'Disease', 'None', (120, 129))
754492	26156831	Survival duration of esophageal adenocarcinoma did not significantly differ between patients with high CA9 expression and those with low expression.	('patients', 'Species', '9606', (84, 92))	('high', 'Var', (98, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('esophageal adenocarcinoma', 'Disease', (21, 46))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (21, 46))	('CA9', 'Protein', (103, 106))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (21, 46))
754493	26156831	High CA9 expression is significantly associated with BMI1, cyclin E, Ki67, MCM4 and MCM7 expression.	('High', 'Var', (0, 4))	('BMI1', 'Gene', (53, 57))	('BMI1', 'Gene', '648', (53, 57))	('MCM4', 'Gene', '4173', (75, 79))	('expression', 'MPA', (9, 19))	('cyclin', 'MPA', (59, 65))	('MCM7', 'Gene', '4176', (84, 88))	('associated', 'Reg', (37, 47))	('MCM4', 'Gene', (75, 79))	('MCM7', 'Gene', (84, 88))
754503	26156831	Inhibition of CA9 has been shown to slow tumor growth, inhibit metastasis, and decrease tumor stem cells in mice.	('slow', 'NegReg', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('metastasis', 'CPA', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (41, 46))	('CA9', 'Gene', (14, 17))	('decrease', 'NegReg', (79, 87))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (88, 93))	('inhibit', 'NegReg', (55, 62))
754507	26156831	Mutations of the common prolyl hydroxylation and pVHL binding domain lead to the loss of CA9 mRNA, and protein.	('VHL', 'Gene', (50, 53))	('VHL', 'Gene', '7428', (50, 53))	('protein', 'Protein', (103, 110))	('Mutations', 'Var', (0, 9))	('loss', 'NegReg', (81, 85))	('CA9 mRNA', 'MPA', (89, 97))
754511	26156831	Amplification and overexpression of cyclin E have been reported in various cancers.	('Amplification', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('reported', 'Reg', (55, 63))	('cancers', 'Disease', (75, 82))	('cyclin E', 'Protein', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('overexpression', 'PosReg', (18, 32))
754517	26156831	In current study, we first explored the relationship of CA9 high expression with gastroesophageal reflux disease including columnar cell metaplasia, Barrett's esophagus, low-and high-grade dysplasia.	("Barrett's esophagus", 'Disease', (149, 168))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (149, 168))	('dysplasia', 'Disease', 'MESH:D004476', (189, 198))	('high expression', 'Var', (60, 75))	('gastroesophageal reflux disease', 'Disease', (81, 112))	('columnar cell metaplasia', 'Disease', (123, 147))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (81, 104))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (81, 112))	('CA9', 'Gene', (56, 59))	('columnar cell metaplasia', 'Disease', 'MESH:D008679', (123, 147))	('dysplasia', 'Disease', (189, 198))
754532	26156831	After endogenous peroxidase activity was quenched and nonspecific binding was blocked, the sections were incubated with mouse monoclonal anti-CA9 (1:200; Thermo Fisher Scientific Pierce, Rockford, IL), anti-BMI1 (1:100; EMD Millipore, Billerica, MA), anti-cyclin E (1:100; Santa Cruz Biotechnology, Santa Cruz, CA), anti-MCM4 (1:50; Santa Cruz, CA), anti-MCM7 (1:50; Santa Cruz, CA) at 4  C overnight, and anti-Ki67 (1:100; Santa Cruz, CA) at room temperature for 20 min.	('MCM7', 'Gene', '4176', (355, 359))	('MCM4', 'Gene', '4173', (321, 325))	('1:50;', 'Var', (327, 332))	('1:50;', 'Var', (361, 366))	('MCM7', 'Gene', (355, 359))	('BMI1', 'Gene', '648', (207, 211))	('MCM4', 'Gene', (321, 325))	('BMI1', 'Gene', (207, 211))	('mouse', 'Species', '10090', (120, 125))
754539	26156831	Kaplan-Meier survival analysis and the log-rank test were used to analyze overall survival between the high CA9 expression group and the low CA9 expression group in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (165, 190))	('high CA9', 'Var', (103, 111))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (165, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))	('expression', 'MPA', (112, 122))
754542	26156831	High CA9 expression occurred predominantly in columnar cell lesions but was rare or absent in squamous cell carcinoma and squamous epithelium (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('High', 'Var', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('squamous cell carcinoma', 'Disease', (94, 117))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 117))	('columnar cell lesions', 'Disease', (46, 67))	('expression', 'MPA', (9, 19))	('occurred', 'Reg', (20, 28))
754543	26156831	We intended to analyze the association of high CA9 expression with clinicopathologic features in the esophageal adenocarcinoma and squamous cell carcinoma groups.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('esophageal adenocarcinoma', 'Disease', (101, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (101, 126))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 154))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (101, 126))	('squamous cell carcinoma', 'Disease', (131, 154))	('expression', 'MPA', (51, 61))	('high', 'Var', (42, 46))
754547	26156831	The odds of high CA9 expression were 2.8 times higher in men than in women.	('high', 'Var', (12, 16))	('CA9', 'Protein', (17, 20))	('expression', 'MPA', (21, 31))	('men', 'Species', '9606', (71, 74))	('men', 'Species', '9606', (57, 60))	('women', 'Species', '9606', (69, 74))
754551	26156831	The median survival duration for patients with esophageal adenocarcinoma in the high CA9 expression group was 20 months, with a mean survival of 40 months.	('patients', 'Species', '9606', (33, 41))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (47, 72))	('esophageal adenocarcinoma', 'Disease', (47, 72))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (47, 72))	('high CA9 expression', 'Var', (80, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
754553	26156831	The survival duration did not significantly differ between patients with high CA9 expression and low CA9 expression (P = .8488).	('CA9', 'Protein', (78, 81))	('CA9', 'Protein', (101, 104))	('patients', 'Species', '9606', (59, 67))	('high', 'Var', (73, 77))	('expression', 'MPA', (105, 115))	('low', 'NegReg', (97, 100))
754554	26156831	The rate of high CA9 expression was statistically associated with BMI1, cyclin E high expression and MCM4, MCM7 and Ki67 expression (P < .001) with Pearson correlation method.	('CA9', 'Gene', (17, 20))	('high', 'Var', (12, 16))	('MCM7', 'Gene', '4176', (107, 111))	('cyclin', 'Protein', (72, 78))	('BMI1', 'Gene', '648', (66, 70))	('MCM4', 'Gene', (101, 105))	('expression', 'MPA', (21, 31))	('high', 'PosReg', (81, 85))	('MCM7', 'Gene', (107, 111))	('BMI1', 'Gene', (66, 70))	('MCM4', 'Gene', '4173', (101, 105))
754558	26156831	However, high CA9 expression was significantly more frequent in glandular lesions than in squamous epithelium (0 %) and squamous cell carcinoma (9 %).	('glandular lesions', 'Disease', (64, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('CA9', 'Protein', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('expression', 'MPA', (18, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 143))	('squamous cell carcinoma', 'Disease', (120, 143))	('high', 'Var', (9, 13))
754563	26156831	CA9 is a well-known hypoxic indicator and plays an important role in maintaining the intracellular pH despite increased extracellular acidosis, thereby promoting cancer cell survival and growth in hypoxic-acidic environments.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('men', 'Species', '9606', (219, 222))	('cancer', 'Disease', (162, 168))	('acidosis', 'Disease', 'MESH:D000138', (134, 142))	('increased', 'PosReg', (110, 119))	('promoting', 'PosReg', (152, 161))	('CA9', 'Var', (0, 3))	('intracellular pH', 'MPA', (85, 101))	('growth', 'CPA', (187, 193))	('acidosis', 'Phenotype', 'HP:0001941', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('hypoxic-acidic', 'Disease', (197, 211))	('hypoxic-acidic', 'Disease', 'MESH:D000326', (197, 211))	('acidosis', 'Disease', (134, 142))
754568	26156831	In our study, the rate of high CA9 expression was very high in esophageal adenocarcinoma (90 %) and precancerous lesions (74 %-94 %) but was very low in esophageal squamous cell carcinoma (9 %).	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (63, 88))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('high', 'Var', (26, 30))	('expression', 'MPA', (35, 45))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (153, 187))	('CA9', 'Protein', (31, 34))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (63, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('precancerous lesions', 'Disease', 'MESH:D011230', (100, 120))	('esophageal adenocarcinoma', 'Disease', (63, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('precancerous lesions', 'Disease', (100, 120))	('esophageal squamous cell carcinoma', 'Disease', (153, 187))
754577	26156831	Many studies have shown that CA9 high expression is associated with worse prognosis in solid tumors than lower or no CA9 expression in them.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('high expression', 'Var', (33, 48))	('solid tumors', 'Disease', (87, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('CA9', 'Gene', (29, 32))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))
754579	26156831	Additionally, the high CA9 expression was not associated with clinicopathologic features such as age, lymph node metastasis, tumor stage, and prognosis but was significantly associated with male sex (P = .0011).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('associated', 'Reg', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('expression', 'MPA', (27, 37))	('tumor', 'Disease', (125, 130))	('male sex', 'Disease', (190, 198))	('high', 'Var', (18, 22))	('CA9', 'Protein', (23, 26))
754582	26156831	Inhibition of CA9 with sulfonamide and/or coumarin inhibitors was recently shown to lead to a potent retardation for the growth of both primary tumors and metastases.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('growth', 'CPA', (121, 127))	('retardation', 'Disease', (101, 112))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('coumarin', 'Chemical', 'MESH:C030123', (42, 50))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('retardation', 'Disease', 'MESH:D008607', (101, 112))	('sulfonamide', 'Chemical', 'MESH:D013449', (23, 34))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('metastases', 'Disease', (155, 165))
754592	26156831	Our findings of the significant association of high CA9 expression with BMI1 imply that CA9 may be involved in esophageal tumorigenesis through esophageal stem cells.	('BMI1', 'Gene', (72, 76))	('high', 'Var', (47, 51))	('involved', 'Reg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('BMI1', 'Gene', '648', (72, 76))	('expression', 'MPA', (56, 66))	('CA9', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
754593	26156831	High CA9 expression was significantly associated with cyclin E expression in esophageal adenocarcinoma and precancerous lesions.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('precancerous lesions', 'Disease', (107, 127))	('cyclin E expression', 'MPA', (54, 73))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (77, 102))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('esophageal adenocarcinoma', 'Disease', (77, 102))	('expression', 'MPA', (9, 19))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (77, 102))	('precancerous lesions', 'Disease', 'MESH:D011230', (107, 127))
754595	26156831	High CA9 expression was significantly associated with MCM4, MCM7 and Ki67 expression in esophageal adenocarcinoma and precancerous lesions.	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('precancerous lesions', 'Disease', (118, 138))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (88, 113))	('MCM4', 'Gene', '4173', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('precancerous lesions', 'Disease', 'MESH:D011230', (118, 138))	('MCM7', 'Gene', '4176', (60, 64))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('expression', 'MPA', (9, 19))	('MCM4', 'Gene', (54, 58))	('Ki67', 'Gene', (69, 73))	('CA9', 'Gene', (5, 8))	('MCM7', 'Gene', (60, 64))
754596	26156831	However, the correlation was low (r = .1388) with Ki67 and relative higher (r = .2946; r = .3106) with MCM4 and MCM7.	('MCM7', 'Gene', (112, 116))	('MCM4', 'Gene', (103, 107))	('correlation', 'Interaction', (13, 24))	('low', 'NegReg', (29, 32))	('higher', 'PosReg', (68, 74))	('MCM7', 'Gene', '4176', (112, 116))	('MCM4', 'Gene', '4173', (103, 107))	('Ki67', 'Var', (50, 54))
754615	24995504	In the canonical pathway, ligation of cytokines to their respective cell-surface receptors induces dimerization and auto-phosphorylation of various tyrosine residues of Janus kinases (JAKs), which then serve as the docking sites for the inactive, monomeric STAT3 molecules.	('JAKs', 'Gene', '16451;3717;16452', (184, 188))	('tyrosine', 'Chemical', 'MESH:D014443', (148, 156))	('dimerization', 'MPA', (99, 111))	('ligation', 'Var', (26, 34))	('auto-phosphorylation', 'MPA', (116, 136))	('JAKs', 'Gene', (184, 188))	('induces', 'Reg', (91, 98))
754622	24995504	STAT3C contains two cysteine substitutions at the residues A661 and N663, leading to the formation of disulfide bridges between two STAT3 molecules and mimicking STAT3 homodimerization that occurs in the normal activation process.	('STAT3 homodimerization', 'MPA', (162, 184))	('A661', 'Var', (59, 63))	('formation of disulfide bridges', 'MPA', (89, 119))	('disulfide', 'Chemical', 'MESH:D004220', (102, 111))	('N663', 'Var', (68, 72))	('cysteine', 'Chemical', 'MESH:D003545', (20, 28))
754623	24995504	It has been demonstrated that STAT3C can effectively induce malignant transformation, and that STATC can transcriptionally increase the expression of many genes that are important in promoting cellular proliferation, resistance to apoptosis, angiogenesis, immune evasion, invasion and metastasis, all of which are hallmarks of cancer.	('metastasis', 'CPA', (285, 295))	('angiogenesis', 'CPA', (242, 254))	('expression', 'MPA', (136, 146))	('cancer', 'Disease', (327, 333))	('STATC', 'Var', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('STAT3C', 'Var', (30, 36))	('cellular proliferation', 'CPA', (193, 215))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('promoting', 'PosReg', (183, 192))	('malignant transformation', 'CPA', (60, 84))	('increase', 'PosReg', (123, 131))	('invasion', 'CPA', (272, 280))	('induce', 'Reg', (53, 59))	('resistance to apoptosis', 'CPA', (217, 240))	('immune evasion', 'MPA', (256, 270))
754627	24995504	To reinforce the concept that STAT3 is oncogenic when it is inappropriately or constitutively activated, many laboratories have shown that the dominant negative STAT3 mutant construct, often labeled STAT3-DN in the literature, can effectively mediate cell cycle arrest and/or induce apoptosis in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('mediate', 'Reg', (243, 250))	('apoptosis', 'CPA', (283, 292))	('cell cycle arrest', 'CPA', (251, 268))	('negative', 'NegReg', (152, 160))	('mutant', 'Var', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('STAT3', 'Gene', (161, 166))	('min', 'Gene', (145, 148))	('cancer', 'Disease', (296, 302))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (251, 268))	('induce', 'PosReg', (276, 282))	('min', 'Gene', '11789', (145, 148))
754642	24995504	In this regard, epigenetic silencing of SOCS3 has been found in various types of cancer, including lung cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma and Barrett-associated esophageal adenocarcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (151, 175))	('cancer', 'Disease', (81, 87))	('neck squamous cell carcinoma', 'Disease', (121, 149))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (121, 149))	('esophageal adenocarcinoma', 'Disease', (199, 224))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (104, 110))	('hepatocellular carcinoma', 'Disease', (151, 175))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('SOCS3', 'Gene', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('SOCS3', 'Gene', '12702', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (151, 175))	('found', 'Reg', (55, 60))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (199, 224))	('epigenetic silencing', 'Var', (16, 36))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (199, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
754643	24995504	Experimental results have revealed that loss of SOCS3 indeed contributes to the activation of STAT3 in cancer cells, thereby promoting their proliferation, survival and motility.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('promoting', 'PosReg', (125, 134))	('STAT3', 'Gene', (94, 99))	('proliferation', 'CPA', (141, 154))	('loss', 'Var', (40, 44))	('motility', 'CPA', (169, 177))	('SOCS3', 'Gene', '12702', (48, 53))	('survival', 'CPA', (156, 164))	('SOCS3', 'Gene', (48, 53))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('activation', 'PosReg', (80, 90))
754644	24995504	SOCS1, another member of the SOCS family, is also frequently silenced by gene methylation, and this biochemical aberrancy has been shown to contribute to constitutive STAT3 activation in a wide range of cancer types.	('methylation', 'Var', (78, 89))	('activation', 'PosReg', (173, 183))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('constitutive STAT3', 'MPA', (154, 172))	('silenced', 'NegReg', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('SOCS1', 'Gene', (0, 5))
754648	24995504	For example, SHP-1, a member of the tyrosine phosphatases highly expressed in normal lymphoid cells, is lost in many types of hematologic malignancies due to epigenetic silencing.	('epigenetic silencing', 'Var', (158, 178))	('lost', 'NegReg', (104, 108))	('tyrosine', 'Chemical', 'MESH:D014443', (36, 44))	('SHP-1', 'Gene', (13, 18))	('hematologic malignancies', 'Disease', 'MESH:D019337', (126, 150))	('SHP-1', 'Gene', '15170', (13, 18))	('hematologic malignancies', 'Disease', (126, 150))
754649	24995504	Loss of SHP-1 has been shown to directly contribute to the constitutive activation of STAT3 in these cancer types, including ALK-positive anaplastic large cell lymphoma, chronic myeloid leukemia and multiple myeloma, since gene transfection of SHP1 in these cells can substantially decrease the level of STAT3 activation.	('multiple myeloma', 'Disease', 'MESH:D009101', (199, 215))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (138, 168))	('SHP1', 'Gene', '15170', (244, 248))	('ALK', 'Gene', (125, 128))	('chronic myeloid leukemia', 'Disease', (170, 194))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('lymphoma', 'Phenotype', 'HP:0002665', (160, 168))	('multiple myeloma', 'Disease', (199, 215))	('ALK', 'Gene', '11682', (125, 128))	('cell lymphoma', 'Phenotype', 'HP:0012191', (155, 168))	('SHP-1', 'Gene', '15170', (8, 13))	('decrease', 'NegReg', (282, 290))	('activation', 'PosReg', (72, 82))	('level', 'MPA', (295, 300))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (178, 194))	('leukemia', 'Phenotype', 'HP:0001909', (186, 194))	('Loss', 'Var', (0, 4))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (170, 194))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (170, 194))	('SHP-1', 'Gene', (8, 13))	('multiple myeloma', 'Phenotype', 'HP:0006775', (199, 215))	('SHP1', 'Gene', (244, 248))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
754651	24995504	Thus, loss of SHP-1 and the constitutive activation of STAT3 form a vicious cycle in these lymphoma cells.	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('loss', 'Var', (6, 10))	('STAT3', 'Gene', (55, 60))	('SHP-1', 'Gene', '15170', (14, 19))	('SHP-1', 'Gene', (14, 19))	('activation', 'PosReg', (41, 51))
754654	24995504	Transfection of PIAS3 into lung cancer cell lines can suppress cell proliferation and enhance the sensitivity of cells to chemotherapeutic drugs.	('PIAS3', 'Gene', '229615', (16, 21))	('enhance', 'PosReg', (86, 93))	('sensitivity of cells', 'CPA', (98, 118))	('lung cancer', 'Disease', (27, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('Transfection', 'Var', (0, 12))	('cell proliferation', 'CPA', (63, 81))	('suppress', 'NegReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))	('PIAS3', 'Gene', (16, 21))
754664	24995504	Normally, the activation status of Src is increased by de-phosphorylation of Y527 and phosphorylation of Y416.	('increased', 'PosReg', (42, 51))	('de-phosphorylation', 'MPA', (55, 73))	('Y527', 'Var', (77, 81))	('activation status', 'MPA', (14, 31))	('Y416', 'Chemical', '-', (105, 109))	('Src', 'Gene', '20779', (35, 38))	('phosphorylation', 'MPA', (86, 101))	('Src', 'Gene', (35, 38))	('Y416', 'Var', (105, 109))
754665	24995504	In cancer cells, de-phosphorylation of Y527 can be due to the activity of tyrosine phosphatases (such as PTP1B), Y527F mutation or deletion of Y527.	('PTP1B', 'Gene', '19246', (105, 110))	('Y527', 'Var', (39, 43))	('Y527', 'Gene', (143, 147))	('PTP1B', 'Gene', (105, 110))	('activity', 'MPA', (62, 70))	('tyrosine phosphatases', 'Enzyme', (74, 95))	('Y527F mutation', 'Var', (113, 127))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tyrosine', 'Chemical', 'MESH:D014443', (74, 82))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('de-phosphorylation', 'MPA', (17, 35))	('Y527F', 'Mutation', 'p.Y527F', (113, 118))	('deletion', 'Var', (131, 139))
754666	24995504	Phosphorylation of Y416, which correlates with Src activation and its malignant transforming ability, can be found in cancer cells.	('cancer', 'Disease', (118, 124))	('Src', 'Gene', '20779', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('Src', 'Gene', (47, 50))	('min', 'Gene', (88, 91))	('Y416', 'Chemical', '-', (19, 23))	('min', 'Gene', '11789', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Y416', 'Var', (19, 23))	('activation', 'PosReg', (51, 61))
754670	24995504	In one study, immortalized mouse embryonic fibroblasts with intact STAT3 expression were transformed by NPM-ALK, whereas STAT3 gene knockout dramatically decreased the malignant transformation by NPM-ALK.	('decreased', 'NegReg', (154, 163))	('mouse', 'Species', '10090', (27, 32))	('NPM', 'Gene', '18148', (196, 199))	('NPM', 'Gene', (196, 199))	('ALK', 'Gene', '11682', (108, 111))	('NPM', 'Gene', '18148', (104, 107))	('STAT3', 'Gene', (67, 72))	('NPM', 'Gene', (104, 107))	('ALK', 'Gene', '11682', (200, 203))	('malignant transformation', 'CPA', (168, 192))	('ALK', 'Gene', (108, 111))	('ALK', 'Gene', (200, 203))	('knockout', 'Var', (132, 140))
754671	24995504	Gain-of-function mutations involving JAKs have been implicated in activating STAT3 in specific types of cancer.	('JAKs', 'Gene', (37, 41))	('JAKs', 'Gene', '16451;3717;16452', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('activating', 'MPA', (66, 76))	('Gain-of-function', 'PosReg', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('STAT3', 'Gene', (77, 82))	('cancer', 'Disease', (104, 110))	('mutations', 'Var', (17, 26))
754672	24995504	JAK2-V617F and other JAK mutants are known to activate STAT3 and contribute to the pathogenesis of chronic myeloproliferative neoplasms and leukemias.	('chronic myeloproliferative neoplasms', 'Disease', (99, 135))	('leukemias', 'Disease', 'MESH:D007938', (140, 149))	('STAT3', 'Gene', (55, 60))	('chronic myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (99, 135))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (107, 135))	('V617F', 'SUBSTITUTION', 'None', (5, 10))	('JAK2', 'Gene', (0, 4))	('activate', 'PosReg', (46, 54))	('neoplasms', 'Phenotype', 'HP:0002664', (126, 135))	('leukemias', 'Disease', (140, 149))	('V617F', 'Var', (5, 10))	('leukemias', 'Phenotype', 'HP:0001909', (140, 149))	('contribute', 'Reg', (65, 75))	('JAK2', 'Gene', '16452', (0, 4))
754673	24995504	Mutations in the kinase domain of the epidermal growth factor receptor also have been reported to sustain STAT3 activation by promoting IL-6 production in lung cancer cells.	('promoting', 'PosReg', (126, 135))	('epidermal growth factor receptor', 'Gene', (38, 70))	('epidermal growth factor receptor', 'Gene', '13649', (38, 70))	('lung cancer', 'Disease', (155, 166))	('IL-6', 'Gene', (136, 140))	('IL-6', 'Gene', '16193', (136, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('Mutations in', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('STAT3 activation', 'MPA', (106, 122))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
754674	24995504	In glioblastoma, a constitutively active mutant of epidermal growth factor receptor was found, and this mutant contributes to and sustains STAT3 activation by inducing a cytokine circuit involving IL-6 and leukemia inhibitory factor, which in turn activates gp130 in the neighboring cells that harbor wild-type epidermal growth factor receptor, leading to an enhanced growth of the entire tumor.	('leukemia', 'Phenotype', 'HP:0001909', (206, 214))	('tumor', 'Phenotype', 'HP:0002664', (389, 394))	('inducing', 'Reg', (159, 167))	('leukemia inhibitory factor', 'Gene', (206, 232))	('epidermal growth factor receptor', 'Gene', '13649', (51, 83))	('gp130', 'Gene', '16195', (258, 263))	('enhanced', 'PosReg', (359, 367))	('epidermal growth factor receptor', 'Gene', '13649', (311, 343))	('IL-6', 'Gene', (197, 201))	('mutant', 'Var', (104, 110))	('STAT3 activation', 'MPA', (139, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('IL-6', 'Gene', '16193', (197, 201))	('tumor', 'Disease', (389, 394))	('epidermal growth factor receptor', 'Gene', (51, 83))	('glioblastoma', 'Disease', (3, 15))	('leukemia inhibitory factor', 'Gene', '16878', (206, 232))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('gp130', 'Gene', (258, 263))	('epidermal growth factor receptor', 'Gene', (311, 343))	('tumor', 'Disease', 'MESH:D009369', (389, 394))	('growth of the', 'CPA', (368, 381))	('cytokine circuit', 'MPA', (170, 186))
754683	24995504	Blocking this positive feedback loop in either cell types was shown to decrease tumor growth and metastasis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Blocking', 'Var', (0, 8))	('decrease', 'NegReg', (71, 79))	('tumor', 'Disease', (80, 85))
754685	24995504	In one study, pyruvate kinase M2 (PKM2), a protein that is known to be essential for the Warburg effect and proliferation of cancer cells, was found to activate STAT3 via catalyzing its phosphorylation at Y705.	('STAT3', 'MPA', (161, 166))	('Y705', 'Var', (205, 209))	('catalyzing', 'MPA', (171, 181))	('PKM2', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('pyruvate kinase M2', 'Gene', '18746', (14, 32))	('activate', 'PosReg', (152, 160))	('cancer', 'Disease', (125, 131))	('PKM2', 'Gene', '18746', (34, 38))	('phosphorylation', 'MPA', (186, 201))	('pyruvate kinase M2', 'Gene', (14, 32))
754690	24995504	Recently, somatic mutations in STAT3 were discovered in hepatocellular adenomas and many types of hematopoietic malignancies, such as T-cell large granular lymphocytic leukemia (T-cell LGL), chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs), diffuse large B-cell lymphoma, and CD30+ T-cell lymphomas.	('granular lymphocytic leukemia', 'Disease', 'MESH:D054066', (147, 176))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('LGL', 'Gene', (185, 188))	('diffuse large B-cell lymphoma', 'Disease', (265, 294))	('lymphoproliferative disorders', 'Disease', (199, 228))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (98, 124))	('lymphoproliferative disorders', 'Disease', 'MESH:D008232', (199, 228))	('lymphomas', 'Disease', 'MESH:D008223', (313, 322))	('STAT3', 'Gene', (31, 36))	('hepatocellular adenomas', 'Disease', (56, 79))	('lymphomas', 'Phenotype', 'HP:0002665', (313, 322))	('lymphoma', 'Phenotype', 'HP:0002665', (286, 294))	('cell lymphoma', 'Phenotype', 'HP:0012191', (281, 294))	('CLPD-NKs', 'Disease', (254, 262))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (56, 79))	('lymphomas', 'Disease', (313, 322))	('CD30', 'Gene', (300, 304))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (279, 294))	('granular lymphocytic leukemia', 'Disease', (147, 176))	('lymphoproliferative disorders', 'Phenotype', 'HP:0005523', (199, 228))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (56, 79))	('T-cell lymphomas', 'Phenotype', 'HP:0012190', (306, 322))	('CLPD-NKs', 'Disease', 'MESH:C531816', (254, 262))	('hematopoietic malignancies', 'Disease', (98, 124))	('CD30', 'Gene', '21941', (300, 304))	('cell lymphoma', 'Phenotype', 'HP:0012191', (308, 321))	('LGL', 'Gene', '16862', (185, 188))	('lymphoma', 'Phenotype', 'HP:0002665', (313, 321))	('mutations', 'Var', (18, 27))
754691	24995504	identified seven STAT3 mutations in 6/114 hepatocellular adenomas examined.	('STAT3', 'Gene', (17, 22))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (42, 65))	('hepatocellular adenomas', 'Disease', (42, 65))	('mutations', 'Var', (23, 32))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (42, 65))	('min', 'Gene', (69, 72))	('min', 'Gene', '11789', (69, 72))
754692	24995504	Notably, all six of these tumors were inflammatory hepatocellular adenomas, suggesting the specificity of somatic STAT3 mutations for this type of hepatocellular tumor.	('hepatocellular tumor', 'Disease', (147, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('hepatocellular adenomas', 'Disease', (51, 74))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (51, 74))	('STAT3', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutations', 'Var', (120, 129))	('hepatocellular tumor', 'Disease', 'MESH:D006528', (147, 167))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (51, 74))	('hepatocellular tumor', 'Phenotype', 'HP:0001402', (147, 167))	('tumors', 'Disease', (26, 32))
754693	24995504	Somatic STAT3 mutations have also been shown to be frequent in T-cell LGL and CLPD-NKs.	('LGL', 'Gene', (70, 73))	('CLPD-NKs', 'Disease', (78, 86))	('CLPD-NKs', 'Disease', 'MESH:C531816', (78, 86))	('LGL', 'Gene', '16862', (70, 73))	('STAT3', 'Gene', (8, 13))	('frequent', 'Reg', (51, 59))	('mutations', 'Var', (14, 23))
754694	24995504	Four independent studies have revealed somatic STAT3 mutations in T-cell LGL, and the reported percentages of cases carrying STAT3 mutations were 4/36 (11%), 33/120 (28%), 31/77 (40%) and 40/55 (73%), respectively.	('LGL', 'Gene', (73, 76))	('STAT3', 'Gene', (47, 52))	('LGL', 'Gene', '16862', (73, 76))	('mutations', 'Var', (53, 62))
754695	24995504	Two independent studies in CLPD-NKs have described the finding of somatic STAT3 mutations occurring in 3/7 (43%) and 15/50 (30%) of the cases, respectively.	('STAT3', 'Gene', (74, 79))	('CLPD-NKs', 'Disease', 'MESH:C531816', (27, 35))	('CLPD-NKs', 'Disease', (27, 35))	('mutations', 'Var', (80, 89))
754696	24995504	It is notable that mutations in Y640 and D661 were shown to account for the vast majority of somatic mutations in the STAT3 gene in both T-cell LGL and CLPD-NKs, representing about 80% of all mutations detected.	('D661', 'Var', (41, 45))	('Y640', 'Var', (32, 36))	('mutations', 'Var', (19, 28))	('STAT3', 'Gene', (118, 123))	('CLPD-NKs', 'Disease', (152, 160))	('CLPD-NKs', 'Disease', 'MESH:C531816', (152, 160))	('LGL', 'Gene', '16862', (144, 147))	('LGL', 'Gene', (144, 147))
754697	24995504	Intriguingly, most of the STAT3 mutations discovered (e.g., Y640F, D661H, D661V, D661Y, and N647I) reside in the SH2 domain that normally directs STAT3 dimerization, and many of these mutations were suggested to induce amino acid changes that confer higher hydrophobicity to the STAT3 SH2 dimerization surface, potentially facilitating phosphorylation of STAT3Y705 and thus the activation of STAT3.	('facilitating', 'PosReg', (323, 335))	('N647I', 'Var', (92, 97))	('phosphorylation', 'MPA', (336, 351))	('D661H', 'Var', (67, 72))	('D661V', 'Mutation', 'p.D661V', (74, 79))	('mutations', 'Var', (32, 41))	('STAT3', 'MPA', (146, 151))	('D661H', 'Mutation', 'p.D661H', (67, 72))	('hydrophobicity', 'MPA', (257, 271))	('higher', 'PosReg', (250, 256))	('Y640F', 'Var', (60, 65))	('Y640F', 'Mutation', 'rs769031989', (60, 65))	('D661V', 'Var', (74, 79))	('D661Y', 'Mutation', 'rs747639500', (81, 86))	('min', 'Gene', (220, 223))	('activation', 'PosReg', (378, 388))	('STAT3', 'Gene', (26, 31))	('D661Y', 'Var', (81, 86))	('min', 'Gene', '11789', (220, 223))	('N647I', 'Mutation', 'rs770986654', (92, 97))
754698	24995504	Correlating with this concept, both the STAT3-Y640F and STAT3-D661V mutants were shown to increase the transcriptional activity of STAT3 in T-cell LGL, leading to the up-regulation of the downstream target genes of the STAT3 pathway including IFNGR2, BCL2L1 and JAK2.	('IFNGR2', 'Gene', '15980', (243, 249))	('increase', 'PosReg', (90, 98))	('STAT3', 'Gene', (131, 136))	('STAT3-D661V', 'Var', (56, 67))	('IFNGR2', 'Gene', (243, 249))	('transcriptional activity', 'MPA', (103, 127))	('Y640F', 'Mutation', 'rs769031989', (46, 51))	('BCL2L1', 'Gene', (251, 257))	('LGL', 'Gene', '16862', (147, 150))	('STAT3-Y640F', 'Var', (40, 51))	('up-regulation', 'PosReg', (167, 180))	('LGL', 'Gene', (147, 150))	('STAT3 pathway', 'Pathway', (219, 232))	('JAK2', 'Gene', (262, 266))	('BCL2L1', 'Gene', '12048', (251, 257))	('D661V', 'Mutation', 'p.D661V', (62, 67))	('JAK2', 'Gene', '16452', (262, 266))
754699	24995504	Moreover, Y640F, one of the most common STAT3 mutations, was shown to allow homodimerization of STAT3 independent of IL-6 or enhance the STAT3 homodimerization in response to IL-6.	('IL-6', 'Gene', '16193', (117, 121))	('allow', 'PosReg', (70, 75))	('Y640F', 'Mutation', 'rs769031989', (10, 15))	('IL-6', 'Gene', (117, 121))	('Y640F', 'Var', (10, 15))	('IL-6', 'Gene', (175, 179))	('IL-6', 'Gene', '16193', (175, 179))	('enhance', 'PosReg', (125, 132))	('STAT3', 'Gene', (40, 45))	('homodimerization', 'MPA', (76, 92))	('STAT3', 'Protein', (96, 101))	('STAT3 homodimerization', 'MPA', (137, 159))
754700	24995504	Recently, a M206K mutation that localizes in the coiled-coil domain of STAT3 was discovered in diffuse large B cell lymphoma, and this mutation was demonstrated to enhance both the STAT3Y705 phosphorylation and its transcriptional activity.	('enhance', 'PosReg', (164, 171))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (109, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (116, 124))	('cell lymphoma', 'Phenotype', 'HP:0012191', (111, 124))	('diffuse', 'Disease', (95, 102))	('M206K', 'Mutation', 'p.M206K', (12, 17))	('large B cell', 'Phenotype', 'HP:0005404', (103, 115))	('transcriptional', 'MPA', (215, 230))	('STAT3', 'Gene', (71, 76))	('STAT3Y705 phosphorylation', 'MPA', (181, 206))	('M206K', 'Var', (12, 17))
754701	24995504	Compared with cells harboring wild-type STAT3, STAT3-M206K mutant cells were resistant to the JAK2 inhibitor TG101348, suggesting that this STAT3 mutant possesses constitutive activity.	('JAK2', 'Gene', '16452', (94, 98))	('STAT3-M206K', 'Var', (47, 58))	('TG101348', 'Chemical', 'MESH:C528327', (109, 117))	('M206K', 'Mutation', 'p.M206K', (53, 58))	('JAK2', 'Gene', (94, 98))
754703	24995504	Thus, inhibition of STAT3 signaling using siRNAs or pharmacological agents can effectively reduce tumor growth by suppressing the expression of these cell-cycle facilitators.	('expression', 'MPA', (130, 140))	('reduce', 'NegReg', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('inhibition', 'Var', (6, 16))	('tumor', 'Disease', (98, 103))	('suppressing', 'NegReg', (114, 125))
754704	24995504	A specific example is the observation that enforced expression of the STAT3-DN construct suppressed the proliferation of head and neck squamous cell carcinoma cells by lowering the expression of Cyclin D1.	('STAT3-DN', 'Var', (70, 78))	('expression', 'MPA', (181, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('Cyclin D1', 'Gene', '12443', (195, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('proliferation', 'CPA', (104, 117))	('suppressed', 'NegReg', (89, 99))	('lowering', 'NegReg', (168, 176))	('Cyclin D1', 'Gene', (195, 204))	('neck squamous cell carcinoma', 'Disease', (130, 158))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (130, 158))
754706	24995504	Resistance to apoptosis: STAT3C has been shown to promote the survival of tumors cells in various models.	('promote', 'PosReg', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('STAT3C', 'Var', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
754707	24995504	In many cancer cell types, STAT3 can transcriptionally increase the expression of various anti-apoptotic proteins involved in the intrinsic apoptotic pathway, such as survivin and the Bcl-2 family members (e.g., Bcl-xL, Bcl-2 and Mcl-1).	('Mcl-1', 'Gene', '17210', (230, 235))	('increase', 'PosReg', (55, 63))	('Bcl-2', 'Gene', '12043', (220, 225))	('cancer', 'Disease', (8, 14))	('expression', 'MPA', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('Bcl-2', 'Gene', '12043', (184, 189))	('Mcl-1', 'Gene', (230, 235))	('Bcl-2', 'Gene', (184, 189))	('Bcl-xL', 'Gene', (212, 218))	('Bcl-xL', 'Gene', '12048', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('survivin', 'Gene', '11799', (167, 175))	('STAT3', 'Var', (27, 32))	('survivin', 'Gene', (167, 175))	('Bcl-2', 'Gene', (220, 225))
754709	24995504	Induction of angiogenesis: STAT3 has been shown to augment tumor angiogenesis in multiple cancer types, such as melanoma, pancreatic cancer, cervical cancer and renal carcinoma.	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('melanoma', 'Disease', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cervical cancer', 'Disease', (141, 156))	('cervical cancer', 'Disease', 'MESH:D002583', (141, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('renal carcinoma', 'Disease', 'MESH:C538614', (161, 176))	('renal carcinoma', 'Disease', (161, 176))	('cancer', 'Disease', (133, 139))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('renal carcinoma', 'Phenotype', 'HP:0005584', (161, 176))	('pancreatic cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('augment', 'PosReg', (51, 58))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('STAT3', 'Var', (27, 32))	('cancer', 'Disease', (90, 96))
754712	24995504	Furthermore, ectopic expression of STAT3C in B16 melanoma cells was found to promote the formation of capillaries in the xenografts established in nude mice.	('B16', 'CellLine', 'CVCL:N540', (45, 48))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('promote', 'PosReg', (77, 84))	('STAT3C', 'Gene', (35, 41))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('formation of capillaries', 'CPA', (89, 113))	('ectopic expression', 'Var', (13, 31))	('nude mice', 'Species', '10090', (147, 156))	('melanoma', 'Disease', (49, 57))
754715	24995504	found that VEGF stimulates STAT3 phosphorylation and nuclear translocation in human dermal microvascular endothelial cells, and inhibition of STAT3 using a dominant negative construct significantly impaired VEGF-induced migration and tube formation of these cells.	('stimulates', 'PosReg', (16, 26))	('min', 'Gene', (158, 161))	('impaired', 'NegReg', (198, 206))	('min', 'Gene', '11789', (158, 161))	('STAT3 phosphorylation', 'MPA', (27, 48))	('nuclear translocation', 'MPA', (53, 74))	('inhibition', 'Var', (128, 138))	('human', 'Species', '9606', (78, 83))	('tube formation of', 'CPA', (234, 251))
754718	24995504	First, STAT3 can trigger epithelial to mesenchymal transition (EMT) by upregulating several key EMT regulators such as Twist-1, Snail and ZEB-1.	('upregulating', 'PosReg', (71, 83))	('trigger', 'PosReg', (17, 24))	('ZEB-1', 'Gene', '21417', (138, 143))	('Twist-1', 'Gene', (119, 126))	('ZEB-1', 'Gene', (138, 143))	('epithelial to mesenchymal transition', 'CPA', (25, 61))	('STAT3', 'Var', (7, 12))	('Twist-1', 'Gene', '22160', (119, 126))	('Snail', 'Gene', (128, 133))	('Snail', 'Gene', '20613', (128, 133))
754719	24995504	Second, STAT3 is known to increase the expression of various matrix metalloproteinases (MMPs), including MMP-1, MMP-2, MMP-7 and MMP-9, which facilitate cancer cell invasiveness by degrading various extracellular matrix proteins.	('MMPs', 'Gene', (88, 92))	('extracellular matrix proteins', 'MPA', (199, 228))	('cancer', 'Disease', (153, 159))	('degrading', 'NegReg', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('MMPs', 'Gene', '17386;17390;17393;4318;17395;17386', (88, 92))	('MMP-2', 'Gene', '17390', (112, 117))	('STAT3', 'Var', (8, 13))	('MMP-1', 'Gene', (105, 110))	('MMP-9', 'Gene', '17395', (129, 134))	('MMP-9', 'Gene', (129, 134))	('expression', 'MPA', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('MMP-7', 'Gene', '17393', (119, 124))	('MMP-1', 'Gene', '17386', (105, 110))	('MMP-7', 'Gene', (119, 124))	('facilitate', 'PosReg', (142, 152))	('increase', 'PosReg', (26, 34))	('MMP-2', 'Gene', (112, 117))
754720	24995504	Third, STAT3 can directly enhance the expression of focal adhesion molecules, such as integrin alpha6 and CTEN (C-terminal tensin-like).	('enhance', 'PosReg', (26, 33))	('C-terminal tensin-like', 'Gene', (112, 134))	('integrin alpha6', 'Gene', '16403', (86, 101))	('expression', 'MPA', (38, 48))	('integrin alpha6', 'Gene', (86, 101))	('CTEN', 'Gene', '217169', (106, 110))	('C-terminal tensin-like', 'Gene', '217169', (112, 134))	('STAT3', 'Var', (7, 12))	('CTEN', 'Gene', (106, 110))	('focal adhesion molecules', 'Protein', (52, 76))
754725	24995504	For example, blocking STAT3 in macrophages has been shown to activate anti-tumor immune responses in a murine model of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('blocking', 'Var', (13, 21))	('activate', 'PosReg', (61, 69))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('STAT3', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('murine', 'Species', '10090', (103, 109))	('tumor', 'Disease', (75, 80))
754730	24995504	In one study, transfection of STAT3C in glioblastoma cells was found to increase the expression of several stem cell factors, such as Sox2, Oct4 and Nanog.	('expression', 'MPA', (85, 95))	('Sox2', 'Gene', (134, 138))	('increase', 'PosReg', (72, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (40, 52))	('Oct4', 'Gene', (140, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('Nanog', 'Gene', '71950', (149, 154))	('Sox2', 'Gene', '20674', (134, 138))	('transfection', 'Var', (14, 26))	('Nanog', 'Gene', (149, 154))	('Oct4', 'Gene', '18999', (140, 144))	('STAT3C', 'Gene', (30, 36))	('glioblastoma', 'Disease', (40, 52))
754732	24995504	Further investigation indicated that the IL-6/JAK2/STAT3 pathway was preferentially active in CD44+CD24- breast cancer stem cells, and inhibition of JAK2 decreased the number of cancer stem cell number and blocked the growth of xenografts in mice.	('decreased', 'NegReg', (154, 163))	('CD44', 'Gene', '12505', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('inhibition', 'Var', (135, 145))	('mice', 'Species', '10090', (242, 246))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('JAK2', 'Gene', (46, 50))	('JAK2', 'Gene', '16452', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('active', 'PosReg', (84, 90))	('CD24', 'Gene', (99, 103))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('IL-6', 'Gene', (41, 45))	('growth of xenografts in mice', 'CPA', (218, 246))	('breast cancer', 'Disease', (105, 118))	('CD44', 'Gene', (94, 98))	('JAK2', 'Gene', (149, 153))	('JAK2', 'Gene', '16452', (149, 153))	('cancer', 'Disease', (178, 184))	('CD24', 'Gene', '12484', (99, 103))	('blocked', 'NegReg', (206, 213))	('IL-6', 'Gene', '16193', (41, 45))
754733	24995504	In glioblastoma, it has been shown that the stem cell factor EZH2 interacts with STAT3 and tri-methylates its K180 residue, thereby activates STAT3 and promotes tumorigenesis.	('EZH2', 'Gene', '14056', (61, 65))	('EZH2', 'Gene', (61, 65))	('K180', 'Var', (110, 114))	('activates', 'PosReg', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('glioblastoma', 'Disease', (3, 15))	('STAT3', 'MPA', (142, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('promotes', 'PosReg', (152, 160))	('tumor', 'Disease', (161, 166))	('interacts', 'Interaction', (66, 75))	('tri-methylates', 'Var', (91, 105))
754736	24995504	discovered that STAT3 interacts with DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), by which STAT3 facilitates gene methylation and silencing of SHP-1 in malignant T lymphocytes; furthermore, blocking the expression of either DNMT1 or STAT3 using siRNA was found to induce DNA demethylation and re-expression of SHP-1 in these cells.	('DNA demethylation', 'MPA', (293, 310))	('DNMT1', 'Gene', (246, 251))	('HDAC1', 'Gene', '433759', (96, 101))	('DNMT1', 'Gene', (62, 67))	('histone deacetylase 1', 'Gene', '433759', (73, 94))	('blocking', 'Var', (212, 220))	('induce', 'Reg', (286, 292))	('DNA methyltransferase 1', 'Gene', (37, 60))	('DNA methyltransferase 1', 'Gene', '13433', (37, 60))	('SHP-1', 'Gene', '15170', (332, 337))	('DNMT1', 'Gene', '13433', (246, 251))	('silencing', 'NegReg', (152, 161))	('SHP-1', 'Gene', '15170', (165, 170))	('re-expression', 'MPA', (315, 328))	('DNMT1', 'Gene', '13433', (62, 67))	('gene methylation', 'MPA', (131, 147))	('facilitates', 'PosReg', (119, 130))	('SHP-1', 'Gene', (332, 337))	('SHP-1', 'Gene', (165, 170))	('HDAC1', 'Gene', (96, 101))	('histone deacetylase 1', 'Gene', (73, 94))
754737	24995504	In another study, it was revealed that K685-acetylated STAT3 cooperates with DNMT1 to silence several tumor suppressor genes, including TP53, SHP-1, SOCS3 and CDKN2A, in melanomas; mutation of STAT3K685 or treatment with resveratrol (a histone deacetylase activator) was found to diminish the tumor-promoting function of STAT3 in melanoma.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('melanomas', 'Disease', 'MESH:D008545', (170, 179))	('min', 'Gene', (282, 285))	('melanomas', 'Disease', (170, 179))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('min', 'Gene', '11789', (282, 285))	('SHP-1', 'Gene', '15170', (142, 147))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('DNMT1', 'Gene', (77, 82))	('CDKN2A', 'Gene', '12578', (159, 165))	('melanoma', 'Phenotype', 'HP:0002861', (330, 338))	('melanoma', 'Disease', (330, 338))	('SOCS3', 'Gene', (149, 154))	('CDKN2A', 'Gene', (159, 165))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('resveratrol', 'Chemical', 'MESH:D000077185', (221, 232))	('SHP-1', 'Gene', (142, 147))	('tumor', 'Disease', (102, 107))	('TP53', 'Gene', (136, 140))	('DNMT1', 'Gene', '13433', (77, 82))	('SOCS3', 'Gene', '12702', (149, 154))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mutation', 'Var', (181, 189))	('tumor', 'Disease', (293, 298))	('melanoma', 'Disease', 'MESH:D008545', (330, 338))	('TP53', 'Gene', '22059', (136, 140))
754738	24995504	demonstrated that histone acetyltransferase p300 is responsible for STAT3 acetylation at K685, and this process can be reversed by histone deacetylase 1.	('histone deacetylase 1', 'Gene', '433759', (131, 152))	('histone acetyltransferase p300', 'Gene', '328572', (18, 48))	('STAT3 acetylation', 'MPA', (68, 85))	('K685', 'Var', (89, 93))	('histone deacetylase 1', 'Gene', (131, 152))	('responsible', 'Reg', (52, 63))	('histone acetyltransferase p300', 'Gene', (18, 48))
754739	24995504	Recently, it also was shown that nuclear localized CD44 facilitates STAT3 acetylation on K685 residue.	('STAT3 acetylation on', 'MPA', (68, 88))	('facilitates', 'PosReg', (56, 67))	('K685', 'Var', (89, 93))	('CD44', 'Gene', '12505', (51, 55))	('CD44', 'Gene', (51, 55))
754742	24995504	Third, in prostate cancer and chronic lymphocytic leukemia, phosphorylation of STAT3Ser727 rather than STAT3Y705 was found to be crucial for the nuclear translocation, DNA binding and the tumor-promoting function of STAT3.	('tumor', 'Disease', (188, 193))	('phosphorylation', 'MPA', (60, 75))	('DNA binding', 'Interaction', (168, 179))	('prostate cancer', 'Disease', 'MESH:D011471', (10, 25))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (30, 58))	('chronic lymphocytic leukemia', 'Disease', (30, 58))	('nuclear translocation', 'MPA', (145, 166))	('prostate cancer', 'Phenotype', 'HP:0012125', (10, 25))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('prostate cancer', 'Disease', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (30, 58))	('STAT3Ser727', 'Var', (79, 90))
754744	24995504	Correlating with this concept, the authors were able to show that the observed oncogenic effect of STAT3 was independent of its phosphorylation at Y705, whereas the N-terminal domain of STAT3 is indispensable, because the N-terminal domain was shown to be required for the dimerization of un-phosphorylated STAT3.	('min', 'Gene', '11789', (227, 230))	('min', 'Gene', (170, 173))	('min', 'Gene', '11789', (170, 173))	('STAT3', 'Gene', (99, 104))	('Y705', 'Var', (147, 151))	('min', 'Gene', (227, 230))	('oncogenic effect', 'CPA', (79, 95))
754746	24995504	More recently, the significance of mitochondrial STAT3 also has been documented in breast cancer, in which it promotes tumor growth and metastasis by suppressing the generation of reactive oxygen species; again, this biological effect is dependent on phosphorylation of STAT3S727 but not that of STAT3Y705.	('tumor', 'Disease', (119, 124))	('STAT3S727', 'Var', (270, 279))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('suppressing', 'NegReg', (150, 161))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('generation of reactive oxygen species', 'MPA', (166, 203))	('breast cancer', 'Disease', (83, 96))	('metastasis', 'CPA', (136, 146))	('promotes', 'PosReg', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (180, 203))
754752	24995504	While the oncogenic effects of STAT3 have been well recognized, a relatively small number of studies published previously have shown that STAT3 carries tumor suppressor functions, a seemingly paradoxical notion.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('min', 'Gene', (185, 188))	('STAT3', 'Var', (138, 143))	('min', 'Gene', '11789', (185, 188))
754755	24995504	Using astrocytes derived from conditional STAT3 knockout mice, the authors found that the simultaneous deletion of STAT3 and shRNA knockdown of PTEN resulted in a dramatic increase in cell proliferation in vitro and tumor formation in SCID mice, whereas siRNA knockdown of PTEN alone (i.e., in the presence of normal STAT3 expression) resulted in significantly less tumorigenic effects in these cells.	('tumor', 'Disease', (366, 371))	('tumor', 'Disease', (216, 221))	('SCID', 'Disease', (235, 239))	('increase', 'PosReg', (172, 180))	('mice', 'Species', '10090', (57, 61))	('SCID', 'Disease', 'MESH:D053632', (235, 239))	('STAT3', 'Gene', (115, 120))	('shRNA', 'Gene', (125, 130))	('mice', 'Species', '10090', (240, 244))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('cell proliferation', 'CPA', (184, 202))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('PTEN', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('deletion', 'Var', (103, 111))
754758	24995504	Interestingly, in the same study using astrocytes harvested from the same conditional STAT3 knockout mice, the authors also found that transfection of EGFRvIII (epidermal growth factor receptor type III variant) in STAT3+/+ astrocytes resulted in tumor formation in SCID mice, whereas the same treatment did not result in any tumor formation in STAT3-/- astrocytes.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('SCID', 'Disease', (266, 270))	('epidermal growth factor receptor', 'Gene', (161, 193))	('epidermal growth factor receptor', 'Gene', '13649', (161, 193))	('mice', 'Species', '10090', (271, 275))	('tumor', 'Disease', (247, 252))	('resulted in', 'Reg', (235, 246))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('mice', 'Species', '10090', (101, 105))	('EGFRvIII', 'Gene', (151, 159))	('tumor', 'Disease', (326, 331))	('transfection', 'Var', (135, 147))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('SCID', 'Disease', 'MESH:D053632', (266, 270))
754761	24995504	Using ras-transformed mouse hepatocytes harvested from homozygous p19ARF knockout mice, the authors found that transfection of STAT3 or STAT3C significantly suppressed tumorigenecity in a SCID mouse xenograft model.	('mice', 'Species', '10090', (82, 86))	('SCID', 'Disease', 'MESH:D053632', (188, 192))	('p19ARF', 'Gene', (66, 72))	('tumor', 'Disease', (168, 173))	('SCID', 'Disease', (188, 192))	('STAT3C', 'Var', (136, 142))	('suppressed', 'NegReg', (157, 167))	('p19ARF', 'Gene', '12578', (66, 72))	('STAT3', 'Var', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mouse', 'Species', '10090', (22, 27))	('mouse', 'Species', '10090', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
754762	24995504	In comparison, transfection of a double STAT3 mutant in which both Y705 and S727 cannot be phosphorylated led to significant tumor growth in SCID mice.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Y705', 'Var', (67, 71))	('S727', 'Var', (76, 80))	('tumor', 'Disease', (125, 130))	('mice', 'Species', '10090', (146, 150))	('SCID', 'Disease', 'MESH:D053632', (141, 145))	('SCID', 'Disease', (141, 145))
754763	24995504	In the same paper, the authors also found that cells transfected with the double STAT3 mutant resulted in liver and lung metastasis after intravenous injection of the cells, while transfection with STAT3 or STAT3C significantly decreased the metastatic potential of these hepatocytes.	('decreased', 'NegReg', (228, 237))	('double STAT3', 'Gene', (74, 86))	('metastatic potential of', 'CPA', (242, 265))	('mutant', 'Var', (87, 93))	('STAT3', 'Gene', (81, 86))	('liver and lung metastasis', 'Disease', 'MESH:D009362', (106, 131))	('resulted in', 'Reg', (94, 105))
754767	24995504	By crossing these animals with conditional STAT3 knockout mice, the authors were able to generate mice with which they assessed the impact of STAT3 knockout in the Apc(Min/+)-carrying intestinal epithelial cells.	('knockout', 'Var', (148, 156))	('Min', 'Gene', '11789', (168, 171))	('STAT3', 'Gene', (142, 147))	('Min', 'Phenotype', 'HP:0200008', (168, 171))	('Apc', 'Gene', '11789', (164, 167))	('Min', 'Gene', (168, 171))	('mice', 'Species', '10090', (58, 62))	('Apc', 'Gene', (164, 167))	('mice', 'Species', '10090', (98, 102))
754768	24995504	While deletion of STAT3 in the intestinal epithelial cells reduced the multiplicity of early adenoma formation (i.e., oncogenic role), ablation of STAT3 in the later stage of tumor progression significantly increased the invasiveness of the tumors and decreased the survival of the animals (i.e., tumor suppressor role).	('reduced', 'NegReg', (59, 66))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumor', 'Disease', (297, 302))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('deletion', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('survival', 'CPA', (266, 274))	('tumor', 'Disease', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('decreased', 'NegReg', (252, 261))	('adenoma', 'Disease', (93, 100))	('STAT3', 'Gene', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('STAT3', 'Gene', (18, 23))	('ablation', 'Var', (135, 143))	('tumors', 'Disease', (241, 247))	('increased', 'PosReg', (207, 216))	('adenoma', 'Disease', 'MESH:D000236', (93, 100))	('multiplicity', 'CPA', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
754770	24995504	It was found that the hepatocytes with STAT3 expression had a significantly less tumor formation induced by chronic carbon tetrachloride, as compared to hepatocytes with STAT3 knockout.	('less', 'NegReg', (76, 80))	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (116, 136))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('STAT3 expression', 'Var', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
754771	24995504	In contrast, hepatocytes with STAT3 expression were found to have a significantly higher tumor formation induced by diethylnitrosamine, as compared to hepatocytes with no STAT3 expression.	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (116, 134))	('higher', 'PosReg', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('diethylnitrosamine', 'MPA', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('STAT3 expression', 'Var', (30, 46))
754772	24995504	In other words, STAT3 can be either oncogenic or tumor suppressive, depending on the use of different carcinogens.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('STAT3', 'Var', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('oncogenic', 'CPA', (36, 45))
754776	24995504	In contrast, in the diethylnitrosamine model, the authors believed that the oncogenic effects of STAT3 are due to the fact that STAT3 can increase the expression of cyclin D1 and suppress the expression of p21.	('increase', 'PosReg', (138, 146))	('p21', 'Gene', (206, 209))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (20, 38))	('STAT3', 'Var', (128, 133))	('cyclin D1', 'Gene', '12443', (165, 174))	('expression', 'MPA', (192, 202))	('expression', 'MPA', (151, 161))	('p21', 'Gene', '12575', (206, 209))	('cyclin D1', 'Gene', (165, 174))	('suppress', 'NegReg', (179, 187))
754780	24995504	found that siRNA knockdown of STAT3 resulted in significantly increased tumor growth, and this observation correlated with increased glucose consumption, lactate production, and expression of HIF-1alpha target genes in the tumor cells.	('increased', 'PosReg', (123, 132))	('glucose consumption', 'MPA', (133, 152))	('increased', 'PosReg', (62, 71))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('expression', 'MPA', (178, 188))	('lactate', 'Chemical', 'MESH:D019344', (154, 161))	('lactate production', 'MPA', (154, 172))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('knockdown', 'Var', (17, 26))	('STAT3', 'Gene', (30, 35))	('glucose', 'Chemical', 'MESH:D005947', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('increased glucose', 'Phenotype', 'HP:0003074', (123, 140))	('HIF-1alpha', 'Gene', '15251', (192, 202))	('HIF-1alpha', 'Gene', (192, 202))
754781	24995504	These findings suggest that one of the mechanisms by which STAT3 inhibits tumorigenesis is mediated by inhibiting aerobic glycolysis in the tumor cells.	('aerobic glycolysis', 'MPA', (114, 132))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('inhibits', 'NegReg', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('inhibiting', 'NegReg', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('STAT3', 'Var', (59, 64))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
754784	24995504	In another study, c-Myc was shown to function as a molecular switch to alter the function of oncostatin M-activated STAT3 in human mammary epithelial cells deficient in both p53 and p16.	('p16', 'Var', (182, 185))	('function', 'MPA', (81, 89))	('alter', 'Reg', (71, 76))	('c-Myc', 'Gene', (18, 23))	('human', 'Species', '9606', (125, 130))	('p53', 'Var', (174, 177))	('c-Myc', 'Gene', '4609', (18, 23))	('oncostatin M-activated STAT3', 'MPA', (93, 121))
754789	24995504	found that that ablation of STAT3 significantly increase the invasiveness of colorectal cancer, a finding that is in parallel to that reported by Musteanu.	('STAT3', 'Gene', (28, 33))	('ablation', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('invasiveness of colorectal cancer', 'Disease', 'MESH:D015179', (61, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('invasiveness of colorectal cancer', 'Disease', (61, 94))	('increase', 'PosReg', (48, 56))
754791	24995504	While the majority of studies evaluating the prognostic value of STAT3 and/or pSTAT3 have pointed to its oncogenic effects, a few studies have reported contradictory observations, with the expression of STAT3/pSTAT3 found to be "paradoxically" associated with a better prognosis in various types of cancer, including those of the head and neck, salivary gland, breast, nasopharynx and rectum.	('STAT3/pSTAT3', 'Var', (203, 215))	('salivary gland', 'Disease', (345, 359))	('breast', 'Disease', (361, 367))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('better', 'PosReg', (262, 268))	('nasopharynx', 'Disease', (369, 380))	('associated', 'Reg', (244, 254))	('rectum', 'Disease', (385, 391))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))
754792	24995504	For instance, high expression of pSTAT3 or nuclear STAT3 in head and neck cancer was found to be associated with a favorable clinical outcome; the progression free survival for patients carrying tumors with high expression of nuclear STAT3 was significantly longer than that of patients carrying tumors with relatively low STAT3 expression.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('progression free survival', 'CPA', (147, 172))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('head and neck cancer', 'Disease', 'MESH:D006258', (60, 80))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('patients', 'Species', '9606', (177, 185))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('longer', 'PosReg', (258, 264))	('tumors', 'Disease', (296, 302))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('patients', 'Species', '9606', (278, 286))	('head and neck cancer', 'Phenotype', 'HP:0012288', (60, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('nuclear STAT3', 'Var', (226, 239))
754793	24995504	In another study including a large cohort of patients with salivary gland tumors, patients carrying tumors with strong nuclear pSTAT3 immunostaining were found to have a better clinical outcome compared with those carrying tumors with moderate or weak nuclear pSTAT3 staining; moreover, strong nuclear pSTAT3 also significantly correlated with a low histologic grade, as well as the absence of lymph node and distant metastases.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('metastases', 'Disease', (417, 427))	('strong nuclear pSTAT3', 'Var', (287, 308))	('tumors', 'Disease', (223, 229))	('correlated', 'Reg', (328, 338))	('patients', 'Species', '9606', (45, 53))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('salivary gland tumors', 'Disease', (59, 80))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('salivary gland tumors', 'Disease', 'MESH:D012468', (59, 80))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('metastases', 'Disease', 'MESH:D009362', (417, 427))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (59, 80))	('tumors', 'Disease', (74, 80))
754794	24995504	In breast cancer, two studies have documented that nuclear pSTAT3 expression significantly correlated with a favorable clinical outcome, although this correlation was restricted to patients with low-grade tumors or node-negative tumors.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumors', 'Disease', (205, 211))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('patients', 'Species', '9606', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('nuclear', 'Var', (51, 58))	('correlated with', 'Reg', (91, 106))	('tumors', 'Disease', (229, 235))	('pSTAT3', 'Gene', (59, 65))
754795	24995504	To illustrate this point, STAT3 was reported to be a marker of worse clinical outcome in head and neck cancer as well as breast cancer, the same types of cancer in which STAT3 was found to be associated with a better clinical outcome in other studies.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('head and neck cancer', 'Phenotype', 'HP:0012288', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (154, 160))	('STAT3', 'Var', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('head and neck cancer', 'Disease', 'MESH:D006258', (89, 109))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('cancer', 'Disease', (128, 134))
754799	24995504	Briefly, STAT3beta is a result of the deletion of the first 50 nucleotides of exon 23, leading to a frame shift that introduces 7 amino acid residues followed by a stop codon.	('min', 'Gene', '11789', (131, 134))	('STAT3beta', 'Disease', (9, 18))	('deletion', 'Var', (38, 46))	('min', 'Gene', (131, 134))
754802	24995504	The difference in their biological behaviors was also highlighted in a study, in which STAT3beta was found to have a higher DNA binding ability than STAT3alpha in COS-7 cells that had been serum starved.	('COS-7', 'CellLine', 'CVCL:0224', (163, 168))	('STAT3beta', 'Var', (87, 96))	('DNA binding', 'Interaction', (124, 135))	('higher', 'PosReg', (117, 123))
754803	24995504	Correlating with these observations, a subsequent study revealed that the negatively charged 55 amino acids present in the C-terminus of STAT3alpha confer a decreased stability of the STAT3alpha dimers, and this difference in the dimer stability between STAT3alpha and STAT3beta is believed to be responsible for the longer half-life and nuclear retention of pSTAT3beta.	('min', 'Gene', '11789', (97, 100))	('STAT3alpha', 'Protein', (184, 194))	('min', 'Gene', (97, 100))	('dimer stability', 'MPA', (230, 245))	('STAT3alpha', 'Gene', (137, 147))	('negatively', 'Var', (74, 84))	('min', 'Gene', (128, 131))	('decreased', 'NegReg', (157, 166))	('min', 'Gene', '11789', (128, 131))	('stability', 'MPA', (167, 176))
754804	24995504	Another study showed that the unique C-terminal 7-amino acid domain of STAT3beta also contributes to the increased nuclear retention of STAT3beta, since with the deletion of this domain was shown to decrease the nuclear retention time of STAT3beta.	('deletion', 'Var', (162, 170))	('nuclear retention time', 'MPA', (212, 234))	('nuclear retention', 'MPA', (115, 132))	('min', 'Gene', '11789', (51, 54))	('STAT3beta', 'Gene', (71, 80))	('decrease', 'NegReg', (199, 207))	('min', 'Gene', (51, 54))	('increased', 'PosReg', (105, 114))	('min', 'Gene', (42, 45))	('min', 'Gene', '11789', (42, 45))
754806	24995504	Without the STAT3 transactivation domain, STAT3beta is expected to be unable to activate promoters carrying the interferon/IL-6:responsive element.	('STAT3beta', 'Var', (42, 51))	('IL-6', 'Gene', (123, 127))	('IL-6', 'Gene', '16193', (123, 127))
754808	24995504	In other studies, it has been demonstrated that STAT3beta can abolish the transcriptional activation of several STAT3 downstream targets including Cyclin D1, Bcl-xL and Mcl-1, leading to inhibition of tumor growth and promotion of apoptosis.	('apoptosis', 'CPA', (231, 240))	('abolish', 'NegReg', (62, 69))	('inhibition', 'NegReg', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('Cyclin D1', 'Gene', '12443', (147, 156))	('Bcl-xL', 'Gene', (158, 164))	('Bcl-xL', 'Gene', '12048', (158, 164))	('transcriptional activation', 'MPA', (74, 100))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('promotion', 'PosReg', (218, 227))	('STAT3beta', 'Var', (48, 57))	('Mcl-1', 'Gene', '17210', (169, 174))	('tumor', 'Disease', (201, 206))	('Cyclin D1', 'Gene', (147, 156))	('Mcl-1', 'Gene', (169, 174))
754810	24995504	In addition to its dominant negative role, STAT3beta is believed to carry other functions, considering the fact that it possesses most of the important STAT3 functional domains including the activation domain (i.e., which carries the tyrosine 705 residue), the Src homology2 (SH2) domain that is responsible for STAT3 dimerization and its binding to the receptor complex (e.g., JAKs), the coiled-coil domain that allows STAT3 to interact with other proteins, and the DNA binding domain.	('interact', 'Interaction', (429, 437))	('binding', 'Interaction', (339, 346))	('min', 'Gene', (21, 24))	('Src', 'Gene', '20779', (261, 264))	('JAKs', 'Gene', (378, 382))	('Src', 'Gene', (261, 264))	('min', 'Gene', '11789', (21, 24))	('JAKs', 'Gene', '16451;3717;16452', (378, 382))	('tyrosine 705', 'Var', (234, 246))	('tyrosine', 'Chemical', 'MESH:D014443', (234, 242))
754812	24995504	In another study, STAT3beta was found to compensate the function of STAT3; specifically, transfection of STAT3beta effectively induced the expression of acute phase genes in STAT3-null hepatocytes challenged with lipopolysaccharide.	('transfection', 'Var', (89, 101))	('STAT3beta', 'Var', (105, 114))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (213, 231))	('acute phase genes', 'Gene', (153, 170))	('expression', 'MPA', (139, 149))	('induced', 'PosReg', (127, 134))
754814	24995504	Another study showed that, compared with the wild-type mice, mice with specific STAT3beta ablation were hypersensitive to lipopolysaccharide-induced inflammation, and these findings correlated with the dramatic alterations of the expression of lipopolysaccharide-responsive genes in the hepatocytes.	('mice', 'Species', '10090', (61, 65))	('STAT3beta', 'Gene', (80, 89))	('hypersensitive', 'Disease', 'MESH:D004342', (104, 118))	('hypersensitive to lipopolysaccharide', 'Phenotype', 'HP:0002848', (104, 140))	('inflammation', 'Disease', 'MESH:D007249', (149, 161))	('hypersensitive', 'Disease', (104, 118))	('alterations', 'Reg', (211, 222))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (122, 140))	('expression', 'MPA', (230, 240))	('mice', 'Species', '10090', (55, 59))	('inflammation', 'Disease', (149, 161))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (244, 262))	('ablation', 'Var', (90, 98))
754816	24995504	The shift from STAT3alpha to STAT3beta was found to dramatically decreased tumor growth, which was shown to be mediated by STAT3beta-specific downstream targets.	('decreased', 'NegReg', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('shift', 'Var', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
754819	24995504	In one study, STAT3beta was found to upregulate and prolong the phosphorylation of STAT3alphaY705 upon stimulation with oncostatin M in murine embryonic fibroblasts.	('phosphorylation', 'MPA', (64, 79))	('upregulate', 'PosReg', (37, 47))	('prolong', 'PosReg', (52, 59))	('murine', 'Species', '10090', (136, 142))	('STAT3alphaY705', 'Var', (83, 97))
754821	24995504	In contrast, in the presence of STAT3beta, phosphorylation of STAT3alphaY705 was sustained at a high level for 120 min.	('min', 'Gene', (115, 118))	('min', 'Gene', '11789', (115, 118))	('STAT3alphaY705', 'Var', (62, 76))	('phosphorylation', 'MPA', (43, 58))
754825	24995504	For instance, transient STAT3beta transfection in murine B16 melanoma cells induced cell cycle arrest as well as apoptosis.	('murine', 'Species', '10090', (50, 56))	('apoptosis', 'CPA', (113, 122))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('transfection', 'Var', (34, 46))	('melanoma', 'Disease', (61, 69))	('B16', 'CellLine', 'CVCL:N540', (57, 60))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('cell cycle arrest', 'CPA', (84, 101))	('STAT3beta', 'Gene', (24, 33))
754826	24995504	Furthermore, electro-injection of STAT3beta cDNA into established B16 melanoma xenografts in SCID mice induced apoptosis and suppressed tumor growth.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('B16', 'CellLine', 'CVCL:N540', (66, 69))	('suppressed', 'NegReg', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('SCID', 'Disease', 'MESH:D053632', (93, 97))	('tumor', 'Disease', (136, 141))	('SCID', 'Disease', (93, 97))	('STAT3beta cDNA', 'Var', (34, 48))	('apoptosis', 'CPA', (111, 120))	('mice', 'Species', '10090', (98, 102))
754827	24995504	In another study, gene transfer of STAT3beta was found to result in marked shrinkage of xenografts in SCID mice, whereas siRNA knockdown of STAT3 resulted no significant effect on breast tumor growth.	('shrinkage', 'NegReg', (75, 84))	('STAT3beta', 'Gene', (35, 44))	('breast tumor', 'Disease', 'MESH:D001943', (180, 192))	('SCID', 'Disease', (102, 106))	('gene transfer', 'Var', (18, 31))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('SCID', 'Disease', 'MESH:D053632', (102, 106))	('breast tumor', 'Disease', (180, 192))	('mice', 'Species', '10090', (107, 111))	('breast tumor', 'Phenotype', 'HP:0100013', (180, 192))
754828	24995504	Interestingly, in one study, apoptosis induced by STAT3beta was found in STAT3beta-transfected cells as well as the bystander non-transfected cells in the same tissue culture, due to the production of TRAIL (TNF-related apoptosis inducing ligand) induced by STAT3beta transfection.	('TNF-related apoptosis inducing ligand', 'Gene', (208, 245))	('TNF-related apoptosis inducing ligand', 'Gene', '22035', (208, 245))	('transfection', 'Var', (268, 280))
754829	24995504	Moreover, it has been shown that transfection of STAT3beta cDNA in a human melanoma cell line increases FAS expression and enhances apoptosis induced by FAS-ligand and UV irradiation.	('apoptosis', 'CPA', (132, 141))	('enhances', 'PosReg', (123, 131))	('FAS', 'Protein', (104, 107))	('human', 'Species', '9606', (69, 74))	('increases', 'PosReg', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('expression', 'MPA', (108, 118))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('FAS-ligand', 'Protein', (153, 163))	('STAT3beta', 'Var', (49, 58))
754830	24995504	A few years later, the same research team reported that STAT3beta can effectively suppress the growth of human melanomas xenografted in nude mice by increasing the expression of TRAIL receptor 2, a pro-apoptotic factor expressed on the cell surface of the tumor cells.	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('TRAIL', 'Protein', (178, 183))	('expression', 'MPA', (164, 174))	('nude mice', 'Species', '10090', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('melanomas', 'Disease', (111, 120))	('STAT3beta', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('suppress', 'NegReg', (82, 90))	('human', 'Species', '9606', (105, 110))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('growth', 'CPA', (95, 101))	('increasing', 'PosReg', (149, 159))	('tumor', 'Disease', (256, 261))
754835	24995504	In other words, accurate evaluation of the biological and clinical significance of STAT3 in human tumor samples will require some understanding of the relevant coexisting biochemical defects (e.g., c-myc, PTEN and p14ARF) as well as the simultaneous evaluation of STAT3alpha and STAT3beta.	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PTEN', 'Var', (205, 209))	('p14ARF', 'Gene', '1029', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('c-myc', 'Gene', '4609', (198, 203))	('c-myc', 'Gene', (198, 203))	('human', 'Species', '9606', (92, 97))	('p14ARF', 'Gene', (214, 220))
754859	22457808	We hypothesize that the aberrant expression of mature miR-145 and miR-143 influence the regulation of target genes and involve in oncogenesis of esophageal cancer.	('miR-145', 'Gene', (54, 61))	('influence', 'Reg', (74, 83))	('aberrant', 'Var', (24, 32))	('miR-143', 'Gene', '406935', (66, 73))	('esophageal cancer', 'Disease', (145, 162))	('regulation of target genes', 'MPA', (88, 114))	('miR-145', 'Gene', '406937', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('miR-143', 'Gene', (66, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('involve in', 'Reg', (119, 129))
754891	22457808	EC9706 showed the lowest expression of miR-143 and miR-145, while KYSE510 had the highest expression.	('EC9706', 'Var', (0, 6))	('miR-143', 'Gene', '406935', (39, 46))	('expression', 'MPA', (25, 35))	('miR-143', 'Gene', (39, 46))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('lowest', 'NegReg', (18, 24))	('miR-145', 'Gene', (51, 58))	('miR-145', 'Gene', '406937', (51, 58))
754892	22457808	Since the expression of miR-145 was almost undetectable in EC9706, the correlation analysis between miR-143 and miR-145 was performed in ESCC cell lines except for EC9706.	('EC9706', 'Var', (59, 65))	('EC9706', 'CellLine', 'CVCL:E307', (164, 170))	('miR-145', 'Gene', (112, 119))	('undetectable', 'NegReg', (43, 55))	('expression', 'MPA', (10, 20))	('EC9706', 'CellLine', 'CVCL:E307', (59, 65))	('miR-143', 'Gene', '406935', (100, 107))	('miR-145', 'Gene', '406937', (112, 119))	('miR-143', 'Gene', (100, 107))	('miR-145', 'Gene', (24, 31))	('miR-145', 'Gene', '406937', (24, 31))
754904	22457808	A early evidence showed that miRNAs were commonly located in fragile sites on chromosomes, preferential sites of translation, deletion and amplification that are often altered in cancers.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('deletion', 'Var', (126, 134))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('amplification', 'MPA', (139, 152))	('cancers', 'Disease', (179, 186))
754907	22457808	Montesano et al and Moskaluk et al all explored 5q was frequent target of deletion in esophageal cancer and may harbor novel tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('deletion', 'Var', (74, 82))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('tumor', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
754982	33392181	A clinical trial study of patients with advanced ESCC found that pembrolizumab (also known as "Keytruda"), acting as a second-line therapy, could remarkably improve OS compared to chemotherapy.	('pembrolizumab', 'Var', (65, 78))	('improve', 'PosReg', (157, 164))	('pembrolizumab', 'Chemical', 'MESH:C582435', (65, 78))	('patients', 'Species', '9606', (26, 34))
754983	33392181	In 2019, the U.S. Food and Drug Administration approved the use of pembrolizumab for patients with advanced ESCC and high PD-L1 expression.	('high', 'Var', (117, 121))	('pembrolizumab', 'Chemical', 'MESH:C582435', (67, 80))	('PD-L1', 'Gene', (122, 127))	('patients', 'Species', '9606', (85, 93))	('expression', 'MPA', (128, 138))	('PD-L1', 'Gene', '29126', (122, 127))	('ESCC', 'Disease', (108, 112))
755020	33392181	We established a risk score model based on the expressions of these six genes and corresponding coefficients for patients with ESCC: risk score = (0.1272 x TSPAN2 expression) + (0.2423 x AMBP expression) + (0.2201 x C6 expression) + (0.1651 x PRLR expression) - (0.2720 x ITLN1 expression) - (0.2724 x MADCAM1 expression).	('0.1272', 'Var', (147, 153))	('PRLR', 'Gene', (243, 247))	('MADCAM1', 'Gene', '8174', (302, 309))	('PRLR', 'Gene', '5618', (243, 247))	('ESCC', 'Disease', (127, 131))	('patients', 'Species', '9606', (113, 121))	('TSPAN2', 'Gene', '10100', (156, 162))	('AMBP', 'Gene', (187, 191))	('MADCAM1', 'Gene', (302, 309))	('ITLN1', 'Gene', (272, 277))	('ITLN1', 'Gene', '55600', (272, 277))	('AMBP', 'Gene', '259', (187, 191))	('TSPAN2', 'Gene', (156, 162))
755090	33392181	Meanwhile, one of the risky genes - TSPAN2 - inhibited macrophage secretion of lipopolysaccharide-induced tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6).	('genes -', 'Var', (28, 35))	('interleukin 6', 'Gene', (150, 163))	('TNF-alpha', 'Gene', '7124', (135, 144))	('TSPAN2', 'Gene', '10100', (36, 42))	('IL-6', 'Gene', '3569', (165, 169))	('TNF-alpha', 'Gene', (135, 144))	('IL-6', 'Gene', (165, 169))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (79, 97))	('interleukin 6', 'Gene', '3569', (150, 163))	('tumor necrosis factor alpha', 'Gene', '7124', (106, 133))	('tumor necrosis factor alpha', 'Gene', (106, 133))	('inhibited', 'NegReg', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TSPAN2', 'Gene', (36, 42))
755094	33392181	For example, TNFSF4 - also known as OX40L - is a ligand of OX40, and its combination with OX40 regulates T-cell proliferation, activation, and survival and even has an effect on cytokine release from T cells.	('has', 'Reg', (161, 164))	('OX40', 'Gene', '7293', (59, 63))	('survival', 'CPA', (143, 151))	('OX40', 'Gene', (59, 63))	('OX40L', 'Gene', '7292', (36, 41))	('regulates', 'Reg', (95, 104))	('TNFSF4', 'Gene', '7292', (13, 19))	('OX40L', 'Gene', (36, 41))	('combination', 'Var', (73, 84))	('OX40', 'Gene', '7293', (90, 94))	('OX40', 'Gene', (90, 94))	('OX40', 'Gene', '7293', (36, 40))	('cytokine release from T cells', 'MPA', (178, 207))	('T-cell proliferation', 'CPA', (105, 125))	('OX40', 'Gene', (36, 40))	('activation', 'CPA', (127, 137))	('effect', 'Reg', (168, 174))	('TNFSF4', 'Gene', (13, 19))
755126	31485619	Similar to other types of cancer, the development of ESCC involves the gradual accumulation of vital gene mutations involved in cell cycle control, cell growth, differentiation, apoptosis, migration and invasion, or other functions, including the inactivation of tumor suppressor genes and activation of oncogenes.	('ESCC', 'Disease', (53, 57))	('oncogenes', 'Gene', (304, 313))	('inactivation', 'Var', (247, 259))	('cancer', 'Disease', (26, 32))	('men', 'Species', '9606', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', (263, 268))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('invasion', 'CPA', (203, 211))	('mutations', 'Var', (106, 115))	('ESCC', 'Disease', 'MESH:C562729', (53, 57))	('migration', 'CPA', (189, 198))
755130	31485619	P53 is one of the most commonly mutated genes in human cancer, the overexpression of epidermal growth factor receptor and P53 mutation induces tumor development, invasion and differentiation.	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('P53', 'Gene', (122, 125))	('human', 'Species', '9606', (49, 54))	('men', 'Species', '9606', (156, 159))	('mutation', 'Var', (126, 134))	('epidermal growth factor receptor', 'Gene', '1956', (85, 117))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (122, 125))	('P53', 'Gene', '7157', (0, 3))	('induces', 'PosReg', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('epidermal growth factor receptor', 'Gene', (85, 117))	('invasion', 'CPA', (162, 170))	('cancer', 'Disease', (55, 61))
755167	31485619	The high expression of PTTG1 also exhibited a relatively poor prognosis through GEPIA survival analysis (Fig.	('PTTG1', 'Gene', '9232', (23, 28))	('high', 'Var', (4, 8))	('PTTG1', 'Gene', (23, 28))
755183	31485619	High expression of COL4A1 is associated with advanced tumors and poor OS and disease-free survival in patients with HCC.	('disease-free survival', 'CPA', (77, 98))	('COL4A1', 'Gene', (19, 25))	('High', 'Var', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('patients', 'Species', '9606', (102, 110))	('COL4A1', 'Gene', '1282', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('HCC', 'Disease', (116, 119))	('associated', 'Reg', (29, 39))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('poor', 'NegReg', (65, 69))	('tumors', 'Disease', (54, 60))
755184	31485619	COL4A1 knockdown decreases cell viability and cell cycle in breast cancer cells.	('breast cancer', 'Disease', (60, 73))	('decreases', 'NegReg', (17, 26))	('cell viability', 'CPA', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('COL4A1', 'Gene', (0, 6))	('cell cycle', 'CPA', (46, 56))	('knockdown', 'Var', (7, 16))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('COL4A1', 'Gene', '1282', (0, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
755193	31485619	The high cytoplasmic expression of phosphorylated CHEK1 was associated with the poor prognosis of breast cancer and also exhibited high expression in ovarian and oral squamous cell carcinoma.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('expression', 'MPA', (136, 146))	('CHEK1', 'Gene', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('breast cancer', 'Disease', (98, 111))	('squamous cell carcinoma', 'Disease', (167, 190))	('phosphorylated', 'Var', (35, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (167, 190))	('ovarian', 'Disease', 'MESH:D010049', (150, 157))	('CHEK1', 'Gene', '1111', (50, 55))	('ovarian', 'Disease', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('associated', 'Reg', (60, 70))
755194	31485619	Therefore, the targeted regulation of CHEK1 may become a novel method for cancer treatment.	('CHEK1', 'Gene', '1111', (38, 43))	('men', 'Species', '9606', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('targeted regulation', 'Var', (15, 34))	('CHEK1', 'Gene', (38, 43))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
755197	31485619	PTTG1 knockdown significantly inhibits bladder cancer cell migration, invasion, metastasis and growth, and induces G0/G1 phase senescence and cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (142, 159))	('bladder cancer', 'Disease', 'MESH:D001749', (39, 53))	('metastasis', 'CPA', (80, 90))	('G0/G1 phase senescence', 'CPA', (115, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('PTTG1', 'Gene', (0, 5))	('bladder cancer', 'Disease', (39, 53))	('cell cycle arrest', 'CPA', (142, 159))	('PTTG1', 'Gene', '9232', (0, 5))	('induces', 'Reg', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('knockdown', 'Var', (6, 15))	('growth', 'CPA', (95, 101))	('invasion', 'CPA', (70, 78))	('inhibits', 'NegReg', (30, 38))
755222	31114334	In vitro assay showed that sfrp2 (Wnt5a antagonist) largely blocked the invasion but not the colony formation of KYSE410 and KYSE520 ESCC cells.	('blocked', 'NegReg', (60, 67))	('Wnt5a', 'Gene', (34, 39))	('Wnt5a', 'Gene', '7474', (34, 39))	('KYSE520', 'Var', (125, 132))	('sfrp2', 'Gene', (27, 32))	('sfrp2', 'Gene', '6423', (27, 32))	('invasion', 'CPA', (72, 80))
755236	31114334	Aberrant expression and location of beta-catenin, a member of the Wnt signaling pathway, regulates the progression of oesophageal cancer.	('Aberrant expression', 'Var', (0, 19))	('regulates', 'Reg', (89, 98))	('beta-catenin', 'Gene', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('oesophageal cancer', 'Disease', 'MESH:D009369', (118, 136))	('oesophageal cancer', 'Disease', (118, 136))	('beta-catenin', 'Gene', '1499', (36, 48))	('progression', 'MPA', (103, 114))
755313	31114334	We previously investigated EGFR expression and telomere in ESCC cells KYSE410 and KYSE520 and found KYSE410 and KYSE520 cells had the most difference in all nine KYSE cell lines.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('KYSE410', 'Var', (100, 107))	('KYSE410', 'Var', (70, 77))
755314	31114334	In this study, we found the high expression and secretion levels of Wnt5a in KYSE410 and KYSE520 ESCC cells (Figure 1D and E), which were subjected to the measure of the ability of Wnt5a-induced cell invasion.	('KYSE520', 'Var', (89, 96))	('KYSE410', 'Var', (77, 84))	('Wnt5a', 'Gene', (68, 73))	('Wnt5a', 'Gene', (181, 186))	('Wnt5a', 'Gene', '7474', (181, 186))	('Wnt5a', 'Gene', '7474', (68, 73))	('expression', 'MPA', (33, 43))	('secretion levels', 'MPA', (48, 64))
755318	31114334	Moreover, sfrp2 did not alter the ability of colony formation of KYSE410 and KYSE520 ESCC cells (Figure 2C and D).	('KYSE520', 'Var', (77, 84))	('colony formation', 'CPA', (45, 61))	('sfrp2', 'Gene', '6423', (10, 15))	('sfrp2', 'Gene', (10, 15))
755322	31114334	Silence of ROR2 gave rise to a significant reduction of cell invasion, which also can be rescued by WT ROR2 overexpression (Figure 3B and C).	('reduction', 'NegReg', (43, 52))	('cell invasion', 'CPA', (56, 69))	('ROR2', 'Gene', (103, 107))	('ROR2', 'Gene', (11, 15))	('ROR2', 'Gene', '4920', (11, 15))	('ROR2', 'Gene', '4920', (103, 107))	('Silence', 'Var', (0, 7))
755324	31114334	Interestingly, ROR1 was strongly associated with ROR2 in KYSE410 cells (Figure 3D).	('ROR2', 'Gene', (49, 53))	('KYSE410', 'Var', (57, 64))	('ROR2', 'Gene', '4920', (49, 53))	('associated', 'Reg', (33, 43))	('ROR1', 'Gene', '4919', (15, 19))	('ROR1', 'Gene', (15, 19))
755327	31114334	The significantly decreased activity of Rac1, Rac2, and RhoA treated with anti-ROR1 mAb were found in KYSE410 ESCC cells (Figure 4A).	('Rac2', 'Gene', '5880', (46, 50))	('Rac1', 'Gene', (40, 44))	('RhoA', 'Gene', (56, 60))	('activity', 'MPA', (28, 36))	('Rac2', 'Gene', (46, 50))	('decreased', 'NegReg', (18, 27))	('RhoA', 'Gene', '387', (56, 60))	('ROR1', 'Gene', '4919', (79, 83))	('KYSE410', 'Var', (102, 109))	('ROR1', 'Gene', (79, 83))	('Rac1', 'Gene', '5879', (40, 44))
755329	31114334	The activation of RhoA, not Rac1 or Rac2, was downregulated in ROR2 knockdown cells, which could be rescued by the WT ROR2 overexpression (Figure 4B and C).	('RhoA', 'Gene', '387', (18, 22))	('ROR2', 'Gene', (63, 67))	('Rac2', 'Gene', (36, 40))	('ROR2', 'Gene', '4920', (118, 122))	('ROR2', 'Gene', (118, 122))	('ROR2', 'Gene', '4920', (63, 67))	('knockdown', 'Var', (68, 77))	('Rac1', 'Gene', '5879', (28, 32))	('downregulated', 'NegReg', (46, 59))	('Rac1', 'Gene', (28, 32))	('Rac2', 'Gene', '5880', (36, 40))	('activation', 'PosReg', (4, 14))	('RhoA', 'Gene', (18, 22))
755330	31114334	Moreover, the combination of ROR1 blockage and ROR2 knockdown showed a similar effect on the decrease of RhoA activity to the single treatment of ROR1 blockage or ROR2 knockdown (Figure 4C).	('ROR2', 'Gene', (47, 51))	('ROR2', 'Gene', '4920', (47, 51))	('ROR2', 'Gene', '4920', (163, 167))	('RhoA', 'Gene', (105, 109))	('ROR1', 'Gene', '4919', (29, 33))	('ROR1', 'Gene', '4919', (146, 150))	('RhoA', 'Gene', '387', (105, 109))	('decrease', 'NegReg', (93, 101))	('ROR2', 'Gene', (163, 167))	('ROR1', 'Gene', (146, 150))	('knockdown', 'Var', (52, 61))	('ROR1', 'Gene', (29, 33))
755332	31114334	Treatment with 1 micromol/L CCG-1423 inhibited the cell invasion of ESCC cells by approximately 59.3% and 66.3% reduction for KYSE410 and KYSE520 cells, respectively (Figure 4D).	('inhibited', 'NegReg', (37, 46))	('cell invasion of ESCC cells', 'CPA', (51, 78))	('CCG-1423', 'Gene', (28, 36))	('reduction', 'NegReg', (112, 121))	('KYSE410', 'Var', (126, 133))	('KYSE520', 'Var', (138, 145))	('CCG-1423', 'Chemical', 'MESH:C523455', (28, 36))
755334	31114334	To study whether RhoA acted as the downstream of DAAM1, we silenced DAAM1 using shRNA and measured the RhoA activity.	('RhoA', 'Gene', (103, 107))	('RhoA', 'Gene', '387', (103, 107))	('DAAM1', 'Gene', (68, 73))	('silenced', 'Var', (59, 67))	('DAAM1', 'Gene', '23002', (68, 73))	('DAAM1', 'Gene', '23002', (49, 54))	('DAAM1', 'Gene', (49, 54))	('RhoA', 'Gene', (17, 21))	('RhoA', 'Gene', '387', (17, 21))
755338	31114334	A significant decrease in active DAAM1 levels was shown after ROR1 blockage or ROR2 knockdown (Figure 5C).	('ROR2', 'Gene', (79, 83))	('knockdown', 'Var', (84, 93))	('blockage', 'Var', (67, 75))	('ROR2', 'Gene', '4920', (79, 83))	('ROR1', 'Gene', '4919', (62, 66))	('decrease', 'NegReg', (14, 22))	('DAAM1', 'Gene', '23002', (33, 38))	('ROR1', 'Gene', (62, 66))	('DAAM1', 'Gene', (33, 38))
755339	31114334	The invasion of DAAM1 knockdown cells was largely inhibited, which could be rescued by the overexpression of WT DAAM1 (Figure 5D).	('DAAM1', 'Gene', '23002', (112, 117))	('knockdown', 'Var', (22, 31))	('invasion', 'CPA', (4, 12))	('DAAM1', 'Gene', (16, 21))	('DAAM1', 'Gene', (112, 117))	('DAAM1', 'Gene', '23002', (16, 21))	('inhibited', 'NegReg', (50, 59))
755344	31114334	We also found that the knockdown of ROR2 disrupted the formation of microfilaments and decreased the length of microfilaments (Figure 6A-C).	('length', 'MPA', (101, 107))	('decreased', 'NegReg', (87, 96))	('knockdown', 'Var', (23, 32))	('disrupted', 'NegReg', (41, 50))	('formation', 'MPA', (55, 64))	('ROR2', 'Gene', (36, 40))	('ROR2', 'Gene', '4920', (36, 40))
755361	31114334	shRNA-mediating silence of DAAM1 inhibits RhoA activity and the invasion of ESCC cells.	('RhoA', 'Gene', '387', (42, 46))	('DAAM1', 'Gene', '23002', (27, 32))	('DAAM1', 'Gene', (27, 32))	('invasion of ESCC cells', 'CPA', (64, 86))	('silence', 'Var', (16, 23))	('inhibits', 'NegReg', (33, 41))	('RhoA', 'Gene', (42, 46))
755395	30850562	(D) Adequate bone marrow, renal, hepatic, and respiratory function (leukocytes >=3000/mm3, neutrophil >=1.5 x 109/L, hemoglobulin level >=9 g/dL, platelets >=100 x 109/L, aspartate aminotransferase and alanine aminotransferase lower than double of the upper normal limit, total serum bilirubin <=1.5 mg/dL, serum creatinine <=1.2 mg/dL, creatinine clearance >=50 mL/min, pulmonary function (FEV1 >1L), and no major electrocardiogram abnormalities.	('>=1.5 x 109/L', 'Var', (102, 115))	('serum bilirubin', 'MPA', (278, 293))	('>=3000/mm3', 'Var', (79, 89))	('serum creatinine', 'MPA', (307, 323))	('total serum bilirubin', 'Phenotype', 'HP:0003573', (272, 293))	('>=9', 'Var', (136, 139))	('alanine aminotransferase', 'Gene', (202, 226))	('lower', 'NegReg', (227, 232))	('alanine aminotransferase', 'Gene', '2875', (202, 226))	('creatinine clearance', 'MPA', (337, 357))	('pulmonary function', 'CPA', (371, 389))
755461	30850562	Although survival analysis indicated no significant difference between the FOLFOX group and the 5-FU and cisplatin group, the FOLFOX regimen was associated with a marginally significant reduction of treatment-related death compared with the 5-FU and cisplatin regimen (1 vs. 6; p = .066).	('cisplatin', 'Chemical', 'MESH:D002945', (250, 259))	('FOLFOX', 'Chemical', '-', (126, 132))	('reduction', 'NegReg', (186, 195))	('death', 'Disease', 'MESH:D003643', (217, 222))	('5-FU', 'Chemical', 'MESH:D005472', (96, 100))	('5-FU', 'Chemical', 'MESH:D005472', (241, 245))	('death', 'Disease', (217, 222))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('FOLFOX', 'Chemical', '-', (75, 81))	('FOLFOX', 'Var', (126, 132))
755503	29301256	It is indicated that due to the dysfunction of above genes, cancer cells are characterized by infinite proliferation, mitochondrial polymorphism, swelling, hyperplasia, cytoskeletal disorders, abnormal skeletal assemblage and changes in cell surface characteristics in esophageal cancer tissues.	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('hyperplasia', 'Disease', (156, 167))	('cancer', 'Disease', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('esophageal cancer', 'Disease', (269, 286))	('cancer', 'Disease', (60, 66))	('changes', 'Reg', (226, 233))	('swelling', 'Disease', (146, 154))	('mitochondrial polymorphism', 'CPA', (118, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (269, 286))	('swelling', 'Disease', 'MESH:D004487', (146, 154))	('hyperplasia', 'Disease', 'MESH:D006965', (156, 167))	('cell surface characteristics', 'CPA', (237, 265))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('dysfunction', 'Var', (32, 43))	('abnormal skeletal', 'Phenotype', 'HP:0000924', (193, 210))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('infinite proliferation', 'CPA', (94, 116))
755562	29301256	We select a core vector C that maximizes  and is a normalized (so that its entries sum to 1) shuffle of the vector  whose components  are determined by a transition function g.  When beta = 0, only the top case in Equation (5) applies; when beta = 1, only the bottom case applies.	('beta', 'Var', (183, 187))	('beta = 1', 'Gene', '10678', (241, 249))	('beta = 1', 'Gene', (241, 249))
755576	28949934	The combination of PD-1 and PD-L1 is the key immune checkpoint receptor to inhibit T-cell activation, inducing impaired immune response and worse prognosis in various cancers.	('PD-1', 'Gene', '5133', (19, 23))	('PD-L1', 'Gene', '29126', (28, 33))	('impaired', 'NegReg', (111, 119))	('inhibit', 'NegReg', (75, 82))	('combination', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('immune response', 'MPA', (120, 135))	('inducing', 'PosReg', (102, 110))	('PD-L1', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('PD-1', 'Gene', (19, 23))	('T-cell activation', 'CPA', (83, 100))
755578	28949934	However, recent literature reported that patients with high expression of PD-1 and PD-L1 had better prognosis in breast cancer, metastatic melanoma, colorectal cancer, pulmonary squamous cell carcinoma, and ovarian cancer.	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('pulmonary squamous cell carcinoma', 'Disease', (168, 201))	('pulmonary squamous cell carcinoma', 'Disease', 'MESH:D002294', (168, 201))	('better', 'PosReg', (93, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('PD-1', 'Gene', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PD-1', 'Gene', '5133', (74, 78))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('patients', 'Species', '9606', (41, 49))	('high expression', 'Var', (55, 70))	('PD-L1', 'Gene', (83, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('colorectal cancer', 'Disease', (149, 166))	('PD-L1', 'Gene', '29126', (83, 88))	('ovarian cancer', 'Disease', (207, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('pulmonary squamous cell carcinoma', 'Phenotype', 'HP:0030359', (168, 201))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))
755582	28949934	Moreover, patients with positive PD-L1 expression had reduced risk for disease relapse compared to those without PD-L1 expression.	('PD-L1', 'Gene', (33, 38))	('expression', 'Var', (39, 49))	('disease relapse', 'CPA', (71, 86))	('PD-L1', 'Gene', (113, 118))	('PD-L1', 'Gene', '29126', (33, 38))	('reduced', 'NegReg', (54, 61))	('patients', 'Species', '9606', (10, 18))	('PD-L1', 'Gene', '29126', (113, 118))
755585	28949934	Particularly the presence of T cells (CD3+) and various T cell subpopulations (e.g., CD4+, CD8+, CD103+) have been shown to be indicators of a better prognosis.	('CD8', 'Gene', (91, 94))	('CD103+', 'Var', (97, 103))	('CD8', 'Gene', '925', (91, 94))	('presence of T cells', 'Phenotype', 'HP:0100828', (17, 36))	('CD4', 'Gene', (85, 88))	('CD4', 'Gene', '920', (85, 88))
755621	28949934	As shown in Table 1-6, increased iCD3+, sCD4+, and iCD8+ lymphocytes were significantly associated with advanced tumor differentiation (p<0.05).	('tumor', 'Disease', (113, 118))	('iCD3+', 'Var', (33, 38))	('sCD4', 'Gene', '79966', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('increased', 'PosReg', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CD8', 'Gene', (52, 55))	('sCD4', 'Gene', (40, 44))	('CD8', 'Gene', '925', (52, 55))
755663	28969100	Overexpression of lncRNA UCA1 correlates with resistance to chemotherapeutics such as cisplatin, gemcitabine, 5-FU, tamoxifen, imatinib and EGFR-TKIs, whereas lncRNA UCA1 knockdown restores drug sensitivity.	('UCA1', 'Gene', '652995', (166, 170))	('EGFR', 'Gene', (140, 144))	('UCA1', 'Gene', (166, 170))	('knockdown', 'Var', (171, 180))	('drug sensitivity', 'Phenotype', 'HP:0020174', (190, 206))	('drug sensitivity', 'MPA', (190, 206))	('resistance to chemotherapeutics', 'MPA', (46, 77))	('lncRNA', 'Gene', (18, 24))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('EGFR', 'Gene', '1956', (140, 144))	('tamoxifen', 'Chemical', 'MESH:D013629', (116, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('5-FU', 'Chemical', 'MESH:D005472', (110, 114))	('UCA1', 'Gene', '652995', (25, 29))	('UCA1', 'Gene', (25, 29))	('gemcitabine', 'MPA', (97, 108))	('restores', 'PosReg', (181, 189))	('tamoxifen', 'MPA', (116, 125))	('imatinib', 'Chemical', 'MESH:D000068877', (127, 135))
755679	28969100	Ectopic expression of lncRNA UCA1 in bladder cancer cell line BLS-211 promoted cancer progression demonstrating that lncRNA UCA1 was oncogenic.	('UCA1', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))	('UCA1', 'Gene', '652995', (29, 33))	('bladder cancer', 'Disease', 'MESH:D001749', (37, 51))	('Ectopic expression', 'Var', (0, 18))	('bladder cancer', 'Disease', (37, 51))	('UCA1', 'Gene', (29, 33))	('BLS-211', 'CellLine', 'CVCL:9W20', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('promoted', 'PosReg', (70, 78))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('UCA1', 'Gene', '652995', (124, 128))
755698	28969100	A recent study reported that knockdown of miR-1 resulted in Ago2-slicer-dependent lncRNA UCA1 overexpression, whereas miR-1 overexpression decreased UCA1 levels in bladder cancer cells.	('overexpression', 'PosReg', (94, 108))	('miR-1', 'Gene', '79187', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('UCA1', 'Gene', '652995', (149, 153))	('knockdown', 'Var', (29, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('UCA1', 'Gene', (149, 153))	('miR-1', 'Gene', (118, 123))	('Ago2', 'Gene', '27161', (60, 64))	('miR-1', 'Gene', '79187', (42, 47))	('UCA1', 'Gene', '652995', (89, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (164, 178))	('bladder cancer', 'Disease', (164, 178))	('UCA1', 'Gene', (89, 93))	('miR-1', 'Gene', (42, 47))	('Ago2', 'Gene', (60, 64))
755699	28969100	postulated that miR-1 targets and cleaves lncRNA UCA1 in an Ago2-dependent manner similar to degradation of protein-coding mRNAs by miRNAs.	('miR-1', 'Gene', '79187', (16, 21))	('cleaves', 'Var', (34, 41))	('Ago2', 'Gene', '27161', (60, 64))	('miR-1', 'Gene', (16, 21))	('UCA1', 'Gene', '652995', (49, 53))	('UCA1', 'Gene', (49, 53))	('Ago2', 'Gene', (60, 64))
755715	28969100	These include aberrant expression of glutathione transferase and topoisomerase II, reduced uptake of water-soluble drugs, enhanced DNA damage repair, enhanced drug metabolism, decreased apoptosis, and increased energy-dependent efflux of chemotherapeutic drugs, all of which reduce the effects of the cancer therapeutics.	('glutathione', 'Protein', (37, 48))	('enhanced', 'PosReg', (122, 130))	('enhanced', 'PosReg', (150, 158))	('increased', 'PosReg', (201, 210))	('reduced', 'NegReg', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('water', 'Chemical', 'MESH:D014867', (101, 106))	('uptake of water-soluble drugs', 'MPA', (91, 120))	('decreased', 'NegReg', (176, 185))	('expression', 'MPA', (23, 33))	('cancer', 'Disease', (301, 307))	('aberrant', 'Var', (14, 22))	('energy-dependent efflux of', 'MPA', (211, 237))	('topoisomerase II', 'Enzyme', (65, 81))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('DNA damage repair', 'MPA', (131, 148))	('apoptosis', 'CPA', (186, 195))	('drug metabolism', 'MPA', (159, 174))
755724	28969100	The expression of lncRNA UCA1 was higher in the T24-cisplatin resistant cells than T24 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('T24-cisplatin resistant', 'Var', (48, 71))	('higher', 'PosReg', (34, 40))	('expression', 'MPA', (4, 14))	('UCA1', 'Gene', '652995', (25, 29))	('UCA1', 'Gene', (25, 29))
755728	28969100	demonstrated that forced expression of lncRNA UCA1 in the bladder cancer cell line UMUC-2 reduced apoptosis upon cisplatin/gemcitabine treatment, whereas silencing of lncRNA UCA1 in the bladder cancer cell line 5637 increased cellular apoptosis.	('gemcitabine', 'Chemical', 'MESH:C056507', (123, 134))	('reduced', 'NegReg', (90, 97))	('UCA1', 'Gene', '652995', (46, 50))	('apoptosis', 'MPA', (98, 107))	('UCA1', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('UCA1', 'Gene', '652995', (174, 178))	('UCA1', 'Gene', (174, 178))	('increased', 'PosReg', (216, 225))	('UMUC-2', 'CellLine', 'CVCL:8155', (83, 89))	('silencing', 'Var', (154, 163))	('bladder cancer', 'Disease', 'MESH:D001749', (186, 200))	('bladder cancer', 'Disease', (186, 200))	('cellular apoptosis', 'CPA', (226, 244))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (186, 200))
755729	28969100	Both in vitro and in vivo experiments confirmed that lncRNA UCA1 induced cisplatin/gemcitabine resistance through activation of CREB by p-AKT and subsequent upregulation of miR-196a-5p.	('activation', 'PosReg', (114, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('miR-1', 'Gene', '79187', (173, 178))	('AKT', 'Gene', (138, 141))	('lncRNA', 'Var', (53, 59))	('UCA1', 'Gene', '652995', (60, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('UCA1', 'Gene', (60, 64))	('miR-1', 'Gene', (173, 178))	('CREB', 'Gene', (128, 132))	('CREB', 'Gene', '1385', (128, 132))	('upregulation', 'PosReg', (157, 169))	('induced', 'Reg', (65, 72))	('cisplatin/gemcitabine resistance', 'MPA', (73, 105))	('AKT', 'Gene', '207', (138, 141))
755737	28969100	However, knockdown of SRPK1 overcomes cisplatin resistance in SKOV3-pcDNA-UCA1 cells and increased Bcl-2 and decreased Bax, Caspase-3 and Caspase-9 expression is observed.	('SRPK1', 'Gene', (22, 27))	('Bax', 'Gene', (119, 122))	('Caspase-3', 'Gene', '836', (124, 133))	('Bcl-2', 'Gene', (99, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('Bax', 'Gene', '581', (119, 122))	('knockdown', 'Var', (9, 18))	('Caspase-9', 'Gene', '842', (138, 147))	('cisplatin resistance', 'MPA', (38, 58))	('UCA1', 'Gene', '652995', (74, 78))	('UCA1', 'Gene', (74, 78))	('Caspase-9', 'Gene', (138, 147))	('Bcl-2', 'Gene', '596', (99, 104))	('increased', 'PosReg', (89, 98))	('SKOV3', 'CellLine', 'CVCL:0532', (62, 67))	('decreased', 'NegReg', (109, 118))	('SRPK1', 'Gene', '6732', (22, 27))	('Caspase-3', 'Gene', (124, 133))	('overcomes', 'NegReg', (28, 37))	('expression', 'MPA', (148, 158))
755739	28969100	observed that lncRNA UCA1 levels were significantly higher in ovarian cancer tissues compared to normal ovarian tissues, and high UCA1 expression was associated with more lymph node metastasis, advanced FIGO stage, and bad response to platinum-based chemotherapy.	('associated', 'Reg', (150, 160))	('UCA1', 'Gene', '652995', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('platinum', 'Chemical', 'MESH:D010984', (235, 243))	('lymph node metastasis', 'CPA', (171, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (62, 76))	('UCA1', 'Gene', '652995', (130, 134))	('expression', 'MPA', (135, 145))	('higher', 'PosReg', (52, 58))	('UCA1', 'Gene', (130, 134))	('ovarian cancer', 'Disease', (62, 76))	('UCA1', 'Gene', (21, 25))	('more', 'PosReg', (166, 170))	('high', 'Var', (125, 129))	('advanced FIGO stage', 'CPA', (194, 213))
755744	28969100	showed that knockdown of lncRNA UCA1 in tamoxifen resistant LCC2 and LCC9 cells increased apoptosis upon tamoxifen treatment accompanied by significant reduction in p-AKT and p-mTOR.	('AKT', 'Gene', (167, 170))	('UCA1', 'Gene', '652995', (32, 36))	('UCA1', 'Gene', (32, 36))	('tamoxifen', 'Chemical', 'MESH:D013629', (40, 49))	('tamoxifen', 'Chemical', 'MESH:D013629', (105, 114))	('increased', 'PosReg', (80, 89))	('knockdown', 'Var', (12, 21))	('mTOR', 'Gene', (177, 181))	('LCC9', 'CellLine', 'CVCL:W648', (69, 73))	('mTOR', 'Gene', '2475', (177, 181))	('AKT', 'Gene', '207', (167, 170))	('apoptosis', 'CPA', (90, 99))	('reduction', 'NegReg', (152, 161))
755752	28969100	Also, knockdown of lncRNA UCA1 prevented the nuclear translocation of beta-catenin, thereby inhibiting the Wnt signaling pathway.	('beta-catenin', 'Gene', (70, 82))	('prevented', 'NegReg', (31, 40))	('beta-catenin', 'Gene', '1499', (70, 82))	('nuclear translocation of', 'MPA', (45, 69))	('UCA1', 'Gene', '652995', (26, 30))	('UCA1', 'Gene', (26, 30))	('Wnt signaling pathway', 'Pathway', (107, 128))	('knockdown', 'Var', (6, 15))	('inhibiting', 'NegReg', (92, 102))
755755	28969100	Further, LCC2 exosomes with impaired UCA1 could not induce tamoxifen resistance in MCF-7 cells.	('induce', 'Reg', (52, 58))	('not', 'NegReg', (48, 51))	('UCA1', 'Gene', '652995', (37, 41))	('MCF-7', 'CellLine', 'CVCL:0031', (83, 88))	('UCA1', 'Gene', (37, 41))	('tamoxifen', 'Chemical', 'MESH:D013629', (59, 68))	('impaired', 'Var', (28, 36))
755759	28969100	Functional analysis indicated that a secondary T790M mutation is the major cause of acquired resistance ; c-MET amplification, PIK3CA mutations (~5%), BRAF mutations and small-cell lung cancer transformation were also associated with acquired resistance.	('cause', 'Reg', (75, 80))	('c-MET', 'Gene', '4233', (106, 111))	('T790M', 'Mutation', 'rs121434569', (47, 52))	('mutations', 'Var', (156, 165))	('acquired resistance', 'MPA', (84, 103))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('T790M', 'Var', (47, 52))	('PIK3CA', 'Gene', (127, 133))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (170, 192))	('BRAF', 'Gene', '673', (151, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('PIK3CA', 'Gene', '5290', (127, 133))	('BRAF', 'Gene', (151, 155))	('c-MET', 'Gene', (106, 111))	('mutations', 'Var', (134, 143))	('associated', 'Reg', (218, 228))	('acquired', 'MPA', (234, 242))	('small-cell lung cancer', 'Disease', (170, 192))
755763	28969100	Functional analysis showed that knockdown of UCA1 in PC9/R cells without T790M mutation partly restored gefitinib sensitivity with increased expression of caspase 3 and caspase 8, whereas H1975 cells with T790M mutation remained gefitinib resistant.	('gefitinib sensitivity', 'MPA', (104, 125))	('T790M', 'Mutation', 'rs121434569', (205, 210))	('caspase 3', 'Gene', (155, 164))	('increased', 'PosReg', (131, 140))	('T790M', 'Var', (73, 78))	('UCA1', 'Gene', (45, 49))	('gefitinib', 'Chemical', 'MESH:D000077156', (104, 113))	('caspase 8', 'Gene', '841', (169, 178))	('caspase 3', 'Gene', '836', (155, 164))	('gefitinib', 'Chemical', 'MESH:D000077156', (229, 238))	('caspase 8', 'Gene', (169, 178))	('expression', 'MPA', (141, 151))	('UCA1', 'Gene', '652995', (45, 49))	('PC9', 'Gene', (53, 56))	('PC9', 'Gene', '255738', (53, 56))	('T790M', 'Mutation', 'rs121434569', (73, 78))	('restored', 'PosReg', (95, 103))	('H1975', 'CellLine', 'CVCL:1511', (188, 193))
755764	28969100	Moreover, both in vitro and in vivo analysis confirmed that lncRNA UCA1 contributed to non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway and EMT.	('activating', 'PosReg', (133, 143))	('AKT', 'Gene', '207', (148, 151))	('T790M', 'Mutation', 'rs121434569', (91, 96))	('mTOR', 'Gene', (152, 156))	('mTOR', 'Gene', '2475', (152, 156))	('AKT', 'Gene', (148, 151))	('UCA1', 'Gene', '652995', (67, 71))	('EMT', 'Gene', (169, 172))	('UCA1', 'Gene', (67, 71))	('EMT', 'Gene', '3702', (169, 172))	('resistance', 'MPA', (106, 116))	('EGFR', 'Gene', '1956', (120, 124))	('non-T790M', 'Var', (87, 96))	('EGFR', 'Gene', (120, 124))
755770	28969100	showed that lncRNA UCA1 levels were higher in SGC7901/ADR cells compared to the parental SGC7901 cells and this resulted in a 4.3 fold increase in IC50 after adriamycin treatment.	('higher', 'PosReg', (36, 42))	('SGC7901/ADR', 'Var', (46, 57))	('increase', 'PosReg', (135, 143))	('UCA1', 'Gene', '652995', (19, 23))	('UCA1', 'Gene', (19, 23))	('adriamycin', 'Chemical', 'MESH:D004317', (158, 168))	('IC50', 'MPA', (147, 151))
755783	28969100	In addition, lncRNA UCA1 overexpression increased Sirt1 expression in PNT2 cells, while silencing of endogenous lncRNA UCA1 decreased Sirt1 expression in LNCaP and 22RV1 cells.	('22RV1', 'CellLine', 'CVCL:1045', (164, 169))	('Sirt1', 'Gene', '23411', (50, 55))	('expression', 'MPA', (140, 150))	('LNCaP', 'CellLine', 'CVCL:0395', (154, 159))	('UCA1', 'Gene', '652995', (119, 123))	('decreased', 'NegReg', (124, 133))	('UCA1', 'Gene', (119, 123))	('silencing', 'Var', (88, 97))	('expression', 'MPA', (56, 66))	('Sirt1', 'Gene', (50, 55))	('Sirt1', 'Gene', (134, 139))	('increased', 'PosReg', (40, 49))	('UCA1', 'Gene', '652995', (20, 24))	('UCA1', 'Gene', (20, 24))	('Sirt1', 'Gene', '23411', (134, 139))
755785	28969100	Interestingly, lncRNA UCA1 and Sirt1 levels were significantly upregulated in 22RV1/DR cells compared to the parental 22RV1 cells and miR-204 was downregulated.	('Sirt1', 'Gene', (31, 36))	('miR-204', 'Gene', (134, 141))	('Sirt1', 'Gene', '23411', (31, 36))	('UCA1', 'Gene', '652995', (22, 26))	('UCA1', 'Gene', (22, 26))	('upregulated', 'PosReg', (63, 74))	('22RV1', 'CellLine', 'CVCL:1045', (118, 123))	('miR-204', 'Gene', '406987', (134, 141))	('22RV1/DR', 'Var', (78, 86))	('22RV1', 'CellLine', 'CVCL:1045', (78, 83))
755791	28969100	The underlying mechanisms of imatinib resistance could be a result of point mutations in the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) kinase domain, amplification of the BCR-ABL gene, and overexpression of the multidrug resistance protein 1 (MRP1) gene in tumor cells.	('tumor', 'Disease', (275, 280))	('murine', 'Species', '10090', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('MRP1', 'Gene', '18669', (261, 265))	('BCR', 'Gene', '613', (144, 147))	('drug resistance', 'Phenotype', 'HP:0020174', (234, 249))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('imatinib', 'Chemical', 'MESH:D000068877', (29, 37))	('multidrug resistance protein 1', 'Gene', (229, 259))	('MRP1', 'Gene', (261, 265))	('multidrug resistance protein 1', 'Gene', '18669', (229, 259))	('BCR', 'Gene', (144, 147))	('leukemia', 'Disease', 'MESH:D007938', (134, 142))	('BCR', 'Gene', '613', (189, 192))	('leukemia', 'Disease', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('overexpression', 'PosReg', (207, 221))	('BCR', 'Gene', (189, 192))	('amplification', 'PosReg', (168, 181))	('point mutations', 'Var', (70, 85))
755793	28969100	Further, MDR1 protein expression was higher in K562/IM-R and lower in K562/IM cells compared to K562 cells.	('K562/IM', 'Var', (70, 77))	('lower', 'NegReg', (61, 66))	('higher', 'PosReg', (37, 43))	('protein', 'Protein', (14, 21))	('MDR1', 'Gene', '5243', (9, 13))	('K562/IM-R', 'Var', (47, 56))	('K562', 'CellLine', 'CVCL:0004', (96, 100))	('K562', 'CellLine', 'CVCL:0004', (70, 74))	('MDR1', 'Gene', (9, 13))	('K562', 'CellLine', 'CVCL:0004', (47, 51))
755794	28969100	Also, lncRNA UCA1 expression was higher in K562/IM-R and lower in K562/IM cells than in K562 cells, which indicated the role of lncRNA UCA1 in IM resistance of CML cells.	('K562', 'CellLine', 'CVCL:0004', (43, 47))	('higher', 'PosReg', (33, 39))	('CML', 'Disease', (160, 163))	('UCA1', 'Gene', '652995', (135, 139))	('UCA1', 'Gene', (135, 139))	('K562/IM-R', 'Var', (43, 52))	('K562', 'CellLine', 'CVCL:0004', (66, 70))	('UCA1', 'Gene', '652995', (13, 17))	('expression', 'MPA', (18, 28))	('UCA1', 'Gene', (13, 17))	('CML', 'Disease', 'MESH:D015464', (160, 163))	('CML', 'Phenotype', 'HP:0005506', (160, 163))	('K562', 'CellLine', 'CVCL:0004', (88, 92))	('K562/IM', 'Var', (66, 73))	('lower', 'NegReg', (57, 62))
755795	28969100	Stable transfection of lncRNA UCA1 in K562 cells markedly upregulated MDR1 mRNA and protein levels and resulted in IM resistance, whereas silencing of UCA1 in K562/IM cells significantly inhibited MDR1 expression.	('MDR1', 'Gene', (197, 201))	('resulted in', 'Reg', (103, 114))	('MDR1', 'Gene', '5243', (70, 74))	('UCA1', 'Gene', '652995', (151, 155))	('silencing', 'Var', (138, 147))	('K562', 'CellLine', 'CVCL:0004', (38, 42))	('MDR1', 'Gene', '5243', (197, 201))	('upregulated', 'PosReg', (58, 69))	('expression', 'MPA', (202, 212))	('IM resistance', 'MPA', (115, 128))	('UCA1', 'Gene', '652995', (30, 34))	('MDR1', 'Gene', (70, 74))	('UCA1', 'Gene', (30, 34))	('K562', 'CellLine', 'CVCL:0004', (159, 163))	('UCA1', 'Gene', (151, 155))	('inhibited', 'NegReg', (187, 196))
755812	28969100	The positive correlation between lncRNA UCA1 expression and poor prognosis in a great number of cancer types as mentioned in the above meta-analysis suggests that lncRNA UCA1 could act as an independent prognostic factor for cancer patients.	('lncRNA', 'Var', (163, 169))	('UCA1', 'Gene', '652995', (170, 174))	('UCA1', 'Gene', '652995', (40, 44))	('UCA1', 'Gene', (170, 174))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (225, 231))	('UCA1', 'Gene', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', (96, 102))
755815	28969100	The majority of these results of drug resistance were from in vitro studies, whereas clinical data was available only in ovarian cancers where high lncRNA UCA1 expression was associated with the response to platinum-based chemotherapy.	('expression', 'MPA', (160, 170))	('UCA1', 'Gene', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('associated with', 'Reg', (175, 190))	('platinum', 'Chemical', 'MESH:D010984', (207, 215))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('ovarian cancers', 'Phenotype', 'HP:0100615', (121, 136))	('ovarian cancers', 'Disease', (121, 136))	('high lncRNA', 'Var', (143, 154))	('ovarian cancers', 'Disease', 'MESH:D010051', (121, 136))	('drug resistance', 'Phenotype', 'HP:0020174', (33, 48))	('UCA1', 'Gene', '652995', (155, 159))
755822	28969100	The two main approaches in RNA targeted therapeutics include double stranded RNA-mediated interference (RNAi) and antisense oligonucleotides (ASO).	('double', 'Var', (61, 67))	('antisense oligonucleotides', 'Var', (114, 140))	('oligonucleotides', 'Chemical', 'MESH:D009841', (124, 140))
755826	28969100	In fact, knockdown of lncRNA UCA1 by short interfering RNAs (siRNA) or short hairpin RNA (shRNA) has been shown to reverse drug resistance in various cancer cells such as bladder cancer, breast cancer, lung cancer, gastric cancer, colorectal cancer, prostate cancer, CML, ovarian cancer.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('colorectal cancer', 'Disease', 'MESH:D015179', (231, 248))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (280, 286))	('prostate cancer', 'Disease', (250, 265))	('gastric cancer', 'Disease', (215, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('drug resistance', 'MPA', (123, 138))	('ovarian cancer', 'Disease', 'MESH:D010051', (272, 286))	('colorectal cancer', 'Disease', (231, 248))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('drug resistance', 'Phenotype', 'HP:0020174', (123, 138))	('CML', 'Phenotype', 'HP:0005506', (267, 270))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', (207, 213))	('UCA1', 'Gene', '652995', (29, 33))	('short', 'MPA', (71, 76))	('UCA1', 'Gene', (29, 33))	('gastric cancer', 'Disease', 'MESH:D013274', (215, 229))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('ovarian cancer', 'Disease', (272, 286))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', (259, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('short', 'MPA', (37, 42))	('knockdown', 'Var', (9, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (272, 286))	('lung cancer', 'Disease', (202, 213))	('bladder cancer', 'Disease', 'MESH:D001749', (171, 185))	('bladder cancer', 'Disease', (171, 185))	('colorectal cancer', 'Phenotype', 'HP:0003003', (231, 248))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (215, 229))	('CML', 'Disease', 'MESH:D015464', (267, 270))	('breast cancer', 'Disease', (187, 200))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', (242, 248))	('CML', 'Disease', (267, 270))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('reverse', 'NegReg', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('prostate cancer', 'Disease', 'MESH:D011471', (250, 265))	('prostate cancer', 'Phenotype', 'HP:0012125', (250, 265))	('cancer', 'Disease', (179, 185))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))
755831	28969100	Thus, Ets-2, C/EBPalpha, HIF-1alpha, and transcriptional complexes (TAZ/YAP/TEAD/SMAD2/3) are potential targets to knockdown the expression of lncRNA UCA1.	('YAP', 'Gene', '10413', (72, 75))	('TAZ', 'Gene', '6901', (68, 71))	('Ets-2', 'Gene', '2114', (6, 11))	('knockdown', 'Var', (115, 124))	('TAZ', 'Gene', (68, 71))	('C/EBPalpha', 'Gene', (13, 23))	('YAP', 'Gene', (72, 75))	('HIF-1alpha', 'Gene', '3091', (25, 35))	('C/EBPalpha', 'Gene', '1050', (13, 23))	('UCA1', 'Gene', '652995', (150, 154))	('UCA1', 'Gene', (150, 154))	('Ets-2', 'Gene', (6, 11))	('HIF-1alpha', 'Gene', (25, 35))
755836	28969100	Direct targeting of the UCA1 genomic locus is another method to knockdown UCA1 expression in malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('malignant tumors', 'Disease', 'MESH:D018198', (93, 109))	('expression', 'MPA', (79, 89))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('UCA1', 'Gene', '652995', (74, 78))	('UCA1', 'Gene', (74, 78))	('knockdown', 'Var', (64, 73))	('malignant tumors', 'Disease', (93, 109))	('UCA1', 'Gene', '652995', (24, 28))	('UCA1', 'Gene', (24, 28))
755858	28510809	Endoscopy and upper gastrointestinal series revealed perforation on the right wall of the middle thoracic esophagus 32-35 cm distant from the incisors and blood clots in stomach (Fig.	('upper gastrointestinal', 'Disease', (14, 36))	('perforation', 'Var', (53, 64))	('upper gastrointestinal', 'Disease', 'MESH:D005767', (14, 36))	('blood clots', 'Phenotype', 'HP:0001907', (155, 166))
755872	28510809	CRT can induce fistula formation by damaging the walls of the esophagus and adjacent organs.	('damaging', 'NegReg', (36, 44))	('induce', 'Reg', (8, 14))	('walls', 'MPA', (49, 54))	('fistula', 'Disease', 'MESH:D005402', (15, 22))	('fistula', 'Disease', (15, 22))	('CRT', 'Var', (0, 3))
755927	24367697	Studies which have assessed all esophageal cancer histologies combined have generally been null for associations with physical activity and sedentary behavior, with only the British Regional Heart Study and a study from Montreal, Canada finding evidence for inverse associations between physical activity and upper digestive (oral/esophagus) malignancies and esophageal cancer, respectively.	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('inverse', 'NegReg', (258, 265))	('malignancies', 'Disease', (342, 354))	('esophageal cancer', 'Disease', (359, 376))	('physical', 'Var', (287, 295))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (359, 376))	('esophageal cancer', 'Disease', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('malignancies', 'Disease', 'MESH:D009369', (342, 354))
756023	20589185	Furthermore, focal areas of brown fat, asymmetric uptake in the vocal cords, and vessel atherosclerosis may lead to false positive results, although these areas are generally better differentiated from areas of esophageal uptake on PET/CT, rather than on PET images.	('vessel atherosclerosis', 'Disease', 'MESH:D050197', (81, 103))	('atherosclerosis', 'Phenotype', 'HP:0002621', (88, 103))	('asymmetric', 'Var', (39, 49))	('vessel atherosclerosis', 'Disease', (81, 103))
756055	33547361	GATA4 mRNA up-regulation and gene amplification occur in BE and its associated cancer, esophageal adenocarcinoma (EAC), and GATA4 gene amplification correlates with poor patient outcomes.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (87, 112))	('up-regulation', 'PosReg', (11, 24))	('esophageal adenocarcinoma', 'Disease', (87, 112))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('GATA4', 'Gene', (124, 129))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (87, 112))	('EAC', 'Phenotype', 'HP:0011459', (114, 117))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('gene amplification', 'Var', (29, 47))	('GATA4', 'Gene', (0, 5))	('cancer', 'Disease', (79, 85))	('mRNA', 'MPA', (6, 10))	('patient', 'Species', '9606', (170, 177))
756074	33547361	For example, embryos lacking p63 develop BE-like metaplasia, and hypomorphic SOX2 mutants develop regional columnar metaplasia in the esophagus and forestomach.	('regional columnar metaplasia', 'Disease', (98, 126))	('BE', 'Phenotype', 'HP:0100580', (41, 43))	('develop', 'Reg', (90, 97))	('BE-like metaplasia', 'CPA', (41, 59))	('SOX2', 'Gene', (77, 81))	('SOX2', 'Gene', '6657', (77, 81))	('mutants', 'Var', (82, 89))
756075	33547361	In this study, we explored the effect of aberrant expression of GATA4 on the epithelial character of mature human esophageal squamous epithelial cells.	('GATA4', 'Gene', (64, 69))	('human', 'Species', '9606', (108, 113))	('aberrant', 'Var', (41, 49))
756084	33547361	We observed higher levels of GATA4 mRNA in NES-B10T cells transduced with the GATA4 expression construct compared with NES-B3T cells, with NES-B10T cell clones expressing an average of 5.3-fold more GATA4 mRNA than NES-B3T cell clones (Fig.	('more', 'PosReg', (194, 198))	('B10T', 'CellLine', 'CVCL:6819', (47, 51))	('higher', 'PosReg', (12, 18))	('construct', 'Var', (95, 104))	('GATA4 mRNA', 'MPA', (29, 39))	('levels', 'MPA', (19, 25))	('NES', 'Gene', '10763', (139, 142))	('NES', 'Gene', '10763', (215, 218))	('NES', 'Gene', '10763', (43, 46))	('GATA4', 'Gene', (78, 83))	('NES', 'Gene', '10763', (119, 122))	('NES', 'Gene', (139, 142))	('NES', 'Gene', (215, 218))	('NES', 'Gene', (43, 46))	('NES', 'Gene', (119, 122))	('B10T', 'CellLine', 'CVCL:6819', (143, 147))
756088	33547361	We found that expression of GATA4 in NES-B10T cells decreased the abundance of all four mRNAs (Fig.	('expression', 'Var', (14, 24))	('GATA4', 'Gene', (28, 33))	('B10T', 'CellLine', 'CVCL:6819', (41, 45))	('decreased', 'NegReg', (52, 61))	('NES', 'Gene', '10763', (37, 40))	('abundance of all four mRNAs', 'MPA', (66, 93))	('NES', 'Gene', (37, 40))
756114	33547361	These data motivated us to examine how GATA4 ectopic expression in human adult normal esophageal squamous cells would affect their squamous identity.	('ectopic expression', 'Var', (45, 63))	('affect', 'Reg', (118, 124))	('GATA4', 'Gene', (39, 44))	('squamous identity', 'CPA', (131, 148))	('human', 'Species', '9606', (67, 72))
756143	33547361	Cells were selected with G418 (350 mg/ml, B3T; 500 mg/ml, B10T) beginning 24 h after infection.	('infection', 'Disease', (85, 94))	('infection', 'Disease', 'MESH:D007239', (85, 94))	('G418', 'Chemical', 'MESH:C010680', (25, 29))	('B10T', 'CellLine', 'CVCL:6819', (58, 62))	('350', 'Var', (31, 34))
756144	33547361	The G418 dose was established as double the concentration required to kill non-infected cells effectively.	('G418', 'Var', (4, 8))	('G418', 'Chemical', 'MESH:C010680', (4, 8))	('infected', 'Disease', 'MESH:D007239', (79, 87))	('infected', 'Disease', (79, 87))
756147	33547361	For quantitative reverse-transcription polymerase chain reaction (qRT-PCR), cDNA synthesized using MMLV and random hexamer primers was amplified using TaqMan Gene Expression Mastermix and TaqMan gene expression assays (GATA4, HS00171403_m1; KRT5, Hs00361185_m1; KRT8, Hs01595539_m1; KRT13, Hs00357961_g1; KRT15, Hs00951967_m1; KRT20, Hs00300643_m1; p63, Hs00978340_m1; CDX2, Hs01078080_m1; VILLIN, Hs01031724_m1; Gata4, Mm00484689_m1; p63, Mm00495793_m1; Krt5, Mm01305291_g1; Krt15, Mm00492972_m1).	('Mm00492972_m1', 'Var', (483, 496))	('Mm01305291_g1', 'Var', (461, 474))	('MMLV', 'Species', '11801', (99, 103))	('KRT20', 'Gene', '54474', (327, 332))	('KRT8', 'Gene', (262, 266))	('KRT20', 'Gene', (327, 332))	('Mm00495793_m1', 'Var', (440, 453))	('KRT8', 'Gene', '3856', (262, 266))
756171	33335548	Patients with aberrant expression of circRNAs had a 2.92-fold increased risk of developing EC.	('Patients', 'Species', '9606', (0, 8))	('aberrant expression', 'Var', (14, 33))	('circRNAs', 'Gene', (37, 45))
756184	33335548	Of course, just as the downregulation of miR-20b, miR-27a, and miR-181a leads to the upregulation of drug-resistant genes in gastric cancer to affect the sensitive of chemotherapy, we also expect circRNA to serve for the precise and individualized treatment of EC.	('downregulation', 'NegReg', (23, 37))	('miR-20b', 'Gene', (41, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('miR-27a', 'Gene', (50, 57))	('affect', 'Reg', (143, 149))	('drug-resistant genes', 'Gene', (101, 121))	('miR-20b', 'Gene', '574032', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('sensitive of chemotherapy', 'MPA', (154, 179))	('miR-27a', 'Gene', '407018', (50, 57))	('upregulation', 'PosReg', (85, 97))	('gastric cancer', 'Disease', (125, 139))	('miR-181a', 'Var', (63, 71))
756201	31406502	In that study, tobacco use, alcohol consumption, low intake of green vegetables, illiteracy, and religion were associated with risk of EC.	('low', 'Var', (49, 52))	('alcohol', 'Chemical', 'MESH:D000438', (28, 35))	('associated', 'Reg', (111, 121))	('tobacco', 'Species', '4097', (15, 22))
756203	31406502	A subgroup of HPV types referred to as high-risk (HR) HPV types have been identified as the etiological agents of anogenital cancers and a subset of head and neck cancers; HPV16 is the most oncogenic type.	('head and neck cancer', 'Disease', 'MESH:D006258', (149, 169))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('head and neck cancers', 'Phenotype', 'HP:0012288', (149, 170))	('HPV', 'Species', '10566', (172, 175))	('HPV', 'Species', '10566', (14, 17))	('neck cancers', 'Disease', (158, 170))	('agents', 'Reg', (104, 110))	('neck cancers', 'Disease', 'MESH:D006258', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('etiological', 'Reg', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('anogenital cancers', 'Disease', (114, 132))	('HPV', 'Species', '10566', (54, 57))	('HPV16', 'Species', '333760', (172, 177))	('head and neck cancer', 'Phenotype', 'HP:0012288', (149, 169))	('anogenital cancers', 'Disease', 'MESH:D009369', (114, 132))	('HPV16', 'Var', (172, 177))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
756204	31406502	HR HPV types encode for two oncoproteins, E6 and E7, that play a key role in carcinogenesis by interacting with cellular proteins (e.g., p53, pRb, PI3K, Notch) involved in the cell cycle, apoptosis, and differentiation (reviewed in).	('PI3K', 'Var', (147, 151))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('carcinogenesis', 'Disease', (77, 91))	('interacting', 'Interaction', (95, 106))	('HR HPV', 'Disease', (0, 6))	('p53', 'Var', (137, 140))	('HR HPV', 'Disease', 'MESH:D030361', (0, 6))
756209	31406502	It is well established that cagA-positive strains are associated with an increased risk of developing gastric cancer.	('increased risk of developing gastric cancer', 'Phenotype', 'HP:0006753', (73, 116))	('gastric cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('cagA', 'Gene', (28, 32))	('strains', 'Var', (42, 49))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('cagA', 'Gene', '6279', (28, 32))
756218	31406502	Cancer cases aged 18 years or older with first primary tumors of the esophagus or gastroesophageal junction were eligible for inclusion (WHO ICD-O-3 codes: C15.0, C15.3, C15.4, C15.5, C15.8, C15.9, and C16.0).	('gastroesophageal junction', 'Disease', 'MESH:D008309', (82, 107))	('tumors of the esophagus', 'Disease', 'MESH:D004938', (55, 78))	('C15.4', 'Var', (170, 175))	('C15.5', 'Var', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('C15.8', 'Var', (184, 189))	('tumors of the esophagus', 'Disease', (55, 78))	('C15.3', 'Var', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('C15.9', 'CellLine', 'CVCL:0H97', (191, 196))	('tumors of the esophagus', 'Phenotype', 'HP:0100751', (55, 78))	('C16.0', 'Var', (202, 207))	('C15.9', 'Var', (191, 196))	('C15.0', 'Var', (156, 161))	('gastroesophageal junction', 'Disease', (82, 107))
756244	31406502	Specimens from 2 cases had dual HPV infections, with the following combinations of genotypes: HPV31 and HPV35 in 1 case and HPV56 and HPV66 in 1 case.	('HPV infections', 'Disease', (32, 46))	('HPV', 'Species', '10566', (104, 107))	('HPV', 'Species', '10566', (124, 127))	('HPV', 'Species', '10566', (94, 97))	('HPV66', 'Var', (134, 139))	('HPV35', 'Species', '10587', (104, 109))	('HPV35', 'Var', (104, 109))	('HPV56', 'Var', (124, 129))	('HPV', 'Species', '10566', (32, 35))	('HPV31', 'Var', (94, 99))	('HPV infections', 'Disease', 'MESH:D030361', (32, 46))	('HPV', 'Species', '10566', (134, 137))
756250	31406502	The following genotypes were identified in the oral cavity: HPV16, HPV18, HPV35, HPV39, HPV53, and HPV66.	('HPV53', 'Var', (88, 93))	('HPV18', 'Var', (67, 72))	('HPV16', 'Species', '333760', (60, 65))	('HPV16', 'Var', (60, 65))	('HPV66', 'Var', (99, 104))	('HPV', 'Species', '10566', (67, 70))	('HPV35', 'Var', (74, 79))	('HPV', 'Species', '10566', (60, 63))	('HPV', 'Species', '10566', (88, 91))	('HPV', 'Species', '10566', (74, 77))	('HPV35', 'Species', '10587', (74, 79))	('HPV', 'Species', '10566', (81, 84))	('HPV', 'Species', '10566', (99, 102))	('HPV39', 'Var', (81, 86))
756251	31406502	Specimens from 2 controls had dual detection, with the following combination of genotypes: HPV18 and HPV39 in 1 control and HPV35 and HPV66 in 1 control.	('HPV18', 'Gene', (91, 96))	('HPV', 'Species', '10566', (124, 127))	('HPV35', 'Var', (124, 129))	('HPV66', 'Var', (134, 139))	('HPV35', 'Species', '10587', (124, 129))	('HPV39', 'Gene', (101, 106))	('HPV', 'Species', '10566', (101, 104))	('HPV', 'Species', '10566', (91, 94))	('HPV', 'Species', '10566', (134, 137))
756269	31406502	A study in Malawi, the country with the highest EC incidence in East Africa, reported a HPV16 positivity of 15% among 40 patients with ESCC undergoing endoscopy with formalin-fixed, paraffin-embedded tissue biopsy specimens tested using multiplex quantitative PCR and in situ hybridization.	('formalin', 'Chemical', 'MESH:D005557', (166, 174))	('ESCC', 'Disease', (135, 139))	('paraffin', 'Chemical', 'MESH:D010232', (182, 190))	('HPV16', 'Gene', (88, 93))	('HPV16', 'Species', '333760', (88, 93))	('positivity', 'Var', (94, 104))	('patients', 'Species', '9606', (121, 129))
756285	31406502	The presence of this gene is considered to be associated with H. pylori virulence and contributes to neoplastic transformation in the gastric mucosa; however, further studies are required to complement these data by determining the CagA antibody levels in serum, and to assess its role, if any, in the development of EC and gastroesophageal junction cancers.	('CagA', 'Gene', (232, 236))	('CagA', 'Gene', '6279', (232, 236))	('neoplastic transformation in the gastric', 'Phenotype', 'HP:0006753', (101, 141))	('H. pylori', 'Species', '210', (62, 71))	('gastroesophageal junction cancers', 'Disease', 'MESH:D008309', (324, 357))	('cancers', 'Phenotype', 'HP:0002664', (350, 357))	('gastroesophageal junction cancers', 'Disease', (324, 357))	('associated', 'Reg', (46, 56))	('presence', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))
756373	30992022	Corresponding 1y-PFS, 2y-PFS and 3y-PFS were 67.6%, 42.6% and 42.6% in patients undergoing nCRT + S and 51.0%, 29.9% and 26.6% in patients undergoing dCRT.	('CRT', 'Gene', '45841', (151, 154))	('3y-PFS', 'Var', (33, 39))	('CRT', 'Gene', (151, 154))	('1y-PFS', 'Var', (14, 20))	('dCRT', 'Gene', (150, 154))	('dCRT', 'Gene', '45841', (150, 154))	('patients', 'Species', '9606', (71, 79))	('2y-PFS', 'Var', (22, 28))	('patients', 'Species', '9606', (130, 138))	('CRT', 'Gene', '45841', (92, 95))	('CRT', 'Gene', (92, 95))
756401	30992022	While we found no data evaluating the impact of tumor location after nCRT + S or dCRT in E-SCC patients, proximal tumor location was associated with decreased OS in patients with pT2-3N0M0 carcinoma after surgery alone.	('CRT', 'Gene', (82, 85))	('CRT', 'Gene', '45841', (70, 73))	('SCC', 'Gene', (91, 94))	('patients', 'Species', '9606', (165, 173))	('pT2-3N0M0', 'Var', (179, 188))	('dCRT', 'Gene', (81, 85))	('OS', 'Chemical', '-', (159, 161))	('tumor', 'Disease', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('CRT', 'Gene', '45841', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('dCRT', 'Gene', '45841', (81, 85))	('carcinoma', 'Disease', (189, 198))	('tumor', 'Disease', (48, 53))	('CRT', 'Gene', (70, 73))	('decreased', 'NegReg', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('patients', 'Species', '9606', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('carcinoma', 'Disease', 'MESH:D002277', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('SCC', 'Gene', '6317', (91, 94))
756428	30947876	It is caused by a mutation in the gene coding for the CF transmembrane conductance regulator (CFTR) protein on chromosome 7.	('caused by', 'Reg', (6, 15))	('CFTR', 'Gene', '1080', (94, 98))	('mutation', 'Var', (18, 26))	('CFTR', 'Gene', (94, 98))
756434	30947876	Risk factors identified for CFLD in this study included male sex, CFTR F508del homozygosity, and history of meconium ileus.	('CFTR', 'Gene', '1080', (66, 70))	('F508del', 'Var', (71, 78))	('ileus', 'Phenotype', 'HP:0002595', (117, 122))	('CFTR', 'Gene', (66, 70))	('CFLD', 'Disease', 'None', (28, 32))	('meconium ileus', 'Disease', (108, 122))	('CFLD', 'Disease', (28, 32))	('history of meconium ileus', 'Phenotype', 'HP:0004401', (97, 122))	('F508del', 'DELETION', 'None', (71, 78))
756439	30947876	Thus, mutations in the CFTR protein can lead to impaired secretion of Cl- and thus lead to the development of viscous bile with reduced flow and alkalinity.	('impaired', 'NegReg', (48, 56))	('CFTR', 'Gene', (23, 27))	('alkalinity', 'MPA', (145, 155))	('reduced', 'NegReg', (128, 135))	('secretion of Cl-', 'MPA', (57, 73))	('CFTR', 'Gene', '1080', (23, 27))	('lead to', 'Reg', (83, 90))	('development of viscous bile', 'MPA', (95, 122))	('mutations', 'Var', (6, 15))
756442	30947876	These changes can lead to periductal inflammation, damage to cholangiocytes, bile duct proliferation, and periportal fibrosis (Figure 2a).	('periductal inflammation', 'Phenotype', 'HP:0012322', (26, 49))	('bile duct proliferation', 'Phenotype', 'HP:0001408', (77, 100))	('inflammation', 'Disease', 'MESH:D007249', (37, 49))	('periportal', 'Disease', (106, 116))	('inflammation', 'Disease', (37, 49))	('changes', 'Var', (6, 13))	('fibrosis', 'Disease', (117, 125))	('periportal fibrosis', 'Phenotype', 'HP:0001405', (106, 125))	('fibrosis', 'Disease', 'MESH:D005355', (117, 125))	('damage', 'CPA', (51, 57))	('lead to', 'Reg', (18, 25))	('bile', 'Disease', (77, 81))
756444	30947876	In addition to these changes, a recent study demonstrated that CFTR regulates toll-like receptor 4 (TLR-4)-dependent inflammatory responses by inhibiting Rous sarcoma oncogene cellular homologue (Src) activity, and mutations in CFTR lead to self-activation of Src leading to increased inflammatory cytokines and disruption of the epithelial barrier.	('sarcoma oncogene cellular homologue', 'Gene', '6714', (159, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('CFTR', 'Gene', '1080', (228, 232))	('sarcoma oncogene cellular homologue', 'Gene', (159, 194))	('TLR-4', 'Gene', (100, 105))	('CFTR', 'Gene', (228, 232))	('Src', 'Gene', (260, 263))	('increased', 'PosReg', (275, 284))	('TLR-4', 'Gene', '7099', (100, 105))	('Src', 'Gene', (196, 199))	('mutations', 'Var', (215, 224))	('toll-like receptor 4', 'Gene', (78, 98))	('Src', 'Gene', '6714', (260, 263))	('inflammatory cytokines', 'MPA', (285, 307))	('Src', 'Gene', '6714', (196, 199))	('toll-like receptor 4', 'Gene', '7099', (78, 98))	('CFTR', 'Gene', '1080', (63, 67))	('activity', 'MPA', (201, 209))	('inhibiting', 'NegReg', (143, 153))	('CFTR', 'Gene', (63, 67))	('self-activation', 'MPA', (241, 256))	('increased inflammatory cytokines', 'Phenotype', 'HP:0012649', (275, 307))
756452	30947876	Of adult patients, 18.3% are obese with body mass index greater than 30, with the majority having CF mutations other than F508del.	('obese', 'Disease', 'MESH:D009765', (29, 34))	('patients', 'Species', '9606', (9, 17))	('obese', 'Disease', (29, 34))	('F508del', 'DELETION', 'None', (122, 129))	('F508del', 'Var', (122, 129))
756463	30947876	In addition, a recent study demonstrated that 19% of patients with PSC carry mutations in CFTR and that 50% had CFTR polymorphisms.	('CFTR', 'Gene', '1080', (90, 94))	('patients', 'Species', '9606', (53, 61))	('PSC', 'Disease', (67, 70))	('CFTR', 'Gene', (112, 116))	('CFTR', 'Gene', '1080', (112, 116))	('mutations', 'Var', (77, 86))	('CFTR', 'Gene', (90, 94))
756470	30947876	However, Woodruff et al demonstrated that AST > 1.5 X ULN or GGT >1.5X ULN were strong predictors of underlying liver disease in patients with CF and Bodewes et al demonstrated a strong correlation between persistently elevated GGT and the development of cirrhosis within 2 years.	('>1.5X', 'Var', (65, 70))	('cirrhosis', 'Disease', (255, 264))	('AST', 'Gene', (42, 45))	('patients', 'Species', '9606', (129, 137))	('GGT', 'Gene', (61, 64))	('AST', 'Gene', '26503', (42, 45))	('liver disease', 'Phenotype', 'HP:0001392', (112, 125))	('GGT', 'Gene', '2678', (228, 231))	('cirrhosis', 'Phenotype', 'HP:0001394', (255, 264))	('liver disease', 'Disease', (112, 125))	('elevated', 'PosReg', (219, 227))	('cirrhosis', 'Disease', 'MESH:D005355', (255, 264))	('liver disease', 'Disease', 'MESH:D008107', (112, 125))	('GGT', 'Gene', (228, 231))	('GGT', 'Gene', '2678', (61, 64))
756492	30947876	The most commonly used is one that was proposed by Debray et al in 2011 which involved at least 2 of following after ruling out other causes of liver disease: hepatomegaly or splenomegaly, abnormal LFTs above the upper limits of normal at least 3 consecutive determinations over 12 months, or ultrasound evidence of liver involvement, with liver biopsies being performed if there was any doubt.	('splenomegaly', 'Disease', 'MESH:D013163', (175, 187))	('hepatomegaly', 'Disease', 'MESH:D006529', (159, 171))	('liver disease', 'Disease', 'MESH:D008107', (144, 157))	('abnormal', 'Var', (189, 197))	('splenomegaly', 'Phenotype', 'HP:0001744', (175, 187))	('hepatomegaly', 'Phenotype', 'HP:0002240', (159, 171))	('hepatomegaly or splenomegaly', 'Phenotype', 'HP:0001433', (159, 187))	('liver involvement', 'Disease', (316, 333))	('splenomegaly', 'Disease', (175, 187))	('liver disease', 'Phenotype', 'HP:0001392', (144, 157))	('liver involvement', 'Disease', 'MESH:D017093', (316, 333))	('liver disease', 'Disease', (144, 157))	('hepatomegaly', 'Disease', (159, 171))
756627	30510939	Furthermore, non-adherence was associated with fewer detections of dysplasia (OR = 0.53, 95%CI: 0.35-0.82).	('dysplasia', 'Disease', (67, 76))	('fewer', 'NegReg', (47, 52))	('dysplasia', 'Disease', 'MESH:D004476', (67, 76))	('non-adherence', 'Var', (13, 26))
756806	24671095	While outside the purview of this study, it is plausible that alterations in these cytokines are part of the constellation of metabolic syndrome and increase risk of Barrett's esophagus.	("Barrett's esophagus", 'Disease', (166, 185))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (166, 185))	('constellation of metabolic syndrome', 'Disease', 'MESH:D008659', (109, 144))	('constellation of metabolic syndrome', 'Disease', (109, 144))	('alterations', 'Var', (62, 73))
756813	17309796	Aberrant nuclear localization of beta-catenin without genetic alterations in beta-catenin or Axin genes in esophageal cancer beta-catenin is a multifunctional protein involved in two apparently independent processes: cell-cell adhesion and signal transduction.	('beta-catenin', 'Gene', '1499', (33, 45))	('Axin', 'Gene', '8312', (93, 97))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', (125, 137))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('nuclear localization', 'MPA', (9, 29))	('Axin', 'Gene', (93, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('beta-catenin', 'Gene', (33, 45))	('beta-catenin', 'Gene', '1499', (125, 137))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', '1499', (77, 89))
756815	17309796	In this study, we investigated the expression pattern of beta-catenin and cyclin D1 using immunohistochemistry and searched for mutations in exon 3 of the beta-catenin gene and Axin gene in esophageal squamous cell carcinoma.	('beta-catenin', 'Gene', (155, 167))	('mutations in', 'Var', (128, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('cyclin D1', 'Gene', '595', (74, 83))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (190, 224))	('beta-catenin', 'Gene', '1499', (155, 167))	('cyclin D1', 'Gene', (74, 83))	('Axin', 'Gene', (177, 181))	('Axin', 'Gene', '8312', (177, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('beta-catenin', 'Gene', (57, 69))	('beta-catenin', 'Gene', '1499', (57, 69))	('esophageal squamous cell carcinoma', 'Disease', (190, 224))
756824	17309796	Sequencing analysis of the Axin cDNA revealed only a splicing variant (108 bp deletion, position 2302-2409) which was present in the paired normal mucosa.	('Axin', 'Gene', '8312', (27, 31))	('108 bp deletion', 'Var', (71, 86))	('Axin', 'Gene', (27, 31))
756832	17309796	In colorectal cancers, mutations of APC or beta-catenin result in stabilization of beta-catenin and a significant accumulation of this protein within the cytoplasm.	('colorectal cancers', 'Disease', 'MESH:D015179', (3, 21))	('beta-catenin', 'Gene', '1499', (43, 55))	('beta-catenin', 'Gene', (83, 95))	('APC', 'Phenotype', 'HP:0005227', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('beta-catenin', 'Gene', '1499', (83, 95))	('colorectal cancers', 'Disease', (3, 21))	('mutations', 'Var', (23, 32))	('accumulation', 'PosReg', (114, 126))	('beta-catenin', 'Gene', (43, 55))	('APC', 'Gene', (36, 39))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('stabilization', 'MPA', (66, 79))	('APC', 'Gene', '324', (36, 39))
756837	17309796	Overexpression of cyclinD1 has been suggested to contribute to oncogenesis by disturbing the cell cycle and has been reported to be an important oncogenic factor in esophageal carcinoma.	('cyclinD1', 'Gene', (18, 26))	('esophageal carcinoma', 'Disease', (165, 185))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (165, 185))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (165, 185))	('cyclinD1', 'Gene', '595', (18, 26))	('cell cycle', 'CPA', (93, 103))	('contribute', 'Reg', (49, 59))	('Overexpression', 'Var', (0, 14))	('disturbing', 'Reg', (78, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
756842	17309796	The progression of this tumor is associated with multiple genetic alterations, including loss of heterozygosity in chromosomes 3p, 5q, 9p, 9q, 13q, 17p, 17q and 18q, and amplification of epidermal growth factor receptor (EGFR), HER-2, c-myc, and cyclin D1.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('epidermal growth factor receptor', 'Gene', '1956', (187, 219))	('amplification', 'Var', (170, 183))	('HER-2', 'Gene', '2064', (228, 233))	('tumor', 'Disease', (24, 29))	('HER-2', 'Gene', (228, 233))	('EGFR', 'Gene', '1956', (221, 225))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('cyclin D1', 'Gene', '595', (246, 255))	('epidermal growth factor receptor', 'Gene', (187, 219))	('EGFR', 'Gene', (221, 225))	('cyclin D1', 'Gene', (246, 255))	('c-myc', 'Gene', '4609', (235, 240))	('c-myc', 'Gene', (235, 240))	('loss', 'NegReg', (89, 93))
756843	17309796	The most frequent genetic alteration in esophageal squamous cell carcinoma is a point mutation in the p53 gene (40-60%) that occurs at a relatively early stage of tumor development.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('esophageal squamous cell carcinoma', 'Disease', (40, 74))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('p53', 'Gene', '7157', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('point mutation', 'Var', (80, 94))	('tumor', 'Disease', (163, 168))	('p53', 'Gene', (102, 105))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (40, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))
756857	17309796	Polymerase chain reaction (PCR) and direct sequencing analysis were performed on the four tumors with nuclear beta-catenin expression.	('beta-catenin', 'Gene', (110, 122))	('beta-catenin', 'Gene', '1499', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('nuclear', 'Var', (102, 109))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))
756880	17309796	Axin gene mutation may have caused the abnormal distribution of beta-catenin.	('caused', 'Reg', (28, 34))	('Axin', 'Gene', (0, 4))	('mutation', 'Var', (10, 18))	('abnormal distribution', 'MPA', (39, 60))	('beta-catenin', 'Gene', (64, 76))	('beta-catenin', 'Gene', '1499', (64, 76))	('Axin', 'Gene', '8312', (0, 4))
756882	17309796	Sequencing analysis of the Axin cDNA revealed a splicing variant (108 bp deletion, position 2302-2409) and a normal cDNA in two of the cases tested.	('Axin', 'Gene', '8312', (27, 31))	('108 bp deletion', 'Var', (66, 81))	('Axin', 'Gene', (27, 31))
756907	17309796	We looked for Axin gene mutations in esophageal squamous cell carcinoma, but found only a splicing variant.	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('Axin', 'Gene', (14, 18))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (37, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('mutations', 'Var', (24, 33))	('Axin', 'Gene', '8312', (14, 18))	('esophageal squamous cell carcinoma', 'Disease', (37, 71))
756968	32024523	While the first two studies explored the association between CDKN2B-AS1 and esophageal cancer by way of genetic mutations, the third did so from the prospective of expression level.	('CDKN2B-AS1', 'Gene', '100048912', (61, 71))	('esophageal cancer', 'Disease', (76, 93))	('association', 'Interaction', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('explored', 'Reg', (28, 36))	('mutations', 'Var', (112, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('CDKN2B-AS1', 'Gene', (61, 71))
756995	32024523	showed that inhibition of MALAT1 can prevent OSCC proliferation whereas its overexpression can promote OSCC.	('OSCC', 'Disease', (103, 107))	('inhibition', 'Var', (12, 22))	('OSCC', 'Disease', 'MESH:D002294', (45, 49))	('prevent', 'NegReg', (37, 44))	('promote', 'PosReg', (95, 102))	('OSCC', 'Disease', 'MESH:D002294', (103, 107))	('MALAT1', 'Gene', '378938', (26, 32))	('OSCC', 'Disease', (45, 49))	('MALAT1', 'Gene', (26, 32))	('overexpression', 'PosReg', (76, 90))
757148	29098164	We found that MISP, KLF10, KLF15, PPP1R18, and RXRbeta proteins could strongly respond to TPA stimulation and activate LCN2 transcriptional expression.	('expression', 'Species', '29278', (140, 150))	('LCN2', 'Gene', '3934', (119, 123))	('activate', 'PosReg', (110, 118))	('TPA', 'Chemical', 'MESH:D013755', (90, 93))	('LCN2', 'Gene', (119, 123))	('transcriptional expression', 'MPA', (124, 150))	('respond to TPA stimulation', 'MPA', (79, 105))	('PPP1R18', 'Var', (34, 41))
757170	29098164	This study aims to further investigate the signal pathways involved in TPA-induced LCN2 gene transcriptional regulation mediated by MISP, KLF10, KLF15, PPP1R18, and RXRbeta.	('PPP1R18', 'Var', (152, 159))	('LCN2', 'Gene', '3934', (83, 87))	('TPA', 'Chemical', 'MESH:D013755', (71, 74))	('LCN2', 'Gene', (83, 87))
757186	29098164	The purpose of the two experiments described above was to validate the effects of MISP, KLF10, KLF15, PPP1R18, and RXRbeta overexpression on LCN2 gene promoter activity.	('expression', 'Species', '29278', (127, 137))	('LCN2', 'Gene', (141, 145))	('PPP1R18', 'Var', (102, 109))	('LCN2', 'Gene', '3934', (141, 145))	('promoter activity', 'MPA', (151, 168))
757188	29098164	At 24 h after transfection with the reporter, cells were pretreated with different kinase inhibitors (U0126, PD98059, SB203580, and SP600125) in a series of doses.	('SP600125', 'Var', (132, 140))	('PD98059', 'Chemical', 'MESH:C093973', (109, 116))	('U0126', 'Var', (102, 107))	('SB203580', 'Var', (118, 126))	('SB203580', 'Chemical', 'MESH:C093642', (118, 126))	('U0126', 'Chemical', 'MESH:C113580', (102, 107))	('PD98059', 'Var', (109, 116))	('SP600125', 'Chemical', 'MESH:C432165', (132, 140))
757202	29098164	These results indicate that nucleoproteins MISP, KLF10, KLF15, PPP1R18, and RXRbeta upregulate LCN2 gene expression at the transcription level and that LCN2 could be a target gene of these nucleoproteins.	('upregulate', 'PosReg', (84, 94))	('LCN2', 'Gene', (152, 156))	('LCN2', 'Gene', '3934', (95, 99))	('MISP', 'Var', (43, 47))	('LCN2', 'Gene', (95, 99))	('expression', 'Species', '29278', (105, 115))	('expression', 'MPA', (105, 115))	('LCN2', 'Gene', '3934', (152, 156))
757204	29098164	At 24 h following transfection, cells were first pretreated with the following kinase inhibitors, MEK1/2 inhibitor (U0126 and PD98059), p38 MAPK inhibitor (SB203580), JNK inhibitor (SP600125), or PKCalpha/beta inhibitor (myristoylated protein kinase C peptide inhibitor), and then induced by 5 ng/ml TPA for an additional 24 h, and the activity of the LCN2 promoter was assessed by luciferase reporter assays.	('LCN2', 'Gene', '3934', (352, 356))	('MEK', 'Gene', (98, 101))	('PKC', 'Gene', (196, 199))	('PD98059', 'Var', (126, 133))	('MEK', 'Gene', '5609', (98, 101))	('PKC', 'Gene', '112476', (196, 199))	('U0126', 'Var', (116, 121))	('SP600125', 'Chemical', 'MESH:C432165', (182, 190))	('PD98059', 'Chemical', 'MESH:C093973', (126, 133))	('LCN2', 'Gene', (352, 356))	('TPA', 'Chemical', 'MESH:D013755', (300, 303))	('U0126', 'Chemical', 'MESH:C113580', (116, 121))	('SB203580', 'Chemical', 'MESH:C093642', (156, 164))	('SB203580', 'Var', (156, 164))	('SP600125', 'Var', (182, 190))
757206	29098164	MEK1/2 inhibitor (U0126 and PD98059) and JNK inhibitor (SP600125) significantly inhibited LCN2 reporter gene induction in a dose-dependent manner (P < 0.01).	('LCN2', 'Gene', (90, 94))	('SP600125', 'Var', (56, 64))	('U0126', 'Chemical', 'MESH:C113580', (18, 23))	('MEK', 'Gene', (0, 3))	('PD98059', 'Var', (28, 35))	('MEK', 'Gene', '5609', (0, 3))	('U0126', 'Var', (18, 23))	('SP600125', 'Chemical', 'MESH:C432165', (56, 64))	('PD98059', 'Chemical', 'MESH:C093973', (28, 35))	('LCN2', 'Gene', '3934', (90, 94))	('inhibited', 'NegReg', (80, 89))
757207	29098164	MEK inhibitors was more effective than JNK inhibitor, with nearly 90% activity being inhibited by PD98059 at 60 muM.	('activity', 'MPA', (70, 78))	('MEK', 'Gene', (0, 3))	('PD98059', 'Chemical', 'MESH:C093973', (98, 105))	('MEK', 'Gene', '5609', (0, 3))	('PD98059', 'Var', (98, 105))
757211	29098164	Following induction of EC109 cells with TPA, the level of p-ERK1/2, peaked at 12 h and then decreased by 24 h, but not ERK1/2, p-JNK, and p-38.	('decreased', 'NegReg', (92, 101))	('TPA', 'Chemical', 'MESH:D013755', (40, 43))	('EC109', 'CellLine', 'CVCL:6898', (23, 28))	('p-ERK1/2', 'Var', (58, 66))
757216	29098164	Our previous study showed that mRNA levels of MISP, KLF10, KLF15, PPP1R18, and RXRbeta could be induced by TPA, indicating they could be TPA-responsive element- (TRE-) binding proteins.	('mRNA levels', 'MPA', (31, 42))	('KLF15', 'Gene', (59, 64))	('TPA', 'Chemical', 'MESH:D013755', (137, 140))	('TPA', 'Chemical', 'MESH:D013755', (107, 110))	('MISP', 'Gene', (46, 50))	('KLF10', 'Gene', (52, 57))	('PPP1R18', 'Var', (66, 73))	('RXRbeta', 'Gene', (79, 86))
757222	29098164	Our previous study found that TPA could induce immortalization of esophageal epithelial cells (SHEEs) into cancer cells (SHEECs).	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('TPA', 'Var', (30, 33))	('immortalization', 'CPA', (47, 62))	('cancer', 'Disease', (107, 113))	('TPA', 'Chemical', 'MESH:D013755', (30, 33))
757225	29098164	Five nucleoproteins MISP, KLF10, KLF15, PPP1R18, and RXRbeta were identified by oligonucleotide trapping, as the binding factors on the TRE under TPA stimulation, and were expressed at varying expression levels in esophageal cancer.	('PPP1R18', 'Var', (40, 47))	('oligonucleotide', 'Chemical', 'MESH:D009841', (80, 95))	('esophageal cancer', 'Disease', (214, 231))	('TPA', 'Chemical', 'MESH:D013755', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('expression', 'Species', '29278', (193, 203))	('esophageal cancer', 'Disease', 'MESH:D004938', (214, 231))	('binding', 'Interaction', (113, 120))
757234	29098164	found TPA-induced invasion and migration of HepG2 cells through a protein kinase C/extracellular signal-regulated kinase (PKC/ERK) pathway.	('TPA-induced', 'Var', (6, 17))	('PKC', 'Gene', (122, 125))	('PKC', 'Gene', '112476', (122, 125))	('migration', 'CPA', (31, 40))	('TPA', 'Chemical', 'MESH:D013755', (6, 9))	('HepG2', 'CellLine', 'CVCL:0027', (44, 49))	('ERK', 'Gene', '5594', (126, 129))	('invasion', 'CPA', (18, 26))	('ERK', 'Gene', (126, 129))
757236	29098164	Under these conditions, MEK activation and ERK phosphorylation led to the upregulation of downstream genes that bind to the LCN2 promoter following addition of TPA, although PKCalpha/PKCbeta inhibition did not affect TPA-mediated LCN2 induction.	('MEK', 'Gene', (24, 27))	('ERK', 'Gene', '5594', (43, 46))	('LCN2', 'Gene', (124, 128))	('PKC', 'Gene', '112476', (183, 186))	('ERK', 'Gene', (43, 46))	('bind', 'Interaction', (112, 116))	('PKC', 'Gene', '112476', (174, 177))	('PKC', 'Gene', (183, 186))	('TPA', 'Chemical', 'MESH:D013755', (217, 220))	('LCN2', 'Gene', '3934', (230, 234))	('TPA', 'Chemical', 'MESH:D013755', (160, 163))	('PKC', 'Gene', (174, 177))	('downstream genes', 'Gene', (90, 106))	('upregulation', 'PosReg', (74, 86))	('MEK', 'Gene', '5609', (24, 27))	('phosphorylation', 'Var', (47, 62))	('activation', 'PosReg', (28, 38))	('LCN2', 'Gene', '3934', (124, 128))	('LCN2', 'Gene', (230, 234))
757255	29124024	Although the need for 3FLND has been well established, 3FLND is technically demanding and is thus associated with complications such as recurrent nerve palsy and anastomosis leakage.	('anastomosis leakage', 'Disease', (162, 181))	('nerve palsy', 'Disease', 'MESH:D010243', (146, 157))	('3FLND', 'Var', (55, 60))	('nerve palsy', 'Disease', (146, 157))	('anastomosis leakage', 'Disease', 'MESH:D003763', (162, 181))
757291	29124024	Univariate analysis revealed that CLNM was a significant predictor of overall survival in patients who received 3FLND, along with pT >=3 or pN3 disease and ECOG stage >=2 (data not shown).	('pN3', 'Gene', (140, 143))	('overall survival', 'MPA', (70, 86))	('CLNM', 'Phenotype', 'HP:0025289', (34, 38))	('CLNM', 'Var', (34, 38))	('CLNM', 'Chemical', '-', (34, 38))	('3FLND', 'Var', (112, 117))	('patients', 'Species', '9606', (90, 98))	('pN3', 'Gene', '6336', (140, 143))
757295	29124024	The odds ratio of recurrent nerve palsy was highest (odds ratio [OR], 6.882; p=0.001) for level VI dissection.	('level VI dissection', 'Var', (90, 109))	('nerve palsy', 'Disease', (28, 39))	('nerve palsy', 'Disease', 'MESH:D010243', (28, 39))
757302	29124024	Advocates of 3FLND assert that 3FLND enables more accurate pathologic nodal staging, which is a well-known prognostic survival factor.	('nodal', 'Gene', '4838', (70, 75))	('3FLND', 'Var', (31, 36))	('nodal', 'Gene', (70, 75))
757396	26104943	A remedy for this gap in clinical practice is important since it has been demonstrated that variation in target volume delineation may impact outcome of therapy and can be improved with atlases that serve as teaching aids in GI tract neoplasms.	('GI tract neoplasms', 'Disease', 'MESH:D004067', (225, 243))	('outcome', 'MPA', (142, 149))	('neoplasms', 'Phenotype', 'HP:0002664', (234, 243))	('variation', 'Var', (92, 101))	('GI tract neoplasms', 'Phenotype', 'HP:0007378', (225, 243))	('impact', 'Reg', (135, 141))	('GI tract neoplasms', 'Disease', (225, 243))
757535	25345779	Overall, the median maximum IMRT dose to the cricopharyngeus/upper esophageal sphincter (UES) was 7080 cGy (IQR 6300 - 7336; N=10).	('7080 cGy', 'Var', (98, 106))	('upper esophageal sphincter', 'Disease', (61, 87))	('upper esophageal sphincter', 'Disease', 'MESH:D009122', (61, 87))
757565	25345779	While IMRT is a useful technique to help reduce normal tissue toxicity and still deliver comparable dose to the tumor, dose inhomogeneity can result in "hot spots" within the treatment volume or closely associated surrounding normal structures.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('toxicity', 'Disease', (62, 70))	('tumor', 'Disease', (112, 117))	('result in', 'Reg', (142, 151))	('dose inhomogeneity', 'Var', (119, 137))
757567	25345779	One recent study found that IMRT increased the risk of cervical esophageal stricture, though the significance may be overstated as there was no incidence of stricture and somewhat decreased use of concurrent chemotherapy in the patients who underwent conventional treatment.	('cervical esophageal stricture', 'Disease', (55, 84))	('esophageal stricture', 'Phenotype', 'HP:0002043', (64, 84))	('patients', 'Species', '9606', (228, 236))	('IMRT', 'Var', (28, 32))
757570	25345779	Specifically, patients treated with endoscopic mucosal resection of neoplastic Barrett's esophagus had nonsignificantly increased odds of developing esophageal stricture if patients had greater than or equal to 25 pack-years of smoking (Adjusted OR 3.33, 95% CI 0.929 - 12.1).	('patients', 'Species', '9606', (173, 181))	('neoplastic', 'Var', (68, 78))	('esophageal stricture', 'Disease', (149, 169))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (79, 98))	('esophageal stricture', 'Phenotype', 'HP:0002043', (149, 169))	('patients', 'Species', '9606', (14, 22))
757655	25373317	Preliminary experiments investigating the transfection of Eca-109 cells showed that >98% the cells were found to emit green fluorescence following transfection (Fig.	('emit green fluorescence', 'MPA', (113, 136))	('Eca', 'Chemical', '-', (58, 61))	('transfection', 'Var', (147, 159))
757754	25185706	Studies indicate that approximately 95% of the cases are KIT positive which confers the tumor with proliferative potential as well as the ability to evade apoptotic pathways.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('proliferative potential', 'CPA', (99, 122))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('KIT positive', 'Var', (57, 69))
757772	25148045	Although OS was significantly better in patients with low TRGs (p = 0.001), there were no significant correlations between ALDH-1, Bmi-1, or Nanog with OS.	('Bmi-1', 'Gene', (131, 136))	('better', 'PosReg', (30, 36))	('TRGs', 'MPA', (58, 62))	('patients', 'Species', '9606', (40, 48))	('low', 'Var', (54, 57))	('Nanog', 'Gene', (141, 146))	('ALDH-1', 'Gene', (123, 129))	('OS', 'Chemical', '-', (152, 154))	('OS', 'Chemical', '-', (9, 11))	('Bmi-1', 'Gene', '648', (131, 136))	('ALDH-1', 'Gene', '216', (123, 129))	('Nanog', 'Gene', '79923', (141, 146))
757785	25148045	For example, previous research indicated that adenosine triphosphate-binding cassette superfamily G member 2 (ABCG2) expression was associated with ESCC patient survival and Notch1 expression was associated with greater pathological grade and shorter OS in ESCC patients.	('OS', 'Chemical', '-', (251, 253))	('patients', 'Species', '9606', (262, 270))	('Notch1', 'Gene', '4851', (174, 180))	('adenosine triphosphate-binding cassette superfamily G member 2', 'Gene', '9429', (46, 108))	('ABCG2', 'Gene', (110, 115))	('ABCG2', 'Gene', '9429', (110, 115))	('patient', 'Species', '9606', (153, 160))	('associated', 'Reg', (132, 142))	('patient', 'Species', '9606', (262, 269))	('ESCC', 'Disease', (148, 152))	('expression', 'Var', (117, 127))	('Notch1', 'Gene', (174, 180))
757809	25148045	Figure 2 shows that TRG after treatment was significantly associated with greater expression of ALDH-1 (p = 0.001), Bmi-1 (p = 0.004), and Nanog (p<0.001).	('ALDH-1', 'Gene', '216', (96, 102))	('expression', 'MPA', (82, 92))	('Nanog', 'Gene', '79923', (139, 144))	('TRG', 'Var', (20, 23))	('Nanog', 'Gene', (139, 144))	('Bmi-1', 'Gene', '648', (116, 121))	('Bmi-1', 'Gene', (116, 121))	('ALDH-1', 'Gene', (96, 102))	('greater', 'PosReg', (74, 81))
757813	25148045	However, OS was significantly better in patients TRG 1-3 than in patients with TRG 4-5 (p = 0.001, Figure 3).	('better', 'PosReg', (30, 36))	('patients', 'Species', '9606', (40, 48))	('TRG 1-3', 'Var', (49, 56))	('OS', 'Chemical', '-', (9, 11))	('patients', 'Species', '9606', (65, 73))
757824	25148045	In Chinese patients with ESCC, nuclear expression of ALDH-1 is associated with poor histological differentiation, lymph node metastasis, TNM stage, and poor 5-year OS.	('ALDH-1', 'Gene', (53, 59))	('lymph node metastasis', 'CPA', (114, 135))	('poor histological differentiation', 'CPA', (79, 112))	('TNM', 'Gene', (137, 140))	('associated', 'Reg', (63, 73))	('ALDH-1', 'Gene', '216', (53, 59))	('ESCC', 'Disease', (25, 29))	('nuclear expression', 'Var', (31, 49))	('patients', 'Species', '9606', (11, 19))	('OS', 'Chemical', '-', (164, 166))	('TNM', 'Gene', '10178', (137, 140))
757870	21890822	EPC2-hTERT and derivatives transformed by either SV40 Large T antigen and Ha-RasV12 (T-TeRAS) or EGFR, p53R175H and cyclin D1 (EPC2-T) were described.	('SV40', 'Var', (49, 53))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('EGFR', 'Gene', '1956', (97, 101))	('cyclin D1', 'Gene', '595', (116, 125))	('EGFR', 'Gene', (97, 101))	('EPC2-T', 'CellLine', 'CVCL:4361', (127, 133))	('cyclin D1', 'Gene', (116, 125))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (0, 10))
757871	21890822	EPC2-hTERT derivatives stably expressing short hairpin RNA (shRNA) directed against NOTCH3 (two cell lines Notch3-A and Notch3-B expressing independent shRNA sequences V2LHS_229748 and N3-B, V2LHS_93017, respectively) or a non-silencing control sequence (Open Biosystems) was described previously.	('Notch3', 'Gene', '4854', (120, 126))	('Notch3-B', 'Gene', '4854', (120, 128))	('Notch3', 'Gene', (120, 126))	('Notch3-B', 'Gene', (120, 128))	('N3', 'Chemical', '-', (185, 187))	('Notch3', 'Gene', '4854', (107, 113))	('Notch3', 'Gene', (107, 113))	('V2LHS_229748', 'Var', (168, 180))	('NOTCH3', 'Gene', (84, 90))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (0, 10))	('NOTCH3', 'Gene', '4854', (84, 90))
757873	21890822	Retroviruses expressing ICN1 or DNMAML1 and tetracycline-inducible lentiviruses (Open Biosystems, Huntsville, AL) expressing short hairpin RNA (shRNA) directed against ZEB1 (clones V2THS_116663 and V2THS_116659), ZEB2 (clones V2THS_95420 and V3THS_373827) or a non-silencing control sequence (clone RHS4743) were produced and transduced as described.	('V2THS_116659', 'Var', (198, 210))	('MAML1', 'Gene', '9794', (34, 39))	('ZEB2', 'Gene', (213, 217))	('N1', 'Chemical', 'MESH:C058271', (26, 28))	('ZEB2', 'Gene', '9839', (213, 217))	('ICN', 'Chemical', '-', (24, 27))	('V3THS_373827', 'Var', (242, 254))	('tetracycline', 'Chemical', 'MESH:D013752', (44, 56))	('MAML1', 'Gene', (34, 39))
757874	21890822	Cells transduced with GFP (for DNMAML1) or tdTomato were selected for the brightest level of fluorescence (top 20%) by flow sorting.	('GFP', 'Var', (22, 25))	('MAML1', 'Gene', '9794', (33, 38))	('MAML1', 'Gene', (33, 38))
757875	21890822	Small interfering RNA (siRNA) directed against NOTCH1 (two independent sequences Notch1-A, HSS181550 and Notch1-B, HSS107249), or a non-silencing scramble control sequence (12935-300)(Invitrogen) was transfected transiently using the Lipofectamine  RNAiMAX reagent (Invitrogen) as described previously.	('Notch1', 'Gene', '4851', (105, 111))	('HSS107249', 'Var', (115, 124))	('Notch1-A', 'Gene', (81, 89))	('NOTCH1', 'Gene', '4851', (47, 53))	('HSS181550', 'Var', (91, 100))	('NOTCH1', 'Gene', (47, 53))	('Notch1-A', 'Gene', '4851', (81, 89))	('Lipofectamine', 'Chemical', 'MESH:C086724', (234, 247))	('Notch1', 'Gene', (105, 111))	('Notch1', 'Gene', (81, 87))	('Notch1', 'Gene', '4851', (81, 87))
757911	21890822	Pharmacological inhibition of Notch signaling by GSI induced similar inhibitory effects upon these Notch target genes (data not shown) as observed in the parental EPC2-hTERT cells.	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (163, 173))	('inhibitory', 'NegReg', (69, 79))	('Notch signaling', 'MPA', (30, 45))	('GSI', 'Chemical', '-', (49, 52))	('inhibition', 'Var', (16, 26))
757929	21890822	ZEB1 knockdown prevented TGF-beta from inducing spindle-shaped cells and suppressing CDH1 (E-cadherin) more efficiently than ZEB2 knockdown (Fig.	('CDH1', 'Gene', '999', (85, 89))	('knockdown', 'Var', (5, 14))	('inducing', 'PosReg', (39, 47))	('ZEB2', 'Gene', '9839', (125, 129))	('ZEB2', 'Gene', (125, 129))	('TGF-beta', 'Gene', '7040', (25, 33))	('spindle-shaped cells', 'CPA', (48, 68))	('CDH1', 'Gene', (85, 89))	('prevented', 'NegReg', (15, 24))	('suppressing', 'NegReg', (73, 84))	('TGF-beta', 'Gene', (25, 33))
757930	21890822	However, knockdown of either ZEB1 or ZEB2 had a limited impact upon TGF-beta-induced N-cadherin expression (Fig.	('N-cadherin', 'Gene', (85, 95))	('ZEB2', 'Gene', '9839', (37, 41))	('knockdown', 'Var', (9, 18))	('N-cadherin', 'Gene', '1000', (85, 95))	('ZEB2', 'Gene', (37, 41))	('TGF-beta', 'Gene', '7040', (68, 76))	('TGF-beta', 'Gene', (68, 76))
757932	21890822	Interestingly, there was also a significant RNAi effect upon anchorage independent growth of EPC2-T cells, where knockdown of ZEB1, but not ZEB2 reduced colony formation in soft agar by 35% (supplementary Fig.	('reduced', 'NegReg', (145, 152))	('ZEB2', 'Gene', '9839', (140, 144))	('agar', 'Chemical', 'MESH:D000362', (178, 182))	('ZEB2', 'Gene', (140, 144))	('colony formation in soft agar', 'CPA', (153, 182))	('knockdown', 'Var', (113, 122))	('ZEB1', 'Gene', (126, 130))	('EPC2-T', 'CellLine', 'CVCL:4361', (93, 99))
757935	21890822	To confirm these findings in an independent cell line, we knocked down ZEBs in HCE7 cells.	('knocked down', 'Var', (58, 70))	('ZEBs', 'Gene', (71, 75))	('HCE7', 'CellLine', 'CVCL:5138', (79, 83))	('ZEBs', 'Chemical', '-', (71, 75))
757940	21890822	In addition, knockdown of ZEBs did not affect transcription factors such as SNAI1 and the miR-200 family (supplementary Fig.	('SNAI1', 'Gene', '6615', (76, 81))	('SNAI1', 'Gene', (76, 81))	('miR-200 family', 'Gene', (90, 104))	('knockdown', 'Var', (13, 22))	('ZEBs', 'Chemical', '-', (26, 30))
757941	21890822	S13C and data not shown) Nonetheless, knockdown of both ZEBs suppressed anchorage independent growth and invasion in HCE7 cells (supplementary Fig.	('invasion', 'CPA', (105, 113))	('suppressed', 'NegReg', (61, 71))	('S13C', 'Mutation', 'p.S13C', (0, 4))	('ZEBs', 'Chemical', '-', (56, 60))	('anchorage independent growth', 'CPA', (72, 100))	('knockdown', 'Var', (38, 47))	('HCE7', 'CellLine', 'CVCL:5138', (117, 121))
757943	21890822	In sum, inhibition of Notch-mediated squamous differentiation may divert the esophageal epithelial cell fate towards that of mesenchymal and raise cellular malignant potential in concert with ZEBs.	('ZEBs', 'Chemical', '-', (192, 196))	('raise', 'PosReg', (141, 146))	('divert', 'NegReg', (66, 72))	('cellular malignant potential', 'CPA', (147, 175))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (77, 97))	('Notch-mediated', 'Gene', (22, 36))	('inhibition', 'Var', (8, 18))	('esophageal epithelia', 'Disease', (77, 97))	('esophageal epithelia', 'Disease', 'MESH:D004941', (77, 97))
757946	21890822	NOTCH1 knockdown did not have an immediate impact upon the basal expression of NOTCH3 and ZEBs (Supplementary Fig.	('ZEBs', 'Chemical', '-', (90, 94))	('NOTCH3', 'Gene', (79, 85))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))	('NOTCH3', 'Gene', '4854', (79, 85))
757950	21890822	Corroborating such observations was spontaneous emergence of spindle-shaped cells compatible with EMT in NOTCH3 knockdown cells (Fig.	('NOTCH3', 'Gene', '4854', (105, 111))	('knockdown', 'Var', (112, 121))	('NOTCH3', 'Gene', (105, 111))
757951	21890822	Furthermore, knockdown of NOTCH3 led to downregulation of the miR-200 family (Supplementary Fig.	('NOTCH3', 'Gene', (26, 32))	('NOTCH3', 'Gene', '4854', (26, 32))	('downregulation', 'NegReg', (40, 54))	('miR-200', 'Gene', (62, 69))	('knockdown', 'Var', (13, 22))
757957	21890822	Inhibition of the CSL-dependent canonical Notch activities abrogates the squamous differentiation program, allowing expansion of cells expressing ZEBs with enhanced malignant potential.	('CSL', 'Gene', (18, 21))	('CSL', 'Gene', '3516', (18, 21))	('malignant potential', 'CPA', (165, 184))	('squamous differentiation program', 'CPA', (73, 105))	('expansion', 'PosReg', (116, 125))	('ZEBs', 'Chemical', '-', (146, 150))	('Inhibition', 'Var', (0, 10))	('abrogates', 'NegReg', (59, 68))	('enhanced', 'PosReg', (156, 164))
757971	21890822	ZEBs are induced during malignant transformation of esophageal cells to negate EGFR oncogene-induced senescence in concert with mutant p53.	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('ZEBs', 'Chemical', '-', (0, 4))	('negate', 'NegReg', (72, 78))	('mutant', 'Var', (128, 134))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))
757982	21890822	ZEB1 knockdown had indirect effects upon ZEB2 expression as described previously.	('knockdown', 'Var', (5, 14))	('ZEB2', 'Gene', '9839', (41, 45))	('ZEB2', 'Gene', (41, 45))	('ZEB1', 'Gene', (0, 4))	('expression', 'MPA', (46, 56))
757990	21890822	Inhibition of canonical Notch signaling impaired squamous differentiation in transformed human esophageal cells (Supplementary Fig.	('human', 'Species', '9606', (89, 94))	('impaired', 'NegReg', (40, 48))	('squamous differentiation', 'CPA', (49, 73))	('Inhibition', 'Var', (0, 10))	('canonical Notch signaling', 'Pathway', (14, 39))
757991	21890822	First and foremost, Notch inhibition resulted in upregulation of ZEBs and enhancement of malignant potentials implicated by EMT, invasion, anchorage-independent growth and tumor formation (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('anchorage-independent growth', 'CPA', (139, 167))	('Notch', 'Gene', (20, 25))	('ZEBs', 'CPA', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('EMT', 'CPA', (124, 127))	('invasion', 'CPA', (129, 137))	('inhibition', 'Var', (26, 36))	('ZEBs', 'Chemical', '-', (65, 69))	('enhancement', 'PosReg', (74, 85))	('malignant potentials implicated', 'CPA', (89, 120))	('upregulation', 'PosReg', (49, 61))
757994	21890822	However, knockdown of NOTCH3 also induced ZEBs and EMT (Fig.	('EMT', 'CPA', (51, 54))	('NOTCH3', 'Gene', '4854', (22, 28))	('ZEBs', 'CPA', (42, 46))	('knockdown', 'Var', (9, 18))	('ZEBs', 'Chemical', '-', (42, 46))	('induced', 'Reg', (34, 41))	('NOTCH3', 'Gene', (22, 28))
758011	21890822	In turn, acquisition of mesenchymal traits as observed in HCE7 cells may require inactivation of NOTCH3.	('inactivation', 'Var', (81, 93))	('NOTCH3', 'Gene', '4854', (97, 103))	('mesenchymal traits', 'CPA', (24, 42))	('HCE7', 'CellLine', 'CVCL:5138', (58, 62))	('NOTCH3', 'Gene', (97, 103))
758073	31579422	TargetScan target gene prediction software identified the 617-624 site at the 3'-end of the 3'-UTR of E2F5 mRNA as a possible site of action of miR-544.	('miR-544', 'Gene', '664613', (144, 151))	('E2F5', 'Gene', (102, 106))	('E2F5', 'Gene', '1875', (102, 106))	('miR-544', 'Gene', (144, 151))	('617-624', 'Var', (58, 65))
758074	31579422	Wild-type (wt) and mutated (mut) putative miR-544-binding sites in E2F5 3'-untranslated region (UTR) were cloned into the downstream region of the luciferase gene in the pGL3-REPORT luciferase vector (Invitrogen; Thermo Fisher Scientific, Inc.).	('E2F5', 'Gene', '1875', (67, 71))	('miR-544', 'Gene', '664613', (42, 49))	('miR-544', 'Gene', (42, 49))	('pGL3', 'Gene', (170, 174))	('mutated', 'Var', (19, 26))	('pGL3', 'Gene', '6391', (170, 174))	('E2F5', 'Gene', (67, 71))
758094	31579422	The results of luciferase assay demonstrated that miR-544 mimics decreased the luciferase activity of wtE2F5 compared with the miR-NC (P<0.05; Fig.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('activity', 'MPA', (90, 98))	('decreased', 'NegReg', (65, 74))	('miR', 'Gene', '220972', (127, 130))	('E2F5', 'Gene', (104, 108))	('miR', 'Gene', (127, 130))	('mimics', 'Var', (58, 64))	('miR-544', 'Gene', '664613', (50, 57))	('E2F5', 'Gene', '1875', (104, 108))	('luciferase', 'Enzyme', (79, 89))	('miR-544', 'Gene', (50, 57))
758106	31579422	The results of flow cytometry demonstrated that the miR-544 mimics significantly increased the apoptotic rate of KYSE450 and TE-1 cells compared with the miR-NC-transfected cells, which was further enhanced by cisplatin (P<0.05; Fig.	('miR', 'Gene', '220972', (154, 157))	('miR', 'Gene', (154, 157))	('mimics', 'Var', (60, 66))	('miR-544', 'Gene', '664613', (52, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (210, 219))	('miR', 'Gene', '220972', (52, 55))	('miR-544', 'Gene', (52, 59))	('enhanced', 'PosReg', (198, 206))	('increased', 'PosReg', (81, 90))	('miR', 'Gene', (52, 55))	('apoptotic rate', 'CPA', (95, 109))
758137	31083325	The overexpression of Grb7 or the coamplification/cooverexpression of Grb7 and members of the ERBB family play essential roles in advanced human cancers and are associated with decreased survival and recurrence of cancers, emphasizing Grb7's value as a prognostic marker and a therapeutic target.	('cancers', 'Disease', (145, 152))	('overexpression', 'PosReg', (4, 18))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('coamplification/cooverexpression', 'Var', (34, 66))	('Grb7', 'Gene', (70, 74))	('human', 'Species', '9606', (139, 144))	('decreased', 'NegReg', (177, 186))	('survival', 'CPA', (187, 195))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('Grb7', 'Protein', (22, 26))	('recurrence', 'CPA', (200, 210))
758145	31083325	Moreover, an increased protein expression level of Grb7 is highly correlated with ERBB2 gene amplification and ERBB2 oncoprotein expression in invasive cancers.	('amplification', 'Var', (93, 106))	('ERBB2', 'Gene', '2064', (82, 87))	('Grb7', 'Protein', (51, 55))	('ERBB2', 'Gene', (82, 87))	('invasive cancers', 'Disease', (143, 159))	('gene amplification', 'Var', (88, 106))	('protein expression level', 'MPA', (23, 47))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('ERBB2', 'Gene', (111, 116))	('ERBB2', 'Gene', '2064', (111, 116))	('increased', 'PosReg', (13, 22))	('invasive cancers', 'Disease', 'MESH:D009362', (143, 159))
758160	31083325	The PH domain has been shown to govern cellular signaling events, such as vesicle trafficking or cytoskeletal organization, and the PH domain of Grb7 has been demonstrated to have protein and/or lipid binding abilities and regulate various cellular functions.	('govern', 'Reg', (32, 38))	('lipid', 'Chemical', 'MESH:D008055', (195, 200))	('lipid', 'MPA', (195, 200))	('PH domain', 'Var', (132, 141))	('protein', 'Protein', (180, 187))	('Grb7', 'Gene', (145, 149))	('regulate', 'Reg', (223, 231))	('vesicle trafficking', 'MPA', (74, 93))	('cellular functions', 'CPA', (240, 258))
758163	31083325	By analyzing protein-protein interactions, deletion of an amphiphilic basic amino acid sequence that is located in the proximal region of the PH domain of Grb7 ablates the calmodulin-binding ability of Grb7.	('ablates', 'NegReg', (160, 167))	('deletion', 'Var', (43, 51))	('basic amino acid', 'Chemical', 'MESH:D024361', (70, 86))	('calmodulin', 'Gene', (172, 182))	('Grb7', 'Gene', (155, 159))	('calmodulin', 'Gene', '801', (172, 182))
758181	31083325	Consistently, EphB1 receptor tyrosine kinase binds to Grb7 and phosphorylates the tyrosine residue of Grb7, which is strongly correlated with EphB1-mediated cell migration.	('Grb7', 'Gene', (102, 106))	('EphB1', 'Gene', '2047', (14, 19))	('binds', 'Interaction', (45, 50))	('EphB1', 'Gene', (14, 19))	('correlated with', 'Reg', (126, 141))	('EphB1', 'Gene', '2047', (142, 147))	('tyrosine', 'Chemical', 'MESH:D014443', (29, 37))	('EphB1', 'Gene', (142, 147))	('tyrosine', 'Chemical', 'MESH:D014443', (82, 90))	('Grb7', 'Protein', (54, 58))	('tyrosine', 'Var', (82, 90))
758183	31083325	Similarly, a specific tyrosine residue (Tyr-1100) of Tek receptor tyrosine kinase functions as a functional docking site for binding to Grb7, whereas the mutated Tyr-1100 of Tek abolishes the Grb7-binding ability and tyrosine phosphorylation of Grb7 by Tek.	('Tek', 'Gene', (174, 177))	('binding', 'Interaction', (125, 132))	('Grb7', 'Protein', (136, 140))	('Grb7-binding', 'Protein', (192, 204))	('Tek', 'Gene', (253, 256))	('Tek', 'Gene', '7010', (174, 177))	('Tyr', 'Chemical', 'MESH:D014443', (162, 165))	('mutated Tyr-1100', 'Var', (154, 170))	('Tyr-1100', 'Var', (162, 170))	('tyrosine', 'Chemical', 'MESH:D014443', (22, 30))	('Grb7', 'Protein', (245, 249))	('Tek', 'Gene', '7010', (253, 256))	('Tek', 'Gene', (53, 56))	('tyrosine phosphorylation', 'MPA', (217, 241))	('Tyr', 'Chemical', 'MESH:D014443', (40, 43))	('abolishes', 'NegReg', (178, 187))	('Tek', 'Gene', '7010', (53, 56))	('Tyr-1100', 'Var', (40, 48))	('tyrosine', 'Chemical', 'MESH:D014443', (66, 74))	('tyrosine', 'Chemical', 'MESH:D014443', (217, 225))
758187	31083325	The binding of Grb7 to the autophosphorylation site, Tyr-397, of FAK results in integrin-mediated cell migration, whereas overexpression of the SH2 domain of Grb7 ablates cell migration towards fibronectin.	('results in', 'Reg', (69, 79))	('ablates', 'NegReg', (163, 170))	('binding', 'Interaction', (4, 11))	('cell migration towards fibronectin', 'CPA', (171, 205))	('Tyr-397', 'Var', (53, 60))	('Grb7', 'Protein', (15, 19))	('Tyr', 'Chemical', 'MESH:D014443', (53, 56))	('integrin-mediated cell migration', 'CPA', (80, 112))	('FAK', 'Gene', (65, 68))
758188	31083325	Additionally, FAK kinase activity but not the Src family kinases (non-receptor tyrosine kinases) are capable of tyrosine phosphorylation of Grb7 that subsequently leads to FAK-mediated cell migration.	('tyrosine phosphorylation', 'MPA', (112, 136))	('FAK-mediated cell migration', 'CPA', (172, 199))	('tyrosine', 'Chemical', 'MESH:D014443', (79, 87))	('Grb7', 'Protein', (140, 144))	('FAK', 'Var', (14, 17))	('leads to', 'Reg', (163, 171))	('tyrosine', 'Chemical', 'MESH:D014443', (112, 120))	('Src', 'Gene', '2534;6714', (46, 49))	('Src', 'Gene', (46, 49))
758189	31083325	Consistently, our studies indicated that FAK enables phosphorylation of Grb7 on at least two tyrosine residues, Tyr-188 and Tyr-338, upon formation of a complex with FAK.	('Tyr', 'Chemical', 'MESH:D014443', (124, 127))	('Tyr-188', 'Var', (112, 119))	('tyrosine', 'Chemical', 'MESH:D014443', (93, 101))	('Grb7', 'Protein', (72, 76))	('Tyr', 'Chemical', 'MESH:D014443', (112, 115))	('Tyr-338', 'Var', (124, 131))	('complex', 'Interaction', (153, 160))	('phosphorylation', 'MPA', (53, 68))
758192	31083325	In contrast, tyrosine phosphorylation-deficient mutants of Grb7 ablate integrin-dependent cell migration and proliferation.	('ablate', 'NegReg', (64, 70))	('tyrosine phosphorylation-deficient mutants', 'Var', (13, 55))	('tyrosine', 'Chemical', 'MESH:D014443', (13, 21))	('Grb7', 'Gene', (59, 63))
758196	31083325	Interestingly, our recent study provided a negative regulatory mechanism for Grb7 via JNK-mediated phosphorylation of Grb7, in which the phospho-Ser194-Pro motif of Grb7 required for binding to peptidyl-prolyl cis/trans isomerase Pin1 facilitates the proteasome-mediated degradation of Grb7 protein.	('JNK', 'Gene', '5599', (86, 89))	('Pin1', 'Gene', (230, 234))	('Grb7', 'Gene', (165, 169))	('binding', 'Interaction', (183, 190))	('Ser194-Pro', 'SUBSTITUTION', 'None', (145, 155))	('Ser194-Pro', 'Var', (145, 155))	('JNK', 'Gene', (86, 89))	('facilitates', 'PosReg', (235, 246))	('Pin1', 'Gene', '5300', (230, 234))	('proteasome-mediated degradation', 'MPA', (251, 282))	('Grb7 protein', 'Protein', (286, 298))
758198	31083325	Although the PH domain of Grb7 is not necessary for the recruitment of Grb7 to focal contacts, the interaction between the PH domain of Grb7 and phospholipids may recruit Grb7 to the plasma membrane.	('Grb7', 'Gene', (136, 140))	('recruit', 'PosReg', (163, 170))	('phospholipids', 'Chemical', 'MESH:D010743', (145, 158))	('Grb7', 'MPA', (171, 175))	('PH domain', 'Var', (123, 132))	('interaction', 'Interaction', (99, 110))
758203	31083325	Consistently, the deletion of the calmodulin-binding domain of Grb7 ablates its nuclear localization.	('Grb7', 'Gene', (63, 67))	('ablates', 'NegReg', (68, 75))	('calmodulin', 'Gene', (34, 44))	('nuclear localization', 'MPA', (80, 100))	('calmodulin', 'Gene', '801', (34, 44))	('deletion', 'Var', (18, 26))
758205	31083325	By size-exclusion chromatography, a single point mutation of Grb7 converting phenylalanine 511 to an arginine, F511R, results in a monomeric status of the SH2 domain of Grb7.	('Grb7', 'Gene', (61, 65))	('F511R', 'Mutation', 'p.F511R', (111, 116))	('results in', 'Reg', (118, 128))	('Grb7', 'Protein', (169, 173))	('phenylalanine 511 to an arginine', 'Mutation', 'p.F511R', (77, 109))	('SH2 domain', 'MPA', (155, 165))	('F511R', 'Var', (111, 116))	('monomeric status', 'MPA', (131, 147))
758206	31083325	Functionally, a dimerization-defective mutant F511R of Grb7 fails to regulate Ras activity and ERK1/2 phosphorylation, suggesting a critical functional effect of the structural status of Grb7 on Grb7-mediated signaling and function.	('Ras', 'CPA', (78, 81))	('dimerization-defective', 'Reg', (16, 38))	('Grb7', 'Gene', (55, 59))	('ERK1/2', 'Gene', (95, 101))	('F511R', 'Var', (46, 51))	('fails', 'NegReg', (60, 65))	('ERK1/2', 'Gene', '5595;5594', (95, 101))	('F511R', 'Mutation', 'p.F511R', (46, 51))
758211	31083325	In contrast, knockdown of GRB7 expression decreases the expression of the anti-apoptotic B-cell lymphoma-2 (BCL-2) and increases the expression of the pro-apoptotic BCL2-associated X, leading to a significant increase in apoptosis.	('expression', 'MPA', (133, 143))	('increases', 'PosReg', (119, 128))	('BCL2', 'Gene', (165, 169))	('decreases', 'NegReg', (42, 51))	('B-cell lymphoma-2', 'Gene', (89, 106))	('B-cell lymphoma-2', 'Gene', '596', (89, 106))	('BCL-2', 'Gene', '596', (108, 113))	('expression', 'MPA', (56, 66))	('GRB7', 'Gene', '2886', (26, 30))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (89, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (96, 104))	('GRB7', 'Gene', (26, 30))	('apoptosis', 'CPA', (221, 230))	('BCL-2', 'Gene', (108, 113))	('knockdown', 'Var', (13, 22))	('BCL2', 'Gene', '596', (165, 169))	('increase', 'PosReg', (209, 217))
758219	31083325	Moreover, the RNA interference (RNAi)-mediated gene silencing of Grb7 together with lapatinib, a dual tyrosine kinase inhibitor that blocks EGFR and ERBB2 signals, contributes to the inhibition of protein kinase B (PKB, also known as AKT) activity and decreased cell viability.	('AKT', 'Gene', (234, 237))	('inhibition', 'NegReg', (183, 193))	('cell viability', 'CPA', (262, 276))	('protein kinase B', 'Gene', (197, 213))	('EGFR', 'Gene', (140, 144))	('Grb7', 'Gene', (65, 69))	('ERBB2', 'Gene', (149, 154))	('decreased', 'NegReg', (252, 261))	('activity', 'MPA', (239, 247))	('protein kinase B', 'Gene', '2185', (197, 213))	('lapatinib', 'Chemical', 'MESH:D000077341', (84, 93))	('AKT', 'Gene', '207', (234, 237))	('PKB', 'Gene', '2185', (215, 218))	('tyrosine', 'Chemical', 'MESH:D014443', (102, 110))	('PKB', 'Gene', (215, 218))	('gene', 'Var', (47, 51))	('EGFR', 'Gene', '1956', (140, 144))	('ERBB2', 'Gene', '2064', (149, 154))
758220	31083325	Moreover, cosilencing of ERBB2 co-amplified genes, including ERBB2 and GRB7, results in increased apoptosis in cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('GRB7', 'Gene', (71, 75))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('apoptosis', 'CPA', (98, 107))	('ERBB2', 'Gene', (61, 66))	('cancers', 'Disease', (111, 118))	('ERBB2', 'Gene', '2064', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('increased', 'PosReg', (88, 97))	('ERBB2', 'Gene', '2064', (25, 30))	('cosilencing', 'Var', (10, 21))	('GRB7', 'Gene', '2886', (71, 75))	('ERBB2', 'Gene', (25, 30))
758223	31083325	Indeed, short hairpin RNA-mediated knockdown of GRB7 expression reduces cancer proliferation and anchorage-independent growth in ERBB2/Grb7-overexpressing breast cancers.	('ERBB2', 'Gene', (129, 134))	('knockdown', 'Var', (35, 44))	('ERBB2', 'Gene', '2064', (129, 134))	('GRB7', 'Gene', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('GRB7', 'Gene', '2886', (48, 52))	('cancer', 'Disease', (162, 168))	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('breast cancers', 'Disease', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('reduces', 'NegReg', (64, 71))	('anchorage-independent growth', 'CPA', (97, 125))	('cancer', 'Disease', (72, 78))
758225	31083325	On the other hand, knockdown of GRB7 expression has been indicated to attenuate ERBB2 and AKT phosphorylation in breast cancer cells, affecting ERBB2-mediated cancer growth in vivo.	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('affecting', 'Reg', (134, 143))	('breast cancer', 'Disease', (113, 126))	('cancer', 'Disease', (120, 126))	('attenuate', 'NegReg', (70, 79))	('ERBB2', 'Gene', (144, 149))	('ERBB2', 'Gene', (80, 85))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('knockdown', 'Var', (19, 28))	('ERBB2', 'Gene', '2064', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ERBB2', 'Gene', '2064', (80, 85))	('AKT', 'Gene', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('GRB7', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('GRB7', 'Gene', '2886', (32, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('AKT', 'Gene', '207', (90, 93))
758226	31083325	Notably, targeted knockdown of genes in the ERBB2 amplicon, including GRB7, leads to an additive effect on the decreased cell-cycle progression and cancer proliferation, emphasizing the importance of GRB7 coamplified with ERBB2 in their contribution to cancer proliferation.	('cancer', 'Disease', (148, 154))	('knockdown', 'Var', (18, 27))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('ERBB2', 'Gene', (222, 227))	('ERBB2', 'Gene', '2064', (44, 49))	('GRB7', 'Gene', '2886', (70, 74))	('GRB7', 'Gene', (70, 74))	('decreased', 'NegReg', (111, 120))	('ERBB2', 'Gene', (44, 49))	('GRB7', 'Gene', '2886', (200, 204))	('GRB7', 'Gene', (200, 204))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (253, 259))	('cell-cycle progression', 'CPA', (121, 143))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('ERBB2', 'Gene', '2064', (222, 227))
758229	31083325	Additionally, the specific Grb7 peptide targeting the SH2 domain of Grb7 efficiently reduces the formation of the Grb7 and ERBB family complex and leads to the attenuation of 3D culture colony formation, which reflects a combination of anti-proliferative and/or pro-apoptotic effects on cancer cells.	('attenuation', 'NegReg', (160, 171))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('ERBB family complex', 'Protein', (123, 142))	('formation', 'MPA', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('Grb7', 'Protein', (114, 118))	('reduces', 'NegReg', (85, 92))	('SH2 domain', 'Var', (54, 64))	('3D culture colony formation', 'CPA', (175, 202))	('Grb7', 'Gene', (68, 72))
758232	31083325	Of note, tyrosine phosphorylation-deficient mutants of Grb7 have been shown to regulate the phosphorylation of AKT, ERK1/2, and paxillin, and subsequently ablate cancer proliferation and anchorage-independent growth.	('AKT', 'Gene', '207', (111, 114))	('ablate', 'NegReg', (155, 161))	('ERK1/2', 'Gene', '5595;5594', (116, 122))	('phosphorylation', 'MPA', (92, 107))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('tyrosine', 'Chemical', 'MESH:D014443', (9, 17))	('Grb7', 'Gene', (55, 59))	('paxillin', 'Protein', (128, 136))	('regulate', 'Reg', (79, 87))	('AKT', 'Gene', (111, 114))	('tyrosine phosphorylation-deficient mutants', 'Var', (9, 51))	('mutants', 'Var', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('ERK1/2', 'Gene', (116, 122))	('anchorage-independent growth', 'CPA', (187, 215))
758235	31083325	Indeed, it has been shown that high Grb7 expressing cancer cells exhibit a higher migratory ability than low Grb7 expressing cells.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('migratory ability', 'CPA', (82, 99))	('higher', 'PosReg', (75, 81))	('Grb7', 'Protein', (36, 40))	('cancer', 'Disease', (52, 58))	('high', 'Var', (31, 35))
758236	31083325	Moreover, tyrosine phosphorylation of Grb7 has also been shown to regulate cancer migration.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('Grb7', 'Protein', (38, 42))	('tyrosine phosphorylation', 'Var', (10, 34))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('regulate', 'Reg', (66, 74))	('tyrosine', 'Chemical', 'MESH:D014443', (10, 18))
758238	31083325	Consistently, knockdown or inhibition of Grb7 expression or the specific kinase activity of Grb7-mediated downstream signals abrogates Grb7-mediated cancer migration.	('abrogates', 'NegReg', (125, 134))	('Grb7', 'Protein', (41, 45))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('Grb7-mediated', 'Protein', (135, 148))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('knockdown', 'Var', (14, 23))	('inhibition', 'NegReg', (27, 37))
758241	31083325	As expected, short hairpin RNA-mediated knockdown of GRB7 expression reduces gap closure migration of cancers in response to the EGF treatment.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('EGF', 'Gene', (129, 132))	('knockdown', 'Var', (40, 49))	('reduces', 'NegReg', (69, 76))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('GRB7', 'Gene', '2886', (53, 57))	('EGF', 'Gene', '1950', (129, 132))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('GRB7', 'Gene', (53, 57))	('cancers', 'Disease', (102, 109))
758244	31083325	In ERBB2 positive cancer cells, knockdown of Grb7 has been found to decrease integrin-mediated RAC1 activation as well as integrin-mediated cell movement.	('decrease', 'NegReg', (68, 76))	('Grb7', 'Gene', (45, 49))	('knockdown', 'Var', (32, 41))	('integrin-mediated cell movement', 'CPA', (122, 153))	('ERBB2', 'Gene', '2064', (3, 8))	('RAC1', 'Gene', '5879', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('ERBB2', 'Gene', (3, 8))	('RAC1', 'Gene', (95, 99))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
758248	31083325	The coexpression of Grb7 with the ERBB family, especially EGFR and ERBB2, is significantly correlated with the invasion of advanced esophageal carcinomas.	('esophageal carcinomas', 'Disease', 'MESH:D004938', (132, 153))	('ERBB2', 'Gene', '2064', (67, 72))	('EGFR', 'Gene', '1956', (58, 62))	('Grb7', 'Protein', (20, 24))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('ERBB2', 'Gene', (67, 72))	('EGFR', 'Gene', (58, 62))	('esophageal carcinomas', 'Disease', (132, 153))	('coexpression', 'Var', (4, 16))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (132, 153))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (132, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('correlated with', 'Reg', (91, 106))
758250	31083325	Due to the identification of metastasis-acquired ERBB2 alterations in patients with breast cancer brain metastases, Grb7 has been recently indicated as one of the most recurrently upregulated genes in cancers.	('patients', 'Species', '9606', (70, 78))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('alterations', 'Var', (55, 66))	('breast cancer brain metastases', 'Disease', (84, 114))	('cancers', 'Disease', (201, 208))	('breast cancer brain metastases', 'Disease', 'MESH:D009362', (84, 114))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('ERBB2', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ERBB2', 'Gene', '2064', (49, 54))
758252	31083325	In addition, specific Grb7 peptides targeting the SH2 domain of Grb7, which blocks EGF/EGFR signal-mediated ERK activation, or knockdown of GRB7, which ablates MMP-9 expression, attenuate cancer invasion.	('ablates', 'NegReg', (152, 159))	('EGFR', 'Gene', '1956', (87, 91))	('ERK', 'Gene', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('blocks', 'NegReg', (76, 82))	('EGF', 'Gene', (87, 90))	('GRB7', 'Gene', (140, 144))	('EGF', 'Gene', '1950', (83, 86))	('GRB7', 'Gene', '2886', (140, 144))	('Grb7', 'Gene', (64, 68))	('attenuate', 'NegReg', (178, 187))	('EGFR', 'Gene', (87, 91))	('cancer', 'Disease', (188, 194))	('EGF', 'Gene', (83, 86))	('expression', 'MPA', (166, 176))	('ERK', 'Gene', '5594', (108, 111))	('EGF', 'Gene', '1950', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('peptides', 'Chemical', 'MESH:D010455', (27, 35))	('MMP-9', 'Gene', '4318', (160, 165))	('knockdown', 'Var', (127, 136))	('MMP-9', 'Gene', (160, 165))
758254	31083325	Consistently, inhibition of the specific kinase activity of Grb7-mediated downstream signals significantly reduces Grb7-mediated cancer invasion.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Grb7-mediated', 'Protein', (115, 128))	('cancer', 'Disease', (129, 135))	('Grb7-mediated', 'Protein', (60, 73))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('specific kinase activity', 'MPA', (32, 56))	('reduces', 'NegReg', (107, 114))	('inhibition', 'Var', (14, 24))
758258	31083325	Cooverexpression or coamplification of Grb7 and the ERBB family has been clinically investigated in human breast cancers, cervical cancers, invasive Barrett's carcinoma, advanced esophageal carcinoma, and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cervical cancers', 'Disease', (122, 138))	('cervical cancers', 'Disease', 'MESH:D002583', (122, 138))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	("invasive Barrett's carcinoma", 'Disease', (140, 168))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancers', 'Disease', 'MESH:D001943', (106, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('breast cancers', 'Disease', (106, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('coamplification', 'Var', (20, 35))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (179, 199))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('Grb7', 'Protein', (39, 43))	('investigated', 'Reg', (84, 96))	('breast cancers', 'Phenotype', 'HP:0003002', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('esophageal carcinoma', 'Disease', (179, 199))	('gastric cancers', 'Disease', (205, 220))	('gastric cancers', 'Phenotype', 'HP:0012126', (205, 220))	('gastric cancers', 'Disease', 'MESH:D013274', (205, 220))	("invasive Barrett's carcinoma", 'Disease', 'MESH:D001471', (140, 168))	('human', 'Species', '9606', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (179, 199))
758267	31083325	Actually, the coexpression of Grb7 with EGFR was significantly related to advanced esophageal carcinomas with extramucosal invasion, whereas this phenomenon was not induced by the sole expression of Grb7 or EGFR.	('Grb7', 'Protein', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('esophageal carcinomas', 'Disease', (83, 104))	('EGFR', 'Gene', '1956', (207, 211))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (83, 104))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', (207, 211))	('coexpression', 'Var', (14, 26))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (83, 104))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('related', 'Reg', (63, 70))
758270	31083325	Moreover, the elevated protein expression of Grb7 is strongly correlated with ERBB2 gene amplification as well as ERBB2 overexpression in invasive breast cancer.	('ERBB2', 'Gene', '2064', (78, 83))	('ERBB2', 'Gene', (114, 119))	('Grb7', 'Protein', (45, 49))	('ERBB2', 'Gene', (78, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('overexpression', 'PosReg', (120, 134))	('invasive breast cancer', 'Disease', (138, 160))	('gene amplification', 'Var', (84, 102))	('invasive breast cancer', 'Disease', 'MESH:D001943', (138, 160))	('protein expression', 'MPA', (23, 41))	('amplification', 'Var', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ERBB2', 'Gene', '2064', (114, 119))	('elevated', 'PosReg', (14, 22))	('correlated', 'Reg', (62, 72))
758271	31083325	Cooverexpression of Grb7 and ERBB2 are strongly associated with a worse prognosis than that of ERBB2 overexpression alone, suggesting the clinical significance of both Grb7 and ERBB2 genes/proteins expression in cancer development.	('ERBB2', 'Gene', (29, 34))	('ERBB2', 'Gene', (177, 182))	('Grb7', 'Protein', (20, 24))	('ERBB2', 'Gene', '2064', (177, 182))	('ERBB2', 'Gene', '2064', (95, 100))	('ERBB2', 'Gene', (95, 100))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('Cooverexpression', 'Var', (0, 16))	('ERBB2', 'Gene', '2064', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
758273	31083325	Of note, our study indicates that the anti-cancer effect is synergized by cotreatment with Herceptin, an ERBB2-targeted monoclonal antibody, plus Grb7 knockdown in ERBB2+ breast cancers, reflecting the tight correlation between Grb7 and ERBB2 in cancer progression and treatment.	('breast cancers', 'Disease', (171, 185))	('ERBB2', 'Gene', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Grb7', 'Gene', (146, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (171, 185))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('ERBB2', 'Gene', '2064', (105, 110))	('cancer', 'Disease', (246, 252))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('ERBB2', 'Gene', (237, 242))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('Herceptin', 'Chemical', 'MESH:D000068878', (91, 100))	('knockdown', 'Var', (151, 160))	('ERBB2', 'Gene', '2064', (237, 242))	('ERBB2', 'Gene', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (43, 49))	('ERBB2', 'Gene', '2064', (164, 169))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancer', 'Disease', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Herceptin', 'Gene', (91, 100))	('breast cancers', 'Disease', 'MESH:D001943', (171, 185))
758277	31083325	In addition, several studies indicated that the inhibition of Grb7 expression reduced motility/invasion and promoted the apoptosis-mediated cell death of malignant cancers.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('malignant cancers', 'Disease', (154, 171))	('Grb7', 'Protein', (62, 66))	('apoptosis-mediated cell death', 'CPA', (121, 150))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('inhibition', 'Var', (48, 58))	('reduced', 'NegReg', (78, 85))	('promoted', 'PosReg', (108, 116))	('malignant cancers', 'Disease', 'MESH:D009369', (154, 171))	('motility/invasion', 'CPA', (86, 103))
758282	31083325	In triple-negative breast cancer (TNBC) patients treated with standard adjuvant anthracycline and taxane therapy, the five-year recurrence rates were 10.5% and 20.4% in the low and the high GRB7 RNA expression groups, respectively.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('TNBC', 'Disease', (34, 38))	('patients', 'Species', '9606', (40, 48))	('anthracycline', 'Chemical', 'MESH:D018943', (80, 93))	('GRB7', 'Gene', '2886', (190, 194))	('GRB7', 'Gene', (190, 194))	('high', 'Var', (185, 189))	('TNBC', 'Disease', 'None', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('taxane', 'Chemical', 'MESH:C080625', (98, 104))	('breast cancer', 'Disease', (19, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))
758283	31083325	In addition, high GBR7 expression was correlated with resistance to neoadjuvant doxorubicin and taxane therapy.	('high', 'Var', (13, 17))	('resistance to neoadjuvant doxorubicin', 'MPA', (54, 91))	('GBR7', 'Gene', (18, 22))	('doxorubicin', 'Chemical', 'MESH:D004317', (80, 91))	('taxane', 'Chemical', 'MESH:C080625', (96, 102))	('correlated', 'Reg', (38, 48))	('expression', 'MPA', (23, 33))
758287	31083325	In agreement with the importance of the SH2 phosphotyrosine binding site of Grb7 in Grb7-mediated signal transduction cascades and cancer malignancy, the specific Grb7 peptide targeting the SH2 phosphotyrosine binding site of Grb7 efficiently blocks Grb7-mediated signal transduction cascades.	('blocks', 'NegReg', (243, 249))	('peptide', 'Var', (168, 175))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (194, 209))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (44, 59))	('Grb7-mediated signal transduction cascades', 'Pathway', (250, 292))	('cancer malignancy', 'Disease', 'MESH:D009369', (131, 148))	('cancer malignancy', 'Disease', (131, 148))
758290	31083325	By protein structure analysis, a specific amino acid arginine 462 (R642) in Grb7 has been identified as mediating the interaction between the SH2 domain of Grb7 and G7-18NATE.	('R642', 'Var', (67, 71))	('Grb7', 'Protein', (156, 160))	('interaction', 'Interaction', (118, 129))	('amino acid arginine', 'Chemical', '-', (42, 61))	('Grb7', 'Gene', (76, 80))	('mediating', 'Reg', (104, 113))	('G7-18NATE', 'Chemical', 'MESH:C509376', (165, 174))
758291	31083325	In contrast, the Grb7 R462S mutant exhibits a significant decrease in binding affinity for G7-18NATE.	('Grb7', 'Gene', (17, 21))	('binding', 'Interaction', (70, 77))	('R462S', 'Mutation', 'p.R462S', (22, 27))	('decrease', 'NegReg', (58, 66))	('R462S', 'Var', (22, 27))	('G7-18NATE', 'Chemical', 'MESH:C509376', (91, 100))
758292	31083325	G7-18NATE has been found to ablate the interaction between Grb7 and the ERBB family in a dose-dependent manner in breast cancer cells.	('ERBB family', 'Protein', (72, 83))	('Grb7', 'Protein', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ablate', 'NegReg', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('G7-18NATE', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('interaction', 'Interaction', (39, 50))	('G7-18NATE', 'Chemical', 'MESH:C509376', (0, 9))	('breast cancer', 'Disease', (114, 127))
758293	31083325	Of note, G7-18NATE also selectively blocked the interaction between Grb7 and FAK and blocked the tyrosine phosphorylation of Grb7, as well as significantly reducing the migration and peritoneal metastasis of pancreatic cancer in preclinical studies.	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (194, 225))	('tyrosine', 'Chemical', 'MESH:D014443', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (208, 225))	('G7-18NATE', 'Var', (9, 18))	('metastasis of pancreatic cancer', 'Disease', (194, 225))	('FAK', 'Gene', (77, 80))	('blocked', 'NegReg', (36, 43))	('blocked', 'NegReg', (85, 92))	('Grb7', 'Protein', (125, 129))	('interaction', 'Interaction', (48, 59))	('tyrosine phosphorylation', 'MPA', (97, 121))	('G7-18NATE', 'Chemical', 'MESH:C509376', (9, 18))	('reducing', 'NegReg', (156, 164))	('Grb7', 'Protein', (68, 72))
758295	31083325	Based on the crystal structure analysis, several studies improved the affinity of specific peptide inhibitors of Grb7, such as G7-B1 and G7-B4, over G7-18NATE.	('G7-B4', 'Var', (137, 142))	('G7-18NATE', 'Chemical', 'MESH:C509376', (149, 158))	('G7-B1', 'Var', (127, 132))	('Grb7', 'Protein', (113, 117))	('improved', 'PosReg', (57, 65))	('affinity', 'MPA', (70, 78))
758298	31083325	By improvement of the drug delivery system, the conjugation of G7-18NATE to cell-penetrating peptides, such as Penetratin, has exhibited effective cytosolic delivery of G7-18NATE and migration inhibition of breast cancer cells.	('G7-18NATE', 'Chemical', 'MESH:C509376', (63, 72))	('cytosolic delivery', 'MPA', (147, 165))	('G7-18NATE', 'Var', (169, 178))	('G7-18NATE', 'Chemical', 'MESH:C509376', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('peptides', 'Chemical', 'MESH:D010455', (93, 101))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('migration inhibition', 'CPA', (183, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('breast cancer', 'Disease', (207, 220))
758301	31083325	Recently, a study indicated a negative correlation between miR-193a-3p and GRB7 in ovarian cancers.	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('negative', 'NegReg', (30, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('ovarian cancers', 'Phenotype', 'HP:0100615', (83, 98))	('miR-193a-3p', 'Var', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('GRB7', 'Gene', '2886', (75, 79))	('ovarian cancers', 'Disease', (83, 98))	('GRB7', 'Gene', (75, 79))	('ovarian cancers', 'Disease', 'MESH:D010051', (83, 98))
758302	31083325	miR-193a-3p has been shown to directly target the 3' UTR of GRB7, suggesting possible Grb7-targeted therapies by tumor suppressor miRNAs.	('tumor', 'Disease', (113, 118))	('GRB7', 'Gene', '2886', (60, 64))	('miR-193a-3p', 'Var', (0, 11))	('GRB7', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
758304	31083325	The tyrosine phosphorylation of EGFR was ablated in GRB7 knockdown ERBB2+ breast cancer, suggesting the effects of Grb7-mediated EGFR activation on the malignancy of ERBB2+ breast cancer.	('ERBB2', 'Gene', '2064', (67, 72))	('ERBB2', 'Gene', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('EGFR', 'Gene', (129, 133))	('malignancy', 'Disease', (152, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('GRB7', 'Gene', (52, 56))	('tyrosine phosphorylation', 'MPA', (4, 28))	('EGFR', 'Gene', (32, 36))	('ERBB2', 'Gene', '2064', (166, 171))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('tyrosine', 'Chemical', 'MESH:D014443', (4, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('breast cancer', 'Disease', (173, 186))	('GRB7', 'Gene', '2886', (52, 56))	('ablated', 'NegReg', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('knockdown', 'Var', (57, 66))	('EGFR', 'Gene', '1956', (129, 133))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Disease', (74, 87))	('ERBB2', 'Gene', (67, 72))	('EGFR', 'Gene', '1956', (32, 36))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))
758311	31083325	Together, these studies suggest that combination treatment with shRNA or peptides targeting Grb7 and chemotherapy, or targeted therapy improves the efficiency of anti-cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('peptides', 'Chemical', 'MESH:D010455', (73, 81))	('Grb7', 'Protein', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('peptides', 'Var', (73, 81))	('improves', 'PosReg', (135, 143))
758324	27835600	Stable YAP1 silencing inhibited the proliferation, migration, and invasion of BGC-823 GC cells in vitro and inhibited the growth of xenograft tumor and hematogenous metastasis of BGC-823 GC cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('inhibited', 'NegReg', (22, 31))	('migration', 'CPA', (51, 60))	('YAP1', 'Gene', (7, 11))	('xenograft tumor', 'Disease', 'MESH:D009369', (132, 147))	('hematogenous metastasis', 'CPA', (152, 175))	('silencing', 'Var', (12, 21))	('proliferation', 'CPA', (36, 49))	('invasion', 'CPA', (66, 74))	('xenograft tumor', 'Disease', (132, 147))	('inhibited', 'NegReg', (108, 117))
758329	27835600	These results suggest that YAP1 is not a direct factor affecting tumor formation, but could accelerate tumor growth and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('YAP1', 'Var', (27, 31))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('accelerate', 'PosReg', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
758345	27835600	YAP1 expression was associated with Borrman's types (P = 0.041), WHO's histological types (P = 0.016), lymph node metastasis (P < 0.001), distant metastasis (P < 0.001), and TNM staging (P < 0.001), but was not associated with age, gender, Lauren's types, depth of invasion, and P62 expression (all P > 0.05) (Table 1).	('lymph node metastasis', 'CPA', (103, 124))	("Lauren's types", 'Disease', (240, 254))	('associated', 'Reg', (20, 30))	('distant metastasis', 'CPA', (138, 156))	("WHO's histological types", 'CPA', (65, 89))	('P62', 'Gene', '10657', (279, 282))	('YAP1', 'Gene', (0, 4))	('TNM', 'Gene', '10178', (174, 177))	("Borrman's types", 'Disease', (36, 51))	('expression', 'Var', (5, 15))	('TNM', 'Gene', (174, 177))	('P62', 'Gene', (279, 282))
758347	27835600	Kaplan-Meier curves showed that overall survival for patients with high-expression of YAP1 was significantly worse than for those with low expression (P < 0.001) (Figure 1I).	('YAP1', 'Gene', (86, 90))	('worse', 'NegReg', (109, 114))	('high-expression', 'Var', (67, 82))	('patients', 'Species', '9606', (53, 61))
758348	27835600	Overall survival for patients with high-expression of P62 was significantly worse than for those in the low-expression group (P = 0.009) (Figure 1J).	('P62', 'Gene', (54, 57))	('worse', 'NegReg', (76, 81))	('patients', 'Species', '9606', (21, 29))	('P62', 'Gene', '10657', (54, 57))	('Overall survival', 'MPA', (0, 16))	('high-expression', 'Var', (35, 50))
758355	27835600	Meanwhile, cells in the vector GES-1 group (GES-1 cells stably transfected with pEGFP-C3) and YAP1 GES-1 group (GES-1 cells stably transfected with pEGFP-C3-YAP1 overexpression) expressed green fluorescence protein (Figure 2C).	('pEGFP-C3', 'Var', (80, 88))	('pEGFP-C3-YAP1', 'Gene', '10413', (148, 161))	('green fluorescence protein', 'Protein', (188, 214))	('pEGFP-C3-YAP1', 'Gene', (148, 161))
758359	27835600	After 24 h of incubation, knockdown of YAP1 led to a reduction of BGC823 cell migration capacity (Figure 3C and 3I), and YAP1 over-expression promoted cell migration ability of GES-1 cells (Figure 3D and 3J).	('over-expression promoted', 'PosReg', (126, 150))	('BGC823', 'CellLine', 'CVCL:3360', (66, 72))	('reduction', 'NegReg', (53, 62))	('YAP1', 'Gene', (121, 125))	('knockdown', 'Var', (26, 35))	('cell migration ability', 'CPA', (151, 173))	('BGC823', 'Gene', (66, 72))	('YAP1', 'Gene', (39, 43))
758360	27835600	EMT was inhibited, as shown by elevated E-cadherin protein expression and decreased vimentin protein expression in the YAP1 shRNA BGC-823 group compared with the BGC-823 and vector BGC-823 groups (Figure 3M).	('EMT', 'CPA', (0, 3))	('E-cadherin', 'Gene', (40, 50))	('E-cadherin', 'Gene', '999', (40, 50))	('vimentin', 'Gene', '7431', (84, 92))	('vimentin', 'Gene', (84, 92))	('elevated', 'PosReg', (31, 39))	('decreased', 'NegReg', (74, 83))	('YAP1 shRNA', 'Var', (119, 129))
758361	27835600	Compared with the BGC-823 and vector BGC-823 groups, beta-catenin protein expression in the YAP1 shRNA BGC-823 group was significantly down-regulated, while the expression of alpha-catenin was obviously elevated (Figure 3M).	('elevated', 'PosReg', (203, 211))	('BGC-823', 'Var', (103, 110))	('expression', 'MPA', (161, 171))	('beta-catenin', 'Gene', (53, 65))	('down-regulated', 'NegReg', (135, 149))	('beta-catenin', 'Gene', '1499', (53, 65))
758364	27835600	qRT-PCR showed that knockdown of YAP1 in the BGC-823 cells displayed down-regulated expressions of HOX transcript antisense RNA (HOTAIR), H19, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), human large tumor suppressor 2 (LATS2)-AS1-001, and LATS2 compared with the BGC-823 and vector BGC-823 groups (all P < 0.05, Figure 3N, 3P, 3R, 3T, 3V and 3X).	('MALAT1', 'Gene', (199, 205))	('H19', 'Gene', '283120', (138, 141))	('HOTAIR', 'Gene', '100124700', (129, 135))	('AS1', 'Gene', '5729', (247, 250))	('YAP1', 'Gene', (33, 37))	('knockdown', 'Var', (20, 29))	('human', 'Species', '9606', (208, 213))	('MALAT1', 'Gene', '378938', (199, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('HOTAIR', 'Gene', (129, 135))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (165, 184))	('expressions', 'MPA', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('LATS2', 'Gene', (260, 265))	('LATS2', 'Gene', '26524', (260, 265))	('HOX transcript antisense RNA', 'Gene', '100124700', (99, 127))	('down-regulated', 'NegReg', (69, 83))	('AS1', 'Gene', (247, 250))	('HOX transcript antisense RNA', 'Gene', (99, 127))	('metastasis-associated lung adenocarcinoma transcript 1', 'Gene', '378938', (143, 197))	('H19', 'Gene', (138, 141))	('large tumor suppressor 2', 'Gene', '26524', (214, 238))	('LATS2', 'Gene', (240, 245))	('LATS2', 'Gene', '26524', (240, 245))	('large tumor suppressor 2', 'Gene', (214, 238))
758365	27835600	Accordingly, the expressions of HOTAIR, H19, MALAT1, LATS2-AS1-001 and LATS2 were elevated in GES-1 cells overexpressing YAP1 compared with the GES-1 and vector GES-1 groups (all P < 0.05, Figures 3O, 3Q, 3S, 3U, 3W and 3Y).	('LATS2', 'Gene', (53, 58))	('expressions', 'MPA', (17, 28))	('LATS2', 'Gene', '26524', (53, 58))	('LATS2', 'Gene', (71, 76))	('LATS2', 'Gene', '26524', (71, 76))	('HOTAIR', 'Gene', (32, 38))	('MALAT1', 'Gene', (45, 51))	('H19', 'Gene', (40, 43))	('elevated', 'PosReg', (82, 90))	('YAP1', 'Var', (121, 125))	('HOTAIR', 'Gene', '100124700', (32, 38))	('H19', 'Gene', '283120', (40, 43))	('LATS2-AS1', 'Gene', (53, 62))	('MALAT1', 'Gene', '378938', (45, 51))	('LATS2-AS1', 'Gene', '100874066;26524;5729', (53, 62))
758367	27835600	Results showed that silencing YAP1 significantly inhibited tumor growth.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('silencing', 'Var', (20, 29))	('inhibited', 'NegReg', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('YAP1', 'Gene', (30, 34))
758372	27835600	Stable knockdown of YAP1 reduced the number of lung metastases (P < 0.05, Figure 4F, 4G, 4O, 4P, and 4N).	('reduced', 'NegReg', (25, 32))	('YAP1', 'Gene', (20, 24))	('knockdown', 'Var', (7, 16))	('lung metastases', 'Disease', (47, 62))	('lung metastases', 'Disease', 'MESH:D009362', (47, 62))
758374	27835600	Moreover, high-expression of YAP1 was associated with Borrman's types, WHO's histological types, lymph node metastasis, distant metastasis, and TNM staging.	('associated', 'Reg', (38, 48))	('lymph node metastasis', 'CPA', (97, 118))	('TNM', 'Gene', '10178', (144, 147))	("Borrman's types", 'Disease', (54, 69))	('distant metastasis', 'CPA', (120, 138))	('YAP1', 'Gene', (29, 33))	('TNM', 'Gene', (144, 147))	('high-expression', 'Var', (10, 25))
758379	27835600	Elevated phosphorylated c-Raf/MEK1/2/ERK1/2 was observed in MKN45 cells stably expressing YAP1, and YAP1 expression could activate ERK1/2 signaling and resulted in c-fos induction.	('Elevated phosphorylated c-', 'Phenotype', 'HP:0003236', (0, 26))	('c-Raf', 'Gene', (24, 29))	('activate', 'PosReg', (122, 130))	('c-fos', 'Gene', '2353', (164, 169))	('YAP1', 'Var', (100, 104))	('ERK1/2 signaling', 'MPA', (131, 147))	('YAP1', 'Gene', (90, 94))	('phosphorylated', 'MPA', (9, 23))	('Elevated', 'PosReg', (0, 8))	('c-fos', 'Gene', (164, 169))	('MEK1/2', 'Gene', '5604;5605', (30, 36))	('c-Raf', 'Gene', '5894', (24, 29))	('MEK1/2', 'Gene', (30, 36))	('induction', 'MPA', (170, 179))
758380	27835600	demonstrated that the inhibition of YAP1 expression sensitized HCC cells to doxorubicin by decreasing the levels of phosphorylated ERK1/2.	('inhibition', 'Var', (22, 32))	('decreasing', 'NegReg', (91, 101))	('levels of phosphorylated ERK1/2', 'MPA', (106, 137))	('sensitized', 'Reg', (52, 62))	('YAP1', 'Gene', (36, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (76, 87))
758383	27835600	It has been reported that accumulation of G1 cells was increased in MKN1 and AGS GC cells in which YAP1 expression was silenced.	('accumulation', 'PosReg', (26, 38))	('AGS', 'Disease', (77, 80))	('AGS', 'Disease', 'MESH:C535607', (77, 80))	('increased', 'PosReg', (55, 64))	('MKN1', 'Var', (68, 72))
758385	27835600	These effects could be attributed to promote EMT as shown by decreased epithelial-related protein E-cadherin expression and increased mesenchymal-related protein vimentin expression when YAP1 is overexpressed; on the other hand, using YAP1 shRNA, EMT was inhibited, as shown by elevated E-cadherin protein expression and decreased vimentin protein expression.	('decreased', 'NegReg', (321, 330))	('EMT', 'CPA', (45, 48))	('vimentin', 'Gene', '7431', (331, 339))	('E-cadherin', 'Gene', (287, 297))	('E-cadherin', 'Gene', (98, 108))	('E-cadherin', 'Gene', '999', (98, 108))	('vimentin', 'Gene', '7431', (162, 170))	('vimentin', 'Gene', (331, 339))	('E-cadherin', 'Gene', '999', (287, 297))	('vimentin', 'Gene', (162, 170))	('YAP1', 'Var', (235, 239))	('elevated', 'PosReg', (278, 286))	('EMT', 'CPA', (247, 250))
758388	27835600	Loss of E-cadherin often induces the up-regulation of the beta-catenin pathway and the transcriptional activity of beta-catenin is closely related to EMT.	('E-cadherin', 'Gene', (8, 18))	('beta-catenin', 'Gene', (58, 70))	('E-cadherin', 'Gene', '999', (8, 18))	('beta-catenin', 'Gene', (115, 127))	('induces', 'Reg', (25, 32))	('beta-catenin', 'Gene', '1499', (58, 70))	('transcriptional activity', 'MPA', (87, 111))	('up-regulation', 'PosReg', (37, 50))	('beta-catenin', 'Gene', '1499', (115, 127))	('Loss', 'Var', (0, 4))
758389	27835600	Combined beta-catenin and YAP1 silencing impairs the growth of human hepatoblastoma cells, while constitutively activated beta-catenin and YAP1 trigger liver tumor development in mice.	('hepatoblastoma', 'Disease', 'MESH:D018197', (69, 83))	('silencing', 'Var', (31, 40))	('beta-catenin', 'Gene', (122, 134))	('human', 'Species', '9606', (63, 68))	('liver tumor', 'Disease', 'MESH:D008113', (152, 163))	('beta-catenin', 'Gene', '1499', (122, 134))	('liver tumor', 'Disease', (152, 163))	('mice', 'Species', '10090', (179, 183))	('beta-catenin', 'Gene', (9, 21))	('liver tumor', 'Phenotype', 'HP:0002896', (152, 163))	('hepatoblastoma', 'Disease', (69, 83))	('impairs', 'NegReg', (41, 48))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (69, 83))	('growth', 'CPA', (53, 59))	('beta-catenin', 'Gene', '1499', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('YAP1', 'Gene', (26, 30))
758392	27835600	Consistent with these previous studies, our results showed that silencing YAP1 reduced the expression of beta-catenin.	('expression', 'MPA', (91, 101))	('reduced', 'NegReg', (79, 86))	('beta-catenin', 'Gene', (105, 117))	('YAP1', 'Gene', (74, 78))	('beta-catenin', 'Gene', '1499', (105, 117))	('silencing', 'Var', (64, 73))
758413	27835600	However, the present study suggests for the first time that YAP1 overexpression could promote tumor growth but do not affect tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('overexpression', 'Var', (65, 79))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (125, 130))	('promote', 'PosReg', (86, 93))	('YAP1', 'Gene', (60, 64))
758420	27835600	Finally, the present study is the first to report that silencing YAP1 in BGC-823 GC cells significantly suppressed hematogenous metastatic spread of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('YAP1', 'Gene', (65, 69))	('silencing', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('suppressed', 'NegReg', (104, 114))
758427	27835600	In addition, stable knockdown of YAP1 inhibited xenograft tumor growth and lung metastasis, but YAP1 was not related to tumorigenesis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('xenograft tumor', 'Disease', 'MESH:D009369', (48, 63))	('lung metastasis', 'Disease', (75, 90))	('lung metastasis', 'Disease', 'MESH:D009362', (75, 90))	('inhibited', 'NegReg', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('knockdown', 'Var', (20, 29))	('xenograft tumor', 'Disease', (48, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('YAP1', 'Gene', (33, 37))	('tumor', 'Disease', (120, 125))
758447	27835600	The primary antibodies were: E-cadherin (1:500, Cell signaling, #3195), Vimentin (1:1000, Cell signaling, #5741), ERK1/2 (1:1000, Cell signaling; #4695), p-ERK1/2 (Thr202/Tyr204) (1:1000, Cell signaling, #9101), alpha-catenin (1:500, Proteintech, Catalog number: 66221-1-Ig), beta-catenin (1:1000, Santa Cruz, sc-7963), and beta-actin (1:1000, Bioss).	('beta-actin', 'Gene', (324, 334))	('E-cadherin', 'Gene', (29, 39))	('E-cadherin', 'Gene', '999', (29, 39))	('Vimentin', 'Gene', (72, 80))	('Vimentin', 'Gene', '7431', (72, 80))	('beta-catenin', 'Gene', (276, 288))	('alpha-catenin', 'Protein', (212, 225))	('beta-catenin', 'Gene', '1499', (276, 288))	('1:1000', 'Var', (290, 296))	('beta-actin', 'Gene', '728378', (324, 334))
758470	27600761	Furthermore, patients whose tumors were double-positive for CDH1 and CTNNB1 had a significantly higher survival rate than those whose tumors were negative for CDH1 or CTNNB1 (log-rank test, p = 0.0192).	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', (28, 34))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('survival rate', 'CPA', (103, 116))	('CTNNB1', 'Gene', (69, 75))	('CDH1', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('higher', 'PosReg', (96, 102))	('double-positive', 'Var', (40, 55))
758475	27600761	Recent studies have found that several genes and molecules are involved in the origin and/or progression of esophageal cancer, including TP53, deleted in esophageal cancer 1 (DEC1), deleted in colorectal cancer (DCC), deleted in lung cancer 1 (DLC1), cyclinD1, and adenomatous polyposis coli (APC).	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('APC', 'Phenotype', 'HP:0005227', (293, 296))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('lung cancer', 'Disease', (229, 240))	('cyclinD1', 'Gene', '595', (251, 259))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('esophageal cancer', 'Disease', (108, 125))	('esophageal cancer', 'Disease', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('TP53', 'Gene', (137, 141))	('deleted', 'Var', (143, 150))	('deleted', 'Var', (182, 189))	('lung cancer', 'Disease', 'MESH:D008175', (229, 240))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('colorectal cancer', 'Phenotype', 'HP:0003003', (193, 210))	('cyclinD1', 'Gene', (251, 259))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (265, 291))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (265, 291))	('DLC1', 'Gene', (244, 248))	('adenomatous polyposis coli', 'Disease', (265, 291))	('TP53', 'Gene', '7157', (137, 141))
758503	27600761	However, the co-expression of CDH1 and CTNNB1 was associated with a significantly longer survival after surgery compared with patients with negative tumors (p = 0.0192) (Fig.	('CTNNB1', 'Gene', (39, 45))	('longer', 'PosReg', (82, 88))	('survival', 'CPA', (89, 97))	('co-expression', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('patients', 'Species', '9606', (126, 134))	('CDH1', 'Gene', (30, 34))
758511	27600761	Few mutations in CTNNB1 and APC occur in the setting of esophageal cancer.	('esophageal cancer', 'Disease', (56, 73))	('CTNNB1', 'Gene', (17, 23))	('APC', 'Phenotype', 'HP:0005227', (28, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (4, 13))
758515	27600761	Therefore, the loss of CDH1 may also contribute to the development of many other types of cancers.	('contribute', 'Reg', (37, 47))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('loss', 'Var', (15, 19))	('CDH1', 'Gene', (23, 27))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
758529	26471236	Subjects were randomized to a 6-month, twice daily (BID) oral treatment of placebo or Poly E (200 mg, 400 mg, or 600 mg).	('men', 'Species', '9606', (67, 70))	('BID', 'Gene', (52, 55))	('200 mg', 'Var', (94, 100))	('Poly E', 'Chemical', 'MESH:C472086', (86, 92))	('BID', 'Gene', '637', (52, 55))
758532	26471236	Of the 44 enrolled subjects, 11 received placebo, and 33 received Poly E. No dose-limiting toxicities were encountered, and a maximum tolerated dose (MTD) was not reached.	('Poly E.', 'Var', (66, 73))	('toxicities', 'Disease', 'MESH:D064420', (91, 101))	('toxicities', 'Disease', (91, 101))	('Poly E', 'Chemical', 'MESH:C472086', (66, 72))
758593	26471236	A Linear Models for Microarray Data (LIMMA) moderated t-statistic was used to test the null hypothesis that the difference between the change in protein concentration upon treatment with Poly E (600 mg) versus placebo: (600time2-600time1)=(0time2-0time1).	('Poly E', 'Chemical', 'MESH:C472086', (187, 193))	('600time2-600time1', 'Var', (220, 237))	('protein concentration', 'MPA', (145, 166))	('men', 'Species', '9606', (177, 180))
758602	26471236	A total of 631 AEs were reported among the 44 randomized, Poly E-treated (451 AEs) and placebo-treated (180 AEs) subjects.	('AEs', 'Chemical', '-', (15, 18))	('AEs', 'Disease', (15, 18))	('AEs', 'Chemical', '-', (78, 81))	('Poly E-treated', 'Var', (58, 72))	('Poly E', 'Chemical', 'MESH:C472086', (58, 64))	('AEs', 'Chemical', '-', (108, 111))
758614	26471236	Grade 1 elevations in creatinine were reported in 18% of Poly E-treated subjects and no placebo-treated subjects.	('Poly E', 'Chemical', 'MESH:C472086', (57, 63))	('elevations in creatinine', 'Phenotype', 'HP:0003259', (8, 32))	('Poly E-treated', 'Var', (57, 71))	('creatinine', 'MPA', (22, 32))	('creatinine', 'Chemical', 'MESH:D003404', (22, 32))	('elevations', 'PosReg', (8, 18))
758616	26471236	The most common non-laboratory AEs reported in Poly E-treated (vs placebo-treated) subjects were gastrointestinal (GI) - nausea (21% vs 0%), abdominal pain/discomfort (15% vs 9%), and diarrhea (12% vs 9%).	('Poly E-treated', 'Var', (47, 61))	('Poly E', 'Chemical', 'MESH:C472086', (47, 53))	('abdominal pain', 'Phenotype', 'HP:0002027', (141, 155))	('nausea', 'Phenotype', 'HP:0002018', (121, 127))	('nausea', 'Disease', (121, 127))	('abdominal pain', 'Disease', (141, 155))	('nausea', 'Disease', 'MESH:D009325', (121, 127))	('diarrhea', 'Phenotype', 'HP:0002014', (184, 192))	('AEs', 'Chemical', '-', (31, 34))	('pain', 'Phenotype', 'HP:0012531', (151, 155))	('diarrhea', 'Disease', (184, 192))	('abdominal pain', 'Disease', 'MESH:D015746', (141, 155))	('diarrhea', 'Disease', 'MESH:D003967', (184, 192))	('gastrointestinal', 'Disease', (97, 113))
758617	26471236	Elevations in ALT (grade 1) were reported in 9% of Poly E-treated and 17% of placebo-treated subjects; elevations in AST (all grade 1) were reported in 9% of Poly E-treated and 27% of placebo-treated subjects.	('ALT', 'MPA', (14, 17))	('Poly E', 'Chemical', 'MESH:C472086', (158, 164))	('AST', 'Gene', (117, 120))	('Poly E-treated', 'Var', (158, 172))	('AST', 'Gene', '26503', (117, 120))	('Poly E', 'Chemical', 'MESH:C472086', (51, 57))	('Poly E-treated', 'Var', (51, 65))
758621	26471236	Thus, although we did not achieve a MTD, the recommended phase 2 dose (RP2D) was determined to be the highest dose tested - Poly E 600 mg BID.	('BID', 'Gene', (138, 141))	('Poly E 600 mg', 'Var', (124, 137))	('men', 'Species', '9606', (50, 53))	('BID', 'Gene', '637', (138, 141))	('Poly E', 'Chemical', 'MESH:C472086', (124, 130))
758661	26471236	Treatment with Poly E or placebo did not reduce the length of Barrett's Epithelium and did not significantly alter the expression of any potential protein biomarker.	('Poly E', 'Var', (15, 21))	('expression', 'MPA', (119, 129))	('Poly E', 'Chemical', 'MESH:C472086', (15, 21))	('reduce', 'NegReg', (41, 47))	('men', 'Species', '9606', (5, 8))
758666	26471236	In the current study, EGCG concentrations of baseline specimens were < 10 pmol/g (within the "undetectable" range of the prostate cancer study) in all except 3 of the subjects - 2 in the placebo and 1 in the 600 mg cohort; and post-treatment EGCG concentrations were in the undetectable range in the following subjects - 5 of 10 (placebo), 3 of 5 (200 mg), 2 of 5 (400 mg), and 3 of 11 (600 mg).	('prostate cancer', 'Disease', 'MESH:D011471', (121, 136))	('EGCG', 'Chemical', 'MESH:C045651', (242, 246))	('600 mg', 'Var', (387, 393))	('EGCG', 'Chemical', 'MESH:C045651', (22, 26))	('prostate cancer', 'Phenotype', 'HP:0012125', (121, 136))	('200 mg', 'Var', (348, 354))	('prostate cancer', 'Disease', (121, 136))	('men', 'Species', '9606', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('400 mg', 'Var', (365, 371))	('men', 'Species', '9606', (237, 240))
758670	26471236	Cyclooxygenase-2 (COX-2) and prostaglandin E2 receptors are upregulated in BE, and Poly E has been shown to decrease COX-2 in colonic mucosa in animal models.	('COX-2', 'Gene', '5743', (18, 23))	('colonic mucosa', 'Disease', 'MESH:D015179', (126, 140))	('upregulated', 'PosReg', (60, 71))	('COX-2', 'Gene', '5743', (117, 122))	('Cyclooxygenase-2', 'Gene', '5743', (0, 16))	('BE', 'Phenotype', 'HP:0100580', (75, 77))	('Cyclooxygenase-2', 'Gene', (0, 16))	('Poly E', 'Var', (83, 89))	('decrease', 'NegReg', (108, 116))	('prostaglandin E2 receptors', 'Protein', (29, 55))	('colonic mucosa', 'Disease', (126, 140))	('COX-2', 'Gene', (18, 23))	('COX-2', 'Gene', (117, 122))	('Poly E', 'Chemical', 'MESH:C472086', (83, 89))
758692	24999355	This study suggests that inhibition of NHE-1 expression or activity or combination of amiloride and guggulsterone could be useful in control of esophageal adenocarcinoma.	('activity', 'MPA', (59, 67))	('amiloride', 'Chemical', 'MESH:D000584', (86, 95))	('NHE-1', 'Gene', (39, 44))	('guggulsterone', 'Chemical', 'MESH:C023617', (100, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('esophageal adenocarcinoma', 'Disease', (144, 169))	('expression', 'MPA', (45, 55))	('inhibition', 'Var', (25, 35))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (144, 169))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (144, 169))
758736	24999355	We found that NHE-1 shRNA transfection reduced tumor cell proliferation (detected by Ki67 immunostaining; Fig.	('Ki67', 'Gene', '17345', (85, 89))	('transfection', 'Var', (26, 38))	('Ki67', 'Gene', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('NHE-1', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('reduced', 'NegReg', (39, 46))	('tumor', 'Disease', (47, 52))
758752	24999355	The data from our current study suggest that inhibition of NHE-1 expression or activity and the combination of amiloride with guggulsterone should be further evaluated as a novel strategy in future control of esophageal adenocarcinoma.	('activity', 'MPA', (79, 87))	('amiloride', 'Chemical', 'MESH:D000584', (111, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (209, 234))	('NHE-1', 'Gene', (59, 64))	('esophageal adenocarcinoma', 'Disease', (209, 234))	('inhibition', 'Var', (45, 55))	('expression', 'MPA', (65, 75))	('guggulsterone', 'Chemical', 'MESH:C023617', (126, 139))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (209, 234))
758759	24999355	A number of studies showed that NHE-1 inhibitors suppressed development and metastasis of lung, gastric, colon, and breast cancers.	('colon', 'Disease', (105, 110))	('breast cancers', 'Disease', 'MESH:D001943', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancers', 'Disease', (116, 130))	('NHE-1', 'Gene', (32, 37))	('gastric', 'Disease', (96, 103))	('metastasis of lung', 'Disease', 'MESH:D009362', (76, 94))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('inhibitors', 'Var', (38, 48))	('colon', 'Disease', 'MESH:D015179', (105, 110))	('suppressed', 'NegReg', (49, 59))	('metastasis of lung', 'Disease', (76, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (116, 130))
758801	22701817	In esophageal keratinocyte culture, nicotine has been shown to cause structural alterations in nAChRs by displacing the local neurotransmitter Ach.	('Ach', 'Chemical', 'MESH:D000109', (143, 146))	('nicotine', 'Chemical', 'MESH:D009538', (36, 44))	('nAChRs', 'Chemical', '-', (95, 101))	('nicotine', 'Var', (36, 44))	('displacing', 'NegReg', (105, 115))
758808	22701817	Additionally, nicotine alters fragile histidine triad gene (FHIT) gene expression through methylation.	('expression', 'MPA', (71, 81))	('FHIT', 'Gene', (60, 64))	('alters', 'Reg', (23, 29))	('fragile histidine triad gene', 'Gene', '2272', (30, 58))	('FHIT', 'Gene', '2272', (60, 64))	('methylation', 'Var', (90, 101))	('fragile histidine triad gene', 'Gene', (30, 58))	('nicotine', 'Chemical', 'MESH:D009538', (14, 22))
758809	22701817	In cellular models of squamous cell carcinoma (SCC), promoter methylation of tumor suppressor p16 and FHIT induces the development of squamous cell carcinoma of the esophagus.	('FHIT', 'Gene', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('squamous cell carcinoma of the esophagus', 'Disease', (134, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('promoter methylation', 'Var', (53, 73))	('FHIT', 'Gene', '2272', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (148, 174))	('induces', 'Reg', (107, 114))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 45))	('p16', 'Gene', (94, 97))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (134, 174))	('p16', 'Gene', '1029', (94, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinoma', 'Disease', (22, 45))	('tumor', 'Disease', (77, 82))
758810	22701817	Methylation of the FHIT promoter in nicotine-treated cells conferred a growth and proliferative advantage through altered expression of genes such as anti-apoptotic genes p53 and p16.	('expression', 'MPA', (122, 132))	('FHIT', 'Gene', (19, 23))	('FHIT', 'Gene', '2272', (19, 23))	('nicotine', 'Chemical', 'MESH:D009538', (36, 44))	('Methylation', 'Var', (0, 11))	('p16', 'Gene', (179, 182))	('altered', 'Reg', (114, 121))	('proliferative advantage', 'CPA', (82, 105))	('p16', 'Gene', '1029', (179, 182))	('p53', 'Gene', (171, 174))	('p53', 'Gene', '7157', (171, 174))
758815	22701817	Shin and Cho demonstrated that nicotine increases the proliferation and migration of gastric cancer cells by inducing COX-2, prostaglandin E2, VEGF release, and activates ERK, and stimulates cancer cell angiogenesis through a COX-2-dependent increase in VEGF and VEGF receptor.	('nicotine', 'Var', (31, 39))	('migration', 'CPA', (72, 81))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (125, 141))	('Cho', 'Chemical', 'MESH:C034482', (9, 12))	('prostaglandin E2', 'MPA', (125, 141))	('proliferation', 'CPA', (54, 67))	('COX-2', 'MPA', (118, 123))	('VEGF', 'Protein', (254, 258))	('cancer', 'Disease', (191, 197))	('VEGF release', 'MPA', (143, 155))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('increase', 'PosReg', (242, 250))	('gastric cancer', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('inducing', 'Reg', (109, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('activates', 'PosReg', (161, 170))	('nicotine', 'Chemical', 'MESH:D009538', (31, 39))	('stimulates', 'PosReg', (180, 190))	('increases', 'PosReg', (40, 49))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('ERK', 'MPA', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('VEGF receptor', 'Protein', (263, 276))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))
758819	22701817	Inhibiting 5-LOX using the protein inhibitor MK886 caused a decrease in invasion and triggered cell cycle arrest by decreasing the relative transcription of cyclin D1, Cyclin E, p-RB, DP-1, and E2F.	('5-LOX', 'Gene', '240', (11, 16))	('p-RB', 'Gene', '5925', (178, 182))	('decrease', 'NegReg', (60, 68))	('invasion', 'CPA', (72, 80))	('MK886', 'Var', (45, 50))	('decreasing', 'NegReg', (116, 126))	('MK886', 'Chemical', 'MESH:C060893', (45, 50))	('cyclin D1', 'Gene', '595', (157, 166))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (95, 112))	('5-LOX', 'Gene', (11, 16))	('cyclin D1', 'Gene', (157, 166))	('p-RB', 'Gene', (178, 182))	('Cyclin E', 'Protein', (168, 176))	('DP-1', 'Protein', (184, 188))	('E2F', 'Protein', (194, 197))	('cell cycle arrest', 'CPA', (95, 112))
758823	22701817	Nicotine has also been shown to decrease the expression of anti-proliferative genes through induction of a microRNA (miRNA) pathway.	('anti-proliferative genes', 'Gene', (59, 83))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('Nicotine', 'Var', (0, 8))	('expression', 'MPA', (45, 55))	('decrease', 'NegReg', (32, 40))
758825	22701817	Knockdown of NF-kappaB markedly reduced cell proliferation, and miRNA-16/21 expression; and knockdown of EP2 and EP4 impaired the NF-kappaB/miRNA pathway.	('NF-kappaB', 'Gene', '4790', (130, 139))	('EP4', 'Gene', '5734', (113, 116))	('NF-kappaB', 'Gene', (130, 139))	('knockdown', 'Var', (92, 101))	('NF-kappaB', 'Gene', '4790', (13, 22))	('reduced', 'NegReg', (32, 39))	('EP4', 'Gene', (113, 116))	('miRNA-16/21', 'Gene', (64, 75))	('expression', 'MPA', (76, 86))	('EP2', 'Gene', (105, 108))	('NF-kappaB', 'Gene', (13, 22))	('EP2', 'Gene', '5732', (105, 108))	('cell proliferation', 'CPA', (40, 58))	('impaired', 'NegReg', (117, 125))
758834	22701817	Nicotine has been shown to increase proliferation by changing the expression of receptors and their phosphorylation patterns in several different mitogenic pathways.	('receptors', 'Protein', (80, 89))	('changing', 'Reg', (53, 61))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('Nicotine', 'Var', (0, 8))	('phosphorylation', 'MPA', (100, 115))	('expression', 'MPA', (66, 76))	('proliferation', 'CPA', (36, 49))	('increase', 'PosReg', (27, 35))
758837	22701817	Similarly, the upregulation of acetylcholine and noradrenaline receptors was induced by nicotine and enhanced the proliferation of colorectal carcinoma cells.	('colorectal carcinoma', 'Disease', (131, 151))	('noradrenaline receptors', 'Protein', (49, 72))	('noradrenaline', 'Chemical', 'MESH:D009638', (49, 62))	('nicotine', 'Chemical', 'MESH:D009538', (88, 96))	('upregulation', 'PosReg', (15, 27))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (131, 151))	('proliferation', 'CPA', (114, 127))	('enhanced', 'PosReg', (101, 109))	('nicotine', 'Var', (88, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('acetylcholine', 'Protein', (31, 44))
758840	22701817	Additional studies have demonstrated that nicotine/smoking stimulates angiogenesis and neovascularization in colon cancer through increases in VEGF, 5-LOX, COX-2, and MMP2/9.	('colon cancer', 'Phenotype', 'HP:0003003', (109, 121))	('MMP2/9', 'Gene', (167, 173))	('nicotine/smoking', 'Var', (42, 58))	('neovascularization', 'CPA', (87, 105))	('VEGF', 'MPA', (143, 147))	('colon cancer', 'Disease', 'MESH:D015179', (109, 121))	('5-LOX', 'Gene', '240', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('COX-2', 'Gene', (156, 161))	('colon cancer', 'Disease', (109, 121))	('stimulates', 'PosReg', (59, 69))	('MMP2/9', 'Gene', '4313;4318', (167, 173))	('nicotine', 'Chemical', 'MESH:D009538', (42, 50))	('increases', 'PosReg', (130, 139))	('angiogenesis', 'CPA', (70, 82))	('5-LOX', 'Gene', (149, 154))
758842	22701817	In this report, nicotine and COX-2 were necessary for induction of fibronectin as demonstrated by siRNA knockdown and chemical inhibition of COX-2 and alpha7- nAChR.	('nicotine', 'Chemical', 'MESH:D009538', (16, 24))	('fibronectin', 'Gene', (67, 78))	('nAChR', 'Gene', '1137', (159, 164))	('fibronectin', 'Gene', '2335', (67, 78))	('inhibition', 'NegReg', (127, 137))	('nAChR', 'Gene', (159, 164))	('knockdown', 'Var', (104, 113))
758875	22701817	Moreover, since nicotine acts through some of the same processes, which promote other types of cancer, it is likely nicotine will accelerate the growth of cancer in co-morbid conditions of the GI tract.	('nicotine', 'Var', (116, 124))	('accelerate', 'PosReg', (130, 140))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('nicotine', 'Chemical', 'MESH:D009538', (16, 24))	('cancer', 'Disease', (95, 101))	('nicotine', 'Chemical', 'MESH:D009538', (116, 124))	('growth', 'MPA', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
758876	20646319	TNFRSF1B A1466G genotype is predictive of clinical efficacy after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma Currently definitive 5-fluorouracil (5-FU)/cisplatin (CDDP) -based chemotherapy is recognized as one of the most promising treatments for esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (342, 359))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (225, 239))	('TNFRSF1B', 'Gene', '7133', (0, 8))	('CDDP', 'Chemical', 'MESH:D002945', (258, 262))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('A1466G', 'Var', (9, 15))	('TNFRSF1B', 'Gene', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (169, 203))	('5-FU', 'Chemical', 'MESH:D005472', (241, 245))	('patients', 'Species', '9606', (155, 163))	('esophageal cancer', 'Disease', (342, 359))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('esophageal squamous cell carcinoma', 'Disease', (169, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (247, 256))	('A1466G', 'Mutation', 'rs1061624', (9, 15))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (94, 108))
758877	20646319	A series of studies performed found genetic polymorphisms and the plasma concentration of 5-FU to be predictive of acute severe toxicities and clinical response.	('toxicities', 'Disease', 'MESH:D064420', (128, 138))	('toxicities', 'Disease', (128, 138))	('5-FU', 'Chemical', 'MESH:D005472', (90, 94))	('genetic polymorphisms', 'Var', (36, 57))
758882	20646319	The genotype of TNFSR1B A1466G, but not M196R/T587G or C1493T, was found to be predictive of clinical response, i.e., a complete response or not (p = 0.040).	('T587G', 'Mutation', 'rs1061622', (46, 51))	('C1493T', 'Var', (55, 61))	('A1466G', 'Mutation', 'rs1061624', (24, 30))	('M196R', 'Var', (40, 45))	('C1493T', 'SUBSTITUTION', 'None', (55, 61))	('M196R', 'SUBSTITUTION', 'None', (40, 45))	('A1466G', 'Var', (24, 30))	('TN', 'Disease', 'MESH:C562719', (16, 18))
758883	20646319	Clinical response was predicted by tumor size (p = 0,002), lymph node metastasis (p = 0.007), distant metastasis (p = 0.001) and disease stage (p < 0.001), but TNFRSF1B A1466G genotype was independent of these factors.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('A1466G', 'Mutation', 'rs1061624', (169, 175))	('distant metastasis', 'CPA', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('TNFRSF1B', 'Gene', (160, 168))	('A1466G', 'Var', (169, 175))	('tumor', 'Disease', (35, 40))	('TNFRSF1B', 'Gene', '7133', (160, 168))	('Clinical response', 'CPA', (0, 17))	('lymph node metastasis', 'CPA', (59, 80))
758884	20646319	Genetic polymorphism of TNFRSF1B A1466G was found to be predictive response in Japanese ESCC patients with a definitive 5-FU/CDDP-based chemoradiotherapy.	('A1466G', 'Mutation', 'rs1061624', (33, 39))	('5-FU', 'Chemical', 'MESH:D005472', (120, 124))	('TNFRSF1B', 'Gene', '7133', (24, 32))	('CDDP', 'Chemical', 'MESH:D002945', (125, 129))	('A1466G', 'Var', (33, 39))	('TNFRSF1B', 'Gene', (24, 32))	('Japanese ESCC', 'Disease', (79, 92))	('patients', 'Species', '9606', (93, 101))
758885	20646319	Further clinical investigation with a large number of patients or experiments in vitro should be performed to assess the predictive value of TNFRSF1B A1466G genotype after chemoradiotherapy.	('A1466G', 'Mutation', 'rs1061624', (150, 156))	('patients', 'Species', '9606', (54, 62))	('TNFRSF1B', 'Gene', '7133', (141, 149))	('A1466G', 'Var', (150, 156))	('TNFRSF1B', 'Gene', (141, 149))
758890	20646319	A series of studies performed to find a marker predictive of clinical outcome after treatment with a definitive 5-FU/CDDP-based chemoradiotherapy found a genetic polymorphism, G-1154A, of vascular endothelial growth factor to be a predictor of severe acute leukopenia and cheilitis, and the plasma concentration of 5-FU to be predictive of clinical response.	('leukopenia', 'Disease', (257, 267))	('G-1154A', 'Mutation', 'rs1570360', (176, 183))	('acute leukopenia', 'Phenotype', 'HP:0002488', (251, 267))	('5-FU', 'Chemical', 'MESH:D005472', (315, 319))	('vascular endothelial growth factor', 'Gene', (188, 222))	('G-1154A', 'Var', (176, 183))	('leukopenia', 'Disease', 'MESH:D007970', (257, 267))	('CDDP', 'Chemical', 'MESH:D002945', (117, 121))	('vascular endothelial growth factor', 'Gene', '7422', (188, 222))	('cheilitis', 'Disease', 'MESH:D002613', (272, 281))	('cheilitis', 'Phenotype', 'HP:0100825', (272, 281))	('cheilitis', 'Disease', (272, 281))	('leukopenia', 'Phenotype', 'HP:0001882', (257, 267))	('5-FU', 'Chemical', 'MESH:D005472', (112, 116))
758892	20646319	Its biological effects are elicited by binding to its two cognate cell surface receptors, TNFRSF1A/TNFR1 (p55/60) and TNFRSF1B/TNFR2 (p75/80), both of which are involved in increasing expression of other cytokines and immuno-regulatory molecules through the activation of nuclear factor kappaB.	('increasing', 'PosReg', (173, 183))	('TNFR1', 'Gene', (99, 104))	('TNFR2', 'Gene', (127, 132))	('p55/60', 'Var', (106, 112))	('TNFRSF1B', 'Gene', '7133', (118, 126))	('TNFR1', 'Gene', '7132', (99, 104))	('p75', 'Gene', (134, 137))	('TNFRSF1B', 'Gene', (118, 126))	('TNFRSF1A', 'Gene', (90, 98))	('TNFR2', 'Gene', '7133', (127, 132))	('p75', 'Gene', '7133', (134, 137))	('expression', 'MPA', (184, 194))	('binding', 'Interaction', (39, 46))	('TNFRSF1A', 'Gene', '7132', (90, 98))
758893	20646319	Single nucleotide polymorphisms (SNPs) in the TNF-alpha, TNFRSF1A and TNFRSF1B genes have been identified, however functional data pertaining to these polymorphisms in scarce.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('scar', 'Phenotype', 'HP:0100699', (168, 172))	('TNFRSF1A', 'Gene', '7132', (57, 65))	('TNF-alpha', 'Gene', '7124', (46, 55))	('TNFRSF1B', 'Gene', '7133', (70, 78))	('TNF-alpha', 'Gene', (46, 55))	('TNFRSF1B', 'Gene', (70, 78))	('TNFRSF1A', 'Gene', (57, 65))
758896	20646319	In this study, genetic polymorphisms of the TNFRSF1B gene, M196R/T587G, A1466G and C1493T, were evaluated in Japanese ESCC patients treated with a definitive 5-FU/CDDP-based chemoradiotherapy, and their predictive values of prognosis or severe acute toxicities were assessed.	('A1466G', 'Var', (72, 78))	('T587G', 'Mutation', 'rs1061622', (65, 70))	('toxicities', 'Disease', 'MESH:D064420', (250, 260))	('M196R', 'SUBSTITUTION', 'None', (59, 64))	('5-FU', 'Chemical', 'MESH:D005472', (158, 162))	('C1493T', 'Var', (83, 89))	('patients', 'Species', '9606', (123, 131))	('CDDP', 'Chemical', 'MESH:D002945', (163, 167))	('C1493T', 'SUBSTITUTION', 'None', (83, 89))	('A1466G', 'Mutation', 'rs1061624', (72, 78))	('toxicities', 'Disease', (250, 260))	('TNFRSF1B', 'Gene', '7133', (44, 52))	('M196R', 'Var', (59, 64))	('TNFRSF1B', 'Gene', (44, 52))
758899	20646319	Genetic polymorphisms of TNFRSF1B; M196R/T587G, A1466G and C1493T, were determined by a TaqMan  MGB probe-based polymerase chain reaction (PCR) using the StepOne  real-time PCR system (Applied Biosystems) and pre-manufactured TaqMan  SNP genotyping assays C_8861232_20 (M196R/T587G, rs1061622), C_8861229_10 (A1466G, rs1061624) and C_8861228_20 (C1493T, rs3397) (Applied Biosystems).	('M196R', 'Var', (35, 40))	('C1493T', 'Var', (59, 65))	('TNFRSF1B', 'Gene', (25, 33))	('rs3397', 'Mutation', 'rs3397', (354, 360))	('A1466G', 'Mutation', 'rs1061624', (48, 54))	('T587G', 'Mutation', 'rs1061622', (41, 46))	('T587G', 'Mutation', 'rs1061622', (276, 281))	('rs1061624', 'Mutation', 'rs1061624', (317, 326))	('C1493T', 'SUBSTITUTION', 'None', (59, 65))	('M196R', 'SUBSTITUTION', 'None', (35, 40))	('M196R', 'Var', (270, 275))	('A1466G', 'Mutation', 'rs1061624', (309, 315))	('CR', 'Chemical', '-', (174, 176))	('TNFRSF1B', 'Gene', '7133', (25, 33))	('rs1061622', 'Mutation', 'rs1061622', (283, 292))	('C1493T', 'Var', (346, 352))	('CR', 'Chemical', '-', (140, 142))	('M196R', 'SUBSTITUTION', 'None', (270, 275))	('A1466G', 'Var', (309, 315))	('C1493T', 'SUBSTITUTION', 'None', (346, 352))
758909	20646319	The clinical response, i.e., CR or non-CR, was predicted by T class (p = 0.002), N class (p = 0.007), M class (p = 0.001) and disease stage (p < 0.001).	('M class', 'Var', (102, 109))	('N class', 'Var', (81, 88))	('CR', 'Chemical', '-', (29, 31))	('CR', 'Chemical', '-', (39, 41))
758911	20646319	Table 2 indicates the association of the TNFRSF1B genetic polymorphisms M196R/T587G, A1466G and C1493T with clinical response in the ESCC patients.	('M196R', 'Var', (72, 77))	('TNFRSF1B', 'Gene', '7133', (41, 49))	('A1466G', 'Mutation', 'rs1061624', (85, 91))	('C1493T', 'Var', (96, 102))	('clinical response', 'CPA', (108, 125))	('TNFRSF1B', 'Gene', (41, 49))	('ESCC', 'Disease', (133, 137))	('M196R', 'SUBSTITUTION', 'None', (72, 77))	('T587G', 'Mutation', 'rs1061622', (78, 83))	('C1493T', 'SUBSTITUTION', 'None', (96, 102))	('A1466G', 'Var', (85, 91))	('association', 'Interaction', (22, 33))	('patients', 'Species', '9606', (138, 146))
758912	20646319	TNFRSF1B A1466G genotype was predictive of clinical response (p = 0.040), whereas M196R/T587G and C1493T were not.	('C1493T', 'Var', (98, 104))	('TNFRSF1B', 'Gene', '7133', (0, 8))	('C1493T', 'SUBSTITUTION', 'None', (98, 104))	('A1466G', 'Var', (9, 15))	('TNFRSF1B', 'Gene', (0, 8))	('M196R', 'Var', (82, 87))	('T587G', 'Mutation', 'rs1061622', (88, 93))	('clinical response', 'CPA', (43, 60))	('M196R', 'SUBSTITUTION', 'None', (82, 87))	('A1466G', 'Mutation', 'rs1061624', (9, 15))
758916	20646319	However, the 2-year survival rate was 25.0%, 60.0% and 50.0% in the patients with the TNFRSF1B genotypes AA1466, AG1466 and GG1466, and the effect of TNFRSF1B A1466G genotype on the overall survival was not significant (Log-rank test).	('AA1466', 'Var', (105, 111))	('AG1466', 'Var', (113, 119))	('TNFRSF1B', 'Gene', '7133', (150, 158))	('TNFRSF1B', 'Gene', (150, 158))	('patients', 'Species', '9606', (68, 76))	('TNFRSF1B', 'Gene', '7133', (86, 94))	('A1466G', 'Mutation', 'rs1061624', (159, 165))	('TNFRSF1B', 'Gene', (86, 94))	('GG1466', 'Var', (124, 130))
758917	20646319	In addition, the effects of TNFRSF1B M196R/T587G, A1466G and C1493T genotypes were not found for severe acute leucopenia, stomatitis or cheilitis (data not shown).	('C1493T', 'SUBSTITUTION', 'None', (61, 67))	('leucopenia', 'Disease', (110, 120))	('A1466G', 'Mutation', 'rs1061624', (50, 56))	('stomatitis', 'Phenotype', 'HP:0010280', (122, 132))	('stomatitis or cheilitis', 'Disease', 'MESH:D013280', (122, 145))	('cheilitis', 'Phenotype', 'HP:0100825', (136, 145))	('M196R', 'Var', (37, 42))	('leucopenia', 'Disease', 'MESH:C536227', (110, 120))	('TNFRSF1B', 'Gene', '7133', (28, 36))	('A1466G', 'Var', (50, 56))	('T587G', 'Mutation', 'rs1061622', (43, 48))	('TNFRSF1B', 'Gene', (28, 36))	('M196R', 'SUBSTITUTION', 'None', (37, 42))	('stomatitis or cheilitis', 'Disease', (122, 145))	('C1493T', 'Var', (61, 67))
758921	20646319	Several clinical investigations have been conducted to assess the predictive value of the genetic polymorphisms TNF-alpha G-308A, TNFRSF1A A36G and G-609T, and TNFRSF1B M196R/T587G, A1466G (or A1663G) and C1493T (or C1690T) regarding susceptibility to various inflammatory disorders, and recently, to cancer.	('TNFRSF1A', 'Gene', (130, 138))	('G-308A', 'Var', (122, 128))	('M196R', 'Var', (169, 174))	('G-609T', 'Mutation', 'rs4149570', (148, 154))	('T587G', 'Mutation', 'rs1061622', (175, 180))	('TNFRSF1B', 'Gene', (160, 168))	('G-308A', 'Mutation', 'rs1800629', (122, 128))	('cancer', 'Disease', (301, 307))	('A36G', 'Var', (139, 143))	('G-609T', 'Var', (148, 154))	('inflammatory disorders', 'Disease', (260, 282))	('A1466G', 'Mutation', 'rs1061624', (182, 188))	('M196R', 'SUBSTITUTION', 'None', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('A36G', 'Mutation', 'rs767455', (139, 143))	('C1493T', 'Var', (205, 211))	('TNF-alpha', 'Gene', '7124', (112, 121))	('inflammatory disorders', 'Disease', 'MESH:D015212', (260, 282))	('TNFRSF1B', 'Gene', '7133', (160, 168))	('TNF-alpha', 'Gene', (112, 121))	('A1466G', 'Var', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('C1690T', 'Var', (216, 222))	('C1690T', 'Mutation', 'c.1690C>T', (216, 222))	('TNFRSF1A', 'Gene', '7132', (130, 138))	('A1663G', 'Mutation', 'c.1663A>G', (193, 199))	('C1493T', 'SUBSTITUTION', 'None', (205, 211))
758922	20646319	As for TNFRSF1B, the SNP M196R/T587G has proved predictive of Crohn's disease, systemic lupus erythematosus and rheumatoid arthritis.	('M196R', 'Var', (25, 30))	('T587G', 'Mutation', 'rs1061622', (31, 36))	("Crohn's disease", 'Disease', 'MESH:D003424', (62, 77))	('systemic lupus erythematosus', 'Disease', (79, 107))	("Crohn's disease", 'Disease', (62, 77))	('arthritis', 'Phenotype', 'HP:0001369', (123, 132))	('TNFRSF1B', 'Gene', '7133', (7, 15))	('M196R', 'SUBSTITUTION', 'None', (25, 30))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (79, 107))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (112, 132))	('TNFRSF1B', 'Gene', (7, 15))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (79, 107))	('rheumatoid arthritis', 'Disease', (112, 132))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (112, 132))	("Crohn's disease", 'Phenotype', 'HP:0100280', (62, 77))
758923	20646319	TNFRSF1B A1466G is not associated with Crohn's disease, but the haplotype 1466A-1493T might be important.	('TNFRSF1B', 'Gene', '7133', (0, 8))	('A1466G', 'Var', (9, 15))	('TNFRSF1B', 'Gene', (0, 8))	('A1466G', 'Mutation', 'rs1061624', (9, 15))	("Crohn's disease", 'Phenotype', 'HP:0100280', (39, 54))	("Crohn's disease", 'Disease', 'MESH:D003424', (39, 54))	("Crohn's disease", 'Disease', (39, 54))
758924	20646319	Recently, TNFRSF1B C1493T has been found to be a risk factor of tobacco-related oral carcinoma.	('tobacco', 'Species', '4097', (64, 71))	('TNFRSF1B', 'Gene', '7133', (10, 18))	('TNFRSF1B', 'Gene', (10, 18))	('oral carcinoma', 'Disease', 'MESH:D020820', (80, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('risk', 'Reg', (49, 53))	('C1493T', 'Var', (19, 25))	('oral carcinoma', 'Disease', (80, 94))	('C1493T', 'SUBSTITUTION', 'None', (19, 25))
758925	20646319	In this study, it was demonstrated that the TNFRSF1B A1466G genotype was a predictive factor of clinical response to treatment with a definitive 5-FU/CDDP-based chemoradiotherapy in Japanese ESCC patients.	('CDDP', 'Chemical', 'MESH:D002945', (150, 154))	('A1466G', 'Mutation', 'rs1061624', (53, 59))	('A1466G', 'Var', (53, 59))	('patients', 'Species', '9606', (196, 204))	('5-FU', 'Chemical', 'MESH:D005472', (145, 149))	('TNFRSF1B', 'Gene', '7133', (44, 52))	('Japanese ESCC', 'Disease', (182, 195))	('TNFRSF1B', 'Gene', (44, 52))
758926	20646319	The TNFRSF1B G-allele at position 1466 is predictive of clinical response, whereas no such association was found for M196R/T587G or C1493T (Table 2).	('M196R', 'Var', (117, 122))	('clinical response', 'CPA', (56, 73))	('TNFRSF1B', 'Gene', '7133', (4, 12))	('M196R', 'SUBSTITUTION', 'None', (117, 122))	('C1493T', 'Var', (132, 138))	('TNFRSF1B', 'Gene', (4, 12))	('C1493T', 'SUBSTITUTION', 'None', (132, 138))	('T587G', 'Mutation', 'rs1061622', (123, 128))
758929	20646319	Clinical response was significantly associated with overall survival (Figure 2), however, TNFRSF1B A1466G genotype had no effect on the overall survival, presumably because it was not associated with death within 1 year after the completion of chemoradiotherapy.	('overall survival', 'MPA', (52, 68))	('A1466G', 'Mutation', 'rs1061624', (99, 105))	('TNFRSF1B', 'Gene', '7133', (90, 98))	('A1466G', 'Var', (99, 105))	('associated', 'Reg', (36, 46))	('TNFRSF1B', 'Gene', (90, 98))
758931	20646319	Genetic polymorphisms of the TNFRSF1B gene, M196R/T587G, A1466G and C1493T, were evaluated in Japanese ESCC patients treated with a definitive 5-FU/CDDP-based chemoradiotherapy.	('5-FU', 'Chemical', 'MESH:D005472', (143, 147))	('C1493T', 'SUBSTITUTION', 'None', (68, 74))	('CDDP', 'Chemical', 'MESH:D002945', (148, 152))	('A1466G', 'Var', (57, 63))	('M196R', 'Var', (44, 49))	('T587G', 'Mutation', 'rs1061622', (50, 55))	('TNFRSF1B', 'Gene', '7133', (29, 37))	('patients', 'Species', '9606', (108, 116))	('TNFRSF1B', 'Gene', (29, 37))	('C1493T', 'Var', (68, 74))	('M196R', 'SUBSTITUTION', 'None', (44, 49))	('A1466G', 'Mutation', 'rs1061624', (57, 63))
758932	20646319	It was found that A1466G, but not M196R/T587G or C1493T, was a predictive factor of clinical response to chemoradiotherapy.	('A1466G', 'Var', (18, 24))	('M196R', 'SUBSTITUTION', 'None', (34, 39))	('C1493T', 'Var', (49, 55))	('C1493T', 'SUBSTITUTION', 'None', (49, 55))	('T587G', 'Mutation', 'rs1061622', (40, 45))	('A1466G', 'Mutation', 'rs1061624', (18, 24))	('M196R', 'Var', (34, 39))
758933	20646319	Clinical response was predicted by TNM classes and disease stage, but A1466G genotype was independent of these factors.	('TN', 'Disease', 'MESH:C562719', (35, 37))	('Clinical response', 'MPA', (0, 17))	('A1466G', 'Var', (70, 76))	('A1466G', 'Mutation', 'rs1061624', (70, 76))
758971	31619265	In subgroup analysis according to RT dose (18 trials with 2860 patients), nCRTS-IFI with dose of >=40Gy significantly improved OS compared to S alone, while nCRTS-IFI with dose of <40Gy did not; both nCRTS-ENI with dose of >=40Gy and < 40Gy showed a significant OS advantage over S alone; and nCRTS-ENI with dose of >=40Gy was ranked the most effective regimen (0.86).	('CRT', 'Gene', (294, 297))	('CRT', 'Gene', (158, 161))	('< 40Gy', 'Var', (234, 240))	('improved', 'PosReg', (118, 126))	('CRT', 'Gene', '799', (201, 204))	('CRT', 'Gene', (201, 204))	('CRT', 'Gene', '799', (75, 78))	('patients', 'Species', '9606', (63, 71))	('CRT', 'Gene', (75, 78))	('OS advantage', 'CPA', (262, 274))	('CRT', 'Gene', '799', (294, 297))	('CRT', 'Gene', '799', (158, 161))
758990	31619265	In subgroup analysis of RT technique, we found that nCRTS-ENI adopting 3D-RT had a significant OS benefit compared to nCRTS-ENI adopting 2D-RT.	('CRT', 'Gene', '799', (53, 56))	('CRT', 'Gene', '799', (119, 122))	('3D-RT', 'Var', (71, 76))	('benefit', 'PosReg', (98, 105))	('CRT', 'Gene', (119, 122))	('CRT', 'Gene', (53, 56))
758994	31619265	Results of two small meta-analysis showed that the incidences of esophageal and lung toxicities were significantly higher in ENI group.	('lung toxicities', 'Disease', 'MESH:D008171', (80, 95))	('esophageal', 'Disease', (65, 75))	('lung toxicities', 'Disease', (80, 95))	('ENI', 'Var', (125, 128))	('higher', 'PosReg', (115, 121))
759046	31602274	For double immunofluorescence staining of CD3, CD11c, CD4, CD8, CTLA-4 or PD-1, and CD103, we used species-paired fluorescently labeled secondary antibodies [donkey anti-rat immunoglobulin G (IgG) (H+L) secondary antibody, Alexa Fluor 488, A-21206; donkey anti-mouse IgG (H+L) secondary antibody, Alexa Fluor 555, A-31570, Invitrogen, Waltham, MA, USA] and tyramide reagent (Alexa Fluor 488 Tyramide Reagent, B40953; Alexa Fluor 555 Tyramide Reagent, B40955, Invitrogen).	('CD103', 'Gene', '3682', (84, 89))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (375, 386))	('CD8', 'Gene', (59, 62))	('donkey', 'Species', '9793', (249, 255))	('CD4', 'Gene', (54, 57))	('PD-1', 'Gene', (74, 78))	('PD-1', 'Gene', '5133', (74, 78))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (223, 234))	('CD11c', 'Gene', '3687', (47, 52))	('CD11c', 'Gene', (47, 52))	('B40953', 'Var', (409, 415))	('mouse', 'Species', '10090', (261, 266))	('Alexa Fluor 488, A-21206', 'Chemical', 'MESH:C504424', (223, 247))	('Alexa Fluor 488 Tyramide', 'Chemical', 'MESH:C504424', (375, 399))	('donkey', 'Species', '9793', (158, 164))	('Tyramide', 'Chemical', 'MESH:C111551', (433, 441))	('B40953', 'Chemical', 'MESH:D001895', (409, 415))	('CD8', 'Gene', '925', (59, 62))	('B40955', 'Chemical', 'MESH:D001895', (451, 457))	('CD103', 'Gene', (84, 89))	('Tyramide', 'Chemical', 'MESH:C111551', (391, 399))	('rat', 'Species', '10116', (170, 173))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (297, 308))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (417, 428))	('CD4', 'Gene', '920', (54, 57))	('tyramide', 'Chemical', 'MESH:C111551', (357, 365))
759124	30098293	Phase I clinical trials in thoracic surgery have demonstrated that IFI with second window indocyanine green (TumorGlow ) can identify sub-centimeter pulmonary nodules, anterior mediastinal masses, and mesothelioma, while use of a folate receptor-targeted near-infrared agent, OTL38, can improve the specificity for diagnosing tumors with folate receptor expression.	('indocyanine green', 'Chemical', 'MESH:D007208', (90, 107))	('tumors', 'Disease', (326, 332))	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('folate', 'Chemical', 'MESH:D005492', (230, 236))	('anterior mediastinal masses', 'Disease', (168, 195))	('tumors', 'Disease', 'MESH:D009369', (326, 332))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('mesothelioma', 'Disease', (201, 213))	('folate', 'Chemical', 'MESH:D005492', (338, 344))	('sub-centimeter', 'Var', (134, 148))	('Tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mesothelioma', 'Disease', 'MESH:D008654', (201, 213))
759162	30098293	We directly compared OTL38 and EC17 in several controlled experiments in vitro using cadaveric human lungs and in vivo using murine flank tumors and confirmed that OTL38 had decreased auto-fluorescence and increased depth of penetration compared to EC17.	('decreased', 'NegReg', (174, 183))	('human', 'Species', '9606', (95, 100))	('flank tumors', 'Disease', (132, 144))	('increased', 'PosReg', (206, 215))	('flank tumors', 'Disease', 'MESH:D021501', (132, 144))	('auto-fluorescence', 'MPA', (184, 201))	('OTL38', 'Var', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('murine', 'Species', '10090', (125, 131))	('depth of penetration', 'CPA', (216, 236))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
759203	30098293	In a follow-up study of IFI with OTL38 for pulmonary squamous cell carcinomas, approximately 70% (9/13) of nodules accumulated OTL38.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (53, 77))	('accumulated', 'PosReg', (115, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('pulmonary squamous cell carcinomas', 'Disease', (43, 77))	('OTL38', 'Var', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('pulmonary squamous cell carcinomas', 'Disease', 'MESH:D002294', (43, 77))
759538	25869390	However, nonadherence to BE biopsy guidelines is associated with significantly decreased dysplasia detection.	('BE', 'Phenotype', 'HP:0100580', (25, 27))	('decreased dysplasia', 'Disease', 'MESH:D012021', (79, 98))	('decreased dysplasia', 'Disease', (79, 98))	('nonadherence', 'Var', (9, 21))
759622	25869390	One recent study reported that patients with multifocal LGD were associated with an increased risk of developing HGD and EA, but Wani et al.	('D', 'Chemical', 'MESH:D003903', (58, 59))	('EA', 'Phenotype', 'HP:0011459', (121, 123))	('D', 'Chemical', 'MESH:D003903', (115, 116))	('HGD', 'Gene', '3081', (113, 116))	('patients', 'Species', '9606', (31, 39))	('HGD', 'Gene', (113, 116))	('multifocal', 'Var', (45, 55))
759628	25869390	Patients with BE with multifocal LGD (confirmed by at least two specialist GI pathologists) have an increased risk for progression of neoplasia compared with those with focal LGD.	('multifocal', 'Var', (22, 32))	('BE', 'Phenotype', 'HP:0100580', (14, 16))	('D', 'Chemical', 'MESH:D003903', (35, 36))	('neoplasia', 'Disease', (134, 143))	('Patients', 'Species', '9606', (0, 8))	('D', 'Chemical', 'MESH:D003903', (177, 178))	('neoplasia', 'Phenotype', 'HP:0002664', (134, 143))	('neoplasia', 'Disease', 'MESH:D009369', (134, 143))
759651	25869390	However, LGD on initial biopsy is an indicator of the potential for disease progression, and a registry with over 1,000 patients reported that LGD present on the index endoscopy was associated with a rate of progression to HGD/EA of 6.5% per year, and 3.1% when tertiary referrals were excluded.	('HGD', 'Gene', '3081', (223, 226))	('HGD', 'Gene', (223, 226))	('LGD', 'Var', (143, 146))	('D', 'Chemical', 'MESH:D003903', (11, 12))	('EA', 'Phenotype', 'HP:0011459', (227, 229))	('D', 'Chemical', 'MESH:D003903', (225, 226))	('D', 'Chemical', 'MESH:D003903', (145, 146))	('patients', 'Species', '9606', (120, 128))
759657	25869390	In the "SURF" RCT of surveillance vs. radiofrequency ablation of participants with confirmed LGD, RFA significantly reduced neoplastic progression to HGD/EA as compared with continued surveillance of BE with LGD (control arm).	('EA', 'Phenotype', 'HP:0011459', (154, 156))	('BE', 'Phenotype', 'HP:0100580', (200, 202))	('tic', 'Phenotype', 'HP:0100033', (68, 71))	('neoplastic progression', 'CPA', (124, 146))	('D', 'Chemical', 'MESH:D003903', (210, 211))	('HGD', 'Gene', '3081', (150, 153))	('participants', 'Species', '9606', (65, 77))	('D', 'Chemical', 'MESH:D003903', (152, 153))	('U', 'Chemical', 'MESH:D014501', (9, 10))	('RFA', 'Var', (98, 101))	('HGD', 'Gene', (150, 153))	('tic', 'Phenotype', 'HP:0100033', (131, 134))	('reduced', 'NegReg', (116, 123))	('D', 'Chemical', 'MESH:D003903', (95, 96))
759663	25869390	Although the best clinical marker(s) for predicting neoplastic progression in BE with LGD remains unclear, ablation of the lesion is associated with improved outcomes in reduced neoplastic progression in a subset of patients with LGD.	('ablation', 'Var', (107, 115))	('lesion', 'Var', (123, 129))	('tic', 'Phenotype', 'HP:0100033', (185, 188))	('tic', 'Phenotype', 'HP:0100033', (59, 62))	('reduced', 'NegReg', (170, 177))	('patients', 'Species', '9606', (216, 224))	('D', 'Chemical', 'MESH:D003903', (88, 89))	('neoplastic progression', 'CPA', (178, 200))	('BE', 'Phenotype', 'HP:0100580', (78, 80))	('D', 'Chemical', 'MESH:D003903', (232, 233))
759703	25869390	Flat type 2b lesions are the most common among patients with dysplasia referred for high-resolution endoscopy at expert centers.	('dysplasia', 'Disease', (61, 70))	('patients', 'Species', '9606', (47, 55))	('Flat type 2b', 'Var', (0, 12))	('dysplasia', 'Disease', 'MESH:D004476', (61, 70))
759705	25869390	Aberrant p16, p16 methylation, or p16 loss in nondysplastic BE is associated with an increased risk of progression to LGD.	('p16', 'Gene', '1029', (14, 17))	('Aberrant', 'Var', (0, 8))	('p16', 'Gene', (34, 37))	('dysplastic', 'Disease', (49, 59))	('LGD', 'Disease', (118, 121))	('p16', 'Gene', '1029', (9, 12))	('dysplastic', 'Disease', 'MESH:D004416', (49, 59))	('p16', 'Gene', (14, 17))	('BE', 'Phenotype', 'HP:0100580', (60, 62))	('tic', 'Phenotype', 'HP:0100033', (56, 59))	('methylation', 'Var', (18, 29))	('p16', 'Gene', '1029', (34, 37))	('D', 'Chemical', 'MESH:D003903', (120, 121))	('loss', 'NegReg', (38, 42))	('p16', 'Gene', (9, 12))
759707	25869390	There is evidence that p16 hypermethylation is an early predictor of progression in BE, especially for LGD.	('hypermethylation', 'Var', (27, 43))	('p16', 'Gene', (23, 26))	('LGD', 'Disease', (103, 106))	('BE', 'Phenotype', 'HP:0100580', (84, 86))	('p16', 'Gene', '1029', (23, 26))	('D', 'Chemical', 'MESH:D003903', (105, 106))
759710	25869390	Aberrant p53, p53 mutation, or p53 loss in nondysplastic BE is associated with an increased risk of developing dysplasia.	('tic', 'Phenotype', 'HP:0100033', (53, 56))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('dysplasia', 'Disease', (111, 120))	('Aberrant', 'Var', (0, 8))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('loss', 'NegReg', (35, 39))	('dysplasia', 'Disease', 'MESH:D004476', (111, 120))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('mutation', 'Var', (18, 26))	('dysplastic', 'Disease', (46, 56))	('dysplastic', 'Disease', 'MESH:D004416', (46, 56))
759713	25869390	There is extensive evidence that p53 overexpression is a predictor of progression in BE, especially for LGD and that p53 overexpression is caused by mutations that lead to a hypersta-ble p53 protein overexpression (that greatly lengthen its half-life).	('caused by', 'Reg', (139, 148))	('LGD', 'Disease', (104, 107))	('mutations', 'Var', (149, 158))	('p53', 'Gene', (117, 120))	('p53', 'Gene', (187, 190))	('p53', 'Gene', '7157', (117, 120))	('half-life', 'MPA', (241, 250))	('p53', 'Gene', '7157', (187, 190))	('overexpression', 'PosReg', (199, 213))	('protein', 'Protein', (191, 198))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('BE', 'Phenotype', 'HP:0100580', (85, 87))	('overexpression', 'PosReg', (121, 135))	('D', 'Chemical', 'MESH:D003903', (106, 107))
759714	25869390	We further examined whether p53 abnormal staining is useful as an adjunct to the histopathological assessment of dysplasia and its utility as a progression marker.	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (28, 31))	('men', 'Species', '9606', (105, 108))	('abnormal', 'Var', (32, 40))	('dysplasia', 'Disease', (113, 122))	('dysplasia', 'Disease', 'MESH:D004476', (113, 122))
759717	25869390	32. p53 aberrant expression combined with histopathological assessment of LGD is more accurate than histopathological assessment alone in specialist centers.	('p53', 'Gene', '7157', (4, 7))	('men', 'Species', '9606', (66, 69))	('men', 'Species', '9606', (124, 127))	('D', 'Chemical', 'MESH:D003903', (76, 77))	('32.', 'Gene', (0, 3))	('aberrant expression', 'Var', (8, 27))	('p53', 'Gene', (4, 7))
759722	25869390	33. p53 aberrant expression combined with histopathological assessment is not useful for the histopathological assessment of dysplastic progression in nondysplastic BE.	('dysplastic', 'Disease', 'MESH:D004416', (154, 164))	('p53', 'Gene', '7157', (4, 7))	('men', 'Species', '9606', (66, 69))	('tic', 'Phenotype', 'HP:0100033', (161, 164))	('men', 'Species', '9606', (117, 120))	('dysplastic', 'Disease', (125, 135))	('dysplastic', 'Disease', 'MESH:D004416', (125, 135))	('p53', 'Gene', (4, 7))	('tic', 'Phenotype', 'HP:0100033', (132, 135))	('aberrant expression', 'Var', (8, 27))	('dysplastic', 'Disease', (154, 164))	('BE', 'Phenotype', 'HP:0100580', (165, 167))
759727	25869390	The use of PPIs (compared with no therapy or histamine receptor type 2 antagonists) is associated with a decrease in progression from benign BE metaplasia to BE neoplasia (dysplasia and EA).	('metaplasia to BE neoplasia', 'Disease', 'MESH:D008679', (144, 170))	('metaplasia to BE neoplasia', 'Disease', (144, 170))	('dysplasia', 'Disease', 'MESH:D004476', (172, 181))	('neoplasia', 'Phenotype', 'HP:0002664', (161, 170))	('EA', 'Phenotype', 'HP:0011459', (186, 188))	('BE', 'Phenotype', 'HP:0100580', (158, 160))	('BE', 'Phenotype', 'HP:0100580', (141, 143))	('dysplasia', 'Disease', (172, 181))	('decrease', 'NegReg', (105, 113))	('PPIs', 'Var', (11, 15))
759731	25869390	Cohort studies demonstrate that the use of PPIs decreased neoplasia development.	('neoplasia', 'Phenotype', 'HP:0002664', (58, 67))	('neoplasia', 'Disease', 'MESH:D009369', (58, 67))	('decreased', 'NegReg', (48, 57))	('PPIs', 'Var', (43, 47))	('men', 'Species', '9606', (75, 78))	('neoplasia', 'Disease', (58, 67))
759870	18940636	The goal of dysphagia rehabilitation is to identify and treat abnormalities of feeding and swallowing while maintaining safe and efficient alimentation and hydration.	('dysphagia', 'Disease', 'MESH:D003680', (12, 21))	('abnormalities', 'Var', (62, 75))	('dysphagia', 'Disease', (12, 21))	('feeding', 'MPA', (79, 86))	('abnormalities of feeding', 'Phenotype', 'HP:0011968', (62, 86))	('dysphagia', 'Phenotype', 'HP:0002015', (12, 21))
759925	18940636	Weak contraction of the tongue and soft palate can cause premature leakage of the bolus into the pharynx, especially with liquids.	('soft palate', 'Disease', (35, 46))	('Weak', 'Var', (0, 4))	('soft palate', 'Disease', 'MESH:C562950', (35, 46))	('liquids', 'Chemical', '-', (122, 129))	('cause', 'Reg', (51, 56))	('premature leakage of the bolus into the pharynx', 'MPA', (57, 104))
759955	33919216	An abnormality in GSH concentration in biological fluids or tissues is often directly associated with several medical diseases, including diabetes, cardiovascular diseases, and cancers.	('GSH', 'Protein', (18, 21))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('GSH', 'Chemical', '-', (18, 21))	('abnormality', 'Var', (3, 14))	('cancers', 'Disease', (177, 184))	('diabetes', 'Disease', (138, 146))	('associated', 'Reg', (86, 96))	('diabetes', 'Disease', 'MESH:D003920', (138, 146))	('cardiovascular diseases', 'Disease', (148, 171))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (148, 171))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (148, 171))	('medical diseases', 'Disease', (110, 126))
759999	33919216	Zinc nitrate [Zn(NO3)2] (99%, 11316158, Fisher Scientific, Taiwan) and hexamethylenetetramine (C6H12N4, 99%) (11387918, Fisher Scientific, Taiwan) with deionized (DI) water were dissolved into two solutions with equal volumes and with molar concentrations of 0.314 and 0.7 M, respectively.	('11316158', 'Var', (30, 38))	('11387918', 'Var', (110, 118))	('water', 'Chemical', 'MESH:D014867', (167, 172))	('Zn(NO3)2', 'Chemical', '-', (14, 22))	('hexamethylenetetramine', 'Chemical', 'MESH:D008709', (71, 93))	('H12N4', 'Species', '142947', (97, 102))	('Zinc nitrate', 'Chemical', 'MESH:C042103', (0, 12))
760039	33919216	This results in the lower absorbance of MoS2/Cu2O than ZnO/Cu2O.	('lower', 'NegReg', (20, 25))	('Cu2O', 'Chemical', '-', (45, 49))	('MoS2', 'Chemical', '-', (40, 44))	('ZnO', 'Chemical', 'MESH:D015034', (55, 58))	('absorbance', 'MPA', (26, 36))	('Cu2O', 'Chemical', '-', (59, 63))	('MoS2/Cu2O', 'Var', (40, 49))
760054	33919216	The response correlation of the N-type photoelectrochemical biosensor to GSSG is greater than that to GSH.	('GSSG', 'Chemical', 'MESH:D019803', (73, 77))	('GSSG', 'Var', (73, 77))	('GSH', 'Chemical', '-', (102, 105))	('response correlation', 'MPA', (4, 24))
760067	33919216	These results were also found in the two types of cancer, namely, CE81T2-1 and CE81T2-4, where the photocurrent increased compared with that in the absence of cancer cell sera; the results are 78% and 308% for CE81T2-1 and CE81T2-4 cancer cells, respectively.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Disease', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('CE81T2-4', 'Var', (223, 231))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('CE81T2-1', 'Var', (210, 218))
760068	33919216	The level of canceration of OE21-1 is greater than that of OE21, and the current value detected by the biosensor exhibits this trend.	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('OE21-1', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))
760069	33919216	The photocurrent of CT81T2-4 outperformed that of CT81T2-1; CT81T2-4 was more severe in cancer level than CT81T2-1.	('CT81T2-4', 'Var', (60, 68))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
760178	33818145	Another study conducted in Brazil showed no difference between squamous cell carcinoma and esophageal adenocarcinoma in terms of prognosis, while poor differentiation histology and tumor size were associated with a worse oncological stage and subsequently decreased survival.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (91, 116))	('tumor', 'Disease', (181, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('squamous cell carcinoma', 'Disease', (63, 86))	('survival', 'MPA', (266, 274))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('esophageal adenocarcinoma', 'Disease', (91, 116))	('poor differentiation', 'Var', (146, 166))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (91, 116))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('decreased', 'NegReg', (256, 265))
760183	33209050	P2RX7 Gene rs1718125 Polymorphism is Related with Postoperative Pain and Fentanyl Intake in Esophageal Cancer Patients Prevention and control of postoperative pains are essential, which affects the prognosis and life quality of patients.	('affects', 'Reg', (186, 193))	('pain', 'Phenotype', 'HP:0012531', (159, 163))	('P2RX7', 'Gene', (0, 5))	('Postoperative Pain', 'Disease', 'MESH:D010149', (50, 68))	('P2RX7', 'Gene', '5027', (0, 5))	('rs1718125', 'Mutation', 'rs1718125', (11, 20))	('Postoperative Pain', 'Disease', (50, 68))	('patients', 'Species', '9606', (228, 236))	('rs1718125 Polymorphism', 'Var', (11, 33))	('Cancer', 'Disease', (103, 109))	('postoperative pains', 'Disease', (145, 164))	('Related', 'Reg', (37, 44))	('postoperative pains', 'Disease', 'MESH:D010149', (145, 164))	('Fentanyl', 'Chemical', 'MESH:D005283', (73, 81))	('Cancer', 'Disease', 'MESH:D009369', (103, 109))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Pain', 'Phenotype', 'HP:0012531', (64, 68))	('pains', 'Phenotype', 'HP:0012531', (159, 164))
760186	33209050	This study enrolling 645 esophageal cancer (EC) patients was aimed to investigate the associations of P2RX7 gene rs1718125 polymorphism with fentanyl intake and postoperative pains in a Chinese Han population.	('P2RX7', 'Gene', (102, 107))	('fentanyl', 'Chemical', 'MESH:D005283', (141, 149))	('P2RX7', 'Gene', '5027', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('associations', 'Interaction', (86, 98))	('cancer', 'Disease', (36, 42))	('pains', 'Phenotype', 'HP:0012531', (175, 180))	('postoperative pains', 'Disease', (161, 180))	('postoperative pains', 'Disease', 'MESH:D010149', (161, 180))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('pain', 'Phenotype', 'HP:0012531', (175, 179))	('rs1718125', 'Var', (113, 122))	('rs1718125', 'Mutation', 'rs1718125', (113, 122))	('patients', 'Species', '9606', (48, 56))
760188	33209050	P2RX7 rs1718125 polymorphism is connected to the postoperative pains and fentanyl use for EC patients.	('fentanyl', 'Chemical', 'MESH:D005283', (73, 81))	('rs1718125', 'Var', (6, 15))	('P2RX7', 'Gene', (0, 5))	('P2RX7', 'Gene', '5027', (0, 5))	('connected', 'Reg', (32, 41))	('postoperative pains', 'Disease', (49, 68))	('pains', 'Phenotype', 'HP:0012531', (63, 68))	('rs1718125', 'Mutation', 'rs1718125', (6, 15))	('postoperative pains', 'Disease', 'MESH:D010149', (49, 68))	('pain', 'Phenotype', 'HP:0012531', (63, 67))	('patients', 'Species', '9606', (93, 101))
760201	33209050	P2RX7 gene variants may influence the function of P2X7 receptor protein, thereby affecting the analgesic efficacy of opioids and the patient sensitivity to postsurgical pains.	('pains', 'Phenotype', 'HP:0012531', (169, 174))	('affecting', 'Reg', (81, 90))	('P2X7 receptor', 'Gene', (50, 63))	('P2RX7', 'Gene', (0, 5))	('P2RX7', 'Gene', '5027', (0, 5))	('pain', 'Phenotype', 'HP:0012531', (169, 173))	('variants', 'Var', (11, 19))	('patient', 'Species', '9606', (133, 140))	('function', 'MPA', (38, 46))	('pains', 'Disease', (169, 174))	('influence', 'Reg', (24, 33))	('P2X7 receptor', 'Gene', '5027', (50, 63))	('analgesic efficacy of opioids', 'MPA', (95, 124))	('pains', 'Disease', 'MESH:D010146', (169, 174))
760202	33209050	Some single-nucleotide polymorphisms (SNPs) in the P2RX7 gene are correlated with pain sensitivity in a diabetic neuropathic pain patient population.	('patient', 'Species', '9606', (130, 137))	('pain', 'Phenotype', 'HP:0012531', (125, 129))	('pain', 'Disease', 'MESH:D010146', (125, 129))	('pain', 'Disease', (125, 129))	('P2RX7', 'Gene', (51, 56))	('correlated with', 'Reg', (66, 81))	('diabetic neuropathic pain', 'Disease', (104, 129))	('single-nucleotide polymorphisms', 'Var', (5, 36))	('pain', 'Phenotype', 'HP:0012531', (82, 86))	('P2RX7', 'Gene', '5027', (51, 56))	('diabetic neuropathic pain', 'Disease', 'MESH:D003920', (104, 129))	('pain', 'Disease', 'MESH:D010146', (82, 86))	('pain', 'Disease', (82, 86))
760203	33209050	A recent Japanese study shows that P2RX7 gene rs1718125 polymorphism influenced fentanyl intake and cold pain sensitivity following painful orofacial cosmetic operation.	('pain', 'Phenotype', 'HP:0012531', (132, 136))	('fentanyl', 'Chemical', 'MESH:D005283', (80, 88))	('pain', 'Disease', 'MESH:D010146', (132, 136))	('pain', 'Disease', (132, 136))	('rs1718125 polymorphism', 'Var', (46, 68))	('polymorphism', 'Var', (56, 68))	('rs1718125', 'Mutation', 'rs1718125', (46, 55))	('pain', 'Phenotype', 'HP:0012531', (105, 109))	('P2RX7', 'Gene', (35, 40))	('P2RX7', 'Gene', '5027', (35, 40))	('cold pain', 'Disease', 'MESH:D010146', (100, 109))	('pain', 'Disease', 'MESH:D010146', (105, 109))	('fentanyl intake', 'MPA', (80, 95))	('pain', 'Disease', (105, 109))	('cold pain', 'Disease', (100, 109))	('influenced', 'Reg', (69, 79))
760220	33209050	The rs1718125 polymorphism of P2RX7 gene was genotyped by polymerase chain reaction (PCR) and direct sequencing.	('P2RX7', 'Gene', '5027', (30, 35))	('P2RX7', 'Gene', (30, 35))	('rs1718125', 'Var', (4, 13))	('rs1718125', 'Mutation', 'rs1718125', (4, 13))
760225	33209050	The distributions of genotypes and alleles of the P2RX7 gene rs1718125 polymorphism in EC patients are provided in Table 2.	('P2RX7', 'Gene', '5027', (50, 55))	('rs1718125', 'Var', (61, 70))	('rs1718125', 'Mutation', 'rs1718125', (61, 70))	('patients', 'Species', '9606', (90, 98))	('P2RX7', 'Gene', (50, 55))
760226	33209050	Our results revealed that P2RX7 rs1718125 polymorphism was associated with ASA classification I/II.	('P2RX7', 'Gene', (26, 31))	('P2RX7', 'Gene', '5027', (26, 31))	('rs1718125 polymorphism', 'Var', (32, 54))	('associated', 'Reg', (59, 69))	('ASA classification I/II', 'Disease', (75, 98))	('rs1718125', 'Mutation', 'rs1718125', (32, 41))	('ASA', 'Chemical', 'MESH:D001241', (75, 78))
760240	33209050	P2RX7 gene variants are involved in the modulation of human pain sensitivity.	('P2RX7', 'Gene', (0, 5))	('P2RX7', 'Gene', '5027', (0, 5))	('variants', 'Var', (11, 19))	('involved', 'Reg', (24, 32))	('pain', 'Phenotype', 'HP:0012531', (60, 64))	('pain', 'Disease', 'MESH:D010146', (60, 64))	('pain', 'Disease', (60, 64))	('human', 'Species', '9606', (54, 59))
760242	33209050	Ide et al uncovered that haplotypes of P2RX7 gene loci were related to both analgesia and cold pain sensitivity of fentanyl.	('fentanyl', 'Chemical', 'MESH:D005283', (115, 123))	('pain', 'Phenotype', 'HP:0012531', (95, 99))	('related to', 'Reg', (60, 70))	('Ide', 'Gene', '3416', (0, 3))	('P2RX7', 'Gene', (39, 44))	('P2RX7', 'Gene', '5027', (39, 44))	('haplotypes', 'Var', (25, 35))	('analgesia and cold pain', 'Disease', 'MESH:D000699', (76, 99))	('Ide', 'Gene', (0, 3))
760243	33209050	Herein, we explored the connections of P2RX7 gene rs1718125 polymorphism with post-surgical pain sensitivity and fentanyl intake in 645 operation-treated EC patients.	('fentanyl', 'Chemical', 'MESH:D005283', (113, 121))	('pain', 'Phenotype', 'HP:0012531', (92, 96))	('rs1718125', 'Var', (50, 59))	('rs1718125', 'Mutation', 'rs1718125', (50, 59))	('patients', 'Species', '9606', (157, 165))	('pain', 'Disease', 'MESH:D010146', (92, 96))	('P2RX7', 'Gene', (39, 44))	('pain', 'Disease', (92, 96))	('P2RX7', 'Gene', '5027', (39, 44))
760250	33209050	Third, whether P2RX7 gene rs1718125 polymorphism affected other postoperative responses was not explored.	('affected', 'Reg', (49, 57))	('rs1718125 polymorphism', 'Var', (26, 48))	('rs1718125', 'Mutation', 'rs1718125', (26, 35))	('P2RX7', 'Gene', (15, 20))	('P2RX7', 'Gene', '5027', (15, 20))
760252	33209050	To sum up, P2RX7 rs1718125 polymorphism correlates with the postoperative pain and fentanyl consumption of EC patients.	('rs1718125', 'Var', (17, 26))	('rs1718125', 'Mutation', 'rs1718125', (17, 26))	('postoperative pain', 'Disease', (60, 78))	('P2RX7', 'Gene', (11, 16))	('P2RX7', 'Gene', '5027', (11, 16))	('pain', 'Phenotype', 'HP:0012531', (74, 78))	('fentanyl consumption', 'MPA', (83, 103))	('postoperative pain', 'Disease', 'MESH:D010149', (60, 78))	('fentanyl', 'Chemical', 'MESH:D005283', (83, 91))	('patients', 'Species', '9606', (110, 118))
760253	33209050	EC, esophageal cancer; PCR, polymerase chain reaction; VAS, visual analog scale; P2RX7, purinergic receptor P2X7; SNP, single-nucleotide polymorphism.	('P2RX7', 'Gene', '5027', (81, 86))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('single-nucleotide polymorphism', 'Var', (119, 149))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('P2RX7', 'Gene', (81, 86))
760297	32751137	Inactivation of the tumor suppressor NOTCH1 gene has been reported in ESCC but not in EAC.	('NOTCH1', 'Gene', '4851', (37, 43))	('NOTCH1', 'Gene', (37, 43))	('reported', 'Reg', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('EAC', 'Chemical', 'MESH:C000430', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ESCC', 'Disease', (70, 74))	('Inactivation', 'Var', (0, 12))	('tumor', 'Disease', (20, 25))
760298	32751137	Interestingly inactivating mutations clustered in defined geographic areas, being more frequent in those ECSSs which affect North American patients than in those aroused in Chinese population.	('inactivating mutations', 'Var', (14, 36))	('patients', 'Species', '9606', (139, 147))	('ECSSs', 'Disease', (105, 110))
760299	32751137	Moreover, germline mutations in the RHBDF2 gene (17q25) which cause tylosis (focal non-epidermolytic palmoplantar keratoderma) have been reported to be markers of genetic familial susceptibility for the early onset of ESSC.	('RHBDF2', 'Gene', (36, 42))	('palmoplantar keratoderma', 'Phenotype', 'HP:0000982', (101, 125))	('-epidermolytic palmoplantar keratoderma', 'Phenotype', 'HP:0007404', (86, 125))	('RHBDF2', 'Gene', '79651', (36, 42))	('cause', 'Reg', (62, 67))	('ESSC', 'Disease', (218, 222))	('germline mutations', 'Var', (10, 28))	('epidermolytic palmoplantar keratoderma', 'Disease', 'MESH:D053546', (87, 125))	('epidermolytic palmoplantar keratoderma', 'Disease', (87, 125))	('tylosis', 'Disease', (68, 75))
760301	32751137	Comparative analysis show that most mutations found in EAC could be already detected in the matched BE which, - at least under genetic profile - identifies an early phase of malignant transformation.	('EAC', 'Chemical', 'MESH:C000430', (55, 58))	('EAC', 'Gene', (55, 58))	('mutations', 'Var', (36, 45))
760302	32751137	Mutations in the PIK3CA oncogene and in the CTNNB1 gene that encodes for beta-catenin are known to occur in BE and changes in several tumor suppressor genes involved in chromatin remodeling, such as ARID1A and SMARCA4 as well as in TP53 and SMAD4 are usually found in tissues with high-grade dysplasia and EAC.	('beta-catenin', 'Gene', (73, 85))	('SMAD4', 'Gene', '4089', (241, 246))	('PIK3CA', 'Gene', '5290', (17, 23))	('beta-catenin', 'Gene', '1499', (73, 85))	('dysplasia', 'Disease', 'MESH:C536170', (292, 301))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('TP53', 'Gene', '7157', (232, 236))	('CTNNB1', 'Gene', (44, 50))	('ARID1A', 'Gene', (199, 205))	('SMARCA4', 'Gene', '6597', (210, 217))	('Mutations', 'Var', (0, 9))	('EAC', 'Chemical', 'MESH:C000430', (306, 309))	('ARID1A', 'Gene', '8289', (199, 205))	('PIK3CA', 'Gene', (17, 23))	('SMAD4', 'Gene', (241, 246))	('TP53', 'Gene', (232, 236))	('dysplasia', 'Disease', (292, 301))	('tumor', 'Disease', (134, 139))	('SMARCA4', 'Gene', (210, 217))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('CTNNB1', 'Gene', '1499', (44, 50))
760303	32751137	Oncogene amplification is typically a late event in EAC progression.	('EAC', 'Chemical', 'MESH:C000430', (52, 55))	('Oncogene', 'Protein', (0, 8))	('amplification', 'Var', (9, 22))	('EAC', 'Disease', (52, 55))
760307	32751137	In conclusion, EACs emerge rather than from the gradual accumulation of tumor-suppressor alterations, from a straighter pathway driven by mutations in TP-53 gene and subsequent acquisition of oncogene amplifications.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('TP-53', 'Gene', (151, 156))	('EACs', 'Disease', (15, 19))	('EAC', 'Chemical', 'MESH:C000430', (15, 18))	('tumor', 'Disease', (72, 77))	('TP-53', 'Gene', '7157', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mutations', 'Var', (138, 147))
760310	32751137	Epigenetic modifications are known to contribute significantly to the pathogenesis of the disease and specific methylation signatures are known to be associated to tumor progression processes and thus emerge as novel actionable markers.	('associated', 'Reg', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('methylation signatures', 'Var', (111, 133))	('contribute', 'Reg', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('Epigenetic', 'MPA', (0, 10))
760314	32751137	One third of HDGC is attributed to hereditary CDH1 mutations.	('mutations', 'Var', (51, 60))	('HDGC', 'Disease', (13, 17))	('CDH1', 'Gene', (46, 50))	('attributed', 'Reg', (21, 31))	('HDGC', 'Disease', 'MESH:D013274', (13, 17))	('CDH1', 'Gene', '999', (46, 50))
760316	32751137	Within respect to the non-hereditary forms of GC, recent molecular profiling studies have allowed the shift from the conventional histological classification systems to four molecularly-based classification groups: (i) EBV-positive cancers (9-10% of gastric AC) harboring high frequency of PI3KCA gene changes (80%), high levels of DNA hypermethylation, mutations in PTEN, SMADA, CDKN2A, ARIDA (55%) and BCOR (23%) and increased copies of JAK2, ERBB2, PD-L1 and PD-1 genes, (ii) microsatellite unstable (MSI) tumors, accounting for 22% of diagnosis, which mainly arise in women and older patients and frequently carry hypermethylation MLH1 promoter in association with recurrent mutations in the PIK3CA, ERBB3, ERBB2 and EGFR genes, (iii) genomically stable (GS) tumors (20% of cases, mainly diffuse-type AC) which mostly affect younger subjects and are enriched with recurrent CDH1 (37%), RHOA (15%) and inactivating ARID1A gene changes.	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (509, 514))	('cancers', 'Disease', (232, 239))	('ERBB3', 'Gene', '2065', (704, 709))	('tumor', 'Phenotype', 'HP:0002664', (763, 768))	('women', 'Species', '9606', (572, 577))	('tumors', 'Disease', (509, 515))	('MLH1', 'Gene', '4292', (635, 639))	('ARID1A', 'Gene', '8289', (918, 924))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', (763, 769))	('JAK2', 'Gene', (439, 443))	('CDH1', 'Gene', '999', (878, 882))	('EGFR', 'Gene', '1956', (721, 725))	('ERBB2', 'Gene', (445, 450))	('PD-L1', 'Gene', (452, 457))	('inactivating', 'Var', (905, 917))	('PTEN', 'Gene', (367, 371))	('tumors', 'Disease', 'MESH:D009369', (509, 515))	('tumors', 'Disease', 'MESH:D009369', (763, 769))	('BCOR', 'Gene', '54880', (404, 408))	('PD-L1', 'Gene', '29126', (452, 457))	('RHOA', 'Gene', '387', (890, 894))	('CDH1', 'Gene', (878, 882))	('RHOA', 'Gene', (890, 894))	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('PIK3CA', 'Gene', '5290', (696, 702))	('ERBB2', 'Gene', '2064', (445, 450))	('changes', 'Var', (930, 937))	('BCOR', 'Gene', (404, 408))	('CDKN2A', 'Gene', (380, 386))	('ERBB3', 'Gene', (704, 709))	('PTEN', 'Gene', '5728', (367, 371))	('patients', 'Species', '9606', (588, 596))	('ERBB2', 'Gene', (711, 716))	('GS', 'Disease', 'MESH:D011125', (759, 761))	('mutations', 'Var', (354, 363))	('EGFR', 'Gene', (721, 725))	('tumors', 'Phenotype', 'HP:0002664', (509, 515))	('JAK2', 'Gene', '3717', (439, 443))	('MLH1', 'Gene', (635, 639))	('mutations', 'Var', (679, 688))	('CDKN2A', 'Gene', '1029', (380, 386))	('ARID1A', 'Gene', (918, 924))	('ERBB2', 'Gene', '2064', (711, 716))	('tumors', 'Phenotype', 'HP:0002664', (763, 769))	('PIK3CA', 'Gene', (696, 702))
760317	32751137	Fusions involving the RHO-family GTPase-activating proteins CLDN18 and ARHGAP26, have been reported as well; (iv) chromosomal unstable (CIN) subtypes which account for 50% of GCs and harbor extensive aneuploidy, TP53 mutations (71%) and increased copy number of several genes encoding for receptor tyrosine kinases and their downstream effectors as EGFR, ERBB2, ERBB3, VEGFA, FGFR2, MET, NRAS/KRAS, JAK2, CD274, PDCD1LG2 and PIK3CA.	('increased', 'PosReg', (237, 246))	('CLDN18', 'Gene', '51208', (60, 66))	('GCs', 'Disease', (175, 178))	('FGFR2', 'Gene', (376, 381))	('PIK3CA', 'Gene', (425, 431))	('PDCD1LG2', 'Gene', (412, 420))	('KRAS', 'Gene', '3845', (393, 397))	('MET', 'Gene', (383, 386))	('VEGFA', 'Gene', '7422', (369, 374))	('NRAS', 'Gene', '4893', (388, 392))	('JAK2', 'Gene', (399, 403))	('FGFR2', 'Gene', '2263', (376, 381))	('KRAS', 'Gene', (393, 397))	('aneuploidy', 'Disease', (200, 210))	('CIN', 'Disease', 'MESH:D007674', (136, 139))	('ARHGAP26', 'Gene', '23092', (71, 79))	('ERBB3', 'Gene', '2065', (362, 367))	('EGFR', 'Gene', (349, 353))	('ERBB2', 'Gene', (355, 360))	('TP53', 'Gene', '7157', (212, 216))	('ARHGAP26', 'Gene', (71, 79))	('CD274', 'Gene', '29126', (405, 410))	('EGFR', 'Gene', '1956', (349, 353))	('PIK3CA', 'Gene', '5290', (425, 431))	('NRAS', 'Gene', (388, 392))	('MET', 'Gene', '79811', (383, 386))	('ERBB2', 'Gene', '2064', (355, 360))	('CLDN18', 'Gene', (60, 66))	('PDCD1LG2', 'Gene', '80380', (412, 420))	('CIN', 'Disease', (136, 139))	('VEGFA', 'Gene', (369, 374))	('aneuploidy', 'Disease', 'MESH:D000782', (200, 210))	('CD274', 'Gene', (405, 410))	('JAK2', 'Gene', '3717', (399, 403))	('mutations', 'Var', (217, 226))	('ERBB3', 'Gene', (362, 367))	('TP53', 'Gene', (212, 216))
760318	32751137	A recent genomic study of gastric cancers identified somatic copy number alterations of seven oncogenes involved in tyrosine kinase/MAP-kinase pathways: KRAS, EGFR, HER2, FGFR1, FGFR2, MET and IGF1R.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('EGFR', 'Gene', '1956', (159, 163))	('FGFR1', 'Gene', '2260', (171, 176))	('MET', 'Gene', (185, 188))	('IGF1R', 'Gene', '3480', (193, 198))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('FGFR2', 'Gene', (178, 183))	('gastric cancers', 'Disease', (26, 41))	('IGF1R', 'Gene', (193, 198))	('gastric cancers', 'Disease', 'MESH:D013274', (26, 41))	('gastric cancers', 'Phenotype', 'HP:0012126', (26, 41))	('KRAS', 'Gene', '3845', (153, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (26, 40))	('HER2', 'Gene', '2064', (165, 169))	('FGFR2', 'Gene', '2263', (178, 183))	('MET', 'Gene', '79811', (185, 188))	('FGFR1', 'Gene', (171, 176))	('KRAS', 'Gene', (153, 157))	('EGFR', 'Gene', (159, 163))	('copy number alterations', 'Var', (61, 84))	('HER2', 'Gene', (165, 169))
760320	32751137	A first example regards the blockade of HER2 signaling which has significantly improved the outlook for esophagogastric cancer patients and has allowed the approval of trastuzumab in HER2-positive metastatic gastric/gastroesophageal junction cancers, as first line approach in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil).	('HER2', 'Gene', '2064', (183, 187))	('HER2', 'Gene', '2064', (40, 44))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('blockade', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (344, 358))	('fluoropyrimidine', 'Chemical', '-', (310, 326))	('improved', 'PosReg', (79, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (294, 303))	('HER2', 'Gene', (183, 187))	('HER2', 'Gene', (40, 44))	('gastric/gastroesophageal junction cancers', 'Disease', 'MESH:D013274', (208, 249))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('trastuzumab', 'Chemical', 'MESH:D000068878', (168, 179))	('gastric cancer', 'Disease', (112, 126))	('patients', 'Species', '9606', (127, 135))	('gastric/gastroesophageal junction cancers', 'Disease', (208, 249))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('capecitabine', 'Chemical', 'MESH:D000069287', (328, 340))
760321	32751137	HER2 is activated most frequently by increased gene copy number, whereas somatic mutations rarely occur.	('activated', 'PosReg', (8, 17))	('HER2', 'Gene', (0, 4))	('increased', 'PosReg', (37, 46))	('HER2', 'Gene', '2064', (0, 4))	('gene copy number', 'Var', (47, 63))
760331	32751137	Amplification/overexpression of the HGF-receptor MET rather than mutated gene can activate receptor tyrosine kinase.	('activate', 'PosReg', (82, 90))	('MET', 'Gene', '79811', (49, 52))	('HGF-receptor', 'Gene', (36, 48))	('receptor tyrosine kinase', 'MPA', (91, 115))	('Amplification/overexpression', 'Var', (0, 28))	('MET', 'Gene', (49, 52))	('HGF-receptor', 'Gene', '4233', (36, 48))
760333	32751137	Notably, a cross talk between amplified MET and EGFR, HER2 and HER3 has been described and can establish a signaling network, allowing constitutive PI3K/AKT cascade activation.	('activation', 'PosReg', (165, 175))	('MET', 'Gene', (40, 43))	('HER3', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (48, 52))	('AKT', 'Gene', '207', (153, 156))	('HER3', 'Gene', '2065', (63, 67))	('HER2', 'Gene', (54, 58))	('EGFR', 'Gene', (48, 52))	('cross talk', 'Reg', (11, 21))	('HER2', 'Gene', '2064', (54, 58))	('AKT', 'Gene', (153, 156))	('MET', 'Gene', '79811', (40, 43))	('amplified', 'Var', (30, 39))
760335	32751137	DNA repair BRCA1/2 genes mutations are implicated in defective DNA repair processes and are known to be associated to the susceptibility towards hereditary breast and ovarian cancers and can occur in other sporadic cancers, among which gastric cancers.	('associated', 'Reg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('mutations', 'Var', (25, 34))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('BRCA1/2', 'Gene', '672;675', (11, 18))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('occur', 'Reg', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('implicated', 'Reg', (39, 49))	('ovarian cancers', 'Phenotype', 'HP:0100615', (167, 182))	('sporadic cancers', 'Disease', 'MESH:D009369', (206, 222))	('DNA repair', 'MPA', (63, 73))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('gastric cancers', 'Disease', (236, 251))	('gastric cancers', 'Disease', 'MESH:D013274', (236, 251))	('gastric cancers', 'Phenotype', 'HP:0012126', (236, 251))	('defective', 'NegReg', (53, 62))	('hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (145, 182))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('sporadic cancers', 'Disease', (206, 222))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('BRCA1/2', 'Gene', (11, 18))
760336	32751137	BRCA1/2 mutations are found in 15% of GCs and are associated with poor patient survival.	('BRCA1/2', 'Gene', '672;675', (0, 7))	('mutations', 'Var', (8, 17))	('GCs', 'Disease', (38, 41))	('patient', 'Species', '9606', (71, 78))	('associated', 'Reg', (50, 60))	('BRCA1/2', 'Gene', (0, 7))
760340	32751137	Strong evidence suggests that alteration in micro-RNA (miRNA) expression acts as important hallmark of cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('micro-RNA', 'Protein', (44, 53))	('alteration', 'Var', (30, 40))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
760380	32751137	Overall, high expression of PD-L1 associated to CD8+, CD3+ and CD57+ TILs and low densities of FOXP3+ TILs represent favorable prognostic factors.	('PD-L1', 'Gene', '29126', (28, 33))	('FOXP3', 'Gene', '50943', (95, 100))	('CD3+', 'Var', (54, 58))	('CD57', 'Gene', (63, 67))	('CD8', 'Gene', (48, 51))	('expression', 'MPA', (14, 24))	('CD57', 'Gene', '27087', (63, 67))	('PD-L1', 'Gene', (28, 33))	('CD8', 'Gene', '925', (48, 51))	('FOXP3', 'Gene', (95, 100))
760396	32751137	Notably, high PD-L1 expression has been associated with the induction of the epithelial-to-mesenchymal transition phenomenon is required to tumor distant spreading.	('PD-L1', 'Gene', '29126', (14, 19))	('expression', 'MPA', (20, 30))	('tumor', 'Disease', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('epithelial-to-mesenchymal transition phenomenon', 'CPA', (77, 124))	('men', 'Species', '9606', (119, 122))	('PD-L1', 'Gene', (14, 19))	('associated', 'Reg', (40, 50))	('high', 'Var', (9, 13))
760429	32751137	Overexpression of TGFB2 has been reported to be positively associated with EMT status and negatively with TMB levels in GC.	('TMB', 'Chemical', '-', (106, 109))	('negatively', 'NegReg', (90, 100))	('TMB levels', 'MPA', (106, 116))	('TGFB2', 'Gene', '7042', (18, 23))	('TGFB2', 'Gene', (18, 23))	('associated', 'Interaction', (59, 69))	('Overexpression', 'Var', (0, 14))	('EMT status', 'CPA', (75, 85))	('positively', 'PosReg', (48, 58))
760440	32751137	The study aims at identifying polymorphisms in the IL-1, tumor necrosis factor-alpha (TNF-alpha) and IL-10 coding genes to clarify the association between those changes and cancer risks to early locate those individuals at higher risks for gastrointestinal malignancies development.	('IL-1', 'Gene', (51, 55))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('IL-1', 'Gene', '3552', (51, 55))	('gastrointestinal malignancies', 'Disease', 'MESH:D004067', (240, 269))	('cancer', 'Disease', (173, 179))	('TNF-alpha', 'Gene', '7124', (86, 95))	('polymorphisms', 'Var', (30, 43))	('IL-1', 'Gene', '3552', (101, 105))	('IL-1', 'Gene', (101, 105))	('TNF-alpha', 'Gene', (86, 95))	('IL-10', 'Gene', '3586', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor necrosis factor-alpha', 'Gene', (57, 84))	('tumor necrosis factor-alpha', 'Gene', '7124', (57, 84))	('gastrointestinal malignancies', 'Disease', (240, 269))	('men', 'Species', '9606', (277, 280))	('IL-10', 'Gene', (101, 106))
760446	32751137	However, the accumulation of passenger and driver genetic changes generate cancer-specific neoepitopes that are recognized by autologous T cells as not-self: these molecules on the surface of cancer cells identify ideal targets for vaccines.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('changes', 'Var', (58, 65))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('genetic changes', 'Var', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
760452	32751137	Although not fully documented in upper GI cancers, the variant III of the EGFR receptor seems to behave as oncogene in several solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('EGFR', 'Gene', (74, 78))	('solid tumors', 'Disease', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('upper GI cancers', 'Disease', 'MESH:D009369', (33, 49))	('upper GI cancers', 'Disease', (33, 49))	('GI cancer', 'Phenotype', 'HP:0007378', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EGFR', 'Gene', '1956', (74, 78))	('solid tumors', 'Disease', 'MESH:D009369', (127, 139))	('men', 'Species', '9606', (23, 26))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('variant III', 'Var', (55, 66))
760467	32751137	For instance, vaccination using peptides derived from human VEGFR 1 and 2 combined with standard chemotherapy can significantly increase the OS of patients carrying advanced GCs.	('peptides', 'Var', (32, 40))	('VEGFR 1 and 2', 'Gene', '2321;3791', (60, 73))	('increase', 'PosReg', (128, 136))	('advanced GCs', 'Disease', (165, 177))	('patients', 'Species', '9606', (147, 155))	('human', 'Species', '9606', (54, 59))
760495	32751137	The efficacy of this approach is now under investigation also in several trials in gastric cancer patients (NCT02862028, NCT03615313 and NCT03182803).	('NCT02862028', 'Var', (108, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('patients', 'Species', '9606', (98, 106))	('gastric cancer', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NCT03182803', 'Var', (137, 148))	('NCT03615313', 'Var', (121, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))
760604	31613226	Therefore, the dysfunction of Hippo/YAP1 pathway could imbalance the regulation, which could cause the cancer initiation.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('imbalance', 'NegReg', (55, 64))	('imbalance', 'Phenotype', 'HP:0002172', (55, 64))	('cause', 'Reg', (93, 98))	('YAP1', 'Gene', (36, 40))	('YAP1', 'Gene', '10413', (36, 40))	('dysfunction', 'Var', (15, 26))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('regulation', 'MPA', (69, 79))
760614	31613226	The results showed YAP1 expression was observed to be significantly related with worse OS, but not with DFS.	('YAP1', 'Gene', (19, 23))	('related', 'Reg', (68, 75))	('YAP1', 'Gene', '10413', (19, 23))	('expression', 'Var', (24, 34))	('worse OS', 'Disease', (81, 89))
760651	30083911	The meta-analysis showed that high expression of PVT1 could predict more lymph node metastasis (LNM) (Odds ratio, OR = 2.83, 95% confidence interval, CI: 1.76-4.54, P < 0.0001), distant metastasis (DM) (OR = 3.60, 95% CI: 1.08-12.03, P = 0.04), advanced clinical stage (OR = 4.37, 95% CI: 3.45-5.54, P < 0.00001) and poor overall survival (Hazard ratio, HR = 2.08, 95% CI: 1.82-2.37, P < 0.00001)in cancer.	('cancer', 'Disease', (399, 405))	('DM', 'Disease', 'MESH:D009223', (198, 200))	('cancer', 'Disease', 'MESH:D009369', (399, 405))	('advanced clinical stage', 'CPA', (245, 268))	('high expression', 'Var', (30, 45))	('more', 'PosReg', (68, 72))	('PVT1', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (399, 405))	('overall survival', 'CPA', (322, 338))	('distant metastasis', 'CPA', (178, 196))	('lymph node metastasis', 'CPA', (73, 94))	('PVT1', 'Gene', '5820', (49, 53))	('poor', 'NegReg', (317, 321))
760682	30083911	Analysis showed that the OR of high PVT1 expression group versus low PVT1 expression group was 2.83 (95% CI: 1.76-4.54, P < 0.0001) (Fig.	('PVT1', 'Gene', '5820', (36, 40))	('PVT1', 'Gene', (69, 73))	('high', 'Var', (31, 35))	('PVT1', 'Gene', (36, 40))	('PVT1', 'Gene', '5820', (69, 73))
760685	30083911	However, in urinary system tumors, the pooled result showed that cancer patients with high PVT1 expression were more likely to develop to LNM through no statistical significance was observed (OR = 1.09, 95% CI: 0.11-10.45, P = 0.94) (Fig.	('develop', 'PosReg', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('LNM', 'Disease', (138, 141))	('urinary system tumors', 'Disease', 'MESH:D001749', (12, 33))	('PVT1', 'Gene', (91, 95))	('urinary system tumors', 'Phenotype', 'HP:0010786', (12, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PVT1', 'Gene', '5820', (91, 95))	('urinary system tumors', 'Disease', (12, 33))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('high', 'Var', (86, 90))	('patients', 'Species', '9606', (72, 80))
760687	30083911	Analysis showed that high PVT1 expression was more prone to DM (OR = 3.60, 95% CI: 1.08-12.03, P = 0.04) (Fig.	('PVT1', 'Gene', (26, 30))	('prone', 'Reg', (51, 56))	('DM', 'Disease', 'MESH:D009223', (60, 62))	('PVT1', 'Gene', '5820', (26, 30))	('high', 'Var', (21, 25))	('expression', 'MPA', (31, 41))
760702	30083911	Results showed that the risk of lymph node metastasis and distant metastasis in high PVT1 expression group was 2.83 and 3.60 folds than those with low PVT1 expression group, respectively.	('PVT1', 'Gene', (85, 89))	('PVT1', 'Gene', (151, 155))	('lymph node metastasis', 'CPA', (32, 53))	('PVT1', 'Gene', '5820', (151, 155))	('PVT1', 'Gene', '5820', (85, 89))	('distant metastasis', 'CPA', (58, 76))	('high', 'Var', (80, 84))
760715	30083911	demonstrated high PVT1 expression exhibited greater lymph node metastasis, venous invasion and a poor OS compared with low PVT1 expression.	('OS', 'Chemical', '-', (102, 104))	('PVT1', 'Gene', (123, 127))	('high', 'Var', (13, 17))	('venous invasion', 'CPA', (75, 90))	('PVT1', 'Gene', '5820', (123, 127))	('expression', 'Var', (23, 33))	('PVT1', 'Gene', (18, 22))	('poor OS', 'CPA', (97, 104))	('greater', 'PosReg', (44, 51))	('PVT1', 'Gene', '5820', (18, 22))	('lymph node metastasis', 'CPA', (52, 73))
760731	30083911	In general, PVT1 expression was significantly associated with metastasis, clinical stage, and poor prognosis in various types of cancer in different systems.	('metastasis', 'CPA', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('PVT1', 'Gene', '5820', (12, 16))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('expression', 'Var', (17, 27))	('associated with', 'Reg', (46, 61))	('PVT1', 'Gene', (12, 16))
760785	30450159	A non-significant reduction in mortality was observed for positive ERbeta tumor expression, when restricting to patients with gastro-esophageal junctional (GEJ) cancer (HR 0.58, 95% CI 0.33, 1.03, p = 0.06).	('ERbeta tumor', 'Disease', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ERbeta tumor', 'Disease', 'MESH:D009369', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('patients', 'Species', '9606', (112, 120))	('positive', 'Var', (58, 66))	('gastro-esophageal junctional (GEJ) cancer', 'Disease', 'MESH:D005764', (126, 167))	('reduction', 'NegReg', (18, 27))
760797	30450159	Androgen receptor (AR) is a key mediator of inflammatory signals in esophageal cancer progression and its expression has been shown to promote cell migration, invasion and proliferation in esophageal cancer in vivo.	('esophageal cancer', 'Disease', (189, 206))	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('promote', 'PosReg', (135, 142))	('proliferation', 'CPA', (172, 185))	('cell migration', 'CPA', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (189, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('Androgen receptor', 'Gene', '367', (0, 17))	('AR', 'Gene', '367', (19, 21))	('Androgen receptor', 'Gene', (0, 17))	('expression', 'Var', (106, 116))	('invasion', 'CPA', (159, 167))	('esophageal cancer', 'Disease', (68, 85))
760815	30450159	Demographic and lifestyle factors did not differ significantly according to sex hormone receptor status and similarly, there were no significant differences in tumor characteristics by ERalpha, ERbeta or AR expression (Table 1).	('AR', 'Gene', '367', (204, 206))	('ERalpha', 'Gene', (185, 192))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('ERbeta', 'Var', (194, 200))	('ERalpha', 'Gene', '2099', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))
760825	30450159	In adjusted analyses, improvements in overall survival (HR 0.71, 95% CI 0.41, 1.21), cancer-specific survival (HR 0.73, 95% CI 0.42, 1.28) and recurrence-free survival (HR 0.89, 95% CI 0.53, 1.48) were observed for patients whose tumors expressed ERbeta compared to those whose tumors were negative for ERbeta, however results were not statistically significant.	('patients', 'Species', '9606', (215, 223))	('overall survival', 'CPA', (38, 54))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumors', 'Disease', (278, 284))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('recurrence-free survival', 'CPA', (143, 167))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', (85, 91))	('improvements', 'PosReg', (22, 34))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('men', 'Species', '9606', (29, 32))	('ERbeta', 'Var', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
760834	30450159	This is the first study to investigate sex hormone receptor expression in EAC patients by tumor location and there was a suggestion that ERbeta expression was associated with a reduction in the risk of all-cause and cancer-specific death in patients with GEJ cancer, albeit findings did not reach statistical significance.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('death', 'Disease', 'MESH:D003643', (232, 237))	('EAC', 'Phenotype', 'HP:0011459', (74, 77))	('death', 'Disease', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('reduction', 'NegReg', (177, 186))	('tumor', 'Disease', (90, 95))	('all-cause', 'CPA', (202, 211))	('patients', 'Species', '9606', (78, 86))	('ERbeta', 'Protein', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('expression', 'Var', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('patients', 'Species', '9606', (241, 249))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('cancer', 'Disease', (259, 265))
760851	30450159	Interestingly, ERbeta has been correlated with improved survival in non-small cell lung adenocarcinoma, particularly in men, although findings from other studies have been mixed and a recent pooled analyses found no association between ERbeta expression and survival in NSCLC patients.	('improved', 'PosReg', (47, 55))	('patients', 'Species', '9606', (276, 284))	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('survival', 'MPA', (56, 64))	('non-small cell lung adenocarcinoma', 'Phenotype', 'HP:0030358', (68, 102))	('cell lung adenocarcinoma', 'Disease', (78, 102))	('small cell lung adenocarcinoma', 'Phenotype', 'HP:0030357', (72, 102))	('ERbeta', 'Var', (15, 21))	('cell lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('NSCLC', 'Disease', (270, 275))	('men', 'Species', '9606', (120, 123))
760853	30450159	AR has been shown to be an important mediator of inflammatory signals in esophageal cancer progression and overexpression of AR in vivo has been shown to promote cell migration, invasion and proliferation in esophageal cancer.	('AR', 'Gene', '367', (125, 127))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('promote', 'PosReg', (154, 161))	('esophageal cancer', 'Disease', (73, 90))	('cell migration', 'CPA', (162, 176))	('overexpression', 'Var', (107, 121))	('AR', 'Gene', '367', (0, 2))	('invasion', 'CPA', (178, 186))	('esophageal cancer', 'Disease', (208, 225))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('proliferation', 'CPA', (191, 204))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))
760856	30450159	In our study, sensitivity analysis suggested that ERbeta expression was associated with more marked reductions in all-cause and cancer-specific mortality in patients diagnosed with GEJ cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('expression', 'Var', (57, 67))	('ERbeta', 'Gene', (50, 56))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('reductions', 'NegReg', (100, 110))	('cancer', 'Disease', (128, 134))
760968	29480665	Chiriva -Internati et al., (2012) demonstrated the aberrant expression of AKAP-4 in PC (prostate cancer), which will potentially be developed as a biomarker in PC (Chiriva-Internati et al., 2012).	('expression', 'MPA', (60, 70))	('AKAP-4', 'Gene', '8852', (74, 80))	('prostate cancer', 'Disease', (88, 103))	('aberrant', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('PC', 'CellLine', 'CVCL:0152', (84, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('PC', 'CellLine', 'CVCL:0152', (160, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('AKAP-4', 'Gene', (74, 80))
761046	28647069	While patient-specific factors influence treatment delays, even when adjusted for higher risk characteristics, surgical resection greater than 8 weeks from diagnosis is independently associated with pathologic upstaging and decreased median survival yet nearly 20% of patients experience significant care delay.	('decreased', 'NegReg', (224, 233))	('patient', 'Species', '9606', (6, 13))	('surgical resection', 'Var', (111, 129))	('median survival', 'MPA', (234, 249))	('upstaging', 'PosReg', (210, 219))	('patient', 'Species', '9606', (268, 275))	('patients', 'Species', '9606', (268, 276))
761069	28647069	These studies demonstrate an improvement in patient survival with adherence to quality guidelines, but also demonstrate the variation in definition of quality metrics.	('patient survival', 'CPA', (44, 60))	('patient', 'Species', '9606', (44, 51))	('improvement', 'PosReg', (29, 40))	('adherence', 'Var', (66, 75))
761081	28647069	These authors also found improved survival with adjuvant therapy in patients with R1 resection, although this remains controversial.	('improved', 'PosReg', (25, 33))	('patients', 'Species', '9606', (68, 76))	('survival', 'MPA', (34, 42))	('R1 resection', 'Var', (82, 94))
761110	29215765	Here, we studied the direct effects of H. pylori on the transformation of esophageal epithelial cells, with particular focus on whether H. pylori exerts its effects by modulating miRNAs and their downstream target genes.	('H. pylori', 'Species', '210', (39, 48))	('miRNAs', 'MPA', (179, 185))	('H. pylori', 'Species', '210', (136, 145))	('modulating', 'Reg', (168, 178))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (74, 94))	('H. pylori', 'Var', (136, 145))	('esophageal epithelia', 'Disease', (74, 94))	('esophageal epithelia', 'Disease', 'MESH:D004941', (74, 94))
761114	29215765	Helicobacter pylori modified the miRNA profiles of esophageal epithelial cells, particularly aberrant silencing of miR-212-3p and miR-361-3p.	('Helicobacter pylori', 'Species', '210', (0, 19))	('esophageal epithelia', 'Disease', (51, 71))	('esophageal epithelia', 'Disease', 'MESH:D004941', (51, 71))	('miR-361-3p', 'Gene', '100500908', (130, 140))	('aberrant', 'Var', (93, 101))	('silencing', 'NegReg', (102, 111))	('miR-212-3p', 'Gene', (115, 125))	('modified', 'Reg', (20, 28))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (51, 71))	('miR-361-3p', 'Gene', (130, 140))	('miRNA profiles', 'MPA', (33, 47))
761116	29215765	Furthermore, we identified COX2 as a target of miR-212-3p, and CDX2 as a target of miR-361-3p.	('miR-212-3p', 'Var', (47, 57))	('miR-361-3p', 'Gene', '100500908', (83, 93))	('COX2', 'Gene', (27, 31))	('miR-361-3p', 'Gene', (83, 93))	('COX2', 'Gene', '5743', (27, 31))	('CDX2', 'Gene', (63, 67))	('CDX2', 'Gene', '1045', (63, 67))
761129	29215765	In this study, we determined the long-term and direct effects of H. pylori on the phenotype of esophageal epithelia cells by using a well-established in vitro model.20 We particularly focused on whether H. pylori exerts its effects through modulating miRNAs and their downstream target genes.	('modulating', 'Reg', (240, 250))	('H. pylori', 'Species', '210', (203, 212))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (95, 115))	('H. pylori', 'Species', '210', (65, 74))	('esophageal epithelia', 'Disease', 'MESH:D004941', (95, 115))	('miRNAs', 'Gene', (251, 257))	('esophageal epithelia', 'Disease', (95, 115))	('H. pylori', 'Var', (203, 212))
761168	29215765	These data indicate that H. pylori might synergistically enhance acidified DCA-induced transformation in normal esophageal epithelial cells.	('acidified DCA-induced', 'Disease', (65, 86))	('esophageal epithelia', 'Disease', (112, 132))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (112, 132))	('H. pylori', 'Species', '210', (25, 34))	('DCA', 'Chemical', 'MESH:D003840', (75, 78))	('esophageal epithelia', 'Disease', 'MESH:D004941', (112, 132))	('H. pylori', 'Var', (25, 34))	('enhance', 'PosReg', (57, 64))
761172	29215765	Thus, prolonged exposure of HET-1A cells to H. pylori seems to aggravate the tumorigenic phenotype conferred by acidified DCA.	('DCA', 'Chemical', 'MESH:D003840', (122, 125))	('aggravate', 'PosReg', (63, 72))	('H. pylori', 'Species', '210', (44, 53))	('H. pylori', 'Var', (44, 53))	('tumorigenic phenotype', 'CPA', (77, 98))	('HET-1A', 'CellLine', 'CVCL:3702', (28, 34))
761177	29215765	Analysis with TargetScan, miRBase, and miRanda identified COX2 as a potential target of miR-212-3p and CDX2 as a potential target of miR-361-3p.	('miR-361-3p', 'Gene', (133, 143))	('miR-361-3p', 'Gene', '100500908', (133, 143))	('CDX2', 'Gene', (103, 107))	('COX2', 'Gene', '5743', (58, 62))	('COX2', 'Gene', (58, 62))	('miR-212-3p', 'Var', (88, 98))	('CDX2', 'Gene', '1045', (103, 107))
761178	29215765	Thus, miR-212-3p and miR-361-3p were selected for further RT-qPCR confirmation experiments.	('miR-212-3p', 'Var', (6, 16))	('miR-361-3p', 'Gene', (21, 31))	('miR-361-3p', 'Gene', '100500908', (21, 31))
761179	29215765	We detected the temporal expression of miR-212-3p and miR-361-3p in esophageal epithelial cells following infection with H. pylori.	('infection', 'Disease', 'MESH:D007239', (106, 115))	('esophageal epithelia', 'Disease', (68, 88))	('miR-361-3p', 'Gene', '100500908', (54, 64))	('H. pylori', 'Species', '210', (121, 130))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (68, 88))	('miR-361-3p', 'Gene', (54, 64))	('miR-212-3p', 'Var', (39, 49))	('esophageal epithelia', 'Disease', 'MESH:D004941', (68, 88))	('infection', 'Disease', (106, 115))
761186	29215765	In Barrett's esophagus, intestinal metaplasia of esophageal epithelium facilitates colonization of H. pylori in the distal esophagus, and therefore exacerbates inflammation.	('metaplasia', 'Disease', (35, 45))	('H. pylori', 'Species', '210', (99, 108))	('inflammation', 'Disease', 'MESH:D007249', (160, 172))	('inflammation', 'Disease', (160, 172))	('exacerbates', 'PosReg', (148, 159))	('colonization', 'CPA', (83, 95))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (3, 22))	('metaplasia', 'Disease', 'MESH:D008679', (35, 45))	('facilitates', 'PosReg', (71, 82))	('intestinal', 'Var', (24, 34))
761187	29215765	Our data suggested that aberrant silencing of miR-212-3p and miR-361-3p may be involved in H. pylori-induced esophageal injury.	('miR-361-3p', 'Gene', (61, 71))	('H. pylori', 'Species', '210', (91, 100))	('silencing', 'NegReg', (33, 42))	('miR-361-3p', 'Gene', '100500908', (61, 71))	('aberrant', 'Var', (24, 32))	('esophageal injury', 'Disease', (109, 126))	('miR-212-3p', 'Protein', (46, 56))	('involved', 'Reg', (79, 87))	('esophageal injury', 'Disease', 'MESH:D004941', (109, 126))
761188	29215765	To explore mechanisms underlying transformation of esophageal epithelial cells induced by H. pylori, we determined whether miR-212-3p and miR-361-3p could post-transcriptionally regulate COX2 and CDX2, respectively.	('miR-361-3p', 'Gene', '100500908', (138, 148))	('miR-212-3p', 'Var', (123, 133))	('esophageal epithelia', 'Disease', (51, 71))	('regulate', 'Reg', (178, 186))	('esophageal epithelia', 'Disease', 'MESH:D004941', (51, 71))	('CDX2', 'Gene', (196, 200))	('miR-361-3p', 'Gene', (138, 148))	('CDX2', 'Gene', '1045', (196, 200))	('H. pylori', 'Species', '210', (90, 99))	('COX2', 'Gene', (187, 191))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (51, 71))	('COX2', 'Gene', '5743', (187, 191))
761189	29215765	Analysis of the human COX2 3'-UTR sequence predicted that the miR-212-3p seed sequence is complementary to a potential binding site of COX2 (Figure 4A).	('COX2', 'Gene', '5743', (135, 139))	('COX2', 'Gene', (135, 139))	('COX2', 'Gene', '5743', (22, 26))	('COX2', 'Gene', (22, 26))	('miR-212-3p', 'Var', (62, 72))	('human', 'Species', '9606', (16, 21))
761190	29215765	We used a luciferase reporter assay to determine whether miR-212-3p could directly target the 3'-UTR of COX2.	('COX2', 'Gene', '5743', (104, 108))	('COX2', 'Gene', (104, 108))	('miR-212-3p', 'Var', (57, 67))
761191	29215765	As shown in Figure 4B, a significant decreased of luciferase activity was observed when HEK-293T cells were transfected with the miR-212-3p mimic compared to the negative control.	('HEK-293T', 'CellLine', 'CVCL:0063', (88, 96))	('luciferase', 'Enzyme', (50, 60))	('miR-212-3p mimic', 'Var', (129, 145))	('activity', 'MPA', (61, 69))	('decreased', 'NegReg', (37, 46))
761193	29215765	Furthermore, we transfected HET-1A cells with the miR-212-3p mimic or inhibitor and then examined the COX2 expression.	('miR-212-3p mimic', 'Var', (50, 66))	('COX2', 'Gene', (102, 106))	('examined', 'Reg', (89, 97))	('COX2', 'Gene', '5743', (102, 106))	('HET-1A', 'CellLine', 'CVCL:3702', (28, 34))
761194	29215765	As shown in Figure 4C,D, ectopic expression of miR-212-3p did not affect COX2 mRNA level, although it led to a significant decrease of COX2 protein expression.	('COX2', 'Gene', '5743', (135, 139))	('miR-212-3p', 'Var', (47, 57))	('COX2', 'Gene', (135, 139))	('decrease', 'NegReg', (123, 131))	('COX2', 'Gene', (73, 77))	('COX2', 'Gene', '5743', (73, 77))
761196	29215765	These data suggested that miR-212-3p downregulates COX2 in esophageal epithelial cells through inhibition of translation rather than mRNA degradation.	('downregulates', 'NegReg', (37, 50))	('miR-212-3p', 'Var', (26, 36))	('translation', 'MPA', (109, 120))	('esophageal epithelia', 'Disease', (59, 79))	('esophageal epithelia', 'Disease', 'MESH:D004941', (59, 79))	('inhibition', 'NegReg', (95, 105))	('COX2', 'Gene', '5743', (51, 55))	('COX2', 'Gene', (51, 55))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (59, 79))	('rat', 'Species', '10116', (121, 124))
761203	29215765	Ectopic miR-212-3p significantly inhibited H. pylori-induced COX2, while miR-212-3p inhibitor augmented COX2 expression in HET-1A cells (Figure 5A).	('H. pylori', 'Species', '210', (43, 52))	('expression', 'MPA', (109, 119))	('COX2', 'Gene', (61, 65))	('augmented', 'PosReg', (94, 103))	('COX2', 'Gene', '5743', (61, 65))	('HET-1A', 'CellLine', 'CVCL:3702', (123, 129))	('Ectopic', 'Var', (0, 7))	('COX2', 'Gene', (104, 108))	('COX2', 'Gene', '5743', (104, 108))	('inhibited', 'NegReg', (33, 42))	('H. pylori-induced', 'Disease', (43, 60))
761207	29215765	Helicobacter pylori infection altered the miRNA profiles of esophageal epithelial cells, particularly aberrant silencing of miR-212-3p and miR-361-3p expression.	('expression', 'MPA', (150, 160))	('miR-212-3p', 'Gene', (124, 134))	('infection', 'Disease', (20, 29))	('miR-361-3p', 'Gene', '100500908', (139, 149))	('Helicobacter pylori', 'Species', '210', (0, 19))	('esophageal epithelia', 'Disease', 'MESH:D004941', (60, 80))	('infection', 'Disease', 'MESH:D007239', (20, 29))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (60, 80))	('miRNA profiles', 'MPA', (42, 56))	('miR-361-3p', 'Gene', (139, 149))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (0, 29))	('Helicobacter', 'Disease', (0, 12))	('altered', 'Reg', (30, 37))	('esophageal epithelia', 'Disease', (60, 80))	('aberrant', 'Var', (102, 110))
761216	29215765	Chronic expression of COX2 plays a crucial role in H. pylori-associated gastric carcinogenesis.32 Moreover, the expression of COX2 is gradually increased during the neoplastic progression of the esophageal mucosa from Barrett's esophagus to adenocarcinoma.33 In the present study, COX2 expression in esophageal epithelial cells was upregulated by either H. pylori or acidified DCA treatment, and this effect was more pronounced when both factors were present.	('DCA', 'Chemical', 'MESH:D003840', (377, 380))	('upregulated', 'PosReg', (332, 343))	('acidified', 'Var', (367, 376))	('COX2', 'Gene', (126, 130))	('esophageal epithelia', 'Disease', (300, 320))	('COX2', 'Gene', '5743', (281, 285))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (218, 237))	('COX2', 'Gene', (22, 26))	('expression', 'MPA', (286, 296))	('H. pylori', 'Disease', (354, 363))	('gastric carcinogenesis', 'Disease', (72, 94))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (300, 320))	('COX2', 'Gene', (281, 285))	('esophageal epithelia', 'Disease', 'MESH:D004941', (300, 320))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (72, 94))	('COX2', 'Gene', '5743', (126, 130))	("Barrett's esophagus to adenocarcinoma", 'Disease', (218, 255))	('H. pylori', 'Species', '210', (354, 363))	('COX2', 'Gene', '5743', (22, 26))	("Barrett's esophagus to adenocarcinoma", 'Disease', 'MESH:D001471', (218, 255))	('H. pylori', 'Species', '210', (51, 60))
761217	29215765	Thus, alteration of these molecules may contribute to the transformation of the phenotype of the esophageal epithelial cells.	('esophageal epithelia', 'Phenotype', 'HP:0012859', (97, 117))	('contribute', 'Reg', (40, 50))	('esophageal epithelia', 'Disease', 'MESH:D004941', (97, 117))	('esophageal epithelia', 'Disease', (97, 117))	('alteration', 'Var', (6, 16))	('rat', 'Species', '10116', (10, 13))
761220	29215765	To further explore the molecular mechanisms of transformation induced by H. pylori, we searched for miRNAs that target COX2 and CDX2 through bioinformatics analysis and found that miR-212-3p could match the sequence of COX2, and miR-361-3p could match CDX2.	('miR-361-3p', 'Gene', (229, 239))	('CDX2', 'Gene', '1045', (128, 132))	('CDX2', 'Gene', (252, 256))	('COX2', 'Gene', (119, 123))	('COX2', 'Gene', '5743', (119, 123))	('miR-361-3p', 'Gene', '100500908', (229, 239))	('H. pylori', 'Species', '210', (73, 82))	('miR-212-3p', 'Var', (180, 190))	('CDX2', 'Gene', '1045', (252, 256))	('COX2', 'Gene', (219, 223))	('COX2', 'Gene', '5743', (219, 223))	('CDX2', 'Gene', (128, 132))
761228	29215765	Here, we identified COX2 as a new target of miR-212-3p, and CDX2 was a target of miR-361-3p in esophageal epithelial cells.	('miR-212-3p', 'Var', (44, 54))	('miR-361-3p', 'Gene', (81, 91))	('CDX2', 'Gene', (60, 64))	('miR-361-3p', 'Gene', '100500908', (81, 91))	('CDX2', 'Gene', '1045', (60, 64))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (95, 115))	('COX2', 'Gene', '5743', (20, 24))	('COX2', 'Gene', (20, 24))	('esophageal epithelia', 'Disease', 'MESH:D004941', (95, 115))	('esophageal epithelia', 'Disease', (95, 115))
761229	29215765	MicroRNAs control gene expression at the post-transcriptional level by binding to the 3'-UTRs of mRNAs, targeting mRNAs for repressing translation or degradation.35 In this study, miRNA mimic or inhibitor caused reciprocal modification of COX2 and CDX2 protein expression, whereas they did not affect COX2 and CDX2 mRNA levels.	('CDX2', 'Gene', (310, 314))	('COX2', 'Gene', (239, 243))	('COX2', 'Gene', (301, 305))	('miRNA mimic', 'Var', (180, 191))	('inhibitor', 'MPA', (195, 204))	('CDX2', 'Gene', '1045', (310, 314))	('COX2', 'Gene', '5743', (239, 243))	('COX2', 'Gene', '5743', (301, 305))	('expression', 'MPA', (261, 271))	('modification', 'Reg', (223, 235))	('protein', 'Protein', (253, 260))	('CDX2', 'Gene', (248, 252))	('CDX2', 'Gene', '1045', (248, 252))
761230	29215765	These data suggested that miR-212-3p and miR-361-3p downregulated COX2 and CDX2 through translation inhibition rather than mRNA degradation.	('rat', 'Species', '10116', (111, 114))	('miR-212-3p', 'Var', (26, 36))	('miR-361-3p', 'Gene', (41, 51))	('CDX2', 'Gene', (75, 79))	('downregulated', 'NegReg', (52, 65))	('miR-361-3p', 'Gene', '100500908', (41, 51))	('COX2', 'Gene', (66, 70))	('CDX2', 'Gene', '1045', (75, 79))	('COX2', 'Gene', '5743', (66, 70))
761240	29215765	In H. pylori-infected esophageal epithelial cells, upregulation of oncoprotein COX2 and CDX2 was associated with aberrant silencing of miR-212-3p and miR-361-3p, respectively.	('upregulation', 'PosReg', (51, 63))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (22, 42))	('CDX2', 'Gene', (88, 92))	('H. pylori', 'Species', '210', (3, 12))	('CDX2', 'Gene', '1045', (88, 92))	('miR-361-3p', 'Gene', '100500908', (150, 160))	('esophageal epithelia', 'Disease', (22, 42))	('miR-212-3p', 'Var', (135, 145))	('COX2', 'Gene', (79, 83))	('silencing', 'NegReg', (122, 131))	('esophageal epithelia', 'Disease', 'MESH:D004941', (22, 42))	('H. pylori-infected', 'Disease', (3, 21))	('COX2', 'Gene', '5743', (79, 83))	('miR-361-3p', 'Gene', (150, 160))
761293	25960847	Considering the low survival rate due to the nature and pre-operative complications of esophageal cancer, the best method for resection would be T.H.E for locally advanced lower third and cardial tumor but manipulation of mediastinal structure during esophagectomy causes arrhythmia and hypotension that might be dangerous.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cardial tumor', 'Disease', 'MESH:D009369', (188, 201))	('esophageal cancer', 'Disease', (87, 104))	('arrhythmia', 'Disease', 'MESH:D001145', (272, 282))	('hypotension', 'Disease', (287, 298))	('cardial tumor', 'Phenotype', 'HP:0100544', (188, 201))	('arrhythmia', 'Phenotype', 'HP:0011675', (272, 282))	('manipulation', 'Var', (206, 218))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('hypotension', 'Phenotype', 'HP:0002615', (287, 298))	('causes', 'Reg', (265, 271))	('arrhythmia', 'Disease', (272, 282))	('cardial tumor', 'Disease', (188, 201))	('hypotension', 'Disease', 'MESH:D007022', (287, 298))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
761295	22930414	Single Nucleotide Polymorphisms of ADH1B, ADH1C and ALDH2 Genes and Esophageal Cancer: A Population-Based Case-Control Study in China Alcohol drinking is a major risk factor for esophageal cancer (EC) and the metabolism of ethanol has been suggested to play an important role in esophageal carcinogenesis.	('esophageal cancer', 'Disease', (178, 195))	('Esophageal Cancer', 'Disease', (68, 85))	('ADH1B', 'Gene', '125', (35, 40))	('ADH1C', 'Gene', (42, 47))	('ethanol', 'Chemical', 'MESH:D000431', (223, 230))	('Alcohol', 'Chemical', 'MESH:D000438', (134, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('Single Nucleotide Polymorphisms', 'Var', (0, 31))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (279, 304))	('ALDH2', 'Gene', '217', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('Alcohol drinking', 'Phenotype', 'HP:0030955', (134, 150))	('esophageal carcinogenesis', 'Disease', (279, 304))	('ALDH2', 'Gene', (52, 57))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ADH1B', 'Gene', (35, 40))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (68, 85))	('ADH1C', 'Gene', '126', (42, 47))
761296	22930414	Epidemiologic studies, including genome-wide association studies (GWAS), have identified single nucleotide polymorphisms (SNPs) in alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) to be associated with esophageal cancer.	('single nucleotide polymorphisms', 'Var', (89, 120))	('alcohol', 'Chemical', 'MESH:D000438', (131, 138))	('esophageal cancer', 'Disease', (219, 236))	('associated', 'Reg', (203, 213))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ADH', 'Gene', '124', (155, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (219, 236))	('ADH', 'Gene', (155, 158))
761297	22930414	Using a population-based case-control study with 858 EC cases and 1,081 controls conducted in Jiangsu Province, China, we aimed to provide further information on the association of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms with esophageal cancer in a Chinese population.	('rs1229984', 'Var', (188, 197))	('rs1229984', 'Mutation', 'rs1229984', (188, 197))	('rs698', 'Var', (207, 212))	('ADH1C', 'Gene', '126', (200, 205))	('esophageal cancer', 'Disease', (251, 268))	('ALDH2', 'Gene', (218, 223))	('esophageal cancer', 'Disease', 'MESH:D004938', (251, 268))	('rs698', 'Mutation', 'rs698', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('ADH1C', 'Gene', (200, 205))	('ADH1B', 'Gene', (181, 186))	('association', 'Interaction', (166, 177))	('ADH1B', 'Gene', '125', (181, 186))	('rs671', 'Mutation', 'rs671', (225, 230))	('ALDH2', 'Gene', '217', (218, 223))
761298	22930414	Results showed that ADH1B (rs1229984) was associated with EC with odds ratios (ORs) of 1.34 (95% confidence interval: 1.08-1.66) for G-allele carriers compared to A/A homozygotes.	('G-allele', 'Var', (133, 141))	('associated', 'Reg', (42, 52))	('rs1229984', 'Var', (27, 36))	('rs1229984', 'Mutation', 'rs1229984', (27, 36))	('ADH1B', 'Gene', (20, 25))	('ADH1B', 'Gene', '125', (20, 25))
761300	22930414	Statistical interactions between ALDH2 (rs671) and alcohol drinking on EC susceptibility in both additive and multiplicative scales were observed.	('rs671', 'Mutation', 'rs671', (40, 45))	('ALDH2', 'Gene', (33, 38))	('alcohol drinking', 'Phenotype', 'HP:0030955', (51, 67))	('alcohol', 'Chemical', 'MESH:D000438', (51, 58))	('ALDH2', 'Gene', '217', (33, 38))	('rs671', 'Var', (40, 45))
761301	22930414	In addition, statistical interaction between ALDH2 and ADH1B polymorphisms on EC susceptibility among never/light drinkers was indicated.	('ADH1B', 'Gene', '125', (55, 60))	('polymorphisms', 'Var', (61, 74))	('interaction', 'Reg', (25, 36))	('ALDH2', 'Gene', '217', (45, 50))	('ADH1B', 'Gene', (55, 60))	('ALDH2', 'Gene', (45, 50))
761302	22930414	We did not observe association of ADH1C polymorphism with EC.	('polymorphism', 'Var', (40, 52))	('ADH1C', 'Gene', '126', (34, 39))	('ADH1C', 'Gene', (34, 39))
761303	22930414	In conclusion, our findings indicated that ADH1B (rs1229984) was associated with esophageal cancer independent of alcohol drinking and tobacco smoking status and alcohol drinking interacted with ALDH2 (rs671) on esophageal cancer susceptibility in this high-risk Chinese population.	('tobacco', 'Species', '4097', (135, 142))	('ADH1B', 'Gene', (43, 48))	('associated', 'Reg', (65, 75))	('rs1229984', 'Var', (50, 59))	('ALDH2', 'Gene', '217', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('rs1229984', 'Mutation', 'rs1229984', (50, 59))	('alcohol drinking', 'Phenotype', 'HP:0030955', (162, 178))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('alcohol', 'Chemical', 'MESH:D000438', (114, 121))	('alcohol', 'Chemical', 'MESH:D000438', (162, 169))	('esophageal cancer', 'Disease', (81, 98))	('alcohol drinking', 'Phenotype', 'HP:0030955', (114, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (212, 229))	('ALDH2', 'Gene', (195, 200))	('ADH1B', 'Gene', '125', (43, 48))	('rs671', 'Mutation', 'rs671', (202, 207))	('esophageal cancer', 'Disease', (212, 229))
761309	22930414	Single-nucleotide polymorphisms (SNPs) of ADH- and ALDH-related genes can lead to structural and functional changes of the enzymes which would influence acetaldehyde levels and may predispose people to cancers.	('people', 'Species', '9606', (192, 198))	('acetaldehyde', 'Chemical', 'MESH:D000079', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('lead to', 'Reg', (74, 81))	('structural', 'MPA', (82, 92))	('ALDH-related genes', 'Gene', (51, 69))	('acetaldehyde levels', 'MPA', (153, 172))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('functional', 'MPA', (97, 107))	('ADH', 'Gene', '124', (42, 45))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('influence', 'Reg', (143, 152))	('changes', 'Reg', (108, 115))	('cancers', 'Disease', (202, 209))	('ADH', 'Gene', (42, 45))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('enzymes', 'Enzyme', (123, 130))	('predispose', 'Reg', (181, 191))
761310	22930414	Among them, three functional SNPs, rs1229984 in ADH1B, rs698 in ADH1C, and rs671 in ALDH2 have been frequently studied on their roles in alcoholism and carcinogenesis.	('ALDH2', 'Gene', (84, 89))	('rs671', 'Mutation', 'rs671', (75, 80))	('rs698', 'Mutation', 'rs698', (55, 60))	('rs1229984', 'Mutation', 'rs1229984', (35, 44))	('alcoholism and carcinogenesis', 'Disease', 'MESH:D063646', (137, 166))	('alcoholism', 'Phenotype', 'HP:0030955', (137, 147))	('ADH1B', 'Gene', (48, 53))	('rs1229984', 'Var', (35, 44))	('ALDH2', 'Gene', '217', (84, 89))	('ADH1C', 'Gene', '126', (64, 69))	('ADH1B', 'Gene', '125', (48, 53))	('rs671', 'Var', (75, 80))	('rs698', 'Var', (55, 60))	('ADH1C', 'Gene', (64, 69))
761311	22930414	The ADH1B (rs1229984) A/A homodimer has been found to have a 40-fold higher enzyme activity than the G/G form.	('enzyme activity', 'MPA', (76, 91))	('rs1229984', 'Mutation', 'rs1229984', (11, 20))	('ADH1B', 'Gene', (4, 9))	('rs1229984', 'Var', (11, 20))	('ADH1B', 'Gene', '125', (4, 9))	('higher', 'PosReg', (69, 75))
761312	22930414	Enzymes encoded by ADH1C (rs698) A allele have been shown to have a 2.5-times higher capacity oxidizing ethanol compared to those encoded by the G allele.	('ethanol', 'Chemical', 'MESH:D000431', (104, 111))	('rs698) A', 'Var', (26, 34))	('higher', 'PosReg', (78, 84))	('ADH1C', 'Gene', '126', (19, 24))	('rs698', 'Mutation', 'rs698', (26, 31))	('ADH1C', 'Gene', (19, 24))	('oxidizing ethanol', 'MPA', (94, 111))
761313	22930414	The ALDH2 rs671 A allele encoded an inactive subunit with restrained ability to metabolize acetaldehyde.	('ALDH2', 'Gene', '217', (4, 9))	('encoded', 'Reg', (25, 32))	('inactive', 'MPA', (36, 44))	('rs671', 'Mutation', 'rs671', (10, 15))	('rs671 A', 'Var', (10, 17))	('ALDH2', 'Gene', (4, 9))	('subunit', 'Protein', (45, 52))	('ability', 'MPA', (69, 76))	('metabolize acetaldehyde', 'MPA', (80, 103))	('acetaldehyde', 'Chemical', 'MESH:D000079', (91, 103))
761314	22930414	Blood acetaldehyde concentrations after consuming alcoholic beverages in individuals carrying ALDH2 A/A and A/G genotype was 6-19 times higher than in those with the G/G genotype.	('A/A', 'Var', (100, 103))	('alcohol', 'Chemical', 'MESH:D000438', (50, 57))	('higher', 'PosReg', (136, 142))	('Blood acetaldehyde concentrations', 'MPA', (0, 33))	('A/G', 'Var', (108, 111))	('acetaldehyde', 'Chemical', 'MESH:D000079', (6, 18))	('ALDH2', 'Gene', '217', (94, 99))	('Blood acetaldehyde concentrations', 'Phenotype', 'HP:0003533', (0, 33))	('ALDH2', 'Gene', (94, 99))
761315	22930414	Epidemiologic studies, including genome-wide association studies (GWAS), have associated genetic variations in ADHs and ALDHs with EC susceptibility.	('ADH', 'Gene', (111, 114))	('ADH', 'Gene', '124', (111, 114))	('genetic variations', 'Var', (89, 107))	('ALDHs', 'Gene', (120, 125))
761317	22930414	The primary aim of this large case-control study was to replicate the associations between esophageal cancer and genetic polymorphisms of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) in a Chinese population.	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ALDH2', 'Gene', '217', (175, 180))	('associations', 'Interaction', (70, 82))	('rs671', 'Var', (182, 187))	('rs1229984', 'Mutation', 'rs1229984', (145, 154))	('rs698', 'Var', (164, 169))	('ADH1C', 'Gene', '126', (157, 162))	('ADH1B', 'Gene', (138, 143))	('ALDH2', 'Gene', (175, 180))	('rs1229984', 'Var', (145, 154))	('rs671', 'Mutation', 'rs671', (182, 187))	('rs698', 'Mutation', 'rs698', (164, 169))	('esophageal cancer', 'Disease', (91, 108))	('ADH1C', 'Gene', (157, 162))	('ADH1B', 'Gene', '125', (138, 143))
761336	22930414	Genotype distributions of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) among controls were all in agreement with Hardy-Weinberg equilibrium (P>0.05).	('ADH1C', 'Gene', '126', (45, 50))	('ALDH2', 'Gene', '217', (63, 68))	('rs671', 'Var', (70, 75))	('ADH1C', 'Gene', (45, 50))	('ADH1B', 'Gene', (26, 31))	('ALDH2', 'Gene', (63, 68))	('rs671', 'Mutation', 'rs671', (70, 75))	('ADH1B', 'Gene', '125', (26, 31))	('rs1229984', 'Mutation', 'rs1229984', (33, 42))	('rs698', 'Var', (52, 57))	('rs1229984', 'Var', (33, 42))	('rs698', 'Mutation', 'rs698', (52, 57))
761337	22930414	After adjusting for potential confounders, the inactive ADH1B (rs1229984) G-allele was positively associated with EC with ORs of 1.88 (95% CI: 1.34-2.64) for G/G homozygotes and 1.19 (95% CI: 0.94-1.51) for A/G heterozygotes, as compared to individuals with the A/A genotype (Table 3).	('rs1229984', 'Mutation', 'rs1229984', (63, 72))	('G/G', 'Var', (158, 161))	('rs1229984', 'Var', (63, 72))	('ADH1B', 'Gene', (56, 61))	('ADH1B', 'Gene', '125', (56, 61))
761338	22930414	We did not observe strong main effects of ADH1C (rs698) and ALDH2 (rs671) polymorphisms on EC susceptibility.	('rs698', 'Mutation', 'rs698', (49, 54))	('rs671', 'Mutation', 'rs671', (67, 72))	('ADH1C', 'Gene', (42, 47))	('ALDH2', 'Gene', (60, 65))	('ADH1C', 'Gene', '126', (42, 47))	('rs698', 'Var', (49, 54))	('rs671', 'Var', (67, 72))	('ALDH2', 'Gene', '217', (60, 65))
761339	22930414	ADH1B (rs1229984) G-allele carriers had consistent 30% increased odds of having EC compared to A/A homozygotes across different strata of alcohol drinking and tobacco smoking (Table 4 and Table 5).	('rs1229984', 'Mutation', 'rs1229984', (7, 16))	('rs1229984', 'Var', (7, 16))	('alcohol drinking', 'Phenotype', 'HP:0030955', (138, 154))	('ADH1B', 'Gene', (0, 5))	('ADH1B', 'Gene', '125', (0, 5))	('alcohol', 'Chemical', 'MESH:D000438', (138, 145))	('tobacco', 'Species', '4097', (159, 166))
761341	22930414	ALDH2 (rs671) A-allele carriers were associated with increased odds of EC among moderate/heavy drinkers and reduced odds of EC among never/light drinkers, while compared to G/G homozygotes.	('reduced', 'NegReg', (108, 115))	('rs671) A-allele carriers', 'Var', (7, 31))	('rs671', 'Mutation', 'rs671', (7, 12))	('ALDH2', 'Gene', (0, 5))	('ALDH2', 'Gene', '217', (0, 5))
761342	22930414	Statistical interactions were detected between ALDH2 (rs671) and alcohol drinking on esophageal cancer susceptibility in both additive and multiplicative scales.	('rs671', 'Mutation', 'rs671', (54, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ALDH2', 'Gene', (47, 52))	('alcohol', 'Chemical', 'MESH:D000438', (65, 72))	('alcohol drinking', 'Phenotype', 'HP:0030955', (65, 81))	('rs671', 'Var', (54, 59))	('esophageal cancer', 'Disease', (85, 102))	('ALDH2', 'Gene', '217', (47, 52))
761343	22930414	Moderate/heavy drinkers with the ALDH2 A/G genotype had the highest risk of EC (OR=2.34, 95% CI: 1.52-3.61) in joint-effect analysis, as compared to never/light drinkers with the G/G genotype.	('ALDH2', 'Gene', '217', (33, 38))	('A/G', 'Var', (39, 42))	('ALDH2', 'Gene', (33, 38))
761346	22930414	In this population-based case-control study among Chinese population, we reported that ADH1B (rs1229984) polymorphism was associated with esophageal cancer and this association was consistently seen across different strata of alcohol drinking and tobacco smoking behaviours.	('associated', 'Reg', (122, 132))	('esophageal cancer', 'Disease', (138, 155))	('alcohol drinking', 'Phenotype', 'HP:0030955', (226, 242))	('tobacco', 'Species', '4097', (247, 254))	('rs1229984) polymorphism', 'Var', (94, 117))	('rs1229984', 'Mutation', 'rs1229984', (94, 103))	('alcohol', 'Chemical', 'MESH:D000438', (226, 233))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('polymorphism', 'Var', (105, 117))	('ADH1B', 'Gene', (87, 92))	('ADH1B', 'Gene', '125', (87, 92))
761347	22930414	We observed statistical interaction between alcohol drinking and ALDH2 (rs671) polymorphism on EC susceptibility, with positive association among moderate/heavy drinkers and inverse association among never/light drinkers.	('polymorphism', 'Var', (79, 91))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('alcohol drinking', 'Phenotype', 'HP:0030955', (44, 60))	('ALDH2', 'Gene', '217', (65, 70))	('positive', 'PosReg', (119, 127))	('rs671', 'Mutation', 'rs671', (72, 77))	('ALDH2', 'Gene', (65, 70))	('rs671) polymorphism', 'Var', (72, 91))
761348	22930414	In addition, we found statistical interaction between ALDH2 (rs671) and ADH1B (rs1229984) on EC susceptibility among never/light drinkers.	('interaction', 'Reg', (34, 45))	('rs671', 'Mutation', 'rs671', (61, 66))	('rs1229984', 'Mutation', 'rs1229984', (79, 88))	('ADH1B', 'Gene', '125', (72, 77))	('ALDH2', 'Gene', (54, 59))	('rs1229984', 'Var', (79, 88))	('ALDH2', 'Gene', '217', (54, 59))	('rs671', 'Var', (61, 66))	('ADH1B', 'Gene', (72, 77))
761350	22930414	Our results on ADH1B (rs1229984) were in accordance with previous studies.	('rs1229984', 'Var', (22, 31))	('rs1229984', 'Mutation', 'rs1229984', (22, 31))	('ADH1B', 'Gene', '125', (15, 20))	('ADH1B', 'Gene', (15, 20))
761351	22930414	In a meta-analysis across Chinese and Japanese populations, the ORs for those with ADH1B A/G and G/G genotype compared to the A/A genotype were 1.60 (95% CI: 1.25-2.00) and 2.17 (95% CI: 1.08-4.34), respectively.	('G/G', 'Var', (97, 100))	('A/G', 'Var', (89, 92))	('ADH1B', 'Gene', (83, 88))	('ADH1B', 'Gene', '125', (83, 88))
761352	22930414	In recent GWASs, ADH1B (rs1229984) has also been identified to be associated with EC with ORs of 1.79 (95% CI: 1.69-1.88) for the G allele in Japanese populations and 0.38 (95% CI: 0.24-0.59) for the A allele in European populations.	('rs1229984', 'Mutation', 'rs1229984', (24, 33))	('rs1229984', 'Var', (24, 33))	('associated', 'Reg', (66, 76))	('ADH1B', 'Gene', '125', (17, 22))	('ADH1B', 'Gene', (17, 22))
761354	22930414	Several studies have reported that G allele was associated with increased intensity of alcohol drinking.	('G allele', 'Var', (35, 43))	('alcohol drinking', 'Phenotype', 'HP:0030955', (87, 103))	('increased', 'PosReg', (64, 73))	('alcohol', 'Chemical', 'MESH:D000438', (87, 94))	('intensity', 'MPA', (74, 83))
761357	22930414	have demonstrated that the salivary and blood ethanol and acetaldehyde levels were higher in G allele carriers than those carry the A allele.	('G allele carriers', 'Var', (93, 110))	('acetaldehyde', 'Chemical', 'MESH:D000079', (58, 70))	('higher', 'PosReg', (83, 89))	('ethanol', 'Chemical', 'MESH:D000431', (46, 53))
761359	22930414	The inactive ALDH2 (rs671) A allele is rare in Western populations, but is highly prevalent and mostly studied among Eastern Asians on its association with cancer, especially among Chinese and Japanese.	('ALDH2', 'Gene', '217', (13, 18))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('rs671', 'Mutation', 'rs671', (20, 25))	('ALDH2', 'Gene', (13, 18))	('rs671) A', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('association', 'Interaction', (139, 150))
761360	22930414	In agreement with most studies, we detected statistical interaction between ALDH2 (rs671) and EC and observed that while compared to those with the G/G genotype, A allele carriers were associated with increased odds of EC among moderate/heavy drinkers, but not among never/light drinkers.	('ALDH2', 'Gene', (76, 81))	('ALDH2', 'Gene', '217', (76, 81))	('rs671', 'Var', (83, 88))	('rs671', 'Mutation', 'rs671', (83, 88))
761361	22930414	A Chinese GWAS indicated multiplicative interaction between alcohol drinking and rs11066015 of ACAD10 (in high linkage disequilibrium [LD] with rs671, r=0.79) on esophageal squamous cell carcinoma (ESCC) risk, with more pronounced risk enhancement seen in drinkers (interaction P = 4.54 x 10-34).	('alcohol', 'Chemical', 'MESH:D000438', (60, 67))	('alcohol drinking', 'Phenotype', 'HP:0030955', (60, 76))	('rs11066015', 'Var', (81, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (173, 196))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (162, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('ACAD10', 'Gene', '80724', (95, 101))	('rs671', 'Mutation', 'rs671', (144, 149))	('rs11066015', 'Mutation', 'rs11066015', (81, 91))	('esophageal squamous cell carcinoma', 'Disease', (162, 196))	('ACAD10', 'Gene', (95, 101))
761362	22930414	The increased risk of A-allele carriers among moderate/heavy drinkers was biologically relevant, indicating the harmful effect of accumulated acetaldehyde after alcohol drinking.	('acetaldehyde', 'MPA', (142, 154))	('A-allele carriers', 'Var', (22, 39))	('alcohol drinking', 'Phenotype', 'HP:0030955', (161, 177))	('alcohol', 'Chemical', 'MESH:D000438', (161, 168))	('acetaldehyde', 'Chemical', 'MESH:D000079', (142, 154))	('acetaldehyde after alcohol drinking', 'Phenotype', 'HP:0003533', (142, 177))
761365	22930414	To examine effect of SNPs on EC not mediated through alcohol drinking, we further adjusted on weekly ethanol intake for the main- and stratified-association of ADH1B (rs1229984) and ALDH2 (rs671) on EC and did not find much difference of the results with and without the adjustment (data not shown).	('rs1229984', 'Var', (167, 176))	('alcohol', 'Chemical', 'MESH:D000438', (53, 60))	('rs671', 'Var', (189, 194))	('ADH1B', 'Gene', (160, 165))	('alcohol drinking', 'Phenotype', 'HP:0030955', (53, 69))	('ALDH2', 'Gene', '217', (182, 187))	('rs671', 'Mutation', 'rs671', (189, 194))	('ADH1B', 'Gene', '125', (160, 165))	('ethanol', 'Chemical', 'MESH:D000431', (101, 108))	('ALDH2', 'Gene', (182, 187))	('rs1229984', 'Mutation', 'rs1229984', (167, 176))
761366	22930414	Furthermore, we found both polymorphisms to be associated with EC among never alcohol drinkers (ORA/G+G/G vs. A/A = 1.41, 95% CI: 1.00-2.01 for ADH1B; ORA/G+A/A vs. G/G = 0.69, 95% CI: 0.48-1.00 for ALDH2; data not shown), which suggested that ADH1B and ALDH2 may be associated with EC through pathways in addition to alcohol drinking.	('alcohol drinking', 'Phenotype', 'HP:0030955', (318, 334))	('ALDH2', 'Gene', '217', (199, 204))	('alcohol', 'Chemical', 'MESH:D000438', (78, 85))	('alcohol', 'Chemical', 'MESH:D000438', (318, 325))	('ALDH2', 'Gene', '217', (254, 259))	('ORA/G+A/A', 'Var', (151, 160))	('ADH1B', 'Gene', '125', (244, 249))	('ADH1B', 'Gene', (144, 149))	('ALDH2', 'Gene', (199, 204))	('ADH1B', 'Gene', (244, 249))	('ALDH2', 'Gene', (254, 259))	('ADH1B', 'Gene', '125', (144, 149))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (78, 94))	('associated', 'Reg', (47, 57))	('associated', 'Reg', (267, 277))
761367	22930414	Although we did not detect gene-gene interaction between ALDH2 (rs671) and ADH1B (rs1229984) on EC among moderate/heavy drinkers, the highest risk of esophageal cancer was found on those carrying ALDH2 A allele and ADHs G allele.	('esophageal cancer', 'Disease', (150, 167))	('rs671', 'Var', (64, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('ADH', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ADH', 'Gene', (215, 218))	('ADH1B', 'Gene', (75, 80))	('ALDH2', 'Gene', (57, 62))	('ADH', 'Gene', '124', (75, 78))	('rs671', 'Mutation', 'rs671', (64, 69))	('ALDH2', 'Gene', '217', (196, 201))	('ADH1B', 'Gene', '125', (75, 80))	('ALDH2', 'Gene', (196, 201))	('rs1229984', 'Mutation', 'rs1229984', (82, 91))	('ADH', 'Gene', '124', (215, 218))	('ALDH2', 'Gene', '217', (57, 62))	('rs1229984', 'Var', (82, 91))
761368	22930414	In a meta-analysis, the highest risk of esophageal cancer was observed among heavy drinkers with ADH1B G/G and ALDH2 A/G genotype (OR=12.45, 95% CI: 2.9-53.46), as compared to those with ADH1B any A and ALDH2 G/G genotype.	('ADH1B', 'Gene', '125', (97, 102))	('ADH1B', 'Gene', (187, 192))	('ALDH2', 'Gene', '217', (203, 208))	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('ADH1B', 'Gene', '125', (187, 192))	('A/G', 'Var', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('ALDH2', 'Gene', (203, 208))	('ALDH2', 'Gene', '217', (111, 116))	('G/G', 'Var', (103, 106))	('ADH1B', 'Gene', (97, 102))	('esophageal cancer', 'Disease', (40, 57))	('ALDH2', 'Gene', (111, 116))
761369	22930414	In the Japanese GWAS which identified both rs671 and rs1229984 as risk loci for esophageal cancer, individuals with ADH1B G/G and ALDH2 A/G genotype had a remarkably higher risk (OR=16.17, 95% CI: 11.55-22.65) than those with ADH1B any A and ALDH2 A/A or G/G genotype.	('ALDH2', 'Gene', (242, 247))	('G/G', 'Var', (122, 125))	('rs671', 'Mutation', 'rs671', (43, 48))	('ADH1B', 'Gene', (226, 231))	('ALDH2', 'Gene', (130, 135))	('esophageal cancer', 'Disease', (80, 97))	('ADH1B', 'Gene', (116, 121))	('ADH1B', 'Gene', '125', (226, 231))	('ADH1B', 'Gene', '125', (116, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ALDH2', 'Gene', '217', (242, 247))	('rs1229984', 'Mutation', 'rs1229984', (53, 62))	('ALDH2', 'Gene', '217', (130, 135))
761370	22930414	Interestingly, statistical interaction of ALDH2 and ADH1B on EC was indicated among never/light drinkers in our study, with the highest risk observed among those with ALDH2 G/G and ADH1B any G genotype.	('ADH1B', 'Gene', '125', (52, 57))	('ALDH2', 'Gene', '217', (42, 47))	('interaction', 'Reg', (27, 38))	('ALDH2', 'Gene', (167, 172))	('ADH1B', 'Gene', (181, 186))	('ALDH2', 'Gene', (42, 47))	('G/G', 'Var', (173, 176))	('ADH1B', 'Gene', '125', (181, 186))	('ADH1B', 'Gene', (52, 57))	('ALDH2', 'Gene', '217', (167, 172))
761372	22930414	Different from ADH1B and ALDH2, ADH1C (rs698) polymorphism is the rate-limiting factor in alcohol metabolism among Western populations and studies from European origins have associated ADH1C polymorphism with EC.	('ADH1C', 'Gene', (185, 190))	('associated', 'Reg', (174, 184))	('ADH1B', 'Gene', (15, 20))	('ADH1C', 'Gene', '126', (32, 37))	('rs698', 'Mutation', 'rs698', (39, 44))	('ALDH2', 'Gene', '217', (25, 30))	('ADH1B', 'Gene', '125', (15, 20))	('polymorphism', 'Var', (191, 203))	('ADH1C', 'Gene', (32, 37))	('alcohol', 'Chemical', 'MESH:D000438', (90, 97))	('ADH1C', 'Gene', '126', (185, 190))	('ALDH2', 'Gene', (25, 30))
761377	22930414	Linkage disequilibrium between ADH1B (rs1229984) and ADH1C (rs698) in our study was minor (r2=0.16, D'=0.41) and could possibly explain the lack of association between ADH1C (rs698) and EC.	('rs1229984', 'Var', (38, 47))	('rs1229984', 'Mutation', 'rs1229984', (38, 47))	('rs698', 'Var', (60, 65))	('rs698', 'Var', (175, 180))	('rs698', 'Mutation', 'rs698', (60, 65))	('ADH1C', 'Gene', '126', (53, 58))	('ADH1C', 'Gene', (53, 58))	('ADH1B', 'Gene', (31, 36))	('rs698', 'Mutation', 'rs698', (175, 180))	('ADH1C', 'Gene', '126', (168, 173))	('ADH1B', 'Gene', '125', (31, 36))	('ADH1C', 'Gene', (168, 173))
761378	22930414	Results on ADH1C (rs698) polymorphism and EC remain sparse and inconsistent, and need to be further elucidated.	('polymorphism', 'Var', (25, 37))	('ADH1C', 'Gene', (11, 16))	('rs698) polymorphism', 'Var', (18, 37))	('ADH1C', 'Gene', '126', (11, 16))	('rs698', 'Mutation', 'rs698', (18, 23))
761383	22930414	In conclusion, ADH1B (rs1229984) polymorphism was associated with esophageal cancer in this high-risk Chinese population.	('ADH1B', 'Gene', (15, 20))	('esophageal cancer', 'Disease', (66, 83))	('ADH1B', 'Gene', '125', (15, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (66, 83))	('polymorphism', 'Var', (33, 45))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rs1229984) polymorphism', 'Var', (22, 45))	('rs1229984', 'Mutation', 'rs1229984', (22, 31))	('associated', 'Reg', (50, 60))
761384	22930414	Gene-environment interaction between alcohol drinking and ALDH2 (rs671) polymorphism on esophageal cancer susceptibility was observed.	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('alcohol drinking', 'Phenotype', 'HP:0030955', (37, 53))	('ALDH2', 'Gene', '217', (58, 63))	('alcohol', 'Chemical', 'MESH:D000438', (37, 44))	('rs671', 'Mutation', 'rs671', (65, 70))	('polymorphism', 'Var', (72, 84))	('ALDH2', 'Gene', (58, 63))	('esophageal cancer', 'Disease', (88, 105))	('rs671) polymorphism', 'Var', (65, 84))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
761385	22930414	Moderate/heavy drinkers carrying ALDH2 A allele and ADHs G allele had the highest risk of esophageal cancer.	('ALDH2', 'Gene', (33, 38))	('A allele', 'Var', (39, 47))	('esophageal cancer', 'Disease', (90, 107))	('ADH', 'Gene', '124', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ALDH2', 'Gene', '217', (33, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('ADH', 'Gene', (52, 55))
761387	22930414	EC Esophageal cancer ADHs alcohol dehydrogenases IARC International Agency of Research on Cancer ALDHs aldehyde dehydrogenases SNPs single-nucleotide polymorphisms GWAS genome-wide association studies ABI Applied Biosystems ORs odds ratios CIs confidence intervals BMI body mass index RERI relative excess risk due to interaction AP attributable proportion due to interaction SI synergy index LD linkage disequilibrium ESCC esophageal squamous cell carcinoma UADT upper aerodigestive tract In this large population-based case-control study in China, we reported an association of ADH1B (rs1229984) with esophageal cancer independent of alcohol drinking and tobacco smoking status.	('alcohol', 'Chemical', 'MESH:D000438', (636, 643))	('IARC', 'Disease', (49, 53))	('UADT', 'Chemical', '-', (459, 463))	('ADH1B', 'Gene', '125', (580, 585))	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs1229984', 'Mutation', 'rs1229984', (587, 596))	('Esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('ADH1B', 'Gene', (580, 585))	('ADH', 'Gene', (580, 583))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (435, 458))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (424, 458))	('SI', 'Disease', 'None', (376, 378))	('IARC', 'Disease', 'None', (49, 53))	('ADH', 'Gene', '124', (580, 583))	('ADH', 'Gene', (21, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (603, 620))	('alcohol', 'Chemical', 'MESH:D000438', (26, 33))	('rs1229984', 'Var', (587, 596))	('ADH', 'Gene', '124', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('esophageal cancer', 'Disease', (603, 620))	('carcinoma', 'Phenotype', 'HP:0030731', (449, 458))	('Esophageal cancer', 'Disease', (3, 20))	('association', 'Interaction', (565, 576))	('cancer', 'Phenotype', 'HP:0002664', (614, 620))	('alcohol drinking', 'Phenotype', 'HP:0030955', (636, 652))	('tobacco', 'Species', '4097', (657, 664))	('esophageal squamous cell carcinoma', 'Disease', (424, 458))
761388	22930414	Multiplicative interactions between alcohol drinking and ALDH2 (rs671) and between ADH1B (rs1229984) and ALDH2 (rs671) among never/light drinkers were detected.	('alcohol drinking', 'Phenotype', 'HP:0030955', (36, 52))	('rs671', 'Var', (64, 69))	('rs671', 'Mutation', 'rs671', (112, 117))	('alcohol', 'Chemical', 'MESH:D000438', (36, 43))	('ALDH2', 'Gene', (57, 62))	('ALDH2', 'Gene', (105, 110))	('rs671', 'Mutation', 'rs671', (64, 69))	('rs1229984', 'Var', (90, 99))	('rs1229984', 'Mutation', 'rs1229984', (90, 99))	('ADH1B', 'Gene', (83, 88))	('ADH1B', 'Gene', '125', (83, 88))	('rs671', 'Var', (112, 117))	('ALDH2', 'Gene', '217', (105, 110))	('ALDH2', 'Gene', '217', (57, 62))
761389	22930414	The results from this study provide further evidence on effect modification of alcohol drinking on the association of ADHs and ALDHs polymorphisms with esophageal cancer in Chinese population.	('ADH', 'Gene', (118, 121))	('polymorphisms', 'Var', (133, 146))	('ALDHs', 'Gene', (127, 132))	('esophageal cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('association', 'Interaction', (103, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('alcohol', 'Chemical', 'MESH:D000438', (79, 86))	('alcohol drinking', 'Phenotype', 'HP:0030955', (79, 95))	('ADH', 'Gene', '124', (118, 121))
761411	23614134	Magnetic resonance imaging (MRI) showed that the pancreatic mass appeared poorly demarcated and hyperintense on T2-weighted image and hypointense on T1-weighted image.	('hypointense', 'Var', (134, 145))	('pancreatic mass', 'Disease', (49, 64))	('pancreatic mass', 'Disease', 'MESH:D010195', (49, 64))
761552	20689571	Paired human fibroblasts HFF cells and their immortalized IF cells, which were generated by expressing E6/E7 of type 16 papilloma viruses, were cultured with RPMI 1640 medium with 10% fetal calf serum.	('papilloma viruses', 'Disease', (120, 137))	('papilloma', 'Phenotype', 'HP:0012740', (120, 129))	('human', 'Species', '9606', (7, 12))	('E6/E7', 'Var', (103, 108))	('HFF', 'CellLine', 'CVCL:3285', (25, 28))	('RPMI 1640 medium', 'Chemical', '-', (158, 174))	('papilloma viruses', 'Disease', 'MESH:D010212', (120, 137))	('calf', 'Species', '9913', (190, 194))
761572	20689571	We further confirmed the deleted E1B55kDa region with two kinds of primer sets that distinguished the deletion and Ad-WT DNA (Figure 1c).	('deletion', 'Var', (102, 110))	('E1B', 'Gene', (33, 36))	('E1B', 'Gene', '594', (33, 36))
761579	20689571	Although the tumors with p53 mutations were more susceptible to Ad-delE1B55 (average IC50: 27.8+-7.1(s.e.))	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('E1B', 'Gene', '594', (70, 73))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (29, 38))	('E1B', 'Gene', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
761584	20689571	Our previous study also showed that Ad-GFP infectivity was not different between HFF and IF cells and that the p53 expression was induced by CDDP in HFF but not in IF cells, showing that the p53 function was lost in IF cells.	('induced', 'Reg', (130, 137))	('CDDP', 'Chemical', 'MESH:D002945', (141, 145))	('p53', 'Gene', (111, 114))	('HFF', 'CellLine', 'CVCL:3285', (81, 84))	('p53', 'Gene', '7157', (111, 114))	('p53', 'Gene', (191, 194))	('p53', 'Gene', '7157', (191, 194))	('expression', 'MPA', (115, 125))	('CDDP', 'Var', (141, 145))	('HFF', 'CellLine', 'CVCL:3285', (149, 152))
761590	20689571	Production of hexon protein was inhibited by either 5-FU or VP-16 irrespective of the treatment procedures.	('VP-16', 'Gene', '3054', (60, 65))	('5-FU', 'Var', (52, 56))	('inhibited', 'NegReg', (32, 41))	('Production of', 'MPA', (0, 13))	('VP-16', 'Gene', (60, 65))	('5-FU', 'Chemical', 'MESH:D005472', (52, 56))	('hexon protein', 'Protein', (14, 27))
761591	20689571	In contrast, E1A production was downregulated by 5-FU administered before the Ad and by VP-16 after the Ad, but was relatively maintained in other treatment schedules.	('downregulated', 'NegReg', (32, 45))	('5-FU', 'Var', (49, 53))	('VP-16', 'Gene', (88, 93))	('E1A production', 'MPA', (13, 27))	('5-FU', 'Chemical', 'MESH:D005472', (49, 53))	('VP-16', 'Gene', '3054', (88, 93))
761609	20689571	The combination with 5-FU, MMC or VP-16 produced greater cytotoxic effects than the treatment with Ad or the agent alone in all the carcinoma cells tested (P<0.05).	('VP-16', 'Gene', '3054', (34, 39))	('carcinoma', 'Disease', 'MESH:D002277', (132, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('5-FU', 'Chemical', 'MESH:D005472', (21, 25))	('MMC', 'Chemical', 'MESH:D016685', (27, 30))	('VP-16', 'Gene', (34, 39))	('cytotoxic effects', 'CPA', (57, 74))	('carcinoma', 'Disease', (132, 141))	('MMC', 'Var', (27, 30))	('5-FU', 'Var', (21, 25))
761612	20689571	These esophageal carcinoma cells showed differential sensitivity to respective agents, but all the cells became more susceptible to the combination than to the agent alone in the case of 5-FU, MMC or VP-16.	('MMC', 'Chemical', 'MESH:D016685', (193, 196))	('VP-16', 'Gene', (200, 205))	('esophageal carcinoma', 'Disease', (6, 26))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (6, 26))	('MMC', 'Var', (193, 196))	('susceptible', 'MPA', (117, 128))	('5-FU', 'Var', (187, 191))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (6, 26))	('5-FU', 'Chemical', 'MESH:D005472', (187, 191))	('VP-16', 'Gene', '3054', (200, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
761637	20689571	Expressed E1A can sensitize the infected cells to chemotherapeutic agents, but the E1A expression was rather inhibited by 5-FU in this study.	('5-FU', 'Chemical', 'MESH:D005472', (122, 126))	('inhibited', 'NegReg', (109, 118))	('E1A', 'Var', (10, 13))	('sensitize', 'Reg', (18, 27))
761651	20689571	Our study showed that 5-FU, VP-16 and MMC enhanced cell cycle at S phase and then induced G2/M phase entry, whereas CDDP induced G1 phase arrest (data not shown).	('MMC', 'Var', (38, 41))	('5-FU', 'Chemical', 'MESH:D005472', (22, 26))	('G2/M phase', 'CPA', (90, 100))	('arrest', 'Disease', 'MESH:D006323', (138, 144))	('VP-16', 'Gene', '3054', (28, 33))	('enhanced', 'PosReg', (42, 50))	('induced', 'Reg', (82, 89))	('arrest', 'Disease', (138, 144))	('cell cycle at S phase', 'CPA', (51, 72))	('MMC', 'Chemical', 'MESH:D016685', (38, 41))	('VP-16', 'Gene', (28, 33))	('5-FU', 'Var', (22, 26))	('CDDP', 'Chemical', 'MESH:D002945', (116, 120))
761665	20689571	A number of agents including a molecular-targeted medicine can also be used in combination with other therapeutics, and a recent study showed that inhibitors of heat-shock protein 90, which are one of the candidates of anticancer agents, enhanced replication of Ad-delE1B55.	('shock', 'Phenotype', 'HP:0031273', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('replication', 'MPA', (247, 258))	('E1B', 'Gene', (268, 271))	('inhibitors', 'Var', (147, 157))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('enhanced', 'PosReg', (238, 246))	('cancer', 'Disease', (223, 229))	('E1B', 'Gene', '594', (268, 271))
761782	32508912	NEU% but not LYM% was included in the factors associated with 5-year mortality in the multivariate analysis, perhaps because LYM% mainly indicates hypersplenism and indirectly responds to portal hypertension.	('hypersplenism', 'Disease', (147, 160))	('portal hypertension', 'MPA', (188, 207))	('hypersplenism', 'Phenotype', 'HP:0001971', (147, 160))	('portal hypertension', 'Phenotype', 'HP:0001409', (188, 207))	('responds', 'Reg', (176, 184))	('hypertension', 'Phenotype', 'HP:0000822', (195, 207))	('LYM%', 'Var', (125, 129))	('indicates', 'Reg', (137, 146))	('hypersplenism', 'Disease', 'MESH:D006971', (147, 160))
761788	31980914	MIS416 is a non-toxic microparticle that activates immunity via the nucleotide-binding oligomerization domain 2 (NOD2) and TLR9 pathways.	('nucleotide-binding oligomerization domain 2', 'Gene', '64127', (68, 111))	('MIS416', 'Chemical', '-', (0, 6))	('immunity', 'CPA', (51, 59))	('NOD2', 'Gene', '64127', (113, 117))	('nucleotide-binding oligomerization domain 2', 'Gene', (68, 111))	('TLR9 pathways', 'Pathway', (123, 136))	('NOD2', 'Gene', (113, 117))	('MIS416', 'Var', (0, 6))	('activates', 'PosReg', (41, 50))
761790	31980914	We conducted a first-in-human clinical trial of CHP-NY-ESO-1 with MIS416 in patients with NY-ESO-1-expressing refractory solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MIS416', 'Var', (66, 72))	('patients', 'Species', '9606', (76, 84))	('human', 'Species', '9606', (24, 29))	('tumors', 'Disease', (127, 133))	('NY-ESO-1', 'Gene', (52, 60))	('MIS416', 'Chemical', '-', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('NY-ESO-1', 'Gene', (90, 98))	('CHP-NY-ESO-1', 'Chemical', '-', (48, 60))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('refractory', 'Disease', (110, 120))	('NY-ESO-1', 'Gene', '1485', (52, 60))	('NY-ESO-1', 'Gene', '1485', (90, 98))
761797	31980914	In a preclinical study, adding anti-PD-1 monoclonal antibody to CHP-NY-ESO-1 and MIS416 induced significant tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('MIS416', 'Var', (81, 87))	('MIS416', 'Chemical', '-', (81, 87))	('CHP-NY-ESO-1', 'Chemical', '-', (64, 76))
761806	31980914	MIS416 is a nontoxic microparticle adjuvant derived from Propionibacterium acnes that activates the immune response via the NOD2 and TLR9 pathways.	('NOD2', 'Gene', '64127', (124, 128))	('MIS416', 'Chemical', '-', (0, 6))	('activates', 'PosReg', (86, 95))	('TLR9 pathways', 'Pathway', (133, 146))	('NOD2', 'Gene', (124, 128))	('Propionibacterium acnes', 'Species', '1747', (57, 80))	('acnes', 'Phenotype', 'HP:0001061', (75, 80))	('immune response', 'CPA', (100, 115))	('MIS416', 'Var', (0, 6))
761807	31980914	MIS416 acts as a Th1 response-skewing adjuvant by promoting the CD8+ T cell response and enhancing the anti-tumor activity of vaccines in a mouse model.	('mouse', 'Species', '10090', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CD8', 'Gene', (64, 67))	('MIS416', 'Chemical', '-', (0, 6))	('enhancing', 'PosReg', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CD8', 'Gene', '925', (64, 67))	('tumor', 'Disease', (108, 113))	('promoting', 'PosReg', (50, 59))	('MIS416', 'Var', (0, 6))
761808	31980914	However, no clinical trials of cancer vaccines with MIS416 as an adjuvant have been reported.	('MIS416', 'Chemical', '-', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('MIS416', 'Var', (52, 58))
761814	31980914	We conducted single-center, open-label, dose-escalation studies of CHP-NY-ESO-1 with MIS416 as an adjuvant in patients with NY-ESO-1-expressing refractory urothelial cancer or castration-resistant prostate cancer and malignant solid tumors to evaluate its safety, tolerability, and immune response.	('refractory urothelial cancer', 'Disease', (144, 172))	('MIS416', 'Var', (85, 91))	('malignant solid tumors', 'Disease', 'MESH:D009369', (217, 239))	('NY-ESO-1', 'Gene', '1485', (71, 79))	('malignant solid tumors', 'Disease', (217, 239))	('NY-ESO-1', 'Gene', '1485', (124, 132))	('NY-ESO-1', 'Gene', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('NY-ESO-1', 'Gene', (124, 132))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('CHP-NY-ESO-1', 'Chemical', '-', (67, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (197, 212))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('MIS416', 'Chemical', '-', (85, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (197, 212))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('prostate cancer', 'Disease', (197, 212))	('refractory urothelial cancer', 'Disease', 'MESH:D014523', (144, 172))	('patients', 'Species', '9606', (110, 118))
761818	31980914	Patients meeting the following criteria were included: histologically documented urothelial cancer, prostate cancer (clinical trial Registration Number UMIN000005246) or malignant solid tumors (UMIN000008006) that were refractory to standard therapy, age >= 20 years, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) scale of 0-2, a life expectancy >= 3 months, adequate organ function and positive tumor expression of NY-ESO-1.	('NY-ESO-1', 'Gene', (439, 447))	('tumor', 'Disease', (186, 191))	('malignant solid tumors', 'Disease', 'MESH:D009369', (170, 192))	('malignant solid tumors', 'Disease', (170, 192))	('tumor', 'Phenotype', 'HP:0002664', (419, 424))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('Patients', 'Species', '9606', (0, 8))	('UMIN000008006', 'Var', (194, 207))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('Oncology', 'Phenotype', 'HP:0002664', (291, 299))	('urothelial cancer', 'Disease', 'MESH:D014523', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('urothelial cancer', 'Disease', (81, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('tumor', 'Disease', (419, 424))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('PS', 'Disease', 'MESH:C562429', (333, 335))	('NY-ESO-1', 'Gene', '1485', (439, 447))	('prostate cancer', 'Disease', (100, 115))	('tumor', 'Disease', 'MESH:D009369', (419, 424))
761820	31980914	Patients were enrolled from March 2011 to February 2017 and received CHP-NY-ESO-1 (0.5 mg/mL)/MIS416 (2 mg/mL) administered at 100 mug/200 mug, 200 mug/200 mug, 200 mug/400 mug or 200 mug/600 mug (cohorts 1, 2, 3 and 4, respectively) every 2 weeks for a total of 6 doses during the treatment phase (clinical trial registration number UMIN000005246 and UMIN000008006) followed by vaccination every 4 weeks (maintenance phase) until disease progression, patient refusal or unacceptable toxicity (UMIN000008007).	('patient', 'Species', '9606', (452, 459))	('MIS416', 'Chemical', '-', (94, 100))	('toxicity', 'Disease', 'MESH:D064420', (484, 492))	('CHP-NY-ESO-1', 'Chemical', '-', (69, 81))	('toxicity', 'Disease', (484, 492))	('Patients', 'Species', '9606', (0, 8))	('UMIN000008006', 'Var', (352, 365))
761837	31980914	Eligible patients were those with NY-ESO-1 expression in >= 1% of tumor cells according to immunohistochemical staining with an E978 monoclonal antibody or >= 1 copy NY-ESO-1/104 copies of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) according to a quantitative real-time PCR (qRT-PCR) analysis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patients', 'Species', '9606', (9, 17))	('tumor', 'Disease', (66, 71))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (189, 229))	('expression', 'Var', (43, 53))	('NY-ESO-1', 'Gene', '1485', (34, 42))	('NY-ESO-1', 'Gene', (166, 174))	('GAPDH', 'Gene', '2597', (231, 236))	('GAPDH', 'Gene', (231, 236))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (189, 229))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('NY-ESO-1', 'Gene', '1485', (166, 174))	('NY-ESO-1', 'Gene', (34, 42))
761840	31980914	NY-ESO-1-overlapping peptides were grouped as follows: anterior half-mix p1-20, p11-30, p21-40, p31-50, p41-60, p51-70, p61-80, p71-90 and p81-100 and posterior half-mix p91-110, p101-120, p111-130, p119-141, p131-150, p139-160, p151-170 and p161-180.	('p41-60', 'Var', (104, 110))	('p71-90', 'Var', (128, 134))	('p151-170', 'Var', (229, 237))	('NY-ESO-1', 'Gene', '1485', (0, 8))	('p21-40', 'Var', (88, 94))	('p31-50', 'Var', (96, 102))	('p51-70', 'Var', (112, 118))	('p139-160', 'Var', (219, 227))	('p81', 'Gene', (139, 142))	('NY-ESO-1', 'Gene', (0, 8))	('p119-141', 'Var', (199, 207))	('p161-180', 'Var', (242, 250))	('p131-150', 'Var', (209, 217))	('p101-120', 'Var', (179, 187))	('p111-130', 'Var', (189, 197))	('p11-30', 'Var', (80, 86))	('p91-110', 'Var', (170, 177))	('p1-20', 'Gene', '1500', (73, 78))	('p81', 'Gene', '7430', (139, 142))	('p1-20', 'Gene', (73, 78))	('p61-80', 'Var', (120, 126))
761851	31980914	Fisher's exact test was used to compare the IgG positivity rates of patients who received CHP-NY-ESO-1 at 100 microg versus those who received CHP-NY-ESO-1 at 200 microg.	('IgG', 'MPA', (44, 47))	('IgG positivity', 'Phenotype', 'HP:0003237', (44, 58))	('CHP-NY-ESO-1', 'Var', (90, 102))	('patients', 'Species', '9606', (68, 76))	('CHP-NY-ESO-1', 'Chemical', '-', (90, 102))	('CHP-NY-ESO-1', 'Chemical', '-', (143, 155))
761870	31980914	We hypothesized that the MIS416 adjuvant affected serum cytokine levels in the early phase.	('affected', 'Reg', (41, 49))	('serum cytokine levels', 'MPA', (50, 71))	('MIS416', 'Var', (25, 31))	('MIS416 adjuvant', 'Chemical', '-', (25, 40))
761882	31980914	Treatment with CHP-NY-ESO-1, anti-PD-1 mAb, CHP-NY-ESO-1 + anti-PD-1 mAb or CHP-NY-ESO-1 + MIS416 could not suppress tumor growth, whereas treatment with CHP-NY-ESO-1 + MIS416 + anti-PD-1 mAb induced significant tumor growth suppression (Fig.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CHP-NY-ESO-1', 'Chemical', '-', (154, 166))	('tumor', 'Disease', (117, 122))	('CHP-NY-ESO-1 +', 'Chemical', '-', (76, 90))	('MIS416', 'Chemical', '-', (169, 175))	('tumor growth suppression', 'Disease', (212, 236))	('CHP-NY-ESO-1 + MIS416 +', 'Var', (154, 177))	('tumor growth suppression', 'Disease', 'MESH:D006130', (212, 236))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('CHP-NY-ESO-1', 'Chemical', '-', (76, 88))	('MIS416', 'Chemical', '-', (91, 97))	('CHP-NY-ESO-1', 'Chemical', '-', (44, 56))	('CHP-NY-ESO-1 +', 'Chemical', '-', (154, 168))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('CHP-NY-ESO-1', 'Chemical', '-', (15, 27))	('CHP-NY-ESO-1 +', 'Chemical', '-', (44, 58))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (212, 217))
761884	31980914	We expected the addition of MIS416 to make CHP-NY-ESO-1 more efficient without compromising safety.	('CHP-NY-ESO-1', 'Chemical', '-', (43, 55))	('MIS416', 'Chemical', '-', (28, 34))	('addition', 'Var', (16, 24))	('MIS416', 'Var', (28, 34))
761887	31980914	In multiple sclerosis (MS) patients who were administered MIS416 intravenously, vascular disorders, including hypertension, were observed in 52.5% of the patients.	('MIS416', 'Chemical', '-', (58, 64))	('vascular disorders', 'Disease', 'MESH:D000783', (80, 98))	('observed', 'Reg', (129, 137))	('multiple sclerosis', 'Disease', (3, 21))	('vascular disorders', 'Disease', (80, 98))	('hypertension', 'Disease', 'MESH:D006973', (110, 122))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (27, 35))	('hypertension', 'Disease', (110, 122))	('multiple sclerosis', 'Disease', 'MESH:D009103', (3, 21))	('hypertension', 'Phenotype', 'HP:0000822', (110, 122))	('MIS416', 'Var', (58, 64))
761888	31980914	In the higher MIS416 dose group (500-600 mug), the frequency of vascular disorders was 83.3%; these included diastolic hypertension in 50.0%, hypertension in 50.0%, and systolic hypertension in 66.7% of the patients.	('patients', 'Species', '9606', (207, 215))	('hypertension', 'Disease', 'MESH:D006973', (178, 190))	('systolic hypertension', 'Phenotype', 'HP:0004421', (169, 190))	('MIS416', 'Chemical', '-', (14, 20))	('hypertension', 'Phenotype', 'HP:0000822', (119, 131))	('500-600 mug', 'Var', (33, 44))	('hypertension', 'Disease', (119, 131))	('hypertension', 'Disease', (178, 190))	('diastolic hypertension', 'Disease', 'MESH:C563897', (109, 131))	('hypertension', 'Phenotype', 'HP:0000822', (178, 190))	('hypertension', 'Disease', 'MESH:D006973', (142, 154))	('vascular disorders', 'Disease', 'MESH:D000783', (64, 82))	('diastolic hypertension', 'Disease', (109, 131))	('hypertension', 'Disease', (142, 154))	('vascular disorders', 'Disease', (64, 82))	('hypertension', 'Disease', 'MESH:D006973', (119, 131))	('hypertension', 'Phenotype', 'HP:0000822', (142, 154))
761889	31980914	These results indicate that MIS416 may cause vascular AEs.	('cause', 'Reg', (39, 44))	('MIS416', 'Chemical', '-', (28, 34))	('vascular AEs', 'Disease', (45, 57))	('MIS416', 'Var', (28, 34))
761893	31980914	In line with the results of a previous study, we found that the antibody response was stronger in patients who received CHP-NY-ESO-1 200 microg than in those who received CHP-NY-ESO-1 100 microg (Table 3).	('CHP-NY-ESO-1', 'Chemical', '-', (120, 132))	('CHP-NY-ESO-1 200 microg', 'Var', (120, 143))	('patients', 'Species', '9606', (98, 106))	('antibody response', 'MPA', (64, 81))	('stronger', 'PosReg', (86, 94))	('CHP-NY-ESO-1', 'Chemical', '-', (171, 183))
761896	31980914	To clarify the effect of MIS416, we compared the titers of IgG1, IgG2 and IgG3 in serum obtained from patients in cohorts 2-4 (CHP-NY-ESO-1 200 microg with MIS416) to those reported in 8 patients enrolled in a previous study by Kageyama et al.	('patients', 'Species', '9606', (187, 195))	('CHP-NY-ESO-1', 'Chemical', '-', (127, 139))	('MIS416', 'Chemical', '-', (25, 31))	('MIS416', 'Var', (156, 162))	('patients', 'Species', '9606', (102, 110))	('MIS416', 'Chemical', '-', (156, 162))	('IgG3', 'Gene', (74, 78))	('IgG3', 'Gene', '3502', (74, 78))
761899	31980914	CHP-NY-ESO-1 induced a prominent IgG1 response with increased IgG2 and IgG3 titers.	('IgG2', 'CPA', (62, 66))	('IgG3', 'Gene', '3502', (71, 75))	('CHP-NY-ESO-1', 'Chemical', '-', (0, 12))	('increased', 'PosReg', (52, 61))	('increased IgG2', 'Phenotype', 'HP:0032299', (52, 66))	('IgG1 response', 'MPA', (33, 46))	('IgG3', 'Gene', (71, 75))	('CHP-NY-ESO-1', 'Var', (0, 12))
761900	31980914	However, adding MIS416 seemed to suppress IgG1, 2 and 3 responses (Supplementary Fig.	('IgG1, 2 and 3', 'Gene', '3502', (42, 55))	('suppress', 'NegReg', (33, 41))	('MIS416', 'Chemical', '-', (16, 22))	('MIS416', 'Var', (16, 22))
761904	31980914	Furthermore, the immune response stimulated by CHP-NY-ESO-1 was not enhanced by increasing the dose of MIS416.	('MIS416', 'Chemical', '-', (103, 109))	('immune response', 'CPA', (17, 32))	('CHP-NY-ESO-1', 'Chemical', '-', (47, 59))	('MIS416', 'Var', (103, 109))
761905	31980914	MIS416 skewed the Th1 response in a mouse model.	('MIS416', 'Chemical', '-', (0, 6))	('Th1 response', 'MPA', (18, 30))	('skewed', 'Reg', (7, 13))	('MIS416', 'Var', (0, 6))	('mouse', 'Species', '10090', (36, 41))
761906	31980914	In vitro, MIS416 was readily internalized by human myeloid and plasmacytoid DCs, resulting in cytokine secretion and cell activation/maturation.	('MIS416', 'Var', (10, 16))	('MIS416', 'Chemical', '-', (10, 16))	('cell activation/maturation', 'CPA', (117, 143))	('human', 'Species', '9606', (45, 50))	('cytokine secretion', 'MPA', (94, 112))
761907	31980914	In this study, the subcutaneous injection of MIS416 caused IL-6 and IL-10 levels to be increased at 6 h after the first vaccination (Fig.	('increased', 'PosReg', (87, 96))	('IL-10', 'Gene', '3586', (68, 73))	('MIS416', 'Chemical', '-', (45, 51))	('IL-10', 'Gene', (68, 73))	('IL-6', 'Gene', (59, 63))	('IL-6', 'Gene', '3569', (59, 63))	('MIS416', 'Var', (45, 51))
761912	31980914	The anti-NY-ESO-1 IgG1 response was also attenuated as the dose of MIS416 increased (Supplementary Fig.	('NY-ESO-1', 'Gene', '1485', (9, 17))	('attenuated', 'NegReg', (41, 51))	('MIS416', 'Var', (67, 73))	('MIS416', 'Chemical', '-', (67, 73))	('NY-ESO-1', 'Gene', (9, 17))
761913	31980914	The NY-ESO-1-specific IgG1 titer was significantly lower in patients who received MIS416 600 mug than in those who received the vaccine without MIS416.	('patients', 'Species', '9606', (60, 68))	('MIS416 600 mug', 'Var', (82, 96))	('NY-ESO-1', 'Gene', '1485', (4, 12))	('IgG1', 'Protein', (22, 26))	('lower', 'NegReg', (51, 56))	('titer', 'MPA', (27, 32))	('MIS416', 'Chemical', '-', (82, 88))	('MIS416', 'Chemical', '-', (144, 150))	('NY-ESO-1', 'Gene', (4, 12))
761914	31980914	Although MIS416 suppressed IL-17 in an MS mouse model, this result has not been confirmed in humans with MS.	('suppressed', 'NegReg', (16, 26))	('humans', 'Species', '9606', (93, 99))	('mouse', 'Species', '10090', (42, 47))	('MIS416', 'Var', (9, 15))	('MIS416', 'Chemical', '-', (9, 15))	('IL-17', 'Protein', (27, 32))
761915	31980914	In our study, IL-17 levels tended to increase as the dose of MIS416 increased (Supplementary Fig.	('MIS416', 'Var', (61, 67))	('increase', 'PosReg', (37, 45))	('MIS416', 'Chemical', '-', (61, 67))
761917	31980914	Based on the findings in a mouse model, we could not predict whether the human innate immune system would be activated by the TLR9 and NOD2 signals included in MIS416, leading to an adaptive immune response.	('mouse', 'Species', '10090', (27, 32))	('MIS416', 'Var', (160, 166))	('NOD2', 'Gene', '64127', (135, 139))	('human', 'Species', '9606', (73, 78))	('NOD2', 'Gene', (135, 139))	('MIS416', 'Chemical', '-', (160, 166))	('leading to', 'Reg', (168, 178))	('TLR9', 'Gene', (126, 130))	('adaptive immune response', 'CPA', (182, 206))
761921	31980914	In vitro, MIS416 stimulated PBMCs, causing them to secrete IL-6, IL-10, IFN-gamma, TNF-alpha and IL-1beta and exhibit an inverse dose-response to MIS416 at 5, 20 and 50 microg/mL.	('TNF-alpha', 'Gene', '7124', (83, 92))	('MIS416', 'Var', (10, 16))	('MIS416', 'Chemical', '-', (10, 16))	('TNF-alpha', 'Gene', (83, 92))	('IFN-gamma', 'Gene', (72, 81))	('IFN-gamma', 'Gene', '3458', (72, 81))	('IL-10', 'Gene', '3586', (65, 70))	('MIS416', 'Chemical', '-', (146, 152))	('IL-1beta', 'Gene', '3552', (97, 105))	('IL-6', 'Gene', (59, 63))	('IL-10', 'Gene', (65, 70))	('IL-1beta', 'Gene', (97, 105))	('IL-6', 'Gene', '3569', (59, 63))
761926	31980914	In a previous study of MS patients, MIS416 was administered intravenously with the expectation that it would move to the liver and act as an immunosuppressive agent; in contrast, in this study, MIS416 was administered subcutaneously with the expectation that it would exert an immune stimulatory effect in a draining lymph node.	('immune stimulatory', 'MPA', (277, 295))	('MIS416', 'Var', (194, 200))	('MIS416', 'Chemical', '-', (194, 200))	('patients', 'Species', '9606', (26, 34))	('MIS416', 'Chemical', '-', (36, 42))
761946	31980914	The combination of CHP-NY-ESO-1 + MIS416 + anti-PD-1 mAb exerted a significant tumor growth suppression effect in the mouse model (Fig.	('CHP-NY-ESO-1 + MIS416 +', 'Var', (19, 42))	('CHP-NY-ESO-1 +', 'Chemical', '-', (19, 33))	('tumor growth suppression', 'Disease', 'MESH:D006130', (79, 103))	('tumor growth suppression', 'Disease', (79, 103))	('mouse', 'Species', '10090', (118, 123))	('anti-PD-1', 'Gene', (43, 52))	('MIS416', 'Chemical', '-', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
762014	30827415	The binding specificity of D11 scFv was previously characterized.	('scFv', 'Gene', '652070', (31, 35))	('binding', 'Interaction', (4, 11))	('scFv', 'Gene', (31, 35))	('D11', 'Var', (27, 30))
762041	30214307	The PPAR pathway inhibitor GW9662 prevented the radiation sensitivity enhancement imparted by MeJ.	('prevented', 'NegReg', (34, 43))	('GW9662', 'Var', (27, 33))	('GW9662', 'Chemical', 'MESH:C457499', (27, 33))	('PPAR', 'Gene', '5465', (4, 8))	('MeJ', 'Chemical', 'MESH:C072239', (94, 97))	('radiation sensitivity', 'CPA', (48, 69))	('PPAR', 'Gene', (4, 8))	('enhancement', 'PosReg', (70, 81))
762042	30214307	After adding GW9662, there were no significant differences between the radiation sensitivities of MeJ-treated and -untreated KY170R cells (P>0.05).	('radiation sensitivities', 'CPA', (71, 94))	('MeJ', 'Chemical', 'MESH:C072239', (98, 101))	('GW9662', 'Chemical', 'MESH:C457499', (13, 19))	('GW9662', 'Var', (13, 19))
762043	30214307	The radiation sensitivity effect of MeJ also depended upon the generation of ROS in KY170R cells; 48 h after irradiation, ROS levels in the MeJ group was twofold higher than in the untreated KY170R cells (P<0.05).	('MeJ', 'Chemical', 'MESH:C072239', (36, 39))	('higher', 'PosReg', (162, 168))	('ROS', 'Chemical', 'MESH:D017382', (122, 125))	('MeJ', 'Chemical', 'MESH:C072239', (140, 143))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('ROS levels', 'MPA', (122, 132))	('MeJ', 'Var', (140, 143))
762045	30214307	Our results indicate that MeJ can increase the radiation sensitivity of AKR1C3-overexpressing KY170R cells by inhibiting the 11-ketoprostaglandin reductase activity of AKR1C3 and increasing cellular ROS levels.	('AKR1C3', 'Gene', '8644', (168, 174))	('AKR1C3', 'Gene', (168, 174))	('MeJ', 'Chemical', 'MESH:C072239', (26, 29))	('radiation sensitivity', 'CPA', (47, 68))	('AKR1C3', 'Gene', (72, 78))	('ROS', 'Chemical', 'MESH:D017382', (199, 202))	('11-ketoprostaglandin reductase activity', 'MPA', (125, 164))	('increasing', 'PosReg', (179, 189))	('AKR1C3', 'Gene', '8644', (72, 78))	('MeJ', 'Var', (26, 29))	('inhibiting', 'NegReg', (110, 120))	('cellular ROS levels', 'MPA', (190, 209))	('increase', 'PosReg', (34, 42))	('prostaglandin', 'Chemical', 'MESH:D011453', (132, 145))
762063	30214307	MeJ also increased ROS levels in many types of human cancer cells.	('MeJ', 'Var', (0, 3))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('increased', 'PosReg', (9, 18))	('increased ROS levels', 'Phenotype', 'HP:0025464', (9, 29))	('MeJ', 'Chemical', 'MESH:C072239', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('ROS levels', 'MPA', (19, 29))	('human', 'Species', '9606', (47, 52))	('ROS', 'Chemical', 'MESH:D017382', (19, 22))
762065	30214307	KY170R is an esophageal squamous cancer cell line.	('KY170R', 'Var', (0, 6))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (13, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('esophageal squamous cancer', 'Disease', (13, 39))	('squamous cancer', 'Phenotype', 'HP:0002860', (24, 39))
762082	30214307	We washed the PVDF membranes in Tween and Tris-Buffered Saline (TTBS) (20 mM Tris, 0.5 M NaCl, 0.05% Tween-20) for 10 min, and then blocked the membranes in 10% skim milk for 1 h. The primary antibodies were diluted with TTBS as follows: anti-AKR1C3 (1:4000, A6229-200U; Sigma-Aldrich Co.), anti-PPARgamma (1:1000; Sigma-Aldrich Co.), beta-actin (1:10,000), and anti-human GAPDH (1:3000).	('AKR1C3', 'Gene', (243, 249))	('1:1000;', 'Var', (307, 314))	('anti-PPARgamma (1:1000', 'Var', (291, 313))	('PVDF', 'Chemical', 'MESH:C024865', (14, 18))	('AKR1C3', 'Gene', '8644', (243, 249))	('A6229-200U; Sigma-Aldrich', 'Disease', (259, 284))	('human', 'Species', '9606', (367, 372))	('A6229-200U; Sigma-Aldrich', 'Disease', 'MESH:D014923', (259, 284))	('beta-actin', 'Protein', (335, 345))	('1:10,000', 'Var', (347, 355))	('anti-human', 'Var', (362, 372))
762097	30214307	Alamar Blue assay results demonstrated that MeJ can inhibit the proliferation of sh-KY170R, KY170R, and scr-KY170R cells in a dose-dependent manner.	('inhibit', 'NegReg', (52, 59))	('MeJ', 'Chemical', 'MESH:C072239', (44, 47))	('Alamar Blue', 'Chemical', 'MESH:C005843', (0, 11))	('sh-KY170R', 'Var', (81, 90))	('proliferation', 'CPA', (64, 77))	('KY170R', 'Var', (92, 98))
762100	30214307	Both the cell index and colony formation assays showed that there were no significant differences in the inhibitory rates of MeJ on KY170R, sh-KY170R, and scr-KY170R cells (Figure 1C and D, P>0.05).	('KY170R', 'Var', (132, 138))	('inhibitory rates', 'MPA', (105, 121))	('MeJ', 'Chemical', 'MESH:C072239', (125, 128))
762108	30214307	We incubated KY170R cells with different concentrations (0, 100, and 200 micromol/L) of MeJ for 24 h. Western blot assays showed MeJ could reduce AKR1C3 protein expression in KY170R cells in a dose-dependent manner.	('MeJ', 'Chemical', 'MESH:C072239', (129, 132))	('MeJ', 'Chemical', 'MESH:C072239', (88, 91))	('protein', 'Protein', (153, 160))	('AKR1C3', 'Gene', (146, 152))	('AKR1C3', 'Gene', '8644', (146, 152))	('MeJ', 'Var', (129, 132))	('reduce', 'NegReg', (139, 145))
762122	30214307	Clone formation results showed that GW9662 decreased the radiation sensitivity effects of MeJ.	('radiation sensitivity effects', 'MPA', (57, 86))	('GW9662', 'Chemical', 'MESH:C457499', (36, 42))	('decreased the radiation sensitivity', 'Phenotype', 'HP:0011133', (43, 78))	('GW9662', 'Var', (36, 42))	('MeJ', 'Chemical', 'MESH:C072239', (90, 93))	('decreased', 'NegReg', (43, 52))
762126	30214307	MeJ could also induce apoptosis and pro-apoptotic autophagy in non-small cell lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('MeJ', 'Var', (0, 3))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (67, 89))	('apoptosis', 'CPA', (22, 31))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MeJ', 'Chemical', 'MESH:C072239', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('pro-apoptotic autophagy', 'CPA', (36, 59))	('cancer', 'Disease', (83, 89))	('induce', 'PosReg', (15, 21))
762129	30214307	Radiation slightly increased the apoptotic rate of KY170R cells (from 4.37% to 15.16%; Figure 5A and B).	('increased', 'PosReg', (19, 28))	('KY170R', 'Var', (51, 57))	('apoptotic rate', 'CPA', (33, 47))	('Rad', 'Gene', '6236', (0, 3))	('Rad', 'Gene', (0, 3))
762133	30214307	ROS can increase the radiation sensitivity of cells.	('ROS', 'Var', (0, 3))	('radiation sensitivity of cells', 'CPA', (21, 51))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('increase', 'PosReg', (8, 16))
762139	30214307	Forty-eight hours after irradiation, ROS levels in the MeJ group were twofold higher than in untreated KY170R cells (Figure 6A).	('MeJ', 'Var', (55, 58))	('higher', 'PosReg', (78, 84))	('ROS levels', 'MPA', (37, 47))	('MeJ', 'Chemical', 'MESH:C072239', (55, 58))	('ROS', 'Chemical', 'MESH:D017382', (37, 40))
762149	30214307	Overexpression of the AKR1C3 gene has been implicated in the radioresistance of several tumor cell types.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('implicated', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Overexpression', 'Var', (0, 14))	('AKR1C3', 'Gene', (22, 28))	('AKR1C3', 'Gene', '8644', (22, 28))	('tumor', 'Disease', (88, 93))
762151	30214307	AKR1C3 overexpression could cause the accumulation of PGF2 (radioresistant substrate) and inhibition of the expression of PPARgamma compared with AKR1C3 low expression cells.	('inhibition', 'NegReg', (90, 100))	('AKR1C3', 'Gene', (0, 6))	('overexpression', 'Var', (7, 21))	('AKR1C3', 'Gene', '8644', (0, 6))	('accumulation', 'PosReg', (38, 50))	('PPARgamma', 'Gene', (122, 131))	('PGF2', 'Gene', (54, 58))	('AKR1C3', 'Gene', (146, 152))	('expression', 'MPA', (108, 118))	('AKR1C3', 'Gene', '8644', (146, 152))	('PGF2', 'Chemical', 'MESH:D015237', (54, 58))
762152	30214307	Overexpression of AKR1C3 is also related to drug resistance in tumor cells.	('tumor', 'Disease', (63, 68))	('related', 'Reg', (33, 40))	('AKR1C3', 'Gene', (18, 24))	('AKR1C3', 'Gene', '8644', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('drug resistance', 'Phenotype', 'HP:0020174', (44, 59))
762153	30214307	In cisplatin, cis-diamminedichloroplatinum (II) (CDDP)-resistant human cancer cell lines, AKR1C3 expression is high.	('cisplatin', 'Chemical', 'MESH:D002945', (3, 12))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('human', 'Species', '9606', (65, 70))	('CDDP', 'Chemical', 'MESH:D002945', (49, 53))	('cis-diamminedichloroplatinum', 'Var', (14, 42))	('cancer', 'Disease', (71, 77))	('AKR1C3', 'Gene', (90, 96))	('AKR1C3', 'Gene', '8644', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('high', 'PosReg', (111, 115))	('expression', 'MPA', (97, 107))	('cis-diamminedichloroplatinum (II)', 'Chemical', 'MESH:D002945', (14, 47))
762154	30214307	Inhibitors of AKR1C3 can enhance sensitivity to CDDP and 5-fluorouracil.	('enhance', 'PosReg', (25, 32))	('CDDP', 'Chemical', 'MESH:D002945', (48, 52))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (57, 71))	('AKR1C3', 'Gene', (14, 20))	('Inhibitors', 'Var', (0, 10))	('AKR1C3', 'Gene', '8644', (14, 20))
762166	30214307	MeJ could increase the radiosensitivity of a human prostate adenocarcinoma cell line (PC-3) by inhibiting the expression of the anti-apoptotic protein Bcl-2.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('Bcl-2', 'Gene', (151, 156))	('MeJ', 'Var', (0, 3))	('inhibiting', 'NegReg', (95, 105))	('prostate adenocarcinoma', 'Disease', (51, 74))	('Bcl-2', 'Gene', '596', (151, 156))	('PC-3', 'CellLine', 'CVCL:0035', (86, 90))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (51, 74))	('human', 'Species', '9606', (45, 50))	('MeJ', 'Chemical', 'MESH:C072239', (0, 3))	('expression', 'MPA', (110, 120))	('radiosensitivity', 'CPA', (23, 39))	('increase', 'PosReg', (10, 18))
762167	30214307	In our study, we found that sub-cytotoxic MeJ could enhance the radiosensitivity of KY170R cells, and the effects were dependent upon the expression of AKR1C3.	('MeJ', 'Var', (42, 45))	('AKR1C3', 'Gene', '8644', (152, 158))	('enhance', 'PosReg', (52, 59))	('AKR1C3', 'Gene', (152, 158))	('MeJ', 'Chemical', 'MESH:C072239', (42, 45))	('radiosensitivity of KY170R cells', 'CPA', (64, 96))	('sub-cytotoxic MeJ', 'Var', (28, 45))
762173	30214307	Inhibition of AKR1C3 activity can skew PGD2 metabolism toward 15d-PGJ2, which can activate the PPARgamma pathway.	('activate', 'PosReg', (82, 90))	('15d-PGJ2', 'Chemical', 'MESH:C477819', (62, 70))	('AKR1C3', 'Gene', (14, 20))	('skew', 'Reg', (34, 38))	('PGD2', 'Chemical', 'MESH:D015230', (39, 43))	('AKR1C3', 'Gene', '8644', (14, 20))	('Inhibition', 'Var', (0, 10))	('PPARgamma pathway', 'Pathway', (95, 112))	('PGD2', 'Gene', (39, 43))
762178	30214307	In human squamous cell carcinoma (SCC) cells with high AKR1C3 gene expression, activation of PPARgamma could decrease SCC proliferation.	('decrease', 'NegReg', (109, 117))	('SCC', 'Gene', (34, 37))	('human', 'Species', '9606', (3, 8))	('AKR1C3', 'Gene', '8644', (55, 61))	('SCC', 'Gene', (118, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('SCC', 'Gene', '6317', (34, 37))	('AKR1C3', 'Gene', (55, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (9, 32))	('squamous cell carcinoma', 'Disease', (9, 32))	('activation', 'PosReg', (79, 89))	('SCC', 'Gene', '6317', (118, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (9, 32))	('high', 'Var', (50, 54))
762179	30214307	The presence of 1 microM GW9662 partially restored the proliferation rate of SCC cells.	('restored', 'PosReg', (42, 50))	('proliferation rate', 'CPA', (55, 73))	('GW9662', 'Var', (25, 31))	('GW9662', 'Chemical', 'MESH:C457499', (25, 31))	('SCC', 'Gene', (77, 80))	('SCC', 'Gene', '6317', (77, 80))
762180	30214307	In our study, the PPARgamma pathway inhibitor, GW9662, decreased the radiosensitivity effects of MeJ.	('GW9662', 'Chemical', 'MESH:C457499', (47, 53))	('radiosensitivity effects', 'CPA', (69, 93))	('decreased', 'NegReg', (55, 64))	('MeJ', 'Chemical', 'MESH:C072239', (97, 100))	('GW9662', 'Var', (47, 53))
762182	30214307	ROS is critical in irradiation-induced cell death, and it can cause cell death via apoptosis, autophagy, and various other pathways.	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('cell death', 'CPA', (68, 78))	('autophagy', 'CPA', (94, 103))	('cause', 'Reg', (62, 67))	('apoptosis', 'CPA', (83, 92))
762183	30214307	In addition to direct ROS, indirect ROS can also cause damage to the mitochondria, leading to prolonged oxidative stress that can further damage cellular DNA.	('indirect ROS', 'Var', (27, 39))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('damage', 'Reg', (138, 144))	('oxidative stress', 'Phenotype', 'HP:0025464', (104, 120))	('cellular DNA', 'MPA', (145, 157))	('ROS', 'Chemical', 'MESH:D017382', (22, 25))	('oxidative stress', 'MPA', (104, 120))
762187	30214307	In our study, MeJ significantly increased ROS generation in KY170R cells, an effect which lasted for up to 72 h after radiation.	('KY170R', 'Var', (60, 66))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('increased ROS generation', 'Phenotype', 'HP:0025464', (32, 56))	('ROS generation', 'MPA', (42, 56))	('MeJ', 'Gene', (14, 17))	('increased', 'PosReg', (32, 41))	('MeJ', 'Chemical', 'MESH:C072239', (14, 17))
762220	30018188	A few years later, Zaphiropoulos et al., hypothesized that circRNAs may be formed also through an exon skipping mechanism.	('cir', 'Gene', '9541', (59, 62))	('cir', 'Gene', (59, 62))	('exon skipping', 'Var', (98, 111))
762258	30018188	miRNAs: In the nucleus, the microprocessor complex of the RNA-binding protein Di George Syndrome Critical Region Gene 8 (DGCR8) together with the RNase III enzyme Drosha, binds and cleaves the basal stem of pri-miRNAs to liberate the stem-loop precursor miRNA (pre-miRNA) of about 65 nucleotides (nt).	('miR', 'Gene', '220972', (211, 214))	('miR', 'Gene', '220972', (265, 268))	('Di George Syndrome Critical Region Gene 8', 'Gene', '54487', (78, 119))	('miR', 'Gene', (211, 214))	('Di George Syndrome Critical Region Gene 8', 'Gene', (78, 119))	('miR', 'Gene', (265, 268))	('DGCR8', 'Gene', (121, 126))	('DGCR8', 'Gene', '54487', (121, 126))	('cleaves', 'Var', (181, 188))	('liberate', 'NegReg', (221, 229))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', '220972', (254, 257))	('RNase III', 'Gene', (146, 155))	('GC', 'Phenotype', 'HP:0012126', (122, 124))	('rat', 'Species', '10116', (225, 228))	('miR', 'Gene', (0, 3))	('miR', 'Gene', (254, 257))	('binds', 'Interaction', (171, 176))	('RNase III', 'Gene', '29102', (146, 155))
762259	30018188	Drosha contains a tandem of RNase III domains (RIIIDs) and a double strand (ds)-RNA binding domain and each domain has a specialized action to cleave accurately at the 11th bp of the hairpin away from the basal single strand junction of the 5' strand and 22 bp from the apical junction.	('rat', 'Species', '10116', (154, 157))	('cleave', 'Var', (143, 149))	('RNase III', 'Gene', '29102', (28, 37))	('RNase III', 'Gene', (28, 37))	('apical junction', 'Phenotype', 'HP:0032176', (270, 285))
762275	30018188	An example of a human gene locus that contains Alu repeats is the Homeodomain Interacting Protein Kinase 3 (HIPK3) locus circularization.	('HIPK3', 'Gene', (108, 113))	('cir', 'Gene', '9541', (121, 124))	('Alu repeats', 'Var', (47, 58))	('Homeodomain Interacting Protein Kinase 3', 'Gene', '10114', (66, 106))	('Homeodomain Interacting Protein Kinase 3', 'Gene', (66, 106))	('human', 'Species', '9606', (16, 21))	('HIPK3', 'Gene', '10114', (108, 113))	('cir', 'Gene', (121, 124))
762285	30018188	Examples of these hybrids are: lnc-pri-miR-21 and lnc-pri-miR-122.	('miR-122', 'Gene', '406906', (58, 65))	('miR-122', 'Gene', (58, 65))	('lnc-pri-miR-21', 'Var', (31, 45))
762291	30018188	For example, miR-155/BIC precursor was found to be highly expressed in pediatric Burkitt lymphoma (BL), while reduced levels of miR-143 and miR-145 were found in the adenomatous and cancer stages of colorectal neoplasia.	('colorectal neoplasia', 'Disease', 'MESH:D009369', (199, 219))	('neoplasia', 'Phenotype', 'HP:0002664', (210, 219))	('lymphoma', 'Phenotype', 'HP:0002665', (89, 97))	('cancer', 'Disease', (182, 188))	('miR-143', 'Gene', '406935', (128, 135))	('miR-145', 'Gene', '406937', (140, 147))	('miR-143', 'Gene', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (81, 97))	('adenomatous', 'Disease', (166, 177))	('adenomatous', 'Disease', 'MESH:D011125', (166, 177))	('miR-145', 'Gene', (140, 147))	('pediatric Burkitt lymphoma', 'Disease', 'MESH:D002051', (71, 97))	('pediatric Burkitt lymphoma', 'Disease', (71, 97))	('BIC', 'Chemical', 'MESH:C100119', (21, 24))	('miR-155/BIC', 'Var', (13, 24))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('colorectal neoplasia', 'Disease', (199, 219))	('BL', 'Phenotype', 'HP:0030080', (99, 101))
762300	30018188	In the Emu-miR155 transgenic mice, under the control of a VH promoter-Ig heavy chain Emu enhancer, miR-155 activated the pre-B stage of differentiation.	('transgenic mice', 'Species', '10090', (18, 33))	('miR155', 'Gene', '387173', (11, 17))	('miR-155', 'Var', (99, 106))	('pre-B stage of differentiation', 'CPA', (121, 151))	('activated', 'PosReg', (107, 116))	('miR155', 'Gene', (11, 17))
762302	30018188	In another study, two mice lymphoma models, miR-21 and miR-155 causes recombination- locus of X-over P1 (Cre-loxP) tetracycline-controlled knock-in mouse, were developed.	('lymphoma', 'Disease', (27, 35))	('miR-155', 'Var', (55, 62))	('mouse', 'Species', '10090', (148, 153))	('lymphoma', 'Disease', 'MESH:D008223', (27, 35))	('tetracycline', 'Chemical', 'MESH:D013752', (115, 127))	('lymphoma', 'Phenotype', 'HP:0002665', (27, 35))	('mice', 'Species', '10090', (22, 26))
762303	30018188	These mice upon induction of miR-21 and miR-155, after three months rearing in the absence of doxycycline food, developed acute lymphadenopathy and splenomegaly.	('splenomegaly', 'Disease', (148, 160))	('lymphadenopathy', 'Disease', (128, 143))	('mice', 'Species', '10090', (6, 10))	('splenomegaly', 'Disease', 'MESH:D013163', (148, 160))	('lymphadenopathy', 'Disease', 'MESH:D008206', (128, 143))	('splenomegaly', 'Phenotype', 'HP:0001744', (148, 160))	('miR-155', 'Var', (40, 47))	('miR-21', 'Var', (29, 35))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (128, 143))	('doxycycline', 'Chemical', 'MESH:D004318', (94, 105))	('developed', 'Reg', (112, 121))
762305	30018188	Anti-miR-21 and anti-miR-155 were placed in nanoparticles composed of (polylactic-co-glycolicacid) (PLGA) and the Peptide nucleic acid (PNA) with a low pH-induced transmembrane structure (pHLIP) and were successfully delivered to the mice and reduced the tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('mice', 'Species', '10090', (234, 238))	('-co-glycolicacid', 'Chemical', '-', (81, 97))	('reduced', 'NegReg', (243, 250))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('anti-miR-155', 'Var', (16, 28))
762323	30018188	Deregulated expression of miRNAs in different cancer types may also reflect a defective miRNA biogenesis mechanism and maturation.	('miR', 'Gene', (88, 91))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('miR', 'Gene', '220972', (26, 29))	('defective', 'NegReg', (78, 87))	('Deregulated', 'Var', (0, 11))	('miR', 'Gene', (26, 29))	('cancer', 'Disease', (46, 52))	('rat', 'Species', '10116', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('expression', 'MPA', (12, 22))	('miR', 'Gene', '220972', (88, 91))
762328	30018188	These mutations impaired the expression of let-7 family as well as other tumor suppressor miRNAs, which derived from the 5' arm of the miRNA hairpins and this finding could explain one of the main mechanisms that induce the formation of Wilms tumors.	('miR', 'Gene', (135, 138))	('Wilms tumors', 'Phenotype', 'HP:0002667', (237, 249))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Wilms tumors', 'Disease', (237, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('let-7 family', 'Protein', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Wilms tumors', 'Disease', 'MESH:D009396', (237, 249))	('impaired', 'NegReg', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))	('expression', 'MPA', (29, 39))	('mutations', 'Var', (6, 15))	('miR', 'Gene', '220972', (135, 138))	('tumor', 'Disease', (243, 248))
762336	30018188	Besides the evidence that miRNA biogenesis perturbation leads to tumorigenesis, a plethora of other mechanisms are involved as well.	('miR', 'Gene', '220972', (26, 29))	('tumor', 'Disease', (65, 70))	('miR', 'Gene', (26, 29))	('perturbation', 'Var', (43, 55))	('leads to', 'Reg', (56, 64))	('plethora', 'Phenotype', 'HP:0001050', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
762361	30018188	One known example is the regulation of HOX genes (HOTAIR and HOXA), a group of genes which controls the body orientation, that is, head-to-tail axis of animals, by the antisense RNA, HOXA transcript at the distal tip, (HOTTIP), which in turn is transcribed by the 5' end of the HOXA gene.	('HOTTIP', 'Gene', (219, 225))	('HOXA', 'Gene', '3197', (183, 187))	('HOXA', 'Gene', (61, 65))	('HOTAIR', 'Gene', (50, 56))	('HOTTIP', 'Gene', '100316868', (219, 225))	('HOXA', 'Gene', (278, 282))	('HOTAIR', 'Gene', '100124700', (50, 56))	('HOXA', 'Gene', '3197', (61, 65))	('HOXA', 'Gene', (183, 187))	('HOXA', 'Gene', '3197', (278, 282))	('antisense RNA', 'Var', (168, 181))
762377	30018188	Deletion of SLERT impairs pre-rRNA transcription and rRNA production, leading to decreased tumorigenesis.	('decreased', 'NegReg', (81, 90))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('SLERT', 'Gene', (12, 17))	('pre-rRNA transcription', 'MPA', (26, 48))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('impairs', 'NegReg', (18, 25))	('rRNA production', 'MPA', (53, 68))	('Deletion', 'Var', (0, 8))
762389	30018188	Upon knockdown of XIST by antisense oligos in human GC cell lines, proliferation and apoptosis were also decreased.	('GC', 'Phenotype', 'HP:0012126', (52, 54))	('rat', 'Species', '10116', (74, 77))	('apoptosis', 'CPA', (85, 94))	('human', 'Species', '9606', (46, 51))	('XIST', 'Gene', '7503', (18, 22))	('proliferation', 'CPA', (67, 80))	('XIST', 'Gene', (18, 22))	('decreased', 'NegReg', (105, 114))	('antisense oligos', 'Var', (26, 42))
762400	30018188	PANDA antisense transcription was found to be exclusively induced by p53 and this lncRNA sequesters the transcription factor NF-YA, which binds the promoter of apoptotic activators such as APAF1, BIK, FAS and LRDD (Figure 2C).	('BIK', 'Gene', (196, 199))	('LRDD', 'Gene', (209, 213))	('NF-YA', 'Gene', (125, 130))	('APAF1', 'Gene', '317', (189, 194))	('antisense transcription', 'MPA', (6, 29))	('NF-YA', 'Gene', '4800', (125, 130))	('LRDD', 'Gene', '55367', (209, 213))	('BIK', 'Gene', '638', (196, 199))	('p53', 'Var', (69, 72))	('ncRNA', 'Gene', (83, 88))	('APAF1', 'Gene', (189, 194))	('ncRNA', 'Gene', '220202', (83, 88))
762405	30018188	Pseudogenes act like "endogenous competitors" and affect miRNA binding on all their gene targets.	('affect', 'Reg', (50, 56))	('Pseudogenes', 'Var', (0, 11))	('miR', 'Gene', (57, 60))	('miR', 'Gene', '220972', (57, 60))
762410	30018188	Depletion of PTENpg1 asRNA alpha in human osteosarcoma cell lines arrested their growth and sensitized cells to the DNA-damaging agent doxorubicin.	('growth', 'MPA', (81, 87))	('osteosarcoma', 'Disease', (42, 54))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('Depletion', 'Var', (0, 9))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))	('sensitized', 'Reg', (92, 102))	('arrested', 'NegReg', (66, 74))	('PTEN', 'Gene', (13, 17))	('human', 'Species', '9606', (36, 41))	('PTEN', 'Gene', '5728', (13, 17))	('doxorubicin', 'Chemical', 'MESH:D004317', (135, 146))
762415	30018188	The same pseudogene was highly expressed in colorectal cancer (CRC) and its expression was positively associated with tumor size, pathological stage and lymphatic metastasis and was exerting its oncogenic function through epigenetically silencing the tumor suppressors p21 and PTEN expression.	('tumor', 'Disease', (251, 256))	('associated', 'Reg', (102, 112))	('colorectal cancer', 'Disease', (44, 61))	('epigenetically silencing', 'Var', (222, 246))	('p21', 'Gene', (269, 272))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('PTEN', 'Gene', (277, 281))	('expression', 'MPA', (76, 86))	('tumor', 'Disease', (118, 123))	('lymphatic metastasis', 'CPA', (153, 173))	('PTEN', 'Gene', '5728', (277, 281))	('colorectal cancer', 'Disease', 'MESH:D015179', (44, 61))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
762418	30018188	Additionally, miR-671 cleaves CDR1as in an Ago2-slicer-dependent manner reducing CDR1 mRNA levels.	('CDR1', 'Gene', '1038', (81, 85))	('CDR1', 'Gene', '1038', (30, 34))	('CDR1', 'Gene', (30, 34))	('CDR1', 'Gene', (81, 85))	('CDR1as', 'Gene', (30, 36))	('Ago2', 'Gene', '27161', (43, 47))	('reducing', 'NegReg', (72, 80))	('CDR1as', 'Gene', '103611090', (30, 36))	('miR-671', 'Gene', '768213', (14, 21))	('miR-671', 'Gene', (14, 21))	('Ago2', 'Gene', (43, 47))	('cleaves', 'Var', (22, 29))
762423	30018188	CiRS-7 inhibits miR-7 repression of its target genes and the miR-671 may liberate miR-7, upon cleavage of ciRS-7 (Figure 2D).	('liberate', 'NegReg', (73, 81))	('miR-671', 'Gene', '768213', (61, 68))	('CiRS-7', 'Gene', '103611090', (0, 6))	('rat', 'Species', '10116', (77, 80))	('inhibits', 'NegReg', (7, 15))	('ciRS-7', 'Gene', (106, 112))	('miR-7', 'Gene', (16, 21))	('miR-7', 'Gene', '10859', (82, 87))	('miR-671', 'Gene', (61, 68))	('cleavage', 'Var', (94, 102))	('miR-7', 'Gene', (82, 87))	('miR-7', 'Gene', '10859', (16, 21))	('ciRS-7', 'Gene', '103611090', (106, 112))	('CiRS-7', 'Gene', (0, 6))
762459	30018188	A-to-I RNA editing by ADAR of pri- and pre-miRNAs may regulate expression and function of their mature counterparts.	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('regulate', 'Reg', (54, 62))	('ADAR', 'Gene', '103', (22, 26))	('expression', 'MPA', (63, 73))	('editing', 'Var', (11, 18))	('ADAR', 'Gene', (22, 26))	('function', 'MPA', (78, 86))
762467	30018188	Moreover, knockdown of ADAR1 changed the cell phenotype of 131 cancer regulators miRNAs and microarray analysis revealed that ADAR1 controls the expression of miRNAs that target genes associated with these phenotypic changes.	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cell', 'MPA', (41, 45))	('ADAR1', 'Gene', '103', (126, 131))	('expression', 'MPA', (145, 155))	('miR', 'Gene', '220972', (159, 162))	('ADAR1', 'Gene', (23, 28))	('miR', 'Gene', (159, 162))	('knockdown', 'Var', (10, 19))	('ADAR1', 'Gene', (126, 131))	('cancer', 'Disease', (63, 69))	('ADAR1', 'Gene', '103', (23, 28))
762470	30018188	In other words, A-to-I editing of miR-455-5p changed completely its biological effect and inhibited melanoma growth and metastasis.	('editing', 'Var', (23, 30))	('biological effect', 'MPA', (68, 85))	('miR', 'Gene', '220972', (34, 37))	('melanoma growth', 'Disease', (100, 115))	('miR', 'Gene', (34, 37))	('melanoma growth', 'Disease', 'MESH:D008545', (100, 115))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('5p', 'Chemical', '-', (42, 44))	('inhibited', 'NegReg', (90, 99))	('changed', 'Reg', (45, 52))
762476	30018188	Many studies have reported that the 5-carbon of cytosine pyrimidine ring can be methylated and methylation of tumor suppressor genes may lead to cancer.	('cancer', 'Disease', (145, 151))	('carbon', 'Chemical', 'MESH:D002244', (38, 44))	('methylation', 'Var', (95, 106))	('lead to', 'Reg', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cytosine pyrimidine', 'Chemical', '-', (48, 67))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
762477	30018188	Since many miRNA promoters are embedded in (CpG) islands of their host genes involved in neoplastic development, it is reasonable that methylation of these DNA regions of tumor suppressive miRNAs may lead to the development and progression of cancers.	('methylation', 'Var', (135, 146))	('lead to', 'Reg', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('development', 'CPA', (212, 223))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('miR', 'Gene', '220972', (189, 192))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (189, 192))	('miR', 'Gene', (11, 14))	('tumor', 'Disease', (171, 176))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('cancers', 'Disease', (243, 250))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('progression', 'CPA', (228, 239))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
762479	30018188	Evidence that miRNA expression is regulated through epigenetic modifications of their promoter came from studies of cancerous and healthy cells treated with DNA-demethylating agents, like 5-Aza-2'-deoxycytidine (5-Aza-CdR) and histone deacetylase inhibitor, 4-phenylbutyric acid (PBA).	('cancerous', 'Disease', 'MESH:D009369', (116, 125))	("5-Aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (188, 210))	('PBA', 'Chemical', 'MESH:C075773', (280, 283))	('4-phenylbutyric acid', 'Chemical', 'MESH:C075773', (258, 278))	('epigenetic modifications', 'Var', (52, 76))	('cancerous', 'Disease', (116, 125))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
762481	30018188	After a combinatorial treatment of these cell lines with 5-Aza-CdR and PBA, miR-127 expression was restored and its target, the proto-oncogene B-cell lymphoma-6 (BCL-6) was repressed (Figure 3B).	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (143, 158))	('BC', 'Phenotype', 'HP:0009725', (162, 164))	('BCL-6', 'Gene', '604', (162, 167))	('5-Aza-CdR', 'Var', (57, 66))	('restored', 'PosReg', (99, 107))	('lymphoma', 'Disease', (150, 158))	('miR-127', 'Gene', '406914', (76, 83))	('PBA', 'Chemical', 'MESH:C075773', (71, 74))	('PBA', 'Gene', (71, 74))	('lymphoma', 'Disease', 'MESH:D008223', (150, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (150, 158))	('expression', 'MPA', (84, 94))	('BCL-6', 'Gene', (162, 167))	('miR-127', 'Gene', (76, 83))
762484	30018188	Among other miRNAs, it was found that the CpG islands in the promoter of miR-34b/c, miR-148 and miR-9 were hypermethylated, therefore underexpressed and their target genes expression, c-myc and CDK6 were consequently highly expressed.	('CDK6', 'Gene', '1021', (194, 198))	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (84, 87))	('highly expressed', 'PosReg', (217, 233))	('miR-34b', 'Gene', '407041', (73, 80))	('underexpressed', 'NegReg', (134, 148))	('c-myc', 'Gene', '4609', (184, 189))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('CDK6', 'Gene', (194, 198))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))	('miR-34b', 'Gene', (73, 80))	('c-myc', 'Gene', (184, 189))	('miR', 'Gene', '220972', (12, 15))	('hypermethylated', 'Var', (107, 122))	('miR', 'Gene', (12, 15))
762485	30018188	Surprisingly, it was observed that hypermethylation of these miRNAs was associated with the metastatic cancer cells in the corresponding lymph nodes.	('hypermethylation', 'Var', (35, 51))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('associated', 'Reg', (72, 82))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
762489	30018188	Furthermore, investigators have analyzed genes with Kyoto Encyclopedia Of Genes and Genomes (KEGG) database, that were regulated by methylation and miRNAs.	('methylation', 'Var', (132, 143))	('miR', 'Gene', '220972', (148, 151))	('miR', 'Gene', (148, 151))	('regulated', 'Reg', (119, 128))
762491	30018188	Overall, these studies indicate that epigenetic mechanisms may control transcription of tumor suppressor miRNAs.	('miR', 'Gene', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('epigenetic mechanisms', 'Var', (37, 58))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('transcription', 'MPA', (71, 84))	('tumor', 'Disease', (88, 93))	('control', 'Reg', (63, 70))	('miR', 'Gene', '220972', (105, 108))
762497	30018188	In the cytoplasm, polyuridylation occurs on polyadenylated and non-polyadenylated RNA such as miRNAs and has been shown to regulate miRNA biogenesis and activity.	('regulate', 'Reg', (123, 131))	('activity', 'MPA', (153, 161))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', (94, 97))	('polyuridylation', 'Var', (18, 33))	('miR', 'Gene', (132, 135))
762506	30018188	An analysis of Dis3L2 targets in mouse embryonic stem cells after an RNA immunoprecipitation assay identified lncRNAs and pseudogenes in DMD pathway.	('ncRNA', 'Gene', '220202', (111, 116))	('pseudogenes', 'Var', (122, 133))	('DMD', 'Disease', 'MESH:D020388', (137, 140))	('DMD', 'Disease', (137, 140))	('mouse', 'Species', '10090', (33, 38))	('ncRNA', 'Gene', (111, 116))
762509	30018188	DMD pathway is a guardian sentinel of the aberrant oligo-uridylated RNA species that should be degraded especially when these RNAs are cancer-related.	('cancer', 'Disease', (135, 141))	('DMD', 'Disease', 'MESH:D020388', (0, 3))	('DMD', 'Disease', (0, 3))	('aberrant', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
762517	30018188	Furthermore, many miRNAs when knocked down, do not influence important biological functions but might respond to external stimulus, such as irradiation.	('miR', 'Gene', '220972', (18, 21))	('knocked down', 'Var', (30, 42))	('miR', 'Gene', (18, 21))	('respond', 'Reg', (102, 109))
762538	30018188	Furthermore, knocking down of HuR and Dicer has increased mRNA and protein levels of KRAS.	('Dicer', 'Gene', (38, 43))	('increased', 'PosReg', (48, 57))	('knocking down', 'Var', (13, 26))	('Dicer', 'Gene', '23405', (38, 43))	('HuR', 'Gene', (30, 33))	('KRAS', 'Gene', (85, 89))	('HuR', 'Gene', '1994', (30, 33))	('KRAS', 'Gene', '3845', (85, 89))
762547	30018188	As mentioned above, in the general view of 3'UTR aberrations are the single nucleotide polymorphism (SNPs) that interrupt cis-acting regulatory elements embedded in the 3'UTR as well as chromosomal translocations that involve the 3'UTR resulting in the loss of miRNA complementary sites.	('interrupt', 'NegReg', (112, 121))	('aberrations', 'Var', (49, 60))	('cis-acting regulatory elements', 'MPA', (122, 152))	('rat', 'Species', '10116', (53, 56))	('loss', 'NegReg', (253, 257))	('miR', 'Gene', '220972', (261, 264))	('miR', 'Gene', (261, 264))
762548	30018188	The SNPs are involved in many types of cancers and they occur frequently in the human genome, at about every hundred base pairs (bp).	('involved', 'Reg', (13, 21))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('human', 'Species', '9606', (80, 85))	('SNPs', 'Var', (4, 8))
762549	30018188	The silent polymorphisms may reside in non-coding genomic regions like miRNAs and 3'UTRs.	('miR', 'Gene', (71, 74))	('polymorphisms', 'Var', (11, 24))	('miR', 'Gene', '220972', (71, 74))
762550	30018188	When polymorphisms fall into an important region of the miRNA seed sequence the regulation of its target genes will be abrogated.	('regulation', 'MPA', (80, 90))	('miR', 'Gene', '220972', (56, 59))	('polymorphisms fall', 'Var', (5, 23))	('miR', 'Gene', (56, 59))	('abrogated', 'NegReg', (119, 128))	('fall', 'Phenotype', 'HP:0002527', (19, 23))
762552	30018188	For example, in lung cancer, a germline SNP in the 3'UTR of KRAS proto-oncogene abrogated the binding site of let-7, thus increasing KRAS protein levels and promoted tumor progression.	('germline SNP in', 'Var', (31, 46))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('let-7', 'Gene', (110, 115))	('binding site', 'Interaction', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('abrogated', 'NegReg', (80, 89))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('increasing', 'PosReg', (122, 132))	('promoted', 'PosReg', (157, 165))	('tumor', 'Disease', (166, 171))	('KRAS', 'Gene', (60, 64))	('KRAS', 'Gene', (133, 137))	('KRAS', 'Gene', '3845', (60, 64))	('KRAS', 'Gene', '3845', (133, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('lung cancer', 'Disease', (16, 27))
762557	30018188	Since tumorigenesis involves genomic alterations, such as chromosomal translocations that may influence or produce proto-oncogenes and onco-suppressors as well as "fusion genes", a recent pioneering study investigated the impact these genomic alterations may have on non-coding RNAs and specifically on circRNAs.	('cir', 'Gene', '9541', (303, 306))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('rat', 'Species', '10116', (247, 250))	('rat', 'Species', '10116', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('cir', 'Gene', (303, 306))	('influence', 'Reg', (94, 103))	('chromosomal translocations', 'Var', (58, 84))	('tumor', 'Disease', (6, 11))
762566	30018188	Dysregulated lncRNAs due to methylation or mutation in single nucleotides may occur in cancer.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutation in single nucleotides', 'Var', (43, 73))	('ncRNA', 'Gene', (14, 19))	('methylation', 'Var', (28, 39))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('occur', 'Reg', (78, 83))	('ncRNA', 'Gene', '220202', (14, 19))
762567	30018188	For example, the reason behind the low expression of lncRNA LOC100130476 in the pathogenesis of esophageal squamous cell carcinoma (ESCC) has been investigated in 123 ESCC patients comparing with the normal tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('SCC', 'Phenotype', 'HP:0002860', (168, 171))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (96, 130))	('LOC100130476', 'Var', (60, 72))	('ncRNA', 'Gene', (54, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('esophageal squamous cell carcinoma', 'Disease', (96, 130))	('ncRNA', 'Gene', '220202', (54, 59))	('patients', 'Species', '9606', (172, 180))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))
762568	30018188	The ESCC patients with low expression or hypermethylation of this lncRNA had a poor prognosis.	('hypermethylation', 'Var', (41, 57))	('patients', 'Species', '9606', (9, 17))	('low', 'NegReg', (23, 26))	('ncRNA', 'Gene', (67, 72))	('expression', 'MPA', (27, 37))	('ncRNA', 'Gene', '220202', (67, 72))	('ESCC', 'Disease', (4, 8))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))
762569	30018188	The aberrant hypermethylation within the three CpG islands regions around the transcription start site of another lncRNA CTC-276P9 was identified in esophageal cancer cells and ESCC tissues and was also related with poor survival of ESCC patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('patients', 'Species', '9606', (238, 246))	('SCC', 'Phenotype', 'HP:0002860', (234, 237))	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('ncRNA', 'Gene', '220202', (115, 120))	('esophageal cancer', 'Disease', (149, 166))	('aberrant hypermethylation', 'Var', (4, 29))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ESCC', 'Disease', (233, 237))	('related with', 'Reg', (203, 215))	('hypermethylation', 'Var', (13, 29))	('ncRNA', 'Gene', (115, 120))
762574	30018188	Three lncRNA PTENP1 tagSNPs, namely, rs7853346 C>G, rs865005 C>T, and rs10971638 G>A were genotyped in 768 GC patients and 768 cancer-free controls in a Chinese population.	('rs7853346', 'Mutation', 'rs7853346', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs10971638', 'Mutation', 'rs10971638', (70, 80))	('rs865005 C>T', 'Var', (52, 64))	('GC', 'Phenotype', 'HP:0012126', (107, 109))	('cancer', 'Disease', (127, 133))	('rs7853346 C>G', 'Var', (37, 50))	('rs10971638 G>A', 'Var', (70, 84))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('rs865005', 'Mutation', 'rs865005', (52, 60))	('PTENP1', 'Gene', (13, 19))	('ncRNA', 'Gene', (7, 12))	('ncRNA', 'Gene', '220202', (7, 12))	('PTENP1', 'Gene', '11191', (13, 19))	('patients', 'Species', '9606', (110, 118))
762575	30018188	Those patients with rs7853346 G allele had significantly reduced risk of GC, compared with those carrying C allele and was more obvious in older subjects (>=60 years), nonsmokers, nondrinkers, and subjects without family history of GC.	('rs7853346 G', 'Var', (20, 31))	('rs7853346', 'Mutation', 'rs7853346', (20, 29))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('GC', 'Phenotype', 'HP:0012126', (232, 234))	('patients', 'Species', '9606', (6, 14))	('reduced', 'NegReg', (57, 64))
762576	30018188	Through bioinformatics analyses, it was found that rs7853346 might change the local folding structure of lncPTENP1 abolishing its sponging effect on miR-106b and miR-93 with a consequent reduction of the tumor suppressor PTEN gene expression (Figure 3G2).	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('PTEN', 'Gene', (108, 112))	('PTEN', 'Gene', '5728', (221, 225))	('miR-93', 'Gene', '407051', (162, 168))	('PTENP1', 'Gene', (108, 114))	('local folding structure', 'MPA', (78, 101))	('miR-106b', 'Gene', '406900', (149, 157))	('reduction', 'NegReg', (187, 196))	('PTEN', 'Gene', '5728', (108, 112))	('PTENP1', 'Gene', '11191', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('miR-106b', 'Gene', (149, 157))	('change', 'Reg', (67, 73))	('expression', 'MPA', (231, 241))	('rs7853346', 'Mutation', 'rs7853346', (51, 60))	('sponging effect', 'MPA', (130, 145))	('PTEN', 'Gene', (221, 225))	('tumor', 'Disease', (204, 209))	('abolishing', 'NegReg', (115, 125))	('miR-93', 'Gene', (162, 168))	('rs7853346', 'Var', (51, 60))
762577	30018188	These data suggest that GC susceptibility can be predicted by lncRNA PTENP1 polymorphism rs7853346.	('PTENP1', 'Gene', (69, 75))	('PTENP1', 'Gene', '11191', (69, 75))	('GC', 'Phenotype', 'HP:0012126', (24, 26))	('rs7853346', 'Mutation', 'rs7853346', (89, 98))	('rs7853346', 'Var', (89, 98))	('ncRNA', 'Gene', (63, 68))	('ncRNA', 'Gene', '220202', (63, 68))
762629	28425347	DeltaDeltaCt = DeltaCt (esophageal cancer)-DeltaCt (control) for RNA samples.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('esophageal cancer', 'Disease', (24, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('DeltaCt', 'Var', (15, 22))
762671	28425347	Overexpression of Bmi-1 in esophageal cancer has been previously reported.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('esophageal cancer', 'Disease', (27, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))	('Bmi-1', 'Gene', '648', (18, 23))	('Overexpression', 'Var', (0, 14))	('Bmi-1', 'Gene', (18, 23))
762680	28425347	Liu et al found that high expression of Bmi-1 was significantly associated with lymph node metastasis and clinical stage but not associated with depth of invasion or distant metastasis, which was consistent with the results of our study.	('associated', 'Reg', (64, 74))	('lymph node metastasis', 'CPA', (80, 101))	('Bmi-1', 'Gene', '648', (40, 45))	('high', 'Var', (21, 25))	('Bmi-1', 'Gene', (40, 45))	('clinical stage', 'CPA', (106, 120))
762691	28425347	We propose that abnormal PcG expression alters the expression of target genes involved in regulation of senescence or the cell cycle in an altered composition of the PRC1 in ESCC.	('alters', 'Reg', (40, 46))	('PcG', 'Gene', (25, 28))	('abnormal PcG', 'Phenotype', 'HP:0003115', (16, 28))	('PRC1', 'Gene', (166, 170))	('expression', 'MPA', (51, 61))	('PRC1', 'Gene', '9055', (166, 170))	('abnormal', 'Var', (16, 24))
762726	28418863	Recently, the genotypes of the GALNT14-rs9679162 single nucleotide polymorphism (SNP) has been shown to be an effective predictor for systemic chemotherapy response in advanced hepatocellular carcinoma (HCC), based on a genome-wide exploration of 500,000 SNPs in human white blood cells, and subsequent prospective and retrospective validations.	('GALNT14', 'Gene', '79623', (31, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('human', 'Species', '9606', (263, 268))	('HCC', 'Gene', (203, 206))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (177, 201))	('hepatocellular carcinoma', 'Disease', (177, 201))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (177, 201))	('single nucleotide polymorphism', 'Var', (49, 79))	('HCC', 'Gene', '619501', (203, 206))	('GALNT14', 'Gene', (31, 38))	('rs9679162', 'Mutation', 'rs9679162', (39, 48))	('HCC', 'Phenotype', 'HP:0001402', (203, 206))
762731	28418863	It would be interesting to know if GALNT14 genotype could be a predictor of chemoradiotherapeutic response in patients with advanced ESCC.	('GALNT14', 'Gene', (35, 42))	('GALNT14', 'Gene', '79623', (35, 42))	('genotype', 'Var', (43, 51))	('patients', 'Species', '9606', (110, 118))
762746	28418863	GALNT14 rs9679162 genotype distributions were significantly associated with therapeutic responses by the Cochran-Armitage Trend test (P = 0.047).	('rs9679162', 'Var', (8, 17))	('rs9679162', 'Mutation', 'rs9679162', (8, 17))	('GALNT14', 'Gene', (0, 7))	('GALNT14', 'Gene', '79623', (0, 7))	('therapeutic responses', 'CPA', (76, 97))	('associated', 'Reg', (60, 70))
762755	28418863	The significant result in the multivariate analysis showed that GALNT14 genotypes and the pre-treatment leukocyte count were independently associated with the time to complete/partial response of CCRT.	('associated with', 'Reg', (139, 154))	('genotypes', 'Var', (72, 81))	('GALNT14', 'Gene', (64, 71))	('GALNT14', 'Gene', '79623', (64, 71))	('CCRT', 'Disease', (196, 200))
762756	28418863	Distribution of GALNT14 rs9679162 genotypes with respect to gender, location of tumor and metastasis stages were shown in Supplementary Table 1.	('GALNT14', 'Gene', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('rs9679162', 'Var', (24, 33))	('rs9679162', 'Mutation', 'rs9679162', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('GALNT14', 'Gene', '79623', (16, 23))	('tumor', 'Disease', (80, 85))
762757	28418863	To further evaluate any potential confounding relationships between GALNT14 genotypes and all the other baseline variables, a logistic regression analysis was performed.	('GALNT14', 'Gene', '79623', (68, 75))	('GALNT14', 'Gene', (68, 75))	('genotypes', 'Var', (76, 85))
762770	28418863	In a genome-wide investigation of consanguineous families, GALNT14 was identified to bear damaging Mendelian mutations which caused embryonic lethality, suggesting the irreplaceable role of GalNac-T14 in human development.	('GALNT14', 'Gene', '79623', (59, 66))	('GalNac-T14', 'Gene', (190, 200))	('caused', 'Reg', (125, 131))	('embryonic lethality', 'Disease', 'MESH:D020964', (132, 151))	('mutations', 'Var', (109, 118))	('GALNT14', 'Gene', (59, 66))	('human', 'Species', '9606', (204, 209))	('embryonic lethality', 'Disease', (132, 151))	('GalNac-T14', 'Gene', '79623', (190, 200))
762773	28418863	Our recent studies also indicated a tight association between GALNT14 genotype and chemotherapy or chemoembolization responses in advanced hepatocellular carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (139, 163))	('hepatocellular carcinoma', 'Disease', (139, 163))	('GALNT14', 'Gene', '79623', (62, 69))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (139, 163))	('GALNT14', 'Gene', (62, 69))	('patients', 'Species', '9606', (164, 172))	('genotype', 'Var', (70, 78))
762774	28418863	It is therefore not surprising to find that GALNT14 genotype also associated with CCRT responses in advanced ESCC patients.	('CCRT responses', 'CPA', (82, 96))	('GALNT14', 'Gene', (44, 51))	('associated with', 'Reg', (66, 81))	('GALNT14', 'Gene', '79623', (44, 51))	('patients', 'Species', '9606', (114, 122))	('genotype', 'Var', (52, 60))
762775	28418863	Recently, a single nucleotide polymorphism (rs9331888) in the 5' untranslated region of the Clusterin gene was shown to be associated with the occurrence of ESCC based on a cross-sectional comparison between ESCC patients and healthy control subjects.	('associated with', 'Reg', (123, 138))	('ESCC', 'Disease', (208, 212))	('ESCC', 'Disease', (157, 161))	('rs9331888', 'Mutation', 'rs9331888', (44, 53))	('rs9331888', 'Var', (44, 53))	('patients', 'Species', '9606', (213, 221))	('Clusterin', 'Gene', (92, 101))	('Clusterin', 'Gene', '1191', (92, 101))	('single nucleotide polymorphism (rs9331888', 'Var', (12, 53))
762779	28418863	However, a meta-analysis of 19 studies on a wide spectrum of ESCC patients showed that VEGF positivity actually correlated with poor prognosis of ESCC patients.	('patients', 'Species', '9606', (151, 159))	('positivity', 'Var', (92, 102))	('VEGF', 'Gene', '7422', (87, 91))	('ESCC', 'Disease', (146, 150))	('VEGF', 'Gene', (87, 91))	('patients', 'Species', '9606', (66, 74))
762795	28418863	They were used for PCR and direct sequencing for a 172-bp intronic region of GALNT14 covering rs9679162.	('GALNT14', 'Gene', '79623', (77, 84))	('rs9679162', 'Var', (94, 103))	('rs9679162', 'Mutation', 'rs9679162', (94, 103))	('GALNT14', 'Gene', (77, 84))
762801	26886278	Alcohol is oxidized primarily by alcohol dehydrogenase (ADH) to acetaldehyde, a substance capable of initiating carcinogenesis by forming adducts with proteins and DNA and causing mutations.	('proteins', 'Protein', (151, 159))	('carcinogenesis', 'Disease', 'MESH:D063646', (112, 126))	('causing', 'Reg', (172, 179))	('alcohol dehydrogenase', 'Gene', '10327', (33, 54))	('mutations', 'Var', (180, 189))	('carcinogenesis', 'Disease', (112, 126))	('acetaldehyde', 'Chemical', 'MESH:D000079', (64, 76))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('adducts', 'Interaction', (138, 145))	('DNA', 'Protein', (164, 167))	('alcohol dehydrogenase', 'Gene', (33, 54))
762824	26886278	Many studies have shown that disturbances of the alcohol dehydrogenase activity play an important role in alcohol-related neoplasms, and knowledge of possible mechanism by which alcohol effects on carcinogenesis has increased in recent years.	('neoplasms', 'Disease', (122, 131))	('disturbances', 'Var', (29, 41))	('neoplasm', 'Phenotype', 'HP:0002664', (122, 130))	('carcinogenesis', 'Disease', (197, 211))	('alcohol dehydrogenase', 'Gene', (49, 70))	('alcohol', 'Chemical', 'MESH:D000438', (178, 185))	('alcohol', 'Chemical', 'MESH:D000438', (106, 113))	('neoplasms', 'Phenotype', 'HP:0002664', (122, 131))	('activity', 'MPA', (71, 79))	('alcohol dehydrogenase', 'Gene', '10327', (49, 70))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))	('carcinogenesis', 'Disease', 'MESH:D063646', (197, 211))	('neoplasms', 'Disease', 'MESH:D009369', (122, 131))
762831	26886278	DNA adducts, such as N 2-ethylidene-2'-deoxyguanosine, N 2-ethyl-2'-deoxyguanosine and 1,N 2-propano-2'-deoxyguanosine, cause polymerase errors and induce mutations in critical genes.	('cause', 'Reg', (120, 125))	("N 2-ethyl-2'-deoxyguanosine", 'Var', (55, 82))	("N 2-ethylidene-2'-deoxyguanosine", 'Chemical', 'MESH:C525837', (21, 53))	('polymerase errors', 'CPA', (126, 143))	("1,N 2-propano-2'-deoxyguanosine", 'Chemical', 'MESH:C553598', (87, 118))	('induce mutations', 'Reg', (148, 164))	('critical genes', 'Gene', (168, 182))	("N 2-ethylidene-2'-deoxyguanosine", 'Var', (21, 53))	("N 2-ethyl-2'-deoxyguanosine", 'Chemical', 'MESH:C492934', (55, 82))
762839	26886278	It is commonly known that ROS can cause oxidative damage to proteins, lipids and nucleic acids.	('oxidative damage to', 'MPA', (40, 59))	('lipids', 'Chemical', 'MESH:D008055', (70, 76))	('cause', 'Reg', (34, 39))	('proteins', 'Protein', (60, 68))	('ROS', 'Var', (26, 29))	('ROS', 'Chemical', 'MESH:D017382', (26, 29))
762850	26886278	Thus, disturbances in RA biosynthesis may provide a possible explanation for why chronic and excessive alcohol intake is a risk for cell proliferation and malignant transformation.	('malignant transformation', 'CPA', (155, 179))	('excessive alcohol', 'Phenotype', 'HP:0030955', (93, 110))	('disturbances', 'Var', (6, 18))	('cell proliferation', 'CPA', (132, 150))	('alcohol', 'Chemical', 'MESH:D000438', (103, 110))	('RA', 'Chemical', 'MESH:D014212', (22, 24))
762856	26886278	Ethanol can also accelerate tumor growth and stimulates progression probably due to induction of angiogenesis.	('tumor', 'Disease', (28, 33))	('accelerate', 'PosReg', (17, 27))	('stimulates', 'PosReg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Ethanol', 'Chemical', 'MESH:D000431', (0, 7))	('progression', 'CPA', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Ethanol', 'Var', (0, 7))
762865	26886278	In Asians, polymorphism of ADH1B and ADH1C genes was associated with the development of alcoholism and susceptibility to alcoholic liver cirrhosis.	('polymorphism', 'Var', (11, 23))	('ADH1C', 'Gene', '126', (37, 42))	('alcoholic liver cirrhosis', 'Disease', 'MESH:D008104', (121, 146))	('men', 'Species', '9606', (80, 83))	('ADH1C', 'Gene', (37, 42))	('ADH1B', 'Gene', (27, 32))	('alcoholism', 'Disease', (88, 98))	('alcoholic liver cirrhosis', 'Disease', (121, 146))	('ADH1B', 'Gene', '125', (27, 32))	('alcoholism', 'Phenotype', 'HP:0030955', (88, 98))	('associated with', 'Reg', (53, 68))	('alcoholism', 'Disease', 'MESH:D000437', (88, 98))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (131, 146))
762912	26886278	Changes in ADH class IV activity can influence on retinol as well as lipid peroxidation products metabolism and many dietary carcinogens removal.	('ADH class IV', 'Enzyme', (11, 23))	('activity', 'MPA', (24, 32))	('dietary carcinogens removal', 'Disease', 'MESH:D063646', (117, 144))	('influence', 'Reg', (37, 46))	('retinol', 'Chemical', 'MESH:D014801', (50, 57))	('dietary carcinogens removal', 'Disease', (117, 144))	('retinol', 'MPA', (50, 57))	('lipid', 'Chemical', 'MESH:D008055', (69, 74))	('lipid peroxidation products metabolism', 'MPA', (69, 107))	('Changes', 'Var', (0, 7))
762956	26886278	The next women malignant disease in which disturbances in ethanol metabolizing enzymes were stated is the cervical cancer.	('malignant disease', 'Disease', (15, 32))	('women', 'Species', '9606', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cervical cancer', 'Disease', (106, 121))	('disturbances', 'Var', (42, 54))	('cervical cancer', 'Disease', 'MESH:D002583', (106, 121))	('ethanol', 'Chemical', 'MESH:D000431', (58, 65))	('malignant disease', 'Disease', 'MESH:D009369', (15, 32))
762962	26886278	The difference of ADH and ALDH activity between cancerous and healthy tissue may cause disorders in the retinol metabolism which can intensify carcinogenesis.	('difference', 'Var', (4, 14))	('cause', 'Reg', (81, 86))	('activity', 'MPA', (31, 39))	('ALDH', 'Protein', (26, 30))	('disorders', 'MPA', (87, 96))	('ADH', 'Protein', (18, 21))	('retinol metabolism', 'MPA', (104, 122))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('cancerous', 'Disease', 'MESH:D009369', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('retinol', 'Chemical', 'MESH:D014801', (104, 111))	('carcinogenesis', 'Disease', (143, 157))	('cancerous', 'Disease', (48, 57))
762971	26886278	Alcohol exposure may lower RA levels either by blocking alcohol dehydrogenase-activated RA biosynthesis due to the competition, as dehydrogenase substrates, between alcohol and vitamin A. Disturbances between ADH and ALDH activities in cancer cells and not-cancerous ovarian tissues can be a factor entangled in ovary carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('Disturbances', 'Var', (188, 200))	('ovary carcinogenesis', 'Disease', 'MESH:D063646', (312, 332))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('ALDH', 'Enzyme', (217, 221))	('alcohol', 'Chemical', 'MESH:D000438', (56, 63))	('ovary carcinogenesis', 'Disease', (312, 332))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('alcohol', 'Chemical', 'MESH:D000438', (165, 172))	('cancerous ovarian', 'Disease', (257, 274))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('cancer', 'Disease', (236, 242))	('RA', 'Chemical', 'MESH:D014212', (27, 29))	('alcohol dehydrogenase', 'Gene', (56, 77))	('ADH', 'Enzyme', (209, 212))	('activities', 'MPA', (222, 232))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('alcohol dehydrogenase', 'Gene', '10327', (56, 77))	('vitamin A', 'Chemical', 'MESH:D014801', (177, 186))	('cancer', 'Disease', (257, 263))	('cancerous ovarian', 'Disease', 'MESH:D010051', (257, 274))	('RA', 'Chemical', 'MESH:D014212', (88, 90))
762975	26886278	Only one cohort study suggested that intermediate and heavy drinking can be associated with carcinogenesis in kidney.	('associated', 'Reg', (76, 86))	('intermediate', 'Var', (37, 49))	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('carcinogenesis', 'Disease', (92, 106))
763005	26886278	The changes in the activities of particular isoenzymes can have also influence on cancer development because of causing disorders in the metabolism of many biologically important substances.	('men', 'Species', '9606', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('changes', 'Var', (4, 11))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('influence', 'Reg', (69, 78))	('causing disorders', 'Reg', (112, 129))	('activities', 'MPA', (19, 29))
763025	28118373	Several studies have reported that PPI reduces post-EVL ulcer size through acid suppression.	('acid suppression', 'MPA', (75, 91))	('ulcer', 'Disease', 'MESH:D014456', (56, 61))	('ulcer', 'Disease', (56, 61))	('EVL', 'Chemical', '-', (52, 55))	('EV', 'Phenotype', 'HP:0002040', (52, 54))	('PPI', 'Var', (35, 38))	('reduces', 'NegReg', (39, 46))
763030	28118373	In addition, accumulating data suggest that PPIs have other important negative effects on events in cirrhosis, such as spontaneous bacterial peritonitis and encephalopathy.	('encephalopathy', 'Disease', (157, 171))	('peritonitis', 'Phenotype', 'HP:0002586', (141, 152))	('cirrhosis', 'Disease', 'MESH:D005355', (100, 109))	('cirrhosis', 'Disease', (100, 109))	('PPIs', 'Var', (44, 48))	('bacterial peritonitis', 'Disease', (131, 152))	('negative', 'NegReg', (70, 78))	('encephalopathy', 'Disease', 'MESH:D001927', (157, 171))	('cirrhosis', 'Phenotype', 'HP:0001394', (100, 109))	('bacterial peritonitis', 'Disease', 'MESH:D010534', (131, 152))	('encephalopathy', 'Phenotype', 'HP:0001298', (157, 171))
763081	28118373	showed that post-EVL ulcers were shallower and healed more quickly compared to ulcers caused by endoscopic injection therapy.	('ulcers', 'Disease', 'MESH:D014456', (21, 27))	('ulcers', 'Disease', (79, 85))	('ulcers', 'Disease', 'MESH:D014456', (79, 85))	('post-EVL', 'Var', (12, 20))	('EV', 'Phenotype', 'HP:0002040', (17, 19))	('EVL', 'Chemical', '-', (17, 20))	('ulcers', 'Disease', (21, 27))
763083	28118373	Although numerous studies demonstrate that PPIs effectively reduce post-procedure ulcer size and accelerate ulcer healing, none have demonstrated altered rebleeding or mortality rates in patients with post-treatment EV bleeding.	('patients', 'Species', '9606', (187, 195))	('bleeding', 'Disease', (219, 227))	('EV bleeding', 'Disease', (216, 227))	('bleeding', 'Disease', (156, 164))	('reduce', 'NegReg', (60, 66))	('ulcer healing', 'Disease', (108, 121))	('accelerate', 'PosReg', (97, 107))	('PPIs', 'Var', (43, 47))	('ulcer', 'Disease', (108, 113))	('ulcer', 'Disease', 'MESH:D014456', (108, 113))	('EV bleeding', 'Disease', 'MESH:D004819', (216, 227))	('EV', 'Phenotype', 'HP:0002040', (216, 218))	('bleeding', 'Disease', 'MESH:D006470', (219, 227))	('ulcer', 'Disease', 'MESH:D014456', (82, 87))	('ulcer', 'Disease', (82, 87))	('accelerate ulcer healing', 'Phenotype', 'HP:0001058', (97, 121))	('ulcer healing', 'Disease', 'MESH:D014456', (108, 121))	('bleeding', 'Disease', 'MESH:D006470', (156, 164))
763086	28118373	PPI was proposed to improve ulcer healing, and hence decrease the rebleeding rate of EV bleeding.	('ulcer healing', 'Disease', (28, 41))	('decrease', 'NegReg', (53, 61))	('bleeding', 'Disease', 'MESH:D006470', (88, 96))	('EV', 'Phenotype', 'HP:0002040', (85, 87))	('bleeding', 'Disease', (88, 96))	('EV bleeding', 'Disease', 'MESH:D004819', (85, 96))	('bleeding', 'Disease', 'MESH:D006470', (68, 76))	('improve', 'PosReg', (20, 27))	('bleeding', 'Disease', (68, 76))	('PPI', 'Var', (0, 3))	('improve ulcer healing', 'Phenotype', 'HP:0001058', (20, 41))	('ulcer healing', 'Disease', 'MESH:D014456', (28, 41))	('EV bleeding', 'Disease', (85, 96))
763088	28118373	observed that the effect of adjuvant therapy with PPI infusion was similar to its combination with vasoconstrictor infusion in terms of the initial hemostasis and very early rebleeding rate, and was associated with fewer adverse events.	('bleeding', 'Disease', (176, 184))	('hemostasis', 'Disease', (148, 158))	('PPI', 'Var', (50, 53))	('hemostasis', 'Disease', 'None', (148, 158))	('bleeding', 'Disease', 'MESH:D006470', (176, 184))
763152	25759630	Following myotomy the ZD may be excised (diverticulectomy), retracted cranially and suspended by suture to the prevertebral fascia or the posterior pharyngeal wall (diverticulopexy), or inverted into the esophageal lumen and oversewn (diverticulum inversion or invagination).	('fascia', 'Disease', (124, 130))	('myotomy', 'Var', (10, 17))	('fascia', 'Disease', 'None', (124, 130))
763182	23898393	Conventional endoscopy using a high-resolution upper gastrointestinal endoscope (GIF-H260Z; Olympus Medical System Corp., Tokyo, Japan) showed a reddish rough mucosal area on the right side of the middle thoracic esophagus, occupying one third of the circumference of the esophagus (Fig.	('H260Z', 'SUBSTITUTION', 'None', (85, 90))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (47, 79))	('upper gastrointestinal endoscope', 'Disease', (47, 79))	('H260Z', 'Var', (85, 90))
763190	23898393	GIF-H260Z was used for evaluation of the horizontal extent of the tumor and marking, and GIF-Q260J for resection of the tumor, respectively.	('Q260J', 'SUBSTITUTION', 'None', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('H260Z', 'SUBSTITUTION', 'None', (4, 9))	('tumor', 'Disease', (66, 71))	('H260Z', 'Var', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Q260J', 'Var', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (120, 125))
763191	23898393	At the time of treatment, the oral border of the tumor was unclear by conventional endoscopy although we used the same endoscope, GIF-H260Z, as in the previous endoscopy (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('H260Z', 'Var', (134, 139))	('H260Z', 'SUBSTITUTION', 'None', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
763379	34001160	In our univariate analysis, the incidence of AL was lower in patients with score 2 than in patients with score 1, though the overall condition of a score 2 was poorer.	('patients', 'Species', '9606', (61, 69))	('score 2', 'Var', (75, 82))	('lower', 'NegReg', (52, 57))	('patients', 'Species', '9606', (91, 99))
763448	32977465	; Validation, S.G., L.E., P.F., T.U.S., S.S. and D.E.B.	('U.S', 'CellLine', 'CVCL:0042', (34, 37))	('S.S.', 'Var', (40, 44))	('P.F.', 'Var', (26, 30))
763484	30988666	Rabbit anti-PPP1CA (CSB-PA030161) and rabbit anti-PAK2 (CSB-PA622641DSR1HU) were purchased from CUSABIO (Wuhan, China).	('CSB-PA030161', 'Var', (20, 32))	('PPP1CA', 'Gene', '5499', (12, 18))	('PAK2', 'Gene', '5062', (50, 54))	('rabbit', 'Species', '9986', (38, 44))	('Rabbit', 'Species', '9986', (0, 6))	('PPP1CA', 'Gene', (12, 18))	('PAK2', 'Gene', (50, 54))
763486	30988666	The antibody of Caveolin (AF0126), Integrin beta-1 (AF5379), Collagen alpha-2(VI) (DF3552), Leiomodin-1 (DF12160) and Vinculin (AF5122) were purchased from Affinity Biosciences (USA).	('DF3552', 'Var', (83, 89))	('Leiomodin-1', 'Gene', (92, 103))	('Vinculin', 'Gene', (118, 126))	('Integrin beta-1', 'Gene', (35, 50))	('Vinculin', 'Gene', '7414', (118, 126))	('DF12160', 'Var', (105, 112))	('Leiomodin-1', 'Gene', '25802', (92, 103))	('Integrin beta-1', 'Gene', '3688', (35, 50))
763547	30988666	Recently, the whole-genome sequencing revealed the diverse models of structural variations in ESCC, which indicted the biological differences among patients.	('patients', 'Species', '9606', (148, 156))	('structural variations', 'Var', (69, 90))	('ESCC', 'Gene', (94, 98))
763552	30988666	In cytoplasmic, the function of PTMA is related to the state of phosphorylation, for example, the Thr7 is the only residue phosphorylated in carcinogenic lymphocytes while the Thr12 or Thr13 phosphorylated in normal lymphocytes.	('Thr7', 'Var', (98, 102))	('Thr13', 'Chemical', '-', (185, 190))	('Thr7', 'Chemical', '-', (98, 102))	('Thr12', 'Chemical', '-', (176, 181))	('carcinogenic', 'Disease', 'MESH:D063646', (141, 153))	('carcinogenic', 'Disease', (141, 153))
763575	28418884	The association between miR-423 rs6505162 polymorphism and cancer susceptibility: a systematic review and meta-analysis The association between miR-423 polymorphism (C > A) and the risk of different cancers are still controversial.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('miR-423', 'Gene', '494335', (24, 31))	('miR-423', 'Gene', '494335', (144, 151))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('rs6505162', 'Mutation', 'rs6505162', (32, 41))	('cancer', 'Disease', (199, 205))	('miR-423', 'Gene', (24, 31))	('miR-423', 'Gene', (144, 151))	('rs6505162', 'Var', (32, 41))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancers', 'Disease', (199, 206))
763579	28418884	Our study indicates that miR-423 rs6505162 might be associated with a reduced risk of cancers, however, this finding need to be evaluated further in larger samples, especially subgroup analyses.	('miR-423', 'Gene', '494335', (25, 32))	('reduced', 'NegReg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs6505162', 'Mutation', 'rs6505162', (33, 42))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('rs6505162', 'Var', (33, 42))	('cancers', 'Disease', (86, 93))	('miR-423', 'Gene', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
763582	28418884	The causal association between genetic alterations and cancer is supported by extensive experimental and epidemiological data.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (55, 61))	('genetic alterations', 'Var', (31, 50))
763587	28418884	The rs6505162 SNP is located in the pre-miR-423 and maps to 17q11.2, with a nucleotide alteration from C to A.	('miR-423', 'Gene', (40, 47))	('miR-423', 'Gene', '494335', (40, 47))	('rs6505162', 'Mutation', 'rs6505162', (4, 13))	('rs6505162', 'Var', (4, 13))
763590	28418884	About ten of 17 published studies have shown no correlation between rs6505162 and risk of different cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancers', 'Disease', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rs6505162', 'Mutation', 'rs6505162', (68, 77))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('rs6505162', 'Var', (68, 77))
763591	28418884	Given the requirement of risk classification in populations, we performed this systematic review and meta-analysis to improve evaluation of the association between miR-423 rs6505162 polymorphism and multiple cancer risks.	('rs6505162', 'Mutation', 'rs6505162', (172, 181))	('association', 'Interaction', (144, 155))	('cancer', 'Disease', (208, 214))	('rs6505162', 'Var', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('miR-423', 'Gene', (164, 171))	('miR-423', 'Gene', '494335', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
763592	28418884	The initial search identified 187 articles on cancer risk and/or clinical outcome assessment for miR-423 rs6505162.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('miR-423', 'Gene', (97, 104))	('cancer', 'Disease', (46, 52))	('miR-423', 'Gene', '494335', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('rs6505162', 'Mutation', 'rs6505162', (105, 114))	('rs6505162', 'Var', (105, 114))
763595	28418884	Table 2 presents summary results concerning the association between miR-423 rs6505162 and the risk of overall cancer.	('cancer', 'Disease', (110, 116))	('rs6505162', 'Mutation', 'rs6505162', (76, 85))	('rs6505162', 'Var', (76, 85))	('association', 'Interaction', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('miR-423', 'Gene', (68, 75))	('miR-423', 'Gene', '494335', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
763596	28418884	The pooled results showed that AA genotype of miR-423 rs6505162 was associated with decreased cancer risk under recessive model (OR = 0.87, 95% CI: 0.78~0.98, P = 0.020) (Figure 3).	('rs6505162', 'Mutation', 'rs6505162', (54, 63))	('miR-423', 'Gene', (46, 53))	('miR-423', 'Gene', '494335', (46, 53))	('rs6505162', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('decreased', 'NegReg', (84, 93))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
763598	28418884	There was a wide variation in the A allele frequency of miR-423 rs6505162 among cancer patients of different races.	('miR-423', 'Gene', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR-423', 'Gene', '494335', (56, 63))	('rs6505162', 'Mutation', 'rs6505162', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('patients', 'Species', '9606', (87, 95))	('rs6505162', 'Var', (64, 73))	('cancer', 'Disease', (80, 86))
763600	28418884	The results of meta-regression analysis showed that cancer types and ethnicity do not affect the association between miR-423 rs6505162 polymorphism and cancer susceptibility (both P > 0.05).	('miR-423', 'Gene', (117, 124))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('rs6505162', 'Mutation', 'rs6505162', (125, 134))	('rs6505162', 'Var', (125, 134))	('miR-423', 'Gene', '494335', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
763602	28418884	To the best of our knowledge, this meta-analysis is the first to comprehensively evaluate the association between miR-423 rs6505162 (C > A) and all cancer risk.	('miR-423', 'Gene', (114, 121))	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('miR-423', 'Gene', '494335', (114, 121))	('association', 'Interaction', (94, 105))	('rs6505162', 'Mutation', 'rs6505162', (122, 131))	('rs6505162', 'Var', (122, 131))
763603	28418884	Our major finding suggested that a significant association between miR-423 rs6505162 and cancer susceptibility was observed in recessive models.	('miR-423', 'Gene', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('rs6505162', 'Mutation', 'rs6505162', (75, 84))	('miR-423', 'Gene', '494335', (67, 74))	('rs6505162', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
763605	28418884	About seven of 17 included studies reported significant association between rs6505162 and risk of different cancers.	('rs6505162', 'Mutation', 'rs6505162', (76, 85))	('rs6505162', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancers', 'Disease', (108, 115))
763606	28418884	Two studies concluded that the A allele of the rs6505162 increased the risk of breast cancer, whereas the same allele presented a decreased risk of developing lung cancer and bladder cancer in two other studies.	('bladder cancer', 'Phenotype', 'HP:0009725', (175, 189))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (175, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lung cancer', 'Disease', (159, 170))	('rs6505162', 'Mutation', 'rs6505162', (47, 56))	('increased', 'PosReg', (57, 66))	('bladder cancer', 'Disease', (175, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('rs6505162', 'Var', (47, 56))	('decreased', 'NegReg', (130, 139))
763608	28418884	After pooling all published studies into the meta-analysis, cancer risk associated with miR-423 rs6505162 allele was significant in the recessive model (AA vs AC/CC).	('rs6505162', 'Mutation', 'rs6505162', (96, 105))	('rs6505162', 'Var', (96, 105))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('miR-423', 'Gene', (88, 95))	('cancer', 'Disease', (60, 66))	('miR-423', 'Gene', '494335', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
763620	28418884	It is known that rs6505162 lies within the first intron of the gene of nuclear speckle splicing regulatory protein (NSRP1), and produces two mature transcripts designated miR-423-3p and miR-423-5p.	('rs6505162', 'Var', (17, 26))	('miR-423', 'Gene', (186, 193))	('NSRP1', 'Gene', (116, 121))	('miR-423', 'Gene', (171, 178))	('miR-423', 'Gene', '494335', (186, 193))	('NSRP1', 'Gene', '84081', (116, 121))	('rs6505162', 'Mutation', 'rs6505162', (17, 26))	('miR-423', 'Gene', '494335', (171, 178))
763624	28418884	Additionally, only two studies suggested that the C to A substitution in rs6505162 promotes the production of mature miR-423 in cell lines from breast cancer and endometrial carcinoma, but the SNP was not correlated with expression of miR-423 in esophageal squamous cell carcinoma.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('breast cancer', 'Disease', (144, 157))	('production', 'MPA', (96, 106))	('endometrial carcinoma', 'Disease', (162, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('miR-423', 'Gene', (117, 124))	('miR-423', 'Gene', (235, 242))	('promotes', 'PosReg', (83, 91))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (162, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('esophageal squamous cell carcinoma', 'Disease', (246, 280))	('rs6505162', 'Mutation', 'rs6505162', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (162, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (257, 280))	('rs6505162', 'Var', (73, 82))	('miR-423', 'Gene', '494335', (117, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (246, 280))	('miR-423', 'Gene', '494335', (235, 242))
763631	28418884	We believe that this is the first quantitative assessment focused on the association between miR-423 rs6505162 alleles and all types of cancer.	('rs6505162', 'Mutation', 'rs6505162', (101, 110))	('rs6505162', 'Var', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('association', 'Interaction', (73, 84))	('miR-423', 'Gene', '494335', (93, 100))	('cancer', 'Disease', (136, 142))	('miR-423', 'Gene', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
763634	28418884	Considering all these factors, our results should be interpreted with caution, but we believe these findings could help to explain the association between miR-423 rs6505162 and cancer risk.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('miR-423', 'Gene', '494335', (155, 162))	('rs6505162', 'Mutation', 'rs6505162', (163, 172))	('rs6505162', 'Var', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('miR-423', 'Gene', (155, 162))	('association', 'Interaction', (135, 146))
763635	28418884	In conclusion, this meta-analysis indicated that miR-423 rs6505162 C > A may reduce the risk of cancer, especially for lung cancer.	('rs6505162 C > A', 'Var', (57, 72))	('cancer', 'Disease', (124, 130))	('reduce', 'NegReg', (77, 83))	('lung cancer', 'Disease', (119, 130))	('miR-423', 'Gene', '494335', (49, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('rs6505162', 'Mutation', 'rs6505162', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('miR-423', 'Gene', (49, 56))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
763637	28418884	In addition, cancer-specific functional characterizations are simultaneously needed to reveal the underlying mechanisms between miR-423 rs6505162 and the etiology of cancer.	('miR-423', 'Gene', (128, 135))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('miR-423', 'Gene', '494335', (128, 135))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('rs6505162', 'Mutation', 'rs6505162', (136, 145))	('rs6505162', 'Var', (136, 145))
763638	28418884	Search terms mainly included ("MIRNA423 microRNA, human" [Supplementary Concept] OR mir-423 OR microrna-423 OR mir423 OR rs6505162) AND ("Carcinoma"[Mesh] OR "Neoplasms"[Mesh] OR malignancy OR tumor OR neoplasia OR carcinoma OR Cancer).	('mir423', 'Gene', (111, 117))	('neoplasia OR carcinoma OR Cancer', 'Disease', 'MESH:D009369', (202, 234))	('"Carcinoma', 'Disease', (137, 147))	('malignancy', 'Disease', 'MESH:D009369', (179, 189))	('human', 'Species', '9606', (50, 55))	('microrna-423', 'Var', (95, 107))	('mir423', 'Gene', '494335', (111, 117))	('"Carcinoma', 'Disease', 'MESH:D002277', (137, 147))	('"Neoplasms', 'Disease', (158, 168))	('neoplasia OR carcinoma OR Cancer', 'Disease', (202, 234))	('neoplasia', 'Phenotype', 'HP:0002664', (202, 211))	('mir-423', 'Gene', '494335', (84, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('Carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('tumor', 'Disease', (193, 198))	('rs6505162', 'Mutation', 'rs6505162', (121, 130))	('mir-423', 'Gene', (84, 91))	('malignancy', 'Disease', (179, 189))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('Neoplasms', 'Phenotype', 'HP:0002664', (159, 168))	('Cancer', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('"Neoplasms', 'Disease', 'MESH:D009369', (158, 168))
763639	28418884	The study was considered eligible if it met the following criteria: (1) designed as case-control or cohort study, (2) evaluated the association between miRNA-423 polymorphism and cancer risk, (3) provided sufficient data (the numbers of genotypes distribution in two groups, respectively) for calculating the OR and its 95% CI.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('polymorphism', 'Var', (162, 174))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('association', 'Interaction', (132, 143))	('cancer', 'Disease', (179, 185))	('miRNA-423', 'Gene', (152, 161))
763640	28418884	Crude ORs together with their corresponding 95% CIs were calculated to assess the strength of association between miRNA-423 rs6505162 and overall cancer risk under dominant and recessive models.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('miRNA-423', 'Gene', (114, 123))	('rs6505162', 'Mutation', 'rs6505162', (124, 133))	('rs6505162', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
763648	28740891	The EM and the ITV margins in cT4 were significantly smaller than those in cT1-T3.	('smaller', 'NegReg', (53, 60))	('cT1', 'Gene', (75, 78))	('cT1', 'Gene', '1489', (75, 78))	('cT4', 'Var', (30, 33))
763668	28740891	Our hypothesis in the present study was that the EM:especially in stage cT4 cases:may be smaller than that in stage cT1-T3 cases because of the influence of tumor invasion to the adjacent structures.	('tumor', 'Disease', (157, 162))	('stage cT4', 'Var', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cT1', 'Gene', '1489', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cT1', 'Gene', (116, 119))	('smaller', 'NegReg', (89, 96))
763687	28740891	The mean EM below the carina in cT4 was significantly smaller than that in cT1-T2 (LR: 0.3 vs 0.9 mm, P < .01; AP: 0.7 vs 1.7 mm, P < .01; SI: 3.0 vs 6.7 mm, P < .01) and than that in cT3 (LR: 0.3 vs 1.0 mm, P = .03; AP: 0.7 vs 2.1 mm, P < .01; SI: 3.0 vs 6.9 mm, P < .01).	('cT1', 'Gene', '1489', (75, 78))	('EM below the carina', 'CPA', (9, 28))	('cT3', 'Gene', '285782', (184, 187))	('cT1', 'Gene', (75, 78))	('SI', 'Disease', 'None', (139, 141))	('cT3', 'Gene', (184, 187))	('smaller', 'NegReg', (54, 61))	('cT4', 'Var', (32, 35))	('SI', 'Disease', 'None', (245, 247))
763693	28740891	We also found that on the CT images, the EM in cT4/below the carina was much smaller than that in cT1-T3 (Fig 3).	('cT1', 'Gene', (98, 101))	('cT1', 'Gene', '1489', (98, 101))	('smaller', 'NegReg', (77, 84))	('cT4/below', 'Var', (47, 56))
763694	28740891	The mean EM below the carina in cT4/below the carina was significantly smaller than that in cT4/above the carina (SI: 2.2 vs 4.5 mm, P < .01).	('cT4/below', 'Var', (32, 41))	('smaller', 'NegReg', (71, 78))	('SI', 'Disease', 'None', (114, 116))
763698	28740891	The ITV margins in cT4/below the carina were significantly smaller than those in cT1-T3 (above and below the carina, all directions: P < .01).	('cT1', 'Gene', (81, 84))	('cT1', 'Gene', '1489', (81, 84))	('smaller', 'NegReg', (59, 66))	('cT4/below', 'Var', (19, 28))
763699	28740891	The ITV margins in cT4/above the carina were smaller than those in cT1-T3 (above the carina; SI: P < .01).	('cT1', 'Gene', (67, 70))	('smaller', 'NegReg', (45, 52))	('cT4/above', 'Var', (19, 28))	('SI', 'Disease', 'None', (93, 95))	('cT1', 'Gene', '1489', (67, 70))
763712	28740891	We found that the EM below the carina in cT4 was significantly smaller compared with that in cT1-T3.	('cT1', 'Gene', (93, 96))	('smaller', 'NegReg', (63, 70))	('cT4', 'Var', (41, 44))	('cT1', 'Gene', '1489', (93, 96))	('EM below the carina', 'CPA', (18, 37))
763722	28740891	The ITV margins with 95% coverage in our datasets in each case were: in cT1-T3, the ITV margins in the LR, AP, and SI directions were 3.0 mm, 3.0 mm, and 5.0 mm for the esophagus above the carina, and 6.0 mm, 6.2 mm, and 12.8 mm for the esophagus below the carina; in cT4/above the carina, the ITV margins in the LR, AP, and SI directions were 2.0 mm, 2.0 mm, and 2.5 mm for the esophagus above the carina, and 5.0 mm, 5.8 mm, and 9.5 mm for the esophagus below the carina; in cT4/below the carina, the ITV margins in the LR, AP, and SI directions were 2.0 mm, 2.0 mm, and 2.5 mm for the esophagus above the carina, and 3.6 mm, 3.8 mm, and 5.0 mm for the esophagus below the carina.	('SI', 'Disease', 'None', (325, 327))	('SI', 'Disease', 'None', (534, 536))	('cT1', 'Gene', (72, 75))	('SI', 'Disease', 'None', (115, 117))	('cT1', 'Gene', '1489', (72, 75))	('cT4/below', 'Var', (477, 486))
763723	28740891	Our study indicated that the ITV margins for cT4 cases could be set smaller than those in cT1-T3 cases.	('cT1', 'Gene', (90, 93))	('cT1', 'Gene', '1489', (90, 93))	('cT4', 'Var', (45, 48))
763737	28740891	Both the EM and the ITV margins in cT4 were significantly smaller than those in cT1-T3.	('cT1', 'Gene', '1489', (80, 83))	('smaller', 'NegReg', (58, 65))	('cT1', 'Gene', (80, 83))	('ITV margins', 'CPA', (20, 31))	('cT4', 'Var', (35, 38))
763739	28740891	If smaller ITV margins can be used for cT4 cases than those generally used, radiation toxicities induced by definitive CRT would be reduced.	('cT4', 'Var', (39, 42))	('radiation toxicities', 'Disease', 'MESH:D004194', (76, 96))	('reduced', 'NegReg', (132, 139))	('radiation toxicities', 'Disease', (76, 96))
763750	28578276	Understanding the mechanisms by which ROS imbalance results in epithelial dysfunction and promotes tumor growth and progression could focus development of new redox-based strategies for therapeutic intervention.	('tumor', 'Disease', (99, 104))	('imbalance', 'Phenotype', 'HP:0002172', (42, 51))	('rat', 'Species', '10116', (173, 176))	('ROS', 'Chemical', 'MESH:D017382', (38, 41))	('progression', 'CPA', (116, 127))	('ROS', 'Protein', (38, 41))	('epithelial dysfunction', 'Disease', 'MESH:D002277', (63, 85))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('epithelial dysfunction', 'Disease', (63, 85))	('promotes', 'PosReg', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('results in', 'Reg', (52, 62))	('imbalance', 'Var', (42, 51))
763754	28578276	For example, aberrant hypermethylation of the DUOX1 and DUOX2 promoters results in downregulation of both DUOXs in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('DUOX1', 'Gene', (46, 51))	('aberrant hypermethylation', 'Var', (13, 38))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('downregulation', 'NegReg', (83, 97))	('DUOX2', 'Gene', '50506', (56, 61))	('DUOX2', 'Gene', (56, 61))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('DUOX1', 'Gene', '53905', (46, 51))
763760	28578276	It has been proposed that increased ROS levels derived from elevated NOX1 expression may stimulate tumor initiation through activation of NF-kappaB signaling.	('tumor', 'Disease', (99, 104))	('expression', 'MPA', (74, 84))	('stimulate', 'PosReg', (89, 98))	('NF-kappaB', 'Gene', '4790', (138, 147))	('increased ROS levels', 'Phenotype', 'HP:0025464', (26, 46))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('increased', 'PosReg', (26, 35))	('elevated', 'Var', (60, 68))	('ROS levels', 'MPA', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('NF-kappaB', 'Gene', (138, 147))	('NOX1', 'Gene', (69, 73))
763784	28578276	DUOX protein immunoblot detection was performed using a mouse monoclonal antibody S-40 that was raised against the human DUOX2 131-540 amino acid fragment.	('mouse', 'Species', '10090', (56, 61))	('human', 'Species', '9606', (115, 120))	('DUOX2', 'Gene', '50506', (121, 126))	('131-540', 'Var', (127, 134))	('DUOX2', 'Gene', (121, 126))
763806	28578276	Resistant clones were selected with 800 mug/mL G418, and then single clones were selected and maintained in RPMI-1640 media supplemented with 2 mM glutamine and 10% FBS, under 500 microg/mL G418 selection.	('G418', 'Chemical', 'MESH:C010680', (47, 51))	('glutamine', 'Chemical', 'MESH:D005973', (147, 156))	('G418', 'Var', (47, 51))	('FBS', 'Disease', 'MESH:D005198', (165, 168))	('RPMI-1640 media', 'Chemical', '-', (108, 123))	('G418', 'Chemical', 'MESH:C010680', (190, 194))	('FBS', 'Disease', (165, 168))
763836	28578276	As a positive control, a single site mutation (H222Q), reported to result in superoxide production, was generated in pCMV-MycDDK-HsNOX4 using Quikchange mutagenesis.	('result', 'Reg', (67, 73))	('rat', 'Species', '10116', (108, 111))	('Myc', 'Gene', '4609', (122, 125))	('Myc', 'Gene', (122, 125))	('superoxide production', 'MPA', (77, 98))	('superoxide', 'Chemical', 'MESH:D013481', (77, 87))	('H222Q', 'Var', (47, 52))	('H222Q', 'Mutation', 'p.H222Q', (47, 52))
763905	28578276	Further mutational analysis of this loop region, through single site mutations of two cysteine residues, provided corroborating results, establishing control of H2O2 production at this loop region.	('mutations', 'Var', (69, 78))	('cysteine', 'Chemical', 'MESH:D003545', (86, 94))	('H2O2', 'MPA', (161, 165))	('H2O2', 'Chemical', 'MESH:D006861', (161, 165))	('rat', 'Species', '10116', (121, 124))
763908	28578276	In comparison, no significant decrease in hydrogen peroxide production was observed following exposure to a range of antibody concentrations, suggesting that while antibody 47-6 binds to the E-loop region, this binding has little to no effect on ROS production.	('binds', 'Interaction', (178, 183))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (42, 59))	('rat', 'Species', '10116', (133, 136))	('ROS', 'Chemical', 'MESH:D017382', (246, 249))	('antibody', 'Var', (164, 172))	('ROS production', 'MPA', (246, 260))
763910	28578276	The site of binding may be crucial, as the known His-222 mutation which results in superoxide production is ~20 amino acids from the site of 47-6 Ab binding (Fig.	('mutation', 'Var', (57, 65))	('superoxide', 'Chemical', 'MESH:D013481', (83, 93))	('His-222', 'Gene', (49, 56))	('His', 'Chemical', 'MESH:D006639', (49, 52))	('superoxide production', 'MPA', (83, 104))	('results in', 'Reg', (72, 82))
763911	28578276	The stability of the antibody binding or epitope position also may not be as effective as direct mutation, or may suggest that this region does not confer significant structural support to the E-loop such that perturbation would result in ROS modification.	('ROS modification', 'MPA', (239, 255))	('perturbation', 'Var', (210, 222))	('result in', 'Reg', (229, 238))	('ROS', 'Chemical', 'MESH:D017382', (239, 242))
763914	28578276	In studies of fetal rat and human hepatocytes, treatment with TGF-beta1 results in oxidative-stress mediated apoptosis.	('treatment', 'Var', (47, 56))	('TGF-beta1', 'Gene', (62, 71))	('oxidative-stress mediated apoptosis', 'MPA', (83, 118))	('human', 'Species', '9606', (28, 33))	('oxidative-stress', 'Phenotype', 'HP:0025464', (83, 99))	('rat', 'Species', '10116', (20, 23))	('results in', 'Reg', (72, 82))
763945	28578276	As expected, the NOX4 knockdown achieved was verified both at the RNA and protein level, leaving the level of p22phox unperturbed.	('knockdown', 'Var', (22, 31))	('p22phox', 'Gene', '1535', (110, 117))	('p22phox', 'Gene', (110, 117))
763959	28578276	Alternatively, disrupting oxidant removal, causing an accumulation of excess ROS in malignant cells, could initiate a beneficial apoptotic cascade.	('initiate', 'Reg', (107, 115))	('disrupting', 'Var', (15, 25))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('excess', 'PosReg', (70, 76))	('ROS', 'Protein', (77, 80))	('apoptotic', 'CPA', (129, 138))
764121	25501097	Based on the medical records, the following data were also collected for each patient: age (<=60 and >60 years), gender (male and female), tumor length (<=3.0 and >3.0 cm), tumor location (upper, middle, and lower), differentiation (well, moderate, and poor), vessel invasion (negative and positive), T stage (T1, T2, T3, and T4a), N stage (N0, N1, N2, and N3), and adjuvant therapy.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('patient', 'Species', '9606', (78, 85))	('vessel invasion', 'CPA', (260, 275))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('T4a', 'Var', (326, 329))	('T stage', 'CPA', (301, 308))
764137	25501097	The 5-year CSS of patients with LC < 1.0 Giga/L was shorter than that of patients with LC >= 1.0 Giga/L in T1-2 group (26.1% vs 66.7%, P = 0.001) and T3-4a group (17.9% vs 33.1%, P = 0.043), respectively (Figure 3A and B).	('LC < 1.0 Giga/L', 'Var', (32, 47))	('shorter', 'NegReg', (52, 59))	('T1-2', 'Gene', (107, 111))	('CSS', 'MPA', (11, 14))	('T1-2', 'Gene', '923;9173;292', (107, 111))	('patients', 'Species', '9606', (18, 26))	('CSS', 'Chemical', '-', (11, 14))	('patients', 'Species', '9606', (73, 81))
764167	25501097	Resectable locally advanced EC refers to T3-T4a or N1-3 and early stage EC refers to T1-2 or N0 according to the 7th edition of the AJCC.	('T1-2', 'Gene', '923;9173;292', (85, 89))	('T3-T4a', 'Var', (41, 47))	('T1-2', 'Gene', (85, 89))	('locally advanced EC', 'Disease', (11, 30))
764237	24973176	Patients who underwent TNE crossed the minimally clinically important threshold scores for pain, choking and gagging significantly more often than those randomized to ECE (Table 2).	('gagging', 'Disease', (109, 116))	('TNE', 'Chemical', '-', (23, 26))	('ECE', 'Chemical', '-', (167, 170))	('Patients', 'Species', '9606', (0, 8))	('TNE', 'Var', (23, 26))	('choking', 'Disease', (97, 104))	('pain', 'Phenotype', 'HP:0012531', (91, 95))	('often', 'PosReg', (136, 141))	('pain', 'Disease', 'MESH:D010146', (91, 95))	('pain', 'Disease', (91, 95))
764277	24973176	As expected, a greater proportion of subjects undergoing TNE reported pain, choking, and gagging compared with those undergoing ECE.	('gagging', 'Disease', (89, 96))	('pain', 'Phenotype', 'HP:0012531', (70, 74))	('TNE', 'Chemical', '-', (57, 60))	('pain', 'Disease', 'MESH:D010146', (70, 74))	('pain', 'Disease', (70, 74))	('TNE', 'Var', (57, 60))	('choking', 'Disease', (76, 83))	('ECE', 'Chemical', '-', (128, 131))
764312	25368748	Furthermore, EMR caused intense thermal denaturation of the lesion, which makes it difficult to perform precise histopathologic evaluation of the piecemeal-resected specimen, needed to determine the risk of lymph node metastasis.	('thermal denaturation', 'MPA', (32, 52))	('men', 'Species', '9606', (170, 173))	('EMR', 'Var', (13, 16))
764417	25054136	Deletion or reduction of histoblood group A or histoblood group B antigen in tumors of A or B individual is correlated with the degree of malignancy and metastatic potential in many types of human cancers.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('reduction', 'NegReg', (12, 21))	('metastatic potential', 'CPA', (153, 173))	('tumors of A', 'Disease', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumors of A', 'Disease', 'MESH:D009369', (77, 88))	('Deletion', 'Var', (0, 8))
764433	23482729	Postoperative hospital stay would be shorter and the level of laboratory parameters especially serum transferrin is higher in EEF in comparison with control group.	('level of laboratory parameters', 'MPA', (53, 83))	('higher', 'PosReg', (116, 122))	('transferrin', 'Gene', '7018', (101, 112))	('transferrin', 'Gene', (101, 112))	('EEF', 'Var', (126, 129))
764465	23482729	On 5th postoperative day there was significant difference of nutritional parameters in both groups with higher serum protein, serum albumin, total calcium, serum transferrin, blood sugar in EEF group in comparison with the control group (Table 2).	('serum protein', 'MPA', (111, 124))	('EEF', 'Var', (190, 193))	('total calcium', 'MPA', (141, 154))	('sugar', 'Chemical', 'MESH:D000073893', (181, 186))	('transferrin', 'Gene', '7018', (162, 173))	('transferrin', 'Gene', (162, 173))	('blood sugar', 'MPA', (175, 186))	('serum albumin', 'MPA', (126, 139))	('calcium', 'Chemical', 'MESH:D002118', (147, 154))	('higher', 'PosReg', (104, 110))
764506	32865623	The NPS was constructed by grouping patients into three cohorts; zero (0) for patients with both normal neutrophil (<= 7.5 x 109/L) and platelet counts (<= 400 x 109/L), one (1) for patients with either a high neutrophil (> 7.5 x 109/L) or platelet count (> 400 x 109/L), and two (2) for patients with both high neutrophil and platelet count.	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (288, 296))	('> 400 x 109/L', 'Var', (256, 269))	('<= 400 x 109/L', 'Var', (153, 167))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (182, 190))	('<= 7.5 x 109/L', 'Var', (116, 130))	('> 7.5', 'Var', (222, 227))
764508	32865623	Patients with normal serum levels of CRP (<= 10 mg/l) and albumin (>= 35 g/l) were given a score of zero.	('albumin', 'Gene', '213', (58, 65))	('albumin', 'Gene', (58, 65))	('CRP', 'Gene', (37, 40))	('Patients', 'Species', '9606', (0, 8))	('CRP', 'Gene', '1401', (37, 40))	('<=', 'Var', (42, 44))
764535	32865623	Similarly, patients with a low NLR experienced five-year DFS and OS of 45.3%, and 49.6%, 1.6 and 1.8 fold better than patients with a high NLR.	('DFS', 'MPA', (57, 60))	('better', 'PosReg', (106, 112))	('low', 'Var', (27, 30))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (118, 126))
764537	32865623	NLR and mGPS have been associated with poor survival in a raft of anatomical cancer sites including breast, colorectal, stomach, and prostate.	('GPS', 'Disease', (9, 12))	('colorectal', 'Disease', (108, 118))	('breast', 'Disease', (100, 106))	('prostate', 'Disease', (133, 141))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('GPS', 'Disease', 'MESH:D055652', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('stomach', 'Disease', (120, 127))	('colorectal', 'Disease', 'MESH:D015179', (108, 118))	('NLR', 'Var', (0, 3))
764548	32865623	More explicitly, recent colorectal cancer research has indicated a strong relationship between suboptimal patient physiological stage, increased comorbidity, and elevated CRP.	('elevated', 'PosReg', (162, 170))	('elevated CRP', 'Phenotype', 'HP:0011227', (162, 174))	('age', 'Gene', (130, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('suboptimal', 'Var', (95, 105))	('patient', 'Species', '9606', (106, 113))	('rectal cancer', 'Phenotype', 'HP:0100743', (28, 41))	('colorectal cancer', 'Disease', (24, 41))	('CRP', 'Gene', (171, 174))	('age', 'Gene', '5973', (130, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (24, 41))	('CRP', 'Gene', '1401', (171, 174))
764678	28536494	Adequate organ function was required in 2 weeks of registration and was defined as: white blood cell account >=3.5x109/L, absolute neutrophil account >=1.5x109/L, platelet >=100x109/L, hemoglobin >=10 g/L, serum creatinine within normal institutional limit, creatinine clearance >=60 mL/min, and aspartate aminotransferase (AST) and bilirubin <2 times of upper normal institutional limits.	('bilirubin', 'Chemical', 'MESH:D001663', (333, 342))	('creatinine', 'Chemical', 'MESH:D003404', (258, 268))	('>=10', 'Var', (196, 200))	('creatinine', 'Chemical', 'MESH:D003404', (212, 222))	('aspartate aminotransferase', 'Gene', (296, 322))	('AST', 'Gene', (324, 327))	('creatinine clearance', 'MPA', (258, 278))	('>=1.5x109/L', 'Var', (150, 161))	('aspartate aminotransferase', 'Gene', '26503', (296, 322))	('AST', 'Gene', '26503', (324, 327))	('bilirubin', 'MPA', (333, 342))	('>=100x109/L', 'Var', (172, 183))	('serum creatinine', 'MPA', (206, 222))	('>=3.5x109/L', 'Var', (109, 120))
764775	26986978	Exclusion criteria included prior thoracic radiation, severe or uncontrolled systemic disease, uncontrolled hypertension (BP >= 160/100), active pregnancy or breast feeding, uncontrolled diarrhea, ANC < 1,500/mm3, platelet count <= 100 K/mm3, serum bilirubin > 1.5 times upper limit of normal, serum creatinine > 1.5 times upper limit of normal or creatinine clearance <= 50 mL/minute, AST or ALT > 2.5 times upper limit of normal, potassium < 4 mmol/L despite supplementation, and serum calcium or magnesium out of the normal range despite supplementation.	('systemic disease', 'Disease', 'MESH:D034721', (77, 93))	('ALT > 2', 'Gene', '84706', (393, 400))	('creatinine clearance', 'MPA', (348, 368))	('serum creatinine', 'MPA', (294, 310))	('serum bilirubin', 'MPA', (243, 258))	('diarrhea', 'Disease', (187, 195))	('hypertension', 'Phenotype', 'HP:0000822', (108, 120))	('out', 'NegReg', (509, 512))	('potassium', 'MPA', (432, 441))	('systemic disease', 'Disease', (77, 93))	('diarrhea', 'Disease', 'MESH:D003967', (187, 195))	('serum calcium', 'MPA', (482, 495))	('AST', 'Gene', '26503', (386, 389))	('<= 100 K/mm3', 'Var', (229, 241))	('ANC', 'Disease', (197, 200))	('severe', 'Disease', (54, 60))	('diarrhea', 'Phenotype', 'HP:0002014', (187, 195))	('hypertension', 'Disease', 'MESH:D006973', (108, 120))	('AST', 'Gene', (386, 389))	('hypertension', 'Disease', (108, 120))	('ALT > 2', 'Gene', (393, 400))	('platelet', 'Disease', (214, 222))
764853	26986978	It is established that inhibition of the VEGF pathway can result in wound healing complications.	('VEGF', 'Gene', '7422', (41, 45))	('inhibition', 'Var', (23, 33))	('wound healing complications', 'CPA', (68, 95))	('wound healing complications', 'Phenotype', 'HP:0001058', (68, 95))	('VEGF', 'Gene', (41, 45))	('result in', 'Reg', (58, 67))
764901	27471393	Even for T2N0M0 patients, a study showed that adjuvant RT could significantly improve survival for the patients with a high risk of poor prognosis.	('improve', 'PosReg', (78, 85))	('survival', 'MPA', (86, 94))	('T2N0M0', 'Var', (9, 15))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (103, 111))
764906	27471393	3DRT has been independently associated with a survival advantage and a higher local tumor control rate in nasopharyngeal carcinoma and NSCLC.	('higher', 'PosReg', (71, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (106, 130))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('NSCLC', 'Disease', (135, 140))	('3DRT', 'Var', (0, 4))	('carcinoma', 'Disease', (121, 130))	('tumor', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('survival advantage', 'CPA', (46, 64))	('carcinoma', 'Disease', 'MESH:D002277', (121, 130))
764965	27471393	Many studies have reported that lymph node recurrence increases dramatically with deeper invasion, higher number of lymph nodes with positive metastases, poorer tumor differentiation, and longer tumor length after esophagectomy.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('lymph node recurrence', 'CPA', (32, 53))	('deeper invasion', 'CPA', (82, 97))	('metastases', 'Disease', (142, 152))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('poorer', 'Var', (154, 160))	('tumor', 'Disease', (161, 166))	('higher number of lymph nodes', 'Phenotype', 'HP:0032536', (99, 127))
764967	27471393	Biomarkers such as Ku80, VEGF, EGFR, and p53 are associated with poor prognosis; however, their relationship with recurrence patterns has rarely been studied.	('EGFR', 'Gene', '1956', (31, 35))	('VEGF', 'Gene', '7422', (25, 29))	('EGFR', 'Gene', (31, 35))	('p53', 'Gene', (41, 44))	('Ku80', 'Var', (19, 23))	('VEGF', 'Gene', (25, 29))	('p53', 'Gene', '7157', (41, 44))
764981	25693076	The current evidence suggests that CEA, Cyfra21-1, p53, SCC-Ag and VEGF-C have a potential diagnostic value for esophageal carcinoma.	('CEA', 'Gene', (35, 38))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('esophageal carcinoma.', 'Phenotype', 'HP:0011459', (112, 133))	('SCC', 'Gene', (56, 59))	('VEGF-C', 'Gene', (67, 73))	('Cyfra21-1', 'Var', (40, 49))	('SCC', 'Gene', '6317', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('CEA', 'Gene', '1048', (35, 38))	('esophageal carcinoma', 'Disease', (112, 132))	('VEGF-C', 'Gene', '7424', (67, 73))
764998	25693076	Computation of the Spearman correlation coefficient between the logit of sensitivity and logit of 1-specificity of CEA, Cyfra21-1, p53 antibody, SCC-Ag and VEGF-C were calculated, indicating no threshold effect, and the positive correlation had no statistical significance.	('CEA', 'Gene', '1048', (115, 118))	('CEA', 'Gene', (115, 118))	('Cyfra21-1', 'Var', (120, 129))	('p53', 'Gene', (131, 134))	('VEGF-C', 'Gene', (156, 162))	('SCC', 'Gene', (145, 148))	('p53', 'Gene', '7157', (131, 134))	('SCC', 'Gene', '6317', (145, 148))	('VEGF-C', 'Gene', '7424', (156, 162))
765019	25693076	Although meta-analysis itself has some bias, the results showed no publication bias in this meta-analysis (CEA, p = 0.339; Cyfra21-1, p = 0.841; p53, p = 0.408; SCC-Ag, p = 0.397).	('SCC', 'Gene', (161, 164))	('CEA', 'Gene', (107, 110))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('SCC', 'Gene', '6317', (161, 164))	('Cyfra21-1', 'Var', (123, 132))	('CEA', 'Gene', '1048', (107, 110))
765021	25693076	The overall specificity of CEA, Cyfra21-1, p53 antibody, SCC-Ag and VEGF-C were 98.0%, 97.8%, 98.4%, 98.0% and 73.2%, respectively.	('SCC', 'Gene', '6317', (57, 60))	('Cyfra21-1', 'Var', (32, 41))	('CEA', 'Gene', '1048', (27, 30))	('VEGF-C', 'Gene', '7424', (68, 74))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('SCC', 'Gene', (57, 60))	('VEGF-C', 'Gene', (68, 74))	('CEA', 'Gene', (27, 30))
765033	25693076	On the other hand, the mean NLR values of CEA, Cyfra21-1, p53 antibody, SCC-Ag and VEGF-C ranged from 0.35 to 0.76, so if the assay results are negative, the probability that this patient has EC ranges from 35% to 76%, which is too high to rule out EC.	('CEA', 'Gene', '1048', (42, 45))	('VEGF-C', 'Gene', (83, 89))	('Cyfra21-1', 'Var', (47, 56))	('SCC', 'Gene', (72, 75))	('VEGF-C', 'Gene', '7424', (83, 89))	('p53', 'Gene', (58, 61))	('SCC', 'Gene', '6317', (72, 75))	('patient', 'Species', '9606', (180, 187))	('CEA', 'Gene', (42, 45))	('p53', 'Gene', '7157', (58, 61))
765044	25693076	In conclusion, current evidence suggests that CEA, Cyfra21-1, p53 antibody, SCC-Ag and VEGF-C are highly specific, but insufficiently sensitive to diagnose EC.	('CEA', 'Gene', '1048', (46, 49))	('VEGF-C', 'Gene', (87, 93))	('SCC', 'Gene', (76, 79))	('CEA', 'Gene', (46, 49))	('insufficiently', 'Disease', 'MESH:D000309', (119, 133))	('insufficiently', 'Disease', (119, 133))	('SCC', 'Gene', '6317', (76, 79))	('VEGF-C', 'Gene', '7424', (87, 93))	('Cyfra21-1', 'Var', (51, 60))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
765045	25693076	Patients with cancer have a higher chance of being CEA-, Cyfra21-1-, p53 antibody-, SCC-Ag- and VEGF-C-positive compared to patients without cancer.	('cancer', 'Disease', (14, 20))	('SCC', 'Gene', '6317', (84, 87))	('VEGF-C', 'Gene', (96, 102))	('p53', 'Gene', (69, 72))	('patients', 'Species', '9606', (124, 132))	('CEA', 'Gene', '1048', (51, 54))	('p53', 'Gene', '7157', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('Cyfra21-1-', 'Var', (57, 67))	('VEGF-C', 'Gene', '7424', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('SCC', 'Gene', (84, 87))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', (141, 147))	('CEA', 'Gene', (51, 54))
765073	19760373	Furthermore, nitric oxide synthase (NOS) knockout mice display consistently higher resting LES pressure and failure of relaxation of the LES in response to swallowing, which is a similar manometric pattern to that of many patients with achalasia.	('nitric oxide synthase', 'Gene', (13, 34))	('failure', 'NegReg', (108, 115))	('achalasia', 'Phenotype', 'HP:0002571', (236, 245))	('patients', 'Species', '9606', (222, 230))	('achalasia', 'Disease', (236, 245))	('knockout', 'Var', (41, 49))	('achalasia', 'Disease', 'MESH:D004931', (236, 245))	('nitric oxide synthase', 'Gene', '18125', (13, 34))	('mice', 'Species', '10090', (50, 54))	('resting LES pressure', 'MPA', (83, 103))	('higher', 'PosReg', (76, 82))
765113	19760373	Further causes include iatrogenic conditions such as an incorrectly constructed or tight fundoplication during antireflux procedures (ARPs) and placement of laparoscopic adjustable gastric banding for the treatment of morbid obesity (Fig.	('iatrogenic conditions', 'Disease', 'MESH:D007049', (23, 44))	('obesity', 'Disease', (225, 232))	('morbid obesity', 'Phenotype', 'HP:0012743', (218, 232))	('ARP', 'Gene', (134, 137))	('incorrectly', 'Var', (56, 67))	('iatrogenic conditions', 'Disease', (23, 44))	('ARP', 'Gene', '10139', (134, 137))	('obesity', 'Phenotype', 'HP:0001513', (225, 232))	('obesity', 'Disease', 'MESH:D009765', (225, 232))
765194	19760373	A 360  Nissen fundoplication has been used in selected series; however, a Nissen fundoplication may hinder esophageal clearance, resulting in progressive postoperative dilatation of the aperistaltic esophagus and recurrent dysphagia.	('dilatation', 'Phenotype', 'HP:0002617', (168, 178))	('recurrent', 'Disease', (213, 222))	('Nissen', 'Disease', (74, 80))	('dysphagia', 'Phenotype', 'HP:0002015', (223, 232))	('hinder', 'NegReg', (100, 106))	('fundoplication', 'Var', (81, 95))	('dysphagia', 'Disease', 'MESH:D003680', (223, 232))	('esophageal clearance', 'MPA', (107, 127))	('dysphagia', 'Disease', (223, 232))	('dilatation', 'MPA', (168, 178))
765251	33392091	In addition, the lung dosimetric parameters involved in this study included V5-V40 (relative volume of total lung treated with >=5-40 Gy) and MLD.	('MLD', 'Disease', 'MESH:D007966', (142, 145))	('V5-V40', 'Var', (76, 82))	('MLD', 'Disease', (142, 145))
765265	33392091	Standard body scan conditions were voltage (125 kVp), current (80 mA), exposure time (13 ms), exposure (680 mAs), rotation angle (178 -182 ), pixel matrix size (384x384), field of view (FOV, 45x18 cm), slice thickness (2.5 mm), and fan-beam type (half-fan).	('rotation angle', 'Disease', 'MESH:D009069', (114, 128))	('384x384', 'Var', (161, 168))	('rotation angle', 'Disease', (114, 128))
765283	33392091	Univariate analysis showed that tumor stage was correlated with >=2 grade RP (chi2 = 2.650, P = 0.008), and other factors, including age, sex, concurrent chemoradiotherapy or lack thereof, COPD status, smoking status, and RT dose, showed no significant differences between the two groups (all Ps > 0.05).	('rad', 'Gene', (69, 72))	('rad', 'Gene', '6236', (159, 162))	('rad', 'Gene', (159, 162))	('>=2', 'Var', (64, 67))	('COPD', 'Gene', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('rad', 'Gene', '6236', (69, 72))	('COPD', 'Gene', '260431', (189, 193))
765284	33392091	V5, V10, V15, V20, V30, and MLD of both lungs were associated with the occurrence of grade >=2 RP (all Ps < 0.05).	('rad', 'Gene', (86, 89))	('V20', 'Var', (14, 17))	('V15', 'Gene', (9, 12))	('V15', 'Gene', '28814', (9, 12))	('associated', 'Reg', (51, 61))	('V30', 'Var', (19, 22))	('MLD', 'Disease', 'MESH:D007966', (28, 31))	('MLD', 'Disease', (28, 31))	('V10', 'Var', (4, 7))	('rad', 'Gene', '6236', (86, 89))
765296	33392091	The model was built as follows: Rad-score = -1.996 e-07xvoxel volume - 4.036 e-03xsmallest axis length + 5.376 e+01xsmall dependence low gray-level emphasis + 1.718 e-07xlarge area low gray-level emphasis - 2.473 e-04xbusyness + 1.041 e+00.	('e-04xbusyness +', 'Var', (213, 228))	('Rad', 'Gene', '6236', (32, 35))	('Rad', 'Gene', (32, 35))
765302	33392091	In addition, the AUC values of the radiomics signature at three different periods were 0.700, 0.663, and 0.699, respectively (primary cohort).	('0.699', 'Var', (105, 110))	('rad', 'Gene', '6236', (35, 38))	('0.663', 'Var', (94, 99))	('rad', 'Gene', (35, 38))
765366	32000467	In the adjusted analysis, patients with advanced stage disease (relative risk [RR], 0.28 in stage III and 0.12 in stage IV compared to stage I), poor performance status, circumferential involvement (RR, 0.61), and male sex (RR, 0.31) were less likely to achieve CR.	('less', 'NegReg', (239, 243))	('men', 'Species', '9606', (193, 196))	('patients', 'Species', '9606', (26, 34))	('circumferential', 'Var', (170, 185))	('poor', 'Var', (145, 149))
765427	32000467	In adjusted analysis, poor CCRT response (HR is 2.82 in PR, 4.47 in SD, and 4.77 in PD compared to CR), poor performance status (HR in ECOG 2-4 is 1.38 compared to ECOG 0), and advanced stage (HR, 1.71; 95% CI, 1.32 to 2.22 in stage I/II compared to stage III/IV) increased the mortality (Table 4).	('increased', 'PosReg', (264, 273))	('CCRT response', 'MPA', (27, 40))	('poor', 'Var', (22, 26))	('mortality', 'Disease', 'MESH:D003643', (278, 287))	('poor', 'Var', (104, 108))	('PD', 'Disease', 'MESH:D010300', (84, 86))	('mortality', 'Disease', (278, 287))
765449	32000467	In adjusted analysis, poor CCRT response, advanced stage (stage III/IV), and poor ECOG performance status independently increased the risk of death, whereas superficial tumor reduced the risk of death.	('death', 'Disease', 'MESH:D003643', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('poor', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('death', 'Disease', (195, 200))	('death', 'Disease', 'MESH:D003643', (142, 147))	('death', 'Disease', (142, 147))	('tumor', 'Disease', (169, 174))
765462	32000467	Advanced stage, poor CCRT response, and poor performance status independently increased the risk of cancer death, whereas superficial tumor reduced the death risk.	('poor', 'Var', (16, 20))	('cancer death', 'Disease', 'MESH:D009369', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('death', 'Disease', 'MESH:D003643', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('increased', 'PosReg', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('death', 'Disease', 'MESH:D003643', (152, 157))	('death', 'Disease', (107, 112))	('death', 'Disease', (152, 157))	('cancer death', 'Disease', (100, 112))	('tumor', 'Disease', (134, 139))
765485	31934893	MiR-133a-3p, 136-5p, 194-5p, 382-5p, and 451a are dysregulated in serum from patients with BE and can differentiate between controls, BE, and EAC patients.	('MiR-133a-3p', 'Var', (0, 11))	('EAC', 'Disease', (142, 145))	('EAC', 'Disease', 'MESH:D004938', (142, 145))	('BE', 'Phenotype', 'HP:0100580', (91, 93))	('BE', 'Phenotype', 'HP:0100580', (134, 136))	('patients', 'Species', '9606', (77, 85))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))	('BE', 'Disease', 'MESH:D001471', (91, 93))	('patients', 'Species', '9606', (146, 154))	('BE', 'Disease', 'MESH:D001471', (134, 136))
765530	31934893	MiR-212-5p, miR-4792, and miR-4783-5p were undetectable by qRT-PCR and excluded from further analysis.	('miR', 'Gene', '220972', (26, 29))	('miR-4792', 'Gene', (12, 20))	('miR', 'Gene', (26, 29))	('miR-4792', 'Gene', '100616448', (12, 20))	('MiR-212-5p', 'Var', (0, 10))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
765547	31934893	Although previous studies have shown a correlation between high BMI and EAC, the trend was not observed in our data set.	('EAC', 'Disease', (72, 75))	('EAC', 'Phenotype', 'HP:0011459', (72, 75))	('EAC', 'Disease', 'MESH:D004938', (72, 75))	('high BMI', 'Var', (59, 67))
765574	31934893	Let-7g-5p directly targets BCL2L1 (BCL-X), and loss of BCL2L1 has been associated with progression to EAC and reduced survival.	('BCL2L1', 'Gene', '598', (55, 61))	('BCL-X', 'Gene', '598', (35, 40))	('reduced', 'NegReg', (110, 117))	('Let-7g', 'Gene', '406890', (0, 6))	('EAC', 'Phenotype', 'HP:0011459', (102, 105))	('Let-7g', 'Gene', (0, 6))	('BCL2L1', 'Gene', (27, 33))	('BCL-X', 'Gene', (35, 40))	('survival', 'CPA', (118, 126))	('EAC', 'Disease', (102, 105))	('loss', 'Var', (47, 51))	('EAC', 'Disease', 'MESH:D004938', (102, 105))	('BCL2L1', 'Gene', (55, 61))	('BCL2L1', 'Gene', '598', (27, 33))
765577	31934893	Loss of miR-193b-3p leads to elevated uPA levels and increases breast cancer progression and invasion, but a role for uPA in BE or EAC has not been reported.	('miR-193b', 'Gene', '574455', (8, 16))	('BE', 'Phenotype', 'HP:0100580', (125, 127))	('elevated', 'PosReg', (29, 37))	('uPA', 'Gene', '5328', (118, 121))	('increases breast cancer', 'Disease', (53, 76))	('uPA', 'Gene', '5328', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('EAC', 'Disease', (131, 134))	('miR-193b', 'Gene', (8, 16))	('increases breast cancer', 'Disease', 'MESH:D001943', (53, 76))	('EAC', 'Disease', 'MESH:D004938', (131, 134))	('BE', 'Disease', 'MESH:D001471', (125, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('invasion', 'CPA', (93, 101))	('EAC', 'Phenotype', 'HP:0011459', (131, 134))	('uPA', 'Gene', (38, 41))	('Loss', 'Var', (0, 4))	('uPA', 'Gene', (118, 121))
765578	31934893	MiR-193b-3p targets ERalpha (ESR1) which is hypermethylated in GERD, BE, and EAC, suggesting that miR-193b-3p and epigenetic silencing may act in parallel to silence ESR1.	('BE', 'Phenotype', 'HP:0100580', (69, 71))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('ESR1', 'Gene', '2099', (166, 170))	('GERD', 'Disease', (63, 67))	('miR-193b', 'Gene', (98, 106))	('EAC', 'Disease', (77, 80))	('ESR1', 'Gene', '2099', (29, 33))	('epigenetic silencing', 'Var', (114, 134))	('ERalpha', 'Gene', (20, 27))	('GERD', 'Disease', 'MESH:D005764', (63, 67))	('BE', 'Disease', 'MESH:D001471', (69, 71))	('ERalpha', 'Gene', '2099', (20, 27))	('ESR1', 'Gene', (166, 170))	('miR-193b', 'Gene', '574455', (98, 106))	('EAC', 'Disease', 'MESH:D004938', (77, 80))	('ESR1', 'Gene', (29, 33))
765579	31934893	MiR-193b-3p also targets CCND1 and ETS1 to induce cell cycle arrest and inhibit migration and invasion.	('arrest', 'Disease', (61, 67))	('CCND1', 'Gene', (25, 30))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('CCND1', 'Gene', '595', (25, 30))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('ETS1', 'Gene', '2113', (35, 39))	('ETS1', 'Gene', (35, 39))	('inhibit', 'NegReg', (72, 79))	('MiR-193b-3p', 'Var', (0, 11))	('induce', 'PosReg', (43, 49))
765580	31934893	Polymorphisms in CCND1 are associated with increased risk of GERD.	('GERD', 'Disease', 'MESH:D005764', (61, 65))	('CCND1', 'Gene', '595', (17, 22))	('GERD', 'Disease', (61, 65))	('Polymorphisms', 'Var', (0, 13))	('associated', 'Reg', (27, 37))	('CCND1', 'Gene', (17, 22))
765582	31934893	Although dysregulation of miR-30d-5p occurs in colon and non-small cell lung cancer, its association with BE or EAC has not been reported.	('colon', 'Disease', (47, 52))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (57, 83))	('BE', 'Disease', 'MESH:D001471', (106, 108))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('EAC', 'Disease', (112, 115))	('non-small cell lung cancer', 'Disease', (57, 83))	('miR-30d', 'Gene', (26, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BE', 'Phenotype', 'HP:0100580', (106, 108))	('EAC', 'Disease', 'MESH:D004938', (112, 115))	('dysregulation', 'Var', (9, 22))	('miR-30d', 'Gene', '407033', (26, 33))
765589	31934893	YAP1 is overexpressed in EAC cell lines relative to BE cell lines, thus suggesting that loss of miR-375 in EAC may promote proliferation and invasion of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('promote', 'PosReg', (115, 122))	('proliferation', 'CPA', (123, 136))	('EAC', 'Disease', 'MESH:D004938', (25, 28))	('BE', 'Phenotype', 'HP:0100580', (52, 54))	('EAC', 'Disease', (107, 110))	('cancer', 'Disease', (153, 159))	('YAP1', 'Gene', (0, 4))	('YAP1', 'Gene', '10413', (0, 4))	('BE', 'Disease', 'MESH:D001471', (52, 54))	('EAC', 'Disease', 'MESH:D004938', (107, 110))	('EAC', 'Phenotype', 'HP:0011459', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('loss', 'Var', (88, 92))	('miR-375', 'Gene', '494324', (96, 103))	('EAC', 'Phenotype', 'HP:0011459', (107, 110))	('EAC', 'Disease', (25, 28))	('miR-375', 'Gene', (96, 103))
765592	31934893	MiR-4485-5p was significantly downregulated in the LGD/HGD/EAC class relative to normal and GERD/BE classes, thus potentially serving as a novel marker of disease severity.	('GERD', 'Disease', (92, 96))	('HGD', 'Gene', (55, 58))	('EAC', 'Disease', 'MESH:D004938', (59, 62))	('downregulated', 'NegReg', (30, 43))	('LGD', 'Disease', (51, 54))	('BE', 'Phenotype', 'HP:0100580', (97, 99))	('MiR-4485-5p', 'Var', (0, 11))	('LGD', 'Disease', 'MESH:D008228', (51, 54))	('EAC', 'Phenotype', 'HP:0011459', (59, 62))	('BE', 'Disease', 'MESH:D001471', (97, 99))	('GERD', 'Disease', 'MESH:D005764', (92, 96))	('EAC', 'Disease', (59, 62))	('HGD', 'Gene', '3081', (55, 58))
765597	31934893	Furthermore, the dysregulation of these miRNA may provide critical insights into the specific cellular physiology changes that occur in Barrett's esophagus and EAC.	('EAC', 'Phenotype', 'HP:0011459', (160, 163))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (136, 155))	('EAC', 'Disease', (160, 163))	('dysregulation', 'Var', (17, 30))	('EAC', 'Disease', 'MESH:D004938', (160, 163))
765617	31438989	Moreover, accumulating studies suggested that S1PR1 coupled to Gi and activated downstream signaling pathways, including the PI3K/AKT, PI3K/Rac, Ras/ERK, NF-kappaB and PLC signaling pathways.	('S1PR1', 'Var', (46, 51))	('activated', 'PosReg', (70, 79))	('ERK', 'Gene', (149, 152))	('PI3', 'Gene', (125, 128))	('PI3', 'Gene', (135, 138))	('PLC signaling pathways', 'Pathway', (168, 190))	('coupled', 'Reg', (52, 59))	('PI3K/Rac', 'Gene', '5290;207', (135, 143))	('AKT', 'Gene', '207', (130, 133))	('PI3', 'Gene', '5266', (125, 128))	('ERK', 'Gene', '5594', (149, 152))	('PI3K/Rac', 'Gene', (135, 143))	('PI3', 'Gene', '5266', (135, 138))	('AKT', 'Gene', (130, 133))	('NF-kappaB', 'Pathway', (154, 163))
765655	31438989	Additionally, ESCC patients with high S1PR1 expression have a shorter overall survival (median survival 47 months,95%CI 0.9370 to 2.360) comparing to patients with low S1PR1 expression (median survival 70 months, 95%CI 0.4236 to 1.067) (Fig.	('S1PR1', 'Gene', (38, 43))	('high', 'Var', (33, 37))	('overall survival', 'MPA', (70, 86))	('shorter', 'NegReg', (62, 69))	('patients', 'Species', '9606', (19, 27))	('ESCC', 'Disease', (14, 18))	('patients', 'Species', '9606', (150, 158))
765660	31438989	To investigate the role of S1PR1 on the proliferation and apoptosis of ESCC cells, S1PR1 expression was knockdown by plasmid-mediated short interfering RNAs (siRNAs) in kyse150 and TE-13 ESCC cells.	('S1PR1', 'Gene', (83, 88))	('TE-13', 'Chemical', '-', (181, 186))	('knockdown', 'Var', (104, 113))
765661	31438989	2, knockdown of S1PR1 decreased proliferation of kyse150 and TE-13 cells (Fig.	('TE-13', 'Chemical', '-', (61, 66))	('S1PR1', 'Gene', (16, 21))	('proliferation of kyse150', 'CPA', (32, 56))	('knockdown', 'Var', (3, 12))	('decreased', 'NegReg', (22, 31))
765663	31438989	Consistently, western blot analysis showed decreased S1PR1, PCNA, BCL-XL, cyclinD1 and increased cleaved caspase-3 in S1PR1 knockdown cells, suggesting that silencing S1PR1 expression may induce cell death through apoptotic pathways (Fig.	('PCNA', 'Gene', (60, 64))	('increased', 'PosReg', (87, 96))	('cyclinD1', 'Gene', '595', (74, 82))	('induce', 'PosReg', (188, 194))	('PCNA', 'Gene', '5111', (60, 64))	('cell death', 'CPA', (195, 205))	('caspase-3', 'Gene', '836', (105, 114))	('cyclinD1', 'Gene', (74, 82))	('caspase-3', 'Gene', (105, 114))	('BCL-XL', 'Gene', (66, 72))	('S1PR1', 'MPA', (53, 58))	('silencing', 'Var', (157, 166))	('apoptotic pathways', 'Pathway', (214, 232))	('decreased', 'NegReg', (43, 52))	('S1PR1', 'Gene', (167, 172))	('BCL-XL', 'Gene', '598', (66, 72))
765668	31438989	To further investigate how S1PR1 promote proliferation and inhibited apoptosis of ESCC cells, GSEA of TCGA database was used, and we found that S1PR1 was positively correlated with the STAT3 pathway in ESCC (Fig.	('promote', 'PosReg', (33, 40))	('GSEA', 'Chemical', '-', (94, 98))	('inhibited', 'NegReg', (59, 68))	('ESCC', 'Disease', (202, 206))	('S1PR1', 'Var', (144, 149))	('apoptosis', 'CPA', (69, 78))	('STAT3 pathway', 'Pathway', (185, 198))	('S1PR1', 'Var', (27, 32))	('proliferation', 'CPA', (41, 54))	('correlated', 'Reg', (165, 175))
765673	31438989	4e, four STAT3 target genes (BCL-XL, myc, Timp-1, and cyclinD1) were decreased when S1PR1 was downregulated by small interfering RNA, and opposite results were observed after S1PR1 was upregulated (Fig.	('Timp-1', 'Gene', (42, 48))	('BCL-XL', 'Gene', '598', (29, 35))	('myc', 'Gene', '4609', (37, 40))	('decreased', 'NegReg', (69, 78))	('cyclinD1', 'Gene', '595', (54, 62))	('cyclinD1', 'Gene', (54, 62))	('S1PR1', 'Gene', (84, 89))	('BCL-XL', 'Gene', (29, 35))	('small interfering', 'Var', (111, 128))	('downregulated', 'NegReg', (94, 107))	('myc', 'Gene', (37, 40))	('Timp-1', 'Gene', '7076', (42, 48))
765674	31438989	To investigate whether S1PR1 promotes ESCC proliferation through the STAT3 signaling pathway in ESCC cells, we inhibited p-STAT3 with SH-4-54 (phosphorylated STAT3 inhibitor as previously reported).	('STAT3 signaling pathway', 'Pathway', (69, 92))	('S1PR1', 'Var', (23, 28))	('SH-4-54', 'Chemical', '-', (134, 141))	('ESCC', 'Disease', (38, 42))	('inhibited', 'NegReg', (111, 120))	('promotes', 'PosReg', (29, 37))
765675	31438989	We observed that kyse150 and TE-13 cells with high level of S1PR1 were more resistant to SH-4-54 than those with a low level of S1PR1 (Additional file 1: Figure S4A, B).	('TE-13', 'Chemical', '-', (29, 34))	('resistant', 'MPA', (76, 85))	('S1PR1', 'Var', (60, 65))	('SH-4-54', 'Chemical', '-', (89, 96))
765678	31438989	To further validate these results, SH-4-54 was added into cells following overexpression of S1PR1, and the effects induced by S1PR1 overexpression were significantly inhibited.	('S1PR1', 'Var', (92, 97))	('overexpression', 'PosReg', (74, 88))	('inhibited', 'NegReg', (166, 175))	('SH-4-54', 'Chemical', '-', (35, 42))
765679	31438989	Besides, the upregulation of PCNA and p-STAT3, BCL-XL induced by LV-S1PR1 was reversed in the ESCC cell (Fig.	('LV-S1PR1', 'Var', (65, 73))	('PCNA', 'Gene', '5111', (29, 33))	('BCL-XL', 'Gene', '598', (47, 53))	('upregulation', 'PosReg', (13, 25))	('p-STAT3', 'MPA', (38, 45))	('BCL-XL', 'Gene', (47, 53))	('PCNA', 'Gene', (29, 33))
765684	31438989	Compared to the group only with S1PR1 expression interference, combination of S1PR1 knockdown and SH-4-54 induced a significant reduction in tumor growth.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('SH-4-54', 'Gene', (98, 105))	('reduction', 'NegReg', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('knockdown', 'Var', (84, 93))	('tumor', 'Disease', (141, 146))	('SH-4-54', 'Chemical', '-', (98, 105))	('S1PR1', 'Gene', (78, 83))
765690	31438989	Bioinformatics analysis of big data has revealed that aberrant expression of some factors, which act as potential biomarkers for cancer diagnosis or prognosis, may be critical in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('aberrant expression', 'Var', (54, 73))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))
765699	31438989	Consistent with previous studies, our results indicated that silencing S1PR1 expression induced apoptosis in kyse150 and TE-13 cells, while S1PR1 overexpression decreased the apoptosis rate of ESCC cells.	('TE-13', 'Chemical', '-', (121, 126))	('S1PR1', 'Gene', (71, 76))	('silencing', 'Var', (61, 70))	('apoptosis', 'CPA', (96, 105))
765705	31438989	STAT3, as a critical transcription factor, was highly phosphorylated in tumorigenesis and the level of phosphorylation was associated with worse prognosis in several cancers, including prostate cancer, HCC, and pancreatic cancer.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('pancreatic cancer', 'Disease', 'MESH:D010190', (211, 228))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('pancreatic cancer', 'Disease', (211, 228))	('prostate cancer', 'Disease', (185, 200))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancers', 'Disease', (166, 173))	('tumor', 'Disease', (72, 77))	('HCC', 'Gene', '619501', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (211, 228))	('phosphorylation', 'Var', (103, 118))	('associated', 'Reg', (123, 133))	('HCC', 'Gene', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('STAT3', 'Gene', (0, 5))
765708	31438989	The phosphorylation of the tyrosine residue (Y705) of STAT3 was firstly identified.	('tyrosine', 'Chemical', 'MESH:D014443', (27, 35))	('phosphorylation', 'MPA', (4, 19))	('STAT3', 'Gene', (54, 59))	('Y705', 'Var', (45, 49))
765710	31438989	Furthermore, it has been known that S1PR1 could be coupled to Gi, and then activates downstream kinases including tyrosine kinases (Src, Ras, JAK2) and serine/threonine kinases (GRKs and CamK) which both could induce STAT3 activation.	('JAK2', 'Gene', (142, 146))	('CamK', 'Gene', '814', (187, 191))	('tyrosine', 'Chemical', 'MESH:D014443', (114, 122))	('tyrosine kinases', 'MPA', (114, 130))	('CamK', 'Gene', (187, 191))	('coupled', 'Interaction', (51, 58))	('S1PR1', 'Var', (36, 41))	('JAK2', 'Gene', '3717', (142, 146))	('activates', 'PosReg', (75, 84))	('serine', 'Chemical', 'MESH:D012694', (152, 158))	('serine/threonine kinases', 'MPA', (152, 176))	('STAT3 activation', 'MPA', (217, 233))
765711	31438989	Mechanically, it has been also reported that that S1PR1 induced JAK2/STAT3 activation through Y705 phosphorylation of STAT3, while induced mTOR/STAT3 activation through S727 phosphorylation of STAT3.	('Y705', 'Var', (94, 98))	('S727 phosphorylation', 'Var', (169, 189))	('STAT3', 'Protein', (118, 123))	('mTOR', 'Gene', (139, 143))	('activation', 'PosReg', (150, 160))	('JAK2', 'Gene', (64, 68))	('activation', 'PosReg', (75, 85))	('mTOR', 'Gene', '2475', (139, 143))	('S1PR1', 'Var', (50, 55))	('JAK2', 'Gene', '3717', (64, 68))
765713	31438989	Interestingly, S1PR1 was also one of the target genes of STAT3 and S1PR1/STAT3 formed a positive feedback loop, which might play important roles in the progression of pancreatic cancer.	('roles', 'Reg', (139, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('S1PR1/STAT3', 'Var', (67, 78))	('pancreatic cancer', 'Disease', (167, 184))	('play', 'Reg', (124, 128))
765714	31438989	Patients with high expression of S1PR1 had a poorer prognosis, indicating S1PR1 could be an effective prognostic predictor for ESCC patients.	('ESCC', 'Disease', (127, 131))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('S1PR1', 'Gene', (33, 38))	('patients', 'Species', '9606', (132, 140))
765803	30171413	reported a significantly lower incidence of stenosis in 29 patients with esophageal cancer who underwent endoscopic resection lesions involving > 3/4th of the esophageal circumference and received prophylactic balloon dilatation begun within 1 week after the operation, as compared to a group that did not receive prophylactic balloon dilatation.	('dilatation', 'Phenotype', 'HP:0002617', (335, 345))	('stenosis', 'MPA', (44, 52))	('esophageal cancer', 'Disease', (73, 90))	('lesions', 'Var', (126, 133))	('lower', 'NegReg', (25, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (59, 67))	('dilatation', 'Phenotype', 'HP:0002617', (218, 228))
765818	30171413	conducted a randomized comparative study of radiotherapy and chemoradiotherapy in patients with T1-3 N0-1 M0 esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('M0 esophageal cancer', 'Disease', (106, 126))	('M0 esophageal cancer', 'Disease', 'MESH:D004938', (106, 126))	('patients', 'Species', '9606', (82, 90))	('T1-3 N0-1', 'Var', (96, 105))	('M0 esophageal cancer', 'Phenotype', 'HP:0011459', (106, 126))
765822	30171413	A prospective phase II clinical study (the JCOG9708 Study) conducted in Japan revealed promising results of chemoradiotherapy (60 Gy, cisplatin + 5-fluorouracil [5-FU]) in cStage I cases, with a complete response rate of 87.5%, 4-year survival rate of 80.5%, and 4-year recurrence-free survival rate of 68.1%, with no occurrences of any Grade >= 4 adverse events.	('JCOG9708', 'CellLine', 'None', (43, 51))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (146, 160))	('cisplatin', 'Var', (134, 143))	('5-FU', 'Chemical', 'MESH:D005472', (162, 166))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('cStage', 'Disease', (172, 178))
766042	31114287	Similarly, reports in Linxian, China showed that general undernourishment, as well as deficiencies in selenium, zinc, folate, riboflavin and vitamins A, C, E and B12 were linked with amplified risk of ESCC.	('men', 'Species', '9606', (69, 72))	('riboflavin', 'Protein', (126, 136))	('deficiencies', 'Var', (86, 98))	('folate', 'Chemical', 'MESH:D005492', (118, 124))	('selenium', 'Chemical', 'MESH:D012643', (102, 110))	('selenium', 'Protein', (102, 110))	('riboflavin', 'Chemical', 'MESH:D012256', (126, 136))	('ESCC', 'Disease', (201, 205))
766051	31114287	Linoleic acid is used to synthesize prostaglandins, and therefore, high levels of linoleic acid lead to increased PGE2 activity in the stomach.	('PGE2', 'Enzyme', (114, 118))	('increased', 'PosReg', (104, 113))	('linoleic acid', 'Var', (82, 95))	('Linoleic acid', 'Chemical', 'MESH:D019787', (0, 13))	('linoleic acid', 'Chemical', 'MESH:D019787', (82, 95))	('activity', 'MPA', (119, 127))	('PGE2', 'Chemical', 'MESH:D015232', (114, 118))	('prostaglandins', 'Chemical', 'MESH:D011453', (36, 50))
766052	31114287	PGE2 represses gastric acid secretion and leads to a reduction in the tone of the muscles that control pyloric and lower esophageal sphincters.	('PGE2', 'Chemical', 'MESH:D015232', (0, 4))	('reduction', 'NegReg', (53, 62))	('PGE2', 'Var', (0, 4))	('esophageal', 'Disease', (121, 131))	('represses', 'NegReg', (5, 14))	('gastric acid secretion', 'MPA', (15, 37))	('esophageal', 'Disease', 'MESH:D004941', (121, 131))
766078	31114287	A large percentage of the genetic variations that occur in the human genome are due to SNPs.	('due', 'Reg', (80, 83))	('genetic variations', 'Var', (26, 44))	('SNPs', 'Disease', (87, 91))	('human', 'Species', '9606', (63, 68))
766084	31114287	Variations at 10q23 in PLCE1 were linked with ESCC (Table 3).	('ESCC', 'Disease', (46, 50))	('PLCE1', 'Gene', (23, 28))	('Variations at 10q23', 'Var', (0, 19))	('PLCE1', 'Gene', '51196', (23, 28))	('linked', 'Reg', (34, 40))
766085	31114287	Alteration in the riboflavin transporter C20 ORF54 on chromosome 20p13 is a risk factor for ESCC.	('ESCC', 'Disease', (92, 96))	('risk factor', 'Reg', (76, 87))	('Alteration', 'Var', (0, 10))	('C20 ORF54', 'Gene', (41, 50))	('riboflavin', 'Chemical', 'MESH:D012256', (18, 28))	('C20 ORF54', 'Gene', '113278', (41, 50))
766086	31114287	ESCC is related to polymorphisms of the ADH enzymes ALDH2 and ADH1B1.	('related', 'Reg', (8, 15))	('polymorphisms', 'Var', (19, 32))	('ADH', 'Gene', '124', (62, 65))	('ADH', 'Gene', (40, 43))	('ALDH2', 'Gene', '217', (52, 57))	('ADH', 'Gene', (62, 65))	('ESCC', 'Disease', (0, 4))	('ADH1B', 'Gene', (62, 67))	('ALDH2', 'Gene', (52, 57))	('ADH1B', 'Gene', '125', (62, 67))	('ADH', 'Gene', '124', (40, 43))
766089	31114287	A significant polymorphism dealing with a single C to T replacement at nucleotide 609 of exon 6 in the NQO1 cDNA affects the NQO1 enzyme activity that induces a Pro187Ser amino acid substitution.	('NQO1', 'Gene', '1728', (125, 129))	('NQO1', 'Gene', '1728', (103, 107))	('Pro187Ser', 'SUBSTITUTION', 'None', (161, 170))	('affects', 'Reg', (113, 120))	('C to T replacement', 'Var', (49, 67))	('Pro187Ser', 'Var', (161, 170))	('induces', 'Reg', (151, 158))	('C to T replacement at nucleotide 609', 'Mutation', 'rs1800566', (49, 85))	('activity', 'MPA', (137, 145))	('NQO1', 'Gene', (103, 107))	('NQO1', 'Gene', (125, 129))
766090	31114287	The NQO1 C609T polymorphism has been related to ECs.	('C609T', 'Var', (9, 14))	('related', 'Reg', (37, 44))	('C609T', 'Mutation', 'rs1800566', (9, 14))	('NQO1', 'Gene', (4, 8))	('ECs', 'Disease', (48, 51))	('NQO1', 'Gene', '1728', (4, 8))
766092	31114287	A meta-analysis showed that the NQO1 C609T polymorphism considerably increases the risk of developing EC.	('increases', 'PosReg', (69, 78))	('NQO1', 'Gene', (32, 36))	('C609T', 'Var', (37, 42))	('NQO1', 'Gene', '1728', (32, 36))	('C609T', 'Mutation', 'rs1800566', (37, 42))
766096	31114287	Mutations and polymorphisms that affect the functioning of these enzymes may affect the ability of the individual to detoxify ethanol, leading to increased exposure of cells to carcinogens such as acetyl aldehyde which is dissolved in the saliva following consumption of alcohol or smoking tobacco (Table 4).	('exposure', 'MPA', (156, 164))	('ability', 'MPA', (88, 95))	('tobacco', 'Species', '4097', (290, 297))	('acetyl aldehyde', 'Chemical', 'MESH:D000079', (197, 212))	('increased', 'PosReg', (146, 155))	('affect', 'Reg', (77, 83))	('Mutations', 'Var', (0, 9))	('alcohol', 'Chemical', 'MESH:D000438', (271, 278))	('detoxify ethanol', 'MPA', (117, 133))	('ethanol', 'Chemical', 'MESH:D000431', (126, 133))
766097	31114287	There is a guanine to adenine SNP within ALDH2 at position 1510, which leads to a lysine at codon position 487.	('guanine', 'Chemical', 'MESH:D006147', (11, 18))	('lysine at codon', 'MPA', (82, 97))	('ALDH2', 'Gene', '217', (41, 46))	('guanine to', 'Var', (11, 21))	('adenine', 'Chemical', 'MESH:D000225', (22, 29))	('lysine', 'Chemical', 'MESH:D008239', (82, 88))	('ALDH2', 'Gene', (41, 46))	('leads to', 'Reg', (71, 79))
766100	31114287	The ADH 1B *two mutant allele results from an SNP in Exon 3 of ADH1B, resulting in a His to Arg substitution at codon 48.	('ADH 1B', 'Gene', (4, 10))	('in a', 'Reg', (80, 84))	('ADH 1B', 'Gene', '125', (4, 10))	('His', 'MPA', (85, 88))	('results from', 'Reg', (30, 42))	('SNP in', 'Var', (46, 52))	('His to Arg substitution at codon 48', 'Mutation', 'rs1229984', (85, 120))	('ADH1B', 'Gene', (63, 68))	('ADH1B', 'Gene', '125', (63, 68))
766106	31114287	This occurs in a manner associated with the number of ADH 1B *one alleles present, with *1/*one homozygous having a greater risk for developing EC than the *1/*two allele.	('ADH 1B', 'Gene', '125', (54, 60))	('ADH 1B', 'Gene', (54, 60))	('*1/*one', 'Var', (88, 95))
766109	31114287	Mutations affecting the function of ALDH2 are so prevalent among East Asian population groups that it is common for individuals in these population groups to have a flushed skin or red blotches on their face, neck and shoulders following consumption of alcohol.	('alcohol', 'Chemical', 'MESH:D000438', (253, 260))	('flushed skin', 'Disease', (165, 177))	('ALDH2', 'Gene', (36, 41))	('Mutations', 'Var', (0, 9))	('flush', 'Phenotype', 'HP:0031284', (165, 170))	('flushed skin', 'Disease', 'MESH:D005483', (165, 177))	('ALDH2', 'Gene', '217', (36, 41))
766112	31114287	This rash results from excess acetyl aldehyde, with the polymorphism most commonly associated with the flush response being the rs671 allele of ALDH2.	('flush response', 'Disease', (103, 117))	('rash', 'Disease', (5, 9))	('ALDH2', 'Gene', '217', (144, 149))	('rash', 'Phenotype', 'HP:0000988', (5, 9))	('acetyl aldehyde', 'Chemical', 'MESH:D000079', (30, 45))	('excess', 'PosReg', (23, 29))	('ALDH2', 'Gene', (144, 149))	('associated', 'Reg', (83, 93))	('rs671', 'Var', (128, 133))	('flush', 'Phenotype', 'HP:0031284', (103, 108))	('rs671', 'Mutation', 'rs671', (128, 133))	('rash', 'Disease', 'MESH:D005076', (5, 9))	('acetyl aldehyde', 'MPA', (30, 45))
766113	31114287	This mutation in ALDH2 and the flush reaction occur in 30%-50% of South East Asians, but it is extremely rare in Europeans and sub-Saharan Africans (Tanzania =0.0025%).	('ALDH2', 'Gene', '217', (17, 22))	('ALDH2', 'Gene', (17, 22))	('flush reaction', 'Disease', (31, 45))	('flush reaction', 'Disease', 'MESH:D005483', (31, 45))	('flush', 'Phenotype', 'HP:0031284', (31, 36))	('mutation', 'Var', (5, 13))
766128	31114287	There are four major subfamilies of human GST genes, which are divided into the categories GST A, M, T and P. Deletion polymorphisms have been observed in two of these families, GSTM1 and GSTT1.	('GST', 'Gene', '373156', (188, 191))	('GST', 'Gene', (42, 45))	('GST', 'Gene', '373156', (178, 181))	('GST', 'Gene', '373156', (42, 45))	('GSTT1', 'Gene', '2952', (188, 193))	('GSTT1', 'Gene', (188, 193))	('P. Deletion polymorphisms', 'Var', (107, 132))	('GST', 'Gene', (91, 94))	('GSTM1', 'Gene', '2944', (178, 183))	('GST', 'Gene', (188, 191))	('human', 'Species', '9606', (36, 41))	('GSTM1', 'Gene', (178, 183))	('GST', 'Gene', (178, 181))	('GST', 'Gene', '373156', (91, 94))
766129	31114287	Polymorphisms of GSTM 1, GSTT1 and GSTP1 have been demonstrated to be linked to susceptibility to various forms of cancer.	('cancer', 'Disease', (115, 121))	('GSTM 1', 'Gene', '2944', (17, 23))	('Polymorphisms', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('GSTP1', 'Gene', (35, 40))	('linked to susceptibility', 'Reg', (70, 94))	('GSTT1', 'Gene', '2952', (25, 30))	('GSTM 1', 'Gene', (17, 23))	('GSTT1', 'Gene', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('GSTP1', 'Gene', '2950', (35, 40))
766132	31114287	Polymorphisms of GSTP1 take part in EC within a pathway of malfunctions in the p53 malignant tumor suppressor gene, which is prevalent in ESCC.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('prevalent', 'Reg', (125, 134))	('malignant tumor', 'Disease', (83, 98))	('Polymorphisms', 'Var', (0, 13))	('GSTP1', 'Gene', (17, 22))	('take part', 'Reg', (23, 32))	('malignant tumor', 'Disease', 'MESH:D018198', (83, 98))	('GSTP1', 'Gene', '2950', (17, 22))	('ESCC', 'Disease', (138, 142))
766136	31114287	These genes affect processes such as proliferation, apoptosis, as well as the motility and invasiveness of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('genes', 'Var', (6, 11))	('affect', 'Reg', (12, 18))	('proliferation', 'CPA', (37, 50))	('apoptosis', 'CPA', (52, 61))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (91, 113))	('invasiveness of cancer', 'Disease', (91, 113))	('motility', 'CPA', (78, 86))
766138	31114287	Silencing of cancer genes mainly occurs through DNA methylation.	('DNA methylation', 'Var', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Silencing', 'NegReg', (0, 9))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))
766139	31114287	Hence, DNA methylation has a role in the deregulation of miRNAs in cancer, and miR-145, miR-30a-3p, miR133a and miR-133b are the possible tumor promoters.	('miR-145', 'Gene', (79, 86))	('miR-133b', 'Gene', (112, 120))	('miRNAs', 'Protein', (57, 63))	('miR-145', 'Gene', '406937', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (138, 143))	('miR133a', 'Var', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('miR-133b', 'Gene', '442890', (112, 120))	('miR-30a-3p', 'Var', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('deregulation', 'MPA', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
766140	31114287	In South Africa, the polymorphisms in miRNA genes have been connected to many cancer types along with ESCC.	('connected', 'Reg', (60, 69))	('ESCC', 'Disease', (102, 106))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('miRNA genes', 'Gene', (38, 49))	('polymorphisms', 'Var', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
766141	31114287	In black South Africans, a polymorphism in miRNA 3184, known as rs6505162, results in associated risks for ESCC.	('polymorphism', 'Var', (27, 39))	('rs6505162', 'Mutation', 'rs6505162', (64, 73))	('miRNA 3184', 'Gene', (43, 53))	('risks', 'Reg', (97, 102))
766142	31114287	The location of the rs6505162 SNP allows it to influence two different miRNAs and a single protein coding gene.	('influence', 'Reg', (47, 56))	('rs6505162', 'Var', (20, 29))	('rs6505162', 'Mutation', 'rs6505162', (20, 29))
766144	31114287	The two miRNAs, miR-423 and miR-3184, are oppositely oriented and overlap at rs6505162.	('miR-3184', 'Gene', (28, 36))	('miR-423', 'Gene', (16, 23))	('miR-3184', 'Gene', '100423003', (28, 36))	('rs6505162', 'Mutation', 'rs6505162', (77, 86))	('miR-423', 'Gene', '494335', (16, 23))	('rs6505162', 'Var', (77, 86))
766146	31114287	Therefore, it is more likely that rs6505162 influences the transcription of miR-3184 rather than that of miR-423.	('rs6505162', 'Var', (34, 43))	('miR-423', 'Gene', (105, 112))	('transcription', 'MPA', (59, 72))	('miR-3184', 'Gene', (76, 84))	('miR-3184', 'Gene', '100423003', (76, 84))	('miR-423', 'Gene', '494335', (105, 112))	('rs6505162', 'Mutation', 'rs6505162', (34, 43))	('influences', 'Reg', (44, 54))
766148	31114287	It was found that the rs6505162 polymorphism was related to increased cancer risk in black African patients who lived in an environment where they were subjected to high levels of smoke inhalation.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('men', 'Species', '9606', (131, 134))	('patients', 'Species', '9606', (99, 107))	('rs6505162', 'Mutation', 'rs6505162', (22, 31))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('rs6505162', 'Var', (22, 31))
766149	31114287	Two other SNPs previously identified as playing a role in EC, rs213210 (miR219-1) and rs7372209 (miR26a-1), were found to interact in both the black and mixed ancestry populations to reduce the risk of cancer development.	('rs213210', 'Mutation', 'rs213210', (62, 70))	('men', 'Species', '9606', (216, 219))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('miR26a-1', 'Gene', (97, 105))	('miR219-1', 'Gene', (72, 80))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('miR26a-1', 'Gene', '407015', (97, 105))	('rs213210', 'Var', (62, 70))	('cancer', 'Disease', (202, 208))	('rs7372209', 'Mutation', 'rs7372209', (86, 95))	('rs7372209', 'Var', (86, 95))	('reduce', 'NegReg', (183, 189))	('miR219-1', 'Gene', '407002', (72, 80))
766150	31114287	Individuals with the genotype AArs213210-CTrs7372209 had a reduced risk of developing ESCC.	('rs7372209', 'Mutation', 'rs7372209', (43, 52))	('AArs213210-CTrs7372209', 'Var', (30, 52))	('reduced', 'NegReg', (59, 66))	('rs213210', 'Mutation', 'rs213210', (32, 40))	('ESCC', 'Disease', (86, 90))
766151	31114287	The SNP rs2910164 C > G in miR-146a increases the risk of individuals developing ESCC within the Han Chinese population, and the increased risk posed by the rs2910164 GG genotype was more notable in cigarette smokers.	('rs2910164', 'Mutation', 'rs2910164', (8, 17))	('ESCC', 'Disease', (81, 85))	('miR-146a', 'Gene', (27, 35))	('rs2910164', 'Var', (157, 166))	('rs2910164', 'Mutation', 'rs2910164', (157, 166))	('SNP rs2910164 C > G', 'Var', (4, 23))	('miR-146a', 'Gene', '406938', (27, 35))
766152	31114287	The rs11614913 TC polymorphism in miR-196a2 is predicted to reduce ESCC risk among females who have never smoked or consumed alcohol.	('TC', 'Chemical', 'MESH:D013667', (15, 17))	('ESCC', 'Disease', (67, 71))	('reduce', 'NegReg', (60, 66))	('rs11614913 TC', 'Var', (4, 17))	('rs11614913', 'Mutation', 'rs11614913', (4, 14))	('miR-196a2', 'Gene', (34, 43))	('miR-196a2', 'Gene', '406973', (34, 43))	('alcohol', 'Chemical', 'MESH:D000438', (125, 132))
766153	31114287	However, in males or those who smoke and drink, the miR-196a2 r s11614913 TC, CC or TC/CC genotype may play a role in increasing the risk of developing ESCC.	('miR-196a2', 'Gene', '406973', (52, 61))	('TC', 'Chemical', 'MESH:D013667', (84, 86))	('TC', 'Chemical', 'MESH:D013667', (74, 76))	('r s11614913', 'Var', (62, 73))	('miR-196a2', 'Gene', (52, 61))	('ESCC', 'Disease', (152, 156))
766154	31114287	Similarly, individuals who did not smoke or drink alcohol and possessed the hsa-miR-34b/c rs4938723 CC genotype had a reduced threat of ESCC.	('alcohol', 'Chemical', 'MESH:D000438', (50, 57))	('miR-34b', 'Gene', '407041', (80, 87))	('reduced', 'NegReg', (118, 125))	('rs4938723 CC', 'Var', (90, 102))	('rs4938723', 'Mutation', 'rs4938723', (90, 99))	('miR-34b', 'Gene', (80, 87))
766155	31114287	The risk of developing ESCC is increased by the SNPs rs6505162 C.A in Hsa-miR-423 and rs531564 CG SNP in pri-miR-124-1.	('rs531564', 'Mutation', 'rs531564', (86, 94))	('ESCC', 'Disease', (23, 27))	('Hsa-miR-423', 'Gene', (70, 81))	('miR-124-1', 'Gene', '406907', (109, 118))	('Hsa-miR-423', 'Gene', '494335', (70, 81))	('rs6505162', 'Mutation', 'rs6505162', (53, 62))	('miR-124-1', 'Gene', (109, 118))	('rs531564 CG', 'Var', (86, 97))	('rs6505162 C.A', 'Var', (53, 66))
766162	31114287	MSI is characterized by increased mutations in microsatellites that arise due to germline MMR gene mutations causing Lynch syndrome.	('Lynch syndrome', 'Disease', (117, 131))	('MMR', 'Gene', (90, 93))	('Lynch syndrome', 'Disease', 'MESH:D003123', (117, 131))	('mutations', 'Var', (99, 108))	('microsatellites', 'Protein', (47, 62))	('MSI', 'Gene', (0, 3))	('causing', 'Reg', (109, 116))	('MSI', 'Gene', '5928', (0, 3))	('mutations', 'Var', (34, 43))
766163	31114287	MSI can also be caused through the epigenetic inactivation of the MLH1 gene and the CpG island methylator phenotype as a consequence of MLH1 hyper-methylation.	('hyper-methylation', 'Var', (141, 158))	('MLH1', 'Gene', '4292', (136, 140))	('MLH1', 'Gene', (136, 140))	('epigenetic inactivation', 'Var', (35, 58))	('MLH1', 'Gene', '4292', (66, 70))	('caused', 'Reg', (16, 22))	('MLH1', 'Gene', (66, 70))	('MSI', 'Gene', (0, 3))	('MSI', 'Gene', '5928', (0, 3))
766167	31114287	In black South Africans, no association between MMR polymorphisms and cancer risk was observed at the SNP level.	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('polymorphisms', 'Var', (52, 65))
766169	31114287	A polymorphism within the DNA repair associated gene MSH3 (Table 6) may interact with cigarette in some cases of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('MSH3', 'Gene', (53, 57))	('MSH3', 'Gene', '4437', (53, 57))	('carcinogenesis', 'Disease', (113, 127))	('interact', 'Reg', (72, 80))	('polymorphism', 'Var', (2, 14))
766172	31114287	Therefore, any mutation or polymorphism decreasing MSH3 activity may increase the risk of developing EC.	('polymorphism', 'Var', (27, 39))	('mutation', 'Var', (15, 23))	('activity', 'MPA', (56, 64))	('decreasing', 'NegReg', (40, 50))	('MSH3', 'Gene', (51, 55))	('MSH3', 'Gene', '4437', (51, 55))
766174	31114287	Promoter methylation in the ML1 promoter of male Han Chinese ESCC patients is associated with a poor prognosis.	('ML1', 'Gene', '51761', (28, 31))	('ML1', 'Gene', (28, 31))	('Promoter methylation', 'Var', (0, 20))	('Pro', 'Chemical', 'MESH:D011392', (0, 3))	('patients', 'Species', '9606', (66, 74))
766191	31114287	One line of evidence that suggests this is the increased levels of estradiol, which is an estrogen receptor agonist, in patients with ESCC, further suggesting that low levels of estrogen are associated with an increased risk of ESCC.	('ESCC', 'Disease', (228, 232))	('increased levels of estradiol', 'Phenotype', 'HP:0025134', (47, 76))	('low levels', 'Var', (164, 174))	('patients', 'Species', '9606', (120, 128))	('estradiol', 'Chemical', 'MESH:D004958', (67, 76))
766196	31114287	Mutations in Cyp1B1 that result in a GG substitution rather than the GA in normal copies decrease the efficacy of the enzyme.	('Cyp1B1', 'Gene', (13, 19))	('substitution', 'Var', (40, 52))	('efficacy', 'MPA', (102, 110))	('decrease', 'NegReg', (89, 97))	('Mutations', 'Var', (0, 9))	('Cyp1B1', 'Gene', '1545', (13, 19))	('enzyme', 'MPA', (118, 124))
766197	31114287	South African individuals homozygous for the mutant allele (GG), and therefore possessing a less-efficient CYP1B1, had a lower risk of developing ESCC.	('mutant', 'Var', (45, 51))	('CYP1B1', 'Gene', (107, 113))	('ESCC', 'Disease', (146, 150))	('CYP1B1', 'Gene', '1545', (107, 113))
766212	31114287	The function and activity of a mutant GSTP1 protein that has an Ile-to-Val substitution (rs947894) are decreased.	('Ile', 'Chemical', 'MESH:D007532', (64, 67))	('rs947894', 'Var', (89, 97))	('rs947894', 'Mutation', 'rs947894', (89, 97))	('function', 'MPA', (4, 12))	('GSTP1', 'Gene', (38, 43))	('decreased', 'NegReg', (103, 112))	('Val', 'Chemical', 'MESH:D014633', (71, 74))	('GSTP1', 'Gene', '2950', (38, 43))	('activity', 'MPA', (17, 25))	('protein', 'Protein', (44, 51))
766213	31114287	This mutant protein is the result of a polymorphism in the GSTP1 gene at codon 105.	('GSTP1', 'Gene', '2950', (59, 64))	('result of', 'Reg', (27, 36))	('polymorphism', 'Var', (39, 51))	('GSTP1', 'Gene', (59, 64))
766214	31114287	Mutations in the p53 gene are prevalent in all cancers including EC.	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('prevalent', 'Reg', (30, 39))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
766216	31114287	This polymorphism is connected to tumorigenesis in a variety of cancers.	('tumor', 'Disease', (34, 39))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('polymorphism', 'Var', (5, 17))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('connected to', 'Reg', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
766218	31114287	The GSTP1 and p53 gene polymorphisms modify selenium-ESCC relation.	('polymorphisms', 'Var', (23, 36))	('modify', 'Reg', (37, 43))	('GSTP1', 'Gene', (4, 9))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('selenium', 'Chemical', 'MESH:D012643', (44, 52))	('GSTP1', 'Gene', '2950', (4, 9))	('selenium-ESCC relation', 'MPA', (44, 66))
766222	31114287	This risk can then be further increased if the polymorphisms in the GSTP1 and the p53 genes are also present.	('polymorphisms', 'Var', (47, 60))	('GSTP1', 'Gene', '2950', (68, 73))	('GSTP1', 'Gene', (68, 73))	('p53', 'Gene', '7157', (82, 85))	('p53', 'Gene', (82, 85))
766274	30201096	Multiple systematic reviews and meta-analyses show that tCS induce remission in EoE and are safe and well-tolerated in the short term, although studies vary in medication type, dosing, method of administration, and duration of treatment, and discontinuation of therapy results in recurrence of active disease.	('EoE', 'Disease', (80, 83))	('tCS', 'Var', (56, 59))	('tCS', 'Chemical', '-', (56, 59))	('active disease', 'Disease', (294, 308))	('EoE', 'Phenotype', 'HP:0410151', (80, 83))
766326	30201096	Many children also exhibited delayed oral motor skills required for feeding, as EoE during early formative years hinders the natural development of these skills.	('EoE', 'Var', (80, 83))	('hinders', 'NegReg', (113, 120))	('children', 'Species', '9606', (5, 13))	('oral motor skills', 'CPA', (37, 54))	('delayed oral motor skills', 'Phenotype', 'HP:0002194', (29, 54))	('natural development of', 'CPA', (125, 147))	('EoE', 'Phenotype', 'HP:0410151', (80, 83))
766366	30201096	There have been two randomized controlled trials with anti-IL-13 agents, the most recent of which was a phase 2 study with RPC4046 showing promising results.	('RPC4046', 'Var', (123, 130))	('IL-13', 'Gene', '3596', (59, 64))	('IL-13', 'Gene', (59, 64))
766505	28979708	Firstly, staining with Lugol's iodine is known to cause retrosternal chest discomfort and carries a risk of allergic reaction.	('cause', 'Reg', (50, 55))	('allergic reaction', 'Disease', 'MESH:D004342', (108, 125))	('retrosternal chest discomfort', 'Disease', (56, 85))	('iodine', 'Chemical', 'MESH:D007455', (31, 37))	('staining', 'Var', (9, 17))	("Lugol's", 'Chemical', 'MESH:C010389', (23, 30))	('allergic reaction', 'Disease', (108, 125))	('chest discomfort', 'Phenotype', 'HP:0100749', (69, 85))	('allergic reaction', 'Phenotype', 'HP:0012393', (108, 125))
766511	28979708	IEE augments the detection, diagnosis and treatment of esophageal SCN.	('esophageal SCN', 'Disease', 'MESH:D004941', (55, 69))	('esophageal SCN', 'Disease', (55, 69))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('augments', 'PosReg', (4, 12))	('IEE', 'Var', (0, 3))	('SCN', 'Phenotype', 'HP:0002860', (66, 69))
766594	28979708	Two patients progressed in spite of RFA (MGIN to HGIN and HGIN to SCC respectively) however both were treated endoscopically and achieved complete response with additional ablations.	('I', 'Chemical', 'MESH:D007455', (51, 52))	('SCC', 'Gene', (66, 69))	('I', 'Chemical', 'MESH:D007455', (43, 44))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('RFA', 'Var', (36, 39))	('SCC', 'Gene', '6317', (66, 69))	('I', 'Chemical', 'MESH:D007455', (60, 61))	('patients', 'Species', '9606', (4, 12))
766642	28854945	Separation of the lesser curvature of the stomach was done by transecting the ligament of the liver and stomach, protecting the right gastric vessel, upward lifting the stomach, pulling the separated left gastric vessel at the pancreatic upper margin, clipping off the vessel with a biological clip and cutting off with a ultrasonic scalpel, and dissecting the lymph nodes of the left gastric artery, splenic artery, and the common hepatic artery.	('pancreatic', 'Disease', (227, 237))	('dissecting', 'Var', (346, 356))	('stomach', 'MPA', (169, 176))	('pulling', 'Var', (178, 185))	('transecting', 'Var', (62, 73))	('clipping', 'Var', (252, 260))	('pancreatic', 'Disease', 'MESH:D010195', (227, 237))
766677	28854945	In recent years, studies have shown that thoracoscopic esophageal cancer resection can shorten recovery time, reduce lung function damage, reduce the incidence rate of postoperative pulmonary complications, and achieve the same effect as open chest surgery.	('postoperative pulmonary complications', 'Disease', (168, 205))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('reduce lung function', 'Phenotype', 'HP:0005952', (110, 130))	('esophageal cancer', 'Disease', (55, 72))	('open chest surgery', 'Phenotype', 'HP:0002783', (238, 256))	('thoracoscopic', 'Var', (41, 54))	('thoracoscopic esophageal cancer', 'Phenotype', 'HP:0100751', (41, 72))	('recovery time', 'MPA', (95, 108))	('lung function damage', 'Disease', (117, 137))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (168, 205))	('pulmonary complications', 'Phenotype', 'HP:0006532', (182, 205))	('reduce', 'NegReg', (139, 145))	('lung function damage', 'Disease', 'MESH:D008171', (117, 137))	('reduce', 'NegReg', (110, 116))
766696	27599779	Although there was no correlation between the tumor progression and the exosome levels, exosome number was the independent prognostic marker and low levels of exosome predicted a poor prognosis (P=0.03).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('low', 'Var', (145, 148))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
766737	27599779	Fluorescent imaging with GFP revealed intracellular foci existed mainly in the cytoplasm among the TE2-CD63-GFP tumor, and the appearance was similar to that of cultured cells (Fig.	('TE2-CD63-GFP', 'Var', (99, 111))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))
766738	27599779	In addition, the presence of GFP-positive, but RFP-negative, small vesicles were confirmed in isolated exosomes from the plasma of TE2-CD63-GFP tumor-bearing mice (3/4), but no GFP-positive particle was confirmed in the group of TE2 tumor (0/4) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (233, 238))	('mice', 'Species', '10090', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('TE2-CD63-GFP', 'Var', (131, 143))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
766739	27599779	The group of nude mice (BALB/c Slc-nu-nu) with subcutaneous tumor composed of TE2-CD63-GFP (tumor volume, 1042+-293 mm3) had higher amount of plasma exosome (1290+-186x108/ml) than the group of mice without tumor (1007+-162x108/ml) (P=0.048; t-test; Fig.	('TE2-CD63-GFP', 'Var', (78, 90))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (47, 65))	('nude mice', 'Species', '10090', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('Slc', 'Gene', (31, 34))	('mice', 'Species', '10090', (18, 22))	('plasma exosome', 'MPA', (142, 156))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('higher', 'PosReg', (125, 131))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (60, 65))	('mice', 'Species', '10090', (194, 198))	('Slc', 'Gene', '18829', (31, 34))
766740	27599779	Concerning the C3H/He mouse groups, the exosome amounts were 911+-382x108/ml in the group without tumor, 979+-194x108/ml in the group with early cancer (1 week after injection), 695+-170x108/ml in the group with advanced cancer (6 weeks after injection).	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('exosome', 'MPA', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('979+-194x108/ml', 'Var', (105, 120))	('695+-170x108/ml', 'Var', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('mouse', 'Species', '10090', (22, 27))	('tumor', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
766841	24887058	Increased waist to hip ratio, but not BMI, was associated with risk of aneuploidy, 9p loss of heterozygosity (LOH) and 17p LOH, suggesting that visceral adipose tissue may be a risk factor for malignant progression.	('loss of', 'NegReg', (86, 93))	('17p LOH', 'Var', (119, 126))	('aneuploidy', 'Disease', (71, 81))	('Increased waist to hip ratio', 'Phenotype', 'HP:0031819', (0, 28))	('aneuploidy', 'Disease', 'MESH:D000782', (71, 81))
766849	24887058	A combination of low grade dysplasia, abnormal DNA ploidy, and Aspergillus oryzae lectin was most accurate at predicting histologic progression.	('dysplasia', 'Disease', (27, 36))	('Aspergillus oryzae', 'Species', '5062', (63, 81))	('dysplasia', 'Disease', 'MESH:D004476', (27, 36))	('abnormal DNA', 'Var', (38, 50))
766850	24887058	For each additional factor of these three, BE patients with LGD had an approximately 4-fold increased odds of progressing to develop EAC or HGD (OR, 3.74; 95% CI, 2.43 - 5.79), whereas the risk increased by a 3-fold (OR, 3.31; 95% CI, 1.81- 6.05) for each additional factor in patients with no dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (294, 303))	('patients', 'Species', '9606', (46, 54))	('EAC', 'Phenotype', 'HP:0011459', (133, 136))	('BE', 'Phenotype', 'HP:0100580', (43, 45))	('patients', 'Species', '9606', (277, 285))	('HGD', 'Disease', (140, 143))	('EAC', 'Disease', (133, 136))	('dysplasia', 'Disease', (294, 303))	('LGD', 'Var', (60, 63))
766854	24887058	Moreover, the positive predictive value for neoplastic progression increased from 15% with LGD to 33% with LGD and aberrant p53 expression.	('p53', 'Gene', (124, 127))	('p53', 'Gene', '7157', (124, 127))	('neoplastic progression', 'CPA', (44, 66))	('increased', 'PosReg', (67, 76))	('aberrant', 'Var', (115, 123))
766914	22241250	Lastly, in a large study in which statin use was ascertained by pharmacy record, statin use for more than five years was associated with a 70% increased risk of esophageal cancer in men (HR: 1.70; 95% CI: 1.05-2.75), though no association was observed among women, nor was an association observed when exposure was defined by any duration of use.	('esophageal cancer', 'Disease', 'MESH:D004938', (161, 178))	('statin', 'Var', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('women', 'Species', '9606', (258, 263))	('men', 'Species', '9606', (260, 263))	('esophageal cancer', 'Disease', (161, 178))	('men', 'Species', '9606', (182, 185))
766939	33173410	Genes encoding HNF1B transcription factors are prone to various types of mutations, causing the occurrence and progression of various diseases, including diabetes, renal insufficiency, and various malignant tumors.	('diabetes', 'Disease', (154, 162))	('malignant tumors', 'Disease', 'MESH:D009369', (197, 213))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('renal insufficiency', 'Disease', (164, 183))	('HNF1B', 'Gene', '6928', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('HNF1B', 'Gene', (15, 20))	('renal insufficiency', 'Disease', 'MESH:D051437', (164, 183))	('renal insufficiency', 'Phenotype', 'HP:0000083', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('causing', 'Reg', (84, 91))	('malignant tumors', 'Disease', (197, 213))	('mutations', 'Var', (73, 82))
766940	33173410	In the present study, we evaluated expression and mutations of HNF1B in different types of cancer from The Cancer Genome Atlas (TCGA) database.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HNF1B', 'Gene', '6928', (63, 68))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('HNF1B', 'Gene', (63, 68))
766946	33173410	The cBio cancer genomics portal was used to explore mutations and copy-number alterations of HNF1B in the TCGA pan-cancer studies.	('mutations', 'Var', (52, 61))	('HNF1B', 'Gene', (93, 98))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (9, 15))	('copy-number alterations', 'Var', (66, 89))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('HNF1B', 'Gene', '6928', (93, 98))
766960	33173410	As shown in Figure 2A, the mutation types of HNF1B included missense mutations, truncating mutations, in-frame mutations and other mutations.	('truncating', 'MPA', (80, 90))	('HNF1B', 'Gene', (45, 50))	('missense mutations', 'Var', (60, 78))	('in-frame mutations', 'Var', (102, 120))	('HNF1B', 'Gene', '6928', (45, 50))
766962	33173410	Additionally, cancer patients with HNF1B mutations are more susceptible to many other gene mutations, including TP53, TTN, MUC16, CSMD3, SYNE1, ZFHX4, LRP1B, XIRP2, PCLO, FLG, FAT4, DNAH5, HYDIN, PIK3CA, USH2A, HMCN1, RYR2, CSMD1, FAT3 and KMT2D (Figure 2C).	('ZFHX4', 'Gene', (144, 149))	('SYNE1', 'Gene', (137, 142))	('MUC16', 'Gene', '94025', (123, 128))	('HNF1B', 'Gene', (35, 40))	('DNAH5', 'Gene', '1767', (182, 187))	('PIK3CA', 'Gene', (196, 202))	('LRP1B', 'Gene', (151, 156))	('XIRP2', 'Gene', (158, 163))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', '7157', (112, 116))	('HYDIN', 'Gene', (189, 194))	('PCLO', 'Gene', (165, 169))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('FAT3', 'Gene', (231, 235))	('SYNE1', 'Gene', '23345', (137, 142))	('TTN', 'Gene', '7273', (118, 121))	('HMCN1', 'Gene', (211, 216))	('mutations', 'Var', (41, 50))	('FLG', 'Gene', (171, 174))	('ZFHX4', 'Gene', '79776', (144, 149))	('FAT4', 'Gene', '79633', (176, 180))	('TTN', 'Gene', (118, 121))	('CSMD3', 'Gene', '114788', (130, 135))	('KMT2D', 'Gene', '8085', (240, 245))	('MUC16', 'Gene', (123, 128))	('CSMD1', 'Gene', '64478', (224, 229))	('DNAH5', 'Gene', (182, 187))	('CSMD1', 'Gene', (224, 229))	('FAT3', 'Gene', '120114', (231, 235))	('FLG', 'Gene', '2312', (171, 174))	('LRP1B', 'Gene', '53353', (151, 156))	('USH2A', 'Gene', (204, 209))	('PIK3CA', 'Gene', '5290', (196, 202))	('HMCN1', 'Gene', '83872', (211, 216))	('CSMD3', 'Gene', (130, 135))	('PCLO', 'Gene', '27445', (165, 169))	('TP53', 'Gene', (112, 116))	('cancer', 'Disease', (14, 20))	('XIRP2', 'Gene', '129446', (158, 163))	('FAT4', 'Gene', (176, 180))	('RYR2', 'Gene', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('HYDIN', 'Gene', '54768', (189, 194))	('KMT2D', 'Gene', (240, 245))	('RYR2', 'Gene', '6262', (218, 222))	('USH2A', 'Gene', '7399', (204, 209))	('HNF1B', 'Gene', '6928', (35, 40))
766980	33173410	As shown in Figure 6A, CD8+ T cell levels were negatively associated with overall survival in the low HNF1B expression group of kidney renal papillary cell carcinoma (KIRP, HR=3.76, P=0.00305) and uveal melanoma (UVM, HR=2.99, P=0.0479).	('CD8', 'Gene', (23, 26))	('kidney renal papillary cell carcinoma', 'Disease', (128, 165))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (135, 165))	('CD8', 'Gene', '925', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (128, 165))	('uveal melanoma', 'Phenotype', 'HP:0007716', (197, 211))	('uveal melanoma', 'Disease', 'MESH:C536494', (197, 211))	('low', 'Var', (98, 101))	('HNF1B', 'Gene', '6928', (102, 107))	('uveal melanoma', 'Disease', (197, 211))	('HNF1B', 'Gene', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('negatively', 'NegReg', (47, 57))
766982	33173410	In the low HNF1B expression group of liver hepatocellular carcinoma (LIHC), CD8+ T cells were revealed to be positively associated with overall survival.	('associated', 'Reg', (120, 130))	('HNF1B', 'Gene', '6928', (11, 16))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (43, 67))	('low', 'Var', (7, 10))	('CD8', 'Gene', '925', (76, 79))	('CD8', 'Gene', (76, 79))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (37, 67))	('liver hepatocellular carcinoma', 'Disease', (37, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('HNF1B', 'Gene', (11, 16))	('overall', 'MPA', (136, 143))
766994	33173410	Moreover, it has been reported that the single nucleotide polymorphism (SNP) of HNF1B can affect the susceptibility of endometrial tumors.	('affect', 'Reg', (90, 96))	('endometrial tumors', 'Disease', 'MESH:D016889', (119, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HNF1B', 'Gene', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('endometrial tumors', 'Disease', (119, 137))	('single nucleotide polymorphism', 'Var', (40, 70))	('HNF1B', 'Gene', '6928', (80, 85))
766995	33173410	conducted gene sequencing studies on endometrial cancer patients and control groups and found that HNF1B gene SNP (rs4430796, G A) can reduce the incidence of endometrial cancer.	('rs4430796', 'Var', (115, 124))	('patients', 'Species', '9606', (56, 64))	('rs4430796', 'Mutation', 'rs4430796', (115, 124))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('endometrial cancer', 'Disease', (37, 55))	('endometrial cancer', 'Phenotype', 'HP:0012114', (37, 55))	('HNF1B', 'Gene', '6928', (99, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('endometrial cancer', 'Disease', 'MESH:D016889', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('HNF1B', 'Gene', (99, 104))	('reduce', 'NegReg', (135, 141))
766998	33173410	Most HNF1B mutations are clustered in the first 4 exons of the gene.	('HNF1B', 'Gene', (5, 10))	('mutations', 'Var', (11, 20))	('HNF1B', 'Gene', '6928', (5, 10))
767000	33173410	A total of 106 HNF1B gene mutations, including gene deletion (34%), missense mutation (31%), frameshift deletion or insertion mutation (15%), nonsense mutation (11%) and splicing point mutation (8%) have been reported.	('frameshift deletion', 'Var', (93, 112))	('HNF1B', 'Gene', '6928', (15, 20))	('HNF1B', 'Gene', (15, 20))	('missense mutation', 'Var', (68, 85))	('insertion mutation', 'Var', (116, 134))	('splicing', 'MPA', (170, 178))	('nonsense mutation', 'Var', (142, 159))	('gene deletion', 'Var', (47, 60))
767001	33173410	According to these results, our study found that HNF1B mutations occurred widely in human cancers and that the most common type is missense mutations.	('cancers', 'Disease', (90, 97))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HNF1B', 'Gene', (49, 54))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('missense mutations', 'Var', (131, 149))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('HNF1B', 'Gene', '6928', (49, 54))
767002	33173410	Additionally, patients with HNF1B mutations are more prone to mutations in other genes, such as TP53, TTN and MUC16.	('TTN', 'Gene', (102, 105))	('mutations', 'Var', (62, 71))	('TP53', 'Gene', (96, 100))	('MUC16', 'Gene', (110, 115))	('TTN', 'Gene', '7273', (102, 105))	('prone', 'Reg', (53, 58))	('MUC16', 'Gene', '94025', (110, 115))	('patients', 'Species', '9606', (14, 22))	('HNF1B', 'Gene', '6928', (28, 33))	('mutations', 'Var', (34, 43))	('TP53', 'Gene', '7157', (96, 100))	('HNF1B', 'Gene', (28, 33))
767014	33173410	HNF1B mutations are widely observed in tumors and interact with different genes in different cancer types, which may be the cause of the distinct prognostic values in cancers.	('interact', 'Reg', (50, 58))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('HNF1B', 'Gene', '6928', (0, 5))	('HNF1B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (39, 45))	('mutations', 'Var', (6, 15))
767200	27904579	Some evidence demonstrated beneficial effects of the procedures in reducing gastric emptying times as well as earlier tolerance of solid diet in patients undergone gastric pull-up surgery, whereas others did not support the use of pyloric drainage procedures in this field.	('gastric emptying times', 'MPA', (76, 98))	('patients', 'Species', '9606', (145, 153))	('gastric emptying', 'Phenotype', 'HP:0002578', (76, 92))	('procedures', 'Var', (53, 63))	('earlier', 'PosReg', (110, 117))	('reducing gastric emptying', 'Phenotype', 'HP:0002578', (67, 92))	('reducing', 'NegReg', (67, 75))	('tolerance of solid diet', 'MPA', (118, 141))
767236	27642589	miRNAs regulate a variety of essential biological functions such as cellular differentiation, apoptosis, and proliferation and thus play critical role in cancer progression.	('role', 'Reg', (146, 150))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('regulate', 'Reg', (7, 15))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('miRNAs', 'Var', (0, 6))	('proliferation', 'CPA', (109, 122))	('apoptosis', 'CPA', (94, 103))	('cellular differentiation', 'CPA', (68, 92))
767239	27642589	Aberrant activation of the Wnt/beta-catenin pathway plays a critical role in tumor initiation, progression, and metastasis of lung cancer.	('activation', 'PosReg', (9, 19))	('tumor initiation', 'Disease', (77, 93))	('beta-catenin', 'Gene', (31, 43))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', '1499', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (112, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor initiation', 'Disease', 'MESH:D009369', (77, 93))	('metastasis of lung cancer', 'Disease', (112, 137))
767241	27642589	Circular RNA-ITCH (cir-ITCH) shared some miRNAs binding sites with the 3'-untranslated region (UTR) of ITCH, including those for miR-7, miR-17, miR-214, miR-128, and miR-216b.	('miR-128', 'Var', (153, 160))	('miR-17', 'Gene', '406952', (136, 142))	('cir', 'Gene', (19, 22))	('ITCH', 'Gene', (103, 107))	('-ITCH', 'Phenotype', 'HP:0000989', (12, 17))	('miR-216b', 'Gene', (166, 174))	('miRNAs', 'MPA', (41, 47))	('ITCH', 'Gene', (23, 27))	('ITCH', 'Gene', (13, 17))	('miR-17', 'Gene', (136, 142))	('ITCH', 'Gene', '83737', (103, 107))	('miR-214', 'Gene', '406996', (144, 151))	('miR-216b', 'Gene', '100126319', (166, 174))	('miR-7', 'Gene', (129, 134))	('ITCH', 'Gene', '83737', (23, 27))	('ITCH', 'Gene', '83737', (13, 17))	('ITCH', 'Phenotype', 'HP:0000989', (103, 107))	('cir', 'Gene', '9541', (19, 22))	('ITCH', 'Phenotype', 'HP:0000989', (23, 27))	('miR-214', 'Gene', (144, 151))	('-ITCH', 'Phenotype', 'HP:0000989', (22, 27))	('miR-7', 'Gene', '10859', (129, 134))	('ITCH', 'Phenotype', 'HP:0000989', (13, 17))
767321	27642589	Previous research has shown that miR-216b, miR-17, miR-214, miR-7, miR-20a, and miR-128 could bind to the 3'-UTR of ITCH and cir-ITCH.	('miR-214', 'Gene', '406996', (51, 58))	('miR-17', 'Gene', (43, 49))	('ITCH', 'Gene', '83737', (129, 133))	('ITCH', 'Phenotype', 'HP:0000989', (116, 120))	('ITCH', 'Phenotype', 'HP:0000989', (129, 133))	('miR-216b', 'Gene', '100126319', (33, 41))	('miR-214', 'Gene', (51, 58))	('ITCH', 'Gene', (116, 120))	('miR-128', 'Var', (80, 87))	('cir', 'Gene', '9541', (125, 128))	('-ITCH', 'Phenotype', 'HP:0000989', (128, 133))	('miR-7', 'Gene', (60, 65))	('miR-17', 'Gene', '406952', (43, 49))	('miR-7', 'Gene', '10859', (60, 65))	('cir', 'Gene', (125, 128))	('ITCH', 'Gene', (129, 133))	('bind', 'Interaction', (94, 98))	('miR-20a', 'Gene', (67, 74))	('miR-20a', 'Gene', '406982', (67, 74))	('ITCH', 'Gene', '83737', (116, 120))	('miR-216b', 'Gene', (33, 41))
767323	27642589	These results were not fully consistent with study in cell lines of esophageal squamous cell carcinoma, in which cir-ITCH acts as a sponge for five miRNAs: miR-216b, miR-17, miR-214, miR-7, and miR-128.	('cir', 'Gene', (113, 116))	('ITCH', 'Phenotype', 'HP:0000989', (117, 121))	('miR-128', 'Var', (194, 201))	('esophageal squamous cell carcinoma', 'Disease', (68, 102))	('miR-7', 'Gene', (183, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('miR-216b', 'Gene', (156, 164))	('ITCH', 'Gene', (117, 121))	('miR-17', 'Gene', '406952', (166, 172))	('miR-7', 'Gene', '10859', (183, 188))	('miR-214', 'Gene', '406996', (174, 181))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('ITCH', 'Gene', '83737', (117, 121))	('cir', 'Gene', '9541', (113, 116))	('miR-17', 'Gene', (166, 172))	('miR-214', 'Gene', (174, 181))	('miR-216b', 'Gene', '100126319', (156, 164))	('-ITCH', 'Phenotype', 'HP:0000989', (116, 121))
767331	27642589	Deregulated Wnt/beta-catenin signaling with cancers has been well documented in tumor initiation, progression, and metastasis, including lung cancer.	('Deregulated', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancers', 'Disease', (44, 51))	('tumor initiation', 'Disease', 'MESH:D009369', (80, 96))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('beta-catenin', 'Gene', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('beta-catenin', 'Gene', '1499', (16, 28))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('tumor initiation', 'Disease', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
767360	26785669	ATG dysregulation has been implicated in immune disorders such as Crohn Disease and ATGs may serve as disease biomarkers.	('dysregulation', 'Var', (4, 17))	('Crohn Disease', 'Phenotype', 'HP:0100280', (66, 79))	('implicated', 'Reg', (27, 37))	('Crohn Disease', 'Disease', 'MESH:D003424', (66, 79))	('ATG', 'Protein', (0, 3))	('Crohn Disease', 'Disease', (66, 79))
767469	26472984	After plasmid transfection of the Eca109 human ESCC cell line, Western blotting revealed that CR-1 interference significantly reduced N-cad and Vim protein expression, while significantly increasing E-cad expression, relative to the mock and negative control groups (P < 0.01, Figure 7).	('Vim', 'Gene', '7431', (144, 147))	('interference', 'Var', (99, 111))	('N-cad', 'Gene', (134, 139))	('E-cad expression', 'MPA', (199, 215))	('human', 'Species', '9606', (41, 46))	('increasing', 'PosReg', (188, 198))	('N-cad', 'Gene', '1000', (134, 139))	('expression', 'Species', '29278', (156, 166))	('expression', 'Species', '29278', (205, 215))	('CR-1', 'Gene', (94, 98))	('Vim', 'Gene', (144, 147))	('reduced', 'NegReg', (126, 133))
767481	26472984	ESCC is the result of multiple genetic and environmental factors that jointly participate in dysregulating a number of oncogenes and tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('participate', 'Reg', (78, 89))	('ESCC', 'Disease', (0, 4))	('dysregulating', 'Var', (93, 106))	('tumor', 'Disease', (133, 138))	('oncogenes', 'Gene', (119, 128))
767499	26472984	Consistent with our findings, anti-EGF-like domain CR-1 antibodies produce apoptosis in cancer cells through significant reduction in activation of the AKT, c-Jun-NH2-terminal kinase, and p38 kinase signaling pathways.	('AKT', 'Pathway', (152, 155))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('EGF', 'Gene', '1950', (35, 38))	('apoptosis', 'CPA', (75, 84))	('c-Jun-NH2-terminal kinase', 'Pathway', (157, 182))	('CR-1', 'Gene', (51, 55))	('activation', 'PosReg', (134, 144))	('antibodies', 'Var', (56, 66))	('EGF', 'Gene', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('p38 kinase signaling pathways', 'Pathway', (188, 217))	('reduction', 'NegReg', (121, 130))
767503	26472984	Therefore, we applied the Transwell assay to assess the migratory ability of ESCC cells after CR-1 silencing.	('migratory ability', 'CPA', (56, 73))	('rat', 'Species', '10116', (59, 62))	('CR-1', 'Gene', (94, 98))	('silencing', 'Var', (99, 108))
767780	22900535	Pope et al., found glutathione levels were lower in gliomas expressing a mutant form of the isocitrate dehydrogenase 1 enzyme characteristic of more aggressive tumors.	('glutathione', 'Chemical', 'MESH:D005978', (19, 30))	('gliomas', 'Disease', (52, 59))	('aggressive tumors', 'Disease', 'MESH:D001523', (149, 166))	('glutathione levels', 'MPA', (19, 37))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('aggressive tumors', 'Disease', (149, 166))	('mutant', 'Var', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('lower', 'NegReg', (43, 48))
767873	22900535	The two studies with T/C < 1, enrolled a total of 21 patients whereas the study showing significantly higher levels in the tumor sampled tissue from 49 patients.	('T/C < 1', 'Var', (21, 28))	('tumor', 'Disease', (123, 128))	('patients', 'Species', '9606', (53, 61))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('patients', 'Species', '9606', (152, 160))
767893	22900535	The results of Corrocher et al., imply that peritumoral tissue glutathione levels are significantly affected by the presence of the tumor when a comparison is made to tissue from control, cancer-free patients.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Disease', (48, 53))	('patients', 'Species', '9606', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('C', 'Chemical', 'MESH:D002244', (15, 16))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer-free', 'Disease', 'MESH:D009369', (188, 199))	('affected', 'Reg', (100, 108))	('glutathione', 'Chemical', 'MESH:D005978', (63, 74))	('tumor', 'Disease', (132, 137))	('cancer-free', 'Disease', (188, 199))	('presence', 'Var', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
767898	22900535	In the study by Lee et al., of viral-associated hepatocellular carcinoma, patient data was limited but well differentiated (n = 8), moderately differentiated (n = 16) and poorly differentiated (n = 2) tumors exhibited glutathione levels of 513 +- 238, 465 +- 194 and 210 +- 110 muM/g-protein, respectively.	('patient', 'Species', '9606', (74, 81))	('glutathione', 'Chemical', 'MESH:D005978', (218, 229))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (48, 72))	('glutathione levels', 'MPA', (218, 236))	('hepatocellular carcinoma', 'Disease', (48, 72))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (48, 72))	('muM', 'Gene', '56925', (278, 281))	('muM', 'Gene', (278, 281))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('465 +- 194', 'Var', (252, 262))
767899	22900535	In contrast, no clear trend with clinical stage was observed with Stage I (n = 17), Stage II (n = 2), Stage III (n = 5) patient tumors contained 460 +- 219, 234 +- 76 and 442 +- 139 muM/g-protein, respectively.	('muM', 'Gene', (182, 185))	('patient', 'Species', '9606', (120, 127))	('clinical', 'Species', '191496', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('460 +- 219', 'Var', (145, 155))	('muM', 'Gene', '56925', (182, 185))
767908	22900535	For patients with high glutathione, the survival level at 24 months was 54% compared with 89% for the low group.	('glutathione', 'Chemical', 'MESH:D005978', (23, 34))	('glutathione', 'Protein', (23, 34))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))
768078	21992930	Critical information is continuously gained regarding how aberrantly expressed miRs contribute to carcinogenesis.	('contribute', 'Reg', (84, 94))	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('carcinogenesis', 'Disease', (98, 112))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('aberrantly expressed', 'Var', (58, 78))
768081	21992930	The current review addresses ways in which altered miR expression contributes to esophageal carcinogenesis, along with how recent discoveries may be applied clinically.	('esophageal carcinogenesis', 'Disease', (81, 106))	('contributes', 'Reg', (66, 77))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('altered', 'Var', (43, 50))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (81, 106))
768114	21992930	The miR 25 -93-106b polycistron is progressively upregulated during normal esophagus -BE- EAC progression and is associated with genomic amplification of the MCM7 locus at chromosome 7q22.1.	('miR 25', 'Gene', '407014', (4, 10))	('associated with', 'Reg', (113, 128))	('MCM7', 'Gene', (158, 162))	('genomic', 'Var', (129, 136))	('upregulated', 'PosReg', (49, 60))	('esophagus -BE- EAC', 'Disease', (75, 93))	('miR 25', 'Gene', (4, 10))	('MCM7', 'Gene', '4176', (158, 162))
768115	21992930	MiRs-93 and -106 appeared to contribute to EAC carcinogenesis by targeting CDKN1A and impacting cell cycle progression.	('impacting', 'NegReg', (86, 95))	('CDKN1A', 'Gene', (75, 81))	('cell cycle progression', 'CPA', (96, 118))	('CDKN1A', 'Gene', '1026', (75, 81))	('MiRs-93', 'Var', (0, 7))	('carcinogenesis', 'Disease', (47, 61))	('targeting', 'Reg', (65, 74))	('carcinogenesis', 'Disease', 'MESH:D063646', (47, 61))
768138	21992930	In addition to altered miR expression levels, changes in miR DNA sequence may also contribute to carcinogenesis.	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (23, 26))	('miR', 'Gene', (57, 60))	('changes', 'Var', (46, 53))	('carcinogenesis', 'Disease', (97, 111))	('altered', 'Reg', (15, 22))	('contribute', 'Reg', (83, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (97, 111))
768139	21992930	The C-T SNP in pre-miR-196a (rs11614913) and the G>C variant in pre-miR-146a increase ESCC risk in the Chinese Han population, the latter SNP being correlated with TNM staging.	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('miR', 'Gene', '220972', (68, 71))	('miR-146a', 'Gene', (68, 76))	('miR', 'Gene', (68, 71))	('increase ESCC', 'Phenotype', 'HP:0003565', (77, 90))	('TNM', 'Gene', (164, 167))	('miR-146a', 'Gene', '406938', (68, 76))	('rs11614913', 'Var', (29, 39))	('increase', 'PosReg', (77, 85))	('G>C', 'Var', (49, 52))	('TNM', 'Gene', '10178', (164, 167))	('rs11614913', 'Mutation', 'rs11614913', (29, 39))	('ESCC', 'Disease', (86, 90))
768141	21992930	demonstrated that promoter hypermethylation reduces miR-375 expression in ESCC, thereby augmenting 3-phopshoinositide-dependent protein kinase 1 (PDK1) expression.	('expression', 'MPA', (60, 70))	('promoter hypermethylation', 'Var', (18, 43))	('miR-375', 'Gene', (52, 59))	('augmenting', 'PosReg', (88, 98))	('3-phopshoinositide-dependent protein kinase 1', 'Gene', (99, 144))	('reduces', 'NegReg', (44, 51))	('3-phopshoinositide-dependent protein kinase 1', 'Gene', '5163', (99, 144))	('PDK1', 'Gene', '5163', (146, 150))	('PDK1', 'Gene', (146, 150))	('expression', 'MPA', (152, 162))	('miR-375', 'Gene', '494324', (52, 59))
768142	21992930	In addition to providing insights into ESCC pathogenesis, altered miR expression patterns offer the potential to reflect cancer dissemination to distant sites and to predict patient survival.	('reflect', 'Reg', (113, 120))	('ESCC', 'Disease', (39, 43))	('patient', 'Species', '9606', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('predict', 'Reg', (166, 173))	('miR', 'Gene', (66, 69))	('miR', 'Gene', '220972', (66, 69))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('altered', 'Var', (58, 65))
768162	21992930	The detection of aberrantly expressed miRs also lay the groundwork for the future development of a whole new class of disease biomarkers and therapeutic targets.	('aberrantly expressed', 'Var', (17, 37))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))
768163	21992930	Esophageal cancer is a devastating disease with a significant incidence and a dismal prognosis MicroRNAs (miRs) are important gene expression regulators Altered miR expression patterns have a significant impact on human disease, particularly in cancers Mir expression analysis provides insight into the mechanisms driving esophageal cancer formation and progression Aberrantly expressed miRs are potential biomarkers to detect the presence of an esophageal tumor, to assess the invasiveness of esophageal cancers, and to predict the patient's prognosis and response to treatment	('Mir', 'Gene', (253, 256))	('esophageal cancer', 'Disease', 'MESH:D004938', (322, 339))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('miR', 'Gene', (387, 390))	('patient', 'Species', '9606', (533, 540))	('Esophageal cancer', 'Disease', (0, 17))	('cancers', 'Disease', 'MESH:D009369', (505, 512))	('esophageal cancer', 'Disease', (322, 339))	('esophageal tumor', 'Disease', 'MESH:D004938', (446, 462))	('miR', 'Gene', '220972', (161, 164))	('miR', 'Gene', '220972', (106, 109))	('Mir', 'Gene', '220972', (253, 256))	('Aberrantly', 'Var', (366, 376))	('human', 'Species', '9606', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('invasiveness of esophageal cancers', 'Disease', (478, 512))	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (457, 462))	('esophageal cancer', 'Disease', 'MESH:D004938', (494, 511))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('miR', 'Gene', (106, 109))	('cancers', 'Disease', (245, 252))	('miR', 'Gene', (161, 164))	('cancers', 'Phenotype', 'HP:0002664', (505, 512))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancers', 'Disease', (505, 512))	('miR', 'Gene', '220972', (387, 390))	('cancer', 'Phenotype', 'HP:0002664', (505, 511))	('esophageal tumor', 'Disease', (446, 462))	('invasiveness of esophageal cancers', 'Disease', 'MESH:D004938', (478, 512))	('esophageal tumor', 'Phenotype', 'HP:0100751', (446, 462))
768196	31885424	Patients with a cM1a tumor according to TNM-6th edition, defined as cervical lymph node involvement, were categorized as having a positive lymph node status (cN+).	('cervical lymph node involvement', 'Phenotype', 'HP:0025289', (68, 99))	('TNM', 'Gene', (40, 43))	('tumor', 'Disease', (21, 26))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cM1a', 'Var', (16, 20))	('TNM', 'Gene', '10178', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
768251	31885424	For example, in patients with HER2 amplified adenocarcinomas of the distal esophagus, HER2 directed therapies have led to a survival benefit.	('HER2', 'Gene', (86, 90))	('survival benefit', 'CPA', (124, 140))	('HER2', 'Gene', '2064', (86, 90))	('amplified', 'Var', (35, 44))	('adenocarcinomas', 'Disease', 'MESH:D000230', (45, 60))	('patients', 'Species', '9606', (16, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('adenocarcinomas', 'Disease', (45, 60))	('HER2', 'Gene', (30, 34))	('HER2', 'Gene', '2064', (30, 34))
768333	31342676	Patients with a  lower than 17.0 mL/kg/min were twice as likely to develop major morbidity than patients with a higher , 38.6% versus 18.4% respectively, P = 0.015.	('major', 'Disease', (75, 80))	('lower', 'Var', (17, 22))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (96, 104))	('develop', 'PosReg', (67, 74))
768345	31342676	Patients with poorer  and AT values below these critical levels were over twice as likely to develop major morbidity than patients with values above the critical levels, and  was independently associated with postoperative major morbidity, which consequently had an adverse influence on long-term survival which was 1.5 times better in the absence of major operative morbidity (OM 5-year survival 97.5% vs. 62.5% for cohort without OM).	('better', 'PosReg', (326, 332))	('major morbidity', 'Disease', (101, 116))	('poorer', 'Var', (14, 20))	('develop', 'PosReg', (93, 100))	('AT', 'Disease', 'None', (26, 28))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (122, 130))	('associated with', 'Reg', (193, 208))
768368	30892391	MNNG induced differentiated and undifferentiated type adenocarcinomas in the esophageal and gastric tissues of rats.	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('MNNG', 'Var', (0, 4))	('undifferentiated type adenocarcinomas', 'Disease', 'MESH:D002277', (32, 69))	('undifferentiated type adenocarcinomas', 'Disease', (32, 69))
768463	30337457	We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter.	('cancer', 'Disease', (70, 76))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
768464	30337457	In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively.	('NOTCH1', 'Gene', '4851', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (47, 53))	('NOTCH1', 'Gene', (112, 118))	('TP53', 'Gene', '7157', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('donor', 'Species', '9606', (27, 32))	('mutations', 'Var', (65, 74))	('TP53', 'Gene', (123, 127))
768465	30337457	Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers.	('esophageal cancers', 'Disease', (102, 120))	('esophageal cancers', 'Disease', 'MESH:D004938', (102, 120))	('NOTCH1', 'Gene', '4851', (32, 38))	('NOTCH1', 'Gene', (32, 38))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('mutations', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
768469	30337457	Deep targeted sequencing of sun-exposed skin from four middle-aged individuals revealed large numbers of mutant clones under positive selection, with around a quarter of skin cells carrying cancer-driving mutations.	('cancer', 'Disease', (190, 196))	('mutant', 'Var', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
768480	30337457	In middle-aged individuals, the number of mutations per cell is approximately ten times lower in normal esophagus than in sun-exposed skin, a difference partially due to the high degree of UV-damage sustained by the skin.	('lower', 'NegReg', (88, 93))	('UV-damage', 'Disease', 'MESH:C563466', (189, 198))	('mutations', 'Var', (42, 51))	('UV-damage', 'Disease', (189, 198))
768481	30337457	Given this, we anticipated that the frequency of cancer-driver mutations in esophagus would be much lower than that in skin.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('esophagus', 'Disease', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
768482	30337457	Unexpectedly, however, analysis of the frequency and size of mutant clones revealed a higher density of cancer-associated mutations in normal esophagus than in sun-exposed skin, suggesting that there is stronger positive selection of clones with mutations in cancer-associated genes.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('mutations', 'Var', (122, 131))	('mutant', 'Var', (61, 67))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (259, 265))
768489	30337457	NFE2L2, TP63 and CUL3 or through epigenetic regulation e.g.	('CUL3', 'Gene', '8452', (17, 21))	('TP63', 'Gene', '8626', (8, 12))	('epigenetic regulation', 'Var', (33, 54))	('CUL3', 'Gene', (17, 21))	('TP63', 'Gene', (8, 12))	('NFE2L2', 'Gene', '4780', (0, 6))	('NFE2L2', 'Gene', (0, 6))
768493	30337457	One unexpected observation was the very high prevalence of NOTCH1 mutations in normal esophagus (Fig.	('mutations', 'Var', (66, 75))	('NOTCH1', 'Gene', '4851', (59, 65))	('normal esophagus', 'Disease', (79, 95))	('NOTCH1', 'Gene', (59, 65))
768494	30337457	Across the nine donors, we detected 2,055 coding mutations in NOTCH1, of which over 98% were non-synonymous, with an average of ~120 different NOTCH1 mutations per cm2 of normal esophagus (Fig.	('donor', 'Species', '9606', (16, 21))	('NOTCH1', 'Gene', '4851', (62, 68))	('NOTCH1', 'Gene', '4851', (143, 149))	('NOTCH1', 'Gene', (143, 149))	('mutations', 'Var', (150, 159))	('NOTCH1', 'Gene', (62, 68))
768496	30337457	As in SCCs, mutations in NOTCH1 in normal esophagus were enriched for truncating mutations (dN/dS>50), including stop-gains, essential splice site mutations and indels (Fig.	('dS', 'Chemical', 'MESH:D003903', (95, 97))	('mutations', 'Var', (12, 21))	('NOTCH1', 'Gene', '4851', (25, 31))	('NOTCH1', 'Gene', (25, 31))	('indels', 'Var', (161, 167))	('truncating', 'MPA', (70, 80))	('dN', 'Chemical', '-', (92, 94))
768497	30337457	Missense mutations were also frequent in NOTCH1, and they were concentrated in five of the 36 extracellular epidermal growth factor (EGF) repeat domains, EGF8-12 (Fig.	('EGF', 'Gene', (154, 157))	('EGF', 'Gene', (133, 136))	('epidermal growth factor', 'Gene', (108, 131))	('EGF', 'Gene', '1950', (133, 136))	('EGF', 'Gene', '1950', (154, 157))	('NOTCH1', 'Gene', (41, 47))	('epidermal growth factor', 'Gene', '1950', (108, 131))	('NOTCH1', 'Gene', '4851', (41, 47))	('Missense mutations', 'Var', (0, 18))
768499	30337457	The most recurrent codon alterations occurred at sites predicted to affect structural residues (calcium-binding motifs, cysteine residues, interdomain packing) or the contact surface with Notch1 ligands (Fig.	('alterations', 'Var', (25, 36))	('contact', 'Interaction', (167, 174))	('Notch1', 'Gene', '4851', (188, 194))	('cysteine', 'Chemical', 'MESH:D003545', (120, 128))	('cysteine residues', 'MPA', (120, 137))	('calcium', 'Chemical', 'MESH:D002118', (96, 103))	('structural residues', 'MPA', (75, 94))	('affect', 'Reg', (68, 74))	('Notch1', 'Gene', (188, 194))
768500	30337457	The large number of positively-selected NOTCH1 mutations provides structural and functional insights into this key regulatory protein.	('NOTCH1', 'Gene', '4851', (40, 46))	('NOTCH1', 'Gene', (40, 46))	('mutations', 'Var', (47, 56))
768501	30337457	On average across the nine donors, 25 to 42% of the cells in normal esophagus harbored NOTCH1 mutations (Fig.	('donor', 'Species', '9606', (27, 32))	('NOTCH1', 'Gene', (87, 93))	('NOTCH1', 'Gene', '4851', (87, 93))	('mutations', 'Var', (94, 103))
768502	30337457	There was a large increase in the frequency of NOTCH1 mutant clones with age.	('mutant', 'Var', (54, 60))	('NOTCH1', 'Gene', '4851', (47, 53))	('NOTCH1', 'Gene', (47, 53))
768504	30337457	This observation is consistent with data from experimental mouse models showing that transgenic inhibition of Notch signaling in a small fraction of cells confers clonal advantage and enables these clones to colonize the normal esophageal epithelium.	('clonal advantage', 'CPA', (163, 179))	('mouse', 'Species', '10090', (59, 64))	('Notch signaling', 'Gene', (110, 125))	('colon', 'Disease', 'MESH:D015179', (208, 213))	('inhibition', 'Var', (96, 106))	('colon', 'Disease', (208, 213))
768505	30337457	The NOTCH1 gene has been widely assumed to be a driver in ESCCs because it is mutated in ~10% of tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('NOTCH1', 'Gene', '4851', (4, 10))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('mutated', 'Var', (78, 85))	('NOTCH1', 'Gene', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
768506	30337457	The observation that, in middle-aged individuals, NOTCH1 is typically mutated in 30 to 80% of the normal esophageal epithelium suggests that NOTCH1 mutations may be less frequent in cancers than in the background of normal tissue from which the cancers develop.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('NOTCH1', 'Gene', '4851', (50, 56))	('mutations', 'Var', (148, 157))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('NOTCH1', 'Gene', (50, 56))	('cancers', 'Disease', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('NOTCH1', 'Gene', '4851', (141, 147))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('NOTCH1', 'Gene', (141, 147))	('mutated', 'Var', (70, 77))
768509	30337457	TP53 is the second most frequently mutated gene in normal esophagus, with ~35 mutations per square centimeter and strong positive selection for both truncating and missense mutations (dN/dS ratios ~150 and ~50, respectively; Fig.	('TP53', 'Gene', '7157', (0, 4))	('dS', 'Chemical', 'MESH:D003903', (187, 189))	('TP53', 'Gene', (0, 4))	('missense mutations', 'Var', (164, 182))	('dN', 'Chemical', '-', (184, 186))
768510	30337457	As in cancer genomes, the missense mutations mostly affect the central DNA-binding domain (Fig.	('missense mutations', 'Var', (26, 44))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('central DNA-binding domain', 'MPA', (63, 89))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('affect', 'Reg', (52, 58))
768511	30337457	Across the nine donors, 5 to 10% of the epithelium carried a TP53 mutation, a fraction that appeared to increase with age, with the oldest donor having TP53 mutations in 20 to 35% of cells (Fig.	('donor', 'Species', '9606', (16, 21))	('donor', 'Species', '9606', (139, 144))	('TP53', 'Gene', '7157', (152, 156))	('TP53', 'Gene', (152, 156))	('mutation', 'Var', (66, 74))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
768512	30337457	Combining the 74 genes studied, global dN/dS ratios for missense and protein-truncating (nonsense and essential splice site) mutations were around 2.2 and 8.6, respectively, with the enrichment of non-synonymous mutations increasing rapidly with clone size (Fig.	('mutations', 'Var', (125, 134))	('protein-truncating', 'NegReg', (69, 87))	('dS', 'Chemical', 'MESH:D003903', (42, 44))	('missense', 'Var', (56, 64))	('dN', 'Chemical', '-', (39, 41))
768513	30337457	Overall, using dN/dS ratios, and considering substitutions and indels in the 14 genes under significant selection, we estimate that there are 3,915 (CI95%: 3,829-3,988) positively-selected driver mutations in the ~17 cm2 of normal esophageal epithelium sequenced in this study, of which 52% are in genes other than NOTCH1 (Methods S6.3).	('NOTCH1', 'Gene', '4851', (315, 321))	('NOTCH1', 'Gene', (315, 321))	('dS', 'Chemical', 'MESH:D003903', (18, 20))	('dN', 'Chemical', '-', (15, 17))	('mutations', 'Var', (196, 205))
768518	30337457	For example, across individuals, NOTCH1 is mutated 5 times more frequently than NOTCH3.	('NOTCH1', 'Gene', '4851', (33, 39))	('NOTCH1', 'Gene', (33, 39))	('NOTCH3', 'Gene', (80, 86))	('mutated', 'Var', (43, 50))	('NOTCH3', 'Gene', '4854', (80, 86))
768519	30337457	Yet, in one donor, we detected nearly the same number of mutations in NOTCH1 and NOTCH3 (Fig.	('donor', 'Species', '9606', (12, 17))	('NOTCH3', 'Gene', '4854', (81, 87))	('mutations', 'Var', (57, 66))	('NOTCH1', 'Gene', '4851', (70, 76))	('NOTCH1', 'Gene', (70, 76))	('NOTCH3', 'Gene', (81, 87))
768520	30337457	Similarly, the oldest donor showed a 2-fold relative enrichment in TP53 mutations compared to other individuals (q-value<1e-15, Likelihood-Ratio Test; Fig.	('donor', 'Species', '9606', (22, 27))	('mutations', 'Var', (72, 81))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
768521	30337457	S5E), consistent with the observation that 20 to 37% of normal esophageal epithelium was TP53 mutant in this donor (Fig.	('donor', 'Species', '9606', (109, 114))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('mutant', 'Var', (94, 100))
768524	30337457	Most cases (14/25) were examples of NOTCH1 bi-allelic inactivation by two mutations.	('NOTCH1', 'Gene', '4851', (36, 42))	('NOTCH1', 'Gene', (36, 42))	('bi-allelic inactivation', 'Var', (43, 66))
768525	30337457	We also observed examples of clones carrying mutations in NOTCH1 and FAT1, NOTCH1 and NOTCH3, and PIK3CA and NOTCH3.	('FAT1', 'Gene', (69, 73))	('mutations', 'Var', (45, 54))	('NOTCH1', 'Gene', '4851', (75, 81))	('NOTCH1', 'Gene', (75, 81))	('PIK3CA', 'Gene', (98, 104))	('NOTCH3', 'Gene', '4854', (109, 115))	('PIK3CA', 'Gene', '5290', (98, 104))	('NOTCH3', 'Gene', (86, 92))	('NOTCH1', 'Gene', '4851', (58, 64))	('NOTCH1', 'Gene', (58, 64))	('FAT1', 'Gene', '2195', (69, 73))	('NOTCH3', 'Gene', '4854', (86, 92))	('NOTCH3', 'Gene', (109, 115))
768526	30337457	In the oldest donor (aged 72-75 years), whose samples showed an enrichment of TP53 mutations, we found a large clone, measuring over 4 mm2, with a founder heterozygous TP53 mutation and three separate subclones each carrying a second TP53 mutation (Fig.	('mutations', 'Var', (83, 92))	('TP53', 'Gene', '7157', (234, 238))	('TP53', 'Gene', (234, 238))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('TP53', 'Gene', '7157', (78, 82))	('donor', 'Species', '9606', (14, 19))	('TP53', 'Gene', (78, 82))	('mutation', 'Var', (173, 181))
768528	30337457	Across all donors, C>T/G>A mutations dominate the spectra with a clear excess of mutations at CpG dinucleotides (Fig.	('C>T/G>A', 'Var', (19, 26))	('donor', 'Species', '9606', (11, 16))	('mutations', 'Var', (81, 90))
768532	30337457	Stratification of the mutation spectra by gene expression level revealed that highly transcribed genes are targets of a process of transcription-coupled mutagenesis that induces T>C changes preferentially at ApT sites in the transcribed strand, a phenomenon previously described in liver cancers (related to COSMIC signature 16) (Fig.	('mutagenesis', 'Var', (153, 164))	('cancers', 'Phenotype', 'HP:0002664', (288, 295))	('liver cancers', 'Phenotype', 'HP:0002896', (282, 295))	('T>C changes', 'MPA', (178, 189))	('liver cancers', 'Disease', 'MESH:D006528', (282, 295))	('liver cancers', 'Disease', (282, 295))	('induces', 'Reg', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
768533	30337457	These signatures are believed to be caused by APOBEC cytidine deaminases and contribute large numbers of mutations in esophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('mutations', 'Var', (105, 114))	('esophageal cancers', 'Disease', 'MESH:D004938', (118, 136))	('caused', 'Reg', (36, 42))	('esophageal cancers', 'Disease', (118, 136))
768535	30337457	Esophageal cancers are characterized by large numbers of copy number changes and structural rearrangements.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('copy number changes', 'Var', (57, 76))	('Esophageal cancers', 'Disease', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('Esophageal cancers', 'Disease', 'MESH:D004938', (0, 18))
768538	30337457	4F) and in virtually all of the samples with a single high-frequency NOTCH1 mutation, confirming that loss of NOTCH1 is typically bi-allelic.	('NOTCH1', 'Gene', '4851', (110, 116))	('NOTCH1', 'Gene', (110, 116))	('mutation', 'Var', (76, 84))	('NOTCH1', 'Gene', '4851', (69, 75))	('NOTCH1', 'Gene', (69, 75))
768543	30337457	With the exception of copy-neutral LOH events in NOTCH1 and an instance of chromosome 3 gain, the 21 genomes appeared largely diploid, without evidence of other copy number changes that may be expected to accumulate by chance over time (Fig.	('LOH', 'Var', (35, 38))	('NOTCH1', 'Gene', (49, 55))	('gain', 'PosReg', (88, 92))	('NOTCH1', 'Gene', '4851', (49, 55))
768544	30337457	The rarity of copy number changes in large clones, none of which had TP53 mutations, suggests that the background rate of copy number changes is low in normal cells of the esophagus or that such changes are negatively selected.	('TP53', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('TP53', 'Gene', '7157', (69, 73))
768546	30337457	We have detected thousands of mutations per cell, hundreds of positively selected clones per square centimeter, and clones with cancer-associated mutations colonizing most of the esophageal epithelium with age, all without grossly detectable changes in histology.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('colon', 'Disease', (156, 161))	('mutations', 'Var', (146, 155))	('colon', 'Disease', 'MESH:D015179', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (30, 39))	('cancer', 'Disease', (128, 134))
768547	30337457	The higher frequency of cancer-associated mutations in normal esophagus than in sun-exposed skin is unexpected, particularly given the lower mutation rate in the esophagus.	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (42, 51))
768548	30337457	Although we found most of the common drivers of ESCC already under selection in normal esophageal epithelium, key differences remain between the genomes of cells in mutant clones in aging normal epithelium and cancer cells.	('cancer', 'Disease', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutant', 'Var', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (210, 216))
768549	30337457	Further, although clones carrying cancer-driver mutations are widespread, the average number of driver mutations per cell in normal esophagus is much lower than that in cancer cells (Fig.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('lower', 'NegReg', (150, 155))	('mutations', 'Var', (103, 112))	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', (34, 40))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
768552	30337457	An unexpected observation is the high frequency of NOTCH1 mutation in aged normal esophagus compared to ESCCs.	('mutation', 'Var', (58, 66))	('NOTCH1', 'Gene', '4851', (51, 57))	('NOTCH1', 'Gene', (51, 57))
768553	30337457	This suggests that ESCCs are more likely to evolve from cells in the epithelium without NOTCH1 mutations.	('mutations', 'Var', (95, 104))	('NOTCH1', 'Gene', (88, 94))	('NOTCH1', 'Gene', '4851', (88, 94))	('ESCCs', 'Disease', (19, 24))
768554	30337457	In contrast, TP53 mutations, which are several-fold less frequent than NOTCH1 mutations, are almost ubiquitous in ESCCs, suggesting that cancers arise from the small fraction of TP53 mutant cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TP53', 'Gene', '7157', (178, 182))	('TP53', 'Gene', (13, 17))	('NOTCH1', 'Gene', (71, 77))	('TP53', 'Gene', (178, 182))	('mutant', 'Var', (183, 189))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('NOTCH1', 'Gene', '4851', (71, 77))	('TP53', 'Gene', '7157', (13, 17))	('mutations', 'Var', (18, 27))
768583	28573183	demonstrated that eccentricity was a strong prognostic indicator for time to death (survival) in sarcoma patients  .	('eccentricity', 'Var', (18, 30))	('sarcoma', 'Disease', 'MESH:D012509', (97, 104))	('sarcoma', 'Disease', (97, 104))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))
768615	25502391	During validation, the sensitivity and specificity of miRNAs for BE diagnosis were as follows: miR-192-5p, 92% and 94%, AUC 0.94 (0.80-0.99, P=0.0004); miR-215-5p, 100% and 94%, AUC 0.98 (0.84-1, P=0.0004); and miR-194-5p, 91% and 94%, AUC 0.96 (0.80-0.99, P=0.0001), respectively.	('miR-192', 'Gene', (95, 102))	('miR-192', 'Gene', '406967', (95, 102))	('miR-215', 'Gene', '406997', (152, 159))	('miR-194-5p', 'Var', (211, 221))	('miR-215', 'Gene', (152, 159))
768660	25502391	We finally selected the following miRNAs for this study: miR-192-5p (240 611 reads per million (RPM) in BE, fold change 7.9 vs GERD), miR-215-5p (69250 RPM in BE, fold change 9.6 vs GERD), and miR-194-5p (8 209 RPM in BE, fold change 6.5 vs GERD), respectively.	('GERD', 'Disease', 'MESH:D005764', (127, 131))	('miR-215', 'Gene', (134, 141))	('miR-192', 'Gene', (57, 64))	('240 611 reads', 'Var', (69, 82))	('GERD', 'Disease', (127, 131))	('miR-192', 'Gene', '406967', (57, 64))	('GERD', 'Disease', 'MESH:D005764', (182, 186))	('GERD', 'Disease', (182, 186))	('GERD', 'Disease', (241, 245))	('miR-215', 'Gene', '406997', (134, 141))	('GERD', 'Disease', 'MESH:D005764', (241, 245))
768679	25502391	In the discovery cohort, the sensitivity and specificity of miRNAs for BE diagnosis were as follows: miR-192-5p, 100 and 95%, P=0.0004; miR-215-5p, 100 and 93%, P=0.0004; and miR-194-5p, 97 and 92%, P=0.0001) (Figure 1).	('miR-215', 'Gene', (136, 143))	('miR-215', 'Gene', '406997', (136, 143))	('miR-192', 'Gene', '406967', (101, 108))	('miR-194-5p', 'Var', (175, 185))	('miR-192', 'Gene', (101, 108))
768680	25502391	In the validation cohort, the sensitivity and specificity were as follows: miR-192-5p, 92 and 94%, area under the curve (AUC) 0.94 (0.80-0.99, P=0.0004); miR-215-5p, 100 and 94%, AUC 0.98 (0.84-1, P=0.0004); and miR-194-5p, 91 and 94%, AUC 0.96 (0.80-0.99, P=0.0001) (Figure 2).	('miR-192', 'Gene', (75, 82))	('miR-194-5p', 'Var', (212, 222))	('miR-215', 'Gene', (154, 161))	('miR-215', 'Gene', '406997', (154, 161))	('miR-192', 'Gene', '406967', (75, 82))
768693	25502391	In addition, comparisons of BE miRNA sequencing data with published data sets of other columnar epithelia in the gastrointestinal tract confirmed the specificity of two of the three miRNAs (-215-5p, -194-5p) to the intestinal-type epithelium.	('columnar epithelia in the gastrointestinal tract', 'Disease', (87, 135))	('columnar epithelia in the gastrointestinal tract', 'Disease', 'MESH:D004067', (87, 135))	('-215-5p', 'Var', (190, 197))
768703	25502391	MicroRNAs -192, -215, -194 coordinately regulate important targets in cell cycle regulation such as Smad interacting protein 1, ZEB2, and p53 and may help us better understand the molecular pathways driving the 'intestinalization' of columnar epithelia in BE with a role in BE development.	('p53', 'Gene', (138, 141))	("'intestinalization", 'PosReg', (211, 229))	('regulate', 'Reg', (40, 48))	('columnar epithelia', 'Disease', (234, 252))	('Smad interacting protein 1', 'Gene', '9839', (100, 126))	('p53', 'Gene', '7157', (138, 141))	('MicroRNAs -192', 'Var', (0, 14))	('columnar epithelia', 'Disease', 'None', (234, 252))	('ZEB2', 'Gene', '9839', (128, 132))	('ZEB2', 'Gene', (128, 132))	('Smad interacting protein 1', 'Gene', (100, 126))
768717	25126570	PPI Network Analysis of mRNA Expression Profile of Ezrin Knockdown in Esophageal Squamous Cell Carcinoma Ezrin, coding protein EZR which cross-links actin filaments, overexpresses and involves invasion, metastasis, and poor prognosis in various cancers including esophageal squamous cell carcinoma (ESCC).	('Carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('overexpresses', 'PosReg', (166, 179))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('Esophageal Squamous Cell Carcinoma', 'Disease', (70, 104))	('EZR', 'Gene', (127, 130))	('esophageal squamous cell carcinoma', 'Disease', (263, 297))	('actin', 'Protein', (149, 154))	('EZR', 'Gene', '7430', (127, 130))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('cancers', 'Disease', (245, 252))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (263, 297))	('Ezrin', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('Knockdown', 'Var', (57, 66))	('Ezrin', 'Gene', (105, 110))	('Ezrin', 'Gene', '7430', (51, 56))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('Ezrin', 'Gene', '7430', (105, 110))
768724	25126570	These analyses based on PPI network have greatly expanded our comprehension of the mRNA expression profile of Ezrin knockdown for future examination of the roles and mechanisms of Ezrin.	('Ezrin', 'Gene', '7430', (110, 115))	('Ezrin', 'Gene', '7430', (180, 185))	('knockdown', 'Var', (116, 125))	('PPI', 'Chemical', '-', (24, 27))	('Ezrin', 'Gene', (180, 185))	('Ezrin', 'Gene', (110, 115))
768735	25126570	Nevertheless, the biological meaning of mRNA expression profile of Ezrin knockdown in ESCC has not been fully mined in our previous reports.	('Ezrin', 'Gene', '7430', (67, 72))	('Ezrin', 'Gene', (67, 72))	('knockdown', 'Var', (73, 82))
768736	25126570	In this study, we reanalyzed the mRNA expression profile of Ezrin knockdown by integrating public PPI network to provide a deep view from a system level, which would be more comprehensive than merely listing the name of genes in the traditional way.	('Ezrin', 'Gene', (60, 65))	('Ezrin', 'Gene', '7430', (60, 65))	('knockdown', 'Var', (66, 75))	('PPI', 'Chemical', '-', (98, 101))
768737	25126570	GSE6233, the mRNA expression profile following Ezrin knockdown in the EC109 ESCC cell line, is available from GEO database (http://www.ncbi.nlm.nih.gov/geo/).	('Ezrin', 'Gene', (47, 52))	('EC109', 'CellLine', 'CVCL:6898', (70, 75))	('knockdown', 'Var', (53, 62))	('Ezrin', 'Gene', '7430', (47, 52))	('GSE6233', 'Chemical', '-', (0, 7))
768758	25126570	These three subnetworks indicated that knockdown of Ezrin greatly disturbed the PPI network in ESCC as hundreds of DEGs interact with thousands of proteins to enlarge the biological consequences.	('PPI', 'Chemical', '-', (80, 83))	('PPI network', 'Pathway', (80, 91))	('disturbed', 'Reg', (66, 75))	('Ezrin', 'Gene', '7430', (52, 57))	('knockdown', 'Var', (39, 48))	('ESCC', 'Disease', (95, 99))	('enlarge', 'PosReg', (159, 166))	('Ezrin', 'Gene', (52, 57))	('interact', 'Interaction', (120, 128))
768773	25126570	We have identified that transcription factor ATF3 was upregulated after Ezrin knockdown in our previous report.	('upregulated', 'PosReg', (54, 65))	('Ezrin', 'Gene', '7430', (72, 77))	('knockdown', 'Var', (78, 87))	('ATF3', 'Gene', '467', (45, 49))	('Ezrin', 'Gene', (72, 77))	('ATF3', 'Gene', (45, 49))
768779	25126570	These results suggested that the knockdown of Ezrin affected various biological activities through the disturbed PPI subnetwork, which were closely consistent with the functions of EZR.	('PPI', 'Gene', (113, 116))	('EZR', 'Gene', '7430', (181, 184))	('PPI', 'Chemical', '-', (113, 116))	('knockdown', 'Var', (33, 42))	('disturbed', 'Reg', (103, 112))	('Ezrin', 'Gene', '7430', (46, 51))	('biological activities', 'CPA', (69, 90))	('affected', 'Reg', (52, 60))	('Ezrin', 'Gene', (46, 51))	('EZR', 'Gene', (181, 184))
768788	25126570	The three PPI subnetworks indicated EZR influent the protein activities through the directly or indirectly interactions with DEGs and other proteins, and its knockdown might affect various biological functions in ESCC.	('DEGs', 'Protein', (125, 129))	('influent', 'Reg', (40, 48))	('EZR', 'Gene', (36, 39))	('interactions', 'Interaction', (107, 119))	('PPI', 'Chemical', '-', (10, 13))	('EZR', 'Gene', '7430', (36, 39))	('knockdown', 'Var', (158, 167))	('ESCC', 'Disease', (213, 217))	('affect', 'Reg', (174, 180))	('protein', 'Protein', (53, 60))	('activities', 'MPA', (61, 71))
768792	25126570	We previously confirmed that the knockdown of Ezrin decreased the invasion of ESCC cells through TGF-beta pathway with a decreased level of p-Smad2/3.	('Smad2/3', 'Gene', (142, 149))	('TGF-beta', 'Gene', '7040', (97, 105))	('knockdown', 'Var', (33, 42))	('decreased', 'NegReg', (52, 61))	('TGF-beta', 'Gene', (97, 105))	('Smad2/3', 'Gene', '4087;4088', (142, 149))	('Ezrin', 'Gene', '7430', (46, 51))	('decreased', 'NegReg', (121, 130))	('invasion of ESCC cells', 'CPA', (66, 88))	('Ezrin', 'Gene', (46, 51))
768793	25126570	demonstrated that the inhibition of SDC-2 abolished HT1080 cell adhesion through the inhibition of TGF-beta-induced Smad2 phosphorylation.	('inhibition', 'Var', (22, 32))	('Smad2', 'Gene', '4087', (116, 121))	('abolished', 'NegReg', (42, 51))	('Smad2', 'Gene', (116, 121))	('inhibition', 'NegReg', (85, 95))	('phosphorylation', 'MPA', (122, 137))	('SDC-2', 'Gene', '6383', (36, 41))	('HT1080', 'Gene', (52, 58))	('HT1080', 'CellLine', 'CVCL:0317', (52, 58))	('TGF-beta', 'Gene', '7040', (99, 107))	('SDC-2', 'Gene', (36, 41))	('TGF-beta', 'Gene', (99, 107))
768796	25126570	Since the Ezrin knockdown induced a wide range change of gene expression profile, it is interesting to understand how this signal is transduced from cell front/surface into nucleus as EZR is a linker of membrane-cytoskeleton.	('Ezrin', 'Gene', '7430', (10, 15))	('EZR', 'Gene', (184, 187))	('knockdown', 'Var', (16, 25))	('Ezrin', 'Gene', (10, 15))	('gene expression profile', 'MPA', (57, 80))	('EZR', 'Gene', '7430', (184, 187))
768798	25126570	Since so many directly and indirectly interacting proteins could translocate into nucleus, it is convinced that knockdown of Ezrin caused great impact on the ESCC gene expression profile.	('expression', 'MPA', (168, 178))	('Ezrin', 'Gene', '7430', (125, 130))	('impact', 'Reg', (144, 150))	('ESCC', 'Disease', (158, 162))	('knockdown', 'Var', (112, 121))	('Ezrin', 'Gene', (125, 130))
768801	25126570	To illustrate the strength of this kind analysis, we applied shortest path algorithm to find the links between knockdown EZR and upregulated ATF3.	('knockdown', 'Var', (111, 120))	('ATF3', 'Gene', (141, 145))	('EZR', 'Gene', (121, 124))	('upregulated', 'PosReg', (129, 140))	('EZR', 'Gene', '7430', (121, 124))	('ATF3', 'Gene', '467', (141, 145))
768817	25126570	In summary, the analyses based on PPI network have greatly expanded our understanding of the mRNA expression profile following Ezrin knockdown in ESCC.	('mRNA expression', 'MPA', (93, 108))	('Ezrin', 'Gene', '7430', (127, 132))	('PPI', 'Chemical', '-', (34, 37))	('Ezrin', 'Gene', (127, 132))	('knockdown', 'Var', (133, 142))
768822	32384712	We have reviewed the current evidence for the role of EVs in affecting cancer hallmark traits by: (i) promoting cell proliferation and escape from apoptosis, (ii) sustaining angiogenesis, (iii) contributing to cancer cell invasion and metastasis, (iv) reprogramming energy metabolism, (v) transferring mutations, and (vi) modulating the tumor microenvironment (TME) by evading immune response and promoting inflammation.	('cancer', 'Disease', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Disease', (337, 342))	('immune response', 'CPA', (377, 392))	('sustaining', 'PosReg', (163, 173))	('contributing', 'Reg', (194, 206))	('escape', 'CPA', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('cell proliferation', 'CPA', (112, 130))	('mutations', 'Var', (302, 311))	('cancer', 'Disease', (71, 77))	('cancer hallmark', 'Disease', (71, 86))	('angiogenesis', 'CPA', (174, 186))	('cancer hallmark', 'Disease', 'MESH:D009369', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('evading', 'Reg', (369, 376))	('inflammation', 'Disease', 'MESH:D007249', (407, 419))	('metastasis', 'CPA', (235, 245))	('modulating', 'Reg', (322, 332))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('invasion', 'CPA', (222, 230))	('promoting', 'PosReg', (397, 406))	('inflammation', 'Disease', (407, 419))	('promoting', 'PosReg', (102, 111))	('reprogramming energy metabolism', 'CPA', (252, 283))
768842	32384712	For example, a study showed that the splicing factor RBM11 present in EVs released by glioblastoma cell lines was transferred to recipient tumor cells and induced the splicing of MDM4 and Cyclin D1 into a more oncogenic isoform, contributing to an increase in survival and impairing apoptosis.	('tumor', 'Disease', (139, 144))	('glioblastoma', 'Disease', (86, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('apoptosis', 'CPA', (283, 292))	('splicing', 'Var', (37, 45))	('RBM11', 'Gene', '54033', (53, 58))	('survival', 'CPA', (260, 268))	('splicing', 'MPA', (167, 175))	('Cyclin D1', 'Gene', '595', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Cyclin D1', 'Gene', (188, 197))	('induced', 'Reg', (155, 162))	('MDM4', 'Gene', '4194', (179, 183))	('MDM4', 'Gene', (179, 183))	('increase', 'PosReg', (248, 256))	('RBM11', 'Gene', (53, 58))	('impairing', 'NegReg', (273, 282))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))
768846	32384712	In melanoma, the transfer of PDGFR-beta mediated by EVs released by melanoma (donor) cells caused an activation of the PI3K/Akt pathway and escape from the MAPK pathway on BRAF mutated (recipient) cells, contributing to cellular proliferation and inhibition of apoptosis.	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('Akt', 'Gene', (124, 127))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('activation', 'PosReg', (101, 111))	('MAPK pathway', 'Pathway', (156, 168))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', (3, 11))	('transfer', 'Var', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('apoptosis', 'CPA', (261, 270))	('BRAF', 'Gene', '673', (172, 176))	('Akt', 'Gene', '207', (124, 127))	('PDGFR-beta', 'Gene', (29, 39))	('escape', 'NegReg', (140, 146))	('cellular proliferation', 'CPA', (220, 242))	('BRAF', 'Gene', (172, 176))	('PDGFR-beta', 'Gene', '5156', (29, 39))
768856	32384712	Moreover, EVs shed by colon cancer cells containing high levels of miR-193a and mir-200b were responsible for the promotion of colon cancer cellular proliferation.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (127, 139))	('colon cancer', 'Disease', 'MESH:D015179', (127, 139))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('mir-200b', 'Gene', '406984', (80, 88))	('miR-193a', 'Var', (67, 75))	('promotion', 'PosReg', (114, 123))	('colon cancer', 'Disease', (127, 139))	('mir-200b', 'Gene', (80, 88))	('colon cancer', 'Disease', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
768857	32384712	Further in vivo work proved the impact of miR-193a and miR200b on tumor progression, using tumor-bearing nude mice or tumor xenografts, respectively, injected with EVs containing the respective miRNAs.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('miR200b', 'Gene', '387243', (55, 62))	('nude mice', 'Species', '10090', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('miR200b', 'Gene', (55, 62))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (91, 96))	('miR-193a', 'Var', (42, 50))
768858	32384712	EVs released by pancreatic cancer cells in vitro transferred miR-23b-3p and miR-222 to neighboring cancer cells in order to promote cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('miR-23b-3p', 'Chemical', '-', (61, 71))	('miR-222', 'Gene', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (16, 33))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', (27, 33))	('miR-222', 'Gene', '407007', (76, 83))	('cell proliferation', 'CPA', (132, 150))	('promote', 'PosReg', (124, 131))	('pancreatic cancer', 'Disease', (16, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (16, 33))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('miR-23b-3p', 'Var', (61, 71))
768871	32384712	In these studies, the angiogenesis process was enhanced via upregulation of the vascular endothelial growth factor (VEGF) on recipient endothelial cells which was caused by the presence of promoting-angiogenic factors on the cargo of EVs, such as lncRNA CCAT2, lncRNA POU3F3, miR-21 or CXCR4 receptor.	('promoting-angiogenic', 'PosReg', (189, 209))	('VEGF', 'Gene', '7422', (116, 120))	('CXCR4', 'Gene', (286, 291))	('POU3F3', 'Gene', (268, 274))	('POU3F3', 'Gene', '5455', (268, 274))	('enhanced', 'PosReg', (47, 55))	('CCAT2', 'Gene', (254, 259))	('angiogenesis process', 'CPA', (22, 42))	('upregulation', 'PosReg', (60, 72))	('VEGF', 'Gene', (116, 120))	('vascular endothelial growth factor', 'Gene', (80, 114))	('CXCR4', 'Gene', '7852', (286, 291))	('miR-21', 'Var', (276, 282))	('CCAT2', 'Gene', '101805488', (254, 259))	('vascular endothelial growth factor', 'Gene', '7422', (80, 114))
768877	32384712	Furthermore, miR-25-3p secreted via EVs shed by colon cancer cells was delivered to vascular endothelial cells, disrupting the integrity of endothelial barriers, and thus inducing vascular permeability and angiogenesis.	('miR-25-3p', 'Chemical', '-', (13, 22))	('colon cancer', 'Disease', (48, 60))	('miR-25-3p', 'Var', (13, 22))	('integrity', 'MPA', (127, 136))	('colon cancer', 'Phenotype', 'HP:0003003', (48, 60))	('angiogenesis', 'CPA', (206, 218))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('inducing', 'PosReg', (171, 179))	('colon cancer', 'Disease', 'MESH:D015179', (48, 60))	('vascular permeability', 'CPA', (180, 201))	('disrupting', 'NegReg', (112, 122))
768878	32384712	An induction of the pre-metastatic niche formation was also observed when EVs derived from colon cancer cells containing miR-25-3p were injected into nude mice.	('colon cancer', 'Disease', 'MESH:D015179', (91, 103))	('miR-25-3p', 'Chemical', '-', (121, 130))	('miR-25-3p', 'Var', (121, 130))	('pre-metastatic niche formation', 'CPA', (20, 50))	('nude mice', 'Species', '10090', (150, 159))	('colon cancer', 'Disease', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))
768879	32384712	Similarly, hepatocellular carcinoma cells secreted EVs containing miR-103 which attenuated the endothelial junction integrity by directly inhibiting the expression of VE-Cadherin, p20-catenin, and zonula occludens 1, thus increasing vascular permeability.	('hepatocellular carcinoma', 'Disease', (11, 35))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (11, 35))	('miR-103', 'Var', (66, 73))	('increasing', 'PosReg', (222, 232))	('VE-Cadherin', 'Gene', (167, 178))	('miR-103', 'Chemical', '-', (66, 73))	('endothelial junction integrity', 'MPA', (95, 125))	('attenuated', 'NegReg', (80, 90))	('inhibiting', 'NegReg', (138, 148))	('p20-catenin', 'Protein', (180, 191))	('VE-Cadherin', 'Gene', '1003', (167, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('expression', 'MPA', (153, 163))	('vascular permeability', 'MPA', (233, 254))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (11, 35))
768881	32384712	Also, EVs from epithelial ovarian cancer cells containing miRNA-141-3p promoted endothelial cell angiogenesis through activation of the JAK/STAT3 and NF-kappaB signaling pathways.	('JAK', 'Gene', '3717', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('activation', 'PosReg', (118, 128))	('NF-kappaB', 'Gene', '4790', (150, 159))	('miRNA-141-3p', 'Var', (58, 70))	('promoted', 'PosReg', (71, 79))	('epithelial ovarian cancer', 'Disease', (15, 40))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (15, 40))	('NF-kappaB', 'Gene', (150, 159))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (15, 40))	('JAK', 'Gene', (136, 139))	('STAT3', 'Gene', '6774', (140, 145))	('endothelial cell angiogenesis', 'CPA', (80, 109))	('miRNA-141-3p', 'Chemical', '-', (58, 70))	('ovarian cancer', 'Phenotype', 'HP:0100615', (26, 40))	('STAT3', 'Gene', (140, 145))
768883	32384712	Moreover, EVs shed by oral cancer cells contained miR-142-3p that could be taken up by recipient endothelial cells, promoting angiogenesis mediated by the protein TGFBR1.	('TGFBR1', 'Gene', '7046', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TGFBR1', 'Gene', (163, 169))	('miR-142-3p', 'Var', (50, 60))	('angiogenesis', 'CPA', (126, 138))	('miR-142-3p', 'Chemical', '-', (50, 60))	('promoting', 'PosReg', (116, 125))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
768884	32384712	Increased vascular density by miR-142-3p was confirmed in vivo using miR-142-3p overexpression in the mouse xenograft model of oral cancer.	('overexpression', 'PosReg', (80, 94))	('cancer', 'Disease', (132, 138))	('miR-142-3p', 'Chemical', '-', (69, 79))	('Increased vascular density', 'Phenotype', 'HP:0002634', (0, 26))	('mouse', 'Species', '10090', (102, 107))	('miR-142-3p', 'Gene', (69, 79))	('vascular', 'MPA', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Increased', 'PosReg', (0, 9))	('miR-142-3p', 'Var', (30, 40))	('miR-142-3p', 'Chemical', '-', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
768891	32384712	The mechanisms proposed include the induction of mesenchymal traits in non-tumor cells, modulation of the androgen receptor and TGF-beta signaling, or the alteration in cellular levels of tetraspanins CD9 and CD151 in the recipient cancer cells.	('cancer', 'Disease', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', (75, 80))	('alteration', 'Reg', (155, 165))	('CD151', 'Gene', '977', (209, 214))	('modulation', 'Var', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('TGF-beta', 'Gene', '7039', (128, 136))	('tetraspanins', 'MPA', (188, 200))	('CD9', 'Gene', (201, 204))	('mesenchymal traits', 'CPA', (49, 67))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('TGF-beta', 'Gene', (128, 136))	('cellular levels', 'MPA', (169, 184))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('androgen receptor', 'Gene', (106, 123))	('CD151', 'Gene', (209, 214))	('androgen receptor', 'Gene', '367', (106, 123))	('CD9', 'Gene', '928', (201, 204))	('induction', 'Reg', (36, 45))
768892	32384712	The horizontal transfer mediated by EVs of molecules responsible for enhancing cellular migration and facilitating invasion of recipient cancer cells was also observed in other cancer cell types.	('cellular migration', 'CPA', (79, 97))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (177, 183))	('EVs', 'Var', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('enhancing', 'PosReg', (69, 78))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('invasion', 'CPA', (115, 123))
768897	32384712	EVs derived from malignant donor cells with the KRAS mutant allele have high amounts of amphiregulin (AREG), which is a ligand for EGFR, increasing the potential invasiveness and metastasis in recipient cells.	('KRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (48, 52))	('increasing', 'PosReg', (137, 147))	('AREG', 'Gene', '374', (102, 106))	('EGFR', 'Gene', '1956', (131, 135))	('amphiregulin', 'Gene', (88, 100))	('EGFR', 'Gene', (131, 135))	('AREG', 'Gene', (102, 106))	('mutant', 'Var', (53, 59))	('amphiregulin', 'Gene', '374', (88, 100))
768903	32384712	Additionally, in EVs shed by hepatocellular carcinoma cancer cell lines, miR-93 and miR-103 were also found to contribute to cancer cell invasiveness.	('hepatocellular carcinoma cancer', 'Disease', 'MESH:D006528', (29, 60))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (54, 60))	('hepatocellular carcinoma cancer', 'Disease', (29, 60))	('miR-93', 'Gene', '407051', (73, 79))	('miR-103', 'Var', (84, 91))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (29, 53))	('miR-93', 'Gene', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('contribute', 'Reg', (111, 121))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('miR-103', 'Chemical', '-', (84, 91))
768905	32384712	Moreover, the presence of miR-103 in EVs derived from tumor-bearing mice was associated with increased vascular permeability and tumor metastasis.	('mice', 'Species', '10090', (68, 72))	('tumor metastasis', 'Disease', (129, 145))	('presence', 'Var', (14, 22))	('vascular permeability', 'CPA', (103, 124))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('miR-103', 'Var', (26, 33))	('tumor', 'Disease', (129, 134))	('tumor metastasis', 'Disease', 'MESH:D009362', (129, 145))	('miR-103', 'Chemical', '-', (26, 33))
768906	32384712	In another study, EVs shed by prostate carcinoma cell lines contained miR-1246 that inhibits N-cadherin and vimentin activities, which then inhibited epithelial-mesenchymal transition (EMT).	('epithelial-mesenchymal transition', 'CPA', (150, 183))	('vimentin', 'Gene', (108, 116))	('activities', 'MPA', (117, 127))	('inhibited', 'NegReg', (140, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('miR-1246', 'Var', (70, 78))	('N-cadherin', 'Gene', (93, 103))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (30, 48))	('prostate carcinoma', 'Disease', (30, 48))	('inhibits', 'NegReg', (84, 92))	('N-cadherin', 'Gene', '1000', (93, 103))	('prostate carcinoma', 'Disease', 'MESH:D011471', (30, 48))	('vimentin', 'Gene', '7431', (108, 116))
768907	32384712	The miR-1246 was detected in EVs isolated from the serum of xenograft mouse models and from the serum of aggressive prostate cancer patients.	('miR-1246', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mouse', 'Species', '10090', (70, 75))	('aggressive prostate cancer', 'Disease', 'MESH:D011471', (105, 131))	('aggressive prostate cancer', 'Disease', (105, 131))	('patients', 'Species', '9606', (132, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (116, 131))
768910	32384712	The presence of miR-99a-5p in EVs released by ovarian cancer cell lines increased fibronectin and vitronectin expression in peritoneal mesothelial cells, promoting cancer cell invasion.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('ovarian cancer', 'Disease', (46, 60))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('vitronectin', 'Gene', (98, 109))	('fibronectin', 'Gene', '2335', (82, 93))	('miR-99a-5p', 'Var', (16, 26))	('promoting', 'PosReg', (154, 163))	('vitronectin', 'Gene', '7448', (98, 109))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', (164, 170))	('expression', 'MPA', (110, 120))	('increased fibronectin', 'Phenotype', 'HP:0032463', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('increased', 'PosReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('miR-99a-5p', 'Chemical', '-', (16, 26))	('fibronectin', 'Gene', (82, 93))
768915	32384712	Interestingly, EVs secreted by breast cancer cells reprogrammed glucose metabolism in recipient non-tumor cells through the transfer of miR-122, which facilitated disease progression.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('disease progression', 'CPA', (163, 182))	('tumor', 'Disease', (100, 105))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('glucose metabolism', 'Disease', (64, 82))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('breast cancer', 'Disease', (31, 44))	('miR-122', 'Gene', '406906', (136, 143))	('miR-122', 'Gene', (136, 143))	('facilitated', 'PosReg', (151, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('transfer', 'Var', (124, 132))	('glucose metabolism', 'Disease', 'MESH:D044882', (64, 82))	('reprogrammed', 'Reg', (51, 63))
768922	32384712	EVs derived from colorectal cancer cells contained the oncogenic mutant beta-catenin which activated WNT signaling in recipient cells with wild-type beta-catenin, promoting cancer progression.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('beta-catenin', 'Protein', (72, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', (173, 179))	('mutant', 'Var', (65, 71))	('colorectal cancer', 'Disease', (17, 34))	('promoting', 'PosReg', (163, 172))	('activated', 'PosReg', (91, 100))	('WNT signaling', 'MPA', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))
768923	32384712	In addition, EVs released by epithelial ovarian cancer cell lines carrying SMAD4 mutations enhanced platinum-resistant phenotype in recipient drug-sensitive ovarian cancer cells, suggesting a possible transfer of SMAD4 mutations through EVs.	('drug-sensitive ovarian cancer', 'Disease', (142, 171))	('epithelial ovarian cancer', 'Disease', (29, 54))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (29, 54))	('drug-sensitive ovarian cancer', 'Disease', 'MESH:D019966', (142, 171))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (29, 54))	('platinum-resistant phenotype', 'CPA', (100, 128))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('SMAD4', 'Gene', (75, 80))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('SMAD4', 'Gene', (213, 218))	('mutations', 'Var', (81, 90))	('ovarian cancer', 'Phenotype', 'HP:0100615', (40, 54))	('SMAD4', 'Gene', '4089', (75, 80))	('enhanced', 'PosReg', (91, 99))	('platinum', 'Chemical', 'MESH:D010984', (100, 108))	('SMAD4', 'Gene', '4089', (213, 218))
768929	32384712	Nevertheless, we should be aware that some reports have shown contradicting data, with EVs inducing an anticancer immune response.	('EVs', 'Var', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('inducing', 'Reg', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
768934	32384712	Indeed, miR-1246 was also detected on EVs released by colon cancer cells and could reprogram macrophages to induce the production of tumor supportive factors, such as IL-10 and metalloproteinases (MMPs).	('MMPs', 'Gene', (197, 201))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('production', 'MPA', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('colon cancer', 'Disease', (54, 66))	('IL-10', 'Gene', (167, 172))	('miR-1246', 'Var', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (133, 138))	('induce', 'PosReg', (108, 114))	('MMPs', 'Gene', '4312', (197, 201))	('metal', 'Chemical', 'MESH:D008670', (177, 182))	('IL-10', 'Gene', '3586', (167, 172))
768935	32384712	demonstrated in vitro that miR-25-3p and miR-921-3p present in EVs secreted by liposarcoma cell lines were capable of stimulating the secretion of the pro-inflammatory cytokine IL-6 from macrophages, which in turn stimulated cancer cell proliferation.	('liposarcoma', 'Phenotype', 'HP:0012034', (79, 90))	('secretion', 'MPA', (134, 143))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('liposarcoma', 'Disease', 'MESH:D008080', (79, 90))	('miR-25-3p', 'Chemical', '-', (27, 36))	('stimulated', 'PosReg', (214, 224))	('IL-6', 'Gene', (177, 181))	('cancer', 'Disease', (225, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('IL-6', 'Gene', '3569', (177, 181))	('miR-921-3p', 'Var', (41, 51))	('miR-25-3p', 'Var', (27, 36))	('liposarcoma', 'Disease', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('stimulating', 'PosReg', (118, 129))
768944	32384712	Furthermore, EVs shed by nasopharyngeal carcinoma cell lines promoted T-cell dysfunction, which was mediated by miR-24-3p through repression of targeting fibroblast growth factor (FGF)11.	('T-cell dysfunction', 'Phenotype', 'HP:0005435', (70, 88))	('miR-24-3p', 'Var', (112, 121))	('carcinoma', 'Disease', 'MESH:D009369', (40, 49))	('T-cell dysfunction', 'Disease', (70, 88))	('promoted', 'PosReg', (61, 69))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (25, 49))	('repression', 'NegReg', (130, 140))	('FGF)11', 'Gene', '2256', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinoma', 'Disease', (40, 49))	('miR-24-3p', 'Chemical', '-', (112, 121))
768945	32384712	Moreover, the miR-24-3p was markedly enriched in EVs derived from nasopharyngeal carcinoma patients' serum when compared to healthy donors and correlated with worse disease-free survival of patients.	('carcinoma', 'Disease', (81, 90))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (190, 198))	('miR-24-3p', 'Chemical', '-', (14, 23))	('carcinoma', 'Disease', 'MESH:D009369', (81, 90))	('miR-24-3p', 'Var', (14, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (66, 90))	('correlated', 'Reg', (143, 153))
768966	32384712	Similarly, primary pancreatic fibroblasts isolated from mice were converted into CAFs-like cells in the presence of EVs released by pancreatic cancer cell lines, in a process mediated by miR-155 contained in the EVs cargo.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('pancreatic', 'Disease', 'MESH:D010195', (132, 142))	('pancreatic', 'Disease', (132, 142))	('pancreatic cancer', 'Disease', (132, 149))	('pancreatic', 'Disease', 'MESH:D010195', (19, 29))	('mice', 'Species', '10090', (56, 60))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('miR-155', 'Var', (187, 194))	('pancreatic', 'Disease', (19, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))
768968	32384712	This was shown in EVs derived from gastric cancer, colorectal cancer, melanoma and lung cancer cells and was mediated by the transfer of miR-27a, miR-10b, miR-155-5p and miR142-3p, respectively.	('miR142-3p', 'Var', (170, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('colorectal cancer', 'Disease', (51, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('miR-27a', 'Gene', '407018', (137, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('mediated by', 'Reg', (109, 120))	('miR-10b', 'Gene', (146, 153))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('miR-155-5p', 'Var', (155, 165))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('miR-10b', 'Gene', '406903', (146, 153))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (70, 94))	('miR-27a', 'Gene', (137, 144))	('gastric cancer', 'Disease', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))
768984	32384712	Indeed, it has been demonstrated that the knock-down of the MDR1 gene in donor cells does not impede the transfer of resistance, suggesting that other mechanisms are involved in this process.	('knock-down', 'Var', (42, 52))	('MDR1', 'Gene', '5243', (60, 64))	('MDR1', 'Gene', (60, 64))	('transfer of resistance', 'MPA', (105, 127))
768989	32384712	Moreover, EVs from drug-resistant chronic myeloid leukemia cells gave rise to an accumulation in recipient cells not only of P-gp and microRNAs (miR-27a, miR-451 and miR-21) related to P-gp expression, but also of the inhibitors of apoptosis proteins XIAP, IAP and survivin.	('miR-27a', 'Gene', '407018', (145, 152))	('miR-21', 'Var', (166, 172))	('miR-451', 'Gene', '574411', (154, 161))	('miR-27a', 'Gene', (145, 152))	('accumulation', 'PosReg', (81, 93))	('XIAP', 'Gene', '331', (251, 255))	('IAP', 'Gene', '961', (252, 255))	('myeloid leukemia', 'Disease', (42, 58))	('IAP', 'Gene', (252, 255))	('miR-451', 'Gene', (154, 161))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('survivin', 'Gene', (265, 273))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (34, 58))	('myeloid leukemia', 'Disease', 'MESH:D007951', (42, 58))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (42, 58))	('IAP', 'Gene', '961', (257, 260))	('survivin', 'Gene', '11799', (265, 273))	('XIAP', 'Gene', (251, 255))	('IAP', 'Gene', (257, 260))
768995	32384712	recently postulated that the EV-mediated transfer of CLIC1 protein induced vincristine resistance in gastric cancer cells in vitro, an effect suggested to be related to the up-regulation of P-gp and Bcl-2.	('CLIC1', 'Gene', (53, 58))	('gastric cancer', 'Disease', (101, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('transfer', 'Var', (41, 49))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('induced', 'PosReg', (67, 74))	('vincristine resistance', 'Phenotype', 'HP:0020174', (75, 97))	('vincristine resistance', 'MPA', (75, 97))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Bcl-2', 'Gene', (199, 204))	('Bcl-2', 'Gene', '596', (199, 204))	('vincristine', 'Chemical', 'MESH:D014750', (75, 86))
769000	32384712	This study also suggested that miR-183-5p possibly induced drug-resistance by modulating MECP2, thus regulating cell proliferation and influencing the biological process of response to hypoxia.	('cell proliferation', 'CPA', (112, 130))	('drug-resistance', 'Phenotype', 'HP:0020174', (59, 74))	('drug-resistance', 'MPA', (59, 74))	('biological process of response', 'CPA', (151, 181))	('miR-183-5p', 'Chemical', '-', (31, 41))	('MECP2', 'Gene', '4204', (89, 94))	('regulating', 'PosReg', (101, 111))	('hypoxia', 'Disease', (185, 192))	('hypoxia', 'Disease', 'MESH:D000860', (185, 192))	('miR-183-5p', 'Var', (31, 41))	('MECP2', 'Gene', (89, 94))	('influencing', 'Reg', (135, 146))	('induced', 'Reg', (51, 58))	('modulating', 'Reg', (78, 88))
769005	32384712	Furthermore, EVs from sorafenib-resistant renal cell carcinoma cell lines promoted resistance to this drug in vitro and in vivo, through the transfer of miR-31-5p which directly promoted down-regulation of MLH1 expression, one of the seven proteins that constitute the mismatch repair system.	('miR-31', 'Gene', '407035', (153, 159))	('promoted', 'PosReg', (74, 82))	('transfer', 'Var', (141, 149))	('resistance to this drug', 'MPA', (83, 106))	('down-regulation', 'NegReg', (187, 202))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (42, 62))	('MLH1', 'Gene', '4292', (206, 210))	('MLH1', 'Gene', (206, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('miR-31', 'Gene', (153, 159))	('sorafenib', 'Chemical', 'MESH:D000077157', (22, 31))	('renal cell carcinoma', 'Disease', (42, 62))	('expression', 'MPA', (211, 221))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (42, 62))
769010	32384712	The same study also observed increased levels of a miRNA panel (miR-204-5p, miR-139-5p, miR-29c-5p, miR-551b-3p, miR-29b-2-5p, and miR-204-3p) in the lung cancer model, when compared to their drug-sensitive counterparts.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('lung cancer', 'Disease', (150, 161))	('miR-29b-2', 'Gene', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('miR-551b-3p', 'Var', (100, 111))	('levels', 'MPA', (39, 45))	('miR-29b-2', 'Gene', '407025', (113, 122))	('increased', 'PosReg', (29, 38))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('miR-204-5p', 'Var', (64, 74))	('miR-139-5p', 'Var', (76, 86))	('miR-29c-5p', 'Var', (88, 98))
769013	32384712	Similarly, the downregulation of miR-100-5p in EVs retrieved from cisplatin-resistance lung cancer cells was capable of inducing resistance in recipient cells, an effect further confirmed in vivo.	('miR-100-5p', 'Var', (33, 43))	('downregulation', 'NegReg', (15, 29))	('inducing', 'Reg', (120, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('resistance', 'MPA', (129, 139))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('miR-100-5p', 'Chemical', '-', (33, 43))
769019	32384712	Additionally, EV-mediated intercellular transfer of lncARSR (which promoted Sunitinib resistance through competitive binding with miR-34/miR-449) increased AXL and c-MET expression in renal cell carcinoma cells.	('Sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('promoted', 'PosReg', (67, 75))	('Sunitinib resistance', 'MPA', (76, 96))	('renal cell carcinoma', 'Disease', (184, 204))	('increased', 'PosReg', (146, 155))	('c-MET', 'Gene', '4233', (164, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (184, 204))	('binding', 'Interaction', (117, 124))	('miR-34', 'Gene', (130, 136))	('AXL', 'Gene', (156, 159))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (184, 204))	('miR-34', 'Gene', '407040', (130, 136))	('c-MET', 'Gene', (164, 169))	('AXL', 'Gene', '558', (156, 159))	('lncARSR', 'Var', (52, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))
769039	32384712	Indeed, it has been suggested that: (a) cancer cells secreting more EVs achieve the greatest levels of resistance and that (b) drug-resistant cells can export larger quantities of drugs into their EVs than drug-sensitive cells.	('export', 'MPA', (152, 158))	('levels', 'MPA', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('drug-resistant', 'Var', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('resistance', 'MPA', (103, 113))
769047	32384712	A comprehensive study in pancreatic ductal adenocarcinoma cell lines reported that an increase of miR-155 expression levels in cells transfected with pre-miR-155 caused an increase in the secretion of EVs and an increase in miR-155 expression levels on the released EVs content.	('increase', 'PosReg', (86, 94))	('increase', 'PosReg', (172, 180))	('miR-155', 'Gene', (98, 105))	('miR-155 expression levels', 'MPA', (224, 249))	('secretion of EVs', 'MPA', (188, 204))	('pre-miR-155', 'Var', (150, 161))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (25, 57))	('increase', 'PosReg', (212, 220))	('pancreatic ductal adenocarcinoma', 'Disease', (25, 57))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (25, 57))	('expression levels', 'MPA', (106, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
769048	32384712	Those EVs delivered miR-155 into other pancreatic ductal adenocarcinoma cancer cells, inducing gemcitabine-resistance in recipient cells.	('inducing', 'PosReg', (86, 94))	('miR-155', 'Var', (20, 27))	('pancreatic ductal adenocarcinoma cancer', 'Disease', 'MESH:D010190', (39, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (39, 71))	('pancreatic ductal adenocarcinoma cancer', 'Disease', (39, 78))	('delivered', 'Reg', (10, 19))	('gemcitabine-resistance', 'MPA', (95, 117))	('gemcitabine', 'Chemical', 'MESH:C056507', (95, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
769082	32296643	Since then, surface markers have been used to identify and isolate CSCs in several types of cancers, for instance, CD24, CD44, CD90, CD133, and CD166 for Gastrointestinal CSC, and it was demonstrated that they are generally tissue specific (Table 1).	('CD24', 'Gene', '100133941', (115, 119))	('CD24', 'Gene', (115, 119))	('CD133', 'Var', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('Gastrointestinal CSC', 'Disease', 'MESH:D005767', (154, 174))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('CD166', 'Gene', (144, 149))	('Gastrointestinal CSC', 'Disease', (154, 174))	('cancers', 'Disease', (92, 99))	('CD90', 'Gene', '7070', (127, 131))	('CD44', 'Gene', '960', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('CD90', 'Gene', (127, 131))	('CD166', 'Gene', '214', (144, 149))	('CD44', 'Gene', (121, 125))
769106	32296643	In this regard, gastric tumor tissues overexpressing LINGO2 shows elevated expression of the angiogenic marker pVEGFR2 and a blood vessel marker CD34, meanwhile the silencing of LINGO2 in Human Umbilical Vein Endothelial Cells (HUVEC) cells results in inhibition of tube formation, suggesting the involvement of positive-LINGO2 CSCs in angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('LINGO2', 'Gene', '158038', (178, 184))	('silencing', 'Var', (165, 174))	('VEGFR2', 'Gene', (112, 118))	('LINGO2', 'Gene', (53, 59))	('CD34', 'Gene', (145, 149))	('gastric tumor', 'Disease', (16, 29))	('inhibition', 'NegReg', (252, 262))	('gastric tumor', 'Disease', 'MESH:D013274', (16, 29))	('gastric tumor', 'Phenotype', 'HP:0006753', (16, 29))	('VEGFR2', 'Gene', '3791', (112, 118))	('elevated', 'PosReg', (66, 74))	('LINGO2', 'Gene', (321, 327))	('Human', 'Species', '9606', (188, 193))	('Umbilical Vein Endothelial', 'CellLine', 'CVCL:2G60', (194, 220))	('LINGO2', 'Gene', (178, 184))	('LINGO2', 'Gene', '158038', (53, 59))	('CD34', 'Gene', '947', (145, 149))	('tube formation', 'CPA', (266, 280))	('LINGO2', 'Gene', '158038', (321, 327))	('expression', 'MPA', (75, 85))
769115	32296643	Meanwhile, EPCs also increases tumorigenesis of CRC cells through angiogenesis.	('increases', 'PosReg', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('EPCs', 'Var', (11, 15))	('tumor', 'Disease', (31, 36))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('angiogenesis', 'CPA', (66, 78))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
769119	32296643	Moreover, VEGF-A/NRP-1 interaction promotes stemness properties in breast cancer (BC) cell lines by activation of Wnt/beta-catenin pathway, since its inhibition relies in the attenuation of HUVEC-tube formation induced by co-culturing with extracts from Breast Cancer Stem Cells (BCSCs).	('NRP-1', 'Gene', '8829', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('BC', 'Phenotype', 'HP:0003002', (280, 282))	('BC', 'Phenotype', 'HP:0003002', (82, 84))	('beta-catenin', 'Gene', (118, 130))	('promotes', 'PosReg', (35, 43))	('VEGF-A', 'Gene', (10, 16))	('interaction', 'Var', (23, 34))	('beta-catenin', 'Gene', '1499', (118, 130))	('Breast Cancer', 'Disease', 'MESH:D001943', (254, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('stemness properties', 'CPA', (44, 63))	('Breast Cancer', 'Disease', (254, 267))	('Cancer', 'Phenotype', 'HP:0002664', (261, 267))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('breast cancer', 'Disease', (67, 80))	('Breast Cancer', 'Phenotype', 'HP:0003002', (254, 267))	('NRP-1', 'Gene', (17, 22))	('VEGF-A', 'Gene', '7422', (10, 16))	('attenuation', 'NegReg', (175, 186))	('HUVEC-tube formation', 'CPA', (190, 210))	('activation', 'PosReg', (100, 110))
769132	32296643	Besides, CD133+ ACC CSCs and xenograft tumors of nude mice injected with these cells show overexpression of VE-Cadherin and VM mediators (MMP-2, MMP-9).	('nude mice', 'Species', '10090', (49, 58))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('MMP-9', 'Gene', '17395', (145, 150))	('MMP-9', 'Gene', (145, 150))	('MMP-2', 'Gene', (138, 143))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('MMP-2', 'Gene', '17390', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('CD133+', 'Var', (9, 15))	('tumors', 'Disease', (39, 45))	('overexpression', 'PosReg', (90, 104))	('VE-Cadherin', 'Protein', (108, 119))
769149	32296643	It has been shown that abnormal blood vessels are capable to obstruct immune response to the tumor, as wells as, the transportation and distribution of oxygen and chemotherapeutics.	('transportation', 'MPA', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('obstruct', 'NegReg', (61, 69))	('tumor', 'Disease', (93, 98))	('oxygen', 'Chemical', 'MESH:D010100', (152, 158))	('abnormal', 'Var', (23, 31))	('abnormal blood vessels', 'Phenotype', 'HP:0002597', (23, 45))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
769156	32296643	Moreover, Ginsenoside Rg3, a derived from ginseng, represses growth cells and CSCs properties in CRC cells, as well as, inhibits angiogenesis-related genes, suppressing vascularization in xenograft tumors.	('inhibits', 'NegReg', (120, 128))	('Ginsenoside', 'Var', (10, 21))	('suppressing', 'NegReg', (157, 168))	('represses', 'NegReg', (51, 60))	('ginseng', 'Species', '4054', (42, 49))	('angiogenesis-related genes', 'Gene', (129, 155))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('Ginsenoside Rg3', 'Chemical', 'MESH:C097367', (10, 25))
769192	31906910	A 65-year-old male patient with a 3-month history of dysphagia was diagnosed with locally advanced thoracic esophageal squamous cell cancer, cT4bN1M0, stage IVA (Union for International Cancer Control TNM 8th edition) (Fig.	('patient', 'Species', '9606', (19, 26))	('dysphagia', 'Disease', 'MESH:D003680', (53, 62))	('thoracic esophageal squamous cell cancer', 'Disease', (99, 139))	('thoracic esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (99, 139))	('dysphagia', 'Disease', (53, 62))	('cT4bN1M0', 'Var', (141, 149))	('TNM', 'Gene', '10178', (201, 204))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (119, 139))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('dysphagia', 'Phenotype', 'HP:0002015', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TNM', 'Gene', (201, 204))
769221	31906910	In the clinical case reported in the present study, tumor location was monitored with cone-beam CT and chest radiography during the course of chemoradiotherapy, which enabled the detection of significant geometrical errors in the tumor location outside of the irradiation fields and subsequently lead to correcting these errors through an adaptive radiotherapy plan to deliver an adequate dose to the targets.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (230, 235))	('errors', 'Var', (216, 222))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
769239	30808397	It has been reported that dietary habits, environmental factors, stress, and genetic mutations could contribute to esophageal cancer.	('contribute', 'Reg', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('genetic mutations', 'Var', (77, 94))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))
769247	30808397	One study further identified that WISP2 expression was enhanced by serum and correlated with serum-induced cell proliferation in breast cancer cells, demonstrating that WISP2 could enhance cell proliferation in breast cancer.	('expression', 'MPA', (40, 50))	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('enhance', 'PosReg', (181, 188))	('enhanced', 'PosReg', (55, 63))	('cell proliferation', 'CPA', (189, 207))	('WISP2', 'Var', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('breast cancer', 'Disease', (211, 224))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('WISP2', 'Gene', (34, 39))
769277	30808397	To establish all the nude mice models of ESCC which were divided into three groups, Eca109 control group, Eca109-empty vector group, Eca109-WISP2 expression.	('ESCC', 'Disease', (41, 45))	('nude mice', 'Species', '10090', (21, 30))	('Eca109-WISP2', 'Var', (133, 145))
769296	30808397	We also observed that the expression of ERK and Slug was downregulated in cells after WISP2 cDNA transfection in ESCC cells (Fig.	('expression', 'MPA', (26, 36))	('downregulated', 'NegReg', (57, 70))	('ERK', 'Gene', '5594', (40, 43))	('ERK', 'Gene', (40, 43))	('Slug', 'Gene', (48, 52))	('transfection', 'Var', (97, 109))
769302	30808397	Our wound healing assay results showed that WISP2 siRNA transfection led to an increase of cell wound healing in Eca109 cells (p = 0.0007) and EC9706 (p = 0.0003) cells (Fig.	('increase', 'PosReg', (79, 87))	('EC9706', 'CellLine', 'CVCL:E307', (143, 149))	('cell wound healing', 'CPA', (91, 109))	('transfection', 'Var', (56, 68))
769303	30808397	We found that WISP2 siRNA transfected cells showed 3-3.5 folds promotion of cell invasion in both Eca109 cells (p < 0.001) and EC9706 (p = 0.0011) compared to control siRNA transfected cells (Fig.	('promotion', 'PosReg', (63, 72))	('EC9706', 'CellLine', 'CVCL:E307', (127, 133))	('cell invasion in', 'CPA', (76, 92))	('EC9706', 'Var', (127, 133))
769314	30808397	Inactivation of PD-L1 restored the susceptibility of resistant cells with WISP2 downregulation to CTL treatment.	('susceptibility', 'MPA', (35, 49))	('PD-L1', 'Gene', (16, 21))	('downregulation', 'NegReg', (80, 94))	('PD-L1', 'Gene', '29126', (16, 21))	('Inactivation', 'Var', (0, 12))
769316	30808397	Further, loss of WISP2 enhanced cancer stem-like phenotype characterized and increased the level of stem cell markers Nanog and Oct3/4, and activated TGF-beta pathway in breast tumor cells.	('breast tumor', 'Phenotype', 'HP:0100013', (170, 182))	('enhanced', 'PosReg', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('WISP2', 'Gene', (17, 22))	('Oct3/4', 'Gene', '5460', (128, 134))	('cancer', 'Disease', (32, 38))	('breast tumor', 'Disease', 'MESH:D001943', (170, 182))	('Oct3/4', 'Gene', (128, 134))	('loss', 'Var', (9, 13))	('TGF-beta', 'Gene', '7040', (150, 158))	('breast tumor', 'Disease', (170, 182))	('activated', 'PosReg', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('increased', 'PosReg', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('TGF-beta', 'Gene', (150, 158))
769318	30808397	HBx (hepatitis B virus X gene) mutants, frequently happened in HBV (hepatitis B virus)-related hepatocellular carcinoma, enhanced cell proliferation and migration via regulation of Wnt/beta-catenin signaling pathway.	('hepatitis', 'Phenotype', 'HP:0012115', (68, 77))	('mutants', 'Var', (31, 38))	('HBx', 'Gene', '944566', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('HBV', 'Gene', (63, 66))	('beta-catenin', 'Gene', '1499', (185, 197))	('migration', 'CPA', (153, 162))	('enhanced', 'PosReg', (121, 129))	('HBx', 'Gene', (0, 3))	('hepatitis', 'Phenotype', 'HP:0012115', (5, 14))	('HBV', 'Species', '10407', (63, 66))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (95, 119))	('hepatitis B virus X gene', 'Gene', (5, 29))	('hepatitis B virus X gene', 'Gene', '944566', (5, 29))	('hepatocellular carcinoma', 'Disease', (95, 119))	('cell proliferation', 'CPA', (130, 148))	('beta-catenin', 'Gene', (185, 197))
769319	30808397	HBx mutants stabilized beta-catenin level via inhibition of GSK3beta in HCC cells, resulted in increased WISP2 and c-Myc.	('mutants', 'Var', (4, 11))	('c-Myc', 'Gene', '4609', (115, 120))	('inhibition', 'NegReg', (46, 56))	('HBx', 'Gene', '944566', (0, 3))	('GSK3beta', 'Gene', (60, 68))	('c-Myc', 'Gene', (115, 120))	('WISP2', 'MPA', (105, 110))	('HBx', 'Gene', (0, 3))	('beta-catenin', 'Gene', (23, 35))	('HCC', 'CellLine', 'CVCL:0C54', (72, 75))	('GSK3beta', 'Gene', '2932', (60, 68))	('stabilized', 'PosReg', (12, 22))	('increased', 'PosReg', (95, 104))	('beta-catenin', 'Gene', '1499', (23, 35))
769335	29488611	The present study aimed to examine the potential role of miRNA (miR)-205-5p in the developmental process of colorectal cancer (CRC) through protein-tyrosine kinase 7 (PTK7).	('PTK7', 'Gene', (167, 171))	('5p', 'Chemical', '-', (73, 75))	('CRC', 'Phenotype', 'HP:0003003', (127, 130))	('PTK7', 'Gene', '5754', (167, 171))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('protein-tyrosine kinase 7', 'Gene', (140, 165))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('protein-tyrosine kinase 7', 'Gene', '5754', (140, 165))	('colorectal cancer', 'Disease', (108, 125))	('miRNA', 'Var', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
769362	29488611	The HT29 and SW480 cells were then transfected with miR-205-5p (50 nM), miR-control (50 nM), inhibitor NC (50 nM), and miR-205-5p inhibitor (50 nM), respectively.	('miR-205', 'Gene', '406988', (52, 59))	('miR-205', 'Gene', (119, 126))	('SW480', 'CellLine', 'CVCL:0546', (13, 18))	('miR-control', 'Var', (72, 83))	('miR-205', 'Gene', '406988', (119, 126))	('5p', 'Chemical', '-', (60, 62))	('5p', 'Chemical', '-', (127, 129))	('miR-205', 'Gene', (52, 59))	('HT29', 'CellLine', 'CVCL:0320', (4, 8))
769381	29488611	MAB4499; R&D Systems, Inc., Minneapolis, MN, USA); anti-GAPDH antibody (1:4,000; cat.	('antibody', 'Var', (62, 70))	('GAPDH', 'Gene', '2597', (56, 61))	('GAPDH', 'Gene', (56, 61))	('MN', 'CellLine', 'CVCL:U508', (41, 43))
769385	29488611	The sequences of the wild-type (WT) and mutant type (Mut) PTK7-3'UTR were amplified by PCR using human genomic DNA of the HT29 cell line and cloned into the pGL3-promoter vector (Promega Corporation, Madison, WI, USA; cat.	('pGL3', 'Gene', '6391', (157, 161))	('PTK7', 'Gene', (58, 62))	('human', 'Species', '9606', (97, 102))	('PTK7', 'Gene', '5754', (58, 62))	('HT29', 'CellLine', 'CVCL:0320', (122, 126))	('mutant', 'Var', (40, 46))	('pGL3', 'Gene', (157, 161))
769398	29488611	The HT29 and SW480 cells were then transfected with hsa-miR-NC (negative control) and the predicted miRNAs (miR-409-5p, miR-205-5p, miR-495-3p, miR-5688, and miR-503-5p, respectively).	('miR-5688', 'Var', (144, 152))	('5p', 'Chemical', '-', (128, 130))	('SW480', 'CellLine', 'CVCL:0546', (13, 18))	('5p', 'Chemical', '-', (166, 168))	('miR-205', 'Gene', (120, 127))	('5p', 'Chemical', '-', (116, 118))	('miR-495-3p', 'Var', (132, 142))	('miR-205', 'Gene', '406988', (120, 127))	('miR-409-5p', 'Var', (108, 118))	('HT29', 'CellLine', 'CVCL:0320', (4, 8))	('miR-503-5p', 'Var', (158, 168))
769409	29488611	The results of the western blot analysis indicated that miR-205-5p also decreased the protein expression levels of PTK7 in the HT29 and SW480 cells; the inhibition of miR-205-5p by the inhibitor increased the protein expression level of PTK7 in HT29 and SW480 cells (Fig.	('miR-205', 'Gene', '406988', (56, 63))	('increased', 'PosReg', (195, 204))	('inhibition', 'Var', (153, 163))	('protein expression level', 'MPA', (209, 233))	('decreased', 'NegReg', (72, 81))	('PTK7', 'Gene', (237, 241))	('miR-205', 'Gene', (167, 174))	('miR-205', 'Gene', (56, 63))	('protein expression levels', 'MPA', (86, 111))	('PTK7', 'Gene', '5754', (237, 241))	('PTK7', 'Gene', (115, 119))	('HT29', 'CellLine', 'CVCL:0320', (127, 131))	('SW480', 'CellLine', 'CVCL:0546', (136, 141))	('HT29', 'CellLine', 'CVCL:0320', (245, 249))	('SW480', 'CellLine', 'CVCL:0546', (254, 259))	('5p', 'Chemical', '-', (64, 66))	('miR-205', 'Gene', '406988', (167, 174))	('5p', 'Chemical', '-', (175, 177))	('PTK7', 'Gene', '5754', (115, 119))
769511	27994502	Studies showed that disfunction or deletion of TUSC3 exert its oncological effects as a modulator by inhibiting glycosylation efficiency and consequently inducing the endoplasmic reticulum stress and cell malignant transformation.	('disfunction', 'Var', (20, 31))	('cell malignant transformation', 'CPA', (200, 229))	('inducing', 'Reg', (154, 162))	('TUSC3', 'Gene', '7991', (47, 52))	('glycosylation efficiency', 'Disease', 'MESH:D018981', (112, 136))	('deletion', 'Var', (35, 43))	('glycosylation efficiency', 'Disease', (112, 136))	('endoplasmic reticulum stress', 'MPA', (167, 195))	('TUSC3', 'Gene', (47, 52))	('inhibiting', 'NegReg', (101, 111))
769539	27994502	Additionally, the positive rate of TUSC3 expressions in patients with differentiated degree 1 showed no difference with those in patients with differentiated degree 2+3 (p=0.131, Table 1).	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (129, 137))	('TUSC3', 'Gene', (35, 40))	('differentiated', 'Var', (70, 84))	('TUSC3', 'Gene', '7991', (35, 40))
769556	27994502	Marta found that TUSC3 plays a role in metastasis and that loss of TUSC3 is negatively related with lymph node metastasis in larynx and pharynx squamous cell carcinomas.	('TUSC3', 'Gene', (17, 22))	('larynx', 'Disease', (125, 131))	('TUSC3', 'Gene', '7991', (67, 72))	('lymph node metastasis', 'CPA', (100, 121))	('negatively', 'NegReg', (76, 86))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (144, 168))	('squamous cell carcinomas', 'Disease', (144, 168))	('TUSC3', 'Gene', '7991', (17, 22))	('TUSC3', 'Gene', (67, 72))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (144, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('loss', 'Var', (59, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))
769576	27994502	We found that low TUSC3 expression group had a significantly poorer OS than those with high TUSC3 expression group (P<0.0001; Figure 4).	('TUSC3', 'Gene', '7991', (92, 97))	('TUSC3', 'Gene', (18, 23))	('TUSC3', 'Gene', '7991', (18, 23))	('TUSC3', 'Gene', (92, 97))	('OS', 'Chemical', 'MESH:D009992', (68, 70))	('low', 'Var', (14, 17))	('poorer', 'NegReg', (61, 67))
769601	27399176	In addition to single-nucleotide variants, copy-number alterations, and alterations of multiple signaling pathways in human ESCC, these studies further demonstrated (1) genomic alterations in a precancerous lesion, atypical hyperplasia; (2) mutual exclusivity of NOTCH1 and PIK3CA mutations; (3) structural variations, including deletions and translocations through non-homologous end joining or alternative end-joining mechanisms and local chromosomal misarrangements through the mechanisms of chromothripsis, kataegis, and breakage-fusion bridge.	('deletions', 'Var', (329, 338))	('PIK3CA', 'Gene', (274, 280))	('chromothripsis', 'Disease', (495, 509))	('NOTCH1', 'Gene', (263, 269))	('PIK3CA', 'Gene', '5290', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('hyperplasia', 'Disease', 'MESH:D006965', (224, 235))	('precancerous lesion', 'Disease', (194, 213))	('translocations', 'Var', (343, 357))	('precancerous lesion', 'Disease', 'MESH:D011230', (194, 213))	('mutations', 'Var', (281, 290))	('human', 'Species', '9606', (118, 123))	('hyperplasia', 'Disease', (224, 235))	('alternative end-joining', 'CPA', (396, 419))	('NOTCH1', 'Gene', '4851', (263, 269))
769607	27399176	Among the single-nucleotide variants, copy-number alterations, and alterations of multiple signaling pathways, SOX2 amplification is clearly a cancer driver leading to ESCC.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('SOX2', 'Gene', (111, 115))	('alterations', 'Reg', (67, 78))	('amplification', 'Var', (116, 129))	('single-nucleotide variants', 'Var', (10, 36))	('cancer', 'Disease', (143, 149))	('leading to', 'Reg', (157, 167))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
769624	27399176	Silencing of DeltaNp63alpha in ESCC cells inhibited cell proliferation and colony formation via downregulation of Akt signaling.	('Akt', 'Gene', (114, 117))	('p63', 'Gene', '8626', (19, 22))	('cell proliferation', 'CPA', (52, 70))	('colony formation', 'CPA', (75, 91))	('inhibited', 'NegReg', (42, 51))	('downregulation', 'NegReg', (96, 110))	('Akt', 'Gene', '207', (114, 117))	('p63', 'Gene', (19, 22))	('Silencing', 'Var', (0, 9))
769629	27399176	CBX3 regulates RNA processing genome-wide, and loss of CBX3 leads to dramatic accumulation of unspliced nascent transcripts and alterations in target gene expression.	('CBX3', 'Gene', (55, 59))	('unspliced nascent transcripts', 'MPA', (94, 123))	('alterations', 'Reg', (128, 139))	('CBX3', 'Gene', '11335', (0, 4))	('CBX3', 'Gene', '11335', (55, 59))	('expression', 'MPA', (155, 165))	('RNA processing', 'MPA', (15, 29))	('loss', 'Var', (47, 51))	('CBX3', 'Gene', (0, 4))	('accumulation', 'PosReg', (78, 90))
769632	27399176	Loss of KLF5 in the context of TP53 deletion drives invasive progression of ESCC, and restoration of KLF5 leads to apoptosis and suppresses cell survival.	('cell survival', 'CPA', (140, 153))	('deletion', 'Var', (36, 44))	('TP53', 'Gene', '7157', (31, 35))	('invasive progression', 'CPA', (52, 72))	('TP53', 'Gene', (31, 35))	('suppresses', 'NegReg', (129, 139))	('KLF5', 'Gene', (101, 105))	('Loss', 'NegReg', (0, 4))	('KLF5', 'Gene', '688', (101, 105))	('KLF5', 'Gene', (8, 12))	('KLF5', 'Gene', '688', (8, 12))	('apoptosis', 'CPA', (115, 124))	('ESCC', 'Disease', (76, 80))
769633	27399176	PARP1 interacts with and poly(ADP-ribosyl)ates SOX2 directly for degradation of SOX2 protein.	('poly(ADP-ribosyl)ates', 'Chemical', '-', (25, 46))	('degradation of SOX2 protein', 'MPA', (65, 92))	('interacts', 'Interaction', (6, 15))	('poly(ADP-ribosyl', 'Var', (25, 41))	('PARP1', 'Gene', (0, 5))	('PARP1', 'Gene', '142', (0, 5))
769634	27399176	As a result, PARP1 knockout enhances SOX2 expression and modifies cell differentiation.	('PARP1', 'Gene', (13, 18))	('knockout', 'Var', (19, 27))	('modifies', 'Reg', (57, 65))	('expression', 'MPA', (42, 52))	('SOX2', 'Protein', (37, 41))	('cell differentiation', 'CPA', (66, 86))	('enhances', 'PosReg', (28, 36))	('PARP1', 'Gene', '142', (13, 18))
769641	27399176	Four approaches are potentially applicable for ESCC: (1) using small interfering RNA (siRNA) to target SOX2 and/or DeltaNp63alpha, although this approach is not feasible at this time; (2) enhancing the immune reaction against cancer cells with overexpressed SOX2 and DeltaNp63alpha participate; and (4) targeting epigenetic modifications in which SOX2 and DeltaNp63alpha are involved.	('enhancing', 'PosReg', (188, 197))	('p63', 'Gene', '8626', (273, 276))	('p63', 'Gene', (121, 124))	('immune', 'MPA', (202, 208))	('epigenetic modifications', 'Var', (313, 337))	('cancer', 'Disease', (226, 232))	('p63', 'Gene', (362, 365))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('p63', 'Gene', '8626', (121, 124))	('p63', 'Gene', (273, 276))	('p63', 'Gene', '8626', (362, 365))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
769642	27399176	For example, specific inhibitors of KDM1A/LSD1, a SOX2-associated protein, selectively impair the growth of SOX2+ lung squamous cell carcinoma, but not that of SOX2- cells.	('LSD1', 'Gene', (42, 46))	('inhibitors', 'Var', (22, 32))	('LSD1', 'Gene', '23028', (42, 46))	('KDM1A', 'Gene', '23028', (36, 41))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (114, 142))	('growth', 'MPA', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('KDM1A', 'Gene', (36, 41))	('impair', 'NegReg', (87, 93))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('lung squamous cell carcinoma', 'Disease', (114, 142))
769643	27399176	Inactivation of KDM1A reduces SOX2 expression, promotes G1 cell cycle arrest, and induces genes for differentiation by selectively modulating the methylation states of H3K4 and H3K9.	('induces', 'Reg', (82, 89))	('H3K9', 'Protein', (177, 181))	('KDM1A', 'Gene', '23028', (16, 21))	('promotes', 'PosReg', (47, 55))	('expression', 'MPA', (35, 45))	('KDM1A', 'Gene', (16, 21))	('genes for differentiation', 'MPA', (90, 115))	('modulating', 'Reg', (131, 141))	('G1 cell cycle arrest', 'CPA', (56, 76))	('methylation states', 'MPA', (146, 164))	('SOX2', 'Protein', (30, 34))	('H3K4', 'Protein', (168, 172))	('reduces', 'NegReg', (22, 29))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (59, 76))	('Inactivation', 'Var', (0, 12))
769645	27399176	Second, there is a possibility of inducing phenotype switching of cancer cells (i.e., transdifferentiation of ESCC cells into adenosquamous cells or even adenocarcinoma cells), as loss of SOX2 and p63 is an early event in intestinal metaplasia of the esophageal squamous epithelium.	('p63', 'Gene', '8626', (197, 200))	('inducing', 'Reg', (34, 42))	('intestinal metaplasia of the esophageal squamous', 'Disease', 'MESH:D000077277', (222, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('adenocarcinoma', 'Disease', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('loss', 'Var', (180, 184))	('adenocarcinoma', 'Disease', 'MESH:D000230', (154, 168))	('SOX2', 'Gene', (188, 192))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('p63', 'Gene', (197, 200))	('cancer', 'Disease', (66, 72))	('intestinal metaplasia of the esophageal squamous', 'Disease', (222, 270))
769720	27110950	Actually, a recent study comparing 74-Gy and 60-Gy photon radiotherapy showed no advantage in both local recurrence and overall survival.10 We assumed that overall toxicities were unacceptably high by photon 74 Gy irradiation.	('photon 74 Gy', 'Var', (201, 213))	('toxicities', 'Disease', 'MESH:D064420', (164, 174))	('toxicities', 'Disease', (164, 174))
769723	27110950	In conclusion, considering these issues, we maintain that PBT at a dose of 66 Gy (RBE) is more appropriate to reduce overall toxicity and improve therapeutic ratios, and identified this as the RD for future clinical trials.	('therapeutic ratios', 'MPA', (146, 164))	('improve', 'PosReg', (138, 145))	('toxicity', 'Disease', 'MESH:D064420', (125, 133))	('toxicity', 'Disease', (125, 133))	('PBT', 'Var', (58, 61))	('reduce', 'NegReg', (110, 116))
769725	25606572	Almost all the epigenetic mechanisms including cytosine methylation and hydroxymethylation, chromatin remodeling and non-coding RNAs have been found associate with carcinogenesis and cancer specific expression profile.	('cancer', 'Disease', (183, 189))	('hydroxymethylation', 'MPA', (72, 90))	('associate', 'Reg', (149, 158))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('cytosine', 'Chemical', 'MESH:D003596', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('carcinogenesis', 'Disease', (164, 178))	('non-coding RNAs', 'Var', (117, 132))	('As', 'Chemical', 'MESH:D001151', (130, 132))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cytosine methylation', 'MPA', (47, 67))
769730	25606572	It is believed that tumor initiation and progression result from acquired genomic alteration within the originally normal cells, however, there's increasing evidence supporting epigenetic impacts and epigenomics alterations in human cancer development without a change of DNA sequence.	('tumor initiation', 'Disease', 'MESH:D009369', (20, 36))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('epigenomics alterations', 'Var', (200, 223))	('human', 'Species', '9606', (227, 232))	('tumor initiation', 'Disease', (20, 36))	('epigenetic', 'Var', (177, 187))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
769731	25606572	Epigenetic impact includes changes in gene expression pattern derived by DNA methylation, histone modifications, ATP-dependent chromatin remodeling and non-coding RNA.	('gene expression pattern', 'MPA', (38, 61))	('ATP', 'Chemical', 'MESH:D000255', (113, 116))	('DNA methylation', 'Var', (73, 88))	('histone modifications', 'MPA', (90, 111))	('changes', 'Reg', (27, 34))
769739	25606572	There are two basic mechanisms by which DNA methylation inhibits gene expression: direct blocking transcriptional activators from binding to cognate DNA sequences; and recruiting transcriptional repressors to silence gene expression through proteins that recognize methylated DNA.	('methylation', 'Var', (44, 55))	('silence', 'NegReg', (209, 216))	('trans', 'Chemical', 'MESH:C057348', (98, 103))	('proteins', 'Protein', (241, 249))	('trans', 'Chemical', 'MESH:C057348', (179, 184))	('inhibits', 'NegReg', (56, 64))	('methylated', 'Var', (265, 275))	('gene expression', 'MPA', (217, 232))	('gene expression', 'MPA', (65, 80))	('transcriptional', 'MPA', (98, 113))	('binding', 'Interaction', (130, 137))	('blocking', 'NegReg', (89, 97))
769740	25606572	Notably, while inversed correlation between gene promoter DNA methylation and gene transcription is wildly observed, gene body methylation which is called intragenic DNA methylation is more likely correlated to other functions such as modulate alternative promoter usage, production of intragenic non-coding RNA transcripts, cotranscriptional splicing, and transcription initiation or elongation.	('alternative promoter usage', 'MPA', (244, 270))	('trans', 'Chemical', 'MESH:C057348', (312, 317))	('methylation', 'Var', (127, 138))	('correlated', 'Reg', (197, 207))	('modulate', 'Var', (235, 243))	('cotranscriptional splicing', 'MPA', (325, 351))	('trans', 'Chemical', 'MESH:C057348', (357, 362))	('trans', 'Chemical', 'MESH:C057348', (83, 88))	('transcription initiation', 'CPA', (357, 381))	('trans', 'Chemical', 'MESH:C057348', (327, 332))
769744	25606572	Newly synthesized DNA is methylated by DNMT1 by its binding to hemimethylated DNA during DNA replication and copying 5mC marks from the parental strand to the newly synthesized strand.	('5mC', 'Chemical', 'MESH:D044503', (117, 120))	('DNMT1', 'Gene', (39, 44))	('copying', 'Var', (109, 116))	('DNMT1', 'Gene', '1786', (39, 44))	('binding', 'Interaction', (52, 59))
769755	25606572	It has been recognized that hypomethylation at highly repetitive sequences such as long interspersed nucleotide elements-1 (LINE-1) and short interspersed nucleotide elements (SINE) are epigenetic marks of cancer cells and tissue.	('short interspersed nucleotide elements', 'Var', (136, 174))	('SINE', 'Disease', (176, 180))	('SINE', 'Disease', 'None', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('hypomethylation', 'Var', (28, 43))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
769758	25606572	Hypomethylation of LINE-1 occurs early during the process of carcinogenesis and the methylation level is usually further decreased in more advanced cancers.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('carcinogenesis', 'Disease', (61, 75))	('decreased', 'NegReg', (121, 130))	('methylation level', 'MPA', (84, 101))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
769759	25606572	Another kind of repetitive sequence, the Alu family, as the most abundant SINE; has also been found to be hypomethylated in breast cancer, colorectal cancer, etc.	('SINE', 'Disease', (74, 78))	('colorectal cancer', 'Disease', 'MESH:D015179', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('SINE', 'Disease', 'None', (74, 78))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('hypomethylated', 'Var', (106, 120))	('breast cancer', 'Disease', (124, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colorectal cancer', 'Disease', (139, 156))
769760	25606572	The hypomethylation induces transcriptional activation of these sequences, which contributes to genomic instability and facilitates tumor progression; therefore, the methylation of CpG dinucleotides in repetitive sequences hosts defense against retrotransposon activation.	('contributes', 'Reg', (81, 92))	('genomic instability', 'CPA', (96, 115))	('facilitates', 'PosReg', (120, 131))	('transcriptional', 'MPA', (28, 43))	('hypomethylation', 'Var', (4, 19))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (181, 198))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('trans', 'Chemical', 'MESH:C057348', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('trans', 'Chemical', 'MESH:C057348', (28, 33))	('tumor', 'Disease', (132, 137))
769761	25606572	In intragenic region, cancer specific DNA methylation alterations have been found in both repeated and unique sequences including exonic and intronic sequences, CpG islands, CpG island shores, insulators, intragenic ncRNA sequences, and 3' terminal regions.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('ncRNA', 'Gene', (216, 221))	('cancer', 'Disease', (22, 28))	('ncRNA', 'Gene', '220202', (216, 221))	('alterations', 'Var', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('methylation alterations', 'Var', (42, 65))
769766	25606572	Furthermore, hypomethylation of various repetitive sequences have been found associated with numerous carcinogenic exposures such as cigarette smoking, oxidative stress, etc.	('hypomethylation', 'Var', (13, 28))	('numerous carcinogenic', 'Disease', (93, 114))	('numerous carcinogenic', 'Disease', 'MESH:D063646', (93, 114))	('oxidative stress', 'Phenotype', 'HP:0025464', (152, 168))	('associated', 'Reg', (77, 87))
769767	25606572	A significant positive correlation between LINE-1 hypomethylation and oxidative stress has been found not only in cancer patients but also in healthy individuals.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('oxidative stress', 'MPA', (70, 86))	('LINE-1', 'Gene', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('oxidative stress', 'Phenotype', 'HP:0025464', (70, 86))	('patients', 'Species', '9606', (121, 129))	('hypomethylation', 'Var', (50, 65))	('cancer', 'Disease', (114, 120))
769768	25606572	The consequences of hypomethylation throughout genomic repetitive sequences are genomic instability and alteration of gene expression, which will likely contribute to tumor heterogeneity and facilitate the survival of cancer cells in different environments.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('alteration', 'Reg', (104, 114))	('cancer', 'Disease', (218, 224))	('genomic instability', 'CPA', (80, 99))	('hypomethylation', 'Var', (20, 35))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('facilitate', 'PosReg', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('gene expression', 'MPA', (118, 133))	('tumor', 'Disease', (167, 172))	('iron', 'Chemical', 'MESH:D007501', (247, 251))	('contribute', 'Reg', (153, 163))
769770	25606572	However, the correlation between methylation status of LINE-1 and cancers are not a one way street; for example, the hypomethylation of LINE-1 significantly increases the risk for head and neck cancers while LINE-1 methylation levels slightly increased with higher pack-years of smoking in blood samples of head and neck cancer patients.	('neck cancer', 'Disease', (316, 327))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('neck cancers', 'Disease', (189, 201))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('head and neck cancer', 'Phenotype', 'HP:0012288', (307, 327))	('cancers', 'Disease', (194, 201))	('neck cancers', 'Disease', 'MESH:D006258', (189, 201))	('head and neck cancer', 'Phenotype', 'HP:0012288', (180, 200))	('neck cancer', 'Disease', 'MESH:D006258', (189, 200))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('patients', 'Species', '9606', (328, 336))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('increases', 'PosReg', (157, 166))	('head and neck cancers', 'Phenotype', 'HP:0012288', (180, 201))	('hypomethylation', 'Var', (117, 132))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('LINE-1', 'Gene', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('neck cancer', 'Disease', 'MESH:D006258', (316, 327))
769773	25606572	Intragenic DNA hypomethylation can also modulate the amount and type of RNA transcripts and thereby contribute to tumor formation and progression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('progression', 'CPA', (134, 145))	('type', 'MPA', (64, 68))	('modulate', 'Reg', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('amount', 'MPA', (53, 59))	('trans', 'Chemical', 'MESH:C057348', (76, 81))	('hypomethylation', 'Var', (15, 30))	('contribute to', 'Reg', (100, 113))	('RNA', 'Gene', (72, 75))
769778	25606572	Notably, some of the cancer cell lines with TGFB2 or PRDM16 gene hypomethylation also displayed cancer cell linked promoter hypermethylation.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('TGFB2', 'Gene', '7042', (44, 49))	('TGFB2', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('hypomethylation', 'Var', (65, 80))	('PRDM16', 'Gene', (53, 59))	('PRDM16', 'Gene', '63976', (53, 59))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('promoter hypermethylation', 'MPA', (115, 140))	('cancer', 'Disease', (96, 102))
769785	25606572	Moreover, human colon adenoma with germ line APC mutations also showed reduced DNA methylation and upregulated Aid, Mbd4, and Gadd45a.	('DNA', 'Protein', (79, 82))	('human', 'Species', '9606', (10, 15))	('upregulated', 'PosReg', (99, 110))	('mutations', 'Var', (49, 58))	('colon adenoma', 'Disease', (16, 29))	('Mbd4', 'Gene', (116, 120))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('reduced', 'NegReg', (71, 78))	('APC', 'Disease', (45, 48))	('colon adenoma', 'Disease', 'MESH:D000236', (16, 29))	('Aid', 'Gene', (111, 114))	('Gadd45a', 'Gene', (126, 133))
769787	25606572	Hypermethylation in tumor suppressor genes thereby silencing the genes by either physically inhibiting the binding of transcription factors, or by recruiting proteins that have transcription repressive properties has been reported in various human cancers.	('proteins', 'Protein', (158, 166))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('cancers', 'Disease', (248, 255))	('trans', 'Chemical', 'MESH:C057348', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('recruiting', 'PosReg', (147, 157))	('genes', 'Gene', (65, 70))	('binding', 'Interaction', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('silencing', 'NegReg', (51, 60))	('transcription factors', 'Protein', (118, 139))	('trans', 'Chemical', 'MESH:C057348', (118, 123))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('human', 'Species', '9606', (242, 247))	('transcription', 'MPA', (177, 190))	('inhibiting', 'NegReg', (92, 102))	('tumor', 'Disease', (20, 25))
769789	25606572	To support this notion, a broad set of carcinogenic exposures have been found associated with hypermethylation of these genes.	('associated', 'Reg', (78, 88))	('carcinogenic', 'Disease', (39, 51))	('hypermethylation', 'Var', (94, 110))	('carcinogenic', 'Disease', 'MESH:D063646', (39, 51))
769790	25606572	RASSF1A methylation was significantly associated with increased asbestos body count.	('RASSF1A', 'Gene', (0, 7))	('asbestos body count', 'Disease', (64, 83))	('asbestos body', 'Phenotype', 'HP:0011002', (64, 77))	('increased', 'PosReg', (54, 63))	('RASSF1A', 'Gene', '11186', (0, 7))	('methylation', 'Var', (8, 19))
769793	25606572	Methylation at the 5' end of genes was found associated with transcriptional silencing whereas methylation in the more downstream portions of the gene body was not.	('transcriptional', 'MPA', (61, 76))	('Methylation', 'Var', (0, 11))	('trans', 'Chemical', 'MESH:C057348', (61, 66))
769794	25606572	In breast cancer cells, hypermethylation of the second exon of antiapoptotic factor BCL-2 has been found associated with its diminished expression.	('hypermethylation', 'Var', (24, 40))	('expression', 'MPA', (136, 146))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('BCL-2', 'Gene', '596', (84, 89))	('diminished', 'NegReg', (125, 135))	('BCL-2', 'Gene', (84, 89))
769796	25606572	DNA hypermethylation may play a role in the etiology and pathogenesis of human cancer.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('role', 'Reg', (32, 36))	('human', 'Species', '9606', (73, 78))	('play', 'Reg', (25, 29))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('hypermethylation', 'Var', (4, 20))
769797	25606572	The epigenetic silencing of MGMT leads to a greater mutation rate in K-RAS and p53 genes in human colorectal cancers.	('MGMT', 'Gene', (28, 32))	('mutation rate', 'MPA', (52, 65))	('p53', 'Gene', (79, 82))	('colorectal cancers', 'Disease', (98, 116))	('p53', 'Gene', '7157', (79, 82))	('epigenetic silencing', 'Var', (4, 24))	('K-RAS', 'Gene', '3845', (69, 74))	('MGMT', 'Gene', '4255', (28, 32))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('K-RAS', 'Gene', (69, 74))	('human', 'Species', '9606', (92, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('greater', 'PosReg', (44, 51))	('colorectal cancers', 'Disease', 'MESH:D015179', (98, 116))
769798	25606572	Likewise, human papillary thyroid cancer samples with preferential hypermethylation of six genes (HIST1H3J, POU4F2, SHOX2, PHKG2, TLX3, and HOXA7) were significantly associated with mutation of BRAF/RAS oncogene.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('human', 'Species', '9606', (10, 15))	('HIST1H3J', 'Gene', (98, 106))	('POU4F2', 'Gene', (108, 114))	('HOXA7', 'Gene', '3204', (140, 145))	('papillary thyroid cancer', 'Disease', (16, 40))	('associated', 'Reg', (166, 176))	('POU4F2', 'Gene', '5458', (108, 114))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (16, 40))	('HIST1H3J', 'Gene', '8356', (98, 106))	('TLX3', 'Gene', (130, 134))	('HOXA7', 'Gene', (140, 145))	('preferential', 'PosReg', (54, 66))	('PHKG2', 'Gene', (123, 128))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (16, 40))	('BRAF', 'Gene', '673', (194, 198))	('SHOX2', 'Gene', '6474', (116, 121))	('TLX3', 'Gene', '30012', (130, 134))	('SHOX2', 'Gene', (116, 121))	('BRAF', 'Gene', (194, 198))	('thyroid cancer', 'Phenotype', 'HP:0002890', (26, 40))	('mutation', 'Var', (182, 190))	('PHKG2', 'Gene', '5261', (123, 128))
769799	25606572	Promoter hypermethylation induced inactivation of BRCA1 and MLH1 results in increased p53 gene mutation in human sporadic breast cancer and microsatellite instability (MSI) in sporadic colorectal cancer respectively.	('colorectal cancer', 'Disease', (185, 202))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('p53', 'Gene', '7157', (86, 89))	('MLH1', 'Gene', (60, 64))	('increased', 'PosReg', (76, 85))	('BRCA1', 'Gene', '672', (50, 55))	('mutation', 'Var', (95, 103))	('p53', 'Gene', (86, 89))	('BRCA1', 'Gene', (50, 55))	('MSI', 'Disease', 'None', (168, 171))	('MLH1', 'Gene', '4292', (60, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (185, 202))	('inactivation', 'Var', (34, 46))	('MSI', 'Disease', (168, 171))	('Promoter', 'Var', (0, 8))	('microsatellite instability', 'MPA', (140, 166))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('breast cancer', 'Disease', (122, 135))	('human', 'Species', '9606', (107, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (185, 202))
769800	25606572	MSI in sporadic colorectal cancer are overwhelmingly due to epigenetic silencing of the MHL1 gene by hypermethylation of its promoter; this hypermethylation usually occurs in a background of widespread CpG island promoter methylation, also referred to as the CpG island methylator phenotype; which has also been found in gastric, lung, liver, ovarian, glioblastomas, endometrial and breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('glioblastomas', 'Disease', 'MESH:D005909', (352, 365))	('endometrial', 'Disease', (367, 378))	('cancers', 'Phenotype', 'HP:0002664', (390, 397))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('breast cancers', 'Disease', 'MESH:D001943', (383, 397))	('breast cancers', 'Disease', (383, 397))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('ovarian', 'Disease', (343, 350))	('colorectal cancer', 'Disease', (16, 33))	('glioblastomas', 'Phenotype', 'HP:0012174', (352, 365))	('lung', 'Disease', (330, 334))	('MHL1', 'Gene', (88, 92))	('hypermethylation', 'Var', (101, 117))	('liver', 'Disease', (336, 341))	('breast cancers', 'Phenotype', 'HP:0003002', (383, 397))	('breast cancer', 'Phenotype', 'HP:0003002', (383, 396))	('MSI', 'Disease', 'None', (0, 3))	('silencing', 'NegReg', (71, 80))	('glioblastomas', 'Disease', (352, 365))	('MSI', 'Disease', (0, 3))	('gastric', 'Disease', (321, 328))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))
769801	25606572	The methylation status of repetitive sequences might affect some of the gene promoter hypermethylation found in human cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('affect', 'Reg', (53, 59))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('gene promoter hypermethylation', 'MPA', (72, 102))	('human', 'Species', '9606', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
769804	25606572	It is speculated that the proximal promoter of MLH1 is protected from heterochromatinization by insulators; which helps to explain that MLH1 is methylated in a lower fraction of tumors compared with other genes such as p16 and DAPK1 in cancer tissue DNA methylation profiling.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('methylated', 'Var', (144, 154))	('MLH1', 'Gene', '4292', (47, 51))	('tumors', 'Disease', (178, 184))	('MLH1', 'Gene', (136, 140))	('MLH1', 'Gene', (47, 51))	('cancer', 'Disease', (236, 242))	('MLH1', 'Gene', '4292', (136, 140))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('p16', 'Gene', (219, 222))	('DAPK1', 'Gene', '1612', (227, 232))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('DAPK1', 'Gene', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('p16', 'Gene', '1029', (219, 222))	('lower', 'NegReg', (160, 165))
769805	25606572	An analysis of human genome SNP density to investigate the relationship between recent mutations and the methylation level in the human population has found that the unmethylated CpGs had a lower mutation rate (1.08%) when compared with methylated CpGs (3.55%).	('unmethylated', 'Var', (166, 178))	('lower', 'NegReg', (190, 195))	('human', 'Species', '9606', (15, 20))	('mutation rate', 'MPA', (196, 209))	('human', 'Species', '9606', (130, 135))
769812	25606572	On the contrary, methylation at H3K9 and H3K27 represents an inactivation of transcription.	('transcription', 'MPA', (77, 90))	('trans', 'Chemical', 'MESH:C057348', (77, 82))	('methylation', 'Var', (17, 28))	('inactivation', 'NegReg', (61, 73))	('H3K9', 'Protein', (32, 36))	('H3K27', 'Protein', (41, 46))
769816	25606572	For example, heterochromatin protein HP1 is essential for heterochromatin formation, which can recognize H3K9me2/3 and in turn recruit the H3K9 specific histone methyltransferases SUV39H1/2 (Suppressor of variegation 3-9 homolog 1/2) and SETDB1 (SET domain, bifurcated 1).	('histone methyltransferases', 'Enzyme', (153, 179))	('H3K9me2/3', 'Var', (105, 114))	('trans', 'Chemical', 'MESH:C057348', (167, 172))	('SETDB1', 'Gene', '9869', (238, 244))	('HP1', 'Gene', '23468', (37, 40))	('SUV39H1/2', 'Gene', '6839', (180, 189))	('HP1', 'Gene', (37, 40))	('Suppressor of variegation 3-9 homolog 1/2', 'Gene', (191, 232))	('Suppressor of variegation 3-9 homolog 1/2', 'Gene', '6839;79723', (191, 232))	('SETDB1', 'Gene', (238, 244))	('recruit', 'PosReg', (127, 134))	('SUV39H1/2', 'Gene', (180, 189))
769817	25606572	A recent study suggests that methylation of histones such as H3K4me3 and H3K27me3 may not be essential for DNA replication in very early drosophila embryos.	('drosophila', 'Species', '7227', (137, 147))	('H3K27me3', 'Var', (73, 81))	('H3K4me3', 'Var', (61, 68))
769820	25606572	Intriguing enough, the H3K9me3 is inducible at OCT4 locus by a chemical recruitment of HP1, and the induced H3K9me3 is heritable even after several generations without the stimulation.	('HP1', 'Gene', (87, 90))	('OCT4', 'Gene', '5460', (47, 51))	('OCT4', 'Gene', (47, 51))	('H3K9me3', 'Var', (108, 115))	('HP1', 'Gene', '23468', (87, 90))
769823	25606572	H3K9me3 is retainable at low levels of promoter methylation and also after 5azaC treatment, but to retain H3K9me3 in the presence of a potent transcriptional activator, high levels of DNA methylation is needed to enhance heterochromatin stability in these cells.	('5azaC', 'Chemical', 'MESH:D001374', (75, 80))	('enhance', 'PosReg', (213, 220))	('H3K9me3', 'Var', (106, 113))	('heterochromatin', 'MPA', (221, 236))	('trans', 'Chemical', 'MESH:C057348', (142, 147))
769825	25606572	Chromatin structure regulates gene transcription through histone displacement, histone variant incorporation, post-translational modifications affecting chromosome condensation, chromosome territories, and DNA looping.	('gene transcription', 'MPA', (30, 48))	('histone variant', 'Var', (79, 94))	('regulates', 'Reg', (20, 29))	('trans', 'Chemical', 'MESH:C057348', (35, 40))	('chromosome condensation', 'CPA', (153, 176))	('trans', 'Chemical', 'MESH:C057348', (115, 120))	('incorporation', 'MPA', (95, 108))	('variant', 'Var', (87, 94))	('histone displacement', 'MPA', (57, 77))
769834	25606572	Some PHD protein specifically recognizes tri- and di-methylated H3K4 (H3K4me3/2), with H3K4me3 as the preferred binding partner.	('H3K4', 'Protein', (64, 68))	('PHD', 'Disease', (5, 8))	('tri-', 'Var', (41, 45))	('PHD', 'Disease', 'MESH:D011547', (5, 8))
769840	25606572	Global loss of acetylation of histone H3 at lysine 9 (H3K9ac), H3K18ac, H4K12ac, H4K16ac, along with loss of trimethylation of histone H4 at lysine 20 (H4K20me3) and H3K4me2/me3 has been observed in various primary tumors and has been linked with tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('loss', 'NegReg', (7, 11))	('lysine', 'Chemical', 'MESH:D008239', (141, 147))	('loss', 'NegReg', (101, 105))	('histone H3', 'Protein', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('H4K12ac', 'Var', (72, 79))	('trimethylation', 'MPA', (109, 123))	('acetylation', 'MPA', (15, 26))	('lysine', 'Chemical', 'MESH:D008239', (44, 50))	('primary tumors', 'Disease', (207, 221))	('H3K4me2/me3', 'Var', (166, 177))	('tumor', 'Disease', (247, 252))	('H3K18ac', 'Var', (63, 70))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('primary tumors', 'Disease', 'MESH:D009369', (207, 221))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('linked', 'Reg', (235, 241))	('H4K16ac', 'Var', (81, 88))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
769842	25606572	H3K27me3 seems to occur mutually exclusive to DNA methylation and promote de novo silencing of genes in different cancers with a few exceptions.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('H3K27me3', 'Var', (0, 8))	('silencing', 'MPA', (82, 91))
769843	25606572	Many genes that are silenced by H3K27me3 in embryonic stem cells are found silenced by DNA methylation in cancer cells, establishing an epigenetic switch from a differentiated state to a "stem cell like" signature of cancer cells.	('H3K27me3', 'Var', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
769844	25606572	Increased H3K27me3 has been linked to poor prognosis in esophageal cancer cases, whereas in breast, prostate, ovarian and pancreatic cancers cases, patients exhibiting lower expression levels of H3K27me3 had significantly shorter overall survival time.	('shorter', 'NegReg', (222, 229))	('patients', 'Species', '9606', (148, 156))	('esophageal cancer', 'Disease', (56, 73))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('ovarian and pancreatic cancers', 'Disease', 'MESH:D010190', (110, 140))	('breast', 'Disease', (92, 98))	('prostate', 'Disease', (100, 108))	('H3K27me3', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (122, 140))	('overall', 'MPA', (230, 237))
769846	25606572	It is reported that prostate cancers driven by oncogene MYC (v-myc avian myelocytomatosis viral oncogene homolog) in mice and human showed a reduced level of H3K27me3, and siRNA knockdown of MYC results in increased levels of H3K27me3 in prostate cancer cell lines.	('prostate cancer', 'Disease', 'MESH:D011471', (20, 35))	('increased', 'PosReg', (206, 215))	('myelocytomatosis viral', 'Disease', (73, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('mice', 'Species', '10090', (117, 121))	('prostate cancers', 'Phenotype', 'HP:0012125', (20, 36))	('prostate cancers', 'Disease', (20, 36))	('H3K27me3', 'MPA', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('myelocytomatosis viral', 'Disease', 'MESH:D001102', (73, 95))	('prostate cancer', 'Disease', 'MESH:D011471', (238, 253))	('prostate cancer', 'Phenotype', 'HP:0012125', (238, 253))	('knockdown', 'Var', (178, 187))	('H3K27me3', 'MPA', (226, 234))	('prostate cancer', 'Disease', (238, 253))	('human', 'Species', '9606', (126, 131))	('reduced', 'NegReg', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('MYC', 'Gene', (56, 59))	('myc', 'Gene', '4609', (63, 66))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('prostate cancers', 'Disease', 'MESH:D011471', (20, 36))	('myc', 'Gene', (63, 66))
769849	25606572	Therefore, H3K27me3 might be an outcome of the dis-regulated upstream epigenetic machinery in different types of cancers.	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('H3K27me3', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
769854	25606572	Structural confirmation induced by histone acetylations usually increases nucleosome mobility and DNA accessibility thereby facilitating transcription.	('acetylations', 'Var', (43, 55))	('DNA accessibility', 'MPA', (98, 115))	('nucleosome mobility', 'MPA', (74, 93))	('increases', 'PosReg', (64, 73))	('trans', 'Chemical', 'MESH:C057348', (137, 142))	('histone', 'Protein', (35, 42))	('facilitating', 'PosReg', (124, 136))	('transcription', 'MPA', (137, 150))
769855	25606572	Aberrant expression of HDAC family has frequently been shown to correlate with aggressive behavior of tumors and poor prognosis.	('aggressive behavior of tumors', 'Disease', (79, 108))	('Aberrant expression', 'Var', (0, 19))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('aggressive behavior of tumors', 'Disease', 'MESH:D001523', (79, 108))	('correlate', 'Reg', (64, 73))	('HDAC', 'Protein', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('aggressive behavior', 'Phenotype', 'HP:0000718', (79, 98))
769857	25606572	Furthermore, in hepatocellular carcinoma, HDAC3 and HDAC5 up-regulation was found correlated with their DNA copy number gains.	('up-regulation', 'PosReg', (58, 71))	('HDAC3', 'Gene', (42, 47))	('HDAC5', 'Gene', (52, 57))	('HDAC5', 'Gene', '10014', (52, 57))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('hepatocellular carcinoma', 'Disease', (16, 40))	('DNA copy number gains', 'Var', (104, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('HDAC3', 'Gene', '8841', (42, 47))
769859	25606572	Cancer mutation density over the genome is strikingly correlated with repressive histone mark H3K9me3 and H3K9me2, indicating a closed chromatin structure is prone to mutation.	('H3K9me2', 'Protein', (106, 113))	('H3K9me3', 'Protein', (94, 101))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('repressive histone mark', 'MPA', (70, 93))	('mutation', 'Var', (7, 15))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
769860	25606572	The reverse correlation has been found with open chromatin marks including H3K4me3 and H3K9ac, which helps to explain why the global loss of these two marks is often observed in primary tumors.	('H3K4me3', 'Var', (75, 82))	('primary tumors', 'Disease', (178, 192))	('primary tumors', 'Disease', 'MESH:D009369', (178, 192))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('H3K9ac', 'Var', (87, 93))
769865	25606572	In addition, histone mark variations in specific gene locations have also been reported in carcinogenesis.	('reported', 'Reg', (79, 87))	('histone mark', 'Protein', (13, 25))	('carcinogenesis', 'Disease', (91, 105))	('carcinogenesis', 'Disease', 'MESH:D063646', (91, 105))	('variations', 'Var', (26, 36))
769867	25606572	For example, H3K9me2, a mark of transcriptional repression; and H3K4me3, a mark of transcriptional activation, were found increased in the promoter regions of several genes involved in the transcription of DNA into RNA and the synthesis of immune response cytokines.	('H3K4me3', 'Var', (64, 71))	('H3K9me2', 'Var', (13, 20))	('trans', 'Chemical', 'MESH:C057348', (189, 194))	('trans', 'Chemical', 'MESH:C057348', (83, 88))	('increased', 'PosReg', (122, 131))	('trans', 'Chemical', 'MESH:C057348', (32, 37))
769875	25606572	H3K4me2 were found increased in association with nickel, arsenic, and iron exposure but not aluminum, manganese, zinc, lead exposure; H3K9ac was positively but not significantly associated with nickel and iron exposure.	('manganese', 'Chemical', 'MESH:D008345', (102, 111))	('H3K9ac', 'Var', (134, 140))	('nickel', 'Chemical', 'MESH:D009532', (49, 55))	('aluminum', 'Chemical', 'MESH:D000535', (92, 100))	('iron', 'Chemical', 'MESH:D007501', (70, 74))	('iron', 'Chemical', 'MESH:D007501', (205, 209))	('nickel', 'Chemical', 'MESH:D009532', (194, 200))	('H3K4me2', 'Var', (0, 7))	('arsenic', 'Chemical', 'MESH:D001151', (57, 64))
769878	25606572	EZH2 catalyzes H3K27me3 in the presence of suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED) which possess a carboxy-terminal domain specifically recognizes histone tails that carry trimethyl-lysine residues.	('H3K27me3', 'Var', (15, 23))	('trimethyl-lysine', 'Var', (204, 220))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('suppressor of zeste 12', 'Gene', (43, 65))	('histone tails', 'Protein', (179, 192))	('suppressor of zeste 12', 'Gene', '23512', (43, 65))	('EED', 'Gene', '8726', (110, 113))	('SUZ12', 'Gene', '23512', (67, 72))	('trimethyl-lysine', 'Chemical', 'MESH:C003712', (204, 220))	('EED', 'Gene', (110, 113))	('embryonic ectoderm development', 'Gene', (78, 108))	('embryonic ectoderm development', 'Gene', '8726', (78, 108))	('SUZ12', 'Gene', (67, 72))
769880	25606572	The deregulation of EZH2 found in cancers includes an over-expression of wild-type protein and a gain-of-function mutation resulting in a switch from tyrosine to histidine at amino acid 641(Y641H); both of which lead to a hyper-trimethylation on H3K27me3.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('H3K27me3', 'Protein', (246, 254))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('EZH2', 'Gene', '2146', (20, 24))	('tyrosine to histidine at amino acid 641', 'Mutation', 'rs267601395', (150, 189))	('EZH2', 'Gene', (20, 24))	('Y641H', 'Var', (190, 195))	('hyper-trimethylation', 'MPA', (222, 242))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('over-expression', 'PosReg', (54, 69))	('Y641H', 'Mutation', 'rs267601395', (190, 195))	('deregulation', 'MPA', (4, 16))	('cancers', 'Disease', (34, 41))	('gain-of-function', 'PosReg', (97, 113))
769883	25606572	A study using four non-small cell lung cancer cell lines found DZNep treatments led to decreased cell proliferation and less anchorage independent growth.	('DZNep', 'Var', (63, 68))	('decreased', 'NegReg', (87, 96))	('lung cancer', 'Disease', (34, 45))	('DZNep', 'Chemical', 'MESH:C048460', (63, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (23, 45))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (19, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('less', 'NegReg', (120, 124))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('cell proliferation', 'CPA', (97, 115))	('anchorage independent growth', 'CPA', (125, 153))
769886	25606572	While epigenetic therapy targeting EZH2 is still at its pre-clinical phase, other epigenetic therapies of different targets have been carried out in phase I/II trial and appeared encouraging.	('EZH2', 'Gene', (35, 39))	('EZH2', 'Gene', '2146', (35, 39))	('epigenetic', 'Var', (6, 16))
769893	23844051	Association of CHRNA5-A3-B4 Variation with Esophageal Squamous Cell Carcinoma Risk and Smoking Behaviors in a Chinese Population CHRNA5-A3-B4, the gene cluster encoding nicotinic acetylcholine receptor subunits, is associated with lung cancer risk and smoking behaviors in people of European descent.	('lung cancer', 'Disease', (231, 242))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('CHRNA5', 'Gene', (15, 21))	('nicotinic acetylcholine receptor', 'Gene', '1137', (169, 201))	('Association', 'Interaction', (0, 11))	('associated', 'Reg', (215, 225))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (43, 77))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('Variation', 'Var', (28, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('acetylcholine', 'Chemical', 'MESH:D000109', (179, 192))	('CHRNA5', 'Gene', '1138', (129, 135))	('Esophageal Squamous Cell Carcinoma', 'Disease', (43, 77))	('Carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cancer', 'Disease', (236, 242))	('CHRNA5', 'Gene', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('choline', 'Chemical', 'MESH:D002794', (185, 192))	('nicotinic acetylcholine receptor', 'Gene', (169, 201))	('people', 'Species', '9606', (273, 279))	('CHRNA5', 'Gene', '1138', (15, 21))
769894	23844051	Because cigarette smoking is also a major risk factor for esophageal squamous cell carcinoma (ESCC), we investigated the associations between variants in CHRNA5-A3-B4 and ESCC risk, as well as smoking behaviors, in a Chinese population.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (58, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('variants', 'Var', (142, 150))	('associations', 'Interaction', (121, 133))	('investigated', 'Reg', (104, 116))	('esophageal squamous cell carcinoma', 'Disease', (58, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('CHRNA5-A3-B4', 'Gene', (154, 166))
769895	23844051	A case-control study of 866 ESCC patients and 952 healthy controls was performed to study the association of polymorphisms (rs667282 and rs3743073) in CHRNA5-A3-B4 with cancer risk using logistic regression models.	('rs3743073', 'Var', (137, 146))	('patients', 'Species', '9606', (33, 41))	('rs667282', 'Mutation', 'rs667282', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('rs3743073', 'Mutation', 'rs3743073', (137, 146))	('rs667282', 'Var', (124, 132))	('ESCC', 'Disease', (28, 32))
769896	23844051	The relationships between CHRNA5-A3-B4 polymorphisms and smoking behaviors that can be quantified by cigarettes smoked per day (CPD) and pack-years of smoking were separately estimated with Kruskal-Wallis tests among all 840 smokers.	('CPD', 'Disease', 'MESH:C565865', (128, 131))	('polymorphisms', 'Var', (39, 52))	('smoking', 'Disease', (57, 64))	('CPD', 'Disease', (128, 131))	('CHRNA5-A3-B4', 'Gene', (26, 38))
769897	23844051	CHRNA5-A3-B4 rs667282 TT/TG genotypes were associated with significantly increased risk of ESCC [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.03 - 1.69, P = 0.029].	('ESCC', 'Disease', (91, 95))	('rs667282', 'Var', (13, 21))	('rs667282', 'DBSNP_MENTION', 'None', (13, 21))
769905	23844051	Recently, genome-wide association (GWA) studies have shown three single nucleotide polymorphisms (SNPs) (rs1051730, rs16969968 and rs8034191 in the CHRNA5-A3-B4 gene cluster, which encodes the nAChR subunits) to be related to lung cancer risk and smoking consumption and addiction behaviors in people of European descent.	('rs8034191', 'Mutation', 'rs8034191', (131, 140))	('addiction behaviors', 'Disease', 'MESH:D019966', (271, 290))	('related', 'Reg', (215, 222))	('rs1051730', 'Mutation', 'rs1051730', (105, 114))	('lung cancer', 'Disease', (226, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('rs8034191', 'Var', (131, 140))	('rs1051730', 'Var', (105, 114))	('smoking consumption', 'Disease', (247, 266))	('rs16969968', 'Var', (116, 126))	('addiction behaviors', 'Disease', (271, 290))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('rs16969968', 'Mutation', 'rs16969968', (116, 126))
769906	23844051	Interestingly, two independent studies found that variants rs667282 and rs3743073 of CHRNA5-A3-B4 can affect lung cancer risk in a Chinese population, similar to rs1051730, rs16969968 and rs8034191 in people of European descent.	('lung cancer', 'Disease', (109, 120))	('rs8034191', 'Var', (188, 197))	('rs667282', 'DBSNP_MENTION', 'None', (59, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('rs16969968', 'Var', (173, 183))	('rs8034191', 'DBSNP_MENTION', 'None', (188, 197))	('rs1051730', 'DBSNP_MENTION', 'None', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rs3743073', 'Var', (72, 81))	('rs667282', 'Var', (59, 67))	('CHRNA5-A3-B4', 'Gene', (85, 97))	('rs16969968', 'DBSNP_MENTION', 'None', (173, 183))	('rs1051730', 'Var', (162, 171))	('affect', 'Reg', (102, 108))	('rs3743073', 'DBSNP_MENTION', 'None', (72, 81))
769907	23844051	Consequently, we investigated the associations of the 2 SNPs at CHRNA5-A3-B4 (rs667282 and rs3743073) with ESCC risk and smoking behaviors in a Chinese population, and we further explored the influence of CHRNA5-A3-B4 polymorphisms on cancer progression.	('associations', 'Interaction', (34, 46))	('rs3743073', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('rs667282', 'Var', (78, 86))	('rs3743073', 'DBSNP_MENTION', 'None', (91, 100))	('rs667282', 'DBSNP_MENTION', 'None', (78, 86))	('ESCC', 'Disease', (107, 111))
769911	23844051	Rs667282 and rs3743073 were genotyped by the 5' nuclease cleavage assay (TaqMan method) obtained from Applied Biosystems (assay ID: C__11942801_10 and C__25648144_10, respectively), which uses two allele-specific TaqMan MGB probes and a PCR primer pair to detect the specific SNP target.	('Rs667282', 'Var', (0, 8))	('rs3743073', 'Var', (13, 22))	('Rs667282', 'Mutation', 'Rs667282', (0, 8))	('rs3743073', 'DBSNP_MENTION', 'None', (13, 22))
769912	23844051	The genotype distribution of rs667282 and rs3743073 among cases and controls and their association with ESCC risk are shown in Table 2.	('rs667282', 'Var', (29, 37))	('rs667282', 'DBSNP_MENTION', 'None', (29, 37))	('rs3743073', 'Var', (42, 51))	('ESCC', 'Disease', (104, 108))	('rs3743073', 'DBSNP_MENTION', 'None', (42, 51))
769913	23844051	The observed genotype frequencies for both polymorphisms were in Hardy-Weinberg equilibrium among the controls (P = 0.33 for rs667282 and P = 0.18 for rs3743073).	('rs667282', 'Var', (125, 133))	('rs667282', 'DBSNP_MENTION', 'None', (125, 133))	('rs3743073', 'Var', (151, 160))	('rs3743073', 'DBSNP_MENTION', 'None', (151, 160))	('Hardy-Weinberg equilibrium', 'Disease', (65, 91))
769914	23844051	The genotypes of rs667282 were markedly distinct in cases and controls irrespective of age, gender, smoking status and drinking status, whereas the allele distribution of rs3743073 was similar between cases and controls.	('rs667282', 'DBSNP_MENTION', 'None', (17, 25))	('rs3743073', 'Var', (171, 180))	('rs3743073', 'DBSNP_MENTION', 'None', (171, 180))	('rs667282', 'Var', (17, 25))
769915	23844051	The TT/TC genotypes of rs667282 exhibited an increased association with ESCC (adjusted OR = 1.32, 95%CI = 1.03 to 1.69, P = 0.029).	('rs667282', 'Var', (23, 31))	('rs667282', 'DBSNP_MENTION', 'None', (23, 31))	('TC', 'Chemical', 'MESH:D013667', (7, 9))	('association', 'Interaction', (55, 66))	('ESCC', 'Disease', (72, 76))
769916	23844051	Rs3743073 did not show a significant association with the risk of ESCC.	('Rs3743073', 'Mutation', 'Rs3743073', (0, 9))	('Rs3743073', 'Var', (0, 9))	('ESCC', 'Disease', (66, 70))
769917	23844051	We further examined the impact of CHRNA5-A3-B4 (rs667282) on ESCC risk, stratified by age, gender, drinking status and smoking status (Table 3).	('rs667282', 'DBSNP_MENTION', 'None', (48, 56))	('ESCC', 'Disease', (61, 65))	('rs667282', 'Var', (48, 56))
769918	23844051	The increased cancer risk accompanied by rs667282 TT/TC genotypes was more notable in younger subjects (<=60 years) (OR = 1.44, 95%CI = 1.04 to 1.98, P = 0.024).	('cancer', 'Disease', (14, 20))	('rs667282', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('rs667282', 'DBSNP_MENTION', 'None', (41, 49))
769919	23844051	As shown in Table 4, we found that there was a weak association between the TT/TC genotypes of rs667282 and advanced clinical stage (OR = 1.30, 95%CI = 0.78 to 1.85, P = 0.137).	('rs667282', 'Var', (95, 103))	('rs667282', 'DBSNP_MENTION', 'None', (95, 103))	('advanced clinical stage', 'CPA', (108, 131))
769920	23844051	Subjects with the CHRNA5-A3-B4 (rs667282) TT/TC genotypes exhibited a tendency to smoke more CPD than those with the CC genotype (mean = 23.1 CPD, 95%CI = 22.3 to 24.0 CPD; mean = 21.5 CPD, 95% CI = 19.9 to 23.2 CPD, respectively), and more pack-years (mean = 36.3 pack-years, 95%CI = 34.7 to 47.8 pack-years; mean = 34.6 pack-years, 95%CI = 31.6 to 37.6 pack-years, respectively).	('rs667282', 'DBSNP_MENTION', 'None', (32, 40))	('TT/TC', 'Var', (42, 47))	('rs667282', 'Var', (32, 40))
769921	23844051	Genotypes of rs3743073 were not associated with CPD and pack-years of smoking.	('CPD', 'Disease', (48, 51))	('rs3743073', 'Var', (13, 22))	('rs3743073', 'DBSNP_MENTION', 'None', (13, 22))
769922	23844051	In this hospital-based case-control study of Chinese individuals, we found that the SNP rs667282 in CHRNA5-A3-B4, the gene cluster encoding nAChR subunits (alpha3, alpha5, and beta4), exhibited significant associations with ESCC risk.	('associations', 'Interaction', (206, 218))	('rs667282', 'Var', (88, 96))	('beta4', 'Gene', '10381', (176, 181))	('beta4', 'Gene', (176, 181))	('rs667282', 'DBSNP_MENTION', 'None', (88, 96))	('ESCC', 'Disease', (224, 228))	('CHRNA5-A3-B4', 'Gene', (100, 112))
769926	23844051	Thus, it is biologically plausible that variants in the gene cluster confer individuals' susceptibility to esophageal cancer, especially ESCC.	('susceptibility', 'Reg', (89, 103))	('esophageal cancer', 'Disease', (107, 124))	('ESCC', 'Disease', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('variants', 'Var', (40, 48))
769927	23844051	Recently, a GWA study in a Japanese population showed that two SNPs in the ALDH2 and ADH1B, which encode dehydrogenases involved in alcohol metabolism, were strongly associated with ESCC risk.	('ALDH2', 'Gene', (75, 80))	('ADH1B', 'Gene', (85, 90))	('ADH1B', 'Gene', '125', (85, 90))	('ESCC', 'Disease', (182, 186))	('SNPs', 'Var', (63, 67))	('associated with', 'Reg', (166, 181))	('alcohol', 'Chemical', 'MESH:D000438', (132, 139))	('ALDH2', 'Gene', '217', (75, 80))
769928	23844051	In the stratified analysis, associations between rs667282 genotypes and ESCC risk were stronger for younger subjects, lighter smokers or drinkers.	('rs667282', 'Var', (49, 57))	('associations', 'Interaction', (28, 40))	('rs667282', 'DBSNP_MENTION', 'None', (49, 57))	('ESCC', 'Disease', (72, 76))
769929	23844051	This phenomenon has also been observed for the key SNP rs1051730 in CHRNA5-A3-B4 in lung cancers in people of European descent.	('rs1051730', 'Var', (55, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lung cancers', 'Phenotype', 'HP:0100526', (84, 96))	('CHRNA5-A3-B4', 'Gene', (68, 80))	('rs1051730', 'DBSNP_MENTION', 'None', (55, 64))	('lung cancers', 'Disease', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('lung cancers', 'Disease', 'MESH:D008175', (84, 96))
769930	23844051	In addition, we also found that rs667282 tended to be a risk factor for advanced tumor clinical stage, although the influence was not significant.	('rs667282', 'DBSNP_MENTION', 'None', (32, 40))	('rs667282', 'Var', (32, 40))	('advanced tumor clinical stage', 'CPA', (72, 101))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
769931	23844051	If the tendency can be confirmed by additional studies with a larger sample, rs667282 might help to accurately predict the clinical course of ESCC.	('ESCC', 'Disease', (142, 146))	('rs667282', 'Var', (77, 85))	('rs667282', 'DBSNP_MENTION', 'None', (77, 85))
769932	23844051	Recently, in a functional magnetic resonance study of smokers, a genetic variation in CHRNA5 was observed to affect reactivity to images of smoking in brain areas related to memory and habitual behaviors, such as the hippocampus and dorsal striatum.	('reactivity to', 'MPA', (116, 129))	('affect', 'Reg', (109, 115))	('memory and habitual behaviors', 'Disease', 'MESH:D008569', (174, 203))	('genetic variation', 'Var', (65, 82))	('CHRNA5', 'Gene', (86, 92))
769933	23844051	reported nominally significant associations between rs667282 and CPD in a study of 3 725 smokers in a Chinese population (P = 0.022).	('rs667282', 'DBSNP_MENTION', 'None', (52, 60))	('CPD', 'Disease', (65, 68))	('rs667282', 'Var', (52, 60))
769977	21843340	For patients with low hand-grip strength, the mean duration to start regular oral intake is significantly longer than those with stronger hands.	('longer', 'PosReg', (106, 112))	('low hand-grip strength', 'Phenotype', 'HP:0003484', (18, 40))	('patients', 'Species', '9606', (4, 12))	('hand-grip', 'Phenotype', 'HP:0001188', (22, 31))	('low', 'Var', (18, 21))
770077	33138060	First, the NCDB was queried for all patients 18 years and older with International Classification of Disease of Oncology, Third Edition (ICD-O-3) topography codes C152-C155 (C152, abdominal esophagus; C153, upper third of the esophagus; C154, middle third of the esophagus; C155, lower third of the esophagus) and C160-C166 (gastric cardia, gastric fundus, gastric body, gastric antrum, gastric pylorus, gastric lesser curvature, and gastric greater curvature).	('gastric fundus', 'Disease', 'MESH:D013274', (341, 355))	('Oncology', 'Phenotype', 'HP:0002664', (112, 120))	('C155', 'Var', (274, 278))	('Classification of Disease', 'Disease', (83, 108))	('C160-C166', 'Var', (314, 323))	('Classification of Disease', 'Disease', 'MESH:D008310', (83, 108))	('C153', 'Var', (201, 205))	('C154', 'Var', (237, 241))	('gastric fundus', 'Disease', (341, 355))
770164	32065218	Functional assays manifested that ZFPM2-AS1 knockdown restrained cell proliferation, migration and invasion, and facilitated cell apoptosis in ESCC.	('ESCC', 'Disease', (143, 147))	('facilitated', 'PosReg', (113, 124))	('invasion', 'CPA', (99, 107))	('restrained', 'NegReg', (54, 64))	('cell proliferation', 'CPA', (65, 83))	('knockdown', 'Var', (44, 53))	('cell apoptosis', 'CPA', (125, 139))	('migration', 'CPA', (85, 94))	('ZFPM2-AS1', 'Gene', (34, 43))	('ZFPM2-AS1', 'Gene', '102723356;23414;5729', (34, 43))
770200	32065218	Further, we detected the expressions of two transcripts (NR_125796.1 and NR_125797.1) of ZFPM2-AS1 in ESCC cell lines (KYSE-140, KYSE-30, EC9706 and TE-10), and human normal esophageal epithelial cell line (HET-1A) was taken as a reference.	('human', 'Species', '9606', (161, 166))	('EC9706', 'CellLine', 'CVCL:E307', (138, 144))	('ZFPM2-AS1', 'Gene', '102723356;23414;5729', (89, 98))	('TE-10', 'CellLine', 'CVCL:1760', (149, 154))	('ZFPM2-AS1', 'Gene', (89, 98))	('NR_125797.1', 'Var', (73, 84))
770201	32065218	The results showed that NR_125796.1 was remarkably up-regulated in ESCC cell lines, particularly in EC9706 and TE-10 cells; whereas NR_125797.1 presented no significant difference (Figure 1C).	('up-regulated', 'PosReg', (51, 63))	('ESCC', 'Disease', (67, 71))	('EC9706', 'CellLine', 'CVCL:E307', (100, 106))	('TE-10', 'CellLine', 'CVCL:1760', (111, 116))	('NR_125796.1', 'Var', (24, 35))
770204	32065218	Through EdU assay, we observed that the proliferative capacity of EC9706 and TE-10 cells was markedly restrained upon ZFPM2-AS1 knockdown (Figure 1E).	('EdU', 'Chemical', '-', (8, 11))	('proliferative capacity', 'CPA', (40, 62))	('knockdown', 'Var', (128, 137))	('ZFPM2-AS1', 'Gene', '102723356;23414;5729', (118, 127))	('EC9706', 'CellLine', 'CVCL:E307', (66, 72))	('ZFPM2-AS1', 'Gene', (118, 127))	('restrained', 'NegReg', (102, 112))	('TE-10', 'CellLine', 'CVCL:1760', (77, 82))
770205	32065218	In TUNEL assay, the depletion of ZFPM2-AS1 substantially promoted the apoptosis in EC9706 and TE-10 cells (Figure 1F).	('promoted', 'PosReg', (57, 65))	('ZFPM2-AS1', 'Gene', (33, 42))	('ZFPM2-AS1', 'Gene', '102723356;23414;5729', (33, 42))	('TE-10', 'CellLine', 'CVCL:1760', (94, 99))	('depletion', 'Var', (20, 29))	('EC9706', 'CellLine', 'CVCL:E307', (83, 89))	('apoptosis', 'CPA', (70, 79))
770208	32065218	These findings suggested that ZFPM2-AS1 (NR_125796.1 but not NR_125797.1) is overexpressed in ESCC and promotes ESCC cell growth.	('ESCC', 'Disease', (112, 116))	('ZFPM2-AS1', 'Gene', '102723356;23414;5729', (30, 39))	('NR_125796.1', 'Var', (41, 52))	('promotes', 'PosReg', (103, 111))	('ZFPM2-AS1', 'Gene', (30, 39))
770223	32065218	The apoptosis of ESCC cells was enhanced with the transfection of miR-3612 mimics (Figure 2L).	('apoptosis', 'CPA', (4, 13))	('enhanced', 'PosReg', (32, 40))	('miR-3612', 'Gene', (66, 74))	('transfection', 'Var', (50, 62))	('miR-3612', 'Gene', '100500817', (66, 74))
770242	32065218	The results demonstrated that p-p65 expression was reduced by silenced ZFPM2-AS1 but was recovered again by up-regulated TRAF4 (Supplementary Figure S2A).	('reduced', 'NegReg', (51, 58))	('up-regulated', 'PosReg', (108, 120))	('p65', 'Gene', '5970', (32, 35))	('silenced', 'Var', (62, 70))	('ZFPM2-AS1', 'Gene', (71, 80))	('TRAF4', 'Gene', (121, 126))	('ZFPM2-AS1', 'Gene', '102723356;23414;5729', (71, 80))	('TRAF4', 'Gene', '9618', (121, 126))	('expression', 'MPA', (36, 46))	('p65', 'Gene', (32, 35))
770246	32065218	The results of qRT-PCR implied that the decreased TRAF4 expression in sh-ZFPM2-AS1 transfected cells was reserved by transfecting pcDNA-TRAF4 (Figure 4A).	('ZFPM2-AS1', 'Gene', (73, 82))	('TRAF4', 'Gene', (50, 55))	('TRAF4', 'Gene', (136, 141))	('transfecting', 'Var', (117, 129))	('TRAF4', 'Gene', '9618', (136, 141))	('TRAF4', 'Gene', '9618', (50, 55))	('expression', 'MPA', (56, 66))	('decreased', 'NegReg', (40, 49))	('ZFPM2-AS1', 'Gene', '102723356;23414;5729', (73, 82))
770247	32065218	EdU assay implied that the suppressed cell proliferation by ZFPM2-AS1 knockdown was abrogated by TRAF4 up-regulation (Figure 4B).	('up-regulation', 'PosReg', (103, 116))	('cell proliferation', 'CPA', (38, 56))	('knockdown', 'Var', (70, 79))	('suppressed', 'NegReg', (27, 37))	('abrogated', 'NegReg', (84, 93))	('TRAF4', 'Gene', (97, 102))	('ZFPM2-AS1', 'Gene', (60, 69))	('ZFPM2-AS1', 'Gene', '102723356;23414;5729', (60, 69))	('EdU', 'Chemical', '-', (0, 3))	('TRAF4', 'Gene', '9618', (97, 102))
770267	32065218	TRAF4, TNF receptor associated factor 4, is targeted by miR-302c-3p and overexpressed in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', (89, 113))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (89, 113))	('TNF receptor associated factor 4', 'Gene', (7, 39))	('miR-302c-3p', 'Var', (56, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('TRAF4', 'Gene', (0, 5))	('overexpressed', 'PosReg', (72, 85))	('TRAF4', 'Gene', '9618', (0, 5))	('TNF receptor associated factor 4', 'Gene', '9618', (7, 39))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (89, 113))
770281	29594245	Concomitant chemotherapy was one of the three regimens: (1) high-dose intermittent 5FU and CDDP (standard-dose FP: SDFP), (2) low-dose continuous 5FU and CDDP (LDFP), or (3) low-dose continuous 5FU (LD5FU).	('low-dose', 'Var', (126, 134))	('5FU', 'Chemical', 'MESH:D005472', (83, 86))	('5FU', 'Chemical', 'MESH:D005472', (201, 204))	('5FU', 'Chemical', 'MESH:D005472', (146, 149))	('SDFP', 'Chemical', '-', (115, 119))	('5FU', 'Chemical', 'MESH:D005472', (194, 197))	('CDDP', 'Gene', (91, 95))	('CDDP', 'Chemical', '-', (91, 95))	('CDDP', 'Chemical', '-', (154, 158))
770285	29594245	LD5FU caused significantly less grade 3-4 leukopenia (9%) compared to SDFP (47%) and LDFP (44%) (p < .001).	('leukopenia', 'Disease', 'MESH:D007970', (42, 52))	('leukopenia', 'Disease', (42, 52))	('SDFP', 'Chemical', '-', (70, 74))	('5FU', 'Chemical', 'MESH:D005472', (2, 5))	('LD5FU', 'Var', (0, 5))	('leukopenia', 'Phenotype', 'HP:0001882', (42, 52))	('less', 'NegReg', (27, 31))
770314	29594245	The SDFP regimen consisted of CDDP 70 mg/m2/d on days 1 and 29 and 5FU 700 mg/m2/d on days 1-4 and 29-32, or CDDP 75 mg/m2/d and 5FU 1000 mg/m2/d on the same corresponding schedule.	('CDDP', 'Var', (109, 113))	('5FU', 'Chemical', 'MESH:D005472', (67, 70))	('CDDP', 'Chemical', '-', (109, 113))	('CDDP', 'Var', (30, 34))	('5FU', 'Chemical', 'MESH:D005472', (129, 132))	('CDDP', 'Chemical', '-', (30, 34))	('SDFP', 'Chemical', '-', (4, 8))
770333	29594245	The median age of the LD5FU group (75 yrs) was significantly higher than those of the LDFP (69 yrs) and SDFP (62 yrs) groups (Table 1; p < .001).	('5FU', 'Chemical', 'MESH:D005472', (24, 27))	('higher', 'PosReg', (61, 67))	('SDFP', 'Chemical', '-', (104, 108))	('LD5FU', 'Var', (22, 27))
770339	29594245	The median total dose was significantly higher for the LD5FU and LDFP groups (both 66 Gy) compared to the SDFP group (60 Gy) (p < .001).	('higher', 'PosReg', (40, 46))	('LDFP', 'Var', (65, 69))	('5FU', 'Chemical', 'MESH:D005472', (57, 60))	('SDFP', 'Chemical', '-', (106, 110))	('LD5FU', 'Var', (55, 60))
770350	29594245	In the LD5FU group, there was significantly less grade 3-4 leukopenia (9%) compared to the SDFP (47%) and LDFP (44%) groups (Suppl.	('leukopenia', 'Disease', (59, 69))	('leukopenia', 'Disease', 'MESH:D007970', (59, 69))	('5FU', 'Chemical', 'MESH:D005472', (9, 12))	('less', 'NegReg', (44, 48))	('LD5FU', 'Var', (7, 12))	('SDFP', 'Chemical', '-', (91, 95))	('leukopenia', 'Phenotype', 'HP:0001882', (59, 69))
770351	29594245	LDFP was also associated with significantly more grade 3 increases in alanine aminotransferase (12%) compared to LD5FU and SDFP (p = .001).	('LDFP', 'Var', (0, 4))	('5FU', 'Chemical', 'MESH:D005472', (115, 118))	('increases in alanine aminotransferase', 'Phenotype', 'HP:0031964', (57, 94))	('alanine aminotransferase', 'MPA', (70, 94))	('SDFP', 'Chemical', '-', (123, 127))	('increases', 'PosReg', (57, 66))
770354	29594245	Although the median of the total RT doses in the LDFP group was significantly higher than that in the SDFP group, this difference did not affect the OS in the multivariate analysis, and we considered it appropriate to unify these two groups.	('higher', 'PosReg', (78, 84))	('SDFP', 'Chemical', '-', (102, 106))	('LDFP', 'Var', (49, 53))	('RT doses', 'MPA', (33, 41))
770359	29594245	By Cox proportional hazard models, the LD5FU did not affect the patients' OS (HR 1.06, 95%CI 0.55-2.05, p = .87) or PFS (HR 0.95, 95%CI 0.50-1.81, p = .87).	('LD5FU', 'Var', (39, 44))	('5FU', 'Chemical', 'MESH:D005472', (41, 44))	('patients', 'Species', '9606', (64, 72))	('PFS', 'MPA', (116, 119))
770361	29594245	Our analyses revealed that the LD5FU regimen was associated with significantly less hematological toxicity compared to the 5FU+CDDP regimens.	('hematological toxicity', 'Disease', 'MESH:D006402', (84, 106))	('5FU', 'Chemical', 'MESH:D005472', (33, 36))	('hematological toxicity', 'Disease', (84, 106))	('5FU', 'Chemical', 'MESH:D005472', (123, 126))	('CDDP', 'Chemical', '-', (127, 131))	('less', 'NegReg', (79, 83))	('LD5FU', 'Var', (31, 36))
770376	29594245	In a systematic review of the toxicity of concurrent CRT for uterine cervical cancer, CDDP significantly increased grade 3-4 leukopenia, grade 3-4 anemia and grade 1-2 thrombocytopenia.	('toxicity', 'Disease', 'MESH:D064420', (30, 38))	('thrombocytopenia', 'Disease', 'MESH:D013921', (168, 184))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (168, 184))	('anemia', 'Phenotype', 'HP:0001903', (147, 153))	('CDDP', 'Chemical', '-', (86, 90))	('leukopenia', 'Disease', (125, 135))	('toxicity', 'Disease', (30, 38))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('leukopenia', 'Disease', 'MESH:D007970', (125, 135))	('CR', 'Chemical', '-', (53, 55))	('thrombocytopenia', 'Disease', (168, 184))	('anemia', 'Disease', 'MESH:D000740', (147, 153))	('increased', 'PosReg', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('anemia', 'Disease', (147, 153))	('CDDP', 'Var', (86, 90))	('leukopenia', 'Phenotype', 'HP:0001882', (125, 135))
770381	29594245	Second, the MST and the 5-year survival rate of the LD5FU group were comparable to those of studies on CRT regimens containing both 5FU and CDDP (Table 4).	('CR', 'Chemical', '-', (103, 105))	('5FU', 'Chemical', 'MESH:D005472', (132, 135))	('MST', 'CPA', (12, 15))	('5FU', 'Chemical', 'MESH:D005472', (54, 57))	('LD5FU', 'Var', (52, 57))	('CDDP', 'Chemical', '-', (140, 144))
770383	29594245	Finally, the LD5FU regimen was associated with significantly less hematological toxicity compared to the 5FU+CDDP regimens.	('hematological toxicity', 'Disease', (66, 88))	('LD5FU', 'Var', (13, 18))	('5FU', 'Chemical', 'MESH:D005472', (15, 18))	('5FU', 'Chemical', 'MESH:D005472', (105, 108))	('CDDP', 'Chemical', '-', (109, 113))	('less', 'NegReg', (61, 65))	('hematological toxicity', 'Disease', 'MESH:D006402', (66, 88))
770455	29020052	Previous studies in Canada (head and neck cancer) and in Ontario (hepatocellular carcinoma) have demonstrated that lower SES is associated with worse survival outcomes.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('head and neck cancer', 'Phenotype', 'HP:0012288', (28, 48))	('hepatocellular carcinoma', 'Disease', (66, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('neck cancer', 'Disease', 'MESH:D006258', (37, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lower', 'Var', (115, 120))	('neck cancer', 'Disease', (37, 48))
770495	29020052	The highest number of EAC cases occurred in persons with ADGs 11 and above (which increased from 43.2% during 1993-1997 to 49.1% during 2008-2012) (S3 Table).	('EAC', 'Disease', (22, 25))	('ADGs', 'Chemical', '-', (57, 61))	('persons', 'Species', '9606', (44, 51))	('ADGs 11', 'Var', (57, 64))	('EAC', 'Phenotype', 'HP:0011459', (22, 25))
770526	27319353	Somatically acquired LINE-1 insertions in normal esophagus undergo clonal expansion in esophageal squamous cell carcinoma Squamous cell carcinoma of the esophagus (SCC) is the most common form of esophageal cancer in the world and is typically diagnosed at an advanced stage when successful treatment is challenging.	('esophageal cancer', 'Disease', (196, 213))	('Squamous cell carcinoma of the esophagus', 'Disease', (122, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('Squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (122, 162))	('SCC', 'Gene', '6317', (164, 167))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (136, 162))	('insertions', 'Var', (28, 38))	('SCC', 'Phenotype', 'HP:0002860', (164, 167))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('LINE-1', 'Gene', (21, 27))	('SCC', 'Gene', (164, 167))
770533	27319353	Of these, 12 insertions appeared to be somatic, not genetically inherited, and sub-clonal (i.e., present in less than one copy per genome equivalent) in the adjacent normal esophagus while clonal in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('insertions', 'Var', (13, 23))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
770545	27319353	We hypothesized that L1 is active in normal squamous epithelium and that resulting L1 insertions in the genome may contribute to esophageal squamous cell tumor development or expand in these tumors as so-called passenger mutations.	('esophageal squamous cell tumor', 'Disease', 'MESH:D000077277', (129, 159))	('expand', 'PosReg', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('esophageal squamous cell tumor', 'Disease', (129, 159))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('insertions', 'Var', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Disease', (191, 197))	('squamous cell tumor', 'Phenotype', 'HP:0002860', (140, 159))	('contribute', 'Reg', (115, 125))
770546	27319353	In cancer cells, we expected that L1 hypomethylation and other effects may create an increasingly hospitable environment for continued L1 expression and mobilization.	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('hypomethylation', 'Var', (37, 52))
770556	27319353	The monoclonal antibody used detects amino acids 35-44 of the ORF1 protein, and is the same antibody we used previously.	('ORF1', 'Gene', '55354', (62, 66))	('ORF1', 'Gene', (62, 66))	('detects', 'Reg', (29, 36))	('protein', 'Protein', (67, 74))	('amino acids 35-44', 'Var', (37, 54))
770574	27319353	Furthermore, we observed weaker ORF1p expression in the normal squamous epithelial tissues of many patients coinciding with insertions that were present in normal tissue originally and expanded in the adjacent malignant lesion.	('ORF1p', 'Gene', '55354', (32, 37))	('expression', 'MPA', (38, 48))	('ORF1p', 'Gene', (32, 37))	('patients', 'Species', '9606', (99, 107))	('weaker', 'NegReg', (25, 31))	('insertions', 'Var', (124, 134))
770591	27319353	By comparing somatic insertions detected by L1-seq in ESCC to the database of non-reference L1 insertions maintained by Ewing, we identified putative unique insertions in the tumor samples and selected them for PCR and sequencing validation.	('tumor', 'Disease', (175, 180))	('insertions', 'Var', (157, 167))	('SCC', 'Gene', (55, 58))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('SCC', 'Gene', '6317', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
770592	27319353	Non-reference insertions are insertions previously detected in the human population but absent from the UCSC human genome browser.	('insertions', 'Var', (14, 24))	('human', 'Species', '9606', (67, 72))	('Non-reference insertions', 'Var', (0, 24))	('human', 'Species', '9606', (109, 114))
770593	27319353	Sub-clonal insertions could be amplified when cells are selectively amplified during tumor initiation and progression; therefore we evaluated every putative insertion with conventional PCR and nested PCR in both normal and tumor DNA (Fig.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('insertion', 'Var', (157, 166))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
770595	27319353	We selected a subset of filtered insertions for validation and using PCR and Sanger sequencing we were able to validate 18 insertions distributed among the four individuals with SCC.	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('SCC', 'Gene', (178, 181))	('insertions', 'Var', (123, 133))	('SCC', 'Gene', '6317', (178, 181))
770596	27319353	After filtering results for the second group of samples, we found 133 potential insertions unique to the tumor, 82 of which were tested.	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('insertions', 'Var', (80, 90))
770597	27319353	Again we selected a subset of filtered insertions and validated 56 insertions distributed among four of the five individuals with 12 of the insertions appearing to be sub-clonal in the adjacent normal esophagus and clonal in the tumor (Fig.	('insertions', 'Var', (140, 150))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))
770600	27319353	Thus, we found sub-clonal insertions in matched normal epithelial tissue at a greater frequency in SCC samples than in the EAC, gastric, pancreatic, and colon cancers previously studied.	('sub-clonal', 'Var', (15, 25))	('SCC', 'Gene', '6317', (99, 102))	('EAC', 'Phenotype', 'HP:0011459', (123, 126))	('colon cancers', 'Disease', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('colon cancers', 'Phenotype', 'HP:0003003', (153, 166))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('pancreatic', 'Disease', 'MESH:D010195', (137, 147))	('colon cancers', 'Disease', 'MESH:D015179', (153, 166))	('SCC', 'Gene', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('pancreatic', 'Disease', (137, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (153, 165))
770602	27319353	If, retrotransposition is an ongoing process in the normal esophagus of some or all individuals, it would be an active source of mutations which could begin or contribute to tumorigenesis.	('tumor', 'Disease', (174, 179))	('contribute', 'Reg', (160, 170))	('mutations', 'Var', (129, 138))	('begin', 'Reg', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
770604	27319353	In the process of tumorigenesis, cells with insertions may have been selectively amplified, making the insertions in the tumor cells easily detectable by conventional PCR (Fig.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (18, 23))	('insertions', 'Var', (103, 113))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
770606	27319353	In addition to the 12 sub-clonal insertions in the normal tissue, we confirmed that 33 of the previously mentioned tumor specific insertions were likely sub-clonal somatic insertions because they were only detectable with nested PCR.	('insertions', 'Var', (130, 140))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))
770609	27319353	For a subset of validated insertions, we identified endonuclease cleavage sites and target site duplications (TSDs) which are both hallmarks of the process of retrotransposition (Table 2).	('insertions', 'Var', (26, 36))	('endonuclease cleavage sites', 'Var', (52, 79))	('duplications', 'Var', (96, 108))	('TSDs', 'Disease', (110, 114))	('TSDs', 'Disease', 'None', (110, 114))
770610	27319353	Four of the aforementioned twenty validated insertions are potentially endonuclease independent, because they lack canonical TSDs and obvious endonuclease cleavage sites.	('TSDs', 'Disease', (125, 129))	('TSDs', 'Disease', 'None', (125, 129))	('insertions', 'Var', (44, 54))	('lack', 'NegReg', (110, 114))
770611	27319353	For 18/72 of the confirmed insertions, we identified TSDs ranging from two base pairs in length to 376 base pairs in our samples with a median size of 12 base-pairs.	('insertions', 'Var', (27, 37))	('TSDs', 'Disease', 'None', (53, 57))	('TSDs', 'Disease', (53, 57))
770616	27319353	The intrinsic activity of LINE-1 in the normal tissue of individuals may contribute to cancer development through the generation of additional mutations which could undergo positive selection during carcinogenesis (Fig.	('cancer', 'Disease', (87, 93))	('contribute', 'Reg', (73, 83))	('intrinsic activity', 'MPA', (4, 22))	('carcinogenesis', 'Disease', 'MESH:D063646', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carcinogenesis', 'Disease', (199, 213))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('mutations', 'Var', (143, 152))
770617	27319353	The genes C8orf37-AS1 and LOC100616530 share an intron into which one of the insertions occurred.	('C8orf37-AS1', 'Gene', (10, 21))	('C8orf37-AS1', 'Gene', '100616530;157657;5729', (10, 21))	('LOC100616530', 'Var', (26, 38))
770619	27319353	Although KCNIP4 is approximately 1.2 Mb in size, the insertions occurred in two different individuals, meaning that this gene was recurrently subjected to L1 insertions (Supp.	('insertions', 'Var', (158, 168))	('KCNIP4', 'Gene', '80333', (9, 15))	('KCNIP4', 'Gene', (9, 15))
770624	27319353	Our findings reveal a statistically significant enrichment of validated somatic insertions into genes previously associated with cancer (P< 1 x 10-10) (40-82).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('somatic insertions', 'Var', (72, 90))	('cancer', 'Disease', (129, 135))
770625	27319353	We considered the probability that a somatic insertion would hit more of the cancer-associated genes than would be expected due to chance alone.	('hit', 'Reg', (61, 64))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('insertion', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
770632	27319353	In order to detect, diagnose, and treat SCC effectively, we need a thorough evaluation of mutations acquired in the normal squamous tissue of the esophagus which transitions to cancer.	('transitions', 'Reg', (162, 173))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('mutations', 'Var', (90, 99))	('SCC', 'Gene', '6317', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('SCC', 'Gene', (40, 43))	('SCC', 'Phenotype', 'HP:0002860', (40, 43))
770640	27319353	Our group and others have firmly established that L1 somatic insertions occur frequently in epithelial cancers and presented evidence that insertions may sometimes contribute to cancer development (; Iskow, et al., 2010).	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('epithelial cancers', 'Disease', (92, 110))	('contribute', 'Reg', (164, 174))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('epithelial cancers', 'Disease', 'MESH:D000077216', (92, 110))	('insertions', 'Var', (139, 149))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
770645	27319353	With conventional PCR, the same insertions were observed only in tumor DNA, demonstrating that a larger number of cells contain the insertions in the tumor.	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('insertions', 'Var', (132, 142))	('tumor', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
770648	27319353	First, it is possible, as previously suggested, that some somatic L1 insertions are acquired in the normal tissue and subsequently expand in the cancer (Fig.	('insertions', 'Var', (69, 79))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (145, 151))
770688	33597040	At present, various blood biomarkers including mutations and methylation status in cell-free DNA, cell-free RNA, noncoding RNAs, proteins, and so on, have been explored to fulfill the purpose of early detection of multiple cancer types via different detection platforms.	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('methylation status', 'Var', (61, 79))	('cancer', 'Disease', (223, 229))
770713	33597040	The largest and smallest AUC of the 26 proteins were 0.770 for ANXA1 and 0.652 for ESM 1, respectively.	('ESM 1', 'Gene', '11082', (83, 88))	('ANXA1', 'Gene', '301', (63, 68))	('0.652', 'Var', (73, 78))	('ESM 1', 'Gene', (83, 88))	('AUC', 'MPA', (25, 28))	('ANXA1', 'Gene', (63, 68))	('0.770', 'Var', (53, 58))
770784	30653162	Large Y-shaped stent was used for patients with stenosis or fistula in bilateral main bronchi.	('fistula', 'Disease', (60, 67))	('patients', 'Species', '9606', (34, 42))	('stenosis', 'Var', (48, 56))	('fistula', 'Disease', 'MESH:D005402', (60, 67))
770785	30653162	Small y-shaped stent was used for patients with stenosis or fistula in bilateral main bronchi.	('fistula', 'Disease', (60, 67))	('patients', 'Species', '9606', (34, 42))	('stenosis', 'Var', (48, 56))	('fistula', 'Disease', 'MESH:D005402', (60, 67))
770925	28442917	A systematic review and pooled analysis were performed to determine whether IFI in definitive chemoradiotherapy was more beneficial than ENI for esophageal cancer.	('esophageal cancer', 'Disease', (145, 162))	('IFI', 'Var', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('ENI', 'Chemical', '-', (137, 140))
770927	28442917	Meanwhile, the incidences of esophageal and lung toxicities were significantly decreased in the IFI arm.	('decreased', 'NegReg', (79, 88))	('IFI', 'Var', (96, 99))	('esophageal and lung toxicities', 'Disease', 'MESH:D008171', (29, 59))
770942	28442917	On the other hand, IFI may increase the risk of nodal failure in unirradiated nodal stations, especially as the pattern of lymph node metastasis is controversial in esophageal cancer.	('esophageal cancer', 'Disease', (165, 182))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('nodal failure', 'Disease', (48, 61))	('nodal failure', 'Disease', 'MESH:D013611', (48, 61))	('IFI', 'Var', (19, 22))
770944	28442917	The purpose of this systematic review and pooled analysis was to investigate whether ENI in definitive radiotherapy is more beneficial than IFI in a large group of patients with esophageal cancer worldwide.	('esophageal cancer', 'Disease', (178, 195))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('patients', 'Species', '9606', (164, 172))	('ENI', 'Chemical', '-', (85, 88))	('ENI', 'Var', (85, 88))
770963	28442917	However, the incidence of distant metastasis was lower among patients who received IFI radiotherapy (RR =0.70, 95% CI =0.51-0.94, P=0.02), with no heterogeneity (I2=33%, P=0.02).	('lower', 'NegReg', (49, 54))	('IFI', 'Var', (83, 86))	('patients', 'Species', '9606', (61, 69))	('distant metastasis', 'CPA', (26, 44))
770967	28442917	In this meta-analysis, the incidences of acute and late lung toxicities were lower in the IFI arm than in the ENI arm, with RR values of 0.58 (95% CI =0.36-0.94, P=0.03) and 0.21 (95% CI =0.05-0.81, P=0.02), respectively.	('lower', 'NegReg', (77, 82))	('IFI', 'Var', (90, 93))	('late lung toxicities', 'Disease', 'MESH:D008171', (51, 71))	('ENI', 'Chemical', '-', (110, 113))	('late lung toxicities', 'Disease', (51, 71))
770968	28442917	The pooled incidence of acute esophagus toxicity was significantly lower in the IFI arm than in the ENI arm (RR value =0.50, 95% CI =0.35-0.71, P<0.0001).	('esophagus toxicity', 'Disease', 'MESH:D004938', (30, 48))	('ENI', 'Chemical', '-', (100, 103))	('IFI', 'Var', (80, 83))	('esophagus toxicity', 'Phenotype', 'HP:0100633', (30, 48))	('lower', 'NegReg', (67, 72))	('esophagus toxicity', 'Disease', (30, 48))
770978	28442917	However, some oncologists claim that IFI may increase the risk of nodal failure in nonirradiated nodal stations.	('nodal failure', 'Disease', (66, 79))	('nodal failure', 'Disease', 'MESH:D013611', (66, 79))	('IFI', 'Var', (37, 40))
770994	28442917	In this particular study, the number of patients given two or more cycles of chemotherapy was higher in the IFI arm (104/119) that in the ENI arm (92/120).	('IFI', 'Var', (108, 111))	('higher', 'PosReg', (94, 100))	('patients', 'Species', '9606', (40, 48))	('ENI', 'Chemical', '-', (138, 141))
770997	28442917	The results of the present study showed that the incidences of acute and late lung toxicities and acute esophagus toxicity were lower in the IFI arm than in the ENI arm.	('esophagus toxicity', 'Phenotype', 'HP:0100633', (104, 122))	('ENI', 'Chemical', '-', (161, 164))	('IFI', 'Var', (141, 144))	('esophagus toxicity', 'Disease', (104, 122))	('late lung toxicities', 'Disease', 'MESH:D008171', (73, 93))	('esophagus toxicity', 'Disease', 'MESH:D004938', (104, 122))	('lower', 'NegReg', (128, 133))	('late lung toxicities', 'Disease', (73, 93))
771002	28442917	In summary, the rate of radiation-related toxicity was significantly lower with IFI than with ENI radiotherapy.	('ENI', 'Chemical', '-', (94, 97))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('lower', 'NegReg', (69, 74))	('IFI', 'Var', (80, 83))	('toxicity', 'Disease', (42, 50))
771024	26912065	An advantage of TAE with NBCA is its high success rate of occlusion even in patients with a coagulopathy; however, there are disadvantages that NBCA could cause ischemic injury and is difficult to handle precisely.	('coagulopathy', 'Disease', 'MESH:D001778', (92, 104))	('coagulopathy', 'Disease', (92, 104))	('NBCA', 'Var', (144, 148))	('patients', 'Species', '9606', (76, 84))	('ischemic injury', 'Disease', 'MESH:D003324', (161, 176))	('TAE', 'Chemical', '-', (16, 19))	('coagulopathy', 'Phenotype', 'HP:0003256', (92, 104))	('ischemic injury', 'Disease', (161, 176))	('cause', 'Reg', (155, 160))	('NBCA', 'Chemical', 'MESH:D004659', (25, 29))	('NBCA', 'Chemical', 'MESH:D004659', (144, 148))
771066	26912065	The most common significant adverse event after PDT is esophageal stricture formation, hemorrhage induced by PDT has not been reported.	('hemorrhage', 'Disease', (87, 97))	('esophageal stricture formation', 'Disease', (55, 85))	('esophageal stricture', 'Phenotype', 'HP:0002043', (55, 75))	('PDT', 'Var', (48, 51))	('hemorrhage', 'Disease', 'MESH:D006470', (87, 97))
771144	26078921	The T4 category that includes tumors that invade local structures has been subclassified into T4a and T4b tumors; T4a tumors are resectable cancers invading adjacent structures such as the pleura, pericardium, or diaphragm, while T4b tumors are unresectable cancers invading other adjacent structures, such as the aorta, vertebral body, or trachea.	('tumors', 'Disease', (106, 112))	('T4a', 'Var', (114, 117))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (258, 265))	('tumors', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Disease', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', (234, 240))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('cancers', 'Disease', (258, 265))
771154	26078921	Tumor location (upper and middle thoracic tumors versus lower thoracic tumors) is important for grouping T2-3N0M0 squamous cell cancers.	('T2-3N0M0', 'Var', (105, 113))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('middle thoracic tumors versus lower thoracic tumors', 'Disease', 'MESH:D013896', (26, 77))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (114, 134))	('squamous cell cancers', 'Disease', (114, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (114, 135))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('squamous cell cancers', 'Disease', 'MESH:D002294', (114, 135))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
771157	26078921	T1N0M0 and T2N0M0 adenocarcinomas are subclassified by histologic grade: G1 and G2 are grouped into one sub-classification, while G3 tumors are grouped into a second subclassification.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('T2N0M0', 'Var', (11, 17))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('adenocarcinomas', 'Disease', 'MESH:D000230', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('adenocarcinomas', 'Disease', (18, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('T1N0M0', 'Var', (0, 6))
771159	26078921	T1N0M0 squamous cell carcinoma is sub-classified according to histologic grade: G1 tumors are opposed to G2 and G3 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('squamous cell carcinoma', 'Disease', (7, 30))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (7, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 30))	('T1N0M0', 'Var', (0, 6))
771160	26078921	For T2N0M0 and T3N0M0 squamous cell carcinoma, the stage groupings follow histologic grade and location (Fig.	('T3N0M0', 'Var', (15, 21))	('T2N0M0', 'Var', (4, 10))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 45))	('squamous cell carcinoma', 'Disease', (22, 45))
771161	26078921	The four combinations range from G1 lower thoracic squamous cell carcinoma (stage IB), which has the best survival, to G2-G4 upper and middle thoracic squamous cell carcinomas (stage IIB), which have the worst prognosis.	('thoracic squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 174))	('thoracic squamous cell carcinoma', 'Disease', 'MESH:D002294', (42, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('thoracic squamous cell carcinoma', 'Disease', (42, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (151, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('G2-G4', 'Var', (119, 124))	('middle thoracic squamous cell carcinomas', 'Disease', (135, 175))	('middle thoracic squamous cell carcinomas', 'Disease', 'MESH:D002294', (135, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
771162	26078921	G2-G4 lower thoracic squamous cell carcinomas and G1 upper and middle thoracic squamous cell carcinomas are grouped together (stage IIA), with an intermediate survival rate.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (79, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('middle thoracic squamous cell carcinomas', 'Disease', (63, 103))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (21, 45))	('thoracic squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 102))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (21, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('IIA', 'Gene', '11981', (132, 135))	('IIA', 'Gene', (132, 135))	('thoracic squamous cell carcinoma', 'Disease', (12, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('thoracic squamous cell carcinoma', 'Disease', 'MESH:D002294', (12, 44))	('squamous cell carcinomas', 'Disease', (21, 45))	('middle thoracic squamous cell carcinomas', 'Disease', 'MESH:D002294', (63, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (79, 103))	('G2-G4', 'Var', (0, 5))
771246	25440928	Because of portosystemic shunting, the normal first-pass extraction by the liver is decreased, and the circulating levels of these toxins increase, thereby contributing to the development of hepatic encephalopathy.	('first-pass extraction by', 'MPA', (46, 70))	('increase', 'PosReg', (138, 146))	('portosystemic', 'Var', (11, 24))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (191, 213))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (191, 213))	('hepatic encephalopathy', 'Disease', (191, 213))	('contributing', 'Reg', (156, 168))	('circulating levels', 'MPA', (103, 121))	('decreased', 'NegReg', (84, 93))	('encephalopathy', 'Phenotype', 'HP:0001298', (199, 213))
771277	25440928	Terlipressin does not increase the plasminogen activator activity, as is seen with vasopressin, but has similar effects on the coronary vasculature.	('plasminogen activator activity', 'MPA', (35, 65))	('vasopressin', 'Gene', (83, 94))	('Terlipressin', 'Var', (0, 12))	('vasopressin', 'Gene', '551', (83, 94))
771308	25440928	In the presence of large high-flow gastric varices and prominent but not bleeding esophageal varices, preemptive esophageal variceal banding may be warranted because BRTO exacerbates portal hypertension and may aggravate esophageal varices.	('gastric varices', 'Phenotype', 'HP:0030169', (35, 50))	('hypertension', 'Disease', (190, 202))	('BRTO', 'Var', (166, 170))	('bleeding esophageal', 'Disease', (73, 92))	('portal hypertension', 'Phenotype', 'HP:0001409', (183, 202))	('esophageal varices', 'Phenotype', 'HP:0002040', (221, 239))	('hypertension', 'Phenotype', 'HP:0000822', (190, 202))	('bleeding esophageal', 'Disease', 'MESH:D006470', (73, 92))	('hypertension', 'Disease', 'MESH:D006973', (190, 202))	('esophageal varices', 'Disease', (221, 239))	('esophageal varices', 'Phenotype', 'HP:0002040', (82, 100))	('aggravate', 'PosReg', (211, 220))	('exacerbates', 'PosReg', (171, 182))
771311	25440928	In the presence of a thrombosed main portal vein, occlusion of the gastrorenal shunt, a by-product of the BRTO procedure, would potentially cause mesenteric venous hypertension, mesenteric ischemia, and possibly thrombosis of the entire splanchnic portal venous circulation.	('venous hypertension', 'Disease', (157, 176))	('thrombosis', 'Disease', (212, 222))	('venous hypertension', 'Disease', 'MESH:D006973', (157, 176))	('cause', 'Reg', (140, 145))	('thrombosed main portal vein', 'Phenotype', 'HP:0030242', (21, 48))	('thrombosis', 'Disease', 'MESH:D013927', (212, 222))	('mesenteric', 'Disease', (178, 188))	('ischemia', 'Disease', (189, 197))	('occlusion', 'Var', (50, 59))	('hypertension', 'Phenotype', 'HP:0000822', (164, 176))	('ischemia', 'Disease', 'MESH:D007511', (189, 197))
771367	23923014	OE21 is a squamous cell carcinoma of the esophagus that is commercially available and is widely used as an esophageal cancer in vitro model.	('OE21', 'Var', (0, 4))	('carcinoma', 'Disease', (24, 33))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (24, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('carcinoma', 'Disease', 'MESH:D002277', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))
771377	23923014	These results are in accordance to the literature where mTHPC alone or vehicle were shown to have no effect but mTHPC treated cells in the presence of light showed significant toxicity in a dose dependent manner.	('mTHPC', 'Var', (112, 117))	('mTHPC', 'Chemical', 'MESH:C072269', (112, 117))	('toxicity', 'Disease', 'MESH:D064420', (176, 184))	('mTHPC', 'Chemical', 'MESH:C072269', (56, 61))	('toxicity', 'Disease', (176, 184))
771625	20638682	Additionally they showed that inhibition of MnSOD increases the effectiveness of adriamycin chemotherapy;;.	('adriamycin chemotherapy', 'MPA', (81, 104))	('effectiveness', 'MPA', (64, 77))	('inhibition', 'Var', (30, 40))	('adriamycin', 'Chemical', 'MESH:D004317', (81, 91))	('increases', 'PosReg', (50, 59))	('MnSOD', 'Gene', (44, 49))
771634	18714356	 OPCML Is a Broad Tumor Suppressor for Multiple Carcinomas and Lymphomas with Frequently Epigenetic Inactivation Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers.	('OPCML', 'Gene', (1, 6))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', (131, 136))	('Multiple Carcinomas and Lymphomas', 'Disease', 'MESH:D008223', (39, 72))	('Epigenetic Inactivation', 'Var', (89, 112))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('silenced', 'Var', (161, 169))	('uncovers', 'Reg', (189, 197))	('OPCML', 'Gene', '4978', (1, 6))	('Lymphomas', 'Phenotype', 'HP:0002665', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (253, 258))	('methylation', 'Var', (177, 188))	('Tumor', 'Phenotype', 'HP:0002664', (18, 23))	('TSG', 'Gene', '57045', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('TSG', 'Gene', (155, 158))	('Carcinomas', 'Phenotype', 'HP:0030731', (48, 58))
771635	18714356	Loss of heterozygosity at 11q25 is common in multiple tumors including nasopharyngeal carcinoma (NPC).	('carcinoma', 'Disease', 'MESH:D002277', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('NPC', 'Gene', (97, 100))	('Loss of heterozygosity', 'Var', (0, 22))	('common', 'Reg', (35, 41))	('multiple tumors', 'Disease', 'MESH:D009369', (45, 60))	('multiple tumors', 'Disease', (45, 60))	('NPC', 'Gene', '4864', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('carcinoma', 'Disease', (86, 95))	('11q25', 'Gene', (26, 31))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (71, 95))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
771639	18714356	Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing.	('OPCML', 'Gene', (51, 56))	('restored', 'PosReg', (42, 50))	('demethylation', 'Var', (28, 41))	('OPCML', 'Gene', '4978', (51, 56))
771640	18714356	We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated.	('methylated', 'Var', (121, 131))	('OPCML', 'Gene', (22, 27))	('OPCML', 'Gene', '4978', (22, 27))
771643	18714356	Epigenetic silencing of tumor suppressor genes (TSGs) is frequently involved in tumor development and progression.	('TSG', 'Gene', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('involved', 'Reg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (24, 29))	('TSG', 'Gene', '57045', (48, 51))	('tumor', 'Disease', (80, 85))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
771653	18714356	It was initially identified as a TSG for epithelial ovarian cancer, being frequently inactivated by hemizygous deletion and promoter methylation.	('promoter methylation', 'Var', (124, 144))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('TSG', 'Gene', (33, 36))	('epithelial ovarian cancer', 'Disease', (41, 66))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (41, 66))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (41, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('TSG', 'Gene', '57045', (33, 36))
771656	18714356	As alternative splicing is a feature of OPCML  and other IgLONs (e.g.	('alternative splicing', 'Var', (3, 23))	('OPCML', 'Gene', (40, 45))	('OPCML', 'Gene', '4978', (40, 45))
771658	18714356	We then examined its epigenetic inactivation in NPC and multiple other tumors which have not been studied for this gene, including esophageal, lung, gastric, hepatocellular, colorectal, breast, cervical and prostate carcinomas, as well as non-Hodgkin and Hodgkin lymphomas.	('NPC', 'Gene', (48, 51))	('Hodgkin lymphomas', 'Phenotype', 'HP:0012189', (255, 272))	('epigenetic inactivation', 'Var', (21, 44))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (255, 271))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('cervical', 'Disease', (194, 202))	('prostate carcinomas', 'Disease', (207, 226))	('lung', 'Disease', (143, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('lymphoma', 'Phenotype', 'HP:0002665', (263, 271))	('NPC', 'Gene', '4864', (48, 51))	('breast', 'Disease', (186, 192))	('colorectal', 'Disease', (174, 184))	('esophageal', 'Disease', (131, 141))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('non-Hodgkin and Hodgkin lymphomas', 'Disease', 'MESH:D008228', (239, 272))	('gastric', 'Disease', (149, 156))	('lymphomas', 'Phenotype', 'HP:0002665', (263, 272))	('hepatocellular', 'Disease', (158, 172))	('prostate carcinomas', 'Disease', 'MESH:D011472', (207, 226))	('non-Hodgkin and Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (239, 271))	('colorectal', 'Disease', 'MESH:D015179', (174, 184))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (207, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
771659	18714356	We further found that OPCML is a stress- and p53-responsive gene; however, its stress response is epigenetically disrupted when the promoter becomes methylated.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('OPCML', 'Gene', (22, 27))	('methylated', 'Var', (149, 159))	('OPCML', 'Gene', '4978', (22, 27))
771663	18714356	Two alternative splice transcripts of OPCML, variant 1 (v1) (NM_002545) and variant 2 (v2) (NM_001012393), were previously identified in human, which differ only in their 5' exons (Fig.	('human', 'Species', '9606', (137, 142))	('NM_002545', 'Var', (61, 70))	('OPCML', 'Gene', (38, 43))	('NM_001012393', 'Var', (92, 104))	('OPCML', 'Gene', '4978', (38, 43))
771666	18714356	Three minor splice forms were also identified, designated v4 (EU562298), v5 (EU562299), and v6 (EU562300) (Fig.	('EU562298', 'Var', (62, 70))	('EU562299', 'Var', (77, 85))	('EU562299', 'CellLine', 'CVCL:8857', (77, 85))	('EU562300', 'Var', (96, 104))
771668	18714356	This analysis did confirm the expression of v1 (EU562295) and identified another alternatively spliced variant v3 (EU562297) which is widely expressed in adult tissues (Fig.	('EU562297', 'Var', (115, 123))	('EU562295', 'Var', (48, 56))	('EU562295', 'CellLine', 'CVCL:8857', (48, 56))	('EU562297', 'CellLine', 'CVCL:8857', (115, 123))
771669	18714356	Further analysis using primers specific to the common exons (exon 2 and 3) of OPCML variants in cell lines without both v1 and v2 transcripts revealed the presence of even more unidentified, alternative promoter usage (Fig.	('OPCML', 'Gene', (78, 83))	('OPCML', 'Gene', '4978', (78, 83))	('v1 and v2', 'Gene', '28299', (120, 129))	('variants', 'Var', (84, 92))
771684	18714356	As methylation of promoter CGI is a well-recognized epigenetic mechanism of TSGs silencing, we thus examined the potential promoter regions of the 2 major variants (v1 and v2).	('TSG', 'Gene', '57045', (76, 79))	('methylation', 'Var', (3, 14))	('v1 and v2', 'Gene', '28299', (165, 174))	('TSG', 'Gene', (76, 79))
771685	18714356	The OPCML-v1 (NM_002545) and v2 (NM_001012393) sequence upstream of their exon 1 was retrieved from the NCBI database and analyzed using promoterinspector (http://www.genomatix.de) and CpG Island Searcher (http://ccnt.hsc.usc.edu/cpgislands2).	('NM_002545', 'Var', (14, 23))	('Searcher', 'Species', '274808', (196, 204))	('OPCML', 'Gene', (4, 9))	('NM_001012393', 'Var', (33, 45))	('OPCML', 'Gene', '4978', (4, 9))
771690	18714356	2C, Figure S1 and Table 1), while no methylation was detected in the eight normal epithelial cell lines, demonstrating that v1 promoter methylation is well correlated with its expression status (Fig.	('rat', 'Species', '10116', (112, 115))	('expression', 'MPA', (176, 186))	('methylation', 'Var', (136, 147))	('correlated', 'Reg', (156, 166))
771694	18714356	To determine whether methylation directly mediates OPCML silencing, carcinoma and lymphoma cell lines (MB231, Hep3B, HepG2, SNU398, SW480 and L1236) were treated with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (Aza), together with or without histone deacetylase inhibitor Trichostatin A (TSA).	('OPCML', 'Gene', (51, 56))	('Aza', 'Chemical', 'MESH:D000077209', (227, 230))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('OPCML', 'Gene', '4978', (51, 56))	('L1236', 'Var', (142, 147))	('L1236', 'Chemical', '-', (142, 147))	('carcinoma and lymphoma', 'Disease', 'MESH:D008223', (68, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('MB231', 'CellLine', 'CVCL:0062', (103, 108))	('Hep3B', 'CellLine', 'CVCL:0326', (110, 115))	('SNU398', 'Chemical', '-', (124, 130))	('Trichostatin A', 'Chemical', 'MESH:C012589', (288, 302))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (203, 225))	('HepG2', 'CellLine', 'CVCL:0027', (117, 122))	('TSA', 'Chemical', 'MESH:C012589', (304, 307))
771696	18714356	OPCML-v1 could also be induced in the colorectal cancer cell line HCT116 which is completely methylated for this gene, by genetic demethylation through double knock-out of both DNA methyltransferases DNMT1 and DNMT3B (DKO cell line) (Fig.	('demethylation', 'Var', (130, 143))	('DNMT1', 'Gene', (200, 205))	('DNMT3B', 'Gene', '1789', (210, 216))	('DNMT1', 'Gene', '1786', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('colorectal cancer', 'Disease', (38, 55))	('OPCML', 'Gene', (0, 5))	('HCT116', 'CellLine', 'CVCL:0291', (66, 72))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('OPCML', 'Gene', '4978', (0, 5))	('DNMT3B', 'Gene', (210, 216))
771700	18714356	The downregulation of OPCML in multiple tumor cell lines might also result from genetic deletion, as it resides in the frequently deleted 11q25 locus.	('deletion', 'Var', (88, 96))	('OPCML', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('genetic deletion', 'Var', (80, 96))	('OPCML', 'Gene', '4978', (22, 27))	('downregulation', 'NegReg', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
771702	18714356	We thus performed multiplex differential genomic DNA PCR to detect OPCML deletion for a region spanning the frequently deleted marker D11S4085 in epithelial ovarian cancer.	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (146, 171))	('epithelial ovarian cancer', 'Disease', (146, 171))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (146, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('OPCML', 'Gene', (67, 72))	('OPCML', 'Gene', '4978', (67, 72))	('deletion', 'Var', (73, 81))	('D11S4085', 'Var', (134, 142))
771704	18714356	Furthermore, our high-resolution 1-Mb array comparative genomic hybridization (aCGH) analysis of NPC and ESCC cell lines revealed the hemizygous deletion of OPCML in only 2 out of 15 cell lines (data not shown).	('NPC', 'Gene', (97, 100))	('OPCML', 'Gene', (157, 162))	('NPC', 'Gene', '4864', (97, 100))	('OPCML', 'Gene', '4978', (157, 162))	('rat', 'Species', '10116', (49, 52))	('deletion', 'Var', (145, 153))
771705	18714356	Thus, downregulation of OPCML appears not to be due to genetic deletion, but rather predominantly to epigenetic silencing.	('rat', 'Species', '10116', (77, 80))	('epigenetic silencing', 'Var', (101, 121))	('downregulation', 'NegReg', (6, 20))	('OPCML', 'Gene', (24, 29))	('OPCML', 'Gene', '4978', (24, 29))
771707	18714356	OPCML-v1 methylation was detected in 98% (42/43) of NPC, 66% (21/32) of esophageal, 91% (10/11) of breast, 64% (7/11) of gastric, 94% (17/18) of colorectal, 57% (4/7) of hepatocellular and 88% (7/8) of cervical carcinomas, as well as in 100% (10/10) of Burkitt lymphoma and 89% (8/9) of nasal lymphoma.	('methylation', 'Var', (9, 20))	('nasal lymphoma', 'Disease', (287, 301))	('colorectal', 'Disease', (145, 155))	('cervical carcinomas', 'Disease', 'MESH:D002575', (202, 221))	('hepatocellular', 'Disease', (170, 184))	('OPCML', 'Gene', (0, 5))	('Burkitt lymphoma', 'Disease', (253, 269))	('gastric', 'Disease', (121, 128))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (253, 269))	('nasal lymphoma', 'Disease', 'MESH:D009668', (287, 301))	('colorectal', 'Disease', 'MESH:D015179', (145, 155))	('lymphoma', 'Phenotype', 'HP:0002665', (261, 269))	('breast', 'Disease', (99, 105))	('OPCML', 'Gene', '4978', (0, 5))	('cervical carcinomas', 'Disease', (202, 221))	('lymphoma', 'Phenotype', 'HP:0002665', (293, 301))	('detected', 'Reg', (25, 33))	('NPC', 'Gene', (52, 55))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (253, 269))	('esophageal', 'Disease', (72, 82))	('NPC', 'Gene', '4864', (52, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))
771708	18714356	Methylation was also detected with low frequency in paired surgical marginal tissues from patients with esophageal carcinoma at the rate of 16% (5/32), and with breast carcinoma at the rate of 25% (1/4), which might be due to the presence of small number of tumor cells disseminated into the adjacent non-tumorious region or an early tumor in the adjacent normal regions.	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('breast carcinoma', 'Disease', 'MESH:D001943', (161, 177))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (104, 124))	('non-tumor', 'Disease', (301, 310))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', (305, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('non-tumor', 'Disease', 'MESH:D009369', (301, 310))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('breast carcinoma', 'Phenotype', 'HP:0003002', (161, 177))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('rat', 'Species', '10116', (132, 135))	('breast carcinoma', 'Disease', (161, 177))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (104, 124))	('tumor', 'Disease', (334, 339))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('esophageal carcinoma', 'Disease', (104, 124))	('rat', 'Species', '10116', (185, 188))
771709	18714356	These results further demonstrated that methylation of OPCML-v1 promoter is frequent in multiple tumors.	('methylation', 'Var', (40, 51))	('OPCML', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('OPCML', 'Gene', '4978', (55, 60))	('rat', 'Species', '10116', (29, 32))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('multiple tumors', 'Disease', (88, 103))	('multiple tumors', 'Disease', 'MESH:D009369', (88, 103))	('frequent', 'Reg', (76, 84))
771718	18714356	We thus sought to establish whether ectopic expression of OPCML-v1 could inhibit tumor cell clonogenicity.	('OPCML', 'Gene', '4978', (58, 63))	('ectopic expression', 'Var', (36, 54))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('OPCML', 'Gene', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('inhibit', 'NegReg', (73, 80))
771725	18714356	OPCML is frequently silenced by promoter methylation rather than genetic deletion in NPC, as well as multiple other carcinomas and lymphomas.	('promoter methylation', 'Var', (32, 52))	('rat', 'Species', '10116', (53, 56))	('OPCML', 'Gene', (0, 5))	('lymphomas', 'Phenotype', 'HP:0002665', (131, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('NPC', 'Gene', (85, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('OPCML', 'Gene', '4978', (0, 5))	('NPC', 'Gene', '4864', (85, 88))	('carcinomas and lymphomas', 'Disease', 'MESH:D008223', (116, 140))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
771734	18714356	Among the IgLON family, OPCML was the first member reported to possess tumor suppressor functions in epithelial ovarian cancer, being frequently silenced genetically and epigenetically at the early step of ovarian carcinogenesis.	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (101, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('epithelial ovarian cancer', 'Disease', (101, 126))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (101, 126))	('silenced', 'NegReg', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('ovarian carcinogenesis', 'Disease', 'MESH:D063646', (206, 228))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ovarian carcinogenesis', 'Disease', (206, 228))	('OPCML', 'Gene', (24, 29))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('tumor', 'Disease', (71, 76))	('epigenetically', 'Var', (170, 184))	('OPCML', 'Gene', '4978', (24, 29))
771738	18714356	Loss of OPCML reduces the intercellular adhesion and heterodimeric complex formation and thus impairs the corresponding signaling pathways, thereby promoting the progress of carcinogenesis.	('heterodimeric complex formation', 'MPA', (53, 84))	('promoting', 'PosReg', (148, 157))	('intercellular adhesion', 'MPA', (26, 48))	('signaling pathways', 'Pathway', (120, 138))	('reduces', 'NegReg', (14, 21))	('OPCML', 'Gene', (8, 13))	('carcinogenesis', 'Disease', 'MESH:D063646', (174, 188))	('carcinogenesis', 'Disease', (174, 188))	('OPCML', 'Gene', '4978', (8, 13))	('impairs', 'NegReg', (94, 101))	('Loss', 'Var', (0, 4))
771748	18714356	Epigenetic gene silencing is associated with the onset and progression of various cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('associated', 'Reg', (29, 39))	('Epigenetic gene silencing', 'Var', (0, 25))
771749	18714356	The frequent, predominant epigenetic inactivation of OPCML in multiple malignancies points to the importance of this gene in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('OPCML', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('malignancies', 'Disease', (71, 83))	('tumor', 'Disease', (125, 130))	('OPCML', 'Gene', '4978', (53, 58))	('epigenetic inactivation', 'Var', (26, 49))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))
771750	18714356	OPCML is a stress- and p53-responsive gene, but this response was often epigenetically impaired by promoter methylation.	('OPCML', 'Gene', (0, 5))	('promoter methylation', 'Var', (99, 119))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))	('OPCML', 'Gene', '4978', (0, 5))
771751	18714356	We speculate that epigenetic silencing of OPCML would impair the cellular protective response to environmental stresses in normal cells, thus promoting the development of cancers.	('impair', 'NegReg', (54, 60))	('OPCML', 'Gene', '4978', (42, 47))	('promoting', 'PosReg', (142, 151))	('epigenetic silencing', 'Var', (18, 38))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('OPCML', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cellular protective response', 'CPA', (65, 93))
771757	18714356	The high incidence of epigenetic inactivation of OPCML in NPC and esophageal carcinoma, both prevalent in our locality, indicates that OPCML methylation could be an epigenetic biomarker for the molecular diagnosis of these tumors.	('OPCML', 'Gene', (135, 140))	('NPC', 'Gene', '4864', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('OPCML', 'Gene', '4978', (135, 140))	('OPCML', 'Gene', '4978', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('esophageal carcinoma', 'Disease', (66, 86))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (66, 86))	('NPC', 'Gene', (58, 61))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (66, 86))	('OPCML', 'Gene', (49, 54))	('epigenetic inactivation', 'Var', (22, 45))
771793	34012728	Further analysis showed that four (cg07589773, cg10474350, cg13011388 and cg15208375 mapped to gene IKZF1, HOXA7, EFS and TSHZ3, respectively) of these 841 DMPs could form and establish a diagnostic model after stratified them with the corresponding normal blood samples and other common human cancers.	('cg07589773', 'Chemical', '-', (35, 45))	('cg15208375', 'Var', (74, 84))	('TSHZ3', 'Gene', (122, 127))	('IKZF1', 'Gene', (100, 105))	('cg15208375', 'Chemical', '-', (74, 84))	('EFS', 'Gene', '10278', (114, 117))	('TSHZ3', 'Gene', '57616', (122, 127))	('HOXA7', 'Gene', '3204', (107, 112))	('human', 'Species', '9606', (288, 293))	('EFS', 'Gene', (114, 117))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Disease', (294, 301))	('cg10474350', 'Chemical', '-', (47, 57))	('cg07589773', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cg10474350', 'Var', (47, 57))	('IKZF1', 'Gene', '10320', (100, 105))	('cg13011388', 'Chemical', '-', (59, 69))	('cg13011388', 'Var', (59, 69))	('HOXA7', 'Gene', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('DMPs', 'Chemical', '-', (156, 160))
771799	34012728	Towards this end, assessment of epigenetic alterations in various human cancers showed a great potential as biomarkers in cancer early diagnosis; for example, detection of aberrant DNA methylation, one of the major forms in epigenetic alterations, had also been observed to associate with development of numerous human diseases, including cancer.	('human', 'Species', '9606', (313, 318))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('human', 'Species', '9606', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('aberrant DNA methylation', 'Var', (172, 196))	('cancer', 'Disease', (339, 345))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('associate', 'Reg', (274, 283))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('cancer', 'Disease', (72, 78))
771800	34012728	Altered DNA methylation showed as an early step in transformation of metaplasia to dysplasia and neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (97, 106))	('Altered', 'Var', (0, 7))	('neoplasia', 'Disease', 'MESH:D009369', (97, 106))	('metaplasia to dysplasia', 'Disease', (69, 92))	('metaplasia to dysplasia', 'Disease', 'MESH:D008679', (69, 92))	('methylation', 'Var', (12, 23))	('neoplasia', 'Disease', (97, 106))
771804	34012728	In ESCC, aberrantly methylated genes were significantly enriched in IL-10 anti-inflammatory signaling and cell communication pathway.	('IL-10', 'Gene', '3586', (68, 73))	('aberrantly methylated genes', 'Var', (9, 36))	('IL-10', 'Gene', (68, 73))	('ESCC', 'Disease', (3, 7))	('cell communication pathway', 'Pathway', (106, 132))
771805	34012728	Different from ESCC, several cancer-associated pathway genes were aberrantly methylated in EAC, including genes in the epithelial-mesenchymal transition (EMT), cell adhesion, Wingless and Int-1 (WNT), and Transforming growth factor (TGF) pathways.	('cancer', 'Disease', (29, 35))	('WNT', 'Gene', (195, 198))	('WNT', 'Gene', '7471', (195, 198))	('Int-1', 'Gene', (188, 193))	('Int-1', 'Gene', '7471', (188, 193))	('EAC', 'Disease', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cell adhesion', 'CPA', (160, 173))	('EAC', 'Phenotype', 'HP:0011459', (91, 94))	('aberrantly methylated', 'Var', (66, 87))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('epithelial-mesenchymal transition', 'CPA', (119, 152))
771828	34012728	The majority of these DMPs were hypermethylated (90%), although their distribution had no distinct difference in TSS200 or TSS1500 (Fig.	('TSS1500', 'Var', (123, 130))	('hypermethylated', 'Var', (32, 47))	('DMPs', 'Chemical', '-', (22, 26))
771829	34012728	The number of the hypermethylated DMPs was reduced dramatically in "opensea", "shelves" and "shores" regions (Fig.	('DMPs', 'Chemical', '-', (34, 38))	('reduced', 'NegReg', (43, 50))	('DMPs', 'Protein', (34, 38))	('hypermethylated', 'Var', (18, 33))
771831	34012728	Moreover, 841 hypermethylated DMPs was reversely associated expression of 320 genes and 57 hypomethylated DMPs were negatively associated with expression of 43 genes based on Spearman correlation analysis of methylome and transcriptome data.	('expression', 'MPA', (60, 70))	('expression', 'MPA', (143, 153))	('DMPs', 'Chemical', '-', (106, 110))	('associated', 'Reg', (49, 59))	('DMPs', 'Chemical', '-', (30, 34))	('negatively', 'NegReg', (116, 126))	('hypermethylated', 'Var', (14, 29))
771833	34012728	After that, we screened hypermethylated DMPs between EAC and normal samples and excluded those with higher methylation levels in normal blood samples than in EAC tissues.	('EAC', 'Phenotype', 'HP:0011459', (53, 56))	('EAC', 'Phenotype', 'HP:0011459', (158, 161))	('hypermethylated', 'Var', (24, 39))	('DMPs', 'Protein', (40, 44))	('DMPs', 'Chemical', '-', (40, 44))
771834	34012728	We found a total of 834 hypermethylated DMPs, among which 649 CpGs also occurred in all six datasets, and heatmap of these 649 CpGs is shown in Fig.	('hypermethylated', 'Var', (24, 39))	('DMPs', 'Gene', (40, 44))	('DMPs', 'Chemical', '-', (40, 44))
771837	34012728	We then performed the binary logistic regression and LASSO methods and identified four CpGs to construct the risk score model (Table 1), in which we utilized the formula: The risk score = 2.186 x beta value of cg07589773 + 0.504 x beta value of cg10474350 + 1.550 x beta value of cg13011388 + 2.371 x beta value of cg15208375.	('cg07589773 + 0.504', 'Var', (210, 228))	('cg10474350', 'Chemical', '-', (245, 255))	('cg10474350 +', 'Var', (245, 257))	('cg13011388', 'Chemical', '-', (280, 290))	('cg15208375', 'Var', (315, 325))	('cg13011388 +', 'Var', (280, 292))	('cg07589773', 'Chemical', '-', (210, 220))	('cg15208375', 'Chemical', '-', (315, 325))
771844	34012728	We identified differential methylated CpGs and stratified by their gene expression and found a total of 841 hypermethylated DMPs with downregulated genes.	('DMPs', 'Chemical', '-', (124, 128))	('hypermethylated', 'Var', (108, 123))	('downregulated', 'NegReg', (134, 147))
771848	34012728	DNA methylation epigenetically modifies gene expression; thus, aberrant gene promoter methylation was associated with cancer development and progression.	('cancer', 'Disease', (118, 124))	('associated', 'Reg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('progression', 'CPA', (141, 152))	('aberrant gene', 'Var', (63, 76))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
771849	34012728	For example, the E3 ubiquitin-protein ligase CHFR showed to be required in maintenance of the antephase checkpoint that regulates cell cycle and was hypermethylated in EAC.	('E3 ubiquitin-protein ligase CHFR', 'Gene', '55743', (17, 49))	('regulates', 'Reg', (120, 129))	('EAC', 'Phenotype', 'HP:0011459', (168, 171))	('E3 ubiquitin-protein ligase CHFR', 'Gene', (17, 49))	('cell cycle', 'CPA', (130, 140))	('hypermethylated', 'Var', (149, 164))
771850	34012728	The promoters of glutathione peroxidase 7 (GPX7) and glutathione S-transferase Mu 2 (GSTM2) were reported to be frequently hypermethylated in 67% and 69% of EAC, respectively, expression of which was also reduced respectively.	('glutathione peroxidase 7', 'Gene', (17, 41))	('GSTM2', 'Gene', (85, 90))	('GPX7', 'Gene', (43, 47))	('glutathione S-transferase Mu 2', 'Gene', '2946', (53, 83))	('glutathione S-transferase Mu 2', 'Gene', (53, 83))	('EAC', 'Phenotype', 'HP:0011459', (157, 160))	('glutathione peroxidase 7', 'Gene', '2882', (17, 41))	('reduced', 'NegReg', (205, 212))	('hypermethylated', 'Var', (123, 138))	('GSTM2', 'Gene', '2946', (85, 90))	('expression', 'MPA', (176, 186))	('EAC', 'Disease', (157, 160))	('GPX7', 'Gene', '2882', (43, 47))
771851	34012728	Moreover, aberrant hypermethylation of the secreted frizzled-related protein 1 (SFRP1) promoter regions associated with reduced SFRP1 expression, which occurred in early EAC, while altered methylation in Eyes absent homolog 4 (EYA4) promoter occurred in esophageal mucosa metaplasia and Barrett's esophagus progression to EAC and hypermethylation of Runt-related transcription factor 3 (RUNX3) promoter was reported as an independent risk factor associated with Barrett's esophagus-related EAC development.	('Eyes absent homolog 4', 'Gene', (204, 225))	('SFRP1', 'Gene', (80, 85))	('Eyes absent', 'Phenotype', 'HP:0000528', (204, 215))	('SFRP1', 'Gene', (128, 133))	('RUNX3', 'Gene', (387, 392))	('EAC', 'Phenotype', 'HP:0011459', (490, 493))	('EYA4', 'Gene', (227, 231))	('EYA4', 'Gene', '2070', (227, 231))	('Runt-related transcription factor 3', 'Gene', '864', (350, 385))	('Runt-related transcription factor 3', 'Gene', (350, 385))	('secreted frizzled-related protein 1', 'Gene', (43, 78))	('reduced', 'NegReg', (120, 127))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (462, 481))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (287, 306))	('expression', 'MPA', (134, 144))	('hypermethylation', 'Var', (330, 346))	('EAC', 'Phenotype', 'HP:0011459', (322, 325))	('secreted frizzled-related protein 1', 'Gene', '6422', (43, 78))	('SFRP1', 'Gene', '6422', (80, 85))	('SFRP1', 'Gene', '6422', (128, 133))	('Eyes absent homolog 4', 'Gene', '2070', (204, 225))	('RUNX3', 'Gene', '864', (387, 392))	('EAC', 'Phenotype', 'HP:0011459', (170, 173))	('EAC development', 'Disease', (490, 505))
771854	34012728	Moreover, EFS protein acts as a scaffolding protein for cell signaling in the immune system and altered EFS expression was associated with cancer development.	('EFS', 'Gene', (10, 13))	('altered', 'Var', (96, 103))	('associated with', 'Reg', (123, 138))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('EFS', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('EFS', 'Gene', '10278', (10, 13))	('expression', 'MPA', (108, 118))	('EFS', 'Gene', '10278', (104, 107))	('cancer', 'Disease', (139, 145))
771855	34012728	In addition, TSHZ3 controls breathing and has been identified as a critical region of the heterozygous deletions at 19q12-q13.11, in development of autism spectrum disorder symptoms.	('TSHZ3', 'Gene', '57616', (13, 18))	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (148, 172))	('autism', 'Phenotype', 'HP:0000717', (148, 154))	('autism spectrum disorder symptoms', 'Disease', (148, 181))	('deletions', 'Var', (103, 112))	('autism spectrum disorder symptoms', 'Disease', 'MESH:D051271', (148, 181))	('TSHZ3', 'Gene', (13, 18))	('breathing', 'MPA', (28, 37))	('controls', 'Reg', (19, 27))
771860	34012728	Further study will validate and investigate the mechanisms underlying aberrant methylation in EAC tumorigenesis.	('EAC', 'Disease', (94, 97))	('aberrant methylation', 'Var', (70, 90))	('EAC', 'Phenotype', 'HP:0011459', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('methylation', 'Var', (79, 90))	('tumor', 'Disease', (98, 103))
772032	32164621	In this 78 patient cohort, high TB was significantly associated with advanced tumor status (pT4: 50.0% vs 22.2%, p = 0.007, pN1/2: 70.8% vs 39.6%, p = 0.011, M1: 20.8% vs 1.9%) and higher histological grade (G3: 25.0% vs 5.7%, p = 0.014).	('pN1/2', 'Gene', (124, 129))	('TB', 'Chemical', '-', (32, 34))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('pN1/2', 'Gene', '5270;351', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patient', 'Species', '9606', (11, 18))	('high TB', 'Var', (27, 34))	('tumor', 'Disease', (78, 83))
772033	32164621	Disease specific survival (DSS) in high TB was significantly inferior compared to that in low TB group (3-y DSS 14.5% vs 67.7%, p < 0.001).	('TB', 'Chemical', '-', (40, 42))	('Disease specific survival', 'Gene', (0, 25))	('DSS', 'Gene', '5376', (108, 111))	('inferior', 'NegReg', (61, 69))	('Disease specific survival', 'Gene', '5376', (0, 25))	('DSS', 'Gene', (27, 30))	('DSS', 'Gene', '5376', (27, 30))	('DSS', 'Gene', (108, 111))	('TB', 'Chemical', '-', (94, 96))	('high TB', 'Var', (35, 42))
772034	32164621	Interestingly, DSS in high TB showed similar to survival in unresected patients.	('DSS', 'Gene', (15, 18))	('DSS', 'Gene', '5376', (15, 18))	('patients', 'Species', '9606', (71, 79))	('high', 'Var', (22, 26))	('TB', 'Chemical', '-', (27, 29))
772035	32164621	In addition, high TB was also associated with advanced tumor status and poor prognosis in patients with neoadjuvant therapy.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('high', 'Var', (13, 17))	('tumor', 'Disease', (55, 60))	('TB', 'Chemical', '-', (18, 20))	('patients', 'Species', '9606', (90, 98))
772036	32164621	Multivariate analysis identified high TB as an independent poor prognostic factors for DSS (HR: 5.206, p = 0.001).	('DSS', 'Gene', (87, 90))	('high', 'Var', (33, 37))	('TB', 'Chemical', '-', (38, 40))	('DSS', 'Gene', '5376', (87, 90))
772037	32164621	This study demonstrated that high TB was strongly associated with advanced tumor status and poor prognosis in resected perihilar cholangiocarcinoma patients.	('high', 'Var', (29, 33))	('patients', 'Species', '9606', (148, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (129, 147))	('TB', 'Chemical', '-', (34, 36))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (129, 147))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('associated', 'Reg', (50, 60))	('tumor', 'Disease', (75, 80))	('cholangiocarcinoma', 'Disease', (129, 147))
772038	32164621	High TB can be a novel poor prognostic factor in resected perihilar cholangiocarcinoma regardless of neoadjuvant therapy.	('TB', 'Chemical', '-', (5, 7))	('cholangiocarcinoma regardless', 'Disease', 'MESH:D018281', (68, 97))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (68, 86))	('cholangiocarcinoma regardless', 'Disease', (68, 97))
772047	32164621	demonstrated that high TB grade was an independent adverse prognostic factor in 195 perihilar cholangiocarcinoma patients by multivariate analysis.	('TB', 'Chemical', '-', (23, 25))	('patients', 'Species', '9606', (113, 121))	('cholangiocarcinoma', 'Disease', (94, 112))	('high', 'Var', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (94, 112))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (94, 112))
772054	32164621	In the field of rectal and esophageal carcinoma, where the use of neoadjuvant therapy is common, there are several reports showing the prognostic significance of high TB in patients who underwent neoajuvant therapy.	('TB', 'Chemical', '-', (167, 169))	('neoajuvant', 'Chemical', '-', (196, 206))	('esophageal carcinoma', 'Disease', (27, 47))	('patients', 'Species', '9606', (173, 181))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (27, 47))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (27, 47))	('rectal', 'Disease', (16, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('high', 'Var', (162, 166))
772055	32164621	These studies have reported the association between high TB and poor prognosis in patients underwent neoadjuvant therapy for esophageal carcinoma and rectal carcinoma.	('rectal carcinoma', 'Phenotype', 'HP:0100743', (150, 166))	('rectal carcinoma', 'Disease', (150, 166))	('patients', 'Species', '9606', (82, 90))	('esophageal carcinoma', 'Disease', (125, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('high', 'Var', (52, 56))	('rectal carcinoma', 'Disease', 'MESH:D012004', (150, 166))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (125, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (125, 145))	('TB', 'Chemical', '-', (57, 59))
772103	32164621	In terms of histologically factors, high TB patients had higher rates of tumor with grade G3 (25% vs. 5.6%, p = 0.013), pT4 (50.0% vs. 22.2%, p = 0.014), lymph node metastasis (70.8% vs. 38.9%, p = 0.009), and distant metastasis (20.8% vs. 1.9%, p = 0.004).	('high TB', 'Var', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('patients', 'Species', '9606', (44, 52))	('higher', 'PosReg', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('pT4', 'CPA', (120, 123))	('tumor', 'Disease', (73, 78))	('TB', 'Chemical', '-', (41, 43))	('lymph node metastasis', 'CPA', (154, 175))	('distant metastasis', 'CPA', (210, 228))
772108	32164621	Interestingly, DSS after initial treatment in high TB patients did not show statistical difference compared to that in 28 unresected patients having locally advanced tumor at our institution in the same period.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('men', 'Species', '9606', (38, 41))	('DSS', 'Gene', (15, 18))	('DSS', 'Gene', '5376', (15, 18))	('high TB', 'Var', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (133, 141))	('tumor', 'Disease', (166, 171))	('TB', 'Chemical', '-', (51, 53))
772111	32164621	Among the patients with neoadjuvant therapy, high TB patients had a significantly higher rate of combined vascular resection (90.9% vs. 48.0%, p = 0.015) compared to low TB patients.	('TB', 'Chemical', '-', (50, 52))	('TB', 'Chemical', '-', (170, 172))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (173, 181))	('combined vascular resection', 'CPA', (97, 124))	('patients', 'Species', '9606', (10, 18))	('high TB', 'Var', (45, 52))
772118	32164621	As shown in Table 4, pre-operative CEA level (>= 5 ng/ml), histological grade G3, T4, N1/2, M1, LV invasion, non-curative resection, and High TB, were identified as poor prognostic factors for DSS by univariate analysis.	('CEA', 'Gene', (35, 38))	('High TB', 'Var', (137, 144))	('DSS', 'Gene', (193, 196))	('DSS', 'Gene', '5376', (193, 196))	('CEA', 'Gene', '5670', (35, 38))	('N1/2', 'Var', (86, 90))	('TB', 'Chemical', '-', (142, 144))
772122	32164621	Among four patient classifications, notably, DSS in only patients with high TB did not show significantly difference compared to DSS in 28 unresected patients.	('patient', 'Species', '9606', (150, 157))	('high TB', 'Var', (71, 78))	('DSS', 'Gene', (129, 132))	('patients', 'Species', '9606', (57, 65))	('patient', 'Species', '9606', (57, 64))	('DSS', 'Gene', '5376', (129, 132))	('patient', 'Species', '9606', (11, 18))	('patients', 'Species', '9606', (150, 158))	('DSS', 'Gene', (45, 48))	('TB', 'Chemical', '-', (76, 78))	('DSS', 'Gene', '5376', (45, 48))
772125	32164621	In all patients, high TB was significantly associated with advanced tumor status including rates of pT4, pN1/2, M1, and histological grade 3.	('tumor', 'Disease', (68, 73))	('pT4', 'Disease', (100, 103))	('TB', 'Chemical', '-', (22, 24))	('pN1/2', 'Gene', (105, 110))	('high TB', 'Var', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('pN1/2', 'Gene', '5270;351', (105, 110))	('associated', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('patients', 'Species', '9606', (7, 15))
772126	32164621	Survival in patients with high TB was significantly inferior than that in patients with low TB.	('patients', 'Species', '9606', (12, 20))	('high', 'Var', (26, 30))	('TB', 'Chemical', '-', (92, 94))	('Survival', 'MPA', (0, 8))	('patients', 'Species', '9606', (74, 82))	('TB', 'Chemical', '-', (31, 33))	('inferior', 'NegReg', (52, 60))
772127	32164621	By multivariate analysis, high TB was identified as one of independent poor prognostic factors for DSS among 4 factors including regional lymph node metastasis, LV invasion, and non-curative resection.	('DSS', 'Gene', '5376', (99, 102))	('DSS', 'Gene', (99, 102))	('TB', 'Chemical', '-', (31, 33))	('high TB', 'Var', (26, 33))
772128	32164621	Interestingly, DSS in high TB group did not show statistical difference compared to that in unresected patients.	('DSS', 'Gene', (15, 18))	('DSS', 'Gene', '5376', (15, 18))	('high', 'Var', (22, 26))	('TB', 'Chemical', '-', (27, 29))	('patients', 'Species', '9606', (103, 111))
772129	32164621	In addition, the impact of high TB in patients with neoadjuvant therapy showed similar results, withhigh TB significantly associated with advanced tumor status and poor prognosis.	('associated', 'Reg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('TB', 'Chemical', '-', (32, 34))	('TB', 'Chemical', '-', (105, 107))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('patients', 'Species', '9606', (38, 46))	('withhigh', 'Var', (96, 104))
772132	32164621	demonstrated high TB as an independent adverse prognostic factor in multivariate analysis, along with higher T stage, lymph node metastasis, and resected margin positive invasive carcinoma.	('invasive carcinoma', 'Disease', 'MESH:D009361', (170, 188))	('high', 'Var', (13, 17))	('invasive carcinoma', 'Disease', (170, 188))	('TB', 'Chemical', '-', (18, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))
772148	32164621	reported similar results to the current study: that the high TB grade was associated with poor histological differentiation, higher pT factor, regional lymph node metastasis, and a higher rate of residual invasive tumor in the resected margin.	('histological differentiation', 'CPA', (95, 123))	('TB', 'Chemical', '-', (61, 63))	('poor', 'NegReg', (90, 94))	('pT factor', 'MPA', (132, 141))	('invasive tumor', 'Disease', 'MESH:D009361', (205, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('invasive tumor', 'Disease', (205, 219))	('higher', 'PosReg', (125, 131))	('regional lymph node metastasis', 'CPA', (143, 173))	('high', 'Var', (56, 60))
772154	32164621	There are several reports showing the significance of high TB in patients who underwent neoajuvant therapy for rectal and esophageal carcinoma.	('esophageal carcinoma', 'Disease', (122, 142))	('high', 'Var', (54, 58))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (122, 142))	('rectal', 'Disease', (111, 117))	('TB', 'Chemical', '-', (59, 61))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (122, 142))	('neoajuvant', 'Chemical', '-', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('patients', 'Species', '9606', (65, 73))
772172	32164621	Our present study demonstrated that high TB at the invasive front of tumors in resected perihilar cholangiocarcinoma patients with or without neoadjuvant therapy, is strongly associated with advanced tumor status and poor prognosis, including DSS/RFS.	('DSS', 'Gene', (243, 246))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('cholangiocarcinoma', 'Disease', (98, 116))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('DSS', 'Gene', '5376', (243, 246))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (200, 205))	('TB', 'Chemical', '-', (41, 43))	('high', 'Var', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('associated with', 'Reg', (175, 190))	('tumors', 'Disease', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
772173	32164621	High TB could be a novel prognostic factor in resected perihilar cholangiocarcinoma even if patients received neoadjuvant therapy.	('High', 'Var', (0, 4))	('TB', 'Chemical', '-', (5, 7))	('cholangiocarcinoma', 'Disease', (65, 83))	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (65, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (65, 83))
772187	32189968	Moreover, HIPK3 was significantly promoted cell proliferation and migration of ESCC cells.	('migration', 'CPA', (66, 75))	('ESCC', 'Disease', 'MESH:C562729', (79, 83))	('HIPK3', 'Var', (10, 15))	('promoted', 'PosReg', (34, 42))	('ESCC', 'Disease', (79, 83))	('cell proliferation', 'CPA', (43, 61))
772212	32189968	Many studies have shown that miRNA aberrant expression is closely related to the occurrence, development and prognosis of malignant tumors by regulating the expression of tumor suppressor genes and oncogenes.	('men', 'Species', '9606', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('miR', 'Gene', (29, 32))	('expression', 'MPA', (157, 167))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('malignant tumors', 'Disease', (122, 138))	('malignant tumors', 'Disease', 'MESH:D009369', (122, 138))	('miR', 'Gene', '751557', (29, 32))	('aberrant expression', 'Var', (35, 54))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('related', 'Reg', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('regulating', 'Reg', (142, 152))
772221	32189968	ESCC cell line (kyse-150, kyse-410, KYSE-510, ECA-109, EC-18 and TE-13) and normal immortalized cell line (NE1) were purchased from the Chinese Academy of Sciences Cell Bank (Shanghai, China).	('TE-13', 'CellLine', 'CVCL:4463', (65, 70))	('ESCC', 'Disease', 'MESH:C562729', (0, 4))	('KYSE-510', 'Var', (36, 44))	('kyse-410', 'Var', (26, 34))	('NE1', 'CellLine', 'CVCL:E306', (107, 110))	('EC', 'Disease', 'MESH:D004938', (55, 57))	('EC', 'Disease', 'MESH:D004938', (46, 48))	('ESCC', 'Disease', (0, 4))
772245	32189968	The overexpression of HIPK3 was positively correlated with late TNM stage, lymph node metastasis and tumor size, but not with other parameters such as age, gender, alcohol As shown in Figure 2A and B, HIPK3 expression was significantly changed after siRNA or LV-HIPK3 transfection, indicating a successful transfection.	('HIPK3', 'Gene', (22, 27))	('HIPK3', 'Gene', (201, 206))	('TNM', 'Gene', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('lymph node metastasis', 'CPA', (75, 96))	('tumor', 'Disease', (101, 106))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('changed', 'Reg', (236, 243))	('overexpression', 'PosReg', (4, 18))	('expression', 'MPA', (207, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('TNM', 'Gene', '10178', (64, 67))	('LV-HIPK3 transfection', 'Var', (259, 280))
772255	32189968	In addition, as shown in Figure 3E, HIPK3 knockdown can significantly increase the expression level of miR-599 in TE-13 cells.	('expression level', 'MPA', (83, 99))	('increase', 'PosReg', (70, 78))	('HIPK3', 'Gene', (36, 41))	('TE-13', 'CellLine', 'CVCL:4463', (114, 119))	('miR-599', 'Var', (103, 110))	('knockdown', 'Var', (42, 51))
772256	32189968	HIPK3 knockdown can significantly up-regulate the expression level of miR-599 in TE-13 cells, while HIPK3 overexpression can significantly down-regulate the expression level of miR-599 in TE-13 cells.	('up-regulate', 'PosReg', (34, 45))	('TE-13', 'CellLine', 'CVCL:4463', (188, 193))	('HIPK3', 'Gene', (0, 5))	('expression level', 'MPA', (50, 66))	('TE-13', 'CellLine', 'CVCL:4463', (81, 86))	('miR-599', 'Gene', (70, 77))	('knockdown', 'Var', (6, 15))	('expression level', 'MPA', (157, 173))	('down-regulate', 'NegReg', (139, 152))
772260	32189968	In summary, these results indicated that circHIPK3 may exert its biological function through miR-599.	('miR-599', 'Var', (93, 100))	('cir', 'Gene', (41, 44))	('cir', 'Gene', '9541', (41, 44))
772271	32189968	As shown in Figure 5E and F, HIPK3 knockdown inhibited c-MYC expression levels, while miR-559 mimics further increased c-MYC expression levels.	('HIPK3', 'Gene', (29, 34))	('knockdown', 'Var', (35, 44))	('c-MYC', 'Gene', (119, 124))	('c-MYC', 'Gene', '4609', (119, 124))	('c-MYC', 'Gene', (55, 60))	('miR-559', 'Gene', '693144', (86, 93))	('c-MYC', 'Gene', '4609', (55, 60))	('inhibited', 'NegReg', (45, 54))	('increased', 'PosReg', (109, 118))	('miR-559', 'Gene', (86, 93))
772275	32189968	In order to further determine the effect of HIPK3 on ESCC progression in vivo, ESCC cells transfected with si-HIPK3 or si-HIPK3/miR-599 agomir were injected subcutaneously into nude mice.	('si-HIPK3', 'Var', (107, 115))	('ESCC', 'Disease', (53, 57))	('ESCC', 'Disease', 'MESH:C562729', (79, 83))	('nude mice', 'Species', '10090', (177, 186))	('ESCC', 'Disease', (79, 83))	('si-HIPK3/miR-599', 'Var', (119, 135))	('ESCC', 'Disease', 'MESH:C562729', (53, 57))
772276	32189968	As shown in Figue 6A-C, the tumor size and tumor weight of the si-HIPK3 group were significantly lower compared with that in the control group.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('lower', 'NegReg', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (43, 48))	('si-HIPK3', 'Var', (63, 71))
772278	32189968	Furthermore, as shown in Figure 6D, HIPK3 silencing significantly inhibited c-MYC expression, while miR-599 agomir treatment further reduced c-MYC expression levels in tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('c-MYC', 'Gene', (76, 81))	('c-MYC', 'Gene', (141, 146))	('tumors', 'Disease', (168, 174))	('HIPK3', 'Gene', (36, 41))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('c-MYC', 'Gene', '4609', (76, 81))	('miR-599', 'Var', (100, 107))	('inhibited', 'NegReg', (66, 75))	('c-MYC', 'Gene', '4609', (141, 146))	('reduced', 'NegReg', (133, 140))	('silencing', 'NegReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('men', 'Species', '9606', (120, 123))
772292	32189968	The results of this study showed that the expression of HIPK3 in cancer tissues and cells was significantly lower than that in normal adjacent normal tissues and normal cells (P<0.05).Moreover, overexpression of HIPK3 was positively correlated with advanced TNM stage and tumor size, but not with other parameters such as age, gender, alcohol consumption, smoking history or differentiation status.HIPK3 silencing inhibited cell viability, promoted apoptosis and reduced cell migration and invasiveness, while HIPK3 overexpression can increase cell viability, inhibit cell apoptosis and increase cell migration and invasion.	('HIPK3', 'Gene', (510, 515))	('silencing', 'Var', (404, 413))	('invasion', 'CPA', (615, 623))	('cancer', 'Disease', (65, 71))	('invasiveness', 'Disease', (490, 502))	('tumor', 'Disease', (272, 277))	('TNM', 'Gene', '10178', (258, 261))	('cell migration', 'CPA', (471, 485))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('TNM', 'Gene', (258, 261))	('invasiveness', 'Disease', 'MESH:D009361', (490, 502))	('inhibited', 'NegReg', (414, 423))	('status.HIPK3', 'Gene', (391, 403))	('inhibit', 'NegReg', (560, 567))	('apoptosis', 'CPA', (449, 458))	('promoted', 'PosReg', (440, 448))	('cell migration', 'CPA', (596, 610))	('increase', 'PosReg', (535, 543))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cell apoptosis', 'CPA', (568, 582))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('alcohol', 'Chemical', 'MESH:D000438', (335, 342))	('cell viability', 'CPA', (424, 438))	('cell viability', 'CPA', (544, 558))	('increase', 'PosReg', (587, 595))	('reduced', 'NegReg', (463, 470))
772304	32189968	Here, for the first time, we identified MYC as a target of miR-599 and showed that the miR-599-MYC axis regulates cell proliferation and migration in ESCC.	('MYC', 'Gene', '4609', (95, 98))	('MYC', 'Gene', '4609', (40, 43))	('ESCC', 'Disease', (150, 154))	('migration', 'CPA', (137, 146))	('MYC', 'Gene', (95, 98))	('regulates', 'Reg', (104, 113))	('MYC', 'Gene', (40, 43))	('miR-599', 'Var', (59, 66))	('cell proliferation', 'CPA', (114, 132))	('ESCC', 'Disease', 'MESH:C562729', (150, 154))
772496	31894852	Therefore, whether Hb corrections can influence the prognosis of patients with esophageal fistula or not needs to be future investigated in future studies.	('esophageal fistula', 'Disease', 'MESH:D004937', (79, 97))	('influence', 'Reg', (38, 47))	('esophageal fistula', 'Disease', (79, 97))	('patients', 'Species', '9606', (65, 73))	('corrections', 'Var', (22, 33))
772535	31036088	Patients must have adequate hematological, renal and hepatic functions defined as: neutrophils >=3.5 x 109/L, granulocytes >=1.5 x 109/L, platelets >=100 x 109/L, urea nitrogen (BUN) <= 1.0 x upper normal limit (UNL), creatinine (Cr) <= 1.0 x upper normal limit (UNL), alanine aminotransferase (ALT), aspartate aminotransferase (AST) <=1.5x UNL; alkaline phosphatase (ALP) <= 1.5x UNL; total bilirubin <=UNL.	('ALP', 'Gene', (368, 371))	('AST', 'Gene', '26503', (329, 332))	('alkaline phosphatase', 'Gene', (346, 366))	('Cr', 'Chemical', 'MESH:D003404', (230, 232))	('alkaline phosphatase', 'Gene', '250', (346, 366))	('aspartate aminotransferase', 'Gene', '26503', (301, 327))	('ALP', 'Gene', '250', (368, 371))	('creatinine', 'MPA', (218, 228))	('Patients', 'Species', '9606', (0, 8))	('alanine aminotransferase', 'Gene', (269, 293))	('aspartate aminotransferase', 'Gene', (301, 327))	('alanine aminotransferase', 'Gene', '2875', (269, 293))	('>=100', 'Var', (148, 153))	('AST', 'Gene', (329, 332))
772552	31036088	For thoracic esophagus, prescription dose is 95% PTV/PGTV 50.40Gy/59.92Gy/28f.	('50.40Gy/59.92Gy/28f', 'Var', (58, 77))	('thoracic esophagus', 'Disease', (4, 22))	('PTV', 'Chemical', '-', (49, 52))
772587	31036088	Generally, the toxicities remain at high levels even after these modifications if dual-drug chemotherapeutic regimen is adopted.	('modifications', 'Var', (65, 78))	('toxicities', 'Disease', 'MESH:D064420', (15, 25))	('toxicities', 'Disease', (15, 25))
772596	31036088	Besides, some retrospective study have shown that in the subgroup of SCC, patients received high-dose irradiation (>=60Gy) had better OS and LCR than those who only received conventional dose (50.4Gy).	('>=60Gy', 'Var', (115, 121))	('better', 'PosReg', (127, 133))	('SCC', 'Gene', (69, 72))	('patients', 'Species', '9606', (74, 82))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('SCC', 'Gene', '6317', (69, 72))	('OS', 'Chemical', 'MESH:D009992', (134, 136))
772597	31036088	Moreover, dosimetry studies have shown that for EC/EGJC, with the help of SIB, one can successfully increase the dose of boost areas without increasing the irradiation of OARs.	('dose', 'MPA', (113, 117))	('EC/EGJC', 'Var', (48, 55))	('increase', 'PosReg', (100, 108))	('SIB', 'Chemical', '-', (74, 77))
772606	31036088	Institutional review board approval was obtained for the 3JECROG P-01 trial from the ethical committee of the Chinese Academy of Medical Sciences (reference number NCC2016 YL-06), of Anyang Cancer Hospital (AZLL 022017002170116), of Tianjin Cancer Hospital (E2018309), of Fujian Cancer Hospital (SQ2019-037-01).	('Anyang Cancer', 'Disease', (183, 196))	('E2018309', 'Var', (258, 266))	('Cancer', 'Phenotype', 'HP:0002664', (190, 196))	('Cancer', 'Disease', (241, 247))	('Cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Cancer', 'Disease', (279, 285))	('Fujian Cancer', 'Disease', (272, 285))	('Anyang Cancer', 'Disease', 'MESH:D009369', (183, 196))	('Fujian Cancer', 'Disease', 'MESH:D009369', (272, 285))	('Cancer', 'Disease', 'MESH:D009369', (241, 247))	('Cancer', 'Phenotype', 'HP:0002664', (241, 247))	('Cancer', 'Disease', 'MESH:D009369', (279, 285))	('Cancer', 'Disease', (190, 196))	('AZLL', 'Var', (207, 211))	('Cancer', 'Disease', 'MESH:D009369', (190, 196))	('SQ2019-037-01', 'CellLine', 'CVCL:K781', (296, 309))
772613	30956903	Core regulatory miRNAs were miR-520a, miR-548am, miR-3184, miR-548d, miR-4725, miR-148a, miR-4659a and key regulatory TFs included MBNL1, SLC26A3, BMP4, ZIC1 and ANKRD7.	('miR-520a', 'Gene', (28, 36))	('BMP4', 'Gene', (147, 151))	('miR-548d', 'Var', (59, 67))	('miR-4659a', 'Gene', '100616348', (89, 98))	('ZIC1', 'Gene', '7545', (153, 157))	('SLC26A3', 'Gene', '1811', (138, 145))	('miR-4725', 'Gene', (69, 77))	('miR-520a', 'Gene', '574467', (28, 36))	('miR-548am', 'Gene', '100616428', (38, 47))	('miR-3184', 'Gene', '100423003', (49, 57))	('BMP4', 'Gene', '652', (147, 151))	('miR-4659a', 'Gene', (89, 98))	('ZIC1', 'Gene', (153, 157))	('MBNL1', 'Gene', (131, 136))	('miR-4725', 'Gene', '100616449', (69, 77))	('miR-548am', 'Gene', (38, 47))	('ANKRD7', 'Gene', (162, 168))	('miR-3184', 'Gene', (49, 57))	('miR-148a', 'Gene', '406940', (79, 87))	('MBNL1', 'Gene', '4154', (131, 136))	('miR-148a', 'Gene', (79, 87))	('SLC26A3', 'Gene', (138, 145))	('ANKRD7', 'Gene', '56311', (162, 168))
772676	30956903	Core regulatory miRNAs of miR-520a, miR-548am, miR-3184, miR-548d, miR-4725, miR-148a, miR-4659a and key regulatory transcriptional factors of MBNL1, SLC26A3, BMP4, ZIC1 and ANKRD7 might provide biological insight into the full repertoire of nCRT response of ESCC.	('BMP4', 'Gene', '652', (159, 163))	('miR-4725', 'Gene', '100616449', (67, 75))	('ANKRD7', 'Gene', (174, 180))	('miR-548am', 'Gene', (36, 45))	('miR-3184', 'Gene', (47, 55))	('MBNL1', 'Gene', (143, 148))	('miR-4659a', 'Gene', '100616348', (87, 96))	('miR-148a', 'Gene', '406940', (77, 85))	('SLC26A3', 'Gene', (150, 157))	('ANKRD7', 'Gene', '56311', (174, 180))	('miR-148a', 'Gene', (77, 85))	('miR-520a', 'Gene', (26, 34))	('miR-548d', 'Var', (57, 65))	('MBNL1', 'Gene', '4154', (143, 148))	('miR-4659a', 'Gene', (87, 96))	('ZIC1', 'Gene', '7545', (165, 169))	('SLC26A3', 'Gene', '1811', (150, 157))	('miR-4725', 'Gene', (67, 75))	('CRT', 'Gene', '799', (243, 246))	('BMP4', 'Gene', (159, 163))	('miR-520a', 'Gene', '574467', (26, 34))	('CRT', 'Gene', (243, 246))	('miR-548am', 'Gene', '100616428', (36, 45))	('miR-3184', 'Gene', '100423003', (47, 55))	('ZIC1', 'Gene', (165, 169))
772685	29974668	Unsurprisingly, the p-LEF1 group exhibited greater EMT, invasion, and migration than did the LV-shOCT4 and negative control groups.	('EMT', 'CPA', (51, 54))	('p-LEF1', 'Var', (20, 26))	('migration', 'CPA', (70, 79))	('OCT4', 'Gene', '5460', (98, 102))	('OCT4', 'Gene', (98, 102))	('invasion', 'CPA', (56, 64))	('greater', 'PosReg', (43, 50))
772726	29974668	Clinicopathological analysis results indicated that positive staining for LEF1 was obviously associated with histological grade, TNM stage, and overall survival rate (Table 2, Figure 1B).	('histological grade', 'CPA', (109, 127))	('LEF1', 'Gene', (74, 78))	('TNM', 'Gene', (129, 132))	('overall survival rate', 'CPA', (144, 165))	('associated', 'Reg', (93, 103))	('positive staining', 'Var', (52, 69))	('TNM', 'Gene', '10178', (129, 132))
772728	29974668	Based on the expression levels of these proteins, all 95 patients were classified into 4 groups: group I (n = 42), high OCT4 and LEF1 intensity; group II (n = 17), high OCT4 but low LEF1 intensity; group III (n = 14), high LEF1 but low OCT4 intensity; and group IV (n = 22), low OCT4 and LEF1 intensity (Figure 1C).	('high', 'Var', (115, 119))	('OCT4', 'Gene', (279, 283))	('high', 'Var', (218, 222))	('expression', 'MPA', (13, 23))	('patients', 'Species', '9606', (57, 65))	('OCT4', 'Gene', '5460', (169, 173))	('OCT4', 'Gene', (169, 173))	('high', 'Var', (164, 168))	('OCT4', 'Gene', '5460', (236, 240))	('OCT4', 'Gene', '5460', (120, 124))	('OCT4', 'Gene', (236, 240))	('OCT4', 'Gene', (120, 124))	('OCT4', 'Gene', '5460', (279, 283))
772729	29974668	In the OCT4-high ESCC groups, the percentage of patients with high LEF1 was 71.2% higher than that in the OCT4-low groups, indicating an association between OCT4 and LEF1 expression (Figure 1E).	('OCT4', 'Gene', (7, 11))	('LEF1', 'Gene', (67, 71))	('high ESCC', 'Phenotype', 'HP:0003565', (12, 21))	('OCT4', 'Gene', '5460', (106, 110))	('OCT4', 'Gene', '5460', (157, 161))	('OCT4', 'Gene', (106, 110))	('OCT4', 'Gene', (157, 161))	('patients', 'Species', '9606', (48, 56))	('OCT4', 'Gene', '5460', (7, 11))	('high', 'Var', (62, 66))
772731	29974668	Additionally, the correlation of OCT4 and LEF1 expression in the same tissue by utilizing Pearson's rank correlation revealed that the aberrant expression of OCT4 was positively associated with the overexpression of LEF1 in ESCC (Figure 1F).	('overexpression', 'PosReg', (198, 212))	('associated', 'Reg', (178, 188))	('OCT4', 'Gene', '5460', (33, 37))	('OCT4', 'Gene', (33, 37))	('LEF1', 'Gene', (216, 220))	('aberrant', 'Var', (135, 143))	('OCT4', 'Gene', '5460', (158, 162))	('OCT4', 'Gene', (158, 162))
772733	29974668	Therefore, the combination of high OCT4 and LEF1 expression can be a prognostic predictor for ESCC.	('OCT4', 'Gene', '5460', (35, 39))	('OCT4', 'Gene', (35, 39))	('LEF1', 'Gene', (44, 48))	('high', 'Var', (30, 34))	('ESCC', 'Disease', (94, 98))
772743	29974668	Western blotting and qRT-PCR results showed that OCT4 and LEF1 expression levels were decreased in LV-shOCT4 Eca109 cells (Figures 2B,C and S2), while LEF1 expression was significantly increased in p-LEF1 Eca109 cells compared with shOCT4 cells (Figures 3A-C and S3).	('OCT4', 'Gene', (49, 53))	('expression levels', 'MPA', (63, 80))	('OCT4', 'Gene', '5460', (104, 108))	('decreased', 'NegReg', (86, 95))	('increased', 'PosReg', (185, 194))	('expression', 'MPA', (156, 166))	('p-LEF1', 'Var', (198, 204))	('OCT4', 'Gene', '5460', (234, 238))	('LEF1', 'Gene', (58, 62))	('OCT4', 'Gene', (234, 238))	('OCT4', 'Gene', '5460', (49, 53))	('OCT4', 'Gene', (104, 108))
772745	29974668	The results of Western blotting and qRT-PCR revealed decreased levels of E-cadherin and increased levels of N-cadherin in the p-LEF1 group, indicating enhanced EMT capacity (Figures 3A,B, and S1D, S3,S4).	('levels', 'MPA', (63, 69))	('E-cadherin', 'Protein', (73, 83))	('p-LEF1', 'Var', (126, 132))	('enhanced', 'PosReg', (151, 159))	('increased', 'PosReg', (88, 97))	('N-cadherin', 'Gene', (108, 118))	('EMT capacity', 'CPA', (160, 172))	('decreased', 'NegReg', (53, 62))	('levels', 'MPA', (98, 104))	('N-cadherin', 'Gene', '1000', (108, 118))
772747	29974668	However, knocking down OCT4 did not enhance the EMT, invasion, and migration abilities in the LV-shOCT4 group.	('EMT', 'CPA', (48, 51))	('invasion', 'CPA', (53, 61))	('migration abilities', 'CPA', (67, 86))	('knocking down', 'Var', (9, 22))	('OCT4', 'Gene', '5460', (23, 27))	('OCT4', 'Gene', (23, 27))	('OCT4', 'Gene', '5460', (99, 103))	('OCT4', 'Gene', (99, 103))
772757	29974668	Moreover, we detected both OCT4 and LEF1 expressions in ESCC tumor specimens and found that the combination of OCT4 and LEF1 was closely related to the surgical outcomes of patients with ESCC.	('ESCC', 'Disease', (187, 191))	('LEF1', 'Gene', (36, 40))	('OCT4', 'Gene', '5460', (111, 115))	('patients', 'Species', '9606', (173, 181))	('OCT4', 'Gene', (111, 115))	('combination', 'Var', (96, 107))	('ESCC tumor', 'Disease', (56, 66))	('LEF1', 'Var', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('OCT4', 'Gene', '5460', (27, 31))	('OCT4', 'Gene', (27, 31))	('ESCC tumor', 'Disease', 'MESH:D004938', (56, 66))	('related to', 'Reg', (137, 147))
772758	29974668	Patients with OCT4high/LEF1high tumors had a poorer prognosis and more aberrant clinicopathological features than the high/low and low/low expression groups, and Spearman's rank correlation results showed that the aberrant expression of LEF1 was positively associated with the overexpression of OCT4 in ESCC.	('associated', 'Reg', (257, 267))	('overexpression', 'PosReg', (277, 291))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('OCT4', 'Gene', '5460', (295, 299))	('OCT4', 'Gene', (295, 299))	('ESCC', 'Disease', (303, 307))	('tumors', 'Disease', (32, 38))	('aberrant expression', 'Var', (214, 233))	('OCT4', 'Gene', '5460', (14, 18))	('OCT4', 'Gene', (14, 18))	('LEF1', 'Gene', (237, 241))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
772768	29974668	Expectedly, the p-LEF1 group exhibited more marked EMT, invasion, and migration than the LV-shOCT4 and negative control groups.	('invasion', 'CPA', (56, 64))	('EMT', 'CPA', (51, 54))	('OCT4', 'Gene', '5460', (94, 98))	('migration', 'CPA', (70, 79))	('OCT4', 'Gene', (94, 98))	('p-LEF1', 'Var', (16, 22))
772828	28651302	EV class F3 (47.6% vs 18.6%, p<0.001) and presence of gastric varices (71.4% vs 43.1%, p=0.004) were more commonly seen in the recurrence group than those in the nonrecurrence group.	('recurrence', 'Disease', (127, 137))	('EV class F3', 'Var', (0, 11))	('gastric varices', 'Disease', (54, 69))	('gastric varices', 'Phenotype', 'HP:0030169', (54, 69))	('EV', 'Chemical', '-', (0, 2))
772963	26498278	2a, ESCC patients with high FAM3C expression had poorer OS than those with low FAM3C expression.	('high FAM3C expression', 'Var', (23, 44))	('patients', 'Species', '9606', (9, 17))	('OS', 'Chemical', '-', (56, 58))	('ESCC', 'Disease', (4, 8))
772972	26498278	Further, the genetic-clinicopathologic correlation analysis indicated that patients with high expression of FAM3C in tumorous specimens tended to have more advanced pT stage, pN stage and a higher TNM stage.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumorous', 'Disease', 'MESH:D009369', (117, 125))	('pN stage', 'CPA', (175, 183))	('high expression', 'Var', (89, 104))	('tumorous', 'Disease', (117, 125))	('patients', 'Species', '9606', (75, 83))	('TNM stage', 'CPA', (197, 206))	('advanced', 'PosReg', (156, 164))	('pT stage', 'CPA', (165, 173))	('FAM3C', 'Gene', (108, 113))
772979	26498278	Early research demonstrated that FAM3C alone was sufficient to induce EMT, tumor growth and metastasis in murine mammary epithelium cell EpH4, independently of TGF-beta activation.	('FAM3C', 'Var', (33, 38))	('EMT', 'CPA', (70, 73))	('metastasis', 'CPA', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('induce', 'PosReg', (63, 69))	('murine', 'Species', '10090', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
772980	26498278	However, a recent research revealed that exogenous FAM3C strictly required co-operation with oncogenic Ras to cause TGF-beta-independent EMT and tumor progression in human hepatocytes.	('FAM3C', 'Var', (51, 56))	('exogenous', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('human', 'Species', '9606', (166, 171))	('tumor', 'Disease', (145, 150))	('cause', 'Reg', (110, 115))	('EMT', 'CPA', (137, 140))
772983	26498278	Patients with high FAM3C expression displayed a remarkably lower rate of 7-year OS than those with low FAM3C expression.	('OS', 'Chemical', '-', (80, 82))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (59, 64))	('high FAM3C expression', 'Var', (14, 35))
772984	26498278	Moreover, with the stratified survival analysis according to the TNM stage, we found that high expression FAM3C could identify the subgroup of patients with poor outcomes among the early clinical stage (TNM stage I-II) cases, but not the advanced clinical stage ( TNM stage III).	('FAM3C', 'Gene', (106, 111))	('clinical', 'Species', '191496', (187, 195))	('patients', 'Species', '9606', (143, 151))	('high expression', 'Var', (90, 105))	('clinical', 'Species', '191496', (247, 255))
773013	22436793	Other recent studies of failure patterns in patients with such tumors included one by Nakamura et al., who found that 42.1% of all patients with T1-2N0M0 disease had evidence of lymph node involvement at surgery; moreover, 46% of those with lower esophageal tumors and 70% of those with abdominal esophageal tumors had lymph node involvement.	('lower esophageal tumors', 'Disease', (241, 264))	('men', 'Species', '9606', (337, 340))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('lower esophageal tumors', 'Disease', 'MESH:D004938', (241, 264))	('abdominal esophageal tumors', 'Disease', (287, 314))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('patients', 'Species', '9606', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', (308, 314))	('patients', 'Species', '9606', (131, 139))	('abdominal esophageal tumors', 'Disease', 'MESH:D004938', (287, 314))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Disease', (258, 264))	('esophageal tumors', 'Phenotype', 'HP:0100751', (297, 314))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('men', 'Species', '9606', (196, 199))	('T1-2N0M0', 'Var', (145, 153))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('esophageal tumors', 'Phenotype', 'HP:0100751', (247, 264))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
773065	22436793	For the 6 patients who experienced celiac failure who had not had this area covered in the radiation field, univariate analysis of potential risk factors for failure were a posttreatment SUV >8.7 (p=0.0126) and an SUV change <=52% (p=0.0089) (Table 3).	('celiac', 'Disease', (35, 41))	('celiac failure', 'Phenotype', 'HP:0002608', (35, 49))	('SUV change', 'MPA', (214, 224))	('patients', 'Species', '9606', (10, 18))	('men', 'Species', '9606', (182, 185))	('SUV', 'Var', (187, 190))
773138	22302717	This yielded a total of 152 highly deregulated miRNAs (110 upand 42 downregulated) based on selection criteria of 4-fold alteration in 50% of EAC lesions as compared to paired nSQ tissue (Supporting Information Table S2).	('EAC', 'Disease', (142, 145))	('upand', 'PosReg', (59, 64))	('miR', 'Gene', '220972', (47, 50))	('downregulated', 'NegReg', (68, 81))	('miR', 'Gene', (47, 50))	('alteration', 'Var', (121, 131))	('lesions', 'Var', (146, 153))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))	('deregulated', 'PosReg', (35, 46))
773155	22302717	These findings suggest that loss of miR-31 may play an important functional role in the metaplasia to dysplasia transition, and that loss of miR-31 may have potential value as an early molecular marker of dysplastic progression.	('loss', 'Var', (28, 32))	('miR-31', 'Gene', '407035', (36, 42))	('miR-31', 'Gene', (141, 147))	('metaplasia to dysplasia', 'Disease', 'MESH:D008679', (88, 111))	('dysplastic', 'Disease', 'MESH:D004416', (205, 215))	('miR-31', 'Gene', '407035', (141, 147))	('miR-31', 'Gene', (36, 42))	('loss', 'Var', (133, 137))	('metaplasia to dysplasia', 'Disease', (88, 111))	('dysplastic', 'Disease', (205, 215))
773176	22302717	In conclusion, by adopting a stringent methodology to determine the timing of miRNA alterations in esophageal neoplasia, we have identified miR-31 and 375 as novel candidate miRNAs whose deregulation is specifically associated with multistep malignant progression in Barrett's esophagus.	('miR-31', 'Gene', (140, 146))	("Barrett's esophagus", 'Disease', (267, 286))	('miR', 'Gene', '220972', (78, 81))	('associated with', 'Reg', (216, 231))	('miR', 'Gene', (140, 143))	('deregulation', 'Var', (187, 199))	('miR', 'Gene', (174, 177))	('esophageal neoplasia', 'Disease', (99, 119))	('miR', 'Gene', (78, 81))	('miR-31', 'Gene', '407035', (140, 146))	('miR', 'Gene', '220972', (174, 177))	('miR', 'Gene', '220972', (140, 143))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (99, 119))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (267, 286))	('neoplasia', 'Phenotype', 'HP:0002664', (110, 119))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (99, 119))
773183	16895604	Both homozygous and hemizygous deletions were detected in FHIT, in four of the cell lines with a preferential deletion of exons 5 and 4.	('FHIT', 'Gene', (58, 62))	('FHIT', 'Gene', '2272', (58, 62))	('deletions', 'Var', (31, 40))	('deletion', 'Var', (110, 118))
773188	16895604	The presence of site specific deletions of FHIT in these cell lines and primary tumors support its possible role in South African ESCC and justifies a wider screening.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('FHIT', 'Gene', (43, 47))	('deletions', 'Var', (30, 39))	('primary tumors', 'Disease', (72, 86))	('FHIT', 'Gene', '2272', (43, 47))	('South African ESCC', 'Disease', (116, 134))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('primary tumors', 'Disease', 'MESH:D009369', (72, 86))
773190	16895604	Both genes have small exons distributed over their respective fragile loci and large intragenic deletions have been detected in a wide variety of malignant and pre-malignant tumors, reviewed in.	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Disease', (174, 180))	('deletions', 'Var', (96, 105))	('detected', 'Reg', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
773199	16895604	The most commonly used method to investigate deletions in FHIT and WWOX is loss of heterozygosity (LOH) analysis in separate assays.	('WWOX', 'Gene', '51741', (67, 71))	('WWOX', 'Gene', (67, 71))	('deletions', 'Var', (45, 54))	('FHIT', 'Gene', (58, 62))	('FHIT', 'Gene', '2272', (58, 62))
773202	16895604	Since genomic deletions and hypermethylation appear to be the main mechanism of FHIT and WWOX inactivation a significant amount of information can be retrieved from the retrospective evaluation of archived paraffin embedded specimens.	('hypermethylation', 'Var', (28, 44))	('paraffin', 'Chemical', 'MESH:D010232', (206, 214))	('WWOX', 'Gene', '51741', (89, 93))	('genomic deletions', 'Var', (6, 23))	('WWOX', 'Gene', (89, 93))	('FHIT', 'Gene', (80, 84))	('FHIT', 'Gene', '2272', (80, 84))
773205	16895604	This assay allowed for the detection of deletions/duplications and relative quantification of both FHIT and WWOX exons in a single run.	('FHIT', 'Gene', (99, 103))	('deletions/duplications', 'Var', (40, 62))	('FHIT', 'Gene', '2272', (99, 103))	('WWOX', 'Gene', '51741', (108, 112))	('WWOX', 'Gene', (108, 112))
773206	16895604	We evaluated its performance investigating FHIT and WWOX deletions in five ESCC South African established cell lines.	('deletions', 'Var', (57, 66))	('FHIT', 'Gene', (43, 47))	('FHIT', 'Gene', '2272', (43, 47))	('WWOX', 'Gene', '51741', (52, 56))	('WWOX', 'Gene', (52, 56))
773217	16895604	The MLPA method initially developed and described by Schouten et al, was used to detect exons specific copy number change in the FHIT and WWOX genes.	('FHIT', 'Gene', (129, 133))	('FHIT', 'Gene', '2272', (129, 133))	('copy number change', 'Var', (103, 121))	('WWOX', 'Gene', '51741', (138, 142))	('WWOX', 'Gene', (138, 142))
773224	16895604	The choice of adequate control probes is important due to the number of genetic alterations that may be present in cancer cells and affect "control probes" themselves.	('cancer', 'Disease', (115, 121))	('genetic alterations', 'Var', (72, 91))	('affect', 'Reg', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
773227	16895604	A complete homozygous deletion of FHIT exon 5 was detected in cell line SNO while the other FHIT exons were under represented.	('SNO', 'Gene', '55206', (72, 75))	('FHIT', 'Gene', (92, 96))	('FHIT', 'Gene', '2272', (92, 96))	('deletion', 'Var', (22, 30))	('FHIT', 'Gene', (34, 38))	('FHIT', 'Gene', '2272', (34, 38))	('SNO', 'Gene', (72, 75))
773228	16895604	Relatives (not shown) and absolute peak heights comparison of tumor to control specimen, showed FHIT exons 4 and 5 deletion in cell line WHCO5 (ratio of 0.55) (Figure 2B), compatible with a hemizygous deletion.	('deletion', 'Var', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('FHIT', 'Gene', (96, 100))	('WHCO5', 'Chemical', '-', (137, 142))	('FHIT', 'Gene', '2272', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
773231	16895604	As for cell line WHCO5, WHCO6 had a preferential deletion of FHIT exons 4 and 5, in addition all FHIT exons in this cell line had a ratio near or below 0.7 compatible with a hemizygous deletion of the full gene.	('FHIT', 'Gene', '2272', (97, 101))	('WHCO6', 'Chemical', '-', (24, 29))	('FHIT', 'Gene', (61, 65))	('FHIT', 'Gene', '2272', (61, 65))	('WHCO5', 'Chemical', '-', (17, 22))	('deletion', 'Var', (49, 57))	('FHIT', 'Gene', (97, 101))
773232	16895604	Cell line WHCO1 had a homogeneous FHIT deletion across all exons consistent with hemizygous deletion.	('WHCO1', 'Chemical', '-', (10, 15))	('deletion', 'Var', (39, 47))	('FHIT', 'Gene', '2272', (34, 38))	('FHIT', 'Gene', (34, 38))
773233	16895604	In both cell lines delineated as SNO and WHCO5, the internal control probes that mapped near the FRA3B locus, at 3p25 and 3p22 respectively were not deleted, although cell line SNO had a homozygous deletion of FHIT exon 5.	('SNO', 'Gene', (33, 36))	('deletion', 'Var', (198, 206))	('SNO', 'Gene', '55206', (33, 36))	('FHIT', 'Gene', (210, 214))	('WHCO5', 'Chemical', '-', (41, 46))	('FRA3B', 'Gene', '2272', (97, 102))	('FRA3B', 'Gene', (97, 102))	('SNO', 'Gene', (177, 180))	('FHIT', 'Gene', '2272', (210, 214))	('SNO', 'Gene', '55206', (177, 180))
773234	16895604	FHIT deletions in these cell lines were specifically confined to the FRA3B region.	('FRA3B', 'Gene', (69, 74))	('FHIT', 'Gene', (0, 4))	('FHIT', 'Gene', '2272', (0, 4))	('FRA3B', 'Gene', '2272', (69, 74))	('deletions', 'Var', (5, 14))
773236	16895604	In cell line WHCO6, which had a preferential deletion of exons 4 and 5 of the FHIT gene, both 3p probes were underrepresented compatible with hemizygous deletion of this region.	('deletion', 'Var', (153, 161))	('FHIT', 'Gene', (78, 82))	('FHIT', 'Gene', '2272', (78, 82))	('deletion', 'Var', (45, 53))	('WHCO6', 'Chemical', '-', (13, 18))
773243	16895604	All cell lines having a deletion in one or more exons of FHIT, had an aberrant FHIT RT-PCR pattern (Figure 4).	('FHIT', 'Gene', (57, 61))	('FHIT', 'Gene', '2272', (57, 61))	('FHIT', 'Gene', (79, 83))	('deletion', 'Var', (24, 32))	('FHIT', 'Gene', '2272', (79, 83))
773248	16895604	RT-PCR specific for exon 5 confirmed the deletion in cell line SNO (results not shown).	('deletion', 'Var', (41, 49))	('SNO', 'Gene', '55206', (63, 66))	('SNO', 'Gene', (63, 66))
773253	16895604	Four tumor specimens showed deletions spanning the FHIT locus.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('deletions', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('FHIT', 'Gene', (51, 55))	('FHIT', 'Gene', '2272', (51, 55))	('tumor', 'Disease', (5, 10))
773255	16895604	ESCC samples delineated as CA1 and CA2 showed a pattern consistent with a hemizygous deletion of the whole FHIT locus; a preferential deletion of exons 7 to 10 was noticeable in CA1 (Figure 5) and included the probe at 3p22.	('CA2', 'Gene', (35, 38))	('CA2', 'Gene', '760', (35, 38))	('deletion', 'Var', (134, 142))	('CA1', 'Gene', '759', (178, 181))	('CA1', 'Gene', (178, 181))	('CA1', 'Gene', '759', (27, 30))	('FHIT', 'Gene', (107, 111))	('FHIT', 'Gene', '2272', (107, 111))	('CA1', 'Gene', (27, 30))
773257	16895604	The tumor specimens delineated as CA3 and CA4 had preferential deletions of FHIT specific exons, FHIT exon 5, and FHIT exons 3 and 4 respectively (Figure 5).	('tumor', 'Disease', (4, 9))	('FHIT', 'Gene', '2272', (97, 101))	('FHIT', 'Gene', '2272', (76, 80))	('CA3', 'Gene', '761', (34, 37))	('FHIT', 'Gene', '2272', (114, 118))	('CA3', 'Gene', (34, 37))	('deletions', 'Var', (63, 72))	('CA4', 'Gene', '762', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('FHIT', 'Gene', (97, 101))	('FHIT', 'Gene', (76, 80))	('CA4', 'Gene', (42, 45))	('FHIT', 'Gene', (114, 118))
773267	16895604	FHIT is altered in a wide variety of tumors, mostly by genomic deletions and/or promoter hypermethylation, which results in inhibition of the FHIT product.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('inhibition', 'NegReg', (124, 134))	('promoter hypermethylation', 'Var', (80, 105))	('altered', 'Reg', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('FHIT', 'Gene', (0, 4))	('FHIT', 'Gene', '2272', (0, 4))	('tumors', 'Disease', (37, 43))	('FHIT', 'Gene', (142, 146))	('FHIT', 'Gene', '2272', (142, 146))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
773268	16895604	Several reports have raised pertinent questions regarding the relevance of FHIT deletion to cancer development: exon skipping alternative transcripts have been found in normal tissues in addition to normal transcripts, the gene lies within an instable genomic region which may be mechanistically deleted and the effect of hemizygous deletion in tumors is unclear.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('FHIT', 'Gene', (75, 79))	('FHIT', 'Gene', '2272', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (345, 351))	('tumors', 'Disease', (345, 351))	('tumors', 'Disease', 'MESH:D009369', (345, 351))	('exon skipping', 'Var', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
773271	16895604	Four of five SA ESCC cell lines and four of ten primary tumors had a FHIT deletion suggesting that FHIT might be of relevance in SA esophageal cancer as found in other parts of the world where the incidence of this type of cancer is high.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('primary tumors', 'Disease', (48, 62))	('FHIT', 'Gene', (99, 103))	('deletion', 'Var', (74, 82))	('esophageal cancer', 'Disease', (132, 149))	('primary tumors', 'Disease', 'MESH:D009369', (48, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('FHIT', 'Gene', '2272', (99, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (132, 149))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('FHIT', 'Gene', (69, 73))	('FHIT', 'Gene', '2272', (69, 73))	('cancer', 'Disease', (223, 229))
773273	16895604	Cell line SNO had a homozygous deletion of exon 5 and no functional transcript.	('SNO', 'Gene', '55206', (10, 13))	('SNO', 'Gene', (10, 13))	('deletion', 'Var', (31, 39))
773274	16895604	The other three cell lines had hemizygous deletion of FHIT exons, with an abnormal expression pattern.	('deletion', 'Var', (42, 50))	('FHIT', 'Gene', (54, 58))	('FHIT', 'Gene', '2272', (54, 58))
773275	16895604	The evaluation of chromosome 3p copy number by FISH as well as the internal control probes on 3p in MLPA established that these deletions were specific for the FRA3B region in ESCC cell lines and in three of four primary tumors.	('ESCC', 'Disease', (176, 180))	('FRA3B', 'Gene', (160, 165))	('primary tumors', 'Disease', (213, 227))	('FRA3B', 'Gene', '2272', (160, 165))	('primary tumors', 'Disease', 'MESH:D009369', (213, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('deletions', 'Var', (128, 137))
773279	16895604	In the present study, FHIT deletions were associated with aberrant transcripts in the cell lines and deletions were observed in a third of primary ESCC tumors.	('FHIT', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('associated', 'Reg', (42, 52))	('ESCC tumors', 'Disease', (147, 158))	('FHIT', 'Gene', '2272', (22, 26))	('ESCC tumors', 'Disease', 'MESH:D004938', (147, 158))	('deletions', 'Var', (27, 36))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
773280	16895604	It would be necessary to screen a larger cohort of primary tumors to evaluate the importance of FHIT and WWOX intragenic deletions in SA ESCC.	('WWOX', 'Gene', '51741', (105, 109))	('WWOX', 'Gene', (105, 109))	('primary tumors', 'Disease', (51, 65))	('FHIT', 'Gene', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('deletions', 'Var', (121, 130))	('primary tumors', 'Disease', 'MESH:D009369', (51, 65))	('FHIT', 'Gene', '2272', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
773284	16895604	Deletions could also represent a later event where FHIT haplo-insufficiency aggravated an already unstable genetic background.	('FHIT haplo-insufficiency', 'Disease', 'MESH:D000309', (51, 75))	('FHIT haplo-insufficiency', 'Disease', (51, 75))	('aggravated', 'PosReg', (76, 86))	('Deletions', 'Var', (0, 9))
773286	16895604	While LOH at the WWOX locus has been reported in ESCC, WWOX is frequently inactivated by promoter hypermethylation, which was not detected in this assay.	('WWOX', 'Gene', '51741', (17, 21))	('WWOX', 'Gene', (17, 21))	('ESCC', 'Disease', (49, 53))	('WWOX', 'Gene', '51741', (55, 59))	('promoter hypermethylation', 'Var', (89, 114))	('WWOX', 'Gene', (55, 59))
773291	16895604	In this study, the assay detected FHIT deletions in four of five SA ESCC cell lines and four of ten primary tumors, which justifies a wider screening in SA ESCC patients.	('deletions', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('primary tumors', 'Disease', (100, 114))	('patients', 'Species', '9606', (161, 169))	('primary tumors', 'Disease', 'MESH:D009369', (100, 114))	('FHIT', 'Gene', (34, 38))	('FHIT', 'Gene', '2272', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('detected', 'Reg', (25, 33))
773402	32787796	Also, the treatment of Helicobacter pylori infection may play an important role in reducing stomach cancer; some studies have shown that giving antibiotics to patients with Helicobacter pylori infection, may reduce the number of pre-cancerous lesions in the stomach and reduce the risk of developing stomach cancer Additionally, advances in cancer treatment and screening strategies have played a key role in increasing survival rate and reducing the mortality rate from cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('reduce', 'NegReg', (270, 276))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (173, 202))	('cancer', 'Phenotype', 'HP:0002664', (471, 477))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('Helicobacter pylori', 'Species', '210', (173, 192))	('mortality', 'Disease', 'MESH:D003643', (451, 460))	('Helicobacter pylori', 'Species', '210', (23, 42))	('infection', 'Disease', (193, 202))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('survival', 'CPA', (420, 428))	('reducing', 'NegReg', (438, 446))	('cancer', 'Disease', (341, 347))	('infection', 'Disease', 'MESH:D007239', (193, 202))	('stomach cancer', 'Disease', 'MESH:D013274', (300, 314))	('stomach cancer', 'Phenotype', 'HP:0012126', (300, 314))	('cancerous lesions', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('increasing', 'PosReg', (409, 419))	('stomach cancer', 'Disease', 'MESH:D013274', (92, 106))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('stomach cancer', 'Phenotype', 'HP:0012126', (92, 106))	('cancer', 'Disease', 'MESH:D009369', (471, 477))	('cancers', 'Disease', 'MESH:D009369', (471, 478))	('infection', 'Disease', (43, 52))	('pylori infection', 'Phenotype', 'HP:0005202', (36, 52))	('cancer', 'Disease', (308, 314))	('pylori infection', 'Phenotype', 'HP:0005202', (186, 202))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('cancer', 'Disease', (100, 106))	('patients', 'Species', '9606', (159, 167))	('cancerous lesions', 'Disease', 'MESH:D009369', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('cancer', 'Disease', (471, 477))	('reduce', 'NegReg', (208, 214))	('mortality', 'Disease', (451, 460))	('Helicobacter pylori', 'Var', (173, 192))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (23, 52))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('stomach cancer', 'Disease', (300, 314))	('cancer', 'Disease', (233, 239))	('stomach cancer', 'Disease', (92, 106))	('cancers', 'Phenotype', 'HP:0002664', (471, 478))	('cancers', 'Disease', (471, 478))	('infection', 'Disease', 'MESH:D007239', (43, 52))
773427	32148378	The 10-year overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS) rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.	('high', 'Var', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('liver cancer', 'Phenotype', 'HP:0002896', (151, 163))	('liver cancer', 'Disease', 'MESH:D006528', (151, 163))	('ORM', 'Gene', (126, 129))	('low', 'NegReg', (122, 125))	('liver cancer', 'Disease', (151, 163))	('patients', 'Species', '9606', (164, 172))	('ORM', 'Gene', '5004', (126, 129))
773435	32148378	Moreover, apoptosis, IFN-alpha responses, IFN-gamma responses and humoral immune responses were upregulated in the ORM2 high group.	('IFN-gamma', 'Gene', '3458', (42, 51))	('IFN-gamma', 'Gene', (42, 51))	('high', 'Var', (120, 124))	('humoral immune responses', 'CPA', (66, 90))	('apoptosis', 'CPA', (10, 19))	('upregulated', 'PosReg', (96, 107))	('IFN-alpha', 'Gene', '3439', (21, 30))	('IFN-alpha', 'Gene', (21, 30))	('ORM2', 'Gene', (115, 119))
773471	32148378	GSE36376 contained 193 cases of non-tumor liver and 240 cases of liver tumor tissues, and GSE14520 contained 220 cases of non-tumor liver and 225 cases of liver tumor tissues.	('liver tumor', 'Disease', (65, 76))	('liver tumor', 'Phenotype', 'HP:0002896', (155, 166))	('tumor liver', 'Phenotype', 'HP:0002896', (36, 47))	('non-tumor liver', 'Disease', (32, 47))	('non-tumor liver', 'Disease', 'MESH:D008113', (122, 137))	('tumor liver', 'Phenotype', 'HP:0002896', (126, 137))	('GSE36376', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('non-tumor liver', 'Disease', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('liver tumor', 'Disease', 'MESH:D008113', (155, 166))	('non-tumor liver', 'Disease', 'MESH:D008113', (32, 47))	('GSE14520', 'Var', (90, 98))	('liver tumor', 'Disease', (155, 166))	('liver tumor', 'Disease', 'MESH:D008113', (65, 76))	('liver tumor', 'Phenotype', 'HP:0002896', (65, 76))
773559	32148378	Furthermore, drug resistance could shorten the survival time of liver cancer patients.	('survival time', 'CPA', (47, 60))	('liver cancer', 'Disease', (64, 76))	('drug resistance', 'Phenotype', 'HP:0020174', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('drug resistance', 'Var', (13, 28))	('shorten', 'NegReg', (35, 42))	('patients', 'Species', '9606', (77, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (64, 76))	('liver cancer', 'Disease', 'MESH:D006528', (64, 76))
773571	32148378	The high ORM2 expression group showed better survival rates in liver cancer patients upon OS, PFS and RFS analysis.	('patients', 'Species', '9606', (76, 84))	('liver cancer', 'Phenotype', 'HP:0002896', (63, 75))	('liver cancer', 'Disease', 'MESH:D006528', (63, 75))	('better', 'PosReg', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('liver cancer', 'Disease', (63, 75))	('high', 'Var', (4, 8))	('ORM2', 'Gene', (9, 13))	('survival rates', 'CPA', (45, 59))
773573	32148378	Besides, the ORM2 high-expression patients group showed a close association with apoptosis, an IFN-alpha response, IFN-gamma response and humoral immune response in liver cancer.	('high-expression', 'Var', (18, 33))	('liver cancer', 'Phenotype', 'HP:0002896', (165, 177))	('liver cancer', 'Disease', 'MESH:D006528', (165, 177))	('ORM2', 'Gene', (13, 17))	('liver cancer', 'Disease', (165, 177))	('IFN-gamma', 'Gene', '3458', (115, 124))	('apoptosis', 'CPA', (81, 90))	('IFN-gamma', 'Gene', (115, 124))	('IFN-alpha', 'Gene', '3439', (95, 104))	('IFN-alpha', 'Gene', (95, 104))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
773585	31061821	For example, anti-apoptotic BCL2 in chronic lymphocytic leukemia (CLL) and other cancers and BMI1 in gastric cancer as well as pancreatic cancer act as a stem cell marker and promoter of migration and invasion.	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('BCL2', 'Gene', '596', (28, 32))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('leukemia', 'Phenotype', 'HP:0001909', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('invasion', 'CPA', (201, 209))	('pancreatic cancer', 'Disease', (127, 144))	('BCL2', 'Gene', (28, 32))	('BMI1', 'Gene', (93, 97))	('gastric cancer', 'Disease', (101, 115))	('anti-apoptotic', 'Var', (13, 27))	('migration', 'CPA', (187, 196))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (36, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('chronic lymphocytic leukemia', 'Disease', (36, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('BMI1', 'Gene', '648', (93, 97))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (36, 64))
773595	31061821	The results showed that although the probability of death in the low-expression group was 1.165 times higher than that in the high-expression group, there was no statistical difference (HR=1.165, 95%CI 0.95-1.44; P=0.150).	('low-expression', 'Var', (65, 79))	('death', 'Disease', 'MESH:D003643', (52, 57))	('death', 'Disease', (52, 57))
773596	31061821	However, in the survival analysis of a single cancer types, we found that low-expression miRNA-15a was significantly associated with worse OS in bladder Carcinoma (HR=1.49, 95%CI 1.11-2.00; P=0.0081), head-neck squamous cell carcinoma (HR=1.43, 95%CI 1.04-1.96; P=0.027), liver hepatocellular carcinoma (HR=1.54, 95%CI 1.08-2.22; P=0.017), lung squamous cell carcinoma (HR=1.69, 95%CI 1.22-2.38; P=0.0014), pancreatic ductal adenocarcinoma (HR=2.22, 95%CI 1.43-3.45; P=0.0002), rectum adenocarcinoma (HR=2.63, 95%CI 1.19-5.88; P=0.013), stomach adenocarcinoma (HR=1.52, 95%CI 1.10-2.08; P=0.011), and uterine corpus endometrial carcinoma (HR=1.69, 95%CI 1.10-2.63; P=0.015), whereas the results were opposite in cervical squamous cell carcinoma (HR=0.55, 95%CI 0.32-0.93; P=0.026) and esophageal carcinoma (HR=0.53, 95%CI 0.34-0.85; P=0.0072) (Figure 3).	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (407, 439))	('head-neck squamous cell carcinoma', 'Disease', (201, 234))	('bladder Carcinoma', 'Phenotype', 'HP:0002862', (145, 162))	('bladder Carcinoma (HR=1.49', 'Disease', 'MESH:D001749', (145, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (430, 439))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (616, 637))	('miRNA-15a', 'Gene', (89, 98))	('pancreatic ductal adenocarcinoma', 'Disease', (407, 439))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (721, 744))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (785, 805))	('head-neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (201, 234))	('liver hepatocellular carcinoma', 'Disease', (272, 302))	('rectum adenocarcinoma', 'Disease', (478, 499))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (340, 368))	('stomach adenocarcinoma', 'Disease', (537, 559))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('uterine corpus endometrial carcinoma', 'Disease', (601, 637))	('Carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (490, 499))	('low-expression', 'Var', (74, 88))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (278, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (345, 368))	('lung squamous cell carcinoma', 'Disease', (340, 368))	('cervical squamous cell carcinoma', 'Disease', (712, 744))	('esophageal carcinoma', 'Disease', (785, 805))
773600	31061821	MiRNA-15a belongs to the miRNA-15 family, which is located on chromosome 13 (13q14) and consists of miRNA-15a/b, miRNA-16-1, miRNA-16-2, miRNA-497, and miRNA-195.	('miRNA-16-1', 'Gene', '406950', (113, 123))	('miRNA-15a/b', 'Var', (100, 111))	('miRNA-195', 'Gene', (152, 161))	('miRNA-195', 'Gene', '406971', (152, 161))	('miRNA-16-1', 'Gene', (113, 123))
773690	30588024	Dong et al reported that mutant TP53 exerted oncogenic functions and promoted EMT in endometrial cancer by binding directly to the miR130b promoter and inhibiting its transcription.	('oncogenic functions', 'CPA', (45, 64))	('mutant', 'Var', (25, 31))	('endometrial cancer', 'Disease', 'MESH:D016889', (85, 103))	('miR130b', 'Gene', (131, 138))	('TP53', 'Gene', '7157', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('TP53', 'Gene', (32, 36))	('miR130b', 'Gene', '406920', (131, 138))	('promoted', 'PosReg', (69, 77))	('endometrial cancer', 'Disease', (85, 103))	('binding', 'Interaction', (107, 114))	('EMT', 'Gene', (78, 81))	('inhibiting', 'NegReg', (152, 162))	('endometrial cancer', 'Phenotype', 'HP:0012114', (85, 103))	('EMT', 'Gene', '3702', (78, 81))	('transcription', 'MPA', (167, 180))
773812	29221176	Nutrition monitoring indicated that plasma level of alpha-Tocopherol was significantly elevated by the dietary supplementation at specific period when compared to the control animals, and the alpha-Tocopherol levels promptly descended as the intervention withdrew (Figure 1B).	('supplementation', 'Var', (111, 126))	('descended', 'NegReg', (225, 234))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (192, 208))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (52, 68))	('elevated', 'PosReg', (87, 95))	('plasma level of alpha-Tocopherol', 'MPA', (36, 68))	('alpha-Tocopherol levels', 'MPA', (192, 215))
773816	29221176	As for the microscopic lesions, no differences were observed on the number of hyperplasia; however, the generation of dysplasia was markedly suppressed by the initiation-stage supplementation, which was significantly less than that in post-initiation supplementation (Figure 1F).	('supplementation', 'Var', (176, 191))	('rat', 'Species', '10116', (108, 111))	('dysplasia', 'Disease', (118, 127))	('dysplasia', 'Disease', 'MESH:D004476', (118, 127))	('suppressed', 'NegReg', (141, 151))	('hyperplasia', 'Disease', (78, 89))	('hyperplasia', 'Disease', 'MESH:D006965', (78, 89))
773822	29221176	Interestingly, alpha-Tocopherol supplementation at the initiation-stage showed more marked inhibition of cell proliferation than the supplementation at post-initiation stage, but no difference was observed in the advanced lesions (i.e.	('rat', 'Species', '10116', (117, 120))	('supplementation', 'Var', (32, 47))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (15, 31))	('inhibition', 'NegReg', (91, 101))	('cell proliferation', 'CPA', (105, 123))	('alpha-Tocopherol', 'Protein', (15, 31))
773833	29221176	In contrast, cell cycle was not significantly altered by alpha-Tocopherol (25, 50 and 100 muM) in KYSE-150 and TE-1 cells (Figure 3D).	('cell cycle', 'CPA', (13, 23))	('25', 'Var', (75, 77))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (57, 73))	('muM', 'Gene', '56925', (90, 93))	('TE-1', 'CellLine', 'CVCL:1759', (111, 115))	('muM', 'Gene', (90, 93))
773840	29221176	It has been known that dysregulation of the PI3K-Akt pathway is implicated in a number of human diseases including cancer, diabetes, cardiovascular diseases and neurological diseases.	('diabetes', 'Disease', 'MESH:D003920', (123, 131))	('cancer', 'Disease', (115, 121))	('dysregulation', 'Var', (23, 36))	('cardiovascular diseases', 'Disease', (133, 156))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (133, 156))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (133, 156))	('neurological diseases', 'Disease', (161, 182))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('human', 'Species', '9606', (90, 95))	('implicated', 'Reg', (64, 74))	('PI3K-Akt pathway', 'Pathway', (44, 60))	('diabetes', 'Disease', (123, 131))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('neurological diseases', 'Disease', 'MESH:D019636', (161, 182))
773843	29221176	Furthermore, the activation of these proteins was dramatically inhibited by the presence of alpha-Tocopherol, suggesting that alpha-Tocopherol significantly attenuated the activation of Akt signaling pathway during ESCC initiation induced by NMBA.	('ESCC', 'Disease', (215, 219))	('attenuated', 'NegReg', (157, 167))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (92, 108))	('alpha-Tocopherol', 'Var', (126, 142))	('NMBA', 'Chemical', 'MESH:C014707', (242, 246))	('Akt signaling pathway', 'Pathway', (186, 207))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (126, 142))	('activation', 'PosReg', (172, 182))
773852	29221176	Furthermore, the phosphorylation of Akt, mdm2, and cdc2 were consistently suppressed by supplementation with alpha-Tocopherol at the early stage when compared to the NMBA group (Figure 5B).	('NMBA', 'Chemical', 'MESH:C014707', (166, 170))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (109, 125))	('suppressed', 'NegReg', (74, 84))	('phosphorylation', 'MPA', (17, 32))	('supplementation', 'Var', (88, 103))	('mdm2', 'Gene', (41, 45))	('cdc2', 'Gene', (51, 55))	('mdm2', 'Gene', '4193', (41, 45))	('Akt', 'Pathway', (36, 39))	('cdc2', 'Gene', '983', (51, 55))
773859	29221176	The tumor suppressor gene PTEN, which is transcriptionally activated by PPARgamma and acts as a major negative regulator of the PI3K/Akt signaling, was also increased by alpha-Tocopherol (Figure 6A).	('tumor', 'Disease', (4, 9))	('PPARgamma', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('activated', 'PosReg', (59, 68))	('increased', 'PosReg', (157, 166))	('PTEN', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (170, 186))
773863	29221176	PPARgamma activation by RGZ significantly inhibited the phosphorylation of Akt and mdm2, whereas the downstream p53, p21, Bad and Bax were inversely increased (Figure 6D).	('Bax', 'Gene', '581', (130, 133))	('p21', 'Gene', '1026', (117, 120))	('p21', 'Gene', (117, 120))	('mdm2', 'Gene', (83, 87))	('Bax', 'Gene', (130, 133))	('Akt', 'Pathway', (75, 78))	('inhibited', 'NegReg', (42, 51))	('RGZ', 'Var', (24, 27))	('p53', 'Gene', (112, 115))	('mdm2', 'Gene', '4193', (83, 87))	('phosphorylation', 'MPA', (56, 71))	('p53', 'Gene', '7157', (112, 115))	('activation', 'PosReg', (10, 20))	('PPARgamma', 'Protein', (0, 9))
773864	29221176	In contrast, PTEN and p53 were suppressed by GW9662.	('p53', 'Gene', (22, 25))	('GW9662', 'Var', (45, 51))	('GW9662', 'Chemical', 'MESH:C457499', (45, 51))	('PTEN', 'Protein', (13, 17))	('p53', 'Gene', '7157', (22, 25))	('suppressed', 'NegReg', (31, 41))
773865	29221176	On the other hand, PPARgamma knockdown with siRNA markedly increased the phosphorylation of Akt and its downstream target molecules (PRAS40, GSK-3alpha, and 4E-BP1), which was significantly inhibited by the presence of alpha-Tocopherol or RGZ (Figure 6E).	('GSK-3alpha', 'Gene', (141, 151))	('knockdown', 'Var', (29, 38))	('PRAS40', 'Gene', '84335', (133, 139))	('4E-BP1', 'Gene', '1978', (157, 163))	('PRAS40', 'Gene', (133, 139))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (219, 235))	('GSK-3alpha', 'Gene', '2931', (141, 151))	('phosphorylation', 'MPA', (73, 88))	('Akt', 'Pathway', (92, 95))	('increased', 'PosReg', (59, 68))	('4E-BP1', 'Gene', (157, 163))
773871	29221176	Though RGZ and GW9662 slightly changed the expression of PPARgamma and PTEN, but they did not significantly altered Akt activation (Figure 7B).	('RGZ', 'Var', (7, 10))	('PTEN', 'Protein', (71, 75))	('PPARgamma', 'Protein', (57, 66))	('expression', 'MPA', (43, 53))	('GW9662', 'Var', (15, 21))	('GW9662', 'Chemical', 'MESH:C457499', (15, 21))	('changed', 'Reg', (31, 38))
773887	29221176	In the Het-1A cell model, we also observed significant increase of apoptosis and expression of pro-apoptotic proteins (Bax and Bad) that induced by alpha-Tocopherol.	('increase', 'PosReg', (55, 63))	('apoptosis', 'CPA', (67, 76))	('Bax', 'Gene', (119, 122))	('alpha-Tocopherol', 'Var', (148, 164))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (148, 164))	('expression', 'MPA', (81, 91))	('Bax', 'Gene', '581', (119, 122))
773890	29221176	For example, gamma- and delta-tocotrienols had potent anti-proliferative activity and induced apoptosis through inhibition of PI3K/PKB in pancreatic cancer cells, but tocopherols were not able to induce the observed effects.	('gamma- and delta-tocotrienols', 'Chemical', '-', (13, 42))	('pancreatic cancer', 'Disease', (138, 155))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('anti-proliferative activity', 'CPA', (54, 81))	('inhibition', 'NegReg', (112, 122))	('PKB', 'Gene', '207;24185', (131, 134))	('tocopherols', 'Chemical', 'MESH:D024505', (167, 178))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('PKB', 'Gene', (131, 134))	('rat', 'Species', '10116', (66, 69))	('apoptosis', 'CPA', (94, 103))	('gamma-', 'Var', (13, 19))
773898	29221176	Previous studies showed that PPARgamma can suppress beta-catenin levels and colon carcinogenesis but only before damage to the APC/beta-catenin pathway, suggesting a potentially important use for PPARgamma ligands as chemopreventive agents in colon cancer.	('beta-catenin', 'Gene', (52, 64))	('APC', 'Disease', 'MESH:D011125', (127, 130))	('beta-catenin', 'Gene', (131, 143))	('colon cancer', 'Disease', 'MESH:D015179', (243, 255))	('colon cancer', 'Phenotype', 'HP:0003003', (243, 255))	('suppress', 'NegReg', (43, 51))	('APC', 'Disease', (127, 130))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (76, 96))	('beta-catenin', 'Gene', '1499', (52, 64))	('colon cancer', 'Disease', (243, 255))	('beta-catenin', 'Gene', '1499', (131, 143))	('colon carcinogenesis', 'Disease', (76, 96))	('PPARgamma', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
773907	29221176	Furthermore, the knockdown of PPARgamma with RNA interference and in combination with alpha-Tocopherol or PPARgamma agonist RGZ consistently suggested that the inhibition of Akt by alpha-Tocopherol was, at least in part, dependent on PPARgamma activation.	('inhibition', 'NegReg', (160, 170))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (181, 197))	('PPARgamma', 'Gene', (30, 39))	('alpha-Tocopherol', 'Chemical', 'MESH:D024502', (86, 102))	('knockdown', 'Var', (17, 26))	('RNA interference', 'MPA', (45, 61))	('Akt', 'Pathway', (174, 177))
773981	25059343	This study was restricted to adult patients (aged 18 years or older) who underwent esophagectomy (defined as Current Procedural Terminology [CPT] codes of 43107, 43108, 43112, 43113, 43116, 43117, 43118, 43121, 43122, 43123, or 43124) for esophageal cancer (defined by International Classification of Diseases, 9th revision codes of 150, 150.1, 150.2, 150.3, 150.4, 150.5, 150.8, 150.9, 151, or 151.0).	('43121', 'Var', (204, 209))	('43113', 'Var', (176, 181))	('43124', 'Var', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('43117', 'Var', (190, 195))	('43112', 'Var', (169, 174))	('esophageal cancer', 'Disease', (239, 256))	('43122', 'Var', (211, 216))	('patients', 'Species', '9606', (35, 43))	('43116', 'Var', (183, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))	('43118', 'Var', (197, 202))
773999	25059343	In addition to using the matching algorithm, multivariable logistic regression analysis was applied to confirm the finding from the matched analysis by predicting the odds of 30-day mortality, overall, and serious morbidity, as well as PLOS for the neoadjuvant patients in comparison to surgery-only patients.	('patients', 'Species', '9606', (261, 269))	('PLOS', 'Disease', (236, 240))	('patients', 'Species', '9606', (300, 308))	('neoadjuvant', 'Var', (249, 260))
774009	25059343	Of note, the rate of venous thromboembolism was significantly higher in neoadjuvant patients when compared with the surgery-only patients (9.3% vs. 5.3%, P = 0.014) (Table 4).	('thromboembolism', 'Phenotype', 'HP:0001907', (28, 43))	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (129, 137))	('venous thromboembolism', 'Disease', (21, 43))	('higher', 'PosReg', (62, 68))	('neoadjuvant', 'Var', (72, 83))	('venous thromboembolism', 'Disease', 'MESH:D054556', (21, 43))
774019	25059343	Both chemotherapy and radiotherapy have been associated with increased risk of developing venous thrombosis.	('venous thrombosis', 'Disease', 'MESH:D020246', (90, 107))	('venous thrombosis', 'Phenotype', 'HP:0004936', (90, 107))	('radiotherapy', 'Var', (22, 34))	('venous thrombosis', 'Disease', (90, 107))	('chemotherapy', 'Var', (5, 17))
774055	18853987	First, iron supplementation before reflux-induced esophageal injury substantially increased the risk of esophageal metaplasia and esophageal adenocarcinoma in animal models.	('supplementation', 'Var', (12, 27))	('iron', 'Chemical', 'MESH:D007501', (7, 11))	('esophageal metaplasia and esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (104, 155))	('esophageal injury', 'Disease', (50, 67))	('esophageal injury', 'Disease', 'MESH:D004941', (50, 67))	('increased', 'PosReg', (82, 91))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (130, 155))
774057	18853987	Second, in vitro experiments indicate iron may induce genetic damage, and that cancer cell division is enhanced in the presence of iron.	('iron', 'Chemical', 'MESH:D007501', (38, 42))	('iron', 'Var', (38, 42))	('genetic damage', 'Disease', 'MESH:D030342', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('genetic damage', 'Disease', (54, 68))	('enhanced', 'PosReg', (103, 111))	('iron', 'Chemical', 'MESH:D007501', (131, 135))	('induce', 'Reg', (47, 53))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
774119	18853987	This is particularly true when risk factors for Barrett's esophagus (i.e., gastroesophageal reflux disease) may also cause esophagitis and low levels of blood loss; however, we also found that low dietary intake (which would not be clearly related to GERD) was also associated with an increased risk of Barrett's esophagus.	('esophagitis', 'Phenotype', 'HP:0100633', (123, 134))	('gastroesophageal reflux disease', 'Disease', (75, 106))	('esophagitis', 'Disease', 'MESH:D004941', (123, 134))	('blood loss', 'Disease', 'MESH:D006473', (153, 163))	('low dietary intake', 'Var', (193, 211))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (75, 98))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (75, 106))	('blood loss', 'Disease', (153, 163))	("Barrett's esophagus", 'Disease', (48, 67))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (48, 67))	('cause', 'Reg', (117, 122))	("Barrett's esophagus", 'Disease', (303, 322))	('esophagitis', 'Disease', (123, 134))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (303, 322))
774136	32607607	The transthoracic group required a longer hospital stay (median 14 vs. 11 days, p < 0.001), ICU stay (median 3 vs. 1 day, p < 0.001), and had a higher 30-day/in-hospital mortality rate (4.0% vs. 1.7%, p = 0.009).	('mortality', 'Disease', 'MESH:D003643', (170, 179))	('transthoracic', 'Var', (4, 17))	('mortality', 'Disease', (170, 179))
774137	32607607	In a propensity score-matched cohort, the transthoracic esophagectomy provided a more extensive lymph node dissection, which resulted in a higher lymph node yield, at the cost of increased morbidity and short-term mortality.	('mortality', 'Disease', (214, 223))	('transthoracic', 'Var', (42, 55))	('lymph node yield', 'CPA', (146, 162))	('higher', 'PosReg', (139, 145))	('mortality', 'Disease', 'MESH:D003643', (214, 223))
774140	32607607	Neoadjuvant chemoradiation (nCRT) following the CROSS regimen with subsequent resection has been the standard treatment for resectable (cT2-4aN0-3M0 and T0-1 N + M0) esophageal carcinoma in the Netherlands since 2010.	('carcinoma', 'Disease', 'MESH:D009369', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('T0-1 N + M0', 'Var', (153, 164))	('carcinoma', 'Disease', (177, 186))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (166, 186))	('cT2', 'Gene', (136, 139))	('cT2', 'Gene', '30848', (136, 139))
774141	32607607	It illustrated a trend towards improved survival for patients after a transthoracic resection, in conjunction with a significant 5-year overall survival benefit for the subgroup of patients with 1-8 positive nodes in the resection specimen.	('improved', 'PosReg', (31, 39))	('patients', 'Species', '9606', (53, 61))	('survival', 'MPA', (40, 48))	('patients', 'Species', '9606', (181, 189))	('transthoracic', 'Var', (70, 83))
774142	32607607	It did, however, describe a higher short-term mortality, longer hospital stay, higher lymph node yield, and lower anastomotic leakage rate in the transthoracic group.	('transthoracic', 'Var', (146, 159))	('anastomotic leakage', 'Disease', 'MESH:D057868', (114, 133))	('mortality', 'Disease', (46, 55))	('anastomotic leakage', 'Disease', (114, 133))	('lymph node yield', 'CPA', (86, 102))	('lower', 'NegReg', (108, 113))	('higher', 'PosReg', (79, 85))	('mortality', 'Disease', 'MESH:D003643', (46, 55))
774177	32607607	on post-neoadjuvant esophageal resection found that resecting up to 25 lymph nodes in ypN0 tumors or resecting up to 30 lymph nodes in ypN + tumors resulted in increased survival.	('ypN0', 'Var', (86, 90))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('survival', 'MPA', (170, 178))	('increased', 'PosReg', (160, 169))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
774178	32607607	Our analysis showed that patients treated by a transthoracic esophagectomy experienced more chyle leakages, pulmonary, and cardiac complications.	('transthoracic', 'Var', (47, 60))	('chyle', 'CPA', (92, 97))	('pulmonary', 'CPA', (108, 117))	('cardiac complications', 'CPA', (123, 144))	('patients', 'Species', '9606', (25, 33))
774179	32607607	The short-term mortality (in-hospital/30-day mortality) was significantly higher in the transthoracic group.	('mortality', 'Disease', (45, 54))	('transthoracic', 'Var', (88, 101))	('higher', 'PosReg', (74, 80))	('mortality', 'Disease', (15, 24))	('mortality', 'Disease', 'MESH:D003643', (45, 54))	('mortality', 'Disease', 'MESH:D003643', (15, 24))
774248	31114759	Considering all the histological specimens of all patients, the greatest distances of the subclinical lesions beyond the gross tumor were 0.79 +- 1.28 cm (cranial) and 0.87 +- 1.00 cm (caudal; Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('patients', 'Species', '9606', (50, 58))	('clinical', 'Species', '191496', (93, 101))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('0.87 +- 1.00', 'Var', (168, 180))
774371	28396760	The patient was diagnosed with G-CSF-producing ESCC T3N2M1, stage IV (according to the Union for International Cancer Control TNM classification of malignant tumors, 7th edition); therefore, radical resection was not recommended.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('malignant tumors', 'Disease', 'MESH:D018198', (148, 164))	('ESCC', 'Disease', (47, 51))	('patient', 'Species', '9606', (4, 11))	('G-CSF', 'Gene', '1440', (31, 36))	('T3N2M1', 'Var', (52, 58))	('G-CSF', 'Gene', (31, 36))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('malignant tumors', 'Disease', (148, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
774472	27399129	After adjustment for patient characteristics, esophageal cancer patients with high individual SES had a 39% lower risk of mortality than those with low individual SES (odds ratio 0.61, 95% confidence interval 0.48-0.77).	('patient', 'Species', '9606', (64, 71))	('high', 'Var', (78, 82))	('patients', 'Species', '9606', (64, 72))	('patient', 'Species', '9606', (21, 28))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('lower', 'NegReg', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
774514	27399129	After multilevel analysis with either hospital or neighborhood as a random effect (adjusting for age at diagnosis, sex, CCIS, urbanization, geographic region, nonsurgical therapy, and hospital characteristics), patients with low individual SES had the poorest survival.	('low', 'Var', (225, 228))	('patients', 'Species', '9606', (211, 219))	('poorest', 'NegReg', (252, 259))	('survival', 'MPA', (260, 268))
774526	27399129	The prognostic factors for longer survival in esophageal cancer include localized stage, family history, gene expression, sex, age, curative treatment, higher neighborhood SES, high individual SES, treatment in university hospital, and treatment by a high-volume surgeon.	('gene expression', 'Var', (105, 120))	('longer', 'PosReg', (27, 33))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
774531	27399129	In patients receiving palliative treatment, high SES was associated with lower mortality, but no effect was found for patients receiving curative treatment.	('high SES', 'Var', (44, 52))	('patients', 'Species', '9606', (3, 11))	('lower', 'NegReg', (73, 78))	('mortality', 'MPA', (79, 88))	('patients', 'Species', '9606', (118, 126))
774830	16283945	Genetic influence also plays a role, women with mutations in the BRCA1 or BRCA2 genes having an elevated risk.	('BRCA1', 'Gene', '672', (65, 70))	('women', 'Species', '9606', (37, 42))	('BRCA2', 'Gene', (74, 79))	('BRCA1', 'Gene', (65, 70))	('BRCA2', 'Gene', '675', (74, 79))	('mutations', 'Var', (48, 57))
774834	16283945	Epidemiological studies have shown that majority of the incidence can be attributed to excess body weight (in turn due to 'unopposed estrogens'), lack of physical activity, exogenous hormones and chronic hyperinsulinemia along with genetic predisposition.	('excess', 'PosReg', (87, 93))	('excess body weight', 'Phenotype', 'HP:0004324', (87, 105))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (204, 220))	('lack', 'Var', (146, 150))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (204, 220))	('hyperinsulinemia', 'Disease', (204, 220))
774848	31290765	Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett's Esophagus to Invasive Esophageal Adenocarcinoma The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett's Esophagus (BE) to esophageal adenocarcinoma.	('Sonic Hedgehog', 'Gene', (196, 210))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (282, 307))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (119, 133))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (254, 273))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (76, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	("Barrett's Esophagus", 'Disease', (254, 273))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (282, 307))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (108, 133))	('inhibition', 'Var', (182, 192))	('Itraconazole', 'Chemical', 'MESH:D017964', (37, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('esophageal adenocarcinoma', 'Disease', (282, 307))	('Adenocarcinoma', 'Disease', (119, 133))	('Sonic Hedgehog', 'Gene', '6469', (196, 210))
774854	31290765	EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033).	('EAC', 'MPA', (0, 3))	('itraconazole', 'Chemical', 'MESH:D017964', (31, 43))	('lower', 'NegReg', (22, 27))	('itraconazole', 'Var', (31, 43))
774855	31290765	Esophageal SHH levels were lower in itraconazole vs control (P = 0.12).	('itraconazole', 'Var', (36, 48))	('Esophageal SHH levels', 'MPA', (0, 21))	('itraconazole', 'Chemical', 'MESH:D017964', (36, 48))	('lower', 'NegReg', (27, 32))
774861	31290765	However, the recently published phase III ASPECT trial demonstrated that a high-dose PPI plus full dose aspirin significantly improves outcome compared with low-dose PPI alone.	('PPI', 'Var', (85, 88))	('outcome', 'MPA', (135, 142))	('aspirin', 'Chemical', 'MESH:D001241', (104, 111))	('improves', 'PosReg', (126, 134))	('rat', 'Species', '10116', (62, 65))
774868	31290765	In preclinical experiments using the intracranial drug-resistant mouse model of medulloblastoma, SMO (D477G), itraconazole exerted comparable effects to the Hh (Smoothened) inhibitor, vismodegib, but itraconazole overcame all reported resistance-conferring smoothened mutants and GLI2 overexpression.	('resistance-conferring', 'Reg', (235, 256))	('medulloblastoma', 'Disease', (80, 95))	('SMO', 'Gene', '319757', (97, 100))	('mouse', 'Species', '10090', (65, 70))	('SMO', 'Gene', (97, 100))	('smoothened', 'Gene', (257, 267))	('mutants', 'Var', (268, 275))	('GLI2', 'Gene', (280, 284))	('overcame', 'PosReg', (213, 221))	('itraconazole', 'Chemical', 'MESH:D017964', (110, 122))	('medulloblastoma', 'Disease', 'MESH:D008527', (80, 95))	('itraconazole', 'Chemical', 'MESH:D017964', (200, 212))	('medulloblastoma', 'Phenotype', 'HP:0002885', (80, 95))	('D477G', 'Mutation', 'rs755399491', (102, 107))	('GLI2', 'Gene', '14633', (280, 284))	('overexpression', 'PosReg', (285, 299))
774930	31290765	Mortality continued from anastomotic strictures, but other animals without strictures also succumbed to peritonitis from intraperitoneal injections.	('peritonitis', 'Phenotype', 'HP:0002586', (104, 115))	('Mortality', 'Disease', 'MESH:D003643', (0, 9))	('anastomotic', 'Var', (25, 36))	('peritonitis', 'Disease', 'MESH:D010534', (104, 115))	('peritonitis', 'Disease', (104, 115))	('Mortality', 'Disease', (0, 9))
774937	31290765	However, the itraconazole arm had significantly fewer rats progressing to EAC, that is, 2 of 24 (8.3%) (95% CI: 1.03, 27%) compared to 10 of 31 (32.3%) (95% CI: 16.68, 51.37%) in the control arm; one-sided Fisher exact test, P = 0.033 (Fig.	('itraconazole', 'Chemical', 'MESH:D017964', (13, 25))	('fewer', 'NegReg', (48, 53))	('EAC', 'Disease', (74, 77))	('rats', 'Species', '10116', (54, 58))	('itraconazole', 'Var', (13, 25))	('progressing', 'Reg', (59, 70))
774953	31290765	Chemopreventive strategies to prevent a debilitating esophagectomy are promising; with recent publication of the phase III ASPECT study showing long-term efficacy of the high-dose PPI esomeprazole and/or high-dose aspirin on progression to HGD or EAC in more than 2500 patients.	('rat', 'Species', '10116', (18, 21))	('PPI', 'Var', (180, 183))	('HGD', 'Disease', (240, 243))	('EAC', 'Disease', (247, 250))	('patients', 'Species', '9606', (269, 277))	('esomeprazole', 'Chemical', 'MESH:D064098', (184, 196))	('aspirin', 'Chemical', 'MESH:D001241', (214, 221))
774956	31290765	Furthermore high-dose PPI is associated with higher risk of side effects such as Clostridium difficile infection, decreased bone density and vitamin B12 deficiency, etc.	('PPI', 'Var', (22, 25))	('bone density', 'CPA', (124, 136))	('deficiency', 'NegReg', (153, 163))	('vitamin B12 deficiency', 'Phenotype', 'HP:0100502', (141, 163))	('vitamin B12', 'Chemical', 'MESH:D014805', (141, 152))	('infection', 'Disease', (103, 112))	('vitamin B12', 'MPA', (141, 152))	('Clostridium difficile infection', 'Phenotype', 'HP:0032167', (81, 112))	('infection', 'Disease', 'MESH:D007239', (103, 112))	('decreased', 'NegReg', (114, 123))	('Clostridium difficile', 'Species', '1496', (81, 102))	('high-dose PPI', 'Var', (12, 25))	('decreased bone density', 'Phenotype', 'HP:0004349', (114, 136))
774972	31290765	Additional limitations of our study include the relatively small sample size of the human and animal cohorts and the limitations on the number of procedural interventions that can be performed in the Levrat model, for example, intraperitoneal drug administration can increase toxicity compared with controls.	('rat', 'Species', '10116', (256, 259))	('intraperitoneal drug administration', 'Var', (227, 262))	('increase', 'PosReg', (267, 275))	('human', 'Species', '9606', (84, 89))	('toxicity', 'Disease', 'MESH:D064420', (276, 284))	('toxicity', 'Disease', (276, 284))	('rat', 'Species', '10116', (203, 206))
775008	32510875	reported that the overall survival (OS) rate of patients who underwent PBT was higher than that of patients who underwent intensity modulated radiation therapy.	('a', 'Gene', '351', (137, 138))	('a', 'Gene', '351', (143, 144))	('a', 'Gene', '351', (41, 42))	('a', 'Gene', '351', (11, 12))	('a', 'Gene', '351', (93, 94))	('a', 'Gene', '351', (49, 50))	('PBT', 'Var', (71, 74))	('a', 'Gene', '351', (100, 101))	('a', 'Gene', '351', (146, 147))	('a', 'Gene', '351', (76, 77))	('patients', 'Species', '9606', (99, 107))	('a', 'Gene', '351', (156, 157))	('a', 'Gene', '351', (32, 33))	('a', 'Gene', '351', (88, 89))	('higher', 'PosReg', (79, 85))	('patients', 'Species', '9606', (48, 56))	('a', 'Gene', '351', (22, 23))
775088	32510875	reported that PBT improved the OS rate among patients compared to X-ray therapy.	('PBT', 'Var', (14, 17))	('a', 'Gene', '351', (58, 59))	('a', 'Gene', '351', (11, 12))	('improved', 'PosReg', (18, 26))	('a', 'Gene', '351', (69, 70))	('a', 'Gene', '351', (35, 36))	('a', 'Gene', '351', (76, 77))	('a', 'Gene', '351', (39, 40))	('patients', 'Species', '9606', (45, 53))	('a', 'Gene', '351', (46, 47))
775111	32510875	27  As shown in Table 4, PBT also caused less severe cardiopulmonary toxicity in the present study.	('A', 'Gene', '351', (4, 5))	('a', 'Gene', '351', (17, 18))	('cardiopulmonary toxicity', 'Disease', (53, 77))	('a', 'Gene', '351', (35, 36))	('a', 'Gene', '351', (29, 30))	('a', 'Gene', '351', (65, 66))	('cardiopulmonary toxicity', 'Disease', 'MESH:D006323', (53, 77))	('PBT', 'Var', (25, 28))	('a', 'Gene', '351', (54, 55))
775129	32024998	Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers.	('frequent', 'Reg', (94, 102))	('head-and-neck', 'Disease', (202, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('colorectal cancers', 'Disease', 'MESH:D015179', (220, 238))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (143, 168))	('esophageal adenocarcinoma', 'Disease', (143, 168))	('colorectal cancers', 'Disease', (220, 238))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (143, 168))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('insertions', 'Var', (57, 67))
775130	32024998	Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications.	('integrations', 'Var', (12, 24))	('delete', 'NegReg', (29, 35))	('Aberrant', 'Var', (0, 8))	('tumor-suppressor', 'Gene', '7248', (116, 132))	('translocations', 'Var', (163, 177))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('megabase-scale regions of a', 'MPA', (36, 63))	('induce', 'Reg', (148, 154))	('removal', 'NegReg', (105, 112))	('tumor-suppressor', 'Gene', (116, 132))
775133	32024998	Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.	('tumor-suppressor', 'Gene', '7248', (64, 80))	('amplification', 'MPA', (102, 115))	('Aberrant', 'Var', (0, 8))	('lead to', 'Reg', (40, 47))	('deletion', 'MPA', (52, 60))	('tumor-suppressor', 'Gene', (64, 80))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
775137	32024998	These L1 source elements are usually transcriptionally repressed, but epigenetic changes that occur in tumors may promote their expression and allow them to retrotranspose.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('allow', 'Reg', (143, 148))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('epigenetic changes', 'Var', (70, 88))	('expression', 'MPA', (128, 138))	('promote', 'PosReg', (114, 121))
775140	32024998	Previous analyses indicate that although a fraction of somatically acquired L1 insertions in cancer may influence gene function, the majority of retrotransposon integrations in a single tumor represent passenger mutations with little or no effect on cancer development.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('insertions', 'Var', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (186, 191))	('gene function', 'MPA', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('influence', 'Reg', (104, 113))
775141	32024998	Nonetheless, L1 elements are capable of promoting other types of genomic structural alterations in the germline and somatically, in addition to canonical L1 insertion events; the effect of these alterations remains largely unexplored in the context of human cancer.	('elements', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (258, 264))	('promoting', 'PosReg', (40, 49))	('human', 'Species', '9606', (252, 257))
775144	32024998	Our analyses identify patterns and mutational mechanisms of structural variation in human cancers that are mediated by L1 retrotransposition.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('structural variation', 'Var', (60, 80))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
775145	32024998	We found that the aberrant integration of L1 retrotransposons has a relevant role in remodeling the architecture of the cancer genome in some human tumors, mainly by promoting megabase-scale deletions that, occasionally, generate genomic consequences that may promote cancer development through the removal of tumor-suppressor genes, such as CDKN2A, or trigger the amplification of oncogenes, such as CCND1.	('aberrant', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('tumor-suppressor', 'Gene', '7248', (310, 326))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CDKN2A', 'Gene', (342, 348))	('human', 'Species', '9606', (142, 147))	('trigger', 'Reg', (353, 360))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('amplification', 'MPA', (365, 378))	('promote', 'PosReg', (260, 267))	('tumor-suppressor', 'Gene', (310, 326))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('CDKN2A', 'Gene', '1029', (342, 348))	('tumors', 'Disease', (148, 154))	('CCND1', 'Gene', '595', (401, 406))	('cancer', 'Disease', (268, 274))	('deletions', 'Var', (191, 200))	('removal', 'NegReg', (299, 306))	('promoting', 'PosReg', (166, 175))	('CCND1', 'Gene', (401, 406))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('tumors', 'Disease', 'MESH:D009369', (148, 154))
775156	32024998	1c), making L1 insertions the most frequent type of structural variation in esophageal adenocarcinoma (Fig.	('esophageal adenocarcinoma', 'Disease', (76, 101))	('structural', 'Var', (52, 62))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('frequent', 'Reg', (35, 43))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (76, 101))
775157	32024998	Furthermore, retrotranspositions are the second-most frequent type of structural variants in head-and-neck squamous and colorectal adenocarcinomas (Fig.	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (120, 146))	('frequent', 'Reg', (53, 61))	('colorectal adenocarcinomas', 'Disease', (120, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('variants', 'Var', (81, 89))
775159	32024998	This analysis revealed an increased L1 retrotransposition rate in tumors with TP53 mutations (Mann-Whitney U-test, P < 0.05; Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (83, 92))	('L1 retrotransposition rate', 'MPA', (36, 62))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('increased', 'PosReg', (26, 35))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))
775162	32024998	We identified 43% (7,979 out of 18,636) somatic retrotranspositions of L1 inserted within gene regions including promoters, of which 66 events hit cancer-associated genes.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('hit', 'Reg', (143, 146))	('retrotranspositions', 'Var', (48, 67))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
775164	32024998	The structural analysis of RNA-sequencing data identified instances in which portions of a somatic retrotransposition within a gene exonize, a process that sometimes involves cancer-associated genes (Supplementary Fig.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('exonize', 'Var', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
775165	32024998	The genome-wide analysis of the distribution of somatic L1 insertions across the cancer genome revealed considerable variation in the rate of L1 retrotransposition (Fig.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('insertions', 'Var', (59, 69))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
775177	32024998	Occasionally, somatic L1 integrations that retain their full length may also act as a source for subsequent somatic retrotransposition events, and may reach high activity rates, leading them to dominate retrotransposition in a given tumor.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('activity rates', 'MPA', (162, 176))	('tumor', 'Disease', (233, 238))	('integrations', 'Var', (25, 37))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
775178	32024998	For example, in a remarkable head-and-neck tumor sample, SA197656, we identified one somatic L1 integration at 4p16.1 that then triggered 18 transductions from its new site, with the next most active element being a germline L1 locus at 22q12.1, which accounted for 15 transductions (Supplementary Table 5).	('integration', 'Var', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('neck tumor', 'Phenotype', 'HP:0012288', (38, 48))	('triggered', 'Reg', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('transductions', 'MPA', (141, 154))
775181	32024998	We developed specific algorithms to systematically identify L1-mediated deletions, and applied these methods across all PCAWG tumors.	('deletions', 'Var', (72, 81))	('L1-mediated', 'Gene', (60, 71))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
775182	32024998	For example, in a lung tumor sample, SA313800, we identified a deletion involving a 1-kb region of 19q12 with hallmarks of being generated by an L1 element (Fig.	('lung tumor', 'Disease', (18, 28))	('lung tumor', 'Phenotype', 'HP:0100526', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('deletion', 'Var', (63, 71))	('lung tumor', 'Disease', 'MESH:D008175', (18, 28))
775183	32024998	For example, in one esophageal tumor sample, SA528932, we found a deletion of 2.5 kb on chromosome 3 mediated by the orphan transduction of a sequence downstream of an L1 locus on chromosome 7 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('esophageal tumor', 'Disease', 'MESH:D004938', (20, 36))	('esophageal tumor', 'Disease', (20, 36))	('esophageal tumor', 'Phenotype', 'HP:0100751', (20, 36))	('deletion', 'Var', (66, 74))
775184	32024998	Owing to the unavailability of PCAWG DNA specimens, we performed a validation of 16 additional somatic L1-mediated deletions that were identified by TraFiC-mem in two head-and-neck cancer cell lines with high retrotransposition rates, NCI-H2009 and NCI-H2087.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('neck cancer', 'Phenotype', 'HP:0012288', (176, 187))	('cancer', 'Disease', (181, 187))	('deletions', 'Var', (115, 124))	('TraFiC-mem', 'Chemical', '-', (149, 159))
775186	32024998	Similarly, in a lung tumor sample, SA313800, we found an interstitial L1-mediated deletion that induced the loss of 51.1 Mb from chromosome X, which included the centromere (Fig.	('loss', 'NegReg', (108, 112))	('lung tumor', 'Disease', (16, 26))	('lung tumor', 'Disease', 'MESH:D008175', (16, 26))	('deletion', 'Var', (82, 90))	('lung tumor', 'Phenotype', 'HP:0100526', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
775187	32024998	L1-mediated deletions were, on occasion, driver events and caused the loss of tumor-suppressor genes.	('deletions', 'Var', (12, 21))	('tumor-suppressor', 'Gene', '7248', (78, 94))	('loss', 'NegReg', (70, 74))	('L1-mediated', 'Gene', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor-suppressor', 'Gene', (78, 94))
775188	32024998	In esophageal tumor sample SA528932, the integration of an L1 transduction from chromosome 7p12.3 to the short arm of chromosome 9 caused a 5.3-Mb clonal deletion that involved the 9p21.3-9p21.2 region.	('esophageal tumor', 'Disease', 'MESH:D004938', (3, 19))	('esophageal tumor', 'Disease', (3, 19))	('short arm', 'Phenotype', 'HP:0009824', (105, 114))	('esophageal tumor', 'Phenotype', 'HP:0100751', (3, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('integration', 'Var', (41, 52))
775193	32024998	A second somatic retrotransposition event bridged from chromosome 5p to an unknown part of the genome, completing a large interstitial copy-number loss on chromosome 5 that involves the centromere.	('copy-number loss', 'Var', (135, 151))	('art', 'Gene', '9048', (84, 87))	('art', 'Gene', (84, 87))
775195	32024998	We also found evidence that L1 integrations can cause duplications of large genomic regions in human cancer.	('human', 'Species', '9606', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cause', 'Reg', (48, 53))	('integrations', 'Var', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('duplications', 'MPA', (54, 66))
775197	32024998	Notably, this duplication increases the copy number of the cyclin C gene, CCNC, which is dysregulated in some tumors.	('cyclin C', 'Gene', '892', (59, 67))	('copy number', 'MPA', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('CCNC', 'Gene', '892', (74, 78))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('cyclin C', 'Gene', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('duplication', 'Var', (14, 25))	('CCNC', 'Gene', (74, 78))	('increases', 'PosReg', (26, 35))
775201	32024998	In esophageal tumor sample SA528848, we identified a cluster of reads on the long arm of chromosome 11 that had the typical hallmarks of an L1-mediated rearrangement (Fig.	('reads', 'Var', (64, 69))	('esophageal tumor', 'Disease', 'MESH:D004938', (3, 19))	('esophageal tumor', 'Disease', (3, 19))	('esophageal tumor', 'Phenotype', 'HP:0100751', (3, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
775205	32024998	8b) followed by two cycles of breakage-fusion-bridge repair could generate similar copy-number patterns with telomere loss and amplification of CCND1.	('CCND1', 'Gene', '595', (144, 149))	('telomere', 'MPA', (109, 117))	('loss', 'NegReg', (118, 122))	('CCND1', 'Gene', (144, 149))	('amplification', 'Var', (127, 140))
775209	32024998	The independent occurrence of these patterns, which involve the amplification of CCND1, in two different tumor samples (SA528848 and SA503541) demonstrates a mutational mechanism mediated by L1 retrotransposition, which likely contributes to the development of human cancer.	('amplification', 'MPA', (64, 77))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('SA503541', 'Chemical', '-', (133, 141))	('contributes', 'Reg', (227, 238))	('human', 'Species', '9606', (261, 266))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('CCND1', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('CCND1', 'Gene', '595', (81, 86))	('tumor', 'Disease', (105, 110))	('SA503541', 'Var', (133, 141))
775212	32024998	Our findings demonstrate that major restructuring of cancer genomes can sometimes emerge from aberrant L1 retrotransposition events in tumors with high retrotransposition rates, particularly in esophageal, lung and head-and-neck cancers.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('tumors', 'Disease', (135, 141))	('lung', 'Disease', (206, 210))	('neck cancer', 'Phenotype', 'HP:0012288', (224, 235))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('esophageal', 'Disease', (194, 204))	('art', 'Gene', (179, 182))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', (229, 235))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('art', 'Gene', '9048', (179, 182))	('head-and-neck cancers', 'Disease', 'MESH:D006258', (215, 236))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('aberrant', 'Var', (94, 102))	('head-and-neck cancers', 'Disease', (215, 236))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
775214	32024998	However, occasionally, L1-mediated deletions may promote cancer-driving rearrangements that involve the loss of tumor-suppressor genes and/or the amplification of oncogenes, representing another mechanism by which cancer clones acquire new mutations that help them to survive and grow.	('L1-mediated', 'Gene', (23, 34))	('loss', 'NegReg', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', (57, 63))	('tumor-suppressor', 'Gene', '7248', (112, 128))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumor-suppressor', 'Gene', (112, 128))	('deletions', 'Var', (35, 44))	('promote', 'PosReg', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
775215	32024998	We expect that structural variants induced by somatic retrotransposition in human cancer are more frequent than we could unambiguously characterize here, given the constraints on the fragment sizes of paired-end sequencing libraries.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('human', 'Species', '9606', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('structural variants', 'Var', (15, 34))
775245	32024998	For each tumor-suppressor gene in the Cancer Gene Census database with mutational data, we stratified the samples into two groups:mutated tumor-suppressor genes and non-mutated tumor-suppressor genes.	('tumor-suppressor', 'Gene', (138, 154))	('tumor-suppressor', 'Gene', '7248', (177, 193))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor-suppressor', 'Gene', (9, 25))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor-suppressor', 'Gene', (177, 193))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutated', 'Var', (130, 137))	('tumor-suppressor', 'Gene', '7248', (138, 154))	('tumor-suppressor', 'Gene', '7248', (9, 25))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
775247	32024998	We further investigated whether there was a TP53 dosage effect as follows: every PCAWG sample was classified into three groups according to TP53 mutational status, namely wild-type, monoallelic and biallelic driver mutation.	('TP53', 'Gene', (140, 144))	('biallelic driver mutation', 'Var', (198, 223))	('monoallelic', 'Var', (182, 193))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('TP53', 'Gene', '7157', (140, 144))
775248	32024998	The same analysis described above was applied to investigate the association between TP53 mutation and other types of structural variation.	('TP53', 'Gene', '7157', (85, 89))	('TP53', 'Gene', (85, 89))	('mutation', 'Var', (90, 98))
775249	32024998	Then, the correlation between the number of MEIs and the structural variant burden was assessed at both the level of the individual tumor type and the level of the pan-cancer using a Spearman's rank test.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('structural', 'Var', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Disease', (132, 137))	('cancer', 'Disease', (168, 174))
775254	32024998	To study the transcriptional impact of a somatic L1 insertion within COSMIC cancer genes and promoters, we used RNA-seq data to compare gene-expression levels in samples with and without somatic L1 insertion.	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('insertion', 'Var', (52, 61))
775255	32024998	For each somatic L1 insertion within a cancer gene or promoter, we compared the gene FPKM between the sample having the insertion (study sample) and the remaining samples of the same tumor type (control samples).	('insertion', 'Var', (120, 129))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('insertion', 'Var', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', (183, 188))
775270	32024998	MEIs supported by at least one Nanopore read in the tumor and absent in the matched normal sample were considered true-positive somatic events, while MEIs not supported by long reads in the tumor and/or present in the matched normal were considered false-positive calls.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('Nanopore', 'Var', (31, 39))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
775271	32024998	We performed validation of 20 somatic L1-mediated rearrangements, mostly deletions, identified in two cancer cell lines with high retrotransposition rates (NCI-H2009 and NCI-H2087).	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('deletions', 'Var', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))
775274	32024998	Somatic and germline variant calls, mutational signatures, subclonal reconstructions, transcript abundance, splice calls and other core data generated by the ICGC/TCGA PCAWG Consortium are available for download at https://dcc.icgc.org/releases/PCAWG.	('dcc', 'Gene', '1630', (223, 226))	('variant', 'Var', (21, 28))	('dcc', 'Gene', (223, 226))
775280	31274650	The National Cancer Database was queried for patients with clinical T1-3N0M0 cancer undergoing upfront esophagectomy from 2004 to 2014.	('Cancer', 'Disease', (13, 19))	('T1-3N0M0', 'Var', (68, 76))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
775308	31274650	Patients with pathologic lymph node involvement had higher rates of more advanced clinical tumor stage, larger tumor size, higher tumor grade, and presence of lymphovascular invasion (all P < 0.001).	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (111, 116))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('men', 'Species', '9606', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('pathologic', 'Var', (14, 24))	('tumor', 'Disease', (91, 96))
775334	31274650	For all esophageal cancers, but particularly for patients with clinical T2N0 cancers, there is a demonstrated lack of reliability in EUS and positron emission tomography-computed tomography staging.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('T2N0', 'Var', (72, 76))	('cancers', 'Disease', (77, 84))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('esophageal cancer', 'Disease', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (49, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (8, 25))
775338	31274650	In a previously published decision analysis examining the role of induction therapy for T2N0 esophageal cancer, we demonstrated that a survival benefit could be expected with induction chemoradiation if there was a 48% probability of upstaging.	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('T2N0', 'Var', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
775342	31274650	Our second clinical example illustrates how the nomogram could be helpful for risk stratifying these early stage patients to decide on treatment or surveillance strategies: the T1N0 patient has a 35% of occult nodal disease after discovery of high-risk pathologic features on endoscopic mucosal resection.	('men', 'Species', '9606', (140, 143))	('patient', 'Species', '9606', (113, 120))	('T1N0', 'Var', (177, 181))	('occult nodal disease', 'Disease', (203, 223))	('patients', 'Species', '9606', (113, 121))	('patient', 'Species', '9606', (182, 189))	('occult nodal disease', 'Disease', 'None', (203, 223))
775346	31274650	This avoids treatment effect on pathologic lymph node assessment, but it is possible that treatment selection bias is present within our sample:the clinical features of patients with T2N0 or T3N0 disease that do not receive induction therapy may be different than the whole population of patients with this stage disease.	('patients', 'Species', '9606', (169, 177))	('T2N0', 'Var', (183, 187))	('patients', 'Species', '9606', (288, 296))	('T3N0 disease', 'Var', (191, 203))	('men', 'Species', '9606', (95, 98))	('men', 'Species', '9606', (60, 63))	('men', 'Species', '9606', (17, 20))
775493	30267473	Moreover, FGFR4 blockade could significantly inhibit the growth of xenograft tumors in vivo.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('blockade', 'Var', (16, 24))	('FGFR4', 'Gene', (10, 15))	('xenograft tumors', 'Disease', 'MESH:D009369', (67, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('inhibit', 'NegReg', (45, 52))	('xenograft tumors', 'Disease', (67, 83))
775522	30267473	For both migration and invasion assays, the cells treated each day with 1 muM H3B-6527 or pure culture media for three days were precultured in FBS-free medium for 12 hours.	('invasion assays', 'CPA', (23, 38))	('H3B', 'Chemical', '-', (78, 81))	('H3B-6527', 'Var', (78, 86))	('migration', 'CPA', (9, 18))
775530	30267473	Furthermore, compared to normal esophageal epithelial cells (FGFR4/beta-actin: 0.652 +- 0.12 in HET-1A), different degrees of FGFR4 overexpression in ESCC cell lines were detected (FGFR4/beta-actin: 1.238 +- 0.11, P < 0.01 in TE-1; 1.404 +- 0.05, P < 0.01 in Eca9706; 2.259 +- 0.14, P < 0.001 in KYSE150; 1.805 +- 0.05, P < 0.001 in Eca109; and 1.918 +- 0.06, P < 0.001 in KYSE450) (Fig 1d,e).	('beta-actin', 'Gene', '728378', (67, 77))	('beta-actin', 'Gene', '728378', (187, 197))	('HET-1A', 'CellLine', 'CVCL:3702', (96, 102))	('beta-actin', 'Gene', (67, 77))	('beta-actin', 'Gene', (187, 197))	('overexpression', 'PosReg', (132, 146))	('Eca9706', 'CellLine', 'CVCL:E307', (259, 266))	('1.918', 'Var', (345, 350))
775531	30267473	The colony formation assays showed that clonogenic survival was suppressed in KYSE150 and KYSE450 cells treated with H3B-6527 compared to cells treated with pure culture media (Fig 2a).	('colony formation assays', 'CPA', (4, 27))	('suppressed', 'NegReg', (64, 74))	('H3B-6527', 'Var', (117, 125))	('clonogenic survival', 'CPA', (40, 59))	('H3B', 'Chemical', '-', (117, 120))
775532	30267473	The optical density values (450 nm) of the KYSE150 cells treated with H3B-6527 decreased by 0.141 (0.845 +- 0.06 vs. 0.704 +- 0.03; P < 0.05), 0.374 (1.156 +- 0.10 vs. 0.782 +- 0.08; P < 0.01), and 1.174 (2.150 +- 0.24 vs. 0.976 +- 0.14; P < 0.01) at 24, 48, and 72 hours, respectively, compared to the cells left untreated (Fig 2c).	('decreased', 'NegReg', (79, 88))	('H3B-6527', 'Var', (70, 78))	('H3B', 'Chemical', '-', (70, 73))	('optical density values', 'MPA', (4, 26))
775533	30267473	In KYSE450 cells treated with H3B-6527, the optical density values (450 nm) decreased by 0.355 (1.115 +- 0.11 vs. 0.760 +- 0.14; P < 0.05) and 0.538 (1.711 +- 0.15 vs. 1.173 +- 0.18; P < 0.05) at 48 and 72 hours, respectively (Fig 2c).	('H3B', 'Chemical', '-', (30, 33))	('H3B-6527', 'Var', (30, 38))	('decreased', 'NegReg', (76, 85))
775535	30267473	With respect to wound-healing assay, closure of the wounds was slower in ESCC cells treated with H3B-6527 (Fig 3a).	('H3B-6527', 'Var', (97, 105))	('H3B', 'Chemical', '-', (97, 100))	('slower', 'NegReg', (63, 69))	('closure of the wounds', 'CPA', (37, 58))
775536	30267473	The migration rates of the KYSE150 cells treated with H3B-6527 decreased by 17.0% (P < 0.01) and 31.3% (P < 0.001) after 12 and 24 hours, respectively, compared to cells left untreated.	('migration rates', 'CPA', (4, 19))	('H3B-6527', 'Var', (54, 62))	('decreased', 'NegReg', (63, 72))	('H3B', 'Chemical', '-', (54, 57))
775537	30267473	In KYSE450 cells treated with H3B-6527, the migration rates decreased by 26.7% (P < 0.01) and 30.6% (P < 0.01) at 48 and 72 hours, respectively (Fig 3b).	('H3B', 'Chemical', '-', (30, 33))	('H3B-6527', 'Var', (30, 38))	('decreased', 'NegReg', (60, 69))	('migration rates', 'CPA', (44, 59))
775539	30267473	The number of migration cells in visual fields decreased by 95 (187 +- 26 vs. 92 +- 10; P < 0.01) in KYSE150 and 129 (276 +- 24 vs. 147 +- 41; P < 0.05) in KYSE450 cells when treated with H3B-6527 (Fig 3d).	('H3B-6527', 'Var', (188, 196))	('H3B', 'Chemical', '-', (188, 191))	('decreased', 'NegReg', (47, 56))
775540	30267473	These results indicated that blocking FGFR4 by H3B-6527 could suppress the migration and invasion of ESCC cells.	('suppress', 'NegReg', (62, 70))	('H3B-6527', 'Var', (47, 55))	('blocking', 'NegReg', (29, 37))	('H3B', 'Chemical', '-', (47, 50))	('FGFR4', 'Gene', (38, 43))
775541	30267473	The results of Western blotting showed that FGFR4 blocking caused a significant increase of epithelial marker E-cadherin (E-cadherin/GAPDH: 0.143 +- 0.06 vs. 0.418 +- 0.03, P < 0.01 in KYSE150; 0.370 +- 0.07 vs. 0.634 +- 0.08, P < 0.05 in KYSE450) and Claudin-1 levels (Claudin-1/GAPDH: 0.359 +- 0.05 vs. 0.679 +- 0.08, P < 0.01 in KYSE150; 0.557 +- 0.05 vs. 0.799 +- 0.02, P < 0.01 in KYSE450) and a decrease of mesenchymal marker N-cadherin (N-cadherin/GAPDH: 1.048 +- 0.06 vs. 0.590 +- 0.03, P < 0.001 in KYSE150; 0.874 +- 0.06 vs. 0.658 +- 0.05, P < 0.01 in KYSE450), Vimentin (Vimentin/GAPDH: 0.957 +- 0.10 vs. 0.696 +- 0.05, P < 0.05 in KYSE150; 1.051 +- 0.08 vs. 0.746 +- 0.07, P < 0.01 in KYSE450), and Snail levels (Snail/GAPDH: 0.986 +- 0.05 vs. 0.640 +- 0.06, P < 0.01 in KYSE150; 1.010 +- 0.11 vs. 0.767 +- 0.08, P < 0.05 in KYSE450) in ESCC cells (Fig 3g,h).	('increase', 'PosReg', (80, 88))	('Vimentin', 'Gene', '7431', (572, 580))	('GAPDH', 'Gene', (591, 596))	('GAPDH', 'Gene', (455, 460))	('Vimentin', 'Gene', (582, 590))	('GAPDH', 'Gene', '2597', (731, 736))	('Claudin-1', 'Gene', (252, 261))	('Snail', 'Gene', (711, 716))	('Vimentin', 'Gene', (572, 580))	('GAPDH', 'Gene', '2597', (280, 285))	('FGFR4', 'Var', (44, 49))	('decrease', 'NegReg', (401, 409))	('E-cadherin', 'Gene', (122, 132))	('N-cadherin', 'Gene', (432, 442))	('E-cadherin', 'Gene', '999', (122, 132))	('N-cadherin', 'Gene', '1000', (432, 442))	('GAPDH', 'Gene', '2597', (133, 138))	('Snail', 'Gene', (725, 730))	('GAPDH', 'Gene', (280, 285))	('GAPDH', 'Gene', (731, 736))	('Claudin-1', 'Gene', '9076', (270, 279))	('Snail', 'Gene', '6615', (711, 716))	('GAPDH', 'Gene', (133, 138))	('N-cadherin', 'Gene', (444, 454))	('N-cadherin', 'Gene', '1000', (444, 454))	('GAPDH', 'Gene', '2597', (591, 596))	('GAPDH', 'Gene', '2597', (455, 460))	('Claudin-1', 'Gene', '9076', (252, 261))	('Snail', 'Gene', '6615', (725, 730))	('Claudin-1', 'Gene', (270, 279))	('Vimentin', 'Gene', '7431', (582, 590))	('E-cadherin', 'Gene', (110, 120))	('E-cadherin', 'Gene', '999', (110, 120))
775544	30267473	We found that blocking FGFR4 not only significantly suppressed the levels of anti-apoptotic protein Bcl-2 (Bcl-2/beta-actin: 0.913 +- 0.12 vs. 0.382 +- 0.08, P < 0.01 in KYSE150; 1.248 +- 0.11 vs. 0.648 +- 0.09, P < 0.01 in KYSE450), but also increased the levels of pro-apoptotic protein Bax (Bax/beta-actin: 0.473 +- 0.07 vs. 0.886 +- 0.09, P < 0.01 in KYSE150; 0.744 +- 0.06 vs. 0.931 +- 0.04, P < 0.05 in KYSE450) (Fig 4c,d).	('Bcl-2', 'Gene', (107, 112))	('Bcl-2', 'Gene', '596', (107, 112))	('Bcl-2', 'Gene', (100, 105))	('Bcl-2', 'Gene', '596', (100, 105))	('Bax', 'Gene', '581', (289, 292))	('beta-actin', 'Gene', '728378', (113, 123))	('levels', 'MPA', (67, 73))	('beta-actin', 'Gene', '728378', (298, 308))	('beta-actin', 'Gene', (113, 123))	('Bax', 'Gene', (294, 297))	('beta-actin', 'Gene', (298, 308))	('blocking', 'Var', (14, 22))	('suppressed', 'NegReg', (52, 62))	('FGFR4', 'Gene', (23, 28))	('increased', 'PosReg', (243, 252))	('Bax', 'Gene', '581', (294, 297))	('Bax', 'Gene', (289, 292))
775546	30267473	Western blot analysis revealed that H3B-6527 could significantly inhibit the phosphorylation of FGFR4 in ESCC cells compared to the control group (p-FGFR4/FGFR4: 0.624 +- 0.05 vs. 0.365 +- 0.08, P < 0.01 in KYSE150; 0.539 +- 0.05 vs. 0.342 +- 0.03, P < 0.01 in KYSE450) (Fig 5).	('phosphorylation', 'MPA', (77, 92))	('H3B', 'Chemical', '-', (36, 39))	('FGFR4', 'Gene', (96, 101))	('inhibit', 'NegReg', (65, 72))	('H3B-6527', 'Var', (36, 44))
775548	30267473	Additionally, in accordance with the inhibition of tumorigenic effects, blocking FGFR4 could significantly decrease the levels of p-AKT (p-AKT/tAKT: 1.043 +- 0.07 vs. 0.608 +- 0.07, P < 0.01 in KYSE150; 1.362 +- 0.09 vs. 0.975 +- 0.05, P < 0.01 in KYSE450) and p-ERK (p-ERK/tERK: 0.981 +- 0.12 vs. 0.531 +- 0.06, P < 0.01 in KYSE150; 1.050 +- 0.07 vs. 0.753 +- 0.09, P < 0.05 in KYSE450) in ESCC cells (Fig 5).	('AKT', 'Gene', (144, 147))	('AKT', 'Gene', '207', (139, 142))	('blocking', 'Var', (72, 80))	('ERK', 'Gene', '2048', (275, 278))	('tumor', 'Disease', (51, 56))	('AKT', 'Gene', (132, 135))	('decrease', 'NegReg', (107, 115))	('AKT', 'Gene', '207', (144, 147))	('FGFR4', 'Gene', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('p-ERK', 'Gene', '9451', (268, 273))	('p-ERK', 'Gene', '9451', (261, 266))	('p-ERK', 'Gene', (268, 273))	('ERK', 'Gene', (270, 273))	('p-ERK', 'Gene', (261, 266))	('ERK', 'Gene', (263, 266))	('AKT', 'Gene', (139, 142))	('AKT', 'Gene', '207', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ERK', 'Gene', '2048', (270, 273))	('ERK', 'Gene', '2048', (263, 266))	('ERK', 'Gene', (275, 278))
775549	30267473	Collectively, our data revealed that blocking FGFR4 by H3B-6527 may affect AKT and ERK signaling in ESCC cells.	('ERK', 'Gene', (83, 86))	('AKT', 'Gene', '207', (75, 78))	('FGFR4', 'Gene', (46, 51))	('H3B-6527', 'Var', (55, 63))	('ESCC', 'Disease', (100, 104))	('AKT', 'Gene', (75, 78))	('blocking', 'NegReg', (37, 45))	('affect', 'Reg', (68, 74))	('H3B', 'Chemical', '-', (55, 58))	('ERK', 'Gene', '2048', (83, 86))
775551	30267473	Compared to the control group, the average volumes of tumors in mice treated by H3B-6527 were decreased (Fig 6a).	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('H3B', 'Chemical', '-', (80, 83))	('decreased', 'NegReg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('mice', 'Species', '10090', (64, 68))	('H3B-6527', 'Var', (80, 88))
775553	30267473	The weight of the tumors in the mice treated with H3B-6527 was also significantly attenuated (7.00 +- 0.80 vs. 2.29 +- 0.37 g, P < 0.001 in KYSE150; 6.37 +- 0.50 vs. 2.30 +- 0.37 g, P < 0.001 in KYSE450) (Fig 6c).	('attenuated', 'NegReg', (82, 92))	('H3B', 'Chemical', '-', (50, 53))	('tumors', 'Disease', (18, 24))	('mice', 'Species', '10090', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('H3B-6527', 'Var', (50, 58))
775555	30267473	The results illustrate that H3B-6527 could inhibit tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('inhibit', 'NegReg', (43, 50))	('H3B-6527', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('H3B', 'Chemical', '-', (28, 31))
775561	30267473	EMT is an important process in cancer metastasis, with 90% of tumors exhibiting different degrees of EMT during tumor development.33, 34, 35 During this process, the epithelial cells attenuate the expression of epithelial characteristics and gain mesenchymal phenotype properties.36, 37 In this study, we surprisingly found that blocking FGFR4 suppressed EMT in ESCC cells, including the upregulation of epithelial markers (E-cadherin and Claudin-1) and the downregulation of mesenchymal markers (N-cadherin, Vimentin, and Snail).	('N-cadherin', 'Gene', '1000', (497, 507))	('FGFR4', 'Gene', (338, 343))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('Claudin-1', 'Gene', '9076', (439, 448))	('cancer metastasis', 'Disease', 'MESH:D009362', (31, 48))	('downregulation', 'NegReg', (458, 472))	('E-cadherin', 'Gene', (424, 434))	('E-cadherin', 'Gene', '999', (424, 434))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('EMT', 'CPA', (355, 358))	('tumors', 'Disease', (62, 68))	('epithelial', 'CPA', (404, 414))	('tumor', 'Disease', (112, 117))	('upregulation', 'PosReg', (388, 400))	('Claudin-1', 'Gene', (439, 448))	('Snail', 'Gene', '6615', (523, 528))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('blocking', 'Var', (329, 337))	('Vimentin', 'Gene', '7431', (509, 517))	('tumor', 'Disease', (62, 67))	('cancer metastasis', 'Disease', (31, 48))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Snail', 'Gene', (523, 528))	('suppressed', 'NegReg', (344, 354))	('N-cadherin', 'Gene', (497, 507))	('Vimentin', 'Gene', (509, 517))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
775562	30267473	This result is consistent with findings in colorectal cancer38 and nasopharyngeal carcinoma.39 Moreover, flow cytometric apoptosis assay showed that FGFR4 blockade could promote apoptosis of ESCC cells, which was consistent with the Western blot results of apoptotic-related factors.	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('FGFR4', 'Gene', (149, 154))	('apoptosis', 'CPA', (178, 187))	('blockade', 'Var', (155, 163))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('colorectal cancer38 and nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (43, 91))	('promote', 'PosReg', (170, 177))
775564	30267473	They play an important role in regulating cell survival, cell cycle, angiogenesis, metastasis, and metabolism.40, 41, 42 Several studies have demonstrated that the PI3K/Akt and MAPK/ERK signaling pathways are activated in the progression of ESCC.43, 44 Additionally, FGFR4 overexpression can promote cell malignant growth, migration, invasion, and suppress apoptosis via the PI3K/Akt and MAPK/ERK pathways in colorectal cancer,38 rhabdomyosarcoma45 and ovarian cancer.31 In this study, we found that blocking FGFR4 could significantly inhibit its phosphorylation and further reduce the levels of phosphorylated AKT and ERK.	('AKT', 'Gene', (611, 614))	('ERK', 'Gene', (393, 396))	('Akt', 'Gene', '207', (380, 383))	('ERK', 'Gene', '2048', (619, 622))	('ERK', 'Gene', '2048', (393, 396))	('colorectal cancer', 'Phenotype', 'HP:0003003', (409, 426))	('cancer', 'Phenotype', 'HP:0002664', (461, 467))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('phosphorylation', 'MPA', (547, 562))	('AKT', 'Gene', '207', (611, 614))	('rhabdomyosarcoma45 and ovarian cancer', 'Disease', 'MESH:D010051', (430, 467))	('reduce', 'NegReg', (575, 581))	('FGFR4', 'Gene', (509, 514))	('Akt', 'Gene', (169, 172))	('levels of phosphorylated', 'MPA', (586, 610))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (430, 446))	('inhibit', 'NegReg', (535, 542))	('ERK', 'Gene', (182, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (409, 426))	('Akt', 'Gene', '207', (169, 172))	('ovarian cancer', 'Phenotype', 'HP:0100615', (453, 467))	('colorectal cancer', 'Disease', (409, 426))	('ERK', 'Gene', (619, 622))	('Akt', 'Gene', (380, 383))	('ERK', 'Gene', '2048', (182, 185))	('blocking', 'Var', (500, 508))
775565	30267473	Therefore, we infer that FGFR4 blockade may affect cell growth, migration, invasion, and apoptosis via PI3K/Akt and MAPK/ERK signaling pathways.	('ERK', 'Gene', (121, 124))	('cell growth', 'CPA', (51, 62))	('ERK', 'Gene', '2048', (121, 124))	('FGFR4', 'Gene', (25, 30))	('Akt', 'Gene', (108, 111))	('invasion', 'CPA', (75, 83))	('apoptosis', 'CPA', (89, 98))	('blockade', 'Var', (31, 39))	('Akt', 'Gene', '207', (108, 111))	('affect', 'Reg', (44, 50))	('migration', 'CPA', (64, 73))
775566	30267473	Furthermore, ESCC tumors in nude mice responded to H3B-6527 treatment with an apparent slowing of growth.	('ESCC tumors', 'Disease', (13, 24))	('growth', 'MPA', (98, 104))	('slowing', 'NegReg', (87, 94))	('ESCC tumors', 'Disease', 'MESH:D004938', (13, 24))	('slowing of growth', 'Phenotype', 'HP:0001510', (87, 104))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('H3B-6527', 'Var', (51, 59))	('nude mice', 'Species', '10090', (28, 37))	('H3B', 'Chemical', '-', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
775571	30267473	The effectiveness of H3B-6527 in ESCC tumor xenografts may be linked to the blocking of FGFR4 in human ESCC cancers.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('ESCC cancers', 'Disease', (103, 115))	('ESCC', 'Disease', (33, 37))	('ESCC cancers', 'Disease', 'MESH:D004938', (103, 115))	('blocking', 'NegReg', (76, 84))	('human', 'Species', '9606', (97, 102))	('H3B-6527', 'Var', (21, 29))	('FGFR4', 'Gene', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('H3B', 'Chemical', '-', (21, 24))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))
775573	30267473	Although studies have shown that blocking FGFR4 by H3B-6527 could attenuate the biological characteristics of ESCC cells in vivo and in vitro, we only used one blocking method in this study.	('FGFR4', 'Gene', (42, 47))	('biological characteristics of ESCC cells in vivo', 'CPA', (80, 128))	('attenuate', 'NegReg', (66, 75))	('H3B-6527', 'Var', (51, 59))	('blocking', 'NegReg', (33, 41))	('H3B', 'Chemical', '-', (51, 54))
775575	30267473	Based on our results, we conclude that blocking FGFR4, which impacts AKT and ERK signaling, can inhibit the cellular proliferation, migration, invasion, and survival of ESCC cells.	('cellular proliferation', 'CPA', (108, 130))	('FGFR4', 'Gene', (48, 53))	('ESCC', 'Disease', (169, 173))	('survival', 'CPA', (157, 165))	('AKT', 'Gene', (69, 72))	('impacts', 'Reg', (61, 68))	('invasion', 'CPA', (143, 151))	('ERK', 'Gene', '2048', (77, 80))	('migration', 'CPA', (132, 141))	('ERK', 'Gene', (77, 80))	('AKT', 'Gene', '207', (69, 72))	('inhibit', 'NegReg', (96, 103))	('blocking', 'Var', (39, 47))
775576	30267473	In addition, blocking FGFR4 by H3B-6527 can lead to tumor regression in esophageal xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('H3B-6527', 'Var', (31, 39))	('esophageal', 'Disease', (72, 82))	('FGFR4', 'Gene', (22, 27))	('blocking', 'NegReg', (13, 21))	('H3B', 'Chemical', '-', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
775578	30294322	Genetic Alterations of TRAF Proteins in Human Cancers The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors.	('Cancers', 'Disease', 'MESH:D009369', (46, 53))	('Cancers', 'Phenotype', 'HP:0002664', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Human', 'Species', '9606', (40, 45))	('TNF', 'Gene', (90, 93))	('TNF', 'Gene', (244, 247))	('tumor necrosis', 'Disease', (58, 72))	('TNF', 'Gene', '7124', (244, 247))	('regulate', 'Reg', (161, 169))	('TNF', 'Gene', '7124', (90, 93))	('Alterations', 'Var', (8, 19))	('tumor necrosis', 'Disease', 'MESH:D009336', (58, 72))	('signal transduction', 'MPA', (174, 193))	('Cancers', 'Disease', (46, 53))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
775581	30294322	Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('loss-of-function', 'NegReg', (41, 57))	('gain-', 'PosReg', (31, 36))	('TRAF', 'Gene', (91, 95))	('human', 'Species', '9606', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('genetic alterations', 'Var', (58, 77))
775583	30294322	Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('genetic alterations', 'Var', (102, 121))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('TRAF proteins', 'Gene', (125, 138))
775587	30294322	With the rapid progress made in next-generation deep sequencing technology and the tremendous efforts put forth on whole genome/exome/transcriptome sequencing and copy number variation (CNV) analyses of cancers at the post-genome era, it has become increasingly clear that genetic alterations of TRAF proteins are commonly present in various human cancers.	('TRAF', 'Gene', (296, 300))	('cancers', 'Disease', 'MESH:D009369', (348, 355))	('cancers', 'Phenotype', 'HP:0002664', (348, 355))	('cancers', 'Disease', (348, 355))	('present', 'Reg', (323, 330))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('genetic alterations', 'Var', (273, 292))	('human', 'Species', '9606', (342, 347))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
775589	30294322	Moreover, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('TRAF proteins', 'Gene', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('genetic alterations', 'Var', (99, 118))
775591	30294322	According to the TCGA and COSMIC datasets of sample size n > 100, the frequency of genetic alterations of TRAF1 is generally <4% in human cancers (Figure 1A).	('genetic alterations', 'Var', (83, 102))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('TRAF1', 'Gene', (106, 111))	('human', 'Species', '9606', (132, 137))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
775592	30294322	The eight human cancers with relatively higher genetic alterations of TRAF1 are pancreatic cancer (3.7%), skin cutaneous melanoma (2.9%) (TCGA, PanCancer Atlas), esophageal cancer (2.8%) (TCGA, PanCancer Atlas), stomach cancer (2.7%), sarcoma (2.4%), ovarian cancer (2.3%) (TCGA, Provisional), lung cancer (2.3%), and prostate cancer (2%) (TCGA, Provisional).	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (106, 129))	('lung cancer', 'Disease', (294, 305))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (111, 129))	('stomach cancer', 'Disease', (212, 226))	('skin cutaneous melanoma', 'Disease', (106, 129))	('pancreatic cancer', 'Disease', (80, 97))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('ovarian cancer', 'Disease', (251, 265))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('ovarian cancer', 'Phenotype', 'HP:0100615', (251, 265))	('esophageal cancer', 'Disease', (162, 179))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('sarcoma', 'Disease', (235, 242))	('lung cancer', 'Disease', 'MESH:D008175', (294, 305))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('stomach cancer', 'Disease', 'MESH:D013274', (212, 226))	('prostate cancer', 'Disease', 'MESH:D011471', (318, 333))	('prostate cancer', 'Phenotype', 'HP:0012125', (318, 333))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('stomach cancer', 'Phenotype', 'HP:0012126', (212, 226))	('prostate cancer', 'Disease', (318, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (294, 305))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('genetic alterations', 'Var', (47, 66))	('TRAF1', 'Gene', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('ovarian cancer', 'Disease', 'MESH:D010051', (251, 265))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
775593	30294322	Deep deletion (copy loss) is less common but also detected in several types of human cancers (Figure 1).	('human', 'Species', '9606', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('detected', 'Reg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Deep deletion', 'Var', (0, 13))
775595	30294322	To date, there are 139 different mutations of the TRAF1 gene detected in human cancers, comprising 80% (111/139) mutations that alter the protein sequence of TRAF1 and 20% (28/139) coding silent mutations (Table 1).	('cancers', 'Disease', (79, 86))	('alter', 'Reg', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TRAF1', 'Gene', (50, 55))	('human', 'Species', '9606', (73, 78))	('mutations', 'Var', (113, 122))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('TRAF1', 'Gene', (158, 163))	('protein sequence', 'MPA', (138, 154))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
775596	30294322	Only 29% (32/111) of the coding-altering mutations of TRAF1 are recurrent and have been detected in at least two patients with various cancers.	('mutations', 'Var', (41, 50))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('patients', 'Species', '9606', (113, 121))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('TRAF1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('coding-altering', 'Reg', (25, 40))
775597	30294322	Interestingly, missense mutations of two specific amino acids are detected in more than three patients: R70C or H in the linker between the Zinc finger and the coiled-coil domain, and M182I of the coiled-coil (also known as TRAF-N) domain of the TRAF1 protein (Figure 3).	('patients', 'Species', '9606', (94, 102))	('TRAF1', 'Gene', (246, 251))	('coiled-coil', 'MPA', (197, 208))	('M182I', 'Mutation', 'p.M182I', (184, 189))	('missense', 'Var', (15, 23))	('R70C', 'Var', (104, 108))	('R70C', 'Mutation', 'p.R70C', (104, 108))	('M182I', 'Var', (184, 189))
775598	30294322	The R70 mutations are detected in 4 patients with stomach, colon, and colorectal cancers (TCGA).	('patients', 'Species', '9606', (36, 44))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('colon', 'Disease', (59, 64))	('R70 mutations', 'Var', (4, 17))	('colorectal cancers', 'Disease', 'MESH:D015179', (70, 88))	('stomach', 'Disease', (50, 57))	('colorectal cancers', 'Disease', (70, 88))	('detected', 'Reg', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
775599	30294322	M182I is documented in 4 patients with melanoma and chronic lymphocytic leukemia (CLL).	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (52, 80))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (52, 80))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('M182I', 'Var', (0, 5))	('patients', 'Species', '9606', (25, 33))	('leukemia', 'Phenotype', 'HP:0001909', (72, 80))	('CLL', 'Phenotype', 'HP:0005550', (82, 85))	('chronic lymphocytic leukemia', 'Disease', (52, 80))	('M182I', 'Mutation', 'p.M182I', (0, 5))
775600	30294322	The functional significance of R70C/H and M182I mutations of TRAF1 remains to be determined.	('R70C', 'Mutation', 'p.R70C', (31, 35))	('R70C/H', 'Var', (31, 37))	('TRAF1', 'Gene', (61, 66))	('M182I', 'Var', (42, 47))	('M182I', 'Mutation', 'p.M182I', (42, 47))
775605	30294322	Gene amplification is the most common TRAF1 genetic alteration in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('Gene amplification', 'Var', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('TRAF1', 'Gene', (38, 43))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
775608	30294322	In this case, TRAF1 upregulation might be the result of epigenetic alterations and/or aberrant activation of NF-kappaB1/2, as TRAF1 is a direct target gene of NF-kappaB.	('NF-kappaB1', 'Gene', '18033', (109, 119))	('activation', 'PosReg', (95, 105))	('NF-kappaB1', 'Gene', (109, 119))	('upregulation', 'PosReg', (20, 32))	('TRAF1', 'Gene', (14, 19))	('epigenetic alterations', 'Var', (56, 78))
775618	30294322	In line with the evidence of TRAF1 overexpression in HLs and NHLs, TRAF1 deficiency inhibits the spontaneous development of small B cell lymphoma in a transgenic mouse model that expresses the human lymphoma-associated NF-kappaB2 mutant p80HT specifically in lymphocytes (p80HT tg mice) (Table 2).	('B cell lymphoma', 'Phenotype', 'HP:0012191', (130, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('p80HT', 'Var', (237, 242))	('spontaneous development', 'CPA', (97, 120))	('small B cell lymphoma', 'Disease', 'MESH:D016393', (124, 145))	('mutant p80HT', 'Var', (230, 242))	('NHLs, TRAF1 deficiency inhibits', 'Disease', 'MESH:C565433', (61, 92))	('HL', 'CellLine', 'CVCL:2492', (62, 64))	('human', 'Species', '9606', (193, 198))	('NHLs', 'Phenotype', 'HP:0012539', (61, 65))	('HL', 'CellLine', 'CVCL:2492', (53, 55))	('cell lymphoma', 'Phenotype', 'HP:0012191', (132, 145))	('HLs', 'Phenotype', 'HP:0012189', (62, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (199, 207))	('lymphoma', 'Disease', (137, 145))	('small B cell lymphoma', 'Disease', (124, 145))	('mice', 'Species', '10090', (281, 285))	('lymphoma', 'Disease', 'MESH:D008223', (137, 145))	('mouse', 'Species', '10090', (162, 167))	('NF-kappaB2', 'Gene', '18034', (219, 229))	('transgenic', 'Species', '10090', (151, 161))	('NF-kappaB2', 'Gene', (219, 229))	('lymphoma', 'Disease', (199, 207))	('HLs', 'Phenotype', 'HP:0012189', (53, 56))	('lymphoma', 'Disease', 'MESH:D008223', (199, 207))	('small B cell', 'Phenotype', 'HP:0010976', (124, 136))
775623	30294322	The frequency of genetic alterations of TRAF2 is generally <6% in human cancers (Figure 1A) based on the TCGA and COSMIC datasets of sample size n > 180.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TRAF2', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
775624	30294322	The eight human cancers with relatively higher genetic alterations of TRAF2 are prostate cancer (5.5%), ovarian cancer (5.1%) (TCGA, Provisional), uterine cancer (4.4%) (TCGA, PanCancer Atlas), esophageal cancer (3.9%) (TCGA, PanCancer Atlas), skin cutaneous melanoma (3.4%) (TCGA, PanCancer Atlas), head and neck squamous cell carcinoma (HNSCC, 3.2%) (TCGA, Provisional), bladder cancer (3.2%) (TCGA, PanCancer Atlas), and stomach cancer (3.1%).	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cancer', 'Disease', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (89, 95))	('stomach cancer', 'Disease', (424, 438))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('Cancer', 'Phenotype', 'HP:0002664', (405, 411))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (309, 337))	('neck squamous cell carcinoma', 'Disease', (309, 337))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('cancer', 'Disease', (16, 22))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('esophageal cancer', 'Disease', (194, 211))	('cancer', 'Disease', 'MESH:D009369', (432, 438))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('bladder cancer', 'Disease', (373, 387))	('cancer', 'Disease', (381, 387))	('bladder cancer', 'Disease', 'MESH:D001749', (373, 387))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TRAF2', 'Gene', (70, 75))	('prostate cancer', 'Disease', (80, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (373, 387))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (244, 267))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (314, 337))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (205, 211))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('stomach cancer', 'Disease', 'MESH:D013274', (424, 438))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('stomach cancer', 'Phenotype', 'HP:0012126', (424, 438))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (249, 267))	('skin cutaneous melanoma', 'Disease', (244, 267))	('genetic alterations', 'Var', (47, 66))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('Cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (155, 161))	('ovarian cancer', 'Disease', (104, 118))	('alterations', 'Var', (55, 66))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('Cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('cancer', 'Disease', (432, 438))	('uterine cancer', 'Phenotype', 'HP:0010784', (147, 161))
775625	30294322	Notably, although not cataloged in TCGA, mutations of TRAF2 are recognized as one of the most frequent somatic mutations in mantle cell lymphoma (MCL, 6.1%, 10/165) and diffuse large B-cell lymphoma (DLBCL, 6%, 6/101) (Figure 1B).	('mutations', 'Var', (41, 50))	('MCL', 'Disease', (146, 149))	('cell lymphoma', 'Phenotype', 'HP:0012191', (185, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('cell lymphoma', 'Phenotype', 'HP:0012191', (131, 144))	('cell lymphoma', 'Disease', 'MESH:D016399', (185, 198))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (124, 144))	('TRAF2', 'Gene', (54, 59))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (183, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('mantle cell lymphoma', 'Disease', (124, 144))	('MCL', 'Disease', 'OMIM:150800', (146, 149))	('cell lymphoma', 'Disease', (185, 198))	('cell lymphoma', 'Disease', 'MESH:D016399', (131, 144))
775627	30294322	Truncation and fusion of TRAF2 are relatively rare but also detected in human cancers (Figure 1).	('fusion', 'Var', (15, 21))	('TRAF2', 'Gene', (25, 30))	('Truncation', 'Var', (0, 10))	('human', 'Species', '9606', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('detected', 'Reg', (60, 68))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
775628	30294322	There are 237 different mutations of TRAF2 detected in human cancers, comprising 86% (205/237) mutations that change the protein sequence of TRAF2 and 14% (32/237) coding silent mutations (Table 1).	('TRAF2', 'Gene', (37, 42))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('protein sequence', 'MPA', (121, 137))	('TRAF2', 'Gene', (141, 146))
775629	30294322	Notably, 45% (92/205) of the coding-altering mutations of TRAF2 are recurrently detected in at least two cancer patients.	('mutations', 'Var', (45, 54))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (112, 120))	('coding-altering', 'Reg', (29, 44))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TRAF2', 'Gene', (58, 63))
775630	30294322	Interestingly, four mutation hotspots of TRAF2 are detected in more than 5 cancer patients, specifically P9, G10, R372, and Q457 (Figure 3).	('TRAF2', 'Gene', (41, 46))	('detected', 'Reg', (51, 59))	('Q457', 'Var', (124, 128))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('G10', 'Var', (109, 112))	('P9', 'Gene', '11340', (105, 107))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('R372', 'Var', (114, 118))
775631	30294322	In particular, the frameshift deletion occurred at P9 (P9fs*77) is found in 16 patients with colon cancer, colorectal cancer (CRC), uterine cancer, stomach cancer, and sarcoma, and an additional missense mutation at P9 (P9S) is also detected in a CRC patient (TCGA).	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('CRC', 'Phenotype', 'HP:0003003', (126, 129))	('found', 'Reg', (67, 72))	('frameshift deletion', 'Var', (19, 38))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('P9', 'Gene', '11340', (51, 53))	('P9 (P9S', 'Gene', '11340', (216, 223))	('stomach cancer', 'Disease', (148, 162))	('colon cancer', 'Disease', (93, 105))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('P9', 'Gene', '11340', (216, 218))	('patient', 'Species', '9606', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('CRC', 'Disease', (247, 250))	('CRC', 'Phenotype', 'HP:0003003', (247, 250))	('cancer', 'Disease', (118, 124))	('stomach cancer', 'Disease', 'MESH:D013274', (148, 162))	('patient', 'Species', '9606', (251, 258))	('stomach cancer', 'Phenotype', 'HP:0012126', (148, 162))	('cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('P9', 'Gene', '11340', (55, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))	('sarcoma', 'Disease', (168, 175))	('cancer', 'Disease', (156, 162))	('uterine cancer', 'Phenotype', 'HP:0010784', (132, 146))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colorectal cancer', 'Disease', (107, 124))	('patients', 'Species', '9606', (79, 87))	('P9', 'Gene', '11340', (220, 222))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('colon cancer', 'Disease', 'MESH:D015179', (93, 105))
775632	30294322	The amino acid right next to P9, G10, also exhibits similar frameshift deletion (G10fs*76) or insertion (G10fs*70) or missense mutation (G10D) in five patients with colon cancer, CRC, gallbladder cancer, and glioblastoma (TCGA).	('G10fs*76', 'Var', (81, 89))	('G10fs*70', 'Mutation', 'p.G10fsX70', (105, 113))	('G10D', 'Var', (137, 141))	('G10D', 'Mutation', 'p.G10D', (137, 141))	('colon cancer', 'Disease', (165, 177))	('CRC', 'Disease', (179, 182))	('frameshift', 'Reg', (60, 70))	('gallbladder cancer', 'Disease', (184, 202))	('CRC', 'Phenotype', 'HP:0003003', (179, 182))	('G10fs*70', 'Var', (105, 113))	('G10fs*76', 'Mutation', 'p.G10fsX76', (81, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (208, 220))	('colon cancer', 'Phenotype', 'HP:0003003', (165, 177))	('P9', 'Gene', '11340', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('glioblastoma', 'Disease', (208, 220))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('gallbladder cancer', 'Disease', 'MESH:D005706', (184, 202))	('glioblastoma', 'Phenotype', 'HP:0012174', (208, 220))	('patients', 'Species', '9606', (151, 159))	('colon cancer', 'Disease', 'MESH:D015179', (165, 177))
775634	30294322	Another amino acid of the TRAF-C domain, Q457, shows complex mutations, including a truncation (Q457*), a frameshift insertion (Q457fs*277), and missense mutations (Q457K or L) in six patients of HNSCC, oral squamous cell carcinoma (OSCC), stomach cancer, melanoma, and breast cancer (TCGA; COSMIC).	('Q457*', 'SUBSTITUTION', 'None', (96, 101))	('Q457fs*277', 'Var', (128, 138))	('stomach cancer', 'Phenotype', 'HP:0012126', (240, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (270, 283))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('Q457K', 'Var', (165, 170))	('melanoma', 'Disease', (256, 264))	('Q457K', 'Mutation', 'p.Q457K', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (270, 283))	('breast cancer', 'Disease', (270, 283))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('Q457*', 'Var', (96, 101))	('missense', 'Var', (145, 153))	('truncation', 'MPA', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('Q457fs*277', 'Mutation', 'p.Q457fsX277', (128, 138))	('stomach cancer', 'Disease', (240, 254))	('melanoma', 'Disease', 'MESH:D008545', (256, 264))	('HNSCC', 'Disease', (196, 201))	('patients', 'Species', '9606', (184, 192))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('oral squamous cell carcinoma', 'Disease', (203, 231))	('stomach cancer', 'Disease', 'MESH:D013274', (240, 254))
775635	30294322	Frameshift mutations occurring at P9 and G10 are functionally equivalent to deletion of TRAF2.	('deletion', 'Var', (76, 84))	('P9', 'Gene', '11340', (34, 36))	('TRAF2', 'Gene', (88, 93))	('G10', 'Var', (41, 44))	('Frameshift mutations', 'Var', (0, 20))
775639	30294322	Inactivating mutations of TRAF2 are frequently detected in human MCL and DLBCL, resulting in elevated activation of NF-kappaB1 and NF-kappaB2 in malignant B cells.	('elevated activation', 'PosReg', (93, 112))	('human', 'Species', '9606', (59, 64))	('NF-kappaB1', 'Gene', '18033', (116, 126))	('NF-kappaB1', 'Gene', (116, 126))	('Inactivating mutations', 'Var', (0, 22))	('MCL', 'Disease', 'OMIM:150800', (65, 68))	('NF-kappaB2', 'Gene', (131, 141))	('TRAF2', 'Gene', (26, 31))	('MCL', 'Disease', (65, 68))	('NF-kappaB2', 'Gene', '18034', (131, 141))
775642	30294322	Similarly in TRAF2DN-tg mice that express a dominant negative form of TRAF2 specifically in lymphocytes (Igh-TRAF2DN), inhibition of TRAF2 also leads to splenomegaly and lymphadenopathy due to constitutive NF-kappaB2 activation and increased numbers of B cells.	('splenomegaly and lymphadenopathy', 'Disease', 'MESH:C536897', (153, 185))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (170, 185))	('leads to', 'Reg', (144, 152))	('mice', 'Species', '10090', (24, 28))	('NF-kappaB2', 'Gene', (206, 216))	('inhibition', 'Var', (119, 129))	('TRAF2', 'Gene', (133, 138))	('Igh', 'Gene', (105, 108))	('increased', 'PosReg', (232, 241))	('negative', 'NegReg', (53, 61))	('Igh', 'Gene', '111507', (105, 108))	('NF-kappaB2', 'Gene', '18034', (206, 216))	('splenomegaly', 'Phenotype', 'HP:0001744', (153, 165))	('activation', 'PosReg', (217, 227))	('TRAF2', 'Gene', (70, 75))
775643	30294322	Remarkably, TRAF2DN/Bcl-2 double-transgenic mice spontaneously develop small B cell lymphoma progressing to leukemia with many similarities to human CLL (Table 2).	('human', 'Species', '9606', (143, 148))	('small B cell', 'Phenotype', 'HP:0010976', (71, 83))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (77, 92))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('cell lymphoma', 'Phenotype', 'HP:0012191', (79, 92))	('CLL', 'Phenotype', 'HP:0005550', (149, 152))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('develop', 'PosReg', (63, 70))	('leukemia', 'Disease', 'MESH:D007938', (108, 116))	('transgenic mice', 'Species', '10090', (33, 48))	('leukemia', 'Disease', (108, 116))	('TRAF2DN/Bcl-2', 'Var', (12, 25))	('small B cell lymphoma', 'Disease', (71, 92))	('small B cell lymphoma', 'Disease', 'MESH:D016393', (71, 92))
775645	30294322	Genetic alterations of TRAF2 are detected in 1-2% of human liver cancers, including deletion, mutation and amplification (TCGA, PanCancer Atlas).	('liver cancer', 'Phenotype', 'HP:0002896', (59, 71))	('liver cancers', 'Phenotype', 'HP:0002896', (59, 72))	('deletion', 'Var', (84, 92))	('TRAF2', 'Gene', (23, 28))	('liver cancers', 'Disease', (59, 72))	('liver cancers', 'Disease', 'MESH:D006528', (59, 72))	('amplification', 'MPA', (107, 120))	('detected', 'Reg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('human', 'Species', '9606', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutation', 'Var', (94, 102))
775647	30294322	In line with human evidence, deletion of both TRAF2 and RIP1 in liver parenchymal cells (LPC) leads to spontaneous development of hepatocellular carcinoma, which results from extensive hepatocyte apoptosis due to hyperactivation of caspase-8 but impaired NF-kappaB activation induced by TNFalpha (Table 2).	('RIP1', 'Gene', (56, 60))	('deletion', 'Var', (29, 37))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (130, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('TRAF2', 'Gene', (46, 51))	('human', 'Species', '9606', (13, 18))	('RIP1', 'Gene', '8737', (56, 60))	('impaired', 'NegReg', (246, 254))	('caspase-8', 'Gene', '841', (232, 241))	('hyperactivation', 'PosReg', (213, 228))	('caspase-8', 'Gene', (232, 241))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (130, 154))	('activation', 'PosReg', (265, 275))	('hepatocyte apoptosis', 'CPA', (185, 205))	('NF-kappaB', 'Protein', (255, 264))	('hepatocellular carcinoma', 'Disease', (130, 154))
775649	30294322	Induced TRAF2 deletion in adult mice results in rapid lethality, in conjunction with increased hepatic necroptosome assembly (Table 2).	('TRAF2', 'Gene', (8, 13))	('rapid lethality', 'MPA', (48, 63))	('mice', 'Species', '10090', (32, 36))	('increased', 'PosReg', (85, 94))	('deletion', 'Var', (14, 22))	('hepatic necroptosome assembly', 'MPA', (95, 124))
775651	30294322	Genetic alterations of TRAF2 are detected in 3-4% of human HNSCC and melanoma (Figure 1A).	('Genetic alterations', 'Var', (0, 19))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('TRAF2', 'Gene', (23, 28))	('human HNSCC', 'Disease', (53, 64))	('detected', 'Reg', (33, 41))	('human', 'Species', '9606', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
775655	30294322	Further in support of a role for TRAF2 in skin tumorigenesis, mutations of the TRAF2-deubiquitinating enzyme CYLD are identified in patients with familial cylindromatosis, a condition that results in benign tumors of skin appendages, and CYLD-/- mice are highly susceptible to chemically induced skin tumors.	('TRAF2-deubiquitinating', 'Gene', (79, 101))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Disease', (207, 213))	('patients', 'Species', '9606', (132, 140))	('tumors', 'Disease', (301, 307))	('familial cylindromatosis', 'Disease', (146, 170))	('skin tumor', 'Phenotype', 'HP:0008069', (42, 52))	('skin tumor', 'Phenotype', 'HP:0008069', (296, 306))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', 'MESH:D009369', (301, 307))	('CYLD', 'Gene', (109, 113))	('mutations', 'Var', (62, 71))	('CYLD', 'Gene', (238, 242))	('skin tumors', 'Disease', (296, 307))	('tumors of skin', 'Phenotype', 'HP:0008069', (207, 221))	('tumors of skin appendages', 'Phenotype', 'HP:0012842', (207, 232))	('familial cylindromatosis', 'Disease', 'MESH:C536611', (146, 170))	('tumor', 'Disease', (301, 306))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (47, 52))	('CYLD', 'Gene', '1540', (109, 113))	('CYLD', 'Gene', '1540', (238, 242))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('skin tumors', 'Disease', 'MESH:D012878', (296, 307))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('skin tumors', 'Phenotype', 'HP:0008069', (296, 307))	('mice', 'Species', '10090', (246, 250))
775656	30294322	Similarly, genetic alterations of TRAF2 are also identified in 2.7% (12/439) of human colon cancers (TCGA, PanCancer Atlas).	('colon cancers', 'Disease', (86, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('colon cancers', 'Phenotype', 'HP:0003003', (86, 99))	('identified', 'Reg', (49, 59))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('colon cancers', 'Disease', 'MESH:D015179', (86, 99))	('human', 'Species', '9606', (80, 85))	('TRAF2', 'Gene', (34, 39))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('genetic alterations', 'Var', (11, 30))
775659	30294322	Interestingly, myeloid cell-specific ablation of TRAF2 markedly exacerbates DSS-induced colitis in mice due to enhanced TLR-induced proinflammatory cytokine expression in macrophages.	('mice', 'Species', '10090', (99, 103))	('colitis', 'Phenotype', 'HP:0002583', (88, 95))	('ablation', 'Var', (37, 45))	('enhanced', 'PosReg', (111, 119))	('colitis', 'Disease', 'MESH:D003092', (88, 95))	('exacerbates', 'PosReg', (64, 75))	('colitis', 'Disease', (88, 95))	('TLR-induced proinflammatory cytokine expression', 'MPA', (120, 167))	('TRAF2', 'Gene', (49, 54))
775662	30294322	It is also noteworthy that genetic alterations of TRAF2 are detected in 2.6% (7/265) of human sarcomas (TCGA) and TRAF2-/- mice display decreased viability of skeletal muscle tissue because of defective TNFalpha-induced NF-kappaB activation in myotubes (Table 2).	('alterations', 'Var', (35, 46))	('defective', 'NegReg', (193, 202))	('TRAF2-/', 'Gene', '7186', (114, 121))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('viability', 'CPA', (146, 155))	('TRAF2', 'Gene', (50, 55))	('genetic alterations', 'Var', (27, 46))	('TNFalpha-induced NF-kappaB', 'Protein', (203, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('activation', 'PosReg', (230, 240))	('human', 'Species', '9606', (88, 93))	('sarcomas', 'Disease', (94, 102))	('TRAF2-/', 'Gene', (114, 121))	('decreased', 'NegReg', (136, 145))	('mice', 'Species', '10090', (123, 127))
775663	30294322	Additionally, specific deletion of TRAF2 in T cells results in decreased numbers of CD8 naive and memory T cells as well as NKT cells, due to impaired IL-15-induced signaling in these cells (Table 2).	('memory T', 'Disease', 'MESH:D008569', (98, 106))	('CD8', 'Gene', '925', (84, 87))	('deletion', 'Var', (23, 31))	('decreased', 'NegReg', (63, 72))	('memory T', 'Disease', (98, 106))	('IL-15-induced signaling', 'MPA', (151, 174))	('CD8', 'Gene', (84, 87))	('impaired', 'NegReg', (142, 150))	('TRAF2', 'Gene', (35, 40))
775665	30294322	Potential causal roles of TRAF2 dysregulation in muscle or T cell tumorigenesis remain to be elucidated.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('dysregulation', 'Var', (32, 45))	('tumor', 'Disease', (66, 71))	('muscle', 'CPA', (49, 55))	('TRAF2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
775672	30294322	Importantly, suppression of TRAF2 in cancer cells harboring a TRAF2 copy number gain inhibits proliferation, NF-kappaB activation, anchorage-independent growth, and tumorigenesis.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('inhibits', 'NegReg', (85, 93))	('copy number', 'Var', (68, 79))	('cancer', 'Disease', (37, 43))	('gain', 'PosReg', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('proliferation', 'CPA', (94, 107))	('activation', 'PosReg', (119, 129))	('TRAF2', 'Gene', (28, 33))	('NF-kappaB', 'Protein', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('anchorage-independent growth', 'CPA', (131, 159))	('TRAF2', 'Gene', (62, 67))	('suppression', 'NegReg', (13, 24))	('tumor', 'Disease', (165, 170))
775674	30294322	Thus, TRAF2 is required for the maintenance of the malignant state in certain cancer cells containing TRAF2 amplification or overexpression, and TRAF2 protein levels also regulate the sensitivity of cancer cells to chemotherapy and radiotherapy.	('amplification', 'Var', (108, 121))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('regulate', 'Reg', (171, 179))	('cancer', 'Disease', (78, 84))	('overexpression', 'Var', (125, 139))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('TRAF2', 'Gene', (102, 107))	('sensitivity', 'MPA', (184, 195))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
775679	30294322	The frequency of genetic alterations of TRAF3 is generally <6% in human cancers (Figure 1A) according to the TCGA and COSMIC datasets of sample size n > 250.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TRAF3', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
775680	30294322	The eight human cancers with relatively higher genetic alterations of TRAF3 are HNSCC (5.4%), lung cancer (5.3%) (TCGA, PanCancer Atlas), cervical cancer (4.7%) (TCGA, PanCancer Atlas), uterine cancer (4.5%) (TCGA, PanCancer Atlas), stomach cancer (4.1%) (TCGA, PanCancer Atlas), bladder cancer (3.6%), ovarian cancer (3.4%) (TCGA, PanCancer Atlas), and skin cutaneous melanoma (3.4%) (TCGA, PanCancer Atlas).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', (311, 317))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('bladder cancer', 'Disease', 'MESH:D001749', (280, 294))	('bladder cancer', 'Disease', (280, 294))	('cancer', 'Disease', (288, 294))	('lung cancer', 'Disease', (94, 105))	('Cancer', 'Phenotype', 'HP:0002664', (265, 271))	('bladder cancer', 'Phenotype', 'HP:0009725', (280, 294))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('stomach cancer', 'Disease', (233, 247))	('HNSCC', 'Disease', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('ovarian cancer', 'Disease', 'MESH:D010051', (303, 317))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (354, 377))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('genetic alterations', 'Var', (47, 66))	('skin cutaneous melanoma', 'Disease', (354, 377))	('stomach cancer', 'Disease', 'MESH:D013274', (233, 247))	('stomach cancer', 'Phenotype', 'HP:0012126', (233, 247))	('TRAF3', 'Gene', (70, 75))	('ovarian cancer', 'Disease', (303, 317))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('melanoma', 'Phenotype', 'HP:0002861', (369, 377))	('uterine cancer', 'Phenotype', 'HP:0010784', (186, 200))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (359, 377))	('cancer', 'Disease', (99, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (303, 317))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
775681	30294322	Interestingly however, a subgroup among the 279 cases of HNSCC cataloged in TCGA, the human papilloma virus-positive (HPV+) HNSCC tumors, has much higher frequency (22%, 8/36) of deep deletions and truncations of TRAF3 than the HPV- HNSCC tumors (Figure 1B).	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('papilloma', 'Phenotype', 'HP:0012740', (92, 101))	('HPV', 'Species', '10566', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('HNSCC tumors', 'Disease', 'MESH:C535575', (233, 245))	('HNSCC tumors', 'Disease', (233, 245))	('HPV', 'Species', '10566', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('HNSCC tumors', 'Disease', 'MESH:C535575', (124, 136))	('HNSCC tumors', 'Disease', (124, 136))	('deep deletions', 'Var', (179, 193))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('human papilloma virus', 'Species', '10566', (86, 107))	('truncations', 'MPA', (198, 209))
775682	30294322	Notably, although not cataloged in TCGA, deletions and mutations of TRAF3 are recognized as one of the most frequent genetic alterations in a variety of B cell malignancies, including gastric marginal zone lymphoma (MZL, 21%), multiple myeloma (MM, 17%), HL (15%), DLBCL (14.3%), splenic MZL (10%), and Waldenstrom's macroglobulinemia (WM, 5.3%) (Figure 1B).	('B cell malignancies', 'Disease', (153, 172))	('gastric marginal zone lymphoma', 'Disease', (184, 214))	("Waldenstrom's macroglobulinemia", 'Disease', 'MESH:D008258', (303, 334))	('TRAF3', 'Gene', (68, 73))	("Waldenstrom's macroglobulinemia", 'Disease', (303, 334))	('gastric marginal zone lymphoma', 'Phenotype', 'HP:0045038', (184, 214))	('multiple myeloma', 'Phenotype', 'HP:0006775', (227, 243))	('lymphoma', 'Phenotype', 'HP:0002665', (206, 214))	('splenic MZL', 'Disease', (280, 291))	('mutations', 'Var', (55, 64))	('multiple myeloma', 'Disease', 'MESH:D009101', (227, 243))	("Waldenstrom's macroglobulinemia", 'Phenotype', 'HP:0005508', (303, 334))	('gastric marginal zone lymphoma', 'Disease', 'MESH:D018442', (184, 214))	('deletions', 'Var', (41, 50))	('B cell malignancies', 'Disease', 'MESH:D015448', (153, 172))	('multiple myeloma', 'Disease', (227, 243))	('HL', 'CellLine', 'CVCL:2492', (255, 257))	('DLBCL', 'Disease', (265, 270))	('MM', 'Disease', 'MESH:D009101', (245, 247))
775684	30294322	Truncation and fusion of TRAF3 are less common but also detected in several different types of human cancers (Figure 1).	('fusion', 'Var', (15, 21))	('human', 'Species', '9606', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('detected', 'Reg', (56, 64))	('cancers', 'Disease', (101, 108))	('Truncation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('TRAF3', 'Gene', (25, 30))
775685	30294322	There are 280 different mutations of TRAF3 detected in human cancers, comprising 90% (253/280) mutations that change the protein sequence of TRAF3 and 10% (27/280) coding silent mutations (Table 1).	('TRAF3', 'Gene', (37, 42))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('protein sequence', 'MPA', (121, 137))	('TRAF3', 'Gene', (141, 146))
775686	30294322	Approximately 43% (108/253) of the coding-altering mutations of TRAF3 are recurrently detected in at least two cancer patients.	('mutations', 'Var', (51, 60))	('coding-altering', 'Reg', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TRAF3', 'Gene', (64, 69))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (118, 126))
775687	30294322	Five mutation hotspots of TRAF3 are identified in more than 5 cancer patients, specifically N16, N285, K286, R310, and R376 (Figure 3).	('K286', 'Chemical', '-', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('K286', 'Var', (103, 107))	('TRAF3', 'Gene', (26, 31))	('N285', 'Var', (97, 101))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('patients', 'Species', '9606', (69, 77))	('R310', 'Var', (109, 113))	('R376', 'Var', (119, 123))	('N16', 'Var', (92, 95))
775688	30294322	TRAF3 mutations at N16 have the highest patient count, including the missense mutation (N16T) identified in 10 patients with HNSCC (COSMIC) and the frameshift deletion (N16fs*3) detected in a patient with splenic MZL.	('mutations at N16', 'Var', (6, 22))	('patient', 'Species', '9606', (40, 47))	('patient', 'Species', '9606', (192, 199))	('frameshift deletion', 'Var', (148, 167))	('TRAF3', 'Gene', (0, 5))	('N16T', 'SUBSTITUTION', 'None', (88, 92))	('N16fs*3', 'Var', (169, 176))	('patient', 'Species', '9606', (111, 118))	('N16T', 'Var', (88, 92))	('patients', 'Species', '9606', (111, 119))
775689	30294322	Mutations at the two consecutive amino acids N285 and K286 of the coiled-coil domain of TRAF3 exhibit the most complex pattern.	('TRAF3', 'Gene', (88, 93))	('coiled-coil domain', 'MPA', (66, 84))	('K286', 'Var', (54, 58))	('K286', 'Chemical', '-', (54, 58))
775690	30294322	N285 contains frameshift deletion (N285fs*38), frameshift insertion (N285fs*13) and missense mutation (N285S) identified in 8 patients with HNSCC, MZL, NPC, CRC, stomach cancer and uterine cancer (TCGA; COSMIC).	('N285fs*38', 'Var', (35, 44))	('cancer', 'Disease', (170, 176))	('stomach cancer', 'Disease', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('patients', 'Species', '9606', (126, 134))	('N285S', 'Mutation', 'p.N285S', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('N285fs*38', 'Mutation', 'p.N285fsX38', (35, 44))	('N285fs', 'Mutation', 'p.N285fsX', (69, 75))	('frameshift deletion (N285fs*38', 'Var', (14, 44))	('uterine cancer', 'Phenotype', 'HP:0010784', (181, 195))	('MZL', 'Disease', (147, 150))	('stomach cancer', 'Disease', 'MESH:D013274', (162, 176))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('N285fs', 'Mutation', 'p.N285fsX', (35, 41))	('stomach cancer', 'Phenotype', 'HP:0012126', (162, 176))	('N285S', 'Var', (103, 108))	('NPC', 'Disease', (152, 155))	('HNSCC', 'Disease', (140, 145))	('cancer', 'Disease', (189, 195))	('N285fs*13', 'Var', (69, 78))	('frameshift insertion (N285fs*13', 'Var', (47, 78))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('CRC', 'Disease', (157, 160))	('CRC', 'Phenotype', 'HP:0003003', (157, 160))
775691	30294322	Similarly, K286 exhibits frameshift deletion (K286fs*7 or fs*11) and truncation (K286*) detected in six patients with B cell malignancies, including MM, CLL and WM.	('K286', 'Chemical', '-', (81, 85))	('K286*', 'Var', (81, 86))	('B cell malignancies', 'Disease', (118, 137))	('K286', 'Var', (11, 15))	('B cell malignancies', 'Disease', 'MESH:D015448', (118, 137))	('K286', 'Chemical', '-', (11, 15))	('detected', 'Reg', (88, 96))	('K286fs', 'Mutation', 'p.K286fsX', (46, 52))	('K286', 'Chemical', '-', (46, 50))	('CLL', 'Phenotype', 'HP:0005550', (153, 156))	('K286fs*7', 'Var', (46, 54))	('MM', 'Disease', 'MESH:D009101', (149, 151))	('truncation', 'MPA', (69, 79))	('fs*11', 'Gene', (58, 63))	('CLL', 'Disease', (153, 156))	('K286*', 'SUBSTITUTION', 'None', (81, 86))	('patients', 'Species', '9606', (104, 112))
775692	30294322	A third amino acid of the coiled-coil domain, R310, is consistently targeted by truncation (R310*) as detected in 8 patients with DLBCL, MM, HNSCC, cervical cancer and uterine cancer (TCGA).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('MM', 'Disease', 'MESH:D009101', (137, 139))	('R310*', 'SUBSTITUTION', 'None', (92, 97))	('HNSCC', 'Disease', (141, 146))	('DLBCL', 'Disease', (130, 135))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('R310*', 'Var', (92, 97))	('R310', 'Var', (46, 50))	('cancer', 'Disease', (157, 163))	('detected', 'Reg', (102, 110))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('uterine cancer', 'Phenotype', 'HP:0010784', (168, 182))
775694	30294322	Many of these truncations, frameshifts and missense mutations have been shown to result in inactivation of TRAF3 by disrupting its interaction with NIK, thereby inducing constitutive NF-kappaB2 activation.	('missense mutations', 'Var', (43, 61))	('inducing', 'Reg', (161, 169))	('NIK', 'Gene', (148, 151))	('NF-kappaB2', 'Gene', '18034', (183, 193))	('activation', 'PosReg', (194, 204))	('frameshifts', 'Var', (27, 38))	('disrupting', 'NegReg', (116, 126))	('inactivation', 'MPA', (91, 103))	('NIK', 'Gene', '9020', (148, 151))	('interaction', 'Interaction', (131, 142))	('NF-kappaB2', 'Gene', (183, 193))	('TRAF3', 'Gene', (107, 112))
775695	30294322	Thus, most of the recurrent genetic alterations of TRAF3 identified in human cancers cause complete loss or inactivation of the TRAF3 protein.	('TRAF3', 'Gene', (51, 56))	('genetic alterations', 'Var', (28, 47))	('TRAF3', 'Gene', (128, 133))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('complete loss', 'Disease', 'MESH:D003638', (91, 104))	('inactivation', 'NegReg', (108, 120))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('protein', 'Protein', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('complete loss', 'Disease', (91, 104))	('human', 'Species', '9606', (71, 76))
775698	30294322	Similar to TRAF2 and also consistent with the frequent deletions and inactivating mutations of TRAF3 identified in human B cell malignancies (Figure 1B), a tumor suppressive role for TRAF3 in B lymphocytes has been demonstrated by in vivo evidence obtained from mouse models.	('B cell malignancies', 'Disease', (121, 140))	('B cell malignancies', 'Disease', 'MESH:D015448', (121, 140))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mouse', 'Species', '10090', (262, 267))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('human', 'Species', '9606', (115, 120))	('TRAF3', 'Gene', (95, 100))	('tumor', 'Disease', (156, 161))	('deletions', 'Var', (55, 64))
775704	30294322	Intriguingly, lymphocyte-specific TRAF3 transgenic mice also develop plasmacytosis, autoimmunity, inflammation, and cancers, which are likely caused by hyper-responsiveness of B cells to antigens and TLR agonists.	('autoimmunity', 'Phenotype', 'HP:0002960', (84, 96))	('autoimmunity', 'Disease', (84, 96))	('transgenic mice', 'Species', '10090', (40, 55))	('inflammation', 'Disease', 'MESH:D007249', (98, 110))	('plasmacytosis', 'Disease', (69, 82))	('plasmacytosis', 'Phenotype', 'HP:0030150', (69, 82))	('TRAF3', 'Gene', (34, 39))	('transgenic', 'Var', (40, 50))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('inflammation', 'Disease', (98, 110))	('autoimmunity', 'Disease', 'MESH:D001327', (84, 96))	('cancers', 'Disease', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('develop', 'PosReg', (61, 68))
775706	30294322	Interestingly, specific deletion of TRAF3 from myeloid cells (granulocytes, monocytes, and macrophages) leads to spontaneous development of histiocytic sarcomas derived from TRAF3-/- tissue-resident macrophages in aging mice.	('TRAF3-/-', 'Gene', '22031', (174, 182))	('TRAF3-/-', 'Gene', (174, 182))	('TRAF3', 'Gene', (36, 41))	('leads to', 'Reg', (104, 112))	('mice', 'Species', '10090', (220, 224))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('histiocytic sarcomas', 'Disease', (140, 160))	('deletion', 'Var', (24, 32))	('histiocytic sarcomas', 'Disease', 'MESH:D054747', (140, 160))
775712	30294322	Transgenic expression of human TLR7/TLR8 in mice deficient for endogenous TLR7/TLR8 drives inflammation and proliferative histiocytosis, which can be reversed by compound deletion of MyD88.	('Transgenic', 'Species', '10090', (0, 10))	('inflammation', 'Disease', 'MESH:D007249', (91, 103))	('compound deletion', 'Var', (162, 179))	('inflammation', 'Disease', (91, 103))	('human', 'Species', '9606', (25, 30))	('MyD88', 'Gene', (183, 188))	('MyD88', 'Gene', '17874', (183, 188))	('histiocytosis', 'Phenotype', 'HP:0100727', (122, 135))	('TLR7/TLR8', 'Gene', (31, 40))	('proliferative histiocytosis', 'MPA', (108, 135))	('mice', 'Species', '10090', (44, 48))	('drives', 'PosReg', (84, 90))
775713	30294322	Collectively, the above in vivo evidence indicates that TRAF3 is a tumor suppressor in macrophages and that dysregulation of the TLR-MyD88-TRAF3-Dok3 axis in macrophages plays causal roles in the pathogenesis of histiocytic sarcoma.	('tumor', 'Disease', (67, 72))	('histiocytic sarcoma', 'Disease', (212, 231))	('Dok3', 'Gene', '27261', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('Dok3', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MyD88', 'Gene', (133, 138))	('dysregulation', 'Var', (108, 121))	('MyD88', 'Gene', '17874', (133, 138))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (212, 231))	('TRAF3', 'Gene', (56, 61))
775714	30294322	However, because histiocytic sarcoma in humans is a rare malignancy with sparse pathologic and cytogenetic data, potential TRAF3 genetic alterations in human histiocytic sarcomas require future investigation.	('malignancy', 'Disease', (57, 67))	('histiocytic sarcoma', 'Disease', (17, 36))	('histiocytic sarcomas', 'Disease', (158, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('humans', 'Species', '9606', (40, 46))	('genetic alterations', 'Var', (129, 148))	('TRAF3', 'Gene', (123, 128))	('human', 'Species', '9606', (152, 157))	('malignancy', 'Disease', 'MESH:D009369', (57, 67))	('histiocytic sarcomas', 'Disease', 'MESH:D054747', (158, 178))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (158, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('human', 'Species', '9606', (40, 45))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (17, 36))
775720	30294322	In line with the in vivo data, mutations and deletions of TRAF3 are detected in 2.3% (10/439) of human colon cancers (TCGA, PanCancer Atlas).	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('colon cancers', 'Phenotype', 'HP:0003003', (103, 116))	('colon cancers', 'Disease', 'MESH:D015179', (103, 116))	('human', 'Species', '9606', (97, 102))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deletions', 'Var', (45, 54))	('detected', 'Reg', (68, 76))	('TRAF3', 'Gene', (58, 63))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('colon cancers', 'Disease', (103, 116))
775727	30294322	Silencing of TRAF3 in ALCL cells not only results in aberrant activation of the NIK-NF-kappaB2 pathway, but also affects the continued PI3K-AKT and JAK-STAT signaling.	('AKT', 'Gene', (140, 143))	('NF-kappaB2', 'Gene', '18034', (84, 94))	('ALCL', 'Phenotype', 'HP:0012193', (22, 26))	('NIK', 'Gene', (80, 83))	('affects', 'Reg', (113, 120))	('TRAF3', 'Gene', (13, 18))	('AKT', 'Gene', '207', (140, 143))	('NF-kappaB2', 'Gene', (84, 94))	('Silencing', 'Var', (0, 9))	('activation', 'PosReg', (62, 72))	('JAK-STAT', 'MPA', (148, 156))	('NIK', 'Gene', '9020', (80, 83))
775732	30294322	The frequency of genetic alterations of TRAF4 is generally <11% in human cancers (Figure 1A) based on the TCGA and COSMIC datasets of sample size n > 100.	('cancers', 'Disease', (73, 80))	('TRAF4', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('genetic alterations', 'Var', (17, 36))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
775733	30294322	The eight human cancers with relatively higher genetic alterations of TRAF4 are pancreatic cancer (10.1%), bladder cancer (7.3%), breast cancer (5.5%), uterine cancer (5.1%) (TCGA, PanCancer Atlas), esophageal cancer (3.2%) (TCGA, Provisional), lung cancer (2.6%), melanoma (2.5%), and ovarian cancer (2.4%) (TCGA, PanCancer Atlas).	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('pancreatic cancer', 'Disease', (80, 97))	('TRAF4', 'Gene', (70, 75))	('cancer', 'Disease', (137, 143))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('Cancer', 'Phenotype', 'HP:0002664', (318, 324))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('lung cancer', 'Disease', (245, 256))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('uterine cancer', 'Phenotype', 'HP:0010784', (152, 166))	('cancer', 'Disease', (294, 300))	('ovarian cancer', 'Disease', 'MESH:D010051', (286, 300))	('lung cancer', 'Phenotype', 'HP:0100526', (245, 256))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (199, 216))	('lung cancer', 'Disease', 'MESH:D008175', (245, 256))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('genetic alterations', 'Var', (47, 66))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('ovarian cancer', 'Disease', (286, 300))	('bladder cancer', 'Disease', (107, 121))	('breast cancer', 'Disease', (130, 143))	('cancer', 'Disease', (115, 121))	('esophageal cancer', 'Disease', (199, 216))	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (286, 300))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (210, 216))
775734	30294322	Deep deletion, truncation and fusion of TRAF4 are relatively rare in human cancers.	('truncation', 'Var', (15, 25))	('fusion', 'Var', (30, 36))	('TRAF4', 'Gene', (40, 45))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Deep deletion', 'Var', (0, 13))
775735	30294322	There are 123 different mutations of TRAF4 detected in human cancers, comprising 85% (105/123) mutations that cause changes in the amino acid sequence of TRAF4 and 15% (18/123) coding silent mutations (Table 1).	('TRAF4', 'Gene', (154, 159))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('changes', 'Reg', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('amino acid sequence', 'MPA', (131, 150))	('silent', 'NegReg', (184, 190))	('TRAF4', 'Gene', (37, 42))
775736	30294322	About 42% (44/105) of the coding-altering mutations of the TRAF4 gene are recurrent and detected in at least two cancer patients, including mostly missense mutations (89%, 39/44), 3 truncations, 1 frameshift deletion, and 1 in frame deletion (Table 1 and Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('frameshift deletion', 'Var', (197, 216))	('TRAF4', 'Gene', (59, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('truncations', 'MPA', (182, 193))	('detected', 'Reg', (88, 96))	('coding-altering', 'Reg', (26, 41))	('missense mutations', 'Var', (147, 165))	('cancer', 'Disease', (113, 119))	('patients', 'Species', '9606', (120, 128))	('mutations', 'Var', (42, 51))
775737	30294322	Only two specific amino acids, R448 and R452 located at the C-terminal TRAF-C domain, are mutated in more than 3 patients (Figure 3).	('R452', 'Var', (40, 44))	('patients', 'Species', '9606', (113, 121))	('R448', 'Var', (31, 35))
775738	30294322	For R448, mixed missense mutations (R448Q or L) and a truncation (R448*) are identified in 4 patients with prostate cancer, uterine cancer, HNSCC, and OSCC.	('prostate cancer', 'Disease', (107, 122))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('R448Q', 'Mutation', 'p.R448Q', (36, 41))	('R448*', 'SUBSTITUTION', 'None', (66, 71))	('uterine cancer', 'Phenotype', 'HP:0010784', (124, 138))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('R448Q or L', 'Var', (36, 46))	('OSCC', 'Disease', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HNSCC', 'Disease', (140, 145))	('patients', 'Species', '9606', (93, 101))	('R448*', 'Var', (66, 71))
775739	30294322	For R452, missense mutations (R452W or Q or L) are detected in four patients with uterine, colorectal and lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('detected', 'Reg', (51, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('uterine', 'Disease', (82, 89))	('colorectal and lung cancers', 'Disease', 'MESH:D015179', (91, 118))	('R452W', 'Var', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (68, 76))	('lung cancers', 'Phenotype', 'HP:0100526', (106, 118))	('R452', 'Var', (4, 8))	('R452W', 'Mutation', 'p.R452W', (30, 35))
775741	30294322	Available human evidence indicates that gene amplification is the most common TRAF4 genetic alteration in cancers and that TRAF4 expression is ubiquitously elevated in many human cancers.	('TRAF4', 'Gene', (78, 83))	('human', 'Species', '9606', (10, 15))	('expression', 'MPA', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('human', 'Species', '9606', (173, 178))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('gene amplification', 'Var', (40, 58))	('cancers', 'Disease', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
775744	30294322	Interestingly, TRAF4-/- dendritic cells (DCs) derived from the null mice exhibit reduced in vivo and in vitro migration.	('mice', 'Species', '10090', (68, 72))	('TRAF4-/-', 'Var', (15, 23))	('reduced', 'NegReg', (81, 88))
775746	30294322	TRAF4 deficiency substantially diminishes IL-17A-induced ERK5 activation and epidermal hyperplasia in mice.	('TRAF4 deficiency', 'Phenotype', 'HP:0040209', (0, 16))	('mice', 'Species', '10090', (102, 106))	('epidermal hyperplasia', 'Disease', (77, 98))	('TRAF4', 'Gene', (0, 5))	('diminishes', 'NegReg', (31, 41))	('deficiency', 'Var', (6, 16))	('ERK5', 'Protein', (57, 61))	('epidermal hyperplasia', 'Disease', 'MESH:D006965', (77, 98))
775747	30294322	In the DMBA/TPA-induced skin cancer model, TRAF4-/- mice exhibit remarkably reduced tumor incidence and tumor numbers.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('skin cancer', 'Phenotype', 'HP:0008069', (24, 35))	('tumor', 'Disease', (104, 109))	('mice', 'Species', '10090', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('skin cancer', 'Disease', (24, 35))	('tumor', 'Disease', (84, 89))	('reduced', 'NegReg', (76, 83))	('DMBA', 'Chemical', 'MESH:C082386', (7, 11))	('TPA', 'Chemical', '-', (12, 15))	('skin cancer', 'Disease', 'MESH:D012878', (24, 35))	('TRAF4-/-', 'Var', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
775754	30294322	The frequency of genetic alterations of TRAF5 is generally <13% in human cancers (Figure 1A) according to the TCGA and COSMIC datasets of sample size n > 140.	('cancers', 'Disease', (73, 80))	('TRAF5', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('genetic alterations', 'Var', (17, 36))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
775755	30294322	The eight human cancers with relatively higher genetic alterations of TRAF5 are breast cancer (12.2%), liver cancer (8.4%) (TCGA, Provisional), uterine cancer (6.4%) (TCGA, PanCancer Atlas), lung cancer (5.3%) (TCGA, Provisional), ovarian cancer (5.1%) (TCGA, Provisional), melanoma (4.0%) (TCGA, Provisional), esophageal cancer (3.8%) (TCGA, Provisional), and prostate cancer (3.3%).	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('TRAF5', 'Gene', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('uterine cancer', 'Phenotype', 'HP:0010784', (144, 158))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancer', 'Disease', (152, 158))	('cancers', 'Disease', (16, 23))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('cancer', 'Disease', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (311, 328))	('ovarian cancer', 'Disease', 'MESH:D010051', (231, 245))	('cancer', 'Disease', (322, 328))	('cancer', 'Disease', (109, 115))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('melanoma', 'Disease', (274, 282))	('liver cancer', 'Disease', 'MESH:D006528', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (370, 376))	('cancer', 'Disease', (196, 202))	('genetic alterations', 'Var', (47, 66))	('esophageal cancer', 'Disease', (311, 328))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('liver cancer', 'Phenotype', 'HP:0002896', (103, 115))	('prostate cancer', 'Disease', 'MESH:D011471', (361, 376))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('prostate cancer', 'Phenotype', 'HP:0012125', (361, 376))	('ovarian cancer', 'Disease', (231, 245))	('liver cancer', 'Disease', (103, 115))	('lung cancer', 'Disease', (191, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('prostate cancer', 'Disease', (361, 376))	('ovarian cancer', 'Phenotype', 'HP:0100615', (231, 245))
775756	30294322	Deep deletion, truncation and fusion of TRAF5 are rare events in human cancers.	('truncation', 'Var', (15, 25))	('fusion', 'Var', (30, 36))	('TRAF5', 'Gene', (40, 45))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('human', 'Species', '9606', (65, 70))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Deep deletion', 'Var', (0, 13))
775757	30294322	There are 188 different mutations of TRAF5 detected in human cancers, comprising 85% (160/188) mutations that alter the amino acid sequence of TRAF5 and 15% (28/188) coding silent mutations (Table 1).	('silent', 'NegReg', (173, 179))	('TRAF5', 'Gene', (143, 148))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('amino acid sequence', 'MPA', (120, 139))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TRAF5', 'Gene', (37, 42))
775758	30294322	Approximately 36% (57/160) of the coding-altering mutations of TRAF5 are recurrent in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('mutations', 'Var', (50, 59))	('TRAF5', 'Gene', (63, 68))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('coding-altering', 'Reg', (34, 49))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
775759	30294322	Mutations of three specific amino acids, R164, T232, and A548, are detected in more than three patients (Figure 3).	('A548', 'Var', (57, 61))	('R164', 'Var', (41, 45))	('T232', 'Var', (47, 51))	('patients', 'Species', '9606', (95, 103))
775760	30294322	Complex alterations of R164 of the zinc finger motif, including truncation (R164*) and missense mutations (R164Q or L), are detected in six patients with uterine, colon and bile duct cancers and DLBCL (TCGA).	('R164*', 'Var', (76, 81))	('R164', 'Var', (23, 27))	('detected', 'Reg', (124, 132))	('colon and bile duct cancers', 'Disease', 'MESH:D001650', (163, 190))	('truncation', 'MPA', (64, 74))	('DLBCL', 'Disease', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('uterine', 'Disease', (154, 161))	('missense mutations (R164Q or L', 'Var', (87, 117))	('R164Q', 'Mutation', 'p.R164Q', (107, 112))	('patients', 'Species', '9606', (140, 148))	('R164*', 'SUBSTITUTION', 'None', (76, 81))	('bile duct cancers', 'Phenotype', 'HP:0030153', (173, 190))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
775761	30294322	Another missense mutation of the zinc finger motif, T232M, is detected in four patients with colon, breast, and prostate cancers (TCGA; COSMIC).	('detected', 'Reg', (62, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('breast', 'Disease', (100, 106))	('T232M', 'Var', (52, 57))	('T232M', 'Mutation', 'p.T232M', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('prostate cancers', 'Phenotype', 'HP:0012125', (112, 128))	('prostate cancers', 'Disease', (112, 128))	('colon', 'Disease', (93, 98))	('patients', 'Species', '9606', (79, 87))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('prostate cancers', 'Disease', 'MESH:D011471', (112, 128))
775762	30294322	Missense mutation A548V of the TRAF-C domain is identified in four patients with uterine, cervical, stomach, and breast cancers (TCGA).	('Missense mutation A548V', 'Var', (0, 23))	('identified', 'Reg', (48, 58))	('breast cancers', 'Disease', (113, 127))	('breast cancers', 'Disease', 'MESH:D001943', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('stomach', 'Disease', (100, 107))	('A548V', 'Var', (18, 23))	('patients', 'Species', '9606', (67, 75))	('uterine', 'Disease', (81, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cervical', 'Disease', (90, 98))	('A548V', 'Mutation', 'p.A548V', (18, 23))	('TRAF-C domain', 'Gene', (31, 44))	('breast cancers', 'Phenotype', 'HP:0003002', (113, 127))
775763	30294322	Although not cataloged in TCGA, TRAF5 mutations are detected in 5% (5/101) of human DLBCL.	('detected', 'Reg', (52, 60))	('mutations', 'Var', (38, 47))	('human', 'Species', '9606', (78, 83))	('TRAF5', 'Gene', (32, 37))	('DLBCL', 'Disease', (84, 89))
775766	30294322	Consistent with human evidence, B cells of TRAF5-/- mice show defects in CD40-induced proliferation and up-regulation of surface molecules and activation markers as well as CD40 plus IL-4-induced Ig production (Table 2).	('up-regulation', 'PosReg', (104, 117))	('activation', 'MPA', (143, 153))	('CD40', 'Var', (173, 177))	('human', 'Species', '9606', (16, 21))	('mice', 'Species', '10090', (52, 56))	('surface molecules', 'MPA', (121, 138))	('CD40-induced', 'Gene', (73, 85))	('IL-4', 'Gene', (183, 187))	('defects', 'NegReg', (62, 69))	('IL-4', 'Gene', '16189', (183, 187))
775769	30294322	TRAF5 deficiency reverses the CD40-LMP1-induced enlargement of the spleen and lymph nodes, decreases the serum levels of IL-6 and autoantibodies that are elevated by CD40-LMP1-tg expression, and also inhibits LMP1-mediated JNK activation in B lymphocytes (Table 2).	('JNK', 'Gene', (223, 226))	('enlargement of the spleen', 'Phenotype', 'HP:0001744', (48, 73))	('LMP1', 'Gene', '17494204', (35, 39))	('TRAF5', 'Gene', (0, 5))	('LMP1', 'Gene', (35, 39))	('enlargement of the spleen', 'Disease', (48, 73))	('LMP1', 'Gene', '17494204', (209, 213))	('deficiency', 'Var', (6, 16))	('JNK', 'Gene', '5599', (223, 226))	('inhibits', 'NegReg', (200, 208))	('enlargement of the spleen', 'Disease', 'MESH:D013163', (48, 73))	('LMP1', 'Gene', (171, 175))	('serum levels of IL-6', 'MPA', (105, 125))	('elevated', 'PosReg', (154, 162))	('LMP1', 'Gene', '17494204', (171, 175))	('LMP1', 'Gene', (209, 213))	('decreases', 'NegReg', (91, 100))	('reverses', 'NegReg', (17, 25))
775771	30294322	Additionally, available in vivo evidence indicates the importance of TRAF5 in the survival, proliferation and differentiation of different T cell subsets as detailed in Table 2, suggesting that TRAF5 malfunction may contribute to T cell malignancies.	('malfunction', 'Var', (200, 211))	('T cell malignancies', 'Phenotype', 'HP:0005517', (230, 249))	('T cell malignancies', 'Disease', 'MESH:D018273', (230, 249))	('T cell malignancies', 'Disease', (230, 249))	('contribute', 'Reg', (216, 226))	('TRAF5', 'Gene', (194, 199))
775772	30294322	However, the evidence of TRAF5 alterations in human T cell lymphomas/leukemias is still lacking.	('leukemias', 'Disease', (69, 78))	('alterations', 'Var', (31, 42))	('lymphomas', 'Phenotype', 'HP:0002665', (59, 68))	('T cell lymphomas', 'Disease', 'MESH:D016399', (52, 68))	('leukemia', 'Phenotype', 'HP:0001909', (69, 77))	('T cell lymphomas', 'Disease', (52, 68))	('leukemias', 'Disease', 'MESH:D007938', (69, 78))	('human', 'Species', '9606', (46, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (52, 67))	('TRAF5', 'Gene', (25, 30))	('cell lymphoma', 'Phenotype', 'HP:0012191', (54, 67))	('T cell lymphomas', 'Phenotype', 'HP:0012190', (52, 68))	('leukemias', 'Phenotype', 'HP:0001909', (69, 78))
775776	30294322	The frequency of genetic alterations of TRAF6 is generally <7% in human cancers (Figure 1A) based on the TCGA and COSMIC datasets of sample size n > 120.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('TRAF6', 'Gene', (40, 45))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
775777	30294322	The eight human cancers with relatively higher genetic alterations of TRAF6 are breast cancer (6.9%), uterine cancer (4.5%) (TCGA, PanCancer Atlas), stomach cancer (4.1%), HNSCC (3.6%), lung cancer (3.4%), bladder cancer (3.1%), sarcoma (3%) (TCGA, Provisional), and ovarian cancer (2.8%) (TCGA, Provisional).	('human', 'Species', '9606', (10, 15))	('TRAF6', 'Gene', (70, 75))	('higher', 'PosReg', (40, 46))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('ovarian cancer', 'Disease', (267, 281))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('sarcoma', 'Disease', (229, 236))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (267, 281))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancer', 'Disease', (191, 197))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', (214, 220))	('stomach cancer', 'Disease', 'MESH:D013274', (149, 163))	('stomach cancer', 'Phenotype', 'HP:0012126', (149, 163))	('cancer', 'Disease', (16, 22))	('uterine cancer', 'Phenotype', 'HP:0010784', (102, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('bladder cancer', 'Disease', 'MESH:D001749', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('bladder cancer', 'Disease', (206, 220))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (157, 163))	('genetic alterations', 'Var', (47, 66))	('lung cancer', 'Disease', (186, 197))	('cancer', 'Disease', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('ovarian cancer', 'Disease', 'MESH:D010051', (267, 281))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('HNSCC', 'Disease', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('stomach cancer', 'Disease', (149, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
775778	30294322	Although not listed in TCGA, TRAF6 amplification is recognized as one of the most frequent genomic alterations in human lung cancer (9.2%, 24/261) and OSCC (10%, 2/20).	('amplification', 'Var', (35, 48))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TRAF6', 'Gene', (29, 34))	('human', 'Species', '9606', (114, 119))	('OSCC', 'Disease', (151, 155))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))
775780	30294322	TRAF6 overexpression is also identified as a prognostic factor for breast and esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('overexpression', 'Var', (6, 20))	('breast and esophageal cancers', 'Disease', 'MESH:D001943', (67, 96))	('TRAF6', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
775781	30294322	Deep deletion of TRAF6 is less common but also detected in several different types of human cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('detected', 'Reg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Deep deletion', 'Var', (0, 13))	('TRAF6', 'Gene', (17, 22))
775782	30294322	Truncation and fusion of TRAF6 are rare in human cancers.	('fusion', 'Var', (15, 21))	('TRAF6', 'Gene', (25, 30))	('Truncation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('human', 'Species', '9606', (43, 48))
775783	30294322	There are 178 different mutations of TRAF6 detected in human cancers, comprising 85% (152/178) mutations that alter the protein sequence of TRAF6 and 15% (26/178) coding silent mutations (Table 1).	('protein sequence', 'MPA', (120, 136))	('human', 'Species', '9606', (55, 60))	('TRAF6', 'Gene', (37, 42))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TRAF6', 'Gene', (140, 145))
775784	30294322	Only 27% (41/152) of the coding-altering mutations of TRAF6 are recurrently detected in at least two cancer patients.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('TRAF6', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (108, 116))	('coding-altering', 'Reg', (25, 40))
775785	30294322	Mutations of only two specific amino acids, R335 and P398, are detected in more than three patients (Figure 3).	('P398', 'Var', (53, 57))	('patients', 'Species', '9606', (91, 99))	('R335', 'Var', (44, 48))
775786	30294322	A truncation (R335*) and missense mutation (R335Q) at R335 within the coiled-coil domain of TRAF6 are detected in five patients with colon and uterine cancers (TCGA).	('uterine cancers', 'Phenotype', 'HP:0010784', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('R335*', 'SUBSTITUTION', 'None', (14, 19))	('patients', 'Species', '9606', (119, 127))	('TRAF6', 'Gene', (92, 97))	('colon and uterine cancers', 'Disease', 'MESH:D015179', (133, 158))	('detected', 'Reg', (102, 110))	('R335Q', 'Mutation', 'p.R335Q', (44, 49))	('uterine cancer', 'Phenotype', 'HP:0010784', (143, 157))	('R335Q', 'Var', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('R335*', 'Var', (14, 19))
775788	30294322	Functional significance of these TRAF6 recurrent mutations in cancer pathogenesis remains to be elucidated.	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TRAF6', 'Gene', (33, 38))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
775790	30294322	However, available in vivo evidence supports potential contributions of TRAF6 dysregulation in tumorigenesis.	('dysregulation', 'Var', (78, 91))	('TRAF6', 'Gene', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
775791	30294322	Consistent with the genetic alterations (mainly amplification and mutation) and frequent overexpression of TRAF6 detected in human epithelial cancers such as breast cancer and uterine cancer (Figure 1A), deletion of TRAF6 in mice results in loss of NF-kappaB activity in epithelia and vasculature during mouse development (Table 2).	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('uterine cancer', 'Phenotype', 'HP:0010784', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('breast cancer', 'Disease', (158, 171))	('NF-kappaB', 'Protein', (249, 258))	('mice', 'Species', '10090', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('TRAF6', 'Gene', (216, 221))	('cancer', 'Disease', (142, 148))	('loss', 'NegReg', (241, 245))	('cancers', 'Disease', (142, 149))	('deletion', 'Var', (204, 212))	('activity', 'MPA', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('human', 'Species', '9606', (125, 130))	('cancer', 'Disease', (165, 171))	('mouse', 'Species', '10090', (304, 309))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
775793	30294322	In line with the in vivo data, knockdown of TRAF6 or inhibition of TRAF6 E3 ligase activity suppresses the survival, proliferation, migration, and metastasis of many human epithelial cancers, including breast, lung, liver, and colon cancers as well as HNSCC.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('colon cancers', 'Disease', 'MESH:D015179', (227, 240))	('colon cancers', 'Disease', (227, 240))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', (183, 190))	('inhibition', 'NegReg', (53, 63))	('proliferation', 'CPA', (117, 130))	('human', 'Species', '9606', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('TRAF6', 'Gene', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('breast', 'Disease', (202, 208))	('liver', 'Disease', (216, 221))	('migration', 'CPA', (132, 141))	('survival', 'CPA', (107, 115))	('HNSCC', 'Disease', (252, 257))	('metastasis', 'CPA', (147, 157))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('activity', 'MPA', (83, 91))	('suppresses', 'NegReg', (92, 102))	('lung', 'Disease', (210, 214))	('colon cancers', 'Phenotype', 'HP:0003003', (227, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('colon cancer', 'Phenotype', 'HP:0003003', (227, 239))	('cancers', 'Disease', (233, 240))	('knockdown', 'Var', (31, 40))
775795	30294322	Hematopoietic-specific deletion of TRAF6 in mice leads to decreased tonic IKKbeta-NF-kappaB activation, impaired hematopoietic stem cell (HSC) self-renewal and loss of hematopoietic stem/progenitor cells (HSPCs) in the bone marrow (BM) (Table 2).	('impaired hematopoietic', 'Disease', (104, 126))	('tonic', 'MPA', (68, 73))	('deletion', 'Var', (23, 31))	('loss', 'NegReg', (160, 164))	('TRAF6', 'Gene', (35, 40))	('IKKbeta-NF-kappaB', 'Protein', (74, 91))	('decreased', 'NegReg', (58, 67))	('impaired hematopoietic', 'Disease', 'MESH:D019337', (104, 126))	('activation', 'MPA', (92, 102))	('mice', 'Species', '10090', (44, 48))
775797	30294322	In the lymphoid lineage, TRAF6 mutations have been detected in 2.1% human DLBCL (TCGA) and 2.4% human cutaneous T cell lymphoma (CTCL).	('detected', 'Reg', (51, 59))	('mutations', 'Var', (31, 40))	('human', 'Species', '9606', (68, 73))	('TRAF6', 'Gene', (25, 30))	('human', 'Species', '9606', (96, 101))	('lymphoma', 'Phenotype', 'HP:0002665', (119, 127))	('cutaneous T cell lymphoma', 'Disease', 'MESH:D016410', (102, 127))	('cutaneous T cell lymphoma', 'Disease', (102, 127))	('cell lymphoma', 'Phenotype', 'HP:0012191', (114, 127))	('cutaneous T cell lymphoma', 'Phenotype', 'HP:0012192', (102, 127))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (112, 127))	('CTCL', 'Phenotype', 'HP:0012192', (129, 133))
775802	30294322	T-TRAF6-/- mice also exhibit increased Th17 differentiation due to enhanced sensitivity of CD4 T cells to TGFbeta signaling, but have defects in generating CD8 memory T cells caused by defective AMPK activation in activated CD8 T cells.	('memory T', 'Disease', (160, 168))	('T-TRAF6-/-', 'Var', (0, 10))	('Th17 differentiation', 'CPA', (39, 59))	('memory T', 'Disease', 'MESH:D008569', (160, 168))	('defects', 'NegReg', (134, 141))	('AMPK activation', 'MPA', (195, 210))	('defective', 'NegReg', (185, 194))	('increased', 'PosReg', (29, 38))	('sensitivity', 'MPA', (76, 87))	('mice', 'Species', '10090', (11, 15))	('CD8', 'Gene', (224, 227))	('CD8', 'Gene', '925', (224, 227))	('CD8', 'Gene', '925', (156, 159))	('CD4', 'Gene', (91, 94))	('CD4', 'Gene', '920', (91, 94))	('CD8', 'Gene', (156, 159))	('enhanced', 'PosReg', (67, 75))
775805	30294322	Furthermore, inhibition of the IRAK1/4-TRAF6 axis sensitizes human T cell ALL (T-ALL) to chemotherapies.	('IRAK1', 'Gene', '3654', (31, 36))	('IRAK1', 'Gene', (31, 36))	('inhibition', 'Var', (13, 23))	('sensitizes', 'Reg', (50, 60))	('T cell ALL (T-ALL)', 'Disease', 'MESH:D054218', (67, 85))	('human', 'Species', '9606', (61, 66))
775809	30294322	In skeletal muscle, TRAF6 deficiency prevents muscle loss and cancer cachexia in response to transplanted tumor growth, improves regeneration of myofibers upon injury and reduces skeletal muscle atrophy upon starvation through regulating NF-kappaB activation/ubiquitin-proteasome/autophagy-lysosomal systems, Akt/FoxO3a/AMPK activation and Notch signaling, respectively.	('Akt', 'Gene', (309, 312))	('muscle loss', 'Disease', 'MESH:D009133', (46, 57))	('regeneration of myofibers', 'CPA', (129, 154))	('muscle atrophy', 'Disease', 'MESH:D009133', (188, 202))	('skeletal muscle atrophy', 'Phenotype', 'HP:0003202', (179, 202))	('injury', 'Disease', 'MESH:D014947', (160, 166))	('Akt', 'Gene', '207', (309, 312))	('TRAF6', 'Gene', (20, 25))	('tumor', 'Disease', (106, 111))	('FoxO3a', 'Gene', (313, 319))	('muscle loss', 'Disease', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('regulating', 'Reg', (227, 237))	('FoxO3a', 'Gene', '2309', (313, 319))	('muscle atrophy', 'Disease', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cachexia', 'Phenotype', 'HP:0004326', (69, 77))	('cancer cachexia', 'Disease', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('deficiency', 'Var', (26, 36))	('cancer cachexia', 'Disease', 'MESH:D002100', (62, 77))	('NF-kappaB', 'Protein', (238, 247))	('improves', 'PosReg', (120, 128))	('injury', 'Disease', (160, 166))	('muscle loss', 'Phenotype', 'HP:0003202', (46, 57))	('reduces', 'NegReg', (171, 178))
775810	30294322	In line with the mouse data, genetic alterations of TRAF6, including amplification, mutation and deletion, are detected in 1% of human glioblastoma and 3% of human sarcoma (TCGA).	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('TRAF6', 'Gene', (52, 57))	('detected', 'Reg', (111, 119))	('mouse', 'Species', '10090', (17, 22))	('human', 'Species', '9606', (158, 163))	('amplification', 'MPA', (69, 82))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('human', 'Species', '9606', (129, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('glioblastoma', 'Disease', (135, 147))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('deletion', 'Var', (97, 105))	('mutation', 'Var', (84, 92))
775814	30294322	Interestingly, the importance of TRAF6-dependent oncogenic pathways in human cancers is also underscored by the findings that TRAF6 mRNA is the direct target of tumor suppressive mi-RNAs, including miR-146a, and miR-141-3p.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('miR-146a', 'Var', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mi-RNAs', 'Var', (179, 186))	('miR-141-3p', 'Var', (212, 222))	('TRAF6', 'Gene', (126, 131))	('tumor', 'Disease', (161, 166))	('human', 'Species', '9606', (71, 76))
775821	30294322	The frequency of genetic alterations of TRAF7 is generally <7% in human cancers (Figure 1A) according to the TCGA and COSMIC datasets of sample size n > 150.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TRAF7', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
775822	30294322	The eight human cancers with relatively higher genetic alterations of TRAF7 are breast cancer (6%), prostate cancer (5.1%), stomach cancer (4.8%) (8), sarcoma (3.8%) (TCGA, Provisional), esophageal cancer (3.3%) (TCGA, PanCancer Atlas), uterine cancer (3.2%) (TCGA, PanCancer Atlas), melanoma (3.1%) (TCGA, PanCancer Atlas), and liver cancer (2.4%) (TCGA, PanCancer Atlas).	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (335, 341))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('stomach cancer', 'Disease', (124, 138))	('Cancer', 'Phenotype', 'HP:0002664', (359, 365))	('breast cancer', 'Disease', (80, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('liver cancer', 'Phenotype', 'HP:0002896', (329, 341))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('TRAF7', 'Gene', (70, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('liver cancer', 'Disease', (329, 341))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', (198, 204))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('cancer', 'Disease', (16, 22))	('melanoma', 'Disease', (284, 292))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('esophageal cancer', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (310, 316))	('uterine cancer', 'Phenotype', 'HP:0010784', (237, 251))	('cancer', 'Disease', (87, 93))	('stomach cancer', 'Disease', 'MESH:D013274', (124, 138))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('stomach cancer', 'Phenotype', 'HP:0012126', (124, 138))	('cancer', 'Disease', (245, 251))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('genetic alterations', 'Var', (47, 66))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Cancer', 'Phenotype', 'HP:0002664', (269, 275))	('liver cancer', 'Disease', 'MESH:D006528', (329, 341))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (132, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('melanoma', 'Disease', 'MESH:D008545', (284, 292))	('prostate cancer', 'Disease', (100, 115))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('sarcoma', 'Disease', (151, 158))
775823	30294322	However, it should be noted that although not yet cataloged in TCGA, the rate of TRAF7 mutation is overwhelmingly high in patients with adenomatoid tumors of the male and female genital tracts (100%, 31/31), secretory meningiomas (97%, 29/30), intraneural perineuriomas (62.5%, 10/16), and meningiomas 23% (182/775) (Figure 1B).	('meningiomas', 'Disease', 'MESH:D008579', (290, 301))	('meningiomas', 'Disease', 'MESH:D008579', (218, 229))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('meningiomas', 'Phenotype', 'HP:0002858', (290, 301))	('meningioma', 'Phenotype', 'HP:0002858', (218, 228))	('intraneural perineuriomas', 'Disease', (244, 269))	('meningiomas', 'Phenotype', 'HP:0002858', (218, 229))	('meningioma', 'Phenotype', 'HP:0002858', (290, 300))	('TRAF7', 'Gene', (81, 86))	('high', 'Reg', (114, 118))	('meningiomas', 'Disease', (290, 301))	('patients', 'Species', '9606', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('meningiomas', 'Disease', (218, 229))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (136, 154))	('mutation', 'Var', (87, 95))	('adenomatoid tumors', 'Disease', (136, 154))	('intraneural perineuriomas', 'Disease', 'MESH:D018317', (244, 269))
775824	30294322	In particular, high frequencies (15-26%) of TRAF7 mutations has been reproducibly detected in multiple studies, and knowledge of TRAF7 mutations has contributed significantly to improving the diagnosis, classification, prognosis, and treatment of patients with meningiomas.	('meningiomas', 'Disease', (261, 272))	('TRAF7', 'Gene', (129, 134))	('mutations', 'Var', (50, 59))	('meningiomas', 'Disease', 'MESH:D008579', (261, 272))	('meningiomas', 'Phenotype', 'HP:0002858', (261, 272))	('TRAF7', 'Gene', (44, 49))	('improving', 'PosReg', (178, 187))	('patients', 'Species', '9606', (247, 255))	('meningioma', 'Phenotype', 'HP:0002858', (261, 271))
775825	30294322	Additionally, deletion of TRAF7 is detected in 67% (18/27) of malignant mesothelioma patients' malignant cells in pleural fluids.	('detected', 'Reg', (35, 43))	('TRAF7', 'Gene', (26, 31))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (62, 84))	('patients', 'Species', '9606', (85, 93))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (62, 84))	('deletion', 'Var', (14, 22))	('malignant mesothelioma', 'Disease', (62, 84))
775826	30294322	Truncation and fusion of TRAF7 are rarely detected in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('Truncation', 'Var', (0, 10))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))	('TRAF7', 'Gene', (25, 30))
775828	30294322	Over half (53%, 174/326) of the TRAF7 coding-altering mutations are recurrently detected in at least two cancer patients.	('TRAF7', 'Gene', (32, 37))	('cancer', 'Disease', (105, 111))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('coding-altering', 'Reg', (38, 53))
775829	30294322	Of particular interest, missense mutations of six specific amino acids located within the C-terminal WD40 repeats, N520, H521, G536, S561, K615, and R641, are identified as mutation hotspots of TRAF7 detected in more than 15 cancer patients (Figure 3).	('H521', 'Var', (121, 125))	('TRAF7', 'Gene', (194, 199))	('R641', 'Var', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('missense', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('G536', 'Var', (127, 131))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Disease', (225, 231))	('N520', 'Var', (115, 119))	('S561', 'Var', (133, 137))	('K615', 'Var', (139, 143))
775830	30294322	N520 mutations (N520S, H, Y, or T) are found in 31 patients with meningioma, mesothelioma, sarcoma and colon cancer.	('meningioma', 'Disease', 'MESH:D008579', (65, 75))	('mesothelioma', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('N520', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('found', 'Reg', (39, 44))	('sarcoma and colon cancer', 'Disease', 'MESH:D015179', (91, 115))	('N520S', 'Mutation', 'p.N520S', (16, 21))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('meningioma', 'Phenotype', 'HP:0002858', (65, 75))	('patients', 'Species', '9606', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('meningioma', 'Disease', (65, 75))	('N520S', 'Var', (16, 21))
775831	30294322	Mutations of the next amino acid H521 (H521R or N) are identified in 15 patients with adenomatoid tumor, perineurioma, and meningioma.	('H521', 'Gene', (33, 37))	('perineurioma', 'Disease', 'MESH:D018317', (105, 117))	('meningioma', 'Disease', (123, 133))	('H521R', 'Mutation', 'p.H521R', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Mutations', 'Var', (0, 9))	('meningioma', 'Disease', 'MESH:D008579', (123, 133))	('meningioma', 'Phenotype', 'HP:0002858', (123, 133))	('adenomatoid tumor', 'Disease', 'MESH:D018254', (86, 103))	('adenomatoid tumor', 'Disease', (86, 103))	('perineurioma', 'Disease', (105, 117))	('patients', 'Species', '9606', (72, 80))
775832	30294322	G536 mutations (G536S or V) are detected in 16 patients with meningioma, pancreatic cancer, mesothelioma and stomach cancer.	('meningioma', 'Disease', (61, 71))	('pancreatic cancer', 'Disease', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('G536', 'Var', (0, 4))	('stomach cancer', 'Phenotype', 'HP:0012126', (109, 123))	('patients', 'Species', '9606', (47, 55))	('meningioma', 'Phenotype', 'HP:0002858', (61, 71))	('detected', 'Reg', (32, 40))	('meningioma', 'Disease', 'MESH:D008579', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('G536S', 'Mutation', 'p.G536S', (16, 21))	('mesothelioma and stomach cancer', 'Disease', 'MESH:D013274', (92, 123))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
775834	30294322	K615E mutations are detected in 15 patients with meningioma and OSCC.	('detected', 'Reg', (20, 28))	('meningioma', 'Disease', 'MESH:D008579', (49, 59))	('K615E', 'Mutation', 'p.K615E', (0, 5))	('OSCC', 'Disease', (64, 68))	('meningioma', 'Disease', (49, 59))	('patients', 'Species', '9606', (35, 43))	('meningioma', 'Phenotype', 'HP:0002858', (49, 59))	('K615E', 'Var', (0, 5))
775835	30294322	R641 mutations (R641H, C, P, or L) are detected in 24 patients with uterine, bile duct, colon, stomach and lung cancers and meningioma (TCGA, PanCancer Atlas).	('meningioma', 'Disease', 'MESH:D008579', (124, 134))	('meningioma', 'Phenotype', 'HP:0002858', (124, 134))	('patients', 'Species', '9606', (54, 62))	('lung cancers', 'Disease', (107, 119))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancers', 'Phenotype', 'HP:0100526', (107, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('uterine', 'Disease', (68, 75))	('R641', 'Var', (0, 4))	('colon', 'Disease', (88, 93))	('bile duct', 'Disease', (77, 86))	('R641H', 'Mutation', 'p.R641H', (16, 21))	('stomach', 'Disease', (95, 102))	('R641H', 'Var', (16, 21))	('detected', 'Reg', (39, 47))	('meningioma', 'Disease', (124, 134))	('lung cancers', 'Disease', 'MESH:D008175', (107, 119))
775836	30294322	Although the functional significance of most TRAF7 mutations is currently unclear, the exceptionally high recurrence and clustering of missense mutations implicate TRAF7 malfunction as a critical pathogenic event in relevant human cancers.	('TRAF7', 'Gene', (45, 50))	('mutations', 'Var', (51, 60))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Disease', (231, 238))	('human', 'Species', '9606', (225, 230))	('TRAF7', 'Gene', (164, 169))	('missense mutations', 'Var', (135, 153))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
775840	30294322	recently reported that de novo missense mutations in TRAF7 cause developmental abnormalities and other clinical symptoms in seven unrelated patients, including developmental delay (5/5), congenital heart defects (6/7), limb and digital anomalies (7/7), and dysmorphic facial features (7/7).	('developmental abnormalities', 'Disease', 'MESH:D006130', (65, 92))	('developmental delay', 'Phenotype', 'HP:0001263', (160, 179))	('developmental delay', 'Disease', (160, 179))	('dysmorphic facial features', 'Phenotype', 'HP:0001999', (257, 283))	('TRAF7', 'Gene', (53, 58))	('congenital heart defects', 'Disease', 'MESH:D006330', (187, 211))	('dysmorphic facial', 'Disease', 'None', (257, 274))	('cause', 'Reg', (59, 64))	('heart defects', 'Phenotype', 'HP:0030680', (198, 211))	('missense mutations', 'Var', (31, 49))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (65, 92))	('patients', 'Species', '9606', (140, 148))	('developmental abnormalities', 'Disease', (65, 92))	('congenital heart defects', 'Disease', (187, 211))	('dysmorphic facial', 'Disease', (257, 274))	('congenital heart defects', 'Phenotype', 'HP:0001627', (187, 211))	('digital anomalies', 'Phenotype', 'HP:0011297', (228, 245))
775841	30294322	TRAF7 mutations identified in this study include a recurrent R655Q mutation found in four patients, and another 3 single mutations each identified in one patient, including K346E, R371G, and T601A.	('R371G', 'Var', (180, 185))	('R655Q', 'Mutation', 'p.R655Q', (61, 66))	('patient', 'Species', '9606', (154, 161))	('R371G', 'Mutation', 'p.R371G', (180, 185))	('T601A', 'Var', (191, 196))	('K346E', 'Mutation', 'p.K346E', (173, 178))	('T601A', 'Mutation', 'c.601T>A', (191, 196))	('K346E', 'Var', (173, 178))	('TRAF7', 'Gene', (0, 5))	('patient', 'Species', '9606', (90, 97))	('patients', 'Species', '9606', (90, 98))	('R655Q', 'Var', (61, 66))
775842	30294322	Interestingly, R371 recurrent mutations are also detected in human cancers (Figure 3).	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('detected', 'Reg', (49, 57))	('cancers', 'Disease', (67, 74))	('R371 recurrent', 'Var', (15, 29))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('human', 'Species', '9606', (61, 66))
775843	30294322	K346 is a ubiquitination site of TRAF7.	('K346', 'Chemical', '-', (0, 4))	('TRAF7', 'Gene', (33, 38))	('K346', 'Var', (0, 4))
775844	30294322	Both K346 and R371 are located in the coiled-coil domain of TRAF7 that is important for TRAF7 homodimerization.	('K346', 'Chemical', '-', (5, 9))	('R371', 'Var', (14, 18))	('K346', 'Var', (5, 9))	('TRAF7', 'Gene', (60, 65))
775845	30294322	The recurrent R655Q mutation has also been previously identified as a de novo event in an autism patient.	('autism', 'Phenotype', 'HP:0000717', (90, 96))	('autism', 'Disease', 'MESH:D001321', (90, 96))	('R655Q', 'Var', (14, 19))	('autism', 'Disease', (90, 96))	('R655Q', 'Mutation', 'p.R655Q', (14, 19))	('patient', 'Species', '9606', (97, 104))
775846	30294322	Both T601 and R665 are located in the C-terminal WD40 repeats of TRAF7, which contain most mutation hotspots of TRAF7 detected in human cancers (Figure 3) and are known to mediate the interaction of TRAF7 with MEKK3 or c-Myb.	('c-Myb', 'Gene', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('MEKK3', 'Protein', (210, 215))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('TRAF7', 'Gene', (112, 117))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('T601', 'Var', (5, 9))	('TRAF7', 'Gene', (65, 70))	('interaction', 'Interaction', (184, 195))	('R665', 'Var', (14, 18))	('c-Myb', 'Gene', '4602', (219, 224))	('human', 'Species', '9606', (130, 135))
775847	30294322	further revealed that transfection of the R665Q, T601A, or R371G mutants of TRAF7 into HEK293T cells results in significantly reduced levels of ERK1/2 phosphorylation, both basal and in response to TNFalpha signaling.	('TRAF7', 'Gene', (76, 81))	('HEK293T', 'CellLine', 'CVCL:0063', (87, 94))	('ERK1/2', 'Gene', (144, 150))	('ERK1/2', 'Gene', '5595;5594', (144, 150))	('T601A', 'Mutation', 'c.601T>A', (49, 54))	('R665Q', 'Var', (42, 47))	('phosphorylation', 'MPA', (151, 166))	('R665Q', 'Mutation', 'p.R665Q', (42, 47))	('R371G', 'Var', (59, 64))	('T601A', 'Var', (49, 54))	('R371G', 'Mutation', 'p.R371G', (59, 64))	('reduced', 'NegReg', (126, 133))
775848	30294322	Consistent with this biochemical evidence, conditional ERK2-/- mice show a phenotype mirroring that observed in the seven patients with TRAF7 mutations, including craniofacial abnormalities, cardiovascular malformations and limb defects.	('mutations', 'Var', (142, 151))	('mice', 'Species', '10090', (63, 67))	('ERK2', 'Gene', '26413', (55, 59))	('TRAF7', 'Gene', (136, 141))	('patients', 'Species', '9606', (122, 130))	('ERK2', 'Gene', (55, 59))	('cardiovascular malformations', 'Phenotype', 'HP:0030680', (191, 219))	('craniofacial abnormalities', 'Disease', (163, 189))	('craniofacial abnormalities', 'Disease', 'MESH:D019465', (163, 189))	('cardiovascular malformations and limb defects', 'Disease', 'MESH:D018376', (191, 236))
775849	30294322	These highly interesting findings warrant further investigation of the in vivo functions of TRAF7 mutations in cancer pathogenesis using animal models.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TRAF7', 'Gene', (92, 97))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
775850	30294322	In addition to the above TRAF7-ERK1/2 pathway revealed by studying TRAF7 mutants of patients with developmental defects, the following TRAF7 signaling pathways have been proposed based on in vitro studies.	('ERK1/2', 'Gene', '5595;5594', (31, 37))	('ERK1/2', 'Gene', (31, 37))	('patients', 'Species', '9606', (84, 92))	('mutants', 'Var', (73, 80))	('TRAF7', 'Gene', (67, 72))	('developmental defects', 'Disease', 'MESH:D009436', (98, 119))	('developmental defects', 'Disease', (98, 119))
775851	30294322	(1) Transfection of tumor-derived TRAF7 mutants (H521R, Y538S, or S561R) but not WT TRAF7 in 293T cells causes increased phosphorylation of RelA and expression of the NF-kappaB target gene L1CAM, which is also elevated in adenomatoid tumors.	('tumor', 'Disease', (234, 239))	('293T', 'CellLine', 'CVCL:0063', (93, 97))	('RelA', 'Gene', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('H521R', 'Mutation', 'p.H521R', (49, 54))	('L1CAM', 'Gene', '3897', (189, 194))	('H521R', 'Var', (49, 54))	('RelA', 'Gene', '5970', (140, 144))	('Y538S', 'Mutation', 'p.Y538S', (56, 61))	('S561R', 'Mutation', 'p.S561R', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (222, 240))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('expression', 'MPA', (149, 159))	('L1CAM', 'Gene', (189, 194))	('Y538S', 'Var', (56, 61))	('TRAF7', 'Gene', (34, 39))	('increased', 'PosReg', (111, 120))	('phosphorylation', 'MPA', (121, 136))	('adenomatoid tumors', 'Disease', (222, 240))	('tumor', 'Disease', (20, 25))
775852	30294322	(2) Overexpression of TRAF7 or TNFalpha induces caspase-dependent apoptosis in HEK293 and HeLa cells via the TRAF7-MEKK3-NF-kappaB/p38/JNK-AP1/CHOP pathway, in which TRAF7 interacts with MEKK3 and potentiates the kinase activity of MEKK3.	('induces', 'Reg', (40, 47))	('CHOP', 'Gene', '1649', (143, 147))	('TNFalpha', 'Gene', (31, 39))	('HeLa', 'CellLine', 'CVCL:0030', (90, 94))	('MEKK3', 'Protein', (187, 192))	('JNK', 'Gene', (135, 138))	('TRAF7', 'Var', (22, 27))	('potentiates', 'PosReg', (197, 208))	('p38', 'Gene', (131, 134))	('CHOP', 'Gene', (143, 147))	('JNK', 'Gene', '5599', (135, 138))	('HEK293', 'CellLine', 'CVCL:0045', (79, 85))	('p38', 'Gene', '5594', (131, 134))	('AP1', 'Gene', (139, 142))	('MEKK3', 'Enzyme', (232, 237))	('AP1', 'Gene', '2353', (139, 142))	('caspase-dependent apoptosis', 'CPA', (48, 75))	('kinase activity', 'MPA', (213, 228))	('interacts', 'Interaction', (172, 181))
775861	30294322	TRAF7 mutations or downregulated protein levels may lead to aberrant NF-kappaB activation or altered signaling of ERK1/2, p38, JNK, c-FLIP, c-Myb, or p53 to drive tumorigenesis.	('NF-kappaB', 'Protein', (69, 78))	('c-FLIP', 'Gene', '8837', (132, 138))	('ERK1/2', 'Gene', (114, 120))	('p53', 'Gene', '7157', (150, 153))	('ERK1/2', 'Gene', '5595;5594', (114, 120))	('tumor', 'Disease', (163, 168))	('c-Myb', 'Gene', '4602', (140, 145))	('c-Myb', 'Gene', (140, 145))	('JNK', 'Gene', (127, 130))	('JNK', 'Gene', '5599', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('p53', 'Gene', (150, 153))	('activation', 'PosReg', (79, 89))	('p38', 'Gene', (122, 125))	('lead', 'Reg', (52, 56))	('mutations', 'Var', (6, 15))	('drive', 'PosReg', (157, 162))	('c-FLIP', 'Gene', (132, 138))	('altered', 'Reg', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('signaling', 'MPA', (101, 110))	('p38', 'Gene', '5594', (122, 125))	('TRAF7', 'Gene', (0, 5))	('downregulated', 'NegReg', (19, 32))
775862	30294322	Further studies are required to clarify the roles and mechanisms of TRAF7 alterations in cancer pathogenesis.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('TRAF7', 'Gene', (68, 73))	('alterations', 'Var', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
775864	30294322	Although the frequency of the genetic alterations of each TRAF is generally low (usually <5%), their combined rate is substantially increased to 10-35% in many types of human cancers (Figure 4) (TCGA).	('increased', 'PosReg', (132, 141))	('genetic alterations', 'Var', (30, 49))	('human', 'Species', '9606', (169, 174))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
775865	30294322	For example, the combined frequency of gene amplification of all seven TRAFs is 35% (709/2015) in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('gene amplification', 'Var', (39, 57))
775866	30294322	The combined frequency of genetic alterations of all seven TRAFs is 23% (71/311) in ovarian cancer (TCGA, Provisional), 19% (77/408) in bladder cancer, 19% (45/240) in uterine cancer, 17% (81/469) in lung cancer (TCGA, PanCancer Atlas), 15% (41/265) in oesophageal cancer, 14% (48/353) in liver cancer (TCGA, PanCancer Atlas), 13% (35/279) in HNSCC, 13% (36/278) in cervical cancer (TCGA, PanCancer Atlas), 13% (58/438) in melanoma (TCGA, PanCancer Atlas), 12% (46/389) in colon cancer (TCGA, PanCancer Atlas), and 10% (106/1013) in prostate cancer.	('ovarian cancer', 'Disease', (84, 98))	('Cancer', 'Phenotype', 'HP:0002664', (496, 502))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (295, 301))	('cancer', 'Disease', (479, 485))	('colon cancer', 'Disease', 'MESH:D015179', (473, 485))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('cancer', 'Disease', (542, 548))	('cancer', 'Disease', (144, 150))	('bladder cancer', 'Disease', (136, 150))	('liver cancer', 'Disease', 'MESH:D006528', (289, 301))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('HNSCC', 'Disease', (343, 348))	('alterations', 'Var', (34, 45))	('oesophageal cancer', 'Disease', (253, 271))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('uterine cancer', 'Phenotype', 'HP:0010784', (168, 182))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('Cancer', 'Phenotype', 'HP:0002664', (392, 398))	('Cancer', 'Phenotype', 'HP:0002664', (312, 318))	('prostate cancer', 'Disease', 'MESH:D011471', (533, 548))	('melanoma', 'Phenotype', 'HP:0002861', (423, 431))	('liver cancer', 'Phenotype', 'HP:0002896', (289, 301))	('colon cancer', 'Disease', (473, 485))	('prostate cancer', 'Phenotype', 'HP:0012125', (533, 548))	('liver cancer', 'Disease', (289, 301))	('prostate cancer', 'Disease', (533, 548))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('oesophageal cancer', 'Disease', 'MESH:D009369', (253, 271))	('cancer', 'Disease', (265, 271))	('melanoma', 'Disease', 'MESH:D008545', (423, 431))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (479, 485))	('cancer', 'Disease', 'MESH:D009369', (542, 548))	('lung cancer', 'Disease', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('Cancer', 'Phenotype', 'HP:0002664', (442, 448))	('colon cancer', 'Phenotype', 'HP:0003003', (473, 485))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', (375, 381))	('melanoma', 'Disease', (423, 431))
775869	30294322	Given the often mutually exclusive genetic alterations of different TRAFs in the same cancer, it is very likely that all seven TRAFs may have non-overlapping and distinct contributions to different aspects or at different stages of the initiation, progression and metastasis of the same cancer.	('genetic alterations', 'Var', (35, 54))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('alterations', 'Var', (43, 54))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
775883	30294322	In particular, consistent with the high frequency of TRAF3 deletions and mutations in HPV+ HNSCC, overexpression of TRAF3 inhibits the growth, migration and chemoresistance of HPV+ HNSCC by decreasing HPV E6 oncoprotein and increasing p53 and RB tumor suppressors.	('deletions', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('chemoresistance', 'CPA', (157, 172))	('RB tumor', 'Disease', (243, 251))	('growth', 'CPA', (135, 141))	('HPV', 'Species', '10566', (201, 204))	('HPV E6 oncoprotein', 'Protein', (201, 219))	('HPV', 'Species', '10566', (176, 179))	('p53', 'Gene', '7157', (235, 238))	('decreasing', 'NegReg', (190, 200))	('HPV', 'Species', '10566', (86, 89))	('HPV+ HNSCC', 'Gene', (86, 96))	('TRAF3', 'Gene', (53, 58))	('inhibits', 'NegReg', (122, 130))	('RB tumor', 'Disease', 'MESH:D012175', (243, 251))	('TRAF3', 'Gene', (116, 121))	('increasing', 'PosReg', (224, 234))	('p53', 'Gene', (235, 238))	('mutations', 'Var', (73, 82))
775887	30294322	Specific deletion of TRAF3 from myeloid cells leads to development of B lymphomas and liver cancer in mice.	('mice', 'Species', '10090', (102, 106))	('B lymphoma', 'Phenotype', 'HP:0012191', (70, 80))	('deletion', 'Var', (9, 17))	('B lymphomas', 'Phenotype', 'HP:0012191', (70, 81))	('liver cancer', 'Phenotype', 'HP:0002896', (86, 98))	('lymphomas', 'Phenotype', 'HP:0002665', (72, 81))	('TRAF3', 'Gene', (21, 26))	('B lymphomas and liver cancer', 'Disease', 'MESH:D006528', (70, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))
775888	30294322	Similarly, lymphocyte-specific TRAF3 transgenic mice develop autoimmunity, inflammation and cancers (such as squamous cell carcinomas of the tongue, salivary gland tumors, and hepatoma).	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (109, 133))	('salivary gland tumors', 'Disease', (149, 170))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (109, 133))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('hepatoma', 'Disease', 'MESH:D006528', (176, 184))	('squamous cell carcinomas of the tongue', 'Phenotype', 'HP:0030413', (109, 147))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('autoimmunity', 'Disease', (61, 73))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('develop', 'PosReg', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('squamous cell carcinomas', 'Disease', (109, 133))	('transgenic', 'Var', (37, 47))	('inflammation', 'Disease', (75, 87))	('transgenic mice', 'Species', '10090', (37, 52))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('salivary gland tumors', 'Disease', 'MESH:D008949', (149, 170))	('autoimmunity', 'Disease', 'MESH:D001327', (61, 73))	('TRAF3', 'Gene', (31, 36))	('autoimmunity', 'Phenotype', 'HP:0002960', (61, 73))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('hepatoma', 'Disease', (176, 184))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (149, 170))	('cancers', 'Disease', (92, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))
775895	30294322	In this article, we have analyzed the current evidence of genetic alterations of the TRAF family in human cancers.	('human', 'Species', '9606', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('genetic alterations', 'Var', (58, 77))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
775896	30294322	The results revealed that genetic alterations of all seven TRAF genes are present in various human cancers and that recurrent mutations of each TRAF gene have been detected in cancer patients.	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Disease', (99, 105))	('genetic alterations', 'Var', (26, 45))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (183, 191))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('TRAF genes', 'Gene', (59, 69))	('detected', 'Reg', (164, 172))	('present', 'Reg', (74, 81))
775897	30294322	In particular, loss-of-function genetic alterations of TRAF2 and TRAF3 are frequently detected in B cell malignancies, and the rates of missense mutations of TRAF7 are overwhelmingly high in adenomatoid tumors, secretory meningiomas and perineuriomas.	('TRAF2', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('missense mutations', 'Var', (136, 154))	('meningiomas and perineuriomas', 'Disease', 'MESH:D018317', (221, 250))	('meningioma', 'Phenotype', 'HP:0002858', (221, 231))	('B cell malignancies', 'Disease', 'MESH:D015448', (98, 117))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('genetic alterations', 'Var', (32, 51))	('B cell malignancies', 'Disease', (98, 117))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (191, 209))	('adenomatoid tumors', 'Disease', (191, 209))	('TRAF3', 'Gene', (65, 70))	('TRAF7', 'Gene', (158, 163))	('meningiomas', 'Phenotype', 'HP:0002858', (221, 232))	('loss-of-function', 'NegReg', (15, 31))
775898	30294322	Gain-of-function alterations (gene amplification and overexpression) are common for TRAF1, TRAF4, TRAF5, and TRAF6 in human cancers, and are also identified for TRAF2 in epithelial cancers.	('TRAF4', 'Gene', (91, 96))	('TRAF5', 'Gene', (98, 103))	('cancers', 'Disease', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('TRAF1', 'Gene', (84, 89))	('overexpression', 'PosReg', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Gain-of-function', 'PosReg', (0, 16))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('human', 'Species', '9606', (118, 123))	('TRAF6', 'Gene', (109, 114))	('alterations', 'Var', (17, 28))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
775899	30294322	Corroborating human evidence, direct causal roles of TRAF genetic alterations (except TRAF7) in tumorigenesis have been demonstrated in vivo with genetically engineered mouse models that have each TRAF gene deleted or overexpressed in specific cell types.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('human', 'Species', '9606', (14, 19))	('TRAF', 'Gene', (53, 57))	('tumor', 'Disease', (96, 101))	('mouse', 'Species', '10090', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('genetic alterations', 'Var', (58, 77))
775900	30294322	Importantly, however, the functional significance of most TRAF point mutations identified in human cancers remains to be assessed in future studies.	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('point mutations', 'Var', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TRAF', 'Gene', (58, 62))
775987	29245945	In addition, a patient's BMI was calculated and classified according to the Asian-specific BMI cutoff values as follows: underweight ( < 18.5 kg/m2); normal weight (18.5-22.9 kg/m2); overweight and obese (>= 23.0 kg/m2).	('patient', 'Species', '9606', (15, 22))	('overweight', 'Phenotype', 'HP:0025502', (183, 193))	('18.5-22.9 kg/m2', 'Var', (165, 180))	('obese', 'Disease', (198, 203))	(' < 18.5 kg/m2', 'Var', (134, 147))	('obese', 'Disease', 'MESH:D009765', (198, 203))
776005	28481876	Forced expression of MCM8 in RWPE1 cells, the immortalized but non-transformed prostate epithelial cell line, exhibited fast cell growth and transformation, while knocked down of MCM8 in PC3, DU145 and LNCaP cells induced cell growth arrest, and decreased tumor volumes and mortality of severe combined immunodeficiency mice xenografted with PC3 and DU145 cells.	('MCM8', 'Gene', (179, 183))	('growth arrest', 'Disease', (227, 240))	('transformation', 'CPA', (141, 155))	('immunodeficiency', 'Disease', (303, 319))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (287, 319))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (294, 319))	('immunodeficiency', 'Disease', 'MESH:D007153', (303, 319))	('decreased tumor', 'Disease', 'MESH:D009369', (246, 261))	('DU145', 'CellLine', 'CVCL:0105', (350, 355))	('mice', 'Species', '10090', (320, 324))	('DU145', 'CellLine', 'CVCL:0105', (192, 197))	('LNCaP', 'CellLine', 'CVCL:0395', (202, 207))	('immunodeficiency', 'Phenotype', 'HP:0002721', (303, 319))	('growth arrest', 'Phenotype', 'HP:0001510', (227, 240))	('cell growth', 'CPA', (125, 136))	('RWPE1', 'CellLine', 'CVCL:3791', (29, 34))	('decreased tumor', 'Disease', (246, 261))	('mortality', 'CPA', (274, 283))	('MCM8', 'Gene', (21, 25))	('knocked down', 'Var', (163, 175))	('growth arrest', 'Disease', 'MESH:D006323', (227, 240))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))
776008	28481876	As a result, our study showed that copy number increase and overexpression of MCM8 may play critical roles in human cancer development.	('MCM8', 'Gene', (78, 82))	('cancer', 'Disease', (116, 122))	('overexpression', 'PosReg', (60, 74))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('human', 'Species', '9606', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('copy number increase', 'Var', (35, 55))	('men', 'Species', '9606', (130, 133))
776017	28481876	Comprehensive genomic and transcriptomic analyses of human cancers had revealed numerous numerical or mutational, or epigenomic changes in the cancer genome that may drive gene expression alterations in cancers.	('epigenomic changes', 'Var', (117, 135))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('alterations', 'Reg', (188, 199))	('gene expression', 'MPA', (172, 187))	('drive', 'Reg', (166, 171))	('cancer', 'Disease', (143, 149))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Disease', (59, 66))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', (203, 209))	('human', 'Species', '9606', (53, 58))	('changes', 'Var', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mutational', 'Var', (102, 112))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancers', 'Disease', (203, 210))
776024	28481876	Forced expression in immortalized prostate epithelial cell lines RWPE1 induced transformation, while knocked down of MCM8 induced growth arrest of PC3, DU145, and LNCaP cells.	('LNCaP', 'CellLine', 'CVCL:0395', (163, 168))	('transformation', 'CPA', (79, 93))	('induced', 'Reg', (71, 78))	('growth arrest', 'Disease', 'MESH:D006323', (130, 143))	('growth arrest', 'Disease', (130, 143))	('RWPE1', 'Gene', (65, 70))	('RWPE1', 'CellLine', 'CVCL:3791', (65, 70))	('growth arrest', 'Phenotype', 'HP:0001510', (130, 143))	('knocked down', 'Var', (101, 113))	('MCM8', 'Gene', (117, 121))	('DU145', 'CellLine', 'CVCL:0105', (152, 157))
776026	28481876	Significant evidence suggests that amplification and overexpression of DNA replication licensing factor have been associated with aggressive human malignancies.	('amplification', 'Var', (35, 48))	('overexpression', 'PosReg', (53, 67))	('malignancies', 'Disease', (147, 159))	('human', 'Species', '9606', (141, 146))	('associated', 'Reg', (114, 124))	('DNA', 'Gene', (71, 74))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))
776037	28481876	In some breast and colon cancer samples, up to 16 copies of MCM8 were found in the genomes of cancer cells, suggesting that the gain of MCM8 was the result of amplification of the genome sequence encoding MCM8 in some of these cancers.	('amplification', 'Var', (159, 172))	('breast and colon cancer', 'Disease', 'MESH:D001943', (8, 31))	('colon cancer', 'Phenotype', 'HP:0003003', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('gain', 'PosReg', (128, 132))	('MCM8', 'Gene', (136, 140))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('cancer', 'Disease', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancers', 'Disease', (227, 234))	('cancer', 'Disease', (94, 100))	('MCM8', 'Gene', (205, 209))
776038	28481876	These analyses suggest that the copy number gain of MCM8 is probably the underlying mechanism of MCM8 overexpression in human malignancies.	('MCM8', 'Gene', (97, 101))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('human', 'Species', '9606', (120, 125))	('copy number gain', 'Var', (32, 48))	('overexpression', 'PosReg', (102, 116))	('malignancies', 'Disease', (126, 138))	('MCM8', 'Gene', (52, 56))
776045	28481876	As shown in figure 1A, the gain of MCM8 was not detected in any of the organ donor prostates and benign prostate tissues adjacent to cancer, while 52% (52/93) of the prostate cancer samples were detected with a gain of MCM8.	('prostate cancer', 'Disease', (166, 181))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (175, 181))	('MCM8', 'Var', (219, 223))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (166, 181))	('donor', 'Species', '9606', (77, 82))	('cancer', 'Disease', (133, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (166, 181))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
776051	28481876	Kaplan-Meir analysis based on the status of MCM8 gain showed that patients with MCM8 gain in their cancer genome had PSA-free survival rate of 33.3%, while patients with no MCM8 gain had the 5-year PSA-free survival rate of 74.5% (figure 1D), suggesting that the gain of MCM8 signals a significantly poorer clinical outcomes (p=7.8 x 10-5) for prostate cancer.	('patients', 'Species', '9606', (156, 164))	('gain', 'PosReg', (85, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (344, 359))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('poorer', 'NegReg', (300, 306))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', (353, 359))	('prostate cancer', 'Phenotype', 'HP:0012125', (344, 359))	('MCM8', 'Var', (80, 84))	('prostate cancer', 'Disease', (344, 359))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('patients', 'Species', '9606', (66, 74))
776061	28481876	To investigate the biological role of MCM8 over-expression in prostate epithelial cells, RWPE1, the immortalized but non-transformed prostate epithelial cells, were transfected with pCDNA4-MCM8-FLAG.	('MCM8', 'Gene', (38, 42))	('RWPE1', 'CellLine', 'CVCL:3791', (89, 94))	('pCDNA4-MCM8-FLAG', 'Var', (182, 198))
776062	28481876	As shown in figure 3A and B, induced expression of MCM8 in RWPE1 cells resulted in an average of 2.5 fold (p<0.01) increase of S-phase and concomitant 32.6% (p<0.01) decrease of G0/G1 phase cells.	('expression', 'Var', (37, 47))	('increase', 'PosReg', (115, 123))	('MCM8', 'Gene', (51, 55))	('RWPE1', 'CellLine', 'CVCL:3791', (59, 64))	('S-phase', 'CPA', (127, 134))	('G0/G1 phase cells', 'CPA', (178, 195))	('decrease', 'NegReg', (166, 174))
776063	28481876	MCM8 expression increased colony formation by 2.8 fold (p<0.01) and anchorage independent growth by 12.7 fold (p<0.01) of RWPE1 cells (figure 3C and D).	('anchorage independent growth', 'CPA', (68, 96))	('colony formation', 'CPA', (26, 42))	('expression', 'Var', (5, 15))	('increased', 'PosReg', (16, 25))	('RWPE1', 'CellLine', 'CVCL:3791', (122, 127))	('MCM8', 'Gene', (0, 4))
776067	28481876	These biological changes were accompanied by drops of DNA replication licensing of Cdt1 (average 66.7% for M8P#5 and M8P#7), MCM6 (average 59.2%) and MCM7 (average 78.7%), suggesting that down-regulation of MCM8 have significant negative impact on DNA replication licensing.	('MCM7', 'Gene', (150, 154))	('Cdt1', 'Gene', '81620', (83, 87))	('MCM6', 'Gene', '4175', (125, 129))	('M8P#7', 'Var', (117, 122))	('Cdt1', 'Gene', (83, 87))	('DNA replication licensing', 'MPA', (54, 79))	('drops', 'NegReg', (45, 50))	('M8P#5', 'Var', (107, 112))	('down-regulation', 'NegReg', (188, 203))	('MCM7', 'Gene', '4176', (150, 154))	('MCM6', 'Gene', (125, 129))
776068	28481876	Similar results were also found when DU145 (51% knocked-down for M8D#1 and 75% for M8D#4) and LNCaP (65% for M8L#3 and 63% M8L#5) cells were knocked down with shRNA specific for MCM8: 65% drop (p<0.01) in S-phase cells and 94% drop (p<0.01) in colony formation for DU145, and 44% drop (p<0.01) in S-phase cells and 91% drop (p<0.01) in colony formation for LNCaP cells.	('drop', 'NegReg', (319, 323))	('S-phase cells', 'CPA', (205, 218))	('LNCaP', 'CellLine', 'CVCL:0395', (94, 99))	('DU145', 'CellLine', 'CVCL:0105', (37, 42))	('drop', 'NegReg', (227, 231))	('colony formation', 'CPA', (336, 352))	('LNCaP', 'CellLine', 'CVCL:0395', (357, 362))	('drop', 'NegReg', (280, 284))	('DU145', 'CellLine', 'CVCL:0105', (265, 270))	('knocked', 'Var', (141, 148))	('drop', 'NegReg', (188, 192))	('colony formation', 'CPA', (244, 260))
776069	28481876	Over-expression of MCM8 in non-transforming prostate epithelial cells RWPE1 (RM8#2 and RM8#9, average 2.3 fold) resulted in 2.5 fold increase of S-phase entry in average (figure 3A and B).	('RWPE1', 'CellLine', 'CVCL:3791', (70, 75))	('RM8', 'Var', (87, 90))	('MCM8', 'Gene', (19, 23))	('S-phase entry', 'MPA', (145, 158))	('increase', 'PosReg', (133, 141))
776074	28481876	As shown in figure 3E-F, mice treated with doxycycline water (5mug/ml) had 74.3% (p<0.01) decrease in tumor volume for M8P#5 cells and 65% (p<0.01) decrease for M8D#1 cells, in comparison with the untreated controls.	('mice', 'Species', '10090', (25, 29))	('doxycycline water', 'Chemical', '-', (43, 60))	('decrease', 'NegReg', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('M8P#', 'Var', (119, 123))	('decrease', 'NegReg', (148, 156))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
776087	28481876	To validate the interaction between MCM8 and cyclin D1 in vitro, MCM8 coding region was segmented into 4 regions: MCM8N (aa2-204), MCM8M1 (aa205-409), MCM8M2 (aa409-618), MCM8C (aa615-880).	('men', 'Species', '9606', (91, 94))	('aa409-618', 'Var', (159, 168))	('cyclin D1', 'Gene', '595', (45, 54))	('aa205-409', 'Var', (139, 148))	('cyclin D1', 'Gene', (45, 54))
776091	28481876	The results of the binding assays indicate that GST-MCM8M1 (aa408-618) bound with cyclin D1 in the cell-free system (figure 4D and E), while GST-MCM8N, GST-MCM8M2, and GST-MCM8C were negative in the binding assays.	('cyclin D1', 'Gene', '595', (82, 91))	('GST-MCM8M1', 'Var', (48, 58))	('bound', 'Interaction', (71, 76))	('cyclin D1', 'Gene', (82, 91))
776094	28481876	A series of deletion mutants of GST-MCM8M1 were assayed to identify the motif that is required for interaction with cyclin D1.	('cyclin D1', 'Gene', '595', (116, 125))	('deletion', 'Var', (12, 20))	('cyclin D1', 'Gene', (116, 125))	('GST-MCM8M1', 'Gene', (32, 42))
776095	28481876	A stretch of 30 amino acid sequence located in 261-290 of MCM8 was found crucial for MCM8 binding with cyclin D1 because the fusion proteins with deletion of this sequence did not bind with cyclin D1, while all proteins containing this sequence bound with cyclin D1 (figure 4D and E).	('cyclin D1', 'Gene', '595', (190, 199))	('deletion', 'Var', (146, 154))	('cyclin D1', 'Gene', (190, 199))	('bind', 'Interaction', (180, 184))	('cyclin D1', 'Gene', '595', (256, 265))	('cyclin D1', 'Gene', (256, 265))	('MCM8', 'Gene', (85, 89))	('cyclin D1', 'Gene', '595', (103, 112))	('bound', 'Interaction', (245, 250))	('cyclin D1', 'Gene', (103, 112))
776097	28481876	Interestingly, in vitro binding assays indicate that the presence of MCM8 produced a multi-protein complex that includes CDK4, cyclin D1and MCM8 (figure 5A).	('CDK4', 'Gene', '1019', (121, 125))	('presence', 'Var', (57, 65))	('cyclin D1', 'Gene', '595', (127, 136))	('MCM8', 'Gene', (69, 73))	('cyclin D1', 'Gene', (127, 136))	('CDK4', 'Gene', (121, 125))
776099	28481876	As shown in figure 5, the presence of recombinant GST-MCM8 enhanced kinase activity of CDK4 and reduced the Km value by 6.8 fold (455 muM vs. 3100 muM) in comparison with cyclin D1/CDK4 alone.	('muM', 'Gene', '56925', (134, 137))	('GST-MCM8', 'Gene', (50, 58))	('muM', 'Gene', (147, 150))	('muM', 'Gene', (134, 137))	('enhanced', 'PosReg', (59, 67))	('cyclin D1', 'Gene', '595', (171, 180))	('Km value', 'MPA', (108, 116))	('cyclin D1', 'Gene', (171, 180))	('CDK4', 'Gene', (181, 185))	('kinase activity', 'MPA', (68, 83))	('presence', 'Var', (26, 34))	('CDK4', 'Gene', '1019', (181, 185))	('CDK4', 'Gene', '1019', (87, 91))	('CDK4', 'Gene', (87, 91))	('muM', 'Gene', '56925', (147, 150))	('reduced', 'NegReg', (96, 103))
776102	28481876	The peptide corresponding to aa261-290 of MCM8 blocked the kinase enhancement effect of MCM8 on CDK4/cyclin D1 complex (figure 5B).	('cyclin D1', 'Gene', '595', (101, 110))	('men', 'Species', '9606', (73, 76))	('cyclin D1', 'Gene', (101, 110))	('kinase enhancement', 'MPA', (59, 77))	('MCM8', 'Gene', (88, 92))	('blocked', 'NegReg', (47, 54))	('aa261-290', 'Var', (29, 38))	('CDK4', 'Gene', (96, 100))	('MCM8', 'Gene', (42, 46))	('CDK4', 'Gene', '1019', (96, 100))
776106	28481876	The in vitro CDK4 kinase activity also showed similar decreases when MCM8 was knocked down in these cell lines (figure 6B).	('knocked down', 'Var', (78, 90))	('decreases', 'NegReg', (54, 63))	('CDK4', 'Gene', (13, 17))	('CDK4', 'Gene', '1019', (13, 17))	('MCM8', 'Gene', (69, 73))
776108	28481876	To examine whether binding of MCM8 with cyclin D1 is required for CDK4 kinase activation, a mutant MCM8 that contains only 31 amino acids from MCM8 (aa1,261-290) and FLAG-TAG sequence was ligated into pCDNA4 to create pCDNA4-CBM-FLAG (cyclin D1 binding motif-FLAG) to interfere the binding between MCM8 and cyclin D1.	('cyclin D1', 'Gene', '595', (307, 316))	('cyclin D1', 'Gene', (307, 316))	('cyclin D1', 'Gene', '595', (235, 244))	('binding', 'Interaction', (282, 289))	('cyclin D1', 'Gene', (235, 244))	('cyclin D1', 'Gene', '595', (40, 49))	('MCM8', 'Gene', (99, 103))	('cyclin D1', 'Gene', (40, 49))	('mutant', 'Var', (92, 98))	('CDK4', 'Gene', (66, 70))	('CDK4', 'Gene', '1019', (66, 70))
776109	28481876	As shown in figure 6A, induction of mutant MCM8 effectively decreased the phosphorylation level of Rb, in comparison with uninduced controls.	('phosphorylation level', 'MPA', (74, 95))	('decreased', 'NegReg', (60, 69))	('Rb', 'Phenotype', 'HP:0009919', (99, 101))	('Rb', 'Gene', '5925', (99, 101))	('MCM8', 'Gene', (43, 47))	('mutant', 'Var', (36, 42))
776110	28481876	Similar decreases were also identified in the in vitro kinase assays (figure 6B), while MCM8 mutant that contains no cyclin D1 binding motif had no impact on Rb phosphorylation (figure 6A-B), DNA replication licensing and cell cycle S-phase entry (figure 3B).	('cyclin D1', 'Gene', (117, 126))	('phosphorylation', 'MPA', (161, 176))	('DNA replication licensing', 'CPA', (192, 217))	('Rb', 'Phenotype', 'HP:0009919', (158, 160))	('MCM8', 'Gene', (88, 92))	('mutant', 'Var', (93, 99))	('Rb', 'Gene', '5925', (158, 160))	('cell cycle S-phase entry', 'CPA', (222, 246))	('cyclin D1', 'Gene', '595', (117, 126))
776113	28481876	Interestingly, over-expression of cyclin D1 partially reversed the inhibitory effect induced by MCM8 knockdown (58-65% for M8P#5 and 41-67% for M8D#1) in cell cycle analysis (figure 6C and D), probably due to forcing more CDK4/cyclin D1 complex formation due to a larger quantity of cyclin D1.	('cell cycle analysis', 'CPA', (154, 173))	('cyclin D1', 'Gene', (227, 236))	('cyclin D1', 'Gene', '595', (283, 292))	('CDK4', 'Gene', (222, 226))	('inhibitory effect', 'MPA', (67, 84))	('cyclin D1', 'Gene', (283, 292))	('complex', 'Interaction', (237, 244))	('more', 'PosReg', (217, 221))	('CDK4', 'Gene', '1019', (222, 226))	('cyclin D1', 'Gene', '595', (34, 43))	('over-expression', 'PosReg', (15, 30))	('MCM8', 'Gene', (96, 100))	('cyclin D1', 'Gene', (34, 43))	('cyclin D1', 'Gene', '595', (227, 236))	('knockdown', 'Var', (101, 110))
776116	28481876	Mutations of MCM8 resulted in human gonadal failure.	('human', 'Species', '9606', (30, 35))	('gonadal failure', 'Disease', 'MESH:D006058', (36, 51))	('MCM8', 'Gene', (13, 17))	('gonadal failure', 'Disease', (36, 51))	('Mutations', 'Var', (0, 9))	('resulted in', 'Reg', (18, 29))
776119	28481876	Most aggressive cancer genomes demonstrate extensive chromosome rearrangement, deletion, and amplification of genes critical to cell survival, growth and migration.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('men', 'Species', '9606', (73, 76))	('aggressive cancer', 'Disease', 'MESH:D009369', (5, 22))	('aggressive cancer', 'Disease', (5, 22))	('amplification', 'MPA', (93, 106))	('chromosome rearrangement', 'CPA', (53, 77))	('deletion', 'Var', (79, 87))
776122	28481876	It is possible that MCM8 serves as one of the assembly factors in building CDK4/cyclin D1 complex since the presence of MCM8 enhanced the recruitment of CDK4/cyclin D1 complex.	('presence', 'Var', (108, 116))	('recruitment', 'MPA', (138, 149))	('men', 'Species', '9606', (145, 148))	('CDK4', 'Gene', '1019', (153, 157))	('CDK4', 'Gene', (153, 157))	('cyclin D1', 'Gene', (80, 89))	('CDK4', 'Gene', (75, 79))	('MCM8', 'Gene', (120, 124))	('cyclin D1', 'Gene', '595', (158, 167))	('CDK4', 'Gene', '1019', (75, 79))	('cyclin D1', 'Gene', (158, 167))	('enhanced', 'PosReg', (125, 133))	('cyclin D1', 'Gene', '595', (80, 89))
776123	28481876	In addition, our analysis showed that MCM8 is crucial in CDK4 activation by significantly lowering the substrate threshold required for CDK4 kinase activation.	('substrate threshold required', 'MPA', (103, 131))	('CDK4', 'Gene', (57, 61))	('MCM8', 'Var', (38, 42))	('CDK4', 'Gene', (136, 140))	('CDK4', 'Gene', '1019', (57, 61))	('CDK4', 'Gene', '1019', (136, 140))	('lowering', 'NegReg', (90, 98))
776125	28481876	Indeed, forced expression of MCM8 in cancer cell lines resulted in dramatic increase of cell entry into S phase in non-transformed cells, while knocked down of MCM8 generates growth arrest of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('MCM8', 'Gene', (29, 33))	('MCM8', 'Gene', (160, 164))	('increase', 'PosReg', (76, 84))	('cancer', 'Disease', (37, 43))	('growth arrest of cancer', 'Disease', (175, 198))	('knocked down', 'Var', (144, 156))	('cell entry into S phase', 'CPA', (88, 111))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('growth arrest', 'Phenotype', 'HP:0001510', (175, 188))	('growth arrest of cancer', 'Disease', 'MESH:D006323', (175, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
776126	28481876	Over-expression of MCM8 may produce two consequences: Promoting cell growth through increasing phosphorylation and inactivation of Rb molecule and promoting DNA recombination that produces abnormal chromosome rearrangements and mutations.	('increasing', 'PosReg', (84, 94))	('promoting', 'PosReg', (147, 156))	('DNA recombination', 'CPA', (157, 174))	('inactivation', 'MPA', (115, 127))	('Promoting', 'PosReg', (54, 63))	('MCM8', 'Gene', (19, 23))	('chromosome rearrangements', 'CPA', (198, 223))	('men', 'Species', '9606', (218, 221))	('cell growth', 'CPA', (64, 75))	('abnormal chromosome', 'Phenotype', 'HP:0031411', (189, 208))	('Over-expression', 'Var', (0, 15))	('Rb', 'Gene', '5925', (131, 133))	('Rb', 'Phenotype', 'HP:0009919', (131, 133))	('phosphorylation', 'MPA', (95, 110))	('mutations', 'MPA', (228, 237))
776127	28481876	As a result, abnormal expression of MCM8 could be one of the fundamental causes that initiate the carcinogenic process.	('carcinogenic process', 'Disease', (98, 118))	('men', 'Species', '9606', (66, 69))	('MCM8', 'Gene', (36, 40))	('abnormal', 'Var', (13, 21))	('expression', 'MPA', (22, 32))	('carcinogenic process', 'Disease', 'MESH:D009385', (98, 118))
776131	28481876	The continuing presence of MCM8 throughout the cell cycle may induce improper DNA synthesis that leads to genome instability of cancer cells, in addition to increased recruitment of larger proportion of cell population into the proliferation cycle.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('induce', 'Reg', (62, 68))	('MCM8', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('leads to', 'Reg', (97, 105))	('recruitment', 'MPA', (167, 178))	('increased', 'PosReg', (157, 166))	('genome instability', 'MPA', (106, 124))	('improper DNA synthesis', 'MPA', (69, 91))	('men', 'Species', '9606', (174, 177))	('cancer', 'Disease', (128, 134))
776133	28481876	Overexpression of MCM8 gene in prostate immortalized epithelial cells inducing marked transformation underlies the important role of this gene in cancer development.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('inducing', 'Reg', (70, 78))	('Overexpression', 'Var', (0, 14))	('men', 'Species', '9606', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('marked transformation', 'CPA', (79, 100))	('MCM8', 'Gene', (18, 22))
776140	28481876	The genomes of these cell lines were tested for a short tandem repeat (STR) DNA profile on eight different loci (CSF1PO, D13S317, D16S539, D5S818, D7S820, THO1, TPOX, and vWA) of the genomes by PCR using the primer sets for CSF1PO, D13S317, D16S539, D5S818, D7S820, TH01, TPOX, vWA recommended by ATCC on April 22, 2016 (latest).	('THO1', 'Gene', (155, 159))	('THO1', 'Gene', '9984', (155, 159))	('D5S818', 'Var', (250, 256))	('D7S820', 'Var', (258, 264))	('D16S539', 'Var', (241, 248))	('men', 'Species', '9606', (287, 290))	('D13S317', 'Var', (232, 239))
776141	28481876	All antibodies were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA), including: Antibodies for MCM6 (sc-55577), MCM7 (sc-9966), MCM8 (sc-47117), Cdt1 (sc-28262), CCND1 (sc-20044), p27 (sc-1641), p21 (sc-6246), CDK4 (sc-136241), Rb (sc-102), pRb (sc-271930) and beta-actin (sc-47778).	('MCM7', 'Gene', (127, 131))	('beta-actin', 'Gene', (276, 286))	('Rb', 'Gene', '5925', (243, 245))	('Cdt1', 'Gene', '81620', (160, 164))	('Cdt1', 'Gene', (160, 164))	('CCND1', 'Gene', '595', (177, 182))	('Rb', 'Gene', '5925', (257, 259))	('MCM7', 'Gene', '4176', (127, 131))	('sc-136241', 'Var', (231, 240))	('CDK4', 'Gene', (225, 229))	('CCND1', 'Gene', (177, 182))	('Rb', 'Phenotype', 'HP:0009919', (243, 245))	('pRb', 'Gene', (256, 259))	('Rb', 'Phenotype', 'HP:0009919', (257, 259))	('p27', 'Gene', '3429', (195, 198))	('beta-actin', 'Gene', '728378', (276, 286))	('pRb', 'Gene', '5925', (256, 259))	('p27', 'Gene', (195, 198))	('CDK4', 'Gene', '1019', (225, 229))	('MCM6', 'Gene', '4175', (110, 114))	('p21', 'Gene', (210, 213))	('p21', 'Gene', '644914', (210, 213))	('MCM6', 'Gene', (110, 114))
776162	28481876	Power analysis were performed based on the assumption that 75% mice xenografted with M8P#5 and M8D#1 without doxycycline treatment may die in 6 weeks, while mice treated with doxycycline may have a mortality of 27% in the same period.	('men', 'Species', '9606', (126, 129))	('mice', 'Species', '10090', (157, 161))	('M8D#1', 'Var', (95, 100))	('doxycycline', 'Chemical', 'MESH:D004318', (109, 120))	('mice', 'Species', '10090', (63, 67))	('M8P#5', 'Var', (85, 90))	('doxycycline', 'Chemical', 'MESH:D004318', (175, 186))
776173	28481876	Groups were segregated based on MCM8 gain or non-gain status (figure 1) or MCM8 expression score>=2 or <2 status (figure 2) or treated with or without doxycycline (figure 3).	('MCM8', 'Gene', (32, 36))	('>=2', 'Var', (96, 99))	('MCM8', 'Gene', (75, 79))	('non-gain', 'NegReg', (45, 53))	('gain', 'PosReg', (37, 41))	('doxycycline', 'Chemical', 'MESH:D004318', (151, 162))
776263	32426838	The roles of LINC00657, miR-26a-5p or CKS2 in the proliferation, migration, invasion, and apoptosis of EC cells were respectively assessed by CCK-8, wound healing assay, transwell invasion assay, and flow cytometry.	('si', 'Chemical', 'MESH:D012825', (184, 186))	('CKS2', 'Gene', (38, 42))	('migration', 'CPA', (65, 74))	('CCK-8', 'Chemical', '-', (142, 147))	('LINC00657', 'Gene', '647979', (13, 22))	('miR-26a-5p', 'Var', (24, 34))	('CKS2', 'Gene', '1164', (38, 42))	('miR-26a-5p', 'Chemical', '-', (24, 34))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('apoptosis', 'CPA', (90, 99))	('LINC00657', 'Gene', (13, 22))	('invasion', 'CPA', (76, 84))	('si', 'Chemical', 'MESH:D012825', (80, 82))
776278	32426838	However, surgical resection, an invasive and complex treatment, may cause severe postoperative complications, thus leading to death.	('leading', 'Reg', (115, 122))	('death', 'Disease', 'MESH:D003643', (126, 131))	('death', 'Disease', (126, 131))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('surgical resection', 'Var', (9, 27))
776280	32426838	The aberrant expression of lncRNAs is observed in diverse cancers, which is critical for the progression of cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('aberrant', 'Var', (4, 12))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('observed', 'Reg', (38, 46))	('lncRNAs', 'Gene', (27, 34))	('cancers', 'Disease', (108, 115))	('si', 'Chemical', 'MESH:D012825', (100, 102))
776284	32426838	suggest that LINC00657 promotes the growth of ESCC cells via mediating miR-615-3p.	('ESCC', 'Disease', (46, 50))	('growth', 'MPA', (36, 42))	('promotes', 'PosReg', (23, 31))	('LINC00657', 'Gene', '647979', (13, 22))	('miR-615', 'Chemical', '-', (71, 78))	('miR-615-3p', 'Var', (71, 81))	('LINC00657', 'Gene', (13, 22))
776288	32426838	Several reports suggest that miR-26a-5p can inhibit the proliferation and metastasis of EC, but the more detailed mechanism of miR-26a-5p in EC still need to be further studied.	('miR-26a-5p', 'Var', (29, 39))	('miR-26a-5p', 'Chemical', '-', (29, 39))	('inhibit', 'NegReg', (44, 51))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('proliferation', 'CPA', (56, 69))	('metastasis', 'CPA', (74, 84))	('miR-26a-5p', 'Chemical', '-', (127, 137))
776290	32426838	Besides, miR-26a-5p is proved to effectively suppress cell proliferation and tumorigenesis through targeting CKS2, and yet the relationship of miR-26a-5p with CKS2 in EC has not been reported.	('suppress', 'NegReg', (45, 53))	('cell proliferation', 'CPA', (54, 72))	('si', 'Chemical', 'MESH:D012825', (87, 89))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('miR-26a-5p', 'Chemical', '-', (9, 19))	('targeting', 'Reg', (99, 108))	('CKS2', 'Gene', '1164', (159, 163))	('CKS2', 'Gene', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CKS2', 'Gene', '1164', (109, 113))	('CKS2', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('miR-26a-5p', 'Chemical', '-', (143, 153))	('tumor', 'Disease', (77, 82))	('miR-26a-5p', 'Var', (9, 19))
776308	32426838	The miR-26a-5p wild-type (WT) or mutant (MUT) putative binding site in 3'-UTR of LINC00657 or cks2 was constructed and cloned into the psiCHECK-2 vector (Promega Corporation).	('LINC00657', 'Gene', '647979', (81, 90))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('psiCHECK', 'Disease', 'None', (135, 143))	('LINC00657', 'Gene', (81, 90))	('cks2', 'Gene', '1164', (94, 98))	('cks2', 'Gene', (94, 98))	('mutant', 'Var', (33, 39))	('miR-26a-5p', 'Chemical', '-', (4, 14))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('psiCHECK', 'Disease', (135, 143))
776322	32426838	The results from CCK-8 assay indicated that EC cell proliferation was obviously inhibited by LINC00657 knockdown (Figure 1C).	('LINC00657', 'Gene', (93, 102))	('CCK-8', 'Chemical', '-', (17, 22))	('knockdown', 'Var', (103, 112))	('EC cell proliferation', 'CPA', (44, 65))	('LINC00657', 'Gene', '647979', (93, 102))	('inhibited', 'NegReg', (80, 89))
776323	32426838	Besides, wound healing assay and transwell invasion assay revealed that LINC00657 knockdown suppressed the migration and invasion of EC cells (Figure 1D,E).	('suppressed', 'NegReg', (92, 102))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('knockdown', 'Var', (82, 91))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('LINC00657', 'Gene', '647979', (72, 81))	('LINC00657', 'Gene', (72, 81))	('si', 'Chemical', 'MESH:D012825', (125, 127))
776324	32426838	Furthermore, EC cell apoptosis was induced by LINC00657 knockdown in comparison with other control groups (Figure 1F).	('LINC00657', 'Gene', (46, 55))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('EC cell apoptosis', 'CPA', (13, 30))	('induced', 'Reg', (35, 42))	('LINC00657', 'Gene', '647979', (46, 55))	('knockdown', 'Var', (56, 65))
776325	32426838	Therefore, the knockdown of LINC00657 effectively suppressed the proliferation, migration and invasion of EC cells and yet induced cell apoptosis.	('cell apoptosis', 'CPA', (131, 145))	('suppressed', 'NegReg', (50, 60))	('proliferation', 'CPA', (65, 78))	('knockdown', 'Var', (15, 24))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('migration', 'CPA', (80, 89))	('LINC00657', 'Gene', '647979', (28, 37))	('induced', 'Reg', (123, 130))	('invasion of EC cells', 'CPA', (94, 114))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('LINC00657', 'Gene', (28, 37))
776329	32426838	The relative luciferase activity in EC cells was greatly decreased by the co-transfection of miR-26a-5p mimic and LINC00657-WT vector, while the activity had no obvious change in other groups.	('miR-26a-5p mimic', 'Var', (93, 109))	('activity', 'MPA', (24, 32))	('miR-26a-5p', 'Chemical', '-', (93, 103))	('LINC00657', 'Gene', (114, 123))	('luciferase', 'Enzyme', (13, 23))	('LINC00657', 'Gene', '647979', (114, 123))	('decreased', 'NegReg', (57, 66))
776334	32426838	RT-qPCR showed that the high level of miR-26a-5p induced by miR-26a-5p mimic was down-regulated by the introduction of LINC00657 plasmid (Figure 2E).	('down-regulated', 'NegReg', (81, 95))	('miR-26a-5p', 'MPA', (38, 48))	('LINC00657', 'Gene', '647979', (119, 128))	('miR-26a-5p', 'Chemical', '-', (60, 70))	('miR-26a-5p mimic', 'Var', (60, 76))	('miR-26a-5p', 'Chemical', '-', (38, 48))	('LINC00657', 'Gene', (119, 128))
776335	32426838	The experimental results revealed that the proliferation (Figure 2F), migration (Figure 2H,I), and invasion (Figure 2J,K) of EC cells was inhibited by miR-26a-5p mimic, which was obviously reversed by the introduction of LINC00657 plasmid.	('LINC00657', 'Gene', (221, 230))	('migration', 'CPA', (70, 79))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('invasion', 'CPA', (99, 107))	('inhibited', 'NegReg', (138, 147))	('LINC00657', 'Gene', '647979', (221, 230))	('miR-26a-5p', 'Var', (151, 161))	('miR-26a-5p', 'Chemical', '-', (151, 161))
776336	32426838	The increase of cell apoptosis induced by miR-26a-5p mimic was changed by the introduction of LINC00657 plasmid (Figure 2G).	('cell apoptosis', 'CPA', (16, 30))	('LINC00657', 'Gene', (94, 103))	('miR-26a-5p', 'Var', (42, 52))	('LINC00657', 'Gene', '647979', (94, 103))	('miR-26a-5p', 'Chemical', '-', (42, 52))	('increase', 'PosReg', (4, 12))	('si', 'Chemical', 'MESH:D012825', (27, 29))
776337	32426838	In addition, RT-qPCR suggested that miR-26a-5p inhibitor suppressed the expression level of miR-26a-5p, which was reversed by the introduction of si-LINC00657 (Figure 2L).	('si', 'Chemical', 'MESH:D012825', (146, 148))	('miR-26a-5p', 'Var', (92, 102))	('LINC00657', 'Gene', (149, 158))	('expression level', 'MPA', (72, 88))	('miR-26a-5p', 'Chemical', '-', (92, 102))	('miR-26a-5p', 'Chemical', '-', (36, 46))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('LINC00657', 'Gene', '647979', (149, 158))	('suppressed', 'NegReg', (57, 67))
776344	32426838	Moreover, qRT-PCR indicated that the transfection of miR-26a-5p mimic in EC cells decreased the expression of CKS2, and yet miR-26a-5p inhibitor increased CKS2 expression in EC cells (Figure 3C).	('CKS2', 'Gene', (110, 114))	('expression', 'MPA', (160, 170))	('miR-26a-5p', 'Chemical', '-', (124, 134))	('CKS2', 'Gene', '1164', (155, 159))	('CKS2', 'Gene', (155, 159))	('miR-26a-5p', 'Chemical', '-', (53, 63))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('increased', 'PosReg', (145, 154))	('expression', 'MPA', (96, 106))	('si', 'Chemical', 'MESH:D012825', (102, 104))	('miR-26a-5p', 'Var', (124, 134))	('decreased', 'NegReg', (82, 91))	('CKS2', 'Gene', '1164', (110, 114))
776345	32426838	Thus, miR-26a-5p negatively targeted CKS2.	('targeted', 'Reg', (28, 36))	('CKS2', 'Gene', '1164', (37, 41))	('CKS2', 'Gene', (37, 41))	('miR-26a-5p', 'Var', (6, 16))	('miR-26a-5p', 'Chemical', '-', (6, 16))	('negatively', 'NegReg', (17, 27))
776347	32426838	The results suggested that CKS2 knockdown considerably suppressed the proliferation (Figure 3D,E), migration (Figure 3F,G), and invasion (Figure 3H,I) of EC cells, and yet induced apoptosis (Figure 3J,K).	('si', 'Chemical', 'MESH:D012825', (132, 134))	('CKS2', 'Gene', (27, 31))	('CKS2', 'Gene', '1164', (27, 31))	('knockdown', 'Var', (32, 41))	('proliferation', 'CPA', (70, 83))	('suppressed', 'NegReg', (55, 65))	('induced', 'Reg', (172, 179))	('migration', 'CPA', (99, 108))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('apoptosis', 'CPA', (180, 189))	('invasion', 'CPA', (128, 136))	('si', 'Chemical', 'MESH:D012825', (186, 188))
776350	32426838	Western blot revealed that the knockdown of CKS2 down-regulated the level of MDM2 and Bcl-2 but up-regulated the level of p53 and Bax (Figure 3L-O).	('Bax', 'Gene', '581', (130, 133))	('Bcl-2', 'Gene', (86, 91))	('level', 'MPA', (68, 73))	('Bcl-2', 'Gene', '596', (86, 91))	('p53', 'MPA', (122, 125))	('down-regulated', 'NegReg', (49, 63))	('CKS2', 'Gene', '1164', (44, 48))	('CKS2', 'Gene', (44, 48))	('Bax', 'Gene', (130, 133))	('knockdown', 'Var', (31, 40))	('up-regulated', 'PosReg', (96, 108))
776354	32426838	The qRT-PCR analysis showed that LINC00657 knockdown decreased the level of CKS2 and yet LINC00657 overexpression increased CKS2 expression, which further confirmed the positive correlation of LINC00657 with CKS2 (Figure 4A).	('CKS2', 'Gene', (124, 128))	('LINC00657', 'Gene', (33, 42))	('LINC00657', 'Gene', (193, 202))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('LINC00657', 'Gene', (89, 98))	('level', 'MPA', (67, 72))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('CKS2', 'Gene', '1164', (76, 80))	('expression', 'MPA', (129, 139))	('CKS2', 'Gene', (76, 80))	('knockdown', 'Var', (43, 52))	('increased', 'PosReg', (114, 123))	('CKS2', 'Gene', '1164', (208, 212))	('CKS2', 'Gene', (208, 212))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('LINC00657', 'Gene', '647979', (33, 42))	('decreased', 'NegReg', (53, 62))	('LINC00657', 'Gene', '647979', (193, 202))	('LINC00657', 'Gene', '647979', (89, 98))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('CKS2', 'Gene', '1164', (124, 128))
776355	32426838	In addition, the inhibition of EC cell proliferation, migration, and invasion induced by LINC00657 knockdown was reversed after the cells co-transfected with si-LINC00657 and CKS2 plasmid (Figure 4B-D).	('si', 'Chemical', 'MESH:D012825', (73, 75))	('LINC00657', 'Gene', '647979', (161, 170))	('LINC00657', 'Gene', '647979', (89, 98))	('migration', 'CPA', (54, 63))	('si', 'Chemical', 'MESH:D012825', (158, 160))	('invasion', 'CPA', (69, 77))	('knockdown', 'Var', (99, 108))	('EC cell proliferation', 'CPA', (31, 52))	('LINC00657', 'Gene', (161, 170))	('LINC00657', 'Gene', (89, 98))	('inhibition', 'NegReg', (17, 27))	('CKS2', 'Gene', '1164', (175, 179))	('CKS2', 'Gene', (175, 179))
776356	32426838	LINC00657 knockdown promoted the apoptosis of EC cells, which was changed by the introduction of CKS2 plasmid (Figure 4E).	('apoptosis', 'CPA', (33, 42))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('LINC00657', 'Gene', '647979', (0, 9))	('CKS2', 'Gene', '1164', (97, 101))	('CKS2', 'Gene', (97, 101))	('promoted', 'PosReg', (20, 28))	('LINC00657', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))
776357	32426838	Moreover, the decrease of MDM2 and Bcl-2 and the increase of p53 and Bax induced by LINC00657 knockdown were reversed by the introduction of CKS2 plasmid (Figure 4F).	('knockdown', 'Var', (94, 103))	('Bcl-2', 'Gene', (35, 40))	('increase', 'PosReg', (49, 57))	('Bcl-2', 'Gene', '596', (35, 40))	('CKS2', 'Gene', '1164', (141, 145))	('CKS2', 'Gene', (141, 145))	('Bax', 'Gene', '581', (69, 72))	('LINC00657', 'Gene', (84, 93))	('p53', 'Protein', (61, 64))	('decrease', 'NegReg', (14, 22))	('Bax', 'Gene', (69, 72))	('LINC00657', 'Gene', '647979', (84, 93))
776361	32426838	Meanwhile, the anticarcinogenic effect of miR-26a-5p and the oncogenic roles of CKS2 were both validated in EC.	('carcinogenic', 'Disease', 'MESH:D063646', (19, 31))	('carcinogenic', 'Disease', (19, 31))	('CKS2', 'Gene', '1164', (80, 84))	('CKS2', 'Gene', (80, 84))	('miR-26a-5p', 'Var', (42, 52))	('miR-26a-5p', 'Chemical', '-', (42, 52))
776362	32426838	Moreover, our study proved the positive correlation between LINC00657 and CKS2, and the knockdown of LINC00657 inhibited CKS2 expression to suppress the proliferation, migration, and invasion of EC cells and induced apoptosis through regulating the MDM2/p53/Bcl2/Bax pathway.	('migration', 'CPA', (168, 177))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('LINC00657', 'Gene', '647979', (101, 110))	('induced', 'Reg', (208, 215))	('Bax', 'Gene', (263, 266))	('si', 'Chemical', 'MESH:D012825', (222, 224))	('Bcl2', 'Gene', (258, 262))	('CKS2', 'Gene', '1164', (74, 78))	('CKS2', 'Gene', (74, 78))	('Bcl2', 'Gene', '596', (258, 262))	('invasion', 'CPA', (183, 191))	('Bax', 'Gene', '581', (263, 266))	('LINC00657', 'Gene', '647979', (60, 69))	('CKS2', 'Gene', '1164', (121, 125))	('CKS2', 'Gene', (121, 125))	('LINC00657', 'Gene', (101, 110))	('expression', 'MPA', (126, 136))	('apoptosis', 'CPA', (216, 225))	('knockdown', 'Var', (88, 97))	('regulating', 'Reg', (234, 244))	('inhibited', 'NegReg', (111, 120))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('si', 'Chemical', 'MESH:D012825', (187, 189))	('proliferation', 'CPA', (153, 166))	('LINC00657', 'Gene', (60, 69))	('suppress', 'NegReg', (140, 148))
776374	32426838	Previous studies have indicated that miR-26a-5p as a tumor suppressor can suppress the cellular growth but induce apoptosis in diverse cancers.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('miR-26a-5p', 'Chemical', '-', (37, 47))	('cancers', 'Disease', (135, 142))	('induce', 'Reg', (107, 113))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('suppress', 'NegReg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('cellular growth', 'CPA', (87, 102))	('apoptosis', 'CPA', (114, 123))	('miR-26a-5p', 'Var', (37, 47))
776375	32426838	Besides, miR-26a-5p has shown an aberrant low expression in ESCC, which promotes cell G1 phase arrest and growth inhibition.	('expression', 'MPA', (46, 56))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('miR-26a-5p', 'Chemical', '-', (9, 19))	('ESCC', 'Gene', (60, 64))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('growth inhibition', 'CPA', (106, 123))	('promotes', 'PosReg', (72, 80))	('low', 'NegReg', (42, 45))	('arrest', 'Disease', (95, 101))	('miR-26a-5p', 'Var', (9, 19))
776376	32426838	In agreement with previous reports, our study found miR-26a-5p functioned as a tumor suppressor in EC cells.	('tumor', 'Disease', (79, 84))	('EC cells', 'Disease', (99, 107))	('miR-26a-5p', 'Var', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('miR-26a-5p', 'Chemical', '-', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
776378	32426838	Furthermore, CKS2 was identified to be a target of miR-26a-5p, and its expression was negatively regulated by miR-26a-5p.	('miR-26a-5p', 'Chemical', '-', (110, 120))	('expression', 'MPA', (71, 81))	('negatively', 'NegReg', (86, 96))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('CKS2', 'Gene', '1164', (13, 17))	('CKS2', 'Gene', (13, 17))	('miR-26a-5p', 'Var', (51, 61))	('miR-26a-5p', 'Var', (110, 120))	('miR-26a-5p', 'Chemical', '-', (51, 61))
776382	32426838	Our work also found that CKS2 knockdown significantly decreased the level of MDM2 and Bcl-2 but increased the level of p53 and Bax, whereas CKS2 overexpression up-regulated the expression of MDM2 and Bcl-2 and yet down-regulated the expression of p53 and Bax.	('Bcl-2', 'Gene', (86, 91))	('expression', 'MPA', (233, 243))	('Bax', 'Gene', (255, 258))	('knockdown', 'Var', (30, 39))	('CKS2', 'Gene', '1164', (140, 144))	('expression', 'MPA', (177, 187))	('down-regulated', 'NegReg', (214, 228))	('p53', 'Gene', (247, 250))	('CKS2', 'Gene', (140, 144))	('Bax', 'Gene', '581', (255, 258))	('si', 'Chemical', 'MESH:D012825', (183, 185))	('Bcl-2', 'Gene', '596', (86, 91))	('si', 'Chemical', 'MESH:D012825', (239, 241))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('Bax', 'Gene', (127, 130))	('decreased', 'NegReg', (54, 63))	('CKS2', 'Gene', '1164', (25, 29))	('CKS2', 'Gene', (25, 29))	('MDM2', 'Gene', (191, 195))	('Bax', 'Gene', '581', (127, 130))	('Bcl-2', 'Gene', (200, 205))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('increased', 'PosReg', (96, 105))	('Bcl-2', 'Gene', '596', (200, 205))	('up-regulated', 'PosReg', (160, 172))	('level', 'MPA', (110, 115))
776392	32426838	Our study observed the aberrantly high expression of MDM2 in EC cells decreased the level of p53, which caused the increase of Bcl-2 and the decrease of Bax, resulting in the inhibition of EC cell apoptosis.	('Bax', 'Gene', (153, 156))	('MDM2', 'Gene', (53, 57))	('decreased', 'NegReg', (70, 79))	('increase', 'PosReg', (115, 123))	('aberrantly', 'Var', (23, 33))	('inhibition', 'NegReg', (175, 185))	('EC cell apoptosis', 'CPA', (189, 206))	('decrease', 'NegReg', (141, 149))	('Bax', 'Gene', '581', (153, 156))	('si', 'Chemical', 'MESH:D012825', (203, 205))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('level of p53', 'MPA', (84, 96))	('Bcl-2', 'Gene', (127, 132))	('Bcl-2', 'Gene', '596', (127, 132))
776411	32313942	Various studies indicate that high expression of HMGA2 is related to poor survival rates in breast cancer, colorectal cancer  and lung cancer patients.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('HMGA2', 'Gene', (49, 54))	('expression', 'MPA', (35, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', (130, 141))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('breast cancer', 'Disease', (92, 105))	('expression', 'Species', '29278', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('high', 'Var', (30, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('survival rates', 'CPA', (74, 88))	('colorectal cancer', 'Disease', (107, 124))	('poor', 'NegReg', (69, 73))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
776412	32313942	Furthermore, there is evidence that oncogenic HMGA2 participates in DNA damage repair, stem cell self-renewal, aggressive tumor growth  and tumor cell differentiation.	('HMGA2', 'Gene', (46, 51))	('participates', 'Reg', (52, 64))	('oncogenic', 'Var', (36, 45))	('stem cell self-renewal', 'CPA', (87, 109))	('DNA', 'MPA', (68, 71))	('aggressive tumor', 'Disease', 'MESH:D001523', (111, 127))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('aggressive tumor', 'Disease', (111, 127))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (140, 145))
776419	32313942	For example, HMGA2 phosphorylation at the acidic C-terminal tail may affect its DNA-binding properties, and HMGA2 SUMOylation may promote promyelocytic leukemia (PML) protein degradation.	('DNA-binding', 'Interaction', (80, 91))	('promote', 'PosReg', (130, 137))	('affect', 'Reg', (69, 75))	('PML', 'Gene', (162, 165))	('SUMOylation', 'Var', (114, 125))	('promyelocytic leukemia', 'Disease', 'MESH:D015473', (138, 160))	('phosphorylation', 'Var', (19, 34))	('promyelocytic leukemia', 'Disease', (138, 160))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (138, 160))	('PML', 'Gene', '5371', (162, 165))	('HMGA2', 'Protein', (13, 18))	('HMGA2 SUMOylation', 'Var', (108, 125))	('PML', 'Phenotype', 'HP:0004836', (162, 165))
776424	32313942	Moreover, it supports the migration of breast cancer cells through GCN5-mediated modulation of microtubule acetylation.	('microtubule acetylation', 'MPA', (95, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('GCN5', 'Gene', (67, 71))	('supports', 'PosReg', (13, 21))	('GCN5', 'Gene', '2648', (67, 71))	('migration', 'CPA', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('modulation', 'Var', (81, 91))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('breast cancer', 'Disease', (39, 52))
776427	32313942	One study found that the abnormal expression of HBXIP was associated with poor prognosis in ESCC.	('abnormal', 'Var', (25, 33))	('ESCC', 'Disease', (92, 96))	('expression', 'MPA', (34, 44))	('HBXIP', 'Gene', (48, 53))	('expression', 'Species', '29278', (34, 44))
776434	32313942	HMGA2 K26 acetylation functionally enhances its DNA binding ability on the target genes and blocks its ubiquitination and proteasomal degradation, thus leading to HMGA2 accumulation and carcinogenesis.	('K26', 'Var', (6, 9))	('HMGA2', 'Gene', (163, 168))	('leading to', 'Reg', (152, 162))	('DNA binding', 'Interaction', (48, 59))	('HMGA2', 'Gene', (0, 5))	('blocks', 'NegReg', (92, 98))	('accumulation', 'PosReg', (169, 181))	('acetylation', 'MPA', (10, 21))	('carcinogenesis', 'Disease', 'MESH:D063646', (186, 200))	('enhances', 'PosReg', (35, 43))	('carcinogenesis', 'Disease', (186, 200))
776441	32313942	The ESCC cell lines KYSE2, KYSE180, KYSE450, KYSE510 and the human embryonic kidney cell line 293T (HEK293T) were obtained from the American Type Culture Collection (ATCC).	('KYSE450', 'CellLine', 'CVCL:1353', (36, 43))	('293T', 'CellLine', 'CVCL:0063', (103, 107))	('KYSE2', 'CellLine', 'CVCL:1351', (20, 25))	('293T', 'CellLine', 'CVCL:0063', (94, 98))	('embryonic kidney', 'Disease', (67, 83))	('KYSE180', 'CellLine', 'CVCL:1349', (27, 34))	('HEK293T', 'CellLine', 'CVCL:0063', (100, 107))	('KYSE510', 'CellLine', 'CVCL:1354', (45, 52))	('KYSE180', 'Var', (27, 34))	('human', 'Species', '9606', (61, 66))	('embryonic kidney', 'Disease', 'MESH:D007674', (67, 83))
776447	32313942	GSK690693 (an inhibitor of Akt), PD98059 (an inhibitor of the upstream kinase of ERK1/2), and SB202190 (an inhibitor of p38) were all purchased from MedChem Express (USA).	('PD98059', 'Chemical', 'MESH:C093973', (33, 40))	('ERK1/2', 'Gene', '5595;5594', (81, 87))	('SB202190', 'Chemical', 'MESH:C090942', (94, 102))	('Akt', 'Gene', '207', (27, 30))	('p38', 'Gene', '5594', (120, 123))	('GSK690693', 'Var', (0, 9))	('GSK690693', 'Chemical', 'MESH:C528328', (0, 9))	('Akt', 'Gene', (27, 30))	('ERK1/2', 'Gene', (81, 87))	('p38', 'Gene', (120, 123))	('PD98059', 'Var', (33, 40))
776495	32313942	In addition, the Kaplan-Meier survival analysis of 151 ESCC patients (Supplementary Table S1) for 80 months demonstrated that high HMGA2 and HBXIP expressions were associated with advanced tumor stage (Supplementary Figure S1A and B) and reduced overall and disease-free survival (Figure 1C-F).	('HBXIP expressions', 'Gene', (141, 158))	('tumor', 'Disease', (189, 194))	('expression', 'Species', '29278', (147, 157))	('patients', 'Species', '9606', (60, 68))	('reduced', 'NegReg', (238, 245))	('high', 'Var', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('ESCC', 'Disease', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('HMGA2', 'Gene', (131, 136))
776500	32313942	Conversely, HBXIP knockdown by siRNA dose-dependently inhibited HMGA2 protein level, whereas had no effect on HMGA2 mRNA level in either KYSE2 or KYSE450 cells (Figure 1H, I and Supplementary Figure S1F, G), implying that HMGA2 could be modulated by oncogenic HBXIP through a posttranscriptional mechanism.	('knockdown', 'Var', (18, 27))	('HBXIP', 'Gene', (12, 17))	('inhibited', 'NegReg', (54, 63))	('KYSE2', 'CellLine', 'CVCL:1351', (137, 142))	('HMGA2 protein level', 'MPA', (64, 83))	('KYSE450', 'CellLine', 'CVCL:1353', (146, 153))
776501	32313942	We also tested the effect of HBXIP overexpression and HBXIP knockdown on the protein levels of HMGA2 in a liver cancer cell line Hep3B and a breast cancer cell line MCF-7.	('tested', 'Reg', (8, 14))	('HBXIP', 'Gene', (54, 59))	('liver cancer', 'Disease', 'MESH:D006528', (106, 118))	('liver cancer', 'Phenotype', 'HP:0002896', (106, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('liver cancer', 'Disease', (106, 118))	('MCF-7', 'CellLine', 'CVCL:0031', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('HMGA2', 'Gene', (95, 100))	('knockdown', 'Var', (60, 69))	('breast cancer', 'Disease', (141, 154))	('expression', 'Species', '29278', (39, 49))	('Hep3B', 'CellLine', 'CVCL:0326', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
776502	32313942	The protein levels of HMGA2 were obviously increased by HBXIP overexpression, while the knockdown of HBXIP significantly reduced the protein levels of HMGA2 in Hep3B cells (Supplementary Figure S1H).	('protein levels', 'MPA', (4, 18))	('expression', 'Species', '29278', (66, 76))	('reduced', 'NegReg', (121, 128))	('knockdown', 'Var', (88, 97))	('increased', 'PosReg', (43, 52))	('protein levels', 'MPA', (133, 147))	('Hep3B', 'CellLine', 'CVCL:0326', (160, 165))	('HBXIP', 'Gene', (101, 106))
776513	32313942	The fragment from 1 to 43 aa contains two lysine residues (K26 and K34) that might be modified by acetylation.	('K26', 'Var', (59, 62))	('lysine', 'Chemical', 'MESH:D008239', (42, 48))	('K34', 'Gene', '3885', (67, 70))	('K34', 'Gene', (67, 70))
776514	32313942	To further confirm the acetylation site, the K26 and K34 residues were mutated to arginine (R, mimics of acetylation-deficient HMGA2) or glutamine (Q, mimics of hyperacetylated HMGA2), either alone (K26R and K34R or K26Q and K34Q) or together (K26/34R or K26/34Q).	('K34Q', 'Mutation', 'p.K34Q', (225, 229))	('K26/34Q', 'Var', (255, 262))	('K26/34R', 'Var', (244, 251))	('K34R', 'Mutation', 'p.K34R', (208, 212))	('arginine', 'Chemical', 'MESH:D001120', (82, 90))	('K34', 'Gene', '3885', (208, 211))	('K34', 'Gene', '3885', (225, 228))	('K34', 'Gene', '3885', (53, 56))	('glutamine', 'Chemical', 'MESH:D005973', (137, 146))	('K26Q', 'Chemical', '-', (216, 220))	('K34', 'Gene', (208, 211))	('K34', 'Gene', (225, 228))	('K34', 'Gene', (53, 56))	('K26Q', 'Var', (216, 220))	('K26R', 'SUBSTITUTION', 'None', (199, 203))	('K26R', 'Var', (199, 203))
776515	32313942	The acetylation level of HMGA2 were no longer elevated by HBXIP in the K26R, K26/34R, K26Q, and K26/34Q mutants (Figure 2G and Supplementary Figure S2G), suggesting that K26 could be the major acetylation site of HMGA2 mediated by HBXIP.	('K26/34Q', 'Var', (96, 103))	('elevated', 'PosReg', (46, 54))	('K26Q', 'Var', (86, 90))	('K26R', 'SUBSTITUTION', 'None', (71, 75))	('K26/34R', 'Var', (77, 84))	('K26R', 'Var', (71, 75))	('acetylation level', 'MPA', (4, 21))	('K26Q', 'Chemical', '-', (86, 90))
776516	32313942	Accordingly, we transfected HEK293T cells with different vectors of HMGA2 including wild-type (WT), K26R mutant and K26Q mutant.	('K26Q mutant', 'Var', (116, 127))	('K26R', 'SUBSTITUTION', 'None', (100, 104))	('K26Q', 'Chemical', '-', (116, 120))	('HMGA2', 'Gene', (68, 73))	('HEK293T', 'CellLine', 'CVCL:0063', (28, 35))	('K26R', 'Var', (100, 104))
776517	32313942	The K26R and K26Q mutant HMGA2 were more stable than WT HMGA2 (Figure 2H and Supplementary Figure S2I).	('K26R', 'SUBSTITUTION', 'None', (4, 8))	('K26Q', 'Chemical', '-', (13, 17))	('K26Q', 'Var', (13, 17))	('K26R', 'Var', (4, 8))	('HMGA2', 'Gene', (25, 30))
776518	32313942	Moreover, the K26R and K26Q mutations abolished the TSA-induced increase in HMGA2 and abrogated the HBXIP-induced stability of HMGA2 (Figure 2I, J and Supplementary Figure S2J, K).	('abolished', 'NegReg', (38, 47))	('abrogated', 'NegReg', (86, 95))	('K26Q', 'Chemical', '-', (23, 27))	('HMGA2', 'Protein', (76, 81))	('HBXIP-induced stability', 'MPA', (100, 123))	('K26R', 'SUBSTITUTION', 'None', (14, 18))	('increase', 'PosReg', (64, 72))	('TSA', 'Chemical', 'MESH:C012589', (52, 55))	('K26Q', 'Var', (23, 27))	('K26R', 'Var', (14, 18))
776520	32313942	Notably, the knockdown of PCAF effectively abolished the HBXIP-mediated increase in HMGA2 acetylation in KYSE2 cells, whereas the silencing of other acetyltransferases, including CBP, p300 and GCN5, showed little effect on HMGA2 acetylation (Figure 3A and Supplementary Figure S3A-D).	('increase', 'PosReg', (72, 80))	('p300', 'Gene', '2033', (184, 188))	('GCN5', 'Gene', '2648', (193, 197))	('PCAF', 'Gene', (26, 30))	('KYSE2', 'CellLine', 'CVCL:1351', (105, 110))	('CBP', 'Gene', '1387', (179, 182))	('HMGA2', 'Protein', (84, 89))	('knockdown', 'Var', (13, 22))	('p300', 'Gene', (184, 188))	('acetylation', 'MPA', (90, 101))	('silencing', 'Var', (130, 139))	('abolished', 'NegReg', (43, 52))	('GCN5', 'Gene', (193, 197))	('CBP', 'Gene', (179, 182))
776522	32313942	Further data showed that the AcK26-HMGA2 antibody recognized acetylated HMGA2-WT at K26, but did not recognize K26Q or K26R mutations (Supplementary Figure S3H).	('K26R', 'SUBSTITUTION', 'None', (119, 123))	('acetylated', 'MPA', (61, 71))	('K26R', 'Var', (119, 123))	('HMGA2-WT', 'Gene', (72, 80))	('K26Q', 'Chemical', '-', (111, 115))
776526	32313942	Intriguingly, PCAF overexpression increased endogenous HMGA2 protein levels (Figure 3G), whereas in K26R mutant-overexpressed cells PCAF lost the capacity of increasing HMGA2 protein levels (Figure 3H), suggesting that K26 in HMGA2 is required for PCAF-induced HMGA2 acetylation.	('expression', 'Species', '29278', (23, 33))	('HMGA2 protein levels', 'MPA', (169, 189))	('lost', 'NegReg', (137, 141))	('mutant-overexpressed', 'Var', (105, 125))	('K26R', 'SUBSTITUTION', 'None', (100, 104))	('increasing', 'PosReg', (158, 168))	('endogenous HMGA2 protein levels', 'MPA', (44, 75))	('increased', 'PosReg', (34, 43))	('K26R', 'Var', (100, 104))
776527	32313942	HBXIP-mediated stabilization of HMGA2 was largely abrogated by PCAF knockdown in KYSE180 cells (Figure 3J and Supplementary Figure S3K).	('stabilization', 'MPA', (15, 28))	('HMGA2', 'Gene', (32, 37))	('abrogated', 'NegReg', (50, 59))	('KYSE180', 'CellLine', 'CVCL:1349', (81, 88))	('PCAF', 'Gene', (63, 67))	('knockdown', 'Var', (68, 77))
776531	32313942	PCAF phosphorylation level was measured after HBXIP overexpression or silencing.	('silencing', 'Var', (70, 79))	('expression', 'Species', '29278', (56, 66))	('PCAF phosphorylation level', 'MPA', (0, 26))
776534	32313942	To screen the kinases responsible for PCAF phosphorylation, we treated KYSE180 cells with three kinase inhibitors, including GSK690693 (an inhibitor of Akt), PD98059 (an inhibitor of the upstream kinase of ERK1/2), and SB202190 (an inhibitor of p38).	('p38', 'Gene', '5594', (245, 248))	('PD98059', 'Var', (158, 165))	('GSK690693', 'Chemical', 'MESH:C528328', (125, 134))	('ERK1/2', 'Gene', (206, 212))	('SB202190', 'Chemical', 'MESH:C090942', (219, 227))	('ERK1/2', 'Gene', '5595;5594', (206, 212))	('Akt', 'Gene', (152, 155))	('p38', 'Gene', (245, 248))	('SB202190', 'Var', (219, 227))	('PD98059', 'Chemical', 'MESH:C093973', (158, 165))	('Akt', 'Gene', '207', (152, 155))	('KYSE180', 'CellLine', 'CVCL:1349', (71, 78))	('GSK690693', 'Var', (125, 134))
776538	32313942	These results were confirmed using siRNA-mediated Akt knockdown (Supplementary Figure S4A and B).	('Akt', 'Gene', '207', (50, 53))	('Akt', 'Gene', (50, 53))	('knockdown', 'Var', (54, 63))
776540	32313942	We firstly transfected KYSE180 cells with plasmids expressing FLAG-HMGA2-WT, FLAG-HMGA2-K26R, FLAG-HMGA2-K26Q, FLAG-HMGA2-WT with PCAF overexpression, and FLAG-HMGA2-WT with PCAF knockdown separately (Figure 5A).	('K26R', 'SUBSTITUTION', 'None', (88, 92))	('KYSE180', 'CellLine', 'CVCL:1349', (23, 30))	('K26Q', 'Chemical', '-', (105, 109))	('K26R', 'Var', (88, 92))	('expression', 'Species', '29278', (139, 149))	('FLAG-HMGA2-K26Q', 'Var', (94, 109))
776543	32313942	Results showed that HMGA2-K26Q occupied the promoter regions of the target genes to a high extent than the HMGA2-WT as determined by ChIP assays (Figure 5B and C).	('HMGA2-K26Q', 'Var', (20, 30))	('promoter', 'MPA', (44, 52))	('K26Q', 'Chemical', '-', (26, 30))
776544	32313942	However, HMGA2-K26R decreased the DNA binding capacity of HMGA2 to the target gene promoters compared to HMGA2-WT in ChIP assays (Figure 5B and C).	('decreased', 'NegReg', (20, 29))	('K26R', 'Var', (15, 19))	('DNA', 'MPA', (34, 37))	('HMGA2', 'Gene', (58, 63))	('K26R', 'SUBSTITUTION', 'None', (15, 19))
776545	32313942	Notably, PCAF overexpression enhanced the HMGA2-WT occupancy to the target gene promoters by ChIP assays (Figure 5B and C).	('overexpression', 'Var', (14, 28))	('expression', 'Species', '29278', (18, 28))	('HMGA2-WT occupancy to', 'MPA', (42, 63))	('enhanced', 'PosReg', (29, 37))	('PCAF', 'Gene', (9, 13))
776546	32313942	The expression of HMGA2-K26Q obviously increased its ability in promoting the proliferation of KYSE180 cells compared to HMGA2-WT (Figure 5D and E).	('expression', 'Species', '29278', (4, 14))	('KYSE180', 'CellLine', 'CVCL:1349', (95, 102))	('HMGA2-K26Q', 'Var', (18, 28))	('increased', 'PosReg', (39, 48))	('K26Q', 'Chemical', '-', (24, 28))	('promoting', 'PosReg', (64, 73))
776547	32313942	However, compared to the HMGA2-WT, the cell proliferation of HMGA2-K26R-expressed group was significantly decreased (Figure 5D and E).	('decreased', 'NegReg', (106, 115))	('cell proliferation', 'CPA', (39, 57))	('K26R', 'SUBSTITUTION', 'None', (67, 71))	('K26R', 'Var', (67, 71))
776549	32313942	However, knockdown of PCAF decreased the ability of HMGA2-WT in promoting the proliferation of KYSE180 cells (Figure 5D and E).	('PCAF', 'Gene', (22, 26))	('knockdown', 'Var', (9, 18))	('KYSE180', 'CellLine', 'CVCL:1349', (95, 102))	('proliferation of KYSE180 cells', 'CPA', (78, 108))	('promoting', 'PosReg', (64, 73))
776553	32313942	The acetylation of specific lysines can increase the stability of a protein through preventing ubiquitination of the same lysine residues.	('ubiquitination', 'MPA', (95, 109))	('lysine', 'Chemical', 'MESH:D008239', (28, 34))	('lysines', 'Chemical', 'MESH:D008239', (28, 35))	('preventing', 'NegReg', (84, 94))	('increase', 'PosReg', (40, 48))	('lysine', 'Chemical', 'MESH:D008239', (122, 128))	('stability', 'MPA', (53, 62))	('acetylation', 'Var', (4, 15))
776557	32313942	Therefore, we assessed the ubiquitination level of the K26R HMGA2 mutant in cells.	('K26R', 'Var', (55, 59))	('K26R', 'SUBSTITUTION', 'None', (55, 59))	('HMGA2', 'Gene', (60, 65))	('ubiquitination level', 'MPA', (27, 47))
776558	32313942	Interestingly, the K26R mutation dramatically reduced HMGA2 ubiquitination, indicating that K26 might also be the target residue for ubiquitination (Figure 6C).	('reduced', 'NegReg', (46, 53))	('K26R', 'Var', (19, 23))	('HMGA2 ubiquitination', 'MPA', (54, 74))	('K26R', 'SUBSTITUTION', 'None', (19, 23))
776559	32313942	Importantly, the inhibition of deacetylases with TSA decreased the ubiquitination of WT but not of the K26R or K26Q HMGA2 mutants (Figure 6D and E).	('K26Q', 'Var', (111, 115))	('decreased', 'NegReg', (53, 62))	('TSA', 'Chemical', 'MESH:C012589', (49, 52))	('HMGA2', 'Gene', (116, 121))	('K26R', 'SUBSTITUTION', 'None', (103, 107))	('deacetylases', 'Enzyme', (31, 43))	('inhibition', 'NegReg', (17, 27))	('ubiquitination', 'MPA', (67, 81))	('K26Q', 'Chemical', '-', (111, 115))	('K26R', 'Var', (103, 107))
776561	32313942	Consistently, HBXIP overexpression upregulated the acetylation and downregulated the ubiquitination of WT HMGA2 but showed no effects on the K26R or K26Q HMGA2 mutants (Figure 6I).	('expression', 'Species', '29278', (24, 34))	('K26R', 'Var', (141, 145))	('ubiquitination', 'MPA', (85, 99))	('K26Q', 'Chemical', '-', (149, 153))	('K26Q', 'Var', (149, 153))	('HMGA2', 'Gene', (154, 159))	('upregulated', 'PosReg', (35, 46))	('K26R', 'SUBSTITUTION', 'None', (141, 145))	('acetylation', 'MPA', (51, 62))	('downregulated', 'NegReg', (67, 80))
776563	32313942	As expected, shRNA-mediated HBXIP silencing disrupted the HMGA2-enhanced cyclin A, SOX2 and hTERT expression at the mRNA level in KYSE180 and KYSE510 cells (Figure 7A and Supplementary Figure S5A), suggesting that HBXIP contributes to HMGA2-mediated transcription.	('KYSE510', 'CellLine', 'CVCL:1354', (142, 149))	('SOX2', 'Gene', (83, 87))	('SOX2', 'Gene', '6657', (83, 87))	('KYSE180', 'CellLine', 'CVCL:1349', (130, 137))	('HMGA2-enhanced', 'PosReg', (58, 72))	('disrupted', 'NegReg', (44, 53))	('hTERT', 'Gene', '7015', (92, 97))	('cyclin A', 'Gene', (73, 81))	('hTERT', 'Gene', (92, 97))	('expression', 'Species', '29278', (98, 108))	('silencing', 'Var', (34, 43))	('cyclin A', 'Gene', '890', (73, 81))	('expression', 'MPA', (98, 108))
776564	32313942	EdU and colony formation assays revealed that ectopic HMGA2 expression significantly promoted KYSE180 and KYSE510 cell proliferation.	('ectopic', 'Var', (46, 53))	('promoted', 'PosReg', (85, 93))	('HMGA2', 'Gene', (54, 59))	('KYSE510', 'CellLine', 'CVCL:1354', (106, 113))	('KYSE180', 'CellLine', 'CVCL:1349', (94, 101))	('expression', 'Species', '29278', (60, 70))
776565	32313942	Moreover, the growth of KYSE180 xenografts in mice was markedly reinforced by HMGA2 overexpression, while this stimulation of tumor xenograft growth was largely abrogated by HBXIP knockdown (Figure 7D-F).	('HMGA2', 'Gene', (78, 83))	('growth', 'CPA', (14, 20))	('overexpression', 'Var', (84, 98))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('KYSE180', 'CellLine', 'CVCL:1349', (24, 31))	('mice', 'Species', '10090', (46, 50))	('expression', 'Species', '29278', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('reinforced', 'PosReg', (64, 74))	('tumor', 'Disease', (126, 131))
776573	32313942	We treated KYSE2 and KYSE450 cells with aspirin and the results showed that aspirin markedly decreased HBXIP and HMGA2 levels in a dose-dependent manner (Figure 8A).	('HMGA2 levels', 'MPA', (113, 125))	('HBXIP', 'MPA', (103, 108))	('decreased', 'NegReg', (93, 102))	('aspirin', 'Chemical', 'MESH:D001241', (40, 47))	('KYSE450', 'CellLine', 'CVCL:1353', (21, 28))	('KYSE2', 'CellLine', 'CVCL:1351', (11, 16))	('aspirin', 'Chemical', 'MESH:D001241', (76, 83))	('aspirin', 'Var', (76, 83))
776590	32313942	Moreover, high HBXIP and HMGA2 levels were associated with advanced tumor stage and poor overall and progression-free survival.	('tumor', 'Disease', (68, 73))	('poor', 'NegReg', (84, 88))	('overall', 'CPA', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('high', 'Var', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('HMGA2', 'Gene', (25, 30))
776595	32313942	Acetylation modifications stimulated lactate dehydrogenase A (LDHA) to undergo degradation leading to weakened glycolysis and lactate production.	('glycolysis', 'MPA', (111, 121))	('degradation', 'MPA', (79, 90))	('LDHA', 'Gene', (62, 66))	('lactate', 'Chemical', 'MESH:D019344', (37, 44))	('Acetylation modifications', 'Var', (0, 25))	('lactate dehydrogenase A', 'Gene', (37, 60))	('weakened', 'NegReg', (102, 110))	('LDHA', 'Gene', '3939', (62, 66))	('lactate', 'Chemical', 'MESH:D019344', (126, 133))	('lactate dehydrogenase A', 'Gene', '3939', (37, 60))	('lactate production', 'MPA', (126, 144))	('modifications', 'Var', (12, 25))	('stimulated', 'Reg', (26, 36))
776596	32313942	Additionally, alpha-tubulin acetylation promotes microtubule stabilization, resulting in persistent directional movement.	('acetylation', 'Var', (28, 39))	('microtubule stabilization', 'MPA', (49, 74))	('alpha-tubulin', 'Gene', (14, 27))	('alpha-tubulin', 'Gene', '10376', (14, 27))	('directional movement', 'CPA', (100, 120))	('promotes', 'PosReg', (40, 48))
776601	32313942	For example, the phosphorylation of the HMGA2 by Cdc2 kinase at Ser-43 and Ser-58 changes its conformation and weakens the strength of binding to the beta-interferon promoter and phosphorylation of HMGA2 by Nek2 is essential for chromatin condensation in meiosis.	('Nek2', 'Gene', '4751', (207, 211))	('Ser-58', 'Var', (75, 81))	('strength', 'MPA', (123, 131))	('phosphorylation', 'MPA', (17, 32))	('phosphorylation', 'MPA', (179, 194))	('weakens', 'NegReg', (111, 118))	('Cdc2', 'Gene', (49, 53))	('HMGA2', 'Gene', (40, 45))	('changes', 'Reg', (82, 89))	('conformation', 'MPA', (94, 106))	('Ser', 'Chemical', 'MESH:D012694', (75, 78))	('binding', 'Interaction', (135, 142))	('Cdc2', 'Gene', '983', (49, 53))	('Ser', 'Chemical', 'MESH:D012694', (64, 67))	('Nek2', 'Gene', (207, 211))
776602	32313942	In addition, SUMOylation of HMGA2 plays a critical role in stimulating HMGA2 function in decreasing PML protein level.	('function', 'MPA', (77, 85))	('HMGA2', 'Gene', (71, 76))	('PML', 'Gene', '5371', (100, 103))	('decreasing', 'NegReg', (89, 99))	('HMGA2', 'Gene', (28, 33))	('PML', 'Phenotype', 'HP:0004836', (100, 103))	('stimulating', 'Reg', (59, 70))	('SUMOylation', 'Var', (13, 24))	('PML', 'Gene', (100, 103))
776611	32313942	It has been reported that a Lys Gln mutation can mimic the acetylated state of lysine (K) mainly because of the structure similarity between the Gln (Q) residue and the acetylated-lysine residue and a Lys Arg mutation eliminates the epsilon-amino group of the lysine residues to mimic the acetylation-deficient state.	('lysine', 'Chemical', 'MESH:D008239', (79, 85))	('lysine', 'Chemical', 'MESH:D008239', (180, 186))	('Lys Gln', 'Chemical', '-', (28, 35))	('Gln', 'Chemical', 'MESH:D005973', (145, 148))	('Gln', 'Chemical', 'MESH:D005973', (32, 35))	('epsilon-amino group of the lysine residues', 'MPA', (233, 275))	('lysine', 'Chemical', 'MESH:D008239', (260, 266))	('Lys Gln', 'Var', (28, 35))	('Lys Arg', 'Chemical', '-', (201, 208))	('acetylation-deficient', 'MPA', (289, 310))	('eliminates', 'NegReg', (218, 228))
776612	32313942	In the present study, we found that the acetylation-mimetic K26Q and acetylation-deficient K26R mutants were more stable than WT HMGA2 following CHX treatment; a possible explanation is that there might be a competition between polyubiquitination and acetylation at the same lysine 26 residue in HMGA2 stability regulation.	('lysine', 'Chemical', 'MESH:D008239', (275, 281))	('K26R', 'SUBSTITUTION', 'None', (91, 95))	('K26Q', 'Chemical', '-', (60, 64))	('K26R', 'Var', (91, 95))	('K26Q', 'Var', (60, 64))	('CHX', 'Chemical', 'MESH:D003513', (145, 148))
776614	32313942	The acetylation-deficient K26R mutants lost the epsilon-amino group of the lysine 26 residue for ubiquitination, therefore preventing ubiquitination and ubiquitination-dependent proteasomal degradation and then leading to HMGA2 protein stability.	('ubiquitination', 'MPA', (134, 148))	('HMGA2', 'MPA', (222, 227))	('mutants', 'Var', (31, 38))	('lost', 'NegReg', (39, 43))	('K26R', 'SUBSTITUTION', 'None', (26, 30))	('ubiquitination-dependent proteasomal degradation', 'MPA', (153, 201))	('leading to', 'Reg', (211, 221))	('epsilon-amino group', 'MPA', (48, 67))	('lysine', 'Chemical', 'MESH:D008239', (75, 81))	('K26R', 'Var', (26, 30))	('ubiquitination', 'MPA', (97, 111))	('preventing', 'NegReg', (123, 133))
776633	31920637	PD-1 Inhibitors in the Advanced Esophageal Cancer Esophageal cancer (EC) is a lethal disease, and ranks 7th in incidence and 6th in mortality worldwide.	('Esophageal Cancer', 'Disease', (32, 49))	('PD-1', 'Gene', (0, 4))	('Esophageal cancer', 'Disease', (50, 67))	('EC', 'Disease', 'MESH:D004938', (69, 71))	('PD-1', 'Gene', '5133', (0, 4))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (32, 49))	('Inhibitors', 'Var', (5, 15))
776636	31920637	Preclinical and clinical studies have found the PD-1/PD-L1 inhibitors activate T lymphocytes, inhibit cancer growth, and improve survival in cancer patients.	('patients', 'Species', '9606', (148, 156))	('T lymphocytes', 'CPA', (79, 92))	('PD-L1', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('survival', 'CPA', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('PD-L1', 'Gene', '29126', (53, 58))	('PD-1', 'Gene', (48, 52))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('activate', 'PosReg', (70, 78))	('PD-1', 'Gene', '5133', (48, 52))	('inhibitors', 'Var', (59, 69))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('improve', 'PosReg', (121, 128))	('inhibit', 'NegReg', (94, 101))	('cancer', 'Disease', (141, 147))
776649	31920637	Preclinical and clinical studies have found the PD-1/PD-L1 inhibitors activate T lymphocytes.	('T lymphocytes', 'CPA', (79, 92))	('PD-L1', 'Gene', (53, 58))	('PD-L1', 'Gene', '29126', (53, 58))	('PD-1', 'Gene', (48, 52))	('activate', 'PosReg', (70, 78))	('PD-1', 'Gene', '5133', (48, 52))	('inhibitors', 'Var', (59, 69))
776741	31920637	For the severe (grade 3-5) irAE, pembrolizumab also had worse record in hypothyroidism (0.4%-2.5% and 0), pneumonitis (0.3%-2.6% and 0.3%), colitis (0.3%-1.2% and 0.3%), and hepatitis (0.4%-1% and 0) than nivolumab.	('pneumonitis', 'Disease', 'MESH:D011014', (106, 117))	('hepatitis', 'Disease', (174, 183))	('hepatitis', 'Phenotype', 'HP:0012115', (174, 183))	('hypothyroidism', 'Phenotype', 'HP:0000821', (72, 86))	('colitis', 'Disease', (140, 147))	('hypothyroidism', 'Disease', (72, 86))	('hepatitis', 'Disease', 'MESH:D056486', (174, 183))	('colitis', 'Phenotype', 'HP:0002583', (140, 147))	('pembrolizumab', 'Var', (33, 46))	('colitis', 'Disease', 'MESH:D003092', (140, 147))	('pneumonitis', 'Disease', (106, 117))	('hypothyroidism', 'Disease', 'MESH:D007037', (72, 86))
776936	24496156	Esophageal and gastric leakage from postoperative anastomoses dehiscence, staple-line dehiscence, or iatrogenic perforation can be a devastating event and have significant impact on patient's morbidity, mortality and quality of life.	('staple-line dehiscence', 'Disease', (74, 96))	('anastomoses dehiscence', 'Phenotype', 'HP:0032156', (50, 72))	('patient', 'Species', '9606', (182, 189))	('impact', 'Reg', (172, 178))	('dehiscence', 'Var', (62, 72))
776963	19674341	The idea of using Mendelian randomization in controlling biased associations was first put forth by Katan, who suggested that the evidence for APOE (apolipoprotein E gene) genetic variants and cholesterol association might help explain the causal effects of very low cholesterol on cancer.	('apolipoprotein E', 'Gene', (149, 165))	('cholesterol', 'Chemical', 'MESH:D002784', (267, 278))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('APOE', 'Gene', (143, 147))	('apolipoprotein E', 'Gene', '348', (149, 165))	('variants', 'Var', (180, 188))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('APOE', 'Gene', '348', (143, 147))	('low cholesterol', 'Phenotype', 'HP:0003146', (263, 278))	('cancer', 'Disease', (282, 288))	('cholesterol', 'Chemical', 'MESH:D002784', (193, 204))
776977	19674341	A single point mutation in ALDH2 results in the 2*2 allele (glutamic acid to lysine substitution at residue 487) and inactivation of the enzyme.	('single point mutation', 'Var', (2, 23))	('results in', 'Reg', (33, 43))	('inactivation', 'NegReg', (117, 129))	('enzyme', 'Enzyme', (137, 143))	('glutamic acid to lysine substitution at residue 487', 'Mutation', 'rs671', (60, 111))	('ALDH2', 'Gene', (27, 32))	('glutamic', 'Var', (60, 68))
776980	19674341	Drinking alcohol is likely to cause unpleasant symptoms such as nausea, drowsiness, and headache in the carriers.	('nausea', 'Disease', (64, 70))	('alcohol', 'Chemical', 'MESH:D000438', (9, 16))	('drowsiness', 'Disease', (72, 82))	('nausea', 'Disease', 'MESH:D009325', (64, 70))	('headache', 'Phenotype', 'HP:0002315', (88, 96))	('drowsiness', 'Phenotype', 'HP:0002329', (72, 82))	('headache', 'Disease', 'MESH:D006261', (88, 96))	('Drinking alcohol', 'Var', (0, 16))	('headache', 'Disease', (88, 96))	('nausea', 'Phenotype', 'HP:0002018', (64, 70))
776986	19674341	performed a meta-analysis on the association between ALDH2 genotype and blood pressure (N = 7,685 from five studies) and hypertension (N = 4,219 from three studies).	('hypertension', 'Phenotype', 'HP:0000822', (121, 133))	('ALDH2', 'Gene', (53, 58))	('blood pressure', 'Disease', (72, 86))	('hypertension', 'Disease', 'MESH:D006973', (121, 133))	('genotype', 'Var', (59, 67))	('hypertension', 'Disease', (121, 133))	('association', 'Interaction', (33, 44))
776994	19674341	assessed whether LCT (lactase) and TAS2R38 (taste receptor, type 2, member 38) gene variants could be used as proxies for dairy and cruciferous vegetable intakes in Mendelian randomization analysis.	('LCT', 'Gene', '3938', (17, 20))	('TAS2R38', 'Gene', (35, 42))	('taste receptor, type 2, member 38', 'Gene', '5726', (44, 77))	('LCT', 'Gene', (17, 20))	('lactase', 'Gene', (22, 29))	('variants', 'Var', (84, 92))	('TAS2R38', 'Gene', '5726', (35, 42))	('lactase', 'Gene', '3938', (22, 29))
776996	19674341	People homozygous for allele-C of LCT SNP rs4988235 C>T have almost undetectable levels of intestinal lactase production compared with people with TC and TT genotypes.	('lactase', 'Gene', '3938', (102, 109))	('LCT', 'Gene', '3938', (34, 37))	('rs4988235 C>T', 'Var', (42, 55))	('people', 'Species', '9606', (135, 141))	('undetectable', 'NegReg', (68, 80))	('People', 'Species', '9606', (0, 6))	('LCT', 'Gene', (34, 37))	('TC', 'Chemical', 'MESH:D013667', (147, 149))	('rs4988235', 'Mutation', 'rs4988235', (42, 51))	('lactase', 'Gene', (102, 109))
776997	19674341	The LCT variant was associated with consumption of dairy products such as ice cream (P = 0.004) and less so for milk intake.	('variant', 'Var', (8, 15))	('associated', 'Reg', (20, 30))	('LCT', 'Gene', (4, 7))	('LCT', 'Gene', '3938', (4, 7))
776999	19674341	Two SNPs in this gene, rs713598 (Pro49Ala) and rs1726866 (Ala262Val), form two haplotypes that refer to taster and non-taster status for a bitter chemical phenylthiocarbamide.	('rs713598', 'Mutation', 'rs713598', (23, 31))	('Pro49Ala', 'Var', (33, 41))	('phenylthiocarbamide', 'Chemical', 'MESH:D010670', (155, 174))	('Pro49Ala', 'SUBSTITUTION', 'None', (33, 41))	('Ala262Val', 'Var', (58, 67))	('rs1726866', 'Var', (47, 56))	('rs713598', 'Var', (23, 31))	('refer', 'Reg', (95, 100))	('Ala262Val', 'SUBSTITUTION', 'None', (58, 67))	('rs1726866', 'Mutation', 'rs1726866', (47, 56))
777001	19674341	The haplotypes of TAS2R38 gene variants were significantly related to cruciferous vegetable intake (P = 0.02).	('variants', 'Var', (31, 39))	('cruciferous vegetable intake', 'Disease', (70, 98))	('TAS2R38', 'Gene', (18, 25))	('haplotypes', 'Var', (4, 14))	('related', 'Reg', (59, 66))	('TAS2R38', 'Gene', '5726', (18, 25))
777002	19674341	The data suggest that LCT and TAS2R38 genetic variants can be used as proxies for intakes of dairy and cruciferous vegetable in Mendelian randomization studies.	('TAS2R38', 'Gene', (30, 37))	('LCT', 'Gene', (22, 25))	('TAS2R38', 'Gene', '5726', (30, 37))	('variants', 'Var', (46, 54))	('LCT', 'Gene', '3938', (22, 25))
777004	19674341	examined the causal effect of lifetime adiposity on carotid intima-media thickness (CIMT, a preclinical marker for atherosclerosis risk) and atherosclerotic risk factors in 2,230 individuals from the Cardiovascular Risk in Young Finns study, using a variant in the FTO gene (fat mass and obesity associated).	('atherosclerotic', 'Disease', (141, 156))	('CIMT', 'Gene', '404677', (84, 88))	('variant', 'Var', (250, 257))	('CIMT', 'Gene', (84, 88))	('atherosclerotic', 'Disease', 'MESH:D050197', (141, 156))	('carotid', 'MPA', (52, 59))	('FTO', 'Gene', '79068', (265, 268))	('obesity', 'Disease', 'MESH:D009765', (288, 295))	('atherosclerosis', 'Disease', (115, 130))	('obesity', 'Disease', (288, 295))	('FTO', 'Gene', (265, 268))	('obesity', 'Phenotype', 'HP:0001513', (288, 295))	('atherosclerotic risk factors', 'Phenotype', 'HP:0002621', (141, 169))	('atherosclerosis', 'Disease', 'MESH:D050197', (115, 130))	('atherosclerosis', 'Phenotype', 'HP:0002621', (115, 130))
777006	19674341	FTO polymorphism rs9939609, which has been reproducibly associated with high adiposity, was used as an IV for lifetime body mass index (BMI).	('FTO', 'Gene', '79068', (0, 3))	('high adiposity', 'MPA', (72, 86))	('FTO', 'Gene', (0, 3))	('rs9939609', 'Var', (17, 26))	('rs9939609', 'Mutation', 'rs9939609', (17, 26))
777021	19674341	A CRP SNP rs1800947, which was related to low CRP levels, was used as a proxy for CRP level.	('CRP', 'Gene', (46, 49))	('CRP', 'Gene', '1401', (46, 49))	('CRP', 'Gene', (2, 5))	('CRP', 'Gene', '1401', (2, 5))	('rs1800947', 'Var', (10, 19))	('CRP', 'Gene', (82, 85))	('CRP', 'Gene', '1401', (82, 85))	('rs1800947', 'Mutation', 'rs1800947', (10, 19))
777023	19674341	examined the causal effects of CRP on nonfatal myocardial infarction (MI), using the genetic data on CRP +1444C>T polymorphism (rs1130864).	('rs1130864', 'Mutation', 'rs1130864', (128, 137))	('CRP', 'Gene', (101, 104))	('+1444C>T', 'Mutation', 'rs1130864', (105, 113))	('myocardial infarction', 'Phenotype', 'HP:0001658', (47, 68))	('CRP', 'Gene', '1401', (101, 104))	('CRP', 'Gene', '1401', (31, 34))	('CRP', 'Gene', (31, 34))	('rs1130864', 'Var', (128, 137))	('myocardial infarction', 'Disease', (47, 68))	('myocardial infarction', 'Disease', 'MESH:D009203', (47, 68))
777027	19674341	examined the causality between CRP and CIMT by determining haplotypes from genetic variants in the CRP gene (rs2794521, rs3091244, rs1800947, rs1130864, and rs1205) in 1,609 young Finns (768 men and 841 women).	('rs3091244', 'Var', (120, 129))	('rs1130864', 'Mutation', 'rs1130864', (142, 151))	('rs1800947', 'Var', (131, 140))	('CRP', 'Gene', (99, 102))	('men', 'Species', '9606', (191, 194))	('rs3091244', 'Mutation', 'rs3091244', (120, 129))	('CRP', 'Gene', '1401', (31, 34))	('rs2794521', 'Mutation', 'rs2794521', (109, 118))	('rs2794521', 'Var', (109, 118))	('CIMT', 'Gene', (39, 43))	('men', 'Species', '9606', (205, 208))	('rs1130864', 'Var', (142, 151))	('women', 'Species', '9606', (203, 208))	('rs1205', 'Mutation', 'rs1205', (157, 163))	('rs1800947', 'Mutation', 'rs1800947', (131, 140))	('CIMT', 'Gene', '404677', (39, 43))	('CRP', 'Gene', '1401', (99, 102))	('CRP', 'Gene', (31, 34))	('rs1205', 'Var', (157, 163))
777032	19674341	Linear regression analysis and Mendelian randomization IV analysis (CRP haplotypes from rs2794521, rs1800947, rs1130864, and rs1205 as instrument) generated conflicting associations of CRP levels with BMI (P = 0.0002), insulin resistance (P = 0.0139), triglycerides (P = 0.0313), and HDL cholesterol (P = 0.0688).	('rs2794521', 'Var', (88, 97))	('cholesterol', 'Chemical', 'MESH:D002784', (288, 299))	('insulin', 'Gene', (219, 226))	('insulin resistance', 'Phenotype', 'HP:0000855', (219, 237))	('CRP', 'Gene', '1401', (185, 188))	('rs1800947', 'Var', (99, 108))	('BMI', 'Disease', (201, 204))	('CRP', 'Gene', (68, 71))	('associations', 'Interaction', (169, 181))	('triglycerides', 'Chemical', 'MESH:D014280', (252, 265))	('rs1130864', 'Mutation', 'rs1130864', (110, 119))	('men', 'Species', '9606', (141, 144))	('rs1205', 'Mutation', 'rs1205', (125, 131))	('HDL cholesterol', 'Disease', (284, 299))	('insulin', 'Gene', '3630', (219, 226))	('CRP', 'Gene', (185, 188))	('rs1205', 'Var', (125, 131))	('rs1800947', 'Mutation', 'rs1800947', (99, 108))	('CRP', 'Gene', '1401', (68, 71))	('rs1130864', 'Var', (110, 119))	('rs2794521', 'Mutation', 'rs2794521', (88, 97))	('triglycerides', 'Disease', (252, 265))
777034	19674341	In a recent study, the causal effects of CRP on diabetes were examined using a Mendelian randomization approach, in which CRP haplotypes (from rs3093077, rs1800947, and rs1205) were used as IVs for CRP level.	('diabetes', 'Disease', (48, 56))	('rs1205', 'Var', (169, 175))	('rs3093077', 'Mutation', 'rs3093077', (143, 152))	('rs1800947', 'Var', (154, 163))	('CRP', 'Gene', (198, 201))	('diabetes', 'Disease', 'MESH:D003920', (48, 56))	('rs1205', 'Mutation', 'rs1205', (169, 175))	('rs1800947', 'Mutation', 'rs1800947', (154, 163))	('from rs3093077', 'Var', (138, 152))	('CRP', 'Gene', '1401', (198, 201))	('CRP', 'Gene', (41, 44))	('CRP', 'Gene', (122, 125))	('CRP', 'Gene', '1401', (41, 44))	('CRP', 'Gene', '1401', (122, 125))
777039	19674341	In addition, analyses of the association between CRP haplotype and diabetes risk were consistently null in three study samples.	('CRP', 'Gene', '1401', (49, 52))	('haplotype', 'Var', (53, 62))	('diabetes', 'Disease', (67, 75))	('CRP', 'Gene', (49, 52))	('diabetes', 'Disease', 'MESH:D003920', (67, 75))
777045	19674341	examined the influence of plasma homocysteine level on the risk of stroke using genetic data on the MTHFR (5,10-methylenetetrahydrofolate reductase) C677T polymorphism, which leads to a high homocysteine level.	('stroke', 'Disease', (67, 73))	('high homocysteine level', 'MPA', (186, 209))	('MTHFR', 'Gene', '4524', (100, 105))	('homocysteine', 'Chemical', 'MESH:D006710', (191, 203))	('homocysteine', 'Chemical', 'MESH:D006710', (33, 45))	('5,10-methylenetetrahydrofolate reductase', 'Gene', '4524', (107, 147))	('stroke', 'Disease', 'MESH:D020521', (67, 73))	('MTHFR', 'Gene', (100, 105))	('stroke', 'Phenotype', 'HP:0001297', (67, 73))	('C677T', 'Mutation', 'rs1801133', (149, 154))	('C677T', 'Var', (149, 154))
777050	19674341	performed a meta-analysis on the associations of MTHFR C677T with circulating homocysteine levels and CHD risk.	('CHD', 'Disease', (102, 105))	('CHD', 'Disease', 'None', (102, 105))	('MTHFR', 'Gene', '4524', (49, 54))	('homocysteine', 'Chemical', 'MESH:D006710', (78, 90))	('C677T', 'Mutation', 'rs1801133', (55, 60))	('associations', 'Interaction', (33, 45))	('C677T', 'Var', (55, 60))	('MTHFR', 'Gene', (49, 54))	('circulating homocysteine levels', 'MPA', (66, 97))
777054	19674341	The missense variant Asp358Ala (rs8192284) in the interleukin-6 receptor gene (IL6R) was significantly related to circulating IL-6 levels.	('Asp358Ala', 'Var', (21, 30))	('IL6R', 'Gene', '3570', (79, 83))	('Asp358Ala', 'SUBSTITUTION', 'None', (21, 30))	('rs8192284', 'Var', (32, 41))	('interleukin-6 receptor gene', 'Gene', '3570', (50, 77))	('IL-6', 'Gene', (126, 130))	('interleukin-6 receptor gene', 'Gene', (50, 77))	('IL6R', 'Gene', (79, 83))	('IL-6', 'Gene', '3569', (126, 130))	('related', 'Reg', (103, 110))	('rs8192284', 'Mutation', 'rs8192284', (32, 41))
777059	19674341	SNP rs2228671 in the LDLR gene was consistently related to a decrease in LDL-C levels by 0.19 mmol/L and 18% (11-24%) decreased risk of CAD (per T allele) in multiple European samples.	('decrease', 'NegReg', (61, 69))	('rs2228671', 'Mutation', 'rs2228671', (4, 13))	('LDLR', 'Gene', (21, 25))	('CAD', 'Disease', (136, 139))	('LDL-C levels', 'MPA', (73, 85))	('LDLR', 'Gene', '3949', (21, 25))	('decreased', 'NegReg', (118, 127))	('SNP rs2228671', 'Var', (0, 13))
777060	19674341	The analysis revealed a highly significant association between the rs2228671 genotype and LDL-C as well as between LDL-C and CAD risk.	('CAD', 'Disease', (125, 128))	('rs2228671', 'Var', (67, 76))	('LDL-C', 'Disease', (90, 95))	('significant association', 'Reg', (31, 54))	('rs2228671', 'Mutation', 'rs2228671', (67, 76))
777061	19674341	The association between rs2228671 and the risk of CAD was abolished with adjustment for LDL-C levels.	('rs2228671', 'Var', (24, 33))	('CAD', 'Disease', (50, 53))	('men', 'Species', '9606', (79, 82))	('rs2228671', 'Mutation', 'rs2228671', (24, 33))
777062	19674341	The findings indicate a causal link among LDLR variant, change in LDL-C levels, and CAD risk.	('CAD', 'Disease', (84, 87))	('LDL-C levels', 'MPA', (66, 78))	('LDLR', 'Gene', (42, 46))	('variant', 'Var', (47, 54))	('LDLR', 'Gene', '3949', (42, 46))
777063	19674341	A body of data shows that low birth weight and fetal overgrowth carry an elevated risk of developing metabolic diseases, such as obesity, insulin resistance, dyslipidemia, hypertension, CHD, and stroke, during adulthood.	('stroke', 'Disease', (195, 201))	('dyslipidemia', 'Disease', 'MESH:D050171', (158, 170))	('hypertension', 'Disease', 'MESH:D006973', (172, 184))	('metabolic diseases', 'Disease', (101, 119))	('CHD', 'Disease', 'None', (186, 189))	('hypertension', 'Disease', (172, 184))	('fetal overgrowth', 'Phenotype', 'HP:0001548', (47, 63))	('obesity', 'Disease', (129, 136))	('fetal overgrowth', 'CPA', (47, 63))	('insulin', 'Gene', (138, 145))	('dyslipidemia', 'Phenotype', 'HP:0003119', (158, 170))	('hypertension', 'Phenotype', 'HP:0000822', (172, 184))	('dyslipidemia', 'Disease', (158, 170))	('insulin resistance', 'Phenotype', 'HP:0000855', (138, 156))	('obesity', 'Disease', 'MESH:D009765', (129, 136))	('low birth weight', 'Phenotype', 'HP:0001518', (26, 42))	('CHD', 'Disease', (186, 189))	('low birth', 'Var', (26, 35))	('metabolic diseases', 'Disease', 'MESH:D008659', (101, 119))	('stroke', 'Phenotype', 'HP:0001297', (195, 201))	('stroke', 'Disease', 'MESH:D020521', (195, 201))	('obesity', 'Phenotype', 'HP:0001513', (129, 136))	('insulin', 'Gene', '3630', (138, 145))
777067	19674341	performed a Mendelian randomization analysis, using maternal FTO SNP rs9939609 (T>A) genotype as IV, to test the causal effect of maternal adiposity on offspring obesity risk.	('obesity', 'Disease', (162, 169))	('FTO', 'Gene', '79068', (61, 64))	('test', 'Reg', (104, 108))	('FTO', 'Gene', (61, 64))	('obesity', 'Phenotype', 'HP:0001513', (162, 169))	('rs9939609', 'Mutation', 'rs9939609', (69, 78))	('rs9939609', 'Var', (69, 78))	('obesity', 'Disease', 'MESH:D009765', (162, 169))
777076	19674341	For instance, an APOE gene variant may affect various lipids (total cholesterol, LDL cholesterol, and apo B) and also cause other metabolic abnormalities; all can influence the same outcome such as cardiovascular disease.	('LDL cholesterol', 'MPA', (81, 96))	('APOE', 'Gene', (17, 21))	('lipids', 'Chemical', 'MESH:D008055', (54, 60))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (198, 220))	('cardiovascular disease', 'Disease', 'MESH:D002318', (198, 220))	('apo B', 'Gene', (102, 107))	('cardiovascular disease', 'Disease', (198, 220))	('cause', 'Reg', (118, 123))	('cholesterol', 'Chemical', 'MESH:D002784', (85, 96))	('metabolic abnormalities', 'Phenotype', 'HP:0001939', (130, 153))	('metabolic abnormalities', 'Disease', 'MESH:D008659', (130, 153))	('variant', 'Var', (27, 34))	('influence', 'Reg', (163, 172))	('lipids', 'MPA', (54, 60))	('metabolic abnormalities', 'Disease', (130, 153))	('cholesterol', 'Chemical', 'MESH:D002784', (68, 79))	('affect', 'Reg', (39, 45))	('apo B', 'Gene', '338', (102, 107))	('APOE', 'Gene', '348', (17, 21))
777079	19674341	Developmental and physiological adaptation may occur during the lifelong exposure to the gene-related changes through permanent alterations in tissue structure and function that offset the genetic influence.	('alterations', 'Reg', (128, 139))	('function', 'CPA', (164, 172))	('changes', 'Var', (102, 109))	('men', 'Species', '9606', (7, 10))	('tissue structure', 'CPA', (143, 159))
777081	19674341	TRD may result from selective survival between conception and entry into the study if the genetic variant of interest causes early mortality and may be widespread in the human genome.	('variant', 'Var', (98, 105))	('causes', 'Reg', (118, 124))	('human', 'Species', '9606', (170, 175))
777122	32459126	Barium sulfate was the most common radiographic contrast material for upper gastrointestinal investigations; however, leakage of barium sulfate into the mediastinum may cause mediastinitis, and the deposition of barium in the alveoli may result in refractory pulmonary infection.	('pulmonary infection', 'Disease', (259, 278))	('Barium sulfate', 'Chemical', 'MESH:D001466', (0, 14))	('pulmonary infection', 'Phenotype', 'HP:0006532', (259, 278))	('result in', 'Reg', (238, 247))	('barium', 'Var', (129, 135))	('mediastinitis', 'Disease', (175, 188))	('leakage', 'MPA', (118, 125))	('barium sulfate', 'Chemical', 'MESH:D001466', (129, 143))	('pulmonary infection', 'Disease', 'MESH:D012141', (259, 278))	('barium', 'Chemical', 'MESH:D001464', (212, 218))	('barium', 'Chemical', 'MESH:D001464', (129, 135))	('cause', 'Reg', (169, 174))
777224	32266126	- Post-surgical interventions, toxicity, and treatment-induced dermatitis management (i.e., radiotherapy, anti-EGFR antibodies).	('dermatitis', 'Disease', 'MESH:D003872', (63, 73))	('dermatitis', 'Disease', (63, 73))	('antibodies', 'Var', (116, 126))	('EGFR', 'Gene', '1956', (111, 115))	('toxicity', 'Disease', 'MESH:D064420', (31, 39))	('toxicity', 'Disease', (31, 39))	('dermatitis', 'Phenotype', 'HP:0011123', (63, 73))	('EGFR', 'Gene', (111, 115))
777281	32266126	All these alterations can lead to psychosocial dysfunction.	('lead to', 'Reg', (26, 33))	('psychosocial dysfunction', 'Disease', 'MESH:C535569', (34, 58))	('alterations', 'Var', (10, 21))	('psychosocial dysfunction', 'Disease', (34, 58))
777343	32266126	Inability to speak, or to do it with a "new voice" totally different from the one that has been "the own voice" during a person's life, involves very important changes in that person's daily life, and can significantly impact on his/her social and familiar relationships, ultimately leading to anxiety, depression, and alterations in self-esteem and self-image.	('changes', 'Reg', (160, 167))	('leading to', 'Reg', (283, 293))	('anxiety', 'Phenotype', 'HP:0000739', (294, 301))	('self-esteem', 'CPA', (334, 345))	('depression', 'Disease', 'MESH:D000275', (303, 313))	('depression', 'Phenotype', 'HP:0000716', (303, 313))	('anxiety', 'Disease', 'MESH:D001007', (294, 301))	('Inability to speak', 'Phenotype', 'HP:0002300', (0, 18))	('impact', 'Reg', (219, 225))	('depression', 'Disease', (303, 313))	('self-image', 'CPA', (350, 360))	('anxiety', 'Disease', (294, 301))	('alterations', 'Reg', (319, 330))	('Inability', 'Var', (0, 9))
777513	28600545	HOTAIR rs7958904 polymorphism is associated with increased cervical cancer risk in a Chinese population Previously, we have identified single nucleotide polymorphisms (SNPs) rs7958904 and rs4759314 in long non-coding RNA HOX transcript antisense RNA (HOTAIR) were significantly associated with risk of colorectal and gastric cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs7958904', 'Var', (174, 183))	('rs7958904', 'Var', (7, 16))	('associated', 'Reg', (278, 288))	('rs4759314', 'Var', (188, 197))	('colorectal and gastric cancer', 'Disease', 'MESH:D013274', (302, 331))	('cancer', 'Disease', (325, 331))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('HOTAIR', 'Gene', '100124700', (0, 6))	('gastric cancer', 'Phenotype', 'HP:0012126', (317, 331))	('increased cervical cancer', 'Phenotype', 'HP:0030159', (49, 74))	('HOTAIR', 'Gene', (0, 6))	('HOTAIR', 'Gene', '100124700', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('cancer', 'Disease', (68, 74))	('rs7958904', 'Mutation', 'rs7958904', (174, 183))	('HOTAIR', 'Gene', (251, 257))	('rs7958904', 'Mutation', 'rs7958904', (7, 16))	('rs4759314', 'Mutation', 'rs4759314', (188, 197))
777517	28600545	The rs7958904 CC genotype was related to an increased risk of cervical cancer compared with the GG/GC genotypes (OR = 1.57, 95% CI = 1.10-2.25).	('rs7958904 CC', 'Var', (4, 16))	('cervical cancer', 'Disease', (62, 77))	('cervical cancer', 'Disease', 'MESH:D002583', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs7958904', 'Mutation', 'rs7958904', (4, 13))	('CC', 'Phenotype', 'HP:0002664', (14, 16))
777518	28600545	TCGA database showed the CC tissues with rs7958904 CC genotype had higher HOTAIR expression than those with GG genotype (P = 0.046).	('higher', 'PosReg', (67, 73))	('CC', 'Phenotype', 'HP:0002664', (25, 27))	('HOTAIR', 'Gene', (74, 80))	('rs7958904 CC', 'Var', (41, 53))	('CC', 'Phenotype', 'HP:0002664', (51, 53))	('HOTAIR', 'Gene', '100124700', (74, 80))	('rs7958904', 'Mutation', 'rs7958904', (41, 50))
777519	28600545	MTT assay demonstrated a growth-promoting role of rs7958904 C allele on CC cells.	('rs7958904 C', 'Var', (50, 61))	('rs7958904', 'Mutation', 'rs7958904', (50, 59))	('CC', 'Phenotype', 'HP:0002664', (72, 74))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('growth-promoting', 'MPA', (25, 41))
777521	28600545	In conclusion, HOTAIR rs7958904 might influence CC susceptibility through modulation of CC cell proliferation, and could serve as a diagnostic biomarker.	('CC', 'Phenotype', 'HP:0002664', (88, 90))	('rs7958904', 'Mutation', 'rs7958904', (22, 31))	('influence', 'Reg', (38, 47))	('modulation', 'Reg', (74, 84))	('HOTAIR', 'Gene', (15, 21))	('HOTAIR', 'Gene', '100124700', (15, 21))	('CC', 'Phenotype', 'HP:0002664', (48, 50))	('rs7958904', 'Var', (22, 31))
777526	28600545	Deregulated lncRNAs have been reported to be involved in pathogenesis of cancers.	('lncRNAs', 'Protein', (12, 19))	('cancers', 'Disease', (73, 80))	('Deregulated', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('involved', 'Reg', (45, 53))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
777530	28600545	Recently, considerable efforts have been made to investigate the effect of genetic variations in the lncRNA genes on the susceptibility of various tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('genetic variations', 'Var', (75, 93))	('lncRNA', 'Gene', (101, 107))
777531	28600545	first reported that the tagging SNP (tagSNP) rs2839698 of H19 was significantly associated with the decreased risk of bladder cancer.	('H19', 'Gene', (58, 61))	('rs2839698', 'Mutation', 'rs2839698', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (118, 132))	('bladder cancer', 'Disease', (118, 132))	('decreased', 'NegReg', (100, 109))	('bladder cancer', 'Phenotype', 'HP:0009725', (118, 132))	('rs2839698', 'Var', (45, 54))	('H19', 'Gene', '283120', (58, 61))
777532	28600545	Hereafter, a number of lncRNA SNPs, such as rs6434568 in the PCGEM1 and rs11655237 in exon 4 of LINC00673 genes, have been found to confers susceptibility to tumorigenesis.	('rs6434568', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('LINC00673', 'Gene', (96, 105))	('PCGEM1', 'Gene', (61, 67))	('susceptibility', 'Reg', (140, 154))	('rs11655237', 'Mutation', 'rs11655237', (72, 82))	('tumorigenesis', 'CPA', (158, 171))	('rs6434568', 'Mutation', 'rs6434568', (44, 53))	('rs11655237', 'Var', (72, 82))	('LINC00673', 'Gene', '100499467', (96, 105))	('PCGEM1', 'Gene', '64002', (61, 67))
777533	28600545	In our previous studies, we observed that two SNPs, rs7958904 and rs4759314, in the HOTAIR gene were significantly associated with colorectal and gastric cancer, respectively.	('HOTAIR', 'Gene', (84, 90))	('rs4759314', 'Mutation', 'rs4759314', (66, 75))	('rs7958904', 'Var', (52, 61))	('HOTAIR', 'Gene', '100124700', (84, 90))	('associated', 'Reg', (115, 125))	('colorectal and gastric cancer', 'Disease', 'MESH:D013274', (131, 160))	('rs4759314', 'Var', (66, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('rs7958904', 'Mutation', 'rs7958904', (52, 61))
777535	28600545	As a result, we identified rs7958904, located in exon 6 of HOTAIR, was significantly associated with increased risk of CC.	('HOTAIR', 'Gene', (59, 65))	('HOTAIR', 'Gene', '100124700', (59, 65))	('CC', 'Phenotype', 'HP:0002664', (119, 121))	('rs7958904', 'Var', (27, 36))	('rs7958904', 'Mutation', 'rs7958904', (27, 36))	('associated', 'Reg', (85, 95))
777539	28600545	Briefly, the three tagging SNPs (i.e., rs4759314, rs7958904, and rs874945) were picked up using Haploview 4.0 software and the threshold for analysis was set as r 2 > 0.8.	('rs7958904', 'Mutation', 'rs7958904', (50, 59))	('rs4759314', 'Var', (39, 48))	('rs7958904', 'Var', (50, 59))	('rs4759314', 'Mutation', 'rs4759314', (39, 48))	('rs874945', 'Mutation', 'rs874945', (65, 73))	('rs874945', 'Var', (65, 73))
777543	28600545	The genotype frequencies of 3 tagging SNPs (i.e., rs4759314, rs7958904 and rs874945) among the controls were all in accordance with HWE (P = 0.294, 0.083 and 0.757, respectively).	('rs4759314', 'Var', (50, 59))	('rs7958904', 'Mutation', 'rs7958904', (61, 70))	('rs4759314', 'Mutation', 'rs4759314', (50, 59))	('rs874945', 'Mutation', 'rs874945', (75, 83))	('rs874945', 'Var', (75, 83))	('rs7958904', 'Var', (61, 70))
777548	28600545	Further stratified analyses by demographic and clinical variables showed that the association of rs7958904 with CC risk was more prominent among the subgroups of age > 49 years, parity <= 1, and having abortion (P = 0.026, OR = 1.70, 95% CI = 1.00-2.88; 0.036, 1.60, 1.05-2.46; and 0.028, 1.73, 1.07-2.80, respectively; Table 2).	('association', 'Interaction', (82, 93))	('CC', 'Phenotype', 'HP:0002664', (112, 114))	('rs7958904', 'Var', (97, 106))	('rs7958904', 'Mutation', 'rs7958904', (97, 106))
777551	28600545	Because rs4759314, rs7958904 and rs874945 were not enrolled in the TCGA SNPs data (Genome-Wide Human SNP Array 6.0), we obtained imputed genotypes of the three SNPs by imputation to the 1000 Genomes Project for the TCGA CESC SNPs data.	('rs4759314', 'Var', (8, 17))	('Human', 'Species', '9606', (95, 100))	('rs7958904', 'Mutation', 'rs7958904', (19, 28))	('rs874945', 'Mutation', 'rs874945', (33, 41))	('rs874945', 'Var', (33, 41))	('rs7958904', 'Var', (19, 28))	('rs4759314', 'Mutation', 'rs4759314', (8, 17))
777552	28600545	1, there was higher HOTAIR expression in the tumors with rs7958904 CC genotype than with wild GG genotype (P = 0.046).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('rs7958904 CC', 'Var', (57, 69))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('higher', 'PosReg', (13, 19))	('rs7958904', 'Mutation', 'rs7958904', (57, 66))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('HOTAIR', 'Gene', (20, 26))	('CC', 'Phenotype', 'HP:0002664', (67, 69))	('HOTAIR', 'Gene', '100124700', (20, 26))
777553	28600545	Although tumors heterozygous for rs7958904 had increased expression of HOTAIR compared with homozygous tumors, the difference was not statistically significant (P = 0.179).	('expression', 'MPA', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('rs7958904', 'Mutation', 'rs7958904', (33, 42))	('HOTAIR', 'Gene', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('HOTAIR', 'Gene', '100124700', (71, 77))	('increased', 'PosReg', (47, 56))	('rs7958904', 'Var', (33, 42))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
777554	28600545	In addition, we observed no allele-specific effects of rs4759314 and rs874945 on HOTAIR expression.	('rs874945', 'Var', (69, 77))	('HOTAIR', 'Gene', (81, 87))	('rs4759314', 'Mutation', 'rs4759314', (55, 64))	('HOTAIR', 'Gene', '100124700', (81, 87))	('rs874945', 'Mutation', 'rs874945', (69, 77))	('rs4759314', 'Var', (55, 64))
777555	28600545	Previously, we identified a growth-inhibiting role of rs7958904 C allele in colorectal cancer LoVo cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('LoVo', 'CellLine', 'CVCL:0399', (94, 98))	('rs7958904 C', 'Var', (54, 65))	('rs7958904', 'Mutation', 'rs7958904', (54, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Disease', (76, 93))	('growth-inhibiting', 'MPA', (28, 45))
777557	28600545	Interestingly, MTT assay showed higher proliferation rate of both HeLa and SiHa cells transfected with rs7958904 C allele than with G allele (Fig.	('SiHa', 'CellLine', 'CVCL:0032', (75, 79))	('higher', 'PosReg', (32, 38))	('proliferation rate', 'CPA', (39, 57))	('rs7958904', 'Mutation', 'rs7958904', (103, 112))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('HeLa', 'CellLine', 'CVCL:0030', (66, 70))	('rs7958904 C', 'Var', (103, 114))
777560	28600545	Functional assays showed higher HOTAIR expression in CC tissues with rs7958904 CC genotype than with GG genotype.	('rs7958904', 'Var', (69, 78))	('HOTAIR', 'Gene', (32, 38))	('CC', 'Phenotype', 'HP:0002664', (79, 81))	('HOTAIR', 'Gene', '100124700', (32, 38))	('higher', 'PosReg', (25, 31))	('CC', 'Phenotype', 'HP:0002664', (53, 55))	('rs7958904', 'Mutation', 'rs7958904', (69, 78))
777563	28600545	Accumulating evidence has suggested that genetic variants in the lncRNAs can modulate individual susceptibility to cancer.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('genetic variants', 'Var', (41, 57))	('modulate', 'Reg', (77, 85))	('lncRNAs', 'Gene', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
777564	28600545	first evaluated the relationship between the tagging SNPs (i.e., rs920778, rs1899663 and 4759314) of HOTAIR and risk of esophageal squamous cell carcinoma (ESCC).	('rs1899663', 'Var', (75, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('CC', 'Phenotype', 'HP:0002664', (158, 160))	('HOTAIR', 'Gene', (101, 107))	('rs920778', 'Mutation', 'rs920778', (65, 73))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('rs920778', 'Var', (65, 73))	('4759314', 'Var', (89, 96))	('HOTAIR', 'Gene', '100124700', (101, 107))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('rs1899663', 'Mutation', 'rs1899663', (75, 84))
777567	28600545	reported that rs920778 was significantly associated with the development and progression of CC.	('progression', 'CPA', (77, 88))	('rs920778', 'Mutation', 'rs920778', (14, 22))	('CC', 'Phenotype', 'HP:0002664', (92, 94))	('associated with', 'Reg', (41, 56))	('rs920778', 'Var', (14, 22))
777569	28600545	In the present study, we evaluated the association of three tagging SNPs (i.e., rs4759314, rs7958904 and 874945) with risk of CC, and found only rs7958904 was significantly associated with risk of CC.	('CC', 'Phenotype', 'HP:0002664', (197, 199))	('CC', 'Phenotype', 'HP:0002664', (126, 128))	('rs7958904', 'Mutation', 'rs7958904', (145, 154))	('rs7958904', 'Var', (145, 154))	('874945', 'Var', (105, 111))	('rs4759314', 'Mutation', 'rs4759314', (80, 89))	('rs7958904', 'Mutation', 'rs7958904', (91, 100))	('associated', 'Reg', (173, 183))	('rs4759314', 'Var', (80, 89))	('rs7958904', 'Var', (91, 100))
777570	28600545	We previously identified rs7958904 was not markedly associated with gastric cancer but related to a decreased risk of colorectal cancer.	('rs7958904', 'Mutation', 'rs7958904', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('rs7958904', 'Var', (25, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('decreased', 'NegReg', (100, 109))	('gastric cancer', 'Disease', (68, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('colorectal cancer', 'Disease', (118, 135))
777571	28600545	We observed a growth-promoting role of rs7958904 C allele on CC cells, which was opposed to its growth-inhibiting effect in colorectal cancer LoVo cells.	('LoVo', 'CellLine', 'CVCL:0399', (142, 146))	('CC', 'Phenotype', 'HP:0002664', (61, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('rs7958904', 'Mutation', 'rs7958904', (39, 48))	('colorectal cancer', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('growth-promoting', 'MPA', (14, 30))	('rs7958904', 'Var', (39, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))
777572	28600545	The opposite effect of rs7958904 on cancer risk may reflect the complex function of HOTAIR and its genetic variation is complex and depends on cell-type context.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('HOTAIR', 'Gene', (84, 90))	('cancer', 'Disease', (36, 42))	('rs7958904', 'Mutation', 'rs7958904', (23, 32))	('HOTAIR', 'Gene', '100124700', (84, 90))	('rs7958904', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
777573	28600545	Another explanation for rs7958904 in relation to CC susceptibility is that the real functional SNP is rs920778, which is in high LD (r 2 = 1) with rs7958904.	('rs920778', 'Var', (102, 110))	('rs7958904', 'Var', (24, 33))	('CC', 'Phenotype', 'HP:0002664', (49, 51))	('rs7958904', 'Mutation', 'rs7958904', (24, 33))	('rs920778', 'Mutation', 'rs920778', (102, 110))	('rs7958904', 'Mutation', 'rs7958904', (147, 156))
777574	28600545	found rs920778 T allele could enhance intronic enhancer activity and increase HOTAIR expression in CC cells.	('rs920778', 'Mutation', 'rs920778', (6, 14))	('increase', 'PosReg', (69, 77))	('CC', 'Phenotype', 'HP:0002664', (99, 101))	('intronic enhancer activity', 'MPA', (38, 64))	('rs920778 T', 'Var', (6, 16))	('HOTAIR', 'Gene', (78, 84))	('HOTAIR', 'Gene', '100124700', (78, 84))	('enhance', 'PosReg', (30, 37))
777575	28600545	Further studies on the interaction effect of rs7958904 C allele and rs920778 T allele on biological behavior of CC cells are warranted.	('rs7958904', 'Mutation', 'rs7958904', (45, 54))	('rs920778', 'Var', (68, 76))	('CC', 'Phenotype', 'HP:0002664', (112, 114))	('rs7958904', 'Var', (45, 54))	('rs920778', 'Mutation', 'rs920778', (68, 76))
777576	28600545	The rs4759314 polymorphism locates in the first intron of HOTAIR.	('HOTAIR', 'Gene', '100124700', (58, 64))	('rs4759314', 'Var', (4, 13))	('rs4759314', 'Mutation', 'rs4759314', (4, 13))	('HOTAIR', 'Gene', (58, 64))
777577	28600545	We previously observed a significant association between rs4759314 and risk of gastric cancer.	('rs4759314', 'Var', (57, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))	('rs4759314', 'Mutation', 'rs4759314', (57, 66))
777578	28600545	However, no significant association was observed between rs4759314 and risk of several tumors including breast, colorectal, and esophageal cancer.	('colorectal', 'Disease', 'MESH:D015179', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('rs4759314', 'Var', (57, 66))	('esophageal cancer', 'Disease', (128, 145))	('colorectal', 'Disease', (112, 122))	('breast', 'Disease', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('rs4759314', 'Mutation', 'rs4759314', (57, 66))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
777579	28600545	The rs874945 polymorphism locates in the 3' near gene of HOTAIR.	('HOTAIR', 'Gene', (57, 63))	('rs874945', 'Var', (4, 12))	('HOTAIR', 'Gene', '100124700', (57, 63))	('rs874945', 'Mutation', 'rs874945', (4, 12))
777580	28600545	In our previous studies, there was no significant association of rs874945 with risk of gastric or colorectal cancer.	('colorectal cancer', 'Disease', (98, 115))	('gastric', 'Disease', 'MESH:D013274', (87, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('gastric', 'Disease', (87, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('rs874945', 'Mutation', 'rs874945', (65, 73))	('rs874945', 'Var', (65, 73))
777581	28600545	Because rs874945 and rs1899663 are in high LD (r 2 = 0.904), the association of rs1899663 with cancer susceptibility was also reviewed.	('rs874945', 'Mutation', 'rs874945', (8, 16))	('rs874945', 'Var', (8, 16))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('rs1899663', 'Mutation', 'rs1899663', (21, 30))	('rs1899663', 'Var', (21, 30))	('cancer', 'Disease', (95, 101))	('rs1899663', 'Mutation', 'rs1899663', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
777582	28600545	No significant association was observed between rs1899663 and risk of cervical, gastric, breast, and esophageal cancer.	('rs1899663', 'Mutation', 'rs1899663', (48, 57))	('rs1899663', 'Var', (48, 57))	('esophageal cancer', 'Disease', (101, 118))	('gastric', 'Disease', 'MESH:D013274', (80, 87))	('cervical', 'Disease', (70, 78))	('gastric', 'Disease', (80, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast', 'Disease', (89, 95))
777583	28600545	In conclusion, we identified rs7958904 in the exon of HOTAIR significantly was associated with increased risk of CC and could influence CC cell proliferation.	('CC', 'Phenotype', 'HP:0002664', (136, 138))	('associated', 'Reg', (79, 89))	('CC', 'Phenotype', 'HP:0002664', (113, 115))	('rs7958904', 'Mutation', 'rs7958904', (29, 38))	('HOTAIR', 'Gene', (54, 60))	('rs7958904', 'Var', (29, 38))	('CC cell proliferation', 'CPA', (136, 157))	('influence', 'Reg', (126, 135))	('HOTAIR', 'Gene', '100124700', (54, 60))
777591	28445969	Furthermore, anti-GPC1 mAb showed a significant tumor growth inhibition with decreased angiogenesis compared with IgG treated controls in ESCC xenografted mice.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('anti-GPC1', 'Var', (13, 22))	('IgG', 'Gene', '668542', (114, 117))	('IgG', 'Gene', (114, 117))	('mice', 'Species', '10090', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('decreased', 'NegReg', (77, 86))	('angiogenesis', 'CPA', (87, 99))
777593	28445969	Anti-GPC1 mAb may have a potent anti-tumor effect and represent a novel treatment option for patients with GPC1-positive ESCC.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Anti-GPC1', 'Var', (0, 9))	('ESCC', 'Disease', (121, 125))	('patients', 'Species', '9606', (93, 101))
777598	28445969	In breast carcinoma, targeted therapy against HER2 using the humanized monoclonal antibody trastuzumab has now become integrated into standard adjuvant treatment regimens and has led to significant improvements in disease-free and overall survival in patients with Her2-positive cancer.	('patients', 'Species', '9606', (251, 259))	('breast carcinoma', 'Phenotype', 'HP:0003002', (3, 19))	('disease-free', 'CPA', (214, 226))	('cancer', 'Disease', (279, 285))	('targeted therapy', 'Var', (21, 37))	('breast carcinoma', 'Disease', (3, 19))	('HER2', 'Gene', '2064', (46, 50))	('improvements', 'PosReg', (198, 210))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('trastuzumab', 'Chemical', 'MESH:D000068878', (91, 102))	('rat', 'Species', '10116', (123, 126))	('human', 'Species', '9606', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('HER2', 'Gene', (46, 50))	('Her2', 'Gene', '2064', (265, 269))	('breast carcinoma', 'Disease', 'MESH:D001943', (3, 19))	('overall survival', 'CPA', (231, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Her2', 'Gene', (265, 269))
777608	28445969	Anti-GPC1 mAb induced significant tumor growth inhibition in ESCC xenograft models via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) dependent and independent manner.	('cytotoxicity', 'Disease', (160, 172))	('tumor', 'Disease', (34, 39))	('cytotoxicity', 'Disease', 'MESH:D064420', (115, 127))	('ESCC', 'Disease', (61, 65))	('cytotoxicity', 'Disease', 'MESH:D064420', (160, 172))	('Anti-GPC1', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('cytotoxicity', 'Disease', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
777609	28445969	Importantly, anti-GPC1 mAb also induced potent tumor growth inhibition in GPC1 positive ESCC patient derived-tumor xenograft models.	('GPC1', 'Gene', (74, 78))	('anti-GPC1', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('patient', 'Species', '9606', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (109, 114))
777610	28445969	Furthermore, minimal toxicity was observed with anti-GPC1 mAb treatment in mice.	('toxicity', 'Disease', (21, 29))	('mice', 'Species', '10090', (75, 79))	('anti-GPC1', 'Var', (48, 57))	('toxicity', 'Disease', 'MESH:D064420', (21, 29))
777623	28445969	In addition, knockdown of GPC1 in TE8 and TE14 cells decreased levels of the anti-apoptotic protein Bcl-w, and increased levels of the pro-apoptotic proteins Bim in TE8 cells and Bak in TE14 cells (Figure 2D), suggesting that suppression of GPC1 protein expression by siRNA resulted in increased apoptosis in these ESCC cell lines.	('levels', 'MPA', (121, 127))	('increased', 'PosReg', (111, 120))	('expression', 'Species', '29278', (254, 264))	('levels of the anti-apoptotic protein Bcl-w', 'MPA', (63, 105))	('GPC1', 'Gene', (26, 30))	('Bim', 'MPA', (158, 161))	('GPC1', 'Gene', (241, 245))	('Bak', 'Chemical', '-', (179, 182))	('protein', 'Protein', (246, 253))	('decreased', 'NegReg', (53, 62))	('suppression', 'NegReg', (226, 237))	('knockdown', 'Var', (13, 22))
777627	28445969	Notably, phosphorylation levels of EGFR (Tyr1068) were decreased in cells transfected with GPC1 siRNA compared with NC-siRNA-treated cells and untreated cells (Figure 2E).	('Tyr1068', 'Var', (41, 48))	('GPC1 siRNA', 'Var', (91, 101))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Gene', '13649', (35, 39))	('decreased', 'NegReg', (55, 64))	('Tyr1068', 'Chemical', '-', (41, 48))	('phosphorylation levels', 'MPA', (9, 31))
777629	28445969	In accordance with the inhibition of phospho-EGFR (Tyr1068), knockdown of GPC1 also decreased levels of phospho-AKT (Thr308), phospho-p70S6K (Thr389) and phospho-p44/42-MAPK (Thr202/Try204) in TE-8 cells (Figure 2E).	('Thr389', 'Chemical', '-', (142, 148))	('p70S6K', 'Gene', (134, 140))	('GPC1', 'Gene', (74, 78))	('EGFR', 'Gene', (45, 49))	('EGFR', 'Gene', '13649', (45, 49))	('Thr308', 'Chemical', '-', (117, 123))	('p70S6K', 'Gene', '72508', (134, 140))	('knockdown', 'Var', (61, 70))	('AKT', 'Gene', '11651', (112, 115))	('Thr202/Try204', 'Var', (175, 188))	('Tyr1068', 'Chemical', '-', (51, 58))	('decreased', 'NegReg', (84, 93))	('AKT', 'Gene', (112, 115))	('p44', 'Gene', (162, 165))	('p44', 'Gene', '99899', (162, 165))	('Thr202', 'Chemical', '-', (175, 181))
777630	28445969	In addition, treatment with the MEK1 inhibitor PD98059 resulted in increased expression of Bim and decreased expression of Bcl-w (Figure 2F) or the PI3 kinase inhibitor Ly294002 resulted in decreased expression of Bcl-w (Figure 2F), consistent with results obtained from GPC1 siRNA transfection studies.	('expression', 'MPA', (77, 87))	('PD98059', 'Var', (47, 54))	('decreased', 'NegReg', (99, 108))	('expression', 'MPA', (109, 119))	('MEK1', 'Gene', (32, 36))	('PD98059', 'Chemical', 'MESH:C093973', (47, 54))	('expression', 'Species', '29278', (200, 210))	('Ly294002', 'Chemical', 'MESH:C085911', (169, 177))	('increased', 'PosReg', (67, 76))	('decreased', 'NegReg', (190, 199))	('expression', 'MPA', (200, 210))	('Bcl-w', 'Protein', (123, 128))	('Bcl-w', 'MPA', (214, 219))	('Ly294002', 'Var', (169, 177))	('expression', 'Species', '29278', (77, 87))	('Bim', 'Gene', (91, 94))	('expression', 'Species', '29278', (109, 119))
777632	28445969	Compared with the control siRNA-transfected TE8 cells, knockdown of GPC1 resulted in decreased activation of phospho-EGFR (Tyr1068) following stimulation with HB-EGF (Figure 2G left panel).	('knockdown', 'Var', (55, 64))	('decreased', 'NegReg', (85, 94))	('EGFR', 'Gene', (117, 121))	('GPC1', 'Gene', (68, 72))	('EGFR', 'Gene', '13649', (117, 121))	('activation', 'PosReg', (95, 105))	('Tyr1068', 'Chemical', '-', (123, 130))
777644	28445969	GPC1-derived peptides 339-358, 388-404 and 405-421 were specifically identified as anti-GPC1 mAb-bound peptide compared with control mouse IgG2a (Figure 3C).	('IgG2a', 'Gene', '668478', (139, 144))	('339-358', 'Var', (22, 29))	('IgG2a', 'Gene', (139, 144))	('388-404', 'Var', (31, 38))	('mouse', 'Species', '10090', (133, 138))
777648	28445969	Treatment with anti-GPC1 mAb antibody at a dose of 50 mg/kg did not cause significant changes in serum chemistry or blood cell counts after 7 days compared with mice treated with IgG2a control antibodies (Supplementary Tables 1, 2).	('IgG2a', 'Gene', (179, 184))	('mice', 'Species', '10090', (161, 165))	('anti-GPC1', 'Var', (15, 24))	('IgG2a', 'Gene', '668478', (179, 184))
777653	28445969	Furthermore, tumor tissues were subcutaneously implanted to the SCID mice to assess the anti-tumor effect of anti-GPC1 mAb.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('SCID', 'Gene', '19090', (64, 68))	('tumor', 'Disease', (93, 98))	('mice', 'Species', '10090', (69, 73))	('SCID', 'Gene', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('anti-GPC1', 'Var', (109, 118))
777655	28445969	Anti-GPC1 mAb significantly inhibited the growth of the ESCC-8 PDX compared with isotype control mouse IgG2a (67.87% +- 6.28% tumor growth inhibition at day 31) and also tumor weight (Figure 4B).	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('IgG2a', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('also tumor', 'Disease', 'MESH:D009369', (165, 175))	('tumor', 'Disease', (170, 175))	('inhibited', 'NegReg', (28, 37))	('growth', 'MPA', (42, 48))	('Anti-GPC1', 'Var', (0, 9))	('mouse', 'Species', '10090', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('also tumor', 'Disease', (165, 175))	('IgG2a', 'Gene', '668478', (103, 108))	('tumor', 'Disease', (126, 131))
777656	28445969	By TUNEL staining, we detected marked apotosis in tumors of anti-GPC1 mAb treated mice compared to control IgG treated mice in both TE14 xenograft and ESCC-8 PDX models (Figure 4C and 4D).	('mice', 'Species', '10090', (82, 86))	('anti-GPC1', 'Var', (60, 69))	('mice', 'Species', '10090', (119, 123))	('apotosis in tumors', 'Disease', 'MESH:D009369', (38, 56))	('IgG', 'Gene', '668542', (107, 110))	('apotosis in tumors', 'Disease', (38, 56))	('IgG', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
777657	28445969	NOD/SCID mice, known to have low natural killer cell activity and no CDC activity and functional B and T cells, were used to assess the contribution of ADCC and CDC to the anti-tumor effect of anti-GPC1 mAb.	('low natural killer cell activity', 'Phenotype', 'HP:0012178', (29, 61))	('anti-GPC1', 'Var', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('SCID', 'Gene', '19090', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mice', 'Species', '10090', (9, 13))	('SCID', 'Gene', (4, 8))	('tumor', 'Disease', (177, 182))
777659	28445969	We found that GPC1 was expressed in vascular endothelium cells in ESCC tumor (Supplementary Figure 3), and tumor angiogenesis might be inhibited by anti-GPC1 mAb in vivo.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('anti-GPC1', 'Var', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (71, 76))	('inhibited', 'NegReg', (135, 144))
777660	28445969	By CD31 staining, we observed significantly decreased blood vessels in anti-GPC1 mAb treated mice compared to control IgG2a (Figure 5B).	('IgG2a', 'Gene', '668478', (118, 123))	('blood vessels', 'CPA', (54, 67))	('CD31', 'Gene', '18613', (3, 7))	('mice', 'Species', '10090', (93, 97))	('IgG2a', 'Gene', (118, 123))	('CD31', 'Gene', (3, 7))	('anti-GPC1', 'Var', (71, 80))	('decreased', 'NegReg', (44, 53))
777661	28445969	These results suggest that anti-GPC1 mAb inhibits tumor growth in vivo in ADCC and CDC dependent and independent manners including inhibition of tumor angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('inhibits', 'NegReg', (41, 49))	('anti-GPC1', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('inhibition', 'NegReg', (131, 141))
777663	28445969	GPC1 was associated with increased proliferation of ESCC through inhibition of apoptosis (Figure 2).	('inhibition', 'NegReg', (65, 75))	('increased', 'PosReg', (25, 34))	('proliferation', 'CPA', (35, 48))	('apoptosis', 'CPA', (79, 88))	('ESCC', 'Disease', (52, 56))	('GPC1', 'Var', (0, 4))	('rat', 'Species', '10116', (42, 45))
777665	28445969	Importantly, we have recently demonstrated that high tumoral expression of GPC1 in ESCC, determined by IHC analysis, was significantly associated with poor prognosis compared to low expression of GPC1 and higher expression of GPC1 associated with elevated chemoresistance to cisplatin.	('ESCC', 'Disease', (83, 87))	('expression', 'Species', '29278', (61, 71))	('expression', 'Species', '29278', (182, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (275, 284))	('expression', 'Species', '29278', (212, 222))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('rat', 'Species', '10116', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('GPC1', 'Var', (75, 79))	('chemoresistance', 'CPA', (256, 271))	('elevated', 'PosReg', (247, 255))	('tumor', 'Disease', (53, 58))
777666	28445969	We also demonstrated that anti-GPC1 mAb (clone 1-12) induced marked tumor growth inhibition in GPC1-positive human ESCC xenograft models.	('tumor', 'Disease', (68, 73))	('anti-GPC1', 'Var', (26, 35))	('human', 'Species', '9606', (109, 114))	('clone 1-12', 'Gene', '22116', (41, 51))	('rat', 'Species', '10116', (15, 18))	('clone 1-12', 'Gene', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
777668	28445969	demonstrated ectopic expression of GPC1 stimulates S phase entry via downregulation of tumor suppressors, including pRb and Cip/Kip cyclin-dependent kinase inhibitors, and upregulation of pro-oncogenic proteins, including cyclin E and cyclin-dependent kinase 2, in the human glioblastoma cell line U87-MG. Silencing of GPC1 expression by siRNA transfection induced G0/G1 growth arrest in TE8 and TE14 cells (Supplementary Figure 4).	('U87-MG', 'CellLine', 'CVCL:0022', (298, 304))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('G0/G1 growth arrest', 'CPA', (365, 384))	('expression', 'Species', '29278', (21, 31))	('tumor', 'Disease', (87, 92))	('Silencing', 'Var', (306, 315))	('glioblastoma', 'Disease', (275, 287))	('expression', 'Species', '29278', (324, 334))	('glioblastoma', 'Disease', 'MESH:D005909', (275, 287))	('glioblastoma', 'Phenotype', 'HP:0012174', (275, 287))	('human', 'Species', '9606', (269, 274))	('GPC1', 'Gene', (319, 323))	('rat', 'Species', '10116', (7, 10))	('growth arrest', 'Phenotype', 'HP:0001510', (371, 384))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
777669	28445969	As shown in Figure 2C, siRNA-mediated knockdown of GPC1 resulted in a significant level of apoptosis in TE8 and TE14 cells via induction of increased expression of the pro-apoptotic proteins Bim and Bik and decreased expression of the anti-apoptotic protein Bcl-w.	('expression', 'MPA', (150, 160))	('expression', 'Species', '29278', (217, 227))	('decreased', 'NegReg', (207, 216))	('GPC1', 'Gene', (51, 55))	('knockdown', 'Var', (38, 47))	('increased', 'PosReg', (140, 149))	('expression of the', 'MPA', (217, 234))	('expression', 'Species', '29278', (150, 160))
777670	28445969	We produced chicken/mouse chimeric mAb against human GPC1, which cross-reacts with mGPC1, and demonstrated marked tumor growth inhibition by anti-GPC1 mAb in SCID mice xenografted with GPC1-positive TE14 cells via ADCC and CDC activity.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('rat', 'Species', '10116', (101, 104))	('mGPC1', 'Gene', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('anti-GPC1', 'Var', (141, 150))	('tumor', 'Disease', (114, 119))	('mice', 'Species', '10090', (163, 167))	('SCID', 'Gene', '19090', (158, 162))	('chicken', 'Species', '9031', (12, 19))	('human', 'Species', '9606', (47, 52))	('SCID', 'Gene', (158, 162))	('mGPC1', 'Gene', '14733', (83, 88))	('mouse', 'Species', '10090', (20, 25))
777671	28445969	Intriguingly, anti-GPC1 mAb also represented potent antitumor effect against GPC1 positive ESCC PDX model, suggesting that the potential usefulness of this mAb in patients with GPC1 positive ESCC.	('patients', 'Species', '9606', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('anti-GPC1', 'Var', (14, 23))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
777672	28445969	In addition, anti-GPC1 mAb also partially inhibited tumor growth in NOD/SCID mice, inhibiting tumor angiogenesis (Figure 5B), suggesting that the possibility of the presence of neutralizing activity of GPC1 in this clone.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mice', 'Species', '10090', (77, 81))	('SCID', 'Gene', (72, 76))	('SCID', 'Gene', '19090', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (52, 57))	('anti-GPC1', 'Var', (13, 22))	('tumor', 'Disease', (94, 99))	('inhibited', 'NegReg', (42, 51))	('inhibiting', 'NegReg', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
777675	28445969	Considering that vascular endothelial growth factor and basic fibroblast growth factor, both of which are known as HBGFs, are important factors for the proliferation of vascular endothelial cells, anti-GPC1 mAb may inhibit tumor growth in vivo by blocking GPC1 as a co-receptor activity of these factors against vascular endothelial cells and inhibiting neovascularization, although further studies are required to completely elucidate this potential mechanism.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('inhibiting', 'NegReg', (343, 353))	('activity', 'MPA', (278, 286))	('inhibit', 'NegReg', (215, 222))	('rat', 'Species', '10116', (159, 162))	('neovascularization', 'CPA', (354, 372))	('GPC1', 'Protein', (256, 260))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('blocking', 'NegReg', (247, 255))	('anti-GPC1', 'Var', (197, 206))
777676	28445969	We further showed that high GPC1 expression is associated with poor prognosis by Kaplan-Meier survival analysis and increased chemo-resistance by clinicopathological analysis.	('high', 'Var', (23, 27))	('expression', 'Species', '29278', (33, 43))	('chemo-resistance', 'CPA', (126, 142))	('expression', 'MPA', (33, 43))	('increased', 'PosReg', (116, 125))	('GPC1', 'Gene', (28, 32))
777677	28445969	In addition, we also showed that GPC1 expression in vitro enhances chemo-resistance of ESCC to cisplatin not by increasing transport and excretion of drugs but by antagonizing apoptosis through upregulating MAPK signaling and Bcl-2 family signaling.	('expression', 'Species', '29278', (38, 48))	('transport', 'MPA', (123, 132))	('increasing', 'PosReg', (112, 122))	('GPC1', 'Gene', (33, 37))	('Bcl-2 family signaling', 'Pathway', (226, 248))	('chemo-resistance', 'MPA', (67, 83))	('expression', 'Var', (38, 48))	('MAPK signaling', 'Pathway', (207, 221))	('antagonizing', 'NegReg', (163, 175))	('excretion of drugs', 'MPA', (137, 155))	('apoptosis', 'CPA', (176, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('enhances', 'PosReg', (58, 66))	('upregulating', 'PosReg', (194, 206))
777683	28445969	Moreover, GPC1 was found to be expressed in lymph node metastases (Figure 1B), suggesting that systemic treatment with anti-GPC1 mAb may also have efficacy in patients with lymph node ESCC metastases.	('metastases', 'Disease', (55, 65))	('metastases', 'Disease', (189, 199))	('anti-GPC1', 'Var', (119, 128))	('metastases', 'Disease', 'MESH:D009362', (189, 199))	('metastases', 'Disease', 'MESH:D009362', (55, 65))	('lymph node ESCC', 'Disease', (173, 188))	('lymph node metastases', 'Disease', 'MESH:D009362', (44, 65))	('lymph node metastases', 'Disease', (44, 65))	('patients', 'Species', '9606', (159, 167))
777685	28445969	In addition to ESCC, increased expression of GPC1 has been reported in pancreatic cancer, breast cancer and glioma and shown to promote the mitogenic, metastatic and angiogenic properties of cancers.	('glioma', 'Disease', (108, 114))	('expression', 'Species', '29278', (31, 41))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('promote', 'PosReg', (128, 135))	('pancreatic cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('increased', 'PosReg', (21, 30))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('mitogenic', 'CPA', (140, 149))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('GPC1', 'Gene', (45, 49))	('expression', 'Var', (31, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))
777686	28445969	Therefore, anti-GPC1 mAb may have anti-tumor efficacy in these GPC1-positive cancers.	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('GPC1-positive cancers', 'Disease', (63, 84))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('anti-GPC1', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', (39, 44))	('GPC1-positive cancers', 'Disease', 'MESH:D009369', (63, 84))
777687	28445969	We are currently conducting studies evaluating the anti-tumor efficacy of anti-GPC1 mAb in xenograft models using cancer types other than ESCC.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('anti-GPC1', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancer', 'Disease', (114, 120))
777694	28445969	PD98059 and Ly294002 were purchased from Cell Signaling Technology (Danvers, MA).	('PD98059', 'Var', (0, 7))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))	('Ly294002', 'Chemical', 'MESH:C085911', (12, 20))	('Ly294002', 'Var', (12, 20))
777715	28445969	C57B/6 mice at 8 weeks were administered with anti-GPC1 mAb (i.p.	('mice', 'Species', '10090', (7, 11))	('anti-GPC1', 'Var', (46, 55))	('C57B', 'SUBSTITUTION', 'None', (0, 4))	('C57B', 'Var', (0, 4))
777962	21991527	In another case series of 66 patients with unresectable esophageal cancer, the SEPS Polyflex was used; in all patients in this study, the insertion of SEPSs led to an improvement in dysphagia.	('patients', 'Species', '9606', (29, 37))	('SEPS', 'Chemical', '-', (151, 155))	('dysphagia', 'Phenotype', 'HP:0002015', (182, 191))	('esophageal cancer', 'Disease', (56, 73))	('SEPS', 'Chemical', '-', (79, 83))	('SEPS Polyflex', 'Chemical', '-', (79, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('dysphagia', 'Disease', 'MESH:D003680', (182, 191))	('insertion', 'Var', (138, 147))	('improvement', 'PosReg', (167, 178))	('patients', 'Species', '9606', (110, 118))	('dysphagia', 'Disease', (182, 191))
778006	21991527	In multivariate analysis, there was a significantly higher complication rate with Polyflex than with Ultraflex stents (odds ratio 2.3, 95% CI 1.2-4.4).	('Polyflex', 'Chemical', '-', (82, 90))	('complication', 'CPA', (59, 71))	('Polyflex', 'Var', (82, 90))	('higher', 'PosReg', (52, 58))
778009	21991527	In another study, 125 patients with dysphagia from inoperable carcinoma of the esophagus or gastric cardia were randomized to placement of an Ultraflex (N = 42), Polyflex stent (N = 41), or Niti-S stent (N = 42).	('dysphagia', 'Disease', 'MESH:D003680', (36, 45))	('gastric cardia', 'Disease', (92, 106))	('dysphagia', 'Phenotype', 'HP:0002015', (36, 45))	('patients', 'Species', '9606', (22, 30))	('gastric cardia', 'Disease', 'MESH:D004938', (92, 106))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (62, 88))	('carcinoma of the esophagus', 'Disease', (62, 88))	('dysphagia', 'Disease', (36, 45))	('Polyflex', 'Var', (162, 170))	('Polyflex stent', 'Chemical', '-', (162, 176))	('carcinoma of the esophagus', 'Disease', 'MESH:D004938', (62, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
778012	21991527	Stent migration occurred more frequently with Polyflex stents which were also associated with more technical difficulties during actual stent placement.	('Stent migration', 'CPA', (0, 15))	('Polyflex stent', 'Chemical', '-', (46, 60))	('Polyflex stents', 'Var', (46, 61))
778014	21991527	The majority of recent studies suggest that despite the comparable efficacy in the treatment of dysphagia between SEMSs and SEPSs, SEMSs are associated with significantly fewer complications than SEPSs for the palliation of malignant dysphagia.	('dysphagia', 'Phenotype', 'HP:0002015', (234, 243))	('SEPS', 'Chemical', '-', (196, 200))	('dysphagia', 'Disease', (96, 105))	('dysphagia', 'Disease', 'MESH:D003680', (234, 243))	('malignant dysphagia', 'Disease', (224, 243))	('dysphagia', 'Phenotype', 'HP:0002015', (96, 105))	('SEPS', 'Chemical', '-', (124, 128))	('dysphagia', 'Disease', 'MESH:D003680', (96, 105))	('fewer', 'NegReg', (171, 176))	('SEMSs', 'Var', (131, 136))	('malignant dysphagia', 'Disease', 'MESH:D003680', (224, 243))	('dysphagia', 'Disease', (234, 243))
778105	26378019	Cranberry proanthocyanidins inhibit esophageal adenocarcinoma in vitro and in vivo through pleiotropic cell death induction and PI3K/AKT/mTOR inactivation Cranberries are rich in bioactive constituents known to improve urinary tract health and more recent evidence supports cranberries possess cancer inhibitory properties.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (36, 61))	('esophageal adenocarcinoma', 'Disease', (36, 61))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('C', 'Chemical', 'MESH:D002244', (155, 156))	('AKT', 'Gene', '207', (133, 136))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (36, 61))	('cancer', 'Disease', (294, 300))	('mTOR', 'Gene', (137, 141))	('inactivation', 'Var', (142, 154))	('mTOR', 'Gene', '2475', (137, 141))	('improve urinary tract', 'Phenotype', 'HP:0000010', (211, 232))	('AKT', 'Gene', (133, 136))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('inhibit', 'NegReg', (28, 35))	('proanthocyanidins', 'Chemical', 'MESH:D044945', (10, 27))
778108	26378019	C-PAC induced caspase-independent cell death mainly via autophagy and low levels of apoptosis in acid-sensitive JHAD1 and OE33 cells, but resulted in cellular necrosis in acid-resistant OE19 cells.	('autophagy', 'CPA', (56, 65))	('necrosis', 'Disease', (159, 167))	('caspase-independent cell death', 'CPA', (14, 44))	('C-PAC', 'Var', (0, 5))	('necrosis', 'Disease', 'MESH:D009336', (159, 167))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))
778109	26378019	Similarly, C-PAC induced necrosis in JHAD1 cells pushed to acid-resistance via repeated exposures to an acidified bile cocktail.	('necrosis', 'Disease', (25, 33))	('bile cocktail', 'Chemical', '-', (114, 127))	('necrosis', 'Disease', 'MESH:D009336', (25, 33))	('C-PAC', 'Var', (11, 16))	('C-PAC', 'Chemical', '-', (11, 16))	('PAC', 'Phenotype', 'HP:0006699', (13, 16))
778110	26378019	C-PAC associated cell death involved PI3K/AKT/mTOR inactivation, pro-apoptotic protein induction (BAX, BAK1, deamidated BCL-xL, Cytochrome C, PARP), modulation of MAPKs (P-P38/P-JNK) and G2-M cell cycle arrest in vitro.	('P38', 'Gene', (172, 175))	('inactivation', 'NegReg', (51, 63))	('Cytochrome C', 'Gene', '54205', (128, 140))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (192, 209))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('BCL-xL', 'Gene', (120, 126))	('pro-apoptotic', 'MPA', (65, 78))	('PI3K/AKT', 'Gene', (37, 45))	('cell death', 'CPA', (17, 27))	('G2-M cell cycle arrest', 'CPA', (187, 209))	('C-PAC', 'Disease', (0, 5))	('PI3K/AKT', 'Gene', '5295;207', (37, 45))	('mTOR', 'Gene', (46, 50))	('BAK1', 'Gene', '578', (103, 107))	('P38', 'Gene', '5594', (172, 175))	('BAK1', 'Gene', (103, 107))	('PARP', 'Gene', '142', (142, 146))	('mTOR', 'Gene', '2475', (46, 50))	('Cytochrome C', 'Gene', (128, 140))	('modulation', 'Var', (149, 159))	('PARP', 'Gene', (142, 146))	('BCL-xL', 'Gene', '598', (120, 126))
778112	26378019	C-PAC is a potent inducer of EAC cell death and is efficacious in vivo at non-toxic behaviorally achievable concentrations, holding promise for preventive or therapeutic interventions in cohorts at increased risk for EAC, a rapidly rising and extremely deadly malignancy.	('C', 'Chemical', 'MESH:D002244', (31, 32))	('EAC', 'Disease', (217, 220))	('deadly malignancy', 'Disease', (253, 270))	('rat', 'Species', '10116', (115, 118))	('C-PAC', 'Var', (0, 5))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('deadly malignancy', 'Disease', 'MESH:D009369', (253, 270))	('C', 'Chemical', 'MESH:D002244', (4, 5))	('C', 'Chemical', 'MESH:D002244', (219, 220))
778122	26378019	The urinary tract health benefits of cranberries are attributable to the unique A-type linkages in cranberry proanthocyanidins (C-PACs) which prevent adhesion of p-fimbriated uropathogenic E. coli.	('E. coli', 'Species', '562', (189, 196))	('A-type', 'Var', (80, 86))	('-PACs', 'Phenotype', 'HP:0006699', (129, 134))	('urinary tract health', 'Disease', (4, 24))	('C-PAC', 'Chemical', '-', (128, 133))	('proanthocyanidins', 'Chemical', 'MESH:D044945', (109, 126))	('prevent', 'NegReg', (142, 149))	('adhesion', 'MPA', (150, 158))	('PAC', 'Phenotype', 'HP:0006699', (130, 133))
778129	26378019	Clinical and preclinical research efforts support that alterations in the susceptibility to cell death underlie neoplastic progression of Barrett's to EAC.	('C', 'Chemical', 'MESH:D002244', (0, 1))	('alterations', 'Var', (55, 66))	('Barrett', 'Disease', (138, 145))	('neoplastic progression', 'CPA', (112, 134))	('C', 'Chemical', 'MESH:D002244', (153, 154))	('rat', 'Species', '10116', (59, 62))	('EAC', 'Disease', (151, 154))	('susceptibility', 'MPA', (74, 88))
778131	26378019	Targeting these pathways is logical for the prevention of esophageal cancer and potentially other cancers in which inflammation and aberrant cell death pathways provide a growth advantage and support resistance to treatment.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('esophageal cancer', 'Disease', (58, 75))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('inflammation', 'Disease', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('aberrant', 'Var', (132, 140))	('cancers', 'Disease', (98, 105))	('growth advantage', 'CPA', (171, 187))
778135	26378019	As illustrated in Figure 1A-1D and Supplemental Figure 1S, flow cytometric results from PI staining alone showed that C-PAC treatment of EAC cells resulted in a dose and time-dependent effect on phase of cell cycle.	('PAC', 'Phenotype', 'HP:0006699', (120, 123))	('rat', 'Species', '10116', (9, 12))	('C-PAC', 'Var', (118, 123))	('C', 'Chemical', 'MESH:D002244', (118, 119))	('C-PAC', 'Chemical', '-', (118, 123))	('phase of cell cycle', 'CPA', (195, 214))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('C', 'Chemical', 'MESH:D002244', (122, 123))
778142	26378019	Similarly, the percentage of OE33 cells in S-phase were significantly reduced by C-PAC, but without an S-phase delay (Supplemental Figure 1S and Figure 1C).	('reduced', 'NegReg', (70, 77))	('OE33 cells', 'CPA', (29, 39))	('C-PAC', 'Var', (81, 86))	('C', 'Chemical', 'MESH:D002244', (153, 154))	('PAC', 'Phenotype', 'HP:0006699', (83, 86))	('C-PAC', 'Chemical', '-', (81, 86))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('C', 'Chemical', 'MESH:D002244', (85, 86))
778148	26378019	C-PAC [50 mug/ml] significantly induced apoptosis and to a lesser extent necrosis in OE33 cells at 24 and 48 hours post-treatment.	('apoptosis', 'CPA', (40, 49))	('necrosis', 'Disease', (73, 81))	('C-PAC [50 mug/ml', 'Var', (0, 16))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('necrosis', 'Disease', 'MESH:D009336', (73, 81))	('induced', 'Reg', (32, 39))
778155	26378019	Conversely, when JHAD1-AR cells were acid-pulsed cell death was not significantly induced (Figure 2D); however, C-PAC treatment of JHAD1-AR cells resulted in significantly increased cell death via late apoptosis (12.6%) and to a greater magnitude cellular necrosis, 17.5% or 8.5-fold, similar to C-PAC induced death in constitutively acid resistant OE19 cells.	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (296, 297))	('PAC', 'Phenotype', 'HP:0006699', (298, 301))	('C-PAC', 'Var', (112, 117))	('increased', 'PosReg', (172, 181))	('C', 'Chemical', 'MESH:D002244', (300, 301))	('necrosis', 'Disease', 'MESH:D009336', (256, 264))	('cell death', 'CPA', (182, 192))	('C-PAC', 'Chemical', '-', (112, 117))	('PAC', 'Phenotype', 'HP:0006699', (114, 117))	('C', 'Chemical', 'MESH:D002244', (112, 113))	('JHAD1-AR', 'Var', (131, 139))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('necrosis', 'Disease', (256, 264))	('C-PAC', 'Chemical', '-', (296, 301))
778158	26378019	In contrast, C-PAC treated JHAD1 cells (Figure 3A, b-d) showed cytoplasmic vacuolization and increased early (6 hours) formation of double and single walled autophagic vesicles.	('increased', 'PosReg', (93, 102))	('C-PAC', 'Chemical', '-', (13, 18))	('C-PAC', 'Var', (13, 18))	('PAC', 'Phenotype', 'HP:0006699', (15, 18))
778163	26378019	JHAD1 cells treated with C-PAC showed the formation of elongated spindle shaped cells and increased cytoplasmic extensions, early cytosolic vacuolization (enlarged inset), cytoplasmic swelling, yet intact nuclei in subpopulations of cells.	('C-PAC', 'Chemical', '-', (25, 30))	('cytoplasmic swelling', 'CPA', (172, 192))	('PAC', 'Phenotype', 'HP:0006699', (27, 30))	('increased', 'PosReg', (90, 99))	('cytoplasmic extensions', 'CPA', (100, 122))	('C-PAC', 'Var', (25, 30))
778168	26378019	Starting at 6 hours, C-PAC strongly induced the autophagy-associated lipidated form of LC3-II in JHAD1 and OE33 cells (Figure 3C P < 0.05, t-test) with increased magnitude at 24 and 48 hours (2.5 to 5.1-fold) supporting early autophagosome formation.	('PAC', 'Phenotype', 'HP:0006699', (23, 26))	('autophagy-associated lipidated form', 'MPA', (48, 83))	('C', 'Chemical', 'MESH:D002244', (21, 22))	('LC3', 'Gene', '84557', (87, 90))	('early autophagosome formation', 'CPA', (220, 249))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('LC3', 'Gene', (87, 90))	('C-PAC', 'Var', (21, 26))	('induced', 'PosReg', (36, 43))	('C-PAC', 'Chemical', '-', (21, 26))	('C', 'Chemical', 'MESH:D002244', (127, 128))	('C', 'Chemical', 'MESH:D002244', (25, 26))
778174	26378019	Cyclin A1 levels were essentially unchanged in C-PAC treated JHAD1 cells; markedly reduced in OE33 cells (1.5-fold and 4.7-fold at 24 and 48 hours); and in OE19 cells, levels were transiently decreased followed by a 1.4-fold increase at 48 hours.	('decreased', 'NegReg', (192, 201))	('reduced', 'NegReg', (83, 90))	('C-PAC', 'Var', (47, 52))	('PAC', 'Phenotype', 'HP:0006699', (49, 52))	('C-PAC', 'Chemical', '-', (47, 52))	('Cyclin A1', 'Gene', '8900', (0, 9))	('Cyclin A1', 'Gene', (0, 9))
778175	26378019	Levels of cyclin B1 were increased in JHAD1 C-PAC treated cells (1.9-fold, 48 hours); whereas, levels declined to undetectable in OE33 cells following C-PAC treatment (24 and 48 hours).	('Levels', 'MPA', (0, 6))	('cyclin B1', 'Gene', (10, 19))	('cyclin B1', 'Gene', '891', (10, 19))	('increased', 'PosReg', (25, 34))	('C-PAC', 'Chemical', '-', (44, 49))	('PAC', 'Phenotype', 'HP:0006699', (46, 49))	('JHAD1 C-PAC', 'Var', (38, 49))	('PAC', 'Phenotype', 'HP:0006699', (153, 156))	('C-PAC', 'Chemical', '-', (151, 156))
778184	26378019	JHAD1 cells reportedly have a somatic mutation in exon 8 resulting in a non-synonymous Gly 266 Glu alteration.	('mutation in', 'Var', (38, 49))	('Gly 266 Glu', 'Mutation', 'rs193920774', (87, 98))	('rat', 'Species', '10116', (103, 106))	('non-synonymous Gly 266 Glu alteration', 'MPA', (72, 109))
778187	26378019	OE33 cells have a p53 mutation in exon 5, resulting in non-functional nuclear protein accumulation and weak expression of P-P53ser46.	('P53', 'Gene', '7157', (124, 127))	('p53', 'Gene', (18, 21))	('mutation', 'Var', (22, 30))	('non-functional nuclear protein accumulation', 'MPA', (55, 98))	('p53', 'Gene', '7157', (18, 21))	('P53', 'Gene', (124, 127))	('expression', 'MPA', (108, 118))
778192	26378019	JNK phosphorylation was generally increased in EAC cells by C-PAC treatment; however, the level, temporality and magnitude differed across cell lines.	('C', 'Chemical', 'MESH:D002244', (49, 50))	('PAC', 'Phenotype', 'HP:0006699', (62, 65))	('JNK phosphorylation', 'MPA', (0, 19))	('C-PAC', 'Chemical', '-', (60, 65))	('treatment', 'Var', (66, 75))	('C-PAC treatment', 'Var', (60, 75))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('increased', 'PosReg', (34, 43))
778197	26378019	C-PAC increased levels of P-p38, a marker generally thought to have a tumor suppressive role.	('increased', 'PosReg', (6, 15))	('p38', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('C-PAC', 'Var', (0, 5))	('levels', 'MPA', (16, 22))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('p38', 'Gene', '5594', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
778201	26378019	Our data support differential activation of MAPK molecules by C-PAC temporally and in a cell-line specific manner.	('activation', 'PosReg', (30, 40))	('MAPK molecules', 'Protein', (44, 58))	('C-PAC', 'Var', (62, 67))	('PAC', 'Phenotype', 'HP:0006699', (64, 67))	('C-PAC', 'Chemical', '-', (62, 67))
778203	26378019	PARP cleavage is considered a hallmark of apoptosis induction, but is also implicated in DNA repair and DNA-damage induced autophagy.	('PARP', 'Gene', (0, 4))	('PARP', 'Gene', '142', (0, 4))	('implicated', 'Reg', (75, 85))	('cleavage', 'Var', (5, 13))
778211	26378019	As shown in Figure 4E, C-PAC treatment strongly inactivated PI3K/AKT/mTOR signaling networks as supported by total loss or significant reduction of P-p70S6k, P-AktThr308 and P-AktSer473 expression in all EAC cell lines 24 and 48 hours post C-PAC treatment.	('P-AktThr308', 'Var', (158, 169))	('C', 'Chemical', 'MESH:D002244', (240, 241))	('PAC', 'Phenotype', 'HP:0006699', (25, 28))	('PI3K/AKT', 'Gene', (60, 68))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('loss', 'NegReg', (115, 119))	('C-PAC', 'Chemical', '-', (23, 28))	('PI3K/AKT', 'Gene', '5295;207', (60, 68))	('P-AktSer473', 'Var', (174, 185))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('inactivated', 'NegReg', (48, 59))	('C', 'Chemical', 'MESH:D002244', (244, 245))	('mTOR', 'Gene', (69, 73))	('reduction', 'NegReg', (135, 144))	('C', 'Chemical', 'MESH:D002244', (206, 207))	('p70S6k', 'Gene', (150, 156))	('PAC', 'Phenotype', 'HP:0006699', (242, 245))	('C-PAC', 'Chemical', '-', (240, 245))	('expression', 'MPA', (186, 196))	('p70S6k', 'Gene', '6198', (150, 156))	('mTOR', 'Gene', '2475', (69, 73))
778215	26378019	C-PAC markedly reduced levels of P-pTEN at 24 and 48 hours (1.6 and 2.4-fold, respectively) in OE33 cells; resulted in minor reductions in OE19 cells, but had little impact in JHAD1 cells indicating a cell line specific effect between pTEN dephosphorylation and AKT inactivation.	('AKT', 'Gene', (262, 265))	('pTEN', 'Gene', '5728', (35, 39))	('pTEN', 'Gene', '5728', (235, 239))	('C-PAC', 'Var', (0, 5))	('reduced', 'NegReg', (15, 22))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('levels', 'MPA', (23, 29))	('C-PAC', 'Chemical', '-', (0, 5))	('pTEN', 'Gene', (35, 39))	('AKT', 'Gene', '207', (262, 265))	('reductions', 'NegReg', (125, 135))	('pTEN', 'Gene', (235, 239))
778225	26378019	C-PAC treatment resulted in increased levels of pro-apoptotic cytochrome C (1.4-fold) and reduced P-ERK levels in C-PAC treated tumors, in line with decreased levels detected in C-PAC treated OE19 cells.	('increased', 'PosReg', (28, 37))	('C-PAC', 'Chemical', '-', (114, 119))	('reduced', 'NegReg', (90, 97))	('P-ERK', 'Gene', '9451', (98, 103))	('cytochrome C', 'Gene', '54205', (62, 74))	('PAC', 'Phenotype', 'HP:0006699', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('PAC', 'Phenotype', 'HP:0006699', (180, 183))	('C-PAC', 'Chemical', '-', (178, 183))	('C-PAC', 'Chemical', '-', (0, 5))	('P-ERK', 'Gene', (98, 103))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('C-PAC', 'Var', (114, 119))	('levels', 'MPA', (38, 44))	('cytochrome C', 'Gene', (62, 74))
778235	26378019	Results of the current study demonstrated that C-PAC has potent EAC cell death inducing capacity and strongly inhibits growth of EAC tumor xenografts.	('C', 'Chemical', 'MESH:D002244', (66, 67))	('C', 'Chemical', 'MESH:D002244', (131, 132))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('C-PAC', 'Var', (47, 52))	('inhibits', 'NegReg', (110, 118))	('rat', 'Species', '10116', (36, 39))	('PAC', 'Phenotype', 'HP:0006699', (49, 52))	('C-PAC', 'Chemical', '-', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EAC', 'Disease', (129, 132))	('C', 'Chemical', 'MESH:D002244', (47, 48))	('tumor', 'Disease', (133, 138))	('EAC cell death inducing', 'CPA', (64, 87))	('growth', 'CPA', (119, 125))
778241	26378019	Importantly, bile and/or acid exposure, well-documented risk factors for EAC, are linked to aberrant MAPK and PI3K/AKT/mTOR signaling.	('aberrant', 'Var', (92, 100))	('MAPK', 'Pathway', (101, 105))	('EAC', 'Disease', (73, 76))	('PI3K/AKT', 'Gene', '5295;207', (110, 118))	('C', 'Chemical', 'MESH:D002244', (75, 76))	('mTOR', 'Gene', (119, 123))	('mTOR', 'Gene', '2475', (119, 123))	('linked', 'Reg', (82, 88))	('PI3K/AKT', 'Gene', (110, 118))
778245	26378019	C-PAC induced cell death via low levels of mainly caspase independent apoptosis and significant autophagy in acid-sensitive JHAD1 and OE33 EAC cells, but mainly through cellular necrosis in OE19 cells which exhibited greater constitutive resistance to acidified bile salt exposure, as well as resistance to apoptosis and autophagy induction, as summarized in Figure 6.	('autophagy', 'CPA', (96, 105))	('necrosis', 'Disease', 'MESH:D009336', (178, 186))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('C-PAC', 'Var', (0, 5))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('bile salt', 'Chemical', 'MESH:D001647', (262, 271))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('necrosis', 'Disease', (178, 186))	('C', 'Chemical', 'MESH:D002244', (4, 5))	('salt exposure', 'Phenotype', 'HP:0000127', (267, 280))
778262	26378019	Caspase-independent PARP cleavage can lead to apoptotic or necrotic cell death and our data suggests a role for autophagy induction as well.	('cleavage', 'Var', (25, 33))	('PARP', 'Gene', (20, 24))	('necrotic cell death', 'Disease', (59, 78))	('necrotic cell death', 'Disease', 'MESH:D003643', (59, 78))	('lead to', 'Reg', (38, 45))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('apoptotic', 'CPA', (46, 55))	('autophagy', 'CPA', (112, 121))	('PARP', 'Gene', '142', (20, 24))
778268	26378019	C-PACs pro-death effects were accompanied by inactivation of PI3K/AKT/mTOR signaling, modulation of MAPKs and a G2-M cell cycle arrest.	('inactivation', 'NegReg', (45, 57))	('mTOR', 'Gene', (70, 74))	('mTOR', 'Gene', '2475', (70, 74))	('modulation', 'Var', (86, 96))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (117, 134))	('PI3K/AKT', 'Gene', (61, 69))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('G2-M cell cycle arrest', 'CPA', (112, 134))	('C-PAC', 'Chemical', '-', (0, 5))	('MAPKs', 'Protein', (100, 105))	('PI3K/AKT', 'Gene', '5295;207', (61, 69))	('-PACs', 'Phenotype', 'HP:0006699', (1, 6))
778278	26378019	C-PAC contains three types of linkages, two common B-type linkages (C4 C6 and C4 C8) and at least one unique A-type ether linkage (C2 O C7) found only in cranberry, chokeberry, plums and avocado.	('C4 C8', 'Var', (78, 83))	('C', 'Chemical', 'MESH:D002244', (131, 132))	('C', 'Chemical', 'MESH:D002244', (68, 69))	('C4 C6', 'Var', (68, 73))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('C-PAC', 'Chemical', '-', (0, 5))	('avocado', 'Species', '3435', (187, 194))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('C', 'Chemical', 'MESH:D002244', (136, 137))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C', 'Chemical', 'MESH:D002244', (4, 5))	('plums', 'Species', '3758', (177, 182))
778295	26378019	Immunoblotting was performed in duplicate or triplicate using commercially available antibodies from Santa Cruz Biotechnology (CD31, Cytochrome C, GAPDH, P16, P21, PCNA) and Cell Signaling (AKT, BAK1, BAX, BCL-xL, Beclin-1, Caspases 3/4/7/8/9, LC3B, Cyclin A1, Cyclin B1, PARP, P-AKTThr308, P-AKTSer47, P-BCL-2Ser70, P-ERK, P-JNK, P-pTEN, P-P38, P-p70S6K, P-mTOR, p70S6K, all P53 family member antibodies and P73) to proteins of interest.	('GAPDH', 'Gene', '2597', (147, 152))	('C', 'Chemical', 'MESH:D002244', (107, 108))	('P53', 'Gene', '7157', (376, 379))	('BAK1', 'Gene', '578', (195, 199))	('BCL-2', 'Gene', (305, 310))	('C', 'Chemical', 'MESH:D002244', (306, 307))	('AKT', 'Gene', '207', (280, 283))	('BAK1', 'Gene', (195, 199))	('AKT', 'Gene', (293, 296))	('C', 'Chemical', 'MESH:D002244', (250, 251))	('P21', 'Gene', '644914', (159, 162))	('Cytochrome C', 'Gene', (133, 145))	('AKT', 'Gene', (190, 193))	('P73', 'Gene', (409, 412))	('LC3B', 'Gene', '81631', (244, 248))	('GAPDH', 'Gene', (147, 152))	('P-ERK', 'Gene', (317, 322))	('BCL-xL', 'Gene', '598', (206, 212))	('mTOR', 'Gene', (358, 362))	('pTEN', 'Gene', (333, 337))	('p70S6K', 'Gene', (364, 370))	('CD31', 'Gene', (127, 131))	('Beclin-1, Caspases 3/4/7/8/9', 'Gene', '8678', (214, 242))	('Cyclin A1', 'Gene', '8900', (250, 259))	('C', 'Chemical', 'MESH:D002244', (144, 145))	('Cyclin A1', 'Gene', (250, 259))	('Cytochrome C', 'Gene', '54205', (133, 145))	('AKT', 'Gene', '207', (293, 296))	('p70S6K', 'Gene', (348, 354))	('pTEN', 'Gene', '5728', (333, 337))	('PARP', 'Gene', '142', (272, 276))	('C', 'Chemical', 'MESH:D002244', (224, 225))	('mTOR', 'Gene', '2475', (358, 362))	('P21', 'Gene', (159, 162))	('P38', 'Gene', '5594', (341, 344))	('AKT', 'Gene', '207', (190, 193))	('P16', 'Gene', '1029', (154, 157))	('BCL-xL', 'Gene', (206, 212))	('C', 'Chemical', 'MESH:D002244', (245, 246))	('Cyclin B1', 'Gene', (261, 270))	('C', 'Chemical', 'MESH:D002244', (207, 208))	('PARP', 'Gene', (272, 276))	('P-ERK', 'Gene', '9451', (317, 322))	('AKT', 'Gene', (280, 283))	('P53', 'Gene', (376, 379))	('C', 'Chemical', 'MESH:D002244', (165, 166))	('C', 'Chemical', 'MESH:D002244', (174, 175))	('C', 'Chemical', 'MESH:D002244', (127, 128))	('Cyclin B1', 'Gene', '891', (261, 270))	('P16', 'Gene', (154, 157))	('P-JNK', 'Var', (324, 329))	('C', 'Chemical', 'MESH:D002244', (261, 262))	('P73', 'Gene', '7161', (409, 412))	('LC3B', 'Gene', (244, 248))	('p70S6K', 'Gene', '6198', (364, 370))	('CD31', 'Gene', '5175', (127, 131))	('P38', 'Gene', (341, 344))	('C', 'Chemical', 'MESH:D002244', (133, 134))	('BCL-2', 'Gene', '596', (305, 310))	('p70S6K', 'Gene', '6198', (348, 354))
778311	26378019	OE33 and JHAD1 cells did not generate tumors in this animal model, even when higher concentrations of cells were injected supporting that OE19 cells are phenotypically more aggressive.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('rat', 'Species', '10116', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('OE19', 'Var', (138, 142))	('rat', 'Species', '10116', (33, 36))
778376	26549697	The average apoAII-ATQ/AT concentrations in samples from healthy controls and patients with stages-I (n = 6), -II (n = 35), -III (n = 36), and -IV (n = 78) IDACP were significantly lower than those in healthy controls (66.7 mug/ml; P = 9.92 x 10-3, 38.8 mug/ml; 2.85 x 10-15, 36.7 mug/ml; 4.02 x 10-13, 36.8 mug/ml and 5.71 x 10-30, 36.4 mug/ml, respectively; Fig.	('apoAII-ATQ/AT', 'Gene', (12, 25))	('IDACP', 'Chemical', '-', (156, 161))	('lower', 'NegReg', (181, 186))	('patients', 'Species', '9606', (78, 86))	('IDACP', 'Var', (156, 161))	('apoAII-ATQ/AT', 'Gene', '336', (12, 25))
778381	26549697	Analysis of the levels of both CA19-9 and apoAII-ATQ/AT by combination ELISA revealed a complementary association between CA19-9 and apoAII-ATQ/AT that increased the diagnostic accuracy in detecting the early stages of IDACP.	('apoAII-ATQ/AT', 'Gene', '336', (133, 146))	('CA19-9', 'Chemical', 'MESH:C086528', (31, 37))	('apoAII-ATQ/AT', 'Gene', (133, 146))	('CA19-9', 'Var', (122, 128))	('increased', 'PosReg', (152, 161))	('IDACP', 'Disease', (219, 224))	('apoAII-ATQ/AT', 'Gene', (42, 55))	('apoAII-ATQ/AT', 'Gene', '336', (42, 55))	('IDACP', 'Chemical', '-', (219, 224))	('CA19-9', 'Chemical', 'MESH:C086528', (122, 128))
778391	26549697	Two-dimensional scatter graphs showing the levels of apoAII-ATQ and apoAII-AT in healthy controls and patients with other gastroenterologic diseases are shown in Fig.	('patients', 'Species', '9606', (102, 110))	('apoAII-AT', 'Var', (68, 77))	('gastroenterologic diseases', 'Phenotype', 'HP:0011024', (122, 148))	('gastroenterologic diseases', 'Disease', 'MESH:D004194', (122, 148))	('ATQ', 'Chemical', 'MESH:C002421', (60, 63))	('gastroenterologic disease', 'Phenotype', 'HP:0011024', (122, 147))	('gastroenterologic diseases', 'Disease', (122, 148))
778400	26549697	The apoAII-ATQ/AT AUC values for distinguishing patients with various gastroenterologic diseases from healthy controls were 0.84 for endocrine neoplasms, 0.92 for IPMNs, 0.816 for MCNs, 0.983 for SCNs, 0.992 for chronic pancreatitis, and 0.951 for other diseases (Supplemental Table 3).	('gastroenterologic diseases', 'Disease', 'MESH:D004194', (70, 96))	('apoAII-ATQ/AT', 'Gene', (4, 17))	('pancreatitis', 'Phenotype', 'HP:0001733', (220, 232))	('endocrine neoplasms', 'Disease', (133, 152))	('apoAII-ATQ/AT', 'Gene', '336', (4, 17))	('endocrine neoplasms', 'Disease', 'MESH:D004701', (133, 152))	('pancreatitis', 'Disease', 'MESH:D010195', (220, 232))	('0.816', 'Var', (170, 175))	('endocrine neoplasms', 'Phenotype', 'HP:0100568', (133, 152))	('MN', 'CellLine', 'CVCL:U508', (165, 167))	('pancreatitis', 'Disease', (220, 232))	('MCNs', 'Disease', (180, 184))	('gastroenterologic disease', 'Phenotype', 'HP:0011024', (70, 95))	('gastroenterologic diseases', 'Disease', (70, 96))	('SCNs', 'Disease', (196, 200))	('gastroenterologic diseases', 'Phenotype', 'HP:0011024', (70, 96))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (212, 232))	('IPMNs', 'Disease', (163, 168))	('neoplasms', 'Phenotype', 'HP:0002664', (143, 152))	('patients', 'Species', '9606', (48, 56))
778430	26549697	To measure an absolute quantity of apoAII-ATQ/AT, we first tried to establish the sandwich ELISA using specific antibodies of both anti-apoAII-AT and -apoAII-ATQ.	('ATQ', 'Chemical', 'MESH:C002421', (158, 161))	('ATQ', 'Chemical', 'MESH:C002421', (42, 45))	('apoAII-ATQ/AT', 'Gene', '336', (35, 48))	('anti-apoAII-AT', 'Var', (131, 145))	('apoAII-ATQ/AT', 'Gene', (35, 48))
778461	26549697	Alterations in the distribution of apoAII-isoforms are associated with not only IDACP but also other pancreatic disorders, such as endocrine tumors of the pancreas, IPMN, MCN, SCN, and chronic pancreatitis.	('Alterations', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('MCN', 'Disease', (171, 174))	('endocrine tumors of the pancreas', 'Disease', 'MESH:D010190', (131, 163))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('associated', 'Reg', (55, 65))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (185, 205))	('pancreatic disorders', 'Disease', 'MESH:D010182', (101, 121))	('IDACP', 'Chemical', '-', (80, 85))	('IDACP', 'Disease', (80, 85))	('pancreatitis', 'Phenotype', 'HP:0001733', (193, 205))	('endocrine tumors of the pancreas', 'Disease', (131, 163))	('apoAII-isoforms', 'Protein', (35, 50))	('pancreatitis', 'Disease', 'MESH:D010195', (193, 205))	('pancreatic disorders', 'Disease', (101, 121))	('SCN', 'Disease', (176, 179))	('MN', 'CellLine', 'CVCL:U508', (167, 169))	('IPMN', 'Disease', (165, 169))	('pancreatitis', 'Disease', (193, 205))
778482	26549697	This research on human subjects was approved by the National Cancer Center Review Board (20-003, 21-140 and 2014-101) and by the Human Tissue Samples Ethics Committee for R&D, Toray Industries Inc. (HC2013-11, HC2013-126, HC2014-14 and HC2014-38).	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', (61, 67))	('HC2013-126', 'CellLine', 'CVCL:G029', (210, 220))	('human', 'Species', '9606', (17, 22))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('HC2014', 'CellLine', 'CVCL:1243', (236, 242))	('HC2014', 'CellLine', 'CVCL:1243', (222, 228))	('Human', 'Species', '9606', (129, 134))	('and HC2014-38', 'Var', (232, 245))
778521	22393371	The physiological function of Reelin was intensively studied in brain, however, recently, RELN was found to be epigenetically silenced in different cancers including pancreatic, gastric and breast cancer.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('epigenetically silenced', 'Var', (111, 134))	('pancreatic', 'Disease', 'MESH:D010195', (166, 176))	('gastric and breast cancer', 'Disease', 'MESH:D013274', (178, 203))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('pancreatic', 'Disease', (166, 176))	('RELN', 'Gene', '5649', (90, 94))	('RELN', 'Gene', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
778527	22393371	During embryo development, organogenesis and wound repair, EMT is tightly controlled temporally and spatially, but when EMT is dysregulated, it will cause fibrosis and invasion and metastasis of carcinoma.	('metastasis of carcinoma', 'Disease', (181, 204))	('fibrosis', 'Disease', 'MESH:D005355', (155, 163))	('fibrosis', 'Disease', (155, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('invasion', 'CPA', (168, 176))	('metastasis of carcinoma', 'Disease', 'MESH:D009362', (181, 204))	('dysregulated', 'Var', (127, 139))	('cause', 'Reg', (149, 154))
778555	22393371	Furthermore, co-transfection of pcDEF-Snail and the RELN promoter region (-514/+76) led to a dose-dependent decrease in luciferase activity (Figure 4D), indicating that Snail has a repressive effect on RELN promoter.	('-514/+76', 'Var', (74, 82))	('RELN', 'Gene', (202, 206))	('RELN', 'Gene', '5649', (202, 206))	('activity', 'MPA', (131, 139))	('luciferase', 'Enzyme', (120, 130))	('RELN', 'Gene', '5649', (52, 56))	('RELN', 'Gene', (52, 56))	('decrease', 'NegReg', (108, 116))	('pcDEF-Snail', 'Var', (32, 43))
778560	22393371	The results demonstrated that RELN knockdown induced a marked increase in cell migration (Figure 5A&B).	('knockdown', 'Var', (35, 44))	('cell migration', 'CPA', (74, 88))	('RELN', 'Gene', '5649', (30, 34))	('RELN', 'Gene', (30, 34))	('increase', 'PosReg', (62, 70))
778562	22393371	Consistent with the transient transfection, stable knockdown of RELN also increased cell motility (Figure 5D).	('increased', 'PosReg', (74, 83))	('cell motility', 'CPA', (84, 97))	('RELN', 'Gene', '5649', (64, 68))	('RELN', 'Gene', (64, 68))	('knockdown', 'Var', (51, 60))
778573	22393371	Moreover, knockdown of RELN in the same cell line led to dramatic increase in the expressions of several mesenchymal markers including vimentin, fibronectin and N-cadherin, suggesting that loss of RELN could endow cells with some mesenchymal traits and stronger mobility (Figure 5).	('loss', 'Var', (189, 193))	('increase', 'PosReg', (66, 74))	('fibronectin', 'Gene', (145, 156))	('expressions', 'MPA', (82, 93))	('fibronectin', 'Gene', '2335', (145, 156))	('vimentin', 'Gene', '7431', (135, 143))	('vimentin', 'Gene', (135, 143))	('endow', 'Reg', (208, 213))	('mesenchymal traits', 'CPA', (230, 248))	('N-cadherin', 'Protein', (161, 171))	('RELN', 'Gene', '5649', (197, 201))	('stronger mobility', 'CPA', (253, 270))	('RELN', 'Gene', '5649', (23, 27))	('RELN', 'Gene', (23, 27))	('knockdown', 'Var', (10, 19))	('RELN', 'Gene', (197, 201))
778574	22393371	Considering the constant expression of E-cadherin in those cells, the knockdown of RELN in KYSE-510 cells was likely to go through a partial EMT transition, which is proposed to assist migration and invasion.	('KYSE-510', 'CellLine', 'CVCL:1354', (91, 99))	('knockdown', 'Var', (70, 79))	('RELN', 'Gene', '5649', (83, 87))	('RELN', 'Gene', (83, 87))	('assist', 'PosReg', (178, 184))	('invasion', 'CPA', (199, 207))	('migration', 'CPA', (185, 194))	('partial EMT transition', 'CPA', (133, 155))
778575	22393371	In this study, knockdown of RELN expression induced ESCC cell migration maintaining E-cadherin expression which functions in cell-cell adhesion, but the mechanism of cell-cell adhesion in the process of ESCC cell migration is still not clear and needs to be further investigated.	('E-cadherin', 'Protein', (84, 94))	('RELN', 'Gene', '5649', (28, 32))	('RELN', 'Gene', (28, 32))	('knockdown', 'Var', (15, 24))
778577	22393371	Snail expression was low in KYSE-510 cells, but was dramatically increased after TGF-beta1 treatment (Figure 4A), and RELN mRNA expression was decreased in a time-dependent manner (Figure 4B).	('TGF-beta1', 'Gene', (81, 90))	('Snail expression', 'MPA', (0, 16))	('increased', 'PosReg', (65, 74))	('treatment', 'Var', (91, 100))	('decreased', 'NegReg', (143, 152))	('RELN', 'Gene', '5649', (118, 122))	('RELN', 'Gene', (118, 122))	('KYSE-510', 'CellLine', 'CVCL:1354', (28, 36))	('TGF-beta1', 'Gene', '7040', (81, 90))
778583	22393371	And RELN promoter was epigenetically regulated through DNA methylation.	('RELN', 'Gene', '5649', (4, 8))	('DNA methylation', 'Var', (55, 70))	('RELN', 'Gene', (4, 8))
778585	22393371	Recently, several groups reported that loss of functional Reelin was implicated in motility and invasion of pancreatic, gastric, and breast cancer.	('gastric', 'Disease', (120, 127))	('breast cancer', 'Disease', (133, 146))	('motility', 'CPA', (83, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('loss of functional', 'Var', (39, 57))	('pancreatic', 'Disease', (108, 118))	('Reelin', 'Protein', (58, 64))	('invasion', 'CPA', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('implicated', 'Reg', (69, 79))	('pancreatic', 'Disease', 'MESH:D010195', (108, 118))
778592	22393371	And we showed that knockdown of Reelin induced the expression of mesenchymal markers and increased cell migration in KYSE510 cells.	('KYSE510', 'CellLine', 'CVCL:1354', (117, 124))	('knockdown', 'Var', (19, 28))	('mesenchymal markers', 'CPA', (65, 84))	('expression', 'MPA', (51, 61))	('Reelin', 'Gene', (32, 38))	('increased', 'PosReg', (89, 98))	('induced', 'PosReg', (39, 46))	('cell migration in KYSE510 cells', 'CPA', (99, 130))
778599	22393371	Human ESCC cell lines KYSE-30, KYSE-140, KYSE-150, KYSE-180, KYSE-410, KYSE-450, KYSE-510, and EC9706 were all established from human ESCC patients.	('Human', 'Species', '9606', (0, 5))	('EC9706', 'CellLine', 'CVCL:E307', (95, 101))	('patients', 'Species', '9606', (139, 147))	('KYSE-510', 'CellLine', 'CVCL:1354', (81, 89))	('ESCC', 'Disease', (134, 138))	('KYSE-410', 'Var', (61, 69))	('human', 'Species', '9606', (128, 133))	('EC9706', 'Var', (95, 101))	('KYSE-510', 'Var', (81, 89))
778692	29419695	Association of microRNA-423 rs6505162 C>A polymorphism with susceptibility and metastasis of colorectal carcinoma Studies have evaluated the association between the SNP miRNA-423 rs6505162 C>A and cancer risk in several cancers with contradictory outcomes.	('metastasis of colorectal carcinoma', 'Disease', 'MESH:D009362', (79, 113))	('rs6505162', 'Var', (28, 37))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('Association', 'Interaction', (0, 11))	('cancer', 'Disease', (197, 203))	('rs6505162 C>A', 'Var', (179, 192))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('metastasis of colorectal carcinoma', 'Disease', (79, 113))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (220, 226))	('rs6505162', 'Mutation', 'rs6505162', (28, 37))	('cancers', 'Disease', (220, 227))	('rs6505162', 'Mutation', 'rs6505162', (179, 188))
778693	29419695	It was reported that miRNA-423 rs6505162 C>A polymorphism was associated with the overall survival and the recurrence-free survival of colorectal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('rs6505162', 'Mutation', 'rs6505162', (31, 40))	('colorectal carcinoma', 'Disease', (135, 155))	('associated', 'Reg', (62, 72))	('rs6505162 C>A', 'Var', (31, 44))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (135, 155))	('miRNA-423', 'Gene', (21, 30))	('recurrence-free survival', 'CPA', (107, 131))
778694	29419695	However, no studies have reported the association between miRNA-423 rs6505162 C>A polymorphism and susceptibility of colorectal carcinoma.	('colorectal carcinoma', 'Disease', (117, 137))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (117, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('rs6505162 C>A', 'Var', (68, 81))	('rs6505162', 'Mutation', 'rs6505162', (68, 77))	('miRNA-423', 'Gene', (58, 67))
778695	29419695	In this study, we investigated the association between miRNA-423 polymorphism with risk and clinicopathological parameters of colorectal carcinoma.	('miRNA-423', 'Gene', (55, 64))	('polymorphism', 'Var', (65, 77))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (126, 146))	('association', 'Interaction', (35, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('colorectal carcinoma', 'Disease', (126, 146))
778697	29419695	Our data indicated the frequencies of rs6505162 genotypes and alleles were significantly different between colorectal carcinoma patients and controls.	('rs6505162', 'Var', (38, 47))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (107, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('colorectal carcinoma', 'Disease', (107, 127))	('patients', 'Species', '9606', (128, 136))	('different', 'Reg', (89, 98))	('rs6505162', 'Mutation', 'rs6505162', (38, 47))
778700	29419695	Furthermore, miR-423 rs6505162 C>A genotype showed a significant association with metastasis in patients (P = .022).	('association', 'Reg', (65, 76))	('miR-423', 'Gene', (13, 20))	('metastasis', 'CPA', (82, 92))	('rs6505162 C>A', 'Var', (21, 34))	('patients', 'Species', '9606', (96, 104))	('rs6505162', 'Mutation', 'rs6505162', (21, 30))	('miR-423', 'Gene', '494335', (13, 20))
778701	29419695	Our study suggested that miR-423 rs6505162 C>A polymorphism was associated with the susceptibility and metastasis of colorectal carcinoma, and that miR-423 rs6505162 C>A polymorphism might be a potential biomarker for colorectal carcinoma.	('associated', 'Reg', (64, 74))	('miR-423', 'Gene', (148, 155))	('miR-423', 'Gene', '494335', (25, 32))	('rs6505162 C>A', 'Var', (33, 46))	('metastasis of colorectal carcinoma', 'Disease', 'MESH:D009362', (103, 137))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (218, 238))	('rs6505162', 'Mutation', 'rs6505162', (156, 165))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (117, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('rs6505162', 'Mutation', 'rs6505162', (33, 42))	('miR-423', 'Gene', '494335', (148, 155))	('colorectal carcinoma', 'Disease', (218, 238))	('metastasis of colorectal carcinoma', 'Disease', (103, 137))	('rs6505162 C>A', 'Var', (156, 169))	('miR-423', 'Gene', (25, 32))
778704	29419695	Previous genetic studies have revealed several single nucleotide polymorphisms (SNPs) are associated with CRC risk, such as those located in MYC, CHIT1, TNF-alpha, XRCC1, and XRCC6 genes.	('CRC', 'Phenotype', 'HP:0003003', (106, 109))	('MYC', 'Gene', (141, 144))	('XRCC6', 'Gene', '2547', (175, 180))	('CHIT1', 'Gene', (146, 151))	('TNF-alpha', 'Gene', '7124', (153, 162))	('XRCC1', 'Gene', (164, 169))	('associated', 'Reg', (90, 100))	('CRC', 'Phenotype', 'HP:0030731', (106, 109))	('TNF-alpha', 'Gene', (153, 162))	('XRCC6', 'Gene', (175, 180))	('single nucleotide polymorphisms', 'Var', (47, 78))	('CRC', 'Disease', (106, 109))	('MYC', 'Gene', '4609', (141, 144))	('CHIT1', 'Gene', '1118', (146, 151))	('XRCC1', 'Gene', '7515', (164, 169))
778705	29419695	Some miRNAs dysregulation are involved in cancer development and progression, functioned as oncogenes and tumor suppressor genes.	('dysregulation', 'Var', (12, 25))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('involved', 'Reg', (30, 38))	('miRNAs', 'Gene', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
778707	29419695	SNPs in miRNA or pre-miRNA genes may alter their maturation or expression, which may contribute to cancer susceptibility and prognosis.	('maturation', 'MPA', (49, 59))	('alter', 'Reg', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('expression', 'MPA', (63, 73))	('SNPs', 'Var', (0, 4))	('contribute', 'Reg', (85, 95))	('cancer', 'Disease', (99, 105))	('miRNA', 'Gene', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('pre-miRNA genes', 'Gene', (17, 32))
778708	29419695	Essentially numerous SNPs in miRNA have been reported to be associated with human cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('miRNA', 'Gene', (29, 34))	('human', 'Species', '9606', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('SNPs', 'Var', (21, 25))	('associated', 'Reg', (60, 70))
778711	29419695	The rs6505162 C>A polymorphism is located in 12 bp from the 3' end of mature miR-423-3p.	('miR-423', 'Gene', '494335', (77, 84))	('rs6505162', 'Mutation', 'rs6505162', (4, 13))	('miR-423', 'Gene', (77, 84))	('rs6505162 C>A', 'Var', (4, 17))
778712	29419695	Studies have evaluated the association between the SNP rs6505162 and cancer risk in several cancers with contradictory outcomes.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('SNP', 'Var', (51, 54))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs6505162', 'Mutation', 'rs6505162', (55, 64))	('rs6505162', 'Var', (55, 64))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (69, 75))
778713	29419695	Hsa-miR-423 rs6505162 C>A polymorphism was associated with reduced breast cancer risk in Caucasian women and increased the risk of esophageal cancer in Chinese population.	('rs6505162 C>A', 'Var', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('reduced', 'NegReg', (59, 66))	('Hsa-miR-423', 'Gene', (0, 11))	('Hsa-miR-423', 'Gene', '494335', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('esophageal cancer', 'Disease', (131, 148))	('rs6505162', 'Mutation', 'rs6505162', (12, 21))	('women', 'Species', '9606', (99, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('increased', 'PosReg', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
778714	29419695	Moreover, hsa-miR-423 rs6505162 C>A polymorphism was reported to be associated with both the overall survival and the recurrence-free survival of CRC.	('recurrence-free survival', 'CPA', (118, 142))	('CRC', 'Disease', (146, 149))	('hsa-miR-423', 'Gene', (10, 21))	('hsa-miR-423', 'Gene', '494335', (10, 21))	('associated', 'Reg', (68, 78))	('rs6505162 C>A', 'Var', (22, 35))	('CRC', 'Phenotype', 'HP:0030731', (146, 149))	('CRC', 'Phenotype', 'HP:0003003', (146, 149))	('rs6505162', 'Mutation', 'rs6505162', (22, 31))
778715	29419695	The data indicates that SNP rs6505162 plays a potential role in CRC development.	('CRC development', 'CPA', (64, 79))	('SNP rs6505162', 'Var', (24, 37))	('CRC', 'Phenotype', 'HP:0030731', (64, 67))	('rs6505162', 'Mutation', 'rs6505162', (28, 37))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))
778716	29419695	However, whether rs6505162 C>A polymorphism affects CRC risk is unclear.	('CRC', 'Disease', (52, 55))	('CRC', 'Phenotype', 'HP:0030731', (52, 55))	('affects', 'Reg', (44, 51))	('CRC', 'Phenotype', 'HP:0003003', (52, 55))	('rs6505162 C>A', 'Var', (17, 30))	('rs6505162', 'Mutation', 'rs6505162', (17, 26))
778717	29419695	In this study, we genotyped the rs6505162 C>A polymorphism in a CRC population to determine the association between miRNA-423 rs6505162 C>A polymorphism and the risk of CRC, as well as clinicopathological parameters of CRC.	('CRC', 'Disease', (169, 172))	('CRC', 'Phenotype', 'HP:0030731', (169, 172))	('CRC', 'Phenotype', 'HP:0003003', (219, 222))	('rs6505162 C>A', 'Var', (126, 139))	('CRC', 'Phenotype', 'HP:0003003', (169, 172))	('rs6505162', 'Mutation', 'rs6505162', (32, 41))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))	('CRC', 'Phenotype', 'HP:0030731', (64, 67))	('rs6505162', 'Var', (32, 41))	('rs6505162', 'Mutation', 'rs6505162', (126, 135))	('CRC', 'Phenotype', 'HP:0030731', (219, 222))
778724	29419695	For the miR-423 rs6505162 C>A polymorphism, fragment sizes of 108 and 19 bp indicated CC homozygote, 127, 108, and 19 bp indicated AC heterozygote, and AA homozygote was designated with 1 band (127 bp) (Fig.	('rs6505162', 'Mutation', 'rs6505162', (16, 25))	('rs6505162 C>A', 'Var', (16, 29))	('miR-423', 'Gene', '494335', (8, 15))	('miR-423', 'Gene', (8, 15))
778725	29419695	The associations between the miRNA-423 rs6505162 C>A genotypes and the risk of CRC were estimated by calculating the odds ratio (OR) and 95% confidence interval (CI), using the multivariate logistic regression analysis adjusted by age and gender.	('miRNA-423', 'Gene', (29, 38))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('rs6505162', 'Mutation', 'rs6505162', (39, 48))	('rs6505162', 'Var', (39, 48))	('CRC', 'Disease', (79, 82))	('CRC', 'Phenotype', 'HP:0030731', (79, 82))	('associations', 'Interaction', (4, 16))
778728	29419695	The detailed genotyping results of miR-423 rs6505162 C>A were listed in Table 2.	('rs6505162 C>A', 'Var', (43, 56))	('rs6505162', 'Mutation', 'rs6505162', (43, 52))	('miR-423', 'Gene', '494335', (35, 42))	('miR-423', 'Gene', (35, 42))
778729	29419695	The genotype distributions of miR-423 rs6505162 C>A frequencies were in agreement with Hardy-Weinberg equilibrium in the controls (P = .059).	('miR-423', 'Gene', '494335', (30, 37))	('miR-423', 'Gene', (30, 37))	('rs6505162', 'Mutation', 'rs6505162', (38, 47))	('rs6505162 C>A', 'Var', (38, 51))
778730	29419695	The genotype frequency distribution of miR-423 rs6505162 C>A was significantly different between patients and controls (P = .015, Table 2).	('rs6505162 C>A', 'Var', (47, 60))	('miR-423', 'Gene', (39, 46))	('miR-423', 'Gene', '494335', (39, 46))	('rs6505162', 'Mutation', 'rs6505162', (47, 56))	('patients', 'Species', '9606', (97, 105))
778731	29419695	Interestingly, the allele distribution of miR-423 rs6505162 C>A was also significantly different between cases and controls (OR = 0.582, 95% CI = 0.355-0.952, P = .030, Table 2).	('different', 'Reg', (87, 96))	('miR-423', 'Gene', '494335', (42, 49))	('rs6505162', 'Mutation', 'rs6505162', (50, 59))	('miR-423', 'Gene', (42, 49))	('rs6505162 C>A', 'Var', (50, 63))
778732	29419695	Table 3 summarized the relationship between miR-423 rs6505162 C>A genotype and clinicopathological parameters.	('miR-423', 'Gene', '494335', (44, 51))	('miR-423', 'Gene', (44, 51))	('rs6505162', 'Mutation', 'rs6505162', (52, 61))	('rs6505162', 'Var', (52, 61))
778733	29419695	A significant association between rs6505162 C>A genotype and metastasis in patients was found (P = .022, Table 3).	('metastasis', 'CPA', (61, 71))	('patients', 'Species', '9606', (75, 83))	('rs6505162 C>A', 'Var', (34, 47))	('rs6505162', 'Mutation', 'rs6505162', (34, 43))
778735	29419695	Genotype in miR-423 rs6505162 C>A showed no significant association with parameters including age, gender, serum carcinoembryonic antigen (CEA), primary tumor extension, lymph node status, and clinical stage in patients.	('miR-423', 'Gene', (12, 19))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('carcinoembryonic antigen', 'Gene', '1084', (113, 137))	('patients', 'Species', '9606', (211, 219))	('rs6505162 C>A', 'Var', (20, 33))	('carcinoembryonic antigen', 'Gene', (113, 137))	('CEA', 'Gene', (139, 142))	('tumor', 'Disease', (153, 158))	('miR-423', 'Gene', '494335', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('CEA', 'Gene', '1084', (139, 142))	('rs6505162', 'Mutation', 'rs6505162', (20, 29))
778736	29419695	Our study investigated the association between miR-423 rs6505162 C>A polymorphism and CRC risk.	('CRC', 'Phenotype', 'HP:0030731', (86, 89))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('miR-423', 'Gene', (47, 54))	('rs6505162', 'Mutation', 'rs6505162', (55, 64))	('miR-423', 'Gene', '494335', (47, 54))	('rs6505162 C>A', 'Var', (55, 68))	('CRC', 'Disease', (86, 89))
778737	29419695	The data indicated that the distributions of miR-423 rs6505162 C>A genotypes and alleles were significantly different between the CRC patients and controls.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('miR-423', 'Gene', '494335', (45, 52))	('patients', 'Species', '9606', (134, 142))	('different', 'Reg', (108, 117))	('rs6505162', 'Mutation', 'rs6505162', (53, 62))	('rs6505162', 'Var', (53, 62))	('CRC', 'Disease', (130, 133))	('CRC', 'Phenotype', 'HP:0030731', (130, 133))	('miR-423', 'Gene', (45, 52))
778738	29419695	Previous studies reported contradictory results on miR-423 rs6505162 C>A polymorphism and cancer risk.	('miR-423', 'Gene', (51, 58))	('miR-423', 'Gene', '494335', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs6505162 C>A', 'Var', (59, 72))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('rs6505162', 'Mutation', 'rs6505162', (59, 68))
778740	29419695	A meta-analysis failed to find any significant association between the risk of breast cancer and miR-423 rs6505162 C>A polymorphism.	('miR-423', 'Gene', (97, 104))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('miR-423', 'Gene', '494335', (97, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('rs6505162', 'Mutation', 'rs6505162', (105, 114))	('rs6505162 C>A', 'Var', (105, 118))
778741	29419695	Contradictory results were also reported in oesophageal cancer, a digestive tract tumors with most studies on rs6505162 C>A polymorphism.	('oesophageal cancer', 'Disease', (44, 62))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('oesophageal cancer', 'Disease', 'MESH:D009369', (44, 62))	('rs6505162', 'Mutation', 'rs6505162', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('digestive tract tumors', 'Phenotype', 'HP:0007378', (66, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tract tumors', 'Disease', 'MESH:D009369', (76, 88))	('tract tumors', 'Disease', (76, 88))	('rs6505162 C>A', 'Var', (110, 123))
778742	29419695	In a population consisted of Black and Mixed Ancestry subjects from South Africa, rs6505162 was positively associated with oesophageal cancer risk in the Black population, but no significant association was found in the Mixed Ancestry group.	('oesophageal cancer', 'Disease', (123, 141))	('oesophageal cancer', 'Disease', 'MESH:D009369', (123, 141))	('associated', 'Reg', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rs6505162', 'Mutation', 'rs6505162', (82, 91))	('rs6505162', 'Var', (82, 91))
778744	29419695	However, no statistical association was found between microRNA-423 rs6505162 polymorphism and esophageal cancer susceptibility in a meta-analysis.	('esophageal cancer', 'Disease', (94, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('rs6505162', 'Mutation', 'rs6505162', (67, 76))	('rs6505162', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('microRNA-423', 'Gene', (54, 66))
778745	29419695	Although the sample size is small, our results suggest that miR-423 rs6505162 C>A polymorphic variants might have an influence on CRC risk.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('miR-423', 'Gene', (60, 67))	('rs6505162', 'Mutation', 'rs6505162', (68, 77))	('rs6505162 C>A', 'Var', (68, 81))	('influence', 'Reg', (117, 126))	('CRC', 'Disease', (130, 133))	('miR-423', 'Gene', '494335', (60, 67))	('CRC', 'Phenotype', 'HP:0030731', (130, 133))
778746	29419695	It was interesting that miR-423 rs6505162 C>A genotype showed significant association with metastasis in CRC patients in our study.	('rs6505162 C>A', 'Var', (32, 45))	('miR-423', 'Gene', '494335', (24, 31))	('patients', 'Species', '9606', (109, 117))	('CRC', 'Disease', (105, 108))	('CRC', 'Phenotype', 'HP:0030731', (105, 108))	('association', 'Reg', (74, 85))	('metastasis', 'CPA', (91, 101))	('rs6505162', 'Mutation', 'rs6505162', (32, 41))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('miR-423', 'Gene', (24, 31))
778747	29419695	These data suggested that miR-423 rs6505162 C>A polymorphism might be a potential prognostic factor in CRC.	('CRC', 'Phenotype', 'HP:0030731', (103, 106))	('miR-423', 'Gene', (26, 33))	('rs6505162 C>A', 'Var', (34, 47))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('miR-423', 'Gene', '494335', (26, 33))	('rs6505162', 'Mutation', 'rs6505162', (34, 43))	('CRC', 'Disease', (103, 106))
778748	29419695	A previous study has identified rs6505162 to be significantly associated with recurrence-free survival and overall survival of CRC patients.	('patients', 'Species', '9606', (131, 139))	('CRC', 'Phenotype', 'HP:0003003', (127, 130))	('overall survival', 'CPA', (107, 123))	('associated', 'Reg', (62, 72))	('recurrence-free survival', 'CPA', (78, 102))	('CRC', 'Phenotype', 'HP:0030731', (127, 130))	('rs6505162', 'Mutation', 'rs6505162', (32, 41))	('CRC', 'Disease', (127, 130))	('rs6505162', 'Var', (32, 41))
778758	29419695	Polymorphisms of several genes were reported to be associated with alcohol consumption or red meat consumption of CRC risk.	('alcohol', 'Chemical', 'MESH:D000438', (67, 74))	('red meat consumption', 'Disease', (90, 110))	('CRC', 'Phenotype', 'HP:0030731', (114, 117))	('Polymorphisms', 'Var', (0, 13))	('associated', 'Reg', (51, 61))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('alcohol consumption', 'Disease', (67, 86))
778759	29419695	Interaction between polymorphism in miR-423 gene and cooking oil fume exposure on the risk of lung cancer was found in a Chinese population.	('polymorphism', 'Var', (20, 32))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('miR-423', 'Gene', (36, 43))	('oil', 'Chemical', 'MESH:D009821', (61, 64))	('lung cancer', 'Disease', (94, 105))	('miR-423', 'Gene', '494335', (36, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
778760	29419695	Association of polymorphism in miR-423 gene with environmental smoke exposure to risk for oesophageal squamous cell carcinoma was reported.	('miR-423', 'Gene', '494335', (31, 38))	('oesophageal squamous cell carcinoma', 'Disease', (90, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 125))	('polymorphism', 'Var', (15, 27))	('Association', 'Interaction', (0, 11))	('miR-423', 'Gene', (31, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))
778761	29419695	To the best of our knowledge, however, interaction between polymorphism in miR-423 gene and environmental factors to the risk of CRC was not reported.	('polymorphism', 'Var', (59, 71))	('miR-423', 'Gene', (75, 82))	('CRC', 'Disease', (129, 132))	('miR-423', 'Gene', '494335', (75, 82))	('CRC', 'Phenotype', 'HP:0030731', (129, 132))	('CRC', 'Phenotype', 'HP:0003003', (129, 132))
778762	29419695	In conclusion, our study suggested that the genotype and allele of miR-423 rs6505162 C>A were significantly associated with the risk of CRC, and rs6505162 C>A genotype was significantly associated with metastasis in patients.	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('rs6505162 C>A', 'Var', (75, 88))	('miR-423', 'Gene', (67, 74))	('rs6505162', 'Mutation', 'rs6505162', (145, 154))	('patients', 'Species', '9606', (216, 224))	('associated', 'Reg', (186, 196))	('associated', 'Reg', (108, 118))	('miR-423', 'Gene', '494335', (67, 74))	('rs6505162', 'Mutation', 'rs6505162', (75, 84))	('CRC', 'Disease', (136, 139))	('rs6505162 C>A', 'Var', (145, 158))	('CRC', 'Phenotype', 'HP:0030731', (136, 139))	('metastasis', 'CPA', (202, 212))
778763	29419695	These data suggested that miR-423 rs6505162 C>A might be a potential biomarker for susceptibility of CRC and metastasis in patients.	('miR-423', 'Gene', (26, 33))	('CRC', 'Phenotype', 'HP:0030731', (101, 104))	('CRC and', 'Disease', (101, 108))	('rs6505162 C>A', 'Var', (34, 47))	('patients', 'Species', '9606', (123, 131))	('CRC', 'Phenotype', 'HP:0003003', (101, 104))	('miR-423', 'Gene', '494335', (26, 33))	('rs6505162', 'Mutation', 'rs6505162', (34, 43))
778829	29535841	Furthermore, in multivariate analysis conducted using the Cox proportional hazards mode, lymph node and distant metastasis showed significant differences (P = 0.01), with patients with lymph node or distant metastasis having a shorter median survival time.	('shorter', 'NegReg', (227, 234))	('lymph node', 'Var', (185, 195))	('patients', 'Species', '9606', (171, 179))	('lymph node', 'CPA', (89, 99))
778915	27194176	Resectable infra-carinal EC (beyond 25 cm from the incisors) or Siewert type I or II gastro-esophageal junctional cancers   Invasive adeno or squamous cell carcinomas   Stage IIB (T1 N1 M0 or T2 N1 M0) or stage III (T3 N1 M0 or T4 N0 N1 M0) tumors according to the 7th Union for International Cancer Control (UICC) classification    Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2   Patients must be eligible for preoperative chemoradiation with either FOLFOX or Paclitaxel-carboplatin   Age >= 18 and <= 75 years   Peripheral neuropathy <= grade 1 according to the NCI-CTC classification   Adequate bone marrow, renal and liver function [neutrophil count >= 1500/mm3, platelet count >= 100 000/mm3, haemoglobin >= 10 g/dl (after transfusion, if required), creatinine < 15 mg/L, clearance of creatinine (Cockcroft formulae) >= 60 ml/min, prothrombin time >= 60 %, AST and ALT <= 2.5 x upper limit of normal, total bilirubin < 1.5 x upper limit of normal, normal serum albumin level)   Start of treatment within 28 days after inclusion   Negative pregnancy test (serum beta-HCG) performed less than 1 week prior to the beginning treatment in females of reproductive age   Patients must covered by government health insurance   Patients must provide written informed consent Patients will be considered for inclusion if they conform to the following criteria: Stage I, IIA or stage IV EC or Siewert 3 gastro-esophageal junctional tumors Contraindications for surgery related to patient comorbidities: PaO2 < 60 mmHg, PaCO2 > 45 mmHg, forced expiratory volume in one second < 1000 ml/s, cirrhosis, myocardial infarction or on-going coronary artery disease, severe peripheral arterial occlusive disease (>= stage II of the Leriche-Fontaine classification), weight loss exceeding 15 % over a 6 months period, other serious illness or medical conditions (such as left ventricular failure or uncontrolled infection) Other malignant tumor within the last 5 years or synchronous malignant tumor Pre-menopausal patients not using adequate contraception Pregnant or breast-feeding woman Auditory disorders Other histological subtypes of EC or type I and II gastro-esophageal junctional tumors which are not either a SCC or ADC Tumors located at the pharyngo-esophageal junction, the cervical esophagus, supra-carinal esophageal tumors or type III gastro-esophageal junctional tumors Distant metastases, including metastasis to supra-clavicular nodes Recurrent laryngeal nerve palsy due to tumor invasion Tumor involvement of adjacent mediastinal structures Length and width of the tumor exceeding 8 and 5 cm, respectively Prior cervical, thoracic and/or abdominal radiotherapy with field overlapping the proposed radiotherapy field Tracheo-esophageal fistula or invasion of the tracheo-bronchial airway Any other synchronous experimental drug treatment Previous hyper sensibility reaction to compounds containing a fluoropyrimidin, platinum salt or a taxane Peripheral sensory neuropathy with functional impairment Yellow fever vaccination, prophylactic use of phenytoin, live-attenuated vaccines Any of the following will exclude patients from participation in the trial: The primary endpoint is composite: it combines both the complete resection (R0) rate and the severe post-operative morbidity rate (grade >= 3) according to the Clavien-Dindo classification.	('tumor', 'Disease', (2345, 2350))	('Auditory disorders', 'Disease', (2104, 2122))	('left ventricular failure', 'Disease', 'MESH:D018487', (1885, 1909))	('FOLFOX', 'Chemical', '-', (481, 487))	('metastases', 'Disease', 'MESH:D009362', (2408, 2418))	('II gastro-esophageal junctional tumors', 'Disease', 'MESH:D005764', (2361, 2399))	('tumor', 'Phenotype', 'HP:0002664', (2008, 2013))	('weight loss', 'Disease', 'MESH:D015431', (1781, 1792))	('tumor', 'Disease', 'MESH:D009369', (2345, 2350))	('synchronous malignant tumor', 'Disease', 'MESH:D009378', (1986, 2013))	('esophageal junctional tumors', 'Phenotype', 'HP:0100751', (2181, 2209))	('weight loss', 'Phenotype', 'HP:0001824', (1781, 1792))	('cirrhosis', 'Disease', (1612, 1621))	('squamous cell carcinomas', 'Disease', (142, 166))	('Patients', 'Species', '9606', (1301, 1309))	('weight loss', 'Disease', (1781, 1792))	('patient', 'Species', '9606', (2029, 2036))	('laryngeal nerve palsy', 'Disease', (2477, 2498))	('tumors', 'Phenotype', 'HP:0002664', (2203, 2209))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('Patients', 'Species', '9606', (1254, 1262))	('Peripheral neuropathy', 'Disease', 'MESH:D010523', (544, 565))	('tumor', 'Phenotype', 'HP:0002664', (1456, 1461))	('Peripheral sensory neuropathy', 'Disease', 'MESH:D000699', (2975, 3004))	('tumors', 'Disease', (2345, 2351))	('myocardial infarction', 'Phenotype', 'HP:0001658', (1623, 1644))	('patient', 'Species', '9606', (1504, 1511))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('tumor', 'Disease', (2203, 2208))	('Yellow fever vaccination', 'Disease', (3032, 3056))	('malignant tumor', 'Disease', (1943, 1958))	('cirrhosis', 'Disease', 'MESH:D005355', (1612, 1621))	('II gastro-esophageal junctional tumors', 'Disease', 'MESH:D005764', (2171, 2209))	('tumors', 'Disease', 'MESH:D009369', (1456, 1462))	('tumor', 'Disease', 'MESH:D009369', (2203, 2208))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (2345, 2351))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (142, 166))	('esophageal junctional tumors', 'Phenotype', 'HP:0100751', (1434, 1462))	('Patients', 'Species', '9606', (1199, 1207))	('peripheral arterial occlusive disease', 'Phenotype', 'HP:0004950', (1689, 1726))	('tumor', 'Disease', (1456, 1461))	('tumor', 'Disease', (241, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('patients', 'Species', '9606', (2029, 2037))	('PaCO2', 'Chemical', '-', (1543, 1548))	('tumor', 'Disease', 'MESH:D009369', (1456, 1461))	('coronary artery disease', 'Disease', 'MESH:D003324', (1657, 1680))	('IIA', 'Disease', 'MESH:C536042', (1395, 1398))	('tumor', 'Disease', (1953, 1958))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('Oncology', 'Phenotype', 'HP:0002664', (353, 361))	('tumors', 'Phenotype', 'HP:0002664', (2345, 2351))	('tumor', 'Disease', 'MESH:D009369', (1953, 1958))	('tumor', 'Disease', (2008, 2013))	('Peripheral sensory neuropathy', 'Phenotype', 'HP:0000763', (2975, 3004))	('tumors', 'Disease', (1456, 1462))	('PaO2 < 60 mmHg', 'Var', (1527, 1541))	('Tumors', 'Disease', 'MESH:D009369', (2244, 2250))	('tumors', 'Disease', (241, 247))	('tumor', 'Disease', 'MESH:D009369', (2008, 2013))	('esophageal tumors', 'Phenotype', 'HP:0100751', (2334, 2351))	('peripheral arterial occlusive disease', 'Disease', (1689, 1726))	('PaO2', 'Chemical', '-', (1527, 1531))	('myocardial infarction', 'Disease', 'MESH:D009203', (1623, 1644))	('Cancer', 'Disease', (293, 299))	('hyper', 'Disease', 'MESH:D053307', (2879, 2884))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (142, 166))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('II gastro-esophageal junctional tumors', 'Disease', (2171, 2209))	('taxane', 'Chemical', 'MESH:C080625', (2968, 2974))	('malignant tumor', 'Disease', 'MESH:D018198', (1943, 1958))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Yellow fever vaccination', 'Disease', 'MESH:D015004', (3032, 3056))	('SCC', 'Gene', '6317', (2233, 2236))	('AST', 'Gene', (892, 895))	('II gastro-esophageal junctional tumors', 'Disease', (2361, 2399))	('Cancer', 'Disease', 'MESH:D009369', (293, 299))	('metastases', 'Disease', (2408, 2418))	('forced expiratory volume in one second', 'Phenotype', 'HP:0032342', (1560, 1598))	('Tumors', 'Phenotype', 'HP:0002664', (2244, 2250))	('neuropathy', 'Phenotype', 'HP:0009830', (555, 565))	('II gastro-esophageal junctional cancers', 'Disease', 'MESH:D005764', (82, 121))	('Tumor', 'Phenotype', 'HP:0002664', (2521, 2526))	('hyper', 'Disease', (2879, 2884))	('gastro-esophageal junctional tumors', 'Disease', 'MESH:D005764', (2364, 2399))	('phenytoin', 'Chemical', 'MESH:D010672', (3078, 3087))	('gastro-esophageal junctional tumors', 'Disease', (1427, 1462))	('tumors', 'Disease', (2393, 2399))	('synchronous malignant tumor', 'Disease', (1986, 2013))	('tumors', 'Phenotype', 'HP:0002664', (1456, 1462))	('Tumors', 'Disease', (2244, 2250))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('gastro-esophageal junctional tumors', 'Disease', 'MESH:D005764', (2174, 2209))	('Patients', 'Species', '9606', (411, 419))	('tumor', 'Disease', (2506, 2511))	('myocardial infarction', 'Disease', (1623, 1644))	('Tracheo-esophageal fistula', 'Disease', 'MESH:D004937', (2749, 2775))	('peripheral arterial occlusive disease', 'Disease', 'MESH:C564658', (1689, 1726))	('laryngeal nerve palsy', 'Disease', 'MESH:D014826', (2477, 2498))	('tumors', 'Disease', 'MESH:D009369', (2393, 2399))	('Tracheo-esophageal fistula', 'Disease', (2749, 2775))	('infection', 'Disease', (1926, 1935))	('tumor', 'Disease', 'MESH:D009369', (2506, 2511))	('normal serum albumin level', 'Phenotype', 'HP:0003073', (983, 1009))	('infection', 'Disease', 'MESH:D007239', (1926, 1935))	('fluoropyrimidin', 'Chemical', '-', (2932, 2947))	('platinum salt', 'Chemical', '-', (2949, 2962))	('left ventricular failure', 'Phenotype', 'HP:0005162', (1885, 1909))	('Peripheral neuropathy', 'Phenotype', 'HP:0009830', (544, 565))	('tumors', 'Disease', 'MESH:D009369', (2203, 2209))	('tumor', 'Disease', (2393, 2398))	('esophageal junctional tumors', 'Phenotype', 'HP:0100751', (2371, 2399))	('tumor', 'Disease', (2598, 2603))	('patients', 'Species', '9606', (3148, 3156))	('fever', 'Phenotype', 'HP:0001945', (3039, 3044))	('tumor', 'Disease', 'MESH:D009369', (2393, 2398))	('cirrhosis', 'Phenotype', 'HP:0001394', (1612, 1621))	('tumor', 'Disease', 'MESH:D009369', (2598, 2603))	('tumors', 'Phenotype', 'HP:0002664', (2393, 2399))	('malignant tumor', 'Disease', 'MESH:D018198', (1998, 2013))	('SCC', 'Gene', (2233, 2236))	('illness', 'Disease', 'MESH:D002908', (1846, 1853))	('tumor', 'Phenotype', 'HP:0002664', (2203, 2208))	('Peripheral neuropathy', 'Disease', (544, 565))	('carboplatin', 'Chemical', 'MESH:D016190', (502, 513))	('Peripheral sensory neuropathy', 'Disease', (2975, 3004))	('Tumor', 'Phenotype', 'HP:0002664', (2244, 2249))	('coronary artery disease', 'Disease', (1657, 1680))	('gastro-esophageal junctional tumors', 'Disease', 'MESH:D005764', (1427, 1462))	('patient', 'Species', '9606', (3148, 3155))	('Tracheo-esophageal fistula', 'Phenotype', 'HP:0002575', (2749, 2775))	('left ventricular failure', 'Disease', (1885, 1909))	('Cancer', 'Phenotype', 'HP:0002664', (293, 299))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('II gastro-esophageal junctional cancers', 'Disease', (82, 121))	('tumors', 'Disease', (2203, 2209))	('neuropathy', 'Phenotype', 'HP:0009830', (2994, 3004))	('AST', 'Gene', '26503', (892, 895))	('IIA', 'Disease', (1395, 1398))	('Paclitaxel', 'Chemical', 'MESH:D017239', (491, 501))	('tumor', 'Phenotype', 'HP:0002664', (1953, 1958))	('Auditory disorders', 'Disease', 'MESH:D006311', (2104, 2122))	('illness', 'Disease', (1846, 1853))	('supra-carinal esophageal tumors or type III gastro-esophageal junctional tumors', 'Disease', 'MESH:D004938', (2320, 2399))
778934	27194176	pR0 = 0.75 and pT0 = 0.55 corresponding respectively to an unacceptable R0 rate of <=75 % and an unacceptable severe postoperative toxicity rate of 45 % or more.	('toxicity', 'Disease', (131, 139))	('pT0 = 0.55', 'Var', (15, 25))	('toxicity', 'Disease', 'MESH:D064420', (131, 139))	('pR0 = 0.75', 'Var', (0, 10))
778936	27194176	Errors rates alphaR = 0.10, alphaT = 0.10, and beta = 0.15 corresponding respectively to a false positive error rate for response of 10 %, a false positive error rate for toxicity of 10 %, and 85 % power.	('toxicity', 'Disease', 'MESH:D064420', (171, 179))	('response', 'MPA', (121, 129))	('alphaR', 'Var', (13, 19))	('toxicity', 'Disease', (171, 179))
779029	24495377	Briefly, case patients eligible for this study were men and women between the age of 30 and 74 years newly diagnosed with histologically confirmed, incident EA (International Classification of Disease for Oncology code [ICD-O] C15.0-C15.9), GCA (ICD-O code C16.0), or DCA (ICD-O codes C16.1-C16.6 and C16.8-C16.9) diagnosed between 1992 and 1997.	('men', 'Species', '9606', (62, 65))	('Oncology', 'Phenotype', 'HP:0002664', (205, 213))	('DCA', 'Disease', (268, 271))	('C16', 'CellLine', 'CVCL:2322', (257, 260))	('GCA', 'Gene', '25801', (241, 244))	('GCA', 'Gene', (241, 244))	('C16', 'CellLine', 'CVCL:2322', (285, 288))	('men', 'Species', '9606', (52, 55))	('women', 'Species', '9606', (60, 65))	('C16', 'CellLine', 'CVCL:2322', (307, 310))	('C16.8-C16.9', 'Var', (301, 312))	('C16', 'CellLine', 'CVCL:2322', (301, 304))	('C16.1-C16.6', 'CellLine', 'CVCL:2322', (285, 296))	('patients', 'Species', '9606', (14, 22))	('C16', 'CellLine', 'CVCL:2322', (291, 294))	('C16.8-C16.9', 'CellLine', 'CVCL:2322', (301, 312))	('C16.1-C16.6', 'Var', (285, 296))
779044	24495377	Cancer sites were coded according to the International Classification of Diseases 9th version (ICD-9) code: any gastrointestinal (ICD-9: 150-159), esophageal (ICD-9: 150), gastric (ICD-9: 151), colorectal (ICD-9: 153-154), hepatic (ICD-9: 155), pancreas (ICD-9: 157), lung (ICD-9: 162), breast (ICD-9: 174), bone/skin/connective tissue (ICD-9: 170-173), oral/upper respiratory organ (ICD-9: 140-149, 160-165), prostate (ICD-9: 185), female reproductive organ (ICD-9: 179-184), lymphatic/hematopoietic (ICD-9: 200, 208) cancer, and cancer of unknown primary site (ICD-9: 199).	('cancer', 'Disease', (519, 525))	('cancer', 'Phenotype', 'HP:0002664', (519, 525))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('hepatic', 'Disease', (223, 230))	('oral/upper respiratory organ', 'Disease', (354, 382))	('colorectal', 'Disease', 'MESH:D015179', (194, 204))	('ICD-9', 'Var', (420, 425))	('female reproductive organ', 'Disease', (433, 458))	('pancreas', 'Disease', 'MESH:D010190', (245, 253))	('cancer', 'Disease', (531, 537))	('cancer', 'Phenotype', 'HP:0002664', (531, 537))	('bone/skin/connective tissue', 'Disease', (308, 335))	('cancer', 'Disease', 'MESH:D009369', (519, 525))	('prostate', 'Disease', (410, 418))	('lung', 'Disease', (268, 272))	('esophageal', 'Disease', (147, 157))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('breast', 'Disease', (287, 293))	('lymphatic/hematopoietic', 'Disease', (477, 500))	('cancer', 'Disease', 'MESH:D009369', (531, 537))	('gastric', 'Disease', (172, 179))	('colorectal', 'Disease', (194, 204))	('Cancer', 'Disease', (0, 6))	('esophageal', 'Disease', 'MESH:D004941', (147, 157))	('pancreas', 'Disease', (245, 253))
779052	24495377	Given that the causal factors for esophageal adenocarcinoma is not entirely known, we chose to adjust for all common risk factors that were suspected to be associated with both gastroesophageal adenocarcinomas and family history of cancer or gastroesophageal disorders: birth place (US born, non-US born), level of education (<high school, high school, some college, college graduate or higher), cigarette smoking status (never, former, and current smoker), body mass index (BMI) at reference age (in quartiles: <=23, >23-25, >25- <= 28, >28 in males, and <=22, >22-25, >25- <= 28.25, >28.25 in females), and history of diabetes were also included as covariates in the analyses.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (183, 208))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (183, 208))	('gastroesophageal disorders', 'Phenotype', 'HP:0011024', (242, 268))	('cancer', 'Disease', (232, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('gastroesophageal adenocarcinomas', 'Disease', (177, 209))	('diabetes', 'Disease', (620, 628))	('<=22', 'Var', (556, 560))	('gastroesophageal disorders', 'Disease', (242, 268))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (34, 59))	('esophageal adenocarcinoma', 'Disease', (34, 59))	('diabetes', 'Disease', 'MESH:D003920', (620, 628))	('gastroesophageal disorders', 'Disease', 'MESH:D005764', (242, 268))	('gastroesophageal adenocarcinomas', 'Disease', 'MESH:D005764', (177, 209))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (34, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
779106	24495377	Low intake of fiber, hiatal hernia, and Barrett's esophagus all have been associated with increased risks of both EA and GCA.	('hiatal hernia', 'Disease', 'MESH:D006551', (21, 34))	('hiatal hernia', 'Disease', (21, 34))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (40, 59))	('GCA', 'Gene', '25801', (121, 124))	('GCA', 'Gene', (121, 124))	('hernia', 'Phenotype', 'HP:0100790', (28, 34))	('hiatal hernia', 'Phenotype', 'HP:0002036', (21, 34))	('Low', 'Var', (0, 3))
779115	24495377	For example, candidate gene studies have consistently found that polymorphisms in the IL-1beta and MTHFR genes were associated with individual susceptibility to both intestinal-type gastric cancer and pancreatic cancer.	('MTHFR', 'Gene', '4524', (99, 104))	('intestinal-type gastric cancer', 'Disease', 'MESH:D013274', (166, 196))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (201, 218))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('pancreatic cancer', 'Disease', (201, 218))	('IL-1beta', 'Gene', '3553', (86, 94))	('MTHFR', 'Gene', (99, 104))	('polymorphisms', 'Var', (65, 78))	('pancreatic cancer', 'Disease', 'MESH:D010190', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('IL-1beta', 'Gene', (86, 94))	('intestinal-type gastric cancer', 'Disease', (166, 196))	('associated', 'Reg', (116, 126))
779135	24495377	CA59636 and CA136725 from the National Cancer Institute, and NIEHS Grant # 5P30 ES07048.	('Cancer', 'Disease', (39, 45))	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('CA136725', 'Var', (12, 20))	('CA59636', 'Var', (0, 7))
779190	22999061	On multivariate analysis, stage IIB (HR, 2.191; P < 0.001), Cyfra21-1 > 3.30 ng/ml (HR, 7.149; P < 0.001), and SCC-Ag > 1.5 mug/L (HR, 2.926; P < 0.001) negatively affects survival of surgically resected stage II ESCC patients.	('SCC', 'Gene', '6317', (214, 217))	('patients', 'Species', '9606', (218, 226))	('negatively', 'NegReg', (153, 163))	('Cyfra21-1', 'Var', (60, 69))	('affects', 'Reg', (164, 171))	('SCC', 'Gene', (111, 114))	('SCC', 'Gene', '6317', (111, 114))	('SCC', 'Gene', (214, 217))	('survival', 'MPA', (172, 180))
779206	22999061	The previous studied have indicated that Cyfra21-1 and SCC-Ag are sensitive tumors marker in malignant disease, particularly in squamous cell type  .	('squamous cell type', 'Disease', (128, 146))	('SCC', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Cyfra21-1', 'Var', (41, 50))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('SCC', 'Gene', '6317', (55, 58))	('malignant disease', 'Disease', 'MESH:D009369', (93, 110))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('malignant disease', 'Disease', (93, 110))
779209	22999061	reported that preoperative Cyfra21-1 was associated with tumor stage in non small cell lung cancer  .	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (72, 98))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (76, 98))	('associated', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('non small cell lung cancer', 'Disease', 'MESH:D002289', (72, 98))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (57, 62))	('Cyfra21-1', 'Var', (27, 36))	('non small cell lung cancer', 'Disease', (72, 98))
779218	22999061	Interestingly, in the subset analyses, Cyfra21-1 and SCC-Ag level displayed statistically significant effect on survival in stage IIB patients.	('SCC', 'Gene', '6317', (53, 56))	('stage IIB', 'Disease', (124, 133))	('Cyfra21-1', 'Var', (39, 48))	('patients', 'Species', '9606', (134, 142))	('significant effect', 'Reg', (90, 108))	('SCC', 'Gene', (53, 56))
779229	32318335	Through our literature research, we also found that silencing of SNHGs through small interfering RNAs or short hairpin RNAs is very effective in both in vitro and in vivo experiments by lowering the aggressiveness of solid cancers.	('aggressiveness of solid cancers', 'Disease', 'MESH:D009369', (199, 230))	('silencing', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('small interfering RNAs', 'Protein', (79, 101))	('men', 'Species', '9606', (177, 180))	('RNAs', 'Protein', (97, 101))	('aggressiveness', 'Phenotype', 'HP:0000718', (199, 213))	('short hairpin RNAs', 'Gene', (105, 123))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('aggressiveness of solid cancers', 'Disease', (199, 230))	('lowering', 'NegReg', (186, 194))
779246	32318335	The C/D box snoRNAs are involved in the 2-O'-methylation of rRNA, and the H/ACA snoRNA cause the pseudouridylation of rRNAs.	('H/ACA', 'Var', (74, 79))	('snoRNA', 'Gene', (12, 18))	("2-O'-methylation", 'MPA', (40, 56))	('snoRNA', 'Gene', '6079', (12, 18))	('ACA snoRNA', 'Phenotype', 'HP:0025267', (76, 86))	('cause', 'Reg', (87, 92))	('snoRNA', 'Gene', '6079', (80, 86))	('pseudouridylation', 'MPA', (97, 114))	('snoRNA', 'Gene', (80, 86))
779251	32318335	However, as the new element of non-coding sequence moves in a protein-coding gene, it results in loss-of-function genetic variants.	('genetic variants', 'Var', (114, 130))	('men', 'Species', '9606', (23, 26))	('loss-of-function', 'NegReg', (97, 113))
779260	32318335	The siRNA knockdown of Zfas only slightly affected the expression of snoRNAs.	('Zfas', 'Chemical', '-', (23, 27))	('snoRNA', 'Gene', '6079', (69, 75))	('expression', 'MPA', (55, 65))	('Zfas', 'Gene', (23, 27))	('snoRNA', 'Gene', (69, 75))	('knockdown', 'Var', (10, 19))
779262	32318335	However, the expression of some SNHGs, such as SNHG17, is regulated by the copy number variations (CNV) of their host gene, this being also correlated with the aggressiveness of non-small cell lung cancer and squamous cell lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('lung cancer', 'Disease', 'MESH:D008175', (223, 234))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))	('SNHG17', 'Gene', '388796', (47, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('copy number variations', 'Var', (75, 97))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('correlated with', 'Reg', (140, 155))	('regulated by', 'Reg', (58, 70))	('aggressiveness', 'Disease', (160, 174))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (178, 204))	('aggressiveness', 'Phenotype', 'HP:0000718', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('aggressiveness', 'Disease', 'MESH:D001523', (160, 174))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (182, 204))	('lung cancer', 'Disease', (193, 204))	('lung cancer', 'Disease', (223, 234))	('expression', 'MPA', (13, 23))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (209, 234))	('SNHG17', 'Gene', (47, 53))
779292	32318335	In esophageal cancer, SNGH1 sponges miR-338 miR-338 is involved in stimulating the radiotherapy-induced apoptosis of esophageal cancer cells, by targeting Survivin gene.	('stimulating', 'PosReg', (67, 78))	('miR-338', 'Var', (36, 43))	('esophageal cancer', 'Disease', (117, 134))	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('radiotherapy-induced apoptosis', 'CPA', (83, 113))	('Survivin gene', 'Gene', (155, 168))	('targeting', 'Reg', (145, 154))
779306	32318335	In lung cancer, SNHG1 acts as a tumor-promoter by sponging miR-145 and miR-101 and enhancing the Wnt/beta-catenin signaling pathway.	('lung cancer', 'Disease', (3, 14))	('miR-101', 'Gene', (71, 78))	('SNHG1', 'Gene', '23642', (16, 21))	('SNHG1', 'Gene', (16, 21))	('beta-catenin', 'Gene', (101, 113))	('enhancing', 'PosReg', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('miR-101', 'Chemical', '-', (71, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('sponging', 'Var', (50, 58))	('beta-catenin', 'Gene', '1499', (101, 113))	('miR-145', 'Gene', (59, 66))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('tumor', 'Disease', (32, 37))	('miR-145', 'Gene', '406937', (59, 66))
779316	32318335	In osteosarcoma, SNHG3 overexpression facilitates cell invasion and migration in vitro, through the inhibition of miR-151a-3p and miR-196a-5p.	('miR-196a-5p', 'Var', (130, 141))	('osteosarcoma', 'Disease', (3, 15))	('SNHG3', 'Gene', '8420', (17, 22))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('overexpression facilitates', 'PosReg', (23, 49))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('cell invasion', 'CPA', (50, 63))	('miR-151a-3p', 'Protein', (114, 125))	('SNHG3', 'Gene', (17, 22))	('inhibition', 'NegReg', (100, 110))
779325	32318335	In gastric cancer, SNHG3 binds to EZH2 and epigenetically silence MED18 (Mediator Complex Subunit 18) expression.	('Mediator Complex Subunit 18', 'Gene', '54797', (73, 100))	('epigenetically', 'Var', (43, 57))	('EZH2', 'Gene', '2146', (34, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('MED18', 'Gene', (66, 71))	('expression', 'MPA', (102, 112))	('binds', 'Interaction', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('EZH2', 'Gene', (34, 38))	('MED18', 'Gene', '54797', (66, 71))	('SNHG3', 'Gene', (19, 24))	('SNHG3', 'Gene', '8420', (19, 24))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('Mediator Complex Subunit 18', 'Gene', (73, 100))
779326	32318335	Furthermore, SNHG3 causes proliferation of colorectal cancer cells by sponging miR-182 and allowing the overexpression of the tumor promoting transcription factor c-MYC.	('overexpression', 'MPA', (104, 118))	('colorectal cancer', 'Disease', (43, 60))	('miR-182', 'Gene', '406958', (79, 86))	('causes', 'Reg', (19, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('SNHG3', 'Gene', '8420', (13, 18))	('sponging', 'Var', (70, 78))	('c-MYC', 'Gene', (163, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (43, 60))	('c-MYC', 'Gene', '4609', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('miR-182', 'Gene', (79, 86))	('SNHG3', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('proliferation', 'CPA', (26, 39))	('tumor', 'Disease', (126, 131))
779333	32318335	In CML patients with rare BCR-ABL variants, this microRNA was found to be down-regulated in imatinib resistant patients compared with imatinib responsive patients.	('CML', 'Disease', 'MESH:D015464', (3, 6))	('variants', 'Var', (34, 42))	('BCR-ABL', 'Gene', (26, 33))	('down-regulated', 'NegReg', (74, 88))	('BCR-ABL', 'Gene', '25', (26, 33))	('patients', 'Species', '9606', (154, 162))	('imatinib', 'Chemical', 'MESH:D000068877', (92, 100))	('CML', 'Disease', (3, 6))	('imatinib', 'Chemical', 'MESH:D000068877', (134, 142))	('patients', 'Species', '9606', (7, 15))	('patients', 'Species', '9606', (111, 119))
779345	32318335	These effects are a consequence of miR-101 and miR-26a sponging.	('miR-101', 'Var', (35, 42))	('miR-26a', 'Gene', '407015', (47, 54))	('miR-26a', 'Gene', (47, 54))	('miR-101', 'Chemical', '-', (35, 42))
779358	32318335	siRNA-mediated inhibition of SNHG7 leads to decreased wound closure speed in scratch assay, lower number of invasive cells in transwell assay, and an increased intracellular level of the proapoptotic marker BAX (Bcl-2-associated X protein), cell cycle inhibitor p21, and anti-invasive adhesion molecule, E-cadherin, while the expression of mesenchymal promoting proteins, namely, N-cadherin, VIM, and SNAIL are increased.	('increased intracellular level', 'Phenotype', 'HP:0003575', (150, 179))	('SNHG7', 'Gene', (29, 34))	('SNAIL', 'Gene', '6615', (401, 406))	('SNAIL', 'Gene', (401, 406))	('BAX', 'Gene', (207, 210))	('cell', 'MPA', (241, 245))	('VIM', 'Gene', '7431', (392, 395))	('BAX', 'Gene', '581', (207, 210))	('expression', 'MPA', (326, 336))	('VIM', 'Gene', (392, 395))	('p21', 'Gene', (262, 265))	('p21', 'Gene', '644914', (262, 265))	('inhibition', 'Var', (15, 25))	('Bcl-2-associated X protein', 'Gene', '581', (212, 238))	('E-cadherin', 'Gene', (304, 314))	('SNHG7', 'Gene', '84973', (29, 34))	('E-cadherin', 'Gene', '999', (304, 314))	('Bcl-2-associated X protein', 'Gene', (212, 238))	('N-cadherin', 'Gene', (380, 390))	('N-cadherin', 'Gene', '1000', (380, 390))	('increased', 'PosReg', (150, 159))	('intracellular level of', 'MPA', (160, 182))	('wound closure speed in scratch assay', 'CPA', (54, 90))	('lower', 'NegReg', (92, 97))	('increased', 'PosReg', (411, 420))	('decreased', 'NegReg', (44, 53))
779366	32318335	In cancer, different components of this pathway acquire gain-of-function mutations.	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('gain-of-function', 'PosReg', (56, 72))	('mutations', 'Var', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
779368	32318335	At the molecular level, SNHG7 silencing lowered VIM and SNAIL level while increasing E-cadherin expression.	('SNAIL', 'Gene', (56, 61))	('VIM', 'Gene', (48, 51))	('lowered', 'NegReg', (40, 47))	('increasing', 'PosReg', (74, 84))	('VIM', 'Gene', '7431', (48, 51))	('E-cadherin', 'Gene', (85, 95))	('E-cadherin', 'Gene', '999', (85, 95))	('silencing', 'Var', (30, 39))	('SNHG7', 'Gene', '84973', (24, 29))	('SNHG7', 'Gene', (24, 29))	('SNAIL', 'Gene', '6615', (56, 61))
779369	32318335	SNHG7 overexpression leads to up-regulation of the antiapoptotic gene Survivin and the cell cycle promoting gene, Cyclin D, through the activation of Notch signaling pathway.	('Notch', 'Gene', (150, 155))	('overexpression', 'Var', (6, 20))	('up-regulation', 'PosReg', (30, 43))	('Cyclin D', 'MPA', (114, 122))	('SNHG7', 'Gene', '84973', (0, 5))	('SNHG7', 'Gene', (0, 5))	('Survivin', 'Protein', (70, 78))	('Notch', 'Gene', '4851;4853', (150, 155))
779372	32318335	The siRNA mediated silencing of SNHG7 increases cleaved PARP and cleaved Caspase 3 levels leading to apoptosis initiation.	('increases', 'PosReg', (38, 47))	('PARP', 'Gene', '142', (56, 60))	('silencing', 'Var', (19, 28))	('SNHG7', 'Gene', '84973', (32, 37))	('SNHG7', 'Gene', (32, 37))	('PARP', 'Gene', (56, 60))	('Caspase 3', 'Gene', (73, 82))	('apoptosis', 'CPA', (101, 110))	('Caspase 3', 'Gene', '836', (73, 82))
779377	32318335	In hepatocellular carcinoma, inhibition of SNHG7 decreases the invasion capacity of malignant cells.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('invasion capacity of malignant cells', 'CPA', (63, 99))	('decreases', 'NegReg', (49, 58))	('SNHG7', 'Gene', '84973', (43, 48))	('SNHG7', 'Gene', (43, 48))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('inhibition', 'Var', (29, 39))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
779378	32318335	The protein expression of RBM5 (RNA binding motif protein 5) was increased after SNHG7 silencing.	('silencing', 'Var', (87, 96))	('protein expression', 'MPA', (4, 22))	('increased', 'PosReg', (65, 74))	('RBM5', 'Gene', (26, 30))	('RBM5', 'Gene', '10181', (26, 30))	('SNHG7', 'Gene', '84973', (81, 86))	('RNA binding motif protein 5', 'Gene', (32, 59))	('SNHG7', 'Gene', (81, 86))	('RNA binding motif protein 5', 'Gene', '10181', (32, 59))
779389	32318335	SNHG12 is involved in different types of malignant diseases by targeting the following microRNAs: miR-424-5p in cervical cancer, miR-320 in gastric cancer, miR-199a-5p in renal cell carcinoma, miR-199a/b in hepatocellular carcinoma, miR-199a/b in gastric cancer, miR-138 in lung cancer, miR-181a in lung cancer, miR-16-5p in thyroid carcinoma, miR-129-5p in laryngeal squamous cell carcinoma, miR-199-5p in renal carcinoma, and miR-195-5p in osteosarcoma.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('miR-138', 'Var', (263, 270))	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (382, 391))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (304, 310))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (368, 391))	('hepatocellular carcinoma', 'Disease', (207, 231))	('cancer', 'Disease', (255, 261))	('renal cell carcinoma', 'Disease', (171, 191))	('gastric cancer', 'Disease', 'MESH:D013274', (247, 261))	('osteosarcoma', 'Disease', (442, 454))	('cancer', 'Disease', (279, 285))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (325, 342))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (171, 191))	('osteosarcoma', 'Disease', 'MESH:D012516', (442, 454))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (413, 422))	('SNHG12', 'Gene', '85028', (0, 6))	('miR-129-5p', 'Gene', (344, 354))	('squamous cell carcinoma', 'Disease', (368, 391))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('lung cancer', 'Disease', (299, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('miR-16-5p', 'Var', (312, 321))	('gastric cancer', 'Disease', (140, 154))	('miR-195', 'Gene', (428, 435))	('miR-199a/b', 'Var', (233, 243))	('renal carcinoma', 'Disease', 'MESH:C538614', (407, 422))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('miR-424', 'Gene', (98, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))	('miR-129-5p', 'Gene', '100302178', (344, 354))	('lung cancer', 'Disease', (274, 285))	('miR-424', 'Gene', '494336', (98, 105))	('renal carcinoma', 'Disease', (407, 422))	('miR-199a/b', 'Var', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('gastric cancer', 'Phenotype', 'HP:0012126', (247, 261))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (207, 231))	('renal carcinoma', 'Phenotype', 'HP:0005584', (407, 422))	('miR-181a', 'Var', (287, 295))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('miR-199a-5p', 'Var', (156, 167))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('malignant diseases', 'Disease', (41, 59))	('miR-195', 'Gene', '406971', (428, 435))	('osteosarcoma', 'Phenotype', 'HP:0002669', (442, 454))	('cancer', 'Disease', (148, 154))	('lung cancer', 'Disease', 'MESH:D008175', (299, 310))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (171, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (368, 391))	('miR-199-5p', 'Var', (393, 403))	('miR-320', 'Var', (129, 136))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (325, 342))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (207, 231))	('malignant diseases', 'Disease', 'MESH:D009369', (41, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (299, 310))	('gastric cancer', 'Disease', (247, 261))	('lung cancer', 'Disease', 'MESH:D008175', (274, 285))	('thyroid carcinoma', 'Disease', (325, 342))	('miR-320', 'Chemical', '-', (129, 136))	('cancer', 'Disease', (121, 127))	('SNHG12', 'Gene', (0, 6))
779399	32318335	In the non-small cell lung cancer, SNHG12 acts as a ceRNA for miR-138 and miR-181a, causing increased proliferation and colony-formation capabilities, as well as impaired apoptosis.	('lung cancer', 'Disease', (22, 33))	('SNHG12', 'Gene', (35, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('impaired', 'NegReg', (162, 170))	('miR-181a', 'Var', (74, 82))	('SNHG12', 'Gene', '85028', (35, 41))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (7, 33))	('apoptosis', 'CPA', (171, 180))	('miR-138', 'Var', (62, 69))	('increased', 'PosReg', (92, 101))	('proliferation', 'CPA', (102, 115))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (11, 33))	('colony-formation capabilities', 'CPA', (120, 149))
779401	32318335	MiR-181a hinders lung cancer cell proliferation and migration by targeting CDK1 (cyclin dependent kinase 1) and KRAS.	('lung cancer', 'Disease', (17, 28))	('hinders', 'NegReg', (9, 16))	('CDK1', 'Gene', (75, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('MiR-181a', 'Var', (0, 8))	('CDK1', 'Gene', '983', (75, 79))	('targeting', 'Reg', (65, 74))	('cyclin dependent kinase 1', 'Gene', (81, 106))	('KRAS', 'Gene', (112, 116))	('cyclin dependent kinase 1', 'Gene', '983', (81, 106))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('KRAS', 'Gene', '3845', (112, 116))
779402	32318335	According to a recent meta-analysis, miR-181a is majorly linked to lung cancer patient's survival rate.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('miR-181a', 'Var', (37, 45))	('patient', 'Species', '9606', (79, 86))	('linked', 'Reg', (57, 63))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
779406	32318335	The main molecular activity of SNHG15 is related to its targeting of miRNAs, as follows: miR-141-3p in hepatocellular carcinoma, miR-338-3p in prostate cancer, miR-211-3p in lung cancer, and miR-211-3p in breast cancer.	('lung cancer', 'Disease', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('miR-141', 'Gene', '406933', (89, 96))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('breast cancer', 'Disease', (205, 218))	('SNHG15', 'Gene', (31, 37))	('hepatocellular carcinoma', 'Disease', (103, 127))	('miR-338-3p', 'Var', (129, 139))	('miR-141', 'Gene', (89, 96))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('SNHG15', 'Gene', '285958', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('prostate cancer', 'Disease', 'MESH:D011471', (143, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (143, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('miR-211-3p', 'Gene', '100302164', (160, 170))	('miR-211-3p', 'Gene', '100302164', (191, 201))	('prostate cancer', 'Disease', (143, 158))	('miR-211-3p', 'Gene', (160, 170))	('miR-211-3p', 'Gene', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))
779408	32318335	SNHG15 is involved in colorectal cancer cell proliferation and migration via miR-141 and miR-338-3p sponging, along with up-regulation of AIF (Allograft Inflammatory Factor 1), and activation of transcription factor SLUG.	('up-regulation', 'PosReg', (121, 134))	('involved', 'Reg', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))	('SNHG15', 'Gene', (0, 6))	('Allograft Inflammatory Factor 1', 'Gene', (143, 174))	('miR-338-3p', 'Var', (89, 99))	('SNHG15', 'Gene', '285958', (0, 6))	('AIF', 'Gene', '199', (138, 141))	('AIF', 'Gene', (138, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('Allograft Inflammatory Factor 1', 'Gene', '199', (143, 174))	('activation', 'PosReg', (181, 191))	('miR-141', 'Gene', '406933', (77, 84))	('SLUG', 'Gene', '6591', (216, 220))	('colorectal cancer', 'Disease', (22, 39))	('miR-141', 'Gene', (77, 84))	('SLUG', 'Gene', (216, 220))	('migration', 'CPA', (63, 72))
779409	32318335	In thyroid cancer, SNHG15 is a ceRNA for miR-510-5p and miR-200a-3p.	('miR-510', 'Gene', '574515', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('SNHG15', 'Gene', '285958', (19, 25))	('thyroid cancer', 'Phenotype', 'HP:0002890', (3, 17))	('thyroid cancer', 'Disease', 'MESH:D013964', (3, 17))	('miR-510', 'Gene', (41, 48))	('thyroid cancer', 'Disease', (3, 17))	('miR-200a-3p', 'Var', (56, 67))	('SNHG15', 'Gene', (19, 25))
779415	32318335	SNHG15 silencing leads to down-regulation of VEGFA (vascular endothelial growth factor A) and CDC42 (cell division cycle 42), both being proangiogenic genes.	('vascular endothelial growth factor A', 'Gene', '7422', (52, 88))	('VEGFA', 'Gene', (45, 50))	('SNHG15', 'Gene', (0, 6))	('down-regulation', 'NegReg', (26, 41))	('vascular endothelial growth factor A', 'Gene', (52, 88))	('CDC42', 'Gene', '998', (94, 99))	('VEGFA', 'Gene', '7422', (45, 50))	('SNHG15', 'Gene', '285958', (0, 6))	('CDC42', 'Gene', (94, 99))	('silencing', 'Var', (7, 16))
779418	32318335	The synchronous coexpression of SNHG and SLUG leads to increased colon cancer cell migration and tumorigenesis capacity.	('colon cancer', 'Disease', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('SNHG', 'Var', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('increased', 'PosReg', (55, 64))	('SLUG', 'Gene', '6591', (41, 45))	('SLUG', 'Gene', (41, 45))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('tumor', 'Disease', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))
779436	32318335	SNHG20 supports glioma cell survival by sponging miR-4486 and up-regulating MDM2-p53 pathway, and silencing p21.	('miR-4486', 'Gene', '100616118', (49, 57))	('SNHG20', 'Gene', (0, 6))	('p21', 'Gene', (108, 111))	('silencing', 'NegReg', (98, 107))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('glioma', 'Disease', (16, 22))	('p21', 'Gene', '644914', (108, 111))	('SNHG20', 'Gene', '654434', (0, 6))	('p53', 'Gene', (81, 84))	('supports', 'PosReg', (7, 15))	('sponging', 'Var', (40, 48))	('MDM2', 'Gene', (76, 80))	('p53', 'Gene', '7157', (81, 84))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('MDM2', 'Gene', '4193', (76, 80))	('miR-4486', 'Gene', (49, 57))	('up-regulating', 'PosReg', (62, 75))
779442	32318335	In lung cancer, SNHG20 overexpression causes increased cell proliferation, invasion, and migration capacity, by changing the DNA methylation pattern, after interaction with EZH2 and epigenetic repression of p21.	('migration capacity', 'CPA', (89, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('p21', 'Gene', (207, 210))	('p21', 'Gene', '644914', (207, 210))	('increased', 'PosReg', (45, 54))	('invasion', 'CPA', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('interaction', 'Interaction', (156, 167))	('SNHG20', 'Gene', (16, 22))	('lung cancer', 'Disease', (3, 14))	('cell proliferation', 'CPA', (55, 73))	('changing', 'Reg', (112, 120))	('epigenetic repression', 'Var', (182, 203))	('EZH2', 'Gene', '2146', (173, 177))	('EZH2', 'Gene', (173, 177))	('overexpression', 'PosReg', (23, 37))	('DNA methylation pattern', 'MPA', (125, 148))	('SNHG20', 'Gene', '654434', (16, 22))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
779450	32318335	The most common signaling pathways activated by SNHGs are: WNT/beta-catenin and mTOR/PI3K/AKT.	('beta-catenin', 'Gene', (63, 75))	('mTOR', 'Gene', (80, 84))	('AKT', 'Gene', (90, 93))	('mTOR', 'Gene', '2475', (80, 84))	('beta-catenin', 'Gene', '1499', (63, 75))	('SNHGs', 'Var', (48, 53))	('AKT', 'Gene', '207', (90, 93))	('signaling pathways', 'Pathway', (16, 34))
779455	32318335	A high level of SNHG1 is associated with poor overall and disease-free survival in all of these malignancies.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('disease-free survival', 'CPA', (58, 79))	('SNHG1', 'Gene', '23642', (16, 21))	('malignancies', 'Disease', (96, 108))	('poor', 'NegReg', (41, 45))	('high level', 'Var', (2, 12))	('SNHG1', 'Gene', (16, 21))
779457	32318335	The oncogenic activity of SNHGs can be impaired by the temporary silencing of SNHGs at RNA level with the help of RNA interference or the permanent deletion of these lncRNAs in cancer cells through genome editing techniques.	('deletion', 'Var', (148, 156))	('cancer', 'Disease', (177, 183))	('oncogenic activity', 'CPA', (4, 22))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('RNA', 'MPA', (114, 117))	('impaired', 'NegReg', (39, 47))	('SNHGs', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('silencing', 'NegReg', (65, 74))
779462	32318335	The induced mutations affected specifically the ability to form secondary Kink-turn structure in each SNORD (SNORD74, SNORD77, and SNORD80).	('SNORD', 'Gene', (131, 136))	('SNORD', 'Gene', '619498', (102, 107))	('SNORD', 'Gene', (118, 123))	('affected', 'Reg', (22, 30))	('secondary Kink-turn structure', 'MPA', (64, 93))	('SNORD77', 'Gene', '692197', (118, 125))	('SNORD80', 'Gene', '26774', (131, 138))	('SNORD', 'Gene', (102, 107))	('mutations', 'Var', (12, 21))	('SNORD', 'Gene', '619498', (118, 123))	('SNORD', 'Gene', (109, 114))	('SNORD', 'Gene', '619498', (131, 136))	('SNORD74', 'Gene', (109, 116))	('SNORD74', 'Gene', '619498', (109, 116))	('SNORD80', 'Gene', (131, 138))	('SNORD77', 'Gene', (118, 125))	('SNORD', 'Gene', '619498', (109, 114))
779463	32318335	Moreover, the editing of PAM located in the D' box of SNORD75 affected the alternative splicing of SNHG, thus showing that snoRNAs can modulate the alternative splicing of their SNHG of origin by affecting the m6A methyltransferase complex.	('alternative splicing', 'MPA', (148, 168))	('modulate', 'Reg', (135, 143))	('PAM', 'Gene', '5066', (25, 28))	('alternative splicing', 'MPA', (75, 95))	('affecting', 'Reg', (196, 205))	('snoRNA', 'Gene', (123, 129))	('SNORD75', 'Gene', '692195', (54, 61))	('PAM', 'Gene', (25, 28))	('snoRNA', 'Gene', '6079', (123, 129))	('affected', 'Reg', (62, 70))	('m6A methyltransferase complex', 'Enzyme', (210, 239))	('SNORD75', 'Gene', (54, 61))	('editing', 'Var', (14, 21))
779465	32318335	The silencing of SNHG1 in colon cancer cells lowered their malignant potential.	('SNHG1', 'Gene', (17, 22))	('colon cancer', 'Phenotype', 'HP:0003003', (26, 38))	('malignant potential', 'CPA', (59, 78))	('lowered', 'NegReg', (45, 52))	('colon cancer', 'Disease', 'MESH:D015179', (26, 38))	('colon cancer', 'Disease', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('SNHG1', 'Gene', '23642', (17, 22))	('silencing', 'Var', (4, 13))
779466	32318335	The knockdown of SNHG6 in glioma causes a reduced growth rate of treated cells.	('SNHG6', 'Gene', '641638', (17, 22))	('reduced', 'NegReg', (42, 49))	('SNHG6', 'Gene', (17, 22))	('growth rate of treated', 'CPA', (50, 72))	('glioma', 'Disease', (26, 32))	('reduced growth rate', 'Phenotype', 'HP:0001510', (42, 61))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('knockdown', 'Var', (4, 13))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
779471	32318335	The data on these non-coding RNAs are abundant, and the validation of their role in the progression and severity of malignant diseases has been made clear during the last year.	('malignant diseases', 'Disease', 'MESH:D009369', (116, 134))	('non-coding RNAs', 'Var', (18, 33))	('malignant diseases', 'Disease', (116, 134))
779473	32318335	SNHGs also activate the signaling pathways commonly involved in cancer development and progression, such as Wnt/beta-catenin and mTOR/PI3K/AKT.	('AKT', 'Gene', '207', (139, 142))	('SNHGs', 'Var', (0, 5))	('signaling pathways', 'Pathway', (24, 42))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mTOR', 'Gene', '2475', (129, 133))	('activate', 'PosReg', (11, 19))	('mTOR', 'Gene', (129, 133))	('AKT', 'Gene', (139, 142))	('beta-catenin', 'Gene', (112, 124))	('men', 'Species', '9606', (78, 81))	('beta-catenin', 'Gene', '1499', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
779519	32190313	Pathological findings of the resected specimen confirmed residual adenocarcinoma at the esophagogastric junction, with the following tumor components identified: Tub1 >tub2 and >por2.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('Tub1 >tub2', 'Var', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('adenocarcinoma', 'Disease', (66, 80))	('tumor', 'Disease', (133, 138))	('adenocarcinoma', 'Disease', 'MESH:D000230', (66, 80))
779578	31620502	For diagnosing stage IV esophageal cancer, FDG-PET scan is superior to a combination of CT and EUS in accuracy (82% with FDG-PET vs 64% with EUS and CT together).	('esophageal cancer', 'Disease', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('FDG', 'Chemical', 'MESH:C554683', (43, 46))	('FDG-PET', 'Var', (121, 128))	('FDG', 'Chemical', 'MESH:C554683', (121, 124))
779649	29863189	Incidence of overall metastasis or recurrence was increased with the EIL of Siewert type II tumors, and this tendency was especially apparent in the mediastinal zones.	('Siewert type II tumors', 'Disease', (76, 98))	('increased', 'PosReg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Siewert type II tumors', 'Disease', 'MESH:D007619', (76, 98))	('EIL', 'Var', (69, 72))	('EIL', 'Chemical', '-', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('metastasis', 'CPA', (21, 31))	('recurrence', 'CPA', (35, 45))
779658	29863189	Rates of overall metastasis or recurrence in the cervical, upper, middle, lower mediastinal, and abdominal zones were significantly higher in the >25 mm EIL group than in the <=25 mm EIL group (P = .007, P = .01, P < .001, P = .002, and P < .001, respectively).	('higher', 'PosReg', (132, 138))	('metastasis', 'CPA', (17, 27))	('EIL', 'Var', (153, 156))	('>25 mm EIL', 'Var', (146, 156))	('EIL', 'Chemical', '-', (153, 156))	('recurrence', 'CPA', (31, 41))	('EIL', 'Chemical', '-', (183, 186))
779660	29863189	Estimated 5-year disease-free survival (DFS) rates for the <=25 mm EIL group and the >25 mm EIL group were 67.1% and 41.3%, respectively (P < .001) (Figure 2A).	('EIL', 'Chemical', '-', (67, 70))	('disease-free survival', 'CPA', (17, 38))	('<=25 mm', 'Var', (59, 66))	('EIL', 'Chemical', '-', (92, 95))
779672	29863189	In the present study, we showed that the EIL was significantly associated with upper and middle mediastinal lymph node metastasis or recurrence.	('associated', 'Reg', (63, 73))	('EIL', 'Var', (41, 44))	('recurrence', 'CPA', (133, 143))	('EIL', 'Chemical', '-', (41, 44))	('mediastinal lymph node metastasis', 'Phenotype', 'HP:0100721', (96, 129))	('middle mediastinal lymph node metastasis', 'Disease', (89, 129))	('middle mediastinal lymph node metastasis', 'Disease', 'MESH:D009362', (89, 129))
779686	29863189	In our study, none of the patients received neoadjuvant therapies and cT1 patients were included; as a result, a point 25 mm from the EGJ was considered the border for an increased risk of upper and middle mediastinal lymph node metastasis or recurrence.	('patients', 'Species', '9606', (74, 82))	('middle mediastinal lymph node metastasis', 'Disease', (199, 239))	('middle mediastinal lymph node metastasis', 'Disease', 'MESH:D009362', (199, 239))	('recurrence', 'CPA', (243, 253))	('patients', 'Species', '9606', (26, 34))	('mediastinal lymph node metastasis', 'Phenotype', 'HP:0100721', (206, 239))	('point 25 mm', 'Var', (113, 124))
779689	29863189	In contrast, upper and middle mediastinal lymph node metastasis or recurrence was rare in the <=25 mm EIL group.	('<=25 mm', 'Var', (94, 101))	('EIL', 'Chemical', '-', (102, 105))	('mediastinal lymph node metastasis', 'Phenotype', 'HP:0100721', (30, 63))	('middle mediastinal lymph node metastasis', 'Disease', (23, 63))	('middle mediastinal lymph node metastasis', 'Disease', 'MESH:D009362', (23, 63))
779690	29863189	However, lower mediastinal lymph node metastasis or recurrence was found in about 10% of patients in the <=25 mm EIL group.	('mediastinal lymph node metastasis', 'Phenotype', 'HP:0100721', (15, 48))	('EIL', 'Chemical', '-', (113, 116))	('lower mediastinal lymph node metastasis', 'CPA', (9, 48))	('patients', 'Species', '9606', (89, 97))	('<=25 mm', 'Var', (105, 112))	('recurrence', 'CPA', (52, 62))
779713	29262672	The mARC was lower in lung V10, V20, and V30 than in 3D-CRT, but could not be proven superior in lung V5.	('V30', 'Var', (41, 44))	('lower', 'NegReg', (13, 18))	('V20', 'Var', (32, 35))	('mARC', 'Gene', (4, 8))	('mARC', 'Gene', '11838', (4, 8))
779758	29262672	Average of monitor units (MU) per fraction were 204.91 +- 12.14 in 3D-CRT, 837.52 +- 379.13 in s-IMRT, and 523.32 +- 71.53 in mARC (p < 0.001).	('mARC', 'Gene', '11838', (126, 130))	('837.52 +- 379.13', 'Var', (75, 91))	('mARC', 'Gene', (126, 130))
779792	29262672	showed that 3D-CRT had lower lung V5 and V10 compared to IMRT and VMAT.	('VMAT', 'Disease', (66, 70))	('VMAT', 'Disease', 'None', (66, 70))	('3D-CRT', 'Var', (12, 18))	('lower', 'NegReg', (23, 28))
779799	29262672	We found that heart preservation effect was better with s-IMRT and mARC than with 3D-CRT.	('s-IMRT', 'Var', (56, 62))	('mARC', 'Gene', '11838', (67, 71))	('heart preservation effect', 'CPA', (14, 39))	('mARC', 'Gene', (67, 71))
779816	27476776	MCM4 and MCM7 may serve as more sensitive proliferative markers for the evaluation of esophageal lesions.	('MCM7', 'Gene', (9, 13))	('esophageal lesions', 'Disease', (86, 104))	('MCM4', 'Var', (0, 4))	('esophageal lesions', 'Disease', 'MESH:D004935', (86, 104))
779818	27476776	Aberrant expressions of MCM proteins have been reported to be promising prognostic markers in a number of malignancies.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('Aberrant', 'Var', (0, 8))	('malignancies', 'Disease', (106, 118))	('MCM proteins', 'Protein', (24, 36))	('expressions', 'MPA', (9, 20))
779823	27476776	In addition, we previously found aberrant expression and amplification of cyclin E significantly increased in dysplastic esophageal lesions.	('dysplastic esophageal lesions', 'Disease', (110, 139))	('increased', 'PosReg', (97, 106))	('expression', 'MPA', (42, 52))	('dysplastic esophageal lesions', 'Disease', 'MESH:D004935', (110, 139))	('cyclin', 'Protein', (74, 80))	('aberrant', 'Var', (33, 41))	('amplification', 'MPA', (57, 70))
779836	27476776	In breast cancer, high level of MCM4 expression was associated with disease progression, ER-negative or high-grade breast tumors, and shorter survival.	('ER-negative', 'Disease', (89, 100))	('breast tumors', 'Disease', 'MESH:D001943', (115, 128))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast tumors', 'Disease', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('associated', 'Reg', (52, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('disease progression', 'CPA', (68, 87))	('MCM4 expression', 'Var', (32, 47))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('breast tumors', 'Phenotype', 'HP:0100013', (115, 128))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('shorter', 'NegReg', (134, 141))
779837	27476776	In the gastrointestinal tract, MCM7 expression was found to be a poor prognostic factor for gastric and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('colorectal cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MCM7 expression', 'Var', (31, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('gastric', 'Disease', (92, 99))
779838	27476776	Studies also showed MCM7 expression had poorer prognosis in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('MCM7 expression', 'Var', (20, 35))	('lung adenocarcinoma', 'Disease', (60, 79))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (60, 79))
779843	24586528	Functional Polymorphisms in Interleukin-23 Receptor and Susceptibility to Esophageal Squamous Cell Carcinoma in Chinese Population As a key element in the T-helper 17 (Th17) cell-mediated inflammatory process, interleukin-23 receptor (IL-23R) plays a crucial role in the pathogenesis of cancer.	('interleukin-23 receptor', 'Gene', '149233', (210, 233))	('Esophageal Squamous Cell Carcinoma', 'Disease', (74, 108))	('interleukin-23 receptor', 'Gene', (210, 233))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (74, 108))	('IL-23R', 'Gene', (235, 241))	('Carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('Polymorphisms', 'Var', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('IL-23R', 'Gene', '149233', (235, 241))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('Interleukin-23 Receptor', 'Gene', (28, 51))	('Interleukin-23 Receptor', 'Gene', '149233', (28, 51))
779844	24586528	Single nucleotide polymorphisms (SNPs) in IL-23R have been frequently studied in several previous case-control cancer studies, but its association with esophageal squamous cell carcinoma (ESCC) in Chinese population has not been investigated.	('SCC', 'Gene', (189, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (152, 186))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('SCC', 'Phenotype', 'HP:0002860', (189, 192))	('SCC', 'Gene', '6317', (189, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('IL-23R', 'Gene', (42, 48))	('esophageal squamous cell carcinoma', 'Disease', (152, 186))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('IL-23R', 'Gene', '149233', (42, 48))
779845	24586528	This study examined whether genetic polymorphisms in IL-23R were associated with ESCC susceptibility.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('SCC', 'Gene', '6317', (82, 85))	('IL-23R', 'Gene', (53, 59))	('associated', 'Reg', (65, 75))	('IL-23R', 'Gene', '149233', (53, 59))	('genetic polymorphisms', 'Var', (28, 49))	('SCC', 'Gene', (82, 85))
779846	24586528	A hospital-based case-control study of 684 ESCC patients and 1064 healthy controls was performed to assess the association between four previous reported IL-23R genotypes (rs6682925, rs6683039, rs1884444 and rs10889677) and ESCC risk.	('SCC', 'Gene', '6317', (225, 228))	('SCC', 'Gene', '6317', (44, 47))	('rs6683039', 'Mutation', 'rs6683039', (183, 192))	('rs1884444', 'Var', (194, 203))	('rs6682925', 'Mutation', 'rs6682925', (172, 181))	('SCC', 'Phenotype', 'HP:0002860', (225, 228))	('rs10889677', 'Mutation', 'rs10889677', (208, 218))	('rs6682925', 'Var', (172, 181))	('rs1884444', 'Mutation', 'rs1884444', (194, 203))	('IL-23R', 'Gene', (154, 160))	('rs10889677', 'Var', (208, 218))	('SCC', 'Gene', (44, 47))	('SCC', 'Gene', (225, 228))	('IL-23R', 'Gene', '149233', (154, 160))	('patients', 'Species', '9606', (48, 56))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('rs6683039', 'Var', (183, 192))
779847	24586528	The results revealed that the C allele of the rs10889677A>C polymorphism in the 3'UTR of IL-23R gene was inversely associated with the risk of ESCC.	('rs10889677A>C', 'Var', (46, 59))	('inversely', 'NegReg', (105, 114))	('SCC', 'Gene', (144, 147))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (46, 59))	('associated', 'Reg', (115, 125))	('SCC', 'Gene', '6317', (144, 147))	('IL-23R', 'Gene', (89, 95))	('IL-23R', 'Gene', '149233', (89, 95))
779848	24586528	The rs10889677AC genotype had significantly decreased cancer risk (odds ratio [OR] = 0.85, 95% confidence interval [CI] = 0.69-1.01) compared to subjects homozygous carriers of rs10889677AA, the risk decreased even further in those carrying rs10889677CC genotype (OR = 0.64, 95% CI = 0.44-0.93).	('rs10889677', 'Mutation', 'rs10889677', (4, 14))	('rs10889677', 'Mutation', 'rs10889677', (241, 251))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('rs10889677', 'Mutation', 'rs10889677', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('rs10889677AC', 'Var', (4, 16))	('rs10889677CC', 'Var', (241, 253))	('decreased', 'NegReg', (44, 53))
779850	24586528	These findings indicated that rs10889677A>C polymorphism in IL-23R may play a protective role in mediating the risk of ESCC.	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('IL-23R', 'Gene', (60, 66))	('rs10889677A>C', 'Var', (30, 43))	('SCC', 'Gene', (120, 123))	('IL-23R', 'Gene', '149233', (60, 66))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (30, 43))
779864	24586528	One of our previous studies have demonstrated that the IL-23R rs10889677A>C SNP may alter IL-23R expression by modifying miR-let-7f binding to the 3'UTR of the IL-23R gene, thereby influence the transcription of IL-23R in vivo and in vitro in breast, lung and nasopharyngeal cancer.	('IL-23R', 'Gene', '149233', (90, 96))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (260, 281))	('binding', 'Interaction', (132, 139))	('rs10889677A>C', 'Var', (62, 75))	('IL-23R', 'Gene', (160, 166))	('influence', 'Reg', (181, 190))	('IL-23R', 'Gene', '149233', (160, 166))	('miR', 'Gene', '220972', (121, 124))	('expression', 'MPA', (97, 107))	('breast', 'Disease', (243, 249))	('IL-23R', 'Gene', (55, 61))	('lung', 'Disease', (251, 255))	('transcription', 'MPA', (195, 208))	('modifying', 'Reg', (111, 120))	('IL-23R', 'Gene', '149233', (55, 61))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (260, 281))	('IL-23R', 'Gene', (212, 218))	('miR', 'Gene', (121, 124))	('alter', 'Reg', (84, 89))	('IL-23R', 'Gene', '149233', (212, 218))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('nasopharyngeal cancer', 'Disease', (260, 281))	('IL-23R', 'Gene', (90, 96))
779876	24586528	All ESCC patients and healthy controls were genotyped for the rs6682925, rs6683039, rs1884444 and rs10889677 polymorphisms.	('SCC', 'Gene', '6317', (5, 8))	('patients', 'Species', '9606', (9, 17))	('rs1884444', 'Var', (84, 93))	('rs6682925', 'Mutation', 'rs6682925', (62, 71))	('rs6682925', 'Var', (62, 71))	('rs1884444', 'Mutation', 'rs1884444', (84, 93))	('rs10889677', 'Var', (98, 108))	('rs10889677', 'Mutation', 'rs10889677', (98, 108))	('SCC', 'Gene', (5, 8))	('rs6683039', 'Var', (73, 82))	('rs6683039', 'Mutation', 'rs6683039', (73, 82))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))
779879	24586528	Data were further stratified by characters to evaluate the stratum variable-related ORs among the IL-23R rs10889677A>C genotypes.	('rs10889677A>C', 'Var', (105, 118))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (105, 118))	('IL-23R', 'Gene', (98, 104))	('IL-23R', 'Gene', '149233', (98, 104))
779880	24586528	To test whether IL-23R polymorphisms are associated with ESCC risk, we performed the genotypic distribution of four candidate SNPs (rs6683039, rs6682925, rs1884444 and rs10889677) of the IL-23R gene between cases and controls.	('rs10889677', 'Var', (168, 178))	('rs10889677', 'Mutation', 'rs10889677', (168, 178))	('SCC', 'Gene', (58, 61))	('rs6683039', 'Var', (132, 141))	('associated', 'Reg', (41, 51))	('rs6682925', 'Mutation', 'rs6682925', (143, 152))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('IL-23R', 'Gene', (187, 193))	('rs6682925', 'Var', (143, 152))	('rs6683039', 'Mutation', 'rs6683039', (132, 141))	('IL-23R', 'Gene', (16, 22))	('SCC', 'Gene', '6317', (58, 61))	('IL-23R', 'Gene', '149233', (16, 22))	('rs1884444', 'Var', (154, 163))	('IL-23R', 'Gene', '149233', (187, 193))	('rs1884444', 'Mutation', 'rs1884444', (154, 163))
779882	24586528	A significant association with low risk of ESCC was observed for the rs10889677A>C SNP (OR for the rs10889677AC genotype, 0.85; 95%CI: 0.69-1.01; OR for the rs10889677CC genotype, 0.64; 95%CI: 0.44-0.93; P trend = 0.004).	('SCC', 'Gene', '6317', (44, 47))	('rs10889677', 'Mutation', 'rs10889677', (157, 167))	('rs10889677', 'Mutation', 'rs10889677', (69, 79))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (69, 82))	('rs10889677AC', 'Var', (99, 111))	('rs10889677CC', 'Var', (157, 169))	('SCC', 'Gene', (44, 47))	('rs10889677', 'Mutation', 'rs10889677', (99, 109))	('rs10889677A>C', 'Var', (69, 82))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))
779883	24586528	The other SNPs, rs6682925 and rs6683039 in the promoter region and rs1884444 in exon 2, were not significantly associated with the risk of ESCC in our study population ( Table 2 ).	('rs6682925', 'Var', (16, 25))	('SCC', 'Phenotype', 'HP:0002860', (140, 143))	('rs1884444', 'Var', (67, 76))	('SCC', 'Gene', '6317', (140, 143))	('rs6683039', 'Var', (30, 39))	('rs6683039', 'Mutation', 'rs6683039', (30, 39))	('rs1884444', 'Mutation', 'rs1884444', (67, 76))	('rs6682925', 'Mutation', 'rs6682925', (16, 25))	('SCC', 'Gene', (140, 143))
779884	24586528	Thus, we may conclude that genetic variant rs10889677CC polymorphism in IL-23R plays a significantly protective role in mediating the risk of ESCC.	('SCC', 'Gene', (143, 146))	('IL-23R', 'Gene', (72, 78))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('SCC', 'Gene', '6317', (143, 146))	('IL-23R', 'Gene', '149233', (72, 78))	('rs10889677', 'Mutation', 'rs10889677', (43, 53))	('rs10889677CC', 'Var', (43, 55))
779885	24586528	A stratification analysis according to by subgroup of age, sex, smoking status, alcohol drinking status, and BMI to further verify the association between the risk of ESCC and IL-23R rs10889677A>C genotypes was conducted.	('SCC', 'Gene', (168, 171))	('SCC', 'Phenotype', 'HP:0002860', (168, 171))	('IL-23R', 'Gene', '149233', (176, 182))	('SCC', 'Gene', '6317', (168, 171))	('rs10889677A>C', 'Var', (183, 196))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (183, 196))	('alcohol drinking', 'Phenotype', 'HP:0030955', (80, 96))	('IL-23R', 'Gene', (176, 182))	('alcohol', 'Chemical', 'MESH:D000438', (80, 87))
779888	24586528	Associations between ESCC susceptibility and IL-23R polymorphisms have not been detected in any population using cases-controls study.	('IL-23R', 'Gene', '149233', (45, 51))	('polymorphisms', 'Var', (52, 65))	('SCC', 'Gene', (22, 25))	('SCC', 'Phenotype', 'HP:0002860', (22, 25))	('SCC', 'Gene', '6317', (22, 25))	('IL-23R', 'Gene', (45, 51))
779890	24586528	Our results obtained by analyzing 684 ESCC patients and 1064 healthy controls showed that the functional variation rs10889677 C in the IL-23R was associated with decreased risk for developing ESCC.	('SCC', 'Gene', '6317', (39, 42))	('IL-23R', 'Gene', (135, 141))	('IL-23R', 'Gene', '149233', (135, 141))	('rs10889677', 'Mutation', 'rs10889677', (115, 125))	('patients', 'Species', '9606', (43, 51))	('decreased', 'NegReg', (162, 171))	('SCC', 'Gene', (193, 196))	('SCC', 'Phenotype', 'HP:0002860', (193, 196))	('SCC', 'Gene', (39, 42))	('rs10889677 C', 'Var', (115, 127))	('SCC', 'Gene', '6317', (193, 196))	('SCC', 'Phenotype', 'HP:0002860', (39, 42))
779893	24586528	Here, our finding also indicated a gene-environment interaction between alcohol use and genetic variation for developing ESCC.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('alcohol use', 'Phenotype', 'HP:0030955', (72, 83))	('SCC', 'Gene', '6317', (122, 125))	('alcohol', 'Chemical', 'MESH:D000438', (72, 79))	('genetic variation', 'Var', (88, 105))
779895	24586528	Combined with our previous study of these polymorphisms in breast, lung, and nasopharyngeal cancers with diverse etiologies, our data further raises the possibility that IL-23R variant might be a common susceptibility factor for human cancer.	('nasopharyngeal cancers', 'Disease', (77, 99))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (77, 98))	('cancer', 'Disease', (92, 98))	('IL-23R', 'Gene', (170, 176))	('cancer', 'Disease', (235, 241))	('variant', 'Var', (177, 184))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('susceptibility', 'Reg', (203, 217))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('IL-23R', 'Gene', '149233', (170, 176))	('human', 'Species', '9606', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('nasopharyngeal cancers', 'Disease', 'MESH:D009303', (77, 99))
779897	24586528	Therefore, it is biologically reasonable that functional IL-23R polymorphisms may play a role in the development of cancer.	('cancer', 'Disease', (116, 122))	('IL-23R', 'Gene', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('play', 'Reg', (82, 86))	('IL-23R', 'Gene', '149233', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('role', 'Reg', (89, 93))	('polymorphisms', 'Var', (64, 77))
779898	24586528	In fact, studies have shown that IL-23R polymorphisms are associated with susceptibility to gastric cancer.	('susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (74, 106))	('associated', 'Reg', (58, 68))	('IL-23R', 'Gene', (33, 39))	('polymorphisms', 'Var', (40, 53))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('IL-23R', 'Gene', '149233', (33, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))
779899	24586528	found in a previous study of gastric cancer, which included 941 cancer patients and 775 Chinese (Guangzhou) control subjects, that the rs10889677CC genotype is associated with a significantly reduced risk of gastric cancer when compared to the more common rs10889677AA genotype (OR = 0.47, 95% CI = 0.31-0.71).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('rs10889677CC', 'Var', (135, 147))	('gastric cancer', 'Disease', 'MESH:D013274', (208, 222))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (216, 222))	('reduced', 'NegReg', (192, 199))	('gastric cancer', 'Disease', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', (64, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (208, 222))	('rs10889677', 'Mutation', 'rs10889677', (256, 266))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (37, 43))	('rs10889677', 'Mutation', 'rs10889677', (135, 145))	('gastric cancer', 'Disease', 'MESH:D013274', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('gastric cancer', 'Disease', (208, 222))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (29, 43))
779900	24586528	Other two independent studies of Chinese population have shown that the rs10889677C allele may increase the risk of oral cancer and ovarian cancer when compared to the rs10889677A allele.	('oral cancer', 'Disease', 'MESH:D009062', (116, 127))	('rs10889677', 'Mutation', 'rs10889677', (168, 178))	('ovarian cancer', 'Disease', (132, 146))	('rs10889677', 'Mutation', 'rs10889677', (72, 82))	('oral cancer', 'Disease', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('increase', 'PosReg', (95, 103))	('rs10889677C', 'Var', (72, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (132, 146))
779902	24586528	Recently, several genome-wide association studies (GWAS) have reported several novel SNPs that are associated with the development of breast cancer.	('associated with', 'Reg', (99, 114))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('SNPs', 'Var', (85, 89))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
779903	24586528	A GWAS of nasopharyngeal carcinoma also reported three susceptibility loci in Chinese population, including rs9510787, rs6774494 and rs1412829.	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (10, 34))	('rs9510787', 'Var', (108, 117))	('rs1412829', 'Mutation', 'rs1412829', (133, 142))	('nasopharyngeal carcinoma', 'Disease', (10, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('rs6774494', 'Var', (119, 128))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (10, 34))	('rs1412829', 'Var', (133, 142))	('rs9510787', 'Mutation', 'rs9510787', (108, 117))	('rs6774494', 'Mutation', 'rs6774494', (119, 128))
779907	24586528	therefore, the association between IL-23R rs10889677A>C polymorphism and the risk for ESCC in Chinese population remains unclear, and case-control studies with large sample sizes and different cancer types are needed.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (42, 55))	('cancer', 'Disease', (193, 199))	('IL-23R', 'Gene', '149233', (35, 41))	('SCC', 'Gene', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('SCC', 'Gene', '6317', (87, 90))	('rs10889677A>C', 'Var', (42, 55))	('IL-23R', 'Gene', (35, 41))
779909	24586528	In addition, it have been confirmed that polymorphisms determined by GWAS also play important role in Esophagus carcinogenesis.	('polymorphisms', 'Var', (41, 54))	('Esophagus carcinogenesis', 'Disease', 'MESH:D063646', (102, 126))	('Esophagus carcinogenesis', 'Disease', (102, 126))
779910	24586528	Evidence for the biological function of the IL-23R rs10889677A>C SNP has been reported in previous studies.	('rs10889677A>C', 'Var', (51, 64))	('IL-23R', 'Gene', (44, 50))	('IL-23R', 'Gene', '149233', (44, 50))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (51, 64))
779911	24586528	Our previous study has demonstrated that the IL-23R rs10889677A>C SNP may affect IL-23R expression by modifying miR-let-7f binding to the 3'UTR of the IL-23R gene.	('binding', 'Interaction', (123, 130))	('IL-23R', 'Gene', '149233', (81, 87))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (52, 65))	('IL-23R', 'Gene', '149233', (45, 51))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('IL-23R', 'Gene', (81, 87))	('IL-23R', 'Gene', '149233', (151, 157))	('IL-23R', 'Gene', (151, 157))	('affect', 'Reg', (74, 80))	('modifying', 'Reg', (102, 111))	('expression', 'MPA', (88, 98))	('IL-23R', 'Gene', (45, 51))	('rs10889677A>C', 'Var', (52, 65))
779917	24586528	Our results regarding associations between the IL-23R rs10889677A>C polymorphism and susceptibility to ESCC were obtained from a case-control study derived from eastern Han Chinese population.	('SCC', 'Gene', '6317', (104, 107))	('rs10889677A>C', 'Var', (54, 67))	('SCC', 'Gene', (104, 107))	('rs10889677A>C', 'DBSNP_MENTION', 'None', (54, 67))	('IL-23R', 'Gene', (47, 53))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('IL-23R', 'Gene', '149233', (47, 53))	('associations', 'Interaction', (22, 34))
779920	24586528	In conclusion, our study demonstrated an association between the IL-23R rs10889677C allele and reduced risk of ESCC.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('rs10889677', 'Mutation', 'rs10889677', (72, 82))	('IL-23R', 'Gene', '149233', (65, 71))	('SCC', 'Gene', '6317', (112, 115))	('rs10889677C', 'Var', (72, 83))	('reduced', 'NegReg', (95, 102))	('IL-23R', 'Gene', (65, 71))	('SCC', 'Gene', (112, 115))
779921	24586528	Together with previous studies, the rs10889677C allele resides in the 3'UTR of the IL-23R gene and results in the inhibition of the interaction with Th17 and Treg cells, which consequentially increases the proliferation rate of T lymphocytes and may explain the observed decrease in ESCC susceptibility.	('SCC', 'Gene', '6317', (284, 287))	('increases', 'PosReg', (192, 201))	('inhibition', 'NegReg', (114, 124))	('proliferation rate', 'CPA', (206, 224))	('Th17', 'Protein', (149, 153))	('IL-23R', 'Gene', '149233', (83, 89))	('decrease', 'NegReg', (271, 279))	('interaction', 'Interaction', (132, 143))	('rs10889677C', 'Var', (36, 47))	('SCC', 'Gene', (284, 287))	('SCC', 'Phenotype', 'HP:0002860', (284, 287))	('rs10889677', 'Mutation', 'rs10889677', (36, 46))	('IL-23R', 'Gene', (83, 89))
779970	19735873	This analysis is given by the following equation (Tables E1-4):   The model consisted of all nonsingular terms (28 terms) including gene expression (yx), p53 mutation status, ras mutation status, tissue of origin, and all possible interactions among terms (Table E5).	('E1-4', 'Gene', (57, 61))	('mutation', 'Var', (158, 166))	('p53', 'Gene', (154, 157))	('E1-4', 'Gene', '4863;6080;106478911;26765;10277', (57, 61))	('p53', 'Gene', '7157', (154, 157))	('interactions', 'Interaction', (231, 243))
780027	33530306	The transcriptionally active component Recombination Signal Binding Protein for Immunoglobulin k J-region (RBPJ) was induced by inflammatory cytokine receptor signaling and phosphorylation of STAT3.	('cytokine receptor', 'Gene', (141, 158))	('phosphorylation', 'Var', (173, 188))	('RBPJ', 'Gene', (107, 111))	('RBPJ', 'Gene', '3516', (107, 111))	('cytokine receptor', 'Gene', '8809', (141, 158))	('induced', 'Reg', (117, 124))
780032	33530306	LS411N cells that are STAT3-deficient and CRT-sensitive (Figure S1A, left panel) were reconstituted with either wild-type STAT3, or signaling-inactive versions, in which critical tyrosine and/or serine phosphorylation sites were inactivated by replacement with phenylalanine or alanine, respectively.	('serine', 'Chemical', 'MESH:D012694', (195, 201))	('tyrosine', 'Chemical', 'MESH:D014443', (179, 187))	('phenylalanine', 'Chemical', 'MESH:D010649', (261, 274))	('LS411N', 'Var', (0, 6))	('alanine', 'Chemical', 'MESH:D000409', (267, 274))	('alanine', 'Chemical', 'MESH:D000409', (278, 285))	('inactivated', 'NegReg', (229, 240))	('phenylalanine', 'Var', (261, 274))	('LS411N', 'CellLine', 'CVCL:1385', (0, 6))	('alanine', 'Var', (278, 285))
780033	33530306	Expression of wild-type, but not mutant STAT3, restored STAT3 transcriptional activity in LS411N cells (Figure 1A, upper left and right panel).	('restored', 'PosReg', (47, 55))	('STAT3', 'Gene', (40, 45))	('mutant', 'Var', (33, 39))	('LS411N', 'CellLine', 'CVCL:1385', (90, 96))	('STAT3 transcriptional activity', 'MPA', (56, 86))
780046	33530306	In accordance with STAT3 deficiency, the CFA survival of LS411N cells remained unaffected by napabucasin (Figure S1F).	('LS411N', 'CellLine', 'CVCL:1385', (57, 63))	('CFA survival', 'CPA', (41, 53))	('napabucasin', 'Chemical', 'MESH:C000621033', (93, 104))	('LS411N', 'Var', (57, 63))
780063	33530306	Together, these data suggest that inhibition of the gp130/STAT3 signaling axis may be applied as therapeutic measure in several entities of CRT-resistant cancers.	('gp130', 'Gene', (52, 57))	('inhibition', 'Var', (34, 44))	('CRT-resistant cancers', 'Disease', 'MESH:D009369', (140, 161))	('gp130', 'Gene', '3572', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('CRT-resistant cancers', 'Disease', (140, 161))
780065	33530306	To now delineate how inflammatory signals control CRT resistance, we analyzed how STAT3 pathway perturbation affects the global transcriptional activity of rectal cancer cells.	('affects', 'Reg', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('global transcriptional activity', 'MPA', (121, 152))	('STAT3 pathway', 'Gene', (82, 95))	('perturbation', 'Var', (96, 108))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('rectal cancer', 'Phenotype', 'HP:0100743', (156, 169))
780068	33530306	+ Hy-IL-6), 2969 genes (siCtrl.	('IL-6', 'Gene', '3569', (5, 9))	('IL-6', 'Gene', (5, 9))	('2969 genes', 'Var', (12, 22))
780080	33530306	Moreover, RBPJ silencing phenocopied STAT3 silencing as silencing of RBPJ alone was as effective as inhibition of STAT3, and the combined interference with both proteins had no additive effect on CRT re-sensitization.	('silencing', 'Var', (56, 65))	('RBPJ', 'Gene', (69, 73))	('RBPJ', 'Gene', '3516', (10, 14))	('RBPJ', 'Gene', '3516', (69, 73))	('STAT3', 'Disease', (37, 42))	('silencing', 'NegReg', (43, 52))	('silencing', 'Var', (15, 24))	('RBPJ', 'Gene', (10, 14))
780087	33530306	Furthermore, in accordance with the presence or absence of NICD, expression of the transcription factor HES1, a main target of active NOTCH signaling, was weak in LS411N cells but readily detected in SW837 and SW1463 cells with signal intensities that are proportional to the NICD positivity and CRT sensitivity of these cells (Figure 5C, upper panel).	('SW1463', 'CellLine', 'CVCL:1718', (210, 216))	('HES1', 'Gene', '3280', (104, 108))	('weak', 'NegReg', (155, 159))	('SW837', 'CellLine', 'CVCL:1729', (200, 205))	('LS411N', 'Var', (163, 169))	('NOTCH', 'Gene', '31293', (134, 139))	('expression', 'MPA', (65, 75))	('NOTCH', 'Gene', (134, 139))	('HES1', 'Gene', (104, 108))	('LS411N', 'CellLine', 'CVCL:1385', (163, 169))
780088	33530306	Thus, as a consequence of inflammatory STAT3 signaling NICD and RBPJ form a functional transcription factor complex in CRT-resistant rectal cancer cells.	('rectal cancer', 'Phenotype', 'HP:0100743', (133, 146))	('NICD', 'Var', (55, 59))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('RBPJ', 'Gene', (64, 68))	('RBPJ', 'Gene', '3516', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
780100	33530306	In fact, high expression of NOTCH2, NOTCH3, and NOTCH4 in the tumors of our patient cohort was associated with impaired disease-free survival, while NOTCH1 had no effect (Figure 5G and Figure S3D).	('NOTCH1', 'Gene', (149, 155))	('NOTCH3', 'Gene', '4854', (36, 42))	('NOTCH2', 'Gene', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('impaired disease-free', 'Disease', 'MESH:D008569', (111, 132))	('NOTCH1', 'Gene', '4851', (149, 155))	('impaired disease-free', 'Disease', (111, 132))	('NOTCH2', 'Gene', '4853', (28, 34))	('patient', 'Species', '9606', (76, 83))	('NOTCH4', 'Gene', (48, 54))	('NOTCH4', 'Gene', '4855', (48, 54))	('NOTCH3', 'Gene', (36, 42))	('high', 'Var', (9, 13))
780114	33530306	Based on all these findings, we propose that this knowledge may be translated into a personalized treatment strategy (see Figure 3D) that includes screening of pretherapeutic tumor biopsies for the presence of phosphorylated STAT3, followed by a combined treatment with CRT and napabucasin in case of phospho-STAT3 positivity.	('tumor', 'Disease', (175, 180))	('napabucasin', 'Chemical', 'MESH:C000621033', (278, 289))	('phosphorylated', 'Var', (210, 224))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
780115	33530306	Noteworthily, phospho-STAT3 can be detected in up to 40% of CRC and up to 60% of esophageal cancer.	('phospho-STAT3', 'Var', (14, 27))	('detected', 'Reg', (35, 43))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('CRC', 'Disease', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('CRC', 'Phenotype', 'HP:0003003', (60, 63))
780127	33530306	Likewise, in non-small cell lung cancer (NSCLC), expression of NOTCH3 was associated with poor survival of patients while in gastric cancer, high expression of all four NOTCH isoforms correlated with a short relapse-free survival.	('NSCLC', 'Disease', (41, 46))	('NOTCH3', 'Gene', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('gastric cancer', 'Disease', (125, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (13, 39))	('patients', 'Species', '9606', (107, 115))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (17, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('NOTCH', 'Gene', '31293', (169, 174))	('NOTCH', 'Gene', (63, 68))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (13, 39))	('NOTCH', 'Gene', '31293', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('expression', 'Var', (49, 59))	('NOTCH', 'Gene', (169, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('non-small cell lung cancer', 'Disease', (13, 39))	('NOTCH3', 'Gene', '4854', (63, 69))
780137	33530306	Site-directed mutagenesis to generate STAT3 mutants harboring amino acid exchanges Y705F, S727A, or Y705F/S727A was performed on wild-type STAT3 cDNA.	('S727A', 'Mutation', 'p.S727A', (90, 95))	('Y705F/S727A', 'Var', (100, 111))	('S727A', 'Mutation', 'p.S727A', (106, 111))	('Y705F', 'Mutation', 'p.Y705F', (100, 105))	('Y705F', 'Mutation', 'p.Y705F', (83, 88))	('Y705F', 'Var', (83, 88))	('STAT3', 'Gene', (38, 43))	('S727A', 'Var', (90, 95))
780151	33530306	Opposite direction analysis (ODA) was employed to identify genes that were significantly upregulated upon Hy-IL-6 stimulation and, inversely, downregulated upon STAT3 silencing.	('IL-6', 'Gene', (109, 113))	('STAT3 silencing', 'Var', (161, 176))	('upregulated', 'PosReg', (89, 100))	('IL-6', 'Gene', '3569', (109, 113))	('downregulated', 'NegReg', (142, 155))
780179	33374592	The proportion of adverse events for any gastrointestinal system cancer relative to all other events was elevated for ranitidine compared to PPIs and other H2 antagonists (PRR 3.66, 95% CI 3.19-4.20).	('ranitidine', 'Chemical', 'MESH:D011899', (118, 128))	('gastrointestinal system cancer', 'Disease', (41, 71))	('ranitidine', 'Var', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('H2', 'Chemical', 'MESH:D003903', (156, 158))	('gastrointestinal system cancer', 'Disease', 'MESH:D004067', (41, 71))
780314	32793455	found that the incidence of reflux esophagitis was lower in patients who underwent gastric tube reconstruction than in patients who underwent reconstruction with the whole stomach.	('reconstruction', 'Var', (96, 110))	('patients', 'Species', '9606', (60, 68))	('gastric tube', 'Disease', (83, 95))	('patients', 'Species', '9606', (119, 127))	('esophagitis', 'Phenotype', 'HP:0100633', (35, 46))	('lower', 'NegReg', (51, 56))	('reflux esophagitis', 'Disease', (28, 46))	('reflux esophagitis', 'Disease', 'MESH:D005764', (28, 46))
780317	32793455	While typical symptoms have been found to respond relatively well to PPIs, that is not the case for atypical symptoms such as respiratory symptoms.	('respiratory symptoms', 'Disease', (126, 146))	('respiratory symptoms', 'Disease', 'MESH:D012818', (126, 146))	('respiratory symptoms', 'Phenotype', 'HP:0011947', (126, 146))	('PPIs', 'Var', (69, 73))
780380	30348939	Then we showed that RIT1 inhibited proliferation, invasion, and migration of ESCC cells, and silencing RIT1 by shRNA promoted tumorigenicity and metastasis in nude mice.	('RIT1', 'Gene', (103, 107))	('invasion', 'CPA', (50, 58))	('silencing', 'Var', (93, 102))	('nude mice', 'Species', '10090', (159, 168))	('metastasis', 'CPA', (145, 155))	('proliferation', 'CPA', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('promoted', 'PosReg', (117, 125))	('inhibited', 'NegReg', (25, 34))	('migration', 'CPA', (64, 73))	('tumor', 'Disease', (126, 131))
780415	30348939	These results suggested that silencing of RIT1 inhibited ESCC tumor growth and proliferation.	('inhibited', 'NegReg', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('silencing', 'Var', (29, 38))	('ESCC tumor', 'Disease', 'MESH:D004938', (57, 67))	('RIT1', 'Gene', (42, 46))	('ESCC tumor', 'Disease', (57, 67))
780423	30348939	WB results showed that the phosphorylated ERK c-JNK, P38 (T180 and Y182), and AKT (S473 and T308) increased in RIT1-knocked-down cells and decreased in RIT1-overexpressed cells (Fig.	('ERK', 'Gene', (42, 45))	('JNK', 'Gene', (48, 51))	('S473', 'Var', (83, 87))	('JNK', 'Gene', '5599', (48, 51))	('phosphorylated', 'MPA', (27, 41))	('P38', 'Gene', '1432', (53, 56))	('Y182', 'Var', (67, 71))	('RIT1-knocked-down', 'Gene', (111, 128))	('AKT', 'Gene', '207', (78, 81))	('T308', 'Var', (92, 96))	('decreased', 'NegReg', (139, 148))	('increased', 'PosReg', (98, 107))	('ERK', 'Gene', '5594', (42, 45))	('P38', 'Gene', (53, 56))	('AKT', 'Gene', (78, 81))
780427	30348939	qRT-PCR results showed significantly decreased expression of epithelial markers E-cadherin and beta-catenin, whereas increased expression of mesenchymal marker Vimentin and Fibronectin in cells with knocked-down RIT1 compared to the control cells (Supplemental Fig.	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '999', (80, 90))	('increased', 'PosReg', (117, 126))	('expression', 'MPA', (127, 137))	('knocked-down', 'Var', (199, 211))	('Vimentin', 'Gene', (160, 168))	('beta-catenin', 'Gene', (95, 107))	('RIT1', 'Gene', (212, 216))	('Fibronectin', 'Gene', '2335', (173, 184))	('Fibronectin', 'Gene', (173, 184))	('decreased', 'NegReg', (37, 46))	('beta-catenin', 'Gene', '1499', (95, 107))	('expression', 'MPA', (47, 57))	('Vimentin', 'Gene', '7431', (160, 168))
780430	30348939	Results showed that, after treatment with CDDP for 48 h, cell viability significantly increased in KYSE150 and ECa109 cells with knockdown of RIT1 (Fig.	('RIT1', 'Gene', (142, 146))	('ECa109', 'CellLine', 'CVCL:6898', (111, 117))	('increased', 'PosReg', (86, 95))	('CDDP', 'Chemical', 'MESH:D002945', (42, 46))	('knockdown', 'Var', (129, 138))	('cell viability', 'CPA', (57, 71))
780434	30348939	Results showed that, in ESCC cells with exogenous knockdown of RIT1, multiple drug-resistant transporter gene ABCG2, stemness-associated gene Smo and ALDH1, and cancer stem cell-related surface marker CD105 and CXCR4 were significantly upregulated (Fig.	('upregulated', 'PosReg', (236, 247))	('CXCR4', 'Gene', '7852', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('knockdown', 'Var', (50, 59))	('Smo', 'Gene', '6608', (142, 145))	('ABCG2', 'Gene', (110, 115))	('CXCR4', 'Gene', (211, 216))	('ABCG2', 'Gene', '9429', (110, 115))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('ALDH1', 'Gene', (150, 155))	('RIT1', 'Gene', (63, 67))	('cancer', 'Disease', (161, 167))	('ALDH1', 'Gene', '216', (150, 155))	('Smo', 'Gene', (142, 145))
780437	30348939	Previous studies showed that RIT1 was overexpressed in about 25% of patients with hepatocellular carcinoma, due to amplification and occasionally mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('amplification', 'Var', (115, 128))	('RIT1', 'Gene', (29, 33))	('overexpressed', 'PosReg', (38, 51))	('patients', 'Species', '9606', (68, 76))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('mutation', 'Var', (146, 154))	('hepatocellular carcinoma', 'Disease', (82, 106))
780438	30348939	Next-generation sequencing revealed activating mutations and locus amplifications of RIT1 in subgroup of patients with myeloid neoplasms.	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (119, 136))	('patients', 'Species', '9606', (105, 113))	('RIT1', 'Gene', (85, 89))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (119, 136))	('locus amplifications', 'Var', (61, 81))	('neoplasms', 'Phenotype', 'HP:0002664', (127, 136))	('activating', 'PosReg', (36, 46))	('myeloid neoplasms', 'Disease', (119, 136))
780450	30348939	Aberrant regulation of MAPK cascades contributes to cancer and other human diseases.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('contributes', 'Reg', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('human', 'Species', '9606', (69, 74))	('MAPK', 'Gene', '5595;5594;26413;5595', (23, 27))	('cancer', 'Disease', (52, 58))	('Aberrant regulation', 'Var', (0, 19))	('MAPK', 'Gene', (23, 27))
458494	30348939	Furthermore, in certain other tumor types, the inhibition of p38 enhances sensitivity to chemotherapy, suggesting that p38 may serve as an oncogene in cancer progression.	('sensitivity to chemotherapy', 'MPA', (74, 101))	('p38', 'Gene', '1432', (119, 122))	('p38', 'Gene', '1432', (61, 64))	('inhibition', 'Var', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('p38', 'Gene', (119, 122))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('enhances', 'PosReg', (65, 73))	('p38', 'Gene', (61, 64))	('tumor', 'Disease', (30, 35))
780454	30348939	In AKT pathway, AKT is a downstream target of the PI3K and plays an important role in cancer cell survival, cell cycle entry, and glucose metabolism.	('AKT', 'Gene', (3, 6))	('AKT', 'Gene', '207', (16, 19))	('glucose metabolism', 'Disease', (130, 148))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('AKT', 'Gene', (16, 19))	('glucose metabolism', 'Disease', 'MESH:D044882', (130, 148))	('PI3K', 'Var', (50, 54))	('AKT', 'Gene', '207', (3, 6))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
780455	30348939	Phosphorylation of AKT promotes tumorigenesis via several oncogenic events, including apoptosis and cell proliferation.	('promotes', 'PosReg', (23, 31))	('Phosphorylation', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('AKT', 'Gene', '207', (19, 22))	('cell proliferation', 'CPA', (100, 118))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('AKT', 'Gene', (19, 22))	('tumor', 'Disease', (32, 37))	('apoptosis', 'CPA', (86, 95))
780458	30348939	Downregulation of E-cadherin, aberrant location of beta-catenin, and nuclear expression of Vimentin are some of its hallmarks.	('aberrant', 'Var', (30, 38))	('Downregulation', 'NegReg', (0, 14))	('beta-catenin', 'Gene', '1499', (51, 63))	('Vimentin', 'Gene', (91, 99))	('beta-catenin', 'Gene', (51, 63))	('nuclear expression', 'MPA', (69, 87))	('Vimentin', 'Gene', '7431', (91, 99))	('E-cadherin', 'Gene', (18, 28))	('E-cadherin', 'Gene', '999', (18, 28))
780477	30348939	The slides were blocked and then primary antibodies [anti-RIT1 (1:800), anti-Ki-67 (1:500), anti- AKTP473 (1:100), AKTP308 (1:100), anti-P-ERK1/2 pT202/Y204 (1:200), anti-c-JNK (1:100), P-c-JNK (1:100), P38 (1:100), and anti-P-P38 PT180/Y182 (1:100)] were applied and incubated at a temperature of 4  C overnight.	('AKT', 'Gene', '207', (115, 118))	('P38', 'Gene', (203, 206))	('JNK', 'Gene', (190, 193))	('JNK', 'Gene', (173, 176))	('JNK', 'Gene', '5599', (173, 176))	('ERK1/2', 'Gene', (139, 145))	('ERK1/2', 'Gene', '5595;5594', (139, 145))	('AKT', 'Gene', (115, 118))	('P38', 'Gene', (227, 230))	('AKT', 'Gene', '207', (98, 101))	('JNK', 'Gene', '5599', (190, 193))	('P38', 'Gene', '1432', (203, 206))	('P38', 'Gene', '1432', (227, 230))	('1:500', 'Var', (84, 89))	('AKT', 'Gene', (98, 101))
780481	30348939	ESCC cell lines KYSE150, KYSE520, KYSE410, KYSE140, KYSE180, and HK1 were supplied by Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ, Braunschweig, Germany), while ESCC cell lines ECa109, ECa18, and immortalized esophageal epithelia cell line NE1 were graciously provided by Professor Libing Son (SYCUCC).	('KYSE140', 'Var', (43, 50))	('esophageal epithelia', 'Disease', (226, 246))	('KYSE180', 'Var', (52, 59))	('esophageal epithelia', 'Disease', 'MESH:D004941', (226, 246))	('von', 'Disease', 'MESH:D014842', (104, 107))	('ECa109', 'CellLine', 'CVCL:6898', (194, 200))	('KYSE520', 'Var', (25, 32))	('HK1', 'Gene', '3098', (65, 68))	('von', 'Disease', (104, 107))	('HK1', 'Gene', (65, 68))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (226, 246))	('NE1', 'CellLine', 'CVCL:E306', (257, 260))
780595	29607947	This work was supported in part by the following grants and foundations: Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS); grant numbers 16K11339, 16K10450, 15H04932, 16K15606, 17K10534 0006, 17K16529 0007 and 17K14982 0001	('17K16529 0007', 'Var', (240, 253))	('16K10450', 'Var', (195, 203))	('16K15606', 'Var', (215, 223))	('Aid', 'Gene', '57379', (83, 86))	('17K10534 0006', 'Var', (225, 238))	('Aid', 'Gene', (83, 86))	('15H04932', 'Var', (205, 213))
780713	28903420	Early TNM stage, application of adjuvant therapy, and high expression of Ki-67 (Hazard Ratio = 0.314, 95% CI: 0.127-0.774; P = 0.012) were found to be favorable prognostic factors of patients with SCCE.	('SCCE', 'Disease', (197, 201))	('high expression', 'Var', (54, 69))	('TNM', 'Gene', '10178', (6, 9))	('Ki-67', 'Gene', (73, 78))	('TNM', 'Gene', (6, 9))	('Ki-67', 'Chemical', '-', (73, 78))	('patients', 'Species', '9606', (183, 191))
780714	28903420	In subgroup analysis, adjuvant therapy could only bring significant survival benefit for patients with high expression of Ki-67 (P = 0.008).	('patients', 'Species', '9606', (89, 97))	('Ki-67', 'Chemical', '-', (122, 127))	('Ki-67', 'Protein', (122, 127))	('high expression', 'Var', (103, 118))
780717	28903420	This study suggested that high expression of Ki-67 may not only serve as a favorable prognostic factor of SCCE but also an indication of providing adjuvant therapy for SCCE patients with surgical resection.	('high', 'Var', (26, 30))	('patients', 'Species', '9606', (173, 181))	('Ki-67', 'Gene', (45, 50))	('SCCE', 'Disease', (106, 110))	('Ki-67', 'Chemical', '-', (45, 50))
780723	28903420	In most of the previous studies, high Ki-67 index was found to be significantly correlated with poor prognosis in patients with tumors, such as lymphoma, bladder cancer, lung cancer, liver malignancies, and even neuroendocrine tumors.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (212, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (154, 168))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('Ki-67', 'Chemical', '-', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Disease', (128, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('liver malignancies', 'Phenotype', 'HP:0002896', (183, 201))	('lymphoma', 'Phenotype', 'HP:0002665', (144, 152))	('neuroendocrine tumors', 'Disease', (212, 233))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('Ki-67', 'Var', (38, 43))	('tumors', 'Disease', (227, 233))	('high Ki-67', 'Var', (33, 43))	('liver malignancies', 'Disease', 'MESH:D009369', (183, 201))	('lung cancer', 'Disease', (170, 181))	('lymphoma', 'Disease', (144, 152))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (212, 233))	('liver malignancies', 'Disease', (183, 201))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('lymphoma', 'Disease', 'MESH:D008223', (144, 152))	('bladder cancer', 'Disease', 'MESH:D001749', (154, 168))	('bladder cancer', 'Disease', (154, 168))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
780724	28903420	However, there were also studies showing that high Ki-67 index was an independent favorable prognostic marker in colorectal cancer.	('high', 'Var', (46, 50))	('colorectal cancer', 'Disease', (113, 130))	('Ki-67', 'Protein', (51, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Ki-67', 'Chemical', '-', (51, 56))
780747	28903420	Since there was no obvious correlation between Ki-67 expression and clinicopathological characteristics of SCCE (including TNM stage), we therefore investigated further on the role of adjuvant therapy in both high Ki-67 index group and low Ki-67 index group.	('Ki-67', 'Chemical', '-', (214, 219))	('Ki-67', 'Chemical', '-', (47, 52))	('TNM', 'Gene', (123, 126))	('Ki-67', 'Chemical', '-', (240, 245))	('high Ki-67 index', 'Var', (209, 225))	('SCCE', 'Disease', (107, 111))	('TNM', 'Gene', '10178', (123, 126))
780764	28903420	Early TNM stage, adjuvant therapy, and high expression of Ki-67 (> 50%) were found to be prognosticators of favorable survival of SCCE patients with surgical resection.	('patients', 'Species', '9606', (135, 143))	('TNM', 'Gene', '10178', (6, 9))	('Ki-67', 'Gene', (58, 63))	('high expression', 'Var', (39, 54))	('SCCE', 'Disease', (130, 134))	('Ki-67', 'Chemical', '-', (58, 63))	('TNM', 'Gene', (6, 9))
780766	28903420	Our subgroup analysis found that in high Ki-67 expression group adjuvant therapy yielded significant survival benefit, while in low Ki-67 expression group adjuvant did not bring significant survival benefit.	('survival', 'CPA', (101, 109))	('Ki-67', 'Chemical', '-', (132, 137))	('high Ki-67 expression', 'Var', (36, 57))	('Ki-67', 'Chemical', '-', (41, 46))
780769	28903420	In most cases, high expression of Ki-67 was found to be associated with poor survival of tumor patients.	('high', 'Var', (15, 19))	('patients', 'Species', '9606', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('Ki-67', 'Chemical', '-', (34, 39))	('associated', 'Reg', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Ki-67', 'Protein', (34, 39))	('tumor', 'Disease', (89, 94))	('poor', 'NegReg', (72, 76))
780776	28903420	However, our further analysis for the role of adjuvant therapy in patients with different Ki-67 expression level found that patients with high Ki-67 index obtained significant survival benefit from adjuvant therapy, indicating that SCCE with high Ki-67 expression responded better to adjuvant therapy (chemoradiotherapy).	('Ki-67', 'Chemical', '-', (143, 148))	('Ki-67', 'Chemical', '-', (247, 252))	('Ki-67', 'Chemical', '-', (90, 95))	('high', 'Var', (138, 142))	('patients', 'Species', '9606', (124, 132))	('patients', 'Species', '9606', (66, 74))	('better', 'PosReg', (274, 280))
780777	28903420	found that esophageal cancer patients with high Ki-67 index obtained significantly higher efficacy rate than patients with low Ki-67 index (73.9% versus 38.5%, P = 0.0013) after receiving neoadjuvant chemoradiotherapy.	('patients', 'Species', '9606', (29, 37))	('efficacy', 'MPA', (90, 98))	('esophageal cancer', 'Disease', (11, 28))	('high', 'Var', (43, 47))	('patients', 'Species', '9606', (109, 117))	('Ki-67', 'Chemical', '-', (127, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (11, 28))	('Ki-67', 'Chemical', '-', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('higher', 'PosReg', (83, 89))
780779	28903420	found that high expression of Ki-67 was significantly related with high response rate of chemotherapy in gastrointestinal neuroendocrine carcinoma (42% versus 15%, P < 0.001).	('gastrointestinal neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (105, 146))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (122, 146))	('related', 'Reg', (54, 61))	('gastrointestinal neuroendocrine carcinoma', 'Disease', (105, 146))	('Ki-67', 'Chemical', '-', (30, 35))	('high expression', 'Var', (11, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('Ki-67', 'Gene', (30, 35))
780782	28903420	In conclusion, our study provided the initial evidence that Ki-67 could serve as a prognostic factor for SCCE, and more importantly, Ki-67 expression level could also serve as an indication of providing adjuvant therapy for SCCE patients with surgical resection in clinical practice.	('patients', 'Species', '9606', (229, 237))	('SCCE', 'Disease', (105, 109))	('Ki-67', 'Chemical', '-', (133, 138))	('Ki-67', 'Chemical', '-', (60, 65))	('expression', 'MPA', (139, 149))	('Ki-67', 'Var', (133, 138))
780802	28903420	We found that high expression of Ki-67 was significantly correlated to better prognosis of SCCE patients, especially for those with adjuvant therapy.	('SCCE', 'Disease', (91, 95))	('high', 'Var', (14, 18))	('Ki-67', 'Gene', (33, 38))	('patients', 'Species', '9606', (96, 104))	('better', 'PosReg', (71, 77))	('Ki-67', 'Chemical', '-', (33, 38))
780806	27431913	Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (71, 94))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('reactive oxygen species', 'MPA', (71, 94))	('mutations', 'Var', (39, 48))
780822	27431913	To date, research has primarily focussed on clonal mitochondrial mutations in relation to esophageal cancer.	('esophageal cancer', 'Disease', (90, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (65, 74))
780823	27431913	Little work has explored the role of random mitochondrial point mutations as a trigger for Barrett's cancer development.	('point mutations', 'Var', (58, 73))	("Barrett's cancer", 'Disease', (91, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	("Barrett's cancer", 'Disease', 'MESH:D001471', (91, 107))	("Barrett's cancer", 'Phenotype', 'HP:0100580', (91, 107))
780859	27431913	Random deletions were significantly increased in SIM matched-normal tissue (mean = 2.983 x 10-5, SEM = 1.178 x 10-5) compared with SIM biopsies (p = 0.031) (Fig.	('SIM', 'Disease', (49, 52))	('Random deletions', 'Var', (0, 16))	('SIM', 'Disease', 'None', (49, 52))	('increased', 'PosReg', (36, 45))	('SIM', 'Disease', (131, 134))	('SIM', 'Disease', 'None', (131, 134))
780868	27431913	Mutagenesis is a catalyst for cancer development, but to date, clonal gene mutations have been the main type of mitochondrial mutations analyzed with respect to esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (161, 181))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (161, 181))	('mutations', 'Var', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('esophageal carcinoma', 'Disease', (161, 181))
780870	27431913	Here we examined alterations in random mitochondrial point mutations/deletions and other markers of mitochondrial instability in the Barrett's esophagus disease sequence using in-vitro, in-vivo and ex-vivo models.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (133, 152))	('point mutations/deletions', 'Var', (53, 78))	("Barrett's esophagus disease", 'Disease', (133, 160))	("Barrett's esophagus disease", 'Disease', 'MESH:D001471', (133, 160))
780871	27431913	Using an in-vitro cell line model, we demonstrated random mitochondrial mutations were significantly elevated in the metaplastic, QH, cells compared with all other points along the Barrett's disease sequence, represented by the different cell lines.	('mutations', 'Var', (72, 81))	('elevated', 'PosReg', (101, 109))	("Barrett's disease", 'Disease', 'MESH:D001471', (181, 198))	("Barrett's disease", 'Phenotype', 'HP:0100580', (181, 198))	('metaplastic', 'CPA', (117, 128))	('mitochondrial', 'MPA', (58, 71))	("Barrett's disease", 'Disease', (181, 198))
780876	27431913	An increased frequency of deletions in SIM compared with HGD/EAC is mirrored in colorectal polyp/cancer studies, both supporting the hypothesis that random mutations/deletions may become redundant as the disease progresses.	('colorectal polyp', 'Disease', (80, 96))	('cancer', 'Disease', (97, 103))	('EAC', 'Phenotype', 'HP:0011459', (61, 64))	('deletions', 'Var', (26, 35))	('colorectal polyp', 'Disease', 'MESH:D003111', (80, 96))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('colorectal polyp', 'Phenotype', 'HP:0200063', (80, 96))	('SIM', 'Disease', (39, 42))	('SIM', 'Disease', 'None', (39, 42))
780877	27431913	It is recognized once malignant cells become established, selection processes ensue, with more aggressive mutations surviving and undergoing subsequent replication, with clonal mutations/deletions and not random ones overtaking the initial catalyst for cancer development at this time in the disease sequence.	('mutations/deletions', 'Var', (177, 196))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('mutations', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
780878	27431913	In this study, surrounding normal tissue demonstrated increased deletions compared with areas of SIM or HGD/EAC, suggesting mitochondrial instability is not just confined to the visible site of pathological tissue abnormality in the esophagus with Barrett's disease, but exerts a field effect, which has been previously demonstrated in colorectal tumors.	('colorectal tumors', 'Disease', (336, 353))	('esophagus', 'Disease', (233, 242))	("Barrett's disease", 'Disease', 'MESH:D001471', (248, 265))	('deletions', 'Var', (64, 73))	('SIM', 'Disease', (97, 100))	('esophagus with Barrett', 'Phenotype', 'HP:0100580', (233, 255))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('SIM', 'Disease', 'None', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('EAC', 'Phenotype', 'HP:0011459', (108, 111))	('pathological tissue abnormality', 'Phenotype', 'HP:0002664', (194, 225))	('colorectal tumors', 'Disease', 'MESH:D015179', (336, 353))	("Barrett's disease", 'Phenotype', 'HP:0100580', (248, 265))	("Barrett's disease", 'Disease', (248, 265))
780884	27431913	In breast cancer, BRCA-1, a tumor suppressor gene, has been shown to play a role in protecting against ROS damage; BRCA-1 mutations have subsequently been implicated in loss of redox balance with increased ROS, and may potentially drive cancer development.	('BRCA-1', 'Gene', (115, 121))	('tumor', 'Disease', (28, 33))	('BRCA-1', 'Gene', '672', (115, 121))	('drive', 'Reg', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('ROS', 'MPA', (206, 209))	('cancer', 'Disease', (10, 16))	('increased', 'PosReg', (196, 205))	('ROS', 'Chemical', 'MESH:D017382', (206, 209))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('cancer', 'Disease', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('BRCA-1', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('BRCA-1', 'Gene', '672', (18, 24))	('loss', 'NegReg', (169, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('redox balance', 'MPA', (177, 190))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('mutations', 'Var', (122, 131))	('cancer', 'Disease', 'MESH:D009369', (237, 243))
780950	25551772	Cells with a 'winner' phenotype create clones which may expand into extensive fields of mutant cells within normal appearing epithelium, favoring the accumulation of further genetic alterations and the evolution of cancer.	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('genetic alterations', 'Var', (174, 193))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', (215, 221))
780951	25551772	Here we focus on how mutations which disrupt the Notch signaling pathway confer a 'super competitor' status on cells in squamous epithelia and consider the broader implications for cancer evolution.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Notch', 'Gene', (49, 54))	('squamous epithelia', 'Disease', 'MESH:D002294', (120, 138))	('squamous epithelia', 'Phenotype', 'HP:0002860', (120, 138))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('squamous epithelia', 'Disease', (120, 138))	('Notch', 'Gene', '31293', (49, 54))	("'super competitor'", 'PosReg', (82, 100))	('mutations', 'Var', (21, 30))
780953	25551772	Genes and pathways reported to function as super competitors in Drosophila include dMyc and Wg, Hpo and Stat pathway mutants, whose homologues are frequently mutated in human cancer.	('dMyc', 'Gene', '31310', (83, 87))	('mutants', 'Var', (117, 124))	('Stat', 'Gene', '42428', (104, 108))	('cancer', 'Disease', (175, 181))	('Hpo', 'Gene', (96, 99))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Hpo', 'Gene', '37247', (96, 99))	('Drosophila', 'Species', '7227', (64, 74))	('human', 'Species', '9606', (169, 174))	('Genes', 'Gene', (0, 5))	('Stat', 'Gene', (104, 108))	('dMyc', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
780954	25551772	To progress into a tumor, an individual mutant cell must generate a clone which persists for sufficient time to acquire additional genomic changes.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('progress', 'PosReg', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('mutant', 'Var', (40, 46))
780955	25551772	Many genetic alterations reduce fitness relative to wild type cells and are eliminated by cell competition, which provides a defense against cancer development in tissues such as the mouse thymus.	('fitness', 'CPA', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('genetic alterations', 'Var', (5, 24))	('mouse', 'Species', '10090', (183, 188))	('reduce', 'NegReg', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
780957	25551772	These may expand to take over large areas from which multiple dysplastic lesions and squamous cell carcinomas arise as additional mutations occur.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (85, 109))	('dysplastic lesions', 'Disease', 'MESH:D021782', (62, 80))	('squamous cell carcinomas', 'Disease', (85, 109))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (85, 109))	('dysplastic lesions', 'Disease', (62, 80))	('mutations', 'Var', (130, 139))
780964	25551772	However, a mutation that tilts progenitor cell fate toward proliferation by increasing the probability of divisions producing 2 progenitor cells is much more likely to create a dominant and persistent clone which may undergo further mutations and progress toward cancer.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Disease', (263, 269))	('increasing', 'PosReg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutation', 'Var', (11, 19))
780965	25551772	Candidate mutations that may alter progenitor fate in EE include those affecting the Notch pathway.	('affecting', 'Reg', (71, 80))	('Notch', 'Gene', (85, 90))	('progenitor fate', 'CPA', (35, 50))	('Notch', 'Gene', '31293', (85, 90))	('mutations', 'Var', (10, 19))	('alter', 'Reg', (29, 34))
780968	25551772	Multiple lines of evidence point to a role for Notch in squamous and esophageal carcinogenesis.Notch receptors are frequently inactivated by mutation in tumors of squamous epithelium.	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('Notch', 'Gene', (95, 100))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (69, 94))	('inactivated', 'NegReg', (126, 137))	('Notch', 'Gene', '31293', (95, 100))	('esophageal carcinogenesis', 'Disease', (69, 94))	('Notch', 'Gene', '31293', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('mutation', 'Var', (141, 149))	('Notch', 'Gene', (47, 52))
780969	25551772	In keratinocytes, Notch activation drives differentiation, while in the squamous epithelium of the epidermis, loss of Notch promotes tumor formation.	('differentiation', 'CPA', (42, 57))	('loss', 'Var', (110, 114))	('Notch', 'Gene', '31293', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Notch', 'Gene', (18, 23))	('promotes', 'PosReg', (124, 132))	('Notch', 'Gene', '31293', (18, 23))	('tumor', 'Disease', (133, 138))	('activation', 'PosReg', (24, 34))	('Notch', 'Gene', (118, 123))
780970	25551772	Motivated by these observations, we performed lineage tracing of esophageal progenitors expressing a dominant negative mutant of Mastermind like 1 (DN-Maml1) which blocks Notch signaling by preventing Nicd-induced transactivation.	('Notch', 'Gene', (171, 176))	('Maml1', 'Gene', (151, 156))	('preventing', 'NegReg', (190, 200))	('Maml1', 'Gene', '103806', (151, 156))	('blocks', 'NegReg', (164, 170))	('Nicd-induced transactivation', 'MPA', (201, 229))	('Notch', 'Gene', '31293', (171, 176))	('negative', 'NegReg', (110, 118))	('mutant', 'Var', (119, 125))
780971	25551772	DN-Maml1 blocks Notch target gene induction and phenocopies the effects of Notch deletion in a range of tissues.	('Maml1', 'Gene', '103806', (3, 8))	('Notch', 'Gene', '31293', (16, 21))	('Notch', 'Gene', '31293', (75, 80))	('deletion', 'Var', (81, 89))	('blocks', 'NegReg', (9, 15))	('Notch', 'Gene', (16, 21))	('Notch', 'Gene', (75, 80))	('Maml1', 'Gene', (3, 8))
780972	25551772	Crucially, in this model, the Maml1 mutant is fused to GFP and targeted conditionally to a ubiquitous locus, allowing mutant cells to be visualized using confocal microscopy following cell labeling.	('Maml1', 'Gene', '103806', (30, 35))	('mutant', 'Var', (118, 124))	('mutant', 'Var', (36, 42))	('Maml1', 'Gene', (30, 35))
780973	25551772	Expression of DN-Maml1 in individual esophageal progenitors confers a strong competitive advantage on the mutant cells, which generate clones that expand rapidly over the weeks following induction (Fig.	('Maml1', 'Gene', '103806', (17, 22))	('mutant', 'Var', (106, 112))	('competitive advantage', 'CPA', (77, 98))	('Maml1', 'Gene', (17, 22))
780974	25551772	In contrast there are no floating mutant clones, indicating that inhibition of Notch signaling has blocked 'terminal' divisions generating 2 differentiating cells.	('inhibition', 'Var', (65, 75))	('Notch', 'Gene', '31293', (79, 84))	('Notch', 'Gene', (79, 84))	('blocked', 'NegReg', (99, 106))
780976	25551772	Quantitative analysis of mutant clone sizes reveals how DN-Maml1 expression alters cell behavior soon after induction (Fig.	('Maml1', 'Gene', '103806', (59, 64))	('cell behavior', 'CPA', (83, 96))	('alters', 'Reg', (76, 82))	('expression', 'Var', (65, 75))	('Maml1', 'Gene', (59, 64))
780977	25551772	For example the stress induced keratin, Krt6, is strongly induced in mutant cells.	('induced', 'PosReg', (58, 65))	('Krt6', 'Gene', (40, 44))	('Krt6', 'Gene', '110309', (40, 44))	('mutant', 'Var', (69, 75))
780978	25551772	Intriguingly, the differentially expressed genes include the transcription factor Sox9, a Notch target which is down regulated in mutant clones.	('Notch', 'Gene', '31293', (90, 95))	('Sox9', 'Gene', '20682', (82, 86))	('Notch', 'Gene', (90, 95))	('down regulated', 'NegReg', (112, 126))	('mutant', 'Var', (130, 136))	('Sox9', 'Gene', (82, 86))
780981	25551772	However studies in Drosophila indicate some super competitor mutations exert a 'bystander effect', actively eliminating wild type cells.	('Drosophila', 'Species', '7227', (19, 29))	('eliminating', 'NegReg', (108, 119))	('wild type cells', 'MPA', (120, 135))	('mutations', 'Var', (61, 70))
780986	25551772	One candidate pathway is the Notch itself, as imbalances in Notch signaling between adjacent cells can alter cell fate of in a variety of epithelia.	('Notch', 'Gene', (60, 65))	('Notch', 'Gene', '31293', (29, 34))	('imbalances', 'Var', (46, 56))	('Notch', 'Gene', '31293', (60, 65))	('Notch', 'Gene', (29, 34))	('alter', 'Reg', (103, 108))	('epithelia', 'Disease', 'None', (138, 147))	('epithelia', 'Disease', (138, 147))	('imbalances', 'Phenotype', 'HP:0002172', (46, 56))
780989	25551772	What is surprising, given the dynamics of mutant cells at early time points, is that a year or more after induction of DNMaml1 mice are healthy and free from esophageal tumors.	('mice', 'Species', '10090', (127, 131))	('mutant', 'Var', (42, 48))	('Maml1', 'Gene', (121, 126))	('Maml1', 'Gene', '103806', (121, 126))	('esophageal tumors', 'Disease', 'MESH:D004938', (158, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('esophageal tumors', 'Phenotype', 'HP:0100751', (158, 175))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('esophageal tumors', 'Disease', (158, 175))	('esophageal tumor', 'Phenotype', 'HP:0100751', (158, 174))	('DNMaml', 'Chemical', '-', (119, 125))
780990	25551772	These changes are reminiscent of epidermis exposed to ultraviolet light, where p53 mutant clones expand exponentially until they reach several thousand cells in size, when crowding occurs and expansion slows.	('p53', 'Gene', '22060', (79, 82))	('p53', 'Gene', (79, 82))	('mutant', 'Var', (83, 89))
780992	25551772	If EE can tolerate Notch inhibiting mutations so effectively, does Notch mutation play a significant role in early carcinogenesis?	('Notch', 'Gene', '31293', (19, 24))	('Notch', 'Gene', '31293', (67, 72))	('mutations', 'Var', (36, 45))	('Notch', 'Gene', (19, 24))	('Notch', 'Gene', (67, 72))
780993	25551772	A carcinogen exposed epithelium may contain numerous cells carrying oncogenic mutations, such as in p53, which will form mutant clones.	('p53', 'Gene', '22060', (100, 103))	('p53', 'Gene', (100, 103))	('mutations', 'Var', (78, 87))
780994	25551772	If a Notch inhibiting mutation occurs in a cell carrying a preexisting mutation, it might confer a super competitor phenotype, creating a field change within which carcinogenesis can progress (Fig.	('Notch', 'Gene', '31293', (5, 10))	('mutation', 'Var', (22, 30))	('mutation', 'Var', (71, 79))	('carcinogenesis', 'CPA', (164, 178))	('Notch', 'Gene', (5, 10))
780995	25551772	Indeed, following single cell induction of DN-Maml1 in nitrosamine treated mice carrying sporadic p53 mutant clones, rare double mutant clones are observed.	('mutant', 'Var', (102, 108))	('p53', 'Gene', '22060', (98, 101))	('mice', 'Species', '10090', (75, 79))	('Maml1', 'Gene', (46, 51))	('Maml1', 'Gene', '103806', (46, 51))	('nitrosamine', 'Chemical', 'MESH:D009602', (55, 66))	('p53', 'Gene', (98, 101))
780998	25551772	Once DN-Maml1 mutant areas have been established in nitrosamine treated mice, they have a several fold higher incidence of tumor formation/unit area than adjacent wild type regions in the same animals, and the lesions formed are significantly larger than those arising from wild type regions.	('higher', 'PosReg', (103, 109))	('tumor', 'Disease', (123, 128))	('mutant', 'Var', (14, 20))	('Maml1', 'Gene', (8, 13))	('Maml1', 'Gene', '103806', (8, 13))	('nitrosamine', 'Chemical', 'MESH:D009602', (52, 63))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
780999	25551772	This argues Notch inhibiting mutations promotes esophageal tumor formation beyond conferring clonal dominance, as has been shown in the epidermis.	('promotes', 'PosReg', (39, 47))	('Notch', 'Gene', '31293', (12, 17))	('mutations', 'Var', (29, 38))	('esophageal tumor', 'Disease', 'MESH:D004938', (48, 64))	('esophageal tumor', 'Disease', (48, 64))	('esophageal tumor', 'Phenotype', 'HP:0100751', (48, 64))	('Notch', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
781000	25551772	Loss of Notch in the epidermis is strongly linked with the induction of systemic immune changes and stromal inflammation.	('Notch', 'Gene', '31293', (8, 13))	('inflammation', 'Disease', (108, 120))	('systemic immune changes', 'CPA', (72, 95))	('linked', 'Reg', (43, 49))	('Loss', 'Var', (0, 4))	('Notch', 'Gene', (8, 13))	('inflammation', 'Disease', 'MESH:D007249', (108, 120))
781001	25551772	Interestingly there is no evidence of epithelial, stromal or systemic immune changes following DN-Maml1 expression in the esophagus, likely reflecting organ specific tuning of the immune system.	('Maml1', 'Gene', (98, 103))	('epithelia', 'Disease', 'None', (38, 47))	('Maml1', 'Gene', '103806', (98, 103))	('epithelia', 'Disease', (38, 47))	('expression', 'Var', (104, 114))
781003	25551772	Areas of apparently normal epithelium have been shown to harbor clonal mutations and generate multiple dysplastic lesions and tumors over time.	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('dysplastic lesions', 'Disease', 'MESH:D021782', (103, 121))	('mutations', 'Var', (71, 80))	('generate', 'Reg', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('dysplastic lesions', 'Disease', (103, 121))
781005	25551772	Understanding how the behavior of cells within these mutant fields changes as they acquire additional genetic damage will be key designing rational strategies to decrease cancer risk in humans with a large burden of mutations.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('mutant', 'Var', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('humans', 'Species', '9606', (186, 192))
781008	25551772	The colonization of the esophageal stem cell niche parallels the effect of 'winner' Wnt pathway, KRas mutations in intestinal epithelium and p53 mutation in transplanted haematopoietic stem cells.	('mutation', 'Var', (145, 153))	('p53', 'Gene', (141, 144))	('KRas', 'Gene', '16653', (97, 101))	('p53', 'Gene', '22060', (141, 144))	('mutations', 'Var', (102, 111))	('KRas', 'Gene', (97, 101))
781009	25551772	In the context of early cancer development, where cells may harbor multiple mutations, such mutants play a crucial role in immortalizing and expanding clones carrying oncogenic genome alterations.	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (76, 85))
781016	24379675	With the help of the fit line on the scatter plot, we classified the patients into three categories according to the PNI, ie, >52, 42-52, and <42.	('patients', 'Species', '9606', (69, 77))	('42-52', 'Var', (131, 136))	('>52', 'Var', (126, 129))
781018	24379675	The 5-year CSS in patients with PNI <42, 42-52, and >52 were 11.0%, 39.1%, and 55.2%, respectively (P<0.001).	('PNI <42', 'Var', (32, 39))	('CSS', 'MPA', (11, 14))	('patients', 'Species', '9606', (18, 26))	('CSS', 'Chemical', '-', (11, 14))
781019	24379675	Multivariate analysis showed that PNI was a significant predictor of CSS (42-52 versus >52, P=0.011; <42 versus PNI >52, P<0.001).	('42-52', 'Var', (74, 79))	('CSS', 'Disease', (69, 72))	('<42', 'Var', (101, 104))	('CSS', 'Chemical', '-', (69, 72))
781042	24379675	With the help of the fit line on the scatter plot, we classified the patients into three categories according to their PNI, ie, <42, 42-52, and >52 (Figure 1).	('patients', 'Species', '9606', (69, 77))	('42-52', 'Var', (133, 138))	('<42', 'Var', (128, 131))
781055	24379675	The cut-off value is usually set at 45, because a PNI <45 is defined as moderate to severe malnutrition.	('PNI <45', 'Var', (50, 57))	('malnutrition', 'Phenotype', 'HP:0004395', (91, 103))	('malnutrition', 'Disease', (91, 103))	('malnutrition', 'Disease', 'MESH:D044342', (91, 103))
781057	24379675	In our study, with the help of the fit line on the scatter plot, we classified the patients into three categories according to PNI, ie, <42, 42-52, and >52.	('patients', 'Species', '9606', (83, 91))	('42-52', 'Var', (141, 146))	('<42', 'Var', (136, 139))
781059	24379675	The 5-year CSS in patients with PNI <42, 42-52, and >52 was 11.0%, 39.1%, and 55.2%, respectively (P<0.001).	('PNI <42', 'Var', (32, 39))	('CSS', 'MPA', (11, 14))	('patients', 'Species', '9606', (18, 26))	('CSS', 'Chemical', '-', (11, 14))
781079	21456015	Higher iSUV was associated with longer tumors (p=0.0001), higher T stage (p=<0.0001), positive N (p=0.0001), higher overall stage (P=<0.0001), lack of cCR (p=0.0002), and squamous cell histology (p=<0.0001).	('longer tumors', 'Disease', 'MESH:D009369', (32, 45))	('cCR', 'CPA', (151, 154))	('higher', 'PosReg', (109, 115))	('higher T stage', 'CPA', (58, 72))	('iSUV', 'Chemical', '-', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('positive N', 'CPA', (86, 96))	('longer tumors', 'Disease', (32, 45))	('overall stage', 'CPA', (116, 129))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('squamous', 'Disease', (171, 179))	('iSUV', 'Var', (7, 11))
781080	21456015	In the univariate analysis, iSUV was associated with OS (Cox model, P=0.016; log-rank test, P=0.002).	('iSUV', 'Var', (28, 32))	('Cox', 'Gene', (57, 60))	('OS', 'Chemical', '-', (53, 55))	('associated', 'Reg', (37, 47))	('iSUV', 'Chemical', '-', (28, 32))	('Cox', 'Gene', '1351', (57, 60))
781146	21456015	Table 4 shows the multivariate analysis using dichotomized iSUV (by the median as the cut off), after adjusting for the effect of lymph node status and tumor grade, iSUV was significantly associated with OS (p=0.024) and the grade of the tumor was also an independent prognosticator (p=0.016).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('associated', 'Reg', (188, 198))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('OS', 'Chemical', '-', (204, 206))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', (238, 243))	('iSUV', 'Var', (165, 169))	('iSUV', 'Chemical', '-', (59, 63))	('iSUV', 'Chemical', '-', (165, 169))
781151	21456015	Fisher's exact test indicated that iSUV was significantly associated with primary site (p<0.0001), T-stage status (p<0.0001), N-status status (p=0.0001), overall stage (p<0.0001), and tumor histology (p<0.0001).	('T-stage status', 'CPA', (99, 113))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('iSUV', 'Var', (35, 39))	('associated', 'Reg', (58, 68))	('iSUV', 'Chemical', '-', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('N-status', 'CPA', (126, 134))	('tumor', 'Disease', (184, 189))	('primary site', 'Disease', (74, 86))	('overall stage', 'CPA', (154, 167))
781152	21456015	For example, 80.5% of squamous cell carcinoma patients had iSUV >/=12.7, while only 40.9% of adenocarcinoma patients had iSUV >/=12.7.	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (108, 116))	('iSUV >/=12.7', 'Var', (59, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 45))	('adenocarcinoma', 'Disease', (93, 107))	('iSUV', 'Chemical', '-', (59, 63))	('squamous cell carcinoma', 'Disease', (22, 45))	('iSUV', 'Chemical', '-', (121, 125))
781171	21456015	reported 48 Japanese patients' data in that iSUV was associated with OS in patients with esophageal squamous cell carcinoma who were treated with surgery alone.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('OS', 'Chemical', '-', (69, 71))	('esophageal squamous cell carcinoma', 'Disease', (89, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('patients', 'Species', '9606', (75, 83))	('iSUV', 'Var', (44, 48))	('iSUV', 'Chemical', '-', (44, 48))	('patients', 'Species', '9606', (21, 29))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (89, 123))
781176	21456015	In contrast, we previously observed that 161 patients who received trimodality therapy, high iSUV was associated with prolonged OS.	('high', 'Var', (88, 92))	('iSUV', 'Gene', (93, 97))	('associated with', 'Reg', (102, 117))	('OS', 'Chemical', '-', (128, 130))	('prolonged OS', 'Disease', (118, 130))	('patients', 'Species', '9606', (45, 53))	('iSUV', 'Chemical', '-', (93, 97))
781272	32228652	4.Ligating and cutting off the tracheoesophageal fistula.	('cutting', 'Var', (15, 22))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (31, 56))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (31, 56))	('tracheoesophageal fistula', 'Disease', (31, 56))
781308	32106831	Overall survival (OS) of the patients treated with surgery following NAC was significantly shorter in the group with high GR than that with low GR status (P = 0.0473).	('patients', 'Species', '9606', (29, 37))	('NAC', 'Chemical', '-', (69, 72))	('OS', 'Chemical', '-', (18, 20))	('Overall survival', 'MPA', (0, 16))	('high GR', 'Var', (117, 124))	('shorter', 'NegReg', (91, 98))
781310	32106831	Biopsy specimens before NAC showed significantly shorter DFS in the high Sgk1 group (P = 0.0095), while both OS and DFS were shorter in the high NDRG1 group (OS, P = 0.0233; DFS, P = 0.0006) than in the respective low groups.	('high', 'Var', (68, 72))	('DFS', 'MPA', (57, 60))	('NAC', 'Chemical', '-', (24, 27))	('Sgk1', 'Gene', (73, 77))	('shorter', 'NegReg', (49, 56))	('shorter', 'NegReg', (125, 132))	('OS', 'Chemical', '-', (109, 111))	('OS', 'Chemical', '-', (158, 160))
781311	32106831	In the high NDRG1 group of biopsy specimens before NAC, the tumor reduction rate by NAC was significantly attenuated (P = 0.021).	('attenuated', 'NegReg', (106, 116))	('NAC', 'Chemical', '-', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('NDRG1', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('high', 'Var', (7, 11))	('NAC', 'Chemical', '-', (84, 87))	('tumor', 'Disease', (60, 65))
781312	32106831	High GR, Sgk1, and NDRG1 statuses in ESCC after NAC was significantly associated with an overall worse prognosis, with no significant changes in their expression levels before and after NAC.	('High GR', 'Var', (0, 7))	('ESCC', 'Disease', (37, 41))	('NDRG1', 'Gene', (19, 24))	('NAC', 'Chemical', '-', (48, 51))	('associated', 'Reg', (70, 80))	('statuses', 'Var', (25, 33))	('NAC', 'Chemical', '-', (186, 189))	('Sgk1', 'Gene', (9, 13))	('ESCC', 'Disease', 'MESH:C562729', (37, 41))
781350	32106831	After washing three times for 5 min each in phosphate-buffered saline (PBS), the reacted slides were incubated in 1% normal goat serum for 30 min at room temperature to reduce nonspecific antibody binding and then incubated at 4  C overnight with rabbit monoclonal antibody against GR (D6H2L, Cell Signaling Technology, Danvers, MA, USA, diluted 1/400), Sgk1 (Y238, Abcam, Cambridge, UK, diluted 1/200), or NDRG1 (EPR5593, Abcam, diluted 1/400).	('Y238', 'Var', (360, 364))	('PBS', 'Chemical', '-', (71, 74))	('nonspecific antibody', 'MPA', (176, 196))	('binding', 'Interaction', (197, 204))	('reduce', 'NegReg', (169, 175))
781362	32106831	Five-year OS rate of the patients harboring high GR status was significantly shorter than those harboring low GR group (P = 0.0473) (Fig.	('OS', 'Chemical', '-', (10, 12))	('high GR status', 'Var', (44, 58))	('OS rate', 'MPA', (10, 17))	('patients', 'Species', '9606', (25, 33))	('shorter', 'NegReg', (77, 84))
781363	32106831	In addition, significantly shorter 5-year OS and DFS were detected in the patients with high Sgk1 than in those with low Sgk1 (OS: P = 0.0055, DFS: P = 0.0240) (Fig.	('high', 'Var', (88, 92))	('OS', 'Chemical', '-', (42, 44))	('shorter', 'NegReg', (27, 34))	('patients', 'Species', '9606', (74, 82))	('Sgk1', 'Gene', (93, 97))	('OS', 'Chemical', '-', (127, 129))
781364	32106831	The 5-year OS and DFS were both significantly shorter in those with high NDRG1 than in those with low NDRG1 (OS: P = 0.0021, DFS: P = 0.0086) (Fig.	('OS', 'Chemical', '-', (11, 13))	('DFS', 'CPA', (18, 21))	('high', 'Var', (68, 72))	('NDRG1', 'Gene', (73, 78))	('OS', 'Chemical', '-', (109, 111))	('shorter', 'NegReg', (46, 53))
781365	32106831	Univariate analysis revealed that patient survival was significantly associated with pT (P = 0.0011) and pN (P = 0.0002), pStage (P = 0.0001), lymphatic invasion (P = 0.0260), vascular invasion (P = 0.0178), RECIST grade (P = 0.0015), histopathological tumor regression grade (P = 0.0432), high GR (P = 0.0479), high Sgk1 (P = 0.0054), and high NDRG1 (P = 0.0033) (Table 2).	('vascular invasion', 'CPA', (176, 193))	('high GR', 'Var', (290, 297))	('patient survival', 'CPA', (34, 50))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('high', 'Var', (312, 316))	('associated', 'Reg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('high', 'Var', (340, 344))	('patient', 'Species', '9606', (34, 41))	('tumor', 'Disease', (253, 258))	('pStage', 'CPA', (122, 128))	('lymphatic invasion', 'CPA', (143, 161))
781368	32106831	In the biopsy specimens of ESCC patients prior to NAC, high GR, Sgk1, and NDRG1 were detected in 54.7% (23/42), 45.2% (19/42), and 42.9% (18/42) of the patients examined, respectively (Table 5).	('patients', 'Species', '9606', (32, 40))	('ESCC', 'Disease', 'MESH:C562729', (27, 31))	('NDRG1', 'Gene', (74, 79))	('ESCC', 'Disease', (27, 31))	('NAC', 'Chemical', '-', (50, 53))	('high GR', 'Var', (55, 62))	('detected', 'Reg', (85, 93))	('patients', 'Species', '9606', (152, 160))	('Sgk1', 'Gene', (64, 68))
781371	32106831	However, a significantly shorter DFS was detected in those with high pre-NAC Sgk1 status compared to those with low status (P = 0.0095) (Fig.	('DFS', 'MPA', (33, 36))	('shorter', 'NegReg', (25, 32))	('NAC', 'Chemical', '-', (73, 76))	('status', 'Var', (82, 88))	('Sgk1', 'Gene', (77, 81))	('high pre-NAC', 'Var', (64, 76))
781372	32106831	Significantly shorter OS and DFS were also detected in those with high pre-NAC NDRG1 status compared to those with low status (OS: P = 0.0233, DFS: P = 0.0006) (Fig.	('shorter', 'NegReg', (14, 21))	('status', 'Var', (85, 91))	('high pre-NAC', 'Var', (66, 78))	('OS', 'Chemical', '-', (22, 24))	('NAC', 'Chemical', '-', (75, 78))	('OS', 'Chemical', '-', (127, 129))	('NDRG1', 'Gene', (79, 84))
781383	32106831	Notably, the high GR, Sgk1, and NDRG1 status in resected specimens were significantly associated with shorter OS in those undergoing NAC.	('NAC', 'Chemical', '-', (133, 136))	('OS', 'Chemical', '-', (110, 112))	('high', 'Var', (13, 17))	('NDRG1', 'Gene', (32, 37))	('shorter OS', 'Disease', (102, 112))	('Sgk1', 'Gene', (22, 26))
781387	32106831	We found that the Sgk1 status in carcinoma cells was not only significantly associated with shorter OS and DFS but also with more advanced pT, pN, and lymphatic vessel invasion in ESCC patients.	('carcinoma cells', 'Disease', 'MESH:D002292', (33, 48))	('OS', 'Chemical', '-', (100, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('lymphatic vessel invasion', 'CPA', (151, 176))	('DFS', 'CPA', (107, 110))	('Sgk1', 'Gene', (18, 22))	('status', 'Var', (23, 29))	('associated', 'Reg', (76, 86))	('ESCC', 'Disease', 'MESH:C562729', (180, 184))	('patients', 'Species', '9606', (185, 193))	('ESCC', 'Disease', (180, 184))	('carcinoma cells', 'Disease', (33, 48))
781391	32106831	In our present study, a high NDRG1 status was significantly associated with shorter OS and DFS, higher pT, and local progression factors such as venous invasion in the patients, which is consistent with the results of previously reported studies.	('NDRG1', 'Gene', (29, 34))	('OS', 'Chemical', '-', (84, 86))	('venous invasion', 'Disease', (145, 160))	('DFS', 'CPA', (91, 94))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (168, 176))	('shorter', 'NegReg', (76, 83))	('higher', 'PosReg', (96, 102))	('status', 'Var', (35, 41))
781404	32106831	A high NDRG1 status in carcinoma cells in pre-NAC biopsy specimens was significantly associated with lower NAC effects, and a high GR and Sgk1 status in carcinoma cells tended to be associated with lower NAC effect.	('carcinoma cells', 'Disease', (23, 38))	('high', 'Var', (2, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('Sgk1', 'Gene', (138, 142))	('NAC', 'Chemical', '-', (107, 110))	('status', 'Var', (13, 19))	('NAC effects', 'MPA', (107, 118))	('lower', 'NegReg', (101, 106))	('NAC', 'Chemical', '-', (204, 207))	('NAC', 'Chemical', '-', (46, 49))	('carcinoma cells', 'Disease', 'MESH:D002292', (153, 168))	('carcinoma cells', 'Disease', (153, 168))	('NDRG1', 'Gene', (7, 12))	('carcinoma cells', 'Disease', 'MESH:D002292', (23, 38))
781406	32106831	Therefore, these results suggest that NAC sensitivity was decreased in tumors with high expression of GR, Sgk1, and NDRG1, resulting in higher residual tumor cells and subsequent adverse clinical outcomes of patients.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('patients', 'Species', '9606', (208, 216))	('Sgk1', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('higher', 'PosReg', (136, 142))	('NAC', 'Chemical', '-', (38, 41))	('decreased', 'NegReg', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (152, 157))	('NAC sensitivity', 'MPA', (38, 53))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('high expression', 'Var', (83, 98))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('NDRG1', 'Gene', (116, 121))	('tumor', 'Disease', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
781408	32106831	We also examined whether a high NDRG1 status in biopsy specimens was significantly associated with decreased therapeutic effects of NAC in patients and observed no significant association.	('decreased', 'NegReg', (99, 108))	('patients', 'Species', '9606', (139, 147))	('high', 'Var', (27, 31))	('NDRG1', 'Gene', (32, 37))	('status', 'Var', (38, 44))	('NAC', 'Chemical', '-', (132, 135))	('therapeutic effects', 'CPA', (109, 128))
781463	30592184	Overall survival of 104 GI-HL patients was worse than that of 1025 GI-1 patients (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.01-1.58, P = 0.037).	('HL', 'Phenotype', 'HP:0012189', (27, 29))	('worse', 'NegReg', (43, 48))	('GI-HL', 'Var', (24, 29))	('patients', 'Species', '9606', (30, 38))	('Overall', 'MPA', (0, 7))	('patients', 'Species', '9606', (72, 80))
781467	30592184	Disease-specific survival was worse in GI-HL patients than in GI-1 patients (HR 1.29, 95% CI 1.00-1.67, P = 0.049, Table 3).	('worse', 'NegReg', (30, 35))	('Disease-specific survival', 'CPA', (0, 25))	('GI-HL', 'Var', (39, 44))	('patients', 'Species', '9606', (67, 75))	('HL', 'Phenotype', 'HP:0012189', (42, 44))	('patients', 'Species', '9606', (45, 53))
781468	30592184	Mortality from other causes appeared to be nonsignificantly higher in GI-HL patients compared with GI-1 patients (HR 1.44, 95% CI 0.81-2.56, P = 0.22).	('patients', 'Species', '9606', (76, 84))	('higher', 'PosReg', (60, 66))	('HL', 'Phenotype', 'HP:0012189', (73, 75))	('GI-HL', 'Var', (70, 75))	('patients', 'Species', '9606', (104, 112))
781469	30592184	In a multivariable model adjusted for treatment characteristics, disease-specific survival remained worse in GI-HL patients than in GI-1 patients (HR 1.33, 95% CI 1.03-1.72, P = 0.03).	('patients', 'Species', '9606', (115, 123))	('GI-HL', 'Var', (109, 114))	('patients', 'Species', '9606', (137, 145))	('worse', 'NegReg', (100, 105))	('disease-specific survival', 'CPA', (65, 90))	('HL', 'Phenotype', 'HP:0012189', (112, 114))
781509	29855512	The molecular and phenotypic changes induced by gimatecan were stronger than that of irinotecan.	('gimatecan', 'Chemical', 'MESH:C433984', (48, 57))	('stronger', 'PosReg', (63, 71))	('irinotecan', 'Chemical', 'MESH:D000077146', (85, 95))	('gimatecan', 'Var', (48, 57))
781525	29855512	This modification enhances rapid agent intake and stable drug interactions with intracellular targets, and also allows the oral administration of gimatecan, which has shown advantages over oral topotecan in terms of the antitumor efficacy and therapeutic index in preclinical studies of non-small lung cancer and colon carcinoma.	('modification', 'Var', (5, 17))	('gimatecan', 'Chemical', 'MESH:C433984', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('colon carcinoma', 'Disease', 'MESH:D015179', (313, 328))	('small lung', 'Phenotype', 'HP:0002089', (291, 301))	('topotecan', 'Chemical', 'MESH:D019772', (194, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (297, 308))	('enhances', 'PosReg', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('non-small lung cancer', 'Disease', (287, 308))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('non-small lung cancer', 'Disease', 'MESH:D002289', (287, 308))	('advantages', 'PosReg', (173, 183))	('rapid agent intake', 'MPA', (27, 45))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('interactions', 'Interaction', (62, 74))	('colon carcinoma', 'Disease', (313, 328))	('non-small lung cancer', 'Phenotype', 'HP:0030358', (287, 308))
781531	29855512	The capacity of gimatecan to inhibit cell proliferation was assessed in ESCC cell lines EC-109, KYSE450, KYSE-140, KYSE-510, TE-1, and TE-10 with gradient dilutions for 48 h, compared with irinotecan.	('inhibit', 'NegReg', (29, 36))	('gimatecan', 'Chemical', 'MESH:C433984', (16, 25))	('EC-109', 'CellLine', 'CVCL:6898', (88, 94))	('irinotecan', 'Chemical', 'MESH:D000077146', (189, 199))	('cell proliferation', 'CPA', (37, 55))	('KYSE-140', 'Var', (105, 113))
781532	29855512	Gimatecan showed strong inhibition in a dose-dependent manner at nanomolar concentration (Fig.	('nanomolar', 'Var', (65, 74))	('inhibition', 'NegReg', (24, 34))	('Gimatecan', 'Chemical', 'MESH:C433984', (0, 9))
781544	29855512	To verify the mechanisms, we increased the dosage of irinotecan, and found that irinotecan could also inhibit topoisomerase I specific activity in a dose- and time-dependent manner in both cell lines (Supplement Fig.	('irinotecan', 'Chemical', 'MESH:D000077146', (53, 63))	('topoisomerase I', 'Enzyme', (110, 125))	('inhibit', 'NegReg', (102, 109))	('irinotecan', 'Chemical', 'MESH:D000077146', (80, 90))	('irinotecan', 'Var', (80, 90))
781564	29855512	For KYSE-450 cells, 10 nM, 20 nM, and 30 nM gimatecan induced 15.77% +- 0.78%, 34.55% +- 0.58%, and 37.93% +- 0.84% apoptotic cells respectively, compared with 5.85% +- 0.1% apoptotic cells in control group (all P < 0.001).	('apoptotic cells', 'CPA', (116, 131))	('gimatecan', 'Protein', (44, 53))	('KYSE-450', 'Var', (4, 12))	('KYSE-450', 'CellLine', 'CVCL:1353', (4, 12))	('gimatecan', 'Chemical', 'MESH:C433984', (44, 53))
781570	29855512	Changes induced by gimatecan were stronger than those induced by the same concentration of irinotecan (Fig.	('stronger', 'PosReg', (34, 42))	('gimatecan', 'Var', (19, 28))	('gimatecan', 'Chemical', 'MESH:C433984', (19, 28))	('irinotecan', 'Chemical', 'MESH:D000077146', (91, 101))
781573	29855512	Taken together, these data clearly indicate that gimatecan induce S-phase arrest, and then activate apoptosis through the pro-apoptotic signaling pathway.	('gimatecan', 'Chemical', 'MESH:C433984', (49, 58))	('gimatecan', 'Var', (49, 58))	('S-phase arrest', 'CPA', (66, 80))	('pro-apoptotic', 'Pathway', (122, 135))	('activate', 'PosReg', (91, 99))	('apoptosis', 'CPA', (100, 109))
781574	29855512	More importantly, gimatecan induced more obvious changes in cell cycle arrest and apoptosis, which was also in accordance with the suppression of tumor growth in vivo.	('gimatecan', 'Var', (18, 27))	('gimatecan', 'Chemical', 'MESH:C433984', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('apoptosis', 'CPA', (82, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('tumor', 'Disease', (146, 151))	('changes', 'Reg', (49, 56))	('cell cycle arrest', 'CPA', (60, 77))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
781586	29855512	In our study, increased expression of phosphorylated p53 was found after gimatecan treatment, which is consistent with this viewpoint.	('increased', 'PosReg', (14, 23))	('gimatecan', 'Chemical', 'MESH:C433984', (73, 82))	('expression', 'MPA', (24, 34))	('phosphorylated', 'Var', (38, 52))	('p53', 'Gene', '7157', (53, 56))	('p53', 'Gene', (53, 56))
781589	29855512	Gimatecan induces S-phase arrest in bladder carcinoma, ovarian carcinoma, and melanoma.	('Gimatecan', 'Var', (0, 9))	('bladder carcinoma', 'Disease', (36, 53))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (55, 72))	('ovarian carcinoma', 'Disease', (55, 72))	('S-phase arrest', 'MPA', (18, 32))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (36, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('Gimatecan', 'Chemical', 'MESH:C433984', (0, 9))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (55, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('bladder carcinoma', 'Disease', 'MESH:D001749', (36, 53))
781594	29855512	Activated p53 may induce not only cell cycle arrest but also apoptosis activation or cellular senescence.	('p53', 'Gene', '7157', (10, 13))	('cell cycle arrest', 'CPA', (34, 51))	('cellular senescence', 'CPA', (85, 104))	('induce', 'Reg', (18, 24))	('Activated', 'Var', (0, 9))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (34, 51))	('apoptosis activation', 'CPA', (61, 81))	('p53', 'Gene', (10, 13))
781595	29855512	Elevation of p53 induces Bax expression, downregulates the anti-apoptotic protein Bcl-2, and activates the caspase 3/7/9-dependent pathway, which is associated with the inhibition of tumor cell growth.	('induces', 'PosReg', (17, 24))	('activates', 'PosReg', (93, 102))	('Elevation', 'Var', (0, 9))	('Bax', 'Gene', '581', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('p53', 'Gene', (13, 16))	('downregulates', 'NegReg', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Bcl-2', 'Gene', '596', (82, 87))	('Bax', 'Gene', (25, 28))	('tumor', 'Disease', (183, 188))	('caspase 3/7/9', 'Gene', (107, 120))	('Bcl-2', 'Gene', (82, 87))	('caspase 3/7/9', 'Gene', '836;840;842', (107, 120))	('expression', 'MPA', (29, 39))	('p53', 'Gene', '7157', (13, 16))
781601	29855512	The modification enhances stability of the drug-enzyme-DNA complex and lactone ring, and ensures rapid agent intake and stable drug interactions with intracellular targets.	('enhances', 'PosReg', (17, 25))	('modification', 'Var', (4, 16))	('interactions', 'Interaction', (132, 144))	('lactone', 'Chemical', 'MESH:D007783', (71, 78))	('stability', 'MPA', (26, 35))
781641	29147183	All 18 tumors were imaged by F-18-FDG PET compared to 16/18 with C-11-Choline.	('18-FDG', 'Chemical', 'MESH:D019788', (31, 37))	('F-18-FDG PET', 'Var', (29, 41))	('C-11-Choline', 'Gene', '1109', (65, 77))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('C-11-Choline', 'Gene', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
781701	29147183	All 18 patients underwent baseline PET imaging with both F-18-FDG and C-11-Choline.	('18-FDG', 'Chemical', 'MESH:D019788', (59, 65))	('C-11-Choline', 'Gene', '1109', (70, 82))	('F-18-FDG', 'Var', (57, 65))	('patients', 'Species', '9606', (7, 15))	('C-11-Choline', 'Gene', (70, 82))
781706	29147183	All 18 patients (100%) had their primary tumor imaged with F-18-FDG in contrast to just 16 (89%) primary tumors successfully imaged with C-11-Choline.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('C-11-Choline', 'Gene', '1109', (137, 149))	('18-FDG', 'Chemical', 'MESH:D019788', (61, 67))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('C-11-Choline', 'Gene', (137, 149))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('primary tumors', 'Disease', (97, 111))	('primary tumors', 'Disease', 'MESH:D009369', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (105, 110))	('F-18-FDG', 'Var', (59, 67))	('patients', 'Species', '9606', (7, 15))
781713	29147183	There was no significant correlation of the initial tumor tracer uptake for either F-18-FDG (n = 9, r = -0.17, p = 0.66) or C-11-Choline (n = 8, r = 0.51, p = 0.19) with pathological response.	('F-18-FDG', 'Var', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('C-11-Choline', 'Gene', '1109', (124, 136))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('C-11-Choline', 'Gene', (124, 136))	('18-FDG', 'Chemical', 'MESH:D019788', (85, 91))
781721	29147183	There was no significant correlation of the mean number of ki-67 positive tumor nuclei in pre treatment tumor samples with initial tumor uptake of either F-18-FDG or C-11-Choline, (C-11-Choline: r = -0.17, p = 0.57, n = 14; F-18-FDG: r = 0.24, p = 0.37, n = 16).	('C-11-Choline', 'Gene', (166, 178))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ki-67', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('C-11-Choline', 'Gene', '1109', (181, 193))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('C-11-Choline', 'Gene', '1109', (166, 178))	('tumor', 'Disease', (131, 136))	('18-FDG', 'Chemical', 'MESH:D019788', (156, 162))	('ki-67', 'Chemical', '-', (59, 64))	('tumor', 'Disease', (74, 79))	('F-18-FDG', 'Var', (154, 162))	('C-11-Choline', 'Gene', (181, 193))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('18-FDG', 'Chemical', 'MESH:D019788', (226, 232))
781736	29147183	Kobori et al found C-11-Choline to be more sensitive in identifying small tumors than F-18-FDG, whilst Jager et al found that irrespective of tumor size, F-18-FDG was superior at imaging of the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (142, 147))	('C-11-Choline', 'Gene', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('18-FDG', 'Chemical', 'MESH:D019788', (88, 94))	('18-FDG', 'Chemical', 'MESH:D019788', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('F-18-FDG', 'Var', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('C-11-Choline', 'Gene', '1109', (19, 31))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumors', 'Disease', (74, 80))
781863	25848305	Clinical significance of ALDH2 rs671 polymorphism in esophageal cancer: evidence from 31 case-control studies Aldehyde dehydrogenase 2 (ALDH2), a critical enzyme for the detoxification of alcohol, is associated with many types of cancers.	('Aldehyde dehydrogenase 2', 'Gene', '217', (110, 134))	('alcohol', 'Chemical', 'MESH:D000438', (188, 195))	('rs671', 'Mutation', 'rs671', (31, 36))	('ALDH2', 'Gene', (136, 141))	('ALDH2', 'Gene', '217', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('rs671 polymorphism', 'Var', (31, 49))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('associated', 'Reg', (200, 210))	('esophageal cancer', 'Disease', (53, 70))	('cancers', 'Disease', (230, 237))	('polymorphism', 'Var', (37, 49))	('ALDH2', 'Gene', (25, 30))	('Aldehyde dehydrogenase 2', 'Gene', (110, 134))	('ALDH2', 'Gene', '217', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
781864	25848305	To verify the relationship of ALDH2 rs671 G>A polymorphism and esophageal cancer (EC), we performed a meta-analysis of a total of 31 published data including 8,510 patients and 16,197 controls.	('rs671', 'Mutation', 'rs671', (36, 41))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('ALDH2', 'Gene', (30, 35))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('rs671 G>A', 'Var', (36, 45))	('ALDH2', 'Gene', '217', (30, 35))
781865	25848305	Although a protective effort was found in the rs671 homozygote comparison (AA/GG: OR=0.69; 95% CI=0.48-0.98), the heterozygote comparison was apparently associated with the risk of EC, particularly in the Chinese population (AG/GG: OR=1.39; 95% CI=1.03-1.87).	('rs671', 'Var', (46, 51))	('rs671', 'Mutation', 'rs671', (46, 51))	('associated', 'Reg', (153, 163))
781868	25848305	The present meta-analysis provided advanced information regarding the association of the ALDH2 A>G polymorphism and EC.	('polymorphism', 'Var', (99, 111))	('ALDH2', 'Gene', (89, 94))	('association', 'Interaction', (70, 81))	('ALDH2', 'Gene', '217', (89, 94))
781879	25848305	Aldehyde dehydrogenase 2 (ALDH2), located at chromosomes 12q24.2, is a major enzyme for acetaldehyde elimination, and its polymorphism determines blood acetaldehyde concentrations after alcohol consumption.	('blood acetaldehyde concentrations', 'Phenotype', 'HP:0003533', (146, 179))	('polymorphism', 'Var', (122, 134))	('ALDH2', 'Gene', '217', (26, 31))	('acetaldehyde', 'Chemical', 'MESH:D000079', (88, 100))	('blood acetaldehyde concentrations', 'MPA', (146, 179))	('ALDH2', 'Gene', (26, 31))	('Aldehyde dehydrogenase 2', 'Gene', (0, 24))	('acetaldehyde', 'Chemical', 'MESH:D000079', (152, 164))	('Aldehyde dehydrogenase 2', 'Gene', '217', (0, 24))	('determines', 'Reg', (135, 145))	('alcohol', 'Chemical', 'MESH:D000438', (186, 193))
781880	25848305	Rs671 G>A (also named Glu487Lys, with the glutamate corresponding to *1 allele, and lysine corresponding to *2 allele) is a nonsynonymous single nucleotide polymorphism (SNP) located in the 12th exon of the ALDH2 gene, which is highly prevalent among the East Asian population.	('ALDH2', 'Gene', (207, 212))	('lysine', 'Chemical', 'MESH:D008239', (84, 90))	('glutamate', 'Chemical', 'MESH:D018698', (42, 51))	('Rs671 G>A', 'Var', (0, 9))	('Glu487Lys', 'Var', (22, 31))	('Glu487Lys', 'SUBSTITUTION', 'None', (22, 31))	('ALDH2', 'Gene', '217', (207, 212))
781881	25848305	The SNP inactivates ALDH2, leading to a high level of acetaldehyde in the blood, which is considered to increase the susceptibility to carcinogenesis.	('increase', 'PosReg', (104, 112))	('ALDH2', 'Gene', '217', (20, 25))	('carcinogenesis', 'Disease', (135, 149))	('acetaldehyde in', 'MPA', (54, 69))	('ALDH2', 'Gene', (20, 25))	('SNP inactivates', 'Var', (4, 19))	('inactivates', 'Var', (8, 19))	('high level of acetaldehyde', 'Phenotype', 'HP:0003533', (40, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (135, 149))	('leading to', 'Reg', (27, 37))	('acetaldehyde', 'Chemical', 'MESH:D000079', (54, 66))
781882	25848305	Increasing evidence suggests that the rs671 polymorphism is correlated to many types of cancer, such as head and neck cancer, gastric cancer, colorectal cancer, and EC.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', (153, 159))	('gastric cancer', 'Disease', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('correlated', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('rs671', 'Var', (38, 43))	('cancer', 'Disease', (134, 140))	('rs671', 'Mutation', 'rs671', (38, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('colorectal cancer', 'Disease', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('head and neck cancer', 'Phenotype', 'HP:0012288', (104, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('neck cancer', 'Disease', 'MESH:D006258', (113, 124))	('neck cancer', 'Disease', (113, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
781886	25848305	PubMed, Embase, MEDLINE, and the Chinese Biomedical Database (CBM) were searched using several search terms: "ALDH2"; "aldehyde dehydrogenase-2"; "polymorphism"; and "esophagus"; "oesophagus"; and "carcinoma or cancer or neoplasm or tumour or tumor".	('polymorphism', 'Var', (147, 159))	('neoplasm or tumour', 'Disease', 'MESH:D009369', (221, 239))	('ALDH2', 'Gene', (110, 115))	('aldehyde dehydrogenase-2', 'Gene', '217', (119, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('"carcinoma or cancer', 'Disease', (197, 217))	('aldehyde dehydrogenase-2', 'Gene', (119, 143))	('ALDH2', 'Gene', '217', (110, 115))	('"carcinoma or cancer', 'Disease', 'MESH:D009369', (197, 217))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('neoplasm', 'Phenotype', 'HP:0002664', (221, 229))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('neoplasm or tumour', 'Disease', (221, 239))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
781887	25848305	The studies selected for our meta-analysis must meet the following criteria: 1) evaluation of the ALDH2 polymorphism and EC risk; 2) the use of a case-control design; and 3) available genotype frequency.	('ALDH2', 'Gene', '217', (98, 103))	('polymorphism', 'Var', (104, 116))	('ALDH2', 'Gene', (98, 103))
781892	25848305	The correlation between the ALDH2 rs671 polymorphism and the EC risk was assessed by the odds ratio (OR) and the 95% confidence interval (CI).	('rs671', 'Var', (34, 39))	('ALDH2', 'Gene', (28, 33))	('ALDH2', 'Gene', '217', (28, 33))	('rs671', 'Mutation', 'rs671', (34, 39))
781897	25848305	Although a number of studies focused on determination of the ALDH2 rs671 polymorphism contributing to EC, the published data still remained unclear.	('rs671', 'Mutation', 'rs671', (67, 72))	('ALDH2', 'Gene', (61, 66))	('contributing', 'Reg', (86, 98))	('rs671', 'Var', (67, 72))	('ALDH2', 'Gene', '217', (61, 66))
781898	25848305	By evaluating the correlation between the ALDH2 rs671 polymorphism and the susceptibility to EC, the present study identified a high relationship in heterozygote comparison (AG/GG: PH<0.001; I2=95.1%), as compared to the homozygote comparison (AA/GG: PH<0.001; I2=74.8%).	('rs671', 'Var', (48, 53))	('rs671', 'Mutation', 'rs671', (48, 53))	('ALDH2', 'Gene', (42, 47))	('ALDH2', 'Gene', '217', (42, 47))
781910	25848305	It has been reported that the mutant ALDH2A allele encodes a catalytically inactive subunit and causes a high blood level of acetaldehyde, which may contribute to susceptibility to carcinogenesis.	('ALDH2', 'Gene', (37, 42))	('high blood level of acetaldehyde', 'Phenotype', 'HP:0003533', (105, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (181, 195))	('high blood level of acetaldehyde', 'MPA', (105, 137))	('causes', 'Reg', (96, 102))	('carcinogenesis', 'Disease', (181, 195))	('ALDH2', 'Gene', '217', (37, 42))	('susceptibility', 'Reg', (163, 177))	('acetaldehyde', 'Chemical', 'MESH:D000079', (125, 137))	('mutant', 'Var', (30, 36))	('contribute', 'Reg', (149, 159))
781912	25848305	The ALDH2 mutation is also associated with increased exposure of the upper digestive tract mucosa to salivary acetaldehyde from drinking alcohol.	('ALDH2', 'Gene', '217', (4, 9))	('exposure', 'MPA', (53, 61))	('alcohol', 'Chemical', 'MESH:D000438', (137, 144))	('mutation', 'Var', (10, 18))	('ALDH2', 'Gene', (4, 9))	('acetaldehyde', 'Chemical', 'MESH:D000079', (110, 122))	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (101, 122))
781913	25848305	After a moderate dose of oral alcohol intake, the salivary acetaldehyde levels in Asians with the inactive ALDH2 AG genotype was two to three times higher than in those with the active ALDH2 GG genotype, which resulted in higher levels of acetaldehyde-related DNA adducts in their lymphocytes.	('acetaldehyde', 'Chemical', 'MESH:D000079', (239, 251))	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (50, 71))	('ALDH2', 'Gene', '217', (185, 190))	('alcohol', 'Chemical', 'MESH:D000438', (30, 37))	('higher', 'PosReg', (222, 228))	('levels', 'MPA', (229, 235))	('salivary acetaldehyde levels', 'MPA', (50, 78))	('inactive', 'Var', (98, 106))	('ALDH2', 'Gene', (185, 190))	('acetaldehyde-related DNA adducts', 'MPA', (239, 271))	('acetaldehyde', 'Chemical', 'MESH:D000079', (59, 71))	('ALDH2', 'Gene', '217', (107, 112))	('ALDH2', 'Gene', (107, 112))	('higher', 'PosReg', (148, 154))
781914	25848305	Although numerous epidemiological studies demonstrated the effects of the ALDH2 rs671 polymorphism on the risk of EC, the results were conflicting and inconclusive based on different combinative sets of genetic and environmental factors.	('effects', 'Reg', (59, 66))	('ALDH2', 'Gene', (74, 79))	('rs671', 'Var', (80, 85))	('ALDH2', 'Gene', '217', (74, 79))	('men', 'Species', '9606', (222, 225))	('rs671', 'Mutation', 'rs671', (80, 85))
781915	25848305	Li et al and Ding et al reported that the rs671 AA genotype is associated with an increased risk of EC.	('rs671', 'Mutation', 'rs671', (42, 47))	('Ding', 'Gene', (13, 17))	('rs671 AA', 'Var', (42, 50))	('Ding', 'Gene', '6045', (13, 17))
781917	25848305	However, Gao et al and Chen et al predicted that the rs671 polymorphism is not associated with EC risk, and it may even reduce the risk.	('risk', 'MPA', (131, 135))	('rs671', 'Var', (53, 58))	('rs671', 'Mutation', 'rs671', (53, 58))	('reduce', 'NegReg', (120, 126))
781918	25848305	Furthermore, Yokoyama et al and Wang et al indicated that the rs671 polymorphism significantly increases the risk of EC in Chinese females, but not in Japanese females.	('rs671', 'Var', (62, 67))	('rs671', 'Mutation', 'rs671', (62, 67))	('increases', 'PosReg', (95, 104))
781937	25848305	We verified the correlation of the ALDH2 rs671 polymorphism and the risk of EC using both hospital-based controls and population-based controls because some biases may exist in hospital-based studies.	('ALDH2', 'Gene', '217', (35, 40))	('rs671', 'Mutation', 'rs671', (41, 46))	('rs671', 'Var', (41, 46))	('ALDH2', 'Gene', (35, 40))
781941	25848305	Third, we conclusively estimated the association between the ALDH2 rs671 G>A polymorphism and EC risk.	('rs671', 'Mutation', 'rs671', (67, 72))	('ALDH2', 'Gene', (61, 66))	('rs671 G>A', 'Var', (67, 76))	('ALDH2', 'Gene', '217', (61, 66))
781944	25848305	We suggest that more clinical studies including larger samples stratified by a genetic-environmental interaction need to be performed to fully clarify the roles of the ALDH2 polymorphisms in the etiology of EC.	('ALDH2', 'Gene', '217', (168, 173))	('men', 'Species', '9606', (94, 97))	('ALDH2', 'Gene', (168, 173))	('polymorphisms', 'Var', (174, 187))
782036	22748473	The presence of any AGR2 staining was 99% sensitive but 63% specific for the diagnosis of adenocarcinoma.	('AGR2', 'Gene', '10551', (20, 24))	('AGR2', 'Gene', (20, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('adenocarcinoma', 'Disease', (90, 104))	('presence', 'Var', (4, 12))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))
782077	22748473	The presence of diffuse AGR2 expression is highly sensitive for adenocarcinoma, particularly in the setting of negative or diminished p63 and cytokeratin 5/6 positivity.	('p63', 'Gene', (134, 137))	('adenocarcinoma', 'Disease', (64, 78))	('p63', 'Gene', '8626', (134, 137))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('AGR2', 'Gene', (24, 28))	('sensitive', 'Reg', (50, 59))	('presence', 'Var', (4, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('cytokeratin 5/6', 'Gene', '3852', (142, 157))	('AGR2', 'Gene', '10551', (24, 28))	('cytokeratin 5/6', 'Gene', (142, 157))
782078	22748473	However, neuroendocrine carcinomas can demonstrate focal (<50%) AGR2 staining is a subset of cases.	('AGR2', 'Gene', (64, 68))	('staining', 'Var', (69, 77))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (9, 34))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (9, 34))	('neuroendocrine carcinomas', 'Disease', (9, 34))	('AGR2', 'Gene', '10551', (64, 68))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (9, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
782079	22748473	MUC5AC is highly specific for esophageal adenocarcinoma, and the presence of MUC5AC positivity in a tumor lacking diffuse p63 and cytokeratin 5/6 can provide evidence of adenocarcinoma.	('p63', 'Gene', (122, 125))	('cytokeratin 5/6', 'Gene', '3852', (130, 145))	('tumor', 'Disease', (100, 105))	('MUC5AC', 'Gene', '4586', (0, 6))	('p63', 'Gene', '8626', (122, 125))	('adenocarcinoma', 'Disease', 'MESH:D000230', (41, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('diffuse', 'MPA', (114, 121))	('MUC5AC', 'Gene', '4586', (77, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (30, 55))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (30, 55))	('adenocarcinoma', 'Disease', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('esophageal adenocarcinoma', 'Disease', (30, 55))	('adenocarcinoma', 'Disease', 'MESH:D000230', (170, 184))	('MUC5AC', 'Gene', (0, 6))	('cytokeratin 5/6', 'Gene', (130, 145))	('adenocarcinoma', 'Disease', (41, 55))	('MUC5AC', 'Gene', (77, 83))	('presence', 'Var', (65, 73))
782157	22128215	Although one would be more likely to find stress-induced hypermetabolism on earlier postoperative days, the increase in the mREE of patients undergoing a transhiatal or transthoracic esophagectomy was almost the same as during the first seven days.	('hypermetabolism', 'Disease', (57, 72))	('mREE', 'MPA', (124, 128))	('transhiatal', 'Var', (154, 165))	('hypermetabolism', 'Disease', 'MESH:C565498', (57, 72))	('patients', 'Species', '9606', (132, 140))
782186	32215746	Safety and feasibility of minimally invasive surgical interventions for esophageal and gastric cancer in the acute setting: a nationwide cohort study Minimally invasive esophagectomy and gastrectomy are increasingly performed and might be superior to their open equivalents in an elective setting.	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('Minimally', 'Var', (150, 159))
782323	29562919	The SE and sdRE of interfractional marker position variation was expected to be affected by registration of the time-averaged CBCT with a snapshot pCT and possible artifacts (e.g., due to swallowing) or several anatomical changes during the radiation treatment course.	('variation', 'Var', (51, 60))	('SE', 'Disease', 'None', (4, 6))	('affected', 'Reg', (80, 88))
782332	29562919	A possible correlation between fiducial marker position variation and tumor/patients' characteristics is possible, e.g., tumors in different regions, or patients with different features might show different movement properties.	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Disease', (70, 75))	('tumors', 'Disease', (121, 127))	('tumor', 'Disease', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('variation', 'Var', (56, 65))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('correlation', 'Reg', (11, 22))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
782380	28402911	In brief, the severity of gastroesophageal varices was classified as follows: F1, straight and small-caliber varices; F2, beady varices; F3, tumor-shaped varices; Cw, white varices; Cb, blue varices; RC0, absence of red color (RC) sign; RC1, a few RC signs; RC2, several RC signs; and RC2, many RC signs.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('RC1', 'Gene', '57332', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('esophageal varices', 'Phenotype', 'HP:0002040', (32, 50))	('RC0', 'Var', (200, 203))	('tumor', 'Disease', (141, 146))	('RC1', 'Gene', (237, 240))	('gastroesophageal varices', 'Phenotype', 'HP:0002040', (26, 50))
782392	28402911	Upper gastrointestinal endoscopy at postoperative month 3 showed the varices Lm, F2, Cb, and RC0 in the middle to lower third of the esophagus and Lg-cCf, F1, Cb, and RC0 in the gastric cardia.	('RC0', 'Var', (93, 96))	('Lg-cCf', 'Var', (147, 153))	('RC0', 'Var', (167, 170))	('gastric cardia', 'Disease', (178, 192))	('gastric cardia', 'Disease', 'MESH:D004938', (178, 192))
782461	23078618	However, high Bmi-1 expression did not show an association with overall survival in both esophageal adenocarcinoma and squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('esophageal adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D000077277', (89, 142))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (89, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('Bmi-1', 'Gene', '648', (14, 19))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('Bmi-1', 'Gene', (14, 19))	('high', 'Var', (9, 13))
782462	23078618	This study demonstrates that high expression Bmi-1 is associated with esophageal adenocarcinoma and precancerous lesions, which implies that Bmi-1 plays an important role in early carcinogenesis in esophageal adenocarcinoma.	('high expression', 'Var', (29, 44))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (198, 223))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (198, 223))	('carcinogenesis', 'Disease', 'MESH:D063646', (180, 194))	('precancerous lesions', 'Disease', 'MESH:D011230', (100, 120))	('Bmi-1', 'Gene', '648', (141, 146))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (70, 95))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (70, 95))	('esophageal adenocarcinoma', 'Disease', (198, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('Bmi-1', 'Gene', '648', (45, 50))	('associated', 'Reg', (54, 64))	('Bmi-1', 'Gene', (141, 146))	('esophageal adenocarcinoma', 'Disease', (70, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Bmi-1', 'Gene', (45, 50))	('precancerous lesions', 'Disease', (100, 120))	('carcinogenesis', 'Disease', (180, 194))
782471	23078618	During these events, a series of genetic and epigenetic aberrations driven by inflammation and oxidative stress contributes to the carcinogenesis.	('carcinogenesis', 'Disease', (131, 145))	('oxidative stress', 'Phenotype', 'HP:0025464', (95, 111))	('inflammation', 'Disease', 'MESH:D007249', (78, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('inflammation', 'Disease', (78, 90))	('epigenetic aberrations', 'Var', (45, 67))
782475	23078618	In addition, deregulation of polycomb-group gene expression leads to cell proliferation and tumor progression .	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('expression', 'MPA', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cell proliferation', 'CPA', (69, 87))	('polycomb-group gene', 'Gene', (29, 48))	('tumor', 'Disease', (92, 97))	('leads to', 'Reg', (60, 68))	('deregulation', 'Var', (13, 25))
782476	23078618	Aberrant Bmi-1 expression has been associated with many solid and hematologic malignancies, including mantle cell lymphoma , Hodgkin lymphoma , B-cell non-Hodgkin lymphoma , gastric carcinoma , hepatocellular carcinoma , colorectal cancer , breast cancer , bladder cancer , nasopharyngeal carcinoma , oral squamous cell carcinoma  and non-small cell lung cancer .	('bladder cancer', 'Disease', (257, 271))	('Bmi-1', 'Gene', (9, 14))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (151, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (320, 329))	('lymphoma', 'Phenotype', 'HP:0002665', (163, 171))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (335, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('bladder cancer', 'Phenotype', 'HP:0009725', (257, 271))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (274, 298))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (301, 329))	('cell lymphoma', 'Phenotype', 'HP:0012191', (109, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('Hodgkin lymphoma', 'Disease', (155, 171))	('oral squamous cell carcinoma', 'Disease', (301, 329))	('Aberrant', 'Var', (0, 8))	('gastric carcinoma', 'Disease', 'MESH:D013274', (174, 191))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (194, 218))	('Hodgkin lymphoma', 'Disease', (125, 141))	('gastric carcinoma', 'Disease', (174, 191))	('expression', 'MPA', (15, 25))	('non-small cell lung cancer', 'Disease', (335, 361))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('colorectal cancer', 'Disease', (221, 238))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (174, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (306, 329))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (350, 361))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (155, 171))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (155, 171))	('solid and', 'Disease', (56, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (194, 218))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (125, 141))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (125, 141))	('nasopharyngeal carcinoma', 'Disease', (274, 298))	('B-cell non-Hodgkin lymphoma', 'Phenotype', 'HP:0012191', (144, 171))	('Bmi-1', 'Gene', '648', (9, 14))	('mantle cell lymphoma', 'Disease', (102, 122))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (335, 361))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (102, 122))	('hematologic malignancies', 'Disease', (66, 90))	('associated', 'Reg', (35, 45))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('hepatocellular carcinoma', 'Disease', (194, 218))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (339, 361))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (274, 298))	('breast cancer', 'Disease', (241, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('bladder cancer', 'Disease', 'MESH:D001749', (257, 271))	('hematologic malignancies', 'Disease', 'MESH:D019337', (66, 90))
782497	23078618	However, Bmi-1 mutation with KRMK blocks Bmi-1 nuclear translocation, which may also cause Bmi-1 staining in the cytoplasm .	('Bmi-1', 'Gene', (9, 14))	('mutation', 'Var', (15, 23))	('blocks', 'NegReg', (34, 40))	('Bmi-1', 'Gene', '648', (91, 96))	('Bmi-1', 'Gene', (91, 96))	('cause', 'Reg', (85, 90))	('nuclear translocation', 'MPA', (47, 68))	('Bmi-1', 'Gene', '648', (41, 46))	('staining', 'MPA', (97, 105))	('Bmi-1', 'Gene', '648', (9, 14))	('Bmi-1', 'Gene', (41, 46))
782509	23078618	However, the percentage of high Bmi-1 expression increased following the histologic changes from squamous epithelium (7%) to columnar cell metaplasia (22%), Barrett's esophagus (22%), low-grade dysplasia (45%), high-grade dysplasia (43%) and esophageal adenocarcinoma (37%) (Table 3).	('squamous epithelium', 'Disease', (97, 116))	('Bmi-1', 'Gene', '648', (32, 37))	('columnar cell metaplasia', 'Disease', 'MESH:D008679', (125, 149))	('expression', 'MPA', (38, 48))	('Bmi-1', 'Gene', (32, 37))	('increased', 'PosReg', (49, 58))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (242, 267))	('esophageal adenocarcinoma', 'Disease', (242, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('dysplasia', 'Disease', (194, 203))	('dysplasia', 'Disease', (222, 231))	('high', 'Var', (27, 31))	("Barrett's esophagus", 'Disease', (157, 176))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (242, 267))	('dysplasia', 'Disease', 'MESH:D004476', (194, 203))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (157, 176))	('dysplasia', 'Disease', 'MESH:D004476', (222, 231))	('columnar cell metaplasia', 'Disease', (125, 149))
782510	23078618	The frequency of high Bmi-1 expression in Barrett's esophagus and columnar cell metaplasia was significantly greater than squamous epithelium (p < 0.05).	('Bmi-1', 'Gene', '648', (22, 27))	('expression', 'MPA', (28, 38))	('Bmi-1', 'Gene', (22, 27))	('high', 'Var', (17, 21))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (42, 61))	('columnar cell metaplasia', 'Disease', (66, 90))	('greater', 'PosReg', (109, 116))	('columnar cell metaplasia', 'Disease', 'MESH:D008679', (66, 90))
782511	23078618	The esophageal adenocarcinoma and low- and high-grade dysplasia groups, also showed significantly greater frequency of high Bmi-1 expression compared with the Barrett's esophagus and columnar cell metaplasia groups (p < 0.05).	('expression', 'MPA', (130, 140))	('Bmi-1', 'Gene', (124, 129))	('dysplasia', 'Disease', (54, 63))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (159, 178))	('high', 'Var', (119, 123))	('dysplasia', 'Disease', 'MESH:D004476', (54, 63))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (4, 29))	('esophageal adenocarcinoma', 'Disease', (4, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('columnar cell metaplasia', 'Disease', (183, 207))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (4, 29))	('greater', 'PosReg', (98, 105))	('columnar cell metaplasia', 'Disease', 'MESH:D008679', (183, 207))	('Bmi-1', 'Gene', '648', (124, 129))
782516	23078618	High expression of Bmi-1 was significantly associated with poor differentiation in esophageal adenocarcinoma (67%) (Table 2).	('Bmi-1', 'Gene', '648', (19, 24))	('poor', 'Disease', (59, 63))	('Bmi-1', 'Gene', (19, 24))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (83, 108))	('associated', 'Reg', (43, 53))	('esophageal adenocarcinoma', 'Disease', (83, 108))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (83, 108))
782519	23078618	For esophageal adenocarcinoma, the overall survival in the group with high Bmi-1 expression was 38.3 months, while the group with non-high Bmi-1 expression was 36.5 months.	('Bmi-1', 'Gene', '648', (139, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('Bmi-1', 'Gene', (139, 144))	('Bmi-1', 'Gene', '648', (75, 80))	('Bmi-1', 'Gene', (75, 80))	('expression', 'Var', (81, 91))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (4, 29))	('esophageal adenocarcinoma', 'Disease', (4, 29))	('high', 'Var', (70, 74))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (4, 29))
782522	23078618	In this cohort, the median overall survival of patients with Bmi-1 amplification was approximately 10 months and patients with no Bmi-1 amplification was 25 months.	('Bmi-1', 'Gene', '648', (61, 66))	('amplification', 'Var', (67, 80))	('patients', 'Species', '9606', (113, 121))	('Bmi-1', 'Gene', (61, 66))	('Bmi-1', 'Gene', '648', (130, 135))	('patients', 'Species', '9606', (47, 55))	('Bmi-1', 'Gene', (130, 135))
782523	23078618	Significant association of overall survival was found with Bmi-1 amplification (p<0.05).	('Bmi-1', 'Gene', '648', (59, 64))	('Bmi-1', 'Gene', (59, 64))	('association', 'Interaction', (12, 23))	('amplification', 'Var', (65, 78))	('overall survival', 'MPA', (27, 43))
782530	23078618	During these events, the accumulation of genetic and epigenetic aberrations driven by inflammation, as well as acid and bile salt stimulation, contributes to the carcinogenesis.	('epigenetic aberrations', 'Var', (53, 75))	('inflammation', 'Disease', (86, 98))	('genetic', 'Var', (41, 48))	('bile salt', 'Chemical', 'MESH:D001647', (120, 129))	('carcinogenesis', 'Disease', 'MESH:D063646', (162, 176))	('carcinogenesis', 'Disease', (162, 176))	('inflammation', 'Disease', 'MESH:D007249', (86, 98))
782532	23078618	Bmi-1 has a role in epigenetic modification as a member of the polycomb-group family, and its abnormal expression may contribute to carcinogenesis .	('contribute', 'Reg', (118, 128))	('carcinogenesis', 'Disease', (132, 146))	('epigenetic modification', 'MPA', (20, 43))	('Bmi-1', 'Gene', '648', (0, 5))	('Bmi-1', 'Gene', (0, 5))	('abnormal', 'Var', (94, 102))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))
782551	23078618	While our study showed high Bmi-1 expression of shows slightly better but not a significant difference in prognosis in esophageal adenocarcinoma, most studies showed that high Bmi-1 expression was associated with poorer prognosis .	('Bmi-1', 'Gene', (28, 33))	('expression', 'MPA', (182, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('esophageal adenocarcinoma', 'Disease', (119, 144))	('high', 'Var', (171, 175))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (119, 144))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (119, 144))	('Bmi-1', 'Gene', '648', (176, 181))	('Bmi-1', 'Gene', '648', (28, 33))	('Bmi-1', 'Gene', (176, 181))
782552	23078618	did report a correlation between high expression of Bmi-1 and better outcome in breast cancer patients .	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (94, 102))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('Bmi-1', 'Gene', '648', (52, 57))	('Bmi-1', 'Gene', (52, 57))
782553	23078618	The non-significant prognosis for esophageal adenocarcinoma was unexpected since other gastrointestinal carcinomas showed worse prognosis with high Bmi-1 expression.	('Bmi-1', 'Gene', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('high', 'Var', (143, 147))	('expression', 'MPA', (154, 164))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (87, 114))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (34, 59))	('esophageal adenocarcinoma', 'Disease', (34, 59))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (34, 59))	('gastrointestinal carcinomas', 'Disease', 'MESH:D004067', (87, 114))	('Bmi-1', 'Gene', '648', (148, 153))	('gastrointestinal carcinomas', 'Disease', (87, 114))
782557	23078618	where they found no association in prognosis between high expression of Bmi-1 and squamous cell carcinoma .	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('squamous cell carcinoma', 'Disease', (82, 105))	('high expression', 'Var', (53, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('Bmi-1', 'Gene', '648', (72, 77))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 105))	('Bmi-1', 'Gene', (72, 77))
782675	19473210	These features are reflected by the high rate of animal survival, and the ability of the surgically-altered rats to achieve rapid gain in body weight and eventually catch up to that of the control rats.	('rat', 'Species', '10116', (108, 111))	('surgically-altered', 'Var', (89, 107))	('rat', 'Species', '10116', (197, 200))	('rats', 'Species', '10116', (108, 112))	('rat', 'Species', '10116', (41, 44))	('body weight', 'CPA', (138, 149))	('gain', 'PosReg', (130, 134))	('rats', 'Species', '10116', (197, 201))
782690	21182180	Alterations in nuclear structure hold high clinical and research relevance, especially in the context of early cancer detection.	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('nuclear structure', 'MPA', (15, 32))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
782702	21182180	Upon derivation cytogenetic analysis of the CP-A cell line showed 11.6% 4N fraction, deleted CDKN2A (p16), wild-type p53, and loss of heterozygosity (LOH) in chromosomes 9p and 5q.	('CDKN2A', 'Gene', (93, 99))	('p53', 'Gene', (117, 120))	('CDKN2A', 'Gene', '1029', (93, 99))	('p16', 'Gene', '1029', (101, 104))	('p53', 'Gene', '7157', (117, 120))	('4N fraction', 'MPA', (72, 83))	('CP-A', 'Gene', '1357', (44, 48))	('p16', 'Gene', (101, 104))	('loss', 'NegReg', (126, 130))	('deleted', 'Var', (85, 92))	('CP-A', 'Gene', (44, 48))
782703	21182180	Analysis of the CP-D cell line showed 19.8% 4N fraction, deleted p16, a single base pair deletion in TP53 codon 302, and 9p and 17p LOH.	('deleted', 'Var', (57, 64))	('p16', 'Gene', '1029', (65, 68))	('CP-D', 'Gene', (16, 20))	('TP53', 'Gene', '7157', (101, 105))	('4N fraction', 'MPA', (44, 55))	('p16', 'Gene', (65, 68))	('TP53', 'Gene', (101, 105))	('CP-D', 'Gene', '1362', (16, 20))
782735	21182180	Genetic and epigenetic abnormalities implicated in cancer initiation and progression inevitably alter the nuclear landscape, resulting in shape, size and textural irregularities in the nucleus.	('cancer initiation', 'Disease', 'MESH:D009369', (51, 68))	('genetic abnormalities', 'Disease', (15, 36))	('cancer initiation', 'Disease', (51, 68))	('size', 'MPA', (145, 149))	('nuclear landscape', 'MPA', (106, 123))	('Genetic', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('resulting in', 'Reg', (125, 137))	('shape', 'MPA', (138, 143))	('alter', 'Reg', (96, 101))	('genetic abnormalities', 'Disease', 'MESH:D030342', (15, 36))	('textural irregularities', 'MPA', (154, 177))
782743	21182180	The addition of 3D immunofluorescence imaging holds promise to reveal, among others, correlations between chromosomal abnormalities or specific tumor suppressor and oncogene mutations and higher order chromatin structure; and, further, how these factors may engender or influence gene expression patterns that predispose to cancer.	('cancer', 'Disease', (324, 330))	('tumor', 'Disease', (144, 149))	('engender', 'Reg', (258, 266))	('chromosomal abnormalities', 'Disease', (106, 131))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (106, 131))	('influence', 'Reg', (270, 279))	('gene expression patterns', 'MPA', (280, 304))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('mutations', 'Var', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (324, 330))
782785	20045534	Causes of cancer death were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes for deaths occurring before 1999 and Tenth Revision (ICD-10) codes (in parentheses) for deaths during 1999-2003: Our primary outcome for this analysis was death from digestive and gastrointestinal cancers, 150-159 (C15-C26); and our secondary mortality outcomes were: Colon, 153 (C18); Rectum,154 (C19-C21); Pancreas, 157 (C25); Esophagus, 150 (C15); Stomach, 151 (C16); and Liver, 155 (C22).	('Stomach', 'Disease', (467, 474))	('Esophagus', 'Disease', (445, 454))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer death', 'Disease', (10, 22))	('digestive and gastrointestinal cancer', 'Phenotype', 'HP:0007378', (282, 319))	('Colon', 'Disease', (384, 389))	('150-159 (C15-C26', 'Var', (322, 338))	('ach', 'Chemical', 'MESH:D000109', (471, 474))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('cancer death', 'Disease', 'MESH:D003643', (10, 22))	('cancers', 'Phenotype', 'HP:0002664', (313, 320))	('Liver', 'Disease', (491, 496))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (296, 320))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (296, 319))	('Pancreas', 'Disease', (424, 432))	('gastrointestinal cancers', 'Disease', (296, 320))
782797	20045534	The presence of MetS was associated with earlier mortality, as was an increase in the incremental number of syndrome components (Figure 1; p < 0.01).	('increase', 'PosReg', (70, 78))	('MetS', 'Disease', (16, 20))	('incremental number of syndrome', 'Disease', 'MESH:D007674', (86, 116))	('incremental number of syndrome', 'Disease', (86, 116))	('presence', 'Var', (4, 12))
782798	20045534	In multivariable models, the presence of MetS (0-2 vs. 3+ components) was associated with about two-fold higher mortality from digestive cancers (HR=1.90 [1.42-2.55]), and there was a graded increase in risk associated with a greater number of prevalent MetS components (P trend < 0.01; Table 2).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('higher', 'PosReg', (105, 111))	('presence', 'Var', (29, 37))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Disease', (137, 144))
782807	20045534	MetS was significantly associated with higher risk for colon, colorectal, esophageal, and liver cancer deaths, but not pancreatic or stomach cancer (Table 4).	('pancreatic or stomach cancer', 'Disease', (119, 147))	('colon', 'Disease', 'MESH:D015179', (55, 60))	('MetS', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('colorectal', 'Disease', (62, 72))	('liver cancer', 'Phenotype', 'HP:0002896', (90, 102))	('colorectal', 'Disease', 'MESH:D015179', (62, 72))	('colon', 'Disease', (55, 60))	('pancreatic or stomach cancer', 'Disease', 'MESH:D010190', (119, 147))	('liver cancer deaths', 'Disease', 'MESH:D006528', (90, 109))	('stomach cancer', 'Phenotype', 'HP:0012126', (133, 147))	('esophageal', 'Disease', (74, 84))	('liver cancer deaths', 'Disease', (90, 109))
782808	20045534	Further adjustment of Model 1 covariates for fitness attenuated the associations by about 10 to 20%, and following this adjustment, only colorectal and esophageal cancer remained significantly associated with the presence of MetS.	('presence', 'Var', (213, 221))	('men', 'Species', '9606', (126, 129))	('men', 'Species', '9606', (14, 17))	('colorectal', 'Disease', 'MESH:D015179', (137, 147))	('esophageal cancer', 'Disease', (152, 169))	('MetS', 'Disease', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('fitness attenuated', 'Disease', (45, 63))	('colorectal', 'Disease', (137, 147))	('associated', 'Reg', (193, 203))	('fitness attenuated', 'Disease', 'MESH:C538265', (45, 63))
782809	20045534	Finally, we described the joint associations between the presence of MetS and other risk factors for digestive cancer mortality.	('MetS', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('presence', 'Var', (57, 65))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
782816	20045534	In this prospective study with an average of 14.4 (SD=7.0) years of follow-up, we found that the presence of MetS at baseline was associated with an approximate two-fold higher in risk for mortality from cancers of the digestive system among men (HR=1.90 [1.42-2.55]).	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('higher', 'PosReg', (170, 176))	('cancers', 'Disease', (204, 211))	('presence', 'Var', (97, 105))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('men', 'Species', '9606', (242, 245))	('MetS', 'Gene', (109, 113))
782817	20045534	We also found that MetS was associated with increased mortality risk for a number of different cancers of the digestive system, including colorectal, esophageal, and liver cancer.	('colorectal', 'Disease', (138, 148))	('esophageal', 'Disease', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('colorectal', 'Disease', 'MESH:D015179', (138, 148))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('liver cancer', 'Phenotype', 'HP:0002896', (166, 178))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('liver cancer', 'Disease', 'MESH:D006528', (166, 178))	('liver cancer', 'Disease', (166, 178))	('MetS', 'Var', (19, 23))
782820	20045534	These findings indicate that the presence of MetS is positively associated with mortality from cancers of the digestive system among overweight and obese men, and suggest that interventions which favorably affect adiposity and other abnormalities associated with the syndrome may reduce risk of premature death from these cancers.	('presence', 'Var', (33, 41))	('associated', 'Reg', (64, 74))	('premature death', 'Disease', (295, 310))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (322, 329))	('cancers', 'Disease', (95, 102))	('premature death', 'Disease', 'MESH:D003643', (295, 310))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('obese', 'Disease', (148, 153))	('overweight', 'Phenotype', 'HP:0025502', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('obese', 'Disease', 'MESH:D009765', (148, 153))	('MetS', 'Disease', (45, 49))	('reduce', 'NegReg', (280, 286))	('cancers', 'Phenotype', 'HP:0002664', (322, 329))	('adiposity', 'MPA', (213, 222))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancers', 'Disease', (322, 329))	('men', 'Species', '9606', (154, 157))
782822	20045534	Our findings are consistent with those from a number of recent studies that have reported positive associations between the presence of the MetS, or a clustering of its components, and adenomatous polyps, incident colon cancer, and mortality from colorectal cancer.	('presence', 'Var', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('adenomatous polyps', 'Disease', (185, 203))	('colon cancer', 'Disease', 'MESH:D015179', (214, 226))	('colon cancer', 'Phenotype', 'HP:0003003', (214, 226))	('MetS', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('colorectal cancer', 'Phenotype', 'HP:0003003', (247, 264))	('colorectal cancer', 'Disease', (247, 264))	('colon cancer', 'Disease', (214, 226))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (185, 203))	('adenomatous polyps', 'Disease', 'MESH:D018256', (185, 203))	('colorectal cancer', 'Disease', 'MESH:D015179', (247, 264))
782846	20045534	For example, the presence of the MetS was associated with a 2-fold higher risk (HR=1.90 [1.42-2.55]) before further adjustment for fitness, but after adjustment, risk was reduced by about 20% (HR=1.52 [1.11-2.09]).	('MetS', 'Var', (33, 37))	('men', 'Species', '9606', (156, 159))	('men', 'Species', '9606', (122, 125))	('presence', 'Var', (17, 25))
782870	32965165	Finally, we find that in invasive liver cancer, KLF5 is absent in the context of p53 loss or mutation.	('liver cancer', 'Phenotype', 'HP:0002896', (34, 46))	('invasive liver cancer', 'Disease', (25, 46))	('invasive liver cancer', 'Disease', 'MESH:D006528', (25, 46))	('p53', 'Gene', (81, 84))	('loss', 'NegReg', (85, 89))	('p53', 'Gene', '7157', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mutation', 'Var', (93, 101))
782872	32965165	For example, KLF5 can be both anti- and pro-tumorigenic in prostate cancer cells, and it can promote proliferation of primary esophageal keratinocytes but inhibit growth of esophageal cancer cells.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('growth', 'CPA', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('KLF5', 'Var', (13, 17))	('proliferation', 'CPA', (101, 114))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Disease', (68, 74))	('prostate cancer', 'Disease', (59, 74))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('promote', 'PosReg', (93, 100))	('tumor', 'Disease', (44, 49))	('inhibit', 'NegReg', (155, 162))
782873	32965165	In terms of cell migration, KLF5 can promote keratinocyte migration by inducing integrin-linked kinase and can promote bladder cancer cell and breast cancer cell migration by upregulating the tyrosine-protein kinase Fyn (FYN) and TNF alpha-induced protein 2 (TNFAIP2), respectively; in contrast, KLF5 loss can also drive the invasive progression of human squamous cell cancers in the context of p53 ablation, and epithelial cell migration is accelerated after KLF5 knock-down.	('FYN', 'Gene', (221, 224))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('cancers', 'Phenotype', 'HP:0002664', (369, 376))	('breast cancer', 'Disease', (143, 156))	('TNFAIP2', 'Gene', '7127', (259, 266))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (355, 376))	('Fyn', 'Gene', (216, 219))	('FYN', 'Gene', '2534', (221, 224))	('bladder cancer', 'Disease', 'MESH:D001749', (119, 133))	('bladder cancer', 'Disease', (119, 133))	('invasive progression', 'CPA', (325, 345))	('promote', 'PosReg', (111, 118))	('p53', 'Gene', '7157', (395, 398))	('inducing', 'Reg', (71, 79))	('TNFAIP2', 'Gene', (259, 266))	('knock-down', 'Var', (465, 475))	('human', 'Species', '9606', (349, 354))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('squamous cell cancers', 'Disease', (355, 376))	('accelerated', 'PosReg', (442, 453))	('upregulating', 'PosReg', (175, 187))	('integrin-linked', 'Enzyme', (80, 95))	('squamous cell cancers', 'Disease', 'MESH:D002294', (355, 376))	('KLF5', 'Gene', (460, 464))	('p53', 'Gene', (395, 398))	('TNF alpha-induced protein 2', 'Gene', '7127', (230, 257))	('promote', 'PosReg', (37, 44))	('Fyn', 'Gene', '2534', (216, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('drive', 'PosReg', (315, 320))	('TNF alpha-induced protein 2', 'Gene', (230, 257))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('epithelial cell migration', 'CPA', (413, 438))
782879	32965165	Specifically, KLF5 inhibited EMT in liver cancer cells and inhibited cell migration only when p53 function was lost.	('liver cancer', 'Disease', (36, 48))	('inhibited', 'NegReg', (19, 28))	('KLF5', 'Var', (14, 18))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('inhibited', 'NegReg', (59, 68))	('cell migration', 'CPA', (69, 83))	('liver cancer', 'Phenotype', 'HP:0002896', (36, 48))	('liver cancer', 'Disease', 'MESH:D006528', (36, 48))	('EMT in', 'CPA', (29, 35))
782883	32965165	Finally, we found that in invasive liver cancer, KLF5 was absent in the context of p53 loss or mutation.	('loss', 'NegReg', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('p53', 'Gene', '7157', (83, 86))	('p53', 'Gene', (83, 86))	('liver cancer', 'Phenotype', 'HP:0002896', (35, 47))	('invasive liver cancer', 'Disease', (26, 47))	('invasive liver cancer', 'Disease', 'MESH:D006528', (26, 47))	('mutation', 'Var', (95, 103))
782884	32965165	Therefore, KLF5 loss could be a valuable diagnostic target for invasive liver cancer when p53 is lost or mutated.	('p53', 'Gene', (90, 93))	('KLF5', 'Protein', (11, 15))	('invasive liver cancer', 'Disease', (63, 84))	('p53', 'Gene', '7157', (90, 93))	('invasive liver cancer', 'Disease', 'MESH:D006528', (63, 84))	('liver cancer', 'Phenotype', 'HP:0002896', (72, 84))	('loss', 'NegReg', (16, 20))	('mutated', 'Var', (105, 112))	('lost', 'NegReg', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
782885	32965165	To investigate the function of KLF5 on EMT in liver cancer cells, we overexpressed or knocked down KLF5 in the liver cancer cell lines HepG2 and Hep3B.	('KLF5', 'Gene', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('liver cancer', 'Phenotype', 'HP:0002896', (111, 123))	('Hep3B', 'CellLine', 'CVCL:0326', (145, 150))	('liver cancer', 'Disease', 'MESH:D006528', (46, 58))	('liver cancer', 'Phenotype', 'HP:0002896', (46, 58))	('knocked', 'Var', (86, 93))	('liver cancer', 'Disease', 'MESH:D006528', (111, 123))	('liver cancer', 'Disease', (46, 58))	('liver cancer', 'Disease', (111, 123))	('HepG2', 'CellLine', 'CVCL:0027', (135, 140))
782888	32965165	Overexpression and knock-down of KLF5 did not alter the expression of E-cadherin and vimentin proteins.	('E-cadherin', 'Gene', '999', (70, 80))	('KLF5', 'Gene', (33, 37))	('vimentin', 'Gene', '7431', (85, 93))	('E-cadherin', 'Gene', (70, 80))	('vimentin', 'Gene', (85, 93))	('knock-down', 'Var', (19, 29))
782894	32965165	To confirm whether KLF5 function in liver cancer cell EMT is dependent on p53 status, we knocked down p53 and then overexpressed or knocked down KLF5 in HepG2 and Hep3B cells.	('liver cancer', 'Disease', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('HepG2', 'CellLine', 'CVCL:0027', (153, 158))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (74, 77))	('KLF5', 'Gene', (145, 149))	('Hep3B', 'CellLine', 'CVCL:0326', (163, 168))	('liver cancer', 'Disease', 'MESH:D006528', (36, 48))	('liver cancer', 'Phenotype', 'HP:0002896', (36, 48))	('p53', 'Gene', (102, 105))	('p53', 'Gene', '7157', (74, 77))	('knocked', 'Reg', (89, 96))	('knocked', 'Var', (132, 139))
782895	32965165	As shown in Figure 1(c), consistent with a previous report, the knock-down of p53 promoted EMT, as decreased expression of E-cadherin and increased expression of vimentin were observed.	('increased', 'PosReg', (138, 147))	('decreased', 'NegReg', (99, 108))	('expression', 'MPA', (109, 119))	('knock-down', 'Var', (64, 74))	('promoted', 'PosReg', (82, 90))	('vimentin', 'Gene', '7431', (162, 170))	('vimentin', 'Gene', (162, 170))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('EMT', 'CPA', (91, 94))	('p53', 'Gene', (78, 81))	('expression', 'MPA', (148, 158))	('p53', 'Gene', '7157', (78, 81))
782896	32965165	Notably, when p53 was knocked down, KLF5 knock-down further decreased the expression of E-cadherin, while overexpression of KLF5 decreased the expression of vimentin.	('expression', 'MPA', (74, 84))	('decreased', 'NegReg', (60, 69))	('E-cadherin', 'Gene', (88, 98))	('expression', 'MPA', (143, 153))	('p53', 'Gene', (14, 17))	('E-cadherin', 'Gene', '999', (88, 98))	('p53', 'Gene', '7157', (14, 17))	('knock-down', 'Var', (41, 51))	('KLF5', 'Gene', (36, 40))	('vimentin', 'Gene', '7431', (157, 165))	('vimentin', 'Gene', (157, 165))
782902	32965165	Notably, KLF5 exhibited a significant cell migration-inhibitory effect in the context of p53 knock-down in both HepG2 and BEL-7402 cells (Figure 2(c)), which confirmed that p53 status determined the effect of KLF5 on liver cancer cell migration, possibly through EMT regulation.	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('p53', 'Gene', (173, 176))	('liver cancer', 'Disease', 'MESH:D006528', (217, 229))	('liver cancer', 'Phenotype', 'HP:0002896', (217, 229))	('HepG2', 'CellLine', 'CVCL:0027', (112, 117))	('BEL-7402', 'CellLine', 'CVCL:5492', (122, 130))	('cell migration-inhibitory', 'CPA', (38, 63))	('p53', 'Gene', '7157', (173, 176))	('p53', 'Gene', (89, 92))	('liver cancer', 'Disease', (217, 229))	('knock-down', 'Var', (93, 103))	('p53', 'Gene', '7157', (89, 92))	('determined', 'Reg', (184, 194))
782904	32965165	Our results show that the expression of Snail, Slug, Twist and ZEB1 was not significantly altered in these two cell lines after KLF5 overexpression and knock-down.	('Snail', 'Gene', (40, 45))	('Slug', 'Gene', (47, 51))	('Snail', 'Gene', '6615', (40, 45))	('ZEB1', 'Gene', '6935', (63, 67))	('Twist', 'Gene', '7291', (53, 58))	('knock-down', 'Var', (152, 162))	('ZEB1', 'Gene', (63, 67))	('Twist', 'Gene', (53, 58))	('Slug', 'Gene', '6591', (47, 51))
782907	32965165	However, the protein expression of ZEB2 was not obviously different after KLF5 overexpression or knock-down in the p53 wild type cell line HepG2 (Figure 3(a)).	('ZEB2', 'Gene', (35, 39))	('HepG2', 'CellLine', 'CVCL:0027', (139, 144))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('ZEB2', 'Gene', '9839', (35, 39))	('knock-down', 'Var', (97, 107))
782908	32965165	To confirm the regulatory effect of KLF5 on ZEB2 in the context of p53 loss, we knocked down p53, then overexpressed or knocked down KLF5 in HepG2 and BEL-7402 cells and examined ZEB2 expression.	('HepG2', 'CellLine', 'CVCL:0027', (141, 146))	('knocked', 'Var', (80, 87))	('ZEB2', 'Gene', (44, 48))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('ZEB2', 'Gene', '9839', (179, 183))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('knocked', 'Var', (120, 127))	('ZEB2', 'Gene', (179, 183))	('BEL-7402', 'CellLine', 'CVCL:5492', (151, 159))	('loss', 'NegReg', (71, 75))	('examined', 'Reg', (170, 178))	('KLF5', 'Gene', (133, 137))	('ZEB2', 'Gene', '9839', (44, 48))
782909	32965165	As shown in Figure 3(b), KLF5 knock-down increased ZEB2 protein expression in the context of p53 knock-down, while KLF5 overexpression decreased ZEB2 protein expression in both the p53 wild type cell lines HepG2 and BEL-7402 after p53 was knocked down.	('p53', 'Gene', (181, 184))	('p53', 'Gene', '7157', (181, 184))	('KLF5', 'Gene', (25, 29))	('ZEB2', 'Gene', (145, 149))	('increased', 'PosReg', (41, 50))	('ZEB2', 'Gene', '9839', (51, 55))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('BEL-7402', 'CellLine', 'CVCL:5492', (216, 224))	('p53', 'Gene', (231, 234))	('p53', 'Gene', '7157', (231, 234))	('decreased', 'NegReg', (135, 144))	('ZEB2', 'Gene', (51, 55))	('knock-down', 'Var', (97, 107))	('ZEB2', 'Gene', '9839', (145, 149))	('HepG2', 'CellLine', 'CVCL:0027', (206, 211))	('knock-down', 'Var', (30, 40))
782915	32965165	Therefore, we screened several p53-induced miRNAs that target ZEB2, including miR-200a, miR-200 c, miR-153 and miR-192, in HepG2 and Hep3B cells after KLF5 overexpression and knock-down (Figure 4(a)).	('miR-200a', 'Gene', (78, 86))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('miR-200a', 'Gene', '406983', (78, 86))	('HepG2', 'CellLine', 'CVCL:0027', (123, 128))	('miR-200 c', 'Gene', '406985', (88, 97))	('ZEB2', 'Gene', '9839', (62, 66))	('miR-200 c', 'Gene', (88, 97))	('miR-153', 'Var', (99, 106))	('ZEB2', 'Gene', (62, 66))	('miR-192', 'Gene', (111, 118))	('miR-192', 'Gene', '406967', (111, 118))	('Hep3B', 'CellLine', 'CVCL:0326', (133, 138))
782920	32965165	As shown in Figure 4(b), KLF5 knock-down decreased the expression of miR-192 in HepG2 and BEL-7402 cells after p53 silencing.	('HepG2', 'CellLine', 'CVCL:0027', (80, 85))	('KLF5', 'Gene', (25, 29))	('silencing', 'Var', (115, 124))	('decreased', 'NegReg', (41, 50))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('expression', 'MPA', (55, 65))	('miR-192', 'Gene', (69, 76))	('miR-192', 'Gene', '406967', (69, 76))	('BEL-7402', 'CellLine', 'CVCL:5492', (90, 98))	('knock-down', 'Var', (30, 40))
782929	32965165	Actually, using chromatin immunoprecipitation (ChIP), we observed a reciprocal increase in KLF5 binding to miR-192 after p53 knock-down in HepG2 and BEL-7402 cells (Figure 5(b)).	('increase', 'PosReg', (79, 87))	('p53', 'Gene', (121, 124))	('HepG2', 'CellLine', 'CVCL:0027', (139, 144))	('KLF5 binding', 'MPA', (91, 103))	('p53', 'Gene', '7157', (121, 124))	('knock-down', 'Var', (125, 135))	('miR-192', 'Gene', (107, 114))	('miR-192', 'Gene', '406967', (107, 114))	('BEL-7402', 'CellLine', 'CVCL:5492', (149, 157))
782932	32965165	Thus, KLF5 loss might be a critical event in human liver cancer invasion in the context of p53 loss or mutation.	('liver cancer', 'Phenotype', 'HP:0002896', (51, 63))	('loss', 'NegReg', (11, 15))	('liver cancer', 'Disease', 'MESH:D006528', (51, 63))	('human', 'Species', '9606', (45, 50))	('liver cancer', 'Disease', (51, 63))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutation', 'Var', (103, 111))	('loss', 'NegReg', (95, 99))	('KLF5', 'Protein', (6, 10))
782933	32965165	Therefore, we used IHC to examine KLF5 expression in liver cancers with and without metastasis in which p53 was lost or mutated.	('liver cancers', 'Disease', (53, 66))	('liver cancers', 'Disease', 'MESH:D006528', (53, 66))	('p53', 'Gene', (104, 107))	('lost', 'NegReg', (112, 116))	('p53', 'Gene', '7157', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('liver cancer', 'Phenotype', 'HP:0002896', (53, 65))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('liver cancers', 'Phenotype', 'HP:0002896', (53, 66))	('mutated', 'Var', (120, 127))
782935	32965165	However, in a case of liver cancer without metastasis (Figure 6(b)), although p53 was mutated in the tumor tissue (elevated and stable protein expression of mutated p53), KLF5 was still positively expressed in the tumor tissue.	('p53', 'Gene', (165, 168))	('elevated', 'PosReg', (115, 123))	('liver cancer', 'Disease', 'MESH:D006528', (22, 34))	('p53', 'Gene', '7157', (165, 168))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('liver cancer', 'Disease', (22, 34))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('p53', 'Gene', (78, 81))	('tumor', 'Disease', (214, 219))	('liver cancer', 'Phenotype', 'HP:0002896', (22, 34))	('mutated', 'Var', (157, 164))	('p53', 'Gene', '7157', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
782939	32965165	Those results suggested that, in the context of p53 loss or mutation, KLF5 loss could be a valuable diagnostic target for invasive liver cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('p53', 'Gene', (48, 51))	('mutation', 'Var', (60, 68))	('loss', 'NegReg', (52, 56))	('p53', 'Gene', '7157', (48, 51))	('KLF5', 'Gene', (70, 74))	('liver cancer', 'Phenotype', 'HP:0002896', (131, 143))	('invasive liver cancer', 'Disease', (122, 143))	('loss', 'NegReg', (75, 79))	('invasive liver cancer', 'Disease', 'MESH:D006528', (122, 143))
782940	32965165	Here, we demonstrate that the regulation of liver cancer cell epithelial-mesenchymal transition (EMT) by KLF5 is context-dependent, and specifically, that the function of KLF5 in liver cancer cell EMT requires p53 mutation or loss.	('liver cancer', 'Disease', (44, 56))	('p53', 'Gene', '7157', (210, 213))	('mutation', 'Var', (214, 222))	('liver cancer', 'Disease', 'MESH:D006528', (179, 191))	('liver cancer', 'Phenotype', 'HP:0002896', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('liver cancer', 'Disease', (179, 191))	('liver cancer', 'Phenotype', 'HP:0002896', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('loss', 'NegReg', (226, 230))	('liver cancer', 'Disease', 'MESH:D006528', (44, 56))	('p53', 'Gene', (210, 213))
782941	32965165	Specifically, KLF5 promotes the migration of bladder cancer cells, breast cancer cells, mouse primary esophageal keratinocytes, bronchial smooth muscle cells and intestinal epithelial cells; in contrast, KLF5 inhibits the migration of HaCaT cells, MCF-10A cells and mouse PDA cells.	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('inhibits', 'NegReg', (209, 217))	('HaCaT cells', 'CellLine', 'CVCL:0038', (235, 246))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('MCF-10A', 'CellLine', 'CVCL:0598', (248, 255))	('migration', 'CPA', (222, 231))	('KLF5', 'Var', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mouse', 'Species', '10090', (88, 93))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('mouse', 'Species', '10090', (266, 271))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))	('bladder cancer', 'Disease', (45, 59))
782942	32965165	Notably, an earlier study revealed that, after KLF5 knock-down, cell migration could occur and EMT-related genes could be expressed only if p53 was mutated or if its expression was ablated.	('occur', 'Reg', (85, 90))	('mutated', 'Var', (148, 155))	('expressed', 'MPA', (122, 131))	('knock-down', 'Var', (52, 62))	('EMT-related genes', 'Gene', (95, 112))	('p53', 'Gene', (140, 143))	('cell migration', 'CPA', (64, 78))	('p53', 'Gene', '7157', (140, 143))
782943	32965165	We also observed that the effect of KLF5 on liver cancer cell migration and EMT was dependent on the silencing or loss of p53, which was consistent with the results of previous studies.	('liver cancer', 'Disease', (44, 56))	('EMT', 'CPA', (76, 79))	('silencing', 'Var', (101, 110))	('loss', 'NegReg', (114, 118))	('p53', 'Gene', '7157', (122, 125))	('liver cancer', 'Phenotype', 'HP:0002896', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('liver cancer', 'Disease', 'MESH:D006528', (44, 56))	('p53', 'Gene', (122, 125))
782953	32965165	For example, p53 can regulate EMT through the targeting of ZEB1 by miR-200s and the targeting of ZEB2 by miR-192.	('miR-192', 'Gene', '406967', (105, 112))	('ZEB2', 'Gene', (97, 101))	('ZEB1', 'Gene', '6935', (59, 63))	('regulate', 'Reg', (21, 29))	('EMT', 'CPA', (30, 33))	('ZEB2', 'Gene', '9839', (97, 101))	('ZEB1', 'Gene', (59, 63))	('p53', 'Gene', (13, 16))	('miR-200s', 'Var', (67, 75))	('p53', 'Gene', '7157', (13, 16))	('miR-192', 'Gene', (105, 112))
782958	32965165	In addition, the target of miR-200s is usually ZEB1, and we did not observe any significant change in ZEB1 expression after KLF5 was altered in p53 wild type and p53-null liver cancer cells.	('miR-200s', 'Var', (27, 35))	('p53', 'Gene', '7157', (144, 147))	('p53', 'Gene', (162, 165))	('liver cancer', 'Disease', (171, 183))	('ZEB1', 'Gene', (47, 51))	('ZEB1', 'Gene', '6935', (102, 106))	('p53', 'Gene', '7157', (162, 165))	('ZEB1', 'Gene', '6935', (47, 51))	('liver cancer', 'Disease', 'MESH:D006528', (171, 183))	('ZEB1', 'Gene', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('liver cancer', 'Phenotype', 'HP:0002896', (171, 183))	('p53', 'Gene', (144, 147))	('altered', 'Reg', (133, 140))
782961	32965165	Almost 80% of p53 mutations in cancer are missense, which results in the synthesis of a stable protein that lacks typical DNA binding activity.	('synthesis of', 'MPA', (73, 85))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('missense', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('results in', 'Reg', (58, 68))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (18, 27))
782964	32965165	Consistently, in invasive esophageal squamous carcinomas in which p53 is mutated or lost early in esophageal tumorigenesis, KLF5 expression is markedly decreased.	('KLF5', 'Protein', (124, 128))	('invasive esophageal squamous carcinomas', 'Disease', (17, 56))	('mutated', 'Var', (73, 80))	('p53', 'Gene', '7157', (66, 69))	('invasive esophageal squamous carcinomas', 'Disease', 'MESH:D000077277', (17, 56))	('p53', 'Gene', (66, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('decreased', 'NegReg', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('lost', 'NegReg', (84, 88))	('tumor', 'Disease', (109, 114))
782965	32965165	Thus, KLF5 loss combined with p53 loss or mutation might be a valuable diagnostic target in invasive cancer.	('loss', 'NegReg', (11, 15))	('invasive cancer', 'Disease', (92, 107))	('p53', 'Gene', (30, 33))	('mutation', 'Var', (42, 50))	('p53', 'Gene', '7157', (30, 33))	('invasive cancer', 'Disease', 'MESH:D009362', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('loss', 'NegReg', (34, 38))	('KLF5', 'Protein', (6, 10))
782966	32965165	In conclusion, we propose a model (Figure 7) in which p53 normally binds to miR-192 but where KLF5 can also bind to miR-192 when p53 binding is lost (as a result of p53 loss or mutation), which then transactivates miR-192 in place of p53 to suppress liver cancer cell EMT.	('p53', 'Gene', (234, 237))	('lost', 'NegReg', (144, 148))	('miR-192', 'Gene', (116, 123))	('liver cancer', 'Phenotype', 'HP:0002896', (250, 262))	('p53', 'Gene', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('miR-192', 'Gene', (76, 83))	('liver cancer', 'Disease', (250, 262))	('miR-192', 'Gene', '406967', (214, 221))	('suppress', 'NegReg', (241, 249))	('transactivates', 'PosReg', (199, 213))	('p53', 'Gene', '7157', (54, 57))	('mutation', 'Var', (177, 185))	('p53', 'Gene', '7157', (165, 168))	('miR-192', 'Gene', '406967', (116, 123))	('loss', 'NegReg', (169, 173))	('p53', 'Gene', (54, 57))	('miR-192', 'Gene', '406967', (76, 83))	('miR-192', 'Gene', (214, 221))	('p53', 'Gene', '7157', (234, 237))	('p53', 'Gene', (165, 168))	('liver cancer', 'Disease', 'MESH:D006528', (250, 262))	('p53', 'Gene', '7157', (129, 132))
782969	32965165	Thus, our findings explain the mechanisms of the p53-dependent effect of KLF5 on liver cancer cell EMT and suggest that KLF5 loss is a valuable diagnostic and therapeutic target for invasive liver cancer, and potentially for other cancers associated with p53 loss or mutation.	('invasive liver cancer', 'Disease', (182, 203))	('mutation', 'Var', (267, 275))	('loss', 'NegReg', (125, 129))	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (255, 258))	('p53', 'Gene', (49, 52))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Disease', (231, 238))	('liver cancer', 'Disease', 'MESH:D006528', (191, 203))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('liver cancer', 'Disease', 'MESH:D006528', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('liver cancer', 'Phenotype', 'HP:0002896', (191, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('liver cancer', 'Phenotype', 'HP:0002896', (81, 93))	('KLF5', 'Gene', (120, 124))	('invasive liver cancer', 'Disease', 'MESH:D006528', (182, 203))	('liver cancer', 'Disease', (81, 93))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('p53', 'Gene', '7157', (255, 258))
783008	31611995	In addition, high mRNA expression of the three transketolase genes was identified to be associated with poorer progression-free survival (PFS) in patients with serous ovarian cancer, especially in patients at an advanced stage.	('patients', 'Species', '9606', (197, 205))	('high', 'Var', (13, 17))	('serous ovarian cancer', 'Disease', (160, 181))	('progression-free survival', 'CPA', (111, 136))	('poorer', 'NegReg', (104, 110))	('transketolase', 'Gene', '7086', (47, 60))	('ovarian cancer', 'Phenotype', 'HP:0100615', (167, 181))	('transketolase', 'Gene', (47, 60))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (160, 181))	('mRNA expression', 'MPA', (18, 33))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
783026	31611995	Overexpression of these genes is associated with poor outcome of patients with esophageal, lung, gastric, breast, colon and urothelial cancer.	('lung', 'Disease', (91, 95))	('breast', 'Disease', (106, 112))	('esophageal', 'Disease', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('gastric', 'Disease', (97, 104))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (65, 73))	('colon and urothelial cancer', 'Disease', 'MESH:D015179', (114, 141))
783027	31611995	Aberrant expression of transketolase family genes has also been observed in ovarian cancer.	('ovarian cancer', 'Disease', (76, 90))	('Aberrant', 'Var', (0, 8))	('observed', 'Reg', (64, 72))	('transketolase', 'Gene', '7086', (23, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('transketolase', 'Gene', (23, 36))	('expression', 'MPA', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ovarian cancer', 'Disease', 'MESH:D010051', (76, 90))
783061	31611995	High TKT expression was also associated with poor PFS in serous ovarian cancer (HR, 1.27; 95% CI, 1.10-1.47; P=0.0010).	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('serous ovarian cancer', 'Disease', (57, 78))	('expression', 'MPA', (9, 19))	('TKT', 'Gene', '7086', (5, 8))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))	('TKT', 'Gene', (5, 8))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (57, 78))
783066	31611995	No differences were observed in PFS between the high and low-TKTL1 expression groups in all patients with ovarian cancer (Fig.	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('patients', 'Species', '9606', (92, 100))	('ovarian cancer', 'Disease', (106, 120))	('TKTL1', 'Gene', '8277', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('high', 'Var', (48, 52))	('TKTL1', 'Gene', (61, 66))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))
783067	31611995	However, stratified analyses demonstrated that high expression of TKTL1 was associated with poor PFS in patients with serous ovarian cancer (HR, 1.27; 95% CI, 1.08-1.50; P=0.0036; Fig.	('TKTL1', 'Gene', '8277', (66, 71))	('PFS', 'Disease', (97, 100))	('poor', 'NegReg', (92, 96))	('high expression', 'Var', (47, 62))	('TKTL1', 'Gene', (66, 71))	('serous ovarian cancer', 'Disease', (118, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (118, 139))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
783076	31611995	High expression of TKTL2 was associated with OS in all patients with ovarian cancer (HR, 1.38; 95% CI, 1.07-1.76; P=0.0110; Fig.	('ovarian cancer', 'Disease', (69, 83))	('High', 'Var', (0, 4))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('TKTL2', 'Gene', (19, 24))	('TKTL2', 'Gene', '84076', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (55, 63))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))	('associated with', 'Reg', (29, 44))
783084	31611995	In addition, high levels of TKTL1 and TKTL2 were associated with poor PFS in patients with ovarian cancer treated with taxol chemotherapy (Table IV).	('TKTL2', 'Gene', '84076', (38, 43))	('TKTL2', 'Gene', (38, 43))	('ovarian cancer', 'Disease', 'MESH:D010051', (91, 105))	('high', 'Var', (13, 17))	('TKTL1', 'Gene', (28, 33))	('PFS', 'Disease', (70, 73))	('ovarian cancer', 'Disease', (91, 105))	('patients', 'Species', '9606', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('poor', 'NegReg', (65, 69))	('taxol', 'Chemical', 'MESH:D017239', (119, 124))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('TKTL1', 'Gene', '8277', (28, 33))
783095	31611995	Further analysis of the association between TKT expression and clinical parameters identified that TKT expression was associated with breast cancer stage and grade, patient age, and tumor size and type; in addition, patients with high TKT expression exhibited a worse outcome compared with that observed in the low-TKT expression group.	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('high', 'Var', (230, 234))	('patient', 'Species', '9606', (216, 223))	('TKT', 'Gene', '7086', (315, 318))	('TKT', 'Gene', (315, 318))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('breast cancer', 'Disease', (134, 147))	('TKT', 'Gene', '7086', (235, 238))	('TKT', 'Gene', '7086', (99, 102))	('TKT', 'Gene', '7086', (44, 47))	('associated', 'Reg', (118, 128))	('TKT', 'Gene', (44, 47))	('TKT', 'Gene', (235, 238))	('TKT', 'Gene', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('patient', 'Species', '9606', (165, 172))	('patients', 'Species', '9606', (216, 224))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
783103	31611995	Only one study is available concerning the prognostic values of TKT in ovarian cancer, which reported that patients with high nuclear TKT expression in peritoneal metastases exhibited shorter OS time compared with that of patients with low TKT protein levels.	('TKT', 'Gene', (64, 67))	('TKT', 'Gene', (134, 137))	('patients', 'Species', '9606', (107, 115))	('TKT', 'Gene', '7086', (240, 243))	('ovarian cancer', 'Disease', 'MESH:D010051', (71, 85))	('metastases', 'Disease', (163, 173))	('TKT', 'Gene', (240, 243))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ovarian cancer', 'Disease', (71, 85))	('patients', 'Species', '9606', (222, 230))	('OS time', 'CPA', (192, 199))	('metastases', 'Disease', 'MESH:D009362', (163, 173))	('TKT', 'Gene', '7086', (64, 67))	('shorter', 'NegReg', (184, 191))	('TKT', 'Gene', '7086', (134, 137))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))	('high nuclear', 'Var', (121, 133))
783107	31611995	In addition, high TKT mRNA expression was associated with poor PFS in all patients with ovarian cancer, as well as in patients with serous-type ovarian cancer.	('mRNA expression', 'MPA', (22, 37))	('TKT', 'Gene', '7086', (18, 21))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('high', 'Var', (13, 17))	('TKT', 'Gene', (18, 21))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ovarian cancer', 'Disease', (88, 102))	('PFS', 'MPA', (63, 66))	('serous-type ovarian cancer', 'Disease', (132, 158))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('serous-type ovarian cancer', 'Disease', 'MESH:D010051', (132, 158))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('poor', 'NegReg', (58, 62))	('patients', 'Species', '9606', (118, 126))	('ovarian cancer', 'Disease', 'MESH:D010051', (88, 102))
783112	31611995	Lin et al demonstrated that the knockdown of TKT prevents vascular endothelial growth factor secretion and inhibits cell proliferation in lung cancer.	('TKT', 'Gene', '7086', (45, 48))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('TKT', 'Gene', (45, 48))	('vascular endothelial growth factor', 'Gene', (58, 92))	('knockdown', 'Var', (32, 41))	('inhibits', 'NegReg', (107, 115))	('vascular endothelial growth factor', 'Gene', '7422', (58, 92))	('prevents', 'NegReg', (49, 57))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('cell proliferation in', 'CPA', (116, 137))
783115	31611995	High expression levels of TKTL1 have been reported to be a significant indicator of poor outcome in colorectal and gastric cancer, esophageal squamous cell carcinoma, and locally advanced rectal and non-small cell lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (199, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('High', 'Var', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('colorectal and gastric cancer', 'Disease', 'MESH:D015179', (100, 129))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (199, 225))	('TKTL1', 'Gene', '8277', (26, 31))	('non-small cell lung cancer', 'Disease', (199, 225))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))	('esophageal squamous cell carcinoma', 'Disease', (131, 165))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (131, 165))	('TKTL1', 'Gene', (26, 31))
783122	31611995	In addition, high TKTL1 mRNA expression levels were significantly associated with poor PFS in patients with serous and endometrioid ovarian cancer.	('serous', 'Disease', (108, 114))	('TKTL1', 'Gene', '8277', (18, 23))	('PFS', 'Disease', (87, 90))	('TKTL1', 'Gene', (18, 23))	('patients', 'Species', '9606', (94, 102))	('high', 'Var', (13, 17))	('endometrioid ovarian cancer', 'Disease', (119, 146))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('poor PFS', 'Disease', (82, 90))	('endometrioid ovarian cancer', 'Disease', 'MESH:D010051', (119, 146))
783134	31611995	By contrast, high TKTL2 mRNA expression was significantly associated with poor PFS and OS in all patients with ovarian cancer.	('ovarian cancer', 'Disease', (111, 125))	('TKTL2', 'Gene', (18, 23))	('associated', 'Reg', (58, 68))	('TKTL2', 'Gene', '84076', (18, 23))	('high', 'Var', (13, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('poor PFS', 'Disease', (74, 82))	('mRNA expression', 'MPA', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (97, 105))
783148	31611995	Yang et al also demonstrated that silencing of TKT significantly reduced cell viability and increased apoptosis in the presence of platinum via glutathione depletion and reactive oxygen species generation in cervical cancer.	('cervical cancer', 'Disease', (208, 223))	('reduced', 'NegReg', (65, 72))	('platinum', 'Chemical', 'MESH:D010984', (131, 139))	('apoptosis', 'CPA', (102, 111))	('cell viability', 'CPA', (73, 87))	('glutathione depletion', 'MPA', (144, 165))	('reactive oxygen species generation', 'MPA', (170, 204))	('oxygen', 'Chemical', 'MESH:D010100', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('increased', 'PosReg', (92, 101))	('TKT', 'Gene', '7086', (47, 50))	('silencing', 'Var', (34, 43))	('cervical cancer', 'Disease', 'MESH:D002583', (208, 223))	('glutathione', 'Chemical', 'MESH:D005978', (144, 155))	('TKT', 'Gene', (47, 50))
783151	31611995	Mechanistically, following TKTL1 knockdown, NADPH levels were reduced and NADP+ levels were increased compared with the levels in the control group, which led to taxol sensitivity in ovarian cancer.	('NADPH', 'Gene', (44, 49))	('TKTL1', 'Gene', '8277', (27, 32))	('ovarian cancer', 'Disease', (183, 197))	('TKTL1', 'Gene', (27, 32))	('led to', 'Reg', (155, 161))	('knockdown', 'Var', (33, 42))	('NADPH', 'Gene', '1666', (44, 49))	('taxol', 'Chemical', 'MESH:D017239', (162, 167))	('ovarian cancer', 'Disease', 'MESH:D010051', (183, 197))	('increased', 'PosReg', (92, 101))	('NADP', 'Chemical', 'MESH:D009249', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('NADP', 'Chemical', 'MESH:D009249', (44, 48))	('taxol sensitivity', 'MPA', (162, 179))	('ovarian cancer', 'Phenotype', 'HP:0100615', (183, 197))	('reduced', 'NegReg', (62, 69))	('NADP+ levels', 'MPA', (74, 86))
783154	31611995	Mutation or loss of function of the TP53 gene is a frequent and important genetic alteration in the development of ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Mutation', 'Var', (0, 8))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('TP53', 'Gene', '7157', (36, 40))	('loss of function', 'NegReg', (12, 28))	('ovarian cancer', 'Disease', 'MESH:D010051', (115, 129))	('TP53', 'Gene', (36, 40))	('ovarian cancer', 'Disease', (115, 129))
783161	31611995	High mRNA expression of the above three transketolase genes was demonstrated to be associated with poor PFS in patients with serous ovarian cancer, especially those at an advanced clinical stage.	('PFS', 'Disease', (104, 107))	('High', 'Var', (0, 4))	('serous ovarian cancer', 'Disease', (125, 146))	('mRNA expression', 'MPA', (5, 20))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (125, 146))	('poor', 'NegReg', (99, 103))	('transketolase', 'Gene', '7086', (40, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('transketolase', 'Gene', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('patients', 'Species', '9606', (111, 119))
783195	31190995	Pembrolizumab is also authorized in the United States in the treatment of mismatch repair-deficient tumors or with microsatellite instability.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('microsatellite instability', 'Var', (115, 141))	('deficient tumors', 'Disease', (90, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('deficient tumors', 'Disease', 'MESH:D009369', (90, 106))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))
783225	31190995	Following KEYNOTE-010, pembrolizumab was approved in 2015 in second line for PD-L1-positive (Tumor proportion score (TPS) >=1%) NSCLC pre-treated by chemotherapy or tyrosine kinase inhibitor (TKI) if epidermal growth factor receptor (EGFR) mutated or anaplastic lymphoma kinase (ALK)-rearranged.	('ALK', 'Gene', '238', (279, 282))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('EGFR', 'Gene', (234, 238))	('mutated', 'Var', (240, 247))	('anaplastic lymphoma kinase', 'Gene', '238', (251, 277))	('epidermal growth factor receptor', 'Gene', (200, 232))	('Tumor', 'Phenotype', 'HP:0002664', (93, 98))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (251, 270))	('PD-L1', 'Gene', (77, 82))	('NSCLC', 'Disease', (128, 133))	('pembrolizumab', 'Chemical', 'MESH:C582435', (23, 36))	('PD-L1', 'Gene', '29126', (77, 82))	('ALK', 'Gene', (279, 282))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('anaplastic lymphoma kinase', 'Gene', (251, 277))	('epidermal growth factor receptor', 'Gene', '1956', (200, 232))	('lymphoma', 'Phenotype', 'HP:0002665', (262, 270))	('EGFR', 'Gene', '1956', (234, 238))
783268	31190995	Two phase II (NCT02607631 and NCT02364076) showed an interesting ORR (24.2% and 22.5%) with pembrolizumab in that context.	('NCT02364076', 'Var', (30, 41))	('pembrolizumab', 'Chemical', 'MESH:C582435', (92, 105))	('NCT02607631', 'Var', (14, 25))
783288	31190995	POLE (polymerase E) mutated (6-12%) and MSI endometrial tumors exhibited significantly elevated TILs, high expression of PD-1 and PD-L1 and greater peritumoral T-lymphocytes supporting trials of immune-checkpoint inhibitors.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('greater', 'PosReg', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (56, 61))	('expression', 'MPA', (107, 117))	('tumor', 'Disease', (152, 157))	('PD-L1', 'Gene', (130, 135))	('PD-1', 'Gene', (121, 125))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('MSI endometrial tumors', 'Disease', 'MESH:D016889', (40, 62))	('PD-1', 'Gene', '5133', (121, 125))	('TILs', 'MPA', (96, 100))	('PD-L1', 'Gene', '29126', (130, 135))	('MSI endometrial tumors', 'Disease', (40, 62))	('elevated', 'PosReg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('mutated', 'Var', (20, 27))
783294	31190995	Homologous recombination deficiencies are a frequent hallmark of serous high-grade ovarian cancer leading to the approval of PARP inhibitors.	('Homologous recombination deficiencies', 'Var', (0, 37))	('PARP', 'Gene', '1302', (125, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('PARP', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ovarian cancer', 'Disease', (83, 97))
783300	31190995	The phase II KEYNOTE-016 was conducted to evaluate pembrolizumab in metastatic CRC with (MMR deficient) or without (MMR proficient) MMR deficiency: The ORR was much higher in MMRd tumor: 40% vs 0%, as was PFS rate: 78 vs 11% for MMR deficient and proficient patients.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('MMR deficiency', 'Disease', (132, 146))	('CR', 'Chemical', '-', (79, 81))	('MMR deficiency', 'Disease', 'MESH:C536143', (132, 146))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('pembrolizumab', 'Chemical', 'MESH:C582435', (51, 64))	('MMRd', 'Var', (175, 179))	('tumor', 'Disease', (180, 185))	('higher', 'PosReg', (165, 171))	('ORR', 'MPA', (152, 155))	('patients', 'Species', '9606', (258, 266))	('metastatic CRC', 'Disease', (68, 82))
783337	31190995	A retrospective study of various tumor types showed that mutational load and T-cell-inflamed microenvironment were predictors of response to pembrolizumab.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('pembrolizumab', 'Chemical', 'MESH:C582435', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutational load', 'Var', (57, 72))	('tumor', 'Disease', (33, 38))
783338	31190995	Another retrospective study including various tumor types demonstrated that a threshold of >=20 mutations/megabase was associated with improved ORR, PFS, and OS .	('mutations/megabase', 'Var', (96, 114))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PFS', 'Disease', (149, 152))	('tumor', 'Disease', (46, 51))	('improved', 'PosReg', (135, 143))	('OS', 'Chemical', '-', (158, 160))	('ORR', 'Disease', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
783340	31190995	An analysis of tumor mutational load in 100,000 cancer genomes identified a novel mutation hotspot in the promoter of the DNA mismatch repair gene PMS2, that was significantly associated with high tumor mutational load.	('PMS2', 'Gene', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('PMS2', 'Gene', '5395', (147, 151))	('mutation', 'Var', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('associated', 'Reg', (176, 186))	('tumor', 'Disease', (15, 20))	('100,000 cancer', 'Disease', 'MESH:D009369', (40, 54))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))
783341	31190995	Whole-exome sequencing also showed that MMR deficient tumors are largely most mutated than MMR proficient tumors (1782 vs 73 somatic mutations per tumors, P=0.007) associated with prolonged PFS for high somatic mutational load.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PFS', 'Var', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('deficient tumors', 'Disease', (44, 60))	('tumors', 'Disease', (54, 60))	('deficient tumors', 'Disease', 'MESH:D009369', (44, 60))
783379	30596104	Results indicated that PT shows more effective antitumor activity as compared with Pan both on EGFR-overexpressed KYSE-450 and KYSE-150 esophageal cancer cells, especially on KYSE-450 cells.	('esophageal cancer', 'Disease', (136, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (136, 153))	('Pan', 'Gene', '51816', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PT', 'Chemical', '-', (23, 25))	('tumor', 'Disease', (51, 56))	('KYSE-150', 'Var', (127, 135))	('EGFR', 'Gene', '1956', (95, 99))	('Pan', 'Gene', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('EGFR', 'Gene', (95, 99))
783396	30596104	Recently, several studies revealed that EGFR or HER2 inhibitors may exhibit antitumor effects in association with persistent promotion of reactive oxygen species (ROS) generation and induced apoptosis.	('inhibitors', 'Var', (53, 63))	('apoptosis', 'CPA', (191, 200))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (138, 161))	('HER2', 'Gene', '2064', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('promotion', 'PosReg', (125, 134))	('tumor', 'Disease', (80, 85))	('ROS', 'Chemical', 'MESH:D017382', (163, 166))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('HER2', 'Gene', (48, 52))
783407	30596104	As previously reported, the variable region of heavy chain and light chain (scFv) of Pan was cloned into the pET-28a(+) vector containing PE38KDEL fragment, respectively.	('Pan', 'Gene', (85, 88))	('PE38KDEL fragment', 'Var', (138, 155))	('Pan', 'Gene', '51816', (85, 88))	('scFv', 'Gene', '652070', (76, 80))	('scFv', 'Gene', (76, 80))
783456	30596104	As shown in Figures 5(a) and 5(b), the percentage of apoptotic cells was significantly increased in the PT-treated cells compared to Pan-treated cells.	('increased', 'PosReg', (87, 96))	('PT', 'Chemical', '-', (104, 106))	('Pan', 'Gene', (133, 136))	('Pan', 'Gene', '51816', (133, 136))	('PT-treated', 'Var', (104, 114))
783483	30596104	Clearly, significant elevation of ROS accumulation was verified in PT-treated KYSE-450 cells compared to Pan-treated cells.	('Pan', 'Gene', (105, 108))	('ROS', 'Chemical', 'MESH:D017382', (34, 37))	('Pan', 'Gene', '51816', (105, 108))	('ROS accumulation', 'MPA', (34, 50))	('PT', 'Chemical', '-', (67, 69))	('elevation of ROS accumulation', 'Phenotype', 'HP:0025464', (21, 50))	('elevation', 'PosReg', (21, 30))	('PT-treated', 'Var', (67, 77))
783511	30364838	Caustic injury occurs when substance with pH < 2 or pH > 12 is ingested.	('pH < 2', 'Var', (42, 48))	('Caustic injury', 'Disease', 'MESH:D058186', (0, 14))	('pH > 12', 'Var', (52, 59))	('Caustic injury', 'Disease', (0, 14))
783528	30364838	The patients with grade IIIb had longer hospital stay and higher rates of complication compared than those with grade IIIa.	('complication', 'CPA', (74, 86))	('patients', 'Species', '9606', (4, 12))	('grade IIIb', 'Var', (18, 28))
783543	30364838	Patients at risks for stricture were those with high endoscopic grade, ingestion of strong acid or alkali, leukocytosis and low thrombin ratio.	('leukocytosis', 'Phenotype', 'HP:0001974', (107, 119))	('thrombin', 'Gene', (128, 136))	('leukocytosis', 'Disease', (107, 119))	('leukocytosis', 'Disease', 'MESH:D007964', (107, 119))	('low thrombin ratio', 'Phenotype', 'HP:0011900', (124, 142))	('ingestion', 'Var', (71, 80))	('stricture', 'Disease', (22, 31))	('thrombin', 'Gene', '2147', (128, 136))	('Patients', 'Species', '9606', (0, 8))	('low', 'Var', (124, 127))
783554	30364838	Injection of mitomycin-C into the stricture site was shown to improve dysphagia score and easy passage of dilators because mitomycin-C inhibited fibroblast proliferation and scar formation without interfering wound healing.	('scar', 'Phenotype', 'HP:0100699', (174, 178))	('scar formation', 'CPA', (174, 188))	('mitomycin-C', 'Chemical', 'MESH:D016685', (123, 134))	('mitomycin-C', 'Chemical', 'MESH:D016685', (13, 24))	('improve', 'PosReg', (62, 69))	('dysphagia', 'Disease', (70, 79))	('dysphagia', 'Phenotype', 'HP:0002015', (70, 79))	('mitomycin-C', 'Var', (123, 134))	('easy passage of dilators', 'MPA', (90, 114))	('dysphagia', 'Disease', 'MESH:D003680', (70, 79))	('inhibited', 'NegReg', (135, 144))	('fibroblast proliferation', 'CPA', (145, 169))
783592	28427178	There are seventeen studies used antibody of FOXM1 with clone sc-502, one study used clone K-19 and four studies did not report the antibody clone.	('FOXM1', 'Gene', '2305', (45, 50))	('used', 'Reg', (28, 32))	('clone sc-502', 'Var', (56, 68))	('FOXM1', 'Gene', (45, 50))
783595	28427178	Results of 8 studies showed that FOXM1 expression was associated with statistically significant poor 3-year DFS (OR = 3.01, 95% CI = 2.21 to 4.12, P < 0.00001), 5-year DFS (OR = 3.22, 95% CI = 2.34 to 4.41, P < 0.00001) and 10-year DFS (OR = 4.41, 95% CI = 1.56 to 12.43, P = 0.005) (Figure 3).	('FOXM1', 'Gene', (33, 38))	('FOXM1', 'Gene', '2305', (33, 38))	('poor', 'NegReg', (96, 100))	('expression', 'Var', (39, 49))
783596	28427178	In the stratified analysis by tumor types, FOXM1 expression was associated with worse 3-year OS of colorectal cancer (OR = 2.56, 95% CI = 1.40 to 4.69, P = 0.002), gastric cancer (OR = 2.85, 95% CI = 1.36 to 5.99, P = 0.006), hepatic cancer (OR = 5.04, 95% CI = 3.17 to 8.02, P < 0.00001), lung cancer (OR = 5.51, 95% CI = 2.98 to 10.19, P < 0.00001) and ovarian cancer (OR = 2.34, 95% CI = 1.30 to 4.20, P = 0.005) (Figure 4).	('lung cancer', 'Phenotype', 'HP:0100526', (290, 301))	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('colorectal cancer', 'Disease', (99, 116))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('ovarian cancer', 'Phenotype', 'HP:0100615', (355, 369))	('hepatic cancer', 'Disease', 'MESH:D008113', (226, 240))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('hepatic cancer', 'Phenotype', 'HP:0002896', (226, 240))	('FOXM1', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('gastric cancer', 'Disease', (164, 178))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))	('lung cancer', 'Disease', (290, 301))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('ovarian cancer', 'Disease', 'MESH:D010051', (355, 369))	('expression', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('hepatic cancer', 'Disease', (226, 240))	('FOXM1', 'Gene', '2305', (43, 48))	('lung cancer', 'Disease', 'MESH:D008175', (290, 301))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('tumor', 'Disease', (30, 35))	('ovarian cancer', 'Disease', (355, 369))
783597	28427178	Consistent with this 3-year OS, FOXM1 expression was associated with worse 5-year OS of gastric cancer (OR = 3.98, 95% CI = 1.74 to 9.12, P = 0.001), hepatic cancer (OR = 3.32, 95% CI = 2.22 to 4.95, P < 0.00001), lung cancer (OR = 8.27, 95% CI = 4.86 to 14.05, P < 0.00001) and ovarian cancer (OR = 3.33, 95% CI = 1.80 to 6.15, P = 0.0001) (Figure 5).	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('lung cancer', 'Disease', (214, 225))	('to 9', 'Species', '1214577', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('FOXM1', 'Gene', '2305', (32, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (279, 293))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('hepatic cancer', 'Disease', (150, 164))	('lung cancer', 'Disease', 'MESH:D008175', (214, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('ovarian cancer', 'Disease', (279, 293))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('gastric cancer', 'Disease', (88, 102))	('FOXM1', 'Gene', (32, 37))	('hepatic cancer', 'Disease', 'MESH:D008113', (150, 164))	('expression', 'Var', (38, 48))	('ovarian cancer', 'Phenotype', 'HP:0100615', (279, 293))	('hepatic cancer', 'Phenotype', 'HP:0002896', (150, 164))
783600	28427178	High expression level of FOXM1 was significantly associated with advanced TNM stage (OR = 2.78, 95% CI = 1.64 to 4.71, P = 0.0002) (Figure 6).	('FOXM1', 'Gene', '2305', (25, 30))	('High', 'Var', (0, 4))	('TNM', 'Gene', (74, 77))	('associated', 'Reg', (49, 59))	('advanced', 'CPA', (65, 73))	('TNM', 'Gene', '10178', (74, 77))	('FOXM1', 'Gene', (25, 30))
783606	28427178	Our study demonstrated that the expression of FOXM1 is a potential biomarker of poor prognosis in most solid tumors, with consistent results of both OS and DFS at 3, 5 and 10 years.	('FOXM1', 'Gene', '2305', (46, 51))	('FOXM1', 'Gene', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('expression', 'Var', (32, 42))	('solid tumors', 'Disease', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))
783612	28427178	However, deregulated FOXM1 signalling in cancer is involved in cell migration, invasion, angiogenesis, stem cell renewal, DNA damage repair and cellular senescence, which impact tumor initiation, progression, metastasis, angiogenesis and drug resistance.	('drug resistance', 'CPA', (238, 253))	('cancer', 'Disease', (41, 47))	('FOXM1', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('impact tumor initiation', 'Disease', (171, 194))	('angiogenesis', 'CPA', (89, 101))	('deregulated', 'Var', (9, 20))	('angiogenesis', 'CPA', (221, 233))	('cellular senescence', 'CPA', (144, 163))	('drug resistance', 'Phenotype', 'HP:0020174', (238, 253))	('progression', 'CPA', (196, 207))	('invasion', 'CPA', (79, 87))	('metastasis', 'CPA', (209, 219))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('impact tumor initiation', 'Disease', 'MESH:D004834', (171, 194))	('FOXM1', 'Gene', '2305', (21, 26))	('cell migration', 'CPA', (63, 77))	('involved', 'Reg', (51, 59))
783613	28427178	These evidences suggest that dysregulated of FOXM1 expression and FOXM1 signal pathway in tumor microenvironment may serve as a key factor in human cancer development.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('FOXM1', 'Gene', (66, 71))	('FOXM1', 'Gene', '2305', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('human', 'Species', '9606', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('dysregulated', 'Var', (29, 41))	('FOXM1', 'Gene', '2305', (66, 71))	('FOXM1', 'Gene', (45, 50))
783617	28427178	In summary, FOXM1 expression in solid tumor tissues is associated with poor survival in most solid tumors, which suggests that FOXM1 is a valuable prognostic biomarker and a promising therapeutic target for solid tumors.	('solid tumor', 'Disease', 'MESH:D009369', (93, 104))	('solid tumors', 'Disease', 'MESH:D009369', (207, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('solid tumors', 'Disease', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('solid tumor', 'Disease', (32, 43))	('FOXM1', 'Gene', (12, 17))	('FOXM1', 'Gene', '2305', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('solid tumors', 'Disease', 'MESH:D009369', (93, 105))	('solid tumor', 'Disease', 'MESH:D009369', (207, 218))	('solid tumor', 'Disease', 'MESH:D009369', (32, 43))	('solid tumors', 'Disease', (207, 219))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('expression', 'Var', (18, 28))	('FOXM1', 'Gene', '2305', (12, 17))	('poor', 'NegReg', (71, 75))	('FOXM1', 'Gene', (127, 132))
783673	25569662	The long diameters of the lesion (tumor size) and the resected tissue sample (specimen size) were significantly greater in the stricture group (P < 0.001), and the time required for tumor resection (resection time) was significantly longer in the stricture group (P < 0.01).	('long diameters of the lesion', 'CPA', (4, 32))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('longer', 'PosReg', (233, 239))	('men', 'Species', '9606', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('greater', 'PosReg', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('stricture', 'Var', (127, 136))
783696	25569662	However, the incidence of stricture may vary depending on the study population; host factors, such as single-nucleotide polymorphisms; and environmental factors, such as dietary habit.	('stricture', 'Disease', (26, 35))	('men', 'Species', '9606', (146, 149))	('single-nucleotide polymorphisms', 'Var', (102, 133))
783717	25511108	Flow cytometry shows ECRG4 on the cell surface of a subset of CD14+ and CD16+ leukocytes.	('CD16', 'Gene', (72, 76))	('ECRG4', 'Gene', (21, 26))	('ECRG4', 'Gene', '84417', (21, 26))	('CD14+', 'Var', (62, 67))	('CD16', 'Gene', '2214', (72, 76))
783725	25511108	On one hand, the degree of its epigenetic silencing by hypermethylation and the decreased levels of C2orf40 gene expression are correlated with tumor growth, progression and metastasis of many types of epithelial cancers, such as esophageal, prostate and breast cancers and to several gliomas and CNS tumors.	('gliomas', 'Disease', 'MESH:D005910', (285, 292))	('epithelial cancers', 'Disease', 'MESH:D000077216', (202, 220))	('esophageal', 'Disease', (230, 240))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('metastasis', 'CPA', (174, 184))	('expression', 'MPA', (113, 123))	('gliomas', 'Phenotype', 'HP:0009733', (285, 292))	('hypermethylation', 'Var', (55, 71))	('decreased', 'NegReg', (80, 89))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('epigenetic', 'MPA', (31, 41))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('tumor', 'Disease', (144, 149))	('prostate', 'Disease', (242, 250))	('correlated', 'Reg', (128, 138))	('C2orf40', 'Gene', (100, 107))	('C2orf40', 'Gene', '84417', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('man', 'Species', '9606', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('breast cancers', 'Disease', 'MESH:D001943', (255, 269))	('breast cancers', 'Disease', (255, 269))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (301, 306))	('gliomas', 'Disease', (285, 292))	('levels', 'MPA', (90, 96))	('CNS tumors', 'Disease', 'MESH:D009369', (297, 307))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('breast cancers', 'Phenotype', 'HP:0003002', (255, 269))	('CNS tumors', 'Disease', (297, 307))	('epithelial cancers', 'Disease', (202, 220))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))
783752	25511108	XL1blue-MRF' E. coli (Agilent Technologies, Santa Clara, CA) was transformed with pUC198, pUC198-EGF or pUC198-CDelta16 phagemid and grown to OD600 = 0.15 in 2xYT broth (1.6% peptone, 1% yeast extract and 0.5% NaCl) with 2% glucose and 50 microg/ml ampicillin.	('glucose', 'Chemical', 'MESH:D005947', (224, 231))	('Tec', 'Gene', (30, 33))	('yeast', 'Species', '4932', (187, 192))	('EGF', 'Gene', '1950', (97, 100))	('Delta16', 'Mutation', 'c.del16', (112, 119))	('E. coli', 'Species', '562', (13, 20))	('NaCl', 'Chemical', 'MESH:D012965', (210, 214))	('Tec', 'Gene', '7006', (30, 33))	('EGF', 'Gene', (97, 100))	('pUC198-CDelta16', 'Var', (104, 119))	('MRF', 'Gene', '108714933', (8, 11))	('MRF', 'Gene', (8, 11))
783797	25511108	While the anti-ECRG4 antibody which recognizes the core extracellular 71-132 amino acids of ECRG4 detected up to 80% of CD16+ cells, antibodies to the Ecrg4133-148 peptide detect less then 15% of cells in these same preparations (Figure 2C).	('ECRG4', 'Gene', '84417', (92, 97))	('ECRG4', 'Gene', '84417', (15, 20))	('Ecrg4133-148', 'Var', (151, 163))	('CD16', 'Gene', '2214', (120, 124))	('CD16', 'Gene', (120, 124))	('ECRG4', 'Gene', (92, 97))	('ECRG4', 'Gene', (15, 20))
783829	25511108	These data support the hypothesis that the TLR4 innate immunity receptor is a cell-surface binding complex that interacts with and can internalize the CDelta16 peptide domain of ECRG4.	('ECRG4', 'Gene', (178, 183))	('internalize', 'MPA', (135, 146))	('interacts', 'Interaction', (112, 121))	('ECRG4', 'Gene', '84417', (178, 183))	('CDelta16', 'Var', (151, 159))	('Delta16', 'Mutation', 'c.del16', (152, 159))	('TLR4', 'Gene', (43, 47))
783834	25511108	This proteolytic shedding most likely occurs at a putative thrombin-like consensus cleavage sequence that releases a CDelta16 ECRG4133-148 pro-inflammatory peptide that has been detected by proteomic analyses in plasma, serum, cerebrospinal fluid and the conditioned media of ECRG4 over expressing cells.	('ECRG4', 'Gene', (126, 131))	('thrombin', 'Gene', '2147', (59, 67))	('ECRG4', 'Gene', '84417', (126, 131))	('ECRG4', 'Gene', (276, 281))	('Delta16', 'Mutation', 'c.del16', (118, 125))	('CDelta16', 'Var', (117, 125))	('ECRG4', 'Gene', '84417', (276, 281))	('thrombin', 'Gene', (59, 67))
783853	25391977	Matrix Metalloproteinase 1, 3, and 9 Polymorphisms and Esophageal Squamous Cell Carcinoma Risk Matrix metalloproteinases (MMPs) are multifunctional zinc-dependent proteinases that play a fundamental role in the pathogenesis of tumors.	('Polymorphisms', 'Var', (37, 50))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('Esophageal Squamous Cell Carcinoma', 'Disease', (55, 89))	('Carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (55, 89))	('Matrix Metalloproteinase 1, 3', 'Gene', '4322;4312', (0, 29))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
783859	25391977	The 2G-5A and 1G-5A haplotypes were associated with a significantly increased risk of ESCC as compared with the 2G-6A haplotype (OR=2.04, 95% CI 1.37-3.04 and OR=3.65, 95% CI 1.26-10.55, respectively).	('1G-5A', 'Var', (14, 19))	('5A', 'Chemical', 'MESH:C006576', (17, 19))	('5A', 'Chemical', 'MESH:C006576', (7, 9))	('2G-5A', 'Var', (4, 9))	('ESCC', 'Disease', (86, 90))
783860	25391977	These findings implicate this MMP3 polymorphism as a contributor to ESCC susceptibility.	('polymorphism', 'Var', (35, 47))	('ESCC', 'Disease', (68, 72))	('MMP3', 'Gene', (30, 34))	('MMP3', 'Gene', '4314', (30, 34))	('implicate', 'Reg', (15, 24))
783870	25391977	Multiple studies concerning the association of these polymorphisms with susceptibility to various malignancies have been conducted, but their findings are inconsistent.	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('association', 'Interaction', (32, 43))	('polymorphisms', 'Var', (53, 66))	('malignancies', 'Disease', (98, 110))
783871	25391977	Therefore, the aim of this current study was to ascertain whether SNPs in the promoters of the MMP1, MMP3, and MMP9 genes are associated with the risk of developing ESCC in a Chinese population.	('associated', 'Reg', (126, 136))	('MMP1', 'Gene', '4312', (95, 99))	('MMP3', 'Gene', '4314', (101, 105))	('MMP9', 'Gene', '4318', (111, 115))	('ESCC', 'Disease', (165, 169))	('MMP9', 'Gene', (111, 115))	('MMP1', 'Gene', (95, 99))	('MMP3', 'Gene', (101, 105))	('SNPs', 'Var', (66, 70))
783886	25391977	The 6A5A and 5A5A genotypes were associated with a significantly higher risk of ESCC as compared with the 6A6A genotype (OR=1.92; 95% CI 1.14-3.23; p=.01 and OR=5.42; 95% CI 2.01-14.63; p<0.01, respectively).	('5A', 'Chemical', 'MESH:C006576', (15, 17))	('5A', 'Chemical', 'MESH:C006576', (13, 15))	('5A', 'Chemical', 'MESH:C006576', (6, 8))	('5A5A', 'Var', (13, 17))	('ESCC', 'Disease', (80, 84))	('6A5A', 'Var', (4, 8))
783887	25391977	Using the 6A allele as a reference, a significant correlation was detected between the presence of the 5A allele and a risk of developing ESCC (OR=1.93; 95% CI 1.34-2.77; p<0.01).	('5A', 'Chemical', 'MESH:C006576', (103, 105))	('ESCC', 'Disease', (138, 142))	('presence', 'Var', (87, 95))
783892	25391977	The 2G-5A and 1G-5A haplotypes were associated with a significantly increased risk of ESCC as compared with the 2G-6A haplotype (OR = 2.04, 95% CI 1.37-3.04 and OR=3.65, 95% CI 1.26-10.55, respectively).	('1G-5A', 'Var', (14, 19))	('5A', 'Chemical', 'MESH:C006576', (17, 19))	('5A', 'Chemical', 'MESH:C006576', (7, 9))	('2G-5A', 'Var', (4, 9))	('ESCC', 'Disease', (86, 90))
783895	25391977	Accordingly, this suggests that MMP3 gene polymorphisms may be useful genetic susceptibility markers for ESCC.	('polymorphisms', 'Var', (42, 55))	('ESCC', 'Disease', (105, 109))	('MMP3', 'Gene', (32, 36))	('MMP3', 'Gene', '4314', (32, 36))
783905	25391977	The MMP1 gene promoter carries a common deletion/insertion polymorphism at position -1607.	('MMP1', 'Gene', (4, 8))	('MMP1', 'Gene', '4312', (4, 8))	('deletion/insertion polymorphism', 'Var', (40, 71))
783907	25391977	Our finding was consistent with the findings of a previous report that found no association between the MMP1 polymorphism and ESCC risk.	('MMP1', 'Gene', '4312', (104, 108))	('MMP1', 'Gene', (104, 108))	('ESCC', 'Disease', (126, 130))	('polymorphism', 'Var', (109, 121))
783913	25391977	Deletion of an adenosine (5A) leads to increased MMP3 transcription compared with the 6A allele in vitro.	('MMP3', 'Gene', '4314', (49, 53))	('5A', 'Chemical', 'MESH:C006576', (26, 28))	('adenosine', 'Chemical', 'MESH:D000241', (15, 24))	('increased', 'PosReg', (39, 48))	('MMP3', 'Gene', (49, 53))	('Deletion', 'Var', (0, 8))
783914	25391977	Therefore, the presence of the MMP3 -1612 5A/6A polymorphism is associated with an increased risk of developing a range of cancers, including colorectal adenoma, hepatocellular carcinoma, and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('MMP3', 'Gene', '4314', (31, 35))	('lung cancer', 'Disease', (192, 203))	('colorectal adenoma', 'Disease', (142, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (162, 186))	('presence', 'Var', (15, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('hepatocellular carcinoma', 'Disease', (162, 186))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (162, 186))	('5A', 'Chemical', 'MESH:C006576', (42, 44))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('MMP3', 'Gene', (31, 35))	('colorectal adenoma', 'Disease', 'MESH:D015179', (142, 160))
783921	25391977	Additionally, the 2G-5A and 1G-5A haplotypes are associated with a higher risk of ESCC.	('1G-5A', 'Var', (28, 33))	('ESCC', 'Disease', (82, 86))	('5A', 'Chemical', 'MESH:C006576', (21, 23))	('5A', 'Chemical', 'MESH:C006576', (31, 33))	('2G-5A', 'Var', (18, 23))
783933	33466226	Multivariate analysis showed that SDD is an independent protective factor for postoperative pneumonia (OR 0.40, 95% CI 0.23-0.67, p < 0.001) and anastomotic leakage (OR 0.46, 95% CI 0.26-0.84, p = 0.011).	('anastomotic leakage', 'Disease', 'MESH:D057868', (145, 164))	('pneumonia', 'Phenotype', 'HP:0002090', (92, 101))	('anastomotic leakage', 'Disease', (145, 164))	('postoperative pneumonia', 'Disease', (78, 101))	('SDD', 'Chemical', 'MESH:C003361', (34, 37))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (78, 101))	('SDD', 'Var', (34, 37))
783939	33466226	Pathogens originating from the gastrointestinal (GI) tract reaching the site of the anastomosis can induce local inflammation with abscess formation, facilitating anastomotic dehiscence and, eventually, anastomotic leakage.	('anastomotic leakage', 'Disease', 'MESH:D057868', (203, 222))	('abscess', 'Phenotype', 'HP:0025615', (131, 138))	('anastomotic leakage', 'Disease', (203, 222))	('abscess', 'Disease', (131, 138))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('Pathogens', 'Var', (0, 9))	('induce', 'Reg', (100, 106))	('inflammation', 'Disease', (113, 125))	('anastomotic dehiscence', 'CPA', (163, 185))
783989	33466226	Median ICU length of stay and hospital length of stay were both longer in patients using SDD (ICU 4 vs. 1 day, p < 0.001; hospital 13 vs. 11 days, p < 0.001).	('ICU', 'MPA', (7, 10))	('longer', 'PosReg', (64, 70))	('SDD', 'Chemical', 'MESH:C003361', (89, 92))	('patients', 'Species', '9606', (74, 82))	('SDD', 'Var', (89, 92))
783993	33466226	In multivariate analysis, SDD was an independent factor associated with a lower risk of pneumonia (OR 0.40, 95% confidence interval (CI) 0.23-0.67, p < 0.001) and anastomotic leakage (OR 0.46, 95% CI 0.26-0.84, p = 0.011), but not with a lower risk of 1-year mortality (OR 1.31, 95% CI 0.80-2.14, p = 0.278) (Table 2).	('SDD', 'Chemical', 'MESH:C003361', (26, 29))	('anastomotic leakage', 'Disease', 'MESH:D057868', (163, 182))	('mortality', 'Disease', (259, 268))	('pneumonia', 'Phenotype', 'HP:0002090', (88, 97))	('anastomotic leakage', 'Disease', (163, 182))	('pneumonia', 'Disease', (88, 97))	('pneumonia', 'Disease', 'MESH:D011014', (88, 97))	('SDD', 'Var', (26, 29))	('mortality', 'Disease', 'MESH:D003643', (259, 268))	('lower', 'NegReg', (74, 79))
784034	30201020	Since it is usually not known which base in a pair was the source of a mutation, the convention is to annotate mutations from the pyrimidine (C > A, T > A, etc.	('pyrimidine', 'Chemical', 'MESH:C030986', (130, 140))	('T > A', 'Var', (149, 154))	('C > A', 'Var', (142, 147))
784036	30201020	Using this system, we quantified the replication strand and timing bias of mutational signatures across 19 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutational', 'Var', (75, 85))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))
784037	30201020	For example, we discovered a strong lagging strand bias of T > G mutations in esophageal adenocarcinoma, suggesting an involvement of oxidative damage to the nucleotide pool in the etiology of the disease.	('esophageal adenocarcinoma', 'Disease', (78, 103))	('T > G mutations', 'Var', (59, 74))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (78, 103))	('involvement', 'Reg', (119, 130))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (78, 103))
784039	30201020	In total, we detected 25 mutational signatures that each corresponded to one of the COSMIC signatures (http://cancer.sanger.ac.uk/cosmic/signatures) and four novel signatures, which were primarily found in samples that had not been previously used for signature extraction (myeloid blood, skin, MSI, and ovarian cancers; Additional file 2: Figures S1-S5).	('mutational', 'Var', (25, 35))	('cancer', 'Disease', (110, 116))	('ovarian cancers', 'Phenotype', 'HP:0100615', (304, 319))	('MSI', 'Disease', (295, 298))	('ovarian cancers', 'Disease', (304, 319))	('ovarian cancers', 'Disease', 'MESH:D010051', (304, 319))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancers', 'Phenotype', 'HP:0002664', (312, 319))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (312, 318))	('corresponded', 'Reg', (57, 69))	('skin', 'Disease', (289, 293))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
784043	30201020	Interestingly, in all these four signatures, the slope of the correlation was significantly steeper in MSI than MSS samples (Additional file 2: Figure S26).	('S26', 'CellLine', 'CVCL:8806', (151, 154))	('MSI', 'Var', (103, 106))	('steeper', 'PosReg', (92, 99))
784045	30201020	It has been recently shown that error-prone Pol alpha-synthesized DNA is retained in vivo, causing an increase of mutations on the lagging strand.	('mutations', 'Var', (114, 123))	('Pol alpha', 'Gene', '5422', (44, 53))	('increase', 'PosReg', (102, 110))	('Pol alpha', 'Gene', (44, 53))
784047	30201020	The most common Pol alpha-induced mismatches normally repaired by MMR are G-dT and C-dT, leading to C > T mutations on the leading strand and C > A mutations on the lagging strand, matching our observations in the MMR-linked signatures.	('C-dT', 'Chemical', 'MESH:C121694', (83, 87))	('Pol alpha', 'Gene', '5422', (16, 25))	('C > A mutations', 'Var', (142, 157))	('G-dT', 'Chemical', '-', (74, 78))	('mismatches', 'Var', (34, 44))	('Pol alpha', 'Gene', (16, 25))	('C > T mutations', 'Var', (100, 115))
784049	30201020	We noticed that mutational signature 14 is also strongly associated with POLE mutations in the data sets by Shlien et al., Alexandrov et al., and in The Cancer Genome Atlas (TCGA).	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (153, 172))	('Cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TCG', 'Chemical', '-', (174, 177))	('mutational signature', 'Var', (16, 36))	('Cancer Genome Atlas', 'Disease', (153, 172))	('POLE', 'Disease', (73, 77))	('associated', 'Reg', (57, 67))
784051	30201020	For example, the frequency of mutations in TCT > A, TCG > T, and TTT > G, the three major components of signature 10, is higher on the lagging strand than on the leading strand in POLE-WT samples, whereas it is higher on the leading strand in POLE-MUT (Additional file 2: Figures S28-S31).	('TCG', 'Chemical', '-', (52, 55))	('TCG > T', 'Gene', (52, 59))	('mutations', 'Var', (30, 39))	('TTT > G', 'Gene', (65, 72))	('higher', 'PosReg', (121, 127))	('TCT > A', 'Gene', (43, 50))
784053	30201020	Our data show a link between DNA replication and exogenous mutagens such as UV light (signature 7), tobacco smoke (signature 4), or aristolochic acid (AA; signature 22).	('tobacco', 'Species', '4097', (100, 107))	('aristolochic acid', 'Chemical', 'MESH:C000228', (132, 149))	('aristolochic', 'Var', (132, 144))	('link', 'Interaction', (16, 20))
784055	30201020	This is consistent with the observation in yeast that a disruption of TLS leads to decreased mutation frequency in late-replicating regions and therefore a more even distribution of mutation frequency between early and late-replicating regions.	('TLS', 'Gene', (70, 73))	('yeast', 'Species', '4932', (43, 48))	('mutation frequency', 'MPA', (93, 111))	('decreased', 'NegReg', (83, 92))	('disruption', 'Var', (56, 66))	('more', 'PosReg', (156, 160))
784059	30201020	Due to the importance of gastro-esophageal and duodeno-gastric reflux in the development of BE and EAC and the resulting oxidative stress, it has been speculated that oxidative damage could cause the mutation patterns characteristic for signature 17.	('gastro-esophageal', 'Disease', (25, 42))	('signature 17', 'Gene', (237, 249))	('gastric reflux', 'Phenotype', 'HP:0002020', (55, 69))	('oxidative stress', 'Phenotype', 'HP:0025464', (121, 137))	('gastro-esophageal', 'Disease', 'MESH:D005764', (25, 42))	('cause', 'Reg', (190, 195))	('mutation', 'Var', (200, 208))
784063	30201020	In contrast, oxidation of guanine in the DNA produces 8-oxo-G, which has been shown to result in C > A mutations when paired with adenine during replication.	('mutations', 'Var', (103, 112))	('adenine', 'Chemical', 'MESH:D000225', (130, 137))	('C > A', 'Gene', (97, 102))	('guanine', 'Chemical', 'MESH:D006147', (26, 33))	('result in', 'Reg', (87, 96))	('8-oxo-G', 'Chemical', '-', (54, 61))
784064	30201020	These C > A mutations are normally prevented by DNA glycosylases in the base excision repair pathway, such as MUTYH and OGG1, which repair 8-oxo-G:A pairs to G:C. However, if an 8-oxo-G:A mismatch resulted from incorporation of 8-oxo-dGTP in the de novo synthesized strand, the "repair" to G:C would actually lead to a T > G mutation.	('mismatch', 'Var', (188, 196))	('8-oxo-G', 'Chemical', '-', (178, 185))	('T > G mutation', 'Disease', (319, 333))	('8-oxo-dGTP', 'Chemical', 'MESH:C078206', (228, 238))	('OGG1', 'Gene', (120, 124))	('OGG1', 'Gene', '4968', (120, 124))	('8-oxo-G', 'Chemical', '-', (139, 146))	('lead to', 'Reg', (309, 316))	('MUTYH', 'Gene', (110, 115))	('MUTYH', 'Gene', '4595', (110, 115))
784066	30201020	Importantly, the mismatch of 8-oxo-G and A has been shown in yeast to be more efficiently repaired into G:C when 8-oxo-G is on the lagging strand template, resulting in an enrichment of T > G mutations on the lagging strand template if the 8-oxoG:A mismatch originated from incorporation of 8-oxo-dGTP opposite A.	('oxo', 'Chemical', '-', (293, 296))	('oxo', 'Chemical', '-', (115, 118))	('mismatch', 'Var', (17, 25))	('oxo', 'Chemical', '-', (242, 245))	('yeast', 'Species', '4932', (61, 66))	('T > G', 'Gene', (186, 191))	('8-oxo-dGTP', 'Chemical', 'MESH:C078206', (291, 301))	('8-oxo-G', 'Chemical', '-', (29, 36))	('8-oxo-G', 'Chemical', '-', (113, 120))	('mutations', 'Var', (192, 201))	('oxo', 'Chemical', '-', (31, 34))
784068	30201020	However, the observation would be in line with a previously hypothesized model in which Pol epsilon has decreased fidelity of replicating 5-methylcytosine, causing an enrichment of C > T mutations in methylated cytosines on the leading strand, especially in samples with deficiency in MMR or Pol epsilon proofreading.	('C > T mutations', 'Var', (181, 196))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (138, 154))	('decreased', 'NegReg', (104, 113))	('causing', 'Reg', (156, 163))	('fidelity', 'MPA', (114, 122))
784074	30201020	The presence of mutational signatures on the one hand and a strong relationship between replication and the risk of cancer on the other therefore need not be mutually exclusive.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mutational signatures', 'Var', (16, 37))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
784089	30201020	It is important to note that the direction of the mutation is relative to the nucleotide in the base pair chosen as the reference, i.e., mutations of a pyrimidine on the leading strand correspond to mutations of a purine on the lagging strand.	('mutations', 'Var', (199, 208))	('pyrimidine', 'Chemical', 'MESH:C030986', (152, 162))	('mutations', 'Var', (137, 146))	('purine', 'Chemical', 'MESH:C030985', (214, 220))
784096	29383151	High levels of TUBB3 expression were also described to be associated with poor clinical outcome in various cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('High levels', 'Var', (0, 11))	('expression', 'MPA', (21, 31))	('TUBB3', 'Gene', (15, 20))	('TUBB3', 'Gene', '10381', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
784116	29383151	However, genetic alterations of betaIII-tubulin are rare in gastric cancer and esophageal adenocarcinoma (TCGA data, provisional).	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('genetic alterations', 'Var', (9, 28))	('gastric cancer', 'Disease', (60, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('esophageal adenocarcinoma', 'Disease', (79, 104))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('betaIII-tubulin', 'Protein', (32, 47))
784133	29383151	In this group multivariate analysis including age, gender, TUBB3 expression and lymph node metastases revealed a strong TUBB3 protein expression (p=0.044) and ypN+ (p=0.003) to be independent prognostic factors for patients with minor response after neoadjuvant therapy (Figure 3C; Table 3A).	('lymph node metastases', 'Disease', 'MESH:D009362', (80, 101))	('patients', 'Species', '9606', (215, 223))	('lymph node metastases', 'Disease', (80, 101))	('expression', 'MPA', (134, 144))	('TUBB3', 'Gene', '10381', (59, 64))	('TUBB3', 'Gene', (59, 64))	('ypN+', 'Var', (159, 163))	('TUBB3', 'Gene', (120, 125))	('TUBB3', 'Gene', '10381', (120, 125))
784135	29383151	High TUBB3 expression is associated with adverse prognosis, including advanced tumor stage, lymph node metastasis and minor response to neoadjuvant therapy.	('High', 'Var', (0, 4))	('tumor', 'Disease', (79, 84))	('expression', 'MPA', (11, 21))	('lymph node metastasis', 'CPA', (92, 113))	('TUBB3', 'Gene', (5, 10))	('TUBB3', 'Gene', '10381', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
784143	29383151	In gastric cancer, high-level expression of TUBB3 is associated with poor response to taxane-based chemotherapy and a significantly shorter progression-free-survival, in prostate adenocarcinomas TUBB3 was shown to be an independent prognostic marker showing a strong link with early PSA recurrence independent of grade and stage.	('taxane', 'Chemical', 'MESH:C080625', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TUBB3', 'Gene', '10381', (44, 49))	('prostate adenocarcinomas', 'Disease', 'MESH:D011471', (170, 194))	('progression-free-survival', 'CPA', (140, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (184, 194))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('high-level expression', 'Var', (19, 40))	('shorter', 'NegReg', (132, 139))	('gastric cancer', 'Disease', (3, 17))	('early PSA', 'Disease', (277, 286))	('prostate adenocarcinomas', 'Disease', (170, 194))	('TUBB3', 'Gene', (44, 49))	('TUBB3', 'Gene', (195, 200))	('TUBB3', 'Gene', '10381', (195, 200))
784147	29383151	focused on biomarkers with potential (in-) sensitivity to (chemo)-therapeutic agents like taxane and emphasized that a carcinoma-cell based TUBB3 expression predicts the insensitivity to a taxane-based therapy most likely by its ability to keep microtubules in a more dynamic state or influence the drug-binding options .	('insensitivity to', 'MPA', (170, 186))	('taxane', 'Chemical', 'MESH:C080625', (189, 195))	('expression', 'Var', (146, 156))	('carcinoma', 'Disease', (119, 128))	('taxane', 'Chemical', 'MESH:C080625', (90, 96))	('TUBB3', 'Gene', '10381', (140, 145))	('drug-binding', 'Interaction', (299, 311))	('predicts', 'Reg', (157, 165))	('microtubules', 'MPA', (245, 257))	('carcinoma', 'Disease', 'MESH:D002277', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('TUBB3', 'Gene', (140, 145))	('influence', 'Reg', (285, 294))
784151	29383151	According to the results of the present study, especially the subgroup of minor responders demonstrated with worse prognosis in association to high TUBB3 protein levels.	('TUBB3', 'Gene', (148, 153))	('TUBB3', 'Gene', '10381', (148, 153))	('high', 'Var', (143, 147))
784165	29344116	Knockdown of TGIF attenuates the proliferation and tumorigenicity of EC109 cells and promotes cisplatin-induced apoptosis A previous study has reported that frequent amplifications of the TG-interacting factor (TGIF) were observed in esophageal squamous cell carcinoma.	('tumorigenicity', 'CPA', (51, 65))	('TGIF', 'Gene', (211, 215))	('EC109', 'CellLine', 'CVCL:6898', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cisplatin-induced', 'MPA', (94, 111))	('esophageal squamous cell carcinoma', 'Disease', (234, 268))	('TGIF', 'Gene', (13, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('promotes', 'PosReg', (85, 93))	('observed', 'Reg', (222, 230))	('attenuates', 'NegReg', (18, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (245, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('proliferation', 'CPA', (33, 46))	('amplifications', 'Var', (166, 180))	('TGIF', 'Gene', '7050', (211, 215))	('TGIF', 'Gene', '7050', (13, 17))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (234, 268))
784169	29344116	TGIF knockdown suppressed EC109 cell proliferation, colony formation in soft agar and tumor growth in nude mice, induced cell cycle arrest in the G1 phase, and promoted cisplatin-induced apoptosis.	('promoted', 'PosReg', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TGIF', 'Gene', '7050', (0, 4))	('induced', 'Reg', (113, 120))	('knockdown', 'Var', (5, 14))	('cisplatin-induced apoptosis', 'CPA', (169, 196))	('colony formation in soft agar', 'CPA', (52, 81))	('tumor', 'Disease', (86, 91))	('nude mice', 'Species', '10090', (102, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('TGIF', 'Gene', (0, 4))	('cell cycle arrest in the G1 phase', 'CPA', (121, 154))	('EC109 cell proliferation', 'CPA', (26, 50))	('suppressed', 'NegReg', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('EC109', 'CellLine', 'CVCL:6898', (26, 31))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))
784170	29344116	In addition, TGIF knockdown significantly reduced the expression of phospho-Rb in EC109 cells.	('expression', 'MPA', (54, 64))	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (42, 49))	('TGIF', 'Gene', (13, 17))	('EC109', 'CellLine', 'CVCL:6898', (82, 87))	('TGIF', 'Gene', '7050', (13, 17))
784171	29344116	The reduced level of full length PARP expression and the increased level of cleaved caspase-3 expression were observed in EC109 cells with the treatment of cisplatin and TGIF knockdown.	('reduced', 'NegReg', (4, 11))	('expression', 'MPA', (38, 48))	('PARP', 'Gene', '1302', (33, 37))	('caspase-3', 'Gene', (84, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('EC109', 'CellLine', 'CVCL:6898', (122, 127))	('TGIF', 'Gene', '7050', (170, 174))	('caspase-3', 'Gene', '836', (84, 93))	('increased', 'PosReg', (57, 66))	('knockdown', 'Var', (175, 184))	('expression', 'MPA', (94, 104))	('PARP', 'Gene', (33, 37))	('TGIF', 'Gene', (170, 174))
784172	29344116	The results suggest that knockdown of TGIF attenuated the proliferation and tumorigenicity of EC109 cells, and promoted cisplatin-induced apoptosis.	('promoted', 'PosReg', (111, 119))	('TGIF', 'Gene', '7050', (38, 42))	('EC109', 'CellLine', 'CVCL:6898', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('TGIF', 'Gene', (38, 42))	('attenuated', 'NegReg', (43, 53))	('cisplatin-induced', 'MPA', (120, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('knockdown', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
784180	29344116	Heterozygous loss of TGIF gene causes holoprosencephaly in humans.	('holoprosencephaly', 'Disease', (38, 55))	('TGIF', 'Gene', '7050', (21, 25))	('TGIF', 'Gene', (21, 25))	('Heterozygous loss', 'Var', (0, 17))	('causes', 'Reg', (31, 37))	('holoprosencephaly', 'Disease', 'MESH:D016142', (38, 55))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (38, 55))	('humans', 'Species', '9606', (59, 65))
784183	29344116	Nakakuki et al reported that frequent amplifications of TGIF were observed in esophageal squamous cell carcinoma (ESCC), which suggests that TGIF might be associated with esophageal tumorigenesis.	('observed', 'Reg', (66, 74))	('esophageal squamous cell carcinoma', 'Disease', (78, 112))	('tumor', 'Disease', (182, 187))	('amplifications', 'Var', (38, 52))	('associated', 'Reg', (155, 165))	('TGIF', 'Gene', '7050', (56, 60))	('TGIF', 'Gene', '7050', (141, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (78, 112))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('TGIF', 'Gene', (56, 60))	('TGIF', 'Gene', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
784185	29344116	In the present study, we knocked down TGIF of EC109 cells with short hairpin RNA (shRNA) lentiviruses and observed the capabilities of proliferation and tumorigenicity of stable TGIF-knocked down EC109 cells in vitro and in vivo.	('EC109', 'CellLine', 'CVCL:6898', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('TGIF', 'Gene', '7050', (38, 42))	('TGIF', 'Gene', '7050', (178, 182))	('EC109', 'CellLine', 'CVCL:6898', (46, 51))	('TGIF', 'Gene', (38, 42))	('tumor', 'Disease', (153, 158))	('TGIF', 'Gene', (178, 182))	('proliferation', 'CPA', (135, 148))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('knocked', 'Var', (25, 32))
784186	29344116	We also observed the effects of TGIF knockdown on cisplatin-induced apoptosis in EC109 cells.	('TGIF', 'Gene', (32, 36))	('cisplatin-induced', 'MPA', (50, 67))	('knockdown', 'Var', (37, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('TGIF', 'Gene', '7050', (32, 36))	('EC109', 'CellLine', 'CVCL:6898', (81, 86))
784206	29344116	The primary antibodies used were listed as following: TGIF (sc-9084), Akt (sc-8312), beta-catenin (sc-7199), CDK4 (sc-260), cyclin A (sc-751), cyclin B1 (sc-752), cyclin D1 (sc-718), p21 (sc-397), p53 (sc-6243), and beta-actin (sc-47778) were obtained from Santa Cruz Biotechnology, Inc., and Rb (#9313S), phospho-Rb (#8516S), c-Myc (#13987S), p65 (#8242S), ERK1/2 (#4695S), Axin1 (#2087S), PARP (#9532S), Bax (#5023S), caspase-3 (#9664S), and caspase-9 (#9508S) were obtained from Cell Signaling Technology, Inc. (Danvers, MA, USA).	('cyclin B1', 'Gene', '891', (143, 152))	('cyclin B1', 'Gene', (143, 152))	('cyclin D1', 'Gene', '595', (163, 172))	('Axin1', 'Gene', '8312', (375, 380))	('caspase-9', 'Gene', (444, 453))	('#9313S', 'Var', (297, 303))	('c-Myc', 'Gene', (327, 332))	('p21', 'Gene', (183, 186))	('cyclin A', 'Gene', (124, 132))	('CDK4', 'Gene', '1019', (109, 113))	('#5023S', 'Var', (411, 417))	('p21', 'Gene', '644914', (183, 186))	('caspase-3', 'Gene', '836', (420, 429))	('beta-actin', 'Gene', '728378', (216, 226))	('p65', 'Gene', (344, 347))	('#9532S', 'Var', (397, 403))	('#8242S', 'Var', (349, 355))	('c-Myc', 'Gene', '4609', (327, 332))	('caspase-3', 'Gene', (420, 429))	('PARP', 'Gene', '1302', (391, 395))	('Bax', 'Gene', (406, 409))	('Akt', 'Gene', (70, 73))	('ERK1/2', 'Gene', (358, 364))	('#9508S', 'Var', (455, 461))	('ERK1/2', 'Gene', '5595;5594', (358, 364))	('#8516S', 'Var', (318, 324))	('p53', 'Gene', '7157', (197, 200))	('Bax', 'Gene', '581', (406, 409))	('Akt', 'Gene', '207', (70, 73))	('TGIF', 'Gene', '7050', (54, 58))	('#2087S', 'Var', (382, 388))	('#9664S', 'Var', (431, 437))	('p65', 'Gene', '5970', (344, 347))	('TGIF', 'Gene', (54, 58))	('PARP', 'Gene', (391, 395))	('p53', 'Gene', (197, 200))	('beta-catenin', 'Gene', (85, 97))	('beta-actin', 'Gene', (216, 226))	('caspase-9', 'Gene', '842', (444, 453))	('beta-catenin', 'Gene', '1499', (85, 97))	('cyclin D1', 'Gene', (163, 172))	('CDK4', 'Gene', (109, 113))	('#4695S', 'Var', (366, 372))	('Axin1', 'Gene', (375, 380))	('#13987S', 'Var', (334, 341))	('cyclin A', 'Gene', '890', (124, 132))
784209	29344116	1B indicated that EC109-shRNA-TGIF cells grew significantly slowly, compared with EC109-shRNA-control cells from 72 h, which suggests that TGIF knockdown suppressed EC109 cell proliferation.	('EC109', 'CellLine', 'CVCL:6898', (18, 23))	('suppressed', 'NegReg', (154, 164))	('TGIF', 'Gene', '7050', (30, 34))	('EC109 cell proliferation', 'CPA', (165, 189))	('slowly', 'NegReg', (60, 66))	('TGIF', 'Gene', (30, 34))	('TGIF', 'Gene', '7050', (139, 143))	('knockdown', 'Var', (144, 153))	('EC109', 'CellLine', 'CVCL:6898', (82, 87))	('EC109', 'CellLine', 'CVCL:6898', (165, 170))	('grew', 'CPA', (41, 45))	('TGIF', 'Gene', (139, 143))
784213	29344116	1D), which suggests that TGIF knockdown significantly suppressed tumor formation and tumor growth of EC109 cells in vivo.	('tumor', 'Disease', (85, 90))	('suppressed', 'NegReg', (54, 64))	('tumor', 'Disease', (65, 70))	('EC109', 'CellLine', 'CVCL:6898', (101, 106))	('TGIF', 'Gene', '7050', (25, 29))	('TGIF', 'Gene', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('knockdown', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
784215	29344116	Our data suggested that TGIF knockdown might induce the inhibition of EC109 cell growth by arresting the cell cycle in the G1 phase.	('inhibition', 'NegReg', (56, 66))	('TGIF', 'Gene', '7050', (24, 28))	('knockdown', 'Var', (29, 38))	('EC109', 'CellLine', 'CVCL:6898', (70, 75))	('TGIF', 'Gene', (24, 28))	('cell cycle in the G1 phase', 'CPA', (105, 131))	('arresting', 'NegReg', (91, 100))	('EC109 cell growth', 'CPA', (70, 87))
784217	29344116	Our findings showed that knockdown of TGIF suppressed the expression of phospho-Rb protein.	('TGIF', 'Gene', '7050', (38, 42))	('TGIF', 'Gene', (38, 42))	('expression of phospho-Rb', 'MPA', (58, 82))	('knockdown', 'Var', (25, 34))	('suppressed', 'NegReg', (43, 53))
784225	29344116	4A), which suggests that TGIF knockdown promoted cisplatin-induced apoptosis in EC109 cells.	('TGIF', 'Gene', '7050', (25, 29))	('promoted', 'PosReg', (40, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('EC109', 'CellLine', 'CVCL:6898', (80, 85))	('TGIF', 'Gene', (25, 29))	('knockdown', 'Var', (30, 39))	('cisplatin-induced', 'MPA', (49, 66))
784226	29344116	In addition, we observed the significantly decreased expression of full length PARP in EC109-shRNA-TGIF cells treated with 12.5 microg/ml of cisplatin as compared with EC109-shRNA-control cells treated with 12.5 microg/ml of cisplatin (Fig.	('EC109', 'CellLine', 'CVCL:6898', (168, 173))	('TGIF', 'Gene', '7050', (99, 103))	('PARP', 'Gene', '1302', (79, 83))	('EC109', 'CellLine', 'CVCL:6898', (87, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (225, 234))	('TGIF', 'Gene', (99, 103))	('PARP', 'Gene', (79, 83))	('expression', 'MPA', (53, 63))	('decreased', 'NegReg', (43, 52))	('cisplatin', 'Var', (141, 150))
784227	29344116	We observed the significantly increased expression of cleaved caspase-3 in EC109-shRNA-TGIF cells treated with 12.5 microg/ml of cisplatin as compared with EC109-shRNA-control cells treated with 12.5 microg/ml of cisplatin (Fig.	('expression', 'MPA', (40, 50))	('cisplatin', 'Var', (129, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (213, 222))	('cleaved', 'MPA', (54, 61))	('TGIF', 'Gene', '7050', (87, 91))	('caspase-3', 'Gene', '836', (62, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('EC109', 'CellLine', 'CVCL:6898', (75, 80))	('EC109', 'CellLine', 'CVCL:6898', (156, 161))	('TGIF', 'Gene', (87, 91))	('increased', 'PosReg', (30, 39))	('caspase-3', 'Gene', (62, 71))
784228	29344116	Our data suggested that TGIF knockdown had effects on the expression of apoptosis-related markers in EC109 cells treated with cisplatin.	('TGIF', 'Gene', '7050', (24, 28))	('knockdown', 'Var', (29, 38))	('EC109', 'CellLine', 'CVCL:6898', (101, 106))	('expression', 'MPA', (58, 68))	('TGIF', 'Gene', (24, 28))	('effects', 'Reg', (43, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))
784232	29344116	In addition, knockdown of TGIF promoted cisplatin-induced apoptosis of EC109 cells.	('TGIF', 'Gene', (26, 30))	('promoted', 'PosReg', (31, 39))	('cisplatin-induced', 'MPA', (40, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('EC109', 'CellLine', 'CVCL:6898', (71, 76))	('TGIF', 'Gene', '7050', (26, 30))	('knockdown', 'Var', (13, 22))
784234	29344116	Dysregualtion of several key factors, including CDK4, cyclin D1, p21 and phospho-Rb could result in G1 phase arrest.	('cyclin D1', 'Gene', '595', (54, 63))	('CDK4', 'Gene', '1019', (48, 52))	('p21', 'Gene', (65, 68))	('cyclin D1', 'Gene', (54, 63))	('G1 phase arrest', 'CPA', (100, 115))	('p21', 'Gene', '644914', (65, 68))	('Dysregualtion', 'Var', (0, 13))	('CDK4', 'Gene', (48, 52))	('result in', 'Reg', (90, 99))
784235	29344116	In this study, we observed that knockdown of TGIF induced cell cycle arrest in the G1 phase accompanied with significantly decreased expression of phospho-Rb protein, while other proteins such as CDK4, cyclin D1 and p21 did not significantly change.	('p21', 'Gene', (216, 219))	('expression', 'MPA', (133, 143))	('cyclin D1', 'Gene', (202, 211))	('phospho-Rb protein', 'Protein', (147, 165))	('TGIF', 'Gene', '7050', (45, 49))	('decreased', 'NegReg', (123, 132))	('p21', 'Gene', '644914', (216, 219))	('knockdown', 'Var', (32, 41))	('cell cycle arrest in the G1 phase', 'CPA', (58, 91))	('CDK4', 'Gene', (196, 200))	('TGIF', 'Gene', (45, 49))	('CDK4', 'Gene', '1019', (196, 200))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (58, 75))	('cyclin D1', 'Gene', '595', (202, 211))
784237	29344116	Our previous data showed that silencing of TGIF induced G1 phase cell cycle arrest along with the decreased expression of phospho-Rb, cyclin D1 and CDK4 in lung cancer cells.	('phospho-Rb', 'Protein', (122, 132))	('G1 phase cell cycle arrest', 'CPA', (56, 82))	('CDK4', 'Gene', '1019', (148, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('decreased', 'NegReg', (98, 107))	('TGIF', 'Gene', (43, 47))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('cyclin D1', 'Gene', '595', (134, 143))	('cyclin D1', 'Gene', (134, 143))	('expression', 'MPA', (108, 118))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (65, 82))	('silencing', 'Var', (30, 39))	('lung cancer', 'Disease', (156, 167))	('TGIF', 'Gene', '7050', (43, 47))	('CDK4', 'Gene', (148, 152))
784238	29344116	Together, the current observations suggests that knockdown of TGIF led to the decreased expression of phospho-Rb not through regulating CDK4 and cyclin D1 expression in esophageal cancer cells.	('knockdown', 'Var', (49, 58))	('phospho-Rb', 'Protein', (102, 112))	('cyclin D1', 'Gene', (145, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (169, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('CDK4', 'Gene', (136, 140))	('expression', 'MPA', (155, 165))	('TGIF', 'Gene', '7050', (62, 66))	('esophageal cancer', 'Disease', (169, 186))	('CDK4', 'Gene', '1019', (136, 140))	('decreased', 'NegReg', (78, 87))	('TGIF', 'Gene', (62, 66))	('expression', 'MPA', (88, 98))	('cyclin D1', 'Gene', '595', (145, 154))
784241	29344116	Deng et al reported that aberrant expression of beta-catenin was identified in 54.3% (114 of 265) of ESCC.	('beta-catenin', 'Gene', '1499', (48, 60))	('ESCC', 'Disease', (101, 105))	('beta-catenin', 'Gene', (48, 60))	('aberrant expression', 'Var', (25, 44))
784246	29344116	However, in this present study, we found that knockdown of TGIF had no obvious effects on the expression of beta-catenin and Axin1 proteins in esophageal cancer cells, which suggests that the wnt/beta-catenin signaling pathway might not be involved in knockdown of TGIF inhibiting the tumorigenicity of esophageal cancer cells.	('knockdown', 'Var', (252, 261))	('TGIF', 'Gene', '7050', (265, 269))	('TGIF', 'Gene', (265, 269))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('esophageal cancer', 'Disease', 'MESH:D004938', (303, 320))	('Axin1', 'Gene', (125, 130))	('beta-catenin', 'Gene', (196, 208))	('beta-catenin', 'Gene', (108, 120))	('beta-catenin', 'Gene', '1499', (196, 208))	('esophageal cancer', 'Disease', (303, 320))	('Axin1', 'Gene', '8312', (125, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('beta-catenin', 'Gene', '1499', (108, 120))	('expression', 'MPA', (94, 104))	('esophageal cancer', 'Disease', (143, 160))	('inhibiting', 'NegReg', (270, 280))	('TGIF', 'Gene', '7050', (59, 63))	('tumor', 'Disease', (285, 290))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('TGIF', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
784249	29344116	In this study, we observed that knockdown of TGIF suppressed the tumorigenicity of esophageal cancer cell of EC109 and cisplatin could repress the expression of TGIF protein.	('suppressed', 'NegReg', (50, 60))	('TGIF', 'Gene', '7050', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('esophageal cancer', 'Disease', (83, 100))	('tumor', 'Disease', (65, 70))	('TGIF', 'Gene', '7050', (45, 49))	('expression', 'MPA', (147, 157))	('knockdown', 'Var', (32, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('TGIF', 'Gene', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TGIF', 'Gene', (45, 49))	('repress', 'NegReg', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('EC109', 'CellLine', 'CVCL:6898', (109, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
784251	29344116	Our data showed that knockdown of TGIF promoted cisplatin-induced apoptosis of EC109 cells, along with the alterations of apoptosis-related markers, such as the decreased level of full length PARP protein expression and the increased level of cleaved caspase-3 protein expression.	('level', 'MPA', (171, 176))	('EC109', 'CellLine', 'CVCL:6898', (79, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('PARP', 'Gene', '1302', (192, 196))	('promoted', 'PosReg', (39, 47))	('decreased', 'NegReg', (161, 170))	('TGIF', 'Gene', '7050', (34, 38))	('PARP', 'Gene', (192, 196))	('caspase-3', 'Gene', '836', (251, 260))	('TGIF', 'Gene', (34, 38))	('apoptosis', 'CPA', (66, 75))	('knockdown', 'Var', (21, 30))	('expression', 'MPA', (205, 215))	('increased', 'PosReg', (224, 233))	('caspase-3', 'Gene', (251, 260))	('cisplatin-induced', 'MPA', (48, 65))
784254	29344116	Liu et al reported that knockdown of TGIF enhanced arsenic trioxide-induced apoptosis in HepG2 cells.	('TGIF', 'Gene', (37, 41))	('enhanced', 'PosReg', (42, 50))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (51, 67))	('HepG2', 'CellLine', 'CVCL:0027', (89, 94))	('TGIF', 'Gene', '7050', (37, 41))	('knockdown', 'Var', (24, 33))	('arsenic trioxide-induced', 'MPA', (51, 75))
784256	29344116	To the best of our knowledge, only one published study reported the association of TGIF amplifications with esophageal cancer.	('association', 'Interaction', (68, 79))	('TGIF', 'Gene', '7050', (83, 87))	('esophageal cancer', 'Disease', (108, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('TGIF', 'Gene', (83, 87))	('amplifications', 'Var', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
784262	29344116	In conclusion, the present study indicates that knockdown of TGIF induces growth inhibition of EC109 cells via arresting cell cycle in the G1 phase by downregulating phospho-Rb.	('arresting', 'NegReg', (111, 120))	('cell cycle in the G1 phase', 'CPA', (121, 147))	('downregulating', 'NegReg', (151, 165))	('phospho-Rb', 'MPA', (166, 176))	('growth inhibition', 'CPA', (74, 91))	('TGIF', 'Gene', (61, 65))	('EC109', 'CellLine', 'CVCL:6898', (95, 100))	('TGIF', 'Gene', '7050', (61, 65))	('knockdown', 'Var', (48, 57))
784288	29254145	The decrease in ATP production at first appears counterintuitive, but the metabolic alterations facilitate biosynthesis of macromolecules necessary to meet the sustained growth of cancer cells.	('ATP', 'Chemical', 'MESH:D000255', (16, 19))	('facilitate', 'PosReg', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('biosynthesis of macromolecules', 'MPA', (107, 137))	('ATP production', 'MPA', (16, 30))	('alterations', 'Var', (84, 95))	('metabolic', 'MPA', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
784299	29254145	We hypothesized that targeting aberrant cellular energetics may be a novel strategy for the treatment of esophageal carcinoma.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (105, 125))	('aberrant', 'Var', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('esophageal carcinoma', 'Disease', (105, 125))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (105, 125))
784336	29254145	In contrast, 10 of 10 mice inoculated with UCP2 knockdown OE33 cells developed tumors which were uniformly much larger than the one control tumor (Figure 4D).	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (140, 145))	('UCP2', 'Gene', (43, 47))	('tumors', 'Disease', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mice', 'Species', '10090', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('knockdown', 'Var', (48, 57))
784341	29254145	To review, decreases in UCP2 will increase the proton gradient between the inner membrane space and the matrix, which will enable ATP synthase (complex V of the ETC) to produce more ATP.	('ATP', 'Chemical', 'MESH:D000255', (182, 185))	('ATP', 'Chemical', 'MESH:D000255', (130, 133))	('ATP', 'MPA', (182, 185))	('increase', 'PosReg', (34, 42))	('proton gradient between the inner membrane space', 'MPA', (47, 95))	('UCP2', 'Gene', (24, 28))	('decreases', 'Var', (11, 20))
784344	29254145	With knockdown of UCP2, ATP levels were increased, whereas in UCP2 overexpressing cells, ATP levels were decreased (Figure 5A).	('UCP2', 'Gene', (18, 22))	('ATP', 'Chemical', 'MESH:D000255', (89, 92))	('knockdown', 'Var', (5, 14))	('ATP levels', 'MPA', (24, 34))	('ATP', 'Chemical', 'MESH:D000255', (24, 27))	('increased', 'PosReg', (40, 49))
784347	29254145	Interestingly, lactate accumulation was significantly higher in UCP2 knockdown cells compared with control cells, whereas, lactate was lower in EACC overexpressing UCP2 (Figure 5C).	('lactate', 'Chemical', 'MESH:D019344', (15, 22))	('higher', 'PosReg', (54, 60))	('lactate', 'Chemical', 'MESH:D019344', (123, 130))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('UCP2', 'Gene', (64, 68))	('lactate accumulation', 'MPA', (15, 35))	('knockdown', 'Var', (69, 78))
784348	29254145	The results revealed that downregulation UCP2 modestly increased HK2 protein expression with no obvious effects on other tested enzymes (Figure 5D).	('HK2', 'Gene', (65, 68))	('increased', 'PosReg', (55, 64))	('UCP2', 'Gene', (41, 45))	('HK2', 'Gene', '3099', (65, 68))	('downregulation', 'Var', (26, 40))
784349	29254145	The increase in HK2 expression with knockdown of UCP2 was similar to the increases of HK2 with DCA and CSC treatment.	('HK2', 'Gene', (16, 19))	('HK2', 'Gene', '3099', (16, 19))	('expression', 'MPA', (20, 30))	('HK2', 'Gene', '3099', (86, 89))	('knockdown', 'Var', (36, 45))	('HK2', 'Gene', (86, 89))	('CSC', 'Chemical', '-', (103, 106))	('DCA', 'Chemical', 'MESH:D003840', (95, 98))	('increase', 'PosReg', (4, 12))	('UCP2', 'Gene', (49, 53))
784353	29254145	When OE33 UCP2 expressing cells were exposed to DCA and CSC, the production of ATP was significantly abrogated compared to controls.	('OE33', 'Var', (5, 9))	('abrogated', 'NegReg', (101, 110))	('production of ATP', 'MPA', (65, 82))	('DCA', 'Chemical', 'MESH:D003840', (48, 51))	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('CSC', 'Chemical', '-', (56, 59))	('UCP2', 'Gene', (10, 14))
784365	29254145	Furthermore, UCP2 nearly completely abrogated the effects associated with DCA and CSC.	('CSC', 'Chemical', '-', (82, 85))	('UCP2', 'Var', (13, 17))	('DCA', 'Disease', (74, 77))	('CSC', 'Disease', (82, 85))	('abrogated', 'NegReg', (36, 45))	('DCA', 'Chemical', 'MESH:D003840', (74, 77))
784373	29254145	They suggest that glycolysis is not driven to maintain energy demands to overcome defective mitochondria; rather, other mitochondrial alterations such as substrate oxidation, ROS production, or mitochondrial DNA mutations may reprogram the mitochondria to assist in malignant progression.	('malignant progression', 'CPA', (266, 287))	('ROS', 'Chemical', 'MESH:D017382', (175, 178))	('mutations', 'Var', (212, 221))	('mitochondrial DNA', 'Gene', (194, 211))	('mitochondrial alterations', 'Phenotype', 'HP:0012103', (120, 145))	('reprogram', 'Reg', (226, 235))
784382	29254145	In beta cells, the absence of UCP2 abolished alternative pathways of proton return in the matrix, increased mitochondrial membrane potential, increased ATP levels, closed KATP channels, and stimulated insulin secretion.	('insulin secretion', 'Disease', (201, 218))	('stimulated', 'PosReg', (190, 200))	('increased', 'PosReg', (142, 151))	('absence', 'Var', (19, 26))	('KATP channels', 'MPA', (171, 184))	('mitochondrial membrane potential', 'MPA', (108, 140))	('ATP', 'Chemical', 'MESH:D000255', (172, 175))	('closed', 'NegReg', (164, 170))	('abolished', 'NegReg', (35, 44))	('increased', 'PosReg', (98, 107))	('insulin secretion', 'Disease', 'MESH:D007333', (201, 218))	('UCP2', 'Gene', (30, 34))	('ATP levels', 'MPA', (152, 162))	('ATP', 'Chemical', 'MESH:D000255', (152, 155))
784383	29254145	The absence of an uncoupling protein should result in an increase the mitochondrial membrane potential with a concomitant increase in ROS production.	('ROS production', 'MPA', (134, 148))	('mitochondrial membrane potential', 'MPA', (70, 102))	('increase in ROS production', 'Phenotype', 'HP:0025464', (122, 148))	('ROS', 'Chemical', 'MESH:D017382', (134, 137))	('increase', 'PosReg', (57, 65))	('absence', 'Var', (4, 11))	('increase', 'PosReg', (122, 130))
784386	29254145	Moreover, knockdown of UCP2 increased the mitochondrial membrane potential (Deltapsim) which reinforces the conclusion that UCP2 alters ATP production and ROS as expected based on its uncoupling activity (Supplementary Figure 9B).	('increased', 'PosReg', (28, 37))	('UCP2', 'Gene', (124, 128))	('mitochondrial membrane potential', 'MPA', (42, 74))	('alters', 'Reg', (129, 135))	('ATP', 'Chemical', 'MESH:D000255', (136, 139))	('ROS', 'Chemical', 'MESH:D017382', (155, 158))	('UCP2', 'Gene', (23, 27))	('ATP production', 'MPA', (136, 150))	('knockdown', 'Var', (10, 19))	('ROS', 'MPA', (155, 158))
784389	29254145	have shown that UCP2 negatively regulates glucose sensing in neurons and its absence prevents obesity-induced loss of glucose sensing.	('glucose sensing in neurons', 'MPA', (42, 68))	('obesity-induced loss of glucose', 'Disease', 'MESH:D009765', (94, 125))	('negatively', 'NegReg', (21, 31))	('regulates', 'Reg', (32, 41))	('absence', 'Var', (77, 84))	('glucose', 'Chemical', 'MESH:D005947', (118, 125))	('obesity', 'Phenotype', 'HP:0001513', (94, 101))	('UCP2', 'Gene', (16, 20))	('obesity-induced loss of glucose', 'Disease', (94, 125))	('glucose', 'Chemical', 'MESH:D005947', (42, 49))
784390	29254145	Overexpression of UCP2 has been reported to trigger metabolic reprogramming favoring oxidative metabolism with increased expression of pyruvate dehydrogenase and OXPHOS and decreased expression of HK2 and pyruvate kinase isoform 2 enzymes.	('UCP2', 'Gene', (18, 22))	('increased', 'PosReg', (111, 120))	('oxidative metabolism', 'MPA', (85, 105))	('HK2', 'Gene', (197, 200))	('HK2', 'Gene', '3099', (197, 200))	('pyruvate', 'MPA', (135, 143))	('expression', 'MPA', (121, 131))	('OXPHOS', 'MPA', (162, 168))	('metabolic reprogramming', 'CPA', (52, 75))	('expression', 'MPA', (183, 193))	('Overexpression', 'Var', (0, 14))	('pyruvate', 'Chemical', 'MESH:D019289', (135, 143))	('pyruvate', 'Chemical', 'MESH:D019289', (205, 213))	('decreased', 'NegReg', (173, 182))
784391	29254145	Our experiments demonstrate that expression of UCP2 negatively regulated glycolysis as noted by decrease in lactate production.	('negatively', 'NegReg', (52, 62))	('glycolysis', 'MPA', (73, 83))	('lactate production', 'MPA', (108, 126))	('expression', 'Var', (33, 43))	('decrease', 'NegReg', (96, 104))	('UCP2', 'Gene', (47, 51))	('regulated', 'Reg', (63, 72))	('lactate', 'Chemical', 'MESH:D019344', (108, 115))
784392	29254145	Consistent with these findings, knockdown of UCP2 significantly increased HK2 protein expression, whereas, overexpression reduced HK2 expression.	('expression', 'MPA', (134, 144))	('HK2', 'Gene', (74, 77))	('HK2', 'Gene', '3099', (74, 77))	('knockdown', 'Var', (32, 41))	('HK2', 'Gene', '3099', (130, 133))	('HK2', 'Gene', (130, 133))	('increased', 'PosReg', (64, 73))	('UCP2', 'Gene', (45, 49))
784394	29254145	Although we could not elucidate the exact mechanism by which UCP2 affected HK2 expression, our results are consistent with others showing that UCP2 functions as a glycolytic regulator in addition to the uncoupling role in the mitochondria.	('expression', 'MPA', (79, 89))	('UCP2', 'Var', (143, 147))	('HK2', 'Gene', (75, 78))	('HK2', 'Gene', '3099', (75, 78))	('affected', 'Reg', (66, 74))
784407	29254145	DCA and CSC appear to alter the metabolism of EAC cells via degradation of UCP2 and re-expression of UCP2 abrogated the effects of DCA and CSC (Figure 7).	('alter', 'Reg', (22, 27))	('DCA', 'Chemical', 'MESH:D003840', (0, 3))	('CSC', 'Chemical', '-', (139, 142))	('re-expression', 'Var', (84, 97))	('UCP2', 'Gene', (101, 105))	('UCP2', 'Protein', (75, 79))	('metabolism', 'MPA', (32, 42))	('DCA', 'Chemical', 'MESH:D003840', (131, 134))	('abrogated', 'NegReg', (106, 115))	('degradation', 'MPA', (60, 71))	('EAC', 'Phenotype', 'HP:0011459', (46, 49))	('CSC', 'Chemical', '-', (8, 11))
784470	28957436	In an attempt to search for biological predictors for RILT, apart from dosimetric parameters, many studies looked at correlations between the risk of pulmonary injury and variations in several profibrogenic and proinflamatory cytokines such as transforming growth factor ss1 (TGF-ss1), tumor necrosis factor-a (TNF-a) interleukin-1(IL-1), IL-6, high-molecular weight mucin-like antigen KL-6, and platelet-derived growth factor -ss (PDGF- ss).	('TNF-a', 'Gene', (311, 316))	('pulmonary injury', 'Disease', 'MESH:D055370', (150, 166))	('TNF-a', 'Gene', '7124', (311, 316))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('pulmonary injury', 'Disease', (150, 166))	('TGF-ss1', 'Gene', (276, 283))	('tumor necrosis factor-a', 'Gene', (286, 309))	('IL-6, high-molecular weight mucin-like antigen KL-6', 'Gene', '3569', (339, 390))	('tumor necrosis factor-a', 'Gene', '7124', (286, 309))	('IL-1', 'Gene', (332, 336))	('variations', 'Var', (171, 181))
784517	28957436	Prognostic factors for RILT were age (OR 0.917, p = 0.008), the volume of the PTV (OR 1.003, p = 0.010), the V20 (OR 1.132, p = 0.004) and V20>20% (OR: 4.050, p = 0,003).	('V20>20', 'Var', (139, 145))	('PTV', 'Chemical', '-', (78, 81))	('RILT', 'Disease', (23, 27))
784554	28957436	identified that high CCL18 expression levels were associated with prolonged OS and PFS in gastric cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('PFS', 'Disease', (83, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('patients', 'Species', '9606', (105, 113))	('expression levels', 'MPA', (27, 44))	('high', 'Var', (16, 20))	('prolonged OS', 'Disease', (66, 78))	('CCL18', 'Gene', (21, 26))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('CCL18', 'Gene', '6362', (21, 26))	('associated', 'Reg', (50, 60))	('gastric cancer', 'Disease', (90, 104))
784565	27605386	Single nucleotide polymorphism (SNP) of rs16917496 located in the miR-502 and SET8 binding site was analyzed in esophageal squamous cell carcinoma (ESCC) patients, the SET8 C/C genotype was independently associated with longer post-operative survival by multivariate analysis (relative risk, 2.250; 95% CI, 1.041-4.857; p = 0.039).	('C/C', 'Var', (173, 176))	('SET8', 'Gene', (168, 172))	('SET8', 'Gene', '387893', (168, 172))	('esophageal squamous cell carcinoma', 'Disease', (112, 146))	('Single nucleotide polymorphism', 'Var', (0, 30))	('miR-502', 'Gene', '574504', (66, 73))	('patients', 'Species', '9606', (154, 162))	('longer', 'PosReg', (220, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('SET8', 'Gene', (78, 82))	('SET8', 'Gene', '387893', (78, 82))	('rs16917496', 'Mutation', 'rs16917496', (40, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (112, 146))	('miR-502', 'Gene', (66, 73))	('rs16917496', 'Var', (40, 50))
784566	27605386	Moreover, the reduced SET8 expression mediated by SET8 C/C genotype was associated with longer ESCC survival.	('reduced', 'NegReg', (14, 21))	('ESCC', 'Disease', (95, 99))	('SET8', 'Gene', (50, 54))	('SET8', 'Gene', '387893', (50, 54))	('expression', 'MPA', (27, 37))	('SET8', 'Gene', '387893', (22, 26))	('C/C', 'Var', (55, 58))	('SET8', 'Gene', (22, 26))	('longer', 'PosReg', (88, 94))
784567	27605386	Functional assay indicated that the SET8 knock down could inhibit proliferation and promote apoptosis of ESCC cells.	('apoptosis', 'CPA', (92, 101))	('promote', 'PosReg', (84, 91))	('proliferation', 'CPA', (66, 79))	('SET8', 'Gene', (36, 40))	('SET8', 'Gene', '387893', (36, 40))	('inhibit', 'NegReg', (58, 65))	('knock down', 'Var', (41, 51))
784568	27605386	The subsequent assay also showed the markedly inhibition of ESCC cell migration and invasion by SET8 knock down.	('invasion', 'CPA', (84, 92))	('inhibition', 'NegReg', (46, 56))	('ESCC', 'Disease', (60, 64))	('knock down', 'Var', (101, 111))	('SET8', 'Gene', (96, 100))	('SET8', 'Gene', '387893', (96, 100))
784569	27605386	Our data suggested that the altering SET8 expression, which is mediated at least partly by miR-502 through changing the binding affinity between miR-502 and SET8 3' UTR, could modify the ESCC outcome by inhibiting the proliferation and invasion as well as promoting the apoptosis of ECSS cell.	('modify', 'Reg', (176, 182))	('ESCC', 'Disease', (187, 191))	('miR-502', 'Gene', (91, 98))	('binding', 'Interaction', (120, 127))	('invasion', 'CPA', (236, 244))	('apoptosis', 'CPA', (270, 279))	('SET8', 'Gene', (157, 161))	('altering', 'Var', (28, 36))	('inhibiting', 'NegReg', (203, 213))	('miR-502', 'Gene', '574504', (145, 152))	('SET8', 'Gene', (37, 41))	('proliferation', 'CPA', (218, 231))	('SET8', 'Gene', '387893', (37, 41))	('promoting', 'PosReg', (256, 265))	('miR-502', 'Gene', '574504', (91, 98))	('miR-502', 'Gene', (145, 152))	('SET8', 'Gene', '387893', (157, 161))	('changing', 'Reg', (107, 115))
784574	27605386	The clinical characteristics including the performance status, the TNM stage and lymph node metastases seem to be the predictive factors for esophageal cancer outcome; moreover, some molecular factors such as p53 mutaion and NF-kappaB expression level also show predictive power for esophageal cancer outcome.	('NF-kappaB', 'Gene', (225, 234))	('esophageal cancer', 'Disease', (141, 158))	('expression level', 'MPA', (235, 251))	('metastases', 'Disease', (92, 102))	('TNM', 'Gene', '10178', (67, 70))	('esophageal cancer', 'Disease', (283, 300))	('mutaion', 'Var', (213, 220))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (283, 300))	('p53', 'Gene', '7157', (209, 212))	('NF-kappaB', 'Gene', '4790', (225, 234))	('metastases', 'Disease', 'MESH:D009362', (92, 102))	('p53', 'Gene', (209, 212))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('TNM', 'Gene', (67, 70))
784576	27605386	Increasing evidences indicated that single nucleotide polymorphisms (SNPs) in the 3' UTR alter the targeted genes' expression and thereby affect an individual's cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('affect', 'Reg', (138, 144))	('alter', 'Reg', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('expression', 'MPA', (115, 125))	('cancer', 'Disease', (161, 167))	('single nucleotide polymorphisms', 'Var', (36, 67))
784578	27605386	Human PrSet7 interacts directly with the DNA replication factor PCNA and shows specific effects at origins of replication, SET8 depletion causes cells to accumulate in S phase with increased DNA damage, moreover, inappropriate SET8 expression also causes S phase defects and increased DNA damage.	('Human', 'Species', '9606', (0, 5))	('SET8', 'Gene', '387893', (227, 231))	('PrSet7', 'Gene', (6, 12))	('PrSet7', 'Gene', '387893', (6, 12))	('expression', 'MPA', (232, 242))	('causes', 'Reg', (248, 254))	('PCNA', 'Gene', (64, 68))	('inappropriate', 'Var', (213, 226))	('SET8', 'Gene', (123, 127))	('depletion', 'NegReg', (128, 137))	('accumulate', 'PosReg', (154, 164))	('SET8', 'Gene', (227, 231))	('DNA damage', 'MPA', (191, 201))	('S phase', 'CPA', (168, 175))	('PCNA', 'Gene', '5111', (64, 68))	('S phase defects', 'CPA', (255, 270))	('DNA damage', 'MPA', (285, 295))	('SET8', 'Gene', '387893', (123, 127))	('increased', 'PosReg', (181, 190))
784580	27605386	In our previous studies, we found the rs16917496 SNP including C/C, C/T and T/T genotypes in the "seed" region of SET8 3' UTR where miR-502 binding was associated with both cancer risk of epithelial ovarian cancer and outcome of hepatocellular carcinoma, small cell lung cancer and non-Hodgkin's lymphomas.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('small cell lung cancer', 'Disease', (255, 277))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (188, 213))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (229, 253))	('cancer', 'Disease', (271, 277))	("Hodgkin's lymphomas", 'Phenotype', 'HP:0012189', (286, 305))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('binding', 'Interaction', (140, 147))	('cancer', 'Disease', (207, 213))	('SET8', 'Gene', '387893', (114, 118))	('miR-502', 'Gene', '574504', (132, 139))	('epithelial ovarian cancer', 'Disease', (188, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('hepatocellular carcinoma', 'Disease', (229, 253))	('associated with', 'Reg', (152, 167))	('rs16917496', 'Mutation', 'rs16917496', (38, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (255, 277))	('rs16917496', 'Var', (38, 48))	("non-Hodgkin's lymphomas", 'Phenotype', 'HP:0012539', (282, 305))	('cancer', 'Disease', (173, 179))	('lymphomas', 'Phenotype', 'HP:0002665', (296, 305))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (188, 213))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	("non-Hodgkin's lymphomas", 'Disease', 'MESH:D008228', (282, 305))	('ovarian cancer', 'Phenotype', 'HP:0100615', (199, 213))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (266, 277))	('SET8', 'Gene', (114, 118))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (229, 253))	("non-Hodgkin's lymphomas", 'Disease', (282, 305))	('miR-502', 'Gene', (132, 139))	('small cell lung cancer', 'Disease', 'MESH:D055752', (255, 277))
784583	27605386	The SET8 genotype based on rs16917496 SNP were genotyped in 180 ESCC patients and 142 controls, the distribution of SET8 genotype followed a Hardy-Weinberg equilibrium.	('rs16917496', 'Mutation', 'rs16917496', (27, 37))	('ESCC', 'Disease', (64, 68))	('patients', 'Species', '9606', (69, 77))	('rs16917496 SNP', 'Var', (27, 41))	('SET8', 'Gene', (116, 120))	('SET8', 'Gene', '387893', (116, 120))	('SET8', 'Gene', (4, 8))	('SET8', 'Gene', '387893', (4, 8))
784584	27605386	The SET8 C/C, C/T and T/T genotype frequencies in controls was comparative to genotype frequency in ESCC patients, no difference for SET8 genotype distribution frequency between ESCC and controls had been found (data not shown).	('C/T', 'Var', (14, 17))	('patients', 'Species', '9606', (105, 113))	('C/C', 'Var', (9, 12))	('ESCC', 'Disease', (100, 104))	('T/T', 'Var', (22, 25))	('SET8', 'Gene', (133, 137))	('SET8', 'Gene', '387893', (133, 137))	('SET8', 'Gene', (4, 8))	('SET8', 'Gene', '387893', (4, 8))
784585	27605386	The ESCC patients were divided into three groups on the basis of their SET8 C/C, C/T and T/T genotype for Kaplan-Meier analysis, the 5 years survival rate of patients were 68.2% for C/C type, 37.7% for C/T and 44.4% for T/T, respectively (Fig.	('patients', 'Species', '9606', (9, 17))	('T/T', 'Var', (220, 223))	('SET8', 'Gene', '387893', (71, 75))	('C/T', 'Var', (202, 205))	('SET8', 'Gene', (71, 75))	('patients', 'Species', '9606', (158, 166))	('C/C type', 'Var', (182, 190))
784586	27605386	The patients with C/C allele was associated with a significantly longer survival time compared with that of C/T and T/T patients (C/C versus C/T, p = 0.016; C/C versus T/T, p = 0.048).	('longer', 'PosReg', (65, 71))	('survival time', 'CPA', (72, 85))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (4, 12))	('C/C allele', 'Var', (18, 28))
784587	27605386	The ESCC patients were divided into two groups as CC versus C/T + T/T SET8 genotypes for further multivariate analysis with the Cox proportional hazards model (Table 2).	('C/T + T/T', 'Var', (60, 69))	('patients', 'Species', '9606', (9, 17))	('SET8', 'Gene', (70, 74))	('SET8', 'Gene', '387893', (70, 74))	('Cox', 'Gene', '1351', (128, 131))	('ESCC', 'Disease', (4, 8))	('Cox', 'Gene', (128, 131))
784593	27605386	After survival analysis with Kplan-Meier method, we found that the patients with the low SET8 expression displayed longer survival length than that of high SET8 patients (five years survival rate, 85.7% vs. 30.0%, p = 0.022).	('SET8', 'Gene', (89, 93))	('SET8', 'Gene', '387893', (89, 93))	('patients', 'Species', '9606', (67, 75))	('low', 'Var', (85, 88))	('SET8', 'Gene', (156, 160))	('SET8', 'Gene', '387893', (156, 160))	('patients', 'Species', '9606', (161, 169))	('survival length', 'CPA', (122, 137))	('longer', 'PosReg', (115, 121))	('expression', 'Var', (94, 104))
784596	27605386	Consistent with immnostainig results in ESCC tissue, a dramatic reduction of Renilla luciferase activity was observed in C/C genotype of SET8.	('reduction of Renilla luciferase activity', 'Disease', (64, 104))	('C/C genotype', 'Var', (121, 133))	('SET8', 'Gene', (137, 141))	('SET8', 'Gene', '387893', (137, 141))	('reduction of Renilla luciferase activity', 'Disease', 'OMIM:612348', (64, 104))
784597	27605386	These results indicate that the rs16917496 SNP in the 3' UTR of SET8 changed the binding affinity between miR-502 and SET8 so as to affect SET8 expression.	('miR-502', 'Gene', '574504', (106, 113))	('affect', 'Reg', (132, 138))	('expression', 'MPA', (144, 154))	('changed', 'Reg', (69, 76))	('SET8', 'Gene', (139, 143))	('rs16917496', 'Mutation', 'rs16917496', (32, 42))	('SET8', 'Gene', '387893', (139, 143))	('SET8', 'Gene', (118, 122))	('SET8', 'Gene', '387893', (118, 122))	('SET8', 'Gene', (64, 68))	('SET8', 'Gene', '387893', (64, 68))	('binding affinity', 'Interaction', (81, 97))	('miR-502', 'Gene', (106, 113))	('rs16917496 SNP', 'Var', (32, 46))
784600	27605386	MTT assay was performed to measure proliferation capacity of Eca109 cells with three different treatments (psi-H1-SET8siRNA, psi-H1 and blank control), the proliferation rate of Eca109 cells was significantly decreased from 24 to 72 hr after psi-H1-SET8siRNA transfection compared with that of psi-H1 and blank control group (p < 0.01, Fig.	('transfection', 'Var', (259, 271))	('men', 'Species', '9606', (100, 103))	('SET8', 'Gene', (114, 118))	('SET8', 'Gene', '387893', (114, 118))	('SET8', 'Gene', (249, 253))	('SET8', 'Gene', '387893', (249, 253))	('proliferation rate', 'CPA', (156, 174))	('MTT', 'Chemical', '-', (0, 3))	('decreased', 'NegReg', (209, 218))
784603	27605386	These results indicated that knockdown of SET8 could inhibit proliferation and induce apoptosis of Eca109 cells.	('SET8', 'Gene', (42, 46))	('SET8', 'Gene', '387893', (42, 46))	('inhibit', 'NegReg', (53, 60))	('knockdown', 'Var', (29, 38))	('induce', 'Reg', (79, 85))	('proliferation', 'CPA', (61, 74))	('apoptosis', 'CPA', (86, 95))
784604	27605386	We evaluate the effects of SET8 knockdown on cell migration and invasion with wound healing assay and transwell assay subsequently, as shown in Fig.	('cell migration', 'CPA', (45, 59))	('knockdown', 'Var', (32, 41))	('SET8', 'Gene', (27, 31))	('SET8', 'Gene', '387893', (27, 31))
784607	27605386	These results indicated that SET8 knock down could inhibit the migration and invasion of Eca109 cells.	('SET8', 'Gene', '387893', (29, 33))	('inhibit', 'NegReg', (51, 58))	('knock down', 'Var', (34, 44))	('SET8', 'Gene', (29, 33))
784610	27605386	These data demonstrated that the SET8 knockdown could inhibit ESCC cell growth in vivo.	('inhibit', 'NegReg', (54, 61))	('SET8', 'Gene', '387893', (33, 37))	('SET8', 'Gene', (33, 37))	('ESCC', 'Disease', (62, 66))	('knockdown', 'Var', (38, 47))
784612	27605386	We showed firstly that the rs16917496 SNP in the miR-502 binding site of the SET8 3' UTR was associated with ESCC survival by multivariate analysis; secondly we showed that the SNP resulting in the T to C transition might destroy the G:C bond in miR-502 and SET8 binding site so as to modulate SET8 expression by immunostaining and luciferase reporter assays; thirdly we showed that SET8 expression was associated with ESCC outcome; finally we showed that the reduced SET8 could inhibit proliferation and invasion as well as increase apotosis for ESCC cell of Eca109.	('SET8', 'Gene', (468, 472))	('rs16917496', 'Mutation', 'rs16917496', (27, 37))	('SET8', 'Gene', '387893', (258, 262))	('increase apotosis', 'Disease', 'MESH:D019586', (525, 542))	('increase apotosis', 'Disease', (525, 542))	('SET8', 'Gene', '387893', (383, 387))	('SET8', 'Gene', '387893', (294, 298))	('SET8', 'Gene', (77, 81))	('miR-502', 'Gene', (49, 56))	('SET8', 'Gene', '387893', (468, 472))	('miR-502', 'Gene', (246, 253))	('SET8', 'Gene', (258, 262))	('proliferation', 'CPA', (487, 500))	('reduced', 'Var', (460, 467))	('SET8', 'Gene', '387893', (77, 81))	('inhibit', 'NegReg', (479, 486))	('miR-502', 'Gene', '574504', (49, 56))	('SET8', 'Gene', (294, 298))	('invasion', 'CPA', (505, 513))	('SET8', 'Gene', (383, 387))	('miR-502', 'Gene', '574504', (246, 253))
784613	27605386	We also assessed the role of SET8 knockdown on ESCC cell of TE1 referring to proliferation, invasion and apoptosis, the same results was obtained as it do in Eca109 cells (data not shown).	('apoptosis', 'CPA', (105, 114))	('invasion', 'CPA', (92, 100))	('SET8', 'Gene', (29, 33))	('SET8', 'Gene', '387893', (29, 33))	('knockdown', 'Var', (34, 43))	('proliferation', 'CPA', (77, 90))
784614	27605386	The expressional level of miR-502 was measured in ESCC tissue and Eca109 cells, there is no expressional difference for miR-502 among ESCC tissue of CC, CT and TT genotype, the miR-502 expressed moderately and the rs16917496 SNP belong to TT type in Eca109 cells (data not shown).	('miR-502', 'Gene', '574504', (120, 127))	('miR-502', 'Gene', (177, 184))	('miR-502', 'Gene', (26, 33))	('miR-502', 'Gene', (120, 127))	('rs16917496', 'Mutation', 'rs16917496', (214, 224))	('rs16917496', 'Var', (214, 224))	('miR-502', 'Gene', '574504', (177, 184))	('miR-502', 'Gene', '574504', (26, 33))
784615	27605386	Our data suggest that the altering SET8 expression, which is mediated at least partly by miR-502, could modify the ESCC outcome by inhibiting the proliferation and invasion as well as promoting the apoptosis of ESCC cell.	('ESCC', 'Disease', (115, 119))	('miR-502', 'Gene', '574504', (89, 96))	('altering', 'Var', (26, 34))	('apoptosis', 'CPA', (198, 207))	('proliferation', 'CPA', (146, 159))	('SET8', 'Gene', (35, 39))	('SET8', 'Gene', '387893', (35, 39))	('promoting', 'PosReg', (184, 193))	('miR-502', 'Gene', (89, 96))	('invasion', 'CPA', (164, 172))	('inhibiting', 'NegReg', (131, 141))	('modify', 'Reg', (104, 110))
784616	27605386	SET8 knockdown also was found to inhibit ESCC cell growth in vivo.	('SET8', 'Gene', (0, 4))	('SET8', 'Gene', '387893', (0, 4))	('inhibit', 'NegReg', (33, 40))	('knockdown', 'Var', (5, 14))	('ESCC', 'Disease', (41, 45))
784618	27605386	The rs16917496 SNP in the miR-502 and SET8 biding site were identified for their relationships to outcome of hepatocellular carcinoma, small cell lung cancer and non-Hodgkin's lymphomas with C/C genotype associating to longer survival in our previous study, which is comparable to our data in ESCC.	('rs16917496', 'Mutation', 'rs16917496', (4, 14))	('small cell lung cancer', 'Disease', 'MESH:D055752', (135, 157))	('rs16917496', 'Var', (4, 14))	("non-Hodgkin's lymphomas", 'Disease', 'MESH:D008228', (162, 185))	('small cell lung cancer', 'Disease', (135, 157))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (109, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('SET8', 'Gene', (38, 42))	("Hodgkin's lymphomas", 'Phenotype', 'HP:0012189', (166, 185))	("non-Hodgkin's lymphomas", 'Disease', (162, 185))	('miR-502', 'Gene', (26, 33))	('hepatocellular carcinoma', 'Disease', (109, 133))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (135, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lymphomas', 'Phenotype', 'HP:0002665', (176, 185))	('SET8', 'Gene', '387893', (38, 42))	('miR-502', 'Gene', '574504', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('relationships', 'Reg', (81, 94))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (109, 133))	("non-Hodgkin's lymphomas", 'Phenotype', 'HP:0012539', (162, 185))
784619	27605386	Consistent with our and Song's data demonstrating that the C/C genotype of SET8 is associated with low expression in breast cancer and hepatocellular carcinoma tissue, we show that the C/C genotype is associated with low protein level and longer survival length of ESCC patients.	('ESCC', 'Disease', (265, 269))	('survival length', 'CPA', (246, 261))	('patients', 'Species', '9606', (270, 278))	('expression', 'MPA', (103, 113))	('longer', 'PosReg', (239, 245))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('protein level', 'MPA', (221, 234))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (135, 159))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('hepatocellular carcinoma', 'Disease', (135, 159))	('breast cancer', 'Disease', (117, 130))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (135, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('C/C', 'Var', (185, 188))	('low', 'NegReg', (217, 220))	('SET8', 'Gene', (75, 79))	('SET8', 'Gene', '387893', (75, 79))
784621	27605386	As a methyltransferase, SET8 methylates lysine 382 of p53 to modulates p53 activity so as to change its transcriptional activity for downstream targets, furthermore, SET8 knockdown has been shown to upregulate cells' sensitivity to cell death and cell cycle arrest following DNA damage by suppressing the biological function of p53.	('SET8', 'Gene', (166, 170))	('p53', 'Gene', '7157', (71, 74))	('knockdown', 'Var', (171, 180))	('p53', 'Gene', (328, 331))	('arrest', 'Disease', (258, 264))	('death', 'Disease', (237, 242))	('p53', 'Gene', (71, 74))	('suppressing', 'NegReg', (289, 300))	('p53', 'Gene', '7157', (54, 57))	('change', 'Reg', (93, 99))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (247, 264))	('modulates', 'Reg', (61, 70))	('SET8', 'Gene', '387893', (24, 28))	('SET8', 'Gene', '387893', (166, 170))	('p53', 'Gene', (54, 57))	('arrest', 'Disease', 'MESH:D006323', (258, 264))	('biological function', 'MPA', (305, 324))	('transcriptional activity for', 'MPA', (104, 132))	('death', 'Disease', 'MESH:D003643', (237, 242))	('p53', 'Gene', '7157', (328, 331))	('upregulate', 'PosReg', (199, 209))	('lysine', 'Chemical', 'MESH:D008239', (40, 46))	('activity', 'MPA', (75, 83))	('SET8', 'Gene', (24, 28))
784622	27605386	SET8 could promote the epithelial-mesenchymal transition (EMT) and enhance the invasion potential of breast cancer cell mostly by methylating the promoters of the TWIST target genes E-cadherin and N-cadherin via its H4K20 monomethylation activity.	('SET8', 'Gene', (0, 4))	('breast cancer', 'Disease', (101, 114))	('SET8', 'Gene', '387893', (0, 4))	('TWIST', 'Gene', '7291', (163, 168))	('E-cadherin', 'Gene', '999', (182, 192))	('N-cadherin', 'Gene', '1000', (197, 207))	('H4K20', 'Protein', (216, 221))	('TWIST', 'Gene', (163, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('E-cadherin', 'Gene', (182, 192))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('promote', 'PosReg', (11, 18))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('enhance', 'PosReg', (67, 74))	('methylating', 'Var', (130, 141))	('epithelial-mesenchymal transition', 'CPA', (23, 56))	('N-cadherin', 'Gene', (197, 207))
784623	27605386	Set8-Numb-p53 signaling axis is an important regulatory pathway for apoptosis and SET8 could methylate Numb to abolish its apoptotic function in breast cancer cells.	('Numb', 'Gene', (5, 9))	('p53', 'Gene', '7157', (10, 13))	('Set8', 'Gene', '387893', (0, 4))	('Numb', 'Gene', '8650', (5, 9))	('Numb', 'Gene', '8650', (103, 107))	('apoptotic function', 'CPA', (123, 141))	('SET8', 'Gene', '387893', (82, 86))	('Set8', 'Gene', (0, 4))	('abolish', 'NegReg', (111, 118))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('SET8', 'Gene', (82, 86))	('Numb', 'Gene', (103, 107))	('breast cancer', 'Disease', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('methylate', 'Var', (93, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('p53', 'Gene', (10, 13))
784624	27605386	Consistent with previous study, we found that SET8 konckdown could inhibit proliferation and invasion as well as increase apoptosis of ESCC.	('ESCC', 'Disease', (135, 139))	('inhibit', 'NegReg', (67, 74))	('konckdown', 'Var', (51, 60))	('apoptosis', 'CPA', (122, 131))	('SET8', 'Gene', (46, 50))	('SET8', 'Gene', '387893', (46, 50))	('increase', 'PosReg', (113, 121))	('invasion', 'CPA', (93, 101))	('proliferation', 'CPA', (75, 88))
784625	27605386	Furthermore, SET8 is functionally required for 53BP1 recruitment during DNA double-strand breaks (DSBs), depletion of SET8 could abrogate 53BP1's accumulation at DSBs so as to make cell sensitive for apoptosis.	('53BP1', 'Gene', (47, 52))	('53BP1', 'Gene', '7158', (47, 52))	('depletion', 'Var', (105, 114))	('53BP1', 'Gene', (138, 143))	('SET8', 'Gene', (118, 122))	('53BP1', 'Gene', '7158', (138, 143))	('abrogate', 'NegReg', (129, 137))	('SET8', 'Gene', '387893', (118, 122))	('men', 'Species', '9606', (60, 63))	('SET8', 'Gene', (13, 17))	('SET8', 'Gene', '387893', (13, 17))	('accumulation', 'MPA', (146, 158))	('apoptosis', 'CPA', (200, 209))	('make', 'Reg', (176, 180))
784627	27605386	Our results indicated that SNPs of microRNA binding site have an effect on cancer outcome, but the results from this study require validation in other populations and in laboratory-based functional studies.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('effect', 'Reg', (65, 71))	('microRNA', 'Protein', (35, 43))	('cancer', 'Disease', (75, 81))	('SNPs', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
784632	27605386	The DNA fragments flanking rs16917496 in the SET8 3' UTR was amplified with the forward primer 5'- TCACGACGGTGCTACCTAAG-3' and reverse primers 5'- CATGCTGGTGTGACACAGTC-3'according to the NCBI database (http://www.ncbi.nlm.nih.gov/snp/) using a PCR Master Mix Kit (Promega).	('rs16917496', 'Mutation', 'rs16917496', (27, 37))	('rs16917496', 'Var', (27, 37))	('men', 'Species', '9606', (12, 15))	('SET8', 'Gene', (45, 49))	('SET8', 'Gene', '387893', (45, 49))
784662	23405077	Survivin -31G>C Polymorphism and Gastrointestinal Tract Cancer Risk: A Meta-Analysis Emerging evidence showed that common functional -31G>C polymorphism (rs9904341 G>C) in the promoter region of the survivin gene is involved in the regulation of survivin expression, thus increasing an individual's susceptibility to gastrointestinal tract (GIT) cancer; but individually published results are inconclusive.	('Gastrointestinal Tract Cancer', 'Disease', (33, 62))	('survivin', 'Gene', '442936', (199, 207))	('Survivin', 'Gene', '442936', (0, 8))	('rs9904341 G>C', 'Var', (154, 167))	('Gastrointestinal Tract Cancer', 'Phenotype', 'HP:0007378', (33, 62))	('survivin', 'Gene', (199, 207))	('-31G>C', 'Mutation', 'rs9904341', (133, 139))	('involved', 'Reg', (216, 224))	('Survivin', 'Gene', (0, 8))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('increasing', 'PosReg', (272, 282))	('Gastrointestinal Tract Cancer', 'Disease', 'MESH:D004067', (33, 62))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('rs9904341', 'Mutation', 'rs9904341', (154, 163))	('gastrointestinal tract (GIT) cancer', 'Disease', 'MESH:D004067', (317, 352))	('-31G>C', 'Mutation', 'rs9904341', (9, 15))	('survivin', 'Gene', '442936', (246, 254))	('survivin', 'Gene', (246, 254))
784663	23405077	The aim of this systematic review and meta-analysis was to derive a more precise estimation of the association between survivin -31G>C polymorphism and GIT cancer risk.	('-31G>C polymorphism', 'Var', (128, 147))	('GIT cancer', 'Disease', (152, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('-31G>C', 'Mutation', 'rs9904341', (128, 134))	('survivin', 'Gene', '442936', (119, 127))	('GIT cancer', 'Disease', 'MESH:D009369', (152, 162))	('association', 'Interaction', (99, 110))	('survivin', 'Gene', (119, 127))
784666	23405077	In the stratified analysis by cancer types, significant associations were observed between survivin -31G>C polymorphism and increased risk of colorectal and gastric cancers.	('gastric cancer', 'Phenotype', 'HP:0012126', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (30, 36))	('polymorphism', 'Var', (107, 119))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (142, 172))	('gastric cancers', 'Phenotype', 'HP:0012126', (157, 172))	('survivin', 'Gene', '442936', (91, 99))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('-31G>C', 'Mutation', 'rs9904341', (100, 106))	('survivin', 'Gene', (91, 99))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
784668	23405077	Results from the current meta-analysis suggests that survivin -31G>C polymorphism might increase the risk of GIT cancer, especially among gastric and colorectal cancers.	('colorectal cancers', 'Disease', 'MESH:D015179', (150, 168))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('GIT cancer', 'Disease', (109, 119))	('polymorphism', 'Var', (69, 81))	('colorectal cancers', 'Disease', (150, 168))	('GIT cancer', 'Disease', 'MESH:D009369', (109, 119))	('gastric', 'Disease', (138, 145))	('increase', 'PosReg', (88, 96))	('-31G>C', 'Mutation', 'rs9904341', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('survivin', 'Gene', '442936', (53, 61))	('survivin', 'Gene', (53, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
784675	23405077	However, the majority of genetic variants that influence susceptibility to GIT cancer are still not well-known.	('GIT cancer', 'Disease', 'MESH:D009369', (75, 85))	('variants', 'Var', (33, 41))	('GIT cancer', 'Disease', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
784678	23405077	Mutations in these candidate genes have already been linked to elevated risks of developing GIT cancers.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('GIT cancers', 'Disease', 'MESH:D009369', (92, 103))	('linked', 'Reg', (53, 59))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('GIT cancers', 'Disease', (92, 103))
784684	23405077	More than 10 common single nucleotide polymorphisms (SNPs) in the promoter region of the survivin gene have been reported, but the -31G>C polymorphism (rs9904341 G>C) is one of the most common variants.	('survivin', 'Gene', '442936', (89, 97))	('survivin', 'Gene', (89, 97))	('rs9904341', 'Mutation', 'rs9904341', (152, 161))	('-31G>C', 'Mutation', 'rs9904341', (131, 137))	('rs9904341 G>C', 'Var', (152, 165))
784687	23405077	Most of the studies support the mechanism in which the expression of survivin gene promotes tumor development and progression by inhibiting apoptosis and increasing cell proliferation.	('inhibiting', 'NegReg', (129, 139))	('survivin', 'Gene', '442936', (69, 77))	('increasing', 'PosReg', (154, 164))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('survivin', 'Gene', (69, 77))	('apoptosis', 'CPA', (140, 149))	('cell proliferation', 'CPA', (165, 183))	('promotes', 'PosReg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('progression', 'CPA', (114, 125))	('expression', 'Var', (55, 65))
784688	23405077	Over-expression of survivin gene has been associated with shorter survival time and poor prognosis in malignancies.	('shorter', 'NegReg', (58, 65))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('malignancies', 'Disease', (102, 114))	('survival time', 'CPA', (66, 79))	('Over-expression', 'Var', (0, 15))	('survivin', 'Gene', '442936', (19, 27))	('survivin', 'Gene', (19, 27))
784691	23405077	Two recent meta-analyses by Srivastava et al and Wang et al have shown that the survivin -31G>C polymorphism might be associated with an increased risk of cancer, especially among Asian populations.	('polymorphism', 'Var', (96, 108))	('survivin', 'Gene', (80, 88))	('-31G>C', 'Mutation', 'rs9904341', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('survivin', 'Gene', '442936', (80, 88))	('associated', 'Reg', (118, 128))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
784696	23405077	Relevant papers published before July 1st, 2012 were identified through a search in PubMed, Embase, Web of Science and CBM databases using the following terms: ("genetic polymorphism" or "polymorphism" or "SNP" or "gene mutation" or "genetic variants") and ("gastrointestinal tract neoplasms" or "cancer of gastrointestinal tract" or "gastrointestinal tract cancer" or "esophageal neoplasms" or "gastrointestinal stromal tumors" or "intestinal neoplasms" or "stomach neoplasms" or "gastric cancer" or "esophageal cancer" or "colorectal cancer" or "intestinal cancer") and ("surviving" or "BIRC5 protein, human" or "EPR-1").	('cancer', 'Disease', 'MESH:D009369', (490, 496))	('esophageal neoplasms', 'Phenotype', 'HP:0100751', (370, 390))	('tumor', 'Phenotype', 'HP:0002664', (421, 426))	('cancer', 'Disease', 'MESH:D009369', (536, 542))	('colorectal cancer', 'Disease', 'MESH:D015179', (525, 542))	('neoplasms', 'Phenotype', 'HP:0002664', (282, 291))	('cancer', 'Disease', 'MESH:D009369', (513, 519))	('cancer', 'Disease', (358, 364))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('human', 'Species', '9606', (604, 609))	('survivin', 'Gene', '442936', (574, 582))	('colorectal cancer', 'Disease', (525, 542))	('gastric cancer', 'Disease', (482, 496))	('cancer', 'Disease', 'MESH:D009369', (559, 565))	('gastrointestinal tract neoplasms', 'Phenotype', 'HP:0007378', (259, 291))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('esophageal cancer', 'Disease', 'MESH:D004938', (502, 519))	('intestinal cancer', 'Disease', (548, 565))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (396, 427))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (396, 427))	('gastrointestinal tract cancer', 'Phenotype', 'HP:0007378', (335, 364))	('BIRC5', 'Gene', '332', (589, 594))	('BIRC5', 'Gene', (589, 594))	('EPR-1"', 'Gene', '332', (615, 621))	('esophageal cancer', 'Disease', (502, 519))	('stomach neoplasms', 'Disease', (459, 476))	('EPR-1"', 'Gene', (615, 621))	('cancer', 'Disease', (490, 496))	('gastric cancer', 'Disease', 'MESH:D013274', (482, 496))	('intestinal neoplasms', 'Disease', 'MESH:D007414', (433, 453))	('esophageal neoplasms', 'Disease', (370, 390))	('stomach neoplasms', 'Disease', 'MESH:D013274', (459, 476))	('stomach neoplasms', 'Phenotype', 'HP:0006753', (459, 476))	('cancer', 'Phenotype', 'HP:0002664', (490, 496))	('cancer', 'Disease', (513, 519))	('cancer', 'Disease', (536, 542))	('cancer', 'Disease', 'MESH:D009369', (358, 364))	('colorectal cancer', 'Phenotype', 'HP:0003003', (525, 542))	('cancer', 'Disease', (297, 303))	('intestinal neoplasms', 'Disease', (433, 453))	('neoplasms', 'Phenotype', 'HP:0002664', (444, 453))	('cancer', 'Phenotype', 'HP:0002664', (536, 542))	('intestinal cancer', 'Disease', 'MESH:D007414', (548, 565))	('survivin', 'Gene', (574, 582))	('gastrointestinal stromal tumors', 'Disease', (396, 427))	('cancer', 'Phenotype', 'HP:0002664', (513, 519))	('cancer', 'Disease', (559, 565))	('cancer of gastrointestinal tract', 'Phenotype', 'HP:0007378', (297, 329))	('neoplasms', 'Phenotype', 'HP:0002664', (467, 476))	('variants', 'Var', (242, 250))	('neoplasms', 'Phenotype', 'HP:0002664', (381, 390))	('gastric cancer', 'Phenotype', 'HP:0012126', (482, 496))	('tumors', 'Phenotype', 'HP:0002664', (421, 427))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('esophageal neoplasms', 'Disease', 'MESH:D004938', (370, 390))
784705	23405077	A summary of the meta-analysis findings of the correlation between survivin -31G>C polymorphism and GIT cancer risk is provided in Table 3.	('polymorphism', 'Var', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('GIT cancer', 'Disease', (100, 110))	('GIT cancer', 'Disease', 'MESH:D009369', (100, 110))	('survivin', 'Gene', '442936', (67, 75))	('survivin', 'Gene', (67, 75))	('-31G>C', 'Mutation', 'rs9904341', (76, 82))
784708	23405077	In the stratified analysis by cancer types, significant associations were observed between survivin -31G>C polymorphism and increased risk of colorectal cancer under all genetic models (allele model: OR = 1.45, 95%CI: 1.20-1.75, P<0.001; dominant model: OR = 1.51, 95%CI: 1.22-1.88, P<0.001; recessive model: OR = 1.58, 95%CI: 1.08-2.32, P = 0.020; homozygous model: OR = 1.84, 95%CI: 1.20-2.82, P = 0.006).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('cancer', 'Disease', (153, 159))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('polymorphism', 'Var', (107, 119))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('colorectal cancer', 'Disease', (142, 159))	('survivin', 'Gene', '442936', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('survivin', 'Gene', (91, 99))	('-31G>C', 'Mutation', 'rs9904341', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
784711	23405077	In addition, we also found an obvious difference in the minor allele frequency (MAF) of survivin -31G>C polymorphism in esophageal cancer patients from these two studies (0.40 vs 0.51).	('polymorphism', 'Var', (104, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('survivin', 'Gene', '442936', (88, 96))	('minor allele frequency', 'MPA', (56, 78))	('survivin', 'Gene', (88, 96))	('esophageal cancer', 'Disease', (120, 137))	('-31G>C', 'Mutation', 'rs9904341', (97, 103))	('patients', 'Species', '9606', (138, 146))
784713	23405077	Further stratification analysis by ethnicity, the results showed that survivin -31G>C polymorphism might be a risk factor for GIT cancer among Asian populations under four genetic models (allele model: OR = 1.29, 95%CI: 1.04-1.61, P = 0.022; recessive model: OR = 1.57, 95%CI: 1.12-2.20, P = 0.009; homozygous model: OR = 1.66, 95%CI: 1.09-2.52, P = 0.018; heterozygous model: OR = 1.50, 95%CI: 1.11-2.02, P = 0.008).	('GIT cancer', 'Disease', 'MESH:D009369', (126, 136))	('GIT cancer', 'Disease', (126, 136))	('survivin', 'Gene', '442936', (70, 78))	('survivin', 'Gene', (70, 78))	('polymorphism', 'Var', (86, 98))	('risk', 'Reg', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('-31G>C', 'Mutation', 'rs9904341', (79, 85))
784714	23405077	Also, we found significant associations between the C carrier (CC+GC) of survivin -31G>C polymorphism and increased risk of GIT cancer among Caucasian populations under the dominant model (OR = 1.50, 95%CI: 1.01-2.22, P = 0.044) (Figure 4).	('polymorphism', 'Var', (89, 101))	('survivin', 'Gene', '442936', (73, 81))	('survivin', 'Gene', (73, 81))	('-31G>C', 'Mutation', 'rs9904341', (82, 88))	('C carrier', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('GIT cancer', 'Disease', (124, 134))	('GIT cancer', 'Disease', 'MESH:D009369', (124, 134))
784715	23405077	Subgroup analyses based on country and source of controls, we found that survivin -31G>C polymorphism might increase the risk of gastrointestinal cancer in Chinese, Greek and Indian populations, but not in Brazilian populations.	('polymorphism', 'Var', (89, 101))	('increase', 'PosReg', (108, 116))	('gastrointestinal cancer', 'Disease', (129, 152))	('survivin', 'Gene', '442936', (73, 81))	('survivin', 'Gene', (73, 81))	('-31G>C', 'Mutation', 'rs9904341', (82, 88))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (129, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (129, 152))
784722	23405077	Therefore, it is biologically plausible that genetic variations of the survivin gene may modulate cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('modulate', 'Reg', (89, 97))	('cancer', 'Disease', (98, 104))	('survivin', 'Gene', '442936', (71, 79))	('survivin', 'Gene', (71, 79))	('genetic variations', 'Var', (45, 63))
784725	23405077	Recent findings suggests that a polymorphism located in promoter region (-31G>C) is associated with the alteration of survivin gene expression.	('alteration', 'Reg', (104, 114))	('survivin', 'Gene', '442936', (118, 126))	('survivin', 'Gene', (118, 126))	('associated', 'Reg', (84, 94))	('-31G>C', 'Var', (73, 79))	('expression', 'MPA', (132, 142))	('-31G>C', 'Mutation', 'rs9904341', (73, 79))
784726	23405077	This mutation re-upregulates the cell-cycle-dependent transcription of the human survivin gene and results in overexpression of survivin at both mRNA and protein levels.	('survivin', 'Gene', '442936', (128, 136))	('survivin', 'Gene', (128, 136))	('cell-cycle-dependent transcription', 'MPA', (33, 67))	('results in', 'Reg', (99, 109))	('human', 'Species', '9606', (75, 80))	('survivin', 'Gene', '442936', (81, 89))	('mutation', 'Var', (5, 13))	('overexpression', 'PosReg', (110, 124))	('survivin', 'Gene', (81, 89))
784732	23405077	However, these meta-analyses did not provide convincing and reliable evidences relevant to survivin -31G>C polymorphism and GIT cancer risk because some relevant case-controlled studies were not included.	('polymorphism', 'Var', (107, 119))	('survivin', 'Gene', '442936', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('GIT cancer', 'Disease', (124, 134))	('-31G>C', 'Mutation', 'rs9904341', (100, 106))	('survivin', 'Gene', (91, 99))	('GIT cancer', 'Disease', 'MESH:D009369', (124, 134))
784736	23405077	Although the exact function of survivin in tumorigenesis is not clear yet, a potential explanation might be that survivin gene mutations increased the ability of survivin as an inhibitor of apoptosis and regulator of cell division.	('survivin', 'Gene', '442936', (31, 39))	('survivin', 'Gene', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('survivin', 'Gene', '442936', (162, 170))	('ability', 'MPA', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('survivin', 'Gene', (162, 170))	('increased', 'PosReg', (137, 146))	('survivin', 'Gene', '442936', (113, 121))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', (43, 48))	('survivin', 'Gene', (113, 121))
784739	23405077	However, we found an obviuos difference in the MAF of survivin -31G>C polymorphism in esophageal cancer patients from these two studies (0.40 vs 0.51).	('polymorphism', 'Var', (70, 82))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('survivin', 'Gene', (54, 62))	('-31G>C', 'Mutation', 'rs9904341', (63, 69))	('survivin', 'Gene', '442936', (54, 62))	('patients', 'Species', '9606', (104, 112))
784743	23405077	More research is needed to determine the association between survivin gene polymorphisms and esophageal cancer risk.	('polymorphisms', 'Var', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('survivin', 'Gene', '442936', (61, 69))	('survivin', 'Gene', (61, 69))
784744	23405077	Further stratified analysis by ethnicity and country, the results identified that survivin -31G>C polymorphism as a risk factor for GIT cancer among both Asian and Caucasian populations, and was also associated with increased risk among Chinese, Greek and Indian populations, but not in Brazilian populations.	('GIT cancer', 'Disease', 'MESH:D009369', (132, 142))	('survivin', 'Gene', (82, 90))	('-31G>C', 'Mutation', 'rs9904341', (91, 97))	('risk', 'Reg', (116, 120))	('polymorphism', 'Var', (98, 110))	('survivin', 'Gene', '442936', (82, 90))	('GIT cancer', 'Disease', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
784748	23405077	Unlike previous meta-analyses, we find that survivin 31G>C polymorphism is associated with increased risk of gastric and colorectal cancers.	('31G>C', 'Mutation', 'c.31G>C', (53, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('colorectal cancers', 'Disease', 'MESH:D015179', (121, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('31G>C polymorphism', 'Var', (53, 71))	('colorectal cancers', 'Disease', (121, 139))	('survivin', 'Gene', '442936', (44, 52))	('survivin', 'Gene', (44, 52))	('gastric', 'Disease', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
784749	23405077	In summary, this meta-analysis suggests that survivin 31G>C polymorphism may be a risk factor for developing GIT cancer, especially among gastric and colorectal cancers.	('colorectal cancers', 'Disease', 'MESH:D015179', (150, 168))	('survivin', 'Gene', '442936', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('GIT cancer', 'Disease', (109, 119))	('survivin', 'Gene', (45, 53))	('colorectal cancers', 'Disease', (150, 168))	('GIT cancer', 'Disease', 'MESH:D009369', (109, 119))	('gastric', 'Disease', (138, 145))	('31G>C', 'Mutation', 'c.31G>C', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('31G>C polymorphism', 'Var', (54, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
784750	23405077	However, further studies are necessary in order to warrant and validate the associations between survivin gene polymorphisms, other gene polymorphisms and GIT cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('survivin', 'Gene', '442936', (97, 105))	('GIT cancer', 'Disease', 'MESH:D009369', (155, 165))	('GIT cancer', 'Disease', (155, 165))	('associations', 'Interaction', (76, 88))	('survivin', 'Gene', (97, 105))	('polymorphisms', 'Var', (111, 124))
784752	21467229	Short telomeres in surrogate tissues (e.g., blood cells) are associated with increased cancer risk in several case-control studies, but findings are inconsistent in prospective studies.	('Short telomeres', 'Phenotype', 'HP:0031413', (0, 15))	('Short telomeres', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('increased cancer', 'Disease', 'MESH:D009369', (77, 93))	('increased cancer', 'Disease', (77, 93))	('associated', 'Reg', (61, 71))
784755	21467229	Studies on bladder, esophageal, gastric, head and neck, ovarian, renal, and overall incident cancer found associations between short telomeres and these cancers.	('cancers', 'Disease', (153, 160))	('renal', 'Disease', (65, 70))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('associations', 'Interaction', (106, 118))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('esophageal', 'Disease', (20, 30))	('head', 'Disease', (41, 45))	('gastric', 'Disease', (32, 39))	('bladder', 'Disease', (11, 18))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('short telomeres', 'Phenotype', 'HP:0031413', (127, 142))	('cancer', 'Disease', (93, 99))	('short telomeres', 'Var', (127, 142))	('ovarian', 'Disease', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ovarian', 'Disease', 'MESH:D010051', (56, 63))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
784758	21467229	In a random effects meta-analysis, short TL was significantly associated with cancer in retrospective studies (pooled OR for the shortest TL quartile compared with the longest: 2.9, 95%CI 1.73 - 4.8, P<0.0001).	('associated with', 'Reg', (62, 77))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('short TL', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
784765	21467229	Very short telomeres and germline mutations in telomere biology genes occur in patients with dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome.	('cancer', 'Disease', (159, 165))	('dyskeratosis congenita', 'Disease', (93, 115))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (93, 115))	('bone marrow failure', 'Disease', (135, 154))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('occur', 'Reg', (70, 75))	('bone marrow failure', 'Disease', 'MESH:D000080983', (135, 154))	('short telomeres', 'Phenotype', 'HP:0031413', (5, 20))	('patients', 'Species', '9606', (79, 87))	('germline mutations', 'Var', (25, 43))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('bone marrow failure', 'Phenotype', 'HP:0005528', (135, 154))
784778	21467229	One publication reported an association between chromosome-specific TL and breast cancer risk, but no overall TL and therefore was excluded from the meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('chromosome-specific', 'Var', (48, 67))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
784786	21467229	Two studies found no association between breast cancer risk and TL, three studies found that short telomeres were significantly associated with increased breast cancer risk, and two case-control studies found that telomeres were significantly longer in breast cancer cases than controls.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('short telomeres', 'Phenotype', 'HP:0031413', (93, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('short telomeres', 'Var', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('breast cancer', 'Disease', (253, 266))
784788	21467229	The same group replicated this finding in a larger, population-based case-control study with 1,067 breast cancer cases and 1,110 controls; an increased risk of premenopausal breast cancer was noted for shortest telomeres (OR=1.61, 95%CI 1.05 - 2.45, Ptrend=0.01).	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('shortest telomeres', 'Var', (202, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (160, 187))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
784795	21467229	However, a subsequent study by the same group, found that short TL specifically on chromosome 9p was significantly associated with increased risk of breast cancer (OR=6.62, 95%CI 2.75 - 15.94, Ptrend<=0.01 ).	('short TL', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('breast cancer', 'Disease', (149, 162))
784800	21467229	This study also found that shorter telomeres were associated with an increased risk of lung cancer (combined OR for lung, renal, and bladder cancer=4.41, 95%CI 2.1 - 9.28, Ptrend=0.001).	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('lung cancer', 'Disease', (87, 98))	('bladder cancer', 'Disease', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('shorter telomeres', 'Var', (27, 44))
784801	21467229	A second retrospective study of TL and lung cancer showed a very strong association in PBLs of individuals with short telomeres and increased risk of lung cancer compared to individuals with longer telomeres (OR=8.73, 95%CI 4.08 - 18.71, Ptrend<=0.0001).	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('short telomeres', 'Var', (112, 127))	('lung cancer', 'Disease', (150, 161))	('lung cancer', 'Disease', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('short telomeres', 'Phenotype', 'HP:0031413', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
784802	21467229	The effect of short telomeres was most pronounced in small cell lung cancer.	('short telomeres', 'Phenotype', 'HP:0031413', (14, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('small cell lung cancer', 'Disease', 'MESH:D055752', (53, 75))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('short telomeres', 'Var', (14, 29))	('small cell lung cancer', 'Disease', (53, 75))
784803	21467229	Another population-based case-control study showed no association between short telomeres and risk of lung cancer (OR=1.58, 95%CI 0.79 - 3.18) based on TL in DNA derived from morning sputum (111 patients, 99 controls).	('short telomeres', 'Var', (74, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('short telomeres', 'Phenotype', 'HP:0031413', (74, 89))	('patients', 'Species', '9606', (195, 203))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))
784807	21467229	The second study evaluated both average and chromosome-specific (17p, 12q, 2p, and 11q) TL in 94 cases with esophageal carcinoma and 94 matched controls.	('esophageal carcinoma', 'Disease', (108, 128))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (108, 128))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (108, 128))	('17p', 'Var', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))
784819	21467229	Stratified analyses showed an increased association with short telomeres only in those with poorly differentiated tumors (TL dichotomized: OR=4.89, 95%CI 1.93 - 12.34, P<0.001, versus OR=0.82, 95%CI 0.29 - 2.28, P=0.07).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('short telomeres', 'Phenotype', 'HP:0031413', (57, 72))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('short telomeres', 'Var', (57, 72))
784826	21467229	Individuals with short telomeres had a significantly increased risk of all smoking related cancers (bladder, lung, and renal cell cancer) (OR=4.41, 95%CI 2.1 - 9.28, Ptrend=0.001).	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('short telomeres', 'Var', (17, 32))	('renal cell cancer', 'Phenotype', 'HP:0005584', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung', 'Disease', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('renal cell cancer', 'Disease', (119, 136))	('short telomeres', 'Phenotype', 'HP:0031413', (17, 32))	('renal cell cancer', 'Disease', 'MESH:C538614', (119, 136))
784848	21467229	The random effect meta-analytic pooled OR for all cancer types combined was 1.96 (95%CI 1.37 - 2.81, P<0.0001) for the quartile with the shortest telomeres compared with the referent quartile of TL with longest telomeres (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('shortest', 'Var', (137, 145))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))
784860	21467229	Patients with germline defects in telomere biology, such as those with DC, have a very high risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('germline defects', 'Var', (14, 30))	('telomere', 'Protein', (34, 42))
784862	21467229	Therefore, it is biologically plausible that individuals with short telomeres, even if they are not as short as in DC, might be at increased risk of cancer compared to individuals with longer telomeres.	('cancer', 'Disease', (149, 155))	('short telomeres', 'Var', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('short telomeres', 'Phenotype', 'HP:0031413', (62, 77))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
784893	21467229	In this chronic inflammatory condition, individuals are at increased risk of colon cancer; patients with higher rates of chromosomal instability and shorter telomeres are at greater risk of progression to colon cancer.	('patients', 'Species', '9606', (91, 99))	('chromosomal instability', 'Var', (121, 144))	('colon cancer', 'Disease', (205, 217))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('chromosomal instability', 'Phenotype', 'HP:0040012', (121, 144))	('shorter', 'NegReg', (149, 156))	('colon cancer', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('colon cancer', 'Phenotype', 'HP:0003003', (205, 217))	('colon cancer', 'Disease', 'MESH:D015179', (205, 217))
784935	33552948	Patients with traditional high-risk prognostic factors were usually received adjuvant CT/CCRT (eg, T3 or advanced stages, lymph node involved, R1/R2 resection, vascular invasion, neural invasion or poor histological differentiation), except for those with physical or other reasons.	('lymph node involved', 'CPA', (122, 141))	('poor histological', 'CPA', (198, 215))	('R1/R2', 'Var', (143, 148))	('neural invasion', 'CPA', (179, 194))	('vascular invasion', 'CPA', (160, 177))	('Patients', 'Species', '9606', (0, 8))	('advanced stages', 'CPA', (105, 120))
784942	33552948	Within the reference range of serum sodium level, the first to fourth quartiles were 135 to 139.6 mmol/liter, 139.6 to 141.05 mmol/liter, 141.05 to 142.4 mmol/liter, and 142.4 to 145 mmol/liter, respectively.	('141.05', 'Var', (138, 144))	('sodium', 'Chemical', 'MESH:D012964', (36, 42))	('139.6', 'Var', (110, 115))
784975	33552948	In the lowest serum sodium subgroup (< 139.6 mmol/liter), S + CT/CCRT significantly improved OS (3-year OS rate, 56.6 vs. 40%, p < 0.001; adjusted HR [95% CI] = 0.55[0.41-0.73]) and DFS (3-year DFS rate, 51.9 vs. 36.2%, p < 0.001; adjusted HR [95% CI] = 0.63[0.48-0.83]) (Figure 3 and Table 4), as compared with Surgery.	('S + CT/CCRT', 'Var', (58, 69))	('DFS', 'MPA', (182, 185))	('sodium', 'Chemical', 'MESH:D012964', (20, 26))	('lowest serum sodium', 'Phenotype', 'HP:0002902', (7, 26))	('improved', 'PosReg', (84, 92))
784976	33552948	In other serum sodium subgroups, there was no consistent statistical evidence supporting that S + CT/CCRT could improve OS or DFS as compared with Surgery (Figure 3 and Table 4).	('DFS', 'Disease', (126, 129))	('sodium', 'Chemical', 'MESH:D012964', (15, 21))	('improve', 'PosReg', (112, 119))	('S + CT/CCRT', 'Var', (94, 105))
785006	33552948	A few studies demonstrated that adjuvant chemotherapy or chemoradiotherapy after curative surgical resection could decrease recurrence and prolong survival in patients with clinical high-risk factors (pT3-4, pN+, or R1/2 resection).	('R1/2 resection', 'Var', (216, 230))	('recurrence', 'MPA', (124, 134))	('pT3-4', 'Var', (201, 206))	('prolong', 'PosReg', (139, 146))	('survival', 'MPA', (147, 155))	('pN', 'Gene', '79650', (208, 210))	('decrease', 'NegReg', (115, 123))	('patients', 'Species', '9606', (159, 167))
785016	33552948	We found that the inflammatory parameters including leukocytes, neutrophils, monocytes and CRP levels were significantly elevated in patients with low sodium levels.	('low sodium levels', 'Phenotype', 'HP:0002902', (147, 164))	('CRP', 'Gene', (91, 94))	('patients', 'Species', '9606', (133, 141))	('neutrophils', 'MPA', (64, 75))	('monocytes', 'MPA', (77, 86))	('CRP', 'Gene', '1401', (91, 94))	('low', 'Var', (147, 150))	('sodium', 'Chemical', 'MESH:D012964', (151, 157))	('leukocytes', 'MPA', (52, 62))	('elevated', 'PosReg', (121, 129))	('inflammatory parameters', 'MPA', (18, 41))
785028	33552948	This work was supported by National Natural Science Foundation of China (grant number 81602731), Ministry of Science and Technology of China (grant number 2017YFC0113101), Department of Science and Technology of Sichuan Province (grant numbers 2019YFS0378 and 2018JY0277), the Cancer Research Foundation of China Anti-cancer Association for Young Scientists (grant number CAYC18A33), and CSCO-Genecast Oncology Research Found (grant number Y-2019Genecast-041).	('Cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('Cancer', 'Disease', 'MESH:D009369', (277, 283))	('2018JY0277', 'Var', (260, 270))	('cancer', 'Disease', (318, 324))	('Cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('Oncology', 'Phenotype', 'HP:0002664', (402, 410))
785087	33178944	There were 28 (54.9%), 11 (21.6%), and 12 (23.5%) patients treated by c-CRT, p-CRT, and IC, respectively.	('c-CRT', 'Var', (70, 75))	('patients', 'Species', '9606', (50, 58))	('p-CRT', 'Var', (77, 82))
785208	30586139	With the exception of EBS, among patients younger than 10 years, there were significantly higher proportions with genetic analysis compared with those older than 10 years (JEB: 35 [83.3%] vs 10 [47.6%], P = .003; DDEB: 32 [71.1%] vs 25 [42.4%], P = .004; and RDEB: 70 [74.5%] vs 114 [60.3%], P < .018).	('EB', 'Disease', 'MESH:D004820', (261, 263))	('EBS', 'Disease', 'MESH:D016110', (22, 25))	('patients', 'Species', '9606', (33, 41))	('RDEB', 'Disease', (259, 263))	('EB', 'Disease', 'MESH:D004820', (173, 175))	('EBS', 'Disease', (22, 25))	('RDEB', 'Disease', 'MESH:D016108', (259, 263))	('DDEB', 'Phenotype', 'HP:0007475', (213, 217))	('EB', 'Disease', 'MESH:D004820', (22, 24))	('EB', 'Disease', 'MESH:D004820', (215, 217))	('genetic analysis', 'Var', (114, 130))
785270	30671046	Although the total bacterial contents are different in six samples (C233-Normal and Tumor, C244-Normal and Tumor, C238-Tumor, and E756) when extracted using homogenization vs. lysis method, no specific extraction protocol provided consistently higher yields.	('E756', 'Var', (130, 134))	('Tumor', 'Phenotype', 'HP:0002664', (119, 124))	('C238-Tumor', 'Disease', (114, 124))	('C244-Normal', 'Var', (91, 102))	('Tumor', 'Phenotype', 'HP:0002664', (107, 112))	('C238-Tumor', 'Disease', 'MESH:D009369', (114, 124))	('C233-Normal', 'Var', (68, 79))	('Tumor', 'Phenotype', 'HP:0002664', (84, 89))
785277	30671046	Only two out of four esophageal samples (E756 and E758) showed a significantly higher abundance of Bacteroidetes using the homogenization method which was also in contrast to the lysis method that yielded higher abundance in gastric cancer samples (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('abundance', 'MPA', (86, 95))	('E756', 'Var', (41, 45))	('gastric cancer', 'Disease', (225, 239))	('gastric cancer', 'Disease', 'MESH:D013274', (225, 239))	('Bacteroidetes', 'MPA', (99, 112))	('E758', 'Var', (50, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (225, 239))	('higher', 'PosReg', (79, 85))
785280	30671046	In contrast, the C233 normal tissue sample seems to have greater bacterial content with the lysis extraction method (Figure 1), whereas significantly more Bacteroidetes was identified in this sample using the homogenization method and no difference in quantitation of Fusobacterium.	('bacterial content', 'MPA', (65, 82))	('C233 normal', 'Var', (17, 28))	('Fusobacterium', 'Species', '851', (268, 281))	('greater', 'PosReg', (57, 64))
785286	30671046	The presence of microbiome at genus level from all five samples, including esophageal tissue E765 and E757, Helicobacter pylori negative gastric sample G005, and H. pylori positive gastric samples G008 and G011 are all highly consistent between the two extraction methods (cosine similarity p < 0.05) (Figure 3).	('Helicobacter pylori', 'Species', '210', (108, 127))	('E757', 'Var', (102, 106))	('H. pylori', 'Species', '210', (162, 171))	('E765', 'Var', (93, 97))
785317	30671046	After subsequent washing steps with buffers AW1 (Qiagen ) and AW2 (Qiagen ), DNA is eluted using the elution buffer provided in the kit.	('AW1', 'Gene', (44, 47))	('AW1', 'Gene', '7727', (44, 47))	('AW2', 'Var', (62, 65))
785565	22213102	Association of Aurora-A (STK15) Kinase Polymorphisms With Clinical Outcome of Esophageal Cancer Treated With Preoperative Chemoradiation Aurora-A/STK15 is a serine/threonine kinase critical for regulated chromosome segregation and cytokinesis.	('Aurora-A', 'Gene', '6790', (137, 145))	('Esophageal Cancer', 'Disease', (78, 95))	('Aurora-A', 'Gene', (137, 145))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('STK15', 'Gene', '6790', (146, 151))	('STK15', 'Gene', (25, 30))	('STK15', 'Gene', '6790', (25, 30))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (78, 95))	('STK15', 'Gene', (146, 151))	('Association', 'Interaction', (0, 11))	('Aurora-A', 'Gene', (15, 23))	('Polymorphisms', 'Var', (39, 52))	('Aurora-A', 'Gene', '6790', (15, 23))
785566	22213102	We investigated the association between 2 nonsynonymous single nucleotide polymorphisms in the coding region of STK15, T91A (Phe31Ile) and G169A (Val57Ile), and clinical outcome of esophageal cancer treated with preoperative chemoradiation.	('T91A', 'Var', (119, 123))	('G169A', 'Var', (139, 144))	('STK15', 'Gene', (112, 117))	('esophageal cancer', 'Disease', (181, 198))	('STK15', 'Gene', '6790', (112, 117))	('Phe31Ile', 'Chemical', '-', (125, 133))	('G169A', 'Mutation', 'rs1047972', (139, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('T91A', 'Mutation', 'rs2273535', (119, 123))	('Val57Ile', 'Mutation', 'rs1047972', (146, 154))
785567	22213102	Genotypes at Phe31Ile and Val57Ile were assessed from peripheral blood lymphocytes of 190 esophageal cancer patients and were correlated to response to treatment, recurrence rate, risk of death, disease-free survival (DFS) and median survival time (MTS).	('Phe31Ile', 'Var', (13, 21))	('Val57Ile', 'Var', (26, 34))	('disease-free', 'Disease', (195, 207))	('death', 'Disease', (188, 193))	('death', 'Disease', 'MESH:D003643', (188, 193))	('esophageal cancer', 'Disease', (90, 107))	('Val57Ile', 'Mutation', 'rs1047972', (26, 34))	('Phe31Ile', 'Chemical', '-', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (108, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('men', 'Species', '9606', (157, 160))
785569	22213102	The heterozygous variant Phe31/Ile variant was significantly associated with tumor recurrence (odds ratio [OR] = 4.39; 95% confidence interval [CI], 2.12-8.94; P < .001), shorter DFS (P = .0001), and shorter MTS (P = .012).	('shorter', 'NegReg', (171, 178))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('shorter', 'NegReg', (200, 207))	('Phe31/Ile', 'SUBSTITUTION', 'None', (25, 34))	('tumor', 'Disease', (77, 82))	('Phe31/Ile', 'Var', (25, 34))
785570	22213102	For patients receiving cisplatin-based therapy, only the variant Phe31/Ile had an adverse effect on response (OR = 2.8; 95% CI, 1.01-5.17; P = .048) and MTS (P = .026).	('MTS', 'CPA', (153, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (23, 32))	('patients', 'Species', '9606', (4, 12))	('response', 'CPA', (100, 108))	('Phe31/Ile', 'Var', (65, 74))	('Phe31/Ile', 'SUBSTITUTION', 'None', (65, 74))
785571	22213102	Our study shows that functional SNPs in the STK15 gene are associated with higher rate of recurrence, higher likelihood of chemoratiotherapy-resistance, shorter DFS, and shorter MTS.	('SNPs', 'Var', (32, 36))	('STK15', 'Gene', '6790', (44, 49))	('STK15', 'Gene', (44, 49))	('DFS', 'MPA', (161, 164))	('shorter', 'NegReg', (153, 160))
785588	22213102	Two coding single nucleotide polymorphisms (SNPs) in the STK15 gene have been reported to fall within in the NH-2 terminal region of the Aurora-A protein and have been associated with functional consequences.	('Aurora-A', 'Gene', '6790', (137, 145))	('STK15', 'Gene', (57, 62))	('single nucleotide polymorphisms', 'Var', (11, 42))	('fall', 'NegReg', (90, 94))	('Aurora-A', 'Gene', (137, 145))	('associated with', 'Reg', (168, 183))	('STK15', 'Gene', '6790', (57, 62))	('fall', 'Phenotype', 'HP:0002527', (90, 94))
785589	22213102	The T91A SNP, which causes an amino acid change at codon 31 from phenylalanine to an isoleucin, was initially associated with enhanced cell transformation in vitro and significantly increased chromosomal instability in human colon cancers.	('phenylalanine', 'Chemical', 'MESH:D010649', (65, 78))	('increased', 'PosReg', (182, 191))	('human', 'Species', '9606', (219, 224))	('colon cancers', 'Disease', (225, 238))	('enhanced', 'PosReg', (126, 134))	('amino', 'MPA', (30, 35))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('chromosomal instability', 'Phenotype', 'HP:0040012', (192, 215))	('T91A', 'Var', (4, 8))	('colon cancers', 'Phenotype', 'HP:0003003', (225, 238))	('cell transformation', 'CPA', (135, 154))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (182, 215))	('chromosomal instability', 'MPA', (192, 215))	('colon cancers', 'Disease', 'MESH:D015179', (225, 238))	('T91A', 'Mutation', 'rs2273535', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
785591	22213102	However, the 91A allele has also been shown to yield protective effects, such as in patients with hereditary nonpolyposis colorectal cancer (HNPCC).	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('HNPCC', 'Disease', 'None', (141, 146))	('patients', 'Species', '9606', (84, 92))	('HNPCC', 'Disease', (141, 146))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (98, 139))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (98, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('91A', 'Var', (13, 16))	('hereditary nonpolyposis colorectal cancer', 'Disease', (98, 139))
785592	22213102	The second functional SNP, the G169A at codon 57, causes an amino acid change from valine to an isoleucine, and reduces Aurora-A kinase activity.	('valine', 'Chemical', 'MESH:D014633', (83, 89))	('isoleucine', 'Chemical', 'MESH:D007532', (96, 106))	('G169A', 'Mutation', 'rs1047972', (31, 36))	('Aurora-A', 'Gene', '6790', (120, 128))	('Aurora-A', 'Gene', (120, 128))	('G169A', 'Var', (31, 36))	('amino acid change', 'MPA', (60, 77))	('reduces', 'NegReg', (112, 119))	('causes', 'Reg', (50, 56))
785593	22213102	The T91A and G169A haplotype combinations (91A-169A; T91-169A) have been shown to be significantly associated with esophageal cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('T91A', 'Var', (4, 8))	('G169A', 'Var', (13, 18))	('T91-169A', 'Var', (53, 61))	('esophageal cancer', 'Disease', (115, 132))	('T91-169A', 'SUBSTITUTION', 'None', (53, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('T91A', 'Mutation', 'rs2273535', (4, 8))	('G169A', 'Mutation', 'rs1047972', (13, 18))	('associated', 'Reg', (99, 109))
785594	22213102	Regulated Aurora-A is critical for maintenance of genomic integrity after DNA damage and the STK15 SNPs disrupt some physiologic functions of Aurora-A; therefore, we hypothesized that the STK T91A and G169A SNPs would mediate CTXRT resistance and lead to adverse outcomes in patients with E/GEJC.	('mediate', 'Reg', (218, 225))	('G169A', 'Var', (201, 206))	('E/GEJC', 'Disease', (289, 295))	('T91A', 'Var', (192, 196))	('STK', 'Var', (188, 191))	('G169A', 'Mutation', 'rs1047972', (201, 206))	('Aurora-A', 'Gene', '6790', (10, 18))	('lead to', 'Reg', (247, 254))	('CTXRT resistance', 'MPA', (226, 242))	('Aurora-A', 'Gene', (10, 18))	('Aurora-A', 'Gene', (142, 150))	('T91A', 'Mutation', 'rs2273535', (192, 196))	('Aurora-A', 'Gene', '6790', (142, 150))	('STK15', 'Gene', '6790', (93, 98))	('STK15', 'Gene', (93, 98))	('patients', 'Species', '9606', (275, 283))	('CTXRT', 'Chemical', '-', (226, 231))
785595	22213102	We discuss our results in 190 patients in whom we studied STK15 T91A and G169A.	('G169A', 'Mutation', 'rs1047972', (73, 78))	('STK15', 'Gene', (58, 63))	('STK15', 'Gene', '6790', (58, 63))	('T91A', 'Mutation', 'rs2273535', (64, 68))	('patients', 'Species', '9606', (30, 38))	('G169A', 'Var', (73, 78))
785611	22213102	We set the study endpoint event as the date of the patient's first recurrence or overall death and applied the Cox proportional hazard model to estimate the hazard ratios (HRs) associated with the Phe31Ile and Val57Ile polymorphisms.	('death', 'Disease', 'MESH:D003643', (89, 94))	('Phe31Ile', 'Chemical', '-', (197, 205))	('death', 'Disease', (89, 94))	('Val57Ile', 'Var', (210, 218))	('patient', 'Species', '9606', (51, 58))	('Phe31Ile', 'Var', (197, 205))	('Val57Ile', 'Mutation', 'rs1047972', (210, 218))
785633	22213102	Compared with patients carrying the wild-type TT genotypes (Phe/Phe), patients with the heterozygous variant AT genotype (Phe31/Ile) were at significantly increased risk of tumor relapse with an adjusted odds ratio (OR) of 4.39 (95% confidence interval [CI], 2.12-8.94) (P < .001).	('patients', 'Species', '9606', (70, 78))	('Phe', 'Chemical', 'MESH:D010649', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('AT', 'Disease', 'None', (109, 111))	('Phe31/Ile', 'SUBSTITUTION', 'None', (122, 131))	('Phe31/Ile', 'Var', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('patients', 'Species', '9606', (14, 22))	('Phe', 'Chemical', 'MESH:D010649', (60, 63))	('Phe', 'Chemical', 'MESH:D010649', (64, 67))
785634	22213102	There was no association for the homozygous variant AA genotype (Ile/Ile) with risk of relapse; however, there was a significant association of combined variant alleles (AT + AA) with risk of relapse with an adjusted OR of 3.73 (95%CI, 2.12-8.94) (P = .016).	('variant', 'Var', (153, 160))	('AT', 'Disease', 'None', (170, 172))	('Ile', 'Chemical', 'MESH:D007532', (65, 68))	('Ile', 'Chemical', 'MESH:D007532', (69, 72))	('relapse', 'Disease', (192, 199))
785635	22213102	Kaplan-Meier estimates demonstrated that both variant allele and combined variant alleles were associated with significantly shorter DFS compared with the wild-type allele (AT: 12.2 months, AT + AA: 12.63 months vs TT: 42.17 months; P = .0001 and 0.0006, respectively).	('DFS', 'MPA', (133, 136))	('variant', 'Var', (46, 53))	('AT', 'Disease', 'None', (173, 175))	('shorter', 'NegReg', (125, 132))	('AT', 'Disease', 'None', (190, 192))
785636	22213102	Although the STK15-T91A SNP was not significantly associated with risk of death, the median survival time (MTS) of patients carrying 1 copy of the Phe31Ile allele was significantly shorter than in patients with the wild-type genotype (MTS, TA: 22.5 months vs TT: 51.3 months; P = .012).	('patients', 'Species', '9606', (115, 123))	('Phe31Ile', 'Var', (147, 155))	('patients', 'Species', '9606', (197, 205))	('T91A', 'Mutation', 'rs2273535', (19, 23))	('shorter', 'NegReg', (181, 188))	('STK15', 'Gene', '6790', (13, 18))	('STK15', 'Gene', (13, 18))	('Phe31Ile', 'Chemical', '-', (147, 155))	('death', 'Disease', 'MESH:D003643', (74, 79))	('death', 'Disease', (74, 79))
785637	22213102	The STK15 Val57Ile polymorphism did not have an effect on clinical outcome (Table 1b).	('Val57Ile', 'Var', (10, 18))	('STK15', 'Gene', '6790', (4, 9))	('STK15', 'Gene', (4, 9))	('Val57Ile', 'Mutation', 'rs1047972', (10, 18))
785638	22213102	When analyzing the effects of the STK15 SNP only within the 134 patients treated with cisplatin-based chemotherapy, the T91A variant Phe31/Ile was significantly associated with lack of response to CTXRT (Table 2a).	('T91A', 'Var', (120, 124))	('Phe31/Ile', 'SUBSTITUTION', 'None', (133, 142))	('patients', 'Species', '9606', (64, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('Phe31/Ile', 'Var', (133, 142))	('STK15', 'Gene', (34, 39))	('STK15', 'Gene', '6790', (34, 39))	('response', 'MPA', (185, 193))	('T91A', 'Mutation', 'rs2273535', (120, 124))	('lack', 'NegReg', (177, 181))	('CTXRT', 'Chemical', '-', (197, 202))
785639	22213102	Patients with the heterozygous variant phenotype (AT) carried a 2.28-fold (95%CI, 1.01-5.17) higher risk of lacking response than patients with homozygous wild-type genotype (P = .048).	('AT', 'Disease', 'None', (50, 52))	('lacking response', 'MPA', (108, 124))	('patients', 'Species', '9606', (130, 138))	('Patients', 'Species', '9606', (0, 8))	('variant', 'Var', (31, 38))
785640	22213102	Similarly, combined variant alleles were significantly associated with lack of response to CTXRT with an adjusted OR of 2.15 (95%CI, 0.98-4.75; P = .047).	('lack', 'NegReg', (71, 75))	('CTXRT', 'Chemical', '-', (91, 96))	('response', 'MPA', (79, 87))	('variant', 'Var', (20, 27))
785641	22213102	In addition, heterozygous Phe31Ile variant genotype and combined variant alleles (AT + AA) were significantly associated with increased risk of relapse (AT OR = 3.76; 95% CI, 1.62-8.70; P = .002; AT + AA OR = 3.42; 95% CI, 1.48-7.96; P = .044).	('AT', 'Disease', 'None', (153, 155))	('AT', 'Disease', 'None', (82, 84))	('Phe31Ile variant', 'Var', (26, 42))	('AT', 'Disease', 'None', (196, 198))	('Phe31Ile', 'Chemical', '-', (26, 34))	('relapse', 'CPA', (144, 151))
785643	22213102	Intriguingly, only the variant Phe31/Ile allele was associated with shorter median survival time (MTS: 20.67 months) compared with the wild-type Phe31/Phe31 allele (MTS: 34.8; P = .026) but the combined variant allele was not (P = .13).	('median survival', 'MPA', (76, 91))	('Phe31', 'Chemical', '-', (31, 36))	('Phe31', 'Chemical', '-', (151, 156))	('Phe31', 'Chemical', '-', (145, 150))	('Phe31/Ile', 'SUBSTITUTION', 'None', (31, 40))	('Phe31/Ile', 'Var', (31, 40))	('shorter', 'NegReg', (68, 75))
785644	22213102	The Val57Ile polymorphism alone was not significantly associated with risk of response to CTXRT, relapse, or death in the cisplatin-treated group (Table 2b).	('death', 'Disease', 'MESH:D003643', (109, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('death', 'Disease', (109, 114))	('Val57Ile', 'Var', (4, 12))	('CTXRT', 'Chemical', '-', (90, 95))	('Val57Ile', 'Mutation', 'rs1047972', (4, 12))
785645	22213102	There were 4 possible STK15 haplotypes derived from the 2 known genotypes (ie, 91T-169G, 91A-169G, 91T-169A, and 91A-169A).	('STK15', 'Gene', (22, 27))	('STK15', 'Gene', '6790', (22, 27))	('91A-169G', 'Var', (89, 97))	('91A-169A', 'Var', (113, 121))	('91T-169A', 'Var', (99, 107))	('91T-169G', 'Var', (79, 87))
785648	22213102	Variant allele at the PheIle31 locus (AT or AA) and wild-type allele at Val57 carried a significant risk of relapse with an adjusted OR of 3.49 (95%CI, 1.54-7.91; P = .03).	('relapse', 'CPA', (108, 115))	('AT', 'Disease', 'None', (38, 40))	('Variant', 'Var', (0, 7))
785649	22213102	The Kaplan-Meier estimates demonstrated that patients with at least 1 variant allele at the Ile31 and Val57 loci had a significantly shorter disease-free survival time of 12.63 months than patients in the reference genotype group (DFS = 42.17; P = .003 (Fig.	('shorter', 'NegReg', (133, 140))	('Ile31', 'Gene', (92, 97))	('disease-free survival time', 'CPA', (141, 167))	('patients', 'Species', '9606', (45, 53))	('variant', 'Var', (70, 77))	('patients', 'Species', '9606', (189, 197))	('Val57', 'Gene', (102, 107))	('Ile', 'Chemical', 'MESH:D007532', (92, 95))
785652	22213102	The 3 major findings of this study are that: 1) the heterozygous variant allele of the Phe31Ile is associated with significantly higher risk of tumor relapse and shorter DFS after preoperative CTXRT, 2) the increasing number of variant alleles at both loci doubles the risk of relapse, and 3) the variant Phe31/Ile alone has an impact on the response to CTXRT, relapse rate, DFS, and median survival in patients receiving cisplatin-based CTXRT.	('Phe31Ile', 'Chemical', '-', (87, 95))	('relapse', 'CPA', (277, 284))	('variant', 'Var', (65, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (422, 431))	('patients', 'Species', '9606', (403, 411))	('Phe31/Ile', 'SUBSTITUTION', 'None', (305, 314))	('impact', 'Reg', (328, 334))	('Phe31Ile', 'Gene', (87, 95))	('shorter', 'NegReg', (162, 169))	('CTXRT', 'Chemical', '-', (354, 359))	('Phe31/Ile', 'Var', (305, 314))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('DFS', 'MPA', (375, 378))	('CTXRT', 'Chemical', '-', (438, 443))	('CTXRT', 'Chemical', '-', (193, 198))	('DFS', 'MPA', (170, 173))	('relapse', 'MPA', (361, 368))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
785653	22213102	STK15 has been linked to tumor development and progression through it amplification and/or overexpression in a variety of human cancers, including colon, bladder, breast, ovarian, liver, pancreas, gastric and lung.	('human', 'Species', '9606', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('lung', 'Disease', (209, 213))	('STK15', 'Gene', (0, 5))	('liver', 'Disease', (180, 185))	('pancreas', 'Disease', (187, 195))	('ovarian', 'Disease', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('overexpression', 'PosReg', (91, 105))	('cancers', 'Disease', (128, 135))	('STK15', 'Gene', '6790', (0, 5))	('breast', 'Disease', (163, 169))	('colon', 'Disease', (147, 152))	('bladder', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', (25, 30))	('linked', 'Reg', (15, 21))	('gastric', 'Disease', (197, 204))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('men', 'Species', '9606', (38, 41))	('gastric', 'Disease', 'MESH:D013274', (197, 204))	('amplification', 'Var', (70, 83))
785655	22213102	It has been also shown that aberrant expression of STK15 leads to deregulation of proteins mediating DNA damage response, such as BRCA1, p53, and CDC25B.	('BRCA1', 'Gene', (130, 135))	('BRCA1', 'Gene', '672', (130, 135))	('deregulation of', 'MPA', (66, 81))	('p53', 'Gene', '7157', (137, 140))	('STK15', 'Gene', '6790', (51, 56))	('proteins', 'Protein', (82, 90))	('CDC25B', 'Gene', '994', (146, 152))	('aberrant expression', 'Var', (28, 47))	('STK15', 'Gene', (51, 56))	('p53', 'Gene', (137, 140))	('CDC25B', 'Gene', (146, 152))
785657	22213102	The Phe31Ile SNP is of special interest since Ewart-Toand et al showed that the variant allele (Ile) was more oncogenic than the wild-type Phe31, was preferentially amplified, and associated with aneuploidy in human cancers.	('aneuploidy', 'Disease', (196, 206))	('more', 'PosReg', (105, 109))	('Phe31', 'Chemical', '-', (4, 9))	('variant', 'Var', (80, 87))	('oncogenic', 'CPA', (110, 119))	('Ile', 'Chemical', 'MESH:D007532', (9, 12))	('aneuploidy', 'Disease', 'MESH:D000782', (196, 206))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Ile', 'Chemical', 'MESH:D007532', (96, 99))	('human', 'Species', '9606', (210, 215))	('preferentially', 'PosReg', (150, 164))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('associated with', 'Reg', (180, 195))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('Phe31', 'Chemical', '-', (139, 144))	('Phe31Ile', 'Chemical', '-', (4, 12))
785658	22213102	In our study the variant Ile imparted the strongest risk of adverse outcome with increased recurrence rate and shortest DFS.	('recurrence', 'CPA', (91, 101))	('increased', 'PosReg', (81, 90))	('variant', 'Var', (17, 24))	('Ile', 'Chemical', 'MESH:D007532', (25, 28))
785659	22213102	One possible functional explanation is that esophageal cancers developing in a STK15 variant Ile background harbor enhanced genomic instability and increased clonal diversity more likely to lead to the generation of clones capable of invasion and metastasis.	('esophageal cancers', 'Disease', (44, 62))	('increased', 'PosReg', (148, 157))	('esophageal cancers', 'Disease', 'MESH:D004938', (44, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('variant', 'Var', (85, 92))	('invasion', 'CPA', (234, 242))	('genomic', 'MPA', (124, 131))	('STK15', 'Gene', (79, 84))	('STK15', 'Gene', '6790', (79, 84))	('Ile', 'Chemical', 'MESH:D007532', (93, 96))	('enhanced', 'PosReg', (115, 123))	('clonal', 'CPA', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('lead', 'Reg', (190, 194))
785661	22213102	Our data suggest that although alone the Val57Ile SNP is not associated with clinical biology, the presence of the Ile variant allele enhances the adverse effect of the adverse effect of the Phe31Ile variant.	('adverse effect', 'MPA', (147, 161))	('Ile', 'Chemical', 'MESH:D007532', (196, 199))	('Phe31Ile variant', 'Var', (191, 207))	('Phe31Ile', 'Chemical', '-', (191, 199))	('Ile', 'Gene', (115, 118))	('enhances', 'PosReg', (134, 142))	('Val57Ile', 'Mutation', 'rs1047972', (41, 49))	('Ile', 'Chemical', 'MESH:D007532', (115, 118))	('Ile', 'Chemical', 'MESH:D007532', (46, 49))
785662	22213102	In vitro, the combination of variant Phe31Ile and Val57Ile significantly reduces Aurora-A kinase activity (to 15% compared with the wild type) and most importantly induces abnormal nuclear morphology and genomic instability in human immortalized fibroblasts.	('Val57Ile', 'Var', (50, 58))	('induces', 'Reg', (164, 171))	('Aurora-A', 'Gene', (81, 89))	('Val57Ile', 'Mutation', 'rs1047972', (50, 58))	('reduces', 'NegReg', (73, 80))	('human', 'Species', '9606', (227, 232))	('Aurora-A', 'Gene', '6790', (81, 89))	('genomic instability', 'CPA', (204, 223))	('variant Phe31Ile', 'Var', (29, 45))	('Phe31Ile', 'Chemical', '-', (37, 45))	('nuclear morphology', 'CPA', (181, 199))
785665	22213102	Further studies are needed to confirm these observations, and to characterize the mechanisms by which these variant differentially modify esophageal cancer outcome.	('esophageal cancer', 'Disease', (138, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('variant', 'Var', (108, 115))	('modify', 'Reg', (131, 137))
785667	22213102	In summary, we found that in esophageal cancer patients undergoing preoperative CTXRT, the heterozygous STK15-Ile31 variant is associated with increased rate of relapse and shorter DFS.	('STK15', 'Gene', '6790', (104, 109))	('patients', 'Species', '9606', (47, 55))	('Ile', 'Chemical', 'MESH:D007532', (110, 113))	('shorter', 'NegReg', (173, 180))	('esophageal cancer', 'Disease', (29, 46))	('CTXRT', 'Chemical', '-', (80, 85))	('DFS', 'MPA', (181, 184))	('variant', 'Var', (116, 123))	('relapse', 'CPA', (161, 168))	('STK15', 'Gene', (104, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
785668	22213102	In particular, for patients who were treated with cisplatin-based combination, it was associated with poor response to CTXRT and shorter survival.	('CTXRT', 'Chemical', '-', (119, 124))	('patients', 'Species', '9606', (19, 27))	('cisplatin-based combination', 'Var', (50, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('shorter', 'NegReg', (129, 136))
785669	22213102	Phe31Ile and Val57Ile variant produce an allele dependent cumulative adverse effect on relapse rate and DFS.	('DFS', 'CPA', (104, 107))	('Phe31Ile', 'Var', (0, 8))	('adverse', 'NegReg', (69, 76))	('Val57Ile', 'Var', (13, 21))	('Val57Ile', 'Mutation', 'rs1047972', (13, 21))	('relapse rate', 'CPA', (87, 99))	('Phe31Ile', 'Chemical', '-', (0, 8))
785678	18676772	Finally, the treatment with GRN163L led to a significant reduction in tumor volume in a subcutaneous tumor model.	('GRN163L', 'Chemical', 'MESH:C519562', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (88, 106))	('reduction', 'NegReg', (57, 66))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('GRN163L', 'Var', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
785683	18676772	Although telomeres play a vital role in the maintenance of genomic integrity and cellular health, telomere dysfunction or excessive telomere shortening caused by mutation or inherited disorder may result in genetic instability and development of cancer.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('result in', 'Reg', (197, 206))	('cancer', 'Disease', (246, 252))	('telomere dysfunction', 'Disease', 'MESH:C536801', (98, 118))	('telomere dysfunction', 'Disease', (98, 118))	('genetic instability', 'CPA', (207, 226))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('inherited disorder', 'Disease', 'MESH:D030342', (174, 192))	('mutation', 'Var', (162, 170))	('inherited disorder', 'Disease', (174, 192))	('telomere shortening', 'Phenotype', 'HP:0031413', (132, 151))
785684	18676772	Consistent with these findings, it has been demonstrated that telomere length may serve as a marker for progression and/or prognosis for cancers such as neuroblastoma, prostate, colon, breast, brain, head and neck, and lung.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('neuroblastoma', 'Disease', 'MESH:D009447', (153, 166))	('lung', 'Disease', (219, 223))	('colon', 'Disease', (178, 183))	('telomere', 'Var', (62, 70))	('neuroblastoma', 'Disease', (153, 166))	('brain', 'Disease', (193, 198))	('breast', 'Disease', (185, 191))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('neuroblastoma', 'Phenotype', 'HP:0003006', (153, 166))	('cancers', 'Disease', (137, 144))	('prostate', 'Disease', (168, 176))
785686	18676772	Telomerase extends telomere length by adding TTAGGG sequences to guanine-rich strand of telomeric DNA.	('TTAGGG sequences', 'Var', (45, 61))	('extends', 'PosReg', (11, 18))	('telomere length', 'CPA', (19, 34))	('guanine', 'Chemical', 'MESH:D006147', (65, 72))
785691	18676772	Conversely, the induction of telomerase in normal human cells increases their life-span in culture and oncogenic conversion in the presence of SV40 T antigen and H-ras.	('S', 'Chemical', '-', (143, 144))	('increases', 'PosReg', (62, 71))	('SV40 T', 'Var', (143, 149))	('H-ras', 'Protein', (162, 167))	('oncogenic conversion', 'CPA', (103, 123))	('telomerase', 'Protein', (29, 39))	('life-span in culture', 'CPA', (78, 98))	('human', 'Species', '9606', (50, 55))
785697	18676772	Since telomeres are shorter in cancer cells relative to normal cells whereas telomerase activity is elevated in most cancers but absent or low in normal somatic cells, the inhibitors of telomerase activity have a strong potential to be used as anti-cancer therapeutics which may inhibit proliferation of tumor cells while having little or no effect on normal cells.	('cancer', 'Disease', (249, 255))	('activity', 'MPA', (88, 96))	('telomeres', 'MPA', (6, 15))	('tumor', 'Disease', (304, 309))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('S', 'Chemical', '-', (0, 1))	('shorter', 'NegReg', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('inhibitors', 'Var', (172, 182))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', (117, 124))	('proliferation', 'CPA', (287, 300))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('inhibit', 'NegReg', (279, 286))	('elevated', 'PosReg', (100, 108))
785708	18676772	Addition of these drugs to cultures pretreated with GRN163L had a significant additive effect on GRN163L-induced cancer cell death.	('GRN163L-induced', 'Var', (97, 112))	('GRN163L', 'Chemical', 'MESH:C519562', (52, 59))	('GRN163L', 'Chemical', 'MESH:C519562', (97, 104))	('cancer cell death', 'Disease', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer cell death', 'Disease', 'MESH:D003643', (113, 130))
785709	18676772	Efficacy of GRN163L was also tested in a murine model in which SCID-mice were subcutaneously inoculated with SEG-1 adenocarcinoma cells and following appearance of palpable tumors, treated with either PBS or GRN163L.	('mice', 'Species', '10090', (68, 72))	('S', 'Chemical', '-', (203, 204))	('GRN163L', 'Var', (208, 215))	('S', 'Chemical', '-', (63, 64))	('GRN163L', 'Chemical', 'MESH:C519562', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('SCID', 'Disease', 'MESH:D053632', (63, 67))	('GRN163L', 'Chemical', 'MESH:C519562', (208, 215))	('murine', 'Species', '10090', (41, 47))	('tumors', 'Disease', (173, 179))	('SCID', 'Disease', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('adenocarcinoma cells', 'Disease', 'MESH:C538614', (115, 135))	('PBS', 'Chemical', 'MESH:D007854', (201, 204))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('S', 'Chemical', '-', (109, 110))	('adenocarcinoma cells', 'Disease', (115, 135))
785720	18676772	Primer sequences of Tel-1, Tel-2, 36B4-U and 36B4-D were previously described.	('36B4-D', 'Var', (45, 51))	('Tel-1', 'Gene', (20, 25))	('Tel-1', 'Gene', '472', (20, 25))	('Tel-2', 'Gene', '51513', (27, 32))	('36B4-U', 'Var', (34, 40))	('Tel-2', 'Gene', (27, 32))
785727	18676772	GRN163L is a palmitoyl (C16) lipid - attached oligonucleotide (5'-Palm-TAGGGTTAGACAA 3'), targeting RNA component of telomerase and has N3'-P5' thio-phosphoramidate back bone.	('telomerase', 'Protein', (117, 127))	('thio-phosphoramidate', 'Chemical', '-', (144, 164))	('C16', 'Chemical', 'MESH:D019308', (24, 27))	('GRN163L', 'Var', (0, 7))	('targeting RNA component', 'MPA', (90, 113))	('lipid', 'Chemical', 'MESH:D008055', (29, 34))	('oligonucleotide', 'Chemical', 'MESH:D009841', (46, 61))	('GRN163L', 'Chemical', 'MESH:C519562', (0, 7))
785737	18676772	One day before this assay, the treated cells were plated on Lab-Tek slides in the presence of mismatch or match (GRN163L) oligonucleotide and the attached cells were stained for beta-galactosidase expression, a marker for cellular senescence.	('Tek', 'Gene', (64, 67))	('oligonucleotide', 'Chemical', 'MESH:D009841', (122, 137))	('GRN163L', 'Gene', (113, 120))	('beta-galactosidase', 'Gene', '2720', (178, 196))	('GRN163L', 'Chemical', 'MESH:C519562', (113, 120))	('beta-galactosidase', 'Gene', (178, 196))	('mismatch', 'Var', (94, 102))	('Tek', 'Gene', '7010', (64, 67))
785752	18676772	GRN163L is a Palmitoyl (C16) lipid - conjugated oligonucleotide N3'-P5'-thio-phosphoramidate targeting template region of RNA component of telomerase (hTR) (Figure 3A).	('Palmitoyl (C16) lipid', 'Chemical', '-', (13, 34))	("oligonucleotide N3'-P5'-thio-phosphoramidate", 'Chemical', '-', (48, 92))	('GRN163L', 'Var', (0, 7))	('hTR', 'Gene', (151, 154))	('hTR', 'Gene', '7012', (151, 154))	('GRN163L', 'Chemical', 'MESH:C519562', (0, 7))
785760	18676772	Similarly, the treatment with 1 muM of GRN163L led to >95% inhibition of telomerase activity in FLO-1 (Figure 3 D) and BIC-1 cells (not shown).	('inhibition', 'NegReg', (59, 69))	('FLO-1', 'Chemical', '-', (96, 101))	('S', 'Chemical', '-', (0, 1))	('GRN163L', 'Var', (39, 46))	('telomerase', 'Enzyme', (73, 83))	('GRN163L', 'Chemical', 'MESH:C519562', (39, 46))	('BIC-1', 'CellLine', 'CVCL:8092', (119, 124))
785765	18676772	Consistent with telomerase activity data 1 muM GRN163L was enough to induce a marked (80%) growth inhibition in FLO-1 cells (Figure 4B).	('growth inhibition', 'CPA', (91, 108))	('GRN163L', 'Var', (47, 54))	('GRN163L', 'Chemical', 'MESH:C519562', (47, 54))	('FLO-1', 'Chemical', '-', (112, 117))
785774	18676772	Interestingly, a large fraction (64+-7%) of SEG-1 cells treated with GRN163L also stained positive for beta-galactosidase.	('S', 'Chemical', '-', (44, 45))	('GRN163L', 'Chemical', 'MESH:C519562', (69, 76))	('GRN163L', 'Var', (69, 76))	('beta-galactosidase', 'Gene', '2720', (103, 121))	('beta-galactosidase', 'Gene', (103, 121))
785777	18676772	These data indicate that GRN163L induced both the senescence and apoptosis in adenocarcinoma cells.	('adenocarcinoma cells', 'Disease', (78, 98))	('GRN163L', 'Chemical', 'MESH:C519562', (25, 32))	('adenocarcinoma cells', 'Disease', 'MESH:C538614', (78, 98))	('senescence', 'CPA', (50, 60))	('GRN163L', 'Var', (25, 32))	('apoptosis', 'CPA', (65, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
785778	18676772	We have also evaluated the impact of other novel agents on GRN163L induced adenocarcinoma cell death.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('GRN163L', 'Chemical', 'MESH:C519562', (59, 66))	('adenocarcinoma cell death', 'Disease', (75, 100))	('GRN163L', 'Var', (59, 66))	('adenocarcinoma cell death', 'Disease', 'MESH:C538614', (75, 100))
785779	18676772	Of several agents tested, a DNA interacting drug "doxorubicin" and a protease inhibitor "ritonavir" had a significant additive effect on GRN163L-induced cell death.	('doxorubicin', 'Chemical', 'MESH:D004317', (50, 61))	('ritonavir', 'Chemical', 'MESH:D019438', (89, 98))	('GRN163L-induced', 'Var', (137, 152))	('GRN163L', 'Chemical', 'MESH:C519562', (137, 144))	('cell death', 'CPA', (153, 163))
785780	18676772	Addition of ritonavir and doxorubicin to cultures pretreated with GRN163L for 10 days led to >=80% cell death within three days of addition (Figure 6A), compared to significantly higher viability of cells treated with either drug alone.	('GRN163L', 'Chemical', 'MESH:C519562', (66, 73))	('doxorubicin', 'Chemical', 'MESH:D004317', (26, 37))	('cell death', 'CPA', (99, 109))	('ritonavir', 'Chemical', 'MESH:D019438', (12, 21))	('GRN163L', 'Var', (66, 73))
785787	18676772	A significant additive effect of doxorubicin and ritonavir was observed on GRN163L induced growth inhibition; and 6) Intraperitoneal injections of GRN163L caused a significant reduction in tumor size in vivo.	('doxorubicin', 'Chemical', 'MESH:D004317', (33, 44))	('reduction', 'NegReg', (176, 185))	('tumor', 'Disease', (189, 194))	('ritonavir', 'Chemical', 'MESH:D019438', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('growth inhibition', 'CPA', (91, 108))	('GRN163L', 'Gene', (75, 82))	('GRN163L', 'Chemical', 'MESH:C519562', (75, 82))	('GRN163L', 'Var', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('GRN163L', 'Chemical', 'MESH:C519562', (147, 154))
785800	18676772	Although for cancers such as cervical, the inhibition of telomerase induces apoptosis within a few days without any requirement of telomere shortening, the cell death in majority of cancer cells occurs after a lag period of few weeks which is probably required for reduction of telomere length below critical limit.	('induces', 'Reg', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('inhibition', 'Var', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancer', 'Disease', (182, 188))	('cancers', 'Disease', (13, 20))	('apoptosis', 'CPA', (76, 85))	('cervical', 'Disease', (29, 37))	('telomere shortening', 'Phenotype', 'HP:0031413', (131, 150))	('telomerase', 'Protein', (57, 67))
785802	18676772	Consistent with this, the inhibitors of telomerase have been shown to induce apoptotic cell death or both the apoptosis and senescence in different cancer cell lines.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('senescence', 'CPA', (124, 134))	('telomerase', 'Protein', (40, 50))	('inhibitors', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('apoptotic cell death', 'CPA', (77, 97))	('induce', 'PosReg', (70, 76))	('apoptosis', 'CPA', (110, 119))
785803	18676772	In our study the adenocarcinoma cells treated with GRN163L stained positive for not only annexin-V, but also for beta-galactosidase, indicating that growth inhibition in these cells was associated with induction of both the senescence and apoptosis.	('positive', 'Reg', (67, 75))	('growth inhibition', 'CPA', (149, 166))	('senescence', 'CPA', (224, 234))	('apoptosis', 'CPA', (239, 248))	('adenocarcinoma cells', 'Disease', 'MESH:C538614', (17, 37))	('GRN163L', 'Chemical', 'MESH:C519562', (51, 58))	('adenocarcinoma cells', 'Disease', (17, 37))	('annexin-V', 'Gene', (89, 98))	('annexin-V', 'Gene', '308', (89, 98))	('beta-galactosidase', 'Gene', '2720', (113, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('beta-galactosidase', 'Gene', (113, 131))	('GRN163L', 'Var', (51, 58))
785804	18676772	Induction of both the senescence and apoptosis in adenocarcinoma cells following inhibition of telomerase is consistent with our earlier observations.	('telomerase', 'Protein', (95, 105))	('adenocarcinoma cells', 'Disease', (50, 70))	('apoptosis', 'CPA', (37, 46))	('inhibition', 'Var', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('senescence', 'CPA', (22, 32))	('adenocarcinoma cells', 'Disease', 'MESH:C538614', (50, 70))
785818	18676772	These data show that telomerase is a potential target for Barrett's esophageal adenocarcinoma and GRN163L is a potent and specific telomerase inhibitor which, either alone or in combination with agents, such as ritonavir and doxorubicin, is suited for in vivo utilization in human clinical trials.	('doxorubicin', 'Chemical', 'MESH:D004317', (225, 236))	('ritonavir', 'Chemical', 'MESH:D019438', (211, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('human', 'Species', '9606', (275, 280))	('GRN163L', 'Var', (98, 105))	("Barrett's esophageal adenocarcinoma", 'Disease', 'MESH:D001471', (58, 93))	("Barrett's esophageal adenocarcinoma", 'Phenotype', 'HP:0100580', (58, 93))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (68, 93))	('GRN163L', 'Chemical', 'MESH:C519562', (98, 105))	("Barrett's esophageal adenocarcinoma", 'Disease', (58, 93))
785838	33672287	In general, cancer cells may be characterized by global DNA hypomethylation and focal hypermethylation.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('global DNA hypomethylation', 'Var', (49, 75))	('focal hypermethylation', 'Var', (80, 102))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
785839	33672287	Loss of DNA methylation is frequently noted within gene promoters, enhancers, non-coding sequences, and repeated elements, which triggers overexpression of several oncogenes, imprinted genes, cancer-testis genes, and transposable elements (TEs).	('triggers', 'Reg', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('Loss', 'NegReg', (0, 4))	('cancer-testis', 'Disease', (192, 205))	('cancer-testis', 'Disease', 'MESH:D013736', (192, 205))	('methylation', 'Var', (12, 23))	('DNA', 'MPA', (8, 11))	('overexpression', 'PosReg', (138, 152))
785840	33672287	In contrast, tumor suppressor genes (TSGs), which are involved in cell proliferation, apoptosis, DNA repair, or immune response, are frequently silenced by the hypermethylation within gene promoter.	('tumor suppressor', 'Gene', (13, 29))	('hypermethylation', 'Var', (160, 176))	('tumor suppressor', 'Gene', '7248', (13, 29))	('silenced', 'NegReg', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
785853	33672287	Some of the KRAB-ZFPs also contain additional domains at their N-terminus, such as "SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA" (SCAN) or "domain of the unknown function" (DUF3669).	('SRE-ZBP', 'Gene', (84, 91))	('ZFP', 'Gene', '55888', (17, 20))	('AW-1', 'Gene', (102, 106))	('ZFP', 'Gene', (17, 20))	('CTfin51', 'Gene', (93, 100))	('SRE-ZBP', 'Gene', '7741', (84, 91))	('DUF3669', 'Var', (171, 178))	('AW-1', 'Gene', '7727', (102, 106))
785872	33672287	This mechanism may be explained by repeated cycles of TE sequence alterations escaping KRAB-ZFP-mediated repression followed by KRAB-ZFP mutations aimed at the adequate recognition and silencing of the novel TE.	('ZFP', 'Gene', '55888', (133, 136))	('ZFP', 'Gene', (133, 136))	('mutations', 'Var', (137, 146))	('silencing', 'NegReg', (185, 194))	('ZFP', 'Gene', '55888', (92, 95))	('alterations', 'Var', (66, 77))	('ZFP', 'Gene', (92, 95))
785874	33672287	Therefore, tight regulation of TE epigenetic status is essential for appropriate development and cell homeostasis, whereas any dysregulation may lead to aberrant differentiation and various pathologic processes, including carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (222, 236))	('aberrant differentiation', 'CPA', (153, 177))	('carcinogenesis', 'Disease', (222, 236))	('dysregulation', 'Var', (127, 140))	('lead to', 'Reg', (145, 152))
785889	33672287	The ZNF471 promoter region occurs frequently methylated in various cancer tissues, including colorectal, tongue squamous cell, breast, gastric, and esophageal cancer (Figure 4).	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('ZNF471', 'Gene', '57573', (4, 10))	('cancer', 'Disease', (67, 73))	('colorectal', 'Disease', (93, 103))	('breast', 'Disease', (127, 133))	('tongue squamous cell', 'Disease', (105, 125))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('methylated', 'Var', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('gastric', 'Disease', (135, 142))	('ZNF471', 'Gene', (4, 10))
785908	33672287	Indeed, ZNF382-related disturbance of the pathway evokes cell apoptosis and impedes proliferation or survival.	('evokes', 'Reg', (50, 56))	('ZNF382', 'Gene', '84911', (8, 14))	('cell apoptosis', 'CPA', (57, 71))	('proliferation or survival', 'CPA', (84, 109))	('ZNF382', 'Gene', (8, 14))	('impedes', 'NegReg', (76, 83))	('disturbance', 'Var', (23, 34))
785914	33672287	ZNF545 is another tumor-related gene, whose expression may be silenced by methylation, as shown in multiple myeloma, as well as in gastric, esophageal, colorectal, breast, and liver cancers (Figure 4).	('expression', 'MPA', (44, 54))	('ZNF545', 'Gene', (0, 6))	('multiple myeloma', 'Phenotype', 'HP:0006775', (99, 115))	('liver cancers', 'Disease', 'MESH:D006528', (176, 189))	('gastric', 'Disease', (131, 138))	('silenced', 'NegReg', (62, 70))	('breast', 'Disease', (164, 170))	('esophageal', 'Disease', (140, 150))	('ZNF545', 'Gene', '284406', (0, 6))	('colorectal', 'Disease', (152, 162))	('tumor', 'Disease', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('liver cancers', 'Phenotype', 'HP:0002896', (176, 189))	('multiple myeloma', 'Disease', 'MESH:D009101', (99, 115))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('liver cancer', 'Phenotype', 'HP:0002896', (176, 188))	('liver cancers', 'Disease', (176, 189))	('multiple myeloma', 'Disease', (99, 115))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('methylation', 'Var', (74, 85))
785915	33672287	In general, the in vitro phenotypic assays in various cancer models indicate that the restoration of ZNF545 expression may result in higher apoptosis and cell cycle arrest (Figure 5), as well as reduced proliferation, migration, and invasiveness.	('arrest', 'Disease', 'MESH:D006323', (165, 171))	('ZNF545', 'Gene', (101, 107))	('restoration', 'Var', (86, 97))	('reduced', 'NegReg', (195, 202))	('proliferation', 'CPA', (203, 216))	('arrest', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('apoptosis', 'CPA', (140, 149))	('migration', 'CPA', (218, 227))	('higher', 'PosReg', (133, 139))	('cancer', 'Disease', (54, 60))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (154, 171))	('ZNF545', 'Gene', '284406', (101, 107))	('expression', 'MPA', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('invasiveness', 'CPA', (233, 245))
785917	33672287	Together with the observation that ZNF545 promoter methylation correlates with poorer clinical outcomes, these data highlight the TSG function of ZNF545 in multiple malignancies.	('ZNF545', 'Gene', (146, 152))	('malignancies', 'Disease', 'MESH:D009369', (165, 177))	('ZNF545', 'Gene', '284406', (35, 41))	('ZNF545', 'Gene', '284406', (146, 152))	('methylation', 'Var', (51, 62))	('malignancies', 'Disease', (165, 177))	('ZNF545', 'Gene', (35, 41))
785926	33672287	HP1beta is responsible for binding to methylated H3K9, thus contributing to heterochromatin's maintenance.	('HP1beta', 'Gene', (0, 7))	('binding', 'Interaction', (27, 34))	('methylated', 'Var', (38, 48))	('H3K9', 'Protein', (49, 53))	('contributing', 'Reg', (60, 72))	('heterochromatin', 'Disease', (76, 91))	('HP1beta', 'Gene', '23468', (0, 7))
785932	33672287	In colorectal tumors, ZNF331 methylation was associated with short overall survival (OS), disease-free survival (DFS), and larger tumor size.	('methylation', 'Var', (29, 40))	('short', 'NegReg', (61, 66))	('colorectal tumors', 'Disease', (3, 20))	('tumor', 'Disease', (14, 19))	('colorectal tumors', 'Disease', 'MESH:D015179', (3, 20))	('overall survival', 'MPA', (67, 83))	('ZNF331', 'Gene', '55422', (22, 28))	('ZNF331', 'Gene', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('disease-free', 'Disease', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
785933	33672287	Moreover, ZNF331 promoter methylation correlated with CpG Island Methylator Phenotype (CIMP) and its markers: MLH1 promoter methylation and BRAF mutation.	('methylation', 'Var', (26, 37))	('ZNF331', 'Gene', (10, 16))	('BRAF', 'Gene', '673', (140, 144))	('ZNF331', 'Gene', '55422', (10, 16))	('MLH1', 'Gene', '4292', (110, 114))	('BRAF', 'Gene', (140, 144))	('MLH1', 'Gene', (110, 114))	('correlated', 'Reg', (38, 48))	('CpG Island Methylator Phenotype', 'Disease', (54, 85))	('mutation', 'Var', (145, 153))
785934	33672287	However, the observed linkage between ZNF331 methylation and CIMP features was contradictory to the similar analysis conducted by Wang and colleagues, in which no such association was noted.	('methylation', 'Var', (45, 56))	('ZNF331', 'Gene', '55422', (38, 44))	('CIMP features', 'Disease', (61, 74))	('ZNF331', 'Gene', (38, 44))
785937	33672287	In the in vitro experiments, ectopic ZNF331 expression resulted in inhibited cell proliferation, cell cycle arrest at the G1/S phase (Figure 5), reduced colony formation, migration, and invasiveness, while apoptosis status remained unchanged.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (97, 114))	('ectopic', 'Var', (29, 36))	('reduced', 'NegReg', (145, 152))	('colony formation', 'CPA', (153, 169))	('inhibited', 'NegReg', (67, 76))	('arrest', 'Disease', 'MESH:D006323', (108, 114))	('invasiveness', 'CPA', (186, 198))	('ZNF331', 'Gene', '55422', (37, 43))	('ZNF331', 'Gene', (37, 43))	('arrest', 'Disease', (108, 114))	('migration', 'CPA', (171, 180))	('cell proliferation', 'CPA', (77, 95))
785958	33672287	The same group also identified a correlation between high KAP1 expression and increased migration and invasion of HeLa cells, demonstrating the ability of KAP1 to promote metastasis.	('KAP1', 'Gene', (155, 159))	('promote', 'PosReg', (163, 170))	('high', 'Var', (53, 57))	('KAP1', 'Gene', '10155', (58, 62))	('HeLa', 'CellLine', 'CVCL:0030', (114, 118))	('KAP1', 'Gene', '10155', (155, 159))	('expression', 'MPA', (63, 73))	('migration', 'CPA', (88, 97))	('increased', 'PosReg', (78, 87))	('metastasis', 'CPA', (171, 181))	('invasion of HeLa cells', 'CPA', (102, 124))	('KAP1', 'Gene', (58, 62))
785986	33672287	In addition to the ATM- and ARF-dependent control, APAK may also be regulated through epigenetic repression.	('ARF', 'Disease', (28, 31))	('APAK', 'Gene', (51, 55))	('ATM', 'Gene', (19, 22))	('ATM', 'Gene', '472', (19, 22))	('ARF', 'Disease', 'MESH:D058186', (28, 31))	('regulated', 'Reg', (68, 77))	('APAK', 'Gene', '147923', (51, 55))	('epigenetic repression', 'Var', (86, 107))
785996	33672287	Moreover, ZNF307 overexpression enhanced apoptosis rate, which was accompanied by higher levels of caspase-3 and BAX, and reduced BCL2.	('overexpression', 'Var', (17, 31))	('BCL2', 'Gene', (130, 134))	('BAX', 'MPA', (113, 116))	('ZNF307', 'Gene', (10, 16))	('higher', 'PosReg', (82, 88))	('caspase-3', 'Gene', '836', (99, 108))	('caspase-3', 'Gene', (99, 108))	('enhanced', 'PosReg', (32, 40))	('BCL2', 'Gene', '596', (130, 134))	('apoptosis rate', 'CPA', (41, 55))	('reduced', 'NegReg', (122, 129))	('ZNF307', 'Gene', '387032', (10, 16))
786007	33672287	From the clinical perspective, high RBAK expression correlated with shorter disease-free survival in lung adenocarcinomas (Figure 6B).	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('expression', 'MPA', (41, 51))	('RBAK', 'Gene', (36, 40))	('lung adenocarcinomas', 'Disease', (101, 121))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (101, 121))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (101, 121))	('RBAK', 'Gene', '57786', (36, 40))	('high', 'Var', (31, 35))	('disease-free survival', 'CPA', (76, 97))	('shorter', 'NegReg', (68, 75))
786018	33672287	ZER6 knockdown resulted in the increased expression of the p53 target, namely p21 (Figure 6B), which negatively regulates the cell cycle (Figure 5).	('cell cycle', 'CPA', (126, 136))	('p53', 'Gene', (59, 62))	('p21', 'Gene', '644914', (78, 81))	('p53', 'Gene', '7157', (59, 62))	('increased', 'PosReg', (31, 40))	('expression', 'MPA', (41, 51))	('regulates', 'Reg', (112, 121))	('knockdown', 'Var', (5, 14))	('ZER6', 'Gene', '57541', (0, 4))	('ZER6', 'Gene', (0, 4))	('p21', 'Gene', (78, 81))
786031	33672287	The study also revealed that ZNF300 silencing promotes cell proliferation, an increase in S phase population (Figure 5), overexpression of PCNA proliferation marker, decreased expression of the cell cycle controllers: p15 and p27, as well as repression of MAPK/ERK pathway.	('ZNF300', 'Gene', '91975', (29, 35))	('repression', 'NegReg', (242, 252))	('ERK', 'Gene', '2048', (261, 264))	('p15', 'Gene', (218, 221))	('p27', 'Gene', '3429', (226, 229))	('p27', 'Gene', (226, 229))	('p15', 'Gene', '1030', (218, 221))	('decreased', 'NegReg', (166, 175))	('ZNF300', 'Gene', (29, 35))	('increase', 'PosReg', (78, 86))	('silencing', 'Var', (36, 45))	('cell proliferation', 'CPA', (55, 73))	('expression', 'MPA', (176, 186))	('overexpression', 'PosReg', (121, 135))	('promotes', 'PosReg', (46, 54))	('ERK', 'Gene', (261, 264))	('S phase population', 'CPA', (90, 108))
786039	33672287	In the phenotypic studies, the cells with higher ZNF300 levels showed reduced proliferation with the concomitant G2 cell cycle arrest (Figure 5).	('reduced', 'NegReg', (70, 77))	('arrest', 'Disease', (127, 133))	('higher', 'Var', (42, 48))	('proliferation', 'CPA', (78, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (116, 133))	('ZNF300', 'Gene', (49, 55))	('ZNF300', 'Gene', '91975', (49, 55))	('arrest', 'Disease', 'MESH:D006323', (127, 133))
786045	33672287	In colorectal cancer, ZKSCAN3 overexpression increased anchorage-independent growth in vitro, orthotopic tumor growth, and liver metastasis in vivo, as well as resistance to the treatment with 5-fluorouracil.	('liver metastasis', 'Disease', 'MESH:D009362', (123, 139))	('liver metastasis', 'Disease', (123, 139))	('ZKSCAN3', 'Gene', '80317', (22, 29))	('increased', 'PosReg', (45, 54))	('resistance', 'CPA', (160, 170))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (193, 207))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('colorectal cancer', 'Disease', (3, 20))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('anchorage-independent growth', 'CPA', (55, 83))	('ZKSCAN3', 'Gene', (22, 29))	('overexpression', 'Var', (30, 44))	('tumor', 'Disease', (105, 110))
786052	33672287	ZKSCAN3 silencing also inhibited the phosphorylation, and thus, activation of the AKT/mTOR pathway (Figure 6B).	('phosphorylation', 'MPA', (37, 52))	('ZKSCAN3', 'Gene', (0, 7))	('inhibited', 'NegReg', (23, 32))	('mTOR', 'Gene', '2475', (86, 90))	('ZKSCAN3', 'Gene', '80317', (0, 7))	('mTOR', 'Gene', (86, 90))	('silencing', 'Var', (8, 17))	('AKT', 'Gene', '207', (82, 85))	('activation', 'PosReg', (64, 74))	('AKT', 'Gene', (82, 85))
786062	33672287	In the in vitro assays, ZNF10 knockdown inhibited proliferation, colony formation, cell cycle progression (Figure 5), migration, and invasion of breast cancer cells.	('ZNF10', 'Gene', '7556', (24, 29))	('cell cycle progression', 'CPA', (83, 105))	('invasion', 'CPA', (133, 141))	('inhibited', 'NegReg', (40, 49))	('proliferation', 'CPA', (50, 63))	('migration', 'CPA', (118, 127))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('knockdown', 'Var', (30, 39))	('ZNF10', 'Gene', (24, 29))	('breast cancer', 'Disease', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('colony formation', 'CPA', (65, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
786063	33672287	Silencing of ZNF10 resulted as well in reduced tumor formation in nude mice.	('ZNF10', 'Gene', '7556', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('ZNF10', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('reduced', 'NegReg', (39, 46))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (47, 52))	('nude mice', 'Species', '10090', (66, 75))
786067	33672287	Silva and colleagues showed that TIPUH1-overexpressing NIH3T3 cells tend to form colonies in soft agar in contrast to anchorage-dependent control cells, while its siRNA-mediated knockdown resulted in impeded proliferation in HCC cell lines.	('agar', 'Chemical', 'MESH:D000362', (98, 102))	('impeded', 'NegReg', (200, 207))	('NIH3T3', 'Gene', (55, 61))	('HCC', 'Phenotype', 'HP:0001402', (225, 228))	('colonies in soft agar', 'CPA', (81, 102))	('NIH3T3', 'CellLine', 'CVCL:0594', (55, 61))	('proliferation', 'CPA', (208, 221))	('TIPUH1', 'Gene', (33, 39))	('knockdown', 'Var', (178, 187))	('TIPUH1', 'Gene', '115509', (33, 39))
786070	33672287	It also suggests that altered expression of TIPUH1 may deregulate the production, maturation, and engineering of mRNAs and/or rRNAs in tumor cells.	('TIPUH1', 'Gene', '115509', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('maturation', 'CPA', (82, 92))	('production', 'MPA', (70, 80))	('deregulate', 'Reg', (55, 65))	('TIPUH1', 'Gene', (44, 50))	('altered', 'Var', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
786075	33672287	Moreover, ZNF233 silencing resulted in hindered tumor growth in nude mice.	('ZNF233', 'Gene', '353355', (10, 16))	('tumor', 'Disease', (48, 53))	('ZNF233', 'Gene', (10, 16))	('nude mice', 'Species', '10090', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('silencing', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('hindered', 'NegReg', (39, 47))
786078	33672287	ZNF133 was also recognized as a factor associated with Alagille syndrome:a genetic disease related to the disruptions in the Notch signaling pathway that predisposes to pediatric HCC.	('pediatric HCC', 'Disease', (169, 182))	('ZNF133', 'Gene', '7692', (0, 6))	('Alagille syndrome', 'Disease', (55, 72))	('disruptions', 'Var', (106, 117))	('ZNF133', 'Gene', (0, 6))	('associated', 'Reg', (39, 49))	('Alagille syndrome', 'Disease', 'MESH:D016738', (55, 72))	('HCC', 'Phenotype', 'HP:0001402', (179, 182))
786083	33672287	While the methylation of imprinted regions is unstable in cancer cells (with the higher frequency of hypermethylation occurrence), imbalanced expression of ZPF57 may have an effect on the epigenetic and transcriptional control of the genes regulated via imprinting.	('ZPF57', 'Gene', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('imbalanced expression', 'Var', (131, 152))	('effect', 'Reg', (174, 180))	('cancer', 'Disease', (58, 64))	('have', 'Reg', (166, 170))
786092	33672287	Their data indicated that ZFP57 overexpression inhibits the proliferation of BRCA cells, both in vitro and in vivo, and this effect was linked to the blockage of the Wnt/beta-catenin signaling pathway (Figure 6A).	('ZFP57', 'Gene', (26, 31))	('BRCA cells', 'CPA', (77, 87))	('beta-catenin', 'Gene', (170, 182))	('overexpression', 'Var', (32, 46))	('BRCA', 'Phenotype', 'HP:0003002', (77, 81))	('beta-catenin', 'Gene', '1499', (170, 182))	('proliferation', 'CPA', (60, 73))	('inhibits', 'NegReg', (47, 55))
786103	33672287	Further molecular profiling elucidated that the DEPDC1/ZNF224 complex inhibits the transcription of the A20 gene responsible for the negative regulation of the NF-kappaB signaling pathway.	('NF-kappaB', 'Gene', (160, 169))	('A20', 'Gene', (104, 107))	('ZNF224', 'Gene', (55, 61))	('transcription', 'MPA', (83, 96))	('inhibits', 'NegReg', (70, 78))	('DEPDC1', 'Gene', (48, 54))	('A20', 'Gene', '7128', (104, 107))	('ZNF224', 'Gene', '7767', (55, 61))	('complex', 'Var', (62, 69))	('NF-kappaB', 'Gene', '4790', (160, 169))	('DEPDC1', 'Gene', '55635', (48, 54))
786112	33672287	Indeed, the silencing of ZNF224 reduced the number of cells in the G2/M phase and led to the accumulation of cells in the G0/G1 phase (Figure 5), emphasizing that ZNF224 is an essential factor supporting cell cycle progression.	('ZNF224', 'Gene', (25, 31))	('cells in the G0/G1 phase', 'CPA', (109, 133))	('ZNF224', 'Gene', (163, 169))	('ZNF224', 'Gene', '7767', (25, 31))	('reduced', 'NegReg', (32, 39))	('accumulation', 'PosReg', (93, 105))	('silencing', 'Var', (12, 21))	('ZNF224', 'Gene', '7767', (163, 169))
786119	33672287	Notably, higher basal ZNF224 expression at diagnosis was associated with improved response to imatinib treatment, suggesting increased apoptosis sensitivity in the patients overexpressing ZNF224.	('apoptosis sensitivity', 'CPA', (135, 156))	('overexpressing', 'Var', (173, 187))	('increased', 'PosReg', (125, 134))	('ZNF224', 'Gene', '7767', (188, 194))	('response to imatinib treatment', 'MPA', (82, 112))	('imatinib', 'Chemical', 'MESH:D000068877', (94, 102))	('improved', 'PosReg', (73, 81))	('ZNF224', 'Gene', (22, 28))	('patients', 'Species', '9606', (164, 172))	('expression', 'MPA', (29, 39))	('ZNF224', 'Gene', (188, 194))	('ZNF224', 'Gene', '7767', (22, 28))	('higher', 'PosReg', (9, 15))
786124	33672287	Thus, restoration of ZNF224 expression was proposed as a promising tool that may overcome drug resistance in CML.	('restoration', 'Var', (6, 17))	('expression', 'MPA', (28, 38))	('drug resistance', 'Phenotype', 'HP:0020174', (90, 105))	('ZNF224', 'Gene', '7767', (21, 27))	('ZNF224', 'Gene', (21, 27))	('CML', 'Phenotype', 'HP:0005506', (109, 112))
786128	33672287	For example, ZNF268b2 was the dominant protein in squamous cervical cancer samples, while ZNF268a expression was low, which means that the imbalanced relative level of these protein isoforms in tissue may lead to carcinogenesis.	('lead to', 'Reg', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ZNF268', 'Gene', (90, 96))	('squamous cervical cancer', 'Disease', (50, 74))	('carcinogenesis', 'Disease', 'MESH:D063646', (213, 227))	('ZNF268', 'Gene', '10795', (13, 19))	('squamous cervical cancer', 'Phenotype', 'HP:0032241', (50, 74))	('imbalanced', 'Var', (139, 149))	('ZNF268', 'Gene', '10795', (90, 96))	('carcinogenesis', 'Disease', (213, 227))	('ZNF268', 'Gene', (13, 19))	('squamous cervical cancer', 'Disease', 'MESH:D002294', (50, 74))
786130	33672287	Furthermore, ZNF268 knockdown impeded tumor growth and increased the expression of apoptosis markers in a nude mouse model.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('impeded', 'NegReg', (30, 37))	('mouse', 'Species', '10090', (111, 116))	('increased', 'PosReg', (55, 64))	('ZNF268', 'Gene', '10795', (13, 19))	('expression', 'MPA', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('knockdown', 'Var', (20, 29))	('ZNF268', 'Gene', (13, 19))
786132	33672287	Opposing effects upon ZNF268 knockdown were observed in ovarian cancer.	('knockdown', 'Var', (29, 38))	('ZNF268', 'Gene', '10795', (22, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (56, 70))	('ovarian cancer', 'Disease', 'MESH:D010051', (56, 70))	('ZNF268', 'Gene', (22, 28))	('ovarian cancer', 'Disease', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
786133	33672287	Its silencing promoted tumor cell growth in vitro and in vivo by mediating the progression of the cell cycle.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mediating', 'Reg', (65, 74))	('promoted', 'PosReg', (14, 22))	('tumor', 'Disease', (23, 28))	('progression of the cell cycle', 'CPA', (79, 108))	('silencing', 'Var', (4, 13))
786172	33672287	Yet, the aberrant genome-wide imprinting, TE activity, and epigenetic repression of gene promoters play a vital role in tumor biology.	('epigenetic repression', 'Var', (59, 80))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('aberrant', 'Var', (9, 17))	('tumor', 'Disease', (120, 125))
786173	33672287	Loss of imprinting (LOI), another frequent event occurring during carcinogenesis, may deregulate the expression from the imprinted regions that harbor genes essential for cell growth, differentiation, and metabolism.	('deregulate', 'Reg', (86, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('imprinting', 'Disease', (8, 18))	('carcinogenesis', 'Disease', (66, 80))	('expression', 'MPA', (101, 111))	('Loss', 'Var', (0, 4))
786177	33672287	Yet, KRAB-ZFPs may bind to many genomic locations, which frequently correlates with a repressive histone mark, namely H3K9me3.	('ZFP', 'Gene', (10, 13))	('H3K9me3', 'Var', (118, 125))	('bind', 'Reg', (19, 23))	('ZFP', 'Gene', '55888', (10, 13))
786204	33275591	To predict the prognosis of EC in the training group, the risk score model was created with the following formula: the risk score=(0.0095xgene expression level of HSPA6)+ (0.0034xgene expression level of S100A12)+ (0.016xgene expression level of NOS2)+ (0.0129xgene expression level of DKK1)+ (0.2706xgene expression level of OSM)+ (-1.6913xgene expression level of AR)+ (0.1402xgene expression level of OXTR).	('HSPA6', 'Gene', (163, 168))	('NOS2', 'Gene', '4843', (246, 250))	('0.0034xgene', 'Var', (172, 183))	('S100A12', 'Gene', '6283', (204, 211))	('OXTR', 'Gene', (404, 408))	('S100A12', 'Gene', (204, 211))	('HSPA6', 'Gene', '3310', (163, 168))	('EC', 'Phenotype', 'HP:0011459', (28, 30))	('NOS2', 'Gene', (246, 250))	('OXTR', 'Gene', '5021', (404, 408))	('DKK1', 'Gene', '22943', (286, 290))	('DKK1', 'Gene', (286, 290))	('0.0095xgene', 'Var', (131, 142))
786214	33275591	OSM, as an inflammatory cytokine, was found to be upregulated in breast cancer, and early therapeutic inhibition of OSM could prevent breast cancer metastasis.	('breast cancer metastasis', 'Disease', (134, 158))	('upregulated', 'PosReg', (50, 61))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('prevent', 'NegReg', (126, 133))	('inhibition', 'Var', (102, 112))	('breast cancer', 'Disease', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('breast cancer metastasis', 'Disease', 'MESH:D001943', (134, 158))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
786257	32923265	The incidence of bleeding is higher in IGV1 (78%) compared to IGV2 (10%).	('higher', 'PosReg', (29, 35))	('bleeding', 'Disease', 'MESH:D006470', (17, 25))	('IGV1', 'Var', (39, 43))	('bleeding', 'Disease', (17, 25))
786274	31740115	The National Cancer Database (NCDB) was used to identify patients with cT1N0M0 esophageal adenocarcinoma (2004-2015) who underwent esophagectomy without induction therapy.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('Cancer', 'Disease', (13, 19))	('age', 'Gene', (136, 139))	('patients', 'Species', '9606', (57, 65))	('age', 'Gene', '5973', (84, 87))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('adenocarcinoma', 'Disease', (90, 104))	('age', 'Gene', '5973', (136, 139))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('age', 'Gene', (84, 87))	('cT1N0M0', 'Var', (71, 78))
786280	31740115	The National Comprehensive Cancer Network (NCCN) guidelines recommend surgery without induction therapy for cT1a-bN0M0 esophageal adenocarcinoma.	('age', 'Gene', '5973', (124, 127))	('adenocarcinoma', 'Disease', (130, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (130, 144))	('Cancer', 'Disease', (27, 33))	('cT1a-bN0M0', 'Var', (108, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (119, 144))	('age', 'Gene', (124, 127))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))
786286	31740115	In the NCDB, patients diagnosed with cT1N0M0 esophageal adenocarcinoma who underwent esophagectomy were identified during a study period of 2004-2015.	('age', 'Gene', (50, 53))	('cT1N0M0', 'Var', (37, 44))	('age', 'Gene', '5973', (50, 53))	('patients', 'Species', '9606', (13, 21))	('age', 'Gene', (90, 93))	('adenocarcinoma', 'Disease', (56, 70))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (45, 70))	('age', 'Gene', '5973', (90, 93))
786296	31740115	Subgroup analyses were performed in patients with cT1a or cT1b esophageal cancer, which was coded in the NCDB from years 2011 onwards after the AJCC introduced the distinction in 2010.	('esophageal cancer', 'Disease', (63, 80))	('patients', 'Species', '9606', (36, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('cT1b', 'Var', (58, 62))	('cT1a', 'Var', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
786303	31740115	In 373 patients with cT1b disease, time to surgery less than 100 days was not associated with improved survival but time to surgery greater than 100 days was associated with worse survival (HR 1.01; 95%CI 1.00-1.01; p=0.0005).	('patients', 'Species', '9606', (7, 15))	('greater than 100 days', 'Var', (132, 153))	('cT1b', 'Gene', (21, 25))
786323	31740115	It is possible that a margin-positive resection occurred due to factors other than delay of surgery, but in our logistic regression, time to surgery was the only variable associated with a margin-positive resection, while other candidate factors like center volume, treatment at an academic center, tumor size, and grade were not significantly associated with it.	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('margin-positive', 'Var', (189, 204))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('tumor', 'Disease', (299, 304))
786332	31740115	The results of the study are also affected by missing data because only a minority of patients with T1N0M0 esophageal adenocarcinoma met criteria for the study.	('adenocarcinoma', 'Disease', 'MESH:D000230', (118, 132))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (107, 132))	('age', 'Gene', (112, 115))	('T1N0M0', 'Var', (100, 106))	('age', 'Gene', '5973', (112, 115))	('adenocarcinoma', 'Disease', (118, 132))	('patients', 'Species', '9606', (86, 94))
786439	30364207	The genetic variation of thymic stromal lymphopoietin (TSLP) and calpain 14 (CAPN14) contributes to EoE, but the answer to how this relates to atopy remains unclear.	('contributes', 'Reg', (85, 96))	('TSLP', 'Gene', (55, 59))	('calpain 14', 'Gene', (65, 75))	('TSLP', 'Gene', '85480', (55, 59))	('CAPN14', 'Gene', '440854', (77, 83))	('pain', 'Phenotype', 'HP:0012531', (68, 72))	('EoE', 'Disease', (100, 103))	('thymic stromal lymphopoietin', 'Gene', '85480', (25, 53))	('CAPN14', 'Gene', (77, 83))	('genetic variation', 'Var', (4, 21))	('calpain 14', 'Gene', '440854', (65, 75))	('thymic stromal lymphopoietin', 'Gene', (25, 53))
786457	30364207	The single nucleotide polymorphism (SNP) of CCL26 (rs2302009) is associated with the risk of suffering from the disease.	('CCL26', 'Gene', (44, 49))	('suffering from the disease', 'Disease', (93, 119))	('single nucleotide polymorphism', 'Var', (4, 34))	('rs2302009', 'Var', (51, 60))	('associated', 'Reg', (65, 75))	('rs2302009', 'Mutation', 'rs2302009', (51, 60))	('CCL26', 'Gene', '10344', (44, 49))
786458	30364207	Six years ago, they described polymorphisms in the promoter region of TGF-beta1 (chromosome 19q13).	('polymorphisms', 'Var', (30, 43))	('TGF-beta1', 'Gene', '7040', (70, 79))	('TGF-beta1', 'Gene', (70, 79))
786459	30364207	More than CC509T, the C allele is associated with a positive response to treatment with corticosteroids and with an increase in its expression in esophageal cells.	('increase', 'PosReg', (116, 124))	('CC509T', 'Var', (10, 16))	('men', 'Species', '9606', (78, 81))	('expression', 'MPA', (132, 142))	('steroids', 'Chemical', 'MESH:D013256', (95, 103))	('positive', 'PosReg', (52, 60))	('CC509T', 'Mutation', 'c.509CC>T', (10, 16))
786461	30364207	In children, a relationship has been found between the variants of the TGF-beta1 gene and the degree of severity of EoE in patients sensitized to food.	('children', 'Species', '9606', (3, 11))	('relationship', 'Reg', (15, 27))	('variants', 'Var', (55, 63))	('patients', 'Species', '9606', (123, 131))	('EoE', 'Disease', (116, 119))	('TGF-beta1', 'Gene', '7040', (71, 80))	('TGF-beta1', 'Gene', (71, 80))
786479	30364207	Secretion of Th2 cytokines can be inhibited by PPIs in a manner similar to corticosteroids in EoE.	('PPIs', 'Var', (47, 51))	('inhibited', 'NegReg', (34, 43))	('steroids', 'Chemical', 'MESH:D013256', (82, 90))	('Secretion of Th2 cytokines', 'MPA', (0, 26))
786518	30364207	The results show that the patients with EoE and normal endoscopy had esophageal distensibility parameters similar to those of normal controls, whereas patients with EoE and stricture or narrow caliber had much lower distensibility than patients with EoE and normal endoscopy.	('narrow caliber', 'Var', (186, 200))	('EoE', 'Disease', (40, 43))	('patients', 'Species', '9606', (236, 244))	('patients', 'Species', '9606', (151, 159))	('stricture', 'Var', (173, 182))	('patients', 'Species', '9606', (26, 34))	('esophageal distensibility parameters', 'MPA', (69, 105))
786639	30364207	OC000459 acts as an oral bioavailable CRTH2 antagonist.	('OC000459', 'Var', (0, 8))	('CRTH2', 'Gene', (38, 43))	('CRTH2', 'Gene', '11251', (38, 43))
786643	30364207	Anti IL-13: A recent trial with QAX576 showed a tendency to improve symptoms with a reduction of eosinophil levels in the esophagus (60% decrease vs. an increase of 23% with placebo).	('QAX576', 'Chemical', '-', (32, 38))	('reduction of eosinophil levels', 'Phenotype', 'HP:0031891', (84, 114))	('symptoms', 'MPA', (68, 76))	('decrease', 'NegReg', (137, 145))	('QAX576', 'Var', (32, 38))	('reduction', 'NegReg', (84, 93))	('eosin', 'Chemical', 'MESH:D004801', (97, 102))	('IL-13', 'Gene', (5, 10))	('IL-13', 'Gene', '3596', (5, 10))	('eosinophil levels in the esophagus', 'MPA', (97, 131))	('improve', 'PosReg', (60, 67))
786669	28404954	Further studies revealed that silence of PVT1 lead to up-regulation of miR-203, and vice versa.	('miR-203', 'Gene', '406986', (71, 78))	('miR-203', 'Gene', (71, 78))	('up-regulation', 'PosReg', (54, 67))	('PVT1', 'Gene', (41, 45))	('PVT1', 'Gene', '5820', (41, 45))	('silence', 'Var', (30, 37))
786670	28404954	Moreover, LASP1 was found to be downregulated after knockdown of PVT1 and overexpression of LASP1 attenuated the tumor-suppressive roles of PVT1 knockdown.	('LASP1', 'Gene', (92, 97))	('tumor', 'Disease', (113, 118))	('downregulated', 'NegReg', (32, 45))	('LASP1', 'Gene', '3927', (10, 15))	('PVT1', 'Gene', (140, 144))	('LASP1', 'Gene', '3927', (92, 97))	('PVT1', 'Gene', (65, 69))	('LASP1', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('PVT1', 'Gene', '5820', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('attenuated', 'NegReg', (98, 108))	('knockdown', 'Var', (52, 61))	('PVT1', 'Gene', '5820', (65, 69))
786671	28404954	Our results suggest that PVT1 promote ESCC progression via functioning as a molecular sponge for miR-203 and LASP1 and provide the first evidence of dysregulated PVT1/miR-203/LASP1 axis in ESCC.	('PVT1', 'Gene', '5820', (162, 166))	('promote', 'PosReg', (30, 37))	('LASP1', 'Gene', '3927', (175, 180))	('miR-203', 'Gene', (97, 104))	('LASP1', 'Gene', (109, 114))	('PVT1', 'Gene', (25, 29))	('LASP1', 'Gene', '3927', (109, 114))	('progression', 'CPA', (43, 54))	('miR-203', 'Gene', '406986', (97, 104))	('LASP1', 'Gene', (175, 180))	('dysregulated', 'Var', (149, 161))	('ESCC', 'Disease', (38, 42))	('ESCC', 'Disease', (189, 193))	('miR-203', 'Gene', '406986', (167, 174))	('miR-203', 'Gene', (167, 174))	('PVT1', 'Gene', (162, 166))	('PVT1', 'Gene', '5820', (25, 29))
786675	28404954	Dysregulation of lncRNAs has been found in various types of carcinomas and serves as tissue-specific oncogenes or tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('lncRNAs', 'Protein', (17, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('found', 'Reg', (34, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('carcinomas', 'Disease', 'MESH:D002277', (60, 70))	('carcinomas', 'Disease', (60, 70))
786677	28404954	Recent studies indicated that PVT1 RNA and MYC protein expression correlated in primary human tumours, and copy number of PVT1 was co-increased in more than 98% of MYC copy number-increased cancers.	('co-increased', 'PosReg', (131, 143))	('copy number', 'Var', (107, 118))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('MYC', 'Gene', '4609', (164, 167))	('MYC', 'Gene', (43, 46))	('human', 'Species', '9606', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumours', 'Disease', (94, 101))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('PVT1', 'Gene', (30, 34))	('cancers', 'Disease', (190, 197))	('MYC', 'Gene', '4609', (43, 46))	('PVT1', 'Gene', '5820', (30, 34))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumours', 'Disease', 'MESH:D009369', (94, 101))	('MYC', 'Gene', (164, 167))	('PVT1', 'Gene', (122, 126))	('PVT1', 'Gene', '5820', (122, 126))	('copy number-increased', 'Var', (168, 189))
786678	28404954	Amplification of PVT1 contributes to the aggressive pathophysiology of ovarian and breast cancer and overexpression of PVT1 is a powerful predictor of tumor progression and overall survival in patients with diverse types of cancer, including gastric cancer and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('PVT1', 'Gene', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('colorectal cancer', 'Phenotype', 'HP:0003003', (261, 278))	('gastric cancer', 'Phenotype', 'HP:0012126', (242, 256))	('PVT1', 'Gene', '5820', (119, 123))	('cancer', 'Disease', (224, 230))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (71, 96))	('overexpression', 'PosReg', (101, 115))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (261, 278))	('gastric cancer', 'Disease', (242, 256))	('patients', 'Species', '9606', (193, 201))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('colorectal cancer', 'Disease', (261, 278))	('Amplification', 'Var', (0, 13))	('gastric cancer', 'Disease', 'MESH:D013274', (242, 256))	('PVT1', 'Gene', (17, 21))	('cancer', 'Disease', (250, 256))	('tumor', 'Disease', (151, 156))	('PVT1', 'Gene', '5820', (17, 21))	('cancer', 'Disease', (272, 278))	('cancer', 'Disease', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
786682	28404954	Copy number gain or amplification of the genomic locus of LASP1 at 17q12 was observed in 20-30% of human breast cancers and identified as a hallmark of high-risk medulloblastoma.	('Copy number gain', 'Disease', (0, 16))	('breast cancers', 'Disease', 'MESH:D001943', (105, 119))	('breast cancers', 'Disease', (105, 119))	('medulloblastoma', 'Disease', (162, 177))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('LASP1', 'Gene', '3927', (58, 63))	('medulloblastoma', 'Phenotype', 'HP:0002885', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('LASP1', 'Gene', (58, 63))	('human', 'Species', '9606', (99, 104))	('breast cancers', 'Phenotype', 'HP:0003002', (105, 119))	('amplification', 'Var', (20, 33))	('medulloblastoma', 'Disease', 'MESH:D008527', (162, 177))	('Copy number gain', 'Disease', 'MESH:D015430', (0, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
786684	28404954	Silencing of LASP1 by RNA interference resulted in a significant inhibition of cell migration and proliferation and attenuation of TGF-beta mediated epithelial-mesenchymal transition (EMT).	('inhibition', 'NegReg', (65, 75))	('cell migration', 'CPA', (79, 93))	('TGF-beta', 'Gene', '7040', (131, 139))	('LASP1', 'Gene', '3927', (13, 18))	('RNA interference', 'MPA', (22, 38))	('LASP1', 'Gene', (13, 18))	('TGF-beta', 'Gene', (131, 139))	('attenuation', 'NegReg', (116, 127))	('Silencing', 'Var', (0, 9))
786694	28404954	These data indicated that dysregulated PVT1 expression might be related to ESCC pathogenesis.	('PVT1', 'Gene', (39, 43))	('expression', 'MPA', (44, 54))	('related', 'Reg', (64, 71))	('ESCC', 'Disease', (75, 79))	('PVT1', 'Gene', '5820', (39, 43))	('dysregulated', 'Var', (26, 38))
786700	28404954	Kaplan-Meier analysis (Supplementary Table1) demonstrated that five year overall survival for patients with high PVT1 expression is 46 months, while is 76 months for those with low PVT1 expression (Figure 1D, Log-rank P < 0.001).	('expression', 'Var', (118, 128))	('patients', 'Species', '9606', (94, 102))	('PVT1', 'Gene', (181, 185))	('PVT1', 'Gene', '5820', (113, 117))	('PVT1', 'Gene', '5820', (181, 185))	('high', 'Var', (108, 112))	('PVT1', 'Gene', (113, 117))
786701	28404954	Moreover, disease-free survival for patients with high PVT1 expression was significantly shorter than those with low PVT1 expression (Figure 1E, Log-rank P = 0.011).	('patients', 'Species', '9606', (36, 44))	('expression', 'Var', (60, 70))	('disease-free survival', 'CPA', (10, 31))	('PVT1', 'Gene', (55, 59))	('PVT1', 'Gene', (117, 121))	('shorter', 'NegReg', (89, 96))	('high', 'Var', (50, 54))	('PVT1', 'Gene', '5820', (55, 59))	('PVT1', 'Gene', '5820', (117, 121))
786708	28404954	qPCR assays revealed that PVT1 expression was significantly reduced in Eca109 and KYSE150 cells (Figure 2B) and elevated in Eca9706 and KYSE140 cells (Supplementary Figure 1A).	('PVT1', 'Gene', (26, 30))	('KYSE140', 'CellLine', 'CVCL:1347', (136, 143))	('Eca9706', 'CellLine', 'CVCL:E307', (124, 131))	('PVT1', 'Gene', '5820', (26, 30))	('elevated', 'PosReg', (112, 120))	('expression', 'MPA', (31, 41))	('reduced', 'NegReg', (60, 67))	('KYSE150', 'CellLine', 'CVCL:1348', (82, 89))	('Eca9706', 'Var', (124, 131))
786709	28404954	Next, MTS assays showed that knockdown of PVT1 expression significantly inhibited cell proliferation in both Eca109 and KYSE150 cell lines compared with the control cells (Figure 2C).	('knockdown', 'Var', (29, 38))	('PVT1', 'Gene', (42, 46))	('inhibited', 'NegReg', (72, 81))	('PVT1', 'Gene', '5820', (42, 46))	('cell proliferation in', 'CPA', (82, 103))	('KYSE150', 'CellLine', 'CVCL:1348', (120, 127))
786712	28404954	Interestingly, western blot analysis indicated that knockdown of PVT1 resulted in an elevated level of the epithelial markers E-cadherin and beta-catenin and reduced level of the mesenchymal marker N-Cadherin (Figure 2F).	('knockdown', 'Var', (52, 61))	('beta-catenin', 'Gene', (141, 153))	('E-cadherin', 'Gene', (126, 136))	('PVT1', 'Gene', (65, 69))	('elevated', 'PosReg', (85, 93))	('E-cadherin', 'Gene', '999', (126, 136))	('beta-catenin', 'Gene', '1499', (141, 153))	('N-Cadherin', 'Gene', (198, 208))	('reduced', 'NegReg', (158, 165))	('N-Cadherin', 'Gene', '1000', (198, 208))	('PVT1', 'Gene', '5820', (65, 69))
786713	28404954	Altogether, our data demonstrated that knockdown of PVT1 could inhibit ESCC proliferation and migration in vitro.	('knockdown', 'Var', (39, 48))	('PVT1', 'Gene', (52, 56))	('ESCC proliferation', 'CPA', (71, 89))	('inhibit', 'NegReg', (63, 70))	('PVT1', 'Gene', '5820', (52, 56))
786720	28404954	Altogether, our data further supported that knockdown of PVT1 suppressed ESCC tumor growth in vivo.	('PVT1', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('PVT1', 'Gene', '5820', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('suppressed', 'NegReg', (62, 72))	('knockdown', 'Var', (44, 53))	('tumor', 'Disease', (78, 83))	('ESCC', 'Disease', (73, 77))
786724	28404954	Furthermore, the qPCR analysis indicated up-regulated expression of miR-203 after knockdown of PVT1 in Eca109 and KYSE150 cells (Figure 4B).	('up-regulated', 'PosReg', (41, 53))	('expression', 'MPA', (54, 64))	('PVT1', 'Gene', (95, 99))	('knockdown', 'Var', (82, 91))	('miR-203', 'Gene', (68, 75))	('KYSE150', 'CellLine', 'CVCL:1348', (114, 121))	('PVT1', 'Gene', '5820', (95, 99))	('miR-203', 'Gene', '406986', (68, 75))
786729	28404954	However, there was no significant decrease in relative luciferase activity for cells transfected with miR-203 mimics compared with control vector-transfected cells in the PVT1-mut group (Figure 4D).	('activity', 'MPA', (66, 74))	('PVT1', 'Gene', (171, 175))	('decrease', 'NegReg', (34, 42))	('PVT1', 'Gene', '5820', (171, 175))	('miR-203', 'Gene', '406986', (102, 109))	('miR-203', 'Gene', (102, 109))	('mimics', 'Var', (110, 116))	('luciferase', 'Enzyme', (55, 65))
786732	28404954	As we have demonstrated that PVT1 affect the expression of the miR-203 and miR-203/LASP1 axis has been reported in various human cancers, it was thus reasonable to hypothesize that expression of LASP1 may be affected by dysregulated PVT1.	('affected', 'Reg', (208, 216))	('miR-203', 'Gene', '406986', (63, 70))	('miR-203', 'Gene', (75, 82))	('human', 'Species', '9606', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('LASP1', 'Gene', (195, 200))	('cancers', 'Disease', (129, 136))	('LASP1', 'Gene', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('miR-203', 'Gene', '406986', (75, 82))	('affect', 'Reg', (34, 40))	('PVT1', 'Gene', (29, 33))	('expression', 'MPA', (181, 191))	('PVT1', 'Gene', '5820', (29, 33))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('reported', 'Reg', (103, 111))	('miR-203', 'Gene', (63, 70))	('LASP1', 'Gene', '3927', (195, 200))	('PVT1', 'Gene', (233, 237))	('LASP1', 'Gene', '3927', (83, 88))	('expression', 'MPA', (45, 55))	('PVT1', 'Gene', '5820', (233, 237))	('dysregulated', 'Var', (220, 232))
786737	28404954	Moreover, the decreased mRNA levels of LASP1 induced by PVT1 knockdown were significantly reversed by ectopic transfection of miR-203 inhibitor or a vector containing the coding sequences but lacking the 3'-UTR of LASP1 (pcDNA-LASP1, Figure 5E).	('LASP1', 'Gene', (39, 44))	('PVT1', 'Gene', '5820', (56, 60))	('decreased', 'NegReg', (14, 23))	('LASP1', 'Gene', '3927', (227, 232))	('LASP1', 'Gene', (227, 232))	('knockdown', 'Var', (61, 70))	('miR-203', 'Gene', (126, 133))	('PVT1', 'Gene', (56, 60))	('LASP1', 'Gene', '3927', (39, 44))	('miR-203', 'Gene', '406986', (126, 133))	('mRNA levels', 'MPA', (24, 35))	('LASP1', 'Gene', '3927', (214, 219))	('LASP1', 'Gene', (214, 219))
786750	28404954	We therefore speculated that PVT1 may regulate ESCC cancer progression through silencing of specific miRNA and found that miR-203 was up-regulated after knockdown of PVT1.	('knockdown', 'Var', (153, 162))	('PVT1', 'Gene', '5820', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('PVT1', 'Gene', '5820', (29, 33))	('miR', 'Gene', '220972', (122, 125))	('ESCC cancer', 'Disease', 'MESH:D004938', (47, 58))	('miR', 'Gene', (122, 125))	('miR-203', 'Gene', (122, 129))	('regulate', 'Reg', (38, 46))	('miR-203', 'Gene', '406986', (122, 129))	('silencing', 'NegReg', (79, 88))	('PVT1', 'Gene', (166, 170))	('ESCC cancer', 'Disease', (47, 58))	('up-regulated', 'PosReg', (134, 146))	('miR', 'Gene', '220972', (101, 104))	('PVT1', 'Gene', (29, 33))	('miR', 'Gene', (101, 104))
786758	28404954	We first found that shRNA-mediated silence of PVT1 resulted in down-regulation of LASP1, which could be reversed by transfection of miR-203 inhibitor or ectopic expression of LASP1 lacking the 3'-UTR.	('LASP1', 'Gene', '3927', (82, 87))	('miR-203', 'Gene', (132, 139))	('silence', 'Var', (35, 42))	('LASP1', 'Gene', (82, 87))	('LASP1', 'Gene', '3927', (175, 180))	('PVT1', 'Gene', '5820', (46, 50))	('miR-203', 'Gene', '406986', (132, 139))	('LASP1', 'Gene', (175, 180))	('PVT1', 'Gene', (46, 50))	('down-regulation', 'NegReg', (63, 78))
786759	28404954	Furthermore, the inhibitor of miR-203 attenuated the migration-suppression ability of PVT1 knockdown in ESCC cells.	('attenuated', 'NegReg', (38, 48))	('miR-203', 'Gene', (30, 37))	('migration-suppression', 'CPA', (53, 74))	('knockdown', 'Var', (91, 100))	('miR-203', 'Gene', '406986', (30, 37))	('PVT1', 'Gene', (86, 90))	('ESCC', 'Disease', (104, 108))	('PVT1', 'Gene', '5820', (86, 90))
786774	28404954	Human embryonic kidney (HEK) 293T cells, human ESCC cell lines KYSE30, KYSE410, KYSE520, KYSE510, KYSE140, and KYSE150, were purchased from the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ, Braunschweig, Germany).	('KYSE510', 'Var', (89, 96))	('Human', 'Species', '9606', (0, 5))	('embryonic kidney', 'Disease', (6, 22))	('KYSE410', 'Var', (71, 78))	('KYSE150', 'Var', (111, 118))	('von', 'Disease', 'MESH:D014842', (162, 165))	('KYSE140', 'CellLine', 'CVCL:1347', (98, 105))	('human', 'Species', '9606', (41, 46))	('KYSE150', 'CellLine', 'CVCL:1348', (111, 118))	('embryonic kidney', 'Disease', 'MESH:D007674', (6, 22))	('293T', 'CellLine', 'CVCL:0063', (29, 33))	('KYSE30', 'Var', (63, 69))	('von', 'Disease', (162, 165))	('KYSE520', 'Var', (80, 87))	('KYSE140', 'Var', (98, 105))	('HEK', 'CellLine', 'CVCL:M624', (24, 27))
786795	28404954	To confirm the direct regulating relationship between miR-203 and LASP1, the full-length 3'-UTR of the LASP1 mRNA (3'-UTR-wt) and a mutant variant (3'-UTR-mut) were amplified by PCR and cloned into the XbaI site of a pGL3-basic vector (Promega).	('pGL3', 'Gene', '6391', (217, 221))	('miR-203', 'Gene', (54, 61))	('mutant', 'Var', (132, 138))	('LASP1', 'Gene', '3927', (103, 108))	('miR-203', 'Gene', '406986', (54, 61))	('LASP1', 'Gene', '3927', (66, 71))	('LASP1', 'Gene', (66, 71))	('LASP1', 'Gene', (103, 108))	('pGL3', 'Gene', (217, 221))
786809	24626331	Overexpression of WRAP53 was significantly correlated with tumor infiltration depth (P = 0.000), clinical stage (P = 0.001), and lymph node metastasis (P = 0.025).	('tumor', 'Disease', (59, 64))	('WRAP53', 'Gene', (18, 24))	('correlated', 'Reg', (43, 53))	('lymph node metastasis', 'CPA', (129, 150))	('WRAP53', 'Gene', '55135', (18, 24))	('Overexpression', 'Var', (0, 14))	('clinical stage', 'CPA', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
786819	24626331	Esophageal carcinogenesis involves multiple cellular alterations, including aberrant cell cycle control, DNA repair, cellular enzymes, and growth factor and nuclear receptors.	('DNA repair', 'CPA', (105, 115))	('cell cycle control', 'CPA', (85, 103))	('Esophageal carcinogenesis', 'Disease', 'MESH:D063646', (0, 25))	('aberrant cell cycle', 'Phenotype', 'HP:0011018', (76, 95))	('Esophageal carcinogenesis', 'Disease', (0, 25))	('aberrant', 'Var', (76, 84))
786882	24626331	Overexpression of WRAP53 significantly correlated with the overall frequency of ESCC (P<0.001,  Table 1 ).	('correlated', 'Reg', (39, 49))	('WRAP53', 'Gene', (18, 24))	('WRAP53', 'Gene', '55135', (18, 24))	('Overexpression', 'Var', (0, 14))	('ESCC', 'Disease', (80, 84))
786897	24626331	have found that some single-nucleotide polymorphisms (SNPs) in WRAP53 modestly increase the risk of serous and endometrioid invasive ovarian cancer.	('increase', 'PosReg', (79, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('WRAP53', 'Gene', (63, 69))	('WRAP53', 'Gene', '55135', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('endometrioid invasive ovarian cancer', 'Disease', 'MESH:D016889', (111, 147))	('invasive ovarian cancer', 'Phenotype', 'HP:0025318', (124, 147))	('single-nucleotide polymorphisms', 'Var', (21, 52))	('endometrioid invasive ovarian cancer', 'Disease', (111, 147))
786898	24626331	SNPs in WRAP53 are found to be overrepresented in women with breast cancer, especially in estrogen receptor-negative breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('overrepresented', 'PosReg', (31, 46))	('SNPs', 'Var', (0, 4))	('breast cancer', 'Disease', (117, 130))	('WRAP53', 'Gene', (8, 14))	('women', 'Species', '9606', (50, 55))	('WRAP53', 'Gene', '55135', (8, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
787032	33671768	Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively.	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('altered', 'Reg', (93, 100))	('toxicity', 'Disease', (4, 12))	('gene', 'MPA', (75, 79))	('resulted in', 'Reg', (63, 74))	('epigenetic modifications', 'Var', (16, 40))	('gene expression', 'MPA', (101, 116))
787041	33671768	Inflammation is thus the most effective intrinsic factor required to repeatedly maintain the states of "tissue damage", "genetic instability", and "growth stimulation".	('Inflammation', 'Disease', 'MESH:D007249', (0, 12))	('genetic instability', 'Var', (121, 140))	('Inflammation', 'Disease', (0, 12))
787042	33671768	Moreover, epigenetic alterations such as aberrant DNA hypermethylation are involved in the inflammation-related cancers.	('involved', 'Reg', (75, 83))	('inflammation-related cancers', 'Disease', 'MESH:D009369', (91, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('aberrant DNA hypermethylation', 'Var', (41, 70))	('rat', 'Species', '10116', (25, 28))	('inflammation-related cancers', 'Disease', (91, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
787064	33671768	When mice were treated with 4-NQO and with ethanol in drinking water, they developed mast cell infiltration and had increased expressions of the inflammatory mediators, 5-lipoxygenase and cyclooxygenase-2 (COX-2), and, thereafter, developed oral dysplasia and squamous cell carcinoma.	('5-lipoxygenase', 'Gene', (169, 183))	('increased', 'PosReg', (116, 125))	('mice', 'Species', '10090', (5, 9))	('COX-2', 'Gene', (206, 211))	('4-NQO', 'Chemical', 'MESH:D015112', (28, 33))	('expressions', 'MPA', (126, 137))	('cyclooxygenase-2', 'Gene', '19225', (188, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (260, 283))	('water', 'Chemical', 'MESH:D014867', (63, 68))	('cyclooxygenase-2', 'Gene', (188, 204))	('rat', 'Species', '10116', (101, 104))	('5-lipoxygenase', 'Gene', '11689', (169, 183))	('mast cell infiltration', 'CPA', (85, 107))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (260, 283))	('4-NQO', 'Var', (28, 33))	('COX-2', 'Gene', '19225', (206, 211))	('developed', 'PosReg', (231, 240))	('oral dysplasia', 'Disease', (241, 255))	('ethanol', 'Chemical', 'MESH:D000431', (43, 50))	('oral dysplasia', 'Disease', 'MESH:D020820', (241, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('squamous cell carcinoma', 'Disease', (260, 283))
787065	33671768	Overactivation of the inhibitor of nuclear factor kappa-B kinase (IKK) complex caused the activation of nuclear factor kappa-B (NF-kB), leading to severe inflammation.	('NF-kB', 'Gene', '81736', (128, 133))	('activation', 'PosReg', (90, 100))	('nuclear factor', 'Protein', (104, 118))	('leading to', 'Reg', (136, 146))	('IKK', 'Gene', (66, 69))	('NF-kB', 'Gene', (128, 133))	('IKK', 'Gene', '12675;16150', (66, 69))	('inflammation', 'Disease', 'MESH:D007249', (154, 166))	('inflammation', 'Disease', (154, 166))	('Overactivation', 'Var', (0, 14))
787066	33671768	In the oral epithelia of IKK subunit beta (IKKbeta) transgenic mice, produced in persistent lichenoid inflammation due to neutrophil, macrophage, and B cell infiltration, spontaneous oral squamous cell carcinomas were formed.	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('IKKbeta', 'Gene', '12675', (43, 50))	('IKK', 'Gene', '12675;16150', (43, 46))	('IKK', 'Gene', '12675;16150', (25, 28))	('lichenoid inflammation', 'Disease', 'MESH:D007249', (92, 114))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (188, 212))	('neu', 'Gene', '13866', (122, 125))	('lichenoid inflammation', 'Disease', (92, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (183, 212))	('rat', 'Species', '10116', (163, 166))	('lichenoid inflammation', 'Phenotype', 'HP:0031452', (92, 114))	('neu', 'Gene', (122, 125))	('IKKbeta', 'Gene', (43, 50))	('IKK', 'Gene', (43, 46))	('transgenic', 'Var', (52, 62))	('oral squamous cell carcinomas', 'Disease', (183, 212))	('transgenic mice', 'Species', '10090', (52, 67))	('IKK', 'Gene', (25, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
787069	33671768	Homozygous deletion of Toll-like receptor 2 (TLR2-/-) using 4-NQO in mice increased the number of tongue-infiltrating M2 macrophages and resulted in the development of tongue cancer.	('rat', 'Species', '10116', (111, 114))	('Toll-like receptor 2', 'Gene', '24088', (23, 43))	('resulted in', 'Reg', (137, 148))	('tongue cancer', 'Disease', (168, 181))	('increased', 'PosReg', (74, 83))	('TLR2-/-', 'Gene', (45, 52))	('Toll-like receptor 2', 'Gene', (23, 43))	('mice', 'Species', '10090', (69, 73))	('tongue cancer', 'Disease', 'MESH:D014062', (168, 181))	('men', 'Species', '9606', (160, 163))	('development of tongue', 'Phenotype', 'HP:0012730', (153, 174))	('deletion', 'Var', (11, 19))	('4-NQO', 'Chemical', 'MESH:D015112', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
787072	33671768	The link between inflammation and esophageal cancer is well-established; in particular, interleukin (IL)-1beta is overexpressed in Barrett's esophagus, and polymorphisms in the IL-1beta gene are associated with Barrett's esophagus.	('associated', 'Reg', (195, 205))	('esophageal cancer', 'Disease', (34, 51))	('IL-1beta', 'Gene', (177, 185))	("Barrett's esophagus", 'Disease', (211, 230))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (211, 230))	('interleukin (IL)-1beta', 'Gene', (88, 110))	('interleukin (IL)-1beta', 'Gene', '16175', (88, 110))	('overexpressed', 'PosReg', (114, 127))	('inflammation', 'Disease', 'MESH:D007249', (17, 29))	("Barrett's esophagus", 'Disease', (131, 150))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (131, 150))	('polymorphisms', 'Var', (156, 169))	('inflammation', 'Disease', (17, 29))
787080	33671768	The C57BL/6 strain is considered to be carcinogenic-tolerant, while the BALB/c strain is moderately sensitive.	('carcinogenic-tolerant', 'Disease', 'MESH:D018149', (39, 60))	('carcinogenic-tolerant', 'Disease', (39, 60))	('C57BL/6', 'Var', (4, 11))	('rat', 'Species', '10116', (93, 96))
787082	33671768	The reason for the highest sensitivity of A/J mice to the development of lung tumors is that they have the K-ras intron 2 polymorphism and, thus, undergo activation of the K-ras oncogene.	('polymorphism', 'Var', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('men', 'Species', '9606', (65, 68))	('lung tumors', 'Disease', 'MESH:D008175', (73, 84))	('activation', 'PosReg', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mice', 'Species', '10090', (46, 50))	('lung tumors', 'Phenotype', 'HP:0100526', (73, 84))	('lung tumors', 'Disease', (73, 84))
787099	33671768	Most of the experimental adenocarcinomas exhibited mutations in K-ras, either in codon 12 or in codon 61.	('K-ras', 'Protein', (64, 69))	('mutations', 'Var', (51, 60))	('exhibited', 'Reg', (41, 50))	('men', 'Species', '9606', (18, 21))	('adenocarcinomas', 'Disease', 'MESH:D000230', (25, 40))	('adenocarcinomas', 'Disease', (25, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))
787100	33671768	Lung adenocarcinoma developed in mice treated with N-nitrosodimethylamine (NDMA) alone showed A-to-G transition (Q61R) at K-ras codon 61, whereas mice treated with NDMA and oropharyngeal administration of silica showed G-to-A transition (G12D) in codon 12.	('Q61R', 'Var', (113, 117))	('Q61R', 'Mutation', 'rs121913240', (113, 117))	('NDMA', 'Chemical', 'MESH:D004128', (75, 79))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('G12D', 'Mutation', 'rs121913529', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('NDMA', 'Chemical', 'MESH:D004128', (164, 168))	('silica', 'Chemical', 'MESH:D012822', (205, 211))	('mice', 'Species', '10090', (146, 150))	('rat', 'Species', '10116', (195, 198))	('min', 'Gene', (69, 72))	('min', 'Gene', (189, 192))	('mice', 'Species', '10090', (33, 37))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('min', 'Gene', '11789', (69, 72))	('min', 'Gene', '11789', (189, 192))	('N-nitrosodimethylamine', 'Chemical', 'MESH:D004128', (51, 73))
787101	33671768	Therefore, among the K-ras mutation profiles of lung cancer, the Q61R to G12D mutations can occur in an inflammatory environment.	('G12D', 'Mutation', 'rs121913529', (73, 77))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('Q61R to G12D', 'Var', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('Q61R', 'Mutation', 'rs121913240', (65, 69))
787102	33671768	Benzo[a]pyrene (B[a]P) is present in tobacco metabolites and is metabolized into epoxide, which induces DNA adducts and causes mutations due to ROS generation, which can together accelerate the process of lung tumorigenesis.	('Benzo[a]pyrene', 'Chemical', 'MESH:D001564', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tobacco', 'Species', '4097', (37, 44))	('rat', 'Species', '10116', (152, 155))	('accelerate', 'PosReg', (179, 189))	('epoxide', 'Chemical', 'MESH:D004852', (81, 88))	('ROS', 'Chemical', 'MESH:D017382', (144, 147))	('tumor', 'Disease', (210, 215))	('ROS generation', 'MPA', (144, 158))	('induces', 'Reg', (96, 103))	('lung', 'Disease', (205, 209))	('B[a]P', 'Chemical', 'MESH:D001564', (16, 21))	('mutations', 'Var', (127, 136))	('DNA adducts', 'MPA', (104, 115))	('rat', 'Species', '10116', (185, 188))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
787103	33671768	C57BL/6 mice exposed to B[a]p with intratracheal LPS administration formed more lung tumors than mice exposed to B[a]p alone.	('lung tumors', 'Phenotype', 'HP:0100526', (80, 91))	('B[a]p', 'Var', (24, 29))	('lung tumors', 'Disease', 'MESH:D008175', (80, 91))	('rat', 'Species', '10116', (61, 64))	('mice', 'Species', '10090', (97, 101))	('mice', 'Species', '10090', (8, 12))	('min', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lung tumors', 'Disease', (80, 91))	('min', 'Gene', '11789', (55, 58))	('rat', 'Species', '10116', (38, 41))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
787107	33671768	The homozygous conditional deletion of mitogen-induced gene 6 (Mig-6d/d) and mutated K-ras (K-RasG12D) occurs in transgenic mouse (Mig-6d/dK-RasG12D) in which a signaling molecule, Mig-6, is deleted and K-ras (G12D) is activated in lung Clara cells.	('Mig-6', 'Gene', '74155', (181, 186))	('Mig-6', 'Gene', (181, 186))	('G12D', 'Mutation', 'rs121913529', (97, 101))	('K-RasG12D', 'Gene', '16653', (92, 101))	('Mig-6', 'Gene', '74155', (63, 68))	('Mig-6', 'Gene', (63, 68))	('Mig-6', 'Gene', '74155', (131, 136))	('mouse', 'Species', '10090', (124, 129))	('deletion', 'Var', (27, 35))	('Mig-6', 'Gene', (131, 136))	('K-RasG12D', 'Gene', '16653', (139, 148))	('transgenic', 'Species', '10090', (113, 123))	('K-RasG12D', 'Gene', (139, 148))	('K-RasG12D', 'Gene', (92, 101))	('G12D', 'Mutation', 'rs121913529', (144, 148))	('G12D', 'Mutation', 'rs121913529', (210, 214))
787122	33671768	The histological types of gastric cancer developed by H. pylori and MNU caused poorly differentiated, signet-ring cells and well-differentiated adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('H. pylori', 'Var', (54, 63))	('caused', 'Reg', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('MNU', 'Gene', (68, 71))	('adenocarcinoma', 'Disease', (144, 158))	('gastric cancer', 'Disease', (26, 40))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('gastric cancer', 'Disease', 'MESH:D013274', (26, 40))	('MNU', 'Chemical', 'MESH:D008770', (68, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (26, 40))	('signet-ring cells', 'Disease', (102, 119))	('poorly differentiated', 'CPA', (79, 100))	('H. pylori', 'Species', '210', (54, 63))
787142	33671768	The homozygous knock-in substitution of a glycoprotein 130 (gp130Y757F/Y757F) mouse carries a mutated gp130 cytokine receptor signaling subunit that cannot bind the negative regulator of cytokine signaling SOCS3 and hyperactivates STAT1 and STAT3 signaling.	('Y757F', 'Mutation', 'p.Y757F', (71, 76))	('STAT3', 'Gene', (241, 246))	('STAT1', 'Gene', '20846', (231, 236))	('Y757F', 'Mutation', 'p.Y757F', (65, 70))	('hyperactivates', 'PosReg', (216, 230))	('STAT1', 'Gene', (231, 236))	('SOCS3', 'Gene', (206, 211))	('mouse', 'Species', '10090', (78, 83))	('SOCS3', 'Gene', '12702', (206, 211))	('gp130Y757F/Y757F', 'Var', (60, 76))	('STAT3', 'Gene', '20848', (241, 246))
787144	33671768	gp130Y757F/Y757F causes the development of those gastric cancer-accompanying hyperplasia, with histological features reminiscent of those intestinal-type and metaplastic gastric tumors in humans.	('men', 'Species', '9606', (35, 38))	('causes', 'Reg', (17, 23))	('gastric tumors', 'Disease', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))	('hyperplasia', 'Disease', (77, 88))	('humans', 'Species', '9606', (188, 194))	('hyperplasia', 'Disease', 'MESH:D006965', (77, 88))	('Y757F', 'Mutation', 'p.Y757F', (5, 10))	('gp130Y757F/Y757F', 'Var', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('min', 'Gene', (119, 122))	('min', 'Gene', '11789', (119, 122))	('gastric tumors', 'Disease', 'MESH:D013274', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('gastric tumors', 'Phenotype', 'HP:0006753', (170, 184))	('Y757F', 'Mutation', 'p.Y757F', (11, 16))	('gastric cancer', 'Disease', (49, 63))
787145	33671768	The stomach-specific expression of human IL-1beta in transgenic mice leads to gastric inflammation and cancer by the early recruitment of myeloid-derived suppressor cells, while T and B cells are not needed for this phenomenon.	('gastric inflammation', 'Disease', 'MESH:D013272', (78, 98))	('gastric inflammation', 'Disease', (78, 98))	('gastric inflammation', 'Phenotype', 'HP:0005263', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('human', 'Species', '9606', (35, 40))	('transgenic mice', 'Species', '10090', (53, 68))	('leads to', 'Reg', (69, 77))	('men', 'Species', '9606', (221, 224))	('IL-1beta', 'Gene', (41, 49))	('expression', 'Var', (21, 31))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('men', 'Species', '9606', (130, 133))
787148	33671768	Carriers of IL-1beta polymorphisms are at risk for human gastric cancer.	('IL-1beta', 'Gene', (12, 20))	('gastric cancer', 'Disease', (57, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('human', 'Species', '9606', (51, 56))	('risk', 'Reg', (42, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('polymorphisms', 'Var', (21, 34))
787159	33671768	HBsAg in hepatocytes induces liver regeneration due to induction of inflammation and the associated ROS, which impairs their ability to replicate and allows the activation of hepatic stem cells.	('induces', 'PosReg', (21, 28))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('HBsAg', 'Var', (0, 5))	('rat', 'Species', '10116', (41, 44))	('ROS', 'Gene', (100, 103))	('inflammation', 'Disease', (68, 80))	('ability', 'MPA', (125, 132))	('liver', 'Disease', (29, 34))	('impairs', 'NegReg', (111, 118))
787184	33671768	Deletion of the ATP7B gene, which is homologous to the Wilson's disease gene, has been identified in LEC rats.	("Wilson's disease", 'Disease', (55, 71))	('ATP7B', 'Gene', '24218', (16, 21))	('ATP7B', 'Gene', (16, 21))	('LEC', 'Gene', (101, 104))	('LEC', 'Gene', '6360', (101, 104))	("Wilson's disease", 'Disease', 'MESH:D006527', (55, 71))	('rats', 'Species', '10116', (105, 109))	('Deletion', 'Var', (0, 8))
787210	33671768	Aberrant lipogenesis in the liver, which is closely linked to obesity and metabolic syndrome, causes nonalcoholic fatty liver disease (NAFLD), which is observed in 75-100% of overweight and obese adults and children.	('overweight', 'Phenotype', 'HP:0025502', (175, 185))	('fatty liver', 'Phenotype', 'HP:0001397', (114, 125))	('lipogenesis', 'MPA', (9, 20))	('nonalcoholic fatty liver disease', 'Disease', (101, 133))	('metabolic syndrome', 'Disease', 'MESH:D024821', (74, 92))	('obese', 'Disease', (190, 195))	('Aberrant', 'Var', (0, 8))	('obesity', 'Phenotype', 'HP:0001513', (62, 69))	('children', 'Species', '9606', (207, 215))	('causes', 'Reg', (94, 100))	('obese', 'Disease', 'MESH:D009765', (190, 195))	('nonalcoholic fatty liver disease', 'Disease', 'MESH:D065626', (101, 133))	('Aberrant lipogenesis', 'Phenotype', 'HP:0009125', (0, 20))	('liver disease', 'Phenotype', 'HP:0001392', (120, 133))	('obesity', 'Disease', (62, 69))	('NAFLD', 'Gene', (135, 140))	('NAFLD', 'Gene', '22084', (135, 140))	('obesity', 'Disease', 'MESH:D009765', (62, 69))	('metabolic syndrome', 'Disease', (74, 92))
787214	33671768	MSG induced beta cell proliferation and caused islet hypertrophy, leading to the development of obesity and steatosis with the infiltration of neutrophils and the onset of diabetes mellitus.	('obesity', 'Phenotype', 'HP:0001513', (96, 103))	('diabetes mellitus', 'Disease', 'MESH:D003920', (172, 189))	('MSG', 'Var', (0, 3))	('hypertrophy', 'Disease', 'MESH:D006984', (53, 64))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (172, 189))	('rat', 'Species', '10116', (133, 136))	('neu', 'Gene', '13866', (143, 146))	('hypertrophy', 'Disease', (53, 64))	('men', 'Species', '9606', (88, 91))	('MSG', 'Chemical', 'MESH:D012970', (0, 3))	('islet', 'Disease', (47, 52))	('rat', 'Species', '10116', (29, 32))	('beta cell proliferation', 'CPA', (12, 35))	('obesity and steatosis', 'Disease', 'MESH:D009765', (96, 117))	('islet hypertrophy', 'Phenotype', 'HP:0004510', (47, 64))	('diabetes mellitus', 'Disease', (172, 189))	('steatosis', 'Phenotype', 'HP:0001397', (108, 117))	('neu', 'Gene', (143, 146))	('leading to', 'Reg', (66, 76))
787227	33671768	It is known that approximately half of human liver tumors have G-T (Q61K) mutations at codon 61 of the H-ras oncogene.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('liver tumors', 'Disease', 'MESH:D008113', (45, 57))	('G-T (Q61K', 'Var', (63, 72))	('H-ras', 'Gene', '3265', (103, 108))	('liver tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Q61K', 'Mutation', 'rs28933406', (68, 72))	('liver tumors', 'Phenotype', 'HP:0002896', (45, 57))	('H-ras', 'Gene', (103, 108))	('human', 'Species', '9606', (39, 44))
787228	33671768	Whole-exome sequencing of liver tumors formed in HFD mice showed that similar G-T point mutations occurred predominantly.	('liver tumors', 'Disease', 'MESH:D008113', (26, 38))	('point mutations', 'Var', (82, 97))	('liver tumors', 'Disease', (26, 38))	('liver tumors', 'Phenotype', 'HP:0002896', (26, 38))	('min', 'Gene', (112, 115))	('min', 'Gene', '11789', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('mice', 'Species', '10090', (53, 57))
787239	33671768	TAA stimulates the infiltration of inflammatory cells, hepatic macrophages, and CD3+ T cells.	('infiltration', 'CPA', (19, 31))	('TAA', 'Var', (0, 3))	('CD3', 'Gene', (80, 83))	('rat', 'Species', '10116', (25, 28))	('TAA', 'Chemical', 'MESH:D013853', (0, 3))	('CD3', 'Gene', '12501', (80, 83))
787243	33671768	CCl4 induced chronic hepatotoxicity, such as fatty change, fibrosis, and cirrhosis, and led to the development of hepatocellular adenomas and HCC.	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (114, 137))	('cirrhosis', 'Disease', (73, 82))	('chronic hepatotoxicity', 'Disease', 'MESH:D056487', (13, 35))	('chronic hepatotoxicity', 'Disease', (13, 35))	('fibrosis', 'Disease', (59, 67))	('led to', 'Reg', (88, 94))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (114, 137))	('cirrhosis', 'Phenotype', 'HP:0001394', (73, 82))	('fatty', 'Disease', (45, 50))	('hepatocellular adenomas', 'Disease', (114, 137))	('fibrosis', 'Disease', 'MESH:D005355', (59, 67))	('CCl4', 'Var', (0, 4))	('cirrhosis', 'Disease', 'MESH:D005355', (73, 82))	('HCC', 'Disease', (142, 145))	('HCC', 'Phenotype', 'HP:0001402', (142, 145))	('men', 'Species', '9606', (106, 109))
787246	33671768	The hepatocyte-specific homozygous deletion of Atg5 (Atg5-/-) mice resulted in increased inflammation and fibrosis and led to the formation of hepatocellular adenomas in the liver that was infiltrated with neutrophils and macrophages.	('hepatocellular adenomas', 'Disease', (143, 166))	('increased', 'PosReg', (79, 88))	('fibrosis', 'Disease', 'MESH:D005355', (106, 114))	('fibrosis', 'Disease', (106, 114))	('mice', 'Species', '10090', (62, 66))	('Atg5', 'Gene', '11793', (53, 57))	('Atg5', 'Gene', '11793', (47, 51))	('neu', 'Gene', (206, 209))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (143, 166))	('inflammation', 'Disease', 'MESH:D007249', (89, 101))	('deletion', 'Var', (35, 43))	('rat', 'Species', '10116', (195, 198))	('neu', 'Gene', '13866', (206, 209))	('inflammation', 'Disease', (89, 101))	('led to', 'Reg', (119, 125))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (143, 166))	('Atg5', 'Gene', (47, 51))	('Atg5', 'Gene', (53, 57))
787250	33671768	The homozygous deletion of the farnesoid X receptor (Fxr-/-) in mice results in the accumulation of high levels of bile acids, which provokes inflammation-induced hepatocarcinogenesis with fibrosis and hepatosteatosis.	('provokes', 'Reg', (133, 141))	('high levels of bile acids', 'MPA', (100, 125))	('deletion', 'Var', (15, 23))	('inflammation-induced hepatocarcinogenesis', 'Disease', 'MESH:D007249', (142, 183))	('Fxr', 'Gene', (53, 56))	('high levels of bile acids', 'Phenotype', 'HP:0012202', (100, 125))	('bile acids', 'Chemical', 'MESH:D001647', (115, 125))	('inflammation-induced hepatocarcinogenesis', 'Disease', (142, 183))	('mice', 'Species', '10090', (64, 68))	('steatosis', 'Phenotype', 'HP:0001397', (208, 217))	('accumulation', 'PosReg', (84, 96))	('Fxr', 'Gene', '20186', (53, 56))	('fibrosis and hepatosteatosis', 'Disease', 'MESH:D005355', (189, 217))
787258	33671768	Due to the insufficient secretion of phospholipids into the bile, mice with a homozygous deletion of the Mdr2 P-glycoprotein (Mdr2-/-) gene develop nonsuppurative inflammatory cholangitis, which mainly contributes to B cells and stimulates tube proliferation, and most mice develop HCC.	('rat', 'Species', '10116', (156, 159))	('tube proliferation', 'CPA', (240, 258))	('develop', 'PosReg', (140, 147))	('rat', 'Species', '10116', (252, 255))	('HCC', 'Phenotype', 'HP:0001402', (282, 285))	('cholangitis', 'Disease', 'MESH:D002761', (176, 187))	('nonsuppurative inflammatory cholangitis', 'Phenotype', 'HP:0030987', (148, 187))	('Mdr2', 'Gene', (126, 130))	('mice', 'Species', '10090', (66, 70))	('phospholipids', 'Chemical', 'MESH:D010743', (37, 50))	('Mdr2', 'Gene', '18670', (105, 109))	('deletion', 'Var', (89, 97))	('cholangitis', 'Disease', (176, 187))	('mice', 'Species', '10090', (269, 273))	('cholangitis', 'Phenotype', 'HP:0030151', (176, 187))	('Mdr2', 'Gene', '18670', (126, 130))	('Mdr2', 'Gene', (105, 109))	('HCC', 'Disease', (282, 285))
787264	33671768	Oncogenic K-ras mutation represents the most frequent and earliest genetic alteration in PDAC patients, which highlights its role as a driver of PDAC.	('mutation', 'Var', (16, 24))	('K-ras', 'Protein', (10, 15))	('patients', 'Species', '9606', (94, 102))	('PDAC', 'Chemical', '-', (89, 93))	('PDAC', 'Chemical', '-', (145, 149))	('PDAC', 'Disease', (89, 93))	('PDAC', 'Phenotype', 'HP:0006725', (89, 93))	('rat', 'Species', '10116', (79, 82))	('Oncogenic', 'Var', (0, 9))	('PDAC', 'Phenotype', 'HP:0006725', (145, 149))
787279	33671768	DSS induces colonic inflammation and its associated dysplasia and carcinomas in guinea pigs, rabbits, hamsters, and mice with clinical and histopathological similarity to human ulcerative colitis (UC).	('dysplasia', 'Disease', (52, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (177, 195))	('colonic inflammation', 'Disease', (12, 32))	('DSS', 'Chemical', 'MESH:D016264', (0, 3))	('colitis', 'Phenotype', 'HP:0002583', (188, 195))	('hamster', 'Species', '10034', (102, 109))	('UC', 'Phenotype', 'HP:0100279', (197, 199))	('mice', 'Species', '10090', (116, 120))	('ulcerative colitis', 'Disease', (177, 195))	('dysplasia', 'Disease', 'MESH:C536170', (52, 61))	('carcinomas', 'Disease', (66, 76))	('colonic inflammation', 'Disease', 'MESH:D007249', (12, 32))	('induces', 'Reg', (4, 11))	('DSS', 'Var', (0, 3))	('ulcerative colitis', 'Disease', 'MESH:D003093', (177, 195))	('rabbits', 'Species', '9986', (93, 100))	('human', 'Species', '9606', (171, 176))	('guinea pigs', 'Species', '10141', (80, 91))	('carcinomas', 'Disease', 'MESH:D009369', (66, 76))
787320	33671768	The Min/Min homozygous mutation of the adenomatous polyposis coli gene in mice is lethal, and mice with a heterozygous mutation (ApcMin/+) survive but develop adenomas throughout the small intestine and only rarely in the colon; however, in humans with hereditary familial adenomatous polyposis, adenomas occur in the colon, duodenum, and rectum.	('Min', 'Gene', '11789', (4, 7))	('familial adenomatous polyposis', 'Disease', (264, 294))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (39, 65))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (39, 65))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (264, 294))	('mice', 'Species', '10090', (94, 98))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (273, 294))	('adenomatous polyposis coli', 'Disease', (39, 65))	('Min', 'Gene', (8, 11))	('Min', 'Gene', '11789', (8, 11))	('mice', 'Species', '10090', (74, 78))	('Min', 'Phenotype', 'HP:0200008', (132, 135))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (39, 60))	('Min', 'Phenotype', 'HP:0200008', (4, 7))	('humans', 'Species', '9606', (241, 247))	('adenomas', 'Disease', 'MESH:D000236', (159, 167))	('adenomas', 'Disease', 'MESH:D000236', (296, 304))	('adenomas', 'Disease', (159, 167))	('adenomas', 'Disease', (296, 304))	('Min', 'Gene', (132, 135))	('mutation', 'Var', (23, 31))	('Min', 'Gene', '11789', (132, 135))	('Min', 'Gene', (4, 7))	('Min', 'Phenotype', 'HP:0200008', (8, 11))
787323	33671768	There are three mouse strains with different codon sites for APC mutations, and the difference in mutation is represented by the difference in tumorigenesis site and number.	('APC', 'Disease', 'MESH:D011125', (61, 64))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('APC', 'Disease', (61, 64))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (65, 74))
787335	33671768	The homozygous deletion of interleukin-10 (IL-10-/-) mice leads to enterocolitis, which is similar to human IBD.	('IL-10', 'Gene', '16153', (43, 48))	('deletion', 'Var', (15, 23))	('enterocolitis', 'Disease', (67, 80))	('IBD', 'Disease', (108, 111))	('IL-10', 'Gene', (43, 48))	('leads to', 'Reg', (58, 66))	('interleukin-10', 'Gene', '16153', (27, 41))	('IBD', 'Disease', 'MESH:D015212', (108, 111))	('enterocolitis', 'Disease', 'MESH:D004760', (67, 80))	('colitis', 'Phenotype', 'HP:0002583', (73, 80))	('IBD', 'Phenotype', 'HP:0002037', (108, 111))	('enterocolitis', 'Phenotype', 'HP:0004387', (67, 80))	('interleukin-10', 'Gene', (27, 41))	('mice', 'Species', '10090', (53, 57))	('human', 'Species', '9606', (102, 107))
787337	33671768	The treatment of IL-10-/- mice with AOM/DSS caused colitis and tumors as a result of microbial activation, but tumor development was suppressed under germ-free conditions.	('colitis', 'Disease', 'MESH:D003092', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('IL-10', 'Gene', (17, 22))	('AOM/DSS', 'Var', (36, 43))	('men', 'Species', '9606', (9, 12))	('tumors', 'Disease', (63, 69))	('colitis', 'Phenotype', 'HP:0002583', (51, 58))	('tumor', 'Disease', (63, 68))	('IL-10', 'Gene', '16153', (17, 22))	('activation', 'PosReg', (95, 105))	('tumor', 'Disease', (111, 116))	('AOM', 'Chemical', 'MESH:D001397', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('microbial', 'CPA', (85, 94))	('mice', 'Species', '10090', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('colitis', 'Disease', (51, 58))	('men', 'Species', '9606', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('caused', 'Reg', (44, 50))	('DSS', 'Chemical', 'MESH:D016264', (40, 43))
787341	33671768	C57BL/6-Ay mice show severe hyperphagia, polydipsia, impaired glucose tolerance, hyperinsulinemia, and hyperlipidemia.	('hyperlipidemia', 'Disease', 'MESH:D006949', (103, 117))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (81, 97))	('hyperlipidemia', 'Phenotype', 'HP:0003077', (103, 117))	('polydipsia', 'Phenotype', 'HP:0001959', (41, 51))	('impaired glucose tolerance', 'Disease', 'MESH:D018149', (53, 79))	('polydipsia', 'Disease', (41, 51))	('hyperphagia', 'Disease', (28, 39))	('C57BL/6-Ay', 'Var', (0, 10))	('impaired glucose tolerance', 'Disease', (53, 79))	('hyperphagia', 'Phenotype', 'HP:0002591', (28, 39))	('hyperinsulinemia', 'Disease', (81, 97))	('hyperphagia', 'Disease', 'MESH:D006963', (28, 39))	('mice', 'Species', '10090', (11, 15))	('hyperlipidemia', 'Disease', (103, 117))	('impaired glucose tolerance', 'Phenotype', 'HP:0040270', (53, 79))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (81, 97))	('polydipsia', 'Disease', 'MESH:D059606', (41, 51))
787343	33671768	Since the diabetes (db) gene encodes the receptor for the obese (ob) gene product, leptin, mutations in the mouse db gene, cause leptin dysfunction, resulting in obesity and diabetes in a syndrome similar to that of human obesity.	('diabetes', 'Disease', (10, 18))	('human', 'Species', '9606', (216, 221))	('leptin dysfunction', 'Disease', (129, 147))	('obesity', 'Disease', 'MESH:D009765', (222, 229))	('leptin dysfunction', 'Disease', 'OMIM:614962', (129, 147))	('diabetes', 'Disease', (174, 182))	('obesity', 'Disease', (162, 169))	('leptin', 'Gene', (83, 89))	('obesity', 'Disease', 'MESH:D009765', (162, 169))	('obese (ob', 'Gene', (58, 67))	('leptin', 'Gene', '16846', (83, 89))	('obesity', 'Phenotype', 'HP:0001513', (222, 229))	('diabetes', 'Disease', 'MESH:D003920', (10, 18))	('leptin', 'Gene', '16846', (129, 135))	('leptin', 'Gene', (129, 135))	('mouse', 'Species', '10090', (108, 113))	('resulting in', 'Reg', (149, 161))	('diabetes', 'Disease', 'MESH:D003920', (174, 182))	('cause', 'Reg', (123, 128))	('obese (ob)', 'Gene', '16846', (58, 68))	('obesity', 'Disease', (222, 229))	('obesity', 'Phenotype', 'HP:0001513', (162, 169))	('mutations', 'Var', (91, 100))
787347	33671768	The homozygous deletion of lactoferrin (Lf-/-) mice showed higher susceptibility to AOM/DSS-induced colitis and developed dysplasia.	('DSS', 'Chemical', 'MESH:D016264', (88, 91))	('lactoferrin', 'Gene', '17002', (27, 38))	('colitis', 'Disease', 'MESH:D003092', (100, 107))	('colitis', 'Disease', (100, 107))	('deletion', 'Var', (15, 23))	('dysplasia', 'Disease', 'MESH:C536170', (122, 131))	('susceptibility', 'Reg', (66, 80))	('AOM', 'Chemical', 'MESH:D001397', (84, 87))	('colitis', 'Phenotype', 'HP:0002583', (100, 107))	('lactoferrin', 'Gene', (27, 38))	('dysplasia', 'Disease', (122, 131))	('higher', 'PosReg', (59, 65))	('mice', 'Species', '10090', (47, 51))	('developed', 'Reg', (112, 121))
787349	33671768	The homozygous deletion of Nrf2 (Nrf2-/-) mice treated with AOM/DSS demonstrates increased colitis and adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Nrf2', 'Gene', (33, 37))	('DSS', 'Chemical', 'MESH:D016264', (64, 67))	('Nrf2', 'Gene', '18024', (27, 31))	('deletion', 'Var', (15, 23))	('rat', 'Species', '10116', (75, 78))	('mice', 'Species', '10090', (42, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('colitis', 'Disease', 'MESH:D003092', (91, 98))	('Nrf2', 'Gene', (27, 31))	('adenocarcinomas', 'Disease', 'MESH:D000230', (103, 118))	('adenocarcinomas', 'Disease', (103, 118))	('colitis', 'Disease', (91, 98))	('AOM', 'Chemical', 'MESH:D001397', (60, 63))	('Nrf2', 'Gene', '18024', (33, 37))	('increased', 'PosReg', (81, 90))	('colitis', 'Phenotype', 'HP:0002583', (91, 98))
787352	33671768	The homozygous deletion of syndecan-1 (Sdc1-/-) mice results in an increased susceptibility to colitis-associated cancer induced by AOM/DSS through IL-6 and STAT3 signaling.	('Sdc1', 'Gene', '20969', (39, 43))	('deletion', 'Var', (15, 23))	('DSS', 'Chemical', 'MESH:D016264', (136, 139))	('colitis', 'Phenotype', 'HP:0002583', (95, 102))	('mice', 'Species', '10090', (48, 52))	('syndecan-1', 'Gene', (27, 37))	('AOM', 'Chemical', 'MESH:D001397', (132, 135))	('STAT3', 'Gene', '20848', (157, 162))	('colitis-associated cancer', 'Disease', (95, 120))	('Sdc1', 'Gene', (39, 43))	('colitis-associated cancer', 'Disease', 'MESH:D009369', (95, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('STAT3', 'Gene', (157, 162))	('syndecan-1', 'Gene', '20969', (27, 37))	('susceptibility', 'Reg', (77, 91))
787353	33671768	Salmonella, a Gram-negative bacterium, causes gastroenteritis and sepsis, as well as intestinal injury in both humans and animals.	('causes', 'Reg', (39, 45))	('gastroenteritis and sepsis', 'Disease', 'MESH:D018805', (46, 72))	('Salmonella', 'Species', '90371', (0, 10))	('Salmonella', 'Var', (0, 10))	('intestinal injury', 'Disease', (85, 102))	('sepsis', 'Phenotype', 'HP:0100806', (66, 72))	('intestinal injury', 'Disease', 'MESH:D007410', (85, 102))	('humans', 'Species', '9606', (111, 117))
787409	33671768	Fe-NTA induced severe acute nephrotoxicity and the infiltration of leukocytes into the proximal tubular epithelium, as well as the resulting oxidative stress and hyperproliferative response.	('oxidative stress', 'MPA', (141, 157))	('hyperproliferative response', 'CPA', (162, 189))	('Fe-NTA', 'Var', (0, 6))	('rat', 'Species', '10116', (57, 60))	('rat', 'Species', '10116', (174, 177))	('Fe-NTA', 'Chemical', 'MESH:C020326', (0, 6))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))	('nephrotoxicity', 'Disease', (28, 42))	('infiltration', 'CPA', (51, 63))	('nephrotoxicity', 'Disease', 'MESH:D007674', (28, 42))
787423	33671768	In response to the DMBA-initiated and TPA-promoted skin carcinogenesis protocols, benign papillomas occur much faster in heterozygous p53 gene deletion (p53+/-) mice compared to wild-type mice.	('mice', 'Species', '10090', (188, 192))	('benign papillomas', 'Disease', 'MESH:D010212', (82, 99))	('mice', 'Species', '10090', (161, 165))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (51, 70))	('papillomas', 'Phenotype', 'HP:0012740', (89, 99))	('faster', 'PosReg', (111, 117))	('TPA', 'Chemical', 'MESH:D013755', (38, 41))	('gene deletion', 'Var', (138, 151))	('papilloma', 'Phenotype', 'HP:0012740', (89, 98))	('skin carcinogenesis', 'Disease', (51, 70))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '22059', (153, 156))	('benign papillomas', 'Disease', (82, 99))	('p53', 'Gene', (134, 137))	('p53', 'Gene', '22059', (134, 137))	('DMBA', 'Chemical', 'MESH:D015127', (19, 23))
787425	33671768	UVB induces signature mutations characterized by C-T or CC-TT mutations at pyrimidine-pyrimidine sequences.	('pyrimidine', 'Chemical', 'MESH:C030986', (75, 85))	('C-T', 'Disease', 'MESH:C537418', (57, 60))	('mutations', 'Var', (62, 71))	('C-T', 'Disease', (49, 52))	('C-T', 'Disease', 'MESH:C537418', (49, 52))	('pyrimidine', 'Chemical', 'MESH:C030986', (86, 96))	('C-T', 'Disease', (57, 60))
787426	33671768	These mutations are detectable in several tumor-suppressor genes, particularly Patched 1 (Ptch1) and p53 in UVB-exposed skin sites.	('Ptch1', 'Gene', (90, 95))	('tumor-suppressor', 'Gene', (42, 58))	('Ptch1', 'Gene', '19206', (90, 95))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '22059', (101, 104))	('tumor-suppressor', 'Gene', '7248', (42, 58))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutations', 'Var', (6, 15))	('Patched 1', 'Gene', '19206', (79, 88))	('Patched 1', 'Gene', (79, 88))
787427	33671768	Since the homozygous deletion of Ptch1 is embryonic, Ptch1+/- mice were used for mating with SKH-1 hairless mice.	('Ptch1', 'Gene', '19206', (33, 38))	('Ptch1', 'Gene', (33, 38))	('Ptch1', 'Gene', (53, 58))	('Ptch1', 'Gene', '19206', (53, 58))	('mice', 'Species', '10090', (62, 66))	('mice', 'Species', '10090', (108, 112))	('deletion', 'Var', (21, 29))
787433	33671768	Homozygous deletions in XP group A (XPA-/-) mice are sensitive to UVB and induced a severe inflammatory response.	('sensitive to UVB', 'MPA', (53, 69))	('XP group A', 'Gene', (24, 34))	('induced', 'Reg', (74, 81))	('deletions', 'Var', (11, 20))	('XPA', 'Gene', (36, 39))	('inflammatory response', 'CPA', (91, 112))	('XPA', 'Gene', '22590', (36, 39))	('mice', 'Species', '10090', (44, 48))
787458	33671768	Spontaneous sarcoma development by inflammation induced by foreign body implantation in mice with heterozygous deletion of p53 (p53+/-) is associated with a higher rate of incidence and shorter tumor latency than those in wild-type mice.	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '22059', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('sarcoma', 'Disease', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('p53', 'Gene', '22059', (123, 126))	('p53', 'Gene', (123, 126))	('tumor', 'Disease', (194, 199))	('rat', 'Species', '10116', (164, 167))	('inflammation', 'Disease', 'MESH:D007249', (35, 47))	('mice', 'Species', '10090', (88, 92))	('deletion', 'Var', (111, 119))	('men', 'Species', '9606', (27, 30))	('inflammation', 'Disease', (35, 47))	('mice', 'Species', '10090', (232, 236))
787462	33671768	Inflammation-related carcinogenesis models of each organ using laboratory animals were organized by the cause of inflammation:that is, chemical or irritant-induced inflammation (Table 1), surgery, hormone or diet-induced inflammation (Table 2), genetically modified host-induced inflammation (Table 3), infection-induced inflammation (Table 4), and foreign body-induced inflammation (Table 5).	('inflammation', 'Disease', 'MESH:D007249', (321, 333))	('infection', 'Disease', (303, 312))	('inflammation', 'Disease', (221, 233))	('infection', 'Disease', 'MESH:D007239', (303, 312))	('inflammation', 'Disease', 'MESH:D007249', (370, 382))	('inflammation', 'Disease', 'MESH:D007249', (164, 176))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('foreign', 'Disease', (349, 356))	('inflammation', 'Disease', (321, 333))	('inflammation', 'Disease', (370, 382))	('inflammation', 'Disease', 'MESH:D007249', (279, 291))	('genetically', 'Var', (245, 256))	('inflammation', 'Disease', (164, 176))	('rat', 'Species', '10116', (67, 70))	('Inflammation', 'Disease', (0, 12))	('inflammation', 'Disease', (113, 125))	('Inflammation', 'Disease', 'MESH:D007249', (0, 12))	('irritant-', 'Phenotype', 'HP:0000737', (147, 156))	('inflammation', 'Disease', 'MESH:D007249', (221, 233))	('inflammation', 'Disease', (279, 291))
787472	33671768	The overall estimates have shown a 11% increase in the risk of all cancers for increased natural logarithm levels of CRP.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('natural logarithm levels', 'Var', (89, 113))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('CRP', 'Gene', (117, 120))
787484	33671768	For instance, rheumatoid arthritis is not linked to cancer risk, even though the inflammatory regions in patients with rheumatoid arthritis show mutations in tumor-suppressor genes at similar frequencies to those of genes in the digestive tract tumors arising from chronic inflammatory reactions.	('rheumatoid arthritis', 'Disease', (14, 34))	('mutations', 'Var', (145, 154))	('digestive tract tumors', 'Phenotype', 'HP:0007378', (229, 251))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (14, 34))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (119, 139))	('tumor-suppressor', 'Gene', '7248', (158, 174))	('tumors', 'Disease', (245, 251))	('arthritis', 'Phenotype', 'HP:0001369', (130, 139))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (14, 34))	('tumor-suppressor', 'Gene', (158, 174))	('rheumatoid arthritis', 'Disease', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('arthritis', 'Phenotype', 'HP:0001369', (25, 34))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (119, 139))
787639	31907488	Mutation clustering was performed, and the fractions of tumor cells carrying each set of mutations (Cancer Cell Fraction, CCF) within each sample were used to determine: 1) the clonal and sub-clonal architecture of each tumor (subclonal CCF <95%, clonal CCF >= 95%); 2) the hierarchy of events; and 3) the distance of these sub-clonal or clonal clusters from the most recent common ancestor (MRCA) (Figure 1a, Extended Data Fig.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', (56, 61))	('mutations', 'Var', (89, 98))	('Cancer', 'Disease', (100, 106))	('Cancer', 'Disease', 'MESH:D009369', (100, 106))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
787641	31907488	TP53 was mutated in the trunk of 16 out of 18 cases, consistent with our knowledge of the disease.	('TP53', 'Gene', '7157', (0, 4))	('mutated', 'Var', (9, 16))	('TP53', 'Gene', (0, 4))
787642	31907488	This contrasts with pancreatic cancer, where deletions and fold-back inversions are more common in metastases, and breast cancer where tandem duplications dominate.	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('fold-back', 'Var', (59, 68))	('metastases', 'Disease', (99, 109))	('deletions', 'Var', (45, 54))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('metastases', 'Disease', 'MESH:D009362', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('common', 'Reg', (89, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('pancreatic cancer', 'Disease', (20, 37))
787643	31907488	Furthermore, the proportion of structural variants found uniquely in metastases or in primary sites was higher than that of SNVs (Figure 2, Extended Data 4a), suggesting an increase in genomic instability in later stages of the disease.	('metastases', 'Disease', (69, 79))	('structural variants', 'Var', (31, 50))	('metastases', 'Disease', 'MESH:D009362', (69, 79))	('increase', 'PosReg', (173, 181))	('genomic instability', 'MPA', (185, 204))
787645	31907488	Ten of eighteen patients (S3, S4, P1-4, P6, P8-10) had both nodal and solid organ metastases, allowing a direct comparison of the genomic architecture between different metastatic sites (Figure 2).	('P1-4', 'Gene', (34, 38))	('patients', 'Species', '9606', (16, 24))	('nodal', 'Gene', (60, 65))	('P1-4', 'Gene', '11102', (34, 38))	('P8-10', 'Var', (44, 49))	('metastases', 'Disease', (82, 92))	('nodal', 'Gene', '4838', (60, 65))	('metastases', 'Disease', 'MESH:D009362', (82, 92))
787647	31907488	an oligometastasis, depicted as a dashed black node on the first branch of the phylogenetic tree, shared the highest congruence to the MRCA, (P1, P4, P10, S3 in Figure 2; Subclones P1_2, P4_3, P10_2, S3_2 in Supplementary Table 5).	('P10', 'Gene', (150, 153))	('P4_3', 'Var', (187, 191))	('congruence', 'MPA', (117, 127))	('P10', 'Gene', '6281', (193, 196))	('P1', 'Var', (142, 144))	('P10', 'Gene', (193, 196))	('P10', 'Gene', '6281', (150, 153))
787654	31907488	The subclones forming diasporas were located in both primary and metastatic tissue in eight cases (P1, P2, P3, S4, P4, P6, P8, P10) and in P9 were unique to metastases (Figure 2).	('P1', 'Var', (99, 101))	('metastases', 'Disease', 'MESH:D009362', (157, 167))	('P10', 'Gene', (127, 130))	('P10', 'Gene', '6281', (127, 130))	('metastases', 'Disease', (157, 167))
787657	31907488	Four out of six cases with extensive spatial sampling (Figure 4) had liver metastases evaluated and three of these contained samples that were more similar to local lymph node metastases than neighboring liver metastases (P4, P6, P8 but not P10).	('P4', 'Var', (222, 224))	('metastases', 'Disease', 'MESH:D009362', (176, 186))	('liver metastases', 'Disease', 'MESH:D009362', (204, 220))	('metastases', 'Disease', 'MESH:D009362', (210, 220))	('P10', 'Gene', '6281', (241, 244))	('liver metastases', 'Disease', (69, 85))	('metastases', 'Disease', (75, 85))	('P10', 'Gene', (241, 244))	('liver metastases', 'Disease', (204, 220))	('liver metastases', 'Disease', 'MESH:D009362', (69, 85))	('metastases', 'Disease', 'MESH:D009362', (75, 85))	('metastases', 'Disease', (176, 186))	('metastases', 'Disease', (210, 220))
787658	31907488	The high number of groups within the liver (up to four) suggested seeding by multiple subclones (seen in P4, P6, P8), whereas the single group in the liver of P10 (orange, group 3) indicated seeding by a common progenitor or a set of closely related cells.	('P10', 'Gene', (159, 162))	('P10', 'Gene', '6281', (159, 162))	('seeding', 'CPA', (66, 73))	('P8', 'Var', (113, 115))
787667	31907488	To examine the timing and speed of metastatic spread we analyzed base substitution mutational signatures, particularly the aging signature which features a predominance of C>T transition in the NpCpG trinucleotide context (Figure 1a, Figure 3).	('trinucleotide', 'Chemical', '-', (200, 213))	('base substitution mutational', 'Var', (65, 93))	('C>T transition', 'Var', (172, 186))
787668	31907488	Signature 1 arises from the spontaneous or enzymatic deamination of methylated cytosines, which is an endogenous process that occurs continuously in both healthy and cancerous cells.	('cancerous', 'Disease', (166, 175))	('cancerous', 'Disease', 'MESH:D009369', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('deamination', 'Var', (53, 64))	('cytosines', 'Chemical', 'MESH:D003596', (79, 88))
787673	31907488	Two diagnostic endoscopic samples from P4 also contained many of the mutations found in the lymph node L2 at autopsy, which had not been previously identified in the primary tumor at autopsy (Figure 2, subclone P4_17, Supplementary Table 5).	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
787674	31907488	Similarly, the biopsy sample from P10 contained a substantial number of mutations from both the oligometastasis that seeded D2 and L4 (Supplementary Table 5, P10_2), and the lineage that later metastasized to multiple sites (Figure 2).	('mutations', 'Var', (72, 81))	('P10', 'Gene', '6281', (158, 161))	('P10', 'Gene', (158, 161))	('P10', 'Gene', (34, 37))	('P10', 'Gene', '6281', (34, 37))
787679	31907488	However, at the time of diagnosis mutations from the truncal cluster and three subclonal clusters later found in the metastases were already present in the plasma (Figure 5a) along with amplifications in MYC and GATA4.	('MYC', 'Gene', '4609', (204, 207))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('GATA4', 'Gene', '2626', (212, 217))	('MYC', 'Gene', (204, 207))	('metastases', 'Disease', (117, 127))	('GATA4', 'Gene', (212, 217))	('mutations', 'Var', (34, 43))
787696	31907488	However, the Big Bang Model proposes neutral dynamics, whereas we observe strong evidence for selection in subclonal populations in the form of dN/dS ratios and the occurrence of subclonal driver amplifications (Figure 2, Extended Data Figure 8, Supplementary Figure 2).	('dN', 'Chemical', 'MESH:C022306', (144, 146))	('dS', 'Chemical', 'MESH:D003903', (147, 149))	('amplifications', 'Var', (196, 210))	('dN/dS ratios', 'MPA', (144, 156))
787705	31907488	Clustering of mutations was carried out using a previously published Bayesian Dirichlet Process method, DPClust (https://github.com/Wedge-Oxford/dpclust), which calculates CCFs of each SNV, taking into account tumor purity and copy number aberrations as previously described.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('mutations', 'Var', (14, 23))	('CCFs', 'MPA', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
787729	31907488	In addition, low depth WGS (median coverage 1, IQR 1-5) was performed to track these mutations spatially in up to 48 solid tissue samples per case, (total=248) and 8 ctDNA samples at autopsy.	('low depth WGS', 'Disease', (13, 26))	('mutations', 'Var', (85, 94))	('low depth WGS', 'Disease', 'MESH:D007222', (13, 26))
787733	31907488	Estimate the 95% confidence intervals as the [0.025,0.975] quantiles of the mean pih values of the mutations assigned to each cluster within MCMC sampling.	('mutations', 'Var', (99, 108))	('pih', 'Gene', (81, 84))	('pih', 'Gene', '5177', (81, 84))
787734	31907488	For each patient, we inferred the number of subclones and the fraction of tumor cells within each subclone by using a previously described Bayesian Dirichlet process (BDP) to cluster mutations according to their mutation copy number.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('mutations', 'Var', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('patient', 'Species', '9606', (9, 16))
787738	31907488	Clusters containing less than 1% of all mutations identified in a tumor were not included in phylogenetic reconstruction.	('tumor', 'Disease', (66, 71))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))
787755	31157294	All ESDs were performed with an upper gastrointestinal endoscope (GIF-Q240 or GIF-Q260J; Olympus Medical Systems, Tokyo, Japan) that was fitted with a transparent hood (F-020, TOP Corporation, Tokyo, Japan).	('upper gastrointestinal endoscope', 'Disease', (32, 64))	('Q260J', 'SUBSTITUTION', 'None', (82, 87))	('Q260J', 'Var', (82, 87))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (32, 64))
787766	31157294	Post-ESD stricture was defined as a patient complaint of dysphagia to soft solids or when a standard endoscope (GIF-Q240 or GIF-Q260J; Olympus) could not be passed through the ESD scar.	('dysphagia to soft solids', 'Disease', (57, 81))	('dysphagia', 'Disease', 'MESH:D003680', (57, 66))	('Q260J', 'Var', (128, 133))	('stricture', 'Disease', (9, 18))	('Post-ESD', 'Disease', (0, 8))	('Q260J', 'SUBSTITUTION', 'None', (128, 133))	('dysphagia to soft solids', 'Disease', 'MESH:D003680', (57, 81))	('scar', 'Phenotype', 'HP:0100699', (180, 184))	('dysphagia', 'Disease', (57, 66))	('dysphagia', 'Phenotype', 'HP:0002015', (57, 66))
787779	30577521	The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype.	('MSI-H', 'Disease', (201, 206))	('MSI-H', 'Disease', 'MESH:D000848', (201, 206))	('PD-L1', 'Gene', (99, 104))	('microsatellite instability', 'MPA', (173, 199))	('PD-L1', 'Gene', '29126', (99, 104))	('defects', 'Var', (127, 134))
401341	30577521	The second subgroup is ESCC2, characterized by the mutation of NOTCH1, ZNF750, KDM6A, KDM2D, PTEN, PIK3R1, and CDK6 amplification.	('PIK3R1', 'Gene', '5295', (99, 105))	('KDM6A', 'Gene', (79, 84))	('PTEN', 'Gene', (93, 97))	('NOTCH1', 'Gene', (63, 69))	('PTEN', 'Gene', '5728', (93, 97))	('KDM2D', 'Gene', (86, 91))	('ZNF750', 'Gene', '79755', (71, 77))	('KDM6A', 'Gene', '7403', (79, 84))	('mutation', 'Var', (51, 59))	('CDK6', 'Gene', (111, 115))	('NOTCH1', 'Gene', '4851', (63, 69))	('ZNF750', 'Gene', (71, 77))	('CDK6', 'Gene', '1021', (111, 115))	('PIK3R1', 'Gene', (99, 105))
787799	30577521	The first subgroup are the tumors with dominant C>A/T mutations, the second subgroup is mainly defective in homologous recombination/chromosome segregation, and the last subgroup has commonly T>G mutation with high mutation burden.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('C>A/T mutations', 'Var', (48, 63))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('T>G mutation', 'Var', (192, 204))
787800	30577521	The last subgroup of tumors with both high mutation loads and high number of neoantigens could be appropriate for the immunotherapy with checkpoint inhibitors.	('mutation loads', 'Var', (43, 57))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
787806	30577521	This group of patients is characterized by TP53 mutation and RAS pathway disruption.	('disruption', 'Reg', (73, 83))	('RAS pathway', 'Pathway', (61, 72))	('mutation', 'Var', (48, 56))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('patients', 'Species', '9606', (14, 22))
787808	30577521	The second most common subgroup are the tumors with microsatellite instability (MSI-H) representing about 22% of the patients.	('MSI-H', 'Disease', 'MESH:D000848', (80, 85))	('microsatellite instability', 'Var', (52, 78))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('MSI-H', 'Disease', (80, 85))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
787811	30577521	Histologically, these tumors are characterized by diffuse histology and genetically by the CDH1/RHOA or CLDN18-ARHGAP mutations.	('CDH1', 'Gene', '999', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('RHOA', 'Gene', (96, 100))	('CLDN18', 'Gene', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('mutations', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('RHOA', 'Gene', '387', (96, 100))	('CLDN18', 'Gene', '51208', (104, 110))	('tumors', 'Disease', (22, 28))	('CDH1', 'Gene', (91, 95))
787812	30577521	The last subgroup of the tumors consists of tumors with Epstein-Barr virus (EBV) infection characterized by mutation of PIK3CA, CDKN2A silencing and PD-L1/2 over-expression which is also discussed in more detail below.	('PD-L1', 'Gene', (149, 154))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('PIK3CA', 'Gene', (120, 126))	('over-expression', 'PosReg', (157, 172))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('silencing', 'NegReg', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('PD-L1', 'Gene', '29126', (149, 154))	('Epstein-Barr virus (EBV) infection', 'Disease', 'MESH:D020031', (56, 90))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutation', 'Var', (108, 116))	('CDKN2A', 'Gene', (128, 134))
787882	30577521	As mentioned above, there are subtypes of gastric cancer that could potentially be candidates for immunotherapy, including MSI-H tumors harboring multiple neoantigens resulting from mismatch repair gene deficiency as well as EBV-positive tumors expressing PD-L1/L2.	('gene deficiency', 'Disease', (198, 213))	('tumors', 'Disease', (129, 135))	('PD-L1', 'Gene', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('PD-L1', 'Gene', '29126', (256, 261))	('tumors', 'Disease', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('MSI-H tumors', 'Disease', (123, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (42, 56))	('mismatch', 'Var', (182, 190))	('gene deficiency', 'Disease', 'MESH:D025063', (198, 213))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('EBV', 'Species', '10376', (225, 228))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('gastric cancer', 'Disease', (42, 56))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('gastric cancer', 'Disease', 'MESH:D013274', (42, 56))	('MSI-H tumors', 'Disease', 'MESH:D009369', (123, 135))
787941	28775789	In addition, some TCR-T clinical trials of targeting NY-ESO-1 and melanoma differentiation antigens MART-1 were terminated, according to low accrual (ClinicalTrials.gov Identifier: NCT00509496, NCT00610311, NCT00612222 and NCT02062359).	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('TCR', 'Gene', (18, 21))	('MART-1', 'Gene', (100, 106))	('melanoma', 'Disease', (66, 74))	('NCT00612222', 'Var', (207, 218))	('NCT02062359', 'Var', (223, 234))	('TCR', 'Gene', '6962', (18, 21))	('NY-ESO-1', 'Gene', '246100', (53, 61))	('NY-ESO-1', 'Gene', (53, 61))	('NCT00509496', 'Var', (181, 192))	('NCT00610311', 'Var', (194, 205))	('MART-1', 'Gene', '2315', (100, 106))
787944	28775789	For example, two different MART-1-special TCR-Ts, DMF5 TCR-T(against gp100:154-162 epitope) and DMF4 TCR-T(against the gp100:209-217 epitope), which had a significant difference in the outcome of treatment.	('TCR', 'Gene', (42, 45))	('gp100', 'Gene', '6490', (69, 74))	('DMF4', 'Var', (96, 100))	('TCR', 'Gene', (101, 104))	('TCR', 'Gene', '6962', (42, 45))	('gp100', 'Gene', (119, 124))	('TCR', 'Gene', '6962', (55, 58))	('gp100', 'Gene', (69, 74))	('gp100', 'Gene', '6490', (119, 124))	('TCR', 'Gene', '6962', (101, 104))	('MART-1', 'Gene', '2315', (27, 33))	('MART-1', 'Gene', (27, 33))	('TCR', 'Gene', (55, 58))
787958	28775789	When adoptive CAR-T gene therapy for hematological malignancies, there are lots of TAAs can be selected, such as CD19, CD20, CD30, CD22, CD138, CD70, BMCA, etc.	('CD30', 'Gene', (125, 129))	('hematological malignancies', 'Disease', 'MESH:D019337', (37, 63))	('BMCA', 'Disease', (150, 154))	('CD138', 'Gene', (137, 142))	('CD30', 'Gene', '943', (125, 129))	('BMCA', 'Chemical', '-', (150, 154))	('CD70', 'Gene', (144, 148))	('CD70', 'Gene', '970', (144, 148))	('CD20', 'Var', (119, 123))	('hematological malignancies', 'Disease', (37, 63))	('CD19', 'Var', (113, 117))	('CD22', 'Gene', (131, 135))	('CD138', 'Gene', '6382', (137, 142))	('CD22', 'Gene', '933', (131, 135))
787971	28775789	A clinical trial of the sequential ACT that CD19-targeted CAR-T and CD20-targeted CAR-T for Diffuse Large B Cell Lymphoma (DLBCL) has been executed (ClinicalTrials.gov Identifier: NCT02737085).	('CD19-targeted', 'Var', (44, 57))	('B Cell Lymphoma', 'Disease', 'MESH:D016393', (106, 121))	('B Cell Lymphoma', 'Phenotype', 'HP:0012191', (106, 121))	('B Cell Lymphoma', 'Disease', (106, 121))	('Lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('CD20-targeted', 'Var', (68, 81))
787981	28775789	The antigen co-expression on tumor tissue and normal tissue can easily induce the "on target, off tumor" toxicity.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('antigen', 'Var', (4, 11))	('tumor', 'Disease', (29, 34))	('induce', 'Reg', (71, 77))	('tumor', 'Disease', (98, 103))	('toxicity', 'Disease', 'MESH:D064420', (105, 113))	('toxicity', 'Disease', (105, 113))
787991	28775789	The Cy/Flu regimen also increased the incidence of severe CRS and grade >=3 neurotoxicity.	('Cy', 'Chemical', 'MESH:D003545', (4, 6))	('Cy/Flu', 'Var', (4, 10))	('neurotoxicity', 'Disease', (76, 89))	('CRS', 'Gene', '7291', (58, 61))	('CRS', 'Gene', (58, 61))	('neurotoxicity', 'Disease', 'MESH:D020258', (76, 89))
787995	28775789	A Chinese clinical trial results demonstrated that cerebral CRS can be triggered by the blood-brain barrier (BBB)-penetrating CD19-directed CAR-T.	('CRS', 'Gene', '7291', (60, 63))	('CD19-directed', 'Var', (126, 139))	('CRS', 'Gene', (60, 63))
788013	28775789	The results of a phase I/II clinical study in recurrent/refractory HER2-positive sarcoma with FRP5-CAR-T demonstrated that the FRP5-CAR-T could persist for 6 weeks without evident toxicities and had a good efficacy of anti-tumor.	('FRP5-CAR-T', 'Var', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('toxicities', 'Disease', (180, 190))	('sarcoma', 'Disease', 'MESH:D012509', (81, 88))	('HER2', 'Gene', (67, 71))	('toxicities', 'Disease', 'MESH:D064420', (180, 190))	('HER2', 'Gene', '2064', (67, 71))	('sarcoma', 'Disease', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))
788017	28775789	For example, C4-27z-redirected and C4opt-27z-redirected CAR-T, two CAR-Ts targeting folate receptor-alpha(FRalpha) expression cancers, exhibited significant proliferation and anti-tumor activity in animal models of human ovarian cancer.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ovarian cancer', 'Disease', 'MESH:D010051', (221, 235))	('C4-27z-redirected', 'Var', (13, 30))	('folate receptor-alpha', 'Gene', (84, 105))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('ovarian cancer', 'Disease', (221, 235))	('tumor', 'Disease', (180, 185))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('CAR-T', 'Gene', (56, 61))	('C4opt-27z-redirected', 'Var', (35, 55))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('folate receptor-alpha', 'Gene', '2348', (84, 105))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('ovarian cancer', 'Phenotype', 'HP:0100615', (221, 235))	('proliferation', 'CPA', (157, 170))	('human', 'Species', '9606', (215, 220))
788029	28775789	Other humanized scFvs contain chA21 (HER2 targeted), 2173 (EGFRvIII targeted) had been constructed and applied in models of human cancer or clinical studies.	('human', 'Species', '9606', (6, 11))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('EGFR', 'Gene', (59, 63))	('HER2', 'Gene', (37, 41))	('cancer', 'Disease', (130, 136))	('chA21', 'Var', (30, 35))	('HER2', 'Gene', '2064', (37, 41))	('human', 'Species', '9606', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('scFv', 'Gene', '652070', (16, 20))	('EGFR', 'Gene', '1956', (59, 63))	('scFv', 'Gene', (16, 20))
788033	28775789	On the one hand the survival time of genetically modified T cells in clinical subject bodies may be too short to induce tumorigenesis, on the other hand the subjects with tumor may have a greater ability to recognize and kill viral vectors-induced mutant antigens than the ability of patients with inherited disorders.	('antigens', 'Protein', (255, 263))	('patients', 'Species', '9606', (284, 292))	('mutant', 'Var', (248, 254))	('inherited disorders', 'Disease', (298, 317))	('recognize', 'MPA', (207, 216))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('ability', 'MPA', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('inherited disorders', 'Disease', 'MESH:D030342', (298, 317))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (120, 125))	('greater', 'PosReg', (188, 195))
788041	28775789	Facilitating the formation of memory T cells, IL-7, IL-15 and IL-21 can promote the survival time and long-term anti-tumor effect of CD19-redirected CAR-T and GD2-redirected CAR-T in vivo .	('IL-15', 'Gene', '3600', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('IL-7', 'Gene', '3574', (46, 50))	('tumor', 'Disease', (117, 122))	('IL-21', 'Gene', (62, 67))	('IL-7', 'Gene', (46, 50))	('GD2', 'Chemical', '-', (159, 162))	('IL-15', 'Gene', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('promote', 'PosReg', (72, 79))	('CD19-redirected', 'Var', (133, 148))	('IL-21', 'Gene', '59067', (62, 67))	('survival time', 'CPA', (84, 97))
788059	28775789	In contrast, the anti-tumor ability of NY-ESO-1/ HLA-DP4-specific peptide p161-180-redirected TCR-T was much weaker.	('TCR', 'Gene', (94, 97))	('weaker', 'NegReg', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('DP4', 'Gene', '51270', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('HLA', 'Gene', '3115', (49, 52))	('DP4', 'Gene', (53, 56))	('NY-ESO-1', 'Gene', '246100', (39, 47))	('TCR', 'Gene', '6962', (94, 97))	('NY-ESO-1', 'Gene', (39, 47))	('tumor', 'Disease', (22, 27))	('HLA', 'Gene', (49, 52))	('p161-180-redirected', 'Var', (74, 93))
788062	28775789	The knockdown of endogenous TCRs will confer a higher level of expression and more efficient antigen recognition of exogenous TCRs.	('TCR', 'Gene', (28, 31))	('more', 'PosReg', (78, 82))	('TCR', 'Gene', '6962', (126, 129))	('higher', 'PosReg', (47, 53))	('TCR', 'Gene', '6962', (28, 31))	('knockdown', 'Var', (4, 13))	('level of expression', 'MPA', (54, 73))	('TCR', 'Gene', (126, 129))	('antigen recognition', 'MPA', (93, 112))
788063	28775789	Even more, the knockout of endogenous TCRs will reduced the probability of TCR gene transfer-induced graft-versus-host-disease.	('TCR', 'Gene', '6962', (75, 78))	('graft-versus-host-disease', 'Disease', 'MESH:D006086', (101, 126))	('knockout', 'Var', (15, 23))	('graft-versus-host-disease', 'Disease', (101, 126))	('reduced', 'NegReg', (48, 55))	('TCR', 'Gene', (75, 78))	('TCR', 'Gene', '6962', (38, 41))	('TCR', 'Gene', (38, 41))
788066	28775789	Even in the presence of the chemotherapeutic agent, the "Off-the-Shelf" CAR-T was still able to effectively destroy CD19+ tumors.	('CD19+', 'Var', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('destroy', 'NegReg', (108, 115))	('tumors', 'Disease', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
788069	28775789	The deficient of CAR-T provide an alternative as a universal donor to adoptive T cells therapy for cancers.	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('CAR-T', 'Gene', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('donor', 'Species', '9606', (61, 66))	('deficient', 'Var', (4, 13))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
788071	28775789	The most valuable thing is that the knockdown of endogenous receptors is equally applicable to both CAR-T and TCR-T, in most cases.	('knockdown', 'Var', (36, 45))	('TCR', 'Gene', '6962', (110, 113))	('TCR', 'Gene', (110, 113))	('CAR-T', 'Disease', (100, 105))
788076	28775789	ET1402L1-special CAR-T was shown robust anti-tumor activity in vivo by intravenous administration or intraperitoneal injection.	('ET1402L1-special', 'Var', (0, 16))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))
788081	28775789	For example, a human IgG1 T-cell receptor mimic monoclonal antibody directed to a peptide (RMFPNAPYL) of WT1 in HLA-A*02 dependent was therapeutically effective, alone and in combination with tyrosine kinase inhibitors (TKIs), against a leukemia with the most common, pan-TKI, gatekeeper resistance mutation, T315I.	('WT1', 'Gene', (105, 108))	('IgG1', 'Gene', (21, 25))	('T-cell receptor', 'Gene', (26, 41))	('T315I', 'Mutation', 'p.T315I', (309, 314))	('T315I', 'Var', (309, 314))	('HLA-A', 'Gene', (112, 117))	('leukemia', 'Disease', (237, 245))	('gatekeeper', 'Species', '111938', (277, 287))	('leukemia', 'Disease', 'MESH:D007938', (237, 245))	('leukemia', 'Phenotype', 'HP:0001909', (237, 245))	('T-cell receptor', 'Gene', '6962', (26, 41))	('WT1', 'Gene', '7490', (105, 108))	('human', 'Species', '9606', (15, 20))	('HLA-A', 'Gene', '3105', (112, 117))
788087	28775789	Perhaps in the future, it can be implemented that relying on high-throughput sequencing technology to find tumor specific antigens (TSA) which are caused by mutations.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (157, 166))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('caused by', 'Reg', (147, 156))
788091	28775789	However, with the abundance weapons being applied, tumors may undergo modulation and deletion of TAA.	('modulation', 'Var', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('deletion', 'Var', (85, 93))	('TAA', 'Gene', (97, 100))
788097	26899170	deconstructSigs confers the ability to define mutational processes driven by environmental exposures, DNA repair abnormalities, and mutagenic processes in individual tumors with implications for precision cancer medicine.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('abnormalities', 'Var', (113, 126))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
788098	26899170	The set of somatic mutations observed in a tumor reflects the varied mutational processes that have been active during its life history, providing insights into the routes taken to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (181, 195))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('carcinogenesis', 'Disease', (181, 195))	('tumor', 'Disease', (43, 48))
788099	26899170	Exogenous mutagens, such as tobacco smoke and ultraviolet light, and endogenous processes, such as APOBEC enzymatic family functional activity or DNA mismatch repair deficiency, result in characteristic patterns of mutation.	('mutation', 'Var', (215, 223))	('result', 'Reg', (178, 184))	('deficiency', 'Disease', (166, 176))	('tobacco', 'Species', '4097', (28, 35))	('deficiency', 'Disease', 'MESH:D007153', (166, 176))
788107	26899170	analyzed approximately five million mutations from over 7000 cancer genomes and exomes to identify a set of 21 signatures found to be present across 30 tumor types.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancer', 'Disease', (61, 67))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
788108	26899170	About half of these signatures could be attributed to known mutational processes, such as tobacco smoke, exposure to ultraviolet light, activity of the APOBEC family of cytidine deaminases, DNA mismatch repair deficiency, or mutations in POLE.	('deficiency', 'Disease', (210, 220))	('mutations', 'Var', (225, 234))	('attributed', 'Reg', (40, 50))	('POLE', 'Gene', (238, 242))	('deficiency', 'Disease', 'MESH:D007153', (210, 220))	('tobacco', 'Species', '4097', (90, 97))	('APOBEC', 'Gene', (152, 158))
788115	26899170	sigs.input < - mut.to.sigs.input(mut.ref = sample.mut.ref, sample.id = "Sample", chr = "chr", pos = "pos", ref = "ref", alt = "alt") The input data frame T is generated by calculating the fraction of mutations found in each of the possible 96 trinucleotide contexts for each tumor sample.	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('mutations', 'Var', (200, 209))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('trinucleotide', 'Chemical', '-', (243, 256))
788121	26899170	First, we exclude any signatures containing a single trinucleotide context making up more than 20 % of the signature definition which is not present in T. This is done to account for the fact that some signatures are almost entirely characterized by mutations in specific trinucleotide contexts, and thus, without mutations found in those contexts, it is unlikely that that signature is active.	('trinucleotide', 'Chemical', '-', (272, 285))	('trinucleotide', 'Chemical', '-', (53, 66))	('mutations', 'Var', (250, 259))	('characterized by', 'Reg', (233, 249))
788137	26899170	This is of particular importance when the profile of the mutational signature is flat or without a strong peak at any of the trinucleotide contexts, as in these instances the mutational process could affect a greater number of trinucleotide contexts and a full profile would only be observed with sufficient mutations.	('affect', 'Reg', (200, 206))	('trinucleotide contexts', 'MPA', (227, 249))	('trinucleotide', 'Chemical', '-', (227, 240))	('mutational', 'Var', (175, 185))	('trinucleotide', 'Chemical', '-', (125, 138))
788138	26899170	For instance, in a colorectal carcinoma (TCGA-D5-6931) the WTSI Mutational Signature Framework determined 20.4 % of the mutational signature present was associated with a POLE hyper-mutator phenotype.	('POLE hyper-mutator', 'MPA', (171, 189))	('colorectal carcinoma', 'Disease', (19, 39))	('associated', 'Reg', (153, 163))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (19, 39))	('mutational', 'Var', (120, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))
788139	26899170	Nevertheless, visual inspection of the mutational profile of this tumor did not reveal the presence of a POLE-associated signature and no evidence existed for the somatic exonuclease domain mutations in POLE that produce this specific pattern of predominantly C > A mutations in a TpCpT context and C > T mutations in a TpCpG context (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('C > T mutations', 'Var', (299, 314))	('tumor', 'Disease', (66, 71))	('C > A mutations', 'Var', (260, 275))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
788143	26899170	Expanding the set of signatures also allowed us to identify outlier samples that appear to harbor a different set of mutational signatures compared with the rest of the cancer type or sample set they were analyzed with.	('mutational', 'Var', (117, 127))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
788146	26899170	In two of these tumors, TCGA-A8-A09Z and TCGA-AN-A0AK, mutations in mismatch repair genes were evident (https://tcga-data.nci.nih.gov/tcga/).	('tumors', 'Disease', (16, 22))	('mismatch repair genes', 'Gene', (68, 89))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
788147	26899170	There was an MLH1 nonstop mutation in TCGA-A8-A09Z and separate MLH1 missense and splice site mutations, as well as an MSH6 frameshift mutation in TCGA-AN-A0AK.	('MLH1', 'Gene', (64, 68))	('MSH6', 'Gene', '2956', (119, 123))	('MLH1', 'Gene', (13, 17))	('mutation', 'Var', (26, 34))	('MLH1', 'Gene', '4292', (64, 68))	('MLH1', 'Gene', '4292', (13, 17))	('MSH6', 'Gene', (119, 123))
788148	26899170	Additionally, TCGA-A8-A09Z had a total of 1438 mutations with 253 small insertions or deletions and TCGA-AN-A0AK had a total of 1317 mutations with 352 small insertions or deletions, both indicative of a microsatellite instability high (MSIH) phenotype.	('MSIH', 'Disease', 'None', (237, 241))	('mutations', 'Var', (47, 56))	('MSIH', 'Disease', (237, 241))	('microsatellite instability high', 'MPA', (204, 235))
788149	26899170	The median number of mutations from the BRCA TCGA cohort is 38 and median number of insertions or deletions is 4.	('BRCA', 'Gene', (40, 44))	('BRCA', 'Gene', '672', (40, 44))	('mutations', 'Var', (21, 30))
788156	26899170	Indeed, in three of the five patients analyzed (L001, L004, and L008), the smoking signature was not assigned at all in the branches.	('patients', 'Species', '9606', (29, 37))	('L004', 'Var', (54, 58))	('L008', 'Var', (64, 68))	('L001', 'Var', (48, 52))
788162	26899170	In addition, in order to shed light on both the prevalence of mutational processes and their dynamics during tumor evolution, we also applied the deconstructSigs package to temporally dissected mutations (Additional file 7), according to published methods.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mutations', 'Var', (194, 203))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
788165	26899170	Interestingly, this signature was found to contribute significantly more to early mutations compared with late mutations in esophageal squamous cell carcinoma but not in esophageal adenocarcinoma (ESCA squamous, p value = 0.006; ESCA adeno, p value = 0.716; Fig.	('esophageal adenocarcinoma', 'Disease', (170, 195))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (170, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (170, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (124, 158))	('mutations', 'Var', (82, 91))	('esophageal squamous cell carcinoma', 'Disease', (124, 158))
788167	26899170	Further, in squamous cell tumors, APOBEC-mediated mutagenesis was found frequently to be a late event, reflecting similar findings in lung adenocarcinomas, head-and-neck tumors, and estrogen receptor-negative breast cancers (p value = 0.03; Fig.	('estrogen receptor', 'Gene', (182, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (134, 153))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (134, 154))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('breast cancers', 'Disease', 'MESH:D001943', (209, 223))	('breast cancers', 'Disease', (209, 223))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('squamous cell tumors', 'Disease', (12, 32))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (134, 154))	('breast cancers', 'Phenotype', 'HP:0003002', (209, 223))	('squamous cell tumors', 'Disease', 'MESH:D002294', (12, 32))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('estrogen receptor', 'Gene', '2099', (182, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('mutagenesis', 'Var', (50, 61))	('lung adenocarcinomas', 'Disease', (134, 154))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (170, 176))	('tumors', 'Disease', (26, 32))
788170	26899170	Indeed, over 50 % of esophageal adenocarcinomas were found to exhibit an enrichment for T > G and T > C mutations at CpTpT sites.	('T > G', 'Var', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (21, 47))	('T > C mutations', 'Var', (98, 113))	('esophageal adenocarcinomas', 'Disease', (21, 47))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (21, 46))
788171	26899170	The majority of these tumors (65 %) showed a tendency for signature 17 to be an early event, often being replaced by signature 1A.	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('signature 17', 'Var', (58, 70))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
788172	26899170	For example, in one such tumor (TCGA-2H-A9GR), early mutations were almost exclusively characterized as signature 17 (90.4 %), while later arising mutations were characterized by an increase in signature 1A at the expense of signature 17.	('increase', 'PosReg', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('signature 1A', 'MPA', (194, 206))	('tumor', 'Disease', (25, 30))	('mutations', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
788201	25013737	The AJCC classification of primary tumor was T3N1M0.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('T3N1M0', 'Var', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))
788235	24647631	Immunoreactivity of FOXC2 was strongly correlated with microvessel density (MVD) (P<0.0001) and poor prognosis (P = 0.0076).	('FOXC2', 'Gene', '2303', (20, 25))	('FOXC2', 'Gene', (20, 25))	('correlated', 'Reg', (39, 49))	('MVD', 'Disease', (76, 79))	('microvessel density', 'CPA', (55, 74))	('Immunoreactivity', 'Var', (0, 16))	('MVD', 'Disease', 'None', (76, 79))
788282	24647631	Stealth Select RNAi (siRNA) for Prox1 (HSS108597) and FOXC2 (HSS142054) was purchased from Invitrogen (Carlsbad, CA, USA).	('HSS108597', 'Var', (39, 48))	('FOXC2', 'Gene', (54, 59))	('Prox1', 'Gene', '5629', (32, 37))	('Prox1', 'Gene', (32, 37))	('HSS142054', 'Var', (61, 70))	('FOXC2', 'Gene', '2303', (54, 59))
788320	24647631	Reduction of VEGF-C was observed following the knockdown of Prox1, whereas VEGF-A expression was attenuated upon treatment with FOXC2-specific siRNA in the KON cells.	('Prox1', 'Gene', (60, 65))	('Prox1', 'Gene', '5629', (60, 65))	('men', 'Species', '9606', (118, 121))	('VEGF-C', 'Gene', '7424', (13, 19))	('knockdown', 'Var', (47, 56))	('Reduction', 'NegReg', (0, 9))	('FOXC2', 'Gene', (128, 133))	('FOXC2', 'Gene', '2303', (128, 133))	('VEGF-A', 'Gene', '7422', (75, 81))	('VEGF-A', 'Gene', (75, 81))	('VEGF-C', 'Gene', (13, 19))
788334	24647631	We speculate that the interactions of Prox1 and VEGF-C are the cause of reduce growth and migration ability of HUVECs by Prox1 knockdown treatment (Fig.	('VEGF-C', 'Gene', (48, 54))	('men', 'Species', '9606', (142, 145))	('interactions', 'Interaction', (22, 34))	('Prox1', 'Gene', (38, 43))	('reduce growth', 'Phenotype', 'HP:0001510', (72, 85))	('knockdown treatment', 'Var', (127, 146))	('VEGF-C', 'Gene', '7424', (48, 54))	('Prox1', 'Gene', '5629', (38, 43))	('Prox1', 'Gene', (121, 126))	('Prox1', 'Gene', '5629', (121, 126))	('reduce', 'NegReg', (72, 78))
788335	24647631	Indeed, it has been defined tumor cells-secreted VEGF-C knockdown inhibits HUVECs proliferation and migration and we also clarified VEGF-C is accelerates angiogenesis in OSCC.	('HUVECs', 'Protein', (75, 81))	('tumor', 'Disease', (28, 33))	('VEGF-C', 'Gene', (49, 55))	('OSCC', 'Disease', (170, 174))	('VEGF-C', 'Gene', '7424', (132, 138))	('VEGF-C', 'Gene', (132, 138))	('inhibits', 'NegReg', (66, 74))	('VEGF-C', 'Gene', '7424', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('angiogenesis', 'CPA', (154, 166))	('accelerates', 'PosReg', (142, 153))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('knockdown', 'Var', (56, 65))
788382	23977343	The majority of mesothelioma has a deletion in the INK4A/ARF locus which encodes the p14 ARF and the p16 INK4A genes, but possesses the wild-type p53 gene.	('INK4A/ARF', 'Gene', (51, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (16, 28))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('INK4A/ARF', 'Gene', '1029', (51, 60))	('p14 ARF', 'Gene', '1029', (85, 92))	('p16 INK4A', 'Gene', '1029', (101, 110))	('deletion', 'Var', (35, 43))	('mesothelioma', 'Disease', (16, 28))	('p14 ARF', 'Gene', (85, 92))	('p16 INK4A', 'Gene', (101, 110))
788383	23977343	Deletion of p16INK4A increases cyclin-dependent kinase 4/6 activities, which subsequently induces pRb phosphorylation and cell cycle progression.	('increases', 'PosReg', (21, 30))	('activities', 'MPA', (59, 69))	('p16', 'Gene', '1029', (12, 15))	('cyclin-dependent kinase 4/6', 'Enzyme', (31, 58))	('pRb phosphorylation', 'MPA', (98, 117))	('induces', 'Reg', (90, 97))	('p16', 'Gene', (12, 15))	('cell cycle progression', 'CPA', (122, 144))	('Deletion', 'Var', (0, 8))
788384	23977343	In contrast, deficiency of p14ARF augments Mdm2 activities and consequently down-regulates p53 expression, which may render mesothelioma cells resistant to chemotherapeutic agents.	('activities', 'MPA', (48, 58))	('p14ARF', 'Gene', '1029', (27, 33))	('Mdm2', 'Gene', (43, 47))	('deficiency', 'Var', (13, 23))	('mesothelioma', 'Disease', (124, 136))	('render', 'Reg', (117, 123))	('augments', 'PosReg', (34, 42))	('p53', 'Gene', (91, 94))	('down-regulates', 'NegReg', (76, 90))	('p14ARF', 'Gene', (27, 33))	('Mdm2', 'Gene', '4193', (43, 47))	('p53', 'Gene', '7157', (91, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('expression', 'MPA', (95, 105))
788403	23977343	All the mesothelioma cells used were defective of p14 and p16 expressions due to either loss of the transcription or deletion of the genomic DNA (Figure S1), and sequencing data confirmed that they possessed the wild-type p53 gene.	('defective', 'NegReg', (37, 46))	('p16', 'Gene', (58, 61))	('loss', 'NegReg', (88, 92))	('transcription', 'MPA', (100, 113))	('mesothelioma', 'Disease', (8, 20))	('p16', 'Gene', '1029', (58, 61))	('p14', 'Gene', (50, 53))	('p53', 'Gene', '7157', (222, 225))	('p53', 'Gene', (222, 225))	('mesothelioma', 'Disease', 'MESH:D008654', (8, 20))	('p14', 'Gene', '1029', (50, 53))	('deletion', 'Var', (117, 125))
788429	23977343	The cell cycle changes, increased S- and G2/M-phase populations and then sub-G1 fractions, were greater with IFN-beta treatments than with IFN-alpha treatments.	('treatments', 'Var', (118, 128))	('IFN-alpha', 'Gene', '3439', (139, 148))	('sub-G1 fractions', 'CPA', (73, 89))	('IFN-alpha', 'Gene', (139, 148))	('IFN-beta', 'Gene', (109, 117))	('cell cycle changes', 'CPA', (4, 22))	('IFN-beta', 'Gene', '3456', (109, 117))	('increased', 'PosReg', (24, 33))
788438	23977343	Cell cycle analyses after IFN-beta treatments showed that NCI-H2052 cells increased S- and G2/M-phase fractions but less significantly augmented sub-G1 population, whereas NCI-H28 cells increased S-phase and then sub-G1 fractions (Table 1).	('NCI-H2052', 'Var', (58, 67))	('IFN-beta', 'Gene', '3456', (26, 34))	('IFN-beta', 'Gene', (26, 34))	('increased', 'PosReg', (74, 83))	('NCI-H28', 'CellLine', 'CVCL:1555', (172, 179))	('NCI-H2052', 'CellLine', 'CVCL:1518', (58, 67))	('sub-G1 population', 'CPA', (145, 162))
788463	23977343	Interestingly, Met-5A cells of mesothelium origin were positive for IL-28Ralpha in contrast to mesothelioma cells, suggesting that IL-28Ralpha expression was activated by a process of immortalization due to expressed SV40 T antigen or was lost during tumorigenesis of mesothelial cells.	('tumor', 'Disease', (251, 256))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('expression', 'MPA', (143, 153))	('IL-28Ralpha', 'Gene', '163702', (68, 79))	('activated', 'PosReg', (158, 167))	('IL-28Ralpha', 'Gene', (131, 142))	('IL-28Ralpha', 'Gene', '163702', (131, 142))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('IL-28Ralpha', 'Gene', (68, 79))	('SV40', 'Var', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('mesothelioma', 'Disease', (95, 107))
788473	23977343	The lack of cell death in type I IFNs-treated Met-5A cells can be associated with the relative insensitivity to type III IFNs because Met-5A cells showed low proliferation activity compared with mesothelioma cells.	('mesothelioma', 'Disease', (195, 207))	('low', 'NegReg', (154, 157))	('insensitivity to type III', 'Phenotype', 'HP:0001976', (95, 120))	('IFN', 'Gene', (33, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (195, 207))	('IFN', 'Gene', '3439', (121, 124))	('Met-5A', 'Var', (134, 140))	('proliferation activity', 'CPA', (158, 180))	('IFN', 'Gene', (121, 124))	('IFN', 'Gene', '3439', (33, 36))
788485	23977343	Our previous study also showed that CDDP treatments increased endogenous p53 levels in mesothelioma cells, and the susceptibility to CDDP was augmented by forced p53 expression.	('forced', 'Var', (155, 161))	('expression', 'Var', (166, 176))	('increased', 'PosReg', (52, 61))	('p53', 'Gene', (162, 165))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('mesothelioma', 'Disease', (87, 99))	('p53', 'Gene', '7157', (162, 165))	('CDDP', 'Chemical', 'MESH:D002945', (36, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('CDDP', 'Chemical', 'MESH:D002945', (133, 137))
788493	23977343	It is currently unknown as to the p14 involvement in the type I IFNs-mediated apoptosis, but difference of genetic backgrounds, such as defective 16 expression and aberrant signal pathways often found in mesothelioma, can be responsible.	('p14', 'Gene', (34, 37))	('IFN', 'Gene', '3439', (64, 67))	('p14', 'Gene', '1029', (34, 37))	('IFN', 'Gene', (64, 67))	('mesothelioma', 'Disease', (204, 216))	('mesothelioma', 'Disease', 'MESH:D008654', (204, 216))	('defective', 'Var', (136, 145))
788545	32797062	retrospectively supported the positive association between the presence of GERD symptoms and the development of both periodontitis and caries.	('presence', 'Var', (63, 71))	('GERD symptoms', 'Gene', (75, 88))	('periodontitis', 'Disease', 'MESH:D010518', (117, 130))	('caries', 'Disease', (135, 141))	('periodontitis', 'Phenotype', 'HP:0000704', (117, 130))	('caries', 'Phenotype', 'HP:0000670', (135, 141))	('periodontitis', 'Disease', (117, 130))
788562	32797062	They observed a significant higher rate of dental erosion, alveolar bone destruction and osteomyelitis in reflux rats compared with controls 30 weeks after the surgery.	('dental erosion', 'CPA', (43, 57))	('reflux', 'Var', (106, 112))	('osteomyelitis', 'Disease', (89, 102))	('rat', 'Species', '10116', (35, 38))	('osteomyelitis', 'Phenotype', 'HP:0002754', (89, 102))	('bone destruction', 'Phenotype', 'HP:0002797', (68, 84))	('rat', 'Species', '10116', (113, 116))	('osteomyelitis', 'Disease', 'MESH:D010019', (89, 102))	('higher', 'PosReg', (28, 34))	('alveolar bone destruction', 'CPA', (59, 84))	('rats', 'Species', '10116', (113, 117))
788633	32377300	According to recently published data, increased endogenous CO production by inducible HO-1, its delivery by novel pharmacological CO-releasing agents, or even the direct inhalation of CO has been considered a promising alternative in future experimental and clinical therapies against various GI disorders.	('GI disorders', 'Disease', (293, 305))	('GI disorders', 'Disease', 'MESH:D005767', (293, 305))	('CO', 'Chemical', 'MESH:D002248', (59, 61))	('GI disorders', 'Phenotype', 'HP:0011024', (293, 305))	('inducible', 'Var', (76, 85))	('CO', 'Chemical', 'MESH:D002248', (184, 186))	('CO', 'Chemical', 'MESH:D002248', (130, 132))	('increased', 'PosReg', (38, 47))	('endogenous CO production', 'MPA', (48, 72))
788673	32377300	Interestingly, CO and H2S donors were demonstrated to reduce aspirin-induced gastric damage and lipid peroxidation observed as documented by an increase in the malondialdehyde (MDA) concentration in the gastric mucosa.	('gastric damage', 'Disease', (77, 91))	('aspirin', 'Chemical', 'MESH:D001241', (61, 68))	('MDA', 'Chemical', 'MESH:D008315', (177, 180))	('reduce', 'NegReg', (54, 60))	('rat', 'Species', '10116', (189, 192))	('donors', 'Var', (26, 32))	('gastric damage', 'Disease', 'MESH:D013272', (77, 91))	('lipid', 'Chemical', 'MESH:D008055', (96, 101))	('rat', 'Species', '10116', (45, 48))	('H2S', 'Chemical', 'MESH:D003903', (22, 25))	('malondialdehyde', 'Chemical', 'MESH:D008315', (160, 175))	('increase', 'PosReg', (144, 152))	('CO', 'Chemical', 'MESH:D002248', (15, 17))	('lipid peroxidation', 'MPA', (96, 114))
788689	32377300	In addition, the release of CO from these molecules requires photoactivation, as it is in the case of CORM-1 and ligand substitution for CORM-2.	('ligand substitution', 'Var', (113, 132))	('CO', 'Chemical', 'MESH:D002248', (137, 139))	('CO', 'Chemical', 'MESH:D002248', (102, 104))	('CO', 'Chemical', 'MESH:D002248', (28, 30))	('release', 'MPA', (17, 24))
788697	32377300	Additionally, in cultured esophageal epithelial cells (EEC), it has been observed that euptailin prevented indomethacin-induced cytotoxicity and upregulated HO-1 expression due to nuclear translocation of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the activation of extracellular signal-regulated kinases (ERKs) and phosphatidylinositol-3-kinase (PI3K)/Akt signaling.	('nuclear factor erythroid 2-related factor 2', 'Gene', '18024', (226, 269))	('euptailin', 'Var', (87, 96))	('cytotoxicity', 'Disease', 'MESH:D064420', (128, 140))	('Nrf2', 'Gene', (271, 275))	('Akt', 'Gene', (386, 389))	('cytotoxicity', 'Disease', (128, 140))	('euptailin', 'Chemical', '-', (87, 96))	('nuclear translocation', 'MPA', (180, 201))	('indomethacin', 'Chemical', 'MESH:D007213', (107, 119))	('phosphatidylinositol-3-kinase', 'Gene', (349, 378))	('prevented', 'NegReg', (97, 106))	('expression', 'MPA', (162, 172))	('upregulated', 'PosReg', (145, 156))	('phosphatidylinositol-3-kinase', 'Gene', '18708', (349, 378))	('HO-1', 'Gene', (157, 161))	('nuclear factor erythroid 2-related factor 2', 'Gene', (226, 269))	('activation', 'PosReg', (285, 295))	('Akt', 'Gene', '11651', (386, 389))
788738	32377300	have shown that exogenous CO can attenuate inflammatory responses in the small intestine of septic mice induced by cecal ligation and puncture.	('mice', 'Species', '10090', (99, 103))	('inflammatory responses', 'CPA', (43, 65))	('exogenous', 'Var', (16, 25))	('attenuate', 'NegReg', (33, 42))	('CO', 'Chemical', 'MESH:D002248', (26, 28))
788770	32377300	provided evidence that CO inhalation (250 ppm) or administration of methylene chloride (MC) can reduce hepatic lipid peroxidation, reestablish total hepatic glutathione and glutathione disulfide (GSH/GSSG) ratio, and reduce hepatocellular injury in a murine model of bilateral hindlimb I/R.	('GSH', 'Chemical', '-', (196, 199))	('CO', 'Chemical', 'MESH:D002248', (23, 25))	('250 ppm', 'Var', (38, 45))	('hepatic lipid peroxidation', 'MPA', (103, 129))	('glutathione', 'Chemical', 'MESH:D005978', (157, 168))	('reduce', 'NegReg', (217, 223))	('MC', 'Chemical', 'MESH:D008752', (88, 90))	('lipid', 'Chemical', 'MESH:D008055', (111, 116))	('GSSG', 'Chemical', 'MESH:D019803', (200, 204))	('murine', 'Species', '10090', (251, 257))	('rat', 'Species', '10116', (58, 61))	('reduce', 'NegReg', (96, 102))	('rat', 'Species', '10116', (206, 209))	('glutathione', 'Chemical', 'MESH:D005978', (173, 184))	('methylene chloride', 'Chemical', 'MESH:D008752', (68, 86))	('hepatocellular injury', 'Disease', 'MESH:D056486', (224, 245))	('hepatocellular injury', 'Disease', (224, 245))	('glutathione disulfide', 'Chemical', 'MESH:D019803', (173, 194))
788777	32377300	This beneficial effect was attributed to the inactivation of KC resulting in the suppression of ROS production.	('inactivation', 'Var', (45, 57))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('ROS production', 'MPA', (96, 110))	('suppression', 'NegReg', (81, 92))
788806	32377300	have demonstrated that low concentrations of CO (10 muM) may inhibit mitochondrial membrane permeabilization (MMP) in isolated mouse liver mitochondria in vitro, possibly by preventing mitochondrial swelling, mitochondrial depolarization, and the opening of a nonspecific pore through inner membrane.	('mouse', 'Species', '10090', (127, 132))	('rat', 'Species', '10116', (12, 15))	('mitochondrial swelling', 'Disease', 'MESH:D028361', (185, 207))	('CO', 'Chemical', 'MESH:D002248', (45, 47))	('mitochondrial membrane permeabilization', 'MPA', (69, 108))	('CO (10 muM', 'Var', (45, 55))	('inhibit', 'NegReg', (61, 68))	('mitochondrial swelling', 'Phenotype', 'HP:0030774', (185, 207))	('rat', 'Species', '10116', (34, 37))	('mitochondrial swelling', 'Disease', (185, 207))	('mitochondrial depolarization', 'MPA', (209, 237))	('preventing', 'NegReg', (174, 184))
788812	32377300	Malfunction of the exocrine part can lead to the development of pancreatitis and even pancreatic cancer.	('pancreatitis', 'Disease', (64, 76))	('pancreatic cancer', 'Disease', (86, 103))	('lead to', 'Reg', (37, 44))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('pancreatitis', 'Phenotype', 'HP:0001733', (64, 76))	('Malfunction', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('pancreatitis', 'Disease', 'MESH:D010195', (64, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
788893	31294391	Some conditions such as stroke; head and neck cancer; surgery to the head, neck or cervical spine; abnormality of cervical spine, (e.g., osteophytes); and abnormality of cranial nerves 5, 7, 9, 10, 11 or 12 are associated with an increased risk of oropharyngeal dysphagia.	('stroke', 'Phenotype', 'HP:0001297', (24, 30))	('dysphagia', 'Phenotype', 'HP:0002015', (262, 271))	('abnormality', 'Var', (155, 166))	('stroke', 'Disease', (24, 30))	('stroke', 'Disease', 'MESH:D020521', (24, 30))	('head and neck cancer', 'Phenotype', 'HP:0012288', (32, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('abnormality of cranial nerves', 'Phenotype', 'HP:0001291', (155, 184))	('oropharyngeal dysphagia', 'Phenotype', 'HP:0200136', (248, 271))	('neck cancer', 'Disease', (41, 52))	('oropharyngeal dysphagia', 'Disease', (248, 271))	('oropharyngeal dysphagia', 'Disease', 'MESH:D003680', (248, 271))	('neck cancer', 'Disease', 'MESH:D006258', (41, 52))	('abnormality', 'Var', (99, 110))
788979	31294391	Data from a Barrett's esophagus surveillance program showed a lower incidence of dysplasia among patients on a PPI compared to those without prior PPI therapy, suggesting a potential preventive effect for esophageal cancer.	('PPI', 'Var', (111, 114))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (12, 31))	('esophag', 'Chemical', '-', (205, 212))	('esophag', 'Chemical', '-', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('esophageal cancer', 'Disease', (205, 222))	('lower', 'NegReg', (62, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (205, 222))	('dysplasia', 'Disease', (81, 90))	('dysplasia', 'Disease', 'MESH:D004476', (81, 90))	('patients', 'Species', '9606', (97, 105))
788980	31294391	Although retrospective, a second report which assessed the number of esophageal and gastric cancers diagnosed subsequent to negative findings on an initial EGD found a significantly greater number of delayed diagnosis for gastric adenocarcinoma among PPI-users (versus non-users); however, there was no difference for esophageal adenocarcinoma between groups.	('gastric cancers', 'Phenotype', 'HP:0012126', (84, 99))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (222, 244))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (318, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('esophageal adenocarcinoma', 'Disease', (318, 343))	('PPI-users', 'Var', (251, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('esophageal and gastric cancers', 'Disease', 'MESH:D013274', (69, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('gastric adenocarcinoma', 'Disease', (222, 244))
789021	31294391	If dysphagia persists after a four-week PPI trial, investigations to assess inflammatory or structural lesions are recommended.	('PPI', 'Var', (40, 43))	('dysphagia', 'Phenotype', 'HP:0002015', (3, 12))	('dysphagia', 'Disease', 'MESH:D003680', (3, 12))	('dysphagia', 'Disease', (3, 12))	('men', 'Species', '9606', (120, 123))
789121	30018482	Esophageal stricture was defined when the standard GIF-Q260J (Olympus) gastroscopy could not pass through the esophageal lumen and if the patient had dysphagia.	('Q260J', 'SUBSTITUTION', 'None', (55, 60))	('Esophageal stricture', 'Phenotype', 'HP:0002043', (0, 20))	('dysphagia', 'Disease', 'MESH:D003680', (150, 159))	('patient', 'Species', '9606', (138, 145))	('dysphagia', 'Disease', (150, 159))	('dysphagia', 'Phenotype', 'HP:0002015', (150, 159))	('Q260J', 'Var', (55, 60))	('not', 'NegReg', (89, 92))	('Esophageal stricture', 'Disease', (0, 20))
789143	30018482	Huang et al compared the efficacy and complication rate between ESD and ESTD using a propensity score matching analysis and observed that ESTD can improve procedure efficacy and reduce injury to muscular layer due to a better view, more efficient vessel coagulation, and longer lasting submucosal liquid cushion.	('injury to muscular layer', 'Disease', (185, 209))	('ESTD', 'Var', (138, 142))	('more', 'PosReg', (232, 236))	('improve', 'PosReg', (147, 154))	('reduce', 'NegReg', (178, 184))	('injury to muscular layer', 'Disease', 'MESH:D016369', (185, 209))
789209	27562616	The risk of PE (HR=0.49, PBE > 0.99) and death without PE (HR=0.49, PBE > 0.99) were also lower for IMRT patients compared to those for 3DCRT patients (Supplementary Table 4).	('PE', 'Phenotype', 'HP:0002202', (55, 57))	('patients', 'Species', '9606', (105, 113))	('PE', 'Phenotype', 'HP:0002202', (12, 14))	('lower', 'NegReg', (90, 95))	('IMRT', 'Var', (100, 104))	('death', 'Disease', (41, 46))	('death', 'Disease', 'MESH:D003643', (41, 46))	('patients', 'Species', '9606', (142, 150))
789214	27562616	In the present study, our results showed that IMRT decreased the incidence and postponed the median onset time of PCE and PE, and increased the survival probability of PCE or death and PE or death compared to 3DCRT.	('PCE', 'Phenotype', 'HP:0001698', (168, 171))	('IMRT', 'Var', (46, 50))	('death', 'Disease', (191, 196))	('postponed', 'NegReg', (79, 88))	('survival', 'CPA', (144, 152))	('PCE', 'Phenotype', 'HP:0001698', (114, 117))	('death', 'Disease', 'MESH:D003643', (175, 180))	('death', 'Disease', (175, 180))	('decreased', 'NegReg', (51, 60))	('PE', 'Phenotype', 'HP:0002202', (122, 124))	('PE', 'Phenotype', 'HP:0002202', (185, 187))	('increased', 'PosReg', (130, 139))	('PCE', 'Disease', (114, 117))	('death', 'Disease', 'MESH:D003643', (191, 196))
789217	27562616	One study that compared the long-term outcomes of EC patients after 3DCRT or IMRT indicated that 3DCRT patients had a significantly greater risk of non cancer-specific death compared to IMRT, while no difference was seen in cancer-specific mortality between the two groups.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('patients', 'Species', '9606', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('death', 'Disease', 'MESH:D003643', (168, 173))	('death', 'Disease', (168, 173))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('3DCRT', 'Var', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (103, 111))	('cancer', 'Disease', (224, 230))
789224	27562616	In conclusion, we found IMRT decreased the incidence, postponed the median onset time of PCE and PE, and increased the survival probability of PCE or death and PE or death compared to 3DCRT.	('PCE', 'Phenotype', 'HP:0001698', (143, 146))	('PE', 'Phenotype', 'HP:0002202', (97, 99))	('death', 'Disease', 'MESH:D003643', (150, 155))	('PE', 'Phenotype', 'HP:0002202', (160, 162))	('death', 'Disease', (150, 155))	('PCE', 'Disease', (89, 92))	('IMRT', 'Var', (24, 28))	('survival', 'MPA', (119, 127))	('postponed', 'NegReg', (54, 63))	('decreased', 'NegReg', (29, 38))	('incidence', 'MPA', (43, 52))	('increased', 'PosReg', (105, 114))	('death', 'Disease', 'MESH:D003643', (166, 171))	('death', 'Disease', (166, 171))	('PCE', 'Phenotype', 'HP:0001698', (89, 92))
789225	27562616	Accounting for effects of other clinically relevant covariates, IMRT was still an independent factor that significantly lowered the risks of PCE, PE, and death.	('IMRT', 'Var', (64, 68))	('lowered', 'NegReg', (120, 127))	('death', 'Disease', 'MESH:D003643', (154, 159))	('death', 'Disease', (154, 159))	('PCE', 'Phenotype', 'HP:0001698', (141, 144))	('PCE', 'Disease', (141, 144))	('PE', 'Phenotype', 'HP:0002202', (146, 148))
789375	24959263	Although the current worldwide standard of esophageal cancer radiation treatment is 3D-CRT, overall survival, locoregional control and non-cancer-related mortality were significantly improved following IMRT compared with those following 3D-CRT.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('improved', 'PosReg', (183, 191))	('locoregional control', 'CPA', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (54, 60))	('IMRT', 'Var', (202, 206))	('esophageal cancer', 'Disease', (43, 60))	('overall survival', 'CPA', (92, 108))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (139, 145))
789399	23119062	In the present study, we found that pericentromeric instability, evidenced by dynamic formation of pericentromeric or centromeric rearrangements, breaks, deletions or iso-chromosomes, was a general phenomenon in human cells immortalized by expression of human papillomavirus type 16 E6 and E7 (HPV16 E6E7).	('human', 'Species', '9606', (212, 217))	('human', 'Species', '9606', (254, 259))	('HPV16', 'Species', '333760', (294, 299))	('deletions', 'Var', (154, 163))	('pericentromeric', 'MPA', (36, 51))	('human papillomavirus type 16', 'Species', '333760', (254, 282))
789400	23119062	In particular, for the first time, we surprisingly found a dramatic increase in the proportion of pericentromeric chromosomal aberrations relative to total aberrations in HPV16 E6E7-expressing cells 72 h after release from aphidicolin (APH)-induced replication stress, with pericentromeric chromosomal aberrations becoming the predominant type of structural aberrations (~70% of total aberrations).	('HPV16', 'Species', '333760', (171, 176))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (290, 313))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (114, 136))	('APH', 'Chemical', 'MESH:D016590', (236, 239))	('HPV16', 'Gene', (171, 176))	('aphidicolin', 'Chemical', 'MESH:D016590', (223, 234))	('E6E7-expressing', 'Var', (177, 192))	('pericentromeric', 'Gene', (98, 113))	('increase', 'PosReg', (68, 76))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (290, 312))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (114, 137))
789402	23119062	This increase in relative proportion of pericentromeric aberrations after release from APH treatment revealed that pericentromeric breaks induced by replication stress are refractory to prompt repair in HPV16 E6E7-expressing epithelial cells.	('APH', 'Chemical', 'MESH:D016590', (87, 90))	('E6E7-expressing', 'Var', (209, 224))	('HPV16', 'Gene', (203, 208))	('HPV16', 'Species', '333760', (203, 208))
789403	23119062	Telomerase-immortalized epithelial cells without HPV16 E6E7 expression did not exhibit such preferential pericentromeric instability after release from APH treatment.	('E6E7 expression', 'Var', (55, 70))	('HPV16', 'Gene', (49, 54))	('pericentromeric instability', 'MPA', (105, 132))	('APH', 'Chemical', 'MESH:D016590', (152, 155))	('HPV16', 'Species', '333760', (49, 54))
789405	23119062	Since HPV16 E6 and E7 inactivate p53 and Rb, and p53 and Rb pathway defects are common in cancer, our finding that pericentromeric regions are refractory to prompt repair after replication stress-induced breakage in HPV16 E6E7-expressing cells may shed light on mechanism of general pericentromeric instability in cancer.	('p53', 'Gene', (49, 52))	('cancer', 'Disease', (314, 320))	('inactivate', 'NegReg', (22, 32))	('p53', 'Gene', '7157', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HPV16', 'Species', '333760', (6, 11))	('HPV16', 'Gene', (216, 221))	('HPV16', 'Species', '333760', (216, 221))	('HPV16', 'Gene', (6, 11))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('defects', 'NegReg', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('E6E7-expressing', 'Var', (222, 237))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (314, 320))
789407	23119062	Amongst various forms of chromosome aberrations, pericentromeric or centromeric translocations, deletions and iso-chromosomes have been frequently observed in human cancers of various origins such as head and neck, breast, lung, bladder, liver, colon, ovary, pancreas, prostate, and uterine cervix.	('uterine cervix', 'Disease', (283, 297))	('liver', 'Disease', (238, 243))	('bladder', 'Disease', (229, 236))	('iso-chromosomes', 'Var', (110, 125))	('centromeric translocations', 'Var', (68, 94))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('pancreas', 'Disease', (259, 267))	('pericentromeric', 'Var', (49, 64))	('uterine cervix', 'Phenotype', 'HP:0030160', (283, 297))	('lung', 'Disease', (223, 227))	('human', 'Species', '9606', (159, 164))	('prostate', 'Disease', (269, 277))	('pancreas', 'Disease', 'MESH:D010190', (259, 267))	('deletions', 'Var', (96, 105))	('observed', 'Reg', (147, 155))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('colon', 'Disease', (245, 250))	('ovary', 'Disease', (252, 257))	('ovary', 'Disease', 'MESH:D010051', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast', 'Disease', (215, 221))
789409	23119062	Centromeric or pericentromeric instability may contribute to cancer development by at least two routes.	('contribute', 'Reg', (47, 57))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('pericentromeric', 'Var', (15, 30))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Centromeric', 'Var', (0, 11))
789417	23119062	In epithelial cells, high-risk HPV E6 can also activate telomerase, which facilitates cellular immortalization, one of the hallmarks of cancer.	('telomerase', 'Enzyme', (56, 66))	('activate', 'PosReg', (47, 55))	('cellular immortalization', 'CPA', (86, 110))	('HPV E6', 'Var', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('facilitates', 'PosReg', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
789419	23119062	Moreover, it has been shown that the expression of HPV16 E6E7 can induce DNA damage and structural chromosome instability independent of telomere dysfunction.	('telomere dysfunction', 'Disease', 'MESH:C536801', (137, 157))	('E6E7', 'Var', (57, 61))	('chromosome instability', 'Phenotype', 'HP:0040012', (99, 121))	('induce', 'Reg', (66, 72))	('telomere dysfunction', 'Disease', (137, 157))	('structural chromosome instability', 'CPA', (88, 121))	('DNA damage', 'CPA', (73, 83))	('HPV16', 'Species', '333760', (51, 56))	('HPV16', 'Gene', (51, 56))
789420	23119062	In the present study, we found nonrandom structural chromosome instability in immortalized human epithelial cells co-expressing HPV16 E6E7 and hTERT, a catalytic subunit of telomerase.	('HPV16', 'Gene', (128, 133))	('HPV16', 'Species', '333760', (128, 133))	('hTERT', 'Gene', (143, 148))	('nonrandom', 'CPA', (31, 40))	('E6E7', 'Var', (134, 138))	('chromosome instability', 'Phenotype', 'HP:0040012', (52, 74))	('hTERT', 'Gene', '7015', (143, 148))	('human', 'Species', '9606', (91, 96))
789421	23119062	In addition, we observed that treatment with aphidicolin, a classical drug causing replication stress, induced chromatid breaks at classical chromosome fragile sites as well as in pericentromeric regions in HPV16 E6E7-expressing cells.	('E6E7-expressing', 'Var', (213, 228))	('HPV16', 'Species', '333760', (207, 212))	('chromatid breaks', 'CPA', (111, 127))	('aphidicolin', 'Chemical', 'MESH:D016590', (45, 56))	('chromatid breaks', 'Phenotype', 'HP:0040012', (111, 127))	('induced', 'Reg', (103, 110))
789422	23119062	In the process of studying the long-term effect of aphidicolin-induced replication stress, we discovered, for the first time, that successive generations of HPV16 E6E7-expressing cells presented elevated proportions of centromeric or pericentromeric aberrations, but not the aberrations occurring at classical chromosome fragile sites, after release from aphidicolin treatment.	('centromeric', 'MPA', (219, 230))	('E6E7-expressing', 'Var', (163, 178))	('HPV16', 'Gene', (157, 162))	('HPV16', 'Species', '333760', (157, 162))	('elevated', 'PosReg', (195, 203))	('aphidicolin', 'Chemical', 'MESH:D016590', (51, 62))	('aphidicolin', 'Chemical', 'MESH:D016590', (355, 366))	('pericentromeric aberrations', 'MPA', (234, 261))
789423	23119062	These results suggest that pericentromeric regions are refractory to prompt repair after replication stress-induced breakage in HPV16 E6E7-expressing cells.	('HPV16', 'Gene', (128, 133))	('E6E7-expressing', 'Var', (134, 149))	('HPV16', 'Species', '333760', (128, 133))
789424	23119062	Two esophageal and two cervical epithelial cell lines co-expressing HPV16 E6E7 and hTERT were examined in this study.	('E6E7', 'Var', (74, 78))	('hTERT', 'Gene', (83, 88))	('HPV16', 'Species', '333760', (68, 73))	('HPV16', 'Gene', (68, 73))	('hTERT', 'Gene', '7015', (83, 88))
789435	23119062	Thus, from the results of clonal pericentromeric aberrations in advanced PDs and the persistent occurrence of non-clonal pericentromeric aberrations in all four cell lines, we concluded that epithelial cells expressing HPV16 E6E7 and hTERT had intrinsic pericentromeric instability.	('hTERT', 'Gene', (234, 239))	('HPV16 E6E7', 'Var', (219, 229))	('PDs', 'Chemical', 'MESH:D010165', (73, 76))	('hTERT', 'Gene', '7015', (234, 239))	('HPV16', 'Species', '333760', (219, 224))	('E6E7', 'Var', (225, 229))
789436	23119062	It is intriguing that the structural chromosomal instability in cells co-expressing HPV16 E6E7 and hTERT cells occurred preferentially in the pericentromeric or centromeric regions.	('hTERT', 'Gene', (99, 104))	('HPV16', 'Gene', (84, 89))	('occurred', 'Reg', (111, 119))	('chromosomal instability', 'Phenotype', 'HP:0040012', (37, 60))	('structural chromosomal instability', 'CPA', (26, 60))	('hTERT', 'Gene', '7015', (99, 104))	('E6E7', 'Var', (90, 94))	('HPV16', 'Species', '333760', (84, 89))
789438	23119062	The four HPV16 E6E7-hTERT-expressing cell lines at PD 80 were treated with 0.6 microg/ml of APH and vehicle (0.1% DMSO) for 24 h, and harvested at the end of treatment.	('DMSO', 'Chemical', 'MESH:D004121', (114, 118))	('PD', 'Disease', 'MESH:D010300', (51, 53))	('E6E7-hTERT-expressing', 'Var', (15, 36))	('APH', 'Chemical', 'MESH:D016590', (92, 95))	('HPV16 E6E7-hTERT', 'CellLine', 'CVCL:4W30', (9, 25))	('HPV16', 'Gene', (9, 14))
789440	23119062	These results demonstrated that pericentromeric regions in HPV16 E6E7-hTERT-expressing cells resembled fragile sites that exhibited instability under APH-induced replication stress, yet the APH-induced instability did not predominantly occur in pericentromeric regions.	('instability', 'MPA', (132, 143))	('HPV16 E6E7-hTERT', 'CellLine', 'CVCL:4W30', (59, 75))	('APH', 'Chemical', 'MESH:D016590', (190, 193))	('HPV16', 'Gene', (59, 64))	('E6E7-hTERT-expressing', 'Var', (65, 86))	('APH', 'Chemical', 'MESH:D016590', (150, 153))
789445	23119062	The question remained as to whether the preferential pericentromeric instability in HPV16 E6E7-hTERT-immortalized cells was due to the expression HPV16 E6E7 or hTERT.	('HPV16', 'Gene', (84, 89))	('pericentromeric instability', 'MPA', (53, 80))	('HPV16 E6E7-hTERT', 'CellLine', 'CVCL:4W30', (84, 100))	('HPV16', 'Species', '333760', (84, 89))	('HPV16', 'Species', '333760', (146, 151))	('hTERT', 'Gene', '7015', (160, 165))	('hTERT', 'Gene', '7015', (95, 100))	('HPV16 E6E7', 'Var', (146, 156))	('hTERT', 'Gene', (160, 165))	('E6E7', 'Var', (152, 156))	('hTERT', 'Gene', (95, 100))
789446	23119062	We then examined whether immortalized cells without HPV16 E6E7 expression also had preferential pericentromeric instability.	('E6E7 expression', 'Var', (58, 73))	('pericentromeric instability', 'CPA', (96, 123))	('HPV16', 'Gene', (52, 57))	('HPV16', 'Species', '333760', (52, 57))
789451	23119062	Inactivation of p16INK4a/Rb pathway and activation of telomerase are the minimal requirements for immortalization of epithelial cells without using viral oncogenes.	('p16INK4a', 'Gene', (16, 24))	('p16INK4a', 'Gene', '1029', (16, 24))	('Inactivation', 'Var', (0, 12))	('telomerase', 'Enzyme', (54, 64))
789452	23119062	The Rb pathway was inactivated through E7 expression in the HPV16 E6E7-hTERT-immortalized cell lines.	('Rb pathway', 'Pathway', (4, 14))	('inactivated', 'NegReg', (19, 30))	('E7 expression', 'Var', (39, 52))	('HPV16 E6E7-hTERT', 'CellLine', 'CVCL:4W30', (60, 76))
789457	23119062	But no non-clonal structural aberrations were found in 100 metaphases of either cell line at both PDs, indicating that NE2-hTERT and NC104-shp16-hTERT cell line had much lower levels of background genomic instability than cell lines immortalized by co-expression of HPV16 E6E7 and hTERT (Table S1).	('p16', 'Gene', '1029', (141, 144))	('hTERT', 'Gene', '7015', (145, 150))	('hTERT', 'Gene', (123, 128))	('HPV16', 'Species', '333760', (266, 271))	('PDs', 'Chemical', 'MESH:D010165', (98, 101))	('background genomic instability', 'MPA', (186, 216))	('hTERT', 'Gene', '7015', (281, 286))	('hTERT', 'Gene', (145, 150))	('p16', 'Gene', (141, 144))	('lower', 'NegReg', (170, 175))	('E6E7', 'Var', (272, 276))	('hTERT', 'Gene', '7015', (123, 128))	('hTERT', 'Gene', (281, 286))
789460	23119062	However, both cell lines exhibited only a few structural aberrations (chromatid breaks, chromosomal arrangements, breaks and deletions pooled) in 100 metaphases 72 h after release from APH treatment, with no significant difference between the frequencies of pericentromeric and non-pericentromeric aberrations (Figure 4B).	('APH', 'Chemical', 'MESH:D016590', (185, 188))	('chromosomal arrangements', 'CPA', (88, 112))	('chromatid breaks', 'Phenotype', 'HP:0040012', (70, 86))	('deletions', 'Var', (125, 134))
789470	23119062	Firstly, we found that HPV16 E6E7 could preferentially induce pericentromeric instability in cells that did not have telomere shortening-mediated chromosome instability.	('chromosome instability', 'Phenotype', 'HP:0040012', (146, 168))	('E6E7', 'Var', (29, 33))	('HPV16', 'Species', '333760', (23, 28))	('HPV16', 'Gene', (23, 28))	('induce', 'Reg', (55, 61))	('telomere shortening', 'Phenotype', 'HP:0031413', (117, 136))	('pericentromeric instability', 'Disease', (62, 89))
789471	23119062	Secondly, pericentromeric chromosomal aberrations (chromosomal rearrangement, breaks and deletions) in HPV16 E6E7-hTERT-expressing cells were surprisingly the predominant type of structural chromosomal aberration (~70% of total aberrations) 72 h (about one population doubling) after release from APH-induced replication stress.	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (26, 49))	('E6E7-hTERT-expressing', 'Var', (109, 130))	('pericentromeric chromosomal', 'Var', (10, 37))	('APH', 'Chemical', 'MESH:D016590', (297, 300))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (190, 212))	('HPV16 E6E7-hTERT', 'CellLine', 'CVCL:4W30', (103, 119))	('HPV16', 'Gene', (103, 108))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (26, 48))
789472	23119062	Of note, pericentromeric aberrations accounted for only about 20% of total chromatid breaks in HPV16 E6E7-hTERT-expressing cells at the end of APH treatment.	('chromatid breaks', 'Phenotype', 'HP:0040012', (75, 91))	('chromatid breaks', 'CPA', (75, 91))	('HPV16', 'Gene', (95, 100))	('E6E7-hTERT-expressing', 'Var', (101, 122))	('HPV16 E6E7-hTERT', 'CellLine', 'CVCL:4W30', (95, 111))	('APH', 'Chemical', 'MESH:D016590', (143, 146))
789474	23119062	Since such preferential residual pericentromeric instability was not detected in hTERT-immortalized cell lines or normal cells, our results suggest that HPV16 E6E7 expression can propagate pericentromeric instability in successive cell generations after replication stress.	('E6E7 expression', 'Var', (159, 174))	('HPV16', 'Gene', (153, 158))	('hTERT', 'Gene', '7015', (81, 86))	('propagate', 'Reg', (179, 188))	('pericentromeric instability', 'MPA', (189, 216))	('HPV16', 'Species', '333760', (153, 158))	('hTERT', 'Gene', (81, 86))
789479	23119062	On the other hand, it has been recently discovered that hyper-condensation of chromatin during mitosis enhances DNA breakage in some fragile sites.	('hyper-condensation', 'Var', (56, 74))	('DNA', 'MPA', (112, 115))	('mitosis', 'Disease', (95, 102))	('mitosis', 'Disease', 'None', (95, 102))	('enhances', 'PosReg', (103, 111))
789483	23119062	In addition, it was shown that HPV16 E6-expressing cells had lower S-phase recovery rates after DNA damage.	('S-phase recovery rates', 'MPA', (67, 89))	('lower', 'NegReg', (61, 66))	('HPV16', 'Species', '333760', (31, 36))	('HPV16', 'Gene', (31, 36))	('E6-expressing', 'Var', (37, 50))
789486	23119062	The above information together may, at least in part, explain our finding that pericentromeric rearrangements became the predominant type of chromosome aberrations in the subsequent generations of HPV16 E6E7-expressing cells.	('HPV16', 'Species', '333760', (197, 202))	('E6E7-expressing', 'Var', (203, 218))	('pericentromeric', 'Disease', (79, 94))
789487	23119062	In our study, the expression of HPV16 E6E7 is a typical example of activation of growth signaling pathways.	('HPV16', 'Species', '333760', (32, 37))	('HPV16', 'Gene', (32, 37))	('activation', 'PosReg', (67, 77))	('E6E7', 'Var', (38, 42))	('growth signaling pathways', 'Pathway', (81, 106))
789489	23119062	Intriguingly, our data showed that epithelial cell lines derived from different organ sites (esophageal and cervical epithelial cells) consistently exhibited preferential pericentromeric instability upon expression of HPV16 E6E7.	('preferential', 'PosReg', (158, 170))	('exhibited', 'Reg', (148, 157))	('HPV16', 'Gene', (218, 223))	('HPV16', 'Species', '333760', (218, 223))	('pericentromeric instability', 'MPA', (171, 198))	('E6E7', 'Var', (224, 228))
789490	23119062	It appears that pericentromeric instability plays a more prominent role than non-pericentromeric instability in contributing to gross chromosome aberration formation in HPV16 E6E7-expressing cells.	('HPV16', 'Species', '333760', (169, 174))	('HPV16', 'Gene', (169, 174))	('gross chromosome aberration formation', 'MPA', (128, 165))	('contributing', 'Reg', (112, 124))	('E6E7-expressing', 'Var', (175, 190))
789491	23119062	It is relevant to note that pericentromeric or centromeric aberrations have been reported to be a common form of chromosome aberrations in cervical cancers, as well as in many other types of cancer.	('cancer', 'Disease', (148, 154))	('pericentromeric', 'Var', (28, 43))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('chromosome aberrations', 'Disease', (113, 135))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('centromeric aberrations', 'Var', (47, 70))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cervical cancers', 'Disease', (139, 155))	('cervical cancers', 'Disease', 'MESH:D002583', (139, 155))
789495	23119062	Two cervical epithelial cell lines (NC104-E6E7hTERT and NC105-E6E7hTERT) and two esophageal epithelial cell lines (NE1-E6E7hTERT and NE2-E7E7hTERT) were immortalized by expression of HPV16-E6E7 and hTERT.	('HPV16', 'Species', '333760', (183, 188))	('hTERT', 'Gene', '7015', (66, 71))	('HPV16-E6E7', 'Var', (183, 193))	('hTERT', 'Gene', (123, 128))	('hTERT', 'Gene', '7015', (46, 51))	('hTERT', 'Gene', '7015', (141, 146))	('hTERT', 'Gene', '7015', (198, 203))	('hTERT', 'Gene', (46, 51))	('hTERT', 'Gene', (141, 146))	('hTERT', 'Gene', (66, 71))	('NC104-E6E7hTERT', 'CellLine', 'CVCL:4W30', (36, 51))	('NC105-E6E7hTERT', 'CellLine', 'CVCL:4W30', (56, 71))	('NE2-E7E7hTERT', 'CellLine', 'CVCL:E306', (133, 146))	('NE1-E6E7hTERT', 'CellLine', 'CVCL:E306', (115, 128))	('hTERT', 'Gene', '7015', (123, 128))	('hTERT', 'Gene', (198, 203))
789549	22606414	X; 18 translocation is a sensitive marker and is demonstrated in 70 to 90% of synovial sarcomas.	('synovial sarcomas', 'Disease', 'MESH:D013584', (78, 95))	('synovial sarcomas', 'Disease', (78, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (87, 95))	('X; 18 translocation', 'Var', (0, 19))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (78, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (78, 95))
789570	21644036	PBMC were harvested with subsequent flow cytometric analysis of MDSC (HLADR- Lin1low/- CD33+ CD11b+) and Treg (CD4+ CD25+ CD127low/- FoxP3+) percentages.	('CD33', 'Gene', '945', (87, 91))	('CD33', 'Gene', (87, 91))	('Treg', 'Chemical', '-', (105, 109))	('CD25', 'Gene', (116, 120))	('CD11b', 'Gene', '3684', (93, 98))	('CD127', 'Gene', (122, 127))	('CD11b', 'Gene', (93, 98))	('HLADR-', 'Var', (70, 76))	('CD4', 'Gene', (111, 114))	('Lin1', 'Gene', '10421', (77, 81))	('CD4', 'Gene', '920', (111, 114))	('FoxP3', 'Gene', '50943', (133, 138))	('Lin1', 'Gene', (77, 81))	('CD25', 'Gene', '3559', (116, 120))	('CD127', 'Gene', '3575', (122, 127))	('FoxP3', 'Gene', (133, 138))
789651	21644036	Inhibition of arginase I restores T-cell function in vitro and induces an antitumor response in vivo.	('T-cell function', 'CPA', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('induces', 'Reg', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('restores', 'PosReg', (25, 33))	('arginase', 'Protein', (14, 22))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (78, 83))
789684	21644036	High IL-13 was associated with lymph node involvement and outcome, with no patient with high expression surviving more than three years following curative resection.	('High', 'Var', (0, 4))	('IL-13', 'Gene', (5, 10))	('outcome', 'Disease', (58, 65))	('IL-13', 'Gene', '3596', (5, 10))	('patient', 'Species', '9606', (75, 82))	('lymph node involvement', 'Disease', (31, 53))
789720	21994875	As a motilin receptor agonist, erythromycin induces peristalsis, stimulates gastrointestinal motility, and shortens gastric emptying time.	('gastric emptying time', 'MPA', (116, 137))	('gastrointestinal motility', 'Disease', (76, 101))	('peristalsis', 'MPA', (52, 63))	('erythromycin', 'Chemical', 'MESH:D004917', (31, 43))	('shortens', 'NegReg', (107, 115))	('erythromycin', 'Var', (31, 43))	('gastric emptying', 'Phenotype', 'HP:0002578', (116, 132))	('stimulates', 'PosReg', (65, 75))	('induces', 'PosReg', (44, 51))	('gastrointestinal motility', 'Disease', 'MESH:D015835', (76, 101))
789722	21994875	Recently, Altraif and colleagues reported in a double-blind randomized trial that erythromycin of 125 mg intravenously administered 30 minutes before endoscopy as compared with placebo significantly increased the proportion of a clear stomach (48.9% versus 23.3%, P < .01), decreased the mean procedural duration (19.0 minutes versus 26.0 minutes, P < .05), and shorten the hospitalized days (3.4 days versus 5.1 days, P < .02) in cirrhotic patients with AVH.	('decreased', 'NegReg', (274, 283))	('patients', 'Species', '9606', (441, 449))	('clear', 'Disease', (229, 234))	('erythromycin', 'Var', (82, 94))	('shorten', 'NegReg', (362, 369))	('erythromycin', 'Chemical', 'MESH:D004917', (82, 94))	('increased', 'PosReg', (199, 208))
789761	21994875	In patients with medium to large (or F2-F3) EV, risk of future bleeding is substantial and primary prophylaxis is indicated.	('F2-F3', 'Var', (37, 42))	('EV', 'Phenotype', 'HP:0002040', (44, 46))	('patients', 'Species', '9606', (3, 11))	('bleeding', 'Disease', 'MESH:D006470', (63, 71))	('bleeding', 'Disease', (63, 71))
789830	20808692	Although they are minor complications, type 1 (intramural) and type 2 (transmural without mediastinal spillage) esophageal ruptures were observed after 12 of 25 (48%) balloon dilations for esophageal strictures caused by radiation injury.	('esophageal strictures', 'Phenotype', 'HP:0002043', (189, 210))	('esophageal ruptures', 'Disease', 'MESH:D004941', (112, 131))	('esophageal strictures', 'Disease', (189, 210))	('balloon dilations', 'Var', (167, 184))	('esophageal ruptures', 'Disease', (112, 131))	('esophageal stricture', 'Phenotype', 'HP:0002043', (189, 209))	('radiation injury', 'Disease', 'MESH:D011832', (221, 237))	('radiation injury', 'Disease', (221, 237))
789888	20808692	For example, dilation with 20-mm balloons caused perforations in two of three patients with peptic pyloric strictures, and dilations to 18 mm caused perforations in two patients with peptic pyloroduodenal strictures.	('peptic pyloric strictures', 'Disease', (92, 117))	('dilations', 'Var', (123, 132))	('patients', 'Species', '9606', (169, 177))	('patients', 'Species', '9606', (78, 86))
789902	19737544	VDR ablation affects carcinogen-induced tumorigenesis in a tissue-specific manner in model systems.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('ablation', 'Var', (4, 12))	('VDR', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
789936	19737544	Specific mutations that cause deletions, frameshift mutations, premature stop codons or splice site abnormalities that impede VDR expression or binding activity, effectively suppress key VDR actions.	('VDR', 'Protein', (126, 129))	('expression', 'MPA', (130, 140))	('activity', 'MPA', (152, 160))	('deletions', 'Var', (30, 39))	('binding', 'Interaction', (144, 151))	('mutations', 'Var', (9, 18))	('key VDR actions', 'MPA', (183, 198))	('suppress', 'NegReg', (174, 182))	('impede', 'NegReg', (119, 125))	('expression', 'Species', '29278', (130, 140))	('premature stop codons', 'Var', (63, 84))	('frameshift mutations', 'Var', (41, 61))
789958	19737544	Furthermore, antagonism of the non-genomic pathway blocks 1alpha,25-(OH)2 D3-mediated OCN expression.	('antagonism', 'Var', (13, 23))	('blocks', 'NegReg', (51, 57))	('non-genomic pathway', 'Pathway', (31, 50))	('expression', 'Species', '29278', (90, 100))
789961	19737544	For example, 1alpha,25-(OH)2 D3 inhibits PTH secretion in the parathyroid glands but stimulates pancreatic beta-cell insulin secretion, inhibits adaptive immunity but enhances some innate immune responses, inhibits differentiation of B lymphocytes but enhances keratinocyte differentiation.	('pancreatic beta-cell insulin secretion', 'Disease', 'MESH:D010195', (96, 134))	('1alpha,25-(OH)2 D3', 'Var', (13, 31))	('inhibits', 'NegReg', (206, 214))	('PTH secretion in the parathyroid glands', 'MPA', (41, 80))	('stimulates', 'PosReg', (85, 95))	('pancreatic beta-cell insulin secretion', 'Disease', (96, 134))	('adaptive immunity', 'MPA', (145, 162))	('enhances', 'PosReg', (252, 260))	('enhances', 'PosReg', (167, 175))	('keratinocyte differentiation', 'CPA', (261, 289))	('rat', 'Species', '10116', (64, 67))	('rat', 'Species', '10116', (263, 266))	('innate immune responses', 'MPA', (181, 204))	('inhibits', 'NegReg', (32, 40))	('differentiation of B lymphocytes', 'CPA', (215, 247))	('PTH', 'Chemical', 'MESH:D010281', (41, 44))	('inhibits', 'NegReg', (136, 144))
789962	19737544	For example, 1alpha,25-(OH)2 D3 has antiproliferative effects in some neoplastic cells but induces a spectrum of growth responses in others.	('spectrum of growth responses', 'MPA', (101, 129))	('1alpha,25-(OH)2 D3', 'Var', (13, 31))	('antiproliferative effects', 'CPA', (36, 61))	('rat', 'Species', '10116', (47, 50))	('induces', 'Reg', (91, 98))
789964	19737544	Furthermore, at low or physiological concentrations, 1alpha,25-(OH)2 D3 may promote proliferation of monocytes or keratinocytes.	('promote', 'PosReg', (76, 83))	('rat', 'Species', '10116', (91, 94))	('rat', 'Species', '10116', (44, 47))	('1alpha,25-(OH)2 D3', 'Var', (53, 71))	('rat', 'Species', '10116', (116, 119))	('proliferation of monocytes or keratinocytes', 'CPA', (84, 127))
789972	19737544	1alpha,25-(OH)2 D3 transcriptional regulation of OPN involves VDR/RXR heterodimer binding and recruitment of coregulators including SRC-1, -2, -3, CBP, p300 and DRIP205 to VDREs within the OPN promoter.	('OPN', 'Gene', (49, 52))	('VDR/RXR', 'Protein', (62, 69))	('men', 'Species', '9606', (101, 104))	('DRIP205', 'Var', (161, 168))	('p300', 'Var', (152, 156))
789973	19737544	Mutation at one or both VDRE sites in the rat OPN promoter substantively suppresses 1alpha,25-(OH)2 D3-mediated transcription of a OPN-promoter luciferase reporter construct.	('Mutation', 'Var', (0, 8))	('rat', 'Species', '10116', (42, 45))	('suppresses', 'NegReg', (73, 83))
789977	19737544	E-cadherin is induced by 1alpha,25-(OH)2 D3 non-genomic rapid actions and suppresses cell growth, partly by inhibition of beta-catenin transcriptional activity.	('inhibition', 'NegReg', (108, 118))	('1alpha,25-(OH)2 D3', 'Var', (25, 43))	('beta-catenin', 'Gene', '84353', (122, 134))	('suppresses', 'NegReg', (74, 84))	('cell growth', 'CPA', (85, 96))	('beta-catenin', 'Gene', (122, 134))	('E-cadherin', 'Protein', (0, 10))
789983	19737544	Disturbance of this equilibrium in early stages of multistep tumorigenesis may have phenotypic effects on cell adhesion, migration and invasion.	('rat', 'Species', '10116', (124, 127))	('tumor', 'Disease', (61, 66))	('migration', 'CPA', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Disturbance', 'Var', (0, 11))	('effects', 'Reg', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cell adhesion', 'CPA', (106, 119))	('invasion', 'CPA', (135, 143))
789984	19737544	Aberrant expression of these genes in early tumorigenesis may influence the subsequent development of abnormal molecular circuitry in evolving cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('Aberrant expression', 'Var', (0, 19))	('men', 'Species', '9606', (94, 97))	('expression', 'Species', '29278', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('influence', 'Reg', (62, 71))	('development of abnormal molecular circuitry', 'CPA', (87, 130))	('tumor', 'Disease', (44, 49))
789994	19737544	VDR ligands significantly increased migration or invasion only in those cells with high constitutive OPN and low E-cadherin.	('rat', 'Species', '10116', (39, 42))	('migration', 'CPA', (36, 45))	('invasion', 'CPA', (49, 57))	('increased', 'PosReg', (26, 35))	('high', 'Var', (83, 87))	('VDR', 'Protein', (0, 3))
789999	19737544	Mice deficient in VDR or key components of the vitamin D synthetic pathway do not manifest any increase of sporadic tumorigenesis.	('VDR', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('vitamin D', 'Chemical', 'MESH:D014807', (47, 56))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (116, 121))	('deficient', 'Var', (5, 14))
790000	19737544	However, VDR ablation alters susceptibility to chemically induced carcinogenesis in a tissue-specific manner.	('alters', 'Reg', (22, 28))	('VDR', 'Gene', (9, 12))	('ablation', 'Var', (13, 21))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('susceptibility', 'MPA', (29, 43))	('carcinogenesis', 'Disease', (66, 80))
790017	19737544	However, high serum serum 25-OHD levels were associated with increased risk of pancreatic cancer in 200 Finnish cases and 400 controls, from this same total cohort.	('pancreatic cancer', 'Disease', 'MESH:D010190', (79, 96))	('pancreatic cancer', 'Disease', (79, 96))	('25-OHD', 'Chemical', '-', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('high', 'Var', (9, 13))
790027	19737544	By this rationale, persistently high serum [25(OH)D] could impede neoplastic progression of colonic adenomas which are common in asymptomatic Western populations, with ultimate reduction of CRC incidence.	('impede', 'NegReg', (59, 65))	('rat', 'Species', '10116', (8, 11))	('colonic adenomas', 'Disease', (92, 108))	('reduction', 'NegReg', (177, 186))	('serum [', 'Var', (37, 44))	('CRC', 'Disease', (190, 193))	('25(OH)D', 'Chemical', '-', (44, 51))	('colonic adenomas', 'Disease', 'MESH:D000236', (92, 108))	('CRC', 'Phenotype', 'HP:0003003', (190, 193))	('neoplastic progression', 'CPA', (66, 88))
790031	19737544	Neoplasms of the pancreas and prostate are characterised by similar disequilibrium involving low E-cadherin and high OPN which could potentially be related to the direct associations between serum [25(OH)D] levels and risks of pancreatic cancer or aggressive prostate cancer.	('aggressive prostate cancer', 'Disease', 'MESH:D011471', (248, 274))	('Neoplasms', 'Phenotype', 'HP:0002664', (0, 9))	('Neoplasms of the pancreas', 'Disease', (0, 25))	('pancreatic cancer', 'Disease', (227, 244))	('aggressive prostate cancer', 'Disease', (248, 274))	('pancreatic cancer', 'Disease', 'MESH:D010190', (227, 244))	('OPN', 'Gene', (117, 120))	('high', 'Var', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('E-cadherin', 'Protein', (97, 107))	('Neoplasms of the pancreas', 'Disease', 'MESH:D010190', (0, 25))	('25(OH)D', 'Chemical', '-', (198, 205))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (227, 244))	('low', 'NegReg', (93, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (259, 274))	('Neoplasms of the pancreas', 'Phenotype', 'HP:0002894', (0, 25))
790154	32756534	A meta-analysis demonstrated that single nucleotide polymorphisms (SNPs) located in the LPA, TPPP, and CEP72 genes were associated with high risk of both EAC and its premalignant precursor.	('single nucleotide polymorphisms', 'Var', (34, 65))	('associated', 'Reg', (120, 130))	('TPPP', 'Gene', '11076', (93, 97))	('EAC', 'Phenotype', 'HP:0011459', (154, 157))	('TPPP', 'Gene', (93, 97))	('CEP72', 'Gene', '55722', (103, 108))	('EAC', 'Disease', (154, 157))	('CEP72', 'Gene', (103, 108))	('LPA', 'Gene', (88, 91))
790180	32756534	The survival curve output by OncoLnc showed that all the hub genes with high expression, in comparison with those with low expression, improved the percentage of late survival, after the 2000-day timepoint (>2000 on the x axis) (Figure 11).	('hub', 'Gene', '1993', (57, 60))	('hub', 'Gene', (57, 60))	('improved', 'PosReg', (135, 143))	('high expression', 'Var', (72, 87))	('late survival', 'CPA', (162, 175))
790190	32756534	Cell division as a functional category includes mechanisms to properly orient and position the mitotic spindle, which is important because incorrect activity related to the spindle contributes to disease, even carcinogenesis.	('activity', 'MPA', (149, 157))	('carcinogenesis', 'Disease', 'MESH:D063646', (210, 224))	('disease', 'Disease', (196, 203))	('contributes to', 'Reg', (181, 195))	('carcinogenesis', 'Disease', (210, 224))	('incorrect', 'Var', (139, 148))
790191	32756534	Echoing the KEGG pathway enrichment analysis, the DEGs were strongly related to the cell cycle.	('KEGG', 'Chemical', '-', (12, 16))	('cell cycle', 'CPA', (84, 94))	('related', 'Reg', (69, 76))	('DEGs', 'Var', (50, 54))
790192	32756534	Dysregulation of the cell cycle leading to endless proliferation of cells has been implicated in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Dysregulation', 'Var', (0, 13))	('cell cycle', 'CPA', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('endless proliferation of cells', 'CPA', (43, 73))	('tumor', 'Disease', (97, 102))	('Dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (0, 31))
790194	32756534	However, inhibition of cell cycle progression alleviates the development of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (76, 86))	('alleviates', 'NegReg', (46, 56))	('malignancy', 'Disease', (76, 86))	('cell cycle progression', 'CPA', (23, 45))	('inhibition', 'Var', (9, 19))
790198	32756534	Intriguingly, those findings differed from those of a similar study using bioinformatics methods conducted by He et al.. Their findings indicated that DEGs related to ECA were mainly enriched in complement and coagulation cascades, mature- onset diabetes in the young, and retinol metabolism.	('diabetes', 'Disease', 'MESH:D003920', (246, 254))	('retinol', 'Chemical', 'MESH:D014801', (273, 280))	('ECA', 'Disease', (167, 170))	('DEGs', 'Var', (151, 155))	('diabetes', 'Disease', (246, 254))	('retinol metabolism', 'MPA', (273, 291))
790202	32756534	showed that MK2206/BEZ235 enhances apoptosis and inhibits tumor growth targeted at AKT phosphorylation in a mouse xenograft model of ESCC and in vitro.	('MK2206/BEZ235', 'Var', (12, 25))	('BEZ235', 'Chemical', 'MESH:C531198', (19, 25))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('ESCC', 'Disease', (133, 137))	('inhibits', 'NegReg', (49, 57))	('mouse', 'Species', '10090', (108, 113))	('enhances', 'PosReg', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('MK2206', 'Chemical', 'MESH:C548887', (12, 18))	('apoptosis', 'CPA', (35, 44))
790203	32756534	Moreover, the combination of MK2206 and BEZ235 boost antitumor effects because of dual PI3K and AKT inhibition.	('MK2206', 'Var', (29, 35))	('BEZ235', 'Chemical', 'MESH:C531198', (40, 46))	('BEZ235', 'Var', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('boost', 'PosReg', (47, 52))	('AKT', 'Pathway', (96, 99))	('MK2206', 'Chemical', 'MESH:C548887', (29, 35))	('tumor', 'Disease', (57, 62))	('inhibition', 'NegReg', (100, 110))
790230	32756534	One clinical study suggested that high TOP2A could serve as a biomarker driving medical therapy.	('TOP2A', 'Gene', '7153', (39, 44))	('high', 'Var', (34, 38))	('TOP2A', 'Gene', (39, 44))
790231	32756534	Another study showed that the knockdown of the long noncoding RNA (lncRNA) DDX11-AS1 reversed paclitaxel (PTX) resistance by means of inhibiting the expression level of TOP2A.	('inhibiting', 'NegReg', (134, 144))	('paclitaxel', 'Chemical', 'MESH:D017239', (94, 104))	('reversed', 'NegReg', (85, 93))	('DDX11-AS1', 'Gene', (75, 84))	('expression level', 'MPA', (149, 165))	('TOP2A', 'Gene', '7153', (169, 174))	('TOP2A', 'Gene', (169, 174))	('knockdown', 'Var', (30, 39))	('PTX', 'Chemical', 'MESH:D017239', (106, 109))	('DDX11-AS1', 'Gene', '100506660;1663;5729', (75, 84))
790240	32756534	Previous clinical trials found that immunotherapies using epitope peptides derived from TTK potentiated cell response and immunity against ESCA.	('cell response', 'CPA', (104, 117))	('epitope peptides derived', 'Var', (58, 82))	('immunity', 'CPA', (122, 130))	('potentiated', 'PosReg', (92, 103))	('ESCA', 'Phenotype', 'HP:0011459', (139, 143))	('TTK', 'Gene', (88, 91))	('ESCA', 'Disease', (139, 143))	('TTK', 'Gene', '7272', (88, 91))
790368	31842816	While AFs are more commonly associated with risk for hepatocellular carcinoma (HCC), evidences have suggested their potential link to the risk of ESCC.	('associated', 'Reg', (28, 38))	('AFs', 'Var', (6, 9))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (53, 77))	('HCC', 'Gene', (79, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('hepatocellular carcinoma', 'Disease', (53, 77))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (53, 77))	('HCC', 'Phenotype', 'HP:0001402', (79, 82))	('HCC', 'Gene', '619501', (79, 82))	('ESCC', 'Disease', (146, 150))
790372	31842816	While the potential mechanisms of AFB1 in ESCC risk remain to be elucidated, in an in vitro study, AFG1, a less toxic variant of AFs, is shown to reduce the expression of HLA-I, TAP-1, and LMP-2, critical components in antigen presentation and antigen processing, in adult esophageal epithelial cells, which can ultimately lead to defect in antigen presentation to T-lymphocytes, potentiating tumorigenesis via escaped immune surveillance, therefore potentially linking AF exposure to esophageal cancer.	('defect', 'MPA', (331, 337))	('TAP-1', 'Gene', (178, 183))	('HLA-I', 'Gene', (171, 176))	('AFG1', 'Gene', (99, 103))	('TAP-1', 'Gene', '6890', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (496, 502))	('tumorigenesis', 'CPA', (393, 406))	('variant', 'Var', (118, 125))	('escaped immune', 'MPA', (411, 425))	('tumor', 'Phenotype', 'HP:0002664', (393, 398))	('LMP-2', 'Gene', '5698', (189, 194))	('AFG1', 'Gene', '246269', (99, 103))	('reduce', 'NegReg', (146, 152))	('LMP-2', 'Gene', (189, 194))	('cancer', 'Disease', (496, 502))	('expression', 'MPA', (157, 167))	('antigen presentation to T-lymphocytes', 'MPA', (341, 378))	('potentiating', 'PosReg', (380, 392))	('cancer', 'Phenotype', 'HP:0002664', (496, 502))
790376	31842816	The mechanisms of toxicity suggest that, while FB1 does not act as direct carcinogen like AFB1, it can be a potent promoter of AFB1-induced tumorigenesis, as FB1 can significantly alter sphingolipid profile in both animals and humans by inhibiting ceramide synthase, which can further affect apoptosis and potentially other signaling pathways.	('sphingolipid', 'Chemical', 'MESH:D013107', (186, 198))	('affect', 'Reg', (285, 291))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('inhibiting', 'NegReg', (237, 247))	('ceramide', 'Chemical', 'MESH:D002518', (248, 256))	('FB1', 'Var', (158, 161))	('toxicity', 'Disease', (18, 26))	('toxicity', 'Disease', 'MESH:D064420', (18, 26))	('sphingolipid profile', 'MPA', (186, 206))	('apoptosis', 'CPA', (292, 301))	('ceramide synthase', 'Enzyme', (248, 265))	('humans', 'Species', '9606', (227, 233))	('alter', 'Reg', (180, 185))
790384	31842816	This study was supported by grants CA94683 (for field study including in the design of the study and data collection) and CA90997 (for laboratory analysis including biomarker analysis and interpretation of data) from National Cancer Institute/National Institutes of Health to Dr. Jia-Sheng Wang.	('Cancer', 'Disease', 'MESH:D009369', (226, 232))	('Cancer', 'Disease', (226, 232))	('CA90997', 'Var', (122, 129))	('Cancer', 'Phenotype', 'HP:0002664', (226, 232))
790494	30988751	In addition, smoking was demonstrated to have an unfavorable impact on tumor control by irradiation in animal models, by exacerbating tissue hypoxia.	('exacerbating', 'PosReg', (121, 133))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('hypoxia', 'Disease', 'MESH:D000860', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('smoking', 'Var', (13, 20))	('hypoxia', 'Disease', (141, 148))	('tumor', 'Disease', (71, 76))
790496	30988751	In the present study, it was speculated that smoking not only induces malignant transformation of normal cells, but may also change tumor-associated genes or associated metabolic activity, thus making tumor cells more aggressive and less sensitive to RT and chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('malignant transformation', 'CPA', (70, 94))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('induces', 'Reg', (62, 69))	('change', 'Reg', (125, 131))	('making', 'Reg', (194, 200))	('metabolic activity', 'MPA', (169, 187))	('more', 'PosReg', (213, 217))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', (132, 137))	('aggressive', 'CPA', (218, 228))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('smoking', 'Var', (45, 52))
790554	30988751	In the subgroup of patients treated with IMRT/3DCRT, the HR for death was 1.53 (95% CI, 1.02-2.30; P=0.039) for former smokers and 3.00 (95% CI, 1.14-7.86; P=0.025) for current smokers, compared with that for never smokers.	('IMRT/3DCRT', 'Var', (41, 51))	('patients', 'Species', '9606', (19, 27))	('death', 'Disease', 'MESH:D003643', (64, 69))	('death', 'Disease', (64, 69))
790558	30988751	The risk of death was also identified to be increased depending on the PYs of cigarettes.	('PY', 'Chemical', '-', (71, 73))	('PYs', 'Var', (71, 74))	('death', 'Disease', 'MESH:D003643', (12, 17))	('death', 'Disease', (12, 17))
790646	28193907	Therefore, we further analyzed the correlation between CXCR4 and the expression of these stem cell genes, and found that CXCR4 was positively correlated with stem cell genes Lgr5 (Figure 1B, R=0.58, p=0.0013), Nanog (Figure 1B, R=0.583, p=0.001) and Sox2 (Figure 1B, R=0.68, p<0.0001).	('Lgr5', 'Gene', '8549', (174, 178))	('Nanog', 'Gene', (210, 215))	('CXCR4', 'Var', (121, 126))	('Sox2', 'Gene', '6657', (250, 254))	('correlated', 'Interaction', (142, 152))	('Sox2', 'Gene', (250, 254))	('Nanog', 'Gene', '79923', (210, 215))	('Lgr5', 'Gene', (174, 178))
790658	28193907	In addition, in order to rule out the possibility that the significant reduction of metastatic tumors in the shCXCR4 group was caused by the impact of CXCR4 on the tumor formation ability of ECSCs, we established a mouse subcutaneous tumor transplantation model.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (221, 239))	('shCXCR4', 'Var', (109, 116))	('reduction', 'NegReg', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mouse', 'Species', '10090', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (95, 100))
790665	28193907	After the transwell migration and matrigel invasion assays, we found that ECSCs' ability to invade and metastasize was significantly enhanced after adding rhCXCL12 (Figure 4F, p<0.001).	('rhCXCL12', 'Var', (155, 163))	('enhanced', 'PosReg', (133, 141))	('rhCXCL12', 'Chemical', '-', (155, 163))
790686	28193907	The result showed that, just as blockage of the CXCL12/CXCR4 axis, blockage of the ERK1/2 signal pathway could result in significant inhibition of ECSCs' disposition of migration and invasion (Figure 6A-6B, p<0.01, p<0.001).	('CXCL12', 'Gene', '6387', (48, 54))	('ERK1/2', 'Gene', '5595;5594', (83, 89))	('ERK1/2', 'Gene', (83, 89))	('blockage', 'Var', (67, 75))	('inhibition', 'NegReg', (133, 143))	('CXCL12', 'Gene', (48, 54))
790688	28193907	The above results confirmed that rhCXCL12 can significantly enhance ECSCs' disposition of invasion and metastasis (Figure 4A-4B) and up-regulate the level of p-ERK1/2 (Figure 5D).	('ERK1/2', 'Gene', (160, 166))	('rhCXCL12', 'Var', (33, 41))	('level', 'MPA', (149, 154))	('ERK1/2', 'Gene', '5595;5594', (160, 166))	('enhance', 'PosReg', (60, 67))	('rhCXCL12', 'Chemical', '-', (33, 41))	('up-regulate', 'PosReg', (133, 144))
790689	28193907	Therefore, in addition to adding rhCXCL12 to the ECSCs migration and invasion models, we also added U0126 in order to block the ERK1/2 signal pathway, and the enhanced ability of ECSCs to invade and metastasize caused by rhCXCL12 was significantly rescued (Figure 6C-6D, p<0.05, p<0.01, p<0.001).	('U0126', 'Chemical', 'MESH:C113580', (100, 105))	('rhCXCL12', 'Var', (221, 229))	('ERK1/2', 'Gene', (128, 134))	('enhanced', 'PosReg', (159, 167))	('ERK1/2', 'Gene', '5595;5594', (128, 134))	('block', 'NegReg', (118, 123))	('rhCXCL12', 'Chemical', '-', (221, 229))	('U0126', 'Var', (100, 105))	('rhCXCL12', 'Chemical', '-', (33, 41))
790694	28193907	reported that EGFR inhibitors inhibited the formation of ECSCs by blocking the EMT transformation of epithelial cancer cells.	('EGFR', 'Gene', '1956', (14, 18))	('epithelial cancer', 'Phenotype', 'HP:0031492', (101, 118))	('EGFR', 'Gene', (14, 18))	('blocking', 'NegReg', (66, 74))	('inhibited', 'NegReg', (30, 39))	('inhibitors', 'Var', (19, 29))	('epithelial cancer', 'Disease', (101, 118))	('epithelial cancer', 'Disease', 'MESH:D000077216', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
790696	28193907	reported that high expression of stem cell marker CD271 was closely associated with the patient's tolerability of chemotherapy and susceptibility to tumor invasion and metastasis, Forghanifard MM et al.	('patient', 'Species', '9606', (88, 95))	('associated', 'Reg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('CD271', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tolerability of chemotherapy', 'CPA', (98, 126))	('high', 'Var', (14, 18))	('tumor', 'Disease', (149, 154))	('CD271', 'Gene', '4804', (50, 55))
790709	28193907	Our study found that ECSCs had increased p-ERK1/2 activity compared with normal esophageal cancer cells, and blockage of CXCL12 or CXCR4 could significantly inhibit the activity of p-ERK1/2, while adding rhCXCL12 could significantly enhance the activity of p-ERK1/2, therefore confirming that ECSCs maintained high activity of p-ERK1/2 by the CXCL12-CXCR4 chemokine axis.	('ERK1/2', 'Gene', '5595;5594', (329, 335))	('CXCL12', 'Gene', (206, 212))	('increased', 'PosReg', (31, 40))	('blockage', 'Var', (109, 117))	('activity', 'MPA', (169, 177))	('rhCXCL12', 'Chemical', '-', (204, 212))	('ERK1/2', 'Gene', (183, 189))	('activity', 'MPA', (245, 253))	('inhibit', 'NegReg', (157, 164))	('ERK1/2', 'Gene', '5595;5594', (183, 189))	('CXCL12', 'Gene', '6387', (121, 127))	('CXCL12', 'Gene', '6387', (343, 349))	('CXCL12', 'Gene', (121, 127))	('enhance', 'PosReg', (233, 240))	('ERK1/2', 'Gene', (259, 265))	('ERK1/2', 'Gene', '5595;5594', (259, 265))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('CXCL12', 'Gene', (343, 349))	('activity', 'MPA', (315, 323))	('esophageal cancer', 'Disease', (80, 97))	('ERK1/2', 'Gene', (43, 49))	('CXCL12', 'Gene', '6387', (206, 212))	('activity', 'MPA', (50, 58))	('ERK1/2', 'Gene', '5595;5594', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ERK1/2', 'Gene', (329, 335))
790716	28193907	To establish stable low CXCL12 and CXCR4 expression ECSCs, ECSCs were transduced with lentivirus carrying CXCR4-shRNA or CXCL12-shRNA (GFP-shRNA as the control), as described previously.	('CXCL12', 'Gene', (121, 127))	('CXCR4-shRNA', 'Var', (106, 117))	('CXCL12', 'Gene', '6387', (24, 30))	('CXCL12', 'Gene', '6387', (121, 127))	('CXCL12', 'Gene', (24, 30))
790781	28430590	What they (57% ROs) concerned is that neoadjuvant CRT may increase the risk of postoperative complications, such as bleeding, anastomotic leakage and healing delay, although CROSS trial has demonstrated that trimodality is associated with similar adverse-event rates compared with surgery alone.	('anastomotic leakage', 'Disease', (126, 145))	('OS', 'Chemical', '-', (176, 178))	('bleeding', 'Disease', 'MESH:D006470', (116, 124))	('healing delay', 'Phenotype', 'HP:0001058', (150, 163))	('neoadjuvant', 'Var', (38, 49))	('bleeding', 'Disease', (116, 124))	('postoperative complications', 'CPA', (79, 106))	('healing delay', 'CPA', (150, 163))
790804	28430590	34% ROs would shrink field to 2 cm superiorly and inferiorly plus primary tumor during giving the definitive concurrent CRT as the INT 0123 trial recommended, although it is not evidence based.	('ROs', 'Var', (4, 7))	('primary tumor', 'Disease', 'MESH:D009369', (66, 79))	('primary tumor', 'Disease', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
790808	28430590	However, several retrospective studies showed IFI is a reasonable treatment strategy with less toxicity as well as not compromising local control and OS.	('IFI', 'Var', (46, 49))	('OS', 'Chemical', '-', (150, 152))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('toxicity', 'Disease', (95, 103))
790881	27269645	found that lung tumours with anaplastic lymphoma kinase (ALK) mutations appeared to have larger pleural effusion and no pleural tails on CT images.	('pleural effusion', 'Disease', 'MESH:D010996', (96, 112))	('pleural effusion', 'Disease', (96, 112))	('lung tumours', 'Disease', 'MESH:D008175', (11, 23))	('anaplastic lymphoma kinase', 'Gene', (29, 55))	('pleural effusion', 'Phenotype', 'HP:0002202', (96, 112))	('ALK', 'Gene', (57, 60))	('lymphoma', 'Phenotype', 'HP:0002665', (40, 48))	('lung tumours', 'Disease', (11, 23))	('lung tumour', 'Phenotype', 'HP:0100526', (11, 22))	('larger', 'PosReg', (89, 95))	('anaplastic lymphoma kinase', 'Gene', '238', (29, 55))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (29, 48))	('ALK', 'Gene', '238', (57, 60))	('mutations', 'Var', (62, 71))
790882	27269645	Contrast-enhanced CT images revealed that the mutation status of von Hippel-Lindau (VHL) in renal cell carcinoma is significantly correlated with the "gross appearance of intratumoural vascularity", "well-defined tumour boundaries", and "enhancement of nodular tumour".	('VHL', 'Disease', (84, 87))	('enhancement', 'PosReg', (238, 249))	('renal cell carcinoma', 'Disease', (92, 112))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('correlated', 'Reg', (130, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('VHL', 'Disease', 'MESH:D006623', (84, 87))	('tumour', 'Disease', (176, 182))	('von Hippel-Lindau', 'Gene', (65, 82))	('nodular tumour', 'Disease', (253, 267))	('mutation', 'Var', (46, 54))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (92, 112))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('nodular tumour', 'Disease', 'MESH:D020518', (253, 267))	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('von Hippel-Lindau', 'Gene', '7428', (65, 82))	('tumour', 'Disease', (213, 219))	('tumour', 'Disease', 'MESH:D009369', (261, 267))	('tumour', 'Disease', (261, 267))
790884	27269645	Studies have therefore proposed that tumour heterogeneity may be associated with the non-uniform distribution of [18F]FDG.	('[18F]FDG', 'Var', (113, 121))	('FDG', 'Chemical', 'MESH:D019788', (118, 121))	('tumour', 'Disease', (37, 43))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
790896	27269645	In pre-clinical model, observed that mice with sarcomas treated with combinations of MK1775, a cell cycle checkpoint inhibitor, and gemcitabine showed a substantial change in the (apparent diffusion coefficient) ADC histogram skewness, kurtosis, entropy, and average ADC shortly after treatment compared to the untreated control group.	('sarcomas', 'Disease', (47, 55))	('entropy', 'MPA', (246, 253))	('ADC histogram skewness', 'MPA', (212, 234))	('change', 'Reg', (165, 171))	('combinations', 'Interaction', (69, 81))	('average ADC', 'MPA', (259, 270))	('gemcitabine', 'Chemical', 'MESH:C056507', (132, 143))	('kurtosis', 'Disease', (236, 244))	('kurtosis', 'Disease', 'None', (236, 244))	('MK1775', 'Chemical', 'MESH:C549567', (85, 91))	('sarcomas', 'Disease', 'MESH:D012509', (47, 55))	('MK1775', 'Var', (85, 91))	('sarcomas', 'Phenotype', 'HP:0100242', (47, 55))	('mice', 'Species', '10090', (37, 41))
790898	27269645	The skewness of K-trans was found to be a promising predictor of progression free survival and overall survival of patients with stage IV head-and-neck cancer.	('patients', 'Species', '9606', (115, 123))	('head-and-neck cancer', 'Disease', 'MESH:D006258', (138, 158))	('head-and-neck cancer', 'Disease', (138, 158))	('skewness', 'Var', (4, 12))	('head-and-neck cancer', 'Phenotype', 'HP:0012288', (138, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
790901	27269645	High baseline SUV uptake is often thought to be associated with aggressive tumour behavior and poor prognosis.	('High', 'Var', (0, 4))	('associated', 'Reg', (48, 58))	('aggressive tumour behavior', 'Disease', 'MESH:D001523', (64, 90))	('SUV uptake', 'MPA', (14, 24))	('aggressive tumour behavior', 'Disease', (64, 90))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
790943	27269645	In a recent study by, volumetric measures, such as contrast enhancing volume, necrosis volume, and total tumour volume, were found to significantly predict GBM mutations, including TP53, NF1, EGFR, RB1, and PDGFRA.	('RB1', 'Gene', '5925', (198, 201))	('NF1', 'Gene', '4763', (187, 190))	('necrosis', 'Disease', 'MESH:D009336', (78, 86))	('NF1', 'Gene', (187, 190))	('TP53', 'Gene', (181, 185))	('mutations', 'Var', (160, 169))	('GBM', 'Gene', (156, 159))	('predict', 'Reg', (148, 155))	('tumour volume', 'Disease', (105, 118))	('PDGFRA', 'Gene', '5156', (207, 213))	('PDGFRA', 'Gene', (207, 213))	('RB1', 'Gene', (198, 201))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('necrosis', 'Disease', (78, 86))	('TP53', 'Gene', '7157', (181, 185))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (192, 196))	('tumour volume', 'Disease', 'MESH:D009369', (105, 118))
790966	27269645	For instance, an image with 1024 discrete intensity values will yield a 21024 x 21024 x 21024 GLCM, which can be computationally intensive.	('yield', 'Reg', (64, 69))	('GLCM', 'Chemical', '-', (94, 98))	('21024', 'Var', (72, 77))
791004	26258795	In these cancers, silencing miR-221/222 could represent a novel anti-tumor approach to inhibit tumor growth and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('silencing', 'Var', (18, 27))	('miR-221/222', 'Gene', '407007;407006', (28, 39))	('cancers', 'Disease', (9, 16))	('tumor', 'Disease', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('miR-221/222', 'Gene', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (95, 100))	('inhibit', 'NegReg', (87, 94))
791027	26258795	Overexpression of miR-221/222 reduced levels of p27Kip1 and CDX2, and knockdown of miR-221/222 increased levels of these proteins in cultured cells.	('miR-221/222', 'Gene', '407007;407006', (83, 94))	('knockdown', 'Var', (70, 79))	('levels of', 'MPA', (105, 114))	('miR-221/222', 'Gene', '407007;407006', (18, 29))	('CDX2', 'Gene', (60, 64))	('CDX2', 'Gene', '1045', (60, 64))	('p27Kip1', 'Gene', '1027', (48, 55))	('miR-221/222', 'Gene', (18, 29))	('miR-221/222', 'Gene', (83, 94))	('reduced', 'NegReg', (30, 37))	('p27Kip1', 'Gene', (48, 55))	('increased', 'PosReg', (95, 104))
791028	26258795	In addition, inhibitors of miR-221/222 reduced growth of xenograft tumors in immunodeficient mice.	('inhibitors', 'Var', (13, 23))	('miR-221/222', 'Gene', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mice', 'Species', '10090', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('reduced', 'NegReg', (39, 46))	('xenograft tumors in immunodeficient', 'Disease', (57, 92))	('xenograft tumors in immunodeficient', 'Disease', 'MESH:D009369', (57, 92))	('miR-221/222', 'Gene', '407007;407006', (27, 38))
791033	26258795	In addition, knockdown of miR-221/222 inhibited cell growth and invasion and increased the radiosensitivity.	('miR-221/222', 'Gene', '407007;407006', (26, 37))	('inhibited', 'NegReg', (38, 47))	('radiosensitivity', 'CPA', (91, 107))	('increased', 'PosReg', (77, 86))	('knockdown', 'Var', (13, 22))	('miR-221/222', 'Gene', (26, 37))
791056	26258795	Inhibition of miR-221 decreased liver cancer cell proliferation, clonogenicity, migration, and invasion and also induced G1 arrest and apoptosis in vitro and in vivo.	('apoptosis', 'CPA', (135, 144))	('invasion', 'CPA', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('decreased liver', 'Phenotype', 'HP:0001410', (22, 37))	('miR-221', 'Gene', (14, 21))	('induced', 'Reg', (113, 120))	('clonogenicity', 'CPA', (65, 78))	('migration', 'CPA', (80, 89))	('liver cancer', 'Phenotype', 'HP:0002896', (32, 44))	('Inhibition', 'Var', (0, 10))	('G1 arrest', 'CPA', (121, 130))	('decreased liver cancer', 'Disease', 'MESH:D006528', (22, 44))	('decreased liver cancer', 'Disease', (22, 44))
791059	26258795	DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, was also a direct target of miR-221.	('mTOR', 'Gene', (58, 62))	('DDIT4', 'Gene', '54541', (35, 40))	('DNA damage-inducible transcript 4', 'Gene', (0, 33))	('miR-221', 'Var', (100, 107))	('mTOR', 'Gene', '2475', (58, 62))	('DNA damage-inducible transcript 4', 'Gene', '54541', (0, 33))	('DDIT4', 'Gene', (35, 40))
791062	26258795	In addition, an miR-221 mimic could accentuate the anti-HCV effect of IFN-alpha in an HCV model, through the inhibition of two members of the suppressor of cytokine signaling (SOCS) family, SOCS1 and SOCS3.	('SOCS3', 'Gene', (200, 205))	('accentuate', 'PosReg', (36, 46))	('SOCS1', 'Gene', '8651', (190, 195))	('miR-221', 'Gene', (16, 23))	('SOCS1', 'Gene', (190, 195))	('inhibition', 'NegReg', (109, 119))	('mimic', 'Var', (24, 29))	('anti-HCV effect', 'MPA', (51, 66))	('SOCS3', 'Gene', '9021', (200, 205))	('IFN-alpha', 'Gene', '3439', (70, 79))	('IFN-alpha', 'Gene', (70, 79))
791070	26258795	In addition, NF-kappaB could be activated by miR-221, since HDAC6 suppressed the translocation of NF-kappaB.	('NF-kappaB', 'Gene', '4790', (98, 107))	('HDAC6', 'Gene', (60, 65))	('translocation', 'MPA', (81, 94))	('NF-kappaB', 'Gene', (98, 107))	('NF-kappaB', 'Gene', '4790', (13, 22))	('miR-221', 'Var', (45, 52))	('NF-kappaB', 'Gene', (13, 22))	('HDAC6', 'Gene', '10013', (60, 65))
791071	26258795	reported that MDM2 (E3 ubiquitin-protein ligase homolog), a known p53 (TP53) modulator, is identified as a direct target of miR-221.	('p53', 'Gene', '7157', (66, 69))	('miR-221', 'Var', (124, 131))	('MDM2', 'Gene', '4193', (14, 18))	('MDM2', 'Gene', (14, 18))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('p53', 'Gene', (66, 69))
791076	26258795	Pancreatic cancer patients with high miR-221 expression had a relatively shorter survival compared to those with lower expression.	('high', 'Var', (32, 36))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('shorter', 'NegReg', (73, 80))	('survival', 'MPA', (81, 89))	('miR-221', 'Gene', (37, 44))	('patients', 'Species', '9606', (18, 26))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
791077	26258795	Antisense to miR-221 suppressed the proliferative capacity, increased the amount of apoptosis, and sensitized the effects of gemcitabine in pancreatic cancer cells with concomitant up-regulation of PTEN, p27Kip1, p57Kip2, and PUMA, which are the tumor suppressors and the predicted targets of miR-221.	('p57Kip2', 'Gene', '1028', (213, 220))	('PTEN', 'Gene', '5728', (198, 202))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('apoptosis', 'CPA', (84, 93))	('sensitized', 'NegReg', (99, 109))	('up-regulation', 'PosReg', (181, 194))	('effects', 'MPA', (114, 121))	('miR-221', 'Gene', (13, 20))	('increased', 'PosReg', (60, 69))	('pancreatic cancer', 'Disease', (140, 157))	('p27Kip1', 'Gene', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('suppressed', 'NegReg', (21, 31))	('p27Kip1', 'Gene', '1027', (204, 211))	('tumor', 'Disease', (246, 251))	('proliferative capacity', 'CPA', (36, 58))	('p57Kip2', 'Gene', (213, 220))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('PTEN', 'Gene', (198, 202))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('gemcitabine', 'Chemical', 'MESH:C056507', (125, 136))	('Antisense', 'Var', (0, 9))
791087	26258795	Downregulation of TRPS1 by miR-221 is critical for PDGF-mediated acquisition of the EMT phenotype.	('TRPS1', 'Gene', (18, 23))	('Downregulation', 'NegReg', (0, 14))	('miR-221', 'Var', (27, 34))	('TRPS1', 'Gene', '7227', (18, 23))
791099	26258795	Selective siRNA-mediated downregulation of either of two software-predicted targets, PIK3R1 (target of miR-29b and miR-221) or MMP-2 (target of miR-29b), also conferred gemcitabine sensitivity to HuH28.	('MMP-2', 'Gene', '4313', (127, 132))	('miR-29b', 'Gene', '407024', (144, 151))	('PIK3R1', 'Gene', '5295', (85, 91))	('MMP-2', 'Gene', (127, 132))	('miR-29b', 'Gene', '407024', (103, 110))	('gemcitabine sensitivity', 'MPA', (169, 192))	('conferred', 'Reg', (159, 168))	('gemcitabine', 'Chemical', 'MESH:C056507', (169, 180))	('miR-29b', 'Gene', (144, 151))	('downregulation', 'NegReg', (25, 39))	('miR-29b', 'Gene', (103, 110))	('PIK3R1', 'Gene', (85, 91))	('miR-221', 'Var', (115, 122))
791100	26258795	Gastrointestinal stromal tumors (GISTs) are characterized by high expression of the KIT receptor tyrosine kinase protein, resulting from oncogenic mutations in the extracellular, juxtamembrane, or kinase domains.	('receptor tyrosine kinase', 'Gene', '5979', (88, 112))	('mutations', 'Var', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('Gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (0, 31))	('Gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (0, 31))	('receptor tyrosine kinase', 'Gene', (88, 112))	('GISTs', 'Phenotype', 'HP:0100723', (33, 38))	('Gastrointestinal stromal tumors', 'Disease', (0, 31))
791104	26258795	analyzed expression of miR-221/222 in six KIT exon 9, three KIT exon 11 mutated, and nine wild-type GISTs.	('miR-221/222', 'Gene', '407007;407006', (23, 34))	('mutated', 'Var', (72, 79))	('GISTs', 'Phenotype', 'HP:0100723', (100, 105))	('miR-221/222', 'Gene', (23, 34))
791106	26258795	p-AKT, AKT, and BCL2 expression were also reduced after miR-221/222 transfection.	('reduced', 'NegReg', (42, 49))	('AKT', 'Gene', (7, 10))	('BCL2', 'Gene', (16, 20))	('transfection', 'Var', (68, 80))	('AKT', 'Gene', '207', (2, 5))	('miR-221/222', 'Gene', '407007;407006', (56, 67))	('AKT', 'Gene', '207', (7, 10))	('AKT', 'Gene', (2, 5))	('miR-221/222', 'Gene', (56, 67))	('BCL2', 'Gene', '596', (16, 20))
791108	26258795	The unraveling of miR-221/222 signaling pathways and networks will be key to understanding the role that deregulated miRNA functioning can play in oncogenic or onco-suppressive processes and may be important for defining novel therapeutic molecules.	('deregulated', 'Var', (105, 116))	('oncogenic', 'CPA', (147, 156))	('onco-suppressive processes', 'CPA', (160, 186))	('miR-221/222', 'Gene', '407007;407006', (18, 29))	('miR-221/222', 'Gene', (18, 29))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', (117, 120))
791117	26093488	Levels of SMAD4, a key mediator of the TGFss pathway, increased after activin treatment of OE33/DKK3, and siSMAD4 significantly decreased matrigel invasion suggesting that DKK3 acts through the TGFbeta pathway.	('matrigel invasion', 'CPA', (138, 155))	('OE33/DKK3', 'Var', (91, 100))	('activin', 'Gene', '83729', (70, 77))	('increased', 'PosReg', (54, 63))	('decreased', 'NegReg', (128, 137))	('activin', 'Gene', (70, 77))
791118	26093488	OE33/DKK3 increased endothelial tube formation, were significantly more resistant to 5-FU and cisplatin, and DKK3 expression was significantly higher in chemoresistant EACs (p<0.005).	('chemoresistant', 'Disease', (153, 167))	('5-FU', 'Chemical', 'MESH:D005472', (85, 89))	('EAC', 'Phenotype', 'HP:0011459', (168, 171))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('resistant to 5-FU', 'MPA', (72, 89))	('OE33/DKK3', 'Var', (0, 9))	('higher', 'PosReg', (143, 149))	('expression', 'MPA', (114, 124))	('DKK3', 'Gene', (109, 113))	('endothelial tube formation', 'CPA', (20, 46))	('increased', 'PosReg', (10, 19))
791119	26093488	In NOD/SCIDgamma mice, OE33/DKK3 cells resulted in tumors at all sites (8/8) while vector cells grew in only 1/8 sites.	('mice', 'Species', '10090', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('resulted in', 'Reg', (39, 50))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('NOD', 'Gene', '1822', (3, 6))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('OE33/DKK3 cells', 'Var', (23, 38))	('NOD', 'Gene', (3, 6))
791134	26093488	Inhibition of DKK3 and its downstream mediators could have a significant clinical impact on the treatment and prevention of micrometastatic disease, especially in patients with locally advanced or regional nodal disease.	('patients', 'Species', '9606', (163, 171))	('nodal disease', 'Disease', (206, 219))	('DKK3', 'Gene', (14, 18))	('micrometastatic disease', 'Disease', (124, 147))	('Inhibition', 'Var', (0, 10))	('locally advanced', 'Disease', (177, 193))	('nodal disease', 'Disease', 'MESH:D013611', (206, 219))
791153	26093488	To evaluate whether stable transfection of DKK3 increases the tumorigenicity of OE33, the number of cells injected was titrated to the lowest number resulting in a palpable tumor after flank injection of OE33/DKK3 but not OE33/Vector.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('increases', 'PosReg', (48, 57))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('OE33/DKK3', 'Var', (204, 213))	('DKK3', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
791156	26093488	At 1x106 cells, OE33/DKK3 resulted in tumors at five weeks while OE33/Vector cells did not.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('resulted in', 'Reg', (26, 37))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('OE33/DKK3', 'Var', (16, 25))
791167	26093488	While treatment of OE33 with 5-azacytidine did not increase DKK3 expression, a combination of 5-azacytidine and trichostatin A increased DKK3 expression on Western suggesting that histone acetylation is involved in the overexpression of DKK3.	('DKK3', 'Gene', (137, 141))	('trichostatin A', 'Chemical', 'MESH:C012589', (112, 126))	('5-azacytidine', 'Chemical', 'MESH:D001374', (94, 107))	('expression', 'MPA', (142, 152))	('5-azacytidine', 'Chemical', 'MESH:D001374', (29, 42))	('increased', 'PosReg', (127, 136))	('5-azacytidine', 'Var', (94, 107))
791168	26093488	To determine the mechanism of action of DKK3 in EAC, the TOP-flash TCF-reporter assay was performed and showed no significant decrease in canonical Wnt pathway activation after transfection of DKK3, a divergent member of the Wnt inhibitor family, into OE33 compared to native and vector controls.	('activation', 'PosReg', (160, 170))	('decrease', 'NegReg', (126, 134))	('TCF', 'Gene', (67, 70))	('TCF', 'Gene', '3172', (67, 70))	('canonical Wnt pathway', 'Pathway', (138, 159))	('EAC', 'Phenotype', 'HP:0011459', (48, 51))	('DKK3', 'Var', (193, 197))
791172	26093488	DAVID pathway analysis of Human Gene ST 2.1 array expression induced by the transfection of DKK3 in OE33 showed that the TGFbeta pathway was significantly increased compared with OE33 vector control (p<0.05).	('TGFbeta pathway', 'Pathway', (121, 136))	('Human', 'Species', '9606', (26, 31))	('increased', 'PosReg', (155, 164))	('transfection', 'Var', (76, 88))	('DKK3', 'Gene', (92, 96))
791174	26093488	OE33/DKK3 cells were significantly more chemoresistant to 5-FU and cisplatin compared to vehicle control (p<0.05) (Figure 5A).	('chemoresistant', 'CPA', (40, 54))	('5-FU', 'Chemical', 'MESH:D005472', (58, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('more', 'PosReg', (35, 39))	('OE33/DKK3', 'Var', (0, 9))
791176	26093488	NSG mice were injected in the flank with 1x106 cells, the lowest number of cells to produce tumors with OE33/DKK3 but not OE33/Vector as described in the Methods.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('mice', 'Species', '10090', (4, 8))	('OE33/DKK3', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
791177	26093488	Five weeks after injection, only 1/8 OE33/Vector sites produced a palpable tumor (2 mm) while all OE33/DKK3 (8/8) tumor sites resulted in tumors (4-5 mm) (Supplemental Figure 2).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('OE33/Vector', 'Var', (37, 48))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (114, 119))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('resulted in', 'Reg', (126, 137))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('OE33/DKK3', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
791194	26093488	DKK3 overexpression may be important in tumor invasion, and matrigel invasion was increased following transfection of DKK3 in Flo and OE33.	('transfection', 'Var', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('matrigel invasion', 'CPA', (60, 77))	('increased', 'PosReg', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('DKK3', 'Gene', (118, 122))
791195	26093488	found that inhibiting SMAD4 in MDA-MB-231 breast carcinoma cells inhibited bone metastases in nude mice.	('nude mice', 'Species', '10090', (94, 103))	('breast carcinoma', 'Phenotype', 'HP:0003002', (42, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('inhibiting', 'Var', (11, 21))	('SMAD4', 'Gene', (22, 27))	('metastases', 'Disease', (80, 90))	('metastases', 'Disease', 'MESH:D009362', (80, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (31, 41))	('breast carcinoma', 'Disease', (42, 58))	('inhibited', 'NegReg', (65, 74))	('breast carcinoma', 'Disease', 'MESH:D001943', (42, 58))
791197	26093488	DKK3 supports capillary formation in gliomas and lymphoma, and our results show an increase in endothelial tube formation in the presence of OE33/DKK3.	('increase', 'PosReg', (83, 91))	('capillary formation', 'CPA', (14, 33))	('OE33/DKK3', 'Var', (141, 150))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('endothelial tube formation', 'CPA', (95, 121))	('gliomas and lymphoma', 'Disease', 'MESH:D005910', (37, 57))	('lymphoma', 'Phenotype', 'HP:0002665', (49, 57))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
791199	26093488	To determine if DKK3 transfection was able to increase the tumorigenicity of OE33, the lowest number of OE33/DKK3, but not OE33/Vector, cells able to produce tumors was determined to be 1x106 cells.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', (59, 64))	('increase', 'PosReg', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('OE33/DKK3', 'Var', (104, 113))	('transfection', 'Var', (21, 33))	('DKK3 transfection', 'Var', (16, 33))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
791209	26093488	DKK3 overexpression is associated with chemoresistance in Saos-2 osteosarcoma, and our results show that OE33/DKK3 cells were significantly more chemoresistant to cisplatin and 5-FU.	('DKK3', 'Gene', (0, 4))	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('osteosarcoma', 'Disease', (65, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('more', 'PosReg', (140, 144))	('overexpression', 'PosReg', (5, 19))	('5-FU', 'Chemical', 'MESH:D005472', (177, 181))	('chemoresistant', 'CPA', (145, 159))	('OE33/DKK3', 'Var', (105, 114))	('associated', 'Reg', (23, 33))
791215	26093488	DKK3 overexpression was increased in chemoresistant tumors, and transfection increased chemoresistance and invasion.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('transfection', 'Var', (64, 76))	('DKK3', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('overexpression', 'PosReg', (5, 19))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('increased', 'PosReg', (77, 86))	('invasion', 'CPA', (107, 115))	('increased', 'PosReg', (24, 33))
791329	22873795	In a series published by Relling and al, of children affected with leukemia and treated with prophylactic cerebral radiotherapy, children who had genetic defect of catabolism of thiopurine and high metabolism of thioguanine were more likely to present secondary brain tumors.	('leukemia', 'Disease', (67, 75))	('brain tumors', 'Disease', (262, 274))	('catabolism of thiopurine', 'MPA', (164, 188))	('high metabolism of thioguanine', 'MPA', (193, 223))	('thiopurine', 'Chemical', '-', (178, 188))	('children', 'Species', '9606', (129, 137))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('children', 'Species', '9606', (44, 52))	('thioguanine', 'Chemical', 'MESH:D013866', (212, 223))	('brain tumors', 'Disease', 'MESH:D001932', (262, 274))	('brain tumors', 'Phenotype', 'HP:0030692', (262, 274))	('genetic defect', 'Var', (146, 160))	('leukemia', 'Phenotype', 'HP:0001909', (67, 75))	('leukemia', 'Disease', 'MESH:D007938', (67, 75))
791330	22873795	Also there are few data supporting the role of polymorphism of DNA repair in cancer related treatments susceptibility.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('DNA repair', 'Gene', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('polymorphism', 'Var', (47, 59))
791412	31078526	Identification of cancer drivers at CTCF insulators in 1,962 whole-genomes Recent studies have shown that mutations at non-coding elements, such as promoters and enhancers, can act as cancer drivers.	('cancer', 'Disease', (184, 190))	('CTCF', 'Gene', '10664', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('CTCF', 'Gene', (36, 40))	('mutations', 'Var', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
791415	31078526	In particular, mutations in an insulator in multiple cancer types, including 16% of melanoma samples, are associated with TGFB1 up-regulation.	('TGFB1', 'Gene', (122, 127))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('up-regulation', 'PosReg', (128, 141))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('mutations', 'Var', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TGFB1', 'Gene', '7040', (122, 127))
791416	31078526	Using CRISPR-Cas9, we find that alterations at two of the most frequently mutated regions in this insulator increase cell growth by 40-50%, supporting the role of this boundary element as a cancer driver.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('increase', 'PosReg', (108, 116))	('alterations', 'Var', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cell growth', 'CPA', (117, 128))
791418	31078526	We developed a computational method that combines recurrence and functional impact of mutations to identify cancer drivers.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
791420	31078526	In particular, mutations in an insulator on chr19 are associated with TGFB1 up-regulation and may point to a novel mechanism of TGF-beta signaling modulation in multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('TGFB1', 'Gene', '7040', (70, 75))	('TGF-beta', 'Gene', (128, 136))	('up-regulation', 'PosReg', (76, 89))	('cancer', 'Disease', (170, 176))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('TGFB1', 'Gene', (70, 75))	('TGF-beta', 'Gene', '7039', (128, 136))
791421	31078526	Whole-genome sequencing (WGS) of tumors has revealed that most somatic mutations occur in non-coding regions.	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutations', 'Var', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', (33, 39))	('occur', 'Reg', (81, 86))
791422	31078526	Although most of these mutations do not impact tumor growth and are called passengers, some of them can act as cancer drivers by conferring growth advantage to promote tumorigenesis.	('promote', 'PosReg', (160, 167))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('growth', 'MPA', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
791426	31078526	In other prominent examples, promoter and enhancer mutations in breast cancer can lead to FOXA1 and ESR1 overexpression, respectively.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('enhancer', 'PosReg', (42, 50))	('mutations', 'Var', (51, 60))	('ESR1', 'Gene', (100, 104))	('overexpression', 'PosReg', (105, 119))	('FOXA1', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('ESR1', 'Gene', '2099', (100, 104))	('FOXA1', 'Gene', '3169', (90, 95))	('breast cancer', 'Disease', (64, 77))
791431	31078526	Disruption of the loop anchor regions, called CTCF/cohesin insulators (hereafter referred to as insulators), can lead to de novo enhancer-promoter interactions and the subsequent dysregulation of associated genes.	('lead to', 'Reg', (113, 120))	('CTCF', 'Gene', '10664', (46, 50))	('dysregulation', 'MPA', (179, 192))	('CTCF', 'Gene', (46, 50))	('enhancer-promoter interactions', 'MPA', (129, 159))	('Disruption', 'Var', (0, 10))
791434	31078526	Although the reasons for the high mutation rates are not completely understood, these studies noted that most of these mutations are likely passengers and do not drive tumor growth.	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('mutations', 'Var', (119, 128))	('tumor', 'Disease', (168, 173))
791435	31078526	found the CTCF insulators of DNA loops show recurrent deletions that alter the expression of LMO2 and TALI oncogenes in T cell acute lymphoblastic leukemia.	('CTCF', 'Gene', (10, 14))	('lymphoblastic leukemia', 'Disease', (133, 155))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('expression', 'MPA', (79, 89))	('deletions', 'Var', (54, 63))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (133, 155))	('LMO2', 'Gene', '4005', (93, 97))	('CTCF', 'Gene', '10664', (10, 14))	('alter', 'Reg', (69, 74))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (133, 155))	('LMO2', 'Gene', (93, 97))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (127, 155))	('T cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (120, 155))
791436	31078526	Thus, some variants at insulators may have a functional role and drive the growth of cancer cells.	('variants', 'Var', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('drive', 'PosReg', (65, 70))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
791440	31078526	Out of 5,042 insulators that show recurrent mutations (i.e., present in 2 or more samples) in 1,962 whole-genomes from 21 cancer types, our method identifies 21 putative drivers.	('cancer', 'Disease', (122, 128))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
791441	31078526	Functional validation of a predicted driver using CTCF ChIP-seq, 3C and CRISPR mutagenesis supports our computational predictions in human melanoma cells.	('mutagenesis', 'Var', (79, 90))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('CTCF', 'Gene', (50, 54))	('human', 'Species', '9606', (133, 138))	('CTCF', 'Gene', '10664', (50, 54))
791444	31078526	We analyzed the patterns of somatic single nucleotide variants (SNVs) in 1,962 genomes from 21 cancer types (Table S1) at constitutive insulators.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('single nucleotide variants', 'Var', (36, 62))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))
791445	31078526	We identified the mutations predicted to disrupt CTCF binding by comparing the TF motif position weight matrix (PWM) score of the mutated vs. the reference sequence (Figure S2A and Table S14).	('CTCF', 'Gene', (49, 53))	('S14', 'Gene', '5714', (187, 190))	('CTCF', 'Gene', '10664', (49, 53))	('S14', 'Gene', (187, 190))	('binding', 'Interaction', (54, 61))	('mutations', 'Var', (18, 27))
791446	31078526	We observe significant enrichment of CTCF motifs predicted to be disrupted due to mutations in 15 out of 21 cancer types analyzed (Figure S2B).	('CTCF', 'Gene', '10664', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (82, 91))	('CTCF', 'Gene', (37, 41))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
791447	31078526	Next, we extracted the tri-nucleotide context of the mutations predicted to disrupt CTCF motifs and compared the distributions of the 96 possible contexts with known signatures of mutational processes in human cancer from COSMIC as a reference control using cosine similarity as the quantitative metric (Figures S2C and S2D).	('CTCF', 'Gene', '10664', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tri-nucleotide', 'Chemical', '-', (23, 37))	('mutations', 'Var', (53, 62))	('human', 'Species', '9606', (204, 209))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('CTCF', 'Gene', (84, 88))	('cancer', 'Disease', (210, 216))
791448	31078526	We find that the tri-nucleotide distributions for CTCF motif-disrupting mutations vary considerably across cancer types and interestingly match the corresponding cancer-specific COSMIC mutational signatures in 9 cancer types (Figure S2D).	('mutations', 'Var', (72, 81))	('tri-nucleotide', 'Chemical', '-', (17, 31))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('motif-disrupting', 'Reg', (55, 71))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CTCF', 'Gene', (50, 54))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('CTCF', 'Gene', '10664', (50, 54))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
791449	31078526	As seen in Figure S2B, these 9 cancer types are also enriched for CTCF motif disruption.	('disruption', 'Var', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CTCF', 'Gene', (66, 70))	('CTCF', 'Gene', '10664', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
791450	31078526	Thus, our results show that enrichment of CTCF motif disruption in multiple cancer types is likely due to neutral mutational processes operative in those cancers.	('disruption', 'Var', (53, 63))	('CTCF', 'Gene', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancers', 'Disease', (154, 161))	('CTCF', 'Gene', '10664', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
791451	31078526	For the remaining 6 cancer types that show enrichment of CTCF motif disruption, but do not closely match any single mutational signature identified in that cancer type, we expect the motif-disrupting mutations are likely either a combination of multiple signatures or may correspond to unknown signatures of longer sequence context.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('CTCF', 'Gene', '10664', (57, 61))	('cancer', 'Disease', (156, 162))	('motif-disrupting', 'Reg', (183, 199))	('motif disruption', 'Var', (62, 78))	('mutations', 'Var', (200, 209))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (20, 26))	('CTCF', 'Gene', (57, 61))
791454	31078526	Our observations are consistent with those of Kaiser et al., who noted that enrichment of functional mutations at binding sites of CTCF and other TFs are likely due to neutral mutational processes, though they did not make a one-to-one comparison with the 30 mutational signatures from COSMIC.	('CTCF', 'Gene', (131, 135))	('CTCF', 'Gene', '10664', (131, 135))	('mutations', 'Var', (101, 110))
791455	31078526	Thus, these results demonstrate that in the computational models for cancer driver detection at CTCF insulators, there is a need to balance the higher functional impact of motif-disrupting mutations and their higher frequency (Figure S3) due to background mutational processes.	('CTCF', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CTCF', 'Gene', '10664', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutations', 'Var', (189, 198))	('cancer', 'Disease', (69, 75))
791456	31078526	We report a novel computational method, CNCDriver, which combines the functional impact of mutations and their recurrence across multiple cancer samples to identify the elements that show signals of positive selection.	('cancer', 'Disease', (138, 144))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))
791458	31078526	To identify the insulators under positive selection, CNCDriver also incorporates the ratio of CTCF motif-disrupting to motif-preserving mutations in the null model, thus balancing the opposite effects of predicted higher functional impact of these mutations with their higher frequency (Figure S3 and Methods).	('CTCF', 'Gene', (94, 98))	('CTCF', 'Gene', '10664', (94, 98))	('mutations', 'Var', (136, 145))
791463	31078526	We note that only 21 insulators are predicted to be under positive selection even though many insulators show high mutational frequencies (Figure S9: grey bars in circles for each cancer type).	('mutational', 'Var', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))
791471	31078526	To further interpret the tumorigenic role of mutations at insulator regions, we examined their clonality status.	('tumor', 'Disease', (25, 30))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
791472	31078526	We performed integrative analysis of tumor purity, copy number alterations and read depth at mutated loci using an approach similar to the one in previous studies (Figures S10A and S10B).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('S10A', 'Var', (172, 176))	('copy number alterations', 'Var', (51, 74))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('S10B', 'Var', (181, 185))	('S10A', 'SUBSTITUTION', 'None', (172, 176))	('S10B', 'SUBSTITUTION', 'None', (181, 185))
791473	31078526	We find that the majority of mutations in both coding and non-coding drivers tend to be clonal, likely pointing to their roles during the early stages of tumor development (Figure S10C and S10D).	('S10C', 'Mutation', 'p.S10C', (180, 184))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('S10D', 'Mutation', 'p.S10D', (189, 193))	('tumor', 'Disease', (154, 159))
791475	31078526	However, the fraction of clonal mutations in insulators (0.60) is significantly lower than that observed in promoters (0.79) (P value = 0.049, Fisher's exact test) suggesting the possibility that mutations at insulators may play a stronger role at later stages in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('mutations', 'Var', (32, 41))	('lower', 'NegReg', (80, 85))	('play', 'Reg', (224, 228))	('mutations', 'Var', (196, 205))	('cancer', 'Disease', (264, 270))
791477	31078526	Based on previous studies, the majority (~80%) of the loop anchors bound by CTCF and cohesin contain CTCF motifs in convergent orientations (i.e.	('cohesin', 'Protein', (85, 92))	('CTCF', 'Gene', (101, 105))	('CTCF', 'Gene', (76, 80))	('CTCF', 'Gene', '10664', (101, 105))	('motifs', 'Var', (106, 112))	('CTCF', 'Gene', '10664', (76, 80))
791479	31078526	For example, in Figure 1C, mutations at the driver insulator with the reverse CTCF motif are predicted to weaken a constitutive loop (red), thereby strengthening an alternate constitutive loop (gray) and a predicted new loop (dotted) through the pairing of the forward CTCF motif with other reverse motifs in the vicinity.	('mutations', 'Var', (27, 36))	('CTCF', 'Gene', '10664', (78, 82))	('CTCF', 'Gene', '10664', (269, 273))	('CTCF', 'Gene', (269, 273))	('weaken', 'NegReg', (106, 112))	('strengthening', 'PosReg', (148, 161))	('constitutive loop', 'MPA', (175, 192))	('CTCF', 'Gene', (78, 82))
791480	31078526	Among these 76 genes, TGFB1, HES1, CUL1 and CDKN2A are involved in curated cancer pathways (Figures 1C, S11C, S11K and S11M).	('HES1', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('CDKN2A', 'Gene', (44, 50))	('TGFB1', 'Gene', (22, 27))	('cancer', 'Disease', (75, 81))	('involved', 'Reg', (55, 63))	('CUL1', 'Gene', (35, 39))	('HES1', 'Gene', '3280', (29, 33))	('S11K', 'Mutation', 'p.S11K', (110, 114))	('CDKN2A', 'Gene', '1029', (44, 50))	('S11M', 'Mutation', 'p.S11M', (119, 123))	('S11C', 'SUBSTITUTION', 'None', (104, 108))	('TGFB1', 'Gene', '7040', (22, 27))	('CUL1', 'Gene', '8454', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('S11C', 'Var', (104, 108))
791481	31078526	Next, we asked whether these 76 genes exhibit differential expression in patients with insulator mutations vs. those without.	('mutations', 'Var', (97, 106))	('expression', 'MPA', (59, 69))	('patients', 'Species', '9606', (73, 81))
791483	31078526	We found that the expression of two neighboring genes is associated with mutations in one insulator driver candidate: TGFB1 (in melanoma and pan-cancer analysis) and CYP2S1 (in melanoma) (Figure 1D and Figure S12A).	('cancer', 'Disease', (145, 151))	('CYP2S1', 'Gene', (166, 172))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('S12A', 'SUBSTITUTION', 'None', (209, 213))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('S12A', 'Var', (209, 213))	('CYP2S1', 'Gene', '29785', (166, 172))	('TGFB1', 'Gene', '7040', (118, 123))	('expression', 'MPA', (18, 28))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('TGFB1', 'Gene', (118, 123))	('mutations', 'Var', (73, 82))	('associated', 'Reg', (57, 67))	('melanoma', 'Disease', (128, 136))
791485	31078526	The mutational frequency of candidate drivers is also lower in other cancer types relative to melanoma, which further decreases the statistical power to detect significant differences in gene expression.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('melanoma', 'Disease', (94, 102))	('lower', 'NegReg', (54, 59))	('mutational frequency', 'Var', (4, 24))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
791486	31078526	For example, matched WGS and RNA-seq data is available for only 3 samples with mutations and 93 without for the candidate driver on chr12 in breast cancer, while it is available for 12 samples with mutations and 68 without for the candidate driver in melanoma.	('chr12', 'Gene', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('melanoma', 'Disease', (251, 259))	('mutations', 'Var', (79, 88))
791487	31078526	The driver candidate (chr19:41,767,305-41,771,623) identified in melanoma and in pan-cancer analysis where mutations are associated with TGFB1 up-regulation (Figures 1B, 1C, 1D and S12 and Table S13) is of particular interest.	('mutations', 'Var', (107, 116))	('TGFB1', 'Gene', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('S12', 'Gene', (181, 184))	('chr19:41,767,305-41,771,623', 'STRUCTURAL_ABNORMALITY', 'None', (22, 49))	('cancer', 'Disease', (85, 91))	('S12', 'Gene', '6268', (181, 184))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('up-regulation', 'PosReg', (143, 156))	('melanoma', 'Disease', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('TGFB1', 'Gene', '7040', (137, 142))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
791489	31078526	We find that the mutation frequency of this insulator is higher in metastatic (19%) relative to primary samples (12%) (Figure S12F), which is consistent with the known role of TGFB1 in melanoma metastasis.	('melanoma metastasis', 'Disease', (185, 204))	('S12F', 'Mutation', 'p.S12F', (126, 130))	('higher', 'Reg', (57, 63))	('mutation', 'Var', (17, 25))	('melanoma metastasis', 'Disease', 'MESH:D009362', (185, 204))	('metastatic', 'CPA', (67, 77))	('TGFB1', 'Gene', '7040', (176, 181))	('TGFB1', 'Gene', (176, 181))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
791490	31078526	Furthermore, this trend is even stronger when analyzing the samples with recurrent mutations (since they are likely the ones under stronger positive selection than non-recurrent mutations), with mutation frequency of 17% for metastatic and 8% for primary melanoma samples (Figure S12F).	('mutations', 'Var', (83, 92))	('metastatic', 'Disease', (225, 235))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('S12F', 'Mutation', 'p.S12F', (280, 284))	('melanoma', 'Disease', (255, 263))	('melanoma', 'Disease', 'MESH:D008545', (255, 263))
791492	31078526	The mutations of this insulator in other cancer types (lung adenocarcinoma, endometrial carcinoma, prostate adenocarcinoma and liver hepatocellular carcinoma) and in particular the relatively high mutational frequency of 9% in colon cancer and 3% in esophageal adenocarcinoma may provide complementary mechanisms to the known genomic alterations (protein-coding mutations and copy number alterations) for modulation of TGF-beta signaling, especially in gastrointestinal cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('TGF-beta', 'Gene', (419, 427))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('endometrial carcinoma, prostate adenocarcinoma', 'Disease', 'MESH:D016889', (76, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('cancer', 'Disease', (470, 476))	('colon cancer', 'Disease', 'MESH:D015179', (227, 239))	('cancer', 'Disease', (41, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('cancers', 'Phenotype', 'HP:0002664', (470, 477))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (127, 157))	('cancer', 'Phenotype', 'HP:0002664', (470, 476))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (453, 477))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (76, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('colon cancer', 'Disease', (227, 239))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (250, 275))	('cancer', 'Disease', 'MESH:D009369', (470, 476))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (4, 13))	('gastrointestinal cancers', 'Disease', (453, 477))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (250, 275))	('liver hepatocellular carcinoma', 'Disease', (127, 157))	('lung adenocarcinoma', 'Disease', (55, 74))	('esophageal adenocarcinoma', 'Disease', (250, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('cancer', 'Disease', (233, 239))	('TGF-beta', 'Gene', '7039', (419, 427))	('mutational', 'Var', (197, 207))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('colon cancer', 'Phenotype', 'HP:0003003', (227, 239))
791500	31078526	Six out of 48 mutations in this insulator are located within the regions bound by CTCF (SNV4, 5, 19, 20, and 21 in Figure S12E), while 39 out of 48 mutations occur at the ChIP-seq peaks of other TFs.	('CTCF', 'Gene', '10664', (82, 86))	('S12E', 'Mutation', 'p.S12E', (122, 126))	('CTCF', 'Gene', (82, 86))	('mutations', 'Var', (14, 23))
791506	31078526	Many SNVs, including recurrent mutations (SNV8, 9, 11, 12, 14 and 18) are located at an YY1 ChIP-seq peak.	('mutations', 'Var', (31, 40))	('YY1', 'Gene', (88, 91))	('YY1', 'Gene', '7528', (88, 91))
791507	31078526	We find that the region spanned by SNV8 to SNV21 bound by many TFs also shows the highest mutational density in other cancer types aside from melanoma (Figure S12B).	('cancer', 'Disease', (118, 124))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('S12B', 'Var', (159, 163))	('TFs', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutational density', 'MPA', (90, 108))	('S12B', 'SUBSTITUTION', 'None', (159, 163))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
791512	31078526	We found increased proliferation in the SNV-edited melanoma cells : 139.8% +/- 7.3 for SNV4 and 149.8% +/- 1.7 for SNV8 : when compared to cells transduced with non-targeting guides (Figure 3D), suggesting that mutations in these regions confer a growth advantage in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanoma', 'Disease', (267, 275))	('mutations', 'Var', (211, 220))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('growth advantage', 'CPA', (247, 263))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
791513	31078526	This study presents a comprehensive analysis of CTCF/cohesin insulator mutations from WGS of 1,962 patients in 21 cancer types.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('CTCF', 'Gene', (48, 52))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('CTCF', 'Gene', '10664', (48, 52))	('cancer', 'Disease', (114, 120))
791514	31078526	We find that background mutational processes in different cancers lead to differential enrichment of mutations predicted to disrupt CTCF motifs; the majority of which are likely to be passengers.	('mutations', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('CTCF', 'Gene', (132, 136))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('CTCF', 'Gene', '10664', (132, 136))	('cancers', 'Disease', (58, 65))
791515	31078526	Using the predicted functional impact of mutations, their frequency and the patterns of CTCF motif-disruption, we developed a computational approach (CNCDriver) to identify insulator regions under positive selection.	('mutations', 'Var', (41, 50))	('CTCF', 'Gene', (88, 92))	('CTCF', 'Gene', '10664', (88, 92))
791517	31078526	Mutations in one of these 21 candidates are associated with differential gene expression that may play a role in tumorigenesis by interfering with the TGF-beta pathway in melanoma and other cancers, especially gastrointestinal.	('tumor', 'Disease', (113, 118))	('TGF-beta', 'Gene', (151, 159))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('TGF-beta', 'Gene', '7039', (151, 159))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('gastrointestinal', 'Disease', (210, 226))	('interfering', 'NegReg', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
791518	31078526	Our hypothesis is supported by functional validation using CRISPR-Cas9 which shows that two of the most frequent mutations increase cell growth by 1.4- and 1.5-fold in melanoma cells.	('cell growth', 'CPA', (132, 143))	('increase', 'PosReg', (123, 131))	('mutations', 'Var', (113, 122))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
791520	31078526	Thus, our study reveals several CTCF insulators as putative drivers and opens the door to multiple experimental validation and mechanistic studies of the tumorigenic impact of mutations in these elements.	('mutations', 'Var', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CTCF', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CTCF', 'Gene', '10664', (32, 36))	('tumor', 'Disease', (154, 159))
791525	31078526	Finally, while we analyzed the impact of SNVs in insulators, CTCF-CTCF loops may also be perturbed by DNA methylation, small insertions or deletions, and structural variations at insulators.	('structural variations', 'Var', (154, 175))	('CTCF-CTCF', 'Gene', '10664', (61, 70))	('perturbed', 'Reg', (89, 98))	('insertions', 'Var', (125, 135))	('CTCF-CTCF', 'Gene', (61, 70))	('DNA methylation', 'Var', (102, 117))	('deletions', 'Var', (139, 148))
791554	31078526	We first define the orientation of CTCF motif (MA0139.1) from the JASPAR 2018 CORE vertebrate (MA0139.1) as CTCF forward direction and the reverse-complement model as CTCF reverse direction (Figure S2A).	('MA0139.1', 'Var', (47, 55))	('CTCF', 'Gene', '10664', (167, 171))	('CTCF', 'Gene', (108, 112))	('CTCF', 'Gene', (35, 39))	('CTCF', 'Gene', '10664', (108, 112))	('CTCF', 'Gene', '10664', (35, 39))	('CTCF', 'Gene', (167, 171))
791557	31078526	Our enhancer set is obtained by the union of TF binding peaks and DHSs from ENCODE, and Segway/ChromHMM-predicted enhancers, which were defined from histone marks (H3K4me1, H3K4me2 and H3K27ac).	('DHSs', 'Disease', 'None', (66, 70))	('H3K4me1', 'Var', (164, 171))	('DHSs', 'Disease', (66, 70))	('H3K4me2', 'Var', (173, 180))
791560	31078526	For pancreatic, kidney, ovarian, colon, esophageal, and prostate, we used the average replication timing signal from HepG2, MCF-7, GM12878, K562, BJ, IMR-90 and SK-N-SH.	('K562', 'CellLine', 'CVCL:0004', (140, 144))	('GM12878', 'Var', (131, 138))	('GM12878', 'Chemical', '-', (131, 138))	('MCF-7', 'CellLine', 'CVCL:0031', (124, 129))	('pancreatic, kidney, ovarian, colon', 'Disease', 'MESH:D010051', (4, 38))	('K562', 'Var', (140, 144))	('HepG2', 'CellLine', 'CVCL:0027', (117, 122))	('BJ', 'CellLine', 'CVCL:6573', (146, 148))
791561	31078526	We used ASCAT (ASCAT version 2.4.2 ) with default parameters to identify copy number alterations, ploidy and purity for the WGS samples in the ICGC MELA-AU project.	('copy number', 'Var', (73, 84))	('ploidy', 'Disease', 'None', (98, 104))	('ploidy', 'Disease', (98, 104))
791565	31078526	A375 cell line was obtained from Dr. Joan Massague (Memorial Sloan Kettering Cancer Center) and cultured in DMEM supplemented with L-glutamine (2mmol/L), penicillin (100U/ml), streptomycin (100ug/ml) and 10% heat-inactivated FBS.	('Cancer', 'Disease', (77, 83))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('streptomycin', 'Chemical', 'MESH:D013307', (176, 188))	('100U/ml', 'Var', (166, 173))	('Cancer', 'Disease', 'MESH:D009369', (77, 83))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('DMEM', 'Chemical', '-', (108, 112))	('penicillin', 'Chemical', 'MESH:D010406', (154, 164))	('L-glutamine', 'Chemical', 'MESH:D005973', (131, 142))	('100ug/ml', 'Var', (190, 198))
791590	31078526	To assess the enrichment of CTCF and other TF motif-disruption events within a specific cancer type, we performed a binomial test to compare the fraction of disrupted TF motifs to the corresponding proportion of the TF motifs abundance.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('CTCF', 'Gene', (28, 32))	('motifs', 'Var', (170, 176))	('CTCF', 'Gene', '10664', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
791591	31078526	To decipher the signatures of mutational processes operative in the TF binding site regions, we used the FunSeq2 annotation of the SNVs that disrupt TF motifs and computed their normalized tri-nucleotide distributions, which determined the motif-disruption signature for each TF for each cancer type (frequency of 96 mutation types equivalent to the six substitution changes and their immediate 5' and 3' sequence context).	('substitution changes', 'Var', (354, 374))	('tri-nucleotide', 'Chemical', '-', (189, 203))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
791594	31078526	In fact, liver cancers harbor five ubiquitous signatures (S1, S4, S5, S12, S16) with high mutation burden as has also been reported in Letouze et al..	('S1', 'Var', (58, 60))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('S16', 'Gene', (75, 78))	('liver cancer', 'Phenotype', 'HP:0002896', (9, 21))	('S16', 'Gene', '6217', (75, 78))	('liver cancers', 'Phenotype', 'HP:0002896', (9, 22))	('S12', 'Gene', (70, 73))	('liver cancers', 'Disease', 'MESH:D006528', (9, 22))	('S12', 'Gene', '6268', (70, 73))	('liver cancers', 'Disease', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
791595	31078526	In order to compute the rate of mutations predicted to cause CTCF motif-disruption within insulator regions, we considered the CTCF motif annotations from FunSeq2 within the flanking stretches of 2,500 nucleotides on both sides of the insulator mid-point.	('CTCF', 'Gene', '10664', (127, 131))	('CTCF', 'Gene', '10664', (61, 65))	('mutations', 'Var', (32, 41))	('CTCF', 'Gene', (127, 131))	('CTCF', 'Gene', (61, 65))
791596	31078526	The mutations that fall into CTCF binding sites were split into motif-disrupting or non-disrupting groups and overlapped with the insulator regions (5 kb windows).	('mutations', 'Var', (4, 13))	('fall', 'Phenotype', 'HP:0002527', (19, 23))	('CTCF', 'Gene', (29, 33))	('CTCF', 'Gene', '10664', (29, 33))
791598	31078526	The CTCF motif-disruption mutation rate of each randomly generated set of changes was computed as explained above and this procedure was repeated 100 times.	('CTCF', 'Gene', (4, 8))	('CTCF', 'Gene', '10664', (4, 8))	('changes', 'Var', (74, 81))
791599	31078526	Finally, the estimate of the expected rate of mutations predicted to cause CTCF motif-disruption was computed as the mean random mutation rate of every position within the windows of insulator regions.	('cause', 'Reg', (69, 74))	('mutations', 'Var', (46, 55))	('CTCF', 'Gene', (75, 79))	('CTCF', 'Gene', '10664', (75, 79))
791601	31078526	The same steps were used for mutations that are not predicted to disrupt CTCF motifs.	('CTCF', 'Gene', '10664', (73, 77))	('mutations', 'Var', (29, 38))	('CTCF', 'Gene', (73, 77))
791602	31078526	The clustering of mutations has been suggested to indicate signal of positive selection in cancer.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (18, 27))
791604	31078526	To identify significantly mutated elements (CDS, promoters, enhancers, lincRNAs and CTCF insulators), we developed CNCDriver (Cornell Non-Coding Driver), which combines mutational recurrence and functional impact of variants to discern signals of positive selection.	('CTCF', 'Gene', (84, 88))	('CTCF', 'Gene', '10664', (84, 88))	('variants', 'Var', (216, 224))
791606	31078526	DHSs, histone modification marks, sensitive, ultra-sensitive, conserved, and highly occupied by transcription factor (HOT) regions) and the predicted impact of variants on TF binding.	('histone', 'MPA', (6, 13))	('binding', 'Interaction', (175, 182))	('DHSs', 'Disease', (0, 4))	('variants', 'Var', (160, 168))	('DHSs', 'Disease', 'None', (0, 4))
791607	31078526	While for promoters and enhancers, a variant's impact on TF binding is assessed for all TF motifs (549 TFs from ENCODE), only motifs for CTCF were used for variants in CTCF insulators.	('CTCF', 'Gene', (168, 172))	('CTCF', 'Gene', '10664', (137, 141))	('CTCF', 'Gene', '10664', (168, 172))	('variant', 'Var', (37, 44))	('CTCF', 'Gene', (137, 141))
791608	31078526	The probability of drawing a mutation is determined by its tri-nucleotide sequence probability across all samples in a given cancer type.	('mutation', 'Var', (29, 37))	('tri-nucleotide', 'Chemical', '-', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
791612	31078526	For CTCF insulators, we also keep the same ratio of mutations predicted to disrupt CTCF motif or not during null background model generation.	('mutations', 'Var', (52, 61))	('CTCF', 'Gene', (4, 8))	('CTCF', 'Gene', (83, 87))	('CTCF', 'Gene', '10664', (4, 8))	('CTCF', 'Gene', '10664', (83, 87))
791615	31078526	noted that signature 9, which is observed in lymphoma, does not exhibit the mutational pattern of AID likely because the AID signal is obscured by mutations caused by the error-prone polymerase eta.	('lymphoma', 'Disease', 'MESH:D008223', (45, 53))	('mutations', 'Var', (147, 156))	('lymphoma', 'Phenotype', 'HP:0002665', (45, 53))	('lymphoma', 'Disease', (45, 53))
791616	31078526	to calculate enrichment of AID signature mutations in candidate elements,  where mutationsmotif is the number of mutations in the AID motif, mutationsC is the number of mutated cytosines, contextC is the total number of cytosines, and contextmotif is the total number of occurrences of the AID motif.	('mutations', 'Var', (41, 50))	('mutationsC', 'Var', (141, 151))	('cytosine', 'Chemical', 'MESH:D003596', (177, 185))	('mutationsmotif', 'Var', (81, 95))	('cytosine', 'Chemical', 'MESH:D003596', (220, 228))
791620	31078526	For a given mutation with alternative read counts (a), reference read counts (r) and total read depth (r + a), the probability of a given CCFi can be estimated from binomial distribution,   Then, for a given mutation with VAFobs, we computed the distribution of posterior probability P(CCFi) over 100 grid points of CCFi uniformly spanned between 0.01 to 1.	('CCF', 'Disease', (316, 319))	('CCF', 'Disease', 'MESH:D003025', (138, 141))	('CCF', 'Disease', (138, 141))	('CCF', 'Disease', 'MESH:D003025', (286, 289))	('CCF', 'Disease', (286, 289))	('VAFobs', 'Chemical', '-', (222, 228))	('mutation', 'Var', (12, 20))	('CCF', 'Disease', 'MESH:D003025', (316, 319))
791622	31078526	Mutations were classified as clonal if the maximum probability of CCFi is in the top quartile of cancer cell fraction (max(P(CCFi))>=0.75); otherwise mutations were classified as subclonal.	('cancer', 'Disease', (97, 103))	('CCF', 'Disease', 'MESH:D003025', (66, 69))	('CCF', 'Disease', (125, 128))	('CCF', 'Disease', 'MESH:D003025', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Mutations', 'Var', (0, 9))	('CCF', 'Disease', (66, 69))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
791627	31078526	In this study, 293 out of 462 mutations (63%) in the 21 insulators identified to be significantly mutated locate within CTCF ChIP-seq peaks.	('CTCF', 'Gene', '10664', (120, 124))	('mutations', 'Var', (30, 39))	('CTCF', 'Gene', (120, 124))
791628	31078526	Although we did not find CTCF M2 motif matched by FIMO (P value: 10-4) upstream of the core motif, 12 mutations are within the window that would bind other domains (ZF9-ZF11) (Supplementary Table S15).	('CTCF', 'Gene', (25, 29))	('S15', 'Gene', '6209', (196, 199))	('ZF9', 'Gene', '1316', (165, 168))	('CTCF', 'Gene', '10664', (25, 29))	('mutations', 'Var', (102, 111))	('ZF9', 'Gene', (165, 168))	('S15', 'Gene', (196, 199))
791629	31078526	Additionally, our major insulator candidate in melanoma has three mutated positions within the CTCF motif (SNV4, chr19:41,768,332 mutated in two patients; SNV10, chr19:41,768,799 in one patient and SNV11, chr19:41,769,800 in two patients, Figure S12E).	('patients', 'Species', '9606', (145, 153))	('patients', 'Species', '9606', (229, 237))	('SNV11', 'Var', (198, 203))	('CTCF', 'Gene', '10664', (95, 99))	('SNV10', 'Var', (155, 160))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('patient', 'Species', '9606', (145, 152))	('melanoma', 'Disease', (47, 55))	('mutated', 'Var', (130, 137))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('patient', 'Species', '9606', (186, 193))	('patient', 'Species', '9606', (229, 236))	('S12E', 'Mutation', 'p.S12E', (246, 250))	('CTCF', 'Gene', (95, 99))
791642	31078526	The Wilcoxon rank-sum test was used to test the significance of the differential gene expression between tumor samples with insulator mutations vs. those without.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('insulator', 'Gene', (124, 133))	('mutations', 'Var', (134, 143))	('tumor', 'Disease', (105, 110))
791644	31078526	We have also compared the expression of genes in tumor samples with insulator mutations versus normal samples, though we note that in melanoma, there is only one normal sample with RNA-seq data available.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))
791648	31078526	We were able to detect significant difference in gene expression when there were 12 samples with mutations vs. 68 samples without mutations for ~2-fold change (CYP2S1) and ~3-fold change (TGFB1) in melanoma.	('TGFB1', 'Gene', '7040', (188, 193))	('mutations', 'Var', (97, 106))	('CYP2S1', 'Gene', (160, 166))	('TGFB1', 'Gene', (188, 193))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('CYP2S1', 'Gene', '29785', (160, 166))
791650	31078526	Thus, given a mutation frequency is 3% and assuming a minimum number of mutated samples needed with matched WGS and RNA-seq data is 10, we will likely need ~300 samples with matched RNA-seq and WGS data to detect meaningful gene expression association in other cancer types with similar fold differences as observed for CYP2S1 and TGFB1.	('CYP2S1', 'Gene', '29785', (320, 326))	('TGFB1', 'Gene', '7040', (331, 336))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('TGFB1', 'Gene', (331, 336))	('mutation', 'Var', (14, 22))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('CYP2S1', 'Gene', (320, 326))
791652	31078526	Enrichment of CTCF motif-disrupting mutations is associated with neutral signatures Novel computational method predicts 21 insulator drivers A predicted driver on chr19 is associated with TGFB1 up-regulation CTCF ChIP-seq, 3C and CRISPR-Cas9 support the computational predictions	('TGFB1', 'Gene', '7040', (188, 193))	('CTCF', 'Gene', (14, 18))	('TGFB1', 'Gene', (188, 193))	('mutations', 'Var', (36, 45))	('up-regulation', 'PosReg', (194, 207))	('CTCF', 'Gene', '10664', (14, 18))	('CTCF', 'Gene', (208, 212))	('CTCF', 'Gene', '10664', (208, 212))
791659	31661124	In addition, the proliferation, cell cycle distribution and apoptosis of A549 and H1299 cells were determined by MTT assay and flow cytometry, respectively, following cell transfection to induce overexpression and knockdown of RFC3.	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('RFC3', 'Gene', '5983', (227, 231))	('cell cycle distribution', 'CPA', (32, 55))	('knockdown', 'Var', (214, 223))	('overexpression', 'PosReg', (195, 209))	('apoptosis', 'CPA', (60, 69))	('RFC3', 'Gene', (227, 231))	('MTT', 'Chemical', 'MESH:C022616', (113, 116))	('H1299', 'CellLine', 'CVCL:0060', (82, 87))
791663	31661124	Furthermore, overexpression of RFC3 increased the invasion and migration of A549 cells, whereas knockdown of RFC3 significantly reduced the invasion and migration of H1299 cells.	('knockdown', 'Var', (96, 105))	('invasion', 'CPA', (50, 58))	('H1299', 'CellLine', 'CVCL:0060', (166, 171))	('reduced', 'NegReg', (128, 135))	('RFC3', 'Gene', '5983', (31, 35))	('RFC3', 'Gene', (31, 35))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('increased', 'PosReg', (36, 45))	('overexpression', 'PosReg', (13, 27))	('RFC3', 'Gene', '5983', (109, 113))	('RFC3', 'Gene', (109, 113))
791669	31661124	Although targeted drugs can be used in some cases to treat patients with mutations in genes such as epidermal growth factor receptor and anaplastic lymphoma kinase, the proportion of such patients is limited and drug resistance limits the long-term efficacy of targeted therapy.	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('drug resistance', 'Phenotype', 'HP:0020174', (212, 227))	('epidermal growth factor receptor', 'Gene', (100, 132))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (137, 156))	('patients', 'Species', '9606', (188, 196))	('mutations', 'Var', (73, 82))	('lymphoma', 'Disease', (148, 156))	('patients', 'Species', '9606', (59, 67))	('lymphoma', 'Disease', 'MESH:D008223', (148, 156))
791672	31661124	It was been reported that overactivation of beta-catenin in the pulmonary epithelium of genetically engineered mice could induce epithelial differentiation defects, promoting cell multiplication, basal cell amplification and lung tumorigenesis.	('tumor', 'Disease', (230, 235))	('basal cell amplification', 'CPA', (196, 220))	('cell multiplication', 'CPA', (175, 194))	('beta-catenin', 'Protein', (44, 56))	('mice', 'Species', '10090', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('overactivation', 'Var', (26, 40))	('epithelial differentiation defects', 'CPA', (129, 163))	('induce', 'Reg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('promoting', 'PosReg', (165, 174))
791676	31661124	Mutations in beta-catenin or adenomatous polyposis coli, which represent the most universal mechanisms underlying abnormal activation of the Wnt/beta-catenin pathway, are infrequent in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (29, 55))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (185, 190))	('beta-catenin', 'Protein', (13, 25))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (29, 55))	('adenomatous polyposis coli', 'Disease', (29, 55))	('NSCLC', 'Disease', (185, 190))
791709	31661124	Receiver operating characteristic curve analysis was performed to determine the cut-off scores for low or high RFC3 expression.	('expression', 'MPA', (116, 126))	('low', 'NegReg', (99, 102))	('high', 'Var', (106, 110))	('RFC3', 'Gene', '5983', (111, 115))	('RFC3', 'Gene', (111, 115))
791752	31661124	Kaplan-Meier analysis indicated that high RFC3 expression could lead to a poor prognosis in cases of lung adenocarcinoma; similar results were determined in analysis of disease-free survival (Fig.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (101, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('high', 'Var', (37, 41))	('RFC3', 'Gene', '5983', (42, 46))	('RFC3', 'Gene', (42, 46))	('lung adenocarcinoma', 'Disease', (101, 120))	('expression', 'MPA', (47, 57))
791761	31661124	In addition, a RFC3 siRNA was transfected into the H1299 cell line to knock down RFC3.	('knock down', 'Var', (70, 80))	('H1299', 'CellLine', 'CVCL:0060', (51, 56))	('RFC3', 'Gene', '5983', (15, 19))	('RFC3', 'Gene', (15, 19))	('RFC3', 'Gene', '5983', (81, 85))	('RFC3', 'Gene', (81, 85))
791762	31661124	S1, the proliferative ability of H1299 and A549 cells was not significantly affected by overexpression or knockdown of RFC3 compared with in the control groups (P>0.05).	('H1299', 'CellLine', 'CVCL:0060', (33, 38))	('knockdown', 'Var', (106, 115))	('proliferative ability', 'CPA', (8, 29))	('A549', 'CellLine', 'CVCL:0023', (43, 47))	('RFC3', 'Gene', '5983', (119, 123))	('RFC3', 'Gene', (119, 123))
791764	31661124	The proportion of H1299 cells in G0/G1 stage was increased when RFC3 was knocked down, whereas the proportion of S stage cells was decreased, indicating that more cells were arrested at G0/G1 stage after RFC3 was knocked down (P<0.05; Fig.	('arrest', 'Disease', (174, 180))	('increased', 'PosReg', (49, 58))	('knocked down', 'Var', (213, 225))	('RFC3', 'Gene', '5983', (204, 208))	('RFC3', 'Gene', (204, 208))	('knocked down', 'Var', (73, 85))	('H1299', 'Var', (18, 23))	('arrest', 'Disease', 'MESH:D006323', (174, 180))	('RFC3', 'Gene', '5983', (64, 68))	('RFC3', 'Gene', (64, 68))	('H1299', 'CellLine', 'CVCL:0060', (18, 23))
791766	31661124	In addition, more apoptotic cells were detected in the H1299 cell line when RFC3 was knocked down in comparison with the control group (P<0.01; Fig.	('H1299', 'CellLine', 'CVCL:0060', (55, 60))	('knocked down', 'Var', (85, 97))	('RFC3', 'Gene', '5983', (76, 80))	('RFC3', 'Gene', (76, 80))	('apoptotic cells', 'CPA', (18, 33))
791768	31661124	Conversely, when erlotinib was added to the H1299 cell line to induce apoptosis, more apoptotic cells were detected in the H1299 cell line when RFC3 was knocked down in comparison with the control group (P<0.05; Fig.	('erlotinib', 'Chemical', 'MESH:C400278', (17, 26))	('RFC3', 'Gene', (144, 148))	('RFC3', 'Gene', '5983', (144, 148))	('H1299', 'CellLine', 'CVCL:0060', (44, 49))	('H1299', 'CellLine', 'CVCL:0060', (123, 128))	('knocked down', 'Var', (153, 165))
791771	31661124	Conversely, after the knockdown of RFC3, the opposite result was observed in H1299 cells (P<0.05; Fig.	('knockdown', 'Var', (22, 31))	('H1299', 'CellLine', 'CVCL:0060', (77, 82))	('RFC3', 'Gene', '5983', (35, 39))	('RFC3', 'Gene', (35, 39))
791774	31661124	However, following RFC3 knockdown in H1299 cells, the expression levels of Wnt1, N-cadherin, beta-catenin, Vimentin, c-MYC and the ratio of p-GSK3-beta (Ser9)/GSK3-beta were decreased, whereas E-cadherin expression was increased.	('expression levels', 'MPA', (54, 71))	('increased', 'PosReg', (219, 228))	('Ser9', 'Chemical', 'MESH:C530429', (153, 157))	('beta-catenin', 'MPA', (93, 105))	('H1299', 'CellLine', 'CVCL:0060', (37, 42))	('RFC3', 'Gene', '5983', (19, 23))	('Wnt1', 'Gene', '7471', (75, 79))	('N-cadherin', 'Gene', (81, 91))	('decreased', 'NegReg', (174, 183))	('GSK3-beta', 'Gene', (142, 151))	('N-cadherin', 'Gene', '1000', (81, 91))	('E-cadherin', 'Gene', (193, 203))	('GSK3-beta', 'Gene', (159, 168))	('Vimentin', 'Gene', '7431', (107, 115))	('E-cadherin', 'Gene', '999', (193, 203))	('c-MYC', 'Gene', '4609', (117, 122))	('RFC3', 'Gene', (19, 23))	('expression', 'MPA', (204, 214))	('knockdown', 'Var', (24, 33))	('GSK3-beta', 'Gene', '2932', (142, 151))	('GSK3-beta', 'Gene', '2932', (159, 168))	('c-MYC', 'Gene', (117, 122))	('Wnt1', 'Gene', (75, 79))	('Vimentin', 'Gene', (107, 115))
791779	31661124	However, it has also been reported that RFC3 mutations in gastric and colorectal cancer result in downregulation of expression or loss of function.	('gastric', 'Disease', (58, 65))	('expression', 'MPA', (116, 126))	('mutations', 'Var', (45, 54))	('loss of function', 'NegReg', (130, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('downregulation', 'NegReg', (98, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('colorectal cancer', 'Disease', (70, 87))	('RFC3', 'Gene', (40, 44))	('RFC3', 'Gene', '5983', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
791794	31661124	Previous studies have observed changes in cell biological behavior after knocking down RFC3.	('RFC3', 'Gene', '5983', (87, 91))	('knocking down', 'Var', (73, 86))	('RFC3', 'Gene', (87, 91))	('cell biological behavior', 'CPA', (42, 66))	('changes', 'Reg', (31, 38))
791796	31661124	The proliferative abilities of A549 and H1299 cells were not significantly affected by overexpression or knockdown of RFC3 compared with in the control groups.	('A549', 'CellLine', 'CVCL:0023', (31, 35))	('proliferative abilities', 'CPA', (4, 27))	('knockdown', 'Var', (105, 114))	('RFC3', 'Gene', '5983', (118, 122))	('RFC3', 'Gene', (118, 122))	('H1299', 'CellLine', 'CVCL:0060', (40, 45))
791798	31661124	However, previous studies have reported that the proliferation curve is significantly decreased when RFC3 is knocked down in the following cell lines: Liver cancer SMMC-7721, ovarian cancer OVCAR-3, breast cancer MDA-MB-231 and MDA-MB-468, and esophageal cancer, OE33 and OE19.	('esophageal cancer', 'Disease', (244, 261))	('breast cancer', 'Disease', 'MESH:D001943', (199, 212))	('RFC3', 'Gene', '5983', (101, 105))	('breast cancer', 'Disease', (199, 212))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (228, 238))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('ovarian cancer', 'Disease', 'MESH:D010051', (175, 189))	('Liver cancer', 'Disease', (151, 163))	('Liver cancer', 'Disease', 'MESH:D006528', (151, 163))	('RFC3', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('Liver cancer', 'Phenotype', 'HP:0002896', (151, 163))	('decreased', 'NegReg', (86, 95))	('ovarian cancer', 'Disease', (175, 189))	('proliferation curve', 'CPA', (49, 68))	('knocked down', 'Var', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (213, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (175, 189))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))
791802	31661124	Notably, hepatocellular and ovarian cancer cell lines were arrested in S phase after RFC3 knockdown.	('RFC3', 'Gene', '5983', (85, 89))	('RFC3', 'Gene', (85, 89))	('hepatocellular and ovarian cancer', 'Disease', 'MESH:D010051', (9, 42))	('ovarian cancer', 'Phenotype', 'HP:0100615', (28, 42))	('knockdown', 'Var', (90, 99))	('arrest', 'Disease', (59, 65))	('S phase', 'CPA', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('arrest', 'Disease', 'MESH:D006323', (59, 65))
791803	31661124	Changes in some cell cycle regulatory proteins have been detected after RFC3 knockdown in hepatocellular carcinoma cell lines, which explains why the hepatocellular carcinoma cell cycle was arrested in S stage after RFC3 knockdown in this previous study.	('RFC3', 'Gene', '5983', (216, 220))	('RFC3', 'Gene', (216, 220))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('cell', 'MPA', (16, 20))	('arrest', 'Disease', 'MESH:D006323', (190, 196))	('hepatocellular carcinoma', 'Disease', (90, 114))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('knockdown', 'Var', (77, 86))	('RFC3', 'Gene', '5983', (72, 76))	('RFC3', 'Gene', (72, 76))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (150, 174))	('arrest', 'Disease', (190, 196))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (150, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('hepatocellular carcinoma', 'Disease', (150, 174))	('Changes', 'Reg', (0, 7))
791804	31661124	The present study demonstrated that upregulation of RFC3 or knockdown of RFC3 could result in corresponding changes in the downstream protein c-MYC in the Wnt/beta-catenin pathway.	('RFC3', 'Gene', '5983', (73, 77))	('c-MYC', 'Gene', (142, 147))	('RFC3', 'Gene', '5983', (52, 56))	('RFC3', 'Gene', (52, 56))	('upregulation', 'PosReg', (36, 48))	('RFC3', 'Gene', (73, 77))	('c-MYC', 'Gene', '4609', (142, 147))	('knockdown', 'Var', (60, 69))	('changes', 'Reg', (108, 115))	('Wnt/beta-catenin pathway', 'Pathway', (155, 179))
791806	31661124	Unlike the effects on hepatocellular carcinoma cells, in this study, the effects of RFC3 on the cell cycle progression of lung adenocarcinoma resulted in G1-S progression, not S-G2 progression.	('effects', 'Var', (73, 80))	('RFC3', 'Gene', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cell cycle progression', 'CPA', (96, 118))	('G1-S progression', 'CPA', (154, 170))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (22, 46))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (22, 46))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (122, 141))	('hepatocellular carcinoma', 'Disease', (22, 46))	('RFC3', 'Gene', '5983', (84, 88))	('resulted in', 'Reg', (142, 153))	('lung adenocarcinoma', 'Disease', (122, 141))
791810	31661124	Whether or not erlotinib was added to H1299 cells to induce apoptosis, knockdown of RFC3 resulted in a significant increase in apoptosis.	('knockdown', 'Var', (71, 80))	('increase', 'PosReg', (115, 123))	('apoptosis', 'CPA', (127, 136))	('erlotinib', 'Chemical', 'MESH:C400278', (15, 24))	('RFC3', 'Gene', '5983', (84, 88))	('RFC3', 'Gene', (84, 88))	('H1299', 'CellLine', 'CVCL:0060', (38, 43))
791817	31661124	When RFC3 was knocked down, the aforementioned effects of RFC3 overexpression were reversed.	('RFC3', 'Gene', '5983', (58, 62))	('RFC3', 'Gene', (58, 62))	('knocked down', 'Var', (14, 26))	('RFC3', 'Gene', '5983', (5, 9))	('RFC3', 'Gene', (5, 9))
791840	31218209	First, we found that pristimerin can induce apoptosis in esophageal cancer in vivo and in vitro.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('pristimerin', 'Chemical', 'MESH:C009043', (21, 32))	('apoptosis', 'CPA', (44, 53))	('pristimerin', 'Var', (21, 32))	('esophageal cancer', 'Disease', (57, 74))	('induce', 'PosReg', (37, 43))
791854	31218209	It has been previously reported that pristimerin inhibits lipopolysaccharide-induced production of inflammatory mediators in murine macrophages via downregulation of nuclear factor- (NF-) kappaB and mitogen-activated protein kinase signal pathways.	('mitogen-activated protein kinase signal pathways', 'Pathway', (199, 247))	('pristimerin', 'Var', (37, 48))	('inhibits', 'NegReg', (49, 57))	('nuclear factor- (NF-) kappaB', 'Gene', '18033', (166, 194))	('pristimerin', 'Chemical', 'MESH:C009043', (37, 48))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (58, 76))	('nuclear factor- (NF-) kappaB', 'Gene', (166, 194))	('murine', 'Species', '10090', (125, 131))	('production of inflammatory mediators', 'MPA', (85, 121))	('downregulation', 'NegReg', (148, 162))
791855	31218209	In this study, we found that pristimerin reduced proliferation and growth and induced cell cycle arrest and apoptosis in Eca109 esophageal cancer cells.	('reduced', 'NegReg', (41, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('esophageal cancer', 'Disease', (128, 145))	('induced', 'Reg', (78, 85))	('proliferation', 'CPA', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cell cycle arrest', 'CPA', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('growth', 'CPA', (67, 73))	('pristimerin', 'Chemical', 'MESH:C009043', (29, 40))	('apoptosis', 'CPA', (108, 117))	('pristimerin', 'Var', (29, 40))
791875	31218209	We found that Bcl-2 was downregulated, whereas caspase-3, caspase-9, and Bax were upregulated by pristimerin in a dose-dependent manner (Figure 1(d)).	('Bcl-2', 'Gene', (14, 19))	('Bax', 'Gene', (73, 76))	('Bcl-2', 'Gene', '596', (14, 19))	('downregulated', 'NegReg', (24, 37))	('upregulated', 'PosReg', (82, 93))	('caspase-9', 'Gene', '842', (58, 67))	('Bax', 'Gene', '581', (73, 76))	('caspase-3', 'Gene', (47, 56))	('pristimerin', 'Var', (97, 108))	('pristimerin', 'Chemical', 'MESH:C009043', (97, 108))	('caspase-3', 'Gene', '836', (47, 56))	('caspase-9', 'Gene', (58, 67))
791883	31218209	As shown in Figure 2, pristimerin led to the accumulation of cells in the G0/G1 phase and a corresponding decrease in G2/M and S phases in both Eca109 (Figure 2(a)) and Ec9706 (Figure 2(b)) cells.	('Ec9706', 'CellLine', 'CVCL:E307', (169, 175))	('accumulation', 'PosReg', (45, 57))	('decrease', 'NegReg', (106, 114))	('cells in', 'CPA', (61, 69))	('pristimerin', 'Var', (22, 33))	('pristimerin', 'Chemical', 'MESH:C009043', (22, 33))
791892	31218209	In the present study, we initially demonstrated that pristimerin induced apoptosis, cell cycle arrest, and autophagy both in vitro and in vivo in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('autophagy', 'CPA', (107, 116))	('esophageal cancer', 'Disease', (146, 163))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('apoptosis', 'CPA', (73, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('pristimerin', 'Chemical', 'MESH:C009043', (53, 64))	('cell cycle arrest', 'CPA', (84, 101))	('pristimerin', 'Var', (53, 64))
791896	31218209	We found that DHA could induce apoptosis, cell cycle arrest, and autophagy in esophageal cancer cells.	('autophagy', 'CPA', (65, 74))	('cell cycle arrest', 'CPA', (42, 59))	('induce', 'PosReg', (24, 30))	('DHA', 'Var', (14, 17))	('apoptosis', 'CPA', (31, 40))	('esophageal cancer', 'Disease', (78, 95))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (42, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('DHA', 'Chemical', 'MESH:C039060', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
791907	31218209	As previously reported, pristimerin significantly induces esophageal cancer cell death through the NF-kappaB pathway.	('NF-kappaB', 'Gene', '4790', (99, 108))	('esophageal cancer cell death', 'Disease', 'MESH:D004938', (58, 86))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('pristimerin', 'Var', (24, 35))	('pristimerin', 'Chemical', 'MESH:C009043', (24, 35))	('NF-kappaB', 'Gene', (99, 108))	('esophageal cancer cell death', 'Disease', (58, 86))	('induces', 'PosReg', (50, 57))
791908	31218209	In contrast, in the present study, we observed a significant decrease in the level of Bcl-2 accompanied by increased levels of Bax, caspase-3, and caspase-9, indicating that pristimerin is able to trigger intrinsic apoptosis thereby inducing esophageal cancer cell death.	('esophageal cancer cell death', 'Disease', (242, 270))	('pristimerin', 'Chemical', 'MESH:C009043', (174, 185))	('Bax', 'Gene', '581', (127, 130))	('decrease', 'NegReg', (61, 69))	('pristimerin', 'Var', (174, 185))	('caspase-3', 'Gene', (132, 141))	('intrinsic apoptosis', 'CPA', (205, 224))	('increased', 'PosReg', (107, 116))	('Bcl-2', 'Gene', (86, 91))	('Bcl-2', 'Gene', '596', (86, 91))	('caspase-9', 'Gene', '842', (147, 156))	('Bax', 'Gene', (127, 130))	('esophageal cancer cell death', 'Disease', 'MESH:D004938', (242, 270))	('caspase-3', 'Gene', '836', (132, 141))	('inducing', 'PosReg', (233, 241))	('caspase-9', 'Gene', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('levels', 'MPA', (117, 123))
791909	31218209	Similar to our results, previous studies have also demonstrated that pristimerin induces apoptosis in various types of cancer cells, such as breast, colon, and colorectal cancers.	('breast', 'Disease', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('apoptosis', 'CPA', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('pristimerin', 'Var', (69, 80))	('cancer', 'Disease', (171, 177))	('pristimerin', 'Chemical', 'MESH:C009043', (69, 80))	('cancer', 'Disease', (119, 125))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('colon', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('colorectal cancers', 'Disease', 'MESH:D015179', (160, 178))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('colorectal cancers', 'Disease', (160, 178))	('induces', 'Reg', (81, 88))
791910	31218209	In addition, previous research indicated that pristimerin could induce G0/G1 phase arrest.	('pristimerin', 'Var', (46, 57))	('pristimerin', 'Chemical', 'MESH:C009043', (46, 57))	('G0/G1 phase arrest', 'CPA', (71, 89))
791912	31218209	Deregulation of cell-cycle control due to aberrant CDK activity is widespread in most cancer types.	('activity', 'MPA', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cell-cycle control', 'CPA', (16, 34))	('aberrant', 'Var', (42, 50))	('CDK', 'Protein', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
791914	31218209	In conclusion, based upon our date, we found that pristimerin could induce the downregulation of cyclin E, CDK2, and CDK4 to lead to the block of G0/G1 transition, which gave rise to cell death in esophageal cancer.	('CDK4', 'Gene', '1019', (117, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('block', 'NegReg', (137, 142))	('cyclin', 'Gene', (97, 103))	('CDK2', 'Gene', '1017', (107, 111))	('cyclin', 'Gene', '5111', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('CDK2', 'Gene', (107, 111))	('downregulation', 'NegReg', (79, 93))	('G0/G1 transition', 'CPA', (146, 162))	('esophageal cancer', 'Disease', (197, 214))	('CDK4', 'Gene', (117, 121))	('pristimerin', 'Var', (50, 61))	('pristimerin', 'Chemical', 'MESH:C009043', (50, 61))
791915	31218209	Here, our microscopy images showed the activation of autophagy, supported by the elevated accumulation of autophagosome, increased by pristimerin.	('pristimerin', 'Var', (134, 145))	('elevated accumulation of autophagosome', 'Phenotype', 'HP:0003736', (81, 119))	('autophagosome', 'CPA', (106, 119))	('autophagy', 'CPA', (53, 62))	('accumulation', 'PosReg', (90, 102))	('pristimerin', 'Chemical', 'MESH:C009043', (134, 145))
791927	31218209	Here, we showed that knockdown of CDKN1B can inhibit esophageal cancer cell growth.	('CDKN1B', 'Gene', (34, 40))	('esophageal cancer', 'Disease', (53, 70))	('CDKN1B', 'Gene', '1027', (34, 40))	('inhibit', 'NegReg', (45, 52))	('knockdown', 'Var', (21, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
791928	31218209	In conclusion, our results demonstrate that pristimerin induces apoptosis, cell cycle arrest, and autophagy in esophageal cancer cells.	('pristimerin', 'Var', (44, 55))	('pristimerin', 'Chemical', 'MESH:C009043', (44, 55))	('apoptosis', 'CPA', (64, 73))	('esophageal cancer', 'Disease', (111, 128))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (75, 92))	('induces', 'Reg', (56, 63))	('autophagy', 'CPA', (98, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cell cycle arrest', 'CPA', (75, 92))
791933	30050135	In this study, we found that the high expression of HDAC6 was associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (96, 130))	('high expression', 'Var', (33, 48))	('associated', 'Reg', (62, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('HDAC6', 'Gene', '10013', (52, 57))	('HDAC6', 'Gene', (52, 57))	('esophageal squamous cell carcinoma', 'Disease', (96, 130))
791934	30050135	Then, we identified that ACY-1215 significantly inhibited cellular proliferation in ESCC, and caused G2/M phase arrest and apoptosis.	('ACY-1215', 'Var', (25, 33))	('caused', 'Reg', (94, 100))	('apoptosis', 'CPA', (123, 132))	('G2/M phase arrest', 'CPA', (101, 118))	('inhibited', 'NegReg', (48, 57))	('cellular proliferation', 'CPA', (58, 80))	('ACY-1215', 'Chemical', 'MESH:C572255', (25, 33))
791939	30050135	Furthermore, the effects of ACY-1215 inhibited ESCC proliferation were validated in a mouse xenograft model in vivo.	('ACY-1215', 'Chemical', 'MESH:C572255', (28, 36))	('inhibited', 'NegReg', (37, 46))	('ACY-1215', 'Var', (28, 36))	('mouse', 'Species', '10090', (86, 91))	('ESCC proliferation', 'CPA', (47, 65))
791940	30050135	In conclusion, our study showed that ACY-1215 suppressed proliferation and promoted apoptosis in ESCC via miR-30d/PI3K/AKT/mTOR and ERK pathways and that ACY-1215 may be a promising antitumor agent in ESCC.	('ERK', 'Gene', (132, 135))	('tumor', 'Disease', (186, 191))	('mTOR', 'Gene', '2475', (123, 127))	('ESCC', 'Disease', (201, 205))	('miR-30d', 'Gene', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('apoptosis', 'CPA', (84, 93))	('AKT', 'Gene', '207', (119, 122))	('ACY-1215', 'Chemical', 'MESH:C572255', (37, 45))	('ACY-1215', 'Var', (37, 45))	('ESCC', 'Disease', (97, 101))	('suppressed', 'NegReg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('miR-30d', 'Gene', '407033', (106, 113))	('ACY-1215', 'Chemical', 'MESH:C572255', (154, 162))	('ACY-1215', 'Var', (154, 162))	('ERK', 'Gene', '5594', (132, 135))	('promoted', 'PosReg', (75, 83))	('proliferation', 'CPA', (57, 70))	('AKT', 'Gene', (119, 122))	('mTOR', 'Gene', (123, 127))
791952	30050135	ACY-1215 activates potent acetylation of alpha-tubulin and multiple stress-related mechanisms to induce tumor cell apoptosis.	('ACY-1215', 'Var', (0, 8))	('acetylation', 'MPA', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('activates', 'PosReg', (9, 18))	('tumor', 'Disease', (104, 109))	('induce', 'PosReg', (97, 103))	('alpha-tubulin', 'Protein', (41, 54))	('ACY-1215', 'Chemical', 'MESH:C572255', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
791953	30050135	Several clinical trials have tested the efficacy of ACY-1215 in malignancies, either as a single treatment or in combination with other agents.	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('ACY-1215', 'Chemical', 'MESH:C572255', (52, 60))	('malignancies', 'Disease', (64, 76))	('ACY-1215', 'Var', (52, 60))	('tested', 'Reg', (29, 35))
791954	30050135	A multicenter phase 1b clinical trial found that ACY-1215 is a safe and well tolerated selective HDAC6 inhibitor in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma.	('ACY-1215', 'Var', (49, 57))	('dexamethasone', 'Chemical', 'MESH:D003907', (150, 163))	('relapsed', 'Disease', (167, 175))	('multiple myeloma', 'Disease', 'MESH:D009101', (190, 206))	('HDAC6', 'Gene', '10013', (97, 102))	('multiple myeloma', 'Phenotype', 'HP:0006775', (190, 206))	('lenalidomide', 'Chemical', 'MESH:D000077269', (133, 145))	('multiple myeloma', 'Disease', (190, 206))	('HDAC6', 'Gene', (97, 102))	('ACY-1215', 'Chemical', 'MESH:C572255', (49, 57))
791956	30050135	In this study, we evaluated the efficacy and the potential mechanisms of ACY-1215 in ESCC.	('ACY-1215', 'Var', (73, 81))	('ACY-1215', 'Chemical', 'MESH:C572255', (73, 81))	('ESCC', 'Disease', (85, 89))
791958	30050135	ACY-1215 inhibited proliferation in ESCC, and caused G2/M phase arrest and apoptosis.	('inhibited', 'NegReg', (9, 18))	('ACY-1215', 'Var', (0, 8))	('apoptosis', 'CPA', (75, 84))	('caused', 'Reg', (46, 52))	('proliferation', 'CPA', (19, 32))	('ACY-1215', 'Chemical', 'MESH:C572255', (0, 8))	('G2/M phase arrest', 'CPA', (53, 70))
791960	30050135	Intriguingly, we further provided evidence that ACY-1215 triggered cell cycle arrest and apoptosis by directly affecting the miR-30d/PI3K/AKT/mTOR and ERK pathways.	('ACY-1215', 'Chemical', 'MESH:C572255', (48, 56))	('mTOR', 'Gene', (142, 146))	('mTOR', 'Gene', '2475', (142, 146))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (67, 84))	('miR-30d', 'Gene', (125, 132))	('apoptosis', 'CPA', (89, 98))	('AKT', 'Gene', (138, 141))	('ACY-1215', 'Var', (48, 56))	('ERK', 'Gene', '5594', (151, 154))	('miR-30d', 'Gene', '407033', (125, 132))	('affecting', 'Reg', (111, 120))	('cell cycle arrest', 'CPA', (67, 84))	('ERK', 'Gene', (151, 154))	('AKT', 'Gene', '207', (138, 141))
791964	30050135	The high expression of HDAC6 was associated with poor prognosis compared with low expression (p = 0.0011, Fig.	('HDAC6', 'Gene', (23, 28))	('high', 'Var', (4, 8))	('HDAC6', 'Gene', '10013', (23, 28))
791966	30050135	The MTT assay revealed that ACY-1215 inhibited cellular proliferation in a dose- and time-dependent manner (Fig.	('ACY-1215', 'Chemical', 'MESH:C572255', (28, 36))	('inhibited', 'NegReg', (37, 46))	('ACY-1215', 'Var', (28, 36))	('cellular proliferation', 'CPA', (47, 69))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))
791970	30050135	The MTT assay revealed that ACY-1215 inhibited cellular proliferation in HUVEC is significantly less than ESCC cells (Fig.	('ACY-1215', 'Chemical', 'MESH:C572255', (28, 36))	('inhibited', 'NegReg', (37, 46))	('ACY-1215', 'Var', (28, 36))	('cellular proliferation', 'CPA', (47, 69))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('less', 'NegReg', (96, 100))
791971	30050135	To clarify the mechanism of ACY-1215 in suppression of tumor cell proliferation, we examined the cell cycle progression and apoptosis in response to varying doses.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ACY-1215', 'Chemical', 'MESH:C572255', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ACY-1215', 'Var', (28, 36))	('tumor', 'Disease', (55, 60))
791977	30050135	To better understand the mechanism by which ACY-1215 caused tumor cell cycle arrest and apoptosis, western blot was carried out to explore the effect of ACY-1215 on its other targets.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('apoptosis', 'CPA', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ACY-1215', 'Chemical', 'MESH:C572255', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ACY-1215', 'Var', (44, 52))	('ACY-1215', 'Chemical', 'MESH:C572255', (44, 52))	('tumor', 'Disease', (60, 65))
791978	30050135	We demonstrated that ACY-1215 effectively reduced PI3K, P-AKT (S473), PRAS40, P-mTOR, and P-ERK1/2 protein levels and increased Rag C protein levels (Fig.	('Rag C protein', 'Gene', (128, 141))	('reduced', 'NegReg', (42, 49))	('PI3K', 'Pathway', (50, 54))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('increased', 'PosReg', (118, 127))	('Rag C protein', 'Gene', '64121', (128, 141))	('AKT', 'Gene', '207', (58, 61))	('PRAS40', 'Gene', '84335', (70, 76))	('PRAS40', 'Gene', (70, 76))	('ACY-1215', 'Chemical', 'MESH:C572255', (21, 29))	('P-ERK1/2 protein levels', 'MPA', (90, 113))	('ACY-1215', 'Var', (21, 29))	('AKT', 'Gene', (58, 61))
791979	30050135	In addition, using GSK690693 (a pan-Akt inhibitor) combined with ACY-1215 treatment the ESCC cells, we detected that co-treatment with GSK690693 could further enhance the ACY-1215-inhibited cell proliferation (Fig.	('ACY-1215', 'Chemical', 'MESH:C572255', (65, 73))	('GSK690693', 'Chemical', 'MESH:C528328', (135, 144))	('GSK690693', 'Var', (135, 144))	('GSK690693', 'Chemical', 'MESH:C528328', (19, 28))	('Akt', 'Gene', (36, 39))	('enhance', 'PosReg', (159, 166))	('ACY-1215', 'Chemical', 'MESH:C572255', (171, 179))	('Akt', 'Gene', '207', (36, 39))
791980	30050135	GSK690693 increased P-AKT due to blocking a negative feedback loop downstream of AKT (PRAS40, Rag C, and P-mTOR) (Fig.	('mTOR', 'Gene', (107, 111))	('AKT', 'Gene', '207', (22, 25))	('AKT', 'Gene', '207', (81, 84))	('mTOR', 'Gene', '2475', (107, 111))	('Rag C', 'Gene', (94, 99))	('negative feedback loop', 'MPA', (44, 66))	('PRAS40', 'Gene', '84335', (86, 92))	('GSK690693', 'Var', (0, 9))	('AKT', 'Gene', (22, 25))	('AKT', 'Gene', (81, 84))	('Rag C', 'Gene', '64121', (94, 99))	('blocking', 'NegReg', (33, 41))	('GSK690693', 'Chemical', 'MESH:C528328', (0, 9))	('PRAS40', 'Gene', (86, 92))	('increased', 'PosReg', (10, 19))
791982	30050135	We found that the levels of Ac-H3K9 and Ac-H4K8 were increased after ACY-1215 treatment (Fig.	('ACY-1215', 'Chemical', 'MESH:C572255', (69, 77))	('levels', 'MPA', (18, 24))	('increased', 'PosReg', (53, 62))	('Ac-H3K9', 'MPA', (28, 35))	('Ac-H4K8', 'Var', (40, 47))
791983	30050135	Having confirmed that ACY-1215 was correlated with epigenetic effects, we used miRNA microarray assay to investigate those miRNAs whose expression was upgraded by ACY-1215 treatment.	('expression', 'MPA', (136, 146))	('ACY-1215', 'Chemical', 'MESH:C572255', (163, 171))	('upgraded', 'PosReg', (151, 159))	('ACY-1215', 'Var', (163, 171))	('ACY-1215', 'Chemical', 'MESH:C572255', (22, 30))
791986	30050135	To validate the results, we used quantitative real-time PCR analysis to demonstrate that miR-30d was significantly overexpressed after ACY-1215 treatment, while PIK3R2 expression decreased (Fig.	('decreased', 'NegReg', (179, 188))	('miR-30d', 'Gene', '407033', (89, 96))	('expression', 'MPA', (168, 178))	('PIK3R2', 'Gene', '5296', (161, 167))	('ACY-1215', 'Chemical', 'MESH:C572255', (135, 143))	('overexpressed', 'PosReg', (115, 128))	('ACY-1215', 'Var', (135, 143))	('miR-30d', 'Gene', (89, 96))	('PIK3R2', 'Gene', (161, 167))
791990	30050135	In summary, these data validated the conclusion that ACY-1215 suppresses proliferation and promotes apoptosis in ESCC by upregulating miR-30d and inhibiting PI3K/AKT/mTOR signaling pathways.	('suppresses', 'NegReg', (62, 72))	('promotes', 'PosReg', (91, 99))	('ESCC', 'Disease', (113, 117))	('AKT', 'Gene', '207', (162, 165))	('proliferation', 'CPA', (73, 86))	('mTOR', 'Gene', (166, 170))	('mTOR', 'Gene', '2475', (166, 170))	('AKT', 'Gene', (162, 165))	('miR-30d', 'Gene', (134, 141))	('ACY-1215', 'Var', (53, 61))	('upregulating', 'PosReg', (121, 133))	('ACY-1215', 'Chemical', 'MESH:C572255', (53, 61))	('inhibiting', 'NegReg', (146, 156))	('miR-30d', 'Gene', '407033', (134, 141))	('apoptosis', 'CPA', (100, 109))
791994	30050135	These findingssuggested that ACY-1215 inhibited tumor growth in vivo.	('tumor', 'Disease', (48, 53))	('ACY-1215', 'Chemical', 'MESH:C572255', (29, 37))	('inhibited', 'NegReg', (38, 47))	('ACY-1215', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
791995	30050135	Several new observations in this study may provide important insights into the efficacy of ACY-1215 and its underlying mechanisms in ESCC.	('ESCC', 'Disease', (133, 137))	('ACY-1215', 'Var', (91, 99))	('ACY-1215', 'Chemical', 'MESH:C572255', (91, 99))
791996	30050135	First of all, we identified a relationship between HDAC6 and ESCC: the high expression of HDAC6 was associated with poor prognosis.	('high', 'Var', (71, 75))	('HDAC6', 'Gene', '10013', (90, 95))	('HDAC6', 'Gene', '10013', (51, 56))	('HDAC6', 'Gene', (51, 56))	('HDAC6', 'Gene', (90, 95))
791998	30050135	Finally, we confirmed that ACY-1215 was correlated with epigenetic modulation in ESCC.	('ACY-1215', 'Var', (27, 35))	('epigenetic modulation', 'Var', (56, 77))	('ESCC', 'Gene', (81, 85))	('correlated', 'Reg', (40, 50))	('ACY-1215', 'Chemical', 'MESH:C572255', (27, 35))
792006	30050135	ACY-1215 is a first-in-class potent and selective HDAC6 inhibitor.	('ACY-1215', 'Var', (0, 8))	('HDAC6', 'Gene', '10013', (50, 55))	('HDAC6', 'Gene', (50, 55))	('ACY-1215', 'Chemical', 'MESH:C572255', (0, 8))
792009	30050135	ACY-1215 in combination with bortezomib can induce apoptosis by activation of endoplasmic reticulum (ER) stress and unfolded protein response in two xenograft mouse models.	('unfolded protein response', 'MPA', (116, 141))	('induce', 'PosReg', (44, 50))	('ACY-1215', 'Var', (0, 8))	('mouse', 'Species', '10090', (159, 164))	('activation', 'PosReg', (64, 74))	('bortezomib', 'Chemical', 'MESH:D000069286', (29, 39))	('apoptosis', 'CPA', (51, 60))	('ACY-1215', 'Chemical', 'MESH:C572255', (0, 8))
792010	30050135	In non-Hodgkin lymphoma cells, ACY-1215 acts synergistically with carfilzomib through multiple stress-related mechanisms, causing increases in DNA damage, G2/M arrest, and inducing mitochondrial injury and apoptosis.	('M arrest', 'Disease', 'MESH:D006323', (158, 166))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (3, 23))	('mitochondrial injury', 'Disease', (181, 201))	('ACY-1215', 'Var', (31, 39))	('inducing', 'PosReg', (172, 180))	('mitochondrial injury', 'Disease', 'MESH:D028361', (181, 201))	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (7, 23))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (3, 23))	('ACY-1215', 'Chemical', 'MESH:C572255', (31, 39))	('apoptosis', 'CPA', (206, 215))	('carfilzomib', 'Chemical', 'MESH:C524865', (66, 77))	('M arrest', 'Disease', (158, 166))	('DNA damage', 'MPA', (143, 153))	('increases', 'PosReg', (130, 139))	('non-Hodgkin lymphoma', 'Disease', (3, 23))
792011	30050135	In glioblastoma, tumor cell growth is significantly inhibited by ACY-1215 through transforming growth factor beta receptor signaling, which induces SMAD2 phosphorylation and increased P21 expression.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('P21', 'Gene', '644914', (184, 187))	('induces', 'PosReg', (140, 147))	('ACY-1215', 'Var', (65, 73))	('phosphorylation', 'MPA', (154, 169))	('tumor', 'Disease', (17, 22))	('expression', 'MPA', (188, 198))	('transforming growth factor beta receptor signaling', 'MPA', (82, 132))	('ACY-1215', 'Chemical', 'MESH:C572255', (65, 73))	('P21', 'Gene', (184, 187))	('SMAD2', 'Gene', (148, 153))	('SMAD2', 'Gene', '4087', (148, 153))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('inhibited', 'NegReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('increased', 'PosReg', (174, 183))
792012	30050135	In BRAF-mutant melanoma cells, ACY-1215 sensitizes vemurafenib-induced cell proliferation inhibition and apoptosis through induction of ER stress and inactivation of ERK.	('ERK', 'Gene', '5594', (166, 169))	('ACY-1215', 'Var', (31, 39))	('inactivation', 'Var', (150, 162))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('apoptosis', 'CPA', (105, 114))	('ERK', 'Gene', (166, 169))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('vemurafenib', 'Chemical', 'MESH:D000077484', (51, 62))	('vemurafenib-induced', 'Gene', (51, 70))	('cell proliferation inhibition', 'CPA', (71, 100))	('BRAF', 'Gene', '673', (3, 7))	('BRAF', 'Gene', (3, 7))	('ACY-1215', 'Chemical', 'MESH:C572255', (31, 39))
792013	30050135	In ESCC, we demonstrated that ACY-1215 inhibited cellular proliferation by inducing G2/M arrest and apoptosis.	('ACY-1215', 'Var', (30, 38))	('M arrest', 'Disease', (87, 95))	('inhibited', 'NegReg', (39, 48))	('ACY-1215', 'Chemical', 'MESH:C572255', (30, 38))	('M arrest', 'Disease', 'MESH:D006323', (87, 95))	('inducing', 'Reg', (75, 83))	('apoptosis', 'CPA', (100, 109))	('cellular proliferation', 'CPA', (49, 71))
792015	30050135	In addition to increasing apoptosis through the commonly activated caspase pathway, we also identified that ACY-1215 increased Bax and Bim protein expression and reduced Bcl2 protein levels.	('Bcl2', 'Gene', '596', (170, 174))	('Bax', 'Gene', '581', (127, 130))	('increased', 'PosReg', (117, 126))	('ACY-1215', 'Var', (108, 116))	('ACY-1215', 'Chemical', 'MESH:C572255', (108, 116))	('reduced', 'NegReg', (162, 169))	('Bcl2', 'Gene', (170, 174))	('Bax', 'Gene', (127, 130))	('Bim', 'Gene', (135, 138))	('Bim', 'Gene', '10018', (135, 138))
792016	30050135	To better understand the mechanism by which ACY-1215 caused tumor cell cycle arrest and apoptosis, we demonstrated that ACY-1215 not only effectively inhibited phosphorylation ERK, but also inhibited PI3K/AKT/mTOR signaling pathways.	('phosphorylation', 'MPA', (160, 175))	('inhibited', 'NegReg', (190, 199))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('AKT', 'Gene', '207', (205, 208))	('ERK', 'Gene', (176, 179))	('ACY-1215', 'Chemical', 'MESH:C572255', (120, 128))	('inhibited', 'NegReg', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('AKT', 'Gene', (205, 208))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ACY-1215', 'Var', (44, 52))	('ACY-1215', 'Chemical', 'MESH:C572255', (44, 52))	('mTOR', 'Gene', (209, 213))	('mTOR', 'Gene', '2475', (209, 213))	('tumor', 'Disease', (60, 65))	('ACY-1215', 'Var', (120, 128))	('ERK', 'Gene', '5594', (176, 179))
792017	30050135	GSK690693 (a pan-Akt inhibitor) combined with ACY-1215 treatment could further enhance the ACY-1215-inhibited cell proliferation.	('Akt', 'Gene', '207', (17, 20))	('ACY-1215', 'Chemical', 'MESH:C572255', (91, 99))	('ACY-1215', 'Chemical', 'MESH:C572255', (46, 54))	('enhance', 'PosReg', (79, 86))	('GSK690693', 'Var', (0, 9))	('GSK690693', 'Chemical', 'MESH:C528328', (0, 9))	('Akt', 'Gene', (17, 20))
792018	30050135	GSK690693 increased P-AKT due to blocking a negative feedback loop downstream of AKT (PRAS40, Rag C, and P-mTOR).	('mTOR', 'Gene', (107, 111))	('AKT', 'Gene', '207', (22, 25))	('AKT', 'Gene', '207', (81, 84))	('mTOR', 'Gene', '2475', (107, 111))	('Rag C', 'Gene', (94, 99))	('negative feedback loop', 'MPA', (44, 66))	('PRAS40', 'Gene', '84335', (86, 92))	('GSK690693', 'Var', (0, 9))	('AKT', 'Gene', (22, 25))	('AKT', 'Gene', (81, 84))	('Rag C', 'Gene', '64121', (94, 99))	('blocking', 'NegReg', (33, 41))	('GSK690693', 'Chemical', 'MESH:C528328', (0, 9))	('PRAS40', 'Gene', (86, 92))	('increased', 'PosReg', (10, 19))
792020	30050135	A recent study showed that ACY-1215 in combination with bendamustine leads to AKT pathway inactivation in lymphoma cells.	('ACY-1215', 'Var', (27, 35))	('lymphoma', 'Disease', (106, 114))	('bendamustine', 'Chemical', 'MESH:D000069461', (56, 68))	('AKT', 'Gene', '207', (78, 81))	('lymphoma', 'Disease', 'MESH:D008223', (106, 114))	('inactivation', 'NegReg', (90, 102))	('lymphoma', 'Phenotype', 'HP:0002665', (106, 114))	('ACY-1215', 'Chemical', 'MESH:C572255', (27, 35))	('AKT', 'Gene', (78, 81))
792021	30050135	The phosphorylation status of AKT, GSK3beta, mTOR, 4EBP1, p90RSK, and p70S6 kinase all declined under treatment with ACY-1215 in combination with bendamustine.	('bendamustine', 'Chemical', 'MESH:D000069461', (146, 158))	('4EBP1', 'Gene', '1978', (51, 56))	('ACY-1215', 'Var', (117, 125))	('4EBP1', 'Gene', (51, 56))	('mTOR', 'Gene', '2475', (45, 49))	('GSK3beta', 'Gene', '2932', (35, 43))	('ACY-1215', 'Chemical', 'MESH:C572255', (117, 125))	('AKT', 'Gene', '207', (30, 33))	('p90RSK', 'Gene', '6195', (58, 64))	('p70S6 kinase', 'MPA', (70, 82))	('phosphorylation status', 'MPA', (4, 26))	('AKT', 'Gene', (30, 33))	('p90RSK', 'Gene', (58, 64))	('declined', 'NegReg', (87, 95))	('GSK3beta', 'Gene', (35, 43))	('mTOR', 'Gene', (45, 49))
792022	30050135	In this study, we identified that ACY-1215 effectively reduced PI3K, P-AKT (S473), PRAS40, and P-mTOR protein levels in ESCC.	('ACY-1215', 'Var', (34, 42))	('AKT', 'Gene', '207', (71, 74))	('mTOR', 'Gene', '2475', (97, 101))	('AKT', 'Gene', (71, 74))	('reduced', 'NegReg', (55, 62))	('mTOR', 'Gene', (97, 101))	('PRAS40', 'Gene', '84335', (83, 89))	('PI3K', 'Pathway', (63, 67))	('PRAS40', 'Gene', (83, 89))	('ACY-1215', 'Chemical', 'MESH:C572255', (34, 42))
792023	30050135	Thus, the effective targeting of multiple downstream effectors suggests that ACY-1215 may be an effective anticancer agent for ESCC.	('cancer', 'Disease', (110, 116))	('ESCC', 'Disease', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ACY-1215', 'Var', (77, 85))	('ACY-1215', 'Chemical', 'MESH:C572255', (77, 85))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
792026	30050135	However, despite ACY-1215 being a first-in-class potent and selective HDAC6 inhibitor, one study found that only higher doses of ACY-1215 triggered acetylation of lysine on histone H3 and histone H4.	('histone H3', 'Protein', (173, 183))	('lysine', 'Protein', (163, 169))	('acetylation', 'MPA', (148, 159))	('lysine', 'Chemical', 'MESH:D008239', (163, 169))	('histone H4', 'Gene', (188, 198))	('histone H4', 'Gene', '8294', (188, 198))	('HDAC6', 'Gene', '10013', (70, 75))	('HDAC6', 'Gene', (70, 75))	('ACY-1215', 'Var', (129, 137))	('ACY-1215', 'Chemical', 'MESH:C572255', (17, 25))	('ACY-1215', 'Chemical', 'MESH:C572255', (129, 137))
792027	30050135	In the present study, we found that ACY-1215 not only triggered acetylation of lysine on histone H3K9 and histone H4K8, but also promoted miR-30d expression.	('lysine', 'Chemical', 'MESH:D008239', (79, 85))	('promoted', 'PosReg', (129, 137))	('miR-30d', 'Gene', (138, 145))	('histone H4', 'Gene', (106, 116))	('acetylation of lysine', 'MPA', (64, 85))	('histone', 'Protein', (89, 96))	('ACY-1215', 'Var', (36, 44))	('ACY-1215', 'Chemical', 'MESH:C572255', (36, 44))	('miR-30d', 'Gene', '407033', (138, 145))	('histone H4', 'Gene', '8294', (106, 116))
792032	30050135	Moreover, we demonstrated here that anti-miR-30d partially reversed the G2/M arrest and apoptosis and AKT signaling caused by ACY-1215 treatment, further indicating that ACY-1215 suppresses proliferation and promotes apoptosis in ESCC through miR-30d/PI3K/AKT/mTOR signaling pathways.	('AKT', 'Gene', '207', (256, 259))	('M arrest', 'Disease', (75, 83))	('proliferation', 'CPA', (190, 203))	('mTOR', 'Gene', '2475', (260, 264))	('ACY-1215', 'Chemical', 'MESH:C572255', (126, 134))	('AKT', 'Gene', (102, 105))	('miR-30d', 'Gene', (41, 48))	('apoptosis', 'MPA', (88, 97))	('miR-30d', 'Gene', '407033', (243, 250))	('ACY-1215', 'Chemical', 'MESH:C572255', (170, 178))	('miR-30d', 'Gene', '407033', (41, 48))	('ACY-1215', 'Var', (170, 178))	('apoptosis', 'CPA', (217, 226))	('AKT', 'Gene', '207', (102, 105))	('AKT', 'Gene', (256, 259))	('promotes', 'PosReg', (208, 216))	('M arrest', 'Disease', 'MESH:D006323', (75, 83))	('suppresses', 'NegReg', (179, 189))	('miR-30d', 'Gene', (243, 250))	('mTOR', 'Gene', (260, 264))
792034	30050135	A selective HDAC6 inhibitor, ACY-1215, inhibited proliferation in ESCC, and caused G2/M phase arrest and apoptosis via miR-30d/PI3K/AKT/mTOR and ERK pathways.	('ERK', 'Gene', (145, 148))	('AKT', 'Gene', '207', (132, 135))	('inhibited', 'NegReg', (39, 48))	('HDAC6', 'Gene', '10013', (12, 17))	('apoptosis', 'CPA', (105, 114))	('proliferation', 'CPA', (49, 62))	('caused', 'Reg', (76, 82))	('ACY-1215', 'Chemical', 'MESH:C572255', (29, 37))	('AKT', 'Gene', (132, 135))	('ACY-1215', 'Var', (29, 37))	('G2/M phase arrest', 'CPA', (83, 100))	('miR-30d', 'Gene', (119, 126))	('mTOR', 'Gene', (136, 140))	('ERK', 'Gene', '5594', (145, 148))	('mTOR', 'Gene', '2475', (136, 140))	('HDAC6', 'Gene', (12, 17))	('miR-30d', 'Gene', '407033', (119, 126))
792035	30050135	Altogether, these findings provide underlying molecular and cellular evidence that ACY-1215 may be a promising antitumor agent in ESCC.	('ACY-1215', 'Chemical', 'MESH:C572255', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('ACY-1215', 'Var', (83, 91))	('ESCC', 'Disease', (130, 134))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
792044	30050135	The following antibodies were purchased from Cell Signaling Technology (Danvers, MA): Survivin (dilution at 1:1000), P21 (1:1000), CDC2 (1:1000), P53 (1:1000), P-P53 (1:1000), CyclinA2 (1:1000), CyclinB1 (1:1000), Bax (1:1000), Bim (1:1000), Bcl2 (1:1000), Cleaved caspase3 (1:1000), Cleaved caspase 9 (1:1000), Cleaved PARP (1:1000), PI3K (1:1000), AKT (1:1000), P-AKT (1:1000), PRAS40 (1:1000), Rag C (1:1000), mTOR (1:1000), P-mTOR (1:1000), ERK1/2 (1:1000), P-ERK1/2 (1:1000).	('AKT', 'Gene', (366, 369))	('P21', 'Gene', (117, 120))	('P53', 'Gene', '7157', (162, 165))	('CyclinB1', 'Gene', '891', (195, 203))	('PRAS40', 'Gene', (380, 386))	('Rag C', 'Gene', (397, 402))	('CyclinB1', 'Gene', (195, 203))	('CyclinA2', 'Gene', (176, 184))	('Bim', 'Gene', (228, 231))	('mTOR', 'Gene', (430, 434))	('1:1000', 'Var', (453, 459))	('mTOR', 'Gene', (413, 417))	('AKT', 'Gene', '207', (366, 369))	('PARP', 'Gene', '1302', (320, 324))	('AKT', 'Gene', '207', (350, 353))	('Bcl2', 'Gene', (242, 246))	('CDC2', 'Gene', '983', (131, 135))	('CDC2', 'Gene', (131, 135))	('mTOR', 'Gene', '2475', (430, 434))	('PRAS40', 'Gene', '84335', (380, 386))	('Bcl2', 'Gene', '596', (242, 246))	('mTOR', 'Gene', '2475', (413, 417))	('Bax', 'Gene', (214, 217))	('caspase 9', 'Gene', (292, 301))	('P21', 'Gene', '644914', (117, 120))	('PARP', 'Gene', (320, 324))	('P53', 'Gene', (162, 165))	('Rag C', 'Gene', '64121', (397, 402))	('P53', 'Gene', (146, 149))	('Bax', 'Gene', '581', (214, 217))	('CyclinA2', 'Gene', '890', (176, 184))	('caspase 9', 'Gene', '842', (292, 301))	('Bim', 'Gene', '10018', (228, 231))	('AKT', 'Gene', (350, 353))	('P53', 'Gene', '7157', (146, 149))
792063	27713635	However, nab-TP resulted in a longer median PFS (6.1 months [95% confidence interval: 5.3-6.9]) than sb-TP (5.0 months [95% confidence interval: 4.4-5.6]) (P=0.029).	('nab-TP', 'Var', (9, 15))	('PFS', 'MPA', (44, 47))	('sb-TP', 'Chemical', '-', (101, 106))	('nab-TP', 'Chemical', '-', (9, 15))
792065	27713635	With statistically significant differences, significantly less grade >=3 peripheral neuropathy, arthralgia, and myalgia occurred in the nab-TP arm (all P<0.05).	('myalgia', 'Disease', (112, 119))	('nab-TP', 'Var', (136, 142))	('arthralgia', 'Disease', (96, 106))	('myalgia', 'Phenotype', 'HP:0003326', (112, 119))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (73, 94))	('arthralgia', 'Phenotype', 'HP:0002829', (96, 106))	('nab-TP', 'Chemical', '-', (136, 142))	('peripheral neuropathy', 'Disease', (73, 94))	('arthralgia', 'Disease', 'MESH:D018771', (96, 106))	('neuropathy', 'Phenotype', 'HP:0009830', (84, 94))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (73, 94))	('less', 'NegReg', (58, 62))	('myalgia', 'Disease', 'MESH:D063806', (112, 119))
792080	27713635	Based on preclinical evidence, numerous clinical studies have confirmed that nab-PTX has higher tumor retention, lower toxicity, and more potent antitumor effects on breast cancer, non-small cell lung carcinoma, pancreatic cancer, melanoma, and ovarian cancer, when compared with solvent-based PTX.	('toxicity', 'Disease', 'MESH:D064420', (119, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (212, 229))	('tumor retention', 'Disease', 'MESH:D016055', (96, 111))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (181, 210))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('non-small cell lung carcinoma', 'Disease', (181, 210))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('nab-PTX', 'Var', (77, 84))	('melanoma', 'Disease', (231, 239))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (185, 210))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('breast cancer', 'Disease', (166, 179))	('ovarian cancer', 'Phenotype', 'HP:0100615', (245, 259))	('pancreatic cancer', 'Disease', (212, 229))	('toxicity', 'Disease', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (181, 210))	('ovarian cancer', 'Disease', 'MESH:D010051', (245, 259))	('nab-PTX', 'Chemical', 'MESH:D017239', (77, 84))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('tumor', 'Disease', (96, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('PTX', 'Chemical', '-', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor retention', 'Disease', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('ovarian cancer', 'Disease', (245, 259))	('higher', 'PosReg', (89, 95))	('tumor', 'Disease', (149, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('PTX', 'Chemical', '-', (294, 297))
792116	27713635	The nab-TP arm demonstrated a higher ORR (50% vs 30%; P=0.082) and DCR (81% vs 65%; P=0.124) than the sb-TP group (Table 3).	('ORR', 'MPA', (37, 40))	('higher', 'PosReg', (30, 36))	('nab-TP', 'Var', (4, 10))	('DCR', 'MPA', (67, 70))	('sb-TP', 'Chemical', '-', (102, 107))	('nab-TP', 'Chemical', '-', (4, 10))	('DCR', 'Chemical', '-', (67, 70))
792119	27713635	In the nab-TP arm, there was an improvement in PFS (median, 6.1 vs 5.0; P=0.029).	('PFS', 'MPA', (47, 50))	('improvement', 'PosReg', (32, 43))	('nab-TP', 'Var', (7, 13))	('nab-TP', 'Chemical', '-', (7, 13))
792122	27713635	Although the occurrence of the most common grades 3 and 4 leukopenia, neutropenia, febrile neutropenia, and anemia was more frequent in nab-TP, no significant difference was observed between the two groups (all P>0.05).	('nab-TP', 'Var', (136, 142))	('neutropenia', 'Disease', (70, 81))	('anemia', 'Disease', 'MESH:D000740', (108, 114))	('leukopenia', 'Disease', 'MESH:D007970', (58, 68))	('neutropenia', 'Phenotype', 'HP:0001875', (91, 102))	('neutropenia', 'Disease', 'MESH:D009503', (70, 81))	('anemia', 'Phenotype', 'HP:0001903', (108, 114))	('nab-TP', 'Chemical', '-', (136, 142))	('neutropenia', 'Disease', (91, 102))	('febrile neutropenia', 'Disease', (83, 102))	('leukopenia', 'Disease', (58, 68))	('febrile neutropenia', 'Disease', 'MESH:D009503', (83, 102))	('leukopenia', 'Phenotype', 'HP:0001882', (58, 68))	('neutropenia', 'Phenotype', 'HP:0001875', (70, 81))	('neutropenia', 'Disease', 'MESH:D009503', (91, 102))	('anemia', 'Disease', (108, 114))
792125	27713635	Significantly less common grade >=3 peripheral neuropathy, arthralgia, and myalgia occurred in the nab-PC arm (all P<0.05).	('peripheral neuropathy', 'Disease', (36, 57))	('myalgia', 'Phenotype', 'HP:0003326', (75, 82))	('neuropathy', 'Phenotype', 'HP:0009830', (47, 57))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (36, 57))	('arthralgia', 'Disease', (59, 69))	('nab-PC', 'Var', (99, 105))	('arthralgia', 'Phenotype', 'HP:0002829', (59, 69))	('nab-PC', 'Chemical', '-', (99, 105))	('arthralgia', 'Disease', 'MESH:D018771', (59, 69))	('myalgia', 'Disease', 'MESH:D063806', (75, 82))	('less', 'NegReg', (14, 18))	('myalgia', 'Disease', (75, 82))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (36, 57))
792133	27713635	According to the results of Kaplan-Meier curve analysis, the endpoint tended to be better in nab-TP, although the difference in OS was not statistically significant.	('nab-TP', 'Chemical', '-', (93, 99))	('OS', 'Chemical', '-', (128, 130))	('nab-TP', 'Var', (93, 99))	('better', 'PosReg', (83, 89))
792140	27713635	Nab-PTX had a tendency to result in longer PFS and OS than TP regimen.	('OS', 'Chemical', '-', (51, 53))	('Nab-PTX', 'Chemical', '-', (0, 7))	('Nab-PTX', 'Var', (0, 7))	('TP', 'Chemical', 'MESH:C011314', (59, 61))	('PFS', 'MPA', (43, 46))
792146	27713635	Although a higher percentage of patients in the nab-TP arm developed anemia, febrile neutropenia, leukopenia, and neutropenia, this difference was not statistically significant.	('developed', 'PosReg', (59, 68))	('neutropenia', 'Phenotype', 'HP:0001875', (85, 96))	('patients', 'Species', '9606', (32, 40))	('anemia', 'Disease', 'MESH:D000740', (69, 75))	('neutropenia', 'Disease', 'MESH:D009503', (85, 96))	('neutropenia', 'Disease', (114, 125))	('anemia', 'Phenotype', 'HP:0001903', (69, 75))	('febrile neutropenia', 'Disease', 'MESH:D009503', (77, 96))	('leukopenia', 'Phenotype', 'HP:0001882', (98, 108))	('nab-TP', 'Var', (48, 54))	('neutropenia', 'Disease', (85, 96))	('neutropenia', 'Disease', 'MESH:D009503', (114, 125))	('leukopenia', 'Disease', (98, 108))	('neutropenia', 'Phenotype', 'HP:0001875', (114, 125))	('nab-TP', 'Chemical', '-', (48, 54))	('leukopenia', 'Disease', 'MESH:D007970', (98, 108))	('febrile neutropenia', 'Disease', (77, 96))	('anemia', 'Disease', (69, 75))
792160	27009857	Subgroup analysis further exhibited an significant association between hyperfibrinogenemia and poor OS (P<0.001), DFS (P<0.001) in esophageal squamous cell carcinoma (P<0.001) and early pathological stage (I-II) (P=0.001).	('DFS', 'Var', (114, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('hyperfibrinogenemia', 'Disease', 'None', (71, 90))	('hyperfibrinogenemia', 'Disease', (71, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (131, 165))	('esophageal squamous cell carcinoma', 'Disease', (131, 165))	('poor OS', 'Disease', (95, 102))	('hyperfibrinogenemia', 'Phenotype', 'HP:0011899', (71, 90))
792180	27009857	As shows in Table 2, patients with older age, male gender, advanced pT caterory, lymph node metastasis, poor histologic differentiation, esophagogastric junction tumor location, weight loss, a history of smoking and alcohol consumption were found to have significantly shorter OS and DFS(P<0.05).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('junction tumor', 'Disease', 'MESH:D009369', (153, 167))	('weight loss', 'Disease', (178, 189))	('shorter', 'NegReg', (269, 276))	('lymph', 'Disease', (81, 86))	('weight loss', 'Phenotype', 'HP:0001824', (178, 189))	('junction tumor', 'Disease', (153, 167))	('poor', 'Var', (104, 108))	('alcohol', 'Chemical', 'MESH:D000438', (216, 223))	('patients', 'Species', '9606', (21, 29))	('DFS', 'CPA', (284, 287))	('esophagogastric junction tumor', 'Phenotype', 'HP:0100751', (137, 167))	('weight loss', 'Disease', 'MESH:D015431', (178, 189))
792228	26670461	Cell cycle antibody array suggested that silencing IGFBP-3 promoted transition from G0/G1 to S phase, perhaps though influencing Smad3 dephosphorylation and retinoblastoma protein (Rb) phosphorylation.	('IGFBP-3', 'Gene', (51, 58))	('silencing', 'Var', (41, 50))	('influencing', 'Reg', (117, 128))	('transition', 'CPA', (68, 78))	('Smad3', 'Gene', (129, 134))	('phosphorylation', 'MPA', (185, 200))	('retinoblastoma', 'Phenotype', 'HP:0009919', (157, 171))	('dephosphorylation', 'MPA', (135, 152))	('promoted', 'PosReg', (59, 67))	('Smad3', 'Gene', '4088', (129, 134))	('retinoblastoma', 'Disease', 'MESH:D012175', (157, 171))	('retinoblastoma', 'Disease', (157, 171))
792246	26670461	We observed that apoptosis related caspase-3 activity was significantly reduced in Kyse-IGFBP-3shRNA cells and TE-1-vector cells.	('activity', 'MPA', (45, 53))	('caspase-3', 'Gene', (35, 44))	('reduced', 'NegReg', (72, 79))	('TE-1', 'Gene', '57816', (111, 115))	('Kyse-IGFBP-3shRNA', 'Var', (83, 100))	('TE-1', 'Gene', (111, 115))	('caspase-3', 'Gene', '836', (35, 44))	('apoptosis', 'CPA', (17, 26))
792253	26670461	2C and D, EdU positive cells were increased among Kyse30-IGFBP-3shRNA cells compared with controls regardless of IR.	('EdU', 'Chemical', 'MESH:C031086', (10, 13))	('increased', 'PosReg', (34, 43))	('EdU positive cells', 'CPA', (10, 28))	('Kyse30-IGFBP-3shRNA', 'Var', (50, 69))
792257	26670461	As shown in Fig 3A,B, we observed that knockdown of IGFBP-3 expression enhanced ESCC cell tumorigenicity, and the ESCC xenografts grew more rapidly in null mice compared with control.	('enhanced', 'PosReg', (71, 79))	('knockdown', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('IGFBP-3', 'Gene', (52, 59))	('tumor', 'Disease', (90, 95))	('mice', 'Species', '10090', (156, 160))	('ESCC', 'Disease', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
792258	26670461	Furthermore, the growth of the Kyse30-IGFBP-3 shRNA tumors after IR significantly increased (from a mean tumors volume of 200 mm3 before IR treatment, adding to 780 +- 80.5 mm3 at the end of treatment), compared with the control (from a mean tumors volume of 200 mm3 to 400 +- 40.7 mm3, before and after the same treatment) (P < 0.05; Fig.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('growth', 'MPA', (17, 23))	('tumors', 'Disease', (52, 58))	('shRNA', 'Gene', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('increased', 'PosReg', (82, 91))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumors', 'Disease', (242, 248))	('Kyse30-IGFBP-3', 'Var', (31, 45))
792270	26670461	We found that after p-Smad3 knockdown, a substantial drop expression of p-RB, P27, P21was displayed but a rise on cyclin E, CDK2 in ESCC cells compared with the control (Fig.	('P21', 'Gene', (83, 86))	('P27', 'Gene', (78, 81))	('Smad3', 'Gene', (22, 27))	('cyclin', 'Gene', (114, 120))	('p-RB', 'Gene', '5925', (72, 76))	('expression', 'MPA', (58, 68))	('Smad3', 'Gene', '4088', (22, 27))	('CDK2', 'Gene', (124, 128))	('CDK2', 'Gene', '1017', (124, 128))	('cyclin', 'Gene', '5111', (114, 120))	('P21', 'Gene', '644914', (83, 86))	('knockdown', 'Var', (28, 37))	('drop', 'NegReg', (53, 57))	('rise', 'PosReg', (106, 110))	('p-RB', 'Gene', (72, 76))	('P27', 'Gene', '10671', (78, 81))
792282	26670461	Caspase-3 activity and the protein expression ratio of Bax/Bcl-2, which are crucial for the induction of apoptosis, also indicated that IGFBP-3 silencing inhibits apoptosis in ESCC cell lines, before and after IR.	('apoptosis', 'CPA', (163, 172))	('inhibits', 'NegReg', (154, 162))	('Caspase-3', 'Gene', (0, 9))	('activity', 'MPA', (10, 18))	('Bax', 'Gene', '581', (55, 58))	('Bcl-2', 'Gene', (59, 64))	('Bax', 'Gene', (55, 58))	('silencing', 'Var', (144, 153))	('IGFBP-3', 'Gene', (136, 143))	('Bcl-2', 'Gene', '596', (59, 64))	('Caspase-3', 'Gene', '836', (0, 9))
792289	26670461	These findings indicate that, in ESCCs with underexpression of IGFBP-3, dividing tumor cells seem to be abundant.	('underexpression', 'Var', (44, 59))	('IGFBP-3', 'Gene', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ESCCs', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
792294	26670461	Furthermore, Rb (phospho-Ser780, -Ser795, -Ser807, and -Ser811) were all significantly increased (data for Rb [phospho-Ser780 and -Ser807] not shown).	('Ser811', 'Chemical', '-', (56, 62))	('increased', 'PosReg', (87, 96))	('Ser807', 'Chemical', '-', (131, 137))	('Ser807', 'Chemical', '-', (43, 49))	('Ser795', 'Chemical', '-', (34, 40))	('Ser780', 'Chemical', '-', (119, 125))	('Ser780', 'Chemical', '-', (25, 31))	('phospho-Ser780', 'Var', (17, 31))
792316	26670461	The human ESCC cell lines Kyse410, Kyse140, Kyse30, EC109, and TE-1 were obtained from the cell bank of the Chinese Academy of the Sciences (Shanghai, China).	('human', 'Species', '9606', (4, 9))	('TE-1', 'Gene', (63, 67))	('Kyse140', 'Var', (35, 42))	('TE-1', 'Gene', '57816', (63, 67))
792333	26670461	When tumors had grown to a volume of 200 mm3, mice were randomized into four groups (eight mice per group): Scramble; IGFBP-3shRNA; Scramble + IR; and IGFBP-3shRNA + IR (IR = ionizing radiation).	('IGFBP-3shRNA + IR', 'Var', (151, 168))	('tumors', 'Disease', (5, 11))	('mice', 'Species', '10090', (91, 95))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('IGFBP-3shRNA', 'Var', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
792353	25866578	Distal Esophageal Strictures Distal esophageal strictures still present a significant challenge because stent placement across the gastroesophageal junction can lead to gastroesophageal reflux disease and aspiration.	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (169, 192))	('stent', 'Var', (104, 109))	('gastroesophageal reflux disease', 'Disease', (169, 200))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (169, 200))	('esophageal reflux', 'Phenotype', 'HP:0002020', (175, 192))	('Distal', 'Disease', (0, 6))	('aspiration', 'Phenotype', 'HP:0002835', (205, 215))	('esophageal strictures', 'Phenotype', 'HP:0002043', (36, 57))	('lead to', 'Reg', (161, 168))	('aspiration', 'Disease', (205, 215))	('Esophageal Strictures', 'Phenotype', 'HP:0002043', (7, 28))	('esophageal stricture', 'Phenotype', 'HP:0002043', (36, 56))
792380	25866578	A form of monopolar electrocautery, APC causes tissue coagulation, desiccation, and destruction via the transfer of energy from the APC probe to the malignant tissue in the form of ionized, electrically conductive argon gas (plasma).	('causes', 'Reg', (40, 46))	('ionized', 'Disease', 'MESH:D004194', (181, 188))	('destruction', 'CPA', (84, 95))	('ionized', 'Disease', (181, 188))	('desiccation', 'CPA', (67, 78))	('tissue coagulation', 'CPA', (47, 65))	('transfer', 'MPA', (104, 112))	('APC', 'Var', (36, 39))
792548	33357046	The methylation and the consequent silencing of these genes may play an important role in the maintenance of stem-like properties in SP cells.	('silencing', 'NegReg', (35, 44))	('stem-like properties', 'CPA', (109, 129))	('methylation', 'Var', (4, 15))	('play', 'Reg', (64, 68))	('SP', 'Chemical', '-', (133, 135))
792585	33357046	KEGG analysis showed that the overlapping differentially methylated genes were mainly involved in long-term depression gap junction and drug addiction such as cocaine addiction (Figure 3C).	('depression', 'Phenotype', 'HP:0000716', (108, 118))	('cocaine addiction', 'Disease', (159, 176))	('depression gap junction', 'Disease', (108, 131))	('involved', 'Reg', (86, 94))	('differentially methylated genes', 'Var', (42, 73))	('depression gap junction', 'Disease', 'MESH:D000275', (108, 131))
792587	33357046	Esophageal carcinoma patients with high levels of LRRK1, NKD2, or ST8SIA2 exhibited a shorter disease-free survival, but there was no statistically significant difference (Figure 5B-5C).	('NKD2', 'Gene', '85409', (57, 61))	('ST8SIA2', 'Gene', (66, 73))	('shorter', 'NegReg', (86, 93))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (0, 20))	('carcinoma', 'Disease', (11, 20))	('high levels', 'Var', (35, 46))	('LRRK1', 'Gene', (50, 55))	('patients', 'Species', '9606', (21, 29))	('ST8SIA2', 'Gene', '8128', (66, 73))	('disease-free survival', 'CPA', (94, 115))	('NKD2', 'Gene', (57, 61))	('LRRK1', 'Gene', '79705', (50, 55))	('carcinoma', 'Disease', 'MESH:D009369', (11, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
792597	33357046	In all ESCC samples, more than 50% of cytosines in CGIs were methylated, which indicates that methylation plays an important role in ESCC.	('methylated', 'Var', (61, 71))	('ESCC', 'Disease', (133, 137))	('cytosines', 'Chemical', 'MESH:D003596', (38, 47))
792771	32460441	To probe the biological function of LINC00338 in ESCC, we examined the effect of LINC00338 knockdown and found that silencing of this lncRNA potently reduced the proliferation, migration and clonogenicity of ESCC cells (Fig.	('ESCC', 'Disease', (208, 212))	('LINC00338', 'Gene', (36, 45))	('LINC00338', 'Gene', (81, 90))	('proliferation', 'CPA', (162, 175))	('migration', 'CPA', (177, 186))	('reduced', 'NegReg', (150, 157))	('LINC00338', 'Gene', '654434', (36, 45))	('LINC00338', 'Gene', '654434', (81, 90))	('silencing', 'Var', (116, 125))	('clonogenicity', 'CPA', (191, 204))
792777	32460441	To test this, we silenced this lncRNA and observed that LINC00094 knockdown significantly inhibited proliferation, migration and clonogenicity in ESCC cells (Fig.	('clonogenicity', 'CPA', (129, 142))	('migration', 'CPA', (115, 124))	('proliferation', 'CPA', (100, 113))	('LINC00094', 'Gene', (56, 65))	('LINC00094', 'Gene', '266655', (56, 65))	('inhibited', 'NegReg', (90, 99))	('knockdown', 'Var', (66, 75))	('ESCC', 'Disease', (146, 150))
792778	32460441	More importantly, RNA-seq data showed that the downregulated PCGs upon LINC00094 knockdown significantly overlapped with those predicted by GloceRNA, strongly validating our method (P = 7.97E-05, hypergeometric test, Fig.	('LINC00094', 'Gene', (71, 80))	('PCGs', 'Chemical', '-', (61, 65))	('downregulated', 'NegReg', (47, 60))	('GloceRNA', 'Chemical', '-', (140, 148))	('LINC00094', 'Gene', '266655', (71, 80))	('knockdown', 'Var', (81, 90))
792784	32460441	In ESCC, we found that knockdown of SNHG10, an uncharacterized lncRNA, reduced proliferation, migration, and clonogenicity in KYSE150 and TE3 cells (Fig.	('clonogenicity', 'CPA', (109, 122))	('proliferation', 'CPA', (79, 92))	('SNHG10', 'Gene', '283596', (36, 42))	('SE', 'Gene', '6713', (128, 130))	('SNHG10', 'Gene', (36, 42))	('migration', 'CPA', (94, 103))	('knockdown', 'Var', (23, 32))	('TE', 'Chemical', '-', (138, 140))	('reduced', 'NegReg', (71, 78))
792790	32460441	For the lncRNA LINC00094, patients with high lncRNA expression have significantly shorter overall survival (OS) than those with the low expression (Fig.	('high', 'Var', (40, 44))	('LINC00094', 'Gene', '266655', (15, 24))	('overall survival', 'MPA', (90, 106))	('patients', 'Species', '9606', (26, 34))	('lncRNA expression', 'MPA', (45, 62))	('LINC00094', 'Gene', (15, 24))	('shorter', 'NegReg', (82, 89))
792792	32460441	As an example for the ceRNA pair of ANAPC10-DLEU2, patients with high expression have significantly shorter OS than those with the low expression in the cohort of 119 patients (the GSE53625 n = 119 dataset) (Fig.	('ANAPC10', 'Gene', (36, 43))	('DLEU2', 'Gene', (44, 49))	('ANAPC10', 'Gene', '10393', (36, 43))	('patients', 'Species', '9606', (167, 175))	('shorter', 'NegReg', (100, 107))	('DLEU2', 'Gene', '8847', (44, 49))	('patients', 'Species', '9606', (51, 59))	('high expression', 'Var', (65, 80))	('SE', 'Gene', '6713', (182, 184))
792807	32460441	The data were involved in gene expression levels associated with either THZ1 or DMSO at indicated time points at 2, 4, 6, and 8 h. We found that although SE/TE-associated lncRNAs and all background PCGs did not display significant downregulation by THZ1, THZ1 resulted in global downregulation of SE/TE-associated ce-lncRNAs at 12 h relative to 0 h (Fig.	('THZ1', 'Chemical', '-', (72, 76))	('THZ1', 'Chemical', '-', (249, 253))	('TE', 'Chemical', '-', (300, 302))	('SE', 'Gene', '6713', (297, 299))	('SE', 'Gene', '6713', (154, 156))	('THZ1', 'Chemical', '-', (255, 259))	('THZ1', 'Var', (255, 259))	('PCGs', 'Chemical', '-', (198, 202))	('downregulation', 'NegReg', (279, 293))	('DMSO', 'Chemical', 'MESH:D004121', (80, 84))	('TE', 'Chemical', '-', (157, 159))
792822	32460441	More importantly, knockdown of TCF3 or KLF5 significantly downregulated expression of LINC00094 (Fig.	('knockdown', 'Var', (18, 27))	('TCF3', 'Gene', '6929', (31, 35))	('TCF3', 'Gene', (31, 35))	('expression', 'MPA', (72, 82))	('downregulated', 'NegReg', (58, 71))	('LINC00094', 'Gene', (86, 95))	('KLF5', 'Gene', (39, 43))	('LINC00094', 'Gene', '266655', (86, 95))	('KLF5', 'Gene', '688', (39, 43))
792857	32460441	Furthermore, we found that THZ1 resulted in global downregulation of SE/TE-ce-lncRNAs.	('TE', 'Chemical', '-', (72, 74))	('SE', 'Gene', '6713', (69, 71))	('THZ1', 'Chemical', '-', (27, 31))	('THZ1', 'Var', (27, 31))	('downregulation', 'NegReg', (51, 65))
792928	32009977	Contrary to any expectations, in ESCC cell lines, NHE1 gene knockdown was found to promote proliferation, migration, and invasion, and to inhibit apoptosis via the activation of PI3K-AKT signaling pathway.	('proliferation', 'CPA', (91, 104))	('AKT', 'Gene', (183, 186))	('rat', 'Species', '10116', (98, 101))	('rat', 'Species', '10116', (109, 112))	('knockdown', 'Var', (60, 69))	('inhibit', 'NegReg', (138, 145))	('NHE1', 'Gene', (50, 54))	('promote', 'PosReg', (83, 90))	('invasion', 'CPA', (121, 129))	('migration', 'CPA', (106, 115))	('apoptosis', 'CPA', (146, 155))	('AKT', 'Gene', '207', (183, 186))
792929	32009977	In fact, NHE1 expression was significantly higher in well-differentiated ESCC tumors compared to that in poorly differentiated ESCC tumors and correlated strongly with the 5-year survival rate being much better in the group with high NHE1 expression.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('higher', 'PosReg', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Disease', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('expression', 'MPA', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('rat', 'Species', '10116', (188, 191))	('NHE1', 'Gene', (9, 13))	('better', 'PosReg', (204, 210))	('ESCC', 'Disease', (73, 77))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('high', 'Var', (229, 233))
792937	32009977	Furthermore, NHE2 may be involved in cell differentiation and longevity because its deficiency is accompanied by a strong, but not total loss of parietal cells in the murine stomach.	('involved', 'Reg', (25, 33))	('deficiency', 'Var', (84, 94))	('murine', 'Species', '10090', (167, 173))	('NHE2', 'Gene', (13, 17))
792942	32009977	However, NHE8 deficiency causes a decrease in gastric mucosal surface pH and an increased incidence of gastric ulcer.	('gastric ulcer', 'Disease', 'MESH:D013276', (103, 116))	('gastric ulcer', 'Disease', (103, 116))	('decrease', 'NegReg', (34, 42))	('NHE8', 'Gene', (9, 13))	('deficiency', 'Var', (14, 24))	('gastric ulcer', 'Phenotype', 'HP:0002592', (103, 116))	('gastric mucosal surface pH', 'CPA', (46, 72))
792946	32009977	NHE1 expression is significantly higher in both human gastric cancer tissue and cells when compared to that in normal gastric tissue and cells, and the inhibition of NHE1 suppresses proliferation, migration, and invasion of gastric cancer cells.	('expression', 'MPA', (5, 15))	('NHE1', 'Gene', (0, 4))	('rat', 'Species', '10116', (200, 203))	('NHE1', 'Gene', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('gastric cancer', 'Disease', 'MESH:D013274', (224, 238))	('proliferation', 'CPA', (182, 195))	('human', 'Species', '9606', (48, 53))	('gastric cancer', 'Disease', (54, 68))	('migration', 'CPA', (197, 206))	('rat', 'Species', '10116', (189, 192))	('inhibition', 'Var', (152, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (224, 238))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (54, 68))	('higher', 'PosReg', (33, 39))	('suppresses', 'NegReg', (171, 181))	('invasion', 'CPA', (212, 220))	('gastric cancer', 'Disease', (224, 238))	('gastric cancer', 'Phenotype', 'HP:0012126', (54, 68))
792950	32009977	In human gastric carcinoma cells (SGC-7901), knocking down NHE1 causes a decrease in cell proliferation, G1/G0 phase arrest, increased apoptosis, and, when SCG-7901 cells are injected subcutaneously into nude mice, a reduced tumorigenic capacity.	('apoptosis', 'CPA', (135, 144))	('rat', 'Species', '10116', (97, 100))	('increased', 'PosReg', (125, 134))	('human', 'Species', '9606', (3, 8))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (9, 26))	('G1/G0 phase arrest', 'CPA', (105, 123))	('tumor', 'Disease', (225, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('SGC', 'Gene', '6443', (34, 37))	('gastric carcinoma', 'Disease', (9, 26))	('nude mice', 'Species', '10090', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('NHE1', 'Gene', (59, 63))	('SCG-7901', 'CellLine', 'CVCL:R992', (156, 164))	('decrease', 'NegReg', (73, 81))	('SGC', 'Gene', (34, 37))	('cell proliferation', 'CPA', (85, 103))	('knocking down', 'Var', (45, 58))	('gastric carcinoma', 'Disease', 'MESH:D013274', (9, 26))	('reduced', 'NegReg', (217, 224))
792951	32009977	Moreover, in human gastric cancer cells of the MKN45 and the MKN74 line, inhibition of NHE1 activity by 2-amino-3H-phenoxazin-3-one (questiomycin A), a derivative of the oxidative phenoxazine, leads to a decrease in pHi and promotes apoptosis.	('decrease', 'NegReg', (204, 212))	('gastric cancer', 'Disease', (19, 33))	('NHE1', 'Protein', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('human', 'Species', '9606', (13, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (19, 33))	('promotes', 'PosReg', (224, 232))	('questiomycin A', 'Chemical', 'MESH:C005512', (133, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('2-amino-3H-phenoxazin-3-one', 'Chemical', 'MESH:C020456', (104, 131))	('apoptosis', 'CPA', (233, 242))	('phenoxazine', 'Chemical', 'MESH:C039203', (180, 191))	('activity', 'MPA', (92, 100))	('inhibition', 'Var', (73, 83))	('pHi', 'MPA', (216, 219))
792952	32009977	Altogether, inhibition of NHE1 causes changes in the ionic composition of the cytosol that are likely to contribute to the pathogenesis of gastric cancer in terms of cell proliferation, cell apoptosis, and cell cycle.	('inhibition', 'Var', (12, 22))	('gastric cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('contribute', 'Reg', (105, 115))	('cell cycle', 'CPA', (206, 216))	('cell proliferation', 'CPA', (166, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('changes', 'Reg', (38, 45))	('ionic composition of the cytosol', 'MPA', (53, 85))	('rat', 'Species', '10116', (178, 181))	('cell', 'CPA', (186, 190))	('NHE1', 'Gene', (26, 30))
792984	32009977	Its deficiency does not lead to intestinal diarrhea in mice.	('mice', 'Species', '10090', (55, 59))	('intestinal diarrhea', 'Disease', 'MESH:D003967', (32, 51))	('deficiency', 'Var', (4, 14))	('intestinal diarrhea', 'Disease', (32, 51))	('diarrhea', 'Phenotype', 'HP:0002014', (43, 51))
793003	32009977	NHE-mediated alterations in the intestinal microenvironment, such as changes in luminal ion concentration and pH, could damage the gut microbiota.	('NHE', 'Gene', (0, 3))	('rat', 'Species', '10116', (17, 20))	('rat', 'Species', '10116', (99, 102))	('gut microbiota', 'CPA', (131, 145))	('luminal ion concentration', 'MPA', (80, 105))	('NHE', 'Gene', '285335', (0, 3))	('alterations', 'Var', (13, 24))	('damage', 'Reg', (120, 126))	('changes', 'Reg', (69, 76))
793004	32009977	For instance, gram-positive bacteria such as Clostridium and Lactobacillus are increased in cecum and colon of NHE2 knockout mice although the total luminal and mucosa-associated bacteria remain unchanged.	('Lactobacillus', 'Enzyme', (61, 74))	('increased', 'PosReg', (79, 88))	('Clostridium', 'CPA', (45, 56))	('knockout', 'Var', (116, 124))	('Clostridium', 'Species', '1496', (45, 56))	('gram-positive bacteria', 'CPA', (14, 36))	('mice', 'Species', '10090', (125, 129))	('NHE2', 'Gene', (111, 115))
793005	32009977	Also NHE3 knockout has an impact on the murine gut microbial environment, which includes a decrease in Lachnospiraceae and Ruminococcaceae (Firmicutes) and an increase in Bacteroidaceae.	('increase', 'PosReg', (159, 167))	('murine', 'Species', '10090', (40, 46))	('murine', 'MPA', (40, 46))	('knockout', 'Var', (10, 18))	('NHE3', 'Gene', (5, 9))	('Lachnospiraceae', 'MPA', (103, 118))	('decrease', 'NegReg', (91, 99))	('Bacteroidaceae', 'MPA', (171, 185))
793007	32009977	Hence, disruption of NHE3 function in gut may modulate the pathogenesis and progression of colitis via alteration of the microbial ecology.	('modulate', 'Reg', (46, 54))	('NHE3', 'Gene', (21, 25))	('colitis', 'Disease', 'MESH:D003092', (91, 98))	('disruption', 'Var', (7, 17))	('colitis', 'Disease', (91, 98))	('colitis', 'Phenotype', 'HP:0002583', (91, 98))	('alteration', 'Reg', (103, 113))	('rat', 'Species', '10116', (107, 110))
793008	32009977	In addition, NHE3 deficiency reinforces the T-cell mediated immune response to a disturbed gut microbiome.	('NHE3', 'Gene', (13, 17))	('reinforces', 'PosReg', (29, 39))	('gut microbiome', 'Species', '749906', (91, 105))	('deficiency', 'Var', (18, 28))	('T-cell mediated immune response', 'CPA', (44, 75))
793009	32009977	Consequently, NHE3 plays an important role in keeping the gut's microbial ecology balanced, and NHE3 malfunction caused by inflammatory cytokines results in the onset and fuels the progress of the IBD.	('IBD', 'Disease', 'MESH:C535541', (197, 200))	('malfunction', 'Var', (101, 112))	('NHE3', 'Gene', (96, 100))	('progress', 'CPA', (181, 189))	('IBD', 'Disease', (197, 200))
793011	32009977	Compared to NHE3 wild-type mice, the diversity of the luminal and mucosal microbiota in NHE3 knockout mice is significantly decreased, and the bacterial composition in their intestine affects the severity of colitis.	('NHE3', 'Gene', (88, 92))	('mice', 'Species', '10090', (102, 106))	('affects', 'Reg', (184, 191))	('colitis', 'Phenotype', 'HP:0002583', (208, 215))	('mice', 'Species', '10090', (27, 31))	('decreased', 'NegReg', (124, 133))	('colitis', 'Disease', 'MESH:D003092', (208, 215))	('colitis', 'Disease', (208, 215))	('knockout', 'Var', (93, 101))	('diversity', 'MPA', (37, 46))
793012	32009977	In summary, NHE3 is essential for the generation and maintenance of an intact microbiota, because NHE3 deficiency is accompanied by the pathogenesis of IBD, probably caused by a disproportion in the bacterial composition.	('NHE3', 'Gene', (98, 102))	('deficiency', 'Var', (103, 113))	('IBD', 'Disease', (152, 155))	('accompanied', 'Reg', (117, 128))	('rat', 'Species', '10116', (42, 45))	('IBD', 'Disease', 'MESH:C535541', (152, 155))
793025	32009977	This is consistent with the observation that activating the Fas receptor - which can induce apoptosis - inhibits NHE1 activity in T-lymphocytes via activation of the Src-like kinase Lck56.	('activity', 'MPA', (118, 126))	('inhibits', 'NegReg', (104, 112))	('Fas', 'Protein', (60, 63))	('activating', 'Var', (45, 55))	('NHE1', 'Protein', (113, 117))	('Src', 'Gene', (166, 169))	('Src', 'Gene', '100341599', (166, 169))
793036	32009977	An increased Wnt/beta-catenin signaling is found also in the absence of NHE8.	('increased', 'PosReg', (3, 12))	('beta-catenin', 'Gene', '1499', (17, 29))	('NHE8', 'Gene', (72, 76))	('absence', 'Var', (61, 68))	('beta-catenin', 'Gene', (17, 29))
793037	32009977	The absence of NHE8 most likely makes a considerable contribution to the development of intestinal tumors, because it is expressed in normal human colon tissue, but cannot be detected in CRC.	('intestinal tumors', 'Disease', (88, 105))	('intestinal tumors', 'Disease', 'MESH:D007414', (88, 105))	('NHE8', 'Gene', (15, 19))	('human', 'Species', '9606', (141, 146))	('absence', 'Var', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
793039	32009977	Finally, NHE8 deficiency is accompanied by an elevated expression of the stem cell marker Lgr5 in the colon.	('elevated', 'PosReg', (46, 54))	('Lgr5', 'Gene', (90, 94))	('NHE8', 'Gene', (9, 13))	('expression', 'MPA', (55, 65))	('deficiency', 'Var', (14, 24))	('Lgr5', 'Gene', '8549', (90, 94))
793058	32009977	Long-term ablation of NHE1 activity in mice attenuates HFD-induced lipid accumulation in liver and preserves insulin sensitivity.	('NHE1', 'Gene', (22, 26))	('insulin', 'Gene', (109, 116))	('insulin', 'Gene', '3630', (109, 116))	('preserves', 'PosReg', (99, 108))	('HFD-induced lipid accumulation in liver', 'MPA', (55, 94))	('ablation', 'Var', (10, 18))	('lipid accumulation in liver', 'Phenotype', 'HP:0006561', (67, 94))	('mice', 'Species', '10090', (39, 43))	('attenuates', 'NegReg', (44, 54))
793063	32009977	In rat hepatocytes, agents promoting liver tumors, such as alpha-hexachlorocyclohexane or phenobarbital, cause an intracellular alkalinization mediated by Na+/H+ antiport.	('liver tumors', 'Disease', (37, 49))	('liver tumors', 'Phenotype', 'HP:0002896', (37, 49))	('phenobarbital', 'Chemical', 'MESH:D010634', (90, 103))	('alpha-hexachlorocyclohexane', 'Chemical', 'MESH:C040534', (59, 86))	('phenobarbital', 'Var', (90, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('rat', 'Species', '10116', (3, 6))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('liver tumors', 'Disease', 'MESH:D008113', (37, 49))
793066	32009977	In vitro, inhibition of NHE1 expression via siRNA-mediated knockdown reduces HCC growth and induces apoptosis.	('NHE1', 'Gene', (24, 28))	('induces', 'Reg', (92, 99))	('HCC', 'Gene', '619501', (77, 80))	('reduces', 'NegReg', (69, 76))	('inhibition', 'Var', (10, 20))	('apoptosis', 'CPA', (100, 109))	('HCC', 'Gene', (77, 80))
793081	32009977	As a digestive organ, the pancreas secretes (i) pancreatic juice containing HCO3- to neutralize the acidic chyme arriving from the stomach and (ii) digestive enzymes that facilitate digestion and absorption of nutrients in the small intestine.	('digestion', 'MPA', (182, 191))	('HCO3-', 'Var', (76, 81))	('acidic chyme arriving', 'MPA', (100, 121))	('HCO3', 'Chemical', 'MESH:C504136', (76, 80))	('facilitate', 'PosReg', (171, 181))	('absorption', 'MPA', (196, 206))	('neutralize', 'MPA', (85, 95))
793091	32009977	In order to address this inconsistency, investigated NHE1 mutant mice (NHE1swe/swe, swe, slow wave epilepsy).	('epilepsy', 'Phenotype', 'HP:0001250', (99, 107))	('mutant', 'Var', (58, 64))	('epilepsy', 'Disease', (99, 107))	('mice', 'Species', '10090', (65, 69))	('NHE1', 'Gene', (53, 57))	('epilepsy', 'Disease', 'MESH:D004827', (99, 107))
793094	32009977	Moreover, NHE1 has no impact on stimulus-secretion coupling, and the NHE inhibitors EIPA and DMA, but not the selective NHE1 inhibitor cariporide, stimulate insulin secretion without pHi changes in both NHE1 wild-type and mutant islets.	('NHE', 'Gene', (120, 123))	('NHE', 'Gene', (10, 13))	('EIPA', 'Chemical', 'MESH:C039614', (84, 88))	('NHE', 'Gene', (203, 206))	('cariporide', 'Chemical', 'MESH:C093373', (135, 145))	('NHE', 'Gene', (69, 72))	('insulin', 'Gene', (157, 164))	('DMA', 'Gene', '3108', (93, 96))	('DMA', 'Gene', (93, 96))	('stimulate', 'PosReg', (147, 156))	('mutant', 'Var', (222, 228))	('insulin', 'Gene', '3630', (157, 164))	('NHE', 'Gene', '285335', (120, 123))	('NHE', 'Gene', '285335', (10, 13))	('NHE', 'Gene', '285335', (69, 72))	('NHE', 'Gene', '285335', (203, 206))
793101	32009977	The data from indicate a pivotal role of NHA2 in both clathrin-mediated endocytosis and insulin secretion in beta-cells, suggesting that defective endo-exocytosis coupling may be the mechanism underlying the secretory deficit observed in NHA2-deficient mice.	('defective', 'Var', (137, 146))	('endo-exocytosis coupling', 'MPA', (147, 171))	('secretory', 'MPA', (208, 217))	('insulin', 'Gene', (88, 95))	('insulin', 'Gene', '3630', (88, 95))	('mice', 'Species', '10090', (253, 257))
793110	32009977	Nonetheless, NHE3 expression and activity in the luminal membranes of mouse pancreatic ducts are measurably affected by CFTR.	('NHE3', 'Gene', (13, 17))	('CFTR', 'Var', (120, 124))	('mouse', 'Species', '10090', (70, 75))	('activity', 'MPA', (33, 41))	('expression', 'MPA', (18, 28))	('affected', 'Reg', (108, 116))
793117	32009977	At the same time, NHE1 favors formation of invadopodial structures required for invasion which is consistent with the general idea that an acidic extracellular pH promotes tumor invasion by stimulation of protease secretion and induction of proinvasive mediators, and also by suppression of apoptosis through intracellular alkalinization.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('NHE1', 'Var', (18, 22))	('apoptosis', 'CPA', (291, 300))	('tumor', 'Disease', (172, 177))	('suppression', 'NegReg', (276, 287))	('stimulation', 'PosReg', (190, 201))	('promotes', 'PosReg', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('protease', 'MPA', (205, 213))
793122	32009977	Inhibition of NHE1 expression or activity leads to tumor cell growth arrest, acidification of the intracellular space, apoptosis and inhibition of glycolysis.	('growth arrest', 'Phenotype', 'HP:0001510', (62, 75))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor cell growth arrest', 'Disease', 'MESH:D006323', (51, 75))	('NHE1', 'Gene', (14, 18))	('tumor cell growth arrest', 'Disease', (51, 75))	('apoptosis', 'CPA', (119, 128))	('inhibition', 'NegReg', (133, 143))	('acidification of the intracellular space', 'MPA', (77, 117))	('activity', 'MPA', (33, 41))	('glycolysis', 'MPA', (147, 157))	('Inhibition', 'Var', (0, 10))
793126	32009977	EIPA also inhibits tumor growth in nude mouse xenografts of HCC cells, suggesting that inhibition of NHE1 could be a potential therapeutic target for the treatment of HCC.	('inhibits', 'NegReg', (10, 18))	('HCC', 'Gene', (167, 170))	('HCC', 'Gene', '619501', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('EIPA', 'Chemical', 'MESH:C039614', (0, 4))	('NHE1', 'Gene', (101, 105))	('HCC', 'Gene', '619501', (167, 170))	('tumor', 'Disease', (19, 24))	('mouse', 'Species', '10090', (40, 45))	('inhibition', 'Var', (87, 97))	('HCC', 'Gene', (60, 63))
793375	29349540	Another series from the Mayo Clinic Arizona found that, when retrospectively assessed by a self-designed questionnaire, global scores for dysphagia and overall quality of life significantly improved under self-dilation compared to the period of endoscopically performed dilations.	('Mayo', 'Species', '162683', (24, 28))	('dysphagia', 'Disease', (138, 147))	('dysphagia', 'Phenotype', 'HP:0002015', (138, 147))	('dysphagia', 'Disease', 'MESH:D003680', (138, 147))	('improved', 'PosReg', (190, 198))	('self-dilation', 'Var', (205, 218))
793402	28337481	Thermal damage to dissected tissues appeared mild, and the extent of muscle injury was lower for WJ-ESD (4, 6, and 8 %) compared with C-ESD (14, 16, and 7 %).	('lower', 'NegReg', (87, 92))	('muscle injury', 'Disease', (69, 82))	('muscle injury', 'Disease', 'MESH:D009135', (69, 82))	('WJ-ESD', 'Var', (97, 103))
793418	28337481	In addition, thermal damage to the muscle layer may cause a scar stenosis even if the resected tissue is small.	('scar', 'Disease', (60, 64))	('thermal damage', 'Var', (13, 27))	('cause', 'Reg', (52, 57))	('scar', 'Phenotype', 'HP:0100699', (60, 64))	('stenosis', 'Disease', 'MESH:D003251', (65, 73))	('stenosis', 'Disease', (65, 73))
793421	27083246	cT2N0 esophageal cancer patients receiving induction therapy or upfront esophagectomy (UE) were identified in the National Cancer Data Base (NCDB).	('cT2N0', 'Var', (0, 5))	('esophageal cancer', 'Disease', (6, 23))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancer', 'Disease', (123, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (6, 23))	('Cancer', 'Disease', 'MESH:D009369', (123, 129))	('patients', 'Species', '9606', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
793451	27083246	Backwards stepwise multivariable logistic regression was performed to identify variables independently associated with being pathologically upstaged from cT2N0 esophageal cancer and receiving adjuvant therapy for upstaged upfront esophagectomy patients.	('esophageal cancer', 'Disease', (160, 177))	('patients', 'Species', '9606', (244, 252))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cT2N0', 'Var', (154, 159))
793456	27083246	Of the cT2N0 patients, 932 (52.2%) had upfront esophagectomy, while 853 (47.8%) received induction therapy (at least two cycles of either chemotherapy or chemoradiation therapy) prior to esophagectomy.	('esophagectomy', 'Disease', (47, 60))	('patients', 'Species', '9606', (13, 21))	('cT2N0', 'Var', (7, 12))
793470	27083246	Factors independently associated with increased likelihood of receiving adjuvant therapy for upstaged upfront esophagectomy patients on multivariate analysis included adenocarcinoma histology (OR 2.8, 95% CI 1.3 - 6.1, p=0.01), increasing pathologic nodal stage (reference: N0, N1: OR 4.7, 2.2 - 10.4, p<0.001, N2: OR 14.4, 3.4 - 60.0, p<0.001), and positive surgical margins (OR 2.6, 1.2 - 5.7, p=0.01), while those associated with a decreased likelihood of receiving adjuvant therapy included increasing age (by year, OR 0.94, 0.91 - 0.97, p<0.001) and increasing length of inpatient stay after esophagectomy (by day, OR 0.95, 0.92 - 0.98, p<0.001).	('positive', 'Var', (350, 358))	('adenocarcinoma', 'Disease', 'MESH:D000230', (167, 181))	('patient', 'Species', '9606', (124, 131))	('patient', 'Species', '9606', (578, 585))	('patients', 'Species', '9606', (124, 132))	('adenocarcinoma', 'Disease', (167, 181))
793474	27083246	It is well known that a diagnosis of cT2N0 esophageal cancer presents a therapeutic dilemma in thoracic oncology due to inaccurate staging techniques at this time.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('oncology', 'Phenotype', 'HP:0002664', (104, 112))	('cT2N0', 'Var', (37, 42))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
793478	27083246	Even when using both PET/CT and EUS staging modalities, the likelihood of cT2N0 esophageal cancer correlating with actual pathologic stage is exceedingly low.	('cT2N0', 'Var', (74, 79))	('esophageal cancer', 'Disease', (80, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
793481	27083246	To date, no randomized controlled trial has evaluated the role of induction therapy in cT2N0 esophageal cancer, likely due to the small numbers of patients that present with this clinical stage (in previous series, approximately 8-9% of esophageal cancer patients).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (237, 254))	('cT2N0', 'Var', (87, 92))	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (237, 254))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('patients', 'Species', '9606', (255, 263))	('patients', 'Species', '9606', (147, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))
793498	27083246	While previous institutional reviews have shown that even though a majority of their patients were receiving both EUS and PET/CT staging, pathologic upstaging after esophagectomy still persisted among 50-60% of cT2N0 patients.	('upstaging', 'PosReg', (149, 158))	('cT2N0', 'Var', (211, 216))	('patients', 'Species', '9606', (217, 225))	('patients', 'Species', '9606', (85, 93))
793500	27083246	Another limitation is the inability to account for all selection biases and factors among patients that receive either induction therapy for cT2N0 esophageal cancer or adjuvant therapy for upstaged upfront cT2N0 esophagectomy patients.	('esophageal cancer', 'Disease', (147, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (147, 164))	('cT2N0', 'Var', (141, 146))	('patients', 'Species', '9606', (226, 234))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
793505	27083246	Additional prospective work is needed to validate this model, based primarily on tumor grade and presence of lymphvascular invasion, as well as to identify other factors associated with pathologic upstaging of cT2N0 esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (216, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cT2N0', 'Var', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('esophageal cancer', 'Disease', (216, 233))	('tumor', 'Disease', (81, 86))
793508	26959234	Risk of Gastrointestinal Cancers among Patients with Appendectomy: A Large-Scale Swedish Register-Based Cohort Study during 1970-2009 Removal of the appendix might induce physiological changes in the gastrointestinal tract, and subsequently play a role in carcinogenesis.	('gastrointestinal tract', 'Disease', (200, 222))	('Removal', 'Var', (134, 141))	('Gastrointestinal Cancers', 'Disease', (8, 32))	('role', 'Reg', (248, 252))	('induce', 'Reg', (164, 170))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (200, 222))	('Patients', 'Species', '9606', (39, 47))	('carcinogenesis', 'Disease', (256, 270))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('physiological changes', 'MPA', (171, 192))	('Cancers', 'Phenotype', 'HP:0002664', (25, 32))	('Gastrointestinal Cancers', 'Disease', 'MESH:D004067', (8, 32))	('play', 'Reg', (241, 245))	('carcinogenesis', 'Disease', 'MESH:D063646', (256, 270))
793518	26959234	The main reasons for the regular use of this operation include: 1) appendicitis is a potential deadly disease; 2) historically, the vermiform appendix was defined as a vestigial organ; and 3) the loss of the appendix is thought to have few, if any, long-term effects.	('appendicitis', 'Disease', 'MESH:D001064', (67, 79))	('appendicitis', 'Disease', (67, 79))	('loss', 'Var', (196, 200))
793519	26959234	However, recent data indicate that the appendix might serve as a reservoir for the colonic microbiome, and therefore the excision of the appendix may affect the components of gastrointestinal microbiome, which ultimately may play a role in the development of gastrointestinal cancers.	('components of gastrointestinal microbiome', 'MPA', (161, 202))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (259, 283))	('play', 'Reg', (225, 229))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (259, 282))	('gastrointestinal cancers', 'Disease', (259, 283))	('colon', 'Disease', (83, 88))	('men', 'Species', '9606', (251, 254))	('role', 'Reg', (232, 236))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('excision', 'Var', (121, 129))	('affect', 'Reg', (150, 156))	('colon', 'Disease', 'MESH:D015179', (83, 88))
793526	26959234	The dataset was then linked to the Swedish Cancer Registry, where all incident gastrointestinal cancer cases (Swedish International Classification of Diseases (ICD) (version 7) = 150 for esophageal cancer, 151 for gastric cancer, 1530-1533/ 1538/1539 for colon cancer (except appendix cancer), and 1540 for rectal cancer) were ascertained.	('gastric cancer', 'Disease', (214, 228))	('colon cancer', 'Phenotype', 'HP:0003003', (255, 267))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('appendix cancer', 'Disease', 'MESH:D001063', (276, 291))	('Cancer', 'Disease', (43, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (214, 228))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (79, 102))	('colon cancer', 'Disease', 'MESH:D015179', (255, 267))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('esophageal cancer', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('rectal cancer', 'Disease', (307, 320))	('rectal cancer', 'Phenotype', 'HP:0100743', (307, 320))	('gastrointestinal cancer', 'Disease', (79, 102))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (79, 102))	('appendix cancer', 'Disease', (276, 291))	('Cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('gastric cancer', 'Phenotype', 'HP:0012126', (214, 228))	('colon cancer', 'Disease', (255, 267))	('rectal cancer', 'Disease', 'MESH:D012004', (307, 320))	('1530-1533/ 1538/1539', 'Var', (230, 250))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
793527	26959234	Esophageal cancer was sub-grouped as esophageal adenocarcinoma and esophageal squamous-cell carcinoma, according to the histopathological diagnoses (patho-anatomic diagnosis, PAD, '096' for esophageal adenocarcinoma and '146' for esophageal squamous-cell carcinoma).	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (190, 215))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (190, 215))	('Esophageal cancer', 'Disease', (0, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('PAD', 'Var', (175, 178))	('esophageal adenocarcinoma', 'Disease', (190, 215))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (37, 62))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (37, 62))	('esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (67, 101))	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('esophageal adenocarcinoma', 'Disease', (37, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal squamous-cell carcinoma', 'Disease', (67, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (241, 264))	('esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (230, 264))	('esophageal squamous-cell carcinoma', 'Disease', (230, 264))
793576	26959234	A Danish study also showed elevated gastric cancer risk after appendectomy, but no altered risks were noted for colon cancer.	('appendectomy', 'Var', (62, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('gastric cancer', 'Disease', (36, 50))	('elevated gastric cancer risk', 'Phenotype', 'HP:0006753', (27, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colon cancer', 'Disease', (112, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
793592	26959234	Moreover, although no evidence suggests that H. pylori infection could directly affect the pathogenesis of appendicitis, the unspecific abdominal pain caused by H. pylori might potentially increase the likelihood of having appendectomy.	('pain', 'Phenotype', 'HP:0012531', (146, 150))	('unspecific abdominal pain', 'Phenotype', 'HP:0002574', (125, 150))	('appendicitis', 'Disease', (107, 119))	('caused', 'Reg', (151, 157))	('affect', 'Reg', (80, 86))	('H. pylori', 'Species', '210', (161, 170))	('abdominal pain', 'Phenotype', 'HP:0002027', (136, 150))	('abdominal pain', 'Disease', 'MESH:D015746', (136, 150))	('H. pylori', 'Species', '210', (45, 54))	('H. pylori infection', 'Phenotype', 'HP:0005202', (45, 64))	('appendectomy', 'Disease', (223, 235))	('infection', 'Disease', (55, 64))	('H. pylori', 'Var', (161, 170))	('appendicitis', 'Disease', 'MESH:D001064', (107, 119))	('infection', 'Disease', 'MESH:D007239', (55, 64))	('increase', 'PosReg', (189, 197))	('abdominal pain', 'Disease', (136, 150))
793601	31399104	High-Mobility Group Box 1 expression predicts survival of patients after resection of adenocarcinoma of the ampulla of Vater Expression of High-Mobility Group Box 1 (HMGB1), a multifunctional protein involved in DNA function as well as cell proliferation, inflammation, and the immune response, has been reported to be prognostic in several types of malignancies.	('High-Mobility Group Box 1', 'Gene', '3146', (0, 25))	('High-Mobility Group Box 1', 'Gene', (139, 164))	('malignancies', 'Disease', 'MESH:D009369', (350, 362))	('High-Mobility Group Box 1', 'Gene', '3146', (139, 164))	('Expression', 'Var', (125, 135))	('malignancies', 'Disease', (350, 362))	('High-Mobility Group Box 1', 'Gene', (0, 25))	('adenocarcinoma', 'Disease', (86, 100))	('HMGB1', 'Gene', (166, 171))	('inflammation', 'Disease', 'MESH:D007249', (256, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('patients', 'Species', '9606', (58, 66))	('inflammation', 'Disease', (256, 268))	('adenocarcinoma', 'Disease', 'MESH:D000230', (86, 100))
793607	31399104	Subgroup analysis showed that high HMGB1 expression was predictive, especially in patients who did not receive adjuvant chemotherapy.	('high', 'Var', (30, 34))	('HMGB1', 'Gene', (35, 40))	('patients', 'Species', '9606', (82, 90))	('expression', 'MPA', (41, 51))
793608	31399104	High HMGB1 expression is an independent predictor of poor prognosis in patients with adenocarcinoma of the ampulla of Vater not treated with adjuvant chemotherapy.	('adenocarcinoma', 'Disease', (85, 99))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('patients', 'Species', '9606', (71, 79))	('expression', 'MPA', (11, 21))	('adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))	('HMGB1', 'Gene', (5, 10))
793625	31399104	The level of lymph-node dissection for ampullary cancer was classified into the following three categories according to the General Rules for Surgical and Pathological Studies on Cancer of the Biliary Tract, 5th edition: D1, dissection of retro-pancreatic lymph-nodes; D2, dissection of pre-pancreatic lymph-nodes, mesenteric lymph-nodes (proximal portion of the superior mesenteric artery, inferior pancreaticoduodenal artery, middle colic artery, and jejunal artery), and lymph-nodes along the distal bile duct in addition to D1 dissection; and D3, dissection of para-aortic lymph-nodes and lymph-nodes around the celiac trunk, common hepatic artery, and hepato-duodenal ligament along with D2 dissection.	('para-aortic lymph-nodes', 'Disease', (565, 588))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('pancreatic', 'Disease', (291, 301))	('pancreatic', 'Disease', 'MESH:D010195', (400, 410))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ampullary cancer', 'Disease', 'MESH:D009369', (39, 55))	('retro-pancreatic lymph-nodes', 'Disease', 'MESH:D000072717', (239, 267))	('pancreatic', 'Disease', 'MESH:D010195', (245, 255))	('Cancer of the Biliary Tract', 'Disease', 'MESH:D001661', (179, 206))	('ampullary cancer', 'Disease', (39, 55))	('Cancer of the Biliary Tract', 'Phenotype', 'HP:0100574', (179, 206))	('retro-pancreatic lymph-nodes', 'Disease', (239, 267))	('pancreatic', 'Disease', (400, 410))	('middle colic artery', 'Disease', 'MESH:D020244', (428, 447))	('dissection', 'Var', (551, 561))	('superior mesenteric artery', 'Phenotype', 'HP:0100859', (363, 389))	('Cancer of the Biliary Tract', 'Disease', (179, 206))	('para-aortic lymph-nodes', 'Disease', 'MESH:D000072717', (565, 588))	('pancreatic', 'Disease', (245, 255))	('pancreatic', 'Disease', 'MESH:D010195', (291, 301))	('celiac trunk', 'Phenotype', 'HP:0012327', (616, 628))	('middle colic artery', 'Disease', (428, 447))
793647	31399104	Patients with high-expression HMGB1 underwent PD more frequently and showed a larger amount of blood loss than patients with low-expression.	('HMGB1', 'Gene', (30, 35))	('blood loss', 'Disease', 'MESH:D006473', (95, 105))	('Patients', 'Species', '9606', (0, 8))	('high-expression', 'Var', (14, 29))	('blood loss', 'Disease', (95, 105))	('PD', 'Disease', 'MESH:D010300', (46, 48))	('patients', 'Species', '9606', (111, 119))
793649	31399104	Kaplan-Meier analysis showed that the 5-year overall survival was significantly less in patients with high HMGB1 expression than in those with low HMGB1 expression (36.1% and 72.4%, respectively; P = 0.025; Fig.	('less', 'NegReg', (80, 84))	('high', 'Var', (102, 106))	('patients', 'Species', '9606', (88, 96))	('HMGB1', 'Gene', (107, 112))	('expression', 'Var', (113, 123))	('overall survival', 'MPA', (45, 61))
793651	31399104	3a), but not for patients who received adjuvant chemotherapy (5-year overall survival in high and low HMGB1 expression: 32.8% and 57.0%, respectively; P = 0.63; Fig.	('patients', 'Species', '9606', (17, 25))	('HMGB1', 'Gene', (102, 107))	('low', 'Var', (98, 101))
793663	31399104	Overexpression of HMGB1 was significantly correlated with poorer overall survival in esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, nasopharyngeal cancer, head and neck cancer, bladder cancer, cervical cancer, and pleural mesothelioma.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('pleural mesothelioma', 'Disease', (266, 286))	('Overexpression', 'Var', (0, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('hepatocellular carcinoma', 'Disease', (158, 182))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal cancer', 'Disease', (85, 102))	('head and neck cancer', 'Disease', 'MESH:D006258', (207, 227))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cervical cancer', 'Disease', (245, 260))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('cervical cancer', 'Disease', 'MESH:D002583', (245, 260))	('colorectal cancer', 'Disease', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('poorer', 'NegReg', (58, 64))	('nasopharyngeal cancer', 'Disease', (184, 205))	('pancreatic cancer', 'Disease', 'MESH:D010190', (139, 156))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (266, 286))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (266, 286))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (184, 205))	('HMGB1', 'Gene', (18, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (229, 243))	('bladder cancer', 'Disease', (229, 243))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('pancreatic cancer', 'Disease', (139, 156))	('head and neck cancer', 'Phenotype', 'HP:0012288', (207, 227))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (158, 182))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('bladder cancer', 'Phenotype', 'HP:0009725', (229, 243))	('overall survival', 'MPA', (65, 81))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (184, 205))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (158, 182))	('gastric cancer', 'Disease', (104, 118))
793671	31399104	Our study demonstrated that high HMGB1 expression was significantly associated with shorter survival for patients with adenocarcinoma of the ampulla of Vater following R0 resection.	('adenocarcinoma', 'Disease', (119, 133))	('patients', 'Species', '9606', (105, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('adenocarcinoma', 'Disease', 'MESH:D000230', (119, 133))	('survival', 'MPA', (92, 100))	('shorter', 'NegReg', (84, 91))	('expression', 'MPA', (39, 49))	('high', 'Var', (28, 32))	('HMGB1', 'Gene', (33, 38))
793673	31399104	Adjuvant chemotherapy for patients with high HMGB1 expression, as well as patients with lymph-node metastasis, may be effective for some patients.	('high', 'Var', (40, 44))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (137, 145))	('HMGB1', 'Gene', (45, 50))	('patients', 'Species', '9606', (26, 34))
793705	30254470	All ESCC samples have been confirmed by pathological examination after endoscopic mucosal dissection (ESD) or surgery; TNM staging was Tis or T1N0M0 (UICC2002).	('TNM', 'Gene', (119, 122))	('TNM', 'Gene', '10178', (119, 122))	('Tis or T1N0M0', 'Var', (135, 148))
793735	30254470	Blocking AXL expression can inhibit the survival, proliferation, migration and invasion of cancer cells and tumor growth of tumor tissue in vivo.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Blocking', 'Var', (0, 8))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', (124, 129))	('AXL', 'Gene', (9, 12))	('tumor', 'Disease', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('AXL', 'Gene', '558', (9, 12))	('inhibit', 'NegReg', (28, 35))	('survival', 'CPA', (40, 48))
793740	30254470	Li et al detected the expression of ARTN in EC cell lines KYSE-150, KYSE-510, EC9706 and TE13 and tissues and corresponding paracancerous tissues using Western blot.	('EC9706', 'CellLine', 'CVCL:E307', (78, 84))	('ARTN', 'Gene', (36, 40))	('paracancerous', 'Disease', 'None', (124, 137))	('ARTN', 'Gene', '9048', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('paracancerous', 'Disease', (124, 137))	('EC9706', 'Var', (78, 84))
793741	30254470	The results showed that the expression of ARTN in cancer tissues was high in paracancerous tissues; they were differentially expressed in various cell lines (KYSE-150>KYSE-510, TE13>EC9706).	('ARTN', 'Gene', '9048', (42, 46))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('paracancerous', 'Disease', (77, 90))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('TE13>EC9706', 'Var', (177, 188))	('EC9706', 'CellLine', 'CVCL:E307', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('KYSE-150>KYSE-510', 'Var', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ARTN', 'Gene', (42, 46))	('paracancerous', 'Disease', 'None', (77, 90))
793751	30254470	BDNF polymorphisms are associated with an increased esophageal sensitivity to experimental electrical stimulation, and BDNF genotypes may be the useful biomarkers of electrical sensitivity in healthy human esophageal tubes.	('increased', 'PosReg', (42, 51))	('esophageal tubes', 'Disease', 'MESH:D004941', (206, 222))	('BDNF', 'Gene', '627', (0, 4))	('BDNF', 'Gene', (119, 123))	('BDNF', 'Gene', (0, 4))	('human', 'Species', '9606', (200, 205))	('esophageal tubes', 'Disease', (206, 222))	('polymorphisms', 'Var', (5, 18))	('BDNF', 'Gene', '627', (119, 123))
793765	30254470	In ESCC cells, inhibit CR-1 gene expression can decrease the stem cells and EMT, tumorigenicity and thus affect the body and the body's ability to transfer.	('CR-1', 'Gene', (23, 27))	('ability to transfer', 'CPA', (136, 155))	('CR-1', 'Gene', '1378', (23, 27))	('affect', 'Reg', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('decrease', 'NegReg', (48, 56))	('inhibit', 'Var', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('body', 'CPA', (116, 120))	('tumor', 'Disease', (81, 86))
793777	30254470	Tumors are triggered by epigenetic or genetic alterations, leading to over-positive feedback or negative feedback of the Hedgehog signaling pathway.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('over-positive', 'PosReg', (70, 83))	('triggered', 'Reg', (11, 20))	('negative', 'NegReg', (96, 104))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('genetic alterations', 'Var', (38, 57))	('epigenetic', 'Var', (24, 34))	('Hedgehog signaling pathway', 'Pathway', (121, 147))
793786	30254470	Sims-Mourtada et al found that blocking the Hh signal enhanced the cytotoxicity of esophageal cancer cells, and the activation of the Hh pathway could promote the regeneration of tumor after chemoradiotherapy and facilitate the chemotherapy of esophageal cancer.	('facilitate', 'PosReg', (213, 223))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('esophageal cancer', 'Disease', (244, 261))	('esophageal cancer', 'Disease', (83, 100))	('cytotoxicity', 'Disease', (67, 79))	('Hh pathway', 'Pathway', (134, 144))	('chemotherapy', 'CPA', (228, 240))	('blocking', 'Var', (31, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))	('promote', 'PosReg', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('enhanced', 'PosReg', (54, 62))	('tumor', 'Disease', (179, 184))
793807	30254470	The overall survival and progression-free survival of patients with a high IL-6 expression in ESCC receiving cisplatin was significantly poorer.	('poorer', 'NegReg', (137, 143))	('patients', 'Species', '9606', (54, 62))	('progression-free survival', 'CPA', (25, 50))	('IL-6', 'Gene', (75, 79))	('expression', 'MPA', (80, 90))	('IL-6', 'Gene', '3569', (75, 79))	('high', 'Var', (70, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))
793810	30254470	Targeted inhibition of IL-6 may be an effective strategy for the treatment of esophageal cancer.	('IL-6', 'Gene', (23, 27))	('Targeted inhibition', 'Var', (0, 19))	('IL-6', 'Gene', '3569', (23, 27))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
793830	28577766	For patients with high-grade dysplasia, the risk of esophageal adenocarcinoma is approximately 6% per year, while those patients with low-grade dysplasia have a cancer incidence rate that lies between that of non-dysplastic Barrett's esophagus and high grade dysplastia.	('high-grade', 'Var', (18, 28))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (209, 243))	('patients', 'Species', '9606', (4, 12))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (52, 77))	('dysplasia', 'Disease', (144, 153))	("non-dysplastic Barrett's esophagus", 'Disease', (209, 243))	('dysplasia', 'Disease', 'MESH:D004476', (144, 153))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (52, 77))	('dysplastia', 'Disease', 'None', (259, 269))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('rat', 'Species', '10116', (178, 181))	('esophageal adenocarcinoma', 'Disease', (52, 77))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (224, 243))	('dysplasia', 'Disease', (29, 38))	('dysplasia', 'Disease', 'MESH:D004476', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('patients', 'Species', '9606', (120, 128))	('dysplastia', 'Disease', (259, 269))
793852	28577766	In 2000, Hanahan and Weinberg proposed the concept that genetic alterations of different molecular pathways alter normal cellular physiologic function, allowing cells to acquire essential cancer "hallmarks" that enable them to transform into malignant cells (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('genetic alterations', 'Var', (56, 75))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('rat', 'Species', '10116', (68, 71))	('cancer', 'Disease', (188, 194))	('alter', 'Reg', (108, 113))
793855	28577766	Finally, the acquisition of these cancer attributes is accelerated by two enabling features: 1) genome instability and mutation, which facilitate the genetic alterations essential for tumorigenesis, and 2) tumor-promoting inflammation, which supports the capabilities endowed by the core hallmarks.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mutation', 'Var', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('rat', 'Species', '10116', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (206, 211))	('inflammation', 'Disease', 'MESH:D007249', (222, 234))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('rat', 'Species', '10116', (61, 64))	('tumor', 'Disease', (184, 189))	('inflammation', 'Disease', (222, 234))	('cancer', 'Disease', (34, 40))	('genome instability', 'CPA', (96, 114))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('genetic', 'MPA', (150, 157))
793862	28577766	For example, colorectal cancers with mutant Ras respond to different chemotherapy than colorectal cancers negative for the Ras mutation.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Ras', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('colorectal cancers', 'Disease', 'MESH:D015179', (13, 31))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('colorectal cancers', 'Disease', 'MESH:D015179', (87, 105))	('colorectal cancers', 'Disease', (13, 31))	('mutant', 'Var', (37, 43))	('colorectal cancers', 'Disease', (87, 105))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))
793863	28577766	Categorization of breast cancers has led to targeted chemotherapy, as tumors with the HER2 mutation respond to specific chemotherapy targeted to the mutation, while other breast cancers do not.	('HER2', 'Gene', (86, 90))	('breast cancers', 'Disease', (171, 185))	('mutation', 'Var', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('HER2', 'Gene', '2064', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('breast cancers', 'Phenotype', 'HP:0003002', (18, 32))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancers', 'Disease', 'MESH:D001943', (18, 32))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('breast cancers', 'Disease', (18, 32))	('breast cancers', 'Phenotype', 'HP:0003002', (171, 185))	('breast cancers', 'Disease', 'MESH:D001943', (171, 185))
793872	28577766	Using complex bioinformatics analyses, they found that the majority of esophageal adenocarcinomas harbored a p53 mutation and that the same p53 mutation could be detected in the non-dysplastic Barrett's metaplasia of patients that progressed to cancer.	('mutation', 'Var', (113, 121))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (71, 97))	('harbored', 'Reg', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('patients', 'Species', '9606', (217, 225))	('cancer', 'Disease', (245, 251))	('esophageal adenocarcinomas', 'Disease', (71, 97))	("non-dysplastic Barrett's metaplasia", 'Disease', 'MESH:D001471', (178, 213))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (71, 96))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	("non-dysplastic Barrett's metaplasia", 'Disease', (178, 213))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
793873	28577766	They found a minority of tumors progressed along the traditional pathway of carcinogenesis, involving the step-wise accumulation of alterations in the p53 and p16 tumor suppressor genes, followed by oncogene activation, and then development of genomic instability.	('p16', 'Gene', '1029', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('activation', 'PosReg', (208, 218))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumors', 'Disease', (25, 31))	('alterations', 'Var', (132, 143))	('tumor', 'Disease', (25, 30))	('p53', 'Gene', '7157', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('p16', 'Gene', (159, 162))	('tumor', 'Disease', (163, 168))	('rat', 'Species', '10116', (136, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))	('p53', 'Gene', (151, 154))	('carcinogenesis', 'Disease', (76, 90))
793875	28577766	In this pathway, the cell first acquired a p53 mutation that gave that cell a growth advantage and allowed it to expand throughout the mucosa.	('growth advantage', 'CPA', (78, 94))	('p53', 'Gene', '7157', (43, 46))	('mutation', 'Var', (47, 55))	('p53', 'Gene', (43, 46))
793877	28577766	Whole genome doubling was then followed by genomic instability and oncogene amplification, resulting in malignancy.	('resulting in', 'Reg', (91, 103))	('malignancy', 'Disease', (104, 114))	('malignancy', 'Disease', 'MESH:D009369', (104, 114))	('oncogene amplification', 'Var', (67, 89))
793890	28577766	Another study examined the mutational load, determined from loss of heterozygosity and microsatellite instability of 10 genomic loci associated with tumor suppressor genes, as a potential biomarker for determining risk of dysplasia and cancer in Barrett's esophagus.	('loss of heterozygosity', 'Var', (60, 82))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('dysplasia and cancer', 'Disease', 'MESH:D009369', (222, 242))	('tumor', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	("Barrett's esophagus", 'Disease', (246, 265))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (246, 265))
793892	28577766	The mutational load score was significantly higher in patients who progressed to HGD/cancer than in patients who did not.	('mutational load', 'Var', (4, 19))	('higher', 'PosReg', (44, 50))	('patients', 'Species', '9606', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('patients', 'Species', '9606', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
793899	28577766	Among the potential molecular biomarkers in Barrett's esophagus, immunostaining for p53 protein alterations has advanced the farthest into clinical practice.	('alterations', 'Var', (96, 107))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (44, 63))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('protein', 'Protein', (88, 95))	('rat', 'Species', '10116', (100, 103))
793901	28577766	Activation of p53 decreases cell proliferation, a process that prevents cells with damaged DNA from undergoing mitosis and perpetuating the genomic damage.	('mitosis', 'Disease', (111, 118))	('decreases', 'NegReg', (18, 27))	('p53', 'Gene', (14, 17))	('mitosis', 'Disease', 'None', (111, 118))	('p53', 'Gene', '7157', (14, 17))	('rat', 'Species', '10116', (40, 43))	('cell proliferation', 'CPA', (28, 46))	('Activation', 'Var', (0, 10))	('prevents', 'NegReg', (63, 71))
793905	28577766	In contrast, mutant p53 protein is stable and overexpression can be easily detected in tissue samples by immunostaining techniques.	('mutant', 'Var', (13, 19))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('protein', 'Protein', (24, 31))
793906	28577766	In addition to overexpression, mutant p53 can also lead to loss of expression in tissue samples, which can also be evaluated by immunostaining.	('mutant', 'Var', (31, 37))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('expression', 'MPA', (67, 77))	('loss', 'NegReg', (59, 63))
793908	28577766	Aberrant p53 expression, defined as overexpression or loss of expression, was identified in 49% of biopsies from progressors compared to 14% in control biopsies who did not progress to HGD or cancer.	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('loss of', 'NegReg', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
793909	28577766	With aberrant p53 expression, the overall relative risk of neoplastic progression increased by a factor of 6.2.	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('expression', 'MPA', (18, 28))	('increased', 'PosReg', (82, 91))	('aberrant', 'Var', (5, 13))	('neoplastic progression', 'CPA', (59, 81))
793910	28577766	Aberrant p53 expression in non-dysplastic Barrett's esophagus was associated with an increased relative risk (RR 4.3) of neoplastic progression, whereas an even higher relative risk (RR 12.2) was seen for low grade dysplasia.	("non-dysplastic Barrett's esophagus", 'Disease', (27, 61))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (42, 61))	('dysplasia', 'Disease', (215, 224))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (27, 61))	('dysplasia', 'Disease', 'MESH:D004476', (215, 224))	('neoplastic progression', 'CPA', (121, 143))
793914	28577766	Aberrant p53 expression was significantly higher in the baseline biopsies of those patients that progressed to HGD or cancer (63.6%) than in those that did not progress (7.5%).	('cancer', 'Disease', (118, 124))	('HGD', 'Disease', (111, 114))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('higher', 'PosReg', (42, 48))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
793915	28577766	Multivariate analysis demonstrated that aberrant p53 expression in baseline Barrett's mucosal biopsies was a significant and independent predictor of progression to neoplasia (hazard ratio, HR 17).	('neoplasia', 'Disease', 'MESH:D009369', (165, 174))	('rat', 'Species', '10116', (183, 186))	('neoplasia', 'Phenotype', 'HP:0002664', (165, 174))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('rat', 'Species', '10116', (29, 32))	('neoplasia', 'Disease', (165, 174))	('expression', 'MPA', (53, 63))	('aberrant', 'Var', (40, 48))
793916	28577766	Recent studies such as these highlight the promise for biomarkers, in particular aberrant p53 expression, to predict cancer progression in Barrett's esophagus either alone or in combination with histology.	('aberrant', 'Var', (81, 89))	('p53', 'Gene', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('p53', 'Gene', '7157', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('expression', 'MPA', (94, 104))	('predict', 'Reg', (109, 116))	('cancer', 'Disease', (117, 123))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (139, 158))
793956	28577766	Among the potential molecular biomarkers, immunostaining for p53 has advanced the farthest into clinical practice with the British Society of Gastroenterology suggesting its use as an adjunct to the routine histologic assessment for dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (233, 242))	('p53', 'Gene', (61, 64))	('immunostaining', 'Var', (42, 56))	('p53', 'Gene', '7157', (61, 64))	('dysplasia', 'Disease', (233, 242))
793968	27546848	Studies in human patients and rodent models of cancer have identified alterations in the microbiota of the stomach, esophagus, and colon that increase the risk for malignancy.	('alterations', 'Var', (70, 81))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('human', 'Species', '9606', (11, 16))	('malignancy', 'Disease', (164, 174))	('cancer', 'Disease', (47, 53))	('rat', 'Species', '10116', (74, 77))	('patients', 'Species', '9606', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('malignancy', 'Disease', 'MESH:D009369', (164, 174))
793973	27546848	While genetic factors leading to an increased risk of cancer have been identified, such as adenomatous polyposis coli (APC) mutations that lead to familial adenomatous polyposis and E-cadherin (CDH1) mutations that lead to hereditary diffuse-type gastric cancer (GC), these mutations do not account for the majority of cases.	('mutations', 'Var', (200, 209))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('familial adenomatous polyposis', 'Disease', (147, 177))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (91, 112))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (147, 177))	('cancer', 'Disease', (255, 261))	('gastric cancer', 'Disease', 'MESH:D013274', (247, 261))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('CDH1', 'Gene', '999', (194, 198))	('gastric cancer', 'Phenotype', 'HP:0012126', (247, 261))	('lead to', 'Reg', (139, 146))	('CDH1', 'Gene', (194, 198))	('cancer', 'Disease', (54, 60))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (91, 117))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (91, 117))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('adenomatous polyposis coli', 'Disease', (91, 117))	('lead to', 'Reg', (215, 222))	('mutations', 'Var', (124, 133))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (156, 177))	('E-cadherin', 'Gene', (182, 192))	('GC', 'Phenotype', 'HP:0012126', (263, 265))	('gastric cancer', 'Disease', (247, 261))	('E-cadherin', 'Gene', '999', (182, 192))	('APC', 'Phenotype', 'HP:0005227', (119, 122))
794027	27546848	Alternatively, changes in the gastric microbiota resulting from the loss of H. pylori may increase the risk for an individual to develop esophageal cancer (Figure 1).	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('changes', 'Reg', (15, 22))	('H. pylori', 'Gene', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('H. pylori', 'Species', '210', (76, 85))	('loss', 'Var', (68, 72))	('esophageal cancer', 'Disease', (137, 154))
794035	27546848	The initiation of CRC can be due to mutations in tumor-suppressor genes such as APC, catenin (cadherin-associated protein) beta 1 (CTNNB1), tumor protein p53 (TP53) and the oncogene Kirsten rat sarcoma viral oncogene homolog (KRAS), leading to a growth advantage in colonic epithelial cells progressing to adenomas and cancer.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('CTNNB1', 'Gene', '84353', (131, 137))	('cancer', 'Disease', (319, 325))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('KRAS', 'Gene', (226, 230))	('CTNNB1', 'Gene', (131, 137))	('APC', 'Phenotype', 'HP:0005227', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('rat', 'Species', '10116', (190, 193))	('growth', 'PosReg', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('APC', 'Gene', (80, 83))	('CRC', 'Disease', (18, 21))	('adenomas', 'Disease', 'MESH:D000236', (306, 314))	('adenomas', 'Disease', (306, 314))	('TP53', 'Gene', '24842', (159, 163))	('CRC', 'Phenotype', 'HP:0003003', (18, 21))	('tumor', 'Disease', (49, 54))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('sarcoma', 'Disease', (194, 201))	('catenin (cadherin-associated protein) beta 1', 'Gene', '84353', (85, 129))	('KRAS', 'Gene', '24525', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutations', 'Var', (36, 45))	('p53', 'Gene', '24842', (154, 157))	('TP53', 'Gene', (159, 163))	('p53', 'Gene', (154, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('tumor', 'Disease', (140, 145))
794040	27546848	While the microbiome contributes to both immune system development and the release of key nutrients and energy from dietary intake, alterations in the microbiome related to chronic inflammation appear to play a role in promoting the increased risk of carcinogenesis seen in inflammatory bowel disease patients.	('chronic inflammation', 'Disease', 'MESH:D007249', (173, 193))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (274, 300))	('promoting', 'PosReg', (219, 228))	('inflammatory bowel disease', 'Disease', (274, 300))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (274, 300))	('alterations', 'Var', (132, 143))	('carcinogenesis', 'Disease', 'MESH:D063646', (251, 265))	('patients', 'Species', '9606', (301, 309))	('carcinogenesis', 'Disease', (251, 265))	('rat', 'Species', '10116', (136, 139))	('chronic inflammation', 'Disease', (173, 193))
794046	27546848	However, no single microbial species has been identified as a causative agent leading to a working model that overall disturbances in the composition, diversity, or functional properties of the colonic microbiota dysregulate the balance between the epithelium and the immune system towards inflammation, dysplasia, and ultimately cancer.	('dysregulate', 'Reg', (213, 224))	('inflammation', 'Disease', 'MESH:D007249', (290, 302))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('dysplasia', 'Disease', (304, 313))	('inflammation', 'Disease', (290, 302))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('dysplasia', 'Disease', 'MESH:D004476', (304, 313))	('disturbances', 'Var', (118, 130))	('cancer', 'Disease', (330, 336))
794057	27546848	APCMin/+ mice possess a point mutation in the murine homolog of the human APC tumor-suppressor gene resulting in spontaneous adenomas, primarily in the small intestine.	('APC tumor', 'Disease', (74, 83))	('adenomas', 'Disease', 'MESH:D000236', (125, 133))	('human', 'Species', '9606', (68, 73))	('adenomas', 'Disease', (125, 133))	('point mutation', 'Var', (24, 38))	('spontaneous', 'CPA', (113, 124))	('APC', 'Phenotype', 'HP:0005227', (0, 3))	('murine', 'Species', '10090', (46, 52))	('Min', 'Phenotype', 'HP:0200008', (3, 6))	('APC tumor', 'Disease', 'MESH:D011125', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mice', 'Species', '10090', (9, 13))	('APC', 'Phenotype', 'HP:0005227', (74, 77))
794060	27546848	Furthermore, mono-association with Bacteroides vulgatus reduced colorectal tumorigenesis in IL10-/- mice versus conventionally housed controls.	('Bacteroides vulgatus', 'Species', '821', (35, 55))	('mice', 'Species', '10090', (100, 104))	('reduced', 'NegReg', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mono-association', 'Var', (13, 29))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('Bacteroides vulgatus', 'Gene', (35, 55))
794080	27446439	In addition, the knockdown of SOX4 expression by short hairpin RNA decreases ESCC cell proliferation and enhances doxorubicin-induced cell senescence.	('enhances', 'PosReg', (105, 113))	('ESCC', 'Disease', (77, 81))	('expression', 'Species', '29278', (35, 45))	('decreases ESCC', 'Phenotype', 'HP:0025022', (67, 81))	('SOX4', 'Gene', (30, 34))	('decreases', 'NegReg', (67, 76))	('knockdown', 'Var', (17, 26))	('short hairpin RNA', 'Gene', (49, 66))	('doxorubicin', 'Chemical', 'MESH:D004317', (114, 125))	('doxorubicin-induced cell senescence', 'MPA', (114, 149))
794091	27446439	In addition, the deregulated expression of SOX4 has been shown to induce an epithelial-to-mesenchymal transition and metastasis in cancer cells.	('cancer', 'Disease', (131, 137))	('epithelial-to-mesenchymal transition', 'CPA', (76, 112))	('induce', 'Reg', (66, 72))	('deregulated', 'Var', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('SOX4', 'Gene', (43, 47))	('expression', 'Species', '29278', (29, 39))	('expression', 'MPA', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
794118	27446439	Following selection with 100 microg/ml of G418 for 2 weeks, two cell lines were obtained in which SOX4 were stably knocked down (Fig.	('SOX4', 'Gene', (98, 102))	('knocked down', 'Var', (115, 127))	('G418', 'Chemical', 'MESH:C010680', (42, 46))
794141	27446439	Previous studies identified various oncogenes that mutated in ESCC, including tumor protein 53 (p53), RB transcriptional corepressor 1, CDKN2A, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha and NOTCH1.	('tumor protein 53', 'Gene', '7157', (78, 94))	('NOTCH1', 'Gene', '4851', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('CDKN2A', 'Gene', (136, 142))	('CDKN2A', 'Gene', '1029', (136, 142))	('tumor protein 53', 'Gene', (78, 94))	('NOTCH1', 'Gene', (219, 225))	('RB transcriptional corepressor 1', 'Gene', '5925', (102, 134))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (144, 181))	('ESCC', 'Gene', (62, 66))	('RB transcriptional corepressor 1', 'Gene', (102, 134))	('mutated', 'Var', (51, 58))
794143	27446439	SOX4 knockdown decreased cell proliferation and enhanced doxorubicin-induced cellular senescence in vitro.	('knockdown', 'Var', (5, 14))	('cell proliferation', 'CPA', (25, 43))	('enhanced', 'PosReg', (48, 56))	('SOX4', 'Gene', (0, 4))	('doxorubicin-induced', 'MPA', (57, 76))	('decreased', 'NegReg', (15, 24))	('doxorubicin', 'Chemical', 'MESH:D004317', (57, 68))
794160	25873175	Activating mutations of PI3KCA have been found in 6 to 20% of H&N and 4-10 % of esophageal SCC, with the hot spot E542K, E545K and H1047R substitutions being the most common.	('PI3KCA', 'Gene', (24, 30))	('Activating', 'PosReg', (0, 10))	('E545K', 'Mutation', 'p.E545K', (121, 126))	('H1047R', 'Mutation', 'p.H1047R', (131, 137))	('SCC', 'Gene', '6317', (91, 94))	('spot', 'Var', (109, 113))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('and', 'Var', (127, 130))	('SCC', 'Gene', (91, 94))	('of esophageal', 'Disease', (77, 90))	('E542K', 'Mutation', 'p.E542K', (114, 119))
794161	25873175	Moreover, increase in PIK3CA copy number has been found in up to 30% of H&N and 40% of esophageal tumors and is associated with poor prognosis.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('increase', 'PosReg', (10, 18))	('copy number', 'Var', (29, 40))	('PIK3CA', 'Gene', '5290', (22, 28))	('esophageal tumors', 'Disease', 'MESH:D004938', (87, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('esophageal tumors', 'Disease', (87, 104))	('esophageal tumors', 'Phenotype', 'HP:0100751', (87, 104))	('PIK3CA', 'Gene', (22, 28))
794163	25873175	In the first-in-human clinical trial of the PI3Kalpha specific inhibitor BYL719 in solid tumors (NCT01387321), we have recently reported that eight patients with H&N tumors harboring PI3KCA mutations had a clinical response to therapy (Juric et al., unpublished results).	('N tumors', 'Disease', 'MESH:D009369', (164, 172))	('patients', 'Species', '9606', (148, 156))	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('PI3KCA', 'Var', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('harboring', 'Gene', (173, 182))	('solid tumors', 'Disease', (83, 95))	('N', 'Chemical', 'MESH:D009584', (164, 165))	('N tumors', 'Disease', (164, 172))	('human', 'Species', '9606', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('PI3Kalpha', 'Gene', '5290', (44, 53))	('PI3Kalpha', 'Gene', (44, 53))
794171	25873175	In terms of PIK3CA status and sensitivity to BYL719, 76% (19/25) of cell lines bearing either mutations or amplification (copy number>4) in PIK3CA were sensitive while only 48% (16/33) of cell lines bearing WT-PIK3CA were sensitive (Figure 1A).	('amplification', 'Var', (107, 120))	('PIK3CA', 'Gene', '5290', (12, 18))	('PIK3CA', 'Gene', (140, 146))	('mutations', 'Var', (94, 103))	('sensitive', 'Reg', (152, 161))	('PIK3CA', 'Gene', '5290', (140, 146))	('PIK3CA', 'Gene', (210, 216))	('PIK3CA', 'Gene', '5290', (210, 216))	('PIK3CA', 'Gene', (12, 18))
794172	25873175	PIK3CA mutation/amplification was the only genomic alteration that predicted sensitivity to BYL719 (Figure S1A).	('PIK3CA', 'Gene', (0, 6))	('sensitivity to BYL719', 'MPA', (77, 98))	('PIK3CA', 'Gene', '5290', (0, 6))	('predicted', 'Reg', (67, 76))	('mutation/amplification', 'Var', (7, 29))
794173	25873175	To study the molecular mechanisms by which acquisition of resistance to BYL719 emerges, we selected four sensitive cell lines bearing either amplified or mutated PIK3CA (CAL33, LB771-HNC, KYSE70 and KYSE180) and exposed them over time to increasing concentrations of BYL719 until resistance emerged (Figure 1B; Figure S1B and S1C).	('LB771-HNC', 'CellLine', 'CVCL:1369', (177, 186))	('PIK3CA', 'Gene', '5290', (162, 168))	('KYSE70', 'Var', (188, 194))	('KYSE180', 'Chemical', '-', (199, 206))	('mutated', 'Var', (154, 161))	('LB771-HNC', 'Var', (177, 186))	('PIK3CA', 'Gene', (162, 168))
794174	25873175	While AKT and its downstream effector PRAS40 were equally suppressed by BYL719 treatment in both parental and resistant cells, mTOR activity was not abolished upon PI3Kalpha inhibition in resistant cells as indicated by persistent phosphorylation of its downstream ribosomal protein S6 (pS6) in residues 235/6 and 240/4 (Figure 1C).	('phosphorylation', 'MPA', (231, 246))	('AKT', 'Gene', (6, 9))	('BYL719', 'Var', (72, 78))	('PI3Kalpha', 'Gene', (164, 173))	('ribosomal protein S6', 'Gene', '6194', (265, 285))	('PI3Kalpha', 'Gene', '5290', (164, 173))	('PRAS40', 'Gene', '84335', (38, 44))	('suppressed', 'NegReg', (58, 68))	('PRAS40', 'Gene', (38, 44))	('ribosomal protein S6', 'Gene', (265, 285))	('mTOR', 'Gene', (127, 131))	('AKT', 'Gene', '207', (6, 9))	('mTOR', 'Gene', '2475', (127, 131))	('pS6', 'Gene', (287, 290))
794177	25873175	We were able to independently demonstrate the causative role of mTOR in resistance to BYL719 in a synthetic lethality shRNA screen for 134 cancer-related genes performed in three BYL719-resistant cell lines (CAL33R, KYSE180R and the intrinsically resistant HSC3).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('KYSE180R', 'Var', (216, 224))	('CAL33R', 'Var', (208, 214))	('HSC3', 'Gene', '150353', (257, 261))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('CAL33R', 'Chemical', '-', (208, 214))	('mTOR', 'Gene', (64, 68))	('HSC3', 'Gene', (257, 261))	('mTOR', 'Gene', '2475', (64, 68))	('KYSE180', 'Chemical', '-', (216, 223))	('N', 'Chemical', 'MESH:D009584', (121, 122))	('cancer', 'Disease', (139, 145))
794178	25873175	We observed that MTOR, which encodes mTOR, was the top gene that when knocked down re-sensitized resistant cells to the antiproliferative activity of BYL719 (Figures 1E; Figure S1E; Table S1).	('MTOR', 'Gene', (17, 21))	('mTOR', 'Gene', (37, 41))	('antiproliferative activity', 'MPA', (120, 146))	('mTOR', 'Gene', '2475', (37, 41))	('knocked', 'Var', (70, 77))	('MTOR', 'Gene', '2475', (17, 21))
794187	25873175	Of note, in LB771-HNC cells EGF was superior to HGF in maintaining S6 phosphorylation and inducing proliferation in the presence of BYL719 (Figure S2D).	('EGF', 'Gene', '1950', (28, 31))	('HGF', 'Gene', (48, 51))	('EGF', 'Gene', (28, 31))	('inducing', 'Reg', (90, 98))	('HGF', 'Gene', '3082', (48, 51))	('LB771-HNC', 'Var', (12, 21))	('proliferation', 'CPA', (99, 112))	('LB771-HNC', 'CellLine', 'CVCL:1369', (12, 21))
794189	25873175	Treatment with BYL719 in combination with erlotinib, an EGFR kinase inhibitor, but not with MGCD235 or crizotinib, another cMET kinase inhibitor, resulted in suppression of S6 phosphorylation (Figure 2E; Figure S2E).	('EGFR', 'Gene', '1956', (56, 60))	('MGCD235', 'Chemical', '-', (92, 99))	('BYL719', 'Var', (15, 21))	('EGFR', 'Gene', (56, 60))	('cMET', 'Gene', '4233', (123, 127))	('crizotinib', 'Chemical', 'MESH:D000077547', (103, 113))	('cMET', 'Gene', (123, 127))	('suppression', 'NegReg', (158, 169))	('S6 phosphorylation', 'MPA', (173, 191))	('erlotinib', 'Chemical', 'MESH:D000069347', (42, 51))
794191	25873175	Based on these results we decided to confirm that activation of EGFR is sufficient to reverse tumor growth inhibition induced by treatment with BYL719 in vivo.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('activation', 'Var', (50, 60))
794198	25873175	In SCC cells with acquired resistance to BYL719, the addition of cetuximab to BYL719 was superior to both agents given alone in reducing S6 phosphorylation (Figure 3A) and in induction of cell death and/or reduction of proliferation (Figure 3B; Figure S3A and S3B).	('cetuximab', 'Gene', (65, 74))	('reduction', 'NegReg', (206, 215))	('proliferation', 'CPA', (219, 232))	('cell death', 'CPA', (188, 198))	('SCC', 'Gene', '6317', (3, 6))	('reducing', 'NegReg', (128, 136))	('BYL719', 'Var', (78, 84))	('SCC', 'Gene', (3, 6))	('cetuximab', 'Chemical', 'MESH:D000068818', (65, 74))
794201	25873175	A similar antitumor activity of the combination of BYL719 and cetuximab was observed also in cells with intrinsic resistance to BYL719, both in vitro (Figure 3E; Table S3) and in vivo (Figure 3F).	('tumor', 'Disease', (14, 19))	('cetuximab', 'Chemical', 'MESH:D000068818', (62, 71))	('BYL719', 'Var', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cetuximab', 'Gene', (62, 71))
794203	25873175	Despite both BYL719 and cetuximab effectively reducing cell viability, the combination was significantly superior to single agent (Figure 3G; Figure S3D; Table S3).	('cell viability', 'CPA', (55, 69))	('cetuximab', 'Chemical', 'MESH:D000068818', (24, 33))	('BYL719', 'Var', (13, 19))	('reducing', 'NegReg', (46, 54))
794205	25873175	Pharmacodynamic analysis of KYSE180 xenografts confirmed that the combination of BYL719 and cetuximab reduced cell proliferation and induced cell death compared to single agent treatment (Figure S3F).	('BYL719', 'Var', (81, 87))	('cetuximab', 'Gene', (92, 101))	('cetuximab', 'Chemical', 'MESH:D000068818', (92, 101))	('combination', 'Interaction', (66, 77))	('cell death', 'CPA', (141, 151))	('cell proliferation', 'CPA', (110, 128))	('KYSE180', 'Chemical', '-', (28, 35))	('reduced', 'NegReg', (102, 109))
794213	25873175	Analysis from the TCGA database indicated that high expression of AXL (among the top 10 up-regulated genes) was associated with poor-prognosis in patients with H&N tumors bearing either mutations or amplification of PIK3CA (Figure S4C and S4D).	('high', 'PosReg', (47, 51))	('N tumors', 'Disease', 'MESH:D009369', (162, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('PIK3CA', 'Gene', (216, 222))	('either', 'Var', (179, 185))	('expression', 'MPA', (52, 62))	('AXL', 'Gene', '558', (66, 69))	('PIK3CA', 'Gene', '5290', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('patients', 'Species', '9606', (146, 154))	('N tumors', 'Disease', (162, 170))	('AXL', 'Gene', (66, 69))
794226	25873175	The higher levels of AXL in our resistant models (CAL33R and KYSAE180R) coincided with increased EGFR and AXL interaction as shown by EGFR-AXL co-immunoprecipitation (Figure 4H).	('increased', 'PosReg', (87, 96))	('AXL', 'Gene', '558', (139, 142))	('EGFR', 'Gene', (134, 138))	('EGFR', 'Gene', '1956', (97, 101))	('interaction', 'Interaction', (110, 121))	('AXL', 'Gene', '558', (21, 24))	('AXL', 'Gene', (139, 142))	('CAL33R', 'Chemical', '-', (50, 56))	('CAL33R', 'Var', (50, 56))	('KYSAE180R', 'Var', (61, 70))	('EGFR', 'Gene', (97, 101))	('higher', 'PosReg', (4, 10))	('AXL', 'Gene', '558', (106, 109))	('AXL', 'Gene', (106, 109))	('EGFR', 'Gene', '1956', (134, 138))	('AXL', 'Gene', (21, 24))	('levels', 'MPA', (11, 17))
794234	25873175	Likewise, knocking-down the expression of AXL in cell lines with acquired resistance to BYL719 re-sensitized the cells to PI3Kalpha inhibition (Figure 5B).	('AXL', 'Gene', (42, 45))	('AXL', 'Gene', '558', (42, 45))	('knocking-down', 'Var', (10, 23))	('PI3Kalpha', 'Gene', '5290', (122, 131))	('PI3Kalpha', 'Gene', (122, 131))
794240	25873175	Tyrosine1173 in EGFR, when phosphorylated, functions as a docking site for phospholipase Cgamma (PLCgamma).	('docking', 'Interaction', (58, 65))	('PLC', 'Gene', (97, 100))	('Tyrosine1173', 'Var', (0, 12))	('EGFR', 'Gene', '1956', (16, 20))	('PLC', 'Gene', '5335', (97, 100))	('Tyrosine1173', 'Chemical', '-', (0, 12))	('EGFR', 'Gene', (16, 20))
794248	25873175	Similarly, inhibition of AXL by R428 prevented the specific interaction between the residue 1173 of EGFR with AXL, as shown in the immunoprecipitation experiment (Figure 6C; Figure S6B) or by proximity ligation assay (Figure S6C).	('AXL', 'Gene', '558', (110, 113))	('EGFR', 'Gene', '1956', (100, 104))	('AXL', 'Gene', (110, 113))	('R428', 'Var', (32, 36))	('EGFR', 'Gene', (100, 104))	('inhibition', 'NegReg', (11, 21))	('R428', 'Chemical', '-', (32, 36))	('AXL', 'Gene', '558', (25, 28))	('interaction', 'Interaction', (60, 71))	('prevented', 'NegReg', (37, 46))	('AXL', 'Gene', (25, 28))	('specific', 'MPA', (51, 59))
794249	25873175	Furthermore, co-treatment with BYL719 and R428 inhibited PLCgamma phosphorylation and cooperated in suppressing S6 phosphorylation in cells with acquired resistance to BYL719 (Figure S6D).	('PLC', 'Gene', (57, 60))	('inhibited', 'NegReg', (47, 56))	('R428', 'Chemical', '-', (42, 46))	('PLC', 'Gene', '5335', (57, 60))	('R428', 'Var', (42, 46))	('suppressing', 'NegReg', (100, 111))	('S6 phosphorylation', 'MPA', (112, 130))
794263	25873175	Moreover, expression of AXL has been shown to induce resistance to targeted agents such as the EGFR/HER2 inhibitors lapatinib, erlotinib and cetuximab by re-activating the AKT, ERK and NF-KB pathways in breast, lung and H&N cancers.	('ERK', 'Gene', '5594', (177, 180))	('AXL', 'Gene', (24, 27))	('resistance', 'MPA', (53, 63))	('re-activating', 'PosReg', (154, 167))	('EGFR', 'Gene', '1956', (95, 99))	('lapatinib', 'Chemical', 'MESH:D000077341', (116, 125))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('breast', 'Disease', (203, 209))	('AKT', 'Gene', (172, 175))	('cetuximab', 'Chemical', 'MESH:D000068818', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ERK', 'Gene', (177, 180))	('N', 'Chemical', 'MESH:D009584', (185, 186))	('H&N cancers', 'Disease', 'MESH:D009369', (220, 231))	('H&N cancers', 'Disease', (220, 231))	('HER2', 'Gene', '2064', (100, 104))	('AXL', 'Gene', '558', (24, 27))	('AKT', 'Gene', '207', (172, 175))	('lung', 'Disease', (211, 215))	('induce', 'PosReg', (46, 52))	('erlotinib', 'Chemical', 'MESH:D000069347', (127, 136))	('expression', 'Var', (10, 20))	('EGFR', 'Gene', (95, 99))	('N', 'Chemical', 'MESH:D009584', (222, 223))	('HER2', 'Gene', (100, 104))
794266	25873175	The specificity of this activation is underscored by the fact that either knockdown or pharmacological inhibition of AXL was sufficient to decrease phosphorylation of this residue in our models.	('AXL', 'Gene', (117, 120))	('knockdown', 'Var', (74, 83))	('AXL', 'Gene', '558', (117, 120))	('phosphorylation of this residue', 'MPA', (148, 179))	('decrease', 'NegReg', (139, 147))
794270	25873175	It remains to be elucidated whether upfront treatment with dual PI3K and EGFR inhibitors would avoid AXL overexpression and prevent or delay the emergence of resistance.	('EGFR', 'Gene', '1956', (73, 77))	('AXL', 'Gene', (101, 104))	('EGFR', 'Gene', (73, 77))	('inhibitors', 'Var', (78, 88))	('avoid', 'NegReg', (95, 100))	('delay', 'NegReg', (135, 140))	('emergence of resistance', 'MPA', (145, 168))	('AXL', 'Gene', '558', (101, 104))
794286	25873175	Six-week-old female athymic NU/NU nude mice purchased from Charles River were injected with 1X107 of KYSE180, KYSE180R and CAL33.	('KYSE180', 'Chemical', '-', (101, 108))	('KYSE180', 'Var', (101, 108))	('KYSE180R', 'Var', (110, 118))	('CAL33', 'Var', (123, 128))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('nude mice', 'Species', '10090', (34, 43))	('KYSE180', 'Chemical', '-', (110, 117))
794287	25873175	5X106 HSC3, 5X106 A253 5X106 HSC2 and 3X106 FaDu subcutaneously in 100 microL culture media/Matrigel (BD Biosciences) 1:5.	('5X106 A253', 'Var', (12, 22))	('HSC3', 'Gene', (6, 10))	('HSC3', 'Gene', '150353', (6, 10))
794302	25873175	These tumors have frequent mutations and amplifications of PIK3CA, which encodes the p110alpha subunit of PI3Kalpha.	('mutations', 'Var', (27, 36))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('amplifications', 'Var', (41, 55))	('PIK3CA', 'Gene', (59, 65))	('tumors', 'Disease', (6, 12))	('p110alpha', 'Gene', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('p110alpha', 'Gene', '5290', (85, 94))	('PIK3CA', 'Gene', '5290', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('PI3Kalpha', 'Gene', '5290', (106, 115))	('PI3Kalpha', 'Gene', (106, 115))
794343	24875401	Variation in exposure to glycidamide may result from polymorphisms in CYP2E1 that cause this enzyme to have different catalytic rates.	('different catalytic rates', 'MPA', (108, 133))	('CYP2E1', 'Gene', (70, 76))	('glycidamide', 'Chemical', 'MESH:C071834', (25, 36))	('result from', 'Reg', (41, 52))	('rat', 'Species', '10116', (128, 131))	('polymorphisms', 'Var', (53, 66))
794346	24875401	Moreover, CYP2E1 knockout mice, compared with the wild type, showed a 95% reduction in acrylamide bioconversion to glycidamide.	('CYP2E1', 'Var', (10, 16))	('acrylamide', 'Chemical', 'MESH:D020106', (87, 97))	('reduction', 'NegReg', (74, 83))	('glycidamide', 'Chemical', 'MESH:C071834', (115, 126))	('acrylamide bioconversion to glycidamide', 'MPA', (87, 126))	('mice', 'Species', '10090', (26, 30))
794377	24875401	In addition, for a given cooked food item, acrylamide levels can be influenced by free sugars and asparagine composition of the raw food, variations in cooking temperatures, varying lengths of cooking time, and different cooking methods used.	('free sugars', 'MPA', (82, 93))	('acrylamide', 'Chemical', 'MESH:D020106', (43, 53))	('acrylamide levels', 'MPA', (43, 60))	('asparagine', 'Chemical', 'MESH:D001216', (98, 108))	('variations', 'Var', (138, 148))	('influenced', 'Reg', (68, 78))	('rat', 'Species', '10116', (165, 168))	('asparagine composition', 'MPA', (98, 120))	('sugars', 'Chemical', 'MESH:D000073893', (87, 93))
794431	24875401	In addition, the ATBC trial was an intervention trial and was not designed to evaluate dietary acrylamide associations with cancer, also the fact that the similar interventions among smokers has previously been shown to increase lung cancer risk, and may have influenced the observed lung cancer associations in Hirvonen et al.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('lung cancer', 'Disease', (229, 240))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('increase', 'PosReg', (220, 228))	('lung cancer', 'Disease', (284, 295))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('interventions', 'Var', (163, 176))	('lung cancer', 'Disease', 'MESH:D008175', (229, 240))	('ATBC', 'Chemical', '-', (17, 21))	('lung cancer', 'Disease', 'MESH:D008175', (284, 295))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('lung cancer', 'Phenotype', 'HP:0100526', (284, 295))	('cancer', 'Disease', (124, 130))	('acrylamide', 'Chemical', 'MESH:D020106', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (234, 240))	('cancer', 'Disease', (289, 295))
794450	24875401	There were no statistically significant associations between dietary acrylamide exposure and total postmenopausal breast cancer (hazard ratio (HR) 1.15; 95% CI 0.86-1.53), ER+ (HR 1.15; 95% CI 0.86-1.53), PR+ (HR 1.47; 95% CI 0.86-2.51), or ER+PR+ (HR 1.43; 95% CI 0.83-2.46), ER- (HR 0.95; 95% CI 0.52-1.72), PR- (HR 0.84; 95% CI 0.63-1.56), or ER-PR- (HR 0.90; 95% CI 0.48-1.68) breast cancer.	('acrylamide', 'Chemical', 'MESH:D020106', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', 'MESH:D001943', (381, 394))	('men', 'Species', '9606', (103, 106))	('breast cancer', 'Disease', (381, 394))	('ER-PR-', 'Var', (346, 352))	('breast cancer', 'Phenotype', 'HP:0003002', (381, 394))	('rat', 'Species', '10116', (136, 139))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
794498	24875401	Overall, the incidence rate ratio for associations between the adducts levels and breast cancer was not statistically significant (IRR 1.5; 95% CI 0.8-3.0).	('IRR', 'Gene', (131, 134))	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('associations', 'Interaction', (38, 50))	('RR 1', 'Gene', '6240', (132, 136))	('IRR', 'Gene', '3645', (131, 134))	('rat', 'Species', '10116', (23, 26))	('adducts', 'Var', (63, 70))	('RR 1', 'Gene', (132, 136))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('rat', 'Species', '10116', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
794500	24875401	In the fully adjusted model, receptor specific analyses revealed significant increased risk for ER+ breast cancer among women with highest adduct levels as compared to the lowest adduct levels(IRR 2.7; 95% CI 1.1-6.6).	('IRR', 'Gene', (193, 196))	('IRR', 'Gene', '3645', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('adduct levels', 'Var', (139, 152))	('women', 'Species', '9606', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))
794549	24875401	High-energy intake itself is associated with obesity and the increased the risk of several cancers, as well as exposure to acrylamide.	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('obesity', 'Phenotype', 'HP:0001513', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('High-energy', 'Var', (0, 11))	('acrylamide', 'Chemical', 'MESH:D020106', (123, 133))	('obesity', 'Disease', 'MESH:D009765', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('obesity', 'Disease', (45, 52))	('associated with', 'Reg', (29, 44))
794564	25043640	Nonetheless, there are no published studies of the relationship between PPARs gene polymorphisms and survival of patients with lung cancer or UADT cancers.	('PPAR', 'Gene', (72, 76))	('lung cancer', 'Disease', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('patients', 'Species', '9606', (113, 121))	('UADT cancers', 'Disease', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('polymorphisms', 'Var', (83, 96))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('PPAR', 'Gene', '5465', (72, 76))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('UADT cancers', 'Disease', 'MESH:D006258', (142, 154))
794566	25043640	We genotyped three potentially functional single nucleotide polymorphisms (SNPs) using Taqman--rs3734254 of the gene PPARD and rs10865710 and rs1801282 of the gene PPARG--and investigated their associations with lung and UADT cancer survival using Cox regression.	('investigated', 'Reg', (175, 187))	('rs3734254', 'Mutation', 'rs3734254', (95, 104))	('rs1801282', 'Mutation', 'rs1801282', (142, 151))	('rs1801282', 'Var', (142, 151))	('PPARD', 'Gene', (117, 122))	('rs10865710', 'Mutation', 'rs10865710', (127, 137))	('associations', 'Interaction', (194, 206))	('PPARD', 'Gene', '5467', (117, 122))	('PPARG', 'Gene', '5468', (164, 169))	('PPARG', 'Gene', (164, 169))	('UADT cancer', 'Disease', (221, 232))	('rs10865710', 'Var', (127, 137))	('UADT cancer', 'Disease', 'MESH:D006258', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
794567	25043640	The variant homozygote CC (vs. TT) of PPARD rs3734254 was inversely associated with mortality of both lung cancer (adjusted hazard ratio [aHR] = 0.63, 95% confidence interval [CI] = 0.42, 0.96) and UADT cancers (aHR = 0.51, 95% CI = 0.27, 0.99).	('associated', 'Reg', (68, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('rs3734254', 'Mutation', 'rs3734254', (44, 53))	('UADT cancers', 'Disease', 'MESH:D006258', (198, 210))	('PPARD', 'Gene', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('PPARD', 'Gene', '5467', (38, 43))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('rs3734254', 'Var', (44, 53))	('UADT cancers', 'Disease', (198, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
794569	25043640	Our findings suggest that lung-cancer patients with the CC variant of PPARD rs3734254 may have a survival advantage over lung-cancer patients with other gene variants.	('rs3734254', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung-cancer', 'Disease', (121, 132))	('lung-cancer', 'Disease', 'MESH:D008175', (121, 132))	('patients', 'Species', '9606', (133, 141))	('PPARD', 'Gene', '5467', (70, 75))	('PPARD', 'Gene', (70, 75))	('lung-cancer', 'Disease', 'MESH:D008175', (26, 37))	('survival advantage', 'CPA', (97, 115))	('patients', 'Species', '9606', (38, 46))	('lung-cancer', 'Disease', (26, 37))	('rs3734254', 'Mutation', 'rs3734254', (76, 85))
794583	25043640	Considering the cancer-related links with PPARs and the lack of epidemiologic studies examining their relation with lung- and UADT- cancer survival, we conducted this study to explore the association between PPARs gene polymorphisms and survival among patients with lung and UADT cancers.	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('cancer', 'Disease', (280, 286))	('UADT- cancer', 'Disease', (126, 138))	('PPAR', 'Gene', '5465', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('lung and UADT cancers', 'Disease', 'MESH:D008175', (266, 287))	('PPAR', 'Gene', '5465', (208, 212))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('association', 'Interaction', (188, 199))	('patients', 'Species', '9606', (252, 260))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('PPAR', 'Gene', (42, 46))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('polymorphisms', 'Var', (219, 232))	('PPAR', 'Gene', (208, 212))	('UADT- cancer', 'Disease', 'MESH:D006258', (126, 138))
794604	25043640	A total of one SNP in the gene PPARD (rs3734254) and four SNPs in the gene PPARG (rs10865710, rs1801282, rs3856806, and rs13306747) were selected.	('rs3856806', 'Var', (105, 114))	('PPARG', 'Gene', '5468', (75, 80))	('rs3734254', 'Mutation', 'rs3734254', (38, 47))	('PPARD', 'Gene', (31, 36))	('rs3856806', 'Mutation', 'rs3856806', (105, 114))	('rs1801282', 'Var', (94, 103))	('rs3734254', 'Var', (38, 47))	('PPARG', 'Gene', (75, 80))	('rs13306747', 'Var', (120, 130))	('rs1801282', 'Mutation', 'rs1801282', (94, 103))	('rs10865710', 'Mutation', 'rs10865710', (82, 92))	('PPARD', 'Gene', '5467', (31, 36))	('rs10865710', 'Var', (82, 92))	('rs13306747', 'Mutation', 'rs13306747', (120, 130))
794606	25043640	SNPs that did not meet the criteria of Hardy-Weinberg equilibrium (HWE) p-value >= Bonferroni-adjusted p-value of 0.01 and a genotyping call rate >= 95% were excluded, leaving rs3734254, rs10865710 and rs1801282 in the analysis.	('rs1801282', 'Mutation', 'rs1801282', (202, 211))	('rs1801282', 'Var', (202, 211))	('rs10865710', 'Var', (187, 197))	('rs10865710', 'Mutation', 'rs10865710', (187, 197))	('rs3734254', 'Mutation', 'rs3734254', (176, 185))	('rs3734254', 'Var', (176, 185))
794620	25043640	The CC (vs. TT) variant of rs3734254 was inversely associated with mortality (cHR = 0.65; 95% CI = 0.44, 0.96).	('associated', 'Reg', (51, 61))	('rs3734254', 'Var', (27, 36))	('inversely', 'NegReg', (41, 50))	('rs3734254', 'Mutation', 'rs3734254', (27, 36))
794623	25043640	When stratified by morphological types, we observed the CC (vs. TT) genotype of rs3734254 was associated with decreased risk of death in LCC in the crude model (cHR = 0.34; 95% CI = 0.12, 0.95) but not in the adjusted model (aHR = 0.32; 95% CI = 0.09, 1.06) or in the recessive models (CC vs. TT+TC).	('death', 'Disease', (128, 133))	('rs3734254', 'Var', (80, 89))	('LCC', 'Phenotype', 'HP:0030360', (137, 140))	('decreased', 'NegReg', (110, 119))	('rs3734254', 'Mutation', 'rs3734254', (80, 89))	('death', 'Disease', 'MESH:D003643', (128, 133))	('TT+TC', 'Chemical', '-', (293, 298))	('LCC', 'Disease', (137, 140))
794625	25043640	No associations were observed between SNP variants of the PPARG gene and lung cancer or UADT cancer mortality.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('UADT cancer', 'Disease', (88, 99))	('UADT cancer', 'Disease', 'MESH:D006258', (88, 99))	('variants', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('PPARG', 'Gene', '5468', (58, 63))	('PPARG', 'Gene', (58, 63))
794626	25043640	We further combined genotypes of all three SNPs (rs3734254, rs10865710 and rs1801282) based on the results from recessive models to evaluate joint effects on survival.	('rs1801282', 'Mutation', 'rs1801282', (75, 84))	('rs3734254', 'Var', (49, 58))	('rs1801282', 'Var', (75, 84))	('rs10865710', 'Mutation', 'rs10865710', (60, 70))	('rs3734254', 'Mutation', 'rs3734254', (49, 58))	('rs10865710', 'Var', (60, 70))
794629	25043640	Lung cancer patients with the CC variant of rs3734254 showed a clear survival advantage over the lung cancer patients of the other two genotypes (Log-rank test: p = 0.02, Figure 1a).	('patients', 'Species', '9606', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('advantage', 'PosReg', (78, 87))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('patients', 'Species', '9606', (109, 117))	('cancer', 'Disease', (5, 11))	('rs3734254', 'Mutation', 'rs3734254', (44, 53))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('survival', 'CPA', (69, 77))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('rs3734254', 'Var', (44, 53))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))
794630	25043640	In UADT cancers, better survival was observed for the rs10865710 GG variant carriers, in comparison with that of the CC/CG carriers; however, the log rank p-value was 0.20 (Figure 2b).	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('UADT cancers', 'Disease', (3, 15))	('better', 'PosReg', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('rs10865710', 'Mutation', 'rs10865710', (54, 64))	('UADT cancers', 'Disease', 'MESH:D006258', (3, 15))	('rs10865710 GG', 'Var', (54, 67))	('CG', 'Chemical', 'MESH:C028505', (120, 122))
794632	25043640	We noted that the inverse association of the CC variant of rs3734254 with cancer mortality was observed primarily in lung-cancer smokers (in the recessive model CC vs. TT+TC: aHR = 0.55; 95% CI = 0.35, 0.87).	('lung-cancer', 'Disease', 'MESH:D008175', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (122, 128))	('lung-cancer', 'Disease', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('TT+TC', 'Chemical', '-', (168, 173))	('rs3734254', 'Mutation', 'rs3734254', (59, 68))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('rs3734254', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('inverse', 'NegReg', (18, 25))
794633	25043640	Among lung-cancer non-smokers, the associations were much weaker (in the recessive model CC vs. TT+TC: aHR = 0.84; 95% CI = 0.31, 2.28); and p-value for the interaction between ever vs. never smokers and the CC vs. TT+TC variants was 0.21.	('TT+TC', 'Chemical', '-', (215, 220))	('lung-cancer', 'Disease', 'MESH:D008175', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('lung-cancer', 'Disease', (6, 17))	('TT+TC', 'Chemical', '-', (96, 101))	('weaker', 'NegReg', (58, 64))	('variants', 'Var', (221, 229))
794635	25043640	We found that the CC variant of rs3734254 of the gene PPARD was inversely associated with mortality in lung cancer and UADT cancers, and the association persisted in lung cancer with semi-Bayesian shrinkage which reduced the issue of false positive findings resulting from multiple comparisons.	('rs3734254', 'Mutation', 'rs3734254', (32, 41))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('UADT cancers', 'Disease', (119, 131))	('PPARD', 'Gene', '5467', (54, 59))	('UADT cancers', 'Disease', 'MESH:D006258', (119, 131))	('rs3734254', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('inversely', 'NegReg', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('lung cancer', 'Disease', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('associated', 'Reg', (74, 84))	('PPARD', 'Gene', (54, 59))
794637	25043640	Among those studies that examined multiple types of cancer, one study on lung cancer in the Chinese population shows that rs2972162 of PPARG is inversely associated with lung cancer, and this association differs little between smokers and non-smokers.	('cancer', 'Disease', (175, 181))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('rs2972162', 'Mutation', 'rs2972162', (122, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('PPARG', 'Gene', '5468', (135, 140))	('PPARG', 'Gene', (135, 140))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('inversely', 'NegReg', (144, 153))	('cancer', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('lung cancer', 'Disease', (170, 181))	('associated', 'Reg', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('rs2972162', 'Var', (122, 131))	('lung cancer', 'Disease', (73, 84))
794638	25043640	Our study was the first to examine the association of polymorphism of PPARs on survival of lung and UADT cancers and we did not find any associations between selected SNPs of PPARG and survival from either lung cancer or UADT cancers.	('UADT cancers', 'Disease', (100, 112))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('lung cancer', 'Disease', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('association', 'Interaction', (39, 50))	('UADT cancers', 'Disease', 'MESH:D006258', (221, 233))	('PPAR', 'Gene', (70, 74))	('PPAR', 'Gene', '5465', (175, 179))	('PPARG', 'Gene', '5468', (175, 180))	('UADT cancers', 'Disease', 'MESH:D006258', (100, 112))	('PPARG', 'Gene', (175, 180))	('lung and UADT cancers', 'Disease', 'MESH:D008175', (91, 112))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('PPAR', 'Gene', '5465', (70, 74))	('UADT cancers', 'Disease', (221, 233))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('polymorphism', 'Var', (54, 66))	('PPAR', 'Gene', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
794639	25043640	Although rs1801282 coding non-synonymous protein resulting Pro-to-Ala exchange of PPAR-gamma2--one isoform of PPAR-gamma--causes reduced transcriptional activity, the lack of expression of PPAR-gamma2 in the lung/UADT tissues may have resulted in the null findings.	('Ala', 'Chemical', 'MESH:D000409', (66, 69))	('PPAR-gamma', 'Gene', '5468', (82, 92))	('rs1801282 coding', 'Var', (9, 25))	('transcriptional activity', 'MPA', (137, 161))	('PPAR-gamma', 'Gene', (189, 199))	('PPAR-gamma', 'Gene', (110, 120))	('exchange', 'Var', (70, 78))	('PPAR-gamma', 'Gene', '5468', (189, 199))	('PPAR-gamma', 'Gene', '5468', (110, 120))	('Pro', 'Chemical', 'MESH:D011392', (59, 62))	('reduced', 'NegReg', (129, 136))	('PPAR-gamma', 'Gene', (82, 92))	('rs1801282', 'Mutation', 'rs1801282', (9, 18))
794641	25043640	PPARD rs3734254 is located on chromosome 6 and at a 3 prime untranslated region(3'-UTR).	('rs3734254', 'Var', (6, 15))	('PPARD', 'Gene', (0, 5))	('rs3734254', 'Mutation', 'rs3734254', (6, 15))	('PPARD', 'Gene', '5467', (0, 5))
794642	25043640	Two other SNPs of the gene PPARD are in LD with rs3734254.	('rs3734254', 'Var', (48, 57))	('rs3734254', 'Mutation', 'rs3734254', (48, 57))	('PPARD', 'Gene', '5467', (27, 32))	('PPARD', 'Gene', (27, 32))
794643	25043640	One is rs2076167 that results in a synonymous change to an asparagine residue and the other is rs1053049 within the PPARD 3'-UTR..	('asparagine', 'Chemical', 'MESH:D001216', (59, 69))	('PPARD', 'Gene', (116, 121))	('results in', 'Reg', (22, 32))	('PPARD', 'Gene', '5467', (116, 121))	('asparagine residue', 'MPA', (59, 77))	('rs1053049', 'Var', (95, 104))	('rs1053049', 'Mutation', 'rs1053049', (95, 104))	('rs2076167', 'Mutation', 'rs2076167', (7, 16))	('synonymous change', 'MPA', (35, 52))	('rs2076167', 'Var', (7, 16))
794644	25043640	The synonymous SNP (rs2076167) may alter the mRNA structure that might influence protein translation and folding.	('mRNA structure', 'MPA', (45, 59))	('protein translation', 'MPA', (81, 100))	('influence', 'Reg', (71, 80))	('rs2076167', 'Mutation', 'rs2076167', (20, 29))	('folding', 'MPA', (105, 112))	('alter', 'Reg', (35, 40))	('rs2076167', 'Var', (20, 29))
794645	25043640	SNPs at 3'-UTR (rs3734254 included in our study and rs1053049 in LD) might impact the stability of the corresponding mRNAs, all of which may affect the activity of PPAR-delta and influence the fate of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('affect', 'Reg', (141, 147))	('rs3734254', 'Mutation', 'rs3734254', (16, 25))	('impact', 'Reg', (75, 81))	('cancer', 'Disease', (201, 207))	('activity', 'MPA', (152, 160))	('influence', 'Reg', (179, 188))	('rs3734254', 'Var', (16, 25))	('stability of', 'MPA', (86, 98))	('PPAR-delta', 'Gene', '5467', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('rs1053049', 'Var', (52, 61))	('rs1053049', 'Mutation', 'rs1053049', (52, 61))	('PPAR-delta', 'Gene', (164, 174))
794655	25043640	Since PPAR-delta plays a pivotal role from energy and blood supply and inflammation reactions to cell differentiation, growth and apoptosis, it is reasonable to assume that the CC genotype of rs37342574 at 3'-UTR of PPARD identified by our study could affect the transcription of PPARD and change the expression of PPAR-delta, eventually increase survival through the interactive network PPAR-delta entangled.	('PPARD', 'Gene', '5467', (280, 285))	('affect', 'Reg', (252, 258))	('PPAR-delta', 'Gene', '5467', (388, 398))	('inflammation', 'Disease', (71, 83))	('PPAR-delta', 'Gene', (388, 398))	('increase', 'PosReg', (338, 346))	('rs37342574', 'Var', (192, 202))	('PPAR-delta', 'Gene', '5467', (315, 325))	('survival', 'CPA', (347, 355))	('PPAR-delta', 'Gene', '5467', (6, 16))	('PPAR-delta', 'Gene', (315, 325))	('PPAR-delta', 'Gene', (6, 16))	('interactive', 'Interaction', (368, 379))	('expression', 'MPA', (301, 311))	('change', 'Reg', (290, 296))	('PPARD', 'Gene', (216, 221))	('rs37342574', 'Mutation', 'rs37342574', (192, 202))	('PPARD', 'Gene', (280, 285))	('PPARD', 'Gene', '5467', (216, 221))	('inflammation', 'Disease', 'MESH:D007249', (71, 83))	('transcription', 'MPA', (263, 276))
794657	25043640	The inverse association between the CC (vs. TT) genotype of rs37342574 and morphology specific cancer survival was strongest for large cell carcinomas (LCC).	('cell carcinomas', 'Disease', (135, 150))	('rs37342574', 'Var', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('large cell carcinomas', 'Phenotype', 'HP:0030360', (129, 150))	('cancer', 'Disease', (95, 101))	('cell carcinomas', 'Disease', 'MESH:C538614', (135, 150))	('rs37342574', 'Mutation', 'rs37342574', (60, 70))	('inverse', 'NegReg', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('LCC', 'Phenotype', 'HP:0030360', (152, 155))
794658	25043640	However, the association between the CC (vs TT) genotype of rs37342574 and LCC mortality was weakened when adjusted for multiple testing and the 95% posterior limits contained the null after introducing a moderate prior to the actual data, which might indicate that the observation was simply due to chance.	('LCC mortality', 'Disease', (75, 88))	('LCC', 'Phenotype', 'HP:0030360', (75, 78))	('rs37342574', 'Var', (60, 70))	('rs37342574', 'Mutation', 'rs37342574', (60, 70))	('weakened', 'NegReg', (93, 101))
794660	25043640	The inverse association between the CC (vs. TT) genotype of rs37342574 and cancer death was much stronger in lung-cancer smokers than in non-smokers, but the power for testing this interaction in our data was low.	('rs37342574', 'Var', (60, 70))	('cancer death', 'Disease', (75, 87))	('lung-cancer', 'Disease', 'MESH:D008175', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer death', 'Disease', 'MESH:D003643', (75, 87))	('rs37342574', 'Mutation', 'rs37342574', (60, 70))	('stronger', 'PosReg', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('inverse', 'NegReg', (4, 11))	('lung-cancer', 'Disease', (109, 120))
794667	25043640	In fact, for the CC variant of PPARD rs3734254 that was still inversely related with lung cancer death even after semi-Bayesian shrinkage with a null prior, the missing of severe lung cancer patients with shorter survival would bias the association towards the null.	('rs3734254', 'Mutation', 'rs3734254', (37, 46))	('patients', 'Species', '9606', (191, 199))	('lung cancer death', 'Disease', 'MESH:D008175', (85, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('rs3734254', 'Var', (37, 46))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('PPARD', 'Gene', (31, 36))	('lung cancer death', 'Disease', (85, 102))	('missing of severe lung', 'Phenotype', 'HP:0005944', (161, 183))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))	('PPARD', 'Gene', '5467', (31, 36))
794671	25043640	We found that the CC variant of PPARD rs3734254 was inversely associated with lung-cancer mortality among diagnosed cases.	('PPARD', 'Gene', (32, 37))	('PPARD', 'Gene', '5467', (32, 37))	('lung-cancer', 'Disease', 'MESH:D008175', (78, 89))	('associated with', 'Reg', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rs3734254', 'Mutation', 'rs3734254', (38, 47))	('inversely', 'NegReg', (52, 61))	('rs3734254', 'Var', (38, 47))	('lung-cancer', 'Disease', (78, 89))
794675	25043640	Lung-cancer cases with the CC variant of rs3734254 may have a survival advantage.	('Lung-cancer', 'Disease', (0, 11))	('survival advantage', 'CPA', (62, 80))	('rs3734254', 'Mutation', 'rs3734254', (41, 50))	('Lung-cancer', 'Disease', 'MESH:D008175', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('rs3734254', 'Var', (41, 50))
794692	23560033	Several studies have demonstrated that aberrant expression of miRNAs is closely related to the pathogenesis and development of cancer, and miRNAs possess discriminatory power as cancer biomarkers.	('miR', 'Gene', '220972', (139, 142))	('related', 'Reg', (80, 87))	('miR', 'Gene', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('expression', 'MPA', (48, 58))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (127, 133))	('aberrant', 'Var', (39, 47))
794700	23560033	In this formula, n is the number needed, ualpha /2 is the test level, alpha is the cutoff value of two-tailed normal distribution, P is the expected value of sensitivity, and delta is the permissible error.	('mul', 'Gene', '4591', (11, 14))	('mul', 'Gene', (11, 14))	('ualpha /2', 'Var', (41, 50))
794751	23560033	The cutoff values of the 3 whole saliva miRNAs (miR-10b*, miR-144, and miR-451) were determined to be 0.74530111, 0.78131771, and 0.79964271, respectively.	('miR', 'Gene', (71, 74))	('0.74530111', 'Var', (102, 112))	('miR-451', 'Gene', '574411', (71, 78))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('miR-144', 'Gene', (58, 65))	('0.79964271', 'Var', (130, 140))	('miR-144', 'Gene', '406936', (58, 65))	('miR', 'Gene', '220972', (58, 61))	('miR-10b', 'Gene', '406903', (48, 55))	('miR', 'Gene', (58, 61))	('miR-451', 'Gene', (71, 78))	('miR', 'Gene', '220972', (48, 51))	('0.78131771', 'Var', (114, 124))	('miR', 'Gene', (48, 51))	('miR-10b', 'Gene', (48, 55))	('miR', 'Gene', '220972', (71, 74))
794754	23560033	By calculating the Younden index, the cutoff values of the 4 saliva supernatant miRNAs (miR-10b*, miR-144, miR-21, and miR-451) were determined to be 1.05078691, 8.08243248, 0.88851054, and 8.48817219, respectively.	('miR', 'Gene', (80, 83))	('miR-144', 'Gene', '406936', (98, 105))	('miR', 'Gene', '220972', (107, 110))	('miR-451', 'Gene', (119, 126))	('8.48817219', 'Var', (190, 200))	('miR-21', 'Gene', (107, 113))	('miR', 'Gene', '220972', (98, 101))	('1.05078691', 'Var', (150, 160))	('miR', 'Gene', (107, 110))	('miR', 'Gene', '220972', (88, 91))	('0.88851054', 'Var', (174, 184))	('miR-144', 'Gene', (98, 105))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (98, 101))	('miR', 'Gene', (88, 91))	('miR', 'Gene', '220972', (80, 83))	('miR-451', 'Gene', '574411', (119, 126))	('miR', 'Gene', (119, 122))	('miR-10b', 'Gene', (88, 95))	('8.08243248', 'Var', (162, 172))	('miR-10b', 'Gene', '406903', (88, 95))	('miR-21', 'Gene', '406991', (107, 113))
794765	23560033	The results also showed no significant differences [p = 0.8251 (miR-10b* vs. miR-21), 0.7699 (miR-10b* vs. miR-451), 0.7102 (miR-10b* vs. miR-144), 0.6079 (miR-21 vs. miR-451), 0.8729 (miR-21 vs. miR-144), and 0.3529 (miR-144 vs. miR-451)].	('miR-144', 'Gene', (196, 203))	('miR-21', 'Gene', '406991', (156, 162))	('miR-144', 'Gene', '406936', (218, 225))	('miR-10b', 'Gene', '406903', (94, 101))	('0.7699', 'Var', (86, 92))	('miR-451', 'Gene', (167, 174))	('miR-451', 'Gene', (230, 237))	('miR-21', 'Gene', (77, 83))	('miR-10b', 'Gene', (125, 132))	('miR-144', 'Gene', (138, 145))	('miR-10b', 'Gene', '406903', (125, 132))	('miR-21', 'Gene', (156, 162))	('miR-451', 'Gene', '574411', (107, 114))	('miR-21', 'Gene', '406991', (185, 191))	('0.3529', 'Var', (210, 216))	('miR-144', 'Gene', (218, 225))	('miR-144', 'Gene', '406936', (196, 203))	('miR-451', 'Gene', (107, 114))	('miR-21', 'Gene', '406991', (77, 83))	('miR-451', 'Gene', '574411', (167, 174))	('miR-10b', 'Gene', (64, 71))	('miR-21', 'Gene', (185, 191))	('miR-451', 'Gene', '574411', (230, 237))	('miR-144', 'Gene', '406936', (138, 145))	('miR-10b', 'Gene', (94, 101))	('miR-10b', 'Gene', '406903', (64, 71))
794769	23560033	The expression levels of these 3 miRNAs in whole saliva and saliva supernatant showed significant correlations [p = 0.000 (miR-10b*), 0.035 (miR-144), and 0.003 (miR-451)].	('miR', 'Gene', '220972', (33, 36))	('miR-10b', 'Gene', '406903', (123, 130))	('miR', 'Gene', (33, 36))	('miR-451', 'Gene', (162, 169))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('expression', 'MPA', (4, 14))	('miR-144', 'Gene', (141, 148))	('0.003', 'Var', (155, 160))	('0.035', 'Var', (134, 139))	('miR-10b', 'Gene', (123, 130))	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', (141, 144))	('miR-144', 'Gene', '406936', (141, 148))	('miR-451', 'Gene', '574411', (162, 169))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))
794783	23560033	reported that salivary mRNAs of DUSP1, H3F3A, OAZ1, S100P, SAT, IL-8, and IL-1 can detect oral cancer more accuately than can plasmatic mRNAs of these genes.	('IL-8', 'Gene', '3576', (64, 68))	('H3F3A', 'Gene', (39, 44))	('SAT', 'Gene', (59, 62))	('detect', 'Reg', (83, 89))	('IL-8', 'Gene', (64, 68))	('OAZ1', 'Gene', '4946', (46, 50))	('S100P', 'Var', (52, 57))	('oral cancer', 'Disease', 'MESH:D009062', (90, 101))	('DUSP1', 'Gene', '1843', (32, 37))	('DUSP1', 'Gene', (32, 37))	('IL-1', 'Gene', '3552', (74, 78))	('oral cancer', 'Disease', (90, 101))	('IL-1', 'Gene', (74, 78))	('S100P', 'SUBSTITUTION', 'None', (52, 57))	('H3F3A', 'Gene', '3020', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('SAT', 'Gene', '6303', (59, 62))	('OAZ1', 'Gene', (46, 50))
794816	23560033	found that not only did the overexpression of miR-144/451 protect cardiomyocytes, but loss of the miR-144/451 cluster impairs ischemic preconditioning-mediated cardioprotection by targeting Rac-1.	('miR-144', 'Gene', '406936', (46, 53))	('miR-144', 'Gene', (98, 105))	('ischemic', 'Disease', (126, 134))	('loss', 'Var', (86, 90))	('miR-144', 'Gene', '406936', (98, 105))	('Rac-1', 'Gene', '5879', (190, 195))	('Rac-1', 'Gene', (190, 195))	('ischemic', 'Disease', 'MESH:D007511', (126, 134))	('miR-144', 'Gene', (46, 53))	('targeting', 'Reg', (180, 189))	('impairs', 'NegReg', (118, 125))
794846	23560033	Thus aberrant expression of miRNAs in saliva may be an early molecular event in the pathogenesis of EC and do not show heterogeneity in EC patients.	('aberrant', 'Var', (5, 13))	('miR', 'Gene', '220972', (28, 31))	('patients', 'Species', '9606', (139, 147))	('miR', 'Gene', (28, 31))
794849	22099875	Aberrant methylation of the PTPRO gene in peripheral blood as a potential biomarker in esophageal squamous cell carcinoma patients Inactivation of protein tyrosine phosphatase receptor-type O (PTPRO), a new member of the PTP family, by hypermethylation has been described in several forms of cancers.	('methylation', 'Var', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('PTPRO', 'Gene', '5800', (28, 33))	('Inactivation', 'NegReg', (131, 143))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('PTPRO', 'Gene', (193, 198))	('protein tyrosine phosphatase receptor-type O', 'Gene', '5800', (147, 191))	('protein tyrosine phosphatase receptor-type O', 'Gene', (147, 191))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('Aberrant methylation', 'Var', (0, 20))	('cancers', 'Disease', 'MESH:D009369', (292, 299))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('PTPRO', 'Gene', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('cancers', 'Disease', (292, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('PTPRO', 'Gene', '5800', (193, 198))	('hypermethylation', 'Var', (236, 252))
794852	22099875	Among matched peripheral blood samples from ESCC patients, 13 (36.1%) of 36 had detectable methylated PTPRO in plasma, and 15 (41.7%) of 36 had it in the buffy coat.	('ESCC', 'Disease', (44, 48))	('PTPRO', 'Gene', (102, 107))	('patients', 'Species', '9606', (49, 57))	('methylated', 'Var', (91, 101))
794853	22099875	In addition, demethylation by 5-aza-dC treatment led to gene reactivation in PTPRO-methylated and -silenced ESCC cell lines.	('5-aza-dC', 'Chemical', 'MESH:D000077209', (30, 38))	('demethylation', 'Var', (13, 26))	('gene reactivation', 'MPA', (56, 73))
794872	22099875	Epigenetic silencing of tumor suppressor genes by aberrant promoter methylation plays a significant role in the initiation and development of cancers, and the presence of methylated tumor suppressor genes in tissue biopsy or body fluids can serve as tumor-specific markers.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('promoter', 'MPA', (59, 67))	('tumor', 'Disease', (182, 187))	('cancers', 'Disease', (142, 149))	('tumor', 'Disease', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('aberrant', 'Var', (50, 58))	('tumor', 'Disease', (250, 255))	('Epigenetic', 'MPA', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
794873	22099875	Previous studies demonstrated methylation-mediated down-regulation of PTPRO expression in rat hepatocellular carcinomas, human chronic lymphocytic leukemia, human lung cancer and some breast cancer cell lines.	('human', 'Species', '9606', (121, 126))	('lymphocytic leukemia', 'Disease', (135, 155))	('rat', 'Species', '10116', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (163, 174))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (127, 155))	('human', 'Species', '9606', (157, 162))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (94, 119))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (135, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('down-regulation', 'NegReg', (51, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('PTPRO', 'Gene', (70, 75))	('rat', 'Species', '10116', (90, 93))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (94, 119))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('expression', 'MPA', (76, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('breast cancer', 'Disease', (184, 197))	('hepatocellular carcinomas', 'Disease', (94, 119))	('methylation-mediated', 'Var', (30, 50))
794902	22099875	Among 36 matched peripheral blood samples, PTPRO was aberrantly methylated in 13 (36.1%) patients in plasma, as well as in 15 (41.7%) patients in buffy coat, i.e., 5 patients in plasma but not in buffy coat, 7 patients in buffy coat but not in plasma, and 8 patients in both plasma and buffy coat.	('aberrantly methylated', 'Var', (53, 74))	('patients', 'Species', '9606', (134, 142))	('PTPRO', 'Gene', (43, 48))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (210, 218))	('patients', 'Species', '9606', (258, 266))	('patients', 'Species', '9606', (166, 174))
794903	22099875	Methylated PTPRO was only observed in plasma or buffy coat from patients whose corresponding primary tumors were also methylated.	('Methylated', 'Var', (0, 10))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('primary tumors', 'Disease', (93, 107))	('primary tumors', 'Disease', 'MESH:D009369', (93, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))
794906	22099875	Methylation of PTPRO was more frequent in primary advanced-stage ESCC tumors (T3/T4) than in earlier T stages (T1/T2) (P = 0.013).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('PTPRO', 'Gene', (15, 20))	('Methylation', 'Var', (0, 11))	('ESCC tumors', 'Disease', (65, 76))	('frequent', 'Reg', (30, 38))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('ESCC tumors', 'Disease', 'MESH:D004938', (65, 76))
794910	22099875	These experiments showed that in cell lines (EC-109, TE-1 and TE-12) that lacked PTPRO expression, PTPRO was methylated, whereas in cell lines expressing PTPRO (HKESC-2 and NE-2), PTPRO was unmethylated (Fig.	('methylated', 'Var', (109, 119))	('PTPRO', 'Gene', (99, 104))	('EC-109', 'CellLine', 'CVCL:6898', (45, 51))
794911	22099875	To determine whether promoter hypermethylation was responsible for PTPRO inactivation, three ESCC cell lines (EC109, TE-1 and TE-12) with hypermethylated PTPRO and silenced PTPRO expression were subjected to 5-aza-dC treatment at a final concentration of 20 mM.	('PTPRO', 'Gene', (173, 178))	('EC109', 'CellLine', 'CVCL:6898', (110, 115))	('rat', 'Species', '10116', (245, 248))	('PTPRO', 'Gene', (154, 159))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (208, 216))	('hypermethylated', 'Var', (138, 153))
794913	22099875	To our knowledge, this is the first report for detection of PTPRO hypermethylation as a non-invasive biomarker for solid tumors in peripheral blood.	('PTPRO hypermethylation', 'Var', (60, 82))	('solid tumors', 'Disease', 'MESH:D009369', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('solid tumors', 'Disease', (115, 127))
794917	22099875	This high frequency of methylation in primary tumors suggests that PTPRO is a common target for epigenetic silencing by methylation in ESCC, and that its methylation may be involved in ESC tumorigenesis.	('ESCC', 'Disease', (135, 139))	('primary tumors', 'Disease', (38, 52))	('tumor', 'Disease', (189, 194))	('epigenetic silencing', 'Var', (96, 116))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('ESC', 'Disease', (185, 188))	('methylation', 'Var', (154, 165))	('primary tumors', 'Disease', 'MESH:D009369', (38, 52))	('methylation', 'Var', (120, 131))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('involved', 'Reg', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
794918	22099875	In PTPRO expression-silenced cell lines, expression was dramatically restored by treatment with the demethylating agent 5-aza-dC, confirming that DNA methylation is a major mechanism regulating PTPRO expression and that aberrant methylation of the PTPRO promoter is directly responsible for transcriptional inactivation of its expression in ESCC cell lines.	('methylation', 'Var', (229, 240))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (120, 128))	('expression', 'MPA', (41, 51))	('inactivation', 'NegReg', (307, 319))	('aberrant methylation', 'Var', (220, 240))	('PTPRO', 'Gene', (248, 253))	('expression', 'MPA', (327, 337))
794923	22099875	Promoter hypermethylation of tumor suppressor genes is not only an important epigenetic event in the development and progression of many human cancers, but it also constitutes a potentially sensitive biomarker for the detection of diseases at early stages by using a trace amount of sample compared with the detection of protein and RNA.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('tumor', 'Disease', (29, 34))	('cancers', 'Disease', (143, 150))	('Promoter hypermethylation', 'Var', (0, 25))
794927	22099875	Methylated DNA in plasma/serum is assumed to reflect abnormal DNA being disseminated from apoptotic or necrotic tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('necrotic tumor', 'Disease', 'MESH:D009369', (103, 117))	('necrotic tumor', 'Disease', (103, 117))	('Methylated', 'Var', (0, 10))
794930	22099875	PTPRO methylation indeed occurred only in the B-cell population of a subset of patients with CLL, but not in normal B or T lymphocytes, indicating that methylated PTPRO in blood cells is cancer-specific.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('CLL', 'Disease', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('patients', 'Species', '9606', (79, 87))	('methylated', 'Var', (152, 162))	('occurred', 'Reg', (25, 33))
794931	22099875	Our data support a high sensitivity and specificity of methylated PTPRO in peripheral blood samples, consistent with previous reports on other tumor suppressor genes.	('tumor', 'Disease', (143, 148))	('methylated', 'Var', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('PTPRO', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
794932	22099875	Identical alterations were detectable in the plasma or buffy coat of 20 (74.1%) of 27 patients positive for methylated PTPRO in the primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('PTPRO', 'Gene', (119, 124))	('methylated', 'Var', (108, 118))	('primary tumors', 'Disease', (132, 146))	('primary tumors', 'Disease', 'MESH:D009369', (132, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('rat', 'Species', '10116', (14, 17))	('patients', 'Species', '9606', (86, 94))
794934	22099875	Moreover, high specificity was indicated by the absence of methylated PTPRO in plasma or buffy coat from either ESCC patients without primary tumor methylation or any of the normal control peripheral blood samples.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('ESCC', 'Disease', (112, 116))	('methylated', 'Var', (59, 69))	('patients', 'Species', '9606', (117, 125))	('absence', 'NegReg', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('PTPRO', 'Gene', (70, 75))
794938	22099875	Given that collection of peripheral blood can be easily conducted as a screening procedure without the necessity for complicated and invasive endoscopic biopsy, detection of methylated DNA in peripheral blood could be developed as a promising tumor marker in screening for primary ESCC within high-risk populations, as well as in detection of minimal residual tumors.	('methylated', 'Var', (174, 184))	('tumors', 'Disease', (360, 366))	('tumor', 'Disease', (360, 365))	('tumors', 'Disease', 'MESH:D009369', (360, 366))	('tumors', 'Phenotype', 'HP:0002664', (360, 366))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('primary ESCC', 'Disease', (273, 285))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('tumor', 'Disease', (243, 248))
794939	22099875	In summary, we have detected methylation of the PTPRO promoter in primary tumors, plasma and buffy coat samples from patients with ESCC.	('detected', 'Reg', (20, 28))	('methylation', 'Var', (29, 40))	('primary tumors', 'Disease', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('primary tumors', 'Disease', 'MESH:D009369', (66, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('patients', 'Species', '9606', (117, 125))	('PTPRO promoter', 'Gene', (48, 62))	('ESCC', 'Disease', (131, 135))
794940	22099875	Because this epigenetic tumor suppressor gene alteration is ubiquitous in ESCC, it represents a novel approach to early diagnosis and monitoring of this deadly disease.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('alteration', 'Var', (46, 56))	('tumor', 'Disease', (24, 29))	('ESCC', 'Disease', (74, 78))	('rat', 'Species', '10116', (50, 53))	('epigenetic', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
795003	33193429	Since then, it has been firmly proven by many researchers worldwide that H. pylori cause more than 90% of duodenal ulcers and up to 80% of gastric ulcers, and has been classified as a class I carcinogen by the World Health Organization due to its ability to promote stomach cancer after chronic infection.	('duodenal ulcers', 'Phenotype', 'HP:0002588', (106, 121))	('stomach cancer', 'Disease', (266, 280))	('gastric ulcers', 'Disease', 'MESH:D013276', (139, 153))	('infection', 'Disease', (295, 304))	('infection', 'Disease', 'MESH:D007239', (295, 304))	('H. pylori', 'Var', (73, 82))	('gastric ulcers', 'Phenotype', 'HP:0002592', (139, 153))	('chronic infection', 'Phenotype', 'HP:0031035', (287, 304))	('gastric ulcers', 'Disease', (139, 153))	('ulcers', 'Disease', (115, 121))	('stomach cancer', 'Disease', 'MESH:D013274', (266, 280))	('cause', 'Reg', (83, 88))	('stomach cancer', 'Phenotype', 'HP:0012126', (266, 280))	('ulcers', 'Disease', (147, 153))	('ulcers', 'Disease', 'MESH:D014456', (115, 121))	('H. pylori', 'Species', '210', (73, 82))	('promote', 'PosReg', (258, 265))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('ulcers', 'Disease', 'MESH:D014456', (147, 153))
795024	33193429	In predispose mice, organoids and tissue culture with mutations in TP53 (tumor suppressor gene), and enhanced c-MYC (oncogenes) expression translocated bacterial effector molecules SopE, SopE2, SopB (Salmonella outer proteins), and SptP (Salmonella protein tyrosine phosphatase), from the Salmonella pathogenicity island 2 (SPI-2), activate the protein kinase B (Akt), or MAPK inhibitors, prevented mouse embryonic fibroblast transformation.	('SopE', 'Species', '2342', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('mice', 'Species', '10090', (14, 18))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SopE', 'Species', '2342', (181, 185))	('tumor', 'Disease', (73, 78))	('Salmonella', 'Species', '90371', (289, 299))	('Salmonella', 'Species', '90371', (200, 210))	('mouse', 'Species', '10090', (399, 404))	('TP53', 'Gene', '22059', (67, 71))	('TP53', 'Gene', (67, 71))	('prevented', 'NegReg', (389, 398))	('mouse embryonic fibroblast transformation', 'CPA', (399, 440))	('Salmonella', 'Species', '90371', (238, 248))
795027	33193429	In mouse models, it has been shown that a dysbiotic community can lead to the development of colorectal cancer.	('mouse', 'Species', '10090', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('dysbiotic', 'Var', (42, 51))	('lead to', 'Reg', (66, 73))	('colorectal cancer', 'Disease', (93, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))
795043	33193429	Subgroup analysis indicated that the risk of cancer was associated with Porphyromonas gingivalis and Prevotella intermedia infection but not Tannerella forsythia, Treponema denticola, Aggregatibacter actinomycetemcomitans, and F. nucleatum infection.	('Porphyromonas gingivalis', 'Var', (72, 96))	('infection', 'Disease', (240, 249))	('infection', 'Disease', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('infection', 'Disease', 'MESH:D007239', (240, 249))	('infection', 'Disease', 'MESH:D007239', (123, 132))	('Tannerella forsythia', 'Species', '28112', (141, 161))	('associated', 'Interaction', (56, 66))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('Aggregatibacter actinomycetemcomitans', 'Species', '714', (184, 221))	('F. nucleatum', 'Species', '851', (227, 239))	('Treponema denticola', 'Species', '158', (163, 182))	('cancer', 'Disease', (45, 51))	('Porphyromonas gingivalis', 'Species', '837', (72, 96))	('Prevotella intermedia', 'Species', '28131', (101, 122))
795049	33193429	LPS was shown to drive pancreatic carcinogenesis, as was the blockade of the MyD88-dependent pathway (via a dendritic cell-mediated deviation to TH2), whereas blockade of TLR4 (via TRIF, TIR-domain-containing adapter-inducing interferon-beta) and blockade of the MyD88 independent (via TRIF) were protective against pancreatic cancer.	('TRIF', 'Gene', (181, 185))	('TLR4', 'Gene', (171, 175))	('interferon-beta', 'Gene', (226, 241))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (23, 48))	('MyD88-dependent pathway', 'Pathway', (77, 100))	('blockade', 'Var', (61, 69))	('TRIF', 'Gene', (286, 290))	('TRIF', 'Gene', '148022', (181, 185))	('pancreatic cancer', 'Disease', (316, 333))	('pancreatic cancer', 'Disease', 'MESH:D010190', (316, 333))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('TH2', 'Chemical', '-', (145, 148))	('drive', 'PosReg', (17, 22))	('TRIF', 'Gene', '148022', (286, 290))	('pancreatic carcinogenesis', 'Disease', (23, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (316, 333))	('interferon-beta', 'Gene', '3456', (226, 241))
795064	33193429	Although the communities vary depending on the study, Porphyromonas and Fusobacterium genera were associated with cancer in most studies ( Table 1 ).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Porphyromonas', 'Species', '1924944', (54, 67))	('Fusobacterium', 'Species', '860', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('associated', 'Reg', (98, 108))	('Porphyromonas', 'Var', (54, 67))	('cancer', 'Disease', (114, 120))
795113	33193429	P. gingivalis, one of the essential periodontal pathogens, increase the invasiveness of oral cancer cells and resistance to chemotherapeutic agents.	('invasiveness of oral cancer', 'Disease', (72, 99))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('resistance', 'CPA', (110, 120))	('invasiveness of oral cancer', 'Disease', 'MESH:D009362', (72, 99))	('increase', 'PosReg', (59, 67))
795115	33193429	P. gingivalis also induces expression of the ZEB1 transcription factor, which controls the epithelial-mesenchymal transition.	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('expression', 'MPA', (27, 37))	('ZEB1', 'Gene', (45, 49))	('ZEB1', 'Gene', '6935', (45, 49))	('induces', 'Reg', (19, 26))
795120	33193429	A detailed review of all the studies where P. gingivalis has been associated with the development of OSCC has been recently published by Lafuente Ibanez de Mendoza et al..  F. nucleatum in esophageal cancer tissues has been associated with shorter survival, suggesting a prognostic biomarker's potential role.	('F. nucleatum', 'Species', '851', (173, 185))	('shorter', 'NegReg', (240, 247))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('F. nucleatum', 'Var', (173, 185))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('P. gingivalis', 'Species', '837', (43, 56))	('cancer', 'Disease', (200, 206))
795172	33193429	Utilization of Check Point Inhibitors (ICIs) has revolutionized cancer treatment across multiple cancer types and has gotten the first since forever FDA endorsement of a tumor agonistic agent in tumors with microsatellite instability (MSI).	('tumors', 'Disease', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (195, 200))	('cancer', 'Disease', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('microsatellite instability', 'Var', (207, 233))	('tumor', 'Disease', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
795175	33193429	It was proposed by Sivan that Bifidobacterium, a particular taxon of microbial commensals, armed anti-tumor resistance and raised the viability of PD-L1 blocking treatment.	('PD-L1', 'Gene', '29126', (147, 152))	('Bifidobacterium', 'Var', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Bifidobacterium', 'Species', '1680', (30, 45))	('raised', 'PosReg', (123, 129))	('armed', 'PosReg', (91, 96))	('PD-L1', 'Gene', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
795199	33193429	In their results, baseline gut microbiota enriched with Faecalibacterium and other Firmicutes was associated with beneficial clinical response compared with patients whose baseline microbiota was driven by Bacteroides.	('patients', 'Species', '9606', (157, 165))	('Faecalibacterium', 'Var', (56, 72))	('beneficial', 'PosReg', (114, 124))	('Bacteroides', 'Species', '28116', (206, 217))
795201	33193429	In colorectal cancer patients, scientists observed that resistance to drugs correlated with an expansion in F. nucleatum in the gut.	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('expansion', 'Var', (95, 104))	('patients', 'Species', '9606', (21, 29))	('F. nucleatum', 'Species', '851', (108, 120))	('resistance to drugs', 'MPA', (56, 75))	('colorectal cancer', 'Disease', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('F. nucleatum', 'Gene', (108, 120))	('correlated', 'Reg', (76, 86))
795213	33193429	Later, in 1883 Friedrich Fehleisen, a German surgeon had identified S. pyogenes as the cause of "erysipelas" and had begun treating patients with cancer with the living cultures of the bacteria with success.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('S. pyogenes', 'Var', (68, 79))	('cause', 'Reg', (87, 92))	('erysipelas', 'Phenotype', 'HP:0001055', (97, 107))	('erysipelas', 'Disease', 'MESH:D004886', (97, 107))	('erysipelas', 'Disease', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('S. pyogenes', 'Species', '1314', (68, 79))	('patients', 'Species', '9606', (132, 140))
795236	33193429	So far, the only strain of S. typhimurium going through a phase I clinical trial is strain VNP20009, which contains deletions in the msbB and purl genes, to attenuate virulence and avoid septic shock.	('septic shock', 'Disease', (187, 199))	('S. typhimurium', 'Species', '90371', (27, 41))	('septic shock', 'Phenotype', 'HP:0100806', (187, 199))	('shock', 'Phenotype', 'HP:0031273', (194, 199))	('deletions', 'Var', (116, 125))	('purl', 'Gene', (142, 146))	('virulence', 'MPA', (167, 176))	('septic shock', 'Disease', 'MESH:D012772', (187, 199))	('msbB', 'Gene', (133, 137))	('avoid', 'PosReg', (181, 186))	('attenuate', 'NegReg', (157, 166))
795267	31752922	OS was significantly longer in patients with ECOG performance score (ECOG PS) < 2 (p = 0.001), lesion length <= 5 cm (p = 0.001), and LD (p = 0.049).	('S', 'Chemical', 'MESH:D013455', (1, 2))	('longer', 'PosReg', (21, 27))	('patients', 'Species', '9606', (31, 39))	('lesion length', 'Var', (95, 108))	('S', 'Chemical', 'MESH:D013455', (75, 76))
795351	31752922	Interestingly, another study comparing the RT and chemotherapy (RT + CT) with surgery and chemotherapy (S + CT) in the management of LD SCCE indirectly favored RT, in which a significantly longer OS with RT + CT compared to S + CT (33.0 vs. 17.5 months, p = 0.02) was observed.	('S', 'Chemical', 'MESH:D013455', (224, 225))	('SCCE', 'Disease', (136, 140))	('S', 'Chemical', 'MESH:D013455', (104, 105))	('longer', 'PosReg', (189, 195))	('RT + CT', 'Var', (204, 211))	('S', 'Chemical', 'MESH:D013455', (197, 198))	('S', 'Chemical', 'MESH:D013455', (136, 137))	('SCCE', 'Disease', 'MESH:D018288', (136, 140))
795357	31752922	In patients with LD, RT + CT is correlated with better survival (p = 0.046).	('patients', 'Species', '9606', (3, 11))	('better', 'PosReg', (48, 54))	('survival', 'MPA', (55, 63))	('RT + CT', 'Var', (21, 28))
795378	31257524	miR-92a-3p promotes the proliferation, migration and invasion of esophageal squamous cell cancer by regulating PTEN Esophageal squamous cell cancer (ESCC) has a high mortality rate.	('proliferation', 'CPA', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('invasion', 'CPA', (53, 61))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (65, 96))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (76, 96))	('PTEN', 'MPA', (111, 115))	('migration', 'CPA', (39, 48))	('Esophageal squamous cell cancer', 'Disease', (116, 147))	('esophageal squamous cell cancer', 'Disease', (65, 96))	('promotes', 'PosReg', (11, 19))	('Esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (116, 147))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (127, 147))	('miR-92a-3p', 'Var', (0, 10))
795379	31257524	MicroRNA (miR)-92a-3p is considered to be a tumor promotor and an oncomiR.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (44, 49))	('MicroRNA', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
795380	31257524	The aim of the present study was to investigate the effect of miR-92a-3p and its target gene on ESCC in terms of proliferation, migration and invasion.	('miR-92a', 'Chemical', '-', (62, 69))	('miR-92a-3p', 'Var', (62, 72))	('ESCC', 'Disease', (96, 100))
795381	31257524	Higher expression of miR-92a-3p was detected in the tissues of patients with ESCC, compared with that in normal tissues.	('ESCC', 'Disease', (77, 81))	('expression', 'MPA', (7, 17))	('Higher', 'PosReg', (0, 6))	('patients', 'Species', '9606', (63, 71))	('miR-92a', 'Chemical', '-', (21, 28))	('miR-92a-3p', 'Var', (21, 31))
795382	31257524	In addition, ESCC cell lines had a higher expression of miR-92a-3p compared with normal esophageal cells.	('expression', 'MPA', (42, 52))	('miR-92a', 'Chemical', '-', (56, 63))	('higher', 'PosReg', (35, 41))	('miR-92a-3p', 'Var', (56, 66))
795385	31257524	Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was detected as a target of miR-92a-3p by a dual luciferase reporter assay.	('miR-92a-3p', 'Var', (91, 101))	('PTEN', 'Gene', '5728', (57, 61))	('miR-92a', 'Chemical', '-', (91, 98))	('PTEN', 'Gene', (57, 61))
795388	31257524	The results of the study revealed that miR-92a-3p promoted the proliferation, migration and invasion of ESCC, and the effect of miR-92a-3p on ESCC was realized by regulating PTEN.	('PTEN', 'Gene', '5728', (174, 178))	('miR-92a', 'Chemical', '-', (128, 135))	('promoted', 'PosReg', (50, 58))	('proliferation', 'CPA', (63, 76))	('invasion of ESCC', 'CPA', (92, 108))	('miR-92a-3p', 'Var', (128, 138))	('miR-92a-3p', 'Var', (39, 49))	('miR-92a', 'Chemical', '-', (39, 46))	('migration', 'CPA', (78, 87))	('PTEN', 'Gene', (174, 178))
795393	31257524	In terms of the clinical cT category, ~20% patients with stage cT4a ESCC have a survival time of 10 years, and <30% patients have a survival time of 5 years.	('ESCC', 'Disease', (68, 72))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (116, 124))	('stage cT4a', 'Var', (57, 67))
795394	31257524	CDKN2A hypermethylation, which is frequent in patients with ESCC, accounts for 40-62% of cases, however, there is lack of valid evidence to confirm methylated CDKN2A as a biomarker for ESCC.	('hypermethylation', 'Var', (7, 23))	('CDKN2A', 'Gene', '1029', (0, 6))	('patients', 'Species', '9606', (46, 54))	('CDKN2A', 'Gene', '1029', (159, 165))	('ESCC', 'Disease', (60, 64))	('ESCC', 'Disease', (185, 189))	('CDKN2A', 'Gene', (0, 6))	('methylated', 'Var', (148, 158))	('CDKN2A', 'Gene', (159, 165))
795398	31257524	The miR-17-92 cluster is composed of six miRNAs (miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a-3p) and is located on chr13q31.3 within the third intron of the C13orf25/MIR17HG gene.	('miR-20a', 'Gene', '406982', (84, 91))	('miR-18a', 'Gene', '406953', (57, 64))	('miR-17', 'Gene', '406952', (49, 55))	('miR-19b', 'Gene', '406980', (75, 82))	('miR-17', 'Gene', (4, 10))	('miR-19a', 'Gene', (66, 73))	('miR-17-92', 'Gene', (4, 13))	('C13orf25', 'Gene', '407975', (168, 176))	('miR-19a', 'Gene', '406979', (66, 73))	('miR-92a-3p', 'Var', (96, 106))	('miR-17', 'Gene', (49, 55))	('miR-17-92', 'Gene', '407975', (4, 13))	('miR-92a', 'Chemical', '-', (96, 103))	('miR-18a', 'Gene', (57, 64))	('C13orf25', 'Gene', (168, 176))	('MIR17HG', 'Gene', '407975', (177, 184))	('MIR17HG', 'Gene', (177, 184))	('miR-17', 'Gene', '406952', (4, 10))	('miR-19b', 'Gene', (75, 82))	('miR-20a', 'Gene', (84, 91))
795400	31257524	The serum levels of miR-92a-3p were reported to be associated with ESCC.	('ESCC', 'Disease', (67, 71))	('associated', 'Reg', (51, 61))	('miR-92a-3p', 'Var', (20, 30))	('serum levels', 'MPA', (4, 16))	('miR-92a', 'Chemical', '-', (20, 27))
795404	31257524	A novel heterozygous mutation in the PTEN gene was reported to be associated with an ovarian germ cell tumor complicated by growing teratoma syndrome and overgrowth in a two-year-old female.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('overgrowth', 'Disease', (154, 164))	('overgrowth', 'Disease', 'MESH:D019214', (154, 164))	('overgrowth', 'Phenotype', 'HP:0001548', (154, 164))	('teratoma', 'Phenotype', 'HP:0009792', (132, 140))	('associated', 'Reg', (66, 76))	('teratoma syndrome', 'Disease', (132, 149))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (37, 41))	('ovarian germ cell tumor', 'Disease', 'MESH:D009373', (85, 108))	('germ cell tumor', 'Phenotype', 'HP:0100728', (93, 108))	('teratoma syndrome', 'Disease', 'MESH:D013724', (132, 149))	('heterozygous mutation', 'Var', (8, 29))	('ovarian germ cell tumor', 'Disease', (85, 108))
795405	31257524	The fibroblast growth factor receptor 2-mediated phosphorylation of PTEN at tyrosine 240 contributes to the radioresistance of glioma.	('contributes', 'Reg', (89, 100))	('tyrosine', 'Chemical', 'MESH:D014443', (76, 84))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('tyrosine 240', 'Var', (76, 88))	('fibroblast growth factor receptor 2', 'Gene', '2263', (4, 39))	('PTEN', 'Gene', (68, 72))	('fibroblast growth factor receptor 2', 'Gene', (4, 39))	('PTEN', 'Gene', '5728', (68, 72))	('radioresistance', 'CPA', (108, 123))	('glioma', 'Disease', (127, 133))
795409	31257524	To investigate the role of the downregulation of PTEN, it was hypothesized in the present study that miR-92a-3p targeted PTEN to exert effects on the progression of ESCC.	('PTEN', 'Gene', '5728', (49, 53))	('PTEN', 'Gene', (121, 125))	('miR-92a', 'Chemical', '-', (101, 108))	('PTEN', 'Gene', '5728', (121, 125))	('ESCC', 'Disease', (165, 169))	('miR-92a-3p', 'Var', (101, 111))	('effects', 'Reg', (135, 142))	('PTEN', 'Gene', (49, 53))
795416	31257524	The ESCC cell lines (Eca-109, EC9706, KYSE-30, KYSE-150 and KYSE-220) and KYSE-510 cell line originate from the esophagus of patients with ESCC and were purchased from CICAMS.	('EC9706', 'CellLine', 'CVCL:E307', (30, 36))	('KYSE-220', 'Var', (60, 68))	('KYSE-510', 'CellLine', 'CVCL:1354', (74, 82))	('EC9706', 'Var', (30, 36))	('KYSE-150', 'Var', (47, 55))	('ESCC', 'Disease', (139, 143))	('patients', 'Species', '9606', (125, 133))
795438	31257524	Subsequently, either the PTEN 3'UTR wild-type or PTEN 3'UTR mutant was cloned into the psi-CHECK-2 vector (Promega Corporation, Madison, WI, USA).	('PTEN', 'Gene', '5728', (49, 53))	('mutant', 'Var', (60, 66))	('PTEN', 'Gene', (25, 29))	('PTEN', 'Gene', '5728', (25, 29))	('PTEN', 'Gene', (49, 53))
795440	31257524	Subsequently, pGL-3 firefly luciferase reporters (1 microg per well) were co-transfected with 50 nmol/l universal mimics control (mimic control) or miR-92a-3p mimics and PTEN 3'UTR wild-type or PTEN 3'UTR mutant using Lipofectamine 2000 reagent (Invitrogen; Thermo Fisher Scientific, Inc.), according to the manufacturer's protocol.	('pGL-3', 'Gene', (14, 19))	('miR-92a', 'Chemical', '-', (148, 155))	('PTEN', 'Gene', (170, 174))	('PTEN', 'Gene', '5728', (170, 174))	('PTEN', 'Gene', (194, 198))	('PTEN', 'Gene', '5728', (194, 198))	('mutant', 'Var', (205, 211))	('pGL-3', 'Gene', '6391', (14, 19))
795444	31257524	It was found that the ESCC cell lines had higher levels of miR-92a-3p, compared with the normal esophagus cells (Fig.	('miR-92a-3p', 'Var', (59, 69))	('higher', 'PosReg', (42, 48))	('levels', 'MPA', (49, 55))	('miR-92a', 'Chemical', '-', (59, 66))
795445	31257524	The miR-92a-3p mimic increased the levels of miR-92a-3p (Fig.	('miR-92a', 'Chemical', '-', (4, 11))	('increased', 'PosReg', (21, 30))	('levels', 'MPA', (35, 41))	('miR-92a-3p', 'Var', (45, 55))	('miR-92a', 'Chemical', '-', (45, 52))
795451	31257524	The miR-92a-3p mimic was found to decrease the protein levels of Bax and cleaved caspase-3 and increase the protein level of Bcl-2 (Fig.	('miR-92a', 'Chemical', '-', (4, 11))	('caspase-3', 'Gene', '836', (81, 90))	('Bcl-2', 'Gene', (125, 130))	('Bcl-2', 'Gene', '596', (125, 130))	('Bax', 'Gene', '581', (65, 68))	('miR-92a-3p mimic', 'Var', (4, 20))	('increase', 'PosReg', (95, 103))	('decrease', 'NegReg', (34, 42))	('caspase-3', 'Gene', (81, 90))	('Bax', 'Gene', (65, 68))
795453	31257524	The miR-92a-3p mimic promoted Eca-109 cell migration, as the Eca-109 cells treated with miR-92a-3p mimic covered the plate in the scratch image captured at 48 h (Fig.	('miR-92a', 'Chemical', '-', (4, 11))	('promoted', 'PosReg', (21, 29))	('miR-92a', 'Chemical', '-', (88, 95))	('Eca-109 cell migration', 'CPA', (30, 52))	('miR-92a-3p mimic', 'Var', (88, 104))
795455	31257524	Therefore, Eca-109 cells treated with the miR-92a-3p mimic had the highest migration rate, whereas Eca-109 cells treated with the miR-92a-3p inhibitor had the lowest migration rate (Fig.	('miR-92a-3p', 'Var', (42, 52))	('miR-92a', 'Chemical', '-', (130, 137))	('miR-92a', 'Chemical', '-', (42, 49))	('migration rate', 'CPA', (75, 89))
795460	31257524	The mutation of the PTEN 3'UTR prevented the alignment of PTEN and miR-92a-3p.	('PTEN', 'Gene', '5728', (58, 62))	('alignment', 'MPA', (45, 54))	('miR-92a-3p', 'Gene', (67, 77))	('miR-92a', 'Chemical', '-', (67, 74))	('prevented', 'NegReg', (31, 40))	('mutation', 'Var', (4, 12))	('PTEN', 'Gene', (20, 24))	('PTEN', 'Gene', '5728', (20, 24))	('PTEN', 'Gene', (58, 62))
795468	31257524	The overexpression of PTEN decreased the levels of p-PI3K and p-Akt in Eca-109 cells.	('decreased', 'NegReg', (27, 36))	('Akt', 'Gene', '207', (64, 67))	('PTEN', 'Gene', (22, 26))	('Akt', 'Gene', (64, 67))	('PTEN', 'Gene', '5728', (22, 26))	('p-PI3K', 'Var', (51, 57))
795471	31257524	The results showed that IGF-1 promoted cell proliferation, PTEN inhibited cell proliferation through inactivation of the PI3K/Akt pathway, and the over-expression of miR-92a-3p inhibited the function of PTEN (Fig.	('over-expression', 'PosReg', (147, 162))	('PTEN', 'Gene', (203, 207))	('inhibited', 'NegReg', (177, 186))	('cell proliferation', 'CPA', (74, 92))	('PTEN', 'Gene', '5728', (203, 207))	('miR-92a', 'Chemical', '-', (166, 173))	('inhibited', 'NegReg', (64, 73))	('Akt', 'Gene', '207', (126, 129))	('miR-92a-3p', 'Var', (166, 176))	('promoted', 'PosReg', (30, 38))	('inactivation', 'NegReg', (101, 113))	('IGF-1', 'Gene', '3479', (24, 29))	('IGF-1', 'Gene', (24, 29))	('function', 'MPA', (191, 199))	('cell proliferation', 'CPA', (39, 57))	('PTEN', 'Gene', (59, 63))	('Akt', 'Gene', (126, 129))	('PTEN', 'Gene', '5728', (59, 63))
795472	31257524	The ESCC cells exhibited a higher expression of miR-92a-3p, compared with that in normal esophageal cells (Fig.	('miR-92a-3p', 'Var', (48, 58))	('expression', 'MPA', (34, 44))	('miR-92a', 'Chemical', '-', (48, 55))	('higher', 'PosReg', (27, 33))	('ESCC', 'Disease', (4, 8))
795473	31257524	1B), which was consistent with the higher expression of miR-92a-3p in EC tissues from patients with ESCC (Fig.	('miR-92a', 'Chemical', '-', (56, 63))	('miR-92a-3p', 'Var', (56, 66))	('expression', 'MPA', (42, 52))	('ESCC', 'Disease', (100, 104))	('higher', 'PosReg', (35, 41))	('patients', 'Species', '9606', (86, 94))
795474	31257524	The miR-92a-3p mimic promoted the expression of miR-92a-3p in ESCC cells (Fig.	('miR-92a', 'Chemical', '-', (4, 11))	('miR-92a-3p', 'Var', (48, 58))	('miR-92a', 'Chemical', '-', (48, 55))	('expression', 'MPA', (34, 44))	('promoted', 'PosReg', (21, 29))
795475	31257524	The miR-92a-3p inhibitor restrained the expression of miR-92a-3p in ESCC cells (Fig.	('expression', 'MPA', (40, 50))	('miR-92a', 'Chemical', '-', (54, 61))	('miR-92a-3p', 'Var', (54, 64))	('miR-92a', 'Chemical', '-', (4, 11))
795476	31257524	Therefore, the overexpression of miR-92a-3p had a positive effect on ESCC cell proliferation.	('miR-92a-3p', 'Var', (33, 43))	('overexpression', 'PosReg', (15, 29))	('miR-92a', 'Chemical', '-', (33, 40))	('ESCC', 'Disease', (69, 73))
795478	31257524	The inhibition of miR-92a-3p promoted ESCC cell apoptosis and activated the Bax/Bcl-2 and caspase-3 signaling pathways (Fig.	('promoted', 'PosReg', (29, 37))	('Bax', 'Gene', (76, 79))	('miR-92a', 'Chemical', '-', (18, 25))	('caspase-3', 'Gene', (90, 99))	('miR-92a-3p', 'Gene', (18, 28))	('Bcl-2', 'Gene', (80, 85))	('Bax', 'Gene', '581', (76, 79))	('Bcl-2', 'Gene', '596', (80, 85))	('ESCC', 'Disease', (38, 42))	('inhibition', 'Var', (4, 14))	('caspase-3', 'Gene', '836', (90, 99))	('activated', 'PosReg', (62, 71))
795479	31257524	In addition, the overexpression of miR-92a-3p inhibited apoptosis and inactivated the Bax/Bcl-2 and caspase-3 signaling pathways (Fig.	('miR-92a', 'Chemical', '-', (35, 42))	('caspase-3', 'Gene', (100, 109))	('apoptosis', 'CPA', (56, 65))	('miR-92a-3p', 'Var', (35, 45))	('Bax', 'Gene', '581', (86, 89))	('Bcl-2', 'Gene', (90, 95))	('inactivated', 'NegReg', (70, 81))	('Bcl-2', 'Gene', '596', (90, 95))	('caspase-3', 'Gene', '836', (100, 109))	('overexpression', 'PosReg', (17, 31))	('Bax', 'Gene', (86, 89))	('inhibited', 'NegReg', (46, 55))
795484	31257524	The overexpression of miR-92a-3p increased ESCC cell migration and invasion, whereas the reduction of miR-92a-3p inhibited ESCC cell migration and invasion (Fig.	('inhibited', 'NegReg', (113, 122))	('invasion', 'CPA', (67, 75))	('ESCC cell migration', 'CPA', (43, 62))	('ESCC', 'Disease', (123, 127))	('invasion', 'CPA', (147, 155))	('increased ESCC', 'Phenotype', 'HP:0003565', (33, 47))	('miR-92a', 'Chemical', '-', (22, 29))	('miR-92a-3p', 'Var', (22, 32))	('increased', 'PosReg', (33, 42))	('reduction', 'NegReg', (89, 98))	('miR-92a', 'Chemical', '-', (102, 109))	('overexpression', 'PosReg', (4, 18))	('miR-92a-3p', 'Var', (102, 112))
795486	31257524	The present study used TargetScan 7.0 to predict the miR-92a-3p target and its related sites, and it was confirmed that the PTEN gene was a target gene of miR-92a-3p by a dual luciferase report assay (Fig.	('miR-92a', 'Chemical', '-', (155, 162))	('miR-92a-3p', 'Var', (155, 165))	('PTEN', 'Gene', (124, 128))	('PTEN', 'Gene', '5728', (124, 128))	('miR-92a', 'Chemical', '-', (53, 60))
795487	31257524	The PTEN gene was found when chromosome 10q23 was examined in 1997; the protein produced by the PTEN gene shared sequence homology with cytoskeletal tensin, and mutations of PTEN generally were detected in cancer.	('PTEN', 'Gene', '5728', (174, 178))	('PTEN', 'Gene', '5728', (4, 8))	('PTEN', 'Gene', '5728', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('PTEN', 'Gene', (174, 178))	('detected', 'Reg', (194, 202))	('mutations', 'Var', (161, 170))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('PTEN', 'Gene', (96, 100))	('PTEN', 'Gene', (4, 8))
795489	31257524	The miR-92a-3p mimic promoted cell proliferation, which may only be attributed partially to the downregulation of PTEN.	('miR-92a', 'Chemical', '-', (4, 11))	('cell proliferation', 'CPA', (30, 48))	('miR-92a-3p mimic', 'Var', (4, 20))	('PTEN', 'Gene', (114, 118))	('promoted', 'PosReg', (21, 29))	('PTEN', 'Gene', '5728', (114, 118))
795490	31257524	The overexpression of miR-92a-3p also inhibited apoptosis and promoted the migration and invasion of PTEN-overexpressing ESCC cells (Fig.	('promoted', 'PosReg', (62, 70))	('PTEN', 'Gene', (101, 105))	('PTEN', 'Gene', '5728', (101, 105))	('invasion', 'CPA', (89, 97))	('inhibited', 'NegReg', (38, 47))	('miR-92a', 'Chemical', '-', (22, 29))	('miR-92a-3p', 'Var', (22, 32))	('migration', 'CPA', (75, 84))	('apoptosis', 'CPA', (48, 57))
795493	31257524	The results of the present study supported that, in ESCC cells, the overexpression of PTEN inhibited the PI3K/Akt pathway, which was promoted by miR-92a-3p (Fig.	('Akt', 'Gene', (110, 113))	('miR-92a-3p', 'Var', (145, 155))	('PTEN', 'Gene', (86, 90))	('promoted', 'PosReg', (133, 141))	('inhibited', 'NegReg', (91, 100))	('PTEN', 'Gene', '5728', (86, 90))	('overexpression', 'PosReg', (68, 82))	('Akt', 'Gene', '207', (110, 113))	('miR-92a', 'Chemical', '-', (145, 152))
795495	31257524	The results showed that IGF-1 promoted cell proliferation, PTEN inhibited cell proliferation through inactivation of the PI3K/Akt pathway, and the overexpression of miR-92a-3p inhibited the function of PTEN.	('miR-92a-3p', 'Var', (165, 175))	('cell proliferation', 'CPA', (74, 92))	('inhibited', 'NegReg', (176, 185))	('inhibited', 'NegReg', (64, 73))	('Akt', 'Gene', '207', (126, 129))	('promoted', 'PosReg', (30, 38))	('inactivation', 'NegReg', (101, 113))	('overexpression', 'PosReg', (147, 161))	('IGF-1', 'Gene', (24, 29))	('function', 'MPA', (190, 198))	('IGF-1', 'Gene', '3479', (24, 29))	('PTEN', 'Gene', (202, 206))	('miR-92a', 'Chemical', '-', (165, 172))	('cell proliferation', 'CPA', (39, 57))	('PTEN', 'Gene', '5728', (202, 206))	('PTEN', 'Gene', (59, 63))	('Akt', 'Gene', (126, 129))	('PTEN', 'Gene', '5728', (59, 63))
795496	31257524	In conclusion, the present study supports the hypothesis that the overexpression of miR-92a-3p promoted the proliferation, migration and invasion and decreased the apoptosis of ESCC cells.	('promoted', 'PosReg', (95, 103))	('ESCC', 'Disease', (177, 181))	('invasion', 'CPA', (137, 145))	('miR-92a', 'Chemical', '-', (84, 91))	('miR-92a-3p', 'Var', (84, 94))	('apoptosis', 'CPA', (164, 173))	('proliferation', 'CPA', (108, 121))	('overexpression', 'PosReg', (66, 80))	('migration', 'CPA', (123, 132))	('decreased', 'NegReg', (150, 159))
795497	31257524	miR-92a-3p inhibited apoptosis via the Bax/Bcl-2 and caspase-3 pathways and promoted proliferation, which may be associated with the PI3K/Akt pathway.	('Bax', 'Gene', '581', (39, 42))	('Akt', 'Gene', (138, 141))	('caspase-3', 'Gene', (53, 62))	('Bax', 'Gene', (39, 42))	('Bcl-2', 'Gene', '596', (43, 48))	('apoptosis', 'CPA', (21, 30))	('Akt', 'Gene', '207', (138, 141))	('Bcl-2', 'Gene', (43, 48))	('miR-92a', 'Chemical', '-', (0, 7))	('inhibited', 'NegReg', (11, 20))	('promoted', 'PosReg', (76, 84))	('caspase-3', 'Gene', '836', (53, 62))	('proliferation', 'CPA', (85, 98))	('miR-92a-3p', 'Var', (0, 10))
795507	31283789	Low OLFM4 was associated with poor differentiation grade in both advanced (60% vs. 34.8%, p = 0.001) and early EAC (39.1% vs. 9.5%, p = 0.023).	('OLFM4', 'Gene', (4, 9))	('differentiation grade', 'CPA', (35, 56))	('Low', 'Var', (0, 3))	('OLFM4', 'Gene', '10562', (4, 9))	('EAC', 'Phenotype', 'HP:0011459', (111, 114))
795508	31283789	Low OLFM4 was independently associated with the presence of LNM in advanced EAC in multivariable analysis (OR 2.7; 95% CI, 1.16-6.41; p = 0.022), but not in early EAC (OR 2.1; 95% CI, 0.46-9.84; p = 0.338).	('OLFM4', 'Gene', (4, 9))	('OLFM4', 'Gene', '10562', (4, 9))	('EAC', 'Phenotype', 'HP:0011459', (163, 166))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))	('LNM', 'Var', (60, 63))
795532	31283789	Patients who underwent esophagectomy with curative intent for pathologically confirmed pT2-pT4 adenocarcinoma of the esophagus or gastro-esophageal junction between 1995 and 2016 in the Erasmus MC University Medical Center, Rotterdam were selected for this study.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('adenocarcinoma of the esophagus', 'Disease', (95, 126))	('pT2-pT4', 'Var', (87, 94))	('gastro-esophageal junction', 'Disease', (130, 156))	('gastro-esophageal junction', 'Disease', 'MESH:D005764', (130, 156))	('Patients', 'Species', '9606', (0, 8))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (95, 126))
795585	31283789	There was no significant difference in OS between EAC with low vs. high OLFM4 expression.	('high', 'Var', (67, 71))	('OLFM4', 'Gene', (72, 77))	('OS', 'Chemical', '-', (39, 41))	('low', 'NegReg', (59, 62))	('OLFM4', 'Gene', '10562', (72, 77))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))
795599	31283789	In fact, in most cancers, a strong association between low OLFM4 and poor tumor differentiation grade was found, including gastric, colon, ovarian and prostate cancer.	('OLFM4', 'Gene', (59, 64))	('gastric', 'Disease', (123, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('tumor', 'Disease', (74, 79))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('OLFM4', 'Gene', '10562', (59, 64))	('colon, ovarian and prostate cancer', 'Disease', 'MESH:D010051', (132, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('low', 'Var', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
795605	31283789	Similar as in advanced EAC, loss of OLFM4 was associated with poor differentiation grade, but no association with LNM status was found.	('EAC', 'Phenotype', 'HP:0011459', (23, 26))	('loss', 'Var', (28, 32))	('OLFM4', 'Gene', '10562', (36, 41))	('poor differentiation grade', 'CPA', (62, 88))	('OLFM4', 'Gene', (36, 41))
795608	31283789	Only one previous study studied the role of OLFM4 in early cancer (pT1a and pT1b gastric cancer, n = 105) and concluded that low OLFM4 expression was independently predictive for LNM.	('low', 'Var', (125, 128))	('pT1', 'Gene', '58492', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('cancer', 'Disease', (89, 95))	('pT1', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('pT1', 'Gene', '58492', (76, 79))	('pT1', 'Gene', (76, 79))	('expression', 'MPA', (135, 145))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('LNM', 'Disease', (179, 182))	('OLFM4', 'Gene', '10562', (129, 134))	('OLFM4', 'Gene', '10562', (44, 49))	('predictive', 'Reg', (164, 174))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('gastric cancer', 'Disease', (81, 95))	('OLFM4', 'Gene', (129, 134))	('cancer', 'Disease', (59, 65))	('OLFM4', 'Gene', (44, 49))
795766	28144151	Potential prognostic factors of esophageal cancer included age (<70 vs >=70 years), gender (female vs male), pathological TNM stage (I-II vs III), tumor size (<3 vs >=3 cm), operation time (<600 vs >=600 min), intraoperative blood loss (<500 vs >=500 mL), LMR (<4 vs >=4), NLR (<1.6 vs >=1.6), PLR (<147 vs >=147), serum SCC antigen level (<1.5 vs >=1.5 ng/mL), and IRB score (2-3 vs 0-1).	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('TNM', 'Gene', '10178', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (321, 324))	('PLR', 'Disease', (294, 297))	('intraoperative blood loss', 'Disease', (210, 235))	('TNM', 'Gene', (122, 125))	('SCC', 'Gene', (321, 324))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('esophageal cancer', 'Disease', (32, 49))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (210, 235))	('<147 vs >=147', 'Var', (299, 312))	('SCC', 'Gene', '6317', (321, 324))
795817	27777774	B7-H1/PD-L1 expression can be increased following treatment with 5-FU in gastrointestinal cancer cell lines, suggesting alternative mechanisms to classic immune-mediated upregulation.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (73, 96))	('5-FU', 'Var', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('5-FU', 'Chemical', 'MESH:D005472', (65, 69))	('PD-L1', 'Gene', (6, 11))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (73, 96))	('increased', 'PosReg', (30, 39))	('expression', 'MPA', (12, 22))	('gastrointestinal cancer', 'Disease', (73, 96))	('PD-L1', 'Gene', '29126', (6, 11))
795829	27777774	B7-H1 is overexpressed in solid cancers, including breast, colon, esophageal, gastric, lung, ovarian and pancreatic cancers, and is often categorized as a poor prognostic factor, although occasionally it has been shown as a favorable factor.	('gastric', 'Disease', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('solid cancers', 'Disease', (26, 39))	('colon', 'Disease', (59, 64))	('breast', 'Disease', (51, 57))	('esophageal', 'Disease', (66, 76))	('lung', 'Disease', (87, 91))	('B7-H1', 'Var', (0, 5))	('solid cancers', 'Disease', 'MESH:D009369', (26, 39))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('overexpressed', 'PosReg', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (105, 123))	('ovarian and pancreatic cancers', 'Disease', 'MESH:D010190', (93, 123))
795832	27777774	However, little is known about the effects of 5-FU treatment on B7-H1 expression in digestive cancers, although 5-FU treatment upregulates B7-H1 in MDA-MB 408 and 435 breast cancer cell lines, but not MCF-7 cells.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))	('5-FU treatment', 'Var', (112, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('upregulates', 'PosReg', (127, 138))	('B7-H1', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('MDA-MB', 'CellLine', 'CVCL:0062', (148, 154))	('MCF-7', 'CellLine', 'CVCL:0031', (201, 206))	('5-FU', 'Chemical', 'MESH:D005472', (46, 50))	('cancers', 'Disease', (94, 101))	('5-FU', 'Chemical', 'MESH:D005472', (112, 116))
795834	27777774	Mutations in the p53 tumor suppressor have been associated with both poor responsiveness to 5-FU and microRNA-34 upregulation of B7-H1.	('microRNA-34', 'MPA', (101, 112))	('poor responsiveness to 5-FU', 'MPA', (69, 96))	('tumor', 'Disease', (21, 26))	('upregulation', 'PosReg', (113, 125))	('Mutations', 'Var', (0, 9))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
795864	27777774	OE33 cells had higher baseline expression (untreated) relative to HCT 116 p53 +/+ and HCT 116 p53 -/- cells.	('p53', 'Gene', (94, 97))	('baseline expression', 'MPA', (22, 41))	('higher', 'PosReg', (15, 21))	('p53', 'Gene', '7157', (94, 97))	('OE33', 'Var', (0, 4))	('p53', 'Gene', (74, 77))	('p53', 'Gene', '7157', (74, 77))
795876	27777774	We also demonstrate that treatment with 5 uM or higher 5-FU can induce B7-H1 upregulation in HCT 116 cells as detected by western blot analysis, regardless of p53 mutational status.	('p53', 'Gene', (159, 162))	('5-FU', 'Var', (55, 59))	('p53', 'Gene', '7157', (159, 162))	('5-FU', 'Chemical', 'MESH:D005472', (55, 59))	('upregulation', 'PosReg', (77, 89))	('B7-H1', 'Gene', (71, 76))
795937	26345989	SVT can cause localized hypertension of splenic veins and create collaterals from spleen to the fundus.	('cause', 'Reg', (8, 13))	('hypertension', 'Phenotype', 'HP:0000822', (24, 36))	('hypertension of splenic veins', 'Disease', 'MESH:D006973', (24, 53))	('SVT', 'Var', (0, 3))	('hypertension of splenic veins', 'Disease', (24, 53))	('collaterals', 'CPA', (65, 76))
795975	24992335	Endoscopic mucosal resection is feasible, even in circumferential BE, but requires piece-meal resection, with suboptimal histological analysis and a risk of residual dysplastic mucosa; furthermore, circumferential mucosal resection leads to severe esophageal strictures in around 37% to 92% of cases, as previously reported in mucosal defects involving more than three-quarters of the esophageal circumference.	('esophageal strictures', 'Phenotype', 'HP:0002043', (248, 269))	('dysplastic mucosa', 'Disease', (166, 183))	('esophageal strictures', 'Disease', (248, 269))	('esophageal stricture', 'Phenotype', 'HP:0002043', (248, 268))	('dysplastic mucosa', 'Disease', 'MESH:D004416', (166, 183))	('mucosal defects', 'Disease', 'MESH:D052016', (327, 342))	('circumferential mucosal', 'Var', (198, 221))	('leads to', 'Reg', (232, 240))	('mucosal defects', 'Disease', (327, 342))
795982	24992335	Furthermore, as reported in the setting of preeclampsia, the presence of lactoferrin in AM can also result in its anti-oxidant properties.	('anti-oxidant properties', 'MPA', (114, 137))	('preeclampsia', 'Phenotype', 'HP:0100602', (43, 55))	('presence', 'Var', (61, 69))	('lactoferrin', 'Gene', '397649', (73, 84))	('lactoferrin', 'Gene', (73, 84))
796026	24992335	Immunohistochemistry staining with anti-alphaSMA antibodies allowed for the semi-quantitative assessment of myofibroblastic activity: mean signals were 1.60+-0.89 and 1.25+-0.5 and mean vascular density was 2+-0.71 and 2.25+-0.96 (p = NS) in the AM1 and control groups, respectively.	('AM1', 'Var', (246, 249))	('vascular density', 'CPA', (186, 202))	('myofibroblastic', 'CPA', (108, 123))	('AM1', 'Species', '408139', (246, 249))
796055	24885118	CAV1 hypermethylation showed highly discriminative ROC curve profiles, clearly distinguishing esophageal adenocarcinomas (EAC) and esophageal squamous cell carcinomas (ESCC) from normal esophagus (NE) (EAC vs. NE, AUROC = 0.839 and p < 0.0001; ESCC vs. NE, AUROC = 0.920 and p < 0.0001).	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('esophageal adenocarcinomas', 'Disease', (94, 120))	('esophageal squamous cell carcinomas', 'Disease', (131, 166))	('CAV1', 'Gene', (0, 4))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (131, 166))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('EAC', 'Phenotype', 'HP:0011459', (202, 205))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (94, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('hypermethylation', 'Var', (5, 21))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (94, 120))	('CAV1', 'Gene', '857', (0, 4))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (142, 166))
796059	24885118	CAV1 promoter hypermethylation is a frequent event in human esophageal carcinomas and is associated with early neoplastic progression in Barrett's esophagus.	('associated with', 'Reg', (89, 104))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (60, 81))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (60, 81))	('promoter hypermethylation', 'Var', (5, 30))	('CAV1', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	("Barrett's esophagus", 'Disease', (137, 156))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (137, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('esophageal carcinomas', 'Disease', (60, 81))	('CAV1', 'Gene', '857', (0, 4))	('human', 'Species', '9606', (54, 59))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (60, 80))
796067	24885118	Aberrant methylation of promoter CpG islands upstream of tumor suppressor genes is now well-established as a major mechanism of gene inactivation in tumorigenesis , including in ESCC and EAC .	('EAC', 'Disease', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('EAC', 'Phenotype', 'HP:0011459', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Aberrant methylation', 'Var', (0, 20))	('tumor', 'Disease', (149, 154))	('ESCC', 'Disease', (178, 182))	('tumor', 'Disease', (57, 62))	('inactivation', 'NegReg', (133, 145))
796069	24885118	Aberrant promoter methylation of CAV1 is associated with inactivation of its expression in breast and colorectal cancers .	('expression', 'MPA', (77, 87))	('colorectal cancers', 'Disease', 'MESH:D015179', (102, 120))	('associated', 'Reg', (41, 51))	('Aberrant', 'Var', (0, 8))	('colorectal cancers', 'Disease', (102, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('CAV1', 'Gene', '857', (33, 37))	('promoter', 'MPA', (9, 17))	('inactivation', 'NegReg', (57, 69))	('breast', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CAV1', 'Gene', (33, 37))
796070	24885118	Therefore, we hypothesized that CAV1 was inactivated via promoter hypermethylation in human esophageal cancers, and that hypermethylation of CAV1 constituted an early event in the genesis of EAC.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('EAC', 'Disease', (191, 194))	('inactivated', 'NegReg', (41, 52))	('CAV1', 'Gene', '857', (141, 145))	('EAC', 'Phenotype', 'HP:0011459', (191, 194))	('hypermethylation', 'Var', (121, 137))	('human', 'Species', '9606', (86, 91))	('promoter hypermethylation', 'Var', (57, 82))	('CAV1', 'Gene', '857', (32, 36))	('esophageal cancers', 'Disease', (92, 110))	('CAV1', 'Gene', (141, 145))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('esophageal cancers', 'Disease', 'MESH:D004938', (92, 110))	('CAV1', 'Gene', (32, 36))
796086	24885118	The mean NMV of CAV1 was significantly higher in ESCC (0.326), EAC (0.294), D (0.254), HGD (0.240), LGD (0.269) and BE (0.374) than in NE (0.134; p < 0.01, Student's t-test).	('0.240', 'Var', (92, 97))	('higher', 'PosReg', (39, 45))	('CAV1', 'Gene', (16, 20))	('BE', 'Chemical', '-', (116, 118))	('NMV', 'MPA', (9, 12))	('0.269', 'Var', (105, 110))	('0.326', 'Var', (55, 60))	('0.294', 'Var', (68, 73))	('EAC', 'Phenotype', 'HP:0011459', (63, 66))	('CAV1', 'Gene', '857', (16, 20))	('0.374', 'Var', (120, 125))
796087	24885118	The frequency of CAV1 hypermethylation was increased in BE (81.7%), D (60%), and EAC (65.7%) vs. NE (25.4%; p < 0.01, p < 0.01 and p < 0.01, respectively; Chi-square for independence test).	('EAC', 'Phenotype', 'HP:0011459', (81, 84))	('CAV1', 'Gene', (17, 21))	('hypermethylation', 'Var', (22, 38))	('BE', 'Chemical', '-', (56, 58))	('increased', 'PosReg', (43, 52))	('CAV1', 'Gene', '857', (17, 21))
796088	24885118	CAV1 was hypermethylated in 21 (80.8%) of 26 ESCCs.	('hypermethylated', 'Var', (9, 24))	('CAV1', 'Gene', '857', (0, 4))	('CAV1', 'Gene', (0, 4))
796102	24885118	Moreover, hypermethylation of the CAV1 promoter was significantly more frequent in premalignant lesions, such as BE and D, as well as in EAC, than in NE (Table  1).	('hypermethylation', 'Var', (10, 26))	('BE', 'Chemical', '-', (113, 115))	('EAC', 'Phenotype', 'HP:0011459', (137, 140))	('frequent', 'Reg', (71, 79))	('CAV1', 'Gene', (34, 38))	('premalignant lesions', 'Disease', (83, 103))	('EAC', 'Disease', (137, 140))	('CAV1', 'Gene', '857', (34, 38))
796104	24885118	These results suggest that hypermethylation of CAV1 may represent an early epigenetic event in these subjects, that the frequency of this epigenetic event increases during esophageal carcinogenesis, and that this event is highly prevalent in human esophageal cancers.	('hypermethylation', 'Var', (27, 43))	('CAV1', 'Gene', (47, 51))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (172, 197))	('increases', 'PosReg', (155, 164))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('esophageal carcinogenesis', 'Disease', (172, 197))	('esophageal cancers', 'Disease', (248, 266))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('CAV1', 'Gene', '857', (47, 51))	('esophageal cancers', 'Disease', 'MESH:D004938', (248, 266))	('human', 'Species', '9606', (242, 247))
796105	24885118	Barrett's carcinogenesis is a multistep process comprising genetic and epigenetic alterations in tumor suppressor genes, cell cycle-regulatory genes, and genes essential for cell-cell adhesion .	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cell cycle-regulatory genes', 'Gene', (121, 148))	('epigenetic alterations', 'Var', (71, 93))	("Barrett's carcinogenesis", 'Disease', (0, 24))	('tumor', 'Disease', (97, 102))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (0, 24))
796113	24885118	In accordance with previous findings , we observed that methylation of CAV1 in EAC cell lines was associated with silenced or reduced expression of CAV1 mRNA.	('CAV1', 'Gene', (71, 75))	('expression', 'MPA', (134, 144))	('CAV1', 'Gene', '857', (148, 152))	('CAV1', 'Gene', '857', (71, 75))	('EAC', 'Phenotype', 'HP:0011459', (79, 82))	('methylation', 'Var', (56, 67))	('CAV1', 'Gene', (148, 152))	('reduced', 'NegReg', (126, 133))
796114	24885118	In this study, reversal of methylation and restoration of CAV1 expression were induced in OE33 cells by 5-Aza-dC treatment (Figure  4).	('CAV1', 'Gene', '857', (58, 62))	('expression', 'MPA', (63, 73))	('methylation', 'Var', (27, 38))	('CAV1', 'Gene', (58, 62))	('5-Aza-dC', 'Var', (104, 112))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (104, 112))
796116	24885118	Although 5-Aza-dC or its derivatives have shown potential as therapeutic anticancer drugs , relatively hypomethylation of CAV1 in EAC and D vs. BE in the current study, and together with previous data on the re-expression of CAV1 in advance cancerf, would make CAV1 not an ideal molecular target for anti-cancer therapy involving demethylation in EAC patients.	('CAV1', 'Gene', '857', (261, 265))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('EAC', 'Disease', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('CAV1', 'Gene', '857', (225, 229))	('EAC', 'Phenotype', 'HP:0011459', (347, 350))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('CAV1', 'Gene', (261, 265))	('CAV1', 'Gene', '857', (122, 126))	('BE', 'Chemical', '-', (144, 146))	('cancer', 'Disease', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (351, 359))	('CAV1', 'Gene', (225, 229))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (9, 17))	('cancer', 'Disease', (305, 311))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('CAV1', 'Gene', (122, 126))	('hypomethylation', 'Var', (103, 118))	('cancer', 'Disease', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
796117	24885118	The current study indicates that hypermethylation of the CAV1 promoter, leading to gene silencing, is a common event in human esophageal cancer and occurs early during Barrett's-associated EAC.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('human', 'Species', '9606', (120, 125))	('CAV1', 'Gene', (57, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('EAC', 'Disease', (189, 192))	('silencing', 'NegReg', (88, 97))	('EAC', 'Phenotype', 'HP:0011459', (189, 192))	("Barrett's-associated EAC", 'Disease', (168, 192))	('hypermethylation', 'Var', (33, 49))	('CAV1', 'Gene', '857', (57, 61))	('occurs', 'Reg', (148, 154))	('esophageal cancer', 'Disease', (126, 143))	('gene', 'MPA', (83, 87))
796130	23470146	Overexpression of Cdc25C was significantly associated with pathologic complete response and better survival of patients with locally advanced esophageal cancer treated with radiotherapy followed by surgery.	('Cdc25C', 'Gene', '995', (18, 24))	('esophageal cancer', 'Disease', (142, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Overexpression', 'Var', (0, 14))	('Cdc25C', 'Gene', (18, 24))	('patients', 'Species', '9606', (111, 119))
796143	23470146	Dysfunction of checkpoints is considered a pathologic hallmark of neoplastic transformation and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (96, 101))	('Dysfunction', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))
796207	23470146	In esophageal carcinoma, several studies have demonstrated that amplification and overexpression of Cyclin D1 are good predictors of prognosis for esophageal carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('esophageal carcinoma', 'Disease', (3, 23))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (3, 23))	('Cyclin D1', 'Gene', (100, 109))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (147, 167))	('amplification', 'Var', (64, 77))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (3, 23))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (147, 167))	('overexpression', 'PosReg', (82, 96))	('patients', 'Species', '9606', (168, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('Cyclin D1', 'Gene', '595', (100, 109))	('esophageal carcinoma', 'Disease', (147, 167))
796209	23470146	We evaluated the expression of Chk2, Cdc25C, and Cyclin D1 under the hypothesis that abnormalities in these cell cycle checkpoint-related proteins may be associated with response to radiotherapy, ultimately having distinct effects on the survival of patients with locally advanced esophageal cancer.	('Chk2', 'Gene', (31, 35))	('Cyclin D1', 'Gene', (49, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (281, 298))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('effects', 'Reg', (223, 230))	('Cdc25C', 'Gene', (37, 43))	('patients', 'Species', '9606', (250, 258))	('having', 'Reg', (207, 213))	('Chk2', 'Gene', '11200', (31, 35))	('Cdc25C', 'Gene', '995', (37, 43))	('Cyclin D1', 'Gene', '595', (49, 58))	('abnormalities', 'Var', (85, 98))	('esophageal cancer', 'Disease', (281, 298))	('associated', 'Reg', (154, 164))
796211	23470146	A SNP of Cyclin D1 gene predicts response to neoadjuvant radiotherapy and prognosis in rectal cancer.	('Cyclin D1', 'Gene', '595', (9, 18))	('Cyclin D1', 'Gene', (9, 18))	('rectal cancer', 'Disease', 'MESH:D012004', (87, 100))	('SNP', 'Var', (2, 5))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rectal cancer', 'Disease', (87, 100))	('predicts', 'Reg', (24, 32))	('rectal cancer', 'Phenotype', 'HP:0100743', (87, 100))
796227	24222893	Integrated Analysis of Long Noncoding RNA and Coding RNA Expression in Esophageal Squamous Cell Carcinoma Tumorigenesis is a complex dynamic biological process that includes multiple steps of genetic and epigenetic alterations, aberrant expression of noncoding RNA, and changes in the expression profiles of coding genes.	('aberrant', 'Var', (228, 236))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('changes', 'Reg', (270, 277))	('Esophageal Squamous Cell Carcinoma', 'Disease', (71, 105))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('expression', 'MPA', (237, 247))	('expression profiles', 'MPA', (285, 304))	('Carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('noncoding', 'Protein', (251, 260))	('Coding RNA', 'Gene', (46, 56))
796228	24222893	We call the collection of those perturbations in genome space the "cancer initiatome."	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('perturbations', 'Var', (32, 45))	('cancer', 'Disease', (67, 73))
796240	24222893	Overexpression of MALAT-1 is highly predictive of poor prognosis and shortened survival time in early stage lung cancer.	('MALAT-1', 'Gene', (18, 25))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('survival time', 'CPA', (79, 92))	('shortened', 'NegReg', (69, 78))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('MALAT-1', 'Gene', '378938', (18, 25))
796289	24204738	Many studies have demonstrated that disruption of microRNA function may be crucial in the disease process, particularly in cancer oncogenesis.	('microRNA function', 'MPA', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('disruption', 'Var', (36, 46))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
796309	24204738	The most significant functions associated with the altered genes include cellular movement, cellular growth and proliferation, cell death, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cellular growth', 'CPA', (92, 107))	('genes', 'Var', (59, 64))	('cell death', 'CPA', (127, 137))	('cellular movement', 'CPA', (73, 90))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
796332	24204738	Figure 5C shows the luciferase signals from co-transfection of miR-139-5p mimics or NC with wild-type or mutant of 3'UTR constructs of NR5A2.	('NR5A2', 'Gene', (135, 140))	('5p', 'Chemical', '-', (71, 73))	('miR-139', 'Gene', (63, 70))	('luciferase', 'Enzyme', (20, 30))	('miR-139', 'Gene', '406931', (63, 70))	('mutant', 'Var', (105, 111))
796348	24204738	The deregulation of miR-139-5p was observed to be a frequent event in ESCC and other types of cancer.	('deregulation', 'Var', (4, 16))	('miR-139', 'Gene', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('miR-139', 'Gene', '406931', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('ESCC', 'Disease', (70, 74))	('cancer', 'Disease', (94, 100))	('5p', 'Chemical', '-', (28, 30))
796371	24204738	Wang further demonstrated the induction of apoptosis in LRH-1 knockdown hepatocellular carcinoma cells.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('hepatocellular carcinoma', 'Disease', (72, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('LRH-1', 'Gene', '2494', (56, 61))	('LRH-1', 'Gene', (56, 61))	('knockdown', 'Var', (62, 71))
796462	32121290	According to molecular features, ESCC can be classified into three different subtypes: ESCC1, with somatic alterations similar to other SCCs, some of them associated with poor prognosis and resistance to chemo-radiotherapy; ESCC2, with a greater leukocyte infiltration and a higher expression of the bone marrow stromal antigen 2 (BST2) immunomodulatory molecule; and the ESCC3 characterized by alterations predicted to activate the Phosphoinositide 3-kinases (PI3K) pathway and aspects as non-identifiable in other SCCs.	('higher', 'PosReg', (275, 281))	('ESCC', 'Disease', (33, 37))	('ESCC', 'Disease', 'MESH:D000077277', (33, 37))	('BST2', 'Gene', (331, 335))	('associated', 'Reg', (155, 165))	('expression', 'MPA', (282, 292))	('bone marrow stromal antigen 2', 'Gene', (300, 329))	('bone marrow stromal antigen 2', 'Gene', '684', (300, 329))	('ESCC', 'Disease', (87, 91))	('ESCC', 'Disease', 'MESH:D000077277', (87, 91))	('ESCC', 'Disease', (224, 228))	('activate', 'PosReg', (420, 428))	('ESCC', 'Disease', 'MESH:D000077277', (224, 228))	('ESCC', 'Disease', 'MESH:D000077277', (372, 376))	('ESCC', 'Disease', (372, 376))	('BST2', 'Gene', '684', (331, 335))	('alterations', 'Var', (395, 406))
796500	32121290	Three co-primary endpoints had to be demonstrated: superiority in terms of OS for the experimental arm in the overall population (intention-to-treat, ITT), in squamous cell tumors, and in tumors with CPS >10%; therefore, the alpha-spending was strictly designed.	('squamous cell tumors', 'Disease', (159, 179))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('CPS', 'Var', (200, 203))	('CPS', 'Chemical', '-', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('OS', 'Gene', '17451', (75, 77))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('squamous cell tumors', 'Phenotype', 'HP:0002860', (159, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Disease', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('squamous cell tumors', 'Disease', 'MESH:D002294', (159, 179))
796504	32121290	Regarding the histology in the PD-L1-positive population, the benefit in terms of survival derived from pembrolizumab derived benefit in CPS >= 10 population seemed to be higher in the ESCC, with a median OS of 10.3 months vs. 6.7 months, whereas mOS was 6.3 months vs. 6.9 months in EAC, although this last component ranked around only 25% of this selected subgroup.	('mOS', 'Gene', (247, 250))	('pembrolizumab', 'Chemical', 'MESH:C582435', (104, 117))	('mOS', 'Gene', '17451', (247, 250))	('OS', 'Gene', '17451', (248, 250))	('PD-L1', 'Gene', '29126', (31, 36))	('higher', 'PosReg', (171, 177))	('OS', 'Gene', '17451', (205, 207))	('CPS', 'Var', (137, 140))	('ESCC', 'Disease', (185, 189))	('ESCC', 'Disease', 'MESH:D000077277', (185, 189))	('survival', 'MPA', (82, 90))	('CPS', 'Chemical', '-', (137, 140))	('PD-L1', 'Gene', (31, 36))
796524	32121290	Although not powered to assess differences among cohorts, after a median follow-up of 2 years, the best results in terms of activity were observed in the N1+I3 cohort, with an ORR of 12%, 24%, and 8%, and a reduction in tumor burden from baseline of 29%, 45%, and 27% in the N3, N1+I3, and N3+I1 arms, respectively.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('N', 'Chemical', 'MESH:D009584', (290, 291))	('activity', 'MPA', (124, 132))	('tumor', 'Disease', (220, 225))	('reduction', 'NegReg', (207, 216))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('N', 'Chemical', 'MESH:D009584', (275, 276))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('N', 'Chemical', 'MESH:D009584', (279, 280))	('N1+I3', 'Var', (154, 159))
796526	32121290	Conversely, mOS was similar among groups: 6.2 months vs. 6.9 months vs. 4.8 months, in the N3, N1 + I3, N3 + I1, respectively.	('N', 'Chemical', 'MESH:D009584', (95, 96))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('N3 + I1', 'Var', (104, 111))	('mOS', 'Gene', (12, 15))	('N1 + I3', 'Var', (95, 102))	('mOS', 'Gene', '17451', (12, 15))	('N', 'Chemical', 'MESH:D009584', (104, 105))
796527	32121290	Despite the improvement in terms of response with the combination of N1+I3 without any advantage in terms of survival, it should be emphasized that this combination was associated with a major incidence of high-grade adverse events of 47% (especially diarrhea and elevation of liver enzymes), compared to 17% of the N3 and 27% of the N3+I1.	('diarrhea', 'Phenotype', 'HP:0002014', (251, 259))	('N1+I3', 'Var', (69, 74))	('diarrhea', 'Disease', (251, 259))	('elevation', 'MPA', (264, 273))	('improvement', 'PosReg', (12, 23))	('diarrhea', 'Disease', 'MESH:D003967', (251, 259))	('N', 'Chemical', 'MESH:D009584', (316, 317))	('N', 'Chemical', 'MESH:D009584', (69, 70))	('N', 'Chemical', 'MESH:D009584', (334, 335))	('elevation of liver enzymes', 'Phenotype', 'HP:0002910', (264, 290))
796530	32121290	In a phase I trial, preliminary interesting data were presented for a new drug M7824, a bifunctional fusion protein composed of a human anti-PD-L1 immunoglobin G1 (IgG1) monoclonal antibody (mAb) fused with two extracellular domains of the transforming growth factor beta (TGFbeta) receptor II, aiming to magnify the response to anti-PD(L)1 therapy through the inhibition of the TGFbeta pathway.	('PD-L1', 'Gene', (141, 146))	('PD-L1', 'Gene', '29126', (141, 146))	('transforming growth factor beta (TGFbeta) receptor II', 'Gene', '7048', (240, 293))	('TGFbeta', 'Gene', '7039', (379, 386))	('TGFbeta', 'Gene', (273, 280))	('PD(L)1', 'Gene', (334, 340))	('M7824', 'Var', (79, 84))	('PD(L)1', 'Gene', '29126', (334, 340))	('TGFbeta', 'Gene', (379, 386))	('TGFbeta', 'Gene', '7039', (273, 280))	('human', 'Species', '9606', (130, 135))
796565	32121290	Tislelizumab is a humanized immunoglobulin G4 (IgG4)-variant monoclonal antibody against programmed cell death protein-1 (PD-1) that competitively blocks binding by both PD-L1 and PD-L2, thus enhancing signaling in a T cell.	('binding', 'Interaction', (154, 161))	('PD-L1', 'Gene', (170, 175))	('PD-L1', 'Gene', '29126', (170, 175))	('signaling in a', 'MPA', (202, 216))	('human', 'Species', '9606', (18, 23))	('enhancing', 'PosReg', (192, 201))	('programmed cell death protein-1', 'Gene', '5133', (89, 120))	('blocks', 'NegReg', (147, 153))	('IgG4', 'Gene', (47, 51))	('-variant', 'Var', (52, 60))	('programmed cell death protein-1', 'Gene', (89, 120))
796596	32121290	At the multivariate analysis, high levels of PD-L1 were correlated with a worse DFS, together with an advanced pathological stage.	('high', 'Var', (30, 34))	('PD-L1', 'Gene', '29126', (45, 50))	('DFS', 'Disease', (80, 83))	('PD-L1', 'Gene', (45, 50))
796600	32121290	The prevalence of PD-L1 positivity was 38%, 24%, and 30%, respectively, for each cohort N3, N1+I3, and N3+I1, and PD-L1 expression did not correlate with tumor response.	('PD-L1', 'Gene', (114, 119))	('N', 'Chemical', 'MESH:D009584', (88, 89))	('N', 'Chemical', 'MESH:D009584', (103, 104))	('positivity', 'Var', (24, 34))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('PD-L1', 'Gene', '29126', (114, 119))	('N3+I1', 'Var', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('N1+I3', 'Var', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PD-L1', 'Gene', (18, 23))	('PD-L1', 'Gene', '29126', (18, 23))	('tumor', 'Disease', (154, 159))
796602	32121290	Mismatch repair deficient (dMMR) tumors harbor 10 to 100 times more mutations than mismatch repair proficient (pMMR) tumors:principally in the repetitive DNA sequences, called microsatellites:which for this reason have developed a very high instability (MSI-H).	('instability', 'MPA', (241, 252))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('dMMR', 'Chemical', '-', (27, 31))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (68, 77))	('tumors', 'Disease', (33, 39))	('N', 'Chemical', 'MESH:D009584', (155, 156))
796610	32121290	DDR alterations were found in a significant proportion of esophageal adenocarcinoma samples (467/2501, 19%), median TMB was 5.0 mut/Mb, and high TMB cases (defined as TMB >=20 mut/Mb) were only 59 (2.4%).	('TMB', 'Chemical', '-', (167, 170))	('alterations', 'Var', (4, 15))	('TMB', 'Chemical', '-', (116, 119))	('DDR', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('TMB', 'Chemical', '-', (145, 148))	('found', 'Reg', (21, 26))	('esophageal adenocarcinoma', 'Disease', (58, 83))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (58, 83))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (58, 83))
796617	32121290	The framework in ESCC is less defined:the presence of Clostridiales and Erysipelotrichaceae in gastric microbiota seem associated with esophageal squamous dysplasia and ESCC.	('ESCC', 'Disease', (169, 173))	('esophageal squamous dysplasia', 'Disease', 'MESH:D000077277', (135, 164))	('Erysipelotrichaceae', 'Var', (72, 91))	('ESCC', 'Disease', 'MESH:D000077277', (169, 173))	('ESCC', 'Disease', (17, 21))	('ESCC', 'Disease', 'MESH:D000077277', (17, 21))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (146, 164))	('esophageal squamous dysplasia', 'Disease', (135, 164))	('associated', 'Reg', (119, 129))
796618	32121290	Furthermore, the presence of Fusobacterium nucleatum seems to be associated with a worse prognosis of esophageal squamous cell carcinoma, probably due to its activation of chemokines.	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('Fusobacterium nucleatum', 'Var', (29, 52))	('Fusobacterium nucleatum', 'Species', '851', (29, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('activation', 'PosReg', (158, 168))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('presence', 'Var', (17, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
796622	32121290	Due to the linkage between the immune system, inflammation, and gut microbiome, many authors hypothesize that long-chain PUFAs could represent a biomarker for patients' healthy gut microbiota and a potential therapeutic agent modulating the composition of the microbiome and subsequently the response to immunotherapy.	('inflammation', 'Disease', 'MESH:D007249', (46, 58))	('modulating', 'Reg', (226, 236))	('inflammation', 'Disease', (46, 58))	('long-chain', 'Var', (110, 120))	('gut microbiome', 'Species', '749906', (64, 78))	('patients', 'Species', '9606', (159, 167))	('PUFAs', 'Chemical', 'MESH:D005231', (121, 126))
796661	31335729	HRs < 1 frequently implied a favorable prognosis in patients with increased serum D-dimer levels.	('increased', 'PosReg', (66, 75))	('serum D-dimer levels', 'MPA', (76, 96))	('patients', 'Species', '9606', (52, 60))	('HRs < 1', 'Var', (0, 7))
796684	31335729	Although the exact mechanism by which D-dimer influences survival outcomes is still unclear, some publications postulated that D-dimer affects carcinoma patients' survival outcome by means of the formation of venous thromboembolisms (VTEs).	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('patients', 'Species', '9606', (153, 161))	('affects', 'Reg', (135, 142))	('carcinoma', 'Disease', (143, 152))	('venous thromboembolisms', 'Disease', (209, 232))	('survival', 'MPA', (163, 171))	('thromboembolisms', 'Phenotype', 'HP:0001907', (216, 232))	('VTEs', 'Disease', 'MESH:D054556', (234, 238))	('VTEs', 'Disease', (234, 238))	('carcinoma', 'Disease', 'MESH:D002277', (143, 152))	('D-dimer', 'Var', (127, 134))	('venous thromboembolisms', 'Disease', 'MESH:D054556', (209, 232))
796726	30541998	Therefore, bilateral esophagostomy was created by interruption of the esophagus in the same manner as in Case 1, and a feeding jejunostomy was created as part of the therapy for the lung abscess to avoid the inflow of saliva through the fistulas and to improve nutrition.	('nutrition', 'MPA', (261, 270))	('improve', 'PosReg', (253, 260))	('abscess', 'Phenotype', 'HP:0025615', (187, 194))	('fistulas', 'Disease', (237, 245))	('fistulas', 'Disease', 'MESH:D005402', (237, 245))	('lung abscess', 'Phenotype', 'HP:0025044', (182, 194))	('inflow', 'MPA', (208, 214))	('lung abscess', 'Disease', (182, 194))	('interruption', 'Var', (50, 62))
796751	30740907	Further analysis found that surgery tended to achieve clinical benefits only for patients with localized disease (T1-4aN0M0).	('localized disease', 'Disease', 'MESH:D012594', (95, 112))	('localized disease', 'Disease', (95, 112))	('patients', 'Species', '9606', (81, 89))	('T1-4aN0M0', 'Var', (114, 123))
796771	30740907	In total, there were 87 864 patients with esophageal malignancy, among which 530 patients (0.6%) with small cell histology were identified using codes (8041, 8042, 8043, and 8045).	('esophageal malignancy', 'Disease', 'MESH:D004938', (42, 63))	('patients', 'Species', '9606', (81, 89))	('8045', 'Var', (174, 178))	('8041', 'Var', (152, 156))	('esophageal malignancy', 'Phenotype', 'HP:0100751', (42, 63))	('8042', 'Var', (158, 162))	('esophageal malignancy', 'Disease', (42, 63))	('8043', 'Var', (164, 168))	('patients', 'Species', '9606', (28, 36))
796832	30740907	Therefore, we propose that surgery should be considered only for patients with localized disease (T1-4aN0M0).	('localized disease', 'Disease', (79, 96))	('patients', 'Species', '9606', (65, 73))	('localized disease', 'Disease', 'MESH:D012594', (79, 96))	('T1-4aN0M0', 'Var', (98, 107))
796839	30740907	Zou et al12 reported that postoperative chemotherapy improves survival only in SCCE patients at stages T3-4N0M0 and T1-4N1-2M0.	('survival', 'MPA', (62, 70))	('al1', 'Gene', (7, 10))	('patients', 'Species', '9606', (84, 92))	('improves', 'PosReg', (53, 61))	('SCCE', 'Disease', (79, 83))	('T1-4N1-2M0', 'Var', (116, 126))	('al1', 'Gene', '1946', (7, 10))	('T3-4N0M0', 'Var', (103, 111))
796845	30740907	Surgery should be considered for patients with localized disease (T1-4aN0M0), and chemotherapy combined with radiotherapy might be recommended for patients with regional and extensive disease.	('localized disease', 'Disease', (47, 64))	('patients', 'Species', '9606', (33, 41))	('localized disease', 'Disease', 'MESH:D012594', (47, 64))	('T1-4aN0M0', 'Var', (66, 75))	('patients', 'Species', '9606', (147, 155))	('men', 'Species', '9606', (136, 139))
796850	30276140	MTT and TUNEL assays were performed to evaluate cell viability after Snail-1 silencing.	('silencing', 'Var', (77, 86))	('Snail-1', 'Gene', (69, 76))	('MTT', 'Chemical', '-', (0, 3))
796899	30276140	Some studies indicated that repression of Snail-1 increased apoptosis in tumor cells, which are consistent with our findings.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('increased', 'PosReg', (50, 59))	('Snail-1', 'Gene', (42, 49))	('apoptosis', 'CPA', (60, 69))	('tumor', 'Disease', (73, 78))	('repression', 'Var', (28, 38))
796901	30276140	reported that silencing of Snail decreased vimentin in the human breast carcinoma in an in vitro study.	('silencing', 'Var', (14, 23))	('human', 'Species', '9606', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('vimentin', 'Protein', (43, 51))	('Snail', 'Gene', (27, 32))	('breast carcinoma', 'Disease', (65, 81))	('breast carcinoma', 'Disease', 'MESH:D001943', (65, 81))	('decreased', 'NegReg', (33, 42))	('breast carcinoma', 'Phenotype', 'HP:0003002', (65, 81))
796909	30276140	These findings imply that siRNA silencing of Snail-1, leading to upmodulation of miR-34a tumor suppressor and downregulation of MMP-1 and MMP-9 metastatic mediators, may interrupt with the migration and invasion of ESCC cells.	('ESCC', 'Disease', (215, 219))	('MMP-1', 'Gene', '17386', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('Snail-1', 'Gene', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('silencing', 'Var', (32, 41))	('interrupt', 'NegReg', (170, 179))	('upmodulation', 'PosReg', (65, 77))	('miR-34a', 'Gene', (81, 88))	('invasion', 'CPA', (203, 211))	('downregulation', 'NegReg', (110, 124))	('MMP-1', 'Gene', (128, 133))	('tumor', 'Disease', (89, 94))	('migration', 'CPA', (189, 198))
796912	30276140	In our survey, let-7a transcript level was augmented after Snail-1-specific siRNA knockdown.	('let-7a', 'Gene', '387244', (15, 21))	('augmented', 'PosReg', (43, 52))	('knockdown', 'Var', (82, 91))	('let-7a', 'Gene', (15, 21))
796915	30276140	Overall, the outcomes of this study implicate that Snail-1 knockdown utilizing siRNA can significantly interrupt esophageal cancer cell migration and reduce metastatic-related factors, vimentin, CXCR4, MMP-9, and induce miR-34a and let-7a in vitro.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('MMP-9', 'MPA', (202, 207))	('induce', 'PosReg', (213, 219))	('let-7a', 'Gene', '387244', (232, 238))	('miR-34a', 'CPA', (220, 227))	('reduce', 'NegReg', (150, 156))	('vimentin', 'MPA', (185, 193))	('interrupt', 'NegReg', (103, 112))	('Snail-1', 'Gene', (51, 58))	('CXCR4', 'MPA', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('let-7a', 'Gene', (232, 238))	('knockdown', 'Var', (59, 68))	('metastatic-related', 'CPA', (157, 175))	('esophageal cancer', 'Disease', (113, 130))
796931	30159412	DSBs are the most lethal as well as the most susceptible DNA damage for carcinogenesis.	('carcinogenesis', 'Disease', (72, 86))	('DSBs', 'Var', (0, 4))	('DSBs', 'Chemical', 'MESH:C007563', (0, 4))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))
796935	30159412	HR is an error free repair, which requires a template DNA and occurs mostly in cells in the S/G2 phase of the cell cycle where DNA is replicated; on the other hand, NHEJ is an error prone repair, which simply rejoins the broken strands of DNA and occurs mostly in G1 phase of the cell cycle, but also has limited activity throughout the cell cycle.	('S/G2', 'Var', (92, 96))	('S/G2', 'SUBSTITUTION', 'None', (92, 96))	('NHEJ', 'Var', (165, 169))
796937	30159412	Phosphorylation of H2AX at serine 139 is an important process to recruit all DNA repair associated proteins and also considered as a reliable marker for DNA DSB.	('recruit', 'PosReg', (65, 72))	('Phosphorylation', 'Var', (0, 15))	('H2AX', 'Gene', '3014', (19, 23))	('serine', 'Chemical', 'MESH:D012694', (27, 33))	('DSB', 'Chemical', 'MESH:C007563', (157, 160))	('H2AX', 'Gene', (19, 23))
796953	30159412	Inhibition of MDC1 during neoplasm associated replication stress might result in accumulation of DNA damage and genomic instability.	('neoplasm', 'Disease', 'MESH:D009369', (26, 34))	('neoplasm', 'Phenotype', 'HP:0002664', (26, 34))	('DNA damage', 'MPA', (97, 107))	('genomic instability', 'CPA', (112, 131))	('Inhibition', 'Var', (0, 10))	('MDC1', 'Gene', (14, 18))	('MDC1', 'Gene', '9656', (14, 18))	('neoplasm', 'Disease', (26, 34))	('accumulation', 'PosReg', (81, 93))
796954	30159412	BRCA1 is an important member of HR repair and is often mutated in breast and ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (77, 91))	('BRCA1', 'Gene', (0, 5))	('mutated', 'Var', (55, 62))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (66, 91))	('BRCA1', 'Gene', '672', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
796962	30159412	FA is another chromosomal instability disorder resulting from mutations in 19 complimentary genes that are important for DNA repair.	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('mutations', 'Var', (62, 71))	('chromosomal instability', 'Phenotype', 'HP:0040012', (14, 37))	('chromosomal instability disorder', 'Disease', 'MESH:D043171', (14, 46))	('chromosomal instability disorder', 'Disease', (14, 46))	('resulting from', 'Reg', (47, 61))
796970	30159412	This observation is important because ANE or ARE nut-chewing habits often results in the development of oral cancer.	('oral cancer', 'Disease', 'MESH:D009062', (104, 115))	('results in', 'Reg', (74, 84))	('oral cancer', 'Disease', (104, 115))	('nut', 'Gene', '256646', (49, 52))	('ARE', 'Chemical', 'MESH:D001115', (45, 48))	('-chewing habits', 'Phenotype', 'HP:0005216', (52, 67))	('ANE', 'Var', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ANE', 'Chemical', '-', (38, 41))	('nut', 'Gene', (49, 52))
796974	30159412	Downregulation of DNA-PKcs and ATM mRNAs by miR-101 transfection and simultaneous treatment with radiation sensitized the cancer cells by inhibiting DSB repair.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('ATM', 'Gene', '472', (31, 34))	('DNA-PKcs', 'Gene', (18, 26))	('Downregulation', 'NegReg', (0, 14))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('DNA-PKcs', 'Gene', '5591', (18, 26))	('DSB repair', 'MPA', (149, 159))	('inhibiting', 'NegReg', (138, 148))	('transfection', 'Var', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('ATM', 'Gene', (31, 34))	('DSB', 'Chemical', 'MESH:C007563', (149, 152))
796976	30159412	Inhibition of 53BP1 in glioblastoma cells post-irradiation showed increased DNA damage associated with mitotic catastrophe.	('DNA damage', 'MPA', (76, 86))	('increased', 'PosReg', (66, 75))	('glioblastoma', 'Disease', 'MESH:D005909', (23, 35))	('53BP1', 'Gene', (14, 19))	('53BP1', 'Gene', '7158', (14, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('Inhibition', 'Var', (0, 10))	('glioblastoma', 'Disease', (23, 35))
796982	30159412	Functionally disabling mutations in these two genes results in Xeroderma pigmentosum, Cockayne's syndrome, and Trichothiodystrophy.	('Xeroderma pigmentosum', 'Disease', 'MESH:D014983', (63, 84))	("Cockayne's syndrome", 'Disease', 'MESH:D003057', (86, 105))	("Cockayne's syndrome", 'Disease', (86, 105))	('mutations', 'Var', (23, 32))	('Xeroderma pigmentosum', 'Disease', (63, 84))	('results in', 'Reg', (52, 62))	('Trichothiodystrophy', 'Disease', (111, 130))
796989	30159412	Mutations in proteins that are involved in MMR results in genomic instability syndrome called microsatellite instability (MIS).	('microsatellite instability', 'Disease', (94, 120))	('MIS', 'Disease', 'None', (122, 125))	('results in', 'Reg', (47, 57))	('Mutations', 'Var', (0, 9))	('genomic instability syndrome', 'Disease', (58, 86))	('proteins', 'Protein', (13, 21))	('MIS', 'Disease', (122, 125))	('genomic instability syndrome', 'Disease', 'MESH:D042822', (58, 86))
796990	30159412	Mutations in MMR are also associated with most of the cancers.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('Mutations', 'Var', (0, 9))	('MMR', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('associated', 'Reg', (26, 36))
796993	30159412	Mutations in these genes are generally associated with MIS or Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC).	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (97, 138))	('MIS', 'Disease', (55, 58))	('Lynch syndrome', 'Disease', (62, 76))	('Lynch syndrome', 'Disease', 'MESH:D003123', (62, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('hereditary nonpolyposis colorectal cancer', 'Disease', (97, 138))	('Mutations', 'Var', (0, 9))	('MIS', 'Disease', 'None', (55, 58))	('associated', 'Reg', (39, 49))	('HNPCC', 'Phenotype', 'HP:0006716', (140, 145))	('HNPCC', 'Disease', 'None', (140, 145))	('HNPCC', 'Disease', (140, 145))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (97, 138))
797007	30159412	Single base modifications like oxidation, methylation, uracil, alkylation, and deamination results in improper formation of DNA double helix.	('DNA double helix', 'MPA', (124, 140))	('alkylation', 'Var', (63, 73))	('uracil', 'Chemical', 'MESH:D014498', (55, 61))	('methylation', 'Var', (42, 53))	('deamination', 'Var', (79, 90))	('oxidation', 'Var', (31, 40))	('uracil', 'Var', (55, 61))
797008	30159412	Mutations in genes that are involved in BER are often associated with cancer.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('associated', 'Reg', (54, 64))
797009	30159412	For example, somatic mutation of Pol beta is found in 30% of cancers and mutations in DNA glycosylase MYH increases the risk of colon cancer.	('colon cancer', 'Disease', (128, 140))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('Pol beta', 'Gene', (33, 41))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('MYH', 'Gene', '4595', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('MYH', 'Gene', (102, 105))	('increases', 'PosReg', (106, 115))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('Pol beta', 'Gene', '5423', (33, 41))	('mutations', 'Var', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
797053	23812217	4-NQO dose-dependently induced pre-malignant and malignant lesions in oral cavity and esophagus in mice that pathologically and morphologically mimicked human oral and esophageal cancer.	('mice', 'Species', '10090', (99, 103))	('esophageal cancer', 'Disease', (168, 185))	('lesions in oral cavity', 'Phenotype', 'HP:0100649', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('human', 'Species', '9606', (153, 158))	('4-NQO', 'Var', (0, 5))	('4-NQO', 'Chemical', 'MESH:D015112', (0, 5))
797054	23812217	Molecularly, 4-NQO inhibited Rarbeta2 but induced expression of phosphorylated extracellular-signal-regulated kinase 1 and 2 (p-ERK1/2) and Cox2 proteins and Rarbeta2 gene promoter methylation in murine tumors.	('4-NQO', 'Chemical', 'MESH:D015112', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('inhibited', 'NegReg', (19, 28))	('tumors', 'Disease', (203, 209))	('induced', 'PosReg', (42, 49))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('Rarbeta2', 'Gene', (158, 166))	('p-ERK1/2', 'Gene', '107808969', (126, 134))	('Cox2', 'Gene', (140, 144))	('murine', 'Species', '10090', (196, 202))	('Rarbeta2', 'Gene', (29, 37))	('Cox2', 'Gene', '5743', (140, 144))	('p-ERK1/2', 'Gene', (126, 134))	('4-NQO', 'Var', (13, 18))	('expression', 'MPA', (50, 60))
797059	23812217	4-NQO-induced cancer in oral cavity and esophagus of mice not only pathologically and morphologically mimicked human oral and esophageal cancer but also shared some molecular alterations (e.g.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('4-NQO', 'Chemical', 'MESH:D015112', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('human', 'Species', '9606', (111, 116))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('4-NQO-induced', 'Var', (0, 13))	('cancer', 'Disease', (137, 143))	('cancer in oral cavity', 'Phenotype', 'HP:0100649', (14, 35))	('rat', 'Species', '10116', (179, 182))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('esophageal cancer', 'Disease', (126, 143))	('mice', 'Species', '10090', (53, 57))
797060	23812217	aberrant expression of Rarb2, p-ERK1/2, and Cox2).	('aberrant', 'Var', (0, 8))	('Cox2', 'Gene', (44, 48))	('Cox2', 'Gene', '5743', (44, 48))	('p-ERK1/2', 'Gene', '107808969', (30, 38))	('p-ERK1/2', 'Gene', (30, 38))	('Rarb2', 'Gene', (23, 28))
797071	23812217	However, the molecular mechanisms responsible for 4-NQO-induced oral and esophageal cancer remain to be defined.	('esophageal cancer', 'Disease', (73, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('4-NQO', 'Chemical', 'MESH:D015112', (50, 55))	('4-NQO-induced', 'Var', (50, 63))
797074	23812217	benzo(a)pyrene diolepoxide (BPDE)] inhibited retinoic acid receptor beta2 (RARbeta2) but induced expression of phosphorylated extracellular-signal-regulated kinase 1 and 2 (p-ERK1/2) and cyclooxygenase 2 (COX2) in oral and esophageal cancer cell lines and that loss of RARbeta2 expression is a common and early event in different human cancer tissues, including oral and esophageal SCC.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('SCC', 'Phenotype', 'HP:0002860', (382, 385))	('cancer', 'Disease', (336, 342))	('oral', 'Disease', (362, 366))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('p-ERK1/2', 'Gene', '107808969', (173, 181))	('loss', 'Var', (261, 265))	('expression', 'MPA', (278, 288))	('p-ERK1/2', 'Gene', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('inhibited', 'NegReg', (35, 44))	('SCC', 'Gene', '6317', (382, 385))	('expression', 'MPA', (97, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (223, 240))	('SCC', 'Gene', (382, 385))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('esophageal cancer', 'Disease', (223, 240))	('BPDE', 'Chemical', 'MESH:D015123', (28, 32))	('human', 'Species', '9606', (330, 335))	('retinoic acid', 'Chemical', 'MESH:D014212', (45, 58))	('cancer', 'Disease', (234, 240))	('RARbeta2', 'Gene', (269, 277))
797075	23812217	BPDE treatment methylated the RARbeta2 gene promoter according to one study, while other studies also showed that 4-NQO was able to inhibit Rarbeta2 but induce Cox2 expression in C57BL6 mice.	('inhibit', 'NegReg', (132, 139))	('BPDE', 'Chemical', 'MESH:D015123', (0, 4))	('Cox2', 'Gene', (160, 164))	('4-NQO', 'Var', (114, 119))	('expression', 'MPA', (165, 175))	('Rarbeta2', 'Gene', (140, 148))	('Cox2', 'Gene', '5743', (160, 164))	('4-NQO', 'Chemical', 'MESH:D015112', (114, 119))	('RARbeta2', 'Gene', (30, 38))	('mice', 'Species', '10090', (186, 190))	('induce', 'PosReg', (153, 159))	('methylated', 'Var', (15, 25))
797077	23812217	Six-week-old C57LB6/129Sv mice were housed in plastic cages in an air-conditioned room with a 12 h light-dark cycle and a basal diet (Taklad Global 19% Protein Extruded Rodent Diet 2919; diet and mice both from Harlan Laboratories, Houston, TX, USA); sterilized water was available ad libitum.	('129Sv', 'Species', '10090', (20, 25))	('mice', 'Species', '10090', (196, 200))	('Harlan Laboratories', 'Disease', (211, 230))	('C57LB6/129Sv', 'Var', (13, 25))	('water', 'Chemical', 'MESH:D014867', (262, 267))	('Harlan Laboratories', 'Disease', 'MESH:D007757', (211, 230))	('mice', 'Species', '10090', (26, 30))
797103	23812217	The antibodies used were anti-c-FOS (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA); anti-COX2 (BD Transduction Laboratories, Lexington, KY, USA); anti-ERK1/2, and p-ERK1/2 (Cell Signaling Technology, Beverly, MA, USA); and anti-beta-actin (Sigma).	('anti-ERK1/2', 'Var', (152, 163))	('c-FOS', 'Gene', '2353', (30, 35))	('p-ERK1/2', 'Gene', '107808969', (169, 177))	('p-ERK1/2', 'Gene', (169, 177))	('c-FOS', 'Gene', (30, 35))	('beta-actin', 'Gene', '728378', (234, 244))	('beta-actin', 'Gene', (234, 244))	('rat', 'Species', '10116', (121, 124))
797129	23812217	Our data showed that 4-NQO dose-dependently induced pre-malignant and malignant lesions in murine oral cavity and esophagus after 8-week treatment with 4-NQO administered in the animals' drinking water followed a16-week waiting period.	('drinking water', 'Chemical', 'MESH:D060766', (187, 201))	('4-NQO', 'Var', (21, 26))	('4-NQO', 'Chemical', 'MESH:D015112', (21, 26))	('induced', 'Reg', (44, 51))	('murine', 'Species', '10090', (91, 97))	('4-NQO', 'Chemical', 'MESH:D015112', (152, 157))
797130	23812217	Table I summarizes the body weight changes of the mice before and after the experiments; results indicated that body weight of 4-NQO-treated mice showed less gain than that of control mice in a dose-dependent manner.	('4-NQO', 'Chemical', 'MESH:D015112', (127, 132))	('body weight', 'CPA', (112, 123))	('mice', 'Species', '10090', (141, 145))	('4-NQO-treated', 'Var', (127, 140))	('mice', 'Species', '10090', (50, 54))	('mice', 'Species', '10090', (184, 188))
797133	23812217	4-NQO induced mild and severe dysplasia and SCC in the oral cavity and esophagus (Figure 1).	('SCC', 'Gene', '6317', (44, 47))	('dysplasia', 'Disease', (30, 39))	('SCC', 'Gene', (44, 47))	('4-NQO', 'Var', (0, 5))	('dysplasia', 'Disease', 'MESH:D004476', (30, 39))	('4-NQO', 'Chemical', 'MESH:D015112', (0, 5))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))
797134	23812217	BrdU immunostaining showed that cells in 4-NQO-induced lesions had greater BrdU incorporation into DNA than did normal tissues.	('BrdU', 'Chemical', 'MESH:D001973', (75, 79))	('4-NQO', 'Chemical', 'MESH:D015112', (41, 46))	('BrdU', 'Chemical', 'MESH:D001973', (0, 4))	('lesions', 'Var', (55, 62))	('greater', 'PosReg', (67, 74))	('BrdU incorporation into DNA', 'MPA', (75, 102))	('rat', 'Species', '10116', (87, 90))
797141	23812217	In our previous study, we showed that tobacco carcinogen BPDE inhibited RARbeta2 expression through methylation of RARbeta2 gene promoter and then in turn up-regulated expression of p-ERK1/2 and COX2 proteins in human esophageal cancer cell lines.	('RARbeta2', 'Gene', (72, 80))	('p-ERK1/2', 'Gene', (182, 190))	('human', 'Species', '9606', (212, 217))	('RARbeta2', 'Gene', (115, 123))	('expression', 'MPA', (168, 178))	('tobacco', 'Species', '4097', (38, 45))	('methylation', 'Var', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('inhibited', 'NegReg', (62, 71))	('esophageal cancer', 'Disease', (218, 235))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))	('p-ERK1/2', 'Gene', '107808969', (182, 190))	('BPDE', 'Chemical', 'MESH:D015123', (57, 61))	('expression', 'MPA', (81, 91))	('up-regulated', 'PosReg', (155, 167))
797144	23812217	Our data showed that 4-NQO did indeed induce Rarbeta2 gene promoter methylation in five randomly selected cases each of oral and esophageal SCC tissues but not in the five control normal tissues.	('4-NQO', 'Var', (21, 26))	('Rarbeta2 gene', 'Gene', (45, 58))	('induce', 'Reg', (38, 44))	('promoter methylation', 'MPA', (59, 79))	('4-NQO', 'Chemical', 'MESH:D015112', (21, 26))	('SCC', 'Phenotype', 'HP:0002860', (140, 143))	('SCC', 'Gene', '6317', (140, 143))	('SCC', 'Gene', (140, 143))
797149	23812217	Moreover, we also determined whether the RARbeta2-led gene pathway was affected by 4-NQO treatment and found that indeed, 4-NQO treatment inhibited RARbeta2 expression and up-regulated p-ERK1/2, c-FOS and COX2 expression in RARbeta2 positive HET-1A and TE-3 cells, but such effects were much less in RARbeta2 negative TE-8 cells (Figure 4C), indicating that expression of RAR-beta2 plays an important role in 4-NQO-induced COX2 expression.	('RARbeta2', 'Gene', (148, 156))	('4-NQO', 'Chemical', 'MESH:D015112', (409, 414))	('HE', 'Chemical', '-', (242, 244))	('4-NQO', 'Chemical', 'MESH:D015112', (122, 127))	('expression', 'MPA', (157, 167))	('up-regulated', 'PosReg', (172, 184))	('4-NQO', 'Chemical', 'MESH:D015112', (83, 88))	('c-FOS', 'Gene', '2353', (195, 200))	('expression', 'MPA', (210, 220))	('p-ERK1/2', 'Gene', '107808969', (185, 193))	('inhibited', 'NegReg', (138, 147))	('4-NQO', 'Var', (122, 127))	('c-FOS', 'Gene', (195, 200))	('p-ERK1/2', 'Gene', (185, 193))	('COX2', 'Gene', (205, 209))
797159	23812217	We performed an additional experiment to assess whether knockdown of COX2 expression is able to inhibit growth of esophageal cancer cells using transient transfection of a COX2 antisense expression vector.	('growth', 'CPA', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('COX2', 'Gene', (69, 73))	('inhibit', 'NegReg', (96, 103))	('knockdown', 'Var', (56, 65))
797160	23812217	Our data show that knockdown of COX2 expression suppressed Ki67 expression (an indicator of cell proliferation) (Figure 7).	('COX2', 'Gene', (32, 36))	('knockdown', 'Var', (19, 28))	('suppressed', 'NegReg', (48, 58))	('Ki67', 'Gene', (59, 63))	('rat', 'Species', '10116', (104, 107))
797161	23812217	However, in COX2-weakly expressing SKGT-4 cells, antisense COX-2 cDNA transfection had less effect on inhibition of tumor cell growth (Figure 7).	('antisense', 'Var', (49, 58))	('SKGT-4', 'CellLine', 'CVCL:2195', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('COX-2', 'Gene', '4513', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('COX-2', 'Gene', (59, 64))	('tumor', 'Disease', (116, 121))
797162	23812217	In the current study, we demonstrated that 4-NQO-induced pre-malignant and malignant lesions in oral cavity and esophagus in mice not only pathologically and morphologically mimicked human oral and esophageal cancers but also shared some molecular alterations (e.g.	('rat', 'Species', '10116', (252, 255))	('rat', 'Species', '10116', (32, 35))	('4-NQO-induced', 'Var', (43, 56))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('mice', 'Species', '10090', (125, 129))	('human', 'Species', '9606', (183, 188))	('esophageal cancers', 'Disease', (198, 216))	('4-NQO', 'Chemical', 'MESH:D015112', (43, 48))	('lesions in oral cavity', 'Phenotype', 'HP:0100649', (85, 107))	('esophageal cancers', 'Disease', 'MESH:D004938', (198, 216))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
797171	23812217	However, the molecular mechanisms responsible for 4-NQO-induced oral and esophageal cancer have yet to be defined.	('esophageal cancer', 'Disease', (73, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('4-NQO', 'Chemical', 'MESH:D015112', (50, 55))	('4-NQO-induced', 'Var', (50, 63))
797172	23812217	Thus, we took this opportunity to compare the gene expressions in 4-NOQ-induced murine esophageal cancer with this type of cancer in humans.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('4-NOQ-induced', 'Var', (66, 79))	('4-NOQ', 'Chemical', '-', (66, 71))	('esophageal cancer', 'Disease', (87, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('humans', 'Species', '9606', (133, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', (123, 129))	('murine', 'Species', '10090', (80, 86))
797180	23812217	also showed higher Cox2 expression but lower Rarbeta2 expression in tongue tissues of 4-NQO-treated mice than in tissues from control mice.	('expression', 'MPA', (54, 64))	('mice', 'Species', '10090', (134, 138))	('higher', 'PosReg', (12, 18))	('expression', 'MPA', (24, 34))	('Rarbeta2', 'Gene', (45, 53))	('4-NQO', 'Chemical', 'MESH:D015112', (86, 91))	('mice', 'Species', '10090', (100, 104))	('Cox2', 'Gene', (19, 23))	('Cox2', 'Gene', '5743', (19, 23))	('4-NQO-treated', 'Var', (86, 99))	('lower', 'NegReg', (39, 44))
797188	23812217	Overexpression of COX2 was reported in oral and esophageal cancer and promoted cell growth, invasion, and metastasis of these types of cancer.	('esophageal cancer', 'Disease', (48, 65))	('cancer', 'Disease', (135, 141))	('invasion', 'CPA', (92, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('oral', 'Disease', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Overexpression', 'Var', (0, 14))	('COX2', 'Gene', (18, 22))	('promoted', 'PosReg', (70, 78))	('metastasis', 'CPA', (106, 116))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cell growth', 'CPA', (79, 90))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
797192	23812217	In conclusion, our current study demonstrates that 4-NQO-induced pre-malignant and malignant lesions in oral cavity and esophagus in mice not only pathologically and morphologically mimicked human oral and esophageal cancer but also shared similar molecular alterations (e.g.	('mice', 'Species', '10090', (133, 137))	('pre-malignant', 'CPA', (65, 78))	('esophageal cancer', 'Disease', (206, 223))	('lesions in oral cavity', 'Phenotype', 'HP:0100649', (93, 115))	('4-NQO', 'Chemical', 'MESH:D015112', (51, 56))	('rat', 'Species', '10116', (40, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (206, 223))	('human', 'Species', '9606', (191, 196))	('4-NQO-induced', 'Var', (51, 64))	('rat', 'Species', '10116', (262, 265))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
797300	33889027	It has been reported that a high CONUT score could increase the incidence of postoperative infection and was an independent risk factor for the survival time, and a high NRS2002 score was associated with prolonged postoperative hospitalization and postoperative complications; however, these assessment tools are cumbersome to use and have little clinical utility.	('increase', 'PosReg', (51, 59))	('high', 'Var', (165, 169))	('postoperative infection', 'Disease', (77, 100))	('postoperative infection', 'Disease', 'MESH:D013530', (77, 100))	('high', 'Var', (28, 32))	('NRS2002', 'Gene', (170, 177))
797309	33889027	The results of the present study also showed that the PNI was an independent prognostic factor for the overall postoperative survival time in patients with gastric cancer, which is consistent with the findings of previous studies.	('PNI', 'Var', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('gastric cancer', 'Disease', (156, 170))	('gastric cancer', 'Disease', 'MESH:D013274', (156, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (156, 170))	('patients', 'Species', '9606', (142, 150))
797310	33889027	As one of the main treatments for patients with stage Ib-III gastric cancer, radiochemotherapy can improve the prognosis and prolong the survival time; however, it can also cause different degrees of toxic side effects.	('survival time', 'CPA', (137, 150))	('improve', 'PosReg', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('prolong', 'NegReg', (125, 132))	('patients', 'Species', '9606', (34, 42))	('III gastric cancer', 'Disease', 'MESH:D013274', (57, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('III gastric cancer', 'Disease', (57, 75))	('prognosis', 'CPA', (111, 120))	('radiochemotherapy', 'Var', (77, 94))
797313	33889027	Studies on the toxic side effects of chemotherapy have shown that female gender, low BMI, and hypoalbuminemia are independent prognostic factors for the hematologic toxic side effects of grade 3-4 chemotherapy.	('low', 'Var', (81, 84))	('low BMI', 'Phenotype', 'HP:0045082', (81, 88))	('hypoalbuminemia', 'Disease', (94, 109))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (94, 109))	('BMI', 'MPA', (85, 88))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (94, 109))
797317	33889027	In patients receiving adjuvant radiochemotherapy for esophageal cancer, patients with a low PNI were more likely to have hematologic toxic side effects of radiotherapy above grade 3, and the correlation coefficient between PNI and toxic side effects was higher than that between lymphocyte count and serum albumin levels.	('hematologic toxic side effects', 'MPA', (121, 151))	('serum albumin', 'Gene', '213', (300, 313))	('serum albumin', 'Gene', (300, 313))	('low', 'Var', (88, 91))	('PNI', 'Gene', (92, 95))	('patients', 'Species', '9606', (3, 11))	('esophageal cancer', 'Disease', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('patients', 'Species', '9606', (72, 80))
797319	33889027	The results of the present study showed that patients with a low PNI were more likely to experience hematologic toxic side effects of radiochemotherapy above grade 3.	('hematologic toxic', 'Disease', (100, 117))	('PNI', 'Gene', (65, 68))	('patients', 'Species', '9606', (45, 53))	('low', 'Var', (61, 64))
797322	33889027	In summary, the results of the present study suggested that the preoperative PNI could predict the severity of hematologic side effects of adjuvant chemotherapy/radiotherapy in patients with gastric cancer, and that the group with a low PNI was more likely to have severe hematologic side effects, which was one of the important factors affecting the prognosis in patients with gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (378, 392))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (378, 392))	('gastric cancer', 'Disease', (191, 205))	('PNI', 'Gene', (77, 80))	('patients', 'Species', '9606', (177, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (191, 205))	('low', 'Var', (233, 236))	('gastric cancer', 'Disease', (378, 392))	('gastric cancer', 'Phenotype', 'HP:0012126', (191, 205))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('patients', 'Species', '9606', (364, 372))	('PNI', 'Gene', (237, 240))
797394	30479565	The human esophageal cancer Cells lines Kyse30 and Kyse150 were kindly provided by Professor Zhan (National Laboratory of Molecular Oncology, China, Beijing), Kyse30-R and Kyse150-R were obtained from their parental strains of Kyse30 and Kyse150, respectively.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (4, 9))	('esophageal cancer', 'Disease', (10, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (10, 27))	('Kyse150-R', 'Var', (172, 181))	('Kyse30-R', 'Var', (159, 167))	('Oncology', 'Phenotype', 'HP:0002664', (132, 140))
797416	30479565	So we detected the migration and invasion ability of resistant cells Kyse30-R and Kyse150-R to see whether they obtained the characteristics of cancer cells.	('detected', 'Reg', (6, 14))	('Kyse150-R', 'Var', (82, 91))	('invasion', 'CPA', (33, 41))	('migration', 'CPA', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('Kyse30-R', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
797417	30479565	These results demonstrated that the Kyse150-R cells acquired some of the features of the cancer cells, whereas the biological features of Kyse30-R cells is different from the cancer cells.	('Kyse150-R', 'Var', (36, 45))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
797423	30479565	The miR-omic and qRT-PCR analyses in Kyse30-R cells versus Kyse30 cells showed that the expression of miR-199a-3p is significantly higher in Kyse30-R cells, resulting in about 16 and 31 folds for the miR-omic and qRT-PCR assays, respectively (Fig.	('miR', 'Gene', '220972', (200, 203))	('miR', 'Gene', (200, 203))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))	('Kyse30-R', 'Var', (141, 149))	('higher', 'PosReg', (131, 137))	('miR', 'Gene', (4, 7))	('miR-199a-3p', 'Gene', '406977', (102, 113))	('miR', 'Gene', '220972', (4, 7))	('expression', 'MPA', (88, 98))	('miR-199a-3p', 'Gene', (102, 113))
797426	30479565	Consistently, the protein level of AK4 is also down-regulated in Kyse30-R and Kyse150-R cells, with the ratio of about 0.57 and 0.31, respectively (Fig.	('AK4', 'Gene', (35, 38))	('protein level', 'MPA', (18, 31))	('AK4', 'Gene', '205', (35, 38))	('down-regulated', 'NegReg', (47, 61))	('Kyse150-R', 'Var', (78, 87))	('Kyse30-R', 'Var', (65, 73))
797429	30479565	As expected, the transfection of 3PM into the Kyse30 and Kyse150 cells indeed increased the miR-199a-3p level to about 1994 and 900 folds, respectively (Fig.	('miR-199a-3p', 'Gene', '406977', (92, 103))	('transfection', 'Var', (17, 29))	('increased', 'PosReg', (78, 87))	('miR-199a-3p', 'Gene', (92, 103))
797430	30479565	This conflict indicates that 3PA might cause the dysregulation of other factors that contribute to the up-regulation of miR-199a-3p level in the Kyse150-R cells.	('dysregulation', 'MPA', (49, 62))	('miR-199a-3p', 'Gene', (120, 131))	('up-regulation', 'PosReg', (103, 116))	('3PA', 'Var', (29, 32))	('miR-199a-3p', 'Gene', '406977', (120, 131))
797431	30479565	Following the changes of the miR-199a-3p, the AK4 level in reversely correlated with the changes of miR-199a-3p, resulting in a much lower AK4 level in Kyse30 and Kyse150 cells whereas a higher AK4 level in Kyse30-R and Kyse150-R cells (Fig.	('miR-199a-3p', 'Gene', '406977', (29, 40))	('miR-199a-3p', 'Gene', (100, 111))	('AK4', 'Gene', '205', (194, 197))	('AK4', 'Gene', '205', (139, 142))	('AK4', 'Gene', (46, 49))	('AK4', 'Gene', (194, 197))	('AK4', 'Gene', (139, 142))	('miR-199a-3p', 'Gene', '406977', (100, 111))	('miR-199a-3p', 'Gene', (29, 40))	('changes', 'Var', (14, 21))	('lower', 'NegReg', (133, 138))	('higher', 'PosReg', (187, 193))	('AK4', 'Gene', '205', (46, 49))
797434	30479565	We found that pZEX-AK4-UTR WT led to a significantly higher luciferase activity in Kyse30 cells than that in Kyse30-R cells (Fig.	('higher', 'PosReg', (53, 59))	('AK4', 'Gene', '205', (19, 22))	('luciferase', 'Enzyme', (60, 70))	('AK4', 'Gene', (19, 22))	('activity', 'MPA', (71, 79))	('Kyse30', 'Var', (83, 89))
797440	30479565	Reversely, transfection of miR-199a-3p antagomiR into Kyse30-R or Kyse150-R cells somewhat decreased the cell survival rate against radiation (Fig.	('miR-199a-3p', 'Gene', (27, 38))	('cell survival rate against radiation', 'CPA', (105, 141))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('Kyse150-R', 'Var', (66, 75))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('miR-199a-3p', 'Gene', '406977', (27, 38))	('decreased', 'NegReg', (91, 100))
797445	30479565	To further elucidate the underlying mechanism of EC radioresistance mediated by miR-199a-3p, we compared the activities of seventeen cancer-related signaling pathways in both Kyse30-R and Kyse150-R versus their parental cells Kyse30 and Kyse150, respectively (Fig.	('compared', 'Reg', (96, 104))	('Kyse150-R', 'Var', (188, 197))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('miR-199a-3p', 'Gene', (80, 91))	('miR-199a-3p', 'Gene', '406977', (80, 91))	('cancer', 'Disease', (133, 139))	('Kyse30-R', 'Var', (175, 183))	('activities', 'MPA', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
797446	30479565	Only three pathways: TGFbeta, MAPK/JNK and IL-6 are up-regulated in the Kyse150 cells, which are in agreement with that of Kyse30 cells.	('MAPK', 'Gene', '5594', (30, 34))	('up-regulated', 'PosReg', (52, 64))	('JNK', 'Gene', '5599', (35, 38))	('IL-6', 'Gene', (43, 47))	('MAPK', 'Gene', (30, 34))	('Kyse150', 'Var', (72, 79))	('TGFbeta', 'Gene', '7040', (21, 28))	('TGFbeta', 'Gene', (21, 28))	('IL-6', 'Gene', '3569', (43, 47))	('JNK', 'Gene', (35, 38))
797469	30479565	In this work, we screened Kyse30-R and Kyse150-R EC radioresistant cells, and find miR-199a-3p/AK4-mediated EC radioresistance, the findings suggest that miR-199a-3p or AK4 may serve as biomarkers for the potential therapeutic treatment of EC.	('AK4', 'Gene', '205', (169, 172))	('AK4', 'Gene', '205', (95, 98))	('AK4', 'Gene', (169, 172))	('miR-199a-3p', 'Gene', '406977', (154, 165))	('miR-199a-3p', 'Gene', (83, 94))	('AK4', 'Gene', (95, 98))	('miR-199a-3p', 'Gene', '406977', (83, 94))	('miR-199a-3p', 'Gene', (154, 165))	('Kyse150-R', 'Var', (39, 48))
797471	29262626	Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma TP53 mutations are considered to be the driving factor in the initiation of esophageal adenocarcinoma (EAC).	('initiation of esophageal adenocarcinoma', 'Disease', (176, 215))	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (190, 215))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (88, 113))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('TP53', 'Gene', '7157', (114, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (190, 215))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('EAC', 'Phenotype', 'HP:0011459', (217, 220))	('TP53', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))	('initiation of esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (176, 215))
797473	29262626	Compared to heterogeneous p53 expression, loss and overexpression were both independently predictive for adverse DFS and OS.	('loss', 'Var', (42, 46))	('DFS', 'Disease', (113, 116))	('OS', 'Chemical', '-', (121, 123))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('overexpression', 'PosReg', (51, 65))
797474	29262626	TP53 mutational status significantly correlated with the IHC categories (p=0.035).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('correlated', 'Reg', (37, 47))	('IHC categories', 'Disease', (57, 71))	('mutational status', 'Var', (5, 22))
797475	29262626	Most of the EAC with loss- or overexpression harbored TP53 mutations (18/20, representing nonsense and missense mutations respectively).	('TP53', 'Gene', (54, 58))	('overexpression', 'PosReg', (30, 44))	('TP53', 'Gene', '7157', (54, 58))	('mutations', 'Var', (59, 68))	('loss-', 'NegReg', (21, 26))	('EAC', 'Phenotype', 'HP:0011459', (12, 15))
797477	29262626	Combined genomic hypomethylation and high frequency of intra-chromosomal breaks was found in a selection of EAC without p53 overexpression.	('hypomethylation', 'Var', (17, 32))	('p53', 'Gene', '7157', (120, 123))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (61, 79))	('EAC', 'Phenotype', 'HP:0011459', (108, 111))	('p53', 'Gene', (120, 123))
797490	29262626	In EAC, mutations in TP53 are detected early in the pathogenesis, likely linked to severe DNA damage in Barrett esophagus (BE) due to the reflux of mixed gastric and duodenal juice into the esophagus.	('TP53', 'Gene', (21, 25))	('Barrett esophagus', 'Disease', (104, 121))	('linked', 'Reg', (73, 79))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('mutations', 'Var', (8, 17))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (104, 121))	('BE', 'Phenotype', 'HP:0100580', (123, 125))	('TP53', 'Gene', '7157', (21, 25))
797491	29262626	Recent genome wide studies proposed that EAC precursor lesions containing TP53 mutations rapidly develop extensive chromosomal instability with subsequent oncogene activation.	('chromosomal instability', 'CPA', (115, 138))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('chromosomal instability', 'Phenotype', 'HP:0040012', (115, 138))	('mutations', 'Var', (79, 88))
797494	29262626	Overexpression is likely due to TP53 mutations which stabilize the affected protein.	('TP53', 'Gene', '7157', (32, 36))	('stabilize', 'PosReg', (53, 62))	('mutations', 'Var', (37, 46))	('protein', 'Protein', (76, 83))	('TP53', 'Gene', (32, 36))
797512	29262626	The risk of recurrence of EAC was increased for patient with p53 overexpression (hazard ratio (HR) 1.91; 95% CI 1.16-3.14) as well as loss of p53 expression (HR 1.57; 95% CI 0.9-2.74) compared to heterogeneous p53 expression.	('EAC', 'Phenotype', 'HP:0011459', (26, 29))	('p53', 'Gene', '7157', (210, 213))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('EAC', 'Disease', (26, 29))	('patient', 'Species', '9606', (48, 55))	('overexpression', 'PosReg', (65, 79))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('expression', 'MPA', (146, 156))	('p53', 'Gene', (210, 213))	('loss', 'Var', (134, 138))
797521	29262626	All EAC with overexpression of p53 as detected by IHC had missense mutations.	('missense mutations', 'Var', (58, 76))	('p53', 'Gene', (31, 34))	('EAC', 'Phenotype', 'HP:0011459', (4, 7))	('p53', 'Gene', '7157', (31, 34))
797523	29262626	Those with more than 40% p53 positive tumor cells all showed missense mutations (n=3), in analogy to EAC with overexpression, while in the lower percentage category two out of four showed a nonsense mutation (one containing both a splice site and stopgain mutation).	('p53', 'Gene', (25, 28))	('tumor', 'Disease', (38, 43))	('p53', 'Gene', '7157', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('missense mutations', 'Var', (61, 79))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('EAC', 'Phenotype', 'HP:0011459', (101, 104))
797524	29262626	EAC cases with heterogeneous p53 expression in the middle group (n=6, 21-40%) demonstrated no underlying TP53 mutations in four and two nonsense mutations.	('mutations', 'Var', (110, 119))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('p53', 'Gene', (29, 32))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('p53', 'Gene', '7157', (29, 32))
797525	29262626	Besides TP53, in total, 21 other proven pathogenic mutations in the following genes SMAD4 (n=7), ARID1A (n=5) , PIK3CA (n=2), DOCK2 (n=6) and ELMO (n=1) were detected, significantly more in EAC with a heterogeneous p53 expression (13/21; p=0.032) (Figure 3 and Supplementary Table 5).	('SMAD4', 'Gene', (84, 89))	('DOCK2', 'Gene', '1794', (126, 131))	('EAC', 'Phenotype', 'HP:0011459', (190, 193))	('mutations', 'Var', (51, 60))	('PIK3CA', 'Gene', '5290', (112, 118))	('EAC', 'Disease', (190, 193))	('p53', 'Gene', (215, 218))	('pathogenic', 'Reg', (40, 50))	('p53', 'Gene', '7157', (215, 218))	('ARID1A', 'Gene', '8289', (97, 103))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('ARID1A', 'Gene', (97, 103))	('DOCK2', 'Gene', (126, 131))	('SMAD4', 'Gene', '4089', (84, 89))	('PIK3CA', 'Gene', (112, 118))
797534	29262626	Only one showed no TP53 anomaly (case 18, no p53 expression), while all others demonstrated either a mutation in TP53 itself (three nonsense, one missense), or amplification of MDM2 or MDM4.	('p53', 'Gene', (45, 48))	('MDM2', 'Gene', '4193', (177, 181))	('anomaly', 'Disease', (24, 31))	('p53', 'Gene', '7157', (45, 48))	('MDM2', 'Gene', (177, 181))	('MDM4', 'Gene', '4194', (185, 189))	('amplification', 'Var', (160, 173))	('MDM4', 'Gene', (185, 189))	('TP53', 'Gene', '7157', (113, 117))	('anomaly', 'Disease', 'MESH:D000014', (24, 31))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('mutation', 'Var', (101, 109))	('TP53', 'Gene', (113, 117))
797535	29262626	This analysis demonstrated that six out of the seven EAC with a hypomethylation profile showed a higher number of breaks compared to the group median, i.e., indicated in red boxes in Figure 4 (including those with the MDM2 and MDM4 amplification), while this was observed for only two of the EAC within the non-hypomethylated group.	('MDM2', 'Gene', '4193', (218, 222))	('MDM2', 'Gene', (218, 222))	('breaks', 'MPA', (114, 120))	('EAC', 'Phenotype', 'HP:0011459', (53, 56))	('hypomethylation profile', 'Var', (64, 87))	('MDM4', 'Gene', '4194', (227, 231))	('MDM4', 'Gene', (227, 231))	('EAC', 'Phenotype', 'HP:0011459', (292, 295))
797536	29262626	These data suggest that there is a correlation between p53 status (protein expression, mutational profile and MDM2/4 amplification), accumulation of other mutations (preferentially in the p53 heterogeneous staining group), preferential presence of a hypomethylated profile in the loss and heterogeneous p53 group, and occurrence of intrachromosomal breaks.	('p53', 'Gene', '7157', (188, 191))	('p53', 'Gene', (303, 306))	('mutations', 'Var', (155, 164))	('hypomethylated profile', 'MPA', (250, 272))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('intrachromosomal breaks', 'Phenotype', 'HP:0040012', (332, 355))	('p53', 'Gene', '7157', (303, 306))	('MDM2', 'Gene', '4193', (110, 114))	('p53', 'Gene', (188, 191))	('MDM2', 'Gene', (110, 114))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (337, 355))	('accumulation', 'PosReg', (133, 145))
797543	29262626	Although, overall, similar results were reported in all three meta-analyses suggesting a negative effect of mutated TP53 on prognosis, the data should be interpreted with caution.	('TP53', 'Gene', (116, 120))	('negative', 'NegReg', (89, 97))	('mutated', 'Var', (108, 115))	('TP53', 'Gene', '7157', (116, 120))
797553	29262626	Prediction of mutational status by IHC could be an alternative, but the prognostic accuracy might depend on the underlying cancer type.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutational', 'Var', (14, 24))
797554	29262626	TP53 mutational frequency rate was 76%, which is comparable to the recent investigations using whole genome or exome sequencing techniques.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutational frequency', 'Var', (5, 25))
797557	29262626	Of interest is that most additional mutations in the other candidate genes investigated were identified in the group with heterogeneous p53 expression, including two cases with regional amplifications of MDM2 or MDM4 (Figure 3).	('MDM2', 'Gene', '4193', (204, 208))	('MDM4', 'Gene', (212, 216))	('MDM2', 'Gene', (204, 208))	('p53', 'Gene', '7157', (136, 139))	('mutations', 'Var', (36, 45))	('identified', 'Reg', (93, 103))	('MDM4', 'Gene', '4194', (212, 216))	('p53', 'Gene', (136, 139))
797558	29262626	In contrast, all EAC with high percentage of p53 positive cells (more than 61%, n=10) showed missense mutations in TP53, which is in line with results of two earlier studies.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('TP53', 'Gene', '7157', (115, 119))	('EAC', 'Phenotype', 'HP:0011459', (17, 20))	('TP53', 'Gene', (115, 119))	('missense mutations', 'Var', (93, 111))
797559	29262626	EAC with loss of p53 expression demonstrated predominantly nonsense mutations, including splicing, stopgain and frameshift mutations (8/10).	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('loss', 'NegReg', (9, 13))	('splicing', 'MPA', (89, 97))	('expression', 'MPA', (21, 31))	('stopgain', 'Disease', (99, 107))	('p53', 'Gene', (17, 20))	('frameshift mutations', 'Var', (112, 132))	('p53', 'Gene', '7157', (17, 20))
797562	29262626	The hypomethylated profile of the most differentiating CpG sites combined with a high frequency of intrachromosomal breaks was predominantly observed in EAC with loss or a heterogeneous p53 pattern (either by a nonsense mutation (n=3) or MDM2/4 amplification (n=2)).	('nonsense mutation', 'Var', (211, 228))	('MDM2', 'Gene', '4193', (238, 242))	('intrachromosomal breaks', 'Phenotype', 'HP:0040012', (99, 122))	('MDM2', 'Gene', (238, 242))	('loss', 'NegReg', (162, 166))	('high frequency of intrachromosomal breaks', 'Phenotype', 'HP:0040012', (81, 122))	('EAC', 'Disease', (153, 156))	('p53', 'Gene', (186, 189))	('heterogeneous', 'MPA', (172, 185))	('p53', 'Gene', '7157', (186, 189))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (104, 122))	('EAC', 'Phenotype', 'HP:0011459', (153, 156))
797571	29262626	However, this is considered unlikely to play an important role, since identical TP53 mutations and homogeneous loss of heterozygosity of the TP53 locus were detected across separated tumor regions in EAC previously, and a homogenous IHC was identified in all cases.	('EAC', 'Disease', (200, 203))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (141, 145))	('TP53', 'Gene', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('mutations', 'Var', (85, 94))	('tumor', 'Disease', (183, 188))	('detected', 'Reg', (157, 165))	('EAC', 'Phenotype', 'HP:0011459', (200, 203))
797576	29262626	Secondly, we have shown that IHC is a good read out for the presence of TP53 mutations mainly in EAC with p53 overexpression and probably in EAC with loss of expression but not in EAC with a heterogeneous p53 expression.	('EAC', 'Disease', (97, 100))	('p53', 'Gene', '7157', (106, 109))	('TP53', 'Gene', '7157', (72, 76))	('expression', 'MPA', (158, 168))	('p53', 'Gene', (205, 208))	('TP53', 'Gene', (72, 76))	('p53', 'Gene', '7157', (205, 208))	('EAC', 'Phenotype', 'HP:0011459', (141, 144))	('mutations', 'Var', (77, 86))	('loss', 'NegReg', (150, 154))	('EAC', 'Phenotype', 'HP:0011459', (97, 100))	('p53', 'Gene', (106, 109))	('EAC', 'Phenotype', 'HP:0011459', (180, 183))	('overexpression', 'PosReg', (110, 124))
797578	29262626	In addition, our study could suggests existence of different pathogenesis of EAC, related to the p53 pathway (TP53 mutational status and MDM2/4 amplification), with downstream additional mutations of other candidate genes, as well as DNA methylation alterations and possibly related chromosomal instability.	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('p53', 'Gene', (97, 100))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('MDM2', 'Gene', '4193', (137, 141))	('MDM2', 'Gene', (137, 141))	('p53', 'Gene', '7157', (97, 100))	('EAC', 'Disease', (77, 80))	('mutations', 'Var', (187, 196))	('chromosomal instability', 'Phenotype', 'HP:0040012', (283, 306))
797580	29262626	All patients had pathologically proven pT2-pT4a adenocarcinoma of the esophagus or at the gastro-esophageal junction.	('patients', 'Species', '9606', (4, 12))	('pT2-pT4a', 'Var', (39, 47))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (48, 79))	('adenocarcinoma of the esophagus', 'Disease', (48, 79))
797606	29262626	BE Barrett esophagus CRT chemoradiotherapy CNV copy number variation DFS disease free survival EAC esophageal adenocarcinoma FFPE formalin-fixed paraffin-embedded GI gastro-intestinal HR hazard ratio IHC immunohistochemistry LGD low grade dysplasia OS overall survival ROC receiver operating characteristics SNV Single Nucleotide Variations	('LGD low', 'Phenotype', 'HP:0410245', (225, 232))	('EAC', 'Phenotype', 'HP:0011459', (95, 98))	('dysplasia', 'Disease', (239, 248))	('copy', 'Var', (47, 51))	('Barrett esophagus', 'Phenotype', 'HP:0100580', (3, 20))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (99, 124))	('formalin', 'Chemical', 'MESH:D005557', (130, 138))	('paraffin', 'Chemical', 'MESH:D010232', (145, 153))	('esophageal adenocarcinoma', 'Disease', (99, 124))	('OS', 'Chemical', '-', (249, 251))	('dysplasia', 'Disease', 'MESH:D004476', (239, 248))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (99, 124))	('BE', 'Phenotype', 'HP:0100580', (0, 2))
797644	28424424	Leukocyte telomere length-related genetic variants in ACYP2 contribute to the risk of esophageal carcinoma in Chinese Han population Short leukocyte telomere length has been associated with significantly increased risk of esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (222, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('associated', 'Reg', (174, 184))	('esophageal carcinoma', 'Disease', (86, 106))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (222, 242))	('variants', 'Var', (42, 50))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (86, 106))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (86, 106))	('ACYP2', 'Gene', (54, 59))	('ACYP2', 'Gene', '98', (54, 59))	('Short leukocyte telomere length', 'Phenotype', 'HP:0031413', (133, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('esophageal carcinoma', 'Disease', (222, 242))
797647	28424424	Therefore, we investigated whether ACYP2 polymorphisms have impact on the risk of esophageal carcinoma in Chinese.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (82, 102))	('ACYP2', 'Gene', (35, 40))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (82, 102))	('polymorphisms', 'Var', (41, 54))	('impact', 'Reg', (60, 66))	('ACYP2', 'Gene', '98', (35, 40))	('esophageal carcinoma', 'Disease', (82, 102))
797649	28424424	We found that 1.34-fold increased risk of esophageal carcinoma is associated with the rs11125529 A allele compared with the rs11125529 C allele (OR=1.29, 95%CI: 1.02-1.62, p=0.030) under the additive model, after adjusted by age and gender.	('rs11125529 A', 'Var', (86, 98))	('esophageal carcinoma', 'Disease', (42, 62))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (42, 62))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (42, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('rs11125529', 'Mutation', 'rs11125529', (86, 96))	('rs11125529', 'Mutation', 'rs11125529', (124, 134))
797650	28424424	We also found rs11896604 and rs17045754 loci increased the esophageal carcinoma risk under the additive model (rs11896604: OR=1.34, 95%CI: 1.03-1.76, p=0.032; rs17045754: OR=1.36, 95%CI: 1.03-1.80, p=0.028).	('rs11896604', 'Var', (14, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('increased', 'PosReg', (45, 54))	('esophageal carcinoma', 'Disease', (59, 79))	('rs17045754', 'Mutation', 'rs17045754', (159, 169))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (59, 79))	('rs17045754', 'Var', (159, 169))	('rs17045754', 'Var', (29, 39))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (59, 79))	('rs17045754', 'Mutation', 'rs17045754', (29, 39))	('rs11896604', 'Mutation', 'rs11896604', (111, 121))	('rs11896604', 'Mutation', 'rs11896604', (14, 24))
797651	28424424	This block was comprised of seven closely linked SNPs: rs1682111, rs843752, rs10439478, rs843645, rs11125529, rs843711 and rs11896604.	('rs10439478', 'Mutation', 'rs10439478', (76, 86))	('rs11125529', 'Mutation', 'rs11125529', (98, 108))	('rs843645', 'Mutation', 'rs843645', (88, 96))	('rs843645', 'Var', (88, 96))	('rs1682111', 'Var', (55, 64))	('rs1682111', 'Mutation', 'rs1682111', (55, 64))	('rs10439478', 'Var', (76, 86))	('rs843711', 'Var', (110, 118))	('rs11896604', 'Mutation', 'rs11896604', (123, 133))	('rs11125529', 'Var', (98, 108))	('rs11896604', 'Var', (123, 133))	('rs843711', 'Mutation', 'rs843711', (110, 118))	('rs843752', 'Mutation', 'rs843752', (66, 74))	('rs843752', 'Var', (66, 74))
797652	28424424	The haplotype analysis detected that haplotype "TTCTATG" increased the risk of esophageal carcinoma (OR=1.38, 95%CI: 1.04-1.82, p=0.025).	('haplotype', 'Var', (37, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('esophageal carcinoma', 'Disease', (79, 99))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (79, 99))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (79, 99))
797663	28424424	in Chinese population of esophageal cancer, and seven susceptibility sites for esophageal cancer were found in five regions (5q11 rs10052657, 21q22 rs2014300, 6p21 rs10484761, 10q23 rs2274223 and 12q24 rsl1066015, rs2074356, rs11066280).	('rs10052657', 'Mutation', 'rs10052657', (130, 140))	('rs2014300', 'Mutation', 'rs2014300', (148, 157))	('esophageal cancer', 'Disease', (79, 96))	('rs2074356', 'Mutation', 'rs2074356', (214, 223))	('rs11066280', 'Var', (225, 235))	('rs10484761', 'Mutation', 'rs10484761', (164, 174))	('esophageal cancer', 'Disease', (25, 42))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs2014300', 'Var', (148, 157))	('rs2074356', 'Var', (214, 223))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (25, 42))	('rs10052657', 'Var', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('rs11066280', 'Mutation', 'rs11066280', (225, 235))	('rs2274223', 'Mutation', 'rs2274223', (182, 191))	('rs2274223', 'Var', (182, 191))	('rs10484761', 'Var', (164, 174))
797664	28424424	found that rs2274223 in PLCE1 associated with ESCC.	('associated', 'Reg', (30, 40))	('ESCC', 'Disease', (46, 50))	('PLCE1', 'Gene', (24, 29))	('PLCE1', 'Gene', '51196', (24, 29))	('rs2274223', 'Mutation', 'rs2274223', (11, 20))	('rs2274223', 'Var', (11, 20))
797666	28424424	Telomere contains repeating nucleotide sequences and a related terminal protein complex that plays a key role in maintaining chromosome integrity and stability, as well as telomere shortening involved in the carcinogenesis and progression of malignant tumors.	('malignant tumors', 'Disease', 'MESH:D018198', (242, 258))	('shortening', 'NegReg', (181, 191))	('chromosome integrity', 'CPA', (125, 145))	('carcinogenesis', 'Disease', (208, 222))	('telomere', 'Var', (172, 180))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('telomere shortening', 'Phenotype', 'HP:0031413', (172, 191))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('malignant tumors', 'Disease', (242, 258))	('carcinogenesis', 'Disease', 'MESH:D063646', (208, 222))
797667	28424424	Associations with telomere length have been reported for cancers of the digestive system.	('Associations', 'Interaction', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('telomere length', 'Var', (18, 33))
797668	28424424	found that telomere length effected the risk of esophageal squamous cell carcinoma risk, telomere too short or too long to increase the risk of esophageal cancer.	('telomere', 'Var', (89, 97))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (48, 82))	('telomere', 'Var', (11, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('effected', 'Reg', (27, 35))	('telomere too short', 'Phenotype', 'HP:0031413', (89, 107))	('esophageal squamous cell carcinoma', 'Disease', (48, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('esophageal cancer', 'Disease', (144, 161))
797669	28424424	A genome-wide meta-analysis identified seven loci, including ACYP2 rs11125529, associated with mean leukocyte telomere length.	('ACYP2', 'Gene', '98', (61, 66))	('associated', 'Reg', (79, 89))	('mean leukocyte telomere length', 'MPA', (95, 125))	('rs11125529', 'Var', (67, 77))	('ACYP2', 'Gene', (61, 66))	('rs11125529', 'Mutation', 'rs11125529', (67, 77))
797671	28424424	So, we want to examined whether the ACYP2 gene polymorphism have impact on the risk of esophageal carcinoma in Chinese population.	('ACYP2', 'Gene', '98', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('esophageal carcinoma', 'Disease', (87, 107))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('ACYP2', 'Gene', (36, 41))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('polymorphism', 'Var', (47, 59))	('impact', 'Reg', (65, 71))
797674	28424424	The rs843740 and rs12615793 was cut off at 5% HWE p level.	('rs12615793', 'Mutation', 'rs12615793', (17, 27))	('rs843740', 'Mutation', 'rs843740', (4, 12))	('rs843740', 'Var', (4, 12))	('rs12615793', 'Var', (17, 27))
797675	28424424	Further genetic models analyses used logistic test, adjusted by age and gender, we found that rs11125529, rs11896604 and rs17045754 loci increased the esophageal carcinoma risk under the additive model (rs11125529: OR=1.34, 95%CI: 1.01-1.77, p=0.04; rs11896604: OR=1.34, 95%CI: 1.03-1.76, p=0.032; rs17045754: OR=1.36, 95%CI: 1.03-1.8, p=0.028) (Table 3).	('esophageal carcinoma', 'Disease', (151, 171))	('rs17045754', 'Mutation', 'rs17045754', (121, 131))	('rs11896604', 'Mutation', 'rs11896604', (250, 260))	('rs17045754', 'Var', (121, 131))	('rs11125529', 'Var', (94, 104))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (151, 171))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (151, 171))	('rs11896604', 'Var', (250, 260))	('rs11896604', 'Mutation', 'rs11896604', (106, 116))	('rs11125529', 'Mutation', 'rs11125529', (203, 213))	('rs11125529:', 'Var', (203, 214))	('increased', 'PosReg', (137, 146))	('rs11896604', 'Var', (106, 116))	('rs11125529', 'Mutation', 'rs11125529', (94, 104))	('rs17045754', 'Mutation', 'rs17045754', (298, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('rs17045754', 'Var', (298, 308))
797676	28424424	This block was comprised of seven closely linked SNPs: rs1682111, rs843752, rs10439478, rs843645, rs11125529, rs843711, rs11896604.	('rs10439478', 'Mutation', 'rs10439478', (76, 86))	('rs11125529', 'Mutation', 'rs11125529', (98, 108))	('rs11896604', 'Mutation', 'rs11896604', (120, 130))	('rs843645', 'Mutation', 'rs843645', (88, 96))	('rs843645', 'Var', (88, 96))	('rs1682111', 'Var', (55, 64))	('rs1682111', 'Mutation', 'rs1682111', (55, 64))	('rs10439478', 'Var', (76, 86))	('rs843711', 'Var', (110, 118))	('rs11896604', 'Var', (120, 130))	('rs11125529', 'Var', (98, 108))	('rs843711', 'Mutation', 'rs843711', (110, 118))	('rs843752', 'Mutation', 'rs843752', (66, 74))	('rs843752', 'Var', (66, 74))
797677	28424424	The haplotype analysis detected that haplotype "TTCTATG" increased the risk of esophageal carcinoma (OR=1.38, 95%CI: 1.04-1.82, p=0.025) (Table 4).	('haplotype', 'Var', (37, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('esophageal carcinoma', 'Disease', (79, 99))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (79, 99))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (79, 99))
797679	28424424	We found that rs11125529, rs11896604 and rs17045754 loci increased the esophageal carcinoma risk Chinese Han population.	('rs17045754', 'Mutation', 'rs17045754', (41, 51))	('rs17045754', 'Var', (41, 51))	('rs11125529', 'Var', (14, 24))	('rs11896604', 'Mutation', 'rs11896604', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('rs11896604', 'Var', (26, 36))	('rs11125529', 'Mutation', 'rs11125529', (14, 24))	('increased', 'PosReg', (57, 66))	('esophageal carcinoma', 'Disease', (71, 91))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (71, 91))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (71, 91))
797684	28424424	Therefore, the mutation of ACYP2 may be related to tumorigenesis.	('mutation', 'Var', (15, 23))	('ACYP2', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('related', 'Reg', (40, 47))	('tumor', 'Disease', (51, 56))	('ACYP2', 'Gene', '98', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
797688	28424424	In our research, we also found that rs11896604 and rs17045754 loci on ACYP2 gene increased the esophageal carcinoma risk.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (95, 115))	('ACYP2', 'Gene', (70, 75))	('rs17045754', 'Mutation', 'rs17045754', (51, 61))	('rs17045754', 'Var', (51, 61))	('rs11896604', 'Mutation', 'rs11896604', (36, 46))	('rs11896604', 'Var', (36, 46))	('ACYP2', 'Gene', '98', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('increased', 'PosReg', (81, 90))	('esophageal carcinoma', 'Disease', (95, 115))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (95, 115))
797690	28424424	by a large case-control study found 7 genes that affect telomere length (TERC, TERT, NAF1, OBFC1, ZNF208, RTEL1 and ACYP2), they determine the ACYP2 rs11125529 locus mutation shortened telomere length in European populations.	('RTEL1', 'Gene', '51750', (106, 111))	('ACYP2', 'Gene', (143, 148))	('rs11125529', 'Var', (149, 159))	('OBFC1', 'Gene', (91, 96))	('ACYP2', 'Gene', '98', (143, 148))	('ACYP2', 'Gene', (116, 121))	('rs11125529', 'Mutation', 'rs11125529', (149, 159))	('OBFC1', 'Gene', '79991', (91, 96))	('ACYP2', 'Gene', '98', (116, 121))	('telomere length', 'MPA', (185, 200))	('NAF1', 'Gene', '92345', (85, 89))	('RTEL1', 'Gene', (106, 111))	('ZNF208', 'Gene', (98, 104))	('NAF1', 'Gene', (85, 89))	('TERC', 'Gene', '7012', (73, 77))	('shortened', 'NegReg', (175, 184))	('TERT', 'Gene', (79, 83))	('ZNF208', 'Gene', '7757', (98, 104))	('TERT', 'Gene', '7015', (79, 83))	('TERC', 'Gene', (73, 77))	('shortened telomere length', 'Phenotype', 'HP:0031413', (175, 200))
797691	28424424	In our study, we found that ACYP2 rs11125529 increased the risk of esophageal cancer.	('increased', 'PosReg', (45, 54))	('rs11125529', 'Mutation', 'rs11125529', (34, 44))	('ACYP2', 'Gene', '98', (28, 33))	('esophageal cancer', 'Disease', (67, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rs11125529', 'Var', (34, 44))	('ACYP2', 'Gene', (28, 33))
797693	28424424	The rs11896604 and rs17045754 loci on the ACYP2 gene were found to be associated with ischemic stroke in a case-control study of 300 patients with ischemic stroke and 300 healthy individuals.	('ischemic stroke', 'Disease', 'MESH:D002544', (147, 162))	('rs11896604', 'Var', (4, 14))	('ACYP2', 'Gene', '98', (42, 47))	('patients', 'Species', '9606', (133, 141))	('stroke', 'Phenotype', 'HP:0001297', (95, 101))	('associated', 'Reg', (70, 80))	('rs11896604', 'Mutation', 'rs11896604', (4, 14))	('ischemic stroke', 'Disease', 'MESH:D002544', (86, 101))	('ischemic stroke', 'Disease', (147, 162))	('ischemic stroke', 'Phenotype', 'HP:0002140', (147, 162))	('stroke', 'Phenotype', 'HP:0001297', (156, 162))	('ischemic stroke', 'Phenotype', 'HP:0002140', (86, 101))	('rs17045754', 'Var', (19, 29))	('ischemic stroke', 'Disease', (86, 101))	('rs17045754', 'Mutation', 'rs17045754', (19, 29))	('ACYP2', 'Gene', (42, 47))
797694	28424424	In a study of ACYP2 and high-altitude pulmonary edema, two sites, rs11896604 and rs12615793, were found to reduce the risk of high-altitude pulmonary edema.	('rs12615793', 'Var', (81, 91))	('pulmonary edema', 'Disease', (140, 155))	('ACYP2', 'Gene', '98', (14, 19))	('pulmonary edema', 'Disease', (38, 53))	('pulmonary edema', 'Disease', 'MESH:D011654', (140, 155))	('pulmonary edema', 'Disease', 'MESH:D011654', (38, 53))	('rs12615793', 'Mutation', 'rs12615793', (81, 91))	('rs11896604', 'Mutation', 'rs11896604', (66, 76))	('pulmonary edema', 'Phenotype', 'HP:0100598', (140, 155))	('reduce', 'NegReg', (107, 113))	('pulmonary edema', 'Phenotype', 'HP:0100598', (38, 53))	('edema', 'Phenotype', 'HP:0000969', (150, 155))	('rs11896604', 'Var', (66, 76))	('ACYP2', 'Gene', (14, 19))	('edema', 'Phenotype', 'HP:0000969', (48, 53))
797696	28424424	So the association between ACYP2 gene polymorphisms and drinking and smoking status in esophageal carcinoma need to be evaluated in future studies.	('ACYP2', 'Gene', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('ACYP2', 'Gene', '98', (27, 32))	('polymorphisms', 'Var', (38, 51))	('esophageal carcinoma', 'Disease', (87, 107))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))
797706	28424424	Among the 14 SNPs were selected, rs11125529 was chosen from previously published polymorphisms associated with telomere length, others were randomly chosen from the published gene ACYP2 associated with telomere length, with minor allele frequencies >5% in the HapMap Chinese Han Beijing population.	('rs11125529', 'Mutation', 'rs11125529', (33, 43))	('rs11125529', 'Var', (33, 43))	('ACYP2', 'Gene', '98', (180, 185))	('ACYP2', 'Gene', (180, 185))
797707	28424424	Fourgenetic models (genotype, dominant, recessive, and additive model) were performed using PLINK software (https://www.cog-genomics.org/plink2), to characterize the potential association of each ACYP2 polymorphism with the risk of esophageal carcinoma.	('polymorphism', 'Var', (202, 214))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (232, 252))	('ACYP2', 'Gene', '98', (196, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (232, 252))	('association', 'Interaction', (176, 187))	('esophageal carcinoma', 'Disease', (232, 252))	('ACYP2', 'Gene', (196, 201))
797760	28292272	We used maximal diameter of residual tumor/tumor bed to describe the size of tumor, which was divided into three groups: <4.5 cm (n = 108, 56.3%), 4.5-8 cm (n = 64, 33.3%) and >8 cm (n = 20, 10.4%).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('4.5-8', 'Var', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (77, 82))
797818	22021678	Nitric oxide synthase-1 homozygous recombinant negative (NOS1-/-) mice demonstrate multiple congenital abnormalities associated with developmental deficiency of NOS1 neurons, including abnormalities in the cerebellum, adrenal medulla, and a pattern of esophageal dilation similar to pediatric pyloric stenosis.	('esophageal dilation', 'Disease', 'MESH:D002311', (252, 271))	('developmental deficiency of NOS1 neurons', 'Disease', (133, 173))	('pyloric stenosis', 'Phenotype', 'HP:0002021', (293, 309))	('congenital abnormalities', 'Disease', 'MESH:D000013', (92, 116))	('congenital abnormalities', 'Disease', (92, 116))	('mice', 'Species', '10090', (66, 70))	('developmental deficiency', 'Phenotype', 'HP:0001263', (133, 157))	('NOS1', 'Gene', '18125', (57, 61))	('multiple congenital abnormalities', 'Phenotype', 'HP:0002804', (83, 116))	('abnormalities in the cerebellum', 'Phenotype', 'HP:0001317', (185, 216))	('developmental deficiency of NOS1 neurons', 'Disease', 'MESH:D009410', (133, 173))	('esophageal dilation', 'Disease', (252, 271))	('NOS1', 'Gene', '18125', (161, 165))	('NOS1', 'Gene', (57, 61))	('NOS1', 'Gene', (161, 165))	('abnormalities', 'Var', (185, 198))
797824	22021678	We evaluated the effect of intraesophageal MnSOD-PL in ameliorating seizures in vagotomized NOS1-/- and C57BL/6NHsd wild-type (WT) mice.	('seizures', 'Disease', (68, 76))	('seizures', 'Phenotype', 'HP:0001250', (68, 76))	('NOS1', 'Gene', '18125', (92, 96))	('C57BL/6NHsd', 'Var', (104, 115))	('MnSOD', 'Gene', (43, 48))	('mice', 'Species', '10090', (131, 135))	('MnSOD', 'Gene', '20656', (43, 48))	('seizure', 'Phenotype', 'HP:0001250', (68, 75))	('NOS1', 'Gene', (92, 96))	('seizures', 'Disease', 'MESH:D012640', (68, 76))
797843	22021678	Eight days after TBI to 9.5 Gy, NOS1-/- and C57BL/6NHsd mice were sacrificed and intravenously perfused with 50 ml of PBS prior to necropsy.	('C57BL/6NHsd', 'Var', (44, 55))	('NOS1', 'Gene', '18125', (32, 36))	('mice', 'Species', '10090', (56, 60))	('NOS1', 'Gene', (32, 36))	('to 9', 'Species', '1214577', (21, 25))	('PBS', 'Chemical', 'MESH:D007854', (118, 121))
797854	22021678	NOS1-/-, NOS1+/-, and C57BL/6NHsd were irradiated to 9.5 Gy TBI (Figure 1).	('C57BL/6NHsd', 'Var', (22, 33))	('NOS1', 'Gene', (0, 4))	('to 9', 'Species', '1214577', (50, 54))	('NOS1', 'Gene', '18125', (9, 13))	('NOS1', 'Gene', (9, 13))	('NOS1', 'Gene', '18125', (0, 4))
797856	22021678	C57BL/6NHsd mice were radioresistant compared to NOS1-/- mice (p=0.0286).	('mice', 'Species', '10090', (57, 61))	('NOS1', 'Gene', (49, 53))	('radioresistant', 'CPA', (22, 36))	('C57BL/6NHsd', 'Var', (0, 11))	('mice', 'Species', '10090', (12, 16))	('NOS1', 'Gene', '18125', (49, 53))
797857	22021678	Thus, deletion of one NOS1 gene copy did not duplicate the radiosensitive phenotype of homozygous deletion NOS1-/- mice.	('NOS1', 'Gene', '18125', (107, 111))	('NOS1', 'Gene', (107, 111))	('deletion', 'Var', (98, 106))	('deletion', 'Var', (6, 14))	('NOS1', 'Gene', '18125', (22, 26))	('mice', 'Species', '10090', (115, 119))	('NOS1', 'Gene', (22, 26))
797868	22021678	No significant differences in the magnitude or pattern of increase in lipid peroxidation in response to irradiation were detected comparing C57BL/6NHsd to NOS1-/- neuronal cell cultures.	('NOS1', 'Gene', '18125', (155, 159))	('C57BL/6NHsd', 'Var', (140, 151))	('lipid', 'Chemical', 'MESH:D008055', (70, 75))	('NOS1', 'Gene', (155, 159))	('lipid peroxidation', 'MPA', (70, 88))
797873	22021678	Histopathological analysis was performed on the esophagus of unirradiated and 9.5 Gy TBI NOS1-/- and C57BL/6NHsd mice (n=3/group).	('NOS1', 'Gene', '18125', (89, 93))	('C57BL/6NHsd', 'Var', (101, 112))	('mice', 'Species', '10090', (113, 117))	('NOS1', 'Gene', (89, 93))
797879	22021678	C57BL/6NHsd and NOS1-/- mice were irradiated to 9.5 Gy TBI 30 days after right vagotomy to allow sufficient time for healing of surgical wounds (Figure 8 and Figure 9, respectively).	('mice', 'Species', '10090', (24, 28))	('C57BL/6NHsd', 'Var', (0, 11))	('NOS1', 'Gene', '18125', (16, 20))	('to 9', 'Species', '1214577', (45, 49))	('NOS1', 'Gene', (16, 20))
797889	22021678	Homozygous deletion recombinant negative NOS1-/- mice have been shown to be radiosensitive to TBI compared to control C57BL/6NHsd mice and die of grand mal seizures as opposed to listlessness and fatigue seen in the controls.	('mice', 'Species', '10090', (130, 134))	('NOS1', 'Gene', (41, 45))	('seizures', 'Phenotype', 'HP:0001250', (156, 164))	('fatigue', 'Phenotype', 'HP:0012378', (196, 203))	('grand mal seizures', 'Phenotype', 'HP:0002069', (146, 164))	('seizure', 'Phenotype', 'HP:0001250', (156, 163))	('mice', 'Species', '10090', (49, 53))	('seizures', 'Disease', (156, 164))	('TBI', 'MPA', (94, 97))	('seizures', 'Disease', 'MESH:D012640', (156, 164))	('fatigue', 'Disease', 'MESH:D005221', (196, 203))	('deletion', 'Var', (11, 19))	('NOS1', 'Gene', '18125', (41, 45))	('die of grand mal seizures', 'Phenotype', 'HP:0007334', (139, 164))	('fatigue', 'Disease', (196, 203))
797893	22021678	These data are similar to those with homozygous but not heterozygous deletion of p53, since only the former leads to an increased radiosensitivity.	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (120, 146))	('p53', 'Gene', '22060', (81, 84))	('p53', 'Gene', (81, 84))	('deletion', 'Var', (69, 77))	('increased', 'PosReg', (120, 129))	('radiosensitivity', 'CPA', (130, 146))
797899	22021678	In both NOS1-/- and C57BL/6NHsd neuronal cell cultures, increasing irradiation doses increased lipid peroxidation.	('lipid', 'Chemical', 'MESH:D008055', (95, 100))	('increased lipid peroxidation', 'Phenotype', 'HP:0025464', (85, 113))	('NOS1', 'Gene', '18125', (8, 12))	('increased lipid', 'Phenotype', 'HP:0003077', (85, 100))	('C57BL/6NHsd', 'Var', (20, 31))	('lipid peroxidation', 'MPA', (95, 113))	('NOS1', 'Gene', (8, 12))	('increased', 'PosReg', (85, 94))
797903	22021678	Thus, absence of the NOS1 gene product does not alter irradiation-induced peroxynitrate formation in whole-brain cultures, perhaps attributable to the low relative number of NOS1 neurons in the fetal brain and in brain-derived cell cultures.	('NOS1', 'Gene', (174, 178))	('NOS1', 'Gene', (21, 25))	('NOS1', 'Gene', '18125', (21, 25))	('peroxynitrate', 'Chemical', 'MESH:D030421', (74, 87))	('NOS1', 'Gene', '18125', (174, 178))	('absence', 'Var', (6, 13))
797905	22021678	Both NOS1-/- and C57BL/6NHsd mice were protected by intraesophageal administration of MnSOD-PL.	('C57BL/6NHsd', 'Var', (17, 28))	('MnSOD', 'Gene', '20656', (86, 91))	('NOS1', 'Gene', '18125', (5, 9))	('MnSOD', 'Gene', (86, 91))	('NOS1', 'Gene', (5, 9))	('mice', 'Species', '10090', (29, 33))
797920	22021678	C57BL/6NHsd mice might have a compensatory function of the left vagus nerve meditated through NOS1, a function absent in NOS1-/- mice.	('NOS1', 'Gene', '18125', (121, 125))	('NOS1', 'Gene', '18125', (94, 98))	('C57BL/6NHsd', 'Var', (0, 11))	('NOS1', 'Gene', (121, 125))	('NOS1', 'Gene', (94, 98))	('mice', 'Species', '10090', (129, 133))	('mice', 'Species', '10090', (12, 16))
797969	22726540	The presence of p53 tumor suppressor gene mutations is common molecular defects in human malignancies, including oral SCC.	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('p53', 'Gene', (16, 19))	('SCC', 'Gene', (118, 121))	('human', 'Species', '9606', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('p53', 'Gene', '7157', (16, 19))	('malignancies', 'Disease', (89, 101))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('SCC', 'Gene', '6317', (118, 121))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', (20, 25))
797970	22726540	p53 mutations may be related to prolonged exposure to immunosuppressive drugs (e.g.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('mutations', 'Var', (4, 13))	('related', 'Reg', (21, 28))
797972	22726540	However, overexpression of the mutated p53 protein, probably related to the inflammatory infiltrate, was detected in epithelium of oral lichen planus without dysplasia.	('overexpression', 'PosReg', (9, 23))	('oral lichen planus without dysplasia', 'Disease', (131, 167))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('protein', 'Protein', (43, 50))	('oral lichen planus without dysplasia', 'Disease', 'MESH:D017676', (131, 167))	('mutated', 'Var', (31, 38))
798224	31709184	According to the manufacturer's instructions, small interfering RNA (siRNA) against IBSP was transfected into IBSP-C2 cells with Lipofectamine 2000 Reagent (Invitrogen).	('IBSP', 'Gene', (110, 114))	('IBSP', 'Gene', '3381', (84, 88))	('IBSP', 'Gene', (84, 88))	('small interfering', 'Var', (46, 63))	('IBSP', 'Gene', '3381', (110, 114))
798247	31709184	The ratio of IBSP gene/GAPDH gene expression in Vec-30, IBSP-C1 and IBSP-C2 cells was 0.0098 +- 0.0053, 0.2617 +- 0.0766, and 0.2854 +- 0.1003, respectively (P < 0.05; Figure 3A).	('IBSP', 'Gene', '3381', (56, 60))	('0.2854 +- 0.1003', 'Var', (126, 142))	('IBSP', 'Gene', (56, 60))	('0.0098 +- 0.0053', 'Var', (86, 102))	('IBSP', 'Gene', (68, 72))	('IBSP', 'Gene', '3381', (68, 72))	('GAPDH', 'Gene', '2597', (23, 28))	('IBSP', 'Gene', '3381', (13, 17))	('IBSP', 'Gene', (13, 17))	('GAPDH', 'Gene', (23, 28))	('0.2617 +- 0.0766', 'Var', (104, 120))
798267	31709184	The abnormal expression of the IBSP gene is closely related to bone metastasis, increased malignant risk and the poor prognosis of breast cancer, prostate cancer and non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (170, 192))	('prostate cancer', 'Disease', 'MESH:D011471', (146, 161))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (166, 192))	('prostate cancer', 'Disease', (146, 161))	('malignant risk', 'CPA', (90, 104))	('related', 'Reg', (52, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('non-small cell lung cancer', 'Disease', (166, 192))	('IBSP', 'Gene', '3381', (31, 35))	('abnormal', 'Var', (4, 12))	('bone metastasis', 'CPA', (63, 78))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('breast cancer', 'Disease', (131, 144))	('expression', 'MPA', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (166, 192))	('IBSP', 'Gene', (31, 35))
798345	30258731	2C); the total of 28 patients who had CRP/albumin ratio >= 9.5 had worse OS compared to the other 35 patients who had CRP/albumin ratio <9.5 (12.0 months versus 25.3 months, P = 0.030, Fig.	('patients', 'Species', '9606', (101, 109))	('CRP', 'Gene', '1401', (38, 41))	('CRP', 'Gene', (118, 121))	('albumin', 'Gene', (122, 129))	('albumin', 'Gene', '213', (122, 129))	('albumin', 'Gene', '213', (42, 49))	('CRP', 'Gene', '1401', (118, 121))	('albumin', 'Gene', (42, 49))	('patients', 'Species', '9606', (21, 29))	('>= 9.5', 'Var', (56, 62))	('CRP', 'Gene', (38, 41))
798349	30258731	3C); the 28 patients who had CRP/albumin ratio >= 9.5 were found to have worse OS in comparison with the 35 patients who had CRP/albumin ratio <9.5 (9.0 months versus 15.9 months, P = 0.002, Fig.	('patients', 'Species', '9606', (12, 20))	('CRP', 'Gene', (125, 128))	('>= 9.5', 'Var', (47, 53))	('CRP', 'Gene', '1401', (125, 128))	('CRP', 'Gene', (29, 32))	('CRP', 'Gene', '1401', (29, 32))	('patients', 'Species', '9606', (108, 116))	('albumin', 'Gene', (33, 40))	('albumin', 'Gene', '213', (33, 40))	('albumin', 'Gene', (129, 136))	('albumin', 'Gene', '213', (129, 136))
798350	30258731	Patients with NLR >= 2.5 (P = 0.012, HR: 2.21, 95% CI [1.19-4.12]) and mGPS >= 1 (P < 0.001, HR: 3.13, 95% CI [1.66-5.88]) had worse OS than others with NLR <2.5 and mGPS of 0 in the multivariable analysis.	('mGPS >= 1', 'Var', (71, 80))	('NLR >= 2.5', 'Var', (14, 24))	('Patients', 'Species', '9606', (0, 8))
798357	30258731	It may cause genetic mutations and instability, suppress antitumor immunity, decrease DNA repair function, and promote the formation of microenvironments, contributing to tumor initiation.	('suppress', 'NegReg', (48, 56))	('instability', 'MPA', (35, 46))	('contributing', 'Reg', (155, 167))	('tumor initiation', 'Disease', (171, 187))	('decrease', 'NegReg', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cause', 'Reg', (7, 12))	('DNA repair', 'MPA', (86, 96))	('genetic mutations', 'Var', (13, 30))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('formation of microenvironments', 'MPA', (123, 153))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor initiation', 'Disease', 'MESH:D009369', (171, 187))	('tumor', 'Disease', (61, 66))	('promote', 'PosReg', (111, 118))
798387	29134539	After the normal DNA of the affected family members was analyzed for the presence of the 212 potential germline variants and subsequently the respective tumors, only one potential germline variant in MSX1 (chr4: 4861985 T > G, c.359T > G, p.V120G, NM_002448) showed loss of the wild type allele in the tumor DNAs of the affected family members.	('chr4: 4861985 T > G', 'Var', (206, 225))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('c.359T > G', 'Var', (227, 237))	('tumor', 'Disease', (302, 307))	('p.V120G', 'Var', (239, 246))	('p.V120G', 'Mutation', 'rs759548721', (239, 246))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('NM_002448', 'Var', (248, 257))	('MSX1', 'Gene', '4487', (200, 204))	('c.359T > G', 'Mutation', 'rs759548721', (227, 237))	('MSX1', 'Gene', (200, 204))	('4861985 T > G', 'Mutation', 'rs759548721', (212, 225))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
798389	29134539	This finding indicates that the germline defect in MSX1 may be associated with Barrett's esophagus and cancer in this particular family.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('MSX1', 'Gene', (51, 55))	('associated', 'Reg', (63, 73))	('MSX1', 'Gene', '4487', (51, 55))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (79, 98))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (79, 98))	("Barrett's esophagus", 'Disease', (79, 98))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('germline defect', 'Var', (32, 47))
798392	29134539	Other risk factors are high age, male gender, Caucasian ethnicity, and obesity.	('obesity', 'Disease', (71, 78))	('obesity', 'Disease', 'MESH:D009765', (71, 78))	('obesity', 'Phenotype', 'HP:0001513', (71, 78))	('Caucasian ethnicity', 'Var', (46, 65))
798395	29134539	biallelic inactivation of a tumor suppressor gene caused by one germline mutation inherited from one parent followed by a somatic second inactivating mutation in the wild type allele.	('biallelic inactivation', 'Var', (0, 22))	('caused by', 'Reg', (50, 59))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
798397	29134539	identified germline mutations in the genes MSR1, ASCC1, and CTHRC1 with the use of a linkage analysis on affected siblings diagnosed with BE or EAC.	('MSR1', 'Gene', '4481', (43, 47))	('BE', 'Phenotype', 'HP:0100580', (138, 140))	('ASCC1', 'Gene', '51008', (49, 54))	('ASCC1', 'Gene', (49, 54))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('CTHRC1', 'Gene', '115908', (60, 66))	('MSR1', 'Gene', (43, 47))	('germline mutations', 'Var', (11, 29))	('CTHRC1', 'Gene', (60, 66))
798398	29134539	Subsequently, we validated the potential germline variants identified in the proband in the normal and tumor DNA of the other affected family members on a Next-Generation sequencing platform.	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('variants', 'Var', (50, 58))
798409	29134539	Germline variants identified by exome sequencing were selected to cause amino-acid changes or splice-site alterations, in addition variants present in the dbSNP135 database or with a frequency of > 1% in ESP6500 and the 1000 Genomes databases were excluded.	('splice-site alterations', 'MPA', (94, 117))	('variants', 'Var', (131, 139))	('cause', 'Reg', (66, 71))	('variants', 'Var', (9, 17))	('amino-acid changes', 'MPA', (72, 90))	('dbSNP135', 'Chemical', '-', (155, 163))
798412	29134539	In addition, the respective tumors of the family members (II.1, II.2) were analyzed for somatic loss of the wild type allele or the presence of an inactivating somatic mutation in the wild type allele.	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('inactivating', 'Var', (147, 159))	('mutation', 'Var', (168, 176))	('loss', 'NegReg', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
798413	29134539	Only one potential germline variant, MSX1 (chr4: 4,861,985 T > G, c.359T > G, p.V120G, NM_002448), showed loss of the wild type allele in both the tumor DNA of family members II.1 and II.2.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('MSX1', 'Gene', '4487', (37, 41))	('p.V120G', 'Var', (78, 85))	('p.V120G', 'Mutation', 'rs759548721', (78, 85))	('c.359T > G', 'Mutation', 'rs759548721', (66, 76))	('c.359T > G', 'Var', (66, 76))	('985 T > G', 'Mutation', 'c.985T>G', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('loss', 'NegReg', (106, 110))	('MSX1', 'Gene', (37, 41))
798417	29134539	The germline variant in MSX1 changed codon 120 from Valine into Glycine.	('120 from Valine into Glycine', 'Mutation', 'rs759548721', (43, 71))	('MSX1', 'Gene', (24, 28))	('MSX1', 'Gene', '4487', (24, 28))	('changed', 'Reg', (29, 36))	('variant', 'Var', (13, 20))	('codon 120', 'MPA', (37, 46))
798419	29134539	This finding indicates that the germline defect in MSX1 may be associated with the high occurrence of BE and EAC in this Dutch family.	('EAC', 'Phenotype', 'HP:0011459', (109, 112))	('MSX1', 'Gene', (51, 55))	('associated', 'Reg', (63, 73))	('MSX1', 'Gene', '4487', (51, 55))	('EAC', 'Disease', (109, 112))	('BE', 'Phenotype', 'HP:0100580', (102, 104))	('germline defect', 'Var', (32, 47))
798425	29134539	(p.R158W, p.F151L, p.P153P), suggesting a prominent role of this germline defect in the development of BE and EAC in this particular family.	('p.F151L', 'Mutation', 'p.F151L', (10, 17))	('p.P153P', 'Mutation', 'rs756949296', (19, 26))	('p.R158W', 'Mutation', 'rs781507762', (1, 8))	('p.P153P', 'Var', (19, 26))	('p.R158W', 'Var', (1, 8))	('EAC', 'Phenotype', 'HP:0011459', (110, 113))	('p.F151L', 'Var', (10, 17))	('BE', 'Phenotype', 'HP:0100580', (103, 105))
798426	29134539	In addition, mutations in MSX1 have also been reported in families with dominantly inherited congenital absence of several permanent teeth, called oligodontia or hypodontia, with or without cleft lip and/or palate, no oligodontia or hypodontia was observed in the proband.	('MSX1', 'Gene', (26, 30))	('oligodontia', 'Phenotype', 'HP:0000677', (147, 158))	('hypodontia', 'Phenotype', 'HP:0000668', (162, 172))	('oligodontia or hypodontia', 'Disease', (218, 243))	('cleft lip and/or palate', 'Disease', (190, 213))	('MSX1', 'Gene', '4487', (26, 30))	('oligodontia or hypodontia', 'Disease', 'MESH:D000848', (147, 172))	('congenital absence', 'Disease', (93, 111))	('cleft lip', 'Phenotype', 'HP:0410030', (190, 199))	('oligodontia or hypodontia', 'Disease', (147, 172))	('reported', 'Reg', (46, 54))	('cleft lip and/or palate', 'Disease', 'MESH:D002971', (190, 213))	('mutations', 'Var', (13, 22))	('oligodontia', 'Phenotype', 'HP:0000677', (218, 229))	('hypodontia', 'Phenotype', 'HP:0000668', (233, 243))	('oligodontia or hypodontia', 'Disease', 'MESH:D000848', (218, 243))
798431	29134539	In addition, it was not possible to test the presence of the MSX1 variant in the father of proband (I.1), also diagnosed with EAC, since no tissues blocks were present.	('MSX1', 'Gene', (61, 65))	('MSX1', 'Gene', '4487', (61, 65))	('EAC', 'Phenotype', 'HP:0011459', (126, 129))	('EAC', 'Disease', (126, 129))	('variant', 'Var', (66, 73))
798532	26138994	Age-related changes can also give rise to abnormal function in lower esophageal sphincter (LES) pressure, decrease LES length, and impair esophageal motility.	('esophageal motility', 'Disease', 'MESH:D015154', (138, 157))	('esophageal sphincter', 'Disease', (69, 89))	('LES length', 'MPA', (115, 125))	('give rise', 'Reg', (29, 38))	('decrease', 'NegReg', (106, 114))	('esophageal sphincter', 'Disease', 'MESH:D009122', (69, 89))	('impair', 'NegReg', (131, 137))	('esophageal motility', 'Disease', (138, 157))	('changes', 'Var', (12, 19))
798537	26138994	High TG levels were also a risk factor associated with CL in this study.	('High TG levels', 'Phenotype', 'HP:0002155', (0, 14))	('TG levels', 'MPA', (5, 14))	('TG', 'Chemical', 'MESH:D014280', (5, 7))	('High', 'Var', (0, 4))
798568	26930409	ADSC porcine status was confirmed by FACS showing cell expression of CD 90+, CD 105+ and CD 45-, CD 31- (ABCell-bio Society, Paris, France).	('CD 31', 'Gene', (97, 102))	('CD 90', 'Gene', '7070', (69, 74))	('CD 105+', 'Var', (77, 84))	('CD 90', 'Gene', (69, 74))	('CD 31', 'Gene', '5175', (97, 102))	('CD 45', 'Gene', '5788', (89, 94))	('CD 45', 'Gene', (89, 94))
798694	25894882	Negative associations for caregiver burden were fatigue of the patient (OR 1.64, 95 % CI 1.18-2.28) and HADS D of the spousal caregiver (OR 1.48, 95 % CI 1.16-1.89).	('fatigue', 'Disease', 'MESH:D005221', (48, 55))	('fatigue', 'Disease', (48, 55))	('HADS', 'Var', (104, 108))	('fatigue', 'Phenotype', 'HP:0012378', (48, 55))	('Negative', 'NegReg', (0, 8))	('caregiver', 'MPA', (26, 35))	('patient', 'Species', '9606', (63, 70))
798820	23669876	Inhibition of the CK2-NCoR network significantly reduced in vivo PC-3 cell tumorigenicity, likely due to transcriptional derepression of IP-10.	('CK2', 'Gene', (18, 21))	('reduced', 'NegReg', (49, 56))	('CK2', 'Gene', '13000', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('derepression', 'PosReg', (121, 133))
798825	23669876	Thus, dysregulation of CK2 in tumor cells may influence apoptotic activity and enhance cell survival.	('influence', 'Reg', (46, 55))	('apoptotic activity', 'CPA', (56, 74))	('cell survival', 'CPA', (87, 100))	('CK2', 'Gene', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('dysregulation', 'Var', (6, 19))	('enhance', 'PosReg', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('CK2', 'Gene', '13000', (23, 26))	('tumor', 'Disease', (30, 35))
798828	23669876	In transgenic mice, CK2alpha overexpression cooperates with c-myc or p53 loss (or mutation) at the lpr locus to promote tumorigenesis.	('myc', 'Gene', (62, 65))	('loss', 'NegReg', (73, 77))	('lpr', 'Gene', (99, 102))	('p53', 'Gene', (69, 72))	('promote', 'PosReg', (112, 119))	('mutation', 'Var', (82, 90))	('myc', 'Gene', '4609', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CK2alpha', 'Gene', '1459', (20, 28))	('lpr', 'Gene', '14102', (99, 102))	('p53', 'Gene', '22060', (69, 72))	('CK2alpha', 'Gene', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('transgenic mice', 'Species', '10090', (3, 18))	('tumor', 'Disease', (120, 125))
798836	23669876	In accordance with these observations, targeting CK2alpha with antisense RNA or inhibitors induces tumor shrinkage in a human prostate cancer xenograft model, suggesting the importance of CK2 in prostate tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Disease', (99, 104))	('human', 'Species', '9606', (120, 125))	('CK2', 'Gene', '13000', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CK2', 'Gene', (49, 52))	('targeting', 'Var', (39, 48))	('prostate tumor', 'Disease', (195, 209))	('CK2alpha', 'Gene', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CK2', 'Gene', '13000', (188, 191))	('prostate tumor', 'Disease', 'MESH:D011471', (195, 209))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('tumor', 'Disease', (204, 209))	('prostate cancer', 'Disease', (126, 141))	('CK2', 'Gene', (188, 191))	('prostate tumor', 'Phenotype', 'HP:0100787', (195, 209))	('CK2alpha', 'Gene', '1459', (49, 57))
798846	23669876	Furthermore, aberrant expression of CK2 has been reported in prostate cancers.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('reported', 'Reg', (49, 57))	('CK2', 'Gene', (36, 39))	('aberrant expression', 'Var', (13, 32))	('prostate cancers', 'Phenotype', 'HP:0012125', (61, 77))	('prostate cancers', 'Disease', (61, 77))	('CK2', 'Gene', '13000', (36, 39))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))	('prostate cancers', 'Disease', 'MESH:D011471', (61, 77))
798850	23669876	Next, we examined the relative level of CK2-mediated NCoR phosphorylation among these cell lines with a phospho-specific NCoR antibody that specifically recognizes phosphorylated Ser-2436 of NCoR as described previously.	('CK2', 'Gene', '13000', (40, 43))	('Ser', 'Chemical', 'MESH:D012694', (179, 182))	('CK2', 'Gene', (40, 43))	('Ser-2436', 'Var', (179, 187))
798857	23669876	1C, immunohistochemical analyses demonstrate elevated levels of phosphor-NCoRS2436 in tumor regions compared with adjacent non-neoplastic prostate tissues, suggesting a possible role for the CK2-NCoR signaling cascade in prostate tumorigenesis.	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('prostate tumor', 'Disease', (221, 235))	('prostate tumor', 'Phenotype', 'HP:0100787', (221, 235))	('CK2', 'Gene', (191, 194))	('tumor', 'Disease', (86, 91))	('neoplastic prostate', 'Phenotype', 'HP:0100787', (127, 146))	('phosphor-NCoRS2436', 'Var', (64, 82))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('CK2', 'Gene', '13000', (191, 194))	('elevated', 'PosReg', (45, 53))	('levels', 'MPA', (54, 60))	('prostate tumor', 'Disease', 'MESH:D011471', (221, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
798864	23669876	To elucidate the relationship between CK2-NCoR signaling and prostate tumorigenesis, we first investigated whether the depletion of NCoR selectively represses IP-10 transcription in PC-3 cells.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('transcription', 'MPA', (165, 178))	('CK2', 'Gene', '13000', (38, 41))	('prostate tumor', 'Disease', (61, 75))	('prostate tumor', 'Phenotype', 'HP:0100787', (61, 75))	('represses', 'NegReg', (149, 158))	('NCoR', 'Gene', (132, 136))	('IP-10', 'Gene', (159, 164))	('depletion', 'Var', (119, 128))	('prostate tumor', 'Disease', 'MESH:D011471', (61, 75))	('CK2', 'Gene', (38, 41))
798865	23669876	2A, inhibition or depletion of CK2 derepressed the transcription of both E-cadherin and IP-10.	('E-cadherin', 'Gene', (73, 83))	('E-cadherin', 'Gene', '999', (73, 83))	('CK2', 'Gene', '13000', (31, 34))	('IP-10', 'Gene', (88, 93))	('inhibition', 'Var', (4, 14))	('transcription', 'MPA', (51, 64))	('depletion', 'Var', (18, 27))	('derepressed', 'NegReg', (35, 46))	('CK2', 'Gene', (31, 34))
798866	23669876	However, NCoR knockdown selectively derepressed IP-10, confirming that the CK2-NCoR network selectively represses IP-10 transcription in PC-3 cells.	('transcription', 'MPA', (120, 133))	('derepressed', 'NegReg', (36, 47))	('CK2', 'Gene', (75, 78))	('represses', 'NegReg', (104, 113))	('IP-10', 'Gene', (114, 119))	('CK2', 'Gene', '13000', (75, 78))	('knockdown', 'Var', (14, 23))
798873	23669876	Since the repressive function of the NCoR corepressor complex depends on HDAC3, we next assessed the effect of knocking down HDAC3 on the invasive growth of PC-3 cells.	('knocking down', 'Var', (111, 124))	('HDAC3', 'Gene', '8841', (125, 130))	('HDAC3', 'Gene', '8841', (73, 78))	('HDAC3', 'Gene', (125, 130))	('HDAC3', 'Gene', (73, 78))	('repressive function', 'MPA', (10, 29))
798887	23669876	4B, a xenograft assay using subcutaneous injection of PC-3 cells into nude mice demonstrated that TBB treatment or stable knockdown of NCoR significantly reduced tumor volume and size compared with control (Fig.	('TBB', 'Chemical', 'MESH:C405354', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('knockdown', 'Var', (122, 131))	('NCoR', 'Gene', (135, 139))	('reduced', 'NegReg', (154, 161))	('nude mice', 'Species', '10090', (70, 79))
798888	23669876	We next examined whether the inhibition of tumorigenecity is attributed to derepression of IP-10 and blocking the CK2-NCoR network.	('IP-10', 'Protein', (91, 96))	('CK2', 'Gene', (114, 117))	('CK2', 'Gene', '13000', (114, 117))	('derepression', 'Var', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('blocking', 'NegReg', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
798898	23669876	As expected, the survival rate of high-Gleason score (>=8) patients was significantly lower than that of low-Gleason score (<=7) patients according to Kaplan-Meier survival curve analyses (Fig.	('high-Gleason score', 'Var', (34, 52))	('patients', 'Species', '9606', (129, 137))	('survival rate', 'CPA', (17, 30))	('lower', 'NegReg', (86, 91))	('patients', 'Species', '9606', (59, 67))
798900	23669876	After stratification of the patients by Gleason score (<=7 and >=8), the survival curves of patient with low Gleason score (<=7) were significantly different among NCoR phosphorylation status, but not in high Gleason score (>=8) group (Supplementary Figure 4).	('low', 'NegReg', (105, 108))	('NCoR', 'Gene', (164, 168))	('patient', 'Species', '9606', (92, 99))	('different', 'Reg', (148, 157))	('patient', 'Species', '9606', (28, 35))	('patients', 'Species', '9606', (28, 36))	('phosphorylation status', 'Var', (169, 191))
798901	23669876	In the Cox proportional hazard model after adjustments for age and Gleason score (continuous variable), the risk of death was significantly increased in patients with high NCoR phosphorylation (hazard ratio, 6.35; p=0.03) compared with patients with low NCoR phosphorylation.	('phosphorylation', 'Var', (177, 192))	('death', 'Disease', 'MESH:D003643', (116, 121))	('death', 'Disease', (116, 121))	('patients', 'Species', '9606', (153, 161))	('high', 'Var', (167, 171))	('patients', 'Species', '9606', (236, 244))	('NCoR', 'Protein', (172, 176))	('increased', 'PosReg', (140, 149))
798909	23669876	CK2 is known to participate in diverse cell signaling and aberrant expression of CK2 is believed to cause tumor development.	('CK2', 'Gene', '13000', (0, 3))	('CK2', 'Gene', (81, 84))	('aberrant expression', 'Var', (58, 77))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cause', 'Reg', (100, 105))	('CK2', 'Gene', '13000', (81, 84))	('CK2', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
798921	23669876	In addition, inhibition of CK2 using TBB induced derepression of IP-10 and suppressed the invasive growth of PC-3 cells.	('CK2', 'Gene', '13000', (27, 30))	('suppressed', 'NegReg', (75, 85))	('derepression', 'MPA', (49, 61))	('IP-10', 'Protein', (65, 70))	('invasive growth of PC-3 cells', 'CPA', (90, 119))	('inhibition', 'Var', (13, 23))	('CK2', 'Gene', (27, 30))	('TBB', 'Gene', (37, 40))	('TBB', 'Chemical', 'MESH:C405354', (37, 40))
798931	23669876	Tumor xenograft assays in mice confirmed that inhibition of the CK2-NCoR signaling network suppresses the in vivo tumorigenecity of PC-3 cells with derepression of IP-10 expression observed.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('inhibition', 'Var', (46, 56))	('suppresses', 'NegReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('CK2', 'Gene', (64, 67))	('CK2', 'Gene', '13000', (64, 67))	('mice', 'Species', '10090', (26, 30))
799034	32732072	The three main subtypes are caused by pathogenic variants in the KRT5 or KRT14 genes, which encode keratins 5 and 14, respectively, and account for 60%-70% of the cases of EBS.	('KRT5', 'Gene', '3852', (65, 69))	('caused by pathogenic', 'Reg', (28, 48))	('variants', 'Var', (49, 57))	('KRT14', 'Gene', '3861', (73, 78))	('KRT14', 'Gene', (73, 78))	('KRT5', 'Gene', (65, 69))	('EBS', 'Disease', (172, 175))
799043	32732072	Pathogenic variants in the PLECgene, which encodes the plectin protein, can result in different subtypes with different inheritance patterns, which together account for up to 8% of cases of EBS.	('account for', 'Reg', (157, 168))	('variants', 'Var', (11, 19))	('Pathogenic', 'Reg', (0, 10))	('plectin', 'Gene', (55, 62))	('EBS', 'Disease', (190, 193))	('PLEC', 'Gene', '5339', (27, 31))	('plectin', 'Gene', '5339', (55, 62))	('PLEC', 'Gene', (27, 31))	('result in', 'Reg', (76, 85))
799047	32732072	In contrast, the subtype with autosomal dominant inheritance, formerly known as Ogna EBS, which is now just intermediate EBS, is characterized by a mild clinical picture, which includes mild skin fragility and the absence of involvement of other organs.	('skin fragility', 'Phenotype', 'HP:0001030', (191, 205))	('mild skin fragility', 'Disease', (186, 205))	('Ogna EBS', 'Chemical', '-', (80, 88))	('autosomal dominant inheritance', 'Var', (30, 60))
799048	32732072	In 2016, two independent studies almost simultaneously identified pathogenic variants in the KLHL24gene, encoding the Kelch-like protein 24, in a total of 15 patients with the EB-compatible phenotype who were not related to each other.	('KLHL24', 'Gene', (93, 99))	('variants', 'Var', (77, 85))	('Kelch-like protein 24', 'Gene', '54800', (118, 139))	('KLHL24', 'Gene', '54800', (93, 99))	('Kelch-like protein 24', 'Gene', (118, 139))	('pathogenic', 'Reg', (66, 76))
799050	32732072	Studies have demonstrated that 85% of patients with pathogenic variants in KLHL24have some cardiac involvement, evidenced by a high level of biomarkers or dilated cardiomyopathy (40%).	('cardiomyopathy', 'Phenotype', 'HP:0001638', (163, 177))	('variants', 'Var', (63, 71))	('cardiac involvement', 'Disease', 'MESH:D006331', (91, 110))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (155, 177))	('dilated cardiomyopathy', 'Disease', (155, 177))	('KLHL24have', 'Gene', (75, 85))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (155, 177))	('myopathy', 'Phenotype', 'HP:0003198', (169, 177))	('cardiac involvement', 'Disease', (91, 110))
799053	32732072	To date, the only dominant pathogenic variant known to be associated with intermediate EBS (formerly Ogna EBS) is c.5998C > T (p. Arg.2000Trp), which leads to the disturbance of plectin by a negative dominant effect.	('disturbance', 'MPA', (163, 174))	('intermediate EBS', 'Disease', (74, 90))	('p. Arg.2000Trp', 'Mutation', 'rs80338756', (127, 141))	('plectin', 'MPA', (178, 185))	('c.5998C > T', 'Var', (114, 125))	('c.5998C > T', 'Mutation', 'rs80338756', (114, 125))
799064	32732072	The phenotypes resulting from pathogenic variants in the ITGA6and ITGB4genes, which encode the alpha6beta4 integrin, are also quite heterogeneous.	('variants', 'Var', (41, 49))	('ITGB4', 'Gene', (66, 71))	('ITGA6', 'Gene', '3655', (57, 62))	('ITGB4', 'Gene', '3691', (66, 71))	('ITGA6', 'Gene', (57, 62))	('pathogenic', 'Reg', (30, 40))
799073	32732072	The dominant form of DEB usually involves substitutions of glycine in the collagenous triple helix domain, although other substitutions, insertions, deletions, and splice site variants have also been described.	('glycine', 'Chemical', 'MESH:D005998', (59, 66))	('glycine', 'Protein', (59, 66))	('involves', 'Reg', (33, 41))	('DEB', 'Disease', (21, 24))	('substitutions', 'Var', (42, 55))
799076	32732072	KEB has autosomal recessive inheritance and is caused by changes in the FERMT1gene, which encodes kindlin-1, a protein associated with integrins and focal adhesions.	('KEB', 'Disease', (0, 3))	('changes', 'Var', (57, 64))	('caused by', 'Reg', (47, 56))	('kindlin-1', 'Gene', '55612', (98, 107))	('FERMT1', 'Gene', (72, 78))	('kindlin-1', 'Gene', (98, 107))	('autosomal recessive inheritance', 'Disease', (8, 39))	('FERMT1', 'Gene', '55612', (72, 78))
799093	32702926	Previous studies have shown that high NLR level before surgery may predict poor prognosis in oral squamous-cell carcinoma, colorectal cancer, and esophageal squamous cell carcinoma (ESCC).	('high', 'Var', (33, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (146, 180))	('NLR level', 'MPA', (38, 47))	('oral squamous-cell carcinoma', 'Disease', (93, 121))	('colorectal cancer', 'Disease', (123, 140))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('esophageal squamous cell carcinoma', 'Disease', (146, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('oral squamous-cell carcinoma', 'Disease', 'MESH:D002294', (93, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))
799122	32702926	Subgroup analysis of stage II disease further implied patients low iNLR had longer survival time compared with their high iNLR counterparts (37 months vs 28 months, chi2 = 16.150, P = .000).	('low iNLR', 'Var', (63, 71))	('stage II disease', 'Disease', 'MESH:D058625', (21, 37))	('patients', 'Species', '9606', (54, 62))	('survival', 'CPA', (83, 91))	('stage II disease', 'Disease', (21, 37))	('longer', 'PosReg', (76, 82))
799140	32702926	The results showed an elevated iNLR was strongly associated with high cumulative incidence of relapse, in other words, patients with high iNLR relapsed earlier than those with low iNLR (P < .0001).	('iNLR', 'MPA', (31, 35))	('patients', 'Species', '9606', (119, 127))	('high iNLR', 'Var', (133, 142))
799145	32702926	It was confirmed that patients with high iNLR had worse prognosis and the OS rate was lower than that of low iNLR group.	('high iNLR', 'Var', (36, 45))	('patients', 'Species', '9606', (22, 30))	('lower', 'NegReg', (86, 91))
799384	31794158	Univariate analysis indicated that patients with depth of primary lesion (T3-4) and high WBC counts (>8000/mm3) tended to have poor PFS (Table 2), whereas SCLN metastases (M1) was associated with poor OS (Table 3).	('metastases', 'Disease', (160, 170))	('high WBC counts', 'Phenotype', 'HP:0020059', (84, 99))	('poor', 'NegReg', (127, 131))	('patients', 'Species', '9606', (35, 43))	('PFS', 'MPA', (132, 135))	('metastases', 'Disease', 'MESH:D009362', (160, 170))	('>8000/mm3', 'Var', (101, 110))
799410	31794158	However, it is well-known that etoposide containing regimens are often associated with severe myelosuppression which was also observed in our study.	('myelosuppression', 'Disease', (94, 110))	('etoposide', 'Chemical', 'MESH:D005047', (31, 40))	('etoposide', 'Var', (31, 40))	('myelosuppression', 'Disease', 'MESH:D001855', (94, 110))	('associated', 'Reg', (71, 81))
799415	31794158	From the results of prognostic analyses, patients with T3-4 stage primary tumors and high WBC counts tended to have worse tumor control, while patients with SCLN metastases showed poor survival.	('metastases', 'Disease', (162, 172))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('high', 'Var', (85, 89))	('patients', 'Species', '9606', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('high WBC counts', 'Phenotype', 'HP:0020059', (85, 100))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('T3-4 stage', 'Var', (55, 65))	('WBC', 'Gene', (90, 93))	('tumor', 'Disease', (122, 127))	('tumors', 'Disease', (74, 80))
799427	31772141	Inhibition of miR-10b-3p weakened the effects of hypoxia on ESCC cell proliferation, migration and invasion, while miR-10b-3p overexpression had the opposite effects.	('ESCC', 'Disease', (60, 64))	('weakened', 'NegReg', (25, 33))	('hypoxia', 'Disease', 'MESH:D000860', (49, 56))	('invasion', 'CPA', (99, 107))	('miR-10b-3p', 'Gene', (14, 24))	('Inhibition', 'Var', (0, 10))	('migration', 'CPA', (85, 94))	('miR-10b-3p', 'Chemical', '-', (14, 24))	('hypoxia', 'Disease', (49, 56))	('miR-10b-3p', 'Chemical', '-', (115, 125))
799428	31772141	Mechanistically, miR-10b-3p acted as cancer-promoting gene by targeting testis specific 10.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('testis specific 10', 'Gene', '80705', (72, 90))	('cancer', 'Disease', (37, 43))	('miR-10b-3p', 'Chemical', '-', (17, 27))	('miR-10b-3p', 'Var', (17, 27))	('testis specific 10', 'Gene', (72, 90))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
799429	31772141	Using a xenograft model, we observed that administration of miR-10b-3p agomir to tumors enhanced their growth and metastasis in vivo.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('miR-10b-3p', 'Chemical', '-', (60, 70))	('miR-10b-3p', 'Var', (60, 70))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('enhanced', 'PosReg', (88, 96))
799431	31772141	These results suggest that miR-10b-3p may be a useful therapeutic target for treating ESCC.	('miR-10b-3p', 'Var', (27, 37))	('miR-10b-3p', 'Chemical', '-', (27, 37))	('ESCC', 'Disease', (86, 90))
799436	31772141	By suppressing the expression of their target genes, miRNAs can promote or inhibit both carcinogenesis and cancer progression.	('expression', 'MPA', (19, 29))	('carcinogenesis', 'Disease', (88, 102))	('promote', 'PosReg', (64, 71))	('miRNAs', 'Var', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('suppressing', 'NegReg', (3, 14))	('inhibit', 'NegReg', (75, 82))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))
799437	31772141	In the present study, we focused on the effects of miR-10b-3p, which was previously shown to correlate with metastasis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('miR-10b-3p', 'Chemical', '-', (51, 61))	('miR-10b-3p', 'Var', (51, 61))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
799438	31772141	In addition, microRNA-10b-3p affects prognosis and the response to neo-adjuvant therapy in pancreatic ductal adenocarcinoma and is predictive of survival in hepatocellular carcinoma patients treated with sorafenib.	('affects', 'Reg', (29, 36))	('pancreatic ductal adenocarcinoma', 'Disease', (91, 123))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (91, 123))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (91, 123))	('sorafenib', 'Chemical', 'MESH:D000077157', (204, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('patients', 'Species', '9606', (182, 190))	('microRNA-10b-3p', 'Var', (13, 28))	('prognosis', 'MPA', (37, 46))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (157, 181))	('3p', 'Chemical', '-', (26, 28))	('-10b', 'Chemical', '-', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('hepatocellular carcinoma', 'Disease', (157, 181))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (157, 181))
799443	31772141	On the other hand, pcDNA-HIF-1alpha transfection induced HIF-1alpha expression, even under normoxic conditions, which in turn led to increased miR-10b-3p expression (Figure 1B).	('HIF-1alpha', 'Gene', '3091', (57, 67))	('expression', 'MPA', (68, 78))	('miR-10b-3p', 'Protein', (143, 153))	('HIF-1alpha', 'Gene', (25, 35))	('miR-10b-3p', 'Chemical', '-', (143, 153))	('HIF-1alpha', 'Gene', '3091', (25, 35))	('HIF-1alpha', 'Gene', (57, 67))	('increased', 'PosReg', (133, 142))	('transfection', 'Var', (36, 48))	('expression', 'MPA', (154, 164))
799448	31772141	We initially showed that increasing miR-10b-3p suppressed TSGA10 expression in both ECA109 and KYSE410 (another ESCC line) cells, which suggests that TSGA10 may be a direct target of miR-10b-3p (Figure 1C).	('TSGA10', 'Gene', '80705', (150, 156))	('miR-10b-3p', 'Chemical', '-', (36, 46))	('suppressed', 'NegReg', (47, 57))	('TSGA10', 'Gene', '80705', (58, 64))	('miR-10b-3p', 'Var', (36, 46))	('TSGA10', 'Gene', (150, 156))	('TSGA10', 'Gene', (58, 64))	('expression', 'MPA', (65, 75))	('miR-10b-3p', 'Chemical', '-', (183, 193))	('KYSE410', 'CellLine', 'CVCL:1352', (95, 102))
799452	31772141	As shown in Figure 1E, miR-10b-3p overexpression decreased the luciferase activity, while mimics-NC had no significant effect on luciferase intensity.	('miR-10b-3p', 'Chemical', '-', (23, 33))	('miR-10b-3p', 'Var', (23, 33))	('overexpression', 'PosReg', (34, 48))	('decreased', 'NegReg', (49, 58))	('activity', 'MPA', (74, 82))	('luciferase', 'Enzyme', (63, 73))
799453	31772141	These results further confirm that TSGA10 is a direct target of miR-10b-3p in ESCC cells.	('ESCC', 'Disease', (78, 82))	('miR-10b-3p', 'Chemical', '-', (64, 74))	('miR-10b-3p', 'Var', (64, 74))	('TSGA10', 'Gene', '80705', (35, 41))	('TSGA10', 'Gene', (35, 41))
799454	31772141	CCK8 assays revealed that under normoxic conditions, miR-10b-3p overexpression promotes ESCC cell viability (Figure 2A).	('overexpression promotes', 'PosReg', (64, 87))	('miR-10b-3p', 'Var', (53, 63))	('ESCC', 'Disease', (88, 92))	('miR-10b-3p', 'Chemical', '-', (53, 63))
799455	31772141	Similarly, miR-10b-3p overexpression also promoted colony formation by the cells (Figure 2C).	('promoted', 'PosReg', (42, 50))	('colony formation by the', 'CPA', (51, 74))	('miR-10b-3p', 'Var', (11, 21))	('miR-10b-3p', 'Chemical', '-', (11, 21))
799456	31772141	A subsequent rescue experiment confirmed that TSGA10 is the functional target of miR-10b-3p in ESCC cells.	('miR-10b-3p', 'Var', (81, 91))	('miR-10b-3p', 'Chemical', '-', (81, 91))	('TSGA10', 'Gene', '80705', (46, 52))	('TSGA10', 'Gene', (46, 52))
799457	31772141	As shown in Figure 2A and 2C, the enhanced ESCC cell proliferation stimulated by miR-10b-3p was reversed by up-regulation of TSGA10.	('ESCC cell proliferation', 'CPA', (43, 66))	('miR-10b-3p', 'Chemical', '-', (81, 91))	('enhanced', 'PosReg', (34, 42))	('up-regulation', 'PosReg', (108, 121))	('miR-10b-3p', 'Var', (81, 91))	('TSGA10', 'Gene', '80705', (125, 131))	('TSGA10', 'Gene', (125, 131))
799461	31772141	Moreover, rescue experiments showed that under hypoxia TSGA10 knockdown restored the cell viability and proliferation that were suppressed by miR-10b-3p inhibition.	('miR-10b-3p', 'Chemical', '-', (142, 152))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('proliferation', 'CPA', (104, 117))	('hypoxia', 'Disease', (47, 54))	('TSGA10', 'Gene', '80705', (55, 61))	('TSGA10', 'Gene', (55, 61))	('restored', 'PosReg', (72, 80))	('cell viability', 'CPA', (85, 99))	('knockdown', 'Var', (62, 71))
799462	31772141	(Figure 2D) We next evaluated the influence of miR-10b-3p on ESCC cell migration and invasion.	('miR-10b-3p', 'Chemical', '-', (47, 57))	('ESCC', 'Disease', (61, 65))	('miR-10b-3p', 'Var', (47, 57))
799463	31772141	Using transwell assays, we observed that ectopic miR-10b-3p significantly enhanced the invasiveness of ESCC cells under normoxic conditions.	('miR-10b-3p', 'Var', (49, 59))	('miR-10b-3p', 'Chemical', '-', (49, 59))	('enhanced', 'PosReg', (74, 82))	('invasiveness of ESCC cells', 'CPA', (87, 113))
799464	31772141	However, up-regulation of TSGA10 diminished the effect of miR-10b-3p on ESCC cells (Figure 3A-3B).	('diminished', 'NegReg', (33, 43))	('TSGA10', 'Gene', (26, 32))	('up-regulation', 'PosReg', (9, 22))	('miR-10b-3p', 'Var', (58, 68))	('miR-10b-3p', 'Chemical', '-', (58, 68))	('TSGA10', 'Gene', '80705', (26, 32))	('ESCC', 'Disease', (72, 76))
799466	31772141	Rescue experiments showed that under hypoxic conditions TSGA10 knockdown restored the migration and invasion of ESCC cells that were inhibited by miR-10b-3p inhibition (Figure 3C-3D).	('migration', 'CPA', (86, 95))	('TSGA10', 'Gene', '80705', (56, 62))	('restored', 'PosReg', (73, 81))	('knockdown', 'Var', (63, 72))	('TSGA10', 'Gene', (56, 62))	('miR-10b-3p', 'Chemical', '-', (146, 156))	('invasion of ESCC cells', 'CPA', (100, 122))
799468	31772141	Subsequent administration of miR-10b-3p agomir to the tumor significantly enhanced tumor growth as compared to that in the negative control group (agomir NC) (Figure 4A and 4B).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-10b-3p agomir', 'Var', (29, 46))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('miR-10b-3p', 'Chemical', '-', (29, 39))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('enhanced', 'PosReg', (74, 82))
799469	31772141	Further analysis showed that the tumor volumes in the miR-10b-3p agomir group were significantly larger than those in the agomir NC group.	('miR-10b-3p', 'Var', (54, 64))	('miR-10b-3p', 'Chemical', '-', (54, 64))	('larger', 'PosReg', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
799471	31772141	The intensity of Ki-67 staining was significantly greater in tumors from the miR-10b-3p agomir group than the agomir NC group (Figure 4C and 4D).	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('miR-10b-3p', 'Var', (77, 87))	('Ki-67', 'Gene', (17, 22))	('intensity', 'MPA', (4, 13))	('greater', 'PosReg', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Ki-67', 'Gene', '17345', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('miR-10b-3p', 'Chemical', '-', (77, 87))
799472	31772141	In addition, staining with hematoxylin and eosin revealed that there were more metastatic nodules present in the lungs of mice treated with miR-10b-3p agomir than agomir NC (Figure 4E and 4F).	('more', 'PosReg', (74, 78))	('miR-10b-3p', 'Chemical', '-', (140, 150))	('mice', 'Species', '10090', (122, 126))	('metastatic nodules', 'CPA', (79, 97))	('miR-10b-3p', 'Var', (140, 150))	('hematoxylin', 'Chemical', 'MESH:D006416', (27, 38))	('eosin', 'Chemical', 'MESH:D004801', (43, 48))
799482	31772141	We also explored the modulatory role of miR-10b-3p in ESCC cells under hypoxia.	('miR-10b-3p', 'Chemical', '-', (40, 50))	('miR-10b-3p', 'Var', (40, 50))	('hypoxia', 'Disease', (71, 78))	('hypoxia', 'Disease', 'MESH:D000860', (71, 78))
799484	31772141	Moreover, we demonstrate that TSGA10 gene is a direct target of miR-10b-3p.	('TSGA10', 'Gene', (30, 36))	('miR-10b-3p', 'Chemical', '-', (64, 74))	('TSGA10', 'Gene', '80705', (30, 36))	('miR-10b-3p', 'Var', (64, 74))
799487	31772141	In ESCC, TSGA10 down-regulation is shown to be associated with a progressive clinical stage, and in vivo assays suggest TSGA10 knockdown significantly accelerates tumor growth and leads to larger tumor volumes.	('larger', 'PosReg', (189, 195))	('TSGA10', 'Gene', '80705', (120, 126))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('TSGA10', 'Gene', (120, 126))	('down-regulation', 'NegReg', (16, 31))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('accelerates', 'PosReg', (151, 162))	('ESCC', 'Disease', (3, 7))	('tumor', 'Disease', (163, 168))	('TSGA10', 'Gene', '80705', (9, 15))	('TSGA10', 'Gene', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('knockdown', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
799508	31772141	The 3'-UTR sequence (wild type (WT) or mutant (MUT)) of TSGA10 mRNA was amplified and cloned into the luciferase reporter vector.	('TSGA10', 'Gene', '80705', (56, 62))	('mutant', 'Var', (39, 45))	('TSGA10', 'Gene', (56, 62))
799511	31772141	MiR-10b-3p agomir (10 nmol) or agomir NC (10 nmol) (Ribobio, China) were injected into the tumor mass every 5 days.	('MiR-10b-3p', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('MiR-10b-3p', 'Chemical', '-', (0, 10))
799586	28969036	In contrast, for tumors growing in the recurrent tumor models, the growth rate was remarkably reduced under CMNa + radiation as comparison with the radiation alone (P=0.032).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('growth', 'MPA', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('reduced', 'NegReg', (94, 101))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', (49, 54))	('CMNa', 'Chemical', 'MESH:C000603632', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('CMNa + radiation', 'Var', (108, 124))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
799604	28969036	In Rezaeian's study, the hypoxia-responsive TRAF6 overexpression promotes breast cancer progression and metastasis to lung and spinal bone, and targeting of TRAF6 reduces breast cancer metastasis, opening up opportunities for therapeutic intervention.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('hypoxia', 'Disease', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TRAF6', 'Gene', '22034', (157, 162))	('metastasis to lung', 'Disease', 'MESH:D009362', (104, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('targeting', 'Var', (144, 153))	('hypoxia', 'Disease', 'MESH:D000860', (25, 32))	('TRAF6', 'Gene', (44, 49))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (171, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('metastasis to lung', 'Disease', (104, 122))	('promotes', 'PosReg', (65, 73))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('opening', 'Disease', 'MESH:D005597', (197, 204))	('TRAF6', 'Gene', '22034', (44, 49))	('breast cancer', 'Disease', (74, 87))	('breast cancer metastasis', 'Disease', (171, 195))	('reduces', 'NegReg', (163, 170))	('TRAF6', 'Gene', (157, 162))	('opening', 'Disease', (197, 204))
799722	28109913	Molecular abnormalities such as chromosomal aneuploidy or tetraploidy, hypermethylation of p16, loss of heterozygosity of p53, and microRNA expression, among others, have been associated with progression to HGD or EAC.	('p16', 'Gene', (91, 94))	('chromosomal aneuploidy', 'Disease', 'MESH:D000782', (32, 54))	('chromosomal aneuploidy', 'Disease', (32, 54))	('EAC', 'Phenotype', 'HP:0011459', (214, 217))	('microRNA expression', 'Var', (131, 150))	('HGD', 'Gene', '3081', (207, 210))	('p53', 'Gene', '7157', (122, 125))	('HGD', 'Gene', (207, 210))	('EAC', 'Disease', (214, 217))	('associated', 'Reg', (176, 186))	('loss of heterozygosity', 'Var', (96, 118))	('p16', 'Gene', '1029', (91, 94))	('p53', 'Gene', (122, 125))	('hypermethylation', 'Var', (71, 87))	('Molecular abnormalities', 'Disease', 'MESH:C567116', (0, 23))	('Molecular abnormalities', 'Disease', (0, 23))	('tetraploidy', 'Var', (58, 69))
799745	28109913	Cryoablation can achieve complete eradication of HGD in a high proportion of patients with BE in retrospective studies, with good durability during a 24-month follow-up period.	('HGD', 'Gene', (49, 52))	('BE', 'Phenotype', 'HP:0100580', (91, 93))	('eradication', 'MPA', (34, 45))	('patients', 'Species', '9606', (77, 85))	('Cryoablation', 'Var', (0, 12))	('HGD', 'Gene', '3081', (49, 52))
799749	28109913	In a multicenter study, PDT resulted in eradication of HGD in 77% of the cases with maintenance of remission in 85% during a 5-year follow-up period.	('HGD', 'Gene', (55, 58))	('PDT', 'Var', (24, 27))	('eradication', 'NegReg', (40, 51))	('HGD', 'Gene', '3081', (55, 58))
799766	28109913	In patients with T1a esophageal adenocarcinoma, esophagectomy may be indicated in cases with poorly differentiated tumors, lymphovascular invasion, or cases in which ablation is technically difficult or failed.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('tumors', 'Disease', (115, 121))	('esophageal adenocarcinoma', 'Disease', (21, 46))	('patients', 'Species', '9606', (3, 11))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (21, 46))	('lymphovascular', 'Disease', (123, 137))	('T1a', 'Var', (17, 20))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (21, 46))
799767	28109913	Traditionally, esophagectomy has been viewed as the standard of care for all patients with T1b esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('esophageal adenocarcinoma', 'Disease', (95, 120))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (95, 120))	('patients', 'Species', '9606', (77, 85))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (95, 120))	('T1b', 'Var', (91, 94))
799782	27270324	Importantly, patients with high EIF3B expression suffered shorter overall and disease-free survival.	('shorter', 'NegReg', (58, 65))	('expression', 'MPA', (38, 48))	('patients', 'Species', '9606', (13, 21))	('high', 'Var', (27, 31))	('EIF3B', 'Gene', (32, 37))
799783	27270324	EIF3B-knockdown cells could form smaller subcutaneous tumors in vivo.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('EIF3B-knockdown', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (41, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
799784	27270324	Finally, we demonstrated EIF3B could activate beta-catenin signaling pathway.	('activate', 'PosReg', (37, 45))	('beta-catenin', 'Gene', '1499', (46, 58))	('EIF3B', 'Var', (25, 30))	('beta-catenin', 'Gene', (46, 58))
799795	27270324	EIF3B accelerated the progression of ESCC via the activation of beta-catenin signaling pathway.	('ESCC', 'Disease', (37, 41))	('activation', 'PosReg', (50, 60))	('EIF3B', 'Var', (0, 5))	('beta-catenin', 'Gene', (64, 76))	('accelerated', 'PosReg', (6, 17))	('beta-catenin', 'Gene', '1499', (64, 76))
799799	27270324	As shown in Figure 1C, the EIF3B expression in EC109 and KYSE510 was higher than that in HEEC (Figure 1C and Supplementary Figure 1).	('EIF3B', 'Gene', (27, 32))	('KYSE510', 'Var', (57, 64))	('HEEC', 'CellLine', 'None', (89, 93))	('expression', 'MPA', (33, 43))	('EC109', 'CellLine', 'CVCL:6898', (47, 52))	('higher', 'PosReg', (69, 75))
799801	27270324	To investigate the correlations between EIF3B expression and clinicopathological features, we employed statistical analysis and found that high expression of EIF3B was positively associated with tumor depth, lymph node metastasis and TNM stage, significantly (P < 0.05) (Table 1).	('associated', 'Reg', (179, 189))	('tumor', 'Disease', (195, 200))	('EIF3B', 'Gene', (158, 163))	('lymph node metastasis', 'CPA', (208, 229))	('TNM stage', 'CPA', (234, 243))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('high', 'Var', (139, 143))
799802	27270324	EIF3B expression was also elevated with the up-grade of tumor histological differentiation level, although the difference did not reach the criterion of significance (Figure 1D), which indicated that high expression of EIF3B was positively correlated with the poor differentiation of tumor.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('correlated', 'Reg', (240, 250))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('up-grade', 'PosReg', (44, 52))	('tumor', 'Disease', (56, 61))	('expression', 'MPA', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('elevated', 'PosReg', (26, 34))	('EIF3B', 'Var', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumor', 'Disease', (284, 289))	('EIF3B', 'Gene', (0, 5))
799805	27270324	In univariate analysis, patients with high EIF3B expression suffered low DFS and OS compared with the ones with low EIF3B expression (P < 0.05).	('DFS', 'CPA', (73, 76))	('high', 'Var', (38, 42))	('low', 'NegReg', (69, 72))	('patients', 'Species', '9606', (24, 32))	('EIF3B', 'Gene', (43, 48))
799806	27270324	Graphic pattern of Kaplan-Meier curves suggested that prognosis was poor for patients with high EIF3B expression (Figure 1E and 1F).	('high', 'Var', (91, 95))	('patients', 'Species', '9606', (77, 85))	('expression', 'MPA', (102, 112))	('EIF3B', 'Gene', (96, 101))
799809	27270324	In addition, in vivo, tumor xenograft assay was performed to verify that EIF3B made a difference in the proliferation ability.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('proliferation ability', 'CPA', (104, 125))	('tumor', 'Disease', (22, 27))	('EIF3B', 'Var', (73, 78))
799811	27270324	It has been reported that EIF3B influence the cell apoptosis and cell cycle in some solid tumors.	('influence', 'Reg', (32, 41))	('cell apoptosis', 'CPA', (46, 60))	('EIF3B', 'Var', (26, 31))	('solid tumors', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cell cycle', 'CPA', (65, 75))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('solid tumors', 'Disease', (84, 96))
799815	27270324	The results showed that Cyclin A and D1 expression was down-regulated after the knockdown of EIF3B, while Cyclin E expression remains almost the same (Figure 3D).	('expression', 'MPA', (40, 50))	('knockdown', 'Var', (80, 89))	('EIF3B', 'Gene', (93, 98))	('down-regulated', 'NegReg', (55, 69))	('Cyclin A and D1', 'Gene', '890;595', (24, 39))
799818	27270324	Thus, we speculated whether EIF3B accelerate the progression of ESCC through beta-catenin pathway.	('ESCC', 'Disease', (64, 68))	('accelerate', 'PosReg', (34, 44))	('EIF3B', 'Var', (28, 33))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', '1499', (77, 89))
799821	27270324	Taken together, our data demonstrated that EIF3B could activate beta-catenin pathway to accelerate the progression of ESCC (Figure 3E).	('ESCC', 'Disease', (118, 122))	('EIF3B', 'Var', (43, 48))	('activate', 'PosReg', (55, 63))	('beta-catenin', 'Gene', (64, 76))	('accelerate', 'PosReg', (88, 98))	('progression', 'CPA', (103, 114))	('beta-catenin', 'Gene', '1499', (64, 76))
799825	27270324	Through the survival analysis, data indicated that patients with high EIF3B expression suffered shorter DFS and OS.	('DFS', 'CPA', (104, 107))	('shorter', 'NegReg', (96, 103))	('EIF3B', 'Gene', (70, 75))	('high', 'Var', (65, 69))	('patients', 'Species', '9606', (51, 59))
799827	27270324	revealed that knockdown of EIF3B could inhibit the G1-S transition in glioblastoma cell lines.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('EIF3B', 'Gene', (27, 32))	('inhibit', 'NegReg', (39, 46))	('G1-S transition', 'CPA', (51, 66))	('glioblastoma', 'Disease', (70, 82))	('knockdown', 'Var', (14, 23))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))
799828	27270324	have found the opposite results that knockdown of EIF3B could facilitate the G1-S transition in colon cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('facilitate', 'PosReg', (62, 72))	('colon cancer', 'Disease', (96, 108))	('knockdown', 'Var', (37, 46))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('EIF3B', 'Gene', (50, 55))	('G1-S transition', 'CPA', (77, 92))
799830	27270324	In the analysis of mechanism, we found that Cyclin A and D1 expression was down-regulated after the knockdown of EIF3B, while Cyclin E expression remains almost the same (Figure 3D).	('expression', 'MPA', (60, 70))	('knockdown', 'Var', (100, 109))	('EIF3B', 'Var', (113, 118))	('Cyclin A and D1', 'Gene', '890;595', (44, 59))	('down-regulated', 'NegReg', (75, 89))
799831	27270324	As Cyclin A is one of the positive regulatory protein for the G2 phase entry and Cyclin D1 for S phase entry, after knockdown of EIF3B, S and G2 phase entry were inhibited.	('Cyclin D1', 'Gene', '595', (81, 90))	('Cyclin A', 'Gene', '890', (3, 11))	('knockdown', 'Var', (116, 125))	('Cyclin D1', 'Gene', (81, 90))	('EIF3B', 'Gene', (129, 134))	('Cyclin A', 'Gene', (3, 11))	('inhibited', 'NegReg', (162, 171))
799832	27270324	Therefore, down-regulation of Cyclin A and D1 after the knockdown of EIF3B is consistent to the cell cycle change that cells in G1 phase were increased, in G2 phase were decreased and in S phase were almost unchanged (Figure 3C).	('EIF3B', 'Gene', (69, 74))	('increased', 'PosReg', (142, 151))	('G2 phase', 'CPA', (156, 164))	('Cyclin A and D1', 'Gene', '890;595', (30, 45))	('cell cycle change', 'Phenotype', 'HP:0011018', (96, 113))	('G1 phase', 'CPA', (128, 136))	('decreased', 'NegReg', (170, 179))	('down-regulation', 'NegReg', (11, 26))	('knockdown', 'Var', (56, 65))
799834	27270324	The exact pathway for EIF3B to accelerate the malignant tumor progression has not been announced.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EIF3B', 'Var', (22, 27))	('malignant tumor', 'Disease', (46, 61))	('accelerate', 'PosReg', (31, 41))	('malignant tumor', 'Disease', 'MESH:D018198', (46, 61))
799835	27270324	have studied the role of EIF3B in bladder and prostate cancer and found that EIF3B could promote tumor progression through up-regulation of integrin alpha5.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('EIF3B', 'Var', (77, 82))	('promote', 'PosReg', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (97, 102))	('integrin alpha5', 'Gene', (140, 155))	('integrin alpha5', 'Gene', '3678', (140, 155))	('bladder and prostate cancer', 'Disease', 'MESH:D001749', (34, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (46, 61))	('up-regulation', 'PosReg', (123, 136))
799838	27270324	They also verified that the bio-functional changes caused by EIF3c depletion match those observed with eIF3B depletion.	('EIF3c', 'Gene', '8663', (61, 66))	('depletion', 'Var', (67, 76))	('eIF3B', 'Gene', (103, 108))	('eIF3B', 'Gene', '8662', (103, 108))	('EIF3c', 'Gene', (61, 66))
799842	27270324	Our data showed that knockdown of EIF3B could down-regulate beta-catenin level and its downstream target gene, Cyclin D1 and c-Myc, protein levels in both two cell lines.	('c-Myc', 'Gene', '4609', (125, 130))	('Cyclin D1', 'Gene', (111, 120))	('protein levels', 'MPA', (132, 146))	('c-Myc', 'Gene', (125, 130))	('beta-catenin', 'Gene', (60, 72))	('down-regulate', 'NegReg', (46, 59))	('beta-catenin', 'Gene', '1499', (60, 72))	('knockdown', 'Var', (21, 30))	('Cyclin D1', 'Gene', '595', (111, 120))	('EIF3B', 'Gene', (34, 39))
799843	27270324	These results indicated that EIF3B could activate the beta-catenin signaling pathway, which lead to the progression of ESCC.	('EIF3B', 'Var', (29, 34))	('activate', 'PosReg', (41, 49))	('lead to', 'Reg', (92, 99))	('ESCC', 'Disease', (119, 123))	('beta-catenin', 'Gene', (54, 66))	('beta-catenin', 'Gene', '1499', (54, 66))
799846	27270324	EIF3B could activate the beta-catenin signaling pathway, including the downstream target gene Cyclin D1 and c-Myc, to induce ESCC cells proliferation and invasion, inhibit apoptosis and interfere cell cycle.	('c-Myc', 'Gene', '4609', (108, 113))	('Cyclin D1', 'Gene', (94, 103))	('cell cycle', 'CPA', (196, 206))	('beta-catenin', 'Gene', '1499', (25, 37))	('EIF3B', 'Var', (0, 5))	('inhibit', 'NegReg', (164, 171))	('invasion', 'CPA', (154, 162))	('c-Myc', 'Gene', (108, 113))	('activate', 'PosReg', (12, 20))	('apoptosis', 'CPA', (172, 181))	('induce', 'PosReg', (118, 124))	('beta-catenin', 'Gene', (25, 37))	('Cyclin D1', 'Gene', '595', (94, 103))	('ESCC', 'Disease', (125, 129))	('interfere', 'NegReg', (186, 195))
799887	27779648	Overexpression of MMP13 was observed in ESCC clinical tissues, and the expression of MMP13 promoted cancer cell aggressiveness.	('promoted', 'PosReg', (91, 99))	('aggressiveness', 'Phenotype', 'HP:0000718', (112, 126))	('expression', 'Var', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer cell aggressiveness', 'Disease', (100, 126))	('MMP13', 'Gene', (85, 90))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (100, 126))
799897	27779648	Therefore, dysregulated expression of miRNAs can disrupt tightly regulated RNA networks in cancer cells.	('tightly regulated RNA networks', 'MPA', (57, 87))	('disrupt', 'NegReg', (49, 56))	('dysregulated', 'Var', (11, 23))	('expression', 'MPA', (24, 34))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
799901	27779648	Moreover, our previous studies demonstrated that ectopic expression of miR-375 suppressed cancer cell aggressiveness in several types of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('suppressed', 'NegReg', (79, 89))	('aggressiveness', 'Phenotype', 'HP:0000718', (102, 116))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer cell aggressiveness', 'Disease', (90, 116))	('miR-375', 'Gene', (71, 78))	('cancer', 'Disease', (137, 143))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (90, 116))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('ectopic expression', 'Var', (49, 67))
799905	27779648	Our present data showed that matrix metalloproteinase 13 (MMP13) was directly regulated by miR-375 in ESCC cells.	('miR-375', 'Var', (91, 98))	('regulated', 'Reg', (78, 87))	('matrix metalloproteinase 13', 'Gene', '4322', (29, 56))	('matrix metalloproteinase 13', 'Gene', (29, 56))	('MMP13', 'Gene', (58, 63))
799906	27779648	Overexpression of MMP13 was observed in ESCC clinical tissues, and knockdown of MMP13 expression markedly inhibited ESCC cell migration and invasion, indicating that MMP13 acted as a cancer-promoting gene in ESCC cells.	('MMP13', 'Gene', (80, 85))	('cancer', 'Disease', (183, 189))	('ESCC', 'Disease', (116, 120))	('knockdown', 'Var', (67, 76))	('inhibited', 'NegReg', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
799916	27779648	HSS106637 and HSS106638; Invitrogen, Carlsbad, CA, USA), and negative control miRNA/siRNA (P/N: AM17111; Applied Biosystems).	('HSS106638', 'Var', (14, 23))	('miR', 'Gene', (78, 81))	('miR', 'Gene', '220972', (78, 81))
799932	27779648	Cell proliferation was significantly suppressed by miR-375 transfection in TE-9 cells in comparison with that of mock or miR-control transfectants (Fig.	('suppressed', 'NegReg', (37, 47))	('TE-9', 'CellLine', 'CVCL:1767', (75, 79))	('miR', 'Gene', '220972', (51, 54))	('transfection', 'Var', (59, 71))	('miR', 'Gene', (51, 54))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('Cell proliferation', 'CPA', (0, 18))
799933	27779648	Migration assays showed that cell migration activity was significantly inhibited by miR-375 transfection in TE-8 and TE-9 cells in comparison with that in mock or miR-control transfectants (Fig.	('miR', 'Gene', '220972', (84, 87))	('transfection', 'Var', (92, 104))	('miR', 'Gene', (84, 87))	('inhibited', 'NegReg', (71, 80))	('TE-9', 'CellLine', 'CVCL:1767', (117, 121))	('cell migration activity', 'CPA', (29, 52))	('miR', 'Gene', '220972', (163, 166))	('miR', 'Gene', (163, 166))
799934	27779648	Additionally, Matrigel invasion assays demonstrated that cell invasion activity was significantly inhibited by miR-375 transfection in TE-8 and TE-9 cells in comparison with that in mock or miR-control transfectants (Fig.	('transfection', 'Var', (119, 131))	('inhibited', 'NegReg', (98, 107))	('Matrigel invasion', 'CPA', (14, 31))	('TE-9', 'CellLine', 'CVCL:1767', (144, 148))	('cell invasion activity', 'CPA', (57, 79))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))	('miR', 'Gene', (190, 193))	('miR', 'Gene', '220972', (190, 193))
799935	27779648	To gain additional insights into the molecular pathways regulated by antitumor miR-375 in ESCC cells, we used a combination of in silico and gene expression analyses.	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('miR-375', 'Var', (79, 86))
799936	27779648	In gene expression analyses, 2,897 and 1,007 genes were downregulated (log2 ratio <-0.5) in TE-8 and TE-9 miR-375 transfectants, respectively, in comparison with that in control transfectants.	('miR-375 transfectants', 'Var', (106, 127))	('transfectants', 'Var', (114, 127))	('downregulated', 'NegReg', (56, 69))	('TE-9', 'CellLine', 'CVCL:1767', (101, 105))	('TE-8', 'Var', (92, 96))
799938	27779648	Our results showed that MMP13 mRNA was significantly reduced in miR-375 transfectants in comparison with that in mock or miR-control transfectants (P<0.0001; Fig.	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('reduced', 'NegReg', (53, 60))	('MMP13 mRNA', 'MPA', (24, 34))	('transfectants', 'Var', (72, 85))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))
799941	27779648	To investigate the functional roles of MMP13 in ESCC cell lines, we performed loss-of-function assays by transfection of si-MMP13 into TE-8 and TE-9 cells.	('si-MMP13', 'Var', (121, 129))	('TE-9', 'CellLine', 'CVCL:1767', (144, 148))	('loss-of-function', 'NegReg', (78, 94))
799943	27779648	To determine which downstream genes were regulated by MMP13, genome-wide gene expression and in silico analyses were performed in TE-8 and TE-9 cells transfected with si-MMP13.	('si-MMP13', 'Var', (167, 175))	('TE-9', 'CellLine', 'CVCL:1767', (139, 143))	('MMP13', 'Gene', (54, 59))
799944	27779648	Our expression analysis showed that a total of 298 genes were commonly downregulated (log2 ratio <-2.0) in TE-8 and TE-9 cells following si-MMP13 transfection.	('transfection', 'Var', (146, 158))	('downregulated', 'NegReg', (71, 84))	('si-MMP13 transfection', 'Var', (137, 158))	('TE-9', 'CellLine', 'CVCL:1767', (116, 120))
799951	27779648	Thus, we found that loss of miR-375 expression enhanced cancer cell aggressiveness in ESCC.	('miR-375', 'Gene', (28, 35))	('loss', 'Var', (20, 24))	('enhanced', 'PosReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer cell aggressiveness', 'Disease', (56, 82))	('aggressiveness', 'Phenotype', 'HP:0000718', (68, 82))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (56, 82))	('ESCC', 'Disease', (86, 90))
799961	27779648	Our present data demonstrated that knockdown of MMP13 markedly reduced cancer cell migration and invasion in ESCC cells.	('knockdown', 'Var', (35, 44))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('reduced', 'NegReg', (63, 70))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MMP13', 'Gene', (48, 53))	('invasion', 'CPA', (97, 105))
799968	27779648	Moreover, cell cycle-promoting genes, e.g., KIF14, CDK1, TOP2A, CDC45 and PAK2, were also downregulated by si-MMP13 in this study.	('CDC45', 'Gene', '8318', (64, 69))	('KIF14', 'Gene', (44, 49))	('PAK2', 'Gene', (74, 78))	('si-MMP13', 'Var', (107, 115))	('KIF14', 'Gene', '9928', (44, 49))	('cell cycle-promoting genes', 'Gene', (10, 36))	('PAK2', 'Gene', '5062', (74, 78))	('CDK1', 'Gene', (51, 55))	('TOP2A', 'Gene', '7153', (57, 62))	('CDC45', 'Gene', (64, 69))	('downregulated', 'NegReg', (90, 103))	('CDK1', 'Gene', '983', (51, 55))	('TOP2A', 'Gene', (57, 62))
799973	27779648	Previous studies have shown that CENPF is a master regulator of prostate cancer malignancy and that high expression of CEPNF is a prognostic indicator of poor survival and metastasis in patients with ESCC.	('CENPF', 'Gene', '1063', (33, 38))	('patients', 'Species', '9606', (186, 194))	('prostate cancer malignancy', 'Disease', 'MESH:D011471', (64, 90))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('high expression', 'Var', (100, 115))	('CEPNF', 'Gene', (119, 124))	('poor', 'NegReg', (154, 158))	('prostate cancer malignancy', 'Disease', (64, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (64, 79))	('CENPF', 'Gene', (33, 38))	('ESCC', 'Disease', (200, 204))	('metastasis', 'CPA', (172, 182))
800034	27094390	reported lymph node metastases in 74 % of patients with pT3 tumors, which raises the question whether depth of tumor invasion is a better predictor of lymph node involvement than the SN procedure.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('lymph node metastases', 'Disease', 'MESH:D009362', (9, 30))	('lymph node metastases', 'Disease', (9, 30))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('pT3', 'Var', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('patients', 'Species', '9606', (42, 50))	('tumor', 'Disease', (60, 65))	('tumors', 'Disease', (60, 66))
800069	19628076	Previous studies have shown that many upper gastrointestinal adenocarcinomas exhibit ERBB2 amplification.	('ERBB2', 'Gene', (85, 90))	('ERBB2', 'Gene', '2064', (85, 90))	('upper gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (38, 76))	('amplification', 'Var', (91, 104))	('upper gastrointestinal adenocarcinomas', 'Disease', (38, 76))
800071	19628076	This study uses siRNA to knockdown ERBB2 in gastrointestinal adenocarcinoma cell lines to evaluate cell viability, apoptosis, and changes in cell cycle.	('gastrointestinal adenocarcinoma', 'Disease', (44, 75))	('changes', 'Reg', (130, 137))	('cell cycle', 'CPA', (141, 151))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))	('gastrointestinal adenocarcinoma', 'Disease', 'MESH:D004067', (44, 75))	('knockdown', 'Var', (25, 34))
800073	19628076	We demonstrate that knockdown of ERBB2 in esophageal and gastric cancer cell lines with known ERBB2 amplification effectively decreases ERBB2 protein levels and decreases cell viability mainly via apoptotic pathways.	('ERBB2', 'Gene', '2064', (33, 38))	('apoptotic', 'CPA', (197, 206))	('decreases', 'NegReg', (161, 170))	('amplification', 'Var', (100, 113))	('gastric cancer', 'Disease', (57, 71))	('ERBB2', 'Gene', '2064', (136, 141))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('ERBB2', 'Gene', (136, 141))	('ERBB2', 'Gene', (94, 99))	('ERBB2', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('ERBB2', 'Gene', '2064', (94, 99))	('cell viability', 'CPA', (171, 185))	('decreases', 'NegReg', (126, 135))
800074	19628076	ERBB2-directed therapy may be of benefit in the subset of patients with gastrointestinal adenocarcinomas exhibiting amplification of ERBB2.	('gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (72, 104))	('ERBB2', 'Gene', (133, 138))	('ERBB2', 'Gene', '2064', (0, 5))	('gastrointestinal adenocarcinomas', 'Disease', (72, 104))	('ERBB2', 'Gene', (0, 5))	('amplification', 'Var', (116, 129))	('patients', 'Species', '9606', (58, 66))	('ERBB2', 'Gene', '2064', (133, 138))
800085	19628076	The ERBB2 oncogene can be activated by point mutations, gene amplification or over-expression.	('point mutations', 'Var', (39, 54))	('ERBB2', 'Gene', '2064', (4, 9))	('gene amplification', 'Var', (56, 74))	('ERBB2', 'Gene', (4, 9))	('over-expression', 'Var', (78, 93))	('activated', 'PosReg', (26, 35))
800086	19628076	It is hypothesized that high ERBB2 expression promotes spontaneous dimerization of the ERBB2 receptor, thus causing constitutive ERBB2 activation and downstream signaling.	('ERBB2', 'Gene', (129, 134))	('ERBB2', 'Gene', (29, 34))	('ERBB2', 'Gene', '2064', (129, 134))	('activation', 'PosReg', (135, 145))	('causing', 'Reg', (108, 115))	('spontaneous dimerization', 'MPA', (55, 79))	('ERBB2', 'Gene', (87, 92))	('high', 'Var', (24, 28))	('ERBB2', 'Gene', '2064', (87, 92))	('downstream signaling', 'MPA', (150, 170))	('ERBB2', 'Gene', '2064', (29, 34))
800087	19628076	Amplification of the ERBB2 gene and/or over-expression of its corresponding protein have been detected in 20-30% of human breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('Amplification', 'Var', (0, 13))	('breast cancers', 'Disease', (122, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('detected', 'Reg', (94, 102))	('protein', 'Protein', (76, 83))	('ERBB2', 'Gene', '2064', (21, 26))	('ERBB2', 'Gene', (21, 26))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('over-expression', 'PosReg', (39, 54))	('human', 'Species', '9606', (116, 121))
800090	19628076	Under current standards of clinical care, patients with ERBB2 amplified tumors receive trastuzumab (Herceptin) in combination with standard chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('amplified', 'Var', (62, 71))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('Herceptin', 'Chemical', 'MESH:D000068878', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('trastuzumab', 'Chemical', 'MESH:D000068878', (87, 98))	('ERBB2', 'Gene', '2064', (56, 61))	('patients', 'Species', '9606', (42, 50))	('ERBB2', 'Gene', (56, 61))
800092	19628076	The purpose of this study was to analyze the effect of ERBB2 knockdown on (1) ERBB2 protein expression, (2) cell viability in cells line with different levels of ERBB2 expression, and (3) the mechanism of cell death (apoptosis or cell cycle arrest).	('cell cycle arrest', 'CPA', (230, 247))	('ERBB2', 'Gene', '2064', (78, 83))	('ERBB2', 'Gene', (78, 83))	('knockdown', 'Var', (61, 70))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (230, 247))	('ERBB2', 'Gene', '2064', (162, 167))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))	('ERBB2', 'Gene', (162, 167))
800093	19628076	We believe that in cell lines with ERBB2 amplification there will be a more significant increase in cell death and apoptosis.	('increase', 'PosReg', (88, 96))	('cell death', 'CPA', (100, 110))	('amplification', 'Var', (41, 54))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))	('apoptosis', 'CPA', (115, 124))
800094	19628076	We show that ERBB2 knockdown via a siRNA model in upper gastrointestinal (GI) adenocarcinoma cell lines effectively decreases ERBB2 protein levels.	('knockdown', 'Var', (19, 28))	('protein levels', 'MPA', (132, 146))	('upper gastrointestinal (GI) adenocarcinoma', 'Disease', 'MESH:D005767', (50, 92))	('ERBB2', 'Gene', '2064', (126, 131))	('ERBB2', 'Gene', '2064', (13, 18))	('ERBB2', 'Gene', (126, 131))	('ERBB2', 'Gene', (13, 18))	('decreases', 'NegReg', (116, 125))
800132	19628076	To access the mechanism by which ERBB2 knockdown induces cell death, apoptosis and cell cycle were analyzed.	('ERBB2', 'Gene', '2064', (33, 38))	('knockdown', 'Var', (39, 48))	('cell death', 'CPA', (57, 67))	('ERBB2', 'Gene', (33, 38))
800136	19628076	We found no suppression of ERBB1 or other genes with this model when mRNA levels were evaluated, indicating that the effect is specific to ERBB2 knockdown (data not shown).	('ERBB2', 'Gene', '2064', (139, 144))	('knockdown', 'Var', (145, 154))	('ERBB1', 'Gene', '1956', (27, 32))	('ERBB1', 'Gene', (27, 32))	('ERBB2', 'Gene', (139, 144))
800138	19628076	Apoptosis is significantly increased in both OE19 and MKN45, the ERBB2 amplified cell lines, with no change in Seg-1.	('increased', 'PosReg', (27, 36))	('OE19', 'Var', (45, 49))	('ERBB2', 'Gene', (65, 70))	('MKN45', 'Var', (54, 59))	('ERBB2', 'Gene', '2064', (65, 70))	('Apoptosis', 'CPA', (0, 9))
800228	23788918	Study on the relationship between TagSNPs and haplotype of hCHK2 and esophageal cancer in Kazakh and Han in Xinjiang To determine the association of hCHK2 rs2278022, rs2602431, and rs2970077 polymorphisms and haplotypes with susceptibility to esophageal cancer in Kazakh and Han in Xinjiang Uygur Autonomous Region.	('association', 'Interaction', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('hCHK2', 'Gene', (149, 154))	('esophageal cancer', 'Disease', (69, 86))	('rs2970077', 'Var', (181, 190))	('rs2602431', 'Var', (166, 175))	('rs2278022', 'Mutation', 'rs2278022', (155, 164))	('rs2970077', 'Mutation', 'rs2970077', (181, 190))	('hCHK2', 'Gene', '11200', (149, 154))	('hCHK2', 'Gene', '11200', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (243, 260))	('hCHK2', 'Gene', (59, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('esophageal cancer', 'Disease', (243, 260))	('rs2602431', 'Mutation', 'rs2602431', (166, 175))	('rs2278022', 'Var', (155, 164))
800230	23788918	Polymorphisms of hCHK2 at rs2278022, rs2602431 and rs2970077 were analyzed by polymerase chain reaction-ligase detection reaction (PCR-LDR).	('rs2602431', 'Mutation', 'rs2602431', (37, 46))	('rs2970077', 'Var', (51, 60))	('rs2278022', 'Mutation', 'rs2278022', (26, 35))	('rs2278022', 'Var', (26, 35))	('rs2602431', 'Var', (37, 46))	('rs2970077', 'Mutation', 'rs2970077', (51, 60))	('hCHK2', 'Gene', (17, 22))	('hCHK2', 'Gene', '11200', (17, 22))
800231	23788918	1) No significant difference was observed in the frequency of hCHK2 at rs2278022, rs2602431 and rs2970077 between the cases and controls in Kazakh and Han (P > 0.05); 2) In Kazakh and Han, the distribution of haplotypes was not significantly different between esophageal cancer cases and controls (P > 0.05).	('rs2602431', 'Mutation', 'rs2602431', (82, 91))	('hCHK2', 'Gene', '11200', (62, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (260, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('rs2278022', 'Var', (71, 80))	('rs2970077', 'Var', (96, 105))	('rs2278022', 'Mutation', 'rs2278022', (71, 80))	('rs2602431', 'Var', (82, 91))	('rs2970077', 'Mutation', 'rs2970077', (96, 105))	('hCHK2', 'Gene', (62, 67))	('esophageal cancer', 'Disease', (260, 277))
800232	23788918	Polymorphisms of hCHK2 at rs2278022, rs2602431 and rs2970077 and haplotypes are unlikely to be associated with the susceptibility to esophageal cancer in Kazakh and Han.	('rs2602431', 'Mutation', 'rs2602431', (37, 46))	('hCHK2', 'Gene', '11200', (17, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('rs2970077', 'Var', (51, 60))	('rs2278022', 'Mutation', 'rs2278022', (26, 35))	('rs2278022', 'Var', (26, 35))	('rs2602431', 'Var', (37, 46))	('rs2970077', 'Mutation', 'rs2970077', (51, 60))	('hCHK2', 'Gene', (17, 22))	('esophageal cancer', 'Disease', (133, 150))	('associated', 'Reg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
800234	23788918	Multiple genes are involved in the process of carcinogenesis, so a single gene polymorphism is insufficient to cause cancer.	('insufficient', 'Disease', (95, 107))	('insufficient', 'Disease', 'MESH:D000309', (95, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('polymorphism', 'Var', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('carcinogenesis', 'Disease', (46, 60))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
800236	23788918	Therefore, based on previous studies, polymorphisms of hCHK2 at rs2278022, rs2602431 and rs2970077 were analyzed by polymerase chain reaction-ligase detection reaction (PCR-LDR) of the Xinjiang Uygur Autonomous Region to compare differences in the distribution frequency of various single nucleotide polymorphism (SNP) genotypes and haplotypes and to determine the molecular mechanism behind the pathogenesis of esophageal cancer.	('hCHK2', 'Gene', '11200', (55, 60))	('esophageal cancer', 'Disease', (412, 429))	('rs2970077', 'Mutation', 'rs2970077', (89, 98))	('rs2602431', 'Mutation', 'rs2602431', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('esophageal cancer', 'Disease', 'MESH:D004938', (412, 429))	('rs2278022', 'Mutation', 'rs2278022', (64, 73))	('rs2278022', 'Var', (64, 73))	('rs2602431', 'Var', (75, 84))	('hCHK2', 'Gene', (55, 60))	('rs2970077', 'Var', (89, 98))
800245	23788918	The goodness of fit between observed and estimated hCHK2 rs2278022, rs2602431 and rs2970077 genotype frequencies according to the Hardy-Weinberg equilibrium was determined by the chi2 test.	('rs2970077', 'Mutation', 'rs2970077', (82, 91))	('hCHK2', 'Gene', '11200', (51, 56))	('goodness', 'Disease', 'None', (4, 12))	('rs2278022', 'Var', (57, 66))	('rs2602431', 'Mutation', 'rs2602431', (68, 77))	('rs2278022', 'Mutation', 'rs2278022', (57, 66))	('goodness', 'Disease', (4, 12))	('rs2602431', 'Var', (68, 77))	('rs2970077', 'Var', (82, 91))	('hCHK2', 'Gene', (51, 56))
800248	23788918	The sequences of hCHK2 rs2278022, rs2602431 and rs2970077 were analyzed by an automated sequencer to determine their genotype (Fig.	('rs2278022', 'Var', (23, 32))	('rs2602431', 'Mutation', 'rs2602431', (34, 43))	('rs2970077', 'Var', (48, 57))	('rs2278022', 'Mutation', 'rs2278022', (23, 32))	('rs2970077', 'Mutation', 'rs2970077', (48, 57))	('hCHK2', 'Gene', (17, 22))	('hCHK2', 'Gene', '11200', (17, 22))	('rs2602431', 'Var', (34, 43))
800249	23788918	The effect of hCHK2 rs2278022, rs2602431 and rs2970077 on the susceptibility of the case and control groups to esophageal cancer is summarized in Table 3.	('rs2602431', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('esophageal cancer', 'Disease', (111, 128))	('rs2970077', 'Var', (45, 54))	('rs2970077', 'Mutation', 'rs2970077', (45, 54))	('hCHK2', 'Gene', (14, 19))	('rs2278022', 'Var', (20, 29))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('rs2602431', 'Mutation', 'rs2602431', (31, 40))	('hCHK2', 'Gene', '11200', (14, 19))	('rs2278022', 'Mutation', 'rs2278022', (20, 29))
800250	23788918	No significant difference was observed in the frequency of hCHK2 at rs2278022, rs2602431 and rs2970077 between the case and control groups of Kazakh and Han.	('hCHK2', 'Gene', (59, 64))	('rs2970077', 'Var', (93, 102))	('rs2970077', 'Mutation', 'rs2970077', (93, 102))	('rs2602431', 'Mutation', 'rs2602431', (79, 88))	('rs2278022', 'Mutation', 'rs2278022', (68, 77))	('hCHK2', 'Gene', '11200', (59, 64))	('rs2602431', 'Var', (79, 88))
800251	23788918	The outcomes of the linkage disequilibrium test on hCHK2 tagSNPs are presented in Figures 3 and 4.  hCHK2 rs2602431, rs2278022 and rs2970077 can form eight haplotypes.	('hCHK2', 'Gene', '11200', (100, 105))	('rs2278022', 'Mutation', 'rs2278022', (117, 126))	('hCHK2', 'Gene', '11200', (51, 56))	('rs2602431', 'Mutation', 'rs2602431', (106, 115))	('rs2970077', 'Var', (131, 140))	('rs2970077', 'Mutation', 'rs2970077', (131, 140))	('rs2602431', 'Var', (106, 115))	('hCHK2', 'Gene', (100, 105))	('rs2278022', 'Var', (117, 126))	('hCHK2', 'Gene', (51, 56))
800256	23788918	Dysregulation of CHK2 would result in a defective DNA damage response, leading to the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('defective', 'NegReg', (40, 49))	('cancer', 'Disease', (101, 107))	('DNA damage response', 'MPA', (50, 69))	('Dysregulation', 'Var', (0, 13))	('CHK2', 'Gene', (17, 21))	('leading to', 'Reg', (71, 81))	('result', 'Reg', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CHK2', 'Gene', '11200', (17, 21))
800257	23788918	Previous studies have focused on whether hCHK2 polymorphism at the 84th codon A252G increases patient susceptibility to cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('increases', 'PosReg', (84, 93))	('A252G', 'Var', (78, 83))	('A252G', 'Mutation', 'rs587780191', (78, 83))	('patient', 'Species', '9606', (94, 101))	('hCHK2', 'Gene', (41, 46))	('polymorphism', 'Var', (47, 59))	('hCHK2', 'Gene', '11200', (41, 46))
800258	23788918	These studies show that the hCHK2 A252G polymorphism leads to higher risk of head and neck squamous cell carcinoma and familial multiple tumor syndromes.	('familial multiple tumor', 'Disease', (119, 142))	('A252G', 'Mutation', 'rs587780191', (34, 39))	('familial multiple tumor', 'Disease', 'MESH:D011125', (119, 142))	('neck squamous cell carcinoma', 'Disease', (86, 114))	('A252G polymorphism', 'Var', (34, 52))	('polymorphism', 'Var', (40, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (86, 114))	('hCHK2', 'Gene', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('hCHK2', 'Gene', '11200', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
800261	23788918	We have shown here that in either the population of Kazakh or Han, there was no statistical difference between the case and control groups in terms of hCHK2 rs2278022, rs2602431 and rs2970077 genotypes or their allele frequency distribution.	('hCHK2', 'Gene', '11200', (151, 156))	('rs2970077', 'Var', (182, 191))	('rs2278022', 'Mutation', 'rs2278022', (157, 166))	('rs2278022', 'Var', (157, 166))	('rs2970077', 'Mutation', 'rs2970077', (182, 191))	('rs2602431', 'Mutation', 'rs2602431', (168, 177))	('hCHK2', 'Gene', (151, 156))	('rs2602431', 'Var', (168, 177))
800263	23788918	It is possible that polymorphism of a single gene may weakly affect tumor development.	('tumor', 'Disease', (68, 73))	('polymorphism', 'Var', (20, 32))	('affect', 'Reg', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
800265	23788918	Data from our analysis of single loci revealed that there is no significant difference between polymorphisms of hCHK2 rs2602431, rs2278022 and rs2970077 and esophageal cancer.	('rs2602431', 'Mutation', 'rs2602431', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('rs2970077', 'Var', (143, 152))	('hCHK2', 'Gene', (112, 117))	('rs2278022', 'Var', (129, 138))	('rs2278022', 'Mutation', 'rs2278022', (129, 138))	('rs2602431', 'Var', (118, 127))	('rs2970077', 'Mutation', 'rs2970077', (143, 152))	('hCHK2', 'Gene', '11200', (112, 117))	('esophageal cancer', 'Disease', (157, 174))
800266	23788918	It is important to note that this finding does not rule out the possibility that the presence of two or more of these polymorphisms in an individual would render the patient more susceptible to esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))	('susceptible', 'MPA', (179, 190))	('more', 'PosReg', (174, 178))	('esophageal cancer', 'Disease', (194, 211))	('render', 'Reg', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('presence', 'Var', (85, 93))	('patient', 'Species', '9606', (166, 173))
800267	23788918	Our current study also shows that the Kazakh population has at least eight haplotypes formed by three SNPs sites at hCHK2 rs2602431, rs2278022 and rs2970077.	('rs2602431', 'Mutation', 'rs2602431', (122, 131))	('rs2970077', 'Var', (147, 156))	('hCHK2', 'Gene', (116, 121))	('rs2278022', 'Var', (133, 142))	('rs2970077', 'Mutation', 'rs2970077', (147, 156))	('hCHK2', 'Gene', '11200', (116, 121))	('rs2278022', 'Mutation', 'rs2278022', (133, 142))	('rs2602431', 'Var', (122, 131))
800268	23788918	In the Han population, hCHK2 rs2602431, rs2278022 and rs2970077 SNPs with haplotype frequencies greater than 0.03 are CTC, TCC, and TTT types.	('rs2602431', 'Mutation', 'rs2602431', (29, 38))	('hCHK2', 'Gene', (23, 28))	('rs2602431', 'Var', (29, 38))	('rs2278022', 'Mutation', 'rs2278022', (40, 49))	('rs2278022', 'Var', (40, 49))	('hCHK2', 'Gene', '11200', (23, 28))	('rs2970077 SNPs', 'Var', (54, 68))	('rs2970077', 'Mutation', 'rs2970077', (54, 63))
800269	23788918	Our findings show that haplotypes of hCHK2 rs2602431, rs2278022 and rs2970077 do not affect the incidence of esophageal cancer in either Kazakh or Han populations.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs2970077', 'Var', (68, 77))	('hCHK2', 'Gene', (37, 42))	('rs2278022', 'Var', (54, 63))	('rs2602431', 'Mutation', 'rs2602431', (43, 52))	('rs2278022', 'Mutation', 'rs2278022', (54, 63))	('rs2970077', 'Mutation', 'rs2970077', (68, 77))	('hCHK2', 'Gene', '11200', (37, 42))	('rs2602431', 'Var', (43, 52))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
800279	20584281	The expression of VEGF-C was found to be higher in Stage2B-4A tumors than in Stage0-2A tumors (p = 0.049).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('VEGF-C', 'Gene', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('expression', 'MPA', (4, 14))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('higher', 'PosReg', (41, 47))	('tumors', 'Disease', (87, 93))	('Stage2B-4A', 'Var', (51, 61))	('VEGF-C', 'Gene', '7424', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
800280	20584281	When the patients were divided into two groups according to their expression levels of VEGF-C (a group of 53 cases with high expression and a group of 53 cases with low expression), the patients with high VEGF-C expression had significantly shorter survival after surgery than the patients with low expression (p = 0.0065).	('patients', 'Species', '9606', (9, 17))	('VEGF-C', 'Gene', '7424', (205, 211))	('shorter', 'NegReg', (241, 248))	('VEGF-C', 'Gene', (87, 93))	('patients', 'Species', '9606', (281, 289))	('survival after surgery', 'CPA', (249, 271))	('VEGF-C', 'Gene', (205, 211))	('VEGF-C', 'Gene', '7424', (87, 93))	('high', 'Var', (200, 204))	('patients', 'Species', '9606', (186, 194))
800281	20584281	Although univariate analysis showed that high expression of VEGF-C was a statistically significant prognostic factor, this was not shown in multivariate analysis.	('VEGF-C', 'Gene', '7424', (60, 66))	('VEGF-C', 'Gene', (60, 66))	('high', 'Var', (41, 45))
800302	20584281	The assay numbers for GAPDH and VEGF-C were as follows: Hs99999905_m1 (GAPDH), Hs01099206_m1 (VEGF-C).	('Hs99999905_m1', 'Var', (56, 69))	('VEGF-C', 'Gene', '7424', (32, 38))	('Hs01099206_m1', 'Var', (79, 92))	('VEGF-C', 'Gene', (94, 100))	('VEGF-C', 'Gene', (32, 38))	('GAPDH', 'Gene', '2597', (71, 76))	('GAPDH', 'Gene', '2597', (22, 27))	('GAPDH', 'Gene', (22, 27))	('GAPDH', 'Gene', (71, 76))	('VEGF-C', 'Gene', '7424', (94, 100))
800306	20584281	We first investigated the expression of VEGF-C in 12 esophageal cancer cell lines (KYSE30, KYSE50, KYSE70, KYSE110, KYSE140, KYSE150, KYSE180, KYSE270, KYSE410, KYSE450, KYSE510, KYSE520), and in the Het-1A cell line.	('KYSE410', 'Var', (152, 159))	('KYSE140', 'Var', (116, 123))	('KYSE270', 'Var', (143, 150))	('KYSE110', 'Var', (107, 114))	('KYSE50', 'Var', (91, 97))	('KYSE150', 'Var', (125, 132))	('VEGF-C', 'Gene', '7424', (40, 46))	('KYSE70', 'Var', (99, 105))	('KYSE180', 'Var', (134, 141))	('KYSE30', 'Var', (83, 89))	('esophageal cancer', 'Disease', (53, 70))	('VEGF-C', 'Gene', (40, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
800307	20584281	In most of the KYSE series of cell lines, especially KYSE410, high levels of VEGF-C were detected, yet in Het-1A, VEGF-C was not detected at all (Fig.	('KYSE410', 'Var', (53, 60))	('VEGF-C', 'Gene', '7424', (77, 83))	('VEGF-C', 'Gene', (114, 120))	('VEGF-C', 'Gene', (77, 83))	('VEGF-C', 'Gene', '7424', (114, 120))
800311	20584281	The expression of VEGF-C was found to be higher in Stage2B-4A tumors than in Stage0-2A tumors (Table 1, Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('VEGF-C', 'Gene', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('expression', 'MPA', (4, 14))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('higher', 'PosReg', (41, 47))	('tumors', 'Disease', (87, 93))	('Stage2B-4A', 'Var', (51, 61))	('VEGF-C', 'Gene', '7424', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
800315	20584281	The patients in the high VEGF-C expression group had significantly shorter survival after surgery than the patients in the low expression group (p = 0.0065 by log-rank test; Fig.	('VEGF-C', 'Gene', (25, 31))	('VEGF-C', 'Gene', '7424', (25, 31))	('high', 'Var', (20, 24))	('survival', 'MPA', (75, 83))	('shorter', 'NegReg', (67, 74))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (107, 115))
800316	20584281	Univariate analysis showed that, among the clinico-pathological factors, the extent of the primary tumor, lymph node metastasis, and high expression of VEGF-C were all statistically significant prognostic factors (Table 2).	('tumor', 'Disease', (99, 104))	('VEGF-C', 'Gene', '7424', (152, 158))	('high', 'Var', (133, 137))	('VEGF-C', 'Gene', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
800337	20584281	They also claimed that the prognosis was significantly worse for patients with tumors positive for VEGF-C than for those with tumors negative for VEGF-C, and that VEGF-C expression was an independent prognostic determinant.	('VEGF-C', 'Gene', '7424', (146, 152))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('VEGF-C', 'Gene', '7424', (99, 105))	('VEGF-C', 'Gene', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('worse', 'NegReg', (55, 60))	('VEGF-C', 'Gene', (146, 152))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (65, 73))	('VEGF-C', 'Gene', (99, 105))	('positive', 'Var', (86, 94))	('VEGF-C', 'Gene', '7424', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
800340	20584281	In this study, the expression of VEGF-C mRNA correlates with lymph node metastasis, and the patients with high VEGF-C-expressing tumors have a poorer prognosis than those with low VEGF-C-expressing tumors.	('expression', 'MPA', (19, 29))	('tumors', 'Disease', (129, 135))	('VEGF-C', 'Gene', (180, 186))	('VEGF-C', 'Gene', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('high', 'Var', (106, 110))	('lymph node metastasis', 'CPA', (61, 82))	('VEGF-C', 'Gene', (33, 39))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('VEGF-C', 'Gene', '7424', (111, 117))	('VEGF-C', 'Gene', '7424', (180, 186))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('VEGF-C', 'Gene', '7424', (33, 39))
800345	20584281	If early esophageal cancer expresses high VEGF-C, the patients have increased risk of lymph node metastasis and thus, a poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('VEGF-C', 'Gene', (42, 48))	('lymph node metastasis', 'CPA', (86, 107))	('high', 'Var', (37, 41))	('patients', 'Species', '9606', (54, 62))	('esophageal cancer', 'Disease', (9, 26))	('VEGF-C', 'Gene', '7424', (42, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (9, 26))
800354	19077221	We divided the study population into four groups: never drinkers, light drinkers (less than 25.0 g of ethanol per day), moderate drinkers (25.0 to 50.0 g of ethanol per day), and heavy drinkers (more than 50.0 g of ethanol per day).	('25.0 to 50.0 g', 'Var', (139, 153))	('less than 25.0', 'Var', (82, 96))	('ethanol', 'Chemical', 'MESH:D000431', (215, 222))	('ethanol', 'Chemical', 'MESH:D000431', (157, 164))	('ethanol', 'Chemical', 'MESH:D000431', (102, 109))
800372	19077221	The study population was then classified into four groups: never drinkers, light drinkers (less than 25.0 g of ethanol per day), moderate drinkers (25.0 to 50.0 g of ethanol per day), and heavy drinkers (more than 50.0 g of ethanol per day).	('ethanol', 'Chemical', 'MESH:D000431', (224, 231))	('ethanol', 'Chemical', 'MESH:D000431', (166, 173))	('ethanol', 'Chemical', 'MESH:D000431', (111, 118))	('less than 25.0', 'Var', (91, 105))	('25.0 to 50.0 g', 'Var', (148, 162))
800412	19077221	In conclusion, our data suggests that alcohol consumption in Japanese men tends to be associated with an increased risk of erosive esophagitis and Barrett's epithelium.	('men', 'Species', '9606', (70, 73))	('alcohol', 'Chemical', 'MESH:D000438', (38, 45))	('esophagitis', 'Phenotype', 'HP:0100633', (131, 142))	('alcohol consumption', 'Var', (38, 57))	("Barrett's epithelium", 'Disease', (147, 167))	('esophagitis', 'Disease', (131, 142))	('esophagitis', 'Disease', 'MESH:D004941', (131, 142))
800462	16884539	The process of simplification could have theoretically led to biases, which could have influenced the participants' choices, which is a possible limitation to the study estimates for the hypothetical utility scores.	('led to', 'Reg', (55, 61))	('biases', 'Var', (62, 68))	('participants', 'Species', '9606', (102, 114))	('influenced', 'Reg', (87, 97))
800471	33663506	Through bioinformatics analysis, we screened a circRNA signature including four circRNAs (hsa_circ_0000005, hsa_circ_0007541, hsa_circ_0008199, hsa_circ_0077536) which can classify the ESCC patients into two groups with significantly different survival (log rank P < 0.001), and found its predictive performance was better than that of the TNM stage(0.84 vs. 0.66; 0.65 vs. 0.62).	('patients', 'Species', '9606', (190, 198))	('hsa_circ_0000005', 'Var', (90, 106))	('hsa_circ_0008199', 'Var', (126, 142))	('ESCC', 'Disease', (185, 189))	('hsa_circ_0007541', 'Var', (108, 124))	('hsa_circ_0077536', 'Var', (144, 160))
800480	33663506	found that the high expression of circRHOT1 was associated with poor prognosis of hepatocellular carcinoma (HCC), and confirmed that circRHOT1 promoted malignant progression of tumors, Liang et al.	('circRHOT1', 'Gene', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('expression', 'MPA', (20, 30))	('circRHOT1', 'Var', (133, 142))	('promoted', 'PosReg', (143, 151))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('tumors', 'Disease', (177, 183))	('hepatocellular carcinoma', 'Disease', (82, 106))
800484	33663506	Research on the pathogenetic and metastatic factor of colon cancer (CC) indicated that circPPP1R12A had a promoting effect and could be a therapeutic target for CC.	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('colon cancer', 'Disease', (54, 66))	('circPPP1R12A', 'Var', (87, 99))	('promoting', 'PosReg', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
800486	33663506	It was found that Hsa_circ_0000337, hsa_circ_0067934 and ciRS-7 were significantly upregulated in ESCC tissues, and may promote tumor cell proliferation, migration and invasion, suggesting that these circRNAs may become potential therapeutic targets for ESCC.	('hsa_circ_0067934', 'Var', (36, 52))	('ciRS-7', 'Gene', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Hsa_circ_0000337', 'Var', (18, 34))	('promote', 'PosReg', (120, 127))	('ESCC', 'Disease', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ciRS-7', 'Gene', '103611090', (57, 63))	('upregulated', 'PosReg', (83, 94))	('tumor', 'Disease', (128, 133))	('invasion', 'CPA', (168, 176))	('migration', 'CPA', (154, 163))
800543	32462769	For either cN0 or cN1-3, Charlson-Deyo Comorbidity Index did not differ among the treatment groups(all p > 0.05).	('Charlson-Deyo', 'Disease', (25, 38))	('cN1', 'Gene', (18, 21))	('cN1', 'Gene', '84618', (18, 21))	('cN0', 'Var', (11, 14))
800634	31976528	Accordingly, PARP inhibitors can induce synthetic lethality in cancer cells having weak HR repair abilities, such as BRCA-mutated cancers.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('PARP', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (130, 136))	('cancers', 'Disease', (130, 137))	('BRCA', 'Gene', (117, 121))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('BRCA', 'Gene', '672', (117, 121))	('synthetic lethality', 'CPA', (40, 59))	('PARP', 'Gene', '142', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('induce', 'PosReg', (33, 39))	('inhibitors', 'Var', (18, 28))	('cancer', 'Disease', (63, 69))
800635	31976528	Recently, PARP inhibitors have been shown to exhibit high radiosensitizing effects in prostate cancer, pancreatic cancer and breast cancer cell lines.	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('pancreatic cancer', 'Disease', (103, 120))	('PARP', 'Gene', (10, 14))	('breast cancer', 'Disease', (125, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('radiosensitizing', 'MPA', (58, 74))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', (86, 101))	('PARP', 'Gene', '142', (10, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('inhibitors', 'Var', (15, 25))
800641	31976528	In a TCGA dataset, we found that 8.2% have BRCA1 and BRCA2 mutations or copy number alterations and 1.5% of patients have PARP1 copy number alterations (see online supplementary Figure S1).	('BRCA1', 'Gene', (43, 48))	('BRCA2', 'Gene', (53, 58))	('copy number alterations', 'Var', (72, 95))	('copy number alterations', 'Var', (128, 151))	('BRCA2', 'Gene', '675', (53, 58))	('mutations', 'Var', (59, 68))	('BRCA1', 'Gene', '672', (43, 48))	('patients', 'Species', '9606', (108, 116))	('PARP1', 'Gene', '142', (122, 127))	('PARP1', 'Gene', (122, 127))
800642	31976528	Furthermore, the other genes, such as ATR and Rad 51, that are necessary to repair DNA damage by irradiation also have mutations or copy number alterations.	('Rad 51', 'Gene', '5888', (46, 52))	('ATR', 'Gene', '545', (38, 41))	('ATR', 'Gene', (38, 41))	('copy number alterations', 'Var', (132, 155))	('mutations', 'Var', (119, 128))	('Rad 51', 'Gene', (46, 52))
800674	31976528	In OE-21 cells, both CDDP and olaparib significantly enhanced the radiation-induced anti-tumor effect, whereas in KYSE-450 cells, which displayed more resistance to radiation, this effect was observed only with olaparib(Fig.	('olaparib', 'Chemical', 'MESH:C531550', (30, 38))	('CDDP', 'Var', (21, 25))	('CDDP', 'Chemical', '-', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('KYSE-450', 'CellLine', 'CVCL:1353', (114, 122))	('olaparib', 'Chemical', 'MESH:C531550', (211, 219))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('enhanced', 'PosReg', (53, 61))
800690	31976528	NHEJ is the primary pathway for repairing DNA damage caused by agents such as 5-FU and CDDP, suggesting that these cells are resistant to general DNA damage.	('CDDP', 'Chemical', '-', (87, 91))	('5-FU', 'Var', (78, 82))	('CDDP', 'Var', (87, 91))	('5-FU', 'Chemical', 'MESH:D005472', (78, 82))
800702	31976528	However, a recent report suggests that a mutation of the Rev7 gene reduces NHEJ activity and stimulates HR.	('Rev7', 'Gene', '10459', (57, 61))	('NHEJ activity', 'MPA', (75, 88))	('mutation', 'Var', (41, 49))	('Rev7', 'Gene', (57, 61))	('reduces', 'NegReg', (67, 74))	('stimulates', 'PosReg', (93, 103))
800710	31976528	However, we believe that there was a high possibility that DNA damage was increased in the olaparib-PT group compared with the olaparib-only group because the olaparib-PT group had lower colony-forming abilities and an increased expression of DNA repair genes.	('PT', 'Chemical', '-', (168, 170))	('PT', 'Chemical', '-', (100, 102))	('olaparib', 'Chemical', 'MESH:C531550', (127, 135))	('DNA repair genes', 'Gene', (243, 259))	('colony-forming abilities', 'CPA', (187, 211))	('lower', 'NegReg', (181, 186))	('olaparib-PT', 'Var', (159, 170))	('olaparib', 'Chemical', 'MESH:C531550', (159, 167))	('olaparib', 'Chemical', 'MESH:C531550', (91, 99))	('increased', 'PosReg', (219, 228))	('expression', 'MPA', (229, 239))
800722	31976528	Protons have been reported to cause more DSBs than photons.	('Protons', 'Var', (0, 7))	('DSBs', 'Disease', (41, 45))	('DSBs', 'Chemical', '-', (41, 45))
800727	31976528	Notably, clinical trials involving a combination of olaparib and radiation therapy have already been initiated for breast cancer, lung cancer and head and neck cancer (NCT02229656, NCT01562210 and NCT02227082, respectively).	('head and neck cancer', 'Disease', 'MESH:D006258', (146, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('NCT02229656', 'Var', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('olaparib', 'Chemical', 'MESH:C531550', (52, 60))	('head and neck cancer', 'Phenotype', 'HP:0012288', (146, 166))	('NCT01562210', 'Var', (181, 192))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('NCT02227082', 'Var', (197, 208))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('lung cancer', 'Disease', (130, 141))
800753	32235026	In a previous study, dietary fiber intake was associated with increased number of Firmicutes and decreased number of gram-negative bacteria.	('increased', 'PosReg', (62, 71))	('decreased', 'NegReg', (97, 106))	('dietary fiber', 'Var', (21, 34))	('Firmicutes', 'CPA', (82, 92))	('fiber', 'Chemical', 'MESH:D004043', (29, 34))
800754	32235026	Conversely, low fiber intake was associated with a high number of gram-negative bacteria, including Prevotella, Neisseria, and Eikenella.	('Eikenella', 'Disease', (127, 136))	('fiber', 'Chemical', 'MESH:D004043', (16, 21))	('Neisseria', 'Disease', (112, 121))	('Neisseria', 'Disease', 'MESH:D006069', (112, 121))	('low fiber', 'Var', (12, 21))	('Prevotella', 'Species', '425941', (100, 110))	('Prevotella', 'Disease', (100, 110))	('gram-negative bacteria', 'MPA', (66, 88))
800757	32235026	The impact of low fiber intake is similar to that of reflux esophagitis or Barrett's esophagus on the esophageal microbiome composition, which will be described in the next section.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (75, 94))	('reflux esophagitis', 'Disease', 'MESH:D005764', (53, 71))	('reflux esophagitis', 'Disease', (53, 71))	('low fiber', 'Var', (14, 23))	('fiber', 'Chemical', 'MESH:D004043', (18, 23))	('esophagitis', 'Phenotype', 'HP:0100633', (60, 71))
800789	32235026	In the previous studies, intratumoral F. nucleatum was associated with poor recurrence-free survival as well as cancer-specific survival in patients with esophageal cancer.	('intratumoral', 'Var', (25, 37))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('poor', 'NegReg', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('F. nucleatum', 'Species', '851', (38, 50))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('recurrence-free survival', 'CPA', (76, 100))
800810	31691514	For instance, Lan et al described that the inhibition of NUAK1 by MIR-145a-5p could inhibit the AKT pathway and reduce nasopharyngeal tumor cell invasion.	('AKT', 'Gene', (96, 99))	('inhibition', 'NegReg', (43, 53))	('reduce', 'NegReg', (112, 118))	('NUAK1', 'Gene', '9891', (57, 62))	('MIR-145a-5p', 'Var', (66, 77))	('inhibit', 'NegReg', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('MIR-145a-5p', 'Chemical', '-', (66, 77))	('AKT', 'Gene', '207', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('nasopharyngeal tumor', 'Phenotype', 'HP:0100630', (119, 139))	('NUAK1', 'Gene', (57, 62))	('tumor', 'Disease', (134, 139))
800833	31691514	Additionally, GALNT1 was the direct target gene of MIR216B, and SNHG7 could act as a ceRNA to sponge MIR216B, and rescue GALNT1 to facilitate colon cancer cell invasion.	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('MIR216B', 'Gene', (101, 108))	('colon cancer', 'Disease', (142, 154))	('MIR216B', 'Gene', '100126319', (101, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('rescue', 'Var', (114, 120))	('facilitate', 'PosReg', (131, 141))	('GALNT1', 'Gene', '2589', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('GALNT1', 'Gene', '2589', (14, 20))	('MIR216B', 'Gene', '100126319', (51, 58))	('GALNT1', 'Gene', (121, 127))	('SNHG7', 'Gene', '84973', (64, 69))	('MIR216B', 'Gene', (51, 58))	('GALNT1', 'Gene', (14, 20))	('SNHG7', 'Gene', (64, 69))
800836	31691514	Knocking down the expression of SNHG1 could reduce the tumor size and suppress cell proliferation and colony formation.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Knocking down', 'Var', (0, 13))	('reduce', 'NegReg', (44, 50))	('suppress', 'NegReg', (70, 78))	('cell proliferation', 'CPA', (79, 97))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SNHG1', 'Gene', '23642', (32, 37))	('tumor', 'Disease', (55, 60))	('colony formation', 'CPA', (102, 118))	('SNHG1', 'Gene', (32, 37))
800843	31691514	It participated in both transcriptional and posttranscriptional regulation.70, 71 In the cytoplasm, SNHG6 could suppress MIR-101-3p, upregulate ZEB1 and CDH2, and accelerate EMT progression.70 In the nucleus, SNHG6 could recruit EZH2 to the promoter of CDKN1B to play the transcriptional regulatory role.70 In another study, downregulation of SNHG6 could augment the phosphorylation level of MAPK1, MAPK8 and MAPK14, while increasing the expression of TP53 and decreasing the expression of EZH2.	('TP53', 'Gene', (452, 456))	('MAPK1', 'Gene', (409, 414))	('SNHG6', 'Gene', (100, 105))	('MAPK8', 'Gene', '5599', (399, 404))	('MAPK1', 'Gene', (392, 397))	('SNHG6', 'Gene', '641638', (343, 348))	('expression', 'MPA', (438, 448))	('CDH2', 'Gene', (153, 157))	('phosphorylation level', 'MPA', (367, 388))	('SNHG6', 'Gene', (209, 214))	('CDKN1B', 'Gene', '1027', (253, 259))	('ZEB1', 'Gene', '6935', (144, 148))	('TP53', 'Gene', '7157', (452, 456))	('EZH2', 'Gene', (229, 233))	('EZH2', 'Gene', '2146', (229, 233))	('expression', 'MPA', (476, 486))	('downregulation', 'Var', (325, 339))	('SNHG6', 'Gene', (343, 348))	('CDH2', 'Gene', '1000', (153, 157))	('MAPK14', 'Gene', (409, 415))	('MAPK8', 'Gene', (399, 404))	('augment', 'PosReg', (355, 362))	('MAPK14', 'Gene', '1432', (409, 415))	('decreasing', 'NegReg', (461, 471))	('MAPK1', 'Gene', '5594', (409, 414))	('MAPK1', 'Gene', '5594', (392, 397))	('EZH2', 'Gene', '2146', (490, 494))	('SNHG6', 'Gene', '641638', (100, 105))	('EZH2', 'Gene', (490, 494))	('increasing', 'PosReg', (423, 433))	('SNHG6', 'Gene', '641638', (209, 214))	('ZEB1', 'Gene', (144, 148))	('CDKN1B', 'Gene', (253, 259))
800870	31691514	It has been shown that the irregular expression status of SNHGs is significantly related to digestive tumors stage, metastasis, infiltration, and poor prognosis in cancers.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('related', 'Reg', (81, 88))	('infiltration', 'Disease', (128, 140))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('digestive tumors', 'Phenotype', 'HP:0007378', (92, 108))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('metastasis', 'CPA', (116, 126))	('irregular', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('SNHGs', 'Gene', (58, 63))
800878	31571988	In ESCC cells, inhibition of 12-LOX caused a decrease in transforming growth factor-beta1 (TGF-beta1)-mediated epithelial-mesenchymal transition (EMT) level, and abilities of migration and invasion were also inhibited.	('transforming growth factor-beta1', 'Gene', '7040', (57, 89))	('inhibited', 'NegReg', (208, 217))	('ESCC', 'Disease', 'MESH:C562729', (3, 7))	('ESCC', 'Disease', (3, 7))	('transforming growth factor-beta1', 'Gene', (57, 89))	('decrease', 'NegReg', (45, 53))	('12-LOX', 'Gene', (29, 35))	('TGF-beta1', 'Gene', '7040', (91, 100))	('inhibition', 'Var', (15, 25))	('TGF-beta1', 'Gene', (91, 100))	('12-LOX', 'Gene', '239', (29, 35))
800938	31571988	The left panel indicated that when the expression of 12-LOX was deregulated, the levels of TGF-beta1 and EMT were also inhibited, and the inhibition was relieved when 12(S)-HETE was added.	('deregulated', 'Var', (64, 75))	('12-LOX', 'Gene', '239', (53, 59))	('levels of', 'MPA', (81, 90))	('inhibited', 'NegReg', (119, 128))	('EMT', 'CPA', (105, 108))	('TGF-beta1', 'Gene', (91, 100))	('expression', 'MPA', (39, 49))	('TGF-beta1', 'Gene', '7040', (91, 100))	('12-LOX', 'Gene', (53, 59))	('12(S)-HETE', 'Chemical', 'MESH:D019377', (167, 177))
801028	29744386	Blood gas analysis performed just before the end of surgery showed pH of 7.41, PCO2 of 41 mm Hg, and PO2 of 119 mm Hg at FiO2 0.5.	('PCO2', 'MPA', (79, 83))	('PO2', 'Var', (101, 104))	('PO2', 'Chemical', 'MESH:C093415', (101, 104))	('FiO2', 'Chemical', '-', (121, 125))	('PCO2', 'Chemical', '-', (79, 83))
801052	29112883	The loss of esophageal surface cells also was assumed to stimulate hyperplasia of progenitor cells in the basal layer of the squamous epithelium, which is a characteristic histologic feature of gastroesophageal reflux disease (GERD).	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (194, 225))	('hyperplasia', 'Disease', (67, 78))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (194, 217))	('GERD', 'Disease', (227, 231))	('GERD', 'Disease', 'MESH:D005764', (227, 231))	('hyperplasia', 'Disease', 'MESH:D006965', (67, 78))	('gastroesophageal reflux disease', 'Disease', (194, 225))	('loss', 'Var', (4, 8))
801070	29112883	Based on these observations, the investigators hypothesized that refluxed acid and bile salts cause esophageal squamous epithelial cells to produce ROS that inactivate PHDs, enabling HIFs to accumulate and to stimulate the production of pro-inflammatory molecules.	('inactivate', 'Var', (157, 167))	('bile salts', 'Chemical', 'MESH:D001647', (83, 93))	('stimulate', 'PosReg', (209, 218))	('production of pro-inflammatory molecules', 'MPA', (223, 263))	('PHDs', 'Gene', (168, 172))	('esophageal squamous epithelial', 'Disease', 'MESH:D000077277', (100, 130))	('ROS', 'Chemical', 'MESH:D017382', (148, 151))	('accumulate', 'PosReg', (191, 201))	('esophageal squamous epithelial', 'Disease', (100, 130))	('refluxed acid', 'Phenotype', 'HP:0002020', (65, 78))	('enabling', 'PosReg', (174, 182))
801079	29112883	Small molecule inhibition of the HIF family of transcription factors is recognized as a potentially valuable therapeutic approach to treat HIF-dependent diseases.	('inhibition', 'NegReg', (15, 25))	('HIF-dependent diseases', 'Disease', 'MESH:D000437', (139, 161))	('HIF-dependent diseases', 'Disease', (139, 161))	('Small molecule', 'Var', (0, 14))
801084	29112883	Diversification of 1 to a variety of HIF-2alpha antagonists focused on three major regions: (1) modification of the left-hand A-ring portion characterized by a nitro-bearing oxadiazole, (2) variation of the central heteroatom-containing linker, and (3) diversification of the right hand aromatic B-ring region.	('HIF-2alpha', 'Gene', (37, 47))	('HIF-2alpha', 'Gene', '2034', (37, 47))	('variation', 'Var', (190, 199))	('nitro', 'Chemical', '-', (160, 165))	('oxadiazole', 'Chemical', 'MESH:D010069', (174, 184))
801088	29112883	While these conformational changes perturb interactions mediated through the beta-sheet observed between isolated PAS domains, additional effects on residues residing on the opposing face of the domain may interfere with key dimer contacts observed in structures of the complete HIF heterdimerization units.	('dimer contacts', 'MPA', (225, 239))	('interactions', 'Interaction', (43, 55))	('PAS', 'Chemical', '-', (114, 117))	('beta-sheet', 'Protein', (77, 87))	('perturb', 'Reg', (35, 42))	('opposing face', 'Phenotype', 'HP:0000324', (174, 187))	('changes', 'Var', (27, 34))	('interfere', 'NegReg', (206, 215))
801104	29112883	These efforts have led to the successful development of well-tolerated HIF-2alpha inhibitors capable of selectively antagonizing HIF-2alpha in vivo in preclinical animal models.	('antagonizing', 'NegReg', (116, 128))	('HIF-2alpha', 'Gene', (71, 81))	('inhibitors', 'Var', (82, 92))	('HIF-2alpha', 'Gene', (129, 139))	('HIF-2alpha', 'Gene', '2034', (71, 81))	('HIF-2alpha', 'Gene', '2034', (129, 139))	('rat', 'Species', '10116', (65, 68))
801105	29112883	Clinical trials of these inhibitors for the treatment of HIF-2alpha driven kidney cancers are ongoing (ClinicalTrials.gov Identifiers: NCT02553356, NCT02293980, NCT03108066, and NCT02974738).	('NCT02974738', 'Var', (178, 189))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('NCT02293980', 'Var', (148, 159))	('kidney cancers', 'Phenotype', 'HP:0009726', (75, 89))	('HIF-2alpha driven kidney cancers', 'Disease', 'MESH:D007680', (57, 89))	('HIF-2alpha driven kidney cancers', 'Disease', (57, 89))	('NCT03108066', 'Var', (161, 172))	('NCT02553356', 'Var', (135, 146))
801125	28109569	Adherence to recommended quality measures is independently associated with improved overall survival in both early and locally advanced stages of esophageal cancer.	('improved', 'PosReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Adherence', 'Var', (0, 9))	('esophageal cancer', 'Disease', (146, 163))	('overall survival', 'MPA', (84, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))
801130	28109569	If a suboptimal esophagectomy is performed, this may result in incomplete resection of disease and allow an aggressive disease to continue to progress, all while exposing the patient to the risk of morbidity and mortality inherent with this surgery.	('aggressive disease', 'Disease', (108, 126))	('patient', 'Species', '9606', (175, 182))	('suboptimal', 'Var', (5, 15))	('incomplete', 'NegReg', (63, 73))	('aggressive disease', 'Disease', 'MESH:D001523', (108, 126))
801134	28109569	The NCDB Participant User File for esophageal cancer was reviewed identify early stage patients (T0-T1N0, or T2N0 if well-differentiated with tumor size <2cm) or locally advanced patients (Stage IIB-StageIIIB).	('T0-T1N0', 'Var', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('esophageal cancer', 'Disease', (35, 52))	('T2N0', 'Var', (109, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('patients', 'Species', '9606', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('Participant', 'Species', '9606', (9, 20))
801143	28109569	From 1998 to 2012, 16,040 early stage esophageal cancer patients (T0-T1N0 or T2N0 if well-differentiated and tumor size <2cm) were identified, of which 4,908 (30.6%) received an esophagectomy.	('patients', 'Species', '9606', (56, 64))	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('T0-T1N0', 'Var', (66, 73))	('T2N0', 'Var', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
801211	27105522	As two major markers of systemic chronic inflammation, the combination of ALB and GLB have showed potential predictive effect on survival among several malignancies.	('combination', 'Var', (59, 70))	('systemic chronic inflammation', 'Disease', 'MESH:D007249', (24, 53))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('malignancies', 'Disease', (152, 164))	('ALB', 'Gene', '213', (74, 77))	('systemic chronic inflammation', 'Disease', (24, 53))	('ALB', 'Gene', (74, 77))	('GLB', 'Gene', (82, 85))
801214	27105522	Furthermore, multivariate COX regression model revealed that AGS was a significant independent predictor for the long-term survival in ESCC patients.	('ESCC', 'Disease', (135, 139))	('AGS', 'Var', (61, 64))	('patients', 'Species', '9606', (140, 148))
801252	27280381	Zn deficiency promotes ESCC by inducing an inflammatory gene signature with up-regulation of cancer-associated inflammation genes & an oncogenic microRNA (miRNA) signature featuring up-regulation of oncogenic miR-31.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('inducing', 'Reg', (31, 39))	('up-regulation', 'PosReg', (76, 89))	('inflammation', 'Disease', (111, 123))	('ESCC', 'Disease', (23, 27))	('an oncogenic microRNA', 'MPA', (132, 153))	('miR-31', 'Gene', '100314232', (209, 215))	('inflammatory gene signature', 'MPA', (43, 70))	('inflammation', 'Disease', 'MESH:D007249', (111, 123))	('deficiency', 'Var', (3, 13))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Zn', 'Chemical', 'MESH:D015032', (0, 2))	('miR-31', 'Gene', (209, 215))
801266	27280381	In addition, Fbxw7, Pdcd4, and Stk40 (tumor-suppressor targets of miR-223, miR-21 and miR-31, respectively) were down-regulated in the markedly deficient cohort at the mRNA and protein level and they were predicted to interact to alter network of target proteins in cancer pathways.	('down-regulated', 'NegReg', (113, 127))	('Pdcd4', 'Gene', (20, 25))	('Pdcd4', 'Gene', '64031', (20, 25))	('Fbxw7', 'Gene', '100360914', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('miR-31', 'Gene', (86, 92))	('miR-31', 'Gene', '100314232', (86, 92))	('alter', 'Reg', (230, 235))	('miR-21', 'Gene', '100314000', (75, 81))	('Stk40', 'Gene', '360230', (31, 36))	('miR-21', 'Gene', (75, 81))	('tumor', 'Disease', (38, 43))	('network of', 'Pathway', (236, 246))	('Fbxw7', 'Gene', (13, 18))	('proteins', 'Protein', (254, 262))	('interact', 'Reg', (218, 226))	('cancer', 'Disease', (266, 272))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('Stk40', 'Gene', (31, 36))	('miR-223', 'Var', (66, 73))
801267	27280381	The data are in accord with the finding that miR-223, miR-21 and miR-31 expression levels play important roles in ESCC and may be useful prognostic biomarkers and therapeutic targets for ESCC.	('ESCC', 'Disease', (114, 118))	('miR-31', 'Gene', '100314232', (65, 71))	('roles', 'Reg', (105, 110))	('miR-31', 'Gene', (65, 71))	('expression', 'MPA', (72, 82))	('miR-21', 'Gene', '100314000', (54, 60))	('miR-21', 'Gene', (54, 60))	('miR-223', 'Var', (45, 52))
801390	25999024	The knockdown of BMI1 by siRNA showed the same phenocopy as the effect of miR-218 on ESCC cells, indicating that BMI1 was a major target of miR-218.	('miR', 'Gene', (74, 77))	('miR', 'Gene', '220972', (74, 77))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('BMI1', 'Gene', (17, 21))	('knockdown', 'Var', (4, 13))
801397	25999024	MicroRNAs (miRNAs or miRs) are a recently discovered class of short non-coding RNAs, approximately 18-24 nucleotides in length, which bind to the 3'-untranslated regions (3'-UTRs) of target mRNAs mainly through complementary base pairing in their mature form, leading to target mRNA degradation or the inhibition of protein synthesis, consequently regulating gene expression at the post-transcriptional level.	('regulating', 'Reg', (348, 358))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('complementary base pairing', 'Var', (211, 237))	('gene expression', 'MPA', (359, 374))	('inhibition', 'NegReg', (302, 312))	('protein synthesis', 'MPA', (316, 333))
801399	25999024	Furthermore, it has been demonstrated that the abnormal expression of miRNAs is associated with the development and progression of cancer and has prognostic significance for ESCC.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('ESCC', 'Disease', (174, 178))	('expression', 'MPA', (56, 66))	('associated', 'Reg', (80, 90))	('abnormal', 'Var', (47, 55))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('significance', 'Reg', (157, 169))
801416	25999024	Subsequently, the EC109 cells were plated in a 24-well plate and co-transfected with 50 ng of psiCHECK-2-BMI1-3'-UTR-wild type or psiCHECK-2-BMI1-3'-UTR-mutant type and with 20 nM of either miR-218 mimics (5'-UUGUGCUUGAUCUAACCAUGU-3') or the miR negative control (miR-NC).	('EC109', 'CellLine', 'CVCL:6898', (18, 23))	("5'-UUGUGCUUGAUCUAACCAUGU-3'", 'Var', (206, 233))	('miR', 'Gene', '220972', (264, 267))	('miR', 'Gene', (264, 267))	('miR', 'Gene', '220972', (242, 245))	('miR', 'Gene', (242, 245))	('miR', 'Gene', (190, 193))	('miR', 'Gene', '220972', (190, 193))
801431	25999024	A total of 400 EC109 cells were seeded in a dish with a diameter of 6 cm and transfected with miR-218 mimics, anti-miR-218 or the negative control(NC), using Lipofectamine 2000 (Life Technologies).	('mimics', 'Var', (102, 108))	('EC109', 'CellLine', 'CVCL:6898', (15, 20))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (158, 176))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))	('miR', 'Gene', '220972', (115, 118))	('miR', 'Gene', (115, 118))
801479	25999024	We first investigated the protein expression of BMI1 in ESCC cells by western blot analysis, and found that the protein expression of BMI1 was decreased by the restoration of miR-218 expression (Fig.	('decreased', 'NegReg', (143, 152))	('miR', 'Gene', '220972', (175, 178))	('BMI1', 'Gene', (134, 138))	('miR', 'Gene', (175, 178))	('restoration', 'Var', (160, 171))	('expression', 'MPA', (183, 193))	('protein expression', 'MPA', (112, 130))
801481	25999024	In order to confirm that miR-218 regulates the expression of BMI1 by directly binding to the putative binding sites in its 3'-UTR, we constructed a luciferase reporter plasmid containing the full-length wild-type BMI1 3'-UTR and mutant-type BMI1 3'-UTR that had 4 point mutations predicted to disrupt miR-218 binding in each of the seed match regions (Fig.	('binding', 'Interaction', (78, 85))	('miR', 'Gene', '220972', (301, 304))	('BMI1', 'Gene', (241, 245))	('binding', 'Interaction', (309, 316))	('mutations', 'Var', (270, 279))	('disrupt', 'NegReg', (293, 300))	('miR', 'Gene', (25, 28))	('BMI1', 'Gene', (61, 65))	('mutant-type', 'Var', (229, 240))	('miR', 'Gene', '220972', (25, 28))	('BMI1', 'Gene', (213, 217))	('miR', 'Gene', (301, 304))
801488	25999024	To explore the effects of BMI1 on ESCC, we used BMI1-siRNA to knockdown BMI1 expression in the EC109 cells.	('BMI1', 'Gene', (72, 76))	('EC109', 'CellLine', 'CVCL:6898', (95, 100))	('knockdown', 'Var', (62, 71))
801490	25999024	MTT assay revealed that the growth rate of EC109 cells transfected with BMI1-siRNA was significantly lower than that of the siRNA-control-transfected cells (Fig.	('BMI1-siRNA', 'Var', (72, 82))	('growth rate', 'CPA', (28, 39))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('lower', 'NegReg', (101, 106))	('EC109', 'CellLine', 'CVCL:6898', (43, 48))
801492	25999024	EdU assay revealed that cell number was significantly reduced in the BMI1-siRNA-transfected EC109 cells (Fig.	('cell number', 'CPA', (24, 35))	('reduced', 'NegReg', (54, 61))	('EC109', 'CellLine', 'CVCL:6898', (92, 97))	('EdU', 'Chemical', 'MESH:C031086', (0, 3))	('BMI1-siRNA-transfected', 'Var', (69, 91))
801493	25999024	The number of apoptotic cells were significantly increased in the BMI1-siRNA-transfected EC109 cells compared with the siRNA-control-transfected cells (Fig.	('increased', 'PosReg', (49, 58))	('BMI1-siRNA-transfected', 'Var', (66, 88))	('EC109', 'CellLine', 'CVCL:6898', (89, 94))
801500	25999024	These results suggested that the overexpression of BMI1 reversed the effects of the aberrant expression of miR-218 on the phenotype of ESCC cells.	('miR', 'Gene', (107, 110))	('ESCC', 'Disease', (135, 139))	('aberrant', 'Var', (84, 92))	('miR', 'Gene', '220972', (107, 110))
801503	25999024	Moreover, we demonstrated that miR-218 negatively regulated BMI1 expression in ESCC cells, suggesting an important role for miR-218 dysregulation in tumorigenesis and the metastasis of ESCC cells.	('BMI1', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('negatively', 'NegReg', (39, 49))	('expression', 'MPA', (65, 75))	('tumor', 'Disease', (149, 154))	('metastasis', 'CPA', (171, 181))	('miR', 'Gene', '220972', (124, 127))	('miR', 'Gene', (124, 127))	('dysregulation', 'Var', (132, 145))
801509	25999024	We then investigated whether the dysregulation of miR-218 is responsible for ESCC cell growth.	('ESCC cell', 'Disease', (77, 86))	('miR', 'Gene', '220972', (50, 53))	('dysregulation', 'Var', (33, 46))	('miR', 'Gene', (50, 53))
801517	25999024	The aberrant expression of BMI1 is involved in cell proliferation, epithelial-mesenchymal transition (EMT), tumor invasion and metastasis in many types of cancer.	('cell proliferation', 'CPA', (47, 65))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('involved', 'Reg', (35, 43))	('tumor', 'Disease', (108, 113))	('aberrant expression', 'Var', (4, 23))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('BMI1', 'Gene', (27, 31))	('cancer', 'Disease', (155, 161))	('metastasis', 'CPA', (127, 137))	('epithelial-mesenchymal transition', 'CPA', (67, 100))
801604	17597535	of Michigan) were grown at 5% CO2 in DMEM supplemented with 4.5 g/L glucose, and L-glutamine (Cellgro, Mediatech, Inc., Herndon, VA), penicillin (100 U/ml), streptomycin (100 U/ml), and 10% fetal bovine serum.	('bovine', 'Species', '9913', (196, 202))	('100 U/ml', 'Var', (171, 179))	('penicillin', 'Chemical', 'MESH:D010406', (134, 144))	('CO2', 'Chemical', '-', (30, 33))	('streptomycin', 'Chemical', 'MESH:D013307', (157, 169))	('100 U/ml', 'Var', (146, 154))
801610	17597535	Exposure to bile salts was achieved through incubation of the cell lines or tissue explants for 1 hour in a mixture of conjugated bile salts designed to resemble what is found in vivo, and consisted of 0.54 mM sodium glycocholate (C26H42NO6Na), 0.1 mM sodium taurocholate (C26H44NO7SNa), 0.2 mM glycocholic acid (C26H43NO6), and 0.1 mM sodium taurochenodeoxycholate (C26H44NNaO6S) at pH 7.4.	('C26H44NNaO6S', 'Var', (367, 379))	('C26H42NO6Na', 'CellLine', 'CVCL:U766', (231, 242))	('C26H44NO7SNa', 'Var', (273, 285))	('C26H43NO6', 'Var', (313, 322))	('C26H44NO7SNa', 'CellLine', 'CVCL:Z204', (273, 285))	('bile salts', 'Chemical', 'MESH:D001647', (12, 22))	('bile salts', 'Chemical', 'MESH:D001647', (130, 140))	('C26H42NO6Na', 'Var', (231, 242))
801656	33836789	Although there were no significant survival differences among non-pCR ESCC patients with pT0N+, pT+N0, or pT+N+, survival rate among pT+N+patients was the poorest.	('pT+N', 'Gene', (133, 137))	('pT0N+', 'Chemical', '-', (89, 94))	('pT+N', 'Gene', (106, 110))	('pT0N+', 'Var', (89, 94))	('pT+N', 'Gene', '5764', (96, 100))	('pT+N', 'Gene', (96, 100))	('patients', 'Species', '9606', (75, 83))	('pT+N', 'Gene', '5764', (133, 137))	('pT+N', 'Gene', '5764', (106, 110))	('patients', 'Species', '9606', (138, 146))
801682	33836789	Low-dose CT images were acquired using a 16-detector row scanner with the following parameters: 120 kV, auto mA (noise index 25.0), 0.6 s tube rotation, 3.75-mm section thickness, 512x512 matrix, and 70-cm field of view.	('512x512', 'Var', (180, 187))	('tube rotation', 'Disease', 'MESH:D009069', (138, 151))	('tube rotation', 'Disease', (138, 151))
801713	33836789	In the present study, we demonstrated that there was no significant survival difference among patients with ESCC categorized as pT0N+, pT+N0, or pT+N+ after treatment consisting of NACRT plus esophagectomy.	('NACRT', 'Chemical', '-', (181, 186))	('patients', 'Species', '9606', (94, 102))	('pT+N', 'Gene', '5764', (145, 149))	('pT+N', 'Gene', '5764', (135, 139))	('pT0N+', 'Chemical', '-', (128, 133))	('pT+N', 'Gene', (145, 149))	('pT0N+', 'Var', (128, 133))	('pT+N', 'Gene', (135, 139))	('ESCC', 'Disease', (108, 112))
801723	33836789	We therefore expected that patients with pT0N+ and, especially, pT+N0 would have better prognoses than those with pT+N+; however, no difference was found in their prognoses.	('better', 'PosReg', (81, 87))	('pT+N', 'Gene', (64, 68))	('pT0N+', 'Chemical', '-', (41, 46))	('pT0N+', 'Var', (41, 46))	('patients', 'Species', '9606', (27, 35))	('pT+N', 'Gene', '5764', (114, 118))	('pT+N', 'Gene', '5764', (64, 68))	('pT+N', 'Gene', (114, 118))
801751	32841543	PFS rates after 1, 3, and 5 years were 58.9%, 34.2%, and 26.9%, respectively, in the ENI arm compared to 64.4%, 30.8%, and 27.7%, respectively, in the IFI arm.	('IFI', 'Chemical', '-', (151, 154))	('ENI', 'Chemical', '-', (85, 88))	('PFS', 'Disease', (0, 3))	('ENI', 'Var', (85, 88))
801772	32841543	We recruited patients to the study and assessed their eligibility based on the following conditions: (1) inoperable, histologically verified, Stage II-III thoracic ESCC; (2) Karnofsky performance status (KPS) >=70; (3) age of 18-75 years; (4) adequate hematological, renal, hepatic, and pulmonary function (defined as a platelets >=100 000 cells/mm3, neutrophils >=1500 cells/mm3, hemoglobin >=9.0 g/dL, serum creatinine <=2.0 mg/dL, bilirubin <= 1.5 x the normal upper level at the institution and transaminase <= 3 x the normal upper level).	('>=70', 'Var', (209, 213))	('transaminase', 'MPA', (499, 511))	('serum creatinine', 'MPA', (404, 420))	('patients', 'Species', '9606', (13, 21))	('age', 'Gene', (219, 222))	('age', 'Gene', (144, 147))	('bilirubin', 'MPA', (434, 443))	('creatinine', 'Chemical', 'MESH:D003404', (410, 420))	('age', 'Gene', '5973', (219, 222))	('age', 'Gene', '5973', (144, 147))	('<=2.0', 'Var', (421, 426))
801790	32841543	Vulnerable organs were limited to the following doses: average heart dose, <=30.0 Gy, average lung dose, <=15.0 Gy; V05, V20, and V30, <=60.0, <=30.0, and <=20.0%, respectively, and maximum spinal cord dose, <=45.0 Gy.	('<=30.0', 'Var', (143, 149))	('<=60.0', 'Var', (135, 141))	('age', 'Gene', (59, 62))	('age', 'Gene', (90, 93))	('<=30.0', 'Var', (75, 81))	('age', 'Gene', '5973', (59, 62))	('age', 'Gene', '5973', (90, 93))
801821	32841543	In our primary results, we found that the incidences of grade >=2 treatment-related esophagitis and grade >=2 acute treatment-related pneumonitis were significantly lower in the IFI arm than in the ENI arm.	('IFI', 'Var', (178, 181))	('pneumonitis', 'Disease', 'MESH:D011014', (134, 145))	('lower', 'NegReg', (165, 170))	('men', 'Species', '9606', (121, 124))	('esophagitis', 'Disease', 'MESH:D004938', (84, 95))	('IFI', 'Chemical', '-', (178, 181))	('men', 'Species', '9606', (71, 74))	('pneumonitis', 'Disease', (134, 145))	('ENI', 'Chemical', '-', (198, 201))	('esophagitis', 'Phenotype', 'HP:0100633', (84, 95))	('esophagitis', 'Disease', (84, 95))
801822	32841543	Our findings demonstrated that IFI could reduce acute treatment-related esophagitis and pneumonitis, which were confirmed by other published studies.	('IFI', 'Var', (31, 34))	('esophagitis', 'Phenotype', 'HP:0100633', (72, 83))	('reduce', 'NegReg', (41, 47))	('IFI', 'Chemical', '-', (31, 34))	('esophagitis and pneumonitis', 'Disease', 'MESH:D011014', (72, 99))	('men', 'Species', '9606', (59, 62))
801824	32841543	A retrospective study using a propensity score matching method found that ENI is superior to IFI in improving OS in patients with ESCC.	('improving', 'PosReg', (100, 109))	('ESCC', 'Disease', (130, 134))	('patients', 'Species', '9606', (116, 124))	('ENI', 'Chemical', '-', (74, 77))	('IFI', 'Chemical', '-', (93, 96))	('ENI', 'Var', (74, 77))
801879	32382698	For cancers like BL (9687/3), HL (9650/3), NHL (9596/3), adult T-cell leukemia (9827/3), KS (9140/3), acute leukemia (9835/3 & 9861/3), chronic leukemia (9863/3 & 9823/3) and multiple myeloma (9732/3) where ICD-0-3 topographical code was not clear, we converted the IDC-0-3 morphological code to ICD10 topographical code for clarity.	('9827/3', 'Var', (80, 86))	('acute leukemia', 'Phenotype', 'HP:0002488', (102, 116))	('multiple myeloma', 'Phenotype', 'HP:0006775', (175, 191))	('adult T-cell leukemia', 'Disease', 'MESH:D015459', (57, 78))	('leukemia', 'Phenotype', 'HP:0001909', (144, 152))	('myeloma', 'Disease', (184, 191))	('chronic leukemia', 'Phenotype', 'HP:0005558', (136, 152))	('adult T-cell leukemia', 'Disease', (57, 78))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('myeloma', 'Disease', 'MESH:D009101', (184, 191))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('acute leukemia', 'Disease', 'MESH:D015470', (102, 116))	('acute leukemia', 'Disease', (102, 116))	('9835/3 & 9861/3', 'Var', (118, 133))
801880	32382698	Although many studies have shown a variety of cancers associated with infectious agents, the attributable fraction (AF) standard formula was applied to a group of cancers classified as carcinogenic in the IARC monograph 100b  namely; cervix (C53), liver (C22.0), stomach (C16), Kaposi's sarcoma (C46), non-Hodgkin's lymphoma (C82-85, C96), Hodgkin's lymphoma (C81), nasopharynx (C11), oropharynx (C10), bladder (C67), vulva (C51), vagina (C52), penis (C60), anus (C21) and bile duct (C22.1).	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (302, 324))	('C10', 'Gene', '113246', (397, 400))	('C11', 'Gene', (379, 382))	('C51', 'Var', (425, 428))	('C10', 'Gene', (397, 400))	('C21', 'Gene', '79718', (464, 467))	('sarcoma', 'Phenotype', 'HP:0100242', (287, 294))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (278, 294))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (306, 324))	("Hodgkin's lymphoma", 'Disease', (340, 358))	('lymphoma', 'Phenotype', 'HP:0002665', (350, 358))	('C60', 'Var', (452, 455))	("non-Hodgkin's lymphoma", 'Disease', (302, 324))	('C11', 'Gene', '1109', (379, 382))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('C53', 'Gene', '80279', (242, 245))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('C82', 'Gene', (326, 329))	('lymphoma', 'Phenotype', 'HP:0002665', (316, 324))	('AF', 'Disease', 'MESH:D001281', (116, 118))	('C67', 'Var', (412, 415))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('C82', 'Gene', '732', (326, 329))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('C21', 'Gene', (464, 467))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (340, 358))	('C53', 'Gene', (242, 245))
802046	30416311	For instance, in cells that provoke hyperacetylation of histones, due to HDAC repression, chromatin is less condensed and favors an increased access of transcription factors to the DNA sequence promoter regions, increasing expression of many genes, that may potentially include oncogenes, leading to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('HDAC', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('genes', 'Gene', (242, 247))	('HDAC', 'Gene', '9734', (73, 77))	('tumor', 'Disease', (300, 305))	('expression', 'MPA', (223, 233))	('increased', 'PosReg', (132, 141))	('hyperacetylation', 'Var', (36, 52))	('increasing', 'PosReg', (212, 222))	('access', 'Interaction', (142, 148))
802047	30416311	On the other hand, in cells that favor hypoacetylation, through HDAC overexpression, there is an increase in cellular proliferation through proteins affecting the cell cycle.	('proteins', 'Protein', (140, 148))	('overexpression', 'PosReg', (69, 83))	('increase', 'PosReg', (97, 105))	('hypoacetylation', 'Var', (39, 54))	('cell cycle', 'CPA', (163, 173))	('cellular proliferation', 'CPA', (109, 131))	('HDAC', 'Gene', (64, 68))	('HDAC', 'Gene', '9734', (64, 68))	('affecting', 'Reg', (149, 158))
802052	30416311	Inhibiting histone deacetylation can cause changes in expression of many genes involved in cell differentiation, apoptosis, angiogenesis, motility, inflammation and metabolism.	('expression', 'MPA', (54, 64))	('inflammation', 'Disease', 'MESH:D007249', (148, 160))	('Inhibiting', 'Var', (0, 10))	('apoptosis', 'CPA', (113, 122))	('inflammation', 'Disease', (148, 160))	('motility', 'CPA', (138, 146))	('changes', 'Reg', (43, 50))	('histone', 'Protein', (11, 18))	('cell differentiation', 'CPA', (91, 111))	('angiogenesis', 'CPA', (124, 136))
802059	30416311	HDAC inhibitors can also induce apoptosis even when caspases enzymes are inhibited, showing the ability to accelerate cell death even in apoptosis-resistant cells, possibly through the activation of autophagy.	('HDAC', 'Gene', (0, 4))	('autophagy', 'CPA', (199, 208))	('HDAC', 'Gene', '9734', (0, 4))	('inhibitors', 'Var', (5, 15))	('accelerate', 'PosReg', (107, 117))	('cell death', 'CPA', (118, 128))
802064	30416311	To answer that, DNMT3B, a methyltransferase that abnormally methylates and suppresses tumor suppressor genes and LSD1, which has been implicated in sustaining cancer cell proliferation were assessed.	('cancer', 'Disease', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('methylates', 'Var', (60, 70))	('tumor', 'Disease', (86, 91))	('DNMT3B', 'Gene', (16, 22))	('suppresses', 'NegReg', (75, 85))	('DNMT3B', 'Gene', '1789', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('LSD1', 'Gene', (113, 117))	('LSD1', 'Gene', '23028', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
802069	30416311	HDAC6 activity, precisely, has been shown to increase macropinocytosis.	('HDAC6', 'Gene', '10013', (0, 5))	('HDAC6', 'Gene', (0, 5))	('activity', 'Var', (6, 14))	('macropinocytosis', 'MPA', (54, 70))	('increase', 'PosReg', (45, 53))
802070	30416311	Supporting the above information, HDAC6 inhibition led to a decrease in cellular migration and endocytosis, through actin remodeling processes, reducing the metastatic capacity of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('inhibition', 'Var', (40, 50))	('decrease', 'NegReg', (60, 68))	('reducing', 'NegReg', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('actin', 'MPA', (116, 121))	('cellular migration', 'CPA', (72, 90))	('endocytosis', 'MPA', (95, 106))	('HDAC6', 'Gene', '10013', (34, 39))	('HDAC6', 'Gene', (34, 39))	('tumor', 'Disease', (180, 185))
802076	30416311	Results from different clinical trials have shown that combination treatment of an HDAC inhibitor with chemotherapy regimens or ionizing radiation leads to an additive/synergistic effect, partly explained through hyper-acetylation mediated DNA relaxation and increased drug penetration.	('DNA relaxation', 'MPA', (240, 254))	('HDAC', 'Gene', (83, 87))	('HDAC', 'Gene', '9734', (83, 87))	('increased', 'PosReg', (259, 268))	('hyper-acetylation', 'Var', (213, 230))	('additive/synergistic', 'Interaction', (159, 179))	('drug penetration', 'CPA', (269, 285))
802077	30416311	Last but not least, HDAC inhibition increases reactive oxygen species (ROS), causing DNA and membrane damage in cancer cells.	('HDAC', 'Gene', (20, 24))	('HDAC', 'Gene', '9734', (20, 24))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (46, 69))	('DNA', 'Disease', (85, 88))	('membrane damage', 'CPA', (93, 108))	('causing', 'Reg', (77, 84))	('inhibition', 'Var', (25, 35))	('ROS', 'Chemical', 'MESH:D017382', (71, 74))	('increases', 'PosReg', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('reactive oxygen species', 'MPA', (46, 69))
802081	30416311	HDAC inhibition leads to activation of various cellular pathways and acetylation of many different cellular proteins.	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('inhibition', 'Var', (5, 15))	('cellular pathways', 'Pathway', (47, 64))	('acetylation', 'MPA', (69, 80))	('activation', 'PosReg', (25, 35))
802109	30416311	In an effort to assess HDAC4's clinical significance in these patients, high expression was statistically significantly associated with unfavorable clinicopathologic characteristics, including higher grade cancer and more advanced T, N and TNM stages.	('associated', 'Reg', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('HDAC4', 'Gene', '9759', (23, 28))	('HDAC4', 'Gene', (23, 28))	('TNM', 'Gene', '10178', (240, 243))	('higher', 'Disease', (193, 199))	('TNM', 'Gene', (240, 243))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('patients', 'Species', '9606', (62, 70))	('high', 'Var', (72, 76))
802110	30416311	Furthermore, patients with high HDAC4 expression showed a 5-year overall survival of 20.15% with a 5-year progression free survival of 30.92%, that were significantly shorter compared to patients with low HDAC4 expression that presentd 68.75% and 53.59% relevant rates respectively.	('patients', 'Species', '9606', (187, 195))	('shorter', 'NegReg', (167, 174))	('HDAC4', 'Gene', '9759', (32, 37))	('HDAC4', 'Gene', '9759', (205, 210))	('HDAC4', 'Gene', (32, 37))	('HDAC4', 'Gene', (205, 210))	('patients', 'Species', '9606', (13, 21))	('high', 'Var', (27, 31))
802118	30416311	Silencing of HAT1, led to an increase in the population of cells arrested in G2 phase and a decrease in cyclinB1, that works as the checkpoint from G2 to M phase.	('decrease', 'NegReg', (92, 100))	('cyclinB1', 'Gene', (104, 112))	('cyclinB1', 'Gene', '891', (104, 112))	('HAT1', 'Gene', '8520', (13, 17))	('increase', 'PosReg', (29, 37))	('G2 phase', 'CPA', (77, 85))	('Silencing', 'Var', (0, 9))	('HAT1', 'Gene', (13, 17))
802127	30416311	Combination treatment with HDAC6/HSP90 inhibition showed the most potent arrest in cellular mitotic activity than any of the drugs administered alone.	('HSP90', 'Gene', '3320', (33, 38))	('inhibition', 'Var', (39, 49))	('HDAC6', 'Gene', '10013', (27, 32))	('HDAC6', 'Gene', (27, 32))	('cellular mitotic activity', 'CPA', (83, 108))	('HSP90', 'Gene', (33, 38))
802128	30416311	In accordance with the above studies, Hu et al addressed the possibility that selenium anti-cancer effect could be due to its interactions with enzymes implicated in histone acetylation.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('interactions', 'Interaction', (126, 138))	('selenium', 'Chemical', 'MESH:D012643', (78, 86))	('selenium', 'Var', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
802132	30416311	Moreover, selenomethionine can help protect against mild esophageal squamous cell dysplasia.	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (68, 91))	('esophageal squamous cell dysplasia', 'Disease', 'MESH:D000077277', (57, 91))	('selenomethionine', 'Chemical', 'MESH:D012645', (10, 26))	('esophageal squamous cell dysplasia', 'Disease', (57, 91))	('selenomethionine', 'Var', (10, 26))
802148	30416311	HDAC inhibitors have also been detected to enhance radiosensitivity in EC.	('HDAC', 'Gene', (0, 4))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (43, 67))	('HDAC', 'Gene', '9734', (0, 4))	('radiosensitivity', 'MPA', (51, 67))	('inhibitors', 'Var', (5, 15))	('enhance', 'PosReg', (43, 50))
802163	27414035	Genetic Variants in the p14ARF/MDM2/TP53 Pathway Are Associated with the Prognosis of Esophageal Squamous Cell Carcinoma Patients Treated with Radical Resection The p14ARF/MDM2/ TP53 pathway is known to play an important role in tumor progression by cell cycle control, although the association between this pathway and the prognosis of esophageal squamous cell carcinoma (ESCC) is unclear.	('TP53', 'Gene', '7157', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('Associated', 'Reg', (53, 63))	('TP53', 'Gene', (36, 40))	('MDM2', 'Gene', '4193', (31, 35))	('MDM2', 'Gene', (172, 176))	('Esophageal Squamous Cell Carcinoma', 'Disease', (86, 120))	('Patients', 'Species', '9606', (121, 129))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (337, 371))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (348, 371))	('p14ARF', 'Gene', (165, 171))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('MDM2', 'Gene', '4193', (172, 176))	('p14ARF', 'Gene', '1029', (24, 30))	('TP53', 'Gene', (178, 182))	('TP53', 'Gene', '7157', (36, 40))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('p14ARF', 'Gene', (24, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (362, 371))	('Variants', 'Var', (8, 16))	('esophageal squamous cell carcinoma', 'Disease', (337, 371))	('Carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('MDM2', 'Gene', (31, 35))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (86, 120))	('p14ARF', 'Gene', '1029', (165, 171))
802166	27414035	According to multivariate Cox hazard analysis and multiple testing, the TC/CC genotype of p14ARF rs3814960 was shown to be strongly related to a decreased overall survival (OS) (HR = 2.77, 95% CI: 1.33-5.75, P = 0.006, Pc = 0.030) and disease-free survival (DFS) (HR = 2.45, 95% CI: 1.30-4.61, P = 0.005, Pc = 0.025).	('overall survival', 'CPA', (155, 171))	('rs3814960', 'Var', (97, 106))	('rs3814960', 'Mutation', 'rs3814960', (97, 106))	('p14ARF', 'Gene', '1029', (90, 96))	('OS', 'Chemical', '-', (173, 175))	('decreased', 'NegReg', (145, 154))	('p14ARF', 'Gene', (90, 96))	('disease-free survival', 'CPA', (235, 256))
802167	27414035	Moreover, patients with the DEL/A +AA genotype of MDM2 rs34886328 had a notably increased OS (HR = 0.27, 95% CI: 0.13-0.56, P = 4.7x10-4, Pc = 0.003) and DFS (HR = 0.22, 95% CI: 0.11-0.43, P = 1.1x10-5, Pc = 6.6x10-5).	('MDM2', 'Gene', (50, 54))	('OS', 'Chemical', '-', (90, 92))	('rs34886328', 'Var', (55, 65))	('DFS', 'MPA', (154, 157))	('increased', 'PosReg', (80, 89))	('DEL/A +AA', 'Var', (28, 37))	('rs34886328', 'Mutation', 'rs34886328', (55, 65))	('patients', 'Species', '9606', (10, 18))	('MDM2', 'Gene', '4193', (50, 54))
802169	27414035	In conclusion, genetic variants of the p14ARF/MDM2/TP53 pathway are significantly related to OS and DFS, and may be predictors of the prognosis of ESCC after surgery.	('genetic variants', 'Var', (15, 31))	('TP53', 'Gene', (51, 55))	('OS', 'Chemical', '-', (93, 95))	('related', 'Reg', (82, 89))	('ESCC', 'Disease', (147, 151))	('p14ARF', 'Gene', '1029', (39, 45))	('DFS', 'Disease', (100, 103))	('predictors', 'Reg', (116, 126))	('MDM2', 'Gene', '4193', (46, 50))	('TP53', 'Gene', '7157', (51, 55))	('MDM2', 'Gene', (46, 50))	('p14ARF', 'Gene', (39, 45))
802170	27414035	We speculate the individuals with the TC/CC genotype of p14ARF rs3814960 and/or the DEL/DEL genotype of MDMD2 rs34886328 should have more aggressive treatment and may greatly benefit from early prediction and prevention of an unfavorable prognosis by genotyping before the initiation of therapy.	('p14ARF', 'Gene', '1029', (56, 62))	('benefit', 'PosReg', (175, 182))	('DEL/DEL', 'Var', (84, 91))	('more', 'PosReg', (133, 137))	('rs34886328', 'Var', (110, 120))	('aggressive treatment', 'CPA', (138, 158))	('MDMD2', 'Gene', (104, 109))	('p14ARF', 'Gene', (56, 62))	('rs34886328', 'Mutation', 'rs34886328', (110, 120))	('rs3814960', 'Var', (63, 72))	('rs3814960', 'Mutation', 'rs3814960', (63, 72))
802172	27414035	In addition to the patient- and treatment- related factors reported by previous studies, including tumor stage and chemoradiotherapy, plasma values of TP53 were recently found to be associated with the prognosis of ESCC.	('ESCC', 'Disease', (215, 219))	('tumor', 'Disease', (99, 104))	('plasma values', 'Var', (134, 147))	('patient', 'Species', '9606', (19, 26))	('TP53', 'Gene', (151, 155))	('associated with', 'Reg', (182, 197))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('TP53', 'Gene', '7157', (151, 155))
802173	27414035	Further, single nucleotide polymorphisms (SNPs) of TP53 were found by us to be related to the development of ESCC previously.	('related to', 'Reg', (79, 89))	('TP53', 'Gene', (51, 55))	('single nucleotide polymorphisms', 'Var', (9, 40))	('ESCC previously', 'Disease', (109, 124))	('TP53', 'Gene', '7157', (51, 55))
802177	27414035	The p14ARF/MDM2/TP53 pathway is therefore critical for normal cell cycle progression, and abnormalities of the p14ARF/MDM2/TP53 pathway are important mechanisms in the development and progression of cancers.	('p14ARF', 'Gene', '1029', (4, 10))	('MDM2', 'Gene', '4193', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('abnormalities', 'Var', (90, 103))	('MDM2', 'Gene', (118, 122))	('p14ARF', 'Gene', '1029', (111, 117))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('p14ARF', 'Gene', (4, 10))	('cancers', 'Disease', (199, 206))	('p14ARF', 'Gene', (111, 117))	('TP53', 'Gene', '7157', (16, 20))	('mechanisms', 'Reg', (150, 160))	('TP53', 'Gene', '7157', (123, 127))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('MDM2', 'Gene', '4193', (11, 15))	('MDM2', 'Gene', (11, 15))	('TP53', 'Gene', (16, 20))	('TP53', 'Gene', (123, 127))
802178	27414035	p14ARF, MDM2 and TP53 have been shown to present frequent mutations in many tumors; However, to the best of our knowledge, no studies have addressed the role of genetic variants of the p14ARF/MDM2/TP53 signaling pathway in the prognosis of ESCC.	('MDM2', 'Gene', '4193', (8, 12))	('p14ARF', 'Gene', '1029', (0, 6))	('MDM2', 'Gene', (8, 12))	('p14ARF', 'Gene', '1029', (185, 191))	('MDM2', 'Gene', '4193', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('MDM2', 'Gene', (192, 196))	('tumors', 'Disease', (76, 82))	('p14ARF', 'Gene', (0, 6))	('ESCC', 'Disease', (240, 244))	('TP53', 'Gene', '7157', (197, 201))	('p14ARF', 'Gene', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (17, 21))	('variants', 'Var', (169, 177))	('TP53', 'Gene', (197, 201))	('TP53', 'Gene', (17, 21))
802179	27414035	We postulated that SNPs in the p14ARF/MDM2/TP53 pathway may be associated with the survival and recurrence of ESCC.	('SNPs', 'Var', (19, 23))	('p14ARF', 'Gene', '1029', (31, 37))	('associated', 'Reg', (63, 73))	('MDM2', 'Gene', '4193', (38, 42))	('MDM2', 'Gene', (38, 42))	('p14ARF', 'Gene', (31, 37))	('ESCC', 'Disease', (110, 114))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
802190	27414035	Haploview software was used to choose the single nucleotide polymorphisms (SNPs) in the p14ARF/MDM2/TP53 pathway.	('single nucleotide polymorphisms', 'Var', (42, 73))	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', (100, 104))	('MDM2', 'Gene', '4193', (95, 99))	('p14ARF', 'Gene', '1029', (88, 94))	('MDM2', 'Gene', (95, 99))	('p14ARF', 'Gene', (88, 94))
802192	27414035	We only selected SNPs that were located in the 5' or 3'-UTR gene region, or were found to be associated with the risk of ESCC by our previous reports, for example rs1042522.	('associated', 'Reg', (93, 103))	('rs1042522', 'Mutation', 'rs1042522', (163, 172))	('ESCC', 'Disease', (121, 125))	('rs1042522', 'Var', (163, 172))
802206	27414035	We found that two SNPs (p14ARF rs3814960 and MDM2 rs34886328) were significantly associated with the prognosis of ESCC (Fig 1), determined by the Kaplan-Meier method.	('ESCC', 'Disease', (114, 118))	('p14ARF', 'Gene', '1029', (24, 30))	('rs3814960', 'Mutation', 'rs3814960', (31, 40))	('p14ARF', 'Gene', (24, 30))	('MDM2', 'Gene', '4193', (45, 49))	('MDM2', 'Gene', (45, 49))	('rs34886328', 'Var', (50, 60))	('associated', 'Reg', (81, 91))	('rs34886328', 'Mutation', 'rs34886328', (50, 60))
802207	27414035	Patients with the TC/CC genotype of p14ARF rs3814960 had significantly decreased OS (P = 0.001) and DFS (P = 0.001), while patients with the DEL/A +AA genotype of MDM2 rs34886328 had significantly increased OS (P < 0.001) and DFS (P < 0.001).	('rs34886328', 'Mutation', 'rs34886328', (168, 178))	('DFS', 'MPA', (226, 229))	('rs3814960', 'Var', (43, 52))	('patients', 'Species', '9606', (123, 131))	('p14ARF', 'Gene', '1029', (36, 42))	('increased', 'PosReg', (197, 206))	('DFS', 'MPA', (100, 103))	('OS', 'Chemical', '-', (207, 209))	('Patients', 'Species', '9606', (0, 8))	('rs3814960', 'Mutation', 'rs3814960', (43, 52))	('MDM2', 'Gene', (163, 167))	('OS', 'Chemical', '-', (81, 83))	('MDM2', 'Gene', '4193', (163, 167))	('decreased', 'NegReg', (71, 80))	('p14ARF', 'Gene', (36, 42))	('rs34886328', 'Var', (168, 178))
802209	27414035	Furthermore, multiple Cox proportional hazard analyses with adjustments for patient sex, age, smoking status, drinking status, tumor length, tumor location, differential degree and tumor stage revealed that the TC/CC genotype of p14ARF rs3814960 was strongly related to a decreased OS (HR = 2.77, 95% CI: 1.33-5.75, P = 0.006, Pc = 0.030) and DFS (HR = 2.45, 95% CI: 1.30-4.61, P = 0.005, Pc = 0.025).	('p14ARF', 'Gene', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (181, 186))	('OS', 'Chemical', '-', (282, 284))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (127, 132))	('decreased', 'NegReg', (272, 281))	('tumor', 'Disease', (141, 146))	('rs3814960', 'Var', (236, 245))	('p14ARF', 'Gene', '1029', (229, 235))	('rs3814960', 'Mutation', 'rs3814960', (236, 245))	('DFS', 'CPA', (343, 346))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('patient', 'Species', '9606', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
802210	27414035	Moreover, patients with the DEL/A +AA genotype of MDM2 rs34886328 had a notably increased OS (HR = 0.27, 95% CI: 0.13-0.56, P = 4.7x10-4, Pc = 0.003) and DFS (HR = 0.22, 95% CI: 0.11-0.43, P = 1.1x10-5, Pc = 6.6x10-5) (Table 3, S2-S7 Tables).	('MDM2', 'Gene', (50, 54))	('OS', 'Chemical', '-', (90, 92))	('rs34886328', 'Var', (55, 65))	('DFS', 'MPA', (154, 157))	('increased', 'PosReg', (80, 89))	('DEL/A +AA', 'Var', (28, 37))	('rs34886328', 'Mutation', 'rs34886328', (55, 65))	('patients', 'Species', '9606', (10, 18))	('MDM2', 'Gene', '4193', (50, 54))
802212	27414035	For these analyses, we defined the TC/CC genotype of p14ARF rs3814960 and the DEL/DEL genotype of MDMD2 rs34886328 as "unfavorable" genotypes, as these genotypes were associated with worse prognosis.	('rs34886328', 'Var', (104, 114))	('p14ARF', 'Gene', '1029', (53, 59))	('rs34886328', 'Mutation', 'rs34886328', (104, 114))	('rs3814960', 'Var', (60, 69))	('rs3814960', 'Mutation', 'rs3814960', (60, 69))	('MDMD2', 'Gene', (98, 103))	('p14ARF', 'Gene', (53, 59))
802215	27414035	The current study evaluated genetic variants of p14ARF, MDM2 and TP53 to discover their potential associations with the prognosis of ESCC patients who underwent radical resection.	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('ESCC', 'Disease', (133, 137))	('p14ARF', 'Gene', (48, 54))	('variants', 'Var', (36, 44))	('associations', 'Interaction', (98, 110))	('MDM2', 'Gene', '4193', (56, 60))	('MDM2', 'Gene', (56, 60))	('patients', 'Species', '9606', (138, 146))	('p14ARF', 'Gene', '1029', (48, 54))
802216	27414035	Among them, two SNPs, p14ARF rs3814960 and MDM2 rs34886328, were found to be significantly associated with the OS and the DFS of ESCC.	('rs34886328', 'Var', (48, 58))	('ESCC', 'Disease', (129, 133))	('MDM2', 'Gene', '4193', (43, 47))	('MDM2', 'Gene', (43, 47))	('rs34886328', 'Mutation', 'rs34886328', (48, 58))	('OS', 'Chemical', '-', (111, 113))	('p14ARF', 'Gene', '1029', (22, 28))	('rs3814960', 'Mutation', 'rs3814960', (29, 38))	('p14ARF', 'Gene', (22, 28))	('associated', 'Reg', (91, 101))
802217	27414035	The TC/CC genotype of p14ARF rs3814960 was strongly related to a decreased OS and DFS.	('rs3814960', 'Var', (29, 38))	('decreased', 'NegReg', (65, 74))	('OS', 'Chemical', '-', (75, 77))	('p14ARF', 'Gene', '1029', (22, 28))	('rs3814960', 'Mutation', 'rs3814960', (29, 38))	('p14ARF', 'Gene', (22, 28))
802218	27414035	Moreover, patients with the DEL/A +AA genotype of MDM2 rs34886328 had a notably increased OS and DFS.	('MDM2', 'Gene', (50, 54))	('OS', 'Chemical', '-', (90, 92))	('DFS', 'CPA', (97, 100))	('rs34886328', 'Var', (55, 65))	('increased', 'PosReg', (80, 89))	('DEL/A +AA', 'Var', (28, 37))	('rs34886328', 'Mutation', 'rs34886328', (55, 65))	('patients', 'Species', '9606', (10, 18))	('MDM2', 'Gene', '4193', (50, 54))
802220	27414035	To the best of our knowledge, this is the first study to address the associations between genetic variants in the p14ARF/MDM2/TP53 pathway and the prognosis of ESCC, and it is the first study to address the associations between rs34886328, rs1632248, and ESCC.	('ESCC', 'Disease', (160, 164))	('TP53', 'Gene', (126, 130))	('associations', 'Interaction', (69, 81))	('p14ARF', 'Gene', '1029', (114, 120))	('rs1632248', 'Mutation', 'rs1632248', (240, 249))	('rs1632248', 'Var', (240, 249))	('ESCC', 'Disease', (255, 259))	('associations', 'Interaction', (207, 219))	('rs34886328', 'Var', (228, 238))	('p14ARF', 'Gene', (114, 120))	('MDM2', 'Gene', '4193', (121, 125))	('rs34886328', 'Mutation', 'rs34886328', (228, 238))	('TP53', 'Gene', '7157', (126, 130))	('MDM2', 'Gene', (121, 125))
802232	27414035	Our study suggests that the p14ARF rs3814960 and MDM2 rs34886328 SNPs can be used as predictive biomarkers of ESCC after radical resection in genotyping assays, in addition to the tumor stage.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('rs3814960', 'Var', (35, 44))	('rs3814960', 'Mutation', 'rs3814960', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('MDM2', 'Gene', (49, 53))	('p14ARF', 'Gene', (28, 34))	('tumor', 'Disease', (180, 185))	('ESCC', 'Disease', (110, 114))	('MDM2', 'Gene', '4193', (49, 53))	('rs34886328', 'Var', (54, 64))	('p14ARF', 'Gene', '1029', (28, 34))	('rs34886328', 'Mutation', 'rs34886328', (54, 64))
802233	27414035	Thus, we speculate the individuals with the TC/CC genotype of p14ARF rs3814960 and/or the DEL/DEL genotype of MDMD2 rs34886328 should have more aggressive treatment and may greatly benefit from early prediction and prevention of an unfavorable prognosis by genotyping before the initiation of therapy.	('rs34886328', 'Mutation', 'rs34886328', (116, 126))	('benefit', 'PosReg', (181, 188))	('p14ARF', 'Gene', (62, 68))	('MDMD2', 'Gene', (110, 115))	('p14ARF', 'Gene', '1029', (62, 68))	('rs34886328', 'Var', (116, 126))	('rs3814960', 'Var', (69, 78))	('DEL/DEL', 'Var', (90, 97))	('rs3814960', 'Mutation', 'rs3814960', (69, 78))
802235	27414035	In addition, in the present study we analyzed the prognostic role of genetic variants of the p14ARF/MDM2/TP53 pathway in ESCC patients who had not received neoadjuvant therapy mainly because chemotherapy and/or radiation may have an impact on the genetic variants in the tumor tissue.	('variants', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Disease', (271, 276))	('p14ARF', 'Gene', '1029', (93, 99))	('MDM2', 'Gene', '4193', (100, 104))	('TP53', 'Gene', '7157', (105, 109))	('MDM2', 'Gene', (100, 104))	('ESCC', 'Disease', (121, 125))	('TP53', 'Gene', (105, 109))	('patients', 'Species', '9606', (126, 134))	('p14ARF', 'Gene', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (271, 276))
802237	27414035	Moreover, rs3814960 and rs34886328 warrant further investigation to identify the causative SNPs and their molecular mechanisms.	('rs34886328', 'Var', (24, 34))	('rs3814960', 'Var', (10, 19))	('rs3814960', 'Mutation', 'rs3814960', (10, 19))	('rs34886328', 'Mutation', 'rs34886328', (24, 34))
802239	27414035	We will also carry out further research to discover the impact of SNPs in the p14ARF/MDM2/TP53 pathway on cancer progression in our cohort.	('p14ARF', 'Gene', (78, 84))	('MDM2', 'Gene', '4193', (85, 89))	('TP53', 'Gene', '7157', (90, 94))	('MDM2', 'Gene', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('TP53', 'Gene', (90, 94))	('cancer', 'Disease', (106, 112))	('p14ARF', 'Gene', '1029', (78, 84))	('SNPs', 'Var', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
802240	27414035	This is the first study to evaluate the associations between genetic variations in tumor tissue in the p14ARF/MDM2/TP53 pathway and the prognosis of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('ESCC', 'Disease', (149, 153))	('p14ARF', 'Gene', '1029', (103, 109))	('tumor', 'Disease', (83, 88))	('TP53', 'Gene', '7157', (115, 119))	('genetic variations', 'Var', (61, 79))	('associations', 'Interaction', (40, 52))	('p14ARF', 'Gene', (103, 109))	('TP53', 'Gene', (115, 119))	('MDM2', 'Gene', '4193', (110, 114))	('MDM2', 'Gene', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
802241	27414035	Two SNPs in the p14ARF/MDM2/TP53 pathway, p14ARF rs3814960 and MDM2 rs34886328, were found to be significantly associated with the OS and DFS of ESCC, and may thus serve as predictors of ESCC, if these results are further validated in a larger population.	('ESCC', 'Disease', (187, 191))	('MDM2', 'Gene', '4193', (23, 27))	('p14ARF', 'Gene', '1029', (42, 48))	('TP53', 'Gene', (28, 32))	('ESCC', 'Disease', (145, 149))	('rs34886328', 'Var', (68, 78))	('rs3814960', 'Var', (49, 58))	('rs34886328', 'Mutation', 'rs34886328', (68, 78))	('p14ARF', 'Gene', (42, 48))	('p14ARF', 'Gene', '1029', (16, 22))	('DFS', 'Disease', (138, 141))	('associated with', 'Reg', (111, 126))	('MDM2', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (28, 32))	('MDM2', 'Gene', (23, 27))	('OS', 'Chemical', '-', (131, 133))	('rs3814960', 'Mutation', 'rs3814960', (49, 58))	('MDM2', 'Gene', '4193', (63, 67))	('p14ARF', 'Gene', (16, 22))
802243	26330015	Aberrant glycosylation has been correlated to several diseases, such as inflammatory skin diseases, diabetes mellitus, cardiovascular disorders, rheumatoid arthritis, Alzheimer's and prion diseases, and cancer.	('cardiovascular disorders', 'Disease', 'MESH:D002318', (119, 143))	('cardiovascular disorders', 'Disease', (119, 143))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('diabetes mellitus', 'Disease', 'MESH:D003920', (100, 117))	('arthritis', 'Phenotype', 'HP:0001369', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('glycosylation', 'MPA', (9, 22))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (100, 117))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (145, 165))	('inflammatory skin diseases', 'Phenotype', 'HP:0011123', (72, 98))	('Aberrant', 'Var', (0, 8))	("Alzheimer's and prion diseases", 'Disease', 'MESH:D000544', (167, 197))	('cardiovascular disorders', 'Phenotype', 'HP:0001626', (119, 143))	('correlated', 'Reg', (32, 42))	('rheumatoid arthritis', 'Disease', (145, 165))	('cancer', 'Disease', (203, 209))	('inflammatory skin diseases', 'Disease', 'MESH:D012871', (72, 98))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('diabetes mellitus', 'Disease', (100, 117))	('inflammatory skin diseases', 'Disease', (72, 98))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (145, 165))
802249	26330015	Aberrant glycosylation has been observed in many diseases such as inflammatory skin diseases, diabetes mellitus, cardiovascular disorders, rheumatoid arthritis, Alzheimer's and prion diseases and cancer.	('inflammatory skin diseases', 'Phenotype', 'HP:0011123', (66, 92))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (94, 111))	('observed', 'Reg', (32, 40))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (139, 159))	('cardiovascular disorders', 'Phenotype', 'HP:0001626', (113, 137))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	("Alzheimer's and prion diseases", 'Disease', 'MESH:D000544', (161, 191))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('glycosylation', 'MPA', (9, 22))	('Aberrant', 'Var', (0, 8))	('rheumatoid arthritis', 'Disease', (139, 159))	('inflammatory skin diseases', 'Disease', 'MESH:D012871', (66, 92))	('diabetes mellitus', 'Disease', (94, 111))	('inflammatory skin diseases', 'Disease', (66, 92))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (139, 159))	('cancer', 'Disease', (196, 202))	('cardiovascular disorders', 'Disease', 'MESH:D002318', (113, 137))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cardiovascular disorders', 'Disease', (113, 137))	('diabetes mellitus', 'Disease', 'MESH:D003920', (94, 111))	('arthritis', 'Phenotype', 'HP:0001369', (150, 159))
802256	26330015	The complementary glycan structures of glycopeptides are assessed from CID tandem MS. Higher-energy collision dissociation creates the diagnostic oxonium ions of glycopeptides at low m/z values, such as 138, 204, 366, etc.	('oxonium', 'Chemical', 'MESH:C027727', (146, 153))	('366', 'Var', (213, 216))	('CID', 'Disease', (71, 74))	('CID', 'Disease', 'None', (71, 74))	('glycan', 'Chemical', 'MESH:D011134', (18, 24))	('glycopeptides', 'Chemical', 'MESH:D006020', (162, 175))	('oxonium ions', 'MPA', (146, 158))	('138', 'Var', (203, 206))	('glycopeptides', 'Chemical', 'MESH:D006020', (39, 52))
802335	26330015	The cell lines were MCF-7, hormone receptor positive and HER2 negative; MDA-MB-453, hormone receptor negative and HER2 positive; and MDA-MB-468, hormone receptor (estrogen receptor and progesterone receptor) and HER 2 negative (triple negative).	('MCF-7', 'CellLine', 'CVCL:0031', (20, 25))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (133, 143))	('MDA-MB-468', 'Var', (133, 143))	('negative', 'NegReg', (62, 70))	('HER2', 'Protein', (57, 61))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (72, 82))
802380	26330015	To improve the detection of glycopeptides, oxonium ions of glycopeptides are used as transitions, including m/z values at 138 (HexNAc-2H2O-CH2O), 274 (NeuAc-H2O), 366 (HexNAc+Hex) and 657 (HexNAc+Hex+NeuAc) as previously described.	('HexNAc', 'Chemical', '-', (127, 133))	('oxonium', 'Chemical', 'MESH:C027727', (43, 50))	('2H2O', 'Chemical', '-', (134, 138))	('H2O', 'Chemical', 'MESH:D014867', (135, 138))	('HexNAc+Hex', 'Var', (168, 178))	('NeuAc-H2O', 'Var', (151, 160))	('H2O', 'Chemical', 'MESH:D014867', (157, 160))	('HexNAc', 'Chemical', '-', (189, 195))	('Hex', 'Chemical', 'MESH:C036260', (168, 171))	('NeuAc', 'Chemical', 'MESH:D019158', (200, 205))	('CH2O', 'Chemical', '-', (139, 143))	('H2O', 'Chemical', 'MESH:D014867', (140, 143))	('Hex', 'Chemical', 'MESH:C036260', (127, 130))	('Hex', 'Chemical', 'MESH:C036260', (175, 178))	('HexNAc', 'Chemical', '-', (168, 174))	('glycopeptides', 'Chemical', 'MESH:D006020', (28, 41))	('glycopeptides', 'Chemical', 'MESH:D006020', (59, 72))	('Hex', 'Chemical', 'MESH:C036260', (196, 199))	('NeuAc', 'Chemical', 'MESH:D019158', (151, 156))	('366 (HexNAc+Hex', 'Var', (163, 178))	('Hex', 'Chemical', 'MESH:C036260', (189, 192))
802387	26330015	By HC enrichment, the abundance of both glycosylation sites at N138 and N397 of ceruloplasmin showed a decrease in disease groups and these changes were statistically validated.	('N', 'Chemical', 'MESH:D009584', (72, 73))	('ceruloplasmin', 'Gene', (80, 93))	('N138', 'Chemical', '-', (63, 67))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('HC', 'Chemical', '-', (3, 5))	('N138', 'Var', (63, 67))	('N397', 'Var', (72, 76))	('decrease', 'NegReg', (103, 111))
802464	19995427	It has been suggested that deregulation of stem cell self-renewal may cause development of malignancies because cancer cells and stem cells share several similarities, such as the ability of self-renewal without loss of proliferation capacity, relative resistance to drugs, radiation, and apoptosis.	('deregulation', 'Var', (27, 39))	('malignancies', 'Disease', (91, 103))	('development', 'Disease', (76, 87))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('men', 'Species', '9606', (83, 86))	('cause', 'Reg', (70, 75))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('self-renewal', 'CPA', (191, 203))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
802471	19995427	Qiao et al found that HIWI was also expressed in spermatocytes and round spermatids during spermatogenesis and increased in testicular seminoma, suggesting that deregulation of HIWI expression may contribute to the occurrence and development of tumour.	('tumour', 'Disease', 'MESH:D009369', (245, 251))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('contribute', 'Reg', (197, 207))	('increased', 'PosReg', (111, 120))	('testicular seminoma', 'Phenotype', 'HP:0100617', (124, 143))	('tumour', 'Disease', (245, 251))	('testicular seminoma', 'Disease', 'MESH:D018239', (124, 143))	('testicular seminoma', 'Disease', (124, 143))	('HIWI', 'Gene', '9271', (177, 181))	('HIWI', 'Gene', (177, 181))	('HIWI', 'Gene', (22, 26))	('round spermatids', 'Phenotype', 'HP:0032560', (67, 83))	('HIWI', 'Gene', '9271', (22, 26))	('deregulation', 'Var', (161, 173))	('men', 'Species', '9606', (237, 240))
802512	19995427	Figure 1b shows typical 98 KD HIWI bands on Kyse140, which is in agreement with the NP_004755 HIWI characterization on NCBI.	('HIWI', 'Gene', '9271', (30, 34))	('HIWI', 'Gene', (94, 98))	('KD HIWI', 'Disease', 'MESH:C537017', (27, 34))	('men', 'Species', '9606', (70, 73))	('HIWI', 'Gene', '9271', (94, 98))	('KD HIWI', 'Disease', (27, 34))	('Kyse140', 'Var', (44, 51))	('HIWI', 'Gene', (30, 34))
802524	19995427	In univariate analysis, patients with low HIWI expression in tumours had a better overall survival than patients with tumour showing moderate or high HIWI expression (p < 0.001, p = 0.014, respectively), while there was no difference between the moderate expression group and high expression group (p = 0.592) (Figure 3).	('HIWI', 'Gene', '9271', (150, 154))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('better', 'PosReg', (75, 81))	('HIWI', 'Gene', (42, 46))	('tumour', 'Disease', (118, 124))	('HIWI', 'Gene', '9271', (42, 46))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('tumour', 'Disease', (61, 67))	('patients', 'Species', '9606', (104, 112))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumours', 'Disease', (61, 68))	('patients', 'Species', '9606', (24, 32))	('low', 'Var', (38, 41))	('overall survival', 'CPA', (82, 98))	('HIWI', 'Gene', (150, 154))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
802527	19995427	In multivariate Cox's regression analysis, we detected a 2.247-fold increased risk of tumour-related death for patients (p = 0.001) whose tumours showed high cytoplasmic HIWI expression compared to patients with low cytoplasmic HIWI expression (Table 3).	('patients', 'Species', '9606', (198, 206))	('HIWI', 'Gene', (170, 174))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('HIWI', 'Gene', '9271', (170, 174))	('HIWI', 'Gene', (228, 232))	('patients', 'Species', '9606', (111, 119))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('HIWI', 'Gene', '9271', (228, 232))	('death', 'Disease', 'MESH:D003643', (101, 106))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('death', 'Disease', (101, 106))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', (86, 92))	('high cytoplasmic', 'Var', (153, 169))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('tumour', 'Disease', (138, 144))	('tumours', 'Disease', (138, 145))
802528	19995427	Still, there was no significant difference in the risk of tumour-related death between patients with high nuclear HIWI expression and low nuclear HIWI expression (p = 0.397).	('HIWI', 'Gene', (146, 150))	('death', 'Disease', 'MESH:D003643', (73, 78))	('patients', 'Species', '9606', (87, 95))	('HIWI', 'Gene', '9271', (146, 150))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('HIWI', 'Gene', (114, 118))	('tumour', 'Disease', (58, 64))	('HIWI', 'Gene', '9271', (114, 118))	('high nuclear', 'Var', (101, 113))	('death', 'Disease', (73, 78))
802535	19995427	Also in pancreas adenocarcinoma, alterations in mRNA expression of HIWI were also shown to be associated with increasing risk of tumour-related death in male patients.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('death', 'Disease', 'MESH:D003643', (144, 149))	('death', 'Disease', (144, 149))	('HIWI', 'Gene', (67, 71))	('tumour', 'Disease', (129, 135))	('alterations', 'Var', (33, 44))	('associated', 'Reg', (94, 104))	('HIWI', 'Gene', '9271', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('pancreas adenocarcinoma', 'Disease', 'MESH:D010190', (8, 31))	('pancreas adenocarcinoma', 'Phenotype', 'HP:0006725', (8, 31))	('mRNA expression', 'MPA', (48, 63))	('patients', 'Species', '9606', (158, 166))	('pancreas adenocarcinoma', 'Disease', (8, 31))
802550	19995427	Furthermore, patients with high cytoplasmic HIWI expression tumours showed a poorer survival than that with low cytoplasmic expression tumours (P < 0.001).	('tumours', 'Phenotype', 'HP:0002664', (135, 142))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (135, 142))	('high cytoplasmic', 'Var', (27, 43))	('tumours', 'Disease', (60, 67))	('patients', 'Species', '9606', (13, 21))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('poorer', 'NegReg', (77, 83))	('survival', 'CPA', (84, 92))	('HIWI expression tumours', 'Disease', 'MESH:D001039', (44, 67))	('HIWI expression tumours', 'Disease', (44, 67))
802596	19584285	Three CN loss regions were found - 3p12.3, 4p15.1, and 9p21.3 - which contain 765 SNPs from seven genes (ie, CTNT3, LOC33897, LOC28529, LOC645716, MTAP, CDKN2A, and CDKN2B; Table 2B).	('CDKN2B', 'Gene', '1030', (165, 171))	('CDKN2A', 'Gene', (153, 159))	('LOC28529', 'Var', (126, 134))	('CDKN2A', 'Gene', '1029', (153, 159))	('LOC33897', 'Var', (116, 124))	('MTAP', 'Gene', (147, 151))	('CTNT3', 'Gene', (109, 114))	('CDKN2B', 'Gene', (165, 171))	('LOC645716', 'Var', (136, 145))	('MTAP', 'Gene', '4507', (147, 151))
802604	19584285	We observed that chromosomal arms with high LOH and CN loss frequently overlapped (ie, 3p, 4p/q, 9p), suggesting that these areas potentially harbor tumor suppressor genes, as illustrated in a previous study that showed high LOH on 9p concurrent with frequent CDKN2A mutations and intragenic allelic losses.	('loss', 'NegReg', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('CDKN2A', 'Gene', (260, 266))	('mutations', 'Var', (267, 276))	('CDKN2A', 'Gene', '1029', (260, 266))	('tumor', 'Disease', (149, 154))
802606	19584285	These data indicate that numerous types of alterations occur in CDKN2A - LOH, CN loss, biallelic loss, germ-line and somatic mutations, and intragenic allelic loss - and that these alterations collectively contribute to the inactivation of CDKN2A.	('inactivation', 'NegReg', (224, 236))	('CDKN2A', 'Gene', (64, 70))	('loss', 'NegReg', (159, 163))	('CDKN2A', 'Gene', '1029', (64, 70))	('biallelic loss', 'Var', (87, 101))	('alterations', 'Var', (43, 54))	('CDKN2A', 'Gene', (240, 246))	('loss', 'NegReg', (81, 85))	('CDKN2A', 'Gene', '1029', (240, 246))
802609	19584285	This is consistent with observations that chromosome-wide CN gain is limited to one or two copies (trisomy or tetrasomy), while high level amplification tends to be a focal event (eg, gene amplification at 11q13 encompassing CCND1).	('CCND1', 'Gene', '595', (225, 230))	('gene amplification at', 'Var', (184, 205))	('CCND1', 'Gene', (225, 230))
802617	19584285	SNP single nucleotide polymorphism ESCC esophageal squamous cell carcinoma LOH loss of heterozygosity CN copy number GCOS GeneChip Operating System NCBI National Center for Biotechnology Information	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('esophageal squamous cell carcinoma', 'Disease', (40, 74))	('single nucleotide polymorphism', 'Var', (4, 34))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (40, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('ESCC', 'Gene', (35, 39))
802653	33614909	demonstrated that phosphorylation of human FSCN1 inhibits its actin-binding and -bundling activities.	('FSCN1', 'Gene', (43, 48))	('actin', 'Gene', '40444', (62, 67))	('inhibits', 'NegReg', (49, 57))	('rat', 'Species', '10116', (7, 10))	('human', 'Species', '9606', (37, 42))	('actin', 'Gene', (62, 67))	('-bundling activities', 'CPA', (80, 100))	('phosphorylation', 'Var', (18, 33))
802655	33614909	Evidence shows that Ser39 is associated with phosphorylation-dependent regulation of FSCN1 actin binding.	('FSCN1', 'Gene', (85, 90))	('actin', 'Gene', (91, 96))	('Ser39', 'Var', (20, 25))	('binding', 'Interaction', (97, 104))	('actin', 'Gene', '40444', (91, 96))	('associated', 'Reg', (29, 39))	('Ser39', 'Chemical', '-', (20, 25))	('phosphorylation-dependent regulation', 'MPA', (45, 81))
802657	33614909	documented that Ser274 can be phosphorylated to modulate the actin-bundling capacity of FSCN1 in human cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('actin', 'Gene', (61, 66))	('Ser274', 'Var', (16, 22))	('Ser274', 'Chemical', '-', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('human', 'Species', '9606', (97, 102))	('actin', 'Gene', '40444', (61, 66))	('cancer', 'Disease', (103, 109))	('FSCN1', 'Gene', (88, 93))	('modulate', 'Reg', (48, 56))
802659	33614909	reported that phosphorylation of FSCN1 at tyrosine 23 and Ser38 is important in cell migration and filopodia formation in esophageal squamous cancer cells.	('tyrosine', 'Chemical', 'MESH:D014443', (42, 50))	('esophageal squamous cancer', 'Disease', 'MESH:D002294', (122, 148))	('squamous cancer', 'Phenotype', 'HP:0002860', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rat', 'Species', '10116', (88, 91))	('cell migration', 'CPA', (80, 94))	('phosphorylation', 'MPA', (14, 29))	('Ser38', 'Chemical', '-', (58, 63))	('filopodia formation', 'CPA', (99, 118))	('important', 'Reg', (67, 76))	('esophageal squamous cancer', 'Disease', (122, 148))	('FSCN1', 'Gene', (33, 38))	('Ser38', 'Var', (58, 63))
802661	33614909	Monoubiquitination is a post-translational modification that regulates FSCN1 actin-bundling activity and dynamics.	('FSCN1', 'Gene', (71, 76))	('regulates', 'Reg', (61, 70))	('actin', 'Gene', (77, 82))	('actin', 'Gene', '40444', (77, 82))	('dynamics', 'MPA', (105, 113))	('Monoubiquitination', 'Var', (0, 18))
802662	33614909	revealed that FSCN1 was monoubiquitinated at two lysine residues (Lys247 and Lys250) in its ABS2.	('Lys250', 'Chemical', '-', (77, 83))	('lysine', 'Chemical', 'MESH:D008239', (49, 55))	('monoubiquitinated', 'MPA', (24, 41))	('Lys250', 'Var', (77, 83))	('FSCN1', 'Gene', (14, 19))	('Lys247', 'Chemical', '-', (66, 72))	('Lys247', 'Var', (66, 72))
802698	33614909	The disruption of the interactions between FSCN1 and microtubules enhances cellular adhesion stability and decreases cell migration.	('FSCN1', 'Gene', (43, 48))	('microtubules', 'Protein', (53, 65))	('rat', 'Species', '10116', (125, 128))	('interactions', 'Interaction', (22, 34))	('cell migration', 'CPA', (117, 131))	('decreases', 'NegReg', (107, 116))	('disruption', 'Var', (4, 14))	('enhances', 'PosReg', (66, 74))	('cellular adhesion stability', 'CPA', (75, 102))
802734	33614909	Studies have also shown that alterations in gene copy numbers are not associated with FSCN1 upregulation.	('rat', 'Species', '10116', (33, 36))	('upregulation', 'PosReg', (92, 104))	('alterations', 'Var', (29, 40))	('FSCN1', 'Gene', (86, 91))
802739	33614909	found that the expression of FSCN1 can be suppressed by p90 ribosomal S6 kinase 2 (RSK2) knockdown in cell lines from diverse human cancers in a CREB-dependent manner.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('human', 'Species', '9606', (126, 131))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('RSK2', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('suppressed', 'NegReg', (42, 52))	('expression', 'MPA', (15, 25))	('CREB', 'Gene', (145, 149))	('knockdown', 'Var', (89, 98))	('FSCN1', 'Gene', (29, 34))	('RSK2', 'Gene', '6197', (83, 87))	('CREB', 'Gene', '1385', (145, 149))
802759	33614909	Depletion of TF Smad3 or Smad4 by short hairpin (sh)RNA was shown to inhibit TGF-beta-induced FSCN1 expression in human MDA-MB-231 cells and A549 cells.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (120, 130))	('TGF-beta', 'Gene', '7039', (77, 85))	('Smad3', 'Gene', (16, 21))	('Smad4', 'Gene', (25, 30))	('Smad4', 'Gene', '4089', (25, 30))	('Depletion', 'Var', (0, 9))	('expression', 'MPA', (100, 110))	('A549', 'CellLine', 'CVCL:0023', (141, 145))	('human', 'Species', '9606', (114, 119))	('FSCN1', 'Gene', (94, 99))	('Smad3', 'Gene', '4088', (16, 21))	('inhibit', 'NegReg', (69, 76))	('TGF-beta', 'Gene', (77, 85))
802765	33614909	HIF-1alpha knockdown by specific small interfering RNA (siRNA) was shown to suppress the expression of FSCN1 under hypoxia.	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('expression', 'MPA', (89, 99))	('suppress', 'NegReg', (76, 84))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('FSCN1', 'Gene', (103, 108))	('hypoxia', 'Disease', (115, 122))	('knockdown', 'Var', (11, 20))	('HIF-1alpha', 'Gene', (0, 10))
802774	33614909	miR-133a/b directly targets FSCN1 in a variety of human cancers and acts as a tumor suppressor.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('FSCN1', 'Gene', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('miR-133a', 'Chemical', '-', (0, 8))	('miR-133a/b', 'Var', (0, 10))	('tumor', 'Disease', (78, 83))	('human', 'Species', '9606', (50, 55))	('targets', 'Reg', (20, 27))
802775	33614909	Furthermore, the FSCN1 gene has been identified as a direct target of several miRNAs, such as miR-143 in chondrosarcoma and esophageal carcinoma, miR-24 in nasopharyngeal and prostate cancer, miR-326 in lung and gastric cancer, and so on (summarized in Figure 4).	('gastric cancer', 'Phenotype', 'HP:0012126', (212, 226))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('miR-24', 'Var', (146, 152))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (105, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('chondrosarcoma and esophageal carcinoma', 'Disease', 'MESH:D004938', (105, 144))	('gastric cancer', 'Disease', (212, 226))	('prostate cancer', 'Disease', 'MESH:D011471', (175, 190))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('prostate cancer', 'Disease', (175, 190))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (124, 144))	('miR-143', 'Gene', '406935', (94, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (212, 226))	('miR-143', 'Gene', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('lung', 'Disease', (203, 207))	('miR-326', 'Gene', (192, 199))	('FSCN1 gene', 'Gene', (17, 27))	('miR-326', 'Gene', '442900', (192, 199))
802784	33614909	It has recently been established that LINC00152 regulates FSCN1 by sponging with miR-632 and miR-185-3p in colorectal cancer.	('miR-632', 'Gene', '693217', (81, 88))	('FSCN1', 'Gene', (58, 63))	('LINC00152', 'Gene', (38, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('miR-185-3p', 'Var', (93, 103))	('colorectal cancer', 'Disease', (107, 124))	('regulates', 'Reg', (48, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))	('LINC00152', 'Gene', '112597', (38, 47))	('miR-632', 'Gene', (81, 88))
802796	33614909	In vitro and in vivo studies have been performed in cancer cell lines using FSCN1 depletion or overexpression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('depletion', 'Var', (82, 91))	('overexpression', 'PosReg', (95, 109))	('FSCN1', 'Gene', (76, 81))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
802803	33614909	However, FSCN1 knockdown did not exhibit any effect on cell proliferation in multiple cancer cell lines, including bladder cancer (5637 and BIU87), chondrosarcoma (JJ012 and SW1353), hepatocellular carcinoma (HLE), lung cancer (H1650), melanoma (BLM, FM3P, and WM793), and oral cancer (SSC-15 and HSC-3) cell lines.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Disease', (215, 226))	('hepatocellular carcinoma', 'Disease', (183, 207))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('cancer', 'Disease', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('lung cancer', 'Disease', 'MESH:D008175', (215, 226))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('cancer', 'Disease', (86, 92))	('rat', 'Species', '10116', (67, 70))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (183, 207))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('chondrosarcoma', 'Disease', 'MESH:D002813', (148, 162))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('melanoma', 'Disease', (236, 244))	('chondrosarcoma', 'Disease', (148, 162))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Disease', (220, 226))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('knockdown', 'Var', (15, 24))	('HSC-3', 'CellLine', 'CVCL:1288', (297, 302))	('WM793', 'CellLine', 'CVCL:8787', (261, 266))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (183, 207))	('cancer', 'Disease', (123, 129))	('SW1353', 'CellLine', 'CVCL:0543', (174, 180))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (148, 162))
802804	33614909	Heterogeneous expression of FSCN1 also does not promote pancreatic cancer (MIA PaCa-2 cell line) cell proliferation.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('Heterogeneous expression', 'Var', (0, 24))	('FSCN1', 'Gene', (28, 33))	('pancreatic cancer', 'Disease', (56, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('rat', 'Species', '10116', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('not', 'NegReg', (44, 47))	('promote', 'PosReg', (48, 55))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (75, 85))
802808	33614909	documented that FSCN1 knockdown suppresses NSCLC (A549 cells) proliferation and tumor growth through the MAPK signaling pathway.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('suppresses', 'NegReg', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('tumor', 'Disease', (80, 85))	('knockdown', 'Var', (22, 31))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('MAPK signaling', 'Pathway', (105, 119))	('NSCLC', 'Disease', (43, 48))	('FSCN1', 'Gene', (16, 21))	('rat', 'Species', '10116', (69, 72))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
802818	33614909	Studies have reported that manipulation of FSCN1 expression in cancer cells affects tumor cell growth and proliferation.	('FSCN1', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('rat', 'Species', '10116', (113, 116))	('manipulation', 'Var', (27, 39))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('proliferation', 'CPA', (106, 119))	('cancer', 'Disease', (63, 69))	('affects', 'Reg', (76, 83))
802826	33614909	However, in melanoma, FSCN1 knockdown did not exhibit inhibitory effects on cell migration but enhanced cell invasion.	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('rat', 'Species', '10116', (84, 87))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('cell invasion', 'CPA', (104, 117))	('knockdown', 'Var', (28, 37))	('enhanced', 'PosReg', (95, 103))	('FSCN1', 'Gene', (22, 27))
802833	33614909	The injection of cancer cells with FSCN1 knockdown into the abdominal cavities of nude mice suppressed metastatic tumor nodes when compared to those injected with control cells.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('suppressed', 'NegReg', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('nude mice', 'Species', '10090', (82, 91))	('FSCN1', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', (114, 119))	('cancer', 'Disease', (17, 23))	('knockdown', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
802837	33614909	Several studies have also documented that targeted inhibition of FSCN1/actin bundling blocks tumor cell migration and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('blocks tumor', 'Disease', (86, 98))	('actin', 'Gene', (71, 76))	('blocks tumor', 'Disease', 'MESH:D006327', (86, 98))	('actin', 'Gene', '40444', (71, 76))	('inhibition', 'Var', (51, 61))	('rat', 'Species', '10116', (107, 110))
802861	33614909	Downregulated FSCN1 in breast cancer cell lines was shown to significantly suppress the cancer stem cell-like phenotype (CD44hi/CD24lo and ALDH+).	('breast cancer', 'Disease', (23, 36))	('Downregulated', 'Var', (0, 13))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('FSCN1', 'Gene', (14, 19))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('suppress', 'NegReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
802862	33614909	FSCN1 knockout in the melanoma WM793 cell line inhibited melanoma stemness.	('FSCN1', 'Gene', (0, 5))	('inhibited', 'NegReg', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('WM793', 'CellLine', 'CVCL:8787', (31, 36))	('melanoma', 'Disease', (57, 65))	('melanoma stemness', 'Disease', (57, 74))	('melanoma stemness', 'Disease', 'MESH:D008545', (57, 74))	('melanoma', 'Disease', (22, 30))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('knockout', 'Var', (6, 14))
802863	33614909	This was attributed to the fact that the expression levels of CD44 were significantly suppressed in FSCN1 knockout WM793 cells.	('expression levels', 'MPA', (41, 58))	('FSCN1', 'Gene', (100, 105))	('knockout', 'Var', (106, 114))	('WM793', 'CellLine', 'CVCL:8787', (115, 120))	('suppressed', 'NegReg', (86, 96))	('CD44', 'Protein', (62, 66))
802868	33614909	To our knowledge, a single study has evaluated the effects of FSCN1 gene polymorphisms in the development and progression of breast cancer.	('FSCN1', 'Gene', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('polymorphisms', 'Var', (73, 86))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
802869	33614909	The study documents that genetic variations in the FSCN1 gene may serve as a marker for early-stage breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('marker', 'Reg', (77, 83))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('FSCN1', 'Gene', (51, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('genetic variations', 'Var', (25, 43))
802909	33614909	In most of the tumor cell lines (Table 1), FSCN1 knockdown by siRNA inhibited cell migration and invasion in vitro.	('FSCN1', 'Gene', (43, 48))	('knockdown', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('inhibited', 'NegReg', (68, 77))	('tumor', 'Disease', (15, 20))	('rat', 'Species', '10116', (86, 89))
802913	33614909	Small molecule inhibitors of FSCN1 can block tumor cell migration, invasion, and metastasis.	('block tumor', 'Disease', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('invasion', 'CPA', (67, 75))	('block tumor', 'Disease', 'MESH:D006327', (39, 50))	('rat', 'Species', '10116', (59, 62))	('FSCN1', 'Gene', (29, 34))	('inhibitors', 'Var', (15, 25))
802923	33614909	However, FSCN1 expression can promote cell migration and metastasis independent of its actin-bundling activity.	('expression', 'Var', (15, 25))	('promote', 'PosReg', (30, 37))	('rat', 'Species', '10116', (46, 49))	('actin', 'Gene', '40444', (87, 92))	('FSCN1', 'Gene', (9, 14))	('actin', 'Gene', (87, 92))
802974	33204151	Accordingly, we divided patients into two groups for each marker: high CD27 group (n = 46) and low CD27 group (n = 80), and high CD70 group (n = 40) and low CD70 group (n = 86).	('CD27', 'MPA', (99, 103))	('high CD70', 'Var', (124, 133))	('low', 'NegReg', (95, 98))	('patients', 'Species', '9606', (24, 32))
802988	33204151	The Kaplan-Meier curves and the Log-rank test showed that CD70 mRNA levels were significantly associated with better overall survival of patients (P=0.041; Figure 3C.	('better', 'PosReg', (110, 116))	('CD70', 'Var', (58, 62))	('patients', 'Species', '9606', (137, 145))	('overall', 'MPA', (117, 124))
803000	33204151	Approximately one-third of patients with Hodgkin's or diffuse large B cell lymphoma had CD27 or CD70 germline defects, and CD70 somatic mutations or deletions were common in diffuse large B cell lymphomas and Burkitt lymphomas, further suggesting that reduced activity of CD27 and CD70 signaling could contribute to development of these malignancies in humans.	('malignancies', 'Disease', (337, 349))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (68, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (217, 225))	('common', 'Reg', (164, 170))	('lymphomas', 'Disease', 'MESH:D008223', (195, 204))	('large B cell', 'Phenotype', 'HP:0005404', (62, 74))	('Hodgkin', 'Disease', (41, 48))	('lymphomas', 'Phenotype', 'HP:0002665', (195, 204))	('CD27', 'Gene', (88, 92))	('lymphoma', 'Disease', (195, 203))	('lymphomas', 'Disease', (217, 226))	('Burkitt lymphomas', 'Disease', 'MESH:D002051', (209, 226))	('CD70', 'Gene', (96, 100))	('lymphoma', 'Disease', 'MESH:D008223', (195, 203))	('patients', 'Species', '9606', (27, 35))	('Burkitt lymphomas', 'Phenotype', 'HP:0030080', (209, 226))	('lymphoma', 'Disease', (75, 83))	('lymphomas', 'Disease', 'MESH:D008223', (217, 226))	('lymphoma', 'Disease', 'MESH:D008223', (75, 83))	('lymphomas', 'Phenotype', 'HP:0002665', (217, 226))	('lymphoma', 'Disease', (217, 225))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (188, 204))	('CD70', 'Gene', (123, 127))	('humans', 'Species', '9606', (353, 359))	('lymphomas', 'Disease', (195, 204))	('lymphoma', 'Disease', 'MESH:D008223', (217, 225))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (188, 203))	("Hodgkin's", 'Disease', 'MESH:D006689', (41, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (195, 203))	('large B cell', 'Phenotype', 'HP:0005404', (182, 194))	('malignancies', 'Disease', 'MESH:D009369', (337, 349))	('Burkitt lymphomas', 'Disease', (209, 226))	('deletions', 'Var', (149, 158))
803006	33204151	However, a previous study of serum CD27 levels in 96 lung cancer patients showed that high CD27 levels were associated with poorer lung cancer prognosis compared to those with low serum CD27 levels.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CD27', 'Protein', (91, 95))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('poorer', 'NegReg', (124, 130))	('patients', 'Species', '9606', (65, 73))	('lung cancer', 'Disease', (131, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('high', 'Var', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('lung cancer', 'Disease', (53, 64))
803008	33204151	Moreover, another previous study reported that CD70 expression in tumor-associated fibroblasts was associated with poor survival of colorectal cancer patients, while an additional study showed an association of CD70 expression with breast cancer to lung-specific metastasis, and that CD70+ cells (but not CD70- cells) possessed self-renewal and differentiation potential.	('breast cancer', 'Disease', (232, 245))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('patients', 'Species', '9606', (150, 158))	('expression', 'Var', (52, 62))	('poor', 'NegReg', (115, 119))	('tumor', 'Disease', (66, 71))	('association', 'Interaction', (196, 207))	('CD70', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CD70+', 'Var', (284, 289))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('self-renewal', 'CPA', (328, 340))	('CD70', 'Gene', (211, 215))	('lung-specific metastasis', 'CPA', (249, 273))	('colorectal cancer', 'Disease', (132, 149))	('differentiation potential', 'CPA', (345, 370))	('associated', 'Reg', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('breast cancer', 'Disease', 'MESH:D001943', (232, 245))
803018	33204151	In our current study, we demonstrated that CD27 and CD70 mRNA levels and protein expression were down-regulated in ESCC tissues and that CD27 and CD70 expression were associated with better overall survival of ESCC patients.	('ESCC', 'Disease', (115, 119))	('patients', 'Species', '9606', (215, 223))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('overall survival', 'CPA', (190, 206))	('protein expression', 'MPA', (73, 91))	('down-regulated', 'NegReg', (97, 111))	('SCC', 'Phenotype', 'HP:0002860', (211, 214))	('CD70', 'Var', (146, 150))	('better', 'PosReg', (183, 189))	('CD27', 'Var', (137, 141))
803021	32123074	In a dietary Zn deficiency-promoted rat ESCC model with miR-31-controlled inflammation pathway up-regulation, systemic antimiR-31 reduces miR-31 level and inflammation, suppressing ESCC development.	('dietary Zn deficiency', 'Disease', (5, 26))	('suppressing', 'NegReg', (169, 180))	('antimiR-31', 'Var', (119, 129))	('rat', 'Species', '10116', (36, 39))	('dietary Zn deficiency', 'Disease', 'MESH:D018798', (5, 26))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('inflammation', 'Disease', (74, 86))	('ESCC development', 'CPA', (181, 197))	('miR-31 level', 'MPA', (138, 150))	('miR-31-controlled', 'Gene', (56, 73))	('up-regulation', 'PosReg', (95, 108))	('reduces', 'NegReg', (130, 137))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))	('inflammation', 'Disease', (155, 167))
803024	32123074	Since miR-31 genetic knockout prevents Zn deficiency-associated ESCC by eliminating or greatly reducing the entire miR-31-EGLN3/STK40-NF-kappaB-controlled inflammatory process, we conclude that miR-31 and downstream signaling proteins should be tested as prognostic and therapeutic targets and inexpensive Zn supplementation should be implemented for ESCC prevention in deficient populations.	('NF-kappaB', 'Gene', '4790', (134, 143))	('Zn', 'Chemical', 'MESH:D015032', (306, 308))	('ESCC', 'Disease', (64, 68))	('miR-31', 'Gene', (6, 12))	('genetic knockout', 'Var', (13, 29))	('Zn', 'Chemical', 'MESH:D015032', (39, 41))	('NF-kappaB', 'Gene', (134, 143))	('reducing', 'NegReg', (95, 103))
803026	32123074	In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 x 10-6).	('NMBA', 'Chemical', 'MESH:C014707', (163, 167))	('high ESCC', 'Phenotype', 'HP:0003565', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('miR-31', 'Gene', (48, 54))	('up-regulation', 'PosReg', (55, 68))	('inflammation', 'Disease', 'MESH:D007249', (88, 100))	('N-nitrosomethylbenzylamine', 'Chemical', 'MESH:C014707', (135, 161))	('knockout', 'Var', (274, 282))	('miR-31', 'Gene', (262, 268))	('ESCC', 'Disease', (216, 220))	('inflammation', 'Disease', (88, 100))	('abrogated', 'NegReg', (283, 292))	('reduced', 'NegReg', (208, 215))	('Zn', 'Chemical', 'MESH:D015032', (5, 7))	('development', 'CPA', (293, 304))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('rat', 'Species', '10116', (28, 31))
803027	32123074	Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout.	('miR-31', 'Gene', (140, 146))	('Zn', 'Chemical', 'MESH:D015032', (71, 73))	('knockout', 'Var', (147, 155))	('abrogation', 'NegReg', (126, 136))	('rats', 'Species', '10116', (84, 88))	('ESCC', 'Disease', (121, 125))
803029	32123074	Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs.	('ESCCs', 'Disease', (105, 110))	('inflammation', 'Disease', (63, 75))	('down-regulation', 'NegReg', (42, 57))	('inflammation', 'Disease', 'MESH:D007249', (63, 75))	('EGLN3', 'Var', (36, 41))	('human', 'Species', '9606', (99, 104))
803030	32123074	miR-31 deletion resulted in suppression of miR-31-associated EGLN3/NF-kappaB-controlled inflammatory pathways.	('NF-kappaB', 'Gene', '4790', (67, 76))	('miR-31', 'Gene', (0, 6))	('NF-kappaB', 'Gene', (67, 76))	('suppression', 'NegReg', (28, 39))	('miR-31-associated', 'Gene', (43, 60))	('deletion', 'Var', (7, 15))
803031	32123074	ESCC-free, Zn-deficient miR-31-/- rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats.	('mutational', 'Var', (138, 148))	('Zn', 'Chemical', 'MESH:D015032', (11, 13))	('miR-31-/-', 'Gene', (24, 33))	('rats', 'Species', '10116', (220, 224))	('Zn', 'Chemical', 'MESH:D015032', (197, 199))	('metabolic changes', 'CPA', (176, 193))	('rat', 'Species', '10116', (220, 223))	('rat', 'Species', '10116', (34, 37))	('metabolic', 'CPA', (92, 101))
803035	32123074	In many populations, and in individuals with chronic alcohol consumption, dietary zinc (Zn) deficiency is implicated in the etiology of ESCC.	('deficiency', 'Var', (92, 102))	('alcohol', 'Chemical', 'MESH:D000438', (53, 60))	('chronic alcohol consumption', 'Phenotype', 'HP:0030955', (45, 72))	('ESCC', 'Disease', (136, 140))	('Zn', 'Chemical', 'MESH:D015032', (88, 90))
803039	32123074	Prolonged Zn deficiency leads to an expanded cancer-associated inflammatory program and an oncogenic miRNA signature, with miR-31 as the top up-regulated species that fuels ESCC development.	('Zn', 'Chemical', 'MESH:D015032', (10, 12))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('deficiency', 'Var', (13, 23))	('expanded', 'PosReg', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('oncogenic miRNA signature', 'MPA', (91, 116))	('cancer', 'Disease', (45, 51))
803045	32123074	Using LNA-antimiR-31, we previously demonstrated in a ZD rat esophageal preneoplasia model overexpressing miR-31 that silencing miR-31 in vivo inhibits the development of esophageal preneoplasia by repressing the miR-31-associated STK40-NF-kappaB (nuclear factor kappaB)-based inflammation signaling.	('neoplasia', 'Phenotype', 'HP:0002664', (185, 194))	('inhibits', 'NegReg', (143, 151))	('miR-31-associated', 'MPA', (213, 230))	('esophageal preneoplasia', 'Disease', 'MESH:D004941', (61, 84))	('repressing', 'PosReg', (198, 208))	('esophageal preneoplasia', 'Disease', (61, 84))	('NF-kappaB', 'Gene', '4790', (237, 246))	('rat', 'Species', '10116', (43, 46))	('inflammation', 'Disease', 'MESH:D007249', (277, 289))	('silencing', 'Var', (118, 127))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('NF-kappaB', 'Gene', (237, 246))	('miR-31', 'Gene', (128, 134))	('rat', 'Species', '10116', (57, 60))	('esophageal preneoplasia', 'Disease', (171, 194))	('inflammation', 'Disease', (277, 289))	('esophageal preneoplasia', 'Disease', 'MESH:D004941', (171, 194))
803046	32123074	Since the end point was the preneoplastic inflammatory esophageal phenotype, we questioned whether miR-31 silencing could suppress progression to ESCC in NMBA-treated Zn-deficient rats.	('Zn', 'Chemical', 'MESH:D015032', (167, 169))	('NMBA', 'Chemical', 'MESH:C014707', (154, 158))	('silencing', 'Var', (106, 115))	('rats', 'Species', '10116', (180, 184))	('suppress', 'NegReg', (122, 130))	('ESCC', 'Disease', (146, 150))	('miR-31', 'Gene', (99, 105))
803065	32123074	1C; n = 8 to 20 rats per group), ZD:antimiR/20-wk esophagus (rats R1 to R4) typically had smaller and fewer tumors vs. ZD:CTRL (R13, R14) or ZD:CTRL-A/20-wk (R15, R16) esophagus showing multiple large/sessile tumors.	('sessile tumors', 'Disease', (201, 215))	('R14', 'Gene', '474169', (133, 136))	('rats', 'Species', '10116', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('R15', 'Gene', (158, 161))	('R16', 'Gene', (163, 166))	('sessile tumors', 'Disease', 'MESH:D009369', (201, 215))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('antimiR/20-wk', 'Var', (36, 49))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('R16', 'Gene', '100361814', (163, 166))	('tumors', 'Disease', (108, 114))	('R15', 'Gene', '474169', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('rats', 'Species', '10116', (16, 20))	('tumors', 'Disease', (209, 215))	('R14', 'Gene', (133, 136))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('fewer', 'NegReg', (102, 107))
803066	32123074	Thus, antimiR delivery (20 wk) led to a large decrease in tumor multiplicity (5.7 vs. 14, P = 4 x 10-5), in large tumor incidence (45 vs. 85%, P = 0.038; size >2 mm), and in ESCC incidence (45 vs. 85%, P = 0.038) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('antimiR', 'Var', (6, 13))	('ESCC', 'CPA', (174, 178))	('decrease', 'NegReg', (46, 54))
803068	32123074	In contrast, a short-term antimiR delivery (5 wk) led to a modest reduction in tumor multiplicity vs. ZD:CTRL rats (9.9 vs. 14, P = 0.002) (Fig.	('tumor', 'Disease', (79, 84))	('antimiR', 'Var', (26, 33))	('rats', 'Species', '10116', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('reduction', 'NegReg', (66, 75))
803069	32123074	To understand the molecular interaction between miR-31 and dietary Zn deficiency in ESCC development, we generated a constitutive miR-31 knockout (KO) rat (Materials and Methods) with deletion of a 466-bp DNA fragment containing miR-31 in one allele by CRISPR/Cas9 technology in the same Sprague-Dawley rat strain as our previous Zn deficiency-associated esophageal tumor studies.	('esophageal tumor', 'Phenotype', 'HP:0100751', (355, 371))	('deficiency-associated esophageal tumor', 'Disease', (333, 371))	('rat', 'Species', '10116', (303, 306))	('deletion', 'Var', (184, 192))	('Zn', 'Chemical', 'MESH:D015032', (330, 332))	('dietary Zn deficiency', 'Disease', (59, 80))	('dietary Zn deficiency', 'Disease', 'MESH:D018798', (59, 80))	('Zn', 'Chemical', 'MESH:D015032', (67, 69))	('rat', 'Species', '10116', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('Sprague-Dawley rat', 'Species', '10116', (288, 306))	('rat', 'Species', '10116', (151, 154))	('miR-31', 'Gene', (229, 235))	('deficiency-associated esophageal tumor', 'Disease', 'MESH:D004938', (333, 371))
803071	32123074	The production of homozygous miR-31 KO rat pups in normal sex ratios showed that miR-31 deletion is well-tolerated in the rat and miR-31-/- rats exhibit no discernible abnormal phenotypes.	('rats', 'Species', '10116', (140, 144))	('deletion', 'Var', (88, 96))	('rat', 'Species', '10116', (140, 143))	('rat', 'Species', '10116', (39, 42))	('rat', 'Species', '10116', (109, 112))	('rat', 'Species', '10116', (122, 125))	('rat', 'Species', '10116', (62, 65))	('miR-31', 'Gene', (81, 87))
803080	32123074	3D) esophagus compared with abundant/intense miR-31 signal in esophageal mucosa and tumor in ZD:miR-31+/+ (Fig.	('miR-31+/+', 'Var', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('miR-31', 'MPA', (45, 51))
803082	32123074	2C), we found small/isolated esophageal tumors (~0.5 mm) in a few ZD:miR-31-/- rats compared with the omnipresent large/sessile tumors (>2 mm) in ZD:miR-31+/+ esophagus.	('esophageal tumors', 'Phenotype', 'HP:0100751', (29, 46))	('miR-31-/-', 'Var', (69, 78))	('sessile tumors', 'Disease', (120, 134))	('esophageal tumor', 'Phenotype', 'HP:0100751', (29, 45))	('isolated esophageal tumors', 'Disease', (20, 46))	('rats', 'Species', '10116', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('sessile tumors', 'Disease', 'MESH:D009369', (120, 134))	('isolated esophageal tumors', 'Disease', 'MESH:D004938', (20, 46))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
803083	32123074	Thus, ZD:miR-31-/- rats had significantly lower esophageal tumor incidence/multiplicity than ZD:miR-31+/+ rats (tumor incidence, 55 vs. 100%, P = 0.007; multiplicity, 1.6 +- 1.7 vs. 11.6 +- 5.1, P = 7 x 10-7) (Fig.	('rats', 'Species', '10116', (106, 110))	('tumor', 'Disease', (59, 64))	('lower', 'NegReg', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('rats', 'Species', '10116', (19, 23))	('esophageal tumor', 'Disease', 'MESH:D004938', (48, 64))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('miR-31-/-', 'Var', (9, 18))	('esophageal tumor', 'Phenotype', 'HP:0100751', (48, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (112, 117))	('esophageal tumor', 'Disease', (48, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
803085	32123074	While ZD:miR-31-/- esophageal epithelia were mostly thin (Fig.	('esophageal epithelia', 'Disease', (19, 39))	('miR-31-/-', 'Var', (9, 18))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (19, 39))	('esophageal epithelia', 'Disease', 'MESH:D004941', (19, 39))
803087	32123074	2F; proliferating cell nuclear antigen [PCNA]), ESCC-bearing ZD:miR-31+/+ esophagus regularly showed uncontrolled cellular proliferation and inflammatory cell infiltrates in the stroma (Fig.	('rat', 'Species', '10116', (165, 168))	('rat', 'Species', '10116', (130, 133))	('rat', 'Species', '10116', (11, 14))	('inflammatory cell infiltrates in', 'CPA', (141, 173))	('PCNA', 'Gene', '25737', (40, 44))	('miR-31+/+', 'Var', (64, 73))	('PCNA', 'Gene', (40, 44))
803091	32123074	None of the six up-regulated inflammation genes was differentially expressed in ZD:antimiR/20-wk vs. ZS:CTRL (SI Appendix, Table S1 and Dataset S2), ZD:miR-31-/- vs. ZS:CTRL esophagus (SI Appendix, Table S1 and Dataset S4), or ZD:miR-31-/- vs. ZS:miR-31-/- esophagus (Dataset S3), although three inflammation genes (S100a8, Cxcl14, and Cxcl1) were moderately up-regulated in ZD:antimiR/5-wk esophagus (SI Appendix, Table S1).	('inflammation', 'Disease', 'MESH:D007249', (29, 41))	('antimiR/5-wk', 'Var', (378, 390))	('SI Appendix', 'Disease', 'MESH:D001063', (185, 196))	('SI Appendix', 'Disease', (185, 196))	('Cxcl1', 'Gene', (336, 341))	('inflammation', 'Disease', (29, 41))	('inflammation', 'Disease', 'MESH:D007249', (296, 308))	('SI Appendix', 'Disease', 'MESH:D001063', (110, 121))	('SI Appendix', 'Disease', (110, 121))	('Cxcl1', 'Gene', '81503', (324, 329))	('Cxcl14', 'Gene', (324, 330))	('S100a8', 'Gene', (316, 322))	('SI Appendix', 'Disease', 'MESH:D001063', (402, 413))	('Cxcl14', 'Gene', '306748', (324, 330))	('SI Appendix', 'Disease', (402, 413))	('inflammation', 'Disease', (296, 308))	('rat', 'Species', '10116', (352, 355))	('up-regulated', 'PosReg', (359, 371))	('S100a8', 'Gene', '116547', (316, 322))	('Cxcl1', 'Gene', (324, 329))	('Cxcl1', 'Gene', '81503', (336, 341))
803092	32123074	Additionally, the expression profile of ZD:miR-31-/- esophagus revealed prominent down-regulation of Ptgs2, S100a9, and S100a8 compared with ZD:CTRL esophagus (ranging from logFC -3.8 to -2.2) (Dataset S5).	('S100a9', 'Gene', (108, 114))	('S100a8', 'Gene', (120, 126))	('Ptgs2', 'Gene', '29527', (101, 106))	('S100a8', 'Gene', '116547', (120, 126))	('S100a9', 'Gene', '94195', (108, 114))	('down-regulation', 'NegReg', (82, 97))	('miR-31-/-', 'Var', (43, 52))	('expression', 'MPA', (18, 28))	('Ptgs2', 'Gene', (101, 106))
803094	32123074	4C) confirmed that these three genes that were markedly up-regulated by Zn deficiency were strikingly restored to normal ZS:CTRL levels in ZD:antimiR/20-wk and ZD:miR-31-/- esophagus.	('restored', 'PosReg', (102, 110))	('Zn', 'Chemical', 'MESH:D015032', (72, 74))	('up-regulated', 'PosReg', (56, 68))	('miR-31-/-', 'Var', (163, 172))	('ZS:CTRL levels', 'MPA', (121, 135))	('deficiency', 'Var', (75, 85))
803095	32123074	4D) showed strong/abundant cytoplasmic staining for all three inflammation markers COX2, S100A8, and S100A9 and their transcription factor NF-kappaB p65 in cancerous ZD:CTRL vs. ZS:CTRL esophagus.	('COX2', 'Gene', '26198', (83, 87))	('inflammation', 'Disease', 'MESH:D007249', (62, 74))	('inflammation', 'Disease', (62, 74))	('NF-kappaB', 'Gene', (139, 148))	('S100A8', 'Gene', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('S100A9', 'Var', (101, 107))	('COX2', 'Gene', (83, 87))	('NF-kappaB', 'Gene', '4790', (139, 148))	('cancerous ZD', 'Disease', (156, 168))	('cancerous ZD', 'Disease', 'MESH:D009369', (156, 168))
803096	32123074	Expression of the same inflammation markers and NF-kappaB p65, a key mediator of inflammation, was reduced in ZD:antimiR/20-wk esophagus and became weak/diffuse in ZD:miR-31-/-, as well as in ZS:miR-31-/- esophagus, both featuring a noninflammatory and nonproliferative esophageal phenotype.	('inflammation', 'Disease', 'MESH:D007249', (23, 35))	('Expression', 'MPA', (0, 10))	('NF-kappaB', 'Gene', (48, 57))	('rat', 'Species', '10116', (263, 266))	('NF-kappaB', 'Gene', '4790', (48, 57))	('inflammation', 'Disease', (23, 35))	('inflammation', 'Disease', 'MESH:D007249', (81, 93))	('inflammation', 'Disease', (81, 93))	('miR-31-/-', 'Var', (167, 176))	('reduced', 'NegReg', (99, 106))
803098	32123074	4A, first and third heatmaps), the human/rat TargetScan tool predicts that miR-31-5p potentially targets MBOAT2, CTNND2, FRK, and EGLN3 (Fig.	('miR-31-5p', 'Var', (75, 84))	('targets', 'Reg', (97, 104))	('CTNND2', 'Gene', (113, 119))	('human', 'Species', '9606', (35, 40))	('FRK', 'Gene', '79209', (121, 124))	('rat', 'Species', '10116', (41, 44))	('MBOAT2', 'Gene', (105, 111))	('FRK', 'Gene', (121, 124))	('EGLN3', 'Var', (130, 135))
803099	32123074	3B, HEK-293FT cells were cotransfected with a vector expressing either the WT or the mutated versions of the 3' untranslated regions (UTRs) of the MBOAT2, CTNND2, and EGLN3 genes, and either premiR-31-5p or scrambled negative control 1.	('EGLN3', 'Gene', (167, 172))	('MBOAT2', 'Gene', (147, 153))	('HEK-293FT', 'CellLine', 'CVCL:6911;0.11283525305814343', (4, 13))	('mutated', 'Var', (85, 92))	('CTNND2', 'Gene', (155, 161))
803100	32123074	The comparative transcriptomics data revealed that genetic miR-31 knockout led to a marked up-regulation of all three miR-31 tumor suppressor targets Egln3 (logFC 1.04, P = 0.00059), Mboat2 (logFC 1.18, P = 1.51E-5), as well as Stk40 (logFC 1.38, P = 1.	('knockout', 'Var', (66, 74))	('Stk40', 'Gene', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('rat', 'Species', '10116', (9, 12))	('Stk40', 'Gene', '360230', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('miR-31', 'Gene', (59, 65))	('miR-31', 'Gene', (118, 124))	('Mboat2', 'Gene', '313997', (183, 189))	('tumor', 'Disease', (125, 130))	('up-regulation', 'PosReg', (91, 104))	('Mboat2', 'Gene', (183, 189))	('Egln3', 'Gene', (150, 155))	('Egln3', 'Gene', '54702', (150, 155))
803116	32123074	Overexpression of the proinflammation markers S100A8, S1009, and COX-2 has been reported in human ESCC.	('inflammation', 'Disease', (25, 37))	('inflammation', 'Disease', 'MESH:D007249', (25, 37))	('ESCC', 'Disease', (98, 102))	('S1009', 'Var', (54, 59))	('S100A8', 'Var', (46, 52))	('human', 'Species', '9606', (92, 97))
803119	32123074	Because EGLN3 and STK40 are negative regulators of NF-kappaB-mediated transcription, their down-regulation unleashed a robust inflammatory response, with strong expression of the inflammation mediator NF-kappaB p65 and its target proinflammation markers COX-2, S100A8, and S100A9 (Fig.	('NF-kappaB', 'Gene', (201, 210))	('STK40', 'Var', (18, 23))	('down-regulation', 'NegReg', (91, 106))	('NF-kappaB', 'Gene', '4790', (51, 60))	('negative', 'NegReg', (28, 36))	('NF-kappaB', 'Gene', '4790', (201, 210))	('inflammation', 'Disease', 'MESH:D007249', (179, 191))	('EGLN3', 'Var', (8, 13))	('unleashed', 'Reg', (107, 116))	('NF-kappaB', 'Gene', (51, 60))	('inflammation', 'Disease', (179, 191))	('inflammation', 'Disease', 'MESH:D007249', (233, 245))	('inflammation', 'Disease', (233, 245))
803142	32123074	In sharp contrast to the ZD:CTRL metabolome, metabolomics analyses of ZD:miR-31-/- vs. ZS:miR-31-/- rat esophagus yielded only 11 significantly altered metabolites (Fig.	('miR-31-/-', 'Var', (73, 82))	('altered', 'Reg', (144, 151))	('miR-31-/-', 'Var', (90, 99))	('metabolites', 'MPA', (152, 163))	('rat', 'Species', '10116', (100, 103))
803150	32123074	These sequences, with relatively high mutational effect, showed significant mutations in genes that might have affected tumor development, nine genes in the R14 sample and 22 genes in the ZD:CTRL R13 mucosal DNA.	('mutations', 'Var', (76, 85))	('R14', 'Gene', '474169', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('R14', 'Gene', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('affected', 'Reg', (111, 119))	('tumor', 'Disease', (120, 125))
803152	32123074	The most commonly affected processes in both HIGH and MODERATE effect mutations were biological regulation, metabolic process, and response to stimulus.	('mutations', 'Var', (70, 79))	('biological regulation', 'CPA', (85, 106))	('HIGH', 'Disease', (45, 49))	('affected', 'Reg', (18, 26))	('HIGH', 'Disease', 'MESH:D052456', (45, 49))	('metabolic process', 'CPA', (108, 125))
803157	32123074	Remarkably, with genetic miR-31 knockout, Zn deficiency per se does not create a precancerous esophageal phenotype in ZD:miR-31-/- rats as it does in WT ZD:miR-31+/+ rats.	('precancerous esophageal', 'Disease', (81, 104))	('miR-31', 'Gene', (25, 31))	('precancerous esophageal', 'Disease', 'MESH:D011230', (81, 104))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('deficiency', 'Var', (45, 55))	('rats', 'Species', '10116', (166, 170))	('rats', 'Species', '10116', (131, 135))	('Zn', 'Chemical', 'MESH:D015032', (42, 44))
803163	32123074	Because inflammation, a hallmark of cancer, is central to the pathogenesis of ESCC, the data suggest that suppression of inflammation is a mechanism by which genetic miR-31 knockout abrogates ESCC development.	('inflammation', 'Disease', 'MESH:D007249', (121, 133))	('inflammation', 'Disease', 'MESH:D007249', (8, 20))	('inflammation', 'Disease', (8, 20))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('knockout', 'Var', (173, 181))	('inflammation', 'Disease', (121, 133))	('ESCC', 'Disease', (192, 196))	('cancer', 'Disease', (36, 42))	('miR-31', 'Gene', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('abrogates', 'NegReg', (182, 191))
803166	32123074	Our in situ miR-31 analysis by ISH and EGLN3/STK40-NF-kappaB-controlled COX-2/S100A8/S100A9 protein expression analysis revealed that genetic miR-31 deletion leads to suppression of the EGLN3/STK40-NF-kappaB-controlled inflammation pathway, opposite of results with ESCC-bearing ZD:CTRL esophagus and of human ESCC tissue, in which miR-31 overexpression suppresses EGLN3, setting free the NF-kappaB p65-controlled inflammation signal.	('deletion', 'Var', (149, 157))	('inflammation', 'Disease', 'MESH:D007249', (414, 426))	('inflammation', 'Disease', (219, 231))	('NF-kappaB', 'Gene', (198, 207))	('human', 'Species', '9606', (304, 309))	('S100A8/S100A9', 'Gene', '6279;6280', (78, 91))	('inflammation', 'Disease', (414, 426))	('S100A8/S100A9', 'Gene', (78, 91))	('NF-kappaB', 'Gene', '4790', (51, 60))	('miR-31', 'Gene', (142, 148))	('NF-kappaB', 'Gene', '4790', (389, 398))	('NF-kappaB', 'Gene', '4790', (198, 207))	('suppression', 'NegReg', (167, 178))	('NF-kappaB', 'Gene', (51, 60))	('EGLN3', 'MPA', (365, 370))	('NF-kappaB', 'Gene', (389, 398))	('inflammation', 'Disease', 'MESH:D007249', (219, 231))	('suppresses', 'NegReg', (354, 364))
803167	32123074	These data establish a connection between oncomiR-31 and EGLN3/STK40-NF-kappaB-controlled signaling in ESCC and establish the mechanism by which miR-31 promotes human ESCC.	('human', 'Species', '9606', (161, 166))	('miR-31', 'Var', (145, 151))	('ESCC', 'Disease', (167, 171))	('NF-kappaB', 'Gene', '4790', (69, 78))	('NF-kappaB', 'Gene', (69, 78))	('ESCC', 'Disease', (103, 107))	('promotes', 'PosReg', (152, 160))
803168	32123074	We predict this could be a mechanism for oncogenic miR-31 in inflammation-associated human cancers such as colorectal cancer, where miR-31 overexpression, EGLN3 down-regulation, and NF-kappaB activation have been reported.	('overexpression', 'PosReg', (139, 153))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('EGLN3', 'Var', (155, 160))	('cancers', 'Disease', (91, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('miR-31', 'Gene', (132, 138))	('NF-kappaB', 'Gene', '4790', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('activation', 'PosReg', (192, 202))	('inflammation', 'Disease', (61, 73))	('colorectal cancer', 'Disease', (107, 124))	('NF-kappaB', 'Gene', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('down-regulation', 'NegReg', (161, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))	('human', 'Species', '9606', (85, 90))
803175	32123074	Remarkably, despite sustained Zn deficiency, genetic miR-31 knockout produced an esophageal metabolome with limited metabolic changes in ZD:miR-31-/- esophagus compared with its ZS:miR-31-/- counterpart.	('ZD:miR-31-/-', 'Var', (137, 149))	('produced', 'Reg', (69, 77))	('esophageal metabolome', 'MPA', (81, 102))	('miR-31', 'Gene', (53, 59))	('Zn', 'Chemical', 'MESH:D015032', (30, 32))
803178	32123074	This genomic instability could be due to exposure of the rat GI tract to the nitrosamine carcinogen NMBA, and the accumulated mutations would likely show the mutational signature recently described for the environmental carcinogen NMBA.	('NMBA', 'Chemical', 'MESH:C014707', (100, 104))	('NMBA', 'Chemical', 'MESH:C014707', (231, 235))	('rat', 'Species', '10116', (57, 60))	('mutations', 'Var', (126, 135))	('due', 'Reg', (34, 37))	('nitrosamine', 'Chemical', 'MESH:D009602', (77, 88))
803180	32123074	But we emphasize that the suppression of epithelial proliferation and associated cellular signal pathways are also necessary for NMBA induction of mutations.	('mutations', 'Var', (147, 156))	('NMBA', 'Chemical', 'MESH:C014707', (129, 133))	('NMBA', 'Gene', (129, 133))	('rat', 'Species', '10116', (59, 62))
803184	32123074	Additionally, our study shows that counteracting the ESCC-promoting effect of dietary Zn-deficiency genetic miR-31 knockout leads to the eliminating of entire biological processes, including the miR-31-EGLN3/STK40-NF-kappaB-controlled inflammatory pathway, esophageal cancer metabolism, and an unstable genome.	('knockout', 'Var', (115, 123))	('NF-kappaB', 'Gene', (214, 223))	('esophageal cancer metabolism', 'Disease', (257, 285))	('esophageal cancer metabolism', 'Disease', 'MESH:D004938', (257, 285))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('miR-31', 'Gene', (108, 114))	('eliminating', 'NegReg', (137, 148))	('Zn-deficiency', 'Disease', (86, 99))	('NF-kappaB', 'Gene', '4790', (214, 223))	('Zn-deficiency', 'Disease', 'MESH:D007153', (86, 99))
803204	32123074	qPCR was performed using the DeltaDeltaCt method of qPCR data analysis and single-tube TaqMan gene expression assays with S100A8 (Rn00587579_g1), S100A9 (Rn00585879_m1), Ptgs2 (Rn01483828_m1), Egln3 (Rn00571341_m1), and Mboat2 (Rn01472966_m1) and normalizers Psmb6 (Rn02377140_g1) and Oaz1 (Rn01408148_g1).	('Rn01483828_m1', 'Var', (177, 190))	('Rn00587579_g1', 'Var', (130, 143))	('Ptgs2', 'Gene', '29527', (170, 175))	('Rn01472966_m1', 'Var', (228, 241))	('Rn02377140_g1', 'Var', (266, 279))	('Mboat2', 'Gene', (220, 226))	('Oaz1', 'Gene', '25502', (285, 289))	('Rn01408148_g1', 'Var', (291, 304))	('Mboat2', 'Gene', '313997', (220, 226))	('Ptgs2', 'Gene', (170, 175))	('Egln3', 'Gene', (193, 198))	('Psmb6', 'Gene', (259, 264))	('Rn00585879_m1', 'Var', (154, 167))	('Psmb6', 'Gene', '29666', (259, 264))	('Egln3', 'Gene', '54702', (193, 198))	('Rn00571341_m1', 'Var', (200, 213))	('Oaz1', 'Gene', (285, 289))
803207	32123074	Substitutions in predicted miR-31-5p binding sites to produce mutated sites unable to bind miR-31-5p were introduced by using the QuikChange II XL Site-Directed Mutagenesis Kit (Stratagene) following the manufacturer's instructions (see oligonucleotides used in SI Appendix, Table S10).	('SI Appendix', 'Disease', (262, 273))	('rat', 'Species', '10116', (180, 183))	('oligonucleotides', 'Chemical', 'MESH:D009841', (237, 253))	('miR-31-5p', 'Gene', (27, 36))	('Substitutions', 'Var', (0, 13))	('SI Appendix', 'Disease', 'MESH:D001063', (262, 273))
803211	32123074	IHC was performed using primary antibodies for PCNA (clone PC-10; Ab-1; Thermo Scientific), KRT14 (NCL-LL002; Novocastra), COX-2 (12282; Cell Signaling), S100A8 (T-1032; BMA), S100A9 (NB110-89726; Novus Biologicals), NF-kappaB p65 (ab7970; Abcam), STK40 (orb101780; Biorbyt), EGLN3 (orb443107; Biorbyt), and MBOAT2 (orb185503; Biorbyt).	('PCNA', 'Gene', '25737', (47, 51))	('PCNA', 'Gene', (47, 51))	('NB110-89726', 'Var', (184, 195))	('NCL', 'Gene', (99, 102))	('orb101780', 'Var', (255, 264))	('NCL', 'Gene', '25135', (99, 102))	('orb185503', 'Var', (316, 325))	('NF-kappaB', 'Gene', '4790', (217, 226))	('KRT14', 'Gene', (92, 97))	('NF-kappaB', 'Gene', (217, 226))	('orb443107;', 'Var', (283, 293))	('KRT14', 'Gene', '287701', (92, 97))	('ab7970', 'Var', (232, 238))
803242	32038497	We rated the claimed statistically significant (P < 0.05) associations between aspirin and cancer risk into four levels:strong, highly suggestive, suggestive, and weak according to the following criteria: P < 10-6, >1,000 cases, P < 0.05 of the largest study in the meta-analysis, I2 <50%, absence of small-study effects (P > 0.1 for Egger's test), the 95% PI excludes the null value, no excess significance bias (P > 0.1), and survived the 10% credibility ceiling (P < 0.05) for strong evidence; P < 10-6, >1,000 cases, P < 0.05 of the largest study in the meta-analysis for highly suggestive evidence; P < 10-3, >1,000 cases for suggestive evidence; and P < 0.05 for weak evidence.	('P <', 'Var', (604, 607))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('aspirin', 'Chemical', 'MESH:D001241', (79, 86))
803373	31016545	In IAPF cases, portal pressure is predicted to be high owing to the anastomosis between the artery and the portal vein.	('IAPF', 'Disease', (3, 7))	('anastomosis', 'Var', (68, 79))	('portal pressure', 'MPA', (15, 30))	('IAPF', 'Disease', 'None', (3, 7))
803374	31016545	Embolizing the branch of the portal vein with the IVR technique to reduce the portal vein pressure may cause embolic material to be swept away, and we think that the risk is high in IAPF cases.	('embolic', 'Disease', (109, 116))	('Embolizing', 'Var', (0, 10))	('IAPF', 'Disease', (182, 186))	('embolic material', 'Phenotype', 'HP:0001907', (109, 125))	('embolic', 'Disease', 'MESH:D004617', (109, 116))	('IAPF', 'Disease', 'None', (182, 186))	('cause', 'Reg', (103, 108))
803397	28083550	The average rates of maternal health management, hospital delivery, and under-three health management were higher in eastern rural China than those in central and western rural China.	('man', 'Species', '9606', (91, 94))	('man', 'Species', '9606', (37, 40))	('men', 'Species', '9606', (97, 100))	('hospital delivery', 'CPA', (49, 66))	('men', 'Species', '9606', (43, 46))	('under-three', 'Var', (72, 83))	('maternal health management', 'CPA', (21, 47))	('higher', 'PosReg', (107, 113))
803444	28083550	Cigarette smoking was also associated with a statistically significant increased risk of stomach cancer.	('Cigarette smoking', 'Var', (0, 17))	('stomach cancer', 'Disease', (89, 103))	('increased risk of stomach cancer', 'Phenotype', 'HP:0006753', (71, 103))	('increased risk of stomach', 'Phenotype', 'HP:0005207', (71, 96))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('stomach cancer', 'Disease', 'MESH:D013274', (89, 103))	('stomach cancer', 'Phenotype', 'HP:0012126', (89, 103))
803469	28083550	Numerous studies targeting certain genes have reported an association of genetic polymorphisms with esophageal cancer risk in the Chinese population.	('association', 'Interaction', (58, 69))	('esophageal cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('genetic polymorphisms', 'Var', (73, 94))
803515	26862846	Sca-1 induced disruption of TGF-beta signaling is required in vivo tumorigenesis in breast cancer models.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('tumor', 'Disease', (67, 72))	('Sca-1', 'Gene', '110454', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('TGF-beta', 'Protein', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Sca-1', 'Gene', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('disruption', 'Var', (14, 24))	('breast cancer', 'Disease', (84, 97))
803527	26862846	The somatic copy number gain in 8q has been associated with most prevalent copy number gain in multiple cancer types.	('copy number gain', 'Var', (12, 28))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('multiple cancer', 'Disease', 'MESH:D009369', (95, 110))	('copy number gain', 'Var', (75, 91))	('multiple cancer', 'Disease', (95, 110))
803550	26862846	Ly6D mRNA expression was significantly increased in triple negative breast cancer (TNBC) (n=700) compared to 2667 sample of non-TNBC (n=2667), grade 3 (n=47) than grade 2 (n=27), grade N1 (n=190) than grade N0 (n=137), tumors with p53 mutation (n=130) than p53 wildtype tumors (n=261), tumors with BRCA1 mutation (n= 38) than BRCA1 wildtype tumors (n=157), ERBB2 positive (n=92) than ERBB2 negative (n=48) tumors, basal type (n=16) than luminal (n=27) in The Cancer Genome Atlas (TCGA) (Unpublished, NCI), Stickeler, Minn, Waddell, Gluck, Bild, Kao, Bittner (unpublished, GSE2109), Farmer, Korde, Richardson, Esserman, Chin, Ginestier, vantVeer, Curtis, Ivshina, Bonnefoi and Hatzis studies.	('mutation', 'Var', (235, 243))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumors', 'Disease', (341, 347))	('tumors', 'Disease', (286, 292))	('Ly6D', 'Gene', '8581', (0, 4))	('ERBB2', 'Gene', '2064', (384, 389))	('p53', 'Gene', '7157', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('mutation', 'Var', (304, 312))	('BRCA1', 'Gene', '672', (298, 303))	('tumors', 'Disease', (406, 412))	('Kao', 'Gene', (545, 548))	('tumors', 'Disease', (270, 276))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('BRCA1', 'Gene', (298, 303))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (459, 478))	('p53', 'Gene', (231, 234))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('BRCA1 wildtype tumors', 'Disease', (326, 347))	('tumors', 'Disease', 'MESH:D009369', (341, 347))	('BRCA1', 'Gene', '672', (326, 331))	('ERBB2', 'Gene', (357, 362))	('BRCA1 wildtype tumors', 'Disease', 'MESH:D009369', (326, 347))	('BRCA1', 'Gene', (326, 331))	('Kao', 'Gene', '26', (545, 548))	('tumors', 'Disease', 'MESH:D009369', (406, 412))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('Curtis', 'Disease', (646, 652))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('Cancer Genome Atlas', 'Disease', (459, 478))	('tumors', 'Disease', (219, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('ERBB2', 'Gene', '2064', (357, 362))	('Cancer', 'Phenotype', 'HP:0002664', (459, 465))	('p53', 'Gene', '7157', (257, 260))	('GSE2109', 'Chemical', '-', (572, 579))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('ERBB2', 'Gene', (384, 389))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('breast cancer', 'Disease', (68, 81))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('Curtis', 'Disease', 'MESH:C537936', (646, 652))	('increased', 'PosReg', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (406, 412))	('p53', 'Gene', (257, 260))	('Ly6D', 'Gene', (0, 4))
803582	26862846	Ly6E mRNA expression was significantly higher in superficial bladder cancer (n=28) than infiltrating bladder cancer (n=81) and high expression of Ly6E was correlated with higher grade (infiltrating grade 3, n=75 vs infiltrating grade 2, n=6) in Sanchez-Carbayo study.	('higher', 'PosReg', (39, 45))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('high', 'Var', (127, 131))	('mRNA expression', 'MPA', (5, 20))	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('bladder cancer', 'Disease', (101, 115))	('Ly6E', 'Gene', (0, 4))	('bladder cancer', 'Disease', (61, 75))	('Ly6E', 'Gene', '4061', (0, 4))	('Ly6E', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('Ly6E', 'Gene', '4061', (146, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))
803583	26862846	Ly6E mRNA expression was significantly higher in medulloblastoma with CTNNB1 mutation (n=8) than CTNNB1 wildtype tumors (n=38), medulloblastoma with CTNNB1 positive by immunohistochemistry (IHC) (n=6) than CTNNB1 IHC negative (n=44), tumors with MycN amplification (n=14) than tumors not amplified for MycN (n=32) in Kool, Robinson and Janoueix-Lerosey studies.	('medulloblastoma', 'Disease', (128, 143))	('higher', 'PosReg', (39, 45))	('tumors', 'Disease', (113, 119))	('mutation', 'Var', (77, 85))	('Ly6E', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('Ly6E', 'Gene', '4061', (0, 4))	('tumors', 'Disease', (277, 283))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('CTNNB1', 'Gene', '1499', (97, 103))	('MycN', 'Gene', (302, 306))	('MycN', 'Gene', (246, 250))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('CTNNB1', 'Gene', '1499', (206, 212))	('CTNNB1', 'Gene', '1499', (70, 76))	('CTNNB1', 'Gene', '1499', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('CTNNB1', 'Gene', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('CTNNB1', 'Gene', (206, 212))	('tumors', 'Disease', (234, 240))	('medulloblastoma', 'Disease', 'MESH:D008527', (49, 64))	('MycN', 'Gene', '4613', (302, 306))	('medulloblastoma', 'Disease', 'MESH:D008527', (128, 143))	('MycN', 'Gene', '4613', (246, 250))	('medulloblastoma', 'Phenotype', 'HP:0002885', (49, 64))	('CTNNB1', 'Gene', (70, 76))	('medulloblastoma', 'Phenotype', 'HP:0002885', (128, 143))	('CTNNB1', 'Gene', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('medulloblastoma', 'Disease', (49, 64))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
803602	26862846	These data show that high Ly6E expression was significantly correlated with poor clinical outcome in glioma, breast, gastric, lung, ovarian and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('Ly6E', 'Gene', (26, 30))	('lung', 'Disease', (126, 130))	('ovarian and colorectal cancer', 'Disease', 'MESH:D015179', (132, 161))	('Ly6E', 'Gene', '4061', (26, 30))	('glioma', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('gastric', 'Disease', (117, 124))	('high', 'Var', (21, 25))	('expression', 'MPA', (31, 41))	('breast', 'Disease', (109, 115))	('clinical', 'Species', '191496', (81, 89))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
803628	26862846	These data show that high Ly6H expression was significantly correlated with poor clinical outcome in in breast, colon, lung, ovarian and gastric cancer.	('Ly6H', 'Gene', '4062', (26, 30))	('colon, lung, ovarian and gastric cancer', 'Disease', 'MESH:D013274', (112, 151))	('breast', 'Disease', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('high', 'Var', (21, 25))	('Ly6H', 'Gene', (26, 30))	('clinical', 'Species', '191496', (81, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
803660	26862846	These data show that high Ly6K expression was significantly correlated with poor clinical outcome in bladder, brain and CNS, kidney, breast, lung and ovarian cancer.	('clinical', 'Species', '191496', (81, 89))	('breast, lung and ovarian cancer', 'Disease', 'MESH:D010051', (133, 164))	('bladder', 'Disease', (101, 108))	('ovarian cancer', 'Phenotype', 'HP:0100615', (150, 164))	('high', 'Var', (21, 25))	('Ly6K', 'Gene', '54742', (26, 30))	('expression', 'MPA', (31, 41))	('kidney', 'Disease', (125, 131))	('Ly6K', 'Gene', (26, 30))	('CNS', 'Disease', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
803678	26862846	Recently experimental validation of the important role for AP-1 activation in promoting LY6K gene expression was observed, whereas the SNP242 C allele or methylation of the CpG site was associated with reduced Ly6K expression via inhibition of AP1, suggesting additional level of complexities in regulation of Ly6 genes.	('reduced', 'NegReg', (202, 209))	('Ly6', 'Gene', '17062', (210, 213))	('Ly6', 'Gene', (210, 213))	('methylation', 'Var', (154, 165))	('AP1', 'Gene', '3727', (244, 247))	('expression', 'MPA', (215, 225))	('AP-1', 'Gene', (59, 63))	('Ly6K', 'Gene', '54742', (210, 214))	('promoting', 'PosReg', (78, 87))	('AP1', 'Gene', (244, 247))	('LY6K', 'Gene', '54742', (88, 92))	('Ly6', 'Gene', '17062', (310, 313))	('SNP242', 'Gene', (135, 141))	('Ly6', 'Gene', (310, 313))	('LY6K', 'Gene', (88, 92))	('inhibition', 'NegReg', (230, 240))	('Ly6K', 'Gene', (210, 214))	('expression', 'MPA', (98, 108))
803701	23614023	For the results of Cox proportional hazards regression analysis, SPMs had a significant influence on survival rates with univariate (HR 2.59,95% CI 2.53to 2.65) and multivariate analysis (HR 2.34, 2.28 to 2.40).	('Cox', 'Gene', (19, 22))	('influence', 'Reg', (88, 97))	('survival rates', 'CPA', (101, 115))	('SPMs', 'Var', (65, 69))	('Cox', 'Gene', '1351', (19, 22))
803713	23614023	Population-based cancer databases have documented the significant impact of SPMs on HNC.It has been estimated that approximately one-third of HNSCC deaths are attributable to SPMs; therefore, estimating their impact on survival ratesis essential.	('HNSCC deaths', 'Disease', 'MESH:D000077195', (142, 154))	('SPMs', 'Var', (175, 179))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('HNC', 'Phenotype', 'HP:0012288', (84, 87))	('HNSCC deaths', 'Disease', (142, 154))	('cancer', 'Disease', (17, 23))	('men', 'Species', '9606', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
803791	23420294	Alterations in the PI3K/Akt signaling pathway have also been implicated in the occurrence and development of human cancer.	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('Alterations', 'Var', (0, 11))	('implicated', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Akt', 'Gene', '207', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('Akt', 'Gene', (24, 27))
803866	23420294	Activated Akt indirectly signals IkappaB phosphorylation, thereby promoting transcription of anti-apoptotic genes, whereas inactivation of Akt promotes apoptosis.	('inactivation', 'Var', (123, 135))	('promoting', 'PosReg', (66, 75))	('Akt', 'Gene', '207', (139, 142))	('anti-apoptotic genes', 'Gene', (93, 113))	('IkappaB', 'Protein', (33, 40))	('Akt', 'Gene', (139, 142))	('phosphorylation', 'MPA', (41, 56))	('transcription', 'MPA', (76, 89))	('Akt', 'Gene', '207', (10, 13))	('apoptosis', 'CPA', (152, 161))	('Akt', 'Gene', (10, 13))
803871	23420294	In the present study, the results revealed that a decrease in the expression of mTOR and p-mTOR along with downregulated expression of p-Akt upon baicalein treatement, corroborated well with the growth inhibition and induction of apoptosis in EC-109 cells.	('EC-109', 'CellLine', 'CVCL:6898', (243, 249))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('Akt', 'Gene', '207', (137, 140))	('expression', 'MPA', (121, 131))	('expression', 'MPA', (66, 76))	('treatement', 'Var', (156, 166))	('mTOR', 'Gene', '2475', (91, 95))	('growth inhibition', 'CPA', (195, 212))	('downregulated', 'NegReg', (107, 120))	('mTOR', 'Gene', (91, 95))	('Akt', 'Gene', (137, 140))	('baicalein', 'Chemical', 'MESH:C006680', (146, 155))	('decrease', 'NegReg', (50, 58))
803889	33979405	Patients receiving nRT had distinctly better survival than those receiving surgical treatment alone (p = 0.008), but had similar survival compared with patients treated with aRT (p = 0.989) or surgery combined with chemotherapy (p = 0.205) in the T3N0/T1-3N+M0 subgroup.	('nRT', 'Var', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (152, 160))	('better', 'PosReg', (38, 44))
803891	33979405	In these carefully selected patients, the present study made the following recommendations: nRT can improve the prognosis of patients with T3N0M0/T1-3N+M0 and T4 Siewert type II GEA, and it seems to be a better treatment for T4 patients.	('patients', 'Species', '9606', (228, 236))	('T3N0M0/T1-3N+M0', 'Var', (139, 154))	('improve', 'PosReg', (100, 107))	('patients', 'Species', '9606', (28, 36))	('prognosis', 'MPA', (112, 121))	('patients', 'Species', '9606', (125, 133))
803906	33979405	In addition, radiotherapy may lead to edema, fibrosis, and normal tissue structure disorder in the surrounding tissues of the tumor, which makes it difficult for the surgeon to perform radical resection and increases the probability of postoperative complications.	('normal tissue structure disorder', 'CPA', (59, 91))	('lead to', 'Reg', (30, 37))	('edema', 'Disease', (38, 43))	('fibrosis', 'Disease', (45, 53))	('fibrosis', 'Disease', 'MESH:D005355', (45, 53))	('radiotherapy', 'Var', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('edema', 'Disease', 'MESH:D004487', (38, 43))	('edema', 'Phenotype', 'HP:0000969', (38, 43))	('tumor', 'Disease', (126, 131))
803926	33979405	Insurance, marital status, age, race, gender, pathological type, tumor grade, T stage, RNE and tumor size were used as matching criteria to estimate propensity scores in the T1-2N0M0 group.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('T1-2N0M0', 'Var', (174, 182))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (95, 100))
803937	33979405	The prognosis of patients undergoing nRT distinctly won upon that of patients undergoing surgical treatment alone (HR 0.765, 95%CI 0.621-0.943; p = 0.008), with median survival times of 48 and 39 months, respectively.	('patients', 'Species', '9606', (69, 77))	('won', 'Reg', (52, 55))	('nRT', 'Var', (37, 40))	('patients', 'Species', '9606', (17, 25))
803950	33979405	What's more, another large retrospective analysis showed that nRT seems to enhance the venture of death among patients with resectable GEA.	('death', 'Disease', 'MESH:D003643', (98, 103))	('death', 'Disease', (98, 103))	('nRT', 'Var', (62, 65))	('enhance', 'PosReg', (75, 82))	('patients', 'Species', '9606', (110, 118))
803955	33979405	With these questions in mind, GEA patients were separated into three subgroups: T1-2N0M0, T3N0/T1-3N+M0, and T4NxM0 to analyze the influence of various therapy options including nRT on the prognosis.	('T1-2N0M0', 'Var', (80, 88))	('T3N0/T1-3N+M0', 'Var', (90, 103))	('patients', 'Species', '9606', (34, 42))	('T4NxM0', 'Var', (109, 115))
803956	33979405	Firstly, the results revealed that nRT was detrimental to prolonged survival in T1-2N0M0 patients.	('T1-2N0M0', 'Var', (80, 88))	('prolonged', 'PosReg', (58, 67))	('patients', 'Species', '9606', (89, 97))
803961	33979405	In addition, the T1-2N0M0 stage esophageal cancer or GEA is a localized disease in which the tumor infiltrates into the submucosal layer and may increase the risk of lymph node metastasis, but removal of tumor lesions and local lymph node dissection may be adequate to bring the disease under control, and additional neoadjuvant or adjuvant therapy may have no prognostic benefit.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer', 'Disease', (43, 49))	('T1-2N0M0 stage', 'Var', (17, 31))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor lesions', 'Disease', (204, 217))	('tumor lesions', 'Disease', 'MESH:D009369', (204, 217))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
803963	33979405	The results of a European multicenter retrospective study, which collected data from 30 European centers of patients undergoing esophageal/ GEA surgery, suggest a remarkable survival advantage from nRT for T3N0M0 carcinoma of esophagus.	('survival advantage', 'CPA', (174, 192))	('carcinoma', 'Disease', (213, 222))	('carcinoma', 'Disease', 'MESH:D009369', (213, 222))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (213, 235))	('T3N0M0', 'Var', (206, 212))	('patients', 'Species', '9606', (108, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))
803964	33979405	This also further confirms our findings that T3N0M0 should be considered as a locally advanced esophageal cancer like T1-3N+M0, which can benefit from neoadjuvant therapy, but the risk of postoperative complications will not increase significantly.	('esophageal', 'Disease', (95, 105))	('T3N0M0', 'Var', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
803967	33979405	We observed that nRT improved the OS of T3N0M0/T1-3N+M0 and T4 stage GEA patients.	('T3N0M0/T1-3N+M0', 'Var', (40, 55))	('patients', 'Species', '9606', (73, 81))	('improved', 'PosReg', (21, 29))
803969	33979405	Most of the GEA patients with stage T4 invade adjacent structures (such as lung, large blood vessels, and trachea), and the prognosis is greatly dismal.	('patients', 'Species', '9606', (16, 24))	('stage T4', 'Var', (30, 38))	('invade', 'Reg', (39, 45))
803989	31112371	35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small-spot IMPT and the remaining 16 of them received VMAT.	('distal', 'Disease', (3, 9))	('esophageal carcinoma', 'Disease', (10, 30))	('VMAT', 'Disease', (146, 150))	('patients', 'Species', '9606', (74, 82))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (10, 30))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (10, 30))	('small-spot', 'Var', (92, 102))	('patients', 'Species', '9606', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('VMAT', 'Disease', 'None', (146, 150))
803990	31112371	In the nominal scenario, small-spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE], lung Dmean, heart Dmean compared with VMAT.	('VMAT', 'Disease', (151, 155))	('small-spot', 'Var', (25, 35))	('lower', 'NegReg', (79, 84))	('V30Gy[RBE]', 'MPA', (101, 111))	('liver Dmean', 'MPA', (85, 96))	('VMAT', 'Disease', 'None', (151, 155))	('heart Dmean', 'MPA', (125, 136))	('lung Dmean', 'MPA', (113, 123))
803991	31112371	In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE], liver V30Gy[RBE], stomach V45Gy[RBE], lung Dmean, V5Gy[RBE], and V20Gy[RBE], cord Dmax and , liver Dmean, heart V20Gy[RBE], and V30Gy[RBE], but IMPT was significantly worse for CTVhigh D95%, , and D5%-D95%, CTVlow D95%, heart Dmean, and V40Gy[RBE], requiring careful and experienced adjustments during the planning process and robustness considerations.	('VMAT', 'Disease', (42, 46))	('V40Gy[RBE', 'Var', (329, 338))	('VMAT', 'Disease', 'None', (42, 46))	('D5%-D95%', 'Var', (289, 297))	('V30Gy[', 'Var', (220, 226))
803992	31112371	Small-spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness.	('VMAT', 'Disease', 'None', (76, 80))	('plan', 'MPA', (123, 127))	('Small-spot', 'Var', (0, 10))	('VMAT', 'Disease', (76, 80))	('decreases', 'NegReg', (16, 25))	('doses', 'MPA', (26, 31))
803998	31112371	However, smaller spot-size plans can exacerbate the negative consequences of patient setup uncertainty and make interplay effects more prominent.25, 31 As a result, we first need to quantify and then mitigate the impact of uncertainties and interplay effects for small-spot IMPT for the treatment of distal esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (318, 325))	('small-spot', 'Var', (263, 273))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('esophageal cancers', 'Disease', (307, 325))	('patient', 'Species', '9606', (77, 84))	('esophageal cancers', 'Disease', 'MESH:D004938', (307, 325))
804037	31112371	Compared to the VMAT plans, IMPT plans did not significantly differ with respect to the following: CTVhigh  (normalized by the prescription doses), CTVhigh D5%-D95% (normalized by the prescription doses), CTVlow dose coverage, and protection of other OARs including kidney V18Gy[RBE], stomach V45Gy[RBE], cord Dmax and , lung V20Gy[RBE], and heart V30Gy[RBE] and V40Gy[RBE] [Figs.	('V40Gy[RBE]', 'Var', (363, 373))	('heart', 'Disease', (342, 347))	('cord Dmax', 'Disease', (305, 314))	('stomach', 'Disease', (285, 292))	('VMAT', 'Disease', 'None', (16, 20))	('VMAT', 'Disease', (16, 20))	('kidney', 'Disease', (266, 272))	('lung', 'Disease', (321, 325))
804039	31112371	Similarly, close proximity of the heart to a tumor resulted in the outliers in heart V30Gy[RBE] and V40Gy[RBE] [Fig.	('heart', 'MPA', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('V40Gy[RBE', 'Var', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
804041	31112371	To avoid vital organs including cord and lungs for this patient, we had to limit target dose coverage and homogeneity to some degree in VMAT, resulting in additional outliers in D5%-D95% [Fig.	('patient', 'Species', '9606', (56, 63))	('D5%-D95% [', 'Var', (178, 188))	('VMAT', 'Disease', 'None', (136, 140))	('VMAT', 'Disease', (136, 140))
804042	31112371	The robustness of IMPT plans was comparable to that of VMAT plans for kidney V18Gy[RBE], liver V30Gy[RBE], stomach V45Gy[RBE], lung Dmean, V5Gy[RBE] and V20Gy[RBE], cord Dmax and , liver Dmean, heart V20Gy[RBE] and V30Gy[RBE].	('VMAT', 'Disease', (55, 59))	('V30Gy[RBE]', 'Var', (215, 225))	('V20Gy[RBE', 'Var', (153, 162))	('V5Gy[RBE', 'Var', (139, 147))	('VMAT', 'Disease', 'None', (55, 59))
804043	31112371	The robustness of IMPT plans was statistically worse than that of VMAT plans for CTVhigh D95% (normalized by the prescription doses), CTVhigh  (normalized by the prescription doses), CTVhigh D5%-D95% (normalized by the prescription doses), CTVlow D95% (normalized by the prescription doses), heart Dmean and V40Gy[RBE] (Fig.	('VMAT', 'Disease', (66, 70))	('CTVhigh', 'Var', (183, 190))	('heart Dmean', 'Disease', (292, 303))	('CTVlow D95%', 'Var', (240, 251))	('V40Gy', 'Var', (308, 313))	('VMAT', 'Disease', 'None', (66, 70))
804045	31112371	Small spot-size IMPT is an attractive modality for the treatment of esophageal cancer.	('Small spot-size', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('esophageal cancer', 'Disease', (68, 85))
804047	31112371	We found that small-spot IMPT achieved similar plan quality as VMAT in terms of target dose coverage, homogeneity, and sparing of most OARs.	('VMAT', 'Disease', (63, 67))	('small-spot', 'Var', (14, 24))	('homogeneity', 'MPA', (102, 113))	('VMAT', 'Disease', 'None', (63, 67))
804052	31112371	Small-spot IMPT should be considered for the routine treatment in patients with distal esophageal carcinoma.	('Small-spot', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('esophageal carcinoma', 'Disease', (87, 107))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('patients', 'Species', '9606', (66, 74))
804066	31112371	Furthermore, more patient data with short/long-term clinical outcomes, perioperative complications, gradation-related toxicities, and patient-reported outcome should be reported to evaluate the potential clinical benefits of small-spot IMPT over VMAT plans.	('toxicities', 'Disease', (118, 128))	('VMAT', 'Disease', 'None', (246, 250))	('patient', 'Species', '9606', (18, 25))	('small-spot', 'Var', (225, 235))	('VMAT', 'Disease', (246, 250))	('toxicities', 'Disease', 'MESH:D064420', (118, 128))	('patient', 'Species', '9606', (134, 141))
804067	31112371	Compared to VMAT, small-spot IMPT significantly improves RT sparing of the heart, liver, and lungs, as well as achieves clinically acceptable plan robustness.	('small-spot', 'Var', (18, 28))	('VMAT', 'Disease', 'None', (12, 16))	('VMAT', 'Disease', (12, 16))	('plan', 'MPA', (142, 146))	('RT sparing', 'MPA', (57, 67))	('improves', 'PosReg', (48, 56))
804068	31112371	Our results support the feasibility and acceptability for the routine clinical use of small-spot IMPT in patients with distal esophageal carcinoma.	('small-spot', 'Var', (86, 96))	('esophageal carcinoma', 'Disease', (126, 146))	('patients', 'Species', '9606', (105, 113))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (126, 146))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (126, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))
804070	30151106	Unusual lymph node metastasis from cancer of the thoracic esophagus A 76-year-old male received concurrent chemoradiotherapy, at a dose of 60 Gy with low-dose 5-fluorouracil, for cT1bN0M0 squamous cell carcinoma of the mid-thoracic esophagus.	('5-fluorouracil', 'Chemical', 'MESH:D005472', (159, 173))	('Unusual lymph node', 'Phenotype', 'HP:0002733', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('squamous cell carcinoma', 'Disease', (188, 211))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('cT1bN0M0', 'Var', (179, 187))	('cancer', 'Disease', (35, 41))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 211))
804104	28423530	Independent predictors for poorer OS were N stage, hoarseness and recurrent laryngeal nerve lymph node (RLN) involvement, and predictors for LRFFS were N stage and EQD2 (equivalent dose in 2 Gy fraction) to gross tumor volume (GTV), with >= 66Gy achieving local control of 94.7%.	('tumor', 'Disease', (213, 218))	('GTV', 'Chemical', '-', (227, 230))	('N stage', 'CPA', (42, 49))	('hoarseness', 'Disease', (51, 61))	('EQD2', 'Var', (164, 168))	('recurrent laryngeal nerve lymph node', 'CPA', (66, 102))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('hoarseness', 'Phenotype', 'HP:0001609', (51, 61))	('LRFFS', 'Disease', (141, 146))	('OS', 'Chemical', '-', (34, 36))
804126	28423530	Positive RLN seen on diagnostic imaging were significantly associated with worse OS, DMFS and PFS, whereas lower N stage (0-1) was associated with significantly better OS, LRFFS, DMFS and PFS.	('DMFS', 'Disease', (85, 89))	('PFS', 'Disease', (94, 97))	('DMFS', 'Chemical', '-', (85, 89))	('DMFS', 'Chemical', '-', (179, 183))	('Positive RLN', 'Var', (0, 12))	('LRFFS', 'Disease', (172, 177))	('OS', 'Chemical', '-', (81, 83))	('RLN', 'Var', (9, 12))	('OS', 'Chemical', '-', (168, 170))
804148	28423530	One study has shown that dose escalation in esophageal cancer based on 18FDG-PET/CT could be achieved up to70Gy safely by SIB technique.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('esophageal cancer', 'Disease', (44, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('18FDG-PET/CT', 'Var', (71, 83))
804150	28423530	There was a trend towards an increase in LRFFS when the EQD2 dose was increased from 56Gy to 66Gy, with 66Gy and above achieving a high LRFFS rate of 94.7%, which was in accordance with one study showing that the 2-year OS rate was significantly better in the patients receiving 66 Gy (55.6% vs 37.5%).	('patients', 'Species', '9606', (260, 268))	('OS', 'Chemical', '-', (220, 222))	('66Gy', 'Var', (104, 108))	('better', 'PosReg', (246, 252))
804161	28423530	Therefore, the RLN chains and supraclavicular/cervical region treatment should be prophylactically covered if not already involved, as evidenced by the fact that patients receiving ENI had significantly better RFFS than those receiving IFI.	('better', 'PosReg', (203, 209))	('patients', 'Species', '9606', (162, 170))	('RFFS', 'MPA', (210, 214))	('ENI', 'Var', (181, 184))
804290	22560576	One of these is RNA polymerase III (POL3) antibody, which relates to severe renal disease in the form of scleroderma renal crisis.	('scleroderma', 'Phenotype', 'HP:0100324', (105, 116))	('scleroderma renal crisis', 'Disease', (105, 129))	('renal disease', 'Phenotype', 'HP:0000112', (76, 89))	('scleroderma renal crisis', 'Disease', 'MESH:D007674', (105, 129))	('renal disease', 'Disease', (76, 89))	('renal disease', 'Disease', 'MESH:D007674', (76, 89))	('POL3', 'Gene', (36, 40))	('antibody', 'Var', (42, 50))
804458	22560576	In addition, those treated with MTX significantly improved and had significantly less relapse compared to those on CS alone.	('MTX', 'Var', (32, 35))	('MTX', 'Chemical', 'MESH:D008727', (32, 35))	('improved', 'PosReg', (50, 58))	('less', 'NegReg', (81, 85))	('relapse', 'CPA', (86, 93))
804463	26275531	Phase I trial of combination of FOLFIRI and pasireotide, a somatostatin analogue, in advanced gastrointestinal malignancies Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors including sst1, 2, 3 and 5 and inhibit insulin like growth factor-1.	('pasireotide', 'Disease', (44, 55))	('binding affinity', 'Interaction', (180, 196))	('somatostatin', 'Gene', (201, 213))	('insulin like growth factor-1', 'Gene', (263, 291))	('FOLFIRI', 'Chemical', '-', (32, 39))	('somatostatin', 'Gene', '6750', (150, 162))	('somatostatin', 'Gene', '6750', (201, 213))	('somatostatin', 'Gene', '6750', (59, 71))	('Pasireotide', 'Var', (124, 135))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('insulin like growth factor-1', 'Gene', '3479', (263, 291))	('somatostatin', 'Gene', (150, 162))	('pasireotide', 'Disease', 'None', (44, 55))	('somatostatin', 'Gene', (59, 71))	('sst1, 2, 3 and 5', 'Gene', '25992', (234, 250))	('inhibit', 'NegReg', (255, 262))	('malignancies', 'Disease', (111, 123))
804559	26275531	In vivo models utilizing mutations associated with low IGF-1 levels or genetic manipulations to decrease ligand levels demonstrates that reduced IGF levels decreases tumor growth.	('IGF-1', 'Gene', (55, 60))	('decreases tumor', 'Disease', (156, 171))	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('decreases tumor', 'Disease', 'MESH:D002303', (156, 171))	('IGF levels', 'MPA', (145, 155))	('ligand levels', 'MPA', (105, 118))	('rat', 'Species', '10116', (126, 129))	('low IGF', 'Phenotype', 'HP:0002850', (51, 58))	('reduced IGF levels', 'Phenotype', 'HP:0002850', (137, 155))	('reduced', 'NegReg', (137, 144))
804584	33495453	Recently, consideration of transcript-level changes within protein coding genes has enabled comprehensive characterization of isoform switching across multiple cancers, and extensive evidence now suggests noncoding transcripts and driver mutations within noncoding regions have important and functional roles in cancer by diverse mechanisms.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancers', 'Disease', (160, 167))	('cancer', 'Disease', (160, 166))	('mutations', 'Var', (238, 247))	('multiple cancer', 'Disease', (151, 166))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Disease', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('multiple cancer', 'Disease', 'MESH:D009369', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
804591	33495453	Likewise, PINT87aa is a circRNA-encoded small peptide, which partially controls cell proliferation and tumorigenesis in cancer cells, is expressed at a reduced level in glioblastoma tissue, and is correlated with tumor grade.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (120, 126))	('PINT87aa', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('N', 'Chemical', 'MESH:D009584', (12, 13))	('reduced', 'NegReg', (152, 159))	('cell proliferation', 'CPA', (80, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (169, 181))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (213, 218))	('glioblastoma', 'Disease', (169, 181))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('correlated', 'Reg', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('controls', 'Reg', (71, 79))
804592	33495453	Cells over-expressing PINT87aa exhibit decreased tumorigenic potential in animal models.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PINT87aa', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('over-expressing', 'PosReg', (6, 21))	('decreased', 'NegReg', (39, 48))
804604	33495453	In addition, analysis of all the GWAS-associated variants and mutations in the Catalog of Somatic Mutations in Cancer (COSMIC) and Human Gene Mutation Database (HGMD) databases revealed that a significant proportion of variants and mutations map to apparent noncoding regions of the human genome (Fig.	('HGMD', 'Disease', 'None', (161, 165))	('map', 'Reg', (242, 245))	('variants', 'Var', (219, 227))	('variants', 'Var', (49, 57))	('HGMD', 'Disease', (161, 165))	('mutations', 'Var', (232, 241))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', (111, 117))	('Human', 'Species', '9606', (131, 136))	('human', 'Species', '9606', (283, 288))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (62, 71))
804606	33495453	2a-d shows the top ~20 examples of COSMIC or HGMD mutations mapped to sORFs, Denovogenes, and Pseudogenes, demonstrating that these regions do indeed harbor mutations.	('HGMD', 'Disease', (45, 49))	('COSMIC', 'Gene', (35, 41))	('HGMD', 'Disease', 'None', (45, 49))	('mutations', 'Var', (50, 59))
804638	33495453	This suggested many nORF transcripts may have prognostic value, particularly in kidney clear cell carcinoma.	('nORF', 'Gene', (20, 24))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (80, 107))	('kidney clear cell carcinoma', 'Disease', (80, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('transcripts', 'Var', (25, 36))
804640	33495453	For a subset of 33 nORF transcripts: (i) the transcript is reproducibly differentially expressed in cancer compared with NAT and GTEx normal tissue, (ii) transcript expression is associated with prognosis (adjusted p-value < 0.05) and (iii) transcripts up-regulated in cancer are associated with poor prognosis, and vice versa.	('poor prognosis', 'CPA', (296, 310))	('associated with', 'Reg', (179, 194))	('transcript', 'MPA', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('transcripts', 'Var', (241, 252))	('up-regulated', 'PosReg', (253, 265))	('prognosis', 'Disease', (195, 204))	('N', 'Chemical', 'MESH:D009584', (121, 122))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
804652	33495453	Methylation, glycosylation, and phosphorylation were found to be significantly enriched in some novel protein datasets and NeXtProt proteins, compared to their individual random controls (Fig.	('Methylation', 'Var', (0, 11))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('glycosylation', 'MPA', (13, 26))	('enriched', 'Reg', (79, 87))	('phosphorylation', 'MPA', (32, 47))
804661	33495453	Figure 5b and c (left panel and right panel) show the number of unique COSMIC and HGMD mutations along with the disease origin of these mutations for sORFs (left panel) and undefined ORFs (right panel) that are conserved in the human genome.	('HGMD', 'Disease', 'None', (82, 86))	('HGMD', 'Disease', (82, 86))	('sORFs', 'Disease', (150, 155))	('mutations', 'Var', (136, 145))	('human', 'Species', '9606', (228, 233))	('mutations', 'Var', (87, 96))
804664	33495453	Figure 5d shows (a) predicted structure of a translated product from the undefined novel ORF in an intergenic region in chr 14, (b) predicted structure of an undefined novel ORF insertion in Rps3a1 ribosomal protein (cyan) with the inserted fragment (red), and (c) predicted structure of an undefined novel ORF product antisense to Raet1.	('Rps3a1', 'Gene', (191, 197))	('insertion', 'Var', (178, 187))	('Rps3a1', 'Gene', '20091', (191, 197))	('Raet1', 'Gene', (332, 337))	('Raet1', 'Gene', '19368', (332, 337))
804731	33495453	To investigate whether the novel protein regions could harbor disease-associated mutations, we mapped mutations from the COSMIC and HGMD databases to nORF peptides.	('HGMD', 'Disease', (132, 136))	('mutations', 'Var', (102, 111))	('HGMD', 'Disease', 'None', (132, 136))
804732	33495453	2 shows examples of COSMIC or HGMD mutations mapped to all human sORFs, Denovogenes, and Pseudogenes demonstrating that these regions do indeed harbor mutations.	('HGMD', 'Disease', 'None', (30, 34))	('human', 'Species', '9606', (59, 64))	('HGMD', 'Disease', (30, 34))	('mutations', 'Var', (35, 44))
804929	31624769	Immunohistochemical staining showing positivity for protein S-100, HMB-45, and melan-A and negativity for CK supports the diagnosis of malignant melanoma.	('S-100', 'Gene', (60, 65))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('positivity', 'Var', (37, 47))	('malignant melanoma', 'Phenotype', 'HP:0002861', (135, 153))	('S-100', 'Gene', '6271', (60, 65))	('malignant melanoma', 'Disease', 'MESH:D008545', (135, 153))	('HMB-45', 'Protein', (67, 73))	('malignant melanoma', 'Disease', (135, 153))	('melan-A', 'Gene', (79, 86))
804937	31624769	Targeted therapies include inhibition of the melanoma-associated genes BRAF and MEK; indeed, BRAF/MEK inhibitor combinations have become a standard therapy for patients with BRAF V600-mutated metastatic melanoma.	('MEK', 'Gene', '5609', (80, 83))	('BRAF', 'Gene', (93, 97))	('MEK', 'Gene', (98, 101))	('patients', 'Species', '9606', (160, 168))	('MEK', 'Gene', '5609', (98, 101))	('BRAF', 'Gene', '673', (71, 75))	('BRAF', 'Gene', '673', (93, 97))	('BRAF', 'Gene', '673', (174, 178))	('BRAF', 'Gene', (71, 75))	('melanoma', 'Disease', (45, 53))	('BRAF', 'Gene', (174, 178))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (203, 211))	('MEK', 'Gene', (80, 83))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('V600-mutated', 'Var', (179, 191))
804939	31624769	On the other hand, BRAF mutations are rare in mucosal melanomas, including esophageal melanoma, and activating mutations of the cell surface receptor tyrosine kinase are discovered more frequently.	('BRAF', 'Gene', '673', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('esophageal melanoma', 'Disease', 'MESH:D008545', (75, 94))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('BRAF', 'Gene', (19, 23))	('esophageal melanoma', 'Disease', (75, 94))	('tyrosine', 'Chemical', 'None', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('mutations', 'Var', (24, 33))	('mucosal melanomas', 'Disease', (46, 63))	('mucosal melanomas', 'Disease', 'MESH:D008545', (46, 63))
805018	30785303	The result of meta-analysis showed that compared with only undergoing RT treatment, JOEI associated with RT can enhance the performance status of patients with EC to about 59%.	('performance', 'MPA', (124, 135))	('JOEI', 'Var', (84, 88))	('JOEI', 'Chemical', '-', (84, 88))	('men', 'Species', '9606', (78, 81))	('patients', 'Species', '9606', (146, 154))	('enhance', 'PosReg', (112, 119))
805057	29290801	Similar to other types of cancers, ESCC is a complex disease with a multistep process of genetic alterations, including activation of oncogenes and inactivation of tumor suppressor genes (TSG).	('tumor', 'Disease', (164, 169))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('activation', 'PosReg', (120, 130))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('oncogenes', 'Protein', (134, 143))	('inactivation', 'Var', (148, 160))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('ESCC', 'Disease', (35, 39))
805070	29290801	To identify deregulated genes during ESCC development, Affymetrix cDNA microarray was applied to compare differentially expressed genes between 4 pairs of ESCC tumors and corresponding adjacent non-tumor tissues (#301, #327, #351 and #363), and one pair of esophageal dysplasia tissue and adjacent normal tissue (#314) (GSE100942).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('#301', 'Var', (213, 217))	('esophageal dysplasia', 'Disease', (257, 277))	('ESCC tumors', 'Disease', (155, 166))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('non-tumor', 'Disease', (194, 203))	('ESCC tumors', 'Disease', 'MESH:D004938', (155, 166))	('non-tumor', 'Disease', 'MESH:D009369', (194, 203))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (257, 277))
805079	29290801	In a Kaplan-Meier survival analysis comparing patients with different RHCG expression levels, high RHCG expression was significantly associated with long survival time (Log-rank test, P < 0.001).	('patients', 'Species', '9606', (46, 54))	('associated with', 'Reg', (133, 148))	('RHCG', 'Gene', (99, 103))	('expression', 'MPA', (104, 114))	('high', 'Var', (94, 98))
805081	29290801	Patients with tumor expressing high RHCG expression had the longest mean survival time of 39.6 months, whereas those without RHCG expression had the worst prognosis, with a mean overall survival of 25.2 months.	('RHCG', 'Gene', (36, 40))	('tumor', 'Disease', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('high', 'Var', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
805082	29290801	Multivariate Cox regression analysis further revealed that loss of RHCG was an independent prognostic marker for the overall survival of ESCC patients (hazard ratio, 0.541; 95% confidence interval, 0.395-0.743; P < 0.001; Table S2).	('patients', 'Species', '9606', (142, 150))	('RHCG', 'Gene', (67, 71))	('ESCC', 'Disease', (137, 141))	('loss', 'Var', (59, 63))
805090	29290801	As compared with untreated cells, methylation was significantly reduced in EC109, KYSE30 and KYSE180 cells treated with 5-aza-dC.	('5-aza-dC', 'Var', (120, 128))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (120, 128))	('reduced', 'NegReg', (64, 71))	('KYSE180', 'CellLine', 'CVCL:1349', (93, 100))	('methylation', 'MPA', (34, 45))
805099	29290801	In contrast, mice injected with RHCG-silenced KYSE520 cells formed much larger tumors than those formed by NTC cells (Fig.	('mice', 'Species', '10090', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('KYSE520', 'Var', (46, 53))
805101	29290801	As loss of RHCG was significantly associated with tumor invasion and lymph node metastasis in ESCC patients, the effect of RHCG on cell motility and tumor metastasis was studied by wound-healing, cell migration and invasion assays.	('associated', 'Reg', (34, 44))	('loss', 'Var', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('patients', 'Species', '9606', (99, 107))	('tumor', 'Disease', (149, 154))	('RHCG', 'Gene', (11, 15))	('tumor metastasis', 'Disease', 'MESH:D009362', (149, 165))	('tumor', 'Disease', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('ESCC', 'Disease', (94, 98))	('tumor metastasis', 'Disease', (149, 165))	('lymph node metastasis', 'CPA', (69, 90))
805102	29290801	The wound-healing assay showed that RHCG could dramatically inhibit tumor cell mobility (Fig.	('tumor', 'Disease', (68, 73))	('inhibit', 'NegReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('RHCG', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
805106	29290801	Conversely, lymph node metastasis was observed in all mice injected with KYSE520-shRHCG cells, whereas 2/5 mice from the control group showed tumor metastasis.	('KYSE520-shRHCG cells', 'Var', (73, 93))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('lymph node metastasis', 'CPA', (12, 33))	('tumor metastasis', 'Disease', 'MESH:D009362', (142, 158))	('tumor metastasis', 'Disease', (142, 158))	('mice', 'Species', '10090', (107, 111))	('mice', 'Species', '10090', (54, 58))	('observed', 'Reg', (38, 46))
805108	29290801	In an attempt to characterize the molecular mechanism by which RHCG inhibits tumor formation and metastasis in ESCC, a genome-wide mRNA expression profiling screen was used to compare gene expression profiles between RHCG-overexpressing KYSE180 cells and their control cells.	('RHCG', 'Var', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('KYSE180', 'CellLine', 'CVCL:1349', (237, 244))	('RHCG-overexpressing', 'Gene', (217, 236))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('inhibits', 'NegReg', (68, 76))	('ESCC', 'Disease', (111, 115))
805126	29290801	The result demonstrated that the active form of NF-kappaB/p65 in nucleus was significantly decreased in RHCG-expressing cells, whereas it was dramatically elevated in RHCG-silenced cells, compared with their control cells (Fig.	('RHCG-expressing', 'Var', (104, 119))	('p65', 'Gene', (58, 61))	('NF-kappaB', 'Gene', '4790', (48, 57))	('active', 'MPA', (33, 39))	('elevated', 'PosReg', (155, 163))	('p65', 'Gene', '5970', (58, 61))	('NF-kappaB', 'Gene', (48, 57))	('decreased', 'NegReg', (91, 100))
805138	29290801	To date, the relationship between inactivation of RHCG and the development of squamous cell carcinoma is still unknown.	('RHCG', 'Gene', (50, 54))	('inactivation', 'Var', (34, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('squamous cell carcinoma', 'Disease', (78, 101))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))
805141	29290801	Ectopic expression of RHCG in ESCC cell lines EC109 and KYSE180 cells could effectively suppress foci formation, colony formation in soft agar, and tumor formation in nude mice, while RHCG silencing in KYSE520 cells could promote these functions.	('silencing', 'Var', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('RHCG', 'Gene', (22, 26))	('tumor', 'Disease', (148, 153))	('Ectopic expression', 'Var', (0, 18))	('nude mice', 'Species', '10090', (167, 176))	('suppress', 'NegReg', (88, 96))	('agar', 'Chemical', 'MESH:D000362', (138, 142))	('foci formation', 'CPA', (97, 111))	('colony formation in soft agar', 'CPA', (113, 142))	('KYSE180', 'CellLine', 'CVCL:1349', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
805151	29290801	A functional study also revealed that ectopic expression of MMP1 promoted tumor growth and metastasis in ESCC.	('ESCC', 'Disease', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('MMP1', 'Gene', (60, 64))	('metastasis', 'CPA', (91, 101))	('ectopic expression', 'Var', (38, 56))	('promoted', 'PosReg', (65, 73))	('tumor', 'Disease', (74, 79))	('MMP1', 'Gene', '4312', (60, 64))
805162	29290801	Chinese ESCC cell lines (HKESC1, EC109 and EC9706) and six Japanese ESCC cell lines (KYSE30, KYSE140, KYSE180, KYSE410, KYSE510, and KYSE520) were kindly provided by Professor Srivastava (Department of Pathology, The University of Hong Kong) in 2004.	('HKESC1', 'CellLine', 'CVCL:D568', (25, 31))	('KYSE410', 'Var', (111, 118))	('KYSE180', 'CellLine', 'CVCL:1349', (102, 109))	('KYSE180', 'Var', (102, 109))	('EC9706', 'CellLine', 'CVCL:E307', (43, 49))
805169	29290801	For in vivo tumorigenic experiment, the cell number used for BALB/cAnN-nu (nude) mice subcutaneous injection was 1x106 (EC109 and KYSE180), and 2x105 (KYSE520).	('mice', 'Species', '10090', (81, 85))	('KYSE180', 'CellLine', 'CVCL:1349', (130, 137))	('EC109', 'Var', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('KYSE180', 'Var', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
805182	29290801	According to ROC curve analyses, the optimum cutoff value for p65 and MMP1 was 100, so SI < 100 was considered low expression, and S >= 100 was considered as high expression.	('p65', 'Gene', '5970', (62, 65))	('p65', 'Gene', (62, 65))	('S >= 100', 'Var', (131, 139))	('MMP1', 'Gene', '4312', (70, 74))	('expression', 'MPA', (115, 125))	('SI', 'Disease', 'None', (87, 89))	('low', 'NegReg', (111, 114))	('MMP1', 'Gene', (70, 74))
805210	27296040	Unexpectedly, survival was significantly lower in the 74-Gy arm, perhaps partly because the 11-day increase in total treatment time required for additional fractions reduced the effectiveness of tumor dose escalation.	('tumor', 'Disease', (195, 200))	('74-Gy', 'Var', (54, 59))	('lower', 'NegReg', (41, 46))	('reduced', 'NegReg', (166, 173))	('survival', 'CPA', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
805217	27296040	Inclusion criteria were histologically/cytologically confirmed stage IIA-IIIB NSCLC, World Health Organization performance status (PS) 0 to 1, suitability for CRT agreed by multidisciplinary team, no prior anticancer therapy, forced expiratory volume >=40% predicted or >=1 L, carbon monoxide diffusing capacity >=40% predicted, hematology and biochemistry baselines suitable for chemotherapy, and glomerular filtration rate >=60 mL/min.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('forced', 'MPA', (226, 232))	('>=40', 'Var', (312, 316))	('NSCLC', 'Disease', (78, 83))	('>=40', 'Var', (251, 255))	('carbon monoxide', 'Chemical', 'MESH:D002248', (277, 292))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('carbon monoxide diffusing capacity', 'MPA', (277, 311))
805312	26731558	Functionally, Tenascin-C interacts with fibronectin and can be defined as an anti-adhesive or adhesion-modulating protein; Tenascin-C increases the invasive and metastasis potential of malignant tumors.	('fibronectin', 'Gene', '2335', (40, 51))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('Tenascin-C', 'Var', (123, 133))	('malignant tumors', 'Disease', (185, 201))	('fibronectin', 'Gene', (40, 51))	('increases', 'PosReg', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('malignant tumors', 'Disease', 'MESH:D018198', (185, 201))
805336	26731558	Fibroblasts were collected from the supernatant by centrifugation at 800 rpm for 8 min, washed twice with PBS, and cultured in D/F12 medium supplemented with 10% FBS and 1% antibiotics.	('FBS', 'Disease', (162, 165))	('PBS', 'Disease', 'MESH:D011535', (106, 109))	('FBS', 'Disease', 'MESH:D005198', (162, 165))	('D/F12', 'Var', (127, 132))	('D/F12', 'SUBSTITUTION', 'None', (127, 132))	('PBS', 'Disease', (106, 109))
805351	26731558	In normal esophageal tissue, only one isoform of Tenascin-C (210 kDa) was identified, whereas at least three isoforms (210 kDa, 250 kDa, and 350 kDa) were found in esophageal cancer tissue (Fig 3A).	('esophageal cancer', 'Disease', (164, 181))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('210 kDa', 'Var', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
805366	26731558	In addition, the 5-year OS and DFS rates of the stroma-Tenascin-C-positive group (37.0% and 29.3%, respectively) were significantly lower than those of the stroma-Tenascin-C-negative group (88.6% and 79.5%, respectively; OS: p < 0.001; DFS: p < 0.001).	('stroma', 'Chemical', '-', (156, 162))	('DFS', 'CPA', (31, 34))	('stroma', 'Chemical', '-', (48, 54))	('lower', 'NegReg', (132, 137))	('stroma-Tenascin-C-positive', 'Var', (48, 74))
805368	26731558	In particular, the 5-year OS and DFS rates of the patients with positive Tenascin-C expression in both cancer cells and stromal fibroblasts (20.0% and 18.0%, respectively) were significantly lower than those of the patients who showed positive Tenascin-C expression in either of the cell types (positive expression in only cancer cells: 83.3% and 70.8%, respectively; positive expression in only stromal fibroblasts: 58.1% and 41.9%, respectively) or those who showed negative expression in both the cell types (94.7% and 89.5%, respectively; OS: p < 0.001; DFS: p < 0.001; Fig 4).	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('patients', 'Species', '9606', (215, 223))	('stroma', 'Chemical', '-', (396, 402))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (323, 329))	('patients', 'Species', '9606', (50, 58))	('Tenascin-C', 'Gene', (73, 83))	('lower', 'NegReg', (191, 196))	('stroma', 'Chemical', '-', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('positive', 'Var', (64, 72))
805369	26731558	Furthermore, the 5-year OS and DFS rates of the Tenascin-C-positive group (positive expression in stroma and cancer, respectively) were significantly lower than those of the Tenascin-C-negative group in lymph node metastasis-negative group.	('lower', 'NegReg', (150, 155))	('Tenascin-C-positive', 'Var', (48, 67))	('stroma and cancer', 'Disease', 'MESH:D009369', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('DFS rates', 'CPA', (31, 40))
805370	26731558	In lymph node metastasis-positive group, the 5-year OS and DFS rates of the Tenascin-C-positive group (positive expression in stroma and cancer, respectively) were also significantly lower than those of the Tenascin-C-negative group (in addition to OS rate of the stroma-Tenascin-C- positive group) (S3 Fig).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('DFS', 'CPA', (59, 62))	('stroma', 'Chemical', '-', (126, 132))	('lower', 'NegReg', (183, 188))	('Tenascin-C-positive', 'Var', (76, 95))	('stroma', 'Chemical', '-', (264, 270))	('stroma and cancer', 'Disease', 'MESH:D009369', (126, 143))
805384	26731558	In a mouse model, Tenascin-C knockdown dramatically inhibited lung metastasis and colonization by breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('Tenascin-C', 'Gene', (18, 28))	('knockdown', 'Var', (29, 38))	('breast cancer', 'Disease', (98, 111))	('mouse', 'Species', '10090', (5, 10))	('lung metastasis', 'CPA', (62, 77))	('inhibited', 'NegReg', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
805387	26731558	Especially, patients with Tenascin-C expression in both cancer cells and stromal fibroblasts showed apparently reduced OS and DFS rates.	('expression', 'Var', (37, 47))	('patients', 'Species', '9606', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('reduced', 'NegReg', (111, 118))	('Tenascin-C', 'Gene', (26, 36))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('stroma', 'Chemical', '-', (73, 79))
805398	26731558	For example, PDGFRalpha expression in CAF was an essential factor in the prognosis of ESCC; PDGFRbeta expression was associated with poorly differentiated tumors; SMA expression in ESCC stromal fibroblasts was associated with a large size of the tumor, advanced pT stage, lymph node metastasis, and poor prognosis.	('SMA expression', 'Var', (163, 177))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('CAF', 'Gene', (38, 41))	('ESCC', 'Disease', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('associated', 'Reg', (117, 127))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('stroma', 'Chemical', '-', (186, 192))	('advanced', 'CPA', (253, 261))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Disease', (155, 161))	('tumor', 'Disease', (246, 251))	('associated', 'Reg', (210, 220))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('PDGFRbeta', 'Gene', (92, 101))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('CAF', 'Gene', '8850', (38, 41))	('lymph node metastasis', 'CPA', (272, 293))
805403	26731558	In particular, statistically significant lower 5-year OS and DFS rates were observed in patients with positive expressions of Tenascin-C and CAF markers in ESCC stromal fibroblasts than in patients with negative expressions of Tenascin-C and CAF markers.	('CAF', 'Gene', '8850', (141, 144))	('positive', 'Var', (102, 110))	('CAF', 'Gene', '8850', (242, 245))	('patients', 'Species', '9606', (88, 96))	('lower', 'NegReg', (41, 46))	('DFS rates', 'CPA', (61, 70))	('stroma', 'Chemical', '-', (161, 167))	('Tenascin-C', 'Gene', (126, 136))	('CAF', 'Gene', (141, 144))	('patients', 'Species', '9606', (189, 197))	('CAF', 'Gene', (242, 245))
805451	23228190	Inclusion criteria were defined: histologically confirmed advanced esophageal or gastric adenocarcinoma, presence of at least one measureable lesion according to RECIST criteria, adequate hematopoietic, hepatic and renal function - defined as: white blood cell (WBC) count >= 3000/mul, absolute neutrophil count (ANC) >= 2000/mul, platelets >= 100000/mul, hemoglobin level >= 9.0 g/dl, total bilirubin < 2 times the upper limit of normal (ULN) , SGOT and SGPT < 2.5 times the UNL (or < 5 x ULN if hepatic metastases are present), glomerular filtration rate (GFR) >= 60ml/min, Eastern Cooperative Oncology Group (ECOG) performance status <= 2.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (81, 103))	('SGPT', 'Gene', (455, 459))	('gastric adenocarcinoma', 'Disease', (81, 103))	('>= 60ml/min', 'Var', (563, 574))	('metastases', 'Disease', 'MESH:D009362', (505, 515))	('>= 3000/mul', 'Var', (273, 284))	('>= 2000/mul', 'Var', (318, 329))	('>= 100000/mul', 'Var', (341, 354))	('hemoglobin level', 'MPA', (356, 372))	('Oncology', 'Phenotype', 'HP:0002664', (596, 604))	('metastases', 'Disease', (505, 515))
805567	33688490	Dyslipidemia was defined as positive medical history, using of lipid-lowering drugs, or if the serum total cholesterol level was >=5.2 mmol/L, serum triglyceride (TG) level >=1.7 mmol/L, serum high-density lipoprotein (HDL) cholesterol level <1.0 mmol/L for male or <1.3 mmol/L for female, or serum low-density lipoprotein (LDL) cholesterol level >=3.4 mmol/L.	('serum triglyceride', 'MPA', (143, 161))	('cholesterol', 'Chemical', 'MESH:D002784', (329, 340))	('serum low-density lipoprotein', 'MPA', (293, 322))	('triglyceride', 'Chemical', 'MESH:D014280', (149, 161))	('TG', 'Chemical', 'MESH:D014280', (163, 165))	('Dyslipidemia', 'Disease', 'MESH:D050171', (0, 12))	('cholesterol', 'Chemical', 'MESH:D002784', (224, 235))	('Dyslipidemia', 'Phenotype', 'HP:0003119', (0, 12))	('Dyslipidemia', 'Disease', (0, 12))	('cholesterol', 'Chemical', 'MESH:D002784', (107, 118))	('>=5.2', 'Var', (129, 134))
805569	33688490	On the contrary, patients with LSM >=7 kPa were defined to have a significant liver fibrosis (>=F2), while an advanced fibrosis (>=F3) was considered if LSM was >=9.6 kPa using the M probe or >=9.3 kPa using the XL probe.	('LSM', 'Var', (31, 34))	('liver fibrosis', 'Phenotype', 'HP:0001395', (78, 92))	('liver fibrosis', 'Disease', (78, 92))	('liver fibrosis', 'Disease', 'MESH:D008103', (78, 92))
805578	33688490	Fourthly, autonomic nervous system dysfunction could represent additional link among NAFLD and GERB, because some data have reported that in NAFLD patients there is a higher prevalence of autonomic disturbance.	('NAFLD', 'Var', (141, 146))	('autonomic nervous system dysfunction', 'Disease', 'MESH:D009422', (10, 46))	('autonomic disturbance', 'MPA', (188, 209))	('autonomic nervous system dysfunction', 'Disease', (10, 46))	('autonomic nervous system dysfunction', 'Phenotype', 'HP:0012332', (10, 46))	('autonomic disturbance', 'Phenotype', 'HP:0012332', (188, 209))
805579	33688490	Finally, NAFLD is associated with obesity, especially with central obesity.	('obesity', 'Phenotype', 'HP:0001513', (34, 41))	('central obesity', 'Disease', 'MESH:D056128', (59, 74))	('central obesity', 'Phenotype', 'HP:0012743', (59, 74))	('associated', 'Reg', (18, 28))	('obesity', 'Phenotype', 'HP:0001513', (67, 74))	('obesity', 'Disease', (34, 41))	('central obesity', 'Disease', (59, 74))	('NAFLD', 'Var', (9, 14))
805613	33596862	Immunohistochemical staining results were S-100 ( +), SOX10 ( +), Ki-67 (10% +), CD34 (-), alphaSMA (-), CK(-), EMA(-), CD117(-), DOG1(-), SMA(-), CD34(-) and desmin (-) (Fig.	('SMA', 'Gene', '6606', (96, 99))	('SMA', 'Gene', (96, 99))	('desmin', 'Gene', '497091', (159, 165))	('desmin', 'Gene', (159, 165))	('SOX10', 'Gene', (54, 59))	('CD34', 'Var', (81, 85))	('CD34', 'Var', (147, 151))	('SMA', 'Gene', (139, 142))	('SMA', 'Gene', '6606', (139, 142))	('SOX10', 'Gene', '481258', (54, 59))
805628	33596862	Immunohistochemical staining: S-100 ( +), SOX10( +), SMA (Focal area +), desmin(-), CD117(-), Dog-1(-), CD34(-), Ki-67(10% +).	('SOX10', 'Gene', '481258', (42, 47))	('desmin', 'Gene', '497091', (73, 79))	('desmin', 'Gene', (73, 79))	('SOX10', 'Gene', (42, 47))	('CD117(-', 'Var', (84, 91))	('SMA', 'Gene', (53, 56))	('SMA', 'Gene', '6606', (53, 56))	('CD34(-', 'Var', (104, 110))
805666	31258777	Using receiver operating characteristic (ROC) curve, the diagnostic value of serum IGFBP7 was demonstrated.	('OC', 'Phenotype', 'HP:0100615', (42, 44))	('IGFBP7', 'Gene', '3490', (83, 89))	('serum', 'Var', (77, 82))	('IGFBP7', 'Gene', (83, 89))
805711	31258777	Since there was no statistic difference between serum IGFBP7 and the clinical data, serum IGFBP7 might be a relative stable marker not affected by the obtained factors but just related to the existence status of the ESCC.	('IGFBP7', 'Gene', '3490', (54, 60))	('IGFBP7', 'Gene', (90, 96))	('IGFBP7', 'Gene', '3490', (90, 96))	('serum', 'Var', (84, 89))	('IGFBP7', 'Gene', (54, 60))
805714	31258777	In addition, as an important parameter for a test used in early detection of cancer, the positive predictive value (PPV) would be 59.1%, 81.3% and 92.9% when standardize disease prevalence of 25%, 50%, and 75%, demonstrating that serum IGFBP7 is a promising marker in both low-risk and high-risk area.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('IGFBP7', 'Gene', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('serum', 'Var', (230, 235))	('IGFBP7', 'Gene', '3490', (236, 242))
805721	31258777	As methylation causes gene silencing of IGFBP7, researchers tried to measure the relationship between IGFBP7 methylation and malignance of cancer, finding that the methylation gave permission to cancer cell proliferation and could develop the tumor.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('IGFBP7', 'Gene', '3490', (40, 46))	('methylation', 'Var', (164, 175))	('methylation', 'Var', (3, 14))	('cancer', 'Disease', (195, 201))	('IGFBP7', 'Gene', '3490', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('malignance of cancer', 'Disease', 'MESH:D009369', (125, 145))	('IGFBP7', 'Gene', (40, 46))	('cancer', 'Disease', (139, 145))	('gene', 'MPA', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('IGFBP7', 'Gene', (102, 108))	('malignance of cancer', 'Disease', (125, 145))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Disease', (243, 248))
805722	31258777	If there is a deletion of IGFBP7, it even promotes the hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (55, 79))	('IGFBP7', 'Gene', '3490', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('hepatocellular carcinoma', 'Disease', (55, 79))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (55, 79))	('promotes', 'PosReg', (42, 50))	('IGFBP7', 'Gene', (26, 32))	('deletion', 'Var', (14, 22))
805743	26468007	Patients in the cisplatin arm were more likely to experience neutropenia and thrombocytopenia, whereas patients in the paclitaxel arm had a higher frequency of neuropathy and alopecia.	('neuropathy', 'Phenotype', 'HP:0009830', (160, 170))	('alopecia', 'Phenotype', 'HP:0001596', (175, 183))	('neutropenia', 'Phenotype', 'HP:0001875', (61, 72))	('thrombocytopenia', 'Disease', (77, 93))	('neuropathy and alopecia', 'Disease', 'MESH:D000505', (160, 183))	('cisplatin', 'Var', (16, 25))	('Patients', 'Species', '9606', (0, 8))	('neutropenia', 'Disease', (61, 72))	('thrombocytopenia', 'Disease', 'MESH:D013921', (77, 93))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (77, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))	('patients', 'Species', '9606', (103, 111))	('paclitaxel', 'Chemical', 'MESH:D017239', (119, 129))	('neutropenia', 'Disease', 'MESH:D009503', (61, 72))
805759	26468007	Patients were required to have at least one measurable metastatic lesion as defined by the Response Criteria in Solid Tumors (RECIST) v1.0, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, a life expectancy of at least 3 months, and adequate hematologic (neutrophil count >= 1500/mm3, platelet count >= 100,000/mm3, hemoglobin >= 9.0 g/dl), renal (serum creatinine <= 1.5 mg/dl or creatinine clearance >= 50 ml/min) and liver function (bilirubin <= 1.5 mg/dl, AST/ALT <= 3 times the upper normal limit).	('Tumors', 'Phenotype', 'HP:0002664', (118, 124))	('AST', 'Gene', '26503', (483, 486))	('>= 1500/mm3', 'Var', (295, 306))	('Patients', 'Species', '9606', (0, 8))	('AST', 'Gene', (483, 486))	('liver function', 'CPA', (443, 457))	('Oncology', 'Phenotype', 'HP:0002664', (163, 171))
805884	25767810	The V 5, V 10, and V 15 for the lungs were also substantially lower for the FSCB designs (Figure 3), with simultaneous increase of the maximum dose of spinal cord, mean dose, and V 40 of the heart.	('V 15', 'Gene', (19, 23))	('FSCB', 'Chemical', '-', (76, 80))	('lower', 'NegReg', (62, 67))	('mean dose', 'MPA', (164, 173))	('V 40', 'MPA', (179, 183))	('FSCB', 'Var', (76, 80))	('increase', 'PosReg', (119, 127))	('V 15', 'Gene', '28814', (19, 23))
806011	32384489	In this meta-analysis of 25 studies, omega-3 PUFAs exerted a protective effect on the risk of digestive system cancers and was shown to possibly decrease the incident risk of cancers by as much as 17%.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('omega-3 PUFAs', 'Chemical', 'MESH:D015525', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('omega-3', 'Var', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('decrease', 'NegReg', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
806012	32384489	Inverse associations were also found between omega-3 PUFAs and the risk of colorectal, oral cavity/pharyngeal, esophageal and large bowel cancers.	('large bowel cancer', 'Phenotype', 'HP:0100834', (126, 144))	('colorectal', 'Disease', 'MESH:D015179', (75, 85))	('Inverse', 'NegReg', (0, 7))	('large bowel', 'Phenotype', 'HP:0002037', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal', 'Disease', (75, 85))	('bowel cancers', 'Disease', (132, 145))	('bowel cancers', 'Disease', 'MESH:D009369', (132, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('esophageal', 'Disease', (111, 121))	('omega-3 PUFAs', 'Chemical', 'MESH:D015525', (45, 58))	('oral cavity/pharyngeal', 'Disease', (87, 109))	('omega-3', 'Var', (45, 52))
806017	32384489	Third, metabolites of omega-3 PUFAs increased the production of PGE3 and decreased the production of PGE2, which was expected to reduce estrogen-stimulated cell growth.	('PGE3', 'Chemical', 'MESH:C033246', (64, 68))	('production', 'MPA', (50, 60))	('production of PGE2', 'MPA', (87, 105))	('decreased', 'NegReg', (73, 82))	('reduce', 'NegReg', (129, 135))	('omega-3 PUFAs', 'Chemical', 'MESH:D015525', (22, 35))	('PGE3', 'MPA', (64, 68))	('increased', 'PosReg', (36, 45))	('PGE2', 'Chemical', 'MESH:D015232', (101, 105))	('metabolites', 'Var', (7, 18))
806020	32384489	First, an interesting finding was that omega-3 PUFAs reduced the risk of digestive system cancers in the case-control studies but not in the cohort studies.	('cancers', 'Disease', (90, 97))	('omega-3 PUFAs', 'Chemical', 'MESH:D015525', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('omega-3', 'Var', (39, 46))	('reduced', 'NegReg', (53, 60))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
806022	32384489	Second, our results indicated that the strongest reduction in the risk of digestive system cancers associated with omega-3 PUFA intake was found in North American and European countries.	('omega-3', 'Var', (115, 122))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('reduction', 'NegReg', (49, 58))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('omega-3 PUFA', 'Chemical', 'MESH:D015525', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
806024	32384489	This is the first evidence showing that omega-3 PUFAs can decrease the risk of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('omega-3', 'Var', (40, 47))	('omega-3 PUFAs', 'Chemical', 'MESH:D015525', (40, 53))	('colorectal cancer', 'Disease', (79, 96))	('decrease', 'NegReg', (58, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))
806027	32384489	In summary, n-3 PUFA intake is inversely associated with the risk of digestive system cancers, especially colorectal, esophageal, large bowel, and oral cavity/pharyngeal cancers.	('esophageal', 'Disease', (118, 128))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('large bowel', 'Disease', (130, 141))	('n-3 PUFA', 'Chemical', 'MESH:D015525', (12, 20))	('cancers', 'Disease', (170, 177))	('n-3', 'Var', (12, 15))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal', 'Disease', 'MESH:D015179', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('large bowel', 'Phenotype', 'HP:0002037', (130, 141))	('colorectal', 'Disease', (106, 116))	('inversely', 'NegReg', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancers', 'Disease', (86, 93))
806037	30123355	Multivariate analysis identified depth of tumor invasion, regional lymph node metastasis, tumor-node-metastasis stage, and CBS and RASSF1A gene methylation status as independent prognostic factors; female gender and high serum folic acid levels were favorable prognostic factors.	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (90, 111))	('tumor', 'Disease', (42, 47))	('CBS', 'Gene', '875', (123, 126))	('methylation', 'Var', (144, 155))	('folic acid', 'Chemical', 'MESH:D005492', (227, 237))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CBS', 'Gene', (123, 126))	('RASSF1A', 'Gene', '11186', (131, 138))	('high serum folic acid levels', 'MPA', (216, 244))	('high serum folic acid levels', 'Phenotype', 'HP:0032164', (216, 244))	('methyl', 'Chemical', 'MESH:C051224', (144, 150))	('RASSF1A', 'Gene', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor-node-metastasis', 'Disease', (90, 111))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
806052	30123355	The destruction of specific gene methylation patterns may not only affect susceptibility to ESCC, but also influence progression once the disease manifests.	('methylation', 'Var', (33, 44))	('ESCC', 'Disease', (92, 96))	('affect', 'Reg', (67, 73))	('methyl', 'Chemical', 'MESH:C051224', (33, 39))	('progression', 'MPA', (117, 128))	('susceptibility', 'MPA', (74, 88))	('influence', 'Reg', (107, 116))
806054	30123355	Genetic factors include gene mutations, loss of genetic heterozygosity, and microsatellite instability, while epigenetic factors include other non-gene-related changes that can be stably transmitted during development and cell proliferation (e.g., DNA methylation, covalent histone modification, chromatin remodeling, gene silencing, and the regulation of non-coding RNA).	('DNA methylation', 'Var', (248, 263))	('covalent', 'MPA', (265, 273))	('microsatellite instability', 'MPA', (76, 102))	('mutations', 'Var', (29, 38))	('loss', 'Var', (40, 44))	('methyl', 'Chemical', 'MESH:C051224', (252, 258))	('men', 'Species', '9606', (213, 216))	('gene', 'CPA', (318, 322))
806055	30123355	Epigenetic modifications can be regulated and reversed under certain conditions, thus providing new ideas for the prevention and treatment of tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('Epigenetic modifications', 'Var', (0, 24))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('men', 'Species', '9606', (134, 137))
806056	30123355	DNA methylation is one of the most important epigenetic modifications.	('methyl', 'Chemical', 'MESH:C051224', (4, 10))	('DNA', 'Var', (0, 3))	('methylation', 'Var', (4, 15))
806058	30123355	Hypermethylation of the promoter regions of tumor suppressor genes is associated with the occurrence and development of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('associated with', 'Reg', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('methyl', 'Chemical', 'MESH:C051224', (5, 11))	('men', 'Species', '9606', (112, 115))	('esophageal cancer', 'Disease', (120, 137))	('tumor', 'Disease', (44, 49))
806060	30123355	Therefore, we investigated the relationship between the hypermethylation of tumor suppressor genes and features of esophageal cancer in order to advance methods for the prevention, early diagnosis, and treatment of the disease.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hypermethylation', 'Var', (56, 72))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('men', 'Species', '9606', (207, 210))	('esophageal cancer', 'Disease', (115, 132))	('methyl', 'Chemical', 'MESH:C051224', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
806084	30123355	Single factor logistic regression analysis showed that the risk of esophageal cancer in the 6.27-8.12 nmol/L group was 0.35-fold that of the <=6.26 nmol/L group (chi2 = 15.28, P < 0.001).	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('6.27-8.12 nmol/L', 'Var', (92, 108))	('esophageal cancer', 'Disease', (67, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))
806085	30123355	Lastly, the risk of developing esophageal cancer in the >10.20 nmol/L group was 0.15-fold that of the <=6.26 nmol/L group (chi2 = 34.64, P < 0.001) (Table 3).	('esophageal cancer', 'Disease', (31, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('>10.20 nmol/L', 'Var', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
806089	30123355	Analysis of the relationship between gene methylation status and the clinicopathological features of patients with esophageal cancer revealed that the methylation status of MTHFR differed significantly according to age, gender, and pathological type of esophageal cancer (chi2 = 12.80, P = 0.005; chi2 = 4.10, P = 0.043; and chi2 = 9.85, P = 0.020, respectively).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (101, 109))	('MTHFR', 'Gene', (173, 178))	('type of esophageal cancer', 'Disease', 'MESH:D004938', (245, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('differed', 'Reg', (179, 187))	('methylation', 'Var', (151, 162))	('methyl', 'Chemical', 'MESH:C051224', (151, 157))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('MTHFR', 'Gene', '4524', (173, 178))	('esophageal cancer', 'Disease', 'MESH:D004938', (253, 270))	('methyl', 'Chemical', 'MESH:C051224', (42, 48))	('type of esophageal cancer', 'Disease', (245, 270))
806095	30123355	In the univariate analysis, gender, pathological type, depth of tumor invasion, regional LNM, TNM stage, serum folic acid levels, and the methylation status of CBS, MGMT, P16, and RASSF1A were significantly associated with the prognosis of esophageal cancer (P < 0.05) (Figure 2A-J).	('RASSF1A', 'Gene', '11186', (180, 187))	('methyl', 'Chemical', 'MESH:C051224', (138, 144))	('CBS', 'Gene', (160, 163))	('RASSF1A', 'Gene', (180, 187))	('CBS', 'Gene', '875', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (240, 257))	('associated with', 'Reg', (207, 222))	('MGMT', 'Gene', '4255', (165, 169))	('esophageal cancer', 'Disease', (240, 257))	('serum folic acid levels', 'MPA', (105, 128))	('P16', 'Gene', '1029', (171, 174))	('tumor', 'Disease', (64, 69))	('P16', 'Gene', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('methylation status', 'Var', (138, 156))	('folic acid', 'Chemical', 'MESH:D005492', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('MGMT', 'Gene', (165, 169))
806096	30123355	In contrast, age, histological type, tumor size, and the methylation status of MTHFR and FHIT were not significantly associated with the prognosis of esophageal cancer (data not shown).	('esophageal cancer', 'Disease', (150, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('MTHFR', 'Gene', '4524', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('associated', 'Reg', (117, 127))	('methyl', 'Chemical', 'MESH:C051224', (57, 63))	('methylation status', 'Var', (57, 75))	('MTHFR', 'Gene', (79, 84))	('FHIT', 'Gene', (89, 93))	('tumor', 'Disease', (37, 42))	('FHIT', 'Gene', '2272', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))
806099	30123355	The survival rates of patients with T1/T2 esophageal cancer were significantly higher than those of patients with T3 esophageal cancer.	('survival rates', 'CPA', (4, 18))	('esophageal cancer', 'Disease', (42, 59))	('T1/T2', 'Var', (36, 41))	('esophageal cancer', 'Disease', (117, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('patients', 'Species', '9606', (22, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('patients', 'Species', '9606', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('higher', 'PosReg', (79, 85))
806102	30123355	Finally, patients with unmethylated CBS, MGMT, P16, and RASSF1A genes had longer survival times than those in whom these genes were methylated (Table 5).	('patients', 'Species', '9606', (9, 17))	('P16', 'Gene', (47, 50))	('methyl', 'Chemical', 'MESH:C051224', (132, 138))	('CBS', 'Gene', (36, 39))	('longer', 'PosReg', (74, 80))	('methyl', 'Chemical', 'MESH:C051224', (25, 31))	('P16', 'Gene', '1029', (47, 50))	('RASSF1A', 'Gene', (56, 63))	('unmethylated', 'Var', (23, 35))	('RASSF1A', 'Gene', '11186', (56, 63))	('MGMT', 'Gene', '4255', (41, 45))	('survival times', 'CPA', (81, 95))	('CBS', 'Gene', '875', (36, 39))	('MGMT', 'Gene', (41, 45))
806103	30123355	Significant prognostic factors in the univariate analysis were entered into the Cox regression model for multivariate analysis, which revealed that the depth of tumor invasion, regional LNM, TNM stage, and CBS and RASSF1A gene methylation were independent prognostic factors for Kazakh patients with esophageal cancer.	('methyl', 'Chemical', 'MESH:C051224', (227, 233))	('RASSF1A', 'Gene', '11186', (214, 221))	('CBS', 'Gene', '875', (206, 209))	('esophageal cancer', 'Disease', (300, 317))	('esophageal cancer', 'Disease', 'MESH:D004938', (300, 317))	('methylation', 'Var', (227, 238))	('CBS', 'Gene', (206, 209))	('Cox', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Cox', 'Gene', '1351', (80, 83))	('RASSF1A', 'Gene', (214, 221))	('tumor', 'Disease', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('patients', 'Species', '9606', (286, 294))
806107	30123355	Aberrant methylation of tumor suppressor gene DNA can promote normal epithelial cells to transform into cancerous esophageal cells, which is an important factor in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('promote', 'PosReg', (54, 61))	('cancerous esophageal', 'Disease', (104, 124))	('tumor', 'Disease', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (24, 29))	('methyl', 'Chemical', 'MESH:C051224', (9, 15))	('Aberrant methylation', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('DNA', 'Gene', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('cancerous esophageal', 'Disease', 'MESH:D004938', (104, 124))
806108	30123355	Tumorigenesis typically involves genome-wide hypomethylation accompanied by hypermethylation at specific sites.	('hypermethylation', 'MPA', (76, 92))	('methyl', 'Chemical', 'MESH:C051224', (49, 55))	('Tumorigenesis', 'CPA', (0, 13))	('hypomethylation', 'Var', (45, 60))	('methyl', 'Chemical', 'MESH:C051224', (81, 87))
806110	30123355	Unlike genetic changes, epigenetic modifications are reversible and can promote certain key tumor suppressor genes in tumors or precancerous lesions by demethylation to achieve early tumor prevention and even treatment of tumors.	('demethylation', 'Var', (152, 165))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('epigenetic modifications', 'Var', (24, 48))	('promote', 'PosReg', (72, 79))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Disease', (222, 228))	('precancerous lesions', 'Disease', (128, 148))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', (222, 227))	('men', 'Species', '9606', (214, 217))	('precancerous lesions', 'Disease', 'MESH:D011230', (128, 148))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', (92, 97))	('methyl', 'Chemical', 'MESH:C051224', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))
806116	30123355	A previous study showed that folic acid deficiency may increase the susceptibility to esophageal cancer and that folic acid is a protective factor for esophageal cancer.	('deficiency', 'Var', (40, 50))	('increase', 'PosReg', (55, 63))	('esophageal cancer', 'Disease', (151, 168))	('folic acid', 'Chemical', 'MESH:D005492', (113, 123))	('folic acid', 'Protein', (29, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('folic acid deficiency', 'Phenotype', 'HP:0100507', (29, 50))	('folic acid', 'Chemical', 'MESH:D005492', (29, 39))
806117	30123355	As a key enzyme for folic acid metabolism, changes in enzyme activity resulting from changes in the MTFHR gene may affect methyl group supply and DNA synthesis.	('affect', 'Reg', (115, 121))	('folic acid', 'Chemical', 'MESH:D005492', (20, 30))	('MTFHR', 'Gene', (100, 105))	('changes', 'Var', (85, 92))	('enzyme activity', 'MPA', (54, 69))	('changes', 'Reg', (43, 50))	('methyl', 'Chemical', 'MESH:C051224', (122, 128))	('DNA synthesis', 'MPA', (146, 159))	('methyl group supply', 'MPA', (122, 141))
806120	30123355	A previous study reported that methylation of the promoter region of the CBS gene leads to the inactivation of CBS messenger RNA, resulting in the loss of cystathionine beta-synthase protein expression, thereby affecting intracellular methylation metabolism and involvement in tumor development.	('CBS', 'Gene', (73, 76))	('CBS', 'Gene', '875', (73, 76))	('methylation', 'Var', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('loss', 'NegReg', (147, 151))	('cystathionine beta-synthase', 'Gene', (155, 182))	('CBS', 'Gene', (111, 114))	('CBS', 'Gene', '875', (111, 114))	('inactivation', 'NegReg', (95, 107))	('intracellular methylation metabolism', 'MPA', (221, 257))	('expression', 'MPA', (191, 201))	('methyl', 'Chemical', 'MESH:C051224', (31, 37))	('affecting', 'Reg', (211, 220))	('men', 'Species', '9606', (269, 272))	('tumor', 'Disease', (277, 282))	('involvement', 'Reg', (262, 273))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('men', 'Species', '9606', (290, 293))	('methyl', 'Chemical', 'MESH:C051224', (235, 241))	('cystathionine beta-synthase', 'Gene', '875', (155, 182))
806121	30123355	Inactivation of the MGMT gene causes DNA damage.	('MGMT', 'Gene', (20, 24))	('causes', 'Reg', (30, 36))	('DNA damage', 'Disease', (37, 47))	('Inactivation', 'Var', (0, 12))	('MGMT', 'Gene', '4255', (20, 24))
806124	30123355	Several studies have reported on the emergence of MGMT gene methylation in the early stages of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('methylation', 'Var', (60, 71))	('MGMT', 'Gene', (50, 54))	('MGMT', 'Gene', '4255', (50, 54))	('methyl', 'Chemical', 'MESH:C051224', (60, 66))	('esophageal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
806127	30123355	Methylation of the P16 gene was detected in 81.0% of cases (n = 81) of esophageal cancer in the Das et al.	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('P16', 'Gene', '1029', (19, 22))	('Methylation', 'Var', (0, 11))	('detected', 'Reg', (32, 40))	('esophageal cancer', 'Disease', (71, 88))	('P16', 'Gene', (19, 22))
806130	30123355	Aberrant methylation of CpG islands in the promoter region of the FHIT gene can lead to epigenetic silencing, which results in loss of function of the gene and involvement in the development of cancer.	('methylation', 'Var', (9, 20))	('lead to', 'Reg', (80, 87))	('loss of function', 'NegReg', (127, 143))	('cancer', 'Disease', (194, 200))	('involvement', 'Reg', (160, 171))	('methyl', 'Chemical', 'MESH:C051224', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('men', 'Species', '9606', (186, 189))	('epigenetic silencing', 'MPA', (88, 108))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Aberrant methylation', 'Var', (0, 20))	('FHIT', 'Gene', (66, 70))	('men', 'Species', '9606', (167, 170))	('FHIT', 'Gene', '2272', (66, 70))
806131	30123355	Early ESCC has a poor prognosis in patients with hypermethylation of the FHIT gene.	('hypermethylation', 'Var', (49, 65))	('methyl', 'Chemical', 'MESH:C051224', (54, 60))	('ESCC', 'Disease', (6, 10))	('FHIT', 'Gene', (73, 77))	('patients', 'Species', '9606', (35, 43))	('FHIT', 'Gene', '2272', (73, 77))
806133	30123355	Mechanisms of RASSF1A gene inactivation include gene deletion, gene mutation, and promoter methylation.	('inactivation', 'NegReg', (27, 39))	('RASSF1A', 'Gene', (14, 21))	('gene deletion', 'Var', (48, 61))	('gene mutation', 'Var', (63, 76))	('methyl', 'Chemical', 'MESH:C051224', (91, 97))	('RASSF1A', 'Gene', '11186', (14, 21))
806134	30123355	RASSF1A gene promoter methylation silences gene transcription and is the most important mechanism of inactivation.	('RASSF1A', 'Gene', (0, 7))	('silences', 'NegReg', (34, 42))	('methyl', 'Chemical', 'MESH:C051224', (22, 28))	('RASSF1A', 'Gene', '11186', (0, 7))	('gene transcription', 'MPA', (43, 61))	('methylation', 'Var', (22, 33))
806139	30123355	Univariate analysis showed that gender, pathological type, depth of tumor invasion, regional LNM, TNM stage, serum folic acid levels, and the methylation of CBS, MGMT, P16, and RASSF1A were associated with the prognosis of patients with esophageal cancer.	('serum folic acid levels', 'MPA', (109, 132))	('P16', 'Gene', (168, 171))	('esophageal cancer', 'Disease', (237, 254))	('associated', 'Reg', (190, 200))	('methylation', 'Var', (142, 153))	('tumor', 'Disease', (68, 73))	('RASSF1A', 'Gene', '11186', (177, 184))	('MGMT', 'Gene', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('RASSF1A', 'Gene', (177, 184))	('folic acid', 'Chemical', 'MESH:D005492', (115, 125))	('CBS', 'Gene', (157, 160))	('CBS', 'Gene', '875', (157, 160))	('methyl', 'Chemical', 'MESH:C051224', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('MGMT', 'Gene', '4255', (162, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (237, 254))	('P16', 'Gene', '1029', (168, 171))	('patients', 'Species', '9606', (223, 231))
806140	30123355	Moreover, multivariate analysis revealed that depth of tumor invasion, regional LNM, TNM stage, and the methylation of CBS and RASSF1A were independent risk factors affecting the prognosis of Kazakh patients with esophageal cancer.	('RASSF1A', 'Gene', (127, 134))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CBS', 'Gene', '875', (119, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (213, 230))	('methyl', 'Chemical', 'MESH:C051224', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('affecting', 'Reg', (165, 174))	('tumor', 'Disease', (55, 60))	('RASSF1A', 'Gene', '11186', (127, 134))	('CBS', 'Gene', (119, 122))	('methylation', 'Var', (104, 115))	('patients', 'Species', '9606', (199, 207))	('esophageal cancer', 'Disease', (213, 230))
806149	30123355	Additionally, we identified CBS methylation status as an independent prognostic factor.	('CBS', 'Gene', '875', (28, 31))	('methylation', 'Var', (32, 43))	('CBS', 'Gene', (28, 31))	('methyl', 'Chemical', 'MESH:C051224', (32, 38))
806150	30123355	Methylation of the CBS gene inactivates cystathionine beta-synthase protein expression.	('inactivates', 'NegReg', (28, 39))	('CBS', 'Gene', '875', (19, 22))	('Methylation', 'Var', (0, 11))	('cystathionine beta-synthase', 'Gene', '875', (40, 67))	('CBS', 'Gene', (19, 22))	('cystathionine beta-synthase', 'Gene', (40, 67))
806152	30123355	reported that the prognosis of patients with RASSF1A gene methylation is poor, which is also consistent with our findings.	('RASSF1A', 'Gene', (45, 52))	('methylation', 'Var', (58, 69))	('RASSF1A', 'Gene', '11186', (45, 52))	('patients', 'Species', '9606', (31, 39))	('methyl', 'Chemical', 'MESH:C051224', (58, 64))
806153	30123355	Methylation silencing of the RASSF1A gene activates the RAS/RASSF1/ERK pathway, which promotes cell proliferation, including in an oncogenic manner.	('cell proliferation', 'CPA', (95, 113))	('RASSF1', 'Gene', '11186', (60, 66))	('ERK', 'Gene', '5594', (67, 70))	('ERK', 'Gene', (67, 70))	('RASSF1', 'Gene', (29, 35))	('Methylation silencing', 'Var', (0, 21))	('RASSF1A', 'Gene', '11186', (29, 36))	('RASSF1', 'Gene', (60, 66))	('promotes', 'PosReg', (86, 94))	('RASSF1', 'Gene', '11186', (29, 35))	('RASSF1A', 'Gene', (29, 36))	('activates', 'PosReg', (42, 51))
806168	30123355	Due to their reversibility, epigenetic modifications, such as DNA methylation, may serve as potential reversible molecular targets for cancer treatment and chemoprevention.	('methyl', 'Chemical', 'MESH:C051224', (66, 72))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('DNA', 'Disease', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('epigenetic', 'Var', (28, 38))	('men', 'Species', '9606', (147, 150))
806170	30123355	The limitation of this study is that only Kazakh-related gene methylation has been associated with the prognosis of esophageal cancer and it has not been compared with that of the Han population.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('methylation', 'Var', (62, 73))	('associated', 'Reg', (83, 93))	('esophageal cancer', 'Disease', (116, 133))	('methyl', 'Chemical', 'MESH:C051224', (62, 68))
806179	28424407	In addition, we also found that patients with low HDAC1 expression showed better overall survival than those with high HDAC1 expression in gastrointestinal malignancy, especially in gastric cancer (HR = 1.88, 95% CI = 1.14-3.12, P = 0.01).	('better', 'PosReg', (74, 80))	('HDAC1', 'Gene', (50, 55))	('low', 'Var', (46, 49))	('patients', 'Species', '9606', (32, 40))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('HDAC1', 'Gene', (119, 124))	('gastrointestinal malignancy', 'Disease', 'MESH:D005767', (139, 166))	('HDAC1', 'Gene', '3065', (50, 55))	('gastrointestinal malignancy', 'Disease', (139, 166))	('HDAC1', 'Gene', '3065', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('gastric cancer', 'Disease', (182, 196))	('expression', 'Var', (56, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))
806219	28424407	However, the OS rate was comparable between patients with low HDAC1 expression and those with high HDAC1 expression in colorectal cancer (HR = 0.87, 95% CI = 0.66-1.13, P = 0.30) (Figure 9A), liver cancer (HR = 1.71, 95% CI = 0.76-3.86, P = 0.19) (Figure 9C) and pancreatic cancer (HR = 1.43, 95% CI = 0.71-2.88, P = 0.32) (Figure 9D).	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('liver cancer', 'Disease', 'MESH:D006528', (192, 204))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (263, 280))	('patients', 'Species', '9606', (44, 52))	('liver cancer', 'Disease', (192, 204))	('colorectal cancer', 'Disease', (119, 136))	('HDAC1', 'Gene', (99, 104))	('HDAC1', 'Gene', (62, 67))	('low', 'Var', (58, 61))	('pancreatic cancer', 'Disease', (263, 280))	('HDAC1', 'Gene', '3065', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('pancreatic cancer', 'Disease', 'MESH:D010190', (263, 280))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('liver cancer', 'Phenotype', 'HP:0002896', (192, 204))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('HDAC1', 'Gene', '3065', (62, 67))
806221	28424407	Therefore, these findings indicate that patients with low HDAC1 expression show better overall survival than those with high HDAC1 expression in gastrointestinal malignancies, especially gastric cancer.	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (145, 174))	('HDAC1', 'Gene', '3065', (125, 130))	('gastric cancer', 'Disease', (187, 201))	('gastric cancer', 'Disease', 'MESH:D013274', (187, 201))	('patients', 'Species', '9606', (40, 48))	('low', 'Var', (54, 57))	('HDAC1', 'Gene', (58, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (187, 201))	('better', 'PosReg', (80, 86))	('HDAC1', 'Gene', (125, 130))	('HDAC1', 'Gene', '3065', (58, 63))	('gastrointestinal malignancies', 'Disease', (145, 174))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
806225	28424407	Finally, we found that gastrointestinal cancer patients with low HDAC1 expression showed better OS than those with high HDAC1 expression, especially with gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('HDAC1', 'Gene', (120, 125))	('patients', 'Species', '9606', (47, 55))	('gastrointestinal cancer', 'Disease', (23, 46))	('low', 'Var', (61, 64))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (23, 46))	('gastric cancer', 'Disease', (154, 168))	('HDAC1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (154, 168))	('HDAC1', 'Gene', '3065', (120, 125))	('HDAC1', 'Gene', '3065', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (23, 46))
806232	28424407	Although there was no correlation between HDAC1 expression and OS of colorectal cancer, liver cancer and pancreatic cancer patients, we found that gastric cancer patients with low HDAC1 expression showed better OS than those with high HDAC1 expression, indicating that HDAC1 might be a good prognostic marker for gastric cancer patients and could help screen out high-risk patients with gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (387, 401))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('gastric cancer', 'Phenotype', 'HP:0012126', (313, 327))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('HDAC1', 'Gene', (180, 185))	('HDAC1', 'Gene', (269, 274))	('expression', 'Var', (186, 196))	('HDAC1', 'Gene', (235, 240))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('patients', 'Species', '9606', (123, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (105, 122))	('gastric cancer', 'Disease', (387, 401))	('liver cancer', 'Disease', 'MESH:D006528', (88, 100))	('gastric cancer', 'Disease', (313, 327))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('patients', 'Species', '9606', (162, 170))	('low', 'Var', (176, 179))	('HDAC1', 'Gene', '3065', (180, 185))	('HDAC1', 'Gene', '3065', (269, 274))	('patients', 'Species', '9606', (328, 336))	('HDAC1', 'Gene', '3065', (235, 240))	('pancreatic cancer', 'Disease', (105, 122))	('colorectal cancer', 'Disease', (69, 86))	('HDAC1', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('liver cancer', 'Phenotype', 'HP:0002896', (88, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (387, 401))	('gastric cancer', 'Disease', 'MESH:D013274', (313, 327))	('liver cancer', 'Disease', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('patients', 'Species', '9606', (373, 381))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('HDAC1', 'Gene', '3065', (42, 47))
806347	27033424	The patients with lymph node metastasis tended to have shortened OS, even though the difference was not significant (MST 10.4 vs. 47.3 months, p = 0.1871, Fig.	('shortened', 'NegReg', (55, 64))	('patients', 'Species', '9606', (4, 12))	('lymph node metastasis', 'Var', (18, 39))
806417	25626930	The most common cause of re-intervention corresponded to postoperative pleural empyema and/or complex pleural effusion (n=5 patients), a patient with a lesion in the left main bronchus and of thoracic duct with secondary chylothorax, hemothorax in a patient with innominate vein injury, an contained evisceration and a paraesophageal abcess.	('chylothorax', 'Phenotype', 'HP:0010310', (221, 232))	('pleural effusion', 'Phenotype', 'HP:0002202', (102, 118))	('postoperative pleural empyema', 'Disease', (57, 86))	('pleural effusion', 'Disease', (102, 118))	('paraesophageal abcess', 'Disease', (319, 340))	('patient', 'Species', '9606', (137, 144))	('pleural empyema', 'Phenotype', 'HP:0011919', (71, 86))	('vein injury', 'Disease', (274, 285))	('vein injury', 'Disease', 'MESH:D020246', (274, 285))	('postoperative pleural empyema', 'Disease', 'MESH:D016724', (57, 86))	('paraesophageal abcess', 'Disease', 'MESH:D006551', (319, 340))	('patient', 'Species', '9606', (124, 131))	('lesion', 'Var', (152, 158))	('hemothorax', 'Phenotype', 'HP:0012151', (234, 244))	('hemothorax', 'Disease', (234, 244))	('pleural effusion', 'Disease', 'MESH:D010996', (102, 118))	('patient', 'Species', '9606', (250, 257))	('patients', 'Species', '9606', (124, 132))
806768	33177894	Toxicity control centres are important as the early contact of some caustic substances can lead to severe systemic effects such as hypocalcemia (phosphoric acid, hydrofluoric acid), hyponatremia (strong acids or alkalis), hypokalemia and acidosis.	('acidosis', 'Phenotype', 'HP:0001941', (238, 246))	('hyponatremia', 'Disease', 'MESH:D007010', (182, 194))	('hypokalemia', 'Disease', 'MESH:D007008', (222, 233))	('acidosis', 'Disease', 'MESH:D000138', (238, 246))	('hydrofluoric acid', 'Chemical', 'MESH:D006858', (162, 179))	('phosphoric acid', 'Chemical', 'MESH:C030242', (145, 160))	('lead to', 'Reg', (91, 98))	('hypocalcemia', 'Disease', (131, 143))	('hypocalcemia', 'Phenotype', 'HP:0002901', (131, 143))	('Toxicity', 'Disease', 'MESH:D064420', (0, 8))	('phosphoric', 'Var', (145, 155))	('hypokalemia', 'Disease', (222, 233))	('hyponatremia', 'Phenotype', 'HP:0002902', (182, 194))	('hyponatremia', 'Disease', (182, 194))	('acidosis', 'Disease', (238, 246))	('Toxicity', 'Disease', (0, 8))	('hypocalcemia', 'Disease', 'MESH:D006996', (131, 143))	('strong acid', 'Chemical', '-', (196, 207))	('hypokalemia', 'Phenotype', 'HP:0002900', (222, 233))
806828	33177894	Persistent dysphagia in the first 3 weeks following caustic substance ingestion is a strong predictive factor for further stricture dilations in children with Grade II and Grade III lesions.	('dysphagia', 'Disease', (11, 20))	('children', 'Species', '9606', (145, 153))	('Grade III', 'Var', (172, 181))	('dysphagia', 'Phenotype', 'HP:0002015', (11, 20))	('Grade II', 'Var', (159, 167))	('dysphagia', 'Disease', 'MESH:D003680', (11, 20))
806862	32209107	A few studies of HER2 protein expression and gene amplification in ESCC have been conducted to date, and varying results have been reported for HER2 status in ESCC.	('ESCC', 'Disease', (67, 71))	('ESCC', 'Disease', 'MESH:D000077277', (67, 71))	('gene amplification', 'Var', (45, 63))	('HER2', 'Gene', (17, 21))	('HER2', 'Gene', (144, 148))	('HER2', 'Gene', '2064', (17, 21))	('HER2', 'Gene', '2064', (144, 148))	('ESCC', 'Disease', 'MESH:D000077277', (159, 163))	('ESCC', 'Disease', (159, 163))
806916	32209107	Based on our results, IHC and DISH have a high concordance rate, and HER2 overexpression among our cases was caused by gene amplification in ESCC.	('gene amplification', 'Var', (119, 137))	('overexpression', 'PosReg', (74, 88))	('caused by', 'Reg', (109, 118))	('HER2', 'Gene', (69, 73))	('ESCC', 'Disease', 'MESH:D000077277', (141, 145))	('ESCC', 'Disease', (141, 145))	('HER2', 'Gene', '2064', (69, 73))
806918	32209107	found 3 of 6 (50%) HER2 equivocal (2+) cases with gene amplification, but Gonzaga et al.	('gene amplification', 'Var', (50, 68))	('HER2', 'Gene', '2064', (19, 23))	('HER2', 'Gene', (19, 23))
806920	32209107	In Zhan's study, HER2 amplification was found in 6 of 45 (13.3%) HER2 equivocal (2+) cases.	('HER2', 'Gene', '2064', (65, 69))	('HER2', 'Gene', (17, 21))	('amplification', 'Var', (22, 35))	('HER2', 'Gene', '2064', (17, 21))	('HER2', 'Gene', (65, 69))
806922	32209107	In our study, 10 of 55 (18.2%) HER2 equivocal (2+) cases showed gene amplification.	('HER2', 'Gene', '2064', (31, 35))	('HER2', 'Gene', (31, 35))	('gene amplification', 'Var', (64, 82))
806924	32209107	used FISH to analyze HER2 gene amplification and found that HER2 gene amplification was associated with tumor differentiation and tumor stage, which is different from our study.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('HER2', 'Gene', (60, 64))	('gene amplification', 'Var', (65, 83))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('HER2', 'Gene', '2064', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('HER2', 'Gene', (21, 25))	('HER2', 'Gene', '2064', (21, 25))	('associated', 'Reg', (88, 98))	('tumor', 'Disease', (130, 135))	('amplification', 'Var', (70, 83))
806930	32209107	HER2 gene amplification occurs in approximately 15 to 20% of breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('amplification', 'Var', (10, 23))	('HER2', 'Gene', (0, 4))	('breast cancers', 'Phenotype', 'HP:0003002', (61, 75))	('HER2', 'Gene', '2064', (0, 4))	('breast cancers', 'Disease', 'MESH:D001943', (61, 75))	('breast cancers', 'Disease', (61, 75))
806933	32209107	Similarly, ESCC patients with HER2 gene amplification might also benefit from trastuzumab treatment.	('benefit', 'PosReg', (65, 72))	('HER2', 'Gene', '2064', (30, 34))	('patients', 'Species', '9606', (16, 24))	('gene amplification', 'Var', (35, 53))	('HER2', 'Gene', (30, 34))	('ESCC', 'Disease', (11, 15))	('ESCC', 'Disease', 'MESH:D000077277', (11, 15))	('trastuzumab', 'Chemical', 'MESH:D000068878', (78, 89))
806949	31775815	Silencing of ZFAS1 contributed to suppressed proliferation, migration, invasion and tumor growth in vitro and induced apoptosis of ESCC cells.	('apoptosis', 'CPA', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('proliferation', 'CPA', (45, 58))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('suppressed', 'NegReg', (34, 44))	('invasion', 'CPA', (71, 79))	('tumor', 'Disease', (84, 89))	('ESCC', 'Disease', 'MESH:C562729', (131, 135))	('migration', 'CPA', (60, 69))	('ZFAS1', 'Gene', (13, 18))	('induced', 'Reg', (110, 117))	('Silencing', 'Var', (0, 9))	('ESCC', 'Disease', (131, 135))
806966	31775815	Interestingly, a previous research has demonstrated that ESCC risks may be altered by the miR-124 polymorphism in the Chinese Kazakh population.	('miR', 'Gene', '22877', (90, 93))	('ESCC', 'Disease', (57, 61))	('altered', 'Reg', (75, 82))	('polymorphism', 'Var', (98, 110))	('miR', 'Gene', (90, 93))	('ESCC', 'Disease', 'MESH:C562729', (57, 61))
806999	31775815	The transfection of sh-ZFAS1, sh-NC, Cy3-Oe-ZFAS1, Cy3-Oe-NC, Cy3-sh-ZFAS1, Cy3-sh-NC, Cy3-miR-124 inhibitor and Cy3-inhibitor NC into cells were strictly in accordance with the steps of the kit of Lipofectamine  RNAiMAX (Invitrogen, Carlsbad, CA, USA).	('miR', 'Gene', (91, 94))	('Cy3-sh-ZFAS1', 'Var', (62, 74))	('miR', 'Gene', '22877', (91, 94))
807000	31775815	After 36 h transfection of Cy3-Oe-ZFAS1, Cy3-Oe-NC, Cy3-sh-ZFAS1, Cy3-sh-NC, Cy3-miR-124 inhibitor and Cy3-inhibitor NC, Eca109 cells (as donor cells) were collected and inoculated with 1 x 105 cells/well into the apical chamber of Transwell culture plate.	('miR', 'Gene', (81, 84))	('miR', 'Gene', '22877', (81, 84))	('apical chamber', 'Phenotype', 'HP:0032176', (214, 228))	('Cy3-sh-ZFAS1', 'Var', (52, 64))	('donor', 'Species', '9606', (138, 143))
807012	31775815	The transwell chamber coated with matrigel was preheated to 37  C. After detachment and transfection, the cells were divided into the same groups as above.	('transfection', 'Var', (88, 100))	('detachment', 'Disease', (73, 83))	('detachment', 'Disease', 'MESH:D012163', (73, 83))
807019	31775815	The vectors of MUT and WT were co-transferred to 293 T cells with mimic-NC or miR-124 mimic together with oe-NC or oe-ZFAS1, respectively.	('miR', 'Gene', '22877', (78, 81))	('miR', 'Gene', (78, 81))	('293 T', 'CellLine', 'CVCL:0063', (49, 54))	('mimic', 'Var', (86, 91))
807022	31775815	The antibodies used in RIP were rabbit anti-Ago2 (ab186733, 1:50, Abcam, Shanghai, China).	('Ago2', 'Gene', (44, 48))	('rabbit', 'Species', '9986', (32, 38))	('ab186733', 'Var', (50, 58))	('Ago2', 'Gene', '27161', (44, 48))
807053	31775815	These findings demonstrated that silencing of ZFAS1 could suppress the proliferation, colony formation, invasion, migration of ESCC cells and tumor growth in vivo but facilitate the cell apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('ZFAS1', 'Gene', (46, 51))	('ESCC', 'Disease', (127, 131))	('tumor', 'Disease', (142, 147))	('migration', 'CPA', (114, 123))	('silencing', 'Var', (33, 42))	('suppress', 'NegReg', (58, 66))	('cell apoptosis', 'CPA', (182, 196))	('proliferation', 'CPA', (71, 84))	('facilitate', 'PosReg', (167, 177))	('invasion', 'CPA', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('ESCC', 'Disease', 'MESH:C562729', (127, 131))	('colony formation', 'CPA', (86, 102))
807071	31775815	The results presented that in relation to the Oe-NC group, miR-124 expression was degraded in the Oe-ZFAS1 group (p < 0.05).	('Oe-ZFAS1', 'Var', (98, 106))	('miR', 'Gene', (59, 62))	('expression', 'MPA', (67, 77))	('degraded', 'NegReg', (82, 90))	('miR', 'Gene', '22877', (59, 62))
807093	31775815	ESCC is caused by a variety of genetic factors which include miRNA dysregulation and single nucleotide polymorphisms (SNPs), and environmental risks as smoking, folate deficiency, hot tea drinking, and alcohol consumption.	('folate deficiency', 'Disease', 'MESH:C562799', (161, 178))	('ESCC', 'Disease', 'MESH:C562729', (0, 4))	('caused by', 'Reg', (8, 17))	('miR', 'Gene', (61, 64))	('folate deficiency', 'Phenotype', 'HP:0100507', (161, 178))	('ESCC', 'Disease', (0, 4))	('miR', 'Gene', '22877', (61, 64))	('folate deficiency', 'Disease', (161, 178))	('alcohol', 'Chemical', 'MESH:D000431', (202, 209))	('single nucleotide polymorphisms', 'Var', (85, 116))
807095	31775815	Also, a study provides new insights about the correlation between ESCC risks that in the Chinese Kazakh population and miR-124 polymorphisms, and the ESCC risks might be altered by miR-124 polymorphism.	('miR', 'Gene', (119, 122))	('polymorphism', 'Var', (189, 201))	('ESCC', 'Disease', 'MESH:C562729', (66, 70))	('polymorphisms', 'Var', (127, 140))	('miR', 'Gene', (181, 184))	('ESCC', 'Disease', (150, 154))	('miR', 'Gene', '22877', (181, 184))	('miR', 'Gene', '22877', (119, 122))	('altered', 'Reg', (170, 177))	('ESCC', 'Disease', (66, 70))	('ESCC', 'Disease', 'MESH:C562729', (150, 154))
807103	31775815	Additionally, the finding from our investigation showed that silencing of ZFAS1 inhibited proliferation, migration and invasion and promoted the apoptosis of ESCC cells.	('ESCC', 'Disease', 'MESH:C562729', (158, 162))	('invasion', 'CPA', (119, 127))	('proliferation', 'CPA', (90, 103))	('ZFAS1', 'Gene', (74, 79))	('ESCC', 'Disease', (158, 162))	('silencing', 'Var', (61, 70))	('migration', 'CPA', (105, 114))	('promoted', 'PosReg', (132, 140))	('inhibited', 'NegReg', (80, 89))	('apoptosis', 'CPA', (145, 154))
807104	31775815	A study showed that the inhibition of lncRNA ZFAS1 suppressed glioma cells proliferation, migration and invasion in vitro.	('lncRNA ZFAS1', 'Gene', (38, 50))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('migration', 'CPA', (90, 99))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('suppressed', 'NegReg', (51, 61))	('inhibition', 'Var', (24, 34))	('invasion', 'CPA', (104, 112))	('glioma', 'Disease', (62, 68))
807110	31775815	A previous study has demonstrated that through the transfer of ZFAS1, exosomes promoted proliferation and migration of gastric cancer cells.	('exo', 'Gene', (70, 73))	('ZFAS1', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('exo', 'Gene', '24127', (70, 73))	('gastric cancer', 'Disease', (119, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('promoted', 'PosReg', (79, 87))	('proliferation', 'CPA', (88, 101))	('migration', 'CPA', (106, 115))	('transfer', 'Var', (51, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))
807121	31775815	3'-UTR 3'-untranslated region AIDS acquired immure deficiency syndrome ANOVA one-way analysis of variance BCA bicinchoninic acid BSA bovine serum albumin DAPI 4',6-diamidino-2-phenylindole 2hci EDTA ethylene diamine tetraacetic acid EdU 5-ethynyl-2'-deoxyuridine EP Eppendorf ESCC esophageal squamous cell carcinoma FBS fetal bovine serum FISH RNA-fluorescence in situ hybridization L length diameter lncRNAs Long non-coding RNAs LNM lymph node metastasis miRNA MicroRNAs MUT mutant type MVBs multivesicular bodies NC mimic-negative control PBS phosphate buffer saline PBST phosphate-buffered saline with Tween PMSF phenylmethylsulphonyl fluoride PVDF Polyvinylidene fluoride RIP RNA immunoprecipitation RIPA radioimmunoprecipitation assay RT-qPCR reverse transcription quantitative polymerase chain reaction SNPs single nucleotide polymorphisms STAT3 signal transducer and activator of transcription 3 W width diameter WT wild type	('esophageal squamous cell carcinoma', 'Disease', (281, 315))	('phosphate', 'Chemical', 'MESH:D010710', (574, 583))	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (237, 262))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (292, 315))	('DAPI', 'Chemical', 'MESH:C007293', (154, 158))	('phenylmethylsulphonyl fluoride', 'Chemical', 'MESH:D005459', (616, 646))	('miR', 'Gene', (456, 459))	("4',6-diamidino-2-phenylindole", 'Chemical', 'MESH:C007293', (159, 188))	('ESCC', 'Disease', 'MESH:C562729', (276, 280))	('BCA', 'Chemical', 'MESH:C047117', (106, 109))	('bovine', 'Species', '9913', (326, 332))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (281, 315))	('EdU', 'Chemical', 'MESH:C031086', (233, 236))	('STAT3', 'Gene', (846, 851))	('phosphate', 'Chemical', 'MESH:D010710', (545, 554))	('Tween', 'Chemical', 'MESH:D011136', (605, 610))	('EDTA', 'Chemical', 'MESH:D004533', (194, 198))	('miR', 'Gene', '22877', (456, 459))	('ESCC', 'Disease', (276, 280))	('bovine', 'Species', '9913', (133, 139))	('Polyvinylidene fluoride', 'Chemical', 'MESH:C024865', (652, 675))	('carcinoma', 'Phenotype', 'HP:0030731', (306, 315))	('STAT3', 'Gene', '6774', (846, 851))	('immure deficiency syndrome', 'Disease', 'MESH:D061325', (44, 70))	('PVDF', 'Chemical', 'MESH:C024865', (647, 651))	('bicinchoninic acid', 'Chemical', 'MESH:C047117', (110, 128))	('PMSF', 'Chemical', 'MESH:D005459', (611, 615))	('signal transducer and activator of transcription 3', 'Gene', '6774', (852, 902))	('immure deficiency syndrome', 'Disease', (44, 70))	('single nucleotide polymorphisms', 'Var', (814, 845))	('ethylene diamine tetraacetic acid', 'Chemical', 'MESH:D004533', (199, 232))
807127	30363984	PAR4 activation could suppress DNMT1 and HDAC2, as well as increase p16 expressions, whereas silencing PAR4 dramatically increased HDAC2 and DNMT1, as well as reduced p16 expressions.	('p16', 'Gene', (68, 71))	('p16', 'Gene', '1029', (68, 71))	('DNMT1', 'Gene', (31, 36))	('DNMT1', 'Gene', (141, 146))	('silencing', 'Var', (93, 102))	('reduced', 'NegReg', (159, 166))	('HDAC2', 'Gene', (131, 136))	('HDAC2', 'Gene', '3066', (131, 136))	('increase', 'PosReg', (59, 67))	('PAR4', 'Gene', (0, 4))	('increased', 'PosReg', (121, 130))	('p16', 'Gene', (167, 170))	('PAR4', 'Gene', (103, 107))	('p16', 'Gene', '1029', (167, 170))	('DNMT1', 'Gene', '1786', (31, 36))	('DNMT1', 'Gene', '1786', (141, 146))	('suppress', 'NegReg', (22, 30))	('HDAC2', 'Gene', '3066', (41, 46))	('HDAC2', 'Gene', (41, 46))
807128	30363984	Importantly, the chromatin immunoprecipitation-PCR (ChIP-PCR) data indicated that treatment of ESCC cells with PAR4-AP remarkably suppressed DNMT1 and HDAC2 enrichments on the p16 promoter.	('PAR4-AP', 'Var', (111, 118))	('suppressed', 'NegReg', (130, 140))	('DNMT1', 'Gene', '1786', (141, 146))	('p16', 'Gene', '1029', (176, 179))	('HDAC2', 'Gene', (151, 156))	('HDAC2', 'Gene', '3066', (151, 156))	('p16', 'Gene', (176, 179))	('DNMT1', 'Gene', (141, 146))
807136	30363984	Recently, studies demonstrated that mice with knockdown PAR4 gene could accelerate tumor growth and reduce cardiomyocyte apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('knockdown', 'Var', (46, 55))	('tumor', 'Disease', (83, 88))	('PAR4', 'Gene', (56, 60))	('accelerate', 'PosReg', (72, 82))	('mice', 'Species', '10090', (36, 40))	('reduce', 'NegReg', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cardiomyocyte apoptosis', 'CPA', (107, 130))
807142	30363984	The promoter methylation inactivation of p16 gene can increase the risk of ESCC.	('promoter methylation inactivation', 'Var', (4, 37))	('ESCC', 'Disease', (75, 79))	('p16', 'Gene', '1029', (41, 44))	('p16', 'Gene', (41, 44))
807143	30363984	Previous studies have demonstrated that DNA methyltransferase 1 (DNMT1) is required for the maintenance of DNA methylation and the deactivation of p16 by DNMT1-mediated methylation that may lead to the development of ESCC.	('deactivation', 'NegReg', (131, 143))	('p16', 'Gene', (147, 150))	('DNMT1', 'Gene', (154, 159))	('ESCC', 'Disease', (217, 221))	('DNA methyltransferase 1', 'Gene', (40, 63))	('methylation', 'Var', (169, 180))	('DNMT1', 'Gene', (65, 70))	('DNMT1', 'Gene', '1786', (154, 159))	('DNA methyltransferase 1', 'Gene', '1786', (40, 63))	('p16', 'Gene', '1029', (147, 150))	('lead to', 'Reg', (190, 197))	('DNMT1', 'Gene', '1786', (65, 70))
807146	30363984	The following reagents were used in this study: the selective PAR4-activating peptide (PAR4-AP) from Bachem; PAR4 control peptide from Tocric Bio-technology; PD98059 (an extracellular regulated protein kinase 1/2, ERK1/2, inhibitor), SB203580 (a p38 mitogen-activated protein kinase (MAPK), p38, inhibitor), and t-butylhydroquinone (tBHQ, an ERK1/2 activator) from Santa Cruz Biotechnology; and U-46619 (an ERK1/2 and p38 activator) from Millipore.	('ERK1/2', 'Gene', (407, 413))	('SB203580', 'Chemical', 'MESH:C093642', (234, 242))	('ERK1/2', 'Gene', (342, 348))	('ERK1/2', 'Gene', '5595;5594', (407, 413))	('extracellular regulated protein kinase 1/2', 'Gene', (170, 212))	('p38', 'Gene', (291, 294))	('ERK1/2', 'Gene', '5595;5594', (342, 348))	('p38', 'Gene', '5594', (418, 421))	('SB203580', 'Var', (234, 242))	('ERK1/2', 'Gene', (214, 220))	('ERK1/2', 'Gene', '5595;5594', (214, 220))	('MAPK', 'Gene', '5595;5594;5595', (284, 288))	('tBHQ', 'Chemical', 'MESH:C018855', (333, 337))	('p38', 'Gene', (246, 249))	('p38', 'Gene', '5594', (291, 294))	('PD98059', 'Chemical', 'MESH:C093973', (158, 165))	('MAPK', 'Gene', (284, 288))	('extracellular regulated protein kinase 1/2', 'Gene', '5595', (170, 212))	('PD98059', 'Var', (158, 165))	('p38', 'Gene', (418, 421))	('p38', 'Gene', '5594', (246, 249))
807174	30363984	As shown in Figure 1(b), DNMT1 and HDAC2 levels were downregulated by PAR4-AP treatment.	('DNMT1', 'Gene', '1786', (25, 30))	('PAR4-AP treatment', 'Var', (70, 87))	('HDAC2', 'Gene', (35, 40))	('HDAC2', 'Gene', '3066', (35, 40))	('DNMT1', 'Gene', (25, 30))	('downregulated', 'NegReg', (53, 66))
807175	30363984	Meanwhile, PAR4-AP treatment of ESCC cells significantly increased p16 protein and mRNA levels compared with the control groups (Figures 2(a) and 2(b)).	('mRNA levels', 'MPA', (83, 94))	('p16', 'Gene', '1029', (67, 70))	('PAR4-AP', 'Var', (11, 18))	('increased', 'PosReg', (57, 66))	('p16', 'Gene', (67, 70))
807177	30363984	To assess the possible effects of MAPK on the regulation of DNMT1, HDAC2, and p16 expression by PAR4, ESCC cells were treated with PAR4-AP for 2 h and pretreated with U-46619 (ERK1/2 and p38 activator), tBHQ (ERK1/2 activator), PD98059 (ERK1/2 inhibitor), or SB203580 (p38 inhibitor) for 60 min.	('ERK1/2', 'Gene', '5595;5594', (209, 215))	('MAPK', 'Gene', '5595;5594;5595', (34, 38))	('ERK1/2', 'Gene', (176, 182))	('p38', 'Gene', (187, 190))	('ERK1/2', 'Gene', '5595;5594', (176, 182))	('p38', 'Gene', '5594', (269, 272))	('DNMT1', 'Gene', '1786', (60, 65))	('U-46619', 'Var', (167, 174))	('SB203580', 'Var', (259, 267))	('MAPK', 'Gene', (34, 38))	('p38', 'Gene', '5594', (187, 190))	('ERK1/2', 'Gene', (237, 243))	('HDAC2', 'Gene', '3066', (67, 72))	('HDAC2', 'Gene', (67, 72))	('ERK1/2', 'Gene', '5595;5594', (237, 243))	('DNMT1', 'Gene', (60, 65))	('PD98059', 'Chemical', 'MESH:C093973', (228, 235))	('SB203580', 'Chemical', 'MESH:C093642', (259, 267))	('p16', 'Gene', (78, 81))	('p38', 'Gene', (269, 272))	('tBHQ', 'Chemical', 'MESH:C018855', (203, 207))	('p16', 'Gene', '1029', (78, 81))	('PD98059', 'Var', (228, 235))	('ERK1/2', 'Gene', (209, 215))
807179	30363984	Compared with PAR4-AP alone, PAR4-AP with U-46619 or tBHQ, activators for ERK1/2 and p38, could induce a decrease of DNMT1 and HDAC2 protein levels to much lower levels, which in turn markedly increased the expression of p16 protein (Figure 2(d)).	('PAR4-AP', 'Var', (29, 36))	('U-46619', 'Var', (42, 49))	('DNMT1', 'Gene', '1786', (117, 122))	('p38', 'Gene', '5594', (85, 88))	('p16', 'Gene', (221, 224))	('ERK1/2', 'Gene', '5595;5594', (74, 80))	('p16', 'Gene', '1029', (221, 224))	('HDAC2', 'Gene', (127, 132))	('HDAC2', 'Gene', '3066', (127, 132))	('increased', 'PosReg', (193, 202))	('ERK1/2', 'Gene', (74, 80))	('p38', 'Gene', (85, 88))	('expression', 'MPA', (207, 217))	('DNMT1', 'Gene', (117, 122))	('decrease', 'NegReg', (105, 113))	('tBHQ', 'Chemical', 'MESH:C018855', (53, 57))
807180	30363984	Meanwhile, PD98059 or SB203580, inhibitors for ERK1/2 and p38, partially or completely blocked the increase of p16 protein expression, which in turn markedly reversed the downexpression of DNMT1 and HDAC2 proteins, compared with PAR4-AP-only groups (Figure 2(d)).	('SB203580', 'Var', (22, 30))	('ERK1/2', 'Gene', '5595;5594', (47, 53))	('SB203580', 'Chemical', 'MESH:C093642', (22, 30))	('PD98059', 'Var', (11, 18))	('downexpression', 'NegReg', (171, 185))	('p16', 'Gene', '1029', (111, 114))	('p38', 'Gene', '5594', (58, 61))	('HDAC2', 'Gene', '3066', (199, 204))	('HDAC2', 'Gene', (199, 204))	('DNMT1', 'Gene', (189, 194))	('PD98059', 'Chemical', 'MESH:C093973', (11, 18))	('ERK1/2', 'Gene', (47, 53))	('p38', 'Gene', (58, 61))	('increase', 'PosReg', (99, 107))	('DNMT1', 'Gene', '1786', (189, 194))	('p16', 'Gene', (111, 114))	('blocked', 'NegReg', (87, 94))
807181	30363984	These results indicated that the effect of PAR4-AP on DNMT1, HDAC2, and p16 expression is associated with MAPK signal pathways.	('MAPK', 'Gene', (106, 110))	('p16', 'Gene', '1029', (72, 75))	('HDAC2', 'Gene', (61, 66))	('HDAC2', 'Gene', '3066', (61, 66))	('MAPK', 'Gene', '5595;5594;5595', (106, 110))	('PAR4-AP', 'Var', (43, 50))	('associated', 'Reg', (90, 100))	('DNMT1', 'Gene', (54, 59))	('DNMT1', 'Gene', '1786', (54, 59))	('p16', 'Gene', (72, 75))
807183	30363984	p16-1, p16-2, and p16-3 are located upstream of the p16 promoter (-1755 bp, -551 bp and- 263 bp), representing the important regulatory regions of p16 gene.	('p16', 'Gene', '1029', (18, 21))	('p16', 'Gene', '1029', (52, 55))	('-1755', 'Var', (66, 71))	('p16', 'Gene', (147, 150))	('p16', 'Gene', (0, 3))	('p16', 'Gene', (7, 10))	('p16', 'Gene', (18, 21))	('p16', 'Gene', (52, 55))	('p16', 'Gene', '1029', (147, 150))	('p16', 'Gene', '1029', (0, 3))	('p16', 'Gene', '1029', (7, 10))
807187	30363984	The PAR4 gene knockdown was able to upregulate the levels of DNMT1 and HDAC2 proteins and genes and suppress p16 protein and gene expression following transfection of PAR4-siRNA with ESCC cells (P > 0.05) (Figures 4(a) and 4(b)).	('levels', 'MPA', (51, 57))	('HDAC2', 'Gene', (71, 76))	('PAR4', 'Gene', (4, 8))	('p16', 'Gene', (109, 112))	('HDAC2', 'Gene', '3066', (71, 76))	('upregulate', 'PosReg', (36, 46))	('DNMT1', 'Gene', (61, 66))	('genes', 'MPA', (90, 95))	('p16', 'Gene', '1029', (109, 112))	('gene expression', 'MPA', (125, 140))	('knockdown', 'Var', (14, 23))	('DNMT1', 'Gene', '1786', (61, 66))	('suppress', 'NegReg', (100, 108))
807189	30363984	Similarly, MTT assay analysis demonstrated that the viability of ESCC cells decreased in a time-dependent manner following PAR4-AP treatment (Figure 5(b)).	('PAR4-AP treatment', 'Var', (123, 140))	('MTT', 'Chemical', 'MESH:C070243', (11, 14))	('decreased', 'NegReg', (76, 85))	('viability', 'CPA', (52, 61))
807190	30363984	Our study demonstrated that the treatment with PAR4-AP inhibited the proliferation of ESCC cells, upregulated p16, and reduced DNMT1 and HDAC2 expression in ESCC cells.	('DNMT1', 'Gene', '1786', (127, 132))	('p16', 'Gene', '1029', (110, 113))	('proliferation', 'CPA', (69, 82))	('ESCC cells', 'CPA', (86, 96))	('expression', 'MPA', (143, 153))	('upregulated', 'PosReg', (98, 109))	('PAR4-AP', 'Var', (47, 54))	('HDAC2', 'Gene', (137, 142))	('HDAC2', 'Gene', '3066', (137, 142))	('p16', 'Gene', (110, 113))	('DNMT1', 'Gene', (127, 132))	('reduced', 'NegReg', (119, 126))	('inhibited', 'NegReg', (55, 64))
807193	30363984	These findings provide evidence that the inhibited proliferation of ESCC cells associated with PAR4-AP may be involved in the promotion of p16 transcription through suppressing DNMT1 and HDAC2 expression via MAPK signals in ESCC cells.	('transcription', 'MPA', (143, 156))	('HDAC2', 'Gene', (187, 192))	('PAR4-AP', 'Var', (95, 102))	('DNMT1', 'Gene', (177, 182))	('p16', 'Gene', '1029', (139, 142))	('MAPK', 'Gene', '5595;5594;5595', (208, 212))	('suppressing', 'NegReg', (165, 176))	('DNMT1', 'Gene', '1786', (177, 182))	('inhibited', 'NegReg', (41, 50))	('expression', 'MPA', (193, 203))	('MAPK', 'Gene', (208, 212))	('HDAC2', 'Gene', '3066', (187, 192))	('p16', 'Gene', (139, 142))	('promotion', 'PosReg', (126, 135))
807199	30363984	It is believed that DNMT1 is required for the deactivation of p16 by DNMT1-mediated methylation that may lead to the development of ESCC.	('DNMT1', 'Gene', '1786', (69, 74))	('methylation', 'Var', (84, 95))	('lead to', 'Reg', (105, 112))	('deactivation', 'NegReg', (46, 58))	('p16', 'Gene', (62, 65))	('DNMT1', 'Gene', (20, 25))	('DNMT1', 'Gene', '1786', (20, 25))	('DNMT1', 'Gene', (69, 74))	('ESCC', 'Disease', (132, 136))	('p16', 'Gene', '1029', (62, 65))
807202	30363984	The inhibition of DNMT1 might reduce DNA methylation in the p16 promoter and increase p16 expression.	('DNMT1', 'Gene', '1786', (18, 23))	('p16', 'Gene', (60, 63))	('DNA methylation', 'MPA', (37, 52))	('reduce', 'NegReg', (30, 36))	('p16', 'Gene', (86, 89))	('inhibition', 'Var', (4, 14))	('p16', 'Gene', '1029', (60, 63))	('expression', 'MPA', (90, 100))	('increase', 'PosReg', (77, 85))	('DNMT1', 'Gene', (18, 23))	('p16', 'Gene', '1029', (86, 89))
807203	30363984	HDAC2 inactivation significantly reduced G1-S cell cycle arrest, restored activity of p16, and promoted apoptosis.	('promoted', 'PosReg', (95, 103))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (46, 63))	('HDAC2', 'Gene', '3066', (0, 5))	('inactivation', 'Var', (6, 18))	('G1-S cell cycle arrest', 'CPA', (41, 63))	('restored', 'PosReg', (65, 73))	('HDAC2', 'Gene', (0, 5))	('activity', 'MPA', (74, 82))	('p16', 'Gene', (86, 89))	('reduced', 'NegReg', (33, 40))	('apoptosis', 'CPA', (104, 113))	('p16', 'Gene', '1029', (86, 89))
807209	30363984	Suppressing DNMT1 could lead to the activation of the esophageal suppressor gene p16.	('Suppressing', 'Var', (0, 11))	('DNMT1', 'Gene', (12, 17))	('activation', 'PosReg', (36, 46))	('p16', 'Gene', '1029', (81, 84))	('DNMT1', 'Gene', '1786', (12, 17))	('esophageal', 'Gene', (54, 64))	('p16', 'Gene', (81, 84))
807222	30363984	The increase in p16 mRNA and protein levels in ESCC cells after PAR4-AP treatment provides a molecular mechanism for PAR4 in the regulation of ESCC carcinogenesis.	('PAR4-AP', 'Var', (64, 71))	('p16', 'Gene', '1029', (16, 19))	('ESCC carcinogenesis', 'Disease', (143, 162))	('increase', 'PosReg', (4, 12))	('p16', 'Gene', (16, 19))	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (143, 162))
807382	29312594	Investigation of TCF7L2, LEP and LEPR polymorphisms with esophageal squamous cell carcinomas Single nucleotide polymorphisms (SNPs) in energy metabolism related gene may be key agents in the development of human malignancies.	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('Single nucleotide polymorphisms', 'Var', (93, 124))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (68, 92))	('esophageal squamous cell carcinomas', 'Disease', (57, 92))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (57, 92))	('malignancies', 'Disease', 'MESH:D009369', (212, 224))	('human', 'Species', '9606', (206, 211))	('LEP', 'Gene', '3952', (25, 28))	('TCF7L2', 'Gene', (17, 23))	('malignancies', 'Disease', (212, 224))	('TCF7L2', 'Gene', '6934', (17, 23))	('LEPR', 'Gene', '3953', (33, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('men', 'Species', '9606', (198, 201))	('LEP', 'Gene', (25, 28))	('LEPR', 'Gene', (33, 37))	('LEP', 'Gene', '3952', (33, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('LEP', 'Gene', (33, 36))
807383	29312594	In this study, we aimed to examine the association of transcription factor 7-like 2, Leptin (LEP) and LEP receptor (LEPR) polymorphisms with esophageal squamous cell carcinoma (ESCC).	('polymorphisms', 'Var', (122, 135))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (141, 175))	('LEP', 'Gene', '3952', (102, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('LEP', 'Gene', '3952', (93, 96))	('LEP', 'Gene', (102, 105))	('LEPR', 'Gene', '3953', (116, 120))	('association', 'Interaction', (39, 50))	('Leptin', 'Gene', (85, 91))	('LEP', 'Gene', '3952', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('LEP', 'Gene', (93, 96))	('LEPR', 'Gene', (116, 120))	('transcription factor 7-like 2', 'Gene', '6934', (54, 83))	('LEP receptor', 'Gene', (102, 114))	('Leptin', 'Gene', '3952', (85, 91))	('LEP', 'Gene', (116, 119))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))	('transcription factor 7-like 2', 'Gene', (54, 83))	('LEP receptor', 'Gene', '3953', (102, 114))
807384	29312594	We found that LEPR rs6588147 AA genotype was associated with ESCC risk (AA vs. GG/GA: adjusted OR=1.90, 95%CI=1.00-3.61, P=0.049).	('LEPR', 'Gene', '3953', (14, 18))	('rs6588147 AA', 'Var', (19, 31))	('ESCC', 'Disease', (61, 65))	('LEPR', 'Gene', (14, 18))	('rs6588147', 'Mutation', 'rs6588147', (19, 28))
807385	29312594	In the stratified analyses, LEPR rs6588147 G>A polymorphism increased the risk of ESCC (<63 years subgroup: AA vs. GG: adjusted OR=2.58, 95%CI=1.00-6.62, P=0.049 and AA vs. GA/GG: adjusted OR=2.71, 95%CI=1.06-6.91, P=0.038; male subgroup: AA vs. GG: adjusted OR=2.19, 95%CI=1.02-4.67, P=0.044 and AA vs. GA/GG: adjusted OR=2.26, 95%CI=1.06-4.80, P=0.035).	('ESCC', 'Disease', (82, 86))	('LEPR', 'Gene', '3953', (28, 32))	('LEPR', 'Gene', (28, 32))	('rs6588147', 'Mutation', 'rs6588147', (33, 42))	('rs6588147 G>A', 'Var', (33, 46))
807387	29312594	In addition, LEPR rs1137101 G>A polymorphism decreased ESCC risk in some subgroups (ever smoking subgroup: GA vs. GG: adjusted OR=0.66, 95%CI=0.44-1.00, P=0.049; ever drinking subgroup: GA vs. GG: adjusted OR=0.54, 95%CI=0.31-0.95, P=0.031 and GA/AA vs. GG: adjusted OR=0.54, 95%CI=0.31-0.93, P=0.027).	('decreased ESCC', 'Phenotype', 'HP:0025022', (45, 59))	('rs1137101', 'Mutation', 'rs1137101', (18, 27))	('decreased', 'NegReg', (45, 54))	('LEPR', 'Gene', (13, 17))	('rs1137101 G>A', 'Var', (18, 31))	('ESCC', 'Disease', (55, 59))	('LEPR', 'Gene', '3953', (13, 17))
807398	29312594	A previous study suggested that TCF7L2 rs7903146 locus might exert its enhancer function by interacting with HMGB1.	('TCF7L2', 'Gene', (32, 38))	('HMGB1', 'Gene', (109, 114))	('HMGB1', 'Gene', '3146', (109, 114))	('TCF7L2', 'Gene', '6934', (32, 38))	('interacting', 'Interaction', (92, 103))	('rs7903146', 'Mutation', 'rs7903146', (39, 48))	('enhancer', 'PosReg', (71, 79))	('rs7903146', 'Var', (39, 48))
807399	29312594	TCF7L2 single-nucleotide polymorphisms (SNPs) are proposed susceptibility factors for the development of cancer.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('men', 'Species', '9606', (97, 100))	('susceptibility', 'Reg', (59, 73))	('TCF7L2', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TCF7L2', 'Gene', '6934', (0, 6))	('single-nucleotide polymorphisms', 'Var', (7, 38))
807400	29312594	Previous studies indicated that TCF7L2 rs7903146 (C/T) polymorphism might influence the risk of breast cancer.	('TCF7L2', 'Gene', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('influence', 'Reg', (74, 83))	('TCF7L2', 'Gene', '6934', (32, 38))	('rs7903146', 'Mutation', 'rs7903146', (39, 48))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('rs7903146', 'Var', (39, 48))
807401	29312594	TCF7L2 rs290481 T>C polymorphism located on near the 3' end of this gene.	('TCF7L2', 'Gene', '6934', (0, 6))	('TCF7L2', 'Gene', (0, 6))	('rs290481', 'Mutation', 'rs290481', (7, 15))	('rs290481 T>C', 'Var', (7, 19))
807412	29312594	Results of meta-analyses found that both rs7799039 A>G and rs2167270 G>A polymorphisms in LEP gene might influence the risk of cancer.	('rs7799039 A>G', 'Var', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs2167270 G>A', 'Var', (59, 72))	('influence', 'Reg', (105, 114))	('rs7799039', 'Mutation', 'rs7799039', (41, 50))	('rs2167270', 'Mutation', 'rs2167270', (59, 68))	('LEP', 'Gene', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('LEP', 'Gene', '3952', (90, 93))	('cancer', 'Disease', (127, 133))
807415	29312594	It is suggested that rs7799039 A>G polymorphism in the upstream region of LEP gene can affect leptin expression, possibly at the transcriptional level, thereby altering adipose secretion levels of the hormone.	('altering', 'Reg', (160, 168))	('leptin', 'Gene', (94, 100))	('LEP', 'Gene', '3952', (74, 77))	('affect', 'Reg', (87, 93))	('rs7799039 A>G', 'Var', (21, 34))	('adipose secretion levels of the hormone', 'MPA', (169, 208))	('LEP', 'Gene', (74, 77))	('expression', 'MPA', (101, 111))	('leptin', 'Gene', '3952', (94, 100))	('rs7799039', 'Mutation', 'rs7799039', (21, 30))
807417	29312594	LEPR rs1137100 G>A, rs1137101 G>A polymorphisms are missense SNPs and may alter the structure and the function of LEPR protein.	('alter', 'Reg', (74, 79))	('rs1137101', 'Mutation', 'rs1137101', (20, 29))	('function', 'MPA', (102, 110))	('LEPR', 'Gene', (114, 118))	('rs1137100 G>A', 'Var', (5, 18))	('LEPR', 'Gene', '3953', (0, 4))	('rs1137100', 'Mutation', 'rs1137100', (5, 14))	('rs1137101 G>A', 'Var', (20, 33))	('LEPR', 'Gene', (0, 4))	('LEPR', 'Gene', '3953', (114, 118))	('structure', 'MPA', (84, 93))
807418	29312594	found LEPR rs1137100 G>A, rs1137101 G>A polymorphisms influence the risk of esophageal adenocarcinoma in Caucasians.	('rs1137101 G>A', 'Var', (26, 39))	('esophageal adenocarcinoma', 'Disease', (76, 101))	('LEPR', 'Gene', '3953', (6, 10))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('LEPR', 'Gene', (6, 10))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (76, 101))	('rs1137101', 'Mutation', 'rs1137101', (26, 35))	('rs1137100 G>A', 'Var', (11, 24))	('rs1137100', 'Mutation', 'rs1137100', (11, 20))	('influence', 'Reg', (54, 63))
807419	29312594	LEPR rs6588147 G>A polymorphism locates on the intron region of LEPR gene.	('LEPR', 'Gene', '3953', (0, 4))	('LEPR', 'Gene', (64, 68))	('LEPR', 'Gene', (0, 4))	('LEPR', 'Gene', '3953', (64, 68))	('rs6588147 G>A', 'Var', (5, 18))	('rs6588147', 'Mutation', 'rs6588147', (5, 14))
807420	29312594	found that LEPR rs6588147 G>A polymorphism affected risk of colon cancer among men.	('men', 'Species', '9606', (79, 82))	('affected', 'Reg', (43, 51))	('colon cancer', 'Phenotype', 'HP:0003003', (60, 72))	('rs6588147', 'Mutation', 'rs6588147', (16, 25))	('colon cancer', 'Disease', 'MESH:D015179', (60, 72))	('LEPR', 'Gene', '3953', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colon cancer', 'Disease', (60, 72))	('LEPR', 'Gene', (11, 15))	('rs6588147 G>A', 'Var', (16, 29))
807421	29312594	However, the association between LEPR rs1137100 G>A, rs1137101 G>A and rs6588147 G>A polymorphisms and ESCC risk remains unknown in Asians.	('rs1137101 G>A', 'Var', (53, 66))	('LEPR', 'Gene', (33, 37))	('rs6588147', 'Mutation', 'rs6588147', (71, 80))	('rs1137101', 'Mutation', 'rs1137101', (53, 62))	('rs1137100 G>A', 'Var', (38, 51))	('LEPR', 'Gene', '3953', (33, 37))	('rs1137100', 'Mutation', 'rs1137100', (38, 47))	('ESCC', 'Disease', (103, 107))	('rs6588147 G>A', 'Var', (71, 84))
807422	29312594	In this case-control study, we aimed to examine the potential association of TCF7L2, LEP and LEPR polymorphisms with the risk of ESCC in Eastern Chinese Han populations.	('LEPR', 'Gene', (93, 97))	('LEP', 'Gene', '3952', (85, 88))	('TCF7L2', 'Gene', (77, 83))	('polymorphisms', 'Var', (98, 111))	('ESCC', 'Disease', (129, 133))	('association', 'Interaction', (62, 73))	('TCF7L2', 'Gene', '6934', (77, 83))	('LEP', 'Gene', (93, 96))	('LEPR', 'Gene', '3953', (93, 97))	('LEP', 'Gene', '3952', (93, 96))	('LEP', 'Gene', (85, 88))
807423	29312594	The TCF7L2 rs7903146 C>T, rs290481 T>C, LEP rs7799039 A>G, rs2167270 G>A and LEPR rs1137100 G>A, rs1137101 G>A and rs6588147 G>A polymorphisms were genotyped by SNPscan genotyping assays in 507 ESCC cases and 1,496 non-cancer controls.	('LEP', 'Gene', '3952', (77, 80))	('rs1137100', 'Mutation', 'rs1137100', (82, 91))	('non-cancer', 'Disease', (215, 225))	('rs1137101', 'Mutation', 'rs1137101', (97, 106))	('LEP', 'Gene', (77, 80))	('LEPR', 'Gene', '3953', (77, 81))	('ESCC', 'Disease', (194, 198))	('rs2167270 G>A', 'Var', (59, 72))	('LEPR', 'Gene', (77, 81))	('TCF7L2', 'Gene', (4, 10))	('rs6588147 G>A', 'Var', (115, 128))	('rs6588147', 'Mutation', 'rs6588147', (115, 124))	('TCF7L2', 'Gene', '6934', (4, 10))	('rs290481 T>C', 'Var', (26, 38))	('rs7799039', 'Mutation', 'rs7799039', (44, 53))	('rs7903146', 'Mutation', 'rs7903146', (11, 20))	('LEP', 'Gene', '3952', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('rs1137100 G>A', 'Var', (82, 95))	('rs7903146 C>T', 'Var', (11, 24))	('rs2167270', 'Mutation', 'rs2167270', (59, 68))	('non-cancer', 'Disease', 'MESH:D009369', (215, 225))	('LEP', 'Gene', (40, 43))	('rs1137101 G>A', 'Var', (97, 110))	('rs290481', 'Mutation', 'rs290481', (26, 34))
807428	29312594	The genotyping success rates for TCF7L2 rs7903146C>T, rs290481 T>C, LEP rs7799039 A>G, rs2167270 G>A and LEPR rs1137100 G>A, rs1137101 G>A and rs6588147 G>A SNPs were 99.50%,99.45%, 99.50%, 99.40%, 99.50%, 99.50% and 99.50%, respectively.	('rs6588147', 'Mutation', 'rs6588147', (143, 152))	('rs290481', 'Mutation', 'rs290481', (54, 62))	('rs7799039', 'Mutation', 'rs7799039', (72, 81))	('LEP', 'Gene', '3952', (68, 71))	('rs2167270', 'Mutation', 'rs2167270', (87, 96))	('LEPR', 'Gene', '3953', (105, 109))	('rs1137101 G>A', 'Var', (125, 138))	('LEP', 'Gene', '3952', (105, 108))	('TCF7L2', 'Gene', (33, 39))	('rs7903146C>T', 'Var', (40, 52))	('LEP', 'Gene', (68, 71))	('TCF7L2', 'Gene', '6934', (33, 39))	('LEPR', 'Gene', (105, 109))	('rs1137101', 'Mutation', 'rs1137101', (125, 134))	('rs7799039 A>G', 'Var', (72, 85))	('rs7903146C>T', 'DBSNP_MENTION', 'None', (40, 52))	('LEP', 'Gene', (105, 108))	('rs290481 T>C', 'Var', (54, 66))	('rs1137100', 'Mutation', 'rs1137100', (110, 119))	('rs2167270 G>A', 'Var', (87, 100))	('rs6588147 G>A', 'Var', (143, 156))
807429	29312594	In addition, the distributions of the TCF7L2 rs7903146C>T, rs290481 T>C, LEP rs7799039 A>G, rs2167270 G>A and LEPR rs1137100 G>A, rs1137101 G>A and rs6588147 G>A genotypes in controls conform to Hardy-Weinberg equilibrium (HWE).	('rs7799039 A>G', 'Var', (77, 90))	('rs1137100', 'Mutation', 'rs1137100', (115, 124))	('rs7903146C>T', 'DBSNP_MENTION', 'None', (45, 57))	('LEP', 'Gene', (110, 113))	('rs290481 T>C', 'Var', (59, 71))	('rs6588147', 'Mutation', 'rs6588147', (148, 157))	('rs6588147 G>A', 'Var', (148, 161))	('rs2167270 G>A', 'Var', (92, 105))	('rs290481', 'Mutation', 'rs290481', (59, 67))	('rs7799039', 'Mutation', 'rs7799039', (77, 86))	('LEP', 'Gene', '3952', (73, 76))	('Hardy-Weinberg equilibrium', 'Disease', (195, 221))	('rs2167270', 'Mutation', 'rs2167270', (92, 101))	('rs1137101 G>A', 'Var', (130, 143))	('LEPR', 'Gene', '3953', (110, 114))	('rs7903146C>T', 'Var', (45, 57))	('LEP', 'Gene', (73, 76))	('TCF7L2', 'Gene', (38, 44))	('LEP', 'Gene', '3952', (110, 113))	('TCF7L2', 'Gene', '6934', (38, 44))	('rs1137101', 'Mutation', 'rs1137101', (130, 139))	('LEPR', 'Gene', (110, 114))
807430	29312594	The genotype distributions of TCF7L2 rs7903146C>T, rs290481 T>C, LEP rs7799039 A>G, rs2167270 G>A and LEPR rs1137100 G>A, rs1137101 G>A and rs6588147 G>A polymorphisms are listed in Table 3.	('LEP', 'Gene', '3952', (102, 105))	('TCF7L2', 'Gene', (30, 36))	('rs290481 T>C', 'Var', (51, 63))	('LEPR', 'Gene', (102, 106))	('rs7903146C>T', 'DBSNP_MENTION', 'None', (37, 49))	('TCF7L2', 'Gene', '6934', (30, 36))	('rs2167270 G>A', 'Var', (84, 97))	('LEP', 'Gene', (102, 105))	('rs6588147', 'Mutation', 'rs6588147', (140, 149))	('rs6588147 G>A', 'Var', (140, 153))	('rs7799039', 'Mutation', 'rs7799039', (69, 78))	('rs290481', 'Mutation', 'rs290481', (51, 59))	('LEP', 'Gene', '3952', (65, 68))	('rs2167270', 'Mutation', 'rs2167270', (84, 93))	('LEP', 'Gene', (65, 68))	('rs1137101 G>A', 'Var', (122, 135))	('rs7799039 A>G', 'Var', (69, 82))	('rs1137101', 'Mutation', 'rs1137101', (122, 131))	('LEPR', 'Gene', '3953', (102, 106))	('rs1137100', 'Mutation', 'rs1137100', (107, 116))	('rs7903146C>T', 'Var', (37, 49))
807431	29312594	In the analysis of LEPR rs6588147 G>A polymorphism, we found significant differences in the distribution of the rs6588147 AA genotype compared with the rs6588147 GG genotype and rs6588147 AA genotype compared with the rs6588147 GA/GG genotypes between 507 ESCC cases and 1,496 controls [AA vs. GG: crude odds ratio (OR) = 1.87, 95% confidence interval (CI) = 1.02-3.43, P = 0.042 and AA vs. GG/GA: crude OR = 1.93, 95% CI = 1.06-3.53, P = 0.031 (Table 3)].	('rs6588147', 'Mutation', 'rs6588147', (218, 227))	('LEPR', 'Gene', (19, 23))	('rs6588147', 'Mutation', 'rs6588147', (112, 121))	('ESCC', 'Disease', (256, 260))	('rs6588147 AA', 'Var', (112, 124))	('rs6588147', 'Mutation', 'rs6588147', (178, 187))	('rs6588147', 'Mutation', 'rs6588147', (24, 33))	('LEPR', 'Gene', '3953', (19, 23))	('rs6588147', 'Mutation', 'rs6588147', (152, 161))
807432	29312594	Results of multivariate linear regression analysis indicated that LEPR rs6588147 G>A polymorphism increased the risk of ESCC.	('rs6588147', 'Mutation', 'rs6588147', (71, 80))	('LEPR', 'Gene', '3953', (66, 70))	('ESCC', 'Disease', (120, 124))	('increased', 'PosReg', (98, 107))	('LEPR', 'Gene', (66, 70))	('rs6588147 G>A', 'Var', (71, 84))
807434	29312594	However, we found that TCF7L2 rs7903146C>T, rs290481 T>C, LEP rs7799039 A>G, rs2167270 G>A and LEPR rs1137100 G>A, rs1137101 G>A polymorphisms were not associated with the development of overall ESCC (Table 3).	('men', 'Species', '9606', (179, 182))	('rs7903146C>T', 'Var', (30, 42))	('TCF7L2', 'Gene', (23, 29))	('TCF7L2', 'Gene', '6934', (23, 29))	('LEPR', 'Gene', (95, 99))	('ESCC', 'Disease', (195, 199))	('rs7903146C>T', 'DBSNP_MENTION', 'None', (30, 42))	('rs2167270 G>A', 'Var', (77, 90))	('LEP', 'Gene', '3952', (58, 61))	('rs290481', 'Mutation', 'rs290481', (44, 52))	('LEP', 'Gene', (58, 61))	('rs290481 T>C', 'Var', (44, 56))	('rs7799039', 'Mutation', 'rs7799039', (62, 71))	('rs1137101 G>A', 'Var', (115, 128))	('LEP', 'Gene', '3952', (95, 98))	('rs2167270', 'Mutation', 'rs2167270', (77, 86))	('rs1137101', 'Mutation', 'rs1137101', (115, 124))	('LEP', 'Gene', (95, 98))	('LEPR', 'Gene', '3953', (95, 99))	('rs1137100', 'Mutation', 'rs1137100', (100, 109))
807435	29312594	Table 4 shows the genotype frequencies of LEP rs7799039 A>G polymorphism in the subgroup analyses.	('LEP', 'Gene', (42, 45))	('LEP', 'Gene', '3952', (42, 45))	('rs7799039 A>G', 'Var', (46, 59))	('rs7799039', 'Mutation', 'rs7799039', (46, 55))
807438	29312594	The genotype frequencies of LEPR rs1137101 G>A polymorphism in the subgroup analyses are showed in Table 5.	('rs1137101 G>A', 'Var', (33, 46))	('LEPR', 'Gene', '3953', (28, 32))	('rs1137101', 'Mutation', 'rs1137101', (33, 42))	('LEPR', 'Gene', (28, 32))
807439	29312594	In ever smoking subgroup, after adjustment for gender, age, BMI and alcohol use, the LEPR rs1137101 GA genotype was associated with the decreased risk of ESCC [GA vs. GG: adjusted OR = 0.66, 95% CI 0.44-1.00, P = 0.049 (Table 5)].	('rs1137101 GA', 'Var', (90, 102))	('men', 'Species', '9606', (38, 41))	('rs1137101', 'Mutation', 'rs1137101', (90, 99))	('alcohol', 'Chemical', 'MESH:D000438', (68, 75))	('LEPR', 'Gene', (85, 89))	('ESCC [', 'Disease', (154, 160))	('alcohol use', 'Phenotype', 'HP:0030955', (68, 79))	('decreased', 'NegReg', (136, 145))	('LEPR', 'Gene', '3953', (85, 89))
807440	29312594	In ever drinking subgroup, after adjustment for gender, smoking status, BMI and age, we found that LEPR rs1137101 GA and GA/AA genotypes decreased the risk of ESCC [GA vs. GG: adjusted OR = 0.54, 95% CI 0.31-0.95, P = 0.031 and GA/AA vs. GG: adjusted OR = 0.54, 95% CI 0.31-0.93, P = 0.027 (Table 5)].	('LEPR', 'Gene', '3953', (99, 103))	('rs1137101', 'Mutation', 'rs1137101', (104, 113))	('LEPR', 'Gene', (99, 103))	('rs1137101 GA', 'Var', (104, 116))	('men', 'Species', '9606', (39, 42))	('decreased', 'NegReg', (137, 146))	('ESCC', 'Disease', (159, 163))
807441	29312594	Table 6 shows the genotype frequencies of LEPR rs6588147 G>A polymorphism in the subgroup analyses.	('LEPR', 'Gene', '3953', (42, 46))	('rs6588147', 'Mutation', 'rs6588147', (47, 56))	('rs6588147 G>A', 'Var', (47, 60))	('LEPR', 'Gene', (42, 46))
807443	29312594	In male subgroup, after adjustment for age, smoking status, BMI and alcohol use, the LEPR rs6588147 AA genotype was associated with the increased risk of ESCC [AA vs. GG: adjusted OR = 2.19, 95% CI 1.02-4.67, P = 0.044 and AA vs. GA/GG: adjusted OR = 2.26, 95% CI 1.06-4.80, P = 0.035 (Table 6)].	('rs6588147 AA', 'Var', (90, 102))	('alcohol', 'Chemical', 'MESH:D000438', (68, 75))	('LEPR', 'Gene', (85, 89))	('ESCC', 'Disease', (154, 158))	('rs6588147', 'Mutation', 'rs6588147', (90, 99))	('men', 'Species', '9606', (30, 33))	('alcohol use', 'Phenotype', 'HP:0030955', (68, 79))	('LEPR', 'Gene', '3953', (85, 89))
807444	29312594	However, in ever drinking subgroup, after adjustment for age, gender, smoking status and BMI, the LEPR rs6588147 GA genotype decreased the risk of ESCC [GA vs. GG: adjusted OR = 0.54, 95% CI 0.31-0.92, P = 0.024 (Table 6)].	('men', 'Species', '9606', (48, 51))	('LEPR', 'Gene', (98, 102))	('decreased', 'NegReg', (125, 134))	('ESCC', 'Disease', (147, 151))	('rs6588147', 'Mutation', 'rs6588147', (103, 112))	('rs6588147 GA', 'Var', (103, 115))	('LEPR', 'Gene', '3953', (98, 102))
807445	29312594	In addition, after a logistic regression analysis, we found that TCF7L2 rs7903146C>T, rs290481 T>C, LEP rs2167270 G>A and LEPR rs1137100 G>A polymorphisms were not associated with the risk of ESCC in any subgroup (data not shown).	('LEP', 'Gene', (122, 125))	('LEP', 'Gene', (100, 103))	('rs7903146C>T', 'DBSNP_MENTION', 'None', (72, 84))	('LEPR', 'Gene', '3953', (122, 126))	('LEP', 'Gene', '3952', (122, 125))	('ESCC', 'Disease', (192, 196))	('rs290481', 'Mutation', 'rs290481', (86, 94))	('LEPR', 'Gene', (122, 126))	('rs290481 T>C', 'Var', (86, 98))	('LEP', 'Gene', '3952', (100, 103))	('rs7903146C>T', 'Var', (72, 84))	('TCF7L2', 'Gene', (65, 71))	('rs1137100', 'Mutation', 'rs1137100', (127, 136))	('rs2167270', 'Mutation', 'rs2167270', (104, 113))	('TCF7L2', 'Gene', '6934', (65, 71))
807448	29312594	In this study, we selected energy metabolism and insulin-sensibility relative gene (TCF7L2, LEP and LEPR) polymorphisms and focused on their susceptibility to ESCC.	('LEP', 'Gene', (100, 103))	('LEP', 'Gene', '3952', (92, 95))	('polymorphisms', 'Var', (106, 119))	('TCF7L2', 'Gene', '6934', (84, 90))	('LEPR', 'Gene', '3953', (100, 104))	('TCF7L2', 'Gene', (84, 90))	('LEP', 'Gene', '3952', (100, 103))	('LEPR', 'Gene', (100, 104))	('insulin', 'Gene', (49, 56))	('LEP', 'Gene', (92, 95))	('insulin', 'Gene', '3630', (49, 56))	('ESCC', 'Disease', (159, 163))
807449	29312594	The association between LEPR rs6588147 G>A polymorphism and the increased risk of overall ESCC was identified.	('LEPR', 'Gene', '3953', (24, 28))	('LEPR', 'Gene', (24, 28))	('ESCC', 'Disease', (90, 94))	('rs6588147', 'Mutation', 'rs6588147', (29, 38))	('rs6588147 G>A', 'Var', (29, 42))
807450	29312594	We also found that LEPR rs6588147 G>A polymorphism increased the risk of ESCC in <63 years and male subgroups.	('LEPR', 'Gene', (19, 23))	('rs6588147 G>A', 'Var', (24, 37))	('rs6588147', 'Mutation', 'rs6588147', (24, 33))	('LEPR', 'Gene', '3953', (19, 23))	('ESCC', 'Disease', (73, 77))
807451	29312594	LEP rs7799039 A>G was associated with the risk of ESCC in >=63 years and BMI >= 24 kg/m2 subgroups.	('LEP', 'Gene', (0, 3))	('rs7799039 A>G', 'Var', (4, 17))	('LEP', 'Gene', '3952', (0, 3))	('rs7799039', 'Mutation', 'rs7799039', (4, 13))	('associated', 'Reg', (22, 32))	('ESCC', 'Disease', (50, 54))
807452	29312594	In addition, LEPR rs1137101 G>A polymorphism decreased the risk of ESCC in ever smoking and ever drinking subgroups.	('rs1137101', 'Mutation', 'rs1137101', (18, 27))	('ESCC', 'Disease', (67, 71))	('decreased', 'NegReg', (45, 54))	('LEPR', 'Gene', (13, 17))	('rs1137101 G>A', 'Var', (18, 31))	('LEPR', 'Gene', '3953', (13, 17))
807453	29312594	There was a difference in the LEPR rs6588147 G>A polymorphism between overall ESCC patients and non-cancer controls.	('LEPR', 'Gene', '3953', (30, 34))	('ESCC', 'Disease', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('LEPR', 'Gene', (30, 34))	('rs6588147', 'Mutation', 'rs6588147', (35, 44))	('rs6588147 G>A', 'Var', (35, 48))	('patients', 'Species', '9606', (83, 91))	('non-cancer', 'Disease', (96, 106))	('non-cancer', 'Disease', 'MESH:D009369', (96, 106))
807455	29312594	The LEPR rs6588147 G>A polymorphism is located on intron of LEPR gene.	('LEPR', 'Gene', '3953', (4, 8))	('LEPR', 'Gene', (60, 64))	('LEPR', 'Gene', (4, 8))	('LEPR', 'Gene', '3953', (60, 64))	('rs6588147', 'Mutation', 'rs6588147', (9, 18))	('rs6588147 G>A', 'Var', (9, 22))
807456	29312594	The intronic polymorphism rs6588147 G>A is located near the regulatory components or splice acceptor site, where any slight variant may lead to the disruption of the splice site and induce aberrant splicing.	('splicing', 'MPA', (198, 206))	('induce', 'Reg', (182, 188))	('rs6588147 G>A', 'Var', (26, 39))	('rs6588147', 'Mutation', 'rs6588147', (26, 35))	('lead to', 'Reg', (136, 143))	('aberrant', 'MPA', (189, 197))	('disruption', 'MPA', (148, 158))
807458	29312594	However, we found that LEPR rs6588147 AA genotype may decrease the risk of ESCC in ever drinking subgroup.	('decrease', 'NegReg', (54, 62))	('ESCC', 'Disease', (75, 79))	('LEPR', 'Gene', (23, 27))	('rs6588147', 'Mutation', 'rs6588147', (28, 37))	('ever drinking', 'Disease', (83, 96))	('LEPR', 'Gene', '3953', (23, 27))	('rs6588147 AA', 'Var', (28, 40))
807462	29312594	Results of several meta-analyses suggested that LEP rs7799039 G allele might decrease the risk of multiple cancers.	('multiple cancers', 'Disease', 'MESH:D009369', (98, 114))	('rs7799039 G', 'Var', (52, 63))	('rs7799039', 'Mutation', 'rs7799039', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('LEP', 'Gene', (48, 51))	('decrease', 'NegReg', (77, 85))	('LEP', 'Gene', '3952', (48, 51))	('multiple cancers', 'Disease', (98, 114))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
807463	29312594	However, there was only one study focused on the relationship between LEP rs7799039 A>G polymorphism and cancer risk in Asian populations.	('LEP', 'Gene', (70, 73))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('rs7799039', 'Mutation', 'rs7799039', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('LEP', 'Gene', '3952', (70, 73))	('rs7799039 A>G', 'Var', (74, 87))
807465	29312594	In this study, we conducted a case-control study focused on the association between LEP rs7799039 A>G polymorphism and ESCC risk with a relatively large sample size.	('ESCC', 'Disease', (119, 123))	('rs7799039', 'Mutation', 'rs7799039', (88, 97))	('LEP', 'Gene', (84, 87))	('rs7799039 A>G', 'Var', (88, 101))	('LEP', 'Gene', '3952', (84, 87))	('association', 'Interaction', (64, 75))
807466	29312594	We found LEP rs7799039 A>G was associated with the decreased risk of ESCC in >=63 years and BMI >= 24 kg/m2 subgroups.	('rs7799039 A>G', 'Var', (13, 26))	('decreased', 'NegReg', (51, 60))	('LEP', 'Gene', (9, 12))	('ESCC', 'Disease', (69, 73))	('rs7799039', 'Mutation', 'rs7799039', (13, 22))	('LEP', 'Gene', '3952', (9, 12))
807468	29312594	In this study, we found that LEP rs7799039 A>G polymorphism was a protective factor for ESCC, suggesting the presence of the LEP rs7799039 G allele, which is associated with the decreased level of LEP, might decrease the risk of ESCC.	('ESCC', 'Disease', (229, 233))	('LEP', 'Gene', '3952', (29, 32))	('ESCC', 'Disease', (88, 92))	('LEP', 'Gene', (125, 128))	('rs7799039', 'Mutation', 'rs7799039', (33, 42))	('rs7799039', 'Mutation', 'rs7799039', (129, 138))	('LEP', 'Gene', (197, 200))	('rs7799039 G', 'Var', (129, 140))	('LEP', 'Gene', (29, 32))	('LEP', 'Gene', '3952', (125, 128))	('LEP', 'Gene', '3952', (197, 200))	('decrease', 'NegReg', (208, 216))
807469	29312594	Several case-control study focused on the relationship of LEPR rs1137101 G>A polymorphism and the risk of cancer.	('rs1137101', 'Mutation', 'rs1137101', (63, 72))	('LEPR', 'Gene', '3953', (58, 62))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('rs1137101 G>A', 'Var', (63, 76))	('cancer', 'Disease', (106, 112))	('LEPR', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
807471	29312594	The evidence of the association between LEPR rs1137101 G>A polymorphism and cancer risk was insufficient in Asians.	('insufficient', 'Disease', 'MESH:D000309', (92, 104))	('LEPR', 'Gene', (40, 44))	('insufficient', 'Disease', (92, 104))	('rs1137101', 'Mutation', 'rs1137101', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('LEPR', 'Gene', '3953', (40, 44))	('rs1137101 G>A', 'Var', (45, 58))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
807472	29312594	A previous study suggested that LEPR rs1137101 G>A polymorphism might be associated with variation in binding with LEP and, as such, inter-individual differences in serum LEP levels.	('LEPR', 'Gene', (32, 36))	('rs1137101 G>A', 'Var', (37, 50))	('binding', 'Interaction', (102, 109))	('LEP', 'Gene', '3952', (171, 174))	('associated', 'Reg', (73, 83))	('LEP', 'Gene', (115, 118))	('LEP', 'Gene', (32, 35))	('LEPR', 'Gene', '3953', (32, 36))	('rs1137101', 'Mutation', 'rs1137101', (37, 46))	('LEP', 'Gene', '3952', (115, 118))	('LEP', 'Gene', '3952', (32, 35))	('LEP', 'Gene', (171, 174))
807474	29312594	LEPR rs1137101 G>A polymorphism may alter the susceptibility of cancer by influencing the ability of binding with LEP.	('rs1137101 G>A', 'Var', (5, 18))	('LEP', 'Gene', (0, 3))	('LEPR', 'Gene', '3953', (0, 4))	('LEP', 'Gene', (114, 117))	('alter', 'Reg', (36, 41))	('LEP', 'Gene', '3952', (0, 3))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('LEPR', 'Gene', (0, 4))	('rs1137101', 'Mutation', 'rs1137101', (5, 14))	('binding', 'Interaction', (101, 108))	('LEP', 'Gene', '3952', (114, 117))	('influencing', 'Reg', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
807475	29312594	We found that the LEPR rs1137101 G>A polymorphism decreased ESCC risk in ever drinking and ever smoking subgroups.	('rs1137101 G>A', 'Var', (23, 36))	('ESCC', 'Disease', (60, 64))	('decreased ESCC', 'Phenotype', 'HP:0025022', (50, 64))	('LEPR', 'Gene', '3953', (18, 22))	('decreased', 'NegReg', (50, 59))	('rs1137101', 'Mutation', 'rs1137101', (23, 32))	('LEPR', 'Gene', (18, 22))
807476	29312594	In the future, function of LEPR rs1137101 G>A polymorphism should be further explored to confirm these primary findings in ESCC.	('LEPR', 'Gene', '3953', (27, 31))	('rs1137101 G>A', 'Var', (32, 45))	('ESCC', 'Disease', (123, 127))	('LEPR', 'Gene', (27, 31))	('rs1137101', 'Mutation', 'rs1137101', (32, 41))
807481	29312594	In summary, our findings suggest that LEPR rs6588147 G>A polymorphism is associated with the increased risk of ESCC in Eastern Chinese Han population.	('rs6588147', 'Mutation', 'rs6588147', (43, 52))	('rs6588147 G>A', 'Var', (43, 56))	('LEPR', 'Gene', '3953', (38, 42))	('LEPR', 'Gene', (38, 42))	('ESCC', 'Disease', (111, 115))
807488	29312594	TCF7L2 rs7903146C>T, rs290481 T>C, LEP rs7799039 A>G, rs2167270 G>A and LEPR rs1137100 G>A, rs1137101 G>A and rs6588147 G>A genotypes were assessed by the SNPscan  kit (Gnensky Biotechologies Inc., Shanghai, China), which is a double ligation and multiplex fluorescence PCR.	('rs290481 T>C', 'Var', (21, 33))	('rs7903146C>T', 'DBSNP_MENTION', 'None', (7, 19))	('LEP', 'Gene', (35, 38))	('rs290481', 'Mutation', 'rs290481', (21, 29))	('rs1137100', 'Mutation', 'rs1137100', (77, 86))	('LEP', 'Gene', (72, 75))	('LEP', 'Gene', '3952', (35, 38))	('LEPR', 'Gene', '3953', (72, 76))	('TCF7L2', 'Gene', (0, 6))	('rs7903146C>T', 'Var', (7, 19))	('rs1137101', 'Mutation', 'rs1137101', (92, 101))	('rs2167270 G>A', 'Var', (54, 67))	('rs6588147', 'Mutation', 'rs6588147', (110, 119))	('rs7799039', 'Mutation', 'rs7799039', (39, 48))	('LEP', 'Gene', '3952', (72, 75))	('TCF7L2', 'Gene', '6934', (0, 6))	('LEPR', 'Gene', (72, 76))	('rs2167270', 'Mutation', 'rs2167270', (54, 63))
807493	29312594	The relationships of TCF7L2 rs7903146C>T, rs290481 T>C, LEP rs7799039 A>G, rs2167270 G>A and LEPR rs1137100 G>A, rs1137101 G>A and rs6588147 G>A polymorphisms with ESCC susceptibility were evaluated by crude ORs and 95% CIs.	('rs1137100', 'Mutation', 'rs1137100', (98, 107))	('rs2167270', 'Mutation', 'rs2167270', (75, 84))	('rs1137101 G>A', 'Var', (113, 126))	('LEPR', 'Gene', '3953', (93, 97))	('TCF7L2', 'Gene', (21, 27))	('LEP', 'Gene', (56, 59))	('rs7903146C>T', 'Var', (28, 40))	('ESCC', 'Disease', (164, 168))	('LEP', 'Gene', '3952', (93, 96))	('TCF7L2', 'Gene', '6934', (21, 27))	('rs1137101', 'Mutation', 'rs1137101', (113, 122))	('LEPR', 'Gene', (93, 97))	('rs7903146C>T', 'DBSNP_MENTION', 'None', (28, 40))	('LEP', 'Gene', (93, 96))	('rs290481 T>C', 'Var', (42, 54))	('rs2167270 G>A', 'Var', (75, 88))	('rs6588147', 'Mutation', 'rs6588147', (131, 140))	('rs6588147 G>A', 'Var', (131, 144))	('LEP', 'Gene', '3952', (56, 59))	('rs290481', 'Mutation', 'rs290481', (42, 50))	('rs1137100 G>A', 'Var', (98, 111))	('rs7799039', 'Mutation', 'rs7799039', (60, 69))	('rs7799039 A>G', 'Var', (60, 73))
807494	29312594	Multivariate linear regression adjusted for age, sex, BMI, alcohol use and smoking status was used to determine the relationships between TCF7L2 rs7903146C>T, rs290481 T>C, LEP rs7799039 A>G, rs2167270 G>A and LEPR rs1137100 G>A, rs1137101 G>A and rs6588147 G>A polymorphisms and ESCC risk with quantitative traits.	('rs1137101 G>A', 'Var', (230, 243))	('LEP', 'Gene', (173, 176))	('rs7799039', 'Mutation', 'rs7799039', (177, 186))	('rs1137101', 'Mutation', 'rs1137101', (230, 239))	('ESCC', 'Disease', (280, 284))	('LEPR', 'Gene', '3953', (210, 214))	('rs290481 T>C', 'Var', (159, 171))	('LEP', 'Gene', '3952', (210, 213))	('rs2167270', 'Mutation', 'rs2167270', (192, 201))	('LEPR', 'Gene', (210, 214))	('rs7903146C>T', 'Var', (145, 157))	('TCF7L2', 'Gene', (138, 144))	('TCF7L2', 'Gene', '6934', (138, 144))	('LEP', 'Gene', (210, 213))	('rs7903146C>T', 'DBSNP_MENTION', 'None', (145, 157))	('rs6588147 G>A', 'Var', (248, 261))	('rs1137100', 'Mutation', 'rs1137100', (215, 224))	('rs6588147', 'Mutation', 'rs6588147', (248, 257))	('alcohol', 'Chemical', 'MESH:D000438', (59, 66))	('rs2167270 G>A', 'Var', (192, 205))	('alcohol use', 'Phenotype', 'HP:0030955', (59, 70))	('rs290481', 'Mutation', 'rs290481', (159, 167))	('LEP', 'Gene', '3952', (173, 176))
807519	26755479	Role of genetic is also clear in the prognostication of colon cancer as detection of microsatellite instability indicates a more favorable outcome.	('colon cancer', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('as', 'Chemical', 'MESH:D001151', (69, 71))	('microsatellite instability', 'Var', (85, 111))	('colon cancer', 'Phenotype', 'HP:0003003', (56, 68))	('colon cancer', 'Disease', 'MESH:D015179', (56, 68))
807569	26755479	In our study based on the univariate analysis, university degree, non-smoking and receiving surgery and combination therapies implied on better survival.	('non-smoking', 'Var', (66, 77))	('as', 'Chemical', 'MESH:D001151', (14, 16))	('better', 'PosReg', (137, 143))
807581	26755479	In a study on esophageal cancer in Iran, patients who received chemotherapy or chemo radiotherapy along with Surgery (HR=0.19) had better survival than patients who received these treatments without Surgery such as only chemotherapy (HR= 0.79) or only radiotherapy (HR=0.63).	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('esophageal cancer', 'Disease', (14, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('patients', 'Species', '9606', (41, 49))	('survival', 'CPA', (138, 146))	('chemo', 'Var', (79, 84))	('as', 'Chemical', 'MESH:D001151', (212, 214))	('better', 'PosReg', (131, 137))	('patients', 'Species', '9606', (152, 160))
807616	26474386	Due to the significant difference in the expression of miR-375 in normal, OLP, and tumor tissue, we sought to determine whether miR-375 plays a key role in the oral malignant process or is merely a downstream result.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-375', 'Var', (128, 135))	('miR-375', 'Gene', (55, 62))	('expression', 'MPA', (41, 51))	('tumor', 'Disease', (83, 88))	('oral malignant process', 'CPA', (160, 182))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
807641	26474386	This is supported by increasing evidence indicating the causal involvement of suppressive miRNAs in inflammation or cancers.	('suppressive', 'Var', (78, 89))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('inflammation or cancers', 'Disease', (100, 123))	('miR', 'Gene', '220972', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('miR', 'Gene', (90, 93))	('inflammation or cancers', 'Disease', 'MESH:D007249', (100, 123))
807648	26474386	Previous studies have suggested that KLF5 is down-regulated by miR-375 in goblet-cells in mice gut mucosa, however, this was not shown directly.	('miR-375', 'Var', (63, 70))	('KLF5', 'Protein', (37, 41))	('down-regulated', 'NegReg', (45, 59))	('mice', 'Species', '10090', (90, 94))
807684	26474386	Antibodies against KLF5 (ab24331, Abcam, Cambridge, UK; dilution 1:500) and BIRC5 (ab76424, Abcam, Cambridge, UK, dilution 1:500) were used as primary antibodies.	('ab24331', 'Var', (25, 32))	('ab76424', 'Var', (83, 90))	('BIRC5', 'Gene', (76, 81))	('BIRC5', 'Gene', '332', (76, 81))
807701	26474386	Immunoblotting was performed with diluted (1:500) anti-KLF5 (Abcam) and (1:5000) anti-Survivin (Abcam) antibodies, with the GAPDH antibody (Zhongshan Golden Bridge) serving as an internal control.	('1:5000', 'Var', (73, 79))	('GAPDH', 'Gene', '2597', (124, 129))	('anti-KLF5', 'Protein', (50, 59))	('GAPDH', 'Gene', (124, 129))
807809	25319372	We here describe the case of a patient with a failed gastric conduit after leakage of the cervical anastomosis and development of a tracheal fistula.	('fistula', 'Disease', 'MESH:D005402', (141, 148))	('cervical anastomosis', 'Phenotype', 'HP:0002949', (90, 110))	('fistula', 'Disease', (141, 148))	('patient', 'Species', '9606', (31, 38))	('leakage', 'Var', (75, 82))
807862	21950812	spray cryotherapy can induce necrosis extending through the esophageal wall; depth of injury is determined by duration of the cryotherapy spray and number of freeze-thaw cycles; and in humans, spray cryotherapy induces necrosis extending into the submucosa and inflammation into the muscularis propria at doses currently being used clinically.	('necrosis', 'Disease', (219, 227))	('spray cryotherapy', 'Var', (193, 210))	('necrosis', 'Disease', 'MESH:D009336', (219, 227))	('necrosis', 'Disease', 'MESH:D009336', (29, 37))	('necrosis', 'Disease', (29, 37))	('inflammation', 'Disease', 'MESH:D007249', (261, 273))	('induce', 'Reg', (22, 28))	('muscularis propria', 'Phenotype', 'HP:0030936', (283, 301))	('humans', 'Species', '9606', (185, 191))	('induces', 'Reg', (211, 218))	('inflammation', 'Disease', (261, 273))
807923	21950812	A 73-year-old man with previous T2N1 tonsillar cancer seven years prior and T4N0 esophageal squamous cell carcinoma three years prior, both treated with concurrent chemotherapy and external beam radiotherapy, presented with a T2N0 esophageal squamous cell carcinoma outside the field of the previous esophageal cancer.	('esophageal squamous cell carcinoma', 'Disease', (81, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (242, 265))	('T4N0', 'Var', (76, 80))	('esophageal cancer', 'Disease', (300, 317))	('esophageal cancer', 'Disease', 'MESH:D004938', (300, 317))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (231, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('man', 'Species', '9606', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('tonsillar cancer', 'Disease', (37, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (81, 115))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('esophageal squamous cell carcinoma', 'Disease', (231, 265))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('tonsillar cancer', 'Disease', 'MESH:D014067', (37, 53))
808002	21950812	Additional investigation and clinical research is needed to optimize control of esophageal pH, and to identify patients at risk for IR or "recurrence," including those with longer segments and increased mutation rates.	('mutation', 'Var', (203, 211))	('esophageal', 'Disease', (80, 90))	('patients', 'Species', '9606', (111, 119))
808029	21950812	Helen M. Shields          hshields@caregroup.harvard.edu        The data supporting a chemopreventative effect of acid suppression in BE leading to a reduction of the risk of HGD and esophageal cancer are conflicting.	('acid suppression', 'Var', (114, 130))	('D', 'Chemical', '-', (177, 178))	('HGD', 'Disease', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('esophageal cancer', 'Disease', (183, 200))	('reduction', 'NegReg', (150, 159))	('esophageal cancer', 'Disease', 'MESH:D004938', (183, 200))
808032	21950812	These authors concluded that variations in acid exposure may contribute to the heterogeneity seen both molecularly and structurally in Barrett's patients.	('patients', 'Species', '9606', (145, 153))	('contribute', 'Reg', (61, 71))	('heterogeneity', 'MPA', (79, 92))	('Barrett', 'Disease', (135, 142))	('variations', 'Var', (29, 39))
808054	21950812	Cancer incidence was 13% in the PDT + PPI group, compared to 28% in the PPI group, with all differences between groups statistically significant.	('D', 'Chemical', '-', (33, 34))	('PDT + PPI', 'Var', (32, 41))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
808057	21950812	One hundred and twenty-seven subjects with either low-grade (n = 64) or high-grade (n = 63) dysplasia were randomized in a 2:1 ratio to either RFA + PPI or PPI alone.	('dysplasia', 'Disease', (92, 101))	('RFA + PPI', 'Var', (143, 152))	('dysplasia', 'Disease', 'MESH:D004476', (92, 101))
808219	23300966	Not only has H.pylori been shown to decrease body weight by suppressing appetite, but it is also been observed in multiple population-based studies to be inversely related to risk of EA.	('suppressing', 'NegReg', (60, 71))	('H.pylori', 'Var', (13, 21))	('appetite', 'MPA', (72, 80))	('decrease body weight', 'Phenotype', 'HP:0004325', (36, 56))	('EA', 'Phenotype', 'HP:0011459', (183, 185))	('suppressing appetite', 'Phenotype', 'HP:0004396', (60, 80))	('H.pylori', 'Species', '210', (13, 21))	('body', 'MPA', (45, 49))	('decrease', 'NegReg', (36, 44))
808234	23071416	The presence of an N atom increases the potency of BPs.	('BPs', 'Chemical', 'MESH:D004164', (51, 54))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('potency', 'MPA', (40, 47))	('presence', 'Var', (4, 12))	('increases', 'PosReg', (26, 35))
808266	23071416	In organ cultures, some BPs have been shown to inhibit the formation of mature osteoclasts by inhibiting the fusion of osteoclast precursors into multinucleated osteoclasts, although this aspect of BP actions is understudied.	('BP', 'Chemical', 'MESH:D004164', (198, 200))	('BP', 'Chemical', 'MESH:D004164', (24, 26))	('BPs', 'Var', (24, 27))	('inhibit', 'NegReg', (47, 54))	('BPs', 'Chemical', 'MESH:D004164', (24, 27))	('inhibiting', 'NegReg', (94, 104))	('formation of mature osteoclasts', 'CPA', (59, 90))
808267	23071416	BPs have been shown to induce osteoclast apoptosis by interfering with adenosine-5'-triphosphate-dependent cellular processes.	('induce', 'PosReg', (23, 29))	('BPs', 'Var', (0, 3))	('BPs', 'Chemical', 'MESH:D004164', (0, 3))	('osteoclast apoptosis', 'CPA', (30, 50))	("adenosine-5'-triphosphate", 'Chemical', 'MESH:D000255', (71, 96))	('interfering', 'NegReg', (54, 65))
808270	23071416	It has now become well established that, at the cellular level, N-containing BPs interfere with the mevalonate pathway.	('BPs', 'Chemical', 'MESH:D004164', (77, 80))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('mevalonate pathway', 'Pathway', (100, 118))	('interfere', 'NegReg', (81, 90))	('mevalonate', 'Chemical', 'MESH:D008798', (100, 110))	('N-containing', 'Var', (64, 76))
808278	23071416	During the period of treatment with BPs, bone resorption does not become progressively lower but reaches a new steady-state level, suggesting that, despite accumulation of BPs in the skeleton, bone turnover still continues, albeit at a slower rate.	('BPs', 'Chemical', 'MESH:D004164', (36, 39))	('bone turnover', 'CPA', (193, 206))	('BPs', 'Var', (172, 175))	('BPs', 'Chemical', 'MESH:D004164', (172, 175))	('men', 'Species', '9606', (26, 29))	('bone resorption', 'Phenotype', 'HP:0002797', (41, 56))
808286	23071416	There is a reduction in bone resorption markers (urine N-terminal telopeptide, serum C-terminal telopeptide) following treatment with BPs by >30% at 1 month, reaching a nadir by 3-6 months.	('reduction', 'NegReg', (11, 20))	('BPs', 'Var', (134, 137))	('men', 'Species', '9606', (124, 127))	('BPs', 'Chemical', 'MESH:D004164', (134, 137))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('bone resorption', 'Phenotype', 'HP:0002797', (24, 39))
808287	23071416	In these trials, BPs also gave rise to modest improvements in BMD, although larger increases were seen at the spine compared with the hip.	('BMD', 'MPA', (62, 65))	('BPs', 'Chemical', 'MESH:D004164', (17, 20))	('men', 'Species', '9606', (53, 56))	('BPs', 'Var', (17, 20))
808305	23071416	Another study compared the effects of weekly alendronate with a single dose of zoledronate, showing that suppression of bone resorption was greater with zoledronate compared with alendronate.	('alendronate', 'Chemical', 'MESH:D019386', (179, 190))	('alendronate', 'Chemical', 'MESH:D019386', (45, 56))	('suppression', 'NegReg', (105, 116))	('zoledronate', 'Chemical', 'MESH:D000077211', (79, 90))	('bone resorption', 'Phenotype', 'HP:0002797', (120, 135))	('zoledronate', 'Chemical', 'MESH:D000077211', (153, 164))	('zoledronate', 'Var', (153, 164))	('bone resorption', 'CPA', (120, 135))
808355	23071416	Recent evidence suggests that BPs can reduce GC-induced osteocyte apoptosis, which may have an impact on the preservation of bone strength.	('reduce', 'NegReg', (38, 44))	('BPs', 'Var', (30, 33))	('BPs', 'Chemical', 'MESH:D004164', (30, 33))
808379	23071416	The abnormalities lead to bone pain, increased deformity, and an increased risk of fracture.	('bone pain', 'Phenotype', 'HP:0002653', (26, 35))	('pain', 'Phenotype', 'HP:0012531', (31, 35))	('fracture', 'Disease', 'MESH:D050723', (83, 91))	('increased deformity', 'Disease', (37, 56))	('fracture', 'Disease', (83, 91))	('bone pain', 'Disease', 'MESH:D010146', (26, 35))	('increased deformity', 'Disease', 'MESH:D009140', (37, 56))	('lead to', 'Reg', (18, 25))	('bone pain', 'Disease', (26, 35))	('abnormalities', 'Var', (4, 17))
808419	23071416	In a head-to-head study of zoledronate and pamidronate, zoledronate reduced the risk of skeletal complications by an additional 20% compared with pamidronate, although overall survival was not significantly different.	('pamidronate', 'Chemical', 'MESH:D000077268', (43, 54))	('skeletal complications', 'CPA', (88, 110))	('zoledronate', 'Chemical', 'MESH:D000077211', (27, 38))	('skeletal complications', 'Phenotype', 'HP:0000924', (88, 110))	('pamidronate', 'Chemical', 'MESH:D000077268', (146, 157))	('skeletal complication', 'Phenotype', 'HP:0000924', (88, 109))	('zoledronate', 'Chemical', 'MESH:D000077211', (56, 67))	('reduced', 'NegReg', (68, 75))	('zoledronate', 'Var', (56, 67))
808488	23071416	It is generally agreed that the beneficial effects of BPs on fracture risk, in osteoporosis, PDB, and in oncology patients with MBD greatly outweigh the known adverse effects.	('MBD', 'Disease', (128, 131))	('osteoporosis', 'Disease', (79, 91))	('BPs', 'Chemical', 'MESH:D004164', (54, 57))	('osteoporosis', 'Disease', 'MESH:D010024', (79, 91))	('PDB', 'Disease', 'None', (93, 96))	('MBD', 'Disease', 'MESH:D012080', (128, 131))	('osteoporosis', 'Phenotype', 'HP:0000939', (79, 91))	('PDB', 'Disease', (93, 96))	('BPs', 'Var', (54, 57))	('oncology', 'Phenotype', 'HP:0002664', (105, 113))	('fracture', 'Disease', (61, 69))	('fracture', 'Disease', 'MESH:D050723', (61, 69))	('patients', 'Species', '9606', (114, 122))
808523	32586439	1), while the basal layer of proliferating cells will express markers of proliferation, including KI67, and will continue to express SOX2 and P63.	('P63', 'Gene', '8626', (142, 145))	('rat', 'Species', '10116', (80, 83))	('rat', 'Species', '10116', (36, 39))	('KI67', 'Var', (98, 102))	('SOX2', 'Gene', (133, 137))	('SOX2', 'Gene', '6657', (133, 137))	('P63', 'Gene', (142, 145))
808583	32586439	In our hands, CultureOne reduces contaminating neural progenitor cells, possibly by promoting differentiation into neurons thus reducing their further proliferation.	('CultureOne', 'Chemical', '-', (14, 24))	('further proliferation', 'CPA', (143, 164))	('CultureOne', 'Var', (14, 24))	('reducing', 'NegReg', (128, 136))	('promoting', 'PosReg', (84, 93))	('rat', 'Species', '10116', (158, 161))	('differentiation into neurons', 'CPA', (94, 122))
808594	32586439	Swirl plate under stereomicroscope until organoids are centered, cut the tip of a 200 muL tip and collect organoids into a new tube.	('muL', 'Gene', '4591', (86, 89))	('muL', 'Gene', (86, 89))	('cut', 'Var', (65, 68))
808666	32586439	In epidermolysis bullosa patients, where mutations in genes encoding structural proteins at the epithelium-mesenchyme junction, disease manifestations within the esophagus may result in strictures and lesions that lead to dysphagia.	('mutations', 'Var', (41, 50))	('dysphagia', 'Disease', 'MESH:D003680', (222, 231))	('epidermolysis bullosa', 'Disease', 'MESH:D004820', (3, 24))	('lead to', 'Reg', (214, 221))	('strictures', 'Disease', (186, 196))	('epidermolysis bullosa', 'Disease', (3, 24))	('patients', 'Species', '9606', (25, 33))	('dysphagia', 'Disease', (222, 231))	('dysphagia', 'Phenotype', 'HP:0002015', (222, 231))	('result in', 'Reg', (176, 185))
808690	33592580	Research has demonstrated that the interaction between programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) is a critical immune checkpoint, and inhibiting PD-1 has been found to exhibit high treatment efficacy for melanoma and is now approved for the treatment of HNSC.	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('inhibiting', 'Var', (174, 184))	('programmed cell death protein-1', 'Gene', '100533201', (55, 86))	('PD-1', 'Gene', (185, 189))	('PD-L1', 'Gene', '574058', (130, 135))	('interaction', 'Interaction', (35, 46))	('programmed cell death protein-1', 'Gene', (55, 86))	('PD-L1', 'Gene', (130, 135))	('HNSC', 'Phenotype', 'HP:0012288', (294, 298))	('programmed cell death ligand-1', 'Gene', (98, 128))	('programmed cell death ligand-1', 'Gene', '574058', (98, 128))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanoma', 'Disease', (244, 252))
808718	33592580	Among them, cg12798052 in the promoter region, cg03030757 and cg18744234 in the gene enhancement region, and cg15267307 in the transcription region were detected with significant hypermethylation (Figure 7).	('cg18744234', 'Var', (62, 72))	('cg18744234', 'Chemical', '-', (62, 72))	('cg12798052', 'Var', (12, 22))	('cg12798052', 'Chemical', '-', (12, 22))	('cg15267307', 'Chemical', '-', (109, 119))	('cg03030757', 'Var', (47, 57))	('cg15267307', 'Var', (109, 119))	('cg03030757', 'Chemical', '-', (47, 57))
808720	33592580	We also observed that the hypermethylation status of cg09490277 was significantly positively correlated with the expression of FANCE, while no significant effect of methylation status at other five methylation sites on the expression of FANCE was observed.	('expression', 'MPA', (113, 123))	('FANCE', 'Gene', '2178', (127, 132))	('FA', 'Phenotype', 'HP:0001994', (127, 129))	('FANCE', 'Gene', '2178', (237, 242))	('correlated', 'Reg', (93, 103))	('FA', 'Phenotype', 'HP:0001994', (237, 239))	('hypermethylation', 'MPA', (26, 42))	('cg09490277', 'Chemical', '-', (53, 63))	('FANCE', 'Gene', (127, 132))	('positively', 'PosReg', (82, 92))	('FANCE', 'Gene', (237, 242))	('cg09490277', 'Var', (53, 63))
808760	33592580	Since FANCE was found to be closely related to the infiltration of a variety of cells in the immune microenvironment, we are interested in whether changes in FANCE expression can predict the prognosis of other cancers.	('FANCE', 'Gene', '2178', (158, 163))	('FA', 'Phenotype', 'HP:0001994', (6, 8))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('changes', 'Var', (147, 154))	('FANCE', 'Gene', (6, 11))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('FANCE', 'Gene', (158, 163))	('cancers', 'Disease', (210, 217))	('predict', 'Reg', (179, 186))	('FA', 'Phenotype', 'HP:0001994', (158, 160))	('FANCE', 'Gene', '2178', (6, 11))
808761	33592580	As shown in Figure 15, in five types of tumors: cervical squamous cell carcinoma, esophageal squamous cell carcinoma, gastric cancer, lung squamous cell carcinoma, and rectal adenocarcinoma, high expression of FANCE predicts a good prognosis.	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('FA', 'Phenotype', 'HP:0001994', (210, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('adenocarcinoma', 'Disease', 'MESH:D000230', (175, 189))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('FANCE', 'Gene', (210, 215))	('gastric cancer', 'Disease', (118, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('FANCE', 'Gene', '2178', (210, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('high expression', 'Var', (191, 206))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (134, 162))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('cervical squamous cell carcinoma', 'Disease', (48, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('adenocarcinoma', 'Disease', (175, 189))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 80))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 162))	('lung squamous cell carcinoma', 'Disease', (134, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
808764	33592580	However, in uterine corpus endometrial carcinoma, sarcoma, pheochromocytoma and paraganglioma, high expression of FANCE is significantly associated with poor prognosis.	('associated', 'Reg', (137, 147))	('FA', 'Phenotype', 'HP:0001994', (114, 116))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (80, 93))	('pheochromocytoma', 'Disease', 'MESH:D010673', (59, 75))	('FANCE', 'Gene', (114, 119))	('endometrial carcinoma', 'Disease', (27, 48))	('FANCE', 'Gene', '2178', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('pheochromocytoma', 'Disease', (59, 75))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (59, 75))	('high expression', 'Var', (95, 110))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Disease', (50, 57))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (27, 48))	('paraganglioma', 'Disease', (80, 93))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (27, 48))	('paraganglioma', 'Disease', 'MESH:D010235', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))
808767	33592580	We found that FANCE was highly expressed in HNSC, and hypomethylation of specific methylation sites could be an important reason for the up-regulation.	('FANCE', 'Gene', (14, 19))	('FANCE', 'Gene', '2178', (14, 19))	('HNSC', 'Phenotype', 'HP:0012288', (44, 48))	('FA', 'Phenotype', 'HP:0001994', (14, 16))	('up-regulation', 'PosReg', (137, 150))	('hypomethylation', 'Var', (54, 69))
808769	33592580	The expression of FANCE significantly suppressed the infiltration levels of CD4+ T cells, neutrophils, macrophages, and DCs, as well as the marker genes of subclasses of CD4+ T cells and M2 macrophage.	('age', 'Gene', '5973', (110, 113))	('FANCE', 'Gene', '2178', (18, 23))	('age', 'Gene', '5973', (197, 200))	('suppressed', 'NegReg', (38, 48))	('CD4', 'Gene', (76, 79))	('FA', 'Phenotype', 'HP:0001994', (18, 20))	('age', 'Gene', (110, 113))	('CD4', 'Gene', (170, 173))	('expression', 'Var', (4, 14))	('CD4', 'Gene', '920', (76, 79))	('CD4', 'Gene', '920', (170, 173))	('age', 'Gene', (197, 200))	('FANCE', 'Gene', (18, 23))
808784	33592580	Novel evidence demonstrated that mutation of FA genes predisposed to development of different cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('mutation', 'Var', (33, 41))	('FA', 'Phenotype', 'HP:0001994', (45, 47))	('FA genes', 'Gene', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('predisposed', 'Reg', (54, 65))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
808785	33592580	Single nucleotide polymorphisms of FANCE in the DNA repair pathways have been associated with increased risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('associated', 'Reg', (78, 88))	('FANCE', 'Gene', (35, 40))	('DNA repair pathways', 'Pathway', (48, 67))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('age', 'Gene', '5973', (117, 120))	('FANCE', 'Gene', '2178', (35, 40))	('FA', 'Phenotype', 'HP:0001994', (35, 37))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('age', 'Gene', (117, 120))
808786	33592580	The study by Bonache showed that FANCE was included in the gene set of 18 genes with loss-of-function variants in breast or ovarian cancer patients, three of which also carried pathogenic variants in known cancer genes.	('variants', 'Var', (102, 110))	('cancer', 'Disease', (132, 138))	('breast or ovarian cancer', 'Disease', 'MESH:D001943', (114, 138))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('patients', 'Species', '9606', (139, 147))	('loss-of-function', 'NegReg', (85, 101))	('FANCE', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (124, 138))	('FANCE', 'Gene', '2178', (33, 38))	('breast or ovarian cancer', 'Disease', (114, 138))	('FA', 'Phenotype', 'HP:0001994', (33, 35))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
808788	33592580	An increased mutation load of variants in FANCE in HNSC patients was observed compared with population-level estimate by Chandrasekharappa.	('increased', 'PosReg', (3, 12))	('patients', 'Species', '9606', (56, 64))	('variants', 'Var', (30, 38))	('FANCE', 'Gene', '2178', (42, 47))	('FA', 'Phenotype', 'HP:0001994', (42, 44))	('mutation load', 'MPA', (13, 26))	('HNSC', 'Phenotype', 'HP:0012288', (51, 55))	('FANCE', 'Gene', (42, 47))
808791	33592580	Disruption of the FA pathway can explain the large chromosomal changes that are common in sporadic cancers.	('FA pathway', 'Pathway', (18, 28))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('sporadic cancers', 'Disease', 'MESH:D009369', (90, 106))	('FA', 'Phenotype', 'HP:0001994', (18, 20))	('sporadic cancers', 'Disease', (90, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Disruption', 'Var', (0, 10))
808795	33592580	Among the 10 methylation sites of FANCE, cg12798052 located in the promoter region showed significant hypomethylation in HNSC patients, which is an important reason for the down-regulation of FANCE expression.	('FA', 'Phenotype', 'HP:0001994', (34, 36))	('cg12798052', 'Chemical', '-', (41, 51))	('HNSC', 'Phenotype', 'HP:0012288', (121, 125))	('FA', 'Phenotype', 'HP:0001994', (192, 194))	('hypomethylation', 'MPA', (102, 117))	('HNSC', 'Disease', (121, 125))	('patients', 'Species', '9606', (126, 134))	('FANCE', 'Gene', (192, 197))	('FANCE', 'Gene', (34, 39))	('cg12798052', 'Var', (41, 51))	('FANCE', 'Gene', '2178', (192, 197))	('FANCE', 'Gene', '2178', (34, 39))
808796	33592580	In addition, the methylation sites cg03030757, cg18744234 and cg15267307 located in the gene enhanced region were also found to be hypomethylated.	('cg15267307', 'Chemical', '-', (62, 72))	('cg15267307', 'Var', (62, 72))	('cg03030757', 'Var', (35, 45))	('cg18744234', 'Chemical', '-', (47, 57))	('cg03030757', 'Chemical', '-', (35, 45))	('cg18744234', 'Var', (47, 57))
808808	33592580	Analysis of CD4+T cell subclasses showed that Treg, Th1, Th2 and Th17 were significantly down-regulated in the group with high expression of FANCE.	('FANCE', 'Gene', (141, 146))	('down-regulated', 'NegReg', (89, 103))	('Th17', 'CPA', (65, 69))	('FANCE', 'Gene', '2178', (141, 146))	('FA', 'Phenotype', 'HP:0001994', (141, 143))	('Treg', 'CPA', (46, 50))	('CD4', 'Gene', (12, 15))	('high expression', 'Var', (122, 137))	('CD4', 'Gene', '920', (12, 15))	('Th1', 'CPA', (52, 55))	('Th2', 'CPA', (57, 60))
808827	33592580	However, Garbati's research suggests that abnormal FA protein function can lead to the pro-inflammatory state of macrophages and induce hematopoietic stem cell depletion.	('lead to', 'Reg', (75, 82))	('induce', 'PosReg', (129, 135))	('FA', 'Phenotype', 'HP:0001994', (51, 53))	('age', 'Gene', (120, 123))	('hematopoietic stem cell depletion', 'CPA', (136, 169))	('abnormal', 'Var', (42, 50))	('age', 'Gene', '5973', (120, 123))	('FA protein', 'Protein', (51, 61))
808831	33592580	Different studies have found that FANCE mutations in breast cancer, sarcoma, colorectal cancer, gastric cancer and esophageal cancer, but its impact on the prognosis of these malignancies has not been reported.	('FA', 'Phenotype', 'HP:0001994', (34, 36))	('cancer', 'Disease', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('age', 'Gene', '5973', (120, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('FANCE', 'Gene', (34, 39))	('cancer', 'Disease', (104, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('FANCE', 'Gene', '2178', (34, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('malignancies', 'Disease', 'MESH:D009369', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('cancer', 'Disease', (126, 132))	('mutations', 'Var', (40, 49))	('malignancies', 'Disease', (175, 187))	('sarcoma', 'Disease', (68, 75))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('breast cancer', 'Disease', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('colorectal cancer', 'Disease', (77, 94))	('age', 'Gene', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', (60, 66))	('gastric cancer', 'Disease', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
808834	33592580	Mutations in FANCE cause damage to the FA pathway, thereby increasing cancer susceptibility.	('FANCE', 'Gene', '2178', (13, 18))	('FA', 'Phenotype', 'HP:0001994', (13, 15))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('age', 'Gene', (28, 31))	('Mutations', 'Var', (0, 9))	('increasing', 'PosReg', (59, 69))	('FA pathway', 'Pathway', (39, 49))	('FA', 'Phenotype', 'HP:0001994', (39, 41))	('FANCE', 'Gene', (13, 18))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('age', 'Gene', '5973', (28, 31))
809019	32646396	In addition, the survival benefit of postdiagnosis aspirin use appeared to be confined to patients with mutated PIK3CA tumors [HR = 0.78, 95%CI(0.50, 0.99)] and was positive for PTGS2 (COX-2) expression [HR = 0.75, 95%CI(0.43, 1.30)].	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('PTGS2', 'Gene', (178, 183))	('mutated', 'Var', (104, 111))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('PTGS2', 'Gene', '5743', (178, 183))	('PIK3CA', 'Gene', '5290', (112, 118))	('aspirin', 'Chemical', 'MESH:D001241', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('COX-2', 'Gene', (185, 190))	('COX-2', 'Gene', '5743', (185, 190))	('PIK3CA', 'Gene', (112, 118))	('patients', 'Species', '9606', (90, 98))
809054	32646396	Four studies (involving 4346 patients) compared the overall survival of colorectal cancer among aspirin users compared with non-aspirin users among those with PIK3CA gene mutation.	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('aspirin', 'Chemical', 'MESH:D001241', (128, 135))	('patients', 'Species', '9606', (29, 37))	('mutation', 'Var', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('aspirin', 'Chemical', 'MESH:D001241', (96, 103))	('PIK3CA', 'Gene', (159, 165))	('colorectal cancer', 'Disease', (72, 89))	('rectal cancer', 'Phenotype', 'HP:0100743', (76, 89))	('PIK3CA', 'Gene', '5290', (159, 165))
809057	32646396	Two studies involving 2451 patients compared the cancer-specific survival in colorectal cancer among aspirin users compared with non-aspirin users among patients with a mutated PIK3CA gene.	('cancer', 'Disease', (88, 94))	('colorectal cancer', 'Disease', (77, 94))	('aspirin', 'Chemical', 'MESH:D001241', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (153, 161))	('mutated', 'Var', (169, 176))	('PIK3CA', 'Gene', '5290', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('rectal cancer', 'Phenotype', 'HP:0100743', (81, 94))	('patients', 'Species', '9606', (27, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('PIK3CA', 'Gene', (177, 183))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('aspirin', 'Chemical', 'MESH:D001241', (101, 108))	('cancer', 'Disease', (49, 55))
809071	32646396	Subgroup analysis indicated that postdiagnosis aspirin use could prolong the long-term survival of patients with PIK3CA gene mutations and high expression of PTGS2 (COX-2).	('mutations', 'Var', (125, 134))	('PTGS2', 'Gene', (158, 163))	('prolong', 'PosReg', (65, 72))	('PIK3CA', 'Gene', (113, 119))	('aspirin', 'Chemical', 'MESH:D001241', (47, 54))	('PTGS2', 'Gene', '5743', (158, 163))	('PIK3CA', 'Gene', '5290', (113, 119))	('patients', 'Species', '9606', (99, 107))	('COX-2', 'Gene', (165, 170))	('COX-2', 'Gene', '5743', (165, 170))
809091	32646396	PTGS2 (COX-2) promotes the inflammatory response and cell proliferation, and high expression of PTGS2 (COX-2) is associated with poor survival in patients with colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('promotes', 'PosReg', (14, 22))	('COX-2', 'Gene', (7, 12))	('colorectal cancer', 'Disease', (160, 177))	('PTGS2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (103, 108))	('poor', 'NegReg', (129, 133))	('inflammatory response', 'CPA', (27, 48))	('PTGS2', 'Gene', (96, 101))	('patients', 'Species', '9606', (146, 154))	('COX-2', 'Gene', '5743', (7, 12))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('rectal cancer', 'Phenotype', 'HP:0100743', (164, 177))	('cell proliferation', 'CPA', (53, 71))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('PTGS2', 'Gene', '5743', (0, 5))	('high expression', 'Var', (77, 92))	('PTGS2', 'Gene', '5743', (96, 101))	('COX-2', 'Gene', (103, 108))
809093	32646396	According to the subgroup analysis in our study, the effects of aspirin use on PIK3CA gene mutation and survival of patients with high expression of PTGS2 (COX-2) was different from that of patients with wildtype PIK3CA and PTGS2 (COX-2)-negative colorectal cancer.	('mutation', 'Var', (91, 99))	('high expression', 'Var', (130, 145))	('patients', 'Species', '9606', (190, 198))	('COX-2', 'Gene', '5743', (231, 236))	('PTGS2', 'Gene', '5743', (149, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (247, 264))	('patients', 'Species', '9606', (116, 124))	('PTGS2', 'Gene', (224, 229))	('colorectal cancer', 'Disease', (247, 264))	('PIK3CA', 'Gene', '5290', (213, 219))	('PIK3CA', 'Gene', '5290', (79, 85))	('COX-2', 'Gene', (156, 161))	('PTGS2', 'Gene', (149, 154))	('rectal cancer', 'Phenotype', 'HP:0100743', (251, 264))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('COX-2', 'Gene', (231, 236))	('PIK3CA', 'Gene', (213, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (247, 264))	('aspirin', 'Chemical', 'MESH:D001241', (64, 71))	('PIK3CA', 'Gene', (79, 85))	('COX-2', 'Gene', '5743', (156, 161))	('PTGS2', 'Gene', '5743', (224, 229))
809094	32646396	These findings provide a basis for the use of aspirin in patients with different types of mutations in colorectal cancer and the result can be used as a preliminary basis for further research.	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('mutations', 'Var', (90, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('patients', 'Species', '9606', (57, 65))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rectal cancer', 'Phenotype', 'HP:0100743', (107, 120))	('aspirin', 'Chemical', 'MESH:D001241', (46, 53))
809103	32646396	In conclusion, based on the results of this study, aspirin can improve OS and CSS in patients with colorectal cancer after diagnosis, especially in those with PIK3CA gene mutations and high PTGS2 (COX-2) gene expression, but it cannot improve OS in patients with esophageal cancer and gastric cancer.	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('colorectal cancer', 'Disease', (99, 116))	('improve', 'PosReg', (63, 70))	('rectal cancer', 'Phenotype', 'HP:0100743', (103, 116))	('PIK3CA', 'Gene', '5290', (159, 165))	('gastric cancer', 'Disease', (285, 299))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('aspirin', 'Chemical', 'MESH:D001241', (51, 58))	('COX-2', 'Gene', (197, 202))	('patients', 'Species', '9606', (85, 93))	('PTGS2', 'Gene', (190, 195))	('CSS', 'CPA', (78, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))	('cancer', 'Disease', (293, 299))	('cancer', 'Disease', (110, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (285, 299))	('patients', 'Species', '9606', (249, 257))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('COX-2', 'Gene', '5743', (197, 202))	('PTGS2', 'Gene', '5743', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('PIK3CA', 'Gene', (159, 165))	('mutations', 'Var', (171, 180))	('gastric cancer', 'Phenotype', 'HP:0012126', (285, 299))	('cancer', 'Disease', (274, 280))	('CSS', 'Chemical', '-', (78, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
809237	29108333	Patients with high plasma D-dimer levels had shorter DFS and OS than that with normal plasma D-dimer (3 year DFS rate: 36.8% Vs 62.9%, P < 0.001, Figure 1A; 3 year OS rate: 47.2% Vs 72.3%, P < 0.001, Figure 1B).	('DFS', 'MPA', (53, 56))	('shorter', 'NegReg', (45, 52))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (61, 63))	('OS', 'Chemical', '-', (164, 166))
809239	29108333	In further analysis, high plasma D-dimer levels were significantly associated with shorter OS for T1-2 patients (P = 0.006) and for T3-4 patients (P = 0.005).	('shorter', 'NegReg', (83, 90))	('patients', 'Species', '9606', (137, 145))	('high', 'Var', (21, 25))	('plasma D-dimer levels', 'MPA', (26, 47))	('OS', 'Chemical', '-', (91, 93))	('patients', 'Species', '9606', (103, 111))
809241	29108333	Similarly, high plasma D-dimer levels were significantly associated with shorter OS for N0 patients (P < 0.001) and for N+ patients (P = 0.005).	('patients', 'Species', '9606', (91, 99))	('high', 'Var', (11, 15))	('patients', 'Species', '9606', (123, 131))	('shorter', 'Disease', (73, 80))	('OS', 'Chemical', '-', (81, 83))
809244	29108333	Patients with high plasma D-dimer levels had an elevated risk of disease progression and death compared to those with normal plasma D-dimer levels.	('disease progression', 'CPA', (65, 84))	('death', 'Disease', 'MESH:D003643', (89, 94))	('death', 'Disease', (89, 94))	('high', 'Var', (14, 18))	('plasma D-dimer', 'MPA', (19, 33))	('Patients', 'Species', '9606', (0, 8))
809304	28928231	Moreover, some studies have reported that circRNAs were concerned with many kinds of human diseases, and were widely involved in numerous physiological and pathological processes, for instance promoting insulin biosynthesis and secretion through the CDR1as/miR-7 pathway, and dysregulation in Alzheimer's disease (AD), Parkinson's disease, and cardiovascular diseases.	('miR-7', 'Gene', '10859', (257, 262))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (293, 312))	("Alzheimer's disease", 'Disease', (293, 312))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (344, 367))	('cir', 'Gene', (42, 45))	('CDR1as', 'Gene', (250, 256))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (293, 312))	('CDR1as', 'Gene', '103611090', (250, 256))	('insulin', 'Gene', (203, 210))	('cir', 'Gene', '9541', (42, 45))	('secretion', 'MPA', (228, 237))	('AD', 'Disease', (314, 316))	('AD', 'Phenotype', 'HP:0002511', (314, 316))	("Parkinson's disease", 'Disease', (319, 338))	('cardiovascular diseases', 'Disease', (344, 367))	('promoting', 'PosReg', (193, 202))	('involved', 'Reg', (117, 125))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (344, 367))	('dysregulation', 'Var', (276, 289))	('miR-7', 'Gene', (257, 262))	('human', 'Species', '9606', (85, 90))	('AD', 'Disease', 'MESH:D000544', (314, 316))	("Parkinson's disease", 'Disease', 'MESH:D010300', (319, 338))	('insulin', 'Gene', '3630', (203, 210))
809305	28928231	Importantly, some findings indicated that dysregulated circRNAs had been verified to be associated with the development of many cancers (Table 1).	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cir', 'Gene', '9541', (55, 58))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('associated', 'Reg', (88, 98))	('cir', 'Gene', (55, 58))	('dysregulated', 'Var', (42, 54))
809318	28928231	Meanwhile, the growth of cancer cells will be significantly deadened after knockdown of circ-BANP with siRNA.	('BANP', 'Gene', '54971', (93, 97))	('cir', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('BANP', 'Gene', (93, 97))	('cir', 'Gene', '9541', (88, 91))	('knockdown', 'Var', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('deadened', 'NegReg', (60, 68))
809319	28928231	Thus, it can be seen that the dysregulation of circRNAs may participate in cell proliferation, differentiation, and invasion in CRC.	('dysregulation', 'Var', (30, 43))	('invasion', 'CPA', (116, 124))	('cir', 'Gene', (47, 50))	('CRC', 'Phenotype', 'HP:0003003', (128, 131))	('participate', 'Reg', (60, 71))	('differentiation', 'CPA', (95, 110))	('cir', 'Gene', '9541', (47, 50))	('CRC', 'Disease', (128, 131))	('cell proliferation', 'CPA', (75, 93))
809354	28928231	Moreover, a study found that lncRpa and circRar1 could modulate miR-671 for inducing the up-regulation of apoptosis-associated factors caspase8 and p38 at the mRNA and protein levels to promote neuronal apoptosis.	('promote', 'PosReg', (186, 193))	('caspase8', 'Gene', '841', (135, 143))	('miR-671', 'Gene', '768213', (64, 71))	('p38', 'Gene', (148, 151))	('cir', 'Gene', (40, 43))	('miR-671', 'Gene', (64, 71))	('caspase8', 'Gene', (135, 143))	('cir', 'Gene', '9541', (40, 43))	('apoptosis-associated', 'Protein', (106, 126))	('neuronal apoptosis', 'CPA', (194, 212))	('p38', 'Gene', '1432', (148, 151))	('up-regulation', 'PosReg', (89, 102))	('modulate', 'Var', (55, 63))
809356	28928231	While knockouts of f-circM9 and f-circPR led to the apoptosis of a large amount of tumor cells, thus the f-circM9 and f-circPR, to some extent, could abate cancer cell apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', (156, 162))	('cir', 'Gene', '9541', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('tumor', 'Disease', (83, 88))	('cir', 'Gene', '9541', (107, 110))	('cir', 'Gene', (120, 123))	('cir', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('knockouts', 'Var', (6, 15))	('abate', 'NegReg', (150, 155))	('apoptosis', 'CPA', (52, 61))	('cir', 'Gene', (34, 37))	('cir', 'Gene', '9541', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cir', 'Gene', '9541', (21, 24))	('cir', 'Gene', (107, 110))
809360	28928231	Thus, the dysregulation of circRNAs may be involved in tumorigenesis, progression, invasion, and metastasis in various cancers.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('dysregulation', 'Var', (10, 23))	('metastasis', 'CPA', (97, 107))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('tumor', 'Disease', (55, 60))	('cancers', 'Disease', (119, 126))	('cir', 'Gene', (27, 30))	('invasion', 'CPA', (83, 91))	('progression', 'CPA', (70, 81))	('cir', 'Gene', '9541', (27, 30))	('involved', 'Reg', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
809412	25739674	Overexpression of EGFR has been associated with poor prognosis of EC patients.	('patients', 'Species', '9606', (69, 77))	('Overexpression', 'Var', (0, 14))	('expression', 'Species', '29278', (4, 14))	('EGFR', 'Gene', (18, 22))
809418	25739674	Most importantly, exogenous induction of YAP1 induces resistance to 5-FU and docetaxcel, while knockdown of YAP sensitizes EC cells to these cytotoxics.	('YAP', 'Gene', '10413', (108, 111))	('YAP', 'Gene', (41, 44))	('resistance to 5-FU', 'MPA', (54, 72))	('5-FU', 'Chemical', 'MESH:D005472', (68, 72))	('YAP', 'Gene', (108, 111))	('cytotoxics', 'Disease', 'MESH:D064420', (141, 151))	('sensitizes', 'Reg', (112, 122))	('knockdown', 'Var', (95, 104))	('docetaxcel', 'Chemical', '-', (77, 87))	('induces', 'PosReg', (46, 53))	('YAP', 'Gene', '10413', (41, 44))	('cytotoxics', 'Disease', (141, 151))
809422	25739674	EGFR overexpression or amplification has been reported in several human tumors including those of head and neck, breast, colon, lung, stomach and esophagus.	('breast', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('EGFR', 'Gene', (0, 4))	('esophagus', 'Disease', (146, 155))	('lung', 'Disease', (128, 132))	('amplification', 'Var', (23, 36))	('overexpression', 'PosReg', (5, 19))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('expression', 'Species', '29278', (9, 19))	('human', 'Species', '9606', (66, 71))	('colon', 'Disease', (121, 126))	('stomach', 'Disease', (134, 141))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
809427	25739674	EGFR activation occurs frequently in Hippo pathway defective mouse liver tumors.	('liver tumors', 'Phenotype', 'HP:0002896', (67, 79))	('EGFR', 'Gene', (0, 4))	('liver tumors', 'Disease', (67, 79))	('Hippo pathway', 'Pathway', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('activation', 'PosReg', (5, 15))	('defective', 'Var', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('mouse', 'Species', '10090', (61, 66))	('liver tumors', 'Disease', 'MESH:D008113', (67, 79))
809429	25739674	In this study, we provide novel information that YAP1 up-regulates EGFR expression at the level of transcription through a TEAD binding site in the EGFR promoter.	('expression', 'Species', '29278', (72, 82))	('YAP1', 'Var', (49, 53))	('expression', 'MPA', (72, 82))	('binding', 'Interaction', (128, 135))	('EGFR', 'Gene', (67, 71))	('up-regulates', 'PosReg', (54, 66))
809437	25739674	Doxycycline inducible YAP1 lentivirus expression plasmid (PIN20YAP) and Lentiviral shRNA plasmids for knockdown YAP1 were previously described.	('expression', 'Species', '29278', (38, 48))	('YAP', 'Gene', (63, 66))	('YAP', 'Gene', '10413', (22, 25))	('knockdown', 'Var', (102, 111))	('YAP', 'Gene', '10413', (112, 115))	('YAP', 'Gene', (22, 25))	('YAP', 'Gene', '10413', (63, 66))	('Doxycycline', 'Chemical', 'MESH:D004318', (0, 11))	('YAP', 'Gene', (112, 115))
809439	25739674	The EGFR promoter (around 2.3k) containing an intact TEAD binding site (TCATTCCT) was amplified using high fidelity PCR with primers (EGFRp23k.F5.Kpn and EGFRp.R1b.Xho) from genomic DNA extracted from SKGT-4 cells with the following sequences: EGFRp23k.F5.Kpn 5' aaaGGTACCgttgctggacaagaggggta 3';EGFRp.R1b.Xho 5' aaaCTCGAGggggctagctcgggactc 3' The native fragment of EGFR promoter (-2286bp to +102bp) was digested with KpnI and XhoI and then cloned into pGL4.22 (Promega, Madison, WI) at the site of KpnI and XhoI.	('pGL4', 'Gene', '6390', (454, 458))	('pGL4', 'Gene', (454, 458))	('SKGT-4', 'CellLine', 'CVCL:2195', (201, 207))	('-2286bp to +102bp', 'Var', (382, 399))
809463	25739674	A transposon mutagenesis screen in a Sav1 mutant background revealed activation of EGFR is a frequent co-occuring event found in 50-60% of tumors.	('mutant', 'Var', (42, 48))	('Sav1', 'Gene', (37, 41))	('EGFR', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('Sav1', 'Gene', '64010', (37, 41))	('activation', 'PosReg', (69, 79))
809467	25739674	Moreover, in SKGT-4 (PIN20YAP) cells, YAP1 induced EGFR expression was diminished by knockdown of YAP1 in doxycycline induced SKGT-4 cells (Figure 2B) confirming the direct regulation of EGFR expression by YAP1.	('EGFR expression', 'MPA', (51, 66))	('YAP', 'Gene', (206, 209))	('expression', 'Species', '29278', (192, 202))	('diminished', 'NegReg', (71, 81))	('YAP', 'Gene', (38, 41))	('YAP', 'Gene', '10413', (26, 29))	('expression', 'Species', '29278', (56, 66))	('YAP', 'Gene', '10413', (98, 101))	('knockdown', 'Var', (85, 94))	('YAP', 'Gene', '10413', (206, 209))	('YAP', 'Gene', '10413', (38, 41))	('YAP', 'Gene', (26, 29))	('doxycycline', 'Chemical', 'MESH:D004318', (106, 117))	('SKGT-4', 'CellLine', 'CVCL:2195', (126, 132))	('SKGT-4', 'CellLine', 'CVCL:2195', (13, 19))	('YAP', 'Gene', (98, 101))
809470	25739674	To determine if EGFR expression is regulated by YAP1 in primary esophageal cells and in other cell types, transfection of human embryonic kidney (HEK293T) cells with constitutively active mutant YAPS127A cDNA or with wild-type YAP1 induced EGFR expression (Figure 2D,left).	('YAPS127A', 'Var', (195, 203))	('human', 'Species', '9606', (122, 127))	('EGFR', 'Gene', (240, 244))	('expression', 'Species', '29278', (21, 31))	('embryonic kidney', 'Disease', (128, 144))	('YAPS127A', 'Mutation', 'rs762471803', (195, 203))	('expression', 'Species', '29278', (245, 255))	('embryonic kidney', 'Disease', 'MESH:D007674', (128, 144))	('HEK293T', 'CellLine', 'CVCL:0063', (146, 153))	('induced', 'Reg', (232, 239))
809471	25739674	In addition, primary murine Esophageal cells that expressed YAP1S127A (DOX+) demonstrated higher EGFR expression than cells without YAP1 induction (Figure 2D, middle).	('expression', 'Species', '29278', (102, 112))	('S127A', 'Mutation', 'rs762471803', (64, 69))	('YAP1S127A', 'Var', (60, 69))	('EGFR', 'Protein', (97, 101))	('murine', 'Species', '10090', (21, 27))	('higher', 'PosReg', (90, 96))	('DOX', 'Chemical', 'MESH:D004318', (71, 74))
809472	25739674	In addition, western blots analysis in hippo deregulated mice tumor cells lines isolated from hippo mutant (Sav-/- and Mst1/2-/-) mice tumor tissues demonstrated elevated EGFR expression compared to the immortalized liver B299 cells (Figure 2D, right), while there is no change in the level of IGFR.	('mice', 'Species', '10090', (57, 61))	('mice', 'Species', '10090', (130, 134))	('elevated', 'PosReg', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Sav-/- and Mst1', 'Gene', '64010;15235', (108, 123))	('mutant', 'Var', (100, 106))	('hippo', 'Gene', (94, 99))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (135, 140))	('expression', 'Species', '29278', (176, 186))	('expression', 'MPA', (176, 186))	('B299', 'CellLine', 'CVCL:D765', (222, 226))	('EGFR', 'Protein', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
809473	25739674	Hence, EGFR can be elevated in multiple cell types by expression of a constitutively active mutant form of YAP1 or by activation of endogenous YAP1 protein that occurs following deletion of Hippo pathway signaling components.	('activation', 'PosReg', (118, 128))	('EGFR', 'Gene', (7, 11))	('elevated', 'PosReg', (19, 27))	('YAP1', 'Gene', (107, 111))	('protein', 'Protein', (148, 155))	('deletion', 'Var', (178, 186))	('endogenous', 'MPA', (132, 142))	('mutant', 'Var', (92, 98))	('expression', 'Species', '29278', (54, 64))
809477	25739674	Upon YAP1S127A induction by doxycycline (DOX+) administration, more than threefold induction of EGFR luciferase activity was observed (Figure 3B, left).	('doxycycline', 'Chemical', 'MESH:D004318', (28, 39))	('EGFR luciferase', 'Enzyme', (96, 111))	('DOX', 'Chemical', 'MESH:D004318', (41, 44))	('induction', 'PosReg', (83, 92))	('activity', 'MPA', (112, 120))	('YAP1S127A', 'Var', (5, 14))
809480	25739674	Induction of EGFR transcriptional activity by YAP1 was greatly diminished, when mutation or deletion of the TEAD binding site in the EGFR promoter were introduced into 293T cells (Figure 3C, right panel).	('EGFR transcriptional activity', 'MPA', (13, 42))	('293T', 'CellLine', 'CVCL:0063', (168, 172))	('deletion', 'Var', (92, 100))	('diminished', 'NegReg', (63, 73))	('YAP1', 'Gene', (46, 50))	('mutation', 'Var', (80, 88))
809481	25739674	Similarly, in SKGT4 EC cells, induction of EGFR transcriptional activity by YAP1 induction upon doxycycline treatment was significantly reduced, when mutation or deletion of the TEAD binding site in the EGFR promoter was introduced (Figure 3D).	('deletion', 'Var', (162, 170))	('SKGT4 EC', 'CellLine', 'CVCL:2195', (14, 22))	('induction', 'MPA', (30, 39))	('mutation', 'Var', (150, 158))	('YAP1', 'Gene', (76, 80))	('reduced', 'NegReg', (136, 143))	('EGFR', 'Gene', (43, 47))	('doxycycline', 'Chemical', 'MESH:D004318', (96, 107))
809482	25739674	Having shown that YAP1 increases EGFR expression, next we sought to determine if YAP1 also increases its phosphorylation.	('phosphorylation', 'MPA', (105, 120))	('expression', 'Species', '29278', (38, 48))	('expression', 'MPA', (38, 48))	('YAP1', 'Var', (18, 22))	('EGFR', 'Protein', (33, 37))
809483	25739674	Increased expression of YAP1 by doxycycline induction in three EC cell lines-SKGT-4, YES-6 and KATO-TN significantly induced phosphorylation of EGFR at pY1068 in concert with the increase in anti-apoptotic protein MCL-1 although not so dramatic change in its protein level (Figure 4A).	('YAP1', 'Gene', (24, 28))	('EGFR', 'Gene', (144, 148))	('doxycycline', 'Chemical', 'MESH:D004318', (32, 43))	('pY1068', 'Var', (152, 158))	('expression', 'Species', '29278', (10, 20))	('Increased', 'PosReg', (0, 9))	('MCL-1', 'Gene', '4170', (214, 219))	('MCL-1', 'Gene', (214, 219))	('phosphorylation', 'MPA', (125, 140))	('SKGT-4', 'CellLine', 'CVCL:2195', (77, 83))	('induced', 'Reg', (117, 124))
809484	25739674	Further, YAP increased and sustained EGF induced phospho-EGFR at pY1068 and its downstream AKT phosphorylation (Figure 4B).	('pY1068', 'Var', (65, 71))	('AKT', 'Gene', '207', (91, 94))	('YAP', 'Gene', '10413', (9, 12))	('YAP', 'Gene', (9, 12))	('AKT', 'Gene', (91, 94))
809489	25739674	SKGT-4 and KATO-TN have constitutively high or low YAP and EGFR expression; and SKGT-4 cells with high YAP1 and EGFR expression have more invasive capacity than KATO-TN cells with low YAP and EGFR (Supplemental Figure 1A).	('EGFR', 'Gene', (112, 116))	('YAP', 'Gene', '10413', (103, 106))	('invasive capacity', 'CPA', (138, 155))	('expression', 'Species', '29278', (117, 127))	('YAP', 'Gene', (51, 54))	('SKGT-4', 'CellLine', 'CVCL:2195', (0, 6))	('YAP', 'Gene', '10413', (184, 187))	('YAP', 'Gene', (103, 106))	('more', 'PosReg', (133, 137))	('SKGT-4', 'CellLine', 'CVCL:2195', (80, 86))	('high', 'Var', (98, 102))	('YAP', 'Gene', (184, 187))	('YAP', 'Gene', '10413', (51, 54))	('expression', 'Species', '29278', (64, 74))
809491	25739674	To further confirm the direct relationship between YAP1 and chemoresistance, induction of YAP1 in both EAC cell line SKGT-4 and ESCC cell line KATO-TN by doxycycline demonstrated more resistant to either 5-FU (Figure 5A) or docetaxel (Figure 5B) than EC cells without YAP1 induction (DOX-).	('docetaxel', 'Chemical', 'MESH:D000077143', (224, 233))	('resistant to', 'MPA', (184, 196))	('SKGT-4', 'CellLine', 'CVCL:2195', (117, 123))	('YAP1', 'Gene', (90, 94))	('doxycycline', 'Chemical', 'MESH:D004318', (154, 165))	('DOX', 'Chemical', 'MESH:D004318', (284, 287))	('5-FU', 'Chemical', 'MESH:D005472', (204, 208))	('induction', 'Var', (77, 86))
809494	25739674	Moreover, as shown in Supplemental Figure 2, when we knocked down EGFR in YAP1 induced EC cells (SKGT-4 DOX+) using Lenti-Crisp system, EC cells become more sensitive to 5-FU treatment which phenocopys the effects by knocking down YAP1 as shown in Figure 5C.	('sensitive', 'MPA', (157, 166))	('EGFR', 'Gene', (66, 70))	('DOX', 'Chemical', 'MESH:D004318', (104, 107))	('SKGT-4', 'CellLine', 'CVCL:2195', (97, 103))	('YAP1', 'Gene', (74, 78))	('5-FU', 'Chemical', 'MESH:D005472', (170, 174))	('more', 'PosReg', (152, 156))	('knocked down', 'Var', (53, 65))
809496	25739674	We have demonstrated that YAP1 is responsible for sustained EGFR overexpression and activation, and hence targeting YAP1 may be an effective means to utmost inhibit EGFR signaling.	('expression', 'Species', '29278', (69, 79))	('targeting', 'Var', (106, 115))	('inhibit', 'NegReg', (157, 164))	('activation', 'MPA', (84, 94))	('overexpression', 'PosReg', (65, 79))	('EGFR', 'Protein', (60, 64))	('EGFR signaling', 'MPA', (165, 179))	('YAP1', 'Gene', (116, 120))
809505	25739674	The result in Figure 6B (right panel) demonstrated that YAP induction (DOX+) made SKGT-4 cells more resistant to 5-FU, however, VP in combination of 5-FU dramatically increases the response of SKGT-4 cells on 5-FU especially in inducible YAP1 expression SKGT-4 (DOX+) cells.	('expression', 'Species', '29278', (243, 253))	('SKGT-4', 'CellLine', 'CVCL:2195', (254, 260))	('YAP', 'Gene', '10413', (56, 59))	('5-FU', 'Chemical', 'MESH:D005472', (149, 153))	('5-FU', 'Chemical', 'MESH:D005472', (209, 213))	('DOX', 'Chemical', 'MESH:D004318', (71, 74))	('YAP', 'Gene', (238, 241))	('DOX', 'Chemical', 'MESH:D004318', (262, 265))	('5-FU', 'Chemical', 'MESH:D005472', (113, 117))	('SKGT-4', 'CellLine', 'CVCL:2195', (193, 199))	('YAP', 'Gene', (56, 59))	('VP', 'Chemical', 'MESH:C038467', (128, 130))	('increases', 'PosReg', (167, 176))	('response', 'MPA', (181, 189))	('inducible', 'Var', (228, 237))	('SKGT-4', 'CellLine', 'CVCL:2195', (82, 88))	('YAP', 'Gene', '10413', (238, 241))
809509	25739674	In this study, we demonstrated for the first time that YAP1 up-regulates EGFR expression at the level of transcription through the intact TEAD binding site.	('expression', 'MPA', (78, 88))	('YAP1', 'Var', (55, 59))	('EGFR', 'Gene', (73, 77))	('up-regulates', 'PosReg', (60, 72))	('expression', 'Species', '29278', (78, 88))
360290	25739674	The Hippo signaling pathway is gaining recognition as an important player in both organ size control and tumorigenesis, since the disruption of several important components (Mst1/2, Sav1 and Lats1/2 and YAP1) in this pathway can lead to tumorigenesis.	('tumor', 'Disease', (237, 242))	('lead to', 'Reg', (229, 236))	('Sav1', 'Gene', '64010', (182, 186))	('disruption', 'Var', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('Sav1', 'Gene', (182, 186))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('Mst1', 'Gene', (174, 178))	('Mst1', 'Gene', '15235', (174, 178))
809514	25739674	EGFR overexpression or amplification has been reported in many human tumors and increased EGFR expression has been associated with advanced disease, development of metastasis and poor clinical prognosis in a subset of tumors including esophageal ESCC and EAC.	('EAC', 'Disease', (255, 258))	('metastasis', 'Disease', 'MESH:D009362', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('human', 'Species', '9606', (63, 68))	('overexpression', 'PosReg', (5, 19))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('EGFR', 'Gene', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('expression', 'MPA', (95, 105))	('EGFR', 'Gene', (0, 4))	('expression', 'Species', '29278', (9, 19))	('associated', 'Reg', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', (218, 224))	('increased', 'PosReg', (80, 89))	('amplification', 'Var', (23, 36))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('advanced disease', 'Disease', (131, 147))	('expression', 'Species', '29278', (95, 105))	('esophageal ESCC', 'Disease', (235, 250))	('metastasis', 'Disease', (164, 174))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
809531	25739674	In contrast, knock down of YAP1 by lentivirus shRNA in EC cells decrease the tumor cell growth advantage and increase 5-FU sensitivity in EC cells which consistent with the recent finding of Huang J et al that knockdown of YAP1 sensitizes ovarian cancer cells to cisplatin and survivin inhibitors.	('5-FU sensitivity', 'MPA', (118, 134))	('knockdown', 'Var', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('YAP1', 'Gene', (27, 31))	('decrease', 'NegReg', (64, 72))	('YAP1', 'Gene', (223, 227))	('ovarian cancer', 'Disease', 'MESH:D010051', (239, 253))	('increase', 'PosReg', (109, 117))	('sensitizes', 'Reg', (228, 238))	('ovarian cancer', 'Disease', (239, 253))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (263, 272))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('knock down', 'Var', (13, 23))	('5-FU', 'Chemical', 'MESH:D005472', (118, 122))	('tumor', 'Disease', (77, 82))	('ovarian cancer', 'Phenotype', 'HP:0100615', (239, 253))
809533	25739674	Therefore, inhibition of YAP1 or in combination of EGFR and plus cytotoxics may be the best way to gain advantage.	('cytotoxics', 'Disease', (65, 75))	('cytotoxics', 'Disease', 'MESH:D064420', (65, 75))	('inhibition', 'Var', (11, 21))	('YAP1', 'Gene', (25, 29))
809538	25739674	Overexpression of EGFR is poor prognosticator but in clinical trials, inhibition of EGFR has not provided benefit for EC patients.	('EGFR', 'Gene', (84, 88))	('patients', 'Species', '9606', (121, 129))	('inhibition', 'Var', (70, 80))	('expression', 'Species', '29278', (4, 14))
809758	24155679	The prognosis of patients with MPRM is considered inferior to that of patients with negative resection margin (NRM), which is defined as no cancer cells at the resection margin.	('patients', 'Species', '9606', (70, 78))	('MPRM', 'Var', (31, 35))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
809796	24155679	Thus, in various studies, the prognosis of patients with MPRM in esophageal cancer has been consistently reported to be inferior to that of patients with NRM, regardless of preoperative therapy.	('esophageal cancer', 'Disease', (65, 82))	('patients', 'Species', '9606', (43, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('patients', 'Species', '9606', (140, 148))	('MPRM', 'Var', (57, 61))
809899	18953412	The most recognized mechanism for decreased expression is due to hypermethylation of the Cdx1 promoter of Cdx1.	('expression', 'MPA', (44, 54))	('Cdx1', 'Gene', (106, 110))	('hypermethylation', 'Var', (65, 81))	('decreased', 'NegReg', (34, 43))	('Cdx1', 'Gene', (89, 93))	('Cdx1', 'Gene', '1044', (106, 110))	('Cdx1', 'Gene', '1044', (89, 93))
809903	18953412	C-myc is regulated in part through mitogenic stimuli, and is activated constitutively in cancer cells through gene amplification, chromosomal translocation, point mutation and mitogenic stimulation.	('chromosomal translocation', 'Var', (130, 155))	('point mutation', 'Var', (157, 171))	('C-myc', 'Gene', '4609', (0, 5))	('activated', 'PosReg', (61, 70))	('gene amplification', 'Var', (110, 128))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('C-myc', 'Gene', (0, 5))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
809938	18953412	The combinatorial expression of these genes leads to one of the two hallmark morphologic features of Barrett's esophagus, namely the production of mucin in a subset of cells (goblet cells in Barrett's esophagus).	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (191, 210))	('combinatorial', 'Var', (4, 17))	('mucin', 'Gene', '100508689', (147, 152))	('mucin', 'Gene', (147, 152))	('leads to', 'Reg', (44, 52))	("Barrett's esophagus", 'Disease', (101, 120))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (101, 120))
809977	18953412	The following Taqman assays (PE Applied Biosystems) used were: TFF1 (Hs00170216_m1), TFF2 (Hs00193719_m1), TFF3 (Hs00173625_m1), Muc2 (Hs00159374_m1), Muc5AC (Hs01365601_m1), Muc13 (Hs00217230_m1), CD164 (Hs00174789_m1), ODC1 (Hs00159739_m1), CA2 (Hs00163869_m1).	('Muc13', 'Gene', '56667', (175, 180))	('Muc2', 'Gene', (129, 133))	('Muc5AC', 'Gene', '4586', (151, 157))	('TFF2', 'Gene', (85, 89))	('Hs00174789_m1', 'Var', (205, 218))	('Muc5AC', 'Gene', (151, 157))	('Muc2', 'Gene', '4583', (129, 133))	('Hs00159374_m1', 'Var', (135, 148))	('Hs00193719_m1', 'Var', (91, 104))	('CA2', 'Gene', (243, 246))	('ODC1', 'Gene', '4953', (221, 225))	('CD164', 'Gene', '8763', (198, 203))	('Hs00217230_m1', 'Var', (182, 195))	('TFF2', 'Gene', '7032', (85, 89))	('Hs00173625_m1', 'Var', (113, 126))	('ODC1', 'Gene', (221, 225))	('Hs00163869_m1', 'Var', (248, 261))	('Hs01365601_m1', 'Var', (159, 172))	('CD164', 'Gene', (198, 203))	('CA2', 'Gene', '760', (243, 246))	('TFF1', 'Gene', '7031', (63, 67))	('Hs00159739_m1', 'Var', (227, 240))	('Muc13', 'Gene', (175, 180))	('Hs00170216_m1', 'Var', (69, 82))	('TFF3', 'Gene', (107, 111))	('TFF1', 'Gene', (63, 67))	('TFF3', 'Gene', '7033', (107, 111))
809981	32183428	FAM84B facilitates cancer cell proliferation and invasion in vitro, and xenograft growth in vivo.	('FAM84B', 'Var', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('facilitates', 'PosReg', (7, 18))	('cancer', 'Disease', (19, 25))	('xenograft growth', 'CPA', (72, 88))	('invasion', 'CPA', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('rat', 'Species', '10116', (38, 41))
809984	32183428	FAM84B shares similarities with the H-Ras-like suppressor (HRASLS) family over their typical LRAT (lecithin:retinal acyltransferase) domain.	('LRAT', 'Gene', '9227', (93, 97))	('FAM84B', 'Var', (0, 6))	('HRASLS', 'Gene', (59, 65))	('LRAT', 'Gene', (93, 97))	('H-Ras-like suppressor', 'Gene', '57110', (36, 57))	('HRASLS', 'Gene', '57110', (59, 65))	('H-Ras-like suppressor', 'Gene', (36, 57))
809985	32183428	This domain contains a catalytic triad, H23, H35, and C113, which constitutes the phospholipase A1/2 and O-acyltransferase activities of HRASLS1-5.	('phospholipase A1/2', 'Gene', '200879;5319', (82, 100))	('HRASLS1-5', 'Gene', (137, 146))	('C113', 'Var', (54, 58))	('phospholipase A1/2', 'Gene', (82, 100))	('HRASLS1-5', 'Gene', '57110;54979;11145;5920;117245', (137, 146))
809986	32183428	FAM84B conserves H23 and H35 but not C113 with both histidine residues residing within a highly conserved motif that FAM84B shares with HRASLS1-5.	('H23', 'Protein', (17, 20))	('FAM84B', 'Var', (117, 123))	('H35', 'Protein', (25, 28))	('HRASLS1-5', 'Gene', (136, 145))	('histidine', 'Chemical', 'MESH:D006639', (52, 61))	('HRASLS1-5', 'Gene', '57110;54979;11145;5920;117245', (136, 145))
809987	32183428	These properties suggest a collaboration of FAM84B with Myc, consistent with the role of the gene desert in strengthening Myc functions.	('FAM84B', 'Var', (44, 50))	('Myc', 'Disease', (56, 59))	('collaboration', 'Reg', (27, 40))	('rat', 'Species', '10116', (34, 37))
809989	32183428	One of the classical genetic events of oncogenesis is amplification of the Myc (c-Myc) oncogene.	('c-Myc', 'Gene', (80, 85))	('c-Myc', 'Gene', '4609', (80, 85))	('amplification', 'Var', (54, 67))
809996	32183428	The unique feature of this gene desert is the existence of multiple (lnRNAs) (PCAT1, PCAT2, POU5F1B, CCAT1, CCAT2, CASC8, CASC11, CASC19, and CASC21) with FAM84B and Myc being the only protein coding genes (Figure 1).	('PCAT1', 'Gene', '100750225', (78, 83))	('CASC19', 'Gene', '103021165', (130, 136))	('FAM84B', 'Var', (155, 161))	('PCAT2', 'Gene', '103164619', (85, 90))	('POU5F1B', 'Gene', (92, 99))	('CASC21', 'Gene', (142, 148))	('CASC11', 'Gene', (122, 128))	('CCAT1', 'Gene', '100507056', (101, 106))	('PCAT2', 'Gene', (85, 90))	('CCAT1', 'Gene', (101, 106))	('PC', 'Phenotype', 'HP:0012125', (78, 80))	('CASC19', 'Gene', (130, 136))	('CASC11', 'Gene', '100270680', (122, 128))	('CCAT2', 'Gene', '101805488', (108, 113))	('CASC8', 'Gene', (115, 120))	('PC', 'Phenotype', 'HP:0012125', (85, 87))	('CASC8', 'Gene', '727677', (115, 120))	('POU5F1B', 'Gene', '5462', (92, 99))	('CCAT2', 'Gene', (108, 113))	('PCAT1', 'Gene', (78, 83))	('CASC21', 'Gene', '103021164', (142, 148))
809997	32183428	In view of Myc being the most-well-studied oncogene and the 8q24 gene desert as a region that is frequently amplified in cancer, FAM84B stands as a promising target for oncogenic activities; nonetheless, its impact on tumorigenesis remained unknown until recently.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('FAM84B', 'Var', (129, 135))	('cancer', 'Disease', (121, 127))
810003	32183428	Besides these SNP variants, amplification of 8q24.21 occurs most frequently in human cancers, including ovarian, colorectal, breast, prostate, and others.	('8q24.21', 'Gene', (45, 52))	('human', 'Species', '9606', (79, 84))	('ovarian', 'Disease', 'MESH:D010049', (104, 111))	('breast', 'Disease', (125, 131))	('prostate', 'Disease', (133, 141))	('ovarian', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('colorectal', 'Disease', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('amplification', 'Var', (28, 41))
810005	32183428	Upregulations of PRNCR1 (prostate cancer non-coding RNA1) occurred in prostate cancer (PC), and precancerous lesions PINs (prostatic intraepithelial neoplasia) and knockdown of PRNCR1 reduced the survival of PC cells and the expression of androgen receptor (AR), indicating an important role of PRNCR1 in facilitating PC via AR signaling (Table 1).	('androgen receptor', 'Gene', '367', (239, 256))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('PRNCR1', 'Gene', '101867536', (177, 183))	('PRNCR1', 'Gene', '101867536', (295, 301))	('knockdown', 'Var', (164, 173))	('PRNCR1', 'Gene', '101867536', (17, 23))	('PC', 'Phenotype', 'HP:0012125', (208, 210))	('AR', 'Gene', '367', (258, 260))	('prostate cancer', 'Disease', 'MESH:D011471', (25, 40))	('survival', 'CPA', (196, 204))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('precancerous lesions PINs', 'Disease', 'MESH:D011230', (96, 121))	('reduced', 'NegReg', (184, 191))	('prostate cancer', 'Disease', (25, 40))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (133, 158))	('Upregulations', 'PosReg', (0, 13))	('PC', 'Phenotype', 'HP:0012125', (318, 320))	('prostate cancer', 'Disease', 'MESH:D011471', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('AR', 'Gene', '367', (325, 327))	('PRNCR1', 'Gene', (177, 183))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (123, 158))	('PRNCR1', 'Gene', (295, 301))	('PC', 'Phenotype', 'HP:0012125', (87, 89))	('PRNCR1', 'Gene', (17, 23))	('prostate cancer', 'Disease', (70, 85))	('prostatic intraepithelial neoplasia', 'Disease', (123, 158))	('precancerous lesions PINs', 'Disease', (96, 121))	('neoplasia', 'Phenotype', 'HP:0002664', (149, 158))	('androgen receptor', 'Gene', (239, 256))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
810020	32183428	HPV integration in the 8q24.21 gene desert upregulates Myc.	('integration', 'Var', (4, 15))	('rat', 'Species', '10116', (9, 12))	('HPV', 'Species', '10566', (0, 3))	('upregulates', 'PosReg', (43, 54))	('Myc', 'Disease', (55, 58))
810025	32183428	Mice deficient in an enhancer element Myc-335 that lies 335kb upstream of Myc are protected from APC (Adenomatous polyposis Coli) mutation-induced intestinal cancer.	('Myc', 'Gene', (74, 77))	('PC', 'Phenotype', 'HP:0012125', (98, 100))	('Adenomatous polyposis Coli', 'Phenotype', 'HP:0005227', (102, 128))	('mutation-induced', 'Var', (130, 146))	('intestinal cancer', 'Disease', 'MESH:D007414', (147, 164))	('intestinal cancer', 'Disease', (147, 164))	('Mice', 'Species', '10090', (0, 4))	('APC (Adenomatous polyposis Coli', 'Gene', '11789', (97, 128))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
810026	32183428	Mice deficient in multiple Myc enhancers, including Myc-196, Myc-335, and Myc-540, within 538kb upstream of Myc, exhibit >50% reductions of Myc expression in colon and prostate.	('Myc expression', 'MPA', (140, 154))	('Myc-335', 'Var', (61, 68))	('reductions', 'NegReg', (126, 136))	('Mice', 'Species', '10090', (0, 4))	('Myc-540', 'Var', (74, 81))	('Myc-196', 'Var', (52, 59))
810027	32183428	Importantly, these mice are more protected from APC mutation-induced intestinal cancer compared to mice deficient in only Myc-335.	('mice', 'Species', '10090', (99, 103))	('intestinal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PC', 'Phenotype', 'HP:0012125', (49, 51))	('APC', 'Disease', 'MESH:D011125', (48, 51))	('intestinal cancer', 'Disease', 'MESH:D007414', (69, 86))	('mutation-induced', 'Var', (52, 68))	('APC', 'Disease', (48, 51))	('mice', 'Species', '10090', (19, 23))
810030	32183428	Variants in the 8q24.21 gene desert also display long-range association with the non-coding PVT1 locus that lies downstream of the Myc locus and thus outside of the gene desert bordered by FAM84B and Myc (Figure 1).	('PVT1', 'Gene', '5820', (92, 96))	('PVT1', 'Gene', (92, 96))	('Variants', 'Var', (0, 8))	('association', 'Interaction', (60, 71))
810031	32183428	A prostate cancer risk variant within the gene desert was reported to facilitate PVT1 transcription through physical association.	('A prostate cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('PVT1', 'Gene', (81, 85))	('variant', 'Var', (23, 30))	('facilitate', 'PosReg', (70, 80))	('A prostate cancer', 'Disease', 'MESH:D011471', (0, 17))	('transcription', 'MPA', (86, 99))	('PVT1', 'Gene', '5820', (81, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (2, 17))
810034	32183428	High levels of lnRNA PVT1 helps to maintain high levels of Myc protein expression in CRC, and ablation of PVT1 prevents Myc from inducing HCT116 cell-derived tumorigenesis.	('tumor', 'Disease', (158, 163))	('ablation', 'Var', (94, 102))	('Myc protein', 'Protein', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('PVT1', 'Gene', (106, 110))	('PVT1', 'Gene', (21, 25))	('PVT1', 'Gene', '5820', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('PVT1', 'Gene', '5820', (21, 25))	('inducing', 'Reg', (129, 137))	('HCT116', 'CellLine', 'CVCL:0291', (138, 144))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))	('prevents', 'NegReg', (111, 119))
810037	32183428	It is an interesting disparity considering the relatively unknown status of FAM84B in tumorigenesis compared to the well-studied oncogenic functions of Myc.	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('FAM84B', 'Var', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))
810039	32183428	FAM84B plays a role in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('FAM84B', 'Var', (0, 6))	('esophageal cancer', 'Disease', (23, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (23, 40))
810040	32183428	Amplification of the FAM84B gene and increases in its expression at the protein level occur in both preclinical lesions and esophageal squamous cell carcinomas (ESCC).	('FAM84B', 'Gene', (21, 27))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (135, 159))	('Amplification', 'Var', (0, 13))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('expression at the protein', 'MPA', (54, 79))	('esophageal squamous cell carcinomas', 'Disease', (124, 159))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (124, 159))	('increases', 'PosReg', (37, 46))
810042	32183428	Knockdown of FAM84B in two ESCC cell lines KYSE150 and TE-1 reduced their proliferation, migration, and invasion in vitro, and knockdown of FAM84B in ESCC CE81T/VGH cells significantly delayed xenograft growth in vivo.	('KYSE150', 'CellLine', 'CVCL:1348', (43, 50))	('delayed', 'NegReg', (185, 192))	('rat', 'Species', '10116', (81, 84))	('rat', 'Species', '10116', (92, 95))	('reduced', 'NegReg', (60, 67))	('migration', 'CPA', (89, 98))	('proliferation', 'CPA', (74, 87))	('invasion', 'CPA', (104, 112))	('FAM84B', 'Var', (140, 146))	('knockdown', 'Var', (127, 136))
810057	32183428	Furthermore, RNA sequencing (RNA-seq) analysis revealed a large number of differentially expressed genes (DEGs) in DU145 FAM84B xenografts compared to DU145 EV tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('DU145', 'CellLine', 'CVCL:0105', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('DU145 FAM84B', 'Var', (115, 127))	('tumors', 'Disease', (160, 166))	('DU145', 'CellLine', 'CVCL:0105', (151, 156))	('differentially expressed genes', 'MPA', (74, 104))
810059	32183428	Structurally, FAM84B shares similarities with the H-Ras-like suppressor (HRASLS) family HRASLS1-5 within their LRAT (lecithin:retinal acyltransferase) homologous domain (Figure 3).	('HRASLS1-5', 'Gene', (88, 97))	('LRAT', 'Gene', (111, 115))	('FAM84B', 'Var', (14, 20))	('LRAT', 'Gene', '9227', (111, 115))	('HRASLS', 'Gene', (73, 79))	('HRASLS', 'Gene', (88, 94))	('H-Ras-like suppressor', 'Gene', '57110', (50, 71))	('HRASLS1-5', 'Gene', '57110;54979;11145;5920;117245', (88, 97))	('H-Ras-like suppressor', 'Gene', (50, 71))	('HRASLS', 'Gene', '57110', (73, 79))	('HRASLS', 'Gene', '57110', (88, 94))
810066	32183428	H-rev107 was identified for reversal of H-Ras-derived transformation of rat fibroblasts, the PLA/AT activities of HRASLS3 suppress H-Ras signaling, and HRASLS3 inhibits K-Ras signaling via a physical association (Table 2).	('K-Ras', 'Gene', (169, 174))	('rat', 'Species', '10116', (72, 75))	('physical association', 'Interaction', (191, 211))	('H-Ras signaling', 'MPA', (131, 146))	('HRASLS3', 'Gene', (114, 121))	('HRASLS3', 'Var', (152, 159))	('inhibits', 'NegReg', (160, 168))	('K-Ras', 'Gene', '24525', (169, 174))	('suppress', 'NegReg', (122, 130))
810068	32183428	This concept is also intriguing considering the similarities shared between FAM84B and the HRASLS family.	('HRASLS', 'Gene', '57110', (91, 97))	('HRASLS', 'Gene', (91, 97))	('FAM84B', 'Var', (76, 82))
810069	32183428	Unlike the HRASLS family, FAM84B does not possess PLA/AT enzymatic activities and will not suppress Ras signaling.	('HRASLS', 'Gene', (11, 17))	('suppress', 'NegReg', (91, 99))	('Ras signaling', 'MPA', (100, 113))	('FAM84B', 'Var', (26, 32))	('HRASLS', 'Gene', '57110', (11, 17))
810070	32183428	With this knowledge, it is an interesting scenario for FAM84B to facilitate Ras signaling via inhibiting the actions of the HRASLS family, and thereby in part contributing to its collaboration with Myc.	('contributing', 'Reg', (159, 171))	('FAM84B', 'Var', (55, 61))	('rat', 'Species', '10116', (186, 189))	('facilitate', 'PosReg', (65, 75))	('HRASLS', 'Gene', (124, 130))	('Ras signaling', 'MPA', (76, 89))	('inhibiting', 'NegReg', (94, 104))	('actions', 'MPA', (109, 116))	('HRASLS', 'Gene', '57110', (124, 130))
810073	32183428	In support of this possibility, mice deficient in the 430kb region encompassing CCAT1, POU5F1B, CCAT2, and CASC8 within the 8q24.21 gene desert (Figure 1) downregulate both FAM84B and Myc expression in mammary gland and prostate.	('deficient', 'Var', (37, 46))	('CCAT2', 'Gene', '101805488', (96, 101))	('CCAT1', 'Gene', '100507056', (80, 85))	('CASC8', 'Gene', (107, 112))	('POU5F1B', 'Gene', (87, 94))	('CASC8', 'Gene', '727677', (107, 112))	('CCAT1', 'Gene', (80, 85))	('CCAT2', 'Gene', (96, 101))	('FAM84B', 'Gene', (173, 179))	('mice', 'Species', '10090', (32, 36))	('downregulate', 'NegReg', (155, 167))	('POU5F1B', 'Gene', '5462', (87, 94))	('Myc', 'Gene', (184, 187))
810074	32183428	Deletion of this region delays the growth of luminal, Her2, and basal breast cancer in MMTV-PuVT, MMTV-Neu, and C3(1)-TAg transgenic mouse models for breast cancer, respectively.	('C3(1)-TAg', 'Disease', 'MESH:C565169', (112, 121))	('luminal', 'Chemical', 'MESH:D010634', (45, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('Her2', 'Gene', '2064', (54, 58))	('transgenic', 'Species', '10090', (122, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('mouse', 'Species', '10090', (133, 138))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('delays', 'NegReg', (24, 30))	('Her2', 'Gene', (54, 58))	('breast cancer', 'Disease', (150, 163))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('basal breast cancer', 'Disease', 'MESH:D001943', (64, 83))	('MMTV', 'Species', '11757', (98, 102))	('growth', 'MPA', (35, 41))	('Deletion', 'Var', (0, 8))	('basal breast cancer', 'Disease', (64, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('MMTV', 'Species', '11757', (87, 91))
810076	32183428	Ovarian cancer and breast cancer are the first (>40%) and fifth (>20%) cancer type with respect to the prevalence of FAM84B and Myc co-amplification.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('FAM84B', 'Var', (117, 123))	('cancer', 'Disease', (8, 14))	('Myc co-amplification', 'Var', (128, 148))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('breast cancer', 'Disease', (19, 32))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
810077	32183428	This co-amplification associates with poor overall survival in breast cancer.	('co-amplification', 'Var', (5, 21))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('poor', 'NegReg', (38, 42))	('overall', 'MPA', (43, 50))
810080	32183428	Among PCs with Myc amplification, 85% of cases have FAM84B concurrently amplified, and among tumors with FAM84B amplification, 96.8% of cases show Myc co-amplification (Figure 4A).	('FAM84B', 'Gene', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('amplification', 'Var', (19, 32))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('Myc co-amplification', 'MPA', (147, 167))	('PC', 'Phenotype', 'HP:0012125', (6, 8))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('FAM84B', 'Var', (105, 111))	('tumors', 'Disease', (93, 99))
810085	32183428	In this regard, we proposed a collaboration between FAM84B and Myc which may involve Ras.	('FAM84B', 'Var', (52, 58))	('Myc', 'Disease', (63, 66))	('rat', 'Species', '10116', (37, 40))
810121	30588031	Functional studies demonstrated that knockdown of CDC7 inhibited proliferation by arresting ESCC cells in the G0/G1 phase and inducing apoptosis.	('apoptosis', 'CPA', (135, 144))	('proliferation', 'CPA', (65, 78))	('inducing', 'Reg', (126, 134))	('CDC7', 'Gene', (50, 54))	('knockdown', 'Var', (37, 46))	('arresting', 'NegReg', (82, 91))	('CDC7', 'Gene', '8317', (50, 54))	('inhibited', 'NegReg', (55, 64))
810123	30588031	Furthermore, knockdown of CDC7 sensitized ESCC cells to Cis and 5-FU.	('sensitized', 'Reg', (31, 41))	('CDC7', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('CDC7', 'Gene', '8317', (26, 30))	('5-FU', 'Chemical', 'MESH:D005472', (64, 68))
810124	30588031	Our results suggest that CDC7 is highly expressed in ESCC tissues, and silencing CDC7 enhances chemosensitivity of ESCC cells, providing a new avenue for ESCC therapy.	('CDC7', 'Gene', '8317', (25, 29))	('CDC7', 'Gene', '8317', (81, 85))	('silencing', 'Var', (71, 80))	('CDC7', 'Gene', (81, 85))	('chemosensitivity', 'CPA', (95, 111))	('enhances', 'PosReg', (86, 94))	('CDC7', 'Gene', (25, 29))
810133	30588031	Accumulating evidence indicates that CDC7 silencing causes p53-independent apoptosis of tumor cells, but not normal cells.	('p53', 'Gene', (59, 62))	('silencing', 'Var', (42, 51))	('p53', 'Gene', '7157', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CDC7', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('CDC7', 'Gene', '8317', (37, 41))
810138	30588031	Functionally, we found that downregulated CDC7 could improve the sensitivity of ESCC to chemotherapy.	('CDC7', 'Gene', '8317', (42, 46))	('CDC7', 'Gene', (42, 46))	('sensitivity', 'MPA', (65, 76))	('downregulated', 'Var', (28, 41))	('improve', 'PosReg', (53, 60))	('ESCC', 'Disease', (80, 84))
810178	30588031	Our results showed that downregulation of CDC7 in KYSE150 cells suppressed proliferation from 1.05 (scrambled siRNA) to 0.74 (Figure 3D, P=0.0093); in addition, inhibited CDC7 kinase activity through PHA-767491 in KYSE150 cells suppressed proliferation from 0.74 (siCDC7) to 0.55 (Figure 3D, P=0.0248), while overexpression of CDC7 in KYSE30 cells showed the opposite effects (Figure 3E, P=0.0094).	('proliferation', 'CPA', (75, 88))	('KYSE30', 'CellLine', 'CVCL:1351', (335, 341))	('CDC7', 'Gene', (327, 331))	('PHA-767491', 'Var', (200, 210))	('CDC7', 'Gene', '8317', (42, 46))	('suppressed', 'NegReg', (64, 74))	('inhibited', 'NegReg', (161, 170))	('CDC7', 'Gene', (266, 270))	('downregulation', 'NegReg', (24, 38))	('CDC7', 'Gene', '8317', (171, 175))	('CDC7', 'Gene', '8317', (327, 331))	('CDC7', 'Gene', '8317', (266, 270))	('KYSE150', 'CellLine', 'CVCL:1348', (50, 57))	('CDC7', 'Gene', (171, 175))	('proliferation', 'CPA', (239, 252))	('suppressed', 'NegReg', (228, 238))	('CDC7', 'Gene', (42, 46))	('KYSE150', 'CellLine', 'CVCL:1348', (214, 221))
810181	30588031	In contrast, overexpression of CDC7 in KYSE30 cells significantly decreased the percentage of cells at the G0/G1 phase and increased the percentage of cells at the S phase (Figure 4B, P=0.0067).	('KYSE30', 'Var', (39, 45))	('increased', 'PosReg', (123, 132))	('CDC7', 'Gene', (31, 35))	('decreased', 'NegReg', (66, 75))	('CDC7', 'Gene', '8317', (31, 35))	('overexpression', 'PosReg', (13, 27))	('KYSE30', 'CellLine', 'CVCL:1351', (39, 45))
810183	30588031	Downregulation of CDC7 in KYSE150 cells increased apoptosis from 6.9% (scrambled siRNA) to 16.8% (Figure 4C, P=0.0178); in addition, inhibited CDC7 kinase activity through PHA-767491 in KYSE150 cells increased apoptosis from 16.8% (siCDC7) to 25.5% (Figure 4C, P=0.0488), while we could not detect any apoptosis in CDC7-transfected KYSE30 cells compared with pcDNA3.1 transfection (Figure 4D).	('CDC7', 'Gene', '8317', (234, 238))	('CDC7', 'Gene', '8317', (315, 319))	('KYSE30', 'CellLine', 'CVCL:1351', (332, 338))	('CDC7', 'Gene', '8317', (143, 147))	('Downregulation', 'NegReg', (0, 14))	('inhibited', 'NegReg', (133, 142))	('CDC7', 'Gene', '8317', (18, 22))	('PHA-767491', 'Var', (172, 182))	('CDC7', 'Gene', (143, 147))	('CDC7', 'Gene', (315, 319))	('KYSE150', 'CellLine', 'CVCL:1348', (186, 193))	('apoptosis', 'CPA', (210, 219))	('KYSE150', 'CellLine', 'CVCL:1348', (26, 33))	('CDC7', 'Gene', (234, 238))	('CDC7', 'Gene', (18, 22))
810185	30588031	To further investigate the effect of CDC7 on migration and invasion of ESCC cells, CDC7 was knocked down in KYSE150 cells using siRNAs and overexpressed in KYSE30 cells using pcDNA3.1-CDC7 vector.	('CDC7', 'Gene', (83, 87))	('CDC7', 'Gene', '8317', (83, 87))	('knocked', 'Var', (92, 99))	('KYSE150', 'CellLine', 'CVCL:1348', (108, 115))	('CDC7', 'Gene', (184, 188))	('CDC7', 'Gene', '8317', (184, 188))	('CDC7', 'Gene', (37, 41))	('KYSE30', 'CellLine', 'CVCL:1351', (156, 162))	('CDC7', 'Gene', '8317', (37, 41))
810188	30588031	In addition, similar results were observed in KYSE150 cells treated with PHA-767491 compared with siCDC7 transfection (Figure 5A and C, P=0.0199, P=0.0042, respectively).	('PHA-767491', 'Var', (73, 83))	('CDC7', 'Gene', (100, 104))	('KYSE150', 'CellLine', 'CVCL:1348', (46, 53))	('CDC7', 'Gene', '8317', (100, 104))
810191	30588031	Results from MTS assay showed that Cis and 5-FU treatment resulted in significantly decreased cell survival in CDC7 knockdown cells as compared with their respective controls (Figure 6A), while overexpression of CDC7 in KYSE30 cells showed the opposite effects (Figure 6B).	('CDC7', 'Gene', '8317', (212, 216))	('5-FU', 'Chemical', 'MESH:D005472', (43, 47))	('CDC7', 'Gene', (111, 115))	('CDC7', 'Gene', '8317', (111, 115))	('knockdown', 'Var', (116, 125))	('KYSE30', 'CellLine', 'CVCL:1351', (220, 226))	('cell survival', 'CPA', (94, 107))	('CDC7', 'Gene', (212, 216))	('decreased', 'NegReg', (84, 93))
810192	30588031	Furthermore, results from apoptosis assay showed that the fraction of apoptotic cells were significantly increased in CDC7 knockdown cells as compared with their respective controls upon Cis and 5-FU treatment (Figure 6C), while overexpression of CDC7 in KYSE30 cells significantly reduced Cis and 5-FU-induced apoptotic cells (Figure 6D).	('5-FU', 'Chemical', 'MESH:D005472', (195, 199))	('5-FU', 'Chemical', 'MESH:D005472', (298, 302))	('reduced', 'NegReg', (282, 289))	('CDC7', 'Gene', (118, 122))	('KYSE30', 'CellLine', 'CVCL:1351', (255, 261))	('CDC7', 'Gene', (247, 251))	('CDC7', 'Gene', '8317', (118, 122))	('increased', 'PosReg', (105, 114))	('knockdown', 'Var', (123, 132))	('CDC7', 'Gene', '8317', (247, 251))
810193	30588031	These results suggest that knockdown of CDC7 sensitizes ESCC cells to chemotherapy.	('ESCC', 'Disease', (56, 60))	('sensitizes', 'Reg', (45, 55))	('knockdown', 'Var', (27, 36))	('CDC7', 'Gene', (40, 44))	('CDC7', 'Gene', '8317', (40, 44))
810196	30588031	Our data showed that CDC7 was highly expressed in ESCC tissues compared with matched adjacent normal tissues, and knockdown of CDC7 sensitizes ESCC cells to Cis and 5-FU.	('CDC7', 'Gene', '8317', (21, 25))	('5-FU', 'Chemical', 'MESH:D005472', (165, 169))	('sensitizes', 'Reg', (132, 142))	('knockdown', 'Var', (114, 123))	('ESCC', 'Disease', (143, 147))	('CDC7', 'Gene', (127, 131))	('CDC7', 'Gene', (21, 25))	('CDC7', 'Gene', '8317', (127, 131))
810200	30588031	For example, IL6 was found to promote chemoresistance in ESCC via CXCR7, and downregulation of HOXA13 sensitizes human ESCC to chemotherapy and might regulate epithelial-to-mesenchymal transition (EMT).	('HOXA13', 'Gene', '3209', (95, 101))	('IL6', 'Gene', '3569', (13, 16))	('epithelial-to-mesenchymal transition', 'CPA', (159, 195))	('promote', 'PosReg', (30, 37))	('IL6', 'Gene', (13, 16))	('CXCR7', 'Gene', '57007', (66, 71))	('ESCC', 'Disease', (119, 123))	('regulate', 'Reg', (150, 158))	('human', 'Species', '9606', (113, 118))	('chemoresistance', 'CPA', (38, 53))	('CXCR7', 'Gene', (66, 71))	('sensitizes', 'Reg', (102, 112))	('HOXA13', 'Gene', (95, 101))	('downregulation', 'Var', (77, 91))
810205	30588031	To further investigate the role of CDC7 in ESCC chemoresistance, we knocked down CDC7 in KYSE150 cells, MTS and flow cytometry were performed to evaluate Cis or 5-FU-induced inhibition and apoptosis in KYSE150 cells, respectively.	('CDC7', 'Gene', '8317', (81, 85))	('KYSE150', 'CellLine', 'CVCL:1348', (202, 209))	('5-FU', 'Chemical', 'MESH:D005472', (161, 165))	('CDC7', 'Gene', (35, 39))	('knocked', 'Var', (68, 75))	('apoptosis', 'CPA', (189, 198))	('CDC7', 'Gene', '8317', (35, 39))	('inhibition', 'NegReg', (174, 184))	('CDC7', 'Gene', (81, 85))	('KYSE150', 'CellLine', 'CVCL:1348', (89, 96))
810206	30588031	MTS assay showed that knockdown of CDC7 decreased cell survival upon Cis or 5-FU exposure (Figure 6A).	('CDC7', 'Gene', (35, 39))	('knockdown', 'Var', (22, 31))	('CDC7', 'Gene', '8317', (35, 39))	('5-FU', 'Chemical', 'MESH:D005472', (76, 80))	('cell survival', 'CPA', (50, 63))	('decreased', 'NegReg', (40, 49))
810207	30588031	Meanwhile, we found that the knockdown of CDC7 promoted Cis or 5-FU-induced apoptosis in KYSE150 cells (Figure 6C), while overexpression of CDC7 in KYSE30 cells showed the opposite effects (Figure 6B and D).	('CDC7', 'Gene', '8317', (140, 144))	('knockdown', 'Var', (29, 38))	('CDC7', 'Gene', '8317', (42, 46))	('promoted', 'PosReg', (47, 55))	('5-FU', 'Chemical', 'MESH:D005472', (63, 67))	('KYSE30', 'CellLine', 'CVCL:1351', (148, 154))	('CDC7', 'Gene', (140, 144))	('Cis', 'MPA', (56, 59))	('apoptosis', 'CPA', (76, 85))	('CDC7', 'Gene', (42, 46))	('KYSE150', 'CellLine', 'CVCL:1348', (89, 96))
810208	30588031	Consistent with Sasi et al's study, our data suggested that knockdown of CDC7 sensitizes ESCC cells to chemotherapy.	('CDC7', 'Gene', '8317', (73, 77))	('ESCC', 'Disease', (89, 93))	('sensitizes', 'Reg', (78, 88))	('knockdown', 'Var', (60, 69))	('CDC7', 'Gene', (73, 77))
810209	30588031	Silencing CDC7 in cancer cells inducing p53-independent apoptosis of tumor cells, but not normal cells, makes CDC7 a very promising target for drug development.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('inducing', 'Reg', (31, 39))	('CDC7', 'Gene', '8317', (10, 14))	('tumor', 'Disease', (69, 74))	('CDC7', 'Gene', '8317', (110, 114))	('p53', 'Gene', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('p53', 'Gene', '7157', (40, 43))	('CDC7', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('CDC7', 'Gene', (110, 114))
810212	30588031	Our results showed that PHA-767491 suppressed proliferation, migration and invasion more significantly than siCDC7, and inducing more apoptosis.	('inducing', 'Reg', (120, 128))	('invasion', 'CPA', (75, 83))	('CDC7', 'Gene', '8317', (110, 114))	('apoptosis', 'CPA', (134, 143))	('proliferation', 'CPA', (46, 59))	('migration', 'CPA', (61, 70))	('suppressed', 'NegReg', (35, 45))	('PHA-767491', 'Var', (24, 34))	('CDC7', 'Gene', (110, 114))
810213	30588031	Liu et al reported that PHA-767491 can function as an NRF2 inhibitor drug candidate for cancer therapy via redox modulation.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('NRF2', 'Gene', '4780', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PHA-767491', 'Var', (24, 34))	('NRF2', 'Gene', (54, 58))
810214	30588031	In addition, Shen et al reported that blockage of Nrf2 suppresses the migration and invasion of ESCC cells in hypoxic microenvironment via EMT pathway.	('migration', 'CPA', (70, 79))	('Nrf2', 'Gene', '4780', (50, 54))	('suppresses', 'NegReg', (55, 65))	('Nrf2', 'Gene', (50, 54))	('blockage', 'Var', (38, 46))
810216	30588031	Thus, these results suggested that PHA-767491-mediated effects on cancer cell proliferation, migration and invasion, and apoptosis may be due to its combined net inhibitory activity on both Cdc7/CDK9 and NRF2.	('CDK9', 'Gene', '1025', (195, 199))	('Cdc7', 'Gene', '8317', (190, 194))	('PHA-767491-mediated', 'Var', (35, 54))	('Cdc7', 'Gene', (190, 194))	('effects', 'Reg', (55, 62))	('migration', 'CPA', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('NRF2', 'Gene', '4780', (204, 208))	('CDK9', 'Gene', (195, 199))	('NRF2', 'Gene', (204, 208))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('inhibitory activity', 'NegReg', (162, 181))	('invasion', 'CPA', (107, 115))	('apoptosis', 'CPA', (121, 130))	('cancer', 'Disease', (66, 72))
810219	30588031	Furthermore, we found that the depletion of CDC7 can inhibit cell proliferation and induce apoptosis in KYSE150 cells.	('inhibit', 'NegReg', (53, 60))	('apoptosis', 'CPA', (91, 100))	('CDC7', 'Gene', (44, 48))	('KYSE150', 'CellLine', 'CVCL:1348', (104, 111))	('induce', 'Reg', (84, 90))	('depletion', 'Var', (31, 40))	('CDC7', 'Gene', '8317', (44, 48))	('cell proliferation', 'CPA', (61, 79))
810221	30588031	Currently, a phase I clinical study is ongoing at Cancer Research UK (NCT03096054) to assess the safety of LY3143921 hydrate (a CDC7 inhibitor) in adult patients with advanced solid tumors, including squamous carcinoma of the esophagus.	('CDC7', 'Gene', (128, 132))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('solid tumors', 'Disease', 'MESH:D009369', (176, 188))	('patients', 'Species', '9606', (153, 161))	('LY3143921', 'Chemical', '-', (107, 116))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (209, 235))	('LY3143921', 'Var', (107, 116))	('CDC7', 'Gene', '8317', (128, 132))	('squamous carcinoma of the esophagus', 'Disease', (200, 235))	('squamous carcinoma of the esophagus', 'Disease', 'MESH:D002294', (200, 235))	('solid tumors', 'Disease', (176, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (200, 218))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
810223	30588031	Depletion of CDC7 can inhibit proliferation, migration and invasion, and induce apoptosis of ESCC cells.	('migration', 'CPA', (45, 54))	('inhibit', 'NegReg', (22, 29))	('Depletion', 'Var', (0, 9))	('CDC7', 'Gene', (13, 17))	('induce', 'Reg', (73, 79))	('invasion', 'CPA', (59, 67))	('apoptosis', 'CPA', (80, 89))	('CDC7', 'Gene', '8317', (13, 17))	('proliferation', 'CPA', (30, 43))
810235	29072050	For instance meiosis induction leads to aneuploidy in cancer cells but the expected haploid cells in the gametogenesis; or while migration of primordial germ cells to the testis is a perquisite for normal gametogenesis, the aberrant migration potential in tumourigenesis leads to metastasis.	('leads to', 'Reg', (271, 279))	('aneuploidy', 'Disease', 'MESH:D000782', (40, 50))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('aberrant', 'Var', (224, 232))	('cancer', 'Disease', (54, 60))	('metastasis', 'CPA', (280, 290))	('tumourigenesis', 'CPA', (256, 270))	('aneuploidy', 'Disease', (40, 50))	('meiosis', 'CPA', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
810239	29072050	On the other hand, numerous researches have highlighted the role of non-coding RNAs in both gametogenic (Luk et al., 2014) and tumorigenic processes (Cheetham et al., 2013; Iranpour et al., 2016; Soudyab et al., 2016).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('gametogenic', 'CPA', (92, 103))	('tumor', 'Disease', (127, 132))	('RNAs', 'Protein', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('non-coding', 'Var', (68, 78))
810251	29072050	Surprisingly, dysregulation of this lncRNA has been shown to be involved in both breast and ovarian cancer tumorigenesis process (Nikpayam et al., 2016; Soudyab et al., 2016) as well as the response of ovarian cancer patients to chemotherapeutic agents (Nikpayam et al., 2016).	('ovarian cancer', 'Disease', 'MESH:D010051', (92, 106))	('involved', 'Reg', (64, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('ovarian cancer', 'Disease', (92, 106))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (217, 225))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('ovarian cancer', 'Phenotype', 'HP:0100615', (202, 216))	('dysregulation', 'Var', (14, 27))	('ovarian cancer', 'Disease', 'MESH:D010051', (202, 216))	('ovarian cancer', 'Disease', (202, 216))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (81, 106))
810283	29072050	DIAPH3 knock down has been associated with imperfect endocytic trafficking, endosomal gathering of EGFR, and induction of EGFR/MEK/ERK signaling leading to increased invasion and metastasis in mice.	('invasion', 'CPA', (166, 174))	('EGFR', 'Gene', (99, 103))	('endosomal gathering', 'MPA', (76, 95))	('MEK', 'Gene', (127, 130))	('DIAPH3', 'Gene', (0, 6))	('increased', 'PosReg', (156, 165))	('endocytic trafficking', 'MPA', (53, 74))	('ERK', 'Gene', (131, 134))	('ERK', 'Gene', '26413', (131, 134))	('mice', 'Species', '10090', (193, 197))	('MEK', 'Gene', '17242', (127, 130))	('imperfect', 'MPA', (43, 52))	('knock down', 'Var', (7, 17))
810285	29072050	Although the exact role of DIAPH3-AS1 in regulation of its putative target is not defined yet, its genomic locus in proximity to RB1 implies its role in cancer pathogenesis considering the fact that this genomic locus is a hot spot region of deletion in prostate, breast and hepatocellular carcinomas (Hager et al., 2012).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (275, 300))	('RB1', 'Gene', '5925', (129, 132))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (275, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('prostate', 'Disease', (254, 262))	('deletion', 'Var', (242, 250))	('cancer', 'Disease', (153, 159))	('breast and hepatocellular carcinomas', 'Disease', 'MESH:D006528', (264, 300))	('DIAPH3-AS1', 'Gene', '100874195;81624;5729', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('RB1', 'Gene', (129, 132))	('DIAPH3-AS1', 'Gene', (27, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (290, 300))
810343	29072050	TP73-AS1 knockdown prevented cell proliferation, triggered apoptosis in esophageal squamous cell carcinoma and increased the chemosensitivity of esophageal cancer cells to 5-FU and cisplatin.	('TP73', 'Gene', '7161', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('5-FU', 'Chemical', 'MESH:D005472', (172, 176))	('TP73', 'Gene', (0, 4))	('AS1', 'Gene', (5, 8))	('triggered', 'Reg', (49, 58))	('apoptosis', 'CPA', (59, 68))	('esophageal squamous cell carcinoma', 'Disease', (72, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (181, 190))	('knockdown', 'Var', (9, 18))	('esophageal cancer', 'Disease', (145, 162))	('cell proliferation', 'CPA', (29, 47))	('prevented', 'NegReg', (19, 28))	('chemosensitivity', 'MPA', (125, 141))	('increased', 'PosReg', (111, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (72, 106))	('AS1', 'Gene', '5729', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
810371	28979723	The histopathological diagnosis was moderately differentiated squamous cell carcinoma with pT1bN0M0, Stage IA.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('squamous cell carcinoma', 'Disease', (62, 85))	('pT1bN0M0', 'Var', (91, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
810374	28979723	In the present case, we clinically diagnosed esophageal carcinoma with right cervical lymph nodes metastasis, T2N2M0, Stage IIIA preoperatively, but the stage was revised to pT1bN0M0, Stage IA on pathological diagnosis.	('esophageal carcinoma', 'Disease', (45, 65))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (45, 65))	('cervical lymph nodes metastasis', 'Phenotype', 'HP:0025289', (77, 108))	('T2N2M0', 'Var', (110, 116))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (45, 65))	('diagnosed', 'Reg', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
810393	28979723	The final diagnosis was esophageal squamous cell carcinoma without lymph node metastasis, pT1bN0M0, Stage IA and CD of the cervical lymph nodes.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (24, 58))	('pT1bN0M0', 'Var', (90, 98))	('esophageal squamous cell carcinoma', 'Disease', (24, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))
810395	28979723	A variant of the multicentric form was later found to be associated with human herpesvirus 8 (HHV-8), which is the same virus found in Kaposi's sarcoma.	('HHV-8', 'Gene', (94, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('variant', 'Var', (2, 9))	('HHV-8', 'Species', '37296', (94, 99))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (135, 151))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (135, 151))	("Kaposi's sarcoma", 'Disease', (135, 151))	('human herpesvirus 8', 'Species', '37296', (73, 92))	('associated', 'Reg', (57, 67))
810412	28979723	In the present case, the preoperative clinical diagnosis was esophageal carcinoma T2N2M0, Stage IIIA, but the stage was revised to pT1bN0M0, Stage IA upon pathological diagnosis.	('esophageal carcinoma', 'Disease', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (61, 81))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (61, 81))	('T2N2M0', 'Var', (82, 88))
810424	22252115	Lack of EGFR mutations benefiting gefitinib treatment in adenocarcinoma of esophagogastric junction The epidermal growth factor receptor (EGFR) inhibitor, gefitinib, has been reported to successfully treat advanced non-small cell lung cancer patients with genetic mutations in EGFR.	('adenocarcinoma', 'Disease', 'MESH:D000230', (57, 71))	('EGFR', 'Gene', '1956', (8, 12))	('EGFR', 'Gene', (138, 142))	('EGFR', 'Gene', '1956', (277, 281))	('patients', 'Species', '9606', (242, 250))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (215, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('EGFR', 'Gene', '1956', (138, 142))	('gefitinib', 'Chemical', 'MESH:D000077156', (155, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('non-small cell lung cancer', 'Disease', (215, 241))	('genetic mutations', 'Var', (256, 273))	('EGFR', 'Gene', (8, 12))	('EGFR', 'Gene', (277, 281))	('adenocarcinoma', 'Disease', (57, 71))	('gefitinib', 'Chemical', 'MESH:D000077156', (34, 43))	('epidermal growth factor receptor', 'Gene', (104, 136))	('epidermal growth factor receptor', 'Gene', '1956', (104, 136))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (219, 241))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (215, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
810425	22252115	The aim of this study was to investigate the existence of EGFR mutations in carcinoma of esophagogastric junction, and also to explore the possibility of treating carcinoma of esophagogastric junction using gefitinib.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinoma of esophagogastric junction', 'Disease', 'MESH:C537006', (76, 113))	('carcinoma of esophagogastric junction', 'Disease', (163, 200))	('EGFR', 'Gene', (58, 62))	('carcinoma of esophagogastric junction', 'Disease', (76, 113))	('gefitinib', 'Chemical', 'MESH:D000077156', (207, 216))	('carcinoma of esophagogastric junction', 'Disease', 'MESH:C537006', (163, 200))
810429	22252115	In exon 20, a variant from CAG to CAA at codon 787 (2361G-> A) was identified in 19 patients, which was a genomic variation of EGFR since it was found in both cancer tissue and white blood cells.	('cancer', 'Disease', (159, 165))	('2361G-> A', 'Mutation', 'rs1050171', (52, 61))	('patients', 'Species', '9606', (84, 92))	('2361G-> A', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('EGFR', 'Gene', '1956', (127, 131))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('CAG to CAA at codon 787', 'Mutation', 'c.787CAG>CAA', (27, 50))	('EGFR', 'Gene', (127, 131))
810430	22252115	This EGFR alteration was a synonymous single nucleotide polymorphism (SNP) since CAA and CAG were encoding the same amino-acid of Glutamine (Q787Q, NCBI database 162093G > A, SNP ID: rs10251977).	('rs10251977', 'Mutation', 'rs10251977', (183, 193))	('Q787Q', 'Var', (141, 146))	('EGFR', 'Gene', '1956', (5, 9))	('162093G > A', 'Mutation', 'g.162093G>A', (162, 173))	('EGFR', 'Gene', (5, 9))	('CAA and CAG', 'Gene', '10194', (81, 92))	('Q787Q', 'Mutation', 'rs1050171', (141, 146))	('Glutamine', 'Chemical', 'MESH:D005973', (130, 139))
810431	22252115	Adenocarcinoma of esophagogastric junction rarely presents EGFR mutation, especially gefitinib-associated mutations such as L858R, or delE746-A750.	('Adenocarcinoma', 'Disease', (0, 14))	('delE746-A750', 'Var', (134, 146))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('EGFR', 'Gene', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('delE746', 'Mutation', 'p.746delE', (134, 141))	('carcinoma of esophagogastric junction', 'Disease', 'MESH:C537006', (5, 42))	('carcinoma of esophagogastric junction', 'Disease', (5, 42))	('L858R', 'Var', (124, 129))	('L858R', 'Mutation', 'rs121434568', (124, 129))	('EGFR', 'Gene', '1956', (59, 63))	('gefitinib', 'Chemical', 'MESH:D000077156', (85, 94))
810441	22252115	Further studies revealed that just the tumor cell with EGFR-TK mutation (L858R, del742-759) could match good response to gefitinib.	('EGFR', 'Gene', '1956', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('EGFR', 'Gene', (55, 59))	('gefitinib', 'Chemical', 'MESH:D000077156', (121, 130))	('del742-759', 'Var', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('del742-759', 'Mutation', 'c.742_759del', (80, 90))	('L858R', 'Var', (73, 78))	('tumor', 'Disease', (39, 44))	('L858R', 'Mutation', 'rs121434568', (73, 78))
810442	22252115	According to the previous researches on EGFR DNA sequencing in Japan, South Korea and China, the incidence of EGFR mutation of NSCLC in Asian population was significantly higher than that in Europe or America.	('NSCLC', 'Disease', (127, 132))	('EGFR', 'Gene', '1956', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('EGFR', 'Gene', (110, 114))	('higher', 'PosReg', (171, 177))	('EGFR', 'Gene', '1956', (40, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('EGFR', 'Gene', (40, 44))	('mutation', 'Var', (115, 123))
810444	22252115	Recently a new EGFR mutation of T790M was discovered that explained the resistance to gefitinib after drug administration.	('T790M', 'Mutation', 'rs121434569', (32, 37))	('T790M', 'Var', (32, 37))	('gefitinib', 'Chemical', 'MESH:D000077156', (86, 95))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('resistance to gefitinib', 'MPA', (72, 95))	('explained', 'Reg', (58, 67))
810445	22252115	On the other hand, based on the mutation mechanisms above pharmacologist could design new inhibitors targeting EGFR mutation locus.	('EGFR', 'Gene', (111, 115))	('mutation', 'Var', (116, 124))	('EGFR', 'Gene', '1956', (111, 115))
810455	22252115	No study on EGFR mutation in adenocarcinoma of esophagogastric junction has been reported so far as we known.	('carcinoma of esophagogastric junction', 'Disease', (34, 71))	('adenocarcinoma', 'Disease', 'MESH:D000230', (29, 43))	('mutation', 'Var', (17, 25))	('EGFR', 'Gene', '1956', (12, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('EGFR', 'Gene', (12, 16))	('carcinoma of esophagogastric junction', 'Disease', 'MESH:C537006', (34, 71))	('adenocarcinoma', 'Disease', (29, 43))
810457	22252115	In this study, we planned to extract DNA from cancer tissue and corresponding peripheral blood cell from patients with EGJ cancer, then perform DNA sequencing of EGFR-TK domain including exons 18, 19, 20 and 21 in order to assess the EGFR mutation in carcinoma cell initially and predict the therapeutic effect of small molecule inhibitor of gefitinib on EGJ cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('EGFR', 'Gene', (234, 238))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('EGFR', 'Gene', (162, 166))	('carcinoma', 'Disease', 'MESH:D002277', (251, 260))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (359, 365))	('EGFR', 'Gene', '1956', (234, 238))	('mutation', 'Var', (239, 247))	('patients', 'Species', '9606', (105, 113))	('EGJ cancer', 'Disease', 'MESH:D009369', (119, 129))	('cancer', 'Disease', (46, 52))	('EGFR', 'Gene', '1956', (162, 166))	('EGJ cancer', 'Disease', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('EGJ cancer', 'Disease', 'MESH:D009369', (355, 365))	('EGJ cancer', 'Disease', (355, 365))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('carcinoma', 'Disease', (251, 260))	('cancer', 'Disease', (123, 129))	('gefitinib', 'Chemical', 'MESH:D000077156', (342, 351))	('cancer', 'Disease', (359, 365))
810468	22252115	In exon 20, a variant from CAG to CAA at codon 787 (2361G-> A) was identified in 19 patients (29.2%) (Figure 1), which was a genomic variation of EGFR since it was found in both cancer tissue and white blood cells.	('2361G-> A', 'Mutation', 'rs1050171', (52, 61))	('EGFR', 'Gene', '1956', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (84, 92))	('2361G-> A', 'Var', (52, 61))	('EGFR', 'Gene', (146, 150))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('CAG to CAA at codon 787', 'Mutation', 'c.787CAG>CAA', (27, 50))
810469	22252115	The discovered EGFR variant in exon 20 was a synonymous mutation because CAA and CAG were encoding the same amino-acid of Glutamine (Q787Q).	('Glutamine', 'Chemical', 'MESH:D005973', (122, 131))	('Q787Q', 'Mutation', 'rs1050171', (133, 138))	('CAA and CAG', 'Gene', '10194', (73, 84))	('Q787Q', 'Var', (133, 138))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))
810471	22252115	Take L858R as example, which is a frequent EGFR mutation in NSCLC where leucine (L) is substituted by arginine (R) at the locus.	('L858R', 'Mutation', 'rs121434568', (5, 10))	('leucine', 'Chemical', 'MESH:D007930', (72, 79))	('arginine', 'Chemical', 'MESH:D001120', (102, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('EGFR', 'Gene', '1956', (43, 47))	('L858R', 'Var', (5, 10))	('NSCLC', 'Disease', (60, 65))	('EGFR', 'Gene', (43, 47))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
810473	22252115	This hypothesis may explain the sensitivity to gefitinib of the patients with EGFR L858R mutation.	('patients', 'Species', '9606', (64, 72))	('L858R', 'Var', (83, 88))	('L858R', 'Mutation', 'rs121434568', (83, 88))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('gefitinib', 'Chemical', 'MESH:D000077156', (47, 56))
810474	22252115	From this concern, if similar mutation exists in carcinoma of esophagogastric junction, the TKI therapy to carcinoma of esophagogastric junction will be promising.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinoma of esophagogastric junction', 'Disease', 'MESH:C537006', (107, 144))	('carcinoma of esophagogastric junction', 'Disease', (49, 86))	('carcinoma of esophagogastric junction', 'Disease', (107, 144))	('mutation', 'Var', (30, 38))	('carcinoma of esophagogastric junction', 'Disease', 'MESH:C537006', (49, 86))
810475	22252115	In our study, carcinoma of esophagogastric junction rarely presents EGFR mutations, especially gefitinib-associated mutations such as L858R and delE746-A750.	('carcinoma of esophagogastric junction', 'Disease', (14, 51))	('delE746-A750', 'Var', (144, 156))	('L858R', 'Mutation', 'rs121434568', (134, 139))	('EGFR', 'Gene', '1956', (68, 72))	('delE746', 'Mutation', 'p.746delE', (144, 151))	('gefitinib', 'Chemical', 'MESH:D000077156', (95, 104))	('carcinoma of esophagogastric junction', 'Disease', 'MESH:C537006', (14, 51))	('EGFR', 'Gene', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('L858R', 'Var', (134, 139))
810479	22252115	In exons 19 and 21 of EGFR, just K754K was found without other mutation identified.	('K754K', 'Mutation', 'p.K754K', (33, 38))	('K754K', 'Var', (33, 38))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
810480	22252115	It was concluded that mutations within the tyrosine kinase domain of EGFR associated with sensitivity of NSCLC patients to gefitinib were not present in Barrett's adenocarcinoma.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('EGFR', 'Gene', '1956', (69, 73))	('gefitinib', 'Chemical', 'MESH:D000077156', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	("Barrett's adenocarcinoma", 'Disease', (153, 177))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('EGFR', 'Gene', (69, 73))	('mutations', 'Var', (22, 31))	('NSCLC', 'Disease', (105, 110))	("Barrett's adenocarcinoma", 'Disease', 'MESH:D001471', (153, 177))	('associated', 'Reg', (74, 84))	('patients', 'Species', '9606', (111, 119))
810482	22252115	A meta-analysis showed that the incidence of EGFR mutations in NSCLC varied according to cigarette-smoking history.	('NSCLC', 'Disease', (63, 68))	('EGFR', 'Gene', (45, 49))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('mutations', 'Var', (50, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('EGFR', 'Gene', '1956', (45, 49))
810483	22252115	The detected EGFR mutations in exons 18, 19, and 21 of the patients with lung cancer were 48.6% in never smokers, 33.9% in former smokers, and 16.6% in current smokers.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('patients', 'Species', '9606', (59, 67))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
810485	22252115	The presence of EGFR exon 19 deletions and L858R in patients with lung adenocarcinoma were found in 15% from former smokers, 6% from current smokers and 52% from never smokers.	('lung adenocarcinoma', 'Disease', (66, 85))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (66, 85))	('L858R', 'Mutation', 'rs121434568', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('EGFR', 'Gene', '1956', (16, 20))	('L858R', 'Var', (43, 48))	('EGFR', 'Gene', (16, 20))	('patients', 'Species', '9606', (52, 60))
810486	22252115	However, there was little report on the correlation between smoking history and EGFR mutation in gastrointestinal carcinoma.	('gastrointestinal carcinoma', 'Disease', (97, 123))	('gastrointestinal carcinoma', 'Phenotype', 'HP:0002672', (97, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('EGFR', 'Gene', '1956', (80, 84))	('mutation', 'Var', (85, 93))	('EGFR', 'Gene', (80, 84))	('gastrointestinal carcinoma', 'Disease', 'MESH:D004067', (97, 123))
810488	22252115	The correlation between smoking history and EGFR mutation in adenocarcinoma of EGJ was not definitely clear here and needs further investigation.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('adenocarcinoma', 'Disease', 'MESH:D000230', (61, 75))	('mutation', 'Var', (49, 57))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('adenocarcinoma', 'Disease', (61, 75))
810491	22252115	A SNP in which both forms lead to the same polypeptide sequence is termed synonymous, as is the case of Q787Q in our study.	('polypeptide sequence', 'MPA', (43, 63))	('Q787Q', 'Mutation', 'rs1050171', (104, 109))	('lead to', 'Reg', (26, 33))	('Q787Q', 'Var', (104, 109))
810492	22252115	Previous studies on EGF gene were carried out and concluded that the SNP of EGF +61 G/A polymorphism was associated with ESCC in a Chinese population and the variant genotypes of GA/AA were associated with a significantly decreased risk of ESCC compared with the wild-type homozygote GG.	('EGF', 'Gene', '1950', (76, 79))	('variant', 'Var', (158, 165))	('+61 G/A', 'Mutation', 'rs4444903', (80, 87))	('EGF', 'Gene', '1950', (20, 23))	('EGF', 'Gene', (20, 23))	('ESCC', 'Disease', (240, 244))	('associated', 'Reg', (105, 115))	('polymorphism', 'Var', (88, 100))	('EGF', 'Gene', (76, 79))	('ESCC', 'Disease', (121, 125))	('decreased', 'NegReg', (222, 231))
810493	22252115	Other investigation suggested no association between EGF gene polymorphism and gastric cancer.	('EGF', 'Gene', (53, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('polymorphism', 'Var', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('EGF', 'Gene', '1950', (53, 56))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
810494	22252115	Choi and co-workers screened several EGFR SNPs in lung cancer cell and five SNPs were identified including 127378C > T, 142285G > A, 162093G > A, 181946C > T and 187114T > C. Meanwhile the SNP of 181946C > T was found be associated with the incidence of lung cancer.	('127378C > T', 'Var', (107, 118))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('lung cancer', 'Disease', (254, 265))	('127378C > T', 'Mutation', 'g.127378C>T', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('142285G > A', 'Mutation', 'g.142285G>A', (120, 131))	('181946C > T', 'Mutation', 'g.181946C>T', (196, 207))	('181946C > T', 'Var', (146, 157))	('EGFR', 'Gene', '1956', (37, 41))	('associated', 'Reg', (221, 231))	('lung cancer', 'Disease', 'MESH:D008175', (254, 265))	('142285G > A', 'Var', (120, 131))	('187114T > C', 'Mutation', 'g.187114T>C', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('187114T > C. Meanwhile', 'Var', (162, 184))	('181946C > T', 'Mutation', 'g.181946C>T', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('lung cancer', 'Disease', (50, 61))	('162093G > A', 'Mutation', 'g.162093G>A', (133, 144))	('162093G > A', 'Var', (133, 144))	('EGFR', 'Gene', (37, 41))
810496	22252115	Kaneko et al reported the same SNP discovery of Q787Q with the rate of 33% in the esophageal squamous cell carcinoma cell, and a significant difference was seen in the overall survival between patients with and without the EGFR heterozygous genotype in their study.	('Q787Q', 'Var', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('patients', 'Species', '9606', (193, 201))	('EGFR', 'Gene', '1956', (223, 227))	('esophageal squamous cell carcinoma cell', 'Disease', (82, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('EGFR', 'Gene', (223, 227))	('esophageal squamous cell carcinoma cell', 'Disease', 'MESH:D000077277', (82, 121))	('Q787Q', 'Mutation', 'rs1050171', (48, 53))
810497	22252115	Could this SNP of Q787Q be a clinically useful biomarker for predicting the prognosis of ESCC or EGJ cancer patients?	('EGJ cancer', 'Disease', 'MESH:D009369', (97, 107))	('Q787Q', 'Var', (18, 23))	('EGJ cancer', 'Disease', (97, 107))	('ESCC', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Q787Q', 'Mutation', 'rs1050171', (18, 23))	('patients', 'Species', '9606', (108, 116))
810500	22252115	EGFR: epidermal growth factor receptor; FDA: Food and Drug Administration SNP: single nucleotide polymorphism; NSCLC: non-small cell lung cancer; EGJ: esophagogastric junction; ESCC: esophageal squamous cell carcinoma.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('EGFR', 'Gene', (0, 4))	('epidermal growth factor receptor', 'Gene', (6, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('NSCLC', 'Disease', (111, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('non-small cell lung cancer', 'Disease', (118, 144))	('single nucleotide polymorphism', 'Var', (79, 109))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (183, 217))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('epidermal growth factor receptor', 'Gene', '1956', (6, 38))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('esophageal squamous cell carcinoma', 'Disease', (183, 217))	('EGFR', 'Gene', '1956', (0, 4))
810594	31651875	One researcher proposed a combination of immunohistochemistry and PCR to detect mutations in the P53 gene.	('P53', 'Gene', '7157', (97, 100))	('P53', 'Gene', (97, 100))	('mutations', 'Var', (80, 89))
810621	31034571	The assessment of immune function in tumor patients is mainly based on parameters concerning the T lymphocyte subsets and NK cells, including the percentages of CD3+, CD4+, and CD8+ T cells and NK cells and the ratio of CD4+/CD8+.	('CD4', 'Gene', '920', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('CD8', 'Gene', '925', (225, 228))	('CD4', 'Gene', (220, 223))	('CD4', 'Gene', '920', (220, 223))	('patients', 'Species', '9606', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('CD3+', 'Var', (161, 165))	('CD8', 'Gene', (177, 180))	('CD8', 'Gene', (225, 228))	('CD8', 'Gene', '925', (177, 180))	('CD4', 'Gene', (167, 170))
810643	31034571	Three months after radiotherapy, if the percentages of CD3+, CD4+, and CD8+ T cells and NK cells were measured as within the normal range, a good recovery of immune function was deemed to have occurred; otherwise, the recovery was considered to have been poor.	('CD4', 'Gene', '920', (61, 64))	('CD8', 'Gene', '925', (71, 74))	('immune function', 'MPA', (158, 173))	('recovery of immune function', 'Phenotype', 'HP:0002721', (146, 173))	('CD3+', 'Var', (55, 59))	('CD4', 'Gene', (61, 64))	('CD8', 'Gene', (71, 74))
810651	31034571	At various stages after radiotherapy, the percentages of CD3+, CD4+, and CD8+ T cells and NK cells and the CD4+/CD8+ ratio showed a dynamic variation.	('CD8', 'Gene', (112, 115))	('CD4', 'Gene', (63, 66))	('CD4', 'Gene', (107, 110))	('CD3+', 'Var', (57, 61))	('CD4', 'Gene', '920', (63, 66))	('CD8', 'Gene', '925', (112, 115))	('CD4', 'Gene', '920', (107, 110))	('CD8', 'Gene', (73, 76))	('CD8', 'Gene', '925', (73, 76))
810658	31034571	Our results showed that the immune parameters (including percentages of CD3+ and CD4+ T cells and NK cells, and the CD4+/CD8+ ratio) were dramatically decreased at the end of radiotherapy in the >300 cm3 group, whereas the percentage of CD8+ T cells statistically increased, as shown in Fig.	('CD4', 'Gene', '920', (116, 119))	('CD3+', 'CPA', (72, 76))	('CD8', 'Gene', (237, 240))	('decreased', 'NegReg', (151, 160))	('CD4', 'Gene', (81, 84))	('CD8', 'Gene', '925', (237, 240))	('>300 cm3', 'Var', (195, 203))	('CD8', 'Gene', (121, 124))	('CD8', 'Gene', '925', (121, 124))	('CD4', 'Gene', '920', (81, 84))	('immune parameters', 'MPA', (28, 45))	('CD4', 'Gene', (116, 119))
810686	31034571	Our study also showed dynamic changes in the percentages of CD3+, CD4+ and CD8+ T cells and NK cells and in the ratio of CD4+ and CD8+ in peripheral blood of esophageal cancer patients at different stages after radiotherapy.	('patients', 'Species', '9606', (176, 184))	('CD4', 'Gene', (66, 69))	('CD8', 'Gene', '925', (75, 78))	('CD8', 'Gene', (130, 133))	('CD4', 'Gene', (121, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('CD3+', 'Var', (60, 64))	('CD4', 'Gene', '920', (66, 69))	('CD8', 'Gene', '925', (130, 133))	('CD4', 'Gene', '920', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('CD8', 'Gene', (75, 78))	('esophageal cancer', 'Disease', (158, 175))
810689	31034571	The presence of numerous inflammatory factors in the tumor microenvironment causes vascular dilatation, amplifies the inflammatory response, promotes the growth and metastasis of tumor cells, and stimulates the production of blood vessels and lymphatic vessels.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('dilatation', 'Phenotype', 'HP:0002617', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('amplifies', 'PosReg', (104, 113))	('inflammatory response', 'CPA', (118, 139))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('stimulates', 'PosReg', (196, 206))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('causes', 'Reg', (76, 82))	('tumor', 'Disease', (53, 58))	('presence', 'Var', (4, 12))	('vascular dilatation', 'CPA', (83, 102))	('promotes', 'PosReg', (141, 149))	('growth', 'CPA', (154, 160))	('tumor', 'Disease', (179, 184))
810707	31034571	On the other hand, radiotherapy indirectly enhances the immune response of patients through activating an inflammatory reaction.	('immune response', 'CPA', (56, 71))	('inflammatory reaction', 'CPA', (106, 127))	('radiotherapy', 'Var', (19, 31))	('enhances', 'PosReg', (43, 51))	('patients', 'Species', '9606', (75, 83))	('activating', 'Reg', (92, 102))
810712	29669094	Our data revealed significant cytotoxicity of OH-GQDs which decreased the viability of HET-1A in a dose and time-dependent manner.	('decreased', 'NegReg', (60, 69))	('cytotoxicity', 'Disease', (30, 42))	('OH-GQDs', 'Var', (46, 53))	('cytotoxicity', 'Disease', 'MESH:D064420', (30, 42))	('viability', 'CPA', (74, 83))	('OH-GQDs', 'Chemical', '-', (46, 53))
810716	29669094	Consistent with the microarray data, OH-GQDs disrupted microtubule structure and inhibited microtubule regrowth around centrosomes in HET-1A cells.	('OH-GQDs', 'Chemical', '-', (37, 44))	('inhibited', 'NegReg', (81, 90))	('microtubule regrowth around centrosomes', 'MPA', (91, 130))	('disrupted', 'NegReg', (45, 54))	('OH-GQDs', 'Var', (37, 44))	('microtubule structure', 'MPA', (55, 76))
810720	29669094	One study showed that GQDs-doxorubicin (Dox) conjugates enhanced the nuclear uptake and DNA cleavage efficiency of Dox and another by) proved that PEGylated GQDs had higher loading capacity and released Dox in a pH-responsive manner.	('higher', 'PosReg', (166, 172))	('Dox', 'Chemical', '-', (203, 206))	('GQDs', 'Chemical', '-', (22, 26))	('loading capacity', 'MPA', (173, 189))	('nuclear uptake', 'CPA', (69, 83))	('GQDs', 'Chemical', '-', (157, 161))	('PEGylated', 'Var', (147, 156))	('Dox', 'Chemical', '-', (115, 118))	('DNA cleavage efficiency', 'CPA', (88, 111))	('enhanced', 'PosReg', (56, 64))	('doxorubicin', 'Chemical', 'MESH:D004317', (27, 38))	('Dox', 'Chemical', '-', (40, 43))	('released Dox', 'MPA', (194, 206))
810721	29669094	Modifying GQDs with specific ligands can increase tumor cells targeted drug delivery.	('GQDs', 'Chemical', '-', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('increase', 'PosReg', (41, 49))	('tumor', 'Disease', (50, 55))	('Modifying', 'Var', (0, 9))
810729	29669094	Although many of these studies indicate good biocompatibility of the GQDs, we and several other groups demonstrated that raw and modified GQDs exhibit obvious cytotoxicity in certain biosystems.	('cytotoxicity', 'Disease', 'MESH:D064420', (159, 171))	('modified', 'Var', (129, 137))	('GQDs', 'Chemical', '-', (138, 142))	('GQDs', 'Chemical', '-', (69, 73))	('cytotoxicity', 'Disease', (159, 171))
810730	29669094	For instance,) showed that GQDs can induce the generation of reactive oxygen species (ROS) and stimulate the expression of several DNA damage response proteins (p53, Rad51, and OGG1) in NIH3T3 cells.	('expression', 'MPA', (109, 119))	('OGG1', 'Gene', '18294', (177, 181))	('stimulate', 'PosReg', (95, 104))	('Rad51', 'Gene', (166, 171))	('OGG1', 'Gene', (177, 181))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (61, 84))	('GQDs', 'Chemical', '-', (27, 31))	('ROS', 'Chemical', 'MESH:D017382', (86, 89))	('NIH3T3', 'CellLine', 'CVCL:0594', (186, 192))	('GQDs', 'Var', (27, 31))	('generation of reactive oxygen species', 'MPA', (47, 84))	('p53', 'Gene', (161, 164))
810731	29669094	Using macrophages as a model, it has also been shown that GQDs promote intracellular ROS generation and activate apoptosis and autophagy signal pathways.	('GQDs', 'Var', (58, 62))	('apoptosis', 'CPA', (113, 122))	('intracellular ROS generation', 'MPA', (71, 99))	('activate', 'PosReg', (104, 112))	('GQDs', 'Chemical', '-', (58, 62))	('promote', 'PosReg', (63, 70))	('autophagy signal pathways', 'CPA', (127, 152))	('ROS', 'Chemical', 'MESH:D017382', (85, 88))
810737	29669094	We found that OH-GQDs significantly inhibited the viability of human esophageal epithelial HET-1A cells.	('OH-GQDs', 'Chemical', '-', (14, 21))	('OH-GQDs', 'Var', (14, 21))	('human', 'Species', '9606', (63, 68))	('inhibited', 'NegReg', (36, 45))
810738	29669094	OH-GQDs blocked cell cycle progression at G0/G1 phase and induced a dose-dependent increase in DNA damage signals.	('increase', 'PosReg', (83, 91))	('blocked', 'NegReg', (8, 15))	('DNA damage signals', 'MPA', (95, 113))	('cell cycle progression at G0/G1 phase', 'CPA', (16, 53))	('OH-GQDs', 'Chemical', '-', (0, 7))	('OH-GQDs', 'Var', (0, 7))
810740	29669094	To further clarify the potential biological mechanism of OH-GQDs' genotoxicity, mRNA microarray was performed on control and OH-GQDs-treated HET-1A cells which revealed that OH-GQDs treatment altered the gene expression profile related to DNA damage repair and cell cycle regulation pathways.	('cell cycle regulation pathways', 'Pathway', (261, 291))	('OH-GQDs', 'Chemical', '-', (125, 132))	('OH-GQDs', 'Chemical', '-', (57, 64))	("OH-GQDs' genotoxicity", 'Disease', 'MESH:C566945', (57, 78))	('gene expression profile', 'MPA', (204, 227))	('OH-GQDs', 'Chemical', '-', (174, 181))	("OH-GQDs' genotoxicity", 'Disease', (57, 78))	('altered', 'Reg', (192, 199))	('OH-GQDs', 'Var', (174, 181))
810741	29669094	More interestingly, we discovered that cytoskeleton-related genes were downregulated by OH-GQDs.	('cytoskeleton-related genes', 'Gene', (39, 65))	('downregulated', 'NegReg', (71, 84))	('OH-GQDs', 'Var', (88, 95))	('OH-GQDs', 'Chemical', '-', (88, 95))
810742	29669094	Consistent with these results, OH-GQDs disrupted microtubule structure and inhibited microtubule regrowth in HET-1A cells.	('disrupted', 'NegReg', (39, 48))	('OH-GQDs', 'Var', (31, 38))	('microtubule regrowth', 'MPA', (85, 105))	('inhibited', 'NegReg', (75, 84))	('OH-GQDs', 'Chemical', '-', (31, 38))	('microtubule structure', 'MPA', (49, 70))
810788	29669094	A significantly increased SSC signal was detected in OH-GQDs-treated cells when compared with control cells, indicating that OH-GQDs entered into cells efficiently.	('OH-GQDs', 'Chemical', '-', (53, 60))	('increased SSC signal', 'Phenotype', 'HP:0002922', (16, 36))	('SSC signal', 'MPA', (26, 36))	('OH-GQDs-treated', 'Var', (53, 68))	('increased', 'PosReg', (16, 25))	('OH-GQDs', 'Chemical', '-', (125, 132))
810790	29669094	The HET-1A cells were exposed to different concentrations (25-200 microg/ml) of OH-GQDs for 24 and 48 h. As shown in Figures 2A and 2B, OH-GQDs significantly reduced the cell proliferation in a dose- and time-dependent manner.	('OH-GQDs', 'Chemical', '-', (136, 143))	('OH-GQDs', 'Chemical', '-', (80, 87))	('cell proliferation', 'CPA', (170, 188))	('OH-GQDs', 'Var', (136, 143))	('reduced', 'NegReg', (158, 165))
810791	29669094	When compared with the untreated group, the viability of HET-1A cells was decreased to 13% and 2% after treated with 100 and 200 microg/ml OH-GQDs respectively for 24 h (Figure 2A).	('OH-GQDs', 'Chemical', '-', (139, 146))	('decreased', 'NegReg', (74, 83))	('OH-GQDs', 'Var', (139, 146))
810793	29669094	We also found that OH-GQDs exhibited obvious cellular toxicity on normal human hepatic cells LO2, human small intestine epithelium cells HIEC-6 and human esophageal cancer cells ECA-109 (Supplementary Figures.	('OH-GQDs', 'Chemical', '-', (19, 26))	('toxicity', 'Disease', (54, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('HIEC-6', 'CellLine', 'CVCL:6C21', (137, 143))	('human', 'Species', '9606', (148, 153))	('human', 'Species', '9606', (73, 78))	('human', 'Species', '9606', (98, 103))	('OH-GQDs', 'Var', (19, 26))	('toxicity', 'Disease', 'MESH:D064420', (54, 62))	('esophageal cancer', 'Disease', (154, 171))
810795	29669094	The HET-1A cells were incubated with 25 and 50 microg/ml OH-GQDs for 24 and 48 h. As shown in Figures 2C and 2D, OH-GQDs significantly induced G0/G1 phase arrest in HET-1A cells.	('OH-GQDs', 'Chemical', '-', (57, 64))	('OH-GQDs', 'Chemical', '-', (113, 120))	('induced', 'Reg', (135, 142))	('OH-GQDs', 'Var', (113, 120))	('G0/G1 phase arrest', 'CPA', (143, 161))
810796	29669094	The percentage of cells blocked in G0/G1 phase increased from 57.2% in the untreated group to 68.78% and 80.83% in the groups treated with 25 and 50 microg/ml OH-GQDs for 24 h, respectively.	('OH-GQDs', 'Var', (159, 166))	('OH-GQDs', 'Chemical', '-', (159, 166))	('G0/G1 phase', 'CPA', (35, 46))
810797	29669094	The percentage of G0/G1 arrested cells increased from 57.7% in control group to 82.02% and 89.16% in the groups treated with 25 and 50 microg/ml OH-GQDs for 48 h, respectively.	('OH-GQDs', 'Chemical', '-', (145, 152))	('increased', 'PosReg', (39, 48))	('OH-GQDs', 'Var', (145, 152))	('G0/G1 arrested cells', 'CPA', (18, 38))
810798	29669094	However, the Annexin V-FITC-staining assays revealed that OH-GQDs significantly induced apoptosis only at the high OH-GQDs dose (100 microg/ml) but not at moderate dose (25 and 50 microg/ml) in HET-1A cells (Supplementary Figure 3).	('apoptosis', 'CPA', (88, 97))	('induced', 'Reg', (80, 87))	('Annexin V', 'Gene', '308', (13, 22))	('Annexin V', 'Gene', (13, 22))	('OH-GQDs', 'Var', (115, 122))	('OH-GQDs', 'Chemical', '-', (58, 65))	('FITC', 'Chemical', 'MESH:D016650', (23, 27))	('OH-GQDs', 'Var', (58, 65))	('OH-GQDs', 'Chemical', '-', (115, 122))
810799	29669094	Our previous data demonstrated that OH-GQDs activated the p53 signaling pathway in the human nonsmall cell lung cancer cell line A549.	('OH-GQDs', 'Chemical', '-', (36, 43))	('nonsmall cell lung cancer', 'Disease', (93, 118))	('p53 signaling pathway', 'Pathway', (58, 79))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (93, 118))	('human', 'Species', '9606', (87, 92))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (93, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('activated', 'PosReg', (44, 53))	('OH-GQDs', 'Var', (36, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('A549', 'CellLine', 'CVCL:0023', (129, 133))
810804	29669094	The results showed that the percentage of gamma-H2AX positive cells increased from 16% to 53%, 58% and 73% following treatment with 25, 50, and 100 microg/ml OH-GQDs, respectively (Figure 3B).	('OH-GQDs', 'Chemical', '-', (158, 165))	('OH-GQDs', 'Var', (158, 165))	('gamma-H2AX', 'Gene', (42, 52))	('increased', 'PosReg', (68, 77))	('gamma-H2AX', 'Gene', '3014', (42, 52))
810808	29669094	Although the frequency of micronucleus increased from 11% to 19%, OH-GQDs did not induce the generation of nucleoplasmic bridges and nuclear buds in HET-1A cells.	('micronucleus', 'CPA', (26, 38))	('OH-GQDs', 'Var', (66, 73))	('OH-GQDs', 'Chemical', '-', (66, 73))
810810	29669094	Consistent with this, we observed that OH-GQDs dramatically promote the generation of ROS in HET-1A cells in a dose- and time-dependent manner (Supplementary Figure 4).	('generation', 'MPA', (72, 82))	('promote', 'PosReg', (60, 67))	('OH-GQDs', 'Chemical', '-', (39, 46))	('ROS', 'Chemical', 'MESH:D017382', (86, 89))	('OH-GQDs', 'Var', (39, 46))	('ROS', 'MPA', (86, 89))
810811	29669094	To understand the potential molecular mechanism through which OH-GQDs disrupted cell cycle progression and induced DNA damage, the gene expression profiles of OH-GQDs-treated and -untreated HET-1A cells were evaluated and compared using microarray.	('DNA damage', 'MPA', (115, 125))	('cell cycle progression', 'CPA', (80, 102))	('induced', 'Reg', (107, 114))	('disrupted', 'NegReg', (70, 79))	('OH-GQDs', 'Chemical', '-', (62, 69))	('OH-GQDs', 'Chemical', '-', (159, 166))	('OH-GQDs', 'Var', (62, 69))
810813	29669094	The data revealed that 8151 genes had a 2-fold or higher change in expression level in the OH-GQDs-treated compared with the untreated cells.	('higher', 'PosReg', (50, 56))	('expression level', 'MPA', (67, 83))	('OH-GQDs-treated', 'Var', (91, 106))	('change', 'Reg', (57, 63))	('OH-GQDs', 'Chemical', '-', (91, 98))
810817	29669094	Our data revealed that OH-GQDs decreased the expression of a number of genes in FA and HR pathways, including the essential factor FANCD2 (Figures.	('HR pathways', 'Pathway', (87, 98))	('OH-GQDs', 'Chemical', '-', (23, 30))	('FANCD2', 'Gene', '2177', (131, 137))	('FANCD2', 'Gene', (131, 137))	('decreased', 'NegReg', (31, 40))	('expression', 'MPA', (45, 55))	('OH-GQDs', 'Var', (23, 30))
810820	29669094	In addition, OH-GQDs also suppressed the expression of DNA-PKcs and ATM in both normal esophageal epithelial cells HET-1A (Figure 6C) and esophageal cancer cells ECA-109 (Supplementary Figure 5B), which are key regulators of DNA double-strand breaks (DSBs) repair pathway.	('DNA-PKcs', 'Gene', (55, 63))	('esophageal cancer', 'Disease', (138, 155))	('suppressed', 'NegReg', (26, 36))	('expression', 'MPA', (41, 51))	('DNA-PKcs', 'Gene', '5591', (55, 63))	('OH-GQDs', 'Chemical', '-', (13, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('ATM', 'Gene', (68, 71))	('ATM', 'Gene', '472', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('OH-GQDs', 'Var', (13, 20))
810821	29669094	Our study revealed that OH-GQDs lead to cell cycle arrest, consistent with altered expression patterns of many cell cycle-related genes in response to OH-GQDs treatment (Figure 6D) which was also validated by Western blotting data (Figure 6E).	('cell cycle arrest', 'CPA', (40, 57))	('expression patterns', 'MPA', (83, 102))	('OH-GQDs', 'Var', (24, 31))	('cell cycle-related genes', 'Gene', (111, 135))	('OH-GQDs', 'Chemical', '-', (151, 158))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (40, 57))	('OH-GQDs', 'Chemical', '-', (24, 31))	('altered', 'Reg', (75, 82))	('OH-GQDs', 'Var', (151, 158))
810822	29669094	Microarray data revealed that OH-GQDs inhibited the expression of MAPs genes (Figure 7A).	('OH-GQDs', 'Chemical', '-', (30, 37))	('MAPs genes', 'Gene', (66, 76))	('inhibited', 'NegReg', (38, 47))	('expression', 'MPA', (52, 62))	('OH-GQDs', 'Var', (30, 37))
810827	29669094	The area of the nucleated microtubules around centrosomes was analyzed in OH-GQDs treated and control cells which showed that microtubule growth was significantly slowed down in the OH-GQDs-treated cells (Figures.	('OH-GQDs', 'Chemical', '-', (74, 81))	('microtubule growth', 'MPA', (126, 144))	('OH-GQDs', 'Chemical', '-', (182, 189))	('slowed down', 'NegReg', (163, 174))	('OH-GQDs-treated', 'Var', (182, 197))
810830	29669094	Our current work showed that OH-GQDs significantly increased the phosphorylation of H2AX at its Ser139 and increased the number of micronucleus in the human esophageal epithelial cell line HET-1A (Figures.	('OH-GQDs', 'Chemical', '-', (29, 36))	('increased', 'PosReg', (51, 60))	('increased', 'PosReg', (107, 116))	('micronucleus', 'CPA', (131, 143))	('human', 'Species', '9606', (151, 156))	('H2AX', 'Gene', '3014', (84, 88))	('H2AX', 'Gene', (84, 88))	('phosphorylation', 'MPA', (65, 80))	('OH-GQDs', 'Var', (29, 36))	('Ser139', 'Chemical', '-', (96, 102))
810839	29669094	However, our study showed that the mRNA levels of several DNA repair genes, such as ATM and DNA-PKcs, were dramatically down-regulated in OH-GQDs-treated cells (Figure 6C).	('mRNA levels', 'MPA', (35, 46))	('down-regulated', 'NegReg', (120, 134))	('ATM', 'Gene', (84, 87))	('DNA-PKcs', 'Gene', '5591', (92, 100))	('OH-GQDs-treated', 'Var', (138, 153))	('DNA repair genes', 'Gene', (58, 74))	('OH-GQDs', 'Chemical', '-', (138, 145))	('ATM', 'Gene', '472', (84, 87))	('DNA-PKcs', 'Gene', (92, 100))
810843	29669094	Therefore, it will be interesting to further determine whether OH-GQDs trigger ER stress and inhibit DNA repair genes expression via E2F1 in the next study (Figure 7E).	('trigger', 'Reg', (71, 78))	('inhibit', 'NegReg', (93, 100))	('ER stress', 'MPA', (79, 88))	('OH-GQDs', 'Var', (63, 70))	('E2F1', 'Gene', '1869', (133, 137))	('E2F1', 'Gene', (133, 137))	('OH-GQDs', 'Chemical', '-', (63, 70))	('DNA repair genes', 'Gene', (101, 117))	('expression', 'MPA', (118, 128))
810844	29669094	OH-GQDs also inhibited the expression of several genes involved in the FA pathway which plays a central role in repairing DNA ICLs and maintaining genome stability.	('OH-GQDs', 'Chemical', '-', (0, 7))	('inhibited', 'NegReg', (13, 22))	('expression', 'MPA', (27, 37))	('genome', 'MPA', (147, 153))	('OH-GQDs', 'Var', (0, 7))
810846	29669094	A germline mutation in any one of these genes leads to the FA syndrome, a rare human genetic disease that causes bone marrow failure and results in a high incidence of tumorigenesis.	('genetic disease', 'Disease', 'MESH:D030342', (85, 100))	('human', 'Species', '9606', (79, 84))	('genetic disease', 'Disease', (85, 100))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('germline mutation', 'Var', (2, 19))	('bone marrow failure', 'Phenotype', 'HP:0005528', (113, 132))	('FA syndrome', 'Disease', (59, 70))	('FA syndrome', 'Disease', 'MESH:C565561', (59, 70))	('leads to', 'Reg', (46, 54))	('bone marrow failure', 'Disease', (113, 132))	('bone marrow failure', 'Disease', 'MESH:D000080983', (113, 132))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
810848	29669094	In addition, the expression of genes related to HR, mismatch repair and base excision repair was also significantly decreased in response to OH-GQDs treatment.	('base', 'MPA', (72, 76))	('OH-GQDs', 'Var', (141, 148))	('expression', 'MPA', (17, 27))	('OH-GQDs', 'Chemical', '-', (141, 148))	('decreased', 'NegReg', (116, 125))
810851	29669094	Consistent with this, we observed that OH-GQDs dramatically induced DNA damage and increased the genomic instability in HET-1A cells.	('OH-GQDs', 'Chemical', '-', (39, 46))	('increased', 'PosReg', (83, 92))	('induced', 'Reg', (60, 67))	('genomic instability', 'CPA', (97, 116))	('DNA damage', 'MPA', (68, 78))	('OH-GQDs', 'Var', (39, 46))
810854	29669094	Here, our data indicated that OH-GQDs have the potential risk to contribute to esophageal carcinogenesis via inducing DNA damage and increasing genomic instability in human esophageal epithelial cells.	('OH-GQDs', 'Chemical', '-', (30, 37))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (79, 104))	('DNA damage', 'MPA', (118, 128))	('esophageal carcinogenesis', 'Disease', (79, 104))	('increasing', 'PosReg', (133, 143))	('genomic', 'MPA', (144, 151))	('OH-GQDs', 'Var', (30, 37))	('inducing', 'Reg', (109, 117))	('human', 'Species', '9606', (167, 172))	('contribute', 'Reg', (65, 75))
810855	29669094	However, although the genotoxicity of OH-GQDs limits its general biomedical application, it can actually prove to be advantageous in cancer therapy.	('OH-GQDs', 'Var', (38, 45))	('advantageous', 'PosReg', (117, 129))	('toxicity', 'Disease', 'MESH:D064420', (26, 34))	('toxicity', 'Disease', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('OH-GQDs', 'Chemical', '-', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
810859	29669094	We found that several cyclins and CDKs were down-regulated in OH-GQDs-treated cells, which was consistent with the G0/G1 cell cycle arrest induced by OH-GQDs.	('OH-GQDs', 'Chemical', '-', (150, 157))	('cyclins', 'Gene', (22, 29))	('down-regulated', 'NegReg', (44, 58))	('G0/G1 cell cycle arrest', 'CPA', (115, 138))	('OH-GQDs', 'Chemical', '-', (62, 69))	('cyclins', 'Gene', '891', (22, 29))	('CDKs', 'Protein', (34, 38))	('OH-GQDs-treated', 'Var', (62, 77))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))
810860	29669094	In addition, our data also revealed that OH-GQDs inhibited expression of many tubulin and MAPs genes.	('OH-GQDs', 'Var', (41, 48))	('MAPs genes', 'Gene', (90, 100))	('tubulin', 'Protein', (78, 85))	('expression', 'MPA', (59, 69))	('OH-GQDs', 'Chemical', '-', (41, 48))	('inhibited', 'NegReg', (49, 58))
810861	29669094	Our study showed that OH-GQDs prevented microtubules assembly and disrupted their structure within cells.	('OH-GQDs', 'Chemical', '-', (22, 29))	('structure within', 'MPA', (82, 98))	('prevented', 'NegReg', (30, 39))	('microtubules assembly', 'MPA', (40, 61))	('disrupted', 'NegReg', (66, 75))	('OH-GQDs', 'Var', (22, 29))
810862	29669094	For instance,) found that GO can directly interact with and disrupt intracellular actin filaments while reported that the nanoparticle C(60)(OH)(20) forms hydrogen bonds with tubulin heterodimer and inhibits microtubule polymerization.	('inhibits', 'NegReg', (199, 207))	('hydrogen bonds', 'MPA', (155, 169))	('interact', 'Interaction', (42, 50))	('tubulin heterodimer', 'Protein', (175, 194))	('C(60)(', 'Var', (135, 141))	('hydrogen', 'Chemical', 'MESH:D006859', (155, 163))	('microtubule polymerization', 'MPA', (208, 234))
810863	29669094	In this study, we only treated cells with OH-GQDs for very short time (only several minutes), but it is already enough to affect microtubule assembly speed.	('affect', 'Reg', (122, 128))	('microtubule assembly speed', 'MPA', (129, 155))	('OH-GQDs', 'Var', (42, 49))	('OH-GQDs', 'Chemical', '-', (42, 49))
810866	29669094	Therefore, the disruption of cytoskeleton system by OH-GQDs might further enhance their genotoxic effects via interfering with DNA repair proteins' transport in cells.	('OH-GQDs', 'Var', (52, 59))	('interfering', 'NegReg', (110, 121))	('genotoxic effects', 'CPA', (88, 105))	("DNA repair proteins' transport in cells", 'MPA', (127, 166))	('OH-GQDs', 'Chemical', '-', (52, 59))	('enhance', 'PosReg', (74, 81))
810867	29669094	In conclusion, we explored the biological effects of OH-GQDs in human esophageal epithelial cells and found that OH-GQDs can induce cell cycle arrest, DNA damage and increase genomic instability.	('human', 'Species', '9606', (64, 69))	('OH-GQDs', 'Chemical', '-', (53, 60))	('genomic instability', 'CPA', (175, 194))	('OH-GQDs', 'Chemical', '-', (113, 120))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (132, 149))	('increase', 'PosReg', (166, 174))	('cell cycle arrest', 'CPA', (132, 149))	('induce', 'PosReg', (125, 131))	('DNA damage', 'CPA', (151, 161))	('OH-GQDs', 'Var', (113, 120))
810868	29669094	Microarray analysis demonstrated that OH-GQDs inhibit the expression of genes associated with multiple signaling pathways such as DNA damage repair, cell cycle progression and cytoskeleton maintenance (Figure 7E).	('OH-GQDs', 'Var', (38, 45))	('inhibit', 'NegReg', (46, 53))	('expression', 'MPA', (58, 68))	('cell cycle progression', 'CPA', (149, 171))	('OH-GQDs', 'Chemical', '-', (38, 45))
810890	29547556	PEGPH20 in combination with nab-paclitaxel and gemcitabine significantly prolongs progression-free survival (PFS), as compared to nab-paclitaxel and gemcitabine (Table 1).	('gemcitabine', 'Chemical', 'MESH:C056507', (47, 58))	('nab', 'Chemical', '-', (28, 31))	('paclitaxel', 'Chemical', 'MESH:D017239', (32, 42))	('nab', 'Chemical', '-', (130, 133))	('PEGPH20', 'Var', (0, 7))	('gemcitabine', 'Chemical', 'MESH:C056507', (149, 160))	('paclitaxel', 'Chemical', 'MESH:D017239', (134, 144))	('progression-free survival', 'CPA', (82, 107))	('PEGPH20', 'Chemical', '-', (0, 7))	('prolongs', 'PosReg', (73, 81))
368716	29547556	Moreover, this study suggested that hyaluronic acid is a potential predictive biomarker of tumor response to PEGPH20.	('PEGPH20', 'Var', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('hyaluronic', 'MPA', (36, 46))	('PEGPH20', 'Chemical', '-', (109, 116))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (36, 51))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
810902	29547556	In a phase IIb study, 140 patients with metastatic pancreatic carcinoma were randomized to receive eryaspase (100 IU/kg on day 3 and day 17 of every 4-weeks cycle) in combination with either gemcitabine or FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin); versus chemotherapy alone (NCT02195180).	('FOLFOX', 'Chemical', '-', (206, 212))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (214, 228))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (51, 71))	('leucovorin', 'Chemical', 'MESH:D002955', (230, 240))	('patients', 'Species', '9606', (26, 34))	('gemcitabine', 'Chemical', 'MESH:C056507', (191, 202))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (246, 257))	('100 IU/kg', 'Var', (110, 119))	('pancreatic carcinoma', 'Disease', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
810906	29547556	Conceivably, patients with pancreatic carcinoma with high expression level of HA may benefit from addition of PEGPH20 to either nab-paclitaxel/gemcitabine or FOLFIRINOX.	('PEGPH20', 'Chemical', '-', (110, 117))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (27, 47))	('gemcitabine', 'Chemical', 'MESH:C056507', (143, 154))	('benefit', 'PosReg', (85, 92))	('patients', 'Species', '9606', (13, 21))	('paclitaxel', 'Chemical', 'MESH:D017239', (132, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (158, 168))	('PEGPH20', 'Var', (110, 117))	('pancreatic carcinoma', 'Disease', (27, 47))	('nab', 'Chemical', '-', (128, 131))
810917	29547556	Results of this study showed that, as compared to either ECF or ECX, FLOT significantly prolonged PFS and OS, associated with lower rate of disease progression, and increased rate of complete resection of tumors (Table 3).	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('lower', 'NegReg', (126, 131))	('EC', 'Phenotype', 'HP:0011459', (57, 59))	('EC', 'Phenotype', 'HP:0011459', (64, 66))	('FLOT', 'Var', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('ECF', 'Chemical', '-', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))	('increased', 'PosReg', (165, 174))	('prolonged', 'PosReg', (88, 97))	('ECX', 'Chemical', '-', (64, 67))
810964	29547556	Results of this study showed that ramucirumab produced statistically significant improvement of the hazard ratio of HCC in patients with hepatic cirrhosis of Child-Pugh 5.	('hepatic cirrhosis', 'Phenotype', 'HP:0001394', (137, 154))	('ramucirumab', 'Chemical', 'MESH:C543333', (34, 45))	('hepatic cirrhosis', 'Disease', (137, 154))	('hazard ratio', 'MPA', (100, 112))	('hepatic cirrhosis', 'Disease', 'MESH:D008103', (137, 154))	('Child', 'Species', '9606', (158, 163))	('ramucirumab', 'Var', (34, 45))	('patients', 'Species', '9606', (123, 131))	('improvement', 'PosReg', (81, 92))	('HCC', 'Disease', (116, 119))	('HCC', 'Phenotype', 'HP:0001402', (116, 119))
810985	29547556	Considering the inhibitory activity of lenvatinib in multiple RTKs including VEGFR2 and FGFR4, it is possible that subsets of patients may particularly benefit from lenvatinib, such as those with elevated serum AFP and FGF19 + HCC (as demonstrated in the study using ramucirumab and BLU-554, respectively).	('AFP', 'Gene', (211, 214))	('VEGFR2', 'Gene', (77, 83))	('lenvatinib', 'Chemical', 'MESH:C531958', (39, 49))	('HCC', 'Phenotype', 'HP:0001402', (227, 230))	('FGF19', 'Gene', '9965', (219, 224))	('AFP', 'Gene', '174', (211, 214))	('BLU', 'Gene', (283, 286))	('FGF19', 'Gene', (219, 224))	('BLU', 'Gene', '51364', (283, 286))	('FGFR4', 'Gene', (88, 93))	('benefit', 'PosReg', (152, 159))	('lenvatinib', 'Var', (165, 175))	('FGFR4', 'Gene', '2264', (88, 93))	('lenvatinib', 'Chemical', 'MESH:C531958', (165, 175))	('patients', 'Species', '9606', (126, 134))	('VEGFR2', 'Gene', '3791', (77, 83))	('ramucirumab', 'Chemical', 'MESH:C543333', (267, 278))
811003	29547556	Results of this study suggest that the combination of nab-paclitaxel with gemcitabine and cisplatin may provide additional survival benefit as compared with historical control using gemcitabine and cisplatin (Table 10).	('gemcitabine', 'Chemical', 'MESH:C056507', (74, 85))	('nab', 'Chemical', '-', (54, 57))	('gemcitabine', 'Chemical', 'MESH:C056507', (182, 193))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('nab-paclitaxel', 'Var', (54, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (198, 207))	('survival benefit', 'CPA', (123, 139))	('paclitaxel', 'Chemical', 'MESH:D017239', (58, 68))
811009	29547556	Metastatic CRC with DNA mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) displays high levels of tumor-associated neoantigens and tumor-infiltrating lymphocytes.	('tumor', 'Disease', (157, 162))	('MSI-H', 'Disease', 'MESH:D000848', (93, 98))	('CR', 'Chemical', '-', (11, 13))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Metastatic CRC', 'Disease', (0, 14))	('mismatch', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (124, 129))	('dMMR', 'Chemical', '-', (51, 55))	('DNA mismatch', 'Var', (20, 32))	('MSI-H', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CRC', 'Phenotype', 'HP:0030731', (11, 14))	('microsatellite instability-high', 'Var', (60, 91))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
811026	29547556	In vitro blockade of BRAFV600 mutation by vemurafenib has been shown to up-regulate epidermal growth factor receptor (EGFR); a combination of the EGFR inhibitor cetuximab and irinotecan can block the EGFR-mediated signaling events.	('EGFR', 'Gene', '1956', (146, 150))	('epidermal growth factor receptor', 'Gene', '1956', (84, 116))	('irinotecan', 'Chemical', 'MESH:D000077146', (175, 185))	('mutation', 'Var', (30, 38))	('vemurafenib', 'Chemical', 'MESH:D000077484', (42, 53))	('up-regulate', 'PosReg', (72, 83))	('EGFR', 'Gene', (146, 150))	('BRAF', 'Gene', '673', (21, 25))	('EGFR', 'Gene', (200, 204))	('EGFR', 'Gene', '1956', (200, 204))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('BRAF', 'Gene', (21, 25))	('epidermal growth factor receptor', 'Gene', (84, 116))	('cetuximab', 'Chemical', 'MESH:D000068818', (161, 170))
811061	29115564	Furthermore, knockdown of CDK4/BCAS2 coincided with the suppressive effects of miR-486 in esophageal cancer cells.	('BCAS2', 'Gene', (31, 36))	('miR-486', 'Gene', (79, 86))	('suppressive', 'NegReg', (56, 67))	('esophageal cancer', 'Disease', (90, 107))	('CDK4', 'Gene', (26, 30))	('CDK4', 'Gene', '1019', (26, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BCAS2', 'Gene', '10286', (31, 36))	('knockdown', 'Var', (13, 22))	('miR-486', 'Gene', '619554', (79, 86))
811071	29115564	It has been reported that mutations of several genes are associated with esophageal cancer, such as p53, FasL and EGFR.	('esophageal cancer', 'Disease', (73, 90))	('EGFR', 'Gene', '1956', (114, 118))	('mutations', 'Var', (26, 35))	('p53', 'Gene', '7157', (100, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('FasL', 'Gene', (105, 109))	('EGFR', 'Gene', (114, 118))	('FasL', 'Gene', '356', (105, 109))	('associated', 'Reg', (57, 67))	('p53', 'Gene', (100, 103))
811087	29115564	Three esophageal cell lines (KYSE150, EC9706 and TE-9) and human normal esophageal epithelial cell line Het-1A were purchased from the Cell Bank of Shanghai Institute of Cell Biology (Chinese Academy of Medical Sciences, Shanghai, China).	('EC9706', 'Var', (38, 44))	('KYSE150', 'Var', (29, 36))	('human', 'Species', '9606', (59, 64))	('EC9706', 'CellLine', 'CVCL:E307', (38, 44))
811097	29115564	The membranes were immunoblotted with the primary antibodies: CDK4 (1:500, ab108357; Abcam, Cambridge, UK), BCAS2 (1:500, ab151293; Abcam), GAPDH (1:500, ab8245; Abcam), p21 (1:500, ab109520; Abcam) and caspase-3 (1:300, ab2171; Abcam) overnight at 4 C. After being rinsed with TBST, the membranes were incubated with secondary antibodies (at a dilution of 1:5,000) conjugated to horseradish peroxidase.	('GAPDH', 'Gene', (140, 145))	('TBS', 'Chemical', 'MESH:D013725', (278, 281))	('CDK4', 'Gene', '1019', (62, 66))	('BCAS2', 'Gene', (108, 113))	('caspase-3', 'Gene', '836', (203, 212))	('p21', 'Gene', (170, 173))	('horseradish', 'Species', '3704', (380, 391))	('1:500', 'Var', (115, 120))	('caspase-3', 'Gene', (203, 212))	('GAPDH', 'Gene', '2597', (140, 145))	('p21', 'Gene', '644914', (170, 173))	('CDK4', 'Gene', (62, 66))	('BCAS2', 'Gene', '10286', (108, 113))
811138	29115564	After overexpression of miR-486 in EC9706 cells, the number of cells invading the basement membrane was significantly lower than that in the NC group (Fig.	('miR-486', 'Gene', '619554', (24, 31))	('EC9706', 'Var', (35, 41))	('EC9706', 'CellLine', 'CVCL:E307', (35, 41))	('overexpression', 'PosReg', (6, 20))	('miR-486', 'Gene', (24, 31))	('lower', 'NegReg', (118, 123))
811143	29115564	When the binding site was mutated, the interaction relationship disappeared and the expression of CDK4/BCAS2 returned to normal, which indicated that miR-486 may be a regulatory factor of the CDK4/BCAS2 sequence (Fig.	('BCAS2', 'Gene', (103, 108))	('miR-486', 'Gene', (150, 157))	('BCAS2', 'Gene', '10286', (197, 202))	('disappeared', 'NegReg', (64, 75))	('BCAS2', 'Gene', (197, 202))	('CDK4', 'Gene', (192, 196))	('miR-486', 'Gene', '619554', (150, 157))	('CDK4', 'Gene', (98, 102))	('mutated', 'Var', (26, 33))	('binding', 'Interaction', (9, 16))	('CDK4', 'Gene', '1019', (192, 196))	('CDK4', 'Gene', '1019', (98, 102))	('expression', 'MPA', (84, 94))	('interaction', 'Interaction', (39, 50))	('BCAS2', 'Gene', '10286', (103, 108))
811149	29115564	The cell cycle was arrested in the G0/G1 phase following the silencing of CDK4 or BCAS2, and could not enter the cell cycle normally (Fig.	('cell cycle', 'CPA', (4, 14))	('BCAS2', 'Gene', '10286', (82, 87))	('CDK4', 'Gene', '1019', (74, 78))	('CDK4', 'Gene', (74, 78))	('arrest', 'Disease', 'MESH:D006323', (19, 25))	('BCAS2', 'Gene', (82, 87))	('silencing', 'Var', (61, 70))	('arrest', 'Disease', (19, 25))
811151	29115564	The above results showed that the knockdown of target genes CDK4/BCAS2 can induce the apoptosis of esophageal cancer cells, but the apoptosis-related downstream proteins were not clear.	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('CDK4', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CDK4', 'Gene', '1019', (60, 64))	('BCAS2', 'Gene', '10286', (65, 70))	('BCAS2', 'Gene', (65, 70))	('knockdown', 'Var', (34, 43))	('induce', 'PosReg', (75, 81))	('apoptosis', 'CPA', (86, 95))	('esophageal cancer', 'Disease', (99, 116))
811153	29115564	The results showed that compared with the NC group, CDK4 and BCAS2 protein expression was decreased, and expression levels of apoptotic signaling molecules p21 and caspase-3 were also downregulated in the siCDK4 and siBCAS2 EC9706 cell groups (Fig.	('CDK4', 'Gene', (52, 56))	('CDK4', 'Gene', '1019', (207, 211))	('CDK4', 'Gene', (207, 211))	('BCAS2', 'Gene', '10286', (218, 223))	('caspase-3', 'Gene', '836', (164, 173))	('BCAS2', 'Gene', (218, 223))	('BCAS2', 'Gene', '10286', (61, 66))	('EC9706', 'CellLine', 'CVCL:E307', (224, 230))	('decreased', 'NegReg', (90, 99))	('BCAS2', 'Gene', (61, 66))	('p21', 'Gene', (156, 159))	('protein', 'Protein', (67, 74))	('caspase-3', 'Gene', (164, 173))	('p21', 'Gene', '644914', (156, 159))	('downregulated', 'NegReg', (184, 197))	('EC9706', 'Var', (224, 230))	('CDK4', 'Gene', '1019', (52, 56))
811154	29115564	After transfected for 48 h, the migration ability of the EC9706 cells following silencing of CDK4/BCAS2 was significantly lower than that noted in the NC group (both p<0.01), which indicated that knockdown of target genes CDK4/BCAS2 could inhibit the motility of esophageal cancer cells (Fig.	('migration ability', 'CPA', (32, 49))	('lower', 'NegReg', (122, 127))	('CDK4', 'Gene', '1019', (93, 97))	('silencing', 'Var', (80, 89))	('motility of', 'CPA', (251, 262))	('BCAS2', 'Gene', '10286', (98, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (263, 280))	('inhibit', 'NegReg', (239, 246))	('EC9706', 'CellLine', 'CVCL:E307', (57, 63))	('CDK4', 'Gene', (222, 226))	('BCAS2', 'Gene', (98, 103))	('CDK4', 'Gene', '1019', (222, 226))	('BCAS2', 'Gene', '10286', (227, 232))	('esophageal cancer', 'Disease', (263, 280))	('knockdown', 'Var', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('CDK4', 'Gene', (93, 97))	('BCAS2', 'Gene', (227, 232))
811156	29115564	These results suggest that knockdown of target genes CDK4/BCAS2 can reduce the migration and invasion abilities of the esophageal cancer cells.	('knockdown', 'Var', (27, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('CDK4', 'Gene', '1019', (53, 57))	('CDK4', 'Gene', (53, 57))	('reduce', 'NegReg', (68, 74))	('invasion abilities of the', 'CPA', (93, 118))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('BCAS2', 'Gene', '10286', (58, 63))	('BCAS2', 'Gene', (58, 63))	('esophageal cancer', 'Disease', (119, 136))
811162	29115564	miRNAs can function as oncogenes or as tumor-suppressor genes, which play an important role in angiogenesis and epithelial-mesenchymal transition and drug resistance in cancer.	('tumor-suppressor', 'Gene', '7248', (39, 55))	('cancer', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor-suppressor', 'Gene', (39, 55))	('miRNAs', 'Var', (0, 6))	('drug resistance', 'Phenotype', 'HP:0020174', (150, 165))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
811171	29115564	The expression of miR-486 was determined in three esophageal squamous carcinoma cell lines and that of EC9706 had a significantly lower level compared to Het-1A (human esophageal epithelial cell line).	('lower', 'NegReg', (130, 135))	('EC9706', 'Var', (103, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('miR-486', 'Gene', '619554', (18, 25))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (61, 79))	('EC9706', 'CellLine', 'CVCL:E307', (103, 109))	('human', 'Species', '9606', (162, 167))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (50, 79))	('esophageal squamous carcinoma', 'Disease', (50, 79))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (50, 79))	('miR-486', 'Gene', (18, 25))
811183	29115564	In the present study, we found that the proliferation and clone formation ability of esophageal cancer cells were inhibited after knockdown of CDK4 and BCAS2 genes, and the ability of migration and invasion was also reduced.	('reduced', 'NegReg', (216, 223))	('clone formation ability', 'CPA', (58, 81))	('BCAS2', 'Gene', (152, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('knockdown', 'Var', (130, 139))	('CDK4', 'Gene', (143, 147))	('CDK4', 'Gene', '1019', (143, 147))	('esophageal cancer', 'Disease', (85, 102))	('BCAS2', 'Gene', '10286', (152, 157))	('inhibited', 'NegReg', (114, 123))
811185	29115564	In addition, p53 is also a target protein of BCAS2, while knockdown of BCAS2 can enhance p53-induced apoptosis.	('BCAS2', 'Gene', (45, 50))	('knockdown', 'Var', (58, 67))	('BCAS2', 'Gene', '10286', (71, 76))	('BCAS2', 'Gene', (71, 76))	('p53', 'Gene', (89, 92))	('p53', 'Gene', (13, 16))	('BCAS2', 'Gene', '10286', (45, 50))	('p53', 'Gene', '7157', (89, 92))	('enhance', 'PosReg', (81, 88))	('p53', 'Gene', '7157', (13, 16))
811187	29115564	After knockdown of CDK4, the level of p21 was detected but the specific regulatory mechanism between CDK4 and p21 warrant further research.	('CDK4', 'Gene', '1019', (101, 105))	('CDK4', 'Gene', (101, 105))	('CDK4', 'Gene', (19, 23))	('p21', 'Gene', (38, 41))	('p21', 'Gene', '644914', (38, 41))	('CDK4', 'Gene', '1019', (19, 23))	('p21', 'Gene', (110, 113))	('p21', 'Gene', '644914', (110, 113))	('knockdown', 'Var', (6, 15))
811192	28789369	Association of TP53 codon 72 genotype polymorphism and environmental factors with esophageal squamous cell carcinoma in the Mongolian population of the Chinese region of Inner Mongolia The present study analyzed the association of tumor protein p53 (TP53) Pro72Arg polymorphism with esophageal squamous cell carcinoma (ESCC) in the Mongolian population of Tongliao (Inner Mongolia, China).	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (294, 317))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (283, 317))	('SCC', 'Gene', '6317', (320, 323))	('polymorphism', 'Var', (265, 277))	('SCC', 'Gene', (320, 323))	('Pro72Arg polymorphism', 'Var', (256, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('tumor', 'Disease', (231, 236))	('TP53', 'Gene', '7157', (15, 19))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('p53', 'Gene', '7157', (245, 248))	('TP53', 'Gene', (250, 254))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('Pro72Arg', 'Mutation', 'rs1042522', (256, 264))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('p53', 'Gene', (245, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal squamous cell carcinoma', 'Disease', (283, 317))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('association', 'Interaction', (216, 227))	('TP53', 'Gene', (15, 19))	('TP53', 'Gene', '7157', (250, 254))
811193	28789369	Restriction fragment length polymorphism-polymerase chain reaction was used to detect the genotype distribution of TP53 Pro72Arg polymorphism in 100 patients with ESCC and 50 healthy controls from the same population.	('patients', 'Species', '9606', (149, 157))	('Pro72Arg', 'Mutation', 'rs1042522', (120, 128))	('SCC', 'Gene', '6317', (164, 167))	('TP53', 'Gene', '7157', (115, 119))	('men', 'Species', '9606', (16, 19))	('TP53', 'Gene', (115, 119))	('Pro72Arg', 'Var', (120, 128))	('SCC', 'Gene', (164, 167))
811196	28789369	Notably, the Pro72 allele was significantly enriched in patients with ESCC compared with its abundance in the healthy control group, and the genotype of Pro/Arg on p53 codon 72 was confirmed to exhibit a significant correlation with ESCC in Mongolian patients.	('patients', 'Species', '9606', (56, 64))	('SCC', 'Gene', (234, 237))	('Pro', 'Chemical', 'MESH:D011392', (153, 156))	('Pro', 'Chemical', 'MESH:D011392', (13, 16))	('SCC', 'Gene', '6317', (234, 237))	('Arg', 'Chemical', 'MESH:D001120', (157, 160))	('SCC', 'Gene', (71, 74))	('correlation', 'Reg', (216, 227))	('patients', 'Species', '9606', (251, 259))	('p53', 'Gene', (164, 167))	('Pro/Arg', 'Var', (153, 160))	('Pro72', 'Var', (13, 18))	('SCC', 'Gene', '6317', (71, 74))	('p53', 'Gene', '7157', (164, 167))
811198	28789369	Mongolian patients who carry the partocular genotype of Arg/Pro or Pro/Pro on p53 codon 72 may be more likely to develop ESCC.	('SCC', 'Gene', (122, 125))	('Pro', 'Chemical', 'MESH:D011392', (67, 70))	('Pro', 'Chemical', 'MESH:D011392', (60, 63))	('Pro', 'Chemical', 'MESH:D011392', (71, 74))	('Arg', 'Chemical', 'MESH:D001120', (56, 59))	('Pro/Pro', 'Var', (67, 74))	('Arg/Pro', 'Var', (56, 63))	('SCC', 'Gene', '6317', (122, 125))	('p53', 'Gene', (78, 81))	('patients', 'Species', '9606', (10, 18))	('develop', 'PosReg', (113, 120))	('p53', 'Gene', '7157', (78, 81))
811199	28789369	Compared with the p53 codon 72 genotype Arg/Arg, the TP53 Pro72 allele increased the risk of ESCC in Mongolian patients by 1.659-fold.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('Pro72', 'Var', (58, 63))	('SCC', 'Gene', (94, 97))	('Pro', 'Chemical', 'MESH:D011392', (58, 61))	('Arg', 'Chemical', 'MESH:D001120', (40, 43))	('SCC', 'Gene', '6317', (94, 97))	('Arg', 'Chemical', 'MESH:D001120', (44, 47))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))	('patients', 'Species', '9606', (111, 119))
811210	28789369	In China, certain studies demonstrated that the genotype Pro/Pro of p53 is a risk factor for ESCC in Chaoshan in Guangdong, Linzhou in Henan and Yanting in Sichuan, but in other places such as Hebei, Cixian or Shexian, the genotype Pro/Pro of p53 is not a risk factor.	('Pro', 'Chemical', 'MESH:D011392', (236, 239))	('Pro', 'Chemical', 'MESH:D011392', (232, 235))	('SCC', 'Gene', (94, 97))	('risk', 'Reg', (77, 81))	('Pro', 'Chemical', 'MESH:D011392', (57, 60))	('Pro', 'Chemical', 'MESH:D011392', (61, 64))	('SCC', 'Gene', '6317', (94, 97))	('p53', 'Gene', (243, 246))	('genotype', 'Var', (48, 56))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (243, 246))	('p53', 'Gene', '7157', (68, 71))
811234	28789369	The association between mutant genotype or allele polymorphism and esophageal cancer risk was calculated by odds ratio (OR) with 95% confidence interval (CI).	('mutant', 'Var', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal cancer', 'Disease', (67, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))
811239	28789369	In the ESCC group, 25.0, 41.7 and 33.3% of patients had Pro/Pro, Pro/Arg and Arg/Arg genotypes, respectively, compared with 14.0, 30.0 and 56.0% of subjects, respectively, in the control group, which indicated that the distribution of genotypes was statistically significant (chi2=7.49, P<0.05) and that the p53 genotype is associated with ESCC in Mongolian patients.	('Pro/Pro', 'Var', (56, 63))	('Arg', 'Chemical', 'MESH:D001120', (69, 72))	('Pro', 'Chemical', 'MESH:D011392', (60, 63))	('Pro', 'Chemical', 'MESH:D011392', (56, 59))	('SCC', 'Gene', '6317', (341, 344))	('patients', 'Species', '9606', (43, 51))	('SCC', 'Gene', (341, 344))	('Pro/Arg', 'Var', (65, 72))	('SCC', 'Gene', (8, 11))	('associated', 'Reg', (324, 334))	('Arg', 'Chemical', 'MESH:D001120', (77, 80))	('Arg', 'Chemical', 'MESH:D001120', (81, 84))	('p53', 'Gene', (308, 311))	('Pro', 'Chemical', 'MESH:D011392', (65, 68))	('p53', 'Gene', '7157', (308, 311))	('SCC', 'Gene', '6317', (8, 11))	('patients', 'Species', '9606', (358, 366))
811240	28789369	The genotype Arg/Pro was the most abundant in the ESCC group, while in the control group, the most abundant genotype was Arg/Arg.	('SCC', 'Gene', (51, 54))	('Arg', 'Chemical', 'MESH:D001120', (121, 124))	('Arg', 'Chemical', 'MESH:D001120', (125, 128))	('SCC', 'Gene', '6317', (51, 54))	('Pro', 'Chemical', 'MESH:D011392', (17, 20))	('Arg', 'Chemical', 'MESH:D001120', (13, 16))	('Arg/Pro', 'Var', (13, 20))
811241	28789369	This demonstrates that Arg/Pro is involved in the occurrence of ESCC in the Mongolian population.	('SCC', 'Gene', (65, 68))	('involved', 'Reg', (34, 42))	('SCC', 'Gene', '6317', (65, 68))	('Pro', 'Chemical', 'MESH:D011392', (27, 30))	('Arg', 'Chemical', 'MESH:D001120', (23, 26))	('Arg/Pro', 'Var', (23, 30))
811244	28789369	A risk analysis was conducted in which genotypes such as Pro/Pro and Arg/Pro were regarded as the exposure factors, and Arg/Arg was regarded as the non-exposure factor (Table IV).	('Arg', 'Chemical', 'MESH:D001120', (124, 127))	('Arg', 'Chemical', 'MESH:D001120', (69, 72))	('Arg/Pro', 'Var', (69, 76))	('Pro', 'Chemical', 'MESH:D011392', (57, 60))	('Arg/Arg', 'Var', (120, 127))	('Pro', 'Chemical', 'MESH:D011392', (61, 64))	('Pro/Pro', 'Var', (57, 64))	('Arg', 'Chemical', 'MESH:D001120', (120, 123))	('Pro', 'Chemical', 'MESH:D011392', (73, 76))
811246	28789369	To the best of our knowledge, the present study is the first report showing the association between TP53 codon 72 polymorphisms and the risk of ESCC in a Mongolian population.	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', (100, 104))	('SCC', 'Gene', (145, 148))	('association', 'Interaction', (80, 91))	('SCC', 'Gene', '6317', (145, 148))	('polymorphisms', 'Var', (114, 127))	('codon 72 polymorphisms', 'Var', (105, 127))
811247	28789369	It was concluded that TP53 codon 72 polymorphisms were associated with an increased risk of developing ESCC through the present hospital-based case-control analysis on a Mongolian population.	('polymorphisms', 'Var', (36, 49))	('SCC', 'Gene', (104, 107))	('TP53', 'Gene', '7157', (22, 26))	('SCC', 'Gene', '6317', (104, 107))	('TP53', 'Gene', (22, 26))
811252	28789369	Besides, cigarette smokers or alcohol drinkers with p53 Arg/Arg or Arg/Pro could have a higher risk of infection by human papilloma virus (HPV) 16, which would increase their ESCC risk.	('HPV) 16', 'Gene', (139, 146))	('human papilloma', 'Gene', (116, 131))	('p53', 'Gene', (52, 55))	('Arg/Pro', 'Var', (67, 74))	('alcohol', 'Chemical', 'MESH:D000438', (30, 37))	('infection', 'Disease', (103, 112))	('infection', 'Disease', 'MESH:D007239', (103, 112))	('HPV', 'Species', '10566', (139, 142))	('SCC', 'Gene', '6317', (176, 179))	('Arg', 'Chemical', 'MESH:D001120', (56, 59))	('papilloma', 'Phenotype', 'HP:0012740', (122, 131))	('SCC', 'Gene', (176, 179))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (30, 46))	('Pro', 'Chemical', 'MESH:D011392', (71, 74))	('p53', 'Gene', '7157', (52, 55))	('human papilloma virus', 'Species', '10566', (116, 137))	('increase', 'PosReg', (160, 168))	('Arg', 'Chemical', 'MESH:D001120', (67, 70))	('Arg', 'Chemical', 'MESH:D001120', (60, 63))
811254	28789369	The 72nd codon of the p53 gene in exon 4 codes for arginine (Arg72R) or proline (Pr72P).	('Pr72P', 'Var', (81, 86))	('codes', 'Reg', (41, 46))	('proline', 'Chemical', 'MESH:D011392', (72, 79))	('p53', 'Gene', (22, 25))	('arginine', 'Chemical', 'MESH:D001120', (51, 59))	('p53', 'Gene', '7157', (22, 25))	('Arg72R', 'Chemical', '-', (61, 67))	('Arg72R', 'Var', (61, 67))
811256	28789369	Therefore, it is possible that the p53 Pro72p subtype may more effectively induce gene expression of nuclear DNA compared with the p53 Arg72R subtype.	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('nuclear', 'Protein', (101, 108))	('gene expression', 'MPA', (82, 97))	('Pro', 'Chemical', 'MESH:D011392', (39, 42))	('Arg72R', 'Chemical', '-', (135, 141))	('p53', 'Gene', (131, 134))	('Pro72p', 'Var', (39, 45))	('p53', 'Gene', '7157', (131, 134))	('induce', 'PosReg', (75, 81))
811257	28789369	The polymorphism of the 72 codon of the p53 gene can affect the induction of cell apoptosis and the repair of damaged DNA, which are functions closely associated with the maintenance of the integrity of the nuclear envelope.	('repair', 'MPA', (100, 106))	('cell apoptosis', 'CPA', (77, 91))	('affect', 'Reg', (53, 59))	('p53', 'Gene', (40, 43))	('p53', 'Gene', '7157', (40, 43))	('polymorphism', 'Var', (4, 16))
811258	28789369	In addition, the polymorphism of the 72 codon of the p53 gene may affect the accumulation of mitochondrial DNA mutations by combining with DNA polymerase gamma.	('combining', 'Interaction', (124, 133))	('polymorphism of', 'Var', (17, 32))	('affect', 'Reg', (66, 72))	('accumulation', 'MPA', (77, 89))	('mitochondrial', 'Gene', (93, 106))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))
811259	28789369	Therefore, the polymorphism of the p53 gene on codon 72 can affect the normal functions of the p53 gene, and may be involved in the prognosis of patients with ESCC.	('patients', 'Species', '9606', (145, 153))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('involved', 'Reg', (116, 124))	('p53', 'Gene', (95, 98))	('SCC', 'Gene', (160, 163))	('affect', 'Reg', (60, 66))	('p53', 'Gene', '7157', (95, 98))	('polymorphism', 'Var', (15, 27))	('SCC', 'Gene', '6317', (160, 163))	('normal functions', 'MPA', (71, 87))
811260	28789369	To the best of our knowledge, the majority of previous Chinese studies have shown that there is an association between the polymorphism of p53 Arg72Pro in Chinese patients with ESCC, and the heterozygous genotype (Arg/Pro) and the mutant homozygous genotype (Pro/Pro) can significantly increase the incidence of esophageal cancer risk.	('patients', 'Species', '9606', (163, 171))	('Pro', 'Chemical', 'MESH:D011392', (263, 266))	('SCC', 'Gene', '6317', (178, 181))	('increase', 'PosReg', (286, 294))	('Pro', 'Chemical', 'MESH:D011392', (259, 262))	('Pro', 'Chemical', 'MESH:D011392', (218, 221))	('Arg72Pro', 'Var', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('p53', 'Gene', (139, 142))	('Arg', 'Chemical', 'MESH:D001120', (214, 217))	('Arg', 'Chemical', 'MESH:D001120', (143, 146))	('p53', 'Gene', '7157', (139, 142))	('Pro', 'Chemical', 'MESH:D011392', (148, 151))	('esophageal cancer', 'Disease', (312, 329))	('association', 'Interaction', (99, 110))	('SCC', 'Gene', (178, 181))	('esophageal cancer', 'Disease', 'MESH:D004938', (312, 329))	('Arg72Pro', 'SUBSTITUTION', 'None', (143, 151))
811262	28789369	For example, the homozygous Pro/Pro polymorphism can increase the risk of esophageal cancer in the population of Korea.	('Pro', 'Chemical', 'MESH:D011392', (32, 35))	('increase', 'PosReg', (53, 61))	('esophageal cancer', 'Disease', (74, 91))	('polymorphism', 'Var', (36, 48))	('Pro', 'Chemical', 'MESH:D011392', (28, 31))	('homozygous Pro/Pro polymorphism', 'Var', (17, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
811264	28789369	In Japan, a previous report revealed that alteration of p53 tumor-suppressor protein was suspected to be the key molecular event in multifocal carcinogenesis.	('p53', 'Gene', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('alteration', 'Var', (42, 52))	('p53', 'Gene', '7157', (56, 59))	('multifocal carcinogenesis', 'Disease', (132, 157))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('multifocal carcinogenesis', 'Disease', 'None', (132, 157))
811268	28789369	Previous studies indicated that the Arg/Arg genotype could increase the risk of HPV-associated tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('increase', 'PosReg', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('Arg', 'Chemical', 'MESH:D001120', (36, 39))	('HPV', 'Species', '10566', (80, 83))	('Arg', 'Chemical', 'MESH:D001120', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('Arg/Arg', 'Var', (36, 43))
811269	28789369	Buller et al demonstrated that the Arg/Pro genotype and borderline ovarian cancer had a close association.	('Arg/Pro', 'Var', (35, 42))	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('Arg', 'Chemical', 'MESH:D001120', (35, 38))	('ovarian cancer', 'Disease', (67, 81))	('Pro', 'Chemical', 'MESH:D011392', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))
811270	28789369	Previous studies on Northern Chinese populations revealed that the homozygous genotype Pro/Pro was an independent risk for ESCC, and it could increase the risk of ESCC by 2-fold compared with that of the Arg/Arg genotype.	('increase', 'PosReg', (142, 150))	('Pro/Pro', 'Var', (87, 94))	('Pro', 'Chemical', 'MESH:D011392', (91, 94))	('SCC', 'Gene', '6317', (164, 167))	('SCC', 'Gene', (124, 127))	('Arg', 'Chemical', 'MESH:D001120', (204, 207))	('Arg', 'Chemical', 'MESH:D001120', (208, 211))	('SCC', 'Gene', '6317', (124, 127))	('SCC', 'Gene', (164, 167))	('Pro', 'Chemical', 'MESH:D011392', (87, 90))
811271	28789369	The present results revealed a significant association between the polymorphism of TP53 codon 72 and the risk of developing ESCC risk in Mongolian patients.	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('SCC', 'Gene', (125, 128))	('patients', 'Species', '9606', (147, 155))	('SCC', 'Gene', '6317', (125, 128))	('polymorphism', 'Var', (67, 79))
811275	28789369	Our results support previous conclusions suggesting different behavior of the p53 Pro72Arg alleles in different cancer types and ethnicities in ESCC.	('Pro72Arg', 'Mutation', 'rs1042522', (82, 90))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('SCC', 'Gene', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Pro72Arg', 'Var', (82, 90))	('p53', 'Gene', (78, 81))	('SCC', 'Gene', '6317', (145, 148))	('p53', 'Gene', '7157', (78, 81))
811277	28789369	Animal models may help to unravel the function of mutations in the codon 72 of the p53 gene in the process of ESCC development.	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('mutations in', 'Var', (50, 62))	('SCC', 'Gene', (111, 114))	('SCC', 'Gene', '6317', (111, 114))	('men', 'Species', '9606', (122, 125))
811281	28404924	SKGT4-shCDK9 cell-derived tumors were significantly smaller than control SKGT4-derived tumors in xenografts (72.89mm3 vs. 270mm3).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SKGT4-shCDK9', 'Var', (0, 12))	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('smaller', 'NegReg', (52, 59))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (26, 32))
811300	28404924	In this study, we compared CDK9 protein expression in matched samples of Barrett's esophagus and invasive carcinoma from patients with esophageal adenocarcinoma and assessed in vitro and in vivo effects of genetic downregulation (shCDK9) and pharmaceutical inhibition of CDK9.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (135, 160))	('esophageal adenocarcinoma', 'Disease', (135, 160))	('downregulation', 'NegReg', (214, 228))	('invasive carcinoma', 'Disease', 'MESH:D009361', (97, 115))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (135, 160))	('genetic', 'Var', (206, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('invasive carcinoma', 'Disease', (97, 115))	('CDK9', 'Gene', (27, 31))	('patients', 'Species', '9606', (121, 129))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (73, 92))
811301	28404924	We also studied mechanism of MCL-1 regulation by CDK9 inhibitors in esophageal adenocarcinoma.	('inhibitors', 'Var', (54, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (68, 93))	('MCL-1', 'Gene', '4170', (29, 34))	('esophageal adenocarcinoma', 'Disease', (68, 93))	('MCL-1', 'Gene', (29, 34))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (68, 93))	('CDK9', 'Gene', (49, 53))
811307	28404924	In xenograft experiments with genetic downregulation (shCDK9) of SKGT4 and control SKGT4 cells, eleven of 20 mice developed at least one tumor with either parenteral SKGT4 or with shCDK9 SKGT4 cells.	('genetic', 'Var', (30, 37))	('men', 'Species', '9606', (19, 22))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('downregulation', 'NegReg', (38, 52))	('developed', 'PosReg', (114, 123))	('mice', 'Species', '10090', (109, 113))	('SKGT4', 'Gene', (65, 70))
811309	28404924	There were 8 tumors in 11 mice with shCDK9 SKGT4 (1 mouse with 2 tumors and 6 mice with 1 tumor).	('tumor', 'Disease', (13, 18))	('2 tumors', 'Disease', 'MESH:D009369', (63, 71))	('tumors', 'Disease', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('2 tumors', 'Disease', (63, 71))	('tumor', 'Disease', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('shCDK9 SKGT4', 'Var', (36, 48))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumors', 'Disease', (13, 19))	('mouse', 'Species', '10090', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('mice', 'Species', '10090', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mice', 'Species', '10090', (78, 82))
811311	28404924	Volume of SKGT4-shCDK9 cell-derived tumors was significantly smaller (Figure 2D and 2E) than those from control SKGT4 cells (72.89 +- 12.88 mm3 versus 270 +- 64.07 mm3, p< 0.01).	('smaller', 'NegReg', (61, 68))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('SKGT4-shCDK9', 'Var', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
811318	28404924	CAN508 (40muM for 72 hours) also increased apoptosis by 2 fold in all three esophageal adenocarcinoma cells compared to untreated controls.	('esophageal adenocarcinoma', 'Disease', (76, 101))	('apoptosis', 'CPA', (43, 52))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (76, 101))	('CAN508', 'Var', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('increased', 'PosReg', (33, 42))	('CAN508', 'Chemical', 'MESH:C568946', (0, 6))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (76, 101))
811321	28404924	In xenograft models, both CAN508 and Flavopiridol caused reduction of tumor growth starting from post-treatment day three with 50.83% reduction with CAN508 (Figure 4A, p<0.01 compared to control) and 63.1% reduction with Flavopiridol (Figure 4B, p<0.001 compared to control) on post-treatment day 21.	('reduction', 'NegReg', (206, 215))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CAN508', 'Chemical', 'MESH:C568946', (149, 155))	('men', 'Species', '9606', (107, 110))	('Flavopiridol', 'Chemical', 'MESH:C077990', (221, 233))	('reduction', 'NegReg', (57, 66))	('tumor', 'Disease', (70, 75))	('CAN508', 'Var', (149, 155))	('CAN508', 'Chemical', 'MESH:C568946', (26, 32))	('reduction', 'NegReg', (134, 143))	('Flavopiridol', 'Chemical', 'MESH:C077990', (37, 49))	('men', 'Species', '9606', (288, 291))	('CAN508', 'Var', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
811324	28404924	Reduction of phosphorylation at ser2 of Poll II CTD and MCL-1 by CAN508 and Flavopiridol was in dose dependent manner and lasted for at least 16 hours (data not shown).	('MCL-1', 'Gene', '4170', (56, 61))	('Flavopiridol', 'Chemical', 'MESH:C077990', (76, 88))	('MCL-1', 'Gene', (56, 61))	('CAN508', 'Var', (65, 71))	('ser2', 'Gene', '3714', (32, 36))	('ser2', 'Gene', (32, 36))	('Reduction', 'NegReg', (0, 9))	('CAN508', 'Chemical', 'MESH:C568946', (65, 71))
811327	28404924	In our experiments, MCL-1 level was significantly higher in cells treated with CDK9 inhibitor and MG132 as compared to cells treated with only CDK9 inhibitor (p<0.05).	('higher', 'PosReg', (50, 56))	('men', 'Species', '9606', (13, 16))	('inhibitor', 'Var', (84, 93))	('CDK9', 'Gene', (79, 83))	('MCL-1', 'Gene', '4170', (20, 25))	('MG132', 'Var', (98, 103))	('MCL-1', 'Gene', (20, 25))	('MG132', 'Chemical', 'MESH:C072553', (98, 103))
811328	28404924	However, the MCL-1 level is significantly lower in cells treated with MG132 and CDK9 inhibitor as compared to MG132 alone (p<0.05).	('MCL-1', 'Gene', (13, 18))	('CDK9', 'Gene', (80, 84))	('inhibitor', 'Var', (85, 94))	('lower', 'NegReg', (42, 47))	('MG132', 'Chemical', 'MESH:C072553', (70, 75))	('MG132', 'Var', (70, 75))	('MG132', 'Chemical', 'MESH:C072553', (110, 115))	('MCL-1', 'Gene', '4170', (13, 18))
811332	28404924	These findings indicate that Flavopiridol and CAN508 regulates MCL-1 predominantly by inhibiting MCL-1 transcription and less so by enhancing proteosomal degradation.	('MCL-1', 'Gene', (63, 68))	('regulates', 'Reg', (53, 62))	('MCL-1', 'Gene', (97, 102))	('MCL-1', 'Gene', '4170', (97, 102))	('CAN508', 'Chemical', 'MESH:C568946', (46, 52))	('inhibiting', 'NegReg', (86, 96))	('Flavopiridol', 'Chemical', 'MESH:C077990', (29, 41))	('transcription', 'MPA', (103, 116))	('proteosomal degradation', 'MPA', (142, 165))	('CAN508', 'Var', (46, 52))	('enhancing', 'PosReg', (132, 141))	('MCL-1', 'Gene', '4170', (63, 68))
811333	28404924	CAN508 treatment with 40 mum for 4 hours showed reduction in c-MYC in OE 33 cells, while no reduction in c-MYC was observed after treatment with CAN 508 in Flo-1 and SKGT4 cells and with lower dose (20 mum) OE 33 cells.	('ser', 'Chemical', 'MESH:D012694', (117, 120))	('c-MYC', 'Gene', '4609', (105, 110))	('c-MYC', 'Gene', '4609', (61, 66))	('CAN508', 'Chemical', 'MESH:C568946', (0, 6))	('CAN508', 'Var', (0, 6))	('CAN 508', 'Chemical', 'MESH:C568946', (145, 152))	('men', 'Species', '9606', (12, 15))	('men', 'Species', '9606', (135, 138))	('c-MYC', 'Gene', (105, 110))	('c-MYC', 'Gene', (61, 66))	('reduction', 'NegReg', (48, 57))
811339	28404924	These findings indicate CDK9 inhibitors reduce binding of transcription factor HIF-1 alpha to -1051 to -901bp region of MCL-1 promoter.	('HIF-1 alpha', 'Gene', '3091', (79, 90))	('inhibitors', 'Var', (29, 39))	('reduce', 'NegReg', (40, 46))	('MCL-1', 'Gene', '4170', (120, 125))	('binding', 'Interaction', (47, 54))	('MCL-1', 'Gene', (120, 125))	('HIF-1 alpha', 'Gene', (79, 90))
811340	28404924	Cells with MCL-1 overexpression had very high levels of MCL-1 compared to MCL-1 expression in control cells (Supplementary Figure 1A).	('overexpression', 'Var', (17, 31))	('MCL-1', 'Gene', (11, 16))	('MCL-1', 'Gene', '4170', (56, 61))	('MCL-1', 'Gene', (56, 61))	('men', 'Species', '9606', (115, 118))	('levels', 'MPA', (46, 52))	('MCL-1', 'Gene', '4170', (74, 79))	('MCL-1', 'Gene', (74, 79))	('MCL-1', 'Gene', '4170', (11, 16))
811342	28404924	All three cell lines with MCL-1 overexpression were significantly more resistant to 40 mum of CAN508 than the control cells (p< 0.05, Supplementary Figure 1B).	('CAN508', 'Chemical', 'MESH:C568946', (94, 100))	('Supplementary Figure 1B', 'Disease', (134, 157))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (134, 157))	('resistant to 40 mum of CAN508', 'MPA', (71, 100))	('overexpression', 'Var', (32, 46))	('MCL-1', 'Gene', '4170', (26, 31))	('more', 'PosReg', (66, 70))	('MCL-1', 'Gene', (26, 31))
811343	28404924	However, only FLO-1 and SKGT4 cells with MCL-1 overexpression were significantly more resistant to Flavopiridol than control cells (Supplementary Figure 1C).	('MCL-1', 'Gene', '4170', (41, 46))	('MCL-1', 'Gene', (41, 46))	('men', 'Species', '9606', (138, 141))	('Flavopiridol', 'Chemical', 'MESH:C077990', (99, 111))	('resistant to Flavopiridol', 'MPA', (86, 111))	('overexpression', 'Var', (47, 61))
811346	28404924	Similarity in cytotoxic effects between genetic downregulation and both CDK9 inhibitors support CDK9 as an important therapeutic target in esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('CDK9', 'Gene', (72, 76))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (139, 164))	('esophageal adenocarcinoma', 'Disease', (139, 164))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (139, 164))	('downregulation', 'NegReg', (48, 62))	('genetic', 'Var', (40, 47))
811349	28404924	In contrast CAN 508 demonstrated higher anti-apoptotic effects in OE33 as compared to Flavopiridol.	('higher', 'PosReg', (33, 39))	('anti-apoptotic effects', 'CPA', (40, 62))	('Flavopiridol', 'Chemical', 'MESH:C077990', (86, 98))	('OE33', 'Var', (66, 70))	('CAN 508', 'Chemical', 'MESH:C568946', (12, 19))
811354	28404924	In both experiments, xenograft tumor growth was significantly inhibited by the CDK9 inhibitors compared to control from day 3 (Flavopiridol) and day 6 (CAN508) to the end of experiment indicating efficacy of both inhibitors in controlling tumor growth in esophageal adenocarcinoma xenografts.	('inhibitors', 'Var', (84, 94))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (255, 280))	('esophageal adenocarcinoma xenografts', 'Disease', 'MESH:D004938', (255, 291))	('men', 'Species', '9606', (14, 17))	('CAN508', 'Chemical', 'MESH:C568946', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('esophageal adenocarcinoma xenografts', 'Disease', (255, 291))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('men', 'Species', '9606', (180, 183))	('inhibited', 'NegReg', (62, 71))	('tumor', 'Disease', (239, 244))	('Flavopiridol', 'Chemical', 'MESH:C077990', (127, 139))	('CDK9', 'Gene', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
811356	28404924	This is likely due to the phosphorylation of Pol II and activation of MCL-1 by alternate pathways in stable shCDK9 cells because of the irreversible effects of stable shCDK9 as compared to reversible effects of transient shCDK9 and CDK9 inhibitors.	('activation', 'PosReg', (56, 66))	('MCL-1', 'Gene', '4170', (70, 75))	('MCL-1', 'Gene', (70, 75))	('shCDK9', 'Var', (167, 173))
811357	28404924	The difference in effects of type (stable vs. transient) of genetic downregulation of CDK9 on critical downstream targets of CDK9 (p-Pol II and MCL-1) is new and additional work with different types of genetic downregulation in esophageal adenocarcinoma and other solid tumor cell lines will provide more insights in understanding mechanism of action of CDK9 and identifying appropriate target for the CDK9 inhibition in esophageal adenocarcinoma.	('MCL-1', 'Gene', (144, 149))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (421, 446))	('esophageal adenocarcinoma', 'Disease', (228, 253))	('esophageal adenocarcinoma', 'Disease', (421, 446))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (228, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (437, 446))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (228, 253))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (421, 446))	('downregulation', 'NegReg', (68, 82))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('downregulation', 'NegReg', (210, 224))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('MCL-1', 'Gene', '4170', (144, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('tumor', 'Disease', (270, 275))	('genetic', 'Var', (60, 67))
811365	28404924	In this study, we for the first time demonstrate that MCL-1 regulation by CDK9 inhibitor is mediated by downregulation of binding of transcription factor HIF-1alpha to MCL-1 promoter.	('MCL-1', 'Gene', '4170', (168, 173))	('binding', 'Interaction', (122, 129))	('CDK9', 'Gene', (74, 78))	('inhibitor', 'Var', (79, 88))	('HIF-1alpha', 'Gene', '3091', (154, 164))	('MCL-1', 'Gene', '4170', (54, 59))	('MCL-1', 'Gene', (54, 59))	('downregulation', 'NegReg', (104, 118))	('HIF-1alpha', 'Gene', (154, 164))	('MCL-1', 'Gene', (168, 173))
811370	28404924	Our findings show that MYC is downregulated with shCDK9 in esophageal adenocarcinoma while MYC downregulation by the CDK9 inhibitors is not consistent across three esophageal adenocarcinoma cell lines.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (59, 84))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (164, 189))	('downregulated', 'NegReg', (30, 43))	('MYC', 'Gene', '4609', (91, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('MYC', 'Gene', '4609', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('MYC', 'Gene', (91, 94))	('esophageal adenocarcinoma', 'Disease', (59, 84))	('MYC', 'Gene', (23, 26))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (164, 189))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (59, 84))	('esophageal adenocarcinoma', 'Disease', (164, 189))	('shCDK9', 'Var', (49, 55))
811371	28404924	As focus of this study was to assess the efficacy and identify a target of pharmaceutical inhibitors of CDK9 in esophageal adenocarcinoma and MYC did not show consistent alterations after CDK9 inhibitor treatment, we chose to study MCL-1 instead of MYC as the CDK9 target in this study.	('MYC', 'Gene', '4609', (249, 252))	('MYC', 'Gene', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (112, 137))	('esophageal adenocarcinoma', 'Disease', (112, 137))	('men', 'Species', '9606', (208, 211))	('MCL-1', 'Gene', (232, 237))	('MYC', 'Gene', '4609', (142, 145))	('MCL-1', 'Gene', '4170', (232, 237))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (112, 137))	('MYC', 'Gene', (249, 252))	('CDK9', 'Gene', (104, 108))	('inhibitors', 'Var', (90, 100))
811378	28404924	Our findings support further exploration of newer CDK9 inhibitors which are more specific and likely to cause lower toxicity with therapeutic doses in patients with esophageal adenocarcinoma compared to the previously used CDK9 inhibitors.	('toxicity', 'Disease', 'MESH:D064420', (116, 124))	('toxicity', 'Disease', (116, 124))	('CDK9', 'Gene', (50, 54))	('patients', 'Species', '9606', (151, 159))	('esophageal adenocarcinoma', 'Disease', (165, 190))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (165, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('inhibitors', 'Var', (55, 65))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))
811415	28404924	Cells with stably down- regulated CDK9 expression by shCDK9 were selected by incubation in a medium containing purimycin for at least 2 weeks.	('purimycin', 'Chemical', '-', (111, 120))	('shCDK9', 'Var', (53, 59))	('CDK9', 'Gene', (34, 38))	('expression', 'MPA', (39, 49))	('down- regulated', 'NegReg', (18, 33))
811426	28404924	We performed ChIP assay to confirm that the reduction of MCL-1 expression by CDK9 inhibitors is at the transcriptional level and to determine whether CDK9 inhibitors affect the binding of transcriptional factors such as HIF-1alpha to MCL-1 promoter.	('MCL-1', 'Gene', '4170', (234, 239))	('MCL-1', 'Gene', (234, 239))	('CDK9', 'Gene', (77, 81))	('affect', 'Reg', (166, 172))	('inhibitors', 'Var', (82, 92))	('reduction', 'NegReg', (44, 53))	('HIF-1alpha', 'Gene', '3091', (220, 230))	('binding', 'Interaction', (177, 184))	('MCL-1', 'Gene', '4170', (57, 62))	('MCL-1', 'Gene', (57, 62))	('HIF-1alpha', 'Gene', (220, 230))
811453	27577071	Expression of immune checkpoints in T cells of esophageal cancer patients Inhibition of immune checkpoint proteins (checkpoints) has become a promising anti-esophageal cancer strategy.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('Inhibition', 'Var', (74, 84))	('esophageal cancer', 'Disease', (47, 64))	('esophageal cancer', 'Disease', (157, 174))
811474	27577071	The expression levels of CD137 and CD160 on CD8+ T cells from esophageal cancer patients were significantly higher than that from normal donors (cancer patients vs. healthy donors, 10.12 +- 2.571% vs. 3.122 +- 0.4173%, p = 0.0150; 48.26 +- 5.225% vs. 33.95 +- 3.807%, p = 0.0400, Figure 2).	('cancer', 'Disease', (145, 151))	('CD8', 'Gene', (44, 47))	('patients', 'Species', '9606', (80, 88))	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('donor', 'Species', '9606', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('higher', 'PosReg', (108, 114))	('expression levels', 'MPA', (4, 21))	('CD8', 'Gene', '925', (44, 47))	('CD160', 'Var', (35, 40))	('patients', 'Species', '9606', (152, 160))	('CD137', 'Gene', (25, 30))	('CD137', 'Gene', '3604', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('donor', 'Species', '9606', (173, 178))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))
811492	27577071	The MFI of BTLA on CD4+ and CD8+ TILs was lower than that of circulating CD4+ and CD8+ T cells from esophageal cancer patients (Figure 4B).	('CD8', 'Gene', (82, 85))	('esophageal cancer', 'Disease', (100, 117))	('CD8', 'Gene', '925', (82, 85))	('lower', 'NegReg', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (118, 126))	('CD8', 'Gene', (28, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('BTLA', 'Gene', (11, 15))	('BTLA', 'Gene', '151888', (11, 15))	('CD8', 'Gene', '925', (28, 31))	('MFI', 'MPA', (4, 7))	('CD4+', 'Var', (19, 23))
811500	27577071	The frequency of PD-1+TIM-3+ cells was significantly increased in the CD4+ T cells in AEM as compared to PBMC from patients (35.10 +- 4.047% vs. 20.03 +- 3.465%, p < 0.0001), but not in CD8+ T cells (35.60 +- 4.918% vs. 36.90 +- 5.235%, p = 0.6019; Figure 6).	('patients', 'Species', '9606', (115, 123))	('CD8', 'Gene', '925', (186, 189))	('PD-1+TIM-3', 'Gene', '100037293', (17, 27))	('increased', 'PosReg', (53, 62))	('CD4+ T', 'Var', (70, 76))	('PD-1+TIM-3', 'Gene', (17, 27))	('CD8', 'Gene', (186, 189))
811501	27577071	The frequency of PD-1+TIM-3+ cells was significantly increased in CD4+ and CD8+ T cell population in tumor tissues compared to AEM (48.28 +- 4.818% vs. 35.10 +- 4.047%, p = 0.0003; 52.63 +- 5.368% vs. 35.60 +- 4.918%, p < 0.0001) and in PBMC (48.28 +- 4.818% vs. 20.03 +- 3.465%, p < 0.0001; 52.63 +- 5.368% vs. 36.90 +- 5.235%, p < 0.0001) from esophageal cancer patients (Figure 6).	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('esophageal cancer', 'Disease', 'MESH:D004938', (346, 363))	('PD-1+TIM-3', 'Gene', '100037293', (17, 27))	('CD8', 'Gene', '925', (75, 78))	('patients', 'Species', '9606', (364, 372))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('CD4+', 'Var', (66, 70))	('increased', 'PosReg', (53, 62))	('PD-1+TIM-3', 'Gene', (17, 27))	('CD8', 'Gene', (75, 78))	('esophageal cancer', 'Disease', (346, 363))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
811558	27418834	The patient selection criteria were age 18-75 years; Eastern Cooperative Oncology Group PS <=2; adequate hematological, hepatic, and adrenal functions (white blood cell count >=4.0x109/L; neutrophil count >=1.5x109/L; platelet count >=100x109/L; hemoglobin >=10 g/dL; ALT and AST <=2.5x upper limits of normal; total bilirubin <=1.5x upper limits of normal; creatinine clearance >=60 mL/min or creatinine <= upper limits of normal); and life expectancy >12 weeks.	('>=60', 'Var', (379, 383))	('total bilirubin', 'MPA', (311, 326))	('>=4.0x109/L', 'Var', (175, 186))	('>=1.5x109/L', 'Var', (205, 216))	('patient', 'Species', '9606', (4, 11))	('AST', 'Gene', (276, 279))	('ALT', 'MPA', (268, 271))	('creatinine clearance', 'MPA', (358, 378))	('life expectancy', 'CPA', (437, 452))	('Oncology', 'Phenotype', 'HP:0002664', (73, 81))	('>=100x109/L', 'Var', (233, 244))	('AST', 'Gene', '26503', (276, 279))	('creatinine', 'MPA', (394, 404))
811682	25269696	These 2 dogs with the highest fraction times of pH < 4 also had the longest duration of a single reflux (65 minutes in the Shar Pei, 38 minutes in the Beauceron) as well as the highest total number of refluxes >5 minutes (n = 14 in the Shar Pei, n = 13 in the Beauceron).	('dogs', 'Species', '9615', (8, 12))	('single reflux', 'MPA', (90, 103))	('pH < 4', 'Var', (48, 54))	('refluxes >5 minutes', 'MPA', (201, 220))
811705	25269696	According to some authors, development of recurrent cough without obvious involvement of the respiratory tract can be the only sign of GER in dogs.7, 9 Microaspirations of gastric contents are discussed as a cause of chronic respiratory disease in humans.1 We could not prove this assumption, as none of the dogs with the highest fraction times of pH < 4 had upper respiratory clinical signs, but we cannot exclude GER of nonacidic contents with our approach.	('humans', 'Species', '9606', (248, 254))	('GER', 'Gene', '59330', (135, 138))	('pH < 4', 'Var', (348, 354))	('GER', 'Gene', (415, 418))	('dogs', 'Species', '9615', (142, 146))	('dogs', 'Species', '9615', (308, 312))	('GER', 'Phenotype', 'HP:0002020', (415, 418))	('respiratory disease', 'Disease', (225, 244))	('GER', 'Gene', (135, 138))	('respiratory disease', 'Disease', 'MESH:D012131', (225, 244))	('respiratory disease', 'Phenotype', 'HP:0011947', (225, 244))	('upper respiratory', 'Disease', (359, 376))	('aspiration', 'Phenotype', 'HP:0002835', (157, 167))	('cough', 'Phenotype', 'HP:0012735', (52, 57))	('GER', 'Gene', '59330', (415, 418))	('GER', 'Phenotype', 'HP:0002020', (135, 138))
811732	22391115	The expression levels of the most upregulated miRNAs (miR-21 and miR-223) and the most downregulated miRNA (miR-375) strongly correlated with esophageal eosinophil levels.	('expression levels', 'MPA', (4, 21))	('esophageal eosinophil levels', 'MPA', (142, 170))	('miR-375', 'Gene', (108, 115))	('upregulated', 'PosReg', (34, 45))	('miR-223', 'Gene', (65, 72))	('miR-223', 'Gene', '407008', (65, 72))	('miR-375', 'Gene', '494324', (108, 115))	('miR-21', 'Var', (54, 60))
811775	22391115	The most upregulated miRNAs included miR-21 and miR-223, and the most downregulated miRNA was miR-375.	('miR-223', 'Gene', '407008', (48, 55))	('upregulated', 'PosReg', (9, 20))	('miR-375', 'Gene', (94, 101))	('miR-223', 'Gene', (48, 55))	('miR-375', 'Gene', '494324', (94, 101))	('miR-21', 'Var', (37, 43))
811776	22391115	To validate the differentially expressed miRNAs, we performed quantitative RT-PCR on a selected set of differentially expressed miRNAs, including miR-21, miR-223, miR-375, let-7c, and miR-203 (Fig 2, A-E).	('let-7c', 'Gene', '406885', (172, 178))	('miR-203', 'Gene', (184, 191))	('miR-375', 'Gene', '494324', (163, 170))	('miR-375', 'Gene', (163, 170))	('miR-203', 'Gene', '406986', (184, 191))	('miR-223', 'Gene', '407008', (154, 161))	('miR-21', 'Var', (146, 152))	('let-7c', 'Gene', (172, 178))	('miR-223', 'Gene', (154, 161))
811799	22391115	This analysis included 6 upregulated miRNAs (miR-21, miR-132, miR-142-3p, miR-146a, miR-146b, and miR-223) and 4 downregulated miRNAs (miR-203, miR-210, miR-365 and miR-375).	('miR-203', 'Gene', '406986', (135, 142))	('miR-132', 'Gene', (53, 60))	('miR-146b', 'Gene', (84, 92))	('miR-142', 'Gene', '406934', (62, 69))	('downregulated', 'NegReg', (113, 126))	('miR-21', 'Var', (45, 51))	('miR-223', 'Gene', '407008', (98, 105))	('miR-375', 'Gene', '494324', (165, 172))	('miR-146b', 'Gene', '574447', (84, 92))	('miR-365', 'Var', (153, 160))	('miR-132', 'Gene', '406921', (53, 60))	('miR-375', 'Gene', (165, 172))	('upregulated', 'PosReg', (25, 36))	('miR-210', 'Gene', '406992', (144, 151))	('miR-146a', 'Gene', (74, 82))	('miR-142', 'Gene', (62, 69))	('miR-203', 'Gene', (135, 142))	('miR-146a', 'Gene', '406938', (74, 82))	('miR-210', 'Gene', (144, 151))	('miR-223', 'Gene', (98, 105))
811810	22391115	Specifically, we identified 21 upregulated and 11 downregulated miRNAs in patients with active EoE, including miR-21 and miR-223 as the most upregulated miRNAs and miR-375 as the most downregulated miRNA in patients with EoE.	('EoE', 'Phenotype', 'HP:0410151', (221, 224))	('patients', 'Species', '9606', (207, 215))	('miR-223', 'Gene', '407008', (121, 128))	('EoE', 'Disease', (95, 98))	('EoE', 'Phenotype', 'HP:0410151', (95, 98))	('patients', 'Species', '9606', (74, 82))	('miR-375', 'Gene', '494324', (164, 171))	('miR-21', 'Var', (110, 116))	('upregulated', 'PosReg', (31, 42))	('miR-223', 'Gene', (121, 128))	('upregulated', 'PosReg', (141, 152))	('downregulated', 'NegReg', (50, 63))	('downregulated', 'NegReg', (184, 197))	('miR-375', 'Gene', (164, 171))
811828	22391115	Indeed, recent human studies on 2 other TH2-associated diseases (atopic dermatitis and ulcerative colitis) have identified a role for miRNA in regulating T-cell proliferation and epithelium-derived chemokine production, as well as upregulating miR-21 in patients with ulcerative colitis and downregulating let-7 in patients with atopic dermatitis.	('atopic dermatitis', 'Phenotype', 'HP:0001047', (329, 346))	('TH2', 'Gene', (40, 43))	('ulcerative colitis', 'Disease', 'MESH:D003093', (268, 286))	('atopic dermatitis', 'Disease', 'MESH:D003876', (329, 346))	('atopic dermatitis', 'Disease', 'MESH:D003876', (65, 82))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (65, 82))	('downregulating', 'NegReg', (291, 305))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (87, 105))	('miRNA', 'Var', (134, 139))	('dermatitis', 'Phenotype', 'HP:0011123', (336, 346))	('let-7', 'Gene', (306, 311))	('dermatitis', 'Phenotype', 'HP:0011123', (72, 82))	('miR-21', 'Gene', (244, 250))	('patients', 'Species', '9606', (315, 323))	('human', 'Species', '9606', (15, 20))	('upregulating', 'PosReg', (231, 243))	('ulcerative colitis', 'Disease', (87, 105))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (268, 286))	('TH2', 'Gene', '15111', (40, 43))	('colitis', 'Phenotype', 'HP:0002583', (98, 105))	('colitis', 'Phenotype', 'HP:0002583', (279, 286))	('ulcerative colitis', 'Disease', (268, 286))	('T-cell proliferation', 'CPA', (154, 174))	('epithelium-derived chemokine production', 'MPA', (179, 218))	('ulcerative colitis', 'Disease', 'MESH:D003093', (87, 105))	('atopic dermatitis', 'Disease', (329, 346))	('atopic dermatitis', 'Disease', (65, 82))	('patients', 'Species', '9606', (254, 262))
811834	22391115	It is notable that several of the EoE-associated miRNAs have recently also been linked with esophageal squamous carcinoma or with Barrett esophagus, including let-7, miR-142-3p, miR-203, miR-210, miR-223, miR-375, and miR-21.	('Barrett esophagus', 'Phenotype', 'HP:0100580', (130, 147))	('miR-210', 'Gene', '406992', (187, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('miR-203', 'Gene', (178, 185))	('esophageal squamous carcinoma', 'Disease', (92, 121))	('miR-375', 'Gene', '494324', (205, 212))	('miR-210', 'Gene', (187, 194))	('miR-142', 'Gene', '406934', (166, 173))	('linked', 'Reg', (80, 86))	('miR-375', 'Gene', (205, 212))	('miR-203', 'Gene', '406986', (178, 185))	('Barrett esophagus', 'Disease', (130, 147))	('miR-21', 'Var', (218, 224))	('let-7', 'Var', (159, 164))	('miR-223', 'Gene', (196, 203))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (92, 121))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (103, 121))	('miR-142', 'Gene', (166, 173))	('EoE', 'Phenotype', 'HP:0410151', (34, 37))	('miR-223', 'Gene', '407008', (196, 203))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (92, 121))
811865	33416144	The present study aimed to determine whether aberrant expression of SOX12 is associated with malignant development of ESCC.	('ESCC', 'Disease', (118, 122))	('SOX12', 'Gene', '6666', (68, 73))	('malignant development', 'CPA', (93, 114))	('men', 'Species', '9606', (110, 113))	('aberrant expression', 'Var', (45, 64))	('SOX12', 'Gene', (68, 73))	('associated', 'Reg', (77, 87))
811867	33416144	Short hairpin RNA (shRNA) targeting SOX12 was transfected into ESCC cells to knock down the expression of SOX12.	('SOX12', 'Gene', '6666', (36, 41))	('SOX12', 'Gene', '6666', (106, 111))	('knock', 'Var', (77, 82))	('SOX12', 'Gene', (36, 41))	('SOX12', 'Gene', (106, 111))	('expression', 'MPA', (92, 102))
811871	33416144	Furthermore, knockdown of the expression of SOX12 inhibited the activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway by decreasing the expression of the JAK2/STAT3 signaling pathway.	('signal transducer and activator of transcription 3', 'Gene', '6774', (104, 154))	('JAK2', 'Gene', '3717', (98, 102))	('expression', 'MPA', (199, 209))	('activation', 'MPA', (64, 74))	('STAT3', 'Gene', '6774', (222, 227))	('JAK2', 'Gene', '3717', (217, 221))	('STAT3', 'Gene', '6774', (156, 161))	('JAK2', 'Gene', (98, 102))	('Janus kinase 2', 'Gene', '3717', (82, 96))	('STAT3', 'Gene', (222, 227))	('STAT3', 'Gene', (156, 161))	('Janus kinase 2', 'Gene', (82, 96))	('SOX12', 'Gene', (44, 49))	('knockdown', 'Var', (13, 22))	('JAK2', 'Gene', (217, 221))	('decreasing', 'NegReg', (184, 194))	('inhibited', 'NegReg', (50, 59))	('SOX12', 'Gene', '6666', (44, 49))
811885	33416144	Previous studies have also revealed that aberrant expression of SOX12 affects the biological behaviors of tumor cells and has a potential prognostic value in various type of tumors, such as liver, breast, and lung cancer, as well as renal carcinoma and acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', (253, 275))	('SOX12', 'Gene', '6666', (64, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('aberrant expression', 'Var', (41, 60))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('breast', 'Disease', (197, 203))	('tumor', 'Disease', (106, 111))	('tumors', 'Disease', (174, 180))	('renal carcinoma', 'Disease', 'MESH:C538614', (233, 248))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (253, 275))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('renal carcinoma', 'Disease', (233, 248))	('renal carcinoma', 'Phenotype', 'HP:0005584', (233, 248))	('leukemia', 'Phenotype', 'HP:0001909', (267, 275))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (253, 275))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (259, 275))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('lung cancer', 'Disease', (209, 220))	('SOX12', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (174, 179))	('affects', 'Reg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('liver', 'Disease', (190, 195))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
811908	33416144	WP1066 (5 microl), an inhibitor of the JAK2/STAT3 signaling pathway, was added to the cell culture medium in the colony formation, Transwell and western blotting assays.	('WP1066', 'Chemical', 'MESH:C519885', (0, 6))	('WP1066', 'Var', (0, 6))	('JAK2', 'Gene', (39, 43))	('STAT3', 'Gene', '6774', (44, 49))	('STAT3', 'Gene', (44, 49))	('JAK2', 'Gene', '3717', (39, 43))
811918	33416144	The primer sequences used were as follows: SOX12 (NM_006943.3) forward, 5'-AGCACCCGTGTGACTCTTTCC-3' and reverse, 5'-AGCAGAACCAAGCCCTGTCTC-3'; GAPDH (NM_001256799.1) forward, 5'-CACCCACTCCTCCACCTTTG-3' and reverse, 5'-CCACCACCCTGTTGCTGTAG-3'.	('GAPDH', 'Gene', '2597', (142, 147))	('GAPDH', 'Gene', (142, 147))	('NM_001256799.1', 'Var', (149, 163))	('SOX12', 'Gene', (43, 48))	('NM_006943.3', 'Var', (50, 61))	('SOX12', 'Gene', '6666', (43, 48))
811948	33416144	Mutational activation of the JAK2/STAT3 signaling pathway is responsible for the malignant transformation and progression of various types of tumors.	('STAT3', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('Mutational', 'Var', (0, 10))	('JAK2', 'Gene', (29, 33))	('STAT3', 'Gene', '6774', (34, 39))	('malignant transformation', 'CPA', (81, 105))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('JAK2', 'Gene', '3717', (29, 33))	('activation', 'PosReg', (11, 21))
811950	33416144	The results revealed that knockdown of SOX12 in ESCC cells decreased the levels of p-JAK2Tyr1007+1008 and p-STAT3Tyr705 (Fig.	('p-JAK2Tyr1007+1008', 'MPA', (83, 101))	('decreased', 'NegReg', (59, 68))	('levels', 'MPA', (73, 79))	('p-STAT3Tyr705', 'Var', (106, 119))	('SOX12', 'Gene', (39, 44))	('knockdown', 'Var', (26, 35))	('SOX12', 'Gene', '6666', (39, 44))
811957	33416144	5, high expression of SOX12 was associated with lower OS (P=0.0341) and DFS (P=0.04) compared with low expression of SOX12.	('SOX12', 'Gene', (117, 122))	('high expression', 'Var', (3, 18))	('lower', 'NegReg', (48, 53))	('SOX12', 'Gene', '6666', (117, 122))	('DFS', 'CPA', (72, 75))	('SOX12', 'Gene', (22, 27))	('SOX12', 'Gene', '6666', (22, 27))
811976	33416144	Furthermore, clinical data revealed that high expression of SOX12 in ESCC tissues was closely associated to the poor prognosis of patients.	('SOX12', 'Gene', '6666', (60, 65))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (130, 138))	('associated', 'Reg', (94, 104))	('SOX12', 'Gene', (60, 65))	('expression', 'MPA', (46, 56))
811981	33416144	However, there were no significant differences in the clinicopathological characteristics between patients with high and low expression of SOX12.	('SOX12', 'Gene', (139, 144))	('high', 'Var', (112, 116))	('patients', 'Species', '9606', (98, 106))	('low', 'NegReg', (121, 124))	('SOX12', 'Gene', '6666', (139, 144))
811989	33416144	In the present study, knockdown of SOX12 in ESCC cells decreased the levels of p-JAK2Tyr1007+1008 and p-STAT3Tyr705, which could be reversed by co-culture with recombinant SOX12 (10 microM).	('SOX12', 'Gene', (172, 177))	('p-JAK2Tyr1007+1008', 'MPA', (79, 97))	('levels', 'MPA', (69, 75))	('SOX12', 'Gene', (35, 40))	('SOX12', 'Gene', '6666', (172, 177))	('p-STAT3Tyr705', 'Var', (102, 115))	('knockdown', 'Var', (22, 31))	('decreased', 'NegReg', (55, 64))	('SOX12', 'Gene', '6666', (35, 40))
811992	33416144	Mutational activation of the JAK2/STAT3 is responsible for the malignant transformation and progression of several types of tumor.	('STAT3', 'Gene', (34, 39))	('malignant transformation', 'CPA', (63, 87))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Mutational', 'Var', (0, 10))	('JAK2', 'Gene', (29, 33))	('tumor', 'Disease', (124, 129))	('responsible', 'Reg', (43, 54))	('STAT3', 'Gene', '6774', (34, 39))	('JAK2', 'Gene', '3717', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
811996	33416144	Aberrantly high levels of SOX12 were indicated to be associated with malignant biological behavior exhibited in ESCC cells and were revealed to be an independent unfavorable prognostic factor for patients with ESCC.	('Aberrantly', 'Var', (0, 10))	('SOX12', 'Gene', '6666', (26, 31))	('patients', 'Species', '9606', (196, 204))	('SOX12', 'Gene', (26, 31))	('malignant biological behavior exhibited', 'CPA', (69, 108))	('associated', 'Reg', (53, 63))	('ESCC', 'Disease', (210, 214))
812060	32793111	After permeabilization with Triton X-100, cells were blocked with 5% normal bovine serum albumin for 30 min and incubated with antiglucose regulated protein 78 (GRP78) (1:500, ab21685, Abcam), antiestrogen receptor alpha (ERalpha) (1:100, ab32063, Abcam), and anti-ERbeta (1:100, ab212351, Abcam), respectively, at 4 C overnight.	('estrogen receptor alpha', 'Gene', (197, 220))	('ERbeta', 'Gene', (265, 271))	('ERalpha', 'Gene', '2099', (222, 229))	('ERalpha', 'Gene', (222, 229))	('1:100', 'Var', (273, 278))	('estrogen receptor alpha', 'Gene', '2099', (197, 220))	('Triton X-100', 'Chemical', 'MESH:D017830', (28, 40))	('GRP78', 'Gene', '3309', (161, 166))	('ERbeta', 'Gene', '2099', (265, 271))	('ab212351', 'Var', (280, 288))	('1:500', 'Var', (169, 174))	('GRP78', 'Gene', (161, 166))
812067	32793111	After blocking with 5% milk, the membranes were incubated with primary antibodies (1:1,000), including anti-GRP78 (ab21685, Abcam), antiactivating transcription factor 6 (ATF6) (ab203119, Abcam), anti-inositol-requiring enzyme 1alpha (IRE1alpha) (ab37117, Abcam), antiprotein kinase RNA-like endoplasmic reticulum kinase (PERK) (70R-17036, Fitzgerald), and anti-beta-actin (E2317, Cell Signaling Technology).	('ATF6', 'Gene', (171, 175))	('beta-actin', 'Gene', '728378', (362, 372))	('beta-actin', 'Gene', (362, 372))	('70R-17036', 'Var', (329, 338))	('E2', 'Chemical', 'MESH:D004958', (374, 376))	('GRP78', 'Gene', '3309', (108, 113))	('GRP78', 'Gene', (108, 113))	('ATF6', 'Gene', '22926', (171, 175))	('PERK', 'Gene', (322, 326))	('antiactivating transcription factor 6', 'Gene', '22926', (132, 169))	('antiactivating transcription factor 6', 'Gene', (132, 169))	('IRE1alpha', 'Gene', (235, 244))	('IRE1alpha', 'Gene', '2081', (235, 244))	('PERK', 'Gene', '9451', (322, 326))
812078	32793111	The results showed that the xenograft weight and the ratio of xenograft weight to body weight in the female mice (0.010375 +- 0.001908 g, 0.00053 +- 0.000101) were significantly lower than that of the male mice (0.039375 +- 0.009952 g, 0.00161 +- 0.000395, P < 0.05) (Figures 2A-D).	('xenograft weight', 'CPA', (28, 44))	('0.010375 +- 0.001908 g', 'Var', (114, 136))	('lower', 'NegReg', (178, 183))	('mice', 'Species', '10090', (206, 210))	('mice', 'Species', '10090', (108, 112))	('0.00053 +- 0.000101', 'Var', (138, 157))
812122	32793111	In recent years, studies showed that the initiation of ERS induces apoptosis in esophageal cancer cells, and manipulation of ERS signaling has been identified as a therapeutic target for the esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('apoptosis', 'CPA', (67, 76))	('ERS', 'Gene', (55, 58))	('initiation', 'Var', (41, 51))	('esophageal cancer', 'Disease', (80, 97))	('induces', 'Reg', (59, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('esophageal cancer', 'Disease', (191, 208))
812195	31579702	Four types of upper gastrointestinal endoscope (GIF-Q240Z, GIF-H260Z, GIF-RQ260Z, and GIF-HQ290; Olympus Optical Co., Tokyo, Japan) were used in this study.	('GIF', 'Gene', (70, 73))	('upper gastrointestinal endoscope', 'Disease', (14, 46))	('Q240Z', 'SUBSTITUTION', 'None', (52, 57))	('GIF', 'Gene', (48, 51))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (14, 46))	('H260Z', 'Var', (63, 68))	('H260Z', 'SUBSTITUTION', 'None', (63, 68))	('GIF', 'Gene', '2694', (59, 62))	('Q240Z', 'Var', (52, 57))	('GIF', 'Gene', '2694', (86, 89))	('GIF', 'Gene', '2694', (48, 51))	('GIF', 'Gene', (86, 89))	('GIF', 'Gene', (59, 62))	('GIF', 'Gene', '2694', (70, 73))
812238	31102336	On subgroup analysis, PORT was shown to significantly improve OS for pT3-4N1M0 compared with the surgery alone, and five-year OS was 41.3% versus 23.5%, respectively (P < 0.001).	('OS', 'Chemical', '-', (62, 64))	('PORT', 'Var', (22, 26))	('pT3', 'Gene', '7694', (69, 72))	('pT3', 'Gene', (69, 72))	('OS', 'Chemical', '-', (126, 128))	('improve', 'PosReg', (54, 61))
812286	30662402	However, studies have demonstrated that radiotherapy is often accompanied by serious adverse reaction (ADRs), further impairing the health-related performance status of cancer patients (Beukema et al.,).	('patients', 'Species', '9606', (176, 184))	('cancer', 'Disease', (169, 175))	('radiotherapy', 'Var', (40, 52))	('impairing', 'NegReg', (118, 127))	('Beukema', 'Disease', (186, 193))	('Beukema', 'Disease', 'None', (186, 193))	('health-related performance status', 'CPA', (132, 165))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
812448	22339451	These agents include radiolabeled amino acids such as methionine for detecting increased protein synthesis, radiolabeled choline for detecting increased membrane lipid synthesis, and radiolabeled acetate for detecting increased cytoplasmic lipid synthesis.	('increased', 'PosReg', (79, 88))	('cytoplasmic lipid synthesis', 'MPA', (228, 255))	('increased', 'PosReg', (143, 152))	('lipid', 'Chemical', 'MESH:D008055', (240, 245))	('membrane lipid synthesis', 'MPA', (153, 177))	('methionine', 'Chemical', 'MESH:D008715', (54, 64))	('acetate', 'Chemical', 'MESH:D000085', (196, 203))	('lipid', 'Chemical', 'MESH:D008055', (162, 167))	('increased', 'PosReg', (218, 227))	('protein synthesis', 'MPA', (89, 106))	('choline', 'Chemical', 'MESH:D002794', (121, 128))	('methionine', 'Var', (54, 64))
812506	22339451	FDG-PET/CT has led to the safe decrease of radiotherapy volumes by better delineation of tumor, enabling radiation dose escalation and, experimentally, allowing definition of regions of tumor at greatest risk for recurrence, permitting redistribution of radiation doses within the tumor to focus on these regions.	('FDG', 'Chemical', 'MESH:D019788', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('men', 'Species', '9606', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('decrease', 'NegReg', (31, 39))	('FDG-PET/CT', 'Var', (0, 10))	('radiation', 'CPA', (105, 114))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('radiotherapy', 'CPA', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
812517	22339451	Furthermore, interobserver variations were decreased when identifying the target volume with FDG-PET/CT compared to CT alone.	('FDG', 'Chemical', 'MESH:D019788', (93, 96))	('decreased', 'NegReg', (43, 52))	('FDG-PET/CT', 'Var', (93, 103))
812518	22339451	In our own experience, a 62 year old male withT2N2b squamous cell carcinoma of left base of tongue had radiotherapy planned out by FDG-PET/CT combined images (Figure 3).	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('squamous cell carcinoma', 'Disease', (52, 75))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 75))	('withT2N2b', 'Var', (42, 51))	('FDG', 'Chemical', 'MESH:D019788', (131, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))
812603	22339451	In high grade gliomas, use of the 11C-MET tracer results in PET images that increased the size of the GTV obtained by more standard approaches in patients treated with radiation therapy; furthermore, treatment planning using MET-PET-based tumor delineation versus CT/MRI images was associated with an improvement in survival.	('tumor delineation', 'Disease', (239, 256))	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('survival', 'MPA', (316, 324))	('GTV', 'Chemical', '-', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('men', 'Species', '9606', (205, 208))	('improvement', 'PosReg', (301, 312))	('MET-PET-based', 'Var', (225, 238))	('men', 'Species', '9606', (308, 311))	('11C-MET', 'Chemical', '-', (34, 41))	('patients', 'Species', '9606', (146, 154))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('gliomas', 'Disease', (14, 21))	('tumor delineation', 'Disease', 'MESH:D009369', (239, 256))
812604	22339451	In tumor delineation of meningiomas, MET-PET also led to a significant increase in the size of the GTV (Figure 6).	('GTV', 'Chemical', '-', (99, 102))	('meningiomas', 'Phenotype', 'HP:0002858', (24, 35))	('size', 'MPA', (87, 91))	('increase', 'PosReg', (71, 79))	('tumor delineation of meningiomas', 'Disease', 'MESH:D008577', (3, 35))	('MET-PET', 'Var', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor delineation of meningiomas', 'Disease', (3, 35))
812638	22339451	Anti-18F-FACBC may become a useful tool in prostate cancer radiotherapy planning based on promising results in prostate cancer imaging.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('prostate cancer', 'Disease', (111, 126))	('Anti-18F-FACBC', 'Var', (0, 14))	('FACBC', 'Chemical', '-', (9, 14))	('prostate cancer', 'Disease', (43, 58))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (43, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (43, 58))
812640	22339451	Especially for NSCLC, FDG-PET has led to the safe decrease of radiotherapy volumes, enabling radiation dose escalation and, experimentally, redistribution of radiation doses within the tumor, along with playing a significant role in monitoring radiotherapy response.	('tumor', 'Disease', (185, 190))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('radiation dose', 'CPA', (93, 107))	('FDG', 'Chemical', 'MESH:D019788', (22, 25))	('NSCLC', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('FDG-PET', 'Var', (22, 29))	('radiotherapy volumes', 'CPA', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('men', 'Species', '9606', (130, 133))	('decrease', 'NegReg', (50, 58))
812646	22339451	The role of anti-18F-FACBC in the radiotherapy management of prostate cancer may emerge in the near future.	('FACBC', 'Chemical', '-', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('prostate cancer', 'Disease', (61, 76))	('prostate cancer', 'Disease', 'MESH:D011471', (61, 76))	('men', 'Species', '9606', (53, 56))	('anti-18F-FACBC', 'Var', (12, 26))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))
812751	33532497	As a result of ROS and ONOO- levels measured in serum, it increased in Veh rats compared with Nor rats but not significantly.	('rats', 'Species', '10116', (98, 102))	('OS', 'Phenotype', 'HP:0025464', (16, 18))	('increased', 'PosReg', (58, 67))	('rats', 'Species', '10116', (75, 79))	('ROS', 'MPA', (15, 18))	('Veh', 'Var', (71, 74))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('ONOO-', 'Chemical', '-', (23, 28))
812754	33532497	As a result of TBARS level measurement in serum and esophagus tissue, TBARS levels of serum and esophagus tissue were significantly increased in Veh rats compared with Nor rats.	('TBARS', 'Chemical', 'MESH:D017392', (70, 75))	('rats', 'Species', '10116', (172, 176))	('TBARS levels', 'MPA', (70, 82))	('increased', 'PosReg', (132, 141))	('TBARS', 'Chemical', 'MESH:D017392', (15, 20))	('rats', 'Species', '10116', (149, 153))	('TBARS level', 'MPA', (15, 26))	('Veh', 'Var', (145, 148))
812761	33532497	And, the p22phox protein expression was significantly increased in Veh rats compared to Nor rats, whereas CLR treatment significantly downregulated p22phox expression (Figure 6).	('rats', 'Species', '10116', (92, 96))	('CLR', 'Gene', '25029', (106, 109))	('Veh', 'Var', (67, 70))	('p22phox', 'Gene', (148, 155))	('downregulated', 'NegReg', (134, 147))	('CLR', 'Gene', (106, 109))	('increased', 'PosReg', (54, 63))	('p22phox', 'Gene', '79129', (148, 155))	('p22phox', 'Gene', '79129', (9, 16))	('rats', 'Species', '10116', (71, 75))	('p22phox', 'Gene', (9, 16))
812763	33532497	The Nrf2 protein expression was downregulated in Veh rats compared with Nor rats, whereas CLR treatment significantly increased Nrf2 expression.	('rats', 'Species', '10116', (53, 57))	('expression', 'MPA', (133, 143))	('downregulated', 'NegReg', (32, 45))	('CLR', 'Gene', '25029', (90, 93))	('Nrf2', 'Gene', '83619', (4, 8))	('protein', 'Protein', (9, 16))	('CLR', 'Gene', (90, 93))	('Nrf2', 'Gene', '83619', (128, 132))	('Nrf2', 'Gene', (4, 8))	('rats', 'Species', '10116', (76, 80))	('Nrf2', 'Gene', (128, 132))	('Veh', 'Var', (49, 52))
812765	33532497	As a result of confirming the expression of MAPK such as p-p38, p-JNK, and c-Jun, the expressions of p-p38 and p-JNK in Veh rats were significantly upregulated compared with Nor rats.	('p38', 'Gene', '81649', (59, 62))	('p38', 'Gene', (59, 62))	('JNK', 'Gene', '116554', (66, 69))	('p38', 'Gene', '81649', (103, 106))	('p38', 'Gene', (103, 106))	('c-Jun', 'MPA', (75, 80))	('rats', 'Species', '10116', (178, 182))	('JNK', 'Gene', (113, 116))	('expressions', 'MPA', (86, 97))	('rats', 'Species', '10116', (124, 128))	('Veh', 'Var', (120, 123))	('JNK', 'Gene', (66, 69))	('JNK', 'Gene', '116554', (113, 116))	('upregulated', 'PosReg', (148, 159))
812769	33532497	The expressions of NF-kappaBp65 and p-IkappaBalpha in Veh rats were significantly upregulated compared with Nor rats.	('rats', 'Species', '10116', (112, 116))	('IkappaBalpha', 'Gene', '25493', (38, 50))	('IkappaBalpha', 'Gene', (38, 50))	('NF-kappaBp65', 'Protein', (19, 31))	('Veh', 'Var', (54, 57))	('upregulated', 'PosReg', (82, 93))	('expressions', 'MPA', (4, 15))	('rats', 'Species', '10116', (58, 62))
812772	33532497	The expressions of iNOS and COX-2 in Veh rats were significantly upregulated compared with Nor rats.	('rats', 'Species', '10116', (95, 99))	('Veh', 'Var', (37, 40))	('rats', 'Species', '10116', (41, 45))	('OS', 'Phenotype', 'HP:0025464', (21, 23))	('expressions', 'MPA', (4, 15))	('iNOS', 'Gene', (19, 23))	('upregulated', 'PosReg', (65, 76))	('iNOS', 'Gene', '24599', (19, 23))	('COX-2', 'Gene', (28, 33))
812774	33532497	Also, in Veh rats, the expressions of TNF-alpha and IL-6 were significantly upregulated compared with Nor rats.	('rats', 'Species', '10116', (106, 110))	('IL-6', 'Gene', '24498', (52, 56))	('rats', 'Species', '10116', (13, 17))	('TNF-alpha', 'Gene', (38, 47))	('Veh', 'Var', (9, 12))	('upregulated', 'PosReg', (76, 87))	('IL-6', 'Gene', (52, 56))	('TNF-alpha', 'Gene', '24835', (38, 47))	('expressions', 'MPA', (23, 34))
812792	33532497	Among them, O2 - and H2O2 activate multiple signaling pathways that cause cell proliferation and apoptosis, elevated vascular tone, fibrosis, and inflammation, and excessive ROS cause mitochondrial damage or dysfunction that causes mitochondrial cell oxidative stress.	('ROS', 'Protein', (174, 177))	('O2 -', 'Var', (12, 16))	('H2O2', 'Var', (21, 25))	('rat', 'Species', '10116', (86, 89))	('mitochondrial cell oxidative stress', 'MPA', (232, 267))	('mitochondrial damage or dysfunction', 'Disease', (184, 219))	('inflammation', 'Disease', 'MESH:D007249', (146, 158))	('cell proliferation', 'CPA', (74, 92))	('ROS', 'Chemical', 'MESH:D017382', (174, 177))	('oxidative stress', 'Phenotype', 'HP:0025464', (251, 267))	('O2 -', 'Chemical', 'MESH:D010100', (12, 16))	('OS', 'Phenotype', 'HP:0025464', (175, 177))	('H2O2', 'Chemical', 'MESH:D006861', (21, 25))	('mitochondrial damage or dysfunction', 'Disease', 'MESH:D028361', (184, 219))	('inflammation', 'Disease', (146, 158))	('fibrosis', 'Disease', (132, 140))	('apoptosis', 'CPA', (97, 106))	('activate', 'PosReg', (26, 34))	('cause', 'Reg', (68, 73))	('cause', 'Reg', (178, 183))	('fibrosis', 'Disease', 'MESH:D005355', (132, 140))	('elevated', 'PosReg', (108, 116))	('vascular tone', 'CPA', (117, 130))	('causes', 'Reg', (225, 231))
812823	27556701	Therefore, we searched for associations between tumor recurrence and cell-free DNA (cfDNA) mutations in blood plasma, which contains genetic markers for various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('mutations', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
812825	27556701	Next-generation sequencing of cfDNA in plasma was performed to identify mutations in 53 cancer-related genes, in which recurrent mutations were previously detected in ESCC.	('SCC', 'Gene', (168, 171))	('mutations', 'Var', (72, 81))	('SCC', 'Phenotype', 'HP:0002860', (168, 171))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('SCC', 'Gene', '6317', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
812829	27556701	Furthermore, the allele frequency of the concordant mutations in cfDNA changed concomitantly with tumor burden and increased approximately 6 months earlier than the detection of tumor recurrences by imaging tests in two patients.	('mutations', 'Var', (52, 61))	('cfDNA', 'Gene', (65, 70))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('changed', 'Reg', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('patients', 'Species', '9606', (220, 228))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
812835	27556701	Based on next-generation sequencing (NGS); droplet digital PCR; and beads, emulsion, amplification, and magnetics (BEAMing), cfDNA harbors genetic alterations associated with various malignancies.	('cfDNA', 'Disease', (125, 130))	('genetic alterations', 'Var', (139, 158))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('malignancies', 'Disease', (183, 195))
812837	27556701	In our previous study, we identified genes with recurrent mutations in Japanese ESCC patients by NGS.	('mutations', 'Var', (58, 67))	('SCC', 'Gene', '6317', (81, 84))	('patients', 'Species', '9606', (85, 93))	('SCC', 'Gene', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))
812847	27556701	We examined the mutational profiles of 53 genes in primary and metastatic tumor samples from 13 patients (Figure 1B and Supplementary Table S1) and identified 56 tumor-specific somatic mutations (mean = 4.3 mutations per patient), including genes with recurrent somatic alterations, e.g., TP53 (92.3%) and FAT3 (23.0%).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('FAT3', 'Gene', '120114', (306, 310))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('TP53', 'Gene', '7157', (289, 293))	('TP53', 'Gene', (289, 293))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('patient', 'Species', '9606', (96, 103))	('tumor', 'Disease', (74, 79))	('FAT3', 'Gene', (306, 310))	('patients', 'Species', '9606', (96, 104))	('mutations', 'Var', (185, 194))	('patient', 'Species', '9606', (221, 228))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
812854	27556701	Mutations in these four genes were identified with 78.9% sensitivity, 100% specificity, and 92.3% accuracy in tumor and cfDNA samples from the patients (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('patients', 'Species', '9606', (143, 151))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
812856	27556701	First, we compared the allele frequencies (AFs) of concordant mutations identified in pretreatment cfDNA samples with those of mutations in post-treatment cfDNA in four cases.	('cfDNA', 'Disease', (99, 104))	('AF', 'Disease', 'MESH:D001281', (43, 45))	('mutations', 'Var', (62, 71))
812861	27556701	These data suggested that concordant mutations in cfDNA change concomitantly with tumor burden.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('change', 'Reg', (56, 62))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cfDNA', 'Gene', (50, 55))	('tumor', 'Disease', (82, 87))
812865	27556701	In case 4, SCC and p53-Ab were negative during the entire follow-up period and all concordant mutations were absent after treatment; however, the AFs of all concordant mutations increased 9 months before recurrence was detected by imaging tests (Figures 4A and 4B).	('SCC', 'Gene', (11, 14))	('SCC', 'Phenotype', 'HP:0002860', (11, 14))	('SCC', 'Gene', '6317', (11, 14))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('AF', 'Disease', 'MESH:D001281', (146, 148))	('mutations', 'Var', (168, 177))	('increased', 'PosReg', (178, 187))
812867	27556701	Intriguingly, although the NOTCHW327C mutation remained absent during follow-up, the AF of TP53R141C gradually increased 6 months before hepatic metastasis was detected.	('TP53', 'Gene', '7157', (91, 95))	('TP53', 'Gene', (91, 95))	('AF', 'Disease', 'MESH:D001281', (85, 87))	('NOTCHW327C', 'Var', (27, 37))
812872	27556701	In the current study, we applied NGS with a multigene panel to detect mutations in plasma samples in ESCC.	('SCC', 'Gene', (102, 105))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('mutations', 'Var', (70, 79))
812873	27556701	Recent exome studies in ESCC have identified mutations in driver genes such as TP53, FAT3, MLL3, and AJUBA.	('mutations', 'Var', (45, 54))	('SCC', 'Gene', (25, 28))	('AJUBA', 'Gene', (101, 106))	('TP53', 'Gene', (79, 83))	('FAT3', 'Gene', (85, 89))	('TP53', 'Gene', '7157', (79, 83))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('MLL3', 'Gene', (91, 95))	('SCC', 'Gene', '6317', (25, 28))	('FAT3', 'Gene', '120114', (85, 89))	('AJUBA', 'Gene', '84962', (101, 106))	('MLL3', 'Gene', '58508', (91, 95))
812877	27556701	We previously observed diverse mutations in driver genes in colorectal cancer among patients with distinctive inter-tumor heterogeneity.	('mutations', 'Var', (31, 40))	('patients', 'Species', '9606', (84, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (116, 121))	('colorectal cancer', 'Disease', (60, 77))
812879	27556701	However, almost all patients with ESCC had mutations of one gene out of the top four genes (Table 2).	('SCC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('mutations', 'Var', (43, 52))	('SCC', 'Gene', '6317', (35, 38))	('patients', 'Species', '9606', (20, 28))
812882	27556701	Moreover, our analysis demonstrated that the AFs of concordant mutations in serial plasma samples are useful not only for evaluating the tumor status, but also for predicting tumor recurrence in ESCC.	('SCC', 'Gene', (196, 199))	('mutations', 'Var', (63, 72))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (137, 142))	('SCC', 'Phenotype', 'HP:0002860', (196, 199))	('SCC', 'Gene', '6317', (196, 199))	('AF', 'Disease', 'MESH:D001281', (45, 47))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
812884	27556701	reported that mutations in cfDNA in pancreatic adenocarcinoma could be detected approximately 6 months before the detection of recurrences by imaging tests, which supported the utility of cfDNA analyses in ESCC in predicting tumor recurrences.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('cfDNA', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (36, 61))	('tumor', 'Disease', (225, 230))	('SCC', 'Gene', (207, 210))	('pancreatic adenocarcinoma', 'Disease', (36, 61))	('SCC', 'Phenotype', 'HP:0002860', (207, 210))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (36, 61))	('mutations', 'Var', (14, 23))	('SCC', 'Gene', '6317', (207, 210))
812888	27556701	In ESCC, CREBBP mutations and deletions of have been recurrently detected, and CREBBP acetyltransferase activities may be tumor suppressive.	('SCC', 'Gene', (4, 7))	('CREBBP', 'Gene', (9, 15))	('CREBBP', 'Gene', '1387', (79, 85))	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('activities', 'MPA', (104, 114))	('deletions', 'Var', (30, 39))	('SCC', 'Gene', '6317', (4, 7))	('mutations', 'Var', (16, 25))	('CREBBP', 'Gene', '1387', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CREBBP', 'Gene', (79, 85))	('tumor', 'Disease', (122, 127))
812891	27556701	We propose that CREBBP might serve a fundamental function in ESCC tumorigenesis and that mutant CREBBP alleles might be frequently released into the bloodstream, as observed in the case of mutated TP53.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CREBBP', 'Gene', (16, 22))	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('tumor', 'Disease', (66, 71))	('CREBBP', 'Gene', '1387', (96, 102))	('SCC', 'Gene', '6317', (62, 65))	('CREBBP', 'Gene', '1387', (16, 22))	('TP53', 'Gene', '7157', (197, 201))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CREBBP', 'Gene', (96, 102))	('mutant', 'Var', (89, 95))	('TP53', 'Gene', (197, 201))	('SCC', 'Gene', (62, 65))
812892	27556701	The AF of mutations in cfDNA was more strongly associated with tumor burden than conventional biomarkers of ESCC.	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('tumor', 'Disease', (63, 68))	('SCC', 'Gene', '6317', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('AF', 'Disease', 'MESH:D001281', (4, 6))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cfDNA', 'Gene', (23, 28))	('SCC', 'Gene', (109, 112))	('mutations', 'Var', (10, 19))	('associated', 'Reg', (47, 57))
812893	27556701	Interestingly, in the two patients with tumor recurrence, the p53-Ab levels did not increase during recurrence, which was not consistent with the AF of the TP53 mutation.	('mutation', 'Var', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('TP53', 'Gene', '7157', (156, 160))	('patients', 'Species', '9606', (26, 34))	('TP53', 'Gene', (156, 160))	('AF', 'Disease', 'MESH:D001281', (146, 148))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
812894	27556701	Although p53-Ab is a circulating antibody against the mutated p53 protein in serum, its sensitivity is remarkably low according to a meta-analysis.	('protein', 'Protein', (66, 73))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('mutated', 'Var', (54, 61))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
812895	27556701	In recent studies, it was demonstrated that ESCC is associated with various hotspot mutations in TP53.	('SCC', 'Gene', (45, 48))	('TP53', 'Gene', '7157', (97, 101))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('SCC', 'Gene', '6317', (45, 48))	('mutations', 'Var', (84, 93))	('TP53', 'Gene', (97, 101))
812896	27556701	In general, the p53-Ab is applied to treat tumors expressing mutated TP53 protein.	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('p53', 'Gene', (16, 19))	('p53', 'Gene', '7157', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutated', 'Var', (61, 68))	('tumors', 'Disease', (43, 49))	('protein', 'Protein', (74, 81))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
812897	27556701	The mutated TP53 gene produces alternative epitopes in the variant TP53 proteins.	('proteins', 'Protein', (72, 80))	('epitopes', 'MPA', (43, 51))	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', '7157', (67, 71))	('variant', 'Var', (59, 66))	('TP53', 'Gene', (67, 71))	('TP53', 'Gene', (12, 16))
812898	27556701	In contrast, the limited epitopes recognized by the TP53-Ab cannot distinguish the variety of esophageal cancer cells with diverse TP53 gene mutations.	('mutations', 'Var', (141, 150))	('TP53', 'Gene', '7157', (52, 56))	('esophageal cancer', 'Disease', (94, 111))	('TP53', 'Gene', (52, 56))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
812900	27556701	Several mutations were detected in tumor samples, but not in cfDNA, and such mutations were absent in serial plasma samples from all patients.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('patients', 'Species', '9606', (133, 141))	('mutations', 'Var', (8, 17))	('tumor', 'Disease', (35, 40))
812901	27556701	Furthermore, in case 6, although the TP53R141C mutation gradually increased before tumor recurrence was detected, the NOTCHW327C mutation remained absent during follow-up.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('NOTCHW327C', 'Var', (118, 128))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
812904	27556701	Tumors evolve by processes of branched evolution via the acquisition of genetic and epigenetic alterations, leading to the formation of various clones of cancer cells, including genetically distinct subclones, which contribute to tumor heterogeneity.	('tumor', 'Disease', (230, 235))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('epigenetic alterations', 'Var', (84, 106))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
812905	27556701	Mutations detected in tumor samples, but not in cfDNA, may be derived from subclones of tumor samples and may rarely affect the formation of metastatic lesions.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (88, 93))	('affect', 'Reg', (117, 123))
812909	27556701	According to the cancer-evolution model, greater diversity of mutations in primary tumors is observed in cancers in stage IV patients than in cancers from stage I-III patients.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Disease', (105, 111))	('cancers', 'Disease', (105, 112))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (125, 133))	('primary tumors', 'Disease', 'MESH:D009369', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('mutations', 'Var', (62, 71))	('cancer', 'Disease', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancers', 'Disease', (142, 149))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (167, 175))	('primary tumors', 'Disease', (75, 89))
812910	27556701	Therefore, the detectability of mutations in cfDNA derived from primary tumors might be reduced in patients with stage IV ESCC, compared to that in other patients.	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('primary tumors', 'Disease', 'MESH:D009369', (64, 78))	('SCC', 'Gene', '6317', (123, 126))	('patients', 'Species', '9606', (154, 162))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (32, 41))	('primary tumors', 'Disease', (64, 78))	('reduced', 'NegReg', (88, 95))	('SCC', 'Gene', (123, 126))
812942	27437104	B cell depletion in the clinic using anti-CD20 antibodies and/or inhibitors of BTK and/or other signaling pathways, may be a useful strategy for augmenting the anti-tumor immune response.	('BTK', 'Gene', '12229', (79, 82))	('augmenting', 'PosReg', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('BTK', 'Gene', (79, 82))	('anti-CD20', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
812964	27437104	demonstrated that human CD19+CD24hiCD38hi peripheral blood B cells suppressed CD4+ T cell IFN-gamma and TNF-alpha production in vitro, with suppressive activity that was dependent on IL-10, CD80, and CD86.	('CD4+ T cell IFN-gamma', 'MPA', (78, 99))	('human', 'Species', '9606', (18, 23))	('TNF-alpha production', 'MPA', (104, 124))	('suppressed', 'NegReg', (67, 77))	('CD19+CD24hiCD38hi', 'Var', (24, 41))	('blood B cells suppressed', 'Phenotype', 'HP:0010976', (53, 77))
812966	27437104	CD19+CD25hi B cells have also been suggested to represent a Breg population in humans with the capability of suppressing CD4+ T cell proliferation and enhancing CTLA-4 and FoxP3 expression on Treg cells in vitro, in a manner dependent on TGF-beta but not IL-10.	('suppressing', 'NegReg', (109, 120))	('expression', 'MPA', (178, 188))	('FoxP3', 'Gene', (172, 177))	('enhancing', 'PosReg', (151, 160))	('CD4+ T cell', 'MPA', (121, 132))	('humans', 'Species', '9606', (79, 85))	('CD19+CD25hi B', 'Var', (0, 13))	('CTLA-4', 'Gene', (161, 167))
812967	27437104	CD5+ B cells have also been implicated in the suppression of anti-tumor immunity in humans through activation of Stat3, a transcription factor that may be involved in production of IL-10.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('humans', 'Species', '9606', (84, 90))	('tumor', 'Disease', (66, 71))	('CD5+', 'Var', (0, 4))	('suppression', 'NegReg', (46, 57))	('activation', 'PosReg', (99, 109))	('Stat3', 'Gene', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
812973	27437104	These findings suggest that IL-21-dependent GrB+ Bregs may attenuate local anti-tumor immune responses in a manner similar to Tregs, by directly inhibiting the proliferation of CD4+ and CD8+ effector T cells.	('GrB+', 'Protein', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('local', 'MPA', (69, 74))	('attenuate', 'NegReg', (59, 68))	('CD8', 'Gene', '925', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Tregs', 'Chemical', '-', (126, 131))	('tumor', 'Disease', (80, 85))	('proliferation', 'CPA', (160, 173))	('inhibiting', 'NegReg', (145, 155))	('Bregs', 'Var', (49, 54))	('CD8', 'Gene', (186, 189))
812975	27437104	The anti-tumor effect conferred by B cell deficiency in all three models was associated with increased T cell and NK cell infiltration and more vigorous Th1 cytokine and cytolytic T cell responses, and in EMT-6 was also associated with decreased proliferation of CD4+FoxP3+ Tregs.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('EMT', 'Gene', '16428', (205, 208))	('increased', 'PosReg', (93, 102))	('more vigorous', 'PosReg', (139, 152))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('deficiency', 'Var', (42, 52))	('Tregs', 'Chemical', '-', (274, 279))	('increased T cell', 'Phenotype', 'HP:0100828', (93, 109))	('EMT', 'Gene', (205, 208))	('tumor', 'Disease', (9, 14))	('proliferation', 'CPA', (246, 259))	('decreased', 'NegReg', (236, 245))
812979	27437104	Pulmonary metastasis of murine 4 T1 breast cancer requires inactivation of antitumor NK cells and expansion of Treg cells.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('breast cancer', 'Disease', (36, 49))	('tumor', 'Disease', (79, 84))	('inactivation', 'Var', (59, 71))	('murine', 'Species', '10090', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Pulmonary metastasis', 'CPA', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
812980	27437104	identified a CD25+CD19+B220+ B cell subset designated as tumor-evoked Bregs (tBregs), that constitutively expressed Stat3 and was expanded in 4 T1 tumor-bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('mice', 'Species', '10090', (161, 165))	('tBregs', 'Chemical', '-', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (57, 62))	('CD25+CD19+B220+', 'Var', (13, 28))
812982	27437104	Furthermore, T cell inhibitory activity was restricted to CD25+, but not CD25- cancer-CM treated B cells.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('T cell', 'CPA', (13, 19))	('CD25+', 'Var', (58, 63))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
812985	27437104	WT mice also developed expansion of FoxP3+ Tregs in peripheral blood in vivo when injected with tBregs, but not control B cells.	('Tregs', 'Chemical', '-', (43, 48))	('mice', 'Species', '10090', (3, 7))	('expansion', 'PosReg', (23, 32))	('FoxP3+', 'Var', (36, 42))	('tBregs', 'Chemical', '-', (96, 102))
812987	27437104	These results indicate that a unique CD25+CD19+B220+ B cell subset that constitutively expresses Stat3 may be expanded by tumors, and may in turn promote tumor metastasis through TGFbeta-dependent conversion of non-Tregs to Tregs.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('TGFbeta', 'Gene', '21803', (179, 186))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('Tregs', 'Chemical', '-', (215, 220))	('TGFbeta', 'Gene', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CD25+CD19+B220+', 'Var', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Tregs', 'Chemical', '-', (224, 229))	('promote', 'PosReg', (146, 153))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (154, 159))
812989	27437104	In the B16 melanoma mouse model, vaccination against either of the tumor-associated antigens (TAA) gp100 or TRP-2 using adenovirus-based vectors suppressed tumor growth in B-cell deficient, but not WT mice.	('mouse', 'Species', '10090', (20, 25))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('TRP-2', 'Gene', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('TRP-2', 'Gene', '104042', (108, 113))	('vaccination', 'Var', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (156, 161))	('gp100', 'Gene', (99, 104))	('mice', 'Species', '10090', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('suppressed', 'NegReg', (145, 155))	('tumor', 'Disease', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
812995	27437104	T2-MZP B cells accumulate in tumor-draining lymph nodes and promote metastasis independently of IL-10 EMT-6 mammary tumors are rejected or show markedly diminished growth in BCDM but growth is restored in BCDM reconstituted with B cells.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('promote', 'PosReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('T2-MZP', 'Var', (0, 6))	('EMT', 'Gene', '16428', (102, 105))	('diminished', 'NegReg', (153, 163))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('growth', 'MPA', (164, 170))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('metastasis', 'CPA', (68, 78))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))	('EMT', 'Gene', (102, 105))
813008	27437104	In this model, B16-F10 melanoma induces accumulation of T2-MZP Bregs in TDLN, which in turn promote tumor growth and metastasis, and appear to do so independently of IL-10 and/or Tregs.	('TDLN', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('promote', 'PosReg', (92, 99))	('T2-MZP', 'Var', (56, 62))	('tumor', 'Disease', (100, 105))	('Tregs', 'Chemical', '-', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('melanoma', 'Disease', (23, 31))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('B16-F10', 'Var', (15, 22))	('accumulation', 'PosReg', (40, 52))	('metastasis', 'CPA', (117, 127))
813016	27437104	Consistent with the finding that CD19+CD25+ tumor-evoked Bregs (tBregs) constitutively express Stat3 and promote tumor growth and metastasis by TGFbeta-dependent conversion of non-Tregs to Tregs, Lee-Chang et al.	('Stat3', 'MPA', (95, 100))	('tumor', 'Disease', (113, 118))	('promote', 'PosReg', (105, 112))	('CD19+CD25+', 'Var', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Tregs', 'Chemical', '-', (189, 194))	('TGFbeta', 'Gene', (144, 151))	('tBregs', 'Chemical', '-', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Tregs', 'Chemical', '-', (180, 185))	('tumor', 'Disease', (44, 49))	('TGFbeta', 'Gene', '21803', (144, 151))
813019	27437104	tBregs treated with RSV also had decreased expression of phosphorylated Stat3 (pStat3) and TGFbeta compared to mock-treated tBregs.	('tBregs', 'Chemical', '-', (0, 6))	('tBregs', 'Chemical', '-', (124, 130))	('TGFbeta', 'Gene', (91, 98))	('RSV', 'Var', (20, 23))	('TGFbeta', 'Gene', '21803', (91, 98))	('phosphorylated', 'MPA', (57, 71))	('decreased', 'NegReg', (33, 42))	('expression', 'MPA', (43, 53))	('RSV', 'Chemical', 'MESH:D000077185', (20, 23))
813020	27437104	Furthermore, RSV-treated tBregs adoptively transferred into 4 T1 tumor-bearing mice lacked the ability to expand FoxP3+ Tregs in vivo and promote lung metastasis as compared to mock-treated tBregs.	('lung metastasis', 'CPA', (146, 161))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tBregs', 'Chemical', '-', (190, 196))	('expand', 'PosReg', (106, 112))	('Tregs', 'Chemical', '-', (120, 125))	('mice', 'Species', '10090', (79, 83))	('FoxP3+', 'Var', (113, 119))	('promote', 'PosReg', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('RSV', 'Chemical', 'MESH:D000077185', (13, 16))	('lacked', 'NegReg', (84, 90))	('tBregs', 'Chemical', '-', (25, 31))
813021	27437104	These findings suggest that inhibition of Stat3 phosphorylation in Bregs, by RSV or other methods, may inhibit tumor growth by preventing the downstream local elaboration of TGF-beta and subsequent promotion of FoxP3+ Tregs.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('TGF-beta', 'Protein', (174, 182))	('Tregs', 'Chemical', '-', (218, 223))	('FoxP3+ Tregs', 'CPA', (211, 223))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('inhibition', 'Var', (28, 38))	('Stat3 phosphorylation', 'MPA', (42, 63))	('tumor', 'Disease', (111, 116))	('promotion', 'PosReg', (198, 207))	('RSV', 'Chemical', 'MESH:D000077185', (77, 80))	('preventing', 'NegReg', (127, 137))	('inhibit', 'NegReg', (103, 110))
813026	27437104	In T- and B-cell deficient Rag1-/- mice, growth of B16 and Lewis Lung cancer (LLC) tumors was augmented following the adoptive transfer of Stat3+/+ B cells, while growth was diminished with adoptive transfer of Stat3-/- B cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Rag1', 'Gene', '19373', (27, 31))	('Lewis Lung cancer (LLC) tumors', 'Disease', 'MESH:D008175', (59, 89))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Rag1', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('B16', 'CPA', (51, 54))	('Lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('augmented', 'PosReg', (94, 103))	('mice', 'Species', '10090', (35, 39))	('growth', 'MPA', (41, 47))	('Stat3+/+ B cells', 'Var', (139, 155))
813027	27437104	Augmented tumor growth with Stat3+/+ B cell adoptive transfer was associated with increased tumor angiogenesis in vivo by Matrigel assay and in vitro in B cell: endothelial cell co-culture assays, and increased expression of pro-angiogenic genes by RNA in vivo.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('increased', 'PosReg', (201, 210))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('increased tumor', 'Disease', 'MESH:D009369', (82, 97))	('increased tumor', 'Disease', (82, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('expression', 'MPA', (211, 221))	('Stat3+/+ B cell', 'Var', (28, 43))
813029	27437104	Furthermore, Stat3 activity in human tumor tissues was associated with increased density of TIL-B cells and significantly increased intratumoral angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (137, 142))	('density', 'CPA', (81, 88))	('human', 'Species', '9606', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('increased', 'PosReg', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('Stat3 activity', 'Var', (13, 27))	('increased', 'PosReg', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
813032	27437104	Inhibition of Stat3 signaling may therefore be a useful means of reducing or reversing Breg promotion of tumor growth.	('Breg', 'Disease', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (105, 110))	('reversing', 'NegReg', (77, 86))
813040	27437104	Bruton's tyrosine kinase (BTK) expression in B cells and macrophages, as a target for regulation of immune-suppressive phenotypes IL-35+ Bregs have been shown to inhibit Th1 and Th17 cells and promote Treg expansion in a mouse model of autoimmune uveitis.	('promote', 'PosReg', (193, 200))	('inhibit', 'NegReg', (162, 169))	('Th17 cells', 'CPA', (178, 188))	('BTK', 'Gene', (26, 29))	('Treg expansion', 'CPA', (201, 215))	('uveitis', 'Phenotype', 'HP:0000554', (247, 254))	('mouse', 'Species', '10090', (221, 226))	("Bruton's tyrosine kinase", 'Gene', (0, 24))	('autoimmune uveitis', 'Disease', 'MESH:D014605', (236, 254))	('BTK', 'Gene', '12229', (26, 29))	('IL-35+ Bregs', 'Var', (130, 142))	('autoimmune uveitis', 'Disease', (236, 254))	("Bruton's tyrosine kinase", 'Gene', '12229', (0, 24))
813050	27437104	These results indicate that inhibition of BTK in tumor-infiltrating B cells may promote macrophage repolarization from an immune-suppressive, tumorigenic M2-type toward a pro-inflammatory, anti-tumor M1-type.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('macrophage', 'CPA', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('BTK', 'Gene', '12229', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (49, 54))	('inhibition', 'Var', (28, 38))	('tumor', 'Disease', (194, 199))	('BTK', 'Gene', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('promote', 'PosReg', (80, 87))
813055	27437104	These findings have provided a rationale for clinical trials examining the use of ibrutinib as adjunctive therapy to gemcitabine and nab-paclitaxel in metastatic pancreatic carcinoma (NCT02562898, NCT02436668).	('pancreatic carcinoma', 'Disease', (162, 182))	('gemcitabine', 'Chemical', 'MESH:C056507', (117, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (162, 182))	('NCT02562898', 'Var', (184, 195))	('ibrutinib', 'Chemical', 'MESH:C551803', (82, 91))	('NCT02436668', 'Var', (197, 208))	('paclitaxel', 'Chemical', 'MESH:D017239', (137, 147))
813057	27437104	However, administration of alpha-CD20 mAb to WT mice with established 4 T1 tumors unexpectedly resulted in significantly enhanced tumor growth and metastasis.	('tumor', 'Disease', (130, 135))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('alpha-CD20 mAb', 'Var', (27, 41))	('mice', 'Species', '10090', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('enhanced', 'PosReg', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('tumor', 'Disease', (75, 80))
813059	27437104	Consistent with these findings in mice, co-culture of human peripheral blood B cells with human breast cancer or colon cancer cells resulted in emergence of a CD20low Breg population that suppressed T-cell activity and was sustained after treatment with alpha-CD20 mAb in vitro.	('T-cell activity', 'CPA', (199, 214))	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('mice', 'Species', '10090', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('suppressed', 'NegReg', (188, 198))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('colon cancer', 'Disease', (113, 125))	('human', 'Species', '9606', (90, 95))	('breast cancer', 'Disease', (96, 109))	('CD20low', 'Var', (159, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('human', 'Species', '9606', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
813061	27437104	Treatment of 4 T1 tumor-bearing mice with CpG-ODN abrogated lung metastasis, and ex vivo B cells derived from CpG-ODN treated tumor-bearing mice induced T cell proliferation and expansion of GrB+CD8+ cytolytic T cells.	('CpG-ODN', 'Chemical', 'MESH:C408982', (42, 49))	('CpG-ODN', 'Chemical', 'MESH:C408982', (110, 117))	('T cell proliferation', 'CPA', (153, 173))	('mice', 'Species', '10090', (140, 144))	('tumor', 'Disease', (18, 23))	('induced', 'PosReg', (145, 152))	('abrogated', 'NegReg', (50, 59))	('lung metastasis', 'CPA', (60, 75))	('CD8', 'Gene', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('CD8', 'Gene', '925', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mice', 'Species', '10090', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('expansion', 'PosReg', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('CpG-ODN', 'Var', (110, 117))	('tumor', 'Disease', (126, 131))
813063	27437104	4-1BBL (CD137L) is an immune co-stimulatory receptor and a member of the TNF receptor family, which activates CD8+ T cells and NK cells via cross-linking of 4-1BB (CD137) expressed primarily on T cells.	('activates', 'PosReg', (100, 109))	('CD137', 'Gene', '21942', (8, 13))	('4-1BBL', 'Gene', '21950', (0, 6))	('4-1BB', 'Gene', (157, 162))	('4-1BBL', 'Gene', (0, 6))	('4-1BB', 'Gene', (0, 5))	('4-1BB', 'Gene', '21942', (157, 162))	('CD137', 'Gene', (8, 13))	('CD137L', 'Gene', (8, 14))	('cross-linking', 'Var', (140, 153))	('4-1BB', 'Gene', '21942', (0, 5))	('CD137', 'Gene', '21942', (164, 169))	('NK cells', 'CPA', (127, 135))	('CD8', 'Gene', (110, 113))	('CD137L', 'Gene', '21950', (8, 14))	('CD137', 'Gene', (164, 169))	('CD8', 'Gene', '925', (110, 113))
813064	27437104	investigators observed that human and murine CD20low Bregs also had reduced 4-1BBL expression compared to normal B cells.	('human', 'Species', '9606', (28, 33))	('4-1BBL', 'Gene', (76, 82))	('4-1BBL', 'Gene', '21950', (76, 82))	('CD20low', 'Var', (45, 52))	('murine', 'Species', '10090', (38, 44))	('reduced', 'NegReg', (68, 75))
813066	27437104	Consistent with the results seen in the 4 T1 murine model, the depletion of B cells using alpha-CD20 mAb in mice inoculated with EMT-6 did not result in tumor rejection as expected, and was associated with a paradoxical increase of CD4+FoxP3+ Tregs in the spleens of treated mice, although a role for 4-1BBL was not investigated in the EMT-6 model.	('murine', 'Species', '10090', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('EMT', 'Gene', (336, 339))	('mice', 'Species', '10090', (275, 279))	('EMT', 'Gene', '16428', (129, 132))	('alpha-CD20 mAb', 'Var', (90, 104))	('CD4+FoxP3+ Tregs', 'CPA', (232, 248))	('EMT', 'Gene', '16428', (336, 339))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('Tregs', 'Chemical', '-', (243, 248))	('4-1BBL', 'Gene', '21950', (301, 307))	('4-1BBL', 'Gene', (301, 307))	('EMT', 'Gene', (129, 132))	('increase', 'PosReg', (220, 228))
813071	27437104	The anti-tumor effect conferred by B cell deficiency was associated with enhanced CD8+ cell infiltration in both tumor types.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('CD8', 'Gene', (82, 85))	('CD8', 'Gene', '925', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('deficiency', 'Var', (42, 52))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('enhanced', 'PosReg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
813073	27437104	In addition, ablation of B cell TGFbetaR2 inhibited oxaliplatin-induced IgA+ plasma cell generation, blocked induction of tumoral PD-L1+ by oxaliplatin and was associated with increased tumoral CTL density and IFN-gamma production, thus implicating TGF-beta signaling in the generation of this Breg subpopulation.	('oxaliplatin-induced IgA+ plasma cell generation', 'MPA', (52, 99))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('blocked', 'NegReg', (101, 108))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('TGFbeta', 'Gene', '21803', (32, 39))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (52, 63))	('induction', 'MPA', (109, 118))	('ablation', 'Var', (13, 21))	('increased tumor', 'Disease', (176, 191))	('tumor', 'Disease', (186, 191))	('IFN-gamma production', 'MPA', (210, 230))	('inhibited', 'NegReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('increased tumor', 'Disease', 'MESH:D009369', (176, 191))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (140, 151))	('TGFbeta', 'Gene', (32, 39))	('tumor', 'Disease', (122, 127))
813077	27437104	These results indicate that treatment with an immunogenic chemotherapeutic agent, oxaliplatin, may induce a CD138+IgA+PD-L1+IL-10+ Breg population generated via a TGFbeta-dependent pathway that limits the effectiveness of oxaliplatin by inhibiting intratumoral CTL infiltration.	('CD138+IgA+PD-L1+IL-10+', 'Var', (108, 130))	('TGFbeta', 'Gene', '21803', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('inhibiting', 'NegReg', (237, 247))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (222, 233))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (82, 93))	('TGFbeta', 'Gene', (163, 170))
813080	27437104	In the K14-HPV16 (HPV16) transgenic mouse model of inflammation-associated de novo epithelial carcinogenesis, the absence of T- and B-lymphocytes (generated by intercrossing with Rag1-/- mice) limits immune cell infiltration and attenuates characteristic markers of premalignancy such as VEGF-A activity, matrix metalloproteinase activity, epithelial hyperproliferation, and development of angiogenic vasculature.	('VEGF-A', 'Gene', '22339', (288, 294))	('absence', 'Var', (114, 121))	('epithelial carcinogenesis', 'Disease', 'MESH:D063646', (83, 108))	('mice', 'Species', '10090', (187, 191))	('activity', 'MPA', (295, 303))	('inflammation', 'Disease', 'MESH:D007249', (51, 63))	('VEGF-A', 'Gene', (288, 294))	('development of angiogenic vasculature', 'CPA', (375, 412))	('Rag1', 'Gene', '19373', (179, 183))	('immune cell infiltration', 'CPA', (200, 224))	('epithelial hyperproliferation', 'CPA', (340, 369))	('Rag1', 'Gene', (179, 183))	('HPV16', 'Species', '333760', (18, 23))	('HPV16', 'Species', '333760', (11, 16))	('activity', 'MPA', (330, 338))	('inflammation', 'Disease', (51, 63))	('matrix metalloproteinase', 'Enzyme', (305, 329))	('mouse', 'Species', '10090', (36, 41))	('epithelial carcinogenesis', 'Disease', (83, 108))	('limits', 'NegReg', (193, 199))	('attenuates', 'NegReg', (229, 239))
813094	27437104	TNFalpha-/- mice treated with DMBA/TPA also had reduced absolute numbers of splenic IL-10+CD19+ cells and increased absolute numbers of CD8+IFN-gamma+ T cells in the spleen and lymph nodes compared to DMBA/TPA-treated WT mice.	('TNFalpha', 'Gene', (0, 8))	('DMBA/TPA', 'Chemical', '-', (201, 209))	('splenic IL-10+CD19+ cells', 'MPA', (76, 101))	('CD8+IFN-gamma', 'Gene', '15978', (136, 149))	('reduced', 'NegReg', (48, 55))	('CD8+IFN-gamma', 'Gene', (136, 149))	('DMBA/TPA', 'Chemical', '-', (30, 38))	('mice', 'Species', '10090', (221, 225))	('TNFalpha', 'Gene', '21926', (0, 8))	('DMBA/TPA', 'Var', (30, 38))	('mice', 'Species', '10090', (12, 16))	('increased', 'PosReg', (106, 115))
813098	27437104	Interestingly, B cell depletion with alpha-CD20 mAb was efficacious in suppressing tumor growth as an adjunct to chemotherapy in the squamous carcinoma mouse model and was efficacious as monotherapy in a mouse model of pancreatic cancer, however treatment with alpha-CD20 mAb accelerated tumor growth in mouse breast cancer models.	('tumor', 'Disease', (83, 88))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (133, 151))	('alpha-CD20', 'Var', (37, 47))	('breast cancer', 'Disease', 'MESH:D001943', (310, 323))	('breast cancer', 'Disease', (310, 323))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('accelerated', 'PosReg', (276, 287))	('pancreatic cancer', 'Disease', 'MESH:D010190', (219, 236))	('squamous carcinoma', 'Disease', 'MESH:D002294', (133, 151))	('mouse', 'Species', '10090', (204, 209))	('tumor', 'Disease', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('pancreatic cancer', 'Disease', (219, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('mouse', 'Species', '10090', (304, 309))	('suppressing', 'NegReg', (71, 82))	('squamous carcinoma', 'Disease', (133, 151))	('mouse', 'Species', '10090', (152, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (219, 236))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('breast cancer', 'Phenotype', 'HP:0003002', (310, 323))
813107	27437104	Inhibition of IKKalpha, STAT3, LTbetaR, as well as B cell-specific LTbeta ablation were each independently capable of delaying CR-CaP growth.	('ablation', 'Var', (74, 82))	('LTbetaR', 'Gene', '17000', (31, 38))	('CR-CaP', 'Chemical', '-', (127, 133))	('CR-CaP growth', 'CPA', (127, 140))	('delaying', 'NegReg', (118, 126))	('LTbeta', 'Gene', (67, 73))	('STAT3', 'Gene', '20848', (24, 29))	('IKKalpha', 'Gene', '12675', (14, 22))	('STAT3', 'Gene', (24, 29))	('LTbetaR', 'Gene', (31, 38))	('IKKalpha', 'Gene', (14, 22))
813111	27437104	showed that hypoxia-driven HIF1alpha expression and stabilization occurred in the early growth stages of both murine KrasG12D PDAC and human PDAC tumors, and that the deletion of pancreas-specific Hif1alpha in mice harboring KrasG12D tumors resulted in accelerated tumor growth and was associated with an influx of intra-pancreatic B cells.	('tumor', 'Disease', (234, 239))	('PDAC', 'Chemical', '-', (126, 130))	('KrasG12D', 'Gene', '16653', (117, 125))	('influx', 'PosReg', (305, 311))	('tumor', 'Disease', (146, 151))	('PDAC', 'Chemical', '-', (141, 145))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('deletion', 'Var', (167, 175))	('PDAC', 'Phenotype', 'HP:0006725', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('PDAC', 'Phenotype', 'HP:0006725', (141, 145))	('murine', 'Species', '10090', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('Hif1alpha', 'Gene', '3091', (197, 206))	('mice', 'Species', '10090', (210, 214))	('HIF1alpha', 'Gene', '15251', (27, 36))	('accelerated', 'PosReg', (253, 264))	('tumor', 'Disease', (265, 270))	('human', 'Species', '9606', (135, 140))	('KrasG12D', 'Gene', '16653', (225, 233))	('HIF1alpha', 'Gene', (27, 36))	('KrasG12D', 'Gene', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('Hif1alpha', 'Gene', (197, 206))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('hypoxia', 'Disease', (12, 19))	('intra-pancreatic', 'Disease', (315, 331))	('KrasG12D', 'Gene', (225, 233))	('intra-pancreatic', 'Disease', 'MESH:D010195', (315, 331))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumors', 'Disease', (234, 240))	('tumors', 'Disease', (146, 152))	('hypoxia', 'Disease', 'MESH:D000860', (12, 19))
813134	27437104	IGKC expression was also associated with better prognosis in non-small cell lung cancer (NSCLC) and colorectal adenocarcinoma (CRC) cohorts.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (65, 87))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (61, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('colorectal adenocarcinoma', 'Disease', (100, 125))	('expression', 'Var', (5, 15))	('non-small cell lung cancer', 'Disease', (61, 87))	('better', 'PosReg', (41, 47))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (100, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (61, 87))	('IGKC', 'Gene', (0, 4))	('NSCLC', 'Disease', (89, 94))	('CR', 'Chemical', 'MESH:D002857', (127, 129))
813136	27437104	Increased tumor infiltration of CD20+ B cells has also been shown to portend a better prognosis among patients with epithelial ovarian cancer (EOC).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('ovarian cancer', 'Phenotype', 'HP:0100615', (127, 141))	('tumor', 'Disease', (10, 15))	('patients', 'Species', '9606', (102, 110))	('epithelial ovarian cancer', 'Disease', (116, 141))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (116, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('CD20+ B cells', 'Var', (32, 45))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
813140	27437104	CD8+ TILs conferred a better prognosis only in the presence of adjacent CD4+ T cell TILs, CD20+ B cell TILs, and CD138+ plasma cells.	('CD8', 'Gene', '925', (0, 3))	('CD20+ B cell', 'Var', (90, 102))	('CD8', 'Gene', (0, 3))
813142	27437104	demonstrated that in patients with EOC, increased tumoral CD20+ and CD138+ expression by IHC was associated with advanced tumor grade, and CD138 expression correlated significantly with reduced overall and cancer-specific survival.	('IHC', 'Gene', (89, 92))	('CD138+', 'Var', (68, 74))	('increased tumor', 'Disease', 'MESH:D009369', (40, 55))	('increased tumor', 'Disease', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('CD138', 'Var', (139, 144))	('reduced', 'NegReg', (186, 193))	('CD20+', 'Var', (58, 63))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', (122, 127))	('expression', 'MPA', (75, 85))
813143	27437104	In patients with primary operable invasive ductal breast cancer, increased CD138+ B-cell infiltration was also independently associated with poorer recurrence-free survival.	('invasive ductal breast cancer', 'Disease', 'MESH:D018270', (34, 63))	('increased', 'PosReg', (65, 74))	('invasive ductal breast cancer', 'Disease', (34, 63))	('poorer', 'NegReg', (141, 147))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('CD138+', 'Var', (75, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
813147	27437104	Alternatively, CD20+ and CD138+ TIL-Bs may function to suppress T cell anti-tumor responses as in Bregs or promote tumor progression by nurturing an inflammatory microenvironment.	('CD138+', 'Var', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('promote', 'PosReg', (107, 114))	('Bregs', 'Disease', (98, 103))	('suppress', 'NegReg', (55, 63))	('CD20+', 'Var', (15, 20))
813148	27437104	In contrast to the conflicting results regarding significance of general tumor infiltration with CD20+ B cells and CD138+ plasma cells in humans, the majority of studies examining infiltration of tumors with B cells that have an established regulatory phenotype (CD38hiCD24hi, CD5 + CD1dhi, CD24hiCD27+, IL-10+) have demonstrated that Breg infiltration is associated with impaired anti-tumor immunity and more aggressive disease.	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('aggressive disease', 'Disease', (410, 428))	('CD24hiCD27+', 'Var', (291, 302))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (386, 391))	('CD38hiCD24hi', 'Var', (263, 275))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('aggressive disease', 'Disease', 'MESH:D001523', (410, 428))	('tumor', 'Disease', 'MESH:D009369', (386, 391))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('CD1', 'Gene', '911', (283, 286))	('Breg infiltration', 'Disease', (335, 352))	('CD1', 'Gene', (283, 286))	('tumors', 'Disease', (196, 202))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('CD1', 'Gene', '911', (115, 118))	('CD1', 'Gene', (115, 118))	('humans', 'Species', '9606', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (196, 202))
813150	27437104	IL-10+ Breg frequency also correlated with clinical staging and disease progression in esophageal cancer patients, as higher frequencies were seen in the peripheral blood of patients with Stage III/IV disease compared to early stage disease patients.	('higher', 'PosReg', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (105, 113))	('esophageal cancer', 'Disease', (87, 104))	('patients', 'Species', '9606', (241, 249))	('stage disease', 'Disease', 'MESH:D058625', (227, 240))	('IV disease', 'Disease', 'MESH:D020432', (198, 208))	('patients', 'Species', '9606', (174, 182))	('IV disease', 'Disease', (198, 208))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('correlated', 'Reg', (27, 37))	('IL-10+ Breg', 'Var', (0, 11))	('stage disease', 'Disease', (227, 240))
813151	27437104	demonstrated that in patients with ovarian cancer and ascites, CD19+IL-10+ Breg frequency was increased in ascitic fluid compared to peripheral blood.	('ascites', 'Disease', 'MESH:D001201', (54, 61))	('ascites', 'Disease', (54, 61))	('ascites', 'Phenotype', 'HP:0001541', (54, 61))	('increased', 'PosReg', (94, 103))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('patients', 'Species', '9606', (21, 29))	('ovarian cancer', 'Disease', 'MESH:D010051', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('CD19+IL-10+', 'Var', (63, 74))	('ovarian cancer', 'Disease', (35, 49))
813152	27437104	Furthermore, frequency of ascitic IL-10+ Bregs correlated with advanced stage and was associated with increased ascitic CD4+FoxP3+ Treg frequency and decreased ascitic CD8+IFN-gamma+ T cell frequency.	('advanced stage', 'CPA', (63, 77))	('CD8+IFN-gamma', 'Gene', (168, 181))	('CD8+IFN-gamma', 'Gene', '15978', (168, 181))	('ascitic', 'MPA', (112, 119))	('decreased ascitic', 'Disease', 'MESH:D001201', (150, 167))	('increased', 'PosReg', (102, 111))	('IL-10+ Bregs', 'Var', (34, 46))	('decreased ascitic', 'Disease', (150, 167))
813154	27437104	Analysis of biopsy specimens from patients with tongue squamous cell carcinoma (TSCC) revealed increased frequency of CD19+IL-10+ Bregs in tumor tissue and metastatic lymph nodes compared to adjacent normal tissue.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 78))	('tongue squamous cell carcinoma', 'Disease', (48, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('CD19+IL-10+ Bregs', 'Var', (118, 135))	('patients', 'Species', '9606', (34, 42))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
813156	27437104	showed that CD19+CD24hiCD38hi IL-10+ Bregs were more prevalent in the peripheral blood of patients with gastric cancer versus healthy controls.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('CD19+CD24hiCD38hi IL-10+', 'Var', (12, 36))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (90, 98))	('gastric cancer', 'Disease', (104, 118))
813157	27437104	In gastric cancer patients, IL-10+ Bregs were more prevalent in tumor tissues versus non-tumoral tissues and peripheral blood.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('prevalent', 'Reg', (51, 60))	('tumor', 'Disease', (64, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('IL-10+', 'Var', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('patients', 'Species', '9606', (18, 26))	('gastric cancer', 'Disease', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
813159	27437104	In patients with CRC, CD24hiCD38hi Bregs and CD24hiCD27+ Bregs were present in tumors and the frequency of CD24hiCD38hi Bregs was significantly elevated in advanced stage tumors.	('CR', 'Chemical', 'MESH:D002857', (17, 19))	('CD24hiCD38hi', 'Var', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumors', 'Disease', (79, 85))	('CD24hiCD38hi', 'Var', (107, 119))	('elevated', 'PosReg', (144, 152))	('patients', 'Species', '9606', (3, 11))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('CRC', 'Disease', (17, 20))	('tumors', 'Disease', (171, 177))	('CD24hiCD27+', 'Var', (45, 56))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
813165	27437104	Peripheral blood CD19+CD24+CD38+ Breg frequency was significantly greater in HCC patients versus healthy controls, and circulating Breg frequency correlated with advanced staging.	('HCC', 'Disease', (77, 80))	('correlated', 'Reg', (146, 156))	('greater', 'PosReg', (66, 73))	('HCC', 'Phenotype', 'HP:0001402', (77, 80))	('patients', 'Species', '9606', (81, 89))	('CD19+CD24+CD38+', 'Var', (17, 32))	('advanced staging', 'CPA', (162, 178))
813166	27437104	SCID mice injected with human MHCC-97 L HCC cells mice together with human CD19+CD24+CD38+ Bregs demonstrated markedly larger tumor growth at 6 weeks and increased serum IL-10 levels compared to SCID mice injected with HCC cells and CD19+CD24-CD38- non-Bregs.	('HCC', 'Phenotype', 'HP:0001402', (40, 43))	('SCID', 'Disease', 'MESH:D053632', (195, 199))	('larger', 'PosReg', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mice', 'Species', '10090', (5, 9))	('HCC', 'Phenotype', 'HP:0001402', (31, 34))	('serum IL-10 levels', 'MPA', (164, 182))	('human', 'Species', '9606', (24, 29))	('CD19+CD24+CD38+', 'Var', (75, 90))	('MHCC-97 L HCC', 'CellLine', 'CVCL:4973', (30, 43))	('SCID', 'Disease', (195, 199))	('mice', 'Species', '10090', (50, 54))	('increased', 'PosReg', (154, 163))	('human', 'Species', '9606', (69, 74))	('SCID', 'Disease', 'MESH:D053632', (0, 4))	('mice', 'Species', '10090', (200, 204))	('HCC', 'Phenotype', 'HP:0001402', (219, 222))	('tumor', 'Disease', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('SCID', 'Disease', (0, 4))
813167	27437104	In in vitro co-culture studies, Bregs increased HCC cell proliferation, promoted secretion of IL-10 and TGF-beta1 and decreased secretion of TNF-alpha compared to non-Bregs.	('HCC', 'Phenotype', 'HP:0001402', (48, 51))	('TGF-beta1', 'Gene', '21803', (104, 113))	('Bregs', 'Var', (32, 37))	('secretion of TNF-alpha', 'MPA', (128, 150))	('HCC cell proliferation', 'CPA', (48, 70))	('TGF-beta1', 'Gene', (104, 113))	('increased HCC', 'Phenotype', 'HP:0001899', (38, 51))	('decreased', 'NegReg', (118, 127))	('increased', 'PosReg', (38, 47))	('promoted', 'PosReg', (72, 80))	('secretion of IL-10', 'MPA', (81, 99))
813168	27437104	Administration of anti-CD40L antibody blocked HCC tumor growth enhancement by Bregs in vivo, blocked enhancement of HCC cell proliferation by Bregs in vitro and decreased IL-10 and TGF-beta1 secretion while promoting an increase of TNFalpha secretion.	('blocked', 'NegReg', (93, 100))	('anti-CD40L', 'Var', (18, 28))	('enhancement', 'PosReg', (63, 74))	('IL-10', 'MPA', (171, 176))	('HCC tumor', 'Disease', 'MESH:D006528', (46, 55))	('decreased', 'NegReg', (161, 170))	('enhancement', 'PosReg', (101, 112))	('TNFalpha', 'Gene', '21926', (232, 240))	('HCC', 'Phenotype', 'HP:0001402', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('TGF-beta1', 'Gene', '21803', (181, 190))	('HCC tumor', 'Disease', (46, 55))	('HCC', 'Phenotype', 'HP:0001402', (116, 119))	('blocked', 'NegReg', (38, 45))	('TNFalpha', 'Gene', (232, 240))	('HCC cell proliferation', 'CPA', (116, 138))	('increase', 'PosReg', (220, 228))	('TGF-beta1', 'Gene', (181, 190))
813169	27437104	These results suggest that an expanded CD19+CD24+CD38+ peripheral blood Breg population in patients with HCC may migrate to the tumor margin and mediate tumor growth via local elaboration of immunosuppressive cytokines IL-10 and TGF-beta, dependent on cognate interactions between CD40L and CD40 on Bregs and HCC cells respectively.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('patients', 'Species', '9606', (91, 99))	('HCC', 'Disease', (105, 108))	('HCC', 'Phenotype', 'HP:0001402', (105, 108))	('CD19+CD24+CD38+', 'Var', (39, 54))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('migrate', 'CPA', (113, 120))	('tumor', 'Disease', (128, 133))	('HCC', 'Phenotype', 'HP:0001402', (309, 312))
813171	27437104	Recently, a novel tumor-promoting PD-1high Breg subset with CD5highCD24-/+CD27high/+CD38dim phenotype was identified in tumor tissues of patients with HCC and correlated with advanced stage and early disease progression.	('tumor', 'Disease', (18, 23))	('CD5highCD24-/+CD27high/+CD38dim', 'Var', (60, 91))	('patients', 'Species', '9606', (137, 145))	('HCC', 'Disease', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('HCC', 'Phenotype', 'HP:0001402', (151, 154))	('tumor', 'Disease', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
813173	27437104	Increased tumor infiltration with PD-1high IL-10-producing Bregs was associated with reduced number and dysfunction of CD8+ cells.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('CD8', 'Gene', (119, 122))	('tumor', 'Disease', (10, 15))	('dysfunction', 'MPA', (104, 115))	('PD-1high IL-10-producing', 'Var', (34, 58))	('CD8', 'Gene', '925', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('reduced', 'NegReg', (85, 92))
813181	27437104	Additionally, Bregs may express a variety of suppressive ligands including PD-L1, PD-1, CD80, CD86, LAP-TGF-beta, Fas-L, CD40L, and OX40L.	('PD-1', 'Gene', (82, 86))	('PD-L1', 'Gene', (75, 80))	('OX40L', 'Gene', (132, 137))	('CD40L', 'Gene', (121, 126))	('OX40L', 'Gene', '22164', (132, 137))	('CD80', 'Var', (88, 92))	('Fas-L', 'Gene', (114, 119))	('LAP', 'Gene', (100, 103))	('LAP', 'Gene', '13708', (100, 103))	('Fas-L', 'Gene', '14103', (114, 119))	('CD86', 'Gene', (94, 98))
813212	26788492	The pathologic stage of the tumor was T2N1Mx according to AJCC TNM classification.	('T2N1Mx', 'Var', (38, 44))	('tumor', 'Disease', (28, 33))	('TNM', 'Gene', '10178', (63, 66))	('TNM', 'Gene', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
813264	26087861	Extrinsic causes may include central nervous system (CNS) lesions involving the DMN or the vagal nerve fibers, while intrinsic loss may be due to loss of the inhibitory ganglion cells in the myenteric plexus.	('loss', 'NegReg', (146, 150))	('central nervous system', 'Disease', (29, 51))	('DMN', 'Chemical', '-', (80, 83))	('lesions', 'Var', (58, 65))
813265	26087861	Kimura was the first to suggest lesions in the CNS could explain the clinical and manometric findings in achalasia.	('lesions', 'Var', (32, 39))	('achalasia', 'Phenotype', 'HP:0002571', (105, 114))	('achalasia', 'Disease', 'MESH:D004931', (105, 114))	('achalasia', 'Disease', (105, 114))
813273	26087861	Thus, these studies suggest that lesions located in the CNS may produce manometric findings of achalasia.	('lesions', 'Var', (33, 40))	('achalasia', 'Phenotype', 'HP:0002571', (95, 104))	('achalasia', 'Disease', (95, 104))	('manometric', 'MPA', (72, 82))	('achalasia', 'Disease', 'MESH:D004931', (95, 104))
813274	26087861	Abnormality in the vagal nerve fiber outside the CNS has also been associated with achalasia.	('achalasia', 'Disease', 'MESH:D004931', (83, 92))	('Abnormality', 'Var', (0, 11))	('achalasia', 'Phenotype', 'HP:0002571', (83, 92))	('associated', 'Reg', (67, 77))	('achalasia', 'Disease', (83, 92))
813287	26087861	However, in patients with achalasia, administration of CCK-OP caused paradoxical increase in LES pressure due to the absence of inhibitory neurons resulting in unopposed direct excitatory effect of CCK-OP on the LES smooth muscle (Fig.	('LES pressure', 'MPA', (93, 105))	('patients', 'Species', '9606', (12, 20))	('direct excitatory effect', 'MPA', (170, 194))	('achalasia', 'Disease', (26, 35))	('achalasia', 'Disease', 'MESH:D004931', (26, 35))	('inhibitory', 'Protein', (128, 138))	('CCK-OP', 'Var', (55, 61))	('absence', 'NegReg', (117, 124))	('increase', 'PosReg', (81, 89))	('unopposed', 'PosReg', (160, 169))	('achalasia', 'Phenotype', 'HP:0002571', (26, 35))
813318	26087861	also showed that achalasia patients with associated HLA allele were found to have higher prevalence of circulating antimyenteric autoantibodies, which supported the autoimmune etiology.	('achalasia', 'Phenotype', 'HP:0002571', (17, 26))	('higher', 'PosReg', (82, 88))	('circulating', 'MPA', (103, 114))	('HLA', 'Var', (52, 55))	('patients', 'Species', '9606', (27, 35))	('achalasia', 'Disease', (17, 26))	('antimyenteric', 'Protein', (115, 128))	('achalasia', 'Disease', 'MESH:D004931', (17, 26))
813459	20651033	However, except for the most consistent deletion of 9p21 across different histologic stages and the loss of heterozygosity (LOH) of p53 in the later stages, the results for other chromosomal aberrations are highly heterogeneous in terms of stage, frequency, and size.	('deletion', 'Var', (40, 48))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (179, 202))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (179, 201))	('p21', 'Gene', (53, 56))	('p21', 'Gene', '644914', (53, 56))
813481	20651033	In BM samples, there were only scattered chromosome losses at 3p14.2 (10%), 9p21 (5%), and 16q23.1 (5%); these three events were the most frequent aberrations in LGD samples (68.4%, 68.4%, and 47.4%, respectively) (Table 2).	('losses', 'NegReg', (52, 58))	('16q23.1', 'Var', (91, 98))	('p21', 'Gene', '644914', (77, 80))	('p21', 'Gene', (77, 80))
813491	20651033	21q loss was also a frequent event in EAC (occurring in 35.1% of cases), suggesting that RUNX1 is a potential TSG involved in the development of EAC.	('TSG', 'Gene', (110, 113))	('21q loss', 'Var', (0, 8))	('TSG', 'Gene', '57045', (110, 113))	('RUNX1', 'Gene', (89, 94))	('men', 'Species', '9606', (137, 140))	('RUNX1', 'Gene', '861', (89, 94))
813493	20651033	Many previous studies have shown an increasing accumulation of chromosomal aberrations during the metaplasia-dysplasia-carcinoma sequence of EAC development and the pathogenesis of other malignancies.	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (98, 128))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (63, 85))	('chromosomal aberrations', 'Var', (63, 86))	('malignancies', 'Disease', 'MESH:D009369', (187, 199))	('metaplasia-dysplasia-carcinoma', 'Disease', (98, 128))	('men', 'Species', '9606', (152, 155))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (63, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('malignancies', 'Disease', (187, 199))
813500	20651033	We confirmed the same deletion in both dysplastic and EAC tissues.	('dysplastic', 'Disease', 'MESH:D004416', (39, 49))	('deletion', 'Var', (22, 30))	('EAC', 'Disease', (54, 57))	('dysplastic', 'Disease', (39, 49))
813503	20651033	Previous studies have shown that bile acid induces inflammation and oxidative stress, which in turn activates CFS regions.	('activates', 'PosReg', (100, 109))	('induces', 'Reg', (43, 50))	('inflammation', 'Disease', (51, 63))	('oxidative stress', 'Phenotype', 'HP:0025464', (68, 84))	('bile acid', 'Var', (33, 42))	('oxidative', 'CPA', (68, 77))	('bile acid', 'Chemical', 'MESH:D001647', (33, 42))	('CFS regions', 'CPA', (110, 121))	('inflammation', 'Disease', 'MESH:D007249', (51, 63))
813505	20651033	found homozygous focal deletions within PDE4D in lung adenocarcinoma.	('deletions', 'Var', (23, 32))	('lung adenocarcinoma', 'Disease', (49, 68))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (49, 68))	('PDE4D', 'Gene', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (49, 68))	('PDE4D', 'Gene', '5144', (40, 45))
813508	20651033	Focal loss of RUNX1 occurred in two LGD and three HGD samples, and 21q loss was frequent in EAC (Table 2).	('loss', 'NegReg', (6, 10))	('RUNX1', 'Gene', '861', (14, 19))	('EAC', 'Disease', (92, 95))	('loss', 'NegReg', (71, 75))	('21q', 'Var', (67, 70))	('RUNX1', 'Gene', (14, 19))
813514	20651033	These data are consistent with previous reports that p16 drives the early progression of metaplasia and that p53 inactivation is a late event that permits further genomic instability and promotes aneuploidy.	('aneuploidy', 'Disease', (196, 206))	('p16', 'Gene', (53, 56))	('genomic instability', 'CPA', (163, 182))	('aneuploidy', 'Disease', 'MESH:D000782', (196, 206))	('metaplasia', 'Disease', 'MESH:D008679', (89, 99))	('p16', 'Gene', '1029', (53, 56))	('permits', 'PosReg', (147, 154))	('p53', 'Gene', (109, 112))	('metaplasia', 'Disease', (89, 99))	('promotes', 'PosReg', (187, 195))	('p53', 'Gene', '7157', (109, 112))	('inactivation', 'Var', (113, 125))
813529	20651033	This study also provided strong evidence that genetic instability, as evidenced by the early and extensive occurrence of microdeletions in CFS regions, and 9p21 loss drive the early progression from metaplasia to dysplasia and that p53 is critical in carcinoma development.	('p21', 'Gene', (157, 160))	('CFS regions', 'Gene', (139, 150))	('metaplasia to dysplasia', 'Disease', (199, 222))	('p21', 'Gene', '644914', (157, 160))	('microdeletions', 'Var', (121, 135))	('carcinoma', 'Disease', (251, 260))	('men', 'Species', '9606', (268, 271))	('p53', 'Gene', (232, 235))	('metaplasia to dysplasia', 'Disease', 'MESH:D008679', (199, 222))	('p53', 'Gene', '7157', (232, 235))	('loss', 'NegReg', (161, 165))	('carcinoma', 'Disease', 'MESH:D002277', (251, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
813533	20332323	Because Selenium Binding Protein 1 (SELENBP1, SBP1, hSP56) has been shown to bind selenium covalently and selenium deficiency has been associated with esophageal adenocarcinoma (EAC), we examined its role in EAC development and its potential effect on chemosensitivity in the presence of selenium.	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('hSP56', 'Gene', (52, 57))	('esophageal adenocarcinoma', 'Disease', (151, 176))	('deficiency', 'Var', (115, 125))	('Selenium Binding Protein 1', 'Gene', (8, 34))	('EAC', 'Phenotype', 'HP:0011459', (178, 181))	('hSP56', 'Gene', '8991', (52, 57))	('SBP1', 'Gene', (46, 50))	('associated with', 'Reg', (135, 150))	('selenium', 'Chemical', 'MESH:D012643', (288, 296))	('SBP1', 'Gene', '1954', (46, 50))	('selenium', 'Chemical', 'MESH:D012643', (82, 90))	('bind', 'Interaction', (77, 81))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (151, 176))	('Selenium Binding Protein 1', 'Gene', '8991', (8, 34))	('selenium', 'Chemical', 'MESH:D012643', (106, 114))	('SELENBP1', 'Gene', (36, 44))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (151, 176))	('EAC', 'Phenotype', 'HP:0011459', (208, 211))
813544	20332323	Organic selenium compounds such as methylseleninic acid appear to enhance response to chemotherapeutic agents such as cisplatin and paclitaxel possibly by down-regulation of antiapoptotic signals.	('selenium', 'Chemical', 'MESH:D012643', (8, 16))	('enhance', 'PosReg', (66, 73))	('antiapoptotic signals', 'MPA', (174, 195))	('paclitaxel', 'Chemical', 'MESH:D017239', (132, 142))	('methylseleninic', 'Var', (35, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('methylseleninic acid', 'Chemical', 'MESH:C008493', (35, 55))	('down-regulation', 'NegReg', (155, 170))	('response to chemotherapeutic', 'MPA', (74, 102))
813600	20332323	Nine patient samples exhibited allelic gain (log2 ratio > 0.7) or amplification (log2 ratio > 0.848) at the SELENBP1 locus (Supplemental Figure 1).	('patient', 'Species', '9606', (5, 12))	('allelic', 'Var', (31, 38))	('amplification', 'MPA', (66, 79))	('SELENBP1', 'Gene', (108, 116))	('gain', 'PosReg', (39, 43))
813606	20332323	To determine whether the loss of SELENBP1 expression was due to internal exon deletion or mutation in the coding region of the gene, RT-PCR-amplified cDNA products from patient tumor samples and cell lines were sequenced and compared to the NCBI Genbank database for SELENBP1 using the BLAST program.	('SELENBP1', 'Gene', (33, 41))	('expression', 'MPA', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('patient', 'Species', '9606', (169, 176))	('loss', 'NegReg', (25, 29))	('internal exon deletion', 'Var', (64, 86))	('tumor', 'Disease', (177, 182))
813607	20332323	PCR amplification of 2 regions denoted as the L and mid2 fragments (Figure 4B) indicated several variants (Figure 4C) including an exon 4 deletion (L, exon 4-), deletions of both exons 3 and 4 (L, exon 3-/4-), and an exon 7 deletion (mid2, exon 7-), suggesting the possibility of alternative splicing of the SELENBP1 transcript.	('deletions', 'Var', (161, 170))	('mid2', 'Gene', (234, 238))	('mid2', 'Gene', '11043', (234, 238))	('mid2', 'Gene', (52, 56))	('mid2', 'Gene', '11043', (52, 56))	('deletion', 'Var', (138, 146))
813608	20332323	Although truncated PCR products were detected in all tumor specimens, tumors with higher levels of exon 3-/4- and exon 7--deleted PCR products (Figure 4C) had lower levels of full length PCR products (Figure 4B).	('levels', 'MPA', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('exon', 'Var', (99, 103))	('full length PCR products', 'MPA', (175, 199))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (70, 75))	('higher', 'PosReg', (82, 88))	('lower', 'NegReg', (159, 164))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('exon 7--deleted', 'Var', (114, 129))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
813610	20332323	Conversely, the 2 tumors that expressed the highest levels of SELENBP1 (36T and 39T) had lower levels of both exon 3-/4- and exon 7--deleted PCR products but higher levels of their respective full length products (Figure 4D).	('lower', 'NegReg', (89, 94))	('exon 3-/4-', 'MPA', (110, 120))	('exon', 'Var', (125, 129))	('full length products', 'MPA', (192, 212))	('higher', 'PosReg', (158, 164))	('SELENBP1', 'Gene', (62, 70))	('tumors', 'Disease', (18, 24))	('levels', 'MPA', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
813611	20332323	Interestingly, direct comparison of tumor sample 45T with its matching normal gastric tissue showed a marked increase in the levels of both exon 3-/4-- and exon 7--deleted PCR products in tumor cDNA (data not shown).	('tumor', 'Disease', (188, 193))	('exon 3-/4--', 'MPA', (140, 151))	('increase', 'PosReg', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('exon', 'Var', (156, 160))	('levels of', 'MPA', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (36, 41))
813616	20332323	To examine the biological significance of SELENBP1 expression in esophageal adenocarcinoma, Flo-1 cells were stably-transfected with either an eGFP-SELENBP1 or a corresponding empty vector plasmid, and levels of SELENBP1 expression were determined by immunoblot analysis.	('eGFP-SELENBP1', 'Var', (143, 156))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (65, 90))	('SELENBP1', 'Gene', (42, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('esophageal adenocarcinoma', 'Disease', (65, 90))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (65, 90))
813628	20332323	Whereas baseline senescence was not consistently different between empty vector-transfected and SELENBP1-transfected Flo-1 cells, SELENBP1-transfected cells had increased levels of senescence following treatment with MSA but not NaS (Figure 6A and B).	('senescence', 'MPA', (181, 191))	('levels', 'MPA', (171, 177))	('increased', 'PosReg', (161, 170))	('MSA', 'Chemical', 'MESH:C008493', (217, 220))	('SELENBP1-transfected', 'Var', (130, 150))
813631	20332323	Bisulfite sequencing of the EAC cell line Flo-1, which demonstrated very low endogenous levels of SELENBP1, revealed the presence of methylated CpG sites in the 5' upstream sequence of SELENBP1, suggesting that diminished SELENBP1 expression might be due, in part, to its promoter methylation.	('diminished', 'NegReg', (211, 221))	('methylated', 'Var', (133, 143))	('SELENBP1', 'Gene', (185, 193))	('EAC', 'Phenotype', 'HP:0011459', (28, 31))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('expression', 'MPA', (231, 241))	('SELENBP1', 'Gene', (222, 230))
813633	20332323	Unbalanced alternative splicing can lead to the overexpression of antagonistic splice variants of genes involved in differentiation, apoptosis, invasion, and metastasis, often correlating with poor prognosis in cancers.	('lead to', 'Reg', (36, 43))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('cancers', 'Disease', (211, 218))	('Unbalanced alternative splicing', 'Var', (0, 31))	('overexpression', 'PosReg', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
813643	20332323	Additionally, MSA but not NaS increased the potency of SN38 (topoisomerase I inhibitor), etoposide (topoisomerase II inhibitor), and the microtubule inhibitor, paclitaxel, in prostate cancer cells.	('etoposide', 'MPA', (89, 98))	('potency', 'MPA', (44, 51))	('SN38', 'Gene', (55, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('prostate cancer', 'Disease', (175, 190))	('SN38', 'Chemical', 'MESH:D000077146', (55, 59))	('MSA', 'Var', (14, 17))	('paclitaxel', 'Chemical', 'MESH:D017239', (160, 170))	('increased', 'PosReg', (30, 39))	('etoposide', 'Chemical', 'MESH:D005047', (89, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (175, 190))	('MSA', 'Chemical', 'MESH:C008493', (14, 17))
813645	20332323	MSA alone caused cell detachment and subsequent PARP cleavage, while NaS-treated cells showed characteristic vacuole formation with no apparent PARP cleavage.	('PARP', 'Gene', '1302', (144, 148))	('PARP', 'Gene', (144, 148))	('MSA', 'Var', (0, 3))	('PARP', 'Gene', '1302', (48, 52))	('PARP', 'Gene', (48, 52))	('cell detachment', 'CPA', (17, 32))	('MSA', 'Chemical', 'MESH:C008493', (0, 3))
813654	20332323	Selenium may also exert cell growth inhibition by modifying the function of pre-existing proteins.	('Selenium', 'Chemical', 'MESH:D012643', (0, 8))	('function of pre-existing proteins', 'MPA', (64, 97))	('cell growth inhibition', 'CPA', (24, 46))	('modifying', 'Reg', (50, 59))	('Selenium', 'Var', (0, 8))
813664	20332323	Although decreased expression of SELENBP1 appeared to be related to epigenetic modification, we also observed increased alternative splice products with predicted premature truncation in a significant number of tumors with diminished SELENBP1 expression.	('SELENBP1', 'Gene', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('expression', 'MPA', (19, 29))	('epigenetic modification', 'Var', (68, 91))	('expression', 'MPA', (243, 253))	('SELENBP1', 'Gene', (234, 242))	('premature truncation', 'MPA', (163, 183))	('increased', 'PosReg', (110, 119))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('diminished', 'NegReg', (223, 233))	('decreased', 'NegReg', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('alternative splice products', 'MPA', (120, 147))
813666	20332323	In conclusion, diminished SELENBP1 expression in esophageal adenocarcinoma appeared to blunt the cellular response to some forms of selenium supplementation, and loss of SELENBP1 might be a marker for limited response to ongoing attempts to utilize selenium as a chemopreventive or chemosensitization agent.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('SELENBP1', 'Gene', (26, 34))	('cellular response to', 'MPA', (97, 117))	('selenium', 'Chemical', 'MESH:D012643', (132, 140))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (49, 74))	('loss', 'Var', (162, 166))	('selenium', 'Chemical', 'MESH:D012643', (249, 257))	('expression', 'MPA', (35, 45))	('SELENBP1', 'Gene', (170, 178))	('esophageal adenocarcinoma', 'Disease', (49, 74))	('blunt', 'NegReg', (87, 92))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (49, 74))	('diminished', 'NegReg', (15, 25))
813667	20332323	Alternatively, the presence of full-length SELENBP1 in cancer tissues might predict better response to chemotherapy treatment and would support selenium-mediated secondary chemoprevention strategies.	('response', 'CPA', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('presence', 'Var', (19, 27))	('selenium', 'Chemical', 'MESH:D012643', (144, 152))	('better', 'PosReg', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('SELENBP1', 'Gene', (43, 51))	('cancer', 'Disease', (55, 61))
813741	33618239	included 162 patients in the study demonstrated that patients with pCR have significantly better long-term survival with 5-year survival for overall in complete, near complete, and partial response patients 34%, 55%, and 27%, respectively (P<0.013).	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (13, 21))	('better', 'PosReg', (90, 96))	('pCR', 'Var', (67, 70))
813747	33618239	including 396 patients with esophageal cancer who underwent esophagectomy after neoadjuvant therapy, concluded that the presence of PNI has an adverse impact for patients with lower survival time.	('esophageal cancer', 'Disease', (28, 45))	('patients', 'Species', '9606', (162, 170))	('PNI', 'Gene', (132, 135))	('survival time', 'CPA', (182, 195))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('lower', 'NegReg', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('presence', 'Var', (120, 128))	('patients', 'Species', '9606', (14, 22))
813788	29285246	In addition, some studies showed that miRNA-211, miRNA-143, miRNA-183, and lncRNA CASC9, HOTAIR, POU3F3 contributed to the development of EC via a variety of mechanisms.	('contributed', 'Reg', (104, 115))	('POU3F3', 'Gene', (97, 103))	('miRNA-183', 'Gene', '406959', (60, 69))	('POU3F3', 'Gene', '5455', (97, 103))	('CASC9', 'Gene', '101805492', (82, 87))	('miRNA-183', 'Gene', (60, 69))	('HOTAIR', 'Gene', (89, 95))	('CASC9', 'Gene', (82, 87))	('miRNA-143', 'Var', (49, 58))	('HOTAIR', 'Gene', '100124700', (89, 95))	('miRNA-211', 'Var', (38, 47))
813804	29285246	The network provided us with the key drivers of EC, including the disruption of PLCD1, PIK3R1, SULT2B1, IMPAD1, CYP3A5, PTK2, MAPK13, GATM, SHMT1, CXCR2 and MET.	('SULT2B1', 'Gene', (95, 102))	('SULT2B1', 'Gene', '6820', (95, 102))	('PTK2', 'Gene', (120, 124))	('SHMT1', 'Gene', (140, 145))	('IMPAD1', 'Gene', (104, 110))	('CXCR2', 'Gene', (147, 152))	('PIK3R1', 'Gene', '5295', (87, 93))	('SHMT1', 'Gene', '6470', (140, 145))	('PTK2', 'Gene', '5747', (120, 124))	('GATM', 'Gene', (134, 138))	('CYP3A5', 'Gene', '1577', (112, 118))	('IMPAD1', 'Gene', '54928', (104, 110))	('CXCR2', 'Gene', '3579', (147, 152))	('CYP3A5', 'Gene', (112, 118))	('disruption', 'Var', (66, 76))	('PLCD1', 'Gene', '5333', (80, 85))	('PLCD1', 'Gene', (80, 85))	('MAPK13', 'Gene', '5603', (126, 132))	('PIK3R1', 'Gene', (87, 93))	('GATM', 'Gene', '2628', (134, 138))	('MAPK13', 'Gene', (126, 132))
813825	29285246	Additionally, the imbalance of oncogene and cancer suppressor gene expression was an crucial mechanism of EC progression, such as the overexpression of p53 signaling pathway and MET and the down-regulation of PLCD1, the encoded protein of which functions as a tumor suppressor in several types of cancer.	('tumor', 'Disease', (260, 265))	('cancer', 'Disease', (297, 303))	('PLCD1', 'Gene', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('imbalance', 'Phenotype', 'HP:0002172', (18, 27))	('overexpression', 'PosReg', (134, 148))	('p53', 'Gene', (152, 155))	('cancer', 'Disease', (44, 50))	('p53', 'Gene', '7157', (152, 155))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('down-regulation', 'NegReg', (190, 205))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('PLCD1', 'Gene', '5333', (209, 214))	('imbalance', 'Var', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
813827	29285246	As one mechanism of tumor invasion and metastasis, aberrant adhesion of tumor cells to extracellular matrix and other cell types has been elucidated to be a typical phenotype of various malignances.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('aberrant', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('adhesion', 'CPA', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (20, 25))
813861	29285246	Pathway-net and signal-net analysis revealed that the aberrant expression of MAPK signaling pathway, PI3K-Akt signaling pathway, pathways in cancer, pathways on cell adhesion, p53 signaling pathway, PLCD1 and PTK2 was extensively implicated with EC occurrence and development.	('PLCD1', 'Gene', (199, 204))	('p53', 'Gene', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('p53', 'Gene', '7157', (176, 179))	('PI3K-Akt signaling pathway', 'Pathway', (101, 127))	('PTK2', 'Gene', '5747', (209, 213))	('PTK2', 'Gene', (209, 213))	('implicated', 'Reg', (230, 240))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('MAPK signaling pathway', 'Pathway', (77, 99))	('PLCD1', 'Gene', '5333', (199, 204))	('cancer', 'Disease', (141, 147))	('aberrant', 'Var', (54, 62))
813920	27272482	We compared patients with a low/normal BMI versus the overweight/obese patients in combination with the absence or presence of sarcopenia, in an attempt to identify a subgroup with better or worse outcome after esophagectomy.	('patients', 'Species', '9606', (12, 20))	('overweight', 'Phenotype', 'HP:0025502', (54, 64))	('patients', 'Species', '9606', (71, 79))	('obese', 'Disease', 'MESH:D009765', (65, 70))	('low/normal', 'Var', (28, 38))	('sarcopenia', 'Disease', 'MESH:D055948', (127, 137))	('obese', 'Disease', (65, 70))	('sarcopenia', 'Disease', (127, 137))
814055	25216531	Apollon knockdown increased cisplatin/docetaxel-induced apoptosis, mitochondrial dysfunction and cytochrome c release in two ESCC cell lines.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('Apollon', 'Gene', (0, 7))	('docetaxel', 'Chemical', 'MESH:D000077143', (38, 47))	('increased', 'PosReg', (18, 27))	('cytochrome c', 'Gene', (97, 109))	('knockdown', 'Var', (8, 17))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (67, 92))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (67, 92))	('cytochrome c', 'Gene', '54205', (97, 109))	('cisplatin/docetaxel-induced', 'MPA', (28, 55))	('apoptosis', 'CPA', (56, 65))	('mitochondrial dysfunction', 'Disease', (67, 92))
814056	25216531	Apollon knockdown potentiated cisplatin/docetaxel-induced long-term cell growth inhibition, and enhanced chemosensitivity of ESCC cells to cisplatin/docetaxel in xenograft tumor models.	('Apollon', 'Gene', (0, 7))	('potentiated', 'PosReg', (18, 29))	('long-term cell growth inhibition', 'CPA', (58, 90))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('enhanced', 'PosReg', (96, 104))	('knockdown', 'Var', (8, 17))	('cisplatin/docetaxel-induced', 'MPA', (30, 57))	('xenograft tumor', 'Disease', 'MESH:D009369', (162, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('docetaxel', 'Chemical', 'MESH:D000077143', (149, 158))	('chemosensitivity', 'CPA', (105, 121))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('docetaxel', 'Chemical', 'MESH:D000077143', (40, 49))	('xenograft tumor', 'Disease', (162, 177))
814057	25216531	Apollon knockdown also enhanced cisplatin/docetaxel-induced activation of caspase-8 (extrinsic pathway) and caspase-9 (intrinsic pathway) in ESCC cells and xenograft tumor models.	('cisplatin/docetaxel-induced', 'MPA', (32, 59))	('Apollon', 'Gene', (0, 7))	('xenograft tumor', 'Disease', (156, 171))	('enhanced', 'PosReg', (23, 31))	('docetaxel', 'Chemical', 'MESH:D000077143', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('caspase-9', 'Enzyme', (108, 117))	('caspase-8', 'Enzyme', (74, 83))	('knockdown', 'Var', (8, 17))	('xenograft tumor', 'Disease', 'MESH:D009369', (156, 171))	('activation', 'PosReg', (60, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))
814079	25216531	Western blotting showed that Apollon protein was highly expressed in Eca109, TE-4, TE-5, TE-8, TE-10, TE-11, EC8712, KYSE30, KYSE150, KYSE180, KYSE510 and EC9760, whereas it was weakly detected in TE-1 and normal esophageal epithelial cells (NEECs) (Fig.	('EC8712', 'CellLine', 'CVCL:E314', (109, 115))	('EC8712', 'Var', (109, 115))	('EC9760', 'CellLine', 'CVCL:5V07', (155, 161))	('KYSE150', 'Var', (125, 132))	('KYSE180', 'Var', (134, 141))	('KYSE510', 'CellLine', 'CVCL:1354', (143, 150))	('KYSE30', 'Var', (117, 123))	('TE-10', 'Var', (95, 100))	('Apollon protein', 'Protein', (29, 44))	('TE-11', 'Var', (102, 107))	('Eca109', 'Var', (69, 75))
814105	25216531	Notably, Kaplan-Meieranalysis showed that overall survival (OS) was significantly worse among patients with Apollon-staining high (P = 0.012) (Fig.	('worse', 'NegReg', (82, 87))	('overall survival', 'MPA', (42, 58))	('patients', 'Species', '9606', (94, 102))	('Apollon-staining high', 'Var', (108, 129))
814108	25216531	To investigate the role of Apollon in chmosensitivity of ESCC cells to cisplatin/docetaxel, we used shRNA to knock down Apollon expression in KYSE510 and Eca109 cells.	('KYSE510', 'CellLine', 'CVCL:1354', (142, 149))	('Apollon', 'Gene', (120, 127))	('knock', 'Var', (109, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))	('docetaxel', 'Chemical', 'MESH:D000077143', (81, 90))
814109	25216531	Apollon knockdown significantly increased cisplatin- or docetaxel-induced apoptosis at different time points, as determined by Annexin V/PI staining (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('Apollon', 'Gene', (0, 7))	('docetaxel', 'Chemical', 'MESH:D000077143', (56, 65))	('Annexin V', 'Gene', '308', (127, 136))	('cisplatin-', 'MPA', (42, 52))	('Annexin V', 'Gene', (127, 136))	('knockdown', 'Var', (8, 17))	('increased', 'PosReg', (32, 41))
814111	25216531	Apollon knockdown strongly potentiated cisplatin- or docetaxel-induced DeltaPsim depolarization at different time points, as detected by Mito Tracker Red staining (Fig.	('Apollon', 'Gene', (0, 7))	('DeltaPsim depolarization', 'MPA', (71, 95))	('knockdown', 'Var', (8, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('Mito', 'Species', '262676', (137, 141))	('docetaxel', 'Chemical', 'MESH:D000077143', (53, 62))	('cisplatin-', 'MPA', (39, 49))	('potentiated', 'PosReg', (27, 38))
814112	25216531	Interestingly, Apollon knockdown also enhanced cisplatin- or docetaxel-induced caspase-9 and caspase-8 activation, as measured by caspase activity assay (Fig.	('caspase-9', 'Enzyme', (79, 88))	('enhanced', 'PosReg', (38, 46))	('knockdown', 'Var', (23, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('caspase-8', 'CPA', (93, 102))	('docetaxel', 'Chemical', 'MESH:D000077143', (61, 70))	('Apollon', 'Gene', (15, 22))	('cisplatin-', 'MPA', (47, 57))	('activation', 'PosReg', (103, 113))
814113	25216531	Moreover, Apollon knockdown enhanced cisplatin- or docetaxel-induced long-term cell growth inhibition, as shown by long-term cell viability with colony formation assay (Fig.	('knockdown', 'Var', (18, 27))	('Apollon', 'Gene', (10, 17))	('docetaxel', 'Chemical', 'MESH:D000077143', (51, 60))	('enhanced', 'PosReg', (28, 36))	('long-term cell growth inhibition', 'CPA', (69, 101))	('cisplatin-', 'MPA', (37, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))
814121	25216531	We found that Smac protein level was dramatically upregulated, whereas Smac mRNA level was not affected, by Apollon knockdown (Fig.	('upregulated', 'PosReg', (50, 61))	('Apollon', 'Gene', (108, 115))	('Smac', 'Chemical', '-', (14, 18))	('knockdown', 'Var', (116, 125))	('Smac', 'Chemical', '-', (71, 75))	('Smac protein level', 'MPA', (14, 32))
814122	25216531	In contrast, the level of ubiquitinated Smac was reduced by Apollon knockdown in KYSE510 cells (Fig.	('reduced', 'NegReg', (49, 56))	('level of ubiquitinated Smac', 'MPA', (17, 44))	('KYSE510', 'CellLine', 'CVCL:1354', (81, 88))	('knockdown', 'Var', (68, 77))	('Apollon', 'Gene', (60, 67))	('Smac', 'Chemical', '-', (40, 44))
814127	25216531	Our data showed that Apollon knockdown potentiated cisplatin-induced Smac release, along with cytochrome c release, caspase-9 and caspase-8 activation in KYSE510 cells.	('knockdown', 'Var', (29, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('Smac', 'Chemical', '-', (69, 73))	('cytochrome c', 'Gene', (94, 106))	('activation', 'PosReg', (140, 150))	('caspase-8', 'Enzyme', (130, 139))	('potentiated', 'PosReg', (39, 50))	('KYSE510', 'CellLine', 'CVCL:1354', (154, 161))	('cytochrome c', 'Gene', '54205', (94, 106))	('caspase-9', 'MPA', (116, 125))	('cisplatin-induced Smac release', 'MPA', (51, 81))	('Apollon', 'Gene', (21, 28))
814129	25216531	Consistent with Western blotting analysis, Annexin V/PI staining and Mito Tracker Red staining demonstrated that Apollon knockdown potentiated cisplatin- or docetaxel-induced apoptotic events, which were reversed by Smac knockdown (Supplementary Fig.	('knockdown', 'Var', (121, 130))	('Annexin V', 'Gene', (43, 52))	('Mito', 'Species', '262676', (69, 73))	('Smac', 'Chemical', '-', (216, 220))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('Annexin V', 'Gene', '308', (43, 52))	('cisplatin-', 'MPA', (143, 153))	('potentiated', 'PosReg', (131, 142))	('apoptotic events', 'CPA', (175, 191))	('Apollon', 'Gene', (113, 120))	('docetaxel', 'Chemical', 'MESH:D000077143', (157, 166))
814130	25216531	Consistently, Smac knockdown reversed the facilitated effects of Apollon knockdown on cisplatin- or docetaxel-induced long-term cell growth suppression in KYSE510 and Eca109 cells (Supplementary Fig.	('cell growth', 'CPA', (128, 139))	('Apollon', 'Gene', (65, 72))	('docetaxel', 'Chemical', 'MESH:D000077143', (100, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('Smac', 'Chemical', '-', (14, 18))	('suppression', 'NegReg', (140, 151))	('KYSE510', 'CellLine', 'CVCL:1354', (155, 162))	('knockdown', 'Var', (73, 82))
814131	25216531	5C) To determine whether Apollon knockdown increases chemosensitivity in vivo, shC and sh1 KYSE510 cells were injected subcutaneously into flanks of nude mice.	('Apollon', 'Gene', (25, 32))	('KYSE510', 'CellLine', 'CVCL:1354', (91, 98))	('nude mice', 'Species', '10090', (149, 158))	('chemosensitivity', 'MPA', (53, 69))	('sh1', 'Gene', '100125848', (87, 90))	('knockdown', 'Var', (33, 42))	('increases', 'PosReg', (43, 52))	('sh1', 'Gene', (87, 90))
814133	25216531	The average tumor volume was slightly decreased in Apollon knockdown cells compared to control cells, but the difference did not reach statistical significance (Fig.	('decreased', 'NegReg', (38, 47))	('Apollon', 'Gene', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('knockdown', 'Var', (59, 68))	('tumor', 'Disease', (12, 17))
814135	25216531	Apollon knockdown resulted in 45.1% and 47.9% inhibition of tumor growth in cisplatin and docetaxel-treated mice, respectively.	('Apollon', 'Gene', (0, 7))	('inhibition', 'NegReg', (46, 56))	('knockdown', 'Var', (8, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('docetaxel', 'Chemical', 'MESH:D000077143', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
814136	25216531	Apollon knockdown enhanced cisplatin- or doxetacel- induced apoptosis in tumor cells in vivo, as shown by TUNEL assay (Fig.	('Apollon', 'Gene', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('knockdown', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cisplatin-', 'MPA', (27, 37))	('enhanced', 'PosReg', (18, 26))	('doxetacel', 'Chemical', '-', (41, 50))	('tumor', 'Disease', (73, 78))
814137	25216531	Apollon knockdown also increased cisplatin- or doxetacel- induced caspase-9 and caspase-8 activation in vivo, as assessed by IHC staining (Fig.	('Apollon', 'Gene', (0, 7))	('activation', 'PosReg', (90, 100))	('caspase-8', 'Enzyme', (80, 89))	('knockdown', 'Var', (8, 17))	('caspase-9', 'Enzyme', (66, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('increased', 'PosReg', (23, 32))	('cisplatin-', 'MPA', (33, 43))	('doxetacel', 'Chemical', '-', (47, 56))
814138	25216531	Finally, Apollon knockdown increased Smac expression in vivo (Fig.	('increased', 'PosReg', (27, 36))	('Apollon', 'Gene', (9, 16))	('Smac expression', 'MPA', (37, 52))	('knockdown', 'Var', (17, 26))	('Smac', 'Chemical', '-', (37, 41))
814139	25216531	Although we failed to find any correlation between Apollon expression and stage or grade for ESCC, we did find that high expression of Apollon was closely associated with poor response to chemotherapy in patients who had undergone cisplatin-based chemotherapy.	('patients', 'Species', '9606', (204, 212))	('high expression', 'Var', (116, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (231, 240))	('Apollon', 'Gene', (135, 142))	('associated with', 'Reg', (155, 170))	('ESCC', 'Disease', (93, 97))
814141	25216531	Abnormal protein expression and disordered signaling pathway, which impede apoptosis, can also lead to the resistance to chemotherapy.	('lead to', 'Reg', (95, 102))	('disordered', 'Disease', 'MESH:D030342', (32, 42))	('protein', 'Protein', (9, 16))	('Abnormal', 'Var', (0, 8))	('disordered', 'Disease', (32, 42))	('resistance to chemotherapy', 'CPA', (107, 133))
814145	25216531	Moreover, high expression of Apollon was associated with short overall survival in patients undergone cisplatin-based chemotherapy.	('overall survival', 'MPA', (63, 79))	('Apollon', 'Protein', (29, 36))	('high', 'Var', (10, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('patients', 'Species', '9606', (83, 91))	('short', 'NegReg', (57, 62))
814148	25216531	Using RNA interference, we found that Apollon knockdown significantly potentiated cisplatin or doxetacel-induced apoptosis, mitochondrial membrane potential collapse, cytochrome c release, caspase activation, and long-term cell growth suppression, hence sensitizing esophageal cancer to cisplatin or doxetacel treatment in vitro and in vivo.	('mitochondrial membrane potential collapse', 'MPA', (124, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (287, 296))	('cell growth suppression', 'CPA', (223, 246))	('caspase', 'CPA', (189, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (266, 283))	('doxetacel', 'Chemical', '-', (95, 104))	('cytochrome c', 'Gene', '54205', (167, 179))	('cisplatin', 'MPA', (82, 91))	('doxetacel', 'Chemical', '-', (300, 309))	('esophageal cancer', 'Disease', (266, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('sensitizing', 'Reg', (254, 265))	('Apollon', 'Gene', (38, 45))	('cytochrome c', 'Gene', (167, 179))	('potentiated', 'PosReg', (70, 81))	('knockdown', 'Var', (46, 55))	('apoptosis', 'CPA', (113, 122))	('activation', 'PosReg', (197, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))
814154	25216531	Both Hao and Ren reported that Apollon deletion did not affect Smac protein levels in Apollon deficient mice in vivo.	('Apollon', 'Gene', (31, 38))	('Smac', 'Chemical', '-', (63, 67))	('mice', 'Species', '10090', (104, 108))	('deletion', 'Var', (39, 47))	('Smac protein levels', 'MPA', (63, 82))
814160	25216531	Apollon knockdown increased Smac protein level, while had no effect on Smac mRNA level in ESCC cells.	('Apollon', 'Gene', (0, 7))	('increased', 'PosReg', (18, 27))	('knockdown', 'Var', (8, 17))	('Smac', 'Chemical', '-', (28, 32))	('Smac protein level', 'MPA', (28, 46))	('Smac', 'Chemical', '-', (71, 75))
814162	25216531	Moreover, Apollon ubiquitinated Smac, consequently facilitated its proteasomal degradation in ESCC cells.	('proteasomal degradation', 'MPA', (67, 90))	('facilitated', 'PosReg', (51, 62))	('Smac', 'Chemical', '-', (32, 36))	('Apollon', 'Var', (10, 17))
814163	25216531	Most importantly, Smac knockdown reversed the sensitization effect of Apollon knockdown on ESCC cells to chemotherapy.	('Smac', 'Chemical', '-', (18, 22))	('knockdown', 'Var', (78, 87))	('sensitization', 'MPA', (46, 59))	('Apollon', 'Gene', (70, 77))
814167	25216531	Upon chemo treatment, Smac is released along with cytochrome c and promotes cytochrome c-dependent caspase activation by neutralizing inhibitor of apoptosis proteins.	('promotes', 'PosReg', (67, 75))	('cytochrome c', 'Gene', (76, 88))	('cytochrome c', 'Gene', (50, 62))	('cytochrome c', 'Gene', '54205', (76, 88))	('cytochrome c', 'Gene', '54205', (50, 62))	('neutralizing', 'Var', (121, 133))	('activation', 'PosReg', (107, 117))	('Smac', 'Chemical', '-', (22, 26))
814169	25216531	Cytoprotective IAPs, ML-IAP (melanoma IAP) and ILP-2 (IAP-like protein 2), exert their antiapoptotic effects through the neutralization of Smac.	('IAP', 'Gene', (38, 41))	('IAP', 'Gene', (24, 27))	('IAP-like protein 2', 'Gene', '112401', (54, 72))	('ML-IAP (melanoma IAP)', 'Disease', 'MESH:D008545', (21, 42))	('Smac', 'Protein', (139, 143))	('IAP', 'Gene', '84061', (54, 57))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('IAP', 'Gene', (15, 18))	('antiapoptotic effects', 'MPA', (87, 108))	('ILP-2', 'Gene', '112401', (47, 52))	('ILP-2', 'Gene', (47, 52))	('IAP', 'Gene', (54, 57))	('IAP', 'Gene', '84061', (24, 27))	('IAP', 'Gene', '84061', (38, 41))	('Smac', 'Chemical', '-', (139, 143))	('neutralization', 'Var', (121, 135))	('IAP', 'Gene', '84061', (15, 18))	('IAP-like protein 2', 'Gene', (54, 72))
814173	25216531	A surprising finding was that apollon knockdown enhanced activation of both caspase 9 and caspase 8 in cisplatin/docitaxel treated ESCC cells in vitro and in vivo.	('caspase 8', 'Gene', '841', (90, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('docitaxel', 'Chemical', '-', (113, 122))	('caspase 8', 'Gene', (90, 99))	('activation', 'PosReg', (57, 67))	('apollon', 'Gene', '57448', (30, 37))	('caspase 9', 'Gene', (76, 85))	('knockdown', 'Var', (38, 47))	('caspase 9', 'Gene', '842', (76, 85))	('apollon', 'Gene', (30, 37))
814177	25216531	We proposed that Apollon knockdown may promote cytochrome c-dependent caspase-9 activation and TNF-a/RIP1-dependent caspase-8 activation through Smac stabilization.	('RIP1', 'Gene', (101, 105))	('Apollon', 'Gene', (17, 24))	('cytochrome c', 'Gene', '54205', (47, 59))	('TNF-a', 'Gene', (95, 100))	('promote', 'PosReg', (39, 46))	('TNF-a', 'Gene', '7124', (95, 100))	('RIP1', 'Gene', '8737', (101, 105))	('cytochrome c', 'Gene', (47, 59))	('Smac', 'Chemical', '-', (145, 149))	('knockdown', 'Var', (25, 34))	('activation', 'PosReg', (80, 90))
814178	25216531	IAP antagonists have attracted increasing interest in triggering cancer cell death and are currently at the preclinical development stage or early clinical testing.	('antagonists', 'Var', (4, 15))	('cancer cell death', 'Disease', 'MESH:D003643', (65, 82))	('IAP', 'Gene', '84061', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('IAP', 'Gene', (0, 3))	('cancer cell death', 'Disease', (65, 82))
814197	25216531	Primary antibodies against Survivin (#2808), Apollon (#8745), Livin (#5471), Smac (#2954), cleaved caspase-8 (#9496), cleaved caspase-9 (#9505), cytochrome c (#4272), alpha-tubulin (#2144), COX IV (#4844), ubiquitin (P4D1, #3936) were purchased from Cell Signaling Technology (Beverly, MA).	('P4D1', 'Var', (217, 221))	('#8745', 'Var', (54, 59))	('Survivin', 'Gene', '11799', (27, 35))	('#9496', 'Var', (110, 115))	('cytochrome c', 'Gene', (145, 157))	('#5471', 'Var', (69, 74))	('#4272', 'Var', (159, 164))	('Survivin', 'Gene', (27, 35))	('#2144', 'Var', (182, 187))	('#2954', 'Var', (83, 88))	('#4844', 'Var', (198, 203))	('#9505', 'Var', (137, 142))	('COX IV', 'Gene', '12857', (190, 196))	('cytochrome c', 'Gene', '54205', (145, 157))	('COX IV', 'Gene', (190, 196))	('#2808', 'Var', (37, 42))	('Smac', 'Chemical', '-', (77, 81))
814199	25216531	Antibodies against NAIP (#ab25968), XIAP (#ab28151), c-IAP1 (#ab108361), c-IAP2 (#ab137393) were from Abcam (Cambridge, MA).	('c-IAP1', 'Gene', (53, 59))	('NAIP', 'Gene', '4671', (19, 23))	('c-IAP2', 'Gene', '330', (73, 79))	('XIAP', 'Gene', (36, 40))	('#ab137393', 'Var', (81, 90))	('#ab25968', 'Var', (25, 33))	('c-IAP2', 'Gene', (73, 79))	('c-IAP1', 'Gene', '329', (53, 59))	('#ab28151', 'Var', (42, 50))	('XIAP', 'Gene', '331', (36, 40))	('NAIP', 'Gene', (19, 23))	('#ab108361', 'Var', (61, 70))
814206	25216531	Of these constructs, transduction of cells with TRCN0000004158 (sh1) and TRCN00000059 (sh2) produced the best knockdown.	('TRCN00000059', 'Disease', (73, 85))	('TRCN00000059', 'Disease', 'None', (73, 85))	('sh1', 'Gene', (64, 67))	('TRCN0000004158', 'Var', (48, 62))	('knockdown', 'MPA', (110, 119))	('sh1', 'Gene', '100125848', (64, 67))
814265	23844320	Additionally the percentage of nodal-positive patients was significantly lower after chemotherapy compared to surgery only (38.6% vs. 19.1%; P=0.018).	('patients', 'Species', '9606', (46, 54))	('nodal-positive', 'Var', (31, 45))	('lower', 'NegReg', (73, 78))
814277	23844320	Patients with resectable tumors (T1N1 or T2~3N0~1, M0) were randomly assigned to CRT (carboplatin, paclitaxel, 41.4 Gy in 23 fractions, 5 days per week) followed by surgery or surgery only.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('T2~3N0~1', 'Var', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('carboplatin', 'Chemical', 'MESH:D016190', (86, 97))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('Patients', 'Species', '9606', (0, 8))	('paclitaxel', 'Chemical', 'MESH:D017239', (99, 109))	('T1N1', 'Var', (33, 37))
814295	23844320	Tegafur is differently metabolized in patients with Asian and European heritage due to polymorphisms of the CYP2A6-Gene, leading to a significantly reduced safety-profile in Western patients, so that S-1 did not acquire widespread acceptance among Western oncologists.	('safety-profile', 'MPA', (156, 170))	('CYP2A6', 'Gene', (108, 114))	('reduced', 'NegReg', (148, 155))	('polymorphisms', 'Var', (87, 100))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (38, 46))	('CYP2A6', 'Gene', '1548', (108, 114))
814304	20647332	Deletion at Fragile Sites is a Common and Early Event in Barrett's Esophagus Barrett's esophagus is a premalignant intermediate to esophageal adenocarcinoma, which develops in the context of chronic inflammation and exposure to bile and acid.	('esophageal adenocarcinoma', 'Disease', (131, 156))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (131, 156))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (77, 96))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (131, 156))	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (57, 76))	('inflammation', 'Disease', 'MESH:D007249', (199, 211))	('inflammation', 'Disease', (199, 211))	('bile and acid', 'Chemical', '-', (228, 241))	('Deletion', 'Var', (0, 8))
814306	20647332	We detected copy number alterations and/or loss of heterozygosity (LOH) at fifty-six fragile sites in 20 patients with premalignant Barrett's esophagus (BE).	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (132, 151))	('patients', 'Species', '9606', (105, 113))	('heterozygosity', 'MPA', (51, 65))	('copy number alterations', 'Var', (12, 35))	('loss', 'NegReg', (43, 47))	("premalignant Barrett's esophagus", 'Disease', (119, 151))	("premalignant Barrett's esophagus", 'Disease', 'MESH:D001471', (119, 151))
814307	20647332	Chromosomal fragile sites are particularly sensitive to DNA breaks and have been shown to be frequent sites of rearrangement or loss in many human cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('loss', 'NegReg', (128, 132))	('Chromosomal fragile sites', 'Phenotype', 'HP:0040012', (0, 25))	('Chromosomal', 'Var', (0, 11))	('human', 'Species', '9606', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('sensitive', 'Reg', (43, 52))
814308	20647332	Copy number losses in early BE were observed at particularly high frequency at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%) and FRA 4D (52.4%), and at lower frequencies in other fragile sites, including FRA1K (42.9%), FRAXC (42.9%), FRA 12B (33.3%) and FRA16D (33.3%).	('FRA16D', 'Gene', '2463', (252, 258))	('losses', 'NegReg', (12, 18))	('FRA3B', 'Gene', '2272', (79, 84))	('FRA1K', 'Gene', (202, 207))	('FRA3B', 'Gene', (79, 84))	('FRA9A', 'Gene', '2425', (92, 97))	('FRA5E', 'Gene', (109, 114))	('FRA 12B', 'Gene', (232, 239))	('FRA5E', 'Gene', '2398', (109, 114))	('FRA1K', 'Gene', '2370', (202, 207))	('FRA 12B', 'Gene', '2449', (232, 239))	('FRA 4D', 'Gene', (127, 133))	('Copy number', 'Var', (0, 11))	('FRA9A', 'Gene', (92, 97))	('FRA 4D', 'Gene', '2391', (127, 133))	('FRA16D', 'Gene', (252, 258))
814311	20647332	Deletion and genomic instability at FRA3B and other fragile sites could thus be a biomarker of genetic damage in BE patients and a potential biomarker of cancer risk.	('FRA3B', 'Gene', '2272', (36, 41))	('FRA3B', 'Gene', (36, 41))	('patients', 'Species', '9606', (116, 124))	('genetic damage', 'Disease', (95, 109))	('genetic damage', 'Disease', 'MESH:D030342', (95, 109))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('genomic instability', 'CPA', (13, 32))	('Deletion', 'Var', (0, 8))
814319	20647332	Widespread genomic instability is believed to facilitate neoplastic progression in BE, as well as many other pre-neoplastic diseases.	('neoplastic progression', 'CPA', (57, 79))	('facilitate', 'PosReg', (46, 56))	('Widespread genomic instability', 'Var', (0, 30))	('neoplastic diseases', 'Disease', 'MESH:D009386', (113, 132))	('neoplastic diseases', 'Disease', (113, 132))
814320	20647332	This process is facilitated the loss and mutation of important cell cycle checkpoint machinery and tumor suppressor loci, such as p16 and p53.	('tumor', 'Disease', (99, 104))	('p53', 'Gene', (138, 141))	('p16', 'Gene', (130, 133))	('p53', 'Gene', '7157', (138, 141))	('mutation', 'Var', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('p16', 'Gene', '1029', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
814322	20647332	Although we have previously focused on sites of known tumor suppressors, we and others have shown that chromosomal "fragile sites" and in particular, FRA3B, have an extremely high rate of deletion in BE patients and in patients that progress to EA.	('FRA3B', 'Gene', (150, 155))	('FRA3B', 'Gene', '2272', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('deletion', 'Var', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('patients', 'Species', '9606', (203, 211))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Disease', (54, 59))
814325	20647332	While instability at specific fragile sites has been linked to different cancers  including breast, prostate, and lung , there is still uncertainty as to whether these fragile site alterations causally contribute to cancer development or are merely "silent markers" of genomic stress.	('alterations', 'Var', (181, 192))	('cancer', 'Disease', (73, 79))	('cancers', 'Disease', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('linked', 'Reg', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('prostate', 'Disease', (100, 108))	('contribute', 'Reg', (202, 212))	('lung', 'Disease', (114, 118))	('breast', 'Disease', (92, 98))	('cancer', 'Disease', (216, 222))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
814327	20647332	Alternatively, breakage at fragile sites could contribute to repeated cycles of bridge-breakage-fusion, potentially promoting the amplification of oncogenes such as Met within the FRA7G region or the prolactin-inducible protein (PIP) gene.	('prolactin-inducible protein', 'Gene', '5304', (200, 227))	('amplification', 'MPA', (130, 143))	('FRA7G', 'Gene', (180, 185))	('FRA7G', 'Gene', '2414', (180, 185))	('PIP', 'Gene', (229, 232))	('prolactin-inducible protein', 'Gene', (200, 227))	('PIP', 'Gene', '5304', (229, 232))	('Met', 'Var', (165, 168))	('promoting', 'PosReg', (116, 125))
814329	20647332	In previous studies of BE patients, copy number loss was detected at two fragile sites (FRA3B and FRA13B).	('FRA3B', 'Gene', (88, 93))	('FRA13B', 'Gene', '2454', (98, 104))	('copy number loss', 'Var', (36, 52))	('patients', 'Species', '9606', (26, 34))	('FRA13B', 'Gene', (98, 104))	('FRA3B', 'Gene', '2272', (88, 93))
814331	20647332	The endoscopic biopsies were analyzed for molecular alterations at chromosome arm 9p CDKN2A locus), chromosome arm 17p (TP53 locus), and DNA content tetraploidy and aneuploidy as previously described .	('aneuploidy', 'Disease', (165, 175))	('tetraploidy', 'Var', (149, 160))	('CDKN2A', 'Gene', (85, 91))	('CDKN2A', 'Gene', '1029', (85, 91))	('aneuploidy', 'Disease', 'MESH:D000782', (165, 175))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
814332	20647332	Two sets of patients were examined; genomic DNA was isolated from paired Barrett's epithelium and gastric samples: 1) 20 patients without high grade dysplasia characterized for chromosome arm 9pLOH and/or 17pLOH in which epithelial cells from selected biopsies were purified by Ki67/DNA content flow sorting.	('patients', 'Species', '9606', (12, 20))	('dysplasia', 'Disease', (149, 158))	('dysplasia', 'Disease', 'MESH:D004476', (149, 158))	('17pLOH', 'Var', (205, 211))	('chromosome arm 9pLOH', 'Var', (177, 197))	('patients', 'Species', '9606', (121, 129))
814335	20647332	DNA content tetraploidy and aneuploidy was not detected in 19 of 20 of the baseline endoscopies.	('tetraploidy', 'Var', (12, 23))	('aneuploidy', 'Disease', (28, 38))	('aneuploidy', 'Disease', 'MESH:D000782', (28, 38))
814343	20647332	Labeling reactions were performed directly with the restricted DNA and a Bioprime labeling kit (Invitrogen) according to the manufacturer's directions in a 50 mul volume with a dNTP pool to final concentrations of 120 muM dATP, 120 muM dGTP, 120 muM dTTP, 60 muM dTTP, and 60 muM Cy5-dUTP or Cy3-dUTP (Perkin-Elmer).	('muM', 'Gene', (218, 221))	('dTTP', 'Chemical', 'MESH:C024157', (263, 267))	('dGTP', 'Chemical', 'MESH:C029603', (236, 240))	('dATP', 'Chemical', 'MESH:C026600', (222, 226))	('dTTP', 'Chemical', 'MESH:C024157', (250, 254))	('muM', 'Gene', '56925', (259, 262))	('dNTP', 'Chemical', 'MESH:D010278', (177, 181))	('muM', 'Gene', '56925', (232, 235))	('muM', 'Gene', '56925', (246, 249))	('Cy3-dUTP', 'Chemical', 'MESH:C088941', (292, 300))	('muM', 'Gene', (232, 235))	('muM', 'Gene', '56925', (276, 279))	('muM', 'Gene', (276, 279))	('Cy5-dUTP', 'Var', (280, 288))	('muM', 'Gene', (246, 249))	('Cy5-dUTP', 'Chemical', 'MESH:C088942', (280, 288))	('muM', 'Gene', '56925', (218, 221))	('muM', 'Gene', (259, 262))
814351	20647332	Log2 intensity ratios for BE samples relative to paired constitutional controls were analyzed per patient for significant regions of copy number loss or gain using the CLAC (Clustering Among Chromosomes) software with a 3 SNP moving window and FDR = 0.01.	('copy number', 'Var', (133, 144))	('loss', 'NegReg', (145, 149))	('patient', 'Species', '9606', (98, 105))	('gain', 'PosReg', (153, 157))
814352	20647332	Copy number differences were manually curated to include only events with an average log2 intensity ratio of > 0.26 or < -0.32, corresponding to a minimum change of 20% between constitutional and test samples.	('< -0.32', 'Var', (119, 126))	('mum', 'Gene', '56925', (151, 154))	('mum', 'Gene', (151, 154))
814354	20647332	The ratio between copy number for BE relative to gastric within the fragile site was then used to identify copy number gains (ratio >= 1.2) or copy number loss (ratio <= 0.8).	('gastric within the fragile', 'Disease', 'MESH:D001929', (49, 75))	('copy number', 'Var', (143, 154))	('gastric within the fragile', 'Disease', (49, 75))	('copy number gains', 'Disease', (107, 124))	('copy number gains', 'Disease', 'MESH:D015430', (107, 124))
814361	20647332	Copy number loss, copy number gain, and/or LOH were indeed detected in two or more patients at genomic regions associated with 56 different fragile sites (Figure 1).	('patients', 'Species', '9606', (83, 91))	('copy number gain', 'Var', (18, 34))	('Copy number loss', 'Var', (0, 16))
814369	20647332	Figure 1B illustrates a clustering analysis of patients showing copy number gain or loss at individual fragile sites; the highest correlation was detected for losses at FRA3B and FRA9A/9C/p16/CDKN2A.	('FRA9A', 'Gene', (179, 184))	('FRA9A', 'Gene', '2425', (179, 184))	('losses', 'Var', (159, 165))	('p16', 'Gene', (188, 191))	('loss', 'NegReg', (84, 88))	('patients', 'Species', '9606', (47, 55))	('CDKN2A', 'Gene', (192, 198))	('p16', 'Gene', '1029', (188, 191))	('CDKN2A', 'Gene', '1029', (192, 198))	('FRA3B', 'Gene', '2272', (169, 174))	('FRA3B', 'Gene', (169, 174))
814370	20647332	We observed that a subset of patients (patient # 6, 12, 15, and 16) had copy number loss detected at several fragile sites including FRAXC, FRA5E, FRA4D, FRA12B, FRA11D, and FRA1K although interestingly, the most frequent copy number losses at FRA3B/FHIT and FRA9A/9C/p16/CDKN2A were not detected in patients 15 & 16.	('FRA12B', 'Gene', (154, 160))	('p16', 'Gene', '1029', (268, 271))	('FRA1K', 'Gene', '2370', (174, 179))	('loss', 'NegReg', (84, 88))	('FRA9A', 'Gene', '2425', (259, 264))	('FRA9A', 'Gene', (259, 264))	('FRA5E', 'Gene', '2398', (140, 145))	('CDKN2A', 'Gene', (272, 278))	('copy number', 'Var', (72, 83))	('patients', 'Species', '9606', (300, 308))	('FRA4D', 'Gene', (147, 152))	('patients', 'Species', '9606', (29, 37))	('FRA11D', 'Gene', (162, 168))	('FRA3B', 'Gene', '2272', (244, 249))	('patient', 'Species', '9606', (300, 307))	('FRA1K', 'Gene', (174, 179))	('CDKN2A', 'Gene', '1029', (272, 278))	('patient', 'Species', '9606', (39, 46))	('FHIT', 'Gene', (250, 254))	('FRA12B', 'Gene', '2449', (154, 160))	('patient', 'Species', '9606', (29, 36))	('FRA5E', 'Gene', (140, 145))	('FHIT', 'Gene', '2272', (250, 254))	('FRA3B', 'Gene', (244, 249))	('FRA11D', 'Gene', '2441', (162, 168))	('FRA4D', 'Gene', '2391', (147, 152))	('p16', 'Gene', (268, 271))
814374	20647332	Results of the STAC analysis are shown in Table 1, which displays the subset of the fragile sites at which copy number losses, copy number gains or LOH were statistically significant by this method.	('copy number gains', 'Disease', 'MESH:D015430', (127, 144))	('copy number gains', 'Disease', (127, 144))	('copy number losses', 'Var', (107, 125))	('LOH', 'NegReg', (148, 151))
814381	20647332	As shown in Table 2, copy number loss was detected at FRA3B and FRA16D in 83.3% (15 of 18) and 40% (6 of 15) of cases, respectively.	('FRA3B', 'Gene', '2272', (54, 59))	('FRA16D', 'Gene', (64, 70))	('FRA3B', 'Gene', (54, 59))	('FRA16D', 'Gene', '2463', (64, 70))	('copy number loss', 'Var', (21, 37))
814382	20647332	Copy number gain was detected at FRA3B in 11.1% (2 of 18) of patients tested.	('FRA3B', 'Gene', '2272', (33, 38))	('patients', 'Species', '9606', (61, 69))	('FRA3B', 'Gene', (33, 38))	('Copy number gain', 'Var', (0, 16))
814383	20647332	Of note, copy changes were just as frequent in cases without dysplasia as in cases with a maximum diagnosis of indefinite for dysplasia (FRA3B, p>0.29; FRA16D, p>0.44).	('mum', 'Gene', (94, 97))	('dysplasia', 'Disease', 'MESH:D004476', (126, 135))	('FRA3B', 'Gene', '2272', (137, 142))	('FRA16D', 'Gene', '2463', (152, 158))	('FRA3B', 'Gene', (137, 142))	('copy changes', 'Var', (9, 21))	('dysplasia', 'Disease', (61, 70))	('dysplasia', 'Disease', 'MESH:D004476', (61, 70))	('mum', 'Gene', '56925', (94, 97))	('dysplasia', 'Disease', (126, 135))	('FRA16D', 'Gene', (152, 158))
814385	20647332	LOH or allelic imbalance (AI) was detected in at least one SNP and at least one BE biopsy within FRA3B in 75.0% (15 of 20) of patients (Table 2).	('detected', 'Reg', (34, 42))	('allelic imbalance', 'Var', (7, 24))	('imbalance', 'Phenotype', 'HP:0002172', (15, 24))	('LOH', 'Disease', (0, 3))	('FRA3B', 'Gene', '2272', (97, 102))	('patients', 'Species', '9606', (126, 134))	('FRA3B', 'Gene', (97, 102))
814387	20647332	To further validate these results, we tested for the extent of copy number losses at FRA3B and FRA16D in populations of BE cells grown in culture, cell lines CPA, CPB, CPC, and CPD  on higher density Agilent 244K SNP arrays.	('FRA16D', 'Gene', (95, 101))	('FRA3B', 'Gene', '2272', (85, 90))	('CPD', 'Disease', 'MESH:C565865', (177, 180))	('FRA3B', 'Gene', (85, 90))	('CPB', 'Gene', '1360', (163, 166))	('CPD', 'Disease', (177, 180))	('CPA', 'Gene', (158, 161))	('losses', 'NegReg', (75, 81))	('FRA16D', 'Gene', '2463', (95, 101))	('tested', 'Reg', (38, 44))	('copy number', 'Var', (63, 74))	('CPB', 'Gene', (163, 166))	('CPA', 'Gene', '1357', (158, 161))
814395	20647332	More than 8 distinct copy loss events were seen within FRA3B/FHIT, seven of which were observed over a 4 year time span.	('FHIT', 'Gene', (61, 65))	('FHIT', 'Gene', '2272', (61, 65))	('copy', 'Var', (21, 25))	('FRA3B', 'Gene', '2272', (55, 60))	('FRA3B', 'Gene', (55, 60))
814396	20647332	This patient also had copy loss at other fragile sites (e.g., FRA16D and FRA7G), some of which showed additional lesions over time (data not shown).	('patient', 'Species', '9606', (5, 12))	('FRA7G', 'Gene', (73, 78))	('FRA16D', 'Gene', (62, 68))	('FRA7G', 'Gene', '2414', (73, 78))	('FRA16D', 'Gene', '2463', (62, 68))	('copy loss', 'Var', (22, 31))
814398	20647332	Using SNP genotyping analysis to profile for LOH and copy number, with confirmation by quantitative PCR and pyrosequencing, we have demonstrated that copy number alteration and/or LOH at chromosomal fragile sites are frequent and early events in BE neoplasia.	('neoplasia', 'Disease', (249, 258))	('chromosomal fragile sites', 'Phenotype', 'HP:0040012', (187, 212))	('neoplasia', 'Disease', 'MESH:D009369', (249, 258))	('neoplasia', 'Phenotype', 'HP:0002664', (249, 258))	('LOH', 'Var', (180, 183))	('copy number alteration', 'Var', (150, 172))
814399	20647332	Copy number loss and LOH was validated at FRA3B and FRA16D using PCR and pyrosequencing.	('FRA16D', 'Gene', (52, 58))	('FRA3B', 'Gene', (42, 47))	('FRA3B', 'Gene', '2272', (42, 47))	('FRA16D', 'Gene', '2463', (52, 58))	('Copy number loss', 'Var', (0, 16))
814400	20647332	Copy number loss at FRA3B is a particularly common early event, being observed in 80% of 20 early-stage endoscopic biopsies.	('FRA3B', 'Gene', '2272', (20, 25))	('FRA3B', 'Gene', (20, 25))	('observed', 'Reg', (70, 78))	('Copy number loss', 'Var', (0, 16))
814402	20647332	While instability at fragile sites has been reported in a number of different cancers, this study demonstrates high frequency of copy number loss and LOH within multiple defined regions associated with chromosomal fragile sites in a premalignant tissue.	('LOH', 'Var', (150, 153))	('copy number loss', 'Var', (129, 145))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('chromosomal fragile sites', 'Phenotype', 'HP:0040012', (202, 227))
814405	20647332	It appears that regions of copy loss and LOH in BE can be narrow and well-conserved, in at least in a subset of fragile sites, and this is most evident in BE at FRA3B.	('FRA3B', 'Gene', (161, 166))	('LOH', 'Var', (41, 44))	('copy loss', 'Var', (27, 36))	('FRA3B', 'Gene', '2272', (161, 166))
814406	20647332	While published studies of various cancers have reported deletions at FRA3B, these deletions range in size from 300 kb to over 2 Mb and deletions consistently constrained to this specific sub-region of FRA3B (60.2-60.6 MB, corresponding to FHIT exons 4-5) have not previously been reported in the literature.	('deletions', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('FRA3B', 'Gene', (202, 207))	('FRA3B', 'Gene', (70, 75))	('FRA3B', 'Gene', '2272', (202, 207))	('FHIT', 'Gene', (240, 244))	('FHIT', 'Gene', '2272', (240, 244))	('FRA3B', 'Gene', '2272', (70, 75))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
814410	20647332	Our data supports the idea of a specific DNA damage profile, similar to asbestos-related lung cancer, where a significant association between copy changes at 11 fragile sites (including FRA19B, FRA22A, and FRA11H) and asbestos-associated alterations by SNP genotyping has been reported.	('FRA11H', 'Gene', '2446', (206, 212))	('lung cancer', 'Disease', (89, 100))	('asbestos', 'Chemical', 'MESH:D001194', (72, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('FRA22A', 'Gene', '2473', (194, 200))	('copy changes', 'Var', (142, 154))	('FRA11H', 'Gene', (206, 212))	('FRA19B', 'Gene', '2470', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('FRA22A', 'Gene', (194, 200))	('asbestos', 'Chemical', 'MESH:D001194', (218, 226))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('FRA19B', 'Gene', (186, 192))
814411	20647332	Thus, measurement of deletion and LOH at fragile sites merits evaluation as a biomarker of cancer risk in BE patients.	('patients', 'Species', '9606', (109, 117))	('LOH', 'Var', (34, 37))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('deletion', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
814434	32255255	In several cancer types, including colorectal, breast, ovarian, and head and neck cancer, the presence of CAFs correlates with poor prognosis (Lai et al., 2012; Marsh et al., 2011; Tsujino et al., 2007; Yamashita et al., 2012).	('head and neck cancer', 'Phenotype', 'HP:0012288', (68, 88))	('colorectal', 'Disease', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('presence', 'Var', (94, 102))	('ovarian', 'Disease', (55, 62))	('head and neck cancer', 'Disease', 'MESH:D006258', (68, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('CAFs', 'Disease', 'None', (106, 110))	('CAFs', 'Disease', (106, 110))	('cancer', 'Disease', (11, 17))	('breast', 'Disease', (47, 53))
814454	32255255	After transfer into gentleMACS C Tubes (Miltenyi Biotec, Bergisch Gladbach, Germany), additional 1 mL of each of the following enzymes was added: DNAse I (500 U mL-1; AppliChem PanReac, Darmstadt, Germany; in PBS), collagenase IV (320 U mL-1; Thermo Fisher Scientific; in PBS), and dispase II (2 U mL-1; Sigma-Aldrich, St. Louis, MO, USA; in PBS).	('mL-1', 'Gene', (237, 241))	('mL-1', 'Gene', '16728', (161, 165))	('PBS', 'Chemical', 'MESH:D007854', (342, 345))	('PBS', 'Chemical', 'MESH:D007854', (209, 212))	('mL-1', 'Gene', '16728', (237, 241))	('PBS', 'Chemical', 'MESH:D007854', (272, 275))	('MACS', 'Gene', '4082', (26, 30))	('mL-1', 'Gene', (298, 302))	('MACS', 'Gene', (26, 30))	('320 U', 'Var', (231, 236))	('mL-1', 'Gene', (161, 165))	('mL-1', 'Gene', '16728', (298, 302))
814693	28053294	In case of SEMS placement bridging the gastroesophageal junction, by contrast, development of gastroesophageal reflux which results in severe ulcerative esophagitis with hemorrhage as well as aspiration pneumonia, and occurrence of stent migration into the stomach which results in recurrent dysphagia or even bowel obstruction have been serious clinical concerns.	('dysphagia', 'Phenotype', 'HP:0002015', (292, 301))	('esophagitis', 'Phenotype', 'HP:0100633', (153, 164))	('aspiration pneumonia', 'Disease', (192, 212))	('bowel obstruction', 'Disease', (310, 327))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (94, 117))	('bowel obstruction', 'Disease', 'MESH:D015212', (310, 327))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (192, 212))	('hemorrhage', 'Disease', 'MESH:D006470', (170, 180))	('bowel obstruction', 'Phenotype', 'HP:0005214', (310, 327))	('ulcerative esophagitis', 'Disease', 'MESH:D014456', (142, 164))	('stent', 'Var', (232, 237))	('gastroesophageal reflux', 'Disease', (94, 117))	('dysphagia', 'Disease', 'MESH:D003680', (292, 301))	('aspiration', 'Phenotype', 'HP:0002835', (192, 202))	('ulcerative esophagitis', 'Disease', (142, 164))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (94, 117))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (39, 64))	('dysphagia', 'Disease', (292, 301))	('gastroesophageal reflux which results in severe ulcerative esophagitis', 'Phenotype', 'HP:0004791', (94, 164))	('recurrent', 'Disease', (282, 291))	('pneumonia', 'Phenotype', 'HP:0002090', (203, 212))	('hemorrhage', 'Disease', (170, 180))	('gastroesophageal junction', 'Disease', (39, 64))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (192, 212))	('results in', 'Reg', (124, 134))
814750	27575990	High SES was also found to be positively associated with WCRB for hygienic habits (OR low vs. mid for inappropriate hygienic behavior = 1.46, 95%CI: 0.74-2.86; OR low vs. high for inappropriate hygienic behavior = 3.31, 95%CI: 0.97-11.26).	('inappropriate hygienic behavior', 'Disease', 'MESH:D001523', (180, 211))	('inappropriate hygienic behavior', 'Disease', (102, 133))	('hygienic habits', 'Disease', (66, 81))	('inappropriate hygienic behavior', 'Disease', (180, 211))	('inappropriate hygienic behavior', 'Disease', 'MESH:D001523', (102, 133))	('hygienic habits', 'Disease', 'MESH:D020323', (66, 81))	('High SES', 'Var', (0, 8))
814837	24065141	In addition, the 5-year survival in these patients with positive REG Ialpha expression was significantly lower than that in patients with negative REG Ialpha expression (42.9 vs. 84.9%; P=0.034).	('lower', 'NegReg', (105, 110))	('expression', 'Species', '29278', (158, 168))	('REG', 'Gene', (147, 150))	('REG', 'Gene', (65, 68))	('expression', 'Species', '29278', (76, 86))	('positive', 'Var', (56, 64))	('patients', 'Species', '9606', (42, 50))	('REG', 'Gene', '5967', (147, 150))	('patients', 'Species', '9606', (124, 132))	('REG', 'Gene', '5967', (65, 68))
814848	24065141	The authors indicated that high expression of REG Ialpha enhanced the chemosensitivity and radiosensitivity of esophageal cancer cells, which may explain the better prognosis of the patients.	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('esophageal cancer', 'Disease', (111, 128))	('REG', 'Gene', '5967', (46, 49))	('chemosensitivity', 'CPA', (70, 86))	('high expression', 'Var', (27, 42))	('expression', 'Species', '29278', (32, 42))	('patients', 'Species', '9606', (182, 190))	('radiosensitivity', 'CPA', (91, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('REG', 'Gene', (46, 49))	('enhanced', 'PosReg', (57, 65))
814855	24065141	In contrast, no clear effect was found in the AD cells in regards to enhanced cell invasion in response to either gene, whereas a positive effect was demonstrated in SCC cells.	('AD', 'Disease', 'MESH:D000544', (46, 48))	('enhanced', 'PosReg', (69, 77))	('SCC', 'Gene', '6317', (166, 169))	('AD', 'Disease', (46, 48))	('SCC', 'Gene', (166, 169))	('gene', 'Var', (114, 118))	('SCC', 'Phenotype', 'HP:0002860', (166, 169))	('cell invasion', 'CPA', (78, 91))
814867	24065141	Likewise, high REG IV expression in colorectal and prostate cancers is linked with a worse prognosis.	('colorectal and prostate cancers', 'Disease', 'MESH:D015179', (36, 67))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('REG IV', 'Gene', '83998', (15, 21))	('REG IV', 'Gene', (15, 21))	('prostate cancers', 'Phenotype', 'HP:0012125', (51, 67))	('high', 'Var', (10, 14))	('expression', 'Species', '29278', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('expression', 'MPA', (22, 32))
814881	24065141	Overexpression of the REG Ialpha gene is a risk factor for poor prognosis in lung cancer patients functioning via different mechanisms in adenocarcinoma and squamous cell carcinoma.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'Species', '29278', (4, 14))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 180))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('REG', 'Gene', '5967', (22, 25))	('patients', 'Species', '9606', (89, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('REG', 'Gene', (22, 25))	('lung cancer', 'Disease', (77, 88))
815026	18722489	However, drug resistance appeared to develop in two distinct phases: 1) at 5 to 75 ng/ml Dox IC50 increased only 3.2- to 5.7-fold, while 2) at 125 ng/ml and above IC50 increased by several dozen and hundred folds (see also supplementary Table S-2).	('increased', 'PosReg', (168, 177))	('drug resistance', 'MPA', (9, 24))	('Dox', 'Chemical', 'MESH:D004317', (89, 92))	('drug resistance', 'Phenotype', 'HP:0020174', (9, 24))	('Dox', 'Var', (89, 92))
815037	18722489	2B and Fig 4B) and no increases in Pgp efflux function were observed by R123 accumulation (Fig.	('R123 accumulation', 'Var', (72, 89))	('Pgp efflux function', 'MPA', (35, 54))	('R123', 'Chemical', 'MESH:D020112', (72, 76))
815053	18722489	All together, the microarray data reinforce the conclusion that the block copolymer prevents alterations of multiple genes that may be implicated in progression of drug resistance in tumors.	('alterations', 'MPA', (93, 104))	('prevents', 'NegReg', (84, 92))	('drug resistance', 'Phenotype', 'HP:0020174', (164, 179))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('block copolymer', 'Var', (68, 83))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('copolymer', 'Chemical', '-', (74, 83))	('tumors', 'Disease', (183, 189))
815083	18722489	It is interesting that cells selected with Dox in the presence of Pluronic in vitro and in vivo exhibited some increase in IC50 compared to parental cells, even though the MDR phenotype was not observed.	('increase', 'PosReg', (111, 119))	('MDR', 'Gene', '18669', (172, 175))	('MDR', 'Gene', (172, 175))	('Pluronic', 'Chemical', 'MESH:D020442', (66, 74))	('Pluronic', 'Var', (66, 74))	('Dox', 'Chemical', 'MESH:D004317', (43, 46))	('IC50', 'MPA', (123, 127))
815085	18722489	They may include altered expression and mutations of topoisomerase II and I, activation of metabolic enzymes such as cellular retinoic binding protein, epoxide hydrolase and thioredoxin, or inhibition of apoptotic signal transduction pathways.	('altered', 'Reg', (17, 24))	('inhibition', 'NegReg', (190, 200))	('topoisomerase II', 'Enzyme', (53, 69))	('expression', 'MPA', (25, 35))	('activation', 'PosReg', (77, 87))	('thioredoxin', 'Gene', (174, 185))	('apoptotic signal transduction pathways', 'Pathway', (204, 242))	('metabolic enzymes', 'Enzyme', (91, 108))	('mutations', 'Var', (40, 49))	('thioredoxin', 'Gene', '22166', (174, 185))	('cellular', 'Protein', (117, 125))	('epoxide hydrolase', 'Enzyme', (152, 169))
815106	32734742	There is increasing interest in whether LPRD can induce chronic damage and inflammation of the laryngeal and pharyngeal mucosae, and whether LPRD can induce a final tumorigenic effect on laryngeal and pharyngeal mucosae.	('LPRD', 'Var', (40, 44))	('induce', 'Reg', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('inflammation', 'Disease', (75, 87))	('chronic damage', 'CPA', (56, 70))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('induce', 'Reg', (150, 156))	('LPRD', 'Var', (141, 145))	('tumor', 'Disease', (165, 170))
815121	32734742	Some studies also demonstrated that LPRD or GERD was a risk factor for laryngeal and hypopharyngeal carcinoma after adjusting for factors such as smoking and drinking in multivariate logistic regression analysis.	('hypopharyngeal carcinoma', 'Disease', 'MESH:D007012', (85, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('laryngeal', 'Disease', (71, 80))	('hypopharyngeal carcinoma', 'Disease', (85, 109))	('hypopharyngeal carcinoma', 'Phenotype', 'HP:0012182', (85, 109))	('LPRD', 'Var', (36, 40))
815129	32734742	performed IHC staining of laryngeal mucosal epithelial tissue test specimens and found that pepsin levels were significantly higher in the laryngeal mucosal epithelium of patients with LPRD than in healthy volunteers (P<0.01).	('pepsin levels', 'MPA', (92, 105))	('LPRD', 'Var', (185, 189))	('higher', 'PosReg', (125, 131))	('patients', 'Species', '9606', (171, 179))
815162	32734742	Furthermore, the enzyme has two highly reactive cysteines on its surface (Cys183 and Cys188), which form a disulfide bond in vivo.	('disulfide', 'Chemical', 'MESH:D004220', (107, 116))	('Cys183', 'Chemical', '-', (74, 80))	('Cys183', 'Var', (74, 80))	('cysteines', 'Chemical', 'MESH:D003545', (48, 57))	('Cys188', 'Chemical', '-', (85, 91))	('Cys188', 'Var', (85, 91))
815173	32734742	Non-acid pepsin may destroy laryngopharyngeal mucosal cells by receptor-mediated endocytosis and increase the expression levels of inflammatory mediators and cytokines in a manner similar to that in the esophageal mucosa of patients with reflux esophagitis.	('reflux esophagitis', 'Disease', (238, 256))	('increase', 'PosReg', (97, 105))	('laryngopharyngeal mucosal', 'CPA', (28, 53))	('destroy', 'NegReg', (20, 27))	('Non-acid pepsin', 'Var', (0, 15))	('receptor-mediated endocytosis', 'MPA', (63, 92))	('reflux esophagitis', 'Disease', 'MESH:D005764', (238, 256))	('expression levels of', 'MPA', (110, 130))	('patients', 'Species', '9606', (224, 232))	('esophagitis', 'Phenotype', 'HP:0100633', (245, 256))
815176	32734742	In laryngeal carcinoma cells, pepsin was shown to induce the epithelial-mesenchymal transition via the IL-8 signaling pathway.	('pepsin', 'Var', (30, 36))	('laryngeal carcinoma', 'Disease', 'MESH:D007822', (3, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('laryngeal carcinoma', 'Disease', (3, 22))	('IL-8', 'Gene', '3576', (103, 107))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (3, 22))	('IL-8', 'Gene', (103, 107))	('induce', 'PosReg', (50, 56))	('epithelial-mesenchymal transition', 'CPA', (61, 94))
815187	32734742	revealed that patients who took PPIs were more likely to suffer esophageal adenocarcinogenesis.	('suffer', 'Reg', (57, 63))	('PPIs', 'Var', (32, 36))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('patients', 'Species', '9606', (14, 22))	('carcinogenesis', 'Disease', (80, 94))
815216	32351453	High body mass index (BMI), namely BMI > 40 kg/m2, has clearly been linked to a greater risk of both common a rare malignancy incidence and mortality rates.	('linked', 'Reg', (68, 74))	('mortality', 'Disease', 'MESH:D003643', (140, 149))	('High body mass index', 'Phenotype', 'HP:0031418', (0, 20))	('malignancy', 'Disease', 'MESH:D009369', (115, 125))	('malignancy', 'Disease', (115, 125))	('mortality', 'Disease', (140, 149))	('BMI > 40 kg/m2', 'Var', (35, 49))
815228	32351453	There is a well-established association between the risk of developing several types of cancers and the presence of an increased BMI (i.e., >= 25 kg/m2).	('increased BMI', 'Phenotype', 'HP:0031418', (119, 132))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('>= 25 kg/m2', 'Var', (140, 151))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BMI', 'MPA', (129, 132))
815260	32351453	Alteration of this fine equilibrium is responsible of adipocyte hypertrophy, mitochondrial dysregulation, endoplasmic reticulum and oxidative stress, ultimately leading to the release of pro-inflammatory factors and finally cellular apoptosis.	('oxidative stress', 'MPA', (132, 148))	('endoplasmic', 'MPA', (106, 117))	('adipocyte', 'MPA', (54, 63))	('Alteration', 'Var', (0, 10))	('responsible', 'Reg', (39, 50))	('adipocyte hypertrophy', 'Phenotype', 'HP:0030759', (54, 75))	('mitochondrial dysregulation', 'MPA', (77, 104))	('cellular apoptosis', 'CPA', (224, 242))	('release of pro-inflammatory factors', 'MPA', (176, 211))	('oxidative stress', 'Phenotype', 'HP:0025464', (132, 148))	('leading to', 'Reg', (161, 171))	('hypertrophy', 'Disease', (64, 75))	('hypertrophy', 'Disease', 'MESH:D006984', (64, 75))
815269	32351453	Epigenetic variations in DNA over time have also been proposed among chief determinants linking obesity and cancer.	('DNA', 'Gene', (25, 28))	('obesity', 'Phenotype', 'HP:0001513', (96, 103))	('obesity', 'Disease', 'MESH:D009765', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('obesity', 'Disease', (96, 103))	('Epigenetic variations', 'Var', (0, 21))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
815298	32351453	BMS induces changes in gut microbiota, which is involved in weight loss, fat deposition normalization, indirectly contributing to cancer risk reduction.	('reduction', 'NegReg', (142, 151))	('weight loss', 'Disease', (60, 71))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('weight loss', 'Phenotype', 'HP:0001824', (60, 71))	('gut microbiota', 'MPA', (23, 37))	('cancer', 'Disease', (130, 136))	('fat deposition', 'MPA', (73, 87))	('BMS', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('weight loss', 'Disease', 'MESH:D015431', (60, 71))	('changes', 'Reg', (12, 19))
815302	32351453	Several authors have demonstrated how NAFLD has presently become the main risk factor for the development of HCC, compared to previously recognized predisposing causes such as hepatitis B and C infection.	('HCC', 'Gene', (109, 112))	('hepatitis', 'Phenotype', 'HP:0012115', (176, 185))	('HCC', 'Gene', '619501', (109, 112))	('C infection', 'Disease', (192, 203))	('men', 'Species', '9606', (101, 104))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('NAFLD', 'Var', (38, 43))	('hepatitis B', 'Disease', 'MESH:D006509', (176, 187))	('C infection', 'Disease', 'MESH:C537418', (192, 203))	('hepatitis B', 'Disease', (176, 187))
815327	32351453	A systematic review and meta-analysis involving six observational studies comparing outcomes in terms of cancer risk and mortality in surgical vs. non-surgical obese subjects concluded that BMS is capable of reducing overall cancer incidence and related mortality.	('mortality', 'Disease', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('obese', 'Disease', 'MESH:D009765', (160, 165))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', (225, 231))	('mortality', 'Disease', 'MESH:D003643', (254, 263))	('obese', 'Disease', (160, 165))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('mortality', 'Disease', 'MESH:D003643', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('reducing', 'NegReg', (208, 216))	('mortality', 'Disease', (254, 263))	('BMS', 'Var', (190, 193))
815351	32351453	Overweight and obesity have been linked to a raised risk of esophageal and gastric cancer development and this has been shown to increase along with rising BMI.	('obesity', 'Disease', 'MESH:D009765', (15, 22))	('esophageal', 'Disease', (60, 70))	('obesity', 'Disease', (15, 22))	('gastric cancer', 'Disease', (75, 89))	('men', 'Species', '9606', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rising BMI', 'Phenotype', 'HP:0031418', (149, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('Overweight', 'Var', (0, 10))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('obesity', 'Phenotype', 'HP:0001513', (15, 22))
815354	32351453	Additionally, hormonal effects generated by dysregulation of insulin and IGF-1 secretion, generally altered in obese subjects, may be implicated in this carcinogenic process.	('obese', 'Disease', (111, 116))	('IGF-1', 'Gene', '3479', (73, 78))	('IGF-1', 'Gene', (73, 78))	('dysregulation', 'Var', (44, 57))	('altered', 'Reg', (100, 107))	('insulin', 'Gene', (61, 68))	('implicated', 'Reg', (134, 144))	('insulin', 'Gene', '3630', (61, 68))	('secretion', 'MPA', (79, 88))	('obese', 'Disease', 'MESH:D009765', (111, 116))	('hormonal effects', 'MPA', (14, 30))	('carcinogenic', 'Disease', 'MESH:D063646', (153, 165))	('carcinogenic', 'Disease', (153, 165))
815391	32351453	BMS not only affects cancer incidence but has also been shown to profoundly influence cancer prognosis.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('BMS', 'Var', (0, 3))	('affects', 'Reg', (13, 20))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))	('influence', 'Reg', (76, 85))
815401	32351453	Available data has shown that obesity is indeed associated with an increased cancer risk and BMS is capable, through several diverse pathways, to generate a significant reduction in overall cancer prevalence and mortality.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('reduction', 'NegReg', (169, 178))	('obesity', 'Disease', 'MESH:D009765', (30, 37))	('mortality', 'Disease', 'MESH:D003643', (212, 221))	('cancer', 'Disease', (77, 83))	('obesity', 'Disease', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mortality', 'Disease', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('obesity', 'Phenotype', 'HP:0001513', (30, 37))	('BMS', 'Var', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
815459	32024132	R1 resection was defined as microscopic residual disease or microscopic positive margin (including tumor <= 1 mm from any margin).	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('microscopic', 'Var', (60, 71))	('tumor', 'Disease', 'MESH:D009369', (99, 104))
815500	32024132	However, most early series reported that dCRT resulted in unsatisfactory local control rates of 33% to 69% in advanced CEC even with RT dose escalation.	('local control', 'CPA', (73, 86))	('dCRT', 'Chemical', '-', (41, 45))	('CEC', 'Disease', (119, 122))	('dCRT', 'Var', (41, 45))
815606	30790117	Copy number gains and losses were defined as changes in the logarithm to the base 2 of the tumor to reference signal intensity ratio (T/R) > 0.3219 and < -0.3219, respectively.	('< -0.3219', 'Var', (152, 161))	('gains', 'PosReg', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('losses', 'NegReg', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('rat', 'Species', '10116', (127, 130))	('Copy number', 'Var', (0, 11))	('tumor', 'Disease', (91, 96))
815643	30790117	Research using esophagogastric junction adenocarcinoma cell line (OE-19) has indicated that TCA causes more increases in cell proliferative activity.	('increases', 'PosReg', (108, 117))	('cell proliferative activity', 'CPA', (121, 148))	('junction adenocarcinoma', 'Disease', 'MESH:D000230', (31, 54))	('rat', 'Species', '10116', (133, 136))	('TCA', 'Var', (92, 95))	('junction adenocarcinoma', 'Disease', (31, 54))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (15, 54))	('TCA', 'Chemical', 'MESH:D013656', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
815657	30790117	Accordingly, genetic polymorphisms between UGT2B specimens might also be actively involved in the metabolism of carcinogens in the digestive tract.	('involved', 'Reg', (82, 90))	('UGT2B', 'Gene', '24862', (43, 48))	('genetic polymorphisms', 'Var', (13, 34))	('metabolism of carcinogens in the', 'MPA', (98, 130))	('men', 'Species', '9606', (54, 57))	('UGT2B', 'Gene', (43, 48))
815673	30747484	Analysis of patient data and quantitative estimation of Cdh23 in human tissues (normal and tumor) also indicated that Cdh23 is down-regulated via promoter methylation in lung adenocarcinoma (AD) and esophageal squamous cell carcinoma (SCC) cells; we also observed a clear inverse correlation between Cdh23 expression and cancer metastasis.	('human', 'Species', '9606', (65, 70))	('SCC', 'Gene', '6317', (235, 238))	('AD', 'Disease', (191, 193))	('SCC', 'Gene', (235, 238))	('tumor', 'Disease', (91, 96))	('cancer metastasis', 'Disease', (321, 338))	('AD', 'Disease', 'MESH:D000544', (191, 193))	('down-regulated', 'NegReg', (127, 141))	('esophageal squamous cell carcinoma', 'Disease', (199, 233))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('lung adenocarcinoma', 'Disease', (170, 189))	('cancer metastasis', 'Disease', 'MESH:D009362', (321, 338))	('promoter methylation', 'Var', (146, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('Cdh23', 'Gene', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('inverse', 'NegReg', (272, 279))	('Cdh23', 'Gene', (118, 123))	('patient', 'Species', '9606', (12, 19))	('SCC', 'Phenotype', 'HP:0002860', (235, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (210, 233))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (199, 233))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))
815690	30747484	The genome-wide association studies of kidney function identified a strong association of Cdh23 with the estimated cross-sectional glomerular filtration rate, and its knockdown in zebrafish embryo resulted in severe edema, suggesting its essential role in normal kidney functions (Gorski et al., 2015).	('edema', 'Disease', (216, 221))	('knockdown', 'Var', (167, 176))	('Cdh23', 'Gene', (90, 95))	('zebrafish', 'Species', '7955', (180, 189))	('edema', 'Disease', 'MESH:D004487', (216, 221))	('edema', 'Phenotype', 'HP:0000969', (216, 221))	('resulted in', 'Reg', (197, 208))	('association', 'Interaction', (75, 86))
815751	30747484	Apart from the changes in the intensity-fluctuation profile, the overall pattern in the RSD values for varying experimental conditions (control, Cdh23-siRNA, GFP+, and siRNA-GFP+) remained the same.	('Cdh23-siRNA', 'Var', (145, 156))	('RSD', 'Disease', (88, 91))	('RSD', 'Disease', 'MESH:D012019', (88, 91))
815756	30747484	On Day 3, as the effect of siRNA progresses, we noticed a significant difference (P < 0.001) in the scrambled-transfected (15.98 +- 2.48) and Cdh23-siRNA-transfected (siRNA, 21.69 +- 3.72) GFP- cells with lower RSD for the latter, reconfirming that the silencing of the intrinsic Cdh23 inhibits cell aggregation (Fig.	('RSD', 'Disease', 'MESH:D012019', (211, 214))	('RSD', 'Disease', (211, 214))	('inhibits', 'NegReg', (286, 294))	('silencing', 'Var', (253, 262))	('Cdh23', 'Gene', (280, 285))
815757	30747484	Following a similar trend, the difference in the RSD between scrambled- (pCdh23, 7.21 +- 2.59) and Cdh23-siRNA-transfected (pCdh23 + siRNA, 19.13 +- 6.43) GFP+ cells was significantly increased (P < 0.01), further evidence that lack of Cdh23 resulted in decreased aggregation of cells (Fig.	('lack', 'Var', (228, 232))	('RSD', 'Disease', (49, 52))	('decreased', 'NegReg', (254, 263))	('pCdh23', 'Gene', '54798', (73, 79))	('pCdh23', 'Gene', (124, 130))	('Cdh23', 'Gene', (236, 241))	('pCdh23', 'Gene', (73, 79))	('aggregation of cells', 'CPA', (264, 284))	('pCdh23', 'Gene', '54798', (124, 130))	('RSD', 'Disease', 'MESH:D012019', (49, 52))
815759	30747484	Overall, the transwell assay and hanging-drop assay jointly indicated that silencing of Cdh23 expression resulted in decreased cell aggregation and enhanced cell migration.	('decreased cell aggregation', 'Disease', (117, 143))	('decreased cell aggregation', 'Disease', 'MESH:D020914', (117, 143))	('cell migration', 'CPA', (157, 171))	('decreased cell aggregation', 'Phenotype', 'HP:0003540', (117, 143))	('enhanced', 'PosReg', (148, 156))	('silencing', 'Var', (75, 84))	('Cdh23', 'Gene', (88, 93))
815775	30747484	In the case of LCTA, we observed a higher population of tissues (12-23% more) that are adjacent to primary tumor (adjacent lung tissue, 68.4%) and malignant (62.5-73.3%), falling in the low-Cdh23 group in comparison with normal lung tissue (50%).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('primary tumor', 'Disease', 'MESH:D009369', (99, 112))	('LC', 'Phenotype', 'HP:0100526', (15, 17))	('LCTA', 'Chemical', '-', (15, 19))	('low-Cdh23', 'Var', (186, 195))	('falling', 'Phenotype', 'HP:0002527', (171, 178))	('primary tumor', 'Disease', (99, 112))
815779	30747484	Similar to our experimental observations, TCGA has also reported a higher percentage of patients with advanced lymph node status [> N1, LUAD, 74%; LUSC, 93%; ESCC (N1), 92%] and metastasis stage (M1, LUAD, 72%; LUSC, 71%, ESCC, 78%) in the low-Cdh23 expression group.	('AD', 'Disease', (138, 140))	('low-Cdh23 expression', 'Var', (240, 260))	('AD', 'Disease', (202, 204))	('patients', 'Species', '9606', (88, 96))	('SCC', 'Gene', (159, 162))	('SCC', 'Gene', (223, 226))	('SCC', 'Phenotype', 'HP:0002860', (223, 226))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('metastasis stage', 'CPA', (178, 194))	('AD', 'Disease', 'MESH:D000544', (202, 204))	('SCC', 'Gene', '6317', (159, 162))	('SCC', 'Gene', '6317', (223, 226))	('advanced lymph node status', 'CPA', (102, 128))	('AD', 'Disease', 'MESH:D000544', (138, 140))
815780	30747484	Overall, in silico analysis and TMA analysis suggest that Cdh23 is decreased in cancer, which is further decreased in advance lymph node stages and metastatic stages, suggesting Cdh23 suppresses cancer cell metastasis.	('cancer', 'Disease', (80, 86))	('TMA', 'Disease', 'MESH:D000783', (32, 35))	('Cdh23', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cdh23', 'Var', (178, 183))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('decreased', 'NegReg', (67, 76))	('TMA', 'Disease', (32, 35))	('decreased', 'NegReg', (105, 114))	('suppresses', 'NegReg', (184, 194))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
815789	30747484	Further, zooming the promoter-region near the 'start' site of Cdh23 at chromosome 10 (73156164-73157954), we observed a CpG island (73156164-73575440) which showed higher methylation for LUAD tumor (n = 463, red) samples than the normal (n = 32, green) cases (Fig.	('methylation', 'MPA', (171, 182))	('Cdh23', 'Gene', (62, 67))	('LUAD tumor', 'Disease', 'MESH:D009369', (187, 197))	('LUAD tumor', 'Disease', (187, 197))	('73156164-73575440', 'Var', (132, 149))	('higher', 'PosReg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
815800	30747484	HeLa cells with the least expression of Cdh23 showed no significant change in the migration at 100 pmol (150.6 +- 10.03) or 200 pmol (154.4 +- 5.42) of Cdh23-siRNA compared with scrambled control (149.4 +- 4.86).	('Cdh23-siRNA', 'Var', (152, 163))	('Cdh23', 'Gene', (40, 45))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))
815802	30747484	5B) with respect to scrambled controls (L132, 152.9 +- 8.13; A549, 151.3 +- 4.8; WRL68, 135.4 +- 8.75), indicating increased cell migration with the silencing of Cdh23.	('increased', 'PosReg', (115, 124))	('cell migration', 'CPA', (125, 139))	('silencing', 'Var', (149, 158))	('Cdh23', 'Gene', (162, 167))	('A549', 'CellLine', 'CVCL:0023', (61, 65))
815805	30747484	As expected, no significant change in RSD was observed for HeLa cells when treated with 100 pmol (7.86 +- 2.59, P = 0.48) or 200 pmol (11.64 +- 2.72, P = 0.093) of Cdh23-siRNA compared with scrambled control (9.11 +- 2.10).	('HeLa', 'CellLine', 'CVCL:0030', (59, 63))	('RSD', 'Disease', (38, 41))	('Cdh23-siRNA', 'Var', (164, 175))	('RSD', 'Disease', 'MESH:D012019', (38, 41))
815806	30747484	L132 showed a decrease in RSD at both 100 pmol (16.62 +- 7.1, P = 0.28) and 200 pmol (15.50 +- 6.29, P = 0.23) compared with scrambled control (18.29 +- 3.15).	('RSD', 'Disease', 'MESH:D012019', (26, 29))	('L132', 'Var', (0, 4))	('decrease', 'NegReg', (14, 22))	('RSD', 'Disease', (26, 29))
815809	30747484	HeLa showed no change in the rate of healing with the silencing of Cdh23.	('silencing', 'Var', (54, 63))	('Cdh23', 'Gene', (67, 72))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))
815810	30747484	However, for L132 and A549, the rate of healing increased significantly with the increase in Cdh23-siRNA; for A549, there was a significant gap-closure on Day 3 for the Cdh23-siRNA sample treated with 200 pmol.	('increased', 'PosReg', (48, 57))	('healing', 'CPA', (40, 47))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('gap-closure', 'CPA', (140, 151))	('A549', 'Var', (110, 114))	('A549', 'CellLine', 'CVCL:0023', (22, 26))
815813	30747484	Similarly, RSD from hanging-drop assay showed no significant difference after Day 1 of silencing (Control, 7.83 +- 4.85; Cdh23-siRNA, 8.80 +- 2.37; Ecdh-shRNA, 12.15 +- 6.94; Cdh23 + Ecdh, 11.05 +- 6.56).	('silencing', 'Var', (87, 96))	('RSD', 'Disease', 'MESH:D012019', (11, 14))	('RSD', 'Disease', (11, 14))
815814	30747484	Although silencing of Cdh23 in cancer cells showed no effect on the canonical beta-catenin signal pathway, suggesting that its prevailing function was cell adhesion (Fig.	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('silencing', 'Var', (9, 18))	('cell adhesion', 'CPA', (151, 164))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('beta-catenin', 'Gene', (78, 90))	('Cdh23', 'Gene', (22, 27))	('beta-catenin', 'Gene', '1499', (78, 90))
815817	30747484	We noticed a predominant expression of IS2 and IS5 in both protein and mRNA forms, in various cancer cell lines including A549 cells (Figs 6A,B and S9a-j).	('IS2', 'Var', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('IS5', 'Var', (47, 50))	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
815819	30747484	Silencing Cdh23 with siRNA, targeting IS1-5, showed a reduced expression of these isoforms (Fig.	('Cdh23', 'Gene', (10, 15))	('IS1-5', 'Gene', (38, 43))	('expression', 'MPA', (62, 72))	('reduced', 'NegReg', (54, 61))	('IS1-5', 'Gene', '260402;282552;55636;100190785;100190985', (38, 43))	('Silencing', 'Var', (0, 9))
815842	30747484	Moreover, silencing of both Ecdh and Cdh23 resulted in increased cell migration and significant cell disaggregation, suggesting both can have a synergistic effect on cancer cell migration (Fig.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cell disaggregation', 'CPA', (96, 115))	('increased', 'PosReg', (55, 64))	('cell migration', 'CPA', (65, 79))	('Cdh23', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Ecdh', 'Gene', (28, 32))	('silencing', 'Var', (10, 19))
815849	30747484	Silencing of Cdh23 in A549 cell lines showed no significant effect on the canonical beta-catenin pathway (Fig.	('Cdh23', 'Gene', (13, 18))	('beta-catenin', 'Gene', (84, 96))	('Silencing', 'Var', (0, 9))	('beta-catenin', 'Gene', '1499', (84, 96))	('A549', 'CellLine', 'CVCL:0023', (22, 26))
815877	30368517	Downregulation of GAS5 in tumor tissues promotes the growth and metastasis of tumors.	('metastasis of tumors', 'Disease', 'MESH:D009362', (64, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('GAS5', 'Gene', '60674', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('metastasis of tumors', 'Disease', (64, 84))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Downregulation', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('GAS5', 'Gene', (18, 22))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('promotes', 'PosReg', (40, 48))
815921	30368517	Results showed that the overall survival of patients with high serum levels of lncRNA GAS5 was significantly better than that of patients with low serum levels of lncRNA GAS5 (p<0.05, Figure 3B) only in stage 4 (p=0.00377) and no significant differences were found in other stages.	('lncRNA', 'Var', (79, 85))	('GAS5', 'Gene', (170, 174))	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (129, 137))	('GAS5', 'Gene', '60674', (86, 90))	('GAS5', 'Gene', '60674', (170, 174))	('high', 'Var', (58, 62))	('GAS5', 'Gene', (86, 90))	('better', 'PosReg', (109, 115))
815933	30368517	It has also been reported that the development of esophageal cancer is also accompanied by decreased expression level of GAS5, and inhibition of GAS5 may serve as a possible target for the treatment of this disease.	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))	('decreased', 'NegReg', (91, 100))	('GAS5', 'Gene', '60674', (121, 125))	('expression level', 'MPA', (101, 117))	('GAS5', 'Gene', '60674', (145, 149))	('esophageal cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('GAS5', 'Gene', (121, 125))	('inhibition', 'Var', (131, 141))	('GAS5', 'Gene', (145, 149))
816001	29108346	They found that patients had a greater 3-year LC (36% vs. 19%, p = 0.011) and disease-free survival (DFS) (25% vs. 10%, p = 0.004) in the high radiation doses arm than those in the low dose group, but that OS was not significantly different (13% vs. 3%, P = 0.054).	('OS', 'Chemical', '-', (206, 208))	('greater', 'PosReg', (31, 38))	('patients', 'Species', '9606', (16, 24))	('high radiation doses', 'Var', (138, 158))	('disease-free survival', 'CPA', (78, 99))
816020	29108346	In our study, the incidence of grade 3 or higher radiation esophagitis was higher in the high radiation dose arm than that in the standard radiation dose arm (10.5 vs.2.2%, p < 0.01).	('high radiation dose', 'Var', (89, 108))	('radiation esophagitis', 'Disease', (49, 70))	('radiation esophagitis', 'Disease', 'MESH:D004194', (49, 70))	('esophagitis', 'Phenotype', 'HP:0100633', (59, 70))
816058	28521815	BMI is expected to increase colorectal, liver and gastric cardia carcinoma specifically in males.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('gastric cardia carcinoma', 'Disease', (50, 74))	('BMI', 'Var', (0, 3))	('liver', 'Disease', (40, 45))	('increase', 'PosReg', (19, 27))	('colorectal', 'Disease', 'MESH:D015179', (28, 38))	('colorectal', 'Disease', (28, 38))	('gastric cardia carcinoma', 'Disease', 'MESH:D004938', (50, 74))
816108	28521815	High BMI was associated with a third of endometrial cancer and 9% in ovarian and 5% in breast cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian', 'Disease', (69, 76))	('ovarian', 'Disease', 'MESH:D010051', (69, 76))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('endometrial cancer', 'Disease', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('High BMI', 'Var', (0, 8))	('endometrial cancer', 'Phenotype', 'HP:0012114', (40, 58))
816114	28521815	Heavy drinking will result in 7% and 3% of liver cancer in males and females respectively, as liver cancer is primarily linked to heavy drinking.	('liver cancer', 'Disease', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('liver cancer', 'Phenotype', 'HP:0002896', (94, 106))	('Heavy drinking', 'Var', (0, 14))	('liver cancer', 'Disease', 'MESH:D006528', (94, 106))	('result in', 'Reg', (20, 29))	('liver cancer', 'Disease', (94, 106))	('liver cancer', 'Phenotype', 'HP:0002896', (43, 55))	('liver cancer', 'Disease', 'MESH:D006528', (43, 55))
816122	28521815	Female specific cancers such as breast and ovarian cancers were less influenced by these factors, with the exception of endometrial cancer, for which 32% were attributable to high BMI.	('endometrial cancer', 'Phenotype', 'HP:0012114', (120, 138))	('cancers', 'Disease', (16, 23))	('endometrial cancer', 'Disease', 'MESH:D016889', (120, 138))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('ovarian cancers', 'Phenotype', 'HP:0100615', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('high', 'Var', (175, 179))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (32, 58))	('endometrial cancer', 'Disease', (120, 138))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
816125	28521815	In females, high BMI and low physical activity will result in a total of 158 and 189 cases of breast cancer respectively (Tables 4 and 5).	('high BMI', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('result in', 'Reg', (52, 61))	('breast cancer', 'Disease', (94, 107))
816138	28521815	High BMI will affect GI cancers, mainly in males, accounting for 41% of the male colorectal cancer cases and 24% of liver cancers.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('liver cancers', 'Disease', (116, 129))	('liver cancers', 'Disease', 'MESH:D006528', (116, 129))	('colorectal cancer', 'Disease', (81, 98))	('affect', 'Reg', (14, 20))	('GI cancers', 'Disease', (21, 31))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('GI cancers', 'Disease', 'MESH:D009369', (21, 31))	('High BMI', 'Var', (0, 8))	('liver cancers', 'Phenotype', 'HP:0002896', (116, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('liver cancer', 'Phenotype', 'HP:0002896', (116, 128))
816149	28521815	Potential protection of Mediterranean diet to cancer is increased in low alcohol drinkers as compared to the heavy drinkers.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (73, 89))	('low alcohol drinkers', 'Var', (69, 89))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('alcohol', 'Chemical', 'MESH:D000438', (73, 80))
816176	28521815	BMI Body Mass Index EGCA Esophageal and gastric cardia GI Gastro intestinal PAF Population Attributable Fraction PM10 or PM2.5 Particulate matter RR Relative Risk WHO World Health Organization	('PM10', 'Var', (113, 117))	('EGCA', 'Chemical', '-', (20, 24))	('GI', 'Disease', 'MESH:D005767', (55, 57))	('gastric cardia', 'Disease', (40, 54))	('gastric cardia', 'Disease', 'MESH:D004938', (40, 54))	('PM2.5 Particulate matter RR', 'Var', (121, 148))
816197	28178195	Targeted inactivation of the SKP2 gene results in the accumulation of p27 and cyclin E, and causes the cell cycle to be blocked in the G1 phase.	('cell cycle', 'CPA', (103, 113))	('SKP2', 'Gene', (29, 33))	('p27', 'Gene', '3429', (70, 73))	('p27', 'Gene', (70, 73))	('inactivation', 'Var', (9, 21))	('SKP2', 'Gene', '6502', (29, 33))	('accumulation', 'PosReg', (54, 66))	('cyclin E', 'Protein', (78, 86))
816208	28178195	In the stable transfection, cells were selected with 200 mug/mL G418 and the pool of SKP2 overexpression was chosen for subsequent experiments.	('SKP2', 'Gene', '6502', (85, 89))	('G418', 'Var', (64, 68))	('G418', 'Chemical', 'MESH:C010680', (64, 68))	('SKP2', 'Gene', (85, 89))
816226	28178195	As shown in Figure 1A, the sequence of SKP2 levels was KYSE510 > KYSE450 > EC9706 > KYSE150.	('EC9706', 'CellLine', 'CVCL:E307', (75, 81))	('SKP2', 'Gene', '6502', (39, 43))	('KYSE150', 'Var', (84, 91))	('KYSE510 > KYSE450 >', 'Var', (55, 74))	('SKP2', 'Gene', (39, 43))
816228	28178195	The MN yields of irradiated KYSE510 with a high level of SKP2 were lower than those of irradiated KYSE150 with a low level of SKP2 (p < 0.01) (Figure 1B).	('SKP2', 'Gene', '6502', (57, 61))	('lower', 'NegReg', (67, 72))	('KYSE510', 'Var', (28, 35))	('SKP2', 'Gene', '6502', (126, 130))	('SKP2', 'Gene', (57, 61))	('MN yields', 'MPA', (4, 13))	('SKP2', 'Gene', (126, 130))
816229	28178195	Meanwhile, the bystander non-irradiated EC9706, co-cultured with irradiated KYSE510, showed a lower MN frequency than bystander cells co-cultured with irradiated KYSE150 (p < 0.01) (Figure 1B).	('irradiated', 'Var', (65, 75))	('EC9706', 'Var', (40, 46))	('lower', 'NegReg', (94, 99))	('MN frequency', 'MPA', (100, 112))	('KYSE510', 'Var', (76, 83))	('EC9706', 'CellLine', 'CVCL:E307', (40, 46))
816230	28178195	These results indicated that SKP2 expression could inhibit RIBE induced by irradiated EC cells.	('expression', 'Var', (34, 44))	('SKP2', 'Gene', (29, 33))	('RIBE', 'MPA', (59, 63))	('inhibit', 'NegReg', (51, 58))	('SKP2', 'Gene', '6502', (29, 33))
816233	28178195	Then, MN assay results showed that the MN frequency in bystander EC9706 cells, co-cultured with transfected KYSE150 cells (with increased SKP2 expression), was lower than that of the control groups (p < 0.05) (Figure 2B).	('SKP2', 'Gene', (138, 142))	('transfected', 'Var', (96, 107))	('MN frequency', 'MPA', (39, 51))	('EC9706', 'CellLine', 'CVCL:E307', (65, 71))	('SKP2', 'Gene', '6502', (138, 142))	('lower', 'NegReg', (160, 165))
816236	28178195	MN assay results showed that the MN frequency in bystander EC9706 cells co-cultured with SKP2 knockdown KYSE510 cells was higher than those of the control groups (p < 0.05).	('knockdown', 'Var', (94, 103))	('higher', 'PosReg', (122, 128))	('SKP2', 'Gene', '6502', (89, 93))	('MN frequency', 'MPA', (33, 45))	('EC9706', 'CellLine', 'CVCL:E307', (59, 65))	('SKP2', 'Gene', (89, 93))
816237	28178195	Thus, the results proved that changes of SKP2 level have effects on the results of RIBE.	('changes', 'Var', (30, 37))	('SKP2', 'Gene', '6502', (41, 45))	('effects', 'Reg', (57, 64))	('results', 'MPA', (72, 79))	('SKP2', 'Gene', (41, 45))
816239	28178195	The amount of gamma-H2AX foci in bystander cells co-cultured with SKP2 positive transfected cells was significantly lower than those of the control groups (p < 0.01) (Figure 4A,B).	('lower', 'NegReg', (116, 121))	('gamma-H2AX', 'Protein', (14, 24))	('SKP2', 'Gene', (66, 70))	('transfected', 'Var', (80, 91))	('gamma-H2AX', 'Chemical', '-', (14, 24))	('SKP2', 'Gene', '6502', (66, 70))
816244	28178195	As shown in Figure 5A, the expression of SKP2 in KYSE 510 cells decreased after RNAi experiments, and Rad51 expression decreased after SKP2 knockdown in RIBE EC9706 cells.	('decreased', 'NegReg', (119, 128))	('EC9706', 'CellLine', 'CVCL:E307', (158, 164))	('decreased', 'NegReg', (64, 73))	('SKP2', 'Gene', (135, 139))	('SKP2', 'Gene', '6502', (41, 45))	('expression', 'MPA', (27, 37))	('Rad51', 'Gene', (102, 107))	('expression', 'MPA', (108, 118))	('Rad51', 'Gene', '5888', (102, 107))	('knockdown', 'Var', (140, 149))	('SKP2', 'Gene', '6502', (135, 139))	('SKP2', 'Gene', (41, 45))
816246	28178195	According to this result, the percentage of apoptosis EC9706 cells co-cultured with irradiated KYSE510 cells, with a low SKP2 level, was significantly higher than those of the control cells (p < 0.05) (Figure 5B).	('SKP2', 'Gene', (121, 125))	('apoptosis', 'CPA', (44, 53))	('EC9706', 'Var', (54, 60))	('higher', 'PosReg', (151, 157))	('SKP2', 'Gene', '6502', (121, 125))	('EC9706', 'CellLine', 'CVCL:E307', (54, 60))
816248	28178195	The percentage of apoptosis EC9706 cells co-cultured with irradiated KYSE 150 cells with a high SKP2 level was significantly lower than those of the control cells (p < 0.05) (Figure 5D).	('EC9706', 'CellLine', 'CVCL:E307', (28, 34))	('SKP2', 'Gene', '6502', (96, 100))	('apoptosis', 'CPA', (18, 27))	('lower', 'NegReg', (125, 130))	('EC9706', 'Var', (28, 34))	('SKP2', 'Gene', (96, 100))
816259	28178195	Thus, we first examined the expression of SKP2 in four EC cells lines, and found that the SKP2 level was highest in KYSE 510 and lowest in KYSE150 cells.	('SKP2', 'Gene', (42, 46))	('highest', 'Reg', (105, 112))	('lowest', 'NegReg', (129, 135))	('SKP2', 'Gene', (90, 94))	('KYSE', 'Var', (116, 120))	('SKP2', 'Gene', '6502', (42, 46))	('SKP2', 'Gene', '6502', (90, 94))
816261	28178195	The MN yields of irradiated KYSE510 with a high level of SKP2 were lower than those of irradiated KYSE150 with a low level of SKP2.	('SKP2', 'Gene', '6502', (57, 61))	('lower', 'NegReg', (67, 72))	('KYSE510', 'Var', (28, 35))	('SKP2', 'Gene', '6502', (126, 130))	('SKP2', 'Gene', (57, 61))	('MN yields', 'MPA', (4, 13))	('SKP2', 'Gene', (126, 130))
816262	28178195	Meanwhile, bystander EC9706 co-cultured with irradiated KYSE510 showed a lower MN frequency than that of bystander cells co-cultured with irradiated KYSE150.	('irradiated', 'Var', (45, 55))	('EC9706', 'CellLine', 'CVCL:E307', (21, 27))	('KYSE510', 'Var', (56, 63))	('lower', 'NegReg', (73, 78))	('MN frequency', 'MPA', (79, 91))	('EC9706', 'Var', (21, 27))
816265	28178195	Conversely, low expression of SKP2 after knockdown promoted RIBE, and this effect was rescued by the SKP2 rescue vector.	('SKP2', 'Gene', (101, 105))	('SKP2', 'Gene', '6502', (30, 34))	('RIBE', 'MPA', (60, 64))	('promoted', 'PosReg', (51, 59))	('SKP2', 'Gene', (30, 34))	('SKP2', 'Gene', '6502', (101, 105))	('low expression', 'Var', (12, 26))
816278	28178195	These results showed that the expression of SKP2 has effects on the damage and repair of RIBE cells via the Rad51 pathway.	('SKP2', 'Gene', '6502', (44, 48))	('Rad51', 'Gene', (108, 113))	('damage', 'CPA', (68, 74))	('Rad51', 'Gene', '5888', (108, 113))	('expression', 'Var', (30, 40))	('effects', 'Reg', (53, 60))	('SKP2', 'Gene', (44, 48))
816557	24265671	They drew a conclusion that the SUV40 method might appear to offer balance between accuracy and reducing risk of underestimating tumor extent.	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('SUV40', 'Var', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (129, 134))
816651	24039944	found that patients with MLRs of 0.01 to 0.19, 0.20 to 0.39, 0.40 to 0.59, and 0.60 and greater had a median survival times of 27.4, 22, 12.8 and 6.5 months (p < 0.001).	('patients', 'Species', '9606', (11, 19))	('0.20', 'Var', (47, 51))	('0.40 to 0.59', 'Var', (61, 73))	('0.60', 'Var', (79, 83))
816652	24039944	However, another study of esophageal adenocarcinoma reported no significant differences in survival of patients with MLRs of 0.25 or less, 0.25 to 0.50, and more than 0.50.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (26, 51))	('0.25 to 0.50', 'Var', (139, 151))	('esophageal adenocarcinoma', 'Disease', (26, 51))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (26, 51))	('patients', 'Species', '9606', (103, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
816665	18632220	COX2 (PTGS2) gene methylation in epithelial, subepithelial lymphocyte and stromal tissue compartments in a spectrum of esophageal squamous neoplasia Previous studies have shown important effects of stromal elements in carcinogenesis.	('PTGS2', 'Gene', '5743', (6, 11))	('PTGS2', 'Gene', (6, 11))	('carcinogenesis', 'Disease', (218, 232))	('squamous neoplasia', 'Phenotype', 'HP:0002860', (130, 148))	('COX2', 'Gene', (0, 4))	('esophageal squamous neoplasia', 'Disease', 'MESH:D000077277', (119, 148))	('neoplasia', 'Phenotype', 'HP:0002664', (139, 148))	('methylation', 'Var', (18, 29))	('carcinogenesis', 'Disease', 'MESH:D063646', (218, 232))	('COX2', 'Gene', '4513', (0, 4))	('esophageal squamous neoplasia', 'Disease', (119, 148))
816668	18632220	In these esopohageal cancer patients, COX-2 gene methylation was more common in subepithelial lymphocytes than in adjacent epithelial or stromal cells in both grades of dysplasia and in foci of invasive cancer.	('common', 'Reg', (70, 76))	('esopohageal cancer', 'Disease', 'MESH:D009369', (9, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('foci of invasive cancer', 'Disease', (186, 209))	('esopohageal cancer', 'Disease', (9, 27))	('dysplasia', 'Disease', (169, 178))	('dysplasia', 'Disease', 'MESH:D004476', (169, 178))	('methylation', 'Var', (49, 60))	('foci of invasive cancer', 'Disease', 'MESH:D009362', (186, 209))	('patients', 'Species', '9606', (28, 36))	('COX-2', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
816670	18632220	COX2 (PTGS2) gene methylation increases with disease severity and is more common in subepithelial lymphocytes than in adjacent epithelial or stromal cells in dysplastic and early invasive esophageal squamous cell cancer foci.	('squamous cell cancer', 'Phenotype', 'HP:0002860', (199, 219))	('dysplastic', 'Disease', 'MESH:D004416', (158, 168))	('PTGS2', 'Gene', '5743', (6, 11))	('PTGS2', 'Gene', (6, 11))	('dysplastic', 'Disease', (158, 168))	('invasive esophageal squamous cell cancer foci', 'Disease', (179, 224))	('invasive esophageal squamous cell cancer foci', 'Disease', 'MESH:D000077277', (179, 224))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('COX2', 'Gene', (0, 4))	('methylation', 'Var', (18, 29))	('COX2', 'Gene', '4513', (0, 4))	('common', 'Reg', (74, 80))	('increases', 'PosReg', (30, 39))
816678	18632220	Methylation of these CpG islands have been shown to cause silencing of several genes in GI cancers, including those involved in transcription, apoptosis, and calcium signaling.	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('silencing', 'MPA', (58, 67))	('Methylation', 'Var', (0, 11))	('genes', 'Gene', (79, 84))	('GI cancers', 'Disease', 'MESH:D009369', (88, 98))	('calcium', 'Chemical', 'MESH:D002118', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('GI cancers', 'Disease', (88, 98))
816680	18632220	Inhibition of COX-2 by non-specific NSAIDS or specific inhibitors of COX-2 causes cell death in gastrointestinal cancer cells.	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (96, 119))	('death', 'Disease', 'MESH:D003643', (87, 92))	('gastrointestinal cancer', 'Disease', (96, 119))	('Inhibition', 'Var', (0, 10))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (96, 119))	('death', 'Disease', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('COX-2', 'Gene', (69, 74))	('COX-2', 'Gene', (14, 19))
816700	18632220	Real-time methylation-specific PCR showed COX-2 (PTGS2) gene methylation to be significantly more common in subepithelial lymphocytes (12/16 (75% of all foci)) than in epithelial foci (3/16 (19%)) or foci of non-lymphocytic stromal tissues (3/17 (18%)) (Fishers Exact p=0.05) (Table II).	('methylation', 'Var', (61, 72))	('PTGS2', 'Gene', (49, 54))	('PTGS2', 'Gene', '5743', (49, 54))	('common', 'Reg', (98, 104))	('Fishers', 'Species', '76720', (254, 261))
816701	18632220	Two of three epithelial samples and all three stromal samples that showed COX2 methylation were adjacent to foci of methylated subepithelial lymphocytes.	('COX2', 'Gene', (74, 78))	('methylation', 'Var', (79, 90))	('COX2', 'Gene', '4513', (74, 78))
816702	18632220	In the current study, COX-2 (PTGS2) gene methylation was more common in subepithelial lymphocytes than in adjacent epithelial or stromal cells in both grades of squamous dysplasia and in foci of invasive esophageal squamous cell carcinoma.	('foci of invasive esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (187, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('methylation', 'Var', (41, 52))	('PTGS2', 'Gene', (29, 34))	('squamous dysplasia', 'Disease', (161, 179))	('squamous dysplasia', 'Disease', 'MESH:D002294', (161, 179))	('PTGS2', 'Gene', '5743', (29, 34))	('common', 'Reg', (62, 68))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (161, 179))
816709	18632220	Thus, COX-2 methylation of subepithelial lymphocytes may represent an adaptive host defense against tumorigenesis.	('tumor', 'Disease', (100, 105))	('methylation', 'Var', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))
816711	18632220	In conclusion, COX-2 (PTGS2) gene methylation was more common in subepithelial lymphocytes than in adjacent epithelial or stromal cells in a histologic spectrum of esophageal squamous disease from low-grade squamous dysplasia to invasive esophageal squamous cell carcinoma.	('squamous disease', 'Phenotype', 'HP:0002860', (175, 191))	('methylation', 'Var', (34, 45))	('common', 'Reg', (55, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (207, 225))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (249, 272))	('esophageal squamous disease', 'Disease', (164, 191))	('squamous dysplasia to invasive esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (207, 272))	('esophageal squamous disease', 'Disease', 'MESH:D000077277', (164, 191))	('PTGS2', 'Gene', '5743', (22, 27))	('PTGS2', 'Gene', (22, 27))
816712	18632220	These findings raise the possibility that methylation of stromal lymphocytes or other stromal tissue compartments may directly or indirectly affect tumorigenesis.	('affect', 'Reg', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('methylation', 'Var', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
816773	31820208	In this study, PET-N+ patients had greater numbers of pathological metastatic nodes than PET-N0, consequently, PET-N+ patients showed a worse 5y-OS and 5y-RFS, similar to previous reports.	('greater', 'PosReg', (35, 42))	('PET-N+', 'Var', (111, 117))	('patients', 'Species', '9606', (22, 30))	('5y-OS', 'CPA', (142, 147))	('pathological metastatic nodes', 'CPA', (54, 83))	('patients', 'Species', '9606', (118, 126))
816774	31820208	Additionally, in this study we revealed DWI-N+ patients also had more pathological metastatic nodes and a worse prognosis than DWI-N0, as well as PET-N status.	('patients', 'Species', '9606', (47, 55))	('more', 'PosReg', (65, 69))	('DWI-N+', 'Var', (40, 46))	('pathological metastatic nodes', 'CPA', (70, 99))
816785	31966912	Moreover, targeted therapy and individualized treatment may be the next hotspots of NAT, and may further improve the prognosis of LAGC patients.	('improve', 'PosReg', (105, 112))	('patients', 'Species', '9606', (135, 143))	('GC', 'Disease', 'MESH:D013274', (132, 134))	('targeted', 'Var', (10, 18))	('GC', 'Phenotype', 'HP:0012126', (132, 134))
816843	31966912	Moreover, NACT resulted in tumor downstaging (T stage, P = 0.002; N stage, P = 0.01) and a higher R0 resection rate (79.3% vs 70.3%, P = 0.03).	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('higher', 'PosReg', (91, 97))	('downstaging', 'NegReg', (33, 44))	('R0 resection', 'CPA', (98, 110))	('NACT', 'Var', (10, 14))
816844	31966912	The PFS (P < 0.001) and 5-year survival rates (36.3% vs 23.0%, P = 0.009) were also improved significantly in patients who received NACT.	('NACT', 'Var', (132, 136))	('PFS', 'CPA', (4, 7))	('5-year survival rates', 'CPA', (24, 45))	('improved', 'PosReg', (84, 92))	('patients', 'Species', '9606', (110, 118))
816897	31966912	Meanwhile, numerous trials in Asia, such as JCOG0405, JCOG1002, NCT01515748, NCT01534546, NCT02555358, and NCT00252161, have provided or will provide more evidence about the best indications for NAT, and physicians should always be critical when adopting the recommendations from foreign guidelines.	('NCT02555358', 'Var', (90, 101))	('NCT00252161', 'Var', (107, 118))	('JCOG0405', 'Chemical', 'MESH:C493960', (44, 52))	('NCT01515748', 'Var', (64, 75))	('JCOG0405', 'Var', (44, 52))	('JCOG1002', 'Chemical', 'MESH:C530561', (54, 62))	('NCT02555358', 'Chemical', 'MESH:C079985', (90, 101))	('NCT01534546', 'Var', (77, 88))
816923	31966912	We are also looking forward to more high-quality studies such as the NCT01534546, NCT02555358, and NCT00252161, which will help to establish a characteristic NAT strategy that is more appropriate for Asian populations.	('NCT02555358', 'Chemical', 'MESH:C079985', (82, 93))	('NCT01534546', 'Var', (69, 80))	('NCT00252161', 'Var', (99, 110))	('NCT02555358', 'Var', (82, 93))
816927	28009736	pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected.	('increasing', 'PosReg', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('increasing', 'PosReg', (119, 129))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('pN+', 'Var', (0, 3))	('decreasing', 'NegReg', (145, 155))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
816929	28009736	In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('poorly differentiated', 'CPA', (146, 167))	('esophageal cancer', 'Disease', (3, 20))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('pN+', 'Var', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('deeper invading', 'CPA', (117, 132))	('longer', 'Disease', (134, 140))
816949	28009736	Presence of pM1 (SDC Figure E2) and squamous cell cancer were predictive, but less so.	('squamous cell cancer', 'Disease', (36, 56))	('squamous cell cancer', 'Disease', 'MESH:D002294', (36, 56))	('pM1', 'Gene', '8834', (12, 15))	('pM1', 'Gene', (12, 15))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (36, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Presence', 'Var', (0, 8))
816952	28009736	Identifying pN+ required fewer resected lymph nodes for deeply invasive, poorly differentiated, or long cancers than for superficial invasion, well-differentiated, or short cancers.	('deeply invasive', 'CPA', (56, 71))	('poorly differentiated', 'CPA', (73, 94))	('long cancers', 'Disease', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('pN+', 'Var', (12, 15))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('short cancers', 'Disease', (167, 180))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('short cancers', 'Disease', 'MESH:D009369', (167, 180))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('long cancers', 'Disease', 'MESH:D009369', (99, 111))
816954	28009736	The same cancer characteristics that predicted presence of pN+ also predicted higher number of positive nodes (Figure 5).	('cancer', 'Disease', (9, 15))	('higher', 'PosReg', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('presence', 'Var', (47, 55))	('pN+', 'Var', (59, 62))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
816963	28009736	The strongest associations with pN+ cancers reflect cancer growth, biology, and histology.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('pN+', 'Var', (32, 35))	('cancer', 'Disease', (36, 42))	('cancers', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
816992	28009736	This study found that extent of lymphadenectomy required to accurately detect pN+ is greatest for early-stage cancers; in our previous study, extent of lymphadenectomy required to maximize survival benefit is greatest for advanced-stage cancers.	('cancers', 'Disease', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('advanced-stage cancers', 'Disease', (222, 244))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Disease', (237, 244))	('pN+', 'Var', (78, 81))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('advanced-stage cancers', 'Disease', 'MESH:D006223', (222, 244))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
817027	26093090	We found that TET2 expression was significantly associated with 5-hmC level (P = 0.003; r = 0.33 by paired t-test; Fig.	('TET2', 'Gene', (14, 18))	('associated', 'Reg', (48, 58))	('expression', 'Var', (19, 29))	('5-hmC', 'Chemical', 'MESH:C011865', (64, 69))	('TET2', 'Gene', '54790', (14, 18))	('5-hmC level', 'MPA', (64, 75))
817042	26093090	When patients were divided into those who expressed high TET2 levels ( >= 0.053, n = 41) and low TET2 (0.0059-0.0529, n = 40), Kaplan-Meier analysis showed the two groups to have similar overall mortality rates (log-rank P = 0.38; Fig.	('TET2', 'Gene', (97, 101))	('patients', 'Species', '9606', (5, 13))	('TET2', 'Gene', '54790', (57, 61))	('0.0059-0.0529', 'Var', (103, 116))	('TET2', 'Gene', (57, 61))	('TET2', 'Gene', '54790', (97, 101))
817048	26093090	Additionally, TET2 expression was significantly associated with 5-hmC level in ESCCs, but TET1 and TET3 were not.	('TET2', 'Gene', (14, 18))	('TET1', 'Gene', (90, 94))	('associated', 'Reg', (48, 58))	('expression', 'Var', (19, 29))	('TET3', 'Gene', (99, 103))	('TET1', 'Gene', '80312', (90, 94))	('TET3', 'Gene', '200424', (99, 103))	('5-hmC', 'Chemical', 'MESH:C011865', (64, 69))	('TET2', 'Gene', '54790', (14, 18))	('5-hmC level', 'MPA', (64, 75))
817049	26093090	Together, these results indicate that TET2 has a central function in converting 5-mC to 5-hmC in esophageal epithelial cells, and reduced TET2 causes decreased 5-hmC level in those cells, leading to ESCC development (Fig.	('TET2', 'Gene', (138, 142))	('5-hmC', 'Chemical', 'MESH:C011865', (160, 165))	('5-hmC', 'Chemical', 'MESH:C011865', (88, 93))	('5-mC', 'Chemical', 'MESH:D044503', (80, 84))	('TET2', 'Gene', '54790', (38, 42))	('ESCC development', 'CPA', (199, 215))	('leading to', 'Reg', (188, 198))	('reduced', 'Var', (130, 137))	('5-hmC level', 'MPA', (160, 171))	('TET2', 'Gene', '54790', (138, 142))	('TET2', 'Gene', (38, 42))	('decreased', 'NegReg', (150, 159))
817056	26093090	Loss of 5-hmC is likely to be common in cancers, and to play an important role in carcinogenesis.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('5-hmC', 'Chemical', 'MESH:C011865', (8, 13))	('cancers', 'Disease', (40, 47))	('carcinogenesis', 'Disease', (82, 96))	('5-hmC', 'Protein', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Loss', 'Var', (0, 4))
817065	26093090	We also found that low 5-hmC expression was loosely associated with poor prognosis in ESCC patients (although not significantly).	('patients', 'Species', '9606', (91, 99))	('low', 'Var', (19, 22))	('ESCC', 'Disease', (86, 90))	('5-hmC', 'Chemical', 'MESH:C011865', (23, 28))
817071	26093090	LINE-1 methylation has been shown to be vary widely in many human neoplasms; LINE-1 hypomethylation is strongly associated with a poor prognosis in several cancer types.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('neoplasms', 'Disease', 'MESH:D009369', (66, 75))	('neoplasms', 'Phenotype', 'HP:0002664', (66, 75))	('neoplasms', 'Disease', (66, 75))	('LINE-1', 'Gene', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('hypomethylation', 'Var', (84, 99))	('associated', 'Reg', (112, 122))	('human', 'Species', '9606', (60, 65))
817188	24978439	Heat Shock Protein 90 (HSP90) and Her2 in Adenocarcinomas of the Esophagus Her2 overexpression and amplification can be found in a significant subset of esophageal adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('esophageal adenocarcinomas', 'Disease', (153, 179))	('HSP90', 'Gene', (23, 28))	('Shock', 'Phenotype', 'HP:0031273', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('amplification', 'Var', (99, 112))	('HSP90', 'Gene', '3320', (23, 28))	('Heat Shock Protein 90', 'Gene', (0, 21))	('Heat Shock Protein 90', 'Gene', '3320', (0, 21))	('Her2', 'Gene', '2064', (75, 79))	('Her2', 'Gene', '2064', (34, 38))	('overexpression', 'PosReg', (80, 94))	('Adenocarcinomas of the Esophagus', 'Disease', 'MESH:C562730', (42, 74))	('Her2', 'Gene', (75, 79))	('Adenocarcinomas of the Esophagus', 'Disease', (42, 74))	('Her2', 'Gene', (34, 38))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (153, 179))
817200	24978439	We and others have demonstrated that esophageal adenocarcinomas show Her2 positivity in a percentage comparable to or even higher than gastric cancer.	('positivity', 'Var', (74, 84))	('gastric cancer', 'Disease', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (37, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('higher', 'PosReg', (123, 129))	('esophageal adenocarcinomas', 'Disease', (37, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('Her2', 'Gene', (69, 73))	('Her2', 'Gene', '2064', (69, 73))
817203	24978439	Some data suggest that deregulated HSP90 expression may also support the effects of oncogenic Her2 and this may represent a potential mechanism of resistance to Her2 directed drugs.	('Her2', 'Gene', (94, 98))	('Her2', 'Gene', '2064', (94, 98))	('deregulated', 'Var', (23, 34))	('expression', 'MPA', (41, 51))	('Her2', 'Gene', (161, 165))	('HSP90', 'Gene', (35, 40))	('effects', 'MPA', (73, 80))	('HSP90', 'Gene', '3320', (35, 40))	('Her2', 'Gene', '2064', (161, 165))
817204	24978439	On the other hand, inhibition of HSP90 may potentiate the effects of anti-cancer drugs targeting client proteins of this molecule.	('HSP90', 'Gene', '3320', (33, 38))	('inhibition', 'Var', (19, 29))	('effects', 'MPA', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('HSP90', 'Gene', (33, 38))	('potentiate', 'PosReg', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
817206	24978439	We have studied the role of Her2 and recently HSP90:among other molecular chaperones:in esophageal adenocarcinomas: overexpression and/or amplification of Her2 were associated with a more aggressive biological behavior in a well characterized collection of primary resected tumors.	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('overexpression', 'PosReg', (116, 130))	('esophageal adenocarcinomas', 'Disease', (88, 114))	('HSP90', 'Gene', (46, 51))	('amplification', 'Var', (138, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('aggressive biological behavior', 'CPA', (188, 218))	('HSP90', 'Gene', '3320', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('Her2', 'Gene', '2064', (28, 32))	('Her2', 'Gene', '2064', (155, 159))	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (188, 218))	('Her2', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumors', 'Disease', (274, 280))	('Her2', 'Gene', (155, 159))	('associated with', 'Reg', (165, 180))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (88, 114))
817238	24978439	Her2 positivity was associated with pT category (p = 0.041), lymph node metastases (p = 0.049) and tumor differentiation (p = 0.036; Table 4), in particular the percentage of Her2 negative tumors was higher in tumors with lower pT-category and without lymph node metastases as compared to Her2 positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('lymph node metastases', 'Disease', 'MESH:D009362', (252, 273))	('lymph node metastases', 'Disease', 'MESH:D009362', (61, 82))	('Her2', 'Gene', (175, 179))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('negative', 'NegReg', (180, 188))	('tumors', 'Disease', (303, 309))	('Her2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (99, 104))	('lower pT', 'Phenotype', 'HP:0032198', (222, 230))	('tumor', 'Disease', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('Her2', 'Gene', '2064', (289, 293))	('positivity', 'Var', (5, 15))	('pT category', 'Disease', (36, 47))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumors', 'Disease', (189, 195))	('tumor', 'Disease', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Her2', 'Gene', (289, 293))	('higher', 'PosReg', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('lymph node metastases', 'Disease', (252, 273))	('lymph node metastases', 'Disease', (61, 82))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('Her2', 'Gene', '2064', (175, 179))	('Her2', 'Gene', '2064', (0, 4))
817242	24978439	The results of our analyses demonstrate an association between the expression of HSP90 and Her2 amplification/expression in esophageal adenocarcinomas which may present at least in a subset of tumors.	('HSP90', 'Gene', (81, 86))	('HSP90', 'Gene', '3320', (81, 86))	('esophageal adenocarcinomas', 'Disease', (124, 150))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('Her2', 'Gene', (91, 95))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (124, 150))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('amplification/expression', 'Var', (96, 120))	('tumors', 'Disease', (193, 199))	('Her2', 'Gene', '2064', (91, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))
817246	24978439	Although only investigated in retrospective analyses, Her2 positivity is presumed to be predictive for anti Her2-directed therapy, which recently successfully has been introduced in the treatment of metastasized gastric and gastro-esophageal adenocarcinomas.	('gastro-esophageal adenocarcinomas', 'Disease', (224, 257))	('Her2', 'Gene', '2064', (108, 112))	('Her2', 'Gene', (54, 58))	('positivity', 'Var', (59, 69))	('gastro-esophageal adenocarcinomas', 'Disease', 'MESH:D005764', (224, 257))	('Her2', 'Gene', '2064', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('Her2', 'Gene', (108, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (247, 257))
817253	24978439	Inhibition of HSP90 may represent a combinatorial attack on multiple oncogenic pathways.	('Inhibition', 'Var', (0, 10))	('HSP90', 'Gene', (14, 19))	('HSP90', 'Gene', '3320', (14, 19))
817260	24978439	A novel HSP90 inhibitor, CH5164840 showed significant antitumor efficacy against gastric and breast cancer models which was even more enhanced when combined with HER2-targeting agents.	('HER2', 'Gene', '2064', (162, 166))	('HSP90', 'Gene', '3320', (8, 13))	('HER2', 'Gene', (162, 166))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('CH5164840', 'Chemical', 'MESH:C570831', (25, 34))	('enhanced', 'PosReg', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CH5164840', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('gastric and breast cancer', 'Disease', 'MESH:D013274', (81, 106))	('HSP90', 'Gene', (8, 13))
817263	24978439	Moreover, this may also be transferred onto other Her2 positive tumors, such as the subset of gastrointestinal adenocarcinomas with Her2 overexpression or amplification.	('Her2', 'Gene', (132, 136))	('amplification', 'Var', (155, 168))	('tumors', 'Disease', (64, 70))	('Her2', 'Gene', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('Her2', 'Gene', '2064', (132, 136))	('gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (94, 126))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Her2', 'Gene', '2064', (50, 54))	('overexpression', 'PosReg', (137, 151))	('gastrointestinal adenocarcinomas', 'Disease', (94, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
817282	22110708	ECRG4 expression was associated with better survival in esophageal and prostate carcinomas, and with inhibition of cell proliferation and migration in esophageal cancer, colorectal cancer and glioma.	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('expression', 'Var', (6, 16))	('esophageal and prostate carcinomas', 'Disease', 'MESH:D004938', (56, 90))	('prostate carcinomas', 'Disease', (71, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('ECRG4', 'Gene', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('rectal cancer', 'Phenotype', 'HP:0100743', (174, 187))	('colorectal cancer', 'Phenotype', 'HP:0003003', (170, 187))	('glioma', 'Disease', (192, 198))	('inhibition', 'NegReg', (101, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('esophageal cancer', 'Disease', (151, 168))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('prostate carcinomas', 'Disease', 'MESH:D011472', (71, 90))	('colorectal cancer', 'Disease', 'MESH:D015179', (170, 187))	('cell proliferation', 'CPA', (115, 133))	('better', 'PosReg', (37, 43))	('colorectal cancer', 'Disease', (170, 187))
817288	22110708	These sets were collected from the National Center for Biotechnology Information (NCBI)/Genbank GEO database (series entry GSE1456, GSE3494, GSE4922, GSE6861/GSE4779) or at the following web address https://genome.unc.edu/pubsup/breastGEO/(Table S1 ).	('GSE4922', 'Var', (141, 148))	('GSE3494', 'Var', (132, 139))	('GSE4779', 'Chemical', '-', (158, 165))	('GSE4922', 'Chemical', '-', (141, 148))	('GSE1456', 'Chemical', '-', (123, 130))	('GSE6861', 'Chemical', '-', (150, 157))	('GSE6861/GSE4779', 'Var', (150, 165))	('GSE1456', 'Var', (123, 130))	('GSE3494', 'Chemical', '-', (132, 139))
817299	22110708	In breast cancer, multiple TSG are hypermethylated and downregulated, including for examples BRCA1, RASSF1A, p16, FHIT, and CDH1 .	('p16', 'Gene', (109, 112))	('FHIT', 'Gene', '2272', (114, 118))	('CDH1', 'Gene', (124, 128))	('RASSF1A', 'Gene', (100, 107))	('RASSF1A', 'Gene', '11186', (100, 107))	('breast cancer', 'Disease', (3, 16))	('CDH1', 'Gene', '999', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('BRCA1', 'Gene', (93, 98))	('p16', 'Gene', '1029', (109, 112))	('downregulated', 'NegReg', (55, 68))	('hypermethylated', 'Var', (35, 50))	('FHIT', 'Gene', (114, 118))
817338	32426699	The mainstay of NPC treatment is chemo-radiation (C/RT) and while dysphagia is a known early and late toxicity of C/RT treatment, the nature of dysphagia post NPC treatment has had limited investigation.	('toxicity', 'Disease', 'MESH:D064420', (102, 110))	('dysphagia', 'Disease', (66, 75))	('toxicity', 'Disease', (102, 110))	('dysphagia', 'Phenotype', 'HP:0002015', (144, 153))	('NPC', 'Phenotype', 'HP:0100630', (159, 162))	('NPC', 'Gene', (16, 19))	('NPC', 'Gene', '4864', (159, 162))	('NPC', 'Phenotype', 'HP:0100630', (16, 19))	('dysphagia', 'Phenotype', 'HP:0002015', (66, 75))	('NPC', 'Gene', '4864', (16, 19))	('dysphagia', 'Disease', 'MESH:D003680', (144, 153))	('C/RT', 'Var', (114, 118))	('dysphagia post NPC', 'Disease', 'MESH:D000077274', (144, 162))	('dysphagia', 'Disease', 'MESH:D003680', (66, 75))	('NPC', 'Gene', (159, 162))	('dysphagia', 'Disease', (144, 153))	('dysphagia post NPC', 'Disease', (144, 162))
817350	32426699	Toxicities in patients who have undergone C/RT refer to the complications that they suffer from as a result of the treatment, as C/RT unavoidably affects structures adjacent to the tumor, impacting their corresponding functions.	('affects', 'Reg', (146, 153))	('tumor', 'Disease', (181, 186))	('Toxicities', 'Disease', (0, 10))	('Toxicities', 'Disease', 'MESH:D064420', (0, 10))	('impacting', 'Reg', (188, 197))	('C/RT', 'Var', (129, 133))	('functions', 'MPA', (218, 227))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
817401	32426699	In other work, the dosage to the pharyngo-esophagus area and the duration of feeding tube dependence were both found to be significantly less in participants with shielding.	('participants', 'Species', '9606', (145, 157))	('less', 'NegReg', (137, 141))	('shielding', 'Var', (163, 172))
817418	32426699	The literature also covered how C/RT affects swallowing function and whether the negative effects can be minimized, as well as whether swallowing treatment is effective on dysphagia.	('dysphagia', 'Disease', (172, 181))	('dysphagia', 'Phenotype', 'HP:0002015', (172, 181))	('affects', 'Reg', (37, 44))	('C/RT', 'Var', (32, 36))	('dysphagia', 'Disease', 'MESH:D003680', (172, 181))	('swallowing function', 'MPA', (45, 64))
817437	32426699	At present, the emerging literature supports that RT techniques, especially shielding and avoiding structures critical for swallowing (the pharyngeal constrictors), can be used to prevent, or at least lessen the severity of, dysphagia.	('lessen', 'NegReg', (201, 207))	('shielding', 'Var', (76, 85))	('dysphagia', 'Disease', (225, 234))	('dysphagia', 'Phenotype', 'HP:0002015', (225, 234))	('dysphagia', 'Disease', 'MESH:D003680', (225, 234))
817455	32010620	In addition, cell death caused by oridonin was strongly inhibited by GSH (1 mM), while GSSG (1 mM) had little effect.	('oridonin', 'Chemical', 'MESH:C011959', (34, 42))	('GSH', 'Chemical', 'MESH:D005978', (69, 72))	('GSSG', 'Chemical', 'MESH:D019803', (87, 91))	('cell death', 'CPA', (13, 23))	('GSH (1 mM', 'Var', (69, 78))	('inhibited', 'NegReg', (56, 65))
817456	32010620	At the same time, we also found that oridonin showed selective cytotoxicity to esophageal squamous carcinoma cell with p53 mutation since mut-p53 cells had lower SLC7A11 expression, a component of the cystine/glutamate antiporter.	('mutation', 'Var', (123, 131))	('p53', 'Gene', (142, 145))	('glutamate', 'Chemical', 'None', (209, 218))	('p53', 'Gene', '7157', (142, 145))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (79, 108))	('cystine', 'Chemical', 'MESH:D003553', (201, 208))	('cytotoxicity to esophageal squamous carcinoma', 'Disease', (63, 108))	('p53', 'Gene', '7157', (119, 122))	('cytotoxicity to esophageal squamous carcinoma', 'Disease', 'MESH:C562729', (63, 108))	('oridonin', 'Chemical', 'MESH:C011959', (37, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('SLC7A11', 'Gene', (162, 169))	('p53', 'Gene', (119, 122))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (90, 108))	('lower', 'NegReg', (156, 161))	('expression', 'MPA', (170, 180))
817459	32010620	Esophageal squamous carcinoma cells with p53-mutation showed hypersensitivity to oridonin because of the suppression of SLC7A11 expression by p53 mutation.	('p53', 'Gene', '7157', (41, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('p53', 'Gene', (142, 145))	('oridonin', 'Chemical', 'MESH:C011959', (81, 89))	('p53', 'Gene', '7157', (142, 145))	('Esophageal squamous carcinoma', 'Disease', 'MESH:C562729', (0, 29))	('SLC7A11', 'Gene', (120, 127))	('suppression', 'NegReg', (105, 116))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (11, 29))	('Esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (0, 29))	('hypersensitivity', 'Disease', (61, 77))	('Esophageal squamous carcinoma', 'Disease', (0, 29))	('hypersensitivity', 'Disease', 'MESH:D004342', (61, 77))	('expression', 'MPA', (128, 138))	('mutation', 'Var', (146, 154))	('p53', 'Gene', (41, 44))
817477	32010620	The following panel of human esophageal cancer cell lines was used; TE-1, KYSE-30, and KYSE-450 (mut-p53); EC109, KYSE70, and KYSE 410 (wt-p53).	('KYSE70', 'Var', (114, 120))	('KYSE 410', 'Var', (126, 134))	('EC109', 'CellLine', 'CVCL:6898', (107, 112))	('p53', 'Gene', (101, 104))	('esophageal cancer', 'Disease', (29, 46))	('p53', 'Gene', '7157', (101, 104))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('EC109', 'Var', (107, 112))	('human', 'Species', '9606', (23, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('TE-1', 'CellLine', 'CVCL:1759', (68, 72))
817479	32010620	TE-1, KYSE-30, KYSE70, and KYSE410 cells were maintained in RPMI 1640 medium.	('KYSE70', 'Var', (15, 21))	('KYSE410', 'Var', (27, 34))	('TE-1', 'CellLine', 'CVCL:1759', (0, 4))
817483	32010620	EC109, KYSE70, KYSE410, TE-1, KYSE-450, and KYSE-30 cells were seed at a density of 5 x 103 per well in 96-well plates.	('KYSE70', 'Var', (7, 13))	('TE-1', 'CellLine', 'CVCL:1759', (24, 28))	('KYSE410', 'Var', (15, 22))	('EC109', 'CellLine', 'CVCL:6898', (0, 5))
817503	32010620	However, TE-1 cells were more sensitive than EC109 cells to oridonin, and the IC50 values of TE-1 cells were significantly reduced regardless of the length of treatment, compared with EC109 cells (Figure 1C, P < 0.01).	('IC50 values', 'MPA', (78, 89))	('EC109', 'CellLine', 'CVCL:6898', (45, 50))	('EC109', 'CellLine', 'CVCL:6898', (184, 189))	('oridonin', 'Chemical', 'MESH:C011959', (60, 68))	('TE-1', 'Var', (93, 97))	('TE-1', 'CellLine', 'CVCL:1759', (93, 97))	('TE-1', 'CellLine', 'CVCL:1759', (9, 13))	('reduced', 'NegReg', (123, 130))
817518	32010620	Of interest, we found that the baseline level of ROS in TE1 cells is much higher compared to EC109 cells (Figures 3A,B) While oridonin (30 and 40 muM) significantly induced intracellular ROS generation at 4 h for both cell lines (P < 0.01), N-acetyl-L-cysteine (NAC), Sulfhydryl-containing antioxidant, can significantly inhibit the ROS production induced by oridonin in EC109 cells and TE-1 cells (Figures 3A,B).	('EC109', 'CellLine', 'CVCL:6898', (371, 376))	('inhibit', 'NegReg', (321, 328))	('Sulfhydryl', 'Chemical', 'MESH:D013438', (268, 278))	('ROS production', 'MPA', (333, 347))	('TE-1', 'CellLine', 'CVCL:1759', (387, 391))	('EC109', 'CellLine', 'CVCL:6898', (93, 98))	('intracellular ROS generation', 'MPA', (173, 201))	('oridonin', 'Chemical', 'MESH:C011959', (359, 367))	('N-acetyl-L-cysteine', 'Var', (241, 260))	('NAC', 'Gene', (262, 265))	('muM', 'Gene', '56925', (146, 149))	('NAC', 'Gene', '7504', (262, 265))	('cysteine', 'Chemical', 'MESH:D003545', (252, 260))	('oridonin', 'Chemical', 'MESH:C011959', (126, 134))	('muM', 'Gene', (146, 149))
817525	32010620	These results also confirmed a significantly different endogenous ROS status comparing with TE1 cells and EC109 cells: in TE1 cells the higher baseline level of oxidative stress has consumed a significant portion of cellular GSH reservoir, thus oridonin dependent GSH depletion would be more apparent in such context.	('GSH', 'Chemical', 'MESH:D005978', (264, 267))	('higher', 'PosReg', (136, 142))	('oridonin', 'Chemical', 'MESH:C011959', (245, 253))	('cellular GSH reservoir', 'MPA', (216, 238))	('GSH', 'Chemical', 'MESH:D005978', (225, 228))	('oxidative stress', 'Phenotype', 'HP:0025464', (161, 177))	('TE1', 'Var', (122, 125))	('EC109', 'CellLine', 'CVCL:6898', (106, 111))
817527	32010620	Our results indicated that cell death caused by oridonin was strongly inhibited by GSH (1 mM) in both EC109 and TE1 cells, while GSSG had little effect.	('oridonin', 'Chemical', 'MESH:C011959', (48, 56))	('GSH', 'Chemical', 'MESH:D005978', (83, 86))	('cell death', 'CPA', (27, 37))	('GSH', 'Var', (83, 86))	('EC109', 'CellLine', 'CVCL:6898', (102, 107))	('inhibited', 'NegReg', (70, 79))	('GSSG', 'Chemical', 'MESH:D019803', (129, 133))
817531	32010620	We found that SLC7A11, transcript and protein levels are significantly lower in cell lines harboring mutant p53 mutations (Figure 5A).	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('SLC7A11', 'MPA', (14, 21))	('mutations', 'Var', (112, 121))	('mutant', 'Var', (101, 107))	('lower', 'NegReg', (71, 76))
817532	32010620	This result is consistent with the previous findings of David et al., that mutant p53 can repress the expression of SLC7A11.	('expression', 'MPA', (102, 112))	('SLC7A11', 'Gene', (116, 123))	('repress', 'NegReg', (90, 97))	('mutant', 'Var', (75, 81))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))
817533	32010620	Furthermore, we detected multiple esophageal squamous carcinoma cell lines (with either wild type p53 or mutant p53) by MTT assay.	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (34, 63))	('esophageal squamous carcinoma', 'Disease', (34, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (45, 63))	('esophageal squamous carcinoma', 'Disease', 'MESH:C562729', (34, 63))	('p53', 'Gene', '7157', (98, 101))	('p53', 'Gene', (98, 101))	('p53', 'Gene', (112, 115))	('MTT', 'Chemical', 'MESH:C022616', (120, 123))	('mutant', 'Var', (105, 111))	('p53', 'Gene', '7157', (112, 115))
817535	32010620	To examine whether such differential oridonin sensitivity is indeed mediated by mutant p53 dependent SLC7A11 downregulation, we investigate whether the sensitivity of wt-p53 esophageal cancer cells to oridonin can be enhanced by knocking down the SLC7A11 gene.	('SLC7A11', 'Gene', (101, 108))	('esophageal cancer', 'Disease', (174, 191))	('downregulation', 'NegReg', (109, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (174, 191))	('mutant', 'Var', (80, 86))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('oridonin', 'Chemical', 'MESH:C011959', (201, 209))	('enhanced', 'PosReg', (217, 225))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('p53', 'Gene', (170, 173))	('SLC7A11', 'Gene', (247, 254))	('knocking down', 'Var', (229, 242))	('p53', 'Gene', '7157', (170, 173))	('oridonin', 'Chemical', 'MESH:C011959', (37, 45))	('sensitivity', 'MPA', (152, 163))
817536	32010620	Indeed, we found that knocking down SLC7A11 (Figure 5F) significantly increased the cytotoxicity of oridonin to EC109 cells, and resulted in increased ROS levels correspondingly (Figure 5G).	('cytotoxicity', 'Disease', (84, 96))	('SLC7A11', 'Gene', (36, 43))	('ROS levels', 'MPA', (151, 161))	('increased', 'PosReg', (70, 79))	('increased', 'PosReg', (141, 150))	('increased ROS levels', 'Phenotype', 'HP:0025464', (141, 161))	('cytotoxicity', 'Disease', 'MESH:D064420', (84, 96))	('EC109', 'CellLine', 'CVCL:6898', (112, 117))	('knocking down', 'Var', (22, 35))	('oridonin', 'Chemical', 'MESH:C011959', (100, 108))
817562	32010620	First, we found that TE1 cells had a higher level of ROS compared to EC109 cells, both oridonin and APR-246 can increase intracellular ROS levels, which can be reversed by NAC.	('EC109', 'CellLine', 'CVCL:6898', (69, 74))	('intracellular ROS levels', 'MPA', (121, 145))	('APR-246', 'Var', (100, 107))	('oridonin', 'Chemical', 'MESH:C011959', (87, 95))	('increase intracellular ROS levels', 'Phenotype', 'HP:0025464', (112, 145))	('NAC', 'Gene', (172, 175))	('NAC', 'Gene', '7504', (172, 175))	('increase', 'PosReg', (112, 120))	('APR-246', 'Chemical', 'MESH:C533410', (100, 107))
817569	32010620	Our data showed that cell lines with higher expression of SLC7A11, such as EC109, KYSE70, and KYSE410 treated with oridonin, respectively, had lower IC50 values after 24 h than cells with lower expression of SLC7A11, such as KYSE450, KYSE30 and TE1 cells.	('expression', 'MPA', (44, 54))	('higher', 'PosReg', (37, 43))	('SLC7A11', 'Gene', (58, 65))	('lower', 'NegReg', (143, 148))	('oridonin', 'Chemical', 'MESH:C011959', (115, 123))	('KYSE70', 'Var', (82, 88))	('IC50 values', 'MPA', (149, 160))	('EC109', 'CellLine', 'CVCL:6898', (75, 80))	('KYSE410', 'Var', (94, 101))
817573	32010620	To interrogate the functional relationship between SLC7A11 and cellular sensitivity to oridonin, we knocked down SLC7A11 in EC109 cells.	('SLC7A11', 'Gene', (113, 120))	('knocked', 'Var', (100, 107))	('EC109', 'CellLine', 'CVCL:6898', (124, 129))	('oridonin', 'Chemical', 'MESH:C011959', (87, 95))
817574	32010620	We found that inhibition of SLC7A11 expression significantly increased the sensitivity of EC109 cells to oridonin and intracellular ROS.	('EC109', 'CellLine', 'CVCL:6898', (90, 95))	('oridonin', 'Chemical', 'MESH:C011959', (105, 113))	('SLC7A11', 'Gene', (28, 35))	('increased', 'PosReg', (61, 70))	('sensitivity', 'MPA', (75, 86))	('inhibition', 'Var', (14, 24))
817579	32010620	For esophageal cancer cells with a high level of SLC7A11, GSH can be synergistically depleted by the combined use of oridonin and gamma-glutamyl cysteine synthetase inhibitor (BSO), leading to irresistible ROS accumulation and cell death.	('oridonin', 'Chemical', 'MESH:C011959', (117, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('SLC7A11', 'Var', (49, 56))	('ROS accumulation', 'MPA', (206, 222))	('depleted', 'NegReg', (85, 93))	('cell death', 'CPA', (227, 237))	('gamma-glutamyl cysteine synthetase', 'Gene', '2729', (130, 164))	('BSO', 'Chemical', 'MESH:D019328', (176, 179))	('GSH', 'Chemical', 'MESH:D005978', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('gamma-glutamyl cysteine synthetase', 'Gene', (130, 164))	('esophageal cancer', 'Disease', (4, 21))
817740	30643356	The second clinical trial studying TIF 2.0 against PPIs was the RESPECT trial, which was a prospective, sham-controlled trial to determine if TIF reduced troublesome regurgitation to a greater extent than PPIs in patients with GERD.	('TIF 2', 'Gene', (35, 40))	('TIF 2', 'Gene', '10499', (35, 40))	('TIF', 'Var', (142, 145))	('reduced', 'NegReg', (146, 153))	('troublesome regurgitation', 'Disease', (154, 179))	('TIF', 'Chemical', '-', (35, 38))	('patients', 'Species', '9606', (213, 221))	('TIF', 'Chemical', '-', (142, 145))
817742	30643356	87 patients with GERD and hiatal hernias <= 2 cm were randomly assigned to groups that underwent TIF and then received 6 mo of placebo, or sham surgery and 6 mo of once- or twice-daily omeprazole (controls, n = 42).	('hiatal hernias', 'Disease', 'MESH:D006551', (26, 40))	('hiatal hernias', 'Disease', (26, 40))	('hiatal hernia', 'Phenotype', 'HP:0002036', (26, 39))	('omeprazole', 'Chemical', 'MESH:D009853', (185, 195))	('TIF', 'Var', (97, 100))	('GERD', 'Disease', (17, 21))	('patients', 'Species', '9606', (3, 11))	('TIF', 'Chemical', '-', (97, 100))	('hernias', 'Phenotype', 'HP:0100790', (33, 40))	('hernia', 'Phenotype', 'HP:0100790', (33, 39))	('hiatal hernias', 'Phenotype', 'HP:0002036', (26, 40))
817747	30643356	Control of esophageal pH improved after TIF (mean 9.3% before and 6.3% after; P < 0.001), but not after sham surgery (mean 8.6% before and 8.9% after).	('improved', 'PosReg', (25, 33))	('TIF', 'Chemical', '-', (40, 43))	('Control', 'MPA', (0, 7))	('esophageal', 'Disease', (11, 21))	('TIF', 'Var', (40, 43))
817753	30643356	Secondary outcomes were: PPI consumption, esophageal acid exposure, reduction in Quality of Life in Reflux and Dyspepsia and Gastrointestinal Symptom Rating Scale scores and healing of reflux esophagitis.	('Reflux and Dyspepsia', 'Disease', 'MESH:D004415', (100, 120))	('Quality of Life', 'MPA', (81, 96))	('esophageal acid', 'Chemical', '-', (42, 57))	('PPI', 'Var', (25, 28))	('reflux esophagitis', 'Disease', (185, 203))	('reflux esophagitis', 'Disease', 'MESH:D005764', (185, 203))	('Dyspepsia', 'Phenotype', 'HP:0410281', (111, 120))	('reduction', 'NegReg', (68, 77))	('esophageal acid exposure', 'MPA', (42, 66))	('esophagitis', 'Phenotype', 'HP:0100633', (192, 203))
817768	30643356	With regards to the stationary esophageal manometry and impedance-pH monitoring performed directly after the procedure, TIF resulted in a marked reduction of both the number of transient LES relaxation (tLESRs) (16.8 +- 1.5 vs 9.2 +- 1.3; P < 0.01) and the number of tLESRs associated with liquid-containing reflux after the procedure (from 11.1 +- 1.6 vs 5.6 +- 0.6; P < 0.01).	('liquid-containing reflux', 'MPA', (290, 314))	('reduction', 'NegReg', (145, 154))	('TIF', 'Chemical', '-', (120, 123))	('transient LES relaxation', 'MPA', (177, 201))	('TIF', 'Var', (120, 123))
817769	30643356	TIF also led to a decrease in the number and proximal extent of reflux episodes and an improvement of acid exposure in the upright position; conversely, TIF had no effect on the number of gas reflux episodes, corroborating the low incidence of post-TIF gas-bloat symptoms.	('TIF', 'Chemical', '-', (249, 252))	('TIF', 'Var', (0, 3))	('reflux episodes', 'Phenotype', 'HP:0002020', (64, 79))	('TIF', 'Chemical', '-', (0, 3))	('improvement', 'PosReg', (87, 98))	('reflux episodes', 'Phenotype', 'HP:0002020', (192, 207))	('acid exposure in the upright position', 'MPA', (102, 139))	('-bloat', 'Phenotype', 'HP:0003270', (256, 262))	('reflux episodes', 'MPA', (64, 79))	('decrease', 'NegReg', (18, 26))	('gas reflux', 'Phenotype', 'HP:0002020', (188, 198))	('TIF', 'Chemical', '-', (153, 156))
817770	30643356	Also of note, the basal LES pressure in the fasted state was increased after TIF (from 13.9 +- 1.0 to 20.5 +- 1.8 mmHg; P < 0.01).	('TIF', 'Chemical', '-', (77, 80))	('increased', 'PosReg', (61, 70))	('basal LES pressure', 'MPA', (18, 36))	('TIF', 'Var', (77, 80))
817771	30643356	Thus, TIF reduces EGJ distensibility, thereby decreasing tLESRs, which is the main mechanism for upright refluxers.	('decreasing', 'NegReg', (46, 56))	('TIF', 'Var', (6, 9))	('reduces', 'NegReg', (10, 17))	('tLESRs', 'MPA', (57, 63))	('TIF', 'Chemical', '-', (6, 9))	('EGJ distensibility', 'MPA', (18, 36))
817772	30643356	We are now exploring the role of TIF among patients with BE - including non-dysplastic Barrett's, and those patients with previous history of Barrett's dysplasia, who have now reached complete remission of intestinal metaplasia (CRIM) by endoscopic resection and/or ablation, but are destined to life-long PPIs.	("non-dysplastic Barrett's", 'Disease', 'MESH:D001471', (72, 96))	('TIF', 'Chemical', '-', (33, 36))	('ablation', 'Var', (266, 274))	('patients', 'Species', '9606', (43, 51))	('non-dysplastic Barrett', 'Disease', (72, 94))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('intestinal metaplasia', 'Disease', (206, 227))	("Barrett's dysplasia", 'Disease', (142, 161))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (206, 227))	("Barrett's dysplasia", 'Disease', 'MESH:D001471', (142, 161))	('patients', 'Species', '9606', (108, 116))
817781	30643356	A potential solution was to ablate the mucosa with argon plasma coagulation (APC), a technique we use for gastric bypass revisions where we ablate the gastric mucosa prior to placing a purse-string suture around the pouch anastomosis to narrow the outlet.	('narrow', 'NegReg', (237, 243))	('argon', 'Chemical', 'MESH:D001128', (51, 56))	('ablate', 'Var', (140, 146))
817785	30643356	Of the 22 patients on daily PPI, 13 patients (59%) were able to discontinue their medication, and 3 patients (14%) were able to reduce their dose.	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (100, 108))	('PPI', 'Var', (28, 31))	('patients', 'Species', '9606', (10, 18))	('discontinue', 'NegReg', (64, 75))	('reduce', 'NegReg', (128, 134))
817825	30643356	In this seminal NEJM study, patients who received RFA had less disease progression (3.6% vs 16.3%, P = 0.03) and fewer cancers (1.2% vs 9.3%, P = 0.045).	('disease progression', 'CPA', (63, 82))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('RFA', 'Var', (50, 53))	('fewer', 'NegReg', (113, 118))	('patients', 'Species', '9606', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('less', 'NegReg', (58, 62))
817834	30643356	We recently presented our initial Hybrid APC series of 17 patients with biopsy proven non-dysplastic BE (NDBE) 59%, low grade dysplasia 18% and HGD 24%.	('low grade', 'Var', (116, 125))	('BE', 'Phenotype', 'HP:0100580', (107, 109))	('non-dysplastic', 'Disease', (86, 100))	('non-dysplastic', 'Disease', 'MESH:D004416', (86, 100))	('BE', 'Phenotype', 'HP:0100580', (101, 103))	('patients', 'Species', '9606', (58, 66))	('dysplasia', 'Disease', (126, 135))	('dysplasia', 'Disease', 'MESH:D004476', (126, 135))
817960	29261789	Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%.	('pancreatic tumors', 'Phenotype', 'HP:0002894', (81, 98))	('colorectal cancer', 'Disease', (137, 154))	('positivity', 'Var', (293, 303))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('patients', 'Species', '9606', (155, 163))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (253, 270))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('pancreatic tumors', 'Disease', 'MESH:D010190', (81, 98))	('tumors', 'Disease', (92, 98))	('pancreatic tumors', 'Disease', (81, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('GCC', 'Gene', (289, 292))	('pancreatic tumors', 'Disease', 'MESH:D010190', (253, 270))	('pancreatic tumors', 'Disease', (253, 270))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('GCC', 'Gene', '2984', (289, 292))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('tumors', 'Disease', (201, 207))
817975	29261789	Formalin-fixed paraffin-embedded tissue microarrays for esophageal, gastric, and pancreatic tumors were procured from commercial sources (US Biomax, Rockville, MD, USA [arrays: STC1021, STC1501, ST8013, ST810a, PA1002, PA1921, and ES8010] and Pantomics, Richmond, CA, USA [arrays: PAC481 and ESC1021]).	('ST8013', 'Var', (195, 201))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('STC1501', 'Var', (186, 193))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (81, 98))	('ES8010]', 'Var', (231, 238))	('PA1002', 'Var', (211, 217))	('PA1921', 'Var', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('STC1021', 'Var', (177, 184))	('ST810a', 'Var', (203, 209))	('pancreatic tumors', 'Disease', 'MESH:D010190', (81, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic tumors', 'Disease', (81, 98))
818031	29261789	They have more similarities with gastric adenocarcinomas with chromosomal instability rather than esophageal SCC.	('gastric adenocarcinomas', 'Disease', (33, 56))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (33, 56))	('SCC', 'Gene', '6317', (109, 112))	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('chromosomal instability', 'Var', (62, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('chromosomal instability', 'Phenotype', 'HP:0040012', (62, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('SCC', 'Gene', (109, 112))
818075	26774180	However, inhibition of Notch and transforming growth factor-beta (TGFB) promoted hepatocyte differentiation .	('TGFB', 'Gene', '7040', (66, 70))	('transforming growth factor-beta', 'Gene', (33, 64))	('TGFB', 'Gene', (66, 70))	('transforming growth factor-beta', 'Gene', '7040', (33, 64))	('inhibition', 'Var', (9, 19))	('hepatocyte differentiation', 'CPA', (81, 107))	('promoted', 'PosReg', (72, 80))
818083	26774180	Pancreatic duct ligation results in Wnt activity and the development of LGR5+ progenitors in the pancreatic ductal epithelium, which can generate mouse pancreatic epithelial organoids.	('Pancreatic duct', 'Disease', 'MESH:D021441', (0, 15))	('pancreatic', 'Disease', 'MESH:D010195', (152, 162))	('pancreatic', 'Disease', 'MESH:D010195', (97, 107))	('pancreatic epithelial', 'Disease', (152, 173))	('pancreatic', 'Disease', (152, 162))	('mouse', 'Species', '10090', (146, 151))	('ligation', 'Var', (16, 24))	('pancreatic', 'Disease', (97, 107))	('Pancreatic duct', 'Disease', (0, 15))	('pancreatic epithelial', 'Disease', 'MESH:D010195', (152, 173))	('Wnt activity', 'CPA', (36, 48))	('rat', 'Species', '10116', (141, 144))
818120	26774180	Epithelial organoids have been used to assess function of the CFTR:mutations in this transporter can cause CF .	('mutations', 'Var', (67, 76))	('CFTR', 'Gene', (62, 66))	('CF', 'Disease', 'MESH:D003550', (62, 64))	('CF', 'Disease', 'MESH:D003550', (107, 109))	('cause', 'Reg', (101, 106))	('CFTR', 'Gene', '1080', (62, 66))
818121	26774180	Although CF is most commonly associated with the pulmonary epithelium, CFTR mutations result in accumulation of thick secretions in the pulmonary and GI tracts.	('thick secretions', 'MPA', (112, 128))	('result in', 'Reg', (86, 95))	('mutations', 'Var', (76, 85))	('CFTR', 'Gene', (71, 75))	('CF', 'Disease', 'MESH:D003550', (71, 73))	('accumulation', 'PosReg', (96, 108))	('CF', 'Disease', 'MESH:D003550', (9, 11))	('CFTR', 'Gene', '1080', (71, 75))
818122	26774180	Dekkers et al identified forskolin-induced swelling of normal epithelial intestinal organoids as a physiologic function of non-mutant CFTR.	('swelling', 'Disease', 'MESH:D004487', (43, 51))	('CFTR', 'Gene', (134, 138))	('non-mutant', 'Var', (123, 133))	('forskolin', 'Chemical', 'MESH:D005576', (25, 34))	('CFTR', 'Gene', '1080', (134, 138))	('swelling', 'Disease', (43, 51))
818125	26774180	Furthermore, correction of CFTR mutations in epithelial organoids from the small intestine of patients with CF, using the CRISPR/Cas9 genome editing system, reduced forskolin-induced swelling .	('forskolin', 'Chemical', 'MESH:D005576', (165, 174))	('correction', 'Var', (13, 23))	('patients', 'Species', '9606', (94, 102))	('CFTR', 'Gene', (27, 31))	('swelling', 'Disease', 'MESH:D004487', (183, 191))	('mutations', 'Var', (32, 41))	('swelling', 'Disease', (183, 191))	('CF', 'Disease', 'MESH:D003550', (108, 110))	('CF', 'Disease', 'MESH:D003550', (27, 29))	('CFTR', 'Gene', '1080', (27, 31))	('reduced', 'NegReg', (157, 164))
818127	26774180	MVID is frequently caused by mutations in myosin Vb (MYO5B) that result in inappropriate localization of apical proteins and enterocyte polarization .	('MVID', 'Disease', (0, 4))	('MVID', 'Disease', 'MESH:C537470', (0, 4))	('enterocyte polarization', 'CPA', (125, 148))	('myosin Vb', 'Gene', '4645', (42, 51))	('localization of apical', 'MPA', (89, 111))	('caused by', 'Reg', (19, 28))	('mutations', 'Var', (29, 38))	('myosin Vb', 'Gene', (42, 51))	('MYO5B', 'Gene', '4645', (53, 58))	('MYO5B', 'Gene', (53, 58))
818128	26774180	Wiegerinck et al identified a mutation in syntaxin 3 (STX3) by whole-exome sequencing in patient with MVID but no mutation in MYO5B.	('MYO5B', 'Gene', (126, 131))	('MVID', 'Disease', (102, 106))	('syntaxin 3', 'Gene', '6809', (42, 52))	('patient', 'Species', '9606', (89, 96))	('STX3', 'Gene', '6809', (54, 58))	('STX3', 'Gene', (54, 58))	('mutation', 'Var', (30, 38))	('syntaxin 3', 'Gene', (42, 52))	('MVID', 'Disease', 'MESH:C537470', (102, 106))	('MYO5B', 'Gene', '4645', (126, 131))
818131	26774180	Using a combination of genome-wide linkage analysis and whole-exome sequencing, Bigorge et al and Avitzur et al identified previously uncharacterized mutations in the tetratricopeptide repeat domain-7A (TTC7A) of patients with MIA and combined immunodeficiency.	('TTC7A', 'Gene', '57217', (203, 208))	('immunodeficiency', 'Phenotype', 'HP:0002721', (244, 260))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (235, 260))	('immunodeficiency', 'Disease', (244, 260))	('immunodeficiency', 'Disease', 'MESH:D007153', (244, 260))	('tetratricopeptide repeat domain-7A', 'Gene', (167, 201))	('MIA', 'Phenotype', 'HP:0004797', (227, 230))	('MIA', 'Disease', 'None', (227, 230))	('mutations', 'Var', (150, 159))	('TTC7A', 'Gene', (203, 208))	('patients', 'Species', '9606', (213, 221))	('tetratricopeptide repeat domain-7A', 'Gene', '57217', (167, 201))	('MIA', 'Disease', (227, 230))
818135	26774180	Enteric anendocrinosis is an extremely rare disease caused by mutations in NEUROG3 that is characterized by severe malabsorptive diarrhea and a lack of intestinal enteroendocrine cells .	('malabsorptive diarrhea', 'Disease', (115, 137))	('NEUROG3', 'Gene', (75, 82))	('anendocrinosis', 'Disease', (8, 22))	('caused', 'Reg', (52, 58))	('rare disease', 'Disease', (39, 51))	('anendocrinosis', 'Disease', 'MESH:C563673', (8, 22))	('rare disease', 'Disease', 'MESH:D035583', (39, 51))	('diarrhea', 'Phenotype', 'HP:0002014', (129, 137))	('malabsorptive diarrhea', 'Disease', 'MESH:C563673', (115, 137))	('mutations', 'Var', (62, 71))
818141	26774180	Disruption of Hif2alpha in mice reduced features of colitis induced by DSS.	('Hif2alpha', 'Gene', (14, 23))	('mice', 'Species', '10090', (27, 31))	('colitis', 'Disease', 'MESH:D003092', (52, 59))	('reduced', 'NegReg', (32, 39))	('colitis', 'Disease', (52, 59))	('colitis', 'Phenotype', 'HP:0002583', (52, 59))	('Hif2alpha', 'Gene', '13819', (14, 23))	('DSS', 'Chemical', '-', (71, 74))	('Disruption', 'Var', (0, 10))
818144	26774180	IBD can also lead to fibrosis in the intestine, and PSC-derived organoids have been used to model a fibrosis-like response to TGFB stimulation that could be reversed by anti-fibrotic drugs .	('fibrosis', 'Disease', 'MESH:D005355', (21, 29))	('fibrosis', 'Disease', (21, 29))	('IBD', 'Phenotype', 'HP:0002037', (0, 3))	('TGFB', 'Gene', (126, 130))	('lead to', 'Reg', (13, 20))	('fibrosis', 'Disease', (100, 108))	('fibrosis', 'Disease', 'MESH:D005355', (100, 108))	('TGFB', 'Gene', '7040', (126, 130))	('IBD', 'Var', (0, 3))	('stimulation', 'PosReg', (131, 142))
818148	26774180	IBD is associated with increased risk for colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('colorectal cancer', 'Disease', (42, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('IBD', 'Phenotype', 'HP:0002037', (0, 3))	('IBD', 'Var', (0, 3))
818150	26774180	Deletion of the antioxidant selenoprotein P exacerbated DSS-induced colitis and tumorigenesis .	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('colitis', 'Disease', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('selenoprotein P', 'Gene', (28, 43))	('colitis', 'Phenotype', 'HP:0002583', (68, 75))	('tumor', 'Disease', (80, 85))	('colitis', 'Disease', 'MESH:D003092', (68, 75))	('exacerbated', 'PosReg', (44, 55))	('DSS', 'Chemical', '-', (56, 59))	('selenoprotein P', 'Gene', '6414', (28, 43))	('Deletion', 'Var', (0, 8))
818160	26774180	Helicobacter pylori cause most cases of peptic ulcer disease by inducing hypersecretion of acid and have been associated with gastric cancer.	('ulcer disease', 'Disease', 'MESH:D014456', (47, 60))	('ulcer disease', 'Disease', (47, 60))	('Helicobacter pylori', 'Species', '210', (0, 19))	('gastric cancer', 'Disease', (126, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('peptic ulcer', 'Phenotype', 'HP:0004398', (40, 52))	('associated', 'Reg', (110, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('Helicobacter pylori', 'Var', (0, 19))	('inducing', 'Reg', (64, 72))	('hypersecretion of acid', 'MPA', (73, 95))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
818166	26774180	Similar to findings from PSC-derived gastric organoids, this study demonstrated that only H pylori variants that expressed CagA increased proliferation in gastric organoids.	('CagA', 'Gene', (123, 127))	('variants', 'Var', (99, 107))	('pylori', 'Species', '210', (92, 98))	('increased', 'PosReg', (128, 137))	('rat', 'Species', '10116', (74, 77))	('proliferation in gastric organoids', 'CPA', (138, 172))	('H pylori', 'Gene', (90, 98))	('rat', 'Species', '10116', (145, 148))
818171	26774180	Absence of mature alpha-defensin reduced intra-luminal bacterial killing, which could be partially restored by expression of human alpha-defensin.	('Absence', 'Var', (0, 7))	('human', 'Species', '9606', (125, 130))	('reduced', 'NegReg', (33, 40))	('intra-luminal bacterial killing', 'CPA', (41, 72))
818180	26774180	Sodhi et al demonstrated that lack of Toll-like receptor-4 (TLR4) protected neonatal mice from hypoxia-induced NEC .	('mice', 'Species', '10090', (85, 89))	('hypoxia', 'Disease', (95, 102))	('hypoxia', 'Disease', 'MESH:D000860', (95, 102))	('Toll-like receptor-4', 'Gene', '21898', (38, 58))	('rat', 'Species', '10116', (19, 22))	('lack', 'Var', (30, 34))	('Toll-like receptor-4', 'Gene', (38, 58))	('TLR4', 'Gene', (60, 64))
818181	26774180	Interestingly, small intestine epithelial organoids generated from these mutant mice had increased in goblet cell differentiation.	('rat', 'Species', '10116', (56, 59))	('small intestine epithelial organoids', 'CPA', (15, 51))	('mutant', 'Var', (73, 79))	('mice', 'Species', '10090', (80, 84))	('increased', 'PosReg', (89, 98))	('goblet cell differentiation', 'CPA', (102, 129))
818189	26774180	Mice given muramyl dipeptide before intestinal insult with doxorubicin had increased crypt survival, not seen in NOD2-knockout mice.	('mice', 'Species', '10090', (127, 131))	('increased', 'PosReg', (75, 84))	('doxorubicin', 'Chemical', 'MESH:D004317', (59, 70))	('muramyl dipeptide', 'Var', (11, 28))	('Mice', 'Species', '10090', (0, 4))	('muramyl dipeptide', 'Chemical', 'MESH:D000119', (11, 28))	('crypt survival', 'CPA', (85, 99))
818192	26774180	Colonic epithelial cells accumulate genetic changes that transform them into adenocarcinomas:intestinal organoids are powerful tools for studying this process.	('changes', 'Var', (44, 51))	('adenocarcinomas', 'Disease', 'MESH:D000230', (77, 92))	('adenocarcinomas', 'Disease', (77, 92))
818201	26774180	Strikingly mutations in Kras, in conjunction with Apc deletion, delayed apoptosis and decreased expression of Bim.	('delayed', 'NegReg', (64, 71))	('mutations', 'Var', (11, 20))	('Kras', 'Gene', (24, 28))	('Bim', 'Gene', (110, 113))	('decreased', 'NegReg', (86, 95))	('apoptosis', 'CPA', (72, 81))	('Bim', 'Gene', '10018', (110, 113))
818202	26774180	Studies in intestinal organoids support the concept that loss of contributes to colorectal carcinogenesis.	('loss of', 'Var', (57, 64))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (80, 105))	('colorectal carcinogenesis', 'Disease', (80, 105))
818203	26774180	CRISPR-Cas9 genome editing has been used to mutate tumor suppressor genes such as APC, SMAD4, and TP53, and the oncogenes KRAS and PI3KCA, in colon epithelial organoids grown from normal human colon tissues .	('mutate', 'Var', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('APC', 'Disease', (82, 85))	('tumor', 'Disease', (51, 56))	('human', 'Species', '9606', (187, 192))	('SMAD4', 'Gene', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('TP53', 'Gene', (98, 102))
818204	26774180	Organoids in which all 5 genes were mutated grew independent of growth factors and had gene expression signatures similar to those of epithelial organoids generated from human colon adenomas.	('colon adenomas', 'Disease', (176, 190))	('mutated', 'Var', (36, 43))	('grew', 'CPA', (44, 48))	('human', 'Species', '9606', (170, 175))	('colon adenomas', 'Disease', 'MESH:D000236', (176, 190))	('rat', 'Species', '10116', (159, 162))
818205	26774180	Organoids containing the 5 mutations formed tumors when transplanted into mice, but with lower frequency than colorectal adenocarcinoma organoids.	('mutations', 'Var', (27, 36))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('colorectal adenocarcinoma', 'Disease', (110, 135))	('mice', 'Species', '10090', (74, 78))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (110, 135))
818207	26774180	Organoids containing inactivating mutations of APC, SMAD4, and TP53 and activating mutations in KRAS also grew independently of growth factors and formed solid tumors following subcutaneous injection into immunocompromised mice .	('inactivating mutations', 'Var', (21, 43))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('APC', 'Disease', 'MESH:D011125', (47, 50))	('TP53', 'Gene', (63, 67))	('solid tumors', 'Disease', (154, 166))	('mice', 'Species', '10090', (223, 227))	('solid tumors', 'Disease', 'MESH:D009369', (154, 166))	('APC', 'Disease', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('SMAD4', 'Gene', (52, 57))	('formed', 'Reg', (147, 153))	('KRAS', 'Gene', (96, 100))
818210	26774180	Consistent with studies linking mutations in the Wnt signaling pathway to human colon adenocarcinoma, organoids with high expression of the Wnt target gene, EphB2, have a transcriptional signature similar to that of intestinal stem cells and are more likely to form tumors following subcutaneous injection into immunocompromised mice .	('expression', 'MPA', (122, 132))	('EphB2', 'Gene', '2048', (157, 162))	('mice', 'Species', '10090', (329, 333))	('colon adenocarcinoma', 'Disease', (80, 100))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (80, 100))	('EphB2', 'Gene', (157, 162))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('human', 'Species', '9606', (74, 79))	('transcriptional', 'MPA', (171, 186))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
818214	26774180	Studies of the response of colon adenocarcinoma organoids to small molecules associated loss-of-function mutations in TP53 with resistance to the MDM2 inhibitor nutlin-3a.	('resistance', 'MPA', (128, 138))	('colon adenocarcinoma organoids', 'Disease', (27, 57))	('colon adenocarcinoma organoids', 'Disease', 'MESH:D003110', (27, 57))	('TP53', 'Gene', (118, 122))	('mutations', 'Var', (105, 114))	('MDM2', 'Gene', '4193', (146, 150))	('MDM2', 'Gene', (146, 150))	('loss-of-function', 'NegReg', (88, 104))
818215	26774180	Organoids from colonic tumors with KRAS mutations were resistant to the anti-EGFR inhibitors cetuximab and BIBW2992 .	('KRAS', 'Gene', (35, 39))	('colonic tumors', 'Disease', (15, 29))	('cetuximab', 'Chemical', 'MESH:D000068818', (93, 102))	('resistant', 'MPA', (55, 64))	('colonic tumors', 'Disease', 'MESH:D015179', (15, 29))	('mutations', 'Var', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
818218	26774180	Li et al generated mouse colonic epithelial-mesenchymal organoids with deletion of Apc, activating mutations in Kras, and lentiviral knockdown of p53 and SMAD4.	('Apc', 'Gene', (83, 86))	('Kras', 'Gene', (112, 116))	('deletion', 'Var', (71, 79))	('mutations', 'Var', (99, 108))	('rat', 'Species', '10116', (13, 16))	('mouse', 'Species', '10090', (19, 24))
818223	26774180	Mouse epithelial-mesenchymal organoids from normal tissue have been transformed into gastric cancer organoids through alterations to Kras or p53 .	('p53', 'Gene', (141, 144))	('alterations', 'Var', (118, 129))	('Kras', 'Gene', (133, 137))	('gastric cancer', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('Mouse', 'Species', '10090', (0, 5))	('rat', 'Species', '10116', (122, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))
818224	26774180	Gastric organoids with activating mutations of Kras or loss of p53 become dysplastic and generate adenocarcinomas in mice.	('Kras', 'Gene', (47, 51))	('p53', 'Gene', (63, 66))	('adenocarcinomas', 'Disease', 'MESH:D000230', (98, 113))	('loss', 'Gene', (55, 59))	('adenocarcinomas', 'Disease', (98, 113))	('mice', 'Species', '10090', (117, 121))	('generate', 'Reg', (89, 97))	('rat', 'Species', '10116', (93, 96))	('dysplastic', 'Disease', 'MESH:D004416', (74, 84))	('mutations', 'Var', (34, 43))	('dysplastic', 'Disease', (74, 84))	('activating', 'PosReg', (23, 33))
818226	26774180	Mutations in the cadherin 1, type 1 gene (CDH1 or ECAD) are associated with hereditary gastric cancer.	('CDH1', 'Gene', (42, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('CDH1', 'Gene', '999', (42, 46))	('cadherin 1', 'Gene', (17, 27))	('ECAD', 'Gene', (50, 54))	('cadherin 1', 'Gene', '999', (17, 27))	('hereditary gastric cancer', 'Disease', (76, 101))	('Mutations', 'Var', (0, 9))	('hereditary gastric cancer', 'Disease', 'MESH:D013274', (76, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ECAD', 'Gene', '999', (50, 54))	('associated', 'Reg', (60, 70))
818228	26774180	Knockdown of TGFBR2 in mouse gastric epithelial-mesenchymal organoids with disruptions in Cdh1 and p53 increased tumorigeniciy when organoids were transplanted back into mice .	('tumor', 'Disease', (113, 118))	('increased', 'PosReg', (103, 112))	('disruptions', 'Var', (75, 86))	('Cdh1', 'Gene', '12550', (90, 94))	('mouse', 'Species', '10090', (23, 28))	('Cdh1', 'Gene', (90, 94))	('mice', 'Species', '10090', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('p53', 'Gene', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('TGFBR2', 'Gene', (13, 19))
818229	26774180	Whole-genome sequencing and epigenetic profiling of gastric cancer and adjacent normal tissue specimens identified mutations in RHOA .	('mutations', 'Var', (115, 124))	('RHOA', 'Gene', (128, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('gastric cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))
818230	26774180	Mouse intestinal epithelial organoids with lentiviral overexpression of RHOA mutants survived in the absence of the ROCK inhibitor, which prevents anoikis, after passage.	('RHOA', 'Gene', (72, 76))	('intestinal epithelia', 'Disease', 'MESH:D007410', (6, 26))	('mutants', 'Var', (77, 84))	('Mouse', 'Species', '10090', (0, 5))	('anoikis', 'Disease', (147, 154))	('intestinal epithelia', 'Disease', (6, 26))
818231	26774180	RHOA mutations therefore seem to promote survival of these cells and contribute to gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (83, 105))	('RHOA', 'Gene', (0, 4))	('promote', 'PosReg', (33, 40))	('survival', 'CPA', (41, 49))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (83, 105))	('mutations', 'Var', (5, 14))	('contribute', 'Reg', (69, 79))
818232	26774180	Studies of organoids generated from patients' tumors could provide more information about the oncogenic effects of RHOA mutations.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patients', 'Species', '9606', (36, 44))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('RHOA', 'Gene', (115, 119))	('rat', 'Species', '10116', (25, 28))	('mutations', 'Var', (120, 129))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
818244	26774180	For example, autoimmune destruction of insulin-producing pancreatic beta cells results in type I diabetes, and loss of enteroendocrine cells leads to anendocrinosis and life-threatening diarrhea .	('type I diabetes', 'Phenotype', 'HP:0100651', (90, 105))	('insulin', 'Gene', (39, 46))	('type I diabetes', 'Disease', 'MESH:D003922', (90, 105))	('loss', 'Var', (111, 115))	('pancreatic', 'Disease', 'MESH:D010195', (57, 67))	('insulin', 'Gene', '3630', (39, 46))	('destruction', 'Var', (24, 35))	('anendocrinosis', 'Disease', (150, 164))	('leads to', 'Reg', (141, 149))	('pancreatic', 'Disease', (57, 67))	('type I diabetes', 'Disease', (90, 105))	('anendocrinosis', 'Disease', 'MESH:C563673', (150, 164))	('diarrhea', 'Disease', 'MESH:D003967', (186, 194))	('diarrhea', 'Phenotype', 'HP:0002014', (186, 194))	('results in', 'Reg', (79, 89))	('diarrhea', 'Disease', (186, 194))
818245	26774180	Dysregulation of gut hormones have also been implicated in obesity and metabolic syndrome.	('obesity', 'Phenotype', 'HP:0001513', (59, 66))	('Dysregulation', 'Var', (0, 13))	('metabolic syndrome', 'Disease', 'MESH:D008659', (71, 89))	('implicated', 'Reg', (45, 55))	('gut', 'Gene', (17, 20))	('metabolic syndrome', 'Disease', (71, 89))	('gut', 'Gene', '110006', (17, 20))	('obesity', 'Disease', 'MESH:D009765', (59, 66))	('obesity', 'Disease', (59, 66))
818248	26774180	Furthermore, lentiviral knockdown of ARX in PSC-derived intestinal organoids led to reduction of CCK and secretin, similar to mice with intestine-specific disruption of Arx .	('CCK', 'Gene', (97, 100))	('mice', 'Species', '10090', (126, 130))	('ARX', 'Gene', (37, 40))	('ARX', 'Gene', '11878', (37, 40))	('reduction', 'NegReg', (84, 93))	('Arx', 'Gene', (169, 172))	('Arx', 'Gene', '11878', (169, 172))	('CCK', 'Gene', '12424', (97, 100))	('secretin', 'MPA', (105, 113))	('knockdown', 'Var', (24, 33))
818256	26774180	Similar to their results with adenoviral inhibition of FOXO1, lentiviral knockdown resulted in an increase in insulin-producing cells.	('lentiviral knockdown', 'Var', (62, 82))	('increase', 'PosReg', (98, 106))	('insulin', 'Gene', (110, 117))	('insulin', 'Gene', '3630', (110, 117))	('knockdown', 'Var', (73, 82))
818279	26774180	Interestingly, inclusion of TESI in the anastomosis increased bowel length 9 months after bowel reconstruction and caused faster weight gain after reconstruction .	('increased', 'PosReg', (52, 61))	('bowel length', 'CPA', (62, 74))	('inclusion', 'Var', (15, 24))	('TESI', 'Chemical', '-', (28, 32))	('weight gain', 'Disease', 'MESH:D015430', (129, 140))	('weight gain', 'Phenotype', 'HP:0004324', (129, 140))	('weight gain', 'Disease', (129, 140))	('faster', 'PosReg', (122, 128))
818289	26774180	Individualized organoids can be used to identify intestine-specific pathophysiologies in complex disease processes, such as lack of forskolin-induced swelling in organoids with mutated CFTR.	('CFTR', 'Gene', '1080', (185, 189))	('swelling', 'Disease', 'MESH:D004487', (150, 158))	('swelling', 'Disease', (150, 158))	('mutated', 'Var', (177, 184))	('CFTR', 'Gene', (185, 189))	('forskolin', 'Chemical', 'MESH:D005576', (132, 141))
818382	27529887	reported that high SUVmax was related with poor prognosis but not survival in patients with esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (92, 112))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (92, 112))	('patients', 'Species', '9606', (78, 86))	('high', 'Var', (14, 18))	('SUVmax', 'MPA', (19, 25))	('esophageal carcinoma', 'Disease', (92, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
818417	25637514	However, the dysregulation of miR-130b had no obvious impact on PTEN mRNA.	('dysregulation', 'Var', (13, 26))	('PTEN', 'Gene', (64, 68))	('PTEN', 'Gene', '5728', (64, 68))	('miR-130b', 'Gene', '406920', (30, 38))	('miR-130b', 'Gene', (30, 38))
818430	25637514	Increasing evidence shows that dysregulation of miRNAs leads to the development and progression of cancers.	('progression of', 'CPA', (84, 98))	('development', 'CPA', (68, 79))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('leads to', 'Reg', (55, 63))	('cancers', 'Disease', (99, 106))	('dysregulation', 'Var', (31, 44))	('miR', 'Gene', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('miR', 'Gene', '22877', (48, 51))
818432	25637514	Studies have shown that aberrant expression of miRNAs affects cell proliferation, apoptosis, metastasis, and sensitivity to chemotherapy and radiotherapy in multiple cancers.	('multiple cancers', 'Disease', 'MESH:D009369', (157, 173))	('affects', 'Reg', (54, 61))	('apoptosis', 'CPA', (82, 91))	('metastasis', 'CPA', (93, 103))	('miR', 'Gene', (47, 50))	('cell proliferation', 'CPA', (62, 80))	('expression', 'Species', '29278', (33, 43))	('aberrant expression', 'Var', (24, 43))	('multiple cancers', 'Disease', (157, 173))	('miR', 'Gene', '22877', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
818482	25637514	In contrast, the viability of ESCC cells was inhibited following transfection with miR-130bi, which was reversed by co-transfection with a PTEN-targeted small interfering RNA.	('miR-130b', 'Gene', (83, 91))	('viability', 'CPA', (17, 26))	('PTEN', 'Gene', (139, 143))	('PTEN', 'Gene', '5728', (139, 143))	('transfection', 'Var', (65, 77))	('inhibited', 'NegReg', (45, 54))	('miR-130b', 'Gene', '406920', (83, 91))
818489	25637514	MiRNAs affect a variety of cellular pathways, and a single miRNA can target multiple genes.	('MiRNAs', 'Var', (0, 6))	('miR', 'Gene', (59, 62))	('cellular pathways', 'Pathway', (27, 44))	('affect', 'Reg', (7, 13))	('miR', 'Gene', '22877', (59, 62))
818497	25637514	The expression of miR-130b is increased in hyperplastic endometrium and increases even further in endometrial cancer, which, along with DICER1 dysfunction, leads to tumor aggression both in vitro and in vivo.	('expression', 'MPA', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('increased', 'PosReg', (30, 39))	('miR-130b', 'Gene', '406920', (18, 26))	('miR-130b', 'Gene', (18, 26))	('tumor aggression', 'Disease', (165, 181))	('endometrial cancer', 'Phenotype', 'HP:0012114', (98, 116))	('DICER1', 'Gene', '23405', (136, 142))	('expression', 'Species', '29278', (4, 14))	('increases', 'PosReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('leads to', 'Reg', (156, 164))	('endometrial cancer', 'Disease', (98, 116))	('tumor aggression', 'Disease', 'MESH:D001523', (165, 181))	('DICER1', 'Gene', (136, 142))	('endometrial cancer', 'Disease', 'MESH:D016889', (98, 116))	('dysfunction', 'Var', (143, 154))	('hyperplastic endometrium', 'Phenotype', 'HP:0040298', (43, 67))	('aggression', 'Phenotype', 'HP:0000718', (171, 181))
818507	25637514	Inhibition of PTEN results in increased levels of activated p-Akt.	('PTEN', 'Gene', (14, 18))	('PTEN', 'Gene', '5728', (14, 18))	('levels of', 'MPA', (40, 49))	('Akt', 'Gene', '207', (62, 65))	('Inhibition', 'Var', (0, 10))	('increased', 'PosReg', (30, 39))	('Akt', 'Gene', (62, 65))
818509	25637514	The proliferation of ESCC cells in vitro and in vivo is promoted by transfections with PTEN expression vectors.	('PTEN', 'Gene', (87, 91))	('proliferation', 'CPA', (4, 17))	('expression vectors', 'Species', '29278', (92, 110))	('PTEN', 'Gene', '5728', (87, 91))	('transfections', 'Var', (68, 81))	('promoted', 'PosReg', (56, 64))
818515	25637514	Moreover, silencing of PTEN expression reversed the effect of miR-130bi on cell proliferation, invasion and migration.	('miR-130b', 'Gene', '406920', (62, 70))	('invasion', 'CPA', (95, 103))	('expression', 'Species', '29278', (28, 38))	('miR-130b', 'Gene', (62, 70))	('PTEN', 'Gene', (23, 27))	('PTEN', 'Gene', '5728', (23, 27))	('silencing', 'Var', (10, 19))	('cell proliferation', 'CPA', (75, 93))
818523	24161135	Telomeres and telomere dynamics: relevance to cancers of the gastrointestinal tract Aberrations in telomere length and telomere maintenance contribute to cancer development.	('cancers of the gastrointestinal tract', 'Disease', (46, 83))	('cancers of the gastrointestinal tract', 'Disease', 'MESH:D004067', (46, 83))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', (154, 160))	('Aberrations', 'Var', (84, 95))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('contribute to', 'Reg', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('telomere', 'Protein', (99, 107))	('cancers of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (46, 83))	('men', 'Species', '9606', (168, 171))
818535	24161135	In healthy cells, erosion of telomere length eventually leads to regulated cell senescence and apoptosis, serving as a means to clear DNA that may be more prone to mutation or altered expression that could lead to infection, cancer, or other disease (see Box 1).	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('apoptosis', 'CPA', (95, 104))	('cancer', 'Disease', (225, 231))	('altered', 'Var', (176, 183))	('leads to', 'Reg', (56, 64))	('lead to', 'Reg', (206, 213))	('mutation', 'Var', (164, 172))	('infection', 'Disease', (214, 223))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('expression', 'MPA', (184, 194))	('erosion', 'Var', (18, 25))	('regulated cell senescence', 'CPA', (65, 90))
818539	24161135	Studies of the basic biology of telomere erosion and maintenance have established that 1) telomere shortening is a fundamental feature of dividing cells and directly related to the age of the cell lineage, and that 2) telomere crisis in the present of defective cell-cycle control can lead to chromosomal instability and a malignant phenotype.	('chromosomal instability', 'MPA', (293, 316))	('defective cell-cycle', 'Phenotype', 'HP:0011018', (252, 272))	('malignant phenotype', 'CPA', (323, 342))	('telomere', 'Var', (218, 226))	('telomere shortening', 'Phenotype', 'HP:0031413', (90, 109))	('chromosomal instability', 'Phenotype', 'HP:0040012', (293, 316))	('lead to', 'Reg', (285, 292))	('men', 'Species', '9606', (120, 123))
818540	24161135	Because telomere erosion is a process that relates to aging at the cellular and tissue level, and is also implicated in carcinogenesis, it is an attractive candidate for studies that seek to explain the increase in incidence of many cancers with increasing age.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('carcinogenesis', 'Disease', 'MESH:D063646', (120, 134))	('telomere', 'Var', (8, 16))	('carcinogenesis', 'Disease', (120, 134))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('implicated', 'Reg', (106, 116))
818586	24161135	Critical shortening of telomeres may lead to activation of telomerase in tumor cells and instead of triggering the expected response to terminate these cells, the activation of telomerase bypasses normal cell senescence.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Critical shortening', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('lead to', 'Reg', (37, 44))	('telomerase', 'Protein', (59, 69))	('tumor', 'Disease', (73, 78))	('shortening of telomeres', 'Phenotype', 'HP:0031413', (9, 32))	('activation', 'PosReg', (45, 55))
818589	24161135	Telomerase function may be up or down-regulated by germline mutations in TERT, and less frequently by TERC.	('Telomerase', 'Enzyme', (0, 10))	('TERC', 'Gene', (102, 106))	('TERT', 'Gene', (73, 77))	('function', 'MPA', (11, 19))	('TERC', 'Gene', '7012', (102, 106))	('down-regulated', 'NegReg', (33, 47))	('germline mutations', 'Var', (51, 69))
818590	24161135	Telomerase may affect somatic tissue cells when activated from dormancy via epigenetic modulation of TERT expression through a variety of transcriptional mediators able to be regulated by exogenous exposures, including oxidative stressors like tobacco exposure that are known to be associated both with telomere length and risk for disease.	('oxidative stressors', 'Phenotype', 'HP:0025464', (219, 238))	('epigenetic modulation', 'Var', (76, 97))	('affect', 'Reg', (15, 21))	('oxidative stress', 'Phenotype', 'HP:0025464', (219, 235))	('tobacco', 'Species', '4097', (244, 251))	('TERT', 'Gene', (101, 105))
818603	24161135	Shorter PBL telomere length is associated with an increased risk for esophageal ESCC, and polymorphisms in the PBL telomere length related 1p34.2 rs621559 and 14q21 rs398652 SNPs are associated with an increased risk for ESCC.	('PBL', 'Gene', (111, 114))	('SCC', 'Gene', '6317', (81, 84))	('rs621559', 'Var', (146, 154))	('SCC', 'Gene', '6317', (222, 225))	('associated', 'Reg', (183, 193))	('rs398652 SNPs', 'Var', (165, 178))	('rs398652', 'Mutation', 'rs398652', (165, 173))	('SCC', 'Gene', (81, 84))	('PBL', 'Gene', (8, 11))	('rs621559', 'Mutation', 'rs621559', (146, 154))	('SCC', 'Gene', (222, 225))	('Shorter', 'NegReg', (0, 7))
818604	24161135	At the tissue level, telomere shortening is detectable in DNA from the precursor lesion of ESCC- carcinoma in situ (CIS).	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('carcinoma in situ', 'Disease', (97, 114))	('ESCC- carcinoma', 'Disease', (91, 106))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (97, 114))	('telomere shortening', 'Phenotype', 'HP:0031413', (21, 40))	('ESCC- carcinoma', 'Disease', 'MESH:D004938', (91, 106))	('telomere', 'Var', (21, 29))	('carcinoma in situ', 'Disease', 'MESH:D002278', (97, 114))
818615	24161135	Environmental stressors that may increase oxidative damage have been associated with telomere shortening, and the increase in cancer risk itself attributable to telomere shortening appears to be potentiated by the effects of oxidative damage related to tobacco use, no use of anti-inflammatory agents and inflammation related to truncal obesity.	('tobacco', 'Species', '4097', (253, 260))	('oxidative damage', 'MPA', (225, 241))	('truncal obesity', 'Phenotype', 'HP:0001956', (329, 344))	('oxidative damage', 'MPA', (42, 58))	('telomere shortening', 'Phenotype', 'HP:0031413', (85, 104))	('cancer', 'Disease', (126, 132))	('inflammation', 'Disease', 'MESH:D007249', (305, 317))	('men', 'Species', '9606', (7, 10))	('telomere', 'Var', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('truncal obesity', 'Disease', 'MESH:D009765', (329, 344))	('associated', 'Reg', (69, 79))	('inflammation', 'Disease', (305, 317))	('truncal obesity', 'Disease', (329, 344))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('increase', 'PosReg', (33, 41))	('obesity', 'Phenotype', 'HP:0001513', (337, 344))	('telomere shortening', 'Phenotype', 'HP:0031413', (161, 180))	('telomere', 'MPA', (85, 93))
818616	24161135	One study of BEAC targeted inhibition of telomerase activity as a treatment approach.	('inhibition', 'Var', (27, 37))	('telomerase', 'Protein', (41, 51))	('men', 'Species', '9606', (71, 74))	('activity', 'MPA', (52, 60))
818620	24161135	Risk factors include male sex; African-American or Asian heritage; untreated H. pylori infection related inflammation; states that cause achlorhydria; tobacco use; alcohol use; intake of food preserved by pickling, drying, smoking or salting; decreased fresh fruit and vegetable intake; family history of a first degree relative with gastric cancer and other hereditary conditions including E-cadherin mutation related gastric cancer, Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome and SMAD4 related juvenile polyposis syndrome.	('gastric cancer', 'Disease', (419, 433))	('mutation', 'Var', (402, 410))	('Lynch syndrome', 'Disease', (435, 449))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('E-cadherin', 'Protein', (391, 401))	('gastric cancer', 'Disease', 'MESH:D013274', (334, 348))	('inflammation', 'Disease', 'MESH:D007249', (105, 117))	('Peutz-Jeghers syndrome', 'Disease', (483, 505))	('juvenile polyposis syndrome', 'Disease', (524, 551))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('familial adenomatous polyposis', 'Disease', (451, 481))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (460, 481))	('juvenile polyposis syndrome', 'Phenotype', 'HP:0004784', (524, 551))	('achlorhydria', 'Disease', 'MESH:D000126', (137, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (419, 433))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (451, 481))	('Lynch syndrome', 'Disease', 'MESH:D003123', (435, 449))	('H. pylori', 'Species', '210', (77, 86))	('alcohol use', 'Phenotype', 'HP:0030955', (164, 175))	('gastric cancer', 'Disease', (334, 348))	('achlorhydria', 'Disease', (137, 149))	('achlorhydria', 'Phenotype', 'HP:0032448', (137, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (334, 348))	('inflammation', 'Disease', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (483, 505))	('gastric cancer', 'Phenotype', 'HP:0012126', (419, 433))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (460, 477))	('tobacco', 'Species', '4097', (151, 158))	('juvenile polyposis syndrome', 'Disease', 'MESH:C537702', (524, 551))	('H. pylori infection', 'Phenotype', 'HP:0005202', (77, 96))
818624	24161135	A portion of gastric (8-23%) and colorectal cancer (20%) are MSI high (MSI-H) with dMMR, but the majority of these cancers are microsatellite stable (MSS) and have proficient mismatch repair (pMMR).	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('MSI-H', 'Disease', (71, 76))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('gastric', 'Disease', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancers', 'Disease', (115, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MSI-H', 'Disease', 'MESH:D000848', (71, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('colorectal cancer', 'Disease', (33, 50))	('microsatellite', 'Var', (127, 141))
818625	24161135	Gastric cancers with dMMR utilize alternative lengthening of telomeres, although concomitant evidence of telomerase activation as a method of telomere elongation is still present in 48% of MSI-H gastric cancer.	('MSI-H gastric cancer', 'Disease', 'MESH:D013274', (189, 209))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('Gastric cancers', 'Disease', (0, 15))	('Gastric cancers', 'Phenotype', 'HP:0012126', (0, 15))	('dMMR', 'Var', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('MSI-H gastric cancer', 'Disease', (189, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('Gastric cancers', 'Disease', 'MESH:D013274', (0, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (195, 209))
818628	24161135	In gastric cancer not characterized by its DNA MMR status, increasing chromosomal instability, inactivation of p53 tumor suppression, and increasing tumor telomere shortening has been reported.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('increasing', 'PosReg', (138, 148))	('p53', 'Gene', (111, 114))	('tumor', 'Disease', (115, 120))	('p53', 'Gene', '7157', (111, 114))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('chromosomal instability', 'Phenotype', 'HP:0040012', (70, 93))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('increasing', 'PosReg', (59, 69))	('tumor', 'Disease', (149, 154))	('gastric cancer', 'Disease', (3, 17))	('telomere shortening', 'Phenotype', 'HP:0031413', (155, 174))	('inactivation', 'Var', (95, 107))	('chromosomal instability', 'MPA', (70, 93))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
818635	24161135	Germline mutations in TERT are associated with increased risk for pancreatic ACA.	('Germline mutations', 'Var', (0, 18))	('TERT', 'Gene', (22, 26))	('pancreatic', 'Disease', (66, 76))	('associated', 'Reg', (31, 41))	('pancreatic', 'Disease', 'MESH:D010195', (66, 76))
818655	24161135	Subtelomeric methylation may prompt chromatin restructuring and remodeling that may influence the telomere length variation associated with hepatocarcinogenesis.	('influence', 'Reg', (84, 93))	('hepatocarcinogenesis', 'Disease', (140, 160))	('telomere length variation', 'MPA', (98, 123))	('Subtelomeric methylation', 'Var', (0, 24))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (140, 160))
818666	24161135	These findings demonstrated that telomere shortening occurs at an early stage of biliary tract cancer development.	('telomere shortening', 'Phenotype', 'HP:0031413', (33, 52))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('biliary tract cancer', 'Disease', 'MESH:D001661', (81, 101))	('biliary tract cancer', 'Disease', (81, 101))	('telomere shortening', 'Var', (33, 52))	('men', 'Species', '9606', (109, 112))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (81, 101))
818673	24161135	showed that most small bowel adenocarcinomas display microsatellite and/or chromosomal instability.	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('chromosomal instability', 'Phenotype', 'HP:0040012', (75, 98))	('small bowel adenocarcinomas', 'Disease', (17, 44))	('chromosomal instability', 'CPA', (75, 98))	('microsatellite', 'Var', (53, 67))	('small bowel adenocarcinomas', 'Disease', 'MESH:D000230', (17, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))
818686	24161135	Depending on the age that CRC develops, up to 20% of sporadic CRC will have defective DNA MMR due to inactivation of the DNA MMR gene MLH1 by the epigenetic phenomenon of hypermethylation of the MLH1 promoter, and patients with MLH1 related CRC will have a better prognosis than those with microsatellite stable (MSS) CRC.	('MLH1', 'Gene', (228, 232))	('DNA MMR', 'Gene', (121, 128))	('MLH1', 'Gene', '4292', (228, 232))	('patients', 'Species', '9606', (214, 222))	('epigenetic', 'Var', (146, 156))	('men', 'Species', '9606', (162, 165))	('MLH1', 'Gene', '4292', (195, 199))	('MLH1', 'Gene', '4292', (134, 138))	('MLH1', 'Gene', (195, 199))	('MLH1', 'Gene', (134, 138))	('inactivation', 'NegReg', (101, 113))	('CRC', 'Disease', (62, 65))	('CRC', 'Disease', (241, 244))	('DNA MMR', 'Gene', (86, 93))	('defective', 'NegReg', (76, 85))	('hypermethylation', 'Var', (171, 187))
818693	24161135	reported that individuals with a TERC-associated SNP (telomerase RNA component) were found to be at higher risk for CRC and have longer PBL telomeres than controls.	('SNP', 'Var', (49, 52))	('longer', 'PosReg', (129, 135))	('telomerase RNA component', 'Gene', (54, 78))	('PBL', 'Gene', (136, 139))	('TERC', 'Gene', '7012', (33, 37))	('telomerase RNA component', 'Gene', '7012', (54, 78))	('CRC', 'Disease', (116, 119))	('TERC', 'Gene', (33, 37))
818701	24161135	observed telomerase positivity in dysplastic polyps and adenocarcinoma samples, with higher levels in cancerous tissues compared to dysplastic ones.	('cancerous', 'Disease', 'MESH:D009369', (102, 111))	('dysplastic ones', 'Disease', 'MESH:D004416', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('positivity', 'Var', (20, 30))	('telomerase positivity', 'Phenotype', 'HP:0030859', (9, 30))	('dysplastic ones', 'Disease', (132, 147))	('higher levels', 'PosReg', (85, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('dysplastic polyps', 'Disease', 'MESH:D011127', (34, 51))	('adenocarcinoma', 'Disease', (56, 70))	('cancerous', 'Disease', (102, 111))	('telomerase', 'Protein', (9, 19))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('dysplastic polyps', 'Disease', (34, 51))
818706	24161135	The authors also observed that in Stage II patients, a high hTERT level identified individuals at greater risk of disease recurrence and death.	('hTERT', 'Gene', (60, 65))	('patients', 'Species', '9606', (43, 51))	('death', 'Disease', 'MESH:D003643', (137, 142))	('death', 'Disease', (137, 142))	('hTERT', 'Gene', '7015', (60, 65))	('high', 'Var', (55, 59))
818728	24161135	However, telomere length measured in peripheral blood alone may not provide the complete telomere profile needed for the development and implementation of early detection, risk stratification, or prognostication for GI tract cancers in patients and may require the use of multiple telomere related features, including the peripheral blood and tumor telomere length and the genetic and epigenetic aberrations of the tumor's TMM.	('GI tract cancer', 'Phenotype', 'HP:0007378', (216, 231))	('tumor', 'Disease', (415, 420))	('men', 'Species', '9606', (142, 145))	('genetic', 'Var', (373, 380))	('men', 'Species', '9606', (128, 131))	('patients', 'Species', '9606', (236, 244))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('GI tract cancers', 'Disease', 'MESH:D004067', (216, 232))	('tumor', 'Disease', 'MESH:D009369', (415, 420))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('epigenetic aberrations', 'Var', (385, 407))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('GI tract cancers', 'Disease', (216, 232))	('tumor', 'Phenotype', 'HP:0002664', (415, 420))	('tumor', 'Disease', (343, 348))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
818757	21080117	Together approximately one third of the world population is considered to be overweight or obese, defined as a body mass index (BMI)>=25 or <30 (overweight) or >=30.	('obese', 'Disease', 'MESH:D009765', (91, 96))	('overweight', 'Phenotype', 'HP:0025502', (77, 87))	('obese', 'Disease', (91, 96))	('<30', 'Var', (140, 143))	('overweight', 'Phenotype', 'HP:0025502', (145, 155))
818767	21080117	For overweight and obese women, relative to those with a BMI<25, the risk of developing cancer was 8% higher for a BMI 25 to 29.9; 18% higher for a BMI 30 to 34.9; 32% higher for a BMI 35 to 39.9; and 62% higher for a BMI>=40.	('women', 'Species', '9606', (25, 30))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('obese', 'Disease', (19, 24))	('BMI 30 to', 'Var', (148, 157))	('higher', 'PosReg', (102, 108))	('overweight', 'Phenotype', 'HP:0025502', (4, 14))	('BMI 25 to 29.9', 'Var', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('obese', 'Disease', 'MESH:D009765', (19, 24))
818813	21080117	A range of strategies have been successful in helping people lose weight, including dietary approaches such as low calorie (ie, 600 cal/day deficit) with or without meal replacements or behavioral therapy.	('low calorie', 'Var', (111, 122))	('men', 'Species', '9606', (177, 180))	('lose', 'NegReg', (61, 65))	('people', 'Species', '9606', (54, 60))	('weight', 'Disease', (66, 72))
818830	21080117	Gu and colleagues found that variations in the circulating IGF-1 and IGFBP-3 levels may be related to the variations in IGF1, SSTR5, IGFBP3, and IGFALS genes.	('IGFALS', 'Gene', (145, 151))	('variations', 'Var', (29, 39))	('related', 'Reg', (91, 98))	('variations', 'Var', (106, 116))	('IGFBP3', 'Gene', '3486', (133, 139))	('IGF1', 'Gene', (120, 124))	('IGFBP-3', 'Gene', (69, 76))	('SSTR5', 'Gene', '6755', (126, 131))	('IGFBP-3', 'Gene', '3486', (69, 76))	('SSTR5', 'Gene', (126, 131))	('IGF-1', 'Gene', '3479', (59, 64))	('IGFALS', 'Gene', '3483', (145, 151))	('IGF-1', 'Gene', (59, 64))	('IGF1', 'Gene', '3479', (120, 124))	('IGFBP3', 'Gene', (133, 139))
818832	21080117	Sex steroid hormones are mainly produced by the adrenal glands, and endogenous hormones include estrogens (E1-estrone and E2-estradiol), androgens (testosterone, androstenedione, dihydrotestosterone, and dehydroepiandrosterone), and progestogens (such as progesterone).	('progesterone', 'Chemical', 'MESH:D011374', (255, 267))	('E1-estrone', 'Var', (107, 117))	('dihydrotestosterone', 'Chemical', 'MESH:D013196', (179, 198))	('E2-estradiol', 'Chemical', 'MESH:D004958', (122, 134))	('steroid', 'Chemical', 'MESH:D013256', (4, 11))	('dehydroepiandrosterone', 'Chemical', 'MESH:D003687', (204, 226))	('androstenedione', 'Chemical', 'MESH:D000735', (162, 177))	('testosterone', 'Chemical', 'MESH:D013739', (148, 160))	('E1-estrone', 'Chemical', 'MESH:D004970', (107, 117))	('testosterone', 'Chemical', 'MESH:D013739', (186, 198))	('E2-estradiol', 'Var', (122, 134))
818869	22344232	The potential impact of LPS on reflux esophagitis may be through relaxation of the lower esophageal sphincter via iNOS and by delaying gastric emptying via COX-2.	('esophageal sphincter', 'Disease', (89, 109))	('delaying', 'NegReg', (126, 134))	('esophageal sphincter', 'Disease', 'MESH:D009122', (89, 109))	('LPS', 'Var', (24, 27))	('COX-2', 'Gene', (156, 161))	('COX-2', 'Gene', '5743', (156, 161))	('reflux esophagitis', 'Disease', 'MESH:D005764', (31, 49))	('gastric emptying', 'MPA', (135, 151))	('reflux esophagitis', 'Disease', (31, 49))	('esophagitis', 'Phenotype', 'HP:0100633', (38, 49))	('delaying gastric emptying', 'Phenotype', 'HP:0002578', (126, 151))
818878	22344232	Imbalance of this system may lead to innate immune (inflammation) and adaptive immune (infectious pathology) responses.	('Imbalance', 'Var', (0, 9))	('adaptive immune', 'CPA', (70, 85))	('inflammation', 'Disease', (52, 64))	('lead to', 'Reg', (29, 36))	('innate immune', 'CPA', (37, 50))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('inflammation', 'Disease', 'MESH:D007249', (52, 64))
818900	22344232	Moreover, the observations of NF-kappaB activation in responses to inflammatory signaling through mutated NOD2 gene in Crohn's disease and through NOD1 in infection with Helicobacter pylori and Chlamydophila pneumoniae raise some interesting possibilities in relation to human cancers developed in these inflammatory diseases.	('cancers', 'Disease', 'MESH:D009369', (277, 284))	("Crohn's disease", 'Phenotype', 'HP:0100280', (119, 134))	("Crohn's disease", 'Disease', 'MESH:D003424', (119, 134))	("Crohn's disease", 'Disease', (119, 134))	('human', 'Species', '9606', (271, 276))	('NOD1', 'Gene', '10392', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('Chlamydophila pneumoniae', 'Species', '83558', (194, 218))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('responses to inflammatory signaling', 'MPA', (54, 89))	('cancers', 'Disease', (277, 284))	('activation', 'PosReg', (40, 50))	('NF-kappaB', 'Gene', (30, 39))	('Helicobacter pylori', 'Species', '210', (170, 189))	('mutated', 'Var', (98, 105))	('NOD1', 'Gene', (147, 151))	('NOD2', 'Gene', (106, 110))	('NF-kappaB', 'Gene', '4790', (30, 39))	('infection', 'Disease', (155, 164))	('infection', 'Disease', 'MESH:D007239', (155, 164))	('NOD2', 'Gene', '64127', (106, 110))
818914	22344232	Studies in a mouse model for sepsis illustrates that in normal mice, the lower esophageal sphincter maintains a basal tone, but LPS causes a dose-dependent fall in the basal tone, and the LPS's effect can be blocked by L-canavanine which is a selective iNOS inhibitor.	('sepsis', 'Disease', 'MESH:D018805', (29, 35))	('esophageal sphincter', 'Disease', (79, 99))	('mouse', 'Species', '10090', (13, 18))	('fall', 'NegReg', (156, 160))	('esophageal sphincter', 'Disease', 'MESH:D009122', (79, 99))	('mice', 'Species', '10090', (63, 67))	('L-canavanine', 'Chemical', 'MESH:D002172', (219, 231))	('basal tone', 'MPA', (112, 122))	('LPS', 'Var', (128, 131))	('sepsis', 'Phenotype', 'HP:0100806', (29, 35))	('sepsis', 'Disease', (29, 35))	('sphincter maintains', 'Phenotype', 'HP:0002839', (90, 109))	('fall', 'Phenotype', 'HP:0002527', (156, 160))	('basal tone', 'MPA', (168, 178))
818915	22344232	In this rodent model, LPS caused a selective increase in iNOS protein and mRNA in both the lower esophageal sphincter and internal anal sphincter without significant changes in the expression of other NOS isozymes.	('esophageal sphincter', 'Disease', (97, 117))	('mRNA', 'MPA', (74, 78))	('esophageal sphincter', 'Disease', 'MESH:D009122', (97, 117))	('iNOS', 'MPA', (57, 61))	('LPS', 'Var', (22, 25))	('increase', 'PosReg', (45, 53))
818918	22344232	Because of these critical functions, deregulated mitogen-activated protein kinases are often found to contribute to the development of many cancers.	('mitogen-activated protein kinases', 'Enzyme', (49, 82))	('deregulated', 'Var', (37, 48))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('contribute', 'Reg', (102, 112))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
818922	22344232	The LPS-delayed gastric emptying can be blocked by NS398 which is a selective COX-2 inhibitor.	('NS398', 'Chemical', 'MESH:C080955', (51, 56))	('LPS-delayed', 'Disease', (4, 15))	('NS398', 'Var', (51, 56))	('COX-2', 'Gene', (78, 83))	('COX-2', 'Gene', '5743', (78, 83))	('delayed gastric emptying', 'Phenotype', 'HP:0002578', (8, 32))
818929	22344232	Since they interfere with normal cellular function necessary to mount immune responses, inhibitors of NF-kB may also cause significant side effects such as increased susceptibility to infections, and liver dysfunction.	('liver dysfunction', 'Disease', 'MESH:D017093', (200, 217))	('susceptibility to infections', 'Phenotype', 'HP:0002719', (166, 194))	('infection', 'Disease', (184, 193))	('cause', 'Reg', (117, 122))	('infection', 'Disease', 'MESH:D007239', (184, 193))	('liver dysfunction', 'Phenotype', 'HP:0001410', (200, 217))	('liver dysfunction', 'Disease', (200, 217))	('interfere', 'NegReg', (11, 20))	('NF-kB', 'Gene', (102, 107))	('inhibitors', 'Var', (88, 98))
818930	22344232	Although limited by clinical side effects, interest remains in the therapeutic potential of NF-kB inhibitors to halt the metaplastic progression of Barrett's esophagus or to treat esophageal adenocarcinoma by inhibiting inflammation.	('halt', 'NegReg', (112, 116))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (180, 205))	("Barrett's esophagus", 'Disease', (148, 167))	('inhibitors', 'Var', (98, 108))	('inhibiting', 'NegReg', (209, 219))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (180, 205))	('NF-kB', 'Gene', (92, 97))	('inflammation', 'Disease', 'MESH:D007249', (220, 232))	('inflammation', 'Disease', (220, 232))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (148, 167))	('metaplastic progression', 'CPA', (121, 144))	('esophageal adenocarcinoma', 'Disease', (180, 205))
818934	22344232	The prodrug L-N6-(1-iminoethyl)lysine 5-tetrazole amide (SC-51), another selective iNOS inhibitor causes marked suppression of exhaled breath NO levels both in healthy control subjects and in patients without significant side effect.	('L-N6-(1-iminoethyl)lysine 5-tetrazole amide', 'Chemical', 'MESH:C487860', (12, 55))	('patients', 'Species', '9606', (192, 200))	('L-N6-', 'Var', (12, 17))	('suppression of exhaled breath', 'Phenotype', 'HP:0002791', (112, 141))	('exhaled breath NO levels', 'MPA', (127, 151))	('suppression', 'NegReg', (112, 123))	('SC-51', 'Chemical', '-', (57, 62))
818955	21976009	Cytoplasmic FoxM1 was correlated with pathological stage and might be a biomarker for advanced ESCC.	('correlated', 'Reg', (22, 32))	('ESCC', 'Disease', (95, 99))	('Cytoplasmic FoxM1', 'Var', (0, 17))	('S', 'Chemical', 'MESH:D013455', (96, 97))
818961	21976009	This gain/loss in copy number of FOXM1 is associated with survival in MPNST.	('P', 'Chemical', 'MESH:D010758', (71, 72))	('gain/loss', 'PosReg', (5, 14))	('associated', 'Reg', (42, 52))	('FOXM1', 'Gene', (33, 38))	('S', 'Chemical', 'MESH:D013455', (73, 74))	('gain/loss', 'NegReg', (5, 14))	('FOXM1', 'Gene', '2305', (33, 38))	('MPNST', 'Disease', (70, 75))	('MPNST', 'Phenotype', 'HP:0100697', (70, 75))	('copy number', 'Var', (18, 29))
819024	21976009	Patients with lower expression of cytoplasmic FoxM1 were more likely in the early stage of ESCC (P = 0.018) than those with higher expression (19/37, 51.4% vs. 6/27, 22.2%, respectively) (Table 1).	('expression', 'MPA', (20, 30))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('lower', 'NegReg', (14, 19))	('ESCC', 'Disease', (91, 95))	('cytoplasmic', 'Var', (34, 45))	('Patients', 'Species', '9606', (0, 8))	('S', 'Chemical', 'MESH:D013455', (92, 93))	('P', 'Chemical', 'MESH:D010758', (97, 98))	('FoxM1', 'Gene', (46, 51))
819026	21976009	Patients with nuclear expression of FoxM1 were younger than those without nuclear FoxM1 (57 vs. 67.13 years, P < 0.001) (Table 2).	('P', 'Chemical', 'MESH:D010758', (109, 110))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('FoxM1', 'Gene', (36, 41))	('Patients', 'Species', '9606', (0, 8))	('nuclear expression', 'Var', (14, 32))
819031	21976009	All of the above findings supported a hypothesis that cytoplasmic FoxM1 might play a role in the progression of ESCC.	('cytoplasmic', 'Var', (54, 65))	('S', 'Chemical', 'MESH:D013455', (113, 114))	('ESCC', 'Disease', (112, 116))	('play', 'Reg', (78, 82))
819032	21976009	Expression of nuclear FoxM1 significantly correlates with the age of ESCC patients, i.e., patients with nuclear FoxM1 are younger than those without nuclear FoxM1.	('nuclear FoxM1', 'Var', (104, 117))	('S', 'Chemical', 'MESH:D013455', (70, 71))	('patients', 'Species', '9606', (74, 82))	('ESCC', 'Disease', (69, 73))	('patients', 'Species', '9606', (90, 98))
819041	21976009	This might finally translate into a significant association between smoking and the absence of nuclear FoxM1 in ESCC patients.	('absence', 'NegReg', (84, 91))	('nuclear', 'Var', (95, 102))	('ESCC', 'Disease', (112, 116))	('FoxM1', 'Gene', (103, 108))	('patients', 'Species', '9606', (117, 125))	('S', 'Chemical', 'MESH:D013455', (113, 114))
819043	21976009	This could be the result of the presence of post-translation modifications in the FoxM1 gene in ESCC.	('S', 'Chemical', 'MESH:D013455', (97, 98))	('FoxM1', 'Gene', (82, 87))	('ESCC', 'Disease', (96, 100))	('presence', 'Reg', (32, 40))	('post-translation modifications', 'Var', (44, 74))
819095	33139779	Specifically, inactivation of p120ctn combined with overexpression of EGFR induces a signaling cascade that leads to hyperactivation of NFkB and a resultant aggressive cell type.	('p120ctn', 'Gene', (30, 37))	('hyperactivation', 'PosReg', (117, 132))	('signaling', 'MPA', (85, 94))	('NFkB', 'Protein', (136, 140))	('p120ctn', 'Gene', '1500', (30, 37))	('EGFR', 'Gene', '1956', (70, 74))	('inactivation', 'Var', (14, 26))	('EGFR', 'Gene', (70, 74))	('overexpression', 'PosReg', (52, 66))	('induces', 'Reg', (75, 82))	('aggressive cell type', 'CPA', (157, 177))
819099	33139779	Inhibition of NFkB activity results in nearly complete loss of Twist2 expression, suggesting that this potential EMT-inducing gene, is a responsive target of NFkB.	('loss', 'NegReg', (55, 59))	('Twist2', 'Gene', (63, 69))	('expression', 'MPA', (70, 80))	('Inhibition', 'Var', (0, 10))	('Twist2', 'Gene', '117581', (63, 69))
819122	33139779	In the EPC1-PE cell population, there was a statistically significant increase in spindle-shaped cells, approximately 600 out of every 1 million.	('EPC1-P', 'CellLine', 'CVCL:4W34', (7, 13))	('spindle-shaped cells', 'CPA', (82, 102))	('increase', 'PosReg', (70, 78))	('EPC1-PE', 'Var', (7, 14))
819134	33139779	2b; n = 3), we saw a dramatic change in Twist2 expression levels in our cells when p120ctn and EGFR was modified compared to control cells (Fig.	('change', 'Reg', (30, 36))	('Twist2', 'Gene', '117581', (40, 46))	('EGFR', 'Gene', (95, 99))	('p120ctn', 'Gene', (83, 90))	('EGFR', 'Gene', '1956', (95, 99))	('modified', 'Var', (104, 112))	('p120ctn', 'Gene', '1500', (83, 90))	('expression levels', 'MPA', (47, 64))	('Twist2', 'Gene', (40, 46))
819162	33139779	IHC analyses of these cells in 3D culture demonstrate that EPC1-PE cells have increased Twist2 expression (Fig.	('EPC1-PE', 'Var', (59, 66))	('Twist2', 'Gene', '117581', (88, 94))	('increased', 'PosReg', (78, 87))	('Twist2', 'Gene', (88, 94))	('EPC1-P', 'CellLine', 'CVCL:4W34', (59, 65))	('expression', 'MPA', (95, 105))
819172	33139779	Again, we see a robust decrease of Twist2 protein levels following NFkB inhibition (Supplementary Figure S1).	('decrease', 'NegReg', (23, 31))	('NFkB', 'Gene', (67, 71))	('Twist2', 'Gene', (35, 41))	('inhibition', 'Var', (72, 82))	('Twist2', 'Gene', '117581', (35, 41))
819177	33139779	Not only does p120ctn and EGFR induce phenotypic and histologic changes that resemble ESCC, but modulation of these clinically relevant proteins leads to key molecular changes as well.	('EGFR', 'Gene', (26, 30))	('modulation', 'Var', (96, 106))	('induce', 'Reg', (31, 37))	('leads to', 'Reg', (145, 153))	('p120ctn', 'Gene', (14, 21))	('p120ctn', 'Gene', '1500', (14, 21))	('EGFR', 'Gene', '1956', (26, 30))	('ESCC', 'Disease', (86, 90))
819178	33139779	Specifically, inactivation of p120ctn combined with overexpression of EGFR induces hyperactivation of NFkB p65 in human esophageal keratinocytes and ESCC.	('NFkB p65', 'Gene', (102, 110))	('p120ctn', 'Gene', (30, 37))	('hyperactivation', 'PosReg', (83, 98))	('p120ctn', 'Gene', '1500', (30, 37))	('EGFR', 'Gene', '1956', (70, 74))	('inactivation', 'Var', (14, 26))	('EGFR', 'Gene', (70, 74))	('human', 'Species', '9606', (114, 119))
819181	33139779	Specifically, we demonstrated high levels of Twist2 when NFkB hyperactivation is induced by modulation of p120ctn and EGFR together in human esophageal keratinocytes.	('p120ctn', 'Gene', (106, 113))	('Twist2', 'Gene', (45, 51))	('NFkB hyperactivation', 'Disease', 'MESH:D011504', (57, 77))	('p120ctn', 'Gene', '1500', (106, 113))	('NFkB hyperactivation', 'Disease', (57, 77))	('human', 'Species', '9606', (135, 140))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('Twist2', 'Gene', '117581', (45, 51))	('modulation', 'Var', (92, 102))
819200	33139779	While NFkB may seem like a clear therapeutic target to slow the progression of ESCC, the challenges are numerous given that inhibition of NFkB, a required component of innate immunity, can lead to long-term immunosuppression and toxicity.	('immunosuppression', 'MPA', (207, 224))	('toxicity', 'Disease', 'MESH:D064420', (229, 237))	('ESCC', 'Disease', (79, 83))	('lead to', 'Reg', (189, 196))	('inhibition', 'Var', (124, 134))	('NFkB', 'Gene', (138, 142))	('toxicity', 'Disease', (229, 237))
819227	33139779	Antibodies for NFkB (1:1000; #4764), pNFkB (1:1000; #3033), ITGA1 (2 mug/ml; #71,747), Vimentin (1:5000; #9855), and E-cadherin (1:1000; #3195) were purchased from Cell Signaling Technology.	('ITGA1', 'Gene', (60, 65))	('NFkB', 'Gene', (15, 19))	('Vimentin', 'Gene', (87, 95))	('1:1000; #3033', 'Var', (44, 57))	('Vimentin', 'Gene', '7431', (87, 95))	('pNFkB', 'Gene', (37, 42))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))	('ITGA1', 'Gene', '3672', (60, 65))
819244	31351524	No GWAS has identified variants specifically associated with consumption of tea, juice, soda, wine, beer, milk or any other common beverage.	('variants', 'Var', (23, 31))	('juice', 'Chemical', '-', (81, 86))	('soda', 'Chemical', 'MESH:D002255', (88, 92))	('associated', 'Reg', (45, 55))
819271	31351524	This region was followed up using fine-mapping genotyping and confirmed single nucleotide polymorphism (SNP)-AD associations within ASTN1.	('ASTN1', 'Gene', '460', (132, 137))	('AD', 'Disease', (109, 111))	('single nucleotide polymorphism', 'Var', (72, 102))	('associations', 'Interaction', (112, 124))	('ASTN1', 'Gene', (132, 137))	('AD', 'Disease', 'MESH:D000437', (109, 111))
819274	31351524	In contrast, bitter taste quality is affected by variants in TAS2R16, TAS2R38, TAS2R43 and TAS2R44 while variants in TAS1R1 and TAS1R3 impact umami and sweet.	('TAS2R16', 'Gene', (61, 68))	('TAS1R1', 'Gene', '80835', (117, 123))	('variants', 'Var', (105, 113))	('TAS2R43', 'Gene', (79, 86))	('sweet', 'MPA', (152, 157))	('variants', 'Var', (49, 57))	('TAS2R16', 'Gene', '50833', (61, 68))	('TAS2R38', 'Gene', '5726', (70, 77))	('TAS1R1', 'Gene', (117, 123))	('TAS1R3', 'Gene', (128, 134))	('bitter taste', 'Phenotype', 'HP:0000224', (13, 25))	('umami', 'MPA', (142, 147))	('impact', 'Reg', (135, 141))	('affected', 'Reg', (37, 45))	('TAS2R38', 'Gene', (70, 77))	('bitter taste quality', 'MPA', (13, 33))	('bitter taste quality', 'Phenotype', 'HP:0000224', (13, 33))	('TAS2R43', 'Gene', '259289', (79, 86))	('TAS1R3', 'Gene', '83756', (128, 134))	('TAS2R44', 'Gene', '259290', (91, 98))	('TAS2R44', 'Gene', (91, 98))
819275	31351524	The most studied is TAS2R38, in particular its three SNPs, which result in two common haplotypes that are named for their amino acid substitutions: PAV (proline, alanine, and valine) and AVI (alanine, valine, and isoleucine).	('PAV', 'Chemical', 'MESH:C060376', (148, 151))	('AVI', 'Chemical', '-', (187, 190))	('alanine', 'MPA', (162, 169))	('alanine', 'Var', (192, 199))	('valine', 'Chemical', 'MESH:D014633', (201, 207))	('alanine', 'Chemical', 'MESH:D000409', (162, 169))	('proline', 'Var', (153, 160))	('valine', 'Var', (201, 207))	('TAS2R38', 'Gene', (20, 27))	('isoleucine', 'Var', (213, 223))	('isoleucine', 'Chemical', 'MESH:D007532', (213, 223))	('proline', 'Chemical', 'MESH:D011392', (153, 160))	('valine', 'Chemical', 'MESH:D014633', (175, 181))	('valine', 'Var', (175, 181))	('TAS2R38', 'Gene', '5726', (20, 27))	('alanine', 'Chemical', 'MESH:D000409', (192, 199))
819276	31351524	TAS2R38 diplotype influences the ability to taste a family of bitter compounds including phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP).	('6-n-propylthiouracil', 'Chemical', 'MESH:D011441', (119, 139))	('6-n-propylthiouracil', 'MPA', (119, 139))	('diplotype', 'Var', (8, 17))	('TAS2R38', 'Gene', (0, 7))	('taste a family of bitter compounds', 'MPA', (44, 78))	('ability', 'MPA', (33, 40))	('phenylthiocarbamide', 'Chemical', 'MESH:D010670', (89, 108))	('influences', 'Reg', (18, 28))	('phenylthiocarbamide', 'MPA', (89, 108))	('PROP', 'Chemical', 'MESH:D011441', (141, 145))	('PTC', 'Chemical', 'MESH:D010670', (110, 113))	('TAS2R38', 'Gene', '5726', (0, 7))
819279	31351524	Variation in TAS2R38 has been linked to coffee, beer, spirits, green tea, sugar content of beverages and total alcohol or drinking status.	('TAS2R38', 'Gene', (13, 20))	('TAS2R38', 'Gene', '5726', (13, 20))	('linked', 'Reg', (30, 36))	('sugar', 'Chemical', 'MESH:D000073893', (74, 79))	('Variation', 'Var', (0, 9))	('alcohol', 'Chemical', 'MESH:D000438', (111, 118))
819280	31351524	Variation in other TASR2 members have also been linked to bitter beverage consumption.	('TASR2', 'Gene', (19, 24))	('bitter beverage consumption', 'Disease', (58, 85))	('TASR2', 'Gene', '10772', (19, 24))	('Variation', 'Var', (0, 9))	('linked', 'Reg', (48, 54))
819282	31351524	Indeed, variants in TAS2R43 linked to increased perception of caffeine; a bitter compound, associates with increased coffee consumption and liking according to candidate-SNP analysis.	('coffee consumption', 'CPA', (117, 135))	('caffeine', 'Chemical', 'MESH:D002110', (62, 70))	('increased', 'PosReg', (107, 116))	('liking', 'CPA', (140, 146))	('variants', 'Var', (8, 16))	('perception', 'MPA', (48, 58))	('TAS2R43', 'Gene', (20, 27))	('increased', 'PosReg', (38, 47))	('TAS2R43', 'Gene', '259289', (20, 27))
819283	31351524	Variation in the TAS1R sweet and umami receptor family has also been linked to alcohol consumption behavior, wine drinking and vodka liking.	('TAS1R', 'Gene', (17, 22))	('linked', 'Reg', (69, 75))	('wine drinking', 'Disease', (109, 122))	('vodka liking', 'Disease', (127, 139))	('alcohol', 'Chemical', 'MESH:D000438', (79, 86))	('Variation', 'Var', (0, 9))	('vodka', 'Chemical', 'MESH:D000431', (127, 132))	('alcohol consumption behavior', 'Disease', (79, 107))
819293	31351524	For example, the ADH1B rs1229984 T allele (48His) results in a 40 to 100-fold higher rate of alcohol to acetaldehyde metabolism (i.e ethanol oxidation).	('higher', 'PosReg', (78, 84))	('48His', 'Chemical', '-', (43, 48))	('rs1229984 T', 'Var', (23, 34))	('alcohol to acetaldehyde metabolism', 'MPA', (93, 127))	('rs1229984', 'Mutation', 'rs1229984', (23, 32))	('ADH1B', 'Gene', (17, 22))	('acetaldehyde', 'Chemical', 'MESH:D000079', (104, 116))	('ADH1B', 'Gene', '125', (17, 22))	('ethanol', 'Chemical', 'MESH:D000431', (133, 140))	('acetaldehyde metabolism', 'Phenotype', 'HP:0003533', (104, 127))	('alcohol', 'Chemical', 'MESH:D000438', (93, 100))
819294	31351524	The ALDH2 rs671 A allele (504Lys) reduces ALDH2 activity and thus decreases acetaldehyde to acetate metabolism (i.e.	('504Lys', 'Var', (26, 32))	('ALDH2', 'Gene', '217', (4, 9))	('ALDH2', 'Gene', '217', (42, 47))	('decreases', 'NegReg', (66, 75))	('activity', 'MPA', (48, 56))	('acetate', 'Chemical', 'MESH:D000085', (92, 99))	('reduces', 'NegReg', (34, 41))	('rs671', 'Mutation', 'rs671', (10, 15))	('Lys', 'Chemical', 'MESH:D008239', (29, 32))	('rs671 A', 'Var', (10, 17))	('ALDH2', 'Gene', (4, 9))	('decreases acetaldehyde', 'Phenotype', 'HP:0003533', (66, 88))	('ALDH2', 'Gene', (42, 47))	('acetaldehyde to acetate metabolism', 'MPA', (76, 110))	('acetaldehyde', 'Chemical', 'MESH:D000079', (76, 88))
819297	31351524	The ADH1B His and ALDH2 Lys variants influence alcohol drinking behavior by elevating blood acetaldehyde levels upon alcohol drinking which ultimately reduces susceptibility to developing alcohol drinking problems.	('variants', 'Var', (28, 36))	('susceptibility', 'MPA', (159, 173))	('ALDH2', 'Gene', (18, 23))	('alcohol drinking', 'Phenotype', 'HP:0030955', (188, 204))	('alcohol drinking', 'Phenotype', 'HP:0030955', (47, 63))	('acetaldehyde', 'Chemical', 'MESH:D000079', (92, 104))	('alcohol', 'Chemical', 'MESH:D000438', (188, 195))	('alcohol', 'Chemical', 'MESH:D000438', (47, 54))	('alcohol drinking behavior', 'MPA', (47, 72))	('elevating', 'Reg', (76, 85))	('alcohol', 'Chemical', 'MESH:D000438', (117, 124))	('alcohol drinking', 'Phenotype', 'HP:0030955', (117, 133))	('Lys', 'Chemical', 'MESH:D008239', (24, 27))	('reduces', 'NegReg', (151, 158))	('influence', 'Reg', (37, 46))	('ALDH2', 'Gene', '217', (18, 23))	('His', 'Chemical', 'MESH:D006639', (10, 13))	('ADH1B', 'Gene', '125', (4, 9))	('Lys variants', 'Var', (24, 36))	('ADH1B', 'Gene', (4, 9))	('blood acetaldehyde levels', 'Phenotype', 'HP:0003533', (86, 111))	('blood acetaldehyde levels', 'MPA', (86, 111))
819299	31351524	Variants in SERINC2, KIAA0040, MTIF2-CCDC88A, and PECR have also been associated with AD in GWAS.	('Variants', 'Var', (0, 8))	('CCDC88A', 'Gene', (37, 44))	('PECR', 'Gene', '55825', (50, 54))	('KIAA0040', 'Gene', (21, 29))	('CCDC88A', 'Gene', '55704', (37, 44))	('associated with', 'Reg', (70, 85))	('SERINC2', 'Gene', (12, 19))	('SERINC2', 'Gene', '347735', (12, 19))	('AD', 'Disease', 'MESH:D000437', (86, 88))	('PECR', 'Gene', (50, 54))	('MTIF2', 'Gene', '4528', (31, 36))	('KIAA0040', 'Gene', '9674', (21, 29))	('AD', 'Disease', (86, 88))	('MTIF2', 'Gene', (31, 36))
819300	31351524	Variation in SERINC2, encoding a transmembrane transporter of L-serine, may potentially alter glycine and glutamate neurotransmission contributing to hyperexcitability and negative affect during alcohol abstinence.	('SERINC2', 'Gene', (13, 20))	('glutamate', 'Chemical', 'MESH:D018698', (106, 115))	('contributing', 'Reg', (134, 146))	('alter', 'Reg', (88, 93))	('glycine', 'Chemical', 'MESH:D005998', (94, 101))	('negative affect', 'Phenotype', 'HP:0031467', (172, 187))	('L-serine', 'Chemical', 'MESH:D012694', (62, 70))	('negative affect', 'MPA', (172, 187))	('alcohol', 'Chemical', 'MESH:D000438', (195, 202))	('hyperexcitability', 'MPA', (150, 167))	('Variation', 'Var', (0, 9))	('SERINC2', 'Gene', '347735', (13, 20))
819305	31351524	Variants at 5q35, 6p21, and 7q32 have also been associated with AD symptoms but not clinically diagnosed AD.	('Variants', 'Var', (0, 8))	('associated', 'Reg', (48, 58))	('AD', 'Disease', (105, 107))	('AD', 'Disease', (64, 66))	('AD', 'Disease', 'MESH:D000437', (105, 107))	('AD', 'Disease', 'MESH:D000437', (64, 66))
819306	31351524	Variants linked to AD may not necessarily equate with habitual alcohol consumption in general population.	('Variants', 'Var', (0, 8))	('AD', 'Disease', (19, 21))	('habitual alcohol consumption', 'Phenotype', 'HP:0030955', (54, 82))	('alcohol', 'Chemical', 'MESH:D000438', (63, 70))	('AD', 'Disease', 'MESH:D000437', (19, 21))
819308	31351524	Variants in CADM2 associated with alcohol consumption have also been associated with cognitive ability, reproductive success, risk-taking propensity and cannabis use.	('Variants', 'Var', (0, 8))	('associated', 'Reg', (69, 79))	('reproductive success', 'CPA', (104, 124))	('risk-taking', 'Phenotype', 'HP:0031472', (126, 137))	('associated', 'Reg', (18, 28))	('alcohol', 'Chemical', 'MESH:D000438', (34, 41))	('risk-taking', 'CPA', (126, 137))	('CADM2', 'Gene', '253559', (12, 17))	('cognitive ability', 'CPA', (85, 102))	('CADM2', 'Gene', (12, 17))	('cannabis use', 'CPA', (153, 165))
819314	31351524	GWAS have identified multiple genetic variants associated with self-reported habitual coffee consumption, many of which point to caffeine-related pathways.	('point to', 'Reg', (120, 128))	('variants', 'Var', (38, 46))	('caffeine', 'Chemical', 'MESH:D002110', (129, 137))	('associated', 'Reg', (47, 57))	('caffeine-related pathways', 'Pathway', (129, 154))
819318	31351524	Genetic variants leading to increased coffee/caffeine consumption associate with lower circulating caffeine levels and higher paraxanthine-to-caffeine ratio suggesting a fast caffeine metabolism phenotype.	('increased', 'PosReg', (28, 37))	('caffeine', 'Chemical', 'MESH:D002110', (45, 53))	('lower', 'NegReg', (81, 86))	('paraxanthine-to-caffeine ratio', 'MPA', (126, 156))	('caffeine', 'Chemical', 'MESH:D002110', (142, 150))	('higher', 'PosReg', (119, 125))	('variants', 'Var', (8, 16))	('circulating caffeine levels', 'MPA', (87, 114))	('paraxanthine', 'Chemical', 'MESH:C021183', (126, 138))	('caffeine', 'Chemical', 'MESH:D002110', (99, 107))	('caffeine', 'Chemical', 'MESH:D002110', (175, 183))
819322	31351524	Variants near MLXIPL, GCKR, SEC16B, TMEM18, AKAP6 and MC4R have no obvious role in coffee or caffeine consumption but have previously been associated with other traits in GWAS notably obesity, glucose and lipids (Table 2).	('Variants', 'Var', (0, 8))	('lipids', 'Chemical', 'MESH:D008055', (205, 211))	('MLXIPL', 'Gene', '51085', (14, 20))	('obesity', 'Phenotype', 'HP:0001513', (184, 191))	('AKAP6', 'Gene', (44, 49))	('SEC16B', 'Gene', (28, 34))	('GCKR', 'Gene', '2646', (22, 26))	('traits', 'Gene', (161, 167))	('AKAP6', 'Gene', '9472', (44, 49))	('MC4R', 'Gene', (54, 58))	('SEC16B', 'Gene', '89866', (28, 34))	('obesity', 'Disease', (184, 191))	('caffeine', 'Chemical', 'MESH:D002110', (93, 101))	('glucose', 'Chemical', 'MESH:D005947', (193, 200))	('associated', 'Reg', (139, 149))	('obesity', 'Disease', 'MESH:D009765', (184, 191))	('MC4R', 'Gene', '4160', (54, 58))	('TMEM18', 'Gene', '129787', (36, 42))	('MLXIPL', 'Gene', (14, 20))	('GCKR', 'Gene', (22, 26))	('traits', 'Gene', '55840', (161, 167))	('TMEM18', 'Gene', (36, 42))
819324	31351524	Pirastu et al has performed GWAS of coffee intake and coffee liking and identified associations with variants in PDSS2 and FIBIN, respectively.	('FIBIN', 'Gene', (123, 128))	('associations', 'Interaction', (83, 95))	('PDSS2', 'Gene', '57107', (113, 118))	('FIBIN', 'Gene', '387758', (123, 128))	('variants', 'Var', (101, 109))	('PDSS2', 'Gene', (113, 118))
819326	31351524	No locus was replicated for total sweet beverage consumption, but a GWAS of SSB yielded significant variants mapping to FTO, a well-established locus for BMI and obesity-related traits.	('obesity', 'Disease', (162, 169))	('FTO', 'Gene', '79068', (120, 123))	('variants', 'Var', (100, 108))	('SSB', 'Chemical', '-', (76, 79))	('traits', 'Gene', '55840', (178, 184))	('traits', 'Gene', (178, 184))	('obesity', 'Phenotype', 'HP:0001513', (162, 169))	('FTO', 'Gene', (120, 123))	('obesity', 'Disease', 'MESH:D009765', (162, 169))
819327	31351524	We found that variants in FTO previously linked to higher BMI were associated with lower SSB consumption regardless of BMI adjustment and is consistent with a previous candidate gene study by Brunkwall et al.	('variants', 'Var', (14, 22))	('FTO', 'Gene', (26, 29))	('lower', 'NegReg', (83, 88))	('SSB consumption', 'MPA', (89, 104))	('men', 'Species', '9606', (129, 132))	('FTO', 'Gene', '79068', (26, 29))	('SSB', 'Chemical', '-', (89, 92))
819330	31351524	To our knowledge, no GWAS has identified variants specifically associated with consumption of tea, juice, milk or any other beverage intake.	('variants', 'Var', (41, 49))	('juice', 'Chemical', '-', (99, 104))	('associated', 'Reg', (63, 73))
819335	31351524	The genetic variant in FTO that increases risk for obesity has also been associated with increased alcohol, coffee and sweet food consumption but lower consumption of soft drinks and SSB according to independent candidate SNP analysis, adjusted for BMI.	('coffee', 'MPA', (108, 114))	('variant', 'Var', (12, 19))	('obesity', 'Phenotype', 'HP:0001513', (51, 58))	('FTO', 'Gene', (23, 26))	('consumption of soft drinks', 'MPA', (152, 178))	('alcohol', 'Chemical', 'MESH:D000438', (99, 106))	('SSB', 'Chemical', '-', (183, 186))	('sweet food', 'Phenotype', 'HP:0030221', (119, 129))	('alcohol', 'MPA', (99, 106))	('lower', 'NegReg', (146, 151))	('obesity', 'Disease', 'MESH:D009765', (51, 58))	('increased', 'PosReg', (89, 98))	('obesity', 'Disease', (51, 58))	('FTO', 'Gene', '79068', (23, 26))
819337	31351524	Neverthless, increasing evidence suggests that a subset of BMI loci contribute to behavioral aspects of obesity by altering food and beverage intake.	('behavioral aspects', 'Phenotype', 'HP:0000708', (82, 100))	('BMI', 'Gene', (59, 62))	('loci', 'Var', (63, 67))	('obesity', 'Phenotype', 'HP:0001513', (104, 111))	('contribute', 'Reg', (68, 78))	('altering', 'Reg', (115, 123))	('obesity', 'Disease', 'MESH:D009765', (104, 111))	('obesity', 'Disease', (104, 111))
819344	31351524	Most of the genetic epidemiological studies of alcohol have focused on the ALDH2 Glu504Lys (rs671) and ADH1B1 Arg48His (rs1229984) polymorphisms, wherein the ALDH2 Lys (A allele) and ADH1B1 His (T allele) variants associate with lower alcohol consumption due to adverse reaction to alcohol as a result of higher circulating acetaldehyde.	('ALDH2', 'Gene', '217', (158, 163))	('ALDH2', 'Gene', (75, 80))	('ADH1B', 'Gene', '125', (103, 108))	('acetaldehyde', 'Chemical', 'MESH:D000079', (324, 336))	('circulating acetaldehyde', 'MPA', (312, 336))	('ADH1B', 'Gene', '125', (183, 188))	('alcohol', 'Chemical', 'MESH:D000438', (47, 54))	('circulating acetaldehyde', 'Phenotype', 'HP:0003533', (312, 336))	('Arg48His', 'Var', (110, 118))	('ADH1B', 'Gene', (103, 108))	('alcohol consumption', 'MPA', (235, 254))	('His', 'Chemical', 'MESH:D006639', (115, 118))	('ALDH2', 'Gene', '217', (75, 80))	('ADH1B', 'Gene', (183, 188))	('rs1229984', 'Var', (120, 129))	('Arg48His', 'SUBSTITUTION', 'None', (110, 118))	('rs671', 'Mutation', 'rs671', (92, 97))	('higher', 'PosReg', (305, 311))	('Lys', 'Chemical', 'MESH:D008239', (87, 90))	('alcohol', 'Chemical', 'MESH:D000438', (235, 242))	('ALDH2', 'Gene', (158, 163))	('variants', 'Var', (205, 213))	('lower', 'NegReg', (229, 234))	('Lys', 'Chemical', 'MESH:D008239', (164, 167))	('alcohol', 'Chemical', 'MESH:D000438', (282, 289))	('Glu504Lys', 'Var', (81, 90))	('Glu504Lys', 'SUBSTITUTION', 'None', (81, 90))	('rs1229984', 'Mutation', 'rs1229984', (120, 129))	('His', 'Chemical', 'MESH:D006639', (190, 193))
819345	31351524	Several studies report that individuals with ALDH2 Lys/Lys genotype have no or a lower risk of esophageal cancer while those with Lys/Glu are at increased risk compared to Glu/Glu.	('Lys', 'Chemical', 'MESH:D008239', (51, 54))	('Glu', 'Chemical', 'MESH:D018698', (172, 175))	('Lys/Lys', 'Var', (51, 58))	('lower', 'NegReg', (81, 86))	('Lys', 'Chemical', 'MESH:D008239', (55, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Glu', 'Chemical', 'MESH:D018698', (176, 179))	('ALDH2', 'Gene', '217', (45, 50))	('ALDH2', 'Gene', (45, 50))	('esophageal cancer', 'Disease', (95, 112))	('Lys', 'Chemical', 'MESH:D008239', (130, 133))	('Glu', 'Chemical', 'MESH:D018698', (134, 137))
819350	31351524	This is further supported by reports of ALDH2-alcohol interactions whereby both Lys/Lys and Lys/Glu are at increased risk of esophageal cancer when they also consume alcohol.	('alcohol interactions', 'Phenotype', 'HP:0030955', (46, 66))	('alcohol', 'Chemical', 'MESH:D000438', (46, 53))	('ALDH2', 'Gene', '217', (40, 45))	('Glu', 'Chemical', 'MESH:D018698', (96, 99))	('ALDH2', 'Gene', (40, 45))	('Lys', 'Chemical', 'MESH:D008239', (80, 83))	('Lys/Lys', 'Var', (80, 87))	('esophageal cancer', 'Disease', (125, 142))	('Lys', 'Chemical', 'MESH:D008239', (92, 95))	('Lys', 'Chemical', 'MESH:D008239', (84, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('Lys/Glu', 'Var', (92, 99))	('interactions', 'Interaction', (54, 66))	('alcohol', 'Chemical', 'MESH:D000438', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
819352	31351524	genotype-specific vs additive, dominant or recessive models) and the need to further account for drinking behavior appears important with regards to ALDH2 Glu504Lys and disregard for these may explain, in part, the inconsistent results in the literature pertaining to ALDH2 and other outcomes.	('ALDH2', 'Gene', (149, 154))	('ALDH2', 'Gene', '217', (268, 273))	('ALDH2', 'Gene', (268, 273))	('ALDH2', 'Gene', '217', (149, 154))	('Glu504Lys', 'Var', (155, 164))	('Glu504Lys', 'SUBSTITUTION', 'None', (155, 164))
819353	31351524	ALDH2 Lys/Lys and Lys/Glu decreased risk of ovarian cancer vs Glu/Glu in a pooled analysis of Asians supporting a causal relationship between high alcohol intake and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('decreased', 'NegReg', (26, 35))	('Lys/Lys', 'Var', (6, 13))	('Lys', 'Chemical', 'MESH:D008239', (10, 13))	('Glu', 'Chemical', 'MESH:D018698', (62, 65))	('Lys', 'Chemical', 'MESH:D008239', (18, 21))	('ALDH2', 'Gene', (0, 5))	('Glu', 'Chemical', 'MESH:D018698', (22, 25))	('Lys/Glu decreased', 'Phenotype', 'HP:0500142', (18, 35))	('ovarian cancer', 'Disease', (44, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (44, 58))	('cancer', 'Disease', (166, 172))	('Lys/Glu', 'Var', (18, 25))	('alcohol', 'Chemical', 'MESH:D000438', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', (52, 58))	('ALDH2', 'Gene', '217', (0, 5))	('Lys', 'Chemical', 'MESH:D008239', (6, 9))	('Glu', 'Chemical', 'MESH:D018698', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))
819356	31351524	The ALDH2 Lys/Lys or Lys/Glu genotypes increased risk of T2D compared to the Glu/Glu genotype.	('Lys', 'Chemical', 'MESH:D008239', (10, 13))	('ALDH2', 'Gene', '217', (4, 9))	('Glu', 'Chemical', 'MESH:D018698', (25, 28))	('Lys', 'Chemical', 'MESH:D008239', (14, 17))	('ALDH2', 'Gene', (4, 9))	('T2D', 'Disease', (57, 60))	('Glu', 'Chemical', 'MESH:D018698', (77, 80))	('Glu', 'Chemical', 'MESH:D018698', (81, 84))	('T2D', 'Disease', 'MESH:D003924', (57, 60))	('Lys/Glu', 'Var', (21, 28))	('Lys', 'Chemical', 'MESH:D008239', (21, 24))	('Lys/Lys', 'Var', (10, 17))
819357	31351524	ALDH2 Lys carriers have an increased risk of CHD, CAD and MI and present with an at-risk lipid profile.	('Lys', 'Chemical', 'MESH:D008239', (6, 9))	('lipid', 'Chemical', 'MESH:D008055', (89, 94))	('AD', 'Disease', 'MESH:D000437', (51, 53))	('ALDH2', 'Gene', (0, 5))	('CHD', 'Disease', (45, 48))	('ALDH2', 'Gene', '217', (0, 5))	('CHD', 'Disease', 'None', (45, 48))	('Lys carriers', 'Var', (6, 18))	('AD', 'Disease', (51, 53))
819361	31351524	Inconsistencies in this area nevertheless arise whereby the Lys variant contributes to a lower risk of T2D (particularly in drinkers) and HTN.	('T2D', 'Disease', (103, 106))	('lower', 'NegReg', (89, 94))	('T2D', 'Disease', 'MESH:D003924', (103, 106))	('Lys', 'Var', (60, 63))	('HTN', 'Disease', (138, 141))	('Lys', 'Chemical', 'MESH:D008239', (60, 63))
819362	31351524	For ADH1B1 Arg48His (rs1229984), each additional Arg variant (high alcohol consumer, slow acetaldehyde producer) increased risk of esophageal and other upper aerodigestive tract cancers (UADT) compared to His/His.	('Arg', 'Chemical', 'MESH:D001120', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Arg48His', 'Var', (11, 19))	('Arg48His', 'SUBSTITUTION', 'None', (11, 19))	('His', 'Chemical', 'MESH:D006639', (209, 212))	('Arg', 'Chemical', 'MESH:D001120', (49, 52))	('upper aerodigestive tract cancers', 'Disease', (152, 185))	('Arg', 'Gene', (49, 52))	('alcohol', 'Chemical', 'MESH:D000438', (67, 74))	('rs1229984', 'Mutation', 'rs1229984', (21, 30))	('UADT', 'Disease', 'MESH:D006258', (187, 191))	('ADH1B', 'Gene', '125', (4, 9))	('upper aerodigestive tract cancers', 'Disease', 'MESH:D006258', (152, 185))	('His', 'Chemical', 'MESH:D006639', (16, 19))	('UADT', 'Disease', (187, 191))	('acetaldehyde', 'Chemical', 'MESH:D000079', (90, 102))	('increased', 'Reg', (113, 122))	('ADH1B', 'Gene', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('esophageal and', 'Disease', (131, 145))	('His', 'Chemical', 'MESH:D006639', (205, 208))
819363	31351524	An interaction with alcohol drinking is also evident with risk being restricted to or even greater among drinkers with Arg/Arg or Arg/His genotypes.	('Arg/Arg', 'Var', (119, 126))	('His', 'Chemical', 'MESH:D006639', (134, 137))	('alcohol drinking', 'Phenotype', 'HP:0030955', (20, 36))	('alcohol', 'Chemical', 'MESH:D000438', (20, 27))	('Arg', 'Chemical', 'MESH:D001120', (123, 126))	('Arg', 'Chemical', 'MESH:D001120', (130, 133))	('Arg', 'Chemical', 'MESH:D001120', (119, 122))	('Arg/His', 'Var', (130, 137))
819365	31351524	In a meta-analysis including individuals of European ethnicity, individuals with an ADH1B His variant presented with lower measures of adiposity, blood pressure and inflammation as well as a reduced risk of CHD than those with Arg/Arg; and most of these associations were null in non-drinkers.	('adiposity', 'MPA', (135, 144))	('variant', 'Var', (94, 101))	('blood pressure', 'MPA', (146, 160))	('ADH1B', 'Gene', (84, 89))	('Arg', 'Chemical', 'MESH:D001120', (227, 230))	('ADH1B', 'Gene', '125', (84, 89))	('reduced', 'NegReg', (191, 198))	('Arg', 'Chemical', 'MESH:D001120', (231, 234))	('lower', 'NegReg', (117, 122))	('His', 'Chemical', 'MESH:D006639', (90, 93))	('measures', 'MPA', (123, 131))	('inflammation', 'Disease', 'MESH:D007249', (165, 177))	('CHD', 'Disease', 'None', (207, 210))	('lower measures of adiposity', 'Phenotype', 'HP:0040063', (117, 144))	('CHD', 'Disease', (207, 210))	('inflammation', 'Disease', (165, 177))
819368	31351524	However, only variants near GCKR and KLB were among the selected loci that have been confirmed by others (Table 2) and several IV SNPs violate MR assumptions and are thus invalid.	('violate', 'Reg', (135, 142))	('KLB', 'Gene', '152831', (37, 40))	('variants', 'Var', (14, 22))	('GCKR', 'Gene', '2646', (28, 32))	('KLB', 'Gene', (37, 40))	('GCKR', 'Gene', (28, 32))
819371	31351524	The vast majority of study IVs included at least SNPs near CYP1A2 and AHR - the strongest and most robust variants linked to coffee drinking behavior (Table 2) and caffeine metabolite levels.	('CYP1A2', 'Gene', '1544', (59, 65))	('AHR', 'Gene', '196', (70, 73))	('variants', 'Var', (106, 114))	('AHR', 'Gene', (70, 73))	('caffeine', 'Chemical', 'MESH:D002110', (164, 172))	('caffeine metabolite levels', 'MPA', (164, 190))	('linked', 'Reg', (115, 121))	('CYP1A2', 'Gene', (59, 65))	('coffee drinking behavior', 'Disease', (125, 149))
819390	31351524	Moreover, there is some evidence to suggest that personal genetic knowledge might demotivate or increase anxiety.	('demotivate', 'NegReg', (82, 92))	('increase anxiety', 'Disease', 'MESH:D001008', (96, 112))	('personal genetic knowledge', 'Var', (49, 75))	('increase anxiety', 'Disease', (96, 112))	('increase anxiety', 'Phenotype', 'HP:0000739', (96, 112))
819449	31782340	Therefore, ADC value has higher diagnosis efficacy in the identification of the degree of histologic grade of esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('esophageal carcinoma', 'Disease', (110, 130))	('ADC', 'Var', (11, 14))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (110, 130))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (110, 130))	('ADC', 'Chemical', '-', (11, 14))
819478	31782340	Our study showed that the cutoff value of ADC for diagnosing poorly differentiated esophageal carcinoma was <=1.25 x 10-3 mm2/s with the sensitivity of 84.3% and specificity of 94.3%.	('ADC', 'Chemical', '-', (42, 45))	('ADC', 'Gene', (42, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('esophageal carcinoma', 'Disease', (83, 103))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('<=1.25', 'Var', (108, 114))
819492	31782340	While biexponential DWI intravoxel incoherent motion (IVIM) might provide more accurate information about water diffusion, which contains true diffusivity (D), fraction of perfusion (f), and pseudodiffusion parameter (D*).	('biexponential', 'Var', (6, 19))	('pseudodiffusion parameter', 'MPA', (191, 216))	('water', 'Chemical', 'MESH:D014867', (106, 111))	('fraction of perfusion', 'MPA', (160, 181))	('true diffusivity', 'MPA', (138, 154))	('water diffusion', 'MPA', (106, 121))
819501	31401336	KLF5 knockdown in EAC cells caused significant decreases in cell migration, proliferation, and EAC-associated gene expression.	('EAC', 'Phenotype', 'HP:0011459', (95, 98))	('cell migration', 'CPA', (60, 74))	('rat', 'Species', '10116', (83, 86))	('KLF5', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('expression', 'MPA', (115, 125))	('rat', 'Species', '10116', (68, 71))	('EAC', 'Phenotype', 'HP:0011459', (18, 21))	('EAC-associated', 'Disease', (95, 109))	('decreases', 'NegReg', (47, 56))
819510	31401336	Canonically, SHH protein is exported out of the cell, where it will bind and inhibit PTCH1 on neighboring cells or the cell of origin; the inhibition of PTCH1 releases the inhibition of SMO, and activated SMO initiates a signaling cascade that ultimately activates GLI2 proteins in the cytoplasm; finally, activated GLI2 translocates to the nucleus, allowing SHH target genes to be expressed (Figure 1).	('inhibition', 'Var', (139, 149))	('inhibition', 'MPA', (172, 182))	('SMO', 'Gene', '6608', (205, 208))	('SMO', 'Gene', '6608', (186, 189))	('SMO', 'Gene', (205, 208))	('SMO', 'Gene', (186, 189))	('PTCH1', 'Gene', (153, 158))	('activates', 'PosReg', (255, 264))
819516	31401336	In another murine study, KLF5Delta/Delta intestines failed to form villi, despite expressing factors known to mediate epithelial-mesenchymal signaling essential for villus formation, including SHH, PTCH1, GLI2, and BMP4.	('GLI2', 'Gene', (205, 209))	('KLF5Delta/Delta', 'Var', (25, 40))	('SHH', 'Gene', (193, 196))	('murine', 'Species', '10090', (11, 17))	('PTCH1', 'Gene', (198, 203))	('BMP4', 'Gene', (215, 219))
819543	31401336	Cell proliferation was measured 0 hours, 24 hours, 72 hours, and 120 hours after siRNA transfection, using Cell Proliferation Reagent WST-1 (Roche, Basel, Switzerland).	('transfection', 'Var', (87, 99))	('rat', 'Species', '10116', (12, 15))	('siRNA', 'Gene', (81, 86))	('rat', 'Species', '10116', (119, 122))
819556	31401336	Higher levels of SHH and GLI1 were observed in OE33 but were not significantly different from levels in HEEpiC (Figure 3, C and D).	('OE33', 'Var', (47, 51))	('GLI1', 'Gene', '2735', (25, 29))	('GLI1', 'Gene', (25, 29))	('SHH', 'MPA', (17, 20))
819566	31401336	In WST-1 assays, KLF5 siRNA caused significant decreases in SKGT4 cell proliferation and cell viability at multiple time points (Figure 5D).	('KLF5 siRNA', 'Var', (17, 27))	('cell viability at multiple time points', 'CPA', (89, 127))	('rat', 'Species', '10116', (78, 81))	('SKGT4', 'Gene', (60, 65))	('decreases', 'NegReg', (47, 56))
819567	31401336	Moreover, scratch assays revealed a significant decrease in SKGT4 cell migration caused by KLF5 knockdown (Fig.	('knockdown', 'Var', (96, 105))	('SKGT4 cell migration', 'CPA', (60, 80))	('rat', 'Species', '10116', (12, 15))	('rat', 'Species', '10116', (74, 77))	('decrease', 'NegReg', (48, 56))	('KLF5', 'Gene', (91, 95))
819571	31401336	Finally, we used immunocytochemistry to determine whether KLF5 siRNA-induced decreases in GLI1 mRNA levels were reflected at the protein level.	('KLF5', 'Var', (58, 62))	('GLI1', 'Gene', (90, 94))	('GLI1', 'Gene', '2735', (90, 94))	('decreases', 'NegReg', (77, 86))
819575	31401336	In support of this theory, inhibition of KLF5 caused significant decreases in expression levels of intestinal- and EAC-associated genes, cell proliferation, cell migration, and colony formation.	('rat', 'Species', '10116', (149, 152))	('KLF5', 'Gene', (41, 45))	('decreases', 'NegReg', (65, 74))	('cell migration', 'CPA', (157, 171))	('cell proliferation', 'CPA', (137, 155))	('EAC-associated genes', 'Gene', (115, 135))	('colony formation', 'CPA', (177, 193))	('inhibition', 'Var', (27, 37))	('expression levels', 'MPA', (78, 95))	('rat', 'Species', '10116', (165, 168))	('EAC', 'Phenotype', 'HP:0011459', (115, 118))
819577	31401336	A previous high-throughput screening approach identified several novel and potent small molecular inhibitors of KLF5, such as Wortmannin, AG17, and AG879, which inhibit proliferation of colon cancer cell lines.	('rat', 'Species', '10116', (176, 179))	('colon cancer', 'Disease', (186, 198))	('small molecular', 'Var', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('proliferation', 'CPA', (169, 182))	('inhibit', 'NegReg', (161, 168))	('KLF5', 'Gene', (112, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (186, 198))	('Wortmannin', 'Chemical', 'MESH:D000077191', (126, 136))	('colon cancer', 'Disease', 'MESH:D015179', (186, 198))
819579	31401336	Moreover, studies have shown that metformin, an anti-type 2 diabetes drug, leads to KLF5 degradation.	('type 2 diabetes', 'Phenotype', 'HP:0005978', (53, 68))	('metformin', 'Var', (34, 43))	('KLF5 degradation', 'MPA', (84, 100))	('metformin', 'Chemical', 'MESH:D008687', (34, 43))	('diabetes', 'Disease', (60, 68))	('diabetes', 'Disease', 'MESH:D003920', (60, 68))
819581	31401336	One potential concern is that if metformin's KLF5-degrading effect is sufficient to affect EAC cells, it may also exert adverse effects on healthy epithelial cells in the GI tract (where KLF5 normally participates in GI epithelial maintenance).	('metformin', 'Chemical', 'MESH:D008687', (33, 42))	('KLF5-degrading', 'MPA', (45, 59))	('EAC', 'Disease', (91, 94))	('affect', 'Reg', (84, 90))	('metformin', 'Var', (33, 42))	('EAC', 'Phenotype', 'HP:0011459', (91, 94))
819583	31401336	Currently, numerous clinical trials are assessing metformin as an adjuvant to conventional chemotherapy in prostate, endometrial, breast, and pancreatic cancer; collectively, metformin has been shown to have a favorable effect on tumor markers, but additional studies and time are required to assess its effect on survival rates.	('tumor', 'Disease', (230, 235))	('metformin', 'Var', (175, 184))	('metformin', 'Chemical', 'MESH:D008687', (50, 59))	('rat', 'Species', '10116', (323, 326))	('pancreatic cancer', 'Disease', (142, 159))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('metformin', 'Chemical', 'MESH:D008687', (175, 184))	('pancreatic cancer', 'Disease', 'MESH:D010190', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (142, 159))
819584	31401336	In particular, GLI1, a canonically specific SHH pathway target gene, was significantly downregulated by KLF5 knockdown; moreover, GLI1 protein levels and nuclear localization both diminished with KLF5 knockdown.	('KLF5', 'Gene', (104, 108))	('protein levels', 'MPA', (135, 149))	('GLI1', 'Gene', (130, 134))	('GLI1', 'Gene', '2735', (15, 19))	('knockdown', 'Var', (109, 118))	('GLI1', 'Gene', (15, 19))	('nuclear localization', 'MPA', (154, 174))	('downregulated', 'NegReg', (87, 100))	('GLI1', 'Gene', '2735', (130, 134))	('diminished', 'NegReg', (180, 190))
819585	31401336	GLI1's mRNA and protein levels were lowered despite significantly increased SHH expression caused by KLF5 knockdown.	('lowered', 'NegReg', (36, 43))	('GLI1', 'Gene', (0, 4))	('increased', 'PosReg', (66, 75))	('KLF5', 'Gene', (101, 105))	('knockdown', 'Var', (106, 115))	('SHH expression', 'MPA', (76, 90))	('GLI1', 'Gene', '2735', (0, 4))
819591	31401336	Thus, while GLI1 expression and protein levels were downregulated in vitro by KLF5 knockdown, this finding may not be present at the tissue level, where stromal cell-derived BMP4 and SOX9 are key factors in BE and EAC development.	('EAC', 'Phenotype', 'HP:0011459', (214, 217))	('protein levels', 'MPA', (32, 46))	('BE', 'Phenotype', 'HP:0100580', (207, 209))	('SOX9', 'Gene', (183, 187))	('GLI1', 'Gene', '2735', (12, 16))	('downregulated', 'NegReg', (52, 65))	('SOX9', 'Gene', '6662', (183, 187))	('KLF5', 'Gene', (78, 82))	('GLI1', 'Gene', (12, 16))	('knockdown', 'Var', (83, 92))
819593	31401336	Secondly, knocking down KLF5 led to decreases in EAC-associated genes, cell proliferation levels, and cell migration rates.	('KLF5', 'Gene', (24, 28))	('rat', 'Species', '10116', (110, 113))	('knocking down', 'Var', (10, 23))	('rat', 'Species', '10116', (83, 86))	('rat', 'Species', '10116', (117, 120))	('decreases', 'NegReg', (36, 45))	('cell migration rates', 'CPA', (102, 122))	('EAC', 'Phenotype', 'HP:0011459', (49, 52))	('EAC-associated genes', 'Gene', (49, 69))	('cell proliferation', 'CPA', (71, 89))
819594	31401336	Thirdly, knockdown of KLF5 led to down-regulation of SHH pathway genes and GLI1 protein levels.	('knockdown', 'Var', (9, 18))	('SHH pathway genes', 'Gene', (53, 70))	('down-regulation', 'NegReg', (34, 49))	('GLI1', 'Gene', '2735', (75, 79))	('GLI1', 'Gene', (75, 79))	('KLF5', 'Gene', (22, 26))
819598	30863120	This meta-analysis aimed to evaluate the relationship between high levels of DBC1 and prognosis in tumor patients.	('tumor', 'Disease', (99, 104))	('patients', 'Species', '9606', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('DBC1', 'Gene', '57805', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('high', 'Var', (62, 66))	('DBC1', 'Gene', (77, 81))
819611	30863120	Multiple studies have reported that high levels of DBC1 are associated with worse prognosis of patients with various human tumors, including gastric carcinoma, breast carcinoma, colorectal cancer, esophageal cancer, diffuse large B cell lymphoma, sarcomas, clear cell renal cell carcinoma, ovarian carcinomas, hepatocellular carcinoma, and osteosarcoma.	('osteosarcoma', 'Disease', (340, 352))	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('osteosarcoma', 'Disease', 'MESH:D012516', (340, 352))	('colorectal cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (310, 334))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (290, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('esophageal cancer', 'Disease', (197, 214))	('ovarian carcinomas', 'Disease', (290, 308))	('breast carcinoma', 'Disease', 'MESH:D001943', (160, 176))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (257, 288))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (290, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('gastric carcinoma', 'Disease', 'MESH:D013274', (141, 158))	('hepatocellular carcinoma', 'Disease', (310, 334))	('B cell lymphoma', 'Disease', 'MESH:D016393', (230, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('gastric carcinoma', 'Disease', (141, 158))	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (141, 158))	('DBC1', 'Gene', (51, 55))	('human', 'Species', '9606', (117, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (298, 308))	('breast carcinoma', 'Phenotype', 'HP:0003002', (160, 176))	('osteosarcoma', 'Phenotype', 'HP:0002669', (340, 352))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (230, 245))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (257, 288))	('high levels', 'Var', (36, 47))	('sarcomas', 'Disease', 'MESH:D012509', (247, 255))	('breast carcinoma', 'Disease', (160, 176))	('lymphoma', 'Phenotype', 'HP:0002665', (237, 245))	('large B cell', 'Phenotype', 'HP:0005404', (224, 236))	('sarcomas', 'Phenotype', 'HP:0100242', (247, 255))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('associated', 'Reg', (60, 70))	('tumors', 'Disease', (123, 129))	('sarcomas', 'Disease', (247, 255))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (310, 334))	('B cell lymphoma', 'Disease', (230, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('DBC1', 'Gene', '57805', (51, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))	('clear cell renal cell carcinoma', 'Disease', (257, 288))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (268, 288))
819613	30863120	Studies have suggested that high DBC1 levels are associated with favorable outcome in patients with hepatocellular carcinoma, gastric cancer, and gallbladder carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('hepatocellular carcinoma', 'Disease', (100, 124))	('DBC1', 'Gene', '57805', (33, 37))	('gastric cancer', 'Disease', (126, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (146, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('DBC1', 'Gene', (33, 37))	('high', 'Var', (28, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('gallbladder carcinoma', 'Disease', (146, 167))	('patients', 'Species', '9606', (86, 94))
819617	30863120	We hypothesized that high levels of DBC1 would be linked to worse outcomes, with the implication that combined targeted strategies should be pursued for clinical development.	('linked', 'Reg', (50, 56))	('DBC1', 'Gene', '57805', (36, 40))	('DBC1', 'Gene', (36, 40))	('high levels', 'Var', (21, 32))
819628	30863120	The association between high levels of DBC1 and OS is illustrated in Figure 2.	('DBC1', 'Gene', (39, 43))	('DBC1', 'Gene', '57805', (39, 43))	('high levels', 'Var', (24, 35))
819631	30863120	The association between DBC1 overexpression and RFS is shown in Figure 3.	('overexpression', 'Var', (29, 43))	('RFS', 'Disease', (48, 51))	('DBC1', 'Gene', '57805', (24, 28))	('DBC1', 'Gene', (24, 28))
819632	30863120	The pooled analysis demonstrated that high levels of DBC1 were associated with poor survival outcome in various tumor patients.	('high levels', 'Var', (38, 49))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('patients', 'Species', '9606', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('DBC1', 'Gene', '57805', (53, 57))	('DBC1', 'Gene', (53, 57))	('survival outcome', 'CPA', (84, 100))	('poor', 'NegReg', (79, 83))
819801	26557912	DNA repair gene ERCC1 C118T polymorphism predicts sensitivity of recurrent esophageal cancer to radiochemotherapy in a Chinese population DNA repair gene polymorphisms could alter DNA repair capacity and therefore associate with tumor sensitivity to radiochemotherapy.	('polymorphism', 'Var', (28, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('C118T', 'Mutation', 'rs11615', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('C118T', 'Var', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('alter', 'Reg', (174, 179))	('polymorphisms', 'Var', (154, 167))	('associate with', 'Reg', (214, 228))	('tumor', 'Disease', (229, 234))	('DNA repair capacity', 'MPA', (180, 199))	('ERCC1', 'Gene', '2067', (16, 21))	('ERCC1', 'Gene', (16, 21))	('esophageal cancer', 'Disease', (75, 92))
819802	26557912	This study assessed excision repair cross-complementing group 1 (ERCC1) C118T and X-ray cross-complementing group 1 (XRCC1) G399A single-nucleotide polymorphisms in esophageal patients for an association with sensitivity to radiation and chemotherapy.	('excision repair cross-complementing group 1', 'Gene', (20, 63))	('patients', 'Species', '9606', (176, 184))	('X-ray cross-complementing group 1', 'Gene', '7515', (82, 115))	('ERCC1', 'Gene', (65, 70))	('G399A single-nucleotide polymorphisms', 'Var', (124, 161))	('association', 'Interaction', (192, 203))	('XRCC1', 'Gene', '7515', (117, 122))	('ERCC1', 'Gene', '2067', (65, 70))	('excision repair cross-complementing group 1', 'Gene', '2067', (20, 63))	('C118T', 'Mutation', 'rs11615', (72, 77))	('esophageal', 'Disease', (165, 175))	('X-ray cross-complementing group 1', 'Gene', (82, 115))	('G399A', 'Mutation', 'rs371169660', (124, 129))	('XRCC1', 'Gene', (117, 122))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (209, 233))	('C118T', 'Var', (72, 77))	('esophageal', 'Disease', 'MESH:D004941', (165, 175))
819803	26557912	Esophageal squamous cell carcinoma patients (n = 118) who relapsed after surgery were enrolled for assessment of ERCC1 C118T and XRCC1 G399A polymorphisms by direct DNA sequencing.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('Esophageal squamous cell carcinoma', 'Disease', (0, 34))	('ERCC1', 'Gene', '2067', (113, 118))	('XRCC1', 'Gene', (129, 134))	('C118T', 'Mutation', 'rs11615', (119, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('G399A', 'Mutation', 'rs371169660', (135, 140))	('C118T', 'Var', (119, 124))	('XRCC1', 'Gene', '7515', (129, 134))	('patients', 'Species', '9606', (35, 43))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (0, 34))	('ERCC1', 'Gene', (113, 118))	('G399A', 'Var', (135, 140))
819805	26557912	ERCC1 C118T was significantly associated with treatment response (C/T vs. C/C + T/T, odds ratio [OR] = 6.035, 95% confidence interval [CI]: 2.114-17.226, P = 0.001) after adjusting for other clinicopathological factors.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('C118T', 'Mutation', 'rs11615', (6, 11))	('treatment response', 'CPA', (46, 64))	('C118T', 'Var', (6, 11))	('associated with', 'Reg', (30, 45))
819806	26557912	Patients carrying the C/T genotype had significantly prolonged overall survival (OS) compared with C/C and T/T (median OS 43.00 vs. 27.00, P = 0.027).	('overall survival', 'MPA', (63, 79))	('Patients', 'Species', '9606', (0, 8))	('C/T', 'Var', (22, 25))	('prolonged', 'PosReg', (53, 62))
819809	26557912	ERCC1 C118T could be a predictive factor for the response to radiotherapy and chemotherapy, but not a prognostic factor for OS in esophageal cancer patients after surgery.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('C118T', 'Mutation', 'rs11615', (6, 11))	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('patients', 'Species', '9606', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('C118T', 'Var', (6, 11))	('esophageal cancer', 'Disease', (130, 147))
819817	26557912	Previous studies have shown that altered expression or functional single nucleotide polymorphisms (SNPs) of these two genes can influence the sensitivity of different human cancers to radiation and chemotherapy through aberrant messenger ribonucleic acid (mRNA) expression, mRNA stability or influencing interactions with other repair proteins.	('interactions', 'Interaction', (304, 316))	('mRNA stability', 'MPA', (274, 288))	('single nucleotide polymorphisms', 'Var', (66, 97))	('influencing', 'Reg', (292, 303))	('influence', 'Reg', (128, 137))	('cancers to radiation', 'Disease', (173, 193))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('sensitivity', 'MPA', (142, 153))	('cancers to radiation', 'Disease', 'MESH:D004194', (173, 193))	('human', 'Species', '9606', (167, 172))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('aberrant', 'Reg', (219, 227))
819818	26557912	Other studies have demonstrated that ERCC1 C118T and XRCC1 G399A polymorphisms were significantly associated with the outcome and survival of lung and colorectal cancer and head and neck SCC patients who were treated with cisplatin-based chemotherapy and radiotherapy.	('SCC', 'Gene', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (151, 168))	('associated with', 'Reg', (98, 113))	('XRCC1', 'Gene', (53, 58))	('G399A', 'Mutation', 'rs371169660', (59, 64))	('lung', 'Disease', (142, 146))	('colorectal cancer', 'Disease', (151, 168))	('cisplatin', 'Chemical', 'MESH:D002945', (222, 231))	('C118T', 'Mutation', 'rs11615', (43, 48))	('XRCC1', 'Gene', '7515', (53, 58))	('SCC', 'Phenotype', 'HP:0002860', (187, 190))	('ERCC1', 'Gene', '2067', (37, 42))	('G399A', 'Var', (59, 64))	('patients', 'Species', '9606', (191, 199))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('C118T', 'Var', (43, 48))	('SCC', 'Gene', '6317', (187, 190))	('ERCC1', 'Gene', (37, 42))
819820	26557912	Indeed, several studies have reported an association between the polymorphisms of DNA repair genes and sensitivity of cancer patients to neoadjuvant radiochemotherapy in Caucasian populations.	('cancer', 'Disease', (118, 124))	('DNA repair genes', 'Gene', (82, 98))	('sensitivity', 'Disease', (103, 114))	('polymorphisms', 'Var', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('patients', 'Species', '9606', (125, 133))
819822	26557912	We therefore conducted a retrospective study to analyze the association between ERCC1 C118T and XRCC1 Arg399Gln polymorphisms and sensitivity to radiotherapy and chemotherapy in Chinese patients with recurrent EC.	('patients', 'Species', '9606', (186, 194))	('XRCC1', 'Gene', '7515', (96, 101))	('C118T', 'Mutation', 'rs11615', (86, 91))	('XRCC1', 'Gene', (96, 101))	('ERCC1', 'Gene', (80, 85))	('ERCC1', 'Gene', '2067', (80, 85))	('Arg399Gln', 'Chemical', '-', (102, 111))	('Arg399Gln', 'Var', (102, 111))	('C118T', 'Var', (86, 91))	('association', 'Interaction', (60, 71))
819837	26557912	The ERCC1 C118T primer sequences were 5'-AGGAGGGCCCTGTGGTTATC-3' and 5'-AGGCTTCTCATAGAAC -3', and XRCC1 G399A primer sequences were 5'-GATCACACCTAACTGGCATCTTC-3' and 5'-CTGGGACCACCTGTGTTC-3'.	('ERCC1', 'Gene', '2067', (4, 9))	('ERCC1', 'Gene', (4, 9))	('XRCC1', 'Gene', (98, 103))	('C118T', 'Mutation', 'rs11615', (10, 15))	('G399A', 'Mutation', 'rs371169660', (104, 109))	('XRCC1', 'Gene', '7515', (98, 103))	('C118T', 'Var', (10, 15))
819840	26557912	A Kaplan-Meier curve and log-rank test were used to compare the disease-free survival (DFS) and overall survival (OS) in different clinicopathological characteristics and genotypes of ERCC1 C118T and XRCC1 Arg399Gln polymorphisms.	('C118T', 'Var', (190, 195))	('Arg399Gln', 'Var', (206, 215))	('Arg399Gln', 'Chemical', '-', (206, 215))	('XRCC1', 'Gene', '7515', (200, 205))	('ERCC1', 'Gene', (184, 189))	('ERCC1', 'Gene', '2067', (184, 189))	('C118T', 'Mutation', 'rs11615', (190, 195))	('XRCC1', 'Gene', (200, 205))
819846	26557912	Of the 118 patients, 104 were analyzed for ERCC1 C118T polymorphisms and 73 for XRCC1 G399A, but only 59 patients were genotyped for both gene polymorphisms.	('patients', 'Species', '9606', (105, 113))	('C118T', 'Mutation', 'rs11615', (49, 54))	('XRCC1', 'Gene', '7515', (80, 85))	('XRCC1', 'Gene', (80, 85))	('G399A', 'Mutation', 'rs371169660', (86, 91))	('polymorphisms', 'Var', (55, 68))	('C118T polymorphisms', 'Var', (49, 68))	('patients', 'Species', '9606', (11, 19))	('G399A', 'Var', (86, 91))	('ERCC1', 'Gene', '2067', (43, 48))	('ERCC1', 'Gene', (43, 48))
819848	26557912	Distribution of ERCC1 C118T and XRCC1 G399A genotypes and alleles in patients with EC are listed in Table 2.	('C118T', 'Mutation', 'rs11615', (22, 27))	('G399A', 'Mutation', 'rs371169660', (38, 43))	('C118T', 'Var', (22, 27))	('patients', 'Species', '9606', (69, 77))	('XRCC1', 'Gene', '7515', (32, 37))	('ERCC1', 'Gene', '2067', (16, 21))	('ERCC1', 'Gene', (16, 21))	('XRCC1', 'Gene', (32, 37))
819850	26557912	The ERCC1 C118T polymorphism was significantly associated with treatment response (chi2 = 13.410, P = 0.001).	('ERCC1', 'Gene', '2067', (4, 9))	('ERCC1', 'Gene', (4, 9))	('C118T', 'Mutation', 'rs11615', (10, 15))	('treatment response', 'CPA', (63, 81))	('associated', 'Reg', (47, 57))	('C118T', 'Var', (10, 15))
819851	26557912	Grade III-IV adverse events were more frequently observed with increasing variant T alleles of ERCC1 C118T.	('C118T', 'Mutation', 'rs11615', (101, 106))	('ERCC1', 'Gene', '2067', (95, 100))	('ERCC1', 'Gene', (95, 100))	('C118T', 'Var', (101, 106))
819852	26557912	A significantly lower incidence of lymph node metastasis was associated with increasing variant alleles of the XRCC1 Arg399Gln polymorphism (chi2 = 8.028, P = 0.015).	('lymph node metastasis', 'CPA', (35, 56))	('Arg399Gln', 'Var', (117, 126))	('lower incidence of lymph node metastasis', 'Phenotype', 'HP:0002732', (16, 56))	('Arg399Gln', 'Chemical', '-', (117, 126))	('XRCC1', 'Gene', '7515', (111, 116))	('XRCC1', 'Gene', (111, 116))	('lower', 'NegReg', (16, 21))
819853	26557912	No statistically significant association was observed between ERCC1 C118T or XRCC1 Arg399Gln genotypes and other clinicopathological characteristics.	('C118T', 'Mutation', 'rs11615', (68, 73))	('Arg399Gln', 'Var', (83, 92))	('XRCC1', 'Gene', (77, 82))	('ERCC1', 'Gene', (62, 67))	('Arg399Gln', 'Chemical', '-', (83, 92))	('ERCC1', 'Gene', '2067', (62, 67))	('C118T', 'Var', (68, 73))	('XRCC1', 'Gene', '7515', (77, 82))
819856	26557912	Multivariate logistic regression analysis showed that ERCC1 C118T was significantly associated with treatment response (C/T vs. C/C + T/T, OR = 6.035, 95% CI: 2.114-17.226, P = 0.001) after adjusting for other clinicopathological factors.	('associated with', 'Reg', (84, 99))	('C118T', 'Var', (60, 65))	('C118T', 'Mutation', 'rs11615', (60, 65))	('treatment response', 'CPA', (100, 118))	('ERCC1', 'Gene', '2067', (54, 59))	('ERCC1', 'Gene', (54, 59))
819858	26557912	However, in 73 patients, there was no significant association between the XRCC1 Arg399Gln polymorphism and treatment response in univariate or multivariate analyses.	('XRCC1', 'Gene', (74, 79))	('patients', 'Species', '9606', (15, 23))	('Arg399Gln', 'Var', (80, 89))	('XRCC1', 'Gene', '7515', (74, 79))	('Arg399Gln', 'Chemical', '-', (80, 89))
819859	26557912	Furthermore, in a subset of 59 patients, after adjusting for other clinicopathological factors and the XRCC1 Arg399Gln polymorphism, ERCC1 C118T was the only predictive factor for response (C/T vs. C/C + T/T, OR = 7.950, 95% CI: 1.769-35.736, P = 0.007).	('response', 'Disease', (180, 188))	('XRCC1', 'Gene', '7515', (103, 108))	('C118T', 'Var', (139, 144))	('C118T', 'Mutation', 'rs11615', (139, 144))	('patients', 'Species', '9606', (31, 39))	('XRCC1', 'Gene', (103, 108))	('ERCC1', 'Gene', '2067', (133, 138))	('ERCC1', 'Gene', (133, 138))	('Arg399Gln', 'Var', (109, 118))	('Arg399Gln', 'Chemical', '-', (109, 118))
819861	26557912	No significant association was observed between the ERCC1 C118T polymorphism and DFS; however, a longer DFS tended to correlate with patients carrying at least one variant allele of XRCC1 Arg399Gln (mDFS: Arg/Arg vs Arg/Gln+Gln/Gln 11.00 vs. 19.00, P = 0.061) (Figs 1, 2).	('Gln', 'Chemical', 'MESH:D005973', (224, 227))	('Arg399Gln', 'Chemical', '-', (188, 197))	('XRCC1', 'Gene', '7515', (182, 187))	('C118T', 'Mutation', 'rs11615', (58, 63))	('Gln', 'Chemical', 'MESH:D005973', (228, 231))	('ERCC1', 'Gene', '2067', (52, 57))	('ERCC1', 'Gene', (52, 57))	('patients', 'Species', '9606', (133, 141))	('Gln', 'Chemical', 'MESH:D005973', (194, 197))	('Arg', 'Chemical', 'MESH:D001120', (205, 208))	('XRCC1', 'Gene', (182, 187))	('Arg', 'Chemical', 'MESH:D001120', (209, 212))	('C118T', 'Var', (58, 63))	('Arg', 'Chemical', 'MESH:D001120', (188, 191))	('Gln', 'Chemical', 'MESH:D005973', (220, 223))	('Arg399Gln', 'Var', (188, 197))	('Arg', 'Chemical', 'MESH:D001120', (216, 219))
819862	26557912	Overall survival was related to lymph node metastasis, response, and the ERCC1 C118T polymorphism, although it was less obvious in the latter.	('C118T', 'Mutation', 'rs11615', (79, 84))	('lymph node metastasis', 'CPA', (32, 53))	('ERCC1', 'Gene', (73, 78))	('ERCC1', 'Gene', '2067', (73, 78))	('response', 'CPA', (55, 63))	('Overall survival', 'CPA', (0, 16))	('C118T', 'Var', (79, 84))
819864	26557912	Suggesting an association of ERCC1 C118T and response, patients carrying the C/T genotype had significantly prolonged OS compared with C/C and T/T (median OS 43 vs. 27, P = 0.027) (Fig 4).	('C118T', 'Var', (35, 40))	('C/T', 'Var', (77, 80))	('C118T', 'Mutation', 'rs11615', (35, 40))	('prolonged', 'PosReg', (108, 117))	('ERCC1', 'Gene', '2067', (29, 34))	('ERCC1', 'Gene', (29, 34))	('patients', 'Species', '9606', (55, 63))
819869	26557912	Patients with ERCC1 T/T experienced significantly more frequent grade III and IV adverse events (OR = 6.857, 95% CI 1.389-33.853, P = 0.018) compared with C/C.	('T/T', 'Var', (20, 23))	('grade', 'Disease', (64, 69))	('ERCC1', 'Gene', '2067', (14, 19))	('ERCC1', 'Gene', (14, 19))	('IV adverse events', 'CPA', (78, 95))	('Patients', 'Species', '9606', (0, 8))
819873	26557912	Neoadjuvant chemotherapy and ERCC1 C118T SNPs were significantly associated with treatment response; however, there was no association of XRCC1 Arg399Gln genotypes with treatment response.	('Arg399Gln', 'Var', (144, 153))	('C118T', 'Var', (35, 40))	('Arg399Gln', 'Chemical', '-', (144, 153))	('XRCC1', 'Gene', '7515', (138, 143))	('treatment response', 'CPA', (81, 99))	('C118T', 'Mutation', 'rs11615', (35, 40))	('associated', 'Reg', (65, 75))	('XRCC1', 'Gene', (138, 143))	('ERCC1', 'Gene', '2067', (29, 34))	('ERCC1', 'Gene', (29, 34))
819874	26557912	ERCC1 C118T SNP was associated with OS in univariate analysis but not in multivariate Cox regression.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('C118T', 'Mutation', 'rs11615', (6, 11))	('Cox', 'Gene', '1351', (86, 89))	('Cox', 'Gene', (86, 89))	('C118T SNP', 'Var', (6, 15))
819875	26557912	The data from this study demonstrates that ERCC1 C118T could be a predictive factor for the response to radiotherapy and chemotherapy, but not a prognostic factor for OS in EC patients after surgery.	('C118T', 'Var', (49, 54))	('patients', 'Species', '9606', (176, 184))	('C118T', 'Mutation', 'rs11615', (49, 54))	('ERCC1', 'Gene', '2067', (43, 48))	('ERCC1', 'Gene', (43, 48))
819876	26557912	To date, ERCC1 C118T and C8092A have been extensively studied in different cancers.	('C8092A', 'Mutation', 'rs3212986', (25, 31))	('C118T', 'Var', (15, 20))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('ERCC1', 'Gene', (9, 14))	('C8092A', 'Var', (25, 31))	('ERCC1', 'Gene', '2067', (9, 14))	('C118T', 'Mutation', 'rs11615', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
819879	26557912	Our data is consistent with that reported by Warnecke-Eberz et al., showing an association between the ERCC1 118 C/T polymorphism and response to neoadjuvant radiochemotherapy in patients with resected EC.	('ERCC1', 'Gene', (103, 108))	('polymorphism', 'Var', (117, 129))	('ERCC1', 'Gene', '2067', (103, 108))	('association', 'Interaction', (79, 90))	('118 C/T', 'Mutation', 'rs11615', (109, 116))	('response', 'MPA', (134, 142))	('patients', 'Species', '9606', (179, 187))
819881	26557912	suggested that there was no association between ERCC1 C118T and a response to radiotherapy or chemotherapy for preoperative neoadjuvant radiochemotherapy of esophageal adenocarcinoma, but in contrast, the expression of ERCC1 mRNA in tumor tissues was indicated as a prognostic factor.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('ERCC1', 'Gene', (219, 224))	('tumor', 'Disease', (233, 238))	('ERCC1', 'Gene', (48, 53))	('ERCC1', 'Gene', '2067', (48, 53))	('ERCC1', 'Gene', '2067', (219, 224))	('C118T', 'Var', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal adenocarcinoma', 'Disease', (157, 182))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (157, 182))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (157, 182))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('C118T', 'Mutation', 'rs11615', (54, 59))
819882	26557912	reported no association between the ERCC1 118 C/T genotype and OS or PFS in locally advanced EC patients after receiving adjuvant chemotherapy.	('ERCC1', 'Gene', '2067', (36, 41))	('PFS', 'Disease', (69, 72))	('C/T', 'Var', (46, 49))	('locally advanced EC', 'Disease', (76, 95))	('patients', 'Species', '9606', (96, 104))	('ERCC1', 'Gene', (36, 41))	('118 C/T', 'Mutation', 'rs11615', (42, 49))
819884	26557912	demonstrated that ERCC1 C8092A SNP was significantly associated with a response to first-line chemotherapy of advanced esophageal carcinoma.	('C8092A SNP', 'Var', (24, 34))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (119, 139))	('C8092A', 'Mutation', 'rs3212986', (24, 30))	('ERCC1', 'Gene', (18, 23))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (119, 139))	('ERCC1', 'Gene', '2067', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('associated with', 'Reg', (53, 68))	('esophageal carcinoma', 'Disease', (119, 139))
819887	26557912	This data is consistent with previous studies detecting tumor response through a single repair gene polymorphism.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('polymorphism', 'Var', (100, 112))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
819888	26557912	On the other hand, there was only a weak association between the ERCC1 C118T genotype and OS, as underlined in multivariate analysis.	('ERCC1', 'Gene', '2067', (65, 70))	('ERCC1', 'Gene', (65, 70))	('C118T', 'Mutation', 'rs11615', (71, 76))	('C118T', 'Var', (71, 76))
819889	26557912	A previous study demonstrated that the pathology complete response (pCR) was significantly associated with XRCC1 G399A in esophageal adenocarcinoma after neoadjuvant radiochemotherapy.	('G399A', 'Mutation', 'rs371169660', (113, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('XRCC1', 'Gene', '7515', (107, 112))	('CR', 'Chemical', '-', (69, 71))	('esophageal adenocarcinoma', 'Disease', (122, 147))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (122, 147))	('XRCC1', 'Gene', (107, 112))	('G399A', 'Var', (113, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (122, 147))
819890	26557912	Individuals with variant alleles (GA+AA) had significantly poorer pCR compared to wild-type carriers (OR = 2.75, 95% CI: 1.14-6.12).	('poorer', 'NegReg', (59, 65))	('pCR', 'Disease', (66, 69))	('variant', 'Var', (17, 24))	('CR', 'Chemical', '-', (67, 69))
819891	26557912	Another biomarker study, the Eastern Cooperative Oncology Group trial E1201, showed that only 6% of subjects with the variant allele (GA+AA) experienced a pCR compared to 28% of subjects with the GG genotype (OR = 5.37, P = 0.062).	('pCR', 'Disease', (155, 158))	('Oncology', 'Phenotype', 'HP:0002664', (49, 57))	('variant', 'Var', (118, 125))	('CR', 'Chemical', '-', (156, 158))
819892	26557912	Although our study did not show an association between the XRCC1 Arg399Gln polymorphism and treatment response with OS (but an agreement with involved nodes), we did determine that patients carrying Arg/Arg had shorter DFS compared with other genotypes.	('Arg', 'Chemical', 'MESH:D001120', (203, 206))	('XRCC1', 'Gene', '7515', (59, 64))	('Arg', 'Chemical', 'MESH:D001120', (65, 68))	('Arg399Gln', 'Var', (65, 74))	('Arg399Gln', 'Chemical', '-', (65, 74))	('Arg/Arg', 'Var', (199, 206))	('DFS', 'MPA', (219, 222))	('XRCC1', 'Gene', (59, 64))	('patients', 'Species', '9606', (181, 189))	('shorter', 'NegReg', (211, 218))	('Arg', 'Chemical', 'MESH:D001120', (199, 202))
819895	26557912	For example, a recent study showed that the ERCC1 C118T polymorphism did not lead to altered cellular ERCC1 protein expression, suggesting that other causative variants or haplotypes linked to ERCC1 C118T might account for this clinical association.	('ERCC1', 'Gene', (44, 49))	('C118T', 'Mutation', 'rs11615', (199, 204))	('C118T', 'Var', (50, 55))	('C118T', 'Var', (199, 204))	('ERCC1', 'Gene', '2067', (44, 49))	('ERCC1', 'Gene', (193, 198))	('C118T', 'Mutation', 'rs11615', (50, 55))	('ERCC1', 'Gene', '2067', (193, 198))	('ERCC1', 'Gene', '2067', (102, 107))	('ERCC1', 'Gene', (102, 107))
819897	26557912	However, there was no association between ERCC1 and XRCC1 polymorphisms and toxicity.	('XRCC1', 'Gene', '7515', (52, 57))	('ERCC1', 'Gene', '2067', (42, 47))	('ERCC1', 'Gene', (42, 47))	('polymorphisms', 'Var', (58, 71))	('toxicity', 'Disease', 'MESH:D064420', (76, 84))	('toxicity', 'Disease', (76, 84))	('XRCC1', 'Gene', (52, 57))	('association', 'Interaction', (22, 33))
819905	26557912	However, to the best of our knowledge, this is the first study that has explored an association between the ERCC1 C118T polymorphism and treatment outcome in recurrent EC in a Chinese population.	('C118T', 'Var', (114, 119))	('recurrent EC', 'Disease', (158, 170))	('ERCC1', 'Gene', '2067', (108, 113))	('ERCC1', 'Gene', (108, 113))	('C118T', 'Mutation', 'rs11615', (114, 119))
819908	24834254	Lesions such as an oesophageal tumor and external pressure effect from a lung tumor or aberrant vessel can lead to mechanical dysphagia.	('mechanical dysphagia', 'Disease', (115, 135))	('lead to', 'Reg', (107, 114))	('oesophageal tumor', 'Disease', 'MESH:D005764', (19, 36))	('lung tumor', 'Disease', 'MESH:D008175', (73, 83))	('dysphagia', 'Phenotype', 'HP:0002015', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mechanical dysphagia', 'Disease', 'MESH:D003680', (115, 135))	('lung tumor', 'Phenotype', 'HP:0100526', (73, 83))	('aberrant', 'Var', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('oesophageal tumor', 'Disease', (19, 36))	('oesophageal tumor', 'Phenotype', 'HP:0100751', (19, 36))	('lung tumor', 'Disease', (73, 83))	('external pressure effect', 'MPA', (41, 65))
819943	21666724	Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification.	('UHRF2', 'Gene', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('Knocking down', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('growth', 'CPA', (45, 51))	('UHRF2', 'Gene', '115426', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('p24', 'Gene', '10959', (94, 97))	('p24', 'Gene', (94, 97))	('breast cancer', 'Disease', (55, 68))	('inhibited', 'NegReg', (31, 40))
819947	21666724	Cancer results from an accumulation of genetic and epigenetic aberrations.	('genetic', 'Var', (39, 46))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('epigenetic aberrations', 'Var', (51, 73))
471310	21666724	Genetic and epigenetic alterations in cancer cells interact directly and indirectly.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('epigenetic alterations', 'Var', (12, 34))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('interact', 'Reg', (51, 59))	('cancer', 'Disease', (38, 44))
819948	21666724	For example, a genetic alteration in the gene encoding an 'epigenetic regulator' can lead to changes within the histone code and DNA methylation, which are subsequently involved in tumorigenesis in multiple tumor types.	('involved', 'Reg', (169, 177))	('lead to changes', 'Reg', (85, 100))	('tumor', 'Disease', (181, 186))	('DNA methylation', 'MPA', (129, 144))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', (207, 212))	('histone code', 'MPA', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('genetic alteration', 'Var', (15, 33))
819949	21666724	Identification and characterization of genetic and epigenetic aberrations, as well as their interconnections, will provide important insights into the pathogenesis of cancer.	('genetic', 'Var', (39, 46))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('epigenetic aberrations', 'Var', (51, 73))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
819962	21666724	Copy number increases at the 9p24 region mostly occurred in small-cell lung, breast and esophageal squamous cancers.	('p24', 'Gene', (30, 33))	('occurred', 'Reg', (48, 56))	('Copy number increases', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('small-cell lung', 'Disease', (60, 75))	('p24', 'Gene', '10959', (30, 33))	('breast and esophageal squamous cancers', 'Disease', 'MESH:D004938', (77, 115))
819967	21666724	Of note, we found that the centromeric boundary of the 9p24 amplicon in KYSE150 cells is located within the coding region of a protein tyrosine phosphatase, receptor type, D (PTPRD) gene, resulting in amplification of the C-terminal region, but deletion of the N-terminal region of the gene (Supplementary Table 1A and Supplementary Figure S2).	('deletion', 'Var', (245, 253))	('C-terminal region', 'MPA', (222, 239))	('PTPRD', 'Gene', (175, 180))	('PTPRD', 'Gene', '5789', (175, 180))	('amplification', 'PosReg', (201, 214))	('p24', 'Gene', '10959', (56, 59))	('protein tyrosine phosphatase, receptor type, D', 'Gene', '5789', (127, 173))	('p24', 'Gene', (56, 59))
819970	21666724	As shown in supplementary Figure S4, compared with the control cells that do not have 9p24 amplification, KYSE150 cells had an elevated copy number of PTPRD intron 8-exon 9, whereas the copy number of PTPRD intron 7-exon 8 in KYSE150 was lower than that of the control, implying that the amplification/deletion break point is located in this region.	('copy number', 'MPA', (136, 147))	('KYSE150', 'Var', (106, 113))	('PTPRD', 'Gene', '5789', (151, 156))	('PTPRD', 'Gene', (151, 156))	('elevated', 'PosReg', (127, 135))	('copy', 'MPA', (186, 190))	('p24', 'Gene', '10959', (87, 90))	('p24', 'Gene', (87, 90))	('PTPRD', 'Gene', '5789', (201, 206))	('PTPRD', 'Gene', (201, 206))
819977	21666724	Accumulated evidence suggests that the common amplicons occurring in breast and other cancers contain multiple oncogenes that could have a role in cancer initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('contain', 'Reg', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast', 'Disease', (69, 75))	('amplicons', 'Var', (46, 55))	('cancer initiation', 'Disease', 'MESH:D009369', (147, 164))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancer initiation', 'Disease', (147, 164))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('oncogenes', 'Gene', (111, 120))
819988	21666724	We therefore sought to examine the biological effect of UHRF2 knockdown on the proliferation of breast cancer cells with 9p24 amplification.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('UHRF2', 'Gene', (56, 61))	('p24', 'Gene', '10959', (122, 125))	('p24', 'Gene', (122, 125))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('UHRF2', 'Gene', '115426', (56, 61))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('knockdown', 'Var', (62, 71))
819995	21666724	Knocking down UHRF2 inhibited the growth of HCC1954 and HCC70 cells by approximate 50%, but had only a minor effect on SUM-52, SUM-102 and MCF10A cells (P<0.01) (Figures 3b and c).	('UHRF2', 'Gene', (14, 19))	('Knocking down', 'Var', (0, 13))	('MCF10A', 'CellLine', 'CVCL:0598', (139, 145))	('growth', 'MPA', (34, 40))	('UHRF2', 'Gene', '115426', (14, 19))	('HCC1954', 'CellLine', 'CVCL:1259', (44, 51))	('inhibited', 'NegReg', (20, 29))
819996	21666724	The inhibition of HCC1954 cell growth by knockdown of UHRF2 was reproduced with the UHRF2 shRNA#1 (data no shown).	('HCC1954 cell growth', 'CPA', (18, 37))	('HCC1954', 'CellLine', 'CVCL:1259', (18, 25))	('UHRF2', 'Gene', '115426', (54, 59))	('inhibition', 'NegReg', (4, 14))	('UHRF2', 'Gene', (84, 89))	('UHRF2', 'Gene', (54, 59))	('knockdown', 'Var', (41, 50))	('UHRF2', 'Gene', '115426', (84, 89))
819997	21666724	Thus, UHRF2 knockdown has a more profound growth inhibition effect on cells with UHRF2 gene amplification than in cells without the amplification.	('UHRF2', 'Gene', '115426', (81, 86))	('UHRF2', 'Gene', (6, 11))	('UHRF2', 'Gene', '115426', (6, 11))	('gene amplification', 'Var', (87, 105))	('growth', 'MPA', (42, 48))	('UHRF2', 'Gene', (81, 86))
820006	21666724	Knocking down UHRF2 affects the expression level of p21Waf1/Cip1 in lung cancer cells.	('UHRF2', 'Gene', (14, 19))	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('Cip1', 'Gene', (60, 64))	('expression level', 'MPA', (32, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('UHRF2', 'Gene', '115426', (14, 19))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('affects', 'Reg', (20, 27))	('Knocking', 'Var', (0, 8))	('Cip1', 'Gene', '1026', (60, 64))
820008	21666724	As shown in Figures 5a and b, UHRF2 knockdown resulted in increased expression of p21Waf1/Cip1 at both the mRNA and protein levels.	('Cip1', 'Gene', (90, 94))	('increased', 'PosReg', (58, 67))	('expression', 'MPA', (68, 78))	('UHRF2', 'Gene', '115426', (30, 35))	('knockdown', 'Var', (36, 45))	('Cip1', 'Gene', '1026', (90, 94))	('UHRF2', 'Gene', (30, 35))
820010	21666724	However, HCC1954 cells harbor an inactivating mutation (Tyr163 Cys163) in the p53 gene.	('Cys163', 'Chemical', '-', (63, 69))	('HCC1954', 'CellLine', 'CVCL:1259', (9, 16))	('Tyr163', 'Chemical', '-', (56, 62))	('p53', 'Gene', (78, 81))	('Tyr163 Cys163', 'Var', (56, 69))	('p53', 'Gene', '7157', (78, 81))
820017	21666724	These data suggest that amplification and overexpression of UHRF2 suppresses the expression of tumor suppressor genes in cancer cells, which may explain its growth-promoting capability.	('UHRF2', 'Gene', '115426', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('amplification', 'Var', (24, 37))	('suppresses', 'NegReg', (66, 76))	('overexpression', 'PosReg', (42, 56))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('UHRF2', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', (121, 127))	('expression', 'MPA', (81, 91))
820022	21666724	We identified four genes, GASC1, UHRF2, KIAA1432 and C9orf123, that were overexpressed in association with copy number increase at the P<0.01 level (see Table 1).	('copy number increase', 'Var', (107, 127))	('KIAA1432', 'Gene', (40, 48))	('KIAA1432', 'Gene', '57589', (40, 48))	('C9orf123', 'Gene', (53, 61))	('overexpressed', 'PosReg', (73, 86))	('GASC1', 'Gene', (26, 31))	('C9orf123', 'Gene', '90871', (53, 61))	('UHRF2', 'Gene', (33, 38))	('GASC1', 'Gene', '23081', (26, 31))	('UHRF2', 'Gene', '115426', (33, 38))
820031	21666724	By contrast, the PTPRD gene, likely inactivated by partial deletion and/or rearrangement, is increasingly thought to be a tumor suppressor gene.	('partial deletion', 'Var', (51, 67))	('PTPRD', 'Gene', '5789', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('PTPRD', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('rearrangement', 'Var', (75, 88))
820032	21666724	Recent studies indicate that inactivation of PTPRD by gene deletion or mutation contributes to the pathogenesis of a wide range of human cancers, including colon, lung, glioblastoma and melanoma.	('colon', 'Disease', 'MESH:D015179', (156, 161))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('inactivation', 'Var', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colon', 'Disease', (156, 161))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('contributes', 'Reg', (80, 91))	('glioblastoma', 'Disease', 'MESH:D005909', (169, 181))	('PTPRD', 'Gene', (45, 50))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('gene deletion', 'Var', (54, 67))	('glioblastoma', 'Disease', (169, 181))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('mutation', 'Var', (71, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('PTPRD', 'Gene', '5789', (45, 50))	('human', 'Species', '9606', (131, 136))	('lung', 'Disease', (163, 167))
820043	21666724	Recent studies demonstrated that UHRF1 has the ability to bind hemi-methylated DNA and methylated H3K9 through its SRA domain and tudor domain, respectively.	('UHRF1', 'Gene', (33, 38))	('bind', 'Interaction', (58, 62))	('UHRF1', 'Gene', '29128', (33, 38))	('ability', 'MPA', (47, 54))	('H3K9', 'Protein', (98, 102))	('methylated', 'Var', (87, 97))
820045	21666724	Interestingly, an unbiased proteomic screen for binding proteins to modified lysines on histone H3 also determined that UHRF2 interacts with dimethylated H3K9 peptide.	('UHRF2', 'Gene', '115426', (120, 125))	('dimethylated', 'MPA', (141, 153))	('modified', 'Var', (68, 76))	('H3K9 peptide', 'Protein', (154, 166))	('lysines', 'Chemical', 'MESH:D008239', (77, 84))	('interacts', 'Interaction', (126, 135))	('UHRF2', 'Gene', (120, 125))
820050	21666724	They revealed that within an approximately 3.5-Mb minimal common region of copy number gain, 10 genes (JAK2, C9orf46, CD274, PDCD1LG2, KIAA1432, KIAA2026, RANBP6, UHRF2, GLDC and GASC1) were upregulated in expression in association with gene amplification.	('KIAA2026', 'Gene', '158358', (145, 153))	('JAK2', 'Gene', '3717', (103, 107))	('PDCD1LG2', 'Gene', (125, 133))	('RANBP6', 'Gene', (155, 161))	('KIAA1432', 'Gene', '57589', (135, 143))	('RANBP6', 'Gene', '26953', (155, 161))	('GLDC', 'Gene', '2731', (170, 174))	('gene amplification', 'Var', (237, 255))	('CD274', 'Gene', (118, 123))	('UHRF2', 'Gene', (163, 168))	('GASC1', 'Gene', (179, 184))	('C9orf46', 'Gene', '55848', (109, 116))	('UHRF2', 'Gene', '115426', (163, 168))	('JAK2', 'Gene', (103, 107))	('KIAA2026', 'Gene', (145, 153))	('gain', 'PosReg', (87, 91))	('copy', 'Var', (75, 79))	('expression', 'MPA', (206, 216))	('upregulated', 'PosReg', (191, 202))	('KIAA1432', 'Gene', (135, 143))	('PDCD1LG2', 'Gene', '80380', (125, 133))	('C9orf46', 'Gene', (109, 116))	('CD274', 'Gene', '29126', (118, 123))	('GLDC', 'Gene', (170, 174))	('GASC1', 'Gene', '23081', (179, 184))
820052	21666724	Their data and our studies share in common the observation that three genes, GASC1, UHRF2 and KIAA1432, are upregulated via gene copy number gains, and that GASC1 is an important gene for the proliferation and survival of cancer cells with 9p24 amplification.	('KIAA1432', 'Gene', '57589', (94, 102))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('p24', 'Gene', '10959', (241, 244))	('p24', 'Gene', (241, 244))	('cancer', 'Disease', (222, 228))	('UHRF2', 'Gene', (84, 89))	('GASC1', 'Gene', (157, 162))	('GASC1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('GASC1', 'Gene', '23081', (157, 162))	('gene copy number gains', 'Var', (124, 146))	('GASC1', 'Gene', '23081', (77, 82))	('upregulated', 'PosReg', (108, 119))	('UHRF2', 'Gene', '115426', (84, 89))	('KIAA1432', 'Gene', (94, 102))
820060	21666724	Array data have been posted at the NCBI GEO database (GEO accession: GSE28989, GSM718287, GSM718288, GSM718289, GSM718290).	('GSM718290', 'Chemical', '-', (112, 121))	('GSM718289', 'Var', (101, 110))	('GSM718288', 'Chemical', '-', (90, 99))	('GSM718288', 'Var', (90, 99))	('GSM718290', 'Var', (112, 121))	('GSM718287', 'Var', (79, 88))	('GSM718289', 'Chemical', '-', (101, 110))	('GSM718287', 'Chemical', '-', (79, 88))
820062	21666724	UHRF2 knockdown was achieved by using the Expression Arrest GIPZ lentiviral shRNAmir system (OpenBiosystems).	('knockdown', 'Var', (6, 15))	('UHRF2', 'Gene', (0, 5))	('UHRF2', 'Gene', '115426', (0, 5))
820101	22359468	In our previous study, QGC was more potent than quercetin on inhibition of experimental reflux esophagitis and indomethacin-induced gastritis in rats.	('reflux esophagitis', 'Disease', (88, 106))	('reflux esophagitis', 'Disease', 'MESH:D005764', (88, 106))	('gastritis', 'Disease', (132, 141))	('QGC', 'Chemical', 'MESH:C443401', (23, 26))	('esophagitis', 'Phenotype', 'HP:0100633', (95, 106))	('indomethacin', 'Chemical', 'MESH:D007213', (111, 123))	('rats', 'Species', '10116', (145, 149))	('quercetin', 'Chemical', 'MESH:D011794', (48, 57))	('gastritis', 'Disease', 'MESH:D005756', (132, 141))	('QGC', 'Var', (23, 26))	('gastritis', 'Phenotype', 'HP:0005263', (132, 141))
820102	22359468	In another previous study, QGC enhanced antioxidant enzyme defense systems via heme oxygenase-1 (HO-1) expression and NF-E2-related factor 2 (Nrf2) translocation involving both ERK and PI3K-Akt pathways as well as PKC pathways in esophageal epithelial cell (EEC).	('ERK', 'Gene', '5594', (177, 180))	('QGC', 'Var', (27, 30))	('esophageal epithelial cell', 'Disease', (230, 256))	('enhanced', 'PosReg', (31, 39))	('NF-E2-related factor 2', 'Gene', '4780', (118, 140))	('expression', 'MPA', (103, 113))	('ERK', 'Gene', (177, 180))	('NF-E2-related factor 2', 'Gene', (118, 140))	('Nrf2', 'Gene', '4780', (142, 146))	('antioxidant enzyme defense systems', 'MPA', (40, 74))	('PI3', 'Gene', '5266', (185, 188))	('QGC', 'Chemical', 'MESH:C443401', (27, 30))	('heme oxygenase-1', 'Gene', '3162', (79, 95))	('Nrf2', 'Gene', (142, 146))	('translocation', 'MPA', (148, 161))	('heme oxygenase-1', 'Gene', (79, 95))	('PKC pathways', 'Pathway', (214, 226))	('PI3', 'Gene', (185, 188))
820112	22359468	QGC is yellow amorphous powder: IR (KBr) cm-1: 3385 (OH), 1657 (C=O), 1651, 1602, 1502 (aromatic ring), 1052 (glucuronide -CO); FAB-MS (neg.)	('1657', 'Var', (58, 62))	('FAB', 'Gene', '2187', (128, 131))	('glucuronide', 'Chemical', 'MESH:D020719', (110, 121))	('1651', 'Var', (70, 74))	('FAB', 'Gene', (128, 131))	('QGC', 'Chemical', 'MESH:C443401', (0, 3))
820171	22359468	Alcohol has many effects on the esophagus and stomach, and changes in these two organs can significantly increase morbidity due to alcohol consumption.	('alcohol', 'Chemical', 'MESH:D000438', (131, 138))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('increase', 'PosReg', (105, 113))	('changes', 'Var', (59, 66))	('morbidity', 'Disease', (114, 123))
820184	22359468	We have already confirmed that QGC enhances antioxidant enzyme defense systems via HO-1 expression and Nrf2 translocation involving both the ERK and PI3K-Akt pathways as well as partial involvement of PKC pathways in EEC.	('EEC', 'Disease', (217, 220))	('HO-1', 'Gene', (83, 87))	('ERK', 'Gene', (141, 144))	('translocation', 'MPA', (108, 121))	('QGC', 'Var', (31, 34))	('ERK', 'Gene', '5594', (141, 144))	('Nrf2', 'Gene', '4780', (103, 107))	('expression', 'MPA', (88, 98))	('antioxidant enzyme defense systems', 'MPA', (44, 78))	('PKC pathways', 'Pathway', (201, 213))	('QGC', 'Chemical', 'MESH:C443401', (31, 34))	('PI3', 'Gene', '5266', (149, 152))	('Nrf2', 'Gene', (103, 107))	('enhances', 'PosReg', (35, 43))	('PI3', 'Gene', (149, 152))
820187	22359468	An HO-1 inhibitor, ZnPP significantly attenuated the cytoprotective effect of eupatilin, one of the pharmacologically active flavones derived from Artemisia plants, in indomethacin-induced cytotoxicity.	('attenuated', 'NegReg', (38, 48))	('flavones', 'Chemical', 'MESH:D047309', (125, 133))	('eupatilin', 'Chemical', 'MESH:C045325', (78, 87))	('cytoprotective effect', 'CPA', (53, 74))	('indomethacin', 'Chemical', 'MESH:D007213', (168, 180))	('cytotoxicity', 'Disease', (189, 201))	('ZnPP', 'Var', (19, 23))	('ZnPP', 'Chemical', 'MESH:C017803', (19, 23))	('cytotoxicity', 'Disease', 'MESH:D064420', (189, 201))
820191	22359468	Overproduction of ROS can cause oxidative stress and disease.	('cause', 'Reg', (26, 31))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('ROS', 'Protein', (18, 21))	('Overproduction', 'Var', (0, 14))	('stress and disease', 'Disease', 'MESH:D004194', (42, 60))	('oxidative stress', 'Phenotype', 'HP:0025464', (32, 48))
820217	20303354	We used esophageal squamous cell lines from patients who had GERD with Barrett's esophagus (NES-B3T & NES-B10T) and without Barrett's esophagus (NES-G2T & NES-G4T) to study effects of acid and bile salts on expression of the CDX2 gene.	('GERD', 'Disease', 'MESH:D005764', (61, 65))	('patients', 'Species', '9606', (44, 52))	('B10T', 'Var', (106, 110))	("Barrett's esophagus", 'Disease', (71, 90))	('GERD', 'Disease', (61, 65))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (71, 90))	('B10T', 'SUBSTITUTION', 'None', (106, 110))	('G2T', 'Mutation', 'c.2G>T', (149, 152))	('acid and bile salts', 'Chemical', '-', (184, 203))	('G4T', 'Mutation', 'c.4G>T', (159, 162))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (124, 143))
820219	20303354	Acid and bile salts increased CDX2 mRNA, protein, and promoter activity in NES-B3T and NES-B10T cells, but not in NES-G2T or NES-G4T cells.	('increased', 'PosReg', (20, 29))	('promoter activity', 'MPA', (54, 71))	('CDX2', 'Enzyme', (30, 34))	('B10T', 'SUBSTITUTION', 'None', (91, 95))	('bile salts', 'Chemical', 'MESH:D001647', (9, 19))	('B10T', 'Var', (91, 95))	('G2T', 'Mutation', 'c.2G>T', (118, 121))	('protein', 'MPA', (41, 48))	('G4T', 'Mutation', 'c.4G>T', (129, 132))
820220	20303354	Inhibition of NF-kappaB abolished the increase in CDX2 promoter activity.	('NF-kappaB', 'Gene', '4790', (14, 23))	('CDX2 promoter activity', 'MPA', (50, 72))	('NF-kappaB', 'Gene', (14, 23))	('Inhibition', 'Var', (0, 10))
820229	20303354	The repeated cycles of injury and repair that accompany chronic inflammation are thought to induce alterations in cellular gene expression patterns, and metaplasias occur when those alterations affect the homeotic genes that control cellular phenotype.	('injury', 'Disease', (23, 29))	('cellular gene expression patterns', 'MPA', (114, 147))	('rat', 'Species', '10116', (103, 106))	('metaplasias', 'Disease', 'MESH:D008679', (153, 164))	('rat', 'Species', '10116', (186, 189))	('injury', 'Disease', 'MESH:D058186', (23, 29))	('affect', 'Reg', (194, 200))	('metaplasias', 'Disease', (153, 164))	('inflammation', 'Disease', 'MESH:D007249', (64, 76))	('alterations', 'Reg', (99, 110))	('inflammation', 'Disease', (64, 76))	('homeotic genes', 'Gene', (205, 219))	('alterations', 'Var', (182, 193))
820249	20303354	We used 4 non-neoplastic, telomerase-immortalized normal esophageal squamous (NES) cell lines that were created from endoscopic biopsy specimens of squamous epithelium in the distal esophagus of GERD patients with long-segment Barrett's esophagus (defined as >=3 cm of specialized intestinal metaplasia in the esophagus) (NES-B3T and NES-B10T) and from GERD patients without Barrett's esophagus (defined as having no endoscopic evidence of Barrett's esophagus, with heartburn occurring at least once a week for >=3 months and /or erosive esophagitis on endoscopy) (NES-G2T and NES-G4T).	('heartburn', 'Phenotype', 'HP:0002020', (466, 475))	('B10T', 'SUBSTITUTION', 'None', (338, 342))	('G4T', 'Mutation', 'c.4G>T', (581, 584))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (227, 246))	('intestinal metaplasia', 'Disease', (281, 302))	('G2T', 'Mutation', 'c.2G>T', (569, 572))	('erosive', 'Disease', (530, 537))	('GERD', 'Disease', (353, 357))	('GERD', 'Disease', (195, 199))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (440, 459))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (375, 394))	('esophagitis', 'Disease', (538, 549))	('esophagitis', 'Disease', 'MESH:D004941', (538, 549))	('GERD', 'Disease', 'MESH:D005764', (353, 357))	('GERD', 'Disease', 'MESH:D005764', (195, 199))	('heartburn', 'Disease', (466, 475))	('esophagitis', 'Phenotype', 'HP:0100633', (538, 549))	('patients', 'Species', '9606', (358, 366))	('patients', 'Species', '9606', (200, 208))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (281, 302))	('B10T', 'Var', (338, 342))
820250	20303354	As previously reported for NES-B3T and NES-G2T cell lines, the NES-B10T and NES-G4T lines express squamous cell markers (cytokeratins 13 and 4), demonstrate cell to cell contact inhibition, and do not exhibit anchorage-independent growth in soft agar (data not shown).	('B10T', 'SUBSTITUTION', 'None', (67, 71))	('B10T', 'Var', (67, 71))	('rat', 'Species', '10116', (152, 155))	('cytokeratins 13', 'Protein', (121, 136))	('cell to cell contact inhibition', 'CPA', (157, 188))	('rat', 'Species', '10116', (127, 130))	('G2T', 'Mutation', 'c.2G>T', (43, 46))	('G4T', 'Mutation', 'c.4G>T', (80, 83))
820268	20303354	Bay11-7085 (Sigma) is a pharmacologic inhibitor that blocks IkappaBalpha phosphorylation.	('IkappaBalpha', 'Gene', '4792', (60, 72))	('Bay11-7085', 'Chemical', 'MESH:C416282', (0, 10))	('Bay11-7085', 'Var', (0, 10))	('IkappaBalpha', 'Gene', (60, 72))	('blocks', 'NegReg', (53, 59))
820269	20303354	Cells transfected with the CDX2 promoter construct were pre-treated with Bay11-7085 at a concentration of 5 muM for 2 hour prior to exposure to acid, bile salts, or the combination of both for 24 hours.	('muM', 'Gene', '56925', (108, 111))	('CDX2', 'Gene', (27, 31))	('Bay11-7085', 'Chemical', 'MESH:C416282', (73, 83))	('muM', 'Gene', (108, 111))	('bile salts', 'Chemical', 'MESH:D001647', (150, 160))	('rat', 'Species', '10116', (96, 99))	('Bay11-7085', 'Var', (73, 83))
820271	20303354	Cells were infected with viral medium containing either recombinant-deficient adenovirus Ad5IkappaBalpha-SR or the corresponding empty vector 2 hours before treatment with either experimental or control medium.. We also introduced a mutation specifically in the NF-kappaB binding site of the pGL-3-CDX2 promoter construct using in vitro-site-directed mutagenesis.	('pGL-3', 'Gene', '6391', (292, 297))	('pGL-3', 'Gene', (292, 297))	('NF-kappaB', 'Gene', '4790', (262, 271))	('mutation', 'Var', (233, 241))	('NF-kappaB', 'Gene', (262, 271))
820280	20303354	We found that exposure to acidic medium, neutral bile salt medium, or acidic bile salt medium for 10 minutes, 3 times a day for 7 days increased CDX2 mRNA and protein expression in esophageal squamous cell lines derived from GERD patients with Barrett's esophagus (NES-B3T and NES-B10T), but not in squamous cell lines derived from GERD patients without Barrett's esophagus (NES-G2T and NES-G4T) (Figure 1A&B).	('CDX2', 'Gene', (145, 149))	('GERD', 'Disease', (332, 336))	('bile salt', 'Chemical', 'MESH:D001647', (49, 58))	('GERD', 'Disease', 'MESH:D005764', (332, 336))	('G4T', 'Mutation', 'c.4G>T', (391, 394))	('bile salt', 'Chemical', 'MESH:D001647', (77, 86))	('B10T', 'SUBSTITUTION', 'None', (281, 285))	('G2T', 'Mutation', 'c.2G>T', (379, 382))	('B10T', 'Var', (281, 285))	('increased', 'PosReg', (135, 144))	('patients', 'Species', '9606', (230, 238))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (244, 263))	('GERD', 'Disease', (225, 229))	('GERD', 'Disease', 'MESH:D005764', (225, 229))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (354, 373))	('patients', 'Species', '9606', (337, 345))
820282	20303354	We found that exposure to acidic medium, neutral bile salt medium, and acidic bile salt medium increased levels of CK20 mRNA (Figure 1C) and MUC-2 mRNA (data not shown) in the NES-B3T and NES-B10T cells, but not in the NES-G2T and NES-G4T cells.	('MUC-2', 'Gene', (141, 146))	('G4T', 'Mutation', 'c.4G>T', (235, 238))	('bile salt', 'Chemical', 'MESH:D001647', (49, 58))	('B10T', 'SUBSTITUTION', 'None', (192, 196))	('G2T', 'Mutation', 'c.2G>T', (223, 226))	('B10T', 'Var', (192, 196))	('bile salt', 'Chemical', 'MESH:D001647', (78, 87))	('CK20', 'Gene', (115, 119))	('CK20', 'Gene', '54474', (115, 119))	('levels', 'MPA', (105, 111))	('increased', 'PosReg', (95, 104))	('MUC-2', 'Gene', '4583', (141, 146))
820283	20303354	CDX2 promoter demethylation has been described as a mechanism underlying acid- and bile salt-mediated increases in CDX2 mRNA expression in esophageal squamous cell lines.	('CDX2', 'Gene', (115, 119))	('mRNA expression', 'MPA', (120, 135))	('CDX2', 'Gene', (0, 4))	('demethylation', 'Var', (14, 27))	('bile salt', 'Chemical', 'MESH:D001647', (83, 92))	('increases', 'PosReg', (102, 111))
820285	20303354	None of our experimental treatments changed the methylation status of the CDX2 promoter in any NES cell line, even though those treatments increased CDX2 mRNA in the NES-B3T and NES-B10T lines (Figure 1A and 2A).	('CDX2', 'Gene', (149, 153))	('methylation', 'MPA', (48, 59))	('increased', 'PosReg', (139, 148))	('mRNA', 'MPA', (154, 158))	('B10T', 'SUBSTITUTION', 'None', (182, 186))	('B10T', 'Var', (182, 186))
820291	20303354	Transfected NES-B3T and NES-B10T cells exposed to acidic, neutral bile salt, and acidic bile salt media exhibited significantly increased CDX2 promoter activity compared to untreated control cells (Figure 4).	('bile salt', 'Chemical', 'MESH:D001647', (88, 97))	('increased', 'PosReg', (128, 137))	('B10T', 'SUBSTITUTION', 'None', (28, 32))	('CDX2', 'Enzyme', (138, 142))	('B10T', 'Var', (28, 32))	('bile salt', 'Chemical', 'MESH:D001647', (66, 75))
820296	20303354	Inhibition of NF-kappaB by treatment with Bay 11-7085 and by mutation of the NF-kappaB binding site prevented the increase in CDX2 promoter activity induced by any of the experimental media in both squamous cell lines (Figure 5A&B).	('increase', 'PosReg', (114, 122))	('NF-kappaB', 'Gene', (77, 86))	('mutation', 'Var', (61, 69))	('NF-kappaB', 'Gene', '4790', (14, 23))	('prevented', 'NegReg', (100, 109))	('NF-kappaB', 'Gene', (14, 23))	('CDX2', 'Gene', (126, 130))	('Bay 11-7085', 'Chemical', 'MESH:C416282', (42, 53))	('NF-kappaB', 'Gene', '4790', (77, 86))
820302	20303354	In untreated NES-B3T and NES-B10T cells, immunofluoresence and Western blotting revealed prominent cytoplasmic expression and slight nuclear expression of both the p50 and p65 subunits (Figure 6 A&B; immunofluoresence for NES-B10T data not shown).	('B10T', 'SUBSTITUTION', 'None', (29, 33))	('p65', 'Gene', '5970', (172, 175))	('B10T', 'Var', (29, 33))	('B10T', 'SUBSTITUTION', 'None', (226, 230))	('B10T', 'Var', (226, 230))	('p50', 'Gene', (164, 167))	('p50', 'Gene', '4790', (164, 167))	('p65', 'Gene', (172, 175))
820317	20303354	After exposure to acid, bile salts or both for 7 days, CDX2 mRNA and protein were expressed in the lines derived from GERD patients with Barrett's esophagus (NES-B3T and NES-B10T), but not in those from GERD patients without Barrett's esophagus (NES-G2T and NES-G4T).	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (225, 244))	('patients', 'Species', '9606', (208, 216))	('bile salts', 'Chemical', 'MESH:D001647', (24, 34))	('GERD', 'Disease', 'MESH:D005764', (118, 122))	('GERD', 'Disease', (203, 207))	('patients', 'Species', '9606', (123, 131))	('B10T', 'Var', (174, 178))	('GERD', 'Disease', 'MESH:D005764', (203, 207))	("Barrett's esophagus", 'Disease', (137, 156))	('G4T', 'Mutation', 'c.4G>T', (262, 265))	('B10T', 'SUBSTITUTION', 'None', (174, 178))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (137, 156))	('G2T', 'Mutation', 'c.2G>T', (250, 253))	('CDX2', 'Gene', (55, 59))	('GERD', 'Disease', (118, 122))
820318	20303354	Moreover, in the NES-B3T and NES-B10T lines, we found that exposure to acid, bile salts, or both increased mRNA expression of CDX2 target genes (CK20 and MUC-2), suggesting that the induced CDX2 is functional.	('B10T', 'SUBSTITUTION', 'None', (33, 37))	('increased', 'PosReg', (97, 106))	('CK20', 'Gene', (145, 149))	('CK20', 'Gene', '54474', (145, 149))	('MUC-2', 'Gene', '4583', (154, 159))	('MUC-2', 'Gene', (154, 159))	('bile salts', 'Chemical', 'MESH:D001647', (77, 87))	('mRNA expression', 'MPA', (107, 122))	('B10T', 'Var', (33, 37))
820322	20303354	Others have reported that acid and bile salts increase CDX2 mRNA expression in HET-1A cells and in certain cancer cell lines by demethylation of the promoter.	('demethylation', 'Var', (128, 141))	('mRNA expression', 'MPA', (60, 75))	('increase', 'PosReg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('acid and bile salts', 'Chemical', '-', (26, 45))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('CDX2', 'Gene', (55, 59))	('cancer', 'Disease', (107, 113))
820323	20303354	In contrast, we did not find that acid and bile salts changed the methylation status of the CDX2 promoter in any of our telomerase-immortalized cell lines, even though those agents clearly increased CDX2 mRNA levels in NES-B3T and NES-B10T cells.	('B10T', 'SUBSTITUTION', 'None', (235, 239))	('B10T', 'Var', (235, 239))	('methylation status', 'MPA', (66, 84))	('CDX2 mRNA levels', 'MPA', (199, 215))	('acid and bile salts', 'Chemical', '-', (34, 53))	('increased', 'PosReg', (189, 198))
820326	20303354	The reasons underlying the disparity between our findings and those of earlier investigators are not clear, but may be related to the presence of the SV40Tag in HET-1A cells, and to the genetic abnormalities of cancer cells.	('genetic abnormalities of cancer', 'Disease', 'MESH:D030342', (186, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('genetic abnormalities of cancer', 'Disease', (186, 217))	('SV40Tag', 'Var', (150, 157))
820330	20303354	We inhibited NF-kappaB activation using three different approaches, and found that all three abolished the transcriptional activation of CDX2 by acid and bile salts in NES-B3T and NES-B10T cells.	('transcriptional activation', 'MPA', (107, 133))	('acid and bile salts', 'Chemical', '-', (145, 164))	('NF-kappaB', 'Gene', '4790', (13, 22))	('CDX2', 'Gene', (137, 141))	('abolished', 'NegReg', (93, 102))	('inhibited', 'NegReg', (3, 12))	('NF-kappaB', 'Gene', (13, 22))	('B10T', 'Var', (184, 188))	('B10T', 'SUBSTITUTION', 'None', (184, 188))
820333	20303354	In adenocarcinoma cells of the gastroesophageal junction, deoxycholic acid has been found to increase activity of the Cdx2 promoter by inducing nuclear translocation and promoter binding of only the p50 subunit.	('adenocarcinoma cells of the gastroesophageal junction', 'Disease', 'MESH:C538614', (3, 56))	('nuclear translocation', 'MPA', (144, 165))	('deoxycholic acid', 'Var', (58, 74))	('increase', 'PosReg', (93, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('inducing', 'PosReg', (135, 143))	('promoter', 'MPA', (170, 178))	('Cdx2', 'Gene', (118, 122))	('p50', 'Gene', (199, 202))	('activity', 'MPA', (102, 110))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (58, 74))	('p50', 'Gene', '4790', (199, 202))
820334	20303354	We found that acid and bile salts induced nuclear translocation of both the p65 and p50 subunits in NES-B3T and NES-B10T cells, but only the p50 subunit bound to the CDX2 promoter.	('acid and bile salts', 'Chemical', '-', (14, 33))	('p50', 'Gene', (84, 87))	('nuclear translocation', 'MPA', (42, 63))	('B10T', 'SUBSTITUTION', 'None', (116, 120))	('p65', 'Gene', '5970', (76, 79))	('B10T', 'Var', (116, 120))	('p50', 'Gene', '4790', (84, 87))	('p50', 'Gene', (141, 144))	('p50', 'Gene', '4790', (141, 144))	('p65', 'Gene', (76, 79))
820373	19014602	And the patients were also divided into three groups stratified by ethanol intake levels defined as non-drinker (less than 1 g/day), light-drinker (1-50 g/day) and heavy-drinker (more than 50 g/day).	('more', 'Var', (179, 183))	('ethanol', 'Chemical', 'MESH:D000431', (67, 74))	('1-50 g/day', 'Var', (148, 158))	('patients', 'Species', '9606', (8, 16))
820416	19014602	Moreover, ET-1 expression has been linked to induction of endothelial cell growth, angiogenesis and epithelial-to-mesenchymal transition resulting in an increased invasiveness and metastases of some tumors.	('metastases of some tumors', 'Disease', 'MESH:D009362', (180, 205))	('epithelial-to-mesenchymal transition', 'CPA', (100, 136))	('expression', 'Var', (15, 25))	('invasiveness', 'CPA', (163, 175))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('linked', 'Reg', (35, 41))	('increased', 'PosReg', (153, 162))	('endothelial cell growth', 'CPA', (58, 81))	('metastases of some tumors', 'Disease', (180, 205))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('ET-1', 'Gene', '1906', (10, 14))	('angiogenesis', 'CPA', (83, 95))	('ET-1', 'Gene', (10, 14))
55532	33045799	Endoscopic treatments of SESCC have better prognoses when the depth of invasion is shallow, and unlike gastric cancer, SESCC invading the muscularis mucosa poses a risk of lymph node metastasis.	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('SESCC', 'Var', (119, 124))	('gastric cancer', 'Disease', (103, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('lymph node metastasis', 'CPA', (172, 193))
820470	33045799	Statement G5 We suggest endoscopic resection for poorly differentiated tubular adenocarcinoma, poorly cohesive carcinoma, or signet ring cell carcinoma meeting the following endoscopic findings: endoscopically estimated tumor size <= 2 cm, endoscopically mucosal cancer, and no ulcer in the tumor (Grade of recommendation: weak, Level of evidence: low).	('carcinoma', 'Disease', 'MESH:D009369', (84, 93))	('<= 2', 'Var', (231, 235))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('ring cell carcinoma', 'Disease', 'MESH:D018279', (132, 151))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('tubular adenocarcinoma', 'Disease', 'MESH:D000230', (71, 93))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('carcinoma', 'Disease', (111, 120))	('carcinoma', 'Disease', (142, 151))	('tubular adenocarcinoma', 'Disease', (71, 93))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('mucosal cancer', 'Disease', (255, 269))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('ulcer', 'Disease', 'MESH:D014456', (278, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('ring cell carcinoma', 'Disease', (132, 151))	('carcinoma', 'Disease', 'MESH:D009369', (111, 120))	('carcinoma', 'Disease', 'MESH:D009369', (142, 151))	('carcinoma', 'Disease', (84, 93))	('ulcer', 'Disease', (278, 283))	('mucosal cancer', 'Disease', 'MESH:D009369', (255, 269))	('tumor', 'Disease', (291, 296))
820494	33045799	In another Korean study on 15 cases of extragastric recurrence published in 2017, 66.7% (4/6) of expanded criteria lesions and 83.3% (5/6) of out-of-indication lesions showed extra-gastric recurrences on CT without any intragastric recurrences, demonstrating the need for follow-up CT in patients with expanded criteria lesions.	('patients', 'Species', '9606', (288, 296))	('extra-gastric recurrences', 'CPA', (175, 200))	('lesions', 'Var', (115, 122))
820502	33045799	Intermediate-to-high grade tumor budding is associated with an increased risk of lymph node metastasis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('lymph node metastasis', 'CPA', (81, 102))	('Intermediate-to-high grade', 'Var', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
820503	33045799	According to some meta-analyses, the presence of tumor budding increases the OR of lymph node metastasis by 3.26- to 7.74- fold.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('increases', 'PosReg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('presence', 'Var', (37, 45))
820524	33045799	in 2015, the rate of en bloc resection was 91.7% for ESD and 46.7% for EMR with an OR of 6.84 (95% CI, 3.30-14.18); ESD had a higher en bloc resection rate than EMR.	('en bloc resection', 'CPA', (133, 150))	('higher', 'PosReg', (126, 132))	('had', 'Gene', '23498', (120, 123))	('ESD', 'Var', (116, 119))	('had', 'Gene', (120, 123))
208347	32507411	According to the survey of Rocco and colleagues in Europe and North America, as well as the data of the ADJUVANT/CTONG1104 Study in China, there are large treatment strategy differences for IIIA-N2 locally advanced non-small cell lung cancer.	('lung cancer', 'Disease', (230, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('men', 'Species', '9606', (160, 163))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (219, 241))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (215, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))	('IIIA-N2', 'Var', (190, 197))
820529	28493959	Novel genetic locus at MHC region for esophageal squamous cell carcinoma in Chinese populations Our previous genome-wide association study (GWAS) identified three independent single nucleotide polymorphisms (SNPs) in human major histocompatibility complex (MHC) region showing association with esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (38, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('human', 'Species', '9606', (217, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('association', 'Reg', (277, 288))	('esophageal squamous cell carcinoma', 'Disease', (294, 328))	('esophageal squamous cell carcinoma', 'Disease', (38, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (305, 328))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (294, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('single nucleotide polymorphisms', 'Var', (175, 206))
820531	28493959	Further validation analysis in an independent case-control cohort confirmed one of the 5 SNPs (rs911178) that showed significant association with ESCC.	('association', 'Interaction', (129, 140))	('ESCC', 'Disease', (146, 150))	('rs911178', 'Var', (95, 103))	('rs911178', 'Mutation', 'rs911178', (95, 103))
820533	28493959	The rs911178 (SCAND3 gene) in MHC region is significantly associated with high risk of ESCC.	('rs911178', 'Var', (4, 12))	('associated', 'Reg', (58, 68))	('rs911178', 'Mutation', 'rs911178', (4, 12))	('ESCC', 'Disease', (87, 91))	('MHC region', 'Gene', (30, 40))
820557	28493959	Further analysis identified 5 SNPs (PGWAS < 10-4) in MHC region for validation: rs17533090 (PGWAS = 9.709E-06, OR = 1.503, 95%CI = 1.254-1.802), rs35399661 (PGWAS = 6.070E-06, OR = 1.712, 95%CI = 1.354-2.166), rs1536501 (PGWAS = 8.874E-04, OR = 1.805, 95%CI = 1.268-2.568), rs911178 (PGWAS = 6.125E-04, OR = 0.644, 95%CI = 0.500-0.830) and rs6901869 (PGWAS = 2.523E-05, OR = 1.973, 95%CI = 1.430-2.722) (Table 2).	('rs1536501', 'Var', (210, 219))	('rs35399661', 'Mutation', 'rs35399661', (145, 155))	('rs17533090', 'Var', (80, 90))	('rs1536501', 'Mutation', 'rs1536501', (210, 219))	('rs6901869', 'Mutation', 'rs6901869', (340, 349))	('rs35399661', 'Var', (145, 155))	('rs911178', 'Var', (274, 282))	('rs911178', 'Mutation', 'rs911178', (274, 282))	('rs17533090', 'Mutation', 'rs17533090', (80, 90))	('rs6901869', 'Var', (340, 349))
820558	28493959	rs17533090 and rs35399661 on 6p21.32 fall within a high LD block between HLA-DQA1 and HLA-DRB1.	('rs35399661', 'Mutation', 'rs35399661', (15, 25))	('HLA-DQA1', 'Gene', '3117', (73, 81))	('HLA-DRB1', 'Gene', '3123', (86, 94))	('HLA-DQA1', 'Gene', (73, 81))	('rs35399661', 'Var', (15, 25))	('rs17533090', 'Mutation', 'rs17533090', (0, 10))	('HLA-DRB1', 'Gene', (86, 94))	('rs17533090', 'Var', (0, 10))	('fall', 'Phenotype', 'HP:0002527', (37, 41))
820559	28493959	rs1536501 on 6p21.31 is located between LEM domain containing 2 (LEMD2) and inositol hexakisphosphate kinase 3 (IP6K3).	('LEM domain containing 2', 'Gene', '221496', (40, 63))	('IP6K3', 'Gene', '117283', (112, 117))	('LEMD2', 'Gene', '221496', (65, 70))	('LEM domain containing 2', 'Gene', (40, 63))	('rs1536501', 'Var', (0, 9))	('IP6K3', 'Gene', (112, 117))	('LEMD2', 'Gene', (65, 70))	('rs1536501', 'Mutation', 'rs1536501', (0, 9))
820560	28493959	rs911178 on 6p22.1 is located 35-kb upstream of SCAN domain containing 3 (SCAND3).	('rs911178', 'Mutation', 'rs911178', (0, 8))	('rs911178', 'Var', (0, 8))	('SCAN domain containing 3', 'Gene', '114821', (48, 72))	('SCAN domain containing 3', 'Gene', (48, 72))
820561	28493959	rs6901869 on 6p21.33 is located between HLA-C genes and HLA complex group 27 (HCG27).	('HLA-C', 'Gene', (40, 45))	('HCG27', 'Gene', (78, 83))	('HLA complex group 27', 'Gene', '253018', (56, 76))	('HLA-C', 'Gene', '3107', (40, 45))	('rs6901869', 'Mutation', 'rs6901869', (0, 9))	('HLA complex group 27', 'Gene', (56, 76))	('HCG27', 'Gene', '253018', (78, 83))	('rs6901869', 'Var', (0, 9))
820562	28493959	rs17533090 and rs35399661 did not pass the HWE test (PHWE <10-5).	('rs35399661', 'Mutation', 'rs35399661', (15, 25))	('rs17533090', 'Var', (0, 10))	('rs17533090', 'Mutation', 'rs17533090', (0, 10))	('rs35399661', 'Var', (15, 25))
820563	28493959	rs1536501 and rs6901869 did not have significant p value (Preplication >0.01).	('rs6901869', 'Mutation', 'rs6901869', (14, 23))	('rs1536501', 'Var', (0, 9))	('rs6901869', 'Var', (14, 23))	('rs1536501', 'Mutation', 'rs1536501', (0, 9))
820568	28493959	In a joint analysis of NCI, Beijing, and our laboratory we identified that SNP rs35597309 at MHC class II gene region was associated with ESCC.	('associated', 'Reg', (122, 132))	('rs35597309', 'Mutation', 'rs35597309', (79, 89))	('MHC class II', 'Gene', (93, 105))	('SNP rs35597309', 'Var', (75, 89))
820569	28493959	The SNP rs911178 is located at upstream of SCAND3 (also known as ZBED9 or ZNF452).	('rs911178', 'Var', (8, 16))	('rs911178', 'Mutation', 'rs911178', (8, 16))	('SCAND3', 'Gene', (43, 49))	('ZBED9', 'Gene', (65, 70))	('ZBED9', 'Gene', '114821', (65, 70))
820576	28493959	In summary, we identified and validated that the rs911178 (SCAND3 gene) in MHC region is significantly associated with the high risk of ESCC through GWAS and TaqMan genotyping assay.	('ESCC', 'Disease', (136, 140))	('rs911178', 'Var', (49, 57))	('rs911178', 'Mutation', 'rs911178', (49, 57))	('associated', 'Reg', (103, 113))
820577	28493959	Further functional studies were needed to elucidate the molecular mechanisms underlying rs911178 on ESCC.	('rs911178', 'Var', (88, 96))	('ESCC', 'Disease', (100, 104))	('rs911178', 'Mutation', 'rs911178', (88, 96))
820585	27807078	Low levels of TFF2 (AUC 87.2%) provided the best discrimination between non-dysplastic BE and BE with cancer, followed by high levels of DCLK1 (AUC 83.4%), low GC ratio (AUC 79.4%) and high LGR5 (AUC 71.4%).	('low', 'Var', (156, 159))	('non-dysplastic', 'Disease', (72, 86))	('non-dysplastic', 'Disease', 'MESH:D004416', (72, 86))	('DCLK1', 'MPA', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('TFF2', 'Gene', (14, 18))
820606	27807078	Human IL-1beta transgenic mice (BE mouse model) generated in our laboratory by targeting expression of IL-1beta to the esophagus using the Epstein Barr virus L2 promoter have been previously described.	('Human', 'Species', '9606', (0, 5))	('Epstein Barr virus', 'Species', '10376', (139, 157))	('transgenic mice', 'Species', '10090', (15, 30))	('mouse', 'Species', '10090', (35, 40))	('targeting', 'Var', (79, 88))	('IL-1beta', 'Gene', (103, 111))
820660	27807078	In the BE mouse model, TFF2 is concordantly absent in esophageal squamous epithelium but abundant in the gastric cardia of IL-1beta mice (Figure 2A) and WT mice (data not shown).	('IL-1beta', 'Var', (123, 131))	('mouse', 'Species', '10090', (10, 15))	('mice', 'Species', '10090', (132, 136))	('gastric cardia', 'Disease', (105, 119))	('TFF2', 'Gene', (23, 27))	('gastric cardia', 'Disease', 'MESH:D004938', (105, 119))	('mice', 'Species', '10090', (156, 160))
820683	27807078	Similar to observations in the inflamed colon, DCLK1+ cells were significantly (ANOVA p<0.0001) amplified in regions of metaplasia in our mouse model of BE and EAC (Figure 4A).	('mouse', 'Species', '10090', (138, 143))	('DCLK1+', 'Var', (47, 53))	('amplified', 'PosReg', (96, 105))
820725	27807078	We recently demonstrated in the colon and intestine that Dclk1+ tuft cells play an important role in modulating the intestinal stem cell niche, since loss of DCLK1+ cells impairs the ability of stem cells to proliferate and expand following injury such as DSS colitis.	('DSS colitis', 'Disease', (256, 267))	('colitis', 'Phenotype', 'HP:0002583', (260, 267))	('DSS colitis', 'Disease', 'MESH:D015417', (256, 267))	('impairs', 'NegReg', (171, 178))	('injury', 'Disease', (241, 247))	('injury', 'Disease', 'MESH:D058186', (241, 247))	('DCLK1+', 'Gene', (158, 164))	('loss', 'Var', (150, 154))
820726	27807078	Furthermore, we have previously shown that Dclk1+ cells are expanded in preneoplastic conditions and in BE, Dclk1+ cells were markedly increased in the cardia and metaplastic tissue over time.	('Dclk1+', 'Gene', (43, 49))	('Dclk1+ cells', 'Var', (108, 120))	('cardia', 'Disease', 'MESH:D004938', (152, 158))	('increased', 'PosReg', (135, 144))	('cardia', 'Disease', (152, 158))	('preneoplastic conditions', 'Disease', (72, 96))	('preneoplastic conditions', 'Disease', 'MESH:D011230', (72, 96))
820732	27807078	The combination of high LGR5 or DCLK1, and low TFF2 or GC ratio into a diagnostic model appears promising in discriminating between non-dysplastic BE and BE associated with EAC.	('DCLK1', 'Gene', (32, 37))	('EAC', 'Disease', (173, 176))	('high', 'Var', (19, 23))	('low', 'NegReg', (43, 46))	('non-dysplastic', 'Disease', (132, 146))	('non-dysplastic', 'Disease', 'MESH:D004416', (132, 146))	('LGR5', 'Gene', (24, 28))	('GC ratio', 'Gene', (55, 63))	('TFF2', 'Gene', (47, 51))
820765	28042232	Long-segment BE has a higher risk for development of EAC.	('men', 'Species', '9606', (45, 48))	('EAC', 'Phenotype', 'HP:0011459', (53, 56))	('men', 'Species', '9606', (8, 11))	('Long-segment', 'Var', (0, 12))	('EAC', 'Gene', '1540', (53, 56))	('EAC', 'Gene', (53, 56))	('BE', 'Phenotype', 'HP:0100580', (13, 15))
820798	28042232	Biomarkers included are aneuploidy/polysomy, p53 loss of heterozygosity (LOH) and p16 LOH.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('loss of heterozygosity', 'NegReg', (49, 71))	('aneuploidy', 'Disease', 'MESH:D000782', (24, 34))	('p16 LOH', 'Var', (82, 89))	('aneuploidy', 'Disease', (24, 34))
820820	28042232	In contrast, activation of this pathway reduces the development of EAC, which could be seen as a possible protective effect in progression.	('activation', 'Var', (13, 23))	('EAC', 'Gene', '1540', (67, 70))	('EAC', 'Gene', (67, 70))	('reduces', 'NegReg', (40, 47))	('EAC', 'Phenotype', 'HP:0011459', (67, 70))	('development', 'CPA', (52, 63))	('men', 'Species', '9606', (59, 62))
820825	28042232	Analysis of mutations in TP53 and cyclin-dependent kinase inhibitor 2A showed less prevalent oncogene activation events.	('TP53', 'Gene', (25, 29))	('mutations', 'Var', (12, 21))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (34, 70))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (34, 70))	('TP53', 'Gene', '7157', (25, 29))
820827	28042232	A model is presented whereby EAC can progress via two separate pathways: TP53 mutation followed by genome doubling versus progressive loss of tumor suppressors in those that do not undergo genome doubling.	('EAC', 'Phenotype', 'HP:0011459', (29, 32))	('TP53', 'Gene', '7157', (73, 77))	('genome doubling', 'CPA', (99, 114))	('mutation', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('EAC', 'Gene', '1540', (29, 32))	('tumor', 'Disease', (142, 147))	('TP53', 'Gene', (73, 77))	('EAC', 'Gene', (29, 32))	('rat', 'Species', '10116', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
820921	27428225	In contrast, high or very high doctor service volume was associated with shorter length of hospital stay and lower medical expenses, which implied that experienced physicians, instead of hospital volume, might be responsible for determining the outcomes and the subsequent medical expenses of acute variceal bleeding.	('lower', 'NegReg', (109, 114))	('high', 'Var', (13, 17))	('variceal bleeding', 'Disease', (299, 316))	('length of hospital stay', 'MPA', (81, 104))	('shorter', 'NegReg', (73, 80))	('medical expenses', 'MPA', (115, 131))	('variceal bleeding', 'Disease', 'MESH:D014648', (299, 316))
820944	22453679	The central role of IL-13 in allergic disorders has been demonstrated by the attenuation of experimental allergic diseases in animals with blockade and/or gene deletion of IL-13 and/or its receptor signaling components.	('IL-13', 'Gene', (172, 177))	('attenuation', 'NegReg', (77, 88))	('allergic disorders', 'Disease', (29, 47))	('allergic diseases', 'Disease', (105, 122))	('allergic diseases', 'Disease', 'MESH:D004342', (105, 122))	('allergic disorders', 'Disease', 'MESH:D004342', (29, 47))	('gene deletion', 'Var', (155, 168))
820947	22453679	Recent early clinical studies with IL-13 neutralizing agents provide evidence that anti-IL-13 holds promise for the treatment of allergic disorders, especially in patient subgroups, based on various gene expression profiles (especially periostin).	('periostin', 'Gene', (236, 245))	('periostin', 'Gene', '10631', (236, 245))	('anti-IL-13', 'Var', (83, 93))	('patient', 'Species', '9606', (163, 170))	('allergic disorders', 'Disease', (129, 147))	('allergic disorders', 'Disease', 'MESH:D004342', (129, 147))
820981	22453679	In addition, we found that miR-375 was inversely correlated with the level of esophageal eosinophils and expression of the mast cell specific genes CPA3 and TPSAB1.	('correlated', 'Reg', (49, 59))	('esophageal eosinophils', 'Disease', (78, 100))	('TPSAB1', 'Gene', (157, 163))	('CPA3', 'Gene', '1359', (148, 152))	('esophageal eosinophils', 'Disease', 'MESH:D004802', (78, 100))	('TPSAB1', 'Gene', '7177', (157, 163))	('miR-375', 'Var', (27, 34))	('expression', 'MPA', (105, 115))	('CPA3', 'Gene', (148, 152))
820997	22453679	TSLP and miR-375 were concomitantly induced by IL-13 in HT-29 cells and knockdown of miR-375 inhibited TSLP production.	('TSLP', 'Gene', (0, 4))	('TSLP', 'Gene', '85480', (0, 4))	('TSLP', 'Gene', (103, 107))	('TSLP', 'Gene', '85480', (103, 107))	('miR-375', 'Gene', (9, 16))	('HT-29', 'CellLine', 'CVCL:0320', (56, 61))	('miR-375', 'Gene', (85, 92))	('inhibited', 'NegReg', (93, 102))	('knockdown', 'Var', (72, 81))
821003	22453679	While IL-13 down-regulates miR-375 and miR-375 and could modulate IL-13 regulated gene expression, whether the over-expression of miR-375 could correct the allergic phenotype in asthma and EE remains to be investigated.	('miR-375', 'Gene', (27, 34))	('asthma', 'Disease', 'MESH:D001249', (178, 184))	('EE', 'Phenotype', 'HP:0410151', (189, 191))	('miR-375', 'Var', (130, 137))	('modulate', 'Reg', (57, 65))	('asthma', 'Phenotype', 'HP:0002099', (178, 184))	('miR-375', 'Gene', (39, 46))	('IL-13 regulated', 'Gene', (66, 81))	('down-regulates', 'NegReg', (12, 26))	('IL-13', 'Gene', (6, 11))	('asthma', 'Disease', (178, 184))
821041	22692860	However, the specific function of CYR61 in cancer is unclear and the literature remains controversial.	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('CYR61', 'Var', (34, 39))
821043	22692860	Further, we investigated whether tumor cell-secreted CYR61 can facilitate cell migration by interacting with the alphaVbeta5 integrin.	('cell migration', 'CPA', (74, 88))	('facilitate', 'PosReg', (63, 73))	('CYR61', 'Var', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('interacting', 'Interaction', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('alphaVbeta5 integrin', 'Protein', (113, 133))	('tumor', 'Disease', (33, 38))
821044	22692860	Using tumor cell lines with low, intermediate and high CYR61 expression and their isogenic variants as a cellular model, we determined that integrin alphaVbeta5 expressed on these tumor cells is required for cell migration.	('CYR61', 'Var', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
821045	22692860	Moreover, we showed that modulation of expression levels of CYR61 in these cancer cells affected their capacity for migration.	('affected', 'Reg', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('CYR61', 'Var', (60, 65))	('capacity for migration', 'CPA', (103, 125))	('expression levels', 'MPA', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
821046	22692860	These results represent an advance to the understanding of the role of CYR61 and alphavbeta5 integrin as proteins that cooperate to mediate cancer cell migration.	('CYR61', 'Var', (71, 76))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('alphavbeta5 integrin', 'Protein', (81, 101))	('mediate', 'Reg', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
821049	22692860	Previous studies have suggested that CYR61 may be a marker for more aggressive phenotypes probably occurring through the ability of CCN proteins to bind and activate cell surface integrins.	('bind', 'Interaction', (148, 152))	('CCN', 'Chemical', '-', (132, 135))	('activate', 'PosReg', (157, 165))	('CYR61', 'Var', (37, 42))	('cell surface integrins', 'Protein', (166, 188))
821053	22692860	High levels of CYR61 were found in malignant gliomas and CYR61 was shown to enhance the tumorigenicity through the integrin-linked kinase signaling pathway.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('malignant gliomas', 'Disease', (35, 52))	('malignant gliomas', 'Disease', 'MESH:D005910', (35, 52))	('CYR61', 'Var', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('enhance', 'PosReg', (76, 83))	('tumor', 'Disease', (88, 93))	('integrin-linked kinase signaling pathway', 'Pathway', (115, 155))	('gliomas', 'Phenotype', 'HP:0009733', (45, 52))
821054	22692860	Moreover, up-regulation and involvement of CYR61 expression was recognized in prostate cancer cells and recently in esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (116, 150))	('prostate cancer', 'Phenotype', 'HP:0012125', (78, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('prostate cancer', 'Disease', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CYR61', 'Var', (43, 48))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (116, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('up-regulation', 'PosReg', (10, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (78, 93))
821055	22692860	Paradoxically, CYR61 is down-regulated in lung cancers and forced expression of CYR61 inhibits tumorigenicity of lung cancer cells.	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('CYR61', 'Var', (80, 85))	('down-regulated', 'NegReg', (24, 38))	('lung cancers', 'Disease', (42, 54))	('inhibits', 'NegReg', (86, 94))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('lung cancers', 'Disease', 'MESH:D008175', (42, 54))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('lung cancers', 'Phenotype', 'HP:0100526', (42, 54))	('tumor', 'Disease', (95, 100))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
821056	22692860	Finally, it was also reported that CYR61 inhibits the growth of endometrial cancer and leiomyomas.	('leiomyomas', 'Disease', 'MESH:D007889', (87, 97))	('inhibits', 'NegReg', (41, 49))	('endometrial cancer', 'Disease', 'MESH:D016889', (64, 82))	('growth', 'MPA', (54, 60))	('leiomyomas', 'Disease', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('endometrial cancer', 'Disease', (64, 82))	('endometrial cancer', 'Phenotype', 'HP:0012114', (64, 82))	('CYR61', 'Var', (35, 40))
821058	22692860	Indeed, the CCN-integrin connection was first demonstrated by the direct binding of CYR61 to integrin alphavbeta3 to mediate endothelial cell adhesion.	('CYR61', 'Var', (84, 89))	('CCN', 'Chemical', '-', (12, 15))	('endothelial cell adhesion', 'CPA', (125, 150))	('integrin alphavbeta3', 'Gene', '3685', (93, 113))	('binding', 'Interaction', (73, 80))	('mediate', 'Reg', (117, 124))	('integrin alphavbeta3', 'Gene', (93, 113))
821060	22692860	On the other hand, CYR61 must interact with both alpha6beta1 and alphavbeta5 to mediate its synergism with TNFalpha, indicating that different integrin pathways can also function in concert to elicit distinct CCN activities.	('synergism', 'MPA', (92, 101))	('CYR61', 'Var', (19, 24))	('TNFalpha', 'Gene', (107, 115))	('CCN', 'Chemical', '-', (209, 212))	('TNFalpha', 'Gene', '7124', (107, 115))	('activities', 'MPA', (213, 223))	('elicit', 'Reg', (193, 199))
821062	22692860	The specific functions of CYR61 and its interactions with integrin alphavbeta5 in cancer are still unclear and the literature remains controversial.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CYR61', 'Var', (26, 31))	('interactions', 'Interaction', (40, 52))
821063	22692860	In our studies we have evaluated the expression levels of CYR61 and integrin subunits alphaV and beta5 in colorectal adenocarcinoma, lung carcinoma, breast carcinoma, esophageal squamous cell carcinoma and squamous cell adenocarcinoma cancer cell lines.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (106, 131))	('breast carcinoma', 'Phenotype', 'HP:0003002', (149, 165))	('breast carcinoma', 'Disease', (149, 165))	('lung carcinoma', 'Disease', (133, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('esophageal squamous cell carcinoma', 'Disease', (167, 201))	('squamous cell adenocarcinoma cancer', 'Disease', 'MESH:D002294', (206, 241))	('squamous cell adenocarcinoma cancer', 'Disease', (206, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('lung carcinoma', 'Disease', 'MESH:D008175', (133, 147))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (167, 201))	('expression', 'MPA', (37, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('breast carcinoma', 'Disease', 'MESH:D001943', (149, 165))	('colorectal adenocarcinoma', 'Disease', (106, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('squamous cell adenocarcinoma', 'Phenotype', 'HP:0002860', (206, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('CYR61', 'Var', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
821064	22692860	Our data indicate that there are low expression levels of CYR61 in the colorectal adenocarcinoma SW620, negligible levels in the lung carcinoma H460 and high expression levels in the esophageal squamous cell carcinoma TE-7 cell line as determined using quantitative real-time PCR and Western blotting techniques.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (71, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('expression', 'MPA', (158, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (183, 217))	('lung carcinoma H460', 'Disease', 'MESH:D008175', (129, 148))	('colorectal adenocarcinoma', 'Disease', (71, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('expression levels', 'MPA', (37, 54))	('lung carcinoma H460', 'Disease', (129, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('SW620', 'CellLine', 'CVCL:0547', (97, 102))	('CYR61', 'Var', (58, 63))	('esophageal squamous cell carcinoma', 'Disease', (183, 217))	('TE-7', 'CellLine', 'CVCL:9972', (218, 222))
821067	22692860	These observations strongly suggest that CYR61 may be involved in the mechanism of tumor cell migration.	('CYR61', 'Var', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('involved', 'Reg', (54, 62))
821075	22692860	The CYR61 cDNA was stably transduced into SW620, H460 and TE-7 cancer cell lines using ViraPower Lentiviral Expression kit (Invitrogen, Carlsbad, CA).	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('SW620', 'CellLine', 'CVCL:0547', (42, 47))	('TE-7', 'CellLine', 'CVCL:9972', (58, 62))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('CYR61', 'Var', (4, 9))	('cancer', 'Disease', (63, 69))
821080	22692860	Human CYR61 (Hs00155479_A1), integrin alpha V (Hs00233808_m1), integrin beta 5 (Hs00174435_m1) and GAPDH (Hs99999905_A1) primer/probes were obtained from ABI (Applied Biosystems, Branchburg, NJ).	('Human', 'Species', '9606', (0, 5))	('GAPDH', 'Gene', (99, 104))	('integrin beta 5', 'Gene', '3693', (63, 78))	('Hs00155479_A1', 'Var', (13, 26))	('integrin alpha V', 'Gene', (29, 45))	('Hs00174435_m1', 'Var', (80, 93))	('Hs00233808_m1', 'Var', (47, 60))	('GAPDH', 'Gene', '2597', (99, 104))	('Hs99999905_A1', 'Var', (106, 119))	('integrin alpha V', 'Gene', '3685', (29, 45))	('integrin beta 5', 'Gene', (63, 78))
821089	22692860	The same blot was used for both, CYR61 and beta-actin detection.	('beta-actin', 'Gene', '728378', (43, 53))	('CYR61', 'Var', (33, 38))	('beta-actin', 'Gene', (43, 53))
821104	22692860	1A) confirmed expression levels of CYR61 in several cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (52, 58))	('CYR61', 'Var', (35, 40))
821106	22692860	The expression levels of CYR61 in H460 cells were 20 times higher and in TE-7 cells 250 times higher compared to the levels of CYR61 in SW620 cells.	('expression levels', 'MPA', (4, 21))	('CYR61', 'Var', (25, 30))	('SW620', 'CellLine', 'CVCL:0547', (136, 141))	('TE-7', 'CellLine', 'CVCL:9972', (73, 77))	('higher', 'PosReg', (59, 65))	('higher', 'PosReg', (94, 100))
821107	22692860	Next, we modeled the isogenic variants of all three cancer cell lines with stably over-expressed and stably knocked-down CYR61 expression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('knocked-down', 'Var', (108, 120))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('CYR61', 'Gene', (121, 126))	('over-expressed', 'PosReg', (82, 96))
821109	22692860	2B) Stable over-expression of CYR61 was obtained in all three cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('over-expression', 'PosReg', (11, 26))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('CYR61', 'Var', (30, 35))
821122	22692860	These observations suggested that CYR61 may be involved in the mechanism of cancer cell migration through the specific interaction with integrin alphaVbeta5.	('interaction', 'Interaction', (119, 130))	('involved', 'Reg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CYR61', 'Var', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('integrin', 'Protein', (136, 144))
821123	22692860	To test this hypothesis, we measured the migratory capabilities of H460 and TE-7 cancer cell lines and their isogenic variants with altered CYR61 expression to determine if the expression of integrin alphaVbeta5 was required for the cell migration on CYR61.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('variants', 'Var', (118, 126))	('cancer', 'Disease', (81, 87))	('CYR61', 'Gene', (140, 145))	('TE-7', 'CellLine', 'CVCL:9972', (76, 80))	('migratory', 'CPA', (41, 50))
821124	22692860	Both H460 and TE-7 cancer cell lines exhibited significantly reduced (30-50% respectively) migration capabilities through uncoated transwell filters after stable knockdown of CYR61.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('TE-7', 'CellLine', 'CVCL:9972', (14, 18))	('cancer', 'Disease', (19, 25))	('migration capabilities through', 'CPA', (91, 121))	('CYR61', 'Gene', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('reduced', 'NegReg', (61, 68))	('knockdown', 'Var', (162, 171))
821125	22692860	H460 and TE-7 cancer cells showed increased migration (25-30% respectively) through the uncoated transwell insert after stable over-expression of CYR61 (Fig.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TE-7', 'CellLine', 'CVCL:9972', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('migration', 'CPA', (44, 53))	('increased', 'PosReg', (34, 43))	('CYR61', 'Var', (146, 151))	('over-expression', 'PosReg', (127, 142))
821126	22692860	6, blocking antibody against integrin alphaVbeta5 was able to diminish migration of all CYR61 isogenic variants of H460 and TE-7 cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('CYR61', 'Gene', (88, 93))	('cancer', 'Disease', (129, 135))	('migration', 'CPA', (71, 80))	('variants', 'Var', (103, 111))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('TE-7', 'CellLine', 'CVCL:9972', (124, 128))	('diminish', 'NegReg', (62, 70))
821127	22692860	The migration were reduced about 80% in all isogenic variants of H460 cells and about 60% in all TE-7 isogenic variants after 1 hour pre-treatment with integrin alphaVbeta5 blocking antibody.	('variants', 'Var', (53, 61))	('migration', 'CPA', (4, 13))	('reduced', 'NegReg', (19, 26))	('TE-7', 'CellLine', 'CVCL:9972', (97, 101))
821128	22692860	In this study, we explored the functions of CYR61 in various cancer cell lines and have determined that CYR61 facilitates the migration of these cells through the integrin alphaVbeta5.	('CYR61', 'Var', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('facilitates', 'PosReg', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('migration', 'CPA', (126, 135))
821129	22692860	Our study confirmed that both CYR61 and integrin alphaVbeta5 and their interactions are required for the migration of cancer cells, which has never been shown before.	('cancer', 'Disease', (118, 124))	('interactions', 'Interaction', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CYR61', 'Var', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
821132	22692860	CYR61 has been found to be differentially expressed in many cancers and is involved in the development and progression of various cancers.	('involved', 'Reg', (75, 83))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('CYR61', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
821133	22692860	Using SW620, H460 and TE-7 cancer cell lines and their isogenic variants with altered expression levels of CYR61 we determined that suppressing/increasing expression and secretion of CYR61 in various tumor cells affects their capacity for migration.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('TE-7', 'CellLine', 'CVCL:9972', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CYR61', 'Var', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('capacity for migration', 'CPA', (226, 248))	('suppressing/increasing', 'PosReg', (132, 154))	('SW620', 'CellLine', 'CVCL:0547', (6, 11))	('expression', 'MPA', (155, 165))	('suppressing/increasing', 'NegReg', (132, 154))	('tumor', 'Disease', (200, 205))	('cancer', 'Disease', (27, 33))	('secretion', 'MPA', (170, 179))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('variants', 'Var', (64, 72))	('CYR61', 'Gene', (107, 112))
821136	22692860	Previously, it was shown that CYR61 is expressed in about 30% of invasive breast carcinomas.	('breast carcinomas', 'Phenotype', 'HP:0003002', (74, 91))	('invasive breast carcinomas', 'Disease', (65, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('breast carcinoma', 'Phenotype', 'HP:0003002', (74, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('CYR61', 'Var', (30, 35))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (65, 91))
821137	22692860	published that CYR61 is consistently found to be over-expressed in pancreatic cancer and the expression intensifies with disease progression.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('CYR61', 'Var', (15, 20))	('over-expressed', 'PosReg', (49, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('pancreatic cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('intensifies', 'PosReg', (104, 115))
821139	22692860	Moreover, recent findings observed high levels of CYR61 in EC109 esophageal squamous cell carcinoma cell lines and it was shown that CYR61 knockdown by RNAi leads to a significant suppression of migration, invasiveness, adhesion, formation of colonies and cell growth.	('EC109', 'CellLine', 'CVCL:6898', (59, 64))	('adhesion', 'CPA', (220, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('knockdown', 'Var', (139, 148))	('esophageal squamous cell carcinoma', 'Disease', (65, 99))	('cell growth', 'CPA', (256, 267))	('formation of colonies', 'CPA', (230, 251))	('migration', 'CPA', (195, 204))	('suppression', 'NegReg', (180, 191))	('CYR61 knockdown', 'Var', (133, 148))	('RNAi', 'Gene', (152, 156))	('invasiveness', 'CPA', (206, 218))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (65, 99))
821141	22692860	On the other hand, lower expression levels of CYR61 were reported in non-small cell lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (73, 95))	('CYR61', 'Var', (46, 51))	('non-small cell lung cancer', 'Disease', (69, 95))	('cell lung cancers', 'Disease', 'MESH:D008175', (79, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lung cancers', 'Phenotype', 'HP:0100526', (84, 96))	('expression levels', 'MPA', (25, 42))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (69, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (69, 95))	('cell lung cancers', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('lower', 'NegReg', (19, 24))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (73, 96))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (69, 95))
821142	22692860	observed that the expression levels of CYR61 can alter dramatically among various lung cancer cell lines.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('expression levels', 'MPA', (18, 35))	('CYR61', 'Var', (39, 44))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('alter', 'Reg', (49, 54))
821143	22692860	They found high expression levels of CYR61 in three and none in five lung cancer cell lines, including H460 non-small cell lung carcinoma line.	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (112, 137))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (108, 137))	('CYR61', 'Var', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('non-small cell lung carcinoma', 'Disease', (108, 137))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('expression levels', 'MPA', (16, 33))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (108, 137))
821144	22692860	Their findings suggesting a tumor suppressor role for CYR61 in non-small cell lung cancer cells is contradictory to our results identifying CYR61 as a promoter of migration in H460 cells.	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('tumor', 'Disease', (28, 33))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (67, 89))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CYR61', 'Var', (140, 145))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (63, 89))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('non-small cell lung cancer', 'Disease', (63, 89))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
821148	22692860	TE-7 squamous cell carcinoma cell line showed the highest expression levels of CYR61 and integrin alphaVbeta5 and demonstrated the strongest migration capabilities.	('CYR61', 'Var', (79, 84))	('expression levels', 'MPA', (58, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('TE-7', 'CellLine', 'CVCL:9972', (0, 4))	('migration capabilities', 'CPA', (141, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('squamous cell carcinoma', 'Disease', (5, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))	('integrin', 'Protein', (89, 97))
821150	22692860	Integrin alphaVbeta5 was shown to mediate CYR61-stimulated fibroblast migration, promote resistance to apoptosis in MCF-7 cells and is essential for CYR61-induced metastasis of tumors growing within a pre-irradiated field.	('resistance to', 'CPA', (89, 102))	('promote', 'PosReg', (81, 88))	('metastasis of tumors', 'Disease', 'MESH:D009362', (163, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('CYR61-stimulated', 'Var', (42, 58))	('fibroblast migration', 'CPA', (59, 79))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('metastasis of tumors', 'Disease', (163, 183))	('MCF-7', 'CellLine', 'CVCL:0031', (116, 121))
821152	22692860	These results confirm for the first time that tumor cell-secreted CYR61 may facilitate cancer cell migration by interacting with the alphaVbeta5 integrin in cells.	('CYR61', 'Var', (66, 71))	('cancer', 'Disease', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('facilitate', 'PosReg', (76, 86))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('alphaVbeta5 integrin', 'Protein', (133, 153))	('interacting', 'Interaction', (112, 123))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
821195	33787569	The results displayed that the number of CD3+, CD4+, CD4+/CD8+, and NK cells was significantly increased after 1 to 2 weeks of treatment with CIK/DC-CIK cells in the treatment group (all P < .05).	('CD4', 'Gene', '920', (47, 50))	('CD8', 'Gene', (58, 61))	('CIK/DC-CIK', 'Var', (142, 152))	('NK cells', 'CPA', (68, 76))	('CD8', 'Gene', '925', (58, 61))	('CD4', 'Gene', (53, 56))	('increased', 'PosReg', (95, 104))	('CD4', 'Gene', '920', (53, 56))	('CD4', 'Gene', (47, 50))
821200	33787569	Specifically, DC-CIK cells can increase T lymphocyte subsets, CIK cells, NK cells, and immunoglobulins in peripheral blood to enhance antitumor immunity.	('NK cells', 'CPA', (73, 81))	('CIK cells', 'CPA', (62, 71))	('enhance', 'PosReg', (126, 133))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('DC-CIK', 'Var', (14, 20))	('increase T lymphocyte', 'Phenotype', 'HP:0100828', (31, 52))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('T lymphocyte subsets', 'CPA', (40, 60))	('increase', 'PosReg', (31, 39))
821240	33787569	The specific indicators studied were complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), ORR equals CR plus PR, and DCR equals CR plus PR and SD.	('stable disease', 'Disease', (84, 98))	('PD', 'Disease', 'MESH:D010300', (126, 128))	('DCR', 'Var', (158, 161))	('complete response', 'Disease', (37, 54))	('progressive disease', 'Disease', 'MESH:D018450', (105, 124))	('progressive disease', 'Disease', (105, 124))	('partial', 'Disease', (61, 68))
821257	33787569	The levels of peripheral serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA-199 and CA-125) were obviously lower in immunotherapy patients than those before treatment (Fig.	('patients', 'Species', '9606', (145, 153))	('lower', 'NegReg', (122, 127))	('levels', 'MPA', (4, 10))	('carbohydrate antigen', 'MPA', (66, 86))	('immunotherapy', 'Var', (131, 144))	('carbohydrate antigen', 'Chemical', '-', (66, 86))	('CEA', 'Gene', (57, 60))	('carcinoembryonic antigen', 'Gene', '1084', (31, 55))	('CEA', 'Gene', '1084', (57, 60))	('carcinoembryonic antigen', 'Gene', (31, 55))
821261	33787569	In addition, the incidence of myelosuppression and gastrointestinal adverse reactions in the immunotherapy group was significantly lower than that in the control group (Fig.	('immunotherapy', 'Var', (93, 106))	('myelosuppression', 'Disease', 'MESH:D001855', (30, 46))	('myelosuppression', 'Disease', (30, 46))	('gastrointestinal', 'Disease', (51, 67))	('lower', 'NegReg', (131, 136))
821284	33787569	Studies have shown that the incidence of fever in patients treated with autologous CIK/DC-CIK cells was as high as 44.9%, while the fever rate during conventional treatment was close to 0, indicating that the cellular immune response and the application of interferon may cause the patients show a fever reaction, which is predictable and easy to handle.	('fever reaction', 'Disease', (298, 312))	('fever', 'Disease', 'MESH:D005334', (132, 137))	('fever', 'Disease', (132, 137))	('patients', 'Species', '9606', (50, 58))	('CIK/DC-CIK cells', 'Var', (83, 99))	('fever', 'Phenotype', 'HP:0001945', (132, 137))	('cause', 'Reg', (272, 277))	('fever', 'Disease', 'MESH:D005334', (298, 303))	('fever', 'Disease', (298, 303))	('patients', 'Species', '9606', (282, 290))	('fever', 'Phenotype', 'HP:0001945', (298, 303))	('fever', 'Disease', 'MESH:D005334', (41, 46))	('fever reaction', 'Disease', 'MESH:D005334', (298, 312))	('fever', 'Disease', (41, 46))	('fever', 'Phenotype', 'HP:0001945', (41, 46))
821285	33787569	The researches suggest that patients with autologous CIK/DC-CIK cell immunotherapy show fewer adverse reactions, with only a small number of patients showing fatigue, muscle soreness, headache, and other similar cold-like symptoms, which consistent with the results of our meta-analysis.	('fatigue', 'Phenotype', 'HP:0012378', (158, 165))	('headache', 'Disease', 'MESH:D006261', (184, 192))	('muscle soreness', 'Disease', (167, 182))	('fatigue', 'Disease', 'MESH:D005221', (158, 165))	('headache', 'Disease', (184, 192))	('muscle soreness', 'Disease', 'MESH:D063806', (167, 182))	('fatigue', 'Disease', (158, 165))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (141, 149))	('autologous', 'Var', (42, 52))	('headache', 'Phenotype', 'HP:0002315', (184, 192))
821291	33787569	Moreover, CIK/DC-CIK immunotherapy can significantly reduce the adverse events caused by chemotherapy, including leukopenia, peripheral neuritis, gastrointestinal side effects, and myelosuppression.	('reduce', 'NegReg', (53, 59))	('CIK/DC-CIK', 'Var', (10, 20))	('gastrointestinal side effects', 'Disease', (146, 175))	('peripheral neuritis', 'Disease', (125, 144))	('leukopenia', 'Phenotype', 'HP:0001882', (113, 123))	('peripheral neuritis', 'Disease', 'MESH:D009443', (125, 144))	('myelosuppression', 'Disease', 'MESH:D001855', (181, 197))	('myelosuppression', 'Disease', (181, 197))	('leukopenia', 'Disease', (113, 123))	('neuritis', 'Phenotype', 'HP:0031002', (136, 144))	('leukopenia', 'Disease', 'MESH:D007970', (113, 123))	('peripheral neuritis', 'Phenotype', 'HP:0009830', (125, 144))
821302	32887319	Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers Cancer remains one of the main causes of human mortality despite significant progress in its diagnostics and therapy achieved in the past decade.	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('human', 'Species', '9606', (126, 131))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Aberrant', 'Var', (0, 8))	('Cancer', 'Disease', (85, 91))	('mortality', 'Disease', (132, 141))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Cancer', 'Disease', 'MESH:D009369', (85, 91))	('mortality', 'Disease', 'MESH:D003643', (132, 141))	('Cancer', 'Disease', (67, 73))
821303	32887319	Massive hypomethylation of retrotransposons, in particular LINE-1, is considered a hallmark of most malignant transformations as it results in the reactivation of retroelements and subsequent genomic instability.	('results in', 'Reg', (132, 142))	('retroelements', 'MPA', (163, 176))	('hypomethylation', 'Var', (8, 23))	('transposons', 'Species', '2387', (32, 43))	('reactivation', 'MPA', (147, 159))	('genomic instability', 'CPA', (192, 211))
821304	32887319	Accumulating data on LINE-1 aberrant methylation in different tumor types indicates its significant role in cancer initiation and progression.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('aberrant methylation', 'Var', (28, 48))	('LINE-1', 'Gene', (21, 27))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
821307	32887319	Our analysis indicates that LINE-1 hypomethylation is a promising candidate biomarker of cancer development, which, however, needs validation in both clinical and laboratory studies to confirm its applicability to different cancer types and/or stages.	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('hypomethylation', 'Var', (35, 50))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
821316	32887319	Epigenetic modification of DNA, in particular methylation of cytosine to 5-methylcytosine, is acknowledged as an important mechanism underlying carcinogenesis.	('DNA', 'Gene', (27, 30))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (73, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (144, 158))	('cytosine', 'Chemical', 'MESH:D003596', (61, 69))	('cytosine', 'Chemical', 'MESH:D003596', (81, 89))	('carcinogenesis', 'Disease', (144, 158))	('methylation of cytosine to 5-methylcytosine', 'MPA', (46, 89))	('Epigenetic modification', 'Var', (0, 23))
821317	32887319	Aberrant promoter methylation is associated with altered expression of oncogenes and tumor suppressor genes.	('tumor', 'Disease', (85, 90))	('expression', 'MPA', (57, 67))	('altered', 'Reg', (49, 56))	('Aberrant', 'Var', (0, 8))	('oncogenes', 'Gene', (71, 80))	('promoter', 'MPA', (9, 17))	('associated', 'Reg', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
821319	32887319	At the same time, global genome hypomethylation observed in repetitive sequences and intergenic regions, is one of the hallmarks of cancer cells, and is suggested to promote oncogenesis by increasing the mobility of transposons, that leads to genomic instability.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('mobility', 'MPA', (204, 212))	('leads to', 'Reg', (234, 242))	('oncogenesis', 'CPA', (174, 185))	('genomic instability', 'MPA', (243, 262))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('hypomethylation', 'Var', (32, 47))	('increasing', 'PosReg', (189, 199))	('promote', 'PosReg', (166, 173))	('transposons', 'Species', '2387', (216, 227))
821327	32887319	Although in many cases L1 transpositional activity or hypomethylation seem to be a part of global cellular dysregulation associated with carcinogenesis, L1s can alter gene expression or modify genomic structure in different ways.	('carcinogenesis', 'Disease', 'MESH:D063646', (137, 151))	('alter', 'Reg', (161, 166))	('gene expression', 'MPA', (167, 182))	('L1s', 'Var', (153, 156))	('L1 transpositional', 'Phenotype', 'HP:0011540', (23, 41))	('carcinogenesis', 'Disease', (137, 151))	('hypomethylation', 'Var', (54, 69))	('modify', 'Reg', (186, 192))	('genomic structure', 'MPA', (193, 210))
821328	32887319	For example, L1 insertion into enhancer of suppression of tumorigenicity 18 (ST18) gene disrupts a negative feedback loop and can play a role in the development of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', (164, 188))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (164, 188))	('suppression of tumorigenicity 18', 'Gene', (43, 75))	('negative feedback loop', 'MPA', (99, 121))	('suppression of tumorigenicity 18', 'Gene', '9705', (43, 75))	('ST18', 'Gene', '9705', (77, 81))	('play', 'Reg', (130, 134))	('L1 insertion', 'Var', (13, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (164, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('ST18', 'Gene', (77, 81))	('disrupts', 'NegReg', (88, 96))
821330	32887319	Such deletions can occasionally remove tumor-suppressor genes (e.g., CDKN2A) or trigger the amplification of oncogenes (e.g., CCND1).	('CCND1', 'Gene', '595', (126, 131))	('amplification', 'MPA', (92, 105))	('trigger', 'Reg', (80, 87))	('CDKN2A', 'Gene', '1029', (69, 75))	('oncogenes', 'MPA', (109, 118))	('remove', 'NegReg', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CCND1', 'Gene', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('CDKN2A', 'Gene', (69, 75))	('deletions', 'Var', (5, 14))
821332	32887319	Thus, it was shown that in cancer cells, L1 retrotransposons could inactivate gene function through insertional mutagenesis, aberrant splicing or DNA breaks, leading to genomic instability.	('inactivate', 'NegReg', (67, 77))	('DNA breaks', 'Var', (146, 156))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('transposons', 'Species', '2387', (49, 60))	('aberrant splicing', 'Var', (125, 142))	('insertional mutagenesis', 'Var', (100, 123))	('leading to', 'Reg', (158, 168))	('gene', 'Protein', (78, 82))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('genomic instability', 'MPA', (169, 188))
821333	32887319	In tumor cells, somatic L1 insertions occur more often in intergenic or heterochromatic regions, in cancer-specific hypomethylation areas and in genes commonly mutated in cancer, indicating an oncogenic nature of L1 transductions.	('tumor', 'Disease', (3, 8))	('insertions', 'Var', (27, 37))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
821342	32887319	L1 hypomethylation assessed by absolute quantitative analysis of methylated alleles (AQAMA) was shown to be an early event in colon cancer progression.	('hypomethylation', 'Var', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colon cancer', 'Phenotype', 'HP:0003003', (126, 138))	('colon cancer', 'Disease', 'MESH:D015179', (126, 138))	('colon cancer', 'Disease', (126, 138))
821344	32887319	There were significant differences in the L1 methylation level depending on CRC stage and prevalence, but no such differences were observed between adenoma and carcinoma, indicating that L1 hypomethylation may potentially serve as a biomarker for early-stage CRC before its transition from premalignant to malignant lesions.	('malignant lesions', 'Disease', 'MESH:D009369', (306, 323))	('differences', 'Reg', (23, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('CRC', 'Disease', (259, 262))	('carcinoma', 'Disease', (160, 169))	('CRC', 'Phenotype', 'HP:0003003', (76, 79))	('adenoma', 'Disease', 'MESH:D000236', (148, 155))	('carcinoma', 'Disease', 'MESH:D009369', (160, 169))	('L1 methylation level', 'MPA', (42, 62))	('hypomethylation', 'Var', (190, 205))	('CRC', 'Phenotype', 'HP:0003003', (259, 262))	('adenoma', 'Disease', (148, 155))	('malignant lesions', 'Disease', (306, 323))
821346	32887319	L1 hypomethylation is also an early event in breast tissue transformation and has been observed in atypical ductal hyperplasia and flat epithelial atypia.	('breast', 'Disease', (45, 51))	('hypomethylation', 'Var', (3, 18))	('flat epithelial atypia', 'Disease', (131, 153))	('hyperplasia', 'Disease', (115, 126))	('hyperplasia', 'Disease', 'MESH:D006965', (115, 126))	('observed', 'Reg', (87, 95))
821349	32887319	Nevertheless, both studies reveal that the L1 methylation status is associated with breast cancer, suggesting its potential as a companion diagnostic marker.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('associated', 'Reg', (68, 78))	('methylation status', 'Var', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))
821354	32887319	Several studies have reported L1 hypomethylation in esophageal squamous cell carcinoma (ESCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (52, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('esophageal squamous cell carcinoma', 'Disease', (52, 86))	('hypomethylation', 'Var', (33, 48))
821355	32887319	revealed significant correlation between smoking history and hypomethylation in noncancerous esophageal mucosa of 109 patients with ESCC, suggesting possible involvement of L1 in the pathogenesis of esophageal cancer due to environmental factors.	('esophageal cancer', 'Disease', (199, 216))	('esophageal cancer', 'Disease', 'MESH:D004938', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (118, 126))	('involvement', 'Reg', (158, 169))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (210, 216))	('hypomethylation', 'Var', (61, 76))	('cancer', 'Disease', (83, 89))
821360	32887319	The hypomethylated status of L1 in prostate cancer has been further confirmed by Santourlidis et al., who observed it in 53% (17/32) of prostate cancer samples analyzed by semiquantitative PCR.	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('prostate cancer', 'Disease', (136, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))	('prostate cancer', 'Disease', (35, 50))	('hypomethylated', 'Var', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
821361	32887319	L1 hypomethylation has also been reported as an early event in the initiation of ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('hypomethylation', 'Var', (3, 18))	('initiation of ovarian cancer', 'Disease', (67, 95))	('initiation of ovarian cancer', 'Disease', 'MESH:D007319', (67, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
821364	32887319	Adequate representation of patient subgroups according to clinical and morphological characteristics and universal detection protocols are necessary requirements to conduct a validation study in order to confirm the reliability of L1 methylation as a cancer diagnostic biomarker.	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('L1 methylation', 'Var', (231, 245))	('patient', 'Species', '9606', (27, 34))	('methylation', 'Var', (234, 245))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (251, 257))
821365	32887319	Hypomethylation of L1 has also been shown to correlate with prognosis for many cancer types (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Hypomethylation', 'Var', (0, 15))	('correlate with', 'Reg', (45, 59))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
821368	32887319	reported a significant correlation between L1 hypomethylation and overall survival of patients with colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('hypomethylation', 'Var', (46, 61))	('colon cancer', 'Disease', 'MESH:D015179', (100, 112))	('colon cancer', 'Disease', (100, 112))	('patients', 'Species', '9606', (86, 94))
821371	32887319	They also found that activation of the proto-oncogene c-Met, a high-affinity receptor for hepatocyte growth factor and a critical element in the growth and metastasis of hepatic tumors, was associated with hypomethylation of L1 inserted upstream of the MET gene.	('MET', 'Gene', '79811', (253, 256))	('hepatocyte growth factor', 'Gene', '3082', (90, 114))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('hypomethylation', 'Var', (206, 221))	('hepatocyte growth factor', 'Gene', (90, 114))	('metastasis of hepatic tumors', 'Disease', (156, 184))	('metastasis of hepatic tumors', 'Disease', 'MESH:D009362', (156, 184))	('activation', 'PosReg', (21, 31))	('c-Met', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('c-Met', 'Gene', '4233', (54, 59))	('MET', 'Gene', (253, 256))
821372	32887319	reported correlation between poor prognosis in patients with hepatocellular carcinoma and hypomethylation of another two L1 5'-UTR sites analyzed by using bisulfite-specific PCR and DNA sequencing.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('patients', 'Species', '9606', (47, 55))	('hypomethylation', 'Var', (90, 105))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (61, 85))	('bisulfite', 'Chemical', 'MESH:C042345', (155, 164))	('hepatocellular carcinoma', 'Disease', (61, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (61, 85))
821373	32887319	The association of L1 hypomethylation with poor prognosis has been observed for esophageal, breast, bladder and lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancers', 'Disease', 'MESH:D008175', (112, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('lung cancers', 'Phenotype', 'HP:0100526', (112, 124))	('esophageal', 'Disease', (80, 90))	('hypomethylation', 'Var', (22, 37))	('breast', 'Disease', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('bladder', 'Disease', (100, 107))	('lung cancers', 'Disease', (112, 124))
821375	32887319	L1 hypomethylation in breast cancer was reported to indicate disease progression, particularly for primary tumors.	('hypomethylation', 'Var', (3, 18))	('breast cancer', 'Disease', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('indicate', 'Reg', (52, 60))
821377	32887319	Although these data support the hypothesis that L1 hypomethylation is a prognostic marker in cancer, contradictory results have been reported in the literature, which could be due to a low number of patients examined.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('hypomethylation', 'Var', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (199, 207))
821378	32887319	Another important reason to interpret the data on L1 methylation with caution is that in many cancers, hypomethylation of L1 may serve as a surrogate indicator of activation of other cancer-related genes involved in tumorigenesis, which represents a major disadvantage of using L1 hypomethylation as a biomarker in cancer prognosis, as well as diagnosis.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Disease', (216, 221))	('activation', 'PosReg', (163, 173))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('cancers', 'Disease', (94, 101))	('cancer', 'Disease', (315, 321))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('hypomethylation', 'Var', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
821379	32887319	Biopsy tissue samples are a standard source of material for tumor molecular analysis used to confirm diagnosis, detect cancer-specific mutations and classify tumor types, as well as to guide therapeutic interventions.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('mutations', 'Var', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
821383	32887319	Tumor cells shed mutated DNA, also known as tumor cirDNA, which is now regarded as a highly specific prognostic marker for some cancers.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('DNA', 'Gene', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('mutated', 'Var', (17, 24))
821384	32887319	Aberrantly methylated cfDNA fragments can be detected in blood by PCR, regardless of tumor localization, and have been reported for all tumor types and development stages.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cfDNA', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Aberrantly methylated', 'Var', (0, 21))	('tumor', 'Disease', (136, 141))
821385	32887319	However, despite all the benefits, only one cancer targeted diagnostic system, the Epi proColon test (Epigenomics AG, Berlin, Germany), which is based on the detection of a methylated Septin 9 gene in cfDNA, has received approval for commercial use from the FDA.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Septin 9', 'Gene', (184, 192))	('methylated', 'Var', (173, 183))	('Septin 9', 'Gene', '10801', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
821386	32887319	Another FDA-approved product from the same company, Epi proLung test, is based on the detection of methylated SHOX2 and PTGER4 genes in bronchial flushes, where DNA at least partially originates from lung tissues.	('detection', 'Reg', (86, 95))	('methylated', 'Var', (99, 109))	('PTGER4', 'Gene', '5734', (120, 126))	('PTGER4', 'Gene', (120, 126))	('SHOX2', 'Gene', '6474', (110, 115))	('flushes', 'Phenotype', 'HP:0031284', (146, 153))	('SHOX2', 'Gene', (110, 115))
821389	32887319	L1 activity caused by derepression, including hypomethylation, has been found to be characteristic for the aging brain and to be associated with age-dependent neurological disorders.	('associated', 'Reg', (129, 139))	('neurological disorders', 'Disease', (159, 181))	('derepression', 'Var', (22, 34))	('neurological disorders', 'Disease', 'MESH:D009422', (159, 181))	('hypomethylation', 'MPA', (46, 61))	('activity', 'MPA', (3, 11))
821391	32887319	Indeed, it has been shown that L1 hypomethylation in cfDNA, but not cellular DNA, from peripheral blood is associated with human age.	('human', 'Species', '9606', (123, 128))	('associated', 'Reg', (107, 117))	('hypomethylation', 'Var', (34, 49))
821392	32887319	On the other hand, the opposite process, hypermethylation of certain promoter regions including those of tumor suppressor genes, can occur during aging and result in the development of various pathologies.	('hypermethylation', 'Var', (41, 57))	('result in', 'Reg', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('pathologies', 'CPA', (193, 204))	('tumor', 'Disease', (105, 110))
821393	32887319	It was shown that L1 hypomethylation in esophageal and oral mucosae was significantly associated with tobacco use and was increased in respiratory epithelium exposed to cigarette smoke.	('hypomethylation', 'Var', (21, 36))	('tobacco', 'Species', '4097', (102, 109))	('associated', 'Reg', (86, 96))	('tobacco use', 'Disease', (102, 113))	('increased', 'PosReg', (122, 131))
821394	32887319	Harmful components of smoke, e.g., nicotine, induce apoptosis in various types of cells, which can release hypomethylated cfDNA into circulation as evidenced by detection of hypomethylated L1 and Alu retrotransposable elements in cfDNA of smokers.	('nicotine', 'Chemical', 'MESH:D009538', (35, 43))	('apoptosis', 'CPA', (52, 61))	('nicotine', 'Var', (35, 43))
821401	32887319	The authors found that L1 MI was significantly higher in patients with both early (I/II) and advanced (III/IV) CRC stages compared to healthy donors, and showed that L1 MI surpassed CEA in the detection of early-stage CRC and had a similar sensitivity for advanced-stage CRC.	('L1 MI', 'Var', (166, 171))	('CRC', 'Phenotype', 'HP:0003003', (271, 274))	('patients', 'Species', '9606', (57, 65))	('higher', 'PosReg', (47, 53))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('CEA', 'Gene', (182, 185))	('L1 MI', 'MPA', (23, 28))	('CEA', 'Gene', '1084', (182, 185))	('CRC', 'Phenotype', 'HP:0003003', (218, 221))
821404	32887319	These results suggest a principal possibility of using methylation of cfDNA-derived L1 as an additional noninvasive biomarker which, in combination with other biomarkers such as FOBT and CEA, can indicate an increase or a decrease of likelihood for advanced CRC and/or distant metastasis.	('CEA', 'Gene', (187, 190))	('decrease', 'NegReg', (222, 230))	('CRC', 'Phenotype', 'HP:0003003', (258, 261))	('CEA', 'Gene', '1084', (187, 190))	('advanced CRC and/or', 'CPA', (249, 268))	('methylation', 'Var', (55, 66))
821405	32887319	Global hypomethylation of L1 in cfDNA has been linked to disease progression in several cancers.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('Global hypomethylation', 'Var', (0, 22))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('linked to', 'Reg', (47, 56))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cfDNA', 'Disease', (32, 37))
821422	32887319	showed that serum levels of unmethylated L1 were higher in patients with stage III-IV melanoma compared to healthy donors (Table 2) and suggested a significant diagnostic potential of the L1 hypomethylation status in cfDNA in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('hypomethylation status', 'Var', (191, 213))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('serum levels', 'MPA', (12, 24))	('patients', 'Species', '9606', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))	('higher', 'PosReg', (49, 55))
821423	32887319	Although these studies used different methods to target distinct CpGs within the L1 promoter region, all of them demonstrated L1 hypomethylation in cfDNA in different cancer types.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('demonstrated', 'Reg', (113, 125))	('cfDNA', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('hypomethylation', 'Var', (129, 144))
821424	32887319	Summarizing these results, one can assume that analysis of L1 methylation status in cfDNA could be either a universal cancer marker or a marker of a number of cancer types.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (118, 124))	('methylation status', 'Var', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cfDNA', 'Disease', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
821432	32887319	Massive hypomethylation of retroelements, in particular L1s, is considered a universal hallmark accompanying many malignant transformations, including gastrointestinal, breast and lung cancers (Figure 3).	('L1s', 'Gene', (56, 59))	('lung cancers', 'Phenotype', 'HP:0100526', (180, 192))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast and lung cancers', 'Disease', 'MESH:D001943', (169, 192))	('gastrointestinal', 'Disease', (151, 167))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('Massive hypomethylation', 'Var', (0, 23))
821434	32887319	In 2019 the Pangea Laboratory issued the Bladder CARE  test, which is a urine assay for bladder cancer detection based on the combination of hyper- and hypomethylation of a three-gene panel, SOX1, IRAK3, and L1.	('SOX1', 'Gene', '6656', (191, 195))	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('bladder cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SOX1', 'Gene', (191, 195))	('hypomethylation', 'Var', (152, 167))	('IRAK3', 'Gene', (197, 202))	('hyper-', 'Var', (141, 147))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('IRAK3', 'Gene', '11213', (197, 202))
821439	32887319	The identification of L1 hypomethylation patterns characteristic for each tumor category is of particular interest.	('hypomethylation', 'Var', (25, 40))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
821452	32709844	Recent genome studies, including The Cancer Genome Atlas (TCGA) project, have identified many genome variations in ESCC by using whole-exome or whole-genome sequencing on clinical tissue samples.	('ESCC', 'Disease', (115, 119))	('Cancer', 'Disease', 'MESH:D009369', (37, 43))	('variations', 'Var', (101, 111))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Cancer', 'Disease', (37, 43))
821453	32709844	Although these studies have revealed an important role of the identified genome alterations in ESCC, it remains unresolved that how the normal epithelial cells may transit by the mutations through precancerous lesions to invasive carcinoma because all these previous studies were in cross-sectional design.	('invasive carcinoma', 'Disease', 'MESH:D009361', (221, 239))	('precancerous lesions', 'Disease', 'MESH:D011230', (197, 217))	('precancerous lesions', 'Disease', (197, 217))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('ESCC', 'Disease', (95, 99))	('invasive carcinoma', 'Disease', (221, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('mutations', 'Var', (179, 188))
821478	32709844	EpiC 4 (n = 110) had a higher expression program for keratinization (e.g., Krt4, Krt13, S100a8, and S100a9).	('expression program', 'MPA', (30, 48))	('Krt13', 'Gene', (81, 86))	('S100a8', 'Var', (88, 94))	('Krt4', 'Gene', (75, 79))	('keratinization', 'Protein', (53, 67))	('expression', 'Species', '29278', (30, 40))	('S100a9', 'Var', (100, 106))
821486	32709844	High level of S100a8 appeared at stage HYP and covered all precancerous and ICA stages whereas the highest levels of Itga6 and Mmp14 were seen at stage ICA although their expressions were also detected in cells across all stages.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('S100a8', 'Var', (14, 20))	('cancerous', 'Disease', 'MESH:D009369', (62, 71))	('ICA', 'Disease', (76, 79))	('expression', 'Species', '29278', (171, 181))	('cancerous', 'Disease', (62, 71))
821490	32709844	We found that the expression levels of Pitx1, Trp53, and Bclaf1, which are known tumor suppressor TFs, were substantially decreased while TFs promoting EMT (e.g., Ets1 and Snai3), immunosuppression (e.g., Eomes), cell migration and invasion (e.g., Creb3 and Elk3) were significantly upregulated.	('cell migration', 'CPA', (213, 227))	('upregulated', 'PosReg', (283, 294))	('Creb3', 'CPA', (248, 253))	('promoting', 'PosReg', (142, 151))	('expression levels', 'MPA', (18, 35))	('Pitx1', 'Gene', (39, 44))	('EMT', 'CPA', (152, 155))	('invasion', 'CPA', (232, 240))	('TFs', 'Var', (138, 141))	('decreased', 'NegReg', (122, 131))	('Bclaf1', 'Gene', (57, 63))	('Trp53', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('expression', 'Species', '29278', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Pitx1', 'Gene', '5307', (39, 44))	('immunosuppression', 'CPA', (180, 197))	('tumor', 'Disease', (81, 86))
821537	32709844	4NQO represents a chemical carcinogen that can specifically induce ESCC in mice and this animal cancer model has been shown to mimic ESCC development in humans.	('mice', 'Species', '10090', (75, 79))	('ESCC', 'Disease', (67, 71))	('humans', 'Species', '9606', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('4NQO', 'Chemical', 'MESH:D015112', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('induce', 'Reg', (60, 66))	('4NQO', 'Var', (0, 4))
821540	32709844	Another interesting and important finding of this study is that the transcriptomic expression pattern of esophageal epithelial cells in 4NQO-induced early lesions is similar to that of esophageal normal epithelial cells in aged mice, while aging is a known risk factor for cancer development in humans.	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('4NQO', 'Chemical', 'MESH:D015112', (136, 140))	('4NQO-induced', 'Var', (136, 148))	('humans', 'Species', '9606', (295, 301))	('expression', 'Species', '29278', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('mice', 'Species', '10090', (228, 232))
821546	32709844	In addition, starting from hyperplasia stage, the macrophages and neutrophils activated by CD4-Th17 cells may form an inflammatory microenvironment during tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('CD4-Th17', 'Var', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('hyperplasia', 'Disease', 'MESH:D006965', (27, 38))	('tumor', 'Disease', (155, 160))	('hyperplasia', 'Disease', (27, 38))
821592	32547097	Loss of miR-204-5p Promotes Tumor Proliferation, Migration, and Invasion Through Targeting YWHAZ/PI3K/AKT Pathway in Esophageal Squamous Cell Carcinoma MicroRNAs dysregulation has been confirmed in multiple malignancies.	('Invasion', 'CPA', (64, 72))	('malignancies', 'Disease', (207, 219))	('miR-204-5p', 'Chemical', '-', (8, 18))	('Migration', 'CPA', (49, 58))	('Squamous Cell Carcinoma', 'Disease', (128, 151))	('Tumor', 'Phenotype', 'HP:0002664', (28, 33))	('miR-204-5p', 'Gene', (8, 18))	('YWHAZ', 'Gene', '7534', (91, 96))	('YWHAZ', 'Gene', (91, 96))	('AKT', 'Gene', '207', (102, 105))	('Tumor Proliferation', 'CPA', (28, 47))	('Carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('malignancies', 'Disease', 'MESH:D009369', (207, 219))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('Loss', 'Var', (0, 4))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('AKT', 'Gene', (102, 105))	('Promotes', 'PosReg', (19, 27))
821593	32547097	This paper reported the molecular mechanism of miR-204-5p in esophageal squamous cell carcinoma (ESCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('esophageal squamous cell carcinoma', 'Disease', (61, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('miR-204-5p', 'Chemical', '-', (47, 57))	('miR-204-5p', 'Var', (47, 57))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (61, 95))
821597	32547097	Luciferase reporter gene assay and RNA-binding protein immunoprecipitation (RIP) were performed to verify the targeting relationship between miR-204-5p and YWHAZ.	('RIP', 'Gene', (76, 79))	('miR-204-5p', 'Var', (141, 151))	('RNA-binding protein immunoprecipitation', 'Gene', '3267', (35, 74))	('RNA-binding protein immunoprecipitation', 'Gene', (35, 74))	('RIP', 'Gene', '3267', (76, 79))	('YWHAZ', 'Gene', (156, 161))	('YWHAZ', 'Gene', '7534', (156, 161))	('miR-204-5p', 'Chemical', '-', (141, 151))
821602	32547097	Moreover, KYSE510 cells of miR-204-5p mimic group showed lower OD450 value, more cell percentage in G1 phase and less cell percentage in S phase, higher apoptosis percentage, and lower migration and invasion cell numbers than control.	('higher', 'PosReg', (146, 152))	('lower', 'NegReg', (179, 184))	('less', 'NegReg', (113, 117))	('G1 phase', 'CPA', (100, 108))	('miR-204-5p mimic', 'Var', (27, 43))	('OD450 value', 'Enzyme', (63, 74))	('miR-204-5p', 'Chemical', '-', (27, 37))	('KYSE510', 'CellLine', 'CVCL:1354', (10, 17))	('apoptosis percentage', 'CPA', (153, 173))	('lower', 'NegReg', (57, 62))
821603	32547097	YWHAZ was directly inhibited by miR-204-5p.	('inhibited', 'NegReg', (19, 28))	('miR-204-5p', 'Chemical', '-', (32, 42))	('miR-204-5p', 'Var', (32, 42))	('YWHAZ', 'Gene', (0, 5))	('YWHAZ', 'Gene', '7534', (0, 5))
821605	32547097	miR-204-5p up-regulation inhibited ESCC growth in vivo.	('up-regulation', 'PosReg', (11, 24))	('miR-204-5p', 'Chemical', '-', (0, 10))	('inhibited', 'NegReg', (25, 34))	('ESCC', 'Disease', (35, 39))	('miR-204-5p', 'Var', (0, 10))
821606	32547097	miR-204-5p inhibits ESCC progression by targeted inhibition of YWHAZ/PI3K/AKT.	('AKT', 'Gene', '207', (74, 77))	('inhibits', 'NegReg', (11, 19))	('ESCC', 'Disease', (20, 24))	('miR-204-5p', 'Chemical', '-', (0, 10))	('AKT', 'Gene', (74, 77))	('YWHAZ', 'Gene', (63, 68))	('inhibition', 'NegReg', (49, 59))	('miR-204-5p', 'Var', (0, 10))	('YWHAZ', 'Gene', '7534', (63, 68))
821613	32547097	MiRNAs have been shown to mediate post-transcriptional regulation of target genes through promoting RNA degradation or translational inhibition and participate in mediating various biological and pathological processes, including proliferation, apoptosis, differentiation, and carcinogenesis.	('participate', 'Reg', (148, 159))	('MiRNAs', 'Var', (0, 6))	('RNA degradation', 'MPA', (100, 115))	('apoptosis', 'CPA', (245, 254))	('carcinogenesis', 'Disease', 'MESH:D063646', (277, 291))	('carcinogenesis', 'Disease', (277, 291))	('promoting', 'PosReg', (90, 99))	('translational', 'MPA', (119, 132))	('differentiation', 'CPA', (256, 271))	('proliferation', 'CPA', (230, 243))
821618	32547097	miR-204-5p has been confirmed to involve in the regulation of multiple human malignant tumor progression, which was also verified to be tumor suppressor in some human tumors such as malignant melanoma and hepatocellular cancer.	('human', 'Species', '9606', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('malignant tumor', 'Disease', (77, 92))	('malignant melanoma and hepatocellular cancer', 'Disease', 'MESH:D006528', (182, 226))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (205, 226))	('miR-204-5p', 'Chemical', '-', (0, 10))	('malignant tumor', 'Disease', 'MESH:D009369', (77, 92))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', (167, 172))	('human', 'Species', '9606', (71, 76))	('miR-204-5p', 'Var', (0, 10))	('malignant melanoma', 'Phenotype', 'HP:0002861', (182, 200))	('involve', 'Reg', (33, 40))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))
821619	32547097	Unfortunately, the function of miR-204-5p in ESCC has not been confirmed currently.	('miR-204-5p', 'Chemical', '-', (31, 41))	('ESCC', 'Disease', (45, 49))	('miR-204-5p', 'Var', (31, 41))
821620	32547097	We hypothesized that miR-204-5p might participate in the regulation of ESCC progression.	('ESCC', 'Disease', (71, 75))	('miR-204-5p', 'Var', (21, 31))	('participate', 'Reg', (38, 49))	('miR-204-5p', 'Chemical', '-', (21, 31))
821621	32547097	Meanwhile, we also noticed that miR-204-5p directly targeted YWHAZ.	('miR-204-5p', 'Chemical', '-', (32, 42))	('targeted', 'Reg', (52, 60))	('YWHAZ', 'Gene', (61, 66))	('miR-204-5p', 'Var', (32, 42))	('YWHAZ', 'Gene', '7534', (61, 66))
821623	32547097	Therefore, this article further investigated whether miR-204-5p regulated the progression of ESCC via interfering with YWHAZ expression.	('interfering', 'NegReg', (102, 113))	('miR-204-5p', 'Chemical', '-', (53, 63))	('miR-204-5p', 'Var', (53, 63))	('YWHAZ', 'Gene', (119, 124))	('YWHAZ', 'Gene', '7534', (119, 124))	('ESCC', 'Disease', (93, 97))
821665	32547097	After incubation of the primary antibody (YWHAZ, p-PI3K, pI3K, p-AKT, and AKT) and related secondary antibodies, streptomycin was used for the biotinylated HRP complex and placed at 37  C for 30 min.	('YWHAZ', 'Gene', (42, 47))	('AKT', 'Gene', (65, 68))	('AKT', 'Gene', '207', (74, 77))	('streptomycin', 'Chemical', 'MESH:D013307', (113, 125))	('AKT', 'Gene', '207', (65, 68))	('AKT', 'Gene', (74, 77))	('YWHAZ', 'Gene', '7534', (42, 47))	('pI3K', 'Var', (57, 61))	('p-PI3K', 'Var', (49, 55))
821680	32547097	The primer sequences used in this research were listed as follows: miR-204-5p-F, 5'-ACACTCCAGCTGGGTTCCCTTTGTCATCCTAT-3', miR-204-5p-R, 5'-CTCAACTGGTGTCGTGGA-3'.	('miR-204-5p-R', 'Var', (121, 133))	('miR-204-5p', 'Chemical', '-', (121, 131))	('miR-204-5p', 'Chemical', '-', (67, 77))	('miR-204-5p-F', 'Var', (67, 79))
821694	32547097	The expression of miR-204-5p in tumor and normal tissues of 97 ESCC patients was subsequently validated.	('miR-204-5p', 'Var', (18, 28))	('miR-204-5p', 'Chemical', '-', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('patients', 'Species', '9606', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('ESCC', 'Disease', (63, 67))	('tumor', 'Disease', (32, 37))
821695	32547097	It could be noted that relative to normal tissues, the expression of miR-204-5p was prominently reduced in ESCC tumor tissues (P< 0.0001) (Figure 1C).	('miR-204-5p', 'Var', (69, 79))	('expression', 'MPA', (55, 65))	('ESCC tumor', 'Disease', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('miR-204-5p', 'Chemical', '-', (69, 79))	('ESCC tumor', 'Disease', 'MESH:D004938', (107, 117))	('reduced', 'NegReg', (96, 103))
821697	32547097	As recorded in Table 1, low miR-204-5p expression was obviously associated with large tumor size and advanced tumor stage (P< 0.05).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('miR-204-5p expression', 'Var', (28, 49))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('low', 'NegReg', (24, 27))	('miR-204-5p', 'Chemical', '-', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
821698	32547097	Interestingly, patients with lower expression of miR-204-5p were always with short overall survival time (Figure 1D).	('short', 'NegReg', (77, 82))	('miR-204-5p', 'Var', (49, 59))	('patients', 'Species', '9606', (15, 23))	('overall', 'MPA', (83, 90))	('miR-204-5p', 'Chemical', '-', (49, 59))
821700	32547097	miR-204-5p expression was noticeably reduced in the 5 ESCC cell lines than that in Het-1A cell line (P< 0.01).	('reduced', 'NegReg', (37, 44))	('Het-1A', 'CellLine', 'CVCL:3702', (83, 89))	('miR-204-5p', 'Var', (0, 10))	('miR-204-5p', 'Chemical', '-', (0, 10))
821701	32547097	In the next study, the biological functions of miR-204-5p in ESCC were analyzed.	('miR-204-5p', 'Var', (47, 57))	('miR-204-5p', 'Chemical', '-', (47, 57))	('ESCC', 'Disease', (61, 65))
821702	32547097	Briefly, TE-1 cells with relatively high miR-204-5p expression were transfected by miR-204-5p inhibitor, whereas KYSE510 cells with relatively low miR-204-5p expression were transfected by miR-204-5p mimic.	('miR-204-5p', 'Chemical', '-', (83, 93))	('transfected', 'Reg', (68, 79))	('KYSE510', 'CellLine', 'CVCL:1354', (113, 120))	('miR-204-5p', 'Chemical', '-', (41, 51))	('miR-204-5p', 'Chemical', '-', (147, 157))	('miR-204-5p', 'Var', (41, 51))	('miR-204-5p', 'Chemical', '-', (189, 199))
821705	32547097	CCK-8 assay showed markedly higher OD450 value of TE-1 cells in miR-204-5p inhibitor group when compared with siNC group (P< 0.01), but remarkably lower OD450 value of KYSE510 cells in miR-204-5p mimic group compared to NC group (P< 0.01) (Figure 2C).	('OD450', 'MPA', (153, 158))	('siNC', 'Disease', (110, 114))	('lower', 'NegReg', (147, 152))	('higher', 'PosReg', (28, 34))	('miR-204-5p', 'Chemical', '-', (64, 74))	('miR-204-5p', 'Chemical', '-', (185, 195))	('KYSE510', 'CellLine', 'CVCL:1354', (168, 175))	('miR-204-5p', 'Var', (64, 74))	('siNC', 'Disease', 'None', (110, 114))	('OD450', 'MPA', (35, 40))
821706	32547097	Moreover, TE-1 cells of miR-204-5p inhibitor group exhibited less cell percentage in G1 phase and more cell percentage in S phase than siNC group (P< 0.05 or P< 0.01).	('S phase', 'CPA', (122, 129))	('more', 'PosReg', (98, 102))	('less', 'NegReg', (61, 65))	('siNC', 'Disease', (135, 139))	('miR-204-5p', 'Chemical', '-', (24, 34))	('miR-204-5p inhibitor', 'Var', (24, 44))	('cell percentage in G1 phase', 'CPA', (66, 93))	('siNC', 'Disease', 'None', (135, 139))
821707	32547097	However, relative to NC group, KYSE510 cells of miR-204-5p mimic group showed more cell percentage in G1 phase and less cell percentage in S phase (P< 0.05) (Figure 2D).	('less', 'NegReg', (115, 119))	('G1 phase', 'CPA', (102, 110))	('more', 'PosReg', (78, 82))	('KYSE510', 'CellLine', 'CVCL:1354', (31, 38))	('miR-204-5p', 'Var', (48, 58))	('S phase', 'CPA', (139, 146))	('miR-204-5p', 'Chemical', '-', (48, 58))
821708	32547097	Compared with siNC group, much lower apoptosis percentage and higher migration and invasion cell numbers were observed in miR-204-5p inhibitor group (P< 0.05 or P< 0.01).	('siNC', 'Disease', (14, 18))	('apoptosis percentage', 'CPA', (37, 57))	('lower', 'NegReg', (31, 36))	('miR-204-5p', 'Chemical', '-', (122, 132))	('higher', 'PosReg', (62, 68))	('miR-204-5p inhibitor', 'Var', (122, 142))	('siNC', 'Disease', 'None', (14, 18))
821710	32547097	The binding site of miR-204-5p and YWHAZ was predicted by TargetScan online software.	('YWHAZ', 'Gene', '7534', (35, 40))	('binding', 'Interaction', (4, 11))	('miR-204-5p', 'Chemical', '-', (20, 30))	('miR-204-5p', 'Var', (20, 30))	('YWHAZ', 'Gene', (35, 40))
821711	32547097	The results indicated that miR-204-5p was with the binding site to YWHAZ in the 3'-UTR region.	('binding', 'Interaction', (51, 58))	('YWHAZ', 'Gene', (67, 72))	('YWHAZ', 'Gene', '7534', (67, 72))	('miR-204-5p', 'Chemical', '-', (27, 37))	('miR-204-5p', 'Var', (27, 37))
821713	32547097	Results of the luciferase reporter gene assay showed that miR-204-5p overexpression significantly decreased the relative luciferase activity of YWHAZ-WT (P< 0.01) whereas no obvious effect was found in YWHAZ-Mut group (Figure 3B).	('overexpression', 'PosReg', (69, 83))	('activity', 'MPA', (132, 140))	('miR-204-5p', 'Chemical', '-', (58, 68))	('YWHAZ', 'Gene', '7534', (144, 149))	('YWHAZ', 'Gene', (144, 149))	('decreased', 'NegReg', (98, 107))	('luciferase', 'Enzyme', (121, 131))	('miR-204-5p', 'Var', (58, 68))	('YWHAZ', 'Gene', '7534', (202, 207))	('YWHAZ', 'Gene', (202, 207))
821714	32547097	Thus, YWHAZ expression was proved to be directly inhibited by miR-204-5p.	('YWHAZ', 'Gene', (6, 11))	('miR-204-5p', 'Chemical', '-', (62, 72))	('YWHAZ', 'Gene', '7534', (6, 11))	('inhibited', 'NegReg', (49, 58))	('miR-204-5p', 'Var', (62, 72))
821726	32547097	Western blot analysis was processed to detect the relative protein expression of p-PI3K/PI3K and p-AKT/AKT.	('AKT', 'Gene', '207', (103, 106))	('AKT', 'Gene', '207', (99, 102))	('AKT', 'Gene', (103, 106))	('AKT', 'Gene', (99, 102))	('p-PI3K/PI3K', 'Var', (81, 92))
821727	32547097	As the results shown in Figure 4F, relative protein expression of p-PI3K/PI3K and p-AKT/AKT was significantly higher in miR-inhibitor and miR-inhibitor+siCtrl than control, while siYWHAZ rescued the effect of miR-inhibitor.	('p-PI3K/PI3K', 'Var', (66, 77))	('miR', 'Gene', '220972', (209, 212))	('AKT', 'Gene', '207', (84, 87))	('miR', 'Gene', (120, 123))	('miR', 'Gene', (209, 212))	('AKT', 'Gene', '207', (88, 91))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', (138, 141))	('AKT', 'Gene', (84, 87))	('siYWHAZ', 'Chemical', '-', (179, 186))	('AKT', 'Gene', (88, 91))	('higher', 'PosReg', (110, 116))	('protein expression', 'MPA', (44, 62))
821730	32547097	As shown in Figure 5A and B, both the tumor volume and weight of miR-204-5p mimic group were prominently lower than that of NC group on the 28th day after subcutaneous injection (P < 0.01).	('lower', 'NegReg', (105, 110))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('weight', 'CPA', (55, 61))	('miR-204-5p mimic', 'Var', (65, 81))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('miR-204-5p', 'Chemical', '-', (65, 75))
821732	32547097	As a result, tumor tissues of miR-204-5p mimic group exhibited much higher miR-204-5p expression and markedly lower YWHAZ expression than that of NC group (P< 0.01) (Figure 5C and D).	('tumor', 'Disease', (13, 18))	('miR-204-5p mimic', 'Var', (30, 46))	('miR-204-5p', 'Chemical', '-', (75, 85))	('higher', 'PosReg', (68, 74))	('miR-204-5p', 'Chemical', '-', (30, 40))	('YWHAZ', 'Gene', (116, 121))	('lower', 'NegReg', (110, 115))	('miR-204-5p expression', 'MPA', (75, 96))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('YWHAZ', 'Gene', '7534', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
821734	32547097	As shown in Figure 5E, the relative expression of YWHAZ, p-PI3K/PI3K, and p-AKT/AKT was significantly decreased after miR-204-5p mimic transfection.	('AKT', 'Gene', '207', (76, 79))	('expression', 'MPA', (36, 46))	('AKT', 'Gene', '207', (80, 83))	('miR-204-5p', 'Chemical', '-', (118, 128))	('YWHAZ', 'Gene', (50, 55))	('AKT', 'Gene', (76, 79))	('miR-204-5p mimic transfection', 'Var', (118, 147))	('AKT', 'Gene', (80, 83))	('YWHAZ', 'Gene', '7534', (50, 55))	('p-PI3K/PI3K', 'Var', (57, 68))	('decreased', 'NegReg', (102, 111))
821736	32547097	The abnormal expression of cancer-related genes will ultimately affect the development of tumors by inducing tumor growth, metastasis as well as a series of complex processes.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', (109, 114))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumors', 'Disease', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('affect', 'Reg', (64, 70))	('metastasis', 'CPA', (123, 133))	('inducing', 'PosReg', (100, 108))
821738	32547097	Regarding the mechanism, miR-204-5p inhibited ESCC progression in vitro and in vivo by targeting YWHAZ/PI3K/AKT.	('YWHAZ', 'Gene', (97, 102))	('AKT', 'Gene', '207', (108, 111))	('ESCC', 'Disease', (46, 50))	('inhibited', 'NegReg', (36, 45))	('YWHAZ', 'Gene', '7534', (97, 102))	('AKT', 'Gene', (108, 111))	('targeting', 'Reg', (87, 96))	('miR-204-5p', 'Chemical', '-', (25, 35))	('miR-204-5p', 'Var', (25, 35))
821739	32547097	The function of miR-204-5p in human malignancies has been reported in recent years.	('human', 'Species', '9606', (30, 35))	('malignancies', 'Disease', (36, 48))	('miR-204-5p', 'Var', (16, 26))	('miR-204-5p', 'Chemical', '-', (16, 26))	('malignancies', 'Disease', 'MESH:D009369', (36, 48))
821740	32547097	Previous research has reported that miR-204-5p expression was reduced in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('miR-204-5p', 'Chemical', '-', (36, 46))	('miR-204-5p', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('reduced', 'NegReg', (62, 69))
821741	32547097	After restoring the expression of miR-204-5p, migration and invasion abilities of the colorectal cancer cells were weakened and the sensitivity of tumor cells to chemotherapy was also enhanced.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('expression', 'MPA', (20, 30))	('weakened', 'NegReg', (115, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('miR-204-5p', 'Var', (34, 44))	('miR-204-5p', 'Chemical', '-', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('sensitivity', 'CPA', (132, 143))	('enhanced', 'PosReg', (184, 192))	('invasion abilities', 'CPA', (60, 78))
821742	32547097	The mechanism involved in this process was that miR-204-5p could directly inhibit RAB22A expression to exert its anti-tumor effect in colorectal cancer.	('expression', 'MPA', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('colorectal cancer', 'Disease', (134, 151))	('RAB22A', 'Gene', '57403', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('miR-204-5p', 'Var', (48, 58))	('inhibit', 'NegReg', (74, 81))	('tumor', 'Disease', (118, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('RAB22A', 'Gene', (82, 88))	('miR-204-5p', 'Chemical', '-', (48, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))
821743	32547097	In papillary thyroid carcinoma, miR-204-5p possessed antitumor effect, which suppressed proliferation and induced apoptosis of papillary thyroid carcinoma cells by inhibiting the expression of IGFBP5.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('inhibiting', 'NegReg', (164, 174))	('induced', 'Reg', (106, 113))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (127, 154))	('IGFBP5', 'Gene', '3488', (193, 199))	('miR-204-5p', 'Chemical', '-', (32, 42))	('miR-204-5p', 'Var', (32, 42))	('papillary thyroid carcinoma', 'Disease', (127, 154))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (13, 30))	('tumor', 'Disease', (57, 62))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (127, 154))	('suppressed', 'NegReg', (77, 87))	('IGFBP5', 'Gene', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (137, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('apoptosis', 'CPA', (114, 123))	('expression', 'MPA', (179, 189))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (3, 30))	('papillary thyroid carcinoma', 'Disease', (3, 30))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('proliferation', 'CPA', (88, 101))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (3, 30))
821745	32547097	miR-204-5p could inhibit hepatocellular cancer cells proliferation in vitro by regulating SIX1 and its downstream genes.	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (25, 46))	('regulating', 'Reg', (79, 89))	('inhibit', 'NegReg', (17, 24))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (25, 46))	('miR-204-5p', 'Chemical', '-', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('SIX1', 'Gene', '6495', (90, 94))	('hepatocellular cancer', 'Disease', (25, 46))	('SIX1', 'Gene', (90, 94))	('miR-204-5p', 'Var', (0, 10))
821746	32547097	Meanwhile, Wang et al reported that miR-204-5p was lower expressed in oral squamous cell carcinoma, and miR-204-5p acted as a  tumor suppressor in oral squamous cell carcinoma via targeting CXCR4.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('miR-204-5p', 'Chemical', '-', (104, 114))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 175))	('CXCR4', 'Gene', (190, 195))	('miR-204-5p', 'Var', (104, 114))	('tumor', 'Disease', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('miR-204-5p', 'Chemical', '-', (36, 46))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('lower', 'NegReg', (51, 56))	('oral squamous cell carcinoma', 'Disease', (147, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('CXCR4', 'Gene', '7852', (190, 195))	('oral squamous cell carcinoma', 'Disease', (70, 98))	('targeting', 'Reg', (180, 189))
821747	32547097	Therefore, most studies have suggested that miR-204-5p played as a tumor suppressor in multiple human malignant tumors, Similar to these studies, this research also illustrated that miR-204-5p acted as a tumor suppressor in ESCC.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('human', 'Species', '9606', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('miR-204-5p', 'Chemical', '-', (44, 54))	('malignant tumors', 'Disease', (102, 118))	('malignant tumors', 'Disease', 'MESH:D009369', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (204, 209))	('miR-204-5p', 'Chemical', '-', (182, 192))	('ESCC', 'Disease', (224, 228))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (112, 117))	('miR-204-5p', 'Var', (182, 192))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
821748	32547097	More importantly, this study demonstrated for the first time that miR-204-5p inhibited ESCC progression via regulating YWHAZ/PI3K/AKT.	('inhibited', 'NegReg', (77, 86))	('YWHAZ', 'Gene', (119, 124))	('ESCC', 'Disease', (87, 91))	('AKT', 'Gene', '207', (130, 133))	('YWHAZ', 'Gene', '7534', (119, 124))	('miR-204-5p', 'Var', (66, 76))	('miR-204-5p', 'Chemical', '-', (66, 76))	('AKT', 'Gene', (130, 133))
821749	32547097	These findings laid reliable theoretical basis for the application of miR-204-5p in the clinical target treatment of ESCC.	('ESCC', 'Disease', (117, 121))	('miR-204-5p', 'Chemical', '-', (70, 80))	('miR-204-5p', 'Var', (70, 80))
821756	32547097	This article proved for the first time that YWHAZ was directly inhibited by miR-204-5p in ESCC.	('YWHAZ', 'Gene', '7534', (44, 49))	('YWHAZ', 'Gene', (44, 49))	('inhibited', 'NegReg', (63, 72))	('miR-204-5p', 'Chemical', '-', (76, 86))	('miR-204-5p', 'Var', (76, 86))
821763	32547097	In this research, miR-204-5p inhibited the development of ESCC partially through suppressing the activation of YWHAZ/PI3K/AKT.	('miR-204-5p', 'Var', (18, 28))	('YWHAZ', 'Gene', (111, 116))	('inhibited', 'NegReg', (29, 38))	('suppressing', 'NegReg', (81, 92))	('miR-204-5p', 'Chemical', '-', (18, 28))	('development', 'CPA', (43, 54))	('YWHAZ', 'Gene', '7534', (111, 116))	('AKT', 'Gene', '207', (122, 125))	('ESCC', 'Disease', (58, 62))	('AKT', 'Gene', (122, 125))
821764	32547097	Collectively, this article discovered that miR-204-5p expression was reduced in ESCC and overexpression of miR-204-5p could inhibit the progression of ESCC by targeting YWHAZ/PI3K/AKT signaling.	('miR-204-5p', 'Var', (107, 117))	('expression', 'MPA', (54, 64))	('YWHAZ', 'Gene', (169, 174))	('progression', 'CPA', (136, 147))	('reduced', 'NegReg', (69, 76))	('miR-204-5p', 'Chemical', '-', (43, 53))	('YWHAZ', 'Gene', '7534', (169, 174))	('ESCC', 'Disease', (151, 155))	('miR-204-5p', 'Protein', (43, 53))	('AKT', 'Gene', (180, 183))	('AKT', 'Gene', '207', (180, 183))	('inhibit', 'NegReg', (124, 131))	('miR-204-5p', 'Chemical', '-', (107, 117))	('ESCC', 'Disease', (80, 84))	('targeting', 'Reg', (159, 168))
821765	32547097	Thus, miR-204-5p might be a novel potential target for the treatment of ESCC.	('miR-204-5p', 'Chemical', '-', (6, 16))	('miR-204-5p', 'Var', (6, 16))	('ESCC', 'Disease', (72, 76))
821767	32547097	(2) miR-204-5p overexpression suppressed ESCC development in vitro.	('miR-204-5p', 'Var', (4, 14))	('overexpression', 'PosReg', (15, 29))	('suppressed', 'NegReg', (30, 40))	('ESCC development', 'CPA', (41, 57))	('miR-204-5p', 'Chemical', '-', (4, 14))
821768	32547097	(3) YWHAZ was directly inhibited by miR-204-5p and was highly expressed in ESCC.	('inhibited', 'NegReg', (23, 32))	('miR-204-5p', 'Chemical', '-', (36, 46))	('miR-204-5p', 'Var', (36, 46))	('YWHAZ', 'Gene', '7534', (4, 9))	('YWHAZ', 'Gene', (4, 9))
821769	32547097	(4) miR-204-5p suppressed ESCC development by inhibiting YWHAZ/PI3K/AKT.	('inhibiting', 'NegReg', (46, 56))	('miR-204-5p', 'Var', (4, 14))	('ESCC development', 'CPA', (26, 42))	('YWHAZ', 'Gene', '7534', (57, 62))	('YWHAZ', 'Gene', (57, 62))	('AKT', 'Gene', '207', (68, 71))	('suppressed', 'NegReg', (15, 25))	('miR-204-5p', 'Chemical', '-', (4, 14))	('AKT', 'Gene', (68, 71))
821770	32547097	(5) miR-204-5p inhibited ESCC growth in vivo by suppressing YWHAZ expression.	('miR-204-5p', 'Var', (4, 14))	('inhibited', 'NegReg', (15, 24))	('YWHAZ', 'Gene', (60, 65))	('ESCC', 'Disease', (25, 29))	('YWHAZ', 'Gene', '7534', (60, 65))	('suppressing', 'NegReg', (48, 59))	('miR-204-5p', 'Chemical', '-', (4, 14))
821823	31011900	A tumor located in the entire stomach (versus gastroesophageal junction/fundus), higher cT-categories (cT3, cT4 and cTx category versus cT0-2), a pN+-category and pNx-category (versus pN-), and diffuse or unknown type adenocarcinoma (versus intestinal type) were associated with incomplete tumor removal (Table 2).	('esophageal', 'Disease', 'MESH:D004941', (52, 62))	('tumor removal', 'Disease', 'MESH:D009369', (290, 303))	('cT3', 'Gene', '285782', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('unknown type adenocarcinoma', 'Disease', 'MESH:D009382', (205, 232))	('cT-categories', 'MPA', (88, 101))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('unknown type adenocarcinoma', 'Disease', (205, 232))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('tumor removal', 'Disease', (290, 303))	('pN+-category', 'Var', (146, 158))	('cT3', 'Gene', (103, 106))	('esophageal', 'Disease', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumor', 'Disease', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('incomplete', 'NegReg', (279, 289))	('tumor', 'Disease', (290, 295))
821857	31011900	The local recurrence was significantly lower in the converted-to-R0 group than in patients with a positive final frozen section.	('patients', 'Species', '9606', (82, 90))	('converted-to-R0', 'Var', (52, 67))	('local recurrence', 'CPA', (4, 20))	('lower', 'NegReg', (39, 44))
821880	30519047	Eighteen studies were retrieved; CTC-positive patients were significantly associated with poor progression-free survival (PFS) (HR=2.61; 95% CI=2.08-3.28) and overall survival (OS) (HR=2.50; 95% CI=2.12-2.94).	('progression-free survival', 'CPA', (95, 120))	('poor', 'NegReg', (90, 94))	('patients', 'Species', '9606', (46, 54))	('overall survival', 'CPA', (159, 175))	('CTC-positive', 'Var', (33, 45))
821881	30519047	CTC-positive patients were also associated with high recurrence (OR=2.84; 95% CI=1.81-4.44) and poor response of chemoradiotherapy (RR=0.64; 95% CI=0.43-0.96).	('CTC-positive', 'Var', (0, 12))	('patients', 'Species', '9606', (13, 21))	('high recurrence', 'CPA', (48, 63))
821926	30519047	In this meta-analysis, it has been demonstrated that CTCs in peripheral blood were significantly associated with poor PFS and OS of esophageal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CTCs', 'Var', (53, 57))	('OS of esophageal cancer', 'Disease', (126, 149))	('PFS', 'Disease', (118, 121))	('OS of esophageal cancer', 'Disease', 'MESH:C567932', (126, 149))	('patients', 'Species', '9606', (150, 158))	('poor PFS', 'Disease', (113, 121))	('associated', 'Reg', (97, 107))
821931	30519047	Furthermore, in the subanalysis of the survival effects, our meta-analysis showed a significant prognostic effect for OS and PFS and demonstrated a higher risk of deaths or tumor progression in the CTC-positive patients than the CTC-negative patients in all subgroups.	('patients', 'Species', '9606', (211, 219))	('PFS', 'Disease', (125, 128))	('deaths or tumor', 'Disease', 'MESH:D003643', (163, 178))	('deaths or tumor', 'Disease', (163, 178))	('CTC-positive', 'Var', (198, 210))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('patients', 'Species', '9606', (242, 250))
821945	30519047	After escaped from primary tumor and shed into blood, CTCs could be activated due to the loss of biological control by primary tumor and the alteration of internal environment, then CTCs can form the new metastasis or recurrence and cause the resistance of chemoradiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('resistance of chemoradiotherapy', 'CPA', (243, 274))	('recurrence', 'CPA', (218, 228))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (27, 32))	('biological', 'MPA', (97, 107))	('cause', 'Reg', (233, 238))	('CTCs', 'Var', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('loss', 'NegReg', (89, 93))
821970	29717405	Obesity is also shown, however, to correlate with an increase in gastroesophageal reflux disease (GERD)-related disorders, including Barrett's esophagus (BE) and esophageal carcinoma.	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (65, 88))	('esophageal reflux', 'Phenotype', 'HP:0002020', (71, 88))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (65, 96))	('Obesity', 'Var', (0, 7))	("Barrett's esophagus", 'Disease', (133, 152))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (133, 152))	('reflux disease', 'Phenotype', 'HP:0002020', (82, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal carcinoma', 'Disease', (162, 182))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('increase', 'PosReg', (53, 61))	('BE', 'Phenotype', 'HP:0100580', (154, 156))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (162, 182))	('gastroesophageal reflux disease', 'Disease', (65, 96))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (162, 182))
821976	29717405	PPIs have also been demonstrated to effectively reduce the duration of esophageal acid exposure in obese patients, across all examined obesity classes.	('esophageal acid', 'Chemical', '-', (71, 86))	('obesity', 'Disease', 'MESH:D009765', (135, 142))	('patients', 'Species', '9606', (105, 113))	('obese', 'Disease', 'MESH:D009765', (99, 104))	('obesity', 'Disease', (135, 142))	('obese', 'Disease', (99, 104))	('reduce', 'NegReg', (48, 54))	('duration of esophageal acid exposure', 'MPA', (59, 95))	('obesity', 'Phenotype', 'HP:0001513', (135, 142))	('PPIs', 'Var', (0, 4))
822017	29717405	A retrospective analysis additionally found that PPI therapy in obese patients is effective for resolution of gastric reflux.	('patients', 'Species', '9606', (70, 78))	('gastric reflux', 'Disease', (110, 124))	('obese', 'Disease', 'MESH:D009765', (64, 69))	('gastric reflux', 'Phenotype', 'HP:0002020', (110, 124))	('obese', 'Disease', (64, 69))	('PPI', 'Var', (49, 52))
822028	29717405	This is further highlighted by the fact that patients who were started on D2 antagonists, such as metoclopramide or domperidone, were also at increased risk of developing BE (OR = 1.241) and then subsequently esophageal carcinoma (OR = 2.588).	('esophageal carcinoma', 'Disease', (209, 229))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('domperidone', 'Var', (116, 127))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (209, 229))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (209, 229))	('domperidone', 'Chemical', 'MESH:D004294', (116, 127))	('metoclopramide', 'Chemical', 'MESH:D008787', (98, 112))	('patients', 'Species', '9606', (45, 53))	('D2 antagonists', 'Protein', (74, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('metoclopramide', 'Var', (98, 112))
822036	29717405	Gastric bypass operations for morbid obesity have also been shown to reduce acid reflux, in addition to reducing BMI and metabolic conditions.	('obesity', 'Phenotype', 'HP:0001513', (37, 44))	('obesity', 'Disease', 'MESH:D009765', (37, 44))	('acid reflux', 'Phenotype', 'HP:0002020', (76, 87))	('obesity', 'Disease', (37, 44))	('morbid obesity', 'Phenotype', 'HP:0012743', (30, 44))	('reducing', 'NegReg', (104, 112))	('acid reflux', 'MPA', (76, 87))	('operations', 'Var', (15, 25))	('reduce', 'NegReg', (69, 75))
822054	28757263	However, it is not clear what proportion of ESCC cells carry these epigenomic aberrations or how they contribute to tumor development.	('SCC', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('SCC', 'Gene', '6317', (45, 48))	('contribute', 'Reg', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('epigenomic aberrations', 'Var', (67, 89))	('tumor', 'Disease', (116, 121))
822059	28757263	Genomic analyses provide evidence for pervasive abnormalities in the ESCC epigenome: epigenetic regulators themselves are frequently altered by genetic changes.	('pervasive abnormalities', 'Disease', (38, 61))	('SCC', 'Gene', (70, 73))	('epigenetic regulators themselves', 'MPA', (85, 117))	('SCC', 'Gene', '6317', (70, 73))	('pervasive abnormalities', 'Disease', 'MESH:D002659', (38, 61))	('genetic changes', 'Var', (144, 159))	('altered', 'Reg', (133, 140))
822063	28757263	Several tumor types have genetic alterations that can be targeted therapeutically, such as HER2+ breast tumors, EGFR+ lung tumors, and BRAF+ melanomas, but such actionable alterations have not been identified in ESCCs.	('breast tumors', 'Disease', 'MESH:D001943', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('breast tumors', 'Phenotype', 'HP:0100013', (97, 110))	('genetic alterations', 'Var', (25, 44))	('BRAF', 'Gene', '673', (135, 139))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('tumor', 'Disease', (123, 128))	('melanomas', 'Disease', (141, 150))	('BRAF', 'Gene', (135, 139))	('lung tumors', 'Disease', 'MESH:D008175', (118, 129))	('HER2', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('lung tumors', 'Phenotype', 'HP:0100526', (118, 129))	('EGFR', 'Gene', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('SCC', 'Gene', '6317', (213, 216))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (8, 13))	('SCC', 'Gene', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('lung tumors', 'Disease', (118, 129))	('melanomas', 'Disease', 'MESH:D008545', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('HER2', 'Gene', '2064', (91, 95))	('EGFR', 'Gene', '1956', (112, 116))	('breast tumors', 'Disease', (97, 110))
822067	28757263	The most frequent high-level amplifications and homozygous deletions involve 11q13.2-q13.3 and 9p21.3 (locus of CDKN2A and CDKN2B), respectively (Table 1).	('CDKN2A', 'Gene', (112, 118))	('CDKN2A', 'Gene', '1029', (112, 118))	('CDKN2B', 'Gene', (123, 129))	('CDKN2B', 'Gene', '1030', (123, 129))	('amplifications', 'Var', (29, 43))
822070	28757263	CCND1 is amplified by breakage fusion bridge cycles, which occurs under conditions of chromosomal instability.	('CCND1', 'Gene', (0, 5))	('chromosomal instability', 'Phenotype', 'HP:0040012', (86, 109))	('CCND1', 'Gene', '595', (0, 5))	('breakage', 'Var', (22, 30))
822071	28757263	This gene is often coamplified with its neighboring oncogene CTTN; its product promotes migration of ESCC cells.	('SCC', 'Gene', '6317', (102, 105))	('promotes', 'PosReg', (79, 87))	('CTTN', 'Gene', (61, 65))	('product', 'Var', (71, 78))	('CTTN', 'Gene', '2017', (61, 65))	('SCC', 'Gene', (102, 105))
822072	28757263	Additional recurrent focal amplifications in ESCC include those at 8p11.23 (FGFR1), 8q24.21 (MYC), 7p11.2 (EGFR), 12p12.1 (KRAS), 12q15 (MDM2), 3q26 (TP63 and PRKCI), 3q26.32-q26.33 (SOX2 and PIK3CA), and 14q13.3 (NKX2-1).	('KRAS', 'Gene', '3845', (123, 127))	('EGFR', 'Gene', (107, 111))	('PIK3CA', 'Gene', '5290', (192, 198))	('KRAS', 'Gene', (123, 127))	('FGFR1', 'Gene', '2260', (76, 81))	('MYC', 'Gene', '4609', (93, 96))	('PRKCI', 'Gene', '5584', (159, 164))	('SOX2', 'Gene', '6657', (183, 187))	('7p11.2', 'Var', (99, 105))	('SOX2', 'Gene', (183, 187))	('MDM2', 'Gene', (137, 141))	('TP63', 'Gene', (150, 154))	('12p12.1', 'Var', (114, 121))	('NKX2-1', 'Gene', '7080', (214, 220))	('3q26', 'Var', (144, 148))	('EGFR', 'Gene', '1956', (107, 111))	('MDM2', 'Gene', '4193', (137, 141))	('PIK3CA', 'Gene', (192, 198))	('NKX2-1', 'Gene', (214, 220))	('TP63', 'Gene', '8626', (150, 154))	('FGFR1', 'Gene', (76, 81))	('SCC', 'Gene', '6317', (46, 49))	('PRKCI', 'Gene', (159, 164))	('MYC', 'Gene', (93, 96))	('SCC', 'Gene', (46, 49))	('3q26.32-q26.33', 'Var', (167, 181))	('14q13.3', 'Var', (205, 212))
822073	28757263	Other frequent homozygous deletions contain 2q22.1-q22.2 (LRP1B), 9p24.1 (PTPRD), and 3p14.2 (FHIT).	('3p14.2', 'Var', (86, 92))	('LRP1B', 'Gene', (58, 63))	('9p24.1', 'Var', (66, 72))	('2q22.1-q22.2', 'Var', (44, 56))	('PTPRD', 'Gene', '5789', (74, 79))	('PTPRD', 'Gene', (74, 79))	('LRP1B', 'Gene', '53353', (58, 63))	('FHIT', 'Gene', (94, 98))	('FHIT', 'Gene', '2272', (94, 98))
822075	28757263	Recently, researchers also have performed high-resolution characterization of structural rearrangements in ESCCs, including intrachromosome insertions, inversions and duplications, and interchromosome translocations.	('SCC', 'Gene', (108, 111))	('inversions', 'Var', (152, 162))	('duplications', 'Var', (167, 179))	('interchromosome translocations', 'Var', (185, 215))	('SCC', 'Gene', '6317', (108, 111))
822077	28757263	Most structural rearrangements are not likely to have pathogenic potential, but a few recurrent ones might be candidate driver events, such as frequent structural breakpoints affecting the KCNB2 gene, or an in-frame fusion between TRAPPC9 and CLVS1.	('CLVS1', 'Gene', (243, 248))	('structural breakpoints', 'Var', (152, 174))	('CLVS1', 'Gene', '157807', (243, 248))	('TRAPPC9', 'Gene', '83696', (231, 238))	('KCNB2', 'Gene', (189, 194))	('TRAPPC9', 'Gene', (231, 238))	('KCNB2', 'Gene', '9312', (189, 194))
822080	28757263	Additional structural rearrangements involving potential oncogenes included MYBL2 duplication, fusions of RUNX1T1-PHACTR1, MAML2-TTC28, ASXL1-RNF170, and FGF19-SHANK2.	('RNF170', 'Gene', (142, 148))	('PHACTR1', 'Gene', (114, 121))	('MYBL2', 'Gene', '4605', (76, 81))	('duplication', 'Var', (82, 93))	('RUNX1T1', 'Gene', '862', (106, 113))	('FGF19', 'Gene', (154, 159))	('FGF19', 'Gene', '9965', (154, 159))	('RNF170', 'Gene', '81790', (142, 148))	('MAML2', 'Gene', (123, 128))	('ASXL1', 'Gene', '171023', (136, 141))	('PHACTR1', 'Gene', '221692', (114, 121))	('TTC28', 'Gene', '23331', (129, 134))	('SHANK2', 'Gene', '22941', (160, 166))	('MAML2', 'Gene', '84441', (123, 128))	('RUNX1T1', 'Gene', (106, 113))	('MYBL2', 'Gene', (76, 81))	('fusions', 'Var', (95, 102))	('ASXL1', 'Gene', (136, 141))	('TTC28', 'Gene', (129, 134))	('SHANK2', 'Gene', (160, 166))
822089	28757263	Like many other cancer types, ESCCs contain prevalent mutations in TP53.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('SCC', 'Gene', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (54, 63))	('SCC', 'Gene', '6317', (31, 34))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
822090	28757263	Other driver mutations are much less frequent in ESCCs (found in fewer than 20% of samples).	('SCC', 'Gene', '6317', (50, 53))	('mutations', 'Var', (13, 22))	('SCC', 'Gene', (50, 53))
822094	28757263	Mutations in FAM135B, EP300, and TET2 have been associated with shorter times of patient survival.	('EP300', 'Gene', (22, 27))	('TET2', 'Gene', '54790', (33, 37))	('FAM135B', 'Gene', (13, 20))	('patient', 'Species', '9606', (81, 88))	('TET2', 'Gene', (33, 37))	('Mutations', 'Var', (0, 9))	('FAM135B', 'Gene', '51059', (13, 20))	('EP300', 'Gene', '2033', (22, 27))	('shorter', 'NegReg', (64, 71))
822096	28757263	Specifically, studies of ESCCs typically sequenced the exomes of 100 to 150 tumor-germline pairs, whereas mathematical analysis estimated that 1000 to 2000 samples are needed to identify with confidence SMGs mutated in 2% to 3% of the population, taking into account the background mutational rate of ESCC.	('SCC', 'Gene', '6317', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('SCC', 'Gene', (302, 305))	('mutated', 'Var', (208, 215))	('SCC', 'Gene', '6317', (302, 305))	('SMG', 'Chemical', '-', (203, 206))	('SCC', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
822100	28757263	Signature 1 is characterized by C > T substitutions at NpCpG trinucleotides and is the most commonly observed signature in ESCC samples.	('substitutions', 'Var', (38, 51))	('NpCpG', 'Gene', (55, 60))	('SCC', 'Gene', (124, 127))	('SCC', 'Gene', '6317', (124, 127))	('C > T substitutions', 'Var', (32, 51))	('trinucleotides', 'Chemical', '-', (61, 75))
822102	28757263	Another clock-like mutation signature found in ESCC is Signature 5, which is characterized by transcriptional strand bias for T > C substitutions at ApTpN trinucleotides.	('SCC', 'Gene', (48, 51))	('trinucleotides', 'Chemical', '-', (155, 169))	('SCC', 'Gene', '6317', (48, 51))	('T > C substitutions', 'Var', (126, 145))	('ApTpN', 'Gene', (149, 154))
822106	28757263	Signature 4, characterized by transcription strand bias for C > A substitutions, is found in a small set of ESCC tissues.	('SCC', 'Gene', (109, 112))	('SCC', 'Gene', '6317', (109, 112))	('C > A substitutions', 'Var', (60, 79))
822110	28757263	Mutations in PIK3CA and ZNF750 were significantly enriched in ESCCs with signature 2 and signature 13, suggesting that elevated APOBEC activity may lead to acquisition of driver mutations in these ESCCs.	('ZNF750', 'Gene', (24, 30))	('SCC', 'Gene', '6317', (198, 201))	('PIK3CA', 'Gene', (13, 19))	('SCC', 'Gene', (63, 66))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('SCC', 'Gene', '6317', (63, 66))	('ZNF750', 'Gene', '79755', (24, 30))	('SCC', 'Gene', (198, 201))
822112	28757263	Nevertheless, these approaches have identified many factors that contribute to esophageal carcinogenesis, such as epigenetic silencing of genes, super-enhancer activation, and RNA editing.	('super-enhancer', 'Var', (145, 159))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (79, 104))	('esophageal carcinogenesis', 'Disease', (79, 104))	('epigenetic silencing', 'Var', (114, 134))	('genes', 'Gene', (138, 143))
822114	28757263	These epigenomic aberrations each contribute to the pathogenesis of ESCC, through different mechanisms.	('SCC', 'Gene', (69, 72))	('SCC', 'Gene', '6317', (69, 72))	('epigenomic aberrations', 'Var', (6, 28))	('contribute', 'Reg', (34, 44))
822115	28757263	Promoter hypermethylation silences tumor suppressor genes such as CDKN2A, CDKN2B, DLC1, LRP1B, and RASSF1A (Table 3).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('silences', 'NegReg', (26, 34))	('DLC1', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('RASSF1A', 'Gene', '11186', (99, 106))	('CDKN2B', 'Gene', (74, 80))	('LRP1B', 'Gene', '53353', (88, 93))	('tumor', 'Disease', (35, 40))	('CDKN2A', 'Gene', '1029', (66, 72))	('CDKN2B', 'Gene', '1030', (74, 80))	('RASSF1A', 'Gene', (99, 106))	('DLC1', 'Gene', '10395', (82, 86))	('CDKN2A', 'Gene', (66, 72))	('LRP1B', 'Gene', (88, 93))	('Promoter hypermethylation', 'Var', (0, 25))
822116	28757263	A few genes encoding microRNAs are also methylated and down-regulated in ESCCs, compared with nonmalignant tissues, including those with anti-proliferative functions, such as microRNA34a and micro-RNA375.	('methylated', 'Var', (40, 50))	('micro-RNA375', 'Gene', '494324', (191, 203))	('SCC', 'Gene', (74, 77))	('down-regulated', 'NegReg', (55, 69))	('micro-RNA375', 'Gene', (191, 203))	('SCC', 'Gene', '6317', (74, 77))
822119	28757263	In addition, hypermethylation of the APC and FHIT promoters was significantly associated with reduced survival times of patients with ESCC, so these might be prognostic factors.	('reduced', 'NegReg', (94, 101))	('APC', 'Disease', (37, 40))	('FHIT', 'Gene', (45, 49))	('SCC', 'Gene', (135, 138))	('FHIT', 'Gene', '2272', (45, 49))	('patients', 'Species', '9606', (120, 128))	('survival times', 'CPA', (102, 116))	('hypermethylation', 'Var', (13, 29))	('SCC', 'Gene', '6317', (135, 138))	('APC', 'Disease', 'MESH:D011125', (37, 40))
822124	28757263	Consistent genome-wide hypomethylation was observed in ESCCs from different cohorts.	('SCC', 'Gene', (56, 59))	('observed', 'Reg', (43, 51))	('SCC', 'Gene', '6317', (56, 59))	('hypomethylation', 'Var', (23, 38))
822125	28757263	LINE-1 hypomethylation was associated with increased chromosomal instability, TP53 mutation, lymph node metastasis, as well as a shorter survival times of patients.	('hypomethylation', 'Var', (7, 22))	('chromosomal instability', 'MPA', (53, 76))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (43, 76))	('mutation', 'Var', (83, 91))	('patients', 'Species', '9606', (155, 163))	('TP53', 'Gene', '7157', (78, 82))	('increased', 'PosReg', (43, 52))	('TP53', 'Gene', (78, 82))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('lymph node metastasis', 'CPA', (93, 114))	('shorter', 'NegReg', (129, 136))	('LINE-1', 'Gene', (0, 6))
822127	28757263	In glioma cells, changes in DNA methylation reduced the binding of CTCF to its motif sequence, disrupting insulated genomic domains.	('CTCF', 'Gene', '10664', (67, 71))	('DNA', 'MPA', (28, 31))	('motif', 'Protein', (79, 84))	('disrupting', 'NegReg', (95, 105))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('changes', 'Var', (17, 24))	('insulated genomic domains', 'MPA', (106, 131))	('binding', 'Interaction', (56, 63))	('reduced', 'NegReg', (44, 51))	('glioma', 'Disease', (3, 9))	('CTCF', 'Gene', (67, 71))
822128	28757263	Thus, the ESCC methylome awaits further characterization through sequence-based approaches, such as reduced representation bisulfite sequencing and whole-genome bisulfite sequencing, which detect methylation changes with high resolution and a high level of sensitivity.	('SCC', 'Gene', (11, 14))	('bisulfite', 'Chemical', 'MESH:C042345', (161, 170))	('SCC', 'Gene', '6317', (11, 14))	('methylation', 'Var', (196, 207))	('bisulfite', 'Chemical', 'MESH:C042345', (123, 132))
822130	28757263	Many mutations detected in ESCCs lie in genes encoding proteins that modify DNA/histone (EP300, CREBBP, and MLL2), genes that remove histone modifications (KDM6A and TET2), and proteins that remodel chromatin structures (ARID1A, ARID2, and SMARCC2).	('SMARCC2', 'Gene', (240, 247))	('SCC', 'Gene', '6317', (28, 31))	('TET2', 'Gene', '54790', (166, 170))	('DNA/histone', 'Protein', (76, 87))	('ARID2', 'Gene', '196528', (229, 234))	('SCC', 'Gene', (28, 31))	('MLL2', 'Gene', '8085', (108, 112))	('SMARCC2', 'Gene', '6601', (240, 247))	('histone modifications', 'MPA', (133, 154))	('CREBBP', 'Gene', (96, 102))	('modify', 'Reg', (69, 75))	('MLL2', 'Gene', (108, 112))	('EP300', 'Gene', '2033', (89, 94))	('KDM6A', 'Gene', '7403', (156, 161))	('mutations', 'Var', (5, 14))	('ARID2', 'Gene', (229, 234))	('ARID1A', 'Gene', (221, 227))	('EP300', 'Gene', (89, 94))	('CREBBP', 'Gene', '1387', (96, 102))	('TET2', 'Gene', (166, 170))	('ARID1A', 'Gene', '8289', (221, 227))	('KDM6A', 'Gene', (156, 161))
822133	28757263	Ectopic expression of EZH2 in ESCC cell lines elevated the overall level of H3K27me3.	('EZH2', 'Gene', (22, 26))	('elevated', 'PosReg', (46, 54))	('SCC', 'Gene', (31, 34))	('Ectopic expression', 'Var', (0, 18))	('SCC', 'Gene', '6317', (31, 34))	('H3K27me3', 'Gene', '126961', (76, 84))	('H3K27me3', 'Gene', (76, 84))	('EZH2', 'Gene', '2146', (22, 26))	('level', 'MPA', (67, 72))
822142	28757263	The ADAR1 gene was reported to be amplified and overexpressed in primary ESCC tissues, and ectopic expression of ADAR1 enhanced a malignant phenotype of ESCC cells.	('SCC', 'Gene', '6317', (154, 157))	('SCC', 'Gene', '6317', (74, 77))	('enhanced', 'PosReg', (119, 127))	('ADAR1', 'Gene', '103', (113, 118))	('malignant phenotype of', 'CPA', (130, 152))	('ectopic expression', 'Var', (91, 109))	('ADAR1', 'Gene', '103', (4, 9))	('SCC', 'Gene', (74, 77))	('SCC', 'Gene', (154, 157))	('ADAR1', 'Gene', (4, 9))	('ADAR1', 'Gene', (113, 118))
822156	28757263	ESCC1 was characterized by enriched genomic aberrations targeting the nuclear factor, erythroid 2 like 2 (NRF2) pathway (NFE2L2, KEAP1, CUL3, and ATG7), as well as amplifications of SOX2, TP63, and YAP1.	('ATG7', 'Gene', (146, 150))	('CUL3', 'Gene', '8452', (136, 140))	('NRF2', 'Gene', '4780', (106, 110))	('YAP1', 'Gene', '10413', (198, 202))	('nuclear factor, erythroid 2 like 2', 'Gene', '4780', (70, 104))	('NFE2L2', 'Gene', '4780', (121, 127))	('TP63', 'Gene', (188, 192))	('YAP1', 'Gene', (198, 202))	('SCC', 'Gene', '6317', (1, 4))	('NRF2', 'Gene', (106, 110))	('amplifications', 'Var', (164, 178))	('TP63', 'Gene', '8626', (188, 192))	('CUL3', 'Gene', (136, 140))	('SCC', 'Gene', (1, 4))	('ATG7', 'Gene', '10533', (146, 150))	('NFE2L2', 'Gene', (121, 127))	('SOX2', 'Gene', (182, 186))	('SOX2', 'Gene', '6657', (182, 186))	('KEAP1', 'Gene', '9817', (129, 134))	('KEAP1', 'Gene', (129, 134))
822157	28757263	ESCC2 was found to be devoid of these genetic alterations, but instead had more frequent mutations or deletions in SMGs such as KDM6A, MLL2, NOTCH1, and ZNF750.	('KDM6A', 'Gene', '7403', (128, 133))	('SMG', 'Chemical', '-', (115, 118))	('deletions', 'Var', (102, 111))	('MLL2', 'Gene', (135, 139))	('ZNF750', 'Gene', '79755', (153, 159))	('KDM6A', 'Gene', (128, 133))	('SCC', 'Gene', (1, 4))	('NOTCH1', 'Gene', '4851', (141, 147))	('SMGs', 'Gene', (115, 119))	('mutations', 'Var', (89, 98))	('MLL2', 'Gene', '8085', (135, 139))	('ZNF750', 'Gene', (153, 159))	('NOTCH1', 'Gene', (141, 147))	('SCC', 'Gene', '6317', (1, 4))
822158	28757263	The minor subtype, ESCC3, had SMARCA4 mutations and fewer CNAs than the ESCC1 or ESCC2 subtypes.	('fewer', 'NegReg', (52, 57))	('SCC', 'Gene', (20, 23))	('SCC', 'Gene', '6317', (82, 85))	('CNAs', 'Disease', (58, 62))	('SCC', 'Gene', (73, 76))	('SCC', 'Gene', '6317', (20, 23))	('SCC', 'Gene', '6317', (73, 76))	('mutations', 'Var', (38, 47))	('SCC', 'Gene', (82, 85))	('SMARCA4', 'Gene', (30, 37))	('SMARCA4', 'Gene', '6597', (30, 37))
822164	28757263	Importantly, 40% of driver mutations were spatially heterogeneous, meaning they could be detected only in some, but not all cancer cells from the same tumor.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
822165	28757263	Mathematical reconstruction of tumor progression showed that these heterogeneous mutations were relatively late events in ESCC development, promoting the expansion of subclones of cancer cells.	('promoting', 'PosReg', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('SCC', 'Gene', '6317', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', (31, 36))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))	('SCC', 'Gene', (123, 126))
822167	28757263	Nevertheless, despite this tendency, several ESCC oncogenes, such as PIK3CA, MTOR, NFE2L2, and KIT, become mutated in a subclonal manner.	('mutated', 'Var', (107, 114))	('KIT', 'Gene', (95, 98))	('MTOR', 'Gene', (77, 81))	('NFE2L2', 'Gene', '4780', (83, 89))	('PIK3CA', 'Gene', (69, 75))	('SCC', 'Gene', (46, 49))	('MTOR', 'Gene', '2475', (77, 81))	('PIK3CA', 'Gene', '5290', (69, 75))	('NFE2L2', 'Gene', (83, 89))	('SCC', 'Gene', '6317', (46, 49))
822169	28757263	In a clinical trial, AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), reduced growth of only gastric tumors with clonal FGFR2 amplification, not those with subclonal amplification of this gene.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('AZD4547', 'Chemical', 'MESH:C572463', (21, 28))	('FGFR2', 'Gene', (138, 143))	('FGFR2', 'Gene', '2263', (138, 143))	('gastric tumors', 'Phenotype', 'HP:0006753', (111, 125))	('FGFR', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('gastric tumors', 'Disease', (111, 125))	('gastric tumors', 'Disease', 'MESH:D013274', (111, 125))	('growth', 'MPA', (96, 102))	('amplification', 'Var', (144, 157))	('reduced', 'NegReg', (88, 95))	('AZD4547', 'Var', (21, 28))
822173	28757263	Other important genomic and epigenomic variations, including copy number and DNA methylation changes, contribute to the spatial diversity within single ESCC tumors.	('ESCC tumors', 'Disease', 'MESH:D004938', (152, 163))	('DNA', 'MPA', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('copy number', 'Var', (61, 72))	('ESCC tumors', 'Disease', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
822174	28757263	Degrees of intratumor heterogeneity and tumor evolution determined by DNA methylation recapitulate those determined by somatic mutations, indicating interactions between genomic and epigenomic events during development of ESCC.	('methylation', 'Var', (74, 85))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('SCC', 'Gene', (223, 226))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('SCC', 'Gene', '6317', (223, 226))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('interactions', 'Interaction', (149, 161))
822177	28757263	Using reduced representation bisulfite sequencing to profile chronic lymphocytic leukemia, Landau et al demonstrated that the degree of intratumor heterogeneity of methylation correlated with shorter time of relapse-free survival.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('shorter', 'NegReg', (192, 199))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (69, 89))	('lymphocytic leukemia', 'Disease', (69, 89))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('methylation', 'Var', (164, 175))	('tumor', 'Disease', (141, 146))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (61, 89))	('bisulfite', 'Chemical', 'MESH:C042345', (29, 38))
822178	28757263	Intratumor heterogeneity of mutation and methylation also associate with outcomes of patients with hepatocellular carcinoma.	('associate with', 'Reg', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('methylation', 'Var', (41, 52))	('patients', 'Species', '9606', (85, 93))	('mutation', 'Var', (28, 36))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('tumor', 'Disease', (5, 10))	('hepatocellular carcinoma', 'Disease', (99, 123))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (99, 123))
822196	28757263	Notably, however, several mutations associated with ESCC were also found in BCH samples, including those in TP53, NOTCH1, CDKN2A, EP300, and MLL2.	('SCC', 'Gene', '6317', (53, 56))	('BCH', 'Chemical', '-', (76, 79))	('MLL2', 'Gene', (141, 145))	('NOTCH1', 'Gene', (114, 120))	('EP300', 'Gene', (130, 135))	('TP53', 'Gene', '7157', (108, 112))	('CDKN2A', 'Gene', (122, 128))	('TP53', 'Gene', (108, 112))	('found', 'Reg', (67, 72))	('CDKN2A', 'Gene', '1029', (122, 128))	('mutations', 'Var', (26, 35))	('MLL2', 'Gene', '8085', (141, 145))	('SCC', 'Gene', (53, 56))	('NOTCH1', 'Gene', '4851', (114, 120))	('EP300', 'Gene', '2033', (130, 135))
822197	28757263	All these mutations were found in BCH, IEN, and ESCC tissues, so they might be early clonal events involved in development of ESCC.	('SCC', 'Gene', (127, 130))	('SCC', 'Gene', (49, 52))	('IEN', 'Phenotype', 'HP:0032187', (39, 42))	('SCC', 'Gene', '6317', (127, 130))	('SCC', 'Gene', '6317', (49, 52))	('BCH', 'Chemical', '-', (34, 37))	('mutations', 'Var', (10, 19))
822198	28757263	Independent studies also showed that TP53 mutations persisted from IEN to invasive cancer.	('invasive cancer', 'Disease', (74, 89))	('invasive cancer', 'Disease', 'MESH:D009362', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('IEN', 'Disease', (67, 70))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('IEN', 'Phenotype', 'HP:0032187', (67, 70))	('mutations', 'Var', (42, 51))
822199	28757263	It is not clear how these mutations promote esophageal tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('promote', 'PosReg', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('mutations', 'Var', (26, 35))
822200	28757263	A model was proposed in which mutations in p53 and Kruppel-like factor 5 (KLF5, a zinc finger-containing transcription factor) contribute to transformation of esophageal squamous cells through de-regulation of the NOTCH1 pathway.	('NOTCH1', 'Gene', '4851', (214, 220))	('NOTCH1', 'Gene', (214, 220))	('Kruppel-like factor 5', 'Gene', '688', (51, 72))	('de-regulation', 'NegReg', (193, 206))	('esophageal squamous', 'Disease', 'MESH:D000077277', (159, 178))	('esophageal squamous', 'Disease', (159, 178))	('Kruppel-like factor 5', 'Gene', (51, 72))	('KLF5', 'Gene', (74, 78))	('mutations', 'Var', (30, 39))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('KLF5', 'Gene', '688', (74, 78))
822202	28757263	In dysplastic esophageal cells, with a TP53 mutation, KLF5 replaces p53 to maintain NOTCH1 transcription.	('mutation', 'Var', (44, 52))	('NOTCH1', 'Gene', (84, 90))	('dysplastic esophageal', 'Disease', 'MESH:D004941', (3, 24))	('KLF5', 'Gene', (54, 58))	('TP53', 'Gene', '7157', (39, 43))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('KLF5', 'Gene', '688', (54, 58))	('NOTCH1', 'Gene', '4851', (84, 90))	('TP53', 'Gene', (39, 43))	('dysplastic esophageal', 'Disease', (3, 24))
822206	28757263	Compared with BCH, LGIEN and HGIEN contain more genomic and epigenomic alterations, including CNAs, gene mutations, loss of heterozygosity, and regions of promoter hypermethylation.	('gene', 'MPA', (100, 104))	('genomic', 'CPA', (48, 55))	('CNAs', 'Disease', (94, 98))	('IEN', 'Phenotype', 'HP:0032187', (21, 24))	('IEN', 'Phenotype', 'HP:0032187', (31, 34))	('BCH', 'Chemical', '-', (14, 17))	('loss of heterozygosity', 'Var', (116, 138))
822210	28757263	In precancer lesions, amplification of 7p11.2 (locus of EGFR), 11q13.2-q13.3 (CCND1), 8q24.21 (MYC), and 3q26.32-q26.33 (SOX2 and PIK3CA) and homozygous deletion of 9p21.3 (CDKN2A) are the most frequently detected aberrations.	('PIK3CA', 'Gene', (130, 136))	('MYC', 'Gene', '4609', (95, 98))	('PIK3CA', 'Gene', '5290', (130, 136))	('CDKN2A', 'Gene', (173, 179))	('SOX2', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('SOX2', 'Gene', '6657', (121, 125))	('EGFR', 'Gene', '1956', (56, 60))	('CDKN2A', 'Gene', '1029', (173, 179))	('CCND1', 'Gene', (78, 83))	('amplification', 'Var', (22, 35))	('EGFR', 'Gene', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('MYC', 'Gene', (95, 98))	('CCND1', 'Gene', '595', (78, 83))	('3q26.32-q26.33', 'Var', (105, 119))	('cancer', 'Disease', (6, 12))
822214	28757263	Some driver genes were also mutated at similar frequencies in IEN compared with matched ESCC samples, including TP53, NOTCH1, CDKN2A, FAT1, PIK3CA, RB1, EP300, and MLL2.	('PIK3CA', 'Gene', (140, 146))	('TP53', 'Gene', '7157', (112, 116))	('NOTCH1', 'Gene', (118, 124))	('RB1', 'Gene', (148, 151))	('SCC', 'Gene', '6317', (89, 92))	('FAT1', 'Gene', '2195', (134, 138))	('EP300', 'Gene', '2033', (153, 158))	('SCC', 'Gene', (89, 92))	('NOTCH1', 'Gene', '4851', (118, 124))	('mutated', 'Var', (28, 35))	('MLL2', 'Gene', '8085', (164, 168))	('CDKN2A', 'Gene', (126, 132))	('PIK3CA', 'Gene', '5290', (140, 146))	('RB1', 'Gene', '5925', (148, 151))	('MLL2', 'Gene', (164, 168))	('EP300', 'Gene', (153, 158))	('TP53', 'Gene', (112, 116))	('IEN', 'Phenotype', 'HP:0032187', (62, 65))	('CDKN2A', 'Gene', '1029', (126, 132))	('FAT1', 'Gene', (134, 138))
822215	28757263	In a mathematical assessment, a large fraction of these mutations was detected as fully clonal in precancerous lesions, so they might provide the cell with a proliferative or survival advantage.	('mutations', 'Var', (56, 65))	('precancerous lesions', 'Disease', 'MESH:D011230', (98, 118))	('precancerous lesions', 'Disease', (98, 118))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('proliferative', 'CPA', (158, 171))	('survival advantage', 'CPA', (175, 193))
822216	28757263	Other alterations detected in dysplasia include hypermethylation at promoters of tumor suppressor genes (CDKN2A, CLDN3, and MT1G) and loss of heterozygosity of microsatellite markers.	('CLDN3', 'Gene', (113, 118))	('CDKN2A', 'Gene', (105, 111))	('microsatellite', 'Protein', (160, 174))	('hypermethylation', 'Var', (48, 64))	('MT1G', 'Gene', (124, 128))	('CDKN2A', 'Gene', '1029', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CLDN3', 'Gene', '1365', (113, 118))	('MT1G', 'Gene', '4495', (124, 128))	('dysplasia', 'Disease', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('dysplasia', 'Disease', 'MESH:D004476', (30, 39))	('loss', 'Var', (134, 138))	('tumor', 'Disease', (81, 86))
822218	28757263	Several signaling pathways are dysregulated in ESCCs via genomic and epigenomic aberrations.	('dysregulated', 'Reg', (31, 43))	('SCC', 'Gene', (48, 51))	('SCC', 'Gene', '6317', (48, 51))	('epigenomic aberrations', 'Var', (69, 91))
822222	28757263	In ESCC samples, gain of function mutations and copy number gains activate NRF2, whereas loss-of-function mutations and copy number loss inhibit KEAP1 and CUL3.	('SCC', 'Gene', (4, 7))	('loss-of-function', 'NegReg', (89, 105))	('KEAP1', 'Gene', '9817', (145, 150))	('SCC', 'Gene', '6317', (4, 7))	('copy number', 'Var', (120, 131))	('gain of function', 'PosReg', (17, 33))	('NRF2', 'Gene', '4780', (75, 79))	('KEAP1', 'Gene', (145, 150))	('gains', 'PosReg', (60, 65))	('mutations', 'Var', (106, 115))	('CUL3', 'Gene', '8452', (155, 159))	('CUL3', 'Gene', (155, 159))	('copy number', 'Var', (48, 59))	('NRF2', 'Gene', (75, 79))	('mutations', 'Var', (34, 43))	('loss inhibit', 'NegReg', (132, 144))
822223	28757263	ATG7, a direct regulator of autophagy-mediated KEAP1 turnover, is also deleted in a subset of ESCCs.	('KEAP1', 'Gene', (47, 52))	('SCC', 'Gene', '6317', (95, 98))	('ATG7', 'Gene', (0, 4))	('ATG7', 'Gene', '10533', (0, 4))	('deleted', 'Var', (71, 78))	('KEAP1', 'Gene', '9817', (47, 52))	('SCC', 'Gene', (95, 98))
822224	28757263	Together, these genomic changes increase activity of the antioxidative pathway in ESCCs, as well as other SCCs (such as HNSCC, LUSC, and skin SCC).	('SCC', 'Gene', (122, 125))	('increase', 'PosReg', (32, 40))	('SCC', 'Gene', '6317', (106, 109))	('antioxidative pathway', 'Pathway', (57, 78))	('SCC', 'Gene', (83, 86))	('SCC', 'Gene', (142, 145))	('SCC', 'Gene', '6317', (122, 125))	('SCC', 'Gene', '6317', (83, 86))	('SCC', 'Gene', '6317', (142, 145))	('changes', 'Var', (24, 31))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))	('LUSC', 'Disease', (127, 131))	('activity', 'MPA', (41, 49))	('SCC', 'Gene', (106, 109))
822232	28757263	SOX2 and TP63 are often coamplified, whereas NOTCH1, NOTCH3, and ZNF750 are frequently mutated in ESCCs and other SCCs.	('SOX2', 'Gene', '6657', (0, 4))	('TP63', 'Gene', '8626', (9, 13))	('mutated', 'Var', (87, 94))	('SCC', 'Gene', '6317', (99, 102))	('NOTCH3', 'Gene', '4854', (53, 59))	('TP63', 'Gene', (9, 13))	('SCC', 'Gene', (114, 117))	('ZNF750', 'Gene', '79755', (65, 71))	('ZNF750', 'Gene', (65, 71))	('SCC', 'Gene', '6317', (114, 117))	('NOTCH1', 'Gene', '4851', (45, 51))	('NOTCH1', 'Gene', (45, 51))	('SCC', 'Gene', (99, 102))	('SOX2', 'Gene', (0, 4))	('NOTCH3', 'Gene', (53, 59))
822234	28757263	Therefore, these genomic changes converge to dysregulate the differentiation program of squamous cells, which can have profound effects on the biology of ESCC.	('SCC', 'Gene', (155, 158))	('dysregulate', 'Reg', (45, 56))	('effects', 'Reg', (128, 135))	('differentiation program', 'CPA', (61, 84))	('SCC', 'Gene', '6317', (155, 158))	('changes', 'Var', (25, 32))
822236	28757263	Some of these dysregulate the cell cycle, such as mutations in TP53 and CDKN2A (as well as deletion and promoter hypermethylation of this gene) and amplifications of CCND1 and CDK6.	('deletion', 'Var', (91, 99))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('mutations', 'Var', (50, 59))	('CDK6', 'Gene', '1021', (176, 180))	('CDKN2A', 'Gene', '1029', (72, 78))	('dysregulate', 'Reg', (14, 25))	('CCND1', 'Gene', '595', (166, 171))	('amplifications', 'Var', (148, 162))	('cell cycle', 'CPA', (30, 40))	('CDK6', 'Gene', (176, 180))	('CDKN2A', 'Gene', (72, 78))	('CCND1', 'Gene', (166, 171))
822239	28757263	Palbociclib and abemaciclib (another small-molecule inhibitor of CDK4 and CDK6) are currently being tested in phase 2 trials of patients with stage 4 LUSC (NCT02785939 and NCT02450539).	('NCT02785939', 'Var', (156, 167))	('CDK6', 'Gene', (74, 78))	('CDK6', 'Gene', '1021', (74, 78))	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('CDK4', 'Gene', '1019', (65, 69))	('CDK4', 'Gene', (65, 69))	('patients', 'Species', '9606', (128, 136))	('NCT02450539', 'Var', (172, 183))
822241	28757263	Many mutations detected in ESCCs affect receptor tyrosine kinase signaling pathways.	('SCC', 'Gene', (28, 31))	('affect', 'Reg', (33, 39))	('mutations', 'Var', (5, 14))	('receptor tyrosine kinase signaling pathways', 'Pathway', (40, 83))	('SCC', 'Gene', '6317', (28, 31))
822242	28757263	ESCCs contain amplifications in EGFR, FGFR1, and KRAS along with activating mutations in PIK3CA.	('KRAS', 'Gene', '3845', (49, 53))	('PIK3CA', 'Gene', (89, 95))	('EGFR', 'Gene', '1956', (32, 36))	('PIK3CA', 'Gene', '5290', (89, 95))	('amplifications', 'Var', (14, 28))	('FGFR1', 'Gene', (38, 43))	('FGFR1', 'Gene', '2260', (38, 43))	('SCC', 'Gene', (1, 4))	('EGFR', 'Gene', (32, 36))	('SCC', 'Gene', '6317', (1, 4))	('KRAS', 'Gene', (49, 53))
822243	28757263	In many ESCCs, PTEN is deleted or contains loss-of-function mutations.	('loss-of-function', 'NegReg', (43, 59))	('PTEN', 'Gene', (15, 19))	('SCC', 'Gene', (9, 12))	('PTEN', 'Gene', '5728', (15, 19))	('mutations', 'Var', (60, 69))	('SCC', 'Gene', '6317', (9, 12))
822244	28757263	Some ESCCs have mutations in ERBB2, ERBB4, MET, and MTOR (Table 4).	('ERBB2', 'Gene', (29, 34))	('MET', 'Gene', (43, 46))	('ERBB2', 'Gene', '2064', (29, 34))	('SCC', 'Gene', (6, 9))	('ERBB4', 'Gene', (36, 41))	('MTOR', 'Gene', '2475', (52, 56))	('mutations', 'Var', (16, 25))	('SCC', 'Gene', '6317', (6, 9))	('ERBB4', 'Gene', '2066', (36, 41))	('MTOR', 'Gene', (52, 56))
822245	28757263	Interestingly, even though these genes are not mutated at high prevalences in ESCCs, their products (ERBB2, MET, and MTOR) are frequently overexpressed, indicating epigenetic, posttranscriptional, or posttranslational alterations (Table 4).	('SCC', 'Gene', (79, 82))	('overexpressed', 'PosReg', (138, 151))	('MTOR', 'Gene', '2475', (117, 121))	('indicating', 'Reg', (153, 163))	('SCC', 'Gene', '6317', (79, 82))	('ERBB2', 'Gene', '2064', (101, 106))	('epigenetic', 'Var', (164, 174))	('ERBB2', 'Gene', (101, 106))	('MTOR', 'Gene', (117, 121))
822247	28757263	Genomic lesions that activate Wnt signaling to beta-catenin have been reported in ESCCs, including disruptions in FAT1 or AJUBA (their products control beta-catenin turnover) and amplification of YAP1 (its product promotes the transcription activity of beta-catenin).	('FAT1', 'Gene', '2195', (114, 118))	('activate', 'PosReg', (21, 29))	('AJUBA', 'Gene', '84962', (122, 127))	('beta-catenin', 'Gene', (152, 164))	('beta-catenin', 'Gene', '1499', (152, 164))	('SCC', 'Gene', '6317', (83, 86))	('AJUBA', 'Gene', (122, 127))	('amplification', 'Var', (179, 192))	('YAP1', 'Gene', '10413', (196, 200))	('SCC', 'Gene', (83, 86))	('beta-catenin', 'Gene', (253, 265))	('beta-catenin', 'Gene', (47, 59))	('beta-catenin', 'Gene', '1499', (253, 265))	('beta-catenin', 'Gene', '1499', (47, 59))	('YAP1', 'Gene', (196, 200))	('FAT1', 'Gene', (114, 118))	('transcription', 'MPA', (227, 240))	('disruptions', 'Var', (99, 110))	('Wnt signaling', 'MPA', (30, 43))
822250	28757263	Other pathways that are dysregulated in ESCCs include the nuclear exportin process (by mutations in XPO1) and homologous recombination pathway (by mutations in BRCA1 and BRCA2).	('BRCA1', 'Gene', (160, 165))	('mutations', 'Var', (147, 156))	('BRCA2', 'Gene', (170, 175))	('SCC', 'Gene', (41, 44))	('nuclear exportin process', 'Pathway', (58, 82))	('SCC', 'Gene', '6317', (41, 44))	('XPO1', 'Gene', (100, 104))	('BRCA2', 'Gene', '675', (170, 175))	('XPO1', 'Gene', '7514', (100, 104))	('BRCA1', 'Gene', '672', (160, 165))	('mutations', 'Var', (87, 96))	('homologous recombination pathway', 'Pathway', (110, 142))
822263	28757263	ADAR adenosine deaminases acting on RNA APOBEC apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like BCH basal cell hyperplasia CIS carcinoma in situ CNA copy number alteration ESCC esophageal squamous cell carcinoma FGFR fibroblast growth factor receptor HGIEN high-grade IEN HNSCC head and neck squamous cell carcinoma IEN intraepithelial neoplasia KLF5 Kruppel-like factor 5 LGIEN low-grade IEN LINE-1 long interspersed nuclear element-1 LUSC squamous cell carcinoma of the lung NRF2 nuclear factor, erythroid 2 like 2 SMG significantly mutated gene WES whole-exome sequencing.	('SCC', 'Gene', '6317', (290, 293))	('SCC', 'Gene', (189, 192))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (457, 492))	('IEN', 'Phenotype', 'HP:0032187', (284, 287))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (471, 492))	('KLF5', 'Gene', (362, 366))	('IEN', 'Phenotype', 'HP:0032187', (332, 335))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (336, 361))	('neck squamous cell carcinoma', 'Disease', (303, 331))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (303, 331))	('SCC', 'Gene', (290, 293))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (457, 492))	('esophageal squamous cell carcinoma', 'Disease', (193, 227))	('nuclear factor, erythroid 2 like 2', 'Gene', '4780', (498, 532))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('CIS', 'Phenotype', 'HP:0030075', (139, 142))	('basal cell hyperplasia', 'Disease', (116, 138))	('NRF2', 'Gene', '4780', (493, 497))	('BCH', 'Chemical', '-', (112, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (308, 331))	('neoplasia', 'Phenotype', 'HP:0002664', (352, 361))	('adenosine deaminases acting on RNA', 'Gene', (5, 39))	('intraepithelial neoplasia', 'Disease', (336, 361))	('carcinoma in situ', 'Disease', (143, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('Kruppel-like factor 5', 'Gene', '688', (367, 388))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (457, 480))	('basal cell hyperplasia', 'Disease', 'MESH:D002280', (116, 138))	('adenosine deaminases acting on RNA', 'Gene', '103', (5, 39))	('HNSCC', 'Phenotype', 'HP:0012288', (288, 293))	('ADAR', 'Gene', (0, 4))	('alteration', 'Var', (177, 187))	('Kruppel-like factor 5', 'Gene', (367, 388))	('IEN', 'Phenotype', 'HP:0032187', (391, 394))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (294, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (193, 227))	('NRF2', 'Gene', (493, 497))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (143, 160))	('basal cell hyperplasia CIS carcinoma in situ', 'Phenotype', 'HP:0002671', (116, 160))	('SMG', 'Chemical', '-', (533, 536))	('KLF5', 'Gene', '688', (362, 366))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('SCC', 'Gene', '6317', (189, 192))	('carcinoma in situ', 'Disease', 'MESH:D002278', (143, 160))	('IEN', 'Phenotype', 'HP:0032187', (405, 408))	('IEN', 'Phenotype', 'HP:0032187', (269, 272))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (336, 361))	('squamous cell carcinoma of the lung', 'Disease', (457, 492))	('carcinoma', 'Phenotype', 'HP:0030731', (471, 480))	('ADAR', 'Gene', '103', (0, 4))
822270	29344220	It was also revealed that knockdown of miR-1470 significantly inhibited migration, and decreased the expression levels of matrix metalloproteinase 2 (MMP2), MMP13 and MMP14.	('MMP2', 'Gene', (150, 154))	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('matrix metalloproteinase 2', 'Gene', '4313', (122, 148))	('migration', 'CPA', (72, 81))	('MMP14', 'Gene', '4323', (167, 172))	('decreased', 'NegReg', (87, 96))	('matrix metalloproteinase 2', 'Gene', (122, 148))	('MMP13', 'Gene', (157, 162))	('expression levels', 'MPA', (101, 118))	('MMP14', 'Gene', (167, 172))	('MMP13', 'Gene', '4322', (157, 162))	('MMP2', 'Gene', '4313', (150, 154))	('knockdown', 'Var', (26, 35))	('inhibited', 'NegReg', (62, 71))
822287	29344220	In the present study, it was demonstrated that miR-1470 was upregulated in ESCC tissues, and knockdown of miR-1470 significantly inhibited proliferation and migration, and promoted senescence, of ESCC cells.	('inhibited', 'NegReg', (129, 138))	('knockdown', 'Var', (93, 102))	('upregulated', 'PosReg', (60, 71))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('miR', 'Gene', (106, 109))	('ESCC', 'Disease', (75, 79))	('miR', 'Gene', '220972', (106, 109))	('proliferation', 'CPA', (139, 152))	('senescence', 'CPA', (181, 191))	('promoted', 'PosReg', (172, 180))
822288	29344220	Furthermore, knockdown of miR-1470 exhibited apoptosis-promoting activity, including downregulation of the anti-apoptotic protein Bcl-2 and upregulation of the pro-apoptotic Bcl-2-associated X protein (BAX).	('miR', 'Gene', '220972', (26, 29))	('Bcl-2-associated X protein', 'Gene', '581', (174, 200))	('miR', 'Gene', (26, 29))	('downregulation', 'NegReg', (85, 99))	('Bcl-2', 'Gene', '596', (174, 179))	('BAX', 'Gene', (202, 205))	('BAX', 'Gene', '581', (202, 205))	('Bcl-2', 'Gene', '596', (130, 135))	('apoptosis-promoting', 'CPA', (45, 64))	('Bcl-2', 'Gene', (130, 135))	('upregulation', 'PosReg', (140, 152))	('knockdown', 'Var', (13, 22))	('Bcl-2', 'Gene', (174, 179))	('Bcl-2-associated X protein', 'Gene', (174, 200))
822290	29344220	The ESCC cell lines including KYSE30, KYSE180, KYSE450, KYSE150 and KYSE510, provided by Dr Yutaka Shimada (Kyoto University, Kyoto, Japan), were cultured in RPMI-1640 medium (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, USA) with 10% fetal bovine serum (FBS; Hyclone; GE Healthcare Life Sciences, Logan, UT, USA).	('bovine', 'Species', '9913', (253, 259))	('KYSE510', 'Var', (68, 75))	('KYSE150', 'Var', (56, 63))	('KYSE510', 'CellLine', 'CVCL:1354', (68, 75))	('RPMI-1640 medium', 'Chemical', '-', (158, 174))	('KYSE180', 'Var', (38, 45))
822314	29344220	The results revealed that KYSE150 and KYSE510 exhibited increased expression levels compared with other cell lines (Fig.	('increased', 'PosReg', (56, 65))	('expression levels', 'MPA', (66, 83))	('KYSE150', 'Var', (26, 33))	('KYSE510', 'Var', (38, 45))	('KYSE510', 'CellLine', 'CVCL:1354', (38, 45))
822319	29344220	Using a Transwell assay, it was identified that knockdown of miR-1470 led to a decrease in the number of migratory KYSE150 and KYSE510 cells (Fig.	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('decrease', 'NegReg', (79, 87))	('KYSE510', 'CellLine', 'CVCL:1354', (127, 134))	('knockdown', 'Var', (48, 57))
822321	29344220	Using RT-qPCR, we found that knockdown of miR-1470 significantly decreased the expression levels of MMP2, MMP13 and MMP14.	('expression levels', 'MPA', (79, 96))	('knockdown', 'Var', (29, 38))	('decreased', 'NegReg', (65, 74))	('MMP2', 'Gene', (100, 104))	('MMP14', 'Gene', '4323', (116, 121))	('MMP14', 'Gene', (116, 121))	('MMP13', 'Gene', (106, 111))	('MMP2', 'Gene', '4313', (100, 104))	('miR', 'Gene', '220972', (42, 45))	('MMP13', 'Gene', '4322', (106, 111))	('miR', 'Gene', (42, 45))
822323	29344220	To investigate the effect of miR-1470 on cell senescence, morphological evaluation of KYSE150 and KYSE510 cells was performed following knockdown of miR-1470 expression.	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('KYSE510', 'CellLine', 'CVCL:1354', (98, 105))	('knockdown', 'Var', (136, 145))	('miR', 'Gene', '220972', (149, 152))	('miR', 'Gene', (149, 152))
822324	29344220	4C and D, compared with the control group, knockdown of miR-1470 markedly decreased anti-apoptotic protein Bcl-2, pro-caspase-12, pro-caspase-3 and increased pro-apoptotic protein BAX.	('caspase', 'Gene', (118, 125))	('Bcl-2', 'Gene', (107, 112))	('caspase', 'Gene', (134, 141))	('Bcl-2', 'Gene', '596', (107, 112))	('pro-caspase-3', 'Gene', '836', (130, 143))	('increased', 'PosReg', (148, 157))	('caspase', 'Gene', '839;841', (134, 141))	('knockdown', 'Var', (43, 52))	('miR', 'Gene', '220972', (56, 59))	('decreased', 'NegReg', (74, 83))	('miR', 'Gene', (56, 59))	('pro-caspase-3', 'Gene', (130, 143))	('BAX', 'Gene', (180, 183))	('BAX', 'Gene', '581', (180, 183))	('pro-apoptotic', 'MPA', (158, 171))	('caspase', 'Gene', '839;841', (118, 125))
822328	29344220	Previous studies have characterized the miRNA expression profiles associated with distinct stages of ESCC, and dysregulation of miRNAs has been demonstrated to serve a role in esophageal carcinogenesis.	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('associated', 'Reg', (66, 76))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (176, 201))	('dysregulation', 'Var', (111, 124))	('miR', 'Gene', '220972', (128, 131))	('esophageal carcinogenesis', 'Disease', (176, 201))	('miR', 'Gene', (128, 131))	('ESCC', 'Disease', (101, 105))
822343	29344220	In the present study, knockdown of miR-1470 significantly induced cell senescence and activated the apoptotic signaling pathway.	('induced', 'PosReg', (58, 65))	('knockdown', 'Var', (22, 31))	('apoptotic signaling pathway', 'Pathway', (100, 127))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('cell senescence', 'CPA', (66, 81))	('activated', 'PosReg', (86, 95))
822352	29021429	IgG4-RD has been found to affects the pancreas, bile duct, lacrimal glands, salivary glands, central nervous system, thyroid, lungs, gastrointestinal tract, kidney, prostate, retroperitoneum, arteries, lymph nodes, skin, and breast.	('lacrimal glands', 'Disease', (59, 74))	('affects', 'Reg', (26, 33))	('gastrointestinal tract', 'Disease', (133, 155))	('pancreas', 'Disease', (38, 46))	('bile duct', 'Disease', (48, 57))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (133, 155))	('IgG4-RD', 'Var', (0, 7))
822428	28423729	Digitalis use was associated with an increased HR for esophageal cancer (adjusted HR=1.26, 95% CI 1.05-1.51), colorectal cancer (HR 1.24, 95% CI 1.18-1.30), and gallbladder cancer (HR 1.66, 95% CI 1.20-2.28).	('Digitalis', 'Var', (0, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('colorectal cancer', 'Disease', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('gallbladder cancer', 'Disease', (161, 179))	('gallbladder cancer', 'Disease', 'MESH:D005706', (161, 179))
822481	28423729	We further performed analyses stratified by histological type, i.e., separately for esophageal squamous cell carcinoma (ICD-7 codes: 150; histological codes using ICD for Oncology, version 3 [ICD-O-3]: 8050-8078, 8083-8084), adenocarcinoma of esophagus and gastric cardia (ICD-7 codes: 150, 151.1; histological codes: 8140-8141, 8143-8145, 8190-8231, 8260- 8263, 8310, 8401, 8480-8490, 8550-8551, 8570-8574, 8576), hepatocellular carcinoma (ICD-7 code: 155.0; histological code: 8170-8176), and cholangiocarcinoma (ICD-7 code: 155.0; histological codes: 8050, 5140-8141, 8160-8161, 8260, 8440, 8480-8500, 8570-8572; or ICD-7 codes: 155.1-155.9; histological codes: 8010, 8020, 8041, 8070, 8140, 8160, 8161, 8260, 8310, 8480, 8490, 8560, 8162-8163), given the known etiological heterogeneity in cancers of different histological type even in the same anatomical sites.	('hepatocellular carcinoma', 'Disease', (415, 439))	('8310', 'Var', (713, 717))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (84, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('8560', 'Var', (731, 735))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (495, 513))	('carcinoma', 'Phenotype', 'HP:0030731', (430, 439))	('cancers', 'Phenotype', 'HP:0002664', (794, 801))	('8160', 'Var', (695, 699))	('cancers', 'Disease', (794, 801))	('cancer', 'Phenotype', 'HP:0002664', (794, 800))	('cholangiocarcinoma', 'Disease', (495, 513))	('8260', 'Var', (707, 711))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (495, 513))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (415, 439))	('8140', 'Var', (689, 693))	('Oncology', 'Phenotype', 'HP:0002664', (171, 179))	('8010', 'Var', (665, 669))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cancers', 'Disease', 'MESH:D009369', (794, 801))	('esophageal squamous cell carcinoma', 'Disease', (84, 118))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (415, 439))	('adenocarcinoma of esophagus and gastric cardia', 'Disease', 'MESH:D004938', (225, 271))	('8070', 'Var', (683, 687))	('carcinoma', 'Phenotype', 'HP:0030731', (504, 513))	('8161', 'Var', (701, 705))
822565	25877866	One investigation of genes encoding the subunits of a nicotinic acetylcholine receptor (CHRNA3 and CHRNA5) found that smokers who carry two specific genetic variants extract a greater amount of nicotine per cigarette and are exposed to a higher internal dose of an NNK per cigarette compared to noncarriers.	('nicotine', 'Chemical', 'MESH:D009538', (194, 202))	('greater', 'PosReg', (176, 183))	('extract', 'MPA', (166, 173))	('NNK', 'Chemical', 'MESH:C016583', (265, 268))	('variants', 'Var', (157, 165))
822580	25877866	's study also showed that r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene, which like 1-HOP is a PAH, is higher in smokers that ultimately go on to develop lung cancer.	('r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene', 'Chemical', 'MESH:C502234', (26, 83))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('PAH', 'Chemical', 'MESH:D011084', (107, 110))	('r-1', 'Var', (26, 29))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
822709	25019155	 RANK rs1805034 T>C Polymorphism Is Associated with Susceptibility of Esophageal Cancer in a Chinese Population Esophageal cancer remains the sixth leading cause of cancer associated death and eighth most common cancer worldwide.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('eighth', 'Disease', (193, 199))	('Esophageal cancer', 'Disease', (112, 129))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('death', 'Disease', (183, 188))	('rs1805034 T>C', 'Var', (6, 19))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('Esophageal Cancer', 'Disease', (70, 87))	('Esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))	('eighth', 'Disease', 'MESH:D061285', (193, 199))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', (165, 171))	('death', 'Disease', 'MESH:D003643', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (70, 87))	('rs1805034', 'Mutation', 'rs1805034', (6, 15))	('cancer', 'Disease', (123, 129))
822710	25019155	Genetic factors, such as single nucleotide polymorphisms (SNPs), may contribute to the carcinogenesis of esophageal cancer.	('single nucleotide polymorphisms', 'Var', (25, 56))	('carcinogenesis of esophageal cancer', 'Disease', (87, 122))	('carcinogenesis of esophageal cancer', 'Disease', 'MESH:D063646', (87, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('contribute', 'Reg', (69, 79))
822712	25019155	The OPG rs3102735 T>C, rs2073618 G>C, RANK rs1805034 T>C, RANKL rs9533156 T>C and rs2277438 A>G were determined by ligation detection reaction method.	('rs1805034', 'Mutation', 'rs1805034', (43, 52))	('rs2073618', 'Mutation', 'rs2073618', (23, 32))	('rs9533156', 'Mutation', 'rs9533156', (64, 73))	('rs3102735', 'Mutation', 'rs3102735', (8, 17))	('rs2277438', 'Mutation', 'rs2277438', (82, 91))	('rs2277438 A>G', 'Var', (82, 95))	('rs2073618 G>C', 'Var', (23, 36))	('rs9533156 T>C', 'Var', (64, 77))
822714	25019155	Our study provides the first evidence that functional polymorphisms RANK rs1805034 T>C may be an indicator for individual susceptibility to ESCC.	('rs1805034 T>C', 'Var', (73, 86))	('rs1805034', 'Mutation', 'rs1805034', (73, 82))	('ESCC', 'Disease', (140, 144))
822723	25019155	Yet, only a subset of individuals exposed to these risk factors eventually develop esophageal cancer, indicating a pivotal role of genetic factors, such as single nucleotide polymorphisms (SNPs), in the esophageal carcinogenesis.	('develop', 'Reg', (75, 82))	('esophageal cancer', 'Disease', (83, 100))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (203, 228))	('esophageal carcinogenesis', 'Disease', (203, 228))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('single nucleotide polymorphisms', 'Var', (156, 187))
822729	25019155	In experimental models, RANKL inhibitors reduced tumor-induced osteolysis in various types of cancer, reduced bone destruction, skeletal tumor progression, as well as tumor burden.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('skeletal tumor', 'Phenotype', 'HP:0010622', (128, 142))	('osteolysis', 'Disease', (63, 73))	('reduced', 'NegReg', (41, 48))	('osteolysis', 'Disease', 'MESH:D010014', (63, 73))	('RANKL', 'Gene', (24, 29))	('tumor', 'Disease', (167, 172))	('cancer', 'Disease', (94, 100))	('skeletal tumor', 'Disease', (128, 142))	('tumor', 'Disease', (137, 142))	('inhibitors', 'Var', (30, 40))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bone destruction', 'CPA', (110, 126))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('bone destruction', 'Phenotype', 'HP:0002797', (110, 126))	('reduced', 'NegReg', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('skeletal tumor', 'Disease', 'MESH:D009369', (128, 142))	('osteolysis', 'Phenotype', 'HP:0002797', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
822738	25019155	Genetic variations in genes encoding RANK, RANKL and OPG were found to affect the rheumatoid arthritis, Paget's disease of bone, hip osteoporotic fracture.	("Paget's disease", 'Disease', (104, 119))	('RANKL', 'Gene', (43, 48))	('arthritis', 'Phenotype', 'HP:0001369', (93, 102))	('affect', 'Reg', (71, 77))	('hip osteoporotic fracture', 'Disease', (129, 154))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (82, 102))	('hip osteoporotic fracture', 'Disease', 'MESH:D058866', (129, 154))	('Genetic variations', 'Var', (0, 18))	('rheumatoid arthritis', 'Disease', (82, 102))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (82, 102))	("Paget's disease", 'Disease', 'MESH:C537701', (104, 119))	('RANK', 'Gene', (37, 41))	('OPG', 'Gene', (53, 56))
822739	25019155	More importantly, in the Caucasian population, a significant association of the SNP rs3102735 (OPG) with the susceptibility to develop breast cancer has been reported.	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rs3102735', 'Mutation', 'rs3102735', (84, 93))	('SNP', 'Var', (80, 83))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
822746	25019155	Variations of demographic characteristics, selected variables, and genotypes of the OPG rs3102735 T>C, rs2073618 G>C, RANK rs1805034 T>C, RANKL rs9533156 T>C and rs2277438 A>G variants between the cases and controls were evaluated using the chi 2 test.	('rs9533156 T>C', 'Var', (144, 157))	('rs2277438', 'Mutation', 'rs2277438', (162, 171))	('rs3102735', 'Mutation', 'rs3102735', (88, 97))	('rs2073618 G>C', 'Var', (103, 116))	('rs1805034', 'Mutation', 'rs1805034', (123, 132))	('rs2277438 A>G', 'Var', (162, 175))	('rs2073618', 'Mutation', 'rs2073618', (103, 112))	('OPG', 'Gene', (84, 87))	('rs3102735 T>C', 'Var', (88, 101))	('rs9533156', 'Mutation', 'rs9533156', (144, 153))
822749	25019155	In all 1315 samples, the success rate of genotyping was 95.13%, 96.35%, 96.43%, 96.43% and 96.81% for OPG rs3102735 C>T, OPG rs2073618 G>C, RANK rs1805034 T>C, RANKL rs9533156 T>C and RANKL rs2277438 A>G, respectively.	('rs2277438', 'Mutation', 'rs2277438', (190, 199))	('rs9533156', 'Mutation', 'rs9533156', (166, 175))	('rs3102735 C>T', 'Var', (106, 119))	('rat', 'Species', '10116', (33, 36))	('rs2277438 A>G', 'Var', (190, 203))	('rs2073618 G>C', 'Var', (125, 138))	('rs9533156 T>C', 'Var', (166, 179))	('rs3102735', 'Mutation', 'rs3102735', (106, 115))	('rs2073618', 'Mutation', 'rs2073618', (125, 134))	('rs1805034', 'Mutation', 'rs1805034', (145, 154))
822751	25019155	The observed genotype frequencies for OPG rs3102735 C>T, OPG rs2073618 G>C, RANK rs1805034 T>C, RANKL rs9533156 T>C and RANKL rs2277438 A>G polymorphisms in the controls were in HWE (p = 0.191, 0.371, 0.531, 0.488 and 0.700, respectively)(Table 2).	('rs9533156 T>C', 'Var', (102, 115))	('rs3102735', 'Mutation', 'rs3102735', (42, 51))	('OPG', 'Gene', (57, 60))	('rs1805034', 'Mutation', 'rs1805034', (81, 90))	('rs2277438 A>G', 'Var', (126, 139))	('rs9533156', 'Mutation', 'rs9533156', (102, 111))	('rs2277438', 'Mutation', 'rs2277438', (126, 135))	('rs3102735 C>T', 'Var', (42, 55))	('rs2073618 G>C', 'Var', (61, 74))	('rs2073618', 'Mutation', 'rs2073618', (61, 70))
822753	25019155	In the recessive model, when the RANK rs1805034 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with a significantly increased risk for ESCC (CC vs. TT/TC: adjusted OR  = 1.52, 95% CI  = 1.03-2.24, p = 0.036).	('rs1805034', 'Var', (38, 47))	('TC', 'Chemical', 'MESH:D013667', (196, 198))	('rs1805034', 'Mutation', 'rs1805034', (38, 47))	('TC', 'Chemical', 'MESH:D013667', (51, 53))	('ESCC', 'Disease', (180, 184))
822754	25019155	When the RANK rs1805034 TT homozygote genotype was used as the reference group, the TC genotype was not associated with the risk of ESCC (TC vs. TT: adjusted OR  = 1.16, 95% CI  = 1.03-2.24, p = 0.231), but the CC genotype was associated with the risk of ECSS (CC vs. TT: adjusted OR  = 1.62, 95% CI  = 1.08-2.44, p = 0.019).	('rs1805034', 'Var', (14, 23))	('TC', 'Chemical', 'MESH:D013667', (84, 86))	('rs1805034', 'Mutation', 'rs1805034', (14, 23))	('ECSS', 'Disease', (255, 259))	('ESCC', 'Disease', (132, 136))	('TC', 'Chemical', 'MESH:D013667', (138, 140))
822755	25019155	In the dominant model, the RANK rs1805034 CC variant was associated with the risk of ESCC as compared with the TT genotype (adjusted OR  = 1.62, 95% CI  = 1.08-2.44, p = 0.019).	('rs1805034', 'Mutation', 'rs1805034', (32, 41))	('rs1805034 CC', 'Var', (32, 44))	('ESCC', 'Disease', (85, 89))
822756	25019155	No association was detected among OPG rs3102735 C>T, OPG rs2073618 G>C, RANKL rs9533156 T>C, RANKL rs2277438 A>G polymorphisms and the risk of ECSS (Table 3).	('rs2277438 A>G', 'Var', (99, 112))	('rs2073618', 'Mutation', 'rs2073618', (57, 66))	('ECSS', 'Disease', (143, 147))	('rs2277438', 'Mutation', 'rs2277438', (99, 108))	('rs9533156', 'Mutation', 'rs9533156', (78, 87))	('rs3102735', 'Mutation', 'rs3102735', (38, 47))	('rs3102735 C>T', 'Var', (38, 51))	('rs2073618 G>C', 'Var', (57, 70))	('rs9533156 T>C', 'Var', (78, 91))
822757	25019155	To evaluate the effects of RANK rs1805034 T>C genotype on ESCC risk according to different age, sex, smoking and alcohol consumption; we performed the stratification analyses (Table 4).	('rs1805034', 'Mutation', 'rs1805034', (32, 41))	('rat', 'Species', '10116', (153, 156))	('alcohol', 'Chemical', 'MESH:D000438', (113, 120))	('ESCC', 'Disease', (58, 62))	('rs1805034 T>C', 'Var', (32, 45))
822758	25019155	A significantly increased risk of ESCC associated with the RANK rs1805034 T>C polymorphism was evident among male patients (CC vs. TT: adjusted OR  = 1.89, 95% CI  = 1.16-3.08, p = 0.011) (TC/CC vs. TT, adjusted OR  = 1.38, 95% CI  = 1.05-1.81, p = 0.022) (CC vs. TT/TC, adjusted OR  = 1.68, 95% CI  = 1.05-2.69, p = 0.031).	('TC', 'Chemical', 'MESH:D013667', (189, 191))	('rs1805034', 'Mutation', 'rs1805034', (64, 73))	('ESCC', 'Disease', (34, 38))	('patients', 'Species', '9606', (114, 122))	('rs1805034 T>C', 'Var', (64, 77))	('TC', 'Chemical', 'MESH:D013667', (267, 269))
822760	25019155	In this hospital-based case-control study of ESCC, we investigated the association of OPG rs3102735 C>T, OPG rs2073618 G>C, RANK rs1805034 T>C, RANKL rs9533156 T>C and RANKL rs2277438 A>G polymorphisms with risk of ESCC in a Chinese population.	('ESCC', 'Disease', (215, 219))	('rs9533156 T>C', 'Var', (150, 163))	('rs3102735 C>T', 'Var', (90, 103))	('rs1805034', 'Mutation', 'rs1805034', (129, 138))	('rs3102735', 'Mutation', 'rs3102735', (90, 99))	('rs2073618', 'Mutation', 'rs2073618', (109, 118))	('OPG', 'Gene', (86, 89))	('rs2073618 G>C', 'Var', (109, 122))	('rs9533156', 'Mutation', 'rs9533156', (150, 159))	('rs2277438', 'Mutation', 'rs2277438', (174, 183))	('rs2277438 A>G', 'Var', (174, 187))
822761	25019155	Our multivariable logistic analyses demonstrated that RANK rs1805034 T>C genotype has an increased risk of ESCC.	('rat', 'Species', '10116', (43, 46))	('rs1805034 T>C', 'Var', (59, 72))	('ESCC', 'Disease', (107, 111))	('rs1805034', 'Mutation', 'rs1805034', (59, 68))
822763	25019155	To our knowledge, this is the first study demonstrating a significant association between the RANK rs1805034 T>C genotype with the susceptibility of ESCC.	('rs1805034', 'Mutation', 'rs1805034', (99, 108))	('ESCC', 'Disease', (149, 153))	('rs1805034 T>C', 'Var', (99, 112))	('rat', 'Species', '10116', (49, 52))
822768	25019155	Genetic variants in the OPG locus have previously been implicated with osteoporotic fracture, bone turnover, bone mineral density, osteonecrosis, diabetic neuroarthropathy as well as ankylosing spondylitis.	('diabetic neuroarthropathy', 'Disease', (146, 171))	('OPG', 'Gene', (24, 27))	('bone turnover', 'Disease', 'MESH:D001851', (94, 107))	('osteonecrosis', 'Disease', (131, 144))	('osteonecrosis', 'Disease', 'MESH:D010020', (131, 144))	('ankylosing spondylitis', 'Disease', (183, 205))	('bone turnover', 'Disease', (94, 107))	('osteoporotic fracture', 'Disease', 'MESH:D058866', (71, 92))	('osteoporotic fracture', 'Disease', (71, 92))	('osteonecrosis', 'Phenotype', 'HP:0010885', (131, 144))	('Genetic variants', 'Var', (0, 16))	('diabetic neuroarthropathy', 'Disease', 'MESH:D003920', (146, 171))	('ankylosing spondylitis', 'Disease', 'MESH:D013167', (183, 205))	('bone mineral density', 'CPA', (109, 129))	('implicated', 'Reg', (55, 65))
822769	25019155	Alterations at the RANK locus and/or functionally related genes, such as RANKL, have also been reported to be associated with rheumatoid arthritis, aortic calcification, bone mineral density and Paget's disease of bone.	('arthritis', 'Phenotype', 'HP:0001369', (137, 146))	('aortic calcification', 'Disease', (148, 168))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (126, 146))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (110, 120))	('aortic calcification', 'Disease', 'MESH:C562942', (148, 168))	("Paget's disease", 'Disease', 'MESH:C537701', (195, 210))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (126, 146))	('rat', 'Species', '10116', (4, 7))	('bone mineral density', 'Disease', (170, 190))	('RANKL', 'Gene', (73, 78))	('rheumatoid arthritis', 'Disease', (126, 146))	("Paget's disease", 'Disease', (195, 210))
822770	25019155	Recently, emerging evidence has indicated an association between OPG/RANK/RANKL gene polymorphisms with carcinogenesis.	('polymorphisms', 'Var', (85, 98))	('carcinogenesis', 'Disease', (104, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('OPG/RANK/RANKL', 'Gene', (65, 79))
822772	25019155	SNP rs3102735 of the OPG gene has been reported to be associated with the susceptibility of breast cancer in Caucasian population.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('SNP rs3102735', 'Var', (0, 13))	('OPG', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('rs3102735', 'Mutation', 'rs3102735', (4, 13))	('associated', 'Reg', (54, 64))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
822773	25019155	Similarly, a genetic variant near the 5'-end of RANK (rs7226991) was associated with a breast cancer risk.	('rs7226991', 'Mutation', 'rs7226991', (54, 63))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('associated with', 'Reg', (69, 84))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('rs7226991', 'Var', (54, 63))
822777	25019155	Using Power and Sample Size Calculation (PS, version 3.0.43, 2009, http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize), considering RANK rs1805034 T>C mutant alleles, the power of our analysis (alpha = 0.05) was 0.946 in 629 ESCC cases and 686 control subjects with adjusted OR 1.52.	('rs1805034 T>C', 'Var', (155, 168))	('rs1805034', 'Mutation', 'rs1805034', (155, 164))	('ESCC', 'Disease', (243, 247))
822815	29785394	They demonstrated that Notch inhibition could induce goblet cell differentiation and reduce cell proliferation, while cellular proliferation and progression of BE could be promoted by Notch activation, suggesting that Notch signaling might play binary roles in regulating Barrett metaplasia and its progression.	('Barrett metaplasia', 'Disease', 'MESH:D001471', (272, 290))	('cellular proliferation', 'CPA', (118, 140))	('cell proliferation', 'CPA', (92, 110))	('Notch inhibition', 'Var', (23, 39))	('reduce', 'NegReg', (85, 91))	('Barrett metaplasia', 'Disease', (272, 290))	('goblet cell differentiation', 'CPA', (53, 80))	('BE', 'Phenotype', 'HP:0100580', (160, 162))	('promoted', 'PosReg', (172, 180))	('induce', 'PosReg', (46, 52))	('progression', 'CPA', (145, 156))
822823	29427302	Reduction of tumor basal cells was restored by knockdown of aryl hydrocarbon receptor nuclear translocator (ARNT) that interacted with SIM2.	('tumor', 'Disease', (13, 18))	('aryl hydrocarbon receptor nuclear translocator', 'Gene', (60, 106))	('tumor basal cell', 'Phenotype', 'HP:0002671', (13, 29))	('ARNT', 'Gene', (108, 112))	('knockdown', 'Var', (47, 56))	('aryl hydrocarbon receptor nuclear translocator', 'Gene', '405', (60, 106))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('Reduction', 'NegReg', (0, 9))	('tumor basal cells', 'Phenotype', 'HP:0002671', (13, 30))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
822838	29427302	TE1, TE3, TE5, TE6, TE8, TE10, and KYSE510 were routinely propagated in RPMI 1640 (Wako, Tokyo, Japan) supplemented with 10% FBS, penicillin and streptomycin.	('TE10', 'Chemical', '-', (25, 29))	('streptomycin', 'Chemical', 'MESH:D013307', (145, 157))	('TE6', 'Var', (15, 18))	('TE8', 'Var', (20, 23))	('FBS', 'Disease', (125, 128))	('penicillin', 'Chemical', 'MESH:D010406', (130, 140))	('KYSE510', 'Var', (35, 42))	('TE10', 'Var', (25, 29))	('FBS', 'Disease', 'MESH:D005198', (125, 128))	('TE8', 'Chemical', '-', (20, 23))
822849	29427302	Cells were plated at 2 x 106 per 10-cm dish, and transfected with either pCMV6-AC-GFP-SIM2 or pCMV6-SIM2s or no insert of pCMV6-neo (OriGene Technologies) by using Lipofectamine 2000 reagent (Invitrogen) according to the manufacturer's protocol.	('pCMV6-SIM2s', 'Var', (94, 105))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (164, 182))	('pCMV6-SIM2s', 'Chemical', '-', (94, 105))	('pCMV6-AC-GFP-SIM2', 'Var', (73, 90))	('pCMV6-neo', 'Chemical', '-', (122, 131))
822887	29427302	To examine the effect of SIM2 on cell differentiation, we next used a 3D culture system which was reported to induce differentiation of squamous cell carcinoma through adhesion restriction.29 Before the SIM2 cDNA transfection experiment, we confirmed both an increase and a decrease of mRNA of differentiation markers (CEA, FLG, IVL, KRT1, LOR, and SPRR1A) and EMT/basal cell markers (VIM and PDPN), respectively,25, 26, 27, 28 in KYSE510, TE8, and T.Tn by the 3D culture (Figure S3).	('decrease', 'NegReg', (274, 282))	('mRNA', 'MPA', (286, 290))	('TE8', 'Chemical', '-', (440, 443))	('EMT/basal cell markers', 'CPA', (361, 383))	('KRT1', 'Gene', '16678', (334, 338))	('IVL', 'Gene', (329, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('KRT1', 'Gene', (334, 338))	('CEA', 'Gene', (319, 322))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('squamous cell carcinoma', 'Disease', (136, 159))	('CEA', 'Gene', '111518', (319, 322))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('IVL', 'Gene', '16447', (329, 332))	('KYSE510', 'Var', (431, 438))
822888	29427302	Overexpression of SIM2 in KYSE510, TE8 and T.Tn followed by the 3D culture appeared to increase spheroid formation more effectively than did the control (Figure 3B).	('T.Tn', 'Var', (43, 47))	('increase', 'PosReg', (87, 95))	('spheroid formation', 'CPA', (96, 114))	('TE8', 'Chemical', '-', (35, 38))	('TE8', 'Var', (35, 38))	('SIM2', 'Gene', (18, 22))	('KYSE510', 'Var', (26, 33))
822889	29427302	Overexpression of SIM2 in KYSE510 and TE8 significantly increased SPRR1A mRNA and decreased VIM and PDPN mRNA at day 3 or 5, and that in T.Tn significantly induced FLG and repressed VIM (Figure 3C).	('FLG', 'CPA', (164, 167))	('repressed VIM', 'CPA', (172, 185))	('TE8', 'Chemical', '-', (38, 41))	('increased', 'PosReg', (56, 65))	('SPRR1A mRNA', 'MPA', (66, 77))	('TE8', 'Var', (38, 41))	('decreased', 'NegReg', (82, 91))	('induced', 'PosReg', (156, 163))	('KYSE510', 'Var', (26, 33))
822890	29427302	To investigate in vitro long term and the in vivo effect of SIM2 in ESCC cells, we established transfectants stably expressing SIM2, KYSE510-SIM2-27, KYSE510-SIM2-37, TE8-SIM2-2, TE8-SIM2-3, T.Tn-SIM2-9, and T.Tn-SIM2-23 (Figure 4A), and their mock-transfected counterparts, KYSE510-Mock, TE8-Mock, T.Tn-Mock.	('TE8-SIM2-3', 'Var', (179, 189))	('TE8', 'Chemical', '-', (289, 292))	('SIM2, KYSE510-SIM2-27, KYSE510-SIM2-37, TE8-SIM2-2', 'Disease', 'OMIM:616098', (127, 177))	('T.Tn-SIM2-9', 'Var', (191, 202))	('TE8', 'Chemical', '-', (167, 170))	('TE8', 'Chemical', '-', (179, 182))
822891	29427302	Given that PDPN is a basal cell marker in normal esophageal mucosa26, 27 and is also a marker of tumor basal cells with high tumor-initiating ability in squamous cell carcinoma,28 we compared the proportion of PDPN-positive cells in the SIM2-transfectants to that in the mock transfectants by flow cytometry using anti-PDPN antibody.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('esophageal mucosa', 'Disease', 'MESH:D004941', (49, 66))	('tumor basal cells', 'Phenotype', 'HP:0002671', (97, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('squamous cell carcinoma', 'Disease', (153, 176))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (153, 176))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('SIM2-transfectants', 'Var', (237, 255))	('tumor basal cell', 'Phenotype', 'HP:0002671', (97, 113))	('esophageal mucosa', 'Disease', (49, 66))
822893	29427302	The PDPN-positive tumor basal cell ratio in KYSE510-Mock was 50.6%, whereas that in KYSE510-SIM2-27 and KYSE510-SIM2-37 was markedly reduced to 2.6% and 2.7%, respectively.	('KYSE510-SIM2-27', 'Var', (84, 99))	('tumor', 'Disease', (18, 23))	('tumor basal cell', 'Phenotype', 'HP:0002671', (18, 34))	('KYSE510-Mock', 'Var', (44, 56))	('KYSE510-SIM2-37', 'Var', (104, 119))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('reduced', 'NegReg', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
822894	29427302	In T.Tn-SIM2-9 and T.Tn-SIM2-23, PDPN-positive tumor basal cell ratios were 58.6% and 42.0%, respectively, and were reduced clearly from 90.3% in T.Tn-Mock.	('tumor basal cell', 'Phenotype', 'HP:0002671', (47, 63))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('T.Tn-SIM2-9', 'Var', (3, 14))	('T.Tn-SIM2-23', 'Var', (19, 31))
822897	29427302	To investigate the effect of SIM2 on tumor formation, we transplanted mock- and SIM2-transfectants of KYSE510 and T.Tn into scid/scid mice subcutaneously, because TE8 had quite low tumor formation ability.	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mice', 'Species', '10090', (134, 138))	('TE8', 'Chemical', '-', (163, 166))	('KYSE510', 'Var', (102, 109))	('SIM2 on tumor', 'Disease', 'MESH:D009369', (29, 42))	('SIM2 on tumor', 'Disease', (29, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
822898	29427302	KYSE510-Mock developed larger tumors than did KYSE510-SIM2-27 and KYSE510-SIM2-37 in 3-7 weeks.	('KYSE510-Mock', 'Var', (0, 12))	('tumors', 'Disease', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
822899	29427302	Although T.Tn-Mock developed tumors in 8-11 weeks, T.Tn-SIM2-9 formed only one small tumor by the 11th week and T.Tn-SIM2-23 formed no tumor (Figure 5A).	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('T.Tn-SIM2-9', 'Var', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
822900	29427302	Xenografts of KYSE510-Mock showed moderate-differentiated histology, and KYSE510-SIM2-27 showed a well-differentiated histology with many cancer pearls (orbicular keratinized regions), which often appear at the central part of the tumor nest in well-differentiated squamous cell carcinomas (Figure 5B,C).	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('cancer', 'Disease', (138, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (265, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (265, 289))	('KYSE510-Mock', 'Var', (14, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (279, 289))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('squamous cell carcinomas', 'Disease', (265, 289))	('tumor', 'Disease', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (265, 289))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('KYSE510-SIM2-27', 'Var', (73, 88))
822913	29427302	IC50 of TE8-SIM2-2, TE8-SIM2-3, T.Tn-SIM2-9 and T.Tn-SIM2-23 on gamma-ray irradiation was also significantly decreased compared with TE8-Mock and T.Tn-Mock, respectively (Figure S7).	('decreased', 'NegReg', (109, 118))	('TE8-SIM2-2', 'Disease', 'MESH:D014923', (8, 18))	('TE8-SIM2-3', 'Var', (20, 30))	('TE8', 'Chemical', '-', (8, 11))	('TE8-SIM2-2', 'Disease', (8, 18))	('T.Tn-SIM2-9', 'Var', (32, 43))	('T.Tn-SIM2-23', 'Var', (48, 60))	('TE8', 'Chemical', '-', (133, 136))	('TE8', 'Chemical', '-', (20, 23))	('IC50', 'MPA', (0, 4))
822918	29427302	Among the 4 siRNAs, a single SOD2 siRNA transfection decreased the viable cell ratio only in the H2O2-treated cells (Figure 7D).	('H2O2', 'Chemical', 'MESH:D006861', (97, 101))	('SOD2', 'Gene', '6648', (29, 33))	('SOD2', 'Gene', (29, 33))	('viable cell ratio', 'CPA', (67, 84))	('decreased', 'NegReg', (53, 62))	('transfection', 'Var', (40, 52))
822922	29427302	Promoter hypomethylation of SIM2 was found in 4 of 5 ESCC cases with high SIM2 expression, whereas hypermethylation was found in 3 of 5 cases with low SIM2 expression (Figure 2C).	('SIM2', 'Gene', (74, 78))	('ESCC', 'Disease', (53, 57))	('SIM2', 'Gene', (28, 32))	('found', 'Reg', (37, 42))	('low SIM2', 'Disease', 'MESH:D009800', (147, 155))	('low SIM2', 'Disease', (147, 155))	('high', 'Var', (69, 73))	('Promoter', 'MPA', (0, 8))	('expression', 'Var', (79, 89))
822928	29427302	In Figure 4B, SIM2 transfection strongly reduced PDPN-positive cells in KYSE510 and T.Tn cells, but the reduction was limited in TE8 cells.	('reduced', 'NegReg', (41, 48))	('transfection', 'Var', (19, 31))	('SIM2', 'Gene', (14, 18))	('PDPN-positive cells', 'CPA', (49, 68))	('TE8', 'Chemical', '-', (129, 132))
822933	29427302	Furthermore, knockdown of ARNT expression in the transient or stable SIM2-transfectants resulted in an increment of PDPN-positive tumor basal cells, suggesting that SIM2 and ARNT cooperatively induce differentiation of PDPN-positive tumor basal cells (Figure 6C,D; S6).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor basal cell', 'Phenotype', 'HP:0002671', (130, 146))	('tumor basal cell', 'Phenotype', 'HP:0002671', (233, 249))	('tumor', 'Disease', (233, 238))	('differentiation', 'CPA', (200, 215))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor basal cells', 'Phenotype', 'HP:0002671', (130, 147))	('increment', 'NegReg', (103, 112))	('knockdown', 'Var', (13, 22))	('tumor basal cells', 'Phenotype', 'HP:0002671', (233, 250))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SIM2-transfectants', 'Gene', (69, 87))	('induce', 'PosReg', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', (130, 135))	('ARNT', 'Gene', (26, 30))
822934	29427302	High SIM2 expression in cancerous tissue did not significantly affect the prognosis of ESCC patients who underwent esophagectomy alone (data not shown); however, in patients who were treated with definitive CRT, high SIM2 expression was associated with a good prognosis (Figure 1C).	('high SIM2 expression', 'Var', (212, 232))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancerous', 'Disease', 'MESH:D009369', (24, 33))	('patients', 'Species', '9606', (92, 100))	('ESCC', 'Disease', (87, 91))	('patients', 'Species', '9606', (165, 173))	('cancerous', 'Disease', (24, 33))
822936	29427302	FANCD2, BRCA1, BARD1, and XRCC5 have been reported to play pivotal roles in the DNA repair pathway, and FANCD2 and BARD1 interact with BRCA1 in the repair of DNA interstrand cross-links and DNA double-strand breaks, respectively.33, 34, 35 SOD2 is known to efficiently catalyze the dismutation of reactive oxygen species,36 which are induced by irradiation.	('SOD2', 'Gene', (240, 244))	('BARD1', 'Gene', '580', (15, 20))	('FANCD2', 'Gene', (0, 6))	('FANCD2', 'Gene', (104, 110))	('BARD1', 'Gene', (15, 20))	('BRCA1', 'Gene', '672', (135, 140))	('XRCC5', 'Gene', (26, 31))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (297, 320))	('respectively.33', 'Var', (216, 231))	('FANCD2', 'Gene', '2177', (104, 110))	('BRCA1', 'Gene', '672', (8, 13))	('BRCA1', 'Gene', (135, 140))	('BARD1', 'Gene', '580', (115, 120))	('XRCC5', 'Gene', '7520', (26, 31))	('BRCA1', 'Gene', (8, 13))	('FANCD2', 'Gene', '2177', (0, 6))	('SOD2', 'Gene', '6648', (240, 244))	('BARD1', 'Gene', (115, 120))
822938	29427302	Among the 4 siRNAs of these 4 genes, only a single SOD2 siRNA transfection decreased the mRNA and the viable cell ratio in the H2O2-treated cells (Figure 7D).	('SOD2', 'Gene', (51, 55))	('mRNA', 'MPA', (89, 93))	('H2O2', 'Chemical', 'MESH:D006861', (127, 131))	('decreased', 'NegReg', (75, 84))	('transfection', 'Var', (62, 74))	('SOD2', 'Gene', '6648', (51, 55))
822939	29427302	Microvessel density in squamous cell carcinoma has been reported to be associated with radiosensitivity.37 Such microvessels were often observed in the thick stroma in well-differentiated ESCC (Figure S10A) and also in the xenograft with a well-differentiated histology of KYSE510 cells (Figure S10B).	('S10A', 'SUBSTITUTION', 'None', (201, 205))	('ESCC', 'Disease', (188, 192))	('thick stroma', 'Disease', 'MESH:C535655', (152, 164))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))	('thick stroma', 'Disease', (152, 164))	('S10A', 'Var', (201, 205))	('S10B', 'Var', (295, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('squamous cell carcinoma', 'Disease', (23, 46))	('S10B', 'SUBSTITUTION', 'None', (295, 299))
822942	29427302	In the left panel, ESCC tumors with high SIM2 expression may maintain squamous differentiation potential of the esophageal mucosa and restrain the expansion of the PDPN-positive tumor basal cell layer.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('ESCC tumors', 'Disease', 'MESH:D004938', (19, 30))	('tumor', 'Disease', (178, 183))	('expression', 'Var', (46, 56))	('maintain', 'PosReg', (61, 69))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', (24, 29))	('tumor basal cell', 'Phenotype', 'HP:0002671', (178, 194))	('SIM2', 'Gene', (41, 45))	('squamous differentiation potential', 'CPA', (70, 104))	('esophageal mucosa', 'Disease', (112, 129))	('ESCC tumors', 'Disease', (19, 30))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('restrain', 'NegReg', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('esophageal mucosa', 'Disease', 'MESH:D004941', (112, 129))	('high', 'Var', (36, 40))
822947	26717044	Using array analysis, we have previously determined that miR-199a-5p was the most downregulated miR in two esophageal cancer cell lines compared to esophageal epithelial cells.	('downregulated', 'NegReg', (82, 95))	('199a', 'Chemical', '-', (61, 65))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('miR', 'Gene', (96, 99))	('miR-199a-5p', 'Var', (57, 68))
822950	26717044	Forced expression of miR-199a-5p in these cells leads to a decrease in the mRNA and protein levels of MAP3K11, due to decreased MAP3K11 mRNA stability.	('MAP3K11', 'Protein', (128, 135))	('miR-199a-5p', 'Var', (21, 32))	('199a', 'Chemical', '-', (25, 29))	('decrease', 'NegReg', (59, 67))	('decreased', 'NegReg', (118, 127))	('MAP3K11', 'Protein', (102, 109))	('mRNA stability', 'MPA', (136, 150))
822952	26717044	Finally, forced expression of miR-199a-5p decreases proliferation of esophageal cancer cells by inducing G2/M arrest.	('proliferation', 'CPA', (52, 65))	('inducing', 'Reg', (96, 104))	('esophageal cancer', 'Disease', (69, 86))	('decreases', 'NegReg', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('199a', 'Chemical', '-', (34, 38))	('G2/M arrest', 'CPA', (105, 116))	('miR-199a-5p', 'Var', (30, 41))
822954	26717044	These findings suggest that miR-199a-5p acts as a tumor suppressor in esophageal cancer cells and that its downregulation contributes to enhanced cellular proliferation by targeting MAP3K11.	('enhanced', 'PosReg', (137, 145))	('cellular proliferation', 'CPA', (146, 168))	('esophageal cancer', 'Disease', (70, 87))	('targeting', 'Reg', (172, 181))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('miR-199a-5p', 'Var', (28, 39))	('downregulation', 'NegReg', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (50, 55))	('MAP3K11', 'Protein', (182, 189))	('199a', 'Chemical', '-', (32, 36))
822966	26717044	miR-199a-5p was found to be the most down-regulated miR in both TE7 and TE10 cells compared to the hESO cells.	('miR-199a-5p', 'Var', (0, 11))	('TE10', 'CellLine', 'CVCL:1760', (72, 76))	('199a', 'Chemical', '-', (4, 8))	('miR', 'Gene', (52, 55))	('down-regulated', 'NegReg', (37, 51))
822967	26717044	Based on miR target prediction programs, miR-199a-5p is predicted to bind mitogen-activated protein kinase kinase kinase 11 (MAP3K11) with high affinity.	('bind', 'Interaction', (69, 73))	('MAP3K11', 'Gene', (125, 132))	('miR-199a-5p', 'Var', (41, 52))	('199a', 'Chemical', '-', (45, 49))	('mitogen-activated protein kinase kinase kinase 11', 'Gene', '26403', (74, 123))	('mitogen-activated protein kinase kinase kinase 11', 'Gene', (74, 123))
822968	26717044	Overexpression of MAP3K11 has been demonstrated in multiple malignancies, but no evidence exists on its expression levels in esophageal cancer.	('malignancies', 'Disease', (60, 72))	('MAP3K11', 'Gene', (18, 25))	('esophageal cancer', 'Disease', (125, 142))	('Overexpression', 'Var', (0, 14))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
822970	26717044	In addition, we describe the phenotypic effects of modulating expression of miR-199a-5p in these cells.	('199a', 'Chemical', '-', (80, 84))	('expression', 'MPA', (62, 72))	('modulating', 'Var', (51, 61))	('miR-199a-5p', 'Gene', (76, 87))
822971	26717044	In array analysis of global miR expression in human esophageal epithelial cells (hESO) and the human esophageal squamous cell cancer lines TE7 and TE10, miR-199a-5p was found to be the most down-regulated miR in both cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('esophageal squamous cell cancer', 'Disease', (101, 132))	('human', 'Species', '9606', (95, 100))	('199a', 'Chemical', '-', (157, 161))	('cancer', 'Disease', (126, 132))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (101, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('miR-199a-5p', 'Var', (153, 164))	('cancer', 'Disease', (217, 223))	('human', 'Species', '9606', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('miR', 'Gene', (28, 31))	('down-regulated', 'NegReg', (190, 204))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (112, 132))	('TE10', 'CellLine', 'CVCL:1760', (147, 151))
822974	26717044	Based on a review of the Target Scan 6 and miRDB target prediction programs, MAP3K11 contains two potential high affinity binding sites for miR-199a-5p.	('miR-199a-5p', 'Var', (140, 151))	('MAP3K11', 'Gene', (77, 84))	('199a', 'Chemical', '-', (144, 148))	('binding', 'Interaction', (122, 129))
822979	26717044	As shown in Figure 2A, transfection efficiency of pre-miR-199a-5p was robust in both TE7 and TE10 cells (a).	('TE10', 'CellLine', 'CVCL:1760', (93, 97))	('199a', 'Chemical', '-', (58, 62))	('transfection', 'MPA', (23, 35))	('pre-miR-199a-5p', 'Var', (50, 65))
822980	26717044	Similarly, transfection of anti-miR-199a-5p was very effective in reducing miR-199a-5p levels in hESO cells (c).	('miR-199a-5p levels', 'MPA', (75, 93))	('199a', 'Chemical', '-', (36, 40))	('199a', 'Chemical', '-', (79, 83))	('reducing', 'NegReg', (66, 74))	('anti-miR-199a-5p', 'Var', (27, 43))
822981	26717044	Following successful transfection of pre-miR-199a-5p, MAP3K11 protein levels are markedly decreased in TE7 and TE10 cells (Figure 2B a/b).	('MAP3K11', 'Gene', (54, 61))	('pre-miR-199a-5p', 'Var', (37, 52))	('TE10', 'CellLine', 'CVCL:1760', (111, 115))	('decreased', 'NegReg', (90, 99))	('199a', 'Chemical', '-', (45, 49))
822983	26717044	Conversely, MAP3K11 protein levels were increased compared to control-miR transfection in hESO cells following transfection of anti-miR-199a-5p (c).	('MAP3K11', 'Protein', (12, 19))	('increased', 'PosReg', (40, 49))	('199a', 'Chemical', '-', (136, 140))	('anti-miR-199a-5p', 'Var', (127, 143))
822984	26717044	There was no change in either Cdc42 or Rac-1 expression following silencing of miR-199a-5p in hESO cells.	('silencing', 'Var', (66, 75))	('miR-199a-5p', 'Gene', (79, 90))	('Rac-1', 'Gene', '19353', (39, 44))	('expression', 'MPA', (45, 55))	('Cdc42', 'Gene', '12540', (30, 35))	('199a', 'Chemical', '-', (83, 87))	('Rac-1', 'Gene', (39, 44))	('Cdc42', 'Gene', (30, 35))
822986	26717044	As seen in Figure 3A, transfection of pre-miR-199a-5p was associated with a decrease in MAP3K11 mRNA levels in TE7 cells.	('transfection', 'Var', (22, 34))	('pre-miR-199a-5p', 'Var', (38, 53))	('decrease', 'NegReg', (76, 84))	('MAP3K11 mRNA levels', 'MPA', (88, 107))	('199a', 'Chemical', '-', (46, 50))
822987	26717044	As anticipated, in hESO cells reduction of miR-199a-5p expression led to an increase in MAP3K11 mRNA levels (Figure 3B).	('miR-199a-5p', 'Var', (43, 54))	('increase', 'PosReg', (76, 84))	('199a', 'Chemical', '-', (47, 51))	('MAP3K11', 'Protein', (88, 95))	('reduction', 'NegReg', (30, 39))
822988	26717044	Figures 3C and 3D depict stability of MAP3K11 in TE7 and hESO cells following modulation of miR199a-5p levels.	('MAP3K11', 'Gene', (38, 45))	('199a', 'Chemical', '-', (95, 99))	('stability', 'MPA', (25, 34))	('modulation', 'Var', (78, 88))
822991	26717044	The stability curve in Figure 3D demonstrates enhanced stability of MAP3K11 mRNA following silencing of miR-199a-5p in hESO cells.	('miR-199a-5p', 'Gene', (104, 115))	('MAP3K11', 'Gene', (68, 75))	('stability', 'MPA', (55, 64))	('199a', 'Chemical', '-', (108, 112))	('enhanced', 'PosReg', (46, 54))	('silencing', 'Var', (91, 100))
822992	26717044	We next sought to determine whether miR-199a-5p directly interacted with MAP3K11 mRNA.	('MAP3K11', 'Gene', (73, 80))	('199a', 'Chemical', '-', (40, 44))	('miR-199a-5p', 'Var', (36, 47))
822997	26717044	Following co-transfection with pre-miR-199a-5p or control miR, there was an approximately 39% reduction in luciferase activity with the F1-Luc construct and a 68.3% reduction in luciferase activity with the F-2 construct.	('reduction', 'NegReg', (94, 103))	('activity', 'MPA', (118, 126))	('199a', 'Chemical', '-', (39, 43))	('luciferase', 'Enzyme', (178, 188))	('pre-miR-199a-5p', 'Var', (31, 46))	('reduction', 'NegReg', (165, 174))	('luciferase', 'Enzyme', (107, 117))	('activity', 'MPA', (189, 197))
822998	26717044	Importantly, following mutation of 3 bases in the seed sequence binding region of the predicted miR-199a-5p binding site in each fragment, the reduction in luciferase activity following co-transfection with pre-miR-199a-5p was completely abrogated.	('199a', 'Chemical', '-', (215, 219))	('luciferase', 'Enzyme', (156, 166))	('mutation', 'Var', (23, 31))	('abrogated', 'NegReg', (238, 247))	('199a', 'Chemical', '-', (100, 104))	('reduction', 'NegReg', (143, 152))	('activity', 'MPA', (167, 175))
822999	26717044	As seen in Figure 5D, mutation of either binding site, with the other binding site left intact, resulted in a partial recovery in luciferase activity following co-transfection with pre-miR-199a-5p compared to the FL WT construct.	('mutation', 'Var', (22, 30))	('recovery', 'PosReg', (118, 126))	('luciferase', 'Enzyme', (130, 140))	('activity', 'MPA', (141, 149))	('199a', 'Chemical', '-', (189, 193))
823000	26717044	Co-transfection of the Mut construct, in which both binding sites were mutated, with pre-miR-199a-5p, resulted in near-complete abrogation of the decrement in luciferase activity, suggesting that both binding sites are functional.	('abrogation', 'NegReg', (128, 138))	('activity', 'MPA', (170, 178))	('mutated', 'Var', (71, 78))	('decrement', 'MPA', (146, 155))	('199a', 'Chemical', '-', (93, 97))	('luciferase', 'Enzyme', (159, 169))
823001	26717044	As a first step in this analysis, as seen in Figure 6A, we observed a decrease in TE7 cellular proliferation following overexpression of miR-199a-5p, with a statistically significant decrease seen after 96 hours in culture.	('TE7 cellular proliferation', 'CPA', (82, 108))	('overexpression', 'PosReg', (119, 133))	('199a', 'Chemical', '-', (141, 145))	('decrease', 'NegReg', (70, 78))	('miR-199a-5p', 'Var', (137, 148))
823008	26717044	Finally, because there is a predicted binding site for miR-199a-5p in the 3' UTR of cyclin D1 mRNA, we investigated whether there was a direct interaction between miR-199a-5p and cyclin D1 mRNA.	('199a', 'Chemical', '-', (59, 63))	('interaction', 'Interaction', (143, 154))	('miR-199a-5p', 'Var', (163, 174))	('199a', 'Chemical', '-', (167, 171))
823009	26717044	Figure 7D shows that there was no change in the level of cyclin D1 mRNA in the pull-down material isolated from TE7 cells following transfection with biotin-labeled miR-199a-5p compared to control.	('199a', 'Chemical', '-', (169, 173))	('biotin', 'Chemical', 'MESH:D001710', (150, 156))	('miR-199a-5p', 'Var', (165, 176))	('cyclin D1', 'MPA', (57, 66))	('transfection', 'Var', (132, 144))
823012	26717044	Forced expression of miR-199a-5p leads to a decrease in MAP3K11 mRNA and protein levels through decreased mRNA stability.	('mRNA stability', 'MPA', (106, 120))	('decrease', 'NegReg', (44, 52))	('decreased', 'NegReg', (96, 105))	('MAP3K11', 'Protein', (56, 63))	('miR-199a-5p', 'Var', (21, 32))	('199a', 'Chemical', '-', (25, 29))
823015	26717044	MiR-199a-5p, also referred to as miR-199-a in earlier literature, has been shown to be downregulated in multiple malignancies where it functions as a tumor suppressor by regulating such processes as cellular proliferation, sensitivity to chemotherapy-induced apoptosis, migration and invasiveness.	('regulating', 'Reg', (170, 180))	('MiR', 'Gene', (0, 3))	('malignancies', 'Disease', (113, 125))	('sensitivity to chemotherapy-induced apoptosis', 'CPA', (223, 268))	('invasiveness', 'CPA', (284, 296))	('MiR', 'Gene', '751557', (0, 3))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('migration', 'CPA', (270, 279))	('199a', 'Chemical', '-', (4, 8))	('downregulated', 'NegReg', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cellular proliferation', 'CPA', (199, 221))	('tumor', 'Disease', (150, 155))	('miR-199-a', 'Var', (33, 42))
823018	26717044	Overexpression of miR-199a-5p led to decreased levels of GRP78, resulting in induction of apoptosis and increased sensitivity to the histone deacetylase inhibitor, trichostatin A.	('GRP78', 'Gene', '14828', (57, 62))	('increased', 'PosReg', (104, 113))	('199a', 'Chemical', '-', (22, 26))	('miR-199a-5p', 'Var', (18, 29))	('trichostatin A', 'Chemical', 'MESH:C012589', (164, 178))	('levels', 'MPA', (47, 53))	('sensitivity to the', 'MPA', (114, 132))	('GRP78', 'Gene', (57, 62))	('apoptosis', 'CPA', (90, 99))	('decreased', 'NegReg', (37, 46))
823019	26717044	In renal cell cancer (RCC) cells, overexpression of miR-199a-5p resulted in the downregulation of GSK-3beta, a serine/threonine kinase involved in NFkappaB signaling.	('GSK-3beta', 'Gene', '56637', (98, 107))	('renal cell cancer', 'Disease', (3, 20))	('RCC', 'Disease', (22, 25))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('199a', 'Chemical', '-', (56, 60))	('renal cell cancer', 'Phenotype', 'HP:0005584', (3, 20))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('miR-199a-5p', 'Var', (52, 63))	('overexpression', 'PosReg', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('GSK-3beta', 'Gene', (98, 107))	('downregulation', 'NegReg', (80, 94))	('renal cell cancer', 'Disease', 'MESH:C538614', (3, 20))
823020	26717044	Proliferation was found to be significantly decreased in RCC cells following overexpression of miR-199a-5p.	('overexpression', 'PosReg', (77, 91))	('199a', 'Chemical', '-', (99, 103))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('Proliferation', 'CPA', (0, 13))	('decreased', 'NegReg', (44, 53))	('miR-199a-5p', 'Var', (95, 106))
823021	26717044	In colorectal cancer cells, miR-199a-5p was found to interact with discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase.	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('discoidin domain receptor 1', 'Gene', (67, 94))	('miR-199a-5p', 'Var', (28, 39))	('colorectal cancer', 'Disease', (3, 20))	('interact', 'Interaction', (53, 61))	('discoidin domain receptor 1', 'Gene', '12305', (67, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('DDR1', 'Gene', (96, 100))	('DDR1', 'Gene', '12305', (96, 100))	('199a', 'Chemical', '-', (32, 36))
823022	26717044	Overexpression of miR-199a-5p led to decreased expression of DDR1 and resulted in decreased invasiveness and migratory ability of the transfected cells.	('decreased invasiveness', 'Disease', (82, 104))	('decreased invasiveness', 'Disease', 'MESH:D009362', (82, 104))	('199a', 'Chemical', '-', (22, 26))	('miR-199a-5p', 'Var', (18, 29))	('DDR1', 'Gene', (61, 65))	('decreased', 'NegReg', (37, 46))	('expression', 'MPA', (47, 57))	('DDR1', 'Gene', '12305', (61, 65))
823023	26717044	In addition, in ovarian cancer cells, miR-199a-5p has been shown to regulate expression of multiple oncogenic targets, suggesting that it may function as a master regulator in these cells.	('miR-199a-5p', 'Var', (38, 49))	('expression', 'MPA', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('ovarian cancer', 'Disease', (16, 30))	('regulate', 'Reg', (68, 76))	('199a', 'Chemical', '-', (42, 46))	('ovarian cancer', 'Phenotype', 'HP:0100615', (16, 30))	('ovarian cancer', 'Disease', 'MESH:D010051', (16, 30))
823024	26717044	Restoration of miR-199a-5p expression in ovarian cancer cells has been shown to increase sensitivity to cisplatin, both through targeting mTOR and by targeting CD44, thereby reducing ovarian cancer stem cell levels.	('mTOR', 'Gene', (138, 142))	('sensitivity to cisplatin', 'MPA', (89, 113))	('increase', 'PosReg', (80, 88))	('Restoration', 'Var', (0, 11))	('199a', 'Chemical', '-', (19, 23))	('reducing', 'NegReg', (174, 182))	('CD44', 'Gene', (160, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ovarian cancer', 'Disease', 'MESH:D010051', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ovarian cancer', 'Disease', 'MESH:D010051', (183, 197))	('miR-199a-5p', 'Gene', (15, 26))	('CD44', 'Gene', '12505', (160, 164))	('mTOR', 'Gene', '56717', (138, 142))	('targeting', 'Reg', (128, 137))	('ovarian cancer', 'Disease', (41, 55))	('ovarian cancer', 'Disease', (183, 197))	('targeting', 'Reg', (150, 159))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (183, 197))
823025	26717044	Finally, miR-199a-5p was also demonstrated to target IkappaB kinase-beta in ovarian cancer cells, resulting in increased sensitivity to TNF-alpha-induced apoptosis following forced expression of miR-199a-5p.	('TNF-alpha', 'Gene', (136, 145))	('miR-199a-5p', 'Var', (195, 206))	('increased', 'PosReg', (111, 120))	('ovarian cancer', 'Disease', (76, 90))	('199a', 'Chemical', '-', (13, 17))	('TNF-alpha', 'Gene', '21926', (136, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('199a', 'Chemical', '-', (199, 203))	('IkappaB kinase-beta', 'Gene', '16150', (53, 72))	('IkappaB kinase-beta', 'Gene', (53, 72))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ovarian cancer', 'Disease', 'MESH:D010051', (76, 90))
823026	26717044	Although miR-199a-5p is generally found to be downregulated in cancer cells, it has been shown to be elevated in gastric adenocarcinomas.	('elevated', 'PosReg', (101, 109))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (113, 136))	('199a', 'Chemical', '-', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('gastric adenocarcinomas', 'Disease', (113, 136))	('downregulated', 'NegReg', (46, 59))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('miR-199a-5p', 'Var', (9, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('cancer', 'Disease', (63, 69))
823028	26717044	miR-199a-5p has been shown to function as an oncogene in gastric cancer cells partially through targeting klotho, which can suppress invasiveness and epithelial-mesenchymal transition.	('suppress', 'NegReg', (124, 132))	('epithelial-mesenchymal transition', 'CPA', (150, 183))	('gastric cancer', 'Disease', (57, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('miR-199a-5p', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('klotho', 'Gene', '16591', (106, 112))	('klotho', 'Gene', (106, 112))	('199a', 'Chemical', '-', (4, 8))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))
823029	26717044	Given the close relationship between gastric and esophageal adenocarcinomas, miR-199a-5p has also been shown to be elevated in esophageal adenocarcinomas and associated with increased stage.	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('esophageal adenocarcinomas', 'Disease', (49, 75))	('elevated', 'PosReg', (115, 123))	('miR-199a-5p', 'Var', (77, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('199a', 'Chemical', '-', (81, 85))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (127, 153))	('increased', 'PosReg', (174, 183))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (49, 75))	('stage', 'Disease', (184, 189))	('esophageal adenocarcinomas', 'Disease', (127, 153))
823037	26717044	In addition, MAP3K11 helps facilitate activation of B-Raf which stimulates ERK 1/2 signaling.	('stimulates', 'PosReg', (64, 74))	('ERK 1/2', 'Gene', (75, 82))	('ERK 1/2', 'Gene', '26417;26413', (75, 82))	('MAP3K11', 'Var', (13, 20))	('B-Raf', 'Gene', (52, 57))	('activation', 'PosReg', (38, 48))	('B-Raf', 'Gene', '109880', (52, 57))
823039	26717044	Silencing of MAP3K11 has been shown to decrease proliferation in colon cancer cells.	('colon cancer', 'Disease', (65, 77))	('decrease', 'NegReg', (39, 47))	('proliferation', 'CPA', (48, 61))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('MAP3K11', 'Gene', (13, 20))	('Silencing', 'Var', (0, 9))
823042	26717044	In ovarian cancer cells, MAP3K11 was found to enhance invasiveness by regulating expression of multiple mixed metalloproteinases.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('invasiveness', 'CPA', (54, 66))	('regulating', 'Reg', (70, 80))	('ovarian cancer', 'Disease', (3, 17))	('enhance', 'PosReg', (46, 53))	('MAP3K11', 'Var', (25, 32))	('expression', 'MPA', (81, 91))
823047	26717044	In melanoma cell lines, overexpression of miR-125b led to a decrease in MAP3K11 levels as well as decreased cell growth and invasiveness.	('decrease', 'NegReg', (60, 68))	('invasiveness', 'CPA', (124, 136))	('cell growth', 'CPA', (108, 119))	('MAP3K11 levels', 'MPA', (72, 86))	('miR-125b', 'Var', (42, 50))	('overexpression', 'PosReg', (24, 38))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('decreased', 'NegReg', (98, 107))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
823051	26717044	As was seen with miR-125b in murine pre-B cells, Song and colleagues have shown that miR-199a-5p was overexpressed in gastric cancer cells, associated with low levels of MAP3K11.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('murine', 'Species', '10090', (29, 35))	('gastric cancer', 'Disease', (118, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('overexpressed', 'PosReg', (101, 114))	('199a', 'Chemical', '-', (89, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('miR-199a-5p', 'Var', (85, 96))
823052	26717044	As expected, silencing miR-199a-5p led to an increase in levels of MAP3K11.	('199a', 'Chemical', '-', (27, 31))	('MAP3K11', 'Protein', (67, 74))	('levels', 'MPA', (57, 63))	('miR-199a-5p', 'Protein', (23, 34))	('silencing', 'Var', (13, 22))	('increase', 'PosReg', (45, 53))
823054	26717044	In these cells, activation of MAP3K11 activates JNK signaling, which in turn stimulates expression of pro-apoptotic proteins Fas Ligand and BH-3 only members of the BCl-2 family.	('JNK', 'Gene', (48, 51))	('stimulates', 'PosReg', (77, 87))	('MAP3K11', 'Gene', (30, 37))	('JNK', 'Gene', '26419', (48, 51))	('activates', 'PosReg', (38, 47))	('activation', 'Var', (16, 26))	('expression', 'MPA', (88, 98))	('BH-3', 'Gene', (140, 144))
823056	26717044	In this study, overexpression of miR-199a-5p with resulting decreased levels of MAP3K11 resulted in decreased cellular proliferation.	('levels', 'MPA', (70, 76))	('decreased', 'NegReg', (60, 69))	('overexpression', 'PosReg', (15, 29))	('cellular proliferation', 'CPA', (110, 132))	('199a', 'Chemical', '-', (37, 41))	('MAP3K11', 'Protein', (80, 87))	('decreased', 'NegReg', (100, 109))	('miR-199a-5p', 'Var', (33, 44))
823058	26717044	In support of this hypothesis, we observed decreased cyclin D1 levels, as well as decreased levels of phosphorylated c-Jun, despite no change in total c-Jun levels following overexpression of miR-199a-5p.	('c-Jun', 'Gene', (151, 156))	('cyclin D1 levels', 'MPA', (53, 69))	('miR-199a-5p', 'Var', (192, 203))	('199a', 'Chemical', '-', (196, 200))	('c-Jun', 'Gene', '16476', (117, 122))	('c-Jun', 'Gene', '16476', (151, 156))	('decreased', 'NegReg', (82, 91))	('decreased', 'NegReg', (43, 52))	('c-Jun', 'Gene', (117, 122))
823059	26717044	Furthermore, we observed decreased cyclin D1 promoter activity following miR-199a-5p transfection.	('199a', 'Chemical', '-', (77, 81))	('decreased', 'NegReg', (25, 34))	('cyclin D1 promoter activity', 'MPA', (35, 62))	('miR-199a-5p transfection', 'Var', (73, 97))
823061	26717044	Although overexpression of miR-199a-5p and downregulation of MAP3K11 may affect proliferation through other mechanisms not evaluated in this study, these data support an important role for cyclin D1 in mediating the observed decreased proliferation in esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (252, 269))	('overexpression', 'PosReg', (9, 23))	('affect', 'Reg', (73, 79))	('downregulation', 'NegReg', (43, 57))	('miR-199a-5p', 'Var', (27, 38))	('proliferation', 'CPA', (80, 93))	('proliferation', 'CPA', (235, 248))	('decreased', 'NegReg', (225, 234))	('MAP3K11', 'Gene', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('199a', 'Chemical', '-', (31, 35))	('esophageal cancer', 'Disease', (252, 269))
823069	26717044	Anti-MAP3K11, anti-Cdc42, anti-c-Jun, anti-Rac-1, anti-cyclin D1 and anti-GAPDH were purchased from Santa Cruz Biotechnology (Dallas, TX).	('Cdc42', 'Gene', '12540', (19, 24))	('Rac-1', 'Gene', (43, 48))	('c-Jun', 'Gene', (31, 36))	('Cdc42', 'Gene', (19, 24))	('GAPDH', 'Gene', '14433', (74, 79))	('Anti-MAP3K11', 'Var', (0, 12))	('GAPDH', 'Gene', (74, 79))	('c-Jun', 'Gene', '16476', (31, 36))	('Rac-1', 'Gene', '19353', (43, 48))
823081	26717044	Briefly, 1 x 105 TE7 cells/well were plated onto 12-well cell culture plates and co-transfected with reporter constructs containing the cyclin D1 promoter (100ng) and either pre-miR-199a-5p (10nM) or control miR in TE7 cells for 36 hours.	('pre-miR-199a-5p', 'Var', (174, 189))	('100ng', 'Var', (156, 161))	('199a', 'Chemical', '-', (182, 186))
823098	25144454	It is conjectured that the imbalance of Th1/Th2 may contribute to the occurrence and development of tumor.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('imbalance', 'Phenotype', 'HP:0002172', (27, 36))	('development', 'CPA', (85, 96))	('tumor', 'Disease', (100, 105))	('Th1', 'Gene', '51497', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Th1', 'Gene', (40, 43))	('contribute', 'Reg', (52, 62))	('imbalance', 'Var', (27, 36))
823189	30352404	In addition, T4 substitution therapy has been correlated with a decreased risk of colorectal cancer.	('colorectal cancer', 'Disease', (82, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('T4 substitution therapy', 'Var', (13, 36))	('rectal cancer', 'Phenotype', 'HP:0100743', (86, 99))	('decreased', 'NegReg', (64, 73))
823357	29524046	LN yield >= 15 was independently associated with fewer intraoperative complications (4.5% vs. 6.8%, OR 0.69 [0.50-0.95]).	('>= 15', 'Var', (9, 14))	('intraoperative complications', 'Disease', (55, 83))	('intraoperative complications', 'Disease', 'MESH:D007431', (55, 83))
823358	29524046	Postoperative complications were more frequent in patients with >=15 LNs than in patients with < 15 LN, but multivariable analysis showed no statistically significant association (Table 3).	('Postoperative complications', 'CPA', (0, 27))	('>=15 LNs', 'Var', (64, 72))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (50, 58))
823364	29524046	It is well known that the type of surgical approach in esophageal resection influences the number of retrieved LNs; i.e., transthoracic as compared with transhiatal approach is associated with a higher number of LNs retrieved, as also seen in the current study.	('transthoracic', 'Var', (122, 135))	('esophageal', 'Disease', (55, 65))	('influences', 'Reg', (76, 86))	('esophageal', 'Disease', 'MESH:D004941', (55, 65))
823383	29560108	For esophageal cancer, the AurkA Phe31-Ile polymorphism has previously been associated with tumor progression.	('Phe31-Ile', 'Var', (33, 42))	('Phe31-Ile', 'Mutation', 'rs2273535', (33, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('AurkA', 'Gene', '6790', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('AurkA', 'Gene', (27, 32))	('associated with', 'Reg', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal cancer', 'Disease', (4, 21))
823390	29560108	These findings indicate that the Aurora-Kinase A Phe31-Ile-polymorphism is a possibly predictive factor for response to radiation in combination with Docetaxel and Aurora-Kinase inhibitor treatments.	('Phe31-Ile', 'Mutation', 'rs2273535', (49, 58))	('Aurora-Kinase A', 'Gene', '100345632', (33, 48))	('Docetaxel', 'Chemical', 'MESH:D000077143', (150, 159))	('Phe31-Ile-polymorphism', 'Var', (49, 71))	('Aurora-Kinase A', 'Gene', (33, 48))	('predictive', 'Reg', (86, 96))
823394	29560108	It has been shown that EGFR targeting significantly improves the overall survival (OS) of HNSCC patients.	('HNSCC', 'Disease', (90, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('targeting', 'Var', (28, 37))	('EGFR', 'Gene', '1956', (23, 27))	('patients', 'Species', '9606', (96, 104))	('improves', 'PosReg', (52, 60))	('EGFR', 'Gene', (23, 27))	('overall survival', 'MPA', (65, 81))
823397	29560108	Moreover, it has been shown that the AurkA Phe31-Ile polymorphism enhances esophageal cancer progression.	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('enhances', 'PosReg', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('AurkA', 'Gene', '6790', (37, 42))	('Phe31-Ile', 'Mutation', 'rs2273535', (43, 52))	('AurkA', 'Gene', (37, 42))	('esophageal cancer', 'Disease', (75, 92))	('Phe31-Ile', 'Var', (43, 52))
823400	29560108	Here we evaluated the Aurora-Kinase A polymorphism as a predictor for treatment outcome of HNSCC cell lines.	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('Aurora-Kinase A', 'Gene', (22, 37))	('Aurora-Kinase A', 'Gene', '100345632', (22, 37))	('polymorphism', 'Var', (38, 50))
823407	29560108	The high expression of AurkA and Survivin (p = 0.020) as well as the combination of AurkA with Akt phosphorylated on Ser 473 (p = 0.031) showed a significantly inferior overall survival (Table 1, Supplementary Figure 1).	('inferior', 'NegReg', (160, 168))	('Akt', 'Gene', '207', (95, 98))	('AurkA', 'Gene', '6790', (84, 89))	('Survivin', 'Protein', (33, 41))	('overall', 'MPA', (169, 176))	('combination', 'Var', (69, 80))	('AurkA', 'Gene', '6790', (23, 28))	('Akt', 'Gene', (95, 98))	('Ser', 'Chemical', 'MESH:D012694', (117, 120))	('AurkA', 'Gene', (84, 89))	('AurkA', 'Gene', (23, 28))
823433	29560108	Concordantly, an increased frequency of the heterocygous AurkA genotype in esophageal carcinomas has been found which has been attributed to enhanced tumor progression.	('AurkA', 'Gene', (57, 62))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (75, 95))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (75, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (75, 96))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('AurkA', 'Gene', '6790', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('enhanced', 'PosReg', (141, 149))	('heterocygous', 'Var', (44, 56))	('esophageal carcinomas', 'Disease', (75, 96))	('tumor', 'Disease', (150, 155))
823434	29560108	The AurkA polymorphism has also been reported for other malignancies as well e.g., breast cancer and hepatocellular carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('polymorphism', 'Var', (10, 22))	('AurkA', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (101, 126))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (101, 126))	('AurkA', 'Gene', '6790', (4, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('hepatocellular carcinomas', 'Disease', (101, 126))	('reported', 'Reg', (37, 45))	('malignancies', 'Disease', (56, 68))
823435	29560108	Evidently, the AurkA polymorphism variant Phe/Ile has a prognostic (i.e., outcome of disease) and predictive (i.e., impact on treatment with Aurora-Kinase inhibitors) value.	('AurkA', 'Gene', '6790', (15, 20))	('Phe', 'Chemical', 'MESH:D010649', (42, 45))	('variant', 'Var', (34, 41))	('AurkA', 'Gene', (15, 20))	('Ile', 'Chemical', 'MESH:D007532', (46, 49))
823442	29560108	We observed a sensitization to radiation by Docetaxel as a function of AurkA polymorphism.	('AurkA', 'Gene', (71, 76))	('sensitization', 'MPA', (14, 27))	('Docetaxel', 'Chemical', 'MESH:D000077143', (44, 53))	('AurkA', 'Gene', '6790', (71, 76))	('sensitization to radiation', 'Phenotype', 'HP:0011133', (14, 40))	('polymorphism', 'Var', (77, 89))
823448	29560108	Our data suggest, that predominantly the heterozygous AurkA polymorphism is associated with the polyploidization.	('AurkA', 'Gene', '6790', (54, 59))	('associated', 'Reg', (76, 86))	('polymorphism', 'Var', (60, 72))	('polyploidization', 'Var', (96, 112))	('AurkA', 'Gene', (54, 59))
823455	29560108	AurkA, AurkB as well as p-Akt Ser 473 and p-Erk1/2 Thr 202/Tyr 204 are overexpressed in the heterozygous cell line SAS.	('Tyr', 'Chemical', 'MESH:D014443', (59, 62))	('AurkA', 'Gene', (0, 5))	('SAS', 'Gene', (115, 118))	('Akt', 'Gene', '207', (26, 29))	('Thr 202/Tyr 204', 'Var', (51, 66))	('AurkB', 'Gene', (7, 12))	('AurkB', 'Gene', '9212', (7, 12))	('Akt', 'Gene', (26, 29))	('AurkA', 'Gene', '6790', (0, 5))	('Thr', 'Chemical', 'MESH:D013912', (51, 54))	('Ser', 'Chemical', 'MESH:D012694', (30, 33))	('SAS', 'Gene', '6302', (115, 118))
823459	29560108	However, it should be noted that low AurkA expression and high p-Akt expression showed the worst survival rates.	('low', 'NegReg', (33, 36))	('Akt', 'Gene', (65, 68))	('AurkA', 'Gene', '6790', (37, 42))	('Akt', 'Gene', '207', (65, 68))	('high', 'Var', (58, 62))	('AurkA', 'Gene', (37, 42))
823467	29560108	Further studies should retrospectively and prospectively address the therapy response as a function of AurkA polymorphism in the clinical setting.	('AurkA', 'Gene', (103, 108))	('polymorphism', 'Var', (109, 121))	('AurkA', 'Gene', '6790', (103, 108))
823470	29560108	The specific PCR for AurkA genotypes at the Phe31Ile site was performed using the Taq-DNA Polymerase All-inclusive Kit (PeqLab, Erlangen, Germany) according the manufacturer's guidelines.	('Phe31Ile', 'SUBSTITUTION', 'None', (44, 52))	('AurkA', 'Gene', '6790', (21, 26))	('AurkA', 'Gene', (21, 26))	('Phe31Ile', 'Var', (44, 52))
823512	28764725	Additionally, EGFR inhibitors induced squamous cell differentiation (defined as increased expression of involucrin and cytokeratin13) in epithelial-like but not mesenchymal-like cells.	('cytokeratin13', 'Gene', '3860', (119, 132))	('squamous', 'Disease', (38, 46))	('EGFR', 'Gene', (14, 18))	('induced', 'Reg', (30, 37))	('inhibitors', 'Var', (19, 29))	('cytokeratin13', 'Gene', (119, 132))
823513	28764725	Cetuximab consistently showed antitumor effects, and increased involucrin expression in TE-11R (epithelial-like)-derived xenograft tumors but not TE-8 (mesenchymal-like)-derived xenograft tumors.	('tumor', 'Disease', (188, 193))	('involucrin expression', 'MPA', (63, 84))	('xenograft tumors', 'Disease', (178, 194))	('TE-11R', 'Var', (88, 94))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('increased', 'PosReg', (53, 62))	('xenograft tumors', 'Disease', 'MESH:D009369', (178, 194))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Cetuximab', 'Chemical', 'MESH:D000068818', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('xenograft tumors', 'Disease', (121, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('xenograft tumors', 'Disease', 'MESH:D009369', (121, 137))	('Cetuximab', 'Gene', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('TE-11R', 'Chemical', '-', (88, 94))
823516	28764725	EGFR inhibitors show antitumor effects on epithelial-like ESCC cells accompanied by promotion of squamous cell differentiation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('EGFR', 'Gene', (0, 4))	('SCC', 'Gene', (59, 62))	('tumor', 'Disease', (25, 30))	('inhibitors', 'Var', (5, 15))	('SCC', 'Gene', '6317', (59, 62))	('promotion', 'PosReg', (84, 93))	('squamous cell differentiation', 'CPA', (97, 126))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
823524	28764725	Recently, EGFR signaling blockade has been shown to promote squamous cell differentiation in skin keratinocytes as well as cutaneous SCCs.	('SCC', 'Gene', '6317', (133, 136))	('blockade', 'Var', (25, 33))	('squamous cell differentiation in skin', 'Phenotype', 'HP:0006739', (60, 97))	('EGFR signaling', 'Gene', (10, 24))	('cutaneous', 'Disease', (123, 132))	('SCC', 'Gene', (133, 136))	('promote', 'PosReg', (52, 59))
823530	28764725	Here, we postulate that the promotion of squamous cell differentiation by EGFR inhibitors may suppress the growth of ESCC cells, which would contribute to establishing "differentiation therapy" for ESCC.	('contribute', 'Reg', (141, 151))	('SCC', 'Gene', (199, 202))	('growth', 'CPA', (107, 113))	('suppress', 'NegReg', (94, 102))	('SCC', 'Gene', (118, 121))	('inhibitors', 'Var', (79, 89))	('squamous cell differentiation', 'CPA', (41, 70))	('SCC', 'Gene', '6317', (199, 202))	('SCC', 'Gene', '6317', (118, 121))	('EGFR', 'Gene', (74, 78))	('promotion', 'PosReg', (28, 37))
823532	28764725	Immortalized-human esophageal epithelial cells (EPC2-hTERT) and derivatives transformed by either EGFR and p53R175H (T-Epi) or SV40 large T antigen and Ha-RasV12 (T-Mes), fetal esophageal fibroblast cells (FEF3), and ESCC cells (HCE4, TE-1, TE-5, TE-8, and TE-11) were described previously.	('p53R175H', 'Var', (107, 115))	('EGFR', 'Gene', (98, 102))	('SCC', 'Gene', '6317', (218, 221))	('p53R175H', 'Mutation', 'p.R53,175H', (107, 115))	('human', 'Species', '9606', (13, 18))	('SV40', 'Var', (127, 131))	('T-Mes', 'Chemical', '-', (163, 168))	('HCE4', 'Chemical', '-', (229, 233))	('SCC', 'Gene', (218, 221))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (48, 58))
823535	28764725	These ESCC cells reportedly do not harbor an EGFR mutation.	('SCC', 'Gene', (7, 10))	('SCC', 'Gene', '6317', (7, 10))	('EGFR', 'Gene', (45, 49))	('mutation', 'Var', (50, 58))
823600	28764725	TE-1, TE-5, TE-11 and TE-11R cells exhibited high expression of E-cadherin and very low expression of vimentin, whereas TE-8 and HCE4 cells showed low expression of E-cadherin and high expression of vimentin (Fig.	('TE-11R', 'Var', (22, 28))	('TE-11', 'Var', (12, 17))	('HCE4', 'Chemical', '-', (129, 133))	('E-cadherin', 'Protein', (64, 74))	('expression', 'MPA', (88, 98))	('expression', 'MPA', (50, 60))	('TE-11R', 'Chemical', '-', (22, 28))
823601	28764725	Therefore, we classified TE-1, TE-5, TE-11, and TE-11R cells as epithelial-like ESCC cells, and TE-8 and HCE4 cells as mesenchymal-like ESCC cells.	('SCC', 'Gene', '6317', (81, 84))	('SCC', 'Gene', '6317', (137, 140))	('TE-11R', 'Chemical', '-', (48, 54))	('SCC', 'Gene', (81, 84))	('HCE4', 'Chemical', '-', (105, 109))	('TE-11R', 'Var', (48, 54))	('SCC', 'Gene', (137, 140))
823602	28764725	In agreement with the results of transformed-esophageal cells treated with EGFR inhibitors, the growth of epithelial-like ESCC cells (TE-1, TE-5, TE-11, and TE-11R) was significantly inhibited by treatment with erlotinib or cetuximab, but that of mesenchymal-like ESCC cells (TE-8 and HCE-4) was not affected (Fig.	('cetuximab', 'Chemical', 'MESH:D000068818', (224, 233))	('SCC', 'Gene', (265, 268))	('HCE', 'Chemical', 'MESH:C007907', (285, 288))	('erlotinib', 'Chemical', 'MESH:D000069347', (211, 220))	('growth', 'CPA', (96, 102))	('SCC', 'Gene', '6317', (123, 126))	('SCC', 'Gene', '6317', (265, 268))	('TE-11R', 'Chemical', '-', (157, 163))	('inhibited', 'NegReg', (183, 192))	('erlotinib', 'Var', (211, 220))	('SCC', 'Gene', (123, 126))
823613	28764725	Xenograft tumors generated from TE-11R and TE-8 were treated with cetuximab to investigate the antitumor effects of EGFR inhibitors on ESCC.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (99, 104))	('cetuximab', 'Chemical', 'MESH:D000068818', (66, 75))	('SCC', 'Gene', (136, 139))	('TE-11R', 'Chemical', '-', (32, 38))	('tumor', 'Disease', (10, 15))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('SCC', 'Gene', '6317', (136, 139))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('inhibitors', 'Var', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('EGFR', 'Gene', (116, 120))
823621	28764725	T-Epi cells are transformed by EGFR and p53R175H, and T-Mes cells by SV40 large T antigen and Ha-RasV12.	('T-Mes', 'Chemical', '-', (54, 59))	('p53R175H', 'Mutation', 'p.R53,175H', (40, 48))	('p53R175H', 'Var', (40, 48))	('SV40 large T', 'Var', (69, 81))
823623	28764725	In the present study, we showed that EGFR inhibitors promoted squamous cell differentiation in epithelial-like esophageal cells accompanied by increased expression of involucrin and CK13.	('increased', 'PosReg', (143, 152))	('promoted', 'PosReg', (53, 61))	('involucrin', 'Protein', (167, 177))	('CK13', 'Gene', '3860', (182, 186))	('squamous cell differentiation', 'CPA', (62, 91))	('CK13', 'Gene', (182, 186))	('inhibitors', 'Var', (42, 52))	('expression', 'MPA', (153, 163))	('EGFR', 'Gene', (37, 41))
823625	28764725	showing that EGFR inhibitors promoted cell differentiation in skin keratinocytes and cutaneous SCC cells via Notch signal activation.	('promoted', 'PosReg', (29, 37))	('SCC', 'Gene', '6317', (95, 98))	('Notch', 'Gene', (109, 114))	('cell differentiation in skin keratinocytes', 'CPA', (38, 80))	('activation', 'PosReg', (122, 132))	('SCC', 'Gene', (95, 98))	('Notch', 'Gene', '4851;4854', (109, 114))	('EGFR', 'Gene', (13, 17))	('inhibitors', 'Var', (18, 28))
823626	28764725	We suspect that the cell-cell contact induced by EGFR inhibitors might be involved in the promotion of squamous cell differentiation because it increases cell-cell interactions such as Notch signaling, which may help to promote squamous cell differentiation.	('Notch', 'Gene', '4851;4854', (185, 190))	('cell-cell interactions', 'CPA', (154, 176))	('cell-cell contact', 'CPA', (20, 37))	('increases', 'PosReg', (144, 153))	('squamous cell differentiation', 'CPA', (228, 257))	('Notch', 'Gene', (185, 190))	('inhibitors', 'Var', (54, 64))	('EGFR', 'Gene', (49, 53))	('squamous', 'Disease', (103, 111))	('promote', 'PosReg', (220, 227))
823627	28764725	In this study, EGFR inhibitors showed antitumor effects in epithelial-like ESCC cells but not in mesenchymal-like ESCC cells.	('tumor', 'Disease', (42, 47))	('SCC', 'Gene', (76, 79))	('inhibitors', 'Var', (20, 30))	('SCC', 'Gene', (115, 118))	('EGFR', 'Gene', (15, 19))	('SCC', 'Gene', '6317', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('SCC', 'Gene', '6317', (115, 118))
823631	28764725	Consistently, esophageal fibroblast cells, which are the mesenchymal cells, were not affected by treatment with EGFR inhibitors or rEGF (Additional file 5 Figure S5).	('EGFR', 'Gene', (112, 116))	('esophageal fibroblast cells', 'CPA', (14, 41))	('inhibitors', 'Var', (117, 127))	('rEGF', 'Gene', '25313', (131, 135))	('rEGF', 'Gene', (131, 135))
823640	28764725	In contrast, EGFR signaling is affected by neither EGFR inhibitors nor rEGF in mesenchymal-like ESCC cells, and thereby squamous cell differentiation and tumor cell growth inhibition do not occur in mesenchymal-like ESCC cells treated with EGFR inhibitors (Fig.	('rEGF', 'Gene', '25313', (71, 75))	('rEGF', 'Gene', (71, 75))	('EGFR', 'Gene', (51, 55))	('SCC', 'Gene', (217, 220))	('affected', 'Reg', (31, 39))	('squamous cell differentiation', 'CPA', (120, 149))	('SCC', 'Gene', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('inhibitors', 'Var', (56, 66))	('EGFR signaling', 'MPA', (13, 27))	('SCC', 'Gene', '6317', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('SCC', 'Gene', '6317', (97, 100))	('tumor', 'Disease', (154, 159))
823641	28764725	Our findings provide novel, mechanistic insights into the effects of EGFR inhibitors on ESCC.	('SCC', 'Gene', '6317', (89, 92))	('EGFR', 'Gene', (69, 73))	('SCC', 'Gene', (89, 92))	('inhibitors', 'Var', (74, 84))
823644	28599478	MicroRNA-375 suppresses esophageal cancer cell growth and invasion by repressing metadherin expression Accumulating evidence indicates that aberrant expression of microRNAs is involved in tumorigenesis, tumor progression and response to therapy.	('tumor', 'Disease', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('metadherin', 'Gene', (81, 91))	('esophageal cancer', 'Disease', (24, 41))	('aberrant', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('suppresses', 'NegReg', (13, 23))	('microRNAs', 'Gene', (163, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('invasion', 'CPA', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('MicroRNA-375', 'Gene', (0, 12))	('involved', 'Reg', (176, 184))	('metadherin', 'Gene', '92140', (81, 91))	('MicroRNA-375', 'Gene', '494324', (0, 12))
823659	28599478	Numerous studies have identified that aberrant expression of miRNAs is associated with tumorigenesis, tumor progression and response to therapy.	('miRNAs', 'Protein', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('aberrant expression', 'Var', (38, 57))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('associated', 'Reg', (71, 81))
823684	28599478	Following transfection, the cell samples were harvested as aforementioned and resuspended in FBS-free DMEM, for seeding in the upper chamber.	('FBS-free DMEM', 'Disease', 'MESH:D005198', (93, 106))	('transfection', 'Var', (10, 22))	('FBS-free DMEM', 'Disease', (93, 106))
823688	28599478	Fragments of sequence from wild-type and mutant MTDH 3'-UTR were amplified by PCR and cloned into a pYr-MirTarget luciferase vector (Changsha Yingrun Biotechnology Co. Ltd.), designated pYr-MTDH-3U and PYr-MTDH-3Umt, respectively.	('MTDH', 'Gene', '92140', (190, 194))	('MTDH', 'Gene', (206, 210))	('mutant', 'Var', (41, 47))	('MTDH', 'Gene', (48, 52))	('MTDH', 'Gene', (190, 194))	('MTDH', 'Gene', '92140', (206, 210))	('MTDH', 'Gene', '92140', (48, 52))
823697	28599478	To explore the roles of miR-375 in esophageal cancer progression, EC109 cells were transfected with miR-375 mimic or a NC.	('EC109', 'CellLine', 'CVCL:6898', (66, 71))	('miR-375', 'Gene', (24, 31))	('miR-375', 'Gene', (100, 107))	('esophageal cancer', 'Disease', (35, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('miR-375', 'Gene', '494324', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('miR-375', 'Gene', '494324', (100, 107))	('mimic', 'Var', (108, 113))
823715	28599478	It has been reported that the aberrant expression of miRNA is associated with tumorigenesis, tumor progression, cancer prognoses and response to therapy.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('associated', 'Reg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (93, 98))	('miRNA', 'Protein', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('aberrant expression', 'Var', (30, 49))
823724	28599478	In hepatocellular carcinoma, ectopic expression of miR-375 decreases cell growth and invasion, and induces G1 arrest and apoptosis.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('induces', 'Reg', (99, 106))	('ectopic expression', 'Var', (29, 47))	('miR-375', 'Gene', (51, 58))	('decreases', 'NegReg', (59, 68))	('hepatocellular carcinoma', 'Disease', (3, 27))	('miR-375', 'Gene', '494324', (51, 58))	('G1 arrest', 'CPA', (107, 116))	('apoptosis', 'CPA', (121, 130))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('cell growth', 'CPA', (69, 80))
823743	28599478	The epithelial marker E-cadherin serves a key role in EMT; its expression represses tumor invasion and metastasis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('E-cadherin', 'Gene', (22, 32))	('E-cadherin', 'Gene', '999', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('represses', 'NegReg', (74, 83))	('expression', 'Var', (63, 73))
823760	26510438	Based on homology with the other NOX isoforms, NOX5 is considered to have the same 6 transmembrane topology supporting 2 heme moieties (proposed to be mediated by H286, H300, H374 and H387 using the sequence for NOX5alphaV1 which is the longest functional isoform as shown in Figure 1) and a C-terminal FAD and NADPH binding dehydrogenase domain.	('heme', 'Chemical', 'MESH:D006418', (121, 125))	('NOX', 'Gene', '5740310', (47, 50))	('NOX', 'Gene', '5740310', (212, 215))	('FAD', 'Chemical', 'MESH:D005182', (303, 306))	('NOX5', 'Gene', '79400', (47, 51))	('NOX5', 'Gene', '79400', (212, 216))	('NOX', 'Gene', (33, 36))	('H387', 'Var', (184, 188))	('H300', 'Var', (169, 173))	('NADPH', 'Gene', (311, 316))	('NADPH', 'Gene', '1666', (311, 316))	('NOX5', 'Gene', (47, 51))	('NOX', 'Gene', (47, 50))	('NOX5', 'Gene', (212, 216))	('NOX', 'Gene', (212, 215))	('H286', 'Var', (163, 167))	('H374', 'Var', (175, 179))	('NOX', 'Gene', '5740310', (33, 36))	('H374', 'CellLine', 'CVCL:V727', (175, 179))
823771	26510438	This prompted the search for additional pathways of post translational regulation and in 2007, it was shown that PMA activates NOX5, in a unique manner that was independent from changes in intracellular calcium.	('NOX5', 'Gene', '79400', (127, 131))	('activates', 'PosReg', (117, 126))	('calcium', 'Chemical', 'MESH:D002118', (203, 210))	('NOX5', 'Gene', (127, 131))	('PMA', 'Chemical', '-', (113, 116))	('PMA', 'Var', (113, 116))
823773	26510438	The mechanism underlying this ability is the direct phosphorylation of NOX5 within a C-terminal region that contains a cluster of serine and threonine residues (T512 and S516, NOX5V1).	('threonine', 'Chemical', 'MESH:D013912', (141, 150))	('NOX5', 'Gene', (176, 180))	('T512', 'Var', (161, 165))	('NOX5', 'Gene', (71, 75))	('S516', 'Var', (170, 174))	('NOX5', 'Gene', '79400', (176, 180))	('phosphorylation', 'MPA', (52, 67))	('serine', 'Chemical', 'MESH:D012694', (130, 136))	('NOX5', 'Gene', '79400', (71, 75))
823774	26510438	Substitution of these residues to alanine, which cannot be phosphorylated, attenuates the ability of protein kinase C (PKC) to activate NOX5.	('Substitution', 'Var', (0, 12))	('NOX5', 'Gene', '79400', (136, 140))	('activate', 'PosReg', (127, 135))	('alanine', 'Chemical', 'MESH:D000409', (34, 41))	('PKC', 'Gene', '5578;5580;5581', (119, 122))	('NOX5', 'Gene', (136, 140))	('attenuates', 'NegReg', (75, 85))	('PKC', 'Gene', (119, 122))
823775	26510438	In contrast, mutation of these residues to negatively charged amino acids, which mimic phosphorylation, resulted in an enzyme with enhanced ability to generate ROS .	('generate ROS', 'MPA', (151, 163))	('mutation', 'Var', (13, 21))	('ability', 'MPA', (140, 147))	('ROS', 'Chemical', 'MESH:D017382', (160, 163))	('enhanced', 'PosReg', (131, 139))
823777	26510438	Interestingly, silencing of PKCepsilon also reduced PMA-stimulated ROS production from NOX5 but the expression of active variants of PKCepsilon, strongly reduced NOX5 activity.	('NOX5', 'Gene', (87, 91))	('PKCepsilon', 'Gene', '5581', (28, 38))	('PKCepsilon', 'Gene', (28, 38))	('PMA', 'Chemical', '-', (52, 55))	('silencing', 'Var', (15, 24))	('NOX5', 'Gene', '79400', (87, 91))	('NOX5', 'Gene', '79400', (162, 166))	('ROS', 'Chemical', 'MESH:D017382', (67, 70))	('reduced', 'NegReg', (44, 51))	('reduced', 'NegReg', (154, 161))	('PKCepsilon', 'Gene', '5581', (133, 143))	('PKCepsilon', 'Gene', (133, 143))	('NOX5', 'Gene', (162, 166))
823779	26510438	The ability to activate NOX5 was not observed with all PKC isoforms and the silencing of PKCdelta actually increased PMA-stimulated NOX5 activity whereas silencing PKCtheta was without effect.	('NOX5', 'Gene', (132, 136))	('PMA', 'Chemical', '-', (117, 120))	('PKC', 'Gene', '5578;5580;5581', (55, 58))	('PKC', 'Gene', (55, 58))	('increased', 'PosReg', (107, 116))	('silencing', 'Var', (76, 85))	('NOX5', 'Gene', '79400', (24, 28))	('PKC', 'Gene', '5578;5580;5581', (164, 167))	('PKC', 'Gene', '5578;5580;5581', (89, 92))	('NOX5', 'Gene', '79400', (132, 136))	('PKC', 'Gene', (89, 92))	('PKC', 'Gene', (164, 167))	('PKCdelta', 'Gene', (89, 97))	('NOX5', 'Gene', (24, 28))	('PKCdelta', 'Gene', '5580', (89, 97))
823781	26510438	The ability of PMA to stimulate NOX5, is reduced in the presence of MEK1 inhibitors (PD98059 and U0126), by silencing MEK1 or expression of a dominant negative MEK1 and occurrs via the phosphorylation of S516 and to a lesser degree by T512.	('MEK1', 'Gene', '5604', (118, 122))	('silencing', 'NegReg', (108, 117))	('PD98059', 'Var', (85, 92))	('MEK1', 'Gene', '5604', (68, 72))	('negative', 'NegReg', (151, 159))	('MEK1', 'Gene', (118, 122))	('MEK1', 'Gene', (160, 164))	('stimulate', 'PosReg', (22, 31))	('NOX5', 'Gene', (32, 36))	('PD98059', 'Chemical', 'MESH:C093973', (85, 92))	('MEK1', 'Gene', (68, 72))	('phosphorylation', 'MPA', (185, 200))	('PMA', 'Chemical', '-', (15, 18))	('U0126', 'Chemical', 'MESH:C113580', (97, 102))	('MEK1', 'Gene', '5604', (160, 164))	('S516', 'Var', (204, 208))	('NOX5', 'Gene', '79400', (32, 36))	('U0126', 'Var', (97, 102))
823787	26510438	Based on prediction tools (GPS) there are likely numerous serine, threonine and tyrosine residues on NOX5 and numerous kinases that may influence the post-translational phosphorylation and activation of NOX5.	('threonine', 'Chemical', 'MESH:D013912', (66, 75))	('serine', 'Var', (58, 64))	('influence', 'Reg', (136, 145))	('NOX5', 'Gene', (101, 105))	('tyrosine', 'Chemical', 'MESH:D014443', (80, 88))	('serine', 'Chemical', 'MESH:D012694', (58, 64))	('post-translational phosphorylation', 'MPA', (150, 184))	('NOX5', 'Gene', '79400', (203, 207))	('GPS', 'Disease', (27, 30))	('NOX5', 'Gene', '79400', (101, 105))	('activation', 'PosReg', (189, 199))	('GPS', 'Disease', 'MESH:D055652', (27, 30))	('NOX5', 'Gene', (203, 207))
823789	26510438	The synergistic interaction between changes in phosphorylation and calcium-dependent occupation of the EF-hands provides for additional levels of control and diversifies the ability of NOX5 to produce an appropriate level of ROS in response to a stimulus (Summarized in Table 1 and Figure 2).	('calcium', 'Chemical', 'MESH:D002118', (67, 74))	('phosphorylation', 'MPA', (47, 62))	('changes', 'Var', (36, 43))	('ROS', 'MPA', (225, 228))	('NOX5', 'Gene', '79400', (185, 189))	('response to a stimulus', 'MPA', (232, 254))	('ROS', 'Chemical', 'MESH:D017382', (225, 228))	('NOX5', 'Gene', (185, 189))
823798	26510438	Dysregulation of Cav-1 has been documented in a number of disease states including atherosclerosis, inflammation, fibrosis and pulmonary hypertension.	('inflammation', 'Disease', (100, 112))	('atherosclerosis', 'Disease', (83, 98))	('Dysregulation', 'Var', (0, 13))	('fibrosis', 'Disease', (114, 122))	('Cav-1', 'Gene', (17, 22))	('hypertension', 'Phenotype', 'HP:0000822', (137, 149))	('atherosclerosis', 'Disease', 'MESH:D050197', (83, 98))	('atherosclerosis', 'Phenotype', 'HP:0002621', (83, 98))	('fibrosis', 'Disease', 'MESH:D005355', (114, 122))	('inflammation', 'Disease', 'MESH:D007249', (100, 112))	('pulmonary hypertension', 'Disease', 'MESH:D006976', (127, 149))	('pulmonary hypertension', 'Disease', (127, 149))	('Cav-1', 'Gene', '857', (17, 22))
823817	26510438	Inhibitors of Hsp90 acutely reduce the ability of NOX5 to produce superoxide and chronic inhibition stimulates the degradation of NOX5 protein expression.	('NOX5', 'Gene', '79400', (130, 134))	('Hsp90', 'Gene', (14, 19))	('ability', 'MPA', (39, 46))	('Hsp90', 'Gene', '3320', (14, 19))	('NOX5', 'Gene', (50, 54))	('Inhibitors', 'Var', (0, 10))	('NOX5', 'Gene', (130, 134))	('degradation', 'MPA', (115, 126))	('produce superoxide', 'MPA', (58, 76))	('inhibition', 'NegReg', (89, 99))	('reduce', 'NegReg', (28, 34))	('NOX5', 'Gene', '79400', (50, 54))	('superoxide', 'Chemical', 'MESH:D013481', (66, 76))
823830	26510438	This was recently shown in an experimental model of atherosclerosis where inhibition of Hsp90 not only reduced the size and complexity of vascular lesions but reduced the levels of ROS and the expression of NOX1 and 2 and also in a model of type II diabetes in which Hsp90 inhibitors potently reduced ROS production and NOX expression in isolated leukocytes, lung tissue, human blood vessels and aorta from db/db mice.	('Hsp90', 'Gene', (88, 93))	('expression', 'MPA', (193, 203))	('atherosclerosis', 'Disease', 'MESH:D050197', (52, 67))	('ROS', 'Chemical', 'MESH:D017382', (301, 304))	('inhibition', 'Var', (74, 84))	('reduced ROS production', 'Phenotype', 'HP:0025464', (293, 315))	('NOX', 'Gene', (207, 210))	('NOX1 and 2', 'Gene', '27035;1536', (207, 217))	('reduced', 'NegReg', (159, 166))	('atherosclerosis', 'Disease', (52, 67))	('human', 'Species', '9606', (372, 377))	('levels', 'MPA', (171, 177))	('ROS', 'MPA', (181, 184))	('atherosclerosis', 'Phenotype', 'HP:0002621', (52, 67))	('NOX', 'Gene', '5740310', (320, 323))	('Hsp90', 'Gene', '3320', (267, 272))	('type II diabetes', 'Disease', (241, 257))	('ROS', 'Chemical', 'MESH:D017382', (181, 184))	('type II diabetes', 'Phenotype', 'HP:0005978', (241, 257))	('reduced', 'NegReg', (103, 110))	('reduced', 'NegReg', (293, 300))	('Hsp90', 'Gene', (267, 272))	('mice', 'Species', '10090', (413, 417))	('expression', 'MPA', (324, 334))	('vascular lesions', 'Disease', 'MESH:D000783', (138, 154))	('NOX', 'Gene', '5740310', (207, 210))	('inhibitors', 'Var', (273, 283))	('size', 'MPA', (115, 119))	('type II diabetes', 'Disease', 'MESH:D003924', (241, 257))	('vascular lesions', 'Disease', (138, 154))	('Hsp90', 'Gene', '3320', (88, 93))	('ROS production', 'MPA', (301, 315))	('NOX', 'Gene', (320, 323))
823835	26510438	Traffic from intracellular membranes to the plasma membrane can be mediated by polybasic domains within the N-terminus of NOX5 (PBR-N) that bind to phosphatidylinositol 4,5-bisphosphate, a phospholipid enriched at the plasma membrane.	('PBR', 'Gene', '706', (128, 131))	('NOX5', 'Gene', '79400', (122, 126))	('PBR', 'Gene', (128, 131))	('NOX5', 'Gene', (122, 126))	('polybasic domains', 'Var', (79, 96))	('phospholipid', 'Chemical', 'MESH:D010743', (189, 201))	('bind', 'Interaction', (140, 144))	('Traffic', 'MPA', (0, 7))	('phosphatidylinositol 4,5-bisphosphate', 'Chemical', 'MESH:D019269', (148, 185))
823837	26510438	The C-terminus of NOX5 contains another conserved polybasic domain that has been called the PBR-C. Mutation of this region reduces NOX5 enzyme activity but does not affect its intracellular location.	('NOX5', 'Gene', (18, 22))	('NOX5', 'Gene', (131, 135))	('Mutation', 'Var', (99, 107))	('NOX5', 'Gene', '79400', (18, 22))	('PBR', 'Gene', '706', (92, 95))	('NOX5', 'Gene', '79400', (131, 135))	('activity', 'MPA', (143, 151))	('PBR', 'Gene', (92, 95))	('reduces', 'NegReg', (123, 130))
823844	26510438	Mass spectrometry identified 4 major sites of S-nitrosylation, C107, C246, C519 and C694.	('S-nitrosylation', 'MPA', (46, 61))	('C519', 'Var', (75, 79))	('C246', 'Var', (69, 73))	('C694', 'Var', (84, 88))	('C519', 'CellLine', 'CVCL:V775', (75, 79))	('C107', 'Var', (63, 67))
823845	26510438	Of these, C694 was the most relevant to changes in function and a conservative mutation to serine, reduced NOX5 activity, S-nitrosylation and the ability of NO to suppress superoxide production.	('NOX5', 'Gene', (107, 111))	('C694', 'Var', (10, 14))	('function', 'MPA', (51, 59))	('NOX5', 'Gene', '79400', (107, 111))	('S-nitrosylation', 'MPA', (122, 137))	('superoxide', 'Chemical', 'MESH:D013481', (172, 182))	('serine', 'Gene', (91, 97))	('superoxide production', 'MPA', (172, 193))	('reduced', 'NegReg', (99, 106))	('suppress superoxide production', 'Phenotype', 'HP:0031837', (163, 193))	('serine', 'Chemical', 'MESH:D012694', (91, 97))
823847	26510438	These results suggest that NO signaling may provide tonic inhibition of NOX isoforms and that loss of NO may reciprocally increase ROS production.	('NOX', 'Gene', (72, 75))	('increase ROS production', 'Phenotype', 'HP:0025464', (122, 145))	('tonic inhibition', 'MPA', (52, 68))	('loss', 'Var', (94, 98))	('ROS production', 'MPA', (131, 145))	('ROS', 'Chemical', 'MESH:D017382', (131, 134))	('NOX', 'Gene', '5740310', (72, 75))	('increase', 'PosReg', (122, 130))
823848	26510438	Increased SUMOylation was found to significantly reduce NOX5 (and other NOX isoform) activity in a variety of cell types, but the mechanisms by which SUMOylation decreased ROS production remain unresolved.	('NOX', 'Gene', (56, 59))	('NOX', 'Gene', (72, 75))	('NOX5', 'Gene', (56, 60))	('SUMOylation', 'Var', (10, 21))	('ROS', 'Chemical', 'MESH:D017382', (172, 175))	('NOX', 'Gene', '5740310', (56, 59))	('ROS production', 'MPA', (172, 186))	('reduce', 'NegReg', (49, 55))	('NOX', 'Gene', '5740310', (72, 75))	('activity', 'MPA', (85, 93))	('NOX5', 'Gene', '79400', (56, 60))
823856	26510438	The first pair of EF hands has a lower affinity for calcium and disruption by mutagenesis does not significantly impact NOX5 function suggesting that they are less crucial for NOX5 function.	('NOX5', 'Gene', '79400', (120, 124))	('calcium', 'Chemical', 'MESH:D002118', (52, 59))	('NOX5', 'Gene', (176, 180))	('NOX5', 'Gene', (120, 124))	('NOX5', 'Gene', '79400', (176, 180))	('mutagenesis', 'Var', (78, 89))	('lower', 'NegReg', (33, 38))	('affinity for', 'MPA', (39, 51))
823859	26510438	The relative expression levels of the 6 NOX5 isoforms varies with cell type and NOX5 V3-5 can function as dominant negatives when co-expressed with the active isoforms, NOX5 V1 and V2 as they have intact C-terminal regions, critical for oligomerization, and insertions that appear to disrupt enzyme activity in the N-terminal region.	('activity', 'MPA', (299, 307))	('NOX5', 'Gene', (80, 84))	('NOX5', 'Gene', (40, 44))	('NOX5', 'Gene', (169, 173))	('insertions', 'Var', (258, 268))	('NOX5', 'Gene', '79400', (80, 84))	('NOX5', 'Gene', '79400', (40, 44))	('NOX5', 'Gene', '79400', (169, 173))
823862	26510438	The coding sequence for the NOX5 protein has greater than 108 reported nonsense, missense and synonymous SNPs (NCBI) with frequencies varying from MAF (Minor Allele Frequency) 0.0005 to 0.31.	('missense', 'Var', (81, 89))	('synonymous SNPs', 'Var', (94, 109))	('nonsense', 'Var', (71, 79))	('NOX5', 'Gene', '79400', (28, 32))	('NOX5', 'Gene', (28, 32))
823863	26510438	Missense SNPs which alter the amino acid composition are present in regions of NOX5 that may impact enzyme function including EF hands, transmembrane regions and the NADPH binding C-terminus.	('EF hands', 'Disease', (126, 134))	('NOX5', 'Gene', '79400', (79, 83))	('NADPH', 'Gene', (166, 171))	('NADPH', 'Gene', '1666', (166, 171))	('Missense SNPs', 'Var', (0, 13))	('NOX5', 'Gene', (79, 83))	('impact', 'Reg', (93, 99))	('enzyme function', 'MPA', (100, 115))
823864	26510438	One SNP that is validated (rs34406284) and two non-validated SNPs (rs369517329, rs370082662) represent missense mutations that encode stop codons.	('rs370082662', 'Var', (80, 91))	('rs34406284', 'Mutation', 'rs34406284', (27, 37))	('rs369517329', 'Mutation', 'rs369517329', (67, 78))	('rs34406284', 'Var', (27, 37))	('rs370082662', 'Mutation', 'rs370082662', (80, 91))	('rs369517329', 'Var', (67, 78))
823865	26510438	Individuals with genes harboring these SNPs would express truncated NOX5 enzymes that are predicted to be inactive.	('express', 'Reg', (50, 57))	('SNPs', 'Var', (39, 43))	('NOX5', 'Gene', (68, 72))	('truncated', 'MPA', (58, 67))	('NOX5', 'Gene', '79400', (68, 72))
823866	26510438	Of the 15 missense mutations encoded by SNPs that were evaluated, 7 resulted in proteins that were expressed well but had little or no enzyme activity (M95K, S254R, T271M, R437Q, R548H, G560R, V707A, NOX5V1).	('R437Q', 'Mutation', 'rs117880022', (172, 177))	('S254R', 'Var', (158, 163))	('R548H', 'Var', (179, 184))	('NOX5', 'Gene', (200, 204))	('S254R', 'Mutation', 'rs150003957', (158, 163))	('G560R', 'Var', (186, 191))	('resulted in', 'Reg', (68, 79))	('G560R', 'Mutation', 'rs188055665', (186, 191))	('T271M', 'Var', (165, 170))	('R437Q', 'Var', (172, 177))	('proteins', 'Protein', (80, 88))	('M95K', 'Mutation', 'rs112069106', (152, 156))	('NOX5', 'Gene', '79400', (200, 204))	('V707A', 'Mutation', 'rs113164499', (193, 198))	('M95K', 'Var', (152, 156))	('T271M', 'Mutation', 'rs145609289', (165, 170))	('R548H', 'Mutation', 'rs2277552', (179, 184))	('V707A', 'Var', (193, 198))
823868	26510438	The demographics of SNPs in the NOX5 gene are varied and an interesting finding is that the SNP encoding R548H has a relatively high frequency among Asians and Africans versus Europeans with South Americans being intermediate (0.115 African Americans, 0.208 Kenyans, 0.119 Nigerians and 0 for Western and Northern Europeans, 0 from Great Brittain, Italy and Spain and 0.086 for Mexicans, 0.046 for Puerto Ricans, 0.067 Columbians).	('NOX5', 'Gene', (32, 36))	('NOX5', 'Gene', '79400', (32, 36))	('R548H', 'Var', (105, 110))	('R548H', 'Mutation', 'rs2277552', (105, 110))
823869	26510438	The SNP encoding W272Ter was predominantly found in Africans (0.074 in African Americans, 0.0625 in Kenyans and 0.108 in Nigerians) versus 0 in other populations.	('0.0625', 'Var', (90, 96))	('W272Ter', 'Mutation', 'rs34406284', (17, 24))	('W272Ter', 'Var', (17, 24))
823871	26510438	The SNP encoding a substitution of the hydrophobic methionine to a charged lysine (M95K, rs112069106) resulted in an enzyme with greatly impaired calcium-dependent activity.	('calcium-dependent activity', 'MPA', (146, 172))	('calcium', 'Chemical', 'MESH:D002118', (146, 153))	('M95K', 'Var', (83, 87))	('impaired', 'NegReg', (137, 145))	('rs112069106', 'Mutation', 'rs112069106', (89, 100))	('lysine', 'Chemical', 'MESH:D008239', (75, 81))	('rs112069106', 'Var', (89, 100))	('methionine', 'Chemical', 'MESH:D008715', (51, 61))	('M95K', 'Mutation', 'rs112069106', (83, 87))
823872	26510438	In contrast, a more conservative substitution of M95 with the hydrophobic valine (rs34097994), resulted in a less significant decrease in activity.	('activity', 'MPA', (138, 146))	('rs34097994', 'Var', (82, 92))	('decrease', 'NegReg', (126, 134))	('rs34097994', 'Mutation', 'rs34097994', (82, 92))	('valine', 'Chemical', 'MESH:D014633', (74, 80))
823873	26510438	Methionine residues in calmodulin have been shown to mediate the interaction with substrates.	('calmodulin', 'Gene', (23, 33))	('interaction', 'Interaction', (65, 76))	('calmodulin', 'Gene', '801', (23, 33))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('Methionine residues', 'Var', (0, 19))	('mediate', 'Reg', (53, 60))
823874	26510438	It is possible that M95, as the only methionine residue in this region, is critical for interaction with the C-terminal REFBD and enzyme activation (Figure 2).	('interaction', 'Interaction', (88, 99))	('methionine', 'Chemical', 'MESH:D008715', (37, 47))	('M95', 'Var', (20, 23))
823875	26510438	While SNPs encoding missense or nonsense mutations within the exons of NOX5 have the potential to directly alter enzyme function, they may represent only part of the impact of genetic differences.	('missense', 'Var', (20, 28))	('NOX5', 'Gene', (71, 75))	('enzyme function', 'MPA', (113, 128))	('nonsense mutations', 'Var', (32, 50))	('alter', 'Reg', (107, 112))	('NOX5', 'Gene', '79400', (71, 75))
823877	26510438	Given the frequency of SNPs encoding NOX5 enzymes with no or close to zero enzyme activity (0.23% to 10.62%) the likelihood of humans inheriting 2 non-functioning alleles must be significant and in some populations, notably Africans, more likely.	('SNPs', 'Var', (23, 27))	('NOX5', 'Gene', (37, 41))	('NOX5', 'Gene', '79400', (37, 41))	('humans', 'Species', '9606', (127, 133))
823879	26510438	On the other hand, the most frequent exonic missense SNP in NOX5 (31%) encodes a well-tolerated mutation (L352F) that has minimal effect on enzyme activity.	('L352F', 'Var', (106, 111))	('L352F', 'Mutation', 'rs12907196', (106, 111))	('NOX5', 'Gene', '79400', (60, 64))	('NOX5', 'Gene', (60, 64))
823889	26510438	Epigenetics may have a more profound role in the regulation of NOX5 expression in different cells types.	('Epigenetics', 'Var', (0, 11))	('NOX5', 'Gene', '79400', (63, 67))	('NOX5', 'Gene', (63, 67))
823890	26510438	The expression of NOX5 has been shown to be negatively influenced by DNA methylationwhich may account for cell-specific regulation and changes in expression in disease states.	('changes', 'Reg', (135, 142))	('NOX5', 'Gene', (18, 22))	('expression', 'MPA', (4, 14))	('NOX5', 'Gene', '79400', (18, 22))	('negatively', 'NegReg', (44, 54))	('DNA', 'Var', (69, 72))
823930	26510438	The loss of dNOX reduces intracellular calcium levels, weakens ovarian contraction and renders the insects sterile.	('reduces', 'NegReg', (17, 24))	('intracellular calcium levels', 'MPA', (25, 53))	('weakens', 'NegReg', (55, 62))	('calcium', 'Chemical', 'MESH:D002118', (39, 46))	('dNOX', 'Gene', (12, 16))	('ovarian contraction', 'CPA', (63, 82))	('renders', 'Reg', (87, 94))	('dNOX', 'Gene', '5740310', (12, 16))	('loss', 'Var', (4, 8))
823933	26510438	Greater information on the existence of individuals and families with inactivating SNPs in NOX5 (as discussed above) may help to resolve this issue.	('NOX5', 'Gene', '79400', (91, 95))	('SNPs', 'Var', (83, 87))	('inactivating', 'NegReg', (70, 82))	('NOX5', 'Gene', (91, 95))
823940	26510438	In DU145 cells, ROS production is calcium-dependent and antisense knockdown of NOX5, but not p22phox or NOX2, inhibits both ROS production and cellular proliferation.	('antisense knockdown', 'Var', (56, 75))	('inhibits', 'NegReg', (110, 118))	('NOX2', 'Gene', (104, 108))	('NOX5', 'Gene', '79400', (79, 83))	('NOX2', 'Gene', '1536', (104, 108))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('ROS production', 'MPA', (124, 138))	('DU145', 'CellLine', 'CVCL:0105', (3, 8))	('cellular proliferation', 'CPA', (143, 165))	('ROS', 'Chemical', 'MESH:D017382', (16, 19))	('p22phox', 'Gene', (93, 100))	('NOX5', 'Gene', (79, 83))	('ROS production', 'MPA', (16, 30))	('calcium', 'Chemical', 'MESH:D002118', (34, 41))	('p22phox', 'Gene', '1535', (93, 100))
823941	26510438	Similarly in PC-3 cells, silencing of NOX5 expression decreased proliferation and increased apoptosis and these effects were mediated by increased signaling through multiple kinases .	('silencing', 'Var', (25, 34))	('apoptosis', 'CPA', (92, 101))	('NOX5', 'Gene', '79400', (38, 42))	('PC-3', 'CellLine', 'CVCL:0035', (13, 17))	('proliferation', 'CPA', (64, 77))	('increased', 'PosReg', (137, 146))	('decreased', 'NegReg', (54, 63))	('increased', 'PosReg', (82, 91))	('NOX5', 'Gene', (38, 42))
823958	26510438	The impact of the loss of NOX5 on reproduction, cancer and cardiovascular disease would answer many of the above questions about the significance of NOX5 to human physiology and pathophysiology.	('NOX5', 'Gene', '79400', (26, 30))	('loss', 'Var', (18, 22))	('cardiovascular disease', 'Disease', (59, 81))	('NOX5', 'Gene', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (59, 81))	('cancer', 'Disease', (48, 54))	('NOX5', 'Gene', (26, 30))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cardiovascular disease', 'Disease', 'MESH:D002318', (59, 81))	('NOX5', 'Gene', '79400', (149, 153))	('human', 'Species', '9606', (157, 162))
824120	23869177	Although this goal was not met in the cisplatin/S-1 arm (HR 0.92; 95% CI, 0.80-1.05; P = 0.20), significant safety advantages were observed in the cisplatin/S-1 arm, compared with the cisplatin/infusional fluorouracil arm, for the rates of grade 3/4 neutropenia (32.3% versus 63.6%), complicated neutropenia (5.0% versus 14.4%), stomatitis (1.3% versus 13.6%), hypokalemia (3.6% versus 10.8%), and treatment-related deaths (2.5% versus 4.9%; P < 0.05).	('hypokalemia', 'Disease', (361, 372))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('neutropenia', 'Disease', (250, 261))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('neutropenia', 'Disease', (296, 307))	('hypokalemia', 'Phenotype', 'HP:0002900', (361, 372))	('stomatitis', 'Disease', 'MESH:D013280', (329, 339))	('neutropenia', 'Phenotype', 'HP:0001875', (250, 261))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('neutropenia', 'Disease', 'MESH:D009503', (250, 261))	('stomatitis', 'Disease', (329, 339))	('hypokalemia', 'Disease', 'MESH:D007008', (361, 372))	('men', 'Species', '9606', (403, 406))	('neutropenia', 'Disease', 'MESH:D009503', (296, 307))	('neutropenia', 'Phenotype', 'HP:0001875', (296, 307))	('S', 'Chemical', 'MESH:D013455', (48, 49))	('stomatitis', 'Phenotype', 'HP:0010280', (329, 339))	('cisplatin/S-1', 'Var', (147, 160))	('S', 'Chemical', 'MESH:D013455', (157, 158))
824123	23869177	Regarding toxicity, 5-FU/leucovorin/oxaliplatin (FLO) seems to be less toxic than 5-FU/leucovorin/cisplatin (FLP), according to a Phase III study that included mostly gastric cancer patients but also patients with gastroesophageal tumors.	('5-FU/leucovorin/oxaliplatin', 'Var', (20, 47))	('FLO', 'Chemical', '-', (49, 52))	('FLP', 'Chemical', '-', (109, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('toxicity', 'Disease', (10, 18))	('leucovorin', 'Chemical', 'MESH:D002955', (87, 97))	('patients', 'Species', '9606', (182, 190))	('gastroesophageal tumors', 'Phenotype', 'HP:0100751', (214, 237))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('gastroesophageal tumors', 'Disease', (214, 237))	('gastroesophageal tumors', 'Disease', 'MESH:D005764', (214, 237))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (36, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	('5-FU', 'Chemical', '-', (20, 24))	('patients', 'Species', '9606', (200, 208))	('toxicity', 'Disease', 'MESH:D064420', (10, 18))	('leucovorin', 'Chemical', 'MESH:D002955', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('gastric cancer', 'Disease', (167, 181))	('5-FU', 'Chemical', '-', (82, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))
824129	23869177	Overexpression of EGFR was detected in 30%-90% of esophagogastric tumors, correlating with increased invasion, dedifferentiation, and worse prognosis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('esophagogastric tumors', 'Disease', (50, 72))	('EGFR', 'Gene', '1956', (18, 22))	('esophagogastric tumors', 'Phenotype', 'HP:0100751', (50, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('EGFR', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('increased', 'PosReg', (91, 100))	('esophagogastric tumors', 'Disease', 'MESH:C537006', (50, 72))	('dedifferentiation', 'CPA', (111, 128))
824130	23869177	In contrast to colorectal and lung cancer, KRAS mutation status and EGFR mutations do not seem to play a role.	('colorectal and lung cancer', 'Disease', 'MESH:D015179', (15, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('KRAS', 'Gene', (43, 47))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', (68, 72))	('KRAS', 'Gene', '3845', (43, 47))	('mutations', 'Var', (73, 82))
824150	23869177	Based on positive Phase II data in gastric cancer patients, trastuzumab was evaluated in a large Phase III trial, including gastric cancer patients and patients with AC of the GEJ if their tumors showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in situ hybridization.	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('overexpression', 'PosReg', (203, 217))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('gene amplification', 'Var', (261, 279))	('HER2', 'Gene', '2064', (221, 225))	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('trastuzumab', 'Chemical', 'MESH:D000068878', (60, 71))	('gastric cancer', 'Disease', (124, 138))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (139, 147))	('tumors', 'Disease', (189, 195))	('gastric cancer', 'Disease', (35, 49))	('patients', 'Species', '9606', (152, 160))	('HER2', 'Gene', (221, 225))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))
824177	23869177	Regarding locally advanced esophageal cancer, several Phase III studies are now recruiting patients to investigate new chemotherapy combinations, such as S-1/cisplatin, S-1/paclitaxel, cisplatin/paclitaxel, and 5-FU/leucovorin/oxaliplatin/docetaxel (FLOT), as first-line treatment (Table 5).	('oxaliplatin', 'Chemical', 'MESH:D000077150', (227, 238))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (91, 99))	('esophageal cancer', 'Disease', (27, 44))	('5-FU', 'Chemical', '-', (211, 215))	('FLO', 'Chemical', '-', (250, 253))	('paclitaxel', 'Chemical', 'MESH:D017239', (173, 183))	('men', 'Species', '9606', (276, 279))	('leucovorin', 'Chemical', 'MESH:D002955', (216, 226))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))	('S', 'Chemical', 'MESH:D013455', (169, 170))	('docetaxel', 'Chemical', 'MESH:D000077143', (239, 248))	('S-1/paclitaxel', 'Var', (169, 183))	('paclitaxel', 'Chemical', 'MESH:D017239', (195, 205))	('S', 'Chemical', 'MESH:D013455', (154, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))
824189	23869177	The radiation dose can be more precisely adjusted to the 3-D shape of the tumor by modulating - or controlling - the intensity of the radiation beam in multiple small volumes.	('modulating', 'Var', (83, 93))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
824200	23869177	Second-line therapy after failure of first-line therapy or tumor recurrence is still experimental, but docetaxel monotherapy, and targeting VEGF-R2 with ramucirumab have improved OS, according to two separate Phase III studies.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('docetaxel', 'Chemical', 'MESH:D000077143', (103, 112))	('VEGF', 'Gene', '7422', (140, 144))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('targeting', 'Var', (130, 139))	('S', 'Chemical', 'MESH:D013455', (180, 181))	('improved', 'PosReg', (170, 178))	('men', 'Species', '9606', (91, 94))	('ramucirumab', 'Chemical', 'MESH:C543333', (153, 164))	('VEGF', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('OS', 'Chemical', '-', (179, 181))
824206	23869177	In addition, with increasing numbers of cancer cells, there is an increase in genetic mutations with each generation that will help cancer cells to escape the toxicity of treatment.	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('genetic mutations', 'Var', (78, 95))	('men', 'Species', '9606', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (40, 46))	('toxicity', 'Disease', 'MESH:D064420', (159, 167))	('help', 'PosReg', (127, 131))	('toxicity', 'Disease', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
824218	22572079	Fisher's exact test resulted in significant median splits for grade >=3 toxicity at V12 = 3.78 cm3 (relative risk [RR] 3.7, p = 0.05), V15 = 1.87 cm3 (RR 13, p = 0.0013), V20 = 0.11 cm3 (RR = 6, p = 0.01), and V22 = 0.0 cm3 (RR 13, p = 0.0013).	('V20 = 0.11 cm3', 'Var', (171, 185))	('V15', 'Gene', (135, 138))	('V12', 'Gene', '28817', (84, 87))	('V12', 'Gene', (84, 87))	('toxicity', 'Disease', 'MESH:D064420', (72, 80))	('V15', 'Gene', '28814', (135, 138))	('toxicity', 'Disease', (72, 80))	('V22 = 0.0 cm3', 'Var', (210, 223))
824294	22572079	For any fixed volume of esophagus, particularly for <=8 cm3, probability of toxicity clearly increases with dose.	('toxicity', 'Disease', 'MESH:D064420', (76, 84))	('<=8 cm3', 'Var', (52, 59))	('toxicity', 'Disease', (76, 84))	('increases', 'PosReg', (93, 102))
824299	22572079	In dose-volume analysis, Fisher's exact test resulted in significant median splits for grade >=3 toxicity at V12 = 3.78 cm3(relative risk [RR] 3.7, p = 0.05), V15 = 1.87 cm3 (RR 13, p = 0.0013), V20 = 0.11 cm3 (RR = 6, p = 0.01), and V22 = 0.0 cm3 (RR 13, p = 0.0013).	('V20 = 0.11 cm3', 'Var', (195, 209))	('grade >=3', 'Disease', (87, 96))	('V15', 'Gene', '28814', (159, 162))	('V12', 'Gene', '28817', (109, 112))	('V12', 'Gene', (109, 112))	('V22 = 0.0 cm3', 'Var', (234, 247))	('toxicity', 'Disease', 'MESH:D064420', (97, 105))	('toxicity', 'Disease', (97, 105))	('V15', 'Gene', (159, 162))
824309	22572079	We further attempt to limit V12Gy to <3.78 cm3, V15Gy to <1.87 cm3, and V20Gy to <0.11 cm3, and the maximum point dose to the esophagus to <22 Gy.	('V12', 'Gene', (28, 31))	('V15', 'Gene', '28814', (48, 51))	('V20Gy', 'Var', (72, 77))	('V12', 'Gene', '28817', (28, 31))	('V15', 'Gene', (48, 51))
824400	33557387	In the meta-analysis with six publications, including four cohort studies and two case-controls, a significant positive association between high SSB consumption and breast cancer risk was observed (RR: 1.14, 95% CI: 1.0-1.3) (Table 2).	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('high', 'Var', (140, 144))
824646	32143580	The acceptable false-negative rate will be increased with 2% because survival of patients with ypN+ is worse than patients who have ypN0, regardless of whether they are missed during clinical response evaluations or not.	('worse', 'NegReg', (103, 108))	('patients', 'Species', '9606', (81, 89))	('ypN+', 'Var', (95, 99))	('patients', 'Species', '9606', (114, 122))	('survival', 'MPA', (69, 77))
824698	32143580	In this large CROSS cohort, 8 of 122 patients with SCC (7%) and 11 of 415 patients with AC (3%) who underwent nCRT followed by a surgical resection had ypT0N+ stage.	('SCC', 'Disease', 'MESH:D002294', (51, 54))	('ypT0N+ stage', 'Var', (152, 164))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (74, 82))	('AC', 'Disease', 'MESH:D000230', (88, 90))	('SCC', 'Disease', (51, 54))
824700	32143580	), suggesting that the higher rate of ypT0N+ patients is mainly caused by the better response of SCC to nCRT according to CROSS.	('SCC', 'Disease', 'MESH:D002294', (97, 100))	('ypT0N+', 'Var', (38, 44))	('patients', 'Species', '9606', (45, 53))	('SCC', 'Disease', (97, 100))
824701	32143580	In an active surveillance strategy that focusses on the primary tumor site only, patients who have ypT0N+ stage run a high risk of developing distant metastases.	('primary tumor', 'Disease', (56, 69))	('patients', 'Species', '9606', (81, 89))	('ypT0N+ stage', 'Var', (99, 111))	('primary tumor', 'Disease', 'MESH:D009369', (56, 69))	('metastases', 'Disease', (150, 160))	('metastases', 'Disease', 'MESH:D009362', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
824790	31441840	Survival was not significantly influenced by tumor type (adeno vs squamous cell carcinoma, P = .214), KPS (>= vs <70, P = .381) or age >=70 (P = .438).	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous cell carcinoma', 'Disease', (66, 89))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 89))	('tumor', 'Disease', (45, 50))	('adeno', 'Disease', (57, 62))	('>=', 'Var', (107, 109))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
824849	31331305	In the univariate analysis, MLN dissection, D1 + dissection of abdominal LNs, longer tumor size, higher pT category, pN category and pM category, undifferentiated histology, and treatment with chemotherapy were associated with statistically worse survival (Table 4).	('tumor', 'Disease', (85, 90))	('higher', 'PosReg', (97, 103))	('D1 + dissection', 'Var', (44, 59))	('worse', 'NegReg', (241, 246))	('MLN dissection', 'Var', (28, 42))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('pT category', 'MPA', (104, 115))
824863	31331305	However, in this study, MLN recurrence rates were higher in patients who underwent MLN dissection, even though more advanced-staged patients had been selected for MLN dissection.	('higher', 'PosReg', (50, 56))	('patients', 'Species', '9606', (60, 68))	('dissection', 'Var', (87, 97))	('patients', 'Species', '9606', (132, 140))	('MLN', 'Disease', (24, 27))
824888	30881487	Therefore, an in-depth study of the regulatory mechanisms involved in disorders of Fbw7 expression and the role of Fbw7 in chemoresistance of gastrointestinal tumors may suggest improvements for early diagnostic screening and targeted therapy.	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (142, 165))	('Fbw7', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('disorders', 'Var', (70, 79))	('Fbw7', 'Gene', '55294', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('Fbw7', 'Gene', (115, 119))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (142, 165))	('gastrointestinal tumors', 'Disease', (142, 165))	('Fbw7', 'Gene', '55294', (115, 119))
824899	30881487	The majority of Fbw7 substrates regulate a number of cell behaviors, including progression through the cell cycle, differentiation and apoptosis.	('regulate', 'Reg', (32, 40))	('apoptosis', 'CPA', (135, 144))	('substrates', 'Var', (21, 31))	('Fbw7', 'Gene', '55294', (16, 20))	('cell behaviors', 'CPA', (53, 67))	('differentiation', 'CPA', (115, 130))	('Fbw7', 'Gene', (16, 20))	('progression through the cell cycle', 'CPA', (79, 113))
824902	30881487	In tumor cells, FBW7 has been demonstrated to possess mutations and deletions, to be methylated or post-transcriptionally modified.	('tumor', 'Disease', (3, 8))	('FBW7', 'Gene', '55294', (16, 20))	('deletions', 'Var', (68, 77))	('mutations', 'Var', (54, 63))	('FBW7', 'Gene', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
824904	30881487	The present review aimed to provide a comprehensive overview of the mechanisms involved in dysfunctional Fbw7 expression caused by mutations in the FBW7 gene.	('mutations', 'Var', (131, 140))	('FBW7', 'Gene', (148, 152))	('caused', 'Reg', (121, 127))	('dysfunctional', 'Var', (91, 104))	('expression', 'MPA', (110, 120))	('FBW7', 'Gene', '55294', (148, 152))	('Fbw7', 'Gene', '55294', (105, 109))	('Fbw7', 'Gene', (105, 109))
824920	30881487	Missense point mutations on three arginine residues (R465, R479 and R505) occurring at the beta propeller phosphorylation-binding site, impair the substrate recognition function of Fbw7.	('Fbw7', 'Gene', (181, 185))	('impair', 'NegReg', (136, 142))	('Fbw7', 'Gene', '55294', (181, 185))	('Missense point mutations', 'Var', (0, 24))	('arginine', 'Chemical', 'MESH:D001120', (34, 42))	('R479', 'Var', (59, 63))	('R465', 'Var', (53, 57))	('R505', 'Var', (68, 72))	('substrate recognition function', 'MPA', (147, 177))
824921	30881487	Additionally, monoallelic or biallelic knockouts or the hypermethylation of the promoter of FBW7 may occur in tumors, in humans and in mice.	('FBW7', 'Gene', '55294', (92, 96))	('hypermethylation', 'Var', (56, 72))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('FBW7', 'Gene', (92, 96))	('monoallelic', 'Var', (14, 25))	('occur', 'Reg', (101, 106))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('mice', 'Species', '10090', (135, 139))	('biallelic knockouts', 'Var', (29, 48))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('humans', 'Species', '9606', (121, 127))
824924	30881487	Specifically, dimerization of Fbw7 improves its affinity for substrates, whereas, post-transcriptional modifications allow Fbw7 to alter between an autocatalytic mode and a substrate degradation mode.	('Fbw7', 'Gene', (30, 34))	('Fbw7', 'Gene', '55294', (123, 127))	('modifications', 'Var', (103, 116))	('Fbw7', 'Gene', '55294', (30, 34))	('affinity for substrates', 'MPA', (48, 71))	('autocatalytic', 'MPA', (148, 161))	('Fbw7', 'Gene', (123, 127))	('substrate', 'MPA', (173, 182))	('improves', 'PosReg', (35, 43))	('alter', 'Reg', (131, 136))	('dimerization', 'MPA', (14, 26))
824925	30881487	A mutation of the CPD at the binding site of Fbw7 decreases the affinity of Fbw7 for a substrate, resulting in downstream substrate accumulation.	('mutation', 'Var', (2, 10))	('Fbw7', 'Gene', (45, 49))	('affinity', 'MPA', (64, 72))	('Fbw7', 'Gene', '55294', (45, 49))	('decreases', 'NegReg', (50, 59))	('Fbw7', 'Gene', (76, 80))	('downstream substrate accumulation', 'MPA', (111, 144))	('Fbw7', 'Gene', '55294', (76, 80))	('binding', 'Interaction', (29, 36))
824926	30881487	In addition to mutations of FBW7 and modifications of product structure subsequent to transcription and translation, the expression of Fbw7 is regulated by a variety of other factors.	('FBW7', 'Gene', (28, 32))	('mutations', 'Var', (15, 24))	('product structure', 'MPA', (54, 71))	('expression', 'MPA', (121, 131))	('regulated', 'Reg', (143, 152))	('Fbw7', 'Gene', (135, 139))	('FBW7', 'Gene', '55294', (28, 32))	('Fbw7', 'Gene', '55294', (135, 139))
824928	30881487	Loss of the deubiquitinase Usp28 monoallele stabilizes and facilitates Fbw7-mediated substrate degradation, whereas, complete knockout of Usp28 promotes the degradation of Fbw7, leading to the accumulation of Fbw7 substrates.	('Fbw7', 'Gene', (209, 213))	('Usp28', 'Gene', '57646', (27, 32))	('Fbw7', 'Gene', (172, 176))	('Usp28', 'Gene', (138, 143))	('Usp28', 'Gene', (27, 32))	('facilitates', 'PosReg', (59, 70))	('Fbw7', 'Gene', '55294', (209, 213))	('promotes', 'PosReg', (144, 152))	('Usp28', 'Gene', '57646', (138, 143))	('Loss', 'NegReg', (0, 4))	('knockout', 'Var', (126, 134))	('Fbw7', 'Gene', '55294', (172, 176))	('accumulation', 'PosReg', (193, 205))	('Fbw7', 'Gene', '55294', (71, 75))	('Fbw7', 'Gene', (71, 75))	('degradation', 'MPA', (157, 168))	('stabilizes', 'MPA', (44, 54))
824935	30881487	The mutation in FBW7, including FBW7 missense mutation in three arginine residues (R465, R479 and R505), which leads to dysfunctional Fbw7, can cause the accumulation of numerous substrates, which may be important in chemoresistance.	('arginine', 'Chemical', 'MESH:D001120', (64, 72))	('Fbw7', 'Gene', (134, 138))	('R465', 'Var', (83, 87))	('FBW7', 'Gene', '55294', (16, 20))	('Fbw7', 'Gene', '55294', (134, 138))	('FBW7', 'Gene', (32, 36))	('cause', 'Reg', (144, 149))	('dysfunctional', 'MPA', (120, 133))	('leads', 'Reg', (111, 116))	('accumulation of numerous substrates', 'MPA', (154, 189))	('FBW7', 'Gene', (16, 20))	('missense mutation', 'Var', (37, 54))	('R479', 'Var', (89, 93))	('R505', 'Var', (98, 102))	('FBW7', 'Gene', '55294', (32, 36))
824943	30881487	In mitosis, the deletion of Fbw7 causes hyperphosphorylation of a serine residue at position 18 of the centromere recognition protein, histone H3-like centromeric protein-A, by cyclin E1/cyclin-dependent kinase 2 (CDK2) resulting in the inability of the centromere to become localized, in addition to increased chromosomal instability and the promotion of tumorigenesis.	('histone H3-like centromeric protein-A', 'Gene', (135, 172))	('chromosomal instability', 'CPA', (311, 334))	('Fbw7', 'Gene', (28, 32))	('promotion', 'PosReg', (343, 352))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('cyclin E1/cyclin-dependent kinase 2', 'Gene', (177, 212))	('deletion', 'Var', (16, 24))	('histone H3-like centromeric protein-A', 'Gene', '1058', (135, 172))	('serine', 'Chemical', 'MESH:D012694', (66, 72))	('cyclin E1/cyclin-dependent kinase 2', 'Gene', '898;1017', (177, 212))	('mitosis', 'Disease', (3, 10))	('hyperphosphorylation', 'MPA', (40, 60))	('CDK2', 'Gene', '1017', (214, 218))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (301, 334))	('CDK2', 'Gene', (214, 218))	('tumor', 'Disease', (356, 361))	('mitosis', 'Disease', 'None', (3, 10))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('Fbw7', 'Gene', '55294', (28, 32))	('increased', 'PosReg', (301, 310))
824946	30881487	Numerous previous studies investigated the association between FBW7 mutations and clinicopathological features of gastrointestinal malignancies (Table I).	('FBW7', 'Gene', (63, 67))	('FBW7', 'Gene', '55294', (63, 67))	('mutations', 'Var', (68, 77))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (114, 143))	('gastrointestinal malignancies', 'Disease', (114, 143))
824947	30881487	A number of the previous studies in Table I suggested that a poor prognosis was closely associated with FBW7 mutations.	('mutations', 'Var', (109, 118))	('FBW7', 'Gene', (104, 108))	('FBW7', 'Gene', '55294', (104, 108))
824948	30881487	In a number of previous studies, it was demonstrated that aberrant Fbw7 expression additionally serves a pivotal role in the resistance of numerous gastrointestinal tumors to chemotherapeutic drugs (Table II).	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('numerous gastrointestinal tumors', 'Disease', 'MESH:D004067', (139, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('aberrant', 'Var', (58, 66))	('Fbw7', 'Gene', (67, 71))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (148, 171))	('Fbw7', 'Gene', '55294', (67, 71))	('numerous gastrointestinal tumors', 'Disease', (139, 171))
824950	30881487	Next-generation sequencing of 648 colorectal cancer specimens demonstrated that the mutational rates of FBW7 in the Chinese population was 5.32%.	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mutational', 'Var', (84, 94))	('colorectal cancer', 'Disease', (34, 51))	('FBW7', 'Gene', '55294', (104, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (34, 51))	('FBW7', 'Gene', (104, 108))
824951	30881487	Disorders in Fbw7 expression caused by FBW7 mutation, including mutation in Arg465 significantly increased the depth of invasion of colorectal cancer and shortened the 5-year overall survival rate of patients.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('Fbw7', 'Gene', (13, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('increased', 'PosReg', (97, 106))	('patients', 'Species', '9606', (200, 208))	('FBW7', 'Gene', '55294', (39, 43))	('shortened', 'NegReg', (154, 163))	('Disorders', 'Reg', (0, 9))	('5-year overall survival rate', 'CPA', (168, 196))	('Fbw7', 'Gene', '55294', (13, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('FBW7', 'Gene', (39, 43))	('Arg465', 'Chemical', '-', (76, 82))	('depth of invasion', 'CPA', (111, 128))	('colorectal cancer', 'Disease', (132, 149))	('mutation in Arg465', 'Var', (64, 82))	('Arg465', 'Var', (76, 82))
824952	30881487	The accumulation of cyclin E and c-Myc caused by dysfunctional Fbw7 expression increases the malignancy of colorectal cancer.	('increases', 'PosReg', (79, 88))	('Fbw7', 'Gene', (63, 67))	('accumulation', 'PosReg', (4, 16))	('c-Myc', 'Gene', '4609', (33, 38))	('malignancy of colorectal cancer', 'Disease', 'MESH:D015179', (93, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('Fbw7', 'Gene', '55294', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cyclin E', 'MPA', (20, 28))	('dysfunctional', 'Var', (49, 62))	('c-Myc', 'Gene', (33, 38))	('malignancy of colorectal cancer', 'Disease', (93, 124))
824961	30881487	A previous Japanese study, which examined liver cancer tissue samples from 66 cases and followed up the survival rates of the patients, demonstrated that tumor-free survival of patients with high Fbw7 expression was considerably longer compared with patients with low Fbw7 expression.	('Fbw7', 'Gene', (196, 200))	('expression', 'Var', (201, 211))	('tumor', 'Disease', (154, 159))	('Fbw7', 'Gene', '55294', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('liver cancer', 'Phenotype', 'HP:0002896', (42, 54))	('liver cancer', 'Disease', 'MESH:D006528', (42, 54))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (250, 258))	('Fbw7', 'Gene', (268, 272))	('liver cancer', 'Disease', (42, 54))	('Fbw7', 'Gene', '55294', (268, 272))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('patients', 'Species', '9606', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('high', 'Var', (191, 195))	('longer', 'PosReg', (229, 235))
824968	30881487	Hepatocellular carcinoma cell lines with increased expression of Fbw7 were more sensitive to doxorubicin and demonstrated decreased EMT.	('increased', 'PosReg', (41, 50))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (0, 24))	('decreased EMT', 'Phenotype', 'HP:0032198', (122, 135))	('EMT', 'CPA', (132, 135))	('more', 'PosReg', (75, 79))	('decreased', 'NegReg', (122, 131))	('Fbw7', 'Gene', (65, 69))	('Fbw7', 'Gene', '55294', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))	('expression', 'Var', (51, 61))	('sensitive to doxorubicin', 'MPA', (80, 104))	('doxorubicin', 'Chemical', 'MESH:D004317', (93, 104))
824970	30881487	To date, four missense mutations, a frame shift mutation and a nonsense mutation of FBW7 have been identified in gastric cancer tissues; and an FBW7 mutation has been identified in early gastric cancer.	('FBW7', 'Gene', '55294', (84, 88))	('gastric cancer', 'Disease', (187, 201))	('FBW7', 'Gene', (144, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('FBW7', 'Gene', '55294', (144, 148))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('FBW7', 'Gene', (84, 88))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (187, 201))	('identified', 'Reg', (167, 177))	('frame shift mutation', 'Var', (36, 56))	('mutation', 'Var', (149, 157))	('identified', 'Reg', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
824972	30881487	A recent Chinese study demonstrated that dysfunctional Fbw7 expression caused by FBW7 mutations were associated with poor tissue differentiation, survival and adjuvant chemotherapy resistance.	('mutations', 'Var', (86, 95))	('poor tissue differentiation', 'CPA', (117, 144))	('FBW7', 'Gene', '55294', (81, 85))	('Fbw7', 'Gene', (55, 59))	('dysfunctional', 'Var', (41, 54))	('Fbw7', 'Gene', '55294', (55, 59))	('adjuvant chemotherapy resistance', 'CPA', (159, 191))	('FBW7', 'Gene', (81, 85))	('survival', 'CPA', (146, 154))
824973	30881487	FBW7 mutations were additionally associated with lymph node metastasis, tumor size and p53 mutations in gastric cancer, leading to a poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('p53', 'Gene', (87, 90))	('tumor', 'Disease', (72, 77))	('p53', 'Gene', '7157', (87, 90))	('FBW7', 'Gene', '55294', (0, 4))	('mutations', 'Var', (5, 14))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('associated', 'Reg', (33, 43))	('mutations', 'Var', (91, 100))	('lymph node metastasis', 'CPA', (49, 70))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('FBW7', 'Gene', (0, 4))	('gastric cancer', 'Disease', (104, 118))
824974	30881487	The tumorigenic effects of FBW7 mutations are manifested as a result of its interactions with numerous substrates.	('tumor', 'Disease', (4, 9))	('FBW7', 'Gene', '55294', (27, 31))	('mutations', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('interactions', 'Interaction', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('FBW7', 'Gene', (27, 31))
824975	30881487	Therefore, screening for FBW7 mutations may improve the diagnosis and detection of early gastric cancer.	('improve', 'PosReg', (44, 51))	('FBW7', 'Gene', '55294', (25, 29))	('gastric cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (30, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('FBW7', 'Gene', (25, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))
824990	30881487	Although previous studies identified an intrinsic association between FBW7 mutations and the pathological features, and prognosis of oral and esophageal squamous cell carcinomas, There are a limited number of studies, to the best of our knowledge, on the regulatory mechanisms of upstream and downstream molecules.	('FBW7', 'Gene', (70, 74))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (153, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('esophageal squamous cell carcinomas', 'Disease', (142, 177))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (142, 177))	('mutations', 'Var', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('FBW7', 'Gene', '55294', (70, 74))
824999	30881487	A KRAS proto-oncogene, GTPase mutation activated extracellular signal-regulated kinase (ERK) to directly bind to a threonine at position 205 of Fbw7, resulting in ERK degradation.	('ERK', 'Gene', '5594', (163, 166))	('extracellular signal-regulated kinase', 'Gene', '5594', (49, 86))	('ERK', 'Gene', (163, 166))	('activated', 'PosReg', (39, 48))	('extracellular signal-regulated kinase', 'Gene', (49, 86))	('ERK', 'Gene', '5594', (88, 91))	('Fbw7', 'Gene', (144, 148))	('mutation', 'Var', (30, 38))	('threonine', 'Chemical', 'MESH:D013912', (115, 124))	('Fbw7', 'Gene', '55294', (144, 148))	('bind', 'Interaction', (105, 109))	('ERK', 'Gene', (88, 91))	('KRAS', 'Gene', (2, 6))	('GTPase', 'Gene', (23, 29))	('KRAS', 'Gene', '3845', (2, 6))	('degradation', 'MPA', (167, 178))
825004	30881487	In a previous study by Yu et al, transfection of Fbw7 into a non-small cell lung cancer cell line, NCI-H1299, which exhibits low endogenous expression levels of Fbw7, significantly increased its chemosensitivity to cisplatin, which was closely associated with the effect of Fbw7 on EMT.	('transfection', 'Var', (33, 45))	('Fbw7', 'Gene', (161, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (65, 87))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (61, 87))	('Fbw7', 'Gene', (49, 53))	('Fbw7', 'Gene', '55294', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('non-small cell lung cancer', 'Disease', (61, 87))	('NCI-H1299', 'CellLine', 'CVCL:0060', (99, 108))	('Fbw7', 'Gene', '55294', (49, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (215, 224))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (61, 87))	('increased', 'PosReg', (181, 190))	('Fbw7', 'Gene', (274, 278))	('chemosensitivity to cisplatin', 'MPA', (195, 224))	('Fbw7', 'Gene', '55294', (274, 278))
825007	30881487	In tumor tissues, the lack of Fbw7 disrupted this process and induced drug resistance in non-small cell lung cancer.	('Fbw7', 'Gene', (30, 34))	('tumor', 'Disease', (3, 8))	('Fbw7', 'Gene', '55294', (30, 34))	('lack', 'Var', (22, 26))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (89, 115))	('drug resistance', 'Phenotype', 'HP:0020174', (70, 85))	('induced', 'Reg', (62, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('non-small cell lung cancer', 'Disease', (89, 115))	('drug resistance', 'MPA', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('disrupted', 'NegReg', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (89, 115))
825008	30881487	Lin et al demonstrated that Fbw7 overexpression inhibited proliferation, invasion and metastasis of the glioma cell lines, U251 and U373, by downregulating Aurora B, Mcl-1 and Notch-1 expression levels, and enhanced the cytotoxicity of temozolomide.	('metastasis of the glioma', 'Disease', (86, 110))	('downregulating', 'NegReg', (141, 155))	('Fbw7', 'Gene', (28, 32))	('enhanced', 'PosReg', (207, 215))	('Aurora B', 'Gene', (156, 164))	('Mcl-1', 'Gene', (166, 171))	('overexpression', 'Var', (33, 47))	('invasion', 'CPA', (73, 81))	('Aurora B', 'Gene', '9212', (156, 164))	('metastasis of the glioma', 'Disease', 'MESH:D009362', (86, 110))	('cytotoxicity', 'Disease', (220, 232))	('inhibited', 'NegReg', (48, 57))	('Notch-1', 'Gene', '4851', (176, 183))	('cytotoxicity', 'Disease', 'MESH:D064420', (220, 232))	('proliferation', 'CPA', (58, 71))	('temozolomide', 'Chemical', 'MESH:D000077204', (236, 248))	('Mcl-1', 'Gene', '4170', (166, 171))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('Fbw7', 'Gene', '55294', (28, 32))	('expression levels', 'MPA', (184, 201))	('Notch-1', 'Gene', (176, 183))	('U251', 'CellLine', 'CVCL:0021', (123, 127))
825011	30881487	Following phosphorylation of GSK3beta at the C-terminus of EgIN2, the latter became ubiquitylated and degraded by Fbw7.	('ubiquitylated', 'MPA', (84, 97))	('GSK3beta', 'Gene', (29, 37))	('EgIN2', 'Gene', (59, 64))	('GSK3beta', 'Gene', '2932', (29, 37))	('Fbw7', 'Gene', (114, 118))	('Fbw7', 'Gene', '55294', (114, 118))	('phosphorylation', 'Var', (10, 25))	('degraded', 'NegReg', (102, 110))
825013	30881487	This process is caused by Fbw7 ubiquitination and degradation of STAT3 and phosphorylated STAT3Tyr705, resulting in the dysfunction of downstream anti-apoptotic proteins, Myc, survivin, Mcl-1, serine/threonine-protein kinase pim-1, B-cell lymphoma-2 (Bcl-2) and Bcl2-associated agonist of cell death.	('STAT3', 'Gene', '6774', (90, 95))	('Myc', 'Gene', '4609', (171, 174))	('pim-1', 'Gene', '5292', (225, 230))	('pim-1', 'Gene', (225, 230))	('Bcl-2', 'Gene', (251, 256))	('dysfunction', 'MPA', (120, 131))	('Fbw7', 'Gene', '55294', (26, 30))	('lymphoma', 'Phenotype', 'HP:0002665', (239, 247))	('death', 'Disease', (294, 299))	('Mcl-1', 'Gene', '4170', (186, 191))	('serine', 'Chemical', 'MESH:D012694', (193, 199))	('Fbw7', 'Gene', (26, 30))	('Bcl-2', 'Gene', '596', (251, 256))	('Myc', 'Gene', (171, 174))	('B-cell lymphoma-2', 'Gene', '596', (232, 249))	('degradation', 'MPA', (50, 61))	('caused by', 'Reg', (16, 25))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (232, 247))	('Mcl-1', 'Gene', (186, 191))	('STAT3', 'Gene', (65, 70))	('survivin', 'Protein', (176, 184))	('Bcl2', 'Gene', (262, 266))	('STAT3', 'Gene', (90, 95))	('death', 'Disease', 'MESH:D003643', (294, 299))	('threonine', 'Chemical', 'MESH:D013912', (200, 209))	('STAT3', 'Gene', '6774', (65, 70))	('Bcl2', 'Gene', '596', (262, 266))	('ubiquitination', 'Var', (31, 45))	('B-cell lymphoma-2', 'Gene', (232, 249))
825014	30881487	Dysfunctional Fbw7 is closely associated with the progression, invasion, metastasis and chemoresistance of tumors as a result of deficiencies in the ubiquitylation and degradation of substrates that serve as oncoproteins in tumor progression.	('progression', 'CPA', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (107, 112))	('metastasis', 'CPA', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('deficiencies', 'NegReg', (129, 141))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('associated', 'Reg', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Fbw7', 'Gene', '55294', (14, 18))	('tumors', 'Disease', (107, 113))	('tumor', 'Disease', (224, 229))	('invasion', 'CPA', (63, 71))	('degradation', 'MPA', (168, 179))	('ubiquitylation', 'MPA', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('substrates', 'Protein', (183, 193))	('Fbw7', 'Gene', (14, 18))	('chemoresistance', 'CPA', (88, 103))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('Dysfunctional', 'Var', (0, 13))
825016	30881487	At the genetic level, FBW7 mutations may lead to increased dysfunctional expression.	('mutations', 'Var', (27, 36))	('dysfunctional expression', 'MPA', (59, 83))	('FBW7', 'Gene', '55294', (22, 26))	('increased', 'PosReg', (49, 58))	('FBW7', 'Gene', (22, 26))
825019	30881487	In addition, mutations in the CPD region of substrates result in a loss of affinity to Fbw7, resulting in dysfunctional ubiquitination by Fbw7.	('dysfunctional ubiquitination', 'Disease', (106, 134))	('Fbw7', 'Gene', (87, 91))	('Fbw7', 'Gene', (138, 142))	('Fbw7', 'Gene', '55294', (87, 91))	('loss', 'NegReg', (67, 71))	('Fbw7', 'Gene', '55294', (138, 142))	('affinity', 'Interaction', (75, 83))	('dysfunctional ubiquitination', 'Disease', 'MESH:C563003', (106, 134))	('mutations', 'Var', (13, 22))
825020	30881487	The frequent presence of mutations in FBW7 in tumors may constitute FBW7 as an early tumor screening gene.	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('FBW7', 'Gene', '55294', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('FBW7', 'Gene', '55294', (38, 42))	('FBW7', 'Gene', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumors', 'Disease', (46, 52))	('FBW7', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('presence', 'Reg', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
825022	30881487	Approaches against Fbw7 in anti-tumor therapy may include knocking out FBW7 variant genes, targeting upstream proteins of Fbw7 and substrates of Fbw7 that have cancer-promoting effects, and exogenously upregulating the expression of Fbw7 to reverse tumorigenesis.	('variant', 'Var', (76, 83))	('Fbw7', 'Gene', '55294', (122, 126))	('upregulating', 'PosReg', (202, 214))	('exogenously', 'Var', (190, 201))	('Fbw7', 'Gene', '55294', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (249, 254))	('Fbw7', 'Gene', (19, 23))	('Fbw7', 'Gene', '55294', (145, 149))	('Fbw7', 'Gene', (122, 126))	('knocking', 'Var', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('Fbw7', 'Gene', (233, 237))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('Fbw7', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('FBW7', 'Gene', (71, 75))	('tumor', 'Disease', (32, 37))	('FBW7', 'Gene', '55294', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('expression', 'MPA', (219, 229))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Fbw7', 'Gene', '55294', (19, 23))
825024	30881487	Similar to Fbw7, mutations of BRD7 may lead to SWI/SNF dysfunction, which causes aberrant gene expression leading to various diseases, including prostate cancer, breast cancer and nasopharyngeal cancer.	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (180, 201))	('lead to', 'Reg', (39, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (145, 160))	('Fbw7', 'Gene', '55294', (11, 15))	('prostate cancer', 'Phenotype', 'HP:0012125', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('prostate cancer', 'Disease', (145, 160))	('leading to', 'Reg', (106, 116))	('mutations', 'Var', (17, 26))	('SNF dysfunction', 'Disease', 'MESH:D006331', (51, 66))	('SNF dysfunction', 'Disease', (51, 66))	('Fbw7', 'Gene', (11, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (180, 201))	('gene expression', 'MPA', (90, 105))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('BRD7', 'Gene', '29117', (30, 34))	('breast cancer', 'Disease', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('nasopharyngeal cancer', 'Disease', (180, 201))	('BRD7', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
825044	29889869	For these locally advanced ESCC patients treated with curative CCRT, N0-2 were significantly associated with superior progression-free survival (PFS) and overall survival (OS) in univariate and multivariable analyses.	('overall survival', 'CPA', (154, 170))	('OS', 'Chemical', '-', (172, 174))	('patients', 'Species', '9606', (32, 40))	('superior', 'PosReg', (109, 117))	('ESCC', 'Disease', (27, 31))	('progression-free survival', 'CPA', (118, 143))	('N0-2', 'Var', (69, 73))
825055	29889869	However, several studies have shown that patients with SCLN metastasis appear to have a better survival rate than those with visceral organ metastasis.	('SCLN metastasis', 'Var', (55, 70))	('SCLN', 'Chemical', '-', (55, 59))	('patients', 'Species', '9606', (41, 49))	('better', 'PosReg', (88, 94))	('survival', 'CPA', (95, 103))
825085	29889869	In addition, we also found that patients with N3 status had worse PFS and OS than those with N0-2 statuses.	('patients', 'Species', '9606', (32, 40))	('N3 status', 'Var', (46, 55))	('PFS', 'MPA', (66, 69))	('OS', 'Chemical', '-', (74, 76))	('worse', 'NegReg', (60, 65))
825090	29889869	Meanwhile, patients with T1-3 status (P = 0.048), N0-2 status (P = 0.004), age less than 60 years old (P = 0.039) and female patients (P = 0.019) were mentioned to have significantly superior PFS than others.	('superior', 'PosReg', (183, 191))	('PFS', 'CPA', (192, 195))	('T1-3', 'Gene', '29123;9173;292', (25, 29))	('T1-3', 'Gene', (25, 29))	('N0-2 status', 'Var', (50, 61))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (125, 133))
825093	29889869	Patients with T1-3 status (P = 0.049) and N0-2 status (P = 0.002) were reported to have better OS than others.	('N0-2 status', 'Var', (42, 53))	('T1-3', 'Gene', '29123;9173;292', (14, 18))	('T1-3', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (95, 97))
825094	29889869	According to a multivariable comparison, N0-2 status (P = 0.007, HR: 0.68, 95% CI: 0.52-0.90) represented the independent predictive factors of superior OS.	('OS', 'Chemical', '-', (153, 155))	('N0-2 status', 'Var', (41, 52))	('superior OS', 'Disease', (144, 155))
825128	29889869	Second, there were more patients with N3 status and upper locations of the primary tumor in the SCLN metastasis group, but no significant differences in overall survival were found between these two groups.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SCLN', 'Chemical', '-', (96, 100))	('tumor', 'Disease', (83, 88))	('patients', 'Species', '9606', (24, 32))	('N3 status', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
825132	28007661	Reactivation of the relevant signaling pathways has also been associated with pathogenesis of esophageal diseases that affect the epithelium and its stem cells in adults.	('esophageal diseases', 'Disease', (94, 113))	('associated', 'Reg', (62, 72))	('Reactivation', 'Var', (0, 12))	('esophageal diseases', 'Disease', 'MESH:D004935', (94, 113))	('signaling pathways', 'Pathway', (29, 47))
825136	28007661	Disruption of this expression pattern leads to various anomalies such as esophageal atresia with or without tracheoesophageal fistula (EA/TEF) where the esophagus is closed as a blind end sac proximally, and in a worse scenario the foregut remains as a single-lumen tube.	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (108, 133))	('leads to', 'Reg', (38, 46))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (108, 133))	('tracheoesophageal fistula', 'Disease', (108, 133))	('esophageal atresia', 'Phenotype', 'HP:0002032', (73, 91))	('esophageal atresia', 'Disease', 'MESH:D004933', (73, 91))	('esophageal atresia', 'Disease', (73, 91))	('Disruption', 'Var', (0, 10))
825137	28007661	Abnormal activities of relevant signaling pathways or abnormal expression of the transcription factors have been associated with the pathogenesis of several common esophageal diseases including eosinophilic esophagitis, Barrett's esophagus, and even cancer.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('esophageal diseases', 'Disease', 'MESH:D004935', (164, 183))	('cancer', 'Disease', (250, 256))	('expression', 'MPA', (63, 73))	("Barrett's esophagus", 'Disease', (220, 239))	('activities', 'MPA', (9, 19))	('eosinophilic esophagitis', 'Disease', (194, 218))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (220, 239))	('eosinophilic esophagitis', 'Phenotype', 'HP:0410151', (194, 218))	('esophagitis', 'Phenotype', 'HP:0100633', (207, 218))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('esophageal diseases', 'Disease', (164, 183))	('abnormal', 'Var', (54, 62))	('signaling pathways', 'Pathway', (32, 50))	('associated', 'Reg', (113, 123))	('eosinophilic esophagitis', 'Disease', 'MESH:D004802', (194, 218))
825150	28007661	Abnormal levels of SOX2 have been associated with pathogenesis of multiple diseases such as anophthalmia-esophageal-genital (AEG) syndrome and even cancer malignancy.	('anophthalmia', 'Phenotype', 'HP:0000528', (92, 104))	('anophthalmia-esophageal-genital (AEG) syndrome', 'Disease', 'MESH:C565948', (92, 138))	('associated', 'Reg', (34, 44))	('even cancer malignancy', 'Disease', (143, 165))	('even cancer malignancy', 'Disease', 'MESH:D009369', (143, 165))	('Abnormal levels', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
825153	28007661	We showed that significant downregulation of SOX2 in the early foregut leads to EA/TEF in SOX2GFP/COND hypomorphic mouse mutants.	('EA/TEF', 'Disease', (80, 86))	('mutants', 'Var', (121, 128))	('mouse', 'Species', '10090', (115, 120))	('downregulation', 'NegReg', (27, 41))	('SOX2GFP/COND', 'Gene', (90, 102))
825156	28007661	It is possible that downregulation of SOX2 promotes the expansion of NKX2.1+ respiratory cells into the dorsal domain, thereby affecting the formation of the epithelial saddle at the very beginning of the separation process.	('NKX2.1', 'Gene', (69, 75))	('SOX2', 'Gene', (38, 42))	('formation of the epithelial saddle', 'CPA', (141, 175))	('downregulation', 'Var', (20, 34))	('NKX2.1', 'Gene', '21869', (69, 75))	('affecting', 'Reg', (127, 136))
825157	28007661	EA/TEF also develops in mutants lacking the Nkx2.1 gene, which is essential for early lung morphogenesis; deletion of NKX2.1 leads to severely hypoplastic lungs.	('hypoplastic lungs', 'Phenotype', 'HP:0002089', (143, 160))	('Nkx2.1', 'Gene', (44, 50))	('NKX2.1', 'Gene', (118, 124))	('hypoplastic lungs', 'Disease', 'None', (143, 160))	('NKX2.1', 'Gene', '21869', (118, 124))	('deletion', 'Var', (106, 114))	('leads to', 'Reg', (125, 133))	('hypoplastic lungs', 'Disease', (143, 160))	('Nkx2.1', 'Gene', '21869', (44, 50))
825158	28007661	In this case it is reasonable to postulate that Nkx2.1 deletion directly impacts the formation of the saddle which fails to move anteriorly to separate the esophagus from the trachea.	('formation', 'MPA', (85, 94))	('Nkx2.1', 'Gene', '21869', (48, 54))	('Nkx2.1', 'Gene', (48, 54))	('fails to move', 'Phenotype', 'HP:0003470', (115, 128))	('deletion', 'Var', (55, 63))	('impacts', 'Reg', (73, 80))
825160	28007661	It was previously shown that inhibition of SOX2 function leads to altered migration of neural progenitor cells in the chick neural tube.	('SOX2', 'Gene', (43, 47))	('inhibition', 'Var', (29, 39))	('altered', 'Reg', (66, 73))	('chick', 'Species', '9031', (118, 123))
825163	28007661	Along these lines examining cytoskeletal organization in the epithelial saddle may reveal surprising results in SOX2 or NKX2.1 mutants.	('SOX2', 'Gene', (112, 116))	('mutants', 'Var', (127, 134))	('NKX2.1', 'Gene', '21869', (120, 126))	('NKX2.1', 'Gene', (120, 126))
825164	28007661	Deletion of the Bmp antagonist Noggin leads to ectopic cartilage nodules in the TEF connecting the trachea and stomach, but whether/how mesenchymal specification contributes to tracheal-esophageal separation remains unknown.	('Noggin', 'Gene', '18121', (31, 37))	('Noggin', 'Gene', (31, 37))	('cartilage nodules', 'Disease', (55, 72))	('leads to', 'Reg', (38, 46))	('tracheal-esophageal separation', 'Phenotype', 'HP:0002575', (177, 207))	('ectopic', 'MPA', (47, 54))	('cartilage nodules', 'Disease', 'MESH:D002357', (55, 72))	('Deletion', 'Var', (0, 8))
825165	28007661	Nevertheless, heterozygous deletion of the transcription factor FOXF1 which is specifically expressed in the mesenchyme leads to reduced growth of the foregut and EA/TEF formation accompanied by fusion of right lung lobes on CD1 genetic background.	('FOXF1', 'Gene', '15227', (64, 69))	('CD1', 'Gene', (225, 228))	('CD1', 'Gene', '111334', (225, 228))	('deletion', 'Var', (27, 35))	('FOXF1', 'Gene', (64, 69))	('growth of the foregut', 'CPA', (137, 158))	('fusion', 'CPA', (195, 201))	('reduced', 'NegReg', (129, 136))
825166	28007661	The phenotypes are similar to what were observed in mutants having defects in sonic hedgehog (Shh) signaling, suggesting that FOXF1 is a downstream target of the pathway.	('Shh', 'Gene', '20423', (94, 97))	('sonic hedgehog', 'Gene', (78, 92))	('defects', 'NegReg', (67, 74))	('mutants', 'Var', (52, 59))	('FOXF1', 'Gene', (126, 131))	('sonic hedgehog', 'Gene', '20423', (78, 92))	('FOXF1', 'Gene', '15227', (126, 131))	('Shh', 'Gene', (94, 97))
825175	28007661	Deletion of the Barx1 gene leads to expansion of canonical Wnt signaling into the dorsal foregut and the mutants display EA/TEF.	('Barx1', 'Gene', (16, 21))	('canonical Wnt signaling into the dorsal foregut', 'MPA', (49, 96))	('Barx1', 'Gene', '12022', (16, 21))	('expansion', 'PosReg', (36, 45))	('mutants', 'Var', (105, 112))	('EA/TEF', 'CPA', (121, 127))	('Deletion', 'Var', (0, 8))
825178	28007661	Notably, it seems that loss of these Wnt antagonists occurs specifically in the foregut of the Barx1 null mutants.	('Barx1', 'Gene', (95, 100))	('Barx1', 'Gene', '12022', (95, 100))	('mutants', 'Var', (106, 113))
825181	28007661	For example, EA/TEF develops in mutants lacking the Bmp antagonist Noggin (Noggin-/-) or Bmp receptors (Shh-Cre; Bmpr1aloxp/-; Bmpr1b-/-), while loss of the Bmp ligand BMP4 results in transient expression of NKX2.1 in the tracheal field at E9.25-E10.5 and tracheal agenesis.	('Bmpr1a', 'Gene', '12166', (113, 119))	('Noggin-/-', 'Gene', (75, 84))	('Shh', 'Gene', '20423', (104, 107))	('Bmpr1a', 'Gene', (113, 119))	('Bmpr1b', 'Gene', (127, 133))	('Noggin-/-)', 'Gene', '18121', (75, 85))	('EA/TEF', 'Disease', (13, 19))	('NKX2.1', 'Gene', '21869', (208, 214))	('Noggin', 'Gene', (75, 81))	('Noggin', 'Gene', (67, 73))	('tracheal agenesis', 'CPA', (256, 273))	('NKX2.1', 'Gene', (208, 214))	('mutants', 'Var', (32, 39))	('BMP4', 'Gene', (168, 172))	('Bmpr1b', 'Gene', '12167', (127, 133))	('BMP4', 'Gene', '12159', (168, 172))	('lacking', 'NegReg', (40, 47))	('Noggin', 'Gene', '18121', (67, 73))	('loss', 'Var', (145, 149))	('Noggin', 'Gene', '18121', (75, 81))	('Shh', 'Gene', (104, 107))
825182	28007661	Moreover, loss of one copy of Bmp4 allele or deletion of Bmp7 rescues the separation defects in Noggin null background, further supporting that balanced Bmp signaling activities are required for the formation of an intact esophagus.	('loss', 'Var', (10, 14))	('Noggin', 'Gene', '18121', (96, 102))	('Noggin', 'Gene', (96, 102))	('Bmp4', 'Gene', '12159', (30, 34))	('rescues', 'PosReg', (62, 69))	('Bmp7', 'Gene', '12162', (57, 61))	('Bmp4', 'Gene', (30, 34))	('deletion', 'Var', (45, 53))	('separation defects', 'MPA', (74, 92))	('Bmp7', 'Gene', (57, 61))
825185	28007661	Consistent with these findings, Sox2 inactivation is able to restore NKX2.1 expression and normal tracheal-esophageal separation in Shh-Cre; Bmpr1aloxp/-; Bmpr1b-/-; Sox2loxp/loxp compounds.	('Bmpr1b', 'Gene', '12167', (155, 161))	('NKX2.1', 'Gene', (69, 75))	('Shh', 'Gene', '20423', (132, 135))	('Sox2', 'Gene', '20674', (32, 36))	('restore', 'PosReg', (61, 68))	('tracheal-esophageal separation', 'CPA', (98, 128))	('Sox2', 'Gene', (166, 170))	('NKX2.1', 'Gene', '21869', (69, 75))	('Sox2', 'Gene', '20674', (166, 170))	('Sox2', 'Gene', (32, 36))	('tracheal-esophageal separation', 'Phenotype', 'HP:0002575', (98, 128))	('Bmpr1b', 'Gene', (155, 161))	('expression', 'MPA', (76, 86))	('Bmpr1a', 'Gene', '12166', (141, 147))	('Bmpr1a', 'Gene', (141, 147))	('inactivation', 'Var', (37, 49))	('Shh', 'Gene', (132, 135))
825187	28007661	Both Wnt2/2b double knockouts (DKO) and Shh-Cre; beta-cateninloxp/loxp mutants display lung and tracheal agenesis.	('Wnt2', 'Gene', '22413', (5, 9))	('Wnt2', 'Gene', (5, 9))	('Shh', 'Gene', (40, 43))	('Shh', 'Gene', '20423', (40, 43))	('mutants', 'Var', (71, 78))
825188	28007661	The expression of NKX2.1 is lost in the mutants and the anterior foregut ends as a single-lumen tube lined by SOX2hi and p63hi esophageal precursors.	('p63', 'Gene', '22061', (121, 124))	('NKX2.1', 'Gene', (18, 24))	('expression', 'MPA', (4, 14))	('lost', 'NegReg', (28, 32))	('p63', 'Gene', (121, 124))	('mutants', 'Var', (40, 47))	('NKX2.1', 'Gene', '21869', (18, 24))
825192	28007661	In addition, Bmp signaling activities are maintained in the foregut of Shh-Cre; beta-cateninloxp/loxp mutants, suggesting that the canonical Wnt and Bmp signaling pathways act in parallel to promote respiratory cell fate and tracheal-esophageal separation.	('mutants', 'Var', (102, 109))	('tracheal-esophageal separation', 'CPA', (225, 255))	('Shh', 'Gene', (71, 74))	('tracheal-esophageal separation', 'Phenotype', 'HP:0002575', (225, 255))	('Shh', 'Gene', '20423', (71, 74))	('respiratory cell fate', 'CPA', (199, 220))	('promote', 'PosReg', (191, 198))
825195	28007661	Deletion of Shh or its downstream effectors GLI2 and GLI3 (GLI2-/-; GLI3+/-) leads to severely hypoplastic lungs and EA/TEF, consistent with the important roles for this pathway in foregut development.	('hypoplastic lungs', 'Phenotype', 'HP:0002089', (95, 112))	('GLI2', 'Gene', '14633', (44, 48))	('Shh', 'Gene', (12, 15))	('GLI2', 'Gene', '14633', (59, 63))	('Shh', 'Gene', '20423', (12, 15))	('hypoplastic lungs', 'Disease', 'None', (95, 112))	('GLI2', 'Gene', (44, 48))	('EA/TEF', 'CPA', (117, 123))	('hypoplastic lungs', 'Disease', (95, 112))	('GLI3', 'Gene', (53, 57))	('GLI3', 'Gene', '14634', (68, 72))	('GLI3', 'Gene', (68, 72))	('GLI2', 'Gene', (59, 63))	('GLI3', 'Gene', '14634', (53, 57))	('Deletion', 'Var', (0, 8))
825196	28007661	The levels of NKX2.1 are significantly reduced in the anterior foregut of GLI2-/-; GLI3+/- mutants accompanied by decreased expression of WNT2/2b and BMP4, supporting a crosstalk of multiple signaling pathways during lung morphogenesis and tracheal-esophageal separation.	('WNT2/2b', 'Gene', '22413;22414', (138, 145))	('levels', 'MPA', (4, 10))	('NKX2.1', 'Gene', (14, 20))	('BMP4', 'Gene', (150, 154))	('GLI3', 'Gene', '14634', (83, 87))	('GLI3', 'Gene', (83, 87))	('tracheal-esophageal separation', 'Phenotype', 'HP:0002575', (240, 270))	('NKX2.1', 'Gene', '21869', (14, 20))	('GLI2', 'Gene', (74, 78))	('decreased', 'NegReg', (114, 123))	('expression', 'MPA', (124, 134))	('mutants', 'Var', (91, 98))	('reduced', 'NegReg', (39, 46))	('WNT2/2b', 'Gene', (138, 145))	('BMP4', 'Gene', '12159', (150, 154))	('GLI2', 'Gene', '14633', (74, 78))
825202	28007661	Rat fetuses fed with food deficient for the RA precursor vitamin A exhibits lung agenesis, while mouse mutants lacking the RA-synthesizing enzyme retinaldehyde dehydrogenase 2 (Raldh2) also present lung agenesis and EA/TEF.	('RA', 'Chemical', 'MESH:D014212', (44, 46))	('RA', 'Chemical', 'MESH:D014212', (123, 125))	('Rat', 'Species', '10116', (0, 3))	('lung agenesis', 'Phenotype', 'HP:0005944', (76, 89))	('mutants', 'Var', (103, 110))	('lung agenesis', 'CPA', (76, 89))	('lung agenesis', 'Phenotype', 'HP:0005944', (198, 211))	('mouse', 'Species', '10090', (97, 102))	('EA/TEF', 'CPA', (216, 222))	('vitamin A', 'Chemical', 'MESH:D014801', (57, 66))	('lacking', 'NegReg', (111, 118))	('lung agenesis', 'CPA', (198, 211))	('Raldh2', 'Gene', '19378', (177, 183))	('retinaldehyde dehydrogenase 2', 'Gene', (146, 175))	('Raldh2', 'Gene', (177, 183))	('retinaldehyde dehydrogenase 2', 'Gene', '19378', (146, 175))
825214	28007661	It was reported that ciliated cells are transiently present in the developing esophagus, suggesting that the epithelial differentiation is arrested in p63 null mutant.	('p63', 'Gene', (151, 154))	('epithelial differentiation', 'CPA', (109, 135))	('null mutant', 'Var', (155, 166))	('p63', 'Gene', '22061', (151, 154))	('arrested', 'NegReg', (139, 147))
825220	28007661	Significant downregulation of SOX2 protein levels leads to a disorganized epithelium in hypomorphic Sox2GFP/COND mutants that have separated esophagus (~60% of total mutants).	('downregulation', 'NegReg', (12, 26))	('Sox2', 'Gene', (100, 104))	('Sox2', 'Gene', '20674', (100, 104))	('SOX2', 'MPA', (30, 34))	('mutants', 'Var', (113, 120))	('disorganized epithelium', 'CPA', (61, 84))
825221	28007661	In addition, SOX2 regulates the commitment of the epithelium to squamous cell fate, and the epithelial cells produce a large amount of mucins (Alcian blue+) in the esophagus of Sox2GFP/COND mutants.	('commitment', 'CPA', (32, 42))	('Sox2', 'Gene', '20674', (177, 181))	('regulates', 'Reg', (18, 27))	('mutants', 'Var', (190, 197))	('Alcian blue+', 'Chemical', 'MESH:D000423', (143, 155))	('Sox2', 'Gene', (177, 181))
825234	28007661	In the embryonic skin deletion of DeltaNp63 results in decreased levels of Jag1, Notch1 and Hes1 while the levels of Notch2, Notch3 and RBPjkappa are increased.	('levels', 'MPA', (65, 71))	('levels', 'MPA', (107, 113))	('Jag1', 'Gene', '16449', (75, 79))	('DeltaNp63', 'Gene', (34, 43))	('RBPj', 'Gene', (136, 140))	('Hes1', 'Gene', (92, 96))	('Hes1', 'Gene', '15205', (92, 96))	('deletion', 'Var', (22, 30))	('Notch3', 'Gene', '18131', (125, 131))	('Notch2', 'Gene', (117, 123))	('Notch2', 'Gene', '18129', (117, 123))	('Notch3', 'Gene', (125, 131))	('RBPj', 'Gene', '19664', (136, 140))	('decreased', 'NegReg', (55, 64))	('Notch1', 'Gene', '18128', (81, 87))	('Jag1', 'Gene', (75, 79))	('Notch1', 'Gene', (81, 87))	('DeltaNp63', 'Chemical', '-', (34, 43))
825236	28007661	While it remains to be determined whether deletion of p63 in the esophagus invokes similar changes in the expression of Notch pathway components, a recent study demonstrated that Notch3 knockdown blocks squamous differentiation of cultured esophageal epithelium.	('Notch', 'Gene', (120, 125))	('Notch', 'Gene', (179, 184))	('blocks', 'NegReg', (196, 202))	('Notch3', 'Gene', '18131', (179, 185))	('Notch3', 'Gene', (179, 185))	('Notch', 'Gene', '18128;18129;18131', (120, 125))	('squamous differentiation', 'CPA', (203, 227))	('p63', 'Gene', '22061', (54, 57))	('deletion', 'Var', (42, 50))	('p63', 'Gene', (54, 57))	('Notch', 'Gene', '18128;18129;18131', (179, 184))
825251	28007661	The authors further found that basal cells expressing high levels of Itgalpha6, ss4, and CD73 are more proliferative and less-differentiated, and retinoic acid treatment promotes self-renewal of this subpopulation.	('ss4', 'Gene', (80, 83))	('self-renewal', 'CPA', (179, 191))	('CD73', 'Gene', '23959', (89, 93))	('CD73', 'Gene', (89, 93))	('promotes', 'PosReg', (170, 178))	('less-differentiated', 'CPA', (121, 140))	('high levels', 'Var', (54, 65))	('Itgalpha6', 'Gene', (69, 78))	('retinoic acid', 'Chemical', 'MESH:D014212', (146, 159))	('proliferative', 'CPA', (103, 116))
825264	28007661	Deletion of Tbx1 leads to the loss of striated muscles in the esophagus while the smooth muscles remain throughout the esophagus.	('striated muscles', 'MPA', (38, 54))	('Tbx1', 'Gene', (12, 16))	('Tbx1', 'Gene', '21380', (12, 16))	('loss', 'NegReg', (30, 34))	('Deletion', 'Var', (0, 8))
825266	28007661	Deletion of Cdo leads to aberrantly proximal location of the boundary, achalasia and megaesophagus.	('leads to', 'Reg', (16, 24))	('Cdo', 'Gene', '57810', (12, 15))	('achalasia', 'Disease', (71, 80))	('achalasia', 'Disease', 'MESH:D004931', (71, 80))	('achalasia', 'Phenotype', 'HP:0002571', (71, 80))	('Cdo', 'Gene', (12, 15))	('Deletion', 'Var', (0, 8))
825268	28007661	Deletion of the Wnt signaling receptor Fz4 also affects the formation of the striated muscle, leading to esophageal distension.	('Fz4', 'Gene', '14366', (39, 42))	('Deletion', 'Var', (0, 8))	('Fz4', 'Gene', (39, 42))	('leading to', 'Reg', (94, 104))	('affects', 'Reg', (48, 55))	('formation of the striated muscle', 'CPA', (60, 92))	('esophageal', 'Disease', (105, 115))
825270	28007661	Foxp1+/-; Foxp2-/- mice also display abnormal smooth muscles, and the striated muscle is absent in the esophagus of the compound mutants.	('compound mutants', 'Var', (120, 136))	('smooth muscles', 'CPA', (46, 60))	('Foxp2', 'Gene', (10, 15))	('Foxp1', 'Gene', '108655', (0, 5))	('mice', 'Species', '10090', (19, 23))	('Foxp1', 'Gene', (0, 5))	('Foxp2', 'Gene', '114142', (10, 15))
825358	25330784	Although circumferential ARMS resulted in very good long-term control of GERD symptoms , it was related to stricture formation necessitating repeat balloon dilation.	('repeat balloon dilation', 'Disease', 'MESH:D000647', (141, 164))	('repeat balloon dilation', 'Disease', (141, 164))	('stricture', 'Disease', (107, 116))	('GERD symptoms', 'MPA', (73, 86))	('circumferential', 'Var', (9, 24))
825365	25330784	We also postulate some remodeling of mucosal flap valve as an effective antireflux mechanism at this anatomical level.	('his', 'Chemical', 'MESH:D006639', (97, 100))	('mucosal flap valve', 'Disease', 'MESH:D000070600', (37, 55))	('antireflux', 'MPA', (72, 82))	('mucosal flap valve', 'Disease', (37, 55))	('remodeling', 'Var', (23, 33))
825401	22174714	Fox proteins have many essential roles in embryonic development, and the mutation or dysregulation of FOX genes is often associated with disease, including cancer.	('dysregulation', 'Var', (85, 98))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('associated', 'Reg', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('FOX genes', 'Gene', (102, 111))	('mutation', 'Var', (73, 81))
825406	22174714	The transcriptional activity of FoxC2 in vascular endothelial cells is modulated by VEGF signaling, and FoxC2 is critical for the migration of endothelial cells toward VEGF or stromal-cell-derived factor 1 (SDF-1) and for the formation of microvessels in vitro.	('FoxC2', 'Var', (104, 109))	('transcriptional', 'MPA', (4, 19))	('SDF-1', 'Gene', '20315', (207, 212))	('VEGF', 'Gene', (168, 172))	('critical', 'Reg', (113, 121))	('VEGF', 'Gene', (84, 88))	('stromal-cell-derived factor 1', 'Gene', '20315', (176, 205))	('VEGF', 'Gene', '22339', (168, 172))	('FoxC2', 'Gene', (32, 37))	('stromal-cell-derived factor 1', 'Gene', (176, 205))	('VEGF', 'Gene', '22339', (84, 88))	('migration', 'CPA', (130, 139))	('SDF-1', 'Gene', (207, 212))
825411	22174714	FoxC2 is also expressed in lymphatic endothelial cells during development, and mutations in human FoxC2 are responsible for the autosomal dominant syndrome lymphedema distichiasis, which is characterized by the obstruction of lymph drainage in the limbs and by the growth of an extra set of eyelashes.	('distichiasis', 'Phenotype', 'HP:0009743', (167, 179))	('lymphedema', 'Phenotype', 'HP:0001004', (156, 166))	('extra set of eyelashes', 'Phenotype', 'HP:0008496', (278, 300))	('obstruction of lymph drainage', 'Phenotype', 'HP:0001004', (211, 240))	('autosomal dominant syndrome lymphedema distichiasis', 'Disease', 'MESH:C537710', (128, 179))	('responsible for', 'Reg', (108, 123))	('FoxC2', 'Gene', (98, 103))	('human', 'Species', '9606', (92, 97))	('mutations', 'Var', (79, 88))
825412	22174714	Congenital lymphatic defects are also observed in FoxC2 mutant mice: heterozygous FoxC2 mutants display hyperplasia of the lymphatic vessels, and homozygous FoxC2 mutants have defective lymphatic valves and abnormal pericyte recruitment of lymphatic vessels.	('Congenital lymphatic defects', 'Disease', (0, 28))	('Congenital lymphatic defects', 'Disease', 'MESH:D044148', (0, 28))	('pericyte recruitment of lymphatic vessels', 'CPA', (216, 257))	('hyperplasia', 'Disease', 'MESH:D006965', (104, 115))	('mutants', 'Var', (163, 170))	('mice', 'Species', '10090', (63, 67))	('FoxC2', 'Gene', (82, 87))	('FoxC2', 'Gene', (157, 162))	('hyperplasia of the lymphatic vessels', 'Phenotype', 'HP:0003759', (104, 140))	('defective', 'NegReg', (176, 185))	('mutants', 'Var', (88, 95))	('Congenital lymphatic defects', 'Phenotype', 'HP:0100763', (0, 28))	('hyperplasia', 'Disease', (104, 115))	('lymphatic valves', 'CPA', (186, 202))
825415	22174714	Homozygous mutations of FoxC2 lead to perinatal lethality, so the role of FoxC2 in melanoma was confirmed by subcutaneously implanting mouse B16 melanoma cells in wild-type and heterozygous FoxC2 mutant (FoxC2+/-) mice.	('perinatal lethality', 'CPA', (38, 57))	('lead to', 'Reg', (30, 37))	('FoxC2', 'Gene', (24, 29))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('FoxC2', 'Gene', (190, 195))	('mouse', 'Species', '10090', (135, 140))	('mutant', 'Var', (196, 202))	('mice', 'Species', '10090', (214, 218))	('melanoma', 'Disease', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
825417	22174714	Matrix metalloproteinase (MMP) 2 expression was also diminished in B16 tumors from FoxC2+/- mice, which is consistent with evidence that MMP2 is important for tumor growth and angiogenesis.	('diminished', 'NegReg', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('FoxC2+/-', 'Var', (83, 91))	('Matrix metalloproteinase (MMP) 2', 'Gene', '17390', (0, 32))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('expression', 'MPA', (33, 43))	('tumors', 'Disease', (71, 77))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('mice', 'Species', '10090', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
825419	22174714	VEGF-A expression was also impaired in B16 tumors from FoxC2+/- mice, and this decline likely limits tumor neovascularization.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('limits', 'NegReg', (94, 100))	('VEGF-A', 'Gene', (0, 6))	('tumor', 'Disease', (101, 106))	('VEGF-A', 'Gene', '22339', (0, 6))	('expression', 'MPA', (7, 17))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('FoxC2+/-', 'Var', (55, 63))	('impaired', 'NegReg', (27, 35))	('tumors', 'Disease', (43, 49))	('tumor', 'Disease', (43, 48))	('mice', 'Species', '10090', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
825420	22174714	The cells responsible for the decline in VEGF-A expression have yet to be identified; however, autocrine VEGF signaling promotes endothelial cell survival, and smooth muscle alpha-actin- (alphaSMA-) positive cancer-associated fibroblasts (CAFs), which are known to express VEGF-A in the tumor microenvironment, were less common in tumors from FoxC2+/- mice than in tumors from wild-type mice.	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('mice', 'Species', '10090', (387, 391))	('cancer', 'Disease', (208, 214))	('VEGF-A', 'Gene', '22339', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', (365, 371))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('VEGF', 'Gene', (105, 109))	('VEGF', 'Gene', (273, 277))	('VEGF-A', 'Gene', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (365, 371))	('tumor', 'Disease', (287, 292))	('VEGF', 'Gene', (41, 45))	('VEGF', 'Gene', '22339', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('VEGF', 'Gene', '22339', (273, 277))	('VEGF', 'Gene', '22339', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor', 'Disease', (365, 370))	('VEGF-A', 'Gene', '22339', (273, 279))	('mice', 'Species', '10090', (352, 356))	('tumors', 'Disease', (331, 337))	('less', 'NegReg', (316, 320))	('FoxC2+/-', 'Var', (343, 351))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('tumors', 'Phenotype', 'HP:0002664', (365, 371))	('tumor', 'Disease', (331, 336))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumors', 'Disease', 'MESH:D009369', (331, 337))	('VEGF-A', 'Gene', (273, 279))
825422	22174714	FoxC2 is also known to regulate the CXCR4-dependent mobilization of endothelial cells and bone-marrow-derived endothelial progenitor cells, so FoxC2 might have a bimodal influence on the contribution of bone-marrow-derived cells to tumor angiogenesis by increasing both cell mobilization and the SDF-1-mediated recruitment of mobilized cells to tumors.	('recruitment', 'CPA', (311, 322))	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('CXCR4', 'Gene', '12767', (36, 41))	('cell mobilization', 'CPA', (270, 287))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('increasing', 'PosReg', (254, 264))	('tumors', 'Phenotype', 'HP:0002664', (345, 351))	('tumor', 'Disease', (345, 350))	('CXCR4', 'Gene', (36, 41))	('SDF-1', 'Gene', (296, 301))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Disease', (345, 351))	('SDF-1', 'Gene', '20315', (296, 301))	('tumors', 'Disease', 'MESH:D009369', (345, 351))	('tumor', 'Disease', (232, 237))	('FoxC2', 'Var', (143, 148))
825428	22174714	The declines in tumor growth and vascularity observed in FoxC2+/- mice were also associated with abnormally low levels of PDGF-B, which is likely attributable to the impaired growth of smooth muscle cells surrounding the tumor blood vessels.	('declines', 'NegReg', (4, 12))	('FoxC2+/-', 'Var', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('PDGF-B', 'Gene', (122, 128))	('mice', 'Species', '10090', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('levels', 'MPA', (112, 118))	('low', 'NegReg', (108, 111))	('tumor', 'Disease', (16, 21))	('PDGF-B', 'Gene', '18591', (122, 128))	('vascularity', 'CPA', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
825430	22174714	The blockade of both VEGF and PDGF receptor-beta signaling in tumor blood vessels with kinase inhibitors also induces tumor vessel regression, and paracrine signaling between pericytes and the tumor endothelium could increase the instability of the tumor vessels of FoxC2+/- mice by reducing VEGF and PDGF-B signaling.	('VEGF', 'Gene', (292, 296))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('mice', 'Species', '10090', (275, 279))	('blockade', 'Var', (4, 12))	('VEGF', 'Gene', '22339', (21, 25))	('PDGF-B', 'Gene', (301, 307))	('VEGF', 'Gene', '22339', (292, 296))	('tumor', 'Disease', (249, 254))	('PDGF-B', 'Gene', '18591', (301, 307))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('reducing', 'NegReg', (283, 291))	('increase', 'PosReg', (217, 225))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (118, 123))	('VEGF', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
825432	22174714	FoxC2 expression has also been reported in esophageal cancer cells, and the survival rate is significantly lower for patients with high levels of FoxC2 expression than for patients with low levels of FoxC2 expression, which suggests that FoxC2 could be used as a novel, independent prognosis factor for patients with esophageal cancer (Table 1).	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('esophageal cancer', 'Disease', (317, 334))	('FoxC2', 'Gene', (146, 151))	('lower', 'NegReg', (107, 112))	('esophageal cancer', 'Disease', 'MESH:D004938', (317, 334))	('survival rate', 'CPA', (76, 89))	('patients', 'Species', '9606', (117, 125))	('high levels', 'Var', (131, 142))	('patients', 'Species', '9606', (172, 180))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('FoxC2', 'Gene', (0, 5))	('patients', 'Species', '9606', (303, 311))
825440	22174714	Notably, tumor cells undergoing EMT acquire a migratory phenotype by ectopically expressing mesenchymal genes, including FoxC2, which first function in the developing embryo, and tumor cells may adopt many other developmental signaling pathways that function in their ancestral precursor cells.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('migratory', 'CPA', (46, 55))	('FoxC2', 'Gene', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('ectopically', 'Var', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('adopt', 'Reg', (195, 200))	('tumor', 'Disease', (9, 14))	('mesenchymal genes', 'Gene', (92, 109))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
825523	21419224	demonstrated a statistically significant or borderline significant inverse association between green tea consumption and risk of esophageal cancer among never smokers (OR = 0.7, 95% CI = 0.5-0.9) or alcohol nondrinkers (OR = 0.8, 95% CI = 0.6-1.1), but not in smokers or alcohol drinkers.	('inverse', 'NegReg', (67, 74))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (271, 287))	('nondrinkers', 'Var', (207, 218))	('alcohol', 'Chemical', 'MESH:D000438', (199, 206))	('alcohol', 'Chemical', 'MESH:D000438', (271, 278))	('esophageal cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
825530	21419224	Using validated urinary biomarkers for tea polyphenol uptake and metabolism, the investigators demonstrated a decreased risk for both esophageal and gastric cancer for the presence of EGC in urine.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('presence', 'Var', (172, 180))	('EGC', 'Gene', (184, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('decreased', 'NegReg', (110, 119))	('polyphenol', 'Chemical', 'MESH:D059808', (43, 53))	('esophageal and gastric cancer', 'Disease', 'MESH:D013274', (134, 163))	('EGC', 'Chemical', 'MESH:C057580', (184, 187))
825531	21419224	The inverse association was stronger in nonsmokers or nondrinkers of alcohol or among those with lower serum level of carotenes (OR = 0.46, 95% CI = 0.26-0.84).	('serum level of carotenes', 'MPA', (103, 127))	('nondrinkers', 'Var', (54, 65))	('lower', 'NegReg', (97, 102))	('alcohol', 'Chemical', 'MESH:D000438', (69, 76))	('carotenes', 'Chemical', 'MESH:D002338', (118, 127))
825538	21419224	showing that high urinary EGC is inversely associated with risk of esophageal cancer.	('high urinary', 'Var', (13, 25))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('EGC', 'Chemical', 'MESH:C057580', (26, 29))
825628	21419224	In contrast, analyses from a population-based case-control study conducted in Shanghai, China (451 cases and 1552 controls) demonstrated a statistically significant inverse association with increased green tea consumption and pancreatic cancer risk.	('pancreatic cancer', 'Disease', 'MESH:D010190', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (226, 243))	('green tea consumption', 'Var', (200, 221))	('inverse', 'NegReg', (165, 172))	('pancreatic cancer', 'Disease', (226, 243))
825690	21419224	Of the five cohort studies, three reported a null association, one reported a postive, but statistically non-significant, association (RR=1.44; 95% CI: 0.89, 2.34; P for trend=0.12), and the remaining one found a statistically significant increased risk of breast cancer with high black tea intake (RR=1.22; 95% CI =1.05-1.42; P for trend=0.007).	('black tea', 'Species', '4442', (281, 290))	('high black', 'Var', (276, 286))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('breast cancer', 'Disease', (257, 270))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))
825699	21419224	Genetic polymorphisms in the enzymes that catalyze the metabolism of tea catechins may also introduce interindividual variability in the in vivo exposure to tea catechins.	('catechins', 'Chemical', 'MESH:D002392', (73, 82))	('introduce', 'Reg', (92, 101))	('catechins', 'Chemical', 'MESH:D002392', (161, 170))	('Genetic polymorphisms', 'Var', (0, 21))
825700	21419224	For example, a single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene results in the valine to methionine amino acid change in codon 108/158 in the cytosolic/membrane-bound form of the protein.	('COMT', 'Gene', '1312', (89, 93))	('valine to methionine amino acid change in codon 108', 'Mutation', 'rs4680', (115, 166))	('COMT', 'Gene', (89, 93))	('catechol-O-methyltransferase', 'Gene', (59, 87))	('single nucleotide polymorphism', 'Var', (15, 45))	('catechol-O-methyltransferase', 'Gene', '1312', (59, 87))	('results in', 'Reg', (100, 110))	('valine to methionine amino acid change', 'MPA', (115, 153))
825701	21419224	This amino acid change is believed to result in a 3- to 4-fold decrease in enzymatic activity, thus diminishing the elimination of tea catechins through urine and increasing the in vivo exposure to tea catechins.	('diminishing', 'NegReg', (100, 111))	('increasing', 'PosReg', (163, 173))	('catechins', 'Chemical', 'MESH:D002392', (202, 211))	('amino', 'Var', (5, 10))	('decrease', 'NegReg', (63, 71))	('catechins', 'Chemical', 'MESH:D002392', (135, 144))	('enzymatic activity', 'MPA', (75, 93))	('elimination of tea catechins through urine', 'MPA', (116, 158))	('change', 'Var', (16, 22))
825702	21419224	One study conducted in a Chinese population demonstrated that regular green tea drinkers with the homozygous low-activity AA COMT genotype had a 35% to 45% reduction in urinary levels of tea catechins as compared with green tea drinkers carrying at least one copy of high-activity COMT G allele.	('COMT', 'Gene', '1312', (125, 129))	('reduction', 'NegReg', (156, 165))	('urinary levels of tea catechins', 'MPA', (169, 200))	('COMT', 'Gene', (281, 285))	('low-activity AA', 'Var', (109, 124))	('COMT', 'Gene', (125, 129))	('catechins', 'Chemical', 'MESH:D002392', (191, 200))	('COMT', 'Gene', '1312', (281, 285))
825705	21419224	reported that consumption of either black tea or green tea was associated with statistically significant reduced risk of breast cancer for women carrying at least one copy of the low-activity COMT allele (OR=0.48; 95% CI: 0.29, 0.77) relative to nondrinkers.	('women', 'Species', '9606', (139, 144))	('COMT', 'Gene', (192, 196))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('low-activity', 'Var', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('reduced', 'NegReg', (105, 112))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('COMT', 'Gene', '1312', (192, 196))	('black tea', 'Species', '4442', (36, 45))
825804	21419224	Compared with nondrinkers, high intake of total tea catechins was associated with approximately 50% reduced risk (OR = 0.49, 95% CI = 0.27-0.91).	('reduced', 'NegReg', (100, 107))	('catechins', 'Chemical', 'MESH:D002392', (52, 61))	('high', 'Var', (27, 31))
825845	33964942	The same was true for targeted inhibition of the upstream regulatory STING protein while knockout of STING expression only delayed the ISG expression induction.	('inhibition', 'NegReg', (31, 41))	('ISG expression', 'MPA', (135, 149))	('knockout', 'Var', (89, 97))	('ISG', 'Chemical', '-', (135, 138))
825968	33964942	Disrupting the downstream transcription factor interferon regulatory factor 3 (IRF-3) in these cells completely abolished ISG induction and the observed radioresistance.	('interferon regulatory factor 3', 'Gene', (47, 77))	('interferon regulatory factor 3', 'Gene', '3661', (47, 77))	('ISG', 'Chemical', '-', (122, 125))	('IRF-3', 'Gene', '3661', (79, 84))	('IRF-3', 'Gene', (79, 84))	('Disrupting', 'Var', (0, 10))	('ISG induction', 'CPA', (122, 135))	('abolished', 'NegReg', (112, 121))	('radioresistance', 'CPA', (153, 168))
825979	33964942	In that regard, pattern-recognition receptors, such as Toll-like receptors, (TLRs) are known to activate innate type I IFN signaling and agonists of TLRs can improve the response to radiotherapy.	('IFN', 'Gene', '3439', (119, 122))	('TLR', 'Gene', (149, 152))	('improve', 'PosReg', (158, 165))	('activate', 'PosReg', (96, 104))	('IFN', 'Gene', (119, 122))	('TLR', 'Gene', (77, 80))	('agonists', 'Var', (137, 145))	('response to radiotherapy', 'CPA', (170, 194))	('TLR', 'Gene', '7099;170743', (149, 152))	('TLR', 'Gene', '7099;170743', (77, 80))
825981	33964942	Interestingly, RNA activated innate immune pathways controlled by RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated protein 5) are significantly less affected by loss-of-function mutations or epigenetic silencing as compared to STING and can be linked type I IFN signaling in a STING-independent manner.	('IFN', 'Gene', '3439', (294, 297))	('less', 'NegReg', (180, 184))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('retinoic acid-inducible gene I', 'Gene', '23586', (73, 103))	('innate immune pathways', 'Pathway', (29, 51))	('epigenetic silencing', 'Var', (227, 247))	('retinoic acid-inducible gene I', 'Gene', (73, 103))	('mutations', 'Var', (214, 223))	('IFN', 'Gene', (294, 297))	('melanoma differentiation-associated protein 5', 'Gene', (115, 160))	('RIG-I', 'Gene', '23586', (66, 71))	('loss-of-function', 'NegReg', (197, 213))	('MDA5', 'Gene', (109, 113))	('melanoma differentiation-associated protein 5', 'Gene', '64135', (115, 160))	('MDA5', 'Gene', '64135', (109, 113))	('RIG-I', 'Gene', (66, 71))
826134	30411076	Pregnancy-related outcomes were obtained from the MBR and included gestational diabetes, preeclampsia, caesarean delivery, low Apgar score (<7) at 5 minutes after birth, low birth weight (<2,500 g), extremely low birth weight (<1,500 g), small for gestational age (birth weight >2 SDs below the sex-specific mean birth weight for gestational age),16 congenital malformations as listed in the MBR, preterm birth (<37 weeks), very preterm birth (<32 weeks), stillbirth, and neonatal mortality (up to 28 days after delivery).	('preterm birth', 'Phenotype', 'HP:0001622', (429, 442))	('<2,500 g', 'Var', (188, 196))	('low', 'Var', (123, 126))	('preterm birth', 'Disease', (397, 410))	('preterm birth', 'Phenotype', 'HP:0001622', (397, 410))	('<1,500 g', 'Var', (227, 235))	('congenital malformations', 'Disease', 'MESH:D000013', (350, 374))	('small for gestational age', 'Phenotype', 'HP:0001518', (238, 263))	('low birth', 'Var', (170, 179))	('gestational diabetes', 'Phenotype', 'HP:0009800', (67, 87))	('preeclampsia', 'Phenotype', 'HP:0100602', (89, 101))	('Apgar score', 'Gene', (127, 138))	('birth weight >2', 'Phenotype', 'HP:0001520', (265, 280))	('gestational diabetes', 'Disease', (67, 87))	('low Apgar score', 'Phenotype', 'HP:0030917', (123, 138))	('low birth weight', 'Phenotype', 'HP:0001518', (170, 186))	('caesarean delivery', 'Phenotype', 'HP:0011410', (103, 121))	('gestational diabetes', 'Disease', 'MESH:D016640', (67, 87))	('low birth weight', 'Phenotype', 'HP:0001518', (209, 225))	('congenital malformations', 'Disease', (350, 374))
826243	28229058	A study that examined the effects of opium on bladder cancer reported that opium addicts develop bladder cancer at a younger age than non-addicts.	('opium', 'Var', (75, 80))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('bladder cancer', 'Disease', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
826263	22313682	In addition, silence of GADD45a expression in ESCC cells inhibited proliferation and promoted apoptosis.	('GADD45a', 'Gene', (24, 31))	('inhibited', 'NegReg', (57, 66))	('GADD45a', 'Gene', '1647', (24, 31))	('promoted', 'PosReg', (85, 93))	('proliferation', 'CPA', (67, 80))	('apoptosis', 'CPA', (94, 103))	('silence', 'Var', (13, 20))
826313	22313682	Moreover, in tissues from stages II, III and IV, the relative GADD45a mRNA levels were 4.0800 +- 1.30220,4.4936 +- 1.25856 and 4.3292 +- 2.69446 respectively.	('mRNA levels', 'MPA', (70, 81))	('4.3292 +- 2.69446', 'Var', (127, 144))	('GADD45a', 'Gene', '1647', (62, 69))	('GADD45a', 'Gene', (62, 69))
826317	22313682	The mean methylation status of most CG pairs was decreased in the tumor group; there were statistically significant difference in the overall combined mean methylation status between two groups (0.0545 +- 0.03067 vs 0.0255 +- 0.01788, P = 0.000).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('methylation status', 'MPA', (9, 27))	('decreased', 'NegReg', (49, 58))	('0.0545 +- 0.03067', 'Var', (195, 212))	('methylation', 'MPA', (156, 167))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CG', 'Chemical', 'MESH:C028505', (36, 38))	('0.0255 +- 0.01788', 'Var', (216, 233))
826321	22313682	As shown in Figure 5, we observed a decreased sensitivity of Eca109 and Kyse510 cells to DDP dependent of time and dose of GADD45alpha-siRNA transfection in the group with knock-down GADD45alpha (Figure 5A,B,C,D).	('DDP', 'Chemical', 'MESH:D002945', (89, 92))	('knock-down', 'Var', (172, 182))	('sensitivity', 'MPA', (46, 57))	('GADD45alpha', 'Gene', (183, 194))	('decreased', 'NegReg', (36, 45))
826332	22313682	In order to investigate the role of GADD45alpha in activating DNA demethylation, we explored the global DNA methylation condition and found global DNA hypomethylation in tumor tissues of ESCC.	('ESCC', 'Disease', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('hypomethylation', 'Var', (151, 166))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))
826333	22313682	Global DNA hypomethylation is considered as a feature of tumorigenic cells; it can cause chromosomal instability, reactivation of transposable elements, and loss of imprinting.	('Global DNA', 'Var', (0, 10))	('reactivation', 'MPA', (114, 126))	('chromosomal instability', 'Phenotype', 'HP:0040012', (89, 112))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('chromosomal instability', 'CPA', (89, 112))	('cause', 'Reg', (83, 88))	('imprinting', 'MPA', (165, 175))	('tumor', 'Disease', (57, 62))	('loss', 'NegReg', (157, 161))
826335	22313682	Promoter hypomethylation has been hypothesized to lead to carcinogenesis by encouraging genomic instability as well as by aberrant activation of oncogenes, thus promoter hypomethylation may participate in the development of ESCC.	('activation', 'PosReg', (131, 141))	('lead to', 'Reg', (50, 57))	('oncogenes', 'Gene', (145, 154))	('promoter hypomethylation', 'Var', (161, 185))	('participate', 'Reg', (190, 201))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('Promoter hypomethylation', 'Var', (0, 24))	('encouraging', 'PosReg', (76, 87))	('carcinogenesis', 'Disease', (58, 72))	('ESCC', 'Disease', (224, 228))	('genomic instability', 'CPA', (88, 107))
826340	22313682	Our finding showed that Eca109 and Kyse510 cells with knock-down GADD45alpha have decreased chemotherapeutic sensitivity to DDP, suggesting GADD45alpha may be play an important role in drug resistance of tumor cells.	('knock-down', 'Var', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('drug resistance', 'Phenotype', 'HP:0020174', (185, 200))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('chemotherapeutic sensitivity to DDP', 'MPA', (92, 127))	('tumor', 'Disease', (204, 209))	('DDP', 'Chemical', 'MESH:D002945', (124, 127))	('GADD45alpha', 'Gene', (65, 76))	('decreased', 'NegReg', (82, 91))
826341	22313682	In next work, we will investigate the mechanisms that GADD45alpha decreases chemotherapeutic sensitivity to DDP.	('chemotherapeutic sensitivity to DDP', 'MPA', (76, 111))	('GADD45alpha', 'Var', (54, 65))	('DDP', 'Chemical', 'MESH:D002945', (108, 111))	('decreases', 'NegReg', (66, 75))
826384	32110216	described a case of pneumothorax with pneumopericardium after lobectomy due to a connection between pleura and pericardium due to a tear in the pericardium.	('pneumopericardium', 'Disease', (38, 55))	('pneumothorax', 'Disease', (20, 32))	('tear', 'Phenotype', 'HP:0009926', (132, 136))	('pneumopericardium', 'Disease', 'MESH:D011026', (38, 55))	('tear', 'Var', (132, 136))	('pneumothorax', 'Phenotype', 'HP:0002107', (20, 32))
826517	32021418	Yan et al have shown that SNHG1 acts as a sponge for miR-338-3p in ESCC progression and the ceRNA regulatory SNHG11/miR-338-3p/CST3 axis decreases ESCC cell growth and induces apoptosis.	('SNHG11', 'Gene', (109, 115))	('ESCC', 'Disease', (67, 71))	('induces', 'Reg', (168, 175))	('miR-338-3p', 'Var', (53, 63))	('SNHG11', 'Gene', '128439', (109, 115))	('CST3', 'Gene', '1471', (127, 131))	('SNHG1', 'Gene', '23642', (26, 31))	('ESCC', 'Disease', (147, 151))	('SNHG1', 'Gene', '23642', (109, 114))	('decreases ESCC', 'Phenotype', 'HP:0025022', (137, 151))	('CST3', 'Gene', (127, 131))	('decreases', 'NegReg', (137, 146))	('apoptosis', 'CPA', (176, 185))	('ESCC', 'Disease', 'MESH:C562729', (67, 71))	('SNHG1', 'Gene', (109, 114))	('SNHG1', 'Gene', (26, 31))	('ESCC', 'Disease', 'MESH:C562729', (147, 151))
826644	31249451	Thus PlGF antibodies or PlGF knockout decreased neo-vascularization, splanchnic blood flow and portal pressure in animal models.	('decreased', 'NegReg', (38, 47))	('knockout', 'Var', (29, 37))	('PlGF', 'Gene', (5, 9))	('PlGF', 'Gene', '5228', (5, 9))	('PlGF', 'Gene', (24, 28))	('splanchnic blood flow', 'CPA', (69, 90))	('neo-vascularization', 'CPA', (48, 67))	('portal pressure', 'CPA', (95, 110))	('PlGF', 'Gene', '5228', (24, 28))
826657	31249451	Another study addressing the expression of Nogo-A in the liver was performed by Hao et al, where the authors reported that Nogo-A was highly expressed in four liver cancer cell lines in vitro and the depletion of Nogo-A protein suppressed cancer cell proliferation.	('Nogo-A', 'Gene', '57142', (213, 219))	('Nogo-A', 'Gene', '57142', (43, 49))	('Nogo-A', 'Gene', '57142', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('liver cancer', 'Phenotype', 'HP:0002896', (159, 171))	('liver cancer', 'Disease', 'MESH:D006528', (159, 171))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('Nogo-A', 'Gene', (43, 49))	('liver cancer', 'Disease', (159, 171))	('Nogo-A', 'Gene', (123, 129))	('cancer', 'Disease', (239, 245))	('Nogo-A', 'Gene', (213, 219))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('suppressed', 'NegReg', (228, 238))	('depletion', 'Var', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
826715	30697567	MIE was associated with longer median procedure times (443.0 versus 312.0 minutes; p<0.001), but a shorter median LOH stay (9.0 versus 10.0 days; p<0.001).	('shorter', 'NegReg', (99, 106))	('MIE', 'Chemical', '-', (0, 3))	('LOH stay', 'MPA', (114, 122))	('LOH', 'Chemical', '-', (114, 117))	('MIE', 'Var', (0, 3))
826720	30697567	MIE patients had more lymph nodes retrieved (15 versus 13; p=0.016) and shorter hospital stays (10 days versus 11 days; p=0.046).	('MIE', 'Chemical', '-', (0, 3))	('lymph nodes retrieved', 'CPA', (22, 43))	('more', 'PosReg', (17, 21))	('patients', 'Species', '9606', (4, 12))	('MIE', 'Var', (0, 3))
826721	30697567	A meta-analysis of 48 studies involving 14,311 patients revealed that compared to open patients, MIE patients experienced less in-hospital mortality, pulmonary complications, PE, and arrhythmias, with no differences in anastomotic leak.	('patients', 'Species', '9606', (101, 109))	('arrhythmias', 'Disease', 'MESH:D001145', (183, 194))	('arrhythmias', 'Disease', (183, 194))	('MIE', 'Chemical', '-', (97, 100))	('arrhythmias', 'Phenotype', 'HP:0011675', (183, 194))	('MIE', 'Var', (97, 100))	('pulmonary complications', 'Phenotype', 'HP:0006532', (150, 173))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (47, 55))	('pulmonary complications', 'Disease', (150, 173))	('anastomotic leak', 'Disease', 'MESH:D057868', (219, 235))	('less', 'NegReg', (122, 126))	('pulmonary complications', 'Disease', 'MESH:D008171', (150, 173))	('anastomotic leak', 'Disease', (219, 235))	('PE', 'Phenotype', 'HP:0002204', (175, 177))
826722	30697567	However, a systematic review and meta-analysis reporting on 6,058 patients treated between 1985 and 2015 resulted in higher hiatal hernia rates in MIE patients compared to open (4.5% versus 1%).	('hiatal hernia', 'Disease', 'MESH:D006551', (124, 137))	('hiatal hernia', 'Disease', (124, 137))	('patients', 'Species', '9606', (151, 159))	('hiatal hernia', 'Phenotype', 'HP:0002036', (124, 137))	('hernia', 'Phenotype', 'HP:0100790', (131, 137))	('higher', 'PosReg', (117, 123))	('MIE', 'Chemical', '-', (147, 150))	('MIE', 'Var', (147, 150))	('patients', 'Species', '9606', (66, 74))
826786	28410227	Therefore, the characterization of highly metastatic variants that were selected by in vivo selection may improve our understanding of the mechanisms driving cancer metastasis.	('cancer metastasis', 'Disease', 'MESH:D009362', (158, 175))	('cancer metastasis', 'Disease', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('variants', 'Var', (53, 61))
826897	27910892	Drug detoxifying enzyme aldehyde dehydrogenase (ALDH) positivity, as a poor prognostic factor, is identified in lung, prostate, breast, colon and esophageal cancers and has been linked to mesenchymal fate of cells and EMT.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mesenchymal fate of', 'CPA', (188, 207))	('DH', 'Disease', 'MESH:D065630', (50, 52))	('colon and esophageal cancers', 'Disease', 'MESH:D004938', (136, 164))	('breast', 'Disease', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('prostate', 'Disease', (118, 126))	('linked', 'Reg', (178, 184))	('lung', 'Disease', (112, 116))	('positivity', 'Var', (54, 64))
826928	27910892	have reported that docetaxel is not cytotoxic for low concentrations (<10 nM) and enhances cell death in concentration dependent manner.	('cell death', 'CPA', (91, 101))	('docetaxel', 'Var', (19, 28))	('enhances', 'PosReg', (82, 90))	('docetaxel', 'Chemical', 'MESH:D000077143', (19, 28))
826938	27910892	The presented platform can be further utilized in cancer research for understanding transcriptomic and genomic variations (e.g., signaling mechanisms, cellular heterogeneity, mutations) and controlling physiochemical parameters (e.g., pH and hypoxia level, matrix stiffness).	('hypoxia', 'Disease', (242, 249))	('hypoxia', 'Disease', 'MESH:D000860', (242, 249))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
826953	27910892	In Stokes flow, the average wall shear stress in the middle of channel is calculated as 1.44 x 10-5 Pa (or 14.4 x 10-5 dynes cm-2), according to the Equation (3) where mu is the dynamic viscosity of the fluid (0.000692 kg m-1 s-1), Q is the volumetric flow rate (2 muL min-1), h is the height of the microchannel (1.55 mm), and w is the width of the microchannel (4 mm).	('Stokes flow', 'Phenotype', 'HP:0012196', (3, 14))	('min-1', 'Gene', '966', (269, 274))	('min-1', 'Gene', (269, 274))	('0.000692', 'Var', (210, 218))
826974	27552970	We performed a systematic literature review to identify peer-reviewed human or animal in vivo original research studies of ghrelin, ghrelin-receptor agonists, or ghrelin genetic variants and the risk, presence, or growth of cancer using structured searches in PubMed database as well as secondary searches of article reference lists, additional reviews and meta-analyses.	('ghrelin', 'Gene', '58991', (123, 130))	('ghrelin', 'Gene', (123, 130))	('variants', 'Var', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ghrelin', 'Gene', '58991', (162, 169))	('human', 'Species', '9606', (70, 75))	('ghrelin', 'Gene', '58991', (132, 139))	('ghrelin', 'Gene', (132, 139))	('ghrelin', 'Gene', (162, 169))	('growth of cancer', 'Disease', 'MESH:D006130', (214, 230))	('growth of cancer', 'Disease', (214, 230))
826975	27552970	Overall, 45 (73.8%) of the 61 studies reviewed, including all 11 involving exogenous ghrelin/ghrelin-receptor agonist treatment, reported either a null (no statistically significant difference) or inverse association of ghrelin/ghrelin-receptor agonists or ghrelin genetic variants with cancer risk, presence or growth; 10 (16.7%) studies reported positive associations; and 6 (10.0%) reported both negative or null and positive associations.	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('ghrelin', 'Gene', '58991', (85, 92))	('ghrelin', 'Gene', '58991', (220, 227))	('ghrelin', 'Gene', (257, 264))	('ghrelin', 'Gene', '58991', (257, 264))	('ghrelin', 'Gene', (220, 227))	('ghrelin', 'Gene', '58991', (93, 100))	('ghrelin', 'Gene', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('associations', 'Interaction', (357, 369))	('ghrelin', 'Gene', (228, 235))	('ghrelin', 'Gene', '58991', (228, 235))	('men', 'Species', '9606', (123, 126))	('variants', 'Var', (273, 281))	('inverse', 'NegReg', (197, 204))	('ghrelin', 'Gene', (85, 92))
826983	27552970	Nonetheless, des-acyl ghrelin appears to have multiple physiologic actions, including modulation (agonism or antagonism) of several of ghrelin's actions that do not require the presence of the ghrelin receptor.	('des-acyl', 'Var', (13, 21))	('ghrelin', 'Gene', '58991', (135, 142))	('acyl', 'Chemical', '-', (17, 21))	('ghrelin receptor', 'Gene', '2693', (193, 209))	('modulation', 'Reg', (86, 96))	('ghrelin', 'Gene', '58991', (193, 200))	('ghrelin', 'Gene', (193, 200))	('ghrelin', 'Gene', (135, 142))	('ghrelin', 'Gene', '58991', (22, 29))	('ghrelin', 'Gene', (22, 29))	('ghrelin receptor', 'Gene', (193, 209))
826984	27552970	The existence of receptors specific to des-acyl ghrelin, as well as additional ghrelin receptors, has been proposed, but not yet demonstrated.	('acyl', 'Chemical', '-', (43, 47))	('ghrelin', 'Gene', '58991', (48, 55))	('ghrelin', 'Gene', (48, 55))	('ghrelin', 'Gene', (79, 86))	('ghrelin', 'Gene', '58991', (79, 86))	('ghrelin receptor', 'Gene', (79, 95))	('des-acyl', 'Var', (39, 47))	('ghrelin receptor', 'Gene', '2693', (79, 95))
826993	27552970	Some consequences of ghrelin dysregulation may be demonstrated in Prader-Willi syndrome, a neurogenetic disorder that is characterized by poor feeding and weight gain in early infancy followed by hyperphagia, impaired satiety, severe obesity, and multiple dysmorphic and psychocognitive developmental problems in childhood and adulthood.	('dysmorphic', 'Disease', (256, 266))	('a neurogenetic disorder', 'Disease', (89, 112))	('obesity', 'Disease', (234, 241))	('weight gain', 'Phenotype', 'HP:0004324', (155, 166))	('hyperphagia', 'Disease', (196, 207))	('hyperphagia', 'Disease', 'MESH:D006963', (196, 207))	('a neurogenetic disorder', 'Disease', 'MESH:D020271', (89, 112))	('obesity', 'Disease', 'MESH:D009765', (234, 241))	('men', 'Species', '9606', (294, 297))	('ghrelin', 'Gene', '58991', (21, 28))	('dysmorphic', 'Disease', 'None', (256, 266))	('developmental problems', 'Phenotype', 'HP:0001263', (287, 309))	('weight gain', 'Disease', 'MESH:D015430', (155, 166))	('Prader-Willi syndrome', 'Disease', (66, 87))	('hyperphagia', 'Phenotype', 'HP:0002591', (196, 207))	('ghrelin', 'Gene', (21, 28))	('poor feeding', 'Phenotype', 'HP:0011968', (138, 150))	('obesity', 'Phenotype', 'HP:0001513', (234, 241))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (66, 87))	('dysregulation', 'Var', (29, 42))	('weight gain', 'Disease', (155, 166))
826997	27552970	One rationale for this research is that endogenous ghrelin stimulates release of GH, which regulates IGF1 concentrations.	('endogenous', 'Var', (40, 50))	('GH', 'Gene', '2688', (81, 83))	('ghrelin', 'Gene', (51, 58))	('ghrelin', 'Gene', '58991', (51, 58))	('stimulates', 'PosReg', (59, 69))	('release of', 'MPA', (70, 80))
827015	27552970	Eligible items were published, original research, peer-reviewed, in vivo studies (including letters) that reported an association between endogenous ghrelin levels, the administration of ghrelin or ghrelin-receptor agonists, or ghrelin gene polymorphisms, with cancer incidence, presence, growth or metastasis, excluding noncancerous growths (e.g.	('growth', 'CPA', (289, 295))	('association', 'Interaction', (118, 129))	('polymorphisms', 'Var', (241, 254))	('ghrelin', 'Gene', '58991', (149, 156))	('ghrelin', 'Gene', '58991', (228, 235))	('cancer', 'Disease', (261, 267))	('ghrelin', 'Gene', '58991', (198, 205))	('cancer', 'Disease', (324, 330))	('metastasis', 'CPA', (299, 309))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('endogenous', 'MPA', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('ghrelin', 'Gene', (149, 156))	('ghrelin', 'Gene', (228, 235))	('ghrelin', 'Gene', '58991', (187, 194))	('ghrelin', 'Gene', (198, 205))	('ghrelin', 'Gene', (187, 194))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (324, 330))
827020	27552970	Of these 61 studies, 50 examined endogenous levels and actions of ghrelin or polymorphisms of ghrelin genes and 11 reported the effects of exogenously administered ghrelin or ghrelin-receptor agonist therapy in association with cancer.	('ghrelin', 'Gene', '58991', (164, 171))	('ghrelin', 'Gene', (164, 171))	('cancer', 'Disease', (228, 234))	('ghrelin', 'Gene', '58991', (66, 73))	('ghrelin', 'Gene', (175, 182))	('ghrelin', 'Gene', '58991', (175, 182))	('polymorphisms', 'Var', (77, 90))	('ghrelin', 'Gene', '58991', (94, 101))	('ghrelin', 'Gene', (66, 73))	('ghrelin', 'Gene', (94, 101))	('examined', 'Reg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
827022	27552970	Ten studies investigated the association between ghrelin gene polymorphisms and cancer risk (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ghrelin', 'Gene', '58991', (49, 56))	('ghrelin', 'Gene', (49, 56))	('investigated', 'Reg', (12, 24))	('polymorphisms', 'Var', (62, 75))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
827023	27552970	An overall count showed that 46 (75.4%) of the studies, including all 11 involving exogenous ghrelin/ghrelin-receptor agonist treatment, reported either a null (no statistically significant difference) or inverse association of ghrelin or ghrelin genetic variants with cancer risk, presence or growth; 9 (14.8%) studies reported positive associations; and 6 (9.8%), including 4 gene studies, reported both negative or null and positive associations (Tables 1 and 2).	('ghrelin', 'Gene', (239, 246))	('associations', 'Interaction', (338, 350))	('variants', 'Var', (255, 263))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('men', 'Species', '9606', (131, 134))	('cancer', 'Disease', (269, 275))	('ghrelin', 'Gene', '58991', (93, 100))	('ghrelin', 'Gene', (93, 100))	('ghrelin', 'Gene', '58991', (228, 235))	('ghrelin', 'Gene', (228, 235))	('ghrelin', 'Gene', '58991', (101, 108))	('ghrelin', 'Gene', (101, 108))	('ghrelin', 'Gene', '58991', (239, 246))	('inverse', 'NegReg', (205, 212))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
827024	27552970	Of the 49 noninterventional studies, 46 were clinical and 3 in animal models, including the 10 studies of genetic polymorphisms of ghrelin genes and cancer, of which 7 reported null or inverse results while 3 showed a link to increased risk (Table 1).	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ghrelin', 'Gene', '58991', (131, 138))	('ghrelin', 'Gene', (131, 138))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('polymorphisms', 'Var', (114, 127))
827034	27552970	Another nested case-control study within a population of 128,992 enrolled in a public health program between 1964 and 1969, including 52 cases of esophageal cancer identified by the year 2000, found a nonsignificant correlation of high serum ghrelin with reduced risk of esophageal cancer in overweight subjects vs controls matched for age, race, sex and date/site of blood draw (P=0.09 for trend), adjusted for BMI and Helicobacter pylori infection.	('reduced', 'NegReg', (255, 262))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('esophageal cancer', 'Disease', (271, 288))	('high', 'Var', (231, 235))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (420, 449))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('esophageal cancer', 'Disease', (146, 163))	('esophageal cancer', 'Disease', 'MESH:D004938', (271, 288))	('Helicobacter pylori infection', 'Disease', (420, 449))	('Helicobacter pylori infection', 'Disease', 'MESH:D016481', (420, 449))	('ghrelin', 'Gene', (242, 249))	('ghrelin', 'Gene', '58991', (242, 249))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('overweight', 'Phenotype', 'HP:0025502', (292, 302))
827035	27552970	In addition, an Australian case-control genetic study (774 esophageal cancer cases vs 1352 controls) found no correlation of the obesity-related ghrelin SNPs sampled (rs468677 (L90Q), rs696217 (M72L)) with esophageal cancer incidence.	('M72L', 'Mutation', 'rs696217', (194, 198))	('esophageal cancer', 'Disease', (59, 76))	('rs696217 (M72L', 'Var', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancer', 'Disease', (206, 223))	('obesity', 'Disease', 'MESH:D009765', (129, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('obesity', 'Disease', (129, 136))	('ghrelin', 'Gene', (145, 152))	('ghrelin', 'Gene', '58991', (145, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (206, 223))	('rs468677', 'Mutation', 'rs468677', (167, 175))	('rs468677 (L90Q', 'Var', (167, 181))	('L90Q', 'Mutation', 'rs468677', (177, 181))	('rs696217', 'Mutation', 'rs696217', (184, 192))	('obesity', 'Phenotype', 'HP:0001513', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
827063	27552970	Three studies assessed associations of multiple ghrelin gene polymorphisms with breast cancer risk.	('polymorphisms', 'Var', (61, 74))	('assessed', 'Reg', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ghrelin', 'Gene', '58991', (48, 55))	('ghrelin', 'Gene', (48, 55))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('associations', 'Interaction', (23, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
827064	27552970	A European study in 1359 breast cancer cases and 2389 matched controls found that carriers of the ghrelin rs171407-G allele had a significantly increased breast cancer risk (OR: 1.2, 95% CI: 1.0-1.4; P=0.02).	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('rs171407-G', 'Var', (106, 116))	('ghrelin', 'Gene', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('rs171407', 'Mutation', 'rs171407', (106, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('ghrelin', 'Gene', '58991', (98, 105))
827079	27552970	Deletion of the ghrelin gene had no significant effect on tumorigenesis in either model.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('ghrelin', 'Gene', '58991', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('ghrelin', 'Gene', (16, 23))	('Deletion', 'Var', (0, 8))
827085	27552970	On the other hand, an animal study did report similar in vitro and in vivo findings that experimental silencing or 'knockdown' of the ghrelin-receptor expression in murine models of endometrial cancer led to reduced tumor growth.	('ghrelin-receptor', 'Protein', (134, 150))	('tumor', 'Disease', (216, 221))	('endometrial cancer', 'Phenotype', 'HP:0012114', (182, 200))	('endometrial cancer', 'Disease', 'MESH:D016889', (182, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('men', 'Species', '9606', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('reduced', 'NegReg', (208, 215))	('murine', 'Species', '10090', (165, 171))	('silencing', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('endometrial cancer', 'Disease', (182, 200))	("'knockdown'", 'Var', (115, 126))
827104	27552970	This analysis found no clear, net effect of ghrelin gene polymorphisms on cancer risk (Table 1), which is consistent with the conclusions of previous meta-analyses that evaluated the same genetic study data across ghrelin and ghrelin-receptor SNPs in patients with varied cancer types.	('polymorphisms', 'Var', (57, 70))	('ghrelin', 'Gene', (214, 221))	('ghrelin', 'Gene', '58991', (226, 233))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('ghrelin', 'Gene', (226, 233))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('ghrelin', 'Gene', '58991', (44, 51))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('patients', 'Species', '9606', (251, 259))	('cancer', 'Disease', (272, 278))	('ghrelin', 'Gene', '58991', (214, 221))	('ghrelin', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
827123	25226614	Moreover, Defb4 silencing in vitro suppresses the tumor cell proliferation, mobility and invasion in esophageal SCC cell line KYSE-150.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('SCC', 'Gene', '6317', (112, 115))	('mobility', 'CPA', (76, 84))	('invasion', 'CPA', (89, 97))	('Defb4', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('silencing', 'Var', (16, 25))	('rat', 'Species', '10116', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('suppresses', 'NegReg', (35, 45))	('tumor', 'Disease', (50, 55))	('SCC', 'Gene', (112, 115))
827140	25226614	The alteration of HBD-2 expression is associated with the development of various diseases related to inflammation such as psoriasis, ulcerative colitis, tuberculosis, pancreatitis, and periodontitis, and associated with clinicopathological features.	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('rat', 'Species', '10116', (8, 11))	('psoriasis', 'Disease', 'MESH:D011565', (122, 131))	('periodontitis', 'Disease', (185, 198))	('pancreatitis', 'Disease', 'MESH:D010195', (167, 179))	('psoriasis', 'Disease', (122, 131))	('ulcerative colitis', 'Disease', 'MESH:D003093', (133, 151))	('pancreatitis', 'Disease', (167, 179))	('expression', 'MPA', (24, 34))	('inflammation', 'Disease', (101, 113))	('alteration', 'Var', (4, 14))	('associated', 'Reg', (204, 214))	('HBD-2', 'Gene', (18, 23))	('HBD-2', 'Gene', '1673', (18, 23))	('associated with', 'Reg', (38, 53))	('periodontitis', 'Disease', 'MESH:D010518', (185, 198))	('periodontitis', 'Phenotype', 'HP:0000704', (185, 198))	('tuberculosis', 'Disease', 'MESH:D014376', (153, 165))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (133, 151))	('tuberculosis', 'Disease', (153, 165))	('pancreatitis', 'Phenotype', 'HP:0001733', (167, 179))	('psoriasis', 'Phenotype', 'HP:0003765', (122, 131))	('ulcerative colitis', 'Disease', (133, 151))	('rat', 'Species', '10116', (137, 140))	('colitis', 'Phenotype', 'HP:0002583', (144, 151))
827149	25226614	Finally, we explored the functional role of HBD-2 in vitro and found that Defb4 knockdown significantly inhibits esophageal carcinoma cell proliferation and mobility.	('mobility', 'CPA', (157, 165))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (113, 133))	('knockdown', 'Var', (80, 89))	('Defb4', 'Gene', (74, 79))	('rat', 'Species', '10116', (146, 149))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (113, 133))	('inhibits', 'NegReg', (104, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('HBD-2', 'Gene', (44, 49))	('HBD-2', 'Gene', '1673', (44, 49))	('esophageal carcinoma', 'Disease', (113, 133))
827174	25226614	To further elucidate the function of HBD-2 in esophageal SCC, we first assessed HBD-2 expression in four esophageal SCC cell lines, KYSE-70, KYSE-150, KYSE-270 and KYSE-410, and one non-tumorigenic epithelial cell line, HET-1A.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('HBD-2', 'Gene', (80, 85))	('SCC', 'Gene', (116, 119))	('HBD-2', 'Gene', '1673', (80, 85))	('HBD-2', 'Gene', (37, 42))	('KYSE-150', 'Var', (141, 149))	('epithelia', 'Disease', 'None', (198, 207))	('SCC', 'Gene', '6317', (57, 60))	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('epithelia', 'Disease', (198, 207))	('SCC', 'Gene', '6317', (116, 119))	('HBD-2', 'Gene', '1673', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('SCC', 'Gene', (57, 60))
827177	25226614	As shown in Figure 5B, Defb4 siRNA inhibited protein expression of HBD-2 compared to negative control cells.	('HBD-2', 'Gene', (67, 72))	('HBD-2', 'Gene', '1673', (67, 72))	('protein expression', 'MPA', (45, 63))	('inhibited', 'NegReg', (35, 44))	('Defb4 siRNA', 'Var', (23, 34))
827179	25226614	The scratch wound healing assay was performed to determine whether Defb4 knockdown can suppress KYSE-150 cell mobility (Figure 5E).	('suppress', 'NegReg', (87, 95))	('Defb4', 'Gene', (67, 72))	('KYSE-150 cell mobility', 'CPA', (96, 118))	('rat', 'Species', '10116', (6, 9))	('knockdown', 'Var', (73, 82))
827183	25226614	We found that KYSE-150 cells transfected with Defb4 siRNA exhibits a significant reduction in number of migratory cells compared to control cells (Figure 5F).	('rat', 'Species', '10116', (107, 110))	('number of migratory cells', 'CPA', (94, 119))	('reduction', 'NegReg', (81, 90))	('Defb4', 'Var', (46, 51))
827187	25226614	Our data also demonstrated that the protein expression of HBD-2 in KYSE-150 is suppressed by PBIT, celecoxib, MK2206, an AKT inhibitor, BEZ235, a dual inhibitor of phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR), cyanidin-3-glucoside (C3G) and cyanidin-3-rutinoside (C3R) (two major anthocyanins in BRB), in a dose-dependent manner (Figure 6B).	('BEZ235', 'Chemical', 'MESH:C531198', (136, 142))	('AKT', 'Gene', '207', (121, 124))	('MK2206', 'Var', (110, 116))	('celecoxib', 'Chemical', 'MESH:D000068579', (99, 108))	('PBIT', 'Chemical', 'MESH:C118852', (93, 97))	('AKT', 'Gene', (121, 124))	('HBD-2', 'Gene', '1673', (58, 63))	('suppressed', 'NegReg', (79, 89))	('MK2206', 'Chemical', 'MESH:C548887', (110, 116))	('rat', 'Species', '10116', (21, 24))	('HBD-2', 'Gene', (58, 63))	('anthocyanins', 'Chemical', 'MESH:D000872', (307, 319))	('cyanidin-3-glucoside (C3G', 'Gene', '2889', (237, 262))	('protein expression', 'MPA', (36, 54))	('mTOR', 'Gene', (230, 234))	('mTOR', 'Gene', '2475', (230, 234))	('mammalian target of rapamycin', 'Gene', '2475', (194, 223))	('mammalian target of rapamycin', 'Gene', (194, 223))
827211	25226614	In addition, activations of NFkappaB and its upstream regulators, AKT and extracellular-signal-regulated kinase (ERK), are suppressed by HBD-2 knockdown (Figure S2B).	('NFkappaB', 'Gene', '4790', (28, 36))	('extracellular-signal-regulated kinase', 'Gene', '5594', (74, 111))	('AKT', 'Gene', (66, 69))	('suppressed', 'NegReg', (123, 133))	('extracellular-signal-regulated kinase', 'Gene', (74, 111))	('HBD-2', 'Gene', '1673', (137, 142))	('ERK', 'Gene', '5594', (113, 116))	('ERK', 'Gene', (113, 116))	('NFkappaB', 'Gene', (28, 36))	('HBD-2', 'Gene', (137, 142))	('knockdown', 'Var', (143, 152))	('activations', 'PosReg', (13, 24))	('AKT', 'Gene', '207', (66, 69))
827222	25226614	MK2206 and BEZ235 have been shown to inhibit tumor formation in xenograft mouse model (Chen unpublished data).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('BEZ235', 'Var', (11, 17))	('tumor', 'Disease', (45, 50))	('inhibit', 'NegReg', (37, 44))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('BEZ235', 'Chemical', 'MESH:C531198', (11, 17))	('mouse', 'Species', '10090', (74, 79))	('MK2206', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
827229	25226614	Moreover, silencing Defb4 suppresses cell proliferation and metastasis in vitro.	('Defb4', 'Gene', (20, 25))	('rat', 'Species', '10116', (49, 52))	('suppresses', 'NegReg', (26, 36))	('silencing', 'Var', (10, 19))
827244	25226614	The expression of Defb4 was determined using Taqman assays: Defb4 (Rn02532184_g1), using GAPDH as reference gene (Rn01775763_g1).	('Defb4', 'Gene', (60, 65))	('Rn02532184_g1', 'Var', (67, 80))	('GAPDH', 'Gene', '2597', (89, 94))	('GAPDH', 'Gene', (89, 94))
827258	25226614	To assess whether previously identified chemopreventive agents for esophageal SCC could modulate HBD-2, esophageal carcinoma cells were treated with different doses of PBIT, celecoxib, MK2206, BEZ235, C3G or C3R.	('PBIT', 'Chemical', 'MESH:C118852', (168, 172))	('HBD-2', 'Gene', (97, 102))	('HBD-2', 'Gene', '1673', (97, 102))	('celecoxib', 'Chemical', 'MESH:D000068579', (174, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('MK2206', 'Chemical', 'MESH:C548887', (185, 191))	('esophageal carcinoma', 'Disease', (104, 124))	('SCC', 'Gene', '6317', (78, 81))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (104, 124))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (104, 124))	('C3R', 'Var', (208, 211))	('BEZ235', 'Chemical', 'MESH:C531198', (193, 199))	('BEZ235', 'Var', (193, 199))	('C3G', 'Var', (201, 204))	('MK2206', 'Var', (185, 191))	('SCC', 'Gene', (78, 81))	('SCC', 'Phenotype', 'HP:0002860', (78, 81))
827307	24009024	Changes in the activity of the ZO-2 interacting transcription factor AP-1 are associated with certain cancers, suggesting that TJ-associated signaling is dysregulated in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('associated', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (170, 176))	('AP-1', 'Gene', '3726', (69, 73))	('activity', 'MPA', (15, 23))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('ZO-2', 'Gene', '9414', (31, 35))	('Changes', 'Var', (0, 7))	('ZO-2', 'Gene', (31, 35))	('AP-1', 'Gene', (69, 73))	('cancers', 'Disease', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
827310	24009024	However, whether these changes can induce tumorigenesis or if they are consequences of tumorigenesis remains unclear.	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('induce', 'Reg', (35, 41))	('changes', 'Var', (23, 30))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
827314	24009024	This suggests that some claudin genes were generated by gene duplication, and that adjacent genes may be coordinately regulated.	('claudin genes', 'Gene', (24, 37))	('gene duplication', 'Var', (56, 72))	('rat', 'Species', '10116', (47, 50))
827318	24009024	By contrast, PKA-mediated phosphorylation of claudin-16 increases Mg2+ transport.	('increases', 'PosReg', (56, 65))	('Mg2+ transport', 'MPA', (66, 80))	('claudin-16', 'Gene', '10686', (45, 55))	('phosphorylation', 'Var', (26, 41))	('claudin-16', 'Gene', (45, 55))	('Mg2+', 'Chemical', '-', (66, 70))
827319	24009024	Other proteins such as mutant WNK lysine-deficient protein kinase 4 (WNK4) also increase paracellular permeability by phosphorylating claudins.	('claudins', 'Protein', (134, 142))	('increase', 'PosReg', (80, 88))	('phosphorylating', 'MPA', (118, 133))	('WNK4', 'Gene', '65266', (69, 73))	('WNK4', 'Gene', (69, 73))	('WNK lysine-deficient protein kinase 4', 'Gene', '65266', (30, 67))	('paracellular permeability', 'MPA', (89, 114))	('WNK lysine-deficient protein kinase 4', 'Gene', (30, 67))	('mutant', 'Var', (23, 29))
827323	24009024	Mutations in claudin genes have been linked to several human diseases.	('Mutations', 'Var', (0, 9))	('linked', 'Reg', (37, 43))	('claudin genes', 'Gene', (13, 26))	('human', 'Species', '9606', (55, 60))
827324	24009024	Sclerosing cholangitis and ichthyosis are associated with CLDN1 mutation, and hypomagnesemia and hypercalcinuria have been linked to mutations in CLDN16 and CLDN19.	('ichthyosis', 'Disease', 'MESH:D007057', (27, 37))	('cholangitis', 'Phenotype', 'HP:0030151', (11, 22))	('CLDN1', 'Gene', (58, 63))	('CLDN16', 'Gene', '10686', (146, 152))	('CLDN16', 'Gene', (146, 152))	('Sclerosing cholangitis', 'Phenotype', 'HP:0030991', (0, 22))	('CLDN1', 'Gene', '9076', (146, 151))	('mutations', 'Var', (133, 142))	('Sclerosing cholangitis', 'Disease', 'MESH:D015209', (0, 22))	('CLDN1', 'Gene', '9076', (58, 63))	('mutation', 'Var', (64, 72))	('CLDN1', 'Gene', (157, 162))	('ichthyosis', 'Phenotype', 'HP:0008064', (27, 37))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (78, 92))	('hypercalcinuria', 'Phenotype', 'HP:0002150', (97, 112))	('associated', 'Reg', (42, 52))	('CLDN19', 'Gene', '149461', (157, 163))	('Sclerosing cholangitis', 'Disease', (0, 22))	('CLDN19', 'Gene', (157, 163))	('CLDN1', 'Gene', (146, 151))	('ichthyosis', 'Disease', (27, 37))	('hypomagnesemia and hypercalcinuria', 'Disease', 'MESH:C537153', (78, 112))	('CLDN1', 'Gene', '9076', (157, 162))	('linked', 'Reg', (123, 129))
827341	24009024	DNA hypermethylation is associated with the downregulation of CLDN11 in gastric cancer cells and CLDN7 in breast cancer cells.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CLDN11', 'Gene', '5010', (62, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('downregulation', 'NegReg', (44, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CLDN7', 'Gene', (97, 102))	('CLDN7', 'Gene', '1366', (97, 102))	('CLDN11', 'Gene', (62, 68))	('gastric cancer', 'Disease', (72, 86))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('hypermethylation', 'Var', (4, 20))
827342	24009024	The association between promoter DNA hypermethylation and low expression of claudin-1 was also reported in estrogen receptor-positive breast cancer.	('claudin-1', 'Gene', (76, 85))	('breast cancer', 'Disease', (134, 147))	('promoter DNA', 'Var', (24, 36))	('estrogen receptor', 'Gene', (107, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('expression', 'MPA', (62, 72))	('estrogen receptor', 'Gene', '2099', (107, 124))	('low', 'NegReg', (58, 61))	('claudin-1', 'Gene', '9076', (76, 85))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
827344	24009024	In addition to DNA methylation, our group reported that loss of repressive histone methylations, including H3K27me3 and H4K20me3, is also associated with the overexpression of claudin-3 and claudin-4 in ovarian cancer and claudin-4 in gastric cancer.	('claudin-3', 'Gene', (176, 185))	('claudin-3', 'Gene', '1365', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('ovarian cancer', 'Phenotype', 'HP:0100615', (203, 217))	('loss', 'NegReg', (56, 60))	('histone', 'Protein', (75, 82))	('gastric cancer', 'Disease', (235, 249))	('H4K20me3', 'Var', (120, 128))	('ovarian cancer', 'Disease', 'MESH:D010051', (203, 217))	('gastric cancer', 'Disease', 'MESH:D013274', (235, 249))	('claudin-4', 'Gene', (190, 199))	('overexpression', 'PosReg', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('claudin-4', 'Gene', (222, 231))	('gastric cancer', 'Phenotype', 'HP:0012126', (235, 249))	('ovarian cancer', 'Disease', (203, 217))	('H3K27me3', 'Var', (107, 115))
827345	24009024	Our study in ovarian cancer suggested that epigenetic derepression in addition to the well-known epigenetic inactivation of tumor suppressor genes may be a possible mechanism underlying the activation of cancer-associated genes.	('cancer', 'Disease', (204, 210))	('activation', 'PosReg', (190, 200))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('ovarian cancer', 'Phenotype', 'HP:0100615', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (13, 27))	('tumor', 'Disease', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('ovarian cancer', 'Disease', (13, 27))	('epigenetic derepression', 'Var', (43, 66))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
827347	24009024	Studies have shown that transcription factors and epigenetic modifications cooperate in the transcriptional regulation of claudin levels.	('rat', 'Species', '10116', (80, 83))	('transcriptional regulation of claudin levels', 'MPA', (92, 136))	('epigenetic modifications', 'Var', (50, 74))	('cooperate', 'Reg', (75, 84))
827355	24009024	Moreover, nonsteroidal anti-inflammatory drugs such as aspirin significantly decrease claudin-7 expression in association with p38 MAPK activation in gastric epithelial cancer cells.	('gastric epithelial cancer', 'Disease', 'MESH:D013274', (150, 175))	('gastric epithelial cancer', 'Disease', (150, 175))	('decrease', 'NegReg', (77, 85))	('expression', 'MPA', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('p38', 'Var', (127, 130))	('activation', 'PosReg', (136, 146))	('aspirin', 'Chemical', 'MESH:D001241', (55, 62))	('claudin-7', 'Protein', (86, 95))	('MAPK', 'Gene', (131, 135))	('epithelial cancer', 'Phenotype', 'HP:0031492', (158, 175))	('MAPK', 'Gene', '5595;5594;5595', (131, 135))
827361	24009024	For example, delocalization of claudin-1 and claudin-4 from TJs in bladder tumors and the effects of altered localization of claudin-7 on the invasiveness of esophageal carcinoma have been reported.	('bladder tumors', 'Disease', 'MESH:D001749', (67, 81))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (158, 178))	('bladder tumors', 'Phenotype', 'HP:0009725', (67, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('claudin-4', 'Gene', (45, 54))	('bladder tumors', 'Disease', (67, 81))	('invasiveness of esophageal carcinoma', 'Disease', 'MESH:D004938', (142, 178))	('claudin-1', 'Gene', '9076', (31, 40))	('delocalization', 'Var', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('invasiveness of esophageal carcinoma', 'Disease', (142, 178))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('claudin-1', 'Gene', (31, 40))
827370	24009024	Claudin-1 overexpressing colon cancer cells formed more colonies in soft agar than did control cells and increased the activity of matrix metalloproteinases (MMPs).	('overexpressing', 'Var', (10, 24))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('MMPs', 'Gene', (158, 162))	('MMPs', 'Gene', '4313;4318', (158, 162))	('colon cancer', 'Phenotype', 'HP:0003003', (25, 37))	('colon cancer', 'Disease', 'MESH:D015179', (25, 37))	('matrix metalloproteinases', 'Enzyme', (131, 156))	('increased', 'PosReg', (105, 114))	('activity', 'MPA', (119, 127))	('colonies in soft agar', 'CPA', (56, 77))	('Claudin-1', 'Gene', (0, 9))	('colon cancer', 'Disease', (25, 37))
827371	24009024	In contrast, inhibition of claudin-1 expression significantly decreased the anchorage-independent growth and invasion of metastatic colon cancer cells with a significant decrease in MMP-9 activity.	('anchorage-independent growth', 'CPA', (76, 104))	('claudin-1', 'Gene', (27, 36))	('MMP-9', 'Gene', '4318', (182, 187))	('decreased', 'NegReg', (62, 71))	('MMP-9', 'Gene', (182, 187))	('colon cancer', 'Disease', (132, 144))	('inhibition', 'Var', (13, 23))	('claudin-1', 'Gene', '9076', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('activity', 'MPA', (188, 196))	('invasion of metastatic', 'CPA', (109, 131))	('decrease', 'NegReg', (170, 178))	('colon cancer', 'Phenotype', 'HP:0003003', (132, 144))	('colon cancer', 'Disease', 'MESH:D015179', (132, 144))
827377	24009024	Claudin-1 knockdown in basal-like breast cancer cells decreases cell migration by affecting the expression of genes involved in EMT.	('affecting', 'Reg', (82, 91))	('rat', 'Species', '10116', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('expression of genes', 'MPA', (96, 115))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('decreases', 'NegReg', (54, 63))	('Claudin-1', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))	('cell migration', 'CPA', (64, 78))
827389	24009024	In this study, knockdown of claudin-3 and claudin-4 enhanced in vivo tumor growth and lung metastasis, whereas a significant growth increase was not observed in vitro.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('claudin-4', 'Gene', (42, 51))	('knockdown', 'Var', (15, 24))	('tumor', 'Disease', (69, 74))	('enhanced', 'PosReg', (52, 60))	('claudin-3', 'Gene', (28, 37))	('lung metastasis', 'CPA', (86, 101))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('claudin-3', 'Gene', '1365', (28, 37))
827390	24009024	TJ formation and cell adhesion is impaired in claudin-3 and claudin-4 knockdown ovarian cancer cells.	('ovarian cancer', 'Disease', (80, 94))	('claudin-3', 'Gene', '1365', (46, 55))	('cell adhesion', 'CPA', (17, 30))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('knockdown', 'Var', (70, 79))	('claudin-3', 'Gene', (46, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TJ formation', 'CPA', (0, 12))	('claudin-4', 'Gene', (60, 69))	('impaired', 'NegReg', (34, 42))
827393	24009024	This study also examined the expression of claudin-3 and claudin-4 in the distal fallopian tube and in tumors from the same patients in six cases of serous ovarian cancer, and high expression of these claudins in both sites was observed in all six patients, suggesting that claudin-3 and claudin-4 are normally expressed in the fallopian tube, and downregulation of claudin-3 or claudin-4 in ovarian cancer promotes tumor growth and metastatic behavior in vivo.	('ovarian cancer', 'Disease', 'MESH:D010051', (156, 170))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('claudin-3', 'Gene', '1365', (366, 375))	('tumors', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (400, 406))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (149, 170))	('patients', 'Species', '9606', (124, 132))	('ovarian cancer', 'Disease', (392, 406))	('tumor', 'Disease', (416, 421))	('ovarian cancer', 'Phenotype', 'HP:0100615', (392, 406))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (416, 421))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('tumor', 'Disease', (103, 108))	('serous ovarian cancer', 'Disease', (149, 170))	('claudin-3', 'Gene', (43, 52))	('claudin-4', 'Gene', (379, 388))	('downregulation', 'Var', (348, 362))	('claudin-3', 'Gene', (274, 283))	('patients', 'Species', '9606', (248, 256))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('promotes', 'PosReg', (407, 415))	('tumor', 'Phenotype', 'HP:0002664', (416, 421))	('metastatic behavior', 'CPA', (433, 452))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('claudin-3', 'Gene', '1365', (43, 52))	('ovarian cancer', 'Disease', 'MESH:D010051', (392, 406))	('claudin-3', 'Gene', (366, 375))	('claudin-3', 'Gene', '1365', (274, 283))
827394	24009024	investigated the effect of the knockdown of these proteins on the expression of EMT markers and showed that inhibition of claudin-3 and claudin-4 promotes EMT in ovarian cancer cells through the downregulation of E-cadherin, upregulation of Twist, and activation of the PI3K pathway.	('EMT', 'CPA', (155, 158))	('upregulation', 'PosReg', (225, 237))	('activation', 'PosReg', (252, 262))	('downregulation', 'NegReg', (195, 209))	('ovarian cancer', 'Phenotype', 'HP:0100615', (162, 176))	('Twist', 'CPA', (241, 246))	('PI3K pathway', 'Pathway', (270, 282))	('claudin-3', 'Gene', (122, 131))	('claudin-3', 'Gene', '1365', (122, 131))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ovarian cancer', 'Disease', 'MESH:D010051', (162, 176))	('inhibition', 'Var', (108, 118))	('E-cadherin', 'Protein', (213, 223))	('claudin-4', 'Gene', (136, 145))	('ovarian cancer', 'Disease', (162, 176))	('promotes', 'PosReg', (146, 154))
827403	24009024	Claudin-4 expression suppresses cell invasion and metastasis in pancreatic cancer.	('Claudin-4', 'Gene', '1364', (0, 9))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('Claudin-4', 'Gene', (0, 9))	('suppresses', 'NegReg', (21, 31))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))	('expression', 'Var', (10, 20))
827406	24009024	The function of claudin-3 or claudin-4 is regulated by phosphorylation via kinases as well as by forced or knockdown expression.	('knockdown', 'Var', (107, 116))	('function', 'MPA', (4, 12))	('claudin-3', 'Gene', '1365', (16, 25))	('claudin-3', 'Gene', (16, 25))	('claudin-4', 'Gene', (29, 38))	('phosphorylation', 'MPA', (55, 70))	('regulated', 'Reg', (42, 51))
827407	24009024	For example, phosphorylation of claudin-3 and claudin-4 by PKA or PKC increases paracellular permeability in ovarian cancer cells via mislocalization of claudins.	('mislocalization', 'MPA', (134, 149))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PKC increases paracellular permeability in ovarian cancer', 'Disease', 'MESH:C537180', (66, 123))	('claudin-3', 'Gene', '1365', (32, 41))	('phosphorylation', 'Var', (13, 28))	('claudin-3', 'Gene', (32, 41))	('claudins', 'Protein', (153, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))
827413	24009024	A recent study suggested a novel role for claudin-6 as a receptor for CPE by showing that the CPE sensitivity of an ovarian cancer cell line that does not express claudin-3 and claudin-4 is decreased in response to claudin-6 knockdown, while ovarian cell lines resistant to the effects of CPE can be made sensitive through claudin-6 overexpression.	('claudin-3', 'Gene', '1365', (163, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (116, 130))	('claudin-3', 'Gene', (163, 172))	('knockdown', 'Var', (225, 234))	('CPE', 'Gene', '10874406', (94, 97))	('ovarian cancer', 'Disease', (116, 130))	('CPE', 'Gene', '10874406', (289, 292))	('CPE', 'Gene', '10874406', (70, 73))	('CPE', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CPE', 'Gene', (70, 73))	('decreased', 'NegReg', (190, 199))	('CPE', 'Gene', (289, 292))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))
827419	24009024	Claudin-7 overexpression in colorectal cancer cells disrupts cell polarization, enhances beta-catenin/Tcf activity and cell proliferation, and thereby promotes tumor formation in vivo in xenograft mice injected with claudin-7 overexpressing colorectal cancer cells.	('cell polarization', 'CPA', (61, 78))	('colorectal cancer', 'Disease', (241, 258))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mice', 'Species', '10090', (197, 201))	('Claudin-7', 'Gene', (0, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('Tcf', 'Gene', '3172', (102, 105))	('Tcf', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('enhances', 'PosReg', (80, 88))	('cell proliferation', 'CPA', (119, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (241, 258))	('overexpression', 'Var', (10, 24))	('disrupts', 'NegReg', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', (160, 165))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('rat', 'Species', '10116', (131, 134))	('promotes', 'PosReg', (151, 159))	('colorectal cancer', 'Disease', (28, 45))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('activity', 'MPA', (106, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (241, 258))
827421	24009024	The migration and invasion of ovarian cancer cells is also enhanced by claudin-7 overexpression.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('migration', 'CPA', (4, 13))	('enhanced', 'PosReg', (59, 67))	('ovarian cancer', 'Disease', (30, 44))	('rat', 'Species', '10116', (7, 10))	('invasion', 'CPA', (18, 26))	('overexpression', 'Var', (81, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))	('claudin-7', 'Protein', (71, 80))
827426	24009024	Claudin-11 decreases the invasiveness of bladder cancer cells, and knockdown of claudin-11 in glioma stem cells promotes cell proliferation, supporting its tumor suppressor function.	('cell proliferation', 'CPA', (121, 139))	('invasiveness of bladder cancer', 'Disease', (25, 55))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('tumor', 'Disease', (156, 161))	('Claudin-11', 'Gene', '5010', (0, 10))	('claudin-11', 'Gene', '5010', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('knockdown', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('invasiveness of bladder cancer', 'Disease', 'MESH:D001749', (25, 55))	('rat', 'Species', '10116', (133, 136))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('decreases', 'NegReg', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('claudin-11', 'Gene', (80, 90))	('Claudin-11', 'Gene', (0, 10))	('promotes', 'PosReg', (112, 120))	('glioma', 'Disease', (94, 100))	('glioma', 'Disease', 'MESH:D005910', (94, 100))
827439	24009024	comprehensively analyzed the clinical and molecular characteristics of the claudin-low subtype of breast cancer in comparison to those of the other subtypes and showed that claudin-low breast tumors are correlated with poor prognosis and enriched in mesenchymal and mammary stem cell-like features.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('breast tumors', 'Phenotype', 'HP:0100013', (185, 198))	('claudin-low', 'Var', (173, 184))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast tumors', 'Disease', 'MESH:D001943', (185, 198))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('breast tumors', 'Disease', (185, 198))
827441	24009024	Collectively, these results may support the high association between low claudin expression and the features of mammary CSC/TICs.	('TIC', 'Phenotype', 'HP:0100033', (124, 127))	('claudin', 'Protein', (73, 80))	('TICs', 'Phenotype', 'HP:0100033', (124, 128))	('TIC', 'Disease', 'None', (124, 127))	('low', 'Var', (69, 72))	('TIC', 'Disease', (124, 127))	('expression', 'MPA', (81, 91))
827450	24009024	First, knockdown of claudin-4 expression in ovarian cancer cells delayed spheroid formation, suggesting the involvement of claudin-4 in the regulation of spheroid formation.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian cancer', 'Disease', 'MESH:D010051', (44, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (44, 58))	('delayed', 'NegReg', (65, 72))	('spheroid formation', 'CPA', (73, 91))	('ovarian cancer', 'Disease', (44, 58))	('knockdown', 'Var', (7, 16))	('claudin-4', 'Gene', (20, 29))
827455	24009024	Independent of its effect on CSC/TICs, overexpressed miR-155 in colorectal cancer cells promotes the migration and invasion of cells through the upregulation of claudin-1 expression.	('upregulation', 'PosReg', (145, 157))	('invasion of cells', 'CPA', (115, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('miR-155', 'Gene', (53, 60))	('colorectal cancer', 'Disease', (64, 81))	('claudin-1', 'Gene', '9076', (161, 170))	('migration', 'CPA', (101, 110))	('TIC', 'Disease', 'None', (33, 36))	('miR-155', 'Gene', '406947', (53, 60))	('overexpressed', 'Var', (39, 52))	('TIC', 'Disease', (33, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('TICs', 'Phenotype', 'HP:0100033', (33, 37))	('promotes', 'PosReg', (88, 96))	('expression', 'MPA', (171, 181))	('claudin-1', 'Gene', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TIC', 'Phenotype', 'HP:0100033', (33, 36))	('rat', 'Species', '10116', (104, 107))
827469	24009024	Consistent with this study, several lines of evidence support the association of high claudin-4 expression with chemoresistance of ovarian cancer.	('ovarian cancer', 'Disease', (131, 145))	('claudin-4', 'Gene', (86, 95))	('association', 'Interaction', (66, 77))	('high', 'Var', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'MPA', (96, 106))	('chemoresistance', 'CPA', (112, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (131, 145))	('ovarian cancer', 'Disease', 'MESH:D010051', (131, 145))
827474	24009024	reported that high claudin-7 protein expression is significantly associated with shorter progression-free survival and poor sensitivity to platinum-based chemotherapy in ovarian cancer patients.	('ovarian cancer', 'Disease', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('progression-free survival', 'CPA', (89, 114))	('platinum', 'Chemical', 'MESH:D010984', (139, 147))	('high', 'Var', (14, 18))	('claudin-7', 'Gene', (19, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (170, 184))	('patients', 'Species', '9606', (185, 193))	('protein', 'Protein', (29, 36))	('expression', 'MPA', (37, 47))	('ovarian cancer', 'Disease', 'MESH:D010051', (170, 184))	('shorter', 'NegReg', (81, 88))
827475	24009024	In line with these clinical observations, claudin-7 knockdown was shown to increase the sensitivity of ovarian cancer cells to cisplatin treatment in this study.	('claudin-7', 'Gene', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('knockdown', 'Var', (52, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('increase', 'PosReg', (75, 83))	('ovarian cancer', 'Disease', (103, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('sensitivity', 'MPA', (88, 99))
827478	24009024	showed that knockdown of claudin-3 or claudin-4 increases the resistance to cisplatin in ovarian cancer cells in vitro and in vivo.	('claudin-4', 'Gene', (38, 47))	('resistance to cisplatin', 'MPA', (62, 85))	('claudin-3', 'Gene', '1365', (25, 34))	('increases', 'PosReg', (48, 57))	('ovarian cancer', 'Disease', 'MESH:D010051', (89, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('knockdown', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ovarian cancer', 'Disease', (89, 103))	('ovarian cancer', 'Phenotype', 'HP:0100615', (89, 103))	('claudin-3', 'Gene', (25, 34))
827483	24009024	that showed an association between high claudin-7 expression and poor sensitivity to platinum-based chemotherapy in ovarian cancer.	('claudin-7', 'Protein', (40, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (116, 130))	('ovarian cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))	('high', 'Var', (35, 39))	('platinum', 'Chemical', 'MESH:D010984', (85, 93))	('expression', 'MPA', (50, 60))
827493	24009024	Furthermore, pathway enrichment analysis identified several key biological pathways repressed by DNA hypermethylation or activated by DNA hypomethylation, and CLDN11 was identified as one of the genes involved in pathways repressed by DNA hypermethylation during the development of cisplatin resistance.	('cisplatin', 'Chemical', 'MESH:D002945', (282, 291))	('hypermethylation', 'Var', (101, 117))	('CLDN11', 'Gene', '5010', (159, 165))	('activated', 'PosReg', (121, 130))	('CLDN11', 'Gene', (159, 165))
827502	24009024	Claudin expression has also been reported as a prognostic indicator as dysregulated claudin expression is associated with the prognosis of cancer patients (Table 4).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('associated', 'Reg', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('dysregulated', 'Var', (71, 83))	('claudin', 'Protein', (84, 91))	('patients', 'Species', '9606', (146, 154))	('expression', 'MPA', (92, 102))	('cancer', 'Disease', (139, 145))
827508	24009024	By contrast, ovarian serous adenocarcinoma patients with high claudin-3 expression show a significantly shorter survival than those with low claudin-3 expression, while claudin-4 expression is not associated with patient survival in this cancer.	('claudin-3', 'Gene', (62, 71))	('cancer', 'Disease', (238, 244))	('claudin-3', 'Gene', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('claudin-3', 'Gene', '1365', (141, 150))	('high', 'Var', (57, 61))	('patient', 'Species', '9606', (43, 50))	('patients', 'Species', '9606', (43, 51))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (13, 42))	('shorter', 'NegReg', (104, 111))	('patient', 'Species', '9606', (213, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('ovarian serous adenocarcinoma', 'Disease', (13, 42))	('survival', 'MPA', (112, 120))	('claudin-3', 'Gene', '1365', (62, 71))
827511	24009024	A study investigating the clinical significance of claudin-4 in breast cancer showed that high claudin-4 expression is associated with significantly shorter overall survival and recurrence-free survival, suggesting a relationship between high claudin-4 expression and poor outcomes of patients with breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('breast cancer', 'Disease', 'MESH:D001943', (299, 312))	('recurrence-free survival', 'CPA', (178, 202))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('breast cancer', 'Disease', (299, 312))	('breast cancer', 'Phenotype', 'HP:0003002', (299, 312))	('shorter', 'NegReg', (149, 156))	('patients', 'Species', '9606', (285, 293))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('high', 'Var', (90, 94))	('overall survival', 'CPA', (157, 173))	('expression', 'MPA', (105, 115))	('claudin-4', 'Gene', (95, 104))	('breast cancer', 'Disease', (64, 77))
827516	24009024	Conversely, positive claudin-4 expression was associated with shorter disease-free survival and claudin-3 was related to longer disease-free survival in luminal types of breast cancer.	('shorter', 'NegReg', (62, 69))	('claudin-3', 'Gene', '1365', (96, 105))	('luminal types', 'Disease', (153, 166))	('expression', 'MPA', (31, 41))	('disease-free survival', 'CPA', (70, 91))	('longer', 'PosReg', (121, 127))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('claudin-3', 'Gene', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', (170, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('positive', 'Var', (12, 20))	('claudin-4', 'Gene', (21, 30))
827518	24009024	One study showed that strong claudin-4 expression is more frequently associated with the intestinal type than the diffuse type of gastric cancer, and high claudin-4 expression is significantly associated with shorter survival, while another study showed that overall survival is decreased in patients with low claudin-4 expression.	('intestinal type', 'Disease', (89, 104))	('claudin-4', 'Protein', (29, 38))	('decreased', 'NegReg', (279, 288))	('gastric cancer', 'Disease', (130, 144))	('associated', 'Reg', (69, 79))	('high', 'Var', (150, 154))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('expression', 'MPA', (39, 49))	('patients', 'Species', '9606', (292, 300))	('shorter', 'NegReg', (209, 216))
827519	24009024	Our group recently reported that high membranous claudin-4 expression is related to better prognosis, while cytoplasmic claudin-4 expression has no significant relationship with patient prognosis.	('expression', 'MPA', (59, 69))	('high membranous', 'Var', (33, 48))	('patient', 'Species', '9606', (178, 185))	('better', 'PosReg', (84, 90))
827520	24009024	Importantly, this study demonstrated that high membranous claudin-4 expression is an independent positive prognostic factor in gastric carcinoma.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (127, 144))	('expression', 'MPA', (68, 78))	('gastric carcinoma', 'Disease', 'MESH:D013274', (127, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('gastric carcinoma', 'Disease', (127, 144))	('high membranous', 'Var', (42, 57))	('rat', 'Species', '10116', (31, 34))
827525	24009024	A recent study further supported the poor prognostic significance of claudin-7 expression in ductal invasive breast cancer by showing that claudin-7 expression is associated with a shorter time to recurrence.	('ductal invasive breast cancer', 'Disease', 'MESH:D018270', (93, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('shorter', 'NegReg', (181, 188))	('claudin-7 expression', 'Var', (139, 159))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ductal invasive breast cancer', 'Disease', (93, 122))	('expression', 'Var', (149, 159))
827530	24009024	An association between claudin-10 gene expression and disease recurrence in hepatocellular carcinoma was suggested by the finding that patients with high expression of claudin-10 had shorter disease-free survival.	('claudin-10', 'Gene', '9071', (23, 33))	('disease-free survival', 'CPA', (191, 212))	('patients', 'Species', '9606', (135, 143))	('association', 'Interaction', (3, 14))	('claudin-10', 'Gene', '9071', (168, 178))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (76, 100))	('claudin-10', 'Gene', (23, 33))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('shorter', 'NegReg', (183, 190))	('hepatocellular carcinoma', 'Disease', (76, 100))	('claudin-10', 'Gene', (168, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('high expression', 'Var', (149, 164))
827532	24009024	Antibodies that specifically recognize the extracellular loops of human claudin-3 or claudin-4 have been successfully produced, and the anti-claudin-4 antibody has shown therapeutic antitumor activity in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('anti-claudin-4', 'Var', (136, 150))	('human', 'Species', '9606', (66, 71))	('claudin-3', 'Gene', (72, 81))	('tumor', 'Disease', (186, 191))	('claudin-3', 'Gene', '1365', (72, 81))
827556	24039884	miRNA is a kind of single-stranded non-coding small RNA that regulates gene expression at the posttranscriptional level by base-pairing with protein-coding mRNAs.	('gene expression', 'MPA', (71, 86))	('regulates', 'Reg', (61, 70))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('base-pairing', 'Var', (123, 135))
827615	24039884	To identify whether these miRNAs were related to human disease, disease information of miRNAs was extracted from the miR2Disease database (March 2011), a manually curated database that provides a comprehensive record of miRNA deregulation involved in various human diseases, including cancers.	('cancers', 'Disease', (285, 292))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('human', 'Species', '9606', (49, 54))	('miR', 'Gene', '220972', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('miR', 'Gene', (220, 223))	('human', 'Species', '9606', (259, 264))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', (117, 120))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('cancers', 'Disease', 'MESH:D009369', (285, 292))	('deregulation', 'Var', (226, 238))
827630	24039884	These results indicate that the dysregulation miRNAs might also play significant and extensive roles in the initiation or development of ESCC through the regulation numerous disease pathways.	('miR', 'Gene', (46, 49))	('disease pathways', 'Pathway', (174, 190))	('dysregulation', 'Var', (32, 45))	('ESCC', 'Disease', (137, 141))	('miR', 'Gene', '220972', (46, 49))
827681	24039884	One group contained 42 patients with high miR-338-3p and low miR-31 expression levels, while the other group was comprised of 47 patients with low miR-338-3p and high miR-31 expression levels.	('miR-31', 'Gene', '407035', (167, 173))	('high', 'Var', (37, 41))	('miR-31', 'Gene', '407035', (61, 67))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('miR', 'Gene', (167, 170))	('patients', 'Species', '9606', (23, 31))	('miR', 'Gene', '220972', (167, 170))	('low', 'NegReg', (57, 60))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))	('patients', 'Species', '9606', (129, 137))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('miR-31', 'Gene', (61, 67))	('miR-31', 'Gene', (167, 173))
827715	24039884	Upregulation of hsa-miR-21 promotes the proliferation, migration and inhibition of apoptosis of ESCC cells through activating the ERK1/2/MAPK pathway, while its knockdown suppresses cell growth, invasion and induced apoptosis by targeting FASL, TIMP3 and RECK genes.	('FASL', 'Gene', (239, 243))	('invasion', 'CPA', (195, 203))	('proliferation', 'CPA', (40, 53))	('inhibition', 'CPA', (69, 79))	('induced', 'Reg', (208, 215))	('migration', 'CPA', (55, 64))	('promotes', 'PosReg', (27, 35))	('RECK', 'Gene', (255, 259))	('knockdown', 'Var', (161, 170))	('cell growth', 'CPA', (182, 193))	('apoptosis', 'CPA', (83, 92))	('ERK1/2', 'Gene', '5595;5594', (130, 136))	('TIMP3', 'Gene', (245, 250))	('TIMP3', 'Gene', '7078', (245, 250))	('apoptosis', 'CPA', (216, 225))	('activating', 'PosReg', (115, 125))	('RECK', 'Gene', '8434', (255, 259))	('hsa-miR-21', 'Gene', (16, 26))	('targeting', 'Reg', (229, 238))	('Upregulation', 'PosReg', (0, 12))	('FASL', 'Gene', '356', (239, 243))	('suppresses', 'NegReg', (171, 181))	('ERK1/2', 'Gene', (130, 136))	('hsa-miR-21', 'Gene', '406991', (16, 26))
827725	24039884	ESCC patients with high-levels of serum miR-31 also have a poorer prognosis in relapse-free survival.	('patients', 'Species', '9606', (5, 13))	('miR-31', 'Gene', '407035', (40, 46))	('relapse-free survival', 'CPA', (79, 100))	('ESCC', 'Disease', (0, 4))	('high-levels', 'Var', (19, 30))	('miR-31', 'Gene', (40, 46))
827726	24039884	Recently, miR-338-3p has also been proven to be downregulated in ESCC, and its aberrant expression increases the risk of ESCC.	('downregulated', 'NegReg', (48, 61))	('aberrant expression', 'Var', (79, 98))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))	('ESCC', 'Disease', (121, 125))	('ESCC', 'Disease', (65, 69))	('increases', 'PosReg', (99, 108))
827763	20924366	In one study, 17pLOH in biopsy specimens from patients with Barrett's esophagus was associated with a 3 year cumulative incidence of cancer of 38% regardless of the presence or absence of dysplasia.	('absence of dysplasia', 'Disease', (177, 197))	('patients', 'Species', '9606', (46, 54))	('17pLOH', 'Var', (14, 20))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (60, 79))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('absence of dysplasia', 'Disease', 'MESH:D004832', (177, 197))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
827766	20924366	For example, a combination panel of aneuploidy/increased tetraploidy, 17pLOH, and 9pLOH (the chromosomal locus for p16) has been investigated in patients with Barrett's esophagus.	('patients', 'Species', '9606', (145, 153))	('9pLOH', 'Var', (82, 87))	('aneuploidy', 'Disease', 'MESH:D000782', (36, 46))	('p16', 'Gene', '1029', (115, 118))	('tetraploidy', 'MPA', (57, 68))	('aneuploidy', 'Disease', (36, 46))	("Barrett's esophagus", 'Disease', (159, 178))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (159, 178))	('p16', 'Gene', (115, 118))
827771	20924366	Amplification of the ERBB2 gene and/or overexpression of HER2, the protein product of ERBB2, have been identified in breast, ovarian, esophageal adenocarcinoma, and gastric cancers, amongst others.	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('breast', 'Disease', (117, 123))	('HER2', 'Gene', '2064', (57, 61))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (134, 159))	('ovarian', 'Disease', (125, 132))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (134, 159))	('identified', 'Reg', (103, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('esophageal adenocarcinoma', 'Disease', (134, 159))	('ERBB2', 'Gene', (86, 91))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('HER2', 'Gene', (57, 61))	('ERBB2', 'Gene', '2064', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('ERBB2', 'Gene', (21, 26))	('overexpression', 'PosReg', (39, 53))	('Amplification', 'Var', (0, 13))	('gastric cancers', 'Disease', (165, 180))	('gastric cancers', 'Disease', 'MESH:D013274', (165, 180))	('ERBB2', 'Gene', '2064', (21, 26))	('gastric cancers', 'Phenotype', 'HP:0012126', (165, 180))
827785	20924366	Patients identified by abnormal pepsinogen ratio can then be referred for endoscopic evaluation.	('abnormal', 'Var', (23, 31))	('Patients', 'Species', '9606', (0, 8))	('pepsinogen ratio', 'MPA', (32, 48))
827788	20924366	The majority of patients with HDGC carry mutations in the tumor suppressor gene CDH1, also known as E-cadherin.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('HDGC', 'Disease', (30, 34))	('CDH1', 'Gene', (80, 84))	('patients', 'Species', '9606', (16, 24))	('CDH1', 'Gene', '999', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('E-cadherin', 'Gene', (100, 110))	('E-cadherin', 'Gene', '999', (100, 110))
827789	20924366	CDH1 mutations have been described in diffuse-type, but not intestinal-type gastric cancer.	('described', 'Reg', (25, 34))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('CDH1', 'Gene', '999', (0, 4))	('diffuse-type', 'Disease', (38, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('CDH1', 'Gene', (0, 4))	('gastric cancer', 'Disease', (76, 90))
827792	20924366	Sequencing of the coding region of CDH1, as well as deletion/duplication analysis, is available for clinical testing (Table 2).	('deletion/duplication', 'Var', (52, 72))	('CDH1', 'Gene', '999', (35, 39))	('CDH1', 'Gene', (35, 39))
827793	20924366	Molecular testing for CDH1 mutations has a detection rate of about 30% in patients who meet clinical criteria for a diagnosis of HDGC in the absence of a known familial disease-causing mutation.	('mutations', 'Var', (27, 36))	('CDH1', 'Gene', '999', (22, 26))	('patients', 'Species', '9606', (74, 82))	('detection', 'Reg', (43, 52))	('CDH1', 'Gene', (22, 26))	('HDGC', 'Disease', (129, 133))
827794	20924366	Since current data suggest that a prophylactic total gastrectomy should be considered in asymptomatic CDH1 mutation carriers, mutation testing for HDGC should never be performed without the support of appropriate genetic and clinical counseling.	('CDH1', 'Gene', '999', (102, 106))	('mutation', 'Var', (107, 115))	('CDH1', 'Gene', (102, 106))
827800	20924366	Since most GISTs respond to targeted therapy with imatinib, it is essential to differentiate GISTs from other tumors considered in the differential diagnosis.	('respond', 'Reg', (17, 24))	('targeted', 'Var', (28, 36))	('imatinib', 'Chemical', 'MESH:D000068877', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('imatinib', 'MPA', (50, 58))
827803	20924366	In addition, mutations in the KIT and PDGFRA genes can be used as biomarkers to aid in predicting a therapeutic response to imatinib therapy; KIT mutations can also be used to predict overall prognosis (Table 2).	('PDGFRA', 'Gene', (38, 44))	('imatinib', 'Chemical', 'MESH:D000068877', (124, 132))	('mutations', 'Var', (146, 155))	('PDGFRA', 'Gene', '5156', (38, 44))	('predict', 'Reg', (176, 183))	('aid', 'Gene', '57379', (80, 83))	('KIT', 'Gene', (30, 33))	('mutations', 'Var', (13, 22))	('aid', 'Gene', (80, 83))
827804	20924366	For example, GIST patients with KIT exon 11 mutations show a significantly higher partial response rate to imatinib (83.5%) than those with KIT exon 9 mutations, no mutations, or mutations in PDGFRA (47.8%).	('PDGFRA', 'Gene', '5156', (192, 198))	('imatinib', 'Chemical', 'MESH:D000068877', (107, 115))	('PDGFRA', 'Gene', (192, 198))	('higher', 'PosReg', (75, 81))	('mutations', 'Var', (44, 53))	('patients', 'Species', '9606', (18, 26))	('KIT exon 11', 'Gene', (32, 43))	('partial response', 'MPA', (82, 98))
827805	20924366	Furthermore, patients whose GISTs harbored KIT exon 11 mutations also had a longer event-free and overall survival than those whose tumors contained KIT exon 9 mutations, wild-type KIT, or wild-type PDGFRA.	('PDGFRA', 'Gene', (199, 205))	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('longer', 'PosReg', (76, 82))	('tumors', 'Disease', (132, 138))	('overall survival', 'CPA', (98, 114))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('KIT exon 11', 'Gene', (43, 54))	('PDGFRA', 'Gene', '5156', (199, 205))
827806	20924366	Additionally, patients with exon 9 mutations in KIT treated with imatinib had a relative risk of disease progression of 171% and a relative risk of death of 190% compared to those treated patients with exon 11 KIT mutations.	('KIT', 'Gene', (48, 51))	('imatinib', 'Chemical', 'MESH:D000068877', (65, 73))	('exon 9 mutations', 'Var', (28, 44))	('disease progression', 'CPA', (97, 116))	('patients', 'Species', '9606', (188, 196))	('death', 'Disease', 'MESH:D003643', (148, 153))	('death', 'Disease', (148, 153))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (35, 44))
827807	20924366	In patients with exon 9 KIT mutations, improved progression-free survival could be achieved with a higher dose of imatinib (800mg vs. 400 mg/day).	('imatinib', 'Chemical', 'MESH:D000068877', (114, 122))	('patients', 'Species', '9606', (3, 11))	('improved', 'PosReg', (39, 47))	('mutations', 'Var', (28, 37))	('KIT', 'Gene', (24, 27))
827810	20924366	Since mutations in the KIT gene are biomarkers of therapeutic response to imatinib, mutation analyses should be pursued regardless of whether the tumor is KIT (CD117) positive or negative by immunohistochemistry.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('KIT', 'Gene', (23, 26))	('imatinib', 'Chemical', 'MESH:D000068877', (74, 82))	('CD117', 'Gene', '3815', (160, 165))	('CD117', 'Gene', (160, 165))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
827833	20924366	The molecular analysis consisted of sequencing of the first exon of KRAS to identify a point mutation, loss of heterozygosity (LOH) in a panel 15 of tumor suppressor genes, and determination of DNA quantity and quantity.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('loss', 'Var', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('KRAS', 'Gene', (68, 72))	('tumor', 'Disease', (149, 154))	('KRAS', 'Gene', '3845', (68, 72))
827834	20924366	The most specific test for detecting mucinous cysts in this cohort was the presence of a KRAS mutation in exon 1 (96% specificity), however the sensitivity was low (45%).	('mucinous cyst', 'Phenotype', 'HP:0200040', (37, 50))	('presence', 'Var', (75, 83))	('mucinous cysts', 'Phenotype', 'HP:0200040', (37, 51))	('KRAS', 'Gene', (89, 93))	('mucinous cysts', 'Disease', (37, 51))	('mutation', 'Var', (94, 102))	('KRAS', 'Gene', '3845', (89, 93))
827851	20924366	Mutations of KRAS which activate signaling have been found to confer resistance to anti-EGFR monoclonal antibody therapies.	('resistance', 'MPA', (69, 79))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (88, 92))	('KRAS', 'Gene', (13, 17))	('EGFR', 'Gene', (88, 92))	('KRAS', 'Gene', '3845', (13, 17))
827852	20924366	In fact, the National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines recommend that all metastatic colorectal tumors should be tested for KRAS mutations before beginning anti-EGFR monoclonal antibody therapy and only in those patients whose tumors contain wild-type KRAS should therapy be initiated.	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('EGFR', 'Gene', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('KRAS', 'Gene', (173, 177))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('Cancer', 'Disease', (36, 42))	('colorectal tumors', 'Disease', 'MESH:D015179', (134, 151))	('tumors', 'Disease', (276, 282))	('EGFR', 'Gene', '1956', (210, 214))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('Oncology', 'Phenotype', 'HP:0002664', (84, 92))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('KRAS', 'Gene', '3845', (301, 305))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('tested', 'Reg', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('KRAS', 'Gene', (301, 305))	('tumors', 'Disease', (145, 151))	('KRAS', 'Gene', '3845', (173, 177))	('patients', 'Species', '9606', (261, 269))	('mutations', 'Var', (178, 187))	('colorectal tumors', 'Disease', (134, 151))
827853	20924366	In general, mutations in KRAS have been found in 30-40% of all colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('mutations', 'Var', (12, 21))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('colorectal cancers', 'Disease', 'MESH:D015179', (63, 81))	('found', 'Reg', (40, 45))	('colorectal cancers', 'Disease', (63, 81))	('KRAS', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('KRAS', 'Gene', '3845', (25, 29))
827857	20924366	Familial adenomatous polyposis (FAP) is an autosomal dominant colon cancer predisposition syndrome, caused by mutations in the APC tumor suppressor gene.	('Familial adenomatous polyposis', 'Disease', 'MESH:D011125', (0, 30))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('caused by', 'Reg', (100, 109))	('mutations', 'Var', (110, 119))	('Familial adenomatous polyposis', 'Disease', (0, 30))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (9, 30))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('FAP', 'Disease', (32, 35))	('APC tumor', 'Disease', (127, 136))	('autosomal dominant colon cancer', 'Disease', (43, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (62, 74))	('FAP', 'Disease', 'MESH:C567782', (32, 35))	('APC tumor', 'Disease', 'MESH:D011125', (127, 136))	('autosomal dominant colon cancer', 'Disease', 'MESH:D015179', (43, 74))
827861	20924366	FAP is most commonly caused by nonsense or frameshift mutations in APC which lead to premature protein truncation and loss of APC function.	('APC', 'Disease', (67, 70))	('loss of APC function', 'Disease', 'MESH:D011125', (118, 138))	('loss of APC function', 'Disease', (118, 138))	('premature', 'MPA', (85, 94))	('FAP', 'Disease', 'MESH:C567782', (0, 3))	('APC', 'Disease', 'MESH:D011125', (126, 129))	('APC', 'Disease', (126, 129))	('nonsense', 'Var', (31, 39))	('frameshift mutations', 'Var', (43, 63))	('caused by', 'Reg', (21, 30))	('FAP', 'Disease', (0, 3))	('protein', 'Protein', (95, 102))	('APC', 'Disease', 'MESH:D011125', (67, 70))
827862	20924366	Full gene sequencing is currently the gold standard for detecting APC mutations (Table 5).	('APC', 'Disease', (66, 69))	('mutations', 'Var', (70, 79))	('APC', 'Disease', 'MESH:D011125', (66, 69))
827865	20924366	reported finding mutations in both alleles of the MUTYH gene in a British family with recessive inheritance of colorectal adenomas and cancer.	('MUTYH', 'Gene', (50, 55))	('cancer', 'Disease', (135, 141))	('MUTYH', 'Gene', '4595', (50, 55))	('colorectal adenomas', 'Disease', (111, 130))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colorectal adenomas', 'Disease', 'MESH:D015179', (111, 130))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
827869	20924366	brain, endometrium, hepatobiliary tract, ovary, pancreas, skin, stomach, small intestine, and upper urinary tract) as a result of a germline mutation in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, and possibly MLH3).	('MSH6', 'Gene', '2956', (198, 202))	('germline mutation', 'Var', (132, 149))	('endometrium', 'Disease', (7, 18))	('hepatobiliary tract', 'Disease', 'MESH:D004066', (20, 39))	('MSH2', 'Gene', (192, 196))	('MSH2', 'Gene', '4436', (192, 196))	('MLH3', 'Gene', '27030', (223, 227))	('MLH3', 'Gene', (223, 227))	('ovary', 'Disease', (41, 46))	('MSH6', 'Gene', (198, 202))	('pancreas', 'Disease', (48, 56))	('ovary', 'Disease', 'MESH:D010051', (41, 46))	('hepatobiliary tract', 'Disease', (20, 39))	('MMR', 'Gene', (174, 177))	('PMS2', 'Gene', (204, 208))	('MLH1', 'Gene', (186, 190))	('PMS2', 'Gene', '5395', (204, 208))	('MLH1', 'Gene', '4292', (186, 190))
827870	20924366	Germline mutations in MLH1 and MSH2 account for the vast majority of mutations in HNPCC families (approximately 90%).	('Germline mutations', 'Var', (0, 18))	('mutations', 'Var', (69, 78))	('MLH1', 'Gene', '4292', (22, 26))	('MLH1', 'Gene', (22, 26))	('HNPCC', 'Disease', 'None', (82, 87))	('HNPCC', 'Disease', (82, 87))	('MSH2', 'Gene', (31, 35))	('MSH2', 'Gene', '4436', (31, 35))
827872	20924366	The term "microsatellite instability" (MSI) has been used to describe tumors with these mutated short sequences of DNA.	('MSI', 'Disease', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mutated', 'Var', (88, 95))	('MSI', 'Disease', 'None', (39, 42))
827874	20924366	Tumor DNA demonstrating abnormalities in two or more of the microsatellite loci are classified as MSI-high (MSI-H).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MSI-H', 'Disease', 'MESH:D000848', (108, 113))	('MSI', 'Disease', (98, 101))	('MSI', 'Disease', 'None', (108, 111))	('MSI', 'Disease', (108, 111))	('MSI-H', 'Disease', (108, 113))	('MSI', 'Disease', 'None', (98, 101))	('abnormalities', 'Var', (24, 37))
827881	20924366	Although a finding of MSI-H is quite sensitive for HNPCC, there are a small proportion of patients with mutations in MMR genes that will not be detected by MSI testing.	('MSI-H', 'Disease', (22, 27))	('mutations', 'Var', (104, 113))	('HNPCC', 'Disease', 'None', (51, 56))	('HNPCC', 'Disease', (51, 56))	('MSI-H', 'Disease', 'MESH:D000848', (22, 27))	('MSI', 'Disease', 'None', (22, 25))	('MSI', 'Disease', 'None', (156, 159))	('MMR genes', 'Gene', (117, 126))	('patients', 'Species', '9606', (90, 98))	('MSI', 'Disease', (22, 25))	('MSI', 'Disease', (156, 159))
827884	20924366	Regardless of whether immunohistochemistry or MSI testing is done initially, DNA testing remains the gold standard for confirming a mutation in a mismatch repair gene.	('MSI', 'Disease', (46, 49))	('mutation', 'Var', (132, 140))	('mismatch repair gene', 'Gene', (146, 166))	('MSI', 'Disease', 'None', (46, 49))
827886	20924366	In regards to these molecular biomarkers predicting response to therapy, patients with stage II or stage III HNPCC colorectal tumors or sporadic colorectal tumors demonstrating MLH1 silencing by methylation have been found to derive either no benefit or a 2-3 fold increase in mortality by adjuvant 5-FU-based chemotherapy (Table 5).	('MLH1', 'Gene', '4292', (177, 181))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('MLH1', 'Gene', (177, 181))	('colorectal tumors', 'Disease', 'MESH:D015179', (145, 162))	('methylation', 'Var', (195, 206))	('colorectal tumors', 'Disease', 'MESH:D015179', (115, 132))	('mortality', 'MPA', (277, 286))	('HNPCC colorectal tumors', 'Disease', (109, 132))	('5-FU', 'Chemical', 'MESH:D005472', (299, 303))	('colorectal tumors', 'Disease', (145, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('silencing', 'NegReg', (182, 191))	('patients', 'Species', '9606', (73, 81))	('HNPCC colorectal tumors', 'Disease', 'MESH:D015179', (109, 132))	('increase', 'PosReg', (265, 273))
827934	33668122	While MDSCs can induce Tregs, they can also suppress effector T cells.	('MDSCs', 'Var', (6, 11))	('Tregs', 'Chemical', '-', (23, 28))	('suppress', 'NegReg', (44, 52))	('effector T cells', 'CPA', (53, 69))	('induce', 'PosReg', (16, 22))	('Tregs', 'CPA', (23, 28))
827948	33668122	Recently, epigenetic dysregulation, which plays a role in tumor angiogenesis and immune evasion, has been proposed as a novel hallmark of cancer.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('epigenetic dysregulation', 'Var', (10, 34))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
827950	33668122	However, further studies are necessary to delineate the role of epigenetic dysregulation and microRNAs in the remodeling of the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('epigenetic dysregulation', 'Var', (64, 88))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
828000	33668122	The loss of APC in colonic epithelial cells induces adenoma formation through beta-catenin activation, resulting in a decrease in the mucus layer and barrier dysfunction.	('APC', 'Disease', (12, 15))	('activation', 'PosReg', (91, 101))	('mucus layer', 'MPA', (134, 145))	('adenoma', 'Disease', 'MESH:D000236', (52, 59))	('decrease', 'NegReg', (118, 126))	('beta-catenin', 'Gene', (78, 90))	('APC', 'Phenotype', 'HP:0005227', (12, 15))	('APC', 'Disease', 'MESH:D011125', (12, 15))	('beta-catenin', 'Gene', '1499', (78, 90))	('induces', 'Reg', (44, 51))	('adenoma', 'Disease', (52, 59))	('loss', 'Var', (4, 8))
828006	33668122	In addition to activating beta-catenin, the loss of APC continuously activates the SFK-YAP pathway by establishing a positive feedback loop through the upregulation of gp130/IL6ST, a common receptor for the IL-6 family cytokines.	('activates', 'Reg', (69, 78))	('beta-catenin', 'Gene', '1499', (26, 38))	('IL6ST', 'Gene', (174, 179))	('gp130', 'Gene', '3572', (168, 173))	('upregulation', 'PosReg', (152, 164))	('YAP', 'Gene', (87, 90))	('IL6ST', 'Gene', '3572', (174, 179))	('APC', 'Phenotype', 'HP:0005227', (52, 55))	('activating', 'PosReg', (15, 25))	('SFK', 'Gene', (83, 86))	('loss', 'Var', (44, 48))	('positive feedback loop', 'MPA', (117, 139))	('SFK', 'Gene', '6714', (83, 86))	('beta-catenin', 'Gene', (26, 38))	('APC', 'Disease', 'MESH:D011125', (52, 55))	('gp130', 'Gene', (168, 173))	('YAP', 'Gene', '10413', (87, 90))	('APC', 'Disease', (52, 55))
828009	33668122	In a mouse experiment using the mouse colon cancer cell line CT-26, IL-6 deletion in mice enhances antitumor immunity by augmenting type-1 immunity, suggesting the immunosuppressive role of IL-6 in the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mouse', 'Species', '10090', (32, 37))	('colon cancer', 'Disease', (38, 50))	('enhances', 'PosReg', (90, 98))	('mice', 'Species', '10090', (85, 89))	('type-1 immunity', 'MPA', (132, 147))	('tumor', 'Disease', (202, 207))	('IL-6', 'Gene', (68, 72))	('mouse', 'Species', '10090', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('CT-26', 'CellLine', 'CVCL:7254', (61, 66))	('tumor', 'Disease', (103, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (38, 50))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('augmenting', 'NegReg', (121, 131))	('colon cancer', 'Disease', 'MESH:D015179', (38, 50))	('deletion', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
828018	33668122	Lastly, cellular senescence and dysregulated innate immunity have been found to cause prolonged chronic inflammation even after the initial stimulus has been removed.	('inflammation', 'Disease', (104, 116))	('innate immunity', 'CPA', (45, 60))	('prolonged chronic inflammation', 'Phenotype', 'HP:0031035', (86, 116))	('dysregulated', 'Var', (32, 44))	('inflammation', 'Disease', 'MESH:D007249', (104, 116))	('cause', 'Reg', (80, 85))	('cellular senescence', 'CPA', (8, 27))
828019	33668122	Epigenetic changes significantly influence the aging process, life span, and induction and progression of age-related diseases, including cancer.	('influence', 'Reg', (33, 42))	('cancer', 'Disease', (138, 144))	('age', 'Gene', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Epigenetic changes', 'Var', (0, 18))	('aging process', 'CPA', (47, 60))	('age', 'Gene', '5973', (106, 109))	('life span', 'CPA', (62, 71))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
828032	33668122	During aging, somatic clones with driver mutations expand in normal tissues, resulting in cancer development.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('resulting in', 'Reg', (77, 89))
828035	33668122	The epithelium accumulates somatic mutations in several genes associated with IL-17 signaling, including NFKBIZ, TRAF3IP2, ZC3H12A, PIGR, and HNRNPF.	('HNRNPF', 'Gene', '3185', (142, 148))	('ZC3H12A', 'Gene', '80149', (123, 130))	('PIGR', 'Gene', (132, 136))	('HNRNPF', 'Gene', (142, 148))	('NFKBIZ', 'Gene', '64332', (105, 111))	('TRAF3IP2', 'Gene', (113, 121))	('IL-17', 'Gene', (78, 83))	('PIGR', 'Gene', '5284', (132, 136))	('NFKBIZ', 'Gene', (105, 111))	('IL-17', 'Gene', '3605', (78, 83))	('TRAF3IP2', 'Gene', '10758', (113, 121))	('ZC3H12A', 'Gene', (123, 130))	('mutations', 'Var', (35, 44))
828040	33668122	The progressive age-related expansion of the esophageal epithelial clones with driver mutations (predominantly NOTCH1) is substantially accelerated by alcohol drinking and heavy smoking.	('mutations', 'Var', (86, 95))	('age', 'Gene', (50, 53))	('age', 'Gene', '5973', (16, 19))	('age', 'Gene', '5973', (50, 53))	('accelerated', 'PosReg', (136, 147))	('alcohol drinking', 'Phenotype', 'HP:0030955', (151, 167))	('alcohol', 'Chemical', 'MESH:D000438', (151, 158))	('NOTCH1', 'Gene', '4851', (111, 117))	('age', 'Gene', (16, 19))	('NOTCH1', 'Gene', (111, 117))
828041	33668122	A high frequency of NOTCH1 and PPM1D mutations are observed in the physiologically normal esophageal epithelial cells, compared to the common mutations in esophageal carcinoma.	('PPM1D', 'Gene', '8493', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('NOTCH1', 'Gene', '4851', (20, 26))	('esophageal carcinoma', 'Disease', (155, 175))	('age', 'Gene', '5973', (95, 98))	('age', 'Gene', '5973', (160, 163))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (155, 175))	('mutations', 'Var', (37, 46))	('NOTCH1', 'Gene', (20, 26))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (155, 175))	('PPM1D', 'Gene', (31, 36))	('age', 'Gene', (95, 98))	('age', 'Gene', (160, 163))
828052	33668122	An animal experiment using the transplantation model of CRC cells demonstrated that a combination of PD-1 antibodies with VEGF inhibition achieved a strong and synergic antitumor effect, consistent with the previous finding that VEGF produced by tumors shapes the immunosuppressive microenvironment.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('antibodies', 'Var', (106, 116))	('CRC', 'Phenotype', 'HP:0003003', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('PD-1', 'Gene', (101, 105))	('combination', 'Interaction', (86, 97))	('tumor', 'Disease', (246, 251))	('tumors', 'Disease', (246, 252))
828063	33067881	The panoramic picture of pepsinogen gene family with pan-cancer The panoramic picture of pepsinogen gene family with pan-cancer It is well known that pepsinogen (PGs), as an important precursor of pepsin performing digestive function, has a good correlation with the occurrence and development of gastric cancer and it is also known that ectopic PGs expression is related to the prognosis of some cancers.	('correlation', 'Reg', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (57, 63))	('related', 'Reg', (364, 371))	('gastric cancer', 'Phenotype', 'HP:0012126', (297, 311))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (397, 404))	('cancers', 'Disease', (397, 404))	('cancer', 'Disease', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('PGs', 'Chemical', 'MESH:D010715', (346, 349))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PGs', 'Chemical', 'MESH:D010715', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('gastric cancer', 'Disease', (297, 311))	('ectopic', 'Var', (338, 345))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('cancers', 'Disease', 'MESH:D009369', (397, 404))	('cancer', 'Disease', (305, 311))	('gastric cancer', 'Disease', 'MESH:D013274', (297, 311))	('cancer', 'Disease', (121, 127))
828065	33067881	This study focused on elucidating the expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their potential role in human cancer.	('human', 'Species', '9606', (175, 180))	('copy number variation', 'Var', (118, 139))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PGs', 'Chemical', 'MESH:D010715', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('PGs', 'Gene', (143, 146))	('cancer', 'Disease', (181, 187))
828066	33067881	Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers.	('CCLE', 'Chemical', '-', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('copy number variation', 'Var', (230, 251))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('Oncomine', 'Chemical', '-', (54, 62))	('tumor', 'Disease', (134, 139))	('PGs', 'Chemical', 'MESH:D010715', (255, 258))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('PGs', 'Chemical', 'MESH:D010715', (124, 127))	('PGs', 'Gene', (255, 258))	('cancers', 'Disease', (394, 401))	('cancer', 'Disease', (394, 400))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', (286, 292))	('cancer', 'Disease', 'MESH:D009369', (286, 292))
828071	33067881	PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer-related pathways.	('signal transduction pathways', 'Pathway', (81, 109))	('PGC', 'Gene', (120, 123))	('PGA5', 'Gene', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PGs', 'Chemical', 'MESH:D010715', (0, 3))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (171, 177))	('PGA5', 'Gene', '5222', (128, 132))	('activation', 'PosReg', (48, 58))	('inhibition', 'NegReg', (62, 72))	('PGC', 'Gene', '5225', (120, 123))	('PGs', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
828077	33067881	Genetic variation analysis showed that PGC gene often mutated in uterine corpus endometrial carcinoma and stomach adenocarcinoma had extensive copy number amplification in various tumor types.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('tumor', 'Disease', (180, 185))	('PGC', 'Gene', '5225', (39, 42))	('mutated', 'Var', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('copy number amplification', 'MPA', (143, 168))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (80, 128))	('PGC', 'Gene', (39, 42))
828078	33067881	PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased.	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (120, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('expression', 'MPA', (4, 14))	('esophageal carcinoma', 'Disease', (87, 107))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('PGC', 'Gene', (185, 188))	('kidney renal papillary cell carcinoma', 'Disease', (113, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (161, 183))	('upregulated', 'PosReg', (193, 204))	('PGC', 'Gene', (0, 3))	('upregulated', 'PosReg', (19, 30))	('PGC', 'Gene', '5225', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('stomach adenocarcinoma', 'Disease', (161, 183))	('PGC', 'Gene', '5225', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('increase', 'PosReg', (40, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (113, 150))	('copy number', 'Var', (52, 63))
828082	33067881	The variation of copy number of PGC gene could affect the PGC expression.	('PGC', 'Gene', (58, 61))	('variation', 'Var', (4, 13))	('copy number', 'Var', (17, 28))	('expression', 'MPA', (62, 72))	('PGC', 'Gene', '5225', (32, 35))	('PGC', 'Gene', (32, 35))	('affect', 'Reg', (47, 53))	('PGC', 'Gene', '5225', (58, 61))
828084	33067881	Based on the next generation sequence data from TCGA and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically including the expression profiles, mutation and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration and prognostic potential in different cancers.	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('cancer', 'Disease', (268, 274))	('cancers', 'Disease', (375, 382))	('PGs', 'Chemical', 'MESH:D010715', (113, 116))	('tumor', 'Disease', (123, 128))	('PGs', 'Chemical', 'MESH:D010715', (237, 240))	('copy number variation', 'Var', (212, 233))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('CCLE', 'Chemical', '-', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('correlation', 'Reg', (251, 262))	('PGs', 'Gene', (237, 240))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (375, 381))
828104	33067881	In this study, by using the multilevel data from TCGA based Pan-Cancer Atlas, Oncomine and Cancer Cell Line Encyclopedia (CCLE), we focused on the elucidating expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their prediction/diagnosis/prognosis potential in pan-cancer.	('Cancer', 'Disease', (91, 97))	('Cancer', 'Disease', (64, 70))	('CCLE', 'Chemical', '-', (122, 126))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('-cancer', 'Disease', 'MESH:D009369', (325, 332))	('-cancer', 'Disease', (325, 332))	('Oncomine', 'Chemical', '-', (78, 86))	('PGs', 'Chemical', 'MESH:D010715', (264, 267))	('copy number variation', 'Var', (239, 260))	('PGs', 'Gene', (264, 267))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
828105	33067881	We totally collected the information of 33 different kinds of tumors in TCGA database (http://cancergenome.nih.gov/), including the information of TPM (Transcripts Per Kilobase Million) expression, mutation, and copy number variation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('copy number variation', 'Var', (212, 233))	('TPM', 'Gene', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('mutation', 'Var', (198, 206))
828110	33067881	CCLE database(https://portals.broadinstitute.org/ccle)was used to identify the PGs expression, mutation, and copy number variation in different cancer cell lines, including all 431 cell lines from six cancer types.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('CCLE', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('PGs', 'Chemical', 'MESH:D010715', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PGs', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (95, 103))
828123	33067881	The frequency of CNV in each cancer type and cell lines was calculated as the proportion of CNV amplification and deletion.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('deletion', 'Var', (114, 122))
828135	33067881	The results showed that in stomach adenocarcinoma and lung squamous cell carcinoma, high expression of PG is a protective factor, and high expression can reduce the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('reduce', 'NegReg', (154, 160))	('high expression', 'Var', (134, 149))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (27, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('stomach adenocarcinoma', 'Disease', (27, 49))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))
828146	33067881	The results show that PGs expression was significantly related to the activation or inhibition of many carcinogenic pathways (Figure 7A), in which PGC and PGA5 are more likely to be associated with carcinogenic processes.	('PGC', 'Gene', (147, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (198, 210))	('associated', 'Reg', (182, 192))	('inhibition', 'NegReg', (84, 94))	('carcinogenic', 'Disease', (198, 210))	('expression', 'Var', (26, 36))	('PGA5', 'Gene', (155, 159))	('PGs', 'Gene', (22, 25))	('PGA5', 'Gene', '5222', (155, 159))	('carcinogenic', 'Disease', 'MESH:D063646', (103, 115))	('carcinogenic', 'Disease', (103, 115))	('activation', 'PosReg', (70, 80))	('related', 'Reg', (55, 62))	('PGs', 'Chemical', 'MESH:D010715', (22, 25))	('PGC', 'Gene', '5225', (147, 150))
828170	33067881	The results showed that PGC gene mutations frequently occurred in uterine corpus endometrial carcinoma and stomach adenocarcinoma (Figure 10A).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('PGC', 'Gene', '5225', (24, 27))	('PGC', 'Gene', (24, 27))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (81, 129))	('mutations', 'Var', (33, 42))	('occurred', 'Reg', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))
828173	33067881	PGA3, PGA4, and PGA5 showed more copy number amplification in lung adenocarcinoma, esophageal carcinoma, kidney chromophobe, and copy number reduction in bladder urothelial carcinoma, lung squamous cell carcinoma, rectum adenocarcinoma, and cholangiocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('copy number', 'Var', (129, 140))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('PGA4', 'Gene', '643847', (6, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('PGA5', 'Gene', (16, 20))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (214, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cholangiocarcinoma', 'Disease', (241, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('copy', 'MPA', (33, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('kidney chromophobe', 'Disease', 'MESH:D000238', (105, 123))	('PGA5', 'Gene', '5222', (16, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal carcinoma', 'Disease', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('kidney chromophobe', 'Disease', (105, 123))	('PGA3', 'Chemical', '-', (0, 4))	('rectum adenocarcinoma', 'Disease', (214, 235))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('PGA4', 'Gene', (6, 10))	('lung adenocarcinoma', 'Disease', (62, 81))	('PGA3', 'Gene', (0, 4))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))
828174	33067881	In addition, CCLE database analysis revealed the mutation status of PGs in different human cancer cell lines, which showed that there were frequent mutations of PGs in colorectal cancer and gastric cancer cell lines (Figure 11).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Disease', (198, 204))	('PGs', 'Chemical', 'MESH:D010715', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PGs', 'Gene', (161, 164))	('CCLE', 'Chemical', '-', (13, 17))	('mutations', 'Var', (148, 157))	('PGs', 'Chemical', 'MESH:D010715', (161, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('rectal cancer', 'Phenotype', 'HP:0100743', (172, 185))	('human', 'Species', '9606', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (179, 185))	('gastric cancer', 'Disease', (190, 204))
828175	33067881	In order to explore whether PGC self-variation affects its expression, we analyzed the correlation between PGs mutation, CNV, and PGs expression.	('PGs', 'Gene', (107, 110))	('PGC', 'Gene', '5225', (28, 31))	('PGC', 'Gene', (28, 31))	('PGs', 'Chemical', 'MESH:D010715', (130, 133))	('expression', 'MPA', (59, 69))	('PGs', 'Chemical', 'MESH:D010715', (107, 110))	('mutation', 'Var', (111, 119))
828176	33067881	The results showed that PGs mutations did not affect the PGs expression in all cancers.	('cancers', 'Disease', (79, 86))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PGs', 'Chemical', 'MESH:D010715', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('PGs', 'Gene', (24, 27))	('mutations', 'Var', (28, 37))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
828179	33067881	In this study, we used the multilevel data of TCGA, Oncomine, and CCLE to reveal the expression and activated pathways, mutation, and copy number variation, prognostic potential of PGs in all 33 types of tumors and 431 cell lines, aiming to clarify the important role of PGs in tumorigenesis and development of cancers.	('Oncomine', 'Chemical', '-', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('copy number variation', 'Var', (134, 155))	('tumor', 'Disease', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('PGs', 'Chemical', 'MESH:D010715', (271, 274))	('CCLE', 'Chemical', '-', (66, 70))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('tumor', 'Disease', (204, 209))	('PGs', 'Chemical', 'MESH:D010715', (181, 184))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
828180	33067881	The results suggest that there was differential expression of PGs between many kinds of cancer tissues and corresponding normal tissues, which is related to the prognosis of patients; PGs expression was closely associated with the activation of cancer-related pathways and immune cell infiltration; the copy number variation of PGC could affect the gene expression.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene expression', 'MPA', (349, 364))	('PGC', 'Gene', (328, 331))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('affect', 'Reg', (338, 344))	('immune cell infiltration', 'CPA', (273, 297))	('activation', 'PosReg', (231, 241))	('cancer', 'Disease', (245, 251))	('PGs', 'Chemical', 'MESH:D010715', (62, 65))	('copy number variation', 'Var', (303, 324))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PGC', 'Gene', '5225', (328, 331))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('associated', 'Reg', (211, 221))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
828199	33067881	The loss of pepsinogen in advanced esophageal squamous cell carcinoma indicates that pepsin is involved in the process of protein synthesis in the esophagus and causes esophageal carcinogenesis.	('pepsin', 'Var', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('causes', 'Reg', (161, 167))	('esophageal carcinogenesis', 'Disease', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('loss', 'NegReg', (4, 8))	('pepsinogen', 'Protein', (12, 22))
828201	33067881	Both lung tissue and gastric mucosa have the same function of producing pepsinogen molecules, 11  and the injury of normal lung tissue could increase the synthesis of pepsinogen C. 22  Some studies have also suggested that the existence of pepsin in respiratory biological samples was caused by gastroesophageal reflux associated lung inhalation.	('increase', 'PosReg', (141, 149))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (295, 318))	('pepsinogen C', 'Gene', '5225', (167, 179))	('injury', 'Var', (106, 112))	('pepsinogen C', 'Gene', (167, 179))	('gastroesophageal reflux', 'Disease', (295, 318))	('pepsin', 'Gene', (240, 246))	('synthesis', 'MPA', (154, 163))	('caused by', 'Reg', (285, 294))
828222	33067881	The results showed that the overall average mutation rate of PGs was 0%-5.3%, and the mutation rate of PGC was higher in stomach adenocarcinoma and endometrial carcinoma.	('higher', 'Reg', (111, 117))	('PGC', 'Gene', '5225', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('PGs', 'Chemical', 'MESH:D010715', (61, 64))	('PGC', 'Gene', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (148, 169))	('mutation', 'Var', (86, 94))	('stomach adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (121, 169))
828223	33067881	It is worth noticed that all PGC, PGA3, and PGA5 genes had a certain degree of mutation in endometrial carcinoma, which is a tumor with high global mutation rate.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PGA3', 'Gene', (34, 38))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('PGA3', 'Chemical', '-', (34, 38))	('PGA5', 'Gene', (44, 48))	('mutation', 'Var', (79, 87))	('PGC', 'Gene', '5225', (29, 32))	('PGC', 'Gene', (29, 32))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (91, 112))	('endometrial carcinoma', 'Disease', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PGA5', 'Gene', '5222', (44, 48))
828224	33067881	31  In addition, CCLE-based analysis of human cancer cell lines showed that most of the PGs mutations were found in colorectal adenocarcinoma and stomach adenocarcinoma cell lines, suggesting PGs mutation may be the key events in tumorigenesis and development of both gastric cancer and colorectal adenocarcinoma.	('CCLE', 'Chemical', '-', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('gastric cancer', 'Disease', (268, 282))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (287, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (268, 282))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('human', 'Species', '9606', (40, 45))	('tumor', 'Disease', (230, 235))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (192, 195))	('mutations', 'Var', (92, 101))	('PGs', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (88, 91))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (268, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('colorectal adenocarcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D000230', (116, 168))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('found', 'Reg', (107, 112))	('colorectal adenocarcinoma', 'Disease', (287, 312))
828225	33067881	In this study, we also found that there was extensive copy number amplification in various tumor types, which may be related to its widespread expression in various tissues.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('copy number amplification', 'Var', (54, 79))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
828227	33067881	The results showed that there was no correlation between PGs mutation and PGs expression in cancer cells.	('PGs', 'Chemical', 'MESH:D010715', (74, 77))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('mutation', 'Var', (61, 69))	('PGs', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
828228	33067881	However, previous studies in our lab have found that PGC gene insertion-deletion fragment polymorphism and single nucleotide polymorphism from human germline cells can affect PGC expression.	('PGC', 'Gene', (175, 178))	('human', 'Species', '9606', (143, 148))	('expression', 'MPA', (179, 189))	('insertion-deletion fragment polymorphism', 'Var', (62, 102))	('single nucleotide polymorphism', 'Var', (107, 137))	('affect', 'Reg', (168, 174))	('PGC', 'Gene', '5225', (53, 56))	('PGC', 'Gene', (53, 56))	('PGC', 'Gene', '5225', (175, 178))
828230	33067881	In cholangiocarcinoma, esophageal cancer, and kidney renal papillary cell carcinoma, PGC expression was upregulated with the increase of copy number, but in stomach adenocarcinoma, both increase and deletion of PGC copy number could lead to the up-regulation of PGC expression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'MPA', (266, 276))	('PGC', 'Gene', '5225', (211, 214))	('stomach adenocarcinoma', 'Disease', (157, 179))	('deletion', 'Var', (199, 207))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('cholangiocarcinoma', 'Disease', (3, 21))	('copy number', 'Var', (215, 226))	('up-regulation', 'PosReg', (245, 258))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (46, 83))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (53, 83))	('PGC', 'Gene', (262, 265))	('upregulated', 'PosReg', (104, 115))	('PGC', 'Gene', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PGC', 'Gene', '5225', (262, 265))	('kidney renal papillary cell carcinoma', 'Disease', (46, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('PGC', 'Gene', (211, 214))	('cancer', 'Disease', (34, 40))	('PGC', 'Gene', '5225', (85, 88))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (157, 179))
828282	33194655	It has also been shown that TXNIP overexpression in T238 cells inhibits tumor growth and decreases metastasis in a mouse model of in situ thyroid cancer.	('T238', 'CellLine', 'CVCL:6299', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('thyroid cancer', 'Phenotype', 'HP:0002890', (138, 152))	('tumor', 'Disease', (72, 77))	('inhibits', 'NegReg', (63, 71))	('mouse', 'Species', '10090', (115, 120))	('overexpression', 'PosReg', (34, 48))	('situ thyroid cancer', 'Disease', (133, 152))	('metastasis', 'CPA', (99, 109))	('situ thyroid cancer', 'Disease', 'MESH:D013964', (133, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('decreases', 'NegReg', (89, 98))	('TXNIP', 'Var', (28, 33))
828284	33194655	The pathogenesis of PTC is related to the dysfunction of many oncogenes, apoptosis-related genes, and tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('dysfunction', 'Var', (42, 53))	('PTC', 'Gene', (20, 23))	('PTC', 'Phenotype', 'HP:0002895', (20, 23))	('PTC', 'Gene', '5979', (20, 23))	('apoptosis-related genes', 'Gene', (73, 96))	('oncogenes', 'Gene', (62, 71))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
828318	33194655	It has also been reported that the NRF2 expression is high in PCA and that knocking down NRF2 can promote TXNIP expression by binding to the TXNIP promoter.	('expression', 'MPA', (40, 50))	('NRF2', 'Gene', '4780', (35, 39))	('NRF2', 'Gene', (89, 93))	('promote', 'PosReg', (98, 105))	('binding', 'Interaction', (126, 133))	('PCA', 'Phenotype', 'HP:0012125', (62, 65))	('NRF2', 'Gene', (35, 39))	('knocking down', 'Var', (75, 88))	('NRF2', 'Gene', '4780', (89, 93))	('TXNIP expression', 'MPA', (106, 122))
828358	33194655	Studies have also confirmed that TXNIP overexpression can inhibit the proliferation of esophageal cancer cells and increase the therapeutic sensitivity of cisplatin and other chemotherapy drugs used for the treatment of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('overexpression', 'PosReg', (39, 53))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('cancer', 'Disease', (231, 237))	('increase', 'PosReg', (115, 123))	('proliferation', 'CPA', (70, 83))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('TXNIP', 'Var', (33, 38))	('cancer', 'Disease', (98, 104))	('inhibit', 'NegReg', (58, 65))	('therapeutic sensitivity of cisplatin', 'MPA', (128, 164))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('men', 'Species', '9606', (212, 215))
828368	33194655	In A549 cells, the combination of gemcitabine and cisplatin results in G0/G1 phase arrest and the upregulation of TXNIP.	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('gemcitabine', 'Chemical', 'MESH:C056507', (34, 45))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('arrest', 'Disease', (83, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('upregulation', 'PosReg', (98, 110))	('TXNIP', 'MPA', (114, 119))	('gemcitabine', 'Var', (34, 45))	('cisplatin', 'Var', (50, 59))
828376	33194655	The mechanism for this is that TXNIP triggers cell death by inhibiting thioredoxin and activating apoptotic signal-regulated kinase 1 (ASK1) signaling.	('inhibiting', 'NegReg', (60, 70))	('TXNIP', 'Var', (31, 36))	('apoptotic signal-regulated kinase 1', 'Gene', '4217', (98, 133))	('activating', 'PosReg', (87, 97))	('ASK1', 'Gene', '4217', (135, 139))	('ASK1', 'Gene', (135, 139))	('death', 'Disease', 'MESH:D003643', (51, 56))	('death', 'Disease', (51, 56))	('thioredoxin', 'Gene', '7295', (71, 82))	('apoptotic signal-regulated kinase 1', 'Gene', (98, 133))	('thioredoxin', 'Gene', (71, 82))
828377	33194655	This drug combination can also kill mutant NSCLC and may therefore be important in the treatment of NSCLC.	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('mutant', 'Var', (36, 42))	('men', 'Species', '9606', (92, 95))	('NSCLC', 'Disease', (43, 48))	('kill', 'Disease', (31, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
828382	33194655	Several studies have shown that D-allose, a rare sugar, can inhibit the growth of many malignancies.	('D-allose', 'Chemical', '-', (32, 40))	('inhibit', 'NegReg', (60, 67))	('D-allose', 'Var', (32, 40))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('sugar', 'Chemical', 'MESH:D000073893', (49, 54))	('malignancies', 'Disease', (87, 99))
828403	33194655	Furthermore, TXNIP is a key factor in the DNA damage and cell aging induced by PRMT5 depletion.	('PRMT5', 'Gene', (79, 84))	('PRMT5', 'Gene', '10419', (79, 84))	('cell aging', 'CPA', (57, 67))	('depletion', 'Var', (85, 94))
828407	33194655	In particular, it has been found that fenofibrate inhibits the proliferation of NB cells, significantly increasing intracellular ROS levels, upregulating TXNIP expression, and promoting cell apoptosis.	('fenofibrate', 'Chemical', 'MESH:D011345', (38, 49))	('proliferation', 'CPA', (63, 76))	('intracellular ROS levels', 'MPA', (115, 139))	('promoting', 'PosReg', (176, 185))	('OS', 'Phenotype', 'HP:0002669', (130, 132))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('upregulating', 'PosReg', (141, 153))	('inhibits', 'NegReg', (50, 58))	('increasing', 'PosReg', (104, 114))	('TXNIP expression', 'MPA', (154, 170))	('fenofibrate', 'Var', (38, 49))
828410	33194655	TXNIP is expressed at low levels in a variety of malignancies and the overexpression of TXNIP inhibits the proliferation of cancer cells, and so it can be considered as a potential tumor suppressor gene.	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('inhibits', 'NegReg', (94, 102))	('TXNIP', 'Var', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('malignancies', 'Disease', (49, 61))	('overexpression', 'PosReg', (70, 84))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
828455	25070012	While the authors never explicitly state that these structures represent NETs, the presence of hypercitrullinated neutrophils and extracellular chromatin bearing this histone modification is strong evidence in support of this identity and is in keeping with the results of Zychlinsky et al.	('hypercitrullinated neutrophils', 'Phenotype', 'HP:0004821', (95, 125))	('hypercitrullinated neutrophils', 'Disease', 'MESH:C564275', (95, 125))	('hypercitrullinated neutrophils', 'Disease', (95, 125))	('modification', 'Var', (175, 187))
828474	25070012	Antibody-mediated neutralization of serum G-CSF inhibited neutrophilia and reduced the sensitivity of neutrophils to PAF.	('neutralization', 'Var', (18, 32))	('neutrophilia', 'Phenotype', 'HP:0011897', (58, 70))	('neutrophilia', 'Disease', (58, 70))	('PAF', 'Gene', (117, 120))	('G-CSF', 'Gene', (42, 47))	('PAF', 'Gene', '109585', (117, 120))	('reduced', 'NegReg', (75, 82))	('inhibited', 'NegReg', (48, 57))	('G-CSF', 'Gene', '12985', (42, 47))	('neutrophilia', 'Disease', 'MESH:C563010', (58, 70))
828488	25070012	In vivo, the authors demonstrate enhanced staining with Ki-67, a marker of proliferation, in B cells within autoimmune lymphoid follicles in addition to enhanced expression of B cell lymphoma 2 (Bcl-2).	('B cell lymphoma 2', 'Gene', (176, 193))	('Ki-67', 'Var', (56, 61))	('B cell lymphoma 2', 'Gene', '12043', (176, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (183, 191))	('expression', 'MPA', (162, 172))	('staining', 'MPA', (42, 50))	('enhanced', 'PosReg', (153, 161))	('Bcl-2', 'Gene', (195, 200))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (176, 191))	('Bcl-2', 'Gene', '12043', (195, 200))	('enhanced', 'PosReg', (33, 41))
828491	25070012	At the experimental level, it appears that neutrophil infiltration of the primary tumor is associated with enhanced growth.	('growth', 'MPA', (116, 122))	('enhanced', 'PosReg', (107, 115))	('primary tumor', 'Disease', (74, 87))	('neutrophil', 'Var', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('primary tumor', 'Disease', 'MESH:D009369', (74, 87))
828526	25070012	Conversely, no difference in growth was observed in vitro between transgenic and WT tumors.	('transgenic', 'Var', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('WT tumors', 'Disease', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('WT tumors', 'Disease', 'MESH:C536751', (81, 90))
828543	25070012	Accordingly, neutrophil depletion with anti-GR1 antibodies resulted in a 57 % reduction in the number of angiogenic lesions, if depletion occurred early in tumor development during the hyperplastic/dysplastic phase.	('GR1', 'Gene', '546644', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('reduction', 'NegReg', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('antibodies', 'Var', (48, 58))	('GR1', 'Gene', (44, 47))	('dysplastic', 'Disease', (198, 208))	('tumor', 'Disease', (156, 161))	('dysplastic', 'Disease', 'MESH:D004416', (198, 208))
828552	25070012	Ablation of neutrophils in dysplastic islet lesions is associated with a reduction in VEGF:VEGFR co-localization by a factor of approximately 90 %.	('dysplastic islet lesions', 'Disease', 'MESH:D007340', (27, 51))	('VEGF', 'Gene', (86, 90))	('VEGF', 'Gene', '22339', (91, 95))	('Ablation', 'Var', (0, 8))	('dysplastic islet', 'Phenotype', 'HP:0004510', (27, 43))	('VEGF', 'Gene', (91, 95))	('VEGF', 'Gene', '22339', (86, 90))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '13649', (92, 96))	('dysplastic islet lesions', 'Disease', (27, 51))	('reduction', 'NegReg', (73, 82))
828553	25070012	Inhibition of MMP-9 with the specific small molecule inhibitor R94138 resulted in a decrease in the frequency of angiogenic switch and a consequent 70-80 % reduction in the number of tumors.	('decrease', 'NegReg', (84, 92))	('MMP-9', 'Gene', (14, 19))	('reduction', 'NegReg', (156, 165))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('R94138', 'Var', (63, 69))	('angiogenic switch', 'CPA', (113, 130))	('tumors', 'Disease', (183, 189))	('MMP-9', 'Gene', '17395', (14, 19))
828555	25070012	In addition, exogenous MMP-9 was able to render non-angiogenic islet lesions into angiogenic ex vivo.	('MMP-9', 'Gene', '17395', (23, 28))	('MMP-9', 'Gene', (23, 28))	('exogenous', 'Var', (13, 22))	('render', 'Reg', (41, 47))
828618	25070012	In keeping with the hypothesis that plasma nucleosomes are at least in part neutrophil derived, the authors demonstrated elevated levels of plasma MPO and S100A8/A9 (calprotectin) in TMA patients compared to healthy controls.	('TMA', 'Disease', 'MESH:D000783', (183, 186))	('patients', 'Species', '9606', (187, 195))	('levels', 'MPA', (130, 136))	('TMA', 'Disease', (183, 186))	('S100A8/A9', 'Var', (155, 164))	('elevated', 'PosReg', (121, 129))
828654	25070012	In keeping with the hypothesis that NETs provide a microenvironment favoring interactions leading to tumor cell dissemination and metastasis, it stands to reason that disrupting NETs may hinder these processes.	('interactions', 'Interaction', (77, 89))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('metastasis', 'CPA', (130, 140))	('hinder', 'NegReg', (187, 193))	('disrupting', 'Var', (167, 177))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
828660	25070012	In particular, the authors noted that DNAse 1 administration was associated with reduced intravascular arrest of neoplastic cells compared to untreated control mice.	('intravascular arrest', 'Disease', 'MESH:D006323', (89, 109))	('DNAse 1', 'Var', (38, 45))	('intravascular arrest', 'Disease', (89, 109))	('mice', 'Species', '10090', (160, 164))	('reduced', 'NegReg', (81, 88))
828665	25070012	A recent Lancet Oncology review highlights the frequency of alpha1-antitrypsin deficiency heterozygotes in a variety of cancers including colon, lung and bladder tumors.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('alpha1-antitrypsin', 'Protein', (60, 78))	('antitrypsin deficiency', 'Phenotype', 'HP:0032025', (67, 89))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Oncology', 'Phenotype', 'HP:0002664', (16, 24))	('deficiency', 'Var', (79, 89))	('colon', 'Disease', (138, 143))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('lung', 'Disease', (145, 149))	('bladder tumors', 'Disease', 'MESH:D001749', (154, 168))	('bladder tumors', 'Phenotype', 'HP:0009725', (154, 168))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('bladder tumors', 'Disease', (154, 168))
828677	25070012	Postoperatively, patients in the sivelestat group experienced reduced duration of mechanical ventilation, reduced duration of SIRS, reduced length of ICU stay and a trend toward reduced overall hospital stay.	('SIRS', 'Disease', (126, 130))	('sivelestat', 'Var', (33, 43))	('sivelestat', 'Chemical', 'MESH:C069195', (33, 43))	('reduced', 'NegReg', (132, 139))	('length', 'MPA', (140, 146))	('SIRS', 'Disease', '-', (126, 130))	('patients', 'Species', '9606', (17, 25))	('reduced', 'NegReg', (178, 185))	('reduced', 'NegReg', (106, 113))	('reduced', 'NegReg', (62, 69))
828792	30973665	Previously, it has been reported that HLA class I expression is downregulated in various cancer cells, including sarcoma (70%),9 and gastric (45%),16 non-small cell lung (30%)15 and esophageal (60%)17 cancer, by immunohistochemistry using EMR 8-5.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 Thus, the degree of loss of HLA class I may differ by organ specificity, suggesting the possibility that the mechanism of mutation and disappearance of HLA class I molecules is organ-dependent.	('mutation', 'Var', (410, 418))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('HLA class I', 'Gene', (38, 49))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Disease', (113, 120))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('downregulated', 'NegReg', (64, 77))
828800	30973665	Because patients enrolled in this study were at a relatively early stage in HCC prognosis, loss or mutations of HLA class I antigens may have not yet occurred in cancer cells, resulting in higher expression of HLA class I in our results compared to those from past literature.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('HCC', 'Phenotype', 'HP:0001402', (76, 79))	('HLA class I antigen', 'Gene', (112, 131))	('HLA class I', 'Protein', (210, 221))	('expression', 'MPA', (196, 206))	('mutations', 'Var', (99, 108))	('HLA class I antigen', 'Gene', '100507436', (112, 131))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('higher', 'PosReg', (189, 195))	('loss', 'NegReg', (91, 95))	('patients', 'Species', '9606', (8, 16))
828821	30973665	Therefore, our findings showed that the expression of HLA class I in cancer cells might be involved in prolonging RFS and OS in the relatively long-term period after surgery in patients with stage I-II HCC.	('involved', 'Reg', (91, 99))	('prolonging', 'PosReg', (103, 113))	('RFS', 'MPA', (114, 117))	('expression', 'Var', (40, 50))	('patients', 'Species', '9606', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('HCC', 'Disease', (202, 205))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('HCC', 'Phenotype', 'HP:0001402', (202, 205))	('cancer', 'Disease', (69, 75))	('HLA class I', 'Protein', (54, 65))
828828	29888170	We have previously demonstrated that DHA reduced viability of esophageal cancer cells in a dose-dependent manner in vitro and induced cell cycle arrest and apoptosis.	('reduced', 'NegReg', (41, 48))	('arrest', 'Disease', 'MESH:D006323', (145, 151))	('esophageal cancer', 'Disease', (62, 79))	('DHA', 'Chemical', 'MESH:C039060', (37, 40))	('arrest', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('induced', 'Reg', (126, 133))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('viability', 'CPA', (49, 58))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (134, 151))	('apoptosis', 'CPA', (156, 165))	('DHA', 'Var', (37, 40))
828830	29888170	In the present study, for the first time, we found that DHA significantly inhibits cell proliferation in xenografted tumor compared with the control.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('DHA', 'Var', (56, 59))	('inhibits', 'NegReg', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('DHA', 'Chemical', 'MESH:C039060', (56, 59))
828837	29888170	There is growing evidence that DHA inhibits the growth of various cancer cells such as cervical cancer cells, pancreatic cancer cells, prostate cancer cells, hepatoma cells, and neuroglioma cells.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (144, 150))	('pancreatic cancer', 'Disease', 'MESH:D010190', (110, 127))	('neuroglioma', 'Disease', (178, 189))	('cervical cancer', 'Disease', 'MESH:D002583', (87, 102))	('cancer', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cervical cancer', 'Disease', (87, 102))	('hepatoma', 'Disease', (158, 166))	('growth', 'CPA', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DHA', 'Var', (31, 34))	('pancreatic cancer', 'Disease', (110, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('inhibits', 'NegReg', (35, 43))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('prostate cancer', 'Disease', 'MESH:D011471', (135, 150))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (135, 150))	('hepatoma', 'Disease', 'MESH:D006528', (158, 166))	('prostate cancer', 'Disease', (135, 150))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (110, 127))	('neuroglioma', 'Disease', 'None', (178, 189))	('DHA', 'Chemical', 'MESH:C039060', (31, 34))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', (66, 72))
828838	29888170	Moreover, DHA also has suppressive effects on the invasion and metastasis of cancer cells.	('metastasis of cancer', 'Disease', (63, 83))	('metastasis of cancer', 'Disease', 'MESH:D009362', (63, 83))	('DHA', 'Var', (10, 13))	('suppressive', 'NegReg', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('DHA', 'Chemical', 'MESH:C039060', (10, 13))
828840	29888170	The mechanism was at least partially due to DHA which induced apoptosis by upregulating the expression of Bax, downregulating Bcl-2, Bcl-xL, and procaspase-3, and increasing caspase-9 activation, which induced cell cycle arrest by downregulating cyclin E, CDK2, and CDK4.	('Bcl-xL', 'Gene', '598', (133, 139))	('CDK4', 'Gene', (266, 270))	('cell cycle', 'CPA', (210, 220))	('Bax', 'Gene', (106, 109))	('procaspase-3', 'Gene', (145, 157))	('arrest', 'Disease', (221, 227))	('caspase-9', 'Gene', (174, 183))	('Bcl-2', 'Gene', '596', (126, 131))	('Bax', 'Gene', '581', (106, 109))	('activation', 'PosReg', (184, 194))	('upregulating', 'PosReg', (75, 87))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (210, 227))	('DHA', 'Chemical', 'MESH:C039060', (44, 47))	('CDK4', 'Gene', '1019', (266, 270))	('CDK2', 'Gene', '1017', (256, 260))	('CDK2', 'Gene', (256, 260))	('increasing', 'PosReg', (163, 173))	('procaspase-3', 'Gene', '836', (145, 157))	('arrest', 'Disease', 'MESH:D006323', (221, 227))	('cyclin E', 'Protein', (246, 254))	('DHA', 'Var', (44, 47))	('expression', 'MPA', (92, 102))	('downregulating', 'NegReg', (111, 125))	('caspase-9', 'Gene', '842', (174, 183))	('Bcl-xL', 'Gene', (133, 139))	('downregulating', 'NegReg', (231, 245))	('Bcl-2', 'Gene', (126, 131))
828851	29888170	Tumors were established by subcutaneous injection of 5 x 106 Eca109 or Ec9706 cells into the flanks of mice, and the success rate was 80%.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Ec9706', 'Var', (71, 77))	('Ec9706', 'CellLine', 'CVCL:E307', (71, 77))	('mice', 'Species', '10090', (103, 107))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
828852	29888170	Tumors with Eca109 were more stable, and tumor with Ec9706 developed more quickly.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Eca109', 'Var', (12, 18))	('tumor', 'Disease', (41, 46))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Ec9706', 'CellLine', 'CVCL:E307', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Ec9706', 'Var', (52, 58))
828853	29888170	At the seventh day, tumors reached around 25 in the Eca109 group and 75 mm3 in the Ec9706 group; the mice of both groups were randomly assigned to four groups (4 in each group).	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mice', 'Species', '10090', (101, 105))	('Eca109', 'Var', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Ec9706', 'CellLine', 'CVCL:E307', (83, 89))
828859	29888170	Briefly, paraffin-embedded sections were incubated overnight with an anti-Ki-67 Ab after microwave antigen retrieval.	('Ki-67', 'Chemical', '-', (74, 79))	('anti-Ki-67', 'Var', (69, 79))	('paraffin', 'Chemical', 'MESH:D010232', (9, 17))	('anti-Ki-67', 'Gene', (69, 79))
828866	29888170	When the tumors reached a volume of around 25 mm3 in Eca109 and 75 mm3 in Ec9706, the mice were randomly assigned to four groups to receive an injection of one thousand DMSO (control), 2, 10, or 50 mg/kg DHA, respectively (as shown in Figure 1).	('DMSO', 'Chemical', 'MESH:D004121', (169, 173))	('Eca109', 'Var', (53, 59))	('DHA', 'Chemical', 'MESH:C039060', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Ec9706', 'Var', (74, 80))	('mice', 'Species', '10090', (86, 90))	('Ec9706', 'CellLine', 'CVCL:E307', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
828869	29888170	Compared with the control group, the tumor growth was significantly suppressed by 22.9%, 48.9%, and 63% in Eca109 (P < 0.05), while 21.1%, 35.3%, and 60% in Eca9706 (P < 0.05) in mice treated with 2, 10, and 50 mg/kg DHA.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mice', 'Species', '10090', (179, 183))	('suppressed', 'NegReg', (68, 78))	('Eca9706', 'Var', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Eca109', 'Var', (107, 113))	('DHA', 'Chemical', 'MESH:C039060', (217, 220))	('Eca9706', 'CellLine', 'CVCL:E307', (157, 164))
828874	29888170	In Eca109, the IOD value remarkably decreased in the 2 mg/kg DHA group (11676.1 +- 924), 10 mg/kg DHA group (6239.8 +- 624), and 50 mg/kg DHA group (687.6 +- 106.6) when compared with the value in the control group (32395.6 +- 1427.2; P < 0.05).	('IOD value', 'MPA', (15, 24))	('11676.1 +- 924', 'Var', (72, 86))	('Eca109', 'Var', (3, 9))	('DHA', 'Chemical', 'MESH:C039060', (61, 64))	('DHA', 'Chemical', 'MESH:C039060', (98, 101))	('DHA', 'Chemical', 'MESH:C039060', (138, 141))	('decreased', 'NegReg', (36, 45))
828875	29888170	In Ec9706, the IOD value remarkably decreased in the 2 mg/kg DHA group (14031 +- 939.3), 10 mg/kg DHA group (8508.6 +- 736), and 50 mg/kg DHA group (1053.2 +- 172.7) when compared with the value in the control group (16642.7 +- 1023.1; P < 0.05, Figures 2 and 3).	('IOD value', 'MPA', (15, 24))	('DHA', 'Chemical', 'MESH:C039060', (61, 64))	('DHA', 'Chemical', 'MESH:C039060', (98, 101))	('Ec9706', 'CellLine', 'CVCL:E307', (3, 9))	('Ec9706', 'Var', (3, 9))	('DHA', 'Chemical', 'MESH:C039060', (138, 141))	('14031 +- 939.3', 'Var', (72, 86))	('decreased', 'NegReg', (36, 45))
828876	29888170	Additionally, the inhibitory effects of DHA therapy on cell proliferation displayed a dose-dependent manner, as Ki-67-positive cells in the 10 mg/kg DHA group (Eca109: 6239.8 +- 624, Ec9706: 8508.6 +- 736) were significantly fewer than those in the 2 mg/kg DHA group (Eca109: 11676.1 +- 924, Ec9706: 14031 +- 939.3), and even fewer Ki-67-positive cells in the 50 mg/kg group (Eca109: 687.6 +- 106.6, Ec9706: 1053.2 +- 172.7) than in the 10 mg/kg group.	('Ki-67-positive cells', 'CPA', (112, 132))	('Ki-67-positive cells', 'CPA', (332, 352))	('Ec9706', 'CellLine', 'CVCL:E307', (183, 189))	('Ki-67', 'Chemical', '-', (112, 117))	('Ki-67', 'Chemical', '-', (332, 337))	('DHA', 'Chemical', 'MESH:C039060', (257, 260))	('Ec9706', 'CellLine', 'CVCL:E307', (400, 406))	('fewer', 'NegReg', (225, 230))	('DHA', 'Chemical', 'MESH:C039060', (40, 43))	('Ec9706: 1053.2', 'Var', (400, 414))	('cell proliferation', 'CPA', (55, 73))	('Ec9706: 8508.6 +- 736', 'Var', (183, 204))	('fewer', 'NegReg', (326, 331))	('Ec9706', 'CellLine', 'CVCL:E307', (292, 298))	('Eca109: 6239.8 +- 624', 'Var', (160, 181))	('DHA', 'Chemical', 'MESH:C039060', (149, 152))
828878	29888170	In Eca109, the IOD value remarkably increased in the 2 mg/kg DHA group (8010.9 +- 1477), 10 mg/kg DHA group (11643.7 +- 744.4), and 50 mg/kg DHA group (22555.5 +- 1542.9) when compared with the value in the control group (5617.7 +- 408; P < 0.05).	('IOD value', 'MPA', (15, 24))	('Eca109', 'Gene', (3, 9))	('DHA', 'Chemical', 'MESH:C039060', (61, 64))	('increased', 'PosReg', (36, 45))	('DHA', 'Chemical', 'MESH:C039060', (98, 101))	('DHA', 'Chemical', 'MESH:C039060', (141, 144))	('11643.7', 'Var', (109, 116))
828879	29888170	In Ec9706, the IOD value remarkably increased in the 2 mg/kg DHA group (6515.8 +- 507), 10 mg/kg DHA group (14915.2 +- 972.1), and 50 mg/kg DHA group (22019.4 +- 1093.1) when compared with the value in the control group (1209.5 +- 118.4; P < 0.05).	('IOD value', 'MPA', (15, 24))	('DHA', 'Chemical', 'MESH:C039060', (97, 100))	('DHA', 'Chemical', 'MESH:C039060', (61, 64))	('DHA', 'Chemical', 'MESH:C039060', (140, 143))	('increased', 'PosReg', (36, 45))	('Ec9706', 'CellLine', 'CVCL:E307', (3, 9))	('Ec9706', 'Var', (3, 9))
828880	29888170	The large amount of apoptosis may be due to the presence of DHA, which was in line with the result of Ki-67 staining.	('Ki-67', 'Chemical', '-', (102, 107))	('apoptosis', 'CPA', (20, 29))	('DHA', 'Var', (60, 63))	('DHA', 'Chemical', 'MESH:C039060', (60, 63))
828901	29888170	analyzed the anticancer activity of DHA in rhabdomyosarcoma cells; the authors came to the conclusion that DHA might represent a novel class of inhibitor by meditating the mammalian target of rapamycin (mTOR), a central controller for cell proliferation and survival in the tumor cells.	('DHA', 'Chemical', 'MESH:C039060', (107, 110))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (43, 59))	('DHA', 'Chemical', 'MESH:C039060', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (43, 59))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('rhabdomyosarcoma', 'Disease', (43, 59))	('mammalian target of rapamycin', 'Gene', '2475', (172, 201))	('DHA', 'Var', (107, 110))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('mammalian target of rapamycin', 'Gene', (172, 201))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('mTOR', 'Gene', (203, 207))	('mTOR', 'Gene', '2475', (203, 207))
828904	29888170	An increase in the ratio of Bax/Bcl-2 stimulates the release of cytochrome c from the mitochondria into the cytosol, and the cytosolic cytochrome c then binds to proapoptotic protease activating factor-1 (Apaf-1), resulting in the activation of an initiator caspase which starts proteolytic events that kill the cell.	('cytochrome c', 'Gene', (135, 147))	('initiator', 'MPA', (248, 257))	('Bax', 'Gene', '581', (28, 31))	('activation', 'PosReg', (231, 241))	('binds', 'Interaction', (153, 158))	('Bcl-2', 'Gene', (32, 37))	('Apaf-1', 'Gene', '317', (205, 211))	('Bcl-2', 'Gene', '596', (32, 37))	('ratio', 'Var', (19, 24))	('cytochrome c', 'Gene', '54205', (135, 147))	('cytochrome c', 'Gene', (64, 76))	('Apaf-1', 'Gene', (205, 211))	('proteolytic', 'MPA', (279, 290))	('Bax', 'Gene', (28, 31))	('cytochrome c', 'Gene', '54205', (64, 76))
828908	29888170	revealed that DHA induced apoptosis, activated caspase-3, and increased the ratio of Bax/Bcl-2 in human hepatoma cells.	('increased', 'PosReg', (62, 71))	('hepatoma', 'Disease', (104, 112))	('hepatoma', 'Disease', 'MESH:D006528', (104, 112))	('activated', 'PosReg', (37, 46))	('DHA', 'Var', (14, 17))	('Bax', 'Gene', '581', (85, 88))	('caspase-3', 'Gene', (47, 56))	('Bax', 'Gene', (85, 88))	('Bcl-2', 'Gene', (89, 94))	('caspase-3', 'Gene', '836', (47, 56))	('Bcl-2', 'Gene', '596', (89, 94))	('human', 'Species', '9606', (98, 103))	('DHA', 'Chemical', 'MESH:C039060', (14, 17))
828912	29888170	Our present TUNEL results indicated that the apoptosis rate of esophageal cancer cells in DHA treatment groups was higher than that in the control group, while the apoptosis rate of esophageal cancer cell in the 2 mg/kg DHA group was apparently lower than that in the 50 mg/kg DHA group.	('DHA', 'Chemical', 'MESH:C039060', (90, 93))	('esophageal cancer', 'Disease', (182, 199))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('DHA', 'Var', (90, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('DHA', 'Chemical', 'MESH:C039060', (277, 280))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('DHA', 'Chemical', 'MESH:C039060', (220, 223))	('higher', 'PosReg', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('apoptosis rate', 'CPA', (45, 59))
828916	29888170	This study suggested that DHA inhibited cell proliferation and induced apoptosis in esophageal cancer, and we did not observe adverse effects.	('apoptosis', 'CPA', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('inhibited', 'NegReg', (30, 39))	('DHA', 'Chemical', 'MESH:C039060', (26, 29))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('DHA', 'Var', (26, 29))	('induced', 'Reg', (63, 70))	('cell proliferation', 'CPA', (40, 58))
828929	26498375	In addition, miRNAs can target up to several hundred mRNAs, which makes them very powerful regulators, and aberrant miRNA expression can disturb a multitude of cell signaling pathways and profoundly influence cancer onset and progression.	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('disturb', 'NegReg', (137, 144))	('aberrant', 'Var', (107, 115))	('miRNA', 'Protein', (116, 121))	('influence', 'Reg', (199, 208))	('cancer', 'Disease', (209, 215))	('cell signaling pathways', 'Pathway', (160, 183))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
828931	26498375	Although the expression differences do not necessarily represent causal events in carcinogenesis, these changes may regulate some genes that are very important during the process of tumor pathogenesis and may contribute to the classification and prognosis of tumors.	('tumor', 'Disease', (182, 187))	('regulate', 'Reg', (116, 124))	('genes', 'Gene', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('contribute', 'Reg', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('carcinogenesis', 'Disease', (82, 96))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumors', 'Disease', (259, 265))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('tumor', 'Disease', (259, 264))	('changes', 'Var', (104, 111))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
828964	26498375	Through detection of nucleic acid or protein in blood, early diagnosis of susceptible populations has also turned into a focus in cancer screening studies.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('nucleic acid', 'Var', (21, 33))	('protein', 'Protein', (37, 44))
828969	26498375	for the first time reported that high expression of miR-103/107 showed a negative prognostic effect on the survival of EC patients.	('high', 'Var', (33, 37))	('negative', 'NegReg', (73, 81))	('survival', 'CPA', (107, 115))	('patients', 'Species', '9606', (122, 130))	('miR-103', 'Chemical', '-', (52, 59))	('miR-103/107', 'Var', (52, 63))
828970	26498375	Moreover, it was found that low expression levels of miR-103/107 demonstrated a close correlation with a long overall and disease-free survival for EC patients.	('miR-103/107', 'Var', (53, 64))	('patients', 'Species', '9606', (151, 159))	('low', 'NegReg', (28, 31))	('expression levels', 'MPA', (32, 49))	('miR-103', 'Chemical', '-', (53, 60))
828974	26498375	Ras is involved in the performance of critical steps in tumorigenesis, and dysregulation of Ras is frequently observed in human cancers.	('observed', 'Reg', (110, 118))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('human', 'Species', '9606', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('dysregulation', 'Var', (75, 88))	('tumor', 'Disease', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
828975	26498375	K-Ras is the most frequently mutated isoform of Ras in cancer and the percentage of human tumors harboring oncogenic Ras mutations is high; therefore, interrupting the Ras-signaling pathway may become a major focus of new drug development.	('mutations', 'Var', (121, 130))	('K-Ras', 'Gene', '3845', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('K-Ras', 'Gene', (0, 5))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('human', 'Species', '9606', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('Ras-signaling pathway', 'Pathway', (168, 189))
828977	26498375	Disregulation of miR-324 was found to be associated with macrophage dysfunction and colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('colon cancer', 'Disease', 'MESH:D015179', (84, 96))	('Disregulation', 'Var', (0, 13))	('associated', 'Reg', (41, 51))	('miR-324', 'Gene', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('macrophage dysfunction', 'Disease', (57, 79))	('colon cancer', 'Disease', (84, 96))	('macrophage dysfunction', 'Disease', 'MESH:D055501', (57, 79))	('miR-324', 'Gene', '442898', (17, 24))
828985	26498375	An early study suggested that accumulation of p53 protein possibly caused by p53 gene mutation is a very early event in human esophageal carcinogenesis, which contributed to our understanding of molecular mechanisms of EC and development of an early biomarker for early diagnosis and treatment studies.	('human', 'Species', '9606', (120, 125))	('accumulation', 'PosReg', (30, 42))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (126, 151))	('p53', 'Gene', (46, 49))	('esophageal carcinogenesis', 'Disease', (126, 151))	('p53', 'Gene', '7157', (46, 49))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('caused', 'Reg', (67, 73))	('mutation', 'Var', (86, 94))
829006	26357655	The mutation of phosphatase and tensin homolog (PTEN), the primary negative regulator of PI3K/Akt signaling, are detected in more than 70% of patients with the Cowden syndrome (CS), and these patients are at increased risk for breast, endometrial, thyroid, and renal carcinomas.	('renal carcinomas', 'Phenotype', 'HP:0005584', (261, 277))	('Cowden syndrome', 'Disease', 'MESH:D006223', (160, 175))	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('breast', 'Disease', (227, 233))	('Cowden syndrome', 'Disease', (160, 175))	('Akt', 'Gene', (94, 97))	('patients', 'Species', '9606', (192, 200))	('endometrial', 'Disease', (235, 246))	('mutation', 'Var', (4, 12))	('thyroid', 'Disease', (248, 255))	('renal carcinomas', 'Disease', 'MESH:C538614', (261, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('carcinomas', 'Phenotype', 'HP:0030731', (267, 277))	('detected', 'Reg', (113, 121))	('Akt', 'Gene', '207', (94, 97))	('renal carcinomas', 'Disease', (261, 277))	('patients', 'Species', '9606', (142, 150))
829007	26357655	In most of sporadic cancers, mTOR activation is the result of activating mutation of PI3KCA, or deletion or loss-function of upstream regulator genes encoding TSC1/2 (tuberous sclerosis complex 1/2), LKB1 (liver kinase B1), or PTEN.	('PI3KCA', 'Gene', (85, 91))	('loss-function', 'NegReg', (108, 121))	('mTOR', 'Gene', '2475', (29, 33))	('activation', 'PosReg', (34, 44))	('liver kinase B1', 'Gene', '6794', (206, 221))	('LKB1', 'Gene', '6794', (200, 204))	('liver kinase B1', 'Gene', (206, 221))	('PTEN', 'Gene', (227, 231))	('activating', 'PosReg', (62, 72))	('sporadic cancers', 'Disease', 'MESH:D009369', (11, 27))	('mutation', 'Var', (73, 81))	('TSC1/2', 'Gene', '7248;7249', (159, 165))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (167, 185))	('PTEN', 'Gene', '5728', (227, 231))	('tuberous sclerosis', 'Disease', (167, 185))	('LKB1', 'Gene', (200, 204))	('sporadic cancers', 'Disease', (11, 27))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('TSC1/2', 'Gene', (159, 165))	('mTOR', 'Gene', (29, 33))	('deletion', 'Var', (96, 104))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))
829008	26357655	Since mTOR is involved in multiple aspects of tumorigenesis, while PTEN is a tumor suppressor, it is assumed that abnormal expression of these two kinds of protein affects patient prognosis and represents a novel target for therapy.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('abnormal', 'Var', (114, 122))	('patient', 'Species', '9606', (172, 179))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('affects', 'Reg', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('PTEN', 'Gene', (67, 71))	('PTEN', 'Gene', '5728', (67, 71))	('mTOR', 'Gene', '2475', (6, 10))	('tumor', 'Disease', (77, 82))	('mTOR', 'Gene', (6, 10))
829181	25049439	On the basis of the above-mentioned observations and our results, we assume that alteration of resistin level can influence systemic inflammatory response in cachexia and metastasis.	('resistin', 'Gene', (95, 103))	('influence', 'Reg', (114, 123))	('systemic inflammatory response', 'MPA', (124, 154))	('alteration', 'Var', (81, 91))	('cachexia', 'Phenotype', 'HP:0004326', (158, 166))	('metastasis', 'CPA', (171, 181))	('cachexia', 'Disease', 'MESH:D002100', (158, 166))	('resistin', 'Gene', '56729', (95, 103))	('cachexia', 'Disease', (158, 166))
829245	21696638	SEREX analysis has also led to the isolation of several antigens known to be associated with malignancy, including a mutated version of p53 tumor suppressor protein in esophageal cancer.	('esophageal cancer', 'Disease', (168, 185))	('mutated', 'Var', (117, 124))	('tumor', 'Disease', (140, 145))	('SEREX', 'Chemical', '-', (0, 5))	('p53', 'Gene', '7157', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('malignancy', 'Disease', 'MESH:D009369', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('malignancy', 'Disease', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('p53', 'Gene', (136, 139))
829361	21696638	This work was supported by 21st Century COE (Center of Excellence) Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grant Sponsor: Grant-in-Aid for Scientific Research (#17591370 and #16390372) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.	('Aid', 'Gene', '57379', (181, 184))	('#17591370', 'Var', (210, 219))	('#16390372', 'Var', (224, 233))	('Aid', 'Gene', (181, 184))
829427	33837053	Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('patients', 'Species', '9606', (5, 13))	('cancer', 'Disease', (67, 73))	('rectal cancer', 'Phenotype', 'HP:0100743', (60, 73))	('immune-partial', 'MPA', (116, 130))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('esophageal cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('metastatic', 'Var', (22, 32))
829453	33837053	Patients were treated with OH2 at three dose levels (106, 107 and 108CCID50/mL) every 2 weeks.	('106', 'Var', (53, 56))	('108CCID50/mL', 'Var', (66, 78))	('OH2', 'Chemical', '-', (27, 30))	('Patients', 'Species', '9606', (0, 8))
829459	33837053	The volume injected to each lesion was based on the longest diameter of the tumor (<=1.5 cm, up to 1 mL; >1.5 to <=2.5 cm, up to 2 mL; >2.5 to <=5.0 cm, up to 4 mL; >5.0 cm, up to 8 mL).	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (76, 81))	('>1.5', 'Var', (105, 109))
829476	33837053	The density of CD8+ and CD3+ stained cells in the intratumoral area plus the invasive margin, if present in the biopsy, were reported as cells/mm2.	('CD8', 'Gene', '925', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('CD3+', 'Var', (24, 28))	('CD8', 'Gene', (15, 18))
829488	33837053	The most frequent TRAE with single agent OH2 was fever (n=18, 45.0%), which typically occurred within the first 24 hours after OH2 injection, and could be managed with antipyretics.	('OH2', 'Chemical', '-', (127, 130))	('OH2', 'Chemical', '-', (41, 44))	('OH2', 'Var', (41, 44))	('fever', 'Disease', 'MESH:D005334', (49, 54))	('fever', 'Disease', (49, 54))	('fever', 'Phenotype', 'HP:0001945', (49, 54))
829490	33837053	Dose-escalation of OH2 in combination with HX008 is ongoing, and no DLTs occurred in the 106CCID50/mL and 107CCID50/mL groups.	('107CCID50/mL', 'Var', (106, 118))	('DLT', 'Gene', '146059', (68, 71))	('DLT', 'Gene', (68, 71))	('106CCID50/mL', 'Var', (89, 101))	('OH2', 'Chemical', '-', (19, 22))
829503	33837053	Although the MTD was not reached in dose-escalation of single agent OH2, we found that the incidence of fever seemed dose-related (1/3 with 106CCID50/mL, 1/4 with 107CCID50/mL and 3/4 with 108CCID50/mL), suggesting an increased risk of fever for patients receiving OH2 at 108CCID50/mL.	('OH2', 'Chemical', '-', (68, 71))	('fever', 'Phenotype', 'HP:0001945', (104, 109))	('fever', 'Disease', 'MESH:D005334', (236, 241))	('fever', 'Disease', (236, 241))	('patients', 'Species', '9606', (246, 254))	('OH2', 'Chemical', '-', (265, 268))	('fever', 'Phenotype', 'HP:0001945', (236, 241))	('106CCID50/mL', 'Var', (140, 152))	('fever', 'Disease', 'MESH:D005334', (104, 109))	('fever', 'Disease', (104, 109))
829505	33837053	On the other hand, clinical responses were noted in patients from both 106CCID50/mL and 107CCID50/mL groups.	('106CCID50/mL', 'Var', (71, 83))	('clinical responses', 'CPA', (19, 37))	('patients', 'Species', '9606', (52, 60))	('107CCID50/mL', 'Var', (88, 100))
829512	33837053	The primary tumors of both patients were mismatch repair-proficient (pMMR) as confirmed by immunochemistry.	('mismatch', 'Var', (41, 49))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
829527	33837053	The two patients who responded to OH2 both had increases in PD-L1 CPS, TPS, CD8+ and CD3+ cell density relative to baseline after treatment.	('CD8', 'Gene', (76, 79))	('OH2', 'Chemical', '-', (34, 37))	('patients', 'Species', '9606', (8, 16))	('OH2', 'Var', (34, 37))	('PD-L1 CPS', 'Disease', (60, 69))	('CD3+ cell density', 'MPA', (85, 102))	('increases', 'PosReg', (47, 56))	('CD8', 'Gene', '925', (76, 79))	('PD-L1 CPS', 'Disease', 'MESH:D010300', (60, 69))	('TPS', 'MPA', (71, 74))
829528	33837053	The representative changes in the tumor microenvironment induced by OH2 are shown in online supplemental figure 1.	('OH2', 'Var', (68, 71))	('OH2', 'Chemical', '-', (68, 71))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
829530	33837053	To date, several genetically modified mutants of HSV-1 have been applied for the treatment of malignant brain tumors, melanoma and other solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mutants', 'Var', (38, 45))	('solid tumor', 'Disease', (137, 148))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('brain tumors', 'Phenotype', 'HP:0030692', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('malignant brain tumors', 'Disease', 'MESH:D001932', (94, 116))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('tumors', 'Disease', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumor', 'Disease', 'MESH:D009369', (137, 148))	('tumors', 'Disease', (110, 116))	('HSV-1', 'Species', '10298', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('HSV-1', 'Gene', (49, 54))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('applied', 'Reg', (65, 72))	('malignant brain tumors', 'Disease', (94, 116))
829587	31653132	Studies have shown that there is a significant relationship between haptoglobin polymorphism and prevalence of some cancers (Awadallah and Atoum, 2004; Carter and Worwood, 2007).	('haptoglobin', 'Gene', '3240', (68, 79))	('haptoglobin', 'Gene', (68, 79))	('polymorphism', 'Var', (80, 92))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
829617	31653132	Furthermore, HP1-2 genotype had the lowest frequency in the patients' group with 6 patients (14.3%); the rate of this genotype in the control group was nine (21.4%).	('lowest', 'NegReg', (36, 42))	('genotype', 'Var', (19, 27))	('patients', 'Species', '9606', (60, 68))	('HP1-2', 'Gene', (13, 18))	('patients', 'Species', '9606', (83, 91))	('HP1-2', 'Gene', '23468', (13, 18))
829634	31653132	It has been shown that haptoglobin genotype is related to the prevalence and progression of various types of cancer (Carter and Worwood, 2007).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('haptoglobin', 'Gene', '3240', (23, 34))	('haptoglobin', 'Gene', (23, 34))	('cancer', 'Disease', (109, 115))	('related', 'Reg', (47, 54))	('genotype', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
829636	31653132	In consonance with our study, several studies have shown that the specific genotype of haptoglobin has a higher prevalence in some cancers (Lai et al., 2010; Levy et al., 2010).	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('higher', 'Reg', (105, 111))	('genotype', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('haptoglobin', 'Gene', '3240', (87, 98))	('haptoglobin', 'Gene', (87, 98))
829638	31653132	Also, in the study of Lee et al., (2009), the HP2-2 genotype of haptoglobin was the most frequent genotype in tracheal cancer, and this genotype was also associated with the severity of tracheal cancer.	('haptoglobin', 'Gene', '3240', (64, 75))	('HP2-2', 'Gene', (46, 51))	('HP2-2', 'Gene', '10550', (46, 51))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('haptoglobin', 'Gene', (64, 75))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tracheal cancer', 'Phenotype', 'HP:0100551', (110, 125))	('cancer', 'Disease', (119, 125))	('tracheal cancer', 'Phenotype', 'HP:0100551', (186, 201))	('associated', 'Reg', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('genotype', 'Var', (52, 60))
829641	31653132	It has been demonstrated that the innate immune response to tumor growth in individuals with the HP-1 allele is reduced compared to those with the HP-2 allele, which could be the reason for tumor growth (Abdullah et al., 2009; Bicho et al., 2013).	('HP-1', 'Gene', '23468', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('innate immune', 'MPA', (34, 47))	('HP-1', 'Gene', (97, 101))	('HP', 'Gene', '3240', (147, 149))	('tumor', 'Disease', (190, 195))	('allele', 'Var', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('reduced', 'NegReg', (112, 119))	('tumor', 'Disease', (60, 65))	('HP', 'Gene', '3240', (97, 99))
829648	31653132	Moreover, MDA, as an end product of lipid peroxidation, has potentially toxic effects and can induce genetic mutations in the DNA structure by binding to DNA (Del Rio et al., 2005).	('genetic mutations', 'Var', (101, 118))	('binding', 'Interaction', (143, 150))	('DNA', 'Gene', (126, 129))	('MDA', 'Chemical', 'MESH:D008315', (10, 13))	('induce', 'Reg', (94, 100))	('mutations', 'Var', (109, 118))	('lipid', 'Chemical', 'MESH:D008055', (36, 41))
829671	31140638	More strikingly, recent clinical and preclinical studies revealed that Lp-PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease.	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (157, 176))	("Alzheimer's disease", 'Disease', (157, 176))	('macular edema', 'Phenotype', 'HP:0040049', (139, 152))	('diabetic macular edema', 'Disease', 'MESH:D008269', (130, 152))	('Lp-PLA2', 'Protein', (71, 78))	('inhibition', 'Var', (79, 89))	('diabetic macular edema', 'Disease', (130, 152))	('edema', 'Phenotype', 'HP:0000969', (147, 152))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (157, 176))
829683	31140638	In addition, the tyrosine nitration of Tyr307 and Tyr335 also moderately contributed to the inactivation of the enzyme.	('Tyr', 'Chemical', 'MESH:C042696', (39, 42))	('Tyr307', 'Var', (39, 45))	('Tyr335', 'Chemical', 'MESH:C115527', (50, 56))	('rat', 'Species', '10116', (29, 32))	('tyrosine', 'Chemical', 'None', (17, 25))	('tyrosine nitration', 'MPA', (17, 35))	('inactivation', 'MPA', (92, 104))	('Tyr335', 'Var', (50, 56))	('Tyr', 'Chemical', 'MESH:C042696', (50, 53))	('rat', 'Species', '10116', (66, 69))
829702	31140638	Further computer modeling revealed that the preferable substrates might be PSox species whose sn-2 ester bonds were in proximity with Ser273 and oxygenated functional groups were hydroxy or hydroperoxy, particularly, at the C9 position of the sn-2 chain.55 Furthermore, Lp-PLA2 possesses transacetylase activity, that is, it can transfer acetyl from PAF to ether- or ester-linked lysophospholipids.31  In general, oxPC, PAF and its analogs are the major substrates for Lp-PLA2, while PSox and other types of oxPL constitute the minor ones.	('PAF', 'Gene', (350, 353))	('Ser', 'Chemical', 'MESH:C530429', (134, 137))	('ester', 'Chemical', 'MESH:D004952', (99, 104))	('ester', 'Chemical', 'MESH:D004952', (367, 372))	('PAF', 'Gene', '9768', (420, 423))	('sn-2 ester', 'Chemical', 'MESH:D014001', (94, 104))	('rat', 'Species', '10116', (459, 462))	('acetyl', 'Chemical', 'MESH:C011632', (338, 344))	('Lp-PLA2', 'Var', (469, 476))	('rat', 'Species', '10116', (60, 63))	('ether', 'Chemical', 'MESH:D004987', (357, 362))	('PAF', 'Gene', '9768', (350, 353))	('acetyl', 'Chemical', 'MESH:C011632', (293, 299))	('oxygen', 'Chemical', 'MESH:D010100', (145, 151))	('PAF', 'Gene', (420, 423))	('hydroxy', 'Chemical', 'MESH:D006880', (179, 186))	('hydroperoxy', 'Chemical', 'MESH:C048495', (190, 201))
829706	31140638	In addition, oxPL species were shown to be chemically linked to naturally occurring human proteins such as apolipoprotein (a) and plasminogen; hence, the covalent lipid adducts might affect the hydrolysis of Lp-PLA2 by accessibility to the sn-2 acyl group.	('apolipoprotein', 'Protein', (107, 121))	('lipid', 'Protein', (163, 168))	('affect', 'Reg', (183, 189))	('Lp-PLA2', 'Protein', (208, 215))	('sn-2 acyl', 'Chemical', 'MESH:C032881', (240, 249))	('human', 'Species', '9606', (84, 89))	('hydrolysis', 'MPA', (194, 204))	('adducts', 'Var', (169, 176))
829711	31140638	Specifically, the residues Tyr205, Trp115, Leu116, and to a lesser extent, Met117, which are part of the N-terminal alpha-helix, are probably essential for binding to LDL,23 whereas a part of the C-terminal alpha-helix (His367 to Lys370) accounts for the association with HDL.61 Additionally, other factors can also affect the association between lipoproteins and Lp-PLA2.	('Tyr205', 'Var', (27, 33))	('affect', 'Reg', (316, 322))	('Trp115', 'Var', (35, 41))	('Leu116', 'Var', (43, 49))	('Tyr', 'Chemical', 'MESH:C042696', (27, 30))	('Met1', 'Gene', (75, 79))	('Lp-PLA2', 'Disease', (364, 371))	('association', 'Interaction', (327, 338))	('Met1', 'Gene', '3004', (75, 79))	('Trp115', 'Chemical', 'MESH:C515678', (35, 41))
829712	31140638	For example, N-linked glycosylation of plasma Lp-PLA2 was shown to hinder its binding to HDL in humans and Asn423 and 433 might be involved in this process.62 Moreover, charged amino acids may also be potentially involved in the interaction with lipoproteins.	('amino', 'Chemical', 'MESH:D000596', (177, 182))	('involved', 'Reg', (213, 221))	('charged amino acids', 'Var', (169, 188))	('interaction', 'Interaction', (229, 240))	('lipoproteins', 'Protein', (246, 258))	('Asn423', 'Chemical', 'MESH:C072935', (107, 113))	('humans', 'Species', '9606', (96, 102))
829718	31140638	A structure-based study revealed that the lack of Trp and Leu in mouse Lp-PLA2 at the positions corresponding to Trp115 and Leu116 in the human protein might be responsible for the varying distribution.	('Trp', 'Chemical', 'MESH:C509690', (50, 53))	('Leu116', 'Var', (124, 130))	('Trp', 'Chemical', 'MESH:C509690', (113, 116))	('Trp', 'Protein', (50, 53))	('mouse', 'Species', '10090', (65, 70))	('human', 'Species', '9606', (138, 143))	('Trp115', 'Chemical', 'MESH:C515678', (113, 119))	('Leu', 'Var', (58, 61))
829725	31140638	In the active site, nucleophilic Ser273 is located at the N-terminus of a core alpha-helix and Asp296 and His351 are positioned suitably to activate Ser273 for catalysis (Figure 2A).	('Ser273', 'Var', (33, 39))	('Asp', 'Chemical', 'MESH:C108952', (95, 98))	('Ser', 'Chemical', 'MESH:C530429', (149, 152))	('His351', 'Var', (106, 112))	('Ser273', 'Var', (149, 155))	('Ser', 'Chemical', 'MESH:C530429', (33, 36))	('Asp296', 'Var', (95, 101))
829726	31140638	The Leu153 and Phe274 of the oxyanion hole stabilize the incipient negative charge present on the tetrahedral intermediate produced during the ester hydrolysis of a substrate.	('incipient negative charge present', 'MPA', (57, 90))	('tetrahedral intermediate produced', 'MPA', (98, 131))	('ester', 'Chemical', 'MESH:D004952', (143, 148))	('Phe274', 'Var', (15, 21))	('rat', 'Species', '10116', (170, 173))	('stabilize', 'PosReg', (43, 52))	('Leu153', 'Var', (4, 10))	('Leu153', 'Chemical', 'MESH:C101068', (4, 10))	('Phe274', 'Chemical', 'MESH:C024774', (15, 21))
829732	31140638	Furthermore, His114, Trp115, and Leu116 show weak electron densities in the ligand-free crystal structure and are predicted to be flexible as a result of the superficial location and predict membrane interactions.	('predict', 'Reg', (183, 190))	('Trp115', 'Gene', (21, 27))	('Leu116', 'Var', (33, 39))	('interactions', 'Interaction', (200, 212))	('electron densities', 'MPA', (50, 68))	('His114', 'Var', (13, 19))	('Trp115', 'Chemical', 'MESH:C515678', (21, 27))	('weak', 'NegReg', (45, 49))	('membrane', 'MPA', (191, 199))
829736	31140638	Nevertheless, the structure of tabun complexed with Lp-PLA2 had an overall Calpha RMSD of 0.5 A compared with the ligand-free structure, which resulted in differences in the contact between Ser273 and its adjacent residues.	('contact', 'Interaction', (174, 181))	('tabun', 'Chemical', 'MESH:C009374', (31, 36))	('Ser', 'Chemical', 'MESH:C530429', (190, 193))	('differences', 'Reg', (155, 166))	('Ser273', 'Var', (190, 196))
829737	31140638	In addition to the covalent bond with Ser273, the double-bonded phospho-oxygen within the five OPs interacted with the backbone amide of Phe274 and Leu153 through hydrogen bonds located in the oxyanion hole of the enzyme.	('hydrogen bonds', 'MPA', (163, 177))	('amide', 'Chemical', 'MESH:D000577', (128, 133))	('Leu153', 'Var', (148, 154))	('Leu153', 'Chemical', 'MESH:C101068', (148, 154))	('Phe274', 'Chemical', 'MESH:C024774', (137, 143))	('Ser', 'Chemical', 'MESH:C530429', (38, 41))	('phospho-oxygen', 'Chemical', 'MESH:D010100', (64, 78))	('Phe274', 'Var', (137, 143))	('interacted', 'Interaction', (99, 109))	('hydrogen', 'Chemical', 'MESH:D006859', (163, 171))
829738	31140638	In the case of the active-site His351, paraoxon and DFP formed a hydrogen bond with the side chain nitrogen of the residue through the oxygen atoms in the alkoxy portion, which prevented the amino acid from reverting to its unprotonated form.	('hydrogen', 'Interaction', (65, 73))	('amino', 'Chemical', 'MESH:D000596', (191, 196))	('DFP', 'Chemical', 'MESH:D007531', (52, 55))	('paraoxon', 'Chemical', 'MESH:D010261', (39, 47))	('nitrogen', 'Chemical', 'MESH:D009584', (99, 107))	('His351', 'Var', (31, 37))	('hydrogen', 'Chemical', 'MESH:D006859', (65, 73))	('oxygen', 'Chemical', 'MESH:D010100', (135, 141))	('alkoxy', 'Chemical', 'MESH:C059688', (155, 161))	('reverting', 'MPA', (207, 216))
829745	31140638	On the basis of the crystal structures of Lp-PLA2 with the OP adducts mentioned above, Kirby et al67 induced a number of histidine mutations near the active site of the enzyme in an endeavor to generate novel OP-hydrolase activity.	('mutations', 'Var', (131, 140))	('histidine', 'Chemical', 'MESH:C115717', (121, 130))	('rat', 'Species', '10116', (198, 201))	('OP-hydrolase', 'Enzyme', (209, 221))	('activity', 'MPA', (222, 230))
829746	31140638	As a result, the W298H mutant displayed novel somanase activity with a k cat of 5 minutes-1 and a K M of 590 muM at pH 7.5, representing a catalytic efficiency of 8.4 x 103 M-1 min-1.	('min-1', 'Gene', '966', (177, 182))	('min-1', 'Gene', (177, 182))	('activity', 'MPA', (55, 63))	('muM', 'Gene', (109, 112))	('W298H', 'Var', (17, 22))	('W298H', 'Mutation', 'p.W298H', (17, 22))	('muM', 'Gene', '56925', (109, 112))	('somanase', 'Protein', (46, 54))
829749	31140638	The pyrimidinone carbonyl of darapladib and compound 1 interacts with the oxyanion hole in the enzyme through two bonds to the backbone amides of Phe274 and Leu153.	('amides', 'Chemical', 'MESH:D000577', (136, 142))	('Phe274', 'Chemical', 'MESH:C024774', (146, 152))	('Phe274', 'Var', (146, 152))	('bonds', 'Interaction', (114, 119))	('interacts', 'Interaction', (55, 64))	('Leu153', 'Var', (157, 163))	('darapladib', 'Chemical', 'MESH:C529040', (29, 39))	('Leu153', 'Chemical', 'MESH:C101068', (157, 163))	('pyrimidinone carbonyl', 'Chemical', 'MESH:D011744', (4, 25))
829750	31140638	In addition, several residues (Leu371, Phe357, Trp298, Leu153, Leu111, and Phe110) display hydrophobic interactions with darapladib.	('Leu153', 'Var', (55, 61))	('Phe', 'Chemical', 'MESH:C026650', (39, 42))	('Leu153', 'Chemical', 'MESH:C101068', (55, 61))	('Phe110', 'Var', (75, 81))	('Trp', 'Chemical', 'MESH:C509690', (47, 50))	('Trp298', 'Var', (47, 53))	('Leu111', 'Chemical', 'MESH:C038361', (63, 69))	('Leu111', 'Var', (63, 69))	('darapladib', 'Chemical', 'MESH:C529040', (121, 131))	('Phe357', 'Chemical', 'MESH:C499892', (39, 45))	('hydrophobic interactions', 'MPA', (91, 115))	('Leu371', 'Var', (31, 37))	('Leu371', 'Chemical', 'MESH:C116795', (31, 37))	('Phe', 'Chemical', 'MESH:C026650', (75, 78))	('Phe357', 'Var', (39, 45))
829751	31140638	The two benzene rings of the biphenyl moiety form an intramolecular edge-to-face pi-stacking interaction with the fluorophenyl ring and extend into a predominantly lipophilic channel toward Phe125.	('Phe125', 'Chemical', 'MESH:C006303', (190, 196))	('biphenyl', 'Chemical', 'MESH:C010574', (29, 37))	('Phe125', 'Var', (190, 196))	('extend', 'Reg', (136, 142))	('fluorophenyl', 'Chemical', 'MESH:C076986', (114, 126))	('benzene', 'Chemical', 'MESH:D001554', (8, 15))
829752	31140638	Apart from two conserved H-bonds, the complex of Lp-PLA2 and 1 formed a third and unique H-bond between the oxygen linked to the pyrimidone ring and the side chain of Gln352.	('Gln352', 'Var', (167, 173))	('pyrimidone', 'Chemical', 'MESH:D011744', (129, 139))	('Lp-PLA2 and 1', 'Gene', '7941', (49, 62))	('oxygen', 'Chemical', 'MESH:D010100', (108, 114))	('H-bond', 'MPA', (89, 95))
829753	31140638	The residues that contribute to the hydrophobic interactions are identical to those presented in the Lp-PLA2 and darapladib complex, except that Gly152 and Phe322 are added while Leu111 and Leu369 are missing.	('Leu111', 'Chemical', 'MESH:C038361', (179, 185))	('Gly152', 'Var', (145, 151))	('darapladib', 'Chemical', 'MESH:C529040', (113, 123))	('Leu369', 'Var', (190, 196))	('Leu111', 'Var', (179, 185))	('Phe', 'Chemical', 'MESH:C026650', (156, 159))	('Phe322', 'Var', (156, 162))
829759	31140638	The crystal structure of compound 3 bound to Lp-PLA2 reveals that the carbonyl of lactam forms two hydrogen bonds to the backbone NH of both Leu153 and Phe274, the cyano fills a small pocket by forming a long H-bond to the backbone NH of Phe357, and the phenyl ring locates in the hydrophobic pocket aligned with Phe110, Ala355, and Phe357.	('Phe', 'Chemical', 'MESH:C026650', (333, 336))	('Phe', 'Chemical', 'MESH:C026650', (152, 155))	('Phe274', 'Chemical', 'MESH:C024774', (152, 158))	('Phe274', 'Var', (152, 158))	('Phe357', 'Chemical', 'MESH:C499892', (238, 244))	('NH', 'Chemical', 'MESH:D000641', (232, 234))	('NH', 'Chemical', 'MESH:D000641', (130, 132))	('cyano', 'Chemical', 'MESH:C448390', (164, 169))	('phenyl', 'Chemical', 'MESH:C064635', (254, 260))	('lactam', 'Chemical', 'MESH:D007769', (82, 88))	('hydrogen', 'Chemical', 'MESH:D006859', (99, 107))	('Phe', 'Chemical', 'MESH:C026650', (238, 241))	('Ala355', 'Chemical', 'MESH:C547125', (321, 327))	('Phe357', 'Chemical', 'MESH:C499892', (333, 339))	('Phe', 'Chemical', 'MESH:C026650', (313, 316))	('Leu153', 'Var', (141, 147))	('Leu153', 'Chemical', 'MESH:C101068', (141, 147))	('carbonyl', 'Chemical', 'MESH:C548957', (70, 78))
829760	31140638	Concurrently, the sulfone moiety sits in the Leu153, Trp298, and Phe322 groove, where the electron withdrawing effect of sulfone might polarize the neighboring CH that then interacts with the electron-rich indolyl of Trp298.	('Trp', 'Chemical', 'MESH:C509690', (53, 56))	('electron withdrawing', 'MPA', (90, 110))	('polarize', 'MPA', (135, 143))	('interacts', 'Interaction', (173, 182))	('Phe', 'Chemical', 'MESH:C026650', (65, 68))	('sulfone', 'Chemical', 'MESH:D013450', (18, 25))	('CH', 'Chemical', 'MESH:C103208', (160, 162))	('sulfone', 'Chemical', 'MESH:D013450', (121, 128))	('Trp', 'Chemical', 'MESH:C509690', (217, 220))	('Leu153', 'Chemical', 'MESH:C101068', (45, 51))	('indolyl', 'Chemical', 'MESH:C030737', (206, 213))	('Leu153', 'Var', (45, 51))
829761	31140638	In particular, the linker between the phenyl and sulfone moiety is vital for maintaining the inhibitory potency, as it can orient the two parts to the respective binding pocket, and the ether oxygen forms a close contact with the side chain of Gln352.	('oxygen', 'Chemical', 'MESH:D010100', (192, 198))	('orient', 'Reg', (123, 129))	('sulfone', 'Chemical', 'MESH:D013450', (49, 56))	('phenyl', 'Chemical', 'MESH:C064635', (38, 44))	('inhibitory potency', 'MPA', (93, 111))	('Gln352', 'Var', (244, 250))	('ether', 'Chemical', 'MESH:D004987', (186, 191))
829762	31140638	Compared with darapladib, compound 3 efficiently utilizes the groove above Trp298 to enhance the potency, as Trp298 appears to be essential for substrate interactions with Ser273.	('rat', 'Species', '10116', (149, 152))	('Trp', 'Chemical', 'MESH:C509690', (75, 78))	('Trp', 'Chemical', 'MESH:C509690', (109, 112))	('Ser', 'Chemical', 'MESH:C530429', (172, 175))	('Trp298', 'Var', (109, 115))	('darapladib', 'Chemical', 'MESH:C529040', (14, 24))	('Trp298', 'Gene', (75, 81))	('potency', 'MPA', (97, 104))	('enhance', 'PosReg', (85, 92))
829765	31140638	The sulfonamide oxygen forms H-bonding interactions with Phe274, Ser273, and Leu153, while an additional H-bond is established between the cyano and backbone of Phe357 as in the case of compound 3.	('Phe274', 'Chemical', 'MESH:C024774', (57, 63))	('Phe274', 'Var', (57, 63))	('Ser', 'Chemical', 'MESH:C530429', (65, 68))	('H-bonding', 'MPA', (29, 38))	('Leu153', 'Var', (77, 83))	('Leu153', 'Chemical', 'MESH:C101068', (77, 83))	('Phe357', 'Chemical', 'MESH:C499892', (161, 167))	('Ser273', 'Var', (65, 71))	('cyano', 'Chemical', 'MESH:C448390', (139, 144))	('sulfonamide', 'Chemical', 'MESH:D013449', (4, 15))	('oxygen', 'Chemical', 'MESH:D010100', (16, 22))
829766	31140638	Phe357, Leu371, Leu111, and Leu121 contribute to hydrophobic interactions via the 4-chloro-3-(trifluoromethyl) phenyl moiety, which sits above the lipoprotein-binding helices on the other side.	('4-chloro-3-(trifluoromethyl) phenyl', 'Chemical', 'MESH:C521926', (82, 117))	('Leu371', 'Var', (8, 14))	('Leu371', 'Chemical', 'MESH:C116795', (8, 14))	('hydrophobic interactions', 'MPA', (49, 73))	('Leu121', 'Var', (28, 34))	('Phe357', 'Var', (0, 6))	('Leu111', 'Chemical', 'MESH:C038361', (16, 22))	('Phe357', 'Chemical', 'MESH:C499892', (0, 6))	('Leu111', 'Var', (16, 22))	('contribute', 'Reg', (35, 45))
829767	31140638	Furthermore, the terminal tolyl moiety of the bis-aryl group in compound 5 inserts into a new pocket and forms pi-stacking interactions with Phe125 and Phe357, resulting from a -22  rotation of the Calpha-Cbeta bond in Phe357.	('interactions', 'Interaction', (123, 135))	('tolyl', 'Chemical', 'MESH:C013308', (26, 31))	('Phe357', 'Chemical', 'MESH:C499892', (152, 158))	('Phe357', 'Var', (219, 225))	('Phe357', 'Chemical', 'MESH:C499892', (219, 225))	('bis-aryl', 'Chemical', 'MESH:C517747', (46, 54))	('Phe125', 'Chemical', 'MESH:C006303', (141, 147))
829768	31140638	The rest of the tolyl is in the van der Waals contact with the side chains of Leu111 and Leu371 and forms an edge-to-face pi-stacking interaction with Phe357.	('Leu371', 'Var', (89, 95))	('Leu371', 'Chemical', 'MESH:C116795', (89, 95))	('Phe357', 'Chemical', 'MESH:C499892', (151, 157))	('Leu111', 'Chemical', 'MESH:C038361', (78, 84))	('Leu111', 'Var', (78, 84))	('tolyl', 'Chemical', 'MESH:C013308', (16, 21))
829769	31140638	Additionally, two direct hydrogen bonds can be found between the amino of the aminoethyoxy moiety and the Leu369 carbonyl as well as between the hydroxyl of the hydroxylmethy moiety and the Gln352 amino.	('carbonyl', 'Chemical', 'MESH:C548957', (113, 121))	('hydroxyl', 'Chemical', 'MESH:D017665', (161, 169))	('amino', 'Chemical', 'MESH:D000596', (197, 202))	('hydrogen', 'Chemical', 'MESH:D006859', (25, 33))	('amino', 'Chemical', 'MESH:D000596', (78, 83))	('aminoethyoxy', 'Chemical', 'MESH:C560084', (78, 90))	('hydroxylmethy', 'Chemical', 'None', (161, 174))	('amino', 'Chemical', 'MESH:D000596', (65, 70))	('hydroxyl', 'Chemical', 'MESH:D017665', (145, 153))	('Leu369', 'Var', (106, 112))	('Gln352', 'Var', (190, 196))
829770	31140638	A small lipophilic subpocket formed by the side chains of Ala355, Tyr160, and Phe357 is appropriately filled by the methoxy moiety.	('Phe357', 'Var', (78, 84))	('Ala355', 'Var', (58, 64))	('Tyr', 'Chemical', 'MESH:C042696', (66, 69))	('Tyr160', 'Var', (66, 72))	('Phe357', 'Chemical', 'MESH:C499892', (78, 84))	('methoxy', 'Chemical', 'MESH:C470596', (116, 123))	('Ala355', 'Chemical', 'MESH:C547125', (58, 64))
829774	31140638	The gene encoding Lp-PLA2 (PLA2G7), whose chromosomal location is in 6p12-21.1, is organized in 12 exons and encodes 441 amino acids.70, 71 Numerous variations were identified within PLA2G7, and the corresponding alterations in physiology and body homeostasis have been illustrated to varying degrees.	('physiology', 'MPA', (228, 238))	('body', 'MPA', (243, 247))	('rat', 'Species', '10116', (276, 279))	('variations', 'Var', (149, 159))	('alterations', 'Reg', (213, 224))	('rat', 'Species', '10116', (217, 220))	('amino', 'Chemical', 'MESH:D000596', (121, 126))
829775	31140638	Since elevated Lp-PLA2 levels were detected in patients with certain diseases, most researchers have focused their attention on variants that considerably weaken Lp-PLA2 activity or function, viz the loss-of-function alleles.	('Lp-PLA2 activity', 'MPA', (162, 178))	('patients', 'Species', '9606', (47, 55))	('function', 'MPA', (182, 190))	('variants', 'Var', (128, 136))	('elevated', 'PosReg', (6, 14))	('weaken', 'NegReg', (155, 161))	('Lp-PLA2 levels', 'MPA', (15, 29))
829776	31140638	The functional and clinical consequences associated with PLA2G7 polymorphisms were summarized in a review by Stafforini24 in 2009, which mainly discussed the research status of Val279Phe, Arg92His, Ile198Thr, and Vla379Ala SNPs at that time.	('Arg92His', 'Var', (188, 196))	('Ile198Thr', 'Chemical', 'MESH:C524377', (198, 207))	('Val279Phe', 'Var', (177, 186))	('Val', 'Chemical', 'MESH:C081489', (177, 180))	('Phe', 'Chemical', 'MESH:C026650', (183, 186))	('Vla379Ala', 'Mutation', 'rs1051931', (213, 222))	('Ile198Thr', 'Var', (198, 207))	('Vla379Ala', 'Var', (213, 222))
829778	31140638	In addition, several diseases that were rarely reported to be associated with PLA2G7 polymorphisms, such as asthma, schizophrenia, CKD, multiple sclerosis, ulcerative colitis, and Kawasaki disease.	('Kawasaki disease', 'Disease', 'MESH:D009080', (180, 196))	('ulcerative colitis', 'Disease', (156, 174))	('CKD', 'Disease', (131, 134))	('schizophrenia', 'Disease', (116, 129))	('asthma', 'Disease', 'MESH:D001249', (108, 114))	('multiple sclerosis', 'Disease', 'MESH:D009103', (136, 154))	('asthma', 'Phenotype', 'HP:0002099', (108, 114))	('CKD', 'Phenotype', 'HP:0012622', (131, 134))	('asthma', 'Disease', (108, 114))	('schizophrenia', 'Disease', 'MESH:D012559', (116, 129))	('ulcerative colitis', 'Disease', 'MESH:D003093', (156, 174))	('schizophrenia', 'Phenotype', 'HP:0100753', (116, 129))	('PLA2G7', 'Gene', (78, 84))	('multiple sclerosis', 'Disease', (136, 154))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (156, 174))	('polymorphisms', 'Var', (85, 98))	('Kawasaki disease', 'Disease', (180, 196))	('colitis', 'Phenotype', 'HP:0002583', (167, 174))	('CKD', 'Disease', 'None', (131, 134))
829779	31140638	A base G to T transition at nucleotide position 994 in exon 9 of PLA2G7 leads to a Val to Phe substitution at residue 279, which is in proximity to the active site of the enzyme.	('substitution', 'Var', (94, 106))	('Val to Phe substitution at residue 279', 'Mutation', 'rs76863441', (83, 121))	('G to T transition at nucleotide position 994', 'Mutation', 'rs1193576445', (7, 51))	('base G to T', 'Var', (2, 13))	('leads to', 'Reg', (72, 80))	('Val', 'Var', (83, 86))
829780	31140638	The V279F mutant gene is codominantly inherited, and the mutant protein is almost undetectable in the plasma of a homozygous person (279FF), as the misfolded protein cannot be secreted normally.24 The prevalence of 279FF was reported to be 0.4%, 1.2%, and 3% in the Chinese, Korean, and Japanese populations, respectively, while it is rare in the Middle Eastern population and almost completely absent in Europeans.72 On the basis of the regional nature of the prevalence, the correlations between the V279F mutation and diseases was widely determined in the East Asian population and focused on the cardiocerebrovascular field.	('person', 'Species', '9606', (125, 131))	('V279F', 'Mutation', 'rs76863441', (4, 9))	('V279F', 'Mutation', 'rs76863441', (502, 507))	('V279F', 'Var', (502, 507))	('cardiocerebrovascular field', 'Disease', (600, 627))	('cardiocerebrovascular field', 'Disease', 'MESH:C536633', (600, 627))
829783	31140638	The results from the studies discussed in these two reviews were inconsistent, as positive, negative, and nonsignificant associations between V279F mutation and diseases were all described in different studies, even for the same type of disease.	('V279F', 'Var', (142, 147))	('negative', 'NegReg', (92, 100))	('diseases', 'Disease', (161, 169))	('V279F', 'Mutation', 'rs76863441', (142, 147))
829786	31140638	One was in a Chinese population, and almost 90 000 individuals with the F279 allele76 were randomly selected for identification the associations of V279F with various vascular diseases.	('associations', 'Interaction', (132, 144))	('vascular diseases', 'Disease', 'MESH:D014652', (167, 184))	('V279F', 'Var', (148, 153))	('V279F', 'Mutation', 'rs76863441', (148, 153))	('vascular diseases', 'Disease', (167, 184))	('F279', 'Var', (72, 76))
829787	31140638	However, neither positive nor negative correlations were demonstrated between V279F and any vascular diseases.	('vascular diseases', 'Disease', 'MESH:D014652', (92, 109))	('vascular diseases', 'Disease', (92, 109))	('rat', 'Species', '10116', (64, 67))	('V279F', 'Var', (78, 83))	('V279F', 'Mutation', 'rs76863441', (78, 83))
829789	31140638	For example, a case-control study demonstrated no significant association between the V279F mutation and ischemic stroke in a Chinese population (OR = 0.82, 95% CI: 0.44-1.24),79 whereas another genetic study established an increased risk despite using the same study population and disease (OR = 2.51, 95% CI: 1.02-5.91, P = .037).80 In the case of atherosclerosis, a significant inverse association of V279F polymorphism with clinical atherosclerosis was indicated in a recent meta-analysis (OR = 0.88, 95% CI: 0.81-0.95, P = .0007),81 whereas another study did not reveal any significant associations between the V279F genotype and subclinical atherosclerosis using Mendelian randomization analyses.82 Therefore, the dramatic reduction of Lp-PLA2 levels in plasma resulting from the V279F mutation is apparent, but the relationship between the V279F mutation and cardiocerebrovascular diseases is unclear.	('ischemic stroke', 'Disease', 'MESH:D002544', (105, 120))	('reduction', 'NegReg', (729, 738))	('atherosclerosis', 'Disease', (647, 662))	('stroke', 'Phenotype', 'HP:0001297', (114, 120))	('atherosclerosis', 'Phenotype', 'HP:0002621', (647, 662))	('ischemic stroke', 'Disease', (105, 120))	('V279F mutation', 'Var', (786, 800))	('V279F', 'Mutation', 'rs76863441', (404, 409))	('atherosclerosis', 'Disease', 'MESH:D050197', (437, 452))	('ischemic stroke', 'Phenotype', 'HP:0002140', (105, 120))	('atherosclerosis', 'Disease', (437, 452))	('V279F', 'Mutation', 'rs76863441', (786, 791))	('V279F', 'Mutation', 'rs76863441', (86, 91))	('atherosclerosis', 'Disease', 'MESH:D050197', (350, 365))	('V279F', 'Mutation', 'rs76863441', (847, 852))	('Lp-PLA2 levels', 'MPA', (742, 756))	('atherosclerosis', 'Disease', (350, 365))	('atherosclerosis', 'Phenotype', 'HP:0002621', (437, 452))	('atherosclerosis', 'Phenotype', 'HP:0002621', (350, 365))	('cardiocerebrovascular diseases', 'Disease', (866, 896))	('rat', 'Species', '10116', (41, 44))	('cardiocerebrovascular diseases', 'Disease', 'MESH:D030342', (866, 896))	('atherosclerosis', 'Disease', 'MESH:D050197', (647, 662))	('V279F', 'Mutation', 'rs76863441', (616, 621))
829790	31140638	In this context, deeper and more comprehensive research may be necessary to elucidate the actual role of the V279F mutation in the pathology of cardiocerebrovascular diseases.	('cardiocerebrovascular diseases', 'Disease', (144, 174))	('cardiocerebrovascular diseases', 'Disease', 'MESH:D030342', (144, 174))	('V279F', 'Mutation', 'rs76863441', (109, 114))	('V279F', 'Var', (109, 114))
829792	31140638	For example, both genotype and allele frequencies of the V279F mutation in Chinese populations with polycystic ovary syndrome (PCOS)83, 84 and acute pancreatitis (AP)85 were significantly higher than those in controls.	('PCOS', 'Disease', 'MESH:D011085', (127, 131))	('pancreatitis', 'Phenotype', 'HP:0001733', (149, 161))	('polycystic ovary syndrome', 'Disease', (100, 125))	('pancreatitis', 'Disease', 'MESH:D010195', (149, 161))	('higher', 'PosReg', (188, 194))	('polycystic ovary syndrome', 'Disease', 'MESH:D011085', (100, 125))	('polycystic ovary', 'Phenotype', 'HP:0000147', (100, 116))	('AP', 'Phenotype', 'HP:0001735', (163, 165))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (143, 161))	('V279F', 'Mutation', 'rs76863441', (57, 62))	('ovary syndrome', 'Phenotype', 'HP:0000137', (111, 125))	('pancreatitis', 'Disease', (149, 161))	('V279F', 'Var', (57, 62))	('PCOS', 'Disease', (127, 131))
829795	31140638	This result implied that the F allele might protect carriers against hypertension, even in the case of persistent overweight for longer than 3 years.87 Nevertheless, some potential limitations existed in these studies, such as lower power in subsidiary analyses due to small sample size and incomplete conclusions regarding the effect of the V279F mutation on diseases resulting from specific inclusion criteria.	('hypertension', 'Phenotype', 'HP:0000822', (69, 81))	('overweight', 'Phenotype', 'HP:0025502', (114, 124))	('hypertension', 'Disease', 'MESH:D006973', (69, 81))	('V279F', 'Mutation', 'rs76863441', (342, 347))	('hypertension', 'Disease', (69, 81))	('V279F', 'Var', (342, 347))
829796	31140638	A systematic screening of the PLA2G7 gene revealed a base A to G alteration at position 1136 of exon 11, which resulted in a valine to alanine replacement at residue 379.88 Peculiarly, the ancestral allele at this position is base A, but the frequency of mutant base G predominantly reaches approximately 80%.77 Although the V379A mutation is relatively common in European and African populations, its effect on plasma Lp-PLA2 activity is unclear until recently.	('valine to alanine replacement at residue 379', 'Mutation', 'rs1051931', (125, 169))	('A to G alteration at position 1136', 'Mutation', 'rs773436278', (58, 92))	('V379A', 'Var', (325, 330))	('alteration', 'Var', (65, 75))	('V379A', 'Mutation', 'rs1051931', (325, 330))
829797	31140638	The increase of plasma Lp-PLA2 activity in the above studies might derive from the wild-type V379 allele though only to a small extent (<10%), that is, a moderate decrease in plasma Lp-PLA2 activity could be attributed to the mutant A379 allele.	('activity', 'MPA', (31, 39))	('mutant A379', 'Var', (226, 237))	('increase of plasma Lp-', 'Phenotype', 'HP:0003141', (4, 26))	('plasma', 'MPA', (175, 181))	('activity', 'MPA', (190, 198))	('decrease', 'NegReg', (163, 171))	('rat', 'Species', '10116', (158, 161))	('increase', 'PosReg', (4, 12))	('A379', 'Var', (233, 237))	('plasma', 'MPA', (16, 22))
829799	31140638	A series of studies on PLA2G7 genetic polymorphisms reported similar conclusions in Chinese subjects with PCOS (P > .05),84 AD (P = .33),85 and CHD with (P = .21) or without blood stasis syndrome (BSS) (P = .98).93 Interestingly, two studies demonstrated increased Lp-PLA2 activity in A379 allele carriers.	('AD', 'Disease', (124, 126))	('increased Lp-', 'Phenotype', 'HP:0003141', (255, 268))	('increased', 'PosReg', (255, 264))	('PCOS', 'Disease', 'MESH:D011085', (106, 110))	('CHD', 'Disease', (144, 147))	('A379 allele carriers', 'Var', (285, 305))	('CHD', 'Disease', 'None', (144, 147))	('rat', 'Species', '10116', (249, 252))	('CHD', 'Phenotype', 'HP:0001677', (144, 147))	('blood stasis syndrome', 'Disease', (174, 195))	('AD', 'Phenotype', 'HP:0002511', (124, 126))	('Lp-PLA2 activity', 'CPA', (265, 281))	('blood stasis syndrome', 'Disease', 'MESH:D054070', (174, 195))	('AD', 'Disease', 'MESH:D000544', (124, 126))	('PCOS', 'Disease', (106, 110))
829801	31140638	Due to its potential impact on plasma Lp-PLA2 activity, the V379A mutation was explored in patients with a variety of diseases.	('V379A', 'Mutation', 'rs1051931', (60, 65))	('patients', 'Species', '9606', (91, 99))	('V379A', 'Var', (60, 65))	('impact', 'Reg', (21, 27))
829803	31140638	In the Chinese population, the frequencies of the A379 allele were not significantly different between patients with AP (P = .71) or PCOS (P = .88) and their respective healthy controls.	('AP', 'Phenotype', 'HP:0001735', (117, 119))	('PCOS', 'Disease', 'MESH:D011085', (133, 137))	('A379', 'Var', (50, 54))	('patients', 'Species', '9606', (103, 111))	('PCOS', 'Disease', (133, 137))
829804	31140638	Moreover, no associations were observed between the V379A genotype and the risks of AP or PCOS (both P > .05).84, 85 As in the case of V279F polymorphism, the correlation studies largely focused on the associations between V379A mutation and vascular diseases.	('V379A', 'Mutation', 'rs1051931', (223, 228))	('vascular diseases', 'Disease', 'MESH:D014652', (242, 259))	('V379A', 'Mutation', 'rs1051931', (52, 57))	('vascular diseases', 'Disease', (242, 259))	('focused', 'Reg', (187, 194))	('AP', 'Phenotype', 'HP:0001735', (84, 86))	('PCOS', 'Disease', (90, 94))	('V279F', 'Var', (135, 140))	('PCOS', 'Disease', 'MESH:D011085', (90, 94))	('V279F', 'Mutation', 'rs76863441', (135, 140))	('V379A', 'Var', (223, 228))	('associations', 'Interaction', (202, 214))
829805	31140638	However, since Stafforini's review, only one investigation has demonstrated a significant association of the V379A polymorphism with vascular diseases.	('rat', 'Species', '10116', (70, 73))	('vascular diseases', 'Disease', 'MESH:D014652', (133, 150))	('V379A', 'Var', (109, 114))	('vascular diseases', 'Disease', (133, 150))	('V379A', 'Mutation', 'rs1051931', (109, 114))
829806	31140638	Liu et al96 detected a role of the V379A variant in increasing the risk of ischemic stroke in northern Chinese Han patients (OR = 1.43, 95% CI: 1.02-2.00, P = .04).	('patients', 'Species', '9606', (115, 123))	('V379A', 'Var', (35, 40))	('ischemic stroke', 'Phenotype', 'HP:0002140', (75, 90))	('ischemic stroke', 'Disease', (75, 90))	('V379A', 'Mutation', 'rs1051931', (35, 40))	('stroke', 'Phenotype', 'HP:0001297', (84, 90))	('ischemic stroke', 'Disease', 'MESH:D002544', (75, 90))
829807	31140638	Due to the significant association of the heterozygous (VA) genotype with large-artery atherosclerotic stroke, even after adjusting for confounding factors (OR = 1.67, 95% CI: 1.13-2.48, P = .01), the authors concluded that the V379A variant might contribute to ischemic stroke susceptibility in the northern Chinese Han population.96  The majority of the newly reported studies observed no obvious contribution of the V379A variant to the susceptibility and severity of vascular diseases.	('artery atherosclerotic stroke', 'Phenotype', 'HP:0007201', (80, 109))	('vascular diseases', 'Disease', (471, 488))	('V379A', 'Mutation', 'rs1051931', (419, 424))	('stroke', 'Phenotype', 'HP:0001297', (103, 109))	('stroke', 'Phenotype', 'HP:0001297', (271, 277))	('atherosclerotic stroke', 'Disease', (87, 109))	('atherosclerotic stroke', 'Disease', 'MESH:D050197', (87, 109))	('ischemic stroke', 'Disease', 'MESH:D002544', (262, 277))	('V379A', 'Mutation', 'rs1051931', (228, 233))	('ischemic stroke', 'Phenotype', 'HP:0002140', (262, 277))	('vascular diseases', 'Disease', 'MESH:D014652', (471, 488))	('ischemic stroke', 'Disease', (262, 277))	('V379A', 'Var', (419, 424))
829809	31140638	In summary, although the relationship between the Lp-PLA2 level and CHD risk was inconclusive, the V379A variant is unlikely to be an apparent CHD risk.	('CHD', 'Disease', (68, 71))	('CHD', 'Disease', 'None', (143, 146))	('CHD', 'Disease', 'None', (68, 71))	('CHD', 'Disease', (143, 146))	('CHD', 'Phenotype', 'HP:0001677', (143, 146))	('CHD', 'Phenotype', 'HP:0001677', (68, 71))	('V379A', 'Var', (99, 104))	('V379A', 'Mutation', 'rs1051931', (99, 104))
829812	31140638	A functional study by Kruse et al95 demonstrated comparable kinetic characteristics between the recombinant mutant Lp-PLA2 and wild type with respect to K M and V max.	('rat', 'Species', '10116', (43, 46))	('mutant', 'Var', (108, 114))	('V max', 'MPA', (161, 166))
829813	31140638	Similarly, Qi et al92 found that R92H was not associated with Lp-PLA2 mass or activity in the Chinese Han population, even after Bonferroni correction.	('R92H', 'Mutation', 'rs1805017', (33, 37))	('activity', 'MPA', (78, 86))	('Lp-PLA2 mass', 'CPA', (62, 74))	('R92H', 'Var', (33, 37))
829814	31140638	Nevertheless, a genome-wide association study including data from five community-based studies revealed a strong association of the R92H mutation with increased Lp-PLA2 mass (P = 2.4 x 10-23, significance threshold P < 5 x 10-8), but a relatively weak association with Lp-PLA2 activity (P = 2.4 x 10-6).90 Furthermore, three studies successively discerned that a significantly increased Lp-PLA2 level was associated with the H92 allele in the Chinese population, and of these, two were about Lp-PLA2 mass and the third was about activity.84, 85, 93 Interestingly, Suchindran et al98 established that the H92 allele was significantly associated with increased plasma Lp-PLA2 mass (P = 5.8 x 10-14) and diminished Lp-PLA2 activity (P = 1.5 x 10-3, significance threshold P < .01).	('increased', 'PosReg', (649, 658))	('plasma Lp-PLA2 mass', 'MPA', (659, 678))	('Lp-PLA2 activity', 'MPA', (712, 728))	('R92H', 'Mutation', 'rs1805017', (132, 136))	('increased plasma Lp-', 'Phenotype', 'HP:0003141', (649, 669))	('H92', 'Var', (604, 607))	('diminished', 'NegReg', (701, 711))	('increased Lp-', 'Phenotype', 'HP:0003141', (377, 390))	('increased Lp-', 'Phenotype', 'HP:0003141', (151, 164))
829816	31140638	In addition, a large genetic study revealed a trend toward an inverse association between Lp-PLA2 activity and the H92 allele (genotype HH vs RR, OR = -0.02, 95% CI: -0.05 to 0.00).89 In a sizable pharmacogenetic analysis reported recently, Yeo et al38 found that the R92H common variant was associated with a slightly reduced Lp-PLA2 activity.	('R92H', 'Mutation', 'rs1805017', (268, 272))	('R92H', 'Var', (268, 272))	('HH', 'Disease', 'MESH:D006432', (136, 138))	('H common variant', 'Species', '762771', (271, 287))	('reduced', 'NegReg', (319, 326))	('Lp-PLA2 activity', 'CPA', (327, 343))
829819	31140638	Along the lines of the results summarized by Stafforini in the European population,100, 101 the H92 variant was associated with an increased risk of vascular diseases in the Chinese population by Zheng et al93 (OR = 1.81, 95% CI: 1.18-2.78),93 Xu et al102 (OR = 1.63, 95% CI: 1.02-2.62), Ma79 (OR = 1.42, 95% CI: 1.02-2.00), Hong et al103 (OR = 2.66, 95% CI: 1.50-4.69), and Chi et al104 (OR = 1.45, 95% CI: 1.16-1.92).	('vascular diseases', 'Disease', 'MESH:D014652', (149, 166))	('vascular diseases', 'Disease', (149, 166))	('H92', 'Gene', (96, 99))	('variant', 'Var', (100, 107))	('associated', 'Reg', (112, 122))
829820	31140638	Additionally, a recent meta-analysis also yielded a significantly positive association between R92H mutation and clinical atherosclerosis (OR = 1.29, 95% CI: 1.09-1.53).81 However, Casas et al89 (OR = 1.07, 95% CI: 0.84-1.36) reported a nonsignificant impact of H92 allele on the risk of CHD in a large-scale genetic study.	('CHD', 'Phenotype', 'HP:0001677', (288, 291))	('atherosclerosis', 'Disease', 'MESH:D050197', (122, 137))	('atherosclerosis', 'Phenotype', 'HP:0002621', (122, 137))	('H92', 'Var', (262, 265))	('CHD', 'Disease', (288, 291))	('R92H', 'Mutation', 'rs1805017', (95, 99))	('CHD', 'Disease', 'None', (288, 291))	('atherosclerosis', 'Disease', (122, 137))
829821	31140638	Nevertheless, only one study, as far as we know, demonstrated a protective role of the H92 variant in acute myocardial infarction (AMI) patients, as patients harboring the wild-type genotype (RR) exhibited poorer AMI-free survival than patients with the RH and HH genotypes during an 8-year follow-up (P = .003).97  The I198T mutation, first termed the Iso195Thr polymorphism, was another common frequency variant found by Bell et al88 in 1997.	('AMI', 'Chemical', 'MESH:C090894', (213, 216))	('patients', 'Species', '9606', (149, 157))	('rat', 'Species', '10116', (56, 59))	('myocardial infarction', 'Phenotype', 'HP:0001658', (108, 129))	('I198T', 'Mutation', 'rs1805018', (320, 325))	('patients', 'Species', '9606', (236, 244))	('myocardial infarction', 'Disease', (108, 129))	('myocardial infarction', 'Disease', 'MESH:D009203', (108, 129))	('patients', 'Species', '9606', (136, 144))	('AMI', 'Chemical', 'MESH:C090894', (131, 134))	('I198T', 'Var', (320, 325))	('HH', 'Disease', 'MESH:D006432', (261, 263))
829822	31140638	The impact of the I198T variant on the plasma Lp-PLA2 level remained inconclusive.88 Qi et al92 found an evident reduction in both Lp-PLA2 mass and activity when carriers homozygous for the minor allele (TT) were compared with the major allele homozygotes (II) in a Chinese population.92 Maiolino et al97 reported increased Lp-PLA2 activity and unnoticeably altered Lp-PLA2 mass in participants harboring the T198 allele.	('Lp-PLA2 mass', 'CPA', (366, 378))	('Lp-PLA2 activity', 'CPA', (324, 340))	('I198T', 'Mutation', 'rs1805018', (18, 23))	('increased Lp-', 'Phenotype', 'HP:0003141', (314, 327))	('increased', 'PosReg', (314, 323))	('T198', 'Var', (409, 413))	('participants', 'Species', '9606', (382, 394))
829824	31140638	In addition to in vivo studies, Kruse et al95 conducted kinetic experiments with the recombinant enzyme containing the I198T variant, revealing a sixfold higher K M value and comparable V max than the wide-type enzyme.	('K M value', 'MPA', (161, 170))	('I198T', 'Var', (119, 124))	('higher', 'PosReg', (154, 160))	('V max', 'MPA', (186, 191))	('I198T', 'Mutation', 'rs1805018', (119, 124))
829825	31140638	Consequently, the authors speculated that the variant influences the plasmatic Lp-PLA2 protein by lowering the substrate affinities rather than its hydrolytic activity.	('Lp-PLA2 protein', 'Protein', (79, 94))	('influences', 'Reg', (54, 64))	('substrate affinities', 'MPA', (111, 131))	('variant', 'Var', (46, 53))	('rat', 'Species', '10116', (132, 135))	('lowering', 'NegReg', (98, 106))	('rat', 'Species', '10116', (116, 119))	('plasmatic', 'MPA', (69, 78))
829827	31140638	A recent study revealed that T198 allele showed no significant effect on aging in Sicilian octogenarians and either risk or age of onset of AD in a Japanese population.86 Similarly, Sankararaman et al106 reported no association between the haplotype of V379A and I198T genotypes and necrotizing enterocolitis in infants in northwest Louisiana, and the variant frequency was not significantly different from that of healthy controls (P = .26).	('colitis', 'Phenotype', 'HP:0002583', (301, 308))	('I198T', 'Var', (263, 268))	('infants', 'Species', '9606', (312, 319))	('association', 'Interaction', (216, 227))	('V379A', 'Var', (253, 258))	('AD', 'Disease', 'MESH:D000544', (140, 142))	('AD', 'Disease', (140, 142))	('I198T', 'Mutation', 'rs1805018', (263, 268))	('necrotizing enterocolitis', 'Disease', (283, 308))	('V379A', 'Mutation', 'rs1051931', (253, 258))	('necrotizing enterocolitis', 'Disease', 'MESH:D020345', (283, 308))	('AD', 'Phenotype', 'HP:0002511', (140, 142))	('enterocolitis', 'Phenotype', 'HP:0004387', (295, 308))
829828	31140638	However, beyond these reports, studies to determine the role of the I198T variant in diseases other than vascular abnormities have rarely been reported in the past few years.	('I198T', 'Var', (68, 73))	('vascular abnormities', 'Disease', 'MESH:C564415', (105, 125))	('vascular abnormities', 'Disease', (105, 125))	('I198T', 'Mutation', 'rs1805018', (68, 73))
829830	31140638	Hong et al103 found that the T198 allele would not affect the risk of CHD in a Chinese population (OR = 1.26, 95% CI: 0.85-1.87).	('CHD', 'Phenotype', 'HP:0001677', (70, 73))	('CHD', 'Disease', (70, 73))	('T198', 'Var', (29, 33))	('CHD', 'Disease', 'None', (70, 73))
829831	31140638	Likewise, Ferguson et al105 failed to uncover a significant association between the I198T polymorphism and coronary artery calcification (CAC).	('I198T', 'Var', (84, 89))	('coronary artery calcification', 'Phenotype', 'HP:0001717', (107, 136))	('coronary artery calcification', 'Disease', 'MESH:D003324', (107, 136))	('artery calcification', 'Phenotype', 'HP:0003207', (116, 136))	('I198T', 'Mutation', 'rs1805018', (84, 89))	('coronary artery calcification', 'Disease', (107, 136))
829832	31140638	A recent meta-analysis also revealed no significant association between the T198 variant and atherosclerosis (OR = 1.12, 95% CI: 0.79-1.59), whereas weak statistical significance was obtained in a subgroup analysis of the Asian/Oriental population (OR = 1.26, 95% CI: 1.06-1.51).81 Furthermore, Zheng et al93 demonstrated that the T198 allele was strongly associated with the risk of CHD with BSS (OR = 1.93, 95% CI: 1.21-3.06) but not associated with the risk of CHD without BSS (OR = 1.47, 95% CI: 0.89-2.44).	('associated', 'Reg', (356, 366))	('CHD', 'Disease', 'None', (384, 387))	('CHD', 'Phenotype', 'HP:0001677', (384, 387))	('T198', 'Var', (331, 335))	('CHD', 'Disease', (464, 467))	('atherosclerosis', 'Disease', (93, 108))	('CHD', 'Disease', 'None', (464, 467))	('CHD', 'Phenotype', 'HP:0001677', (464, 467))	('BSS', 'Disease', (393, 396))	('atherosclerosis', 'Phenotype', 'HP:0002621', (93, 108))	('rat', 'Species', '10116', (316, 319))	('CHD', 'Disease', (384, 387))	('atherosclerosis', 'Disease', 'MESH:D050197', (93, 108))
829833	31140638	Such a limited association was also observed in three studies included in Stafforini's review.101, 107, 108 Interestingly, two additional unrelated studies revealed quite different effects of the T198 allele on cardiovascular disease (CVD).	('effects', 'Reg', (181, 188))	('cardiovascular disease', 'Disease', 'MESH:D002318', (211, 233))	('CVD', 'Phenotype', 'HP:0001626', (235, 238))	('cardiovascular disease', 'Disease', (211, 233))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (211, 233))	('T198', 'Var', (196, 200))
829834	31140638	Both in SNP (OR = 0.69, 95% CI: 0.53-0.90) and haplotype analyses, Hoffmann et al109 reported lower risks of CAD resulting from the T198 allele, which was more frequent in healthy controls.	('AD', 'Disease', (110, 112))	('AD', 'Phenotype', 'HP:0002511', (110, 112))	('T198', 'Var', (132, 136))	('lower', 'NegReg', (94, 99))	('AD', 'Disease', 'MESH:D000544', (110, 112))
829835	31140638	In contrast, Chi et al104 identified that the T198 allele was more prevalent in CHD patients and was associated with a higher risk of CHD (OR = 1.51, 95% CI: 1.23-1.97).	('CHD', 'Phenotype', 'HP:0001677', (80, 83))	('CHD', 'Disease', (134, 137))	('patients', 'Species', '9606', (84, 92))	('CHD', 'Disease', 'None', (134, 137))	('T198', 'Var', (46, 50))	('CHD', 'Phenotype', 'HP:0001677', (134, 137))	('CHD', 'Disease', 'None', (80, 83))	('CHD', 'Disease', (80, 83))
829837	31140638	The Gln281Arg mutation (rs201256712) could lead to a Gln to Arg replacement at residue 281, which occurs rarely in exon 9 of PLA2G7 (minor allele frequency (MAF) < 0.5%).110 Three studies determined the impact of the variant on plasma Lp-PLA2 activity and revealed its effect on the reduction in enzymatic activity, though to a different extent among the three investigations.77, 110, 111 Furthermore, two studies using computational modeling found that the Q281R variant was deleterious to the structure and function of Lp-PLA2.112, 113 To identify rare loss-of-function mutations of the Lp-PLA2 gene (MAF < 0.5%), Song et al99 resequenced the exons of PLA2G7 in 2000 samples from a Western European population.	('Gln281Arg', 'Mutation', 'rs201256712', (4, 13))	('Gln to Arg replacement at residue 281', 'Mutation', 'rs201256712', (53, 90))	('mutations', 'Var', (572, 581))	('ester', 'Chemical', 'MESH:D004952', (685, 690))	('Lp-PLA2', 'Gene', (589, 596))	('Q281R', 'Mutation', 'rs201256712', (458, 463))	('rs201256712', 'Mutation', 'rs201256712', (24, 35))	('loss-of-function', 'NegReg', (555, 571))
829838	31140638	Among the 19 nonsynonymous SNPs obtained, the Arg82His mutation (rs144983904, MAF = 0.08%) was predicted to be damaging for protein function.99 Two large-scale recent genetic studies also reported a similar negative impact on plasma Lp-PLA2 activity, while all three investigations failed to find an association of this mutation with various cardiovascular traits.38, 77 The I317N mutation (rs201842579) was first demonstrated in Japanese subjects who carried an A to T transition at nucleotide 950 in exon 10 and a substitution of Asn for Ile at codon 317.111 Such a rare mutation was likely to generate a new N-linked glycosylation site on Lp-PLA2, disturb the secretion of the mature enzyme, and result in a deficiency in plasma Lp-PLA2 levels.	('disturb', 'NegReg', (651, 658))	('rs201842579', 'Mutation', 'rs201842579', (391, 402))	('rat', 'Species', '10116', (421, 424))	('I317N', 'Mutation', 'rs201842579', (375, 380))	('Asn for Ile at codon 317', 'Mutation', 'rs201842579', (532, 556))	('N-linked glycosylation site', 'MPA', (611, 638))	('A to T transition at nucleotide 950', 'Mutation', 'rs201842579', (463, 498))	('rs201842579', 'Var', (391, 402))	('rs144983904', 'Mutation', 'rs144983904', (65, 76))	('mutation', 'Var', (573, 581))	('secretion', 'MPA', (663, 672))	('plasma Lp-PLA2 levels', 'MPA', (725, 746))	('rat', 'Species', '10116', (600, 603))	('deficiency', 'NegReg', (711, 721))	('Arg82His', 'Mutation', 'rs144983904', (46, 54))
829839	31140638	This finding was supported by Yeo et al38 in a large pharmacogenetic meta-analysis, where they described decreased enzymatic activity resulting from the I317N mutation.	('enzymatic activity', 'MPA', (115, 133))	('I317N', 'Var', (153, 158))	('decreased', 'NegReg', (105, 114))	('I317N', 'Mutation', 'rs201842579', (153, 158))
829840	31140638	In addition, the authors revealed that the rare Leu389Ser variant (rs34159425, MAF = 0.03%) was deleterious to Lp-PLA2 activity and that the rare Thr278Met variant (rs147252565, MAF = 0.01%) was also likely to be a null allele but was too uncommon to generate significant results.38 Similarly, Polfus et al114 found that the L389S mutation was strongly associated with decreased Lp-PLA2 activity but not with incident CHD (hazard ratio [HR] = 0.92, 95% CI: 0.35-1.49, P = .78) or cardiovascular-related mortality in African-Americans.	('CHD', 'Disease', 'None', (418, 421))	('CHD', 'Disease', (418, 421))	('CHD', 'Phenotype', 'HP:0001677', (418, 421))	('rs34159425', 'Mutation', 'rs34159425', (67, 77))	('rs147252565', 'Mutation', 'rs147252565', (165, 176))	('L389S', 'Var', (325, 330))	('Leu389Ser', 'Mutation', 'rs34159425', (48, 57))	('Thr278Met', 'Mutation', 'rs147252565', (146, 155))	('L389S', 'Mutation', 'rs34159425', (325, 330))	('rat', 'Species', '10116', (430, 433))	('rat', 'Species', '10116', (255, 258))	('decreased', 'NegReg', (369, 378))	('Lp-PLA2', 'Enzyme', (379, 386))
829841	31140638	A nonsense variant at codon 287, Gln287Ter or Q287X mutation (rs140020965), resulted in premature termination of protein translation.	('protein translation', 'MPA', (113, 132))	('Q287X', 'Var', (46, 51))	('Q287X', 'Mutation', 'rs140020965', (46, 51))	('Gln287Ter', 'Var', (33, 42))	('Gln287Ter', 'Mutation', 'rs140020965', (33, 42))	('rs140020965', 'Mutation', 'rs140020965', (62, 73))
829842	31140638	In all three studies mentioning this rare variant, researchers found that carriers had greatly reduced plasma Lp-PLA2 activity but no significant difference in the risk of CHD compared with noncarriers.38, 77, 114 Another premature termination was observed at codon 63 due to an insertion of adenine at nucleotide 191 in exon 3 (Ins191), which would partly impair enzymatic function to a degree.111 Intron mutations were also assessed for their contribution to plasma Lp-PLA2 level or disease progression.	('adenine', 'Chemical', 'MESH:D000225', (292, 299))	('plasma Lp-PLA2 level', 'MPA', (461, 481))	('CHD', 'Disease', 'None', (172, 175))	('CHD', 'Disease', (172, 175))	('CHD', 'Phenotype', 'HP:0001677', (172, 175))	('insertion', 'Var', (279, 288))	('Ins191', 'Gene', (329, 335))
829843	31140638	Among them, rs7756935 caught the attention of researchers, probably owing to the perfect linkage disequilibrium with the Val379Ala mutation (rs1051931).	('rs7756935', 'Mutation', 'rs7756935', (12, 21))	('rs1051931', 'Var', (141, 150))	('rs1051931', 'Mutation', 'rs1051931', (141, 150))	('rs7756935', 'Var', (12, 21))	('Val', 'Chemical', 'MESH:C081489', (121, 124))	('Val379Ala', 'Var', (121, 130))
829845	31140638	Grallert et al90 reported that the minor allele of rs7756935 was associated with an increased Lp-PLA2 activity but not with Lp-PLA2 mass, while no significant effect was observed by Ferguson et al105 on either mass or activity.	('rs7756935', 'Var', (51, 60))	('increased Lp-', 'Phenotype', 'HP:0003141', (84, 97))	('rs7756935', 'Mutation', 'rs7756935', (51, 60))	('increased', 'PosReg', (84, 93))	('Lp-PLA2 activity', 'CPA', (94, 110))
829846	31140638	Further, neither demonstrated an association between the rs7756935 and CHD or CAD.	('rs7756935', 'Mutation', 'rs7756935', (57, 66))	('AD', 'Phenotype', 'HP:0002511', (79, 81))	('CHD', 'Phenotype', 'HP:0001677', (71, 74))	('CHD', 'Disease', 'None', (71, 74))	('rs7756935', 'Var', (57, 66))	('rat', 'Species', '10116', (24, 27))	('CHD', 'Disease', (71, 74))	('AD', 'Disease', 'MESH:D000544', (79, 81))	('AD', 'Disease', (79, 81))
829847	31140638	On the other hand, Xu et al102 revealed that the minor allele C of rs7756935 acted as a protective factor against CHD in Chinese females (OR = 0.59, 95% CI: 0.35-1.00, P = .05).	('rs7756935', 'Mutation', 'rs7756935', (67, 76))	('CHD', 'Disease', (114, 117))	('CHD', 'Disease', 'None', (114, 117))	('rs7756935', 'Var', (67, 76))	('CHD', 'Phenotype', 'HP:0001677', (114, 117))
829848	31140638	Rs2216465 is another well-studied mutation, in which the rare allele homozygotes might have lower plasma Lp-PLA2 activity than the common allele homozygotes.89 Casas et al89 revealed that this intronic variant was not associated with CHD, and Sutton et al101 detected only a nominally significant association between rs2216465 and CAD outcome in their study, where the significance disappeared after multifactor adjustment.	('rs2216465', 'Mutation', 'rs2216465', (317, 326))	('CHD', 'Disease', 'None', (234, 237))	('CHD', 'Disease', (234, 237))	('CHD', 'Phenotype', 'HP:0001677', (234, 237))	('AD', 'Disease', 'MESH:D000544', (332, 334))	('rs2216465', 'Var', (317, 326))	('AD', 'Phenotype', 'HP:0002511', (332, 334))	('Rs2216465', 'Mutation', 'Rs2216465', (0, 9))	('AD', 'Disease', (332, 334))
829849	31140638	However, Ferguson et al105 did not observe an association between rs2216465 and plasma Lp-PLA2 mass or activity, whereas a significant association was detected with CAC.	('rs2216465', 'Mutation', 'rs2216465', (66, 75))	('activity', 'MPA', (103, 111))	('CAC', 'Disease', (165, 168))	('rs2216465', 'Var', (66, 75))
829850	31140638	In addition, a number of other intronic variants in the PLA2G7 gene were also explored, and their impact on the function and expression of Lp-PLA2 was preliminarily demonstrated with respect to the susceptibility and severity of diseases.90, 105  Furthermore, numerous variants located in the 5' upstream, 5'-untranslated region (5'-UTR), and 3'-UTR might be associated with the plasma Lp-PLA2 level and even certain diseases.	('diseases', 'Disease', (417, 425))	('plasma Lp-PLA2 level', 'MPA', (379, 399))	('associated', 'Reg', (359, 369))	('variants', 'Var', (269, 277))	('rat', 'Species', '10116', (172, 175))
829851	31140638	Rs1421378, an intergenic variant, might impair plasma Lp-PLA2 activity with a gene-dose effect,89 although two studies did not observe any significant association.98, 105 Moreover, Casas et al89 were unsuccessful in detecting the clear involvement of this common variant with CHD risk, while Ferguson et al105 demonstrated a strong association of rs1421378 and CAC.	('impair', 'NegReg', (40, 46))	('rat', 'Species', '10116', (317, 320))	('CAC', 'Disease', (361, 364))	('CHD', 'Disease', 'None', (276, 279))	('rs1421378', 'Var', (347, 356))	('CHD', 'Disease', (276, 279))	('rs1421378', 'Mutation', 'rs1421378', (347, 356))	('Rs1421378', 'Mutation', 'Rs1421378', (0, 9))	('CHD', 'Phenotype', 'HP:0001677', (276, 279))
829852	31140638	A 5'-UTR variant (rs9395208) might not be associated with Lp-PLA2 activity and mass in the Chinese population,92 but in the same population, another study found the minor allele of rs9395208 to be a protective factor for CHD (OR = 0.78, 95% CI: 0.62-0.98, P = .03).115 However, Grallert et al90 established that this variant was significantly associated with Lp-PLA2 mass but not with activity or prevalence of CHD or CAD in participants of European ancestry.	('AD', 'Disease', (419, 421))	('variant', 'Var', (317, 324))	('associated', 'Reg', (343, 353))	('rs9395208', 'Mutation', 'rs9395208', (18, 27))	('CHD', 'Disease', (411, 414))	('CHD', 'Disease', 'None', (411, 414))	('CHD', 'Phenotype', 'HP:0001677', (411, 414))	('Lp-PLA2 mass', 'CPA', (359, 371))	('participants', 'Species', '9606', (425, 437))	('CHD', 'Phenotype', 'HP:0001677', (221, 224))	('CHD', 'Disease', 'None', (221, 224))	('AD', 'Disease', 'MESH:D000544', (419, 421))	('rs9395208', 'Mutation', 'rs9395208', (181, 190))	('CHD', 'Disease', (221, 224))	('AD', 'Phenotype', 'HP:0002511', (419, 421))
829853	31140638	Rs12528857 is an example of a 3'-UTR variant that might increase plasma Lp-PLA2 mass without affecting the activity.98 In this context, Sutton et al101 did not observe any association between this variant and CAD outcomes in tested subgroups after adjusting for cardiovascular risk factors.	('AD', 'Disease', (210, 212))	('Rs12528857', 'Mutation', 'Rs12528857', (0, 10))	('increase', 'PosReg', (56, 64))	('plasma Lp-PLA2 mass', 'MPA', (65, 84))	('AD', 'Phenotype', 'HP:0002511', (210, 212))	('increase plasma Lp-', 'Phenotype', 'HP:0003141', (56, 75))	('AD', 'Disease', 'MESH:D000544', (210, 212))	('Rs12528857', 'Var', (0, 10))
829854	31140638	In addition, Gregson et al77 regarded a splice donor variant, c.109 + 2T > C (rs142974898), as a loss-of-function mutation that was unrelated to CHD risk.	('c.109 + 2T > C (rs142974898', 'Var', (62, 89))	('c.109 + 2T > C', 'Mutation', 'rs142974898', (62, 76))	('CHD', 'Disease', 'None', (145, 148))	('CHD', 'Disease', (145, 148))	('donor variant', 'Species', '9606', (47, 60))	('CHD', 'Phenotype', 'HP:0001677', (145, 148))	('loss-of-function', 'NegReg', (97, 113))	('rs142974898', 'Mutation', 'rs142974898', (78, 89))
829856	31140638	Certain variants are more prevalent in specific populations, such as the V279F and I317N variants in East Asians, the Q287X variant in whites and the L389S variant in African ancestral populations.	('I317N', 'Mutation', 'rs201842579', (83, 88))	('L389S', 'Mutation', 'rs34159425', (150, 155))	('I317N', 'Var', (83, 88))	('Q287X', 'Var', (118, 123))	('L389S', 'Var', (150, 155))	('V279F', 'Var', (73, 78))	('V279F', 'Mutation', 'rs76863441', (73, 78))	('Q287X', 'Mutation', 'rs140020965', (118, 123))
829857	31140638	By contrast, the minor alleles of the V379A, R92H, and I198T variants are more common among various ethnic groups, with a frequency of more than 5%.	('I198T', 'Mutation', 'rs1805018', (55, 60))	('R92H', 'Var', (45, 49))	('V379A', 'Var', (38, 43))	('I198T', 'Var', (55, 60))	('R92H', 'Mutation', 'rs1805017', (45, 49))	('V379A', 'Mutation', 'rs1051931', (38, 43))
829862	31140638	In particular, in a recent large-scale study that included more than 260 000 total participants, the researchers genotyped four rare loss-of-function mutations (c.109 + 2T > C, R82H, V279F, and Q287X) and one common modest-impact variant (V379A) in PLA2G7.	('R82H', 'Mutation', 'rs144983904', (177, 181))	('loss-of-function', 'NegReg', (133, 149))	('V379A', 'Var', (239, 244))	('c.109 + 2T > C', 'Var', (161, 175))	('Q287X', 'Mutation', 'rs140020965', (194, 199))	('c.109 + 2T > C', 'Mutation', 'rs142974898', (161, 175))	('Q287X', 'Var', (194, 199))	('V379A', 'Mutation', 'rs1051931', (239, 244))	('V279F', 'Var', (183, 188))	('V279F', 'Mutation', 'rs76863441', (183, 188))	('R82H', 'Var', (177, 181))	('participants', 'Species', '9606', (83, 95))
829865	31140638	Thus, the authors concluded that Lp-PLA2 is unlikely to be a causal risk factor in CHD.77 In contrast, Ferguson et al105 found a nonsignificant association of numerous SNPs in PLA2G7 with Lp-PLA2 activity or mass, but a strong association with CAC.	('PLA2G7', 'Gene', (176, 182))	('CHD', 'Disease', (83, 86))	('CHD', 'Disease', 'None', (83, 86))	('CHD', 'Phenotype', 'HP:0001677', (83, 86))	('SNPs', 'Var', (168, 172))	('CAC', 'Disease', (244, 247))
829866	31140638	Consequently, they concluded that genetic variation in PLA2G7 might relate to CHD independent of the circulating Lp-PLA2 levels.	('CHD', 'Disease', 'None', (78, 81))	('PLA2G7', 'Gene', (55, 61))	('CHD', 'Disease', (78, 81))	('CHD', 'Phenotype', 'HP:0001677', (78, 81))	('relate', 'Reg', (68, 74))	('genetic variation', 'Var', (34, 51))
829867	31140638	Although the clinical consequence of PLA2G7 SNPs for vascular complications, particularly macrovascular abnormalities, remains unclear, they do not seem to be either risk or protective factors.	('SNPs', 'Var', (44, 48))	('macrovascular abnormalities', 'Disease', 'MESH:D002869', (90, 117))	('vascular complications', 'Disease', (53, 75))	('macrovascular abnormalities', 'Disease', (90, 117))	('vascular complications', 'Disease', 'MESH:D014652', (53, 75))
829868	31140638	During acetylsalicylic acid therapy, Postula et al120 and Peng et al121 observed that the minor allele of rs7756935 was associated with increased platelet activity in Caucasians with type 2 diabetes and a Chinese population with ischemic stroke, respectively, signifying a higher risk of aspirin resistance in carriers than noncarriers.	('aspirin', 'Chemical', 'MESH:D001241', (288, 295))	('type 2 diabetes', 'Disease', 'MESH:D003924', (183, 198))	('ischemic stroke', 'Phenotype', 'HP:0002140', (229, 244))	('rs7756935', 'Mutation', 'rs7756935', (106, 115))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (183, 198))	('ischemic stroke', 'Disease', (229, 244))	('increased platelet', 'Phenotype', 'HP:0001894', (136, 154))	('stroke', 'Phenotype', 'HP:0001297', (238, 244))	('acetylsalicylic acid', 'Chemical', 'MESH:D001241', (7, 27))	('type 2 diabetes', 'Disease', (183, 198))	('increased', 'PosReg', (136, 145))	('platelet activity', 'MPA', (146, 163))	('rs7756935', 'Var', (106, 115))	('ischemic stroke', 'Disease', 'MESH:D002544', (229, 244))
829870	31140638	Moreover, the knowledge acquired from the studies on vascular diseases could be applied to other diseases, which might uncover the unanticipated impact of PLA2G7 variants on certain diseases or specific treatments.	('variants', 'Var', (162, 170))	('vascular diseases', 'Disease', 'MESH:D014652', (53, 70))	('vascular diseases', 'Disease', (53, 70))
829884	31140638	In addition, a twofold increase in plasma Lp-PLA2 activity was detected at 24 hours following LPS exposure, but no change was observed at 12 hours.	('LPS', 'Disease', (94, 97))	('exposure', 'Var', (98, 106))	('plasma', 'MPA', (35, 41))	('LPS', 'Disease', 'MESH:C536528', (94, 97))	('increase', 'PosReg', (23, 31))
829892	31140638	Apart from PPAR-gamma, activation of PPAR-alpha would generate a robust increase in Lp-PLA2 mRNA expression in murine hepatocytes, which subsequently contributed to the production and secretion of 1-palmitoyl lysoPC.146 Additionally, Du et al147 indicated that VLDL receptor deletion in mice probably caused diminished expression of Lp-PLA2 from macrophages, which was mediated by Reln (Reelin, a VLDLR ligand) and Dab2 (disabled-2, a cytoplasmic adapter protein).147  Altogether, the differences in the severity of the challenge, phase of the disease, susceptibility to stimulation, and state of cellular activation or differentiation might account for the diverse results.	('PPAR-alpha', 'Gene', (37, 47))	('disabled-2', 'Gene', '13132', (421, 431))	('Dab2', 'Gene', '13132', (415, 419))	('Reelin', 'Gene', '19699', (387, 393))	('Dab2', 'Gene', (415, 419))	('VLDL receptor', 'Gene', (261, 274))	('PPAR-alpha', 'Gene', '19013', (37, 47))	('ether', 'Chemical', 'MESH:D004987', (474, 479))	('mice', 'Species', '10090', (287, 291))	('VLDL receptor', 'Gene', '22359', (261, 274))	('1-palmitoyl', 'Chemical', 'MESH:C032023', (197, 208))	('Reln', 'Gene', '19699', (381, 385))	('Reln', 'Gene', (381, 385))	('rat', 'Species', '10116', (58, 61))	('deletion', 'Var', (275, 283))	('murine', 'Species', '10090', (111, 117))	('disabled-2', 'Gene', (421, 431))	('Reelin', 'Gene', (387, 393))
829926	31140638	The researchers unexpectedly discovered that darapladib treatment resulted in improved alertness and activity in DMHC animals compared with untreated DMHC animals.	('DM', 'Phenotype', 'HP:0000819', (150, 152))	('activity', 'CPA', (101, 109))	('alertness', 'CPA', (87, 96))	('darapladib', 'Chemical', 'MESH:C529040', (45, 55))	('DMHC', 'Var', (113, 117))	('darapladib', 'Gene', (45, 55))	('improved', 'PosReg', (78, 86))	('DM', 'Phenotype', 'HP:0000819', (113, 115))	('HC', 'Phenotype', 'HP:0003124', (115, 117))	('HC', 'Phenotype', 'HP:0003124', (152, 154))
829932	31140638	These two alterations within neuronal cells potentially induced functional disruption and pathological changes, which could be recovered to nearly normal levels using darapladib.186  A phase II trial, which was carried out to reproduce these findings in a relevant AD population, also demonstrated that Lp-PLA2 inhibition could offer beneficial effects on AD progression.	('Lp-PLA2', 'Protein', (303, 310))	('darapladib', 'Chemical', 'MESH:C529040', (167, 177))	('beneficial effects', 'PosReg', (334, 352))	('inhibition', 'Var', (311, 321))	('AD', 'Disease', 'MESH:D000544', (356, 358))	('AD', 'Disease', (356, 358))	('AD', 'Phenotype', 'HP:0002511', (356, 358))	('AD', 'Disease', 'MESH:D000544', (265, 267))	('AD', 'Phenotype', 'HP:0002511', (265, 267))	('rat', 'Species', '10116', (292, 295))	('rat', 'Species', '10116', (14, 17))	('AD', 'Disease', (265, 267))
829949	31140638	Moreover, the diminished retinal vasopermeability induced by inhibition of Lp-PLA2 was independent of the vascular endothelial growth factor (VEGF) signaling axis, and intravitreal VEGF neutralization combined with darapladib treatment synergistically inhibited diabetes-induced vasopermeability.	('VEGF', 'Gene', (142, 146))	('neutralization', 'Var', (186, 200))	('vascular endothelial growth factor', 'Gene', (106, 140))	('diabetes', 'Disease', (262, 270))	('inhibited', 'NegReg', (252, 261))	('retinal vasopermeability', 'MPA', (25, 49))	('inhibition', 'Var', (61, 71))	('VEGF', 'Gene', '7422', (181, 185))	('diabetes', 'Disease', 'MESH:D003920', (262, 270))	('vascular endothelial growth factor', 'Gene', '7422', (106, 140))	('VEGF', 'Gene', '7422', (142, 146))	('diminished', 'NegReg', (14, 24))	('VEGF', 'Gene', (181, 185))	('Lp-PLA2', 'Gene', (75, 82))	('darapladib', 'Chemical', 'MESH:C529040', (215, 225))
829950	31140638	Further mechanistic studies revealed that elevated plasma lysoPC and the production of Lp-PLA2 could act on the luminal side of the endothelium to induce vascular leakage in diabetes, which required signaling by the VEGF receptor 2.	('diabetes', 'Disease', 'MESH:D003920', (174, 182))	('induce', 'Reg', (147, 153))	('VEGF', 'Gene', '7422', (216, 220))	('plasma lysoPC', 'MPA', (51, 64))	('vascular leak', 'Disease', (154, 167))	('vascular leak', 'Disease', 'MESH:D019559', (154, 167))	('VEGF', 'Gene', (216, 220))	('vascular leak', 'Phenotype', 'HP:0030005', (154, 167))	('elevated', 'PosReg', (42, 50))	('diabetes', 'Disease', (174, 182))	('Lp-PLA2', 'Var', (87, 94))
829953	31140638	Furthermore, the DMHC pigs exhibited a significantly higher incidence of IgG-labeled neurons (ganglion cells) in the ganglion cell layer (GCL) of the retina compared with the controls.	('higher', 'PosReg', (53, 59))	('DM', 'Phenotype', 'HP:0000819', (17, 19))	('HC', 'Phenotype', 'HP:0003124', (19, 21))	('CL', 'Disease', 'None', (139, 141))	('pigs', 'Species', '9823', (22, 26))	('DMHC', 'Var', (17, 21))	('IgG-labeled', 'Protein', (73, 84))
829963	31140638	Aberrant Lp-PLA2 expression exists in a variety of cancers, and most tumor tissues show higher level compared with normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (69, 74))	('Lp-PLA2', 'Protein', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
829972	31140638	Similarly, diminished tumor cell invasion and proliferation were detected after silencing PLA2G7.	('silencing', 'Var', (80, 89))	('PLA2G7', 'Gene', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('diminished', 'NegReg', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('proliferation', 'CPA', (46, 59))	('rat', 'Species', '10116', (53, 56))	('tumor', 'Disease', (22, 27))
829984	31140638	The ability of PLA2G7 to improve the predictive power of the gene signatures probably results from the regulation of the tumor microenvironment, and an elevated level of PLA2G7 was a predictor of increased survival following anti-cytotoxic T lymphocyte-associated antigen-4 directed therapy.206 Owing to the autoimmune toxicity induced by immunotherapy, the discovery of the biomarkers, especially blood biomarkers such as PLA2G7, is valuable and could aid the identification of the subset of patients who can benefit from immunotherapy and simultaneously exhibit low risk for autoimmune toxicity.207, 208 Furthermore, PLA2G7 was also identified as a diagnostic marker via a microarray technique for profiling the transcriptome of esophageal cancer cells.	('PLA2G7', 'Var', (619, 625))	('esophageal cancer', 'Disease', 'MESH:D004938', (731, 748))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('patients', 'Species', '9606', (493, 501))	('cancer', 'Phenotype', 'HP:0002664', (742, 748))	('autoimmune toxicity', 'Disease', 'MESH:D064420', (308, 327))	('tumor', 'Disease', (121, 126))	('autoimmune toxicity', 'Disease', 'MESH:D064420', (577, 596))	('autoimmune toxicity', 'Phenotype', 'HP:0002960', (308, 327))	('autoimmune toxicity', 'Phenotype', 'HP:0002960', (577, 596))	('esophageal cancer', 'Disease', (731, 748))	('autoimmune toxicity', 'Disease', (308, 327))	('autoimmune toxicity', 'Disease', (577, 596))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
830022	31140638	Among them, GSK2647544 was a potent and specific inhibitor of Lp-PLA2 disclosed in an early patent.245 In human subjects, GSK2647544 administration was well tolerated for single oral doses up to 750 mg and displayed no significant adverse events.254 Remarkably, oral single doses of 125 mg GSK2647544 resulted in improved PK performance compared with single doses of 160 mg darapladib (area under curve [AUC](0- ): 2506 ng h/mL of GSK2647544 vs 645 ng h/mL of darapladib, ng h/mL; C max: 457 ng/mL of GSK2647544 vs 18 ng/mL of darapladib, ng/mL).	('GSK2647544', 'Var', (431, 441))	('human', 'Species', '9606', (106, 111))	('darapladib', 'Chemical', 'MESH:C529040', (374, 384))	('improved', 'PosReg', (313, 321))	('GSK2647544', 'Var', (290, 300))	('darapladib', 'Chemical', 'MESH:C529040', (460, 470))	('PK performance', 'MPA', (322, 336))	('rat', 'Species', '10116', (161, 164))	('GSK2647544', 'Var', (501, 511))	('rat', 'Species', '10116', (141, 144))	('darapladib', 'Chemical', 'MESH:C529040', (527, 537))
830025	31140638	However, another study reported that GSK2647544 might be a moderate to strong CYP3A4 inhibitor, suggesting potential adverse drug-drug interaction.	('CYP3A4', 'Gene', '1576', (78, 84))	('adverse drug-drug interaction', 'Phenotype', 'HP:0020172', (117, 146))	('rat', 'Species', '10116', (63, 66))	('CYP3A4', 'Gene', (78, 84))	('GSK2647544', 'Var', (37, 47))
830034	31140638	Previous studies revealed that GSK2647544 had an improved PK profile compared with darapladib in human subjects.254 Indeed, we detected greater plasma exposure of GSK2647544 than that of darapladib when dosed orally to SD rats (GSK2647544: C max, 0.78 mug/mL; AUC (0- ), 3.38 mug h/mL at 25 mg/kg and darapladib: C max, 0.15 mug/mL; AUC(0- ), 2.11 mug h/mL at 50 mg/kg).	('GSK2647544', 'Var', (163, 173))	('plasma exposure', 'MPA', (144, 159))	('human', 'Species', '9606', (97, 102))	('darapladib', 'Chemical', 'MESH:C529040', (301, 311))	('darapladib', 'Chemical', 'MESH:C529040', (83, 93))	('darapladib', 'Chemical', 'MESH:C529040', (187, 197))	('rats', 'Species', '10116', (222, 226))
830035	31140638	However, GSK2647544 showed a limited elimination half-life in vivo (t 1/2 = 2.08 hours) and poor metabolic stability (CLint = 74.4 ml/min/kg) in further evaluation with rat liver S9 fractions.	('rat', 'Species', '10116', (169, 172))	('metabolic', 'MPA', (97, 106))	('CL', 'Disease', 'None', (118, 120))	('elimination half-life', 'MPA', (37, 58))	('GSK2647544', 'Var', (9, 19))
830055	31140638	Under the guidance of the crystal structures of inhibitors bound to Lp-PLA2, they designed a hydroxypropyl group to occupy a narrow channel formed by Leu153 and Gln352 (compound 30, Figure 13D), a methoxy group from C-2 of the n-propyl to fill the small pocket formed by the side chain of Ala355 (compound 31), and an aminoethoxy moiety from position 6 of the central aryl ring that points toward the solvent to modulate the physicochemical properties and reduce the lipophilicity of the template (compound 5, Figure 13E).	('lipophilicity of the template', 'MPA', (467, 496))	('aminoethoxy', 'Chemical', 'MESH:C110685', (318, 329))	('Ala355', 'Chemical', 'MESH:C547125', (289, 295))	('C-2', 'Gene', (216, 219))	('Gln352', 'Var', (161, 167))	('Leu153', 'Var', (150, 156))	('Leu153', 'Chemical', 'MESH:C101068', (150, 156))	('methoxy', 'Chemical', 'MESH:C470596', (197, 204))	('reduce', 'NegReg', (456, 462))	('modulate', 'Reg', (412, 420))	('hydroxypropyl', 'Chemical', 'MESH:C070276', (93, 106))	('C-2', 'Gene', '717', (216, 219))	('n-propyl', 'Chemical', 'MESH:C026498', (227, 235))
830064	31140638	The potency was also reflected in the crystal structure of 35 in complex with Lp-PLA2, as the gem-dimethyl motif tightly filled the groove between the side chains of Leu153, Trp298, and Phe322.	('Leu153', 'Var', (166, 172))	('dimethyl', 'Chemical', 'MESH:C032720', (98, 106))	('Leu153', 'Chemical', 'MESH:C101068', (166, 172))	('Trp', 'Chemical', 'MESH:C509690', (174, 177))	('Trp298', 'Var', (174, 180))	('Phe322', 'Var', (186, 192))	('Phe', 'Chemical', 'MESH:C026650', (186, 189))
830065	31140638	The ether oxygen of the linker oriented the phenyl ring into the pocket lined with Phe110, Ala355, and Phe357 and formed close contact with the side chain of Gln352.	('phenyl ring', 'MPA', (44, 55))	('ether', 'Chemical', 'MESH:D004987', (4, 9))	('phenyl', 'Chemical', 'MESH:C064635', (44, 50))	('Phe', 'Chemical', 'MESH:C026650', (103, 106))	('oxygen', 'Chemical', 'MESH:D010100', (10, 16))	('Phe357', 'Var', (103, 109))	('Phe', 'Chemical', 'MESH:C026650', (83, 86))	('Ala355', 'Chemical', 'MESH:C547125', (91, 97))	('Phe110', 'Var', (83, 89))	('Phe357', 'Chemical', 'MESH:C499892', (103, 109))
830084	31140638	The calculated value of K i for SB-222657 was 40 nM, while it was only weakly active on lecithin:cholesterol acyltransferase and completely inactive against paraoxonase.	('SB-222657', 'Chemical', 'MESH:C118636', (32, 41))	('lecithin:cholesterol acyltransferase', 'Gene', '3931', (88, 124))	('lecithin:cholesterol acyltransferase', 'Gene', (88, 124))	('SB-222657', 'Var', (32, 41))	('paraoxon', 'Chemical', 'MESH:D010261', (157, 165))
830086	31140638	After screening 4480 compounds and performing SAR studies, Jeong et al improved a weakly active hit (IC50 = 3.8 muM) containing an oxime moiety to a highly potent compound 40 (IC50 = 50 nM), based on the whole human plasma assay under identical conditions.262, 263 Compound HT-01 was likely to bind to Lp-PLA2 in a covalent manner and was first identified as an activity-based probe for another serine hydrolase DAGLbeta.	('muM', 'Gene', (112, 115))	('conditions.262', 'Var', (245, 259))	('HT-01', 'Gene', (274, 279))	('DAGLbeta', 'Gene', (412, 420))	('serine', 'Chemical', 'MESH:C047902', (395, 401))	('human', 'Species', '9606', (210, 215))	('bind', 'Interaction', (294, 298))	('HT-01', 'CellLine', 'CVCL:9726', (274, 279))	('muM', 'Gene', '56925', (112, 115))	('DAGLbeta', 'Gene', '747', (412, 420))	('oxime', 'Chemical', 'MESH:D010091', (131, 136))
830090	31140638	The amides of xanthurenic acid were other specific scaffolds of Lp-PLA2 inhibitors.266 Initially, Lin et al267 identified novel inhibitors of Lp-PLA2 with amides of the xanthurenic acid moiety, and AX10185 had an IC50 value of 27 nM in human plasma assays.	('human', 'Species', '9606', (236, 241))	('IC50', 'MPA', (213, 217))	('xanthurenic acid', 'Chemical', 'MESH:C028330', (169, 185))	('amides', 'Chemical', 'MESH:D000577', (4, 10))	('amides', 'Chemical', 'MESH:D000577', (155, 161))	('Lp-PLA2', 'Gene', (142, 149))	('amides', 'Var', (155, 161))	('AX10185', 'Var', (198, 205))	('AX10185', 'Chemical', 'MESH:C541510', (198, 205))	('xanthurenic acid', 'Chemical', 'MESH:C028330', (14, 30))
830103	31140638	Recently, two large-scale genetic studies established that PLA2G7 variants that reduced Lp-PLA2 activity to levels comparable to darapladib had no effect on the risk of CHD and outcomes.	('darapladib', 'Chemical', 'MESH:C529040', (129, 139))	('variants', 'Var', (66, 74))	('reduced', 'NegReg', (80, 87))	('CHD', 'Disease', 'None', (169, 172))	('CHD', 'Disease', (169, 172))	('CHD', 'Phenotype', 'HP:0001677', (169, 172))	('Lp-PLA2 activity', 'MPA', (88, 104))
830104	31140638	These results deny, to a certain extent, a causal role of Lp-PLA2 during atherosclerotic progression and are consistent with an early genetic study on PLA2G7 variants that resulted in a modest reduction in Lp-PLA2 activity.77, 89, 114 Therefore, we speculate that a comprehensive genetic study before the clinical trial may be conducive to the identification of the fundamental disease pathways.	('variants', 'Var', (158, 166))	('atherosclerotic', 'Disease', (73, 88))	('atherosclerotic', 'Disease', 'MESH:D050197', (73, 88))
830107	31140638	Among them, one common variant (rs181937009) conferred risk in the placebo arm but reduced the risk in the darapladib arm, suggesting of an improved outcome with the minor allele following treatment with darapladib compared with placebo.38 Similarly, another SNP of PLA2G7 (rs1805018) was reported to affect plasma TG levels in response to supplementation with fish oil-derived long-chain n-3 PUFAs, signifying the interindividual variability in plasma TG levels following n-3 PUFA supplementation.122 Furthermore, ischemic stroke patients carrying the rs1051931 and rs7756935 variants (AA-CC haplotype) were found to have a considerably higher risk of aspirin resistance than noncarriers (OR = 8.23, 95% CI: 1.59-42.63).121 Accordingly, through the determination of the consequences of mutations, particularly, loss-of-function variants, within potential therapeutic target genes by systematic and large-scale human genetic studies, predicting the potential efficacy and safety of the compounds aimed at these targets is possible.	('mutations', 'Var', (787, 796))	('patients', 'Species', '9606', (531, 539))	('PUFA', 'Gene', '9933', (477, 481))	('variants', 'Var', (829, 837))	('loss-of-function', 'NegReg', (812, 828))	('PUFA', 'Gene', (393, 397))	('ischemic stroke', 'Disease', 'MESH:D002544', (515, 530))	('stroke', 'Phenotype', 'HP:0001297', (524, 530))	('rs181937009', 'Mutation', 'rs181937009', (32, 43))	('human', 'Species', '9606', (911, 916))	('aspirin', 'Chemical', 'MESH:D001241', (653, 660))	('PUFA', 'Gene', (477, 481))	('rs7756935', 'Mutation', 'rs7756935', (567, 576))	('PUFA', 'Gene', '9933', (393, 397))	('darapladib', 'Chemical', 'MESH:C529040', (204, 214))	('ischemic stroke', 'Disease', (515, 530))	('AA', 'Gene', '351', (587, 589))	('PUFAs', 'Chemical', 'None', (393, 398))	('rs1051931', 'Mutation', 'rs1051931', (553, 562))	('darapladib', 'Chemical', 'MESH:C529040', (107, 117))	('rs1805018', 'Mutation', 'rs1805018', (274, 283))	('ischemic stroke', 'Phenotype', 'HP:0002140', (515, 530))
830109	31140638	Divergence seems to be ubiquitous among Lp-PLA2 studies, including the results of epidemiologic studies, the impacts of genetic mutations, and the role of Lp-PLA2 in inflammation and disease progression.	('mutations', 'Var', (128, 137))	('inflammation', 'Disease', (166, 178))	('inflammation', 'Disease', 'MESH:D007249', (166, 178))
830111	31140638	Both the substrates (PAF and oxLDL) and products (lysoPC) of Lp-PLA2 hydrolytic action were demonstrated to be proinflammatory mediators.13, 148 Consequently, the accumulation of any of these mediators resulting from a fluctuation in Lp-PLA2 activity could theoretically promote the inflammation process.	('PAF', 'Gene', (21, 24))	('fluctuation', 'Var', (219, 230))	('inflammation', 'Disease', 'MESH:D007249', (283, 295))	('rat', 'Species', '10116', (99, 102))	('accumulation', 'PosReg', (163, 175))	('PAF', 'Gene', '9768', (21, 24))	('inflammation', 'Disease', (283, 295))	('promote', 'PosReg', (271, 278))	('rat', 'Species', '10116', (14, 17))
830116	31140638	Furthermore, lysoPC, particularly the 16:0 lysoPC, a main product of Lp-PLA2, was associated with several diseases, including NASH,228 DR,37 CAVD,274 and CNS diseases.14 Therefore, we assume that alterations in the lysoPC level, the ratio between Lp-PLA2 and lysoPC, or even the proportion among Lp-PLA2, lysoPC, and oxLDL may be an alternative monitoring metric for determining the role of Lp-PLA2 in various diseases.	('CAVD', 'Disease', (141, 145))	('rat', 'Species', '10116', (200, 203))	('CAVD', 'Disease', 'MESH:C535984', (141, 145))	('rat', 'Species', '10116', (233, 236))	('CNS diseases', 'Disease', 'MESH:D002493', (154, 166))	('CNS diseases', 'Disease', (154, 166))	('alterations', 'Var', (196, 207))
830140	31638260	The knockdown of Tex10 led to the inhibition of cell proliferation, the induction of apoptosis and cell cycle arrest, and decreased the stemness, migratory and invasive capacity of the EC109 cells.	('cell cycle arrest', 'CPA', (99, 116))	('decreased the stemness', 'Disease', (122, 144))	('cell proliferation', 'CPA', (48, 66))	('Tex10', 'Gene', (17, 22))	('apoptosis', 'CPA', (85, 94))	('invasive capacity', 'CPA', (160, 177))	('Tex10', 'Gene', '54881', (17, 22))	('inhibition', 'NegReg', (34, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (99, 116))	('decreased the stemness', 'Disease', 'MESH:D020295', (122, 144))	('knockdown', 'Var', (4, 13))	('EC109', 'CellLine', 'CVCL:6898', (185, 190))
830141	31638260	Furthermore, the silencing of Tex10 enhanced the sensitivity of the ESCC cells to 5-fluorouracil.	('Tex10', 'Gene', '54881', (30, 35))	('Tex10', 'Gene', (30, 35))	('ESCC', 'Disease', (68, 72))	('sensitivity', 'MPA', (49, 60))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (82, 96))	('enhanced', 'PosReg', (36, 44))	('silencing', 'Var', (17, 26))	('ESCC', 'Disease', 'MESH:C562729', (68, 72))
830204	31638260	To assess the expression levels of Tex10 mRNA, a large cohort of patients with ESCC from the public datasets, GSE23400 and GSE20347, was analyzed in Oncomine  according to the instructions provided.	('ESCC', 'Disease', 'MESH:C562729', (79, 83))	('Tex10', 'Gene', (35, 40))	('ESCC', 'Disease', (79, 83))	('patients', 'Species', '9606', (65, 73))	('Tex10', 'Gene', '54881', (35, 40))	('GSE20347', 'Var', (123, 131))	('GSE23400', 'Var', (110, 118))
830219	31638260	The results indicated that the silencing of Tex10 significantly inhibited the proliferation of the EC109 cells (P<0.05 and P<0.01; Fig.	('silencing', 'Var', (31, 40))	('Tex10', 'Gene', '54881', (44, 49))	('Tex10', 'Gene', (44, 49))	('inhibited', 'NegReg', (64, 73))	('proliferation of the EC109 cells', 'CPA', (78, 110))	('EC109', 'CellLine', 'CVCL:6898', (99, 104))
830221	31638260	Furthermore, the downregulation of anti-apoptotic factor, Bcl-2, was observed following the knockdown of Tex10 (Fig.	('Bcl-2', 'Gene', '596', (58, 63))	('Tex10', 'Gene', '54881', (105, 110))	('knockdown', 'Var', (92, 101))	('anti-apoptotic factor', 'MPA', (35, 56))	('downregulation', 'NegReg', (17, 31))	('Bcl-2', 'Gene', (58, 63))	('Tex10', 'Gene', (105, 110))
830222	31638260	The effects of Tex10 knockdown on the cell cycle distribution were then investigated.	('knockdown', 'Var', (21, 30))	('Tex10', 'Gene', '54881', (15, 20))	('Tex10', 'Gene', (15, 20))
830224	31638260	Taken together, these results fully demonstrate that the knockdown of Tex10 suppresses ESCC cell proliferation, induces cell apoptosis and blocks cell cycle progression.	('induces', 'Reg', (112, 119))	('ESCC', 'Disease', 'MESH:C562729', (87, 91))	('cell apoptosis', 'CPA', (120, 134))	('knockdown', 'Var', (57, 66))	('cell cycle progression', 'CPA', (146, 168))	('Tex10', 'Gene', (70, 75))	('ESCC', 'Disease', (87, 91))	('Tex10', 'Gene', '54881', (70, 75))	('blocks', 'NegReg', (139, 145))	('suppresses', 'NegReg', (76, 86))
830226	31638260	The results indicated that the knockdown of Tex10 led to a considerable decrease in the number and size of spheroids (P<0.01; Fig.	('decrease', 'NegReg', (72, 80))	('Tex10', 'Gene', '54881', (44, 49))	('knockdown', 'Var', (31, 40))	('Tex10', 'Gene', (44, 49))
830227	31638260	Furthermore, the mRNA levels of stem the cell-specific markers, SRY-Box 2 (Sox2), Nanog and octamer-binding transcription factor 4 (Oct4), and the CSC-associated markers, c-Myc, polycomb ring finger (Bmi1), ATP binding cassette subfamily G member 2 (ABCG2), CD133, CD44 and CD24, decreased significantly in the EC109 cells following the knockdown of Tex10 (P<0.05 and P<0.01; Fig.	('Tex10', 'Gene', '54881', (350, 355))	('ATP binding cassette subfamily G member 2', 'Gene', (207, 248))	('Sox2', 'Gene', '6657', (75, 79))	('ABCG2', 'Gene', (250, 255))	('EC109', 'CellLine', 'CVCL:6898', (311, 316))	('mRNA levels', 'MPA', (17, 28))	('CD44', 'Gene', '960', (265, 269))	('ABCG2', 'Gene', '9429', (250, 255))	('knockdown', 'Var', (337, 346))	('CD44', 'Gene', (265, 269))	('Tex10', 'Gene', (350, 355))	('octamer-binding transcription factor 4', 'Gene', '5460', (92, 130))	('CD24', 'Gene', (274, 278))	('Bmi1', 'Gene', (200, 204))	('Oct4', 'Gene', '5460', (132, 136))	('SRY-Box 2', 'Gene', '6657', (64, 73))	('Bmi1', 'Gene', '648', (200, 204))	('Nanog', 'Gene', '79923', (82, 87))	('SRY-Box 2', 'Gene', (64, 73))	('Nanog', 'Gene', (82, 87))	('Sox2', 'Gene', (75, 79))	('c-Myc', 'Gene', (171, 176))	('CD133', 'Gene', (258, 263))	('ATP binding cassette subfamily G member 2', 'Gene', '9429', (207, 248))	('CD133', 'Gene', '8842', (258, 263))	('octamer-binding transcription factor 4', 'Gene', (92, 130))	('CD24', 'Gene', '100133941', (274, 278))	('Oct4', 'Gene', (132, 136))	('c-Myc', 'Gene', '4609', (171, 176))	('decreased', 'NegReg', (280, 289))
830228	31638260	Furthermore, the protein expression levels of CD44 and CD24 were downregulated following the knockdown of Tex10 (Fig.	('knockdown', 'Var', (93, 102))	('Tex10', 'Gene', (106, 111))	('CD44', 'Gene', (46, 50))	('Tex10', 'Gene', '54881', (106, 111))	('downregulated', 'NegReg', (65, 78))	('protein expression levels', 'MPA', (17, 42))	('CD24', 'Gene', '100133941', (55, 59))	('CD24', 'Gene', (55, 59))	('CD44', 'Gene', '960', (46, 50))
830229	31638260	The present study therefore established that Tex10 silencing severely impairs the self-renewal capacity of CSCs.	('silencing', 'Var', (51, 60))	('self-renewal capacity of CSCs', 'CPA', (82, 111))	('Tex10', 'Gene', (45, 50))	('impairs', 'NegReg', (70, 77))	('Tex10', 'Gene', '54881', (45, 50))
830231	31638260	Thus, to explore the potential role of Tex10 in promoting chemoresistance, the effect of 5-fluorouracil on the survival of EC109 cells in which Tex10 was knocked down was further investigated.	('EC109', 'CellLine', 'CVCL:6898', (123, 128))	('Tex10', 'Gene', '54881', (39, 44))	('Tex10', 'Gene', '54881', (144, 149))	('Tex10', 'Gene', (144, 149))	('knocked down', 'Var', (154, 166))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (89, 103))	('chemoresistance', 'CPA', (58, 73))	('Tex10', 'Gene', (39, 44))
830237	31638260	Transwell assays indicated that the silencing of Tex10 markedly suppressed the migration of the EC109 cells.	('EC109', 'CellLine', 'CVCL:6898', (96, 101))	('suppressed', 'NegReg', (64, 74))	('Tex10', 'Gene', (49, 54))	('silencing', 'Var', (36, 45))	('migration of the EC109 cells', 'CPA', (79, 107))	('Tex10', 'Gene', '54881', (49, 54))
830238	31638260	Furthermore, the invasion of the EC109 cells significantly decreased following Tex10 knockdown.	('decreased', 'NegReg', (59, 68))	('Tex10', 'Gene', (79, 84))	('Tex10', 'Gene', '54881', (79, 84))	('EC109', 'CellLine', 'CVCL:6898', (33, 38))	('knockdown', 'Var', (85, 94))	('invasion of the EC109 cells', 'CPA', (17, 44))
830240	31638260	It was observed that the morphology of the EC109 cells with stable Tex10 knockdown changed from a spindle-like mesenchymal morphology to an epithelial cobblestone-like appearance (Fig.	('epithelial cobblestone-like appearance', 'CPA', (140, 178))	('Tex10', 'Gene', '54881', (67, 72))	('changed', 'Reg', (83, 90))	('Tex10', 'Gene', (67, 72))	('EC109', 'CellLine', 'CVCL:6898', (43, 48))	('spindle-like mesenchymal morphology', 'CPA', (98, 133))	('knockdown', 'Var', (73, 82))
830241	31638260	The morphological changes were further supported by phalloidin staining, indicating that the EC109 cells in which Tex10 was silenced exhibited a cobblestone-like shape and shrunken F-actin fibers compared to the scrambled shRNA-transfected cells (Fig.	('shrunken', 'NegReg', (172, 180))	('phalloidin', 'Chemical', 'MESH:D010590', (52, 62))	('EC109', 'CellLine', 'CVCL:6898', (93, 98))	('cobblestone-like shape', 'CPA', (145, 167))	('silenced', 'Var', (124, 132))	('Tex10', 'Gene', (114, 119))	('exhibited', 'Reg', (133, 142))	('Tex10', 'Gene', '54881', (114, 119))
830249	31638260	5D, the silencing of Tex10 markedly reduced the protein levels of cyclin D1, c-Myc and TCF4.	('cyclin D1', 'Gene', '595', (66, 75))	('cyclin D1', 'Gene', (66, 75))	('TCF4', 'Gene', (87, 91))	('TCF4', 'Gene', '6925', (87, 91))	('Tex10', 'Gene', (21, 26))	('silencing', 'Var', (8, 17))	('c-Myc', 'Gene', '4609', (77, 82))	('Tex10', 'Gene', '54881', (21, 26))	('reduced', 'NegReg', (36, 43))	('c-Myc', 'Gene', (77, 82))
830261	31638260	The results of the present study demonstrated that the silencing of Tex10 impaired cell stemness through the reduction of the expression of Sox2, Nanog and Oct4.	('impaired cell stemness', 'Disease', 'MESH:D020295', (74, 96))	('Sox2', 'Gene', (140, 144))	('Oct4', 'Gene', '5460', (156, 160))	('expression', 'MPA', (126, 136))	('Nanog', 'Gene', (146, 151))	('Tex10', 'Gene', '54881', (68, 73))	('Tex10', 'Gene', (68, 73))	('silencing', 'Var', (55, 64))	('reduction', 'NegReg', (109, 118))	('Oct4', 'Gene', (156, 160))	('impaired cell stemness', 'Disease', (74, 96))	('Sox2', 'Gene', '6657', (140, 144))	('Nanog', 'Gene', '79923', (146, 151))
830262	31638260	In addition, it was indicated that the knockdown of Tex10 in the EC109 cells enhanced the sensitivity of the cells to 5-fluorouracil.	('EC109', 'CellLine', 'CVCL:6898', (65, 70))	('enhanced', 'PosReg', (77, 85))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (118, 132))	('knockdown', 'Var', (39, 48))	('sensitivity', 'MPA', (90, 101))	('Tex10', 'Gene', '54881', (52, 57))	('Tex10', 'Gene', (52, 57))
830265	31638260	The present study confirmed that the silencing of Tex10 substantially reduced ESCC cell migration and invasion, and Tex10 expression was associated with morphological changes and the expression of EMT markers; thesilencing of Tex10 upregulated E-cadherin and downregulates vimentin, Slug, beta-catenin expression in ESCC cells, suggesting that Tex10 promotes EMT in vitro.	('downregulates', 'NegReg', (259, 272))	('Tex10', 'Gene', '54881', (50, 55))	('vimentin', 'Gene', '7431', (273, 281))	('vimentin', 'Gene', (273, 281))	('Tex10', 'Gene', (344, 349))	('E-cadherin', 'Gene', (244, 254))	('E-cadherin', 'Gene', '999', (244, 254))	('Tex10', 'Gene', (50, 55))	('expression', 'MPA', (302, 312))	('silencing', 'Var', (37, 46))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('upregulated', 'PosReg', (232, 243))	('Slug', 'Gene', (283, 287))	('reduced', 'NegReg', (70, 77))	('Tex10', 'Gene', '54881', (116, 121))	('Tex10', 'Gene', '54881', (226, 231))	('ESCC', 'Disease', 'MESH:C562729', (316, 320))	('ESCC', 'Disease', (78, 82))	('Tex10', 'Gene', (116, 121))	('thesilencing', 'Var', (210, 222))	('beta-catenin', 'Gene', (289, 301))	('Tex10', 'Gene', (226, 231))	('invasion', 'CPA', (102, 110))	('beta-catenin', 'Gene', '1499', (289, 301))	('Tex10', 'Gene', '54881', (344, 349))	('Slug', 'Gene', '6591', (283, 287))	('ESCC', 'Disease', (316, 320))
830269	31638260	The present study established that the silencing of Tex10 decreased the expression of beta-catenin and the target genes, TCF4, cyclin D1 and c-Myc, suggesting that pharmacological targeting of Tex10 to block Wnt/beta-catenin signaling and inhibit EMT is an attractive strategy with which to prevent tumor metastasis in ESCC.	('Tex10', 'Gene', '54881', (193, 198))	('inhibit', 'NegReg', (239, 246))	('decreased', 'NegReg', (58, 67))	('TCF4', 'Gene', (121, 125))	('silencing', 'Var', (39, 48))	('tumor metastasis', 'Disease', (299, 315))	('Tex10', 'Gene', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('ESCC', 'Disease', 'MESH:C562729', (319, 323))	('expression', 'MPA', (72, 82))	('cyclin D1', 'Gene', (127, 136))	('beta-catenin', 'Gene', (212, 224))	('beta-catenin', 'Gene', '1499', (212, 224))	('beta-catenin', 'Gene', (86, 98))	('beta-catenin', 'Gene', '1499', (86, 98))	('ESCC', 'Disease', (319, 323))	('c-Myc', 'Gene', (141, 146))	('Tex10', 'Gene', '54881', (52, 57))	('cyclin D1', 'Gene', '595', (127, 136))	('EMT', 'CPA', (247, 250))	('c-Myc', 'Gene', '4609', (141, 146))	('TCF4', 'Gene', '6925', (121, 125))	('tumor metastasis', 'Disease', 'MESH:D009362', (299, 315))	('Tex10', 'Gene', (52, 57))
830273	31638260	Q18054 to XX) and the Bureau of Science and Technology and Intellectual Property Nanchong City, China (NSMC20170466 to XX, 18SXHZ0211 to XL, 18SXHZ0210 to RX).	('18SXHZ0211', 'Chemical', 'MESH:C506401', (123, 133))	('18SXHZ0210 to', 'Var', (141, 154))	('18SXHZ0211 to XL', 'Var', (123, 139))	('RX', 'Chemical', 'MESH:C096849', (155, 157))	('Q18054', 'Chemical', 'MESH:C000295', (0, 6))	('NSMC20170466 to', 'Var', (103, 118))
830276	30619505	PIK3CA mutations are frequent in esophageal squamous cell carcinoma associated with chagasic megaesophagus and are associated with a worse patient outcome Chronic diseases such as chagasic megaesophagus (secondary to Chagas' disease) have been suggested as etiological factors for esophageal squamous cell carcinoma; however, the molecular mechanisms involved are poorly understood.	('esophageal squamous cell carcinoma', 'Disease', (281, 315))	("Chagas' disease", 'Disease', 'MESH:D014355', (217, 232))	('Chronic diseases', 'Disease', (155, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (292, 315))	('esophageal squamous cell carcinoma', 'Disease', (33, 67))	('Chronic diseases', 'Disease', 'MESH:D002908', (155, 171))	('PIK3CA', 'Gene', '5290', (0, 6))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (281, 315))	('mutations', 'Var', (7, 16))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (33, 67))	('associated', 'Reg', (115, 125))	('frequent', 'Reg', (21, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('chagasic megaesophagus', 'Disease', (180, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (306, 315))	('associated', 'Reg', (68, 78))	('chagasic megaesophagus', 'Disease', (84, 106))	("Chagas' disease", 'Disease', (217, 232))	('PIK3CA', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('patient', 'Species', '9606', (139, 146))
830277	30619505	We analyzed hotspot PIK3CA gene mutations in a series of esophageal squamous cell carcinomas associated or not with chagasic megaesophagus, as well as, in chagasic megaesophagus biopsies.	('PIK3CA', 'Gene', (20, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('PIK3CA', 'Gene', '5290', (20, 26))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (68, 92))	('associated', 'Reg', (93, 103))	('mutations', 'Var', (32, 41))	('esophageal squamous cell carcinomas', 'Disease', (57, 92))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (57, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))
830280	30619505	PIK3CA hotspot mutations in exons 9 and 20 were evaluated by PCR followed by direct sequencing technique.	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (15, 24))	('PIK3CA', 'Gene', (0, 6))
830281	30619505	PIK3CA mutations were identified in 21.7% (5 out of 23) of CM/ESCC cases, in 10.5% (4 out of 38) of ESCC and in only 3.6% (1 case out of 28) of CM cases.	('CM', 'Disease', 'MESH:D009202', (144, 146))	('CM', 'Disease', 'MESH:D009202', (59, 61))	('PIK3CA', 'Gene', (0, 6))	('ESCC', 'Disease', (100, 104))	('identified', 'Reg', (22, 32))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (7, 16))
830282	30619505	In the CM/ESCC group, PIK3CA mutations were significantly associated with lower survival (mean 5 months), when compared to wild-type patients (mean 2.0 years).	('CM', 'Disease', 'MESH:D009202', (7, 9))	('PIK3CA', 'Gene', '5290', (22, 28))	('patients', 'Species', '9606', (133, 141))	('survival', 'MPA', (80, 88))	('mutations', 'Var', (29, 38))	('lower', 'NegReg', (74, 79))	('PIK3CA', 'Gene', (22, 28))
830283	30619505	No other significant associations were observed between PIK3CA mutations and patients' clinical features or TP53 mutation profile.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('PIK3CA', 'Gene', (56, 62))	('patients', 'Species', '9606', (77, 85))	('PIK3CA', 'Gene', '5290', (56, 62))
830284	30619505	This is the first report on the presence of PIK3CA mutations in esophageal cancer associated with chagasic megaesophagus.	('PIK3CA', 'Gene', (44, 50))	('associated', 'Reg', (82, 92))	('mutations', 'Var', (51, 60))	('PIK3CA', 'Gene', '5290', (44, 50))	('chagasic megaesophagus', 'Disease', (98, 120))	('presence', 'Reg', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
830285	30619505	The detection of PIK3CA mutations in benign chagasic megaesophagus lesions suggests their putative role in esophageal squamous cell carcinoma development and opens new opportunities for targeted-therapies for these diseases.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('PIK3CA', 'Gene', (17, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('PIK3CA', 'Gene', '5290', (17, 23))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))	('role', 'Reg', (99, 103))	('mutations', 'Var', (24, 33))
830295	30619505	Recently, our group showed the high frequency (13/32, 40.6%) of TP53 mutations in ESCC associated with chagasic megaesophagus.	('mutations', 'Var', (69, 78))	('associated', 'Reg', (87, 97))	('ESCC', 'Gene', (82, 86))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('chagasic megaesophagus', 'Disease', (103, 125))
830299	30619505	Recurrent PI3KCA oncogenic mutations were identified in several types of tumors, including colorectal, breast, ovary, gastric, and recently in ESSC.	('mutations', 'Var', (27, 36))	('identified', 'Reg', (42, 52))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('breast', 'Disease', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('colorectal', 'Disease', (91, 101))	('PI3KCA', 'Gene', (10, 16))	('ovary', 'Disease', (111, 116))	('gastric', 'Disease', (118, 125))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('ESSC', 'Disease', (143, 147))
830300	30619505	The mutations occur mainly in exons 9 (E542K and E545K) and 20 (H1047R).	('E542K', 'Var', (39, 44))	('H1047R', 'Var', (64, 70))	('E545K', 'Mutation', 'rs104886003', (49, 54))	('E545K', 'Var', (49, 54))	('E542K', 'Mutation', 'rs121913273', (39, 44))	('H1047R', 'Mutation', 'rs121913279', (64, 70))
830301	30619505	Recently, it was shown that PIK3CA mutations, namely H1047R, also disrupt cellular genetic stability, increasing the frequency of chromosomal errors and leading to tetraploidy.	('disrupt', 'NegReg', (66, 73))	('H1047R', 'Var', (53, 59))	('cellular genetic stability', 'CPA', (74, 100))	('leading to', 'Reg', (153, 163))	('PIK3CA', 'Gene', (28, 34))	('chromosomal errors', 'Disease', 'MESH:D012030', (130, 148))	('tetraploidy', 'CPA', (164, 175))	('increasing', 'PosReg', (102, 112))	('PIK3CA', 'Gene', '5290', (28, 34))	('H1047R', 'Mutation', 'rs121913279', (53, 59))	('chromosomal errors', 'Disease', (130, 148))
830302	30619505	Importantly, therapeutic strategies targeting the PIK3/Akt signaling pathway have been developed and could constitute effective treatment options for patients harboring PI3KCA mutations.	('Akt', 'Gene', (55, 58))	('mutations', 'Var', (176, 185))	('patients', 'Species', '9606', (150, 158))	('PIK3', 'Gene', (50, 54))	('PI3KCA', 'Gene', (169, 175))	('Akt', 'Gene', '207', (55, 58))	('PIK3', 'Gene', '5294', (50, 54))
830303	30619505	Therefore, in the current study we performed the mutation analysis of PIK3CA gene in patients with ESCC and chagasic megaesophagus associated or not with ESCC, and searched for associations between the mutation status and patients' clinical and pathological features.	('patients', 'Species', '9606', (222, 230))	('associated', 'Reg', (131, 141))	('ESCC', 'Disease', (99, 103))	('PIK3CA', 'Gene', (70, 76))	('mutation', 'Var', (49, 57))	('patients', 'Species', '9606', (85, 93))	('PIK3CA', 'Gene', '5290', (70, 76))
830320	30619505	The PIK3CA mutation analysis showed the presence of mutations in 21.7% of patients in CM/ESCC group, followed by 10.5% in ESCC group and 3.6% in CM group (Fig.	('mutations', 'Var', (52, 61))	('patients', 'Species', '9606', (74, 82))	('PIK3CA', 'Gene', (4, 10))	('CM', 'Disease', 'MESH:D009202', (86, 88))	('CM', 'Disease', 'MESH:D009202', (145, 147))	('PIK3CA', 'Gene', '5290', (4, 10))
830321	30619505	With the exception of three variants (A1027D, K1030R and T1053K), all the other mutations have already been reported in the Catalogue of Somatic Mutations in Cancer database - COSMIC (http://cancer.sanger.ac.uk/cosmic) (Fig.	('T1053K', 'Mutation', 'p.T1053K', (57, 63))	('T1053K', 'Var', (57, 63))	('A1027D', 'Var', (38, 44))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Cancer', 'Disease', (158, 164))	('Cancer', 'Disease', 'MESH:D009369', (158, 164))	('A1027D', 'Mutation', 'p.A1027D', (38, 44))	('K1030R', 'Mutation', 'rs778000986', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('K1030R', 'Var', (46, 52))
830323	30619505	Furthermore, we assessed the role of PIK3CA mutations on patients' overall survival in both groups affected by cancer (CM/ESCC and ESCC) (Fig.	('PIK3CA', 'Gene', '5290', (37, 43))	('CM', 'Disease', 'MESH:D009202', (119, 121))	('patients', 'Species', '9606', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('PIK3CA', 'Gene', (37, 43))
830324	30619505	In CM/ESCC group, we observed that the presence of PIK3CA mutations was significantly associated with a lower survival rate from the diagnosis of cancer compared to wild-type patients (Fig.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('survival', 'MPA', (110, 118))	('CM', 'Disease', 'MESH:D009202', (3, 5))	('presence', 'Var', (39, 47))	('PIK3CA', 'Gene', (51, 57))	('lower', 'NegReg', (104, 109))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('PIK3CA', 'Gene', '5290', (51, 57))
830325	30619505	The mean patients' overall survival in cases from the CM/ESCC group mutated for the PIK3CA was 5 months, in comparison with 2.0 years for wild-type PIK3CA patients (Log-rank, p < 0.001) (Table 5).	('patients', 'Species', '9606', (9, 17))	('PIK3CA', 'Gene', '5290', (148, 154))	('PIK3CA', 'Gene', '5290', (84, 90))	('patients', 'Species', '9606', (155, 163))	('PIK3CA', 'Gene', (84, 90))	('PIK3CA', 'Gene', (148, 154))	('mutated', 'Var', (68, 75))	('CM', 'Disease', 'MESH:D009202', (54, 56))
830326	30619505	Additionally, we evaluated the association of PIK3CA and TP53 mutation status, and no association was found (Table 4).	('PIK3CA', 'Gene', '5290', (46, 52))	('association', 'Interaction', (31, 42))	('mutation status', 'Var', (62, 77))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('PIK3CA', 'Gene', (46, 52))
830329	30619505	In the present study, we investigated the frequency of PIK3CA mutations in regions of hotspot (exons 9 and 20) in patients with chagasic megaesophagus associated with esophageal squamous cell carcinoma (CM/ESCC) and compared with patients with esophageal squamous cell carcinoma without chagasic megaesophagus (ESCC) and patients with chagasic megaesophagus without esophageal squamous cell carcinoma (CM).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (244, 278))	('CM', 'Disease', 'MESH:D009202', (203, 205))	('CM', 'Disease', 'MESH:D009202', (402, 404))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('esophageal squamous cell carcinoma', 'Disease', (167, 201))	('esophageal squamous cell carcinoma', 'Disease', (366, 400))	('patients', 'Species', '9606', (321, 329))	('associated', 'Reg', (151, 161))	('PIK3CA', 'Gene', '5290', (55, 61))	('patients', 'Species', '9606', (114, 122))	('mutations', 'Var', (62, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('esophageal squamous cell carcinoma', 'Disease', (244, 278))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (167, 201))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (366, 400))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (377, 400))	('patients', 'Species', '9606', (230, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (391, 400))	('PIK3CA', 'Gene', (55, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
830331	30619505	This is the first report of PIK3CA mutation in ESCC that developed in the context of chagasic megaesophagus and the significant frequency of mutations (~ 22%) suggest that PIK3CA plays an important role in the carcinogenesis of CM/ESCC patients.	('PIK3CA', 'Gene', (28, 34))	('patients', 'Species', '9606', (236, 244))	('PIK3CA', 'Gene', (172, 178))	('CM', 'Disease', 'MESH:D009202', (228, 230))	('PIK3CA', 'Gene', '5290', (172, 178))	('PIK3CA', 'Gene', '5290', (28, 34))	('mutation', 'Var', (35, 43))
830332	30619505	Moreover, the presence of PIK3CA mutation in a benign lesion further supports the putative role of chagasic megaesophagus as an ESCC-related condition.	('mutation', 'Var', (33, 41))	('ESCC-related', 'Disease', (128, 140))	('PIK3CA', 'Gene', '5290', (26, 32))	('presence', 'Reg', (14, 22))	('chagasic megaesophagus', 'Disease', (99, 121))	('PIK3CA', 'Gene', (26, 32))
830333	30619505	The frequency of mutations identified in our study is in line with that reported in the literature for ESCC patients, with frequencies varying from 2.2 to 32.8% (Table 6).	('ESCC', 'Disease', (103, 107))	('mutations', 'Var', (17, 26))	('patients', 'Species', '9606', (108, 116))
830335	30619505	The PIK3CA gene is often mutated in several tumors types and most of its mutations occur in hotspot regions, such as E542K and E545A located in the helical domain (exon 9), and H1047R and H1047L in the kinase domain (exon 20).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('H1047R', 'Var', (177, 183))	('H1047L', 'Var', (188, 194))	('E542K', 'Mutation', 'rs121913273', (117, 122))	('PIK3CA', 'Gene', (4, 10))	('H1047R', 'Mutation', 'rs121913279', (177, 183))	('E545A', 'Mutation', 'rs121913274', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('PIK3CA', 'Gene', '5290', (4, 10))	('E545A', 'Var', (127, 132))	('E542K', 'Var', (117, 122))	('H1047L', 'Mutation', 'rs121913279', (188, 194))
830336	30619505	These mutations lead to the activation of the PIK3 pathway and have a great potential in oncogenic activities.	('PIK3', 'Gene', (46, 50))	('activation', 'PosReg', (28, 38))	('oncogenic activities', 'CPA', (89, 109))	('PIK3', 'Gene', '5294', (46, 50))	('mutations', 'Var', (6, 15))
830337	30619505	Interestingly, most of these mutations (E545A, H1047R and H1047L) occurred in patients in the CM/ESCC group and only one (E545A) in one patient in the ESCC group.	('patient', 'Species', '9606', (136, 143))	('patient', 'Species', '9606', (78, 85))	('occurred', 'Reg', (66, 74))	('H1047L', 'Mutation', 'rs121913279', (58, 64))	('H1047L', 'Var', (58, 64))	('CM', 'Disease', 'MESH:D009202', (94, 96))	('E545A', 'Mutation', 'rs121913274', (40, 45))	('H1047R', 'Var', (47, 53))	('patients', 'Species', '9606', (78, 86))	('E545A', 'Mutation', 'rs121913274', (122, 127))	('E545A', 'Var', (40, 45))	('H1047R', 'Mutation', 'rs121913279', (47, 53))
830338	30619505	We also identified other previously described important mutations (Table 3), the D549H mutation observed in the CM/ESCC group was reported in vulva and hepatocellular cancer; R524K mutation found in the ESCC group was reported in colorectal cancer; and the R555K mutation was reported in ovary cancer.	('vulva', 'Disease', (142, 147))	('R555K', 'Var', (257, 262))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (152, 173))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (152, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (230, 247))	('reported', 'Reg', (218, 226))	('ovary cancer', 'Phenotype', 'HP:0100615', (288, 300))	('D549H', 'Var', (81, 86))	('D549H', 'Mutation', 'p.D549H', (81, 86))	('reported', 'Reg', (130, 138))	('colorectal cancer', 'Disease', (230, 247))	('R524K', 'Var', (175, 180))	('R555K', 'Mutation', 'rs104886000', (257, 262))	('R524K', 'Mutation', 'rs104885999', (175, 180))	('CM', 'Disease', 'MESH:D009202', (112, 114))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('ovary cancer', 'Disease', (288, 300))	('colorectal cancer', 'Phenotype', 'HP:0003003', (230, 247))	('ovary cancer', 'Disease', 'MESH:D010051', (288, 300))	('hepatocellular cancer', 'Disease', (152, 173))
830339	30619505	Interestingly, it is important to note that we identified three mutations in exon 20 that have not yet been reported (A1027D and K1030R in CM/ESCC group; T1053K in CM group).	('K1030R', 'Var', (129, 135))	('K1030R', 'Mutation', 'rs778000986', (129, 135))	('T1053K', 'Var', (154, 160))	('T1053K', 'Mutation', 'p.T1053K', (154, 160))	('A1027D', 'Var', (118, 124))	('CM', 'Disease', 'MESH:D009202', (139, 141))	('A1027D', 'Mutation', 'p.A1027D', (118, 124))	('CM', 'Disease', 'MESH:D009202', (164, 166))
830340	30619505	All these mutations occurred in patients with chagasic megaesophagus whose mutational profile of PIK3CA was never reported.	('patients', 'Species', '9606', (32, 40))	('chagasic megaesophagus', 'Disease', (46, 68))	('occurred', 'Reg', (20, 28))	('mutations', 'Var', (10, 19))	('PIK3CA', 'Gene', (97, 103))	('PIK3CA', 'Gene', '5290', (97, 103))
830341	30619505	Importantly, we observed that CM/ESCC patients harboring PIK3CA mutations were associated with lower overall survival, suggesting its role as a prognostic biomarker in this group of patients.	('lower', 'NegReg', (95, 100))	('PIK3CA', 'Gene', '5290', (57, 63))	('overall survival', 'MPA', (101, 117))	('mutations', 'Var', (64, 73))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (38, 46))	('CM', 'Disease', 'MESH:D009202', (30, 32))	('PIK3CA', 'Gene', (57, 63))
830342	30619505	Interestingly, the results of our analyzes of the survival of the mutated patients differ from those reported by others studies, especially in regions of some risk such as Asia, in which patients with ESCC with mutations of the PIK3CA gene had a favorable overall survival compared to patients wild-type.	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (211, 220))	('overall', 'MPA', (256, 263))	('patients', 'Species', '9606', (285, 293))	('ESCC', 'Disease', (201, 205))	('PIK3CA', 'Gene', (228, 234))	('PIK3CA', 'Gene', '5290', (228, 234))
830343	30619505	Notably, inhibitors of the PIK3-Akt-mTOR pathway have been developed as cancer target therapy alternatives, and patients harboring PIK3CA gene mutations could be potential candidates for such therapeutic approach.	('Akt', 'Gene', '207', (32, 35))	('PIK3', 'Gene', (27, 31))	('mTOR', 'Gene', (36, 40))	('Akt', 'Gene', (32, 35))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PIK3', 'Gene', (131, 135))	('patients', 'Species', '9606', (112, 120))	('PIK3', 'Gene', '5294', (27, 31))	('PIK3', 'Gene', '5294', (131, 135))	('PIK3CA', 'Gene', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('PIK3CA', 'Gene', '5290', (131, 137))	('mutations', 'Var', (143, 152))	('cancer', 'Disease', (72, 78))
830346	30619505	Therefore, we can hypothesize that a subset of ESCC and CM/ESCC patients with PIK3CA mutations may benefit from these targeted-therapies and consequently improve their dismal survival.	('PIK3CA', 'Gene', (78, 84))	('improve', 'PosReg', (154, 161))	('CM', 'Disease', 'MESH:D009202', (56, 58))	('benefit', 'PosReg', (99, 106))	('patients', 'Species', '9606', (64, 72))	('ESCC', 'Disease', (47, 51))	('PIK3CA', 'Gene', '5290', (78, 84))	('mutations', 'Var', (85, 94))	('dismal survival', 'MPA', (168, 183))
830347	30619505	In conclusion, this is the first study that analyzed and identified PIK3CA activating mutations in patients with esophageal squamous cell carcinomas associated with chagasic megaesophagus (CM/ESCC), which were associated with a worse outcome.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (124, 148))	('mutations', 'Var', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('PIK3CA', 'Gene', (68, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('CM', 'Disease', 'MESH:D009202', (189, 191))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (113, 148))	('patients', 'Species', '9606', (99, 107))	('associated', 'Reg', (149, 159))	('PIK3CA', 'Gene', '5290', (68, 74))	('esophageal squamous cell carcinomas', 'Disease', (113, 148))	('activating', 'PosReg', (75, 85))	('chagasic megaesophagus', 'Disease', (165, 187))
830348	30619505	Moreover, the identification of mutations in benign chagasic megaesophagus suggests their putative role in the etiology of esophageal squamous cell carcinoma and opens new opportunities for the treatment of these neglected patients with targeted-therapies.	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('esophageal squamous cell carcinoma', 'Disease', (123, 157))	('mutations', 'Var', (32, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('patients', 'Species', '9606', (223, 231))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (123, 157))
830352	29506494	Targeted next generation sequencing identified clinically actionable mutations in patients with esophageal sarcomatoid carcinoma Esophageal sarcomatoid carcinoma (ESC) is a rare disease with a mixture of both carcinomatous and sarcomatous components in the tumor.	('mutations', 'Var', (69, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('Esophageal sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (129, 161))	('patients', 'Species', '9606', (82, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (227, 234))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (140, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('Esophageal sarcomatoid carcinoma', 'Disease', (129, 161))	('esophageal sarcomatoid carcinoma', 'Disease', (96, 128))	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (209, 238))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (107, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('esophageal sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (96, 128))
830354	29506494	TP53 alterations were identified in all patients.	('TP53', 'Gene', '7157', (0, 4))	('patients', 'Species', '9606', (40, 48))	('alterations', 'Var', (5, 16))	('TP53', 'Gene', (0, 4))
830356	29506494	Members of downstream RAS and PI3-kinase pathways are also mutated in 10 patients, and PIK3CA is the top mutated gene in these pathways.	('PIK3CA', 'Gene', '5290', (87, 93))	('patients', 'Species', '9606', (73, 81))	('mutated', 'Var', (59, 66))	('PIK3CA', 'Gene', (87, 93))
830357	29506494	In addition, we identified mutations on histone modification genes in 5 patients, including histone acetyltransferase gene EP300 and its homologue CREBBP, lysine methyltransferase genes KMT2A and KMT2B, and lysine demethylase gene KDM5A.	('mutations', 'Var', (27, 36))	('KMT2A', 'Gene', (186, 191))	('CREBBP', 'Gene', '1387', (147, 153))	('KDM5A', 'Gene', (231, 236))	('EP300', 'Gene', (123, 128))	('KMT2B', 'Gene', '9757', (196, 201))	('histone modification genes', 'Gene', (40, 66))	('EP300', 'Gene', '2033', (123, 128))	('KMT2A', 'Gene', '4297', (186, 191))	('CREBBP', 'Gene', (147, 153))	('KDM5A', 'Gene', '5927', (231, 236))	('KMT2B', 'Gene', (196, 201))	('patients', 'Species', '9606', (72, 80))
830358	29506494	Finally, mismatch repair (MMR) genes and proofreading gene POLE all together were mutated in one third of the ESC patients.	('mismatch repair (MMR) genes', 'Gene', (9, 36))	('patients', 'Species', '9606', (114, 122))	('mutated', 'Var', (82, 89))	('ESC', 'Disease', (110, 113))
830369	29506494	Moreover, clinically actionable mutations were identified in the majority of patients, suggesting the potential of involving targeted drugs into future treatment to improve the long-term survival rates of this disease.	('improve', 'PosReg', (165, 172))	('patients', 'Species', '9606', (77, 85))	('mutations', 'Var', (32, 41))
830379	29506494	ADTEx (http://adtex.sourceforge.net) was used to identify copy number variations (CNVs) using a normal human HapMap DNA sample NA18535, and the cutoff of log2 ratio was set at +-0.6 for copy number changes (corresponding to 1.5-fold copy number gain and 0.65-fold copy number loss).	('human', 'Species', '9606', (103, 108))	('changes', 'Var', (198, 205))	('copy number', 'Var', (233, 244))	('gain', 'PosReg', (245, 249))	('copy', 'Var', (186, 190))
830380	29506494	The vcf files contain both single-nucleotide polymorphism (SNPs) and small insertions/deletions (indels) were annotated by ANNOVAR against the following databases: dbSNP (v138), 1000Genome, ExAC, COSMIC (v70), ClinVAR, and SIFT.	('SIFT', 'Disease', 'None', (223, 227))	('single-nucleotide polymorphism', 'Var', (27, 57))	('SIFT', 'Disease', (223, 227))
830391	29506494	All EP300 mutations are in its histone acetyltransferase (HAT) domain and the mutation Y1414C which has already been reported as an inactivating mutation occurred in two patients.	('patients', 'Species', '9606', (170, 178))	('EP300', 'Gene', '2033', (4, 9))	('Y1414C', 'Var', (87, 93))	('EP300', 'Gene', (4, 9))	('Y1414C', 'Mutation', 'p.Y1414C', (87, 93))
830392	29506494	In addition, 4 cases have mutations in KMT2B, KDM5A or KMT2A, all of which are components of histone methyltransferase complex (HMT).	('KMT2A', 'Gene', '4297', (55, 60))	('KDM5A', 'Gene', (46, 51))	('histone methyltransferase', 'Gene', (93, 118))	('KMT2B', 'Gene', (39, 44))	('KDM5A', 'Gene', '5927', (46, 51))	('mutations', 'Var', (26, 35))	('KMT2B', 'Gene', '9757', (39, 44))	('KMT2A', 'Gene', (55, 60))	('histone methyltransferase', 'Gene', '56979', (93, 118))
830394	29506494	Eleven out of 15 patients have at least one nonsynonymous mutation or structural variation in RTKs, including MET, CSF1R, FLT3, FLT1, ETBB2, FGFR4 and PDGFRB, and their occurrences were mutually exclusive from each other.	('CSF1R', 'Gene', (115, 120))	('PDGFRB', 'Gene', (151, 157))	('FLT1', 'Gene', (128, 132))	('FGFR4', 'Gene', '2264', (141, 146))	('FGFR4', 'Gene', (141, 146))	('ETBB2', 'Gene', (134, 139))	('FLT3', 'Gene', '2322', (122, 126))	('structural variation', 'Var', (70, 90))	('CSF1R', 'Gene', '1436', (115, 120))	('FLT1', 'Gene', '2321', (128, 132))	('MET', 'Gene', (110, 113))	('RTKs', 'Gene', (94, 98))	('patients', 'Species', '9606', (17, 25))	('FLT3', 'Gene', (122, 126))	('PDGFRB', 'Gene', '5159', (151, 157))
830395	29506494	As to the downstream elements of RTKs, PIK3CA is altered in 5 cases and 2 of them are copy number gain.	('copy number gain', 'Var', (86, 102))	('altered', 'Reg', (49, 56))	('PIK3CA', 'Gene', '5290', (39, 45))	('PIK3CA', 'Gene', (39, 45))
830396	29506494	The other 3 variants are E545K, M1043 V and H1047L, all of which have been reported to increase the catalytic activity of the p110alpha subunit of PIK3CA.	('M1043 V', 'Mutation', 'rs1057519936', (32, 39))	('M1043 V', 'Var', (32, 39))	('increase', 'PosReg', (87, 95))	('H1047L', 'Mutation', 'rs121913279', (44, 50))	('PIK3CA', 'Gene', (147, 153))	('E545K', 'Mutation', 'rs104886003', (25, 30))	('p110alpha', 'Gene', '5290', (126, 135))	('PIK3CA', 'Gene', '5290', (147, 153))	('E545K', 'Var', (25, 30))	('p110alpha', 'Gene', (126, 135))	('catalytic activity', 'MPA', (100, 118))	('H1047L', 'Var', (44, 50))
830399	29506494	Meanwhile, the loss of RB1 gene was observed in 3 cases (20%) either by copy number loss or frameshift alteration, which is higher than its prevalence in ESCC (9%).	('copy number loss', 'Var', (72, 88))	('ESCC', 'Disease', (154, 158))	('loss', 'NegReg', (15, 19))	('RB1', 'Gene', (23, 26))	('RB1', 'Gene', '5925', (23, 26))	('frameshift alteration', 'Var', (92, 113))
830401	29506494	The NOTCH pathway is also frequently dysregulated in ESC patients as we identified four NOTCH1 mutations (27%) (Fig.	('NOTCH1', 'Gene', '4851', (88, 94))	('NOTCH1', 'Gene', (88, 94))	('patients', 'Species', '9606', (57, 65))	('mutations', 'Var', (95, 104))	('NOTCH pathway', 'Pathway', (4, 17))
830402	29506494	1a) and one FBXW7 inactive mutation H460R (Additional file 1: Table S1).	('FBXW7', 'Gene', (12, 17))	('H460R', 'Var', (36, 41))	('H460R', 'Mutation', 'p.H460R', (36, 41))	('FBXW7', 'Gene', '55294', (12, 17))
830404	29506494	Mutations of NOTCH1 are commonly identified in ESCC (13%), acute and chronic lymphoblastic leukemia and suggested as oncogenic.	('chronic lymphoblastic leukemia', 'Disease', (69, 99))	('chronic lymphoblastic leukemia', 'Phenotype', 'HP:0005550', (69, 99))	('ESCC', 'Disease', (47, 51))	('NOTCH1', 'Gene', '4851', (13, 19))	('NOTCH1', 'Gene', (13, 19))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (77, 99))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (33, 43))	('chronic lymphoblastic leukemia', 'Disease', 'MESH:D015451', (69, 99))
830405	29506494	On the other hand, FBXW7 is a tumor suppressor and its inactivation could result in the constitutive activation of NOTCH1, cyclin E, c-Myc and other oncogenic factors.	('FBXW7', 'Gene', (19, 24))	('NOTCH1', 'Gene', (115, 121))	('cyclin E', 'MPA', (123, 131))	('activation', 'PosReg', (101, 111))	('inactivation', 'Var', (55, 67))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('c-Myc', 'Gene', '4609', (133, 138))	('FBXW7', 'Gene', '55294', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('c-Myc', 'Gene', (133, 138))	('NOTCH1', 'Gene', '4851', (115, 121))	('tumor', 'Disease', (30, 35))
830406	29506494	The tumor mutation burden (TMB) is defined as the number of non-synonymous and indel mutations per mega base (Mb) and it is ranged from 7.8 to 22.2 with a median of 11.1 in these patients (Fig.	('tumor', 'Disease', (4, 9))	('TMB', 'Chemical', '-', (27, 30))	('indel mutations', 'Var', (79, 94))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('non-synonymous', 'Var', (60, 74))	('patients', 'Species', '9606', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
830407	29506494	Notably, one third of the patients have either missense mutations or truncations in the mismatch repair (MMR) genes (MSH2, MLH1, PMS2, PMS1) and DNA polymerase POLE (Fig.	('missense mutations', 'Var', (47, 65))	('MLH1', 'Gene', '4292', (123, 127))	('MLH1', 'Gene', (123, 127))	('MSH2', 'Gene', '4436', (117, 121))	('PMS1', 'Gene', (135, 139))	('patients', 'Species', '9606', (26, 34))	('PMS1', 'Gene', '5378', (135, 139))	('MSH2', 'Gene', (117, 121))	('PMS2', 'Gene', (129, 133))	('PMS2', 'Gene', '5395', (129, 133))	('truncations', 'Var', (69, 80))
830408	29506494	During variant annotation in ANNOVAR, SIFT tool was used to predict the influence of these mutations to their protein functions and ClinVar was used for the clinical significance annotation.	('SIFT', 'Disease', (38, 42))	('SIFT', 'Disease', 'None', (38, 42))	('protein', 'Protein', (110, 117))	('mutations', 'Var', (91, 100))
830409	29506494	We found that half of these mutations (patient #3, 4, 5) were predicted to be neutral in SIFT, and ClinVar only identified MSH2 R929X (patient #3) as a pathogenic variant (Table 2).	('patient', 'Species', '9606', (135, 142))	('MSH2', 'Gene', (123, 127))	('patient', 'Species', '9606', (39, 46))	('MSH2', 'Gene', '4436', (123, 127))	('pathogenic', 'Reg', (152, 162))	('SIFT', 'Disease', 'None', (89, 93))	('R929X', 'Mutation', 'rs551060742', (128, 133))	('R929X', 'Var', (128, 133))	('SIFT', 'Disease', (89, 93))
830411	29506494	Patient #1 harbored one predicted-deleterious MSH2 mutation, but demonstrated similar TMB as others.	('TMB', 'Chemical', '-', (86, 89))	('mutation', 'Var', (51, 59))	('MSH2', 'Gene', (46, 50))	('MSH2', 'Gene', '4436', (46, 50))	('Patient', 'Species', '9606', (0, 7))
830412	29506494	Only patient #2, whom was predicted to have functionally deleterious mutations in PMS1, MSH2 and POLE, had a TMB of 22 mutations per MB, the highest among all studied cases.	('mutations', 'Var', (69, 78))	('MSH2', 'Gene', '4436', (88, 92))	('patient', 'Species', '9606', (5, 12))	('TMB', 'Chemical', '-', (109, 112))	('PMS1', 'Gene', (82, 86))	('PMS1', 'Gene', '5378', (82, 86))	('MSH2', 'Gene', (88, 92))
830415	29506494	In this study, clinically actionable mutations were defined as mutations showing sensitivity to existing targeted therapies or drugs in clinical trials, or having been approved to influence the outcomes of targeted therapies, regardless of the cancer types in the original trials.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('mutations', 'Var', (37, 46))	('influence', 'Reg', (180, 189))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
830417	29506494	Taking TP53 for example, supportive evidences include: 1) patients with carcinomas demonstrated better responses to bevacizumab treatment if carrying TP53 mutations; 2) patients with sarcomas showed better responses to pazopanib treatment.	('TP53', 'Gene', (150, 154))	('TP53', 'Gene', (7, 11))	('pazopanib', 'Chemical', 'MESH:C516667', (219, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('carcinomas', 'Disease', 'MESH:D002277', (72, 82))	('bevacizumab', 'Chemical', 'MESH:D000068258', (116, 127))	('TP53', 'Gene', '7157', (150, 154))	('TP53', 'Gene', '7157', (7, 11))	('responses', 'MPA', (103, 112))	('better', 'PosReg', (96, 102))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (169, 177))	('sarcomas', 'Disease', 'MESH:D012509', (183, 191))	('mutations', 'Var', (155, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (183, 191))	('carcinomas', 'Disease', (72, 82))	('sarcomas', 'Disease', (183, 191))
830422	29506494	Typically, TP53 was mutated in all ESC cases, which is comparable to 93% in ESCC.	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutated', 'Var', (20, 27))	('ESC', 'Disease', (35, 38))
830423	29506494	Besides, histone modifier genes show a high mutation rate in both ESC (40%) and ESCC (63%), and EP300 and its homolog CREBBP are the most commonly mutated genes.	('CREBBP', 'Gene', (118, 124))	('mutation', 'Var', (44, 52))	('ESC', 'Disease', (66, 69))	('histone modifier genes', 'Gene', (9, 31))	('CREBBP', 'Gene', '1387', (118, 124))	('EP300', 'Gene', (96, 101))	('EP300', 'Gene', '2033', (96, 101))	('ESCC', 'Disease', (80, 84))
830427	29506494	In addition, 5 out of 15 (33%) patients have PIK3CA alterations, much higher than what was observed in ESCC (5%) (p = 0.0002).	('PIK3CA', 'Gene', (45, 51))	('patients', 'Species', '9606', (31, 39))	('alterations', 'Var', (52, 63))	('PIK3CA', 'Gene', '5290', (45, 51))
830430	29506494	Due to the limit sample size, we are not be able to link PIK3CA alterations to the possibility of early diagnosis or poor prognosis, but PIK3CA alterations are now clinically actionable with potential responses to PI3K/AKT/mTOR inhibitors.	('mTOR', 'Gene', '2475', (223, 227))	('PIK3CA', 'Gene', (137, 143))	('AKT', 'Gene', (219, 222))	('AKT', 'Gene', '207', (219, 222))	('PIK3CA', 'Gene', '5290', (57, 63))	('PIK3CA', 'Gene', '5290', (137, 143))	('alterations', 'Var', (144, 155))	('mTOR', 'Gene', (223, 227))	('PIK3CA', 'Gene', (57, 63))
830433	29506494	Despite 5 patients carried mutations on MMR and proofreading genes, half of them were predicted to be benign.	('mutations', 'Var', (27, 36))	('proofreading genes', 'Gene', (48, 66))	('patients', 'Species', '9606', (10, 18))	('MMR', 'Gene', (40, 43))
830512	29433514	The model showed that the patients who had percentual SMI change over the median (- 2.98%) had better survival than those whose SMI had decreased more (p = 0.049; HR - 0.609; HR 95% CI 0.297-0.997).	('survival', 'CPA', (102, 110))	('change', 'Var', (58, 64))	('SMI', 'Chemical', '-', (54, 57))	('patients', 'Species', '9606', (26, 34))	('better', 'PosReg', (95, 101))	('SMI', 'Chemical', '-', (128, 131))
830539	28881608	Also detected were rare hot-spot mutations in EGFR and PIK3CA, whereas no mutations were found in K-Ras or B-Raf.	('K-Ras', 'Gene', '3845', (98, 103))	('K-Ras', 'Gene', (98, 103))	('EGFR', 'Gene', '1956', (46, 50))	('mutations', 'Var', (33, 42))	('PIK3CA', 'Gene', (55, 61))	('B-Raf', 'Gene', (107, 112))	('EGFR', 'Gene', (46, 50))	('PIK3CA', 'Gene', '5290', (55, 61))	('B-Raf', 'Gene', '673', (107, 112))
830540	28881608	Theliatinib exhibited strong antitumor activity in PDECX models with high EGFR expression, including remarkable tumor regression in two PDECX models with both EGFR gene amplification and protein overexpression.	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('EGFR', 'Gene', '1956', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Theliatinib', 'Chemical', '-', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('EGFR', 'Gene', (159, 163))	('EGFR', 'Gene', '1956', (74, 78))	('expression', 'Var', (79, 89))	('tumor', 'Disease', (33, 38))	('high', 'Var', (69, 73))	('EGFR', 'Gene', (74, 78))
830541	28881608	However, the efficacy of theliatinib was diminished in models with PI3KCA mutations or FGFR1 overexpression in addition to high EGFR expression.	('EGFR', 'Gene', '1956', (128, 132))	('efficacy', 'MPA', (13, 21))	('EGFR', 'Gene', (128, 132))	('mutations', 'Var', (74, 83))	('PI3KCA mutations', 'Var', (67, 83))	('diminished', 'NegReg', (41, 51))	('theliatinib', 'Chemical', '-', (25, 36))	('FGFR1', 'Gene', (87, 92))	('FGFR1', 'Gene', '2260', (87, 92))	('overexpression', 'PosReg', (93, 107))
830542	28881608	This study demonstrates that theliatinib could potentially benefit EC patients with high EGFR protein expression without mutations or aberrant activities of associated factors, such as PI3KCA or FGFR1.	('patients', 'Species', '9606', (70, 78))	('theliatinib', 'Chemical', '-', (29, 40))	('high', 'Var', (84, 88))	('EGFR', 'Gene', (89, 93))	('expression', 'MPA', (102, 112))	('benefit', 'PosReg', (59, 66))	('FGFR1', 'Gene', (195, 200))	('FGFR1', 'Gene', '2260', (195, 200))	('PI3KCA', 'Disease', (185, 191))	('EGFR', 'Gene', '1956', (89, 93))
830548	28881608	Overexpression of EGFR is commonly found in EC and is associated with poor prognosis.	('Overexpression', 'Var', (0, 14))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))
830549	28881608	Unlike colon or lung cancers, K-Ras mutations are less frequent in EC.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('K-Ras', 'Gene', '3845', (30, 35))	('lung cancers', 'Phenotype', 'HP:0100526', (16, 28))	('colon or lung cancers', 'Disease', 'MESH:D008175', (7, 28))	('mutations', 'Var', (36, 45))	('K-Ras', 'Gene', (30, 35))	('colon or lung cancers', 'Disease', (7, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))
830550	28881608	This suggests that inhibition of EGFR pathway maybe therapeutically beneficial to EC patients with EGFR overexpression.	('EGFR', 'Gene', (99, 103))	('inhibition', 'Var', (19, 29))	('EGFR', 'Gene', '1956', (33, 37))	('patients', 'Species', '9606', (85, 93))	('EGFR', 'Gene', (33, 37))	('EGFR', 'Gene', '1956', (99, 103))
830553	28881608	Subsequently, a TRANS-COG trial that was prospectively as part of the COG trial demonstrated that gefitinib significantly enhanced overall survival in patients carrying EGFR gene amplification (HR = 0.19, p = 0.007) and EGFR gene copy number gain (HR = 0.53, p = 0.042).	('gene amplification', 'Var', (174, 192))	('enhanced', 'PosReg', (122, 130))	('EGFR', 'Gene', (220, 224))	('overall survival', 'MPA', (131, 147))	('EGFR', 'Gene', '1956', (169, 173))	('patients', 'Species', '9606', (151, 159))	('TRANS-COG', 'Chemical', '-', (16, 25))	('gefitinib', 'Chemical', 'MESH:D000077156', (98, 107))	('EGFR', 'Gene', (169, 173))	('EGFR', 'Gene', '1956', (220, 224))
830554	28881608	A recent pre-clinical study showed that esophageal tumor cell lines with high polysomy of EGFR were sensitive to gefitinib.	('esophageal tumor', 'Disease', (40, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('esophageal tumor', 'Phenotype', 'HP:0100751', (40, 56))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (90, 94))	('high polysomy', 'Var', (73, 86))	('esophageal tumor', 'Disease', 'MESH:D004938', (40, 56))	('sensitive', 'MPA', (100, 109))	('gefitinib', 'Chemical', 'MESH:D000077156', (113, 122))
830555	28881608	These findings suggested that EGFR directed therapy could be beneficial to esophageal cancer patients with high EGFR protein expression or gene copy number.	('EGFR', 'Gene', (112, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('EGFR', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('protein', 'Protein', (117, 124))	('expression', 'MPA', (125, 135))	('EGFR', 'Gene', '1956', (112, 116))	('gene copy number', 'Var', (139, 155))	('esophageal cancer', 'Disease', (75, 92))	('EGFR', 'Gene', '1956', (30, 34))	('patients', 'Species', '9606', (93, 101))
830562	28881608	Further we conducted quantitative PCR analysis and found in 8 out of 69 specimens showing EGFR gene copy number gain (>= 2.0; Table 1).	('gain', 'PosReg', (112, 116))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (90, 94))	('copy number', 'Var', (100, 111))
830564	28881608	Interestingly, all 8 specimens with EGFR gene copy number gain demonstrated an EGFR H score >= 290 (Supplementary Table 1).	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('gain', 'PosReg', (58, 62))	('gene copy number', 'Var', (41, 57))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', (36, 40))
830567	28881608	Next, we successfully performed DNA extraction and Sanger sequencing in 66 out of 70 samples to determine hot spot mutations in EGFR, PIK3CA, K-Ras and B-Raf genes.	('PIK3CA', 'Gene', (134, 140))	('mutations', 'Var', (115, 124))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('PIK3CA', 'Gene', '5290', (134, 140))	('B-Raf', 'Gene', '673', (152, 157))	('K-Ras', 'Gene', '3845', (142, 147))	('K-Ras', 'Gene', (142, 147))	('B-Raf', 'Gene', (152, 157))
830569	28881608	A substitution was identified in the kinase domain (exon 21; c.2549 A>T, H850L) of the EGFR (Table 1).	('H850L', 'Var', (73, 78))	('EGFR', 'Gene', '1956', (87, 91))	('c.2549 A>T', 'Mutation', 'c.2549A>T', (61, 71))	('EGFR', 'Gene', (87, 91))	('c.2549 A>T', 'Var', (61, 71))	('H850L', 'Mutation', 'p.H850L', (73, 78))
830570	28881608	However, the L858 mutation or frame shift mutations were not detected in the patient tumor samples (Table 1).	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('patient', 'Species', '9606', (77, 84))	('L858', 'Var', (13, 17))
830571	28881608	Further, as shown in Supplementary Table 1, synonymous single nucleotide polymorphisms (SNPs) were detected in 18 patient samples in exon 20 (c.2361G>A, p.Q787Q) and 1 patient in the exon 19 (c.2235 G>A, p.K745K) of the EGFR.	('c.2235 G>A', 'Mutation', 'rs376452156', (192, 202))	('EGFR', 'Gene', (220, 224))	('EGFR', 'Gene', '1956', (220, 224))	('p.Q787Q', 'Mutation', 'rs1050171', (153, 160))	('patient', 'Species', '9606', (168, 175))	('detected', 'Reg', (99, 107))	('c.2361G>A', 'Mutation', 'rs1050171', (142, 151))	('p.K745K', 'Mutation', 'rs376452156', (204, 211))	('patient', 'Species', '9606', (114, 121))	('c.2235 G>A', 'Var', (192, 202))	('c.2361G>A', 'Var', (142, 151))
830572	28881608	A PIK3CA hot-spot mutation (E542K) was detected in exon 9 in 1 patient sample (Table 1).	('PIK3CA', 'Gene', '5290', (2, 8))	('E542K', 'Mutation', 'rs121913273', (28, 33))	('patient', 'Species', '9606', (63, 70))	('PIK3CA', 'Gene', (2, 8))	('E542K', 'Var', (28, 33))
830582	28881608	The IC50 of theliatinib against EGFR and EGFR T790M/L858R mutant was 3 and 22 nM, respectively (Supplementary Table 2).	('theliatinib', 'Chemical', '-', (12, 23))	('EGFR', 'Gene', (41, 45))	('T790M', 'Var', (46, 51))	('EGFR', 'Gene', '1956', (32, 36))	('L858R', 'Mutation', 'rs121434568', (52, 57))	('EGFR', 'Gene', (32, 36))	('EGFR', 'Gene', '1956', (41, 45))	('T790M', 'SUBSTITUTION', 'None', (46, 51))
830586	28881608	We observed that the two PDECX models with EGFR gene amplification (PDECX1T0326 and PDECX1T0950) were most sensitive to theliatinib treatment demonstrating tumor regression of 32% and 75%, respectively, at the end of study (Figure 4 and Table 4).	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('theliatinib', 'Chemical', '-', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('PDECX1T0950', 'Var', (84, 95))	('EGFR', 'Gene', '1956', (43, 47))	('tumor', 'Disease', (156, 161))	('EGFR', 'Gene', (43, 47))
830589	28881608	Gefitinib also displayed anti-tumor activity in these two models with EGFR gene amplification (Figure 4A and Figure 4D).	('EGFR', 'Gene', '1956', (70, 74))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('EGFR', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('gene amplification', 'Var', (75, 93))
830594	28881608	However, the efficacy of theliatinib was attenuated in PDECX1T0472 and PDECX1T0327 that also had high EGFR expression, probably due to other gene alterations, such as PIK3CA mutation in PDECX1T0472 and FGFR1 overexpression in PDECX1T0327 (Figure 5A and Table 4).	('PDECX1T0472', 'Var', (55, 66))	('attenuated', 'NegReg', (41, 51))	('high', 'PosReg', (97, 101))	('overexpression', 'PosReg', (208, 222))	('PIK3CA', 'Gene', '5290', (167, 173))	('mutation', 'Var', (174, 182))	('efficacy', 'MPA', (13, 21))	('expression', 'MPA', (107, 117))	('FGFR1', 'Gene', (202, 207))	('theliatinib', 'Chemical', '-', (25, 36))	('FGFR1', 'Gene', '2260', (202, 207))	('EGFR', 'Gene', '1956', (102, 106))	('PIK3CA', 'Gene', (167, 173))	('EGFR', 'Gene', (102, 106))	('PDECX1T0327', 'Var', (71, 82))
830595	28881608	In fact, the PDECX1T0327 model demonstrated rapid tumor regression upon treatment with AZD4547 (12 mg/kg), a selective FGFR inhibitor, suggesting that FGFR may be a stronger driver in this tumor than EGFR.	('tumor', 'Disease', (189, 194))	('AZD4547', 'Var', (87, 94))	('AZD4547', 'Chemical', 'MESH:C572463', (87, 94))	('EGFR', 'Gene', '1956', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('EGFR', 'Gene', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (50, 55))
830597	28881608	In models with medium or low EGFR expression (PDECX1T0474 and PDECX1T0773), theliatinib demonstrated low to moderate efficacy (Figure 5B and Table 4).	('PDECX1T0773', 'Var', (62, 73))	('PDECX1T0474', 'Var', (46, 57))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('theliatinib', 'Chemical', '-', (76, 87))
830606	28881608	The two PDECX models with EGFR gene amplification were most sensitive to theliatinib treatment with rapid and robust tumor regression.	('EGFR', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('gene amplification', 'Var', (31, 49))	('EGFR', 'Gene', '1956', (26, 30))	('theliatinib', 'Chemical', '-', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
830609	28881608	Therefore, our study indicates that tumors with EGFR gene amplification and high EGFR expression may demonstrate improved object response rate (ORR), whereas tumors with high EGFR expression without EGFR gene amplification may demonstrate improved progression free survival (PFS) with or without ORR.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('EGFR', 'Gene', '1956', (48, 52))	('object response rate', 'CPA', (122, 142))	('improved', 'PosReg', (239, 247))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (158, 164))	('gene amplification', 'Var', (53, 71))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('EGFR', 'Gene', (81, 85))	('EGFR', 'Gene', (175, 179))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('EGFR', 'Gene', (199, 203))	('EGFR', 'Gene', (48, 52))	('expression', 'MPA', (86, 96))	('EGFR', 'Gene', '1956', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('progression free survival', 'CPA', (248, 273))	('improved', 'PosReg', (113, 121))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', '1956', (199, 203))
830611	28881608	The presence of EGFR activating mutations is an established predictive biomarker in non-small cell lung cancer (NSCLC) with in-frame deletions of exon 19 (E746_A750) and L858R substitution in exon 21 accounting for > 90% of all activating mutations.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (84, 110))	('activating', 'PosReg', (21, 31))	('non-small cell lung cancer', 'Disease', (84, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('L858R', 'Mutation', 'rs121434568', (170, 175))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (88, 110))	('E746_A750', 'Var', (155, 164))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('L858R', 'Var', (170, 175))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (84, 110))	('EGFR', 'Gene', '1956', (16, 20))	('NSCLC', 'Disease', (112, 117))	('EGFR', 'Gene', (16, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
830612	28881608	However, these mutations are distinctly less common in esophageal cancer.	('common', 'Reg', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (15, 24))	('esophageal cancer', 'Disease', (55, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))
830614	28881608	However, a novel EGFR H850L mutation in exon 21 was found in 1 patient and the biological significance of this mutation needs to be determined in future.	('H850L', 'Var', (22, 27))	('patient', 'Species', '9606', (63, 70))	('EGFR', 'Gene', '1956', (17, 21))	('H850L', 'Mutation', 'p.H850L', (22, 27))	('EGFR', 'Gene', (17, 21))
830615	28881608	Further, we found that in 27% (18/66) of cases, an EGFR SNP at codon 787 of exon 20 was present, similar to a previous finding in Japanese ESCC patients in which Q787Q SNP was reported to be associated with decreased overall survival in the patients that received chemoradiotherapy.	('Q787Q', 'Mutation', 'rs1050171', (162, 167))	('Q787Q', 'Var', (162, 167))	('EGFR', 'Gene', (51, 55))	('patients', 'Species', '9606', (144, 152))	('decreased', 'NegReg', (207, 216))	('overall survival', 'MPA', (217, 233))	('patients', 'Species', '9606', (241, 249))	('EGFR', 'Gene', '1956', (51, 55))
830616	28881608	Interestingly, Q787Q SNP was also identified in head and neck cancer cell lines and patient samples and was associated with higher sensitivity to gefitinib.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('sensitivity to', 'MPA', (131, 145))	('Q787Q', 'Mutation', 'rs1050171', (15, 20))	('gefitinib', 'Chemical', 'MESH:D000077156', (146, 155))	('Q787Q SNP', 'Var', (15, 24))	('head and neck cancer', 'Phenotype', 'HP:0012288', (48, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('higher', 'PosReg', (124, 130))	('patient', 'Species', '9606', (84, 91))
830617	28881608	In our anti-tumor studies, one PDECX model (1T0994, H score 230) that carried Q787Q SNP was insensitive to theliatinib.	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('Q787Q', 'Mutation', 'rs1050171', (78, 83))	('Q787Q SNP', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('theliatinib', 'Chemical', '-', (107, 118))
830618	28881608	Therefore, the molecular details between Q787Q SNP and response to EGFR-TKIs need to be investigated further.	('EGFR', 'Gene', (67, 71))	('Q787Q', 'Var', (41, 46))	('Q787Q', 'Mutation', 'rs1050171', (41, 46))	('EGFR', 'Gene', '1956', (67, 71))
830619	28881608	Overall, EGFR hot-spot mutations were rare in our study.	('mutations', 'Var', (23, 32))	('EGFR', 'Gene', (9, 13))	('EGFR', 'Gene', '1956', (9, 13))
830623	28881608	This unique feature may result in better target engagement for theliatinib compared to erlotinib or gefitinib, leading to stronger anti-tumor activity in tumors with wild type EGFR activation due to gene amplification or protein overexpression.	('gene amplification', 'Var', (199, 217))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('overexpression', 'PosReg', (229, 243))	('stronger', 'PosReg', (122, 130))	('theliatinib', 'Chemical', '-', (63, 74))	('tumor', 'Disease', (154, 159))	('protein', 'Protein', (221, 228))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('EGFR', 'Gene', (176, 180))	('erlotinib', 'Chemical', 'MESH:D000069347', (87, 96))	('tumor', 'Disease', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('gefitinib', 'Chemical', 'MESH:D000077156', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('activation', 'PosReg', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Disease', (154, 160))	('EGFR', 'Gene', '1956', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
830624	28881608	Our study also demonstrates that aberrant function of other receptor tyrosine kinase receptors or somatic mutations in down-stream targets such as FGFR overexpression or PIK3CA mutation can influence drug sensitivity of EC to EGFR TKIs.	('PIK3CA', 'Gene', '5290', (170, 176))	('mutation', 'Var', (177, 185))	('drug sensitivity', 'Phenotype', 'HP:0020174', (200, 216))	('tyrosine', 'Chemical', 'MESH:D014443', (69, 77))	('FGFR', 'Gene', (147, 151))	('drug sensitivity', 'MPA', (200, 216))	('aberrant function', 'Var', (33, 50))	('EGFR', 'Gene', '1956', (226, 230))	('PIK3CA', 'Gene', (170, 176))	('influence', 'Reg', (190, 199))	('EGFR', 'Gene', (226, 230))
830625	28881608	The frequency of PIK3CA mutations in EC varies from 0% to 21%.	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))
830627	28881608	In our study, one EC sample with a PIK3CA E542K mutation on exon 9 and the corresponding PDECX1T0472 showed moderate sensitivity to theliatinib treatment with 84% TGI, which was lower than two other PDECX models with similar EGFR H scores, 1T0781 and 1T1315, without any PIK3CA mutation.	('sensitivity', 'MPA', (117, 128))	('E542K', 'Mutation', 'rs121913273', (42, 47))	('PIK3CA', 'Gene', (271, 277))	('EGFR', 'Gene', '1956', (225, 229))	('PIK3CA', 'Gene', (35, 41))	('PIK3CA', 'Gene', '5290', (271, 277))	('E542K', 'Var', (42, 47))	('EGFR', 'Gene', (225, 229))	('PIK3CA', 'Gene', '5290', (35, 41))	('theliatinib', 'Chemical', '-', (132, 143))
830628	28881608	This suggested that the PIK3CA hot-spot mutations may attenuate the sensitivity to EGFR inhibitors.	('EGFR', 'Gene', '1956', (83, 87))	('PIK3CA', 'Gene', (24, 30))	('EGFR', 'Gene', (83, 87))	('mutations', 'Var', (40, 49))	('PIK3CA', 'Gene', '5290', (24, 30))	('attenuate', 'NegReg', (54, 63))
830630	28881608	FGFR1 gene amplification was reported in ESCC with a frequency of 6% to 21% and protein overexpression in 17% of ESCC.	('overexpression', 'PosReg', (88, 102))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('ESCC', 'Disease', (41, 45))	('amplification', 'Var', (11, 24))
830633	28881608	Interestingly, treatment with a FGFR inhibitor AZD4547 induced rapid tumor regression, suggesting that FGFR1 overexpression was driving the tumor growth in the specific model.	('AZD4547', 'Chemical', 'MESH:C572463', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('FGFR1', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('AZD4547', 'Var', (47, 54))	('FGFR1', 'Gene', '2260', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (140, 145))
830641	28881608	Furthermore, aberrant activation or gene mutations of other targets such as PI3K and FGFR diminished the anti-tumor activity of the EGFR TKIs, especially, theliatinib.	('FGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (132, 136))	('theliatinib', 'Chemical', '-', (155, 166))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('activation', 'PosReg', (22, 32))	('EGFR', 'Gene', (132, 136))	('gene mutations', 'Var', (36, 50))	('diminished', 'NegReg', (90, 100))	('aberrant', 'Var', (13, 21))
830652	28881608	Tumor-bearing mice were daily administered oral doses of test compounds (Theliatinib in 0.5% CMC-Na; Gefitinib in 0.5% Tween-80 and AZD4547 in 1% Tween-80 (tested only in the PDECX 1T0327 model)) or vehicle control.	('Gefitinib', 'Chemical', 'MESH:D000077156', (101, 110))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tween-80', 'Chemical', 'MESH:D011136', (119, 127))	('AZD4547', 'Var', (132, 139))	('mice', 'Species', '10090', (14, 18))	('AZD4547', 'Chemical', 'MESH:C572463', (132, 139))	('CMC-Na', 'Chemical', '-', (93, 99))	('Theliatinib', 'Chemical', '-', (73, 84))	('Gefitinib', 'Gene', (101, 110))	('Tween-80', 'Chemical', 'MESH:D011136', (146, 154))
830678	28881608	Hotspots mutations in exon 19, 20 and 21 of EGFR gene, exon 9 and 20 of PIK3CA gene, exon 2 and 3 of K-Ras gene and exon 11 and 15 of B-Raf gene were detected in tumor samples by the Genewiz Inc., using ABI3730XL sequence analyzer.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', (162, 167))	('B-Raf', 'Gene', '673', (134, 139))	('B-Raf', 'Gene', (134, 139))	('PIK3CA', 'Gene', (72, 78))	('K-Ras', 'Gene', '3845', (101, 106))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('PIK3CA', 'Gene', '5290', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('K-Ras', 'Gene', (101, 106))
830679	28881608	The primers for detecting hot spot mutations in EGFR, PIK3CA, K-Ras and B-Raf are listed in Supplementary Table 4.	('EGFR', 'Gene', '1956', (48, 52))	('B-Raf', 'Gene', '673', (72, 77))	('PIK3CA', 'Gene', '5290', (54, 60))	('EGFR', 'Gene', (48, 52))	('K-Ras', 'Gene', '3845', (62, 67))	('K-Ras', 'Gene', (62, 67))	('B-Raf', 'Gene', (72, 77))	('PIK3CA', 'Gene', (54, 60))	('mutations', 'Var', (35, 44))
830770	28443201	A locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at the highest risk for ESSC.	('ESSC', 'Disease', (140, 144))	('rs35597309', 'Mutation', 'rs35597309', (47, 57))	('rs35597309', 'Var', (47, 57))
830926	22902758	Whites with low HBV activity have a low risk for developing HCC, so surveillance generally is not recommended, in contrast to white patients with high viral load and active hepatitis.	('activity', 'MPA', (20, 28))	('low', 'Var', (12, 15))	('hepatitis', 'Disease', 'MESH:D056486', (173, 182))	('HCC', 'Gene', '619501', (60, 63))	('men', 'Species', '9606', (103, 106))	('HCC', 'Phenotype', 'HP:0001402', (60, 63))	('HBV', 'Species', '10407', (16, 19))	('hepatitis', 'Phenotype', 'HP:0012115', (173, 182))	('active hepatitis', 'Phenotype', 'HP:0200120', (166, 182))	('HBV', 'Gene', (16, 19))	('hepatitis', 'Disease', (173, 182))	('patients', 'Species', '9606', (132, 140))	('HCC', 'Gene', (60, 63))
830937	22902758	The risk of variceal bleeding and liver-related mortality is significantly reduced with beta-blocker therapies, and therapy was shown to be cost-effective in primary prophylaxis of variceal bleeding.	('variceal bleeding', 'Disease', (12, 29))	('liver-related mortality', 'CPA', (34, 57))	('variceal bleeding', 'Disease', (181, 198))	('variceal bleeding', 'Disease', 'MESH:D014648', (12, 29))	('reduced', 'NegReg', (75, 82))	('beta-blocker', 'Var', (88, 100))	('variceal bleeding', 'Disease', 'MESH:D014648', (181, 198))
830965	27670291	Thus, stathmin may be an attractive target for drug design as targeting this molecule could simultaneously inhibit several aspects of tumor progression.	('inhibit', 'NegReg', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('targeting', 'Var', (62, 71))	('tumor', 'Disease', (134, 139))
830989	27670291	Phosphoinositide 3-kinase PI3 K/mTOR/HSP90 is shown as a possible signal target for p-stathmin S38- high-endometrial cancer cases.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Phosphoinositide 3-kinase', 'Gene', (0, 25))	('mTOR', 'Gene', '2475', (32, 36))	('p-stathmin', 'Var', (84, 94))	('mTOR', 'Gene', (32, 36))	('Phosphoinositide 3-kinase', 'Gene', '5290', (0, 25))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('S38-', 'Var', (95, 99))	('cancer', 'Disease', (117, 123))	('HSP90', 'Gene', (37, 42))	('HSP90', 'Gene', '3320', (37, 42))	('endometrial cancer', 'Phenotype', 'HP:0012114', (105, 123))
830991	27670291	And low levels of Siva1 and Ser16-phosphorylated stathmin correlate with high metastatic states of human breast cancer cells.	('Ser16-phosphorylated', 'Var', (28, 48))	('Siva1', 'Gene', '10572', (18, 23))	('Siva1', 'Gene', (18, 23))	('high metastatic states', 'CPA', (73, 95))	('Ser16', 'Chemical', '-', (28, 33))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('human', 'Species', '9606', (99, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
830995	27670291	The inhibition of LMP1 expression attenuates the interaction of ERK with stathmin and promotes microtubule depolymerization.	('attenuates', 'NegReg', (34, 44))	('LMP1', 'Gene', (18, 22))	('ERK', 'Gene', '5594', (64, 67))	('interaction', 'Interaction', (49, 60))	('inhibition', 'Var', (4, 14))	('ERK', 'Gene', (64, 67))	('promotes', 'PosReg', (86, 94))	('LMP1', 'Gene', '9260', (18, 22))	('microtubule depolymerization', 'MPA', (95, 123))
830996	27670291	Stathmin depletion causes significant inhibition of HGF-induced WAVE2 transport and lamellipodia formation.	('Stathmin', 'Gene', (0, 8))	('WAVE2', 'Gene', (64, 69))	('HGF', 'Gene', '3082', (52, 55))	('HGF', 'Gene', (52, 55))	('inhibition', 'NegReg', (38, 48))	('lamellipodia formation', 'CPA', (84, 106))	('WAVE2', 'Gene', '10163', (64, 69))	('Stathmin', 'Gene', '3925', (0, 8))	('depletion', 'Var', (9, 18))
830998	27670291	Stathmin silencing also reduces the activity of CDC25, Aurora A and Plk1.	('Plk1', 'Gene', '5347', (68, 72))	('Stathmin', 'Gene', (0, 8))	('reduces', 'NegReg', (24, 31))	('silencing', 'Var', (9, 18))	('Aurora A', 'Gene', '6790', (55, 63))	('activity', 'MPA', (36, 44))	('Plk1', 'Gene', (68, 72))	('Aurora A', 'Gene', (55, 63))	('CDC25', 'Gene', (48, 53))	('CDC25', 'Gene', '995', (48, 53))	('Stathmin', 'Gene', '3925', (0, 8))
831000	27670291	Homo sapiens leucine rich repeat containing 4 (LRRC4) is epigenetically inactivated commonly in glioma.	('leucine rich repeat containing 4', 'Gene', (13, 45))	('LRRC4', 'Gene', (47, 52))	('LRRC4', 'Gene', '64101', (47, 52))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('leucine rich repeat containing 4', 'Gene', '64101', (13, 45))	('epigenetically inactivated', 'Var', (57, 83))	('Homo sapiens', 'Species', '9606', (0, 12))	('glioma', 'Disease', (96, 102))
831011	27670291	Furthermore, silence of stathmin down-regulates the expression of Nf-kappaB (p65), which indicates that stathmin might play its oncogenic role by an interaction with Nf-kappaB pathway (Fig.	('stathmin', 'Gene', (24, 32))	('p65', 'Gene', (77, 80))	('Nf-kappaB', 'Gene', (66, 75))	('interaction', 'Interaction', (149, 160))	('expression', 'MPA', (52, 62))	('Nf-kappaB', 'Gene', (166, 175))	('p65', 'Gene', '5970', (77, 80))	('Nf-kappaB', 'Gene', '4790', (66, 75))	('Nf-kappaB', 'Gene', '4790', (166, 175))	('down-regulates', 'NegReg', (33, 47))	('silence', 'Var', (13, 20))
831012	27670291	Stathmin depletion suppresses the expression of hypoxia-induced factor-1alpha (HIF-1alpha) and VEGF, and impedes the phosphorylation of ribosomal protein S6 kinase 1 (S6 K) and Akt, which means stathmin play a critical role in the mTOR/HIF-1alpha/VEGF signally pathway.	('Stathmin', 'Gene', (0, 8))	('expression', 'MPA', (34, 44))	('HIF-1alpha', 'Gene', (236, 246))	('impedes', 'NegReg', (105, 112))	('VEGF', 'Gene', '7422', (247, 251))	('suppresses', 'NegReg', (19, 29))	('HIF-1alpha', 'Gene', '3091', (79, 89))	('phosphorylation', 'MPA', (117, 132))	('mTOR', 'Gene', (231, 235))	('VEGF', 'Gene', (247, 251))	('Stathmin', 'Gene', '3925', (0, 8))	('hypoxia', 'Disease', (48, 55))	('depletion', 'Var', (9, 18))	('Akt', 'Gene', (177, 180))	('mTOR', 'Gene', '2475', (231, 235))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('Akt', 'Gene', '207', (177, 180))	('HIF-1alpha', 'Gene', (79, 89))	('HIF-1alpha', 'Gene', '3091', (236, 246))	('VEGF', 'Gene', '7422', (95, 99))	('S6 K', 'Mutation', 'p.S6K', (167, 171))	('VEGF', 'Gene', (95, 99))
831016	27670291	Knockdown of stathmin promotes the effects of indoly-chalcones CITs (CIT-026, CIT-214, CIT-223) to bring down microtubule destabilization, result in cell death and decelerate cell proliferation.	('result in', 'Reg', (139, 148))	('cell proliferation', 'CPA', (175, 193))	('CIT-214', 'Var', (78, 85))	('decelerate', 'NegReg', (164, 174))	('bring', 'Reg', (99, 104))	('indoly-chalcones CITs', 'Chemical', '-', (46, 67))	('cell death', 'CPA', (149, 159))	('stathmin', 'Gene', (13, 21))	('microtubule destabilization', 'MPA', (110, 137))	('CIT-223', 'Var', (87, 94))
831018	27670291	And inhibition of Rlim (a Ring H2 zinc finger protein) increases the expression of stathmin, and leads to cell proliferation of human osteosarcoma cell lines.	('cell proliferation', 'CPA', (106, 124))	('osteosarcoma', 'Disease', (134, 146))	('osteosarcoma', 'Disease', 'MESH:D012516', (134, 146))	('Rlim', 'Gene', (18, 22))	('expression', 'MPA', (69, 79))	('increases', 'PosReg', (55, 64))	('inhibition', 'Var', (4, 14))	('leads to', 'Reg', (97, 105))	('human', 'Species', '9606', (128, 133))	('Rlim', 'Gene', '51132', (18, 22))	('stathmin', 'Gene', (83, 91))	('osteosarcoma', 'Phenotype', 'HP:0002669', (134, 146))
831023	27670291	Oxidative stress from menadione-generated superoxide induces JNK-dependent stathmin phosphorylation at Ser-16, Ser-25 and Ser-38 in hepatocytes.	('Ser', 'Chemical', 'MESH:D012694', (122, 125))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('stathmin phosphorylation', 'MPA', (75, 99))	('Ser', 'Chemical', 'MESH:D012694', (103, 106))	('menadione', 'Chemical', 'MESH:D024483', (22, 31))	('JNK', 'Gene', (61, 64))	('Ser', 'Chemical', 'MESH:D012694', (111, 114))	('Oxidative stress', 'MPA', (0, 16))	('Ser-38', 'Var', (122, 128))	('superoxide', 'Chemical', 'MESH:D013481', (42, 52))	('JNK', 'Gene', '5599', (61, 64))
831026	27670291	And, stathmin knockdown improves the chemosensitivity of gastric cancer cells to docetaxel, making the percentage of cells at the sub-G1 stage increase and promote apoptosis.	('gastric cancer', 'Disease', (57, 71))	('chemosensitivity', 'MPA', (37, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('apoptosis', 'CPA', (164, 173))	('stathmin', 'Gene', (5, 13))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('knockdown', 'Var', (14, 23))	('improves', 'PosReg', (24, 32))	('increase', 'PosReg', (143, 151))	('docetaxel', 'Chemical', 'MESH:D000077143', (81, 90))	('promote', 'PosReg', (156, 163))
831027	27670291	Research shows paclitaxel reduces the expression of stathmin, and combination of stathmin silencing with paclitaxel treatment enhances microtubules polymerization and tumor cell apoptosis.	('expression', 'MPA', (38, 48))	('silencing', 'Var', (90, 99))	('paclitaxel', 'Chemical', 'MESH:D017239', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('enhances', 'PosReg', (126, 134))	('paclitaxel', 'Chemical', 'MESH:D017239', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('reduces', 'NegReg', (26, 33))	('stathmin', 'Gene', (81, 89))	('microtubules polymerization', 'MPA', (135, 162))	('tumor', 'Disease', (167, 172))
831029	27670291	The JAK2(V617F) mutation potentially leads to inhibition of stathmin activity via constitutive STAT3 phosphorylation.	('V617F', 'SUBSTITUTION', 'None', (9, 14))	('inhibition', 'NegReg', (46, 56))	('STAT3', 'Gene', '6774', (95, 100))	('V617F', 'Var', (9, 14))	('STAT3', 'Gene', (95, 100))	('stathmin', 'Enzyme', (60, 68))
831030	27670291	Therefore, combination of stathmin silencing and ruxolitinib treatment can reduce cell proliferation and clonal growth, and increase apoptosis induced by ruxolitinib (Fig.	('increase', 'PosReg', (124, 132))	('silencing', 'Var', (35, 44))	('clonal growth', 'CPA', (105, 118))	('reduce', 'NegReg', (75, 81))	('cell proliferation', 'CPA', (82, 100))	('apoptosis', 'CPA', (133, 142))	('ruxolitinib', 'Chemical', 'MESH:C540383', (49, 60))	('stathmin', 'Gene', (26, 34))	('ruxolitinib', 'Chemical', 'MESH:C540383', (154, 165))
831032	27670291	Research shows knockdown of stathmin inhibits the proliferation of glioma cells, induces apoptosis, arrests the cell cycle at G2/M phase in glioma stem cells (GSCs), and also suppresses the migration/invasion.	('cell cycle at G2/M phase', 'CPA', (112, 136))	('arrests', 'NegReg', (100, 107))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('knockdown', 'Var', (15, 24))	('glioma', 'Disease', (67, 73))	('suppresses', 'NegReg', (175, 185))	('apoptosis', 'CPA', (89, 98))	('migration/invasion', 'CPA', (190, 208))	('induces', 'Reg', (81, 88))	('glioma', 'Disease', (140, 146))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('inhibits', 'NegReg', (37, 45))	('stathmin', 'Gene', (28, 36))
831040	27670291	In addition, stathmin silencing significantly impedes cell proliferation and mobility of neuroblastoma cells, polyploidy of hepatoma cells and esophageal squamous cell carcinoma cells, and remarkably retards cell migration and invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('neuroblastoma', 'Phenotype', 'HP:0003006', (89, 102))	('cell proliferation', 'CPA', (54, 72))	('retards cell migration', 'Disease', 'MESH:D014085', (200, 222))	('esophageal squamous cell carcinoma', 'Disease', (143, 177))	('polyploidy of hepatoma', 'Disease', 'MESH:D011123', (110, 132))	('neuroblastoma', 'Disease', 'MESH:D009447', (89, 102))	('silencing', 'Var', (22, 31))	('polyploidy of hepatoma', 'Disease', (110, 132))	('stathmin', 'Gene', (13, 21))	('neuroblastoma', 'Disease', (89, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (143, 177))	('retards cell migration', 'Disease', (200, 222))	('impedes', 'NegReg', (46, 53))
831045	27670291	It is reported that the knockdown of proapoptotic protein SIVA activates the expression of stathmin, which promotes cell mobility and migration and the growth of xenotransplanted tumors, but silencing of ankyrin repeat and KH domain containing 1 protein (ANKHD1) plays an inverse function that leads to stathmin inactivation, inhibits cell migration and the growth of xenotransplanted, which possibly depends on the inhibition mechanism of SIVA/stathmin pathway.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('stathmin', 'MPA', (303, 311))	('ankyrin repeat and KH domain containing 1', 'Gene', '54882', (204, 245))	('xenotransplanted tumors', 'Disease', (162, 185))	('SIVA', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('SIVA', 'Gene', (440, 444))	('silencing', 'Var', (191, 200))	('xenotransplanted tumors', 'Disease', 'MESH:D009369', (162, 185))	('ANKHD1', 'Gene', '54882', (255, 261))	('SIVA', 'Gene', '10572', (440, 444))	('cell migration', 'CPA', (335, 349))	('SIVA', 'Gene', '10572', (58, 62))	('ANKHD1', 'Gene', (255, 261))	('inhibits', 'NegReg', (326, 334))	('growth of xenotransplanted', 'CPA', (358, 384))	('inactivation', 'NegReg', (312, 324))	('cell mobility', 'CPA', (116, 129))
831047	27670291	It is shown that MCPyV small tumor antigen enhances microtubule destabilization of the MCC cells by modulating the phosphorylation status of stathmin, which results in the motility, migration and metastasis of Merkel cell carcinoma (Fig.	('migration', 'CPA', (182, 191))	('MCPyV', 'Var', (17, 22))	('motility', 'CPA', (172, 180))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('phosphorylation status', 'MPA', (115, 137))	('modulating', 'Reg', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('enhances', 'PosReg', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('MCPyV', 'Species', '493803', (17, 22))	('microtubule destabilization', 'MPA', (52, 79))	('tumor', 'Disease', (29, 34))	('metastasis of Merkel cell carcinoma', 'Disease', 'MESH:D015266', (196, 231))	('results in', 'Reg', (157, 167))	('metastasis of Merkel cell carcinoma', 'Disease', (196, 231))
831051	27670291	Evidence on the relation between MicroRNAs and malignant tumor has been suggested that some aberrant miRNA expressions promote the development of cancers, but the others play a negative function in tumorigenesis.	('cancers', 'Disease', (146, 153))	('aberrant', 'Var', (92, 100))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('malignant tumor', 'Disease', 'MESH:D018198', (47, 62))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('promote', 'PosReg', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (57, 62))	('malignant tumor', 'Disease', (47, 62))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (101, 104))
831057	27670291	And study reveals that aberrant miR-223 contributes to aggressiveness of malignant pleural mesothelioma (MPM) by regulating stathmin and both are also in turn regulated by the JNK signally pathway (Fig.	('JNK', 'Gene', (176, 179))	('miR-223', 'Gene', '407008', (32, 39))	('aggressiveness of malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (55, 103))	('JNK', 'Gene', '5599', (176, 179))	('aggressiveness of malignant pleural mesothelioma', 'Disease', (55, 103))	('regulating', 'Reg', (113, 123))	('miR-223', 'Gene', (32, 39))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (83, 103))	('stathmin', 'MPA', (124, 132))	('aberrant', 'Var', (23, 31))	('aggressiveness', 'Phenotype', 'HP:0000718', (55, 69))
831060	27670291	It is suggested that long term colonization of Helicobacter pylori in gastric mucosa increases the risk of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Helicobacter pylori', 'Var', (47, 66))	('gastric cancer', 'Disease', (107, 121))	('Helicobacter pylori', 'Species', '210', (47, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))
831065	27670291	Interestingly, miR-101 expression inhibits the autophagy of hepatocellular carcinoma HepG2 cells by modulating the activity of stathmin, and enhances apoptosis of hepatocellular carcinoma cells by inhibition of autophagy.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (163, 187))	('apoptosis', 'CPA', (150, 159))	('expression', 'Var', (23, 33))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('autophagy', 'CPA', (47, 56))	('inhibition', 'NegReg', (197, 207))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (163, 187))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (60, 84))	('hepatocellular carcinoma', 'Disease', (163, 187))	('autophagy', 'CPA', (211, 220))	('HepG2', 'CellLine', 'CVCL:0027', (85, 90))	('hepatocellular carcinoma', 'Disease', (60, 84))	('miR', 'Gene', '220972', (15, 18))	('enhances', 'PosReg', (141, 149))	('inhibits', 'NegReg', (34, 42))	('modulating', 'Reg', (100, 110))	('activity', 'MPA', (115, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('miR', 'Gene', (15, 18))
831069	27670291	Research shows these biological effects of microRNAs on tumors are involved in stathmin signal, influencing the cell cycle control, proliferation, migration and drug resistance.	('cell cycle control', 'CPA', (112, 130))	('drug resistance', 'CPA', (161, 176))	('drug resistance', 'Phenotype', 'HP:0020174', (161, 176))	('migration', 'CPA', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('influencing', 'Reg', (96, 107))	('proliferation', 'CPA', (132, 145))	('tumors', 'Disease', (56, 62))	('microRNAs', 'Var', (43, 52))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
831074	27670291	Meanwhile, ERK-mediated stathmin is involved in taxol resistance, because blockage of ERK signal improves the sensitivity of tumor cells to taxol.	('taxol', 'Chemical', 'MESH:D017239', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('blockage', 'Var', (74, 82))	('taxol', 'Chemical', 'MESH:D017239', (140, 145))	('ERK', 'Gene', '5594', (86, 89))	('ERK', 'Gene', '5594', (11, 14))	('ERK', 'Gene', (11, 14))	('improves', 'PosReg', (97, 105))	('ERK', 'Gene', (86, 89))
831075	27670291	Over-expression of antiapoptotic protein Bcl-2 has been shown to induce chemoresistance.	('Bcl-2', 'Gene', (41, 46))	('Bcl-2', 'Gene', '596', (41, 46))	('induce', 'PosReg', (65, 71))	('Over-expression', 'Var', (0, 15))	('chemoresistance', 'CPA', (72, 87))
831077	27670291	Dramatically, knockdown of stathmin combined with paclitaxel remarkably promotes the efficacy of inhibiting proliferation of esophageal squamous cell cancer, and leads to a significantly higher proportion of cells at G2/M phase, and this antiproliferative effect was accompanied by an increase in apoptosis rates and morphology changes.	('increase', 'PosReg', (285, 293))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (125, 156))	('knockdown', 'Var', (14, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))	('proliferation', 'CPA', (108, 121))	('morphology changes', 'CPA', (317, 335))	('promotes', 'PosReg', (72, 80))	('apoptosis rates', 'CPA', (297, 312))	('esophageal squamous cell cancer', 'Disease', (125, 156))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (136, 156))	('inhibiting', 'NegReg', (97, 107))	('stathmin', 'Gene', (27, 35))	('higher', 'PosReg', (187, 193))	('cells at G2/M phase', 'CPA', (208, 227))
831078	27670291	After treated by paclitaxel or vincristine, esophageal squamous cell carcinoma (ESCC) cells of stathmin silencing are more likely to enter G2 but less likely to enter mitosis than control cells, suggesting that silencing of stathmin gene increases sensitivity of ESCC to paclitaxel and vincristine through G2/M phase block.	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('ESCC', 'Disease', (263, 267))	('silencing', 'Var', (104, 113))	('esophageal squamous cell carcinoma', 'Disease', (44, 78))	('stathmin', 'Gene', (95, 103))	('vincristine', 'Chemical', 'MESH:D014750', (31, 42))	('sensitivity', 'MPA', (248, 259))	('mitosis', 'Disease', (167, 174))	('silencing', 'Var', (211, 220))	('increases', 'PosReg', (238, 247))	('G2/M phase block', 'CPA', (306, 322))	('mitosis', 'Disease', 'None', (167, 174))	('vincristine', 'Chemical', 'MESH:D014750', (286, 297))	('stathmin', 'Gene', (224, 232))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (44, 78))	('paclitaxel', 'Chemical', 'MESH:D017239', (17, 27))	('paclitaxel', 'Chemical', 'MESH:D017239', (271, 281))
831083	27670291	Research shows that stathmin silencing recovers the chemosensitivity of gastric cancer cells to docetaxel, arrests cells at the sub-G1 stage, induces apoptosis and inhibits the growth of transplantation tumor.	('stathmin', 'Gene', (20, 28))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('arrests', 'NegReg', (107, 114))	('inhibits', 'NegReg', (164, 172))	('docetaxel', 'Chemical', 'MESH:D000077143', (96, 105))	('silencing', 'Var', (29, 38))	('apoptosis', 'CPA', (150, 159))	('induces', 'Reg', (142, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('recovers', 'PosReg', (39, 47))	('cells at the sub-G1 stage', 'CPA', (115, 140))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('chemosensitivity', 'MPA', (52, 68))	('gastric cancer', 'Disease', (72, 86))
831085	27670291	Moreover, depletion of stathmin by antisense oligodeoxynucleotide promotes the antitumor effects of docetaxel to gastric cancer cells, and combination treatment of stathmin inhibition and docetaxel shows a synergistic effect.	('antisense oligodeoxynucleotide', 'Var', (35, 65))	('docetaxel', 'Chemical', 'MESH:D000077143', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (83, 88))	('docetaxel', 'Chemical', 'MESH:D000077143', (100, 109))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('promotes', 'PosReg', (66, 74))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (45, 65))	('depletion', 'MPA', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
831087	27670291	Knock-down of stathmin enhances sensitivity to paclitaxel in endometrial carcinoma cells and also enhances the cytotoxic effect of paclitaxel to retinoblastoma.	('sensitivity to paclitaxel', 'MPA', (32, 57))	('paclitaxel', 'Chemical', 'MESH:D017239', (131, 141))	('endometrial carcinoma cells', 'Disease', 'MESH:D016889', (61, 88))	('retinoblastoma', 'Disease', 'MESH:D012175', (145, 159))	('retinoblastoma', 'Disease', (145, 159))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (61, 82))	('Knock-down', 'Var', (0, 10))	('enhances', 'PosReg', (98, 106))	('enhances', 'PosReg', (23, 31))	('endometrial carcinoma cells', 'Disease', (61, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('retinoblastoma', 'Phenotype', 'HP:0009919', (145, 159))	('cytotoxic effect', 'CPA', (111, 127))	('paclitaxel', 'Chemical', 'MESH:D017239', (47, 57))	('stathmin', 'Gene', (14, 22))
831089	27670291	Glioma stem cells (GSCs) are usually resistant to chemotherapy and radiotherapy, but silencing of stathmin can improve the sensitivity of glioma stem cells to temozolomide.	('sensitivity', 'MPA', (123, 134))	('glioma', 'Disease', (138, 144))	('temozolomide', 'Chemical', 'MESH:D000077204', (159, 171))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('stathmin', 'Gene', (98, 106))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('Glioma', 'Disease', (0, 6))	('silencing', 'Var', (85, 94))	('improve', 'PosReg', (111, 118))
831091	27670291	Surprisingly, down-regulation of stathmin significantly enhances the reversion of ADM resistance in MG63/dox by As2O3, and As2O3 also reverse ADM resistance in MG63/dox cells by down-regulation of stathmin.	('down-regulation', 'NegReg', (14, 29))	('ADM', 'Gene', (142, 145))	('As2O3', 'Chemical', 'MESH:D000077237', (123, 128))	('dox', 'Chemical', 'MESH:D004317', (165, 168))	('stathmin', 'Gene', (197, 205))	('ADM', 'Gene', '133', (142, 145))	('ADM', 'Gene', (82, 85))	('stathmin', 'Gene', (33, 41))	('As2O3', 'Var', (112, 117))	('down-regulation', 'NegReg', (178, 193))	('reversion', 'MPA', (69, 78))	('As2O3', 'Chemical', 'MESH:D000077237', (112, 117))	('dox', 'Chemical', 'MESH:D004317', (105, 108))	('ADM', 'Gene', '133', (82, 85))	('enhances', 'PosReg', (56, 64))	('As2O3', 'Var', (123, 128))
831092	27670291	In addition, 5-FU chemoresponse to the classical colorectal cancer can be improved by silencing of stathmin via a caspase-6 (CASP6)-dependent signal.	('5-FU', 'Chemical', 'MESH:D005472', (13, 17))	('silencing', 'Var', (86, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('caspase-6', 'Gene', (114, 123))	('CASP6', 'Gene', '839', (125, 130))	('caspase-6', 'Gene', '839', (114, 123))	('colorectal cancer', 'Disease', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('CASP6', 'Gene', (125, 130))	('stathmin', 'Gene', (99, 107))
831093	27670291	Interestingly, the function of stathmin is independent of p53 but requires phosphorylations at S25 or S38.	('p53', 'Gene', (58, 61))	('S38', 'Var', (102, 105))	('p53', 'Gene', '7157', (58, 61))	('S25', 'Var', (95, 98))
831097	27670291	For instance, knockdown of stathmin significantly reduces pancreatic cancer cell viability, colony formation, and even retards pancreatic tumor growth in nude mice.Although leukemia is not a solid tumor, stathmin silencing still reduces cell proliferation and clonogenicity of U937 and Namalwa leukemia cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))	('silencing', 'Var', (213, 222))	('leukemia', 'Disease', (294, 302))	('leukemia', 'Disease', 'MESH:D007938', (294, 302))	('U937', 'CellLine', 'CVCL:0007', (277, 281))	('solid tumor', 'Disease', (191, 202))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('leukemia', 'Phenotype', 'HP:0001909', (173, 181))	('Namalwa leukemia', 'Disease', (286, 302))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('solid tumor', 'Disease', 'MESH:D009369', (191, 202))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('cell proliferation', 'CPA', (237, 255))	('retards pancreatic tumor', 'Disease', 'MESH:D010190', (119, 143))	('retards pancreatic tumor', 'Disease', (119, 143))	('reduces', 'NegReg', (229, 236))	('leukemia', 'Disease', (173, 181))	('leukemia', 'Disease', 'MESH:D007938', (173, 181))	('clonogenicity', 'CPA', (260, 273))	('pancreatic cancer', 'Disease', (58, 75))	('Namalwa leukemia', 'Disease', 'MESH:D007938', (286, 302))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('stathmin', 'Gene', (204, 212))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (127, 143))	('nude mice', 'Species', '10090', (154, 163))	('leukemia', 'Phenotype', 'HP:0001909', (294, 302))
831098	27670291	More widely, siRNA-mediated silencing of stathmin has been shown to suppress the proliferation, invasion and metastasis of nasopharyngeal carcinoma (NPC) cells, hepatoma, retinoblastoma, endometrial carcinoma, bladder cancer and glioma, and significantly induces the apoptosis of tumor cells.	('bladder cancer', 'Disease', 'MESH:D001749', (210, 224))	('bladder cancer', 'Disease', (210, 224))	('bladder cancer', 'Phenotype', 'HP:0009725', (210, 224))	('endometrial carcinoma', 'Disease', (187, 208))	('hepatoma', 'Disease', 'MESH:D006528', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('stathmin', 'Gene', (41, 49))	('retinoblastoma', 'Phenotype', 'HP:0009919', (171, 185))	('apoptosis', 'CPA', (267, 276))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (123, 147))	('metastasis of nasopharyngeal carcinoma', 'Disease', (109, 147))	('metastasis of nasopharyngeal carcinoma', 'Disease', 'MESH:D009362', (109, 147))	('retinoblastoma', 'Disease', (171, 185))	('invasion', 'CPA', (96, 104))	('silencing', 'Var', (28, 37))	('tumor', 'Disease', (280, 285))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (187, 208))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (187, 208))	('hepatoma', 'Disease', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('NPC', 'Phenotype', 'HP:0100630', (149, 152))	('induces', 'Reg', (255, 262))	('glioma', 'Disease', (229, 235))	('retinoblastoma', 'Disease', 'MESH:D012175', (171, 185))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('suppress', 'NegReg', (68, 76))	('glioma', 'Disease', 'MESH:D005910', (229, 235))	('proliferation', 'CPA', (81, 94))
831099	27670291	Adenovirus-mediated gene transfer of anti-stathmin ribozyme inhibits cell proliferation and clonogenicity in both ER-positive and ER-negative breast cancer cells and knockdown of stathmin can attenuate the miR-101-mediated enhancement of cell growth and metastasis.	('clonogenicity', 'CPA', (92, 105))	('knockdown', 'Var', (166, 175))	('attenuate', 'NegReg', (192, 201))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('miR', 'Gene', '220972', (206, 209))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('miR', 'Gene', (206, 209))	('breast cancer', 'Disease', (142, 155))	('cell proliferation', 'CPA', (69, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('inhibits', 'NegReg', (60, 68))
831101	27670291	To lung cancer cells, knockdown of stathmin results in a remarkable decrease in cellular proliferation and invasion, and monoclonal antibodies against stathmin also inhibit the proliferation of human lung carcinoma QG-56 cells, and even result in a significantly higher apoptosis rate.	('cellular proliferation', 'CPA', (80, 102))	('stathmin', 'Gene', (35, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('knockdown', 'Var', (22, 31))	('invasion', 'CPA', (107, 115))	('decrease', 'NegReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('inhibit', 'NegReg', (165, 172))	('stathmin', 'Gene', (151, 159))	('lung carcinoma', 'Disease', (200, 214))	('lung cancer', 'Disease', (3, 14))	('apoptosis rate', 'CPA', (270, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('higher', 'PosReg', (263, 269))	('QG-56', 'CellLine', 'CVCL:6943', (215, 220))	('human', 'Species', '9606', (194, 199))	('proliferation', 'CPA', (177, 190))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('lung carcinoma', 'Disease', 'MESH:D008175', (200, 214))
831102	27670291	The depletion of stathmin by antisense oligodeoxynucleotide significantly inhibits the proliferation of gastric cancer cells.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('antisense oligodeoxynucleotide', 'Var', (29, 59))	('proliferation', 'CPA', (87, 100))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (39, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('inhibits', 'NegReg', (74, 82))	('depletion', 'MPA', (4, 13))	('stathmin', 'Gene', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gastric cancer', 'Disease', (104, 118))
831104	27670291	Bifunctional small hairpin RNAs (bi-shRNAs) is functional miRNA/siRNA composite; one study shows that a single intratumoral injection of pbi-sh-stathmin reduces growth of tumor xenograft derived from colorectal cancer CCL-247 cells, and also significantly inhibits the growth of tumorgrafts derived from primary melanoma and osteosarcoma xenograft.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('colorectal cancer', 'Disease', 'MESH:D015179', (200, 217))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('miR', 'Gene', '220972', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('reduces', 'NegReg', (153, 160))	('colorectal cancer', 'Disease', (200, 217))	('pbi-sh-stathmin', 'Var', (137, 152))	('osteosarcoma', 'Phenotype', 'HP:0002669', (325, 337))	('tumor', 'Disease', (116, 121))	('miR', 'Gene', (58, 61))	('melanoma', 'Disease', 'MESH:D008545', (312, 320))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('osteosarcoma xenograft', 'Disease', 'MESH:D012516', (325, 347))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('CCL', 'Chemical', 'MESH:D002433', (218, 221))	('growth', 'CPA', (269, 275))	('tumor', 'Disease', (279, 284))	('growth', 'MPA', (161, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (200, 217))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('melanoma', 'Disease', (312, 320))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Disease', (171, 176))	('osteosarcoma xenograft', 'Disease', (325, 347))	('inhibits', 'NegReg', (256, 264))
831105	27670291	In human cancers, stathmin is usually overexpressed and anti-stathmin treatment usually reduces cell proliferation, clonal growth, cell motility, metastasis and increases apoptosis.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('metastasis', 'CPA', (146, 156))	('reduces', 'NegReg', (88, 95))	('human', 'Species', '9606', (3, 8))	('apoptosis', 'CPA', (171, 180))	('anti-stathmin', 'Var', (56, 69))	('cell proliferation', 'CPA', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('clonal growth', 'CPA', (116, 129))	('cell motility', 'CPA', (131, 144))	('increases', 'PosReg', (161, 170))
831108	27670291	However, the abnormal expression of stathmin in tumor cells has provided to be a feasible approach for the development of stathmin-dependent molecular targeting therapy.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('abnormal', 'Var', (13, 21))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
831110	27670291	Stathmin expression has been found to be increased in a variety of cancers and high expression of stathmin can potentially promote cell proliferation, motility and metastasis of malignant tumors.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('motility', 'CPA', (151, 159))	('Stathmin', 'Gene', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('cancers', 'Disease', (67, 74))	('metastasis of malignant tumors', 'Disease', (164, 194))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('metastasis of malignant tumors', 'Disease', 'MESH:D009362', (164, 194))	('promote', 'PosReg', (123, 130))	('expression', 'MPA', (9, 19))	('stathmin', 'Gene', (98, 106))	('cell proliferation', 'CPA', (131, 149))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('high expression', 'Var', (79, 94))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Stathmin', 'Gene', '3925', (0, 8))
831111	27670291	However, many target-specific anti-stathmin investigations have been demonstrated to reduce cell proliferation, clonal growth, cell motility and metastasis, and to increase apoptosis of malignant tumors.	('increase apoptosis of malignant tumors', 'Disease', (164, 202))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('reduce', 'NegReg', (85, 91))	('clonal growth', 'CPA', (112, 125))	('increase apoptosis of malignant tumors', 'Disease', 'MESH:D018198', (164, 202))	('cell proliferation', 'CPA', (92, 110))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('anti-stathmin', 'Var', (30, 43))
831168	27152887	The 95% confidence interval (thin lines) allowed a rather large range in GTV position to be predicted by the fiducial: +-5 mm in the AP and +-10 mm in the SI directions.	('SI', 'Disease', 'None', (155, 157))	('+-5 mm', 'Var', (119, 125))	('+-10 mm', 'Var', (140, 147))	('GTV', 'Chemical', '-', (73, 76))
831230	24926382	However, in the HET-1A cell line, JWA-siRNA transfection significantly inhibited the expression of p-p38 and demonstrated no effect on the expression levels of p-ERK1/2 and p-JNK.	('expression', 'MPA', (85, 95))	('transfection', 'Var', (44, 56))	('JWA', 'Gene', (34, 37))	('inhibited', 'NegReg', (71, 80))	('p38', 'Gene', (101, 104))	('JNK', 'Gene', (175, 178))	('expression', 'MPA', (139, 149))	('JNK', 'Gene', '5599', (175, 178))	('p38', 'Gene', '5594', (101, 104))	('JWA', 'Gene', '10550', (34, 37))
831239	24926382	Furthermore, previous studies in mice and cervical carcinoma HeLa cells in vitro have shown that the expression level of JWA affects tumor proliferation, invasion and apoptosis via the MAPK pathway.	('cervical carcinoma HeLa', 'Disease', (42, 65))	('cervical carcinoma HeLa', 'Disease', 'MESH:D002575', (42, 65))	('JWA', 'Gene', '10550', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('MAPK', 'Gene', '5595;5594;5595', (185, 189))	('expression', 'Var', (101, 111))	('apoptosis', 'CPA', (167, 176))	('MAPK', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('JWA', 'Gene', (121, 124))	('invasion', 'CPA', (154, 162))	('tumor', 'Disease', (133, 138))	('mice', 'Species', '10090', (33, 37))	('affects', 'Reg', (125, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
831253	24926382	Secondary antibodies [AP-conjugated anti-mouse IgG (S372B; Promega, Fitchburg, WI, USA) and AP-conjugated anti-rabbit IgG (S372B; Promega)] were added and the membranes were incubated for 2 h at room temperature.	('S372B', 'Var', (52, 57))	('mouse', 'Species', '10090', (41, 46))	('rabbit', 'Species', '9986', (111, 117))	('S372B', 'Var', (123, 128))	('S372B', 'SUBSTITUTION', 'None', (123, 128))	('S372B', 'SUBSTITUTION', 'None', (52, 57))
831265	24926382	Bai et al demonstrated that the migration and invasion abilities of melanoma cells were inhibited following JWA knockdown.	('inhibited', 'NegReg', (88, 97))	('JWA', 'Gene', '10550', (108, 111))	('JWA', 'Gene', (108, 111))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('knockdown', 'Var', (112, 121))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))
831276	24926382	As with other malignant tumors, esophageal carcinomas are associated with changes occurring to genes.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (32, 53))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('changes', 'Var', (74, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('malignant tumors', 'Disease', (14, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('esophageal carcinomas', 'Disease', (32, 53))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (32, 53))	('malignant tumors', 'Disease', 'MESH:D018198', (14, 30))
831285	24926382	The results indicate that JWA knockdown has inhibitory effects on apoptosis in both normal and cancer cells.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('JWA', 'Gene', '10550', (26, 29))	('cancer', 'Disease', (95, 101))	('apoptosis', 'CPA', (66, 75))	('knockdown', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('JWA', 'Gene', (26, 29))
831287	24926382	In the present study, following knockdown of the tumor suppressor gene JWA, the proliferation of Eca109 and HET-1A cells accelerated.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('proliferation', 'CPA', (80, 93))	('knockdown', 'Var', (32, 41))	('tumor', 'Disease', (49, 54))	('JWA', 'Gene', '10550', (71, 74))	('JWA', 'Gene', (71, 74))	('accelerated', 'PosReg', (121, 132))
831291	24926382	Chen et al indicated that the overexpression of JWA in HeLa, B16 and HCCLM3 cancer cells effectively inhibited cell migration; however, cell migration was significantly accelerated as a result of JWA knockdown.	('knockdown', 'Var', (200, 209))	('JWA', 'Gene', (196, 199))	('JWA', 'Gene', '10550', (196, 199))	('cell migration', 'CPA', (111, 125))	('accelerated', 'PosReg', (169, 180))	('overexpression', 'PosReg', (30, 44))	('JWA', 'Gene', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('HeLa', 'CellLine', 'CVCL:0030', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('inhibited', 'NegReg', (101, 110))	('cancer', 'Disease', (76, 82))	('cell migration', 'CPA', (136, 150))	('JWA', 'Gene', '10550', (48, 51))
831292	24926382	The present results indicate that migration and invasion were significantly enhanced following transfection with JWA-siRNA compared with those in untreated cells.	('transfection', 'Var', (95, 107))	('JWA', 'Gene', '10550', (113, 116))	('enhanced', 'PosReg', (76, 84))	('invasion', 'CPA', (48, 56))	('JWA', 'Gene', (113, 116))
831295	24926382	Chen et al demonstrated that in HeLa cells, PMA and As2O3 led to the phosphorylation of MEK and ERK, whereas JWA knockdown blocked MEK and ERK phosphorylation.	('MEK', 'Gene', '5609', (88, 91))	('As2O3', 'Var', (52, 57))	('As2O3', 'Chemical', 'MESH:D000077237', (52, 57))	('HeLa', 'CellLine', 'CVCL:0030', (32, 36))	('ERK', 'Gene', '5594', (139, 142))	('ERK', 'Gene', (139, 142))	('PMA', 'Chemical', 'MESH:D013755', (44, 47))	('JWA', 'Gene', '10550', (109, 112))	('blocked', 'NegReg', (123, 130))	('ERK', 'Gene', '5594', (96, 99))	('MEK', 'Gene', (131, 134))	('phosphorylation', 'MPA', (69, 84))	('MEK', 'Gene', '5609', (131, 134))	('MEK', 'Gene', (88, 91))	('JWA', 'Gene', (109, 112))	('ERK', 'Gene', (96, 99))
831301	24926382	However, in a JWA-knockout JAr cell model, VP16 (etoposide phosphate), was unable to activate the phosphorylation of JNK and p38, thus apoptosis decreased.	('apoptosis', 'CPA', (135, 144))	('VP16', 'Chemical', 'MESH:D005047', (43, 47))	('phosphorylation', 'MPA', (98, 113))	('JWA', 'Gene', '10550', (14, 17))	('JNK', 'Gene', '5599', (117, 120))	('VP16', 'Var', (43, 47))	('p38', 'Gene', (125, 128))	('JWA', 'Gene', (14, 17))	('decreased', 'NegReg', (145, 154))	('etoposide phosphate', 'Chemical', 'MESH:C061400', (49, 68))	('p38', 'Gene', '5594', (125, 128))	('JNK', 'Gene', (117, 120))
831302	24926382	However, in the present study, a significant reduction in the level of p-JNK was observed in Eca109 cells following JWA knockdown, whereas the JNK expression did not decrease.	('JNK', 'Gene', (73, 76))	('JWA', 'Gene', (116, 119))	('JNK', 'Gene', '5599', (73, 76))	('knockdown', 'Var', (120, 129))	('JWA', 'Gene', '10550', (116, 119))	('JNK', 'Gene', (143, 146))	('reduction', 'NegReg', (45, 54))	('JNK', 'Gene', '5599', (143, 146))
831303	24926382	In the third MAPK pathway, the protein levels of p38 and p-p38 did not change in the Eca109 cells; however, the p-p38 level decreased in the HET-1A cells following JWA knockdown.	('MAPK', 'Gene', (13, 17))	('p38', 'Gene', (59, 62))	('MAPK', 'Gene', '5595;5594;5595', (13, 17))	('p38', 'Gene', (114, 117))	('decreased', 'NegReg', (124, 133))	('p38', 'Gene', '5594', (59, 62))	('p38', 'Gene', '5594', (49, 52))	('p38', 'Gene', '5594', (114, 117))	('JWA', 'Gene', '10550', (164, 167))	('knockdown', 'Var', (168, 177))	('p38', 'Gene', (49, 52))	('JWA', 'Gene', (164, 167))
831335	18764945	The identification of mutations within SCFFbx4-alphaBcrystallin ligase in primary tumors provides mechanistic insight into cyclin D1 accumulation in human cancer.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('SCFFbx4-alphaBcrystallin', 'Gene', (39, 63))	('human', 'Species', '9606', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
831336	18764945	Furthermore, analysis of mouse models expressing cyclin D1 mutants refractory to degradation indicate that nuclear cyclin D1/CDK4 kinase triggers DNA re-replication and genomic instability.	('DNA re-replication', 'CPA', (146, 164))	('mutants', 'Var', (59, 66))	('genomic instability', 'CPA', (169, 188))	('mouse', 'Species', '10090', (25, 30))	('triggers', 'Reg', (137, 145))	('nuclear cyclin', 'Var', (107, 121))
831342	18764945	Thr-286 phosphorylated cyclin D1 is recognized by Fbx4 and the co-factor alphaB crystallin and is subsequently poly-ubiquitylated and degraded by the 26S proteasome.	('Fbx4', 'Gene', (50, 54))	('degraded', 'NegReg', (134, 142))	('Fbx4', 'Gene', '26272', (50, 54))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('cyclin D1', 'Protein', (23, 32))	('Thr-286', 'Var', (0, 7))
831344	18764945	Indeed, mutations that directly impact on cyclin D1 nuclear export and subsequent proteolysis have been identified in human tumors.	('impact', 'Reg', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('nuclear export', 'MPA', (52, 66))	('cyclin D1', 'Protein', (42, 51))	('mutations', 'Var', (8, 17))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (118, 123))	('proteolysis', 'MPA', (82, 93))
831347	18764945	Indeed mutations that interfere with Thr-286 phosphorylation occur, but are rare.	('phosphorylation', 'MPA', (45, 60))	('Thr-286', 'Protein', (37, 44))	('Thr', 'Chemical', 'MESH:D013912', (37, 40))	('mutations', 'Var', (7, 16))
831348	18764945	Such mutations have been noted in endometrial and esophageal cancer.	('noted', 'Reg', (25, 30))	('mutations', 'Var', (5, 14))	('endometrial', 'Disease', (34, 45))	('esophageal cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
831349	18764945	For example, of single-base substitutions in the CCND1 gene changing proline-287 (Pro-287) to a serine or threonine residue in endometrioid endometrial carcinoma correlates with overexpression of cyclin D1 in the nucleus of neoplastic cells.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('Pro-287) to a serine', 'Mutation', 'p.P287S', (82, 102))	('CCND1', 'Gene', '595', (49, 54))	('changing', 'Reg', (60, 68))	('overexpression', 'PosReg', (178, 192))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (140, 161))	('endometrioid endometrial carcinoma', 'Disease', 'MESH:D016889', (127, 161))	('endometrioid endometrial carcinoma', 'Disease', (127, 161))	('proline', 'Chemical', 'MESH:D011392', (69, 76))	('threonine', 'Chemical', 'MESH:D013912', (106, 115))	('proline-287', 'MPA', (69, 80))	('single-base substitutions', 'Var', (16, 41))	('CCND1', 'Gene', (49, 54))
831350	18764945	Significantly, subsequent analyses revealed that disruption of Pro-287 abrogates GSK3beta-dependent phosphorylation of Thr-286, resulting in nuclear localization of cyclin D1, and deletion of residues 289-292 impairs cyclin D1 binding to CRM1, also resulting in nuclear accumulation.	('GSK3beta', 'Gene', '2932', (81, 89))	('impairs', 'NegReg', (209, 216))	('cyclin D1', 'Protein', (217, 226))	('Thr', 'Chemical', 'MESH:D013912', (119, 122))	('CRM1', 'Gene', '7514', (238, 242))	('abrogates', 'NegReg', (71, 80))	('CRM1', 'Gene', (238, 242))	('nuclear localization', 'MPA', (141, 161))	('binding', 'Interaction', (227, 234))	('deletion of residues 289-292', 'Var', (180, 208))	('Thr-286', 'Gene', (119, 126))	('GSK3beta', 'Gene', (81, 89))	('disruption', 'Var', (49, 59))	('cyclin', 'Protein', (165, 171))	('nuclear accumulation', 'MPA', (262, 282))
831351	18764945	In accordance with endometrial cancer studies, recently identified cyclin D1 mutations in esophageal cancer and tumor-derived cell lines also disrupt Thr-286 phosphorylation.	('Thr-286 phosphorylation', 'MPA', (150, 173))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Thr', 'Chemical', 'MESH:D013912', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('endometrial cancer', 'Disease', (19, 37))	('disrupt', 'NegReg', (142, 149))	('esophageal cancer', 'Disease', (90, 107))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cyclin D1', 'Gene', (67, 76))	('mutations', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('endometrial cancer', 'Phenotype', 'HP:0012114', (19, 37))	('endometrial cancer', 'Disease', 'MESH:D016889', (19, 37))	('tumor', 'Disease', (112, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))
831352	18764945	Sequencing of cyclin D1 (CCND1) in a panel of 90 patient esophageal carcinomas revealed mutation of Thr-286 to arginine and a deletion of C-terminal residues 266-295.	('CCND1', 'Gene', (25, 30))	('mutation', 'Var', (88, 96))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (57, 77))	('Thr-286 to arginine', 'Mutation', 'p.T286R', (100, 119))	('Thr-286', 'Var', (100, 107))	('CCND1', 'Gene', '595', (25, 30))	('C-terminal residues', 'MPA', (138, 157))	('patient', 'Species', '9606', (49, 56))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (57, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('esophageal carcinomas', 'Disease', (57, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (57, 78))
831354	18764945	Alternative splicing may also contribute to cancer specific accumulation of cyclin D1 proteins that cannot undergo cytoplasmic degradation.	('cyclin D1 proteins', 'Protein', (76, 94))	('proteins', 'Protein', (86, 94))	('contribute', 'Reg', (30, 40))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Alternative splicing', 'Var', (0, 20))	('accumulation', 'PosReg', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
831357	18764945	As might be anticipated, expression of cyclin D1b promotes neoplastic transformation in vitro, much like the phosphorylation-deficient T286A mutant.	('neoplastic transformation', 'CPA', (59, 84))	('cyclin D1b', 'Protein', (39, 49))	('T286A', 'Mutation', 'c.286T>A', (135, 140))	('expression', 'Var', (25, 35))	('promotes', 'PosReg', (50, 58))
831366	18764945	Significantly, recent assessment of the Fbx4 sequence in primary esophageal carcinoma samples identified hemizygous, missense mutations in 14 percent of the tumors; no mutations occurred in alphaB crystallin or CCND1 genes in tumors expressing mutated Fbx4.	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('CCND1', 'Gene', (211, 216))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (65, 85))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mutated', 'Var', (244, 251))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('Fbx4', 'Gene', '26272', (40, 44))	('Fbx4', 'Gene', (252, 256))	('missense mutations', 'Var', (117, 135))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumors', 'Disease', (157, 163))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (65, 85))	('Fbx4', 'Gene', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal carcinoma', 'Disease', (65, 85))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('Fbx4', 'Gene', '26272', (252, 256))	('CCND1', 'Gene', '595', (211, 216))
831367	18764945	A high percentage of mutations reside within a putative Fbx4 dimerization domain, while others target Ser-12 in the N-terminus.	('Fbx4', 'Gene', '26272', (56, 60))	('Fbx4', 'Gene', (56, 60))	('Ser-12', 'Chemical', '-', (102, 108))	('mutations', 'Var', (21, 30))
831368	18764945	Additionally, one mutation identified within the F box domain results in production of a dominant negative protein incapable of recruiting Skp1 and Cul1.	('negative', 'NegReg', (98, 106))	('Cul1', 'Gene', (148, 152))	('protein', 'Protein', (107, 114))	('Skp1', 'Gene', '6500', (139, 143))	('mutation', 'Var', (18, 26))	('Skp1', 'Gene', (139, 143))	('Cul1', 'Gene', '8454', (148, 152))
831376	18764945	Fbx4 homodimerization is dependent on Ser-12 phosphorylation; disruption of this residue impairs the ubiquitylation activity of this ligase.	('ubiquitylation activity', 'MPA', (101, 124))	('Ser-12', 'Chemical', '-', (38, 44))	('impairs', 'NegReg', (89, 96))	('Fbx4', 'Gene', (0, 4))	('disruption', 'Var', (62, 72))	('Fbx4', 'Gene', '26272', (0, 4))
831377	18764945	The tumorigenic potential of Fbx4 mutations disrupting phosphorylation and dimerization was assessed in vitro, revealing that such mutations are indeed transforming.	('tumor', 'Disease', (4, 9))	('disrupting', 'NegReg', (44, 54))	('Fbx4', 'Gene', (29, 33))	('Fbx4', 'Gene', '26272', (29, 33))	('dimerization', 'MPA', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('phosphorylation', 'MPA', (55, 70))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutations', 'Var', (34, 43))
831378	18764945	These findings suggest that mutation of Ser-12 or residues within the Fbx4 dimerization domain impairs ligase function, contributing to cyclin D1 accumulation.	('contributing', 'Reg', (120, 132))	('Fbx4', 'Gene', '26272', (70, 74))	('Ser-12', 'Gene', (40, 46))	('impairs', 'NegReg', (95, 102))	('function', 'MPA', (110, 118))	('cyclin D1 accumulation', 'MPA', (136, 158))	('mutation', 'Var', (28, 36))	('ligase', 'Protein', (103, 109))	('Fbx4', 'Gene', (70, 74))	('Ser-12', 'Chemical', '-', (40, 46))
831380	18764945	Aberrant nuclear accumulation of cyclin D1 during S-phase drives cell transformation in vitro and B-cell lymphomagenesis in mice.	('Aberrant', 'Var', (0, 8))	('cell transformation', 'CPA', (65, 84))	('B-cell lymphomagenesis', 'CPA', (98, 120))	('nuclear accumulation', 'MPA', (9, 29))	('mice', 'Species', '10090', (124, 128))	('cyclin D1', 'Protein', (33, 42))	('B-cell lymphomagenesis', 'Phenotype', 'HP:0012191', (98, 120))
831384	18764945	The failure to degrade Cdt1 during S-phase has been shown to contribute to DNA re-replication in several systems.	('DNA', 'MPA', (75, 78))	('contribute', 'Reg', (61, 71))	('Cdt1', 'Gene', '81620', (23, 27))	('failure', 'Var', (4, 11))	('Cdt1', 'Gene', (23, 27))
831389	18764945	Taken together, data elucidating the role of nuclear cyclin D1 in neoplastic transformation support a model wherein disruption of cyclin D1 phosphorylation or SCFFbx4-alphaBcrystallin activation generate genomic instability, ultimately driving tumor formation (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', (244, 249))	('disruption', 'Var', (116, 126))	('genomic instability', 'CPA', (204, 223))	('cyclin', 'Protein', (130, 136))	('driving', 'Reg', (236, 243))	('generate', 'Reg', (195, 203))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
831391	18764945	Chronic activation of checkpoints may provide selective pressure for deletion or mutation of critical tumor suppressors such as p53.	('p53', 'Gene', '7157', (128, 131))	('p53', 'Gene', (128, 131))	('mutation', 'Var', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('deletion', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
831392	18764945	Consistent with this notion, cyclin D1T286A-dependent tumorigenesis is accompanied by activation of the DNA damage checkpoint pathway and loss of p53.	('loss', 'NegReg', (138, 142))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cyclin D1T286A-dependent', 'Var', (29, 53))	('activation', 'PosReg', (86, 96))	('DNA damage checkpoint pathway', 'Pathway', (104, 133))
831394	18764945	Provided with this new data suggesting that cyclin D1-dependent kinase contributes to neoplasia at least in part through perturbations in DNA replication and loss of genomic integrity, can we utilize this information for increased therapeutic modalities?	('genomic integrity', 'CPA', (166, 183))	('DNA', 'Protein', (138, 141))	('neoplasia', 'Phenotype', 'HP:0002664', (86, 95))	('neoplasia', 'Disease', 'MESH:D009369', (86, 95))	('perturbations', 'Var', (121, 134))	('loss', 'NegReg', (158, 162))	('contributes', 'Reg', (71, 82))	('neoplasia', 'Disease', (86, 95))
831395	18764945	One scenario might be to take advantage of the fact that tumors harbouring mutations in cyclin D1 or Fbx4 have a compromised DNA damage checkpoint due to loss of p53.	('Fbx4', 'Gene', '26272', (101, 105))	('p53', 'Gene', (162, 165))	('p53', 'Gene', '7157', (162, 165))	('cyclin D1', 'Gene', (88, 97))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('DNA damage checkpoint', 'MPA', (125, 146))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutations', 'Var', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('loss', 'NegReg', (154, 158))	('Fbx4', 'Gene', (101, 105))	('compromised', 'NegReg', (113, 124))
831398	18764945	Consistent with this notion of oncogene addiction, treatment of mammary epithelial cells derived from murine tumors harbouring a MMTV-T286A transgene with the CDK4/6 inhibitor PD0332991 triggered G1 arrest.	('arrest', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('MMTV', 'Species', '11757', (129, 133))	('murine', 'Species', '10090', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('T286A', 'Mutation', 'c.286T>A', (134, 139))	('arrest', 'Disease', 'MESH:D006323', (199, 205))	('MMTV-T286A transgene', 'Var', (129, 149))
831400	18764945	Furthermore, mutations targeting SCFFbx4-alphaB crystallin in human cancers implicate ligase function in cyclin D1 overexpression and subsequent nuclear accumulation of active cyclin D1/CDK4 complexes.	('complexes', 'Interaction', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('nuclear accumulation', 'MPA', (145, 165))	('cancers', 'Disease', (68, 75))	('ligase', 'Protein', (86, 92))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('SCFFbx4-alphaB', 'Gene', (33, 47))	('implicate', 'Reg', (76, 85))	('cyclin D1', 'Protein', (105, 114))	('mutations', 'Var', (13, 22))	('overexpression', 'PosReg', (115, 129))
831403	33239613	CircCNTNAP3-TP53-positive feedback loop suppresses malignant progression of esophageal squamous cell carcinoma Mutation or downregulation of p53 (encoded by TP53) accelerates tumorigenesis and malignant progression in esophageal squamous cell carcinoma (ESCC).	('TP53', 'Gene', (157, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('p53', 'Gene', '7157', (141, 144))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (76, 110))	('malignant progression', 'CPA', (193, 214))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (229, 252))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (218, 252))	('TP53', 'Gene', (12, 16))	('TP53', 'Gene', '7157', (157, 161))	('tumor', 'Disease', (175, 180))	('p53', 'Gene', (141, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('downregulation', 'NegReg', (123, 137))	('suppresses', 'NegReg', (40, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('accelerates', 'PosReg', (163, 174))	('TP53', 'Gene', '7157', (12, 16))	('malignant progression', 'CPA', (51, 72))	('Mutation', 'Var', (111, 119))	('esophageal squamous cell carcinoma', 'Disease', (76, 110))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('esophageal squamous cell carcinoma', 'Disease', (218, 252))
831416	33239613	It has been reported that more than half of human cancers, including ESCC, have no wild-type p53 function due to deletion or mutation.	('human', 'Species', '9606', (44, 49))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('p53', 'Gene', (93, 96))	('deletion', 'Var', (113, 121))	('p53', 'Gene', '7157', (93, 96))	('cancers', 'Disease', (50, 57))	('function', 'MPA', (97, 105))	('ESCC', 'Disease', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutation', 'Var', (125, 133))
831420	33239613	Recent studies have demonstrated that p53 and its network are also regulated by noncoding RNAs at multiple levels.	('noncoding RNAs', 'Var', (80, 94))	('p53', 'Gene', (38, 41))	('regulated', 'Reg', (67, 76))	('p53', 'Gene', '7157', (38, 41))
831421	33239613	For example, long noncoding RNA PURPL promotes the progression of colorectal cancer by inhibiting the expression of p53.	('expression', 'MPA', (102, 112))	('long noncoding', 'Var', (13, 27))	('promotes', 'PosReg', (38, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('p53', 'Gene', '7157', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('inhibiting', 'NegReg', (87, 97))	('p53', 'Gene', (116, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
831477	33239613	To test the binding specificity, the sequences that interacted with the miR-513a-5p seed sequence were mutated (from GGCCCATATCTGTGAA to CGAATCCCAACCGTT), and the wild-type and mutant p53 3'-UTR was inserted into the pGL3 basic vector (Promega).	('p53', 'Gene', '7157', (184, 187))	('mutant', 'Var', (177, 183))	('p53', 'Gene', (184, 187))
831481	33239613	We suspect that the circRNA transcribed by CNTNAP3 protects esophageal tissue from malignancy and that the loss of cCNTNAP3 may lead to ESCC.	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('loss', 'Var', (107, 111))	('CNTNAP3', 'Gene', (43, 50))	('CNTNAP3', 'Gene', (116, 123))	('malignancy', 'Disease', (83, 93))	('lead to', 'Reg', (128, 135))	('CNTNAP3', 'Gene', '79937', (43, 50))	('CNTNAP3', 'Gene', '79937', (116, 123))
831497	33239613	RTCA, colony formation, EdU assays showed that knockdown of cCNTNAP3 promoted cell proliferation, while overexpression of cCNTNAP3 suppressed cell growth in Eca-109 cells (Fig.	('cell growth', 'CPA', (142, 153))	('knockdown', 'Var', (47, 56))	('CNTNAP3', 'Gene', (61, 68))	('CNTNAP3', 'Gene', (123, 130))	('promoted', 'PosReg', (69, 77))	('suppressed', 'NegReg', (131, 141))	('EdU', 'Chemical', 'MESH:C031086', (24, 27))	('CNTNAP3', 'Gene', '79937', (61, 68))	('CNTNAP3', 'Gene', '79937', (123, 130))	('cell proliferation', 'CPA', (78, 96))
831515	33239613	We also conducted a biotinylated miR-513a-5p pull-down experiment, the results showed that the enrichment of cCNTNAP3 in the capture portion of mutant miR-513a-5p was significantly reduced compared with that of the wild-type miR-513a-5p (Fig.	('reduced', 'NegReg', (181, 188))	('capture', 'MPA', (125, 132))	('enrichment', 'MPA', (95, 105))	('biotin', 'Chemical', 'MESH:D001710', (20, 26))	('CNTNAP3', 'Gene', '79937', (110, 117))	('mutant', 'Var', (144, 150))	('miR-513a-5p', 'Gene', (151, 162))	('CNTNAP3', 'Gene', (110, 117))
831516	33239613	Furthermore, we found that there is a significant negative correlation (R2 = -0.3815, P < 0.001, n = 48) between cCNTNAP3 and miR-513a-5p in ESCC tissues (Fig.	('CNTNAP3', 'Gene', (114, 121))	('negative', 'NegReg', (50, 58))	('miR-513a-5p', 'Var', (126, 137))	('CNTNAP3', 'Gene', '79937', (114, 121))	('ESCC', 'Disease', (141, 145))
831517	33239613	Finally, the FISH analysis showed that miR-513a-5p co-localized with cCNTNAP3 in the cytoplasm (Fig.	('CNTNAP3', 'Gene', '79937', (70, 77))	('CNTNAP3', 'Gene', (70, 77))	('miR-513a-5p', 'Var', (39, 50))
831518	33239613	In summary, these results demonstrated that cCNTNAP3 could directly bind miR-513a-5p.	('CNTNAP3', 'Gene', '79937', (45, 52))	('miR-513a-5p', 'Var', (73, 84))	('bind', 'Interaction', (68, 72))	('CNTNAP3', 'Gene', (45, 52))
831519	33239613	MiR-513a-5p has been reported to be a risk factor for breast cancer.	('breast cancer', 'Disease', (54, 67))	('MiR-513a-5p', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('MiR-513a-5p', 'Chemical', '-', (0, 11))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
831520	33239613	RTCA, colony formation, and EdU assays revealed that knockdown of cCNTNAP3 successfully promoted cell proliferation, while the promotion of cell proliferation by cCNTNAP3 was reversed by co-transfection with miR-513a-5p inhibitor.	('promoted', 'PosReg', (88, 96))	('cell proliferation', 'CPA', (140, 158))	('CNTNAP3', 'Gene', (163, 170))	('CNTNAP3', 'Gene', (67, 74))	('knockdown', 'Var', (53, 62))	('CNTNAP3', 'Gene', '79937', (163, 170))	('CNTNAP3', 'Gene', '79937', (67, 74))	('cell proliferation', 'CPA', (97, 115))	('EdU', 'Chemical', 'MESH:C031086', (28, 31))
831524	33239613	We found that p53 mRNA was a candidate that could be targeted by miR-513a-5p using three publicly available algorithms (Fig.	('p53', 'Gene', '7157', (14, 17))	('miR-513a-5p', 'Var', (65, 76))	('p53', 'Gene', (14, 17))
831528	33239613	A dual-luciferase reporter assay indicated that co-transfection of miR-513a-5p and p53 wild-type reporter plasmids markedly attenuated the luciferase activity (Fig.	('luciferase', 'Enzyme', (139, 149))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('attenuated', 'NegReg', (124, 134))	('miR-513a-5p', 'Var', (67, 78))	('activity', 'MPA', (150, 158))
831529	33239613	These findings confirmed that p53 was indeed a direct target of miR-513a-5p.	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('miR-513a-5p', 'Var', (64, 75))
831530	33239613	After that, we performed western blot assays to determine p53 protein levels after cCNTNAP3 silenced or overexpressed.	('silenced', 'Var', (92, 100))	('CNTNAP3', 'Gene', (84, 91))	('CNTNAP3', 'Gene', '79937', (84, 91))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
831532	33239613	However, the expression level of mutant p53 did not significantly change in KYSE-450 and TE-1 cells (Fig.	('TE-1', 'CellLine', 'CVCL:1759', (89, 93))	('mutant', 'Var', (33, 39))	('p53', 'Gene', '7157', (40, 43))	('p53', 'Gene', (40, 43))
831533	33239613	S4A), it is likely due to the longer banishment period of the mutant p53 protein.	('p53', 'Gene', '7157', (69, 72))	('protein', 'Protein', (73, 80))	('mutant', 'Var', (62, 68))	('p53', 'Gene', (69, 72))
831540	33239613	Interestingly, we used siRNA to knock down the expression of p53 and observed that cCNTNAP3 levels were significantly downregulated in Eca-109 but not in KYSE-450 and TE-1 cells.	('TE-1', 'CellLine', 'CVCL:1759', (167, 171))	('knock', 'Var', (32, 37))	('CNTNAP3', 'Gene', (84, 91))	('CNTNAP3', 'Gene', '79937', (84, 91))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('downregulated', 'NegReg', (118, 131))
831546	33239613	Subsequently, we knocked down RBM25 using siRNA (si-RBM25) and used qRT-PCR to examine the expression of cCNTNAP3.	('CNTNAP3', 'Gene', '79937', (106, 113))	('RBM25', 'Gene', '58517', (30, 35))	('knocked', 'Var', (17, 24))	('RBM25', 'Gene', (30, 35))	('CNTNAP3', 'Gene', (106, 113))	('RBM25', 'Gene', '58517', (52, 57))	('RBM25', 'Gene', (52, 57))
831547	33239613	The results showed that cCNTNAP3 was significantly downregulated in which RBM25 was knocked down.	('RBM25', 'Gene', '58517', (74, 79))	('CNTNAP3', 'Gene', '79937', (25, 32))	('RBM25', 'Gene', (74, 79))	('downregulated', 'NegReg', (51, 64))	('CNTNAP3', 'Gene', (25, 32))	('knocked down', 'Var', (84, 96))
831555	33239613	Kaplan-Meier survival curves showed that patients with higher levels of cCNTNAP3 exhibited a longer overall survival (Fig.	('higher levels', 'Var', (55, 68))	('CNTNAP3', 'Gene', (73, 80))	('overall survival', 'CPA', (100, 116))	('CNTNAP3', 'Gene', '79937', (73, 80))	('patients', 'Species', '9606', (41, 49))	('longer', 'PosReg', (93, 99))
831568	33239613	Furthermore, a significant inverse correlation occurred between cCNTNAP3 and miR-513a-5p in ESCC tissues.	('CNTNAP3', 'Gene', '79937', (65, 72))	('ESCC', 'Disease', (92, 96))	('inverse', 'NegReg', (27, 34))	('miR-513a-5p', 'Var', (77, 88))	('CNTNAP3', 'Gene', (65, 72))
831569	33239613	Therefore, it is likely that cCNTNAP3 can serve as a sponge for miR-513a-5p and thus perform a series of functions.	('miR-513a-5p', 'Var', (64, 75))	('CNTNAP3', 'Gene', '79937', (30, 37))	('CNTNAP3', 'Gene', (30, 37))
831570	33239613	The deletion or mutation of p53 is a crucial feature of ESCC, and it drives tumor progression, metabolism, and metastasis.	('ESCC', 'Disease', (56, 60))	('drives', 'Reg', (69, 75))	('p53', 'Gene', (28, 31))	('mutation', 'Var', (16, 24))	('metastasis', 'CPA', (111, 121))	('p53', 'Gene', '7157', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('deletion', 'Var', (4, 12))	('metabolism', 'CPA', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
831572	33239613	Subsequently, we confirmed the direct binding of miR-513a-5p and p53 mRNA 3'-UTR by dual-luciferase reporting assay, which indicated that miR-513a-5p regulates the expression of the p53 protein by targeting p53 mRNA.	('p53', 'Gene', (65, 68))	('targeting', 'Reg', (197, 206))	('p53', 'Gene', '7157', (65, 68))	('regulates', 'Reg', (150, 159))	('p53', 'Gene', '7157', (182, 185))	('expression', 'MPA', (164, 174))	('miR-513a-5p', 'Var', (138, 149))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '7157', (207, 210))	('protein', 'Protein', (186, 193))	('p53', 'Gene', (182, 185))
831584	33239613	In all ESCC patients, the mutation rate of the p53 gene is 55-75%.	('patients', 'Species', '9606', (12, 20))	('mutation', 'Var', (26, 34))	('ESCC', 'Disease', (7, 11))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
831585	33239613	Thus, many ESCC patients will still test positive for wild-type p53.	('wild-type', 'Var', (54, 63))	('patients', 'Species', '9606', (16, 24))	('ESCC', 'Disease', (11, 15))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
831588	33239613	In our experiments, we found that the mutant p53 protein is not significantly regulated by cCNTNAP3, which also reflects the stability of the mutant p53 protein and the complexity of its regulatory mechanism.	('mutant', 'Var', (38, 44))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('p53', 'Gene', (149, 152))	('protein', 'Protein', (49, 56))	('p53', 'Gene', '7157', (149, 152))	('CNTNAP3', 'Gene', (92, 99))	('mutant', 'Var', (142, 148))	('CNTNAP3', 'Gene', '79937', (92, 99))
831589	33239613	However, we think cCNTNAP3 is also valuable in ESCC with p53 mutations, and further studies should be performed to obtain more data regarding its mechanisms of action.	('ESCC', 'Disease', (47, 51))	('CNTNAP3', 'Gene', (19, 26))	('mutations', 'Var', (61, 70))	('p53', 'Gene', (57, 60))	('CNTNAP3', 'Gene', '79937', (19, 26))	('p53', 'Gene', '7157', (57, 60))
831657	32176086	When the airway is severely occluded, compressed, infiltrated, or even bleeds, the patient experiences worsened respiratory distress, suffocation, or even death.	('respiratory distress', 'Phenotype', 'HP:0002098', (112, 132))	('death', 'Disease', (155, 160))	('bleeds', 'Var', (71, 77))	('patient', 'Species', '9606', (83, 90))	('death', 'Disease', 'MESH:D003643', (155, 160))	('worsened', 'PosReg', (103, 111))	('respiratory distress', 'Disease', 'MESH:D012128', (112, 132))	('respiratory distress', 'Disease', (112, 132))	('worsened respiratory distress', 'Phenotype', 'HP:0002093', (103, 132))	('suffocation', 'Disease', (134, 145))
831686	32176086	However, CPB is more likely to increase postoperative bleeding and potential complications such as liver and kidney dysfunction, and the establishment of CPB technology is difficult and time-consuming, causing great trauma to patients and more complications in later infections, so it is not an ideal support method.	('causing', 'Reg', (202, 209))	('trauma', 'Disease', (216, 222))	('infections', 'Disease', 'MESH:D007239', (267, 277))	('postoperative bleeding', 'Disease', 'MESH:D019106', (40, 62))	('complications', 'Reg', (244, 257))	('postoperative bleeding', 'Disease', (40, 62))	('infections', 'Disease', (267, 277))	('liver and kidney dysfunction', 'Disease', 'MESH:D051437', (99, 127))	('increase postoperative bleeding', 'Phenotype', 'HP:0004846', (31, 62))	('patients', 'Species', '9606', (226, 234))	('CPB', 'Var', (9, 12))	('kidney dysfunction', 'Phenotype', 'HP:0000083', (109, 127))	('trauma', 'Disease', 'MESH:D014947', (216, 222))	('increase', 'PosReg', (31, 39))
831793	31490855	We found similar pH-MII parameters in children with low and high Manterola scores, possibly because of a larger day-to-day variability of pH-MII studies in EA patients, or perhaps disturbed impedance patterns make pH-MII studies unsuitable for GER detection in EA patients.	('GER', 'Gene', '59330', (244, 247))	('EA', 'Phenotype', 'HP:0002032', (261, 263))	('high', 'Var', (60, 64))	('GER', 'Gene', (244, 247))	('impedance patterns', 'MPA', (190, 208))	('Manterola', 'Gene', (65, 74))	('GER', 'Phenotype', 'HP:0002020', (244, 247))	('EA', 'Phenotype', 'HP:0002032', (156, 158))	('patients', 'Species', '9606', (264, 272))	('patients', 'Species', '9606', (159, 167))	('children', 'Species', '9606', (38, 46))
831798	31490855	Stasis of fluids was mostly present in Z3-Z4, at the level of the esophageal anastomosis.	('esophageal anastomosis', 'Disease', (66, 88))	('Z3-Z4', 'Chemical', 'MESH:C017788', (39, 44))	('esophageal anastomosis', 'Phenotype', 'HP:0100628', (66, 88))	('esophageal anastomosis', 'Disease', 'MESH:D004941', (66, 88))	('Z3-Z4', 'Var', (39, 44))	('Stasis of fluids', 'MPA', (0, 16))
831856	31558856	The generation of TA autoantibodies is thought to occur in response to mutations, over-expression or abnormal processing, which lead to the formation of altered or novel epitopes, aberrantly high expression levels resulting in loss of tolerance and abnormal post-translational modifications, such as acetylation, glycosylation and phosphorylation, all of which could create a neoepitope, enhance self-epitope presentation or expose antigens normally located in immune-privileged sites (e.g., cancer-testis antigens).	('self-epitope presentation', 'MPA', (396, 421))	('loss', 'NegReg', (227, 231))	('enhance', 'PosReg', (388, 395))	('phosphorylation', 'Var', (331, 346))	('tolerance', 'MPA', (235, 244))	('cancer', 'Phenotype', 'HP:0002664', (492, 498))	('expression', 'MPA', (196, 206))	('neoepitope', 'MPA', (376, 386))	('glycosylation', 'MPA', (313, 326))	('mutations', 'Var', (71, 80))	('acetylation', 'MPA', (300, 311))	('aberrantly', 'Var', (180, 190))	('expose', 'PosReg', (425, 431))	('antigens', 'MPA', (432, 440))	('cancer', 'Disease', (492, 498))	('cancer', 'Disease', 'MESH:D009369', (492, 498))	('create', 'Reg', (367, 373))
831867	31558856	Autoantibodies against p53 in the diagnosis of ESCC have been evaluated in 17 studies (Table 2), and the sensitivities vary largely between reports (7%-60%) while less variance is observed in the specificity (range 89.5%-100%, Table 2).	('ESCC', 'Disease', (47, 51))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('ESCC', 'Disease', 'MESH:C562729', (47, 51))	('Autoantibodies', 'Var', (0, 14))
831883	31558856	These studies all show that the combined detection of autoantibodies against several antigens in the panel can greatly increase sensitivity in the diagnosis of ESCC.	('ESCC', 'Disease', (160, 164))	('ESCC', 'Disease', 'MESH:C562729', (160, 164))	('autoantibodies', 'Var', (54, 68))	('sensitivity', 'MPA', (128, 139))	('increase', 'PosReg', (119, 127))
831892	31558856	This suggests potential clinical applications for autoantibody combinations to diagnose ESCC.	('ESCC', 'Disease', (88, 92))	('combinations', 'Var', (63, 75))	('ESCC', 'Disease', 'MESH:C562729', (88, 92))
831972	30460345	The number of patients who underwent lymph node dissection was limited (upper MLN, N = 30; lower MLN, N = 51), but the therapeutic index was relatively high for upper MLN (#105 + #106: 8.9) and lower MLN (#110: 12.2), as shown in Table 2.	('therapeutic index', 'MPA', (119, 136))	('#105 + #106', 'Var', (172, 183))	('patients', 'Species', '9606', (14, 22))
832084	30186956	The lack of ALDH2 is also a significant risk factor for SCC, because it leads to the accumulation of acetaldehyde, which has been proven to be carcinogenic for various organs.	('ALDH2', 'Gene', (12, 17))	('accumulation', 'PosReg', (85, 97))	('acetaldehyde', 'MPA', (101, 113))	('SCC', 'Gene', (56, 59))	('carcinogenic', 'Disease', 'MESH:D063646', (143, 155))	('carcinogenic', 'Disease', (143, 155))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('lack', 'Var', (4, 8))	('leads to', 'Reg', (72, 80))	('SCC', 'Gene', '6317', (56, 59))	('ALDH2', 'Gene', '217', (12, 17))	('acetaldehyde', 'Chemical', 'MESH:D000079', (101, 113))
832330	24806725	The risk of bladder cancer was related to CTPV cumulative exposure, as was the risk of lung cancer (with a trend of borderline significance), although the rate of lung cancer was similar to that of the British Columbia population.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('CTPV', 'Var', (42, 46))	('CTPV', 'Chemical', '-', (42, 46))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('bladder cancer', 'Disease', 'MESH:D001749', (12, 26))	('bladder cancer', 'Disease', (12, 26))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('British Columbia', 'Disease', (202, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Disease', (163, 174))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('bladder cancer', 'Phenotype', 'HP:0009725', (12, 26))	('British Columbia', 'Disease', 'OMIM:176500', (202, 218))
832332	24806725	The risk of NHL and kidney cancer also increased with CTPV exposure although the overall rates were the same as the general population, but the numbers were small.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('kidney cancer', 'Phenotype', 'HP:0009726', (20, 33))	('NHL', 'Phenotype', 'HP:0012539', (12, 15))	('kidney cancer', 'Disease', (20, 33))	('CTPV', 'Var', (54, 58))	('CTPV', 'Chemical', '-', (54, 58))	('NHL', 'Disease', (12, 15))	('kidney cancer', 'Disease', 'MESH:D007680', (20, 33))
832493	24806725	As bladder cancers are often associated with amines or nitroso compounds, these have been proposed as etiological factors, but studies have shown the potential for exposure to any significant quantity of these to be small, although plausible.	('bladder cancers', 'Disease', 'MESH:D001749', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('amines', 'Var', (45, 51))	('bladder cancers', 'Disease', (3, 18))	('nitroso compounds', 'Var', (55, 72))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('nitroso compounds', 'Chemical', 'MESH:D009603', (55, 72))	('associated', 'Reg', (29, 39))	('amines', 'Chemical', 'MESH:D000588', (45, 51))	('bladder cancers', 'Phenotype', 'HP:0009725', (3, 18))
832536	19027227	Hypermethylation was detected in 78.9% of esophageal adenocarcinomas, in 100% of Barrett's intraepithelial neoplasia, in 88.9% of Barrett's metaplasia, but only in 21.4% of normal esophageal mucosa samples (P < 0.001) and correlated significantly with downregulation of MGMT transcripts (P = 0.048) and protein expression (P = 0.02).	('esophageal adenocarcinomas', 'Disease', (42, 68))	("Barrett's metaplasia", 'Disease', (130, 150))	("Barrett's intraepithelial neoplasia", 'Disease', (81, 116))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('downregulation', 'NegReg', (252, 266))	('Hypermethylation', 'Var', (0, 16))	('MGMT', 'Gene', (270, 274))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (42, 68))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (91, 116))	('MGMT', 'Gene', '4255', (270, 274))	('protein expression', 'MPA', (303, 321))	("Barrett's intraepithelial neoplasia", 'Disease', 'MESH:D001471', (81, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (130, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
832538	19027227	We conclude, that aberrant promoter methylation of MGMT is a frequent and early event during tumorigenesis of Barrett's esophagus.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('aberrant', 'Var', (18, 26))	('tumor', 'Disease', (93, 98))	("Barrett's esophagus", 'Disease', (110, 129))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (110, 129))	('MGMT', 'Gene', (51, 55))	('MGMT', 'Gene', '4255', (51, 55))
832539	19027227	High prevalence of MGMT hypermethylation may represent a candidate marker for improved diagnosis and targeted therapy in Barrett's adenocarcinoma.	('hypermethylation', 'Var', (24, 40))	("Barrett's adenocarcinoma", 'Disease', (121, 145))	('MGMT', 'Gene', '4255', (19, 23))	('MGMT', 'Gene', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	("Barrett's adenocarcinoma", 'Disease', 'MESH:D001471', (121, 145))
832545	19027227	Thus, hypermethylation of CpG islands located in the promoter of putative tumor suppressor genes is now firmly established as an important mechanism for gene inactivation and is gradually becoming a focus in carcinogenesis of BA.	('inactivation', 'NegReg', (158, 170))	('hypermethylation', 'Var', (6, 22))	('carcinogenesis', 'Disease', (208, 222))	('BA', 'Chemical', '-', (226, 228))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (208, 222))
832548	19027227	If not removed, O6-methylguanine can preferentially mispair with thymine rather than cytosine during replication, thus causing G:C to A:T mutations, which may initiate carcinogenesis if the mutations occur in tumor-related genes.	('O6-methylguanine', 'Var', (16, 32))	('tumor', 'Disease', (209, 214))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (16, 32))	('carcinogenesis', 'Disease', 'MESH:D063646', (168, 182))	('thymine', 'Chemical', 'MESH:D013941', (65, 72))	('cytosine', 'Chemical', 'MESH:D003596', (85, 93))	('carcinogenesis', 'Disease', (168, 182))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('causing', 'Reg', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
832549	19027227	Indeed, it has been shown that MGMT inactivation is associated with G:C to A:T mutations in K-ras and p53 in a variety of human primary carcinomas such as colorectal and gastric carcinoma, non-small cell lung cancer and astrocytomas.	('human', 'Species', '9606', (122, 127))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (189, 215))	('MGMT', 'Gene', (31, 35))	('K-ras', 'Gene', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('carcinomas', 'Disease', 'MESH:D002277', (136, 146))	('mutations', 'Var', (79, 88))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (193, 215))	('astrocytomas', 'Disease', (220, 232))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (189, 215))	('p53', 'Gene', '7157', (102, 105))	('MGMT', 'Gene', '4255', (31, 35))	('K-ras', 'Gene', '3845', (92, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('p53', 'Gene', (102, 105))	('gastric carcinoma', 'Disease', 'MESH:D013274', (170, 187))	('non-small cell lung cancer', 'Disease', (189, 215))	('carcinomas', 'Disease', (136, 146))	('colorectal', 'Disease', (155, 165))	('gastric carcinoma', 'Disease', (170, 187))	('astrocytomas', 'Disease', 'MESH:D001254', (220, 232))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (170, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
832551	19027227	Several reports have demonstrated that MGMT function is frequently lost in association with hypermethylation of the CpG islands within the MGMT promoter in several human malignancies.	('malignancies', 'Disease', (170, 182))	('human', 'Species', '9606', (164, 169))	('MGMT', 'Gene', (139, 143))	('MGMT', 'Gene', '4255', (139, 143))	('MGMT', 'Gene', (39, 43))	('malignancies', 'Disease', 'MESH:D009369', (170, 182))	('hypermethylation', 'Var', (92, 108))	('MGMT', 'Gene', '4255', (39, 43))
832552	19027227	Promoter hypermethylation of MGMT and its association with loss or reduction of MGMT protein expression have also been reported to occur in gastrointestinal malignancies, including esophageal squamous-cell carcinoma, sporadic and ulcerative colitis-associated colorectal carcinomas, and gastric cancers.	('esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (181, 215))	('MGMT', 'Gene', (29, 33))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (230, 248))	('esophageal squamous-cell carcinoma', 'Disease', (181, 215))	('loss', 'NegReg', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('Promoter hypermethylation', 'Var', (0, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('gastric cancers', 'Disease', (287, 302))	('gastric cancers', 'Disease', 'MESH:D013274', (287, 302))	('gastric cancers', 'Phenotype', 'HP:0012126', (287, 302))	('carcinomas', 'Phenotype', 'HP:0030731', (271, 281))	('MGMT', 'Gene', '4255', (80, 84))	('reduction', 'NegReg', (67, 76))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (140, 169))	('colitis', 'Phenotype', 'HP:0002583', (241, 248))	('colorectal carcinomas', 'Disease', (260, 281))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (260, 281))	('gastrointestinal malignancies', 'Disease', (140, 169))	('cancers', 'Phenotype', 'HP:0002664', (295, 302))	('ulcerative colitis', 'Disease', (230, 248))	('protein', 'Protein', (85, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (287, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('MGMT', 'Gene', '4255', (29, 33))	('ulcerative colitis', 'Disease', 'MESH:D003093', (230, 248))	('MGMT', 'Gene', (80, 84))	('occur', 'Reg', (131, 136))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('expression', 'MPA', (93, 103))
832594	19027227	In all methylated cases, unmethylated bands were also visible in the samples investigated, which may result from methylation of only one allele, heterogeneity in tumor cell populations, or admixed normal cells within or adjacent to the lesions of interest.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('methylation', 'Var', (113, 124))	('tumor', 'Disease', (162, 167))	('methylated', 'Var', (7, 17))	('result from', 'Reg', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
832596	19027227	In BA, MGMT methylation was detected in 37/47 cases (78.9%), whereas the epigenetic modification of the gene promoter occurred only in 6/29 cases (21.4%) of the non-dysplastic esophageal squamous mucosa (P < 0.001).	('MGMT', 'Gene', '4255', (7, 11))	('MGMT', 'Gene', (7, 11))	('BA', 'Chemical', '-', (3, 5))	('detected', 'Reg', (28, 36))	('non-dysplastic esophageal squamous mucosa', 'Disease', 'MESH:D000077277', (161, 202))	('non-dysplastic esophageal squamous mucosa', 'Disease', (161, 202))	('methylation', 'Var', (12, 23))
832597	19027227	In BE without or with intraepithelial neoplasia, MGMT methylation occurred in 24/27 cases (88.9%) and in 13/13 cases (100%), respectively.	('MGMT', 'Gene', '4255', (49, 53))	('neoplasia', 'Phenotype', 'HP:0002664', (38, 47))	('MGMT', 'Gene', (49, 53))	('occurred', 'Reg', (66, 74))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (22, 47))	('methylation', 'Var', (54, 65))	('intraepithelial neoplasia', 'Disease', (22, 47))	('BE', 'Chemical', '-', (3, 5))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (22, 47))
832601	19027227	Although the difference among BE, IN and BA was not statistically significant, methylation occurred with an increasing frequency along neoplastic progression, with the largest increase found between NT and non-dysplastic BE, and a further increase in the development of intraepithelial neoplasia and BA.	('BE', 'Chemical', '-', (30, 32))	('non-dysplastic', 'Disease', (206, 220))	('increase', 'PosReg', (176, 184))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (270, 295))	('BA', 'Chemical', '-', (41, 43))	('BA', 'Chemical', '-', (300, 302))	('intraepithelial neoplasia', 'Disease', (270, 295))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (270, 295))	('IN', 'Phenotype', 'HP:0032187', (34, 36))	('neoplasia', 'Phenotype', 'HP:0002664', (286, 295))	('increase', 'PosReg', (239, 247))	('methylation', 'Var', (79, 90))	('non-dysplastic', 'Disease', 'MESH:D004416', (206, 220))	('BE', 'Chemical', '-', (221, 223))
832603	19027227	In general, hypermethylation was tightly correlated with the loss of MGMT mRNA and protein expression, underlining the validity of our methylation analysis.	('loss', 'NegReg', (61, 65))	('MGMT', 'Gene', '4255', (69, 73))	('hypermethylation', 'Var', (12, 28))	('MGMT', 'Gene', (69, 73))
832604	19027227	Methylation of the MGMT promoter in BA was associated with a concomitant decrease in the level of MGMT mRNA expression compared to unmethylated samples (Fig.	('Methylation', 'Var', (0, 11))	('MGMT', 'Gene', '4255', (19, 23))	('MGMT', 'Gene', (19, 23))	('decrease', 'NegReg', (73, 81))	('MGMT', 'Gene', (98, 102))	('BA', 'Chemical', '-', (36, 38))	('MGMT', 'Gene', '4255', (98, 102))
832607	19027227	Inverse correlation was found between methylation and immunohistochemical protein expression with a significant reduction of the MGMT protein level in methylated samples compared to unmethylated samples (P = 0.02, Fig.	('methylated', 'Var', (151, 161))	('MGMT', 'Gene', '4255', (129, 133))	('MGMT', 'Gene', (129, 133))	('reduction', 'NegReg', (112, 121))
832617	19027227	There is increasing evidence that inactivation and loss of MGMT are involved in the pathogenesis of different gastrointestinal malignancies.	('involved', 'Reg', (68, 76))	('loss', 'Var', (51, 55))	('inactivation', 'Var', (34, 46))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (110, 139))	('MGMT', 'Gene', (59, 63))	('gastrointestinal malignancies', 'Disease', (110, 139))	('MGMT', 'Gene', '4255', (59, 63))
832622	19027227	It still needs to be clarified in future studies whether methylation of normal mucosa reflects an epigenetic field effect in the surrounding areas of cancer or points towards an elevated risk of developing into metaplastic and neoplastic lesions.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('methylation', 'Var', (57, 68))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (227, 245))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('neoplastic lesions', 'Disease', (227, 245))	('neoplastic lesions', 'Disease', 'MESH:D051437', (227, 245))
832623	19027227	The slightly higher frequency of MGMT hypermethylation for intraepithelial neoplasia compared to BA in our study may be attributed to the fact that the samples were microdissected from paraffin sections, and there were a lower number of unmethylated stromal cells in the samples compared to BA.	('hypermethylation', 'Var', (38, 54))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (59, 84))	('paraffin', 'Chemical', 'MESH:D010232', (185, 193))	('MGMT', 'Gene', (33, 37))	('MGMT', 'Gene', '4255', (33, 37))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (59, 84))	('BA', 'Chemical', '-', (97, 99))	('intraepithelial neoplasia', 'Disease', (59, 84))	('BA', 'Chemical', '-', (291, 293))
832629	19027227	Hypermethylation in normal tissue was always accompanied by MGMT methylation in matching tumor tissue.	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('MGMT', 'Gene', (60, 64))	('MGMT', 'Gene', '4255', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('accompanied', 'Reg', (45, 56))
832632	19027227	Our findings suggest that MGMT methylation occurs at the metaplastic step, rather than being cancer-specific.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('methylation', 'Var', (31, 42))	('MGMT', 'Gene', (26, 30))	('MGMT', 'Gene', '4255', (26, 30))
832633	19027227	Because MGMT methylation occurs commonly and early in Barrett's metaplasia, it may be specific to transformed premalignant or malignant epithelium.	('methylation', 'Var', (13, 24))	('MGMT', 'Gene', '4255', (8, 12))	('MGMT', 'Gene', (8, 12))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (54, 74))	("Barrett's metaplasia", 'Disease', (54, 74))
832634	19027227	Furthermore, the findings of our current study emphasize that MGMT inactivation is an early event in Barrett's carcinogenesis and support the functional role MGMT hypermethylation seems to play in esophageal neoplastic transformation in the pathogenesis of BA.	('inactivation', 'Var', (67, 79))	('MGMT', 'Gene', (62, 66))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (101, 125))	('esophageal neoplastic', 'Disease', 'MESH:D004938', (197, 218))	('MGMT', 'Gene', '4255', (62, 66))	('hypermethylation', 'Var', (163, 179))	('BA', 'Chemical', '-', (257, 259))	('esophageal neoplastic', 'Disease', (197, 218))	('MGMT', 'Gene', '4255', (158, 162))	("Barrett's carcinogenesis", 'Disease', (101, 125))	('MGMT', 'Gene', (158, 162))
832637	19027227	In our study, we could show a gradual increase in the frequency of MGMT hypermethylation with histopathological and clinical progression of the disease.	('MGMT', 'Gene', '4255', (67, 71))	('increase', 'PosReg', (38, 46))	('MGMT', 'Gene', (67, 71))	('hypermethylation', 'Var', (72, 88))
832638	19027227	These data suggest that loss of MGMT may promote tumorigenesis and implies a possible prognostic value of promoter hypermethylation of a certain gene profile which might include MGMT.	('loss', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('MGMT', 'Gene', '4255', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('MGMT', 'Gene', '4255', (32, 36))	('tumor', 'Disease', (49, 54))	('promote', 'PosReg', (41, 48))	('MGMT', 'Gene', (32, 36))	('MGMT', 'Gene', (178, 182))
832639	19027227	Because MGMT is frequently methylated in BE, DYS and BA, it may find application in screening or surveillance as part of a panel of markers.	('DYS', 'Disease', (45, 48))	('methylated', 'Var', (27, 37))	('MGMT', 'Gene', '4255', (8, 12))	('MGMT', 'Gene', (8, 12))	('BE', 'Chemical', '-', (41, 43))	('BA', 'Chemical', '-', (53, 55))
832640	19027227	However, to identify patients with Barrett's esophagus at increased risk of progression to dysplasia or BA, and to explore the value of methylated MGMT as an independent risk factor for Barrett's esophagus and BA, further methylation studies containing a detailed endoscopic surveillance program are needed.	('methylated', 'Var', (136, 146))	('esophagus', 'Disease', (196, 205))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (186, 205))	('BA', 'Chemical', '-', (104, 106))	('BA', 'Chemical', '-', (210, 212))	('patients', 'Species', '9606', (21, 29))	('dysplasia', 'Disease', (91, 100))	('MGMT', 'Gene', (147, 151))	('dysplasia', 'Disease', 'MESH:D004476', (91, 100))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (35, 54))	('MGMT', 'Gene', '4255', (147, 151))
832641	19027227	Loss of MGMT protein expression is not commonly caused by deletion, mutation or rearrangement of the MGMT gene or mRNA instability.	('MGMT', 'Gene', (101, 105))	('mutation', 'Var', (68, 76))	('MGMT', 'Gene', '4255', (101, 105))	('expression', 'MPA', (21, 31))	('MGMT', 'Gene', '4255', (8, 12))	('Loss', 'NegReg', (0, 4))	('MGMT', 'Gene', (8, 12))	('rearrangement', 'Var', (80, 93))	('deletion', 'Var', (58, 66))
832642	19027227	In parallel, MGMT has been frequently observed to be down-regulated by promoter hypermethylation and is an early epigenetic alteration in a wide variety of human tumor malignancies.	('human', 'Species', '9606', (156, 161))	('tumor malignancies', 'Disease', (162, 180))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('promoter hypermethylation', 'Var', (71, 96))	('tumor malignancies', 'Disease', 'MESH:D018198', (162, 180))	('MGMT', 'Gene', (13, 17))	('MGMT', 'Gene', '4255', (13, 17))	('down-regulated', 'NegReg', (53, 67))
832643	19027227	Our data provide compelling evidence for the strong relationship between MGMT promoter methylation and gene silencing in Barrett's adenocarcinoma.	('MGMT', 'Gene', (73, 77))	("Barrett's adenocarcinoma", 'Disease', (121, 145))	('silencing', 'NegReg', (108, 117))	('MGMT', 'Gene', '4255', (73, 77))	('gene', 'Var', (103, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	("Barrett's adenocarcinoma", 'Disease', 'MESH:D001471', (121, 145))
832645	19027227	Since methylation of MGMT in general is a frequent event of already early tumor stages, further loss of protein expression in progressed tumor stages might be caused by additional epigenetic or genetic alterations of the MGMT expression, by an increase in the number of tumor cells methylated, and/or by certain methylation pattern within the MGMT promoter.	('genetic alterations', 'Var', (194, 213))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('increase', 'PosReg', (244, 252))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MGMT', 'Gene', '4255', (221, 225))	('methylation', 'Var', (6, 17))	('MGMT', 'Gene', (343, 347))	('MGMT', 'Gene', '4255', (21, 25))	('loss', 'NegReg', (96, 100))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('protein expression', 'MPA', (104, 122))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (270, 275))	('epigenetic', 'Var', (180, 190))	('MGMT', 'Gene', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('MGMT', 'Gene', '4255', (343, 347))	('MGMT', 'Gene', (21, 25))
832648	19027227	In contrast, for non-small cell lung cancer and head and neck cancer, MGMT hypermeythylation proved to be a useful prognostic marker for tumor outcome and patient's survival, and was associated with poorer prognosis.	('tumor', 'Disease', (137, 142))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (17, 43))	('MGMT', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('hypermeythylation', 'Var', (75, 92))	('MGMT', 'Gene', '4255', (70, 74))	('head and neck cancer', 'Phenotype', 'HP:0012288', (48, 68))	('patient', 'Species', '9606', (155, 162))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (21, 43))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (17, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('head and neck cancer', 'Disease', 'MESH:D006258', (48, 68))	('non-small cell lung cancer', 'Disease', (17, 43))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
832649	19027227	Furthermore, in a complex methylation study of BA, there was a strong trend towards poorer survival and earlier tumor recurrence for patients, whose tumors were methylated for a group of genes, including MGMT.	('survival', 'CPA', (91, 99))	('tumor', 'Disease', (112, 117))	('BA', 'Chemical', '-', (47, 49))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('patients', 'Species', '9606', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('methylated', 'Var', (161, 171))	('MGMT', 'Gene', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Disease', (149, 154))	('MGMT', 'Gene', '4255', (204, 208))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('poorer', 'NegReg', (84, 90))
832650	19027227	In our study, regarding survival and the prognostic value of MGMT hypermethylation, no definitive conclusions could be drawn since follow-up of the cohort was still ongoing, and survival data are not available yet.	('MGMT', 'Gene', (61, 65))	('MGMT', 'Gene', '4255', (61, 65))	('hypermethylation', 'Var', (66, 82))
832651	19027227	Alkylating agents are highly reactive mutagens and carcinogens, and their analogous compounds are used for the treatment of human malignancies.	('human', 'Species', '9606', (124, 129))	('malignancies', 'Disease', (130, 142))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))	('Alkylating', 'Var', (0, 10))
832653	19027227	Conversely, MGMT silencing through methylation of its promoter induces low expression of MGMT protein and decreases its DNA repair activity.	('MGMT', 'Gene', (89, 93))	('low', 'NegReg', (71, 74))	('MGMT', 'Gene', '4255', (89, 93))	('decreases', 'NegReg', (106, 115))	('MGMT', 'Gene', (12, 16))	('DNA repair activity', 'MPA', (120, 139))	('MGMT', 'Gene', '4255', (12, 16))	('methylation', 'Var', (35, 46))	('silencing', 'NegReg', (17, 26))	('expression', 'MPA', (75, 85))
832656	19027227	MGMT gene expression is known as a major contributing factor for the development of resistance to alkylating chemotherapeutic agents, and MGMT inactivation is accepted as a relevant prognostic marker and predictor of chemosensitivity in glioblastomas, head and neck cancer, and lymphomas.	('MGMT', 'Gene', (0, 4))	('lymphomas', 'Disease', (278, 287))	('lymphomas', 'Disease', 'MESH:D008223', (278, 287))	('MGMT', 'Gene', (138, 142))	('inactivation', 'Var', (143, 155))	('MGMT', 'Gene', '4255', (138, 142))	('head and neck cancer', 'Disease', 'MESH:D006258', (252, 272))	('glioblastomas', 'Phenotype', 'HP:0012174', (237, 250))	('lymphomas', 'Phenotype', 'HP:0002665', (278, 287))	('head and neck cancer', 'Phenotype', 'HP:0012288', (252, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('glioblastomas', 'Disease', 'MESH:D005909', (237, 250))	('MGMT', 'Gene', '4255', (0, 4))	('glioblastomas', 'Disease', (237, 250))
832657	19027227	Thus, targeted inactivation of MGMT could improve the effectiveness of currently used alkylating agents against cancer.	('effectiveness', 'MPA', (54, 67))	('MGMT', 'Gene', '4255', (31, 35))	('cancer', 'Disease', (112, 118))	('MGMT', 'Gene', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('improve', 'PosReg', (42, 49))	('targeted inactivation', 'Var', (6, 27))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
832660	19027227	Detection of MGMT inactivation by promoter methylation might potentially provide new targets for both chemotherapeutic intervention and improved diagnosis of Barrett's adenocarcinoma.	("Barrett's adenocarcinoma", 'Disease', 'MESH:D001471', (158, 182))	('inactivation', 'Var', (18, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	("Barrett's adenocarcinoma", 'Disease', (158, 182))	('MGMT', 'Gene', (13, 17))	('MGMT', 'Gene', '4255', (13, 17))
832674	24039846	Alterations in the expression of miRNAs are associated with a variety of diseases including cancer, where they show tumor-specific expression signatures.	('associated', 'Reg', (44, 54))	('miRNAs', 'Gene', (33, 39))	('expression', 'MPA', (19, 29))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (116, 121))
832716	24039846	PCR primers for the fibroblast markers TGFbeta1 (MIM: 190180), FGF1 (MIM: 131220), STAT3 (MIM: 102582), STAG2 (MIM: 300826), TIMP3 (MIM: 188826), COL4A1 (MIM: 120130) and for the CAF markers ACTA2 (MIM: 102620), FAP (MIM: 600403), S100A4 (MIM: 114210) and CSPG4 (MIM: 601172) were designed over exon boundaries in order to amplify the most common splicing variants of each gene without amplifying the genomic DNA.	('FAP', 'Gene', '2191', (212, 215))	('MIM', 'Var', (198, 201))	('TGFbeta1', 'Gene', (39, 47))	('S100A4', 'Gene', (231, 237))	('STAG2', 'Gene', '10735', (104, 109))	('CAF', 'Gene', '8850', (179, 182))	('STAG2', 'Gene', (104, 109))	('MIM: 114210', 'Var', (239, 250))	('ACTA2', 'Gene', (191, 196))	('CAF', 'Gene', (179, 182))	('ACTA2', 'Gene', '59', (191, 196))	('STAT3', 'Gene', (83, 88))	('S100A4', 'Gene', '6275', (231, 237))	('COL4A1', 'Gene', '1282', (146, 152))	('CSPG4', 'Gene', (256, 261))	('FAP', 'Gene', (212, 215))	('CSPG4', 'Gene', '1464', (256, 261))	('TIMP3', 'Gene', (125, 130))	('STAT3', 'Gene', '6774', (83, 88))	('TIMP3', 'Gene', '7078', (125, 130))	('TGFbeta1', 'Gene', '7040', (39, 47))	('FGF1', 'Gene', (63, 67))	('FGF1', 'Gene', '2246', (63, 67))	('COL4A1', 'Gene', (146, 152))
832732	24039846	The obtained qRT-PCR data demonstrate that miR-21 levels are significantly higher in tumors with high stroma (P = 0.04), as compared to those with low levels of stroma ( Figure 2E ).	('higher', 'PosReg', (75, 81))	('miR-21', 'Gene', '406991', (43, 49))	('miR-21', 'Gene', (43, 49))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('high', 'Var', (97, 101))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
832791	21286719	Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual.	('esophageal adenocarcinoma', 'Disease', (111, 136))	('Genetic variation', 'Var', (0, 17))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (111, 136))	('Oncology', 'Phenotype', 'HP:0002664', (235, 243))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (111, 136))	('radiation toxicity', 'Disease', 'MESH:D004194', (75, 93))	('radiation toxicity', 'Disease', (75, 93))	('platinum pathways', 'Pathway', (35, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('platinum', 'Chemical', 'MESH:D010984', (35, 43))	('radiation', 'Pathway', (21, 30))	('patients', 'Species', '9606', (97, 105))
832792	21286719	Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy.	('association', 'Interaction', (34, 45))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (180, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (219, 228))	('toxicity', 'Disease', 'MESH:D064420', (154, 162))	('toxicity', 'Disease', (154, 162))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (180, 205))	('single-nucleotide polymorphisms', 'Var', (54, 85))	('platinum', 'Chemical', 'MESH:D010984', (106, 114))	('esophageal adenocarcinoma', 'Disease', (180, 205))
832797	21286719	The variant alleles of the XRCC2 5' flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005).	('Ile-105-Val', 'Mutation', 'rs1695', (93, 104))	('toxicity', 'Disease', 'MESH:D064420', (202, 210))	('toxicity', 'Disease', (202, 210))	('XRCC2', 'Gene', (27, 32))	('associated with', 'Reg', (145, 160))	('variant', 'Var', (4, 11))
832806	21286719	In the last decade, interest has grown in the concept that individual genetic profiles, particularly genetic polymorphisms, may contribute to therapy-related normal tissue toxicity.	('polymorphisms', 'Var', (109, 122))	('toxicity', 'Disease', 'MESH:D064420', (172, 180))	('toxicity', 'Disease', (172, 180))	('normal tissue', 'MPA', (158, 171))	('contribute', 'Reg', (128, 138))
832812	21286719	It is hypothesized that deficient DNA repair increases risk for developing cancer by lowering the normal cell's ability to repair carcinogen-induced damage.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('DNA', 'Gene', (34, 37))	('cancer', 'Disease', (75, 81))	('deficient', 'Var', (24, 33))	('lowering', 'NegReg', (85, 93))	('ability to repair carcinogen-induced damage', 'MPA', (112, 155))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
832813	21286719	On the other hand, in patients with cancer, deficient DNA repair may increase tumor response to radio-or cytotoxic chemotherapy, by lowering the tumor cell's capacity to repair radiation or chemotherapy lesions.	('increase', 'PosReg', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Disease', (36, 42))	('deficient', 'Var', (44, 53))	('patients', 'Species', '9606', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', (78, 83))	('DNA repair', 'Gene', (54, 64))	('lowering', 'NegReg', (132, 140))
832821	21286719	We chose genes involved in platinum influx, efflux, and detoxification, as well as those involved in repairing cisplatin lesions through nucleotide excision repair (NER) or mismatch repair (MMR) and repairing radiation lesions through double-stranded break repair (DSBR) and base excision repair (BER).	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('cisplatin lesions', 'MPA', (111, 128))	('DSBR', 'Chemical', '-', (265, 269))	('mismatch', 'Var', (173, 181))	('nucleotide', 'Var', (137, 147))	('platinum', 'Chemical', 'MESH:D010984', (27, 35))
832824	21286719	Preoperative toxicity data were collected as part of E1201 during and up to 4-6 weeks following the completion of RCT.	('E1201', 'Var', (53, 58))	('toxicity', 'Disease', (13, 21))	('toxicity', 'Disease', 'MESH:D064420', (13, 21))
832833	21286719	Baseline clinicopathologic traits of the ancillary cohort were: median age 57 years (range 38-76); male 88%; white 93%, black 2%, Hispanic 2%, Asian 3%; node-negative (T2-3N0M0) 28%, node-positive (T1-3N1M0 or T1-3N0-1M1a) 72%; ECOG performance status 0 (65%) and 1 (35%); mid-(2%) and lower thoracic (45%) esophagus, gastroesophageal junction (48%), esophagus not otherwise specified (3%), and unknown (2%).	('esophagus not otherwise specified', 'Disease', (351, 384))	('gastroesophageal junction', 'Disease', 'MESH:D008309', (318, 343))	('gastroesophageal junction', 'Disease', (318, 343))	('T1-3N0-1M1a', 'Var', (210, 221))
832838	21286719	For GST-Pi Ile-105-Val, 0 of 21 subjects with AA (major homozygote) genotype had grade 3-4 radiation-related toxicity, compared to 12 (31%) of 39 patients with GG or GA (variant) genotypes (Table 2, P = 0.005).	('Ile-105-Val', 'Var', (11, 22))	('Ile-105-Val', 'Mutation', 'rs1695', (11, 22))	('GST-Pi Ile-105-Val', 'Var', (4, 22))	('patients', 'Species', '9606', (146, 154))	('toxicity', 'Disease', 'MESH:D064420', (109, 117))	('toxicity', 'Disease', (109, 117))
832844	21286719	In this study, using a multicenter trial cohort in which robust toxicity data was available, we found that variant alleles at 2 SNP loci:XRCC2 or GST-Pi:were each linked to serious acute radiation-related toxicity that was probably or definitely related to cisplatin-based RCT.	('toxicity', 'Disease', 'MESH:D064420', (64, 72))	('variant', 'Var', (107, 114))	('linked to', 'Reg', (163, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (257, 266))	('XRCC2', 'Gene', (137, 142))	('toxicity', 'Disease', 'MESH:D064420', (205, 213))	('toxicity', 'Disease', (205, 213))	('toxicity', 'Disease', (64, 72))	('GST-Pi', 'Gene', (146, 152))
832847	21286719	In addition, under the hypothesis that chemotherapeutic agents and radiotherapy exert their effects through multiple steps and genes, we evaluated the possibility that possessing a variant allele across a greater number of radiation/platin pathways may influence toxicity; however, we did not identify any associations.	('toxicity', 'Disease', (263, 271))	('platin', 'Chemical', 'MESH:D010984', (233, 239))	('influence', 'Reg', (253, 262))	('radiation/platin pathways', 'Pathway', (223, 248))	('variant', 'Var', (181, 188))	('toxicity', 'Disease', 'MESH:D064420', (263, 271))
832857	21286719	We found that 65% of EAC subjects possessed a variant allele in the GST-Pi SNP, and that 31% of these subjects experienced acute serious radiation-related dysphagia or pain, compared to zero subjects without a variant allele (P = 0.005).	('pain', 'Phenotype', 'HP:0012531', (168, 172))	('GST-Pi SNP', 'Gene', (68, 78))	('variant', 'Var', (46, 53))	('pain', 'Disease', 'MESH:D010146', (168, 172))	('dysphagia', 'Disease', (155, 164))	('pain', 'Disease', (168, 172))	('experienced', 'Reg', (111, 122))	('EAC', 'Phenotype', 'HP:0011459', (21, 24))	('dysphagia', 'Phenotype', 'HP:0002015', (155, 164))	('dysphagia', 'Disease', 'MESH:D003680', (155, 164))	('EAC', 'Disease', (21, 24))
832861	21286719	In the GST-Pi locus (exon 5) which we studied, the G and A alleles code for valine and isoleucine, respectively, which reside in an electrophile-binding active site of the GST-Pi peptide.	('isoleucine', 'Var', (87, 97))	('isoleucine', 'Chemical', 'MESH:D007532', (87, 97))	('valine', 'Var', (76, 82))	('code', 'Reg', (67, 71))	('valine', 'Chemical', 'MESH:D014633', (76, 82))
832867	21286719	We found that 28% of EAC subjects had a variant allele (i.e., GA or GG) in the XRCC2 5' flanking SNP, and that 47% of these subjects had serious acute radiation-related dysphagia or pain, compared to 9% of subjects without the variant allele (P = 0.005).	('pain', 'Phenotype', 'HP:0012531', (182, 186))	('pain', 'Disease', 'MESH:D010146', (182, 186))	('pain', 'Disease', (182, 186))	('EAC', 'Phenotype', 'HP:0011459', (21, 24))	('to 9', 'Species', '1214577', (197, 201))	('variant', 'Var', (40, 47))	('dysphagia', 'Disease', (169, 178))	('dysphagia', 'Phenotype', 'HP:0002015', (169, 178))	('EAC', 'Disease', (21, 24))	('dysphagia', 'Disease', 'MESH:D003680', (169, 178))
832870	21286719	Failure to repair DSBs can lead to mutations, apoptosis, tumor predisposition, and carcinogenesis.	('DSBs', 'Chemical', '-', (18, 22))	('apoptosis', 'CPA', (46, 55))	('Failure', 'Var', (0, 7))	('mutations', 'CPA', (35, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('lead to', 'Reg', (27, 34))	('carcinogenesis', 'Disease', (83, 97))	('tumor', 'Disease', (57, 62))
832871	21286719	Nonsynonymous SNPs in XRCC2 have been associated with cancer risk and outcomes, but not with skin complications due to radiotherapy.	('associated', 'Reg', (38, 48))	('Nonsynonymous SNPs', 'Var', (0, 18))	('XRCC2', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('skin complications', 'Disease', 'MESH:D017445', (93, 111))	('skin complications', 'Disease', (93, 111))	('outcomes', 'CPA', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
832872	21286719	A recent case-control study found that the variant allele of the SNP in the 5' flanking sequence of XRCC2, analyzed in the current study, was linked to reduced bladder cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('reduced bladder', 'Phenotype', 'HP:0005343', (152, 167))	('reduced', 'NegReg', (152, 159))	('bladder cancer', 'Disease', (160, 174))	('variant', 'Var', (43, 50))	('XRCC2', 'Gene', (100, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))
832873	21286719	This association, together with the link we found between the variant (G) allele and higher toxicity after RCT, does not support the hypothesis that alleles leading to higher toxicity (presumably through reduced DNA repair) increase cancer risk.	('toxicity', 'Disease', 'MESH:D064420', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('toxicity', 'Disease', (92, 100))	('toxicity', 'Disease', (175, 183))	('reduced', 'NegReg', (204, 211))	('increase cancer', 'Disease', (224, 239))	('DNA repair', 'MPA', (212, 222))	('variant', 'Var', (62, 69))	('increase cancer', 'Disease', 'MESH:D009369', (224, 239))	('toxicity', 'Disease', 'MESH:D064420', (92, 100))
832878	21286719	In conclusion, using a multicenter well-defined study population with robust endpoint ascertainment, we found two SNPs involved in radiation/platin pathways to be associated with serious radiation toxicity probably/definitely related to radiotherapy.	('SNPs', 'Var', (114, 118))	('radiation toxicity', 'Disease', 'MESH:D004194', (187, 205))	('platin', 'Chemical', 'MESH:D010984', (141, 147))	('radiation toxicity', 'Disease', (187, 205))	('associated with', 'Reg', (163, 178))
832906	32785797	The esophageal carcinoma was finally diagnosed as ypT1bN0M0 (ypStageI).	('esophageal carcinoma', 'Disease', (4, 24))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (4, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (4, 24))	('ypT1bN0M0', 'Var', (50, 59))
832962	30671663	The study included 20 patients in each group (Duette: 18M + 2F; mean age 74 years; Captivator: 17M + 3F; mean age 72 years) with a mean length of BE of C4M6 in the Duette and C3M5 in the Captivator group, p = NS (Table 1).	('BE', 'Phenotype', 'HP:0100580', (146, 148))	('patients', 'Species', '9606', (22, 30))	('BE', 'Disease', 'MESH:D001471', (146, 148))	('C3M5', 'Var', (175, 179))	('C4M6', 'Var', (152, 156))
833009	30679163	A jetPEI nanocarrier was used as the vehicle for anti-LIMS1 siRNAs in mouse models of cancer therapeutics.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mouse', 'Species', '10090', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('anti-LIMS1', 'Var', (49, 59))	('cancer', 'Disease', (86, 92))
833011	30679163	High LIMS1 level was associated with advanced TNM stage and poor prognosis of tumour patients.	('TNM', 'Gene', (46, 49))	('High', 'Var', (0, 4))	('LIMS1 level', 'MPA', (5, 16))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (78, 84))	('patients', 'Species', '9606', (85, 93))	('TNM', 'Gene', '10178', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
833013	30679163	Mechanistically, LIMS1 enhanced GLUT1 expression and membrane translocation, which facilitated tumor cell adaptation to the glucose deprivation stress.	('GLUT1', 'Gene', (32, 37))	('membrane translocation', 'MPA', (53, 75))	('enhanced', 'PosReg', (23, 31))	('GLUT1', 'Gene', '6513', (32, 37))	('LIMS1', 'Var', (17, 22))	('expression', 'MPA', (38, 48))	('glucose deprivation stress', 'Disease', (124, 150))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('glucose deprivation stress', 'Disease', 'MESH:D000079225', (124, 150))	('tumor', 'Disease', (95, 100))	('facilitated', 'PosReg', (83, 94))
833015	30679163	Inhibition of LIMS1 with jetPEI nanocarrier-delivered anti-LIMS1 siRNAs significantly increased cell death and suppressed tumour growth.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('increased', 'PosReg', (86, 95))	('Inhibition', 'NegReg', (0, 10))	('anti-LIMS1', 'Var', (54, 64))	('tumour', 'Disease', (122, 128))	('LIMS1', 'Gene', (14, 19))	('cell death', 'CPA', (96, 106))	('suppressed', 'NegReg', (111, 121))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
833030	30679163	LIMS1 was also shown to directly inhibit phosphatase 1alpha (PP1alpha):an Akt1-regulating protein:to activate Akt1 phosphorylation.	('LIMS1', 'Var', (0, 5))	('Akt1', 'Gene', '207', (74, 78))	('inhibit', 'NegReg', (33, 40))	('Akt1', 'Gene', (110, 114))	('Akt1', 'Gene', (74, 78))	('PP1alpha', 'Gene', (61, 69))	('Akt1', 'Gene', '207', (110, 114))	('activate', 'PosReg', (101, 109))	('PP1alpha', 'Gene', '5499', (61, 69))	('phosphorylation', 'MPA', (115, 130))
833040	30679163	IHC was used to detect LIMS1, HIF1, pAKT (S473) and pAKT (T308) in tumor tissues.	('HIF1', 'Gene', '3091', (30, 34))	('S473', 'Var', (42, 46))	('T308', 'Var', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('AKT', 'Gene', '207', (37, 40))	('HIF1', 'Gene', (30, 34))	('AKT', 'Gene', '207', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('AKT', 'Gene', (37, 40))	('tumor', 'Disease', (67, 72))	('AKT', 'Gene', (53, 56))
833065	30679163	PANC-1 cells transfected with pcDNA-HIF1A or control vector (pcDNA-vector) were transfected with pGL3-LIMS1-promoter, pGL3-LIMS1-promoter mutation (MUT), or pGL3-empty vectors (pGL3.1 EV).	('pcDNA-HIF1A', 'Var', (30, 41))	('pGL3', 'Gene', '6391', (157, 161))	('pGL3', 'Gene', (97, 101))	('pGL3', 'Gene', (118, 122))	('pGL3', 'Gene', (177, 181))	('pGL3', 'Gene', '6391', (97, 101))	('pGL3', 'Gene', '6391', (118, 122))	('pGL3', 'Gene', (157, 161))	('PANC-1', 'CellLine', 'CVCL:0480', (0, 6))	('pGL3', 'Gene', '6391', (177, 181))
833086	30679163	As shown in Supplementary Table S1, high expression of LIMS1 was strongly correlated with advanced tumor size (P = 0.021, chi-square tests), T stage (P = 0.036, chi-square tests), regional lymph node involvement (P = 0.019, chi-square tests), pTNM staging (P = 0.017, chi-square tests) and blood vessel infiltration (P = 0.046, chi-square tests).	('tumor', 'Disease', (99, 104))	('high expression', 'Var', (36, 51))	('blood vessel infiltration', 'CPA', (290, 315))	('regional lymph node involvement', 'CPA', (180, 211))	('TNM', 'Gene', '10178', (244, 247))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('TNM', 'Gene', (244, 247))	('correlated', 'Reg', (74, 84))	('T stage', 'CPA', (141, 148))	('LIMS1', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
833089	30679163	As shown in Supplementary Table S2, a high mRNA level of LIMS1 was significantly correlated with advanced tumor size (P = 0.044, unpaired t tests), T staging (P = 0.024, unpaired t tests), regional lymph node involvement (P = 0.028, unpaired t tests), differentiation (P = 0.012, unpaired t tests) and pTNM staging (P = 0.005, unpaired t tests).	('T staging', 'CPA', (148, 157))	('regional lymph node involvement', 'CPA', (189, 220))	('LIMS1', 'Gene', (57, 62))	('high mRNA', 'Var', (38, 47))	('TNM', 'Gene', '10178', (303, 306))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('differentiation', 'CPA', (252, 267))	('correlated', 'Reg', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TNM', 'Gene', (303, 306))	('tumor', 'Disease', (106, 111))
833095	30679163	High LIMS1 expression was significantly correlated with poor overall survival of patients (Suppl.	('High', 'Var', (0, 4))	('LIMS1', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('patients', 'Species', '9606', (81, 89))	('overall', 'MPA', (61, 68))
833097	30679163	To explore the roles of LIMS1 in tumor progression, we established stable cell lines in which LIMS1 was overexpressed or knocked down (Fig.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('overexpressed', 'PosReg', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('knocked', 'Var', (121, 128))	('tumor', 'Disease', (33, 38))	('LIMS1', 'Gene', (94, 99))
833100	30679163	2B, the cell mortality rate of MIA PaCa-2 tissues with LIMS1 knockdown was strongly elevated (8.33 +- 1.81 vs 23.01 +- 6.14; P < 0.0001, unpaired t test).	('elevated', 'PosReg', (84, 92))	('knockdown', 'Var', (61, 70))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (31, 41))	('LIMS1', 'Gene', (55, 60))	('cell mortality rate', 'CPA', (8, 27))
833102	30679163	Furthermore, LIMS1 knockdown resulted in reduced tumor growth, whereas LIMS1 overexpression significantly enhanced the tumor growth (Fig.	('tumor growth', 'Disease', (49, 61))	('reduced', 'NegReg', (41, 48))	('tumor growth', 'Disease', 'MESH:D006130', (49, 61))	('LIMS1', 'Gene', (71, 76))	('enhanced', 'PosReg', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('knockdown', 'Var', (19, 28))	('LIMS1', 'Gene', (13, 18))	('tumor growth', 'Disease', (119, 131))	('tumor growth', 'Disease', 'MESH:D006130', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
833109	30679163	In contrast, LIMS1 knockdown significantly reduced the survival of MIA PaCa-2 and PANC-1 cells (unpaired t tests).	('knockdown', 'Var', (19, 28))	('survival', 'CPA', (55, 63))	('LIMS1', 'Gene', (13, 18))	('PANC-1', 'CellLine', 'CVCL:0480', (82, 88))	('reduced', 'NegReg', (43, 50))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (67, 77))
833122	30679163	The AKT1 inhibitor MK2206 completely abrogated the LIMS1-induced phosphorylation AKT1, mTOR and 4EBP1, as well as LIMS1-induced HIF1A expression.	('4EBP1', 'Gene', '1978', (96, 101))	('mTOR', 'Gene', '2475', (87, 91))	('4EBP1', 'Gene', (96, 101))	('expression', 'MPA', (134, 144))	('AKT1', 'Gene', '207', (4, 8))	('AKT1', 'Gene', (81, 85))	('AKT1', 'Gene', (4, 8))	('MK2206', 'Var', (19, 25))	('abrogated', 'NegReg', (37, 46))	('phosphorylation', 'MPA', (65, 80))	('HIF1A', 'Gene', (128, 133))	('AKT1', 'Gene', '207', (81, 85))	('MK2206', 'Chemical', 'MESH:C548887', (19, 25))	('mTOR', 'Gene', (87, 91))
833124	30679163	In vivo, MK2206 and rapamycin showed similar growth-inhibiting effects as well as LIMS1 knockdown (Suppl.	('MK2206', 'Var', (9, 15))	('LIMS1', 'Gene', (82, 87))	('knockdown', 'Var', (88, 97))	('rapamycin', 'Chemical', 'MESH:D020123', (20, 29))	('MK2206', 'Chemical', 'MESH:C548887', (9, 15))	('growth-inhibiting', 'CPA', (45, 62))
833127	30679163	Since LIMS1 facilitates the survival of tumor cells in oxygen-glucose deprivation conditions, we examined the effects of LIMS1 on PDAC glucose uptake using 2-deoxyglucose (2-DG) in vitro.	('LIMS1', 'Var', (6, 11))	('2-deoxyglucose', 'Chemical', 'MESH:D003847', (156, 170))	('oxygen-glucose deprivation conditions', 'Disease', (55, 92))	('glucose', 'Chemical', 'MESH:D005947', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('glucose', 'Chemical', 'MESH:D005947', (135, 142))	('survival', 'CPA', (28, 36))	('facilitates', 'PosReg', (12, 23))	('2-DG', 'Chemical', 'MESH:D003847', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('PDAC', 'Chemical', '-', (130, 134))	('oxygen-glucose deprivation conditions', 'Disease', 'MESH:D000860', (55, 92))	('glucose', 'Chemical', 'MESH:D005947', (62, 69))
833129	30679163	Conversely, LIMS1 knockdown substantially reduced the uptake of 2-DG in PDAC cells.	('knockdown', 'Var', (18, 27))	('LIMS1', 'Gene', (12, 17))	('reduced', 'NegReg', (42, 49))	('2-DG', 'Chemical', 'MESH:D003847', (64, 68))	('PDAC', 'Chemical', '-', (72, 76))	('uptake of 2-DG', 'MPA', (54, 68))
833130	30679163	This was well supported by the evidence that tumor cells with high LIMS1 expression had an elevated extracellular acidification rate in vitro (Suppl.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('elevated', 'PosReg', (91, 99))	('LIMS1', 'Gene', (67, 72))	('tumor', 'Disease', (45, 50))	('high', 'Var', (62, 66))	('extracellular acidification rate', 'MPA', (100, 132))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
833134	30679163	Our data indicated that LIMS1 significantly enhanced the uptake of 18FDG (Fig.	('18FDG', 'Chemical', '-', (67, 72))	('LIMS1', 'Var', (24, 29))	('enhanced', 'PosReg', (44, 52))	('uptake', 'MPA', (57, 63))
833136	30679163	To determine whether LIMS1 correlates with glucose uptake in human cancer patients, we used PET/CT scanning to compare the standardised 18FDG uptake between LIMS1 high and LIMS1 low patients.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('high', 'Var', (163, 167))	('cancer', 'Disease', (67, 73))	('LIMS1', 'Gene', (157, 162))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('glucose', 'Chemical', 'MESH:D005947', (43, 50))	('18FDG', 'Chemical', '-', (136, 141))	('patients', 'Species', '9606', (182, 190))	('human', 'Species', '9606', (61, 66))
833137	30679163	S11, PDAC, esophageal carcinoma and lung adenocarcinoma patients with high LIMS1 expression levels also had substantially higher standardised 18FDG uptake values.	('patients', 'Species', '9606', (56, 64))	('standardised 18FDG uptake values', 'MPA', (129, 161))	('S11', 'Gene', (0, 3))	('18FDG', 'Chemical', '-', (142, 147))	('LIMS1', 'Gene', (75, 80))	('esophageal carcinoma', 'Disease', (11, 31))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (36, 55))	('higher', 'PosReg', (122, 128))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (11, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (11, 31))	('lung adenocarcinoma', 'Disease', (36, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (36, 55))	('PDAC', 'Chemical', '-', (5, 9))	('S11', 'Gene', '6267', (0, 3))	('high', 'Var', (70, 74))	('expression', 'MPA', (81, 91))
833140	30679163	Next, we investigated the mechanism underlying LIMS1 activation of GLUT1 expression to facilitate glucose uptake.	('LIMS1', 'Var', (47, 52))	('GLUT1', 'Gene', '6513', (67, 72))	('facilitate', 'PosReg', (87, 97))	('glucose', 'Chemical', 'MESH:D005947', (98, 105))	('glucose uptake', 'CPA', (98, 112))	('GLUT1', 'Gene', (67, 72))
833142	30679163	Intriguingly, LIMS1 also increased the GLUT1 mRNA levels in polysomes (Fig.	('GLUT1', 'Gene', '6513', (39, 44))	('GLUT1', 'Gene', (39, 44))	('increased', 'PosReg', (25, 34))	('LIMS1', 'Var', (14, 19))
833143	30679163	4G), suggesting that GLUT1 translation was promoted by LIMS1.	('LIMS1', 'Var', (55, 60))	('GLUT1', 'Gene', '6513', (21, 26))	('GLUT1', 'Gene', (21, 26))	('promoted', 'PosReg', (43, 51))
833147	30679163	Additionally, when AKT signalling was inhibited by MK2206, the LIMS1-induced GLUT1 overexpression was inhibited(Fig.	('GLUT1', 'Gene', (77, 82))	('GLUT1', 'Gene', '6513', (77, 82))	('inhibited', 'NegReg', (102, 111))	('AKT', 'Gene', '207', (19, 22))	('MK2206', 'Chemical', 'MESH:C548887', (51, 57))	('inhibited', 'NegReg', (38, 47))	('overexpression', 'PosReg', (83, 97))	('AKT', 'Gene', (19, 22))	('MK2206', 'Var', (51, 57))
833148	30679163	When GLUT1 expression was knocked down, the LIMS1-induced 2-DG uptake (Fig.	('GLUT1', 'Gene', '6513', (5, 10))	('knocked down', 'Var', (26, 38))	('2-DG uptake', 'MPA', (58, 69))	('2-DG', 'Chemical', 'MESH:D003847', (58, 62))	('GLUT1', 'Gene', (5, 10))
833153	30679163	To determine whether HIF1 transcriptionally regulates LIMS1 expression in cancer cells, we established stable cell lines in which HIF1A was overexpressed or knocked down (Fig.	('HIF1', 'Gene', '3091', (21, 25))	('knocked down', 'Var', (157, 169))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('HIF1', 'Gene', (130, 134))	('cancer', 'Disease', (74, 80))	('HIF1', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('HIF1', 'Gene', '3091', (130, 134))
833158	30679163	To determine whether HRE1 is necessary for HIF1A to transactivate the LIMS1 promoter, we mutated this HIF1A binding site from ACGTG to ACATG.	('ACATG', 'Chemical', '-', (135, 140))	('HIF1A', 'Gene', (102, 107))	('ACGTG', 'Chemical', '-', (126, 131))	('mutated', 'Var', (89, 96))
833160	30679163	S12A, the correlation between the mRNA levels of LIMS1 and HIF1A reached 0.702 (P < 0.0001, Spearman correlation analysis).	('S12A', 'Var', (0, 4))	('HIF1A', 'Gene', (59, 64))	('S12A', 'SUBSTITUTION', 'None', (0, 4))	('LIMS1', 'Gene', (49, 54))
833162	30679163	S12B; 564.80 +- 228.10 vs 290.06 +- 158.28; P < 0.0001, unpaired t test), suggesting that HIF1 increased LIMS1 expression in PDAC.	('HIF1', 'Gene', (90, 94))	('LIMS1', 'Gene', (105, 110))	('HIF1 increased', 'Phenotype', 'HP:0030269', (90, 104))	('S12B', 'SUBSTITUTION', 'None', (0, 4))	('PDAC', 'Chemical', '-', (125, 129))	('expression', 'MPA', (111, 121))	('HIF1', 'Gene', '3091', (90, 94))	('increased', 'PosReg', (95, 104))	('S12B', 'Var', (0, 4))
833164	30679163	S12C, LIMS1 expression co-localised with HIF1A in consecutive sections of the PDAC tissues.	('S12C', 'Var', (0, 4))	('PDAC', 'Chemical', '-', (78, 82))	('LIMS1', 'Gene', (6, 11))	('S12C', 'Mutation', 'p.S12C', (0, 4))
833168	30679163	Then, in transplanted tumor tissues from mice, HIF1A overexpression significantly increased LIMS1 level and vice versa (Suppl.	('HIF1A', 'Gene', (47, 52))	('mice', 'Species', '10090', (41, 45))	('LIMS1 level', 'MPA', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('overexpression', 'Var', (53, 67))	('tumor', 'Disease', (22, 27))	('increased', 'PosReg', (82, 91))
833171	30679163	The ectopic expression of HIF1A significantly promoted PDAC cell survival, and HIF1A knockdown strongly inhibited survival under oxygen-glucose deprivation stress.	('HIF1A', 'Gene', (26, 31))	('promoted', 'PosReg', (46, 54))	('oxygen', 'Chemical', 'MESH:D010100', (129, 135))	('PDAC', 'Chemical', '-', (55, 59))	('glucose deprivation stress', 'Disease', 'MESH:D000079225', (136, 162))	('HIF1A', 'Gene', (79, 84))	('PDAC cell survival', 'CPA', (55, 73))	('knockdown', 'Var', (85, 94))	('survival', 'CPA', (114, 122))	('glucose deprivation stress', 'Disease', (136, 162))	('inhibited', 'NegReg', (104, 113))
833176	30679163	LIMS1 knockdown abrogated the HIF1-induced increase in cell survival and tumor growth (Suppl.	('HIF1', 'Gene', '3091', (30, 34))	('tumor growth', 'Disease', (73, 85))	('tumor growth', 'Disease', 'MESH:D006130', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cell survival', 'CPA', (55, 68))	('LIMS1', 'Gene', (0, 5))	('HIF1', 'Gene', (30, 34))	('abrogated', 'NegReg', (16, 25))	('increase', 'PosReg', (43, 51))	('knockdown', 'Var', (6, 15))
833177	30679163	S12H & I; unpaired t test), whereas LIMS1 overexpression relieved the inhibitory effect of HIF1A knockdown on cell survival and tumor growth (Suppl.	('on cell', 'CPA', (107, 114))	('tumor growth', 'Disease', (128, 140))	('tumor growth', 'Disease', 'MESH:D006130', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('HIF1A', 'Var', (91, 96))	('the inhibitory', 'MPA', (66, 80))	('S12H', 'Mutation', 'p.S12H', (0, 4))
833183	30679163	The inhibition of LIMS1 blocked AKT/mTOR signal pathway and resulted in decreased HIF1A and GLUT1 expression in tumor tissues (Supplementary Figure S15), leading to an remarkable increase of cell mortality (Fig.	('mTOR', 'Gene', '2475', (36, 40))	('S15', 'Gene', (148, 151))	('inhibition', 'Var', (4, 14))	('AKT', 'Gene', '207', (32, 35))	('decreased', 'NegReg', (72, 81))	('LIMS1', 'Gene', (18, 23))	('tumor', 'Disease', (112, 117))	('increase', 'PosReg', (179, 187))	('cell mortality', 'CPA', (191, 205))	('GLUT1', 'Gene', '6513', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('HIF1A', 'Gene', (82, 87))	('mTOR', 'Gene', (36, 40))	('AKT', 'Gene', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('S15', 'Gene', '6209', (148, 151))	('blocked', 'NegReg', (24, 31))	('GLUT1', 'Gene', (92, 97))	('expression', 'MPA', (98, 108))
833194	30679163	Although knockdown of LIMS1 had negligible effects on cancer cell apoptosis under normal culture conditions, LIMS1 was critical for cancer cell survival under oxygen-glucose deprivation.	('cancer', 'Disease', (132, 138))	('knockdown', 'Var', (9, 18))	('LIMS1', 'Gene', (22, 27))	('glucose', 'Chemical', 'MESH:D005947', (166, 173))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (54, 60))	('oxygen', 'Chemical', 'MESH:D010100', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
833195	30679163	Mechanistically, LIMS1 enhances glucose uptake by increasing the expression levels of GLUT1, possibly through ILK-mediated phosphorylation and activation of PKB/AKT.	('increasing', 'PosReg', (50, 60))	('expression levels', 'MPA', (65, 82))	('LIMS1', 'Var', (17, 22))	('glucose', 'Chemical', 'MESH:D005947', (32, 39))	('PKB/AKT', 'Gene', '207', (157, 164))	('enhances', 'PosReg', (23, 31))	('PKB/AKT', 'Gene', (157, 164))	('GLUT1', 'Gene', (86, 91))	('ILK', 'Gene', '3611', (110, 113))	('GLUT1', 'Gene', '6513', (86, 91))	('glucose uptake', 'CPA', (32, 46))	('ILK', 'Gene', (110, 113))
833214	30679163	LIMS1 overexpression significantly rescued the inhibitory effect of HIF1A knockdown on GLUT1 expression.	('HIF1A', 'Gene', (68, 73))	('knockdown', 'Var', (74, 83))	('GLUT1', 'Gene', (87, 92))	('inhibitory effect', 'MPA', (47, 64))	('GLUT1', 'Gene', '6513', (87, 92))
833221	30679163	Although the anti-LIMS1 siRNA significantly inhibited LIMS1 expression and tumor growth, siRNAs were not yet an ideal agent for clinical usage.	('expression', 'MPA', (60, 70))	('LIMS1', 'Gene', (54, 59))	('inhibited', 'NegReg', (44, 53))	('anti-LIMS1', 'Var', (13, 23))	('tumor growth', 'Disease', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor growth', 'Disease', 'MESH:D006130', (75, 87))
833442	30271668	Besides under conditions of inflammation and bacteria (Helicobacter Pylori), the formation of nitrate related nitrosamine was enhanced.	('inflammation', 'Disease', (28, 40))	('enhanced', 'PosReg', (126, 134))	('Helicobacter', 'Var', (55, 67))	('nitrosamine', 'Chemical', 'MESH:D009602', (110, 121))	('formation of nitrate related nitrosamine', 'MPA', (81, 121))	('nitrate', 'Chemical', 'MESH:D009566', (94, 101))	('inflammation', 'Disease', 'MESH:D007249', (28, 40))	('Helicobacter Pylori', 'Species', '210', (55, 74))
833448	30271668	An investigation in Korea, where the intake of dietary nitrates (390-742 mg/day) is considerably higher than that of European countries (52-156 mg/day) and China (422.8 mg/day), showed that no correlation was found between high intake of nitrate and cancer.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('nitrates', 'Chemical', 'MESH:D009566', (55, 63))	('nitrate', 'Chemical', 'MESH:D009566', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('nitrate', 'Chemical', 'MESH:D009566', (238, 245))	('390-742 mg/day', 'Var', (65, 79))
833464	30271668	The aortic pulse wave velocity was improved, and the platelet-monocyte aggregates reduced in nitrate supplemental patients which resulting in decreased blood pressure.	('blood pressure', 'MPA', (152, 166))	('improved', 'PosReg', (35, 43))	('nitrate', 'Var', (93, 100))	('decreased blood pressure', 'Phenotype', 'HP:0002615', (142, 166))	('decreased', 'NegReg', (142, 151))	('aortic pulse wave velocity', 'MPA', (4, 30))	('nitrate', 'Chemical', 'MESH:D009566', (93, 100))	('platelet-monocyte aggregates', 'CPA', (53, 81))	('reduced', 'NegReg', (82, 89))	('patients', 'Species', '9606', (114, 122))
833480	28938617	ESCC patients with high ZFAS1 expression had a poor overall survival (OS).	('overall survival', 'MPA', (52, 68))	('expression', 'MPA', (30, 40))	('high', 'Var', (19, 23))	('patients', 'Species', '9606', (5, 13))	('OS', 'Chemical', '-', (70, 72))	('ZFAS1', 'Gene', '441951', (24, 29))	('ZFAS1', 'Gene', (24, 29))
833506	28938617	Next, the median ZFAS1 expression was used as a cutoff value to divide patients into two groups based on high ZFAS1 expression or low ZFAS1 expression.	('high', 'Var', (105, 109))	('expression', 'MPA', (116, 126))	('ZFAS1', 'Gene', (110, 115))	('expression', 'MPA', (140, 150))	('ZFAS1', 'Gene', '441951', (134, 139))	('patients', 'Species', '9606', (71, 79))	('low', 'NegReg', (130, 133))	('ZFAS1', 'Gene', '441951', (17, 22))	('ZFAS1', 'Gene', (134, 139))	('ZFAS1', 'Gene', '441951', (110, 115))	('ZFAS1', 'Gene', (17, 22))
833514	28938617	Univariate analysis showed that poorly or undifferentiated, advanced T stage, and high ZFAS1 expression were poor prognostic factors in the primary cohort (P < 0.01, Table 2).	('ZFAS1', 'Gene', (87, 92))	('expression', 'MPA', (93, 103))	('ZFAS1', 'Gene', '441951', (87, 92))	('high', 'Var', (82, 86))
833516	28938617	In the validation cohort, high ZFAS1 expression also correlated with poor OS, and ZFAS1 expression was also found to be an independent prognostic factor.	('ZFAS1', 'Gene', (31, 36))	('ZFAS1', 'Gene', '441951', (82, 87))	('high', 'Var', (26, 30))	('correlated', 'Reg', (53, 63))	('poor OS', 'Disease', (69, 76))	('ZFAS1', 'Gene', (82, 87))	('ZFAS1', 'Gene', '441951', (31, 36))	('expression', 'MPA', (37, 47))	('OS', 'Chemical', '-', (74, 76))
833525	28938617	found that ZFAS1 is highly expressed in normal breast tissue and down-regulated in breast cancer tissue, and the knockdown of ZFAS1 in an epithelial cell line of breast cancer promoted cell proliferation, which suggested that ZFAS1 might be a tumor suppressor gene in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ZFAS1', 'Gene', '441951', (226, 231))	('cell proliferation', 'CPA', (185, 203))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('down-regulated', 'NegReg', (65, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('tumor', 'Disease', (243, 248))	('ZFAS1', 'Gene', (11, 16))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('breast cancer', 'Disease', (268, 281))	('ZFAS1', 'Gene', '441951', (11, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('knockdown', 'Var', (113, 122))	('ZFAS1', 'Gene', (126, 131))	('breast cancer', 'Disease', (162, 175))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('ZFAS1', 'Gene', '441951', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('ZFAS1', 'Gene', (226, 231))	('promoted', 'PosReg', (176, 184))
833533	28938617	In vitro experiments also showed that gastric cancer cell proliferation decreased and apoptosis increased after ZFAS1 knockdown.	('increased', 'PosReg', (96, 105))	('ZFAS1', 'Gene', '441951', (112, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (38, 52))	('knockdown', 'Var', (118, 127))	('decreased', 'NegReg', (72, 81))	('ZFAS1', 'Gene', (112, 117))	('gastric cancer', 'Disease', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (38, 52))	('apoptosis', 'CPA', (86, 95))
833535	28938617	Experiments in vivo also showed that knockdown of ZFAS1 inhibited the tumorigenic ability of gastric cancer cells, and mechanistic experiments validated that ZFAS1 could promote the proliferation of gastric cancer cells by inhibiting the expression of KLF2 and NKD2.	('knockdown', 'Var', (37, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (199, 213))	('proliferation', 'CPA', (182, 195))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('NKD2', 'Gene', (261, 265))	('KLF2', 'Gene', '10365', (252, 256))	('ZFAS1', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('NKD2', 'Gene', '85409', (261, 265))	('KLF2', 'Gene', (252, 256))	('expression', 'MPA', (238, 248))	('gastric cancer', 'Disease', (93, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (199, 213))	('ZFAS1', 'Gene', '441951', (50, 55))	('inhibiting', 'NegReg', (223, 233))	('ZFAS1', 'Gene', (158, 163))	('inhibited', 'NegReg', (56, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('tumor', 'Disease', (70, 75))	('ZFAS1', 'Gene', '441951', (158, 163))	('gastric cancer', 'Disease', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('promote', 'PosReg', (170, 177))
833540	28938617	In addition, in vitro experiments demonstrated that ZFAS1 knockdown in glioma cells inhibited the proliferation and invasion of glioma cells.	('glioma', 'Disease', (128, 134))	('glioma', 'Disease', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('ZFAS1', 'Gene', '441951', (52, 57))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('knockdown', 'Var', (58, 67))	('ZFAS1', 'Gene', (52, 57))	('inhibited', 'NegReg', (84, 93))
833541	28938617	EMT and Notch signaling pathways in glioma cells were inactivated after ZFAS1 knockdown.	('EMT', 'Gene', (0, 3))	('EMT', 'Gene', '3702', (0, 3))	('knockdown', 'Var', (78, 87))	('glioma', 'Disease', (36, 42))	('ZFAS1', 'Gene', '441951', (72, 77))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('Notch signaling pathways', 'Pathway', (8, 32))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('inactivated', 'NegReg', (54, 65))	('ZFAS1', 'Gene', (72, 77))
833543	28938617	In lung cancer, high ZFAS1 expression was significantly related to the poor prognosis.	('lung cancer', 'Disease', (3, 14))	('high', 'Var', (16, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('expression', 'MPA', (27, 37))	('ZFAS1', 'Gene', '441951', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('ZFAS1', 'Gene', (21, 26))	('related', 'Reg', (56, 63))
833547	28938617	Moreover, our data indicated that patients with high ZFAS1 expression have a significantly shorter OS than those with low ZFAS1 expression.	('ZFAS1', 'Gene', '441951', (53, 58))	('OS', 'Chemical', '-', (99, 101))	('ZFAS1', 'Gene', '441951', (122, 127))	('ZFAS1', 'Gene', (53, 58))	('ZFAS1', 'Gene', (122, 127))	('patients', 'Species', '9606', (34, 42))	('high', 'Var', (48, 52))	('shorter', 'NegReg', (91, 98))	('expression', 'Var', (59, 69))
833608	28469981	TaqMan probes are shown as follows: GAPDH, Hs99999905_m1; VIM, Hs00185584_m1; TWIST, Hs00361186_m1; FN1, Hs00365058_m1; CDH1, Hs00170423_m1; CDH2, Hs00983056_m1; COL17A1, Hs00990036_m1; MKI67, Hs01032443_m1; TP63, Hs00978339_m1; FLG, Hs00856927_g1 (Applied Biosystems).	('CDH2', 'Gene', '1000', (141, 145))	('COL17A1', 'Gene', (162, 169))	('VIM', 'Gene', '7431', (58, 61))	('Hs00990036_m1', 'Var', (171, 184))	('TP63', 'Gene', (208, 212))	('Hs00365058_m1', 'Var', (105, 118))	('VIM', 'Gene', (58, 61))	('FLG', 'Gene', '2312', (229, 232))	('TP63', 'Gene', '8626', (208, 212))	('FN1', 'Gene', '2335', (100, 103))	('COL17A1', 'Gene', '1308', (162, 169))	('MKI67', 'Gene', (186, 191))	('MKI67', 'Gene', '4288', (186, 191))	('Hs00978339_m1', 'Var', (214, 227))	('FN1', 'Gene', (100, 103))	('CDH2', 'Gene', (141, 145))	('CDH1', 'Gene', '999', (120, 124))	('Hs00983056_m1', 'Var', (147, 160))	('Hs00856927_g1', 'Var', (234, 247))	('Hs00361186_m1', 'Var', (85, 98))	('CDH1', 'Gene', (120, 124))	('FLG', 'Gene', (229, 232))
833731	26656367	The patients treated with RFA tended to have a larger tumor size (72.2 vs 57.3 mm; P = 0.13) and larger circumferential extension of the tumor than those treated with ESD (P = 0.01).	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('RFA', 'Var', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
833752	26656367	We found a lower stenosis rate (27%) for the patients treated with RFA, and these patients also required fewer sessions of dilatation (median, 3 vs 13; P = 0.04).	('stenosis rate', 'MPA', (17, 30))	('patients', 'Species', '9606', (82, 90))	('RFA', 'Var', (67, 70))	('lower', 'NegReg', (11, 16))	('patients', 'Species', '9606', (45, 53))	('dilatation', 'Phenotype', 'HP:0002617', (123, 133))
833773	27435280	Patients with cT1cN + cM0 and cT2-4acNxcM0 esophageal and junctional adenocarcinoma are eligible.	('cT1cN + cM0', 'Var', (14, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('cT2', 'Gene', (30, 33))	('Patients', 'Species', '9606', (0, 8))	('cT2', 'Gene', '30848', (30, 33))	('adenocarcinoma', 'Disease', (69, 83))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))
833782	27435280	With regard to perioperative chemotherapy, specifically two multicenter trials (MAGIC and ACCORD-07) found a significant increase in overall survival with cisplatin-fluoropyrimidine-based perioperative chemotherapy plus surgery compared to surgery alone.	('cisplatin-fluoropyrimidine-based', 'Var', (155, 187))	('increase', 'PosReg', (121, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('overall survival', 'MPA', (133, 149))	('fluoropyrimidine', 'Chemical', '-', (165, 181))
833807	27435280	Eligible patients must meet all of the following criteria: Patients with tumors of squamous, adenosquamous or other non-adenocarcinoma histology Patients with advanced inoperable or metastatic esophageal adenocarcinoma Esophageal adenocarcinoma staged cT1N0 and cT4b Esophageal adenocarcinoma cT4a evaluated as not curatively-resectable by the local surgical investigator.	('esophageal adenocarcinoma', 'Disease', (193, 218))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Esophageal adenocarcinoma', 'Disease', (267, 292))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (267, 292))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (267, 292))	('Patients', 'Species', '9606', (145, 153))	('Esophageal adenocarcinoma', 'Disease', (219, 244))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (219, 244))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (219, 244))	('cT4b', 'Var', (262, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('tumors of squamous, adenosquamous', 'Disease', 'MESH:D018196', (73, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('non-adenocarcinoma', 'Disease', 'MESH:D000230', (116, 134))	('patients', 'Species', '9606', (9, 17))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (193, 218))	('non-adenocarcinoma', 'Disease', (116, 134))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (193, 218))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('Patients', 'Species', '9606', (59, 67))
833877	26833333	Cancer genomes harbor various somatic forms of genetic alterations spanning from nucleotide-level alterations (e.g., point mutations and small insertions/deletions) to large chromosomal events (e.g., structural variations and copy-number changes), some of which can contribute to tumor development.	('copy-number changes', 'Var', (226, 245))	('contribute', 'Reg', (266, 276))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('point mutations', 'Var', (117, 132))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('structural variations', 'Var', (200, 221))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (280, 285))
833879	26833333	The main types of mechanisms known to cause SVs in human cancer include homologous recombination, nonreplicative nonhomologous repair, and replication-based mechanisms.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('human', 'Species', '9606', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('homologous', 'Var', (72, 82))
833880	26833333	Generally, homologous recombination can occur by non-allelic homologous recombination (NAHR), and deficiency in homologous recombination is implicated as a major source of cancer genome instability.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('non-allelic', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('deficiency', 'Disease', (98, 108))	('cancer', 'Disease', (172, 178))	('deficiency', 'Disease', 'MESH:D007153', (98, 108))
833881	26833333	Recently, single catastrophic events causing genomic shattering followed by incorrect re-joining of the fragmented DNA, termed chromothripsis, is receiving greater attention as a major mechanism generating complex SVs in human cancer.	('chromothripsis', 'Disease', (127, 141))	('chromothripsis', 'Disease', 'MESH:D000072837', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('human', 'Species', '9606', (221, 226))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Disease', (227, 233))	('genomic', 'Var', (45, 52))
833882	26833333	It is well known that SVs have implications in treatment and prediction of individual's outcome because genome-scale rearrangements can play an unappreciated role in cancer through their ability to move blocks of adjacent genes simultaneously or form gene fusion, leading to concurrent oncogenic events.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('move', 'Reg', (198, 202))	('rearrangements', 'Var', (117, 131))	('oncogenic events', 'CPA', (286, 302))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
833884	26833333	In addition, gene amplification, a selective copy-number increase of genomic segments through DNA rearrangements, is a clinically important form of genome instability in cancer, because gene amplification causes advanced tumors and acquired therapy resistance.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('gene amplification', 'Var', (13, 31))	('therapy resistance', 'CPA', (241, 259))	('cancer', 'Disease', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('gene amplification', 'Var', (186, 204))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (221, 227))	('causes', 'Reg', (205, 211))
833885	26833333	Continuous DNA breaks and rearrangements through chromothripsis, chromoplexy, or a breakage-fusion-bridge (BFB) cycle have been implicated as underlying mechanisms for gene amplification or fusion in human cancer.	('chromoplexy', 'CPA', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('chromothripsis', 'Disease', (49, 63))	('chromothripsis', 'Disease', 'MESH:D000072837', (49, 63))	('human', 'Species', '9606', (200, 205))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('rearrangements', 'Var', (26, 40))
833890	26833333	Unlike chromothripsis, which refers to an oncogenic mechanism operating on a global level and occurring in one or several chromosomes, kataegis has been found to operate locally, generating large numbers of mutations (or hotspots of hypermutations) in small regions of the genome.	('mutations', 'Var', (207, 216))	('chromothripsis', 'Disease', 'MESH:D000072837', (7, 21))	('chromothripsis', 'Disease', (7, 21))
833891	26833333	On the other hand, similar to chromothripsis, kataegis most likely causes a large number of substitution mutations to occur in a region of the genome at one time rather than accumulating in a step-wise fashion.	('chromothripsis', 'Disease', (30, 44))	('substitution mutations', 'Var', (92, 114))	('chromothripsis', 'Disease', 'MESH:D000072837', (30, 44))
833894	26833333	Our findings revealed different mutational mechanisms for the formation of amplification of cancer-associated genes in ESCC.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('ESCC', 'Disease', (119, 123))	('amplification', 'Var', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
833901	26833333	verified the accuracy of Meerkat by applying it to two HapMap genomes (NA18507 and NA12878) that were sequenced at high coverage on the Illumina platform and for which complex deletions have been previously reported.	('Meerkat', 'Species', '37032', (25, 32))	('NA12878', 'Var', (83, 90))	('NA18507', 'Var', (71, 78))
833907	26833333	To assess the significance of SV enrichment on chromosomes, we required the number of locally arranged genomes to be more than 50 and clustered chromosomes to have a high SVs mutation rate per Mb exceeding three times the length of the interquartile range from the 75th percentile of the chromosome counts for each tumor.	('mutation', 'Var', (175, 183))	('SVs', 'Gene', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', (315, 320))
833917	26833333	The primers used were designed against exon 18 of TRAPPC9 (MIM: 611966) forward (5'-CGGAATTCACCCTGGAAGCTGTCCTG-3') and exon 4 of CLVS1 (MIM: 611292) reverse (5'-CCCTCGAGCTGCAACCCTTCAATGGC-3') or against exon 1 of EIF3E (MIM: 602210) forward (5'-CGGAATTCATGGCGGAGTACG-3') and exon 5 of RAD51B (MIM: 602948) reverse (5'-CCCTCGAGCTTTCAGCACTAAATG-3').	('EIF3E', 'Gene', (213, 218))	('RAD51B', 'Gene', (285, 291))	('RAD51B', 'Gene', '5890', (285, 291))	('GC', 'Phenotype', 'HP:0012126', (185, 187))	('GC', 'Phenotype', 'HP:0012126', (168, 170))	('CLVS1', 'Gene', '157807', (129, 134))	('EIF3E', 'Gene', '3646', (213, 218))	('TRAPPC9', 'Gene', (50, 57))	('GC', 'Phenotype', 'HP:0012126', (101, 103))	('CLVS1', 'Gene', (129, 134))	('TRAPPC9', 'Gene', '83696', (50, 57))	('MIM: 602948', 'Var', (293, 304))	('GC', 'Phenotype', 'HP:0012126', (256, 258))	('GC', 'Phenotype', 'HP:0012126', (171, 173))
833920	26833333	Slides were stained with Cytocell enumeration probes against interesting genes FGFR1 (MIM: 136350)/CEN8 (Z-2072, Zytovision, German), CCND1 (MIM: 168461)/CEN11 (Z-2071, Zytovision, German), TRAPPC9, CLVS1, EIF3E, and RAD51B, conjugated with FITC or Cy3.5 (Rainbow Scientific).	('EIF3E', 'Gene', (206, 211))	('CLVS1', 'Gene', (199, 204))	('Cy3', 'Chemical', '-', (249, 252))	('CCND1', 'Gene', (134, 139))	('FGFR1', 'Gene', (79, 84))	('MIM', 'Var', (141, 144))	('TRAPPC9', 'Gene', (190, 197))	('FGFR1', 'Gene', '2260', (79, 84))	('EIF3E', 'Gene', '3646', (206, 211))	('CLVS1', 'Gene', '157807', (199, 204))	('RAD51B', 'Gene', (217, 223))	('CCND1', 'Gene', '595', (134, 139))	('RAD51B', 'Gene', '5890', (217, 223))	('TRAPPC9', 'Gene', '83696', (190, 197))	('FITC', 'Chemical', 'MESH:D016650', (241, 245))
833934	26833333	Three siRNAs targeting LETM2 and one negative control siRNA (NC) (Guangzhou RiboBio) were used to knock down LETM2 in ESCC cell lines (KYSE150 and ECA109).	('LETM2', 'Gene', '137994', (23, 28))	('knock down', 'Var', (98, 108))	('LETM2', 'Gene', (23, 28))	('LETM2', 'Gene', '137994', (109, 114))	('LETM2', 'Gene', (109, 114))
833935	26833333	Meanwhile, FGFR1 (siRNA #1: 5'-AGTGGCTTATTAATTCCGATA-3'; siRNA #2: 5'-GCTTGCCAATGGCGGACTCAA-3'; siRNA #3: 5'-GAATGAGTACGGCAGCATCAA-3') or WHSC1L1 (siRNA #1: 5'-CGAGAGTATAAAGGTCATAAA-3'; siRNA #2: 5'-CCATCATCAATCAGTGTGTAT-3'; siRNA #3: 5'-GCTTCCATTACGATGCACAAA-3') were knocked down in TE-1 and KYSE150 cells, respectively.	('GC', 'Phenotype', 'HP:0012126', (74, 76))	('GC', 'Phenotype', 'HP:0012126', (35, 37))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('WHSC1L1', 'Gene', (138, 145))	('GC', 'Phenotype', 'HP:0012126', (81, 83))	('FGFR1', 'Gene', (11, 16))	('knocked down', 'Var', (269, 281))	('FGFR1', 'Gene', '2260', (11, 16))	('WHSC1L1', 'Gene', '54904', (138, 145))	('GC', 'Phenotype', 'HP:0012126', (120, 122))
833950	26833333	We observed no homology at TDs within ESCC genomes, further supporting the underlying mechanism that requires no microhomology or existence of nonhomology-based mechanism to form TDs and complex deletions in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('deletions', 'Var', (195, 204))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (208, 213))
833951	26833333	Across 31 ESCC genomes, we found that 3,376 SVs occurred in the region of genes and were predicted to directly disrupt sequence of gene such as CDKN2A (MIM: 600160), NOTCH1 (MIM: 190198), NF1 (MIM: 613113), and FANCD2 (MIM: 613984), and 492 genes contained a breakpoint in two or more tumors.	('NOTCH1', 'Gene', '4851', (166, 172))	('MIM: 190198', 'Var', (174, 185))	('MIM: 600160', 'Var', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('NOTCH1', 'Gene', (166, 172))	('NF1', 'Gene', (188, 191))	('CDKN2A', 'Gene', (144, 150))	('FANCD2', 'Gene', '2177', (211, 217))	('tumors', 'Disease', (285, 291))	('NF1', 'Gene', '4763', (188, 191))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('FANCD2', 'Gene', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('CDKN2A', 'Gene', '1029', (144, 150))	('MIM', 'Var', (193, 196))	('MIM: 613984', 'Var', (219, 230))
833952	26833333	Specifically, 29 out of 31 ESCCs harbored CDKN2A deletion; of which, 13 ESCCs had supporting SVs responsible for CDKN2A deletion and 2 out of these 13 genomes demonstrated complex deletions (ESCC-14T and ESCC-28T) (Figures 1B and S1).	('ESCC-14T', 'Var', (191, 199))	('CDKN2A', 'Gene', (113, 119))	('CDKN2A', 'Gene', (42, 48))	('CDKN2A', 'Gene', '1029', (113, 119))	('CDKN2A', 'Gene', '1029', (42, 48))	('ESCC-28T', 'Var', (204, 212))
833953	26833333	Notably, all deletions from tumor genomes of these 13 ESCCs were homozygous deletion with both focal deletion and arm-level loss.	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('deletions', 'Var', (13, 22))
833955	26833333	In addition, we also found that NOTCH1 was directly disrupted by TDs in two ESCCs (Figure S2).	('TDs', 'Var', (65, 68))	('NOTCH1', 'Gene', '4851', (32, 38))	('NOTCH1', 'Gene', (32, 38))
833965	26833333	In addition to general transition between two copy number states, we found a high-level focal amplification (<500 kb, 38,155,351-38,570,827 Mb) rearranged by chromothripsis on chromosome 8p that corresponds to FGFR1 and LETM2 in this tumor.	('FGFR1', 'Gene', '2260', (210, 215))	('tumor', 'Disease', (234, 239))	('chromothripsis', 'Disease', 'MESH:D000072837', (158, 172))	('rearranged', 'Var', (144, 154))	('FGFR1', 'Gene', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('chromothripsis', 'Disease', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('LETM2', 'Gene', '137994', (220, 225))	('LETM2', 'Gene', (220, 225))
833966	26833333	Importantly, no breakpoints were observed within this amplified region, suggesting a strong positive selection of FGFR1 and LETM2 amplifications during ESCC progression/evolution.	('amplifications', 'Var', (130, 144))	('LETM2', 'Gene', (124, 129))	('FGFR1', 'Gene', '2260', (114, 119))	('LETM2', 'Gene', '137994', (124, 129))	('FGFR1', 'Gene', (114, 119))
833972	26833333	Further functional studies indicated that knockdown of FGFR1 dramatically suppressed cell proliferation, cell migration, and invasion in TE-1 and KYSE150 cells (Figures S5A-S5C).	('FGFR1', 'Gene', '2260', (55, 60))	('cell migration', 'CPA', (105, 119))	('cell proliferation', 'CPA', (85, 103))	('suppressed', 'NegReg', (74, 84))	('FGFR1', 'Gene', (55, 60))	('invasion', 'CPA', (125, 133))	('knockdown', 'Var', (42, 51))
833982	26833333	Our result showed that LETM2 knockdown prevented cell proliferation but had no statistical suppression of cell migration and invasion in KYSE150 and ECA109 cells (Figure 2F).	('prevented', 'NegReg', (39, 48))	('knockdown', 'Var', (29, 38))	('LETM2', 'Gene', '137994', (23, 28))	('LETM2', 'Gene', (23, 28))	('cell proliferation', 'CPA', (49, 67))	('suppression', 'NegReg', (91, 102))	('cell migration', 'CPA', (106, 120))
833985	26833333	This fusion variant was predicted to result in an in-frame fusion of the TRAPPC9 5' UTR and exon 1-18 with the CLVS1 exon 4-5 and 3' UTR (Figure 3A).	('variant', 'Var', (12, 19))	('TRAPPC9', 'Gene', '83696', (73, 80))	('CLVS1', 'Gene', (111, 116))	('result in', 'Reg', (37, 46))	('TRAPPC9', 'Gene', (73, 80))	('CLVS1', 'Gene', '157807', (111, 116))
833993	26833333	The first exon of EIF3E on chromosome 8, encoding the eukaryotic translation initiation factor 3 subunit, was predicted to join with the last two exons of RAD51B on chromosome 14, a protein that catalyzes repair of DSBs through the process of homologous recombination and are critical for genome stability (Figure 3D).	('RAD51B', 'Gene', '5890', (155, 161))	('RAD51B', 'Gene', (155, 161))	('EIF3E', 'Gene', (18, 23))	('EIF3E', 'Gene', '3646', (18, 23))	('DSBs', 'Var', (215, 219))
833998	26833333	Interestingly, translocation of RAD51B with other genes has been reported, for example, HMGA2-RAD51B in uterine leiomyoma.	('HMGA2', 'Gene', '8091', (88, 93))	('RAD51B', 'Gene', (94, 100))	('RAD51B', 'Gene', '5890', (94, 100))	('HMGA2', 'Gene', (88, 93))	('RAD51B', 'Gene', '5890', (32, 38))	('RAD51B', 'Gene', (32, 38))	('leiomyoma', 'Disease', (112, 121))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (104, 121))	('translocation', 'Var', (15, 28))	('leiomyoma', 'Disease', 'MESH:D007889', (112, 121))
834000	26833333	Since the N- and C-terminal domains of RAD51B were important to interact with other proteins to catalyze the repair of DNA double-strand breaks, we speculate that the in-frame fusions of EIF3E-RAD51B might cause disruption of EIF3E and RAD51B function, which could result in deregulated homologous recombination or translation initiation, contributing to the tumorigenesis of ESCC.	('deregulated', 'Reg', (275, 286))	('contributing', 'Reg', (339, 351))	('RAD51B', 'Gene', (193, 199))	('EIF3E', 'Gene', '3646', (226, 231))	('RAD51B', 'Gene', '5890', (236, 242))	('EIF3E', 'Gene', (187, 192))	('homologous recombination', 'MPA', (287, 311))	('ESCC', 'Disease', (376, 380))	('EIF3E', 'Gene', '3646', (187, 192))	('translation initiation', 'MPA', (315, 337))	('RAD51B', 'Gene', (39, 45))	('tumor', 'Disease', (359, 364))	('cause', 'Reg', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('RAD51B', 'Gene', '5890', (193, 199))	('RAD51B', 'Gene', (236, 242))	('function', 'MPA', (243, 251))	('fusions', 'Var', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('RAD51B', 'Gene', '5890', (39, 45))	('disruption', 'NegReg', (212, 222))	('EIF3E', 'Gene', (226, 231))
834009	26833333	analyzed the mutational signatures of 21 breast cancers and identified kataegis, a distinct hypermutation phenomenon, in 61% of breast cancers, indicating a direct relevance to tumor initiation and progression.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancers', 'Phenotype', 'HP:0003002', (41, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('breast cancers', 'Disease', 'MESH:D001943', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancers', 'Disease', (41, 55))	('tumor initiation', 'Disease', 'MESH:D009369', (177, 193))	('breast cancers', 'Phenotype', 'HP:0003002', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('kataegis', 'Var', (71, 79))	('breast cancers', 'Disease', 'MESH:D001943', (128, 142))	('breast cancers', 'Disease', (128, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('tumor initiation', 'Disease', (177, 193))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
834014	26833333	Notably, fold-back inversions on chromosome 11 enriched in a minor cluster around CCND1 locus (69,455,873-69,469,242 Mb) at 11q11.3 (Figure 5D).	('fold-back inversions', 'Var', (9, 29))	('CCND1', 'Gene', (82, 87))	('CCND1', 'Gene', '595', (82, 87))	('69,455,873-69,469,242', 'Var', (95, 116))
834018	26833333	Amplification of CCND1 has been reported in a variety of tumors and might contribute to tumorigenesis.	('Amplification', 'Var', (0, 13))	('CCND1', 'Gene', '595', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('contribute', 'Reg', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('reported', 'Reg', (32, 40))	('tumor', 'Disease', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumor', 'Disease', (57, 62))	('CCND1', 'Gene', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
834021	26833333	Our results demonstrated that at least two mutational mechanisms, focal amplification via BFB cycles and inter-chromosomal translocations, result in CCND1 amplification in ESCC.	('amplification', 'Var', (155, 168))	('result in', 'Reg', (139, 148))	('CCND1', 'Gene', (149, 154))	('CCND1', 'Gene', '595', (149, 154))	('ESCC', 'Disease', (172, 176))
834022	26833333	Additionally, we observed that regions amplified by BFB cycles harbor oncogenes such as EGFR (MIM: 131550) (2/31), ERBB2 (MIM: 164870) (1/31), MMPs (1/31), and MYC (MIM: 190080) (1/31) (Figure 6), suggesting that BFB plays an important role in gene amplification in ESCC tumors.	('ESCC tumors', 'Disease', 'MESH:D004938', (266, 277))	('MIM: 164870', 'Var', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('BFB', 'Gene', (52, 55))	('MYC', 'Gene', '4609', (160, 163))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('MYC', 'Gene', (160, 163))	('EGFR', 'Gene', '1956', (88, 92))	('ERBB2', 'Gene', '2064', (115, 120))	('ESCC tumors', 'Disease', (266, 277))	('ERBB2', 'Gene', (115, 120))	('EGFR', 'Gene', (88, 92))
834024	26833333	EGFR is an established therapeutic target that is often overexpressed as a consequence of gene amplification in human cancers including ESCCs.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('EGFR', 'Gene', (0, 4))	('ESCCs', 'Disease', (136, 141))	('gene amplification', 'Var', (90, 108))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('human', 'Species', '9606', (112, 117))	('EGFR', 'Gene', '1956', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
834029	26833333	Consistently, frequent arm-level changes were observed in ESCC, including frequent copy-number gains of 3q, 5p, 7p, 8q, 12p, 17p, 20p, and 20q and universal deletions affecting 3p, 4p, 4q, 5q, 10p, 13q, and 21q (Figure S9A).	('deletions', 'Var', (157, 166))	('17p', 'Chemical', 'MESH:D000077713', (125, 128))	('ESCC', 'Disease', (58, 62))	('gains', 'PosReg', (95, 100))	('13q', 'Chemical', '-', (198, 201))
834032	26833333	This analysis yielded 11 amplification peaks and 13 deletion peaks, including cancer genes EGFR, CDK6 (MIM: 603368), AKT1 (MIM: 164730), MYC, CCND1, CDKN2A, and others (Table S6).	('CCND1', 'Gene', (142, 147))	('CDKN2A', 'Gene', '1029', (149, 155))	('EGFR', 'Gene', (91, 95))	('CDK6', 'Gene', '1021', (97, 101))	('AKT1', 'Gene', '207', (117, 121))	('CCND1', 'Gene', '595', (142, 147))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('MIM: 164730', 'Var', (123, 134))	('MYC', 'Gene', '4609', (137, 140))	('AKT1', 'Gene', (117, 121))	('amplification', 'MPA', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('CDK6', 'Gene', (97, 101))	('CDKN2A', 'Gene', (149, 155))	('MYC', 'Gene', (137, 140))	('EGFR', 'Gene', '1956', (91, 95))
834037	26833333	Moreover, CDCA7 knockdown led to the decrease of phospho-ERK1/2, an essential downstream component of MAPK pathway regulating cell proliferation, whereas no significant effect was seen in AKT pathway (Figure 8A).	('decrease', 'NegReg', (37, 45))	('ERK1/2', 'Gene', (57, 63))	('knockdown', 'Var', (16, 25))	('AKT', 'Gene', '207', (188, 191))	('ERK1/2', 'Gene', '5595;5594', (57, 63))	('CDCA7', 'Gene', (10, 15))	('AKT', 'Gene', (188, 191))
834038	26833333	Indeed, we observed a positive and highly significant enrichment of the expression of cell proliferation or apoptosis-associated target genes, including FGF21 ([MIM: 609436] a MAPK pathway-related gene) and cell-apoptosis-associated genes TRAIL-R, CASP10 (MIM: 601762), IL1R1 (MIM: 147810), CASP7 (MIM: 601761), BCL2 (MIM: 151430), and CASP9 (MIM: 602234).	('MIM: 601761', 'Var', (298, 309))	('CASP10', 'Gene', '843', (248, 254))	('CASP9', 'Gene', '842', (336, 341))	('BCL2', 'Gene', (312, 316))	('IL1R1', 'Gene', '3554', (270, 275))	('FGF21', 'Gene', '26291', (153, 158))	('CASP7', 'Gene', '840', (291, 296))	('FGF21', 'Gene', (153, 158))	('CASP10', 'Gene', (248, 254))	('TRAIL-R', 'Gene', (239, 246))	('MIM: 602234', 'Var', (343, 354))	('MIM: 601762', 'Var', (256, 267))	('CASP9', 'Gene', (336, 341))	('MIM: 147810', 'Var', (277, 288))	('MIM: 151430', 'Var', (318, 329))	('IL1R1', 'Gene', (270, 275))	('BCL2', 'Gene', '596', (312, 316))	('CASP7', 'Gene', (291, 296))
834040	26833333	In addition, CDCA7 knockdown led to the increased expression levels of TRAIL-R, CASP10, IL1R1, and CASP7 and the decreased expression levels of BCL2 and CASP9 (Figure 8E and Table S8), indicating that these genes might be critical for CDCA7 to regulate cell apoptosis.	('expression levels', 'MPA', (123, 140))	('CASP7', 'Gene', (99, 104))	('IL1R1', 'Gene', '3554', (88, 93))	('knockdown', 'Var', (19, 28))	('BCL2', 'Gene', (144, 148))	('CASP9', 'Gene', (153, 158))	('expression levels', 'MPA', (50, 67))	('TRAIL-R', 'Gene', (71, 78))	('CASP10', 'Gene', (80, 86))	('increased', 'PosReg', (40, 49))	('CASP7', 'Gene', '840', (99, 104))	('CDCA7', 'Gene', (13, 18))	('CASP9', 'Gene', '842', (153, 158))	('IL1R1', 'Gene', (88, 93))	('decreased', 'NegReg', (113, 122))	('BCL2', 'Gene', '596', (144, 148))	('CASP10', 'Gene', '843', (80, 86))
834043	26833333	Furthermore, our data provide the potential mechanisms for oncogene amplification or fusion gene formation, which might be critical for tumorigenesis of ESCC.	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('oncogene amplification', 'Var', (59, 81))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('fusion gene formation', 'Var', (85, 106))	('tumor', 'Disease', (136, 141))	('ESCC', 'Disease', (153, 157))
834044	26833333	In studying SVs across ESCC genomes, we observed locally rearranged SVs with either limited (e.g., chromothripsis or kataegis) or substantial (e.g., BFB) copy-number states (Figure S3).	('chromothripsis', 'Disease', (99, 113))	('copy-number', 'Var', (154, 165))	('chromothripsis', 'Disease', 'MESH:D000072837', (99, 113))
834047	26833333	Besides copy-number alterations, translocations in chromothripsis led to gene fusions (e.g., TRAPPC9-CLVS1, EIF3E-RAD51B) (Figure S3).	('led to', 'Reg', (66, 72))	('CLVS1', 'Gene', '157807', (101, 106))	('chromothripsis', 'Disease', (51, 65))	('RAD51B', 'Gene', (114, 120))	('RAD51B', 'Gene', '5890', (114, 120))	('translocations', 'Var', (33, 47))	('TRAPPC9', 'Gene', '83696', (93, 100))	('CLVS1', 'Gene', (101, 106))	('EIF3E', 'Gene', (108, 113))	('TRAPPC9', 'Gene', (93, 100))	('chromothripsis', 'Disease', 'MESH:D000072837', (51, 65))	('EIF3E', 'Gene', '3646', (108, 113))	('gene fusions', 'MPA', (73, 85))
834062	26833333	Although TP53, which has been linked to chromothripsis in human cancers, was mutated at high frequency in both ESCC and EAC, we found that the frequency of chromothripsis tended to be lower in ESCC than in EAC.	('ESCC', 'Disease', (193, 197))	('human', 'Species', '9606', (58, 63))	('EAC', 'Phenotype', 'HP:0011459', (206, 209))	('EAC', 'Phenotype', 'HP:0011459', (120, 123))	('mutated', 'Var', (77, 84))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('TP53', 'Gene', '7157', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('TP53', 'Gene', (9, 13))	('cancers', 'Disease', (64, 71))	('chromothripsis', 'Disease', (156, 170))	('lower', 'NegReg', (184, 189))	('chromothripsis', 'Disease', (40, 54))	('chromothripsis', 'Disease', 'MESH:D000072837', (156, 170))	('chromothripsis', 'Disease', 'MESH:D000072837', (40, 54))	('ESCC', 'Disease', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
834071	26833333	The whole-genome sequencing data of 31 pairs of tumors and matched normal tissues reported in this paper have been deposited to the European Genome-phenome Archive (EGA) under accession numbers EGAS00001001487 and EGAS00001000709.	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('EGAS00001000709', 'Var', (214, 229))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
834079	24705451	The sensitivity and specificity of MRI for identifying cancer vs. no-cancer was 89.1% and 80% respectively, as compared to 45.5% and 57.5% for endoscopy.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('MRI', 'Var', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', (55, 61))
834164	32357936	Several dosimetric parameters correlated with the risk of esophagitis (Dmax, Dmean, D5cc, V20, V30, V35, V40).	('V40', 'Var', (105, 108))	('V20', 'Var', (90, 93))	('esophagitis', 'Phenotype', 'HP:0100633', (58, 69))	('esophagitis', 'Disease', (58, 69))	('Dmean', 'Chemical', '-', (77, 82))	('V35', 'Gene', '28474', (100, 103))	('correlated', 'Reg', (30, 40))	('V30', 'Var', (95, 98))	('Dmax', 'Chemical', '-', (71, 75))	('esophagitis', 'Disease', 'MESH:D004938', (58, 69))	('V35', 'Gene', (100, 103))	('D5cc', 'Var', (84, 88))
834206	32357936	As displayed in Table 2, several dosimetric parameters correlated with the risk of esophagitis (Dmax, Dmean, D5cc, V20, V30, V35, V40).	('V35', 'Gene', (125, 128))	('correlated', 'Reg', (55, 65))	('Dmax', 'Chemical', '-', (96, 100))	('V40', 'Var', (130, 133))	('Dmean', 'Chemical', '-', (102, 107))	('V20', 'Var', (115, 118))	('esophagitis', 'Phenotype', 'HP:0100633', (83, 94))	('esophagitis', 'Disease', (83, 94))	('V35', 'Gene', '28474', (125, 128))	('esophagitis', 'Disease', 'MESH:D004938', (83, 94))	('V30', 'Var', (120, 123))	('D5cc', 'Var', (109, 113))
834207	32357936	Furthermore, concomitant chemotherapy significantly increased the risk of esophagitis (e.g., for Dmax > 39 Gy from 23 to 46%), while oral steroid medication reduced it.	('Dmax > 39 Gy', 'Var', (97, 109))	('Dmax', 'Chemical', '-', (97, 101))	('esophagitis', 'Disease', 'MESH:D004938', (74, 85))	('steroid', 'Chemical', 'MESH:D013256', (138, 145))	('esophagitis', 'Disease', (74, 85))	('esophagitis', 'Phenotype', 'HP:0100633', (74, 85))
834209	32357936	The significant variables shown in Table 2 were carried forward to multi-nominal logistic regression analysis, which demonstrated that concomitant chemotherapy (odds ratio 3.7 (1.1-12.4), p = 0.03), lack of steroid medication (odds ratio 4.4 (1.1-17.2), p = 0.04) and Dmax (odds ratio 1.1 (1.01-1.20), p = 0.025) were associated with higher rates of esophagitis.	('esophagitis', 'Phenotype', 'HP:0100633', (350, 361))	('esophagitis', 'Disease', (350, 361))	('Dmax', 'Chemical', '-', (268, 272))	('Dmax', 'Var', (268, 272))	('steroid', 'Chemical', 'MESH:D013256', (207, 214))	('esophagitis', 'Disease', 'MESH:D004938', (350, 361))
834212	32357936	With Dmean <=20 Gy 65% of patients remained free from esophagitis, compared to only 31% if Dmean exceeded 20 Gy (p = 0.02, 2-tailed Fisher exact probability test).	('Dmean <=20 Gy', 'Var', (5, 18))	('Dmean', 'Chemical', '-', (5, 10))	('free', 'Disease', (44, 48))	('Dmean', 'Chemical', '-', (91, 96))	('esophagitis', 'Disease', 'MESH:D004938', (54, 65))	('patients', 'Species', '9606', (26, 34))	('esophagitis', 'Disease', (54, 65))	('esophagitis', 'Phenotype', 'HP:0100633', (54, 65))
834227	32357936	Treatment-related grade >= 3 dysphagia and esophagitis occurred in 3 and 5% of patients in the 60-Gy-arm versus 12 and 17% in the 74-Gy-arm, respectively (p = 0.0005 and < 0.0001).	('60-Gy-arm', 'Var', (95, 104))	('dysphagia', 'Disease', 'MESH:D003680', (29, 38))	('dysphagia', 'Disease', (29, 38))	('esophagitis', 'Disease', 'MESH:D004938', (43, 54))	('dysphagia', 'Phenotype', 'HP:0002015', (29, 38))	('patients', 'Species', '9606', (79, 87))	('men', 'Species', '9606', (5, 8))	('esophagitis', 'Phenotype', 'HP:0100633', (43, 54))	('esophagitis', 'Disease', (43, 54))
834238	32357936	In own patients with high Dmax, a reduction of Dmean was associated with lower rates of esophagitis.	('Dmean', 'MPA', (47, 52))	('Dmean', 'Chemical', '-', (47, 52))	('high', 'Var', (21, 25))	('esophagitis', 'Disease', 'MESH:D004938', (88, 99))	('Dmax', 'Chemical', '-', (26, 30))	('reduction', 'NegReg', (34, 43))	('esophagitis', 'Phenotype', 'HP:0100633', (88, 99))	('lower', 'NegReg', (73, 78))	('esophagitis', 'Disease', (88, 99))	('patients', 'Species', '9606', (7, 15))
834264	31740661	HIC-5 knockdown in CAFs inhibited the migration and invasion of ESCC cells in vitro.	('HIC-5', 'Gene', '7041', (0, 5))	('HIC-5', 'Gene', (0, 5))	('ESCC', 'Disease', (64, 68))	('CAF', 'Gene', (19, 22))	('inhibited', 'NegReg', (24, 33))	('CAF', 'Gene', '8850', (19, 22))	('knockdown', 'Var', (6, 15))	('ESCC', 'Disease', 'MESH:C562729', (64, 68))
834265	31740661	Supernatant CCL2 levels of CAFs were significantly higher after TGF-beta stimulation and lower after knocking down HIC-5 expression, independent of TGF-beta treatment.	('lower', 'NegReg', (89, 94))	('TGF-beta', 'Gene', '7040', (148, 156))	('knocking down', 'Var', (101, 114))	('TGF-beta', 'Gene', (148, 156))	('expression', 'MPA', (121, 131))	('CCL2', 'Gene', '6347', (12, 16))	('CAF', 'Gene', (27, 30))	('TGF-beta', 'Gene', (64, 72))	('HIC-5', 'Gene', (115, 120))	('TGF-beta', 'Gene', '7040', (64, 72))	('HIC-5', 'Gene', '7041', (115, 120))	('CCL2', 'Gene', (12, 16))	('higher', 'PosReg', (51, 57))	('CAF', 'Gene', '8850', (27, 30))
834284	31740661	Hydrogen peroxide-inducible clone 5 (HIC-5), also known as transforming growth factor beta-1-induced transcript 1 (TGFbeta1i1), was first identified to be induced by H2O2 and TGF-beta1.	('HIC-5', 'Gene', (37, 42))	('TGFbeta1i1', 'Gene', '7041', (115, 125))	('Hydrogen peroxide-inducible clone 5', 'Gene', (0, 35))	('H2O2', 'Var', (166, 170))	('TGFbeta1i1', 'Gene', (115, 125))	('transforming growth factor beta-1-induced transcript 1', 'Gene', '7041', (59, 113))	('Hydrogen peroxide-inducible clone 5', 'Gene', '7041', (0, 35))	('H2O2', 'Chemical', 'MESH:D014867', (166, 170))	('TGF-beta1', 'Gene', '7040', (175, 184))	('HIC-5', 'Gene', '7041', (37, 42))	('TGF-beta1', 'Gene', (175, 184))
834351	31740661	Male sex (P = 0.002), moderate differentiation (P = 0.015), poor differentiation (P = 0.013), and high HIC-5 expression in the stroma (P = 0.002) were independent risk factors for lymph node metastasis according to multivariate logistic regression analysis (Supplementary Table S3).	('lymph node metastasis', 'CPA', (180, 201))	('expression', 'MPA', (109, 119))	('poor', 'CPA', (60, 64))	('HIC-5', 'Gene', '7041', (103, 108))	('high', 'Var', (98, 102))	('HIC-5', 'Gene', (103, 108))
834356	31740661	2e; P < 0.05) after co-culture with HIC-5 knockdown CAFs.	('CAF', 'Gene', '8850', (52, 55))	('HIC-5', 'Gene', (36, 41))	('CAF', 'Gene', (52, 55))	('HIC-5', 'Gene', '7041', (36, 41))	('knockdown', 'Var', (42, 51))
834360	31740661	Taken together, these results suggested that the expression of HIC-5 in CAFs might enhance esophageal cancer cell migration and invasion.	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('CAF', 'Gene', '8850', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('HIC-5', 'Gene', '7041', (63, 68))	('HIC-5', 'Gene', (63, 68))	('esophageal cancer', 'Disease', (91, 108))	('enhance', 'PosReg', (83, 90))	('CAF', 'Gene', (72, 75))	('invasion', 'CPA', (128, 136))	('expression', 'Var', (49, 59))
834361	31740661	RNA-seq and bioinformatics analyses were performed to analyze differentially expressed genes in HIC-5 knockdown CAFs and control CAFs.	('CAF', 'Gene', (112, 115))	('CAF', 'Gene', (129, 132))	('HIC-5', 'Gene', '7041', (96, 101))	('knockdown', 'Var', (102, 111))	('CAF', 'Gene', '8850', (112, 115))	('CAF', 'Gene', '8850', (129, 132))	('HIC-5', 'Gene', (96, 101))
834365	31740661	Overall, HIC-5 knockdown shifted the CAF gene expression profile to favor proliferation upregulation.	('knockdown', 'Var', (15, 24))	('CAF', 'Gene', (37, 40))	('upregulation', 'PosReg', (88, 100))	('HIC-5', 'Gene', '7041', (9, 14))	('CAF', 'Gene', '8850', (37, 40))	('proliferation', 'CPA', (74, 87))	('HIC-5', 'Gene', (9, 14))
834369	31740661	3e, qRT-PCR demonstrated that the expression of CCL2, IL-1beta, and MMP2 were significantly downregulated in HIC-5 knockdown CAFs.	('CAF', 'Gene', (125, 128))	('IL-1beta', 'Gene', (54, 62))	('CCL2', 'Gene', '6347', (48, 52))	('HIC-5', 'Gene', (109, 114))	('expression', 'MPA', (34, 44))	('knockdown', 'Var', (115, 124))	('MMP2', 'Gene', '4313', (68, 72))	('IL-1beta', 'Gene', '3553', (54, 62))	('CCL2', 'Gene', (48, 52))	('CAF', 'Gene', '8850', (125, 128))	('MMP2', 'Gene', (68, 72))	('HIC-5', 'Gene', '7041', (109, 114))	('downregulated', 'NegReg', (92, 105))
834372	31740661	Supernatant CCL2 levels were significantly higher after TGF-beta stimulation and, notably, were lower after knocking down HIC-5 expression, independent of TGF-beta treatment (Fig.	('HIC-5', 'Gene', '7041', (122, 127))	('TGF-beta', 'Gene', '7040', (56, 64))	('HIC-5', 'Gene', (122, 127))	('TGF-beta', 'Gene', (155, 163))	('higher', 'PosReg', (43, 49))	('lower', 'NegReg', (96, 101))	('TGF-beta', 'Gene', (56, 64))	('CCL2', 'Gene', '6347', (12, 16))	('knocking down', 'Var', (108, 121))	('expression', 'MPA', (128, 138))	('CCL2', 'Gene', (12, 16))	('TGF-beta', 'Gene', '7040', (155, 163))
834376	31740661	Both tumor volume and tumor weight showed no statistic difference between the HIC-5 knockdown CAFs group and the control group (Fig.	('CAF', 'Gene', '8850', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('knockdown', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (5, 10))	('CAF', 'Gene', (94, 97))	('HIC-5', 'Gene', '7041', (78, 83))	('HIC-5', 'Gene', (78, 83))
834380	31740661	Besides, in consistence with prior observation, CCL2 expression in tumors was also downregulated when knocking down HIC-5 in CAFs.	('HIC-5', 'Gene', '7041', (116, 121))	('CCL2', 'Gene', '6347', (48, 52))	('HIC-5', 'Gene', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('CAF', 'Gene', '8850', (125, 128))	('knocking down', 'Var', (102, 115))	('CCL2', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('downregulated', 'NegReg', (83, 96))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('expression', 'MPA', (53, 63))	('tumors', 'Disease', (67, 73))	('CAF', 'Gene', (125, 128))
834385	31740661	HIC-5 knockdown increased the cell migration rate in CAFs but did not have the same impact on NFs, which was demonstrated through both wound-healing assays (Fig.	('HIC-5', 'Gene', '7041', (0, 5))	('HIC-5', 'Gene', (0, 5))	('CAF', 'Gene', (53, 56))	('CAF', 'Gene', '8850', (53, 56))	('increased', 'PosReg', (16, 25))	('cell migration rate', 'CPA', (30, 49))	('knockdown', 'Var', (6, 15))
834386	31740661	HIC-5 knockdown in CAFs substantially enhanced the expression of F-actin, as would be expected in the case of increased mobility (Fig.	('HIC-5', 'Gene', '7041', (0, 5))	('HIC-5', 'Gene', (0, 5))	('CAF', 'Gene', (19, 22))	('enhanced', 'PosReg', (38, 46))	('F-actin', 'Protein', (65, 72))	('CAF', 'Gene', '8850', (19, 22))	('expression', 'MPA', (51, 61))	('knockdown', 'Var', (6, 15))
834390	31740661	CAFs and NFs demonstrated a distinct pattern of expression alterations upon HIC-5 knockdown.	('expression', 'MPA', (48, 58))	('knockdown', 'Var', (82, 91))	('HIC-5', 'Gene', '7041', (76, 81))	('CAF', 'Gene', (0, 3))	('CAF', 'Gene', '8850', (0, 3))	('HIC-5', 'Gene', (76, 81))	('alterations', 'Reg', (59, 70))
834396	31740661	RAC1 expression was dramatically higher in HIC-5 knockdown CAFs than in control CAFs, but was not different between the two NF groups (Fig.	('HIC-5', 'Gene', (43, 48))	('knockdown', 'Var', (49, 58))	('expression', 'MPA', (5, 15))	('higher', 'PosReg', (33, 39))	('CAF', 'Gene', '8850', (80, 83))	('CAF', 'Gene', (59, 62))	('RAC1', 'Gene', '5879', (0, 4))	('HIC-5', 'Gene', '7041', (43, 48))	('RAC1', 'Gene', (0, 4))	('CAF', 'Gene', '8850', (59, 62))	('CAF', 'Gene', (80, 83))
834424	31740661	Moreover, SMAD2 depletion enhances SMAD3 activity and vice versa, indicating a dynamic balance between these two mediators to regulate cell activities.	('SMAD2', 'Gene', '4087', (10, 15))	('depletion', 'Var', (16, 25))	('SMAD2', 'Gene', (10, 15))	('SMAD3', 'Gene', '4088', (35, 40))	('SMAD3', 'Gene', (35, 40))	('enhances', 'PosReg', (26, 34))	('activity', 'MPA', (41, 49))
834425	31740661	We found that SMAD2 phosphorylation was increased and that SMAD3 phosphorylation was decreased when HIC-5 was knocked down in CAFs, whereas SMAD2/3 phosphorylation was not significantly different in NFs.	('SMAD2', 'Gene', (140, 145))	('decreased', 'NegReg', (85, 94))	('SMAD2', 'Gene', '4087', (140, 145))	('SMAD3', 'Gene', '4088', (59, 64))	('SMAD2', 'Gene', (14, 19))	('SMAD3', 'Gene', (59, 64))	('SMAD2', 'Gene', '4087', (14, 19))	('CAF', 'Gene', (126, 129))	('HIC-5', 'Gene', '7041', (100, 105))	('HIC-5', 'Gene', (100, 105))	('phosphorylation', 'MPA', (20, 35))	('SMAD2/3', 'Gene', '4087;4088', (140, 147))	('increased', 'PosReg', (40, 49))	('knocked down', 'Var', (110, 122))	('CAF', 'Gene', '8850', (126, 129))	('SMAD2/3', 'Gene', (140, 147))
834433	31740661	We identified that RAC1 was dramatically upregulated in HIC-5 knockdown CAFs compared with that in control CAFs, but displayed little if any differences between the two NF groups.	('RAC1', 'Gene', '5879', (19, 23))	('CAF', 'Gene', '8850', (72, 75))	('CAF', 'Gene', '8850', (107, 110))	('HIC-5', 'Gene', '7041', (56, 61))	('RAC1', 'Gene', (19, 23))	('upregulated', 'PosReg', (41, 52))	('HIC-5', 'Gene', (56, 61))	('CAF', 'Gene', (72, 75))	('CAF', 'Gene', (107, 110))	('knockdown', 'Var', (62, 71))
834435	31740661	Several metabolic pathways were altered according to the RNA-seq analysis comparing HIC-5 knockdown CAFs and control CAFs.	('CAF', 'Gene', '8850', (117, 120))	('knockdown', 'Var', (90, 99))	('metabolic pathways', 'Pathway', (8, 26))	('altered', 'Reg', (32, 39))	('CAF', 'Gene', (100, 103))	('HIC-5', 'Gene', '7041', (84, 89))	('HIC-5', 'Gene', (84, 89))	('CAF', 'Gene', (117, 120))	('CAF', 'Gene', '8850', (100, 103))
834440	31740661	Our RNA-seq data showed that silencing HIC-5 in CAFs altered several metabolic pathways, including the FoxO signaling pathway and the AMPK signaling pathway, which indicates that HIC-5 may participate in crosstalk between CAFs and cancer cells by influencing the production of metabolites.	('metabolic pathways', 'Pathway', (69, 87))	('CAF', 'Gene', (222, 225))	('production of metabolites', 'MPA', (263, 288))	('HIC-5', 'Gene', (39, 44))	('silencing', 'Var', (29, 38))	('cancer', 'Disease', (231, 237))	('altered', 'Reg', (53, 60))	('HIC-5', 'Gene', '7041', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('FoxO signaling pathway', 'Pathway', (103, 125))	('influencing', 'Reg', (247, 258))	('HIC-5', 'Gene', (179, 184))	('participate', 'Reg', (189, 200))	('AMPK signaling pathway', 'Pathway', (134, 156))	('CAF', 'Gene', '8850', (48, 51))	('HIC-5', 'Gene', '7041', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('CAF', 'Gene', '8850', (222, 225))	('CAF', 'Gene', (48, 51))
834446	31740661	NFs did not demonstrate significant changes in cell movement abilities upon HIC-5 interference, likely due to their quiescent status in the absence of cancer cell stimulation.	('cell movement', 'CPA', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('interference', 'Var', (82, 94))	('HIC-5', 'Gene', '7041', (76, 81))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('HIC-5', 'Gene', (76, 81))
834462	29422263	Using aldehyde-induced adducts to monitor AUD may also be important when considering that approximately 540 million people bear a genetic variant of aldehyde dehydrogenase 2 (ALDH2), predisposing this population to aldehyde-induced toxicity with alcohol use.	('toxicity', 'Disease', (232, 240))	('alcohol', 'Chemical', 'MESH:D000438', (246, 253))	('aldehyde', 'Chemical', 'MESH:D000447', (149, 157))	('ALDH2', 'Gene', '217', (175, 180))	('aldehyde dehydrogenase 2', 'Gene', (149, 173))	('aldehyde', 'Chemical', 'MESH:D000447', (215, 223))	('predisposing', 'Reg', (183, 195))	('genetic variant', 'Var', (130, 145))	('AUD', 'Phenotype', 'HP:0030955', (42, 45))	('people', 'Species', '9606', (116, 122))	('ALDH2', 'Gene', (175, 180))	('aldehyde', 'Chemical', 'MESH:D000447', (6, 14))	('alcohol use', 'Phenotype', 'HP:0030955', (246, 257))	('toxicity', 'Disease', 'MESH:D064420', (232, 240))	('aldehyde dehydrogenase 2', 'Gene', '217', (149, 173))	('variant', 'Var', (138, 145))
834467	29422263	this is concerning as nearly 540 million people of East Asian descent are carriers of the aldehyde dehydrogenase 2 (ALDH2) genetic variant, ALDH2*2, and cannot metabolize acetaldehyde (the metabolite of alcohol) efficiently.	('metabolize acetaldehyde', 'MPA', (160, 183))	('variant', 'Var', (131, 138))	('ALDH2', 'Gene', '217', (140, 145))	('ALDH2', 'Gene', (116, 121))	('acetaldehyde', 'Chemical', 'MESH:D000079', (171, 183))	('ALDH2', 'Gene', (140, 145))	('not', 'NegReg', (156, 159))	('aldehyde dehydrogenase 2', 'Gene', '217', (90, 114))	('aldehyde dehydrogenase 2', 'Gene', (90, 114))	('alcohol', 'Chemical', 'MESH:D000438', (203, 210))	('ALDH2', 'Gene', '217', (116, 121))	('people', 'Species', '9606', (41, 47))
834492	29422263	The ROS produced causes lipid peroxidation of the cell membrane which forms toxic reactive aldehydes including malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE).	('HNE', 'Gene', (157, 160))	('lipid peroxidation of the cell membrane', 'MPA', (24, 63))	('ROS', 'Var', (4, 7))	('4-hydroxynonenal', 'Chemical', 'MESH:C027576', (137, 153))	('MDA', 'Chemical', 'MESH:D008315', (128, 131))	('ROS', 'Chemical', 'MESH:D017382', (4, 7))	('lipid', 'Chemical', 'MESH:D008055', (24, 29))	('causes', 'Reg', (17, 23))	('malondialdehyde', 'MPA', (111, 126))	('malondialdehyde', 'Chemical', 'MESH:D008315', (111, 126))	('HNE', 'Gene', '1991', (157, 160))	('reactive aldehydes', 'Chemical', '-', (82, 100))
834506	29422263	This occurs when aldehyde-induced protein adducts form on cytochrome CYP2E1 and function as an auto-feedback mechanism to reduce aldehyde accumulation.	('reduce', 'NegReg', (122, 128))	('protein', 'Protein', (34, 41))	('CYP2E1', 'Gene', (69, 75))	('adducts', 'Var', (42, 49))	('aldehyde', 'Chemical', 'MESH:D000447', (129, 137))	('aldehyde', 'Chemical', 'MESH:D000447', (17, 25))	('aldehyde accumulation', 'MPA', (129, 150))	('CYP2E1', 'Gene', '1571', (69, 75))
834512	29422263	Individuals with an ALDH2*2 genetic variant tend to limit alcohol consumption due to the unpleasant side effects of acetaldehyde accumulation, including elevated heart rate and facial flushing .	('ALDH2', 'Gene', '217', (20, 25))	('elevated heart rate', 'Phenotype', 'HP:0001649', (153, 172))	('acetaldehyde accumulation', 'Phenotype', 'HP:0003533', (116, 141))	('facial flushing', 'Disease', (177, 192))	('elevated', 'PosReg', (153, 161))	('variant', 'Var', (36, 43))	('alcohol', 'Chemical', 'MESH:D000438', (58, 65))	('acetaldehyde', 'Chemical', 'MESH:D000079', (116, 128))	('ALDH2', 'Gene', (20, 25))	('limit', 'NegReg', (52, 57))	('heart rate', 'MPA', (162, 172))	('rat', 'Species', '10116', (168, 171))	('alcohol consumption', 'MPA', (58, 77))	('facial flushing', 'Disease', 'MESH:D005483', (177, 192))	('acetaldehyde accumulation', 'MPA', (116, 141))	('flushing', 'Phenotype', 'HP:0031284', (184, 192))
834513	29422263	Although the ALDH2*2 genotype is considered to curb alcohol consumption, there are concerning trends that the number of heterozygotes for the ALDH2*2 genetic variant with AUD are steadily rising in East Asian countries.	('ALDH2', 'Gene', '217', (13, 18))	('ALDH2', 'Gene', '217', (142, 147))	('variant', 'Var', (158, 165))	('ALDH2', 'Gene', (13, 18))	('AUD', 'Phenotype', 'HP:0030955', (171, 174))	('rising', 'PosReg', (188, 194))	('ALDH2', 'Gene', (142, 147))	('alcohol', 'Chemical', 'MESH:D000438', (52, 59))
834514	29422263	Heterozygotes for the ALDH2*2 variant who consume alcohol are associated with an increased risk for developing head and neck related cancers, including esophageal cancer, compared to individuals with the ALDH2*1 variant.	('ALDH2', 'Gene', (204, 209))	('ALDH2', 'Gene', (22, 27))	('alcohol', 'Chemical', 'MESH:D000438', (50, 57))	('esophageal cancer', 'Disease', (152, 169))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('variant', 'Var', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('ALDH2', 'Gene', '217', (204, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('ALDH2', 'Gene', '217', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
834516	29422263	Consistent with these data, in human esophageal keratinocytes, a ~15 fold increase in N2-ethylidene-dG concentrations were observed upon siRNA knockdown of ALDH2 relative to untreated human keratinocytes in vitro.	('rat', 'Species', '10116', (110, 113))	('ALDH2', 'Gene', (156, 161))	('rat', 'Species', '10116', (50, 53))	('increase', 'PosReg', (74, 82))	('rat', 'Species', '10116', (192, 195))	('human', 'Species', '9606', (31, 36))	('N2-ethylidene-dG concentrations', 'MPA', (86, 117))	('N2-ethylidene-dG', 'Chemical', 'MESH:C525837', (86, 102))	('human', 'Species', '9606', (184, 189))	('knockdown', 'Var', (143, 152))	('ALDH2', 'Gene', '217', (156, 161))
834525	29422263	Individuals with an ALDH2*2 variant might receive lower scores on an AUDIT or AUDIT-C questionnaire since, as discussed, smaller quantities of alcohol produce intoxicating effects in individuals heterozygotic for ALDH2*2 compared to ALDH2*1.	('ALDH2', 'Gene', '217', (20, 25))	('ALDH2', 'Gene', '217', (213, 218))	('ALDH2', 'Gene', '217', (233, 238))	('ALDH2', 'Gene', (20, 25))	('intoxicating effects', 'MPA', (159, 179))	('ALDH2', 'Gene', (213, 218))	('alcohol', 'Chemical', 'MESH:D000438', (143, 150))	('AUD', 'Phenotype', 'HP:0030955', (78, 81))	('AUD', 'Phenotype', 'HP:0030955', (69, 72))	('ALDH2', 'Gene', (233, 238))	('variant', 'Var', (28, 35))
834539	29422263	These findings are relevant because hybrid adducts can cause increased development of scar tissue and fibrosis compared to individual adducts .	('fibrosis', 'Disease', 'MESH:D005355', (102, 110))	('fibrosis', 'Disease', (102, 110))	('scar', 'Phenotype', 'HP:0100699', (86, 90))	('hybrid', 'Var', (36, 42))	('men', 'Species', '9606', (78, 81))
834540	29422263	In addition, aldehyde-induced adducts can directly activate immune cells, Kupffer cells, and endothelial cells to produce profibrogenic mediators .	('adducts', 'Var', (30, 37))	('produce profibrogenic mediators', 'MPA', (114, 145))	('activate', 'PosReg', (51, 59))	('aldehyde', 'Chemical', 'MESH:D000447', (13, 21))	('immune cells', 'CPA', (60, 72))
834542	29422263	Autoimmunity to aldehyde-induced adducts might also be implicated in the pathogenesis of alcoholic liver disease.	('adducts', 'Var', (33, 40))	('Autoimmunity', 'Disease', (0, 12))	('aldehyde', 'Chemical', 'MESH:D000447', (16, 24))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (89, 112))	('alcoholic liver disease', 'Disease', (89, 112))	('Autoimmunity', 'Phenotype', 'HP:0002960', (0, 12))	('liver disease', 'Phenotype', 'HP:0001392', (99, 112))	('Autoimmunity', 'Disease', 'MESH:D001327', (0, 12))	('implicated', 'Reg', (55, 65))
834547	29422263	Although further studies are warranted, these studies taken together suggest that antibodies against aldehyde-induced protein adducts might have potential as putative biomarkers to stratify liver disease severity in AUD.	('rat', 'Species', '10116', (183, 186))	('aldehyde', 'Chemical', 'MESH:D000447', (101, 109))	('liver disease', 'Phenotype', 'HP:0001392', (190, 203))	('antibodies', 'Var', (82, 92))	('liver disease', 'Disease', (190, 203))	('liver disease', 'Disease', 'MESH:D008107', (190, 203))	('AUD', 'Phenotype', 'HP:0030955', (216, 219))
834549	29422263	Alcohol consumption associated with developing hepatocellular carcinoma is caused by transversion of p53 at codon 249 (by a G to T transversion).	('transversion', 'Var', (85, 97))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (47, 71))	('hepatocellular carcinoma', 'Disease', (47, 71))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (47, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
834560	29422263	Recently, an effective method of quantifying N2-ethyl-dG was developed using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) with hydrophobic interaction chromatography (HILIC) in order to improve the ionization efficiency of detecting N2-ethyl-dG.	('ionization', 'Disease', 'MESH:D004194', (112, 122))	('N2-ethyl-dG', 'Var', (274, 285))	('ionization', 'Disease', 'MESH:D004194', (239, 249))	('ionization', 'Disease', (112, 122))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (274, 285))	('improve', 'PosReg', (227, 234))	('ionization', 'Disease', (239, 249))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (45, 56))
834562	29422263	This is encouraging since a LC-ESI-MS/MS system may allow for quantification of N2-ethyl-dG without requiring additional tools such as a nano-electrospray interface in order to detect N2-ethyl-dG; potentially making N2-ethyl-dG quantification easier and more feasible .	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (80, 91))	('N2-ethyl-dG', 'Var', (184, 195))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (184, 195))	('detect', 'Reg', (177, 183))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (216, 227))
834567	29422263	Further application of this and similar methods may uncover a subset of the proteome and/or novel putative protein targets previously unrecognized to being modified by aldheyde-induced adducts.	('protein', 'Protein', (107, 114))	('adducts', 'Var', (185, 192))	('aldheyde', 'Chemical', '-', (168, 176))
834582	29422263	These modifications are called aldehyde-induced adducts and can lead to cellular damage that can potentially result in alcohol-induced complications such as cancer or cardiomyopathy.	('modifications', 'Var', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('lead to', 'Reg', (64, 71))	('alcohol', 'Chemical', 'MESH:D000438', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('result in', 'Reg', (109, 118))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (167, 181))	('cardiomyopathy', 'Disease', 'MESH:D009202', (167, 181))	('cellular', 'MPA', (72, 80))	('aldehyde', 'Chemical', 'MESH:D000447', (31, 39))	('cancer', 'Disease', (157, 163))	('cardiomyopathy', 'Disease', (167, 181))
834584	29422263	The ALDH2*2 variant severely limits aldehyde metabolism after alcohol consumption and results in facial flushing and tachycardia.	('facial flushing', 'Disease', (97, 112))	('ALDH2', 'Gene', '217', (4, 9))	('variant', 'Var', (12, 19))	('aldehyde', 'Chemical', 'MESH:D000447', (36, 44))	('limits', 'NegReg', (29, 35))	('tachycardia', 'Phenotype', 'HP:0001649', (117, 128))	('tachycardia', 'Disease', (117, 128))	('ALDH2', 'Gene', (4, 9))	('tachycardia', 'Disease', 'MESH:D013610', (117, 128))	('flushing', 'Phenotype', 'HP:0031284', (104, 112))	('facial flushing', 'Disease', 'MESH:D005483', (97, 112))	('alcohol', 'Chemical', 'MESH:D000438', (62, 69))	('results in', 'Reg', (86, 96))	('aldehyde metabolism', 'MPA', (36, 55))
834585	29422263	Frequent alcohol consumption by people heterozygous for the ALDH2*2 variant is associated with an increased risk of developing head and neck cancers, including esophageal cancer.	('alcohol', 'Chemical', 'MESH:D000438', (9, 16))	('ALDH2', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('neck cancers', 'Disease', 'MESH:D006258', (136, 148))	('head and neck cancers', 'Phenotype', 'HP:0012288', (127, 148))	('people', 'Species', '9606', (32, 38))	('esophageal cancer', 'Disease', (160, 177))	('variant', 'Var', (68, 75))	('Frequent alcohol consumption', 'Phenotype', 'HP:0030955', (0, 28))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('ALDH2', 'Gene', '217', (60, 65))	('neck cancers', 'Disease', (136, 148))
834600	29422263	ALDH2*2 The East Asian variant coding for ALDH2, caused by a single point mutation of guanine to adenine which decreases the ability to metabolize reactive aldehydes by 60-90% when compared to those carriers of the ALDH2*1 gene.	('mutation', 'Var', (74, 82))	('guanine', 'Chemical', 'MESH:D006147', (86, 93))	('reactive aldehydes', 'Chemical', '-', (147, 165))	('ability to metabolize reactive aldehydes', 'MPA', (125, 165))	('ALDH2', 'Gene', '217', (42, 47))	('ALDH2', 'Gene', (215, 220))	('ALDH2', 'Gene', (0, 5))	('adenine', 'Chemical', 'MESH:D000225', (97, 104))	('decreases', 'NegReg', (111, 120))	('ALDH2', 'Gene', (42, 47))	('ALDH2', 'Gene', '217', (215, 220))	('ALDH2', 'Gene', '217', (0, 5))
834603	29422263	CYP2E1 activity generates ROS that cause aldehyde formation through lipid peroxidation.	('lipid peroxidation', 'MPA', (68, 86))	('lipid', 'Chemical', 'MESH:D008055', (68, 73))	('CYP2E1', 'Gene', (0, 6))	('cause', 'Reg', (35, 40))	('aldehyde', 'Chemical', 'MESH:D000447', (41, 49))	('rat', 'Species', '10116', (20, 23))	('ROS', 'Var', (26, 29))	('CYP2E1', 'Gene', '1571', (0, 6))	('ROS', 'Chemical', 'MESH:D017382', (26, 29))	('aldehyde formation', 'MPA', (41, 59))
834637	29223109	aneuploidy, copy number alterations and deletion of the p16 tumor suppressor gene.	('p16', 'Gene', '1029', (56, 59))	('deletion', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('copy number alterations', 'Var', (12, 35))	('p16', 'Gene', (56, 59))	('tumor', 'Disease', (60, 65))	('aneuploidy', 'Var', (0, 10))
834641	29223109	We focused on neoplastic progression and found a set of genes representing potential biomarkers which might help to create a more standardized, reproducible and reliable diagnostic procedure in order to stratify patients with BE in terms of their risk to develop cancer.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Disease', (263, 269))	('patients', 'Species', '9606', (212, 220))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('genes', 'Var', (56, 61))	('BE', 'Phenotype', 'HP:0100580', (226, 228))
834689	29223109	INHBA overexpression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcinoma.	('cell proliferation', 'CPA', (30, 48))	('INHBA', 'Gene', '3624', (0, 5))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (88, 113))	('epigenetically regulated', 'Var', (60, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('promotes', 'PosReg', (21, 29))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('INHBA', 'Gene', (0, 5))
834690	29223109	Overexpression of activin A in esophageal squamous cell carcinoma has been associated with advanced nodal status, clinical stage, and a worse overall prognosis.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (31, 65))	('activin', 'Gene', '83729', (18, 25))	('esophageal squamous cell carcinoma', 'Disease', (31, 65))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('activin', 'Gene', (18, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
834714	29223109	Since retinoic acid regulates the proliferation, differentiation, and apoptosis of premalignant and malignant cells during carcinogenesis, it is conceivable that a disturbance of its formation leads to various disorders including malignancy.	('malignancy', 'Disease', 'MESH:D009369', (230, 240))	('disturbance', 'Var', (164, 175))	('malignancy', 'Disease', (230, 240))	('retinoic acid', 'Chemical', 'MESH:D014212', (6, 19))	('leads to', 'Reg', (193, 201))	('apoptosis', 'CPA', (70, 79))	('disorders', 'Disease', (210, 219))
834726	29223109	Aberrant expression of REG4 was associated with the growth, survival, adhesion and resistance to apoptosis of tumor cells (e.g.).	('survival', 'CPA', (60, 68))	('Aberrant expression', 'Var', (0, 19))	('growth', 'CPA', (52, 58))	('REG4', 'Gene', (23, 27))	('adhesion', 'CPA', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('REG4', 'Gene', '83998', (23, 27))	('associated', 'Reg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
834728	29223109	Patients suffering from esophageal cancer with an amplification of GATA6 have a poorer survival.	('amplification', 'Var', (50, 63))	('esophageal cancer', 'Disease', (24, 41))	('GATA6', 'Gene', (67, 72))	('GATA6', 'Gene', '2627', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('Patients', 'Species', '9606', (0, 8))
834759	29888281	ME-NBI (Olympus Medical System Corporation, Tokyo, Japan) reported that, in patients at high risk for developing ESCC, ME-NBI can improve the diagnosis of esophageal neoplasia.	('improve', 'PosReg', (130, 137))	('ESCC', 'Disease', (113, 117))	('ME-NBI', 'Var', (119, 125))	('neoplasia', 'Phenotype', 'HP:0002664', (166, 175))	('esophageal neoplasia', 'Phenotype', 'HP:0100751', (155, 175))	('esophageal neoplasia', 'Disease', (155, 175))	('esophageal neoplasia', 'Disease', 'MESH:D009369', (155, 175))
834766	29888281	Diagnostic ME-NBI was performed in studies with a magnifying endoscope (GIF-H260Z or GIF-Q240Z; Olympus) and a 19-in high-resolution liquid-crystal monitor (OEV191H; Olympus).	('Q240Z', 'Var', (89, 94))	('H260Z', 'Var', (76, 81))	('H260Z', 'SUBSTITUTION', 'None', (76, 81))	('Q240Z', 'SUBSTITUTION', 'None', (89, 94))
834803	28161553	Esophageal dose was primarily defined by D2cc (the minimum dose to the most exposed 2cc of the esophagus), and lung dose by V20Gy (the volume of both lungs not involved with gross disease that received at least 20Gy), both of which have been previously correlated with toxicity.	('toxicity', 'Disease', 'MESH:D064420', (269, 277))	('toxicity', 'Disease', (269, 277))	('D2cc', 'Chemical', '-', (41, 45))	('V20Gy', 'Var', (124, 129))	('D2cc', 'Var', (41, 45))	('lung', 'MPA', (111, 115))
834843	28161553	The rate of pneumonitis in the UM Cohort was 32/125(25%) and 11/125(9%), respectively, for Grades >=2 and >=3.	('pneumonitis', 'Disease', (12, 23))	('>=3', 'Var', (106, 109))	('pneumonitis', 'Disease', 'MESH:D011014', (12, 23))
834906	32308595	Computed tomography and esophagogastroduodenoscopy revealed esophageal squamous cell carcinoma with metastatic mediastinal and abdominal para-aortic lymph nodes, clinical stage IVB, cT4bN2M1, according to the Union for International Cancer Control eighth edition.	('cT4bN2M1', 'Var', (182, 190))	('esophageal squamous cell carcinoma', 'Disease', (60, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('Cancer', 'Disease', 'MESH:D009369', (233, 239))	('Cancer', 'Disease', (233, 239))	('Cancer', 'Phenotype', 'HP:0002664', (233, 239))	('abdominal para-aortic lymph', 'Disease', 'MESH:D017544', (127, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('abdominal para-aortic lymph', 'Disease', (127, 154))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (60, 94))
834914	32308595	Chromosomal test revealed a complex karyotype as follows: 47, XY, add(5)(q13), add(6)(p21), add(18)(q21), -21, +marx2[13]/48, idem, +8[1]/46, idem, der(1)add(1)(p34)add(1)(q21), -add(6).	('p21', 'Gene', (86, 89))	('der(1)add(1)(p34)add', 'Disease', 'MESH:C535733', (148, 168))	('p21', 'Gene', '644914', (86, 89))	('add(6', 'Var', (79, 84))	('add(18)(q21', 'Var', (92, 103))
834931	32308595	The chromosomal abnormality +8 is frequently observed in myelodysplastic syndrome.	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (57, 81))	('chromosomal abnormality +8', 'Var', (4, 30))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (57, 81))	('observed', 'Reg', (45, 53))	('myelodysplastic syndrome', 'Disease', (57, 81))
834975	29636641	Aberrant activity of STAT3 correlates with tumor growth, invasion and metastasis, which makes it a potential therapeutic target of cancer.	('cancer', 'Disease', (131, 137))	('metastasis', 'CPA', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('STAT3', 'Gene', (21, 26))	('invasion', 'CPA', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Aberrant activity', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('STAT3', 'Gene', '6774', (21, 26))
834976	29636641	To explore the biological role of STAT3 in esophageal cancer, we used small hairpin RNA to knockdown the expression of the STAT3 gene in the esophageal carcinoma ECA109 cell line and the cell apoptosis, cell cycle and cell migration were investigated.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('STAT3', 'Gene', (34, 39))	('STAT3', 'Gene', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('knockdown', 'Var', (91, 100))	('STAT3', 'Gene', '6774', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('esophageal cancer', 'Disease', (43, 60))	('STAT3', 'Gene', '6774', (123, 128))	('esophageal carcinoma ECA109', 'Disease', (141, 168))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (141, 161))	('esophageal carcinoma ECA109', 'Disease', 'MESH:D004938', (141, 168))
834978	29636641	Our results showed that knockdown of STAT3 in ECA109 cells induced noticeable apoptotic morphological changes like cell shrinkage, apoptotic vacuoles, membrane blebbing time-dependently.	('STAT3', 'Gene', '6774', (37, 42))	('cell shrinkage', 'CPA', (115, 129))	('membrane blebbing', 'CPA', (151, 168))	('apoptotic vacuoles', 'CPA', (131, 149))	('STAT3', 'Gene', (37, 42))	('apoptotic vacuoles', 'Phenotype', 'HP:0003736', (131, 149))	('apoptotic morphological changes', 'CPA', (78, 109))	('knockdown', 'Var', (24, 33))
834981	29636641	Furthermore, STAT3 knockdown suppressed the expression of matrix metalloproteinases-9, sushi domain containing 2 and urokinase plasminogen activator in ECA109 cells and inhibited cell migration ability.	('expression', 'MPA', (44, 54))	('matrix metalloproteinases-9', 'Protein', (58, 85))	('sushi domain containing 2', 'Gene', (87, 112))	('knockdown', 'Var', (19, 28))	('cell migration ability', 'CPA', (179, 201))	('sushi domain containing 2', 'Gene', '56241', (87, 112))	('STAT3', 'Gene', '6774', (13, 18))	('inhibited', 'NegReg', (169, 178))	('STAT3', 'Gene', (13, 18))	('suppressed', 'NegReg', (29, 39))
835036	29636641	2, we could see that the pSi-STAT3 plasmid induced apparent morphological changes like cell shrinkage, apoptotic vacuoles, membrane blebbing and forming the floating cells which appeared after transfection for 48 h and got worse after 72 h. These indicated that knockdown of STAT3 could induce morphological changes of the ECA109 cells in a time-dependent manner.	('STAT3', 'Gene', (275, 280))	('STAT3', 'Gene', '6774', (29, 34))	('morphological changes', 'CPA', (294, 315))	('apoptotic vacuoles', 'Phenotype', 'HP:0003736', (103, 121))	('STAT3', 'Gene', (29, 34))	('induce', 'Reg', (287, 293))	('STAT3', 'Gene', '6774', (275, 280))	('knockdown', 'Var', (262, 271))
835041	29636641	Consistently, pSi-STAT3 transfection significantly increased the number of TUNEL-positive apoptotic cells, but few or no apoptotic cells were seen in the pSi-Scramble treated or untreated groups (Fig.	('STAT3', 'Gene', (18, 23))	('increased', 'PosReg', (51, 60))	('TUNEL-positive apoptotic cells', 'CPA', (75, 105))	('transfection', 'Var', (24, 36))	('STAT3', 'Gene', '6774', (18, 23))
835048	29636641	Cell cycle progression is a highly-ordered and tightly-regulated process which involves multiple checkpoints that assess extracellular growth signals, cell size and DNA integrity, hence the dysregulation of the cell cycle is one of the most frequent alteration during tumor development.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('dysregulation', 'Var', (190, 203))	('tumor', 'Disease', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
835056	29636641	It has been found that cancer cells harboring aberrant STAT3 activity had elevated levels of anti-apoptotic and cell cycle regulating proteins like cyclin D1 and c-Myc.	('cyclin D1', 'Gene', '595', (148, 157))	('STAT3', 'Gene', (55, 60))	('cyclin D1', 'Gene', (148, 157))	('elevated', 'PosReg', (74, 82))	('c-Myc', 'Gene', (162, 167))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('aberrant', 'Var', (46, 54))	('activity', 'MPA', (61, 69))	('cell cycle', 'CPA', (112, 122))	('STAT3', 'Gene', '6774', (55, 60))	('levels of anti-apoptotic and', 'MPA', (83, 111))	('c-Myc', 'Gene', '4609', (162, 167))
835087	29636641	Further, all the aforementioned genes are also related to tumor invasion and metastasis, we presumed that the STAT3 knockdown may inhibit the invasion and metastasis of ECA109 cells as well.	('STAT3', 'Gene', '6774', (110, 115))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('inhibit', 'NegReg', (130, 137))	('STAT3', 'Gene', (110, 115))	('knockdown', 'Var', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
835092	29254243	PPARG c.1347C>T polymorphism is associated with cancer susceptibility: from a case-control study to a meta-analysis Recently, several studies suggested that PPARG c.1347C>T polymorphism was correlated with cancer risk.	('c.1347C>T', 'Mutation', 'rs3856806', (163, 172))	('correlated', 'Reg', (190, 200))	('c.1347C>T', 'Var', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('PPARG', 'Gene', '5468', (157, 162))	('PPARG', 'Gene', (157, 162))	('PPARG', 'Gene', '5468', (0, 5))	('cancer', 'Disease', (48, 54))	('PPARG', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('c.1347C>T', 'Mutation', 'rs3856806', (6, 15))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
835093	29254243	In this study, we performed a case-control study on the relationship of PPARG c.1347C>T polymorphism with risk of non-small cell lung cancer (NSCLC) and subsequently carried out a meta-analysis to further assess the association between PPARG c.1347C>T and overall cancer.	('NSCLC', 'Disease', (142, 147))	('c.1347C>T', 'Var', (78, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('cancer', 'Disease', (264, 270))	('c.1347C>T', 'Mutation', 'rs3856806', (242, 251))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('non-small cell lung cancer', 'Disease', (114, 140))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('PPARG', 'Gene', '5468', (72, 77))	('PPARG', 'Gene', (72, 77))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (114, 140))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('PPARG', 'Gene', '5468', (236, 241))	('c.1347C>T', 'Mutation', 'rs3856806', (78, 87))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (118, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('PPARG', 'Gene', (236, 241))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (114, 140))
835095	29254243	In the meta-analysis, we found a significant association between PPARG c.1347C>T polymorphism and overall cancer risk (T vs. C: OR, 1.13; 95% CI, 1.03-1.23; P = 0.006; TT vs. CC: OR, 1.29; 95% CI, 1.07-1.56; P = 0.008, CT/TT vs. CC: OR, 1.11; 95% CI, 1.02-1.21; P = 0.014 and TT vs. CT/CC: OR, 1.26; 95% CI, 1.04-1.52; P = 0.016).	('c.1347C>T', 'Mutation', 'rs3856806', (71, 80))	('c.1347C>T', 'Var', (71, 80))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('PPARG', 'Gene', '5468', (65, 70))	('PPARG', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
835096	29254243	In a subgroup analysis by ethnicity, evidence of significant association between PPARG c.1347C>T polymorphism and cancer risk was found among Asians and mixed populations.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('PPARG', 'Gene', '5468', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('PPARG', 'Gene', (81, 86))	('c.1347C>T', 'Var', (87, 96))	('c.1347C>T', 'Mutation', 'rs3856806', (87, 96))	('cancer', 'Disease', (114, 120))
835097	29254243	In a subgroup analysis by cancer type, PPARG c.1347C>T polymorphism was associated with risk of esophageal cancer and glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('PPARG', 'Gene', '5468', (39, 44))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('esophageal cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('associated', 'Reg', (72, 82))	('c.1347C>T', 'Mutation', 'rs3856806', (45, 54))	('PPARG', 'Gene', (39, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('glioblastoma', 'Disease', (118, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))	('cancer', 'Disease', (107, 113))	('c.1347C>T', 'Var', (45, 54))
835098	29254243	In addition, in a subgroup analysis by origin of cancer cell, evidence of significant association between PPARG c.1347C>T polymorphism and cancer risk was also found among epithelial tumor.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('epithelial tumor', 'Phenotype', 'HP:0031492', (172, 188))	('c.1347C>T', 'Mutation', 'rs3856806', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('c.1347C>T', 'Var', (112, 121))	('epithelial tumor', 'Disease', (172, 188))	('PPARG', 'Gene', '5468', (106, 111))	('PPARG', 'Gene', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('epithelial tumor', 'Disease', 'MESH:D002277', (172, 188))	('cancer', 'Disease', (139, 145))
835099	29254243	In conclusion, the findings indicate PPARG c.1347C>T polymorphism may increase the susceptibility of cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('c.1347C>T', 'Mutation', 'rs3856806', (43, 52))	('PPARG', 'Gene', (37, 42))	('PPARG', 'Gene', '5468', (37, 42))	('c.1347C>T', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
835113	29254243	Recently, a number of studies focused on the association of PPARG polymorphisms with cancer risk.	('association', 'Interaction', (45, 56))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('PPARG', 'Gene', '5468', (60, 65))	('PPARG', 'Gene', (60, 65))	('polymorphisms', 'Var', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
835114	29254243	PPARG NM_015869.4:c.34C>G (rs1801282 C>G) and NM_138712.3: c.1347C>T (rs3856806 C>T) polymorphisms are two common single nucleotide polymorphisms (SNPs).	('rs3856806', 'Mutation', 'rs3856806', (70, 79))	('c.1347C>T', 'SUBSTITUTION', 'None', (59, 68))	('NM_015869.4:c.34C>G', 'Mutation', 'rs1801282', (6, 25))	('PPARG', 'Gene', '5468', (0, 5))	('rs1801282', 'Mutation', 'rs1801282', (27, 36))	('PPARG', 'Gene', (0, 5))	('rs1801282 C>G', 'Var', (27, 40))	('c.1347C>T', 'Var', (59, 68))	('rs3856806 C>T', 'Var', (70, 83))
835115	29254243	A meta-analysis indicated the PPARG c.34C>G polymorphism was associated with the risk of cancer in Asians.	('c.34C>G', 'Mutation', 'rs1801282', (36, 43))	('c.34C>G', 'Var', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('PPARG', 'Gene', '5468', (30, 35))	('cancer', 'Disease', (89, 95))	('PPARG', 'Gene', (30, 35))	('associated', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
835116	29254243	However, the association of PPARG c.1347C>T polymorphism with cancer risk was not found.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('c.1347C>T', 'Mutation', 'rs3856806', (34, 43))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('c.1347C>T', 'Var', (34, 43))	('PPARG', 'Gene', '5468', (28, 33))	('PPARG', 'Gene', (28, 33))
835118	29254243	Although more and more case-control studies focused on the relationship of the PPARG c.1347C>T polymorphism with cancer susceptibility, the obtained findings remained conflicting.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('c.1347C>T', 'Mutation', 'rs3856806', (85, 94))	('cancer', 'Disease', (113, 119))	('c.1347C>T', 'Var', (85, 94))	('PPARG', 'Gene', '5468', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('PPARG', 'Gene', (79, 84))
835120	29254243	Therefore, in this study, we designed a case-control study and assessed the relationship between PPARG c.1347C>T polymorphism and risk of non-small cell lung cancer (NSCLC) in Eastern Chinese Han population.	('PPARG', 'Gene', (97, 102))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (138, 164))	('NSCLC', 'Disease', (166, 171))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (138, 164))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('c.1347C>T', 'Mutation', 'rs3856806', (103, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (166, 171))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (142, 164))	('c.1347C>T', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('non-small cell lung cancer', 'Disease', (138, 164))	('PPARG', 'Gene', '5468', (97, 102))
835121	29254243	To address the association between PPARG c.1347C>T polymorphism and cancer risk more precisely, we carried out a comprehensive meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PPARG', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('PPARG', 'Gene', '5468', (35, 40))	('cancer', 'Disease', (68, 74))	('c.1347C>T', 'Var', (41, 50))	('c.1347C>T', 'Mutation', 'rs3856806', (41, 50))
835123	29254243	The SNP information of PPARG c.1347C>T is shown in Table 2.	('c.1347C>T', 'Mutation', 'rs3856806', (29, 38))	('PPARG', 'Gene', (23, 28))	('PPARG', 'Gene', '5468', (23, 28))	('c.1347C>T', 'Var', (29, 38))
835124	29254243	Table 2 summarizes the minor allele frequency (MAF) of PPARG c.1347C>T polymorphism and Hardy-Weinberg Equilibrium (HWE) in controls.	('PPARG', 'Gene', (55, 60))	('c.1347C>T', 'Mutation', 'rs3856806', (61, 70))	('c.1347C>T', 'Var', (61, 70))	('Hardy-Weinberg Equilibrium', 'Disease', (88, 114))	('PPARG', 'Gene', '5468', (55, 60))
835125	29254243	The frequencies of PPARG c.1347 CC, CT and TT genotypes were 57.01%, 38.00% and 4.99% in 521 NSCLC patients and 61.32%, 34.50%, and 4.18% in 1,030 non-cancer controls, respectively.	('NSCLC', 'Disease', (93, 98))	('PPARG', 'Gene', '5468', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('PPARG', 'Gene', (19, 24))	('patients', 'Species', '9606', (99, 107))	('non-cancer', 'Disease', (147, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('non-cancer', 'Disease', 'MESH:D009369', (147, 157))	('c.1347 CC', 'Var', (25, 34))
835126	29254243	The genotype distribution of PPARG c.1347C>T polymorphism is listed in Table 3.	('c.1347C>T', 'Var', (35, 44))	('PPARG', 'Gene', '5468', (29, 34))	('PPARG', 'Gene', (29, 34))	('c.1347C>T', 'Mutation', 'rs3856806', (35, 44))
835127	29254243	When compared with the frequency of c.1347 CC genotype, the frequency of c.1347 CT genotype was not difference between the NSCLC patients and controls (crude OR = 1.19, 95% CI: 0.95-1.48, P = 0.130).	('NSCLC', 'Disease', (123, 128))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('c.1347', 'Var', (73, 79))
835128	29254243	When compared with the frequency of c.1347 CC genotype, there was also no difference in the frequency of c.1347 TT genotype between the NSCLC patients and the controls (crude OR = 1.29, 95% CI: 0.78-2.13, P = 0.329).	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('c.1347', 'Var', (105, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('patients', 'Species', '9606', (142, 150))	('NSCLC', 'Disease', (136, 141))
835129	29254243	When c.1347 CC genotype was used as reference, there was also no difference in the frequency of c.1347 TT/CT genotype between the NSCLC patients and the controls (crude OR = 1.20, 95% CI: 0.97-1.48, P = 0.102).	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('c.1347', 'Var', (96, 102))	('patients', 'Species', '9606', (136, 144))	('NSCLC', 'Disease', (130, 135))
835130	29254243	In addition, When c.1347 CC/CT genotype was used as reference, we found that there was no difference in the frequency of c.1347 TT genotype between the NSCLC patients and the controls (crude OR = 1.20, 95% CI: 0.73-1.98, P = 0.465).	('c.1347', 'Var', (121, 127))	('NSCLC', 'Disease', (152, 157))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('patients', 'Species', '9606', (158, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (152, 157))
835132	29254243	Next, we carried out a pooled analysis to determine the potential relationship between PPARG c.1347C>T polymorphism and overall cancer risk.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('c.1347C>T', 'Mutation', 'rs3856806', (93, 102))	('c.1347C>T', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PPARG', 'Gene', '5468', (87, 92))	('PPARG', 'Gene', (87, 92))	('cancer', 'Disease', (128, 134))
835134	29254243	The characteristic of the included studies and PPARG c.1347C>T genotypes in different study are listed in Tables 4, 5.	('c.1347C>T', 'Var', (53, 62))	('PPARG', 'Gene', '5468', (47, 52))	('c.1347C>T', 'Mutation', 'rs3856806', (53, 62))	('PPARG', 'Gene', (47, 52))
835135	29254243	Overall, we found a significant association between PPARG c.1347C>T polymorphism and the increased risk of cancer (T vs. C: OR, 1.13; 95% CI, 1.03-1.23; P = 0.006; TT vs. CC: OR, 1.29; 95% CI, 1.07-1.56; P = 0.008, CT/TT vs. CC: OR, 1.11; 95% CI, 1.02-1.21; P = 0.014 and TT vs. CT/CC: OR, 1.26; 95% CI, 1.04-1.52; P = 0.016; Table 6 and Figure 2).	('PPARG', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('c.1347C>T', 'Mutation', 'rs3856806', (58, 67))	('c.1347C>T', 'Var', (58, 67))	('cancer', 'Disease', (107, 113))	('PPARG', 'Gene', '5468', (52, 57))
835136	29254243	In a subgroup analysis by the ethnicity, evidence of significant association between PPARG c.1347C>T polymorphism and increased risk of cancer were also found among Asians, and mixed populations, but not Caucasians (Table 6).	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('c.1347C>T', 'Var', (91, 100))	('c.1347C>T', 'Mutation', 'rs3856806', (91, 100))	('PPARG', 'Gene', '5468', (85, 90))	('cancer', 'Disease', (136, 142))	('PPARG', 'Gene', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
835137	29254243	In a subgroup analysis by cancer type, c.1347C>T polymorphism was associated with the risk of esophageal cancer, and glioblastoma, but not biliary tract, breast, colorectal, melanoma, ovarian and other cancers (Table 6).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (26, 32))	('c.1347C>T', 'Var', (39, 48))	('cancer', 'Disease', (105, 111))	('esophageal cancer', 'Disease', (94, 111))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('glioblastoma', 'Disease', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('colorectal, melanoma, ovarian and other cancers', 'Disease', 'MESH:D015179', (162, 209))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('associated', 'Reg', (66, 76))	('c.1347C>T', 'Mutation', 'rs3856806', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Disease', (202, 208))	('glioblastoma', 'Disease', 'MESH:D005909', (117, 129))
835138	29254243	In addition, in a subgroup analysis by the origin of cancer cell, evidence of significant association between PPARG c.1347C>T polymorphism and an increased risk of cancer were also found among epithelial tumor (Table 6).	('epithelial tumor', 'Disease', 'MESH:D002277', (193, 209))	('epithelial tumor', 'Phenotype', 'HP:0031492', (193, 209))	('PPARG', 'Gene', '5468', (110, 115))	('PPARG', 'Gene', (110, 115))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('c.1347C>T', 'Var', (116, 125))	('c.1347C>T', 'Mutation', 'rs3856806', (116, 125))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('epithelial tumor', 'Disease', (193, 209))
835149	29254243	In this study, we explored the relationship of PPARG c.1347C>T polymorphism with NSCLC risk.	('c.1347C>T', 'Var', (53, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('PPARG', 'Gene', '5468', (47, 52))	('c.1347C>T', 'Mutation', 'rs3856806', (53, 62))	('PPARG', 'Gene', (47, 52))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
835151	29254243	In the case-control study, we found an association between PPARG c.1347C>T polymorphism and a tendency to increased risk of NSCLC.	('NSCLC', 'Disease', (124, 129))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('PPARG', 'Gene', '5468', (59, 64))	('c.1347C>T', 'Var', (65, 74))	('c.1347C>T', 'Mutation', 'rs3856806', (65, 74))	('PPARG', 'Gene', (59, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
835152	29254243	Along with a meta-analysis, we found that PPARG c.1347C>T polymorphism was associated with the increased risk of overall cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PPARG', 'Gene', (42, 47))	('c.1347C>T', 'Mutation', 'rs3856806', (48, 57))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('associated', 'Reg', (75, 85))	('PPARG', 'Gene', '5468', (42, 47))	('cancer', 'Disease', (121, 127))	('c.1347C>T', 'Var', (48, 57))
835153	29254243	To the best of our knowledge, this study is the first case-control study focusing on the association between PPARG c.1347C>T polymorphism and NSCLC risk in Asians.	('c.1347C>T', 'Mutation', 'rs3856806', (115, 124))	('NSCLC', 'Disease', (142, 147))	('PPARG', 'Gene', '5468', (109, 114))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('PPARG', 'Gene', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('c.1347C>T', 'Var', (115, 124))	('association', 'Interaction', (89, 100))
835155	29254243	Considering the fact that a common SNP may make a small-to-moderate contribution to the risk of cancer, this pooled-analysis urges the necessity of adequate sample sizes to get a precise measurement between PPARG c.1347C>T polymorphism and the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('PPARG', 'Gene', '5468', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('PPARG', 'Gene', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('c.1347C>T', 'Mutation', 'rs3856806', (213, 222))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('c.1347C>T', 'Var', (213, 222))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (259, 265))
835156	29254243	Several individual studies have reported positive signals of PPARG c.1347C>T polymorphism with cancer risk; however, others observed null association.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('c.1347C>T', 'Var', (67, 76))	('PPARG', 'Gene', '5468', (61, 66))	('cancer', 'Disease', (95, 101))	('c.1347C>T', 'Mutation', 'rs3856806', (67, 76))	('PPARG', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
835159	29254243	In PPARG exon 6, a C to T substitution is a synonymous polymorphism which encodes histidine either with PPARG c.1347 C or T allele.	('PPARG', 'Gene', '5468', (104, 109))	('PPARG', 'Gene', (104, 109))	('c.1347 C or', 'Var', (110, 121))	('histidine', 'Chemical', 'MESH:D006639', (82, 91))	('PPARG', 'Gene', '5468', (3, 8))	('PPARG', 'Gene', (3, 8))
835160	29254243	The findings of previous epidemiological studies showed a relationship of this polymorphism with metabolic diseases such as type 2 diabetes and atherosclerosis.	('relationship', 'Interaction', (58, 70))	('type 2 diabetes', 'Disease', 'MESH:D003924', (124, 139))	('polymorphism', 'Var', (79, 91))	('atherosclerosis', 'Disease', 'MESH:D050197', (144, 159))	('atherosclerosis', 'Phenotype', 'HP:0002621', (144, 159))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (124, 139))	('metabolic diseases', 'Disease', (97, 115))	('type 2 diabetes', 'Disease', (124, 139))	('atherosclerosis', 'Disease', (144, 159))	('metabolic diseases', 'Disease', 'MESH:D008659', (97, 115))
835161	29254243	It is proposed that the C to T substitution may modulate the expression of PPARG by altering mRNA processing or translation.	('C to T', 'Var', (24, 30))	('PPARG', 'Gene', '5468', (75, 80))	('translation', 'MPA', (112, 123))	('mRNA processing', 'MPA', (93, 108))	('PPARG', 'Gene', (75, 80))	('altering', 'Reg', (84, 92))	('modulate', 'Reg', (48, 56))	('expression', 'MPA', (61, 71))
835162	29254243	A tendency of increased risk was observed for PPARG c.1347C>T polymorphism with NSCLC risk, and an increased risk was also found in the subsequent meta-analysis.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('PPARG', 'Gene', '5468', (46, 51))	('PPARG', 'Gene', (46, 51))	('NSCLC', 'Disease', (80, 85))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('c.1347C>T', 'Var', (52, 61))	('c.1347C>T', 'Mutation', 'rs3856806', (52, 61))
835163	29254243	These consistent findings demonstrated that PPARG c.1347C>TC>T polymorphism might influence the development of cancer.	('c.1347C>TC', 'Var', (50, 60))	('influence', 'Reg', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('PPARG', 'Gene', '5468', (44, 49))	('c.1347C>TC', 'SUBSTITUTION', 'None', (50, 60))	('PPARG', 'Gene', (44, 49))	('cancer', 'Disease', (111, 117))	('development of', 'CPA', (96, 110))
835165	29254243	Finally, we only focused on c.1347C>T polymorphism in PPARG gene, and did not consider other susceptibility genes or polymorphisms.	('PPARG', 'Gene', (54, 59))	('c.1347C>T', 'Mutation', 'rs3856806', (28, 37))	('c.1347C>T', 'Var', (28, 37))	('PPARG', 'Gene', '5468', (54, 59))
835166	29254243	In conclusion, this case-control study in Eastern Chinese Han populations, along with a comprehensive meta-analysis, identify the association of PPARG c.1347C>T polymorphism with an increased risk of cancer, even in Asians, esophageal cancer, glioblastoma and epithelial tumor subgroups.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('glioblastoma', 'Disease', 'MESH:D005909', (243, 255))	('epithelial tumor', 'Disease', (260, 276))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('epithelial tumor', 'Phenotype', 'HP:0031492', (260, 276))	('epithelial tumor', 'Disease', 'MESH:D002277', (260, 276))	('c.1347C>T', 'Var', (151, 160))	('PPARG', 'Gene', '5468', (145, 150))	('glioblastoma', 'Disease', (243, 255))	('PPARG', 'Gene', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('esophageal cancer', 'Disease', 'MESH:D004938', (224, 241))	('glioblastoma', 'Phenotype', 'HP:0012174', (243, 255))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('esophageal cancer', 'Disease', (224, 241))	('cancer', 'Disease', (235, 241))	('c.1347C>T', 'Mutation', 'rs3856806', (151, 160))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Disease', (200, 206))
835167	29254243	Nevertheless, for some practical reasons, we hope that more case-control studies with the detailed environmental data to further explore the molecular mechanism of PPARG c.1347C>T polymorphism with development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('c.1347C>T', 'Var', (170, 179))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('PPARG', 'Gene', '5468', (164, 169))	('PPARG', 'Gene', (164, 169))	('c.1347C>T', 'Mutation', 'rs3856806', (170, 179))
835180	29254243	PPARG c.1347C>T polymorphism (NP_005028.4: p.His449His) was analyzed using SNPscanTM genotyping assay (Genesky Biotechologies Inc., Shanghai, China).	('p.His449His', 'Var', (43, 54))	('c.1347C', 'Var', (6, 13))	('PPARG', 'Gene', '5468', (0, 5))	('c.1347C>T', 'Mutation', 'rs3856806', (6, 15))	('PPARG', 'Gene', (0, 5))	('p.His449His', 'SUBSTITUTION', 'None', (43, 54))
835183	29254243	To further determine the relationship between PPARG c.1347C>T variants and cancer susceptibility, we carried out a meta-analysis.	('PPARG', 'Gene', '5468', (46, 51))	('PPARG', 'Gene', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('c.1347C>T', 'Var', (52, 61))	('c.1347C>T', 'Mutation', 'rs3856806', (52, 61))
835185	29254243	The search was performed with the terms of (Peroxisome proliferator activated receptor gamma or PPARG) and (NP_005028.4: p.His449His or His449His or H449H or C161T or C1431T or rs3856806 or c.1347C>T) and (polymorphism or variant) and (cancer or carcinoma).	('c.1347C>T', 'Var', (190, 199))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('H449H', 'Mutation', 'rs3856806', (149, 154))	('p.His449His', 'Var', (121, 132))	('H449H', 'Var', (149, 154))	('C161T', 'Mutation', 'rs3856806', (158, 163))	('p.His449His', 'SUBSTITUTION', 'None', (121, 132))	('Peroxisome proliferator activated receptor gamma', 'Gene', '5468', (44, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('Peroxisome proliferator activated receptor gamma', 'Gene', (44, 92))	('carcinoma', 'Disease', (246, 255))	('PPARG', 'Gene', '5468', (96, 101))	('PPARG', 'Gene', (96, 101))	('cancer', 'Disease', (236, 242))	('rs3856806', 'Mutation', 'rs3856806', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('c.1347C>T', 'Mutation', 'rs3856806', (190, 199))	('carcinoma', 'Disease', 'MESH:D002277', (246, 255))	('C161T', 'Var', (158, 163))	('C1431T', 'Mutation', 'rs3856806', (167, 173))	('C1431T', 'Var', (167, 173))
835186	29254243	In our analysis, eligible studies had to meet the inclusion criteria: (1) focusing on the association between PPARG c.1347C>T polymorphism and cancer risk; (2) designed as a case-control or cohort study; (3) data could be extracted from the publications (genotypes of cases and controls); (4) published in English language; (5) genotype distribution was consistent with HWE in controls.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('PPARG', 'Gene', '5468', (110, 115))	('PPARG', 'Gene', (110, 115))	('c.1347C>T', 'Var', (116, 125))	('c.1347C>T', 'Mutation', 'rs3856806', (116, 125))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
835189	29254243	Crude ORs with their 95% CIs were used to examine the strength of relationship between PPARG c.1347C>T polymorphism and cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('c.1347C>T', 'Mutation', 'rs3856806', (93, 102))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('PPARG', 'Gene', '5468', (87, 92))	('PPARG', 'Gene', (87, 92))	('c.1347C>T', 'Var', (93, 102))
835242	29158796	The median follow-up time was 15.5 months (interquartile range 8.0-25.4 months), The 2- and 3-year estimated OS, LRFFS, DMFS and PFS were 43.5%, 60.5%, 79.9% and 34.6%, and 35.2%, 58.5%, 77.8% and 29.4%, respectively (Figure 1).	('OS', 'Chemical', '-', (109, 111))	('LRFFS', 'Disease', (113, 118))	('DMFS', 'Var', (120, 124))	('DMFS', 'Chemical', '-', (120, 124))
835314	28294486	In cases of high PD-L1 expression at the invasive front, significantly greater depth of tumor invasion, EMT, and less CD8+ lymphocyte infiltration were observed.	('high', 'Var', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('less', 'NegReg', (113, 117))	('EMT', 'CPA', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CD8', 'Gene', '925', (118, 121))	('PD-L1', 'Gene', (17, 22))	('CD8', 'Gene', (118, 121))	('greater', 'PosReg', (71, 78))	('tumor', 'Disease', (88, 93))	('expression', 'MPA', (23, 33))
835322	28294486	For antigen retrieval, the specimens were pretreated in an autoclave for PD-L1 (121 C, 10 min, in 0.01 M citrate buffer; pH 6.0) and ZEB1 (121 C, 20 min, in Target EDTA, pH 9.0), and CD8 (121 C, 20 min, in 0.01 M citrate buffer; pH 6.0), E-cadherin (121 C, 15 min, in 0.01 M citrate buffer; pH 6.0).	('EDTA', 'Chemical', 'MESH:D004492', (164, 168))	('citrate', 'Chemical', 'MESH:D019343', (105, 112))	('121 C,', 'Var', (250, 256))	('CD8', 'Gene', (183, 186))	('CD8', 'Gene', '925', (183, 186))	('citrate', 'Chemical', 'MESH:D019343', (213, 220))	('citrate', 'Chemical', 'MESH:D019343', (275, 282))
835336	28294486	The siRNAs specific for Twist and Snail were HSS144372 and HSS186975 (referred as Twist-1 and Twist-2, respectively) and HSS143995 and HSS143996 (referred as Snail-1 and Snail-2, respectively).	('HSS144372', 'Chemical', '-', (45, 54))	('Snail-1', 'Gene', (158, 165))	('HSS144372', 'Var', (45, 54))	('Snail-1', 'Gene', '6615', (158, 165))	('Twist-2', 'Gene', (94, 101))	('HSS186975', 'Var', (59, 68))	('Twist-1', 'Gene', (82, 89))	('Twist-2', 'Gene', '117581', (94, 101))	('HSS186975', 'Chemical', '-', (59, 68))	('Snail-2', 'Gene', (170, 177))	('HSS143995', 'Var', (121, 130))	('HSS143996', 'Var', (135, 144))	('Snail-2', 'Gene', '6591', (170, 177))	('Twist-1', 'Gene', '7291', (82, 89))
835348	28294486	The 5-year OS rate in the patients with PD-L1 positive expression was significantly poorer than those with negative expression (39.2% vs 67.0%, P = 0.0112).	('poorer', 'NegReg', (84, 90))	('PD-L1', 'Gene', (40, 45))	('positive expression', 'Var', (46, 65))	('patients', 'Species', '9606', (26, 34))
835349	28294486	The 5-year RFS rate in the patients with PD-L1 positive expression was also worse than those with negative expression (22.4% vs 57.8%, P = 0.0040) (Fig.	('RFS', 'MPA', (11, 14))	('positive expression', 'Var', (47, 66))	('worse', 'NegReg', (76, 81))	('patients', 'Species', '9606', (27, 35))	('PD-L1', 'Gene', (41, 46))
835353	28294486	The 5-year OS rate in the patients with ZEB1 high and low expression was 36.2% and 60.1%, respectively (P = 0.0271).	('high', 'Var', (45, 49))	('ZEB1', 'Gene', (40, 44))	('low', 'NegReg', (54, 57))	('patients', 'Species', '9606', (26, 34))
835354	28294486	The 5-year RFS rate in patients with ZEB1 high and low expression was 32.0% and 38.3%, respectively (P = 0.1836) (Fig.	('patients', 'Species', '9606', (23, 31))	('ZEB1', 'Gene', (37, 41))	('RFS', 'Disease', (11, 14))	('expression', 'MPA', (55, 65))	('low', 'NegReg', (51, 54))	('high', 'Var', (42, 46))
835361	28294486	In the present study, patients with PD-L1 positive expression had significantly poorer prognosis than those with negative expression.	('PD-L1', 'Gene', (36, 41))	('patients', 'Species', '9606', (22, 30))	('poorer', 'NegReg', (80, 86))	('positive expression', 'Var', (42, 61))
835363	28294486	For patients in whom overexpression of tumor PD-L1 was observed prior to treatment, anti-PD-1/PD-L1 directed therapy could lead to improved clinical outcomes.13 Thus, high PD-L1 expression may be a predictive marker for efficacy of PD-1/PD-L1 directed immune therapy.	('PD-1', 'Gene', (232, 236))	('PD-1', 'Gene', '5133', (232, 236))	('PD-1', 'Gene', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('high', 'Var', (167, 171))	('PD-1', 'Gene', '5133', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (39, 44))	('PD-L1', 'Gene', (172, 177))
835421	26865098	In a randomized, placebo-controlled trial with selenomethionine and celecoxib for 10 months, selenomethionine improved squamous histology in 115 patients with mild esophageal dysplasia, but not in 125 patients with severe dysplasia.	('patients', 'Species', '9606', (145, 153))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (164, 184))	('selenomethionine', 'Var', (93, 109))	('patients', 'Species', '9606', (201, 209))	('selenomethionine', 'Chemical', 'MESH:D012645', (47, 63))	('celecoxib', 'Chemical', 'MESH:D000068579', (68, 77))	('improved', 'PosReg', (110, 118))	('dysplasia', 'Disease', (222, 231))	('esophageal dysplasia', 'Disease', (164, 184))	('dysplasia', 'Disease', (175, 184))	('dysplasia', 'Disease', 'MESH:D004476', (222, 231))	('squamous', 'Disease', (119, 127))	('selenomethionine', 'Chemical', 'MESH:D012645', (93, 109))	('dysplasia', 'Disease', 'MESH:D004476', (175, 184))
835427	26865098	Unexpectedly, increased lung cancer incidence (by 18%) was observed in the beta-carotene group.	('increased lung cancer', 'Disease', (14, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('beta-carotene', 'Chemical', 'MESH:D019207', (75, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('beta-carotene', 'Var', (75, 88))	('increased lung cancer', 'Disease', 'MESH:D008175', (14, 35))
835428	26865098	For example, supplementation with alpha-tocopheryl acetate was found to reduce the incidence of prostate cancer by 45% in a secondary endpoint analysis of the ABTC study.	('ABTC', 'Chemical', '-', (159, 163))	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('alpha-tocopheryl acetate', 'Chemical', 'MESH:D024502', (34, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('alpha-tocopheryl acetate', 'Protein', (34, 58))	('supplementation', 'Var', (13, 28))	('prostate cancer', 'Disease', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('men', 'Species', '9606', (19, 22))	('reduce', 'NegReg', (72, 78))
835430	26865098	CARET also indicated the combination of beta-carotene and vitamin A may increase the risk of death from lung cancer, cardiovascular disease, and other causes in smokers and workers exposed to asbestos.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('increase', 'PosReg', (72, 80))	('cardiovascular disease', 'Disease', (117, 139))	('combination', 'Var', (25, 36))	('vitamin A', 'Chemical', 'MESH:D014801', (58, 67))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (117, 139))	('lung cancer', 'Disease', (104, 115))	('death', 'Disease', 'MESH:D003643', (93, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('beta-carotene', 'Chemical', 'MESH:D019207', (40, 53))	('cardiovascular disease', 'Disease', 'MESH:D002318', (117, 139))	('death', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('asbestos', 'Chemical', 'MESH:D001194', (192, 200))
835449	26865098	In the subsequently published results on the 7-12 year follow-up of this study, subjects receiving alpha-tocopheryl acetate had a hazard ratio of 1.17 for developing prostate cancer.	('prostate cancer', 'Disease', (166, 181))	('alpha-tocopheryl acetate', 'Chemical', 'MESH:D024502', (99, 123))	('prostate cancer', 'Disease', 'MESH:D011471', (166, 181))	('alpha-tocopheryl acetate', 'Var', (99, 123))	('rat', 'Species', '10116', (137, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (166, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
835450	26865098	It was noted that, in the SELECT, the alpha-T supplementation caused a 50% decrease in median plasma gamma-T levels.	('supplementation', 'Var', (46, 61))	('decrease', 'NegReg', (75, 83))	('EC', 'Chemical', 'MESH:D002392', (29, 31))	('alpha-T', 'Chemical', 'MESH:C024566', (38, 45))	('men', 'Species', '9606', (52, 55))	('gamma-T', 'Chemical', '-', (101, 108))
125895	26865098	Another possibility is that some of these subjects already had preneoplastic lesions when entering the trial, and the supplementation with high doses of alpha-T promoted prostate cancer development.	('prostate cancer', 'Disease', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('men', 'Species', '9606', (124, 127))	('men', 'Species', '9606', (193, 196))	('promoted', 'PosReg', (161, 169))	('prostate cancer', 'Disease', 'MESH:D011471', (170, 185))	('alpha-T', 'Chemical', 'MESH:C024566', (153, 160))	('prostate cancer', 'Phenotype', 'HP:0012125', (170, 185))	('supplementation', 'Var', (118, 133))
835457	26865098	However, recent studies from our research team at Rutgers University have demonstrated the inhibition of cancer formation and growth in the lung, colon, mammary gland and prostate by gamma-T, delta-T and a tocopherol mixture that is rich in gamma-T (named gamma-TmT).	('tea', 'Gene', (42, 45))	('tea', 'Gene', '11988', (42, 45))	('gamma-T', 'Var', (183, 190))	('gamma-T', 'Chemical', '-', (256, 263))	('gamma-TmT', 'Chemical', '-', (256, 265))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('tocopherol', 'Chemical', 'MESH:D024505', (206, 216))	('rat', 'Species', '10116', (81, 84))	('delta-T', 'Chemical', '-', (192, 199))	('inhibition', 'NegReg', (91, 101))	('colon', 'Disease', (146, 151))	('gamma-T', 'Chemical', '-', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('delta-T', 'Var', (192, 199))	('gamma-T', 'Chemical', '-', (183, 190))	('growth', 'CPA', (126, 132))
835459	26865098	We also demonstrated that delta-T was more active than gamma-T in inhibiting cancer cell growth in culture, human lung cancer H1299 cell tumorigenesis in a xenograft model, colon carcinogenesis induced by azoxymethane in rats, and PhIP-induced prostate carcinogenesis in CYP1A-humanized mice; whereas alpha-T was ineffective in these models.	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('delta-T', 'Var', (26, 33))	('H1299', 'CellLine', 'CVCL:0060', (126, 131))	('PhIP', 'Chemical', 'MESH:C049584', (231, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('alpha-T', 'Chemical', 'MESH:C024566', (301, 308))	('rat', 'Species', '10116', (15, 18))	('rat', 'Species', '10116', (221, 224))	('inhibiting', 'NegReg', (66, 76))	('cancer', 'Disease', (119, 125))	('prostate carcinogenesis', 'Disease', (244, 267))	('gamma-T', 'Chemical', '-', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (277, 282))	('tumor', 'Disease', (137, 142))	('cancer', 'Disease', (77, 83))	('delta-T', 'Chemical', '-', (26, 33))	('lung cancer', 'Disease', (114, 125))	('rats', 'Species', '10116', (221, 225))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (173, 193))	('azoxymethane', 'Chemical', 'MESH:D001397', (205, 217))	('mice', 'Species', '10090', (287, 291))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('human', 'Species', '9606', (108, 113))	('prostate carcinogenesis', 'Disease', 'MESH:D063646', (244, 267))	('colon carcinogenesis', 'Disease', (173, 193))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
835461	26865098	In these studies, the commonly observed inhibitory actions of delta-T and gamma-T were the quenching of reactive oxygen and nitrogen species, the lowering of prostaglandin E2 and leukotriene B4 levels, and the enhancing of cancer cell apoptosis.	('lowering of prostaglandin E2', 'Phenotype', 'HP:0003566', (146, 174))	('prostaglandin E2', 'MPA', (158, 174))	('reactive oxygen and nitrogen species', 'Chemical', '-', (104, 140))	('quenching', 'NegReg', (91, 100))	('gamma-T', 'Chemical', '-', (74, 81))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (158, 174))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('gamma-T', 'Var', (74, 81))	('leukotriene B4', 'Chemical', 'MESH:D007975', (179, 193))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('enhancing', 'PosReg', (210, 219))	('delta-T', 'Chemical', '-', (62, 69))	('delta-T', 'Var', (62, 69))	('cancer', 'Disease', (223, 229))	('lowering', 'NegReg', (146, 154))	('leukotriene B4 levels', 'MPA', (179, 200))
835462	26865098	Recent studies in prostate cancer cell lines also showed that delta-T was more effective than gamma-T and alpha-T in inhibiting cell proliferation and the P13K/AKT.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('alpha-T', 'Chemical', 'MESH:C024566', (106, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (18, 33))	('prostate cancer', 'Phenotype', 'HP:0012125', (18, 33))	('P13K', 'Var', (155, 159))	('inhibiting', 'NegReg', (117, 127))	('cell proliferation', 'CPA', (128, 146))	('delta-T', 'Chemical', '-', (62, 69))	('gamma-T', 'Chemical', '-', (94, 101))	('rat', 'Species', '10116', (140, 143))	('delta-T', 'Var', (62, 69))	('prostate cancer', 'Disease', (18, 33))	('P13K', 'SUBSTITUTION', 'None', (155, 159))
835465	26865098	At the supra-nutritional levels, gamma-T, delta-T and gamma-TmT prevent cancer, whereas alpha-T is not effective.	('gamma-TmT', 'Chemical', '-', (54, 63))	('gamma-TmT', 'Var', (54, 63))	('gamma-T', 'Chemical', '-', (33, 40))	('gamma-T', 'Chemical', '-', (54, 61))	('gamma-T', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('delta-T', 'Chemical', '-', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('prevent', 'Reg', (64, 71))	('alpha-T', 'Chemical', 'MESH:C024566', (88, 95))	('delta-T', 'Var', (42, 49))	('cancer', 'Disease', (72, 78))
835482	26865098	It has been reported that in rats, supplementation with folic acid at an early stage of carcinogenesis decreased colon carcinogenesis, whereas supplementation at the late stage enhanced colon carcinogenesis.	('colon carcinogenesis', 'Disease', 'MESH:D063646', (113, 133))	('carcinogenesis decreased colon carcinogenesis', 'Disease', (88, 133))	('men', 'Species', '9606', (149, 152))	('folic acid', 'Chemical', 'MESH:D005492', (56, 66))	('decreased colon', 'Phenotype', 'HP:0005210', (103, 118))	('rats', 'Species', '10116', (29, 33))	('men', 'Species', '9606', (41, 44))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (186, 206))	('supplementation', 'Var', (35, 50))	('colon carcinogenesis', 'Disease', (186, 206))	('enhanced', 'PosReg', (177, 185))	('carcinogenesis decreased colon carcinogenesis', 'Disease', 'MESH:D063646', (88, 133))
835500	26865098	The major tea polyphenols, also known as catechins, are (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), and (-)-epicatechin (EC) and their structures are shown in Figure 3.	('EGC', 'Chemical', 'MESH:C057580', (88, 91))	('-)-epigallocatechin', 'Var', (96, 115))	('(-)-epicatechin', 'Chemical', 'MESH:D002392', (160, 175))	('ECG', 'Chemical', 'MESH:C062669', (150, 153))	('(-)-epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (56, 86))	('EGCG', 'Chemical', 'MESH:C045651', (88, 92))	('(-)-epigallocatechin', 'Chemical', 'MESH:C057580', (95, 115))	('catechins', 'Chemical', 'MESH:D002392', (41, 50))	('EC', 'Chemical', 'MESH:D002392', (177, 179))	('EC', 'Chemical', 'MESH:D002392', (150, 152))	('(-)-epicatechin', 'Chemical', 'MESH:D002392', (123, 138))	('polyphenols', 'Chemical', 'MESH:D059808', (14, 25))	('EGC', 'Chemical', 'MESH:C057580', (117, 120))	('(-)-epicatechin-3-gallate', 'Chemical', 'MESH:C062669', (123, 148))	('(-)-epigallocatechin', 'Chemical', 'MESH:C057580', (56, 76))	('tea', 'Gene', (10, 13))	('tea', 'Gene', '11988', (10, 13))
835568	26865098	However, a recent study of ApcMin mice on a high-fat diet showed a nonlinear dose-response of resveratrol: the lowest dose of resveratrol (0.00007% in the diet) suppressed intestinal adenoma development better than a higher dose (0.0143% in diet) did.	('resveratrol', 'Chemical', 'MESH:D000077185', (126, 137))	('mice', 'Species', '10090', (34, 38))	('resveratrol', 'Chemical', 'MESH:D000077185', (94, 105))	('suppressed', 'NegReg', (161, 171))	('adenoma', 'Disease', 'MESH:D000236', (183, 190))	('0.00007%', 'Var', (139, 147))	('men', 'Species', '9606', (198, 201))	('adenoma', 'Disease', (183, 190))
835576	26865098	When the bioavailability is significantly increased, for example, by the use of nanoparticles, toxicity should be an important concern.	('increased', 'PosReg', (42, 51))	('nanoparticles', 'Var', (80, 93))	('toxicity', 'Disease', (95, 103))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('bioavailability', 'MPA', (9, 24))
835602	23344023	The complexity is increased further by alternative splicing of VEGF-A, VEGF-B and PlGF, and proteolytic processing of VEGF-C and VEGF-D.	('VEGF-B', 'Gene', (71, 77))	('VEGF-C', 'Gene', (118, 124))	('PlGF', 'Gene', (82, 86))	('alternative splicing', 'Var', (39, 59))	('VEGF-A', 'Gene', '7422', (63, 69))	('VEGF-A', 'Gene', (63, 69))	('VEGF-D', 'Gene', (129, 135))	('VEGF-D', 'Gene', '2277', (129, 135))	('PlGF', 'Gene', '5228', (82, 86))	('VEGF-B', 'Gene', '7423', (71, 77))
835612	23344023	A structural study has shown that human VEGF-C is covalently linked by two disulfide bridges between Cys156 and Cys165 in the crystal structure.	('Cys156', 'Var', (101, 107))	('human', 'Species', '9606', (34, 39))	('Cys165', 'Chemical', '-', (112, 118))	('Cys165', 'Var', (112, 118))	('VEGF-C', 'Gene', (40, 46))	('disulfide', 'Chemical', 'MESH:D004220', (75, 84))	('Cys156', 'Chemical', '-', (101, 107))
835613	23344023	A study generated VEGF-C point mutants by replacement of Cys with Ser indicating Cys165 but not Cys156 is involved in dimer formation, and Cys156 mutant efficiently binds VEGFR-3 but not VEGFR-2.	('Ser', 'Chemical', 'MESH:D012694', (66, 69))	('Cys165', 'Chemical', '-', (81, 87))	('VEGF-C', 'Gene', (18, 24))	('Cys', 'Chemical', 'MESH:D003545', (139, 142))	('Cys', 'Chemical', 'MESH:D003545', (81, 84))	('Cys156', 'Chemical', '-', (96, 102))	('VEGFR-2', 'Gene', '3791', (187, 194))	('VEGFR-3', 'Protein', (171, 178))	('Cys', 'Chemical', 'MESH:D003545', (57, 60))	('Cys156', 'Chemical', '-', (139, 145))	('Cys156 mutant', 'Var', (139, 152))	('Cys', 'Chemical', 'MESH:D003545', (96, 99))	('binds', 'Interaction', (165, 170))	('VEGFR-2', 'Gene', (187, 194))
835614	23344023	However, the reported mutation of Cys156 into Ala in VEGF-C suggests that the ratio of monomeric molecules is increased resulting in the loss of binding to both VEGFR-2 and VEGFR-3.	('VEGFR-2', 'Gene', '3791', (161, 168))	('Cys156', 'Var', (34, 40))	('ratio of monomeric molecules', 'MPA', (78, 106))	('increased', 'PosReg', (110, 119))	('VEGF-C', 'Gene', (53, 59))	('binding', 'Interaction', (145, 152))	('VEGFR-2', 'Gene', (161, 168))	('loss', 'NegReg', (137, 141))	('VEGFR-3', 'Gene', (173, 180))	('Cys156 into Ala', 'Mutation', 'p.C156A', (34, 49))
835622	23344023	Previous studies have indicated that VEGF-C binding requires Ig-Loops 1 and 2 in VEGFR-3, whereas binding to VEGFR-2 involves Loops 2 and 3.	('VEGFR-2', 'Gene', (109, 116))	('Ig-Loops 1', 'Var', (61, 71))	('VEGF-C', 'Protein', (37, 43))	('VEGFR-2', 'Gene', '3791', (109, 116))	('binding', 'Interaction', (44, 51))	('VEGFR-3', 'Gene', (81, 88))
835633	23344023	It was also shown that RNAi-induced knockdown of VEGF-C suppresses cell growth, invasion and migration in human non-small cell lung cancer (NSCLC) cells; moreover, down-regulation of VEGF-C is accompanied by decreased signaling of ERK, p38 and Akt pathways that are mediated via CXCR4, CCR7, VEGFR-2 and VEGFR-3.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (112, 138))	('human', 'Species', '9606', (106, 111))	('VEGFR-2', 'Gene', (292, 299))	('CCR7', 'Gene', (286, 290))	('decreased', 'NegReg', (208, 217))	('Akt', 'Gene', (244, 247))	('p38', 'Gene', '5594', (236, 239))	('ERK', 'Gene', '5594', (231, 234))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('non-small cell lung cancer', 'Disease', (112, 138))	('knockdown', 'Var', (36, 45))	('down-regulation', 'NegReg', (164, 179))	('CCR7', 'Gene', '1236', (286, 290))	('Akt', 'Gene', '207', (244, 247))	('suppresses', 'NegReg', (56, 66))	('NSCLC', 'Disease', (140, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('ERK', 'Gene', (231, 234))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (112, 138))	('invasion', 'CPA', (80, 88))	('VEGFR-2', 'Gene', '3791', (292, 299))	('VEGF-C', 'Gene', (49, 55))	('cell growth', 'CPA', (67, 78))	('VEGF-C', 'Gene', (183, 189))	('p38', 'Gene', (236, 239))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (116, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('CXCR4', 'Gene', '7852', (279, 284))	('CXCR4', 'Gene', (279, 284))	('signaling', 'MPA', (218, 227))
835636	23344023	Conversely, in transgenic mice, the overexpression of soluble VEGFR-3 can suppress lymphangiogenesis.	('lymphangiogenesis', 'CPA', (83, 100))	('overexpression', 'PosReg', (36, 50))	('VEGFR-3', 'Gene', (62, 69))	('transgenic mice', 'Species', '10090', (15, 30))	('suppress', 'NegReg', (74, 82))	('soluble', 'Var', (54, 61))
835640	23344023	In addition, a recent study also suggested that in mice bearing orthotopical xenografts with VEGF-C knockdown human lung carcinoma cells caused inhibition of lymphangiogenesis in tumor and surrounding tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('knockdown', 'Var', (100, 109))	('mice', 'Species', '10090', (51, 55))	('VEGF-C', 'Gene', (93, 99))	('lung carcinoma', 'Disease', 'MESH:D008175', (116, 130))	('lung carcinoma', 'Disease', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('human', 'Species', '9606', (110, 115))	('inhibition', 'NegReg', (144, 154))	('tumor', 'Disease', (179, 184))
835644	23344023	A recent study indicated the possibility that VEGF-C via VEGFR-2/VEGFR-3 heterodimers may actually induce angiogenic sprouts.	('induce', 'PosReg', (99, 105))	('angiogenic sprouts', 'CPA', (106, 124))	('heterodimers', 'Var', (73, 85))	('VEGFR-2', 'Gene', (57, 64))	('VEGF-C', 'Gene', (46, 52))	('VEGFR-2', 'Gene', '3791', (57, 64))
835651	23344023	Furthermore, if mutated, the activation of proto-oncogenes to oncogenes occurs in virtually all types of cancers, which have the potential to promote neoplastic transformation.	('activation', 'PosReg', (29, 39))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('proto-oncogenes', 'Gene', (43, 58))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('mutated', 'Var', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('neoplastic transformation', 'CPA', (150, 175))	('promote', 'PosReg', (142, 149))
835677	23344023	A recent report has indicated that HSPG may be a novel co-receptor in VEGFR-3 activation by VEGF-C. Silencing lymphatic heparan sulfate chain biosynthesis reduced VEGF-C-mediated downstream ERK activation and inhibited VEGFR-3 receptor-dependent binding of VEGF-C to the lymphatic endothelial surface.	('HSPG', 'Gene', (35, 39))	('activation', 'PosReg', (194, 204))	('Silencing', 'Var', (100, 109))	('VEGF-C-mediated', 'Enzyme', (163, 178))	('reduced', 'NegReg', (155, 162))	('ERK', 'Gene', '5594', (190, 193))	('inhibited', 'NegReg', (209, 218))	('heparan sulfate', 'Chemical', 'MESH:D006497', (120, 135))	('ERK', 'Gene', (190, 193))	('HSPG', 'Gene', '6383', (35, 39))	('lymphatic heparan sulfate chain biosynthesis', 'MPA', (110, 154))	('binding', 'Interaction', (246, 253))
835682	23344023	In acute myeloid leukemia (AML), increased expression of VEGF-C and VEGFR-3 in bone marrow samples was first reported by Fielder et al.. High VEGF-C expressed levels may be an indicator for adverse prognosis and decreased drug responsiveness in patients with AML.	('decreased', 'NegReg', (212, 221))	('High', 'Var', (137, 141))	('AML', 'Phenotype', 'HP:0004808', (27, 30))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('VEGF-C', 'Gene', (142, 148))	('patients', 'Species', '9606', (245, 253))	('AML', 'Disease', 'MESH:D015470', (259, 262))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('drug responsiveness', 'MPA', (222, 241))	('AML', 'Phenotype', 'HP:0004808', (259, 262))	('AML', 'Disease', (259, 262))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('acute myeloid leukemia', 'Disease', (3, 25))	('AML', 'Disease', (27, 30))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
835689	23344023	The expression of VEGF-C in human prostate cancer also facilitates lymph node metastasis and tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('human', 'Species', '9606', (28, 33))	('VEGF-C', 'Gene', (18, 24))	('prostate cancer', 'Disease', (34, 49))	('tumor', 'Disease', (93, 98))	('lymph node metastasis', 'CPA', (67, 88))	('facilitates', 'PosReg', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('expression', 'Var', (4, 14))	('prostate cancer', 'Disease', 'MESH:D011471', (34, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
835697	23344023	Furthermore, in two histological types of esophageal tumors, squamous cell carcinoma and adenocarcinoma, high VEGF-C expression tends to correlate with poor survival in squamous cell cancer but not in adenocarcinoma of the esophagus.	('squamous cell cancer', 'Disease', 'MESH:D002294', (169, 189))	('adenocarcinoma', 'Disease', 'MESH:D000230', (201, 215))	('VEGF-C', 'Gene', (110, 116))	('adenocarcinoma', 'Disease', 'MESH:D000230', (89, 103))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('esophageal tumors', 'Disease', (42, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('esophageal tumors', 'Disease', 'MESH:D004938', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('poor', 'NegReg', (152, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('esophageal tumors', 'Phenotype', 'HP:0100751', (42, 59))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 84))	('adenocarcinoma', 'Disease', (201, 215))	('adenocarcinoma of the esophagus', 'Disease', (201, 232))	('high', 'Var', (105, 109))	('adenocarcinoma', 'Disease', (89, 103))	('squamous cell cancer', 'Disease', (169, 189))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (169, 189))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (201, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('squamous cell carcinoma', 'Disease', (61, 84))
835699	23344023	Clinical significance of high VEGF-C expression in patients with esophageal cancer is associated with lymph node metastasis and poor prognosis.	('esophageal cancer', 'Disease', (65, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('high', 'Var', (25, 29))	('lymph node metastasis', 'CPA', (102, 123))	('expression', 'MPA', (37, 47))	('patients', 'Species', '9606', (51, 59))	('VEGF-C', 'Gene', (30, 36))
835718	23344023	In addition, high-level expression of VEGF-C in ovarian cancer tissues could be involved in the more advanced clinical stages, which is probably due to the influence on MMP-2 expression, lymph vessel density, microvessel density, and low apoptotic index.	('high-level', 'Var', (13, 23))	('expression', 'MPA', (175, 185))	('MMP-2', 'Gene', '4313', (169, 174))	('lymph vessel density', 'CPA', (187, 207))	('expression', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('apoptotic index', 'CPA', (238, 253))	('MMP-2', 'Gene', (169, 174))	('ovarian cancer', 'Disease', (48, 62))	('involved', 'Reg', (80, 88))	('influence', 'Reg', (156, 165))	('microvessel density', 'CPA', (209, 228))	('VEGF-C', 'Gene', (38, 44))
835722	23344023	VEGF-C is therefore an attractive target for cancer therapy using an anti-VEGF-C antibody to prevent disease progression.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('anti-VEGF-C', 'Gene', (69, 80))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('anti-VEGF-C', 'Var', (69, 80))	('cancer', 'Disease', (45, 51))
835728	23344023	In addition, combination therapy with the anti-VEGFR-2 and anti-VEGFR-3 blocking antibodies diminishes metastases with a greater effect than either antibody alone.	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('VEGFR-2', 'Gene', (47, 54))	('anti-VEGFR-3', 'Var', (59, 71))	('combination', 'Interaction', (13, 24))	('diminishes', 'NegReg', (92, 102))	('metastases', 'Disease', (103, 113))	('VEGFR-2', 'Gene', '3791', (47, 54))
835735	23344023	Mice were implanted s.c. with tumors derived from metastatic cancer cells expressing high levels of VEGF-C leading to a significantly higher incidence of lymph node metastases.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('VEGF-C', 'Gene', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('higher', 'PosReg', (134, 140))	('cancer', 'Disease', (61, 67))	('lymph node metastases', 'Disease', (154, 175))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Mice', 'Species', '10090', (0, 4))	('lymph node metastases', 'Disease', 'MESH:D009362', (154, 175))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('high levels', 'Var', (85, 96))
835745	23344023	Multi-kinase inhibitor E7080, a potent inhibitor of both VEGFR-2 and VEGFR-3 kinase, effectively prevented regional lymph node metastases and further tumor growth.	('VEGFR-2', 'Gene', (57, 64))	('lymph node metastases', 'Disease', 'MESH:D009362', (116, 137))	('E7080', 'Chemical', 'MESH:C531958', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('lymph node metastases', 'Disease', (116, 137))	('prevented', 'NegReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('E7080', 'Var', (23, 28))	('VEGFR-2', 'Gene', '3791', (57, 64))	('tumor', 'Disease', (150, 155))
835748	23344023	Accumulating evidence reveals that RNA-mediated knockdown of VEGF-C results in a significant inhibition of cancer progression.	('inhibition', 'NegReg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('VEGF-C', 'Gene', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('knockdown', 'Var', (48, 57))
835750	23344023	Furthermore, silencing the expression of VEGFR-2 or VEGFR-3 has also been proposed to be an effective method to reduce the metastatic potential.	('VEGFR-2', 'Gene', '3791', (41, 48))	('reduce', 'NegReg', (112, 118))	('VEGFR-2', 'Gene', (41, 48))	('expression', 'MPA', (27, 37))	('metastatic potential', 'CPA', (123, 143))	('VEGFR-3', 'Gene', (52, 59))	('silencing', 'Var', (13, 22))
835762	23056210	Furthermore, a significant correlation between high GOLPH3 expression and shorter overall survival time was found in different subgroups of ESCC patients stratified by the clinical stage, T classification, and lymph node metastasis.	('shorter', 'NegReg', (74, 81))	('patients', 'Species', '9606', (145, 153))	('GOLPH3', 'Gene', (52, 58))	('high', 'Var', (47, 51))	('ESCC', 'Disease', (140, 144))	('expression', 'MPA', (59, 69))	('overall survival', 'MPA', (82, 98))
835768	23056210	The etiology of esophageal cancer is a complex process that involves cumulative mutations in multiple genes, but its exact pathogenesis is still unclear.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('esophageal cancer', 'Disease', (16, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (16, 33))	('mutations', 'Var', (80, 89))
835770	23056210	Previous reports have shown that genetic changes frequently associated with the development of esophageal cancer include the p53 mutation, inactivation of p16, cyclin D1 amplification, and overexpression of c-Myc or EGFR .	('EGFR', 'Gene', (216, 220))	('cyclin D1', 'Gene', '595', (160, 169))	('amplification', 'Var', (170, 183))	('p16', 'Gene', '1029', (155, 158))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('mutation', 'Var', (129, 137))	('cyclin D1', 'Gene', (160, 169))	('p53', 'Gene', (125, 128))	('c-Myc', 'Gene', '4609', (207, 212))	('p53', 'Gene', '7157', (125, 128))	('overexpression', 'PosReg', (189, 203))	('p16', 'Gene', (155, 158))	('EGFR', 'Gene', '1956', (216, 220))	('inactivation', 'Var', (139, 151))	('esophageal cancer', 'Disease', (95, 112))	('c-Myc', 'Gene', (207, 212))	('associated', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
835783	23056210	Expression data were normalized to the geometric mean of the housekeeping gene GAPDH to control the variability in expression levels, and then analyzed using the 2-DeltaDeltact method, where DeltaDeltaCt = DeltaCtGOLPH3 - DeltaCtGAPDH.	('DeltaDeltaCt', 'Var', (191, 203))	('GAPDH', 'Gene', (79, 84))	('GAPDH', 'Gene', '2597', (229, 234))	('GAPDH', 'Gene', (229, 234))	('GAPDH', 'Gene', '2597', (79, 84))
835788	23056210	Tumor cell proportions were scored as follows: 0 (no positive tumor cells); 1 (<10% positive tumor cells); 2 (10-35% positive tumor cells); 3 (35-75% positive tumor cells) and 4 (>75% positive tumor cells).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('35-75', 'Var', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (93, 98))	('10-35', 'Var', (110, 115))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', (126, 131))
835795	23056210	qRT-PCR and western blotting analyses were respectively conducted to determine the levels of GOLPH3 mRNA and protein, in both normal human esophageal epithelial cells and ESCC cell lines, including KYSE-30, KYSE-140, KYSE-180, ECa-109, KYSE-510, KYSE-520, KYSE-410, 108Ca, TE-1, EC18, and HKESC-1.	('KYSE-520', 'Var', (246, 254))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (139, 159))	('KYSE-410', 'Var', (256, 264))	('HKESC-1', 'CellLine', 'CVCL:D568', (289, 296))	('KYSE-140', 'Var', (207, 215))	('KYSE-180', 'Var', (217, 225))	('human', 'Species', '9606', (133, 138))
835809	23056210	More specifically, the median survival time of patients with high expression levels of GOLPH3 protein was only 15 months, whereas the median survival time of those with low levels of GOLPH3 was 45 months.	('high expression', 'Var', (61, 76))	('GOLPH3', 'Gene', (87, 93))	('patients', 'Species', '9606', (47, 55))	('protein', 'Protein', (94, 101))
835814	23056210	Similarly, the overall survival was significantly shorter in patients with high GOLPH3 expression in both the T1+T2 subgroup (n = 54, P<0.0001; Figure 3C) and the T3+T4 subgroup (n = 101, P<0.0001; Figure 3D), or in lymph node metastasis negative (n = 78, P = 0.003; Figure 3E) and positive patients (n = 77, P<0.0001; Figure 3F).	('GOLPH3', 'Gene', (80, 86))	('high', 'Var', (75, 79))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (291, 299))	('expression', 'MPA', (87, 97))	('overall survival', 'CPA', (15, 31))	('shorter', 'NegReg', (50, 57))
835819	23056210	Furthermore, deletion of Vps35 in budding yeast leads to rapamycin hypersensitivity, consistent with an impairment of TORC1 signaling.	('hypersensitivity,', 'Disease', 'MESH:D004342', (67, 84))	('leads to', 'Reg', (48, 56))	('rapamycin', 'Chemical', 'MESH:D020123', (57, 66))	('yeast', 'Species', '4932', (42, 47))	('deletion', 'Var', (13, 21))	('TORC1', 'Gene', (118, 123))	('TORC1', 'Gene', '382056', (118, 123))	('Vps35', 'Gene', (25, 30))
835821	23056210	In xenograft experiments conducted in immunodeficient mice, tumor cells with overexpressed GOLPH3 showed increased sensitivity to therapy with the TORC1 inhibitor, rapamycin.	('TORC1', 'Gene', (147, 152))	('TORC1', 'Gene', '382056', (147, 152))	('immunodeficient', 'Disease', 'MESH:D007153', (38, 53))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('immunodeficient', 'Disease', (38, 53))	('rapamycin', 'Chemical', 'MESH:D020123', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('sensitivity', 'MPA', (115, 126))	('increased', 'PosReg', (105, 114))	('overexpressed', 'Var', (77, 90))	('mice', 'Species', '10090', (54, 58))	('tumor', 'Disease', (60, 65))	('GOLPH3', 'Gene', (91, 97))
835825	23056210	In addition, GOLPH3 and GOLPH3L knockdown by small interfering RNA prevented the proliferation of human rhabdomyosarcoma cell lines.	('prevented', 'NegReg', (67, 76))	('GOLPH3L', 'Gene', (24, 31))	('small interfering', 'Var', (45, 62))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (104, 120))	('GOLPH3L', 'Gene', '55204', (24, 31))	('RNA', 'Gene', (63, 66))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (104, 120))	('rhabdomyosarcoma', 'Disease', (104, 120))	('proliferation', 'CPA', (81, 94))	('human', 'Species', '9606', (98, 103))
835829	23056210	In consistence with these studies, our results reveal that high GOLPH3 expression is an independent prognostic factor of ESCC patients.	('expression', 'MPA', (71, 81))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (126, 134))	('ESCC', 'Disease', (121, 125))	('GOLPH3', 'Gene', (64, 70))
835837	23056210	ESCC patients expressing high levels of GOLPH3 also exhibit a substantially lower 5-year overall survival rate than GOLPH3-low expression patients.	('high levels', 'Var', (25, 36))	('patients', 'Species', '9606', (5, 13))	('lower', 'NegReg', (76, 81))	('overall survival', 'MPA', (89, 105))	('patients', 'Species', '9606', (138, 146))
835859	31833863	Direct comparisons have suggested that there is an incremental yield in dysplasia detection using adjunctive VLE, when compared with surveillance with gold standard 4-quadrant random biopsies alone.	('dysplasia', 'Disease', 'MESH:D015792', (72, 81))	('dysplasia', 'Disease', (72, 81))	('men', 'Species', '9606', (56, 59))	('adjunctive', 'Var', (98, 108))
835871	31833863	The aim of this study was to determine whether the addition of WATS-3D would increase the yield of dysplasia detection after a complete examination with high-definition white light endoscopy (HDWLE), NBI, VLE with laser marking, and SP biopsies.	('dysplasia', 'Disease', 'MESH:D015792', (99, 108))	('WATS-3D', 'Var', (63, 70))	('dysplasia', 'Disease', (99, 108))	('increase', 'PosReg', (77, 85))
835896	31833863	The mean Prague classification of the BE surveyed during the procedures was C2M3.	('BE', 'Phenotype', 'HP:0100580', (38, 40))	('C2M3', 'Var', (76, 80))	('Prague', 'Disease', (9, 15))	('BE', 'Disease', 'MESH:D001471', (38, 40))
835935	30420492	 TP73 G4C14-A4T14 polymorphism and cancer susceptibility: evidence from 36 case-control studies G4C14-A4T14 polymorphism of TP73 gene has been reported with a potential association in cancer risks through affected cell homeostasis; however the results were not consistent.	('cancer', 'Disease', (184, 190))	('association', 'Reg', (169, 180))	('TP73', 'Gene', '7161', (124, 128))	('TP73', 'Gene', (124, 128))	('polymorphism', 'Var', (108, 120))	('G4C14-A4T14 polymorphism', 'Var', (96, 120))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('TP73', 'Gene', '7161', (1, 5))	('TP73', 'Gene', (1, 5))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (35, 41))
835936	30420492	We performed a comprehensive meta-analysis to explore the associations between G4C14-A4T14 polymorphism and cancer susceptibility.	('associations', 'Interaction', (58, 70))	('G4C14-A4T14', 'Var', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
835939	30420492	The pooled results present a significantly higher risk of G4C14-A4T14 polymorphism in all the five genetic models, as well as in the subgroups of Caucasian, cervical cancer, colorectal cancer, H-B subgroup and comfort to Hardy-Weinberg equilibrium subgroup.	('G4C14-A4T14 polymorphism', 'Var', (58, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (174, 191))	('higher', 'PosReg', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('polymorphism', 'Var', (70, 82))	('cervical cancer', 'Disease', 'MESH:D002583', (157, 172))	('colorectal cancer', 'Disease', (174, 191))	('cervical cancer', 'Disease', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colorectal cancer', 'Disease', 'MESH:D015179', (174, 191))
835942	30420492	G4C14-A4T14 polymorphism might be a potential biomarker for judging the tumorigenesis of cervical cancer and colorectal cancer.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('cervical cancer', 'Disease', 'MESH:D002583', (89, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('cervical cancer', 'Disease', (89, 104))	('polymorphism', 'Var', (12, 24))	('G4C14-A4T14', 'Gene', (0, 11))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
835948	30420492	In the past decades, biological scientists have reported that environmental factors, genetic mutations and the multiple interactions between them mainly affect the process of tumorigenesis, and the new research results are also on the road, such as epigenetic control.	('tumor', 'Disease', (175, 180))	('interactions', 'Interaction', (120, 132))	('affect', 'Reg', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('genetic mutations', 'Var', (85, 102))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
835952	30420492	G4A (rs2273953) and C14T (rs1801173), the two single-nucleotide polymorphisms (SNPs) of TP73 at positions 4 (G>A) and 14 (C>T), are incomplete linkage disequilibrium with each other, so we called it as G4C14-A4T14.	('C14T', 'Mutation', 'rs1801173', (20, 24))	('TP73', 'Gene', '7161', (88, 92))	('rs2273953', 'Var', (5, 14))	('TP73', 'Gene', (88, 92))	('rs1801173', 'Var', (26, 35))	('rs1801173', 'Mutation', 'rs1801173', (26, 35))	('G4A', 'Mutation', 'rs2273953', (0, 3))	('14 (C>T)', 'Mutation', 'rs1801173', (118, 126))	('rs2273953', 'Mutation', 'rs2273953', (5, 14))
835953	30420492	G4C14-A4T14 is located at the upstream of TP73 promoter in exon 2, it could influence the expression of TP73 through a stem-loop structure.	('TP73', 'Gene', '7161', (104, 108))	('TP73', 'Gene', (104, 108))	('G4C14-A4T14', 'Var', (0, 11))	('TP73', 'Gene', '7161', (42, 46))	('TP73', 'Gene', (42, 46))	('expression', 'MPA', (90, 100))	('influence', 'Reg', (76, 85))
835954	30420492	In recent years, G4C14-A4T14 polymorphism of TP73 was identified implicated in the tumorigenesis of a variety of cancer types, including breast cancer, colorectal cancer, lung cancer, cervical cancer, esophageal cancer and so on.	('cervical cancer', 'Disease', (184, 199))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('cervical cancer', 'Disease', 'MESH:D002583', (184, 199))	('cancer', 'Disease', (193, 199))	('tumor', 'Disease', (83, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('colorectal cancer', 'Disease', (152, 169))	('esophageal cancer', 'Disease', 'MESH:D004938', (201, 218))	('implicated in', 'Reg', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('TP73', 'Gene', '7161', (45, 49))	('esophageal cancer', 'Disease', (201, 218))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('TP73', 'Gene', (45, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('G4C14-A4T14 polymorphism', 'Var', (17, 41))	('lung cancer', 'Disease', (171, 182))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (176, 182))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))
835956	30420492	Therefore, we conducted a comprehensive meta-analysis to explore the association between G4C14-A4T14 polymorphism and cancer susceptibility.	('cancer', 'Disease', (118, 124))	('G4C14-A4T14', 'Gene', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('polymorphism', 'Var', (101, 113))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
835958	30420492	The full-text of the remaining articles was further carefully inspected to determine whether to report the correlation of between G4C14-A4T14 polymorphism and cancer susceptibility.	('cancer', 'Disease', (159, 165))	('G4C14-A4T14', 'Gene', (130, 141))	('polymorphism', 'Var', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
835959	30420492	All the eligible studies should fulfill the following inclusion criteria: (1) case-control studies focus on the correlation between G4C14-A4T14 polymorphism and cancer susceptibility; (2) genotype frequency of the cases and controls could be obtained directly or indirectly through calculation; and (3) articles in English or Chinese.	('polymorphism', 'Var', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('G4C14-A4T14', 'Gene', (132, 143))
835960	30420492	ORs with corresponding 95% CIs were performed to measure the strength of the relationship between G4C14-A4T14 polymorphism and cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('polymorphism', 'Var', (110, 122))	('G4C14-A4T14', 'Gene', (98, 109))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
835966	30420492	After reviewing titles and abstracts, we excluded 1537 publications not investigating the association between TP73 G4C14-A4T14 polymorphism and cancer risk.	('polymorphism', 'Var', (127, 139))	('TP73', 'Gene', '7161', (110, 114))	('TP73', 'Gene', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
835969	30420492	Table 2 listed the main results of current meta-analysis work of polymorphisms in G4C14-A4T14 and risk of cancer.	('G4C14-A4T14', 'Gene', (82, 93))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('polymorphisms', 'Var', (65, 78))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
835970	30420492	The pooled results of the 36 included studies had shown that G4C14-A4T14 polymorphism conferred a significantly higher overall risk to cancer susceptibility in all the five genetic models, allelic contrast model (GC vs. AT: OR = 1.139, 95% CI = 1.048-1.238, P=0.002), homozygote comparison model (GC/GC vs. AT/AT: OR = 1.320, 95% CI = 1.071-1.627, P=0.009), heterozygote comparison model (GC/AT vs. AT/AT: OR = 1.123, 95% CI = 1.012-1.245, P=0.028), dominant comparison model (GC/GC+GC/AT vs. AT/AT: OR = 1.152, 95% CI = 1.044-1.272, P=0.005) and recessive comparison model (GC/GC vs. GC/AT+AT/AT: OR = 1.273, 95% CI = 1.038-1.563, P=0.021) (Table 2 and Figure 2).	('cancer', 'Disease', (135, 141))	('higher', 'PosReg', (112, 118))	('G4C14-A4T14 polymorphism', 'Var', (61, 85))	('polymorphism', 'Var', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
835971	30420492	After overall pooled analysis, we also conducted stratification analysis by cancer type, in order to obtain more precise result about the G4C14-A4T14 polymorphism and cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('G4C14-A4T14', 'Var', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
835972	30420492	As shown in Table 2 and Figure 3, the subgroup analysis of six enrolled colorectal cancer related studies have shown that G4C14-A4T14 polymorphism was related to an increased cancer risk in allelic contrast model (GC vs. AT: OR = 1.204, 95% CI = 1.044-1.389, P=0.011), homozygote comparison model (GC/GC vs. AT/AT: OR = 1.820, 95% CI = 1.270-2.608, P=0.001) and recessive comparison model (GC/GC vs. GC/AT+AT/AT: OR = 1.760, 95% CI = 1.241-2.496, P=0.002).	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('G4C14-A4T14 polymorphism', 'Var', (122, 146))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('colorectal cancer', 'Disease', (72, 89))	('polymorphism', 'Var', (134, 146))	('cancer', 'Disease', (83, 89))
835974	30420492	The meta-analysis revealed an increasing risk of cancer caused by G4C14-A4T14 polymorphism in allelic contrast model (GC vs. AT: OR = 1.189, 95% CI = 1.016-1.392, P=0.031), heterozygote comparison model (GC/AT vs. AT/AT: OR = 1.413, 95% CI = 1.159-1.722, P=0.001) and dominant comparison model (GC/GC+GC/AT vs. AT/AT: OR = 1.338, 95% CI = 1.106-1.618, P=0.003) (Table 2, Figure 4).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('G4C14-A4T14', 'Var', (66, 77))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
835975	30420492	We also performed subgroup analysis of breast cancer, esophageal cancer, gastric cancer, lung cancer and squamous cell carcinoma of the head and neck, no significant association was found between G4C14-A4T14 polymorphism and these carcinomas in all five genetic models (Table 2 and Figures S1-S4).	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 128))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', (39, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('carcinomas', 'Disease', 'MESH:D002277', (231, 241))	('squamous cell carcinoma', 'Disease', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('polymorphism', 'Var', (208, 220))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (119, 149))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('lung cancer', 'Disease', (89, 100))	('G4C14-A4T14', 'Gene', (196, 207))	('esophageal cancer', 'Disease', (54, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('carcinomas', 'Disease', (231, 241))	('gastric cancer', 'Disease', (73, 87))
835977	30420492	The remarkable result shown a noticeable upgrade cancer risk of G4C14-A4T14 polymorphism of the hospital-based control subgroup in allelic contrast model (GC vs. AT: OR = 1.213, 95%CI = 1.079-1.365, P=0.001), homozygote comparison model (GC/GC vs. AT/AT: OR = 1.625, 95% CI = 1.210-2.183 P=0.001), dominant comparison model (GC/GC+GC/AT vs. AT/AT: OR = 1.204, 95% CI = 1.042-1.392, P=0.012) and recessive comparison model (GC/GC vs. GC/AT+AT/AT: OR = 1.545, 95% CI = 1.139-2.094, P=0.005), while there was no significant result of the heterozygote comparison model (GC/AT vs. AT/AT: OR = 1.134, 95% CI = 0.964-1.334, P=0.129).	('upgrade', 'PosReg', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('G4C14-A4T14', 'Var', (64, 75))	('cancer', 'Disease', (49, 55))
835979	30420492	As shown in Table 2 and Figure S7, the subgroup that conforms to HWE was uncovered responsible to the remarkable increasing cancer risk of G4C14-A4T14 polymorphism in allelic contrast model (GC vs. AT: OR = 1.138, 95%CI = 1.044-1.239, P=0.003), homozygote comparison model (GC/GC vs. AT/AT: OR = 1.342, 95% CI = 1.085-1.659, P=0.007), dominant comparison model (GC/GC+GC/AT vs. AT/AT: OR = 1.138, 95% CI = 1.032-1.255, P=0.010) and recessive comparison model (GC/GC vs. GC/AT+AT/AT: OR = 1.309, 95% CI = 1.063-1.613, P=0.011), whereas the other four case-control studies that do not conform to HWE did not influence the result in overall cancer (Table 2 and Figure S7).	('cancer', 'Disease', (124, 130))	('polymorphism', 'Var', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (638, 644))	('cancer', 'Disease', 'MESH:D009369', (638, 644))	('G4C14-A4T14', 'Var', (139, 150))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (638, 644))
835991	30420492	In the past decades, almost 146 unique variations had been reported (shown in the Biomuta database), while numerous studies had probed into the relationship of G4C14-A4T14 polymorphism and cancer genomics.	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('variations', 'Var', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('G4C14-A4T14', 'Gene', (160, 171))	('cancer', 'Disease', (189, 195))
835992	30420492	G4A (rs2273953) and C14T (rs1801173) polymorphisms are located at position 4 (G to A) and 14 (C to T) of exon 2 5'-untranslated region, which might influence the initiating AUG codon through constructing a stem-loop.	('4 (G to A', 'Mutation', 'rs2273953', (75, 84))	('14 (C to T', 'Mutation', 'rs1801173', (90, 100))	('C14T', 'Mutation', 'rs1801173', (20, 24))	('rs2273953', 'Var', (5, 14))	('rs1801173', 'Var', (26, 35))	('rs1801173', 'Mutation', 'rs1801173', (26, 35))	('influence', 'Reg', (148, 157))	('rs2273953', 'Mutation', 'rs2273953', (5, 14))	('G4A', 'Mutation', 'rs2273953', (0, 3))
835993	30420492	reported that G4C14-A4T14 polymorphism was not associated with the cancer susceptibility of cervical cancer in Uighur and Japanese, respectively.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (101, 107))	('cervical cancer', 'Disease', 'MESH:D002583', (92, 107))	('G4C14-A4T14 polymorphism', 'Var', (14, 38))	('cervical cancer', 'Disease', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('polymorphism', 'Var', (26, 38))
835994	30420492	revealed that G4C14-A4T14 polymorphism leads to an increasing risk of cervical cancer, as well as the newest study conducted by Feng et al..As colorectal cancer, Hamajima et al.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('colorectal cancer', 'Disease', (143, 160))	('G4C14-A4T14 polymorphism', 'Var', (14, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('cervical cancer', 'Disease', (70, 85))	('cervical cancer', 'Disease', 'MESH:D002583', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))	('polymorphism', 'Var', (26, 38))
835995	30420492	reported that GC/AT and AT/AT genotypes were significantly associated with colorectal cancer risk in Korean population.	('colorectal cancer', 'Disease', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('AT/AT', 'Var', (24, 29))	('associated', 'Reg', (59, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('GC/AT', 'Var', (14, 19))
835996	30420492	also uncovered that no remarkable differences of genotype frequencies in cancers and controls, but they found that AT/AT genotype might cause the poor prognosis of colorectal cancer.	('cancers', 'Disease', (73, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (164, 181))	('colorectal cancer', 'Disease', (164, 181))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (164, 181))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('AT/AT genotype', 'Var', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
835998	30420492	indicated that both AT/AT and GC/AT variants were associated with a remarkable decreased risk for lung cancer, distinguishingly, Li et al.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('decreased', 'NegReg', (79, 88))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('variants', 'Var', (36, 44))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))
835999	30420492	suggested that the AT/AT and GC/AT genotypes were related with a statistically significantly increased risk for lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('GC/AT', 'Var', (29, 34))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('AT/AT', 'Var', (19, 24))
836001	30420492	Among these publications concerned about G4C14-A4T14 polymorphism and cancer risk, the result is not consistent.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('G4C14-A4T14', 'Gene', (41, 52))	('polymorphism', 'Var', (53, 65))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
836002	30420492	conducted a meta-analysis about G4C14-A4T14 polymorphism and cervical cancer, they only enrolled 5 studies, as well as Liu et al., they only enrolled 5 studies about lung cancer.	('G4C14-A4T14', 'Gene', (32, 43))	('cervical cancer', 'Disease', 'MESH:D002583', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('cervical cancer', 'Disease', (61, 76))	('polymorphism', 'Var', (44, 56))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
836003	30420492	All in all, our recent updated meta-analysis draws a comprehensive, precise and convincible result, which is that G4C14-A4T14 polymorphism of TP73 is strongly associated with the increasing cancer risk, especially for Caucasian, cervical cancer and colorectal cancer.	('colorectal cancer', 'Disease', (249, 266))	('TP73', 'Gene', '7161', (142, 146))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', (238, 244))	('cervical cancer', 'Disease', (229, 244))	('cervical cancer', 'Disease', 'MESH:D002583', (229, 244))	('TP73', 'Gene', (142, 146))	('associated with', 'Reg', (159, 174))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('G4C14-A4T14 polymorphism', 'Var', (114, 138))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (249, 266))	('cancer', 'Disease', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('colorectal cancer', 'Disease', 'MESH:D015179', (249, 266))	('polymorphism', 'Var', (126, 138))
836004	30420492	Therefore, in the future, G4C14-A4T14 polymorphism might be a useful diagnostic marker for cervical cancer and colorectal cancer, especially in Caucasian population.	('polymorphism', 'Var', (38, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('cervical cancer', 'Disease', (91, 106))	('cervical cancer', 'Disease', 'MESH:D002583', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('G4C14-A4T14 polymorphism', 'Var', (26, 50))
836005	30420492	On the other hand, for researchers, other polymorphisms of TP73 should be focused on to assess whether they change cancer risks.	('TP73', 'Gene', '7161', (59, 63))	('cancer', 'Disease', (115, 121))	('TP73', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('polymorphisms', 'Var', (42, 55))	('change', 'Reg', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
836006	30420492	The current result about G4C14-A4T14 polymorphism and cancer risk should be cautiously interpreted, because there are some limitations.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('G4C14-A4T14', 'Gene', (25, 36))	('polymorphism', 'Var', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
836038	30574087	This downregulation has been correlated with the hypermethylation of a specific CpG site in the 5' UTR region of TMEM25 gene in a high proportion of tumor samples.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('hypermethylation', 'Var', (49, 65))	('downregulation', 'NegReg', (5, 19))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('TMEM25', 'Gene', (113, 119))	('tumor', 'Disease', (149, 154))	('TMEM25', 'Gene', '84866', (113, 119))
836040	30574087	The expression of TMEM25 was correlated with a better overall survival and associated with a longer survival time for patients who received adjuvant chemotherapy.	('better', 'PosReg', (47, 53))	('TMEM25', 'Gene', '84866', (18, 24))	('survival', 'CPA', (100, 108))	('expression', 'Var', (4, 14))	('overall', 'MPA', (54, 61))	('TMEM25', 'Gene', (18, 24))	('patients', 'Species', '9606', (118, 126))
836051	30574087	Indeed, ectopic expression of TMEM7 in two TMEM7 deficient hepatocarcinoma cell lines decreased tumor growth in nude mice.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('TMEM7 deficient hepatocarcinoma cell lines decreased tumor', 'Disease', 'MESH:D005935', (43, 101))	('ectopic expression', 'Var', (8, 26))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TMEM7', 'Gene', (30, 35))	('nude mice', 'Species', '10090', (112, 121))
836055	30574087	analyzed the methylation profile of TMEM176A promoter in 13 cell lines (BIC1, TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Segl, KYSE150, YES2, and COLO680N) and 267 primary esophageal squamous cell carcinoma.	('KYSE520', 'Var', (130, 137))	('KYSE150', 'Var', (145, 152))	('KYSE180', 'Var', (103, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('KYSE410', 'Var', (112, 119))	('YES2', 'Gene', '7526', (154, 158))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (190, 224))	('TMEM176A', 'Gene', '55365', (36, 44))	('KYSE140', 'Var', (94, 101))	('YES2', 'Gene', (154, 158))	('KYSE450', 'Var', (121, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('COLO', 'Species', '307630', (164, 168))	('TMEM176A', 'Gene', (36, 44))	('esophageal squamous cell carcinoma', 'Disease', (190, 224))
836056	30574087	The results showed the loss of TMEM176 expression in 12 cell lines (TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Segl, KYSE150, YES2, and COLO680N) in association with a complete methylation of its promoter.	('KYSE180', 'Var', (93, 100))	('TMEM176', 'Gene', (31, 38))	('YES2', 'Gene', '7526', (144, 148))	('TMEM', 'Chemical', '-', (31, 35))	('KYSE520', 'Var', (120, 127))	('KYSE140', 'Var', (84, 91))	('KYSE150', 'Var', (135, 142))	('KYSE410', 'Var', (102, 109))	('COLO', 'Species', '307630', (154, 158))	('YES2', 'Gene', (144, 148))	('KYSE450', 'Var', (111, 118))	('loss', 'NegReg', (23, 27))	('COLO680N', 'Var', (154, 162))	('expression', 'MPA', (39, 49))
836058	30574087	This methylation and TMEM176A decreased expression were correlated with poor overall survival.	('expression', 'MPA', (40, 50))	('methylation', 'Var', (5, 16))	('TMEM176A', 'Gene', (21, 29))	('decreased', 'NegReg', (30, 39))	('TMEM176A', 'Gene', '55365', (21, 29))
836063	30574087	The results also showed a normal expression of TMEM176A in LS180 and SW620 cell lines, a decreased expression in HT29 and SW480 cell lines and a total loss of expression in LOVO, HCT116, RKO, and DLD1 cell lines respectively associated with no methylation, partial methylation and total methylation of TMEM176A promoter.	('expression', 'MPA', (99, 109))	('TMEM176A', 'Gene', (47, 55))	('SW480', 'CellLine', 'CVCL:0546', (122, 127))	('partial methylation', 'Var', (257, 276))	('TMEM176A', 'Gene', '55365', (302, 310))	('TMEM176A', 'Gene', '55365', (47, 55))	('HT29', 'CellLine', 'CVCL:0320', (113, 117))	('expression', 'MPA', (159, 169))	('HCT116', 'CellLine', 'CVCL:0291', (179, 185))	('TMEM176A', 'Gene', (302, 310))	('SW620', 'CellLine', 'CVCL:0547', (69, 74))	('loss', 'NegReg', (151, 155))	('decreased', 'NegReg', (89, 98))
836079	30574087	This hypothesis may also be true for prostate cancer since miR-152-3p downregulation and promoter methylation were found to be prevalent in primary prostate cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('primary prostate cancers', 'Disease', 'MESH:D011471', (140, 164))	('prostate cancer', 'Phenotype', 'HP:0012125', (37, 52))	('miR-152', 'Gene', '406943', (59, 66))	('primary prostate cancers', 'Disease', (140, 164))	('prostate cancer', 'Disease', (37, 52))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('miR-152', 'Gene', (59, 66))	('prostate cancer', 'Disease', 'MESH:D011471', (37, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (148, 163))	('prostate cancers', 'Phenotype', 'HP:0012125', (148, 164))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('prostate cancer', 'Phenotype', 'HP:0012125', (148, 163))	('downregulation', 'NegReg', (70, 84))	('promoter methylation', 'Var', (89, 109))	('prevalent', 'Reg', (127, 136))
836085	30574087	Nucleoporin deregulation has been implicated in several malignancies such as breast cancers in multiple tumors including melanoma, pancreatic, colon, gastric, prostate, esophageal, lung cancer, and lymphomas.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('breast cancers', 'Disease', 'MESH:D001943', (77, 91))	('melanoma', 'Disease', (121, 129))	('breast cancers', 'Disease', (77, 91))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('implicated', 'Reg', (34, 44))	('breast cancers', 'Phenotype', 'HP:0003002', (77, 91))	('pancreatic', 'Disease', (131, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('Nucleoporin', 'Gene', '729857', (0, 11))	('multiple tumors', 'Disease', 'MESH:D009369', (95, 110))	('lymphomas', 'Phenotype', 'HP:0002665', (198, 207))	('lung cancer', 'Disease', (181, 192))	('deregulation', 'Var', (12, 24))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('lymphomas', 'Disease', (198, 207))	('multiple tumors', 'Disease', (95, 110))	('gastric', 'Disease', (150, 157))	('malignancies', 'Disease', (56, 68))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('lymphoma', 'Phenotype', 'HP:0002665', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('esophageal', 'Disease', (169, 179))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('colon', 'Disease', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('lymphomas', 'Disease', 'MESH:D008223', (198, 207))	('Nucleoporin', 'Gene', (0, 11))	('prostate', 'Disease', (159, 167))	('pancreatic', 'Disease', 'MESH:D010195', (131, 141))
836100	30574087	One study on ovarian cancer showed that high expression of TMEM97 was correlated with high histological grade and tumor recurrence.	('high', 'Var', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('TMEM97', 'Gene', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('ovarian cancer', 'Phenotype', 'HP:0100615', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('ovarian cancer', 'Disease', 'MESH:D010051', (13, 27))	('TMEM97', 'Gene', '27346', (59, 65))	('tumor', 'Disease', (114, 119))	('expression', 'MPA', (45, 55))	('high histological grade', 'CPA', (86, 109))	('ovarian cancer', 'Disease', (13, 27))	('correlated', 'Reg', (70, 80))
836101	30574087	All these studies demonstrated that TMEM97 expression could affect the prognosis of NSCLC, SQCLC, ovarian and breast cancer patients.	('TMEM97', 'Gene', '27346', (36, 42))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (98, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('expression', 'Var', (43, 53))	('SQCLC', 'Disease', (91, 96))	('TMEM97', 'Gene', (36, 42))	('NSCLC', 'Disease', (84, 89))	('affect', 'Reg', (60, 66))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('patients', 'Species', '9606', (124, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
836120	30574087	TMEM158 is overexpressed in Wilms tumors (also known as nephroblastoma) with somatic mutations in catenin beta-1 gene suggesting a relationship between the Ras and Wnt signaling pathways.	('nephroblastoma', 'Disease', 'MESH:D009396', (56, 70))	('Wilms tumors', 'Phenotype', 'HP:0002667', (28, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('Wilms tumors', 'Disease', (28, 40))	('catenin beta-1', 'Gene', (98, 112))	('nephroblastoma', 'Disease', (56, 70))	('overexpressed', 'PosReg', (11, 24))	('TMEM158', 'Gene', '25907', (0, 7))	('TMEM158', 'Gene', (0, 7))	('Wilms tumors', 'Disease', 'MESH:D009396', (28, 40))	('mutations', 'Var', (85, 94))	('catenin beta-1', 'Gene', '1499', (98, 112))	('nephroblastoma', 'Phenotype', 'HP:0002667', (56, 70))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
836123	30574087	Furthermore, TMEM158 knockdown inhibited tumor growth of HO-8910 cell line in nude mice highlighting the role of this protein in tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('HO-8910', 'CellLine', 'CVCL:6868', (57, 64))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (41, 46))	('TMEM158', 'Gene', '25907', (13, 20))	('nude mice', 'Species', '10090', (78, 87))	('TMEM158', 'Gene', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (21, 30))
836124	30574087	TMEM158 silencing led to the deregulation of the expression of different genes, including a downregulation of ICAM1 and VCAM1 expression.	('ICAM1', 'Gene', (110, 115))	('downregulation', 'NegReg', (92, 106))	('expression', 'MPA', (126, 136))	('VCAM1', 'Gene', '7412', (120, 125))	('TMEM158', 'Gene', '25907', (0, 7))	('silencing', 'Var', (8, 17))	('TMEM158', 'Gene', (0, 7))	('deregulation', 'MPA', (29, 41))	('expression', 'MPA', (49, 59))	('ICAM1', 'Gene', '3383', (110, 115))	('VCAM1', 'Gene', (120, 125))
836125	30574087	TMEM158 silencing also impaired the TGF-beta signaling pathway.	('TGF-beta', 'Gene', '7040', (36, 44))	('TMEM158', 'Gene', '25907', (0, 7))	('silencing', 'Var', (8, 17))	('impaired', 'NegReg', (23, 31))	('TMEM158', 'Gene', (0, 7))	('TGF-beta', 'Gene', (36, 44))
836128	30574087	Indeed, the silencing of this gene impaired cell proliferation, induced cell cycle arrest and decreased the migration and invasive ability of NSCLC cells.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('cell proliferation', 'CPA', (44, 62))	('induced', 'Reg', (64, 71))	('NSCLC', 'Disease', (142, 147))	('arrest', 'Disease', (83, 89))	('silencing', 'Var', (12, 21))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('decreased', 'NegReg', (94, 103))	('impaired', 'NegReg', (35, 43))
836130	30574087	A marked decrease in tumor weight (50%) was evidenced when TMEM48 was silenced.	('TMEM48', 'Gene', (59, 65))	('tumor', 'Disease', (21, 26))	('silenced', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('decrease', 'NegReg', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
836137	30574087	Further investigations showed that TMEM14A knockdown may down-regulate the protein expression of PCNA, cyclins and MMPs.	('MMPs', 'Gene', (115, 119))	('PCNA', 'Gene', '5111', (97, 101))	('knockdown', 'Var', (43, 52))	('cyclins', 'Gene', '891', (103, 110))	('MMPs', 'Gene', '4316', (115, 119))	('TMEM14A', 'Gene', (35, 42))	('TMEM14A', 'Gene', '28978', (35, 42))	('cyclins', 'Gene', (103, 110))	('PCNA', 'Gene', (97, 101))	('down-regulate', 'NegReg', (57, 70))	('protein expression', 'MPA', (75, 93))
836141	30574087	Indeed, the silencing of TMEM97 expression in glioma U373 and U87 cells inhibited cell proliferation and cell cycle progression associated with a decrease in cyclin B1, E, CDK2 and CDK4 expression, but also in cell invasiveness.	('CDK2', 'Gene', (172, 176))	('cell invasiveness', 'CPA', (210, 227))	('CDK4', 'Gene', '1019', (181, 185))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('TMEM97', 'Gene', (25, 31))	('cell proliferation', 'CPA', (82, 100))	('U87', 'Gene', (62, 65))	('decrease', 'NegReg', (146, 154))	('TMEM97', 'Gene', '27346', (25, 31))	('silencing', 'Var', (12, 21))	('cell cycle progression', 'CPA', (105, 127))	('inhibited', 'NegReg', (72, 81))	('cyclin B1, E', 'Gene', '891', (158, 170))	('glioma', 'Disease', (46, 52))	('CDK4', 'Gene', (181, 185))	('expression', 'MPA', (186, 196))	('CDK2', 'Gene', '1017', (172, 176))	('glioma', 'Disease', 'MESH:D005910', (46, 52))	('U87', 'Gene', '641648', (62, 65))
836144	30574087	The invalidation of TMEM97 also induced an inhibition of cell migration and invasion by reducing the expression of cyclin B1 and WAVE2.	('WAVE2', 'Gene', (129, 134))	('inhibition', 'NegReg', (43, 53))	('TMEM97', 'Gene', '27346', (20, 26))	('cyclin B1', 'Gene', '891', (115, 124))	('cyclin B1', 'Gene', (115, 124))	('WAVE2', 'Gene', '10163', (129, 134))	('invalidation', 'Var', (4, 16))	('TMEM97', 'Gene', (20, 26))	('invasion', 'CPA', (76, 84))	('expression', 'MPA', (101, 111))	('cell migration', 'CPA', (57, 71))	('reducing', 'NegReg', (88, 96))
836148	30574087	TMEM16A knockdown in SW620 cell line inhibited cell proliferation, migration and invasion.	('TMEM16A', 'Gene', '55107', (0, 7))	('inhibited', 'NegReg', (37, 46))	('knockdown', 'Var', (8, 17))	('invasion', 'CPA', (81, 89))	('SW620', 'CellLine', 'CVCL:0547', (21, 26))	('migration', 'CPA', (67, 76))	('TMEM16A', 'Gene', (0, 7))	('cell proliferation', 'CPA', (47, 65))
836150	30574087	Furthermore, invalidation of TMEM16A expression led to a delay in cell cycle progression.	('cell cycle progression', 'CPA', (66, 88))	('invalidation', 'Var', (13, 25))	('TMEM16A', 'Gene', (29, 36))	('TMEM16A', 'Gene', '55107', (29, 36))	('delay', 'NegReg', (57, 62))
836157	30574087	TMEM16A silencing was also shown to induce apoptosis in human prostate cancer PC3 cells by upregulating TGF-beta signaling.	('TMEM16A', 'Gene', '55107', (0, 7))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('apoptosis', 'CPA', (43, 52))	('TGF-beta', 'Gene', (104, 112))	('PC3', 'CellLine', 'CVCL:0035', (78, 81))	('silencing', 'Var', (8, 17))	('human', 'Species', '9606', (56, 61))	('prostate cancer', 'Disease', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TGF-beta', 'Gene', '7040', (104, 112))	('TMEM16A', 'Gene', (0, 7))	('induce', 'PosReg', (36, 42))	('upregulating', 'PosReg', (91, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))
836159	30574087	The invalidation of TMEM16A expression in these cell lines using siRNA showed an implication of this protein in cell migration but not in the proliferation illustrating that TMEM16A modulates the metastatic potential of pancreatic cancer cells.	('TMEM16A', 'Gene', '55107', (174, 181))	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('modulates', 'Reg', (182, 191))	('TMEM16A', 'Gene', '55107', (20, 27))	('invalidation', 'Var', (4, 16))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('metastatic potential', 'CPA', (196, 216))	('TMEM16A', 'Gene', (174, 181))	('cell migration', 'CPA', (112, 126))	('TMEM16A', 'Gene', (20, 27))	('pancreatic cancer', 'Disease', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
836173	30574087	Moreover, in vivo analysis showed that the number of lung metastatic nodules increased in the mice transplanted with cell lines expressing cytosolic TMEM88.	('cytosolic', 'Var', (139, 148))	('mice', 'Species', '10090', (94, 98))	('TMEM88', 'Gene', (149, 155))	('increased', 'PosReg', (77, 86))	('lung metastatic nodules', 'CPA', (53, 76))
836178	30574087	It seems that several TMEM proteins are involved in tumor growth through TGF-beta pathway modulation in order to facilitate malignant progression (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TGF-beta', 'Gene', '7040', (73, 81))	('TGF-beta', 'Gene', (73, 81))	('tumor', 'Disease', (52, 57))	('modulation', 'Var', (90, 100))	('malignant progression', 'CPA', (124, 145))	('TMEM', 'Chemical', '-', (22, 26))	('facilitate', 'PosReg', (113, 123))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
836184	30574087	Furthermore, the knockdown of TMEM140 led to a decreased cell adhesion, migration and invasion.	('migration', 'CPA', (72, 81))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (47, 70))	('TMEM140', 'Gene', '55281', (30, 37))	('TMEM140', 'Gene', (30, 37))	('knockdown', 'Var', (17, 26))	('cell adhesion', 'CPA', (57, 70))	('invasion', 'CPA', (86, 94))	('decreased', 'NegReg', (47, 56))
836185	30574087	It has also been shown that the invalidation of this protein inhibited tumor growth in vivo with a decrease in the size and the weight of tumors in the invalidated group compared to the control group.	('inhibited', 'NegReg', (61, 70))	('tumor', 'Disease', (138, 143))	('weight of tumors', 'Disease', (128, 144))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('decrease', 'NegReg', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (71, 76))	('size', 'CPA', (115, 119))	('weight of tumors', 'Disease', 'MESH:D015431', (128, 144))	('invalidation', 'Var', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
836191	30574087	Invalidation of TMEM45B in A549 and NCI-H1975 cells led to the inhibition of cell proliferation, migration, and invasion highlighting its role in tumor growth in lung cancer.	('TMEM45B', 'Gene', (16, 23))	('TMEM45B', 'Gene', '120224', (16, 23))	('A549', 'CellLine', 'CVCL:0023', (27, 31))	('migration', 'CPA', (97, 106))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('NCI-H1975', 'CellLine', 'CVCL:1511', (36, 45))	('Invalidation', 'Var', (0, 12))	('invasion', 'CPA', (112, 120))	('tumor', 'Disease', (146, 151))	('lung cancer', 'Disease', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('inhibition', 'NegReg', (63, 73))	('cell proliferation', 'CPA', (77, 95))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
836195	30574087	Its knockdown suppressed the prolifreation, migration, and invasion of U2OS cells in vitro as well as tumor growth in nude mice.	('prolifreation', 'CPA', (29, 42))	('nude mice', 'Species', '10090', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('suppressed', 'NegReg', (14, 24))	('invasion', 'CPA', (59, 67))	('migration', 'CPA', (44, 53))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', (102, 107))	('U2OS', 'CellLine', 'CVCL:0042', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
836199	30574087	Although mutagenic alterations have long been associated with cancer development or drug resistance, epigenetic modifications and tumor microenvironment have also been linked to chemoresistance.	('linked', 'Reg', (168, 174))	('mutagenic alterations', 'Var', (9, 30))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('chemoresistance', 'CPA', (178, 193))	('associated', 'Reg', (46, 56))	('drug resistance', 'Phenotype', 'HP:0020174', (84, 99))	('epigenetic modifications', 'Var', (101, 125))	('tumor', 'Disease', (130, 135))
836200	30574087	Both epigenetic modifications and the tumor microenvironment can impact the expression or the localization of several TMEMs leading to a deregulation of treatment responses.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('epigenetic modifications', 'Var', (5, 29))	('TMEM', 'Chemical', '-', (118, 122))	('deregulation', 'MPA', (137, 149))	('expression', 'MPA', (76, 86))	('localization', 'MPA', (94, 106))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('TMEMs', 'Gene', (118, 123))	('treatment responses', 'MPA', (153, 172))	('impact', 'Reg', (65, 71))
836206	30574087	The hypomethylation of TMEM88 promoter observed in ovarian cancer led to an increased expression of the protein and to platinum resistance.	('TMEM88', 'Gene', (23, 29))	('hypomethylation', 'Var', (4, 19))	('increased', 'PosReg', (76, 85))	('protein', 'Protein', (104, 111))	('platinum resistance', 'CPA', (119, 138))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (51, 65))	('expression', 'MPA', (86, 96))	('platinum', 'Chemical', 'MESH:D010984', (119, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (51, 65))	('ovarian cancer', 'Disease', (51, 65))
836209	30574087	Furthermore, the invalidation of TMEM88 in cisplatin resistant cells increased the sensitivity of the cells to the chemotherapeutic drug.	('increased', 'PosReg', (69, 78))	('sensitivity', 'MPA', (83, 94))	('invalidation', 'Var', (17, 29))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('TMEM88', 'Gene', (33, 39))
836224	30574087	Furthermore, in two lung cancer cell lines, A549 and H460, the silencing of TMEM98 inhibited cell proliferation and suppressed the invasion and the migration of cancer cells meaning that this protein can have an impact in tumor growth.	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('inhibited', 'NegReg', (83, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (25, 31))	('H460', 'CellLine', 'CVCL:0459', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('TMEM98', 'Gene', (76, 82))	('suppressed', 'NegReg', (116, 126))	('invasion and', 'CPA', (131, 143))	('lung cancer', 'Disease', (20, 31))	('cell proliferation', 'CPA', (93, 111))	('TMEM98', 'Gene', '26022', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Disease', (222, 227))	('A549', 'CellLine', 'CVCL:0023', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('impact', 'Reg', (212, 218))	('silencing', 'Var', (63, 72))
836232	30574087	Furthermore, the silencing of TMEM88 restored p53 phosphorylation and activation under cisplatin or doxorubicin treatment.	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('phosphorylation', 'MPA', (50, 65))	('TMEM88', 'Gene', (30, 36))	('p53', 'Gene', (46, 49))	('activation', 'MPA', (70, 80))	('p53', 'Gene', '7157', (46, 49))	('doxorubicin', 'Chemical', 'MESH:D004317', (100, 111))	('silencing', 'Var', (17, 26))	('restored', 'PosReg', (37, 45))
836269	29863119	According to the literature, BMI < 18.5 (underweight) is associated with particularly high rates of both complications and death.	('death', 'Disease', (123, 128))	('death', 'Disease', 'MESH:D003643', (123, 128))	('BMI < 18.5', 'Var', (29, 39))
836277	29863119	However, as mortality is significantly higher with LAR and PD for patients with BMI > 30 in Japan and the USA, respectively, the influences of obesity may vary not only among surgical procedures but also according to race.	('obesity', 'Phenotype', 'HP:0001513', (143, 150))	('higher', 'PosReg', (39, 45))	('mortality', 'MPA', (12, 21))	('PD', 'Disease', 'MESH:D010300', (59, 61))	('obesity', 'Disease', 'MESH:D009765', (143, 150))	('BMI > 30', 'Var', (80, 88))	('obesity', 'Disease', (143, 150))	('patients', 'Species', '9606', (66, 74))
836283	29863119	A high BMI may increase the risk of postoperative leakage, which is an important postoperative complication,24, 25, 26 but being underweight may increase the risk of postoperative chylothorax.18, 19 Many studies have demonstrated that operative times become increasingly prolonged as BMI increases.18, 19, 21, 24  East Asia is the source of several reviews on the influences of obesity on gastric cancer surgery, reflecting the high morbidity associated with this cancer in the region.15, 27  Chen et al11 reported an obesity paradox wherein overall survival was significantly better in patients with BMI > 25 than in those with normal BMI.	('gastric cancer', 'Disease', (389, 403))	('cancer', 'Disease', (397, 403))	('gastric cancer', 'Disease', 'MESH:D013274', (389, 403))	('obesity', 'Disease', 'MESH:D009765', (518, 525))	('obesity', 'Phenotype', 'HP:0001513', (378, 385))	('cancer', 'Phenotype', 'HP:0002664', (464, 470))	('better', 'PosReg', (577, 583))	('obesity', 'Disease', (518, 525))	('cancer', 'Disease', 'MESH:D009369', (464, 470))	('gastric cancer', 'Phenotype', 'HP:0012126', (389, 403))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('obesity', 'Disease', 'MESH:D009765', (378, 385))	('patients', 'Species', '9606', (587, 595))	('cancer', 'Disease', (464, 470))	('obesity', 'Disease', (378, 385))	('BMI > 25', 'Var', (601, 609))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('obesity', 'Phenotype', 'HP:0001513', (518, 525))
836284	29863119	Nonetheless, other than the aforementioned report, many studies failed to demonstrate any influence of obesity on long-term survival.28, 29, 30, 31 By contrast, Struecker et al28 described short-term survival (postoperative death) as being significantly poorer in patients with BMI > 30, whereas Kurita et al29 described survival as tending to be less favorable in those with BMI > 25.	('BMI > 30', 'Var', (278, 286))	('postoperative death', 'Disease', 'MESH:D010149', (210, 229))	('poorer', 'NegReg', (254, 260))	('postoperative death', 'Disease', (210, 229))	('obesity', 'Phenotype', 'HP:0001513', (103, 110))	('patients', 'Species', '9606', (264, 272))	('obesity', 'Disease', 'MESH:D009765', (103, 110))	('obesity', 'Disease', (103, 110))
836297	29863119	Several studies have identified a high risk of surgical site infection (SSI) with obesity.43, 44 Similar adverse influences have been recognized for surgical procedures such as right hemicolectomy,45 LAR,46, 47 Hartmann surgery,48 Miles surgery,49 and robotic surgery.50 Moreover, obesity might reportedly be an independent risk factor for leakage.51, 52  A meta-analysis (n = 4550) of laparoscopic surgery by Fung et al53 found that, for colorectal cancer surgery, SSI, leakage, morbidity, and conversion rate are significantly higher in patients with BMI > 30 than in those with normal BMI.	('conversion', 'CPA', (495, 505))	('obesity', 'Phenotype', 'HP:0001513', (82, 89))	('higher', 'PosReg', (529, 535))	('obesity', 'Phenotype', 'HP:0001513', (281, 288))	('BMI > 30', 'Var', (553, 561))	('leakage', 'CPA', (471, 478))	('colorectal cancer', 'Disease', (439, 456))	('obesity', 'Disease', 'MESH:D009765', (82, 89))	('obesity', 'Disease', 'MESH:D009765', (281, 288))	('cancer', 'Phenotype', 'HP:0002664', (450, 456))	('obesity', 'Disease', (82, 89))	('patients', 'Species', '9606', (539, 547))	('obesity', 'Disease', (281, 288))	('morbidity', 'CPA', (480, 489))	('colorectal cancer', 'Disease', 'MESH:D015179', (439, 456))	('SSI', 'Disease', (466, 469))	('colorectal cancer', 'Phenotype', 'HP:0003003', (439, 456))
836301	29863119	Our group conducted a large-scale review to examine the impacts of obesity on hepatic resection and found that obesity (BMI > 30) prolonged operative time by approximately 50 min as compared to surgery on non-obese patients undergoing hepatectomy of more than one segment apart from the lateral segment (n = 14 903).12 In addition, Yokoo et al57, studying a similar surgical group, reported BMI > 30 to potentially be a risk factor for blood transfusion and BMI > 35 to be a risk factor for unplanned intubation (n = 14 970).	('obesity', 'Disease', 'MESH:D009765', (67, 74))	('patients', 'Species', '9606', (215, 223))	('obesity', 'Disease', (111, 118))	('obesity', 'Disease', (67, 74))	('blood', 'Disease', (436, 441))	('obesity', 'Phenotype', 'HP:0001513', (111, 118))	('non-obese', 'Disease', (205, 214))	('BMI > 35', 'Var', (458, 466))	('non-obese', 'Disease', 'MESH:D009765', (205, 214))	('obesity', 'Phenotype', 'HP:0001513', (67, 74))	('BMI > 30', 'Var', (391, 399))	('obesity', 'Disease', 'MESH:D009765', (111, 118))
836302	29863119	In a similar report, Langella et al58 noted that resection time, blood loss, and rate of pulmonary complications tended to rise if BMI > 30, and that obesity may negatively influence all three of these factors.	('resection time', 'CPA', (49, 63))	('obesity', 'Disease', 'MESH:D009765', (150, 157))	('BMI > 30', 'Var', (131, 139))	('obesity', 'Disease', (150, 157))	('blood loss', 'Disease', (65, 75))	('pulmonary complications', 'Phenotype', 'HP:0006532', (89, 112))	('pulmonary complications', 'Disease', (89, 112))	('obesity', 'Phenotype', 'HP:0001513', (150, 157))	('blood loss', 'Disease', 'MESH:D006473', (65, 75))	('rise', 'PosReg', (123, 127))	('pulmonary complications', 'Disease', 'MESH:D008171', (89, 112))
836309	29863119	Given these observations, increased BMI, which correlates with soft pancreatic consistency, a known risk factor for pancreatic fistula, might be among its causes.71, 72 Obesity is frequently reported to exert no influence on operative mortality in patients with pancreatic malignancies, as is the case with surgeries on other organs.68, 69, 70  In pancreaticoduodenectomy, numerous reviews have also consistently described obesity as exerting a negative influence.73, 74, 75, 76, 77 Aoki et al73, applying a risk model (n = 17 564), suggested BMI > 25 to potentially be a factor predicting severe complications (Clavien Dindo Classification Grade 4 or higher) including pancreatic fistula (International Study Group Pancreatic Fistula Grade C).	('Pancreatic Fistula', 'Disease', (716, 734))	('pancreatic', 'Disease', (348, 358))	('obesity', 'Phenotype', 'HP:0001513', (423, 430))	('pancreatic', 'Disease', 'MESH:D010195', (68, 78))	('pancreatic fistula', 'Phenotype', 'HP:0100844', (116, 134))	('pancreatic', 'Disease', (116, 126))	('Obesity', 'Phenotype', 'HP:0001513', (169, 176))	('pancreatic', 'Disease', 'MESH:D010195', (670, 680))	('soft pancreatic consistency', 'Disease', (63, 90))	('pancreatic fistula', 'Disease', 'MESH:D010185', (116, 134))	('pancreatic fistula', 'Disease', (116, 134))	('Pancreatic Fistula', 'Disease', 'MESH:D010185', (716, 734))	('pancreatic malignancies', 'Disease', (262, 285))	('pancreatic', 'Disease', 'MESH:D010195', (262, 272))	('pancreatic', 'Disease', (68, 78))	('increased BMI', 'Phenotype', 'HP:0031418', (26, 39))	('obesity', 'Disease', (423, 430))	('pancreatic', 'Disease', (670, 680))	('pancreatic malignancies', 'Phenotype', 'HP:0002894', (262, 285))	('pancreatic fistula', 'Phenotype', 'HP:0100844', (670, 688))	('Pancreatic Fistula', 'Phenotype', 'HP:0100844', (716, 734))	('obesity', 'Disease', 'MESH:D009765', (423, 430))	('patients', 'Species', '9606', (248, 256))	('pancreatic fistula', 'Disease', 'MESH:D010185', (670, 688))	('pancreatic fistula', 'Disease', (670, 688))	('pancreatic', 'Disease', (262, 272))	('BMI > 25', 'Var', (543, 551))	('pancreatic', 'Disease', 'MESH:D010195', (348, 358))	('pancreatic', 'Disease', 'MESH:D010195', (116, 126))	('pancreatic malignancies', 'Disease', 'MESH:D010190', (262, 285))	('soft pancreatic consistency', 'Disease', 'MESH:D010190', (63, 90))
836311	29863119	Pecorelli et al76 reported VFA to be an independent risk factor for pancreatic fistula, similar to its influence as a risk factor for pancreatic fistula after gastrectomy.	('pancreatic fistula', 'Disease', (134, 152))	('pancreatic fistula', 'Disease', (68, 86))	('pancreatic fistula', 'Disease', 'MESH:D010185', (134, 152))	('pancreatic fistula', 'Disease', 'MESH:D010185', (68, 86))	('pancreatic fistula', 'Phenotype', 'HP:0100844', (134, 152))	('VFA', 'Var', (27, 30))	('pancreatic fistula', 'Phenotype', 'HP:0100844', (68, 86))
836329	28410214	Our previous study indicated that DNA hypermethylation of the C2ORF40 promoter could downregulate its transcript level in human breast cancer cells.	('human', 'Species', '9606', (122, 127))	('C2ORF40', 'Gene', (62, 69))	('DNA hypermethylation', 'Var', (34, 54))	('C2ORF40', 'Gene', '84417', (62, 69))	('downregulate', 'NegReg', (85, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('transcript level', 'MPA', (102, 118))
836331	28410214	Restoration of C2ORF40 expression could significantly suppress proliferation, migration and invasion of breast and other cancer cells.	('C2ORF40', 'Gene', (15, 22))	('proliferation', 'CPA', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('invasion', 'CPA', (92, 100))	('Restoration', 'Var', (0, 11))	('breast', 'Disease', (104, 110))	('suppress', 'NegReg', (54, 62))	('migration', 'CPA', (78, 87))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('C2ORF40', 'Gene', '84417', (15, 22))	('cancer', 'Disease', (121, 127))	('expression', 'MPA', (23, 33))
836332	28410214	These data indicated that restoration of C2ORF40 could serve as therapeutic potential in human malignant tumors.	('human', 'Species', '9606', (89, 94))	('malignant tumors', 'Disease', (95, 111))	('C2ORF40', 'Gene', '84417', (41, 48))	('malignant tumors', 'Disease', 'MESH:D018198', (95, 111))	('C2ORF40', 'Gene', (41, 48))	('restoration', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
836339	28410214	We first confirmed that loss of C2ORF40 protein expression was found correlated with the clinicopathologic characteristics of human breast cancer using our clinical samples and restoration of C2ORF40 arrested cancer cell cycle progression at M phase by cell cycle synchronization techniques.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('C2ORF40', 'Gene', '84417', (192, 199))	('human', 'Species', '9606', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('restoration', 'Var', (177, 188))	('clinical samples', 'Species', '191496', (156, 172))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Disease', (209, 215))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('C2ORF40', 'Gene', '84417', (32, 39))	('C2ORF40', 'Gene', (32, 39))	('protein', 'Protein', (40, 47))	('breast cancer', 'Disease', (132, 145))	('C2ORF40', 'Gene', (192, 199))	('loss', 'NegReg', (24, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('cancer', 'Disease', (139, 145))
836349	28410214	These data demonstrated the closely correlation between C2ORF40 protein expression deficiency and the clinicopathologic characteristics of human breast cancer.	('deficiency', 'Var', (83, 93))	('C2ORF40', 'Gene', '84417', (56, 63))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('C2ORF40', 'Gene', (56, 63))	('human', 'Species', '9606', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('protein', 'Protein', (64, 71))
836357	28410214	In colony formation assay, treatment with C2ORF40MPF significantly decreased the numbers and sizes of clones in BT549 (Figure 2G) and MDA-MB-231 (Figure 2H) cells.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (134, 144))	('C2ORF40MPF', 'Chemical', '-', (42, 52))	('C2ORF40MPF', 'Var', (42, 52))	('BT549', 'CellLine', 'CVCL:1092', (112, 117))	('decreased', 'NegReg', (67, 76))
836358	28410214	Furthermore, lung cancer cell viability was also inhibited by C2ORF40MPF in a time- and dose-dependent manner (Supplementary Figure 2A and 2B).	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('C2ORF40MPF', 'Var', (62, 72))	('C2ORF40MPF', 'Chemical', '-', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('inhibited', 'NegReg', (49, 58))
836359	28410214	Therefore, we concluded that C2ORF40MPF could inhibit breast and lung cancer cell viability.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('inhibit', 'NegReg', (46, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('C2ORF40MPF', 'Chemical', '-', (29, 39))	('C2ORF40MPF', 'Var', (29, 39))	('breast and lung cancer', 'Disease', 'MESH:D001943', (54, 76))
836361	28410214	In the present study, we then evaluated the effect of C2ORF40MPF on the migration and invasion of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('C2ORF40MPF', 'Chemical', '-', (54, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('migration', 'CPA', (72, 81))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('invasion', 'CPA', (86, 94))	('C2ORF40MPF', 'Var', (54, 64))
836365	28410214	As shown in Figure 3C and 3D, C2ORF40MPF significantly inhibited the invasion of BT549 and MDA-MB-231 cells.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (91, 101))	('BT549', 'CellLine', 'CVCL:1092', (81, 86))	('inhibited', 'NegReg', (55, 64))	('C2ORF40MPF', 'Chemical', '-', (30, 40))	('C2ORF40MPF', 'Var', (30, 40))
836366	28410214	Collectively, these results indicated that C2ORF40MPF inhibited migration and invasion of human breast cancer cells.	('inhibited', 'NegReg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('human', 'Species', '9606', (90, 95))	('breast cancer', 'Disease', (96, 109))	('C2ORF40MPF', 'Var', (43, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('C2ORF40MPF', 'Chemical', '-', (43, 53))
836372	28410214	As shown in the Figure 4E, C2ORF40MPF could make the fraction of control cells in the G2/M phase of cell cycle declining slower.	('C2ORF40MPF', 'Chemical', '-', (27, 37))	('C2ORF40MPF', 'Var', (27, 37))	('declining slower', 'NegReg', (111, 127))
836377	28410214	When the tumor volume reached 75 to 100 mm3, mice were treated with C2ORF40MPF once per day for 23 days.	('C2ORF40MPF', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('mice', 'Species', '10090', (45, 49))	('C2ORF40MPF', 'Chemical', '-', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))
836378	28410214	The final results indicated that C2ORF40MPF could significantly inhibit the tumor growth (Figure 5A) and induce a decrease in tumor weight (Figure 5B) and volume (Figure 5C).	('decrease', 'NegReg', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('inhibit', 'NegReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('C2ORF40MPF', 'Chemical', '-', (33, 43))	('C2ORF40MPF', 'Var', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (126, 131))
836379	28410214	These results suggested that C2ORF40MPF could serve as a potential therapeutic treatment for breast cancer growth.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('C2ORF40MPF', 'Chemical', '-', (29, 39))	('C2ORF40MPF', 'Var', (29, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))
836383	28410214	For the first time, we demonstrated that this mimic peptide (C2ORF40MPF) could suppress cell proliferation and invasion of breast and lung cancer cells in vitro and inhibit the tumor growth in the xenograft mice model, indicating that this mimic peptide has therapeutic potentials.	('tumor', 'Disease', (177, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('C2ORF40MPF', 'Chemical', '-', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('invasion', 'CPA', (111, 119))	('breast and lung cancer', 'Disease', 'MESH:D001943', (123, 145))	('mice', 'Species', '10090', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cell proliferation', 'CPA', (88, 106))	('C2ORF40MPF', 'Var', (61, 71))	('suppress', 'NegReg', (79, 87))	('inhibit', 'NegReg', (165, 172))
836386	28410214	A large body of evidence has shown that restoration of C2ORF40 expression could inhibit cancer cell proliferation, migration and invasion in vitro and in vivo.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('inhibit', 'NegReg', (80, 87))	('expression', 'MPA', (63, 73))	('C2ORF40', 'Gene', '84417', (55, 62))	('C2ORF40', 'Gene', (55, 62))	('restoration', 'Var', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
836454	26912435	In vivo PET imaging and ex vivo biodistribution studies in mice with breast, lung and esophageal cancer xenografts consistently showed enhanced 89Zr-ACKR3-mAb uptake in high ACKR3 expressing tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('high', 'Var', (169, 173))	('mice', 'Species', '10090', (59, 63))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('89Zr-ACKR3-mAb uptake', 'MPA', (144, 165))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('breast, lung and esophageal cancer', 'Disease', 'MESH:D004938', (69, 103))	('enhanced', 'PosReg', (135, 143))	('tumors', 'Disease', (191, 197))
836467	26912435	Attesting to this fact, small molecule ACKR3 inhibitors have been shown to limit tumor growth in syngenic mouse models of human breast cancer, B lymphoma and lung carcinoma mouse models.	('human', 'Species', '9606', (122, 127))	('ACKR3', 'Gene', (39, 44))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (145, 153))	('limit', 'NegReg', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung carcinoma', 'Disease', 'MESH:D008175', (158, 172))	('B lymphoma', 'Disease', (143, 153))	('mouse', 'Species', '10090', (173, 178))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('inhibitors', 'Var', (45, 55))	('B lymphoma', 'Phenotype', 'HP:0012191', (143, 153))	('mouse', 'Species', '10090', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('lung carcinoma', 'Disease', (158, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('B lymphoma', 'Disease', 'MESH:D016393', (143, 153))
836470	26912435	Perhaps more important is that ACKR3 silencing results in reversal of TGF-beta1-induced changes on epithelial-mesenchymal transition, cancer cell invasion and migration.	('ACKR3', 'Gene', (31, 36))	('TGF-beta1', 'Gene', '7040', (70, 79))	('migration', 'CPA', (159, 168))	('TGF-beta1', 'Gene', (70, 79))	('silencing', 'Var', (37, 46))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('epithelial-mesenchymal transition', 'CPA', (99, 132))
836471	26912435	Patients with high ACKR3 and TGF-beta1 levels, however, exhibited worse prognosis and survival rates.	('survival rates', 'CPA', (86, 100))	('ACKR3', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('TGF-beta1', 'Gene', '7040', (29, 38))	('Patients', 'Species', '9606', (0, 8))	('TGF-beta1', 'Gene', (29, 38))
836494	26912435	ACKR3 Expression levels were evaluated by flow cytometry and were shown to be in the order of 231-ACKR3>MCF7>MDA-MB-231-CXCR4 (231-CXCR4)>KYSE520>HCC95>231 (Fig.	('CXCR4', 'Gene', (131, 136))	('CXCR4', 'Gene', '7852', (120, 125))	('CXCR4', 'Gene', (120, 125))	('KYSE520', 'Var', (138, 145))	('MCF7', 'CellLine', 'CVCL:0031', (104, 108))	('MDA-MB-231-CXCR4', 'CellLine', 'CVCL:0062', (109, 125))	('CXCR4', 'Gene', '7852', (131, 136))	('HCC95', 'CellLine', 'CVCL:5137', (146, 151))
836498	26912435	The highest 231-ACKR3 to 231 tumor ratio (5.1+-0.4) was observed with a 9MBq/100microg (250microCi/100microg) mAb dose per mouse (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mouse', 'Species', '10090', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('9MBq', 'Chemical', '-', (72, 76))	('9MBq/100microg', 'Var', (72, 86))
836499	26912435	PET-CT imaging of NOG mice baring 231-ACKR3 and 231 tumors over 120h indicated preferential uptake of 89Zr-ACKR3-mAb by 231-ACKR3, compared to 231, tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('preferential', 'PosReg', (79, 91))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('231-ACKR3', 'Var', (120, 129))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('mice', 'Species', '10090', (22, 26))
836506	26912435	89Zr-ACKR3-mAb-PET successfully visualized ACKR3 overexpressing ER+ luminal A MCF-7 breast cancer xenografts in NOG mice (Fig.	('mice', 'Species', '10090', (116, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('MCF-7', 'CellLine', 'CVCL:0031', (78, 83))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ER+ luminal', 'Var', (64, 75))	('breast cancer', 'Disease', (84, 97))
836511	26912435	In KYSE520/231 xenografts, 89Zr-ACKR3-mAb was preferentially retained in high ACKR3 expressing KYSE520, compared to 231 control tumors (Fig.	('KYSE520', 'Var', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('preferentially', 'PosReg', (46, 60))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))
836512	26912435	Ex vivo biodistribution in these xenografts showed 10.7+-0.4%ID/g in KYSE520 and 5.9+-0.2%ID/g in 231 tumors, 48hrs post injection (Fig.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('KYSE520', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
836513	26912435	ImmunoPET imaging following in vivo blocking, as well the corresponding in vivo image analysis, demonstrated a significant reduction (11.46+-3.47%ID/cc) in 89Zr-ACKR3-mAb uptake by KYSE520 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Disease', (189, 195))	('KYSE520', 'Var', (181, 188))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('reduction', 'NegReg', (123, 132))	('89Zr-ACKR3-mAb uptake', 'MPA', (156, 177))
836514	26912435	This ACKR3-mediated uptake was also supported by enhanced ACKR3 immunoreactivity in excised KYSE520, compared to 231, tumors (Fig.	('KYSE520', 'Var', (92, 99))	('enhanced', 'PosReg', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('ACKR3 immunoreactivity', 'MPA', (58, 80))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
836515	26912435	While 125I-ACKR3-mAb was initially non-specifically taken up by 231 tumors, preferential uptake and retention by 231-ACKR3 tumors was observed 120hrs post injection (Fig.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('preferential', 'PosReg', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('125I-ACKR3-mAb', 'Var', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
836516	26912435	Non-specific retention of 125I-ACKR3-mAb was observed in the thyroid (owing to in vivo de-iodination), liver, spleen, lungs, small intestines and kidneys.	('kidney', 'Disease', 'MESH:D007674', (146, 152))	('kidney', 'Disease', (146, 152))	('125I-ACKR3-mAb', 'Var', (26, 40))
836523	26912435	In addition, in agreement with the ACKR3 specificity shown for the 11G8 clone, our in vitro data also support preferential selectivity of 89Zr-ACKR3-mAb for ACKR3 over CXCR4.	('CXCR4', 'Gene', '7852', (168, 173))	('CXCR4', 'Gene', (168, 173))	('89Zr-ACKR3-mAb', 'Var', (138, 152))
836534	26912435	Similar bone accumulation of Zr-89 has been observed with other antibodies such as the 89Zr-labeled J591 mAb, currently in clinical trials for immunoPET of the prostate-specific membrane antigen in prostate cancer patients.	('patients', 'Species', '9606', (214, 222))	('Zr-89', 'Var', (29, 34))	('prostate cancer', 'Disease', (198, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('prostate cancer', 'Disease', 'MESH:D011471', (198, 213))	('prostate cancer', 'Phenotype', 'HP:0012125', (198, 213))
836539	21637470	Gains at 5p and 7q, and deletions at 4p, 9p, and 11q were significant prognostic factors for patients with ESCC.	('deletions at', 'Var', (24, 36))	('ESCC', 'Disease', (107, 111))	('patients', 'Species', '9606', (93, 101))
836540	21637470	Gains at 6p and 20p, and losses at 10p and 10q were the most significant imbalances, both in primary carcinoma and in metastases, which suggested that these regions may harbor oncogenes and tumor suppressor genes.	('imbalance', 'Phenotype', 'HP:0002172', (73, 82))	('Gains', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('primary carcinoma', 'Disease', 'MESH:D002277', (93, 110))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('metastases', 'Disease', (118, 128))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('tumor', 'Disease', (190, 195))	('primary carcinoma', 'Disease', (93, 110))	('imbalances', 'Phenotype', 'HP:0002172', (73, 83))	('losses', 'NegReg', (25, 31))
836547	21637470	In addition to environmental components, several genetic factors are associated with esophageal carcinogenesis, such as chromosomal aneuploidy, allelic deletions, activation of oncogenes and inactivation of tumor suppressor genes.	('esophageal carcinogenesis', 'Disease', (85, 110))	('activation', 'PosReg', (163, 173))	('chromosomal aneuploidy', 'Disease', (120, 142))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('associated', 'Reg', (69, 79))	('chromosomal aneuploidy', 'Disease', 'MESH:D000782', (120, 142))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('oncogenes', 'Protein', (177, 186))	('allelic deletions', 'Var', (144, 161))	('inactivation', 'Var', (191, 203))	('tumor', 'Disease', (207, 212))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (85, 110))
836560	21637470	Together, the numerous variants of FISH technology have allowed the accurate identification of chromosomal DNA sequences of interest and facilitated the screening of the whole genome for gains and losses associated with carcinogenesis.	('gains', 'PosReg', (187, 192))	('losses', 'NegReg', (197, 203))	('carcinogenesis', 'Disease', 'MESH:D063646', (220, 234))	('variants', 'Var', (23, 31))	('carcinogenesis', 'Disease', (220, 234))
836561	21637470	SKY analyses detected 195 translocations, 13 deletions and two duplications in the eight cell lines, with the most frequently amplified genes being PIK3CA (3q26) and TP63 (3q28).	('PIK3CA', 'Gene', '5290', (148, 154))	('TP63', 'Gene', (166, 170))	('TP63', 'Gene', '8626', (166, 170))	('deletions', 'Var', (45, 54))	('PIK3CA', 'Gene', (148, 154))
836565	21637470	For the cell line KYSE 180, M-FISH analysis detected loss of DNA copy number on chromosomes 4p, 5q, 6q, 9, 10p, 12p, 13, 14p, 15p, 18p, 18q, 20, 22 and Y, and chromosomal gains and translocations mainly on chromosomes 1, 2p, 3, 4p, 5p, 5q, 6p, 7, 8, 10q, 11, 12q, 14q, 16, 17q, 19 and Xp.	('M-FISH', 'Species', '119488', (28, 34))	('DNA copy', 'Gene', (61, 69))	('loss', 'NegReg', (53, 57))	('gains', 'PosReg', (171, 176))	('translocations', 'Var', (181, 195))
836569	21637470	The alterations detected affected most of the genome and involved regions harboring many known oncogenes and tumor suppressor genes, as well regions not yet associated with such genes.	('alterations', 'Var', (4, 15))	('affected', 'Reg', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
836572	21637470	In addition, genomic profiles of primary carcinomas have revealed imbalances affecting most of the chromosomes, such as gains on 1q, 3q, 5p, 7p, 8q, 11q, 13q, 18p, 20q and Xq, and losses on 1p, 3p, 4p, 8p, 9p, 18q, 19, 22q and Y. Focal losses at 9p13, focal gains at 5p15, 8p12-11.2, 8q24, 11q13 and 14q32, and amplifications at 1p34, 2p24, 2q24-34, 3q22-ter, 7p12-22, 8q13-qter, 11p11.2, 11q13, 12p11.2, 13q21-34, 17q12, 20q12-13 and Xq27-28 are also commons findings.	('primary carcinoma', 'Disease', (33, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('imbalance', 'Phenotype', 'HP:0002172', (66, 75))	('carcinomas', 'Disease', (41, 51))	('carcinomas', 'Disease', 'MESH:D002277', (41, 51))	('losses', 'NegReg', (236, 242))	('Xq27-28', 'Var', (435, 442))	('primary carcinoma', 'Disease', 'MESH:D002277', (33, 50))	('imbalances', 'Phenotype', 'HP:0002172', (66, 76))
836578	21637470	Elevated rates of aneuploidy were frequently observed in chromosomes 3, 8, 10, 12, 17 and 20 in ESCC and its precursor dysplastic lesions.	('dysplastic lesions', 'Disease', (119, 137))	('dysplastic lesions', 'Disease', 'MESH:D021782', (119, 137))	('ESCC', 'Disease', (96, 100))	('aneuploidy', 'Var', (18, 28))
836581	21637470	Gains involving 3q, 5p, 1q and 11q13-14 and losses involving 4 and 13q are significantly correlated with the pathological stage, whereas a gain of 8q and loss of 4p are linked to nodal metastasis; similarly, a gain of 2p and loss of 4 and 11q14-qter are associated with distant organ metastasis.	('Gains', 'Var', (0, 5))	('distant organ metastasis', 'CPA', (270, 294))	('gain', 'PosReg', (210, 214))	('loss', 'Var', (225, 229))	('nodal metastasis', 'Disease', 'MESH:D009362', (179, 195))	('losses', 'NegReg', (44, 50))	('correlated', 'Reg', (89, 99))	('nodal metastasis', 'Disease', (179, 195))
836582	21637470	Gains involving 1q, 3q, 5p and 11q13-14 and losses involving 4 and 13q are critical for the development of ESCC, whereas a gain of 2p and 8q and loss of 4 and 11q14-qter are later events associated with tumor progression and thought to confer metastatic potential to the disease.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('loss', 'Var', (145, 149))	('losses', 'NegReg', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('gain', 'PosReg', (123, 127))	('ESCC', 'Disease', (107, 111))
836593	21637470	However, LOH on chromosome 18q is common in several cancers, with frequencies of 55%-67% in colorectal cancer, 90% in pancreatic cancer, 59% in ovarian cancer and 40%-84% in head and neck squamous cell carcinoma.	('cancers', 'Disease', (52, 59))	('neck squamous cell carcinoma', 'Disease', (183, 211))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (183, 211))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('pancreatic cancer', 'Disease', (118, 135))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (174, 211))	('ovarian cancer', 'Disease', (144, 158))	('colorectal cancer', 'Disease', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('LOH on chromosome', 'Var', (9, 26))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
836594	21637470	In these cancers, frequent LOH on chromosome 18q correlates with tumor growth, aggressive tumor behavior and tumorigenesis.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('LOH on', 'Var', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('cancers', 'Disease', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (79, 104))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('aggressive tumor behavior', 'Disease', (79, 104))	('tumor', 'Disease', (109, 114))
836602	21637470	FISH assays revealed the amplification of PLK1 (polo-like kinase 1), an essential gene for the maintenance of genomic stability during mitosis; this gene may therefore be a useful prognostic marker.	('PLK1', 'Gene', '5347', (42, 46))	('mitosis', 'Disease', (135, 142))	('mitosis', 'Disease', 'None', (135, 142))	('polo-like kinase 1', 'Gene', '5347', (48, 66))	('polo-like kinase 1', 'Gene', (48, 66))	('amplification', 'Var', (25, 38))	('PLK1', 'Gene', (42, 46))
836604	21637470	PRKCI gene amplification was highly correlated with protein overexpression.	('protein overexpression', 'MPA', (52, 74))	('correlated', 'Reg', (36, 46))	('PRKCI', 'Gene', (0, 5))	('PRKCI', 'Gene', '5584', (0, 5))	('amplification', 'Var', (11, 24))
836613	21637470	Specific chromosomal imbalances are associated with the progression of esophageal tumors.	('esophageal tumors', 'Disease', 'MESH:D004938', (71, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('esophageal tumors', 'Phenotype', 'HP:0100751', (71, 88))	('esophageal tumors', 'Disease', (71, 88))	('imbalances', 'Phenotype', 'HP:0002172', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('chromosomal imbalances', 'Var', (9, 31))	('associated with', 'Reg', (36, 51))	('imbalance', 'Phenotype', 'HP:0002172', (21, 30))
836615	21637470	Gene overexpression most frequently affects oncogenes such as YES1,TYMS, HEC, TGIF, NCOA3, BTAK, DCR3, E2F1, MYC, EGFR, EGR2, CCND, FGF3/FGF4, EMS1, SAS, ERBB2, PDGFR1, BCL2, MDS1 and PRKCI, whereas genomic losses lead to the deletion of suppressor tumor genes such as CDKN2A, MTAP and TP53.	('HEC', 'Gene', (73, 76))	('PRKCI', 'Gene', '5584', (184, 189))	('CDKN2A', 'Gene', '1029', (269, 275))	('EGR2', 'Gene', '1959', (120, 124))	('MDS1', 'Gene', (175, 179))	('ERBB2', 'Gene', '2064', (154, 159))	('MYC', 'Gene', '4609', (109, 112))	('YES1', 'Gene', '7525', (62, 66))	('NCOA3', 'Gene', '8202', (84, 89))	('MDS1', 'Gene', '2122', (175, 179))	('tumor', 'Disease', (249, 254))	('SAS', 'Gene', '6302', (149, 152))	('TYMS', 'Gene', (67, 71))	('E2F1', 'Gene', (103, 107))	('HEC', 'Gene', '10403', (73, 76))	('affects', 'Reg', (36, 43))	('EGR2', 'Gene', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('TGIF', 'Gene', '3586', (78, 82))	('TP53', 'Gene', '7157', (286, 290))	('BCL2', 'Gene', '596', (169, 173))	('PDGFR1', 'Gene', (161, 167))	('BTAK', 'Gene', (91, 95))	('DCR3', 'Gene', (97, 101))	('EGFR', 'Gene', (114, 118))	('EMS1', 'Gene', '2017', (143, 147))	('E2F1', 'Gene', '1869', (103, 107))	('SAS', 'Gene', (149, 152))	('NCOA3', 'Gene', (84, 89))	('PRKCI', 'Gene', (184, 189))	('YES1', 'Gene', (62, 66))	('FGF4', 'Gene', (137, 141))	('TGIF', 'Gene', (78, 82))	('losses', 'NegReg', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('MTAP', 'Gene', (277, 281))	('deletion', 'Var', (226, 234))	('DCR3', 'Gene', '8771', (97, 101))	('MTAP', 'Gene', '4507', (277, 281))	('CDKN2A', 'Gene', (269, 275))	('MYC', 'Gene', (109, 112))	('BCL2', 'Gene', (169, 173))	('PDGFR1', 'Gene', '5159', (161, 167))	('FGF3', 'Gene', (132, 136))	('EMS1', 'Gene', (143, 147))	('ERBB2', 'Gene', (154, 159))	('TYMS', 'Gene', '7298', (67, 71))	('FGF3', 'Gene', '2248', (132, 136))	('TP53', 'Gene', (286, 290))	('EGFR', 'Gene', '1956', (114, 118))	('FGF4', 'Gene', '2249', (137, 141))	('BTAK', 'Gene', '6790', (91, 95))
836627	18989634	P53 is tightly regulated, normally expressed at low levels; however, mutation of the gene encoding P53 (TP53) can result in abnormal P53 protein accumulation which has been associated with neoplasia.	('P53', 'Gene', (105, 108))	('neoplasia', 'Disease', 'MESH:D009369', (189, 198))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('P53', 'Gene', '7157', (105, 108))	('neoplasia', 'Phenotype', 'HP:0002664', (189, 198))	('result in', 'Reg', (114, 123))	('P53', 'Gene', (99, 102))	('P53', 'Gene', (133, 136))	('P53', 'Gene', '7157', (99, 102))	('P53', 'Gene', '7157', (133, 136))	('mutation', 'Var', (69, 77))	('P53', 'Gene', (0, 3))	('associated', 'Reg', (173, 183))	('P53', 'Gene', '7157', (0, 3))	('neoplasia', 'Disease', (189, 198))
836628	18989634	There is evidence that the nature and distribution of TP53 mutations may reflect exposure to etiologic factors.	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))	('mutations', 'Var', (59, 68))
836629	18989634	For example, chemical carcinogens in tobacco smoke generally produce transversion mutations, while endogenous mutagens, such as nitric oxide, cause mostly transition mutations.	('transversion mutations', 'Var', (69, 91))	('nitric oxide', 'Chemical', 'MESH:D009569', (128, 140))	('tobacco', 'Species', '4097', (37, 44))	('produce', 'Reg', (61, 68))
836630	18989634	Furthermore, a strong correlation exists between missense mutations in TP53 and high levels of protein accumulation, so P53 immunohistochemistry has been used as a marker for mutation.	('P53', 'Gene', '7157', (72, 75))	('P53', 'Gene', (120, 123))	('P53', 'Gene', '7157', (120, 123))	('high levels of protein accumulation', 'MPA', (80, 115))	('missense mutations', 'Var', (49, 67))	('P53', 'Gene', (72, 75))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
836653	18989634	Five models were evaluated for the following risk factors: cigarette smoking (never, former, current), BMI (< 25, 25-30, 30+), GERD (No/Yes), any NSAID use (non-users of any NSAID, any type), and aspirin use (non-users of any NSAID, aspirin use only).	('aspirin', 'Chemical', 'MESH:D001241', (196, 203))	('aspirin', 'Chemical', 'MESH:D001241', (233, 240))	('< 25', 'Var', (108, 112))	('aspirin', 'Disease', (196, 203))
836665	18989634	As expected, excess BMI was significantly associated with increased risks of esophageal adenocarcinoma and to a lesser extent, gastric cardia adenocarcinoma (Table 3).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('excess BMI', 'Phenotype', 'HP:0031418', (13, 23))	('BMI', 'Gene', (20, 23))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (77, 102))	('excess', 'Var', (13, 19))	('esophageal adenocarcinoma', 'Disease', (77, 102))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (127, 156))	('gastric cardia adenocarcinoma', 'Disease', (127, 156))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (77, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
836667	18989634	For example, for non-cardia gastric cancer, the OR comparing P53+ to P53- cases was 1.16 (95% CI= 0.64-2.10) for those with BMI 25-30 and 2.5 (95% CI=0.98-6.40) for those with BMI >30.	('gastric cancer', 'Phenotype', 'HP:0012126', (28, 42))	('P53', 'Gene', (61, 64))	('P53', 'Gene', '7157', (61, 64))	('non-cardia gastric cancer', 'Disease', (17, 42))	('BMI 25-30', 'Var', (124, 133))	('P53', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('P53', 'Gene', '7157', (69, 72))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (17, 42))
836671	18989634	GERD was not associated with risk for non-cardia gastric adenocarcinoma, but was inversely related to esophageal squamous cell carcinoma, regardless of P53 overexpression.	('P53', 'Gene', '7157', (152, 155))	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('non-cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (38, 71))	('non-cardia gastric adenocarcinoma', 'Disease', (38, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('GERD', 'Var', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('P53', 'Gene', (152, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
836681	18989634	Esophageal squamous cell carcinomas among smokers have been reported with excess transversion TP53 mutations, which is consistent with the mutation signature of tobacco carcinogens, such as polycyclic aromatic hydrocarbons and nitrosamines.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('transversion', 'Var', (81, 93))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (190, 222))	('TP53', 'Gene', '7157', (94, 98))	('nitrosamines', 'Chemical', 'MESH:D009602', (227, 239))	('TP53', 'Gene', (94, 98))	('tobacco', 'Species', '4097', (161, 168))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (11, 35))	('mutations', 'Var', (99, 108))	('Esophageal squamous cell carcinomas', 'Disease', (0, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('Esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (0, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))
836683	18989634	In contrast, the TP53 mutation signatures in esophageal and gastric adenocarcinomas feature transition mutations at CpG sites, which is consistent with the role of endogenous mutagens, such as oxyradicals and nitrogen oxyradicals, rather than exogenous carcinogens as found in cigarette smoke.	('mutations', 'Var', (103, 112))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (60, 83))	('mutation', 'Var', (22, 30))	('gastric adenocarcinomas', 'Disease', (60, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('esophageal', 'Disease', (45, 55))	('nitrogen', 'Chemical', 'MESH:D009584', (209, 217))	('TP53', 'Gene', '7157', (17, 21))	('esophageal', 'Disease', 'MESH:D004941', (45, 55))	('TP53', 'Gene', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
836685	18989634	Elevated BMI has been associated with excess risk of esophageal adenocarcinoma, and to a lesser extent with gastric cardia adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (53, 78))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (53, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('BMI', 'MPA', (9, 12))	('gastric cardia adenocarcinoma', 'Disease', (108, 137))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (53, 78))	('Elevated BMI', 'Phenotype', 'HP:0031418', (0, 12))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (108, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Elevated', 'Var', (0, 8))
836688	18989634	In addition, mutation of TP53 has been related to dietary factors, including high intake of fat, protein, or nitrites in gastric cancers, suggesting that differences in BMI-related risk by P53 expression status may be in part a function of nutrient intake.	('P53', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('TP53', 'Gene', (25, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('mutation', 'Var', (13, 21))	('related', 'Reg', (39, 46))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('BMI-related', 'Disease', (169, 180))	('P53', 'Gene', '7157', (26, 29))	('TP53', 'Gene', '7157', (25, 29))	('gastric cancers', 'Disease', (121, 136))	('P53', 'Gene', (189, 192))	('gastric cancers', 'Disease', 'MESH:D013274', (121, 136))	('gastric cancers', 'Phenotype', 'HP:0012126', (121, 136))	('P53', 'Gene', '7157', (189, 192))	('nitrites', 'Chemical', 'MESH:D009573', (109, 117))
836689	18989634	GERD has been associated with increased risk for esophageal adenocarcinomas, and may act through a chronic inflammatory process that increases the likelihood of TP53 mutation in esophageal tissue.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('TP53', 'Gene', (161, 165))	('esophageal adenocarcinomas', 'Disease', (49, 75))	('esophageal', 'Disease', (178, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (49, 75))	('esophageal', 'Disease', (49, 59))	('esophageal', 'Disease', 'MESH:D004941', (178, 188))	('increases', 'PosReg', (133, 142))	('TP53', 'Gene', '7157', (161, 165))	('mutation', 'Var', (166, 174))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (49, 74))	('esophageal', 'Disease', 'MESH:D004941', (49, 59))
836690	18989634	However, the association with GERD in our study did not vary significantly by P53 overexpression, perhaps because not all TP53 mutations result in P53 overexpression, or because P53 is not central to the multi-stage progression from GERD to adenocarcinoma.	('TP53', 'Gene', (122, 126))	('P53', 'Gene', (78, 81))	('GERD', 'Disease', (30, 34))	('P53', 'Gene', (123, 126))	('P53', 'Gene', (147, 150))	('P53', 'Gene', (178, 181))	('GERD to adenocarcinoma', 'Disease', 'MESH:D005764', (233, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('P53', 'Gene', '7157', (178, 181))	('P53', 'Gene', '7157', (78, 81))	('P53', 'Gene', '7157', (123, 126))	('P53', 'Gene', '7157', (147, 150))	('GERD to adenocarcinoma', 'Disease', (233, 255))	('mutations', 'Var', (127, 136))	('TP53', 'Gene', '7157', (122, 126))
836694	18989634	This study took advantage of previous work demonstrating that mutations of TP53 often result in overexpression of P53.	('result in', 'Reg', (86, 95))	('TP53', 'Gene', '7157', (75, 79))	('mutations', 'Var', (62, 71))	('P53', 'Gene', (114, 117))	('P53', 'Gene', (76, 79))	('overexpression', 'MPA', (96, 110))	('P53', 'Gene', '7157', (114, 117))	('TP53', 'Gene', (75, 79))	('P53', 'Gene', '7157', (76, 79))
836695	18989634	However, there are limitations to using protein expression as a marker for TP53 mutation, since it has been shown that 30-35% of tumors harboring TP53 mutations do not result in protein accumulation.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('TP53', 'Gene', '7157', (146, 150))	('protein accumulation', 'MPA', (178, 198))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('TP53', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('TP53', 'Gene', (75, 79))	('TP53', 'Gene', '7157', (75, 79))	('mutations', 'Var', (151, 160))
836709	19293780	Patients with metaplastic columnar epithelium with goblet cells showed a DI of 1.15+-0.12, HI of 18.2+-2.1, mild aneuploidy in 54% of the cases, and 5N-EC in 15% of the cases, all of which were signifi cantly higher than in controls.	('5N-EC', 'Var', (149, 154))	('aneuploidy', 'Disease', 'MESH:D000782', (113, 123))	('5N-EC', 'Chemical', '-', (149, 154))	('Patients', 'Species', '9606', (0, 8))	('HI', 'Chemical', '-', (91, 93))	('aneuploidy', 'Disease', (113, 123))
836722	19293780	It is well known that chromosomal and genetic instability is a major factor in the pathogenesis of esophageal adenocarcinoma.	('chromosomal', 'Var', (22, 33))	('esophageal adenocarcinoma', 'Disease', (99, 124))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (99, 124))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (99, 124))
836760	19293780	Of the patients with aneuploid peaks, the majority (94%) showed mild aneuploidy, and 6% showed moderate aneuploidy.	('aneuploid', 'Var', (21, 30))	('aneuploidy', 'Disease', (69, 79))	('aneuploidy', 'Disease', (104, 114))	('aneuploidy', 'Disease', 'MESH:D000782', (69, 79))	('aneuploidy', 'Disease', 'MESH:D000782', (104, 114))	('patients', 'Species', '9606', (7, 15))
836773	19293780	The histogram of the patient with columnar mucosa with goblet cells shows an aneuploid G0/G1 peak (DI=1.24), an elevated HI of 20, increased cells in the S phase and one cell with DI>5N.	('G0/G1 peak', 'MPA', (87, 97))	('HI of 20', 'MPA', (121, 129))	('increased', 'PosReg', (131, 140))	('patient', 'Species', '9606', (21, 28))	('HI', 'Chemical', '-', (121, 123))	('elevated', 'PosReg', (112, 120))	('DI>5N', 'Chemical', '-', (180, 185))	('cells in the S phase', 'CPA', (141, 161))	('aneuploid', 'Var', (77, 86))
836774	19293780	The DNA histogram of the patient with columnar mucosa without goblet cells also shows similar abnormalities, including an aneuploid G0/G1 peak (DI=1.20), an HI of 23, increased S-phase cells and one cell with DI>5N.	('G0/G1', 'Gene', (132, 137))	('DI>5N', 'Chemical', '-', (209, 214))	('S-phase cells', 'CPA', (177, 190))	('patient', 'Species', '9606', (25, 32))	('increased', 'PosReg', (167, 176))	('aneuploid', 'Var', (122, 131))	('HI', 'Chemical', '-', (157, 159))
836785	19293780	Overall, the DNA content parameters were statistically similar in non-goblet epithelium from patients with low-density goblet cells compared with patients with high-density goblet cells.	('DNA content', 'MPA', (13, 24))	('patients', 'Species', '9606', (146, 154))	('patients', 'Species', '9606', (93, 101))	('low-density', 'Var', (107, 118))
836786	19293780	Furthermore, the non-goblet epithelia from patients with either low- or high-density goblet cells were statistically similar to the non-goblet epithelium from patients with columnar metaplasia, but without goblet cells.	('patients', 'Species', '9606', (43, 51))	('columnar metaplasia', 'Disease', (173, 192))	('low-', 'Var', (64, 68))	('patients', 'Species', '9606', (159, 167))	('columnar metaplasia', 'Disease', 'MESH:D008679', (173, 192))
836798	19293780	Our results showed that metaplastic esophageal columnar epithelium with goblet cells shows frequent, albeit early, DNA content abnormalities, including the presence of aneuploid G0/G1 peaks, increased cellular DNA content heterogeneity, and emergence of cells with elevated 5N-EC.	('cellular DNA content heterogeneity', 'MPA', (201, 235))	('DNA content abnormalities', 'MPA', (115, 140))	('increased', 'PosReg', (191, 200))	('5N-EC', 'Chemical', '-', (274, 279))	('G0/G1', 'Gene', (178, 183))	('aneuploid', 'Var', (168, 177))
836805	19293780	In fact, increased cellular DNA heterogeneity may result from an increased number of cells in the S/G2 phases of the cell cycle due to increased cell proliferation, or it may be due to the appearance of newly formed neoplastic clones.	('increased', 'PosReg', (65, 74))	('increased', 'PosReg', (9, 18))	('increased', 'PosReg', (135, 144))	('S/G2', 'Var', (98, 102))	('cell proliferation', 'CPA', (145, 163))	('S/G2', 'SUBSTITUTION', 'None', (98, 102))	('cellular DNA heterogeneity', 'MPA', (19, 45))
836810	19293780	Previous studies in breast cancer have shown that cells with DNA content outside of the G0/G1 peak, also known as the scatter index, may be a marker of increased chromosomal instability and poor clinical outcome.	('chromosomal instability', 'CPA', (162, 185))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (152, 185))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('increased', 'PosReg', (152, 161))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('chromosomal instability', 'Phenotype', 'HP:0040012', (162, 185))	('DNA content', 'Var', (61, 72))
836811	19293780	In fact, previous molecular studies in BE have shown aneuploidy and chromosomal instability characterized by abnormalities in P53, P16, and P21 cell cycle genes and proteins.	('P16', 'Gene', '1029', (131, 134))	('chromosomal instability', 'Phenotype', 'HP:0040012', (68, 91))	('BE', 'Phenotype', 'HP:0100580', (39, 41))	('aneuploidy', 'Disease', (53, 63))	('P53', 'Gene', (126, 129))	('chromosomal instability', 'CPA', (68, 91))	('P21', 'Gene', '644914', (140, 143))	('abnormalities', 'Var', (109, 122))	('P21', 'Gene', (140, 143))	('P16', 'Gene', (131, 134))	('P53', 'Gene', '7157', (126, 129))	('cell cycle genes', 'Gene', (144, 160))	('aneuploidy', 'Disease', 'MESH:D000782', (53, 63))
836827	19293780	These conclusions are further supported by reports of development of dysplasia or adenocarcinoma in patients with metaplastic columnar epithelium of the esophagus regardless of the presence or absence of goblet cells.	('dysplasia or adenocarcinoma', 'Disease', (69, 96))	('dysplasia or adenocarcinoma', 'Disease', 'MESH:D000230', (69, 96))	('patients', 'Species', '9606', (100, 108))	('metaplastic', 'Var', (114, 125))
836836	19293780	Chromosomal and genetic instability is a major factor in the pathogenesis of Barrett's-associated adenocarcinoma.	('adenocarcinoma', 'Disease', (98, 112))	('Chromosomal', 'Var', (0, 11))	('adenocarcinoma', 'Disease', 'MESH:D000230', (98, 112))
836845	31926400	In a propensity score-matched analysis of 123 patient pairs, adjuvant chemoradiation was associated with improved survival compared to no adjuvant therapy (adjusted HR 0.30; 95%CI [0.22, 0.40]).	('improved', 'PosReg', (105, 113))	('patient', 'Species', '9606', (46, 53))	('adjuvant', 'Var', (61, 69))	('survival', 'MPA', (114, 122))
836851	31926400	Incomplete resections occur in approximately 8-20% of patients and are associated with poor survival ranging from 9 to 17 months and an increased risk of recurrence.	('patients', 'Species', '9606', (54, 62))	('poor', 'NegReg', (87, 91))	('survival', 'MPA', (92, 100))	('Incomplete', 'Var', (0, 10))
836880	31926400	The use of adjuvant therapy in esophageal cancer is largely derived from the Intergroup 0116 study, where 556 patients with T1-4N0-3M0 gastric or gastroesophageal adenocarcinoma were randomized to receive surgery alone or surgery with adjuvant chemoradiotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('gastroesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (146, 177))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('age', 'Gene', '5973', (36, 39))	('age', 'Gene', (157, 160))	('T1-4N0-3M0', 'Var', (124, 134))	('age', 'Gene', '5973', (157, 160))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('gastric', 'Disease', (135, 142))	('gastroesophageal adenocarcinoma', 'Disease', (146, 177))	('age', 'Gene', (36, 39))	('patients', 'Species', '9606', (110, 118))
836894	31926400	Wong and colleagues examined the role of adjuvant radiation in patients with pT1-4N1-3M0 esophageal cancer, and found that adjuvant radiation alone was associated with improved survival compared to no adjuvant therapy in unadjusted analysis in a subgroup of patients with margin-positive resection.	('age', 'Gene', '5973', (94, 97))	('improved', 'PosReg', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('survival', 'MPA', (177, 185))	('patients', 'Species', '9606', (63, 71))	('age', 'Gene', (94, 97))	('patients', 'Species', '9606', (258, 266))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('pT1-4N1-3M0', 'Var', (77, 88))
836895	31926400	A third NCDB analysis of patients with margin-positive resections in a smaller, early cohort (2003-2006) demonstrated worse five-year survival for patients with margin-positive resections compared to margin-negative resections, and a survival benefit for adjuvant chemoradiotherapy compared to no adjuvant therapy.	('worse', 'NegReg', (118, 123))	('patients', 'Species', '9606', (147, 155))	('margin-positive', 'Var', (161, 176))	('patients', 'Species', '9606', (25, 33))
837017	20140245	RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH significantly inhibited cell growth and colony formation.	('ESCC', 'Disease', (56, 60))	('NEFH', 'Gene', (39, 43))	('accelerated', 'PosReg', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('increased', 'PosReg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('knockdown', 'Var', (26, 35))	('tumor', 'Disease', (98, 103))	('inhibited', 'NegReg', (170, 179))
837018	20140245	Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase, via activation of the Akt/beta-catenin pathway, resulting in enhanced aerobic glycolysis and mitochondrial dysfunction.	('pyruvate', 'Chemical', 'MESH:D019289', (37, 45))	('NEFH', 'Gene', (8, 12))	('pyruvate dehydrogenase', 'Gene', '54704', (84, 106))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (201, 226))	('mitochondrial dysfunction', 'Disease', (201, 226))	('pyruvate dehydrogenase', 'Gene', (84, 106))	('enhanced', 'PosReg', (169, 177))	('activation', 'PosReg', (112, 122))	('beta-catenin', 'Gene', (134, 146))	('beta-catenin', 'Gene', '1499', (134, 146))	('Akt', 'Gene', (130, 133))	('aerobic glycolysis', 'MPA', (178, 196))	('Loss', 'Var', (0, 4))	('up-regulation', 'PosReg', (20, 33))	('pyruvate kinase-M2 type', 'Enzyme', (37, 60))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (201, 226))	('Akt', 'Gene', '207', (130, 133))	('pyruvate', 'Chemical', 'MESH:D019289', (84, 92))	('down-regulation', 'NegReg', (65, 80))
837020	20140245	Loss of NEFH activates the Akt/beta-catenin pathway and increases glycolysis and mitochondrial dysfunction.	('mitochondrial dysfunction', 'Disease', (81, 106))	('NEFH', 'Gene', (8, 12))	('beta-catenin', 'Gene', (31, 43))	('increases', 'PosReg', (56, 65))	('beta-catenin', 'Gene', '1499', (31, 43))	('Akt', 'Gene', (27, 30))	('Akt', 'Gene', '207', (27, 30))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (81, 106))	('activates', 'PosReg', (13, 22))	('glycolysis', 'MPA', (66, 76))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (81, 106))	('Loss', 'Var', (0, 4))
837021	20140245	Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('methylated', 'Var', (18, 28))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('NEFH', 'Gene', (29, 33))
837024	20140245	Amplification and over-expression of cyclin D1, alterations in the p53 and p16 pathways, and mutations of p53 and retinoblastoma are involved in development of ESCC.	('involved', 'Reg', (133, 141))	('p53', 'Gene', '7157', (106, 109))	('ESCC', 'Disease', (160, 164))	('alterations', 'Reg', (48, 59))	('mutations', 'Var', (93, 102))	('cyclin D1', 'Gene', '595', (37, 46))	('over-expression', 'PosReg', (18, 33))	('p16', 'Gene', '1029', (75, 78))	('cyclin D1', 'Gene', (37, 46))	('p53', 'Gene', (67, 70))	('retinoblastoma', 'Disease', (114, 128))	('p53', 'Gene', '7157', (67, 70))	('retinoblastoma', 'Disease', 'MESH:D012175', (114, 128))	('retinoblastoma', 'Phenotype', 'HP:0009919', (114, 128))	('p53', 'Gene', (106, 109))	('p16', 'Gene', (75, 78))
837025	20140245	In addition, hypermethylation of gene promoters and the corresponding loss of gene expression are now recognized as a hallmark of human cancer.	('loss', 'NegReg', (70, 74))	('gene expression', 'MPA', (78, 93))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('hypermethylation', 'Var', (13, 29))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('human', 'Species', '9606', (130, 135))
837026	20140245	Most of the epigenetically silenced genes identified possess tumor suppressive activity.	('epigenetically silenced genes', 'Var', (12, 41))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
837028	20140245	We have focused on the discovery of additional tumor suppressor genes in ESCC inactivated by promoter methylation.	('promoter methylation', 'Var', (93, 113))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ESCC', 'Disease', (73, 77))	('tumor', 'Disease', (47, 52))
837032	20140245	Deletion of the NH2 terminus or mutation of one or more of the exon 3 inhibits the ubiquitin-mediated degradation of beta-catenin, increasing its availability as a transcriptional activator.	('beta-catenin', 'Gene', (117, 129))	('inhibits', 'NegReg', (70, 78))	('beta-catenin', 'Gene', '1499', (117, 129))	('NH2', 'Gene', (16, 19))	('availability', 'MPA', (146, 158))	('ubiquitin-mediated degradation', 'MPA', (83, 113))	('increasing', 'PosReg', (131, 141))	('mutation', 'Var', (32, 40))	('Deletion', 'Var', (0, 8))
837033	20140245	In colorectal cancers and several other tumors, loss of control of intracellular beta-catenin levels through mutation to either beta-catenin or APC result in stabilization of beta-catenin and accumulation of the protein in the cytoplasm.	('colorectal cancers', 'Disease', 'MESH:D015179', (3, 21))	('beta-catenin', 'Gene', (128, 140))	('APC', 'Phenotype', 'HP:0005227', (144, 147))	('beta-catenin', 'Gene', '1499', (128, 140))	('beta-catenin', 'Gene', (81, 93))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('beta-catenin', 'Gene', (175, 187))	('tumors', 'Disease', (40, 46))	('accumulation', 'PosReg', (192, 204))	('beta-catenin', 'Gene', '1499', (81, 93))	('beta-catenin', 'Gene', '1499', (175, 187))	('APC', 'Gene', (144, 147))	('stabilization', 'MPA', (158, 171))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('protein', 'Protein', (212, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('colorectal cancers', 'Disease', (3, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('mutation', 'Var', (109, 117))	('loss', 'NegReg', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('APC', 'Gene', '324', (144, 147))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
837035	20140245	In the development of esophageal cancer, dysfunction of Wnt/beta-catenin signaling has been implicated, however, in contrast to colorectal cancer, mutation in adenomatous polyposis coli (APC) or beta-catenin gene is a rare event in esophageal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('mutation', 'Var', (147, 155))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (159, 185))	('Wnt', 'Gene', '7471', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal cancer', 'Disease', (128, 145))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (159, 185))	('APC', 'Gene', '324', (187, 190))	('adenomatous polyposis coli', 'Disease', (159, 185))	('esophageal cancer', 'Disease', (22, 39))	('APC', 'Phenotype', 'HP:0005227', (187, 190))	('esophageal cancer', 'Disease', 'MESH:D004938', (232, 249))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('beta-catenin', 'Gene', (60, 72))	('APC', 'Gene', (187, 190))	('esophageal cancer', 'Disease', (232, 249))	('beta-catenin', 'Gene', '1499', (60, 72))	('beta-catenin', 'Gene', (195, 207))	('beta-catenin', 'Gene', '1499', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))	('Wnt', 'Gene', (56, 59))
837042	20140245	Fibroblasts cells expressing high amounts of NEFH were strongly misshapen, multinucleated, and had many inclusions, typical changes seen in neuropathies.	('multinucleated', 'CPA', (75, 89))	('neuropathies', 'Phenotype', 'HP:0009830', (140, 152))	('neuropathies', 'Disease', (140, 152))	('NEFH', 'Var', (45, 49))	('misshapen', 'CPA', (64, 73))	('neuropathies', 'Disease', 'MESH:D009422', (140, 152))	('inclusions', 'MPA', (104, 114))
837046	20140245	Its expression is down-regulated by hypermethylation of the CpG island in the promoter, and loss of NEFH increases glycolysis and mitochondrial dysfunction through activation of the Akt/beta-catenin pathway.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (130, 155))	('expression', 'MPA', (4, 14))	('beta-catenin', 'Gene', (186, 198))	('NEFH', 'Gene', (100, 104))	('hypermethylation', 'Var', (36, 52))	('Akt', 'Gene', '207', (182, 185))	('activation', 'PosReg', (164, 174))	('down-regulated', 'NegReg', (18, 32))	('beta-catenin', 'Gene', '1499', (186, 198))	('loss', 'Var', (92, 96))	('Akt', 'Gene', (182, 185))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (130, 155))	('increases', 'PosReg', (105, 114))	('glycolysis', 'MPA', (115, 125))	('mitochondrial dysfunction', 'Disease', (130, 155))
837047	20140245	Epigenetic silencing of the NEFH gene in ESCC seems to be responsible for increased beta-catenin expression, leading to activation of beta-catenin/TCF-dependent transcription and key downstream effectors, leading to ESCC progression.	('TCF', 'Gene', (147, 150))	('TCF', 'Gene', '3172', (147, 150))	('beta-catenin', 'Gene', '1499', (134, 146))	('leading to', 'Reg', (205, 215))	('activation', 'PosReg', (120, 130))	('ESCC', 'Disease', (216, 220))	('increased', 'PosReg', (74, 83))	('beta-catenin', 'Gene', (84, 96))	('ESCC', 'Disease', (41, 45))	('NEFH gene', 'Gene', (28, 37))	('Epigenetic silencing', 'Var', (0, 20))	('beta-catenin', 'Gene', (134, 146))	('beta-catenin', 'Gene', '1499', (84, 96))	('expression', 'MPA', (97, 107))
837049	20140245	All 12 ESCC cell lines tested and 65% (13/20) of PT harbored NEFH promoter methylation, whereas no methylation was found in paired normal samples (PN) (0%) and two non-tumorigenic cell lines, HEK293 (Fig.	('methylation', 'Var', (75, 86))	('tumor', 'Disease', (168, 173))	('HEK293', 'CellLine', 'CVCL:0045', (192, 198))	('NEFH promoter', 'Gene', (61, 74))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
837052	20140245	MSP analysis in primary ESCC tissues from five more patients demonstrated NEFH promoter methylation in 3 cases while the remaining two did not harbor methylation (Fig.	('methylation', 'Var', (88, 99))	('patients', 'Species', '9606', (52, 60))	('NEFH promoter', 'Gene', (74, 87))
837054	20140245	Moreover, NEFH expression was reactivated by 5-Aza-dC in all ESCC cell lines, and the reactivation was stronger in TE5, KYSE140, KYSE150, and KYSE520 but decreased or minimally different in TE3 or KYSE410 when both 5-Aza-dC and 300 nM TSA were used (Fig.	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (215, 223))	('NEFH expression', 'Gene', (10, 25))	('KYSE140', 'Var', (120, 127))	('TE5', 'Var', (115, 118))	('KYSE150', 'Var', (129, 136))	('reactivated', 'PosReg', (30, 41))	('5-Aza-dC', 'Var', (45, 53))	('KYSE140', 'CellLine', 'CVCL:1347', (120, 127))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (45, 53))	('stronger', 'PosReg', (103, 111))	('KYSE520', 'Var', (142, 149))	('TSA', 'Chemical', 'MESH:C012589', (235, 238))
837055	20140245	Although NEFH was expressed in KYSE30 at baseline, it was further increased by 5-Aza-dC (Fig.	('5-Aza-dC', 'Var', (79, 87))	('increased', 'PosReg', (66, 75))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (79, 87))
837060	20140245	A significant increase in clonogenic cell growth was observed in cells with diminished NEFH expression (N12 and N20) (Fig.	('N20', 'CellLine', 'CVCL:D427', (112, 115))	('clonogenic cell growth', 'CPA', (26, 48))	('NEFH', 'Gene', (87, 91))	('N20', 'Var', (112, 115))	('diminished', 'NegReg', (76, 86))	('increase', 'PosReg', (14, 22))
837061	20140245	Increased cell proliferation was also observed in N12 and N20 cells compared to control cells (C2) (Fig.	('N20', 'CellLine', 'CVCL:D427', (58, 61))	('N12', 'Var', (50, 53))	('cell proliferation', 'CPA', (10, 28))	('Increased', 'PosReg', (0, 9))	('N20', 'Var', (58, 61))
837062	20140245	The population of N12 and N20 cells residing in the G0/G1 phase yet decreased in the G2 phase compared to C2 cells (Fig.	('decreased', 'NegReg', (68, 77))	('N20', 'CellLine', 'CVCL:D427', (26, 29))	('N20', 'Var', (26, 29))
837063	20140245	In addition, in vitro invasive activity was increased in N12 and N20 cells (Fig.	('increased', 'PosReg', (44, 53))	('N20', 'CellLine', 'CVCL:D427', (65, 68))	('N20', 'Var', (65, 68))	('N12', 'Var', (57, 60))
837064	20140245	When cells were incubated in 10% serum medium, the number of cells passing into the chamber increased about 2.5- and 7-fold in N12 and N20 cells respectively, compared to C2 cells (Fig.	('N20', 'Var', (135, 138))	('increased', 'PosReg', (92, 101))	('N12', 'Var', (127, 130))	('N20', 'CellLine', 'CVCL:D427', (135, 138))
837065	20140245	Under HGF treatment, the invasive activity of N12 and N20 cells increased about 3.5- and 8-fold, respectively, compared to C2 cells (Fig.	('HGF', 'Gene', (6, 9))	('N20', 'Var', (54, 57))	('HGF', 'Gene', '3082', (6, 9))	('invasive activity', 'CPA', (25, 42))	('increased', 'PosReg', (64, 73))	('N20', 'CellLine', 'CVCL:D427', (54, 57))
837067	20140245	Tumor development was observed 10 days after injection in both flanks injected with control or either N12 (n = 6) or N20 cells (n = 11).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor development', 'CPA', (0, 17))	('N12', 'Var', (102, 105))	('N20', 'CellLine', 'CVCL:D427', (117, 120))	('N20 cells', 'Var', (117, 126))
837071	20140245	The expression of proliferating cell nuclear antigen (PCNA), a marker for cell proliferation, increased in N12 and N20 cells.	('N20', 'Var', (115, 118))	('proliferating cell nuclear antigen', 'Gene', (18, 52))	('PCNA', 'Gene', '5111', (54, 58))	('increased', 'PosReg', (94, 103))	('expression', 'MPA', (4, 14))	('proliferating cell nuclear antigen', 'Gene', '5111', (18, 52))	('N20', 'CellLine', 'CVCL:D427', (115, 118))	('N12', 'Var', (107, 110))	('PCNA', 'Gene', (54, 58))
837082	20140245	Phosphorylated Akt triggers a network that positively regulates G1/S cell cycle progression through inactivation of Gsk3beta, direct phosphorylation of beta-catenin at Ser552, which enhances beta-catenin nuclear accumulation and increased beta-catenin-TCF/Lef transcriptional activity.	('inactivation', 'Var', (100, 112))	('beta-catenin', 'Gene', (152, 164))	('beta-catenin', 'Gene', (191, 203))	('nuclear accumulation', 'MPA', (204, 224))	('Akt', 'Gene', (15, 18))	('beta-catenin', 'Gene', '1499', (152, 164))	('TCF', 'Gene', '3172', (252, 255))	('Ser552', 'Chemical', '-', (168, 174))	('beta-catenin', 'Gene', (239, 251))	('beta-catenin', 'Gene', '1499', (191, 203))	('beta-catenin', 'Gene', '1499', (239, 251))	('Ser552', 'Var', (168, 174))	('Akt', 'Gene', '207', (15, 18))	('cell cycle progression', 'CPA', (69, 91))	('Gsk3beta', 'Gene', '2932', (116, 124))	('TCF', 'Gene', (252, 255))	('Lef', 'Chemical', '-', (256, 259))	('enhances', 'PosReg', (182, 190))	('regulates', 'Reg', (54, 63))	('increased', 'PosReg', (229, 238))	('phosphorylation', 'Var', (133, 148))	('Gsk3beta', 'Gene', (116, 124))
837084	20140245	Increased Gsk3beta phosphorylation and decreased total Gsk3beta level were observed in N12 and N20 compared to C2 cells (Fig.	('Gsk3beta', 'Gene', (55, 63))	('Gsk3beta', 'Gene', '2932', (55, 63))	('N20', 'CellLine', 'CVCL:D427', (95, 98))	('Increased Gsk3beta phosphorylation', 'Phenotype', 'HP:0003240', (0, 34))	('decreased', 'NegReg', (39, 48))	('N20', 'Var', (95, 98))	('Gsk3beta', 'Gene', '2932', (10, 18))	('Increased', 'PosReg', (0, 9))	('Gsk3beta', 'Gene', (10, 18))	('N12', 'Var', (87, 90))
837086	20140245	Both Gsk3beta and casein kinase-1 (CK1) phosphorylate beta-catenin at Ser33/Ser37/Thr41 and at Thr41/Ser45, respectively, leading to the degradation of beta-catenin through the ubiquitin pathway.	('Gsk3beta', 'Gene', '2932', (5, 13))	('Ser45', 'Chemical', '-', (101, 106))	('Thr41', 'Chemical', '-', (82, 87))	('Ser37', 'Chemical', '-', (76, 81))	('beta-catenin', 'Gene', (152, 164))	('Gsk3beta', 'Gene', (5, 13))	('CK1', 'Species', '2498238', (35, 38))	('Thr41', 'Chemical', '-', (95, 100))	('beta-catenin', 'Gene', (54, 66))	('Ser33', 'Chemical', '-', (70, 75))	('degradation', 'MPA', (137, 148))	('beta-catenin', 'Gene', '1499', (152, 164))	('Ser33/Ser37/Thr41', 'Var', (70, 87))	('ubiquitin pathway', 'Pathway', (177, 194))	('beta-catenin', 'Gene', '1499', (54, 66))
837088	20140245	In NEFH down-regulated cells, phosphorylation of beta-catenin at Ser33/Ser37/Thr41 and at Thr41/Ser45 decreased with a concomitant increase of total beta-catenin.	('beta-catenin', 'Gene', (49, 61))	('phosphorylation', 'MPA', (30, 45))	('Thr41', 'Chemical', '-', (90, 95))	('Ser45', 'Chemical', '-', (96, 101))	('increase', 'PosReg', (131, 139))	('beta-catenin', 'Gene', (149, 161))	('Ser33', 'Chemical', '-', (65, 70))	('Thr41', 'Chemical', '-', (77, 82))	('beta-catenin', 'Gene', '1499', (49, 61))	('NEFH', 'Gene', (3, 7))	('Ser33/Ser37/Thr41', 'Var', (65, 82))	('Ser37', 'Chemical', '-', (71, 76))	('beta-catenin', 'Gene', '1499', (149, 161))	('down-regulated', 'NegReg', (8, 22))	('decreased', 'NegReg', (102, 111))
837089	20140245	In contrast, phosphorylation of beta-catenin at Ser675 increased in N12 and N20 cells.	('Ser675', 'Chemical', '-', (48, 54))	('phosphorylation', 'MPA', (13, 28))	('increased', 'PosReg', (55, 64))	('beta-catenin', 'Gene', (32, 44))	('Ser675', 'Var', (48, 54))	('beta-catenin', 'Gene', '1499', (32, 44))	('N20', 'CellLine', 'CVCL:D427', (76, 79))
837094	20140245	The protein level of PK-M2 increased in N12 and N20 compared to C2 cells, whereas PDH decreased (Fig.	('N20', 'Var', (48, 51))	('protein level', 'MPA', (4, 17))	('increased', 'PosReg', (27, 36))	('N12', 'Var', (40, 43))	('PDH', 'Gene', (82, 85))	('PK-M2', 'Gene', '5315', (21, 26))	('N20', 'CellLine', 'CVCL:D427', (48, 51))	('PDH', 'Gene', '54704', (82, 85))	('PK-M2', 'Gene', (21, 26))
837101	20140245	The luciferase reporters, TOPflash and FOPflash, which have either wild-type (TOP) or mutated (FOP) binding sites for the beta-catenin-TCF4/Lef complex, were used to characterize the transcriptional activity of the beta-catenin-TCF/Lef complex.	('mutated', 'Var', (86, 93))	('Lef', 'Chemical', '-', (140, 143))	('beta-catenin', 'Gene', '1499', (122, 134))	('TCF', 'Gene', (228, 231))	('TCF', 'Gene', '3172', (228, 231))	('beta-catenin', 'Gene', (215, 227))	('TCF', 'Gene', (135, 138))	('TCF', 'Gene', '3172', (135, 138))	('Lef', 'Chemical', '-', (232, 235))	('beta-catenin', 'Gene', (122, 134))	('beta-catenin', 'Gene', '1499', (215, 227))
837106	20140245	We found that the transcriptional levels of beta-catenin, cyclin D1 and MMP-7 were elevated significantly in N20 compared to C2 cells (Fig.	('N20', 'CellLine', 'CVCL:D427', (109, 112))	('N20', 'Var', (109, 112))	('MMP-7', 'Gene', '4316', (72, 77))	('beta-catenin', 'Gene', (44, 56))	('transcriptional levels', 'MPA', (18, 40))	('MMP-7', 'Gene', (72, 77))	('cyclin D1', 'Gene', '595', (58, 67))	('elevated', 'PosReg', (83, 91))	('beta-catenin', 'Gene', '1499', (44, 56))	('cyclin D1', 'Gene', (58, 67))
837108	20140245	We also tested protein expression in control and KYSE140 cells expressing NEFH.	('NEFH', 'Var', (74, 78))	('tested', 'Reg', (8, 14))	('KYSE140', 'CellLine', 'CVCL:1347', (49, 56))	('protein expression', 'MPA', (15, 33))
837109	20140245	While the level of total Akt was similar in the two cell types, phosphorylated Akt was decreased by NEFH (Fig.	('decreased', 'NegReg', (87, 96))	('NEFH', 'Var', (100, 104))	('Akt', 'Gene', '207', (25, 28))	('Akt', 'Gene', '207', (79, 82))	('phosphorylated', 'MPA', (64, 78))	('Akt', 'Gene', (25, 28))	('Akt', 'Gene', (79, 82))
837111	20140245	In contrast, the expression of Gsk3beta, and phosphorylation of beta-cateninSer33/Ser37/Thr41 and beta-cateninThr41/Ser45 were increased by NEFH.	('beta-cateninThr41/Ser45', 'Protein', (98, 121))	('Thr41', 'Chemical', '-', (110, 115))	('beta-cateninSer33', 'Chemical', '-', (64, 81))	('expression', 'MPA', (17, 27))	('NEFH', 'Var', (140, 144))	('beta-cateninThr41', 'Chemical', '-', (98, 115))	('Gsk3beta', 'Gene', '2932', (31, 39))	('Thr41', 'Chemical', '-', (88, 93))	('phosphorylation', 'MPA', (45, 60))	('Ser37', 'Chemical', '-', (82, 87))	('Ser45', 'Chemical', '-', (116, 121))	('beta-cateninSer33/Ser37/Thr41', 'Protein', (64, 93))	('Gsk3beta', 'Gene', (31, 39))	('increased', 'PosReg', (127, 136))
837112	20140245	The expression of cyclin D1 and MMP-7, downstream targets of beta-catenin-TCF/Lef signaling, were down-regulated by NEFH.	('beta-catenin', 'Gene', '1499', (61, 73))	('cyclin D1', 'Gene', (18, 27))	('NEFH', 'Var', (116, 120))	('Lef', 'Chemical', '-', (78, 81))	('MMP-7', 'Gene', '4316', (32, 37))	('expression', 'MPA', (4, 14))	('beta-catenin', 'Gene', (61, 73))	('TCF', 'Gene', (74, 77))	('TCF', 'Gene', '3172', (74, 77))	('cyclin D1', 'Gene', '595', (18, 27))	('down-regulated', 'NegReg', (98, 112))	('MMP-7', 'Gene', (32, 37))
837113	20140245	In addition, an increase of PDH and concomitant decrease of PK-M2 at the mRNA and protein level were observed in NEFH-expressing cells (Fig.	('PDH', 'Gene', '54704', (28, 31))	('PK-M2', 'Gene', '5315', (60, 65))	('PK-M2', 'Gene', (60, 65))	('increase', 'PosReg', (16, 24))	('decrease', 'NegReg', (48, 56))	('PDH', 'Gene', (28, 31))	('NEFH-expressing', 'Var', (113, 128))
837114	20140245	These results indicate that the expression of proteins involved in beta-catenin-TCF/Lef signaling as well as levels of PK-M2 and PDH are altered by NEFH.	('PDH', 'Gene', (129, 132))	('PK-M2', 'Gene', '5315', (119, 124))	('PK-M2', 'Gene', (119, 124))	('beta-catenin', 'Gene', '1499', (67, 79))	('expression of proteins', 'MPA', (32, 54))	('PDH', 'Gene', '54704', (129, 132))	('levels', 'MPA', (109, 115))	('TCF', 'Gene', (80, 83))	('TCF', 'Gene', '3172', (80, 83))	('beta-catenin', 'Gene', (67, 79))	('NEFH', 'Var', (148, 152))	('Lef', 'Chemical', '-', (84, 87))	('altered', 'Reg', (137, 144))
837119	20140245	Cell population at the LR increased in N20 (2.34%) compared to C2 cells (0.46%).	('N20', 'CellLine', 'CVCL:D427', (39, 42))	('Cell population at the LR', 'CPA', (0, 25))	('N20', 'Var', (39, 42))	('increased', 'PosReg', (26, 35))
837124	20140245	Energy production by O2 consumption is required for cell survival, but dysfunctional mitochondria generate reactive oxygen species (ROS), resulting in cell dysfunction or death.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (107, 130))	('dysfunctional', 'Var', (71, 84))	('cell dysfunction', 'Disease', (151, 167))	('cell dysfunction', 'Disease', 'MESH:C538614', (151, 167))	('reactive oxygen species', 'MPA', (107, 130))	('ROS', 'Chemical', 'MESH:D017382', (132, 135))	('death', 'CPA', (171, 176))	('O2', 'Chemical', 'MESH:D010100', (21, 23))
837128	20140245	The distribution of ROS in C2 cells was shifted toward increased ROS by H2O2 treatment, whereas little change in N12 and N20 cells was observed.	('H2O2', 'Chemical', 'MESH:D006861', (72, 76))	('treatment', 'Var', (77, 86))	('ROS', 'Chemical', 'MESH:D017382', (20, 23))	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('increased', 'PosReg', (55, 64))	('H2O2 treatment', 'Var', (72, 86))	('N20', 'CellLine', 'CVCL:D427', (121, 124))	('ROS', 'MPA', (65, 68))
837138	20140245	Significant increases of oxygen consumption and ATP generation were observed in NEFH-transfected cells (Fig.	('oxygen', 'Chemical', 'MESH:D010100', (25, 31))	('NEFH-transfected', 'Var', (80, 96))	('ATP', 'Gene', (48, 51))	('oxygen consumption', 'CPA', (25, 43))	('increases', 'PosReg', (12, 21))	('ATP', 'Gene', '51761', (48, 51))
837144	20140245	Activation of Akt with increased expression of beta-catenin and PK-M2 was observed in C2 cells with PTEN gene knockdown (Fig.	('PTEN', 'Gene', (100, 104))	('knockdown', 'Var', (110, 119))	('Akt', 'Gene', (14, 17))	('PTEN', 'Gene', '5728', (100, 104))	('beta-catenin', 'Gene', '1499', (47, 59))	('PK-M2', 'Gene', '5315', (64, 69))	('PK-M2', 'Gene', (64, 69))	('gene knockdown', 'Var', (105, 119))	('Activation', 'PosReg', (0, 10))	('increased', 'PosReg', (23, 32))	('expression', 'MPA', (33, 43))	('beta-catenin', 'Gene', (47, 59))	('Akt', 'Gene', '207', (14, 17))
837145	20140245	Gsk3beta knockdown slightly increased the expression of PK-M2 in N20 cells, but not in C2 cells (Fig.	('increased', 'PosReg', (28, 37))	('knockdown', 'Var', (9, 18))	('expression', 'MPA', (42, 52))	('Gsk3beta', 'Gene', '2932', (0, 8))	('N20', 'CellLine', 'CVCL:D427', (65, 68))	('PK-M2', 'Gene', '5315', (56, 61))	('PK-M2', 'Gene', (56, 61))	('Gsk3beta', 'Gene', (0, 8))
837154	20140245	The up-regulated PDH by beta-catenin knockdown was not further enhanced by the overexpression of NEFH, indicating that beta-catenin is required for the inverse regulation of PK-M2 and PDH by NEFH.	('beta-catenin', 'Gene', (24, 36))	('PDH', 'Gene', (184, 187))	('beta-catenin', 'Gene', '1499', (119, 131))	('PDH', 'Gene', '54704', (184, 187))	('knockdown', 'Var', (37, 46))	('beta-catenin', 'Gene', '1499', (24, 36))	('PDH', 'Gene', (17, 20))	('PK-M2', 'Gene', '5315', (174, 179))	('PK-M2', 'Gene', (174, 179))	('beta-catenin', 'Gene', (119, 131))	('PDH', 'Gene', '54704', (17, 20))	('up-regulated', 'PosReg', (4, 16))
837162	20140245	The reduced O2 consumption and ATP level in N20 cells were increased by beta-catenin knockdown (Fig.	('N20', 'CellLine', 'CVCL:D427', (44, 47))	('reduced', 'NegReg', (4, 11))	('beta-catenin', 'Gene', (72, 84))	('O2', 'Chemical', 'MESH:D010100', (12, 14))	('ATP', 'Gene', (31, 34))	('ATP', 'Gene', '51761', (31, 34))	('beta-catenin', 'Gene', '1499', (72, 84))	('O2 consumption', 'MPA', (12, 26))	('knockdown', 'Var', (85, 94))	('increased', 'PosReg', (59, 68))
837163	20140245	S5 a) and ROS level (data not shown) were not influenced by the beta-catenin knockdown in both C2 and N20 cells.	('N20', 'CellLine', 'CVCL:D427', (102, 105))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('ROS level', 'MPA', (10, 19))	('knockdown', 'Var', (77, 86))	('beta-catenin', 'Gene', (64, 76))	('beta-catenin', 'Gene', '1499', (64, 76))
837164	20140245	The increased lactate concentration in N20 cells returned to the level of C2 cells by beta-catenin knockdown (Fig.	('N20', 'CellLine', 'CVCL:D427', (39, 42))	('beta-catenin', 'Gene', (86, 98))	('beta-catenin', 'Gene', '1499', (86, 98))	('knockdown', 'Var', (99, 108))	('lactate', 'Chemical', 'MESH:D019344', (14, 21))	('returned', 'PosReg', (49, 57))	('increased', 'PosReg', (4, 13))	('lactate concentration', 'MPA', (14, 35))
837165	20140245	In 24 hrs, cell viability was not significantly decreased by the low expression of beta-catenin, but inhibition of cell growth by beta-catenin knockdown was observed after 3 days of incubation (Fig.	('inhibition', 'NegReg', (101, 111))	('beta-catenin', 'Gene', (83, 95))	('cell growth', 'CPA', (115, 126))	('beta-catenin', 'Gene', '1499', (83, 95))	('knockdown', 'Var', (143, 152))	('beta-catenin', 'Gene', (130, 142))	('beta-catenin', 'Gene', '1499', (130, 142))
837169	20140245	However, reduction in the cell viability in N20 cells was significantly enhanced by 2-DG (Fig.	('N20', 'CellLine', 'CVCL:D427', (44, 47))	('2-DG', 'Var', (84, 88))	('2-DG', 'Chemical', 'MESH:D003847', (84, 88))	('reduction', 'NegReg', (9, 18))	('enhanced', 'PosReg', (72, 80))	('cell viability', 'CPA', (26, 40))
837175	20140245	LY294002 and Wortmannin (1 microM), an irreversible PI3K inhibitor, had little influence on phospho-Akt levels in N20 cells (Fig.	('LY294002', 'Var', (0, 8))	('Akt', 'Gene', (100, 103))	('Wortmannin', 'Chemical', 'MESH:D000077191', (13, 23))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('Akt', 'Gene', '207', (100, 103))	('N20', 'CellLine', 'CVCL:D427', (114, 117))
837178	20140245	Interestingly, decrease of Gsk3beta phosphorylation and increase of beta-catenin phosphorylation at Ser33/Ser37/Thr41 and at Thr41/Ser45 were caused only by API-2.	('Thr41', 'Chemical', '-', (125, 130))	('decrease', 'NegReg', (15, 23))	('increase', 'PosReg', (56, 64))	('Ser45', 'Chemical', '-', (131, 136))	('Thr41', 'Chemical', '-', (112, 117))	('Gsk3beta', 'Gene', '2932', (27, 35))	('Ser33/Ser37/Thr41', 'Var', (100, 117))	('Ser37', 'Chemical', '-', (106, 111))	('Ser33', 'Chemical', '-', (100, 105))	('beta-catenin', 'Gene', (68, 80))	('Gsk3beta', 'Gene', (27, 35))	('API-2', 'Gene', '330', (157, 162))	('phosphorylation', 'MPA', (36, 51))	('API-2', 'Gene', (157, 162))	('beta-catenin', 'Gene', '1499', (68, 80))
837190	20140245	These results indicate that cancer cells with loss of NEFH are more susceptible to inhibitors that decrease Akt activation and glycolysis.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Akt', 'Gene', (108, 111))	('activation', 'PosReg', (112, 122))	('loss', 'Var', (46, 50))	('decrease', 'NegReg', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('Akt', 'Gene', '207', (108, 111))	('glycolysis', 'MPA', (127, 137))	('cancer', 'Disease', (28, 34))	('NEFH', 'Gene', (54, 58))
837191	20140245	Increased expression and nuclear localization of beta-catenin protein were reported in ESCC; however, the mechanism of beta-catenin accumulation was unknown in the absence of mutations of either beta-catenin or the adenomatous polyposis coli (APC).	('adenomatous polyposis coli', 'Disease', (215, 241))	('beta-catenin', 'Gene', (49, 61))	('beta-catenin', 'Gene', '1499', (119, 131))	('APC', 'Gene', '324', (243, 246))	('beta-catenin', 'Gene', '1499', (195, 207))	('beta-catenin', 'Gene', '1499', (49, 61))	('expression', 'MPA', (10, 20))	('beta-catenin', 'Gene', (195, 207))	('Increased', 'PosReg', (0, 9))	('ESCC', 'Disease', (87, 91))	('beta-catenin', 'Gene', (119, 131))	('mutations', 'Var', (175, 184))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (215, 241))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (215, 241))	('APC', 'Phenotype', 'HP:0005227', (243, 246))	('APC', 'Gene', (243, 246))	('nuclear localization', 'MPA', (25, 45))
837192	20140245	Here, we show that NEFH is a tumor suppressor gene, and that promoter methylation of NEFH gene decreases gene expression and increase the activity of beta-catenin.	('beta-catenin', 'Gene', '1499', (150, 162))	('gene expression', 'MPA', (105, 120))	('activity', 'MPA', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('increase', 'PosReg', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('NEFH', 'Gene', (85, 89))	('tumor', 'Disease', (29, 34))	('promoter methylation', 'Var', (61, 81))	('beta-catenin', 'Gene', (150, 162))	('decreases', 'NegReg', (95, 104))
837193	20140245	Even though precise mechanisms on how NEFH regulates b-catenin are still needs to be further elucidated, epigenetic silencing of the NEFH gene in ESCC seems to be responsible for increased beta-catenin expression, leading to activation of beta-catenin/TCF-dependent transcription and key downstream effectors, leading to ESCC tumorigenesis.	('beta-catenin', 'Gene', (189, 201))	('leading to', 'Reg', (310, 320))	('b-catenin', 'Gene', (53, 62))	('NEFH', 'Gene', (133, 137))	('b-catenin', 'Gene', '1499', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('activation', 'PosReg', (225, 235))	('ESCC', 'Disease', (321, 325))	('expression', 'MPA', (202, 212))	('beta-catenin', 'Gene', '1499', (189, 201))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('TCF', 'Gene', (252, 255))	('TCF', 'Gene', '3172', (252, 255))	('beta-catenin', 'Gene', '1499', (239, 251))	('beta-catenin', 'Gene', (239, 251))	('tumor', 'Disease', (326, 331))	('epigenetic silencing', 'Var', (105, 125))	('increased', 'PosReg', (179, 188))
837198	20140245	Previous studies have shown that TCF-dependent transcriptional activity in ESCC cell lines are increased by mutant beta-catenin as compared to wild-type counterparts.	('transcriptional activity', 'MPA', (47, 71))	('beta-catenin', 'Gene', (115, 127))	('mutant', 'Var', (108, 114))	('TCF', 'Gene', (33, 36))	('TCF', 'Gene', '3172', (33, 36))	('beta-catenin', 'Gene', '1499', (115, 127))	('increased', 'PosReg', (95, 104))
837202	20140245	Oncogenic alterations that increase Akt kinase activity stimulate aerobic glycolysis (increased glucose transport and lactate production, but reduce the cellular activity of mitochondria in many cancers.	('increased', 'PosReg', (86, 95))	('stimulate', 'PosReg', (56, 65))	('reduce', 'NegReg', (142, 148))	('lactate', 'Chemical', 'MESH:D019344', (118, 125))	('Akt', 'Gene', (36, 39))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('activity', 'MPA', (47, 55))	('increase', 'PosReg', (27, 35))	('Akt', 'Gene', '207', (36, 39))	('alterations', 'Var', (10, 21))	('cellular activity of mitochondria', 'MPA', (153, 186))	('aerobic glycolysis', 'MPA', (66, 84))	('glucose', 'Chemical', 'MESH:D005947', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('increased glucose', 'Phenotype', 'HP:0003074', (86, 103))	('glucose transport', 'MPA', (96, 113))	('lactate production', 'MPA', (118, 136))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))
837204	20140245	In the present study, we demonstrated that loss of NEFH resulted in a Akt-beta-catenin-dependent reprogramming of glucose and energy metabolism that included increased glycolysis accompanied by a reciprocal decrease in cellular respiration.	('cellular respiration', 'MPA', (219, 239))	('Akt', 'Gene', (70, 73))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('NEFH', 'Gene', (51, 55))	('beta-catenin', 'Gene', (74, 86))	('glycolysis', 'MPA', (168, 178))	('Akt', 'Gene', '207', (70, 73))	('loss', 'Var', (43, 47))	('decrease', 'NegReg', (207, 215))	('increased', 'PosReg', (158, 167))	('beta-catenin', 'Gene', '1499', (74, 86))
837210	20140245	Sequences of these TBE matched the consensus for TCF-binding CTTTG(A/T)(A/T) or the inverted sequences (A/T)(A/T)CAAAG ; CTTTGAT (-639 bp), CTTTGAA (-1342 bp), CTTTGAA (-1355 bp), CTTTGTA (-2148 bp) and an inverted match TTCAAAG (-2921 bp) in the PDH promoter, and three inverted matches TACAAAG (-3374 bp), TTCAAAG (-3859 bp), and AACAAAG (-4836 bp) in the PK-M2 promoter.	('TCA', 'Chemical', 'MESH:D014238', (222, 225))	('PK-M2', 'Gene', (358, 363))	('TCF', 'Gene', (49, 52))	('-1355 bp', 'Var', (169, 177))	('-3859 bp', 'Var', (317, 325))	('TCF', 'Gene', '3172', (49, 52))	('TBE', 'Chemical', '-', (19, 22))	('PDH', 'Gene', (247, 250))	('-4836 bp', 'Var', (341, 349))	('TCA', 'Chemical', 'MESH:D014238', (309, 312))	('-3374 bp', 'Var', (297, 305))	('-1342 bp', 'Var', (149, 157))	('-2148 bp', 'Var', (189, 197))	('PDH', 'Gene', '54704', (247, 250))	('PK-M2', 'Gene', '5315', (358, 363))
837214	20140245	S4 a-S4c), but increases cellular sensitivity to 2-DG, a glycolysis inhibitor.	('increases', 'PosReg', (15, 24))	('cellular sensitivity to 2-DG', 'MPA', (25, 53))	('2-DG', 'Chemical', 'MESH:D003847', (49, 53))	('S4 a-S4c', 'Var', (0, 8))
837218	20140245	Akt was activated by 2-DG treatment in both C2 and N20 cells (data not shown), but it is unrelated to glycolysis inhibition of 2-DG.	('activated', 'PosReg', (8, 17))	('2-DG treatment', 'Var', (21, 35))	('2-DG', 'Chemical', 'MESH:D003847', (21, 25))	('2-DG', 'Chemical', 'MESH:D003847', (127, 131))	('N20', 'CellLine', 'CVCL:D427', (51, 54))	('Akt', 'Gene', '207', (0, 3))	('Akt', 'Gene', (0, 3))
837225	20140245	Twelve ESCC cell lines, TE1, TE2, TE3, TE4, TE5, KYSE30, KYSE70, KYSE140, KYSE150, KYSE200, KYSE410, and KYSE520 were obtained from the Cell Response Center for Biomedical Research Institute, Department of Aging and Cancer, Tohoku University (TE series) and kindly provided by Dr. Shimada in the Department of Surgery, Kyoto University (KYSE series).	('KYSE520', 'Var', (105, 112))	('KYSE70', 'Var', (57, 63))	('KYSE410', 'Var', (92, 99))	('TE2', 'Gene', (29, 32))	('KYSE140', 'Var', (65, 72))	('Cancer', 'Disease', (216, 222))	('KYSE200', 'Var', (83, 90))	('KYSE140', 'CellLine', 'CVCL:1347', (65, 72))	('KYSE150', 'Var', (74, 81))	('Cancer', 'Disease', 'MESH:D009369', (216, 222))	('Cancer', 'Phenotype', 'HP:0002664', (216, 222))	('KYSE30', 'Var', (49, 55))	('TE2', 'Gene', '8260', (29, 32))
837251	20140245	TOPflash has four copies of wild-type Tcf binding site, and FOPflash has three copies of mutant TCF binding site upstream of the E1B TATA box and Luciferase open reading frame.	('TCF', 'Gene', (96, 99))	('TCF', 'Gene', '3172', (96, 99))	('Tcf', 'Gene', '3172', (38, 41))	('Tcf', 'Gene', (38, 41))	('mutant', 'Var', (89, 95))
837258	20140245	pCIneo-beta-cat expressing wild-type beta-catenin and pCIneo-beta-cat-S33Y expressing mutant beta-catenin that has a defect in Gsk3beta-dependent phosphorylation of beta-catenin was kindly given by Dr. Bert Vogelstein from the Johns Hopkins University.	('beta-catenin', 'Gene', (93, 105))	('mutant', 'Var', (86, 92))	('beta-catenin', 'Gene', '1499', (165, 177))	('Gsk3beta', 'Gene', '2932', (127, 135))	('beta-catenin', 'Gene', (37, 49))	('S33Y', 'Mutation', 'rs121913400', (70, 74))	('Gsk3beta', 'Gene', (127, 135))	('beta-catenin', 'Gene', '1499', (93, 105))	('beta-catenin', 'Gene', '1499', (37, 49))	('beta-catenin', 'Gene', (165, 177))
837265	19562338	Antibodies against MUC1 were associated with a favorable prognosis while antibodies against p53 were associated with poor disease outcome.	('Antibodies', 'Var', (0, 10))	('MUC1', 'Gene', (19, 23))	('MUC1', 'Gene', '4582', (19, 23))	('p53', 'Gene', (92, 95))	('associated', 'Reg', (101, 111))	('p53', 'Gene', '7157', (92, 95))
837267	19562338	Disturbance of self-tolerance can lead to autoimmune diseases that are characterized by chronic inflammation and/or tissue destruction.	('self-tolerance', 'Protein', (15, 29))	('autoimmune diseases', 'Disease', (42, 61))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (42, 61))	('lead to', 'Reg', (34, 41))	('Disturbance', 'Var', (0, 11))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('autoimmune diseases', 'Disease', 'MESH:D001327', (42, 61))	('inflammation', 'Disease', (96, 108))	('self-tolerance', 'Phenotype', 'HP:0100716', (15, 29))
837269	19562338	Apart from a loss of self-tolerance that is considered important for the development of autoimmune diseases, immune responses in cancer patients may be initiated by alterations in the tumor itself that result in increased immunogenicity of self-antigens.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('autoimmune diseases', 'Disease', (88, 107))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (88, 107))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('increased', 'PosReg', (212, 221))	('immunogenicity of self-antigens', 'MPA', (222, 253))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('initiated by', 'Reg', (152, 164))	('tumor', 'Disease', (184, 189))	('patients', 'Species', '9606', (136, 144))	('self-tolerance', 'Phenotype', 'HP:0100716', (21, 35))	('autoimmune diseases', 'Disease', 'MESH:D001327', (88, 107))	('immune responses', 'CPA', (109, 125))	('alterations', 'Var', (165, 176))
837272	19562338	p53), posttranslational modifications with immunological relevance (e.g.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('posttranslational modifications', 'Var', (6, 37))
837314	19562338	Most data exist for p53, where antibody prevalence was associated with p53 overexpression or p53 mutations that lead to subsequent extensive accumulation of the protein in the cell.	('mutations', 'Var', (97, 106))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('overexpression', 'PosReg', (75, 89))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('accumulation', 'PosReg', (141, 153))
837316	19562338	demonstrated a strong correlation between antibodies against Her2/neu and Her2/neu overexpression in breast cancer (82% antibodies in cases with strong expression versus no antibodies in cases with weak expression).	('Her2/neu', 'Gene', '2064', (61, 69))	('Her2/neu', 'Gene', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('antibodies', 'Var', (42, 52))	('overexpression', 'PosReg', (83, 97))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('Her2/neu', 'Gene', (61, 69))	('breast cancer', 'Disease', (101, 114))	('Her2/neu', 'Gene', '2064', (74, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
837327	19562338	p53 is mutated in over 50% of all cancers such as esophageal, lung, colorectal, and ovarian and humoral immune responses can be observed that correlate to accumulation of the mutated protein in the cell.	('p53', 'Gene', (0, 3))	('esophageal', 'Disease', (50, 60))	('p53', 'Gene', '7157', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('accumulation', 'PosReg', (155, 167))	('lung', 'Disease', (62, 66))	('protein', 'Protein', (183, 190))	('esophageal', 'Disease', 'MESH:D004941', (50, 60))	('colorectal', 'Disease', (68, 78))	('ovarian', 'Disease', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('mutated', 'Var', (175, 182))
837329	19562338	It has also been speculated that specific p53 mutations are associated with antibody production and that p53 antibodies might reflect specific mutations that lead to a more aggressive tumor.	('p53', 'Gene', (42, 45))	('mutations', 'Var', (46, 55))	('p53', 'Gene', '7157', (42, 45))	('lead to', 'Reg', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('antibody production', 'MPA', (76, 95))	('aggressive tumor', 'Disease', 'MESH:D001523', (173, 189))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('aggressive tumor', 'Disease', (173, 189))	('associated', 'Reg', (60, 70))
837330	19562338	Furthermore, two mechanisms explaining a tumor promoting role of p53 antibodies in tumor immunosurveillance have been described: Antibodies directed against p53 could inhibit antigen uptake by antigen presenting cells through the formation of immune complexes.	('Antibodies', 'Var', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('antigen uptake by antigen presenting cells', 'MPA', (175, 217))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('p53', 'Gene', '7157', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (83, 88))	('inhibit', 'NegReg', (167, 174))	('immune complexes', 'Interaction', (243, 259))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('p53', 'Gene', (157, 160))
837333	19562338	Although antibodies against p53 could be found in patients with premalignant oral lesions and in heavy smokers with risk for development of lung cancer, the clinical utility of p53 antibody serology in monitoring high risk individuals needs to be evaluated in prospective studies.	('found', 'Reg', (41, 46))	('p53', 'Gene', (28, 31))	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('patients', 'Species', '9606', (50, 58))	('p53', 'Gene', '7157', (28, 31))	('premalignant oral lesions', 'Disease', 'MESH:D020820', (64, 89))	('p53', 'Gene', (177, 180))	('p53', 'Gene', '7157', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('antibodies', 'Var', (9, 19))	('oral lesions', 'Phenotype', 'HP:0100649', (77, 89))	('premalignant oral lesions', 'Disease', (64, 89))
837339	19562338	Altered glycosylation patterns of MUC1 may induce immune responses on the cellular and humoral level and tumor vaccines and monoclonal antibodies based on this antigen are tested in clinical trials.	('immune', 'MPA', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Altered', 'Var', (0, 7))	('glycosylation patterns', 'MPA', (8, 30))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('induce', 'Reg', (43, 49))	('MUC1', 'Gene', (34, 38))	('MUC1', 'Gene', '4582', (34, 38))	('tumor', 'Disease', (105, 110))
837340	19562338	The presence of MUC1 antibodies has been associated with improved survival in early stage patients with ovarian, gastric, lung, pancreatic or breast cancer.	('survival', 'MPA', (66, 74))	('ovarian', 'Disease', (104, 111))	('pancreatic or breast cancer', 'Disease', (128, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('MUC1', 'Gene', (16, 20))	('MUC1', 'Gene', '4582', (16, 20))	('pancreatic or breast cancer', 'Disease', 'MESH:D010190', (128, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('improved', 'PosReg', (57, 65))	('presence', 'Var', (4, 12))	('lung', 'Disease', (122, 126))	('patients', 'Species', '9606', (90, 98))	('gastric', 'Disease', (113, 120))
837350	19562338	Interestingly, although no clinical effects in terms of survival benefit have been reported for endogenous Her2/neu antibodies, it has been shown that these antibodies can modulate the transforming properties of Her2/neu signaling towards an anti-proliferative state, similar to what has been demonstrated for the therapeutic Her2/neu antibody.	('Her2/neu', 'Gene', '2064', (326, 334))	('Her2/neu', 'Gene', '2064', (212, 220))	('Her2/neu', 'Gene', (107, 115))	('antibodies', 'Var', (157, 167))	('modulate', 'Reg', (172, 180))	('Her2/neu', 'Gene', '2064', (107, 115))	('transforming properties', 'MPA', (185, 208))	('Her2/neu', 'Gene', (212, 220))	('Her2/neu', 'Gene', (326, 334))
837352	19562338	In support of this hypothesis, high titers of endogenous Her2/neu antibodies induced by vaccination with peptides were shown to improve survival.	('Her2/neu', 'Gene', '2064', (57, 65))	('peptides', 'Var', (105, 113))	('survival', 'CPA', (136, 144))	('Her2/neu', 'Gene', (57, 65))	('improve', 'PosReg', (128, 135))	('peptides', 'Chemical', 'MESH:D010455', (105, 113))
837364	19562338	While this might be primarily related to increased exposure with the antigen, antibodies might also reflect p53 mutations that lead to a more aggressive tumor behavior.	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', (108, 111))	('lead to', 'Reg', (127, 134))	('aggressive tumor', 'Disease', 'MESH:D001523', (142, 158))	('mutations', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('aggressive tumor', 'Disease', (142, 158))
837379	32833352	However, the modified Collard anastomosis is accompanied by an increased anastomotic leakage rate.	('anastomotic leakage', 'Disease', 'MESH:D057868', (73, 92))	('increased', 'PosReg', (63, 72))	('Collard anastomosis', 'Disease', 'MESH:C563598', (22, 41))	('anastomotic leakage', 'Disease', (73, 92))	('Collard anastomosis', 'Disease', (22, 41))	('modified', 'Var', (13, 21))
837384	32833352	In many patients, overall survival is closely associated with a successful anastomosis and the avoidance of anastomotic tension and maintaining the blood supply to the tip of the gastric conduit, which may be impacted by the type of anastomosis, is critical.	('anastomotic tension', 'Disease', 'MESH:D057868', (108, 127))	('anastomotic tension', 'Disease', (108, 127))	('anastomosis', 'Var', (75, 86))	('patients', 'Species', '9606', (8, 16))
837419	32833352	Anastomotic leakage was defined as follows: (i) leaks confirmed by endoscopy, chest computed tomography (CT), and/or surgical exploration;17 and (ii) disruption of the anastomosis that leads to the leakage of the intraluminal content sufficient to cause clinical symptoms.	('Anastomotic leakage', 'Disease', (0, 19))	('leakage of the intraluminal content', 'MPA', (198, 233))	('disruption', 'Var', (150, 160))	('Anastomotic leakage', 'Disease', 'MESH:D057868', (0, 19))
837447	32833352	The results of the present study reported that modified Collard anastomosis yielded significantly lower rates of anastomotic stricture compared with hand-sewn anastomosis.	('Collard anastomosis', 'Disease', 'MESH:C563598', (56, 75))	('Collard anastomosis', 'Disease', (56, 75))	('modified', 'Var', (47, 55))	('anastomotic stricture', 'MPA', (113, 134))	('lower', 'NegReg', (98, 103))
837454	32833352	One of the superiorities of the modified Collard anastomosis is its large anastomotic diameter.	('modified', 'Var', (32, 40))	('Collard anastomosis', 'Disease', 'MESH:C563598', (41, 60))	('Collard anastomosis', 'Disease', (41, 60))
837464	32833352	Furthermore, the suboptimal intake of nutrients could cause continuous weight loss which is considered as an independent risk factor for oncological prognosis.	('suboptimal', 'Var', (17, 27))	('weight loss', 'Disease', (71, 82))	('weight loss', 'Disease', 'MESH:D015431', (71, 82))	('weight loss', 'Phenotype', 'HP:0001824', (71, 82))
837466	32833352	One of the technical reasons for the high leakage rate could be due to resection of the tips of both the gastric conduit and esophagus which could cause more anastomotic tension.	('anastomotic tension', 'Disease', (158, 177))	('leakage', 'MPA', (42, 49))	('cause', 'Reg', (147, 152))	('anastomotic tension', 'Disease', 'MESH:D057868', (158, 177))	('resection', 'Var', (71, 80))	('more', 'PosReg', (153, 157))
837467	32833352	Meanwhile, in clinical practice, oversewing the staple line may contribute to additional ischemia, leading to dehiscence of the suture and staple line.	('oversewing', 'Var', (33, 43))	('ischemia', 'Disease', (89, 97))	('dehiscence', 'CPA', (110, 120))	('ischemia', 'Disease', 'MESH:D007511', (89, 97))
837470	32833352	In conclusion, a modified Collard cervical esophagogastric anastomosis in the neck is associated with a lower anastomotic stricture and dysphagia rate, compared with end-to-side hand-sewn anastomosis.	('dysphagia', 'Phenotype', 'HP:0002015', (136, 145))	('anastomotic stricture and dysphagia', 'Disease', 'MESH:D003680', (110, 145))	('esophagogastric anastomosis', 'Phenotype', 'HP:0100628', (43, 70))	('lower', 'NegReg', (104, 109))	('modified', 'Var', (17, 25))
837471	32811852	Tumoral and paratumoral NK cells and CD8+ T cells of esophageal carcinoma patients express high levels of CD47 In a limited number of human malignancies, anti-CD47 therapy leads to the rapid clearance of tumor cells by macrophages.	('CD8', 'Gene', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('esophageal', 'Disease', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('CD47', 'MPA', (106, 110))	('carcinoma', 'Disease', (64, 73))	('human', 'Species', '9606', (134, 139))	('CD8', 'Gene', '925', (37, 40))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Disease', (16, 21))	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (53, 73))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('anti-CD47', 'Var', (154, 163))	('carcinoma', 'Disease', 'MESH:D009369', (64, 73))	('malignancies', 'Disease', (140, 152))	('tumor', 'Disease', (204, 209))
837472	32811852	In esophageal squamous cell carcinoma, anti-CD47 treatment has shown promising results in vitro.	('anti-CD47', 'Var', (39, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))
837476	32811852	High expression of CD47 in tissue-infiltrating NK cells and CD8+ T cells in EC patients can, therefore, affect the efficacy of anti-CD47 therapy in EC.	('affect', 'Reg', (104, 110))	('efficacy', 'MPA', (115, 123))	('CD8', 'Gene', '925', (60, 63))	('anti-CD47', 'Var', (127, 136))	('patients', 'Species', '9606', (79, 87))	('CD47', 'Gene', (19, 23))	('CD8', 'Gene', (60, 63))
837483	32811852	An anti-CD47 antibody would presumably increase tumor cell phagocytosis and antitumor CD8+ T cell response priming.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('anti-CD47', 'Gene', (3, 12))	('anti-CD47', 'Var', (3, 12))	('tumor', 'Disease', (80, 85))	('CD8', 'Gene', (86, 89))	('increase', 'PosReg', (39, 47))	('CD8', 'Gene', '925', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
837497	32811852	However, the data indicated that the proportions of CD47-expressing NK cells and CD8+ T cells were higher than those of the corresponding nonlymphocytes.	('CD8', 'Gene', (81, 84))	('CD47-expressing', 'Var', (52, 67))	('CD8', 'Gene', '925', (81, 84))
837506	32811852	A previous report has shown that anti-CD47 antibody increased T cell-mediated cytotoxicity when incubated with the effector and target cells.	('anti-CD47', 'Var', (33, 42))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('increased', 'PosReg', (52, 61))	('cytotoxicity', 'Disease', (78, 90))
837508	32811852	4, pretreatment of PBMCs with anti-CD47 antibody for 18-20 h had no impact on cytotoxicity (Fig.	('anti-CD47', 'Var', (30, 39))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('anti-CD47', 'Gene', (30, 39))	('cytotoxicity', 'Disease', (78, 90))
837511	32811852	In this study, we show that in addition to tumor cells, the majority of tumoral and paratumoral NK cells and CD8+ T cells also express CD47, and the levels of its expression are even higher than in the parallel nonlymphocyte cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('higher', 'PosReg', (183, 189))	('CD8', 'Gene', (109, 112))	('tumoral', 'Disease', (88, 95))	('tumoral', 'Disease', 'MESH:D009369', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CD47', 'Var', (135, 139))	('tumor', 'Disease', (72, 77))	('CD8', 'Gene', '925', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumoral', 'Disease', (72, 79))	('tumoral', 'Disease', 'MESH:D009369', (72, 79))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (88, 93))
837517	32811852	Regardless of this, the levels of CD47 on the surface of the tested NK cells and CD8+ T cells were mostly higher than in the parallel nonlymphocyte cell fraction, which contains tumor cells in the tumoral compartment.	('tumoral', 'Disease', (197, 204))	('tumoral', 'Disease', 'MESH:D009369', (197, 204))	('tumor', 'Disease', (178, 183))	('CD8', 'Gene', (81, 84))	('CD8', 'Gene', '925', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('higher', 'PosReg', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('levels', 'MPA', (24, 30))	('CD47', 'Var', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (197, 202))
837519	32811852	Whether the use of anti-CD47 immunotherapy would also trigger apoptosis in CD47-expressing populations of tumoral and paratumoral NK cells and CD8+ T cells in EC patients or only alter the effector functions of these immune cells needs to be determined.	('anti-CD47', 'Var', (19, 28))	('patients', 'Species', '9606', (162, 170))	('trigger', 'Reg', (54, 61))	('alter', 'Reg', (179, 184))	('CD8', 'Gene', (143, 146))	('tumoral', 'Disease', (122, 129))	('tumoral', 'Disease', 'MESH:D009369', (122, 129))	('tumoral', 'Disease', (106, 113))	('tumoral', 'Disease', 'MESH:D009369', (106, 113))	('apoptosis', 'CPA', (62, 71))	('CD8', 'Gene', '925', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CD47-expressing', 'Gene', (75, 90))
837520	32811852	On the other hand, blocking CD47 can also prevent the augmentation of Fas/CD95-mediated apoptosis in TILs.	('CD47', 'Protein', (28, 32))	('CD95', 'Gene', (74, 78))	('prevent', 'NegReg', (42, 49))	('CD95', 'Gene', '355', (74, 78))	('blocking', 'Var', (19, 27))
837522	32811852	However, regardless of which of these mechanisms prevail in infiltrating NK cells and CD8+ T cells, anti-CD47 immunotherapy in EC will modulate the tumor immune microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('modulate', 'Reg', (135, 143))	('tumor', 'Disease', (148, 153))	('CD8', 'Gene', (86, 89))	('CD8', 'Gene', '925', (86, 89))	('anti-CD47', 'Var', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
837524	32811852	The findings of this study indicate that the administration of anti-CD47 immunotherapy can impact the tumoral and paratumoral infiltrating lymphocytes of EC patients.	('tumoral', 'Disease', 'MESH:D009369', (118, 125))	('impact', 'Reg', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumoral', 'Disease', (102, 109))	('tumoral', 'Disease', 'MESH:D009369', (102, 109))	('patients', 'Species', '9606', (157, 165))	('anti-CD47', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumoral', 'Disease', (118, 125))
837532	32811852	The antibodies were anti-CD45 AF700 (Exbio, Prague, Czech Republic), anti-CD3 PerCP-Cy5.5 (Thermo Scientific), anti-CD56 FITC (Exbio), and anti-CD47 APC (BioLegend, San Diego, CA).	('CD56', 'Gene', (116, 120))	('CD45', 'Gene', (25, 29))	('CD45', 'Gene', '5788', (25, 29))	('APC', 'Disease', 'MESH:D011125', (149, 152))	('APC', 'Disease', (149, 152))	('anti-CD3 PerCP-Cy5.5', 'Var', (69, 89))	('CD56', 'Gene', '4684', (116, 120))	('FITC', 'Chemical', 'MESH:D016650', (121, 125))
837537	32811852	The cells were stained as above using the anti-CD45 AF700 (Exbio), anti-CD3 PerCP-Cy5.5 (Thermo Scientific), and anti-CD56 FITC and anti-CD107a PE (Exbio) antibodies.	('CD45', 'Gene', '5788', (47, 51))	('CD107a', 'Gene', (137, 143))	('CD107a', 'Gene', '3916', (137, 143))	('FITC', 'Chemical', 'MESH:D016650', (123, 127))	('CD45', 'Gene', (47, 51))	('CD56', 'Gene', '4684', (118, 122))	('anti-CD3', 'Var', (67, 75))	('CD56', 'Gene', (118, 122))
837551	32253638	Manipulating endosomal pH by epigenetic reprogramming, small molecules, or nanoparticles may offer promising new options in cancer therapy.	('epigenetic reprogramming', 'Var', (29, 53))	('cancer', 'Disease', (124, 130))	('pH', 'Gene', '5053', (23, 25))	('Manipulating', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
837553	32253638	Dysregulation of cellular pH is an established hallmark of malignancy.	('Dysregulation', 'Var', (0, 13))	('malignancy', 'Disease', (59, 69))	('pH', 'Gene', '5053', (26, 28))	('malignancy', 'Disease', 'MESH:D009369', (59, 69))
837596	32253638	Cl- flux is critical for endocytosis in renal tissue where defects in CLC-5 (gene name CLCN5) underlie Dent's disease characterized by proximal tubule dysfunction and low molecular weight proteinuria.	('tubule dysfunction', 'Disease', (144, 162))	('CLC-5', 'Gene', '1184', (70, 75))	('proteinuria', 'Disease', 'MESH:D011507', (188, 199))	('CLC-5', 'Gene', (70, 75))	('tubule dysfunction', 'Disease', 'MESH:D007673', (144, 162))	('proximal tubule dysfunction', 'Phenotype', 'HP:0000114', (135, 162))	('underlie', 'Reg', (94, 102))	('low molecular weight proteinuria', 'Phenotype', 'HP:0003126', (167, 199))	('CLCN5', 'Gene', '1184', (87, 92))	('CLCN5', 'Gene', (87, 92))	('proteinuria', 'Phenotype', 'HP:0000093', (188, 199))	("Dent's disease", 'Disease', 'MESH:C538212', (103, 117))	('proteinuria', 'Disease', (188, 199))	("Dent's disease", 'Disease', (103, 117))	('defects', 'Var', (59, 66))
837597	32253638	Consistent with their essential role in pH regulation, loss of function mutations in the chloride transporter isoform, CLC-7 (gene name CLCN7), phenocopy V-ATPase defects in the fatal disorder, osteopetrosis in which defective acidification by osteoclasts results in failure to remodel bone.	('CLC-7', 'Gene', '1186', (119, 124))	('mutations', 'Var', (72, 81))	('CLCN7', 'Gene', '1186', (136, 141))	('pH', 'Gene', '5053', (40, 42))	('defects', 'Var', (163, 170))	('defective', 'Var', (217, 226))	('defective acidification', 'Phenotype', 'HP:0031033', (217, 240))	('osteopetrosis', 'Disease', (194, 207))	('osteopetrosis', 'Disease', 'MESH:D010022', (194, 207))	('osteopetrosis', 'Phenotype', 'HP:0011002', (194, 207))	('acidification', 'MPA', (227, 240))	('fatal disorder', 'Disease', 'MESH:C535933', (178, 192))	('loss of function', 'NegReg', (55, 71))	('CLC-7', 'Gene', (119, 124))	('CLCN7', 'Gene', (136, 141))	('ATP', 'Chemical', 'MESH:D000255', (156, 159))	('fatal disorder', 'Disease', (178, 192))
837606	32253638	Similarly, NHE5 is a potent acidifier of recycling endosomes in rat pheochromocytoma PC12 cells, and attenuation of NHE5 expression via shRNA decreased the steady state level of Tropomyosin Receptor Kinase A (TrkA) on the plasma membrane.	('attenuation', 'Var', (101, 112))	('PC12', 'CellLine', 'CVCL:0481', (85, 89))	('Tropomyosin Receptor Kinase A', 'Gene', '59109', (178, 207))	('Tropomyosin Receptor Kinase A', 'Gene', (178, 207))	('pheochromocytoma', 'Disease', (68, 84))	('decreased', 'NegReg', (142, 151))	('TrkA', 'Gene', (209, 213))	('rat', 'Species', '10116', (64, 67))	('TrkA', 'Gene', '59109', (209, 213))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (68, 84))	('pheochromocytoma', 'Disease', 'MESH:D010673', (68, 84))	('NHE5', 'Gene', (116, 120))
837611	32253638	This is consistent with the majority of studies, which report that NHE6, NHE7 and NHE9 alkalinize the compartmental lumen, in contrast to the "plasma membrane" subtype isoforms, NHE3 and NHE5 that acidify endosomal lumen.	('alkalinize', 'Reg', (87, 97))	('NHE6', 'Gene', (67, 71))	('NHE3', 'Gene', '6550', (178, 182))	('NHE7', 'Gene', '84679', (73, 77))	('NHE3', 'Gene', (178, 182))	('NHE6', 'Gene', '10479', (67, 71))	('NHE9', 'Var', (82, 86))	('NHE7', 'Gene', (73, 77))
837620	32253638	Along with the evolutionary selection of cancer-driving mutations, the acidic tumor microenvironment favors and drives cancer progression, particularly in local invasion and metastasis, genetic instability, cancer stem cells, epigenetic alterations, proliferation, and survival.	('favors', 'PosReg', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('epigenetic alterations', 'Var', (226, 248))	('cancer', 'Disease', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (119, 125))	('local invasion', 'CPA', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('survival', 'CPA', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('rat', 'Species', '10116', (257, 260))	('rat', 'Species', '10116', (241, 244))	('proliferation', 'CPA', (250, 263))	('genetic', 'Var', (186, 193))	('acidic tumor', 'Disease', 'MESH:D009369', (71, 83))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('acidic tumor', 'Disease', (71, 83))	('cancer', 'Disease', 'MESH:D009369', (119, 125))
837621	32253638	Acidic extracellular pH between 6.4 and 6.8 was found to increase lysosome size and promote anterograde trafficking to the cell periphery resulting in increased secretion of proteolytic enzymes.	('increased', 'PosReg', (151, 160))	('lysosome size', 'CPA', (66, 79))	('promote', 'PosReg', (84, 91))	('secretion of proteolytic enzymes', 'MPA', (161, 193))	('pH', 'Gene', '5053', (21, 23))	('Acidic', 'Var', (0, 6))	('increase', 'PosReg', (57, 65))	('anterograde trafficking to', 'CPA', (92, 118))
837623	32253638	In recent years, significant progress has been made towards elucidating the cellular processes and signaling pathways that link endosomal pH, and particularly dysregulated expression or activity of intracellular NHE isoforms to oncogenesis and chemoresistance.	('NHE', 'Gene', (212, 215))	('chemoresistance', 'CPA', (244, 259))	('dysregulated', 'Var', (159, 171))	('activity', 'MPA', (186, 194))	('NHE', 'Gene', '285335', (212, 215))	('pH', 'Gene', '5053', (138, 140))	('oncogenesis', 'CPA', (228, 239))
837633	32253638	found that silencing NHE6 but not NHE9 increased endosomal drug sequestration, even under normoxia.	('silencing', 'Var', (11, 20))	('NHE6', 'Gene', '10479', (21, 25))	('rat', 'Species', '10116', (71, 74))	('endosomal drug sequestration', 'MPA', (49, 77))	('NHE6', 'Gene', (21, 25))
837640	32253638	Consistent with high amplification of SLC9A9 (Figure 3), NHE9 was found to be a prognostic predictor for poor survival in esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('esophageal squamous cell carcinoma', 'Disease', (122, 156))	('SLC9A9', 'Gene', (38, 44))	('NHE9', 'Gene', (57, 61))	('high amplification', 'Var', (16, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (122, 156))	('SLC9A9', 'Gene', '285195', (38, 44))
837647	32253638	The increased chemoradiation resistance with NHE9 expression was also shown in xenograft model in mice.	('expression', 'Var', (50, 60))	('chemoradiation resistance', 'CPA', (14, 39))	('increased', 'PosReg', (4, 13))	('NHE9', 'Gene', (45, 49))	('mice', 'Species', '10090', (98, 102))
837650	32253638	showed that NHE9 increases anti-apoptotic and pro-survival pathways such as p-GSK3b, Bcl-2, beta-catenin, p-Akt and p-Src to inhibit cleavage of PARP or Caspase-3.	('GSK3b', 'Gene', '2932', (78, 83))	('Caspase-3', 'Gene', (153, 162))	('anti-apoptotic', 'CPA', (27, 41))	('Bcl-2', 'Gene', (85, 90))	('Src', 'Gene', (118, 121))	('Akt', 'Gene', (108, 111))	('PARP', 'Gene', '1302', (145, 149))	('Akt', 'Gene', '207', (108, 111))	('Src', 'Gene', '6714', (118, 121))	('Bcl-2', 'Gene', '596', (85, 90))	('inhibit', 'NegReg', (125, 132))	('increases', 'PosReg', (17, 26))	('GSK3b', 'Gene', (78, 83))	('NHE9', 'Var', (12, 16))	('Caspase-3', 'Gene', '836', (153, 162))	('beta-catenin', 'Gene', (92, 104))	('beta-catenin', 'Gene', '1499', (92, 104))	('PARP', 'Gene', (145, 149))	('cleavage', 'MPA', (133, 141))
837655	32253638	Using patient derived glioblastoma cell lines they demonstrated that up regulated expression of NHE9 significantly alkalinized endosomal lumen, to pH ~6.5.	('glioblastoma', 'Disease', (22, 34))	('patient', 'Species', '9606', (6, 13))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('pH', 'Gene', '5053', (147, 149))	('expression', 'Var', (82, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('rat', 'Species', '10116', (58, 61))	('up regulated', 'PosReg', (69, 81))	('alkalinized endosomal lumen', 'MPA', (115, 142))	('NHE9', 'Gene', (96, 100))
837657	32253638	Similarly, high levels of NHE9 expression correlated with increased metastasis and worse prognosis in colorectal cancer patients, where a positive correlation with EGFR signaling was also noted.	('colorectal cancer', 'Disease', (102, 119))	('increased', 'PosReg', (58, 67))	('NHE9', 'Protein', (26, 30))	('rectal cancer', 'Phenotype', 'HP:0100743', (106, 119))	('expression', 'MPA', (31, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('patients', 'Species', '9606', (120, 128))	('metastasis', 'CPA', (68, 78))	('high', 'Var', (11, 15))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
837658	32253638	Post-translational oncogenic activation of EGFR was dependent on alkalinization of endosomal pH because autism-associated loss-of-function mutations, S438P and L236S, failed to phenocopy wild type NHE9 in glioblastoma cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('loss-of-function', 'NegReg', (122, 138))	('autism', 'Phenotype', 'HP:0000717', (104, 110))	('autism', 'Disease', 'MESH:D001321', (104, 110))	('L236S', 'Var', (160, 165))	('L236S', 'Mutation', 'rs113649536', (160, 165))	('S438P', 'Var', (150, 155))	('autism', 'Disease', (104, 110))	('S438P', 'Mutation', 'rs1181244744', (150, 155))	('glioblastoma', 'Disease', (205, 217))	('EGFR', 'Gene', (43, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (205, 217))	('pH', 'Gene', '5053', (93, 95))
837663	32253638	Functional restoration of miR-135a by ectopic expression in GBM cell lines resulted in down regulation of SLC9A9 transcript, acidification of endosomal pH and decreased GBM cell proliferation and migration.	('miR-135a', 'Gene', (26, 34))	('down regulation', 'NegReg', (87, 102))	('rat', 'Species', '10116', (16, 19))	('transcript', 'MPA', (113, 123))	('SLC9A9', 'Gene', (106, 112))	('ectopic expression', 'Var', (38, 56))	('decreased', 'NegReg', (159, 168))	('pH', 'Gene', '5053', (152, 154))	('rat', 'Species', '10116', (199, 202))	('SLC9A9', 'Gene', '285195', (106, 112))	('rat', 'Species', '10116', (185, 188))	('GBM cell proliferation', 'CPA', (169, 191))
837667	32253638	showed that NHE5 knockdown and treatment with the V-ATPase inhibitor bafilomycin had independent and additive effects in alkalinizing TfR-positive recycling endosomal compartments by small, but significant amounts of ~0.2-0.3 pH units.	('bafilomycin', 'Chemical', '-', (69, 80))	('NHE5', 'Gene', (12, 16))	('pH', 'Gene', '5053', (226, 228))	('TfR', 'Gene', (134, 137))	('ATP', 'Chemical', 'MESH:D000255', (52, 55))	('knockdown', 'Var', (17, 26))	('TfR', 'Gene', '64678', (134, 137))
837668	32253638	Surface levels of the receptor tyrosine kinase MET decreased with NHE5 knockdown, with concomitant reduction in downstream activation by hepatocyte growth factor (HGF) of PI3K/Akt pathway and activities of critical regulators of cytoskeleton remodelers such as the Rho family small GTPase protein, Rac1, and CDC42 (Figure 2D).	('Rac1', 'Gene', '363875', (298, 302))	('MET', 'Gene', '24553', (47, 50))	('decreased', 'NegReg', (51, 60))	('GTP', 'Chemical', 'MESH:D006160', (282, 285))	('activation', 'PosReg', (123, 133))	('NHE5', 'Gene', (66, 70))	('hepatocyte growth factor', 'Gene', '3082', (137, 161))	('Rac1', 'Gene', (298, 302))	('reduction', 'NegReg', (99, 108))	('hepatocyte growth factor', 'Gene', (137, 161))	('activities', 'MPA', (192, 202))	('CDC42', 'Gene', (308, 313))	('MET', 'Gene', (47, 50))	('receptor tyrosine kinase', 'Gene', '5979', (22, 46))	('CDC42', 'Gene', '998', (308, 313))	('Surface levels', 'MPA', (0, 14))	('HGF', 'Gene', '3082', (163, 166))	('Akt', 'Gene', (176, 179))	('knockdown', 'Var', (71, 80))	('receptor tyrosine kinase', 'Gene', (22, 46))	('HGF', 'Gene', (163, 166))	('Akt', 'Gene', '207', (176, 179))
837670	32253638	showed that NHE5 knockdown abrogated the recycling of MET receptor, but not Tfn receptors, whereas the endosome recycling inhibitor, primaquine, inhibited recycling of both MET and Tfn.	('abrogated', 'NegReg', (27, 36))	('MET', 'Gene', '24553', (54, 57))	('knockdown', 'Var', (17, 26))	('primaquine', 'Chemical', 'MESH:D011319', (133, 143))	('NHE5', 'Gene', (12, 16))	('MET', 'Gene', (173, 176))	('recycling', 'MPA', (155, 164))	('recycling', 'MPA', (41, 50))	('MET', 'Gene', (54, 57))	('MET', 'Gene', '24553', (173, 176))	('inhibited', 'NegReg', (145, 154))
837671	32253638	further showed that NHE5 increases the total level of EGFR and MET while abrogating the downstream signaling proteins' activation in C6 rat glioma cells.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('EGFR', 'MPA', (54, 58))	('increases', 'PosReg', (25, 34))	('glioma', 'Disease', (140, 146))	('MET', 'Gene', (63, 66))	('MET', 'Gene', '24553', (63, 66))	('rat', 'Species', '10116', (136, 139))	('NHE5', 'Var', (20, 24))	("downstream signaling proteins' activation", 'MPA', (88, 129))	('abrogating', 'NegReg', (73, 83))
837685	32253638	Gene disruption of NHE8 causes mice to become more susceptible to spontaneous colitis, dysbiosis, and increased epithelial cell proliferation.	('epithelial cell proliferation', 'CPA', (112, 141))	('colitis', 'Disease', 'MESH:D003092', (78, 85))	('rat', 'Species', '10116', (135, 138))	('colitis', 'Phenotype', 'HP:0002583', (78, 85))	('dysbiosis', 'Disease', (87, 96))	('dysbiosis', 'Disease', 'MESH:D064806', (87, 96))	('Gene disruption', 'Var', (0, 15))	('NHE8', 'Gene', (19, 23))	('mice', 'Species', '10090', (31, 35))	('increased', 'PosReg', (102, 111))	('more', 'PosReg', (46, 50))	('colitis', 'Disease', (78, 85))
837700	32253638	In a comprehensive molecular characterization of human colon and rectal cancer, whole-genome sequencing of 276 samples revealed SLC9A9 was one of 7 most frequent targets of mutation in hypermutated cancers.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('SLC9A9', 'Gene', '285195', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('colon', 'Disease', 'MESH:D003110', (55, 60))	('human', 'Species', '9606', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Disease', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutation', 'Var', (173, 181))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('rectal cancer', 'Phenotype', 'HP:0100743', (65, 78))	('colon', 'Disease', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('SLC9A9', 'Gene', (128, 134))	('cancer', 'Disease', (72, 78))
837707	32253638	Gene amplification events were more common in SLC9A9, especially in cervical, ovarian and head and neck cancers, and in lung squamous cell carcinoma (Figure 3).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('cervical', 'Disease', (68, 76))	('Gene amplification events', 'Var', (0, 25))	('SLC9A9', 'Gene', (46, 52))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 148))	('lung squamous cell carcinoma', 'Disease', (120, 148))	('ovarian and head and neck cancers', 'Disease', 'MESH:D006258', (78, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('SLC9A9', 'Gene', '285195', (46, 52))	('common', 'Reg', (36, 42))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('head and neck cancers', 'Phenotype', 'HP:0012288', (90, 111))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (120, 148))
837708	32253638	In contrast, majority of patients across all cancer types had shallow deletions in SLC9A6.	('SLC9A6', 'Gene', '10479', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('shallow deletions', 'Var', (62, 79))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('SLC9A6', 'Gene', (83, 89))	('cancer', 'Disease', (45, 51))
837709	32253638	For SLC9A9, gene amplification was observed in 14% of esophageal squamous cell carcinoma, 9% of cervical squamous cell carcinoma, and 6% of non-small cell lung cancer patients.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('cervical squamous cell carcinoma', 'Disease', (96, 128))	('lung cancer', 'Disease', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('esophageal squamous cell carcinoma', 'Disease', (54, 88))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 128))	('SLC9A9', 'Gene', '285195', (4, 10))	('gene amplification', 'Var', (12, 30))	('observed', 'Reg', (35, 43))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('patients', 'Species', '9606', (167, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('SLC9A9', 'Gene', (4, 10))
837710	32253638	On the other hand, the most frequently observed genetic alterations in SLC9A6 were gene mutations, reported in 7% of endometrial carcinoma, 3% of melanoma, and 2% of non-small cell lung cancer patients.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (117, 138))	('melanoma', 'Disease', (146, 154))	('patients', 'Species', '9606', (193, 201))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (170, 192))	('endometrial carcinoma', 'Disease', (117, 138))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('SLC9A6', 'Gene', '10479', (71, 77))	('rat', 'Species', '10116', (60, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (166, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('SLC9A6', 'Gene', (71, 77))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (117, 138))	('genetic alterations', 'Var', (48, 67))
837711	32253638	Thus, genetic alterations in SLC9A9 and SLC9A6 are cancer type-specific and isoform-specific, which should be taken into consideration when trying to target endosomal NHE in cancer.	('rat', 'Species', '10116', (18, 21))	('SLC9A6', 'Gene', (40, 46))	('SLC9A9', 'Gene', '285195', (29, 35))	('rat', 'Species', '10116', (128, 131))	('NHE', 'Gene', '285335', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('SLC9A6', 'Gene', '10479', (40, 46))	('cancer', 'Disease', (51, 57))	('SLC9A9', 'Gene', (29, 35))	('genetic alterations', 'Var', (6, 25))	('NHE', 'Gene', (167, 170))
837712	32253638	Recurring somatic mutations in cancer have been proposed to confer selective advantage, such as charge-changing mutations in pH sensing.	('charge-changing', 'Reg', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('advantage', 'PosReg', (77, 86))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('pH', 'Gene', '5053', (125, 127))	('cancer', 'Disease', (31, 37))
837713	32253638	Despite the cancer-specific enrichment of mutation incidents in SLC9A6, the overall somatic mutation frequencies for both SLC9A9 and SLC9A6 were comparable at 1.5% and 1.1%, respectively (Figure 4).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('SLC9A9', 'Gene', (122, 128))	('SLC9A6', 'Gene', (133, 139))	('cancer', 'Disease', (12, 18))	('SLC9A6', 'Gene', (64, 70))	('mutation', 'Var', (42, 50))	('SLC9A9', 'Gene', '285195', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('SLC9A6', 'Gene', '10479', (133, 139))	('SLC9A6', 'Gene', '10479', (64, 70))
837714	32253638	In SLC9A9, the most frequent mutation, S355L, was present in four uterine endometrioid carcinoma and one tubular stomach adenocarcinoma patients; Interestingly, according to the dbPTM database (http://dbptm.mbc.nctu.edu.tw/index.php), S355 residue is a potential phosphorylation site, which may influence the function and trafficking of NHE9.	('NHE9', 'Gene', (337, 341))	('influence', 'Reg', (295, 304))	('function', 'MPA', (309, 317))	('SLC9A9', 'Gene', (3, 9))	('tubular stomach adenocarcinoma', 'Disease', (105, 135))	('patients', 'Species', '9606', (136, 144))	('S355 residue', 'Var', (235, 247))	('trafficking', 'MPA', (322, 333))	('tubular stomach adenocarcinoma', 'Disease', 'MESH:D000230', (105, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (74, 96))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (74, 96))	('S355L', 'Mutation', 'rs552019939', (39, 44))	('SLC9A9', 'Gene', '285195', (3, 9))	('endometrioid carcinoma', 'Disease', (74, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
837715	32253638	Other post-translational modification sites that were mutated are N96Y, an N-glycosylation site, and Y631*, a tyrosine phosphorylation site.	('Y631*', 'Var', (101, 106))	('tyrosine', 'Chemical', 'MESH:D014443', (110, 118))	('N96Y', 'Mutation', 'p.N96Y', (66, 70))	('Y631*', 'SUBSTITUTION', 'None', (101, 106))	('N96Y', 'Var', (66, 70))
837716	32253638	Mutation at R468 in the predicted cytosolic domain of NHE6 was observed in four patients: R468Q in one head and neck squamous cell carcinoma patient, R468* in one rectal adenocarcinoma patient and one uterine endometrioid carcinoma patient, and R468L in one cutaneous melanoma patient.	('patients', 'Species', '9606', (80, 88))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (209, 231))	('patient', 'Species', '9606', (185, 192))	('R468Q', 'Var', (90, 95))	('NHE6', 'Gene', '10479', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('R468L', 'Var', (245, 250))	('neck squamous cell carcinoma', 'Disease', (112, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (112, 140))	('R468Q', 'Mutation', 'p.R468Q', (90, 95))	('endometrioid carcinoma', 'Disease', (209, 231))	('patient', 'Species', '9606', (141, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('R468*', 'Var', (150, 155))	('adenocarcinoma', 'Disease', (170, 184))	('patient', 'Species', '9606', (80, 87))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))	('melanoma', 'Disease', (268, 276))	('NHE6', 'Gene', (54, 58))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (258, 276))	('patient', 'Species', '9606', (277, 284))	('R468*', 'SUBSTITUTION', 'None', (150, 155))	('adenocarcinoma', 'Disease', 'MESH:D000230', (170, 184))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (209, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('R468L', 'Mutation', 'p.R468L', (245, 250))	('patient', 'Species', '9606', (232, 239))	('melanoma', 'Disease', 'MESH:D008545', (268, 276))
837717	32253638	Overall, of gene alterations in SLC9A9, 81% were missense mutations, 14% truncating mutations, and 4% fusion events while, in SLC9A6, 84% were missense mutations and 16% were truncations (Figure 4).	('SLC9A9', 'Gene', (32, 38))	('missense', 'Var', (49, 57))	('SLC9A6', 'Gene', (126, 132))	('SLC9A9', 'Gene', '285195', (32, 38))	('SLC9A6', 'Gene', '10479', (126, 132))	('rat', 'Species', '10116', (21, 24))	('alterations', 'Var', (17, 28))
837718	32253638	While the pathogenicity of missense mutations remains to be assessed, truncating mutations within the conserved, transmembrane NHE coding region are likely to be detrimental to protein function and stability.	('missense', 'Var', (27, 35))	('NHE', 'Gene', '285335', (127, 130))	('protein', 'Protein', (177, 184))	('stability', 'MPA', (198, 207))	('truncating mutations', 'Var', (70, 90))	('NHE', 'Gene', (127, 130))	('detrimental', 'NegReg', (162, 173))
837726	32253638	These findings suggest that the absence of NHE6 is related to tumor progression.	('NHE6', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('absence', 'Var', (32, 39))	('tumor', 'Disease', (62, 67))	('related', 'Reg', (51, 58))	('NHE6', 'Gene', '10479', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
837824	31676895	Multivariable adjusted odds ratio in the prolonged TTS group was for ypT0: 0.99 (95% CI 0.64-1.53), ypN0: 1.14 (95% CI 0.79-1.66), and ypT0N0: 0.96 (95% CI 0.61-1.52), compared to standard TTS (Table 3).	('TTS', 'Chemical', '-', (51, 54))	('ypT0', 'Var', (69, 73))	('ypT0N0', 'Var', (135, 141))	('ypN0', 'Var', (100, 104))	('TTS', 'Chemical', '-', (189, 192))
837837	31676895	There was significantly higher clinical T-stage in the prolonged TTS group, which was included in the multivariable adjusted analyses.	('clinical T-stage', 'CPA', (31, 47))	('TTS', 'Chemical', '-', (65, 68))	('prolonged TTS', 'Var', (55, 68))	('higher', 'PosReg', (24, 30))
837848	31676895	Pathologic tumor stage ypT0 and ypN1-N3 was associated with significantly decreased survival compared to all other patients.	('patients', 'Species', '9606', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('survival', 'MPA', (84, 92))	('ypN1-N3', 'Var', (32, 39))	('ypT0', 'Var', (23, 27))	('decreased', 'NegReg', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
837865	30297438	Not surprisingly, perturbation of TJ protein expression or function and/or disruption of TJ integrity is associated with a variety of diseases, including skin, intestinal and lung diseases, and cancers (Table 1).	('intestinal', 'Disease', (160, 170))	('lung diseases', 'Disease', 'MESH:D008171', (175, 188))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('function', 'MPA', (59, 67))	('lung diseases', 'Disease', (175, 188))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (194, 201))	('expression', 'MPA', (45, 55))	('disruption', 'NegReg', (75, 85))	('skin', 'Disease', (154, 158))	('perturbation', 'Var', (18, 30))	('lung diseases', 'Phenotype', 'HP:0002088', (175, 188))	('associated', 'Reg', (105, 115))
837894	30297438	Interestingly, TJ proteins CLDN1 and OCLN have been shown to be essential entry factors for the hepatitis C virus (HCV).	('HCV', 'Species', '11103', (115, 118))	('hepatitis', 'Phenotype', 'HP:0012115', (96, 105))	('CLDN1', 'Var', (27, 32))	('hepatitis C virus', 'Disease', (96, 113))
837900	30297438	For instance, knockout of CLDN7 in mice has severe intestinal defects including mucosal ulcerations, epithelial cell sloughing and inflammation, which leads to the death of the mice.	('epithelial cell sloughing', 'CPA', (101, 126))	('leads to', 'Reg', (151, 159))	('mucosal ulcerations', 'Disease', (80, 99))	('mucosal ulcerations', 'Disease', 'MESH:D014456', (80, 99))	('inflammation', 'Disease', 'MESH:D007249', (131, 143))	('inflammation', 'Disease', (131, 143))	('intestinal', 'Disease', (51, 61))	('death', 'Disease', 'MESH:D003643', (164, 169))	('death', 'Disease', (164, 169))	('mice', 'Species', '10090', (35, 39))	('CLDN7', 'Gene', (26, 31))	('mice', 'Species', '10090', (177, 181))	('knockout', 'Var', (14, 22))
837907	30297438	However, a double knockout of CLDN15 with CLDN2 chronically reduces the paracellular flow of Na+ from the intestinal submucosa into the lumen resulting in shunting of the nutrient absorption, malnourishment and death.	('CLDN15', 'Gene', '60363', (30, 36))	('CLDN2', 'Gene', (42, 47))	('death', 'Disease', (211, 216))	('CLDN15', 'Gene', (30, 36))	('malnourishment', 'Disease', (192, 206))	('reduces', 'NegReg', (60, 67))	('shunting of the nutrient absorption', 'MPA', (155, 190))	('double knockout', 'Var', (11, 26))	('death', 'Disease', 'MESH:D003643', (211, 216))
837913	30297438	Perturbed TJ protein expression or function alters downstream signaling that targets cellular pathways relevant for epithelial homeostasis, invasion, chronic inflammation and cancer (Zeb-1/E-cadherin, Wnt signaling, MMP9/Notch signaling and Src/PI3K/Akt signaling).	('cancer', 'Disease', (175, 181))	('downstream signaling', 'MPA', (51, 71))	('E-cadherin', 'Gene', (189, 199))	('E-cadherin', 'Gene', '999', (189, 199))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('inflammation', 'Disease', (158, 170))	('alters', 'Reg', (44, 50))	('Akt', 'Gene', (250, 253))	('Zeb-1', 'Gene', '6935', (183, 188))	('protein', 'Protein', (13, 20))	('Akt', 'Gene', '207', (250, 253))	('Src', 'Gene', (241, 244))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('MMP9', 'Gene', '4318', (216, 220))	('MMP9', 'Gene', (216, 220))	('Src', 'Gene', '6714', (241, 244))	('function', 'MPA', (35, 43))	('Perturbed', 'Var', (0, 9))	('Zeb-1', 'Gene', (183, 188))	('cellular pathways', 'Pathway', (85, 102))	('inflammation', 'Disease', 'MESH:D007249', (158, 170))
837914	30297438	Furthermore, disruption of TJs during infection or injury can result in increased permeability with translocation of bacteria and luminal antigen, which in turn increase IL-6/Stat3 signaling contributing to carcinogenesis (Figure 2).	('permeability', 'MPA', (82, 94))	('increased', 'PosReg', (72, 81))	('TJs', 'Gene', (27, 30))	('infection', 'Disease', (38, 47))	('carcinogenesis', 'Disease', (207, 221))	('IL-6', 'Gene', '3569', (170, 174))	('disruption', 'Var', (13, 23))	('infection', 'Disease', 'MESH:D007239', (38, 47))	('Stat3', 'Gene', (175, 180))	('translocation', 'MPA', (100, 113))	('increase', 'PosReg', (161, 169))	('luminal', 'Chemical', 'MESH:D010634', (130, 137))	('Stat3', 'Gene', '6774', (175, 180))	('carcinogenesis', 'Disease', 'MESH:D063646', (207, 221))	('increase IL-6', 'Phenotype', 'HP:0030783', (161, 174))	('IL-6', 'Gene', (170, 174))
837915	30297438	Delocalization of TJ proteins from their normal membrane-tethered expression appears to be common among inflammatory diseases and GI cancers.	('GI cancers', 'Disease', (130, 140))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('GI cancer', 'Phenotype', 'HP:0007378', (130, 139))	('common', 'Reg', (91, 97))	('Delocalization', 'Var', (0, 14))	('GI cancers', 'Disease', 'MESH:D009369', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('inflammatory diseases', 'Disease', (104, 125))
837917	30297438	Inhibition of MEK1 activity recruited all three proteins to the cell membrane leading to a restoration of the TJ barrier function in these cells.	('proteins', 'Protein', (48, 56))	('restoration', 'MPA', (91, 102))	('MEK1', 'Gene', '5604', (14, 18))	('recruited', 'PosReg', (28, 37))	('Inhibition', 'Var', (0, 10))	('MEK1', 'Gene', (14, 18))	('rat', 'Species', '10116', (96, 99))	('TJ barrier function', 'MPA', (110, 129))
837925	30297438	Indeed, it has been shown that DNA hypermethylation associated with the downregulation of CLDN11 in gastric cancer cells and CLDN7 in colon cancer cells.	('hypermethylation', 'Var', (35, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('CLDN11', 'Gene', '5010', (90, 96))	('CLDN7', 'Gene', (125, 130))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('colon cancer', 'Phenotype', 'HP:0003003', (134, 146))	('colon cancer', 'Disease', 'MESH:D015179', (134, 146))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('downregulation', 'NegReg', (72, 86))	('colon cancer', 'Disease', (134, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('gastric cancer', 'Disease', (100, 114))	('CLDN11', 'Gene', (90, 96))
837926	30297438	Furthermore, loss of repressive histone methylations, including H3K27me3 and H4K20me3, is associated with the overexpression of CLDN4 in gastric cancer.	('CLDN4', 'Gene', (128, 133))	('histone', 'Protein', (32, 39))	('H3K27me3', 'Var', (64, 72))	('H4K20me3', 'Var', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastric cancer', 'Disease', (137, 151))	('repressive', 'MPA', (21, 31))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('loss', 'NegReg', (13, 17))	('CLDN4', 'Gene', '1364', (128, 133))	('overexpression', 'PosReg', (110, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
837930	30297438	Perturbation of the epithelial barrier function as well as TJ protein function and expression are hallmarks of GI disease including CRC.	('CRC', 'Disease', (132, 135))	('hallmarks of GI disease', 'Disease', 'MESH:D005767', (98, 121))	('hallmarks of GI disease', 'Disease', (98, 121))	('TJ protein', 'Protein', (59, 69))	('function', 'MPA', (70, 78))	('R', 'Chemical', 'MESH:D001120', (133, 134))	('expression', 'MPA', (83, 93))	('GI disease', 'Phenotype', 'HP:0011024', (111, 121))	('Perturbation', 'Var', (0, 12))
837934	30297438	Upregulation or aberrant tissue expression of CLDNs may contribute to neoplasia by altering TJ structure and function or affecting cell signaling pathways.	('aberrant', 'Var', (16, 24))	('neoplasia', 'Disease', (70, 79))	('Upregulation', 'PosReg', (0, 12))	('altering', 'Reg', (83, 91))	('cell signaling pathways', 'Pathway', (131, 154))	('neoplasia', 'Disease', 'MESH:D009369', (70, 79))	('CLDNs', 'Gene', (46, 51))	('neoplasia', 'Phenotype', 'HP:0002664', (70, 79))	('TJ structure', 'CPA', (92, 104))	('affecting', 'Reg', (121, 130))	('function', 'MPA', (109, 117))	('contribute', 'Reg', (56, 66))	('CLDNs', 'Gene', 'None', (46, 51))
837937	30297438	Silencing of the expression and/or function of these proteins modulates CLDN expression and induces loss of polarity and EMT.	('expression', 'MPA', (77, 87))	('EMT', 'CPA', (121, 124))	('modulates', 'Reg', (62, 71))	('CLDN', 'Gene', (72, 76))	('CLDN', 'Gene', 'None', (72, 76))	('function', 'MPA', (35, 43))	('polarity', 'MPA', (108, 116))	('Silencing', 'Var', (0, 9))	('loss', 'NegReg', (100, 104))
837938	30297438	Interestingly, genetic modulation of CLDN proteins in mice or cancer cells can similarly affect these signaling cascades, suggesting a feedback regulation.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mice', 'Species', '10090', (54, 58))	('genetic modulation', 'Var', (15, 33))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('CLDN', 'Gene', (37, 41))	('affect', 'Reg', (89, 95))	('CLDN', 'Gene', 'None', (37, 41))
837948	30297438	Here it is worth noting that the outcome from a series of studies have now provided ample evidence for a role of deregulated CLDN1 expression in promoting invasive and metastatic abilities of the colon cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('deregulated', 'Var', (113, 124))	('promoting', 'PosReg', (145, 154))	('colon cancer', 'Phenotype', 'HP:0003003', (196, 208))	('colon cancer', 'Disease', 'MESH:D015179', (196, 208))	('expression', 'MPA', (131, 141))	('CLDN1', 'Gene', (125, 130))	('colon cancer', 'Disease', (196, 208))
837949	30297438	Notably, CLDN1 expression was sufficient to induce metastatic abilities in a colon cancer cell line that normally does not metastasize well in vivo.	('induce', 'PosReg', (44, 50))	('expression', 'Var', (15, 25))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colon cancer', 'Disease', (77, 89))	('CLDN1', 'Gene', (9, 14))	('metastatic abilities', 'CPA', (51, 71))
837950	30297438	In contrast, stable genetic inhibition of CLDN1 in a poorly differentiated, highly metastatic and CLDN1 high colon cancer cell significantly inhibited its metastatic abilities in a splenic model of CRC metastasis.	('colon cancer', 'Phenotype', 'HP:0003003', (109, 121))	('CLDN1', 'Gene', (98, 103))	('genetic inhibition', 'Var', (20, 38))	('high colon cancer', 'Disease', 'MESH:D015179', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('high colon cancer', 'Disease', (104, 121))	('CLDN1', 'Gene', (42, 47))	('R', 'Chemical', 'MESH:D001120', (199, 200))	('inhibited', 'NegReg', (141, 150))
837975	30297438	Several lines of evidence indicate that disruption or loss-of-function of TJs contributes to the pathogenesis of cholestatic diseases including primary biliary cholangitis and primary sclerosing cholangitis.	('biliary cholangitis', 'Disease', (152, 171))	('sclerosing cholangitis', 'Disease', (184, 206))	('cholestatic diseases', 'Disease', (113, 133))	('cholestatic diseases', 'Disease', 'MESH:D002779', (113, 133))	('disruption', 'Var', (40, 50))	('cholangitis', 'Phenotype', 'HP:0030151', (195, 206))	('cholangitis', 'Phenotype', 'HP:0030151', (160, 171))	('primary biliary cholangitis', 'Phenotype', 'HP:0002613', (144, 171))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (184, 206))	('sclerosing cholangitis', 'Disease', 'MESH:D015209', (184, 206))	('biliary cholangitis', 'Disease', 'MESH:D008105', (152, 171))	('TJs', 'Gene', (74, 77))	('loss-of-function', 'NegReg', (54, 70))
837976	30297438	Interestingly, mutations in CLDN1 are associated with neonatal ichthyosis and sclerosing cholangitis (NISCH) syndrome where deficient CLDN1 expression may contribute to paracellular bile leakage through deficient TJs.	('CLDN1', 'Gene', (134, 139))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (78, 100))	('associated', 'Reg', (38, 48))	('cholangitis', 'Phenotype', 'HP:0030151', (89, 100))	('mutations', 'Var', (15, 24))	('ichthyosis', 'Phenotype', 'HP:0008064', (63, 73))	('neonatal ichthyosis and sclerosing cholangitis (NISCH) syndrome', 'Disease', 'MESH:C564365', (54, 117))	('deficient', 'NegReg', (203, 212))	('CLDN1', 'Gene', (28, 33))	('paracellular bile leakage', 'MPA', (169, 194))	('contribute', 'Reg', (155, 165))	('deficient', 'Var', (124, 133))
837977	30297438	Mutations in ZO-2 have been described in familiar hypercholanemia.	('ZO-2', 'Gene', '9414', (13, 17))	('ZO-2', 'Gene', (13, 17))	('hypercholanemia', 'Disease', (50, 65))	('Mutations', 'Var', (0, 9))	('described', 'Reg', (28, 37))	('hypercholanemia', 'Disease', 'MESH:C564336', (50, 65))
837981	30297438	Of note, TJ alteration in epithelia outside the liver can also contribute to liver disease.	('liver disease', 'Disease', 'MESH:D008107', (77, 90))	('TJ alteration', 'Var', (9, 22))	('rat', 'Species', '10116', (16, 19))	('liver disease', 'Phenotype', 'HP:0001392', (77, 90))	('contribute', 'Reg', (63, 73))	('liver disease', 'Disease', (77, 90))
837982	30297438	Indeed, dysfunction of the intestinal epithelial barrier - due to or unrelated to (aetiological factor(s) of) the underlying liver disease - has been associated with the pathogenesis of chronic liver disease and the development of complications in cirrhosis by favouring translocation of bacteria and bacterial products from the intestinal lumen into the systemic circulation.	('associated', 'Reg', (150, 160))	('translocation of', 'MPA', (271, 287))	('cirrhosis', 'Disease', (248, 257))	('liver disease', 'Phenotype', 'HP:0001392', (125, 138))	('liver disease', 'Disease', (125, 138))	('chronic liver disease', 'Disease', (186, 207))	('liver disease', 'Phenotype', 'HP:0001392', (194, 207))	('chronic liver disease', 'Disease', 'MESH:D058625', (186, 207))	('dysfunction', 'Var', (8, 19))	('favouring', 'PosReg', (261, 270))	('cirrhosis', 'Disease', 'MESH:D005355', (248, 257))	('liver disease', 'Disease', 'MESH:D008107', (125, 138))	('cirrhosis', 'Phenotype', 'HP:0001394', (248, 257))	('liver disease', 'Disease', 'MESH:D008107', (194, 207))
837992	30297438	Interestingly, no cellular function for CD81-CLDN1 interaction has been reported so far and disruption of these complexes by defined anti-CLDN1 antibodies prevents HCV infection without affecting TJ integrity or any detectable adverse effect.	('CD81', 'Gene', (40, 44))	('anti-CLDN1', 'Gene', (133, 143))	('CD81', 'Gene', '975', (40, 44))	('antibodies', 'Var', (144, 154))	('disruption', 'Reg', (92, 102))	('prevents', 'NegReg', (155, 163))	('HCV infection', 'Disease', (164, 177))	('HCV infection', 'Disease', 'MESH:D006526', (164, 177))
837993	30297438	Indeed, several lines of evidence support a model in which the non-junctional form of CLDN1 rather than CLDN1 localized within TJ mediates HCV entry.	('non-junctional', 'Var', (63, 77))	('HCV entry', 'MPA', (139, 148))	('rat', 'Species', '10116', (92, 95))	('HCV', 'Species', '11103', (139, 142))	('CLDN1', 'Gene', (86, 91))	('mediates', 'Reg', (130, 138))
837999	30297438	It is of interest to note that in experimental model systems using a liver tumor cell lines some HCV genotypes have been reported to be able to use either CLDN1 or CLDN6 through mutation in the HCV E1 envelope protein.	('liver tumor', 'Disease', 'MESH:D008113', (69, 80))	('liver tumor', 'Phenotype', 'HP:0002896', (69, 80))	('liver tumor', 'Disease', (69, 80))	('mutation', 'Var', (178, 186))	('HCV', 'Species', '11103', (97, 100))	('HCV', 'Species', '11103', (194, 197))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))
838004	30297438	Indeed, imaging studies evidenced a co-localization between OCLN and HCV E2 in the endoplasmic reticulum of hepatoma cells.	('HCV', 'Species', '11103', (69, 72))	('hepatoma', 'Disease', 'MESH:D006528', (108, 116))	('E2', 'Chemical', 'MESH:D004958', (73, 75))	('HCV E2', 'Gene', (69, 75))	('OCLN', 'Var', (60, 64))	('co-localization', 'Reg', (36, 51))	('hepatoma', 'Disease', (108, 116))
838013	30297438	The importance of the subcellular localization of OCLN for HCV entry is also underscored by the fact that only OCLN and its splice variant OCLN-ex7ext that both localize to the plasma membrane are able to promote HCV entry in contrast to other OCLN splice variants that exhibit an intracellular localization.	('HCV', 'Species', '11103', (59, 62))	('promote', 'PosReg', (205, 212))	('OCLN', 'Var', (111, 115))	('HCV', 'Species', '11103', (213, 216))	('HCV entry', 'MPA', (213, 222))
838024	30297438	From these studies, it appears that expression of CLDNs is associated with more severe disease and/or bad prognosis in HCC patients (Table 2): epigenetic silencing of CLDN14 was significantly associated with advanced tumor state and tumor aggressiveness; CLDN11 downregulation by miR-99 has been associated with metastasis of HCC; and CLDN3 downregulation has been suggested to promote EMT via Wnt- -catenin signaling.	('epigenetic silencing', 'Var', (143, 163))	('associated', 'Reg', (192, 202))	('HCC', 'Gene', '619501', (326, 329))	('CLDNs', 'Gene', 'None', (50, 55))	('HCC', 'Gene', '619501', (119, 122))	('tumor aggressiveness', 'Disease', (233, 253))	('miR', 'Gene', '220972', (280, 283))	('HCC', 'Gene', (119, 122))	('HCC', 'Gene', (326, 329))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', (233, 238))	('EMT', 'CPA', (386, 389))	('Wnt- -catenin signaling', 'CPA', (394, 417))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('CLDN11', 'Gene', (255, 261))	('miR', 'Gene', (280, 283))	('CLDN11', 'Gene', '5010', (255, 261))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (233, 253))	('aggressiveness', 'Phenotype', 'HP:0000718', (239, 253))	('CLDN14', 'Gene', (167, 173))	('CLDN3', 'Gene', '1365', (335, 340))	('CLDNs', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('CLDN14', 'Gene', '23562', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('CLDN3', 'Gene', (335, 340))	('promote', 'PosReg', (378, 385))	('downregulation', 'NegReg', (262, 276))	('metastasis', 'CPA', (312, 322))	('downregulation', 'NegReg', (341, 355))
838049	30297438	In addition, recent studies have investigated the anti-tumor effect of anti-CLDN1 and anti-CLDN2 mAbs using cancer cell models (Table 3).	('anti-CLDN1', 'Var', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('anti-CLDN2', 'Var', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
838062	30297438	Administration of CLDN1-specific antibodies has been shown to be very safe in various animal and human-cell based models without any adverse effects on the liver or other organs such as the gut or skin.	('human', 'Species', '9606', (97, 102))	('rat', 'Species', '10116', (8, 11))	('antibodies', 'Var', (33, 43))	('CLDN1-specific', 'Gene', (18, 32))
838117	29290793	Epigenomic characterization of a p53-regulated 3p22.2 tumor suppressor that inhibits STAT3 phosphorylation via protein docking and is frequently methylated in esophageal and other carcinomas Rationale: Oncogenic STAT3 signaling activation and 3p22-21.3 locus alteration are common in multiple tumors, especially carcinomas of the nasopharynx, esophagus and lung.	('alteration', 'Var', (259, 269))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('carcinomas', 'Disease', (180, 190))	('p53', 'Gene', '7157', (33, 36))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('multiple tumors', 'Disease', 'MESH:D009369', (284, 299))	('esophagus', 'Disease', (343, 352))	('STAT3', 'Gene', (212, 217))	('carcinomas', 'Disease', 'MESH:D002277', (312, 322))	('carcinomas', 'Phenotype', 'HP:0030731', (312, 322))	('lung', 'Disease', (357, 361))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('protein', 'Protein', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('p53', 'Gene', (33, 36))	('STAT3', 'Gene', '6774', (212, 217))	('STAT3', 'Gene', (85, 90))	('carcinomas', 'Disease', 'MESH:D002277', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('inhibits', 'NegReg', (76, 84))	('STAT3', 'Gene', '6774', (85, 90))	('multiple tumors', 'Disease', (284, 299))	('carcinomas', 'Disease', (312, 322))	('carcinomas of the nasopharynx', 'Phenotype', 'HP:0100630', (312, 341))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('tumor', 'Disease', (293, 298))	('tumor', 'Disease', (54, 59))
838123	29290793	DLEC1 methylation was frequently detected in ESCC tumors and correlated with lymph node metastasis, tumor recurrence and progression, with DLEC1 as the most frequently methylated among the established 3p22.2 tumor suppressors (RASSF1A, PLCD1 and ZMYND10/BLU).	('tumor', 'Disease', (100, 105))	('DLEC1', 'Gene', '9940', (139, 144))	('PLCD1', 'Gene', '5333', (236, 241))	('RASSF1A', 'Gene', '11186', (227, 234))	('ZMYND10', 'Gene', '51364', (246, 253))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('PLCD1', 'Gene', (236, 241))	('RASSF1A', 'Gene', (227, 234))	('ESCC tumors', 'Disease', 'MESH:D004938', (45, 56))	('methylation', 'Var', (6, 17))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', (50, 55))	('DLEC1', 'Gene', '9940', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('DLEC1', 'Gene', (139, 144))	('lymph node metastasis', 'CPA', (77, 98))	('detected', 'Reg', (33, 41))	('BLU', 'Gene', (254, 257))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('ESCC tumors', 'Disease', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('correlated', 'Reg', (61, 71))	('ZMYND10', 'Gene', (246, 253))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('BLU', 'Gene', '51364', (254, 257))	('DLEC1', 'Gene', (0, 5))
838129	29290793	The YXXQ motifs of DLEC1 are crucial for its inhibition of STAT3 phosphorylation, and disruption of these motifs restores STAT3 phosphorylation through abolishing DLEC1 binding to STAT3.	('STAT3', 'Gene', (180, 185))	('disruption', 'Var', (86, 96))	('restores', 'PosReg', (113, 121))	('STAT3', 'Gene', '6774', (122, 127))	('binding', 'Interaction', (169, 176))	('STAT3', 'Gene', '6774', (59, 64))	('DLEC1', 'Gene', (163, 168))	('STAT3', 'Gene', (59, 64))	('DLEC1', 'Gene', (19, 24))	('DLEC1', 'Gene', '9940', (163, 168))	('STAT3', 'Gene', (122, 127))	('DLEC1', 'Gene', '9940', (19, 24))	('abolishing', 'NegReg', (152, 162))	('STAT3', 'Gene', '6774', (180, 185))
838130	29290793	Conclusions: Our study demonstrates, for the first time, predominant epigenetic silencing of DLEC1 in ESCC, and a novel mechanistic link of epigenetic DLEC1 disruption with oncogenic STAT3 signaling in multiple carcinomas.	('multiple carcinomas', 'Disease', (202, 221))	('STAT3', 'Gene', '6774', (183, 188))	('DLEC1', 'Gene', (93, 98))	('epigenetic silencing', 'Var', (69, 89))	('ESCC', 'Disease', (102, 106))	('STAT3', 'Gene', (183, 188))	('DLEC1', 'Gene', (151, 156))	('DLEC1', 'Gene', '9940', (151, 156))	('DLEC1', 'Gene', '9940', (93, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('disruption', 'Var', (157, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('epigenetic', 'Var', (140, 150))	('multiple carcinomas', 'Disease', 'MESH:C537656', (202, 221))
838131	29290793	Chromosomal locus 3p22-21.3 frequently has abnormalities like loss of heterozygosity (LOH) in multiple cancers, including esophageal squamous cell (ESCC), lung and nasopharyngeal (NPC) carcinomas.	('esophageal squamous', 'Disease', 'MESH:D000077277', (122, 141))	('esophageal squamous', 'Disease', (122, 141))	('multiple cancers', 'Disease', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('loss of heterozygosity', 'Var', (62, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('multiple cancers', 'Disease', 'MESH:D009369', (94, 110))	('lung and nasopharyngeal (NPC) carcinomas', 'Disease', 'MESH:D052556', (155, 195))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))
838132	29290793	Thus, as a typical tumor suppressor gene (TSG) locus, allele loss at 3p21.3 has been shown to be the early premalignant change detected in lung and breast cancers.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('breast cancers', 'Disease', 'MESH:D001943', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('TSG', 'Gene', '57045', (42, 45))	('3p21.3', 'Gene', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('breast cancers', 'Phenotype', 'HP:0003002', (148, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('lung', 'Disease', (139, 143))	('tumor', 'Disease', (19, 24))	('allele loss', 'Var', (54, 65))	('breast cancers', 'Disease', (148, 162))	('TSG', 'Gene', (42, 45))
838137	29290793	DLEC1 methylation/downregulation has been shown to be significantly related to disease progression and poor prognosis of some cancers including lung, ovarian and breast; thus, it is a potential biomarker for tumor diagnosis.	('lung', 'Disease', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('related', 'Reg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('breast', 'Disease', (162, 168))	('DLEC1', 'Gene', '9940', (0, 5))	('cancers', 'Disease', (126, 133))	('tumor', 'Disease', (208, 213))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('ovarian', 'Disease', (150, 157))	('ovarian', 'Disease', 'MESH:D010051', (150, 157))	('methylation/downregulation', 'NegReg', (6, 32))	('DLEC1', 'Gene', (0, 5))	('methylation/downregulation', 'Var', (6, 32))
838155	29290793	S1A), with homozygous deletion of DLEC1 in one cell line (EC1) (Fig.	('EC1', 'Gene', (58, 61))	('DLEC1', 'Gene', (34, 39))	('EC1', 'Gene', '4819', (58, 61))	('DLEC1', 'Gene', '9940', (34, 39))	('deletion', 'Var', (22, 30))	('EC1', 'Gene', (36, 39))	('EC1', 'Gene', '4819', (36, 39))
838158	29290793	These results suggest that DLEC1 is disrupted through both epigenetic and, less frequently, genetic (LOH/deletion) mechanisms in ESCC and other carcinomas.	('carcinomas', 'Disease', (144, 154))	('carcinomas', 'Disease', 'MESH:D002277', (144, 154))	('ESCC', 'Disease', (129, 133))	('DLEC1', 'Gene', (27, 32))	('DLEC1', 'Gene', '9940', (27, 32))	('disrupted', 'NegReg', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('epigenetic', 'Var', (59, 69))
838173	29290793	After the treatment, DLEC1 expression was increased in cell lines of ESCC, lung and NPC with silenced DLEC1, and even more dramatically increased with Aza+TSA treatment, accompanied by increased unmethylated alleles and decreased methylated alleles as detected by both MSP and BGS (Fig.	('increased', 'PosReg', (42, 51))	('decreased', 'NegReg', (220, 229))	('DLEC1', 'Gene', (21, 26))	('DLEC1', 'Gene', '9940', (21, 26))	('NPC', 'Gene', (84, 87))	('TSA', 'Chemical', 'MESH:C012589', (155, 158))	('silenced', 'Var', (93, 101))	('expression', 'MPA', (27, 37))	('NPC', 'Gene', '4864', (84, 87))	('Aza+TSA', 'Var', (151, 158))	('methylated', 'MPA', (230, 240))	('DLEC1', 'Gene', '9940', (102, 107))	('increased', 'PosReg', (136, 145))	('unmethylated', 'MPA', (195, 207))	('DLEC1', 'Gene', (102, 107))	('increased', 'PosReg', (185, 194))	('Aza', 'Chemical', 'MESH:D000077209', (151, 154))
838182	29290793	In another cohort, DLEC1 methylation was detected in 48% (40/83) of ESCC primary tissues (Fig.	('ESCC', 'Disease', (68, 72))	('methylation', 'Var', (25, 36))	('DLEC1', 'Gene', (19, 24))	('DLEC1', 'Gene', '9940', (19, 24))	('detected', 'Reg', (41, 49))
838183	29290793	Overall, DLEC1 is methylated in 54% (67/124) of primary ESCC tumors, which correlates with its downregulation.	('methylated', 'Var', (18, 28))	('DLEC1', 'Gene', (9, 14))	('DLEC1', 'Gene', '9940', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('ESCC tumors', 'Disease', (56, 67))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('ESCC tumors', 'Disease', 'MESH:D004938', (56, 67))
838185	29290793	There was a significant correlation between DLEC1 methylation with ESCC tumor size and lymph node metastasis, but not with age, gender, stage, grade, or differentiation in our cohort (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ESCC tumor', 'Disease', 'MESH:D004938', (67, 77))	('DLEC1', 'Gene', '9940', (44, 49))	('ESCC tumor', 'Disease', (67, 77))	('lymph node metastasis', 'CPA', (87, 108))	('DLEC1', 'Gene', (44, 49))	('methylation', 'Var', (50, 61))
838186	29290793	Further analysis of TCGA datasets showed that esophageal and lung cancer patients with low methylation or high expression of DLEC1 had longer survival (Fig.	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('methylation', 'Var', (91, 102))	('DLEC1', 'Gene', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (73, 81))	('high expression', 'Var', (106, 121))	('DLEC1', 'Gene', '9940', (125, 130))	('survival', 'CPA', (142, 150))	('low', 'NegReg', (87, 90))	('esophageal and lung cancer', 'Disease', 'MESH:D004938', (46, 72))	('longer', 'PosReg', (135, 141))
838187	29290793	DLEC1 methylation/expression was also significantly associated with disease progression and age of esophageal and lung cancer patients (Table S1, Table S2).	('esophageal and lung cancer', 'Disease', 'MESH:D004938', (99, 125))	('methylation/expression', 'Var', (6, 28))	('associated', 'Reg', (52, 62))	('methylation/expression', 'MPA', (6, 28))	('disease', 'Disease', (68, 75))	('patients', 'Species', '9606', (126, 134))	('DLEC1', 'Gene', '9940', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('DLEC1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
838190	29290793	DLEC1 methylation was also detected in 74% (37/50) of NPC tumors but no (0/3) normal nasopharyngeal tissues, as well as in 57% (35/61) of lung carcinomas (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('NPC tumors', 'Disease', 'MESH:D052556', (54, 64))	('detected', 'Reg', (27, 35))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('lung carcinomas', 'Disease', (138, 153))	('NPC tumors', 'Disease', (54, 64))	('methylation', 'Var', (6, 17))	('DLEC1', 'Gene', '9940', (0, 5))	('lung carcinomas', 'Disease', 'MESH:D008175', (138, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('DLEC1', 'Gene', (0, 5))
838192	29290793	These results indicate the importance of tumor-specific DLEC1 methylation in the pathogenesis of ESCC and other carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('DLEC1', 'Gene', (56, 61))	('DLEC1', 'Gene', '9940', (56, 61))	('methylation', 'Var', (62, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('carcinomas', 'Disease', (112, 122))	('carcinomas', 'Disease', 'MESH:D002277', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('ESCC', 'Disease', (97, 101))
838195	29290793	In splice variant T1 (NCBI accession number: AY789462), exon 8 was spliced out resulting in in-frame deletion with the exception of L479 V421 (ttg gtg).	('variant T1', 'CellLine', 'CVCL:7204', (10, 20))	('deletion', 'Var', (101, 109))	('L479 V421', 'Var', (132, 141))
838199	29290793	Amplifying larger fragments using primers on exon 5 and 13 detected another transcript variant DLEC1T3 (NCBI accession number: AY789464), lacking exons 8, 9, 11 and frame 1 of exon 13, with its translation stopped at exon 10 with premature truncation (Fig.	('premature truncation', 'MPA', (230, 250))	('variant DLEC1T3', 'CellLine', 'CVCL:6F79', (87, 102))	('lacking', 'NegReg', (138, 145))	('DLEC1T3', 'Gene', (95, 102))	('variant', 'Var', (87, 94))
838206	29290793	Monolayer colony formation assay showed significant reduction (down to ~10-40%) in colony numbers and sizes in ESCC, lung and NPC carcinoma cells with ectopically expressed DLEC1 (Fig.	('ectopically expressed', 'Var', (151, 172))	('NPC carcinoma', 'Disease', (126, 139))	('DLEC1', 'Gene', (173, 178))	('colony numbers', 'CPA', (83, 97))	('DLEC1', 'Gene', '9940', (173, 178))	('NPC carcinoma', 'Disease', 'MESH:D052556', (126, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('reduction', 'NegReg', (52, 61))
838215	29290793	Ectopic expression of DLEC1 dramatically suppressed the migration and invasion of ESCC, lung and NPC carcinoma cells in transwell assays (Fig.	('migration', 'CPA', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('ESCC', 'Disease', (82, 86))	('suppressed', 'NegReg', (41, 51))	('Ectopic expression', 'Var', (0, 18))	('DLEC1', 'Gene', (22, 27))	('DLEC1', 'Gene', '9940', (22, 27))	('NPC carcinoma', 'Disease', (97, 110))	('lung', 'Disease', (88, 92))	('invasion', 'CPA', (70, 78))	('NPC carcinoma', 'Disease', 'MESH:D052556', (97, 110))
838218	29290793	Moreover, expression of DLEC1 disassembled the formation of actin stress fibers in carcinoma cells (Fig.	('DLEC1', 'Gene', (24, 29))	('DLEC1', 'Gene', '9940', (24, 29))	('carcinoma', 'Disease', (83, 92))	('carcinoma', 'Disease', 'MESH:D002277', (83, 92))	('formation of actin stress fibers', 'MPA', (47, 79))	('expression', 'Var', (10, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
838223	29290793	Stem cell markers (STAT3, CD44, ABCG2, TWIST and KLF4) were downregulated in ESCC and lung carcinoma cells after DLEC1 expression, with the effect more potent in lung carcinoma cells (Fig.	('DLEC1', 'Gene', (113, 118))	('TWIST', 'Gene', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('lung carcinoma', 'Disease', (162, 176))	('TWIST', 'Gene', '7291', (39, 44))	('CD44', 'Gene', '960', (26, 30))	('KLF4', 'Gene', '9314', (49, 53))	('CD44', 'Gene', (26, 30))	('Stem cell markers', 'CPA', (0, 17))	('lung carcinoma', 'Disease', 'MESH:D008175', (86, 100))	('DLEC1', 'Gene', '9940', (113, 118))	('STAT3', 'Gene', (19, 24))	('ABCG2', 'Gene', (32, 37))	('ABCG2', 'Gene', '9429', (32, 37))	('lung carcinoma', 'Disease', 'MESH:D008175', (162, 176))	('downregulated', 'NegReg', (60, 73))	('STAT3', 'Gene', '6774', (19, 24))	('KLF4', 'Gene', (49, 53))	('expression', 'Var', (119, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('lung carcinoma', 'Disease', (86, 100))
838230	29290793	Western blot confirmed significantly decreased levels of p-ERK (Thr202/Tyr204), p-AKT (Ser473), p-STAT3 (Tyr705 and Ser727) and active-beta-catenin in DLEC1-expressing carcinoma cells (Fig.	('AKT', 'Gene', '207', (82, 85))	('levels', 'MPA', (47, 53))	('Ser727', 'Var', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('ERK', 'Gene', (59, 62))	('carcinoma', 'Disease', (168, 177))	('beta-catenin', 'Gene', (135, 147))	('DLEC1', 'Gene', (151, 156))	('beta-catenin', 'Gene', '1499', (135, 147))	('Tyr705', 'Var', (105, 111))	('ERK', 'Gene', '2048', (59, 62))	('STAT3', 'Gene', (98, 103))	('Tyr705', 'Chemical', '-', (105, 111))	('carcinoma', 'Disease', 'MESH:D002277', (168, 177))	('decreased', 'NegReg', (37, 46))	('Ser727', 'Chemical', '-', (116, 122))	('AKT', 'Gene', (82, 85))	('Ser473', 'Var', (87, 93))	('Ser473', 'Chemical', '-', (87, 93))	('STAT3', 'Gene', '6774', (98, 103))	('DLEC1', 'Gene', '9940', (151, 156))	('Tyr204', 'Chemical', '-', (71, 77))	('Thr202', 'Chemical', '-', (64, 70))
838234	29290793	Exogenously expressed DLEC1 greatly suppressed the p-STAT3 levels at both Tyr705 and Ser727 sites in STAT3C-transfected carcinoma cells, with no changes in STAT3 total protein levels (Fig.	('carcinoma', 'Disease', (120, 129))	('STAT3', 'Gene', '6774', (101, 106))	('suppressed', 'NegReg', (36, 46))	('Ser727', 'Chemical', '-', (85, 91))	('STAT3', 'Gene', '6774', (53, 58))	('STAT3', 'Gene', (101, 106))	('STAT3', 'Gene', '6774', (156, 161))	('STAT3', 'Gene', (53, 58))	('carcinoma', 'Disease', 'MESH:D002277', (120, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('STAT3', 'Gene', (156, 161))	('Tyr705', 'Var', (74, 80))	('DLEC1', 'Gene', (22, 27))	('DLEC1', 'Gene', '9940', (22, 27))	('Ser727', 'Var', (85, 91))	('Tyr705', 'Chemical', '-', (74, 80))
838247	29290793	Results showed a strong interaction between endogenous DLEC1 and STAT3/p-STAT3 (Tyr705) in HEK293T cells by immunoprecipitation, accompanied by relatively weaker co-precipitation of JAK2.	('Tyr705', 'Var', (80, 86))	('interaction', 'Interaction', (24, 35))	('HEK293T', 'CellLine', 'CVCL:0063', (91, 98))	('Tyr705', 'Chemical', '-', (80, 86))	('JAK2', 'Gene', '3717', (182, 186))	('co-precipitation', 'MPA', (162, 178))	('DLEC1', 'Gene', (55, 60))	('STAT3', 'Gene', (73, 78))	('DLEC1', 'Gene', '9940', (55, 60))	('STAT3', 'Gene', '6774', (65, 70))	('weaker', 'NegReg', (155, 161))	('STAT3', 'Gene', (65, 70))	('JAK2', 'Gene', (182, 186))	('STAT3', 'Gene', '6774', (73, 78))
838249	29290793	Similarly, exogenous DLEC1 could be co-IP with both STAT3/p-STAT3 (Tyr705) and JAK2 (Fig.	('STAT3', 'Gene', (52, 57))	('DLEC1', 'Gene', (21, 26))	('STAT3', 'Gene', '6774', (52, 57))	('DLEC1', 'Gene', '9940', (21, 26))	('JAK2', 'Gene', '3717', (79, 83))	('STAT3', 'Gene', '6774', (60, 65))	('Tyr705', 'Var', (67, 73))	('Tyr705', 'Chemical', '-', (67, 73))	('STAT3', 'Gene', (60, 65))	('JAK2', 'Gene', (79, 83))
838258	29290793	8B), confirming the regulation of STAT3 phosphorylation/signaling by YXXQ motifs of DLEC1.	('STAT3', 'Gene', (34, 39))	('YXXQ motifs', 'Var', (69, 80))	('DLEC1', 'Gene', '9940', (84, 89))	('STAT3', 'Gene', '6774', (34, 39))	('DLEC1', 'Gene', (84, 89))
838267	29290793	Nowadays, epigenetic identification of tumor-specific promoter CpG methylation becomes a new efficient way for TSG discovery.	('epigenetic', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('TSG', 'Gene', (111, 114))	('TSG', 'Gene', '57045', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('methylation', 'Var', (67, 78))
838268	29290793	Our group has previously identified DLEC1 methylation and silencing in gastric, colon, hepatocellular, renal and prostate cancers, as well as non-Hodgkin and Hodgkin lymphomas.	('prostate cancers', 'Phenotype', 'HP:0012125', (113, 129))	('non-Hodgkin and Hodgkin lymphomas', 'Disease', 'MESH:D008228', (142, 175))	('renal and prostate cancers', 'Disease', 'MESH:D007680', (103, 129))	('silencing', 'MPA', (58, 67))	('hepatocellular', 'Disease', (87, 101))	('DLEC1', 'Gene', '9940', (36, 41))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (158, 174))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('lymphomas', 'Phenotype', 'HP:0002665', (166, 175))	('Hodgkin lymphomas', 'Phenotype', 'HP:0012189', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('gastric', 'Disease', (71, 78))	('methylation', 'Var', (42, 53))	('colon', 'Disease', (80, 85))	('lymphoma', 'Phenotype', 'HP:0002665', (166, 174))	('DLEC1', 'Gene', (36, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
838269	29290793	DLEC1 methylation has also been frequently detected in other carcinomas including nasopharyngeal, lung, breast and ovarian.	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('breast and ovarian', 'Disease', 'MESH:D010051', (104, 122))	('methylation', 'Var', (6, 17))	('nasopharyngeal', 'Disease', (82, 96))	('detected', 'Reg', (43, 51))	('carcinomas', 'Disease', 'MESH:D002277', (61, 71))	('DLEC1', 'Gene', '9940', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('carcinomas', 'Disease', (61, 71))	('DLEC1', 'Gene', (0, 5))	('lung', 'Disease', (98, 102))
838280	29290793	The YXXQ motif is crucial for STAT3 activation in response to multiple signaling receptors through phosphorylation at its Tyr 705 and Ser727 sites.	('Tyr', 'Chemical', 'MESH:D014443', (122, 125))	('Ser727', 'Chemical', '-', (134, 140))	('phosphorylation', 'MPA', (99, 114))	('STAT3', 'Gene', '6774', (30, 35))	('STAT3', 'Gene', (30, 35))	('Tyr 705', 'Var', (122, 129))	('Ser727', 'Var', (134, 140))
838281	29290793	For example, acylglycerol kinase potentiates JAK2/STAT3 signaling in ESCC; Epstein-Barr virus (EBV)-encoded proteins constitutively activated STAT3 in NPC; and, EGFR mutation mediates STAT3 activation via IL-6 production in lung cancer.	('IL-6', 'Gene', (205, 209))	('STAT3', 'Gene', '6774', (184, 189))	('STAT3', 'Gene', (142, 147))	('acylglycerol kinase', 'Gene', (13, 32))	('STAT3', 'Gene', '6774', (50, 55))	('potentiates', 'PosReg', (33, 44))	('STAT3', 'Gene', '6774', (142, 147))	('NPC', 'Gene', '4864', (151, 154))	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('EGFR', 'Gene', (161, 165))	('acylglycerol kinase', 'Gene', '55750', (13, 32))	('JAK2', 'Gene', '3717', (45, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('activation', 'PosReg', (190, 200))	('JAK2', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('mutation', 'Var', (166, 174))	('IL-6', 'Gene', '3569', (205, 209))	('STAT3', 'Gene', (184, 189))	('lung cancer', 'Disease', (224, 235))	('EBV', 'Species', '10376', (95, 98))	('STAT3', 'Gene', (50, 55))	('ESCC', 'Disease', (69, 73))	('NPC', 'Gene', (151, 154))
838287	29290793	Epigenetic silencing has been found to be the predominant cause of DLEC1 inactivation, as only rare mutations of DLEC1 have been detected in multiple carcinoma tissues from TCGA cohorts even with large sample sizes, suggesting a dominant role of epigenetic disruption of DLEC1 in carcinoma pathogenesis.	('DLEC1', 'Gene', (113, 118))	('DLEC1', 'Gene', '9940', (113, 118))	('multiple carcinoma', 'Disease', (141, 159))	('carcinoma', 'Disease', 'MESH:D002277', (280, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('inactivation', 'NegReg', (73, 85))	('DLEC1', 'Gene', (271, 276))	('DLEC1', 'Gene', '9940', (271, 276))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('multiple carcinoma', 'Disease', 'MESH:C537656', (141, 159))	('Epigenetic', 'Var', (0, 10))	('DLEC1', 'Gene', '9940', (67, 72))	('carcinoma', 'Disease', (280, 289))	('DLEC1', 'Gene', (67, 72))	('epigenetic disruption', 'Var', (246, 267))	('carcinoma', 'Disease', (150, 159))
838288	29290793	In this study, we also found four alternative splicings of DLEC1; however, further investigations of these variants are needed, including their functional significance, relative proportion to other longer functional transcripts, as well as possible connection between the splicing and CpG methylation of the DLEC1 gene body.	('DLEC1', 'Gene', '9940', (59, 64))	('DLEC1', 'Gene', (59, 64))	('DLEC1', 'Gene', (308, 313))	('variants', 'Var', (107, 115))	('DLEC1', 'Gene', '9940', (308, 313))
838291	29290793	As DLEC1 methylation is tumor-specific in ESCC and detectable even in immortalized normal esophageal epithelial cells, it might serve as a non-invasive epigenetic biomarker for the early detection of ESCC.	('methylation', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('DLEC1', 'Gene', (3, 8))	('DLEC1', 'Gene', '9940', (3, 8))	('tumor', 'Disease', (24, 29))	('ESCC', 'Disease', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('ESCC', 'Disease', (200, 204))
838292	29290793	We also found that DLEC1 methylation is correlated with ESCC recurrence and progression, suggesting its potential even as a marker for prognosis prediction in carcinoma patients.	('ESCC', 'Disease', (56, 60))	('carcinoma', 'Disease', 'MESH:D002277', (159, 168))	('patients', 'Species', '9606', (169, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('methylation', 'Var', (25, 36))	('carcinoma', 'Disease', (159, 168))	('correlated', 'Reg', (40, 50))	('DLEC1', 'Gene', (19, 24))	('DLEC1', 'Gene', '9940', (19, 24))
838293	29290793	In parallel, DLEC1 methylation has been shown to be of good biomarker value in other malignancies, including non-small cell lung, gastric, hepatocellular, renal and oral carcinomas, as well as pre-invasive lesions of breast cancer.	('DLEC1', 'Gene', (13, 18))	('DLEC1', 'Gene', '9940', (13, 18))	('methylation', 'Var', (19, 30))	('malignancies', 'Disease', 'MESH:D009369', (85, 97))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', (217, 230))	('non-small cell lung', 'Disease', (109, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('malignancies', 'Disease', (85, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('hepatocellular', 'Disease', (139, 153))	('gastric', 'Disease', (130, 137))	('renal and oral carcinomas', 'Disease', 'MESH:C538614', (155, 180))
838294	29290793	Moreover, DLEC1 methylation has been detected in plasma samples from lung cancer patients, and sera of Hodgkin lymphoma patients.	('DLEC1', 'Gene', (10, 15))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('DLEC1', 'Gene', '9940', (10, 15))	('patients', 'Species', '9606', (81, 89))	('Hodgkin lymphoma', 'Disease', (103, 119))	('lung cancer', 'Disease', (69, 80))	('detected', 'Reg', (37, 45))	('patients', 'Species', '9606', (120, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (103, 119))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (103, 119))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('methylation', 'Var', (16, 27))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))
838295	29290793	In summary, our study demonstrates the first evidence of predominant, tumor-specific, DLEC1 methylation in ESCC with its biomarker value.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('methylation', 'Var', (92, 103))	('DLEC1', 'Gene', (86, 91))	('DLEC1', 'Gene', '9940', (86, 91))	('tumor', 'Disease', (70, 75))	('ESCC', 'Disease', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
838298	29290793	Our identification of DLEC1 as a negative regulator of STAT3 signaling reveals a mechanistic link between 3p22 alteration and oncogenic STAT3 signaling activation in multiple carcinoma pathogeneses.	('activation', 'PosReg', (152, 162))	('STAT3', 'Gene', (55, 60))	('multiple carcinoma', 'Disease', (166, 184))	('3p22', 'Protein', (106, 110))	('multiple carcinoma', 'Disease', 'MESH:C537656', (166, 184))	('STAT3', 'Gene', '6774', (136, 141))	('DLEC1', 'Gene', (22, 27))	('DLEC1', 'Gene', '9940', (22, 27))	('STAT3', 'Gene', (136, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('alteration', 'Var', (111, 121))	('STAT3', 'Gene', '6774', (55, 60))
838314	29290793	Antibodies used were: cleaved caspase-3 (#9661), cleaved poly (ADP-ribose) polymerase (#9541), AKT-total (#4691), phospho-AKT(Ser473) (#4060), JAK2 (#9945S), phospho-SAPK/JNK (Thr183/Tyr185) (#6251S), STAT3 (#9139S), phospho-STAT3 (Tyr705) (9145S) and phospho-STAT3 (Ser 727), E-cadherin (#4065) (9134) (Cell Signaling, Beverly, MA); Flag M2 (F3165), Vimentin (V6630), DLEC1 (HPA019077) and beta-actin (AC-74) (Sigma-Aldrich, St. Louis, MO); anti-mouse Ig G-HRP (P0161), anti-rabbit Ig G-HRP (P0448) (Dako ,Glostrup, Denmark); Twist (sc-15393; Santa Cruz, CA, USA); a-tubulin (Lab Vision Corporation, Fremont, CA); V5-Tag (MCA1360; AbD Serotec, Raleigh, NC).	('Vimentin', 'Gene', (351, 359))	('JAK2', 'Gene', '3717', (143, 147))	('STAT3', 'Gene', '6774', (201, 206))	('AKT', 'Gene', '207', (122, 125))	('DLEC1', 'Gene', '9940', (369, 374))	('beta-actin', 'Gene', '728378', (391, 401))	('Twist', 'Gene', (527, 532))	('AKT', 'Gene', '207', (95, 98))	('JAK2', 'Gene', (143, 147))	('Tyr', 'Chemical', 'MESH:D014443', (232, 235))	('STAT3', 'Gene', (260, 265))	('STAT3', 'Gene', (225, 230))	('Tyr', 'Chemical', 'MESH:D014443', (183, 186))	('rabbit', 'Species', '9986', (476, 482))	('STAT3', 'Gene', '6774', (260, 265))	('beta-actin', 'Gene', (391, 401))	('DLEC1', 'Gene', (369, 374))	('Tyr705', 'Chemical', '-', (232, 238))	('Ser473', 'Chemical', '-', (126, 132))	('Twist', 'Gene', '7291', (527, 532))	('AKT', 'Gene', (122, 125))	('STAT3', 'Gene', '6774', (225, 230))	('mouse', 'Species', '10090', (447, 452))	('E-cadherin', 'Gene', (277, 287))	('E-cadherin', 'Gene', '999', (277, 287))	('STAT3', 'Gene', (201, 206))	('MCA1360;', 'Var', (623, 631))	('Vimentin', 'Gene', '7431', (351, 359))	('AKT', 'Gene', (95, 98))
838401	28794639	More importantly, KIAA1522 depletion significantly suppressed the growth of ESCC xenograft tumors and lung metastasis of ESCC cells in nude mice.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('growth', 'CPA', (66, 72))	('nude mice', 'Species', '10090', (135, 144))	('lung metastasis of', 'CPA', (102, 120))	('ESCC xenograft tumors', 'Disease', 'MESH:D004938', (76, 97))	('KIAA1522 depletion', 'Var', (18, 36))	('suppressed', 'NegReg', (51, 61))	('ESCC xenograft tumors', 'Disease', (76, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('depletion', 'Var', (27, 36))
838402	28794639	At the molecular level, inhibition of KIAA1522 expression markedly reduced the phosphorylated extracellular signal-regulated kinase (ERK) levels in both suspended and adherent ESCC cells, suggesting that KIAA1522 might promote cell proliferation and survival via the ERK cascade.	('KIAA1522', 'Gene', (38, 46))	('survival', 'CPA', (250, 258))	('extracellular signal-regulated kinase', 'Gene', '5594', (94, 131))	('ERK', 'Gene', '5594', (267, 270))	('ERK', 'Gene', '5594', (133, 136))	('promote', 'PosReg', (219, 226))	('reduced', 'NegReg', (67, 74))	('cell proliferation', 'CPA', (227, 245))	('ERK', 'Gene', (133, 136))	('ERK', 'Gene', (267, 270))	('KIAA1522', 'Var', (204, 212))	('inhibition', 'NegReg', (24, 34))	('extracellular signal-regulated kinase', 'Gene', (94, 131))
838408	28794639	However, the relationship between abnormal KIAA1522 expression and malignant tumors remains unclear.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('malignant tumors', 'Disease', 'MESH:D018198', (67, 83))	('abnormal', 'Var', (34, 42))	('KIAA1522', 'Gene', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('malignant tumors', 'Disease', (67, 83))
838410	28794639	In addition, we found that KIAA1522 overexpression promotes the proliferation of NSCLC cells in vitro, suggesting that KIAA1522 is an oncogene.	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('promotes', 'PosReg', (51, 59))	('proliferation', 'CPA', (64, 77))	('KIAA1522', 'Var', (119, 127))	('NSCLC', 'Disease', (81, 86))	('KIAA1522', 'Gene', (27, 35))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
838422	28794639	The blots were blocked and incubated with an antibody against KIAA1522 (Sigma), phosphorylated extracellular signal-regulated kinase (pERK) (Thr202/Tyr204), or extracellular signal-regulated kinase (ERK) (CST, Beverly, MI, USA).	('ERK', 'Gene', '5594', (135, 138))	('pERK', 'Gene', (134, 138))	('extracellular signal-regulated kinase', 'Gene', '5594', (160, 197))	('Thr202/Tyr204', 'Var', (141, 154))	('pERK', 'Gene', '9451', (134, 138))	('ERK', 'Gene', (135, 138))	('extracellular signal-regulated kinase', 'Gene', '5594', (95, 132))	('Thr202', 'Chemical', '-', (141, 147))	('extracellular signal-regulated kinase', 'Gene', (160, 197))	('ERK', 'Gene', '5594', (199, 202))	('Tyr204', 'Chemical', '-', (148, 154))	('extracellular signal-regulated kinase', 'Gene', (95, 132))	('ERK', 'Gene', (199, 202))
838441	28794639	KIAA1522 was mainly localized in the cytoplasm of esophageal epithelia cells (Figure 1).	('esophageal epithelia', 'Disease', (50, 70))	('esophageal epithelia', 'Disease', 'MESH:D004941', (50, 70))	('KIAA1522', 'Var', (0, 8))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (50, 70))
838448	28794639	The results showed that depletion of KIAA1522 by siRNA significantly induced apoptosis in KYSE510 and KYSE150 cells cultured in suspension compared with that measured in parental or non-silencing siRNA-transfected cells (Figure 4B and C).	('KYSE150', 'CellLine', 'CVCL:1348', (102, 109))	('apoptosis', 'CPA', (77, 86))	('KIAA1522', 'Var', (37, 45))	('siRNA', 'Gene', (49, 54))	('depletion', 'MPA', (24, 33))	('induced', 'Reg', (69, 76))
838450	28794639	First, we confirmed that stable knockdown of KIAA1522 markedly impaired anoikis resistance of KYSE150 and KYSE510 cells (Figure 5A).	('KYSE150', 'CellLine', 'CVCL:1348', (94, 101))	('knockdown', 'Var', (32, 41))	('anoikis resistance', 'CPA', (72, 90))	('impaired', 'NegReg', (63, 71))	('KIAA1522', 'Gene', (45, 53))
838452	28794639	As a result, KIAA1522 knockdown significantly abrogated the ability of KYSE150 cells to form metastatic foci in the lungs of nude mice (Figure 5B-D), indicating that KIAA1522 expression promotes tumor metastases in vivo.	('nude mice', 'Species', '10090', (125, 134))	('tumor metastases', 'Disease', (195, 211))	('abrogated', 'NegReg', (46, 55))	('KIAA1522', 'Var', (166, 174))	('tumor metastases', 'Disease', 'MESH:D009362', (195, 211))	('KYSE150', 'CellLine', 'CVCL:1348', (71, 78))	('promotes', 'PosReg', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
838453	28794639	Specifically, depletion of KIAA1522 expression distinctly abrogated ERK activity in both adherent and suspension-cultured ESCC cells (Figure 6), indicating that KIAA1522 facilitates the proliferation and survival of ESCC cells at least partially through activating the ERK signaling pathway.	('abrogated', 'NegReg', (58, 67))	('activating', 'PosReg', (254, 264))	('proliferation', 'CPA', (186, 199))	('activity', 'MPA', (72, 80))	('ERK', 'Gene', '5594', (68, 71))	('facilitates', 'PosReg', (170, 181))	('KIAA1522', 'Gene', (27, 35))	('ERK', 'Gene', (68, 71))	('depletion', 'MPA', (14, 23))	('ERK', 'Gene', '5594', (269, 272))	('KIAA1522', 'Var', (161, 169))	('ERK', 'Gene', (269, 272))	('survival', 'CPA', (204, 212))
838454	28794639	Furthermore, our current data show that KIAA1522 potentiates ERK activity in ESCC cells under both adherent and suspension culture conditions.	('ERK', 'Gene', '5594', (61, 64))	('ERK', 'Gene', (61, 64))	('KIAA1522', 'Var', (40, 48))	('potentiates', 'PosReg', (49, 60))
838459	28794639	Our previous data reveal that KIAA1522 overexpression promotes the proliferation of human NSCLC cells in vitro, suggesting that it acts as an oncogene.	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('proliferation', 'CPA', (67, 80))	('overexpression', 'Var', (39, 53))	('human', 'Species', '9606', (84, 89))	('KIAA1522', 'Gene', (30, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))	('promotes', 'PosReg', (54, 62))
838460	28794639	Anoikis resistance allows the survival of malignant tumor cells in blood vessels and the lymphatic system and their metastasis to distant sites, and thus contributes to tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('contributes', 'Reg', (154, 165))	('Anoikis', 'Var', (0, 7))	('tumor', 'Disease', (52, 57))	('survival', 'CPA', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('metastasis', 'CPA', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
838461	28794639	More importantly, KIAA1522 depletion prominently inhibits the lung metastasis of ESCC cells in nude mice.	('inhibits', 'NegReg', (49, 57))	('ESCC', 'Disease', (81, 85))	('KIAA1522 depletion', 'Var', (18, 36))	('lung metastasis of', 'CPA', (62, 80))	('nude mice', 'Species', '10090', (95, 104))	('depletion', 'Var', (27, 36))
838462	28794639	At the molecular level, the inhibition of KIAA1522 expression evidently reduces pERK levels in both adherent and suspension-cultured ESCC cells, suggesting that high KIAA1522 expression enhances the proliferation and metastasis potentials of ESCC cells by activating the ERK cascade.	('enhances', 'PosReg', (186, 194))	('proliferation', 'CPA', (199, 212))	('KIAA1522', 'Gene', (166, 174))	('reduces', 'NegReg', (72, 79))	('metastasis potentials', 'CPA', (217, 238))	('ERK', 'Gene', '5594', (81, 84))	('ERK', 'Gene', (81, 84))	('high', 'Var', (161, 165))	('pERK', 'Gene', '9451', (80, 84))	('ERK', 'Gene', '5594', (271, 274))	('pERK', 'Gene', (80, 84))	('activating', 'Reg', (256, 266))	('ERK', 'Gene', (271, 274))
838463	28794639	Consistently, we have found that KIAA1522 triggers ERK phosphorylation in NSCLC cells.	('ERK', 'Gene', (51, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('ERK', 'Gene', '5594', (51, 54))	('NSCLC', 'Disease', (74, 79))	('KIAA1522', 'Var', (33, 41))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('triggers', 'Reg', (42, 50))
838465	28794639	In summary, this study shows that KIAA1522 protein expression is upregulated in a subset of ESCC tissues and that KIAA1522 overexpression might promote tumor formation and progression of ESCC cells by enhancing their malignant proliferation ability and anoikis resistance through the activation of the ERK signaling pathway.	('ESCC', 'Disease', (187, 191))	('anoikis resistance', 'CPA', (253, 271))	('KIAA1522', 'Gene', (114, 122))	('overexpression', 'Var', (123, 137))	('ERK', 'Gene', '5594', (302, 305))	('ESCC', 'Disease', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('ERK', 'Gene', (302, 305))	('progression', 'CPA', (172, 183))	('malignant proliferation ability', 'CPA', (217, 248))	('tumor', 'Disease', (152, 157))	('promote', 'PosReg', (144, 151))	('enhancing', 'PosReg', (201, 210))	('upregulated', 'PosReg', (65, 76))	('KIAA1522', 'Gene', (34, 42))	('protein', 'Protein', (43, 50))
838467	28542283	Recent genome-wide association studies (GWAS) in Chinese esophageal cancer patients have demonstrated six high-risk candidate single nucleotide polymorphisms (SNPs).	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (75, 83))	('esophageal cancer', 'Disease', (57, 74))	('single nucleotide polymorphisms', 'Var', (126, 157))
838474	28542283	Kaplan-Meier and Cox regression analyses were carried out to evaluate the associations between genetic variants and overall survival.	('variants', 'Var', (103, 111))	('associations', 'Interaction', (74, 86))	('Cox', 'Gene', (17, 20))	('Cox', 'Gene', '1351', (17, 20))
838475	28542283	Four of the 20 SNPs identified as high-risk SNPs in Chinese esophageal cancer showed increased risk for Chinese lung cancer, which included rs3769823 (OR = 1.26; 95% CI = 1.107-1.509; P = 0.02), rs10931936 (OR = 1.283; 95% CI = 1.100-1.495; P = 0.04), rs2244438 (OR = 1.294; 95% CI = 1.098-1.525; P = 0.04) and rs13016963 (OR = 1.268; 95% CI = 1.089-1.447; P = 0.04).	('rs2244438', 'Var', (252, 261))	('rs2244438', 'Mutation', 'rs2244438', (252, 261))	('rs13016963', 'Var', (311, 321))	('rs13016963', 'Mutation', 'rs13016963', (311, 321))	('rs3769823', 'Mutation', 'rs3769823', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('rs10931936', 'Var', (195, 205))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('rs3769823', 'Var', (140, 149))	('esophageal cancer', 'Disease', (60, 77))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('rs10931936', 'Mutation', 'rs10931936', (195, 205))
838478	28542283	The present study identified four high-risk SNPs at 2q33 locus for Chinese lung cancer and demonstrated the shared susceptibility loci at 2q33 region for Chinese lung and esophageal cancers.	('lung cancer', 'Disease', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('SNPs', 'Var', (44, 48))	('lung and esophageal cancers', 'Disease', 'MESH:D004938', (162, 189))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))
838482	28542283	Accumulating evidence indicates that lung and esophageal cancers share many common genetic variants, such as deletion of CASP and CYP2A6 gene, SOX2 expression, IFGR-IGFBP axis and WDHD1, especially in an Asian population.	('deletion', 'Var', (109, 117))	('CYP2A6', 'Gene', '1548', (130, 136))	('WDHD1', 'Gene', '11169', (180, 185))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('CASP', 'Gene', (121, 125))	('CASP', 'Gene', '9595', (121, 125))	('CYP2A6', 'Gene', (130, 136))	('WDHD1', 'Gene', (180, 185))	('lung and esophageal cancers', 'Disease', 'MESH:D004938', (37, 64))	('SOX2', 'Gene', '6657', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('SOX2', 'Gene', (143, 147))	('IFGR-IGFBP axis', 'Gene', (160, 175))
838483	28542283	Recently, a couple of genome-wide association studies (GWAS) demonstrated that a group of common genetic variants increase the risk to tumors from esophagus, lung and stomach.	('lung', 'Disease', (158, 162))	('increase', 'PosReg', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('variants', 'Var', (105, 113))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('stomach', 'Disease', (167, 174))
838504	28542283	Finally, five SNPs (rs3769823, rs10931936, rs2244438, rs13016963, rs7578456) were significant association with the increased risk of lung cancer in the high-incidence area of ESCC in northern China with p value of 0.001, 0.002, 0.002, 0.002 and 0.007.	('rs13016963', 'Var', (54, 64))	('rs2244438', 'Var', (43, 52))	('rs2244438', 'Mutation', 'rs2244438', (43, 52))	('rs3769823', 'Mutation', 'rs3769823', (20, 29))	('rs7578456', 'Var', (66, 75))	('lung cancer', 'Disease', (133, 144))	('rs13016963', 'Mutation', 'rs13016963', (54, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('rs10931936', 'Mutation', 'rs10931936', (31, 41))	('rs3769823', 'Var', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('rs10931936', 'Var', (31, 41))	('rs7578456', 'Mutation', 'rs7578456', (66, 75))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('association', 'Reg', (94, 105))
838506	28542283	The other four SNPs (rs3769823, rs2244438, rs10931936, and rs13016963) showed significant associations with the increased risk of lung cancer with p value of 0.02, 0.04, 0.04 and 0.04, respectively.	('rs10931936', 'Var', (43, 53))	('rs2244438', 'Var', (32, 41))	('rs2244438', 'Mutation', 'rs2244438', (32, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('rs3769823', 'Mutation', 'rs3769823', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rs3769823', 'Var', (21, 30))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('rs13016963', 'Var', (59, 69))	('rs13016963', 'Mutation', 'rs13016963', (59, 69))	('associations', 'Reg', (90, 102))	('rs10931936', 'Mutation', 'rs10931936', (43, 53))	('lung cancer', 'Disease', (130, 141))
838508	28542283	To test whether these ESCC and lung cancer susceptibility SNPs variants correlate with the overall survival of lung cancer patients, we performed Kaplan-Meier survival analyses.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('variants', 'Var', (63, 71))	('ESCC', 'Disease', (22, 26))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('lung cancer', 'Disease', (31, 42))	('patients', 'Species', '9606', (123, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
838510	28542283	599 patients were genotyped for rs3769823, 579 for rs10931936, 600 for rs2244438, 596 for 13016963, respectively.	('rs2244438', 'Var', (71, 80))	('13016963', 'Var', (90, 98))	('rs3769823', 'Var', (32, 41))	('rs10931936', 'Mutation', 'rs10931936', (51, 61))	('rs10931936', 'Var', (51, 61))	('patients', 'Species', '9606', (4, 12))	('rs3769823', 'Mutation', 'rs3769823', (32, 41))	('rs2244438', 'Mutation', 'rs2244438', (71, 80))
838514	28542283	Kaplan-Meier curves of OS for rs2244438, rs13016963 genotypes were shown in Figs 3 and 4, respectively, and Log-rank analysis showed no significant differences between OS and these genotypes (log-rank P = 0.101, P = 0.938, P = 0.711, respectively).	('rs2244438', 'Var', (30, 39))	('rs2244438', 'Mutation', 'rs2244438', (30, 39))	('rs13016963', 'Mutation', 'rs13016963', (41, 51))	('rs13016963', 'Var', (41, 51))
838525	28542283	Our data revealed that four functional polymorphisms at 2q33 (rs13016963, rs3769823, rs10931936, rs2244438) out of 20 SNPs were associated with the risk of lung cancer (P< 0.01) and ESCC of Chinese Han as well.	('rs3769823', 'Var', (74, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('rs10931936', 'Var', (85, 95))	('rs13016963', 'Var', (62, 72))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('rs2244438', 'Mutation', 'rs2244438', (97, 106))	('rs13016963', 'Mutation', 'rs13016963', (62, 72))	('associated', 'Reg', (128, 138))	('rs2244438', 'Var', (97, 106))	('rs3769823', 'Mutation', 'rs3769823', (74, 83))	('lung cancer', 'Disease', (156, 167))	('rs10931936', 'Mutation', 'rs10931936', (85, 95))
838527	28542283	Unlike highly penetrant germline mutations causing 'hereditary' cancers, such as CDKN2A mutations in melanoma and BRCA1 mutations in breast cancer, lung cancer and ESCC belong to 'sporadic' ('non-hereditary') malignant phenotype but a number of recent studies of heritability assessment suggests that these phenotypes (include twelve cancer types) of sporadic tumors share common genetic variants.	('cancer', 'Disease', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	("'hereditary' cancers", 'Disease', 'MESH:D009369', (51, 71))	('sporadic tumors', 'Disease', 'MESH:D009369', (351, 366))	('mutations', 'Var', (88, 97))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (120, 129))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('cancer', 'Disease', (334, 340))	('breast cancer', 'Disease', (133, 146))	('CDKN2A', 'Gene', (81, 87))	('cancer', 'Disease', (64, 70))	('BRCA1', 'Gene', '672', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('lung cancer', 'Disease', (148, 159))	('BRCA1', 'Gene', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (360, 366))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('cancer', 'Disease', (140, 146))	('CDKN2A', 'Gene', '1029', (81, 87))	("'hereditary' cancers", 'Disease', (51, 71))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('sporadic tumors', 'Disease', (351, 366))
838528	28542283	In other words, the genetic variants in cancer susceptibility play important roles in several common cancers and more loci of remaining polygenic components should be discovered continuously.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('roles', 'Reg', (77, 82))	('genetic variants', 'Var', (20, 36))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
838529	28542283	In fact, more novel cancer susceptibility loci identified by GWAS and contribution of all genetic variants to malignant disease should be simultaneously taken into consideration instead of just few known loci.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('malignant disease', 'Disease', 'MESH:D009369', (110, 127))	('cancer', 'Disease', (20, 26))	('malignant disease', 'Disease', (110, 127))	('variants', 'Var', (98, 106))
838530	28542283	Numerous studies investigated whether variation in the CASP8 gene region alters cancer risk, including cancers of lung, breast, pancreas, non-Hodgkin lymphoma, head and neck.	('variation', 'Var', (38, 47))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CASP8', 'Gene', '841', (55, 60))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (142, 158))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('non-Hodgkin lymphoma', 'Disease', (138, 158))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (138, 158))	('cancers of lung', 'Disease', (103, 118))	('pancreas', 'Disease', (128, 136))	('lymphoma', 'Phenotype', 'HP:0002665', (150, 158))	('CASP8', 'Gene', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('alters', 'Reg', (73, 79))	('breast', 'Disease', (120, 126))	('cancers of lung', 'Disease', 'MESH:D008175', (103, 118))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (138, 158))
838531	28542283	We identified two new loci (rs3769823, rs10931936) mapping to a genomic region harboring CASP8 which associated with risk of both ESCC and lung cancer of Chinese Han.	('lung cancer', 'Disease', (139, 150))	('rs3769823', 'Mutation', 'rs3769823', (28, 37))	('CASP8', 'Gene', (89, 94))	('CASP8', 'Gene', '841', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('ESCC', 'Disease', (130, 134))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('rs3769823', 'Var', (28, 37))	('rs10931936', 'Mutation', 'rs10931936', (39, 49))	('associated', 'Reg', (101, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('rs10931936', 'Var', (39, 49))
838532	28542283	We are the first to report that SNPs mapping to ALS2CR12 and TRAK2 were significantly associated with ESCC and lung cancer of Chinese Han.	('SNPs mapping', 'Var', (32, 44))	('ALS2CR12', 'Gene', '130540', (48, 56))	('ESCC', 'Disease', (102, 106))	('ALS2CR12', 'Gene', (48, 56))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('associated', 'Reg', (86, 96))	('TRAK2', 'Gene', (61, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('TRAK2', 'Gene', '66008', (61, 66))
838535	28542283	Therefore, rs10931936 genotype group that map to CASP8 need further investigation to elucidate.	('rs10931936', 'Var', (11, 21))	('rs10931936', 'Mutation', 'rs10931936', (11, 21))	('CASP8', 'Gene', (49, 54))	('CASP8', 'Gene', '841', (49, 54))
838536	28542283	Further research should focus on the association between functional polymorphisms at 2q33 (rs13016963, rs3769823, rs10931936, rs2244438) and risk of lung cancer from different ethnics, other tumor types and as well as the association with chemotherapy treatments in China.	('rs13016963', 'Var', (91, 101))	('rs13016963', 'Mutation', 'rs13016963', (91, 101))	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('rs2244438', 'Var', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('rs2244438', 'Mutation', 'rs2244438', (126, 135))	('rs3769823', 'Mutation', 'rs3769823', (103, 112))	('rs10931936', 'Mutation', 'rs10931936', (114, 124))	('rs3769823', 'Var', (103, 112))	('tumor', 'Disease', (191, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('rs10931936', 'Var', (114, 124))	('lung cancer', 'Disease', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
838537	28542283	So far, at least three studies on GWAS reported that rs8034191 was involved in the susceptibility to lung cancer.	('involved', 'Reg', (67, 75))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('rs8034191', 'Mutation', 'rs8034191', (53, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('rs8034191', 'Var', (53, 62))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
838538	28542283	However, our data from particular Chinese region found that rs8034191 was not associated with the risk of lung cancer.	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rs8034191', 'Mutation', 'rs8034191', (60, 69))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('rs8034191', 'Var', (60, 69))
838539	28542283	Furthermore, other investigations provided similar evidence that other SNPs may not modify the genetic risk of lung cancer, which include rs8034191, rs4975616, rs2352028, rs1926293.	('rs1926293', 'Mutation', 'rs1926293', (171, 180))	('rs1926293', 'Var', (171, 180))	('rs8034191', 'Var', (138, 147))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('rs2352028', 'Var', (160, 169))	('rs4975616', 'Var', (149, 158))	('rs4975616', 'Mutation', 'rs4975616', (149, 158))	('rs8034191', 'Mutation', 'rs8034191', (138, 147))	('lung cancer', 'Disease', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('rs2352028', 'Mutation', 'rs2352028', (160, 169))
838540	28542283	Our present results suggest that four genetic variants in 2q33 may contribute to the susceptibility to both lung and esophageal cancers in Han Chinese.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('susceptibility', 'Reg', (85, 99))	('lung and esophageal cancers', 'Disease', 'MESH:D004938', (108, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('variants', 'Var', (46, 54))	('2q33', 'Gene', (58, 62))	('contribute', 'Reg', (67, 77))
838541	28542283	However, we did not find an association between these four lung cancer risk variants with survival.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('variants', 'Var', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
838542	28542283	In addition, our findings also showed that 16 common genetic variants that have been previously identified in lung cancer, ESCC or GA by GWAS were not associated with lung cancer susceptibility in the Han Chinese population.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('associated', 'Reg', (151, 161))	('ESCC', 'Disease', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('variants', 'Var', (61, 69))
838558	26603024	This trial supported that preoperative chemoradiotherapy should be the new standard of care for the management of patients with EUS T3-4 or N1 tumors.	('EUS T3-4', 'Var', (128, 136))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('men', 'Species', '9606', (106, 109))
838631	26499111	The analysis shows that the NBT + EBRT group has higher overall survival rate and local control rate than that of the 3D-CRT group.	('overall survival', 'CPA', (56, 72))	('EBRT', 'Chemical', '-', (34, 38))	('local control', 'CPA', (82, 95))	('NBT', 'Chemical', 'MESH:D009580', (28, 31))	('higher', 'PosReg', (49, 55))	('NBT + EBRT', 'Var', (28, 38))
838632	26499111	The acute toxicity effects were acceptable for both groups of patients with the NBT + EBRT group showing higher rates of leukopenia and thrombocytopenia and the 3D-CRT group showing higher rates on fistula and massive bleeding.	('leukopenia', 'Phenotype', 'HP:0001882', (121, 131))	('leukopenia', 'Disease', (121, 131))	('NBT', 'Chemical', 'MESH:D009580', (80, 83))	('thrombocytopenia', 'Disease', (136, 152))	('NBT + EBRT', 'Var', (80, 90))	('bleeding', 'Disease', 'MESH:D006470', (218, 226))	('toxicity', 'Disease', 'MESH:D064420', (10, 18))	('leukopenia', 'Disease', 'MESH:D007970', (121, 131))	('toxicity', 'Disease', (10, 18))	('bleeding', 'Disease', (218, 226))	('fistula', 'Disease', 'MESH:D005402', (198, 205))	('thrombocytopenia', 'Disease', 'MESH:D013921', (136, 152))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (136, 152))	('patients', 'Species', '9606', (62, 70))	('EBRT', 'Chemical', '-', (86, 90))	('fistula', 'Disease', (198, 205))
838633	26499111	The patients treated with NBT + EBRT showed better oncologic outcomes than those treated with 3D-CRT.	('EBRT', 'Chemical', '-', (32, 36))	('NBT', 'Chemical', 'MESH:D009580', (26, 29))	('oncologic outcomes', 'CPA', (51, 69))	('patients', 'Species', '9606', (4, 12))	('NBT + EBRT', 'Var', (26, 36))
838634	26499111	The toxicity effects were acceptable for both groups with the NBT + EBRT group showing higher rates on the acute effects and the 3D-CRT group showing higher rates on the late effects.	('NBT + EBRT', 'Var', (62, 72))	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('EBRT', 'Chemical', '-', (68, 72))	('higher rates', 'PosReg', (87, 99))	('toxicity', 'Disease', (4, 12))	('NBT', 'Chemical', 'MESH:D009580', (62, 65))
838646	26499111	The first group of 545 patients were treated at the Changzhi Cancer Hospital with NBT + EBRT, and the second group of 339 patients were treated at the Sichuan cancer hospital with 3D-CRT (i.e.	('cancer', 'Disease', (159, 165))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('EBRT', 'Chemical', '-', (88, 92))	('patients', 'Species', '9606', (23, 31))	('Changzhi Cancer', 'Disease', 'MESH:D009369', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('NBT', 'Chemical', 'MESH:D009580', (82, 85))	('patients', 'Species', '9606', (122, 130))	('Changzhi Cancer', 'Disease', (52, 67))	('NBT + EBRT', 'Var', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
838648	26499111	The primary tumors of the patients were limited to the esophagus, with or without the presence of involved regional lymph nodes, i.e., T2-4, N0-1, M0 according to the 2002 American Joint Committee on Cancer (AJCC) clinical staging system.	('Cancer', 'Phenotype', 'HP:0002664', (200, 206))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('T2-4', 'Var', (135, 139))	('Cancer', 'Disease', (200, 206))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('Cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
838723	26499111	Other authors reported that the patients treated with 3D-CRT have better OS and LC than that of conventional radiotherapy alone in many types of cancer.	('cancer', 'Disease', (145, 151))	('patients', 'Species', '9606', (32, 40))	('LC', 'Chemical', '-', (80, 82))	('OS', 'Chemical', '-', (73, 75))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('better', 'PosReg', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('3D-CRT', 'Var', (54, 60))
838725	26499111	We believe that there are at least two factors making the NBT + EBRT more effective than 3D-CRT in treating the localized ESCC.	('EBRT', 'Chemical', '-', (64, 68))	('ESCC', 'Disease', (122, 126))	('localized ESCC', 'Disease', (112, 126))	('NBT', 'Chemical', 'MESH:D009580', (58, 61))	('NBT', 'Var', (58, 61))
838730	26499111	In terms of radiation related toxicity effects, this study shows that the NBT + EBRT group showed significantly higher rates of leukopenia and thrombocytopenia (P < 0.001 and P < 0.001) than that of the 3D-CRT group.	('toxicity', 'Disease', 'MESH:D064420', (30, 38))	('higher', 'PosReg', (112, 118))	('thrombocytopenia', 'Disease', (143, 159))	('toxicity', 'Disease', (30, 38))	('leukopenia', 'Disease', 'MESH:D007970', (128, 138))	('leukopenia', 'Disease', (128, 138))	('NBT', 'Chemical', 'MESH:D009580', (74, 77))	('NBT + EBRT', 'Var', (74, 84))	('thrombocytopenia', 'Disease', 'MESH:D013921', (143, 159))	('leukopenia', 'Phenotype', 'HP:0001882', (128, 138))	('EBRT', 'Chemical', '-', (80, 84))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (143, 159))
838740	26499111	In this cohort of patients with ESCC treated with NBT + EBRT were associated with better oncologic outcomes than those of 3D-CRT.	('ESCC', 'Disease', (32, 36))	('NBT', 'Chemical', 'MESH:D009580', (50, 53))	('oncologic outcomes', 'CPA', (89, 107))	('better', 'PosReg', (82, 88))	('NBT + EBRT', 'Var', (50, 60))	('patients', 'Species', '9606', (18, 26))	('EBRT', 'Chemical', '-', (56, 60))
838741	26499111	NBT + EBRT were associated with a higher rate of acute irradiation toxicity.	('NBT + EBRT', 'Var', (0, 10))	('EBRT', 'Chemical', '-', (6, 10))	('NBT', 'Chemical', 'MESH:D009580', (0, 3))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))	('toxicity', 'Disease', (67, 75))
838742	26499111	3D-CRT has the higher rate of late toxicity esophageal fistulas.	('toxicity esophageal fistulas', 'Disease', 'MESH:D004937', (35, 63))	('3D-CRT', 'Var', (0, 6))	('toxicity esophageal fistulas', 'Disease', (35, 63))
838784	25245383	It is reported that nuclear immunoreactivity of p53 is a good surrogate of TP53 mutations .	('p53', 'Gene', (48, 51))	('mutations', 'Var', (80, 89))	('p53', 'Gene', '7157', (48, 51))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
838799	25245383	Overall survival ratio was significantly lower in the patients with synchronous MPMN than those with metachronous MPMN (adjusted hazard ratio 0.50, P <0.001).	('Overall survival', 'MPA', (0, 16))	('patients', 'Species', '9606', (54, 62))	('lower', 'NegReg', (41, 46))	('synchronous MPMN', 'Var', (68, 84))
838801	25245383	In particular, tobacco smoking causes cancers of the lung, oral cavity, naso-, oro-, and hypopharynx, nasal cavity and accessory sinuses, larynx, esophagus, stomach, pancreas, colorectum, liver, kidney (body and pelvis), ureter, urinary bladder, uterine cervix and ovary (mucinous), and myeloid leukemia .	('tobacco smoking', 'Var', (15, 30))	('tobacco', 'Species', '4097', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancers of the lung', 'Disease', (38, 57))	('myeloid leukemia', 'Disease', 'MESH:D007951', (287, 303))	('larynx', 'Disease', (138, 144))	('esophagus', 'Disease', (146, 155))	('pancreas', 'Disease', 'MESH:D010190', (166, 174))	('cancers of the lung', 'Disease', 'MESH:D008175', (38, 57))	('leukemia', 'Phenotype', 'HP:0001909', (295, 303))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (287, 303))	('colorectum', 'Disease', (176, 186))	('causes', 'Reg', (31, 37))	('pancreas', 'Disease', (166, 174))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('myeloid leukemia', 'Disease', (287, 303))	('ureter', 'Disease', (221, 227))
838808	25245383	If the nature of the hereditary predisposition is similar to that of childhood cancers, i.e., an inherited mutation that reduces the subsequent number of mutations necessary in each cell of the target organ, then such individuals may have a high rate of spontaneous tumors and a unique sensitivity to environmental agents .	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('childhood cancers', 'Disease', 'MESH:C536928', (69, 86))	('childhood cancers', 'Disease', (69, 86))	('tumors', 'Disease', (266, 272))	('reduces', 'NegReg', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('mutation', 'Var', (107, 115))	('tumors', 'Disease', 'MESH:D009369', (266, 272))
838810	25245383	They found that tobacco habit and three genetic polymorphisms, including Tp53 (Arg72Arg), XRCC1 (Arg399His), and meH (Tyr113His), formed the best model for developing tobacco-associated MPMN .	('tobacco-associated MPMN', 'Disease', (167, 190))	('Arg72Arg', 'Var', (79, 87))	('Arg399His', 'Var', (97, 106))	('tobacco', 'Species', '4097', (167, 174))	('Tp53', 'Gene', (73, 77))	('Tyr113His', 'SUBSTITUTION', 'None', (118, 127))	('Tyr113His', 'Var', (118, 127))	('Tp53', 'Gene', '7157', (73, 77))	('Arg399His', 'SUBSTITUTION', 'None', (97, 106))	('tobacco', 'Species', '4097', (16, 23))
838815	25245383	In the present case, immunoreactivity of p53 in tumor cells was different among SCCs, suggesting that these cancers were polyclonal, although distinct genetic abnormalities including loss of heterogeneity, gene mutations, and influence of oncogenic viral infection may be necessary to definitely determine polyclonality.	('SCC', 'Gene', '6317', (80, 83))	('gene mutations', 'Var', (206, 220))	('p53', 'Gene', '7157', (41, 44))	('tumor', 'Disease', (48, 53))	('genetic abnormalities', 'Disease', 'MESH:D030342', (151, 172))	('oncogenic viral infection', 'Disease', 'MESH:D000074723', (239, 264))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('p53', 'Gene', (41, 44))	('genetic abnormalities', 'Disease', (151, 172))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('SCC', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('oncogenic viral infection', 'Disease', (239, 264))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cancers', 'Disease', (108, 115))	('heterogeneity', 'MPA', (191, 204))
838817	25245383	According to the report from the International Agency for Research on Cancer , high-grade UC is likely to have high level amplifications and TP53 mutations.	('mutations', 'Var', (146, 155))	('high-grade UC', 'Disease', (79, 92))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('amplifications', 'MPA', (122, 136))
838841	21415356	The chronic increase in circulating glucose and lipids may in turn further impair insulin secretion, and the aberrations in the insulin-like growth factor pathways and steroid hormone metabolism may play a role in predisposing diabetics to cancer.	('insulin', 'Gene', (128, 135))	('lipids', 'Chemical', 'MESH:D008055', (48, 54))	('steroid hormone metabolism', 'MPA', (168, 194))	('increase in circulating glucose', 'Phenotype', 'HP:0003074', (12, 43))	('insulin', 'Gene', '3630', (128, 135))	('diabetics to cancer', 'Disease', 'MESH:D003920', (227, 246))	('insulin secretion', 'Disease', (82, 99))	('insulin', 'Gene', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('increase', 'PosReg', (12, 20))	('steroid hormone', 'Chemical', 'MESH:D013256', (168, 183))	('insulin', 'Gene', '3630', (82, 89))	('glucose', 'Chemical', 'MESH:D005947', (36, 43))	('aberrations', 'Var', (109, 120))	('diabetics to cancer', 'Disease', (227, 246))	('play', 'Reg', (199, 203))	('insulin secretion', 'Disease', 'MESH:D007333', (82, 99))	('impair', 'NegReg', (75, 81))
838871	21415356	The diabetics group had higher percentages of non-whites than the non-diabetics group.	('diabetic', 'Disease', 'MESH:D003920', (4, 12))	('non-whites', 'Var', (46, 56))	('higher', 'PosReg', (24, 30))	('diabetic', 'Disease', (4, 12))	('diabetic', 'Disease', 'MESH:D003920', (70, 78))	('diabetic', 'Disease', (70, 78))
838892	21415356	This amelioration of diabetes has been shown consistently in obese patients undergoing gastric bypass surgery and somewhat consistently in patients undergoing surgery for other indications, such as gastric cancer or gastric ulcer disease In particular, bypass surgery alters the dietary exposure of the gastric cardia tissue.	('gastric cardia', 'Disease', (303, 317))	('gastric bypass surgery', 'Disease', (87, 109))	('obese', 'Disease', 'MESH:D009765', (61, 66))	('gastric cancer', 'Disease', (198, 212))	('gastric ulcer disease', 'Disease', (216, 237))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (67, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('diabetes', 'Disease', 'MESH:D003920', (21, 29))	('gastric cardia', 'Disease', 'MESH:D004938', (303, 317))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('gastric ulcer disease', 'Disease', 'MESH:D013276', (216, 237))	('gastric ulcer', 'Phenotype', 'HP:0002592', (216, 229))	('obese', 'Disease', (61, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('bypass surgery', 'Var', (253, 267))	('alters', 'Reg', (268, 274))	('diabetes', 'Disease', (21, 29))
838976	32727517	IFI6 depletion inhibits esophageal squamous cell carcinoma progression through reactive oxygen species accumulation via mitochondrial dysfunction and endoplasmic reticulum stress Esophageal squamous cell carcinoma (ESCC) is one of the most lethal forms of adult cancer with poor prognosis.	('depletion', 'Var', (5, 14))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 58))	('inhibits', 'NegReg', (15, 23))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (120, 145))	('reactive oxygen species accumulation', 'Phenotype', 'HP:0025464', (79, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('esophageal squamous cell carcinoma', 'Disease', (24, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (120, 145))	('cancer', 'Disease', (262, 268))	('mitochondrial dysfunction', 'Disease', (120, 145))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (79, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 213))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (24, 58))	('IFI6', 'Gene', '2537', (0, 4))	('IFI6', 'Gene', (0, 4))	('squamous cell carcinoma', 'Disease', (190, 213))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('reactive oxygen species accumulation', 'MPA', (79, 115))
838988	32727517	High IFI6 expression correlates with aggressive disease phenotype and poor prognosis in ESCC patients.	('ESCC', 'Disease', (88, 92))	('IFI6', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('aggressive disease', 'Disease', (37, 55))	('expression', 'MPA', (10, 20))	('aggressive disease', 'Disease', 'MESH:D001523', (37, 55))	('patients', 'Species', '9606', (93, 101))	('IFI6', 'Gene', '2537', (5, 9))
838989	32727517	IFI6 depletion suppresses proliferation and induces apoptosis by increasing ROS accumulation.	('suppresses', 'NegReg', (15, 25))	('depletion', 'Var', (5, 14))	('IFI6', 'Gene', '2537', (0, 4))	('IFI6', 'Gene', (0, 4))	('increasing', 'PosReg', (65, 75))	('apoptosis', 'CPA', (52, 61))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('ROS', 'Protein', (76, 79))	('proliferation', 'CPA', (26, 39))
838990	32727517	Mechanistically, IFI6 ablation induces mitochondrial calcium overload by activating mitochondrial Ca2+ uniporter and subsequently ROS production.	('ROS production', 'MPA', (130, 144))	('ROS', 'Chemical', 'MESH:D017382', (130, 133))	('IFI6', 'Gene', '2537', (17, 21))	('calcium', 'Chemical', 'MESH:D002118', (53, 60))	('IFI6', 'Gene', (17, 21))	('mitochondrial Ca2+ uniporter', 'Gene', (84, 112))	('induces', 'Reg', (31, 38))	('ablation', 'Var', (22, 30))	('activating', 'PosReg', (73, 83))	('mitochondrial Ca2+ uniporter', 'Gene', '90550', (84, 112))	('mitochondrial calcium overload', 'MPA', (39, 69))
838991	32727517	Following IFI6 ablation, mitochondrial ROS accumulation is also induced by mitochondrial supercomplex assembly suppression and oxidative phosphorylation dysfunction, while IFI6 overexpression produces the opposite effects.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('accumulation', 'PosReg', (43, 55))	('ablation', 'Var', (15, 23))	('suppression', 'NegReg', (111, 122))	('IFI6', 'Gene', '2537', (10, 14))	('IFI6', 'Gene', '2537', (172, 176))	('IFI6', 'Gene', (10, 14))	('mitochondrial supercomplex assembly', 'Protein', (75, 110))	('IFI6', 'Gene', (172, 176))	('oxidative phosphorylation dysfunction', 'MPA', (127, 164))	('mitochondrial', 'MPA', (25, 38))
838992	32727517	Furthermore, energy starvation induced by IFI6 inhibition drives endoplasmic reticulum stress through disrupting endoplasmic reticulum calcium uptake, which upregulates NOX4-derived ROS production in an ATF3-dependent manner.	('endoplasmic reticulum calcium uptake', 'MPA', (113, 149))	('ROS', 'Chemical', 'MESH:D017382', (182, 185))	('inhibition', 'Var', (47, 57))	('disrupting', 'NegReg', (102, 112))	('NOX4', 'Gene', '50507', (169, 173))	('calcium', 'Chemical', 'MESH:D002118', (135, 142))	('ATF3', 'Gene', '467', (203, 207))	('upregulates', 'PosReg', (157, 168))	('IFI6', 'Gene', '2537', (42, 46))	('IFI6', 'Gene', (42, 46))	('NOX4', 'Gene', (169, 173))	('ATF3', 'Gene', (203, 207))
839000	32727517	In contrast, ROS can enhance chronic inflammation and induce genotoxic damage in cancer cells.	('ROS', 'Var', (13, 16))	('genotoxic damage', 'Disease', (61, 77))	('enhance', 'PosReg', (21, 28))	('inflammation', 'Disease', 'MESH:D007249', (37, 49))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('genotoxic damage', 'Disease', 'MESH:D009422', (61, 77))	('cancer', 'Disease', (81, 87))	('inflammation', 'Disease', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('induce', 'Reg', (54, 60))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))
839006	32727517	As a byproduct of oxidative metabolism, ROS are released through the electron transport chain (ETC), and aberrant ROS production consequently profoundly influences tumor initiation and progression, as stated previously.	('tumor', 'Disease', (164, 169))	('influences', 'Reg', (153, 163))	('ROS', 'Chemical', 'MESH:D017382', (114, 117))	('ROS', 'Protein', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('progression', 'CPA', (185, 196))	('aberrant', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('ROS', 'Chemical', 'MESH:D017382', (40, 43))
839007	32727517	As a player in the redox balance, the endoplasmic reticulum (ER) has a well-established role in protein synthesis/folding, which is highly sensitive to cellular redox dynamics, and dysregulation of disulfide bond formation due to endoplasmic stress ultimately induces ER oxidative stress and aberrant ER function.	('induces', 'Reg', (260, 267))	('ER function', 'MPA', (301, 312))	('dysregulation', 'Var', (181, 194))	('oxidative stress', 'Phenotype', 'HP:0025464', (271, 287))	('disulfide', 'Chemical', 'MESH:D004220', (198, 207))	('ER oxidative stress', 'MPA', (268, 287))
839016	32727517	Finally, we found that IFI6 inhibition induced ATP deprivation-mediated ER stress, which in turn elevated NOX4 expression in an ATF3-dependent manner and enhanced ROS production.	('elevated', 'PosReg', (97, 105))	('ATF3', 'Gene', (128, 132))	('NOX4', 'Gene', (106, 110))	('IFI6', 'Gene', '2537', (23, 27))	('ATP', 'Chemical', 'MESH:D000255', (47, 50))	('IFI6', 'Gene', (23, 27))	('enhanced', 'PosReg', (154, 162))	('enhanced ROS production', 'Phenotype', 'HP:0025464', (154, 177))	('inhibition', 'Var', (28, 38))	('ROS', 'Chemical', 'MESH:D017382', (163, 166))	('NOX4', 'Gene', '50507', (106, 110))	('ROS production', 'MPA', (163, 177))	('ATF3', 'Gene', '467', (128, 132))
839017	32727517	Therefore, disrupting IFI6 is a promising therapeutic strategy for ESCC.	('IFI6', 'Gene', (22, 26))	('ESCC', 'Disease', (67, 71))	('IFI6', 'Gene', '2537', (22, 26))	('disrupting', 'Var', (11, 21))
839018	32727517	Lipofectamine 3000 (L3000015), MitoSOX (M36008), carboxy-H2DCFDA (C400) and the anti-IFI6 antibody (1:1000, PA5-99824) were purchased from Invitrogen (CA, USA).	('L3000015', 'Var', (20, 28))	('M36008', 'Var', (40, 46))	('IFI6', 'Gene', '2537', (85, 89))	('IFI6', 'Gene', (85, 89))	('C400', 'Var', (66, 70))	('Lipofectamine', 'Chemical', 'MESH:C086724', (0, 13))	('carboxy-H2DCFDA', 'Chemical', '-', (49, 64))
839019	32727517	RPMI-1640 (72400047), penicillin and streptomycin (10378016), and Fetal bovine serum (FBS) (16140071) were obtained from Gibco (CA, USA).	('penicillin', 'Chemical', 'MESH:D010406', (22, 32))	('streptomycin', 'Chemical', 'MESH:D013307', (37, 49))	('RPMI-1640', 'Chemical', '-', (0, 9))	('16140071', 'Var', (92, 100))	('10378016', 'Var', (51, 59))	('72400047', 'Var', (11, 19))
839020	32727517	N-acetyl-L-cysteine (NAC) (A7250), PEG-catalase (CAT) (C1345), dithiothreitol (DDT) (45839), MitoTEMPO (SML0737), ATP (A6559), BAPTA-AM (A4926), Phenformin (PHE) (P7045), Cyclopiazonic acid (CPA) (C1530), Tunicamycin (Tunica) (654380) and Thapsigargin (Tg) (T9033) were purchased from Sigma-Aldrich (Munich, Germany).	('BAPTA', 'Chemical', 'MESH:C025603', (127, 132))	('MitoTEMPO', 'Chemical', 'MESH:C555916', (93, 102))	('Thapsigargin', 'Chemical', 'MESH:D019284', (239, 251))	('NAC', 'Chemical', 'MESH:D000111', (21, 24))	('CAT', 'Gene', '847', (49, 52))	('DDT', 'Gene', (79, 82))	('CPA', 'Chemical', 'MESH:C000543', (191, 194))	('Cyclopiazonic acid', 'Chemical', 'MESH:C000543', (171, 189))	('PEG-catalase', 'Gene', '847', (35, 47))	('N-acetyl-L-cysteine', 'Chemical', 'MESH:D000111', (0, 19))	('ATP', 'Chemical', 'MESH:D000255', (114, 117))	('Tunicamycin', 'Chemical', 'MESH:D014415', (205, 216))	('dithiothreitol', 'Chemical', 'MESH:D004229', (63, 77))	('P7045', 'Var', (163, 168))	('CAT', 'Gene', (49, 52))	('PEG-catalase', 'Gene', (35, 47))	('PHE', 'Chemical', 'MESH:D010629', (157, 160))	('Tunica', 'Chemical', 'MESH:D014415', (205, 211))	('C1530', 'Var', (197, 202))	('Tg', 'Chemical', 'MESH:D019284', (253, 255))	('Phenformin', 'Chemical', 'MESH:D010629', (145, 155))	('654380', 'Var', (227, 233))	('DDT', 'Gene', '1652', (79, 82))	('Tunica', 'Chemical', 'MESH:D014415', (218, 224))
839026	32727517	The human ESCC cell lines Eca109, TE-1, Ec9706, Kyse150, and Kyse410 and the normal esophageal squamous epithelial cell line Het-1a were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China).	('human', 'Species', '9606', (4, 9))	('TE-1', 'CellLine', 'CVCL:1759', (34, 38))	('Kyse410', 'Var', (61, 68))	('Ec9706', 'Var', (40, 46))	('Ec9706', 'CellLine', 'CVCL:E307', (40, 46))	('Het-1', 'CellLine', 'CVCL:3702', (125, 130))
839079	32727517	Furthermore, different fragments (containing bp - 3000 to + 1, - 2000 to + 1, or - 1000 to + 1) of the human NOX4 promoter were synthesized and subcloned into the pGL3 vector (Promega, WI, USA).	('human', 'Species', '9606', (103, 108))	('pGL3', 'Gene', (163, 167))	('NOX4', 'Gene', '50507', (109, 113))	('NOX4', 'Gene', (109, 113))	('pGL3', 'Gene', '6391', (163, 167))	('bp - 3000 to + 1', 'Var', (45, 61))
839095	32727517	Consistent with this observation, statistical analysis revealed that aberrant IFI6 protein levels were significantly correlated with tumor grade, the depth of invasion, TNM stage (Table S1).	('IFI6', 'Gene', '2537', (78, 82))	('IFI6', 'Gene', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('aberrant', 'Var', (69, 77))	('TNM', 'Gene', '10178', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('TNM', 'Gene', (169, 172))	('correlated', 'Reg', (117, 127))
839097	32727517	1f, high IFI6 expression predicted an unfavorable prognosis (IFI6-High vs. IFI6-Medium, Plog rank = 0.036; IFI6-Medium v.s IFI6-Low, Plog rank = 0.012; Plog rank trend < 0.001).	('IFI6', 'Gene', '2537', (61, 65))	('IFI6', 'Gene', '2537', (75, 79))	('IFI6', 'Gene', '2537', (123, 127))	('IFI6', 'Gene', (75, 79))	('IFI6', 'Gene', (61, 65))	('IFI6', 'Gene', (123, 127))	('high', 'Var', (4, 8))	('IFI6', 'Gene', '2537', (107, 111))	('IFI6', 'Gene', (107, 111))	('IFI6', 'Gene', '2537', (9, 13))	('IFI6', 'Gene', (9, 13))
839116	32727517	Consistent with the EdU assay results, IFI6 inhibition significantly induced ESCC cell apoptosis (Fig.	('IFI6', 'Gene', (39, 43))	('inhibition', 'Var', (44, 54))	('IFI6', 'Gene', '2537', (39, 43))	('ESCC', 'Disease', (77, 81))	('induced', 'Reg', (69, 76))
839117	32727517	In the reciprocal experiment, cell proliferation markedly increased by IFI6 overexpression, whereas ESCC cell apoptosis was significantly inhibited following IFI6 overexpression (Figure S2A-C).	('IFI6', 'Gene', '2537', (71, 75))	('increased', 'PosReg', (58, 67))	('cell proliferation', 'CPA', (30, 48))	('IFI6', 'Gene', (71, 75))	('overexpression', 'Var', (76, 90))	('IFI6', 'Gene', '2537', (158, 162))	('IFI6', 'Gene', (158, 162))	('inhibited', 'NegReg', (138, 147))
839119	32727517	2c, f, g), we then investigated cellular ROS levels following IFI6 silencing.	('IFI6', 'Gene', (62, 66))	('silencing', 'Var', (67, 76))	('IFI6', 'Gene', '2537', (62, 66))	('ROS', 'Chemical', 'MESH:D017382', (41, 44))
839120	32727517	IFI6 inhibition significantly enhanced the generation of cellular ROS, as represented by the live cell ROS indicator carboxy-H2DCFDA (Fig.	('enhanced', 'PosReg', (30, 38))	('inhibition', 'Var', (5, 15))	('ROS', 'Chemical', 'MESH:D017382', (66, 69))	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('IFI6', 'Gene', '2537', (0, 4))	('carboxy-H2DCFDA', 'Chemical', '-', (117, 132))	('IFI6', 'Gene', (0, 4))	('cellular ROS', 'MPA', (57, 69))
839122	32727517	Accordingly, we sought to determine whether the augmented cellular oxidative environment caused by altered IFI6 expression is responsible for the reduction in cell viability.	('augmented', 'PosReg', (48, 57))	('cellular oxidative environment', 'MPA', (58, 88))	('IFI6', 'Gene', '2537', (107, 111))	('IFI6', 'Gene', (107, 111))	('cell', 'MPA', (159, 163))	('altered', 'Var', (99, 106))	('reduction', 'NegReg', (146, 155))	('expression', 'MPA', (112, 122))
839129	32727517	4b, Figure S3B), which supported the role of ROS in the IFI6 silencing-induced reduction in cell viability.	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('silencing-induced', 'Var', (61, 78))	('cell viability', 'CPA', (92, 106))	('IFI6', 'Gene', '2537', (56, 60))	('reduction', 'NegReg', (79, 88))	('IFI6', 'Gene', (56, 60))
839132	32727517	To explore the role of mitochondria in ROS generation after alterations in IFI6 expression, we used the mitochondrial ROS-specific probe MitoSOX to detect mitochondrial ROS production in Eca109 and TE-1 cells.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('IFI6', 'Gene', '2537', (75, 79))	('IFI6', 'Gene', (75, 79))	('ROS', 'Chemical', 'MESH:D017382', (169, 172))	('ROS', 'Chemical', 'MESH:D017382', (118, 121))	('alterations', 'Var', (60, 71))	('mitochondrial ROS production', 'MPA', (155, 183))	('TE-1', 'CellLine', 'CVCL:1759', (198, 202))
839133	32727517	IFI6 silencing led to an elevation in mitochondrial ROS levels, whereas mitochondrial ROS production was significantly inhibited in cells overexpressing IFI6 (Fig.	('mitochondrial ROS production', 'MPA', (72, 100))	('IFI6', 'Gene', '2537', (153, 157))	('mitochondrial ROS levels', 'MPA', (38, 62))	('silencing', 'Var', (5, 14))	('IFI6', 'Gene', '2537', (0, 4))	('ROS', 'Chemical', 'MESH:D017382', (86, 89))	('inhibited', 'NegReg', (119, 128))	('IFI6', 'Gene', (0, 4))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('elevation', 'PosReg', (25, 34))	('IFI6', 'Gene', (153, 157))
839140	32727517	We next sought to determine whether inhibiting calcium uptake by mitochondria would reverse IFI6 silencing-induced mitochondrial ROS production.	('IFI6', 'Gene', '2537', (92, 96))	('IFI6', 'Gene', (92, 96))	('mitochondrial ROS production', 'MPA', (115, 143))	('silencing-induced', 'Var', (97, 114))	('calcium', 'Chemical', 'MESH:D002118', (47, 54))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))
839143	32727517	Based on the above findings, we sought to determine whether the abundance of IFI6 might modulate the expression of mitochondrial calcium channels.	('abundance', 'Var', (64, 73))	('IFI6', 'Gene', '2537', (77, 81))	('IFI6', 'Gene', (77, 81))	('mitochondrial', 'MPA', (115, 128))	('modulate', 'Reg', (88, 96))	('calcium', 'Chemical', 'MESH:D002118', (129, 136))	('expression', 'MPA', (101, 111))
839148	32727517	5g-h, treatment with this mitochondrial ROS scavenger completely reversed the IFI6 silencing-induced increase in mitochondrial Ca2+ uptake.	('IFI6', 'Gene', '2537', (78, 82))	('IFI6', 'Gene', (78, 82))	('silencing-induced', 'Var', (83, 100))	('increase', 'PosReg', (101, 109))	('mitochondrial Ca2+ uptake', 'MPA', (113, 138))	('ROS', 'Chemical', 'MESH:D017382', (40, 43))	('Ca2+', 'Chemical', 'MESH:D000069285', (127, 131))
839149	32727517	Furthermore, following IFI6 ablation, pharmacological inhibition of MCU with DS16570511 partially prevented IFI6 silencing-induced mitochondrial ROS generation (Fig.	('prevented', 'NegReg', (98, 107))	('IFI6', 'Gene', '2537', (23, 27))	('IFI6', 'Gene', (23, 27))	('silencing-induced', 'NegReg', (113, 130))	('ROS', 'Chemical', 'MESH:D017382', (145, 148))	('mitochondrial ROS generation', 'MPA', (131, 159))	('IFI6', 'Gene', '2537', (108, 112))	('IFI6', 'Gene', (108, 112))	('DS16570511', 'Chemical', '-', (77, 87))	('DS16570511', 'Var', (77, 87))
839150	32727517	Taken together, these observations imply that after IFI6 knockdown, the increased level of mitochondrial ROS may disrupt the redox regulation of the mitochondrial MCU, which in turn leads to mitochondrial calcium overload and, subsequently, mitochondrial ROS accumulation.	('ROS', 'Chemical', 'MESH:D017382', (105, 108))	('ROS', 'Chemical', 'MESH:D017382', (255, 258))	('calcium', 'Chemical', 'MESH:D002118', (205, 212))	('increased', 'PosReg', (72, 81))	('leads to', 'Reg', (182, 190))	('knockdown', 'Var', (57, 66))	('IFI6', 'Gene', '2537', (52, 56))	('redox regulation of the mitochondrial MCU', 'MPA', (125, 166))	('IFI6', 'Gene', (52, 56))	('mitochondrial calcium overload', 'MPA', (191, 221))	('disrupt', 'NegReg', (113, 120))	('accumulation', 'PosReg', (259, 271))	('mitochondrial ROS', 'MPA', (241, 258))
839152	32727517	The driving contributor to mitochondrial ROS generation following IFI6 ablation remains to be explored.	('mitochondrial ROS generation', 'MPA', (27, 55))	('ROS', 'Chemical', 'MESH:D017382', (41, 44))	('ablation', 'Var', (71, 79))	('IFI6', 'Gene', '2537', (66, 70))	('IFI6', 'Gene', (66, 70))
839155	32727517	To clarify the alternative reason why mitochondrial ROS production was increased following IFI6 knockdown, we measured ATP levels in ESCC cell lines after IFI6 silencing or overexpression and compared them with those in the corresponding parental cell lines.	('overexpression', 'PosReg', (173, 187))	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('IFI6', 'Gene', (91, 95))	('silencing', 'Var', (160, 169))	('IFI6', 'Gene', '2537', (91, 95))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('increased', 'PosReg', (71, 80))	('IFI6', 'Gene', '2537', (155, 159))	('mitochondrial ROS production', 'MPA', (38, 66))	('IFI6', 'Gene', (155, 159))
839159	32727517	6c, the basal cellular OCR and maximum respiration rate were significantly elevated in IFI6-overexpressing Eca109 cells compared with parental Eca109 cells.	('mum', 'Gene', (35, 38))	('elevated', 'PosReg', (75, 83))	('mum', 'Gene', '56925', (35, 38))	('IFI6', 'Gene', '2537', (87, 91))	('basal cellular OCR', 'CPA', (8, 26))	('IFI6', 'Gene', (87, 91))	('Eca109', 'Var', (107, 113))
839168	32727517	These observations confirmed that altered IFI6 expression levels might play a role in energy handling and mitochondrial dysfunction.	('mitochondrial dysfunction', 'Disease', (106, 131))	('altered', 'Var', (34, 41))	('energy handling', 'MPA', (86, 101))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (106, 131))	('play', 'Reg', (71, 75))	('role', 'Reg', (78, 82))	('IFI6', 'Gene', '2537', (42, 46))	('IFI6', 'Gene', (42, 46))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (106, 131))	('expression levels', 'MPA', (47, 64))
839172	32727517	Moreover, silencing IFI6 decreased the signal of NDUFB8, RISP or COXIV at the CI + CIII2 + CIVn and CI + CIII2 positions compared with those in parental ESCC cells.	('signal', 'MPA', (39, 45))	('RISP', 'Gene', (57, 61))	('CIII2 +', 'Chemical', '-', (83, 90))	('NDUFB8', 'Gene', '4714', (49, 55))	('decreased', 'NegReg', (25, 34))	('IFI6', 'Gene', '2537', (20, 24))	('NDUFB8', 'Gene', (49, 55))	('IFI6', 'Gene', (20, 24))	('COXIV', 'Gene', '1327', (65, 70))	('COXIV', 'Gene', (65, 70))	('RISP', 'Gene', '7386', (57, 61))	('silencing', 'Var', (10, 19))
839174	32727517	In addition, IFI6 ablation resulted in a decreased signal at the CIII2 + CIVn position, while overexpressing IFI6 had the opposite effect, as detected by immunoblotting with anti-RISP and anti-COXIV antibodies (Fig.	('IFI6', 'Gene', '2537', (109, 113))	('IFI6', 'Gene', (109, 113))	('CIII2 +', 'Chemical', '-', (65, 72))	('COXIV', 'Gene', '1327', (193, 198))	('IFI6', 'Gene', (13, 17))	('RISP', 'Gene', '7386', (179, 183))	('IFI6', 'Gene', '2537', (13, 17))	('decreased', 'NegReg', (41, 50))	('RISP', 'Gene', (179, 183))	('COXIV', 'Gene', (193, 198))	('signal', 'MPA', (51, 57))	('ablation', 'Var', (18, 26))
839178	32727517	Collectively, our data suggested two causes of elevated mitochondrial ROS following IFI6 silencing: first and the driving cause, impaired respiratory complex function and supercomplex assembly, which decreases the efficiency of OXPHOS and in its turn accumulates mitochondrial ROS; Secondly, the altered redox state of MCU induces mitochondrial Ca2+ overload and subsequently adds to mitochondrial ROS production.	('ROS', 'Chemical', 'MESH:D017382', (398, 401))	('Ca2+', 'Chemical', 'MESH:D000069285', (345, 349))	('IFI6', 'Gene', '2537', (84, 88))	('IFI6', 'Gene', (84, 88))	('mitochondrial Ca2+ overload', 'MPA', (331, 358))	('induces', 'Reg', (323, 330))	('ROS', 'Chemical', 'MESH:D017382', (277, 280))	('decreases', 'NegReg', (200, 209))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('impaired respiratory complex', 'Phenotype', 'HP:0008972', (129, 157))	('accumulates', 'PosReg', (251, 262))	('adds', 'PosReg', (376, 380))	('mitochondrial ROS', 'MPA', (263, 280))	('silencing', 'Var', (89, 98))	('mitochondrial ROS production', 'MPA', (384, 412))	('elevated', 'PosReg', (47, 55))	('efficiency', 'MPA', (214, 224))	('OXPHOS', 'MPA', (228, 234))	('mitochondrial ROS', 'MPA', (56, 73))
839181	32727517	As expected, IFI6 depletion led to a dramatic increase in cellular ROS levels.	('cellular ROS levels', 'MPA', (58, 77))	('IFI6', 'Gene', '2537', (13, 17))	('IFI6', 'Gene', (13, 17))	('increase', 'PosReg', (46, 54))	('ROS', 'Chemical', 'MESH:D017382', (67, 70))	('depletion', 'Var', (18, 27))
839184	32727517	8a, b), implying that in addition to mitochondria, IFI6 silencing induces ROS production via another source and that supplying cells with exogenous ATP could block this pathway.	('silencing', 'Var', (56, 65))	('ROS production', 'MPA', (74, 88))	('induces', 'Reg', (66, 73))	('IFI6', 'Gene', '2537', (51, 55))	('IFI6', 'Gene', (51, 55))	('ATP', 'Chemical', 'MESH:D000255', (148, 151))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))
839187	32727517	Among a panel of NOX isoforms, NOX4 was substantially upregulated following IFI6 silencing in Eca109 and TE-1 cells (Fig.	('upregulated', 'PosReg', (54, 65))	('NOX4', 'Gene', (31, 35))	('TE-1', 'CellLine', 'CVCL:1759', (105, 109))	('silencing', 'Var', (81, 90))	('IFI6', 'Gene', (76, 80))	('IFI6', 'Gene', '2537', (76, 80))	('NOX4', 'Gene', '50507', (31, 35))
839189	32727517	As shown previously, cellular ROS levels increased after IFI6 ablation, while this increase was mitigated after treatment with NOX4 shRNA.	('IFI6', 'Gene', '2537', (57, 61))	('increased', 'PosReg', (41, 50))	('IFI6', 'Gene', (57, 61))	('cellular ROS levels', 'MPA', (21, 40))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))	('NOX4', 'Gene', '50507', (127, 131))	('ROS levels increased', 'Phenotype', 'HP:0025464', (30, 50))	('ablation', 'Var', (62, 70))	('NOX4', 'Gene', (127, 131))
839199	32727517	Among these ER stress mediators, the transcription factor ATF3 exhibited the most dramatic elevation following IFI6 knockdown, implying that ATF3 might play a pivotal role in IFI6 silencing-mediated ER stress.	('ATF3', 'Gene', (58, 62))	('ATF3', 'Gene', (141, 145))	('elevation', 'PosReg', (91, 100))	('IFI6', 'Gene', '2537', (175, 179))	('knockdown', 'Var', (116, 125))	('IFI6', 'Gene', (175, 179))	('IFI6', 'Gene', '2537', (111, 115))	('ATF3', 'Gene', '467', (58, 62))	('transcription', 'MPA', (37, 50))	('ATF3', 'Gene', '467', (141, 145))	('IFI6', 'Gene', (111, 115))
839201	32727517	These results indicate that IFI6 silencing is the initial event and is followed by ATP shortage and ER stress induction with subsequent elevation of NOX4 expression, which finally leads to increased cellular ROS levels independent of the mitochondrial source.	('ROS', 'Chemical', 'MESH:D017382', (208, 211))	('ATP', 'Chemical', 'MESH:D000255', (83, 86))	('NOX4', 'Gene', '50507', (149, 153))	('elevation', 'PosReg', (136, 145))	('silencing', 'Var', (33, 42))	('expression', 'MPA', (154, 164))	('IFI6', 'Gene', (28, 32))	('IFI6', 'Gene', '2537', (28, 32))	('increased', 'PosReg', (189, 198))	('NOX4', 'Gene', (149, 153))	('increased cellular ROS', 'Phenotype', 'HP:0025464', (189, 211))	('ATP shortage', 'Disease', (83, 95))	('cellular ROS levels', 'MPA', (199, 218))
839204	32727517	As predicted, ATF3 silencing inhibited the increase in NOX4 expression induced by IFI6 silencing, indicating that ATF3 may be the predominant transcriptional regulator of NOX4 upon alteration of IFI6 expression (Fig.	('expression', 'MPA', (60, 70))	('silencing', 'Var', (87, 96))	('inhibited', 'NegReg', (29, 38))	('NOX4', 'Gene', (171, 175))	('NOX4', 'Gene', '50507', (55, 59))	('IFI6', 'Gene', (82, 86))	('IFI6', 'Gene', '2537', (82, 86))	('silencing', 'Var', (19, 28))	('NOX4', 'Gene', (55, 59))	('alteration', 'Var', (181, 191))	('ATF3', 'Gene', (114, 118))	('IFI6', 'Gene', (195, 199))	('ATF3', 'Gene', '467', (14, 18))	('IFI6', 'Gene', '2537', (195, 199))	('NOX4', 'Gene', '50507', (171, 175))	('ATF3', 'Gene', (14, 18))	('ATF3', 'Gene', '467', (114, 118))
839205	32727517	We next explored the molecular mechanism could be responsible for the regulation of ER stress and subsequently ATF3 activation following IFI6 alteration.	('alteration', 'Var', (142, 152))	('ATF3', 'Gene', (111, 115))	('IFI6', 'Gene', '2537', (137, 141))	('IFI6', 'Gene', (137, 141))	('activation', 'PosReg', (116, 126))	('ATF3', 'Gene', '467', (111, 115))
839206	32727517	For this, we constructed plasmids containing ATF3 promoter fragments and transfected them into ESCC cells with or without IFI6 overexpression.	('IFI6', 'Gene', '2537', (122, 126))	('IFI6', 'Gene', (122, 126))	('ATF3', 'Gene', '467', (45, 49))	('fragments', 'Var', (59, 68))	('ATF3', 'Gene', (45, 49))
839213	32727517	9d and S7B, IFI6 knockdown decreased ER Ca2+ uptake, which was reversed by MFN2 upregulation.	('IFI6', 'Gene', '2537', (12, 16))	('IFI6', 'Gene', (12, 16))	('decreased', 'NegReg', (27, 36))	('ER Ca2+ uptake', 'MPA', (37, 51))	('MFN2', 'Gene', (75, 79))	('Ca2+', 'Chemical', 'MESH:D000069285', (40, 44))	('knockdown', 'Var', (17, 26))	('MFN2', 'Gene', '9927', (75, 79))
839225	32727517	Moreover, mutation of either region #1 (AAGGACTCACT) or region #2 (ACTAATGTCATG) markedly suppressed ATF3-induced transcriptional activation of NOX4 (Fig.	('ATF3', 'Gene', (101, 105))	('NOX4', 'Gene', (144, 148))	('CAT', 'Gene', '847', (75, 78))	('CAT', 'Gene', (75, 78))	('mutation', 'Var', (10, 18))	('NOX4', 'Gene', '50507', (144, 148))	('suppressed', 'NegReg', (90, 100))	('ATF3', 'Gene', '467', (101, 105))
839229	32727517	Notably, tumor growth was significantly inhibited following IFI6 knockdown, whereas upregulation of IFI6 produced the opposite effect (Fig.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('IFI6', 'Gene', '2537', (60, 64))	('inhibited', 'NegReg', (40, 49))	('IFI6', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('IFI6', 'Gene', (100, 104))	('tumor', 'Disease', (9, 14))	('IFI6', 'Gene', '2537', (100, 104))	('knockdown', 'Var', (65, 74))
839234	32727517	We observed that IFI6 knockdown compromised the growth of primary tumors in xenograft model, and this effect was partially rescued by DS16570511 administration (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('primary tumors', 'Disease', (58, 72))	('IFI6', 'Gene', '2537', (17, 21))	('IFI6', 'Gene', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('primary tumors', 'Disease', 'MESH:D001932', (58, 72))	('knockdown', 'Var', (22, 31))	('DS16570511', 'Chemical', '-', (134, 144))	('compromised', 'NegReg', (32, 43))	('DS16570511', 'Var', (134, 144))
839237	32727517	As expected, IFI6 overexpression promoted ESCC cells proliferation, while this effect was completely reversed after PHE treatment (Fig.	('promoted', 'PosReg', (33, 41))	('IFI6', 'Gene', '2537', (13, 17))	('IFI6', 'Gene', (13, 17))	('overexpression', 'Var', (18, 32))	('ESCC', 'Disease', (42, 46))	('PHE', 'Chemical', 'MESH:D010629', (116, 119))
839244	32727517	Mechanistically, we showed that IFI6 ablation inhibited OXPHOS efficiency and mitochondrial supercomplex assembly, which appeared to contribute to the decreased mitochondrial ROS generation in ESCC cells.	('IFI6', 'Gene', (32, 36))	('mitochondrial ROS generation', 'MPA', (161, 189))	('mitochondrial supercomplex assembly', 'MPA', (78, 113))	('ROS', 'Chemical', 'MESH:D017382', (175, 178))	('ablation', 'Var', (37, 45))	('decreased', 'NegReg', (151, 160))	('OXPHOS efficiency', 'MPA', (56, 73))	('inhibited', 'NegReg', (46, 55))	('IFI6', 'Gene', '2537', (32, 36))
839246	32727517	In addition, our rescue experiments showed that IFI6 silencing elevated ER-derived ROS accumulation by driving ER stress accompanied by a substantial increase in ATF3 expression and subsequent transcriptional activation of NOX4.	('ATF3', 'Gene', '467', (162, 166))	('ATF3', 'Gene', (162, 166))	('NOX4', 'Gene', (223, 227))	('IFI6', 'Gene', (48, 52))	('NOX4', 'Gene', '50507', (223, 227))	('transcriptional', 'MPA', (193, 208))	('ER-derived ROS accumulation', 'MPA', (72, 99))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('silencing', 'Var', (53, 62))	('IFI6', 'Gene', '2537', (48, 52))	('increase', 'PosReg', (150, 158))	('elevated', 'PosReg', (63, 71))	('ER stress', 'MPA', (111, 120))	('expression', 'MPA', (167, 177))
839248	32727517	The induction of ER stress and concomitant upregulation of ATF3 following IFI6 silencing is possibly mediated by the decreased ER Ca2+ pools due to the reduced activity of SERCA.	('IFI6', 'Gene', '2537', (74, 78))	('IFI6', 'Gene', (74, 78))	('ATF3', 'Gene', '467', (59, 63))	('decreased', 'NegReg', (117, 126))	('reduced', 'NegReg', (152, 159))	('activity', 'MPA', (160, 168))	('SERCA', 'Gene', '489', (172, 177))	('SERCA', 'Gene', (172, 177))	('upregulation', 'PosReg', (43, 55))	('silencing', 'Var', (79, 88))	('ER Ca2+ pools', 'MPA', (127, 140))	('ATF3', 'Gene', (59, 63))	('Ca2+', 'Chemical', 'MESH:D000069285', (130, 134))
839249	32727517	Finally, via knockdown and overexpression experiments, we validated the antiproliferative effect of IFI6 depletion in a nude mouse model of ESCC.	('antiproliferative effect', 'CPA', (72, 96))	('depletion', 'Var', (105, 114))	('mouse', 'Species', '10090', (125, 130))	('ESCC', 'Disease', (140, 144))	('IFI6', 'Gene', (100, 104))	('IFI6', 'Gene', '2537', (100, 104))
839250	32727517	Collectively, these observations imply the potential therapeutic value of IFI6 inhibition in ESCC.	('inhibition', 'Var', (79, 89))	('ESCC', 'Disease', (93, 97))	('IFI6', 'Gene', '2537', (74, 78))	('IFI6', 'Gene', (74, 78))
839254	32727517	IFI6 silencing promoted ROS production, consistent with previous findings by another group.	('promoted', 'PosReg', (15, 23))	('ROS production', 'MPA', (24, 38))	('ROS', 'Chemical', 'MESH:D017382', (24, 27))	('silencing', 'Var', (5, 14))	('IFI6', 'Gene', '2537', (0, 4))	('IFI6', 'Gene', (0, 4))
839259	32727517	Jang and Javadov recently showed that complex I and II subunit depletion elevated mitochondrial ROS production in the heart but impaired respirasome formation and ATP production.	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('mitochondrial ROS production', 'MPA', (82, 110))	('respirasome formation', 'MPA', (137, 158))	('ATP production', 'MPA', (163, 177))	('elevated mitochondrial ROS production', 'Phenotype', 'HP:0025464', (73, 110))	('depletion', 'Var', (63, 72))	('ATP', 'Chemical', 'MESH:D000255', (163, 166))	('elevated', 'PosReg', (73, 81))	('impaired', 'NegReg', (128, 136))
839260	32727517	A As altered IFI6 expression can alter cellular ATP production and OXPHOS efficiency, we hypothesized that the decreased mitochondrial supercomplex assembly following IFI6 silencing may enhance mitochondrial ROS production, reflecting the efficiency of the OXPHOS complex.	('alter', 'Reg', (33, 38))	('IFI6', 'Gene', '2537', (13, 17))	('IFI6', 'Gene', '2537', (167, 171))	('IFI6', 'Gene', (13, 17))	('IFI6', 'Gene', (167, 171))	('decreased', 'NegReg', (111, 120))	('mitochondrial ROS production', 'MPA', (194, 222))	('mitochondrial supercomplex assembly', 'MPA', (121, 156))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('ROS', 'Chemical', 'MESH:D017382', (208, 211))	('enhance', 'PosReg', (186, 193))	('silencing', 'Var', (172, 181))
839262	32727517	Consistent with this hypothesis, IFI6 depletion decreased the content of complexes I, III and IV in the mitochondrial supercomplex, while the expression of the individual respiratory complexes did not change.	('IFI6', 'Gene', (33, 37))	('decreased', 'NegReg', (48, 57))	('depletion', 'Var', (38, 47))	('content', 'MPA', (62, 69))	('IFI6', 'Gene', '2537', (33, 37))
839266	32727517	As calcium influx into mitochondria leads to the induction of programmed cell death, we assumed that dysregulated mitochondrial calcium dynamics could lead to mitochondrial dysfunction, contribute to ROS production, and ultimately induce cell apoptosis following IFI6 depletion.	('mitochondrial calcium dynamics', 'MPA', (114, 144))	('cell apoptosis', 'CPA', (238, 252))	('calcium', 'Chemical', 'MESH:D002118', (128, 135))	('IFI6', 'Gene', '2537', (263, 267))	('IFI6', 'Gene', (263, 267))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (159, 184))	('programmed cell', 'CPA', (62, 77))	('dysregulated', 'Var', (101, 113))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (159, 184))	('lead to', 'Reg', (151, 158))	('mitochondrial dysfunction', 'Disease', (159, 184))	('ROS production', 'MPA', (200, 214))	('calcium', 'Chemical', 'MESH:D002118', (3, 10))	('ROS', 'Chemical', 'MESH:D017382', (200, 203))	('induce', 'Reg', (231, 237))	('contribute', 'Reg', (186, 196))
839267	32727517	Indeed, we observed a significant increase in the Tg-induced mitochondrial Ca2+ uptake after IFI6 depletion.	('Ca2+', 'Chemical', 'MESH:D000069285', (75, 79))	('Tg', 'Chemical', 'MESH:D019284', (50, 52))	('depletion', 'Var', (98, 107))	('IFI6', 'Gene', '2537', (93, 97))	('increase', 'PosReg', (34, 42))	('IFI6', 'Gene', (93, 97))	('mitochondrial Ca2+ uptake', 'MPA', (61, 86))
839269	32727517	Calcium released from the ER and that present in the cytosol is transported into mitochondria via VDAC1, MCU, and NCLX; however, our expression analysis revealed no overt alterations in these components of the mitochondrial calcium uptake machinery upon IFI6 knockdown.	('VDAC1', 'Gene', (98, 103))	('knockdown', 'Var', (259, 268))	('NCLX', 'Gene', (114, 118))	('IFI6', 'Gene', '2537', (254, 258))	('IFI6', 'Gene', (254, 258))	('VDAC1', 'Gene', '7416', (98, 103))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	('calcium', 'Chemical', 'MESH:D002118', (224, 231))	('NCLX', 'Gene', '80024', (114, 118))
839271	32727517	showed that the redox regulation of MCU plays a role in mitochondrial calcium dynamics and oxidation; oxidation of MCU facilitated higher-order MCU oligomer formation and increased the MCU calcium uptake rate, mitochondrial ROS accumulation, and calcium overload-induced cell death.	('calcium', 'Chemical', 'MESH:D002118', (189, 196))	('oxidation', 'Var', (102, 111))	('calcium overload-induced cell death', 'CPA', (246, 281))	('ROS', 'Chemical', 'MESH:D017382', (224, 227))	('mitochondrial ROS accumulation', 'MPA', (210, 240))	('higher-order MCU oligomer formation', 'MPA', (131, 166))	('calcium', 'Chemical', 'MESH:D002118', (246, 253))	('facilitated', 'PosReg', (119, 130))	('MCU', 'Gene', (115, 118))	('MCU calcium uptake rate', 'CPA', (185, 208))	('calcium', 'Chemical', 'MESH:D002118', (70, 77))	('increased', 'PosReg', (171, 180))
839272	32727517	Consistent with this observation, pharmacological inhibition of MCU with DS16570511 partially prevented IFI6 silencing-induced mitochondrial ROS elevation.	('ROS elevation', 'Phenotype', 'HP:0025464', (141, 154))	('ROS', 'Chemical', 'MESH:D017382', (141, 144))	('DS16570511', 'Chemical', '-', (73, 83))	('DS16570511', 'Var', (73, 83))	('IFI6', 'Gene', '2537', (104, 108))	('prevented', 'NegReg', (94, 103))	('IFI6', 'Gene', (104, 108))	('mitochondrial ROS', 'MPA', (127, 144))	('elevation', 'PosReg', (145, 154))
839273	32727517	Taken together, these data suggest that the insufficient OXPHOS resulting from IFI6 silencing causes the accumulation of excess mitochondrial ROS, which promotes the oxidation of MCU, which in turns leads to increased MCU Ca2+ uptake and concomitant mitochondrial Ca2+ overload, disruption of mitochondrial Ca2+ dynamics further adds to ROS production.	('Ca2+', 'Chemical', 'MESH:D000069285', (222, 226))	('Ca2+', 'Chemical', 'MESH:D000069285', (264, 268))	('ROS', 'Chemical', 'MESH:D017382', (142, 145))	('silencing', 'Var', (84, 93))	('oxidation', 'MPA', (166, 175))	('ROS production', 'MPA', (337, 351))	('increased', 'PosReg', (208, 217))	('IFI6', 'Gene', (79, 83))	('IFI6', 'Gene', '2537', (79, 83))	('Ca2+', 'Chemical', 'MESH:D000069285', (307, 311))	('ROS', 'Chemical', 'MESH:D017382', (337, 340))	('MCU Ca2+ uptake', 'MPA', (218, 233))	('promotes', 'PosReg', (153, 161))	('mitochondrial Ca2+', 'MPA', (250, 268))
839278	32727517	Here, we demonstrated that IFI6 depletion led to induction of ER stress possibly mediated by an ATP shortage through interference with mitochondrial OXPHOS.	('depletion', 'Var', (32, 41))	('mitochondrial OXPHOS', 'MPA', (135, 155))	('IFI6', 'Gene', '2537', (27, 31))	('IFI6', 'Gene', (27, 31))	('ATP', 'Chemical', 'MESH:D000255', (96, 99))	('interference', 'NegReg', (117, 129))	('ER stress', 'MPA', (62, 71))
839283	32727517	However, additional studies were necessary to decipher how ER Ca2+ depletion mediated by IFI6 silencing contributes to ER stress and especially, the transcriptional activation of ATF3.	('silencing', 'Var', (94, 103))	('transcriptional activation', 'MPA', (149, 175))	('Ca2+', 'Chemical', 'MESH:D000069285', (62, 66))	('ATF3', 'Gene', '467', (179, 183))	('IFI6', 'Gene', '2537', (89, 93))	('contributes', 'Reg', (104, 115))	('IFI6', 'Gene', (89, 93))	('ER Ca2+ depletion', 'MPA', (59, 76))	('ER stress', 'MPA', (119, 128))	('ATF3', 'Gene', (179, 183))
839284	32727517	We also revealed that NOX4, which was identified as a key player in cellular ROS production following IFI6 knockdown, was regulated by ER stress and the associated transcription factor ATF3.	('knockdown', 'Var', (107, 116))	('NOX4', 'Gene', (22, 26))	('IFI6', 'Gene', '2537', (102, 106))	('IFI6', 'Gene', (102, 106))	('regulated', 'Reg', (122, 131))	('NOX4', 'Gene', '50507', (22, 26))	('ATF3', 'Gene', '467', (185, 189))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('ATF3', 'Gene', (185, 189))
839290	32727517	Mechanically, inhibition of IFI6 suppresses mitochondrial supercomplex formation, which leads to OXPHOS deficiency and concomitant mitochondrial ROS overproduction.	('mitochondrial ROS', 'MPA', (131, 148))	('mitochondrial supercomplex formation', 'MPA', (44, 80))	('suppresses', 'NegReg', (33, 43))	('OXPHOS deficiency', 'Disease', (97, 114))	('overproduction', 'PosReg', (149, 163))	('ROS', 'Chemical', 'MESH:D017382', (145, 148))	('IFI6', 'Gene', '2537', (28, 32))	('IFI6', 'Gene', (28, 32))	('leads to', 'Reg', (88, 96))	('inhibition', 'Var', (14, 24))	('OXPHOS deficiency', 'Disease', 'MESH:C535470', (97, 114))
839293	32727517	Taken together, our data indicated the carcinogenesis of IFI6 in ESCC and revealed that knockdown of IFI6 suppressed proliferation and induced apoptosis by increasing ROS accumulation.	('ROS accumulation', 'MPA', (167, 183))	('IFI6', 'Gene', '2537', (57, 61))	('ROS', 'Chemical', 'MESH:D017382', (167, 170))	('IFI6', 'Gene', (57, 61))	('carcinogenesis', 'Disease', (39, 53))	('proliferation', 'CPA', (117, 130))	('knockdown', 'Var', (88, 97))	('suppressed', 'NegReg', (106, 116))	('apoptosis', 'CPA', (143, 152))	('ESCC', 'Disease', (65, 69))	('IFI6', 'Gene', (101, 105))	('carcinogenesis', 'Disease', 'MESH:D063646', (39, 53))	('IFI6', 'Gene', '2537', (101, 105))	('increasing', 'PosReg', (156, 166))
839294	32727517	We further found that mitochondrial ROS accumulation is induced by the suppression of mitochondrial supercomplex assembly and mitochondrial calcium overload; IFI6 inhibition also upregulated NOX4-derived ROS production in an ATF3-dependent manner through ER stress induction.	('NOX4', 'Gene', '50507', (191, 195))	('IFI6', 'Gene', '2537', (158, 162))	('ATF3', 'Gene', (225, 229))	('IFI6', 'Gene', (158, 162))	('upregulated', 'PosReg', (179, 190))	('NOX4', 'Gene', (191, 195))	('mitochondrial ROS accumulation', 'MPA', (22, 52))	('calcium', 'Chemical', 'MESH:D002118', (140, 147))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('ROS', 'Chemical', 'MESH:D017382', (204, 207))	('ATF3', 'Gene', '467', (225, 229))	('inhibition', 'Var', (163, 173))
839305	32256021	It has been reported that LNs along recurrent laryngeal nerves (RLNs) are highly involved in esophageal carcinoma; in addition, LNs along RLNs are considered to be associated with cervical nodal metastasis and even an indication for cervical LN dissection.	('nodal', 'Gene', (189, 194))	('cervical nodal metastasis', 'Phenotype', 'HP:0025289', (180, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('associated', 'Reg', (164, 174))	('esophageal carcinoma', 'Disease', (93, 113))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (93, 113))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (93, 113))	('LNs', 'Var', (128, 131))	('nodal', 'Gene', '4838', (189, 194))
839363	31126307	Multivariate analyses showed that lung V20 (hazard ratio, 1.09; 95% CI: 1.04-1.14; p < 0.001) and lung V5 (hazard ratio, 1.02; 95% CI: 1.00-1.05; p = 0.03) were associated with OS when adjusting for surgical margin and pathological treatment response.	('lung V5', 'Var', (98, 105))	('OS', 'Chemical', '-', (177, 179))	('associated', 'Reg', (161, 171))	('lung V20', 'Var', (34, 42))
839419	31126307	Multivariate analysis showed that R1 resection (hazard ratio [HR], 3.63; 95% confidence interval [CI]: 1.59-8.28, p = 0.002), TRG 2/3 (HR, 2.84; 95% CI: 1.50-5.37, p = 0.001), lung V20 (HR, 1.09; 95% CI: 1.04-1.14; p < 0.001) and lung V5 (HR, 1.02; 95% CI: 1.00-1.05; p = 0.03) were associated with OS.	('R1 resection', 'Var', (34, 46))	('OS', 'Chemical', '-', (299, 301))	('lung V5', 'Var', (230, 237))	('lung V20', 'Var', (176, 184))	('TRG 2', 'Gene', '7196', (126, 131))	('TRG 2', 'Gene', (126, 131))	('associated', 'Reg', (283, 293))
839420	31126307	The R1 resection (HR, 4.16; 95% CI: 2.11-8.19, p < 0.001), TRG 2/3 (HR, 2.31; 95% CI: 1.30-4.12, p = 0.004), and lung V20 (HR, 1.07; 95% CI: 1.03-1.12; p = 0.001) were associated with PFS.	('associated', 'Reg', (168, 178))	('PFS', 'Disease', (184, 187))	('lung V20', 'Var', (113, 121))	('TRG 2', 'Gene', '7196', (59, 64))	('TRG 2', 'Gene', (59, 64))
839422	31126307	The OS and PFS were significantly lower in patients with lung V20 > 23% or V5 > 56%.	('V5 > 56', 'Var', (75, 82))	('OS', 'Chemical', '-', (4, 6))	('patients', 'Species', '9606', (43, 51))	('lower', 'NegReg', (34, 39))	('PFS', 'CPA', (11, 14))	('lung V20 > 23', 'Var', (57, 70))
839424	31126307	For lung V5 cutoff value of <=56 and > 56%, the 5-year OS and PFS were 81.5% vs. 23.4% (p < 0.001) and 66.7% vs. 29.7% (p < 0.001), respectively.	('lung V5', 'Gene', (4, 11))	('OS', 'Chemical', '-', (55, 57))	('> 56%', 'Var', (37, 42))
839429	31126307	Constraining the lung dose may minimize the risk of postoperative pulmonary complications and improve survival outcomes in patients with esophageal cancer receiving trimodal therapy.	('postoperative pulmonary complications', 'Disease', (52, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('trimodal', 'Chemical', '-', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('patients', 'Species', '9606', (123, 131))	('postoperative pulmonary complications', 'Disease', 'MESH:D011183', (52, 89))	('survival outcomes', 'CPA', (102, 119))	('Constraining', 'Var', (0, 12))	('improve', 'PosReg', (94, 101))	('pulmonary complications', 'Phenotype', 'HP:0006532', (66, 89))	('minimize', 'NegReg', (31, 39))	('esophageal cancer', 'Disease', (137, 154))
839434	31126307	We found that patients with either or both lung V20 > 23% and V5 > 56% had poorer survival outcomes than patients with both lung V20 <= 23% and V5 <= 56%.	('patients', 'Species', '9606', (105, 113))	('> 56%', 'Var', (65, 70))	('survival outcomes', 'CPA', (82, 99))	('patients', 'Species', '9606', (14, 22))	('poorer', 'NegReg', (75, 81))
839462	31126307	The use of a 41.4 Gy dose is increasing, and several studies also reported 41.4 Gy was associated with reduced perioperative mortality and increased rates of esophagectomy without negatively impacting OS, R0 resection, or complete pathologic response.	('41.4 Gy', 'Var', (75, 82))	('reduced', 'NegReg', (103, 110))	('increased', 'PosReg', (139, 148))	('OS', 'Chemical', '-', (201, 203))	('esophagectomy', 'Disease', (158, 171))	('perioperative', 'CPA', (111, 124))
839555	29348866	This study suggests that chromatin modifiers contribute to CD8+ T-cell exclusion and antigen presentation capacity of HPV-negative SCCHN, supporting that targeting of specific PMTs and/or PDMTs could enhance CD8+ T-cell infiltration and increase the proportion of patients that may benefit from immunotherapy.	('CD8', 'Gene', (208, 211))	('CD8', 'Gene', '925', (208, 211))	('increase', 'PosReg', (237, 245))	('PMTs', 'Gene', (176, 180))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', '925', (59, 62))	('PDMTs', 'Var', (188, 193))	('patients', 'Species', '9606', (264, 272))	('enhance', 'PosReg', (200, 207))
839561	29348866	Immune escape in SCCHN occurs through various mechanisms, including (1) exclusion/restriction of cytotoxic CD8+ T-cell trafficking in the tumor microenvironment, (2) suppression of anti-tumor immune response through activation of immune checkpoint molecules and their receptors, or infiltration of the tumor tissue by immune suppressive cells such as T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2 macrophages, (3) loss of tumor-associated antigens through somatic mutations or decreased expression of HLA or the antigen presenting machinery (APM) components, and (4) lack of or decreased expression of immune active tumor-associated antigens.	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('SCCHN', 'Disease', (17, 22))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (186, 191))	('APM', 'Gene', (572, 575))	('tumor', 'Phenotype', 'HP:0002664', (452, 457))	('mutations', 'Var', (494, 503))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('CD8', 'Gene', (107, 110))	('expression', 'MPA', (517, 527))	('lack', 'NegReg', (597, 601))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (646, 651))	('decreased', 'NegReg', (507, 516))	('tumor', 'Disease', 'MESH:D009369', (646, 651))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('expression', 'MPA', (618, 628))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (302, 307))	('HLA', 'Protein', (531, 534))	('tumor', 'Disease', (452, 457))	('CD8', 'Gene', '925', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('tumor', 'Phenotype', 'HP:0002664', (646, 651))	('decreased', 'NegReg', (608, 617))	('APM', 'Gene', '290', (572, 575))	('tumor', 'Disease', 'MESH:D009369', (452, 457))	('loss', 'NegReg', (444, 448))
839564	29348866	The Cancer Genome Atlas (TCGA) recently revealed a plethora of genetic alterations in chromatin modifiers in multiple cancer types, including SCCHN.	('genetic alterations', 'Var', (63, 82))	('SCCHN', 'Disease', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('multiple cancer', 'Disease', 'MESH:D009369', (109, 124))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('plethora', 'Phenotype', 'HP:0001050', (51, 59))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('multiple cancer', 'Disease', (109, 124))
839566	29348866	More specifically, a recent study showed that the PMT enhancer of zeste homologue 2 (EZH2) and DNA-methyltransferase 1 (DNMT-1) transcriptionally repress Th1-type chemokines, CXCL9 and CXCL10, and that inhibition of both EZH2 and DNMT-1 increased CD8+ T-cell trafficking, reduced tumor growth and improved the efficacy of PD-L1 checkpoint blockade in a mouse ovarian cancer model.	('increased', 'PosReg', (237, 246))	('PD-L1', 'Gene', '60533', (322, 327))	('inhibition', 'Var', (202, 212))	('DNMT-1', 'Gene', '13433', (230, 236))	('Th1-type chemokines', 'MPA', (154, 173))	('ovarian cancer', 'Disease', 'MESH:D010051', (359, 373))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('reduced', 'NegReg', (272, 279))	('CD8', 'Gene', (247, 250))	('DNMT-1', 'Gene', (120, 126))	('tumor', 'Disease', (280, 285))	('ovarian cancer', 'Disease', (359, 373))	('CXCL10', 'MPA', (185, 191))	('PD-L1', 'Gene', (322, 327))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('ovarian cancer', 'Phenotype', 'HP:0100615', (359, 373))	('DNMT-1', 'Gene', (230, 236))	('DNA-methyltransferase 1', 'Gene', '13433', (95, 118))	('efficacy', 'MPA', (310, 318))	('mouse', 'Species', '10090', (353, 358))	('DNMT-1', 'Gene', '13433', (120, 126))	('DNA-methyltransferase 1', 'Gene', (95, 118))	('CD8', 'Gene', '925', (247, 250))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('improved', 'PosReg', (297, 305))
839567	29348866	found that EZH2 transcriptionally represses the expression and production of CXCL9 and CXCL10 through H3K27 tri-methylation in colon cancer cells, and that overexpression of EZH2 was associated with decreased CD8+ and CD4+ T-cell tumor infiltration as well as poor prognosis in colon cancer patients.	('CD8', 'Gene', (209, 212))	('colon cancer', 'Disease', (278, 290))	('CXCL9', 'MPA', (77, 82))	('EZH2', 'Gene', (11, 15))	('H3K27', 'Protein', (102, 107))	('overexpression', 'PosReg', (156, 170))	('decreased', 'NegReg', (199, 208))	('colon cancer', 'Phenotype', 'HP:0003003', (127, 139))	('expression', 'MPA', (48, 58))	('patients', 'Species', '9606', (291, 299))	('production', 'MPA', (63, 73))	('colon cancer', 'Phenotype', 'HP:0003003', (278, 290))	('CD4', 'Gene', '920', (218, 221))	('represses', 'NegReg', (34, 43))	('tumor', 'Disease', (230, 235))	('tri-methylation', 'Var', (108, 123))	('EZH2', 'Gene', (174, 178))	('colon cancer', 'Disease', 'MESH:D015179', (127, 139))	('CD8', 'Gene', '925', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('colon cancer', 'Disease', 'MESH:D015179', (278, 290))	('CD4', 'Gene', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('CXCL10', 'MPA', (87, 93))	('colon cancer', 'Disease', (127, 139))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
839583	29348866	In our analysis, we included PMTs and PDMTs that are known to induce not only repressive histone marks but also activating marks, as it is possible that activating marks may induce the expression of miRNAs that could silence specific chemokines, HLA class I or APM molecules.	('APM', 'Gene', (261, 264))	('induce', 'Reg', (174, 180))	('silence', 'NegReg', (217, 224))	('expression', 'MPA', (185, 195))	('specific', 'Protein', (225, 233))	('APM', 'Gene', '290', (261, 264))	('miRNAs', 'Var', (199, 205))	('HLA class I', 'Protein', (246, 257))
839591	29348866	Based on this preclinical evidence, SMYD3 has been under investigation as an anticancer target for the identification of specific drug compounds, and SMYD3 inhibitors that suppress the growth of SMYD3-overexpressing cancer cells were recently reported in the literature.	('inhibitors', 'Var', (156, 166))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', (81, 87))	('growth', 'MPA', (185, 191))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('SMYD3', 'Gene', (150, 155))	('suppress', 'NegReg', (172, 180))
839595	29348866	siRNA-mediated knockdown of SMYD3 led to upregulation of the mRNA transcripts of CD8+ T-cell attracting chemokines CXCL9, CXCL10 and CXCL11 in both HN-6 and HN-SCC-151 cell lines (Figure 4A).	('CD8', 'Gene', (81, 84))	('HN-6', 'Gene', (148, 152))	('SMYD3', 'Gene', (28, 33))	('knockdown', 'Var', (15, 24))	('CD8', 'Gene', '925', (81, 84))	('CXCL11', 'Gene', '6373', (133, 139))	('CXCL11', 'Gene', (133, 139))	('mRNA transcripts', 'MPA', (61, 77))	('HN-6', 'Gene', '100463482', (148, 152))	('CXCL10', 'MPA', (122, 128))	('upregulation', 'PosReg', (41, 53))	('HN-SCC-151', 'CellLine', 'CVCL:V279', (157, 167))
839597	29348866	SMYD3 knockdown resulted in a significant increase of CXCL9, CXCL10 and CXCL11 protein levels, compared with the siNC group (Figure 4B).	('CXCL9', 'MPA', (54, 59))	('SMYD3', 'Gene', (0, 5))	('CXCL11', 'Gene', '6373', (72, 78))	('CXCL11', 'Gene', (72, 78))	('knockdown', 'Var', (6, 15))	('increase', 'PosReg', (42, 50))
839598	29348866	Under similar experimental conditions, we also assessed the effect of siRNA-mediated knockdown of SMYD3 on the expression levels of HLA class I and APM molecules.	('APM', 'Gene', (148, 151))	('expression', 'MPA', (111, 121))	('HLA class I', 'Protein', (132, 143))	('knockdown', 'Var', (85, 94))	('SMYD3', 'Gene', (98, 103))	('APM', 'Gene', '290', (148, 151))
839599	29348866	SMYD3 knockdown downregulated tri-methylated H3K4 (H3K4me3) and resulted in the increase of TAP1 transcript and protein levels in HN-6 and HN-SCC-151 cell lines (Figure 4C, 4D).	('SMYD3', 'Gene', (0, 5))	('increase', 'PosReg', (80, 88))	('HN-6', 'Gene', '100463482', (130, 134))	('HN-SCC-151', 'CellLine', 'CVCL:V279', (139, 149))	('tri-methylated', 'MPA', (30, 44))	('HN-6', 'Gene', (130, 134))	('knockdown', 'Var', (6, 15))	('TAP1', 'Gene', (92, 96))	('downregulated', 'NegReg', (16, 29))
839605	29348866	previously demonstrated that the production of a subset of chemokines by melanoma cells was essential for the induction of T-cell infiltration in metastatic melanoma lesions and concordantly, the absence of expression of these chemokines was associated with a non-T-cell inflamed phenotype.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('melanoma lesions', 'Disease', 'MESH:D008545', (157, 173))	('absence', 'Var', (196, 203))	('melanoma lesions', 'Disease', (157, 173))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('non-T-cell inflamed', 'Disease', (260, 279))	('melanoma', 'Disease', (157, 165))	('expression', 'MPA', (207, 217))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
839610	29348866	Activating STAT3 mutations have been shown to block chemokine expression in melanoma cells and cause T-cell exclusion.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('cause', 'Reg', (95, 100))	('T-cell exclusion', 'CPA', (101, 117))	('block', 'NegReg', (46, 51))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('STAT3', 'Gene', '6774', (11, 16))	('chemokine expression', 'MPA', (52, 72))	('mutations', 'Var', (17, 26))	('STAT3', 'Gene', (11, 16))
839616	29348866	showed that DNA methyltransferase inhibitors upregulate the expression of endogenous retroviral genes, and that this triggers a type I IFN response and potentiates the antitumor effects of anti-CTLA4 treatment in a murine melanoma model.	('expression', 'MPA', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('CTLA4', 'Gene', '12477', (194, 199))	('murine', 'Species', '10090', (215, 221))	('tumor', 'Disease', (172, 177))	('potentiates', 'PosReg', (152, 163))	('triggers', 'Reg', (117, 125))	('inhibitors', 'Var', (34, 44))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('type I IFN response', 'MPA', (128, 147))	('melanoma', 'Disease', (222, 230))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('CTLA4', 'Gene', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('upregulate', 'PosReg', (45, 55))
839619	29348866	PMTs and PDMTs, a large class of epigenetic modulators, are frequently genetically altered in a wide variety of cancer types and function through direct methylation of histone and non-histone proteins.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('altered', 'Reg', (83, 90))	('histone', 'Protein', (168, 175))	('non-histone proteins', 'Protein', (180, 200))	('PMTs', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('methylation', 'Var', (153, 164))
839620	29348866	Other than the work performed by the Zou group showing that EZH2 produced by colon cancer cells mediates transcriptional silencing of Th1-type CXCL9 and CXCL10 chemokines, and causes subsequent CD8+ T-cell exclusion, no other studies have systematically explored the potential function of PMTs and PDMTs as one of the key factors of CD8+ T-cell exclusion or antigenicity in solid tumors.	('CD8', 'Gene', (194, 197))	('CXCL10 chemokines', 'MPA', (153, 170))	('CD8', 'Gene', '925', (194, 197))	('CD8', 'Gene', (333, 336))	('solid tumors', 'Disease', (374, 386))	('CD8', 'Gene', '925', (333, 336))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('EZH2', 'Var', (60, 64))	('causes', 'Reg', (176, 182))	('colon cancer', 'Disease', (77, 89))	('solid tumors', 'Disease', 'MESH:D009369', (374, 386))	('tumors', 'Phenotype', 'HP:0002664', (380, 386))	('silencing', 'NegReg', (121, 130))
839627	29348866	We further validated and functionally analyzed the negative correlation of one of these PMTs, SMYD3, with chemokines and APM components, by showing that siRNA-mediated knockdown of SMYD3 led to upregulation of the transcript and protein levels of CXCL9, CXCL10, CXCL11 and TAP1 in two HPV-negative SCCHN cell lines.	('SMYD3', 'Gene', (181, 186))	('APM', 'Gene', (121, 124))	('TAP1', 'MPA', (273, 277))	('upregulation', 'PosReg', (194, 206))	('CXCL9', 'MPA', (247, 252))	('CXCL11', 'Gene', (262, 268))	('CXCL11', 'Gene', '6373', (262, 268))	('knockdown', 'Var', (168, 177))	('CXCL10', 'MPA', (254, 260))	('APM', 'Gene', '290', (121, 124))
839630	29348866	Furthermore, it would be of paramount importance to determine whether PMTs affect tumor T-cell infiltration or tumor immunogenicity through direct methylation of substrates involved in these processes.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('PMTs', 'Var', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (111, 116))	('affect', 'Reg', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
839638	29348866	The PMT/PDMTs were further sorted out based on the hypothesis that if these genes induce CD8+ T-cell exclusion, they should exhibit a significant negative correlation (P < 0.05) with CD8 mRNA.	('CD8', 'Gene', (89, 92))	('induce', 'PosReg', (82, 88))	('CD8', 'Gene', '925', (89, 92))	('negative', 'NegReg', (146, 154))	('CD8', 'Gene', (183, 186))	('genes', 'Var', (76, 81))	('CD8', 'Gene', '925', (183, 186))
839733	26411750	There are manifold reasons for aberrant nutrition after esophagectomy, including altered anatomy, early satiety, loss of appetite, taste and smell, and the post-surgery dumping syndrome.	('loss of appetite', 'Disease', (113, 129))	('loss of appetite', 'Phenotype', 'HP:0004396', (113, 129))	('aberrant', 'Var', (31, 39))	('dumping syndrome', 'Disease', (169, 185))	('loss of appetite', 'Disease', 'MESH:D001068', (113, 129))
839849	28210084	All ESD procedures were performed using a single-channel upper gastrointestinal endoscope (GIF-Q260J; Olympus Medical Systems, Tokyo, Japan), a water-jet system (OFP; Olympus), and a high frequency generator (ICC200 or VIO300D; Erbe Elektromedizin Ltd., Germany).	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (57, 89))	('Q260J', 'Var', (95, 100))	('water', 'Chemical', 'MESH:D014867', (144, 149))	('Q260J', 'SUBSTITUTION', 'None', (95, 100))	('upper gastrointestinal endoscope', 'Disease', (57, 89))
839905	26967246	The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer The stability and integrity of the human genome are maintained by the DNA damage repair (DDR) system.	('aberrant epigenetic changes', 'Var', (22, 49))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('human', 'Species', '9606', (80, 85))	('human', 'Species', '9606', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('DNA', 'Gene', (53, 56))	('cancer', 'Disease', (86, 92))
839909	26967246	Aberrant methylation patterns in DNA damage repair genes may serve as predictive, diagnostic, prognostic and chemosensitive markers of human cancer.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('DNA damage repair genes', 'Gene', (33, 56))	('human', 'Species', '9606', (135, 140))	('Aberrant methylation patterns', 'Var', (0, 29))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
839914	26967246	In patients with hereditary non-polyposis colorectal cancer (HNPCC), germ-line defects in mismatch-repair genes (primarily MLH1 and MSH2) confer a lifetime risk of colorectal cancer (CRC) of approximately 80%.	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (17, 59))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('hereditary non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (17, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (164, 181))	('MLH1', 'Gene', (123, 127))	('MSH2', 'Gene', (132, 136))	('HNPCC', 'Phenotype', 'HP:0006716', (61, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('defects', 'Var', (79, 86))	('CRC', 'Phenotype', 'HP:0003003', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('patients', 'Species', '9606', (3, 11))	('colorectal cancer', 'Disease', 'MESH:D015179', (164, 181))	('MSH2', 'Gene', '4436', (132, 136))	('colorectal cancer', 'Disease', (164, 181))	('hereditary non-polyposis colorectal cancer', 'Disease', (17, 59))	('HNPCC', 'Disease', 'None', (61, 66))	('HNPCC', 'Disease', (61, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))
839915	26967246	Germline mutations in MSH2 and MLH1 account for approximately 60% of HNPCC, while nearly one-third of HNPCC patients do not show MMR gene mutations, which may be attribute to epigenetic silencing.	('Germline mutations', 'Var', (0, 18))	('MSH2', 'Gene', (22, 26))	('HNPCC', 'Disease', (69, 74))	('HNPCC', 'Disease', 'None', (69, 74))	('MSH2', 'Gene', '4436', (22, 26))	('account', 'Reg', (36, 43))	('HNPCC', 'Phenotype', 'HP:0006716', (102, 107))	('MLH1', 'Gene', (31, 35))	('patients', 'Species', '9606', (108, 116))	('HNPCC', 'Disease', 'None', (102, 107))	('HNPCC', 'Disease', (102, 107))	('HNPCC', 'Phenotype', 'HP:0006716', (69, 74))
839916	26967246	Somatic inactivation of the mismatch-repair gene MLH1 occurs in approximately 15% of patients with sporadic colorectal cancers by promoter region methylation in bialleles.	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('inactivation', 'NegReg', (8, 20))	('sporadic colorectal cancers', 'Disease', (99, 126))	('patients', 'Species', '9606', (85, 93))	('MLH1', 'Gene', (49, 53))	('methylation', 'Var', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('sporadic colorectal cancers', 'Disease', 'MESH:D015179', (99, 126))
839917	26967246	Heterozygous germline mutations in breast cancer susceptibility gene 1/2 (BRCA1/2) are responsible for a large fraction of hereditary breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('breast cancers', 'Phenotype', 'HP:0003002', (134, 148))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('BRCA1/2', 'Gene', (74, 81))	('germline mutations', 'Var', (13, 31))	('hereditary breast cancers', 'Disease', (123, 148))	('breast cancer', 'Disease', (35, 48))	('responsible for', 'Reg', (87, 102))	('hereditary breast cancers', 'Disease', 'MESH:D001943', (123, 148))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('BRCA1/2', 'Gene', '672;675', (74, 81))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
839918	26967246	The risk of developing breast cancer by age 70 is 50-70% for BRCA1/2 mutation carriers.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('mutation', 'Var', (69, 77))	('BRCA1/2', 'Gene', (61, 68))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('BRCA1/2', 'Gene', '672;675', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
839919	26967246	While BRCA1 and BRCA2 mutations affect a minority of breast cancer patients (fewer than 5%), BRCA1 and BRCA2 were silenced by promoter region hypermethylation in 9% and 2% of sporadic breast cancer, respectively.	('BRCA2', 'Gene', (103, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('hypermethylation', 'Var', (142, 158))	('BRCA2', 'Gene', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('breast cancer', 'Disease', (53, 66))	('silenced', 'NegReg', (114, 122))	('BRCA2', 'Gene', '675', (103, 108))	('patients', 'Species', '9606', (67, 75))	('mutations', 'Var', (22, 31))	('BRCA2', 'Gene', '675', (16, 21))	('BRCA1', 'Gene', '672', (6, 11))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('BRCA1', 'Gene', (6, 11))	('BRCA1', 'Gene', '672', (93, 98))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('BRCA1', 'Gene', (93, 98))	('breast cancer', 'Disease', (184, 197))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
839920	26967246	O6-methylguanine-DNA methyltransferase (MGMT) is mutated in 17.5% and methylated in 44% of human esophageal squamous cell carcinoma.	('O6-methylguanine-DNA methyltransferase', 'Gene', (0, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (97, 131))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (0, 38))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))	('methylated', 'Var', (70, 80))	('esophageal squamous cell carcinoma', 'Disease', (97, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('human', 'Species', '9606', (91, 96))
839921	26967246	Thus, aberrant epigenetic changes may play more important roles than gene mutations in DNA damage repair genes to drive carcinogenesis.	('aberrant epigenetic changes', 'Var', (6, 33))	('carcinogenesis', 'Disease', (120, 134))	('drive', 'PosReg', (114, 119))	('carcinogenesis', 'Disease', 'MESH:D063646', (120, 134))
839922	26967246	MGMT removes alkyl groups from O6-methylguanine that are formed as a result of erroneous methylation by S-adenosylmethionine, and it also removes other alkylations at the O6-position of guanine that are induced by dietary nitrosamines or chemotherapy agents such as temozolomide (TMZ), dacarbazine (DTIC) and carmustine (BCNU).	('MGMT', 'Gene', (0, 4))	('carmustine', 'Chemical', 'MESH:D002330', (309, 319))	('BCNU', 'Chemical', 'MESH:D002330', (321, 325))	('nitrosamines', 'Chemical', 'MESH:D009602', (222, 234))	('erroneous', 'Var', (79, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (280, 283))	('guanine', 'Chemical', 'MESH:D006147', (186, 193))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (104, 124))	('alkylations', 'MPA', (152, 163))	('removes', 'NegReg', (138, 145))	('guanine', 'Chemical', 'MESH:D006147', (40, 47))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (31, 47))	('alkyl groups', 'MPA', (13, 25))	('MGMT', 'Gene', '4255', (0, 4))	('DTIC', 'Chemical', 'MESH:D003606', (299, 303))	('temozolomide', 'Chemical', 'MESH:D000077204', (266, 278))	('dacarbazine', 'Chemical', 'MESH:D003606', (286, 297))
839924	26967246	If O6-methylguanine is not repaired by MGMT and MMR, G:C to A:T transition mutations will lead to carcinogenesis when they occur in cancer-related genes, such as K-ras and p53.	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('cancer', 'Disease', (132, 138))	('K-ras', 'Gene', (162, 167))	('K-ras', 'Gene', '3845', (162, 167))	('carcinogenesis', 'Disease', (98, 112))	('MGMT', 'Gene', '4255', (39, 43))	('p53', 'Gene', '7157', (172, 175))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('MGMT', 'Gene', (39, 43))	('mutations', 'Var', (75, 84))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (3, 19))	('lead to', 'Reg', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('p53', 'Gene', (172, 175))
839925	26967246	MGMT is frequently methylated in various tumors, including gliomas (40%), diffuse large B-cell lymphoma (36%), colorectal cancer (46%), gastric cancer (36.8%), non-small cell lung cancer (21%), esophageal cancer (44%) and head and neck cancers (60.8%).	('methylated', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('gliomas', 'Disease', (59, 66))	('B-cell lymphoma', 'Disease', (88, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))	('MGMT', 'Gene', '4255', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (160, 186))	('lymphoma', 'Phenotype', 'HP:0002665', (95, 103))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('esophageal cancer', 'Disease', (194, 211))	('colorectal cancer', 'Disease', (111, 128))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('head and neck cancers', 'Phenotype', 'HP:0012288', (222, 243))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('non-small cell lung cancer', 'Disease', (160, 186))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('MGMT', 'Gene', (0, 4))	('head and neck cancers', 'Disease', 'MESH:D006258', (222, 243))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('gastric cancer', 'Disease', (136, 150))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))
839928	26967246	Because 8-oxodG DNA lesions do not block DNA replication, they lead to mispairing with A and result in GC to TA transversions, the most predominant somatic mutations in lung, breast, ovarian, gastric and colorectal cancers.	('8-oxodG', 'Chemical', 'MESH:C067134', (8, 15))	('gastric', 'Disease', (192, 199))	('transversions', 'Var', (112, 125))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('ovarian', 'Disease', (183, 190))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('colorectal cancers', 'Disease', (204, 222))	('lung', 'Disease', (169, 173))	('lead to', 'Reg', (63, 70))	('colorectal cancers', 'Disease', 'MESH:D015179', (204, 222))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast', 'Disease', (175, 181))	('mispairing', 'MPA', (71, 81))
839930	26967246	Mutations and single nucleotide polymorphisms (SNPs) in BER genes are associated with numerous cancers, such as UNG2 (uracil DNA glycosylase) mutations in glioblastoma, MED1 (mediator complex subunit 1) mutations in colorectal cancer, and OGG1 (8-oxoguanine DNA glycosylase) mutations in lung cancer.	('MED1', 'Gene', (169, 173))	('UNG2', 'Gene', '7374', (112, 116))	('colorectal cancer', 'Disease', (216, 233))	('glioblastoma', 'Disease', (155, 167))	('single nucleotide polymorphisms', 'Var', (14, 45))	('lung cancer', 'Disease', 'MESH:D008175', (288, 299))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('numerous cancers', 'Disease', (86, 102))	('MED1', 'Gene', '5469', (169, 173))	('8-oxoguanine DNA glycosylase', 'Gene', (245, 273))	('mutations', 'Var', (142, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (288, 299))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('associated', 'Reg', (70, 80))	('Mutations', 'Var', (0, 9))	('8-oxoguanine DNA glycosylase', 'Gene', '4968', (245, 273))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BER', 'Gene', (56, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (216, 233))	('OGG1', 'Gene', (239, 243))	('OGG1', 'Gene', '4968', (239, 243))	('UNG2', 'Gene', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('mutations', 'Var', (203, 212))	('uracil DNA glycosylase', 'Gene', (118, 140))	('mutations', 'Var', (275, 284))	('lung cancer', 'Disease', (288, 299))	('uracil DNA glycosylase', 'Gene', '7374', (118, 140))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('numerous cancers', 'Disease', 'MESH:D009369', (86, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (216, 233))
839931	26967246	The X-ray repair cross-complementing gene 1 (XRCC1) polymorphism, Arg399Gln, increased the occurrence of p53 mutations in human lung cancer.	('human', 'Species', '9606', (122, 127))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('Arg399Gln', 'Var', (66, 75))	('XRCC1', 'Gene', '7515', (45, 50))	('increased', 'PosReg', (77, 86))	('X-ray repair cross-complementing gene 1', 'Gene', (4, 43))	('Arg399Gln', 'SUBSTITUTION', 'None', (66, 75))	('X-ray repair cross-complementing gene 1', 'Gene', '7515', (4, 43))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('XRCC1', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
839932	26967246	Aberrant methylation of BER genes were found in a variety of cancers.	('Aberrant', 'Var', (0, 8))	('BER genes', 'Gene', (24, 33))	('found', 'Reg', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('methylation', 'MPA', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
839934	26967246	Aberrant DNA methylation of the TDG (thymine DNA glycosylase) gene is reported in multiple myeloma cells and is related to genomic instability in multiple myeloma.	('thymine DNA glycosylase', 'Gene', (37, 60))	('multiple myeloma', 'Phenotype', 'HP:0006775', (82, 98))	('multiple myeloma', 'Disease', 'MESH:D009101', (146, 162))	('Aberrant DNA methylation', 'Var', (0, 24))	('TDG', 'Gene', '6996', (32, 35))	('reported', 'Reg', (70, 78))	('multiple myeloma', 'Phenotype', 'HP:0006775', (146, 162))	('multiple myeloma', 'Disease', (146, 162))	('related to', 'Reg', (112, 122))	('thymine DNA glycosylase', 'Gene', '6996', (37, 60))	('TDG', 'Gene', (32, 35))	('multiple myeloma', 'Disease', 'MESH:D009101', (82, 98))	('multiple myeloma', 'Disease', (82, 98))
839935	26967246	Promoter region hypermethylation of MED1 is reported frequently in colorectal and ovarian cancers.	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('MED1', 'Gene', '5469', (36, 40))	('MED1', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ovarian cancers', 'Phenotype', 'HP:0100615', (82, 97))	('hypermethylation', 'Var', (16, 32))	('colorectal and ovarian cancers', 'Disease', 'MESH:D015179', (67, 97))	('reported', 'Reg', (44, 52))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))
839938	26967246	Germline mutations in WRN are the cause of Werner syndrome, an autosomal recessive disorder characterized by premature aging, genomic instability, and predisposition to cancer.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Disease', (169, 175))	('Werner syndrome', 'Disease', 'MESH:D014898', (43, 58))	('Werner syndrome', 'Disease', (43, 58))	('WRN', 'Gene', '7486', (22, 25))	('cause', 'Reg', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('WRN', 'Gene', (22, 25))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (63, 91))	('autosomal recessive disorder', 'Disease', (63, 91))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
839940	26967246	A study in colorectal cancer showed that epigenetic inactivation of WRN leads to loss of WRN-associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors.	('colorectal cancer', 'Disease', 'MESH:D015179', (11, 28))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (129, 162))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (11, 28))	('apoptosis', 'CPA', (167, 176))	('epigenetic inactivation', 'Var', (41, 64))	('increased', 'PosReg', (129, 138))	('colorectal cancer', 'Disease', (11, 28))	('WRN', 'Gene', '7486', (89, 92))	('chromosomal instability', 'Phenotype', 'HP:0040012', (139, 162))	('WRN', 'Gene', '7486', (68, 71))	('activity', 'MPA', (116, 124))	('WRN', 'Gene', (89, 92))	('loss', 'NegReg', (81, 85))	('WRN', 'Gene', (68, 71))	('chromosomal instability', 'CPA', (139, 162))
839941	26967246	Promoter region methylation of the WRN gene has been reported frequently in colorectal (37.9%), non-small cell lung (37.5%), gastric (25%), prostate (20%), breast (17.2%), and thyroid (12.5%) cancers, chondro-sarcomas (33.3%), and non-Hodgkin lymphoma (23.7%).	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (231, 251))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('colorectal', 'Disease', 'MESH:D015179', (76, 86))	('cancers', 'Disease', (192, 199))	('thyroid', 'Disease', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('chondro-sarcomas', 'Disease', (201, 217))	('non-small cell lung', 'Disease', (96, 115))	('breast', 'Disease', (156, 162))	('chondro-sarcomas', 'Disease', 'MESH:D012509', (201, 217))	('WRN', 'Gene', '7486', (35, 38))	('WRN', 'Gene', (35, 38))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('prostate', 'Disease', (140, 148))	('colorectal', 'Disease', (76, 86))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (235, 251))	('sarcomas', 'Phenotype', 'HP:0100242', (209, 217))	('lymphoma', 'Phenotype', 'HP:0002665', (243, 251))	('non-Hodgkin lymphoma', 'Disease', (231, 251))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (231, 251))	('gastric', 'Disease', (125, 132))	('methylation', 'Var', (16, 27))
839945	26967246	It is a rare autosomal recessive disease caused by biallelic inactivating mutations in genes involved in nucleotide excision repair.	('biallelic inactivating mutations', 'Var', (51, 83))	('autosomal recessive disease', 'Disease', (13, 40))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (13, 40))	('caused', 'Reg', (41, 47))
839946	26967246	Patients with mutations in XP genes are extremely sensitive to UV and have extraordinarily high incidences of non-melanoma skin cancer and melanoma, as well as other solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (166, 178))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('skin cancer', 'Phenotype', 'HP:0008069', (123, 134))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('sensitive to UV', 'MPA', (50, 65))	('XP genes', 'Gene', (27, 35))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (110, 134))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('Patients', 'Species', '9606', (0, 8))	('non-melanoma skin cancer', 'Disease', (110, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('solid tumors', 'Disease', (166, 178))	('mutations', 'Var', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
839950	26967246	ERCC1 (excision repair cross-complementation group 1) was methylated in 37.5% of gliomas.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('methylated', 'Var', (58, 68))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))
839952	26967246	XPG was methylated in 20% of ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (29, 44))	('ovarian cancers', 'Disease', (29, 44))	('XPG', 'Gene', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('ovarian cancers', 'Disease', 'MESH:D010051', (29, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (29, 43))	('XPG', 'Gene', '2073', (0, 3))	('methylated', 'Var', (8, 18))
839954	26967246	Defective MMR increases mutation rates up to 1,000-fold and leads to microsatellite instability (MSI) resulting in carcinogenesis.	('mutation rates', 'MPA', (24, 38))	('increases', 'PosReg', (14, 23))	('microsatellite instability', 'MPA', (69, 95))	('Defective', 'Var', (0, 9))	('carcinogenesis', 'Disease', 'MESH:D063646', (115, 129))	('leads to', 'Reg', (60, 68))	('carcinogenesis', 'Disease', (115, 129))	('MMR', 'Gene', (10, 13))
839955	26967246	The MSI status of a tumor can be detected by five microsatellite markers which are composed of two mononucleotide repeats (BAT25, BAT26) and three dinucleotide repeats (D2S123, D5S346 and D17S250).	('dinucleotide', 'Chemical', 'MESH:D015226', (147, 159))	('mononucleotide', 'Chemical', '-', (99, 113))	('D2S123', 'Var', (169, 175))	('BAT26', 'Gene', (130, 135))	('D5S346', 'Var', (177, 183))	('D17S250', 'Var', (188, 195))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('BAT25', 'Var', (123, 128))	('tumor', 'Disease', (20, 25))
839958	26967246	Inactivation of germline mutations within at least one of four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) can be found in approximately 70% of cases, and 95% of the mutations occur in hMSH2 or hMLH1.	('hMLH1', 'Gene', '4292', (201, 206))	('MSH2', 'Gene', (92, 96))	('MSH2', 'Gene', '4436', (92, 96))	('MSH6', 'Gene', '2956', (98, 102))	('hMLH1', 'Gene', (201, 206))	('hMSH2', 'Gene', '4436', (192, 197))	('PMS2', 'Gene', (108, 112))	('mutations', 'Var', (173, 182))	('hMSH2', 'Gene', (192, 197))	('PMS2', 'Gene', '5395', (108, 112))	('MSH6', 'Gene', (98, 102))	('MSH2', 'Gene', (193, 197))	('MSH2', 'Gene', '4436', (193, 197))	('MLH1', 'Gene', (86, 90))
839960	26967246	Germline MMR mutations that give rise to HNPCC account for ~3% of all CRCs.	('HNPCC', 'Disease', 'None', (41, 46))	('MMR', 'Gene', (9, 12))	('HNPCC', 'Disease', (41, 46))	('CRCs', 'Disease', (70, 74))	('CRC', 'Phenotype', 'HP:0003003', (70, 73))	('mutations', 'Var', (13, 22))	('HNPCC', 'Phenotype', 'HP:0006716', (41, 46))
839961	26967246	In contrast to HNPCC, sporadic cancers are rarely found to have mutations in the MLH1 or MSH2 genes.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('MSH2', 'Gene', (89, 93))	('HNPCC', 'Phenotype', 'HP:0006716', (15, 20))	('MLH1', 'Gene', (81, 85))	('HNPCC, sporadic cancers', 'Disease', 'MESH:D009369', (15, 38))	('MSH2', 'Gene', '4436', (89, 93))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))
839964	26967246	The study found that 80% of MSH2-deficient HNPCC patients harbored germline mutations in MSH2.	('germline mutations', 'Var', (67, 85))	('MSH2', 'Gene', (89, 93))	('MSH2', 'Gene', (28, 32))	('harbored', 'Reg', (58, 66))	('HNPCC', 'Phenotype', 'HP:0006716', (43, 48))	('MSH2', 'Gene', '4436', (89, 93))	('MSH2', 'Gene', '4436', (28, 32))	('patients', 'Species', '9606', (49, 57))	('MSH2-deficient HNPCC', 'Disease', (28, 48))	('MSH2-deficient HNPCC', 'Disease', 'MESH:D007153', (28, 48))
839966	26967246	Moreover, 63% (7/11) of MSH2 methylated CRCs had a simultaneous pathogenic germline MSH2 mutation, but no methylation was found in matched normal tissues, suggesting that methylation may be the required "second hit" in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('mutation', 'Var', (89, 97))	('MSH2', 'Gene', (24, 28))	('MSH2', 'Gene', '4436', (24, 28))	('pathogenic', 'Reg', (64, 74))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('methylated', 'Var', (29, 39))	('CRC', 'Phenotype', 'HP:0003003', (40, 43))	('tumors', 'Disease', (225, 231))	('MSH2', 'Gene', (84, 88))	('MSH2', 'Gene', '4436', (84, 88))
839968	26967246	Promoter region hypermethylation of MLH1 is also found in other sporadic tumors, including adult T-cell leukemia/lymphoma (6%), gastric cancer (21.6%), head and neck squamous cell carcinomas (28.6%), non-small cell lung cancer (55.8%), oral squamous cell carcinoma (76%), esophageal squamous cell carcinoma (23%), pancreatic cancer (23%), ovarian cancer (37.5%), and breast cancer (31.3%).	('gastric cancer', 'Disease', (128, 142))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('hypermethylation', 'Var', (16, 32))	('esophageal squamous cell carcinoma', 'Disease', (272, 306))	('T-cell leukemia/lymphoma', 'Disease', 'MESH:D016399', (97, 121))	('ovarian cancer', 'Disease', (339, 353))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('MLH1', 'Gene', (36, 40))	('ovarian cancer', 'Phenotype', 'HP:0100615', (339, 353))	('non-small cell lung cancer', 'Disease', (200, 226))	('gastric cancer', 'Disease', 'MESH:D013274', (128, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (283, 306))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('sporadic tumors', 'Disease', (64, 79))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (152, 190))	('pancreatic cancer', 'Disease', 'MESH:D010190', (314, 331))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (236, 264))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('neck squamous cell carcinomas', 'Disease', (161, 190))	('T-cell leukemia/lymphoma', 'Disease', (97, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('found', 'Reg', (49, 54))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (272, 306))	('oral squamous cell carcinoma', 'Disease', (236, 264))	('sporadic tumors', 'Disease', 'MESH:D009369', (64, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (367, 380))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (152, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (161, 190))	('pancreatic cancer', 'Disease', (314, 331))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (200, 226))	('breast cancer', 'Disease', 'MESH:D001943', (367, 380))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (241, 264))	('breast cancer', 'Disease', (367, 380))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (204, 226))	('ovarian cancer', 'Disease', 'MESH:D010051', (339, 353))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (166, 190))	('T-cell leukemia/lymphoma', 'Phenotype', 'HP:0005517', (97, 121))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (314, 331))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (200, 226))
839969	26967246	In addition to somatic methylation, germline epimutation, a condition in which a person has hypermethylation of one allele of MLH1 in somatic cells throughout the body, increased the risk of CRC by 60% for first-degree relatives of MLH1-methylated cases.	('CRC', 'Disease', (191, 194))	('increased', 'PosReg', (169, 178))	('MLH1', 'Gene', (126, 130))	('CRC', 'Phenotype', 'HP:0003003', (191, 194))	('person', 'Species', '9606', (81, 87))	('hypermethylation', 'Var', (92, 108))	('germline', 'Var', (36, 44))
839978	26967246	There are numerous proteins involved in DSB repair, and inactivation of DSB repair genes is associated with various tumors.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('DSB repair genes', 'Gene', (72, 88))	('inactivation', 'Var', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('associated', 'Reg', (92, 102))
839980	26967246	Promoter region methylation of XRCC5 was reported in 21% of non-small cell lung cancers (NSCLCs).	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (60, 87))	('XRCC5', 'Gene', '7520', (31, 36))	('NSCLCs', 'Phenotype', 'HP:0030358', (89, 95))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (64, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancers', 'Phenotype', 'HP:0100526', (75, 87))	('non-small cell lung cancers', 'Disease', (60, 87))	('NSCLC', 'Disease', (89, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (64, 86))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (60, 86))	('XRCC5', 'Gene', (31, 36))	('methylation', 'Var', (16, 27))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (60, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
839988	26967246	Germline mutations in the BRCA1 and BRCA2 genes are the most important causes of hereditary breast and ovarian cancer.	('Germline mutations', 'Var', (0, 18))	('BRCA1', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('BRCA2', 'Gene', (36, 41))	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (81, 117))	('BRCA1', 'Gene', '672', (26, 31))	('BRCA2', 'Gene', '675', (36, 41))	('causes', 'Reg', (71, 77))
839989	26967246	While there is not a direct procedure to estimate the prevalence of BRCA1/2 mutations in the general population, it is estimated that nearly 50% of the mutations would be in BRCA1 and 50% in BRCA2.	('BRCA1/2', 'Gene', '672;675', (68, 75))	('BRCA1', 'Gene', (174, 179))	('BRCA1', 'Gene', (68, 73))	('mutations', 'Var', (152, 161))	('BRCA2', 'Gene', (191, 196))	('BRCA1/2', 'Gene', (68, 75))	('BRCA2', 'Gene', '675', (191, 196))	('BRCA1', 'Gene', '672', (68, 73))	('BRCA1', 'Gene', '672', (174, 179))
839990	26967246	Lifetime cancer risks in BRCA mutation carriers are 60-80% for breast cancer and 20-40% for ovarian cancer.	('cancer', 'Disease', (9, 15))	('ovarian cancer', 'Disease', 'MESH:D010051', (92, 106))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('BRCA', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ovarian cancer', 'Disease', (92, 106))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('mutation', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('BRCA', 'Gene', '672', (25, 29))
839991	26967246	Mutations in BRCA genes cannot account for all cases of hereditary breast and ovarian cancer.	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (56, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Mutations', 'Var', (0, 9))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('BRCA', 'Gene', '672', (13, 17))	('BRCA', 'Gene', (13, 17))
839994	26967246	In addition to germline mutations in these genes occurring in FA, somatic mutations and epigenetic silencing of these genes occur in a variety of cancers in the general population (non-FA patients).	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('FA', 'Phenotype', 'HP:0001994', (62, 64))	('FA', 'Phenotype', 'HP:0001994', (185, 187))	('patients', 'Species', '9606', (188, 196))	('occur', 'Reg', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('epigenetic silencing', 'Var', (88, 108))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
839997	26967246	FANCC was methylated in 1 of 143 acute myeloid leukemia (AML) cases and 3 of 97 acute lymphoblastic leukemia (ALL) cases, while FANCL was found to be methylated in one ALL sample.	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (80, 108))	('ALL', 'Phenotype', 'HP:0006721', (168, 171))	('FANCC', 'Gene', (0, 5))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (80, 108))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (33, 55))	('methylated', 'Var', (10, 20))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (33, 55))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (86, 108))	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (39, 55))	('AML', 'Disease', 'MESH:D015470', (57, 60))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('FANCL', 'Gene', (128, 133))	('FA', 'Phenotype', 'HP:0001994', (128, 130))	('AML', 'Disease', (57, 60))	('FANCL', 'Gene', '55120', (128, 133))	('ALL', 'Phenotype', 'HP:0006721', (110, 113))	('AML', 'Phenotype', 'HP:0004808', (57, 60))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('acute myeloid leukemia', 'Disease', (33, 55))	('FANCC', 'Gene', '2176', (0, 5))	('acute lymphoblastic leukemia', 'Disease', (80, 108))
839998	26967246	BRCA1/BRCA2 mutations are often found in hereditary breast and ovarian cancers, while somatic mutations of BRCA1/BRCA2 are rare in sporadic breast and ovarian cancers.	('BRCA1', 'Gene', '672', (107, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('BRCA2', 'Gene', (113, 118))	('BRCA1', 'Gene', (107, 112))	('sporadic breast and ovarian cancers', 'Disease', 'MESH:D001943', (131, 166))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('BRCA2', 'Gene', (6, 11))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA2', 'Gene', '675', (113, 118))	('BRCA1', 'Gene', (0, 5))	('found', 'Reg', (32, 37))	('ovarian cancers', 'Phenotype', 'HP:0100615', (151, 166))	('hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (41, 78))	('ovarian cancers', 'Phenotype', 'HP:0100615', (63, 78))	('BRCA2', 'Gene', '675', (6, 11))	('mutations', 'Var', (12, 21))
839999	26967246	BRCA1 methylation is observed in approximately 11-14% of breast cancers and 5%-31% of ovarian cancers.	('breast cancers', 'Disease', 'MESH:D001943', (57, 71))	('breast cancers', 'Disease', (57, 71))	('BRCA1', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('methylation', 'Var', (6, 17))	('observed', 'Reg', (21, 29))	('ovarian cancers', 'Disease', (86, 101))	('breast cancers', 'Phenotype', 'HP:0003002', (57, 71))	('ovarian cancers', 'Phenotype', 'HP:0100615', (86, 101))	('BRCA1', 'Gene', '672', (0, 5))	('ovarian cancers', 'Disease', 'MESH:D010051', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
840000	26967246	BRCA1 methylation is also found in gastric (1.4%), colorectal (10.75%), non-small cell lung (18.6%), bladder (12.1%) and pancreatic cancers (46%).	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('BRCA1', 'Gene', (0, 5))	('bladder', 'Disease', (101, 108))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (121, 139))	('gastric', 'Disease', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('found', 'Reg', (26, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))	('methylation', 'Var', (6, 17))	('non-small cell lung', 'Disease', (72, 91))	('BRCA1', 'Gene', '672', (0, 5))	('pancreatic cancers', 'Disease', 'MESH:D010190', (121, 139))	('pancreatic cancers', 'Disease', (121, 139))	('colorectal', 'Disease', 'MESH:D015179', (51, 61))	('colorectal', 'Disease', (51, 61))
840001	26967246	BRCA2 methylation is reported in NSCLC (42%).	('BRCA2', 'Gene', '675', (0, 5))	('methylation', 'Var', (6, 17))	('BRCA2', 'Gene', (0, 5))	('NSCLC', 'Disease', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))
840004	26967246	CHFR methylation is regarded as a docetaxel sensitive marker.	('CHFR', 'Gene', (0, 4))	('CHFR', 'Gene', '55743', (0, 4))	('methylation', 'Var', (5, 16))	('docetaxel', 'Chemical', 'MESH:D000077143', (34, 43))
840005	26967246	Re-expression of CHFR induced G2/M phase arrest and increased resistance to docetaxel in esophageal cancer cells.	('esophageal cancer', 'Disease', (89, 106))	('G2/M phase arrest', 'CPA', (30, 47))	('increased', 'PosReg', (52, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('resistance to docetaxel', 'MPA', (62, 85))	('docetaxel', 'Chemical', 'MESH:D000077143', (76, 85))	('Re-expression', 'Var', (0, 13))	('CHFR', 'Gene', '55743', (17, 21))	('CHFR', 'Gene', (17, 21))
840008	26967246	Methylation of p16 has been demonstrated to sensitize gastric cancer to 5-fluorouracil therapy.	('p16', 'Gene', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Methylation', 'Var', (0, 11))	('gastric cancer', 'Disease', (54, 68))	('p16', 'Gene', '1029', (15, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (54, 68))	('sensitize', 'Reg', (44, 53))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (72, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (54, 68))
840010	26967246	Therefore, the cell cycle is disrupted by P16 methylation and the cell number in the S-phase is increased.	('methylation', 'Var', (46, 57))	('increased', 'PosReg', (96, 105))	('cell number in the S-phase', 'CPA', (66, 92))	('cell cycle', 'CPA', (15, 25))	('P16', 'Gene', (42, 45))	('disrupted', 'Reg', (29, 38))	('P16', 'Gene', '1029', (42, 45))
840013	26967246	MSI and DNA repair gene mutations have been used as diagnostic and prognostic markers in various tumors.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (97, 103))	('MSI', 'Gene', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (24, 33))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('DNA repair gene', 'Gene', (8, 23))
840014	26967246	Germ-line mutations in MLH1 and MSH2 suggest a very high risk of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('MLH1', 'Gene', (23, 27))	('colorectal cancer', 'Disease', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MSH2', 'Gene', (32, 36))	('mutations', 'Var', (10, 19))	('MSH2', 'Gene', '4436', (32, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))
840015	26967246	The prognosis is much better in sporadic colorectal cancers with a mismatch repair deficiency.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('sporadic colorectal cancers', 'Disease', (32, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('better', 'Reg', (22, 28))	('sporadic colorectal cancers', 'Disease', 'MESH:D015179', (32, 59))	('deficiency', 'Var', (83, 93))	('mismatch', 'Var', (67, 75))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
840016	26967246	The overall breast cancer and ovarian cancer risks for BRCA1 mutation carriers by age 70 years are 50-70% and 40-50%, respectively.	('breast cancer', 'Disease', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('mutation', 'Var', (61, 69))	('BRCA1', 'Gene', '672', (55, 60))	('ovarian cancer', 'Disease', (30, 44))	('BRCA1', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))
840018	26967246	Methylation of DDR genes has been detected in various cancers.	('detected', 'Reg', (34, 42))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('Methylation', 'Var', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('DDR genes', 'Gene', (15, 24))
840021	26967246	While, silencing MGMT by promoter region hypermethylation sensitizes glioma cells to alkylating agents.	('glioma', 'Disease', (69, 75))	('hypermethylation', 'Var', (41, 57))	('alkylating agents', 'MPA', (85, 102))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('MGMT', 'Gene', '4255', (17, 21))	('sensitizes', 'Reg', (58, 68))	('silencing', 'NegReg', (7, 16))	('MGMT', 'Gene', (17, 21))
840025	26967246	MLH1 methylation may serve as an early detection marker for esophageal cancer.	('methylation', 'Var', (5, 16))	('MLH1', 'Gene', (0, 4))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
840026	26967246	MLH1 methylation was reported to be a good prognostic marker in colorectal and pancreatic cancers.	('methylation', 'Var', (5, 16))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (79, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('MLH1', 'Gene', (0, 4))	('colorectal and pancreatic cancers', 'Disease', 'MESH:D010190', (64, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))
840027	26967246	CHFR methylation is associated with an increased risk of disease recurrence and poor survival in NSCLC and CRC.	('CHFR', 'Gene', (0, 4))	('CRC', 'Disease', (107, 110))	('CHFR', 'Gene', '55743', (0, 4))	('methylation', 'Var', (5, 16))	('NSCLC', 'Disease', (97, 102))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))
840028	26967246	The OGG1 gene is frequently methylated in different cancers, and silencing of its expression by promoter region methylation is associated with poor prognosis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('expression', 'MPA', (82, 92))	('breast cancer', 'Disease', (161, 174))	('methylation', 'Var', (112, 123))	('OGG1', 'Gene', (4, 8))	('OGG1', 'Gene', '4968', (4, 8))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('silencing', 'NegReg', (65, 74))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
840035	26967246	Cytotoxic effects of alkylating agents are mediated primarily through methylation of O6-guanine, which leads to DNA double strand breaks and subsequent inhibition of DNA replication and apoptosis.	('inhibition', 'NegReg', (152, 162))	('Cytotoxic', 'Disease', 'MESH:D064420', (0, 9))	('leads to', 'Reg', (103, 111))	('methylation', 'Var', (70, 81))	('O6-guanine', 'Chemical', '-', (85, 95))	('Cytotoxic', 'Disease', (0, 9))	('DNA', 'MPA', (166, 169))	('apoptosis', 'CPA', (186, 195))	('DNA double strand breaks', 'MPA', (112, 136))
840039	26967246	Since CpG island hypermethylation of MGMT is the major cause of loss of its expression in gliomas, MGMT methylated glioma patients are more sensitive to alkylating agents.	('gliomas', 'Disease', (90, 97))	('glioma', 'Disease', (115, 121))	('glioma', 'Disease', (90, 96))	('gliomas', 'Disease', 'MESH:D005910', (90, 97))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('loss', 'NegReg', (64, 68))	('expression', 'MPA', (76, 86))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('MGMT', 'Gene', (37, 41))	('MGMT', 'Gene', (99, 103))	('MGMT', 'Gene', '4255', (37, 41))	('patients', 'Species', '9606', (122, 130))	('MGMT', 'Gene', '4255', (99, 103))	('hypermethylation', 'Var', (17, 33))	('gliomas', 'Phenotype', 'HP:0009733', (90, 97))
840043	26967246	Similar DNA damage effects can be mediated by radiotherapy through alkylation of O6-guanine.	('alkylation', 'Var', (67, 77))	('O6-guanine', 'Chemical', '-', (81, 91))	('O6-guanine', 'Protein', (81, 91))
840044	26967246	Methylation of MGMT sensitized glioma patients to radiotherapy or combined TMZ and radiotherapy.	('sensitized', 'Reg', (20, 30))	('Methylation', 'Var', (0, 11))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('MGMT', 'Gene', '4255', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('MGMT', 'Gene', (15, 19))	('TMZ', 'Chemical', 'MESH:D000077204', (75, 78))	('patients', 'Species', '9606', (38, 46))	('glioma', 'Disease', (31, 37))
840048	26967246	Methylation of ERCC1 is associated with cisplatin sensitivity in glioma cell lines.	('cisplatin sensitivity', 'MPA', (40, 61))	('glioma', 'Disease', (65, 71))	('associated', 'Reg', (24, 34))	('Methylation', 'Var', (0, 11))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('ERCC1', 'Gene', '2067', (15, 20))	('ERCC1', 'Gene', (15, 20))
840050	26967246	BRCA1 methylation has been found to predict significantly higher response rates to cisplatin treatment in patients with triple-negative breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('BRCA1', 'Gene', (0, 5))	('response rates to cisplatin treatment', 'MPA', (65, 102))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('methylation', 'Var', (6, 17))	('patients', 'Species', '9606', (106, 114))	('higher', 'PosReg', (58, 64))	('BRCA1', 'Gene', '672', (0, 5))
840051	26967246	FANCF methylation is correlated with cisplatin sensitivity in ovarian cancer cells.	('cisplatin sensitivity', 'MPA', (37, 58))	('FANCF', 'Gene', '2188', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('FANCF', 'Gene', (0, 5))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (62, 76))	('methylation', 'Var', (6, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('correlated', 'Reg', (21, 31))	('ovarian cancer', 'Disease', (62, 76))
840052	26967246	Demethylation of FANCF leads to acquired cisplatinum resistance.	('FA', 'Phenotype', 'HP:0001994', (17, 19))	('FANCF', 'Gene', '2188', (17, 22))	('cisplatinum', 'Chemical', 'MESH:D002945', (41, 52))	('acquired cisplatinum resistance', 'MPA', (32, 63))	('Demethylation', 'Var', (0, 13))	('FANCF', 'Gene', (17, 22))	('leads to', 'Reg', (23, 31))
840053	26967246	CHFR methylation is a docetaxel sensitive marker in human esophageal, breast, gastric and other cancers.	('CHFR', 'Gene', (0, 4))	('CHFR', 'Gene', '55743', (0, 4))	('methylation', 'Var', (5, 16))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast', 'Disease', (70, 76))	('human', 'Species', '9606', (52, 57))	('esophageal', 'Disease', (58, 68))	('docetaxel', 'Chemical', 'MESH:D000077143', (22, 31))	('gastric and other cancers', 'Disease', 'MESH:D013274', (78, 103))
840054	26967246	MLH1 methylation is a resistance marker of oxaliplatin in human gastric cancer.	('methylation', 'Var', (5, 16))	('human', 'Species', '9606', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('MLH1', 'Gene', (0, 4))	('gastric cancer', 'Disease', (64, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (43, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))
840056	26967246	Methylation of ATM sensitized glioma and colorectal cancer cells to ionizing radiation therapy.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ATM', 'Gene', (15, 18))	('Methylation', 'Var', (0, 11))	('colorectal cancer', 'Disease', (41, 58))	('ATM', 'Gene', '472', (15, 18))	('glioma', 'Disease', (30, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('sensitized', 'Reg', (19, 29))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
840057	26967246	As described above, disruption of DNA repair can promote genetic instability and further lead to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('lead to', 'Reg', (89, 96))	('disruption', 'Var', (20, 30))	('tumor', 'Disease', (97, 102))	('genetic instability', 'CPA', (57, 76))	('promote', 'PosReg', (49, 56))	('DNA repair', 'Gene', (34, 44))
840058	26967246	On the other hand, defects in DNA damage repair sensitize cancer cells to DNA damaging agents.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('defects', 'Var', (19, 26))	('cancer', 'Disease', (58, 64))	('sensitize', 'Reg', (48, 57))
840060	26967246	In MLH1 methylated ovarian and colon cancer xenografts, cancer cells were sensitized to carboplatin, cisplatin, TMZ and epirubicin after re-expression of MLH1 by decitabine.	('cisplatin', 'MPA', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('TMZ', 'Chemical', 'MESH:D000077204', (112, 115))	('sensitized', 'Reg', (74, 84))	('cancer', 'Disease', (56, 62))	('methylated', 'Var', (8, 18))	('epirubicin', 'MPA', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('colon cancer', 'Phenotype', 'HP:0003003', (31, 43))	('carboplatin', 'Chemical', 'MESH:D016190', (88, 99))	('decitabine', 'Chemical', 'MESH:D000077209', (162, 172))	('cancer', 'Disease', (37, 43))	('carboplatin', 'MPA', (88, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('MLH1', 'Gene', (3, 7))	('epirubicin', 'Chemical', 'MESH:D015251', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('TMZ', 'MPA', (112, 115))	('ovarian and colon cancer', 'Disease', 'MESH:D010051', (19, 43))
840061	26967246	Another study demonstrated that demethylation of MLH1 was induced by low-dose 5-aza-dC and the sensitivity of radiotherapy was enhanced in colorectal cancer.	('enhanced', 'PosReg', (127, 135))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (78, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (139, 156))	('demethylation', 'MPA', (32, 45))	('induced', 'Reg', (58, 65))	('MLH1', 'Gene', (49, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (139, 156))	('5-aza-dC', 'Var', (78, 86))	('sensitivity', 'MPA', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colorectal cancer', 'Disease', (139, 156))
840065	26967246	While, SGI-110 is controversial in the treatment of gastric and ovarian cancer in combination with oxaliplatin in patients with MLH1 methylation.	('SGI', 'Gene', (7, 10))	('methylation', 'Var', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('SGI', 'Gene', '6406', (7, 10))	('gastric and ovarian cancer', 'Disease', 'MESH:D013274', (52, 78))	('MLH1', 'Gene', (128, 132))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (99, 110))	('patients', 'Species', '9606', (114, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))
840067	26967246	XPG methylation leads to disruption of the NER system and is related to resistance of nemorubicin, a doxorubicin derivative.	('disruption', 'MPA', (25, 35))	('XPG', 'Gene', '2073', (0, 3))	('XPG', 'Gene', (0, 3))	('methylation', 'Var', (4, 15))	('related', 'Reg', (61, 68))	('nemorubicin', 'Chemical', 'MESH:C000609287', (86, 97))	('NER system', 'MPA', (43, 53))	('doxorubicin', 'Chemical', 'MESH:D004317', (101, 112))
840069	26967246	The concept of synthetic lethality originates from studies in drosophila model systems in which a combination of mutations in two or more separate genes leads to cell death.	('mutations', 'Var', (113, 122))	('leads to', 'Reg', (153, 161))	('drosophila', 'Species', '7227', (62, 72))	('cell death', 'CPA', (162, 172))
840070	26967246	Although only less than 10% of sporadic ovarian cancer and 5% of breast cancer harbored BRCA1 mutations, BRCA1 methylation is observed in approximately 11-14% of breast cancer and 5%-31% of ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('sporadic ovarian cancer', 'Disease', 'MESH:D010051', (31, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('observed', 'Reg', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('BRCA1', 'Gene', '672', (88, 93))	('BRCA1', 'Gene', '672', (105, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (190, 204))	('BRCA1', 'Gene', (88, 93))	('BRCA1', 'Gene', (105, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (40, 54))	('mutations', 'Var', (94, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('sporadic ovarian cancer', 'Disease', (31, 54))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Disease', (162, 175))	('ovarian cancer', 'Disease', (190, 204))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('breast cancer', 'Disease', (65, 78))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (40, 54))
840073	26967246	Targeting RAD52 can also induce synthetic lethality in BRCA-deficient leukemias.	('leukemias', 'Phenotype', 'HP:0001909', (70, 79))	('RAD52', 'Gene', '5893', (10, 15))	('BRCA-deficient leukemias', 'Disease', 'MESH:D007938', (55, 79))	('BRCA-deficient leukemias', 'Disease', (55, 79))	('synthetic lethality', 'MPA', (32, 51))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('Targeting', 'Var', (0, 9))	('RAD52', 'Gene', (10, 15))
840074	26967246	In addition, colorectal cancer cells with defects in MSH2 or MLH1 are sensitized to methotrexate.	('defects', 'Var', (42, 49))	('MSH2', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('MSH2', 'Gene', '4436', (53, 57))	('MLH1', 'Gene', (61, 65))	('sensitized', 'Reg', (70, 80))	('colorectal cancer', 'Disease', (13, 30))	('methotrexate', 'Chemical', 'MESH:D008727', (84, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
840076	26967246	Thus, pharmacological inhibition of the "backup" pathway in combination with DNA damage will selectively kill cancer cells but spare their normal counterparts.	('pharmacological inhibition', 'Var', (6, 32))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
840077	26967246	DNA damage repair deficiency was found in various human cancers by gene mutation or promoter region hypermethylation, including MLH1, MSH2, MGMT, BRCA1, BRCA2 and others.	('cancers', 'Disease', (56, 63))	('hypermethylation', 'Var', (100, 116))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('gene mutation', 'Var', (67, 80))	('BRCA2', 'Gene', (153, 158))	('MSH2', 'Gene', (134, 138))	('BRCA1', 'Gene', '672', (146, 151))	('MSH2', 'Gene', '4436', (134, 138))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('promoter', 'MPA', (84, 92))	('BRCA1', 'Gene', (146, 151))	('BRCA2', 'Gene', '675', (153, 158))	('human', 'Species', '9606', (50, 55))	('deficiency', 'NegReg', (18, 28))	('MGMT', 'Gene', (140, 144))	('MGMT', 'Gene', '4255', (140, 144))
840080	26967246	Blockade of this pathway with antibodies to PD-1 or its ligands has led to remarkable clinical responses in patients with many different types of cancer.	('PD-1', 'Gene', (44, 48))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('PD-1', 'Gene', '5133', (44, 48))	('Blockade', 'NegReg', (0, 8))	('antibodies', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('patients', 'Species', '9606', (108, 116))
840081	26967246	Epigenetic inactivation of DNA damage repair genes could induce gene mutations and lead to alterations in the expression of tumor-associated self-antigens, therefore altering the antigenicity of the tumor.	('tumor', 'Disease', (199, 204))	('DNA', 'Gene', (27, 30))	('gene mutations', 'MPA', (64, 78))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('alterations', 'Reg', (91, 102))	('altering', 'Reg', (166, 174))	('expression', 'MPA', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('induce', 'Reg', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('antigenicity', 'MPA', (179, 191))	('Epigenetic inactivation', 'Var', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
840088	26967246	Thus, inhibition of these immune checkpoints can enhance T-cell responses and mediate effective antitumor activity in MMR defective cancers.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('enhance T-cell responses', 'Phenotype', 'HP:0005419', (49, 73))	('tumor', 'Disease', (100, 105))	('defective cancers', 'Disease', (122, 139))	('enhance', 'PosReg', (49, 56))	('defective cancers', 'Disease', 'MESH:D009369', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('inhibition', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('T-cell responses', 'CPA', (57, 73))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
840089	26967246	In addition to the MMR system, deficiencies of other DNA damage repair pathways play important roles in tumorigenesis.	('deficiencies', 'Var', (31, 43))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
840095	26967246	MGMT methylation serves as a sensitive marker for alkylating agents in glioma patients, and CHFR methylation sensitizes esophageal cancer cells to docetaxel.	('MGMT', 'Gene', (0, 4))	('docetaxel', 'Chemical', 'MESH:D000077143', (147, 156))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('glioma', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('patients', 'Species', '9606', (78, 86))	('sensitizes', 'Reg', (109, 119))	('CHFR', 'Gene', (92, 96))	('CHFR', 'Gene', '55743', (92, 96))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('esophageal cancer', 'Disease', (120, 137))	('MGMT', 'Gene', '4255', (0, 4))	('methylation', 'Var', (97, 108))
840105	27748414	Deficiencies in B vitamins may increase the probability of disruption of this metabolic pathway and result in aberrations in DNA methylation, imbalance in DNA precursors, and deficiency in DNA repair, each of which can contribute to carcinogenesis.	('Deficiencies', 'Var', (0, 12))	('imbalance', 'Phenotype', 'HP:0002172', (142, 151))	('carcinogenesis', 'Disease', 'MESH:D063646', (233, 247))	('deficiency', 'Disease', 'MESH:D007153', (175, 185))	('B', 'Chemical', 'MESH:D001895', (16, 17))	('contribute', 'Reg', (219, 229))	('DNA repair', 'MPA', (189, 199))	('DNA methylation', 'MPA', (125, 140))	('carcinogenesis', 'Disease', (233, 247))	('imbalance in DNA precursors', 'MPA', (142, 169))	('deficiency', 'Disease', (175, 185))	('increase', 'PosReg', (31, 39))
840112	27748414	However, a multicenter population-based case-control study in the United States found that the participants with high riboflavin intake had a non-significantly increased risk for OSCC or gastric cardia adenocarcinoma (GCA).	('high', 'Var', (113, 117))	('participants', 'Species', '9606', (95, 107))	('gastric cardia adenocarcinoma', 'Disease', (187, 216))	('high riboflavin intake', 'Phenotype', 'HP:0100504', (113, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('OSCC', 'Disease', (179, 183))	('riboflavin', 'Chemical', 'MESH:D012256', (118, 128))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (187, 216))
840149	27748414	When modeled as a continuous variable, serum riboflavin was significantly inversely associated with the risk of OSCC (HR: 0.94; 95% CI: 0.90 to 0.98) (Table 4).	('inversely', 'NegReg', (74, 83))	('riboflavin', 'Chemical', 'MESH:D012256', (45, 55))	('OSCC', 'Disease', (112, 116))	('serum', 'Var', (39, 44))
840192	27748414	A study in Urguay, however, found a decreased risk of esophageal cancer with a high dietary folate intake, but the cases of esophageal cancer were not divided by histology.	('high dietary folate', 'Phenotype', 'HP:0032164', (79, 98))	('esophageal cancer', 'Disease', (124, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('esophageal cancer', 'Disease', (54, 71))	('high', 'Var', (79, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('folate', 'Chemical', 'MESH:D005492', (92, 98))	('decreased', 'NegReg', (36, 45))
840194	27748414	In this study, serum vitamin B12 was inversely associated with OSCC, but this association was limited to the the analysis where serum vitamin B12 as a continuous variable.	('serum vitamin', 'Var', (15, 28))	('B12', 'Gene', '4709', (142, 145))	('associated', 'Interaction', (47, 57))	('inversely', 'NegReg', (37, 46))	('B12', 'Gene', (29, 32))	('B12', 'Gene', '4709', (29, 32))	('B12', 'Gene', (142, 145))	('OSCC', 'Disease', (63, 67))
840317	25266014	These studies demonstrate a role for LPR in laryngeal inflammatory disease, similar to what is known for GERD in the esophagus.	('laryngeal inflammatory disease', 'Disease', (44, 74))	('rat', 'Species', '10116', (21, 24))	('LPR', 'Var', (37, 40))	('GERD', 'Disease', 'MESH:D005764', (105, 109))	('GERD', 'Disease', (105, 109))
840348	25266014	RBD, sold in the food industry as red dye E162 (CHR Hansen, Milwaukee, Wisconsin), is known to contain high levels of the red dye compounds betacyanin and betalain.	('betacyanin', 'MPA', (140, 150))	('betacyanin', 'Chemical', 'MESH:D050859', (140, 150))	('E162', 'Var', (42, 46))	('betalain', 'MPA', (155, 163))
840370	25266014	Our results show that C-PAC significantly induces EAC cell death via apoptosis, autophagy, and necrosis.	('C-PAC', 'Var', (22, 27))	('autophagy', 'CPA', (80, 89))	('PAC', 'Phenotype', 'HP:0006699', (24, 27))	('C-PAC', 'Chemical', '-', (22, 27))	('EAC', 'Disease', (50, 53))	('induces', 'Reg', (42, 49))	('necrosis', 'Disease', (95, 103))	('apoptosis', 'CPA', (69, 78))	('necrosis', 'Disease', 'MESH:D009336', (95, 103))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))
840372	25266014	C-PAC maximally induces ROS levels in JHAD1 and OE33 cells, resulting in cell death via apoptosis and autophagy; yet C-PAC modestly increases ROS levels in OE19 cells, resulting in necrotic cell death.	('PAC', 'Phenotype', 'HP:0006699', (119, 122))	('apoptosis', 'CPA', (88, 97))	('ROS levels', 'MPA', (24, 34))	('necrotic cell death', 'Disease', 'MESH:D003643', (181, 200))	('necrotic cell death', 'Disease', (181, 200))	('ROS', 'Chemical', 'MESH:D017382', (24, 27))	('ROS', 'Chemical', 'MESH:D017382', (142, 145))	('C-PAC', 'Chemical', '-', (117, 122))	('increases ROS levels', 'Phenotype', 'HP:0025464', (132, 152))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('C-PAC', 'Var', (117, 122))	('autophagy', 'CPA', (102, 111))	('induces', 'Reg', (16, 23))	('cell death', 'CPA', (73, 83))	('ROS', 'MPA', (142, 145))
840373	25266014	C-PAC also induces protein expression of cell cycle markers (p16/p21) and causes an S-phase delay and cell cycle arrest at G2/M in EAC cells.	('EAC', 'Phenotype', 'HP:0011459', (131, 134))	('causes', 'Reg', (74, 80))	('S-phase delay', 'CPA', (84, 97))	('p21', 'Gene', (65, 68))	('cell cycle', 'CPA', (41, 51))	('induces', 'Reg', (11, 18))	('p16', 'Gene', (61, 64))	('p21', 'Gene', '644914', (65, 68))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (102, 119))	('C-PAC', 'Var', (0, 5))	('protein expression', 'MPA', (19, 37))	('cell cycle arrest at G2/M', 'CPA', (102, 127))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('p16', 'Gene', '1029', (61, 64))
840374	25266014	C-PAC differentially affected expression of additional cancer-linked proteins, including P-ERK1/2, BCLxL, MMP2, TRF-1, and P-4EBP1 in JHAD1 versus OE19 cells, potentially linking it to differing constitutive oxidative states, variable apoptosis resistance, and, in turn, selective activation of cell death pathways.	('P-4EBP1', 'Var', (123, 130))	('activation', 'PosReg', (281, 291))	('BCLxL', 'Gene', (99, 104))	('ERK', 'Gene', (91, 94))	('PAC', 'Phenotype', 'HP:0006699', (2, 5))	('C-PAC', 'Chemical', '-', (0, 5))	('BCLxL', 'Gene', '598', (99, 104))	('MMP2', 'Gene', (106, 110))	('cancer-linked proteins', 'Disease', 'MESH:D009369', (55, 77))	('affected', 'Reg', (21, 29))	('TRF-1', 'Gene', '7013', (112, 117))	('C-PAC', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('MMP2', 'Gene', '4313', (106, 110))	('expression', 'MPA', (30, 40))	('cell', 'CPA', (295, 299))	('ERK', 'Gene', '5594', (91, 94))	('cancer-linked proteins', 'Disease', (55, 77))	('TRF-1', 'Gene', (112, 117))
840399	26256958	In addition, unlike early gastric cancer (EGC), which harbors a favorable prognosis, advanced gastric cancer (AGC) is still challenging; over 50% of patients with AGC experience cancer recurrence in their life-time.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('gastric cancer', 'Disease', (94, 108))	('patients', 'Species', '9606', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('gastric cancer', 'Disease', (26, 40))	('AGC', 'Var', (163, 166))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (102, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (26, 40))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('EGC', 'Chemical', '-', (42, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (26, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))
840476	26256958	Although understanding of the molecular genetic underpinnings of gastric cancer has lagged behind that for other solid cancers, recent efforts to better understand gastric cancer biology has led to the discovery of a handful of genetic alterations specific to cancer cells: overexpressed proteins are present in cancer cells but not in normal cells, and specific mutant proteins drive cancer growth and survival.	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('solid cancers', 'Disease', (113, 126))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (312, 318))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))	('proteins', 'Protein', (370, 378))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('cancer', 'Disease', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', (119, 125))	('proteins', 'Protein', (288, 296))	('cancer', 'Disease', 'MESH:D009369', (385, 391))	('gastric cancer', 'Disease', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('survival', 'CPA', (403, 411))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Disease', (260, 266))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('mutant', 'Var', (363, 369))	('drive', 'PosReg', (379, 384))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('solid cancers', 'Disease', 'MESH:D009369', (113, 126))	('gastric cancer', 'Disease', (65, 79))	('cancer', 'Disease', (385, 391))
840500	26256958	Another potential candidate marker for predicting prognosis and chemo-responsiveness in gastric cancer is microsatellite instability (MSI).	('MSI', 'Disease', 'None', (134, 137))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MSI', 'Disease', (134, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('microsatellite instability', 'Var', (106, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))
840506	26256958	Recently, The Cancer Genome Atlas Research Network reported the results of molecular classification of gastric cancer through integrative genomic analyses, which suggested that gastric cancer could be divided into four subtypes: 1) Epstein-Barr virus-related tumors that exhibit recurrent PIK3CA mutation, hypermethylation of DNA, and overexpression of PD-L1/2; 2) MSI represented by elevated mutation rates and MLH1 silencing, which is one of the main MMR genes; 3) genomically stable tumors that are strongly related with diffuse histology, RHOA mutations, and CLDN18-ARHGAP fusion; and 4) chromosomal instability that mainly comprise intestinal histology, TP53 mutation, and focal amplification of receptor tyrosine kinases.	('gastric cancer', 'Disease', 'MESH:D013274', (177, 191))	('chromosomal', 'Disease', (592, 603))	('intestinal histology', 'Disease', (637, 657))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('Cancer', 'Disease', (14, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('tumors', 'Disease', 'MESH:D009369', (486, 492))	('receptor tyrosine kinases', 'Enzyme', (701, 726))	('TP53', 'Gene', '7157', (659, 663))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', (259, 265))	('gastric cancer', 'Phenotype', 'HP:0012126', (177, 191))	('Cancer', 'Disease', 'MESH:D009369', (14, 20))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('related', 'Reg', (511, 518))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('chromosomal instability', 'Phenotype', 'HP:0040012', (592, 615))	('tumors', 'Phenotype', 'HP:0002664', (486, 492))	('gastric cancer', 'Disease', (177, 191))	('TP53', 'Gene', (659, 663))	('tumor', 'Phenotype', 'HP:0002664', (486, 491))	('MSI', 'Disease', 'None', (365, 368))	('gastric cancer', 'Disease', (103, 117))	('Epstein-Barr virus', 'Species', '10376', (232, 250))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('focal amplification', 'Var', (678, 697))	('MSI', 'Disease', (365, 368))	('tumors', 'Disease', (486, 492))
840507	26256958	Further, another study reported that gastric cancer can be classified into four molecular subtypes as follows: microsatellite unstable, microsatellite stable (MSS) with/without TP53 mutation, and MSS with epithelial-to-mesenchymal transition (EMT) type.	('gastric cancer', 'Disease', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('epithelial-to-mesenchymal transition', 'CPA', (205, 241))	('microsatellite', 'MPA', (111, 125))	('TP53', 'Gene', '7157', (177, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))	('mutation', 'Var', (182, 190))	('TP53', 'Gene', (177, 181))
840523	25863539	The UCSC Cancer Genomics Browser's Kaplan-Meier plot suggested that patients in the high HNF1A-AS1 expression subgroup experienced worse overall survival compared to the low expression subgroup.	('high', 'Var', (84, 88))	('worse', 'NegReg', (131, 136))	('patients', 'Species', '9606', (68, 76))	('overall survival', 'MPA', (137, 153))	('HNF1A-AS1', 'Gene', (89, 98))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('HNF1A-AS1', 'Gene', '283460', (89, 98))
840537	25863539	Emerging evidence suggests that the dysregulation of lncRNAs is linked with the development and metastasis of various types of cancers including lung cancer, making a complete understanding of their biological functions in EMT important for understanding the molecular biology of lung adenocarcinoma metastasis and progression.	('dysregulation', 'Var', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (280, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('lung adenocarcinoma metastasis', 'Disease', 'MESH:D009362', (280, 310))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('lung cancer', 'Disease', (145, 156))	('linked', 'Reg', (64, 70))	('lung adenocarcinoma metastasis', 'Disease', (280, 310))	('cancers', 'Disease', (127, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
840541	25863539	These results indicated that the dysregulation of HNF1A-AS1 could participate in esophageal adenocarcinoma.	('dysregulation', 'Var', (33, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('HNF1A-AS1', 'Gene', (50, 59))	('esophageal adenocarcinoma', 'Disease', (81, 106))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (81, 106))	('HNF1A-AS1', 'Gene', '283460', (50, 59))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (81, 106))	('participate', 'Reg', (66, 77))
840553	25863539	The browser's Kaplan-Meier plot suggests that the patients in the high HNF1A-AS1 expression subgroup (red line) have worse overall survival compared to the low expression subgroup (green line).	('patients', 'Species', '9606', (50, 58))	('worse', 'NegReg', (117, 122))	('overall survival', 'MPA', (123, 139))	('HNF1A-AS1', 'Gene', (71, 80))	('high', 'Var', (66, 70))	('HNF1A-AS1', 'Gene', '283460', (71, 80))	('expression', 'MPA', (81, 91))
840560	25863539	At 48 h post-transfection, HNF1A-AS1 expression was knocked down by approximately 80% in A549 and SPC-A1 cells by si-HNF1A-AS1 transfection when compared with the scrambled siRNA (Figure 2B).	('HNF1A-AS1', 'Gene', (27, 36))	('HNF1A-AS1', 'Gene', (117, 126))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('transfection', 'Var', (127, 139))	('HNF1A-AS1', 'Gene', '283460', (27, 36))	('HNF1A-AS1', 'Gene', '283460', (117, 126))	('expression', 'MPA', (37, 47))	('knocked down', 'NegReg', (52, 64))
840565	25863539	Compared to the scrambled siRNA-transfected cells, HNF1A-AS1 knockdown resulted in a significant decrease in A549 and SPC-A1 cell viability as monitored by a MTT assay (Figure 3A and 3B).	('MTT', 'Chemical', 'MESH:C070243', (158, 161))	('HNF1A-AS1', 'Gene', (51, 60))	('HNF1A-AS1', 'Gene', '283460', (51, 60))	('knockdown', 'Var', (61, 70))	('decrease', 'NegReg', (97, 105))	('A549', 'CellLine', 'CVCL:0023', (109, 113))
840568	25863539	However, siRNA-mediated knockdown of HNF1A-AS1 in SPC-A1 did not promote G1 arrest (Figure 3E and 3F).	('HNF1A-AS1', 'Gene', '283460', (37, 46))	('knockdown', 'Var', (24, 33))	('HNF1A-AS1', 'Gene', (37, 46))	('G1 arrest', 'CPA', (73, 82))
840572	25863539	Fourteen days after injection, HNF1A-AS1 knock-down dramatically inhibited tumor growth compared to the control group, as demonstrated by substantially reduced tumor size and weight (Figure 4A-4C).	('HNF1A-AS1', 'Gene', (31, 40))	('HNF1A-AS1', 'Gene', '283460', (31, 40))	('knock-down', 'Var', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('reduced', 'NegReg', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('inhibited', 'NegReg', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', (75, 80))
840574	25863539	The down-regulation of HNF1A-AS1 in tumors after sh-HNF1A-AS1 transfection was confirmed by qRT-PCR analysis (Figure 4D).	('HNF1A-AS1', 'Gene', (52, 61))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('HNF1A-AS1', 'Gene', '283460', (52, 61))	('HNF1A-AS1', 'Gene', (23, 32))	('HNF1A-AS1', 'Gene', '283460', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('transfection', 'Var', (62, 74))	('tumors', 'Disease', (36, 42))	('down-regulation', 'NegReg', (4, 19))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
840577	25863539	Decreased HNF1A-AS1 expression impeded A549 cell migration by 61% and 49% when knocked down by siRNA1 and siRNA2, respectively (Figure 5A and 5B), and by 61% and 43% in SPC-A1 (Figure 5C and 5D).	('HNF1A-AS1', 'Gene', '283460', (10, 19))	('expression', 'MPA', (20, 30))	('Decreased', 'NegReg', (0, 9))	('impeded', 'NegReg', (31, 38))	('A549', 'CellLine', 'CVCL:0023', (39, 43))	('HNF1A-AS1', 'Gene', (10, 19))	('knocked', 'Var', (79, 86))
840582	25863539	HNF1A-AS1 knock-down led to a reduction in the number of metastatic nodules compared with the control group (Figure 5E, 5F).	('knock-down', 'Var', (10, 20))	('reduction', 'NegReg', (30, 39))	('HNF1A-AS1', 'Gene', '283460', (0, 9))	('HNF1A-AS1', 'Gene', (0, 9))
840589	25863539	DNA methylation is a key epigenetic mechanism involved in transcriptional regulation that has been associated with a large number of human malignancies.	('malignancies', 'Disease', (139, 151))	('methylation', 'Var', (4, 15))	('human', 'Species', '9606', (133, 138))	('malignancies', 'Disease', 'MESH:D009369', (139, 151))	('associated', 'Reg', (99, 109))
840609	25863539	LncRNA dysregulation may be involved in epigenetics and participate in cancer growth and metastasis.	('participate', 'Reg', (56, 67))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('involved', 'Reg', (28, 36))	('LncRNA', 'Protein', (0, 6))	('dysregulation', 'Var', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('metastasis', 'CPA', (89, 99))	('epigenetics', 'MPA', (40, 51))
840618	25863539	In addition, HNF1A-AS1 knockdown significantly inhibited lung adenocarcinoma cell viability, G1-G0 phase arrest, migration, and invasion both in vitro and in vivo.	('HNF1A-AS1', 'Gene', '283460', (13, 22))	('inhibited', 'NegReg', (47, 56))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('G1-G0 phase arrest', 'CPA', (93, 111))	('knockdown', 'Var', (23, 32))	('lung adenocarcinoma', 'Disease', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('migration', 'CPA', (113, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('HNF1A-AS1', 'Gene', (13, 22))	('invasion', 'CPA', (128, 136))
840653	25863539	We observed that the silencing of HNF1A-AS1 in lung adenocarcinoma cells dramatically blocked tumor growth and metastasis in vivo and in vitro, raising the possibility that HNF1A-AS1 could be a promising new therapeutic target for highly aggressive lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('HNF1A-AS1', 'Gene', '283460', (34, 43))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (249, 268))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('aggressive lung adenocarcinoma', 'Disease', (238, 268))	('tumor', 'Disease', (94, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('HNF1A-AS1', 'Gene', (173, 182))	('HNF1A-AS1', 'Gene', '283460', (173, 182))	('blocked', 'NegReg', (86, 93))	('lung adenocarcinoma', 'Disease', (47, 66))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (249, 268))	('aggressive lung adenocarcinoma', 'Disease', 'MESH:D000077192', (238, 268))	('silencing', 'Var', (21, 30))	('HNF1A-AS1', 'Gene', (34, 43))
840700	25614244	Association between PLCE1 rs2274223 A > G polymorphism and cancer risk: proof from a meta-analysis Phospholipase C epsilon 1 (PLCE1) plays an important role in cell growth, differentiation and oncogenesis.	('Phospholipase C epsilon 1', 'Gene', '51196', (99, 124))	('Phospholipase C epsilon 1', 'Gene', (99, 124))	('cell growth', 'CPA', (160, 171))	('rs2274223', 'Mutation', 'rs2274223', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('rs2274223 A > G', 'Var', (26, 41))	('PLCE1', 'Gene', (126, 131))	('differentiation', 'CPA', (173, 188))	('PLCE1', 'Gene', '51196', (126, 131))	('PLCE1', 'Gene', (20, 25))	('PLCE1', 'Gene', '51196', (20, 25))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('oncogenesis', 'CPA', (193, 204))
840701	25614244	An increasing number of individual studies have investigated the association between PLCE1 rs2274223 polymorphism and cancer risk, but the conclusions are inconclusive.	('cancer', 'Disease', (118, 124))	('investigated', 'Reg', (48, 60))	('rs2274223', 'Mutation', 'rs2274223', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('PLCE1', 'Gene', (85, 90))	('PLCE1', 'Gene', '51196', (85, 90))	('rs2274223', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
840702	25614244	The pooled results indicated that PLCE1 rs2274223 A > G polymorphism was associated with an increased risk of overall cancer (G vs. A: OR = 1.15, 95% CI = 1.06-1.25; GG vs. AA: OR = 1.30, 95% CI = 1.10-1.55; GA vs. AA: OR = 1.18, 95% CI = 1.08-1.30; GG/GA vs. AA: OR = 1.20, 95% CI = 1.08-1.32; GG vs. GA/AA: OR = 1.22, 95% CI = 1.04-1.42).	('cancer', 'Disease', (118, 124))	('rs2274223', 'Mutation', 'rs2274223', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs2274223 A > G', 'Var', (40, 55))	('PLCE1', 'Gene', (34, 39))	('PLCE1', 'Gene', '51196', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
840703	25614244	The stratification analysis showed the polymorphism was significantly associated with an increased risk of esophageal squamous cell carcinoma (ESCC) other than gastric cancer (GC), especially among the subgroups of Asian, high quality score, sample size > 1000 and the studies consistent with Hardy-Weinberg equilibrium (HWE).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('gastric cancer', 'Disease', (160, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('gastric cancer', 'Disease', 'MESH:D013274', (160, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('GC', 'Phenotype', 'HP:0012126', (176, 178))	('associated', 'Reg', (70, 80))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (160, 174))	('polymorphism', 'Var', (39, 51))
840704	25614244	This meta-analysis demonstrated that PLCE1 rs2274223 A > G polymorphism may be associated with increased susceptibility to cancer, especially for ESCC.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('susceptibility', 'Reg', (105, 119))	('PLCE1', 'Gene', (37, 42))	('rs2274223', 'Mutation', 'rs2274223', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('rs2274223 A > G', 'Var', (43, 58))	('PLCE1', 'Gene', '51196', (37, 42))	('cancer', 'Disease', (123, 129))	('ESCC', 'Disease', (146, 150))
840710	25614244	In 2010, Abnet et al firstly performed a GWAS of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in Chinese populations and identified variants located in the PLCE1 gene at chromosome 10q23 had a genome-wide significantly correlation with gastric cardia cancer (GCA) and ESCC.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (73, 107))	('gastric cardia cancer', 'Disease', (257, 278))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('PLCE1', 'Gene', (177, 182))	('GC', 'Phenotype', 'HP:0012126', (65, 67))	('PLCE1', 'Gene', '51196', (177, 182))	('esophageal squamous cell carcinoma', 'Disease', (73, 107))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (257, 278))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('variants', 'Var', (153, 161))	('ESCC', 'Disease', (289, 293))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('GC', 'Phenotype', 'HP:0012126', (280, 282))	('gastric cancer', 'Disease', (49, 63))	('correlation with', 'Reg', (240, 256))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))
840712	25614244	Later, Wu et al further confirmed seven single nucleotide polymorphisms (SNPs) at five regions significantly associated with ESCC, among which is PLCE1 rs2274223 that has also been found in the former two GWASs.	('PLCE1', 'Gene', '51196', (146, 151))	('associated', 'Reg', (109, 119))	('rs2274223', 'Var', (152, 161))	('ESCC', 'Disease', (125, 129))	('rs2274223', 'Mutation', 'rs2274223', (152, 161))	('PLCE1', 'Gene', (146, 151))
840713	25614244	Rs2274223, located in the 26th exon of the PLCE1 gene, is a non-synonymous SNP that can cause the amino acid change from histidine to arginine.	('Rs2274223', 'Mutation', 'Rs2274223', (0, 9))	('arginine', 'Chemical', 'MESH:D001120', (134, 142))	('PLCE1', 'Gene', (43, 48))	('PLCE1', 'Gene', '51196', (43, 48))	('amino acid change from histidine to arginine', 'MPA', (98, 142))	('histidine', 'Chemical', 'MESH:D006639', (121, 130))	('Rs2274223', 'Var', (0, 9))	('cause', 'Reg', (88, 93))
840714	25614244	Since three related GWASs were completed, SNP rs2274223 in PLCE1 became one of the most studied polymorphic loci.	('PLCE1', 'Gene', '51196', (59, 64))	('rs2274223', 'Mutation', 'rs2274223', (46, 55))	('PLCE1', 'Gene', (59, 64))	('SNP rs2274223', 'Var', (42, 55))
840716	25614244	Therefore, we performed a meta-analysis of all eligible case-control studies to systematically estimate the effects of PLCE1 rs2274223 A > G polymorphism on the susceptibility to cancer.	('rs2274223', 'Mutation', 'rs2274223', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PLCE1', 'Gene', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PLCE1', 'Gene', '51196', (119, 124))	('cancer', 'Disease', (179, 185))	('rs2274223 A > G', 'Var', (125, 140))
840718	25614244	The associations of PLCE1 rs2274223 polymorphism with the risk of different types of cancer were shown in Table 2, Figure 2.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('rs2274223', 'Mutation', 'rs2274223', (26, 35))	('cancer', 'Disease', (85, 91))	('rs2274223', 'Var', (26, 35))	('PLCE1', 'Gene', (20, 25))	('PLCE1', 'Gene', '51196', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('associations', 'Interaction', (4, 16))
840719	25614244	In GC, stratification analysis by genotyping methods showed that rs2274223 was significantly associated with the risk of GC using TaqMan (G vs. A: OR = 1.20, 95% CI = 1.04-1.39; GA vs. AA: OR = 1.27, 95% CI = 1.12-1.44; GG/GA vs. AA: OR = 1.28, 95% CI = 1.10-1.49).	('GC', 'Phenotype', 'HP:0012126', (3, 5))	('GC', 'Phenotype', 'HP:0012126', (121, 123))	('associated', 'Reg', (93, 103))	('rs2274223', 'Mutation', 'rs2274223', (65, 74))	('rs2274223', 'Var', (65, 74))
840720	25614244	Furthermore, in the stratified analysis by HWE in controls, we found a significant increased association between PLCE1 rs2274223 polymorphism and ESCC risk in the studies consistent with HWE (G vs. A: OR = 1.29, 95% CI = 1.13-1.47; GG vs. AA: OR = 1.62, 95% CI = 1.21-2.15; GA vs. AA: OR = 1.32, 95% CI = 1.19-1.46; GG/GA vs. AA: OR = 1.37, 95% CI = 1.20-1.56; GG vs. GA/AA: OR = 1.42, 95% CI = 1.10-1.83) (Table 3).	('rs2274223 polymorphism', 'Var', (119, 141))	('PLCE1', 'Gene', (113, 118))	('association', 'Interaction', (93, 104))	('rs2274223', 'Mutation', 'rs2274223', (119, 128))	('polymorphism', 'Var', (129, 141))	('PLCE1', 'Gene', '51196', (113, 118))	('ESCC', 'Disease', (146, 150))
840721	25614244	In the meta-analysis, we comprehensively evaluate the association between PLCE1 rs2274223 polymorphism and cancer risk through 22 studies with 13188 cases and 14666 controls.	('rs2274223', 'Mutation', 'rs2274223', (80, 89))	('rs2274223', 'Var', (80, 89))	('PLCE1', 'Gene', (74, 79))	('PLCE1', 'Gene', '51196', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
840722	25614244	We observed the genetic variation significantly increased the risk of overall cancer, especially for ESCC.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('increased', 'Reg', (48, 57))	('genetic variation', 'Var', (16, 33))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('ESCC', 'Disease', (101, 105))
840728	25614244	Simultaneously, an increasing amount of studies start to investigate the association of PLCE1 rs2274223 polymorphism on the susceptibility of different cancer.	('rs2274223', 'Mutation', 'rs2274223', (94, 103))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('rs2274223', 'Var', (94, 103))	('PLCE1', 'Gene', (88, 93))	('PLCE1', 'Gene', '51196', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
840729	25614244	To our knowledge, PLCE1 mutation is closely associated with many diseases, such as nephrotic syndrome and cardiac hypertrophy.	('associated', 'Reg', (44, 54))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (106, 125))	('nephrotic syndrome', 'Disease', (83, 101))	('nephrotic syndrome', 'Phenotype', 'HP:0000100', (83, 101))	('cardiac hypertrophy', 'Disease', (106, 125))	('mutation', 'Var', (24, 32))	('PLCE1', 'Gene', (18, 23))	('nephrotic syndrome', 'Disease', 'MESH:D009404', (83, 101))	('PLCE1', 'Gene', '51196', (18, 23))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (106, 125))
840730	25614244	Although the PLCE1 rs2274223 polymorphism is associated with a high risk of cancers, the exact mechanism is still unknown.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('rs2274223', 'Mutation', 'rs2274223', (19, 28))	('rs2274223', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('associated', 'Reg', (45, 55))	('PLCE1', 'Gene', (13, 18))	('PLCE1', 'Gene', '51196', (13, 18))
840734	25614244	Two previously meta-analyses have investigated the association between PLCE1 rs2274223 and different kinds of cancer.	('cancer', 'Disease', (110, 116))	('PLCE1', 'Gene', (71, 76))	('association', 'Interaction', (51, 62))	('rs2274223', 'Mutation', 'rs2274223', (77, 86))	('rs2274223', 'Var', (77, 86))	('PLCE1', 'Gene', '51196', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
840735	25614244	Both of them demonstrated that the polymorphism increased the risk of cancer in the pooling analysis, which was the same with ours.	('increased', 'PosReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('polymorphism', 'Var', (35, 47))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
840736	25614244	In the stratification analysis, the former publication showed that PLCE1 rs2274223 polymorphism contributed to the high risk of esophageal and gastric cancer in Asians.	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('esophageal', 'Disease', 'MESH:D004941', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('PLCE1', 'Gene', (67, 72))	('gastric cancer', 'Disease', (143, 157))	('PLCE1', 'Gene', '51196', (67, 72))	('esophageal', 'Disease', (128, 138))	('rs2274223 polymorphism', 'Var', (73, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('rs2274223', 'Mutation', 'rs2274223', (73, 82))
840738	25614244	Therefore, the association between the PLCE1 rs2274223 polymorphism and EAC risk was ambiguous.	('rs2274223', 'Var', (45, 54))	('PLCE1', 'Gene', (39, 44))	('EAC', 'Disease', (72, 75))	('PLCE1', 'Gene', '51196', (39, 44))	('EAC', 'Phenotype', 'HP:0011459', (72, 75))	('rs2274223', 'Mutation', 'rs2274223', (45, 54))
840739	25614244	The latter study identified PLCE1 rs2274223 polymorphism was associated with the risk of upper aerodigestive tract cancer (ESCC, EC, HNC and SCCHN) but not with gastric and colorectal cancer.	('colorectal cancer', 'Disease', (173, 190))	('upper aerodigestive tract cancer', 'Disease', (89, 121))	('gastric', 'Disease', 'MESH:D013274', (161, 168))	('gastric', 'Disease', (161, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (89, 121))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('HNC', 'Phenotype', 'HP:0012288', (133, 136))	('associated', 'Reg', (61, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))	('rs2274223', 'Mutation', 'rs2274223', (34, 43))	('rs2274223', 'Var', (34, 43))	('PLCE1', 'Gene', (28, 33))	('HNC', 'Disease', (133, 136))	('PLCE1', 'Gene', '51196', (28, 33))
840741	25614244	Some studies have discovered some sequence variants in the region of chromosome, such as 5p15.33 and 8q24, are associated with risk of different cancer types, so we speculated that rs2274223 may be the specific site associated with different cancer types.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('associated', 'Reg', (216, 226))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('associated', 'Reg', (111, 121))	('rs2274223', 'Mutation', 'rs2274223', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('rs2274223', 'Var', (181, 190))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
840742	25614244	However, in the further subgroup analyses, we found rs2274223 significantly associated with an increased risk of ESCC rather than GC which suggested it has no non-specific effect on different types of cancer.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('ESCC', 'Disease', (113, 117))	('rs2274223', 'Var', (52, 61))	('cancer', 'Disease', (201, 207))	('associated', 'Reg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('GC', 'Phenotype', 'HP:0012126', (130, 132))	('rs2274223', 'Mutation', 'rs2274223', (52, 61))
840743	25614244	So, it appropriate or not to calculate the association of genetic variation with the risk of cancer by pooling the data from different type of cancer remains open to question although researchers have always done this way.	('genetic variation', 'Var', (58, 75))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
840744	25614244	Additionally, further functional studies should be carried out to explore the mechanism underlying the variant-related associations with cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('variant-related', 'Var', (103, 118))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('associations', 'Interaction', (119, 131))
840748	25614244	In conclusion, the meta-analysis suggests that PLCE1 rs2274223 polymorphism may be associated with increased susceptibility to cancer, especially for ESCC.	('susceptibility', 'Reg', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs2274223', 'Mutation', 'rs2274223', (53, 62))	('rs2274223', 'Var', (53, 62))	('PLCE1', 'Gene', (47, 52))	('ESCC', 'Disease', (150, 154))	('PLCE1', 'Gene', '51196', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
840751	25614244	Study focus on the association of PLCE1 rs2274223 polymorphism and cancer susceptibility; (c).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('rs2274223', 'Mutation', 'rs2274223', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs2274223', 'Var', (40, 49))	('PLCE1', 'Gene', (34, 39))	('PLCE1', 'Gene', '51196', (34, 39))	('association', 'Interaction', (19, 30))
840753	25614244	The genetic association between the PLCE1 rs2274223 polymorphism and the risk of cancer was evaluated by the pooled odds ratios (OR) and 95% confidence interval (CI).	('rs2274223', 'Var', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('PLCE1', 'Gene', (36, 41))	('PLCE1', 'Gene', '51196', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('rs2274223', 'Mutation', 'rs2274223', (42, 51))
840819	25009662	In addition, the results showed that in tumors with low and intermediate differentiation, the expression of CD146 was higher than that in highly differentiated tumors (55.6, 50.0 and 31.3% respectively), although the differences were not statistically significant.	('higher', 'PosReg', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('CD146', 'Gene', '4162', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('CD146', 'Gene', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('expression', 'MPA', (94, 104))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', (40, 46))	('low', 'Var', (52, 55))
840937	23613667	The AUC was calculated as 0.789 (95% confidence interval, 0.581 to 0.925) for prediction of CR by DeltaSUVmax of the main tumor.	('DeltaSUVmax', 'Var', (98, 109))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CR', 'Chemical', '-', (92, 94))	('tumor', 'Disease', (122, 127))
840939	23613667	Multivariable analysis identified an independent and positive association of DeltaSUVmax with pathologic CR of the main tumor (Table 2).	('DeltaSUVmax', 'Var', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CR', 'Chemical', '-', (105, 107))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
840947	23613667	Patients showing pathological CR appear to have better survival than those with stable disease or PR, although statistical significance was not reached (p=0.286 and p=0.444, respectively) (Fig.	('PR', 'Chemical', '-', (98, 100))	('better', 'PosReg', (48, 54))	('pathological', 'Var', (17, 29))	('Patients', 'Species', '9606', (0, 8))	('CR', 'Chemical', '-', (30, 32))	('survival', 'MPA', (55, 63))
840982	22367141	MicroRNAs could also influence the biological behaviors of esophageal cancer cells, such as cellular proliferation, apoptosis, invasion and metastasis.	('MicroRNAs', 'Var', (0, 9))	('esophageal cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('apoptosis', 'CPA', (116, 125))	('cellular proliferation', 'CPA', (92, 114))	('biological behaviors', 'CPA', (35, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('influence', 'Reg', (21, 30))
840983	22367141	MicroRNAs were also associated with multi-drug resistance of esophageal cancer.	('MicroRNAs', 'Var', (0, 9))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('drug resistance', 'Phenotype', 'HP:0020174', (42, 57))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('associated with', 'Reg', (20, 35))	('esophageal cancer', 'Disease', (61, 78))	('multi-drug resistance', 'MPA', (36, 57))
841104	22367141	The miRNA profiles of tumor tissues could be regulated by oncogenes, tumor suppressing genes and epigenetics.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (69, 74))	('miR', 'Gene', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('miR', 'Gene', '220972', (4, 7))	('epigenetics', 'Var', (97, 108))	('tumor', 'Disease', (22, 27))	('regulated', 'Reg', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
841113	22367141	Kan reported the expression of miR-106b-25 polycystron, which is an oncogene for tumor transformation, was upregulated in ADC, which might result from elevated copy numbers of MCM7.	('polycystron', 'Chemical', '-', (43, 54))	('copy numbers', 'Var', (160, 172))	('MCM7', 'Gene', '4176', (176, 180))	('ADC', 'Disease', (122, 125))	('miR-106b', 'Gene', (31, 39))	('expression', 'MPA', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('MCM7', 'Gene', (176, 180))	('miR-106b', 'Gene', '406900', (31, 39))	('elevated', 'PosReg', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('upregulated', 'PosReg', (107, 118))	('tumor', 'Disease', (81, 86))
841132	22367141	Emerging evidence suggests aberrantly expressed miRNAs might regulate MDR-related genes expression and play key roles in MDR.	('regulate', 'Reg', (61, 69))	('MDR', 'Disease', (121, 124))	('aberrantly expressed', 'Var', (27, 47))	('miR', 'Gene', '220972', (48, 51))	('MDR-related genes', 'Gene', (70, 87))	('miR', 'Gene', (48, 51))	('expression', 'MPA', (88, 98))
841146	18649358	Replication of a genome-wide case-control study of esophageal squamous cell carcinoma In a previous pilot case-control study of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) and matched controls from a high-risk area in China, we identified 38 single nucleotide polymorphisms (SNPs) associated with ESCC located in or near one of 33 genes.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (155, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('ESCC', 'Disease', (322, 326))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (51, 85))	('single nucleotide polymorphisms', 'Var', (267, 298))	('esophageal squamous cell carcinoma', 'Disease', (155, 189))	('esophageal squamous cell carcinoma', 'Disease', (51, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
841147	18649358	Among 36 evaluable SNPs, four were significant in one or more analyses, including SNPs located in EPHB1, PGLYRP2, PIK3C3, and SLC9A9, although the odds ratios (ORs) for these genotypes were modest.	('SLC9A9', 'Gene', (126, 132))	('PGLYRP2', 'Gene', (105, 112))	('SNPs', 'Var', (82, 86))	('PGLYRP2', 'Gene', '114770', (105, 112))	('EPHB1', 'Gene', (98, 103))	('SLC9A9', 'Gene', '285195', (126, 132))
841148	18649358	Associations were found with EPHB1/rs1515366 (OR 0.92, 95% CI 0.86-0.99; p = 0.019), PIK3C3/rs52911 (OR 0.93, 95% CI 0.88-0.99; p = 0.02), and PGLYRP2/rs959117 (OR 0.93, 95% CI, 0.86-1.01; p = 0.061) in general linear models (additive mode); and the genotype distribution differed between cases and controls for SLC9A9/rs956062 (p = 0.024).	('Associations', 'Interaction', (0, 12))	('rs959117', 'Mutation', 'rs959117', (151, 159))	('rs1515366', 'Mutation', 'rs1515366', (35, 44))	('PIK3C3/rs52911', 'Var', (85, 99))	('SLC9A9', 'Gene', (312, 318))	('PGLYRP2', 'Gene', (143, 150))	('rs956062', 'Mutation', 'rs956062', (319, 327))	('EPHB1/rs1515366', 'Gene', (29, 44))	('SLC9A9', 'Gene', '285195', (312, 318))	('rs52911', 'Mutation', 'rs52911', (92, 99))	('PGLYRP2', 'Gene', '114770', (143, 150))
841152	18649358	Past studies suggested that family history of ESCC, low levels of selenium and vitamin E, as well as tooth loss were associated with a higher risk of ESCC.	('ESCC', 'Disease', (46, 50))	('tooth loss', 'Disease', 'MESH:D016388', (101, 111))	('low levels of selenium and vitamin E', 'Phenotype', 'HP:0100513', (52, 88))	('vitamin E', 'Chemical', 'MESH:D014810', (79, 88))	('tooth loss', 'Phenotype', 'HP:0006480', (101, 111))	('ESCC', 'Disease', (150, 154))	('tooth loss', 'Disease', (101, 111))	('selenium', 'Chemical', 'MESH:D012643', (66, 74))	('selenium', 'MPA', (66, 74))	('low', 'Var', (52, 55))
841176	18649358	Of these 36 SNPs, four (EPHB1/rs1515366, PGLYRP2/rs959117, PIK3C3/ rs52911, and SLC9A9/rs956062) were statistically significantly associated with ESCC in one or more of the tests we applied: EPHB1/rs1515366 (p = 0.049), PIK3C3/rs52911 (p = 0.015), and SLC9A9/rs956062 (p = 0.024) were significant based on case-control differences in genotype frequencies (Table II); and PIK3C3/rs52911 (OR 0.93, 95% CI 0.88-0.99; p = 0.02) and EPHB1/rs1515366 (OR 0.92, 95% CI 0.86-0.99; p = 0.019) were significant in GLM additive models.	('SLC9A9', 'Gene', (252, 258))	('rs1515366', 'Mutation', 'rs1515366', (434, 443))	('SLC9A9', 'Gene', '285195', (80, 86))	('rs52911', 'Mutation', 'rs52911', (378, 385))	('rs52911', 'Mutation', 'rs52911', (227, 234))	('PIK3C3/rs52911', 'Var', (371, 385))	('rs959117', 'Mutation', 'rs959117', (49, 57))	('SLC9A9', 'Gene', '285195', (252, 258))	('rs956062', 'Mutation', 'rs956062', (87, 95))	('EPHB1/rs1515366', 'Var', (428, 443))	('PGLYRP2', 'Gene', (41, 48))	('rs1515366', 'Mutation', 'rs1515366', (197, 206))	('SLC9A9', 'Gene', (80, 86))	('rs52911', 'Mutation', 'rs52911', (67, 74))	('ESCC', 'Disease', (146, 150))	('rs956062', 'Mutation', 'rs956062', (259, 267))	('rs1515366', 'Mutation', 'rs1515366', (30, 39))	('PGLYRP2', 'Gene', '114770', (41, 48))
841181	18649358	Two SNPs (rs11716850, rs17712258) showed a significant difference in genotype distribution between cases and controls, however, neither SNP was significant in the GLM analysis (Table II).	('rs17712258', 'Var', (22, 32))	('rs11716850', 'Var', (10, 20))	('rs11716850', 'Mutation', 'rs11716850', (10, 20))	('rs17712258', 'Mutation', 'rs17712258', (22, 32))
841182	18649358	rs11716850 and rs17712258 are noncoding SNPs located in intron 13 and the 3' region of EPHB1.	('rs17712258', 'Var', (15, 25))	('EPHB1', 'Gene', (87, 92))	('rs17712258', 'Mutation', 'rs17712258', (15, 25))	('rs11716850', 'Mutation', 'rs11716850', (0, 10))	('rs11716850', 'Var', (0, 10))
841184	18649358	Thus, rs11716850 and rs17712258 together, represent a second signal in EPHB1 associated with ESCC.	('rs17712258', 'Var', (21, 31))	('rs17712258', 'Mutation', 'rs17712258', (21, 31))	('EPHB1', 'Gene', (71, 76))	('associated', 'Reg', (77, 87))	('ESCC', 'Disease', (93, 97))	('rs11716850', 'Mutation', 'rs11716850', (6, 16))	('rs11716850', 'Var', (6, 16))
841186	18649358	rs892145 (OR 1.06, 95% CI 1.00-1.12; p = 0.049) and rs4264508 (OR 0.94, 95% CI 0.89-0.99; p = 0.017) were both significant in GLM analysis; rs4264508 also showed a different genotype distribution (p =0.033) (Table II).	('rs4264508', 'Var', (140, 149))	('rs4264508', 'Var', (52, 61))	('rs4264508', 'Mutation', 'rs4264508', (140, 149))	('rs892145', 'Var', (0, 8))	('rs892145', 'Mutation', 'rs892145', (0, 8))	('rs4264508', 'Mutation', 'rs4264508', (52, 61))
841187	18649358	rs892145 is a nonsynonymous coding SNP (lysine to methionine at position 270) located in exon 2; rs4264508 is in intron 2 of PGLYRP2.	('rs4264508', 'Mutation', 'rs4264508', (97, 106))	('rs892145', 'Var', (0, 8))	('lysine to methionine at position 270', 'Mutation', 'rs892145', (40, 76))	('PGLYRP2', 'Gene', '114770', (125, 132))	('rs4264508 is', 'Var', (97, 109))	('PGLYRP2', 'Gene', (125, 132))	('rs892145', 'Mutation', 'rs892145', (0, 8))
841188	18649358	These two significant SNPs in PGLYRP2 are not in LD (D' =0.64, r2=0.44) with each other and represent two distinct signals associated with ESCC.	('associated', 'Reg', (123, 133))	('PGLYRP2', 'Gene', (30, 37))	('SNPs', 'Var', (22, 26))	('PGLYRP2', 'Gene', '114770', (30, 37))	('ESCC', 'Disease', (139, 143))
841190	18649358	Among the 19 SNPs genotyped in SLC9A9, 18 were evaluable, including three (rs838598, rs16853475, and rs10804689) with statistically significant differences in the distribution of their genotype frequencies; rs16853475 (OR 0.91, 95% CI 0.85-0.98; p = 0.012), and rs10804689 (OR 1.08, 95% CI 1.01-1.15; p = 0.016) were also significantly different in GLM analyses (Table II).	('SLC9A9', 'Gene', '285195', (31, 37))	('rs10804689', 'Var', (101, 111))	('rs16853475', 'Var', (207, 217))	('rs16853475', 'Var', (85, 95))	('rs16853475', 'Mutation', 'rs16853475', (207, 217))	('rs10804689', 'Var', (262, 272))	('rs10804689', 'Mutation', 'rs10804689', (262, 272))	('rs16853475', 'Mutation', 'rs16853475', (85, 95))	('SLC9A9', 'Gene', (31, 37))	('rs10804689', 'Mutation', 'rs10804689', (101, 111))	('rs838598', 'Var', (75, 83))	('rs838598', 'Mutation', 'rs838598', (75, 83))	('different', 'Reg', (336, 345))
841191	18649358	Altogether, four SNPs in SLC9A9 were associated with ESCC and none of these SNPs were in LD with each other.	('SLC9A9', 'Gene', '285195', (25, 31))	('ESCC', 'Disease', (53, 57))	('SNPs', 'Var', (17, 21))	('SLC9A9', 'Gene', (25, 31))	('associated', 'Reg', (37, 47))
841196	18649358	ESCC familial aggregation is striking and suggests that a subset of this population carried genetic variants resulting in ESCC susceptibility.	('familial aggregation', 'Disease', 'MESH:D020914', (5, 25))	('variants', 'Var', (100, 108))	('ESCC', 'Disease', (122, 126))	('familial aggregation', 'Disease', (5, 25))
841198	18649358	Choosing the common allele as the referent, four SNPs (rs1515366, rs4264508, rs52911, rs16853475) from the GLM revealed the minor allele as protective and the major allele as the risk allele for ESCC susceptibility.	('rs4264508', 'Var', (66, 75))	('rs1515366', 'Mutation', 'rs1515366', (55, 64))	('ESCC', 'Disease', (195, 199))	('rs52911', 'Mutation', 'rs52911', (77, 84))	('rs52911', 'Var', (77, 84))	('rs16853475', 'Var', (86, 96))	('rs1515366', 'Var', (55, 64))	('rs16853475', 'Mutation', 'rs16853475', (86, 96))	('rs4264508', 'Mutation', 'rs4264508', (66, 75))
841199	18649358	The exceptions were rs892145 and rs10804689, where the variant was the risk allele for ESCC.	('rs10804689', 'Var', (33, 43))	('ESCC', 'Disease', (87, 91))	('rs10804689', 'Mutation', 'rs10804689', (33, 43))	('rs892145', 'Var', (20, 28))	('rs892145', 'Mutation', 'rs892145', (20, 28))
841223	18649358	95% CI 95% confidence interval CHB Han Chinese in Beijing dbSNP single nucleotide polymorphism database D' D-prime E-06 10 to the -6 power EPHB1 Ephrin receptor EPHB1 ESCC esophageal squamous cell carcinoma GI gastrointestinal GLM general linear model HapMap International HapMap Project HWE Hardy-Weinburg equilibrium LD linkage disequilibrium MOLA multiplex oligonucleotide ligation assay NCBI National Center for Biotechnology Information OR odds ratio P P-value PCR polymerase chain reaction, PGLYRP2, peptidoglycan recognition protein 2 PIK3C3 phosphatidylinositol 3-kinase, class 3 r2 r-squared SLC9A9 solute carrier family 9, isoform A9 SNPs single nucleotide polymorphisms WNT wingless-type gene family	('SLC9A9', 'Gene', '285195', (601, 607))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (172, 206))	('oligonucleotide', 'Chemical', 'MESH:D009841', (360, 375))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (183, 206))	('PGLYRP2', 'Gene', (497, 504))	('solute carrier family 9', 'Gene', '284525', (608, 631))	('gastrointestinal', 'Disease', 'MESH:D005767', (210, 226))	('single nucleotide polymorphisms', 'Var', (649, 680))	('PGLYRP2', 'Gene', '114770', (497, 504))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('SLC9A9', 'Gene', (601, 607))	('solute carrier family 9', 'Gene', (608, 631))	('esophageal squamous cell carcinoma', 'Disease', (172, 206))	('gastrointestinal', 'Disease', (210, 226))	('carcinoma GI', 'Phenotype', 'HP:0002672', (197, 209))
841225	32564632	The central gut microbiota population has the capability to regulate normal inflammatory, immune, and metabolic functions, and disturbance in the balance of the normal microbiota population can subsequently induce pathological responses that closely relate with the mechanistic development and progression of cancer in various forms and sites.	('gut', 'Gene', '110006', (12, 15))	('disturbance', 'Var', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('induce', 'Reg', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('gut', 'Gene', (12, 15))	('metabolic', 'CPA', (102, 111))	('cancer', 'Disease', (309, 315))
841226	32564632	As a disease with major socioeconomic burden partly due to its current therapeutic options, modulating the imbalanced gut microbiota represents a novel option not only as an adjuvant therapy to relieve cancer treatment-related symptoms but also to influence cancer progression itself.	('gut', 'Gene', '110006', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('imbalance', 'Phenotype', 'HP:0002172', (107, 116))	('cancer', 'Disease', (258, 264))	('modulating', 'Var', (92, 102))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (202, 208))	('influence', 'Reg', (248, 257))	('relieve', 'PosReg', (194, 201))	('gut', 'Gene', (118, 121))
841271	32564632	As mentioned previously, due to the fact that there is a specific set of bacteria that normally inhabit the gut mucosal layers, any changes that can cause a shift in the bacterial population toward any "unwanted" bacteria could induce pathogenic reactions and this so-called pathogenic reaction could cause different reactions and induce different forms of cancer in various sites.	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('cause', 'Reg', (301, 306))	('induce', 'Reg', (331, 337))	('induce', 'Reg', (228, 234))	('changes', 'Var', (132, 139))	('cancer', 'Disease', (357, 363))	('cancer', 'Disease', 'MESH:D009369', (357, 363))	('gut', 'Gene', (108, 111))	('reactions', 'CPA', (317, 326))	('gut', 'Gene', '110006', (108, 111))	('pathogenic reactions', 'CPA', (235, 255))
841277	32564632	With regard to pathogenic bacteria, several strains have been linked to cancer.	('strains', 'Var', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('linked', 'Reg', (62, 68))	('cancer', 'Disease', (72, 78))
841304	32564632	One of the main consequences of this is the decrease of the key cytokine IL-2 that is already known to be pivotal in modulating the differentiation of CD4+ regulatory T-cells into T-helper 1 or T-helper 2 cells while subsequently inhibiting T-helper 17 differentiation, thereby serving as a so-called "regulator" for Th1- and Th2-regulated immune responses.	('decrease', 'NegReg', (44, 52))	('CD4+', 'Var', (151, 155))	('IL-2', 'Gene', '3558', (73, 77))	('modulating', 'Reg', (117, 127))	('inhibiting', 'NegReg', (230, 240))	('IL-2', 'Gene', (73, 77))	('T-helper 17 differentiation', 'CPA', (241, 268))	('CD4', 'Species', '1151252', (151, 154))
841309	32564632	It has been shown how disturbances in the gut microbiota population balance could cause unwanted bacteria to prosper and exert their pathological and carcinogenic effects; thus, maintaining an intact and normal gut microbiota is essential to prevent such phenomena.	('gut', 'Gene', '110006', (211, 214))	('cause', 'Reg', (82, 87))	('carcinogenic', 'Disease', 'MESH:D063646', (150, 162))	('carcinogenic', 'Disease', (150, 162))	('disturbances', 'Var', (22, 34))	('pathological', 'CPA', (133, 145))	('gut', 'Gene', (42, 45))	('prosper', 'CPA', (109, 116))	('gut', 'Gene', '110006', (42, 45))	('gut', 'Gene', (211, 214))
841369	32564632	Unfortunately, although most of the aforementioned drugs have the potential to alter the microbiota population, most of the alterations reported have a negative effect toward microbiota population balance, meaning that rather than shifting the population toward the needed population for a positive health outcome, those therapies could rather induce dysbiosis and subsequent pathological consequences.	('therapies', 'Var', (321, 330))	('alterations', 'Var', (124, 135))	('induce', 'Reg', (344, 350))	('dysbiosis', 'Disease', (351, 360))	('alter', 'Reg', (79, 84))	('dysbiosis', 'Disease', 'MESH:D064806', (351, 360))
841380	32564632	Modulating gut microbiota to relieve the burden of cancer is a novel yet important option as a future therapeutic possibility, especially as an additional therapeutic option to increase the efficacy and safety of other cancer treatment modalities through its central immune modulation mechanism.	('Modulating', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('gut', 'Gene', (11, 14))	('increase', 'PosReg', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('gut', 'Gene', '110006', (11, 14))	('cancer', 'Disease', (219, 225))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
841492	31612042	In addition, genetic polymorphisms in the autophagy related 5 gene predict survival and recurrence in patients with early-stage ESCC.	('survival', 'CPA', (75, 83))	('recurrence', 'CPA', (88, 98))	('autophagy related 5', 'Gene', '9474', (42, 61))	('genetic polymorphisms', 'Var', (13, 34))	('patients', 'Species', '9606', (102, 110))	('ESCC', 'Disease', 'MESH:C562729', (128, 132))	('predict', 'Reg', (67, 74))	('autophagy related 5', 'Gene', (42, 61))	('ESCC', 'Disease', (128, 132))
841495	31612042	A critical tumor suppressor gene, p53, is typically found to harbor mutations or deletions in several human malignancies, including ESCC; it can inhibit cell cycle progression by inducing p21.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('malignancies', 'Disease', (108, 120))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('deletions', 'Var', (81, 90))	('inducing', 'Reg', (179, 187))	('tumor', 'Disease', (11, 16))	('malignancies', 'Disease', 'MESH:D009369', (108, 120))	('ESCC', 'Disease', 'MESH:C562729', (132, 136))	('cell cycle progression', 'CPA', (153, 175))	('p21', 'Gene', '1026', (188, 191))	('mutations', 'Var', (68, 77))	('p21', 'Gene', (188, 191))	('ESCC', 'Disease', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('inhibit', 'NegReg', (145, 152))	('human', 'Species', '9606', (102, 107))
841500	31612042	The aforementioned changes lead to the induction of invasive and migratory properties in cancer cells.	('changes', 'Var', (19, 26))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('induction', 'Reg', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
841535	31612042	In addition, the expression of TGF-beta and p-Smad2/3 was significantly downregulated in the Cis 20 mM group compared with the control (P<0.01; Fig.	('TGF-beta', 'Gene', (31, 39))	('Cis 20 mM', 'Var', (93, 102))	('expression', 'MPA', (17, 27))	('TGF-beta', 'Gene', '7040', (31, 39))	('p-Smad2/3', 'Gene', (44, 53))	('downregulated', 'NegReg', (72, 85))
841538	31612042	After treating ESCC cells with 20 mM Cis plus TGF-beta, the number of cells in the S phase increased, whereas that in the G0/G1 phase was notably decreased compared with treatment with Cis alone (Fig.	('ESCC', 'Disease', (15, 19))	('TGF-beta', 'Gene', '7040', (46, 54))	('Cis', 'Var', (37, 40))	('decreased', 'NegReg', (146, 155))	('TGF-beta', 'Gene', (46, 54))	('ESCC', 'Disease', 'MESH:C562729', (15, 19))	('increased', 'PosReg', (91, 100))
841553	31612042	The cell cycle is a well-regulated intracellular program that maintains normal cell division and growth; however, deregulation of the cell cycle machinery frequently occurs various human malignancies, promoting abnormal and uncontrollable cell growth, as well as acquisition of aggressive metastatic features.	('human', 'Species', '9606', (181, 186))	('acquisition', 'Reg', (263, 274))	('deregulation', 'Var', (114, 126))	('promoting', 'PosReg', (201, 210))	('malignancies', 'Disease', 'MESH:D009369', (187, 199))	('aggressive metastatic features', 'CPA', (278, 308))	('malignancies', 'Disease', (187, 199))	('abnormal', 'CPA', (211, 219))
841558	31612042	In the present study, the proliferation of ESCC cells was inhibited, accompanied a decrease in cyclin D1 expression and increase in p53 and p21 expression following treatment with Cis compared with the control group.	('Cis', 'Var', (180, 183))	('ESCC', 'Disease', (43, 47))	('p53', 'Gene', (132, 135))	('expression', 'MPA', (144, 154))	('p53', 'Gene', '7157', (132, 135))	('cyclin D1', 'Gene', '595', (95, 104))	('ESCC', 'Disease', 'MESH:C562729', (43, 47))	('decrease', 'NegReg', (83, 91))	('cyclin D1', 'Gene', (95, 104))	('inhibited', 'NegReg', (58, 67))	('increase', 'PosReg', (120, 128))	('p21', 'Gene', '1026', (140, 143))	('expression', 'MPA', (105, 115))	('proliferation', 'CPA', (26, 39))	('p21', 'Gene', (140, 143))
841564	31612042	In addition, accumulating evidence has demonstrated that inhibition of EMT contributes to improved treatment and prognosis of ESCC.	('ESCC', 'Disease', 'MESH:C562729', (126, 130))	('inhibition', 'Var', (57, 67))	('treatment', 'CPA', (99, 108))	('improved', 'PosReg', (90, 98))	('EMT', 'Protein', (71, 74))	('ESCC', 'Disease', (126, 130))
841566	31612042	In addition, Cis inhibited invasion and migration of ESCC cells.	('Cis', 'Var', (13, 16))	('ESCC', 'Disease', 'MESH:C562729', (53, 57))	('inhibited', 'NegReg', (17, 26))	('ESCC', 'Disease', (53, 57))
841567	31612042	Furthermore, Cis increased the expression of E-cad and decreased N-cad, Slug and Vimentin expression, which are well-established EMT-associated proteins.	('increased', 'PosReg', (17, 26))	('Vimentin', 'Gene', '7431', (81, 89))	('Slug', 'Gene', '6591', (72, 76))	('Cis', 'Var', (13, 16))	('decreased', 'NegReg', (55, 64))	('expression', 'MPA', (31, 41))	('expression', 'MPA', (90, 100))	('N-cad', 'Gene', (65, 70))	('N-cad', 'Gene', '1000', (65, 70))	('Vimentin', 'Gene', (81, 89))	('E-cad', 'Gene', '999', (45, 50))	('Slug', 'Gene', (72, 76))	('E-cad', 'Gene', (45, 50))
841570	31612042	In conclusion, this mechanistic study is, to the best of our knowledge, the first to reveal that Cis suppresses the proliferation, invasion, migration and EMT in ESCC cells, which may prove to be of value in guiding clinical diagnosis and treatment.	('migration', 'CPA', (141, 150))	('EMT', 'CPA', (155, 158))	('invasion', 'CPA', (131, 139))	('suppresses', 'NegReg', (101, 111))	('ESCC', 'Disease', 'MESH:C562729', (162, 166))	('proliferation', 'CPA', (116, 129))	('ESCC', 'Disease', (162, 166))	('Cis', 'Var', (97, 100))
841584	30082829	Accumulating evidence is now unveiling that dysregulation of circRNA plays vital roles in human cancer pathogenesis.	('dysregulation', 'Var', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('human', 'Species', '9606', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
841586	30082829	Moreover, it was reported that soak up of miR-7 by ciRS-7 resulted in release and reactivation of genes previously repressed by miR-7 during the development of brain.	('ciRS-7', 'Gene', '103611090', (51, 57))	('miR-7', 'Gene', '10859', (42, 47))	('miR-7', 'Gene', (128, 133))	('soak up', 'Var', (31, 38))	('reactivation', 'MPA', (82, 94))	('ciRS-7', 'Gene', (51, 57))	('miR-7', 'Gene', '10859', (128, 133))	('release', 'MPA', (70, 77))	('miR-7', 'Gene', (42, 47))
841600	30082829	Kaplan-Meier analysis also manifested that ESCC subjects with highly expressed ciRS-7 or lowly expressed miR-7 possessed inferior overall survival (OS) and disease-free survival (DFS) to those with lowly expressed ciRS-7 or highly expressed miR-7, respectively (Fig.	('ciRS-7', 'Gene', '103611090', (79, 85))	('ESCC', 'Disease', (43, 47))	('miR-7', 'Gene', '10859', (241, 246))	('ciRS-7', 'Gene', '103611090', (214, 220))	('miR-7', 'Gene', (105, 110))	('ciRS-7', 'Gene', (79, 85))	('inferior', 'NegReg', (121, 129))	('lowly expressed', 'Var', (89, 104))	('miR-7', 'Gene', '10859', (105, 110))	('disease-free survival', 'CPA', (156, 177))	('overall survival', 'CPA', (130, 146))	('ciRS-7', 'Gene', (214, 220))	('miR-7', 'Gene', (241, 246))
841607	30082829	The growth curve indicated that tumors in mice injected with miR-7 overexpressing cells have lower growth rate compared with those injected with ciRS-7 overexpressing or miR-7/ciRS-7 double overexpressing cells (Fig.	('miR-7', 'Gene', '10859', (61, 66))	('ciRS-7', 'Gene', '103611090', (176, 182))	('overexpressing', 'Var', (67, 81))	('miR-7', 'Gene', (170, 175))	('mice', 'Species', '10090', (42, 46))	('ciRS-7', 'Gene', '103611090', (145, 151))	('growth rate', 'MPA', (99, 110))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('lower', 'NegReg', (93, 98))	('ciRS-7', 'Gene', (176, 182))	('miR-7', 'Gene', '10859', (170, 175))	('miR-7', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('ciRS-7', 'Gene', (145, 151))	('lower growth', 'Phenotype', 'HP:0001510', (93, 105))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
841634	30082829	Patients with high HOXB13 expression showed significant shorter overall survival and disease-free survival than those with low HOXB13 expression (Fig.	('HOXB13', 'Gene', '10481', (19, 25))	('disease-free survival', 'CPA', (85, 106))	('HOXB13', 'Gene', (19, 25))	('HOXB13', 'Gene', '10481', (127, 133))	('shorter', 'NegReg', (56, 63))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'CPA', (64, 80))	('HOXB13', 'Gene', (127, 133))
841636	30082829	Furthermore, samples with high ciRS-7 or low miR-7 expression tended to show elevated HOXB13 expression (Fig.	('HOXB13', 'Gene', (86, 92))	('miR-7', 'Gene', (45, 50))	('ciRS-7', 'Gene', '103611090', (31, 37))	('high', 'Var', (26, 30))	('miR-7', 'Gene', '10859', (45, 50))	('HOXB13', 'Gene', '10481', (86, 92))	('low', 'Var', (41, 44))	('elevated', 'PosReg', (77, 85))	('expression', 'MPA', (93, 103))	('ciRS-7', 'Gene', (31, 37))	('expression', 'MPA', (51, 61))
841637	30082829	Western blot analysis of 12 paired fresh samples further confirmed elevated HOXB13 as well as downstream p65 phosphorylation level in patients with ciRS-7 high and miR-7 low expression than those with ciRS-7 low and miR-7 high expression (Fig.	('HOXB13', 'Gene', (76, 82))	('miR-7', 'Gene', '10859', (216, 221))	('p65', 'Gene', (105, 108))	('elevated', 'PosReg', (67, 75))	('ciRS-7', 'Gene', (148, 154))	('miR-7', 'Gene', '10859', (164, 169))	('ciRS-7', 'Gene', '103611090', (148, 154))	('p65', 'Gene', '5970', (105, 108))	('patients', 'Species', '9606', (134, 142))	('miR-7', 'Gene', (216, 221))	('ciRS-7', 'Gene', '103611090', (201, 207))	('HOXB13', 'Gene', '10481', (76, 82))	('low expression', 'Var', (170, 184))	('miR-7', 'Gene', (164, 169))	('ciRS-7', 'Gene', (201, 207))	('high', 'Var', (155, 159))
841663	30082829	Dysregulation of the HOX gene expression has been shown in diverse cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('HOX gene', 'Gene', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
841664	30082829	As a member of the HOX gene family, high levels of HOXB13 promote tumorigenesis in different types of tumors such as prostate cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HOXB13', 'Gene', (51, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Disease', (66, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('promote', 'PosReg', (58, 65))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('HOXB13', 'Gene', '10481', (51, 57))	('high levels', 'Var', (36, 47))	('prostate cancer', 'Disease', (117, 132))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
841670	30082829	More importantly, knockdown of ciRS-7 resulted in expansive reactivation and amplification of the tumor-suppressive roles of miR-7 as one molecular ciRS-7 could sponge more than 70 endogenous miR-7 molecular.	('amplification', 'PosReg', (77, 90))	('knockdown', 'Var', (18, 27))	('ciRS-7', 'Gene', '103611090', (31, 37))	('miR-7', 'Gene', '10859', (192, 197))	('miR-7', 'Gene', (125, 130))	('ciRS-7', 'Gene', '103611090', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ciRS-7', 'Gene', (31, 37))	('miR-7', 'Gene', '10859', (125, 130))	('tumor', 'Disease', (98, 103))	('ciRS-7', 'Gene', (148, 154))	('expansive reactivation', 'MPA', (50, 72))	('miR-7', 'Gene', (192, 197))
841794	26545174	The procedure time to perform the endoscopic resection was significantly less for MBM (11 minutes, IQR 7-16) compared to ER-cap (22 minutes, IQR: 11-32).	('cap', 'Chemical', '-', (124, 127))	('less', 'NegReg', (73, 77))	('MBM', 'Var', (82, 85))
841860	28529610	found that silencing c-Met by using c-Met small interfering RNAs (siRNAs) can attenuate tumor growth.	('silencing', 'Var', (11, 20))	('c-Met', 'Gene', (21, 26))	('c-Met', 'Gene', '4233', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('c-Met', 'Gene', (36, 41))	('c-Met', 'Gene', '4233', (36, 41))	('tumor', 'Disease', (88, 93))	('attenuate', 'NegReg', (78, 87))
841861	28529610	Hepatocyte growth factor (HGF) is widely expressed in mesenchymal cells as a ligand of c-Met and aberrant HGF/c-Met axis is known to correlate with tumor growth, metastasis and reccurrence in many malignancies.	('metastasis', 'CPA', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('correlate with', 'Reg', (133, 147))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('c-Met', 'Gene', (87, 92))	('HGF', 'Gene', '3082', (26, 29))	('Hepatocyte growth factor', 'Gene', '3082', (0, 24))	('HGF', 'Gene', (106, 109))	('c-Met', 'Gene', '4233', (87, 92))	('HGF', 'Gene', (26, 29))	('tumor', 'Disease', (148, 153))	('c-Met', 'Gene', (110, 115))	('HGF', 'Gene', '3082', (106, 109))	('c-Met', 'Gene', '4233', (110, 115))	('aberrant', 'Var', (97, 105))	('malignancies', 'Disease', 'MESH:D009369', (197, 209))	('Hepatocyte growth factor', 'Gene', (0, 24))	('malignancies', 'Disease', (197, 209))
841866	28529610	As such, inhibition of c-Met expression coupled with radiotherapy may represent a promising option for the treatment of radioresistant esophageal cancer.	('esophageal cancer', 'Disease', (135, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('c-Met', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('c-Met', 'Gene', '4233', (23, 28))	('inhibition', 'Var', (9, 19))
841874	28529610	The antibodies were as follows: GAPDH (Cell Signaling Technology), Akt (Cell Signaling Technology), p-Akt (Cell Signaling Technology), c-Met (Bioworld Technology), p-Met (Tyr 1234/1235) (Cell Signaling Technology), gammaH2AX (Cell Signaling Technology).	('p-Met (Tyr 1234/1235', 'Var', (164, 184))	('Akt', 'Gene', (67, 70))	('Akt', 'Gene', '207', (102, 105))	('c-Met', 'Gene', (135, 140))	('gammaH2AX', 'Chemical', '-', (215, 224))	('c-Met', 'Gene', '4233', (135, 140))	('gammaH2AX', 'Var', (215, 224))	('GAPDH', 'Gene', '2597', (32, 37))	('GAPDH', 'Gene', (32, 37))	('Akt', 'Gene', (102, 105))	('Tyr', 'Chemical', 'MESH:D014443', (171, 174))	('Akt', 'Gene', '207', (67, 70))
841924	28529610	These data suggest that inhibition of c-Met phosphorylation results in a delay of DNA double strand breaks repair following irradiation.	('c-Met', 'Gene', (38, 43))	('c-Met', 'Gene', '4233', (38, 43))	('DNA double strand breaks repair', 'MPA', (82, 113))	('inhibition', 'Var', (24, 34))	('delay', 'NegReg', (73, 78))
841933	28529610	Fortunately, molecular therapies have rapidly developed in recent years, targeting aberrantly expressed receptor tyrosine kinases.	('receptor tyrosine kinase', 'Gene', (104, 128))	('receptor tyrosine kinase', 'Gene', '5979', (104, 128))	('aberrantly', 'Var', (83, 93))
841935	28529610	Overexpression and dysregulation of c-Met has been verified tightly related to poor prognosis and survival in advanced esophageal cancer patients.	('dysregulation', 'Var', (19, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('related', 'Reg', (68, 75))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('c-Met', 'Gene', (36, 41))	('c-Met', 'Gene', '4233', (36, 41))	('esophageal cancer', 'Disease', (119, 136))
841942	28529610	As previously reported, phosphorylation of c-Met can activate PI3K/Akt pathway which has been shown to play a critical role in cell proliferation and survival.	('Akt', 'Gene', (67, 70))	('c-Met', 'Gene', '4233', (43, 48))	('c-Met', 'Gene', (43, 48))	('activate', 'PosReg', (53, 61))	('phosphorylation', 'Var', (24, 39))	('Akt', 'Gene', '207', (67, 70))
841947	28529610	DNA repair following double-stranded DNA breaks requires a variant histone protein called H2A.X.	('histone', 'Protein', (67, 74))	('H2A.X', 'Gene', '3014', (90, 95))	('H2A.X', 'Gene', (90, 95))	('double-stranded', 'Var', (21, 36))
841952	28529610	demonstrated that high levels of c-Met were related to radioresistance, while small interfering RNA knockdown of c-MET enhanced the response to IR in non-small cell lung cell lines.	('knockdown', 'Var', (100, 109))	('c-MET', 'Gene', '4233', (113, 118))	('c-Met', 'Gene', (33, 38))	('c-Met', 'Gene', '4233', (33, 38))	('radioresistance', 'CPA', (55, 70))	('c-MET', 'Gene', (113, 118))	('response to IR', 'MPA', (132, 146))	('enhanced', 'PosReg', (119, 127))
841969	28529610	While Dai and his colleagues found that crizotinib caused G2/M arrest by increasing phosphorylation of Cdc2 and decreasing Cyclin B1 in primary effusion lymphoma cell lines.	('Cdc2', 'Gene', '983', (103, 107))	('Cyclin B1', 'Gene', (123, 132))	('primary effusion lymphoma', 'Disease', (136, 161))	('lymphoma', 'Phenotype', 'HP:0002665', (153, 161))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (136, 161))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (136, 161))	('decreasing', 'NegReg', (112, 122))	('G2/M arrest', 'Disease', (58, 69))	('crizotinib', 'Chemical', 'MESH:D000077547', (40, 50))	('Cdc2', 'Gene', (103, 107))	('increasing', 'PosReg', (73, 83))	('crizotinib', 'Var', (40, 50))	('Cyclin B1', 'Gene', '891', (123, 132))	('phosphorylation', 'MPA', (84, 99))
841970	28529610	Yu represented c-Met inhibitor SU11274 radiosensitized prostate cell DU145 through abrogating G2/M arrest induced by irradiation.	('abrogating', 'NegReg', (83, 93))	('c-Met', 'Gene', (15, 20))	('SU11274', 'Var', (31, 38))	('SU11274', 'Chemical', 'MESH:C478479', (31, 38))	('c-Met', 'Gene', '4233', (15, 20))	('DU145', 'CellLine', 'CVCL:0105', (69, 74))	('G2/M arrest induced by irradiation', 'MPA', (94, 128))
841978	28529610	demonstrated that c-Met inhibitor PF2341066 induced apoptosis through improving DNA damage and regulating DNA repair/damage-related proteins such as RRM2 and XRCC5.	('improving', 'PosReg', (70, 79))	('regulating', 'Reg', (95, 105))	('c-Met', 'Gene', (18, 23))	('DNA damage', 'MPA', (80, 90))	('c-Met', 'Gene', '4233', (18, 23))	('DNA repair/damage-related proteins', 'MPA', (106, 140))	('PF2341066', 'Var', (34, 43))	('RRM2', 'Gene', (149, 153))	('XRCC5', 'Gene', (158, 163))	('RRM2', 'Gene', '6241', (149, 153))	('apoptosis', 'CPA', (52, 61))	('XRCC5', 'Gene', '7520', (158, 163))	('PF2341066', 'Chemical', 'MESH:D000077547', (34, 43))
842066	28460467	In conclusion, current study has demonstrated that luteolin can induce cell cycle arrest in G2/M phase and apoptosis through mitochondrial pathway in EC1 and KYSE450 cell lines, and in vivo study has also demonstrated that luteolin can significantly inhibit the growth of tumor in ESCC xenograft mouse models.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('luteolin', 'Chemical', 'MESH:D047311', (223, 231))	('EC1', 'Gene', (150, 153))	('mouse', 'Species', '10090', (296, 301))	('tumor', 'Disease', (272, 277))	('inhibit', 'NegReg', (250, 257))	('mitochondrial pathway', 'Pathway', (125, 146))	('ESCC', 'Disease', (281, 285))	('luteolin', 'Var', (51, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (71, 88))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('cell cycle arrest', 'CPA', (71, 88))	('apoptosis', 'CPA', (107, 116))	('luteolin', 'Chemical', 'MESH:D047311', (51, 59))	('EC1', 'Gene', '4819', (150, 153))
842115	17114082	Overall, modifications of the GTV changed the treatment plan in 18 of 34 patients, and affected the percentage of total lung volume receiving >20 Gy in 25 of 34 patients.	('treatment', 'CPA', (46, 55))	('GTV', 'Gene', (30, 33))	('modifications', 'Var', (9, 22))	('patients', 'Species', '9606', (161, 169))	('affected', 'Reg', (87, 95))	('patients', 'Species', '9606', (73, 81))	('changed', 'Reg', (34, 41))
842142	31213825	Polymorphism of miRNA and esophageal cancer risk: an updated systemic review and meta-analysis Background: Accumulating evidence has demonstrated that single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) (referred to as miR-SNPs) participate in the process of carcinogenesis by altering the expression and structure of mature miRNAs.	('miR', 'Gene', '29116', (204, 207))	('carcinogenesis', 'Disease', 'MESH:D063646', (268, 282))	('microRNAs', 'Gene', (193, 202))	('miR', 'Gene', (204, 207))	('participate', 'Reg', (238, 249))	('structure', 'MPA', (314, 323))	('miR', 'Gene', '29116', (334, 337))	('miR', 'Gene', (228, 231))	('esophageal cancer', 'Disease', 'MESH:D004938', (26, 43))	('miR', 'Gene', '29116', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('miR', 'Gene', (334, 337))	('miR', 'Gene', (16, 19))	('esophageal cancer', 'Disease', (26, 43))	('single nucleotide polymorphisms', 'Var', (151, 182))	('miR', 'Gene', '29116', (228, 231))	('expression', 'MPA', (299, 309))	('altering', 'Reg', (286, 294))	('carcinogenesis', 'Disease', (268, 282))
842143	31213825	However, the associations between several previously reported miR-SNPs, including miR-196a2 rs11614913, miR-146a rs2910164, miR-34b/c rs4938723, and miR-423 rs6505162 and the susceptibility of esophageal squamous cell carcinoma (ESCC) remain controversial.	('miR', 'Gene', '29116', (124, 127))	('miR-146a', 'Gene', '406938', (104, 112))	('rs2910164', 'Var', (113, 122))	('rs6505162', 'Var', (157, 166))	('miR', 'Gene', (124, 127))	('miR-34b', 'Gene', '407041', (124, 131))	('esophageal squamous cell carcinoma', 'Disease', (193, 227))	('rs4938723', 'Mutation', 'rs4938723', (134, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('rs4938723', 'Var', (134, 143))	('miR', 'Gene', '29116', (82, 85))	('rs2910164', 'Mutation', 'rs2910164', (113, 122))	('miR-34b', 'Gene', (124, 131))	('miR', 'Gene', '29116', (104, 107))	('miR', 'Gene', (82, 85))	('miR-423', 'Gene', '494335', (149, 156))	('rs11614913', 'Var', (92, 102))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (193, 227))	('miR-196a2', 'Gene', '406973', (82, 91))	('miR', 'Gene', '29116', (62, 65))	('miR', 'Gene', (104, 107))	('miR', 'Gene', '29116', (149, 152))	('rs11614913', 'Mutation', 'rs11614913', (92, 102))	('miR-196a2', 'Gene', (82, 91))	('miR', 'Gene', (62, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('miR-146a', 'Gene', (104, 112))	('miR', 'Gene', (149, 152))	('rs6505162', 'Mutation', 'rs6505162', (157, 166))	('miR-423', 'Gene', (149, 156))
842145	31213825	The pooled analysis indicated that individuals with the variant TT genotype of rs11614913 in miR-196a2 gene have a significantly decreased risk of ESCC compared with CC genotype (OR =0.83, 95% CI: 0.73-0.95).	('miR-196a2', 'Gene', '406973', (93, 102))	('rs11614913', 'Mutation', 'rs11614913', (79, 89))	('ESCC', 'Disease', (147, 151))	('miR-196a2', 'Gene', (93, 102))	('decreased', 'NegReg', (129, 138))	('rs11614913', 'Var', (79, 89))
842146	31213825	The significantly reduced risk of ESCC was also observed in the polymorphisms of the miR-34b/c rs4938723 locus.	('rs4938723', 'Mutation', 'rs4938723', (95, 104))	('miR-34b', 'Gene', (85, 92))	('miR-34b', 'Gene', '407041', (85, 92))	('reduced', 'NegReg', (18, 25))	('ESCC', 'Disease', (34, 38))	('rs4938723', 'Var', (95, 104))	('polymorphisms', 'Var', (64, 77))
842147	31213825	However, no significant associations were observed in the miR-146a rs2910164 and miR-423 rs6505162 with the susceptibility of ESCC in any genetic model.	('miR-146a', 'Gene', '406938', (58, 66))	('rs2910164', 'Mutation', 'rs2910164', (67, 76))	('rs2910164', 'Var', (67, 76))	('miR-146a', 'Gene', (58, 66))	('miR-423', 'Gene', (81, 88))	('ESCC', 'Disease', (126, 130))	('miR-423', 'Gene', '494335', (81, 88))	('rs6505162', 'Mutation', 'rs6505162', (89, 98))	('rs6505162', 'Var', (89, 98))
842148	31213825	Conclusion: Our results suggested that the polymorphisms of miR-196a and miR-34b/c genes were related to the risk of ESCC, especially among Chinese.	('polymorphisms', 'Var', (43, 56))	('miR', 'Gene', '29116', (73, 76))	('miR', 'Gene', (60, 63))	('ESCC', 'Disease', (117, 121))	('miR-34b', 'Gene', '407041', (73, 80))	('miR', 'Gene', '29116', (60, 63))	('miR', 'Gene', (73, 76))	('miR-34b', 'Gene', (73, 80))	('related', 'Reg', (94, 101))
842155	31213825	Furthermore, accumulating evidence showed that specific SNPs in miRNA genes (miR-SNPs) can influence the function of the corresponding miRNA by modulating the transcription of the primary transcript, the pri-miRNA and pre-miRNA processing and maturation, and miRNA-mRNA interactions and thereby affect the risk of developing cancer.	('miR', 'Gene', (135, 138))	('miR', 'Gene', (77, 80))	('miR', 'Gene', (222, 225))	('miR', 'Gene', '29116', (259, 262))	('maturation', 'CPA', (243, 253))	('transcription', 'MPA', (159, 172))	('miR', 'Gene', (259, 262))	('modulating', 'Reg', (144, 154))	('cancer', 'Disease', (325, 331))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('interactions', 'Interaction', (270, 282))	('miR', 'Gene', '29116', (208, 211))	('miR', 'Gene', '29116', (64, 67))	('affect', 'Reg', (295, 301))	('miR', 'Gene', (208, 211))	('miR', 'Gene', '29116', (135, 138))	('influence', 'Reg', (91, 100))	('miR', 'Gene', (64, 67))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('miR', 'Gene', '29116', (222, 225))	('miR', 'Gene', '29116', (77, 80))	('primary transcript', 'MPA', (180, 198))	('function', 'MPA', (105, 113))	('SNPs', 'Var', (56, 60))
842156	31213825	Therefore, investigations into the genetic variations of miRNAs involved in ESCC may provide new insights into the pathogenesis and help in finding novel biomarkers of this disease.	('genetic variations', 'Var', (35, 53))	('involved', 'Reg', (64, 72))	('miR', 'Gene', (57, 60))	('miR', 'Gene', '29116', (57, 60))	('ESCC', 'Disease', (76, 80))
842159	31213825	For the SNP rs4938723 in miR-34b/c, two articles reported that CC genotype and C allele could decrease the risk of ESCC.	('rs4938723', 'Mutation', 'rs4938723', (12, 21))	('miR-34b', 'Gene', (25, 32))	('miR-34b', 'Gene', '407041', (25, 32))	('decrease', 'NegReg', (94, 102))	('SNP rs4938723', 'Var', (8, 21))
842160	31213825	Therefore, we conducted this meta-analysis in order to comprehensively analyze the associations between the SNPs in four ESCC-involving miRNAs, including miR-196a2 rs11614913, miR-146a rs2910164, miR-34b/c rs4938723, and miR-423 rs6505162, and the susceptibility to ESCC and to evaluate their potential as a risk-predicting biomarker for ESCC.	('ESCC-involving', 'Disease', (121, 135))	('miR-423', 'Gene', (221, 228))	('ESCC', 'Disease', (266, 270))	('associations', 'Interaction', (83, 95))	('miR-146a', 'Gene', '406938', (176, 184))	('rs4938723', 'Var', (206, 215))	('miR', 'Gene', (196, 199))	('rs6505162', 'Var', (229, 238))	('miR', 'Gene', '29116', (154, 157))	('miR-34b', 'Gene', '407041', (196, 203))	('rs2910164', 'Mutation', 'rs2910164', (185, 194))	('miR', 'Gene', (154, 157))	('miR-34b', 'Gene', (196, 203))	('rs4938723', 'Mutation', 'rs4938723', (206, 215))	('miR', 'Gene', '29116', (176, 179))	('miR-423', 'Gene', '494335', (221, 228))	('miR', 'Gene', '29116', (136, 139))	('miR-196a2', 'Gene', '406973', (154, 163))	('rs11614913', 'Var', (164, 174))	('miR', 'Gene', (176, 179))	('miR', 'Gene', '29116', (221, 224))	('miR-196a2', 'Gene', (154, 163))	('rs11614913', 'Mutation', 'rs11614913', (164, 174))	('miR', 'Gene', (136, 139))	('rs6505162', 'Mutation', 'rs6505162', (229, 238))	('rs2910164', 'Var', (185, 194))	('miR-146a', 'Gene', (176, 184))	('miR', 'Gene', '29116', (196, 199))	('ESCC', 'Disease', (338, 342))	('miR', 'Gene', (221, 224))
842161	31213825	The following keywords were used for literature retrieval: "esophageal cancer OR esophageal neoplasms OR esophageal squamous cell carcinoma OR esophageal adenocarcinoma" AND "polymorphism or variation OR susceptibility" and "microRNA OR miRNA OR microRNAs".	('neoplasms', 'Phenotype', 'HP:0002664', (92, 101))	('esophageal adenocarcinoma', 'Disease', (143, 168))	('esophageal cancer', 'Disease', (60, 77))	('esophageal neoplasms', 'Disease', (81, 101))	('esophageal squamous cell carcinoma', 'Disease', (105, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal neoplasms', 'Disease', 'MESH:D004938', (81, 101))	('esophageal neoplasms', 'Phenotype', 'HP:0100751', (81, 101))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (105, 139))	('miR', 'Gene', '29116', (237, 240))	('polymorphism', 'Var', (175, 187))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (143, 168))	('miR', 'Gene', (237, 240))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (143, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('variation', 'Var', (191, 200))
842162	31213825	Studies were included in the meta-analysis only if they met all of the following criteria: (1) an evaluation of the association between the polymorphisms of miR-196a2 rs11614913, miR-146a rs2910164, miR-34b/c rs4938723 and miR-423 rs6505162 locus and ESCC susceptibility (with full text); (2) a case-control study; (3) detailed genotype data were available for calculating ORs and the corresponding 95% CI; and (4) the genotype distribution of the studies had to be consistent with a Hardy-Weinberg equilibrium (HWE) in the control group (P>0.05).	('association', 'Interaction', (116, 127))	('miR-34b', 'Gene', '407041', (199, 206))	('rs11614913', 'Mutation', 'rs11614913', (167, 177))	('miR-423', 'Gene', '494335', (223, 230))	('miR-146a', 'Gene', (179, 187))	('miR-196a2', 'Gene', (157, 166))	('rs4938723', 'Mutation', 'rs4938723', (209, 218))	('rs6505162', 'Mutation', 'rs6505162', (231, 240))	('miR-196a2', 'Gene', '406973', (157, 166))	('rs2910164', 'Mutation', 'rs2910164', (188, 197))	('ESCC', 'Disease', (251, 255))	('miR-146a', 'Gene', '406938', (179, 187))	('rs11614913', 'Var', (167, 177))	('rs2910164', 'Var', (188, 197))	('miR-34b', 'Gene', (199, 206))	('miR-423', 'Gene', (223, 230))	('Hardy-Weinberg equilibrium', 'Disease', (484, 510))	('rs4938723', 'Var', (209, 218))
842165	31213825	The RNAfold Web Server was used to analyze the potential secondary structure modification caused by the mutant allele of miRNAs polymorphisms (http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi).	('miR', 'Gene', (121, 124))	('mutant', 'Var', (104, 110))	('secondary structure modification', 'MPA', (57, 89))	('miR', 'Gene', '29116', (121, 124))
842168	31213825	Six studies involving 3505 cases and 4386 controls investigated the association between miR-196a2 rs11614913 T>C variant and ESCC susceptibility; The meta-analysis results were summarized in Table 2.	('rs11614913', 'Mutation', 'rs11614913', (98, 108))	('investigated', 'Reg', (51, 63))	('miR-196a2', 'Gene', (88, 97))	('rs11614913 T>C', 'Var', (98, 112))	('miR-196a2', 'Gene', '406973', (88, 97))	('ESCC', 'Disease', (125, 129))
842169	31213825	The decreased risk of ESCC was also found in the recessive model (TT vs CT/CC: OR=0.86, 95%CI: 0.77-0.96, P=0.005, I2=81.3%) (Figure 3) and allele model (T vs C: OR=0.93, 95%CI: 0.87-0.99, P=0.021, I2=76.8%) (Figure 4)  Four studies focused on miR-34b/c rs4938723 T>C, which included 2161 ESCC and 2447 controls; The pooled analysis indicated that the polymorphisms of the miR-34b/c rs4938723 locus was correlated with decreased risk of ESCC in the domain model (CC/CT vs.TT, OR=0.87, 95%CI: 0.77-0.98, P=0.018, I2=3.9%) (Figure 5), recessive model (CC vs CT+TT, OR=0.68, 95%CI: 0.56-0.83, P<0.001, I2=0.0%)(Figure 6), allele model (C vs T, OR=0.85, 95%CI: 0.78-0.93, P<0.001, I2=0.0%) (Figure 7) and CC vs.TT (OR=0.65, 95%CI: 0.52-0.79, P<0.001, I2=0.0%) (Figure 8).	('polymorphisms', 'Var', (352, 365))	('decreased', 'NegReg', (419, 428))	('miR-34b', 'Gene', (373, 380))	('rs4938723', 'Mutation', 'rs4938723', (254, 263))	('miR-34b', 'Gene', '407041', (373, 380))	('miR-34b', 'Gene', (244, 251))	('rs4938723', 'Mutation', 'rs4938723', (383, 392))	('ESCC', 'Disease', (437, 441))	('miR-34b', 'Gene', '407041', (244, 251))
842170	31213825	For miR-146a rs2910164 C>G polymorphism, six relevant studies with 3120 cases and 4036 controls were included in this meta-analysis.	('rs2910164', 'Mutation', 'rs2910164', (13, 22))	('miR-146a', 'Gene', (4, 12))	('miR-146a', 'Gene', '406938', (4, 12))	('rs2910164 C>G', 'Var', (13, 26))
842171	31213825	At last, six studies with 3083 patients and 4483 controls reported the association of miR-423 rs6505162 C>A polymorphism with the risk of ESCC.	('rs6505162', 'Mutation', 'rs6505162', (94, 103))	('miR-423', 'Gene', '494335', (86, 93))	('patients', 'Species', '9606', (31, 39))	('association', 'Interaction', (71, 82))	('miR-423', 'Gene', (86, 93))	('ESCC', 'Disease', (138, 142))	('rs6505162 C>A', 'Var', (94, 107))
842173	31213825	For miR-196a2 rs11614913, the meta-analysis results indicated the existence of significant heterogeneity in the overall analysis.	('miR-196a2', 'Gene', '406973', (4, 13))	('rs11614913', 'Var', (14, 24))	('rs11614913', 'Mutation', 'rs11614913', (14, 24))	('miR-196a2', 'Gene', (4, 13))
842174	31213825	Although the heterogeneity analysis result was negative for the miR-34b/c rs4938723, we still performed subgroup analyses based on study population (Chinese Han/Chinese Kazakh) and source of controls (hospital/population) to further explore the potential correlation of miR-34b/c rs4938723 polymorphism with the susceptibility of ESCC.	('rs4938723', 'Mutation', 'rs4938723', (74, 83))	('miR-34b', 'Gene', (270, 277))	('miR-34b', 'Gene', '407041', (270, 277))	('miR-34b', 'Gene', (64, 71))	('miR-34b', 'Gene', '407041', (64, 71))	('ESCC', 'Disease', (330, 334))	('polymorphism', 'Var', (290, 302))	('rs4938723 polymorphism', 'Var', (280, 302))	('rs4938723', 'Mutation', 'rs4938723', (280, 289))
842175	31213825	The sensitivity analysis of miR-196a2 rs11614913 was conducted by sequentially removing one individual study per time to weigh the influence of each study on the overall meta-analysis.	('miR-196a2', 'Gene', (28, 37))	('rs11614913', 'Mutation', 'rs11614913', (38, 48))	('rs11614913', 'Var', (38, 48))	('miR-196a2', 'Gene', '406973', (28, 37))
842177	31213825	The recessive model for miR-196a2 rs11614913 was then subjected to the trial sequential analysis to further strengthen the robustness of its association with ESCC risk.	('rs11614913', 'Mutation', 'rs11614913', (34, 44))	('association', 'Interaction', (141, 152))	('ESCC', 'Disease', (158, 162))	('miR-196a2', 'Gene', (24, 33))	('miR-196a2', 'Gene', '406973', (24, 33))	('rs11614913', 'Var', (34, 44))
842179	31213825	We conducted an RNA secondary structure analysis of the miR-196a2 rs11614913 polymorphisms using the RNAfold Web server.	('rs11614913', 'Var', (66, 76))	('rs11614913', 'Mutation', 'rs11614913', (66, 76))	('miR-196a2', 'Gene', '406973', (56, 65))	('miR-196a2', 'Gene', (56, 65))
842180	31213825	This SNP decreased the minimum free energy (MFE) from -52.02 kcal/mol of the C allele to -46.52 kcal/mol of the T allele, suggesting a less stable secondary structure for the variant T allele, and therefore this variant might affect the stability of the secondary structure of miR-196a2.	('less', 'NegReg', (135, 139))	('stability', 'MPA', (237, 246))	('miR-196a2', 'Gene', (277, 286))	('secondary structure', 'MPA', (254, 273))	('minimum free energy', 'MPA', (23, 42))	('miR-196a2', 'Gene', '406973', (277, 286))	('variant', 'Var', (175, 182))	('decreased', 'NegReg', (9, 18))	('variant', 'Var', (212, 219))	('affect', 'Reg', (226, 232))
842181	31213825	This meta-analysis shows that overall, variant TT genotype and T allele carriers of the rs116149138473 polymorphism of miR-196a2 gene are correlated to reduced risk for ESCC, especially among Chinese population (Table 2 and Figures 2-4).	('ESCC', 'Disease', (169, 173))	('reduced', 'NegReg', (152, 159))	('miR-196a2', 'Gene', (119, 128))	('variant', 'Var', (39, 46))	('rs116149138473', 'Var', (88, 102))	('miR-196a2', 'Gene', '406973', (119, 128))	('rs116149138473', 'DBSNP_MENTION', 'None', (88, 102))
842182	31213825	The miR-196a2 polymorphism site rs11614913 is located in the mature sequence of miR-196a-3p (passenger strand), and it could lead to less efficient processing of the miRNA precursor to its mature form and therefore reduce the capacity of mature miR-196a-3p in regulating target genes.	('miR', 'Gene', (80, 83))	('miR', 'Gene', (245, 248))	('processing', 'MPA', (148, 158))	('rs11614913', 'Mutation', 'rs11614913', (32, 42))	('miR', 'Gene', '29116', (166, 169))	('reduce', 'NegReg', (215, 221))	('miR', 'Gene', '29116', (80, 83))	('miR', 'Gene', '29116', (245, 248))	('less efficient', 'NegReg', (133, 147))	('miR', 'Gene', (4, 7))	('regulating', 'MPA', (260, 270))	('miR-196a2', 'Gene', (4, 13))	('rs11614913', 'Var', (32, 42))	('miR-196a2', 'Gene', '406973', (4, 13))	('miR', 'Gene', '29116', (4, 7))	('miR', 'Gene', (166, 169))	('capacity', 'MPA', (226, 234))
842183	31213825	Another research reported that miR-196a2 rs11614913 not only influences the levels of mature miR-196a but also has an effect on target gene expression.	('rs11614913', 'Var', (41, 51))	('miR', 'Gene', '29116', (93, 96))	('miR-196a2', 'Gene', '406973', (31, 40))	('effect', 'Reg', (118, 124))	('miR', 'Gene', (31, 34))	('rs11614913', 'Mutation', 'rs11614913', (41, 51))	('miR-196a2', 'Gene', (31, 40))	('miR', 'Gene', (93, 96))	('influences', 'Reg', (61, 71))	('miR', 'Gene', '29116', (31, 34))	('target gene expression', 'MPA', (128, 150))
842184	31213825	Our further RNA secondary structure analysis suggested that the variant T allele might affect the stability of the secondary structure of miR-196a2.	('affect', 'Reg', (87, 93))	('variant', 'Var', (64, 71))	('stability', 'MPA', (98, 107))	('miR-196a2', 'Gene', (138, 147))	('miR-196a2', 'Gene', '406973', (138, 147))
842185	31213825	In the subgroup analyses, we did not find rs116149138473 polymorphism of miR-196a2 gene was associated with the ESCC risk in the population-based studies.	('rs116149138473', 'Var', (42, 56))	('rs116149138473', 'DBSNP_MENTION', 'None', (42, 56))	('ESCC', 'Disease', (112, 116))	('miR-196a2', 'Gene', (73, 82))	('associated', 'Reg', (92, 102))	('miR-196a2', 'Gene', '406973', (73, 82))
842187	31213825	Moreover, our meta-analysis found that the CC genotype or C allele of miR-34b/c rs4938723 had significant associations with decreased risk of ESCC, especially among Chinese Han population (Table 3 and Figures 5-8).	('rs4938723', 'Var', (80, 89))	('decreased', 'NegReg', (124, 133))	('rs4938723', 'Mutation', 'rs4938723', (80, 89))	('miR-34b', 'Gene', (70, 77))	('ESCC', 'Disease', (142, 146))	('miR-34b', 'Gene', '407041', (70, 77))
842188	31213825	The miR-34b/c rs4938723 is located in CpG islands in miR-34b/c promoter region and may take part in the epigenetic silencing of miR-34b/c.	('miR-34b', 'Gene', (128, 135))	('miR-34b', 'Gene', (53, 60))	('miR-34b', 'Gene', '407041', (128, 135))	('miR-34b', 'Gene', '407041', (53, 60))	('rs4938723', 'Mutation', 'rs4938723', (14, 23))	('miR-34b', 'Gene', (4, 11))	('miR-34b', 'Gene', '407041', (4, 11))	('epigenetic silencing', 'MPA', (104, 124))	('rs4938723', 'Var', (14, 23))	('take part', 'Reg', (87, 96))
842189	31213825	To the best of our knowledge, this study is the first systematic review and meta-analysis to evaluate the association of miR-34b/c rs4938723 with the risk of ESCC.	('miR-34b', 'Gene', '407041', (121, 128))	('association', 'Interaction', (106, 117))	('rs4938723', 'Var', (131, 140))	('ESCC', 'Disease', (158, 162))	('rs4938723', 'Mutation', 'rs4938723', (131, 140))	('miR-34b', 'Gene', (121, 128))
842190	31213825	In addition, we also conducted pooled analysis with the other two polymorphisms, miR-146a rs2910164 G>C and miR-423 rs6505162 C>A.	('rs2910164 G>C', 'Var', (90, 103))	('rs2910164', 'Mutation', 'rs2910164', (90, 99))	('miR-423', 'Gene', '494335', (108, 115))	('rs6505162 C>A', 'Var', (116, 129))	('miR-146a', 'Gene', (81, 89))	('miR-146a', 'Gene', '406938', (81, 89))	('rs6505162', 'Mutation', 'rs6505162', (116, 125))	('miR-423', 'Gene', (108, 115))
842193	31213825	A meta-analysis by Ji et al has evaluated the association between miR-196a2 rs11614913, miR-146a rs2910164, and miR-423 rs6505162 polymorphisms and esophageal cancer risk.	('miR-196a2', 'Gene', '406973', (66, 75))	('rs2910164', 'Mutation', 'rs2910164', (97, 106))	('rs11614913', 'Var', (76, 86))	('rs2910164', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('miR-423', 'Gene', (112, 119))	('esophageal cancer', 'Disease', (148, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('miR-146a', 'Gene', '406938', (88, 96))	('miR-196a2', 'Gene', (66, 75))	('association', 'Interaction', (46, 57))	('rs11614913', 'Mutation', 'rs11614913', (76, 86))	('rs6505162', 'Mutation', 'rs6505162', (120, 129))	('miR-423', 'Gene', '494335', (112, 119))	('rs6505162', 'Var', (120, 129))	('miR-146a', 'Gene', (88, 96))
842201	31213825	And these results also suggested that the biological functions of genetic variations in miRNAs might be influenced by ethnics, ages and environment factors (smoking, drinking).	('miR', 'Gene', (88, 91))	('genetic variations', 'Var', (66, 84))	('miR', 'Gene', '29116', (88, 91))	('influenced', 'Reg', (104, 114))
842203	31213825	The present study indicated that the polymorphisms of miR-196a2 rs11614913 and miR-34b/c rs4938723 are associated with decreased risk of ESCC, especially in Chinese people.	('miR-34b', 'Gene', '407041', (79, 86))	('people', 'Species', '9606', (165, 171))	('decreased', 'NegReg', (119, 128))	('rs4938723', 'Mutation', 'rs4938723', (89, 98))	('miR-34b', 'Gene', (79, 86))	('miR-196a2', 'Gene', '406973', (54, 63))	('ESCC', 'Disease', (137, 141))	('rs11614913', 'Mutation', 'rs11614913', (64, 74))	('rs11614913', 'Var', (64, 74))	('rs4938723', 'Var', (89, 98))	('miR-196a2', 'Gene', (54, 63))
842204	31213825	However, the current data suggested that miR-146a rs2910164 or miR-423 rs6505162 are not related to the susceptibility of ESCC in any genetic model.	('rs2910164', 'Var', (50, 59))	('miR-423', 'Gene', '494335', (63, 70))	('rs2910164', 'Mutation', 'rs2910164', (50, 59))	('ESCC', 'Disease', (122, 126))	('miR-146a', 'Gene', '406938', (41, 49))	('miR-146a', 'Gene', (41, 49))	('rs6505162', 'Mutation', 'rs6505162', (71, 80))	('rs6505162', 'Var', (71, 80))	('miR-423', 'Gene', (63, 70))
842207	30874331	In some such cancers, Ras and Raf are hotspots for mutations, which cause continuous activation of this pathway.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (51, 60))	('activation', 'PosReg', (85, 95))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancers', 'Disease', (13, 20))
842216	30874331	Germline loss-of-function mutations in Spred1 causes Legius syndrome, which shows a similar phenotype to NF1 with cafe-au-lait spots and axillary freckling, but without cutaneous neurofibromas, or any detectable NF1 mutation.5 After this report, it was shown that Spred1 binds to neurofibromin (encoded by NF1) by its EVH-1 domain and recruits neurofibromin to the plasma membrane, which explains the overlapping features of the two human diseases.6 Spreds are also known to regulate inflammatory signaling in various organs.	('cutaneous neurofibromas', 'Disease', (169, 192))	('Legius syndrome', 'Disease', (53, 68))	('mutations', 'Var', (26, 35))	('regulate', 'Reg', (475, 483))	('neurofibromin', 'Gene', (344, 357))	('NF1', 'Gene', '4763', (212, 215))	('EVH', 'Chemical', '-', (318, 321))	('Legius syndrome', 'Disease', 'MESH:C548032', (53, 68))	('neurofibromin', 'Gene', '4763', (280, 293))	('cutaneous neurofibromas', 'Phenotype', 'HP:0100698', (169, 192))	('neurofibromas', 'Phenotype', 'HP:0001067', (179, 192))	('NF1', 'Gene', (212, 215))	('NF1', 'Gene', '4763', (306, 309))	('neurofibromin', 'Gene', '4763', (344, 357))	('NF1', 'Gene', '4763', (105, 108))	('inflammatory signaling', 'MPA', (484, 506))	('axillary freckling', 'Phenotype', 'HP:0000997', (137, 155))	('freckling', 'Phenotype', 'HP:0001480', (146, 155))	('NF1', 'Gene', (306, 309))	('human', 'Species', '9606', (433, 438))	('NF1', 'Gene', (105, 108))	('cafe-au-lait spots', 'Phenotype', 'HP:0000957', (114, 132))	('cutaneous neurofibromas', 'Disease', 'MESH:D009455', (169, 192))	('neurofibromin', 'Gene', (280, 293))
842231	30874331	The Sprouty/Spred family is one of the most important negative regulators of ERK signaling, and thus, evidence of its antitumorigenic efficacy has accumulated (Tables 1 and 2).1-4,19,32-60  It is thought that deregulation of the Ras/Raf/ERK pathway in HCC is due to downregulation of the negative regulators, including Sproutys, Spreds, and dual-specificity phosphatases.	('Sprouty', 'Gene', '38424', (319, 326))	('deregulation', 'Var', (209, 221))	('Sprouty', 'Gene', (319, 326))	('downregulation', 'NegReg', (266, 280))	('HCC', 'Gene', '619501', (252, 255))	('Sprouty', 'Gene', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Sprouty', 'Gene', '38424', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('HCC', 'Gene', (252, 255))	('tumor', 'Disease', (122, 127))	('Ras/Raf/ERK pathway', 'Pathway', (229, 248))
842235	30874331	The expression of Sprouty2 is reported to be reduced in human CRC and is inversely correlated with the expression of miR-21.37 The expression level of Sprouty4 is also reduced in human CRC due to DNA methylation and serves as an independent predictor of overall survival.36 The expression of Sprouty2, which promotes the cytotoxic effect of 5-fluorouracil and metformin, is downregulated by miR-21 in a human colon cancer cell line.65 Sprouty2 also increases the sensitivity to gefitinib, an EGFR inhibitor, by increasing the expression of phosphorylated and total EGFR in human CRC cell lines.2 Moreover, in colon cancer cells, Sprouty2 induces PTEN expression and suppresses the PI3K-Akt pathway in addition to the Ras/Raf/ERK pathway.37 However, in contrast, Holgren's group reported that Sprouty2 is upregulated in human CRC samples and functions as an oncogene by inducing the expression of c-Met.38 The same group showed that the downregulation of Sprouty2 induces E-cadherin and p21 expression and inhibits EMT and cell proliferation.39 Sprouty2 also increases ZEB1 expression through Akt and Src activation and induces EMT in colon cancer cells.66  A study about Spreds and CRC was carried out using an azoxymethane/DSS-induced colon tumor model.9 The number and size of colon tumors in Spred2-/- mice were lower and smaller than those in WT mice.9 Knockdown of Spred2 in a human colon cancer cell line modestly increased the cell proliferation and migration.9 To elucidate the role of Spreds in CRC, further investigation is necessary.	('colon cancer', 'Disease', (1134, 1146))	('colon cancer', 'Disease', (1388, 1400))	('colon cancer', 'Disease', 'MESH:D015179', (609, 621))	('EGFR', 'Gene', '1956', (492, 496))	('Sprouty2', 'Gene', '24064', (792, 800))	('colon tumor', 'Disease', 'MESH:D015179', (1279, 1290))	('azoxymethane', 'Chemical', 'MESH:D001397', (1211, 1223))	('cancer', 'Phenotype', 'HP:0002664', (615, 621))	('tumor', 'Phenotype', 'HP:0002664', (1285, 1290))	('colon tumors', 'Disease', 'MESH:D015179', (1279, 1291))	('colon cancer', 'Disease', 'MESH:D015179', (409, 421))	('human', 'Species', '9606', (819, 824))	('Sprouty2', 'Gene', (629, 637))	('colon tumor', 'Phenotype', 'HP:0100273', (1279, 1290))	('Sprouty2', 'Gene', '24064', (292, 300))	('Sprouty2', 'Gene', (18, 26))	('human', 'Species', '9606', (1382, 1387))	('human', 'Species', '9606', (573, 578))	('mice', 'Species', '10090', (1305, 1309))	('colon cancer', 'Disease', (609, 621))	('colon tumors', 'Phenotype', 'HP:0100273', (1279, 1291))	('Spred2', 'Gene', (1370, 1376))	('E-cadherin', 'Gene', (971, 981))	('Sprouty2', 'Gene', '24064', (435, 443))	('human', 'Species', '9606', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (415, 421))	('EGFR', 'Gene', (565, 569))	('Sprouty2', 'Gene', '24064', (1044, 1052))	('colon tumor', 'Disease', 'MESH:D015179', (1236, 1247))	('Sprouty2', 'Gene', (954, 962))	('colon tumors', 'Disease', (1279, 1291))	('E-cadherin', 'Gene', '999', (971, 981))	('colon cancer', 'Phenotype', 'HP:0003003', (1134, 1146))	('ZEB1', 'Gene', (1068, 1072))	('colon cancer', 'Phenotype', 'HP:0003003', (1388, 1400))	('colon tumor', 'Phenotype', 'HP:0100273', (1236, 1247))	('tumor', 'Phenotype', 'HP:0002664', (1242, 1247))	('colon cancer', 'Disease', (409, 421))	('PTEN', 'Gene', (646, 650))	('Src', 'Gene', (1100, 1103))	('colon tumor', 'Disease', (1236, 1247))	('DSS', 'Gene', (1224, 1227))	('EGFR', 'Gene', (492, 496))	('EMT', 'Gene', (1127, 1130))	('Sprouty2', 'Gene', (792, 800))	('EMT', 'Gene', (1014, 1017))	('EMT', 'Gene', '3702', (1127, 1130))	('EMT', 'Gene', '3702', (1014, 1017))	('human', 'Species', '9606', (403, 408))	('Sprouty2', 'Gene', '24064', (629, 637))	('colon cancer', 'Disease', 'MESH:D015179', (1134, 1146))	('Sprouty2', 'Gene', '24064', (18, 26))	('Sprouty2', 'Gene', (292, 300))	('colon cancer', 'Disease', 'MESH:D015179', (1388, 1400))	('colon cancer', 'Phenotype', 'HP:0003003', (609, 621))	('cancer', 'Phenotype', 'HP:0002664', (1394, 1400))	('Src', 'Gene', '6714', (1100, 1103))	('human', 'Species', '9606', (179, 184))	('p21', 'Gene', (986, 989))	('cell proliferation', 'CPA', (1434, 1452))	('PTEN', 'Gene', '5728', (646, 650))	('DSS', 'Gene', '5376', (1224, 1227))	('p21', 'Gene', '644914', (986, 989))	('cancer', 'Phenotype', 'HP:0002664', (1140, 1146))	('colon cancer', 'Phenotype', 'HP:0003003', (409, 421))	('Knockdown', 'Var', (1357, 1366))	('Sprouty2', 'Gene', (1044, 1052))	('Sprouty2', 'Gene', '24064', (954, 962))	('EGFR', 'Gene', '1956', (565, 569))	('Sprouty2', 'Gene', (435, 443))	('tumors', 'Phenotype', 'HP:0002664', (1285, 1291))	('mice', 'Species', '10090', (1350, 1354))	('increased', 'PosReg', (1420, 1429))	('ZEB1', 'Gene', '6935', (1068, 1072))
842244	30874331	In B-cell lymphoma, Sprouty2 is epigenetically silenced and promotes cell proliferation.2 Sprouty2 is also downregulated in chronic lymphocytic leukemia and is an important negative regulator of B-cell receptor-mediated ERK activation.52 In multiple myeloma, Sprouty2 is downregulated by miR-21 expression.15, 86 High expression of Sprouty4 is associated with a favorable prognosis in patients with AML.53  From a large series of 230 pediatric acute lymphoblastic and myeloblastic leukemias, Spred1 mutations were found.60 In 1 of the 4 patients with Legius syndrome, a loss-of-function frameshift Spred1 mutation was detected.	('leukemia', 'Phenotype', 'HP:0001909', (144, 152))	('AML', 'Disease', (399, 402))	('multiple myeloma', 'Disease', (241, 257))	('lymphoma', 'Phenotype', 'HP:0002665', (10, 18))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (3, 18))	('patients', 'Species', '9606', (537, 545))	('Sprouty2', 'Gene', (90, 98))	('Sprouty2', 'Gene', '24064', (259, 267))	('Sprouty2', 'Gene', '24064', (20, 28))	('patients', 'Species', '9606', (385, 393))	('mutation', 'Var', (605, 613))	('leukemias', 'Phenotype', 'HP:0001909', (481, 490))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (3, 18))	('multiple myeloma', 'Phenotype', 'HP:0006775', (241, 257))	('myeloblastic leukemias', 'Disease', 'MESH:D015470', (468, 490))	('Legius syndrome', 'Disease', (551, 566))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (124, 152))	('myeloblastic leukemias', 'Disease', (468, 490))	('leukemia', 'Phenotype', 'HP:0001909', (481, 489))	('chronic lymphocytic leukemia', 'Disease', (124, 152))	('frameshift', 'Var', (587, 597))	('B-cell lymphoma', 'Disease', (3, 18))	('Legius syndrome', 'Disease', 'MESH:C548032', (551, 566))	('Sprouty2', 'Gene', '24064', (90, 98))	('Sprouty2', 'Gene', (259, 267))	('multiple myeloma', 'Disease', 'MESH:D009101', (241, 257))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (124, 152))	('loss-of-function', 'NegReg', (570, 586))	('Sprouty2', 'Gene', (20, 28))	('Spred1', 'Gene', (598, 604))	('myeloblastic leukemias', 'Phenotype', 'HP:0012324', (468, 490))	('AML', 'Disease', 'MESH:D015470', (399, 402))
842250	30874331	However, as mentioned above, Sprouty1, Sprouty2, and Sprouty4 function as oncogenes in some types of cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('Sprouty2', 'Gene', '24064', (39, 47))	('Sprouty1', 'Gene', '24063', (29, 37))	('cancer', 'Disease', (101, 107))	('Sprouty4', 'Var', (53, 61))	('Sprouty2', 'Gene', (39, 47))	('Sprouty1', 'Gene', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
842324	29050283	In the glandular stomach, there existed more atypical hyperplasia cases in the MNNG plus omeprazole groups than the MNNG-treated group, and one carcinoma was induced in the MNNG plus high dose omeprazole group.	('omeprazole', 'Chemical', 'MESH:D009853', (89, 99))	('carcinoma', 'Disease', (144, 153))	('MNNG', 'Chemical', 'MESH:D008769', (79, 83))	('hyperplasia', 'Disease', (54, 65))	('MNNG', 'Chemical', 'MESH:D008769', (173, 177))	('MNNG', 'Var', (79, 83))	('carcinoma', 'Disease', 'MESH:D002277', (144, 153))	('omeprazole', 'Chemical', 'MESH:D009853', (193, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('MNNG', 'Chemical', 'MESH:D008769', (116, 120))	('hyperplasia', 'Disease', 'MESH:D006965', (54, 65))
842336	29050283	However, a marked number of PPI prescriptions are often inappropriate, potentially resulting in diverse adverse effects, including gastric parietal cell hyperplasia, gland cyst, hypergastrinemia, fundic gland polyp, etc., with the underlying mechanism barely revealed.	('hypergastrinemia', 'Phenotype', 'HP:0500167', (178, 194))	('prescriptions', 'Var', (32, 45))	('fundic gland polyp', 'Disease', (196, 214))	('fundic gland polyp', 'Disease', 'MESH:D011127', (196, 214))	('gastric parietal cell hyperplasia', 'Disease', (131, 164))	('hypergastrinemia', 'Disease', (178, 194))	('resulting in', 'Reg', (83, 95))	('PPI', 'Var', (28, 31))	('gastric parietal cell hyperplasia', 'Disease', 'MESH:D013274', (131, 164))	('hypergastrinemia', 'Disease', 'None', (178, 194))	('gland cyst', 'Disease', (166, 176))
842337	29050283	A recent study showed dose-dependent inhibition of lysosomal enzyme activities by PPIs in cultured cells and mouse spleen.	('lysosomal enzyme', 'Enzyme', (51, 67))	('mouse', 'Species', '10090', (109, 114))	('PPIs', 'Var', (82, 86))	('inhibition', 'NegReg', (37, 47))
842343	29050283	However, omeprazole treatment decreased mouse body weight, and mice were lighter in the MNNG-treated subgroup than in the non-MNNG-treated subgroup (Figure 2A).	('MNNG', 'Chemical', 'MESH:D008769', (126, 130))	('MNNG-treated', 'Var', (88, 100))	('mouse body weight', 'CPA', (40, 57))	('mice', 'Species', '10090', (63, 67))	('omeprazole', 'Chemical', 'MESH:D009853', (9, 19))	('MNNG', 'Chemical', 'MESH:D008769', (88, 92))	('lighter', 'NegReg', (73, 80))	('mouse', 'Species', '10090', (40, 45))	('decreased', 'NegReg', (30, 39))
842361	29050283	In serum, the ACP level was lower in both the high dose (t = -2.501, P = 0.028) and low dose (t = -1.892, P = 0.083) omeprazole groups than the control group; compared to the MNNG group, the ACP concentration was significantly lower in the MNNG plus omeprazole groups (MNNG + low dose omeprazole vs. MNNG: t = -4.315, P = 0.001; MNNG + high dose omeprazole vs. MNNG: t = -7.432, P = 0.000); and it was even lower in the MNNG + high dose omeprazole group compared to the MNNG + low dose omeprazole group (t = -2.326, P = 0.038).	('MNNG', 'Chemical', 'MESH:D008769', (470, 474))	('MNNG', 'Chemical', 'MESH:D008769', (240, 244))	('omeprazole', 'Chemical', 'MESH:D009853', (117, 127))	('omeprazole', 'Chemical', 'MESH:D009853', (285, 295))	('ACP concentration', 'MPA', (191, 208))	('lower', 'NegReg', (227, 232))	('omeprazole', 'Chemical', 'MESH:D009853', (346, 356))	('MNNG', 'Chemical', 'MESH:D008769', (175, 179))	('ACP level', 'MPA', (14, 23))	('MNNG', 'Chemical', 'MESH:D008769', (420, 424))	('omeprazole', 'Chemical', 'MESH:D009853', (250, 260))	('lower', 'NegReg', (407, 412))	('MNNG', 'Chemical', 'MESH:D008769', (300, 304))	('MNNG', 'Chemical', 'MESH:D008769', (269, 273))	('omeprazole', 'Chemical', 'MESH:D009853', (486, 496))	('MNNG + high', 'Var', (420, 431))	('MNNG', 'Chemical', 'MESH:D008769', (361, 365))	('omeprazole', 'Chemical', 'MESH:D009853', (437, 447))	('MNNG', 'Chemical', 'MESH:D008769', (329, 333))
842362	29050283	In spleen, the ACP level was lower in the high dose omeprazole group than the control group (t = -2.623, P = 0.031); compared to the MNNG group, the ACP concentration was lower in the MNNG plus omeprazole groups (MNNG + low dose omeprazole vs. MNNG: t = -1.960, P = 0.074; MNNG + high dose omeprazole vs. MNNG: t = -4.053, P = 0.002); and it was even lower in the MNNG + high dose omeprazole group compared to the MNNG + low dose omeprazole group (t = -1.926, P = 0.078).	('omeprazole', 'Chemical', 'MESH:D009853', (381, 391))	('MNNG', 'Chemical', 'MESH:D008769', (184, 188))	('MNNG', 'Chemical', 'MESH:D008769', (414, 418))	('MNNG', 'Var', (364, 368))	('ACP level', 'MPA', (15, 24))	('omeprazole', 'Chemical', 'MESH:D009853', (229, 239))	('ACP concentration', 'MPA', (149, 166))	('omeprazole', 'Chemical', 'MESH:D009853', (52, 62))	('lower', 'NegReg', (351, 356))	('omeprazole', 'Chemical', 'MESH:D009853', (194, 204))	('MNNG', 'Chemical', 'MESH:D008769', (133, 137))	('omeprazole', 'Chemical', 'MESH:D009853', (290, 300))	('MNNG', 'Chemical', 'MESH:D008769', (213, 217))	('MNNG', 'Chemical', 'MESH:D008769', (244, 248))	('MNNG', 'Chemical', 'MESH:D008769', (364, 368))	('lower', 'NegReg', (29, 34))	('omeprazole', 'Chemical', 'MESH:D009853', (430, 440))	('MNNG', 'Chemical', 'MESH:D008769', (273, 277))	('MNNG', 'Chemical', 'MESH:D008769', (305, 309))	('lower', 'NegReg', (171, 176))
842363	29050283	Interestingly, the ACP levels in the MNNG-treated subgroups were higher in spleen than in serum, which is opposed to the corresponding comparison patterns in the non-MNNG-treated subgroups.	('MNNG-treated', 'Var', (37, 49))	('ACP levels', 'MPA', (19, 29))	('MNNG', 'Chemical', 'MESH:D008769', (166, 170))	('higher', 'PosReg', (65, 71))	('MNNG', 'Chemical', 'MESH:D008769', (37, 41))
842391	29050283	In mice, PPI administration increased the number of parietal cells with enhanced expression of water or ion transport proteins which were associated with fundic gland polyp development.	('increased', 'PosReg', (28, 37))	('fundic gland polyp', 'Disease', (154, 172))	('PPI', 'Var', (9, 12))	('fundic gland polyp', 'Disease', 'MESH:D011127', (154, 172))	('water', 'Chemical', 'MESH:D014867', (95, 100))	('mice', 'Species', '10090', (3, 7))	('enhanced', 'PosReg', (72, 80))	('expression of water or ion transport proteins', 'MPA', (81, 126))
842393	29050283	In Hp-infected Mongolian gerbils, long-term PPI administration was shown to promote adenocarcinoma genesis, which was associated with the progression of atrophic corpus gastritis.	('promote', 'PosReg', (76, 83))	('Mongolian gerbils', 'Species', '10047', (15, 32))	('PPI', 'Var', (44, 47))	('adenocarcinoma genesis', 'Disease', (84, 106))	('atrophic corpus gastritis', 'Disease', (153, 178))	('Hp', 'Species', '210', (3, 5))	('adenocarcinoma genesis', 'Disease', 'MESH:D000230', (84, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('gastritis', 'Phenotype', 'HP:0005263', (169, 178))	('atrophic corpus gastritis', 'Disease', 'MESH:D005757', (153, 178))
842394	29050283	Neuroendocrine tumor development was also enhanced in long-term high-dose PPI-treated gerbils.	('Neuroendocrine tumor', 'Disease', (0, 20))	('Neuroendocrine tumor', 'Disease', 'MESH:D018358', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('enhanced', 'PosReg', (42, 50))	('Neuroendocrine tumor', 'Phenotype', 'HP:0100634', (0, 20))	('PPI-treated', 'Var', (74, 85))
842411	29050283	PPIs are easily activated and prone to bind cysteine-containing peptides at pH of 5, and its systematic distribution potentially greatly inhibits the intracellular V-ATP enzyme and alkalizing the lysosome, which weakens its activities and facilitates cancer progression.	('intracellular V-ATP enzyme', 'MPA', (150, 176))	('distribution', 'Var', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('activities', 'MPA', (224, 234))	('lysosome', 'MPA', (196, 204))	('cysteine-containing', 'Protein', (44, 63))	('peptides', 'Chemical', 'MESH:D010455', (64, 72))	('bind', 'Interaction', (39, 43))	('cysteine', 'Chemical', 'MESH:D003545', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (251, 257))	('facilitates', 'PosReg', (239, 250))	('inhibits', 'NegReg', (137, 145))	('alkalizing', 'MPA', (181, 191))	('weakens', 'NegReg', (212, 219))
842432	29050283	The findings could propose the potential clinical hypothesis that long-term PPI application might increase the incidence of adenocarcinoma of the GEJ among people with a significant intake of pickled food.	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('people', 'Species', '9606', (156, 162))	('increase', 'PosReg', (98, 106))	('adenocarcinoma', 'Disease', (124, 138))	('adenocarcinoma', 'Disease', 'MESH:D000230', (124, 138))	('PPI', 'Var', (76, 79))
842573	25041229	When evaluating the LES, the total wall thickness, but not the muscularis propria thickness was significantly greater in patients with IRP>=15 mmHg compared to patients with IRP<15 mmHg (p=0.01).	('patients', 'Species', '9606', (160, 168))	('total wall', 'MPA', (29, 39))	('muscularis propria', 'Phenotype', 'HP:0030936', (63, 81))	('greater', 'PosReg', (110, 117))	('patients', 'Species', '9606', (121, 129))	('IRP>=15 mmHg', 'Var', (135, 147))
842574	25041229	Overall, among patients with IRP>=15, those with EGJOO were found to have the greatest esophageal wall, muscularis propria, and LES thickness whereas among patients with IRP<15, those with DES had greatest wall thickness.	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (15, 23))	('LES', 'MPA', (128, 131))	('muscularis propria', 'Phenotype', 'HP:0030936', (104, 122))	('EGJOO', 'Var', (49, 54))	('esophageal wall', 'CPA', (87, 102))	('DES', 'Chemical', 'MESH:D004054', (189, 192))
842586	25041229	The major finding was that EUS identified clinically significant lesions that altered patient management in 15% of these patients suggesting it to be clinically useful to further evaluate patients with these HRM findings with potential mechanical or anatomical causation.	('patient', 'Species', '9606', (188, 195))	('patient', 'Species', '9606', (121, 128))	('patients', 'Species', '9606', (188, 196))	('lesions', 'Var', (65, 72))	('patient', 'Species', '9606', (86, 93))	('altered', 'Reg', (78, 85))	('patients', 'Species', '9606', (121, 129))
842647	24558423	The establishment and recruitment procedures of the NIH-AARP Diet and Health Study, a large prospective cohort study investigating the association between diet and other factors and risk of cancer, have been described in detail elsewhere.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('NIH-AARP', 'Var', (52, 60))	('men', 'Species', '9606', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('men', 'Species', '9606', (13, 16))
842655	24558423	We classified tumors with site codes C15.0- C15.9 as esophageal cancers, site code C16.0 as gastric cardia tumors, and site codes C16.1- C16.9 as noncardia tumors.	('C15.0- C15.9', 'Var', (37, 49))	('noncardia tumors', 'Disease', 'MESH:D009369', (146, 162))	('gastric cardia tumors', 'Disease', 'MESH:D004938', (92, 113))	('gastric cardia tumors', 'Disease', (92, 113))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('C16.9', 'CellLine', 'CVCL:2322', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('noncardia tumors', 'Disease', (146, 162))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', (156, 162))	('esophageal cancers', 'Disease', (53, 71))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('esophageal cancers', 'Disease', 'MESH:D004938', (53, 71))
842656	24558423	We treated C16.8 and C16.9 (gastric tumors without specific location information) as noncardia cancers.	('gastric tumors', 'Disease', 'MESH:D013274', (28, 42))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('C16.9', 'CellLine', 'CVCL:2322', (21, 26))	('gastric tumors', 'Disease', (28, 42))	('C16.8', 'Var', (11, 16))	('C16.9', 'Var', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('noncardia cancers', 'Disease', 'MESH:D009369', (85, 102))	('gastric tumors', 'Phenotype', 'HP:0006753', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('noncardia cancers', 'Disease', (85, 102))
842738	24212960	MVD in the VEGF positive group was higher than in the negative group (CT, p = 0.034; P, p = 0.030; M, p = 0.032) as is shown in Table 2.	('VEGF', 'Gene', (11, 15))	('MVD', 'MPA', (0, 3))	('positive', 'Var', (16, 24))	('VEGF', 'Gene', '7422', (11, 15))	('higher', 'PosReg', (35, 41))
842748	24212960	In general, the MVD has been quantified by immunohistochemical staining of tumor blood vessels with the use of antibodies, including CD31, CD34, von Willebrand Factor (vWF) or Factor VIII-related antigen (FVIII) and CD105.	('Factor VIII-related antigen', 'Gene', '2157', (176, 203))	('CD34', 'Gene', (139, 143))	('vWF', 'Gene', (168, 171))	('CD34', 'Gene', '947', (139, 143))	('von Willebrand Factor', 'Gene', '7450', (145, 166))	('Factor VIII-related antigen', 'Gene', (176, 203))	('FVIII', 'Gene', (205, 210))	('CD31', 'Gene', (133, 137))	('vWF', 'Gene', '7450', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CD31', 'Gene', '5175', (133, 137))	('von Willebrand Factor', 'Gene', (145, 166))	('FVIII', 'Gene', '2157', (205, 210))	('CD105', 'Var', (216, 221))	('tumor', 'Disease', (75, 80))
842767	24212960	The moderate to strong VEGF expression in GITC was significantly associated with a high MVD, in agreement with the findings in esophageal and gastric cancer and colorectal carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (161, 181))	('gastric cancer', 'Disease', (142, 156))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('GITC', 'Phenotype', 'HP:0002672', (42, 46))	('associated', 'Reg', (65, 75))	('VEGF', 'Gene', (23, 27))	('MVD', 'MPA', (88, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('expression', 'Var', (28, 38))	('colorectal carcinoma', 'Disease', (161, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('VEGF', 'Gene', '7422', (23, 27))
842771	24212960	The MVD association with VEGF expression was in concordance with the increase of blood vessels in the CT, P and M regions from GITC with positive VEGF immunoreactions, confirming that these tumors increase their vasculature at expenses of at least VEGF.	('GITC', 'Phenotype', 'HP:0002672', (127, 131))	('VEGF', 'Gene', (248, 252))	('increase', 'PosReg', (69, 77))	('VEGF', 'Gene', (146, 150))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('increase', 'PosReg', (197, 205))	('VEGF', 'Gene', '7422', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('expression', 'Var', (30, 40))	('vasculature', 'MPA', (212, 223))	('VEGF', 'Gene', '7422', (248, 252))	('VEGF', 'Gene', '7422', (146, 150))	('tumors', 'Disease', (190, 196))	('blood vessels', 'CPA', (81, 94))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('VEGF', 'Gene', (25, 29))
842800	24212960	Thus, the impact of these changes are reflected in the improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of cytotoxic drugs to tumor cells, the efficacy of radiotherapy and the effectors immune cells (e.g., T lymphocytes).	('tumor', 'Disease', (99, 104))	('metabolic profile', 'MPA', (74, 91))	('changes', 'Var', (26, 33))	('T lymphocytes', 'CPA', (251, 264))	('improvement', 'PosReg', (55, 66))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('delivery', 'MPA', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
842875	20376881	People who drank >= 100 g/day had a higher AST/ALT ratio, higher prevalence of being a current smoker, a greater chance of being overweight, and were more likely to do less exercise than the other groups.	('higher', 'PosReg', (36, 42))	('AST', 'Gene', '26503', (43, 46))	('overweight', 'Phenotype', 'HP:0025502', (129, 139))	('People', 'Species', '9606', (0, 6))	('AST', 'Gene', (43, 46))	('>= 100 g/day', 'Var', (17, 29))
842901	20376881	In conjunction with findings from earlier research groups, our study shows that low and moderate alcohol intake (1-24 g/day) was also associated with an increased risk of esophageal cancer (HR = 2.2 for incidence and HR = 1.9 for mortality from esophageal cancer).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('low', 'Var', (80, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (171, 188))	('esophageal cancer', 'Disease', (171, 188))	('esophageal cancer', 'Disease', (245, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('esophageal cancer', 'Disease', 'MESH:D004938', (245, 262))	('alcohol', 'Chemical', 'MESH:D000438', (97, 104))
842902	20376881	There are many reports highlighting the fact that heavy alcohol drinking is associated with an elevated risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('esophageal cancer', 'Disease', (112, 129))	('alcohol', 'Chemical', 'MESH:D000438', (56, 63))	('alcohol drinking', 'Phenotype', 'HP:0030955', (56, 72))	('heavy alcohol drinking', 'Var', (50, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
842903	20376881	Epidemiological reports from South India, the US, Northern Italy, and Hong Kong concordantly reported that alcohol intake below 140 g/week is linked to a slight increase or even decrease in risk for esophageal cancer.	('esophageal cancer', 'Disease', (199, 216))	('esophageal cancer', 'Disease', 'MESH:D004938', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('decrease', 'NegReg', (178, 186))	('below 140 g/week', 'Var', (122, 138))	('alcohol', 'Chemical', 'MESH:D000438', (107, 114))
842934	33946439	In particular, miR-21-5p and miR-146b-5p were significantly upregulated and miR-210-3p was significantly downregulated in tumor tissues compared with normal tissues.	('miR-210-3p', 'Var', (76, 86))	('upregulated', 'PosReg', (60, 71))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('miR-21-5p', 'Gene', (15, 24))	('miR-21-5p', 'Gene', '406997', (15, 24))	('miR-210-3p', 'Chemical', '-', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('miR-146b-5p', 'Var', (29, 40))	('tumor', 'Disease', (122, 127))	('downregulated', 'NegReg', (105, 118))
842935	33946439	The same differential expression of miR-21-5p, miR-146b-5p, and miR-210-3p was detected in ESCC cell lines compared with normal esophageal epithelial cells in vitro.	('detected', 'Reg', (79, 87))	('miR-210-3p', 'Chemical', '-', (64, 74))	('miR-146b-5p', 'Var', (47, 58))	('ESCC', 'Disease', (91, 95))	('miR-21-5p', 'Gene', (36, 45))	('miR-21-5p', 'Gene', '406997', (36, 45))	('miR-210-3p', 'Var', (64, 74))
842936	33946439	However, transfection of ESCC cells with miR-210-3p and miR-21-5p mimics or inhibitors had partial effects on cell proliferation and invasion in vitro.	('miR-210-3p', 'Var', (41, 51))	('miR-21-5p', 'Gene', (56, 65))	('miR-21-5p', 'Gene', '406997', (56, 65))	('miR-210-3p', 'Chemical', '-', (41, 51))	('cell proliferation', 'CPA', (110, 128))	('invasion in vitro', 'CPA', (133, 150))
842947	33946439	Biopsy tends to induce mucosal ulceration and may cause scarring changes over time, which in turn could lead to submucosal fibrosis and associated bleeding and perforation.	('Biopsy', 'Var', (0, 6))	('cause', 'Reg', (50, 55))	('submucosal fibrosis', 'Disease', (112, 131))	('mucosal ulceration', 'Disease', (23, 41))	('scarring changes', 'CPA', (56, 72))	('bleeding', 'Disease', 'MESH:D006470', (147, 155))	('bleeding', 'Disease', (147, 155))	('scarring', 'Phenotype', 'HP:0100699', (56, 64))	('mucosal ulceration', 'Disease', 'MESH:D014456', (23, 41))	('induce', 'Reg', (16, 22))	('lead to', 'Reg', (104, 111))	('perforation', 'CPA', (160, 171))	('submucosal fibrosis', 'Disease', 'MESH:D005355', (112, 131))
842953	33946439	The most highly differentially expressed clusters were all oncomiRs and included miR-146b-5p, miR-21-5p, and miR-210-3p.	('miR-146b-5p', 'Var', (81, 92))	('highly', 'PosReg', (9, 15))	('miR-210-3p', 'Chemical', '-', (109, 119))	('miR-21-5p', 'Gene', (94, 103))	('miR-21-5p', 'Gene', '406997', (94, 103))	('miR-210-3p', 'Var', (109, 119))	('differentially', 'Reg', (16, 30))
842954	33946439	The expression levels of miR-146b-5p and miR-21-5p were 3.02-fold and 2.75-fold higher, respectively, in tumors compared with normal tissues.	('expression levels', 'MPA', (4, 21))	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('miR-21-5p', 'Gene', (41, 50))	('miR-21-5p', 'Gene', '406997', (41, 50))	('miR-146b-5p', 'Var', (25, 36))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('higher', 'PosReg', (80, 86))
842955	33946439	In contrast, the miR-210-3p expression level in tumor tissue was only about one-third (0.33-fold) of the level detected in adjacent normal tissue.	('miR-210-3p', 'Var', (17, 27))	('tumor', 'Disease', (48, 53))	('miR-210-3p', 'Chemical', '-', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
842959	33946439	We selected miR-21-5p, miR-146b-5p, and miR-210-3p for this analysis because they were the three most differentially expressed miRNAs between ESCC tumor and adjacent normal tissues in the microarray analysis, and because insufficient total RNA was available for qRT-PCR analysis of additional miRNAs.	('miR-210-3p', 'Chemical', '-', (40, 50))	('tumor', 'Disease', (147, 152))	('miR-146b-5p', 'Var', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('miR-21-5p', 'Gene', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('miR-21-5p', 'Gene', '406997', (12, 21))	('ESCC', 'Disease', (142, 146))	('miR-210-3p', 'Var', (40, 50))
842960	33946439	Consistent with the microarray analysis, we found that miR-21-5p and miR-146b-5p were upregulated by 4.32-fold +- 2.08 (standard deviation) and 4.96-fold +- 3.30, respectively, and miR-210-3p was downregulated by 0.45-fold +- 0.06 in ESCC tissues compared with adjacent normal tissues (Figure 4A).	('miR-210-3p', 'Chemical', '-', (181, 191))	('miR-21-5p', 'Gene', (55, 64))	('miR-21-5p', 'Gene', '406997', (55, 64))	('downregulated', 'NegReg', (196, 209))	('miR-146b-5p', 'Var', (69, 80))	('ESCC', 'Disease', (234, 238))	('upregulated', 'PosReg', (86, 97))
842961	33946439	Furthermore, the four ESCC cell lines KYSE150, KYSE180, KYSE850, and KYSE 960 also expressed significantly higher levels of miR-21-5p and miR-146b-5p and significantly lower levels of miR-210-3p compared with Het-1A normal esophageal epithelial cells (Figure 4B).	('KYSE850', 'Var', (56, 63))	('miR-210-3p', 'MPA', (184, 194))	('miR-21-5p', 'Gene', (124, 133))	('lower', 'NegReg', (168, 173))	('miR-21-5p', 'Gene', '406997', (124, 133))	('KYSE 960', 'Var', (69, 77))	('KYSE180', 'Var', (47, 54))	('KYSE850', 'CellLine', 'CVCL:8511', (56, 63))	('miR-146b-5p', 'Var', (138, 149))	('miR-210-3p', 'Chemical', '-', (184, 194))	('higher', 'PosReg', (107, 113))	('KYSE150', 'Var', (38, 45))
842975	33946439	miR-21-5p, miR-210-3p, and miR-146b-5p were quantified in tissue samples and cell lines by qRT-PCR using human TaqMan MicroRNA Assay Kits (Applied Biosystems, Foster City, CA, USA), according to the manufacturer's instructions.	('miR-210-3p', 'Chemical', '-', (11, 21))	('miR-146b-5p', 'Var', (27, 38))	('Kit', 'Gene', (133, 136))	('human', 'Species', '9606', (105, 110))	('miR-21-5p', 'Gene', (0, 9))	('miR-21-5p', 'Gene', '406997', (0, 9))	('Kit', 'Gene', '3815', (133, 136))
842979	33946439	All cells were maintained in a humidified 5% CO2 atmosphere at 37  C. miR-21-5p and miR-210-3p mimics and inhibitors and a control RNA sequence were obtained from Thermo Scientific (Waltham, MA, USA).	('miR-21-5p', 'Gene', (70, 79))	('miR-21-5p', 'Gene', '406997', (70, 79))	('miR-210-3p', 'Var', (84, 94))	('CO2', 'Chemical', 'MESH:D002245', (45, 48))	('miR-210-3p', 'Chemical', '-', (84, 94))
842984	33946439	We identified miR-21-5p and miR-146b-5p as two upregulated miRNAs and miR-210-3p as a significantly downregulated miRNA in ESCC tissues compared with matched normal tissues.	('miR-21-5p', 'Gene', (14, 23))	('miR-21-5p', 'Gene', '406997', (14, 23))	('miR-210-3p', 'Var', (70, 80))	('upregulated', 'PosReg', (47, 58))	('ESCC', 'Disease', (123, 127))	('downregulated', 'NegReg', (100, 113))	('miR-210-3p', 'Chemical', '-', (70, 80))	('miR-146b-5p', 'Var', (28, 39))	('miRNA', 'MPA', (114, 119))
842989	33946439	Dysregulation of miRNAs is associated with the development and progression of various cancers.	('Dysregulation', 'Var', (0, 13))	('miRNAs', 'Protein', (17, 23))	('associated', 'Reg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
842990	33946439	In the present study, we identified miR-21-5p and miR-146b-5p as significantly upregulated miRNAs in ESCC tumor tissues and cell lines.	('miR-146b-5p', 'Var', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('miRNAs', 'MPA', (91, 97))	('miR-21-5p', 'Gene', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('upregulated', 'PosReg', (79, 90))	('ESCC', 'Disease', (101, 105))	('miR-21-5p', 'Gene', '406997', (36, 45))	('tumor', 'Disease', (106, 111))
842992	33946439	High expression of miR-21 is associated with shorter disease-free survival in several gastrointestinal malignancies.	('miR-21', 'Gene', (19, 25))	('High', 'Var', (0, 4))	('shorter', 'NegReg', (45, 52))	('miR-21', 'Gene', '406991', (19, 25))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('malignancies', 'Disease', (103, 115))	('disease-free survival', 'CPA', (53, 74))
842995	33946439	To clarify the functional role of differentially expressed miRNAs in ESCC, we analyzed the effects of miR-21-5p and miR-210-3p overexpression and inhibition on ESCC cell proliferation and invasion in vitro.	('ESCC', 'Disease', (160, 164))	('miR-210-3p', 'Chemical', '-', (116, 126))	('invasion', 'CPA', (188, 196))	('miR-210-3p', 'Var', (116, 126))	('miR-21-5p', 'Gene', (102, 111))	('miR-21-5p', 'Gene', '406997', (102, 111))
842996	33946439	Previous work showed that co-transfection of miR-203-3p and miR-21-5p mimics synergistically inhibited the proliferation, migration, and invasion of ESCC cells.	('ESCC', 'Disease', (149, 153))	('proliferation', 'CPA', (107, 120))	('invasion', 'CPA', (137, 145))	('miR-203-3p', 'Var', (45, 55))	('migration', 'CPA', (122, 131))	('inhibited', 'NegReg', (93, 102))	('miR-21-5p', 'Gene', (60, 69))	('miR-203-3p', 'Chemical', '-', (45, 55))	('miR-21-5p', 'Gene', '406997', (60, 69))
842997	33946439	Thus, whether and how miR-21-5p, miR-146b-5p, and miR-210-3p affect ESCC cell malignancy remain to be clarified.	('ESCC cell', 'Disease', (68, 77))	('miR-21-5p', 'Gene', (22, 31))	('affect', 'Reg', (61, 67))	('miR-210-3p', 'Var', (50, 60))	('miR-21-5p', 'Gene', '406997', (22, 31))	('miR-210-3p', 'Chemical', '-', (50, 60))	('miR-146b-5p', 'Var', (33, 44))
843064	32752094	Abnormalities in CNTN1 expression associate with cancer progression and poor prognosis.	('Abnormalities', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CNTN1', 'Gene', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('associate', 'Reg', (34, 43))	('cancer', 'Disease', (49, 55))
843071	32752094	Aberrant expression of CAMs has been shown to associate with invasive phenotype of tumour cells.	('tumour', 'Disease', (83, 89))	('Aberrant expression', 'Var', (0, 19))	('CAMs', 'Gene', (23, 27))	('associate', 'Reg', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))
843088	32752094	Specifically, the CNTN1 mutants show an overt ataxia phenotype by day 10 which subsequently progresses to pronounced smaller size, emaciated appearance and uncontrolled movement by day 15.	('uncontrolled movement', 'Phenotype', 'HP:0007738', (156, 177))	('mutants', 'Var', (24, 31))	('CNTN1', 'Gene', (18, 23))	('ataxia', 'Phenotype', 'HP:0001251', (46, 52))	('ataxia', 'Disease', 'MESH:D001259', (46, 52))	('ataxia', 'Disease', (46, 52))
843095	32752094	The knockdown of CNTN1 via in utero electroporation resulted in significantly delayed radical migration mediated by RhoA activation, a Rho-GTPase critical for actin cytoskeletal reorganization.	('delayed', 'NegReg', (78, 85))	('RhoA', 'Gene', '387', (116, 120))	('CNTN1', 'Gene', (17, 22))	('RhoA', 'Gene', (116, 120))	('radical migration', 'CPA', (86, 103))	('knockdown', 'Var', (4, 13))
843097	32752094	A previous report also described a lethal form of congenital myopathy possibly caused by the loss of CNTN1 in the neuromuscular junction due to a familial mutation.	('myopathy', 'Phenotype', 'HP:0003198', (61, 69))	('congenital myopathy', 'Disease', 'MESH:D009224', (50, 69))	('loss', 'Var', (93, 97))	('caused by', 'Reg', (79, 88))	('CNTN1', 'Gene', (101, 106))	('congenital myopathy', 'Disease', (50, 69))
843105	32752094	Furthermore, NCAM localized in membrane compartments binds and stimulates fibroblast growth factor receptor 1 (FGFR1) through its fibronectin type III (F3) domains and activates MAPK-mediated cell migration in non-neural cells.	('NCAM', 'Var', (13, 17))	('FGFR1', 'Gene', '2260', (111, 116))	('fibronectin', 'Gene', '2335', (130, 141))	('fibroblast growth factor receptor 1', 'Gene', (74, 109))	('fibroblast growth factor receptor 1', 'Gene', '2260', (74, 109))	('FGFR1', 'Gene', (111, 116))	('fibronectin', 'Gene', (130, 141))	('stimulates', 'PosReg', (63, 73))	('MAPK-mediated cell migration in non-neural cells', 'CPA', (178, 226))	('activates', 'PosReg', (168, 177))
843107	32752094	Indeed, the correlation between deregulated NCAM expression and poor prognosis has been found in different cancer types including neuroblastoma, myeloma, acute myeloid leukemia, pancreatic cancer, and small cell lung cancer.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (154, 176))	('neuroblastoma', 'Disease', 'MESH:D009447', (130, 143))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('myeloma', 'Disease', 'MESH:D009101', (145, 152))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (178, 195))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('NCAM', 'Gene', (44, 48))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (201, 223))	('expression', 'MPA', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('myeloma', 'Disease', (145, 152))	('deregulated', 'Var', (32, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (178, 195))	('acute myeloid leukemia', 'Disease', (154, 176))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', (189, 195))	('pancreatic cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('small cell lung cancer', 'Disease', 'MESH:D055752', (201, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('neuroblastoma', 'Disease', (130, 143))	('cancer', 'Disease', (217, 223))	('neuroblastoma', 'Phenotype', 'HP:0003006', (130, 143))	('small cell lung cancer', 'Disease', (201, 223))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (154, 176))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (160, 176))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
843108	32752094	However, as the central nervous system was the only defective organ in CNTN1 deficient mice, the protein is not a major contributor to the development of other organs at least in mice.	('CNTN1', 'Gene', (71, 76))	('mice', 'Species', '10090', (87, 91))	('deficient', 'Var', (77, 86))	('mice', 'Species', '10090', (179, 183))
843113	32752094	Amplifications and gains of genomic materials are frequent in this region for malignant gliomas and astrocytoma.	('malignant gliomas', 'Disease', 'MESH:D005910', (78, 95))	('astrocytoma', 'Disease', 'MESH:D001254', (100, 111))	('gains', 'PosReg', (19, 24))	('astrocytoma', 'Disease', (100, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('Amplifications', 'Var', (0, 14))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('malignant gliomas', 'Disease', (78, 95))
843131	32752094	discovered that while the knockdown of CNTN1 did not influence lung cancer cell proliferation, it significantly reduced cancer cell's invasive abilities both in vitro and in xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('invasive abilities', 'CPA', (134, 152))	('lung cancer', 'Disease', (63, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('knockdown', 'Var', (26, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('cancer', 'Disease', (68, 74))	('reduced', 'NegReg', (112, 119))	('CNTN1', 'Gene', (39, 44))
843138	32752094	Similarly, CNTN1 expression was elevated in multidrug resistance (MDR) A549/cisplatin (A549/DDP) cells compared to its progenitor A549 lung cancer cells, and the silencing of CNTN1 rendered both cells higher cisplatin sensitivity and upregulated cisplatin-induced apoptosis, leading to inhibition of tumor invasion and metastasis.	('cisplatin', 'Chemical', 'MESH:D002945', (208, 217))	('lung cancer', 'Disease', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('expression', 'MPA', (17, 27))	('upregulated', 'PosReg', (234, 245))	('cisplatin', 'Chemical', 'MESH:D002945', (246, 255))	('A549', 'CellLine', 'CVCL:0023', (71, 75))	('silencing', 'Var', (162, 171))	('elevated', 'PosReg', (32, 40))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('CNTN1', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('higher', 'PosReg', (201, 207))	('cisplatin sensitivity', 'MPA', (208, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('tumor', 'Disease', (300, 305))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('CNTN1', 'Gene', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('A549', 'CellLine', 'CVCL:0023', (130, 134))	('inhibition', 'NegReg', (286, 296))
843139	32752094	This enhanced chemoresistance of lung cancer cells induced by CNTN1 overexpression was also found to be attributable to PI3K/AKT activated EMT enhancement (Figure 4).	('AKT', 'Gene', '207', (125, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('chemoresistance', 'CPA', (14, 29))	('AKT', 'Gene', (125, 128))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('CNTN1', 'Gene', (62, 67))	('enhanced', 'PosReg', (5, 13))	('enhancement', 'PosReg', (143, 154))	('overexpression', 'Var', (68, 82))	('lung cancer', 'Disease', (33, 44))
843149	32752094	Recent study has shown that a reduction in CNTN1 expression alone was sufficient to reverse the enhanced migration ability of esophageal cancer cells attributable to ectopic VEFGC expression in vitro.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('VEFGC', 'Gene', (174, 179))	('CNTN1', 'Gene', (43, 48))	('enhanced', 'PosReg', (96, 104))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('reduction', 'NegReg', (30, 39))	('cancer', 'Disease', (137, 143))	('migration ability', 'CPA', (105, 122))	('ectopic', 'Var', (166, 173))	('expression', 'Var', (180, 190))
843153	32752094	demonstrated that CNTN1 expression was directly regulated by Flt4 stimulation or inhibition, and this alteration was robustly associated with enhanced or reduced OSCC cell proliferation and migration correspondingly.	('OSCC cell proliferation', 'CPA', (162, 185))	('migration', 'CPA', (190, 199))	('inhibition', 'Var', (81, 91))	('expression', 'MPA', (24, 34))	('Flt4', 'Gene', (61, 65))	('stimulation', 'PosReg', (66, 77))	('CNTN1', 'Gene', (18, 23))	('Flt4', 'Gene', '2324', (61, 65))	('enhanced', 'PosReg', (142, 150))	('reduced', 'NegReg', (154, 161))	('regulated', 'Reg', (48, 57))
843156	32752094	The OSCC cells with CNTN1 knocked-down exhibits significant reduction in invasion but not proliferative properties, which is in line with previous findings demonstrating that CNTN1 may promote progression of cancer cells through exclusive activation of metastatic pathways.	('cancer', 'Disease', (208, 214))	('CNTN1', 'Gene', (175, 180))	('CNTN1', 'Gene', (20, 25))	('knocked-down', 'Var', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('reduction', 'NegReg', (60, 69))	('proliferative properties', 'CPA', (90, 114))	('activation', 'PosReg', (239, 249))	('promote', 'PosReg', (185, 192))	('invasion', 'CPA', (73, 81))	('metastatic', 'CPA', (253, 263))	('progression', 'CPA', (193, 204))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
843167	32752094	Further analysis showed that silencing or knockdown of CNTN1 expression resulted in suppression of proliferation, invasion and migration capabilities in PC cells concurrent with a reduced PI3K/AKT signaling.	('AKT', 'Gene', '207', (193, 196))	('migration capabilities', 'CPA', (127, 149))	('silencing', 'Var', (29, 38))	('PC', 'CellLine', 'CVCL:0152', (153, 155))	('reduced', 'NegReg', (180, 187))	('AKT', 'Gene', (193, 196))	('suppression', 'NegReg', (84, 95))	('CNTN1', 'Gene', (55, 60))	('invasion', 'CPA', (114, 122))	('proliferation', 'CPA', (99, 112))	('knockdown', 'Var', (42, 51))
843168	32752094	CNTN1 inhibition also increased expression of E-cadherin while reduced N-cadherin and Vimentin, suggesting an inhibition of the EMT process pivotal in cancer metastases (Figure 4).	('inhibition', 'NegReg', (110, 120))	('Vimentin', 'Gene', (86, 94))	('reduced', 'NegReg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('N-cadherin', 'Gene', '1000', (71, 81))	('CNTN1', 'Gene', (0, 5))	('cancer metastases', 'Disease', (151, 168))	('E-cadherin', 'Protein', (46, 56))	('Vimentin', 'Gene', '7431', (86, 94))	('increased', 'PosReg', (22, 31))	('inhibition', 'Var', (6, 16))	('EMT process', 'CPA', (128, 139))	('expression', 'MPA', (32, 42))	('N-cadherin', 'Gene', (71, 81))	('cancer metastases', 'Disease', 'MESH:D009362', (151, 168))
843170	32752094	Silencing of CNTN1 with short hairpin RNA (shRNA) inhibited cellular malignant phenotype and reduced expression of pluripotent markers such as CD44, octamer-binding transcription factor 4 (OCT-4), and Nanog.	('octamer-binding transcription factor 4', 'Gene', (149, 187))	('CD44', 'Gene', '960', (143, 147))	('Nanog', 'Gene', '79923', (201, 206))	('reduced', 'NegReg', (93, 100))	('CNTN1', 'Gene', (13, 18))	('OCT-4', 'Gene', '5460', (189, 194))	('CD44', 'Gene', (143, 147))	('OCT-4', 'Gene', (189, 194))	('cellular malignant phenotype', 'CPA', (60, 88))	('Nanog', 'Gene', (201, 206))	('octamer-binding transcription factor 4', 'Gene', '5460', (149, 187))	('expression', 'MPA', (101, 111))	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (50, 59))
843171	32752094	CNTN1 silencing sensitized Dox-resistant PC cells and inhibited PI3K/AKT signaling in vivo.	('inhibited', 'NegReg', (54, 63))	('PC', 'CellLine', 'CVCL:0152', (41, 43))	('Dox-resistant PC', 'Disease', (27, 43))	('AKT', 'Gene', (69, 72))	('CNTN1', 'Gene', (0, 5))	('Dox', 'Chemical', 'MESH:D000077143', (27, 30))	('AKT', 'Gene', '207', (69, 72))	('silencing', 'Var', (6, 15))
843173	32752094	In a study investigating breast cancer (BC), ectopic CNTN1 overexpression enhanced cell proliferation, invasion, migration as well as cell cycle progression from G1 to S phase in breast cancer cells in vitro.	('cell cycle progression from G1 to S phase', 'CPA', (134, 175))	('BC', 'Phenotype', 'HP:0003002', (40, 42))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cell proliferation', 'CPA', (83, 101))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (179, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('breast cancer', 'Disease', (25, 38))	('overexpression enhanced', 'PosReg', (59, 82))	('ectopic', 'Var', (45, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('migration', 'CPA', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('invasion', 'CPA', (103, 111))	('CNTN1', 'Gene', (53, 58))
843174	32752094	Notably, CNTN1 overexpression also enhanced breast cancer xenograft tumor growth in vivo in nude mice.	('tumor', 'Disease', (68, 73))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('nude mice', 'Species', '10090', (92, 101))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('enhanced', 'PosReg', (35, 43))	('overexpression', 'Var', (15, 29))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CNTN1', 'Gene', (9, 14))
843177	32752094	Among the 5 subtypes, we noticed a significant higher level of CNTN1 in HER2-E in a population consisting of 50 DNA microarray studies (n = 9254) and in the population of three RNA-seq investigation (n = 4712) (Figure 5).	('HER2', 'Gene', (72, 76))	('CNTN1', 'Var', (63, 68))	('higher', 'PosReg', (47, 53))	('HER2', 'Gene', '2064', (72, 76))
843182	32752094	In both positively correlated gene populations, enrichment in the terms of extracellular matrix organization (GO:0030198) and cell adhesion (GO:0007155) in Biological Process (BP) was observed in BC (All patients, Table 2).	('patients', 'Species', '9606', (204, 212))	('cell adhesion', 'CPA', (126, 139))	('GO:0007155', 'Var', (141, 151))	('BC', 'Phenotype', 'HP:0003002', (196, 198))	('extracellular matrix organization', 'CPA', (75, 108))
843185	32752094	As well, CNTN1 expression was found to be an independent prognostic factor for OS (hazard ratio 2.383, 95% confidence interval 1.262-4.503; p = 0.007) and DFS (disease free survival) (hazard ratio 2.356, 95% confidence interval 1.370-4.049; p = 0.002) in HCC patients.	('expression', 'Var', (15, 25))	('patients', 'Species', '9606', (259, 267))	('HCC', 'Disease', (255, 258))	('DFS', 'Disease', (155, 158))	('HCC', 'Phenotype', 'HP:0001402', (255, 258))	('CNTN1', 'Gene', (9, 14))	('DFS', 'Disease', 'None', (155, 158))
843186	32752094	RET/PTC3 (Ret proto-oncogene and Ret-activating protein ELE1) rearrangement is the most frequent genetic alteration in thyroid cancer and most functions of RET are mediated through pathways including ERK, JNK, and PI3K/AKT.	('thyroid cancer', 'Disease', 'MESH:D013964', (119, 133))	('Ret', 'Gene', (10, 13))	('mediated', 'Reg', (164, 172))	('thyroid cancer', 'Phenotype', 'HP:0002890', (119, 133))	('Ret', 'Gene', (33, 36))	('RET', 'Gene', '5979', (0, 3))	('ERK', 'Gene', '5594', (200, 203))	('ELE1', 'Gene', '8031', (56, 60))	('JNK', 'Gene', (205, 208))	('Ret', 'Gene', '5979', (10, 13))	('JNK', 'Gene', '5599', (205, 208))	('PTC3', 'Gene', '8031', (4, 8))	('Ret', 'Gene', '5979', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('AKT', 'Gene', (219, 222))	('ERK', 'Gene', (200, 203))	('PTC3', 'Gene', (4, 8))	('RET', 'Gene', (0, 3))	('RET', 'Gene', '5979', (156, 159))	('thyroid cancer', 'Disease', (119, 133))	('functions', 'MPA', (143, 152))	('ELE1', 'Gene', (56, 60))	('rearrangement', 'Var', (62, 75))	('AKT', 'Gene', '207', (219, 222))	('RET', 'Gene', (156, 159))
843192	32752094	Functionally, CNTN1 silencing in vitro restrained thyroid cancer cell migration and invasion abilities.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('thyroid cancer', 'Phenotype', 'HP:0002890', (50, 64))	('thyroid cancer', 'Disease', (50, 64))	('restrained', 'NegReg', (39, 49))	('CNTN1', 'Gene', (14, 19))	('invasion abilities', 'CPA', (84, 102))	('silencing', 'Var', (20, 29))	('thyroid cancer', 'Disease', 'MESH:D013964', (50, 64))
843197	32752094	The Notch signaling pathway is highly conserved, and its dysregulation is associated with many cancers.	('dysregulation', 'Var', (57, 70))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('Notch signaling pathway', 'Pathway', (4, 27))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('associated', 'Reg', (74, 84))
843204	32752094	While these analyses support a positive association between high CNTN1 expression and poor OS in cancers, this association might be cancer-type specific at least at the level of mRNA; high CNTN1 expression displays a reverse association with poor OS in LGG (Figure 6c).	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('expression', 'MPA', (71, 81))	('cancer', 'Disease', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('CNTN1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('CNTN1', 'Gene', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('high CNTN1', 'Gene', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('high', 'Var', (184, 188))	('poor OS in LGG', 'Disease', (242, 256))
843212	32752094	For example, a Cre-LoxP system can be explored in which mice carrying the transgene insertion of a strong translational and transcriptional termination (STOP) sequence flanked by loxP or FRT sites between the promoter sequence and CNTN1 which can be crossed with mice carrying tissue-specific promoters.	('mice', 'Species', '10090', (56, 60))	('mice', 'Species', '10090', (263, 267))	('transgene insertion', 'Var', (74, 93))	('CNTN1', 'Gene', (231, 236))	('insertion', 'Var', (84, 93))
843217	32752094	High CNTN1 expression was associated with biochemical recurrence following radical proctectomy in PC.	('CNTN1', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('biochemical recurrence', 'Disease', (42, 64))	('PC', 'CellLine', 'CVCL:0152', (98, 100))	('associated with', 'Reg', (26, 41))
843223	32752094	In view of the critical aspect of communications between cancer and stroma, proper adhesion is critical for cancer evolution or progression, targeting CNTN1 might thus be a useful option.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CNTN1', 'Gene', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('targeting', 'Var', (141, 150))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
843245	32752094	Indeed, silencing or inhibition of CNTN1 in experimental models have already highlighted its suitability as a potential target in lung, gastric, prostate, thyroid cancers, and oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (176, 204))	('thyroid cancer', 'Phenotype', 'HP:0002890', (155, 169))	('prostate', 'Disease', (145, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('silencing', 'Var', (8, 17))	('thyroid cancers', 'Disease', (155, 170))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (176, 204))	('gastric', 'Disease', (136, 143))	('thyroid cancers', 'Disease', 'MESH:D013964', (155, 170))	('CNTN1', 'Gene', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('lung', 'Disease', (130, 134))	('inhibition', 'NegReg', (21, 31))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
843343	30718927	We identify a mean of 4.4 driver events per tumor, derived more commonly from mutations rather than copy number alterations, and compare these mutations to the exome-wide mutational excess using dN/dS calculations.	('dS', 'Chemical', 'MESH:D003903', (198, 200))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('dN', 'Chemical', '-', (195, 197))
843353	30718927	The PCAWG ICGC analysis also identified a significantly mutated enhancer associated with TP53TG1.	('TP53TG1', 'Gene', (89, 96))	('mutated', 'Var', (56, 63))	('TP53TG1', 'Gene', '11257', (89, 96))	('enhancer', 'PosReg', (64, 72))
843356	30718927	These features include highly recurrent mutations within a gene (dNdScv, ActivedriverWGS, MutSigCV2), high functional impact mutations within a gene (OncodriveFM, ActivedriverWGS), mutation clustering (OncodriveClust, eDriver and eDriver3D) and recurrent amplification or deletion of genes (GISTIC) undergoing concurrent over or under-expression (see Methods) (Fig.	('mutations', 'Var', (125, 134))	('genes', 'Gene', (284, 289))	('dNdScv', 'Chemical', '-', (65, 71))	('MutSigCV', 'Chemical', '-', (90, 98))	('mutations', 'Var', (40, 49))	('mutation', 'Var', (181, 189))	('deletion', 'Var', (272, 280))	('over', 'PosReg', (321, 325))	('amplification', 'Var', (255, 268))
843362	30718927	We also found five tumor suppressor genes where copy number loss was not necessarily associated with expression modulation but tightly associated with presence of mutations leading to LOH, for example ARID1A and CDH11.	('CDH11', 'Gene', (212, 217))	('mutations', 'Var', (163, 172))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('associated', 'Reg', (135, 145))	('tumor', 'Disease', (19, 24))	('ARID1A', 'Gene', '8289', (201, 207))	('ARID1A', 'Gene', (201, 207))	('CDH11', 'Gene', '1009', (212, 217))
843364	30718927	Such a pattern of extrachromosomal amplification via double minutes has been previously noted in EAC and other neoplasms, and hence we refer to this amplification class with ultra-high amplification (ploidy adjusted copy number >10) as 'extrachromosomal-like'.	('EAC', 'Disease', (97, 100))	('double minutes', 'Var', (53, 67))	('neoplasms', 'Disease', 'MESH:D009369', (111, 120))	('neoplasms', 'Disease', (111, 120))	('extrachromosomal', 'MPA', (18, 34))	('neoplasm', 'Phenotype', 'HP:0002664', (111, 119))	('EAC', 'Phenotype', 'HP:0011459', (97, 100))	('neoplasms', 'Phenotype', 'HP:0002664', (111, 120))
843369	30718927	However, oncogenes, like ERBB2, only contain missense drivers that form clusters to activate gene function in a specific manner.	('missense drivers', 'Var', (45, 61))	('gene function', 'MPA', (93, 106))	('ERBB2', 'Gene', '2064', (25, 30))	('activate', 'PosReg', (84, 92))	('ERBB2', 'Gene', (25, 30))
843370	30718927	Mutational hotspots in EAC or other cancer types (Supplementary Table 7 and Supplementary Data) are indicated in Figure 3a.	('EAC', 'Phenotype', 'HP:0011459', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('Mutational', 'Var', (0, 10))	('cancer', 'Disease', (36, 42))	('EAC', 'Disease', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
843372	30718927	We note that several of these drivers have been previously associated with gastric and colorectal cancer (Supplementary Table 8).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('drivers', 'Var', (30, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('associated', 'Reg', (59, 69))	('gastric and colorectal cancer', 'Disease', 'MESH:D013274', (75, 104))
843376	30718927	Using hierarchal clustering of drivers, we noted that TP53 mutant cases had significantly more copy number drivers (Wilcoxon test, two-sided, P = 0.0032, Supplementary Figs.	('TP53', 'Gene', (54, 58))	('copy number drivers', 'MPA', (95, 114))	('mutant', 'Var', (59, 65))	('TP53', 'Gene', '7157', (54, 58))	('more', 'PosReg', (90, 94))
843379	30718927	A large number of driver genes have upregulated expression in comparison to normal controls; for example, TP53 has upregulated RNA expression in wild-type tumor tissue and in cases with non-truncating mutations but RNA expression is lost upon gene truncation.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('RNA', 'Gene', (127, 130))	('expression', 'MPA', (131, 141))	('TP53', 'Gene', (106, 110))	('non-truncating mutations', 'Var', (186, 210))	('TP53', 'Gene', '7157', (106, 110))	('upregulated', 'PosReg', (115, 126))
843380	30718927	In depth analysis of different TP53 mutation types reveals significant heterogeneity within non-truncating mutations (Supplementary Fig.	('TP53', 'Gene', '7157', (31, 35))	('non-truncating mutations', 'Var', (92, 116))	('TP53', 'Gene', (31, 35))
843390	30718927	Activation of the Wnt pathway occurs in 19% of cases either by mutation of phospho-residues at the N terminus of beta-catenin, which prevent degradation, or loss of Wnt destruction complex components like APC.	('APC', 'Disease', (205, 208))	('degradation', 'MPA', (141, 152))	('prevent', 'NegReg', (133, 140))	('APC', 'Disease', 'MESH:D011125', (205, 208))	('mutation', 'Var', (63, 71))	('Activation', 'PosReg', (0, 10))	('beta-catenin', 'Gene', (113, 125))	('Wnt pathway', 'Pathway', (18, 29))	('loss', 'NegReg', (157, 161))	('beta-catenin', 'Gene', '1499', (113, 125))
843393	30718927	Wnt dysregulation was associated with hyper-mutated cases (> 500 exonic SNVs or Indels, Fisher's exact test, two-sided, P = 2.98 x 10-5, OR = 9.3), as was mutation in immune pathway genes (B2M and JAK1, > 500 exonic SNVs or Indels, Fisher's exact test, two-sided, P = 6.27 x 10-6, OR = 35.7).	('> 500 exonic SNVs', 'Var', (59, 76))	('JAK1', 'Gene', (197, 201))	('Wnt dysregulation', 'Disease', (0, 17))	('B2M', 'Gene', '567', (189, 192))	('JAK1', 'Gene', '3716', (197, 201))	('B2M', 'Gene', (189, 192))	('mutation', 'Var', (155, 163))
843396	30718927	Events in two genes conferred significantly poorer prognosis after multiple hypothesis correction: GATA4 amplification (HR = 0.54, 95% CI = 0.38-0.78, P = 0.0008) and SMAD4 mutation or homozygous deletion (HR = 0.60, 95% CI = 0.42-0.84, P = 0.003), which were present in 31% of EACs (Fig.	('SMAD4', 'Gene', '4089', (167, 172))	('SMAD4', 'Gene', (167, 172))	('EAC', 'Phenotype', 'HP:0011459', (278, 281))	('GATA4', 'Gene', '2626', (99, 104))	('amplification', 'PosReg', (105, 118))	('GATA4', 'Gene', (99, 104))	('poorer', 'NegReg', (44, 50))	('mutation', 'Var', (173, 181))
843399	30718927	5c), and we also found GATA4 amplifications were prognostic in a cohort of TCGA pancreatic cancers (HR = 0.38, 95% CI = 0.18-0.80, P = 0.011) (Fig.	('prognostic', 'Reg', (49, 59))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('GATA4', 'Gene', '2626', (23, 28))	('GATA4', 'Gene', (23, 28))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('amplifications', 'Var', (29, 43))	('pancreatic cancers', 'Disease', 'MESH:D010190', (80, 98))	('pancreatic cancers', 'Disease', (80, 98))
843402	30718927	We also noted stark survival differences between cases with SMAD4 events and cases in which TGFbeta receptors were mutated (Fig.	('SMAD4', 'Gene', '4089', (60, 65))	('SMAD4', 'Gene', (60, 65))	('TGFbeta receptors', 'Gene', (92, 109))	('mutated', 'Var', (115, 122))
843403	30718927	We found Wnt pathway mutations had a strong association with well differentiated tumours (P = 0.001, OR = 2.9, Fisher's test, two-sided, see Methods; Fig.	('mutations', 'Var', (21, 30))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('well differentiated tumours', 'Disease', 'MESH:D009837', (61, 88))	('Wnt', 'Gene', (9, 12))	('well differentiated tumours', 'Disease', (61, 88))
843404	30718927	Female cases (n = 81) were enriched for KRAS mutation (P = 0.001, Fisher's exact test, two-sided) and TP53 wild-type status (P = 0.006, Fisher's exact test, two-sided) (Fig.	('TP53', 'Gene', (102, 106))	('KRAS', 'Gene', (40, 44))	('mutation', 'Var', (45, 53))	('KRAS', 'Gene', '3845', (40, 44))	('TP53', 'Gene', '7157', (102, 106))
843406	30718927	Aside from TP53, which has been problematic to target clinically so far, we found a number of drugs with predicted sensitivity in >10% of EACs, including EZH2 inhibitors for some SWI/SNF mutant cancers (23%, and 28% including all SWI/SNF EAC drivers), and BET inhibitors, which target KRAS activated and MYC amplified cases (25%).	('EZH2', 'Gene', (154, 158))	('EZH2', 'Gene', '2146', (154, 158))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('TP53', 'Gene', '7157', (11, 15))	('cancers', 'Disease', (194, 201))	('MYC', 'Gene', (304, 307))	('SWI/SNF', 'Gene', (179, 186))	('BET', 'Gene', (256, 259))	('KRAS', 'Gene', '3845', (285, 289))	('TP53', 'Gene', (11, 15))	('MYC', 'Gene', '4609', (304, 307))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('EAC', 'Phenotype', 'HP:0011459', (138, 141))	('KRAS', 'Gene', (285, 289))	('BET', 'Gene', '92737', (256, 259))	('mutant', 'Var', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('EAC', 'Phenotype', 'HP:0011459', (238, 241))	('EACs', 'Disease', (138, 142))
843412	30718927	Such EAC cell lines had comparable sensitivity to T47D, which is derived from an ER-positive breast cancer, where CDK4/6 inhibitors have been FDA approved.	('CDK4/6', 'Gene', (114, 120))	('EAC', 'Phenotype', 'HP:0011459', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('CDK4/6', 'Gene', '1019;1021', (114, 120))	('T47D', 'Var', (50, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))
843413	30718927	We noted three cell lines that were highly resistant, with little drug effect even at 4,000 nM concentrations, similar to a known Rb mutant resistant line breast cancer cell line (MDA-MB-468).	('Rb', 'Chemical', 'MESH:D012413', (130, 132))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (180, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('mutant', 'Var', (133, 139))
843414	30718927	Two of these three cell lines harbor amplification of CCNE1, which is known to drive resistance to CDK4/6 inhibitors by bypassing CDK4/6 and causing Rb phosphorylation via CDK2 activation.	('CCNE1', 'Gene', '898', (54, 59))	('bypassing', 'NegReg', (120, 129))	('causing', 'Reg', (141, 148))	('CCNE1', 'Gene', (54, 59))	('CDK4/6', 'Gene', (99, 105))	('activation', 'PosReg', (177, 187))	('CDK4/6', 'Gene', (130, 136))	('amplification', 'Var', (37, 50))	('CDK2', 'Gene', (172, 176))	('CDK2', 'Gene', '1017', (172, 176))	('phosphorylation', 'MPA', (152, 167))	('Rb', 'Chemical', 'MESH:D012413', (149, 151))	('CDK4/6', 'Gene', '1019;1021', (99, 105))	('CDK4/6', 'Gene', '1019;1021', (130, 136))
843418	30718927	Despite rigorous analyses to detect selected events, assessment of the global excess of mutations by dNdScv suggests that we are unable to detect all mutations selected in EAC, similar to many other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('dNdScv', 'Gene', (101, 107))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('dNdScv', 'Chemical', '-', (101, 107))	('EAC', 'Phenotype', 'HP:0011459', (172, 175))	('cancer', 'Disease', (199, 205))	('EAC', 'Disease', (172, 175))
843419	30718927	Many of these undetected driver mutations are hence likely to be spread across a large number of genes, whereby each is mutated at very low frequency across EAC patients.	('EAC', 'Disease', (157, 160))	('mutations', 'Var', (32, 41))	('patients', 'Species', '9606', (161, 169))	('EAC', 'Phenotype', 'HP:0011459', (157, 160))
843424	30718927	We have noted a three-way association between hyper-mutation, Wnt activation and loss of immune signalling genes such as B2M.	('B2M', 'Gene', (121, 124))	('B2M', 'Gene', '567', (121, 124))	('hyper-mutation', 'Var', (46, 60))	('loss', 'Gene', (81, 85))	('activation', 'PosReg', (66, 76))
843425	30718927	However, Wnt dysregulation and mutation of immune pathway genes such as B2M have been previously linked to immune escape, suggesting this may be an acquired mechanism to prevent immune surveillance caused by hyper-mutation.	('mutation', 'Var', (31, 39))	('immune surveillance', 'MPA', (178, 197))	('linked', 'Reg', (97, 103))	('B2M', 'Gene', (72, 75))	('B2M', 'Gene', '567', (72, 75))	('prevent', 'NegReg', (170, 177))
843432	30718927	The extensive in vitro validation of identified biomarkers for CDK4/6 inhibitors in EAC across 16 cell lines and organoids is persuasive of possible clinical benefit using a targeted approach.	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('EAC', 'Disease', (84, 87))	('CDK4/6', 'Gene', '1019;1021', (63, 69))	('inhibitors', 'Var', (70, 80))	('CDK4/6', 'Gene', (63, 69))
843433	30718927	In summary, this work provides a detailed compendium of mutations and copy number alterations undergoing selection in EAC, which have clinically relevant impact on tumor behaviour.	('tumor', 'Disease', (164, 169))	('mutations', 'Var', (56, 65))	('EAC', 'Gene', (118, 121))	('copy number alterations', 'Var', (70, 93))	('impact', 'Reg', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('EAC', 'Phenotype', 'HP:0011459', (118, 121))
843439	30718927	To run OncodriverFM, Polyphen and SIFT were used to score the functional impact of each missense non-synonymous mutation (from 0 non-impactful to 1 highly impactful); synonymous mutations were given a score of 0 impact, and truncating mutations (nonsense and frameshift mutations) were given a score of 1.	('SIFT', 'Disease', (34, 38))	('SIFT', 'Disease', 'None', (34, 38))	('frameshift mutations', 'Var', (259, 279))	('synonymous mutations', 'Var', (167, 187))
843451	30718927	This is due to frequent non-amplification associated overexpression of MYC when compared to normal controls, and otherwise MYC is well evidenced by a very close proximity to the peak centre (top 4 genes) and its high rate of amplification (19%).	('MYC', 'Gene', '4609', (71, 74))	('overexpression', 'PosReg', (53, 67))	('MYC', 'Gene', '4609', (123, 126))	('non-amplification', 'Var', (24, 41))	('MYC', 'Gene', (71, 74))	('MYC', 'Gene', (123, 126))
843452	30718927	However, while expression modulation is a requirement for selection of CNV only drivers, it is not sufficient evidence alone, and hence we grouped such genes into those which have been characterized as drivers previously in other cancer types (high confidence EAC copy number drivers) and other genes (candidate EAC copy number drivers), which await functional validation.	('EAC', 'Phenotype', 'HP:0011459', (260, 263))	('EAC', 'Phenotype', 'HP:0011459', (312, 315))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('genes', 'Var', (152, 157))
843453	30718927	We used fragile site regions detected in Wala et al.. We also defined regions that may be recurrently heterozygous deleted, without any significant expression modulations, to allow LOH of tumor suppressor gene mutations.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mutations', 'Var', (210, 219))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
843464	30718927	Genomic analysis of 551 esophageal adenocarcinomas identifies new driver mutations and biomarkers associated with poor prognosis.	('mutations', 'Var', (73, 82))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (24, 50))	('esophageal adenocarcinomas', 'Disease', (24, 50))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (24, 49))
843466	26157832	Severe Ulcerative Esophagitis Induced by Crizotinib Therapy Crizotinib is an oral tyrosine-kinase inhibitor that inhibits anaplastic lymphoma kinase (ALK) in gene-rearranged non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (174, 200))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (178, 200))	('anaplastic lymphoma kinase', 'Gene', '238', (122, 148))	('Crizotinib', 'Chemical', 'MESH:D000077547', (41, 51))	('anaplastic lymphoma kinase', 'Gene', (122, 148))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (174, 200))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (122, 141))	('Esophagitis', 'Disease', 'MESH:D004941', (18, 29))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('ALK', 'Gene', '238', (150, 153))	('non-small cell lung cancer', 'Disease', (174, 200))	('gene-rearranged', 'Var', (158, 173))	('inhibits', 'NegReg', (113, 121))	('ALK', 'Gene', (150, 153))	('NSCLC', 'Disease', (202, 207))	('Ulcerative Esophagitis', 'Phenotype', 'HP:0004791', (7, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Esophagitis', 'Phenotype', 'HP:0100633', (18, 29))	('Esophagitis', 'Disease', (18, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))	('Crizotinib', 'Chemical', 'MESH:D000077547', (60, 70))
843470	26157832	In 2011, the Food and Drug Administration (FDA) approved the Vysis ALK Break-Apart FISH Probe Kit for the detection of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC), while concurrently granting approval for an agent directed at this target.	('rearrangements', 'Var', (157, 171))	('NSCLC', 'Disease', (203, 208))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (175, 201))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (179, 201))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('ALK', 'Gene', (147, 150))	('ALK', 'Gene', '238', (147, 150))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (175, 201))	('anaplastic lymphoma kinase', 'Gene', (119, 145))	('ALK', 'Gene', '238', (67, 70))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (119, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (130, 138))	('non-small cell lung cancer', 'Disease', (175, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('anaplastic lymphoma kinase', 'Gene', '238', (119, 145))	('ALK', 'Gene', (67, 70))
843490	26157832	His swallowing started to improve 1 week after crizotinib was held, and within 2 weeks of his presentation he was able to resume oral intake.	('swallowing', 'MPA', (4, 14))	('crizotinib', 'Chemical', 'MESH:D000077547', (47, 57))	('crizotinib', 'Var', (47, 57))	('improve', 'PosReg', (26, 33))
843510	26157832	However, CMV most commonly causes multiple, deep ulcers at the lower esophageal sphincter, and Candida infection results in white mucosal plaque-like lesions.	('Candida infection', 'Disease', (95, 112))	('Candida infection', 'Disease', 'MESH:C536777', (95, 112))	('deep ulcers', 'Disease', 'MESH:D014456', (44, 55))	('deep ulcers', 'Disease', (44, 55))	('causes', 'Reg', (27, 33))	('results in', 'Reg', (113, 123))	('CMV', 'Var', (9, 12))
843519	25839328	Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC.	('c.1633G>A', 'Var', (64, 73))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('p.Glu542Lys', 'Mutation', 'rs121913273', (47, 58))	('c.1624G>A', 'Var', (36, 45))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('PIK3CA', 'Gene', (10, 16))	('c.1633G>A', 'Mutation', 'rs104886003', (64, 73))	('p.Glu545Lys', 'Mutation', 'rs104886003', (75, 86))	('c.1624G>A', 'Mutation', 'rs121913273', (36, 45))	('APOBEC-signature', 'Gene', (106, 122))	('PIK3CA', 'Gene', '5290', (10, 16))	('EC', 'Phenotype', 'HP:0011459', (110, 112))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
843520	25839328	In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8.	('CBX4', 'Gene', '8535', (80, 84))	('amplifications', 'Var', (62, 76))	('CBX8', 'Gene', '57332', (89, 93))	('CBX4', 'Gene', (80, 84))	('CBX8', 'Gene', (89, 93))
843527	25839328	The processes of DNA damage and repair, which produce the somatic mutations in a cancer genome, leave a signature of mutation.	('mutations', 'Var', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
843529	25839328	Exome-wide investigations have characterized somatic point mutations in ESCC and identified the ESCC-associated genes ZNF750 (MIM 610226), FAT1 (MIM 600976), FAT2 (MIM 604269), and FAM135B, and point mutations in genes such as PLCE1 (MIM 608414), XPF (MIM 133520), ALDH2 (MIM 100650), and MTHFR (MIM 607093) show different signatures between smokers and non-smokers with ESCC.	('MIM 608414', 'Var', (234, 244))	('MTHFR', 'Gene', (289, 294))	('XPF', 'Gene', '2072', (247, 250))	('MIM 607093', 'Var', (296, 306))	('FAT2', 'Gene', (158, 162))	('ZNF750', 'Gene', (118, 124))	('MIM 604269', 'Var', (164, 174))	('MIM 133520', 'Var', (252, 262))	('ALDH2', 'Gene', (265, 270))	('FAM135B', 'Gene', '51059', (181, 188))	('MIM 610226', 'Var', (126, 136))	('MIM 100650', 'Var', (272, 282))	('PLCE1', 'Gene', (227, 232))	('point mutations', 'Var', (194, 209))	('PLCE1', 'Gene', '51196', (227, 232))	('FAM135B', 'Gene', (181, 188))	('ALDH2', 'Gene', '217', (265, 270))	('MTHFR', 'Gene', '4524', (289, 294))	('XPF', 'Gene', (247, 250))	('ESCC-associated', 'Disease', (96, 111))	('MIM 600976', 'Var', (145, 155))	('FAT2', 'Gene', '2196', (158, 162))	('ESCC', 'Disease', (371, 375))
843530	25839328	In this study, we performed whole-genome sequencing (WGS) of 14 and whole-exome sequencing (WES) of 90 ESCC tumors and adjacent normal tissue from individuals recruited from the Taihang Mountains of north-central China and combined our data with those of 88 previously reported samples to extract the mutational signatures that cause somatic mutations in ESCC and identify driver genes or pathways contributing to this highly fetal disease in Chinese individuals.	('fetal disease', 'Disease', (426, 439))	('fetal disease', 'Disease', 'MESH:D005315', (426, 439))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ESCC tumors', 'Disease', (103, 114))	('mutations', 'Var', (342, 351))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('ESCC tumors', 'Disease', 'MESH:D004938', (103, 114))	('ESCC', 'Gene', (355, 359))
843541	25839328	Normal esophageal epithelium cell lines SHEE and HEEPIC and the following ESCC lines were used in this study: EC9706, Eca109, TE1, TE12, TE13, Caes17, KYSE2, KYSE30, KYSE140, KYSE150, KYSE410, KYSE510, KYSE450, and KYSE680.	('KYSE510', 'CellLine', 'CVCL:1354', (193, 200))	('KYSE410', 'Var', (184, 191))	('EC9706', 'Var', (110, 116))	('KYSE450', 'Var', (202, 209))	('KYSE30', 'Var', (158, 164))	('EC', 'Phenotype', 'HP:0011459', (110, 112))	('KYSE680', 'Var', (215, 222))	('EC9706', 'CellLine', 'CVCL:E307', (110, 116))	('KYSE140', 'Var', (166, 173))	('KYSE2', 'Var', (151, 156))	('KYSE150', 'Var', (175, 182))	('KYSE510', 'Var', (193, 200))
843571	25839328	The median IRS was chosen to define the individuals, and the ratio of tumor to matched normal tissue (TIRS/NIRS) was used to compare the protein of interest with significantly high amounts (TIRS/NIRS > 2), high amounts (1 < TIRS/NIRS < 2), low amounts (TIRS/NIRS < 1), or no change (TIRS/NIRS = 1) in tumor tissue to that in matched normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Disease', (70, 75))	('TIRS/NIRS > 2', 'Var', (190, 203))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('1 < TIRS/NIRS < 2', 'Var', (220, 237))	('tumor', 'Disease', (301, 306))	('high', 'PosReg', (176, 180))
843573	25839328	We injected 2 x 106 KYSE150 cells stably depleted of ZNF750, scrambled control vector, wild-type ZNF750, or p.Ser70* ZNF750 into nude mice (n = 6 mice/group).	('mice', 'Species', '10090', (134, 138))	('nude mice', 'Species', '10090', (129, 138))	('p.Ser70* ZNF750', 'Var', (108, 123))	('p.Ser70*', 'Mutation', 'p.S70*', (108, 116))	('mice', 'Species', '10090', (146, 150))	('ZNF750', 'Gene', (53, 59))
843583	25839328	Signature A was characterized by C>G, C>T, and C>A mutations at TpCpX trinucleotides (suggesting collateral damage following DNA-element retrotransposition or exogenous viruses) and was associated with mutations in the APOBEC family of cytidine deaminases.	('mutations', 'Var', (51, 60))	('C>G', 'Var', (33, 36))	('APOBEC family of cytidine deaminases', 'Enzyme', (219, 255))	('trinucleotides', 'Chemical', '-', (70, 84))	('C>T', 'Var', (38, 41))	('C>A mutations', 'Var', (47, 60))	('TpCpX', 'Gene', (64, 69))	('EC', 'Phenotype', 'HP:0011459', (223, 225))	('associated', 'Reg', (186, 196))	('mutations', 'Var', (202, 211))
843584	25839328	Moreover, hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) on the SMG PIK3CA (MIM 171834) were significantly enriched in ESCC tumors that had an APOBEC signature (p = 0.0028, Fisher's exact test, one-sided), implicating APOBEC activity as a key driver of PIK3CA mutagenesis in ESCC.	('ESCC tumors', 'Disease', (144, 155))	('c.1624G>A', 'Var', (29, 38))	('c.1633G>A', 'Mutation', 'rs104886003', (57, 66))	('c.1624G>A', 'Mutation', 'rs121913273', (29, 38))	('PIK3CA', 'Gene', '5290', (93, 99))	('ESCC tumors', 'Disease', 'MESH:D004938', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('EC', 'Phenotype', 'HP:0011459', (247, 249))	('PIK3CA', 'Gene', (278, 284))	('p.Glu545Lys', 'Mutation', 'rs104886003', (68, 79))	('PIK3CA', 'Gene', '5290', (278, 284))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('EC', 'Phenotype', 'HP:0011459', (172, 174))	('c.1633G>A', 'Var', (57, 66))	('PIK3CA', 'Gene', (93, 99))	('p.Glu542Lys', 'Mutation', 'rs121913273', (40, 51))
843585	25839328	Signature B was characterized by an enrichment of C>T mutations at XpCpG trinucleotides as a result of an elevated rate of spontaneous 5-methyl-cytosine deamination.	('XpCpG', 'Gene', (67, 72))	('trinucleotides', 'Chemical', '-', (73, 87))	('elevated', 'PosReg', (106, 114))	('5-methyl-cytosine', 'Chemical', 'MESH:D044503', (135, 152))	('C>T mutations', 'Var', (50, 63))	('spontaneous 5-methyl-cytosine deamination', 'MPA', (123, 164))
843597	25839328	Moreover, silencing CBX4 and CBX8 in KYSE2 and KYSE510 cells (which harbor high endogenous expression) significantly inhibited cell proliferation, colony formation, and cell invasion (Figures 2C-2E; Figure S6).	('CBX8', 'Gene', '57332', (29, 33))	('CBX8', 'Gene', (29, 33))	('CBX4', 'Gene', (20, 24))	('cell proliferation', 'CPA', (127, 145))	('KYSE510', 'CellLine', 'CVCL:1354', (47, 54))	('cell invasion', 'CPA', (169, 182))	('colony formation', 'CPA', (147, 163))	('inhibited', 'NegReg', (117, 126))	('CBX4', 'Gene', '8535', (20, 24))	('silencing', 'Var', (10, 19))
843598	25839328	These results suggest that CBX4 and CBX8 amplification and the resultant protein upregulation contribute to the development of ESCC and that they might thus serve as potential drug targets for ESCC treatment.	('CBX4', 'Gene', (27, 31))	('ESCC', 'Disease', (127, 131))	('CBX8', 'Gene', (36, 40))	('upregulation', 'PosReg', (81, 93))	('amplification', 'Var', (41, 54))	('protein', 'MPA', (73, 80))	('CBX4', 'Gene', '8535', (27, 31))	('contribute', 'Reg', (94, 104))	('CBX8', 'Gene', '57332', (36, 40))
843599	25839328	We next applied the MutSigCV method to identify SMGs in the combined 192 ESCC tumors (Figure S1E) and discovered nine such genes driven by point mutations (false discovery rate, q < 0.1) and six further genes with p < 0.01 (Figure 3A).	('point mutations', 'Var', (139, 154))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ESCC tumors', 'Disease', (73, 84))	('ESCC tumors', 'Disease', 'MESH:D004938', (73, 84))
843600	25839328	Eleven of these 15 genes:including AJUBA, ZNF750, FAT1, FBXW7 (MIM 606278), and PTCH1 (MIM 601309) and the chromatin-remodeling genes CREBBP (MIM 600140) and BAP1 (MIM 603089):harbored frequent inactivating mutations.	('MIM 600140', 'Var', (142, 152))	('PTCH1', 'Gene', '5727', (80, 85))	('BAP1', 'Gene', (158, 162))	('CREBBP', 'Gene', (134, 140))	('MIM 606278', 'Var', (63, 73))	('CREBBP', 'Gene', '1387', (134, 140))	('BAP1', 'Gene', '8314', (158, 162))	('PTCH1', 'Gene', (80, 85))
843602	25839328	As in other cancers, particularly EAC, this analysis also identified well-known cancer-associated genes, such as TP53 (MIM 191170), PIK3CA, and CDKN2A (MIM 600160), as SMGs in ESCC, thus providing evidence of common dysfunctions in cell-cycle control and apoptotic signaling.	('dysfunctions', 'Disease', 'MESH:D009461', (216, 228))	('PIK3CA', 'Gene', (132, 138))	('MIM 600160', 'Var', (152, 162))	('cancer', 'Disease', (80, 86))	('MIM 191170', 'Var', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CDKN2A', 'Gene', (144, 150))	('TP53', 'Gene', (113, 117))	('ESCC', 'Disease', (176, 180))	('CDKN2A', 'Gene', '1029', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PIK3CA', 'Gene', '5290', (132, 138))	('dysfunctions', 'Disease', (216, 228))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('cancer', 'Disease', (12, 18))	('EAC', 'Phenotype', 'HP:0011459', (34, 37))	('TP53', 'Gene', '7157', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
843606	25839328	The following AJUBA mutations were identified and verified in four tumor samples: two stop-gain mutations (c.985G>T [p.Glu329*] and c.1057C>T [p.Gln353*]) and two frameshift indels (c.790_791insT [p.Val264fs*] and c.152delG [p.Gly51fs*]) in the 104-individual cohort and one frameshift insertion (c.1249_1250insA [p.Ala417fs*]) and one splice-site mutation in two individuals from our previous cohort (Figure 3B; Figure S7A; Table S3).	('c.790_791insT [p.Val264fs*]', 'Var', (182, 209))	('c.1249_1250insA', 'Mutation', 'c.1249_1250insA', (297, 312))	('p.Gln353*', 'Mutation', 'rs898956652', (143, 152))	('p.Val264fs', 'Mutation', 'p.V264fsX', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('c.152delG', 'Mutation', 'c.152delG', (214, 223))	('c.790_791insT', 'Mutation', 'c.790_791insT', (182, 195))	('p.Ala417fs', 'Mutation', 'p.A417fsX', (314, 324))	('c.1057C>T [', 'Var', (132, 143))	('p.Gly51fs', 'Mutation', 'p.G51fsX', (225, 234))	('c.1057C>T', 'Mutation', 'rs898956652', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('p.Glu329*', 'Mutation', 'p.E329*', (117, 126))	('c.985G>T', 'Mutation', 'c.985G>T', (107, 115))	('tumor', 'Disease', (67, 72))	('c.1249_1250insA [p.Ala417fs*]', 'Var', (297, 326))	('c.985G>T [p.Glu329*]', 'Var', (107, 127))	('c.152delG [p.Gly51fs*]', 'Var', (214, 236))
843607	25839328	In support of this possibility, immunoblot analysis showed the presence of truncated AJUBA in ESCC tumors (Figure 4A).	('AJUBA', 'Protein', (85, 90))	('presence', 'Reg', (63, 71))	('ESCC tumors', 'Disease', (94, 105))	('ESCC tumors', 'Disease', 'MESH:D004938', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('truncated', 'Var', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
843608	25839328	AJUBA knockdown in KYSE140 and KYSE510 cells led to increased cell growth, colony formation, cell migration, and cell invasion (Figure S8).	('cell invasion', 'CPA', (113, 126))	('increased', 'PosReg', (52, 61))	('KYSE140', 'Var', (19, 26))	('KYSE510', 'Var', (31, 38))	('colony formation', 'CPA', (75, 91))	('cell migration', 'CPA', (93, 107))	('knockdown', 'Var', (6, 15))	('KYSE510', 'CellLine', 'CVCL:1354', (31, 38))	('cell growth', 'CPA', (62, 73))
843609	25839328	Moreover, exogenous levels of wild-type AJUBA in KYSE30 and KYSE150 cells with low endogenous AJUBA levels suppressed cell growth, cell migration, and cell invasion; these effects were abrogated by AJUBA alterations (p.Gln353* and p.Val264fs*; Figures 4B-4F).	('p.Val264fs*', 'Var', (231, 242))	('cell growth', 'CPA', (118, 129))	('p.Gln353*', 'Mutation', 'rs898956652', (217, 226))	('p.Val264fs', 'Mutation', 'p.V264fsX', (231, 241))	('cell migration', 'CPA', (131, 145))	('cell invasion', 'CPA', (151, 164))	('suppressed', 'NegReg', (107, 117))	('abrogated', 'NegReg', (185, 194))	('p.Gln353*', 'Var', (217, 226))
843610	25839328	Together with our genetic observations, these functional data indicate that AJUBA might act as a tumor suppressor in ESCC and that the AJUBA mutations observed in ESCC abrogate its tumor-suppressive function.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (181, 186))	('mutations', 'Var', (141, 150))	('AJUBA', 'Gene', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('ESCC', 'Disease', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('abrogate', 'NegReg', (168, 176))
843611	25839328	Mutations in ZNF750, a tumor-associated gene located at 17q25, were identified in 6% of ESCC tumors.	('ZNF750', 'Gene', (13, 19))	('ESCC tumors', 'Disease', (88, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ESCC tumors', 'Disease', 'MESH:D004938', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('identified', 'Reg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
843612	25839328	We identified 11 somatic mutations, of which we verified (via Sanger sequencing) six, including two nonsense mutations (c.620G>A [p.Trp207*] and c.209C>A [p.Ser70*]), one indel (c.108_111del [p.Glu37Lysfs*]), and three missense mutations (c.96T>A [p.Phe32Leu], c.1520A>C [p.Asp507Ala], and c.1508C>G [p.Ser503Cys]) in ZNF750 in the 104-individual cohort.	('c.1520A>C', 'Mutation', 'c.1520A>C', (261, 270))	('c.108_111del', 'Mutation', 'c.108_111del', (178, 190))	('c.1520A>C', 'Var', (261, 270))	('c.96T>A', 'Mutation', 'c.96T>A', (239, 246))	('c.1508C>G', 'Mutation', 'c.1508C>G', (290, 299))	('c.1508C>G [', 'Var', (290, 301))	('p.Phe32Leu', 'Mutation', 'p.F32L', (248, 258))	('p.Trp207*', 'Mutation', 'p.W207*', (130, 139))	('p.Glu37Lys', 'SUBSTITUTION', 'None', (192, 202))	('p.Glu37Lys', 'Var', (192, 202))	('p.Ser503Cys', 'Mutation', 'p.S503C', (301, 312))	('c.209C>A', 'Mutation', 'c.209C>A', (145, 153))	('c.96T>A', 'Var', (239, 246))	('ZNF750', 'Gene', (318, 324))	('c.620G>A [', 'Var', (120, 130))	('c.209C>A [', 'Var', (145, 155))	('c.620G>A', 'Mutation', 'c.620G>A', (120, 128))	('p.Ser70*', 'Mutation', 'p.S70*', (155, 163))	('p.Asp507Ala', 'Mutation', 'p.D507A', (272, 283))
843613	25839328	In addition, five (c.414C>A [p.Cys138*], c.770C>A [p.Ser257*], c.85C>T [p.Gln29*], c.625_626insAA [p.Ala209fs*], and c.1621G>A [p.Ala541Thr]) out of 11 somatic mutations were verified by Sanger sequencing in our previous cohort (n = 88; Figure 3B).	('c.414C>A', 'Mutation', 'rs746929883', (19, 27))	('c.1621G>A', 'Mutation', 'rs757421399', (117, 126))	('c.770C>A [', 'Var', (41, 51))	('p.Ala541Thr', 'Mutation', 'rs370489037', (128, 139))	('c.625_626insAA [p.Ala209fs*]', 'Var', (83, 111))	('c.85C>T [p.Gln29*]', 'Var', (63, 81))	('c.1621G>A [p.Ala541Thr', 'Var', (117, 139))	('c.625_626insAA', 'Mutation', 'c.625_626insAA', (83, 97))	('p.Gln29*', 'Mutation', 'rs762091224', (72, 80))	('c.414C>A [p.Cys138*]', 'Var', (19, 39))	('c.770C>A', 'Mutation', 'rs368921956', (41, 49))	('p.Ser257*', 'Mutation', 'rs368921956', (51, 60))	('c.85C>T', 'Mutation', 'rs762091224', (63, 70))	('p.Cys138*', 'Mutation', 'rs746929883', (29, 38))	('p.Ala209fs', 'Mutation', 'p.A209fsX', (99, 109))
843614	25839328	Additionally, ZNF750 deletions, but no somatic mutations, were observed in 3 out of 14 tumor samples in the WGS set (21%, G-score > 0.23) and validated with a qPCR copy-number assay.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('deletions', 'Var', (21, 30))	('ZNF750', 'Gene', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
843615	25839328	The qPCR copy-number assay also determined that four out of six tumor samples harboring ZNF750 mutations or indels in the 90-sample WES set were affected by deletions, indicating that inactivation of both alleles had occurred in these individuals (Figures S9A-S9C).	('tumor', 'Disease', (64, 69))	('deletions', 'Var', (157, 166))	('ZNF750', 'Gene', (88, 94))	('mutations', 'Var', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('affected', 'Reg', (145, 153))
843617	25839328	Moreover, individuals with tumors harboring ZNF750 mutations had higher cytoplasmic expression levels than did those lacking ZNF750 mutations (Figure 5A).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (51, 60))	('cytoplasmic expression levels', 'MPA', (72, 101))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('higher', 'PosReg', (65, 71))	('ZNF750', 'Gene', (44, 50))
843618	25839328	Mislocalization of a truncated (p.Ser70*) ZNF750 (Figure 5B) indicated that cytoplasm translocation was partly caused by loss of the C-terminal nuclear localization sequence.	('Mislocalization', 'MPA', (0, 15))	('ZNF750', 'Gene', (42, 48))	('loss', 'NegReg', (121, 125))	('C-terminal nuclear localization sequence', 'MPA', (133, 173))	('p.Ser70*', 'Var', (32, 40))	('p.Ser70*', 'Mutation', 'p.S70*', (32, 40))	('cytoplasm translocation', 'MPA', (76, 99))
843619	25839328	For investigating a function for ZNF750 in tumorigenesis, shRNA-mediated stable ZNF750 depletion was followed by transfection with wild-type or altered (p.Ser70* or p.Trp207*) ZNF750 in KYSE150 and KYSE140 cells.	('p.Ser70*', 'Mutation', 'p.S70*', (153, 161))	('ZNF750', 'Gene', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ZNF750', 'Gene', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('p.Ser70*', 'Var', (153, 161))	('p.Trp207*', 'Mutation', 'p.W207*', (165, 174))	('p.Trp207*', 'Var', (165, 174))
843620	25839328	Moreover, functional studies demonstrated that wild-type ZNF750 inhibited cell growth, migration, and invasion, and this effect was abrogated by altered (p.Ser70* or p.Trp207*) ZNF750 (Figure 5C; Figures S9D and S9E).	('p.Ser70*', 'Var', (154, 162))	('S9E', 'Mutation', 'p.S9E', (212, 215))	('p.Ser70*', 'Mutation', 'p.S70*', (154, 162))	('p.Trp207*', 'Mutation', 'p.W207*', (166, 175))	('inhibited', 'NegReg', (64, 73))	('abrogated', 'NegReg', (132, 141))	('invasion', 'CPA', (102, 110))	('p.Trp207*', 'Var', (166, 175))	('cell growth', 'CPA', (74, 85))	('ZNF750', 'Gene', (177, 183))	('ZNF750', 'Gene', (57, 63))
843621	25839328	Finally, ZNF750 depletion and p.Ser70* ZNF750 markedly increased tumor size in the xenograft system in mice, whereas wild-type ZNF750 significantly decreased it (Figure 5D).	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('depletion', 'Var', (16, 25))	('mice', 'Species', '10090', (103, 107))	('increased', 'PosReg', (55, 64))	('p.Ser70*', 'Mutation', 'p.S70*', (30, 38))	('ZNF750 depletion', 'Var', (9, 25))	('ZNF750', 'Gene', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('p.Ser70*', 'Var', (30, 38))
843623	25839328	FAT1, which encodes a cadherin-like protein commonly expressed in epithelial tissues, was mutated in 15% of ESCC tumors.	('mutated', 'Var', (90, 97))	('ESCC tumors', 'Disease', (108, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('ESCC tumors', 'Disease', 'MESH:D004938', (108, 119))	('FAT1', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
843625	25839328	FAT1 inactivation, via mutations that affect the cytoplasmic domain, leads to aberrant Wnt/beta-catenin signaling in multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('aberrant', 'MPA', (78, 86))	('leads to', 'Reg', (69, 77))	('beta-catenin', 'Gene', (91, 103))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('mutations', 'Var', (23, 32))	('inactivation', 'NegReg', (5, 17))	('beta-catenin', 'Gene', '1499', (91, 103))	('FAT1', 'Gene', (0, 4))
843626	25839328	This observation indicates that mutations affecting FAT1 extracellular domains might disrupt cell-cell associations and increase invasiveness and thus potentially contribute to ESCC tumorigenesis.	('FAT1', 'Gene', (52, 56))	('tumor', 'Disease', (182, 187))	('cell-cell associations', 'CPA', (93, 115))	('mutations', 'Var', (32, 41))	('disrupt', 'NegReg', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('increase invasiveness', 'Disease', (120, 141))	('contribute', 'Reg', (163, 173))	('increase invasiveness', 'Disease', 'MESH:D009361', (120, 141))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
843627	25839328	FBXW7 mutations were observed in eight ESCC tumors in our cohort: these included two nonsense mutations (c.1005T>A [p.Cys335*] and c.409G>T [p.Glu137*]), one frameshift deletion (c.736_739del [p.Gly247Profs*] and inactivating mutations), and five missense mutations predicted to be deleterious by SIFT and PolyPhen-2 analyses (Table S3).	('p.Gly247Pro', 'SUBSTITUTION', 'None', (193, 204))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('c.409G>T', 'Mutation', 'c.409G>T', (131, 139))	('c.1005T>A [p.Cys335*]', 'Var', (105, 126))	('c.736_739del', 'Mutation', 'c.736_739del', (179, 191))	('c.409G>T', 'Var', (131, 139))	('p.Cys335*', 'Mutation', 'p.C335*', (116, 125))	('ESCC tumors', 'Disease', 'MESH:D004938', (39, 50))	('PolyPhen-2', 'Chemical', '-', (306, 316))	('FBXW7', 'Gene', (0, 5))	('c.1005T>A', 'Mutation', 'c.1005T>A', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('p.Gly247Pro', 'Var', (193, 204))	('p.Glu137*', 'Mutation', 'p.E137*', (141, 150))	('mutations', 'Var', (6, 15))	('ESCC tumors', 'Disease', (39, 50))
843628	25839328	FBXW7 mutations and copy-number loss and a subsequent decreased FBXW7 level have been observed in various cancer types.	('copy-number loss', 'Var', (20, 36))	('FBXW7 level', 'MPA', (64, 75))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('FBXW7', 'Gene', (0, 5))	('cancer', 'Disease', (106, 112))	('decreased', 'NegReg', (54, 63))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
843629	25839328	Inactivating mutations in several chromatin-remodeling genes, including CREBBP and BAP1, frequently occurred in our 104 ESCC samples.	('CREBBP', 'Gene', '1387', (72, 78))	('BAP1', 'Gene', (83, 87))	('Inactivating mutations', 'Var', (0, 22))	('CREBBP', 'Gene', (72, 78))	('occurred', 'Reg', (100, 108))	('BAP1', 'Gene', '8314', (83, 87))
843631	25839328	Inactivating CREBBP and EP300 mutations have been reported in various human cancer types.	('EP300', 'Gene', (24, 29))	('EP300', 'Gene', '2033', (24, 29))	('Inactivating', 'Var', (0, 12))	('CREBBP', 'Gene', (13, 19))	('human', 'Species', '9606', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('reported', 'Reg', (50, 58))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('CREBBP', 'Gene', '1387', (13, 19))
843632	25839328	We also identified mutations in BAP1, which encodes a nuclear deubiquitinase involved in chromatin remodeling.	('BAP1', 'Gene', '8314', (32, 36))	('BAP1', 'Gene', (32, 36))	('mutations', 'Var', (19, 28))
843633	25839328	BAP1 mutations have been reported in renal carcinoma and uveal melanoma, but not in ESCC to date.	('reported', 'Reg', (25, 33))	('BAP1', 'Gene', (0, 4))	('renal carcinoma', 'Disease', (37, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('mutations', 'Var', (5, 14))	('renal carcinoma', 'Phenotype', 'HP:0005584', (37, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('BAP1', 'Gene', '8314', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('renal carcinoma', 'Disease', 'MESH:C538614', (37, 52))
843637	25839328	Eleven recurrent mutated genes involving the cell-cycle regulatory pathway were identified, and TP53, CDKN2A, and RB1 (MIM 614041) accounted for 88%, 8%, and 2%, respectively (Table S3).	('RB1', 'Gene', (114, 117))	('TP53', 'Gene', (96, 100))	('MIM', 'Var', (119, 122))	('CDKN2A', 'Gene', (102, 108))	('RB1', 'Gene', '5925', (114, 117))	('CDKN2A', 'Gene', '1029', (102, 108))	('cell-cycle regulatory pathway', 'Pathway', (45, 74))	('TP53', 'Gene', '7157', (96, 100))
843639	25839328	Genes involved in the PI3K-AKT-mTOR pathway were mutated in 29% of 104 tumors, and PIK3CA was the most significantly altered gene (17%).	('mutated', 'Var', (49, 56))	('AKT', 'Gene', (27, 30))	('mTOR', 'Gene', (31, 35))	('mTOR', 'Gene', '2475', (31, 35))	('PIK3CA', 'Gene', '5290', (83, 89))	('AKT', 'Gene', '207', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('PIK3CA', 'Gene', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
843641	25839328	Hence, these data shed light on the essential role of dysregulation of these critical pathways in tumorigenesis of ESCC.	('ESCC', 'Disease', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('dysregulation', 'Var', (54, 67))
843642	25839328	The APOBEC family can deaminate cytosine to uracil within DNA, leading to mutation clusters in various types of cancer.	('cytosine', 'Chemical', 'MESH:D003596', (32, 40))	('EC', 'Phenotype', 'HP:0011459', (8, 10))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('APOBEC', 'Gene', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('uracil', 'Chemical', 'MESH:D014498', (44, 50))	('leading to', 'Reg', (63, 73))	('mutation clusters', 'Var', (74, 91))
843644	25839328	APOBEC3B, acting on lentiviral replication intermediates constituting an innate pathway of antiretroviral defense, was reported to be present in high amounts in ESCC, suggesting that it might be an attractive candidate for the mechanisms underlying mutation signature A in ESCC.	('mutation', 'Var', (249, 257))	('ESCC', 'Disease', (273, 277))	('APOBEC3B', 'Gene', (0, 8))	('APOBEC3B', 'Gene', '9582', (0, 8))	('EC', 'Phenotype', 'HP:0011459', (4, 6))
843645	25839328	In our cohort and that from Song et al., at least 47% of ESCC tumors had an APOBEC signature, suggesting that APOBEC-catalyzed genomic uracil lesions are responsible for a large proportion of mutations in ESCC.	('ESCC tumors', 'Disease', 'MESH:D004938', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('uracil lesions', 'Phenotype', 'HP:0012127', (135, 149))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('responsible', 'Reg', (154, 165))	('uracil', 'Chemical', 'MESH:D014498', (135, 141))	('ESCC tumors', 'Disease', (57, 68))	('EC', 'Phenotype', 'HP:0011459', (114, 116))	('EC', 'Phenotype', 'HP:0011459', (80, 82))	('mutations', 'Var', (192, 201))	('ESCC', 'Gene', (205, 209))
843647	25839328	CBX4 and CBX8 are major transcriptional repressors that epigenetically modify chromatin and exert important functions in cell-cycle regulation, DNA repair, cell differentiation, cell senescence, and cell death.	('CBX8', 'Gene', '57332', (9, 13))	('chromatin', 'MPA', (78, 87))	('CBX4', 'Gene', (0, 4))	('cell death', 'CPA', (199, 209))	('modify', 'Reg', (71, 77))	('DNA repair', 'CPA', (144, 154))	('CBX8', 'Gene', (9, 13))	('cell differentiation', 'CPA', (156, 176))	('cell-cycle regulation', 'CPA', (121, 142))	('epigenetically', 'Var', (56, 70))	('cell senescence', 'CPA', (178, 193))	('functions', 'Reg', (108, 117))	('CBX4', 'Gene', '8535', (0, 4))
843651	25839328	Using functional studies, we found that AJUBA and ZNF750 (previously known but with unknown function in ESCC) act as tumor suppressors and that mutations in these genes abrogated their tumor-suppressive effects.	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('abrogated', 'NegReg', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('ZNF750', 'Gene', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('mutations', 'Var', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
843652	25839328	Therefore, AJUBA and ZNF750 mutations encoding truncated or disrupted proteins might contribute to ESCC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ZNF750', 'Gene', (21, 27))	('proteins', 'Protein', (70, 78))	('tumor', 'Disease', (104, 109))	('contribute', 'Reg', (85, 95))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
843657	25839328	Epidemiologic studies have shown that in addition to smoking, alcohol consumption, and family history, the known risk factors for ESCC were thought to be hot food and N-nitroso compounds in northern China, whereas chewing of fermented areca nut has been shown to be independently associated with ESCC in southern China.	('areca nut', 'Species', '184783', (235, 244))	('N-nitroso', 'Var', (167, 176))	('ESCC', 'Disease', (130, 134))	('N-nitroso compounds', 'Chemical', '-', (167, 186))	('alcohol', 'Chemical', 'MESH:D000438', (62, 69))	('ESCC', 'Disease', (296, 300))	('associated', 'Reg', (280, 290))
843660	25839328	Furthermore, we have provided functional evidence of inactivating mutations in AJUBA and ZNF750, amplification of CBX4 and CBX8, and genomic aberrations targeting the cell cycle and NOTCH, PI3K, and Hh signaling pathways.	('amplification', 'Var', (97, 110))	('ZNF750', 'Gene', (89, 95))	('CBX8', 'Gene', '57332', (123, 127))	('CBX4', 'Gene', '8535', (114, 118))	('NOTCH', 'Pathway', (182, 187))	('inactivating mutations', 'Var', (53, 75))	('CBX8', 'Gene', (123, 127))	('cell cycle', 'Pathway', (167, 177))	('CBX4', 'Gene', (114, 118))	('PI3K', 'Pathway', (189, 193))	('targeting', 'Reg', (153, 162))	('Hh signaling pathways', 'Pathway', (199, 220))	('AJUBA', 'Gene', (79, 84))
843662	25839328	Further studies are required to explore how APOBEC family members and oncogenic ZNF750, AJUBA, CBX4, and CBX8 contribute to mutagenesis in ESCC, whether these genes are promising for drug discovery, and whether the therapies targeting PI3K and/or Hh signaling pathways are particularly promising strategies for ESCC.	('CBX8', 'Gene', (105, 109))	('mutagenesis', 'Var', (124, 135))	('ZNF750', 'Gene', (80, 86))	('CBX4', 'Gene', '8535', (95, 99))	('EC', 'Phenotype', 'HP:0011459', (48, 50))	('contribute', 'Reg', (110, 120))	('CBX8', 'Gene', '57332', (105, 109))	('ESCC', 'Disease', (139, 143))	('CBX4', 'Gene', (95, 99))
843673	25254241	Moreover, LOXL2 modulates focal adhesions, tight junctions, and cell polarity complexes in basal breast carcinoma cells through activation of the FAK signaling pathway.	('LOXL2', 'Var', (10, 15))	('activation', 'PosReg', (128, 138))	('FAK signaling pathway', 'Pathway', (146, 167))	('focal adhesions', 'Protein', (26, 41))	('breast carcinoma', 'Phenotype', 'HP:0003002', (97, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('tight junctions', 'CPA', (43, 58))	('breast carcinoma', 'Disease', (97, 113))	('breast carcinoma', 'Disease', 'MESH:D001943', (97, 113))	('modulates', 'Reg', (16, 25))	('cell polarity complexes', 'CPA', (64, 87))
843685	25254241	These two PPI subnetworks indicated that overexpression of LOXL2-WT or LOXL2-e13 greatly perturbed the PPI network in ESCC cells due to DEGs interacting with hundreds and thousands of proteins to achieve the biological consequences of the LOX2 protein itself.	('LOX', 'Gene', '4015', (59, 62))	('LOX', 'Gene', (59, 62))	('PPI network', 'Pathway', (103, 114))	('DEGs', 'Var', (136, 140))	('proteins', 'Protein', (184, 192))	('LOX', 'Gene', '4015', (71, 74))	('LOX', 'Gene', '4015', (239, 242))	('perturbed', 'NegReg', (89, 98))	('LOX', 'Gene', (71, 74))	('interacting', 'Interaction', (141, 152))	('LOX', 'Gene', (239, 242))
843686	25254241	Other sequence feature annotations from PIR_SUPERFAMILY indicated LOXL2-e13-DEGs were characterized by "histone H2B," "chaperone HSP70," and "serpin," while LOXL2-WT-DEGs were annotated by "zinc finger protein ZFP-36."	('serpin', 'Protein', (142, 148))	('HSP70', 'Gene', (129, 134))	('HSP70', 'Gene', '3308', (129, 134))	('LOXL2-e13-DEGs', 'Var', (66, 80))
843688	25254241	As for LOXL2-WT-DEGs, four carcinoma-related KEGG pathways were found: "hsa04010:MAPK signaling pathway," "hsa04110:Cell cycle," "hsa04115:p53 signaling pathway," and "hsa05200:Pathways in cancer."	('hsa04110', 'Var', (107, 115))	('carcinoma', 'Disease', 'MESH:D002277', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('Cell cycle', 'CPA', (116, 126))	('carcinoma', 'Disease', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('p53 signaling pathway', 'Pathway', (139, 160))	('MAPK signaling pathway', 'Pathway', (81, 103))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
843693	25254241	Much evidence has indicated that splicing abnormalities are a hallmark of cancer.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('splicing abnormalities', 'Var', (33, 55))
843694	25254241	The potential roles for splice variants in cancer might involve cell migration, cell growth, hormone responsiveness, apoptosis, and response to chemotherapy.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('splice variants', 'Var', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cell migration', 'CPA', (64, 78))	('cell growth', 'CPA', (80, 91))
843698	25254241	This indicates that the expression of tumour-specific splice variants significantly affects many cellular events, critical for cancer biology, which are still far from being illustrated.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('splice variants', 'Var', (54, 69))	('affects', 'Reg', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cellular', 'MPA', (97, 105))	('cancer', 'Disease', (127, 133))	('tumour', 'Disease', (38, 44))
843704	25254241	Interference of SERPINB1 promotes migration and invasion of HCC cells, with an apparent increase in the level of active matrix metalloproteinase-2 (MMP2).	('promotes', 'PosReg', (25, 33))	('matrix metalloproteinase-2', 'Gene', (120, 146))	('increase', 'PosReg', (88, 96))	('SERPINB1', 'Gene', (16, 24))	('MMP2', 'Gene', (148, 152))	('MMP2', 'Gene', '4313', (148, 152))	('matrix metalloproteinase-2', 'Gene', '4313', (120, 146))	('Interference', 'Var', (0, 12))	('SERPINB1', 'Gene', '1992', (16, 24))	('HCC', 'CellLine', 'CVCL:0C54', (60, 63))	('invasion', 'CPA', (48, 56))	('migration', 'CPA', (34, 43))
843705	25254241	It is interesting to note that SERPINB1 is also decreased 1.58-fold upon LOXL2-e13 overexpression.	('LOXL2-e13', 'Var', (73, 82))	('decreased', 'NegReg', (48, 57))	('overexpression', 'PosReg', (83, 97))	('SERPINB1', 'Gene', (31, 39))	('SERPINB1', 'Gene', '1992', (31, 39))
843712	25254241	In support of this, we find VEGF is upregulated 1.68-fold in the e13-WT-DEGs.	('VEGF', 'Gene', '7422', (28, 32))	('upregulated', 'PosReg', (36, 47))	('VEGF', 'Gene', (28, 32))	('e13-WT-DEGs', 'Var', (65, 76))
843714	25254241	Loss of ITGA3 prevents skin tumor formation by promoting epidermal turnover and depletion of slow-cycling cells.	('epidermal turnover', 'CPA', (57, 75))	('skin tumor', 'Phenotype', 'HP:0008069', (23, 33))	('depletion of slow-cycling cells', 'MPA', (80, 111))	('skin tumor', 'Disease', (23, 33))	('ITGA3', 'Gene', (8, 13))	('skin tumor', 'Disease', 'MESH:D012878', (23, 33))	('prevents', 'NegReg', (14, 22))	('promoting', 'PosReg', (47, 56))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
843717	25254241	So it is expected that LOXL2-e13 causes broad changes in mRNA expression profile, including some critical tumor-related genes, enabling LOXL2-e13 to play new and specific roles in ESCC compared to its wild-type counterpart.	('changes', 'Reg', (46, 53))	('mRNA expression profile', 'MPA', (57, 80))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('LOXL2-e13', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('LOXL2-e13', 'Var', (136, 145))	('ESCC', 'Disease', (180, 184))	('tumor', 'Disease', (106, 111))
843733	21712961	Urinary 8-OHdG has been reported to be strongly association with diabetes mellitus, chronic renal failure, and cancer.	('renal failure', 'Phenotype', 'HP:0000083', (92, 105))	('diabetes mellitus', 'Disease', 'MESH:D003920', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('association', 'Reg', (48, 59))	('chronic renal failure', 'Disease', 'MESH:D007676', (84, 105))	('8-OHdG', 'Chemical', 'MESH:C067134', (8, 14))	('chronic renal failure', 'Phenotype', 'HP:0003774', (84, 105))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (65, 82))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('diabetes mellitus', 'Disease', (65, 82))	('Urinary', 'Var', (0, 7))	('chronic renal failure', 'Disease', (84, 105))
843768	21712961	Moreover, investigators have reported a high concentration of 8-OHdG in renal cell carcinoma cells, as well as in urine samples from patients with carcinoma of female genitalia, in malignant breast tissues with invasive ductal carcinoma, and in colorectal tumor tissues, gastric cancer tissues, and lung cancer tissues.	('colorectal tumor', 'Disease', (245, 261))	('carcinoma', 'Disease', (147, 156))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('carcinoma', 'Disease', 'MESH:D002277', (83, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (271, 285))	('carcinoma', 'Disease', 'MESH:D002277', (227, 236))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (211, 236))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('lung cancer', 'Disease', (299, 310))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (72, 92))	('invasive ductal carcinoma', 'Disease', (211, 236))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (220, 236))	('genitalia', 'Disease', (167, 176))	('genitalia', 'Disease', 'MESH:D012734', (167, 176))	('carcinoma', 'Disease', 'MESH:D002277', (147, 156))	('gastric cancer', 'Phenotype', 'HP:0012126', (271, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('8-OHdG', 'Var', (62, 68))	('renal cell carcinoma', 'Disease', (72, 92))	('lung cancer', 'Disease', 'MESH:D008175', (299, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (72, 92))	('carcinoma', 'Disease', (227, 236))	('carcinoma', 'Disease', (83, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (299, 310))	('colorectal tumor', 'Disease', 'MESH:D015179', (245, 261))	('8-OHdG', 'Chemical', 'MESH:C067134', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('gastric cancer', 'Disease', (271, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
843856	32006900	Among them, the serine/threonine phosphatase PPM1D, also referred to as wild-type p53-induced phosphatase 1 (Wip1) or protein phosphatase 2C delta (PP2Cdelta), is emerging as an important oncoprotein due to its negative regulation on a number of crucial cancer suppressor pathways.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('wild-type p53-induced phosphatase 1', 'Gene', '8493', (72, 107))	('Wip1', 'Gene', '8493', (109, 113))	('Wip1', 'Gene', (109, 113))	('PPM1D', 'Var', (45, 50))	('phosphatase 2C delta', 'Gene', '8493', (126, 146))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('phosphatase 2C delta', 'Gene', (126, 146))	('cancer', 'Disease', (254, 260))	('wild-type p53-induced phosphatase 1', 'Gene', (72, 107))	('serine', 'Chemical', 'MESH:D012694', (16, 22))	('negative regulation', 'NegReg', (211, 230))	('PP2Cdelta', 'Gene', '8493', (148, 157))	('PP2Cdelta', 'Gene', (148, 157))
843857	32006900	Initially identified as a p53-regulated gene, PPM1D has been afterwards found amplified and more recently mutated in many human cancers such as breast cancer.	('human', 'Species', '9606', (122, 127))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('PPM1D', 'Var', (46, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
843860	32006900	Consecutive research on PPM1D and its relationship with cancer is essential, as it ultimately contributes to the etiology and treatment of cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('contributes', 'Reg', (94, 105))	('cancer', 'Disease', (139, 145))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('PPM1D', 'Var', (24, 29))
843861	32006900	PPM1D, also known as (PPM1D, PPMID, PP2Cdelta or IDDGIP), is a wild-type p53-induced phosphatase 1 (Wip1).	('wild-type p53-induced phosphatase 1', 'Gene', '8493', (63, 98))	('PP2Cdelta', 'Gene', '8493', (36, 45))	('PP2Cdelta', 'Gene', (36, 45))	('Wip1', 'Gene', '8493', (100, 104))	('Wip1', 'Gene', (100, 104))	('wild-type p53-induced phosphatase 1', 'Gene', (63, 98))	('PPM1D', 'Var', (0, 5))
843863	32006900	At present, PPM1D has been found to be amplified and overexpressed in various tumors and is currently considered to be an oncogene.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PPM1D', 'Var', (12, 17))	('overexpressed', 'PosReg', (53, 66))
843864	32006900	This article reviews the relationship between PPM1D and cancer as well as advances in studies of its inhibitors as anti-cancer agents.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('age', 'Gene', (127, 130))	('PPM1D', 'Var', (46, 51))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('age', 'Gene', '5973', (127, 130))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
843870	32006900	The authors observed mouse embryos and various adult tissues including mammary gland, uterus, ovary, adrenal gland, skin and testis in different periods and found that PPM1D mRNA seems to be universally expressed in all tissues and has very high level of expression in testis.	('mouse', 'Species', '10090', (21, 26))	('expression', 'MPA', (255, 265))	('ovary', 'Disease', (94, 99))	('PPM1D mRNA', 'Var', (168, 178))	('ovary', 'Disease', 'MESH:D010051', (94, 99))
843871	32006900	Although the expression level fluctuates during development, PPM1D is also expressed at all embryonic stages.	('expression', 'MPA', (13, 23))	('age', 'Gene', (104, 107))	('PPM1D', 'Var', (61, 66))	('age', 'Gene', '5973', (104, 107))
843872	32006900	In order to further determine the normal biological function of PPM1D in mammalian organisms, the authors obtained PPM1D+/-, PPM1D-/- and PPM1D+/+ through gene recombination.	('mammalian', 'Species', '9606', (73, 82))	('PPM1D+/-', 'Var', (115, 123))	('PPM1D-/-', 'Var', (125, 133))	('PPM1D+/+ through', 'Var', (138, 154))
843874	32006900	The results showed that the male mice with PPM1D-/- genotype had smaller body size, atrophic reproductive organs, reduced fertility and life span, and that their 2-year survival rate was less than 20%, while the survival rate of female mice with PPM1D-/-, all PPM1D+/- and PPM1D+/+ mice was about 80% in the same period.	('less', 'NegReg', (187, 191))	('mice', 'Species', '10090', (236, 240))	('reduced', 'NegReg', (114, 121))	('mice', 'Species', '10090', (282, 286))	('PPM1D-/-', 'Var', (43, 51))	('life span', 'CPA', (136, 145))	('smaller', 'NegReg', (65, 72))	('reduced fertility', 'Phenotype', 'HP:0000144', (114, 131))	('mice', 'Species', '10090', (33, 37))
843875	32006900	Moreover, PPM1D-/- male mice also showed increased susceptibility to pathogens and weakened T and B cell functions, resulting in death of all infected PPM1D-/- male mice within 11 days after influenza virus infection, while the survival rate of PPM1D+/- heterozygote mice infected with virus at the same time was as high as 80%.	('virus infection', 'Disease', 'MESH:D001102', (201, 216))	('mice', 'Species', '10090', (165, 169))	('virus infection', 'Disease', (201, 216))	('mice', 'Species', '10090', (24, 28))	('infected', 'Disease', 'MESH:D007239', (272, 280))	('infected', 'Disease', 'MESH:D007239', (142, 150))	('susceptibility', 'MPA', (51, 65))	('PPM1D-/-', 'Var', (151, 159))	('PPM1D-/-', 'Var', (10, 18))	('weakened', 'NegReg', (83, 91))	('death', 'NegReg', (129, 134))	('infected', 'Disease', (272, 280))	('infected', 'Disease', (142, 150))	('mice', 'Species', '10090', (267, 271))
843876	32006900	However, it is noteworthy that PPM1D-/- mice did not show any signs of tumor.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('PPM1D-/-', 'Var', (31, 39))	('mice', 'Species', '10090', (40, 44))	('tumor', 'Disease', (71, 76))
843880	32006900	This study measured PPM1D mRNA content in human embryonic fibroblasts, breast cancer cells, ovarian cancer cells, non-small cell lung cancer cells, renal cancer, T lymphocyte leukemia cell lines, etc.	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('leukemia', 'Phenotype', 'HP:0001909', (175, 183))	('ovarian cancer', 'Disease', (92, 106))	('human', 'Species', '9606', (42, 47))	('renal cancer', 'Disease', (148, 160))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('renal cancer', 'Phenotype', 'HP:0009726', (148, 160))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('breast cancer', 'Disease', (71, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('renal cancer', 'Disease', 'MESH:D007680', (148, 160))	('T lymphocyte leukemia', 'Disease', (162, 183))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (114, 140))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PPM1D', 'Var', (20, 25))	('lymphocyte leukemia', 'Phenotype', 'HP:0005526', (164, 183))	('ovarian cancer', 'Disease', 'MESH:D010051', (92, 106))	('lung cancer', 'Disease', (129, 140))	('T lymphocyte leukemia', 'Disease', 'MESH:D015458', (162, 183))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (118, 140))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
843881	32006900	and determined the high expression of PPM1D in breast cancer cell lines BT474 and MCF7.	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('MCF7', 'CellLine', 'CVCL:0031', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('PPM1D', 'Var', (38, 43))
843883	32006900	The research on the relationship between PPM1D and the occurrence and development of tumor has been started since then, and we will make a systematic review for this.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('PPM1D', 'Var', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
843885	32006900	Inactivation of p38MAPK (product of mapk14) in vivo through overexpression of PPM1D accelerates tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('accelerates', 'PosReg', (84, 95))	('p38', 'Gene', (16, 19))	('tumor', 'Disease', (96, 101))	('PPM1D', 'Var', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mapk14', 'Gene', '1432', (36, 42))	('Inactivation', 'Var', (0, 12))	('mapk14', 'Gene', (36, 42))	('p38', 'Gene', '1432', (16, 19))
843888	32006900	Interestingly, PPM1D amplification is related to ERBB2 expression.	('expression', 'MPA', (55, 65))	('PPM1D', 'Var', (15, 20))	('related', 'Reg', (38, 45))	('ERBB2', 'Gene', (49, 54))	('ERBB2', 'Gene', '2064', (49, 54))
843889	32006900	Some researchers have proposed that PPM1D phosphatase plays a role in MKK6/p38 MAPK signaling pathway to promote ErbB2-driven breast tumor occurrence.	('breast tumor', 'Disease', (126, 138))	('promote', 'PosReg', (105, 112))	('ErbB2', 'Gene', (113, 118))	('p38 MAPK', 'Gene', '26416', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('breast tumor', 'Phenotype', 'HP:0100013', (126, 138))	('PPM1D', 'Var', (36, 41))	('p38 MAPK', 'Gene', (75, 83))	('ErbB2', 'Gene', '2064', (113, 118))	('MKK6', 'Gene', '5608', (70, 74))	('breast tumor', 'Disease', 'MESH:D001943', (126, 138))	('MKK6', 'Gene', (70, 74))
843890	32006900	Meanwhile, some scholars found that 35% of PPM1D mRNA was up-regulated in invasive breast cancer samples.	('up-regulated', 'PosReg', (58, 70))	('invasive breast cancer', 'Disease', 'MESH:D001943', (74, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('invasive breast cancer', 'Disease', (74, 96))	('PPM1D', 'Var', (43, 48))
843891	32006900	The overexpression of PPM1D was negatively correlated with the overexpression of p-p38 MAPK, suggesting that PPM1D overexpression eliminated the steady-state balance maintained by p38-p53-PPM1D pathway.	('p38 MAPK', 'Gene', (83, 91))	('steady-state balance maintained', 'MPA', (145, 176))	('eliminated', 'NegReg', (130, 140))	('p38', 'Gene', (83, 86))	('p38', 'Gene', (180, 183))	('p38 MAPK', 'Gene', '26416', (83, 91))	('p38', 'Gene', '1432', (83, 86))	('PPM1D', 'Var', (109, 114))	('p38', 'Gene', '1432', (180, 183))
843892	32006900	Inhibiting BRCA1 expression can effectively reduce PPM1D expression, thus enhancing the activity of p38MAPK and effectively improving cell survival rate.	('p38', 'Gene', (100, 103))	('improving', 'PosReg', (124, 133))	('cell survival rate', 'CPA', (134, 152))	('Inhibiting', 'Var', (0, 10))	('reduce', 'NegReg', (44, 50))	('BRCA1', 'Gene', '672', (11, 16))	('activity', 'MPA', (88, 96))	('BRCA1', 'Gene', (11, 16))	('p38', 'Gene', '1432', (100, 103))	('PPM1D expression', 'MPA', (51, 67))	('enhancing', 'PosReg', (74, 83))
843896	32006900	Other scholars have evaluated the genetic risk of breast cancer, put forward the important role of single nucleotide polymorphisms (SNPs) in cancer diagnosis, and proposed that PPM1D gene mutation will increase the genetic risk of breast cancer.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mutation', 'Var', (188, 196))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('PPM1D', 'Var', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('increase', 'PosReg', (202, 210))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('breast cancer', 'Disease', (231, 244))
843898	32006900	For patients with PPM1D mutation in blood, routine sequencing was used to check PPM1D mutation in tumor tissue samples.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PPM1D mutation', 'Var', (18, 32))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (98, 103))
843899	32006900	The results showed that in 719 patients with breast cancer, the mutation rate was less than 0.3%, with truncating mutations in exon 6 as the main mutation, which may be related to previous chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('truncating mutations in', 'Var', (103, 126))	('breast cancer', 'Disease', (45, 58))	('patients', 'Species', '9606', (31, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))
843901	32006900	pointed out that the important reason for the occurrence of genetic breast cancer is the mutation of susceptible genes, including BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM and PPM1D.	('TP53', 'Gene', '7157', (144, 148))	('BRCA1', 'Gene', (130, 135))	('TP53', 'Gene', (144, 148))	('BRCA2', 'Gene', '675', (137, 142))	('BRCA1', 'Gene', '672', (130, 135))	('ATM', 'Gene', '472', (163, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('mutation', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('PTEN', 'Gene', (157, 161))	('BRCA2', 'Gene', (137, 142))	('PPM1D', 'Var', (171, 176))	('PTEN', 'Gene', '5728', (157, 161))	('genetic breast cancer', 'Disease', (60, 81))	('ATM', 'Gene', (163, 166))	('CHEK2', 'Gene', '11200', (150, 155))	('genetic breast cancer', 'Disease', 'MESH:D001943', (60, 81))	('CHEK2', 'Gene', (150, 155))
843902	32006900	These mutations are crucial to early onset and the increased risk of familial breast cancer, and lead to 90% of hereditary breast cancer cases.	('familial breast cancer', 'Disease', 'MESH:D001943', (69, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('familial breast cancer', 'Disease', (69, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hereditary breast cancer', 'Disease', 'MESH:D061325', (112, 136))	('lead to', 'Reg', (97, 104))	('mutations', 'Var', (6, 15))	('hereditary breast cancer', 'Disease', (112, 136))
843906	32006900	In TNBC MC6 cell line, inhibition of PPM1D can increase the sensitivity of the cancer cells to platinum drugs.	('PPM1D', 'Gene', (37, 42))	('MC6', 'CellLine', 'CVCL:W203', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('inhibition', 'Var', (23, 33))	('platinum', 'Chemical', 'MESH:D010984', (95, 103))	('increase', 'PosReg', (47, 55))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
843909	32006900	It was found that breast cancer samples from clinical patients highly expressed estrogen receptor and progesterone receptor, and PPM1D amplification was significantly correlated with HER2, TOP2A and CCND1 amplification.	('CCND1', 'Gene', '595', (199, 204))	('TOP2A', 'Gene', (189, 194))	('HER2', 'Gene', '2064', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('PPM1D amplification', 'Var', (129, 148))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('patients', 'Species', '9606', (54, 62))	('breast cancer', 'Disease', (18, 31))	('correlated', 'Reg', (167, 177))	('estrogen receptor', 'Gene', (80, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('estrogen receptor', 'Gene', '2099', (80, 97))	('progesterone receptor', 'Gene', (102, 123))	('CCND1', 'Gene', (199, 204))	('progesterone receptor', 'Gene', '5241', (102, 123))	('TOP2A', 'Gene', '7153', (189, 194))	('HER2', 'Gene', (183, 187))
843911	32006900	The results showed that the expression of PPM1D reached a peak at 16 hours under the treatment of 10 nM E2.	('PPM1D', 'Var', (42, 47))	('expression', 'MPA', (28, 38))	('E2', 'Chemical', 'MESH:D004958', (104, 106))
843916	32006900	The results of follow-up for 10 years showed that PPM1D (+) itself is a prognostic factor for breast cancer.	('PPM1D (+', 'Var', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
843917	32006900	The expression of PPM1D could reduce the 10-year survival rate of patients from more than 70% to less than 50%, and what's more, the 10-year survival rate of patients with PPM1D(+)p21(-) is lower (nearly 30%).	('PPM1D', 'Var', (18, 23))	('p21', 'Gene', '1026', (180, 183))	('reduce', 'NegReg', (30, 36))	('p21', 'Gene', (180, 183))	('10-year survival rate', 'CPA', (41, 62))	('patients', 'Species', '9606', (158, 166))	('patients', 'Species', '9606', (66, 74))
843918	32006900	PPM1D overexpression predicts poor prognosis in esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (48, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('esophageal squamous cell carcinoma', 'Disease', (48, 82))	('overexpression', 'PosReg', (6, 20))	('PPM1D', 'Var', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
843920	32006900	Immunohistochemical staining showed that the positive expression of PPM1D protein in tumor tissues of patients with ESCC accounts for 70 cases (69.3%), while the control group accounts for only 15 cases (14.9%), with significant difference.	('tumor', 'Disease', (85, 90))	('ESCC', 'Disease', (116, 120))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('protein', 'Protein', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('positive expression', 'PosReg', (45, 64))	('PPM1D', 'Var', (68, 73))
843921	32006900	Moreover, the expression of PPM1D mRNA in tumor patients is also significantly higher than that of the control group.	('PPM1D', 'Var', (28, 33))	('tumor', 'Disease', (42, 47))	('expression', 'MPA', (14, 24))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('higher', 'PosReg', (79, 85))	('mRNA', 'Protein', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
843922	32006900	The expression of PPM1D in patients with metastatic ESCC is significantly higher than that in patients with non-metastatic ESCC.	('metastatic ESCC', 'Disease', (41, 56))	('patients', 'Species', '9606', (94, 102))	('PPM1D', 'Var', (18, 23))	('higher', 'PosReg', (74, 80))	('expression', 'MPA', (4, 14))	('patients', 'Species', '9606', (27, 35))
843923	32006900	Follow-up data show that the 5-year survival rate of patients with high expression of PPM1D in tumors is less than 20%, while that of patients with negative PPM1D is about 50%, suggesting that PPM1D may be a new marker for metastasis and prognosis of ESCC patients.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (53, 61))	('less', 'NegReg', (105, 109))	('patients', 'Species', '9606', (256, 264))	('patients', 'Species', '9606', (134, 142))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('expression', 'MPA', (72, 82))	('PPM1D', 'Var', (193, 198))	('ESCC', 'Disease', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('PPM1D', 'Gene', (86, 91))	('tumors', 'Disease', (95, 101))
843926	32006900	It was found that smoking and drinking contributed the most to gene mutation, and age itself was also a risk factor.	('gene mutation', 'Var', (63, 76))	('age', 'Gene', (82, 85))	('age', 'Gene', '5973', (82, 85))
843929	32006900	Compared to the mutations of esophageal cancer, the normal esophageal epithelia has obvious overrepresentation of NOTCH1 and PPM1D mutations.	('age', 'Gene', (64, 67))	('mutations', 'Var', (131, 140))	('NOTCH1', 'Gene', (114, 120))	('overrepresentation', 'PosReg', (92, 110))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (59, 79))	('age', 'Gene', (34, 37))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('age', 'Gene', '5973', (64, 67))	('PPM1D', 'Gene', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('age', 'Gene', '5973', (34, 37))	('NOTCH1', 'Gene', '4851', (114, 120))
843932	32006900	also confirmed that overexpression of PPM1D inhibited CHK2's ability to detect and repair cell cycle damage in colon cancer cells, leading to malignant progression of cancer.	('ability', 'MPA', (61, 68))	('colon cancer', 'Disease', (111, 123))	('cancer', 'Disease', (167, 173))	('cell cycle', 'CPA', (90, 100))	('overexpression', 'PosReg', (20, 34))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('detect', 'MPA', (72, 78))	('inhibited', 'NegReg', (44, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (111, 123))	('malignant progression', 'CPA', (142, 163))	('cancer', 'Disease', (117, 123))	('PPM1D', 'Var', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CHK2', 'Gene', (54, 58))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('age', 'Gene', (104, 107))	('colon cancer', 'Disease', 'MESH:D015179', (111, 123))	('leading to', 'Reg', (131, 141))	('CHK2', 'Gene', '11200', (54, 58))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('age', 'Gene', '5973', (104, 107))
843933	32006900	Some scholars have pointed out that PPM1D can activate downstream p38MAPK and JNK signaling pathways independent of p53 in colon cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (123, 135))	('colon cancer', 'Disease', 'MESH:D015179', (123, 135))	('p38', 'Gene', '1432', (66, 69))	('JNK', 'Gene', (78, 81))	('PPM1D', 'Var', (36, 41))	('activate', 'PosReg', (46, 54))	('colon cancer', 'Disease', (123, 135))	('JNK', 'Gene', '5599', (78, 81))	('p38', 'Gene', (66, 69))
843934	32006900	analyzed the expression of PPM1D protein and mRNA in colorectal cancer and normal tissues.	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('colorectal cancer', 'Disease', (53, 70))	('mRNA', 'MPA', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('PPM1D', 'Var', (27, 32))
843937	32006900	Using lentiviral shRNA to reduce the expression of PPM1D in RKO cells, Yin et al.	('expression', 'MPA', (37, 47))	('PPM1D', 'Var', (51, 56))	('RKO', 'CellLine', 'CVCL:0504', (60, 63))	('reduce', 'NegReg', (26, 32))
843939	32006900	demonstrated that the deletion of PPM1D inhibited the development of radiation-induced intestinal tumors.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('inhibited', 'NegReg', (40, 49))	('deletion', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PPM1D', 'Gene', (34, 39))	('intestinal tumors', 'Disease', (87, 104))	('intestinal tumors', 'Disease', 'MESH:D007414', (87, 104))
843940	32006900	Apart from interfering with the development of colon cancer, PPM1D also contributes to the drug resistance of colon cancer.	('colon cancer', 'Disease', (110, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('contributes', 'Reg', (72, 83))	('PPM1D', 'Var', (61, 66))	('drug resistance', 'CPA', (91, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('colon cancer', 'Disease', 'MESH:D015179', (110, 122))	('colon cancer', 'Disease', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('drug resistance', 'Phenotype', 'HP:0020174', (91, 106))
843943	32006900	However, some scholars have found that overexpression of PPM1D in p53-negative tumors makes them sensitive to chemotherapeutics and protects normal tissues from side effects of anticancer therapy.	('overexpression', 'PosReg', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('sensitive', 'MPA', (97, 106))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('PPM1D', 'Var', (57, 62))	('cancer', 'Disease', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
843944	32006900	In clonal hematopoiesis of leukemia, mutations in TP53 and PPM1D seem to lead to clonal growth, which may result in subsequent malignant tumors.	('hematopoiesis of leukemia', 'Disease', 'MESH:C536227', (10, 35))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('leukemia', 'Phenotype', 'HP:0001909', (27, 35))	('malignant tumors', 'Disease', (127, 143))	('PPM1D', 'Gene', (59, 64))	('TP53', 'Gene', '7157', (50, 54))	('malignant tumors', 'Disease', 'MESH:D009369', (127, 143))	('result in', 'Reg', (106, 115))	('mutations', 'Var', (37, 46))	('hematopoiesis of leukemia', 'Disease', (10, 35))	('clonal growth', 'CPA', (81, 94))	('TP53', 'Gene', (50, 54))	('lead to', 'Reg', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
843947	32006900	found that myelodysplastic syndrome was related to mutation of PPM1D and that chemotherapy could cause mutation of PPM1D and TP53.	('myelodysplastic syndrome', 'Disease', (11, 35))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (11, 35))	('related', 'Reg', (40, 47))	('TP53', 'Gene', '7157', (125, 129))	('PPM1D', 'Gene', (63, 68))	('TP53', 'Gene', (125, 129))	('mutation', 'Var', (51, 59))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (11, 35))	('PPM1D', 'Gene', (115, 120))
843948	32006900	However, for the treatment of hematological tumors, patients with PPM1D mutation are more likely to need growth factor therapy.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('PPM1D mutation', 'Var', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('hematological tumors', 'Disease', (30, 50))	('hematological tumors', 'Disease', 'MESH:D019337', (30, 50))	('patients', 'Species', '9606', (52, 60))
843950	32006900	Among them, PPM1D mutations were associated with hematological diseases such as myelodysplastic syndrome, leukemia and lymphoma.	('PPM1D mutations', 'Var', (12, 27))	('hematological diseases', 'Disease', 'MESH:D006402', (49, 71))	('leukemia', 'Disease', (106, 114))	('lymphoma', 'Disease', 'MESH:D008223', (119, 127))	('leukemia', 'Disease', 'MESH:D007938', (106, 114))	('leukemia', 'Phenotype', 'HP:0001909', (106, 114))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (80, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (119, 127))	('hematological diseases', 'Disease', (49, 71))	('associated', 'Reg', (33, 43))	('myelodysplastic syndrome', 'Disease', (80, 104))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (80, 104))	('lymphoma', 'Disease', (119, 127))	('mutations', 'Var', (18, 27))
843951	32006900	Previous studies indicated that PPM1D gene was amplified and overexpressed in leukemia.	('leukemia', 'Disease', (78, 86))	('leukemia', 'Phenotype', 'HP:0001909', (78, 86))	('leukemia', 'Disease', 'MESH:D007938', (78, 86))	('PPM1D gene', 'Var', (32, 42))	('overexpressed', 'PosReg', (61, 74))
843953	32006900	PPM1D inhibitor can increase the proportion of HL-60 differentiating into neutrophils, and also induce G1 cell cycle arrest in HL-60 cells.	('HL-60', 'Protein', (47, 52))	('induce', 'Reg', (96, 102))	('HL-60', 'CellLine', 'CVCL:0002', (47, 52))	('arrest', 'Disease', (117, 123))	('HL-60', 'CellLine', 'CVCL:0002', (127, 132))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (106, 123))	('PPM1D', 'Var', (0, 5))	('arrest', 'Disease', 'MESH:D006323', (117, 123))	('increase', 'PosReg', (20, 28))
843954	32006900	Their results suggest that PPM1D may be a potential therapeutic target for hematopoietic diseases, including leukemia.	('hematopoietic diseases', 'Disease', (75, 97))	('hematopoietic diseases', 'Disease', 'MESH:D019337', (75, 97))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('leukemia', 'Disease', (109, 117))	('leukemia', 'Disease', 'MESH:D007938', (109, 117))	('PPM1D', 'Var', (27, 32))
843961	32006900	After analyzing the expression of PPM1D in 18 pairs of osteosarcoma tissues and control tissues, Long et al.	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('osteosarcoma', 'Disease', (55, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (55, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('PPM1D', 'Var', (34, 39))
843962	32006900	found that the expression of PPM1D in osteosarcoma was significantly higher than that in control tissues, and that PPM1D mRNA was highly expressed in U2OS and MG63 cells.	('U2OS', 'CellLine', 'CVCL:0042', (150, 154))	('OS', 'Phenotype', 'HP:0002669', (152, 154))	('osteosarcoma', 'Phenotype', 'HP:0002669', (38, 50))	('PPM1D', 'Var', (115, 120))	('osteosarcoma', 'Disease', (38, 50))	('osteosarcoma', 'Disease', 'MESH:D012516', (38, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('MG63', 'CellLine', 'CVCL:0426', (159, 163))	('PPM1D', 'Var', (29, 34))	('expression', 'MPA', (15, 25))	('higher', 'PosReg', (69, 75))
843964	32006900	In addition, expression levels of PPM1D mRNA and protein in osteosarcoma tissue are higher than those in non-cancerous tissue.	('osteosarcoma', 'Disease', 'MESH:D012516', (60, 72))	('expression levels', 'MPA', (13, 30))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('cancer', 'Disease', (109, 115))	('osteosarcoma', 'Phenotype', 'HP:0002669', (60, 72))	('osteosarcoma', 'Disease', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PPM1D', 'Var', (34, 39))	('higher', 'PosReg', (84, 90))
843967	32006900	also found that the intervention of PPM1D can reduce the cell viability of Ewing sarcoma, showing the target effect of PPM1D in Ewing sarcoma treatment.	('reduce', 'NegReg', (46, 52))	('Ewing sarcoma', 'Disease', (75, 88))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (128, 141))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (128, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (75, 88))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (75, 88))	('PPM1D', 'Var', (36, 41))	('Ewing sarcoma', 'Disease', (128, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('cell viability', 'CPA', (57, 71))
843968	32006900	performed immunohistochemical determination of PPM1D in 60 non-small cell lung cancer (NSCLC) tissues and 20 normal lung tissues, and found PPM1D expression in 38 lung cancer tissues, but negative expression in normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('lung cancer', 'Disease', (74, 85))	('NSCLC', 'Disease', (87, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('PPM1D', 'Var', (47, 52))	('lung cancer', 'Disease', (163, 174))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('PPM1D', 'Var', (140, 145))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))
843970	32006900	It was also observed that the expression of PPM1D was negatively correlated with the expression of p38MAPK, p53 and p16.	('expression', 'MPA', (85, 95))	('expression', 'MPA', (30, 40))	('p38', 'Gene', '1432', (99, 102))	('p16', 'Gene', (116, 119))	('p38', 'Gene', (99, 102))	('negatively', 'NegReg', (54, 64))	('p16', 'Gene', '1029', (116, 119))	('p53', 'Var', (108, 111))	('PPM1D', 'Var', (44, 49))
843971	32006900	Among 117 cases of NSCLC, 81 cases expressed PPM1D, but there was no expression or only weak expression in 15 normal lung tissues.	('NSCLC', 'Phenotype', 'HP:0030358', (19, 24))	('PPM1D', 'Var', (45, 50))	('expressed', 'Reg', (35, 44))	('NSCLC', 'Disease', (19, 24))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))
843972	32006900	The data of follow-up for more than 6 years show that the 6-year survival rate of lung cancer patients with high PPM1D expression is less than 20%, while the survival rate of lung cancer patients with low PPM1D expression is more than 40%.	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (94, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Disease', (82, 93))	('lung cancer', 'Disease', (175, 186))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('less', 'NegReg', (133, 137))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('high PPM1D expression', 'Var', (108, 129))
843975	32006900	Not only can PPM1D be expressed in lung cancer tissues, but it can also mediate the regulation of amyloid protein-binding protein 2 (APPBP2) on lung cancer tissues as an intermediate molecule of pathway.	('PPM1D', 'Var', (13, 18))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('lung cancer', 'Disease', (144, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('amyloid protein-binding protein 2', 'Gene', '10513', (98, 131))	('APPBP2', 'Gene', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('APPBP2', 'Gene', '10513', (133, 139))	('amyloid protein-binding protein 2', 'Gene', (98, 131))
843976	32006900	observed an ectopic expression of APPBP2, PPM1D and SPOP in human NSCLC tissues.	('PPM1D', 'Var', (42, 47))	('SPOP', 'Gene', '8405', (52, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('NSCLC', 'Disease', (66, 71))	('SPOP', 'Gene', (52, 56))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('ectopic expression', 'MPA', (12, 30))	('APPBP2', 'Gene', (34, 40))	('human', 'Species', '9606', (60, 65))	('APPBP2', 'Gene', '10513', (34, 40))
843979	32006900	studied the role of mir-16 in lung cancer and confirmed that PPM1D was the target gene of mir-16 in lung cancer cell line A459.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('mir-16', 'Gene', (20, 26))	('lung cancer', 'Disease', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('mir-16', 'Gene', '51573', (20, 26))	('mir-16', 'Gene', (90, 96))	('lung cancer', 'Disease', (100, 111))	('PPM1D', 'Var', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('mir-16', 'Gene', '51573', (90, 96))
843981	32006900	PPM1D snRNA treatment in A459 and H1299 cells could also reduce the proliferation of tumor cells and induce cell cycle arrest in G0/G1 phase.	('tumor', 'Disease', (85, 90))	('reduce', 'NegReg', (57, 63))	('arrest', 'Disease', (119, 125))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (108, 125))	('H1299', 'CellLine', 'CVCL:0060', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('induce', 'Reg', (101, 107))	('arrest', 'Disease', 'MESH:D006323', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('PPM1D', 'Var', (0, 5))
843983	32006900	studied 3236 patients with ovarian cancer and found that 0.37% of them had chimeric mutations in PPM1D.	('ovarian cancer', 'Disease', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('patients', 'Species', '9606', (13, 21))	('ovarian cancer', 'Phenotype', 'HP:0100615', (27, 41))	('chimeric mutations', 'Var', (75, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (27, 41))	('PPM1D', 'Gene', (97, 102))
843985	32006900	The authors believe that these PPM1D mutations are related to chemotherapy, but not to the susceptibility of primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('mutations', 'Var', (37, 46))	('PPM1D', 'Gene', (31, 36))	('related', 'Reg', (51, 58))
843986	32006900	observed 1,295 cases of ovarian cancer and concluded that in the absence of a family history of cancer, PPM1D chimeric mutation could make women more susceptible to ovarian cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('women', 'Species', '9606', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (24, 38))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (32, 38))	('PPM1D chimeric mutation', 'Var', (104, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (24, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('ovarian cancer', 'Disease', 'MESH:D010051', (165, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('ovarian cancer', 'Disease', (24, 38))	('cancer', 'Disease', (96, 102))	('ovarian cancer', 'Disease', (165, 179))
843987	32006900	transfected PPM1D siRNA into ovarian cancer cell SKOV3 and found that after PPM1D was inhibited, the percentage of tumor cell apoptosis increased, the expression of P53 increased, and the Bax/bcl2 ratio also increased.	('ovarian cancer', 'Disease', (29, 43))	('tumor', 'Disease', (115, 120))	('age', 'Gene', (108, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('P53', 'Gene', (165, 168))	('bcl2', 'Gene', '596', (192, 196))	('SKOV3', 'CellLine', 'CVCL:0532', (49, 54))	('age', 'Gene', '5973', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('increased', 'PosReg', (169, 178))	('expression', 'MPA', (151, 161))	('bcl2', 'Gene', (192, 196))	('Bax', 'Gene', (188, 191))	('increased', 'PosReg', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('P53', 'Gene', '7157', (165, 168))	('increased', 'PosReg', (136, 145))	('Bax', 'Gene', '581', (188, 191))	('ovarian cancer', 'Disease', 'MESH:D010051', (29, 43))	('PPM1D', 'Var', (76, 81))	('inhibited', 'NegReg', (86, 95))
843989	32006900	Moreover, overexpression of PPM1D can inhibit proliferation, migration and invasion of ovarian cancer cells in SKOV3 and OVCA433 cells and mouse metastatic tumor models.	('PPM1D', 'Var', (28, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('proliferation', 'CPA', (46, 59))	('migration', 'CPA', (61, 70))	('mouse', 'Species', '10090', (139, 144))	('invasion of ovarian cancer', 'Disease', (75, 101))	('overexpression', 'PosReg', (10, 24))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('inhibit', 'NegReg', (38, 45))	('invasion of ovarian cancer', 'Disease', 'MESH:D009362', (75, 101))	('SKOV3', 'CellLine', 'CVCL:0532', (111, 116))
843990	32006900	At the same time, they substantiated that PPM1D can inhibit ovarian cancer metastasis through negative regulation of p-ATM, p-Akt and Snail.	('PPM1D', 'Var', (42, 47))	('inhibit', 'NegReg', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('Snail', 'Gene', '6615', (134, 139))	('Snail', 'Gene', (134, 139))	('ATM', 'Gene', (119, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('Akt', 'Gene', '207', (126, 129))	('ovarian cancer', 'Disease', (60, 74))	('ATM', 'Gene', '472', (119, 122))	('negative', 'NegReg', (94, 102))	('Akt', 'Gene', (126, 129))
843993	32006900	PPM1D not only can be used as a gene target for ovarian cancer, but also plays an important role in relieving drug resistance of ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('ovarian cancer', 'Disease', 'MESH:D010051', (129, 143))	('relieving', 'NegReg', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('ovarian cancer', 'Disease', (129, 143))	('drug resistance', 'Phenotype', 'HP:0020174', (110, 125))	('PPM1D', 'Var', (0, 5))	('ovarian cancer', 'Disease', (48, 62))	('drug resistance', 'MPA', (110, 125))
843995	32006900	In sensitive cells, cisplatin (CDDP) induces PPM1D nuclear rejection and proteasome degradation, thus allowing CDDP to induce Chk1 and p53 activation and eventually initiate cell apoptosis.	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('CDDP', 'Chemical', '-', (111, 115))	('activation', 'PosReg', (139, 149))	('proteasome degradation', 'MPA', (73, 95))	('PPM1D', 'Var', (45, 50))	('p53', 'Protein', (135, 138))	('CDDP', 'Chemical', '-', (31, 35))	('cell apoptosis', 'CPA', (174, 188))	('nuclear rejection', 'MPA', (51, 68))	('Chk1', 'Gene', (126, 130))	('Chk1', 'Gene', '1111', (126, 130))	('induce', 'Reg', (119, 125))
843996	32006900	However, in chemoresistant cells, Akt activation and overexpression stabilize PPM1D, leading to sustained PPM1D expression and nuclear localization, which inhibits Chk1 and p53 activity and reduces apoptosis, thus contributing to CDDP resistance in cancer cells.	('p53', 'Protein', (173, 176))	('apoptosis', 'CPA', (198, 207))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('inhibits', 'NegReg', (155, 163))	('Akt', 'Gene', (34, 37))	('Chk1', 'Gene', (164, 168))	('activity', 'MPA', (177, 185))	('cancer', 'Disease', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('Akt', 'Gene', '207', (34, 37))	('Chk1', 'Gene', '1111', (164, 168))	('reduces', 'NegReg', (190, 197))	('contributing', 'Reg', (214, 226))	('nuclear localization', 'MPA', (127, 147))	('PPM1D', 'Var', (106, 111))	('CDDP', 'Chemical', '-', (230, 234))	('expression', 'MPA', (112, 122))
843997	32006900	PPM1D, as a target molecule of AKT, plays an important role in eliminating chemotherapeutic drug resistance.	('eliminating', 'NegReg', (63, 74))	('AKT', 'Gene', (31, 34))	('chemotherapeutic drug resistance', 'MPA', (75, 107))	('PPM1D', 'Var', (0, 5))	('AKT', 'Gene', '207', (31, 34))	('drug resistance', 'Phenotype', 'HP:0020174', (92, 107))
844000	32006900	found that the expression of PPM1D protein and mRNA in human pancreatic cancer tissues was significantly higher than that in normal pancreas.	('higher', 'PosReg', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (55, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('mRNA', 'MPA', (47, 51))	('PPM1D', 'Var', (29, 34))	('expression', 'MPA', (15, 25))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('pancreatic cancer', 'Disease', (61, 78))
844001	32006900	The expression of PPM1D in pancreatic cancer tissues was related to tumor size (2cm as the boundary), case classification, lymph node metastasis and vascular invasion.	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('PPM1D', 'Var', (18, 23))	('pancreatic cancer', 'Disease', (27, 44))	('pancreatic cancer', 'Disease', 'MESH:D010190', (27, 44))	('expression', 'MPA', (4, 14))	('related', 'Reg', (57, 64))	('vascular invasion', 'CPA', (149, 166))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('lymph node metastasis', 'CPA', (123, 144))
844002	32006900	Further mechanism study showed that the expression of PPM1D mRNA and protein in PANC-1 and MIA Paca-2 cell lines was higher.	('expression', 'MPA', (40, 50))	('higher', 'PosReg', (117, 123))	('PANC-1', 'CellLine', 'CVCL:0480', (80, 86))	('MIA Paca-2', 'CellLine', 'CVCL:0428', (91, 101))	('PPM1D', 'Var', (54, 59))
844003	32006900	High expression of PPM1D can significantly promote the proliferation, invasion and migration of cancer cells through wnt/beta-catenin pathway.	('promote', 'PosReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('proliferation', 'CPA', (55, 68))	('beta-catenin', 'Gene', (121, 133))	('PPM1D', 'Var', (19, 24))	('beta-catenin', 'Gene', '1499', (121, 133))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('invasion', 'CPA', (70, 78))	('migration', 'CPA', (83, 92))
844004	32006900	Down-regulation of PPM1D expression with PPM1D siRNA significantly increased aspp2 and p38MAPK/p53, and promoted apoptosis of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('PPM1D', 'Gene', (19, 24))	('PPM1D', 'Var', (41, 46))	('p38', 'Gene', (87, 90))	('expression', 'MPA', (25, 35))	('aspp2', 'Gene', (77, 82))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Down-regulation', 'NegReg', (0, 15))	('increased', 'PosReg', (67, 76))	('aspp2', 'Gene', '7159', (77, 82))	('p38', 'Gene', '1432', (87, 90))	('promoted', 'PosReg', (104, 112))
844005	32006900	Experiments in nude mice also confirmed that PPM1D siRNA could significantly reduce tumors, suggesting that PPM1D is a carcinogenic gene of pancreatic cancer.	('reduce', 'NegReg', (77, 83))	('nude mice', 'Species', '10090', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('PPM1D', 'Var', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('PPM1D', 'Var', (108, 113))	('carcinogenic gene of pancreatic cancer', 'Disease', (119, 157))	('carcinogenic gene of pancreatic cancer', 'Disease', 'MESH:D006527', (119, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
844006	32006900	Other studies indicated the independent predictive effect of PPM1D on pancreatic cancer patients and that the 3-year survival rate of patients with high PPM1D expression was 0%, while the 10-year survival rate of patients with low PPM1D expression was 10%.	('patients', 'Species', '9606', (88, 96))	('pancreatic cancer', 'Disease', (70, 87))	('patients', 'Species', '9606', (134, 142))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('PPM1D', 'Var', (61, 66))	('high PPM1D expression', 'Var', (148, 169))	('patients', 'Species', '9606', (213, 221))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))
844009	32006900	found that PPM1D is expressed in glioma cell line U87-MG. After silencing PPM1D and treating the cell with TMZ, they showed that PPM1D gene silencing can better inhibit TMZ-induced cell proliferation and induce cell apoptosis and cell cycle arrest, and that PIK3R1/AKT pathway plays a role in various functions of glioma cells.	('cell apoptosis', 'CPA', (211, 225))	('glioma', 'Disease', (314, 320))	('PIK3R1', 'Gene', (258, 264))	('glioma', 'Disease', 'MESH:D005910', (314, 320))	('glioma', 'Disease', (33, 39))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (230, 247))	('glioma', 'Phenotype', 'HP:0009733', (314, 320))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('PPM1D gene silencing', 'Var', (129, 149))	('cell proliferation', 'CPA', (181, 199))	('PIK3R1', 'Gene', '5295', (258, 264))	('AKT', 'Gene', (265, 268))	('arrest', 'Disease', (241, 247))	('induce', 'PosReg', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('U87-MG', 'CellLine', 'CVCL:0022', (50, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (107, 110))	('TMZ', 'Chemical', 'MESH:D000077204', (169, 172))	('inhibit', 'NegReg', (161, 168))	('arrest', 'Disease', 'MESH:D006323', (241, 247))	('AKT', 'Gene', '207', (265, 268))
844010	32006900	It has been reported that PPM1D is highly expressed in glands of gastric cancer tissues, while almost no PPM1D is expressed in normal gastric mucosa.	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('PPM1D', 'Var', (26, 31))	('gastric cancer', 'Disease', (65, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))
844012	32006900	Therefore, the expression of PPM1D in cancer tissues could be used as an indicator of poor prognosis of gastric cancer patients.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (119, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('PPM1D', 'Var', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gastric cancer', 'Disease', (104, 118))
844013	32006900	proposed that the expression of PPM1D in human gastric cancer tissues is related to the size of tumors and the dephosphorylation of Chk2.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('gastric cancer', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (96, 102))	('human', 'Species', '9606', (41, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('PPM1D', 'Var', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('dephosphorylation', 'MPA', (111, 128))	('Chk2', 'Gene', '11200', (132, 136))	('Chk2', 'Gene', (132, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('related', 'Reg', (73, 80))
844014	32006900	In addition, carrying out experiments in HEK293 and MKN-74 gastric cancer cells, the authors suggest that ionizing radiation (IR) can induce PPM1D up-regulation and inhibition of CHK2, leading to down-regulation of p53.	('PPM1D', 'Var', (141, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('p53', 'Protein', (215, 218))	('CHK2', 'Gene', (179, 183))	('HEK293', 'CellLine', 'CVCL:0045', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('down-regulation', 'NegReg', (196, 211))	('up-regulation', 'PosReg', (147, 160))	('gastric cancer', 'Disease', (59, 73))	('CHK2', 'Gene', '11200', (179, 183))	('inhibition', 'NegReg', (165, 175))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))
844016	32006900	The expression of PPM1D in nasopharyngeal carcinoma is significantly higher than that in normal tissues.	('PPM1D', 'Var', (18, 23))	('carcinoma', 'Disease', (42, 51))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (27, 51))	('expression', 'MPA', (4, 14))	('carcinoma', 'Disease', 'MESH:D009369', (42, 51))	('higher', 'PosReg', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
844019	32006900	Transfection of PPM1D siRNA into nasopharyngeal carcinoma CNE2 cells significantly reduces the proliferation, invasion and migration of tumor cells, increases apoptosis, and promotes protein expressions of p53 and p16.	('p16', 'Gene', (214, 217))	('promotes', 'PosReg', (174, 182))	('carcinoma', 'Disease', (48, 57))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (33, 57))	('increases', 'PosReg', (149, 158))	('reduces', 'NegReg', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('p16', 'Gene', '1029', (214, 217))	('PPM1D', 'Var', (16, 21))	('carcinoma', 'Disease', 'MESH:D009369', (48, 57))	('protein expressions', 'MPA', (183, 202))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('CNE2', 'CellLine', 'CVCL:6889', (58, 62))	('p53', 'Protein', (206, 209))	('tumor', 'Disease', (136, 141))	('apoptosis', 'CPA', (159, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
844020	32006900	It is suggested that PPM1D may participate in the development of nasopharyngeal carcinoma by regulating p53-p16 pathway.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('p16', 'Gene', '1029', (108, 111))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (65, 89))	('carcinoma', 'Disease', 'MESH:D009369', (80, 89))	('carcinoma', 'Disease', (80, 89))	('p16', 'Gene', (108, 111))	('participate', 'Reg', (31, 42))	('regulating', 'Reg', (93, 103))	('PPM1D', 'Var', (21, 26))
844021	32006900	The expression of PPM1D in hepatocellular carcinoma is significantly higher than that in normal liver tissues.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (27, 51))	('PPM1D', 'Var', (18, 23))	('expression', 'MPA', (4, 14))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (27, 51))	('higher', 'PosReg', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('hepatocellular carcinoma', 'Disease', (27, 51))
844022	32006900	Immunohistochemistry showed that PPM1D protein is highly expressed in hepatocellular carcinoma tissues, but hardly expressed in normal tissues.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (70, 94))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 94))	('PPM1D', 'Var', (33, 38))	('hepatocellular carcinoma', 'Disease', (70, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))
844023	32006900	The expression of PPM1D in hepatocellular carcinoma is associated with family history, tumor size, alpha-fetoprotein (alpha-FP), TNM stage and recurrence.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (27, 51))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('PPM1D', 'Var', (18, 23))	('alpha-fetoprotein', 'Gene', (99, 116))	('age', 'Gene', '5973', (135, 138))	('associated', 'Reg', (55, 65))	('tumor', 'Disease', (87, 92))	('TNM', 'Gene', (129, 132))	('alpha-FP', 'Gene', '174', (118, 126))	('TNM', 'Gene', '10178', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('age', 'Gene', (135, 138))	('alpha-FP', 'Gene', (118, 126))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (27, 51))	('alpha-fetoprotein', 'Gene', '174', (99, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('hepatocellular carcinoma', 'Disease', (27, 51))
844026	32006900	These results suggest that high expression of PPM1D is associated with poor clinical prognosis of patients with hepatocellular carcinoma.	('PPM1D', 'Var', (46, 51))	('patients', 'Species', '9606', (98, 106))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('hepatocellular carcinoma', 'Disease', (112, 136))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))
844029	32006900	In contrast, knockdown of miR-29c greatly enhanced the proliferation of HepG2 cells and inhibited cell apoptosis.	('inhibited', 'NegReg', (88, 97))	('cell apoptosis', 'CPA', (98, 112))	('miR-29c', 'Gene', '407026', (26, 33))	('proliferation', 'CPA', (55, 68))	('miR-29c', 'Gene', (26, 33))	('enhanced', 'PosReg', (42, 50))	('HepG2', 'CellLine', 'CVCL:0027', (72, 77))	('knockdown', 'Var', (13, 22))
844030	32006900	These studies confirmed that the target of biological effect of miR-29c is PPM1D, and proposed that miR-29c can be used as an intervention target for liver cancer.	('liver cancer', 'Phenotype', 'HP:0002896', (150, 162))	('liver cancer', 'Disease', 'MESH:D006528', (150, 162))	('liver cancer', 'Disease', (150, 162))	('miR-29c', 'Gene', '407026', (64, 71))	('miR-29c', 'Gene', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('PPM1D', 'Var', (75, 80))	('miR-29c', 'Gene', (100, 107))	('miR-29c', 'Gene', '407026', (100, 107))
844032	32006900	The expression of PPM1D protein and mRNA in human renal cell carcinoma is significantly higher than that in normal kidney tissues.	('human', 'Species', '9606', (44, 49))	('higher', 'PosReg', (88, 94))	('mRNA', 'MPA', (36, 40))	('protein', 'Protein', (24, 31))	('PPM1D', 'Var', (18, 23))	('renal cell carcinoma', 'Disease', (50, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (50, 70))	('expression', 'MPA', (4, 14))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (50, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))
844034	32006900	PPM1D shRNA can inhibit the proliferation, migration and invasion of 786-O and RLC-310 renal cancer cells, while overexpression of PPM1D promotes the growth and invasion of these cells in vitro.	('inhibit', 'NegReg', (16, 23))	('promotes', 'PosReg', (137, 145))	('invasion', 'CPA', (57, 65))	('proliferation', 'CPA', (28, 41))	('PPM1D', 'Var', (131, 136))	('invasion', 'CPA', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('renal cancer', 'Phenotype', 'HP:0009726', (87, 99))	('RLC-310 renal cancer', 'Disease', 'MESH:D007680', (79, 99))	('RLC-310 renal cancer', 'Disease', (79, 99))	('migration', 'CPA', (43, 52))	('growth', 'CPA', (150, 156))	('PPM1D', 'Var', (0, 5))
844035	32006900	Survival analysis showed that the 5-year survival rate of patients with high expression of PPM1D in renal cell carcinoma was 0%, while that of patients with low expression of PPM1D was more than 20%.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (100, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('patients', 'Species', '9606', (143, 151))	('PPM1D', 'Var', (91, 96))	('patients', 'Species', '9606', (58, 66))	('renal cell carcinoma', 'Disease', (100, 120))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (100, 120))
844036	32006900	Regression analysis showed that the depth of T3+T4, Fuhrman grade of G3-G4, distant metastasis and high expression of PPM1D are risk factors for poor prognosis of renal cancer patients.	('PPM1D', 'Gene', (118, 123))	('T3+T4', 'Var', (45, 50))	('distant metastasis', 'CPA', (76, 94))	('patients', 'Species', '9606', (176, 184))	('renal cancer', 'Disease', (163, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('renal cancer', 'Phenotype', 'HP:0009726', (163, 175))	('G3-G4', 'Gene', (69, 74))	('renal cancer', 'Disease', 'MESH:D007680', (163, 175))
844037	32006900	shRNA-mediated PPM1D knockdown significantly inhibited cell growth and colony formation in bladder cancer cell lines 5637 and T24, increased the proportion of G0/G1 phase cells, and decreased the proportion of S and G2 phase cells.	('increased', 'PosReg', (131, 140))	('PPM1D knockdown', 'Var', (15, 30))	('decreased', 'NegReg', (182, 191))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('colony formation', 'CPA', (71, 87))	('bladder cancer', 'Disease', (91, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('inhibited', 'NegReg', (45, 54))	('knockdown', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('G0/G1 phase cells', 'CPA', (159, 176))	('cell growth', 'CPA', (55, 66))
844038	32006900	These results suggest that PPM1D is a target molecule for bladder cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('PPM1D', 'Var', (27, 32))
844041	32006900	The expression of PPM1D in prostate cancer is significantly higher than that in benign prostatic hyperplasia (BPH) control group, and the expression of PPM1D is related to Gleason score, T stage and lymph node infiltration.	('prostate cancer', 'Disease', 'MESH:D011471', (27, 42))	('PPM1D', 'Var', (152, 157))	('prostate cancer', 'Phenotype', 'HP:0012125', (27, 42))	('higher', 'PosReg', (60, 66))	('age', 'Gene', '5973', (191, 194))	('benign prostatic hyperplasia', 'Disease', (80, 108))	('expression', 'MPA', (4, 14))	('BPH', 'Phenotype', 'HP:0008711', (110, 113))	('benign prostatic hyperplasia', 'Phenotype', 'HP:0008711', (80, 108))	('PPM1D', 'Gene', (18, 23))	('prostate cancer', 'Disease', (27, 42))	('related', 'Reg', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('age', 'Gene', (191, 194))	('benign prostatic hyperplasia', 'Disease', 'MESH:D011470', (80, 108))
844042	32006900	Kaplan-Meier curve analysis showed that the 10-year survival rate of PPM1D positive prostate cancer patients was about 50%, while that of PPM1D negative prostate cancer patients was more than 90%.	('patients', 'Species', '9606', (169, 177))	('prostate cancer', 'Disease', (84, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('PPM1D positive', 'Var', (69, 83))	('prostate cancer', 'Disease', (153, 168))
844043	32006900	COX risk model regression analysis showed that the difference of survival rate was mainly related to PPM1D protein expression, Gleason score and T stage.	('age', 'Gene', '5973', (149, 152))	('PPM1D', 'Var', (101, 106))	('Gleason', 'Disease', (127, 134))	('age', 'Gene', (149, 152))
844044	32006900	In order to further study the mechanism of PPM1D in prostate cancer, Jiao et al.	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('PPM1D', 'Var', (43, 48))	('prostate cancer', 'Disease', (52, 67))
844045	32006900	transfected prostate cancer cell lines CP-3 and LNCaP with PPM1D siRNA and found that PPM1D knockdown inhibits the proliferation, migration and invasion of PC-3 and LNCaP cells.	('prostate cancer', 'Disease', (12, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('PC-3', 'CellLine', 'CVCL:0035', (156, 160))	('prostate cancer', 'Phenotype', 'HP:0012125', (12, 27))	('LNCaP cells', 'CPA', (165, 176))	('knockdown', 'Var', (92, 101))	('invasion', 'CPA', (144, 152))	('proliferation', 'CPA', (115, 128))	('LNCaP', 'CellLine', 'CVCL:0395', (165, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (12, 27))	('PPM1D knockdown', 'Var', (86, 101))	('migration', 'CPA', (130, 139))	('LNCaP', 'CellLine', 'CVCL:0395', (48, 53))	('PPM1D', 'Var', (59, 64))	('inhibits', 'NegReg', (102, 110))
844046	32006900	reported that PPM1D protein expression in prostate cancer LNCaP cells increased significantly after exposure to irradiation.	('PPM1D', 'Var', (14, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('increased', 'PosReg', (70, 79))	('protein', 'Protein', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('prostate cancer', 'Disease', (42, 57))	('LNCaP', 'CellLine', 'CVCL:0395', (58, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (42, 57))
844048	32006900	Further studies have confirmed that PPM1D directly interacts with BAX and dephosphorylates it.	('BAX', 'Gene', (66, 69))	('BAX', 'Gene', '581', (66, 69))	('PPM1D', 'Var', (36, 41))	('dephosphorylates', 'MPA', (74, 90))	('interacts', 'Interaction', (51, 60))
844049	32006900	Overexpression of PPM1D and BAX in BAX deficient cells can greatly reduce cell apoptosis, reflecting the downregulation of BAX activity by PPM1D.	('reduce', 'NegReg', (67, 73))	('BAX', 'Gene', (123, 126))	('BAX', 'Gene', '581', (123, 126))	('downregulation', 'NegReg', (105, 119))	('BAX', 'Gene', (35, 38))	('PPM1D', 'Var', (139, 144))	('BAX', 'Gene', (28, 31))	('cell apoptosis', 'CPA', (74, 88))	('BAX', 'Gene', '581', (35, 38))	('BAX', 'Gene', '581', (28, 31))	('activity', 'MPA', (127, 135))
844050	32006900	In addition to the various tumors mentioned above, a large number of studies have shown that PPM1D inhibition can also become a new way to treat oral cancer/laryngeal cancer, neuroblastoma and melanoma.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('PPM1D', 'Var', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('cancer', 'Disease', (167, 173))	('tumors', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('inhibition', 'NegReg', (99, 109))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('neuroblastoma and melanoma', 'Disease', 'MESH:D009447', (175, 201))	('cancer', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('neuroblastoma', 'Phenotype', 'HP:0003006', (175, 188))
844051	32006900	PPM1D is amplified and overexpressed in a number of human tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (58, 64))	('human', 'Species', '9606', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('PPM1D', 'Var', (0, 5))
844052	32006900	Based on Mouse genetic studies and data from RNAi-mediated depletion of PPM1D in cancer cell lines, PPM1D was proposed as an attractive pharmacological target.	('Mouse', 'Species', '10090', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('PPM1D', 'Var', (100, 105))	('cancer', 'Disease', (81, 87))	('PPM1D', 'Gene', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
844054	32006900	In spite of a valuable tool compound, the two phosphoric acid moieties on the peptide strictly limit cell entry and the binding of PPM1D.	('limit', 'NegReg', (95, 100))	('binding', 'Interaction', (120, 127))	('PPM1D', 'Var', (131, 136))	('cell entry', 'CPA', (101, 111))	('phosphoric acid', 'Chemical', 'MESH:C030242', (46, 61))
844057	32006900	Compound M321237 was identified through screening chemical libraries based on its ability to repress PPM1D protein phosphatase activity in vitro.	('M321237', 'Chemical', '-', (9, 16))	('PPM1D', 'Var', (101, 106))	('repress', 'NegReg', (93, 100))	('protein phosphatase', 'Enzyme', (107, 126))	('M321237', 'Var', (9, 16))	('activity', 'MPA', (127, 135))
844058	32006900	Cell viability assay demonstrated that M321237 sensitizes breast cancer MCF-7 cells to doxorubicin.	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('MCF-7', 'CellLine', 'CVCL:0031', (72, 77))	('sensitizes', 'Reg', (47, 57))	('M321237', 'Chemical', '-', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))	('M321237', 'Var', (39, 46))
844059	32006900	In vivo studies showed that M321237 reduced tumor volumes in xenograft models; nonetheless, the selectivity of M321237 to PPM1D was never validated.	('M321237', 'Chemical', '-', (28, 35))	('M321237', 'Chemical', '-', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('M321237', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('reduced', 'NegReg', (36, 43))	('tumor', 'Disease', (44, 49))
844061	32006900	CCT007093 suppresses cell viability in p53-proficient tumor cells carrying amplified PPM1D.	('CCT007093', 'Chemical', 'MESH:C000591540', (0, 9))	('CCT007093', 'Var', (0, 9))	('cell viability', 'CPA', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('amplified PPM1D', 'Var', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PPM1D', 'Var', (85, 90))	('tumor', 'Disease', (54, 59))	('suppresses', 'NegReg', (10, 20))
844062	32006900	Alternatively, CCT007093 inhibits UV-induced apoptosis in skin keratinocytes through blocking activation of JNK, suggesting that the inhibitor is less specific to WIP1.	('inhibits', 'NegReg', (25, 33))	('JNK', 'Gene', '5599', (108, 111))	('WIP1', 'Gene', (163, 167))	('CCT007093', 'Chemical', 'MESH:C000591540', (15, 24))	('CCT007093', 'Var', (15, 24))	('blocking', 'NegReg', (85, 93))	('JNK', 'Gene', (108, 111))	('WIP1', 'Gene', '8493', (163, 167))
844063	32006900	Additionally, CCT007093 was shown to inhibit cell proliferation irrespective of the presence of WIP1 in U2OS cells, confirming its off-target effect.	('WIP1', 'Gene', (96, 100))	('CCT007093', 'Chemical', 'MESH:C000591540', (14, 23))	('CCT007093', 'Var', (14, 23))	('U2OS', 'CellLine', 'CVCL:0042', (104, 108))	('inhibit', 'NegReg', (37, 44))	('cell proliferation', 'CPA', (45, 63))	('WIP1', 'Gene', '8493', (96, 100))	('OS', 'Phenotype', 'HP:0002669', (106, 108))
844064	32006900	In addition, CCT007093 treatment does not affect levels of p53-pS15 and gammaH2AX, both of which are well-established substrates of WIP1.	('CCT007093', 'Chemical', 'MESH:C000591540', (13, 22))	('CCT007093', 'Var', (13, 22))	('WIP1', 'Gene', (132, 136))	('p53-pS15', 'Var', (59, 67))	('WIP1', 'Gene', '8493', (132, 136))	('gammaH2AX', 'Var', (72, 81))
844066	32006900	These data indicate that CCT007093 does not impede WIP1 in cells and emphasize the urgent need to verify the specificity of small molecule inhibitors in cell models, including the CRISPR/Cas9-mediated target gene knockout.	('CCT007093', 'Var', (25, 34))	('WIP1', 'Gene', '8493', (51, 55))	('CCT007093', 'Chemical', 'MESH:C000591540', (25, 34))	('WIP1', 'Gene', (51, 55))
844068	32006900	In addition, the specificity of SPI-001 to PPM1D protein phosphatase was determined to be about 50 times higher than that of another PP2C phosphatase PPM1A.	('SPI', 'Gene', '1113', (32, 35))	('higher', 'PosReg', (105, 111))	('protein phosphatase', 'Enzyme', (49, 68))	('PPM1A', 'Gene', (150, 155))	('SPI', 'Gene', (32, 35))	('PPM1A', 'Gene', '5494', (150, 155))	('PPM1D', 'Var', (43, 48))
844070	32006900	In human colorectal cancer HCT-116 cells expressing truncated PPM1D, SPI-001 treatment does not affect cell proliferation, nonetheless combination treatment with SPI-001 and doxorubicin enhances cell growth inhibition by increasing p53 phosphorylation at Ser15.	('enhances', 'PosReg', (186, 194))	('combination', 'Interaction', (135, 146))	('human', 'Species', '9606', (3, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (9, 26))	('Ser15', 'Chemical', '-', (255, 260))	('colorectal cancer', 'Disease', (9, 26))	('truncated PPM1D', 'Var', (52, 67))	('increasing', 'PosReg', (221, 231))	('doxorubicin', 'Chemical', 'MESH:D004317', (174, 185))	('phosphorylation', 'MPA', (236, 251))	('HCT-116', 'CellLine', 'CVCL:0291', (27, 34))	('SPI', 'Gene', (69, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (9, 26))	('SPI', 'Gene', '1113', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('p53', 'Protein', (232, 235))	('cell growth inhibition', 'CPA', (195, 217))	('SPI', 'Gene', (162, 165))	('SPI', 'Gene', '1113', (162, 165))
844074	32006900	The peptide properties of these lead compounds led to poor cell permeability and consequently stimulated the further exploration of structure-activity relationship that produces GSK2830371.	('poor', 'NegReg', (54, 58))	('GSK2830371', 'Chemical', 'MESH:C587624', (178, 188))	('GSK2830371', 'Var', (178, 188))	('cell permeability', 'MPA', (59, 76))
844076	32006900	It is noteworthy that GSK2830371 also rapidly reduces the level of PPM1D protein in cancer cells through a mechanism that has not been fully described.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('GSK2830371', 'Var', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('level of PPM1D protein', 'MPA', (58, 80))	('reduces', 'NegReg', (46, 53))	('GSK2830371', 'Chemical', 'MESH:C587624', (22, 32))
844077	32006900	Moreover, cell proliferation studies showed that GSK2830371 effectively inhibited the proliferation of cancer cells carrying PPM1D amplification while retaining WT p53, e.g.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('proliferation', 'CPA', (86, 99))	('PPM1D amplification', 'Var', (125, 144))	('GSK2830371', 'Chemical', 'MESH:C587624', (49, 59))	('inhibited', 'NegReg', (72, 81))	('GSK2830371', 'Var', (49, 59))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
844080	32006900	Inhibition of PPM1D by GSK2830371 up-regulates expression of p53 target genes such as CDKN1A, PUMA, and BAX, leading to cell cycle arrest, but is not enough to induce cell death.	('up-regulates', 'PosReg', (34, 46))	('PUMA', 'Gene', (94, 98))	('arrest', 'Disease', 'MESH:D006323', (131, 137))	('GSK2830371', 'Chemical', 'MESH:C587624', (23, 33))	('GSK2830371', 'Var', (23, 33))	('BAX', 'Gene', (104, 107))	('arrest', 'Disease', (131, 137))	('BAX', 'Gene', '581', (104, 107))	('PUMA', 'Gene', '27113', (94, 98))	('CDKN1A', 'Gene', (86, 92))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (120, 137))	('CDKN1A', 'Gene', '1026', (86, 92))	('expression', 'MPA', (47, 57))
844086	32006900	The growth inhibition assay demonstrated that C23 has a remarkable cytotoxicity on MCF-7 cells (IC50: 0.98 muM) but not MCF-12A cells compared to CCT007093.	('C23', 'Var', (46, 49))	('cytotoxicity', 'Disease', (67, 79))	('MCF-7', 'CellLine', 'CVCL:0031', (83, 88))	('CCT007093', 'Chemical', 'MESH:C000591540', (146, 155))	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))	('MCF-12A', 'CellLine', 'CVCL:3744', (120, 127))
844087	32006900	The docking simulation for binding mode of C23 to the PPM1D phosphatase domain shows that C23 is buried into the catalytic site consisting of Asp105, Arg110, Arg243, Arg258, Arg259, Gln265, Phe268, Asp314, Arg364, Asp366, and Asn367.	('Phe268', 'Var', (190, 196))	('Asp314', 'Chemical', '-', (198, 204))	('Arg259', 'Chemical', '-', (174, 180))	('Arg258', 'Var', (166, 172))	('Arg364', 'Chemical', '-', (206, 212))	('Arg364', 'Var', (206, 212))	('Asp366', 'Chemical', '-', (214, 220))	('Arg259', 'Var', (174, 180))	('Phe268', 'Chemical', '-', (190, 196))	('Arg110', 'Chemical', '-', (150, 156))	('Asp314', 'Var', (198, 204))	('Arg243', 'Chemical', '-', (158, 164))	('Asn367', 'Chemical', '-', (226, 232))	('Arg258', 'Chemical', '-', (166, 172))	('Arg243', 'Var', (158, 164))	('Gln265', 'Var', (182, 188))	('Gln265', 'Chemical', '-', (182, 188))	('Arg110', 'Var', (150, 156))	('Asp366', 'Var', (214, 220))	('Asp105', 'Chemical', '-', (142, 148))	('Asp105', 'Var', (142, 148))	('Asn367', 'Var', (226, 232))
844088	32006900	The carbonyl oxygen atom and the nitrogen atom in C23 heteroaromatic ring form two hydrogen bonds with side chains of Arg258 and Asp105, which leads to a stable binding model of C23.	('Arg258', 'Var', (118, 124))	('leads to', 'Reg', (143, 151))	('binding', 'Interaction', (161, 168))	('C23', 'Gene', (50, 53))	('oxygen', 'Chemical', 'MESH:D010100', (13, 19))	('nitrogen', 'Chemical', 'MESH:D009584', (33, 41))	('hydrogen', 'Chemical', 'MESH:D006859', (83, 91))	('Asp105', 'Chemical', '-', (129, 135))	('Arg258', 'Chemical', '-', (118, 124))	('Asp105', 'Var', (129, 135))
844090	32006900	In addition to the direct inhibition of PPM1D phosphatase activity, C23 suppresses high glucose induction of PPM1D expression through heat shock protein 27 (HSP27) induction and subsequent inhibition of ROS/NF-kB pathway.	('OS', 'Phenotype', 'HP:0002669', (204, 206))	('ROS', 'Chemical', '-', (203, 206))	('high glucose', 'Phenotype', 'HP:0003074', (83, 95))	('high glucose induction', 'MPA', (83, 105))	('shock', 'Phenotype', 'HP:0031273', (139, 144))	('induction', 'PosReg', (164, 173))	('PPM1D', 'Gene', (109, 114))	('C23', 'Var', (68, 71))	('HSP27', 'Gene', (157, 162))	('expression', 'MPA', (115, 125))	('glucose', 'Chemical', 'MESH:D005947', (88, 95))	('heat shock protein 27', 'Gene', '3315', (134, 155))	('heat shock protein 27', 'Gene', (134, 155))	('HSP27', 'Gene', '3315', (157, 162))	('ROS/NF-kB pathway', 'Pathway', (203, 220))	('suppresses', 'NegReg', (72, 82))	('inhibition', 'NegReg', (189, 199))
844094	32006900	PPM1D phosphatase is an important negative regulator of p53 pathway and DNA damage response.	('age', 'Gene', (79, 82))	('PPM1D', 'Var', (0, 5))	('p53 pathway', 'Pathway', (56, 67))	('age', 'Gene', '5973', (79, 82))
844095	32006900	Overexpressed PPM1D damages p53 function and promotes tumorigenesis, generally in concert with activation of other oncogenes.	('PPM1D', 'Var', (14, 19))	('age', 'Gene', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('age', 'Gene', '5973', (23, 26))	('promotes', 'PosReg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('p53', 'Protein', (28, 31))	('function', 'MPA', (32, 40))
844096	32006900	Amplification, overexpression or mutation of PPM1D are closely related to many human tumors.	('human', 'Species', '9606', (79, 84))	('overexpression', 'PosReg', (15, 29))	('mutation', 'Var', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('PPM1D', 'Gene', (45, 50))	('related', 'Reg', (63, 70))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
844097	32006900	In contrast, loss of PPM1D dramatically postpones cancer development in mice and depletion of PPM1D by genetic approach reactivates p53 and hinders proliferation in p53-proficient cancers.	('p53', 'Protein', (132, 135))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('proliferation', 'CPA', (148, 161))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancers', 'Disease', (180, 187))	('depletion', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('PPM1D', 'Var', (94, 99))	('reactivates', 'NegReg', (120, 131))	('hinders', 'NegReg', (140, 147))	('mice', 'Species', '10090', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('loss', 'Var', (13, 17))	('cancer', 'Disease', (180, 186))	('postpones', 'NegReg', (40, 49))
844100	32006900	Notably, GSK2830371 is bioavailable by oral administration, and its ability to inhibit the growth of cancer cells in vivo has been confirmed in xenograft models.	('inhibit', 'NegReg', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('GSK2830371', 'Chemical', 'MESH:C587624', (9, 19))	('GSK2830371', 'Var', (9, 19))
844101	32006900	At the same time, GSK2830371 is promptly inactivated in plasma, limiting its further clinical application.	('limiting', 'NegReg', (64, 72))	('GSK2830371', 'Chemical', 'MESH:C587624', (18, 28))	('GSK2830371', 'Var', (18, 28))
844104	32006900	The existing studies show that the inhibition of PPM1D will be the most effective in cancers with WT p53 and amplification or mutations of PPM1D.	('PPM1D', 'Var', (49, 54))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('amplification', 'Var', (109, 122))	('mutations', 'Var', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('PPM1D', 'Gene', (139, 144))
844106	32006900	Although mice are well tolerated to loss of PPM1D, there is new evidence that a lack of PPM1D in the immune system induces an inflammatory environment.	('inflammatory environment', 'MPA', (126, 150))	('PPM1D', 'Var', (88, 93))	('mice', 'Species', '10090', (9, 13))	('induces', 'Reg', (115, 122))	('lack', 'Var', (80, 84))
844164	31124967	Wu et al found that the peptide p286-1Y2L9L of CD8+ T cell epitope was derived from cancer-testis antigen MAGE-4.	('CD8', 'Gene', (47, 50))	('cancer-testis', 'Disease', 'MESH:D013736', (84, 97))	('MAGE-4', 'Gene', '4103', (106, 112))	('CD8', 'Gene', '925', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('p286-1Y2L9L', 'Var', (32, 43))	('MAGE-4', 'Gene', (106, 112))	('cancer-testis', 'Disease', (84, 97))
844226	30867663	T4a tumor only invades the visceral peritoneum, and T4b invades adjacent structures.	('tumor', 'Disease', (4, 9))	('T4a', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
844243	28414310	Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance High CD44 expression is associated with enhanced malignant potential in esophageal squamous cell carcinoma (ESCC), amongst the deadliest of all human carcinomas.	('carcinomas', 'Disease', 'MESH:D002277', (294, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('human', 'Species', '9606', (288, 293))	('CD44', 'Gene', (149, 153))	('malignant potential', 'CPA', (193, 212))	('esophageal squamous cell carcinoma', 'Disease', (216, 250))	('High', 'Var', (144, 148))	('CD44', 'Gene', '960', (49, 53))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (216, 250))	('oxidative stress', 'Phenotype', 'HP:0025464', (83, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('CD44', 'Gene', (49, 53))	('enhanced', 'PosReg', (184, 192))	('CD44', 'Gene', '960', (149, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (294, 304))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (227, 250))	('carcinomas', 'Disease', (294, 304))
844244	28414310	Although alterations in autophagy and CD44 expression are associated with poor patient outcomes in various cancer types, the relationship between autophagy and cells with high CD44 expression remains incompletely understood.	('CD44', 'Gene', (176, 180))	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('alterations', 'Var', (9, 20))	('CD44', 'Gene', '960', (38, 42))	('patient', 'Species', '9606', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('CD44', 'Gene', (38, 42))	('expression', 'MPA', (43, 53))	('cancer', 'Disease', (107, 113))	('autophagy', 'CPA', (24, 33))	('CD44', 'Gene', '960', (176, 180))
844250	28414310	During CD44H cell generation, transformed keratinocytes display evidence of mitophagy, including mitochondrial fragmentation, decreased mitochondrial content and mitochondrial translocation of Parkin, essential in mitophagy.	('mitochondrial content', 'MPA', (136, 157))	('decreased', 'NegReg', (126, 135))	('CD44H', 'Chemical', '-', (7, 12))	('decreased mitochondrial content', 'Phenotype', 'HP:0040013', (126, 157))	('Parkin', 'Gene', (193, 199))	('mitochondrial fragmentation', 'CPA', (97, 124))	('mitophagy', 'CPA', (76, 85))	('mitochondrial translocation', 'MPA', (162, 189))	('CD44H', 'Var', (7, 12))
844251	28414310	RNA interference-mediated Parkin depletion attenuates CD44H cell generation.	('depletion', 'Var', (33, 42))	('attenuates', 'NegReg', (43, 53))	('CD44H cell generation', 'CPA', (54, 75))	('CD44H', 'Chemical', '-', (54, 59))	('RNA', 'MPA', (0, 3))
844254	28414310	Tumor cells with high CD44 expression have been linked to poor patient outcomes in human cancer Enhanced self-renewal, tumor-initiating capacity and chemoresistance have been attributed to subsets of cancer cells with high CD44 expression in esophageal squamous cell carcinoma (ESCC), among the deadliest of human cancers.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('esophageal squamous cell carcinoma', 'Disease', (242, 276))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (314, 321))	('cancer', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (314, 320))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Enhanced', 'PosReg', (96, 104))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (242, 276))	('CD44', 'Gene', '960', (223, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (253, 276))	('patient', 'Species', '9606', (63, 70))	('human', 'Species', '9606', (308, 313))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('CD44', 'Gene', (223, 227))	('self-renewal', 'CPA', (105, 117))	('cancers', 'Disease', 'MESH:D009369', (314, 321))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('tumor', 'Disease', (119, 124))	('cancer', 'Disease', (314, 320))	('high', 'Var', (218, 222))	('CD44', 'Gene', '960', (22, 26))	('human', 'Species', '9606', (83, 88))	('CD44', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Disease', (200, 206))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))
844271	28414310	High cleaved LC3 expression was detected in 43 of 129 informative cases (Figure 1A) and was associated with reduced cause-specific postsurgical survival (Figure 1B).	('reduced', 'NegReg', (108, 115))	('High cleaved', 'Var', (0, 12))	('LC3', 'Gene', (13, 16))	('LC3', 'Gene', '84557', (13, 16))
844272	28414310	Further review of clinicopathological data revealed that high cleaved LC3 correlated significantly with lymphatic and vascular involvement, lymph node and distant metastases, and advanced disease stage (Table 1).	('advanced disease', 'Disease', (179, 195))	('metastases', 'Disease', (163, 173))	('high cleaved', 'Var', (57, 69))	('LC3', 'Gene', '84557', (70, 73))	('advanced disease', 'Disease', 'MESH:D020178', (179, 195))	('LC3', 'Gene', (70, 73))	('metastases', 'Disease', 'MESH:D009362', (163, 173))
844276	28414310	Although neither agent significantly impacted TE11 tumor volume (Supplementary Figure S1C), tumors from Lys05-treated animals displayed a trend toward decreased volume and evidence of involution at a frequency of 50% as compared to 16.7% in vehicle-treated animals (Supplementary Table S1 and Supplementary Figure S1D).	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (51, 56))	('decreased', 'NegReg', (151, 160))	('involution', 'CPA', (184, 194))	('volume', 'MPA', (161, 167))	('TE11', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Lys05', 'Chemical', 'MESH:C573930', (104, 109))	('tumors', 'Disease', (92, 98))	('tumor', 'Disease', (92, 97))	('impacted', 'Reg', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('Lys05-treated', 'Var', (104, 117))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
844277	28414310	Additionally, 87.5% of tumors from HCQ-treated animals displayed cystic changes, as compared to 33.3% of tumors from vehicle-treated animals (Supplementary Table S1 and Supplementary Figure S1D).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('cystic changes', 'CPA', (65, 79))	('HCQ-treated', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('HCQ', 'Chemical', 'MESH:D006886', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
844278	28414310	As these findings suggest that autophagy inhibition is associated with less aggressive tumor phenotypes, we suspected that HCQ and Lys05 impacted cells with high CD44 expression and enhanced malignant potential in the context of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('expression', 'MPA', (167, 177))	('HCQ', 'Chemical', 'MESH:D006886', (123, 126))	('enhanced', 'PosReg', (182, 190))	('aggressive tumor', 'Disease', 'MESH:D001523', (76, 92))	('CD44', 'Gene', '960', (162, 166))	('Lys05', 'Chemical', 'MESH:C573930', (131, 136))	('malignant potential', 'CPA', (191, 210))	('CD44', 'Gene', (162, 166))	('Lys05', 'Var', (131, 136))	('aggressive tumor', 'Disease', (76, 92))
844279	28414310	Indeed, HCQ or Lys05 decreased intratumoral content of ESCC cells with high CD44 expression (Figure 2A, B) as well as those with EMT characteristics (Figure 2C).	('CD44', 'Gene', '960', (76, 80))	('CD44', 'Gene', (76, 80))	('decreased', 'NegReg', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('HCQ', 'Chemical', 'MESH:D006886', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Lys05', 'Chemical', 'MESH:C573930', (15, 20))	('tumor', 'Disease', (36, 41))	('expression', 'MPA', (81, 91))	('Lys05', 'Var', (15, 20))
844282	28414310	Both HCQ and Lys05 enhanced expression of Histone H2A.X phosphorylated at Serine 139 (p-H2A.XSer139), a surrogate marker for oxidative stress (Figure 2D).	('Serine', 'Chemical', 'MESH:D012694', (74, 80))	('Lys05', 'Chemical', 'MESH:C573930', (13, 18))	('HCQ', 'Chemical', 'MESH:D006886', (5, 8))	('expression', 'MPA', (28, 38))	('XSer139', 'Chemical', '-', (92, 99))	('Lys05', 'Var', (13, 18))	('oxidative stress', 'Phenotype', 'HP:0025464', (125, 141))	('p-H2A', 'Mutation', 'p.H2A', (86, 91))	('enhanced', 'PosReg', (19, 27))
844288	28414310	The mesenchymal nature of CD44H cells was further confirmed upon epithelial reconstitution studies in 3-dimensional (3D) organotypic culture (OTC) where CD44H cells exhibited invasion and robust alpha-smooth muscle actin expression (alphaSMA)(Supplementary Figure S5A).	('alpha-smooth', 'MPA', (195, 207))	('CD44H', 'Var', (153, 158))	('invasion', 'CPA', (175, 183))	('CD44H', 'Chemical', '-', (153, 158))	('CD44H', 'Chemical', '-', (26, 31))
844290	28414310	Purified CD44H cells also displayed properties consistent with enhanced malignant potential, including colony formation capability and resistance to 5-fluorouracil (5FU) and cisplatin (CDDP) (Supplementary Figure S5B, C), as well as expression of genes associated with stemness, including WNT5A, BMI1 and KLF4 (Supplementary Figure S5D).	('expression', 'MPA', (233, 243))	('CD44H', 'Chemical', '-', (9, 14))	('WNT5A', 'Gene', (289, 294))	('KLF4', 'Gene', '9314', (305, 309))	('enhanced', 'PosReg', (63, 71))	('CD44H', 'Var', (9, 14))	('S5B', 'Gene', (213, 216))	('BMI1', 'Gene', '648', (296, 300))	('WNT5A', 'Gene', '7474', (289, 294))	('Supplementary Figure S5D', 'Disease', (311, 335))	('cisplatin', 'Chemical', 'MESH:D002945', (174, 183))	('malignant potential', 'CPA', (72, 91))	('S5B', 'Gene', '5711', (213, 216))	('resistance', 'MPA', (135, 145))	('KLF4', 'Gene', (305, 309))	('colony formation capability', 'CPA', (103, 130))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (149, 163))	('CDDP', 'Chemical', 'MESH:D002945', (185, 189))	('Supplementary Figure S5D', 'Disease', 'MESH:D017034', (311, 335))	('BMI1', 'Gene', (296, 300))	('5FU', 'Chemical', 'MESH:D005472', (165, 168))
844291	28414310	CD44 isoform switching as a result of alternative splicing has been described during EMT.	('CD44', 'Gene', '960', (0, 4))	('CD44', 'Gene', (0, 4))	('alternative splicing', 'Var', (38, 58))
844307	28414310	A time course study revealed that purified EPC2T CD44L cells displayed LC3-II induction 24 hours following TGF-beta stimulation (Figure 5C), indicating that AV accumulation is an early event in keratinocyte EMT.	('EPC2T', 'CellLine', 'CVCL:4361', (43, 48))	('TGF-beta', 'Gene', (107, 115))	('CD44', 'Gene', '960', (49, 53))	('EPC2T', 'Var', (43, 48))	('AV', 'Chemical', '-', (157, 159))	('LC3', 'Gene', '84557', (71, 74))	('CD44', 'Gene', (49, 53))	('LC3', 'Gene', (71, 74))	('TGF-beta', 'Gene', '7040', (107, 115))
844311	28414310	To distinguish between these possibilities, we carried out autophagic flux assays utilizing CQ at a concentration of 1 mug/ml, the dose at which AV accumulation was maximal in EPC2T cells without significant induction of apoptosis (Supplementary Figure S10A, B).	('EPC2T', 'Var', (176, 181))	('AV', 'Chemical', '-', (145, 147))	('S10A', 'SUBSTITUTION', 'None', (253, 257))	('EPC2T', 'CellLine', 'CVCL:4361', (176, 181))	('S10A', 'Var', (253, 257))	('CQ', 'Chemical', 'MESH:D002738', (92, 94))
844312	28414310	In purified CD44L EPC2T cells, AV accumulation was detected by Cyto-ID flow cytometry and LC3-II protein expression upon treatment with TGF-beta or CQ, with further upregulation upon co-treatment (Figure 6A, B), This suggests enhanced autophagy flux in keratinocytes undergoing TGF-beta-mediated EMT, a finding that was corroborated in OKF6T cells (Supplementary Figure S11A).	('TGF-beta', 'Gene', '7040', (278, 286))	('CD44', 'Gene', '960', (12, 16))	('AV', 'Chemical', '-', (31, 33))	('TGF-beta', 'Gene', (278, 286))	('enhanced', 'PosReg', (226, 234))	('S11A', 'Var', (370, 374))	('autophagy flux', 'CPA', (235, 249))	('LC3', 'Gene', '84557', (90, 93))	('CD44', 'Gene', (12, 16))	('LC3', 'Gene', (90, 93))	('S11A', 'SUBSTITUTION', 'None', (370, 374))	('OKF6T', 'CellLine', 'CVCL:L222', (336, 341))	('CQ', 'Chemical', 'MESH:D002738', (148, 150))	('EPC2T', 'CellLine', 'CVCL:4361', (18, 23))	('TGF-beta', 'Gene', '7040', (136, 144))	('upregulation', 'PosReg', (165, 177))	('TGF-beta', 'Gene', (136, 144))
844314	28414310	Moreover, TGF-beta-mediated CD44H cell expansion was significantly attenuated in the presence of CQ in both EPC2T and OKF6T cells (Figure 6E, F; Supplementary Figure S11B), indicating that autophagic flux is required for EMT-mediated CD44L to CD44H cell conversion in esophageal and oral keratinocytes.	('CD44', 'Gene', '960', (243, 247))	('TGF-beta', 'Gene', (10, 18))	('CD44H', 'Chemical', '-', (28, 33))	('OKF6T', 'CellLine', 'CVCL:L222', (118, 123))	('CD44', 'Gene', (243, 247))	('CQ', 'Chemical', 'MESH:D002738', (97, 99))	('CD44', 'Gene', '960', (234, 238))	('attenuated', 'NegReg', (67, 77))	('CD44', 'Gene', '960', (28, 32))	('S11B', 'SUBSTITUTION', 'None', (166, 170))	('CD44', 'Gene', (234, 238))	('S11B', 'Var', (166, 170))	('TGF-beta', 'Gene', '7040', (10, 18))	('EPC2T', 'CellLine', 'CVCL:4361', (108, 113))	('CD44', 'Gene', (28, 32))	('CD44H', 'Chemical', '-', (243, 248))
844319	28414310	OKF6T cells also displayed enhanced cell death and ROS upon co-treatment with TGF-beta and CQ (Supplementary Figure S12A, B).	('cell death', 'CPA', (36, 46))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('enhanced', 'PosReg', (27, 35))	('ROS', 'CPA', (51, 54))	('S12A', 'SUBSTITUTION', 'None', (116, 120))	('OKF6T', 'CellLine', 'CVCL:L222', (0, 5))	('S12A', 'Var', (116, 120))	('CQ', 'Chemical', 'MESH:D002738', (91, 93))	('TGF-beta', 'Gene', '7040', (78, 86))	('TGF-beta', 'Gene', (78, 86))
844325	28414310	A requirement for mitophagy in CD44H cell generation was evident as genetic depletion of PARK2 suppressed TGF-beta-mediated CD44H cell expansion to level comparable to that seen with inhibition of BECN1 (Figure 9E; Supplementary Figure S14).	('TGF-beta', 'Gene', (106, 114))	('suppressed', 'NegReg', (95, 105))	('PARK2', 'Gene', (89, 94))	('BECN1', 'Gene', (197, 202))	('CD44H', 'Chemical', '-', (31, 36))	('CD44H', 'Chemical', '-', (124, 129))	('TGF-beta', 'Gene', '7040', (106, 114))	('BECN1', 'Gene', '8678', (197, 202))	('depletion', 'Var', (76, 85))	('PARK2', 'Gene', '5071', (89, 94))
844336	28414310	We also demonstrate that mitophagy is activated during EMT-mediated CD44H expansion, facilitating clearance of dysfunctional mitochondria and modulation of oxidative stress (Figures 9-10).	('dysfunctional mitochondria', 'Disease', (111, 137))	('CD44H', 'Chemical', '-', (68, 73))	('modulation', 'Reg', (142, 152))	('CD44H expansion', 'Var', (68, 83))	('oxidative stress', 'MPA', (156, 172))	('mitophagy', 'CPA', (25, 34))	('activated', 'PosReg', (38, 47))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (111, 137))	('oxidative stress', 'Phenotype', 'HP:0025464', (156, 172))
844353	28414310	As such, it is tempting to speculate that differential cell fates induced by TGF-beta in non-transformed (wild type p53) and transformed (overexpression of mutant p53, EGFR and Cyclin D1) esophageal keratinocytes may be related to the ability of these cells to modulate mitophagy via p53.	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('mitophagy', 'CPA', (270, 279))	('Cyclin D1', 'Gene', '595', (177, 186))	('p53', 'Gene', (163, 166))	('p53', 'Gene', '7157', (163, 166))	('Cyclin D1', 'Gene', (177, 186))	('p53', 'Gene', '7157', (116, 119))	('TGF-beta', 'Gene', '7040', (77, 85))	('p53', 'Gene', (284, 287))	('induced', 'Reg', (66, 73))	('p53', 'Gene', '7157', (284, 287))	('mutant', 'Var', (156, 162))	('modulate', 'Reg', (261, 269))	('TGF-beta', 'Gene', (77, 85))	('p53', 'Gene', (116, 119))
844354	28414310	In addition to regulating ROS, mitophagy may be activated by ROS, including O2-.	('O2', 'Chemical', 'MESH:D013481', (76, 78))	('ROS', 'Var', (61, 64))	('ROS', 'MPA', (26, 29))	('mitophagy', 'CPA', (31, 40))	('activated', 'PosReg', (48, 57))	('ROS', 'Chemical', 'MESH:D017382', (26, 29))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
844360	28414310	In a cohort of chemoradiotherapy naive ESCC patients, we demonstrate that high cleaved LC3 expression correlates with poor clinical outcome, consistent with the findings of Hao et al.	('expression', 'MPA', (91, 101))	('patients', 'Species', '9606', (44, 52))	('high', 'Var', (74, 78))	('LC3', 'Gene', '84557', (87, 90))	('LC3', 'Gene', (87, 90))
844361	28414310	Pharmacological autophagy or mitophagy impairment in ESCC xenograft tumors decreased intratumoral content of cells with high CD44 expression (Figures 2 and 10), supporting autophagy as tumor-promoting factor in ESCC.	('tumor', 'Disease', (68, 73))	('CD44', 'Gene', (125, 129))	('tumor', 'Disease', (185, 190))	('expression', 'MPA', (130, 140))	('mitophagy impairment in ESCC xenograft tumors', 'Disease', 'MESH:D004938', (29, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('high', 'Var', (120, 124))	('tumor', 'Disease', (90, 95))	('mitophagy impairment in ESCC xenograft tumors', 'Disease', (29, 74))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CD44', 'Gene', '960', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('decreased', 'NegReg', (75, 84))
844362	28414310	Given the association between high cleaved LC3 expression and metastasis in ESCC patients (Table 1), it is of interest to determine the influence of autophagy or mitophagy inhibition upon ESCC metastasis.	('LC3', 'Gene', (43, 46))	('metastasis', 'CPA', (62, 72))	('high cleaved', 'Var', (30, 42))	('patients', 'Species', '9606', (81, 89))	('LC3', 'Gene', '84557', (43, 46))	('ESCC', 'Disease', (76, 80))	('expression', 'MPA', (47, 57))
844363	28414310	Our findings offer pretreatment with autophagy or mitophagy inhibitors as a mechanism to deplete cells with high CD44 expression and induce oxidative stress prior to intervention with neoadjuvant therapies, many of which require ROS for tumoricidal activity.	('CD44', 'Gene', '960', (113, 117))	('tumor', 'Disease', (237, 242))	('oxidative stress', 'Phenotype', 'HP:0025464', (140, 156))	('CD44', 'Gene', (113, 117))	('ROS', 'Chemical', 'MESH:D017382', (229, 232))	('high', 'Var', (108, 112))	('deplete', 'NegReg', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('expression', 'MPA', (118, 128))	('oxidative stress', 'MPA', (140, 156))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('induce', 'Reg', (133, 139))
844375	28414310	siRNA sequences directed against PARK2 (Silencer Select s224170 and s10043; 10 nm; Thermo Fisher Scientific), BECN1 (BECN1; Silencer Select s16537 and s16358; 10 nm; Thermo Fisher Scientific) or a non-silencing control sequence (Silencer Select Negative Control #1; 10 nm; Thermo Fisher Scientific) were transfected with Lipofectamine RNAi Max reagent (Thermo Fisher Scientific) as described previously.	('BECN1', 'Gene', '8678', (117, 122))	('s16358', 'Var', (151, 157))	('s10043', 'Var', (68, 74))	('Lipofectamine', 'Chemical', 'MESH:C086724', (321, 334))	('BECN1', 'Gene', '8678', (110, 115))	('PARK2', 'Gene', '5071', (33, 38))	('PARK2', 'Gene', (33, 38))	('BECN1', 'Gene', (117, 122))	('BECN1', 'Gene', (110, 115))
844377	28414310	The following TaqMan  gene expression assays were utilized: Hs01081473_m1 for CD44s, Hs01081480_m1 for CD44v3-v10, and Hs1075866_m1 for CD44v2-v10.	('CD44s', 'Gene', (78, 83))	('Hs01081480_m1', 'Var', (85, 98))	('CD44', 'Gene', (78, 82))	('CD44', 'Gene', '960', (136, 140))	('CD44', 'Gene', (136, 140))	('CD44', 'Gene', '960', (103, 107))	('Hs1075866_m1', 'Var', (119, 131))	('CD44s', 'Gene', '960', (78, 83))	('Hs01081473_m1', 'Var', (60, 73))	('CD44', 'Gene', (103, 107))	('CD44', 'Gene', '960', (78, 82))
844392	28414310	Western blotting was performed as described previously using the following primary antibodies: rabbit anti-LC3B (1:1000; 2775; Cell Signaling Technology), mouse anti-p62/SQSTM1 (D-3) (1:1000; sc-28359; Cell Signaling Technology), rabbit anti-Beclin1 antibody (1:1000; 3738; Cell Signaling Technology), mouse anti-E-cadherin (1:10000; 610182; BD Biosciences), mouse anti-N-cadherin (1:1000; 610921; BD Biosciences), and mouse anti-beta-Actin (AC-74) (1:10000; A5316; Sigma-Aldrich).	('N-cadherin', 'Gene', (370, 380))	('1:1000; 610921', 'Var', (382, 396))	('N-cadherin', 'Gene', '1000', (370, 380))	('SQSTM1', 'Gene', '8878', (170, 176))	('mouse', 'Species', '10090', (302, 307))	('LC3B', 'Gene', (107, 111))	('p62', 'Gene', '8878', (166, 169))	('p62', 'Gene', (166, 169))	('LC3B', 'Gene', '81631', (107, 111))	('mouse', 'Species', '10090', (419, 424))	('beta-Actin', 'Gene', (430, 440))	('E-cadherin', 'Gene', (313, 323))	('Beclin1', 'Gene', '8678', (242, 249))	('E-cadherin', 'Gene', '999', (313, 323))	('beta-Actin', 'Gene', '728378', (430, 440))	('rabbit', 'Species', '9986', (95, 101))	('mouse', 'Species', '10090', (155, 160))	('rabbit', 'Species', '9986', (230, 236))	('SQSTM1', 'Gene', (170, 176))	('mouse', 'Species', '10090', (359, 364))	('Beclin1', 'Gene', (242, 249))
844400	28414310	Anti-CD44 clone G44-26 recognizes an epitope in the extracellular amino-terminal region of CD44 which consists of the nonvariable exons 1 to 5, allowing for detection of the standard isoforms of CD44 as well as variant isoforms.	('variant', 'Var', (211, 218))	('CD44', 'Gene', (5, 9))	('detection', 'Reg', (157, 166))	('CD44', 'Gene', '960', (91, 95))	('CD44', 'Gene', '960', (195, 199))	('CD44', 'Gene', (91, 95))	('CD44', 'Gene', (195, 199))	('CD44', 'Gene', '960', (5, 9))
844417	28840196	Trapping and proliferation of target cells on C60 fullerene nano fibres The ratio of the surface area to the volume of materials increases in inverse proportion to their size and therefore the surface area of nanostructures and nanomaterials is extremely large compared to that of macroscopic materials of the same volume, thanks to which it is supposed that chemical and biochemical reactions may be greatly enhanced and target molecules and cells may be efficiently trapped on the surface of nanomaterials.	('enhanced', 'PosReg', (409, 417))	('fullerene', 'Chemical', 'MESH:D037741', (50, 59))	('C60', 'Var', (46, 49))
844466	28840196	We also investigated the proliferation of TE2 and DLD-1 cells trapped on the antibody, which had been immobilised on the surface of the fibres, and found that the growth rate of the cells trapped on the anti-EpCAM/GMBS/MPTMS/C60-fibres was higher than that of the native cells.	('anti-EpCAM/GMBS/MPTMS/C60-fibres', 'Var', (203, 235))	('growth rate', 'CPA', (163, 174))	('GMBS', 'Chemical', 'MESH:C032138', (214, 218))	('MPTMS', 'Chemical', 'MESH:C102833', (219, 224))	('higher', 'PosReg', (240, 246))
844471	28431406	The activated ERK downregulates STAT1 expression in ESCC cell lines and U0126 increases expression of STAT1.	('ERK', 'Gene', (14, 17))	('U0126', 'Chemical', 'MESH:C113580', (72, 77))	('expression', 'MPA', (38, 48))	('downregulates', 'NegReg', (18, 31))	('STAT1', 'Gene', (32, 37))	('increases', 'PosReg', (78, 87))	('U0126', 'Var', (72, 77))	('expression', 'MPA', (88, 98))
844487	28431406	By studying ESCC cell lines and tumor samples collected from the Chaoshan areas, we previously published that STAT1 is a tumor suppressor of ESCC and this protein is frequently down-regulated in ESCC; importantly, the STAT1low phenotype significantly correlates with a worse clinical outcome.	('down-regulated', 'NegReg', (177, 191))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (121, 126))	('STAT1', 'Gene', (110, 115))	('ESCC', 'Disease', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('STAT1low', 'Var', (218, 226))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
844488	28431406	In mouse embryonic fibroblasts, it was found that ERK mediates STAT1 phosphorylation at S727 and increases proteasomal degradation of STAT1.	('at S727', 'Var', (85, 92))	('mouse', 'Species', '10090', (3, 8))	('increases', 'PosReg', (97, 106))	('ERK', 'Gene', (50, 53))	('proteasomal degradation', 'MPA', (107, 130))	('STAT1 phosphorylation', 'MPA', (63, 84))	('S727', 'Var', (88, 92))
844491	28431406	The importance of the ERK/STAT1 axis in ESCC is highlighted by the observation that the ERKhigh/STAT1low phenotype significantly correlates with a worse clinical outcome in ESCC patients.	('ERKhigh/STAT1low', 'Var', (88, 104))	('patients', 'Species', '9606', (178, 186))	('ESCC', 'Disease', (173, 177))
844493	28431406	In keeping with this hypothesis, treatment of KYSE510 and KYSE150 with varying concentrations (0-10 muM) of U0126, a MEK/ERK inhibitor, increased the levels of STAT1 and p-STAT1 in a dose-dependent manner (Figure 1A).	('men', 'Species', '9606', (38, 41))	('increased', 'PosReg', (136, 145))	('KYSE150', 'CellLine', 'CVCL:1348', (58, 65))	('muM', 'Gene', '56925', (100, 103))	('p-STAT1', 'MPA', (170, 177))	('U0126', 'Chemical', 'MESH:C113580', (108, 113))	('MEK', 'Gene', (117, 120))	('STAT1', 'MPA', (160, 165))	('muM', 'Gene', (100, 103))	('MEK', 'Gene', '5609', (117, 120))	('U0126', 'Gene', (108, 113))	('levels', 'MPA', (150, 156))	('KYSE150', 'Var', (58, 65))	('KYSE510', 'Var', (46, 53))
844495	28431406	Since KYSE150 expresses a relatively low level of p-STAT1 serine 727 at the steady state, we can't detect it by using western blots which subjected to a longer exposure.	('KYSE150', 'CellLine', 'CVCL:1348', (6, 13))	('p-STAT1 serine 727', 'MPA', (50, 68))	('KYSE150', 'Var', (6, 13))	('serine', 'Chemical', 'MESH:D012694', (58, 64))
844496	28431406	As shown in Figure 1B, transfection of the HA-tagged, MEK1 plasmid resulted in further reduction of STAT1 and p-STAT1 in KYSE150 cell line.	('MEK1', 'Gene', '5604', (54, 58))	('MEK1', 'Gene', (54, 58))	('transfection', 'Var', (23, 35))	('p-STAT1', 'MPA', (110, 117))	('KYSE150', 'CellLine', 'CVCL:1348', (121, 128))	('reduction', 'NegReg', (87, 96))	('STAT1', 'MPA', (100, 105))
844504	28431406	Poor cell differentiation and high p-ERK staining were found to be independent risk factors for ESCC patients (relative risk = 1.45 and 2.27, respectively).	('p-ERK', 'Gene', '9451', (35, 40))	('patients', 'Species', '9606', (101, 109))	('Poor cell differentiation', 'CPA', (0, 25))	('p-ERK', 'Gene', (35, 40))	('high', 'Var', (30, 34))	('ESCC patients', 'Disease', (96, 109))
844508	28431406	Specifically, patients with tumors that are p-ERKlow and STAT1high expression survived significantly longer than the other 3 groups.	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('STAT1high expression', 'Var', (57, 77))	('p-ERK', 'Gene', '9451', (44, 49))	('p-ERK', 'Gene', (44, 49))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
844521	28431406	In the same study, we found that patients with STAT1 low tumors had a significantly worse clinical outcome; gene transfection of STAT1 into ESCC cells was found to effectively induce apoptosis, highlighting the biological importance of STAT1 in this tumor.	('gene transfection', 'Var', (108, 125))	('patients', 'Species', '9606', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('induce', 'PosReg', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('STAT1', 'Gene', (129, 134))	('low tumors', 'Disease', 'MESH:D009800', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (57, 62))	('apoptosis', 'CPA', (183, 192))	('tumor', 'Disease', (250, 255))	('low tumors', 'Disease', (53, 63))
844526	28431406	Specifically, the inhibition of the ERK pathway represents an efficient way of blocking proliferation, metastasis, and angiogenesis in cancer cells.	('blocking', 'NegReg', (79, 87))	('cancer', 'Disease', (135, 141))	('inhibition', 'Var', (18, 28))	('angiogenesis', 'CPA', (119, 131))	('ERK pathway', 'Pathway', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('proliferation', 'CPA', (88, 101))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('metastasis', 'CPA', (103, 113))
844527	28431406	Since ERK fulfills an essential role in responding to hepatocyte growth factor (HGF), the obstruction of this pathway downregulates the hypoxia-inducible factor 1a (HIF-1a), a master regulator of angiogenesis, as well as MMP-3/-9/-14 and CD44, important regulators of cell invasion.	('HIF-1a', 'Gene', '3091', (165, 171))	('HIF-1a', 'Gene', (165, 171))	('HGF', 'Gene', '3082', (80, 83))	('CD44', 'Gene', '960', (238, 242))	('hepatocyte growth factor', 'Gene', '3082', (54, 78))	('hypoxia-inducible factor 1a', 'Gene', '3091', (136, 163))	('CD44', 'Gene', (238, 242))	('hypoxia-inducible factor 1a', 'Gene', (136, 163))	('obstruction', 'Var', (90, 101))	('HGF', 'Gene', (80, 83))	('hepatocyte growth factor', 'Gene', (54, 78))	('downregulates', 'NegReg', (118, 131))
844530	28431406	In this paper, we found high p-ERK expression was a significant risk factor for ESCC patients, however, the total ERK expression did not show significance.	('p-ERK', 'Gene', '9451', (29, 34))	('expression', 'MPA', (35, 45))	('p-ERK', 'Gene', (29, 34))	('patients', 'Species', '9606', (85, 93))	('high', 'Var', (24, 28))	('ESCC patients', 'Disease', (80, 93))
844531	28431406	The possible reason is that the phosphorylation at both the threonine 202 and tyrosine 204 residues of ERK1 or threonine 185 and tyrosine 187 residues of ERK2 is required for full enzymatic activation of ERK.	('tyrosine 187', 'Var', (129, 141))	('threonine', 'Chemical', 'MESH:D013912', (111, 120))	('ERK2', 'Gene', (154, 158))	('ERK1', 'Gene', '5595', (103, 107))	('tyrosine', 'Chemical', 'MESH:D014443', (78, 86))	('tyrosine', 'Chemical', 'MESH:D014443', (129, 137))	('threonine 185', 'Var', (111, 124))	('ERK1', 'Gene', (103, 107))	('threonine', 'Chemical', 'MESH:D013912', (60, 69))	('phosphorylation', 'MPA', (32, 47))	('tyrosine 204', 'Var', (78, 90))	('ERK2', 'Gene', '5594', (154, 158))
844561	27242341	Dosimetric comparison of carbon ion and X-ray radiotherapy for Stage IIIA non-small cell lung cancer The present study compared the dose-volume histograms of patients with Stage IIIA non-small cell lung cancer (NSCLC) treated with carbon ion radiotherapy with those of patients treated with X-ray radiotherapy.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (187, 209))	('non-small cell lung cancer', 'Disease', (74, 100))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('patients', 'Species', '9606', (158, 166))	('patients', 'Species', '9606', (269, 277))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (183, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (74, 100))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))	('cancer', 'Disease', (94, 100))	('non-small cell lung cancer', 'Disease', (183, 209))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (78, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (203, 209))	('NSCLC', 'Disease', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (74, 100))	('carbon', 'Chemical', 'MESH:D002244', (25, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (183, 209))	('Stage IIIA', 'Var', (172, 182))	('carbon', 'Chemical', 'MESH:D002244', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
844571	27242341	The RTOG0617 study, which compared high-dose and standard-dose radiotherapies for Stage IIIA and IIIB NSCLC, showed that patients treated with high-dose radiotherapy had a worse clinical outcome than those treated with standard doses.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('high-dose radiotherapy', 'Var', (143, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('NSCLC', 'Disease', (102, 107))	('patients', 'Species', '9606', (121, 129))
844594	27242341	The clinical stage of the patients was T1-3N2M0 (n = 9) and T3N1M0 (n = 1) (Table 1).	('T1-3N2M0', 'Var', (39, 47))	('T3N1M0', 'Var', (60, 66))	('patients', 'Species', '9606', (26, 34))
844612	27242341	The following dosimetric parameters were assessed: the dose covering 2% of the target volume (D2%), D50%, D95%, D98%, and the homogeneity index (HI) for PTVs.	('D95%', 'Var', (106, 110))	('PTV', 'Chemical', '-', (153, 156))	('D50', 'Var', (100, 103))	('D98%', 'Var', (112, 116))
844615	27242341	There was no difference between the two treatments in D95% for PTV1, which included prophylactic lymph nodes.	('PTV1', 'Gene', (63, 67))	('D95', 'Var', (54, 57))	('PTV', 'Chemical', '-', (63, 66))
844623	27242341	Maximum spinal cord dose, esophageal V50, bone V10, V30 and V50, and trachea & PBT V50 were lower with carbon ion radiotherapy than with X-ray radiotherapy.	('carbon', 'Chemical', 'MESH:D002244', (103, 109))	('esophageal V50', 'CPA', (26, 40))	('trachea &', 'CPA', (69, 78))	('V50', 'Var', (60, 63))	('were', 'NegReg', (87, 91))	('V30', 'MPA', (52, 55))	('bone V10', 'CPA', (42, 50))
844629	27242341	There is increased transmission of X-rays and the lateral scatter of electrons out of the beam pathway can lead to an increased penumbra width in low-density tissue compared with in water-density tissue.	('penumbra', 'MPA', (128, 136))	('transmission', 'MPA', (19, 31))	('increased', 'PosReg', (9, 18))	('increased', 'PosReg', (118, 127))	('low-density', 'Var', (146, 157))	('rays', 'Species', '255564', (37, 41))
844643	27242341	One randomized Phase III trial of X-ray radiotherapy with chemotherapy for NSCLC showed that Grade 3 or greater esophagitis occurs in 14% of patients treated with cisplatin and docetaxel, and in 6% of patients treated with mitomycin, vindesine and cisplatin.	('Grade', 'Disease', (93, 98))	('patients', 'Species', '9606', (201, 209))	('vindesine', 'Chemical', 'MESH:D014751', (234, 243))	('esophagitis', 'Phenotype', 'HP:0100633', (112, 123))	('esophagitis', 'Disease', 'MESH:D004941', (112, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (248, 257))	('esophagitis', 'Disease', (112, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('docetaxel', 'Chemical', 'MESH:D000077143', (177, 186))	('NSCLC', 'Disease', (75, 80))	('mitomycin', 'Chemical', 'MESH:D016685', (223, 232))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('cisplatin', 'Var', (163, 172))	('patients', 'Species', '9606', (141, 149))
844645	27242341	Esophageal mean dose and V50 were significantly lower with carbon ion radiotherapy than with X-ray radiotherapy.	('lower', 'NegReg', (48, 53))	('carbon ion radiotherapy', 'Var', (59, 82))	('carbon', 'Chemical', 'MESH:D002244', (59, 65))	('Esophageal mean dose', 'MPA', (0, 20))	('V50', 'MPA', (25, 28))
844737	26169148	Our finding of a possible inverse association between anthocyanidin intake and BE is consistent with two previous studies of esophageal adenocarcinoma conducted in the U.S. that found a significant decrease in odds of invasive cancer associated with increased anthocyanidin intake.	('decrease', 'NegReg', (198, 206))	('esophageal adenocarcinoma', 'Disease', (125, 150))	('inverse', 'NegReg', (26, 33))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (125, 150))	('invasive cancer', 'Disease', (218, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('anthocyanidin', 'Chemical', 'MESH:D000872', (54, 67))	('invasive cancer', 'Disease', 'MESH:D009362', (218, 233))	('anthocyanidin', 'Chemical', 'MESH:D000872', (260, 273))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (125, 150))	('anthocyanidin intake', 'Var', (260, 280))
844808	26161051	CMV has been associated with gastric ulceration in immunocompromised hosts, in whom it can cause multiple large, shallow ulcerations.	('gastric ulceration', 'Disease', 'MESH:D013276', (29, 47))	('associated', 'Reg', (13, 23))	('CMV', 'Var', (0, 3))	('gastric ulceration', 'Disease', (29, 47))
844867	24829644	Alterations in oncogenes, tumor suppressor genes as well as alterations in microRNA expression have been known to involve in the pathogenesis of ESCC.	('involve', 'Reg', (114, 121))	('Alterations', 'Var', (0, 11))	('oncogenes', 'Protein', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('microRNA', 'Protein', (75, 83))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('alterations', 'Var', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('ESCC', 'Disease', (145, 149))
844874	24829644	Mutations in p53 and MTS1 genes have been reported in ESCC cases.	('ESCC cases', 'Disease', (54, 64))	('MTS1', 'Gene', '1029', (21, 25))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('reported', 'Reg', (42, 50))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('MTS1', 'Gene', (21, 25))	('p53', 'Gene', '7157', (13, 16))
844876	24829644	have reported that p53 protein accumulation occurs quite frequently in ESD cases, therefore concluding that the p53 mutation is an early event in the pathogenesis of ESCC.	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('mutation', 'Var', (116, 124))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '7157', (112, 115))	('ESCC', 'Disease', (166, 170))
844878	24829644	According to these researchers, Rb LOH was significantly more frequent in tumors with p53 mutations.	('Rb', 'Phenotype', 'HP:0009919', (32, 34))	('mutations', 'Var', (90, 99))	('p53', 'Gene', '7157', (86, 89))	('Rb', 'Gene', '5925', (32, 34))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('p53', 'Gene', (86, 89))
844879	24829644	They have concluded that concurrent alteration of Rb and p53 genes is an important mechanism for the development of ESCC.	('Rb', 'Phenotype', 'HP:0009919', (50, 52))	('Rb', 'Gene', '5925', (50, 52))	('alteration', 'Var', (36, 46))	('ESCC', 'Disease', (116, 120))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('p53', 'Gene', (57, 60))	('p53', 'Gene', '7157', (57, 60))
844880	24829644	The results of a study from Japan have shown that alteration of the deleted in lung cancer 1 (DLC1) gene may be involved in development of ESCC.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('involved', 'Reg', (112, 120))	('alteration', 'Var', (50, 60))	('SCC', 'Phenotype', 'HP:0002860', (140, 143))	('lung cancer', 'Disease', (79, 90))	('DLC1', 'Gene', '10395', (94, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('DLC1', 'Gene', (94, 98))	('ESCC', 'Disease', (139, 143))
844884	24829644	Therefore, it was proposed that alterations in the APC and MCC genes have important roles in the pathogenesis and progression of ESCC.	('roles', 'Reg', (84, 89))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('ESCC', 'Disease', (129, 133))	('APC', 'Phenotype', 'HP:0005227', (51, 54))	('alterations', 'Var', (32, 43))	('MCC genes', 'Gene', (59, 68))	('APC', 'Disease', 'MESH:D011125', (51, 54))	('APC', 'Disease', (51, 54))
844886	24829644	Inactivation of the WW domain containing oxireductase (WWO X) gene, as reported by Kuroki et al.	('WW domain containing oxireductase', 'Gene', '51741', (20, 53))	('WWO X', 'Gene', (55, 60))	('WWO X', 'Gene', '51741', (55, 60))	('WW domain containing oxireductase', 'Gene', (20, 53))	('Inactivation', 'Var', (0, 12))
844899	24829644	have proposed that inactivation of the FEZ1 gene may play a role in the development of ESCC.	('FEZ1', 'Gene', (39, 43))	('play', 'Reg', (53, 57))	('role', 'Reg', (60, 64))	('FEZ1', 'Gene', '9638', (39, 43))	('ESCC', 'Disease', (87, 91))	('inactivation', 'Var', (19, 31))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))
844904	24829644	Overexpression of the gene amplified in squamous cell carcinoma 1 (GASC1) was also shown to be related to the development of ESCC.	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('GASC1', 'Gene', (67, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('squamous cell carcinoma', 'Disease', (40, 63))	('Overexpression', 'Var', (0, 14))	('GASC1', 'Gene', '23081', (67, 72))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (40, 63))	('related to', 'Reg', (95, 105))	('ESCC', 'Disease', (125, 129))
844905	24829644	suggested the inactivation of esophageal cancer related gene 4 (ECRG4) due to hypermethylation as an important mechanism in the development of ESCC.	('esophageal cancer related gene 4', 'Gene', '84417', (30, 62))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('ECRG4', 'Gene', (64, 69))	('esophageal cancer related gene 4', 'Gene', (30, 62))	('inactivation', 'NegReg', (14, 26))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('ESCC', 'Disease', (143, 147))	('ECRG4', 'Gene', '84417', (64, 69))	('hypermethylation', 'Var', (78, 94))
844910	24829644	Allelic losses on chromosomes 5q  and 17q  were found in ESCC patients.	('ESCC', 'Disease', (57, 61))	('Allelic losses', 'Var', (0, 14))	('patients', 'Species', '9606', (62, 70))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))
844912	24829644	used quantitative methylation-specific PCR techniques to evaluate the accuracy of methylation in selected genes in esophageal balloon cytology specimens for identifying ESD.	('esophageal balloon', 'Disease', (115, 133))	('esophageal balloon', 'Disease', 'MESH:D054549', (115, 133))	('ESD', 'Disease', (169, 172))	('methylation', 'Var', (82, 93))
844914	24829644	found mutations in Fanconi anemia genes (including FANCD2, FANCE, FANCL and FANCA)  as well as in BRCA2 (FANCD1) gene  in ESCC cases from northeast of Iran.	('Fanconi anemia', 'Phenotype', 'HP:0001994', (19, 33))	('FANCL', 'Gene', (66, 71))	('FANCA', 'Gene', (76, 81))	('FANCD1', 'Gene', '675', (105, 111))	('FANCL', 'Gene', '55120', (66, 71))	('BRCA2', 'Gene', '675', (98, 103))	('FANCD2', 'Gene', (51, 57))	('ESCC', 'Disease', (122, 126))	('mutations', 'Var', (6, 15))	('FANCD2', 'Gene', '2177', (51, 57))	('FANCD1', 'Gene', (105, 111))	('Fanconi anemia', 'Disease', (19, 33))	('Fanconi anemia', 'Disease', 'MESH:D005199', (19, 33))	('FANCA', 'Gene', '2175', (76, 81))	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('anemia', 'Phenotype', 'HP:0001903', (27, 33))	('BRCA2', 'Gene', (98, 103))	('FANCE', 'Gene', (59, 64))	('FANCE', 'Gene', '2178', (59, 64))
844916	24829644	Their results showed that 93% and 96% of cases had at least one microsatellite DNA alterations in their tumor and serum, respectively.	('microsatellite DNA', 'Var', (64, 82))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
844917	24829644	reported a higher frequency of polymorphisms of CYP1A1 m1, CYP1A1 m2, CYP2A6*9, and ADH2*1 genes in population with high ESCC rates in northeast of Iran.	('CYP2A6', 'Gene', (70, 76))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('CYP1A1', 'Gene', (59, 65))	('ADH2*1', 'Gene', (84, 90))	('CYP1A1', 'Gene', '1543', (59, 65))	('CYP1A1', 'Gene', '1543', (48, 54))	('polymorphisms', 'Var', (31, 44))	('high ESCC', 'Phenotype', 'HP:0003565', (116, 125))	('CYP2A6', 'Gene', '1548', (70, 76))	('ESCC', 'Disease', (121, 125))	('CYP1A1', 'Gene', (48, 54))
844918	24829644	The risk of ESCC may increase in rare combination of GSTT1 null genotype and GSTP1 Val/Val variant.	('Val/Val variant', 'Var', (83, 98))	('GSTT1', 'Gene', (53, 58))	('GSTP1', 'Gene', (77, 82))	('SCC', 'Phenotype', 'HP:0002860', (13, 16))	('GSTT1', 'Gene', '2952', (53, 58))	('ESCC', 'Disease', (12, 16))	('GSTP1', 'Gene', '2950', (77, 82))	('null genotype', 'Var', (59, 72))	('increase', 'PosReg', (21, 29))
844931	24829644	reported decreased expression of miRNA-203 and miRNA-205 and increased expression of miRNA-21 in ESCC patients.	('miRNA-203', 'Gene', (33, 42))	('expression', 'MPA', (71, 81))	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('expression', 'MPA', (19, 29))	('miRNA-205', 'Var', (47, 56))	('patients', 'Species', '9606', (102, 110))	('miRNA-21', 'Gene', '406991', (85, 93))	('increased', 'PosReg', (61, 70))	('decreased', 'NegReg', (9, 18))	('miRNA-203', 'Gene', '406986', (33, 42))	('ESCC', 'Disease', (97, 101))	('miRNA-21', 'Gene', (85, 93))
844938	24829644	In a study from Iran, individuals with GSTP1 Ile/Ile variants have more susceptibility to ESCC in smokers, while non-smokers with this genotype seem to be protected.	('GSTP1', 'Gene', '2950', (39, 44))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('susceptibility', 'Reg', (72, 86))	('ESCC', 'Disease', (90, 94))	('variants', 'Var', (53, 61))	('GSTP1', 'Gene', (39, 44))
844940	24829644	According to Montesano et al., a strong relationship between p53 mutation and tobacco smoking in ESCC patients exists.	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('tobacco', 'Species', '4097', (78, 85))	('ESCC', 'Disease', (97, 101))	('patients', 'Species', '9606', (102, 110))	('mutation', 'Var', (65, 73))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('tobacco smoking', 'Disease', (78, 93))
844964	22350411	As a result of these modifications CS/DS contains structural microdomains endowed with biological information.	('DS', 'Chemical', 'MESH:D003903', (38, 40))	('CS/DS', 'Disease', (35, 40))	('modifications', 'Var', (21, 34))	('CS', 'Chemical', 'MESH:D002586', (35, 37))
844969	22350411	Removal of the CS/DS chains has been demonstrated to inhibit angiogenesis, proliferation, and invasion of melanoma cells.	('CS/DS', 'Protein', (15, 20))	('inhibit', 'NegReg', (53, 60))	('CS', 'Chemical', 'MESH:D002586', (15, 17))	('Removal', 'Var', (0, 7))	('angiogenesis', 'CPA', (61, 73))	('DS', 'Chemical', 'MESH:D003903', (18, 20))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('proliferation', 'CPA', (75, 88))	('melanoma', 'Disease', (106, 114))
845016	22350411	In a distinct incubation, 2 mU of chondroitinase B only was added to the GAG samples, in the presence of 0.1% BSA and 1 muM CaCl2 to specifically cleave at IdoA of DSs.	('IdoA', 'Gene', (156, 160))	('DS', 'Chemical', 'MESH:D003903', (164, 166))	('chondroitin', 'Chemical', 'MESH:D002807', (34, 45))	('IdoA', 'Chemical', 'MESH:D007067', (156, 160))	('cleave', 'Var', (146, 152))	('CaCl2', 'Chemical', 'MESH:D002122', (124, 129))
845064	22350411	Further, DS-epi1-downregulated shRNA-a and shRNA-b cells displayed an altered morphology with less prominent plasma membrane protrusions (Fig.	('altered', 'Reg', (70, 77))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('less', 'NegReg', (94, 98))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('plasma membrane protrusions', 'MPA', (109, 136))	('DS-epi1-downregulated', 'Var', (9, 30))
845177	31956360	Subgroup analysis was carried out based on statistical approach, and the results revealed that high MMP-14 expression in both log rank (HR = 1.86, 95% CI: 1.57-2.28, P < 0.001) and multivariate analysis (HR = 2.64, 95% CI: 1.95-3.58, P < 0.001) were significant associated with poor OS (Table 3).	('associated', 'Reg', (262, 272))	('high', 'Var', (95, 99))	('expression', 'MPA', (107, 117))	('poor OS', 'Disease', (278, 285))	('MMP-14', 'Gene', (100, 106))	('MMP-14', 'Gene', '4323', (100, 106))
845185	31956360	For OS, a highly significant correlation was revealed between high MMP-14 expression level and poor prognosis (HR = 2.2, P<0.001) (Figure 4A).	('high', 'Var', (62, 66))	('MMP-14', 'Gene', (67, 73))	('poor prognosis', 'CPA', (95, 109))	('MMP-14', 'Gene', '4323', (67, 73))
845195	31956360	We found that high expression of MMP-14 may be an independent poor prognostic factor (OS, HR = 1.98, 95% Cl: 1.76-2.22, P < 0.001 and DFS/PFS, HR = 3.61, 95% Cl: 2.39-5.43, P < 0.001), particularly in multivariate analysis group (HR = 2.64, 95% CI: 1.95-3.58, P < 0.001), and patients with gastric cancer (HR = 2.21, 95% CI: 1.76-2.77, P < 0.001) and HCC (HR = 2.14, 95% CI: 1.35-2.19, P < 0.001) and oral cancer(HR = 1.69, 95% CI: 1.30-3.20, P < 0.001).	('patients', 'Species', '9606', (276, 284))	('MMP-14', 'Gene', (33, 39))	('oral cancer', 'Disease', 'MESH:D009062', (401, 412))	('MMP-14', 'Gene', '4323', (33, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (290, 304))	('HCC', 'Phenotype', 'HP:0001402', (351, 354))	('oral cancer', 'Disease', (401, 412))	('high', 'Var', (14, 18))	('gastric cancer', 'Disease', (290, 304))	('gastric cancer', 'Disease', 'MESH:D013274', (290, 304))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('HCC', 'Disease', (351, 354))	('HCC', 'Disease', 'MESH:D006528', (351, 354))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
845258	30854051	All 52 esophageal cancer showed hyperintense on T2WI (Figs.	('esophageal cancer', 'Disease', (7, 24))	('T2WI', 'Protein', (48, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (7, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('hyperintense', 'Var', (32, 44))
845343	29483950	In case of a gene translocation (hypothysing, that ER81 has a 5' fusion-partner) this antibody is able to detect an overexpression caused by these protein products.	('ER81', 'Gene', (51, 55))	('ER81', 'Gene', '2115', (51, 55))	('overexpression', 'PosReg', (116, 130))	('gene translocation', 'Var', (13, 31))
845367	29483950	Kaplan-Meier analysis shows a significant correlation between high cMK2 expression and reduced patients' survival.	('patients', 'Species', '9606', (95, 103))	('reduced', 'NegReg', (87, 94))	('expression', 'MPA', (72, 82))	("patients' survival", 'CPA', (95, 113))	('high', 'Var', (62, 66))	('MK2', 'Gene', '9261', (68, 71))	('MK2', 'Gene', (68, 71))
845368	29483950	Patients with high expression of cMK2 showed a significantly lower (median = 14.5, mean = 24.9 months), while patients with low or absent cMK2 levels had longer OS (median = 20, mean = 35.35 months), p= 0.00949 log-rank test (= Mantel-Haenszel test).	('MK2', 'Gene', '9261', (34, 37))	('lower', 'NegReg', (61, 66))	('MK2', 'Gene', (34, 37))	('Patients', 'Species', '9606', (0, 8))	('MK2', 'Gene', '9261', (139, 142))	('MK2', 'Gene', (139, 142))	('high expression', 'Var', (14, 29))	('patients', 'Species', '9606', (110, 118))
845369	29483950	Patients with high cMK2 expression had a 5 years OS at of 11.27% compared with 19.19% for patients with low or absent cMK2.	('MK2', 'Gene', '9261', (20, 23))	('MK2', 'Gene', (20, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('MK2', 'Gene', '9261', (119, 122))	('MK2', 'Gene', (119, 122))	('patients', 'Species', '9606', (90, 98))
845371	29483950	Analyzing expression levels of nETV1 and cETV1, Kaplan-Meier analysis demonstrated a significant correlation with high nETV1 expression and improved patients' OS.	('improved', 'PosReg', (140, 148))	('patients', 'Species', '9606', (149, 157))	('high', 'Var', (114, 118))	('ETV1', 'Gene', (120, 124))	('ETV1', 'Gene', '2115', (120, 124))	('ETV1', 'Gene', (42, 46))	('expression', 'MPA', (125, 135))	('ETV1', 'Gene', '2115', (42, 46))	('ETV1', 'Gene', (32, 36))	('ETV1', 'Gene', '2115', (32, 36))
845372	29483950	Patients with high nETV1 levels showed significantly better OS (median = 42.82, mean = 53.5 months), p= 0.00507 log-rank test, while patients with low or absent nETV1 expression had a shorter OS (median = 16.89, mean = 30 months).	('patients', 'Species', '9606', (133, 141))	('ETV1', 'Gene', (20, 24))	('ETV1', 'Gene', '2115', (20, 24))	('high', 'Var', (14, 18))	('ETV1', 'Gene', (162, 166))	('Patients', 'Species', '9606', (0, 8))	('ETV1', 'Gene', '2115', (162, 166))	('better', 'PosReg', (53, 59))
845373	29483950	Patients with high nETV1 expression had an OS at 5 years of 35% compared with 15.5% for patients with low or absent nETV1 (Figure X).	('patients', 'Species', '9606', (88, 96))	('ETV1', 'Gene', (20, 24))	('ETV1', 'Gene', '2115', (20, 24))	('ETV1', 'Gene', (117, 121))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('ETV1', 'Gene', '2115', (117, 121))
845377	29483950	In subgroup analysis of patients with AC, cases with high expression of cMK2 showed a significantly lower OS (median = 15.31, mean = 26.64 months), while patients with low or absent cMK2 levels had longer OS (median = 24.24, mean = 40 months), p=0.0156 log-rank test.	('MK2', 'Gene', (73, 76))	('MK2', 'Gene', '9261', (183, 186))	('MK2', 'Gene', (183, 186))	('lower', 'NegReg', (100, 105))	('patients', 'Species', '9606', (154, 162))	('MK2', 'Gene', '9261', (73, 76))	('patients', 'Species', '9606', (24, 32))	('high expression', 'Var', (53, 68))
845378	29483950	Patients with high cMK2 expression had an OS at 5 years of 13.5% compared with 21.69% for patients with low or absent cMK2 (Figure X).	('MK2', 'Gene', '9261', (20, 23))	('MK2', 'Gene', (20, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('MK2', 'Gene', '9261', (119, 122))	('MK2', 'Gene', (119, 122))	('patients', 'Species', '9606', (90, 98))
845379	29483950	Evaluating the expression of ETV1 in AC, patients with high nETV1 levels showed significantly better OS (median = 50.26, mean = 57.97 months) while patients with low or absent nETV1 expression had a shorter OS (median = 17.15, mean 32.17 months).	('patients', 'Species', '9606', (148, 156))	('ETV1', 'Gene', '2115', (29, 33))	('ETV1', 'Gene', (61, 65))	('ETV1', 'Gene', '2115', (177, 181))	('ETV1', 'Gene', '2115', (61, 65))	('patients', 'Species', '9606', (41, 49))	('better', 'PosReg', (94, 100))	('high', 'Var', (55, 59))	('ETV1', 'Gene', (29, 33))	('ETV1', 'Gene', (177, 181))
845380	29483950	Patients with high nETV1 expression had an OS at 5 years of 27.27% compared with 17.68% for patients with low or absent nETV1 (Figure X).	('ETV1', 'Gene', (20, 24))	('patients', 'Species', '9606', (92, 100))	('ETV1', 'Gene', '2115', (20, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('ETV1', 'Gene', (121, 125))	('ETV1', 'Gene', '2115', (121, 125))
845387	29483950	In multivariate analysis of AC tumors, high cMK2 expression was an independent negative prognostic factor for OS (p=0.04; RR 1.38, 1.01-1.89) (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('high', 'Var', (39, 43))	('tumors', 'Disease', (31, 37))	('MK2', 'Gene', (45, 48))	('negative', 'NegReg', (79, 87))	('MK2', 'Gene', '9261', (45, 48))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))
845388	29483950	Evaluating nETV1 expression in AC tumors with multivariate analysis, a nearly significant (p=0.05; RR 0.47, 0.22-1.00) decrease of 53% in risk in OS for patients with high nETV1 expression could be found (Table 4).	('ETV1', 'Gene', '2115', (173, 177))	('ETV1', 'Gene', '2115', (12, 16))	('tumors', 'Disease', (34, 40))	('decrease', 'NegReg', (119, 127))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('patients', 'Species', '9606', (153, 161))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'Var', (17, 27))	('ETV1', 'Gene', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('ETV1', 'Gene', (173, 177))
845393	29483950	We demonstrated that overexpression of cMK2 in AEC is associated with significantly poorer OS and that overexpression of nETV1 in EAC is associated with significantly better OS.	('ETV1', 'Gene', (122, 126))	('overexpression', 'Var', (21, 35))	('EC', 'Chemical', '-', (48, 50))	('ETV1', 'Gene', '2115', (122, 126))	('poorer', 'NegReg', (84, 90))	('EAC', 'Gene', '1540', (130, 133))	('MK2', 'Gene', '9261', (40, 43))	('MK2', 'Gene', (40, 43))	('EAC', 'Gene', (130, 133))
845487	27890867	High resistin is risk of breast cancer in pre- and post-menopausal females and promotes growth and aggressiveness of tumor cells through STAT3 activation in breast cancer.	('STAT3', 'Gene', (137, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('STAT3', 'Gene', '6774', (137, 142))	('aggressiveness', 'Phenotype', 'HP:0000718', (99, 113))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('aggressiveness of tumor', 'Disease', (99, 122))	('breast cancer', 'Disease', (157, 170))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('resistin', 'Gene', (5, 13))	('men', 'Species', '9606', (56, 59))	('activation', 'PosReg', (143, 153))	('aggressiveness of tumor', 'Disease', 'MESH:D001523', (99, 122))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('promotes', 'PosReg', (79, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('resistin', 'Gene', '56729', (5, 13))
845508	27890867	A large study using 8,571 Korean men, who underwent comprehensive screening and endoscopy, demonstrated that high BMI increased the risk of reflux esophagitis with dose-dependent pattern.	('esophagitis', 'Phenotype', 'HP:0100633', (147, 158))	('high BMI', 'Var', (109, 117))	('reflux esophagitis', 'Disease', 'MESH:D005764', (140, 158))	('reflux esophagitis', 'Disease', (140, 158))	('BMI increased', 'Phenotype', 'HP:0031418', (114, 127))	('men', 'Species', '9606', (33, 36))
845516	27890867	Additionally, alterations in the secretion of adiponectin and leptin from adipocytes is a proposed link between obesity and Barrett's esophagus and EAC.	('alterations', 'Var', (14, 25))	('EAC', 'Disease', (148, 151))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (124, 143))	('EAC', 'Phenotype', 'HP:0011459', (148, 151))	('adiponectin', 'Gene', '9370', (46, 57))	('obesity', 'Disease', 'MESH:D009765', (112, 119))	('link', 'Reg', (99, 103))	('obesity', 'Disease', (112, 119))	('adiponectin', 'Gene', (46, 57))	('leptin', 'Gene', '3952', (62, 68))	('leptin', 'Gene', (62, 68))	('esophagus', 'Disease', (134, 143))	('secretion', 'MPA', (33, 42))	('obesity', 'Phenotype', 'HP:0001513', (112, 119))
845524	27890867	It is known that GERD can lead to erosive esophagitis, progressing to a metaplastic, specialized intestinal epithelium (Barrett's esophagus).	('lead to', 'Reg', (26, 33))	('esophagitis', 'Disease', (42, 53))	('esophagitis', 'Phenotype', 'HP:0100633', (42, 53))	('GERD', 'Var', (17, 21))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (120, 139))	('esophagitis', 'Disease', 'MESH:D004941', (42, 53))
845534	27890867	A polymorphism in IGF-I gene is associated with BE, and a polymorphism in IGF-I receptor modifies the effect of obesity on the risk of BE and EAC.	('BE', 'Phenotype', 'HP:0100580', (135, 137))	('IGF-I', 'Gene', (74, 79))	('polymorphism', 'Var', (58, 70))	('obesity', 'Disease', 'MESH:D009765', (112, 119))	('obesity', 'Disease', (112, 119))	('IGF-I', 'Gene', '3479', (18, 23))	('IGF-I receptor', 'Gene', '3480', (74, 88))	('IGF-I receptor', 'Gene', (74, 88))	('modifies', 'Reg', (89, 97))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))	('associated', 'Reg', (32, 42))	('IGF-I', 'Gene', (18, 23))	('polymorphism', 'Var', (2, 14))	('IGF-I', 'Gene', '3479', (74, 79))	('BE', 'Phenotype', 'HP:0100580', (48, 50))	('obesity', 'Phenotype', 'HP:0001513', (112, 119))
845543	27890867	However, a large cross sectional study using 3,922 screening persons demonstrated colorectal adenoma had a positive association with VAT and high waist circumference when they were considered separately but only VAT contributed to colorectal adenoma when both were considered simultaneously.	('colorectal adenoma', 'Disease', 'MESH:D015179', (231, 249))	('high waist circumference', 'Phenotype', 'HP:0031819', (141, 165))	('persons', 'Species', '9606', (61, 68))	('VAT', 'Disease', 'None', (133, 136))	('colorectal adenoma', 'Disease', 'MESH:D015179', (82, 100))	('VAT', 'Disease', 'None', (212, 215))	('VAT', 'Disease', (133, 136))	('colorectal adenoma', 'Disease', (231, 249))	('high', 'Var', (141, 145))	('VAT', 'Disease', (212, 215))	('colorectal adenoma', 'Disease', (82, 100))
845552	27890867	In summary, BMI appears to increase the risk of CRC in men, but less in women.	('CRC', 'Disease', (48, 51))	('men', 'Species', '9606', (55, 58))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('men', 'Species', '9606', (74, 77))	('BMI', 'Var', (12, 15))	('women', 'Species', '9606', (72, 77))
845560	27890867	The first "hit" includes accumulation of fat in hepatocytes, which is associated with insulin resistance, and fatty acid metabolism dysregulation that leads to steatosis.	('leads to', 'Reg', (151, 159))	('fatty acid', 'Chemical', 'MESH:D005227', (110, 120))	('accumulation', 'PosReg', (25, 37))	('insulin', 'Gene', '3630', (86, 93))	('steatosis', 'Phenotype', 'HP:0001397', (160, 169))	('steatosis', 'Disease', 'MESH:D005234', (160, 169))	('insulin', 'Gene', (86, 93))	('steatosis', 'Disease', (160, 169))	('fatty acid metabolism', 'MPA', (110, 131))	('dysregulation', 'Var', (132, 145))	('insulin resistance', 'Phenotype', 'HP:0000855', (86, 104))
845571	27890867	It seems that NAFLD causes HCC via cirrhosis, even if the exact pathogenesis is unclear.	('cirrhosis', 'Phenotype', 'HP:0001394', (35, 44))	('causes', 'Reg', (20, 26))	('HCC', 'Gene', (27, 30))	('cirrhosis', 'Disease', (35, 44))	('HCC', 'Gene', '619501', (27, 30))	('HCC', 'Phenotype', 'HP:0001402', (27, 30))	('NAFLD', 'Var', (14, 19))	('cirrhosis', 'Disease', 'MESH:D005355', (35, 44))
845583	27890867	High BMI (BMI of >=30 kg/m2) was associated with an increased risk of pancreatic cancer compared with normal (BMI of <23 kg/m2).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 87))	('pancreatic cancer', 'Disease', (70, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('High BMI', 'Var', (0, 8))
845585	27890867	Furthermore, high BMI is associated with decreased survival in patients with pancreatic cancer.	('BMI', 'MPA', (18, 21))	('high', 'Var', (13, 17))	('decreased', 'NegReg', (41, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (63, 71))	('pancreatic cancer', 'Disease', (77, 94))	('survival', 'MPA', (51, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
845589	27890867	In stratified analysis, obesity (BMI>25) was associated with an increased risk of cardia gastric cancer (OR, 1.55) and gastric cancer among non-Asians (OR, 1.24) but had no association with noncardia gastric cancer and Asian gastric cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (225, 239))	('gastric cancer', 'Disease', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('gastric cancers', 'Disease', (225, 240))	('gastric cancers', 'Disease', 'MESH:D013274', (225, 240))	('gastric cancers', 'Phenotype', 'HP:0012126', (225, 240))	('obesity', 'Phenotype', 'HP:0001513', (24, 31))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (225, 239))	('BMI>25', 'Var', (33, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cardia gastric cancer', 'Disease', 'MESH:D013274', (82, 103))	('cardia gastric cancer', 'Disease', (82, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('obesity', 'Disease', (24, 31))	('cardia gastric cancer', 'Disease', 'MESH:D013274', (193, 214))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('noncardia gastric cancer', 'Disease', (190, 214))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (190, 214))	('obesity', 'Disease', 'MESH:D009765', (24, 31))
845610	27890867	In one cohort study of 25,291 colon cancer patients who received treatment in adjuvant chemotherapy trials, obesity and underweight status were associated independently with inferior outcomes.	('underweight status', 'Var', (120, 138))	('patients', 'Species', '9606', (43, 51))	('obesity', 'Phenotype', 'HP:0001513', (108, 115))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('men', 'Species', '9606', (70, 73))	('colon cancer', 'Disease', 'MESH:D015179', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colon cancer', 'Disease', (30, 42))	('obesity', 'Disease', 'MESH:D009765', (108, 115))	('obesity', 'Disease', (108, 115))
845711	26445608	used the Surveillance, Epidemiology, and End Results database to retrospectively evaluate the benefit of adjuvant RT in T3-4N0M0 or T1-4N1M0 esophageal cancer patients definitively treated with esophagectomy.	('esophageal cancer', 'Disease', (141, 158))	('T3-4N0M0', 'Var', (120, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('T1-4N1M0', 'Var', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (159, 167))
845713	26445608	For American Joint Committee on Cancer (AJCC) stage III esophageal carcinoma (T3N1M0 or T4N0-1M0), in which 346 patients had surgery alone and 231 patients received PORT, PORT significantly improved the median OS from 15 to 19 months and the three-year OS rate from 18.2% to 28.9% (P < 0.001).	('Cancer', 'Disease', (32, 38))	('OS', 'Chemical', '-', (210, 212))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('esophageal carcinoma', 'Disease', (56, 76))	('patients', 'Species', '9606', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('patients', 'Species', '9606', (147, 155))	('improved', 'PosReg', (190, 198))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (56, 76))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (56, 76))	('T4N0-1M0', 'Var', (88, 96))	('T3N1M0', 'Var', (78, 84))	('OS', 'Chemical', '-', (253, 255))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
845739	26445608	However, in the present study, we found that IMRT caused 3.1% gastrointestinal bleeding, which was higher than gastrointestinal bleeding rates of 1.1% and 1.0% reported previously.	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (62, 87))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (111, 136))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (62, 87))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (111, 136))	('IMRT', 'Var', (45, 49))	('gastrointestinal bleeding', 'Disease', (62, 87))	('gastrointestinal bleeding', 'Disease', (111, 136))
845798	25620903	Chemotherapy may also cause fulminant hepatitis in patients who have a history of hepatitis B virus infection (negative for HBs antigen and positive for HBc antibody or HBs antibody).	('cause', 'Reg', (22, 27))	('hepatitis', 'Disease', (38, 47))	('hepatitis', 'Phenotype', 'HP:0012115', (38, 47))	('hepatitis', 'Disease', 'MESH:D056486', (82, 91))	('hepatitis B virus infection', 'Disease', 'MESH:D006509', (82, 109))	('hepatitis B virus infection', 'Disease', (82, 109))	('hepatitis', 'Disease', 'MESH:D056486', (38, 47))	('HBs antigen', 'Protein', (124, 135))	('hepatitis', 'Disease', (82, 91))	('negative', 'NegReg', (111, 119))	('Chemotherapy', 'Var', (0, 12))	('patients', 'Species', '9606', (51, 59))	('fulminant hepatitis', 'Phenotype', 'HP:0004787', (28, 47))	('hepatitis', 'Phenotype', 'HP:0012115', (82, 91))	('HBc antibody', 'Phenotype', 'HP:0032146', (153, 165))
845952	25620903	At the time of revising the guidelines, the timing of adjuvant chemotherapy with cisplatin + 5-FU was examined in the JCOG9907 study (1999-2006), and it was found that neoadjuvant chemotherapy yielded significantly improved overall survival in comparison to postoperative chemotherapy.	('overall survival', 'MPA', (224, 240))	('5-FU', 'Chemical', 'MESH:D005472', (93, 97))	('neoadjuvant', 'Var', (168, 179))	('improved', 'PosReg', (215, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))
845961	25620903	According to a meta-analysis that addressed surgery preceded by neoadjuvant chemoradiotherapy vs. surgery alone, when the 3-year survival rate was used as an end point, neoadjuvant chemoradiotherapy (20-45 Gy) in patients with resectable carcinoma was associated with a significant increase in operation-related mortality within 90 postoperative days.	('carcinoma', 'Disease', 'MESH:D002277', (238, 247))	('neoadjuvant chemoradiotherapy', 'Var', (169, 198))	('operation-related mortality', 'MPA', (294, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('carcinoma', 'Disease', (238, 247))	('patients', 'Species', '9606', (213, 221))
845966	25620903	Postoperative chemotherapy: A randomized controlled trial (JCOG9204 study) comparing surgery with and without postoperative chemotherapy (cisplatin + 5-FU, 2 courses) carried out in Japan demonstrated that postoperative chemotherapy resulted in a significant increase in the disease-free survival rate as compared to surgery alone, although there was no significant difference in the overall survival rate.	('5-FU', 'Chemical', 'MESH:D005472', (150, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('disease-free survival rate', 'CPA', (275, 301))	('increase', 'PosReg', (259, 267))	('postoperative', 'Var', (206, 219))
846014	25620903	Concurrent chemoradiotherapy is indicated for patients with T1-4N0-3M0 carcinoma (UICC-TNM classification, 2009 edition) in good general condition and for those with locally advanced carcinoma up to metastasis to the supraclavicular lymph nodes (M1).	('patients', 'Species', '9606', (46, 54))	('carcinoma', 'Disease', 'MESH:D002277', (183, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('TNM', 'Gene', '10178', (87, 90))	('carcinoma', 'Disease', 'MESH:D002277', (71, 80))	('T1-4N0-3M0', 'Var', (60, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinoma', 'Disease', (183, 192))	('TNM', 'Gene', (87, 90))	('carcinoma', 'Disease', (71, 80))
846021	25620903	Definitive irradiation is the most suitable for cases with T1-4N0-3M0 carcinoma (UICC-TNM classification, 2009 edition) and cases with locally advanced disease up to metastasis to the supraclavicular nodes (M1).	('T1-4N0-3M0', 'Var', (59, 69))	('carcinoma', 'Disease', 'MESH:D002277', (70, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('TNM', 'Gene', '10178', (86, 89))	('carcinoma', 'Disease', (70, 79))	('TNM', 'Gene', (86, 89))
846064	25620903	In addition, irradiation of the cervical area may cause hypothyroidism a few years post-irradiation.	('cause', 'Reg', (50, 55))	('hypothyroidism', 'Phenotype', 'HP:0000821', (56, 70))	('hypothyroidism', 'Disease', (56, 70))	('irradiation', 'Var', (13, 24))	('hypothyroidism', 'Disease', 'MESH:D007037', (56, 70))
846072	25620903	Patients who can be the target of definitive chemoradiotherapy include T1-3N0-3M0 cases (UICC-TNM classification, 2009 edition), unresectable T4N0-3M0 cases, and cases with locally advanced disease up to metastasis to the supraclavicular nodes (M1).	('T4N0-3M0', 'Var', (142, 150))	('TNM', 'Gene', '10178', (94, 97))	('Patients', 'Species', '9606', (0, 8))	('TNM', 'Gene', (94, 97))	('T1-3N0-3M0', 'Var', (71, 81))
846077	25620903	In a randomized controlled trial of radiation monotherapy (64 Gy) and concurrent chemoradiotherapy (5-FU + cisplatin + radiation 50 Gy) for T1-4N0-1M0 esophageal carcinoma (corresponding to UICC-TNM classification, 2002 edition) carried out by the US Radiation Therapy Oncology Group (RTOG), the 5-year survival rate was 0 % for the former and 26 % for the latter; the latter treatment yielded significantly better results (p < 0.0001).	('Oncology', 'Phenotype', 'HP:0002664', (269, 277))	('esophageal carcinoma ', 'Gene', (151, 172))	('TNM', 'Gene', '10178', (195, 198))	('men', 'Species', '9606', (381, 384))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('5-FU', 'Chemical', 'MESH:D005472', (100, 104))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (151, 171))	('TNM', 'Gene', (195, 198))	('T1-4N0-1M0', 'Var', (140, 150))	('esophageal carcinoma ', 'Gene', '259307', (151, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
846079	25620903	In addition, a randomized controlled study (RTOG9405/INT0123) carried out succeedingly to RTOG 85-01 that compared chemoradiotherapy using standard-dose (50.4 Gy) and high-dose (64.8 Gy) radiation in patients with T1-4N0-1M0 esophageal carcinoma (corresponding to UICC-TNM classification, 2002 edition) revealed no superiority of high-dose radiation over standard-dose radiation in terms of the median survival time, the 2-year survival rate, and the local control rate, and concluded that the standard radiation dose for chemoradiotherapy using a combination of 5-FU plus cisplatin should be 50.4 Gy (1.8 Gy x 28 times).	('5-FU', 'Chemical', 'MESH:D005472', (563, 567))	('patients', 'Species', '9606', (200, 208))	('TNM', 'Gene', '10178', (269, 272))	('esophageal carcinoma ', 'Gene', '259307', (225, 246))	('T1-4N0-1M0', 'Var', (214, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('TNM', 'Gene', (269, 272))	('esophageal carcinoma ', 'Gene', (225, 246))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (225, 245))	('cisplatin', 'Chemical', 'MESH:D002945', (573, 582))
846092	25620903	Among other possible adverse events during chemoradiotherapy for esophageal carcinoma, special attention should be paid to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) attributable to cisplatin and leukoencephalopathy attributable to 5-FU.	('cisplatin', 'Var', (211, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('inappropriate secretion of antidiuretic hormone', 'Disease', 'MESH:D007177', (139, 186))	('esophageal carcinoma', 'Disease', (65, 85))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (65, 85))	('leukoencephalopathy', 'Disease', (225, 244))	('SIADH', 'Disease', (188, 193))	('5-FU', 'Chemical', 'MESH:D005472', (261, 265))	('cisplatin', 'Chemical', 'MESH:D002945', (211, 220))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (65, 85))	('leukoencephalopathy', 'Phenotype', 'HP:0002352', (225, 244))	('leukoencephalopathy', 'Disease', 'MESH:D056784', (225, 244))	('inappropriate secretion of antidiuretic hormone', 'Disease', (139, 186))	('SIADH', 'Disease', 'MESH:D007177', (188, 193))
846225	25620903	According to the NCCN guidelines, preoperative therapy is indicated for cases with T1b, N1, T2 to resectable T4, and resectable Stage IVA disease.	('T1b', 'Var', (83, 86))	('IVA disease', 'Disease', (134, 145))	('IVA disease', 'Disease', 'MESH:C538167', (134, 145))	('T2 to', 'Var', (92, 97))
846280	24452533	Conventional and molecular cytogenetic analyses revealed chromosomal gains of 7q and losses of 1p and 3p to be the most prominent alterations in chordoma.	('chordoma', 'Disease', (145, 153))	('chromosomal gains of 7q', 'Var', (57, 80))	('chordoma', 'Disease', 'MESH:D002817', (145, 153))	('losses', 'NegReg', (85, 91))	('chordoma', 'Phenotype', 'HP:0010762', (145, 153))
846281	24452533	In addition, loss of heterozygosity (LOH) and genome-wide linkage studies have already been successfully used to narrow down and define candidate regions for chordoma development on 1p36.13 and 7q33.	('p36', 'Gene', '302', (183, 186))	('chordoma', 'Disease', 'MESH:D002817', (158, 166))	('chordoma', 'Phenotype', 'HP:0010762', (158, 166))	('narrow down', 'NegReg', (113, 124))	('chordoma', 'Disease', (158, 166))	('loss', 'Var', (13, 17))	('p36', 'Gene', (183, 186))
846327	24452533	2-3) could be analyzed demonstrating the following clonal aberrations: t(1;19),t(1;8),del(2)(q),del(4)(p),der(7),t(8;15),t(10;17),der(12)t(8;12),t(7;13), t(14;?	('2', 'Gene', '10630', (135, 136))	('t(8;15', 'Var', (113, 119))	('der(7', 'Var', (106, 111))	('2', 'Gene', '10630', (0, 1))	('del(4)(p', 'Var', (96, 104))	('t(10;17', 'Var', (121, 128))	('t(7;13', 'Var', (145, 151))	('2', 'Gene', '10630', (142, 143))	('2', 'Gene', '10630', (90, 91))
846330	24452533	Overall, we found 166 chromosomal aberrations (0-14 per tumor; median 4 per tumor) in 33 chordomas.	('chordomas', 'Disease', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('chordomas', 'Disease', 'MESH:D002817', (89, 98))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('chordoma', 'Phenotype', 'HP:0010762', (89, 97))	('chromosomal aberrations', 'Var', (22, 45))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (22, 45))
846334	24452533	The distribution of deletions, gains and the total number of aberrations in tumors are shown in Table II and Fig.	('gains', 'PosReg', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('deletions', 'Var', (20, 29))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
846386	24452533	Furthermore, in vitro silencing of T induces growth arrest of chordoma cells.	('growth arrest of chordoma', 'Disease', 'MESH:D002817', (45, 70))	('growth arrest of chordoma', 'Disease', (45, 70))	('silencing', 'Var', (22, 31))	('chordoma', 'Phenotype', 'HP:0010762', (62, 70))
846387	24452533	Recently, duplication of the transcription factor T was shown to be associated with the development of chordoma in a few families.	('associated with', 'Reg', (68, 83))	('chordoma', 'Disease', 'MESH:D002817', (103, 111))	('chordoma', 'Phenotype', 'HP:0010762', (103, 111))	('duplication', 'Var', (10, 21))	('chordoma', 'Disease', (103, 111))
846389	24452533	Furthermore, amplification of T was described in a subgroup of sporadic chordoma.	('sporadic chordoma', 'Disease', 'MESH:D002817', (63, 80))	('chordoma', 'Phenotype', 'HP:0010762', (72, 80))	('amplification', 'Var', (13, 26))	('described', 'Reg', (36, 45))	('sporadic chordoma', 'Disease', (63, 80))
846398	24452533	In univariate survival analysis, a significant association of CD24 expression with shortened patient overall survival (5-year survival rate 91.9 versus 83.8%; p=0.031; log rank test) and disease-free survival (5-year progression rate 88.3 versus 57.0%; p=0.0008) was demonstrated.	('expression', 'Var', (67, 77))	('patient overall survival', 'CPA', (93, 117))	('shortened', 'NegReg', (83, 92))	('patient', 'Species', '9606', (93, 100))	('CD24', 'Gene', (62, 66))	('disease-free survival', 'CPA', (187, 208))
846399	24452533	Kaplan-Meier curves and Cox regression analysis of their prostate cancer study showed that CD24 expression was strongly linked to significantly earlier disease progression (relative risk, 3.2), which was especially pronounced in organ-confined or moderately differentiated primary prostate tumors.	('2', 'Gene', '10630', (190, 191))	('prostate cancer', 'Disease', (57, 72))	('primary prostate tumors', 'Disease', (273, 296))	('disease progression', 'CPA', (152, 171))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('earlier', 'PosReg', (144, 151))	('primary prostate tumors', 'Disease', 'MESH:D011471', (273, 296))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('2', 'Gene', '10630', (93, 94))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('expression', 'Var', (96, 106))
846488	34003875	Currently, evidence shows that an abnormal expression of lncRNA is closely related to the occurrence, metastasis and stage of tumours.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('related', 'Reg', (75, 82))	('abnormal', 'Var', (34, 42))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('tumours', 'Disease', 'MESH:D009369', (126, 133))	('metastasis', 'CPA', (102, 112))	('tumours', 'Disease', (126, 133))	('expression', 'MPA', (43, 53))	('lncRNA', 'Protein', (57, 63))
846492	34003875	The high expression of LINC00958 has also been shown to promote the occurrence and development of certain cancers, including bladder cancer, oral cancer, pancreatic cancer, gastric cancer, cervical cancer and glioma.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('high expression', 'Var', (4, 19))	('cancers', 'Disease', (106, 113))	('cancer', 'Disease', (106, 112))	('glioma', 'Disease', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gastric cancer', 'Disease', (173, 187))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('cancer', 'Disease', (198, 204))	('promote', 'PosReg', (56, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))	('oral cancer', 'Disease', 'MESH:D009369', (141, 152))	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('gastric cancer', 'Disease', 'MESH:D013274', (173, 187))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (133, 139))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('cancer', 'Disease', (165, 171))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('pancreatic cancer', 'Disease', (154, 171))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('LINC00958', 'Gene', '100506305', (23, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (173, 187))	('oral cancer', 'Disease', (141, 152))	('LINC00958', 'Gene', (23, 32))	('development', 'CPA', (83, 94))
846495	34003875	In addition, we verified miR-510-5p, a tumour suppressor to be a target miRNA of LINC00958, and suggested that the antitumor effect of miR-510-5p might be related to its target gene SPOCK1.	('tumor', 'Disease', (119, 124))	('SPOCK1', 'Gene', '6695', (182, 188))	('miR-510-5p', 'Chemical', '-', (25, 35))	('tumour', 'Disease', (39, 45))	('miR-510-5p', 'Chemical', '-', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('LINC00958', 'Gene', '100506305', (81, 90))	('SPOCK1', 'Gene', (182, 188))	('miR-510-5p', 'Var', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('LINC00958', 'Gene', (81, 90))	('tumour', 'Disease', 'MESH:D009369', (39, 45))
846498	34003875	For the knockdown of LINC00958, siRNA-LINC00958-1 CCUUUGUUUCCAAAGGUUACC, siRNA-LINC00958-2 GCCUUAAAACUCACAUAGAGA and siRNA-LINC00958-3 GCGAAACUCCAUCUAAAAAAA (KeyGEN BioTECH, Nanjing, China) were designed and synthesised.	('LINC00958', 'Gene', (123, 132))	('LINC00958', 'Gene', (79, 88))	('LINC00958', 'Gene', (21, 30))	('LINC00958', 'Gene', (38, 47))	('knockdown', 'Var', (8, 17))	('LINC00958', 'Gene', '100506305', (123, 132))	('BioTECH', 'Gene', (165, 172))	('LINC00958', 'Gene', '100506305', (21, 30))	('LINC00958', 'Gene', '100506305', (38, 47))	('LINC00958', 'Gene', '100506305', (79, 88))	('BioTECH', 'Gene', '57449', (165, 172))
846506	34003875	The bioinformatics-based ENCORI (The Encyclopedia of RNA Interactomes) website (http://starbase.sysu.edu.cn/) was used to predict the binding site of LINC00958 and miR-510-5p.	('miR-510-5p', 'Var', (164, 174))	('LINC00958', 'Gene', '100506305', (150, 159))	('LINC00958', 'Gene', (150, 159))	('binding', 'Interaction', (134, 141))	('miR-510-5p', 'Chemical', '-', (164, 174))
846532	34003875	Three siRNAs were designed for the knockdown of LINC00958.	('LINC00958', 'Gene', (48, 57))	('knockdown', 'Var', (35, 44))	('LINC00958', 'Gene', '100506305', (48, 57))
846535	34003875	The results showed that the overexpression of LINC00958 promoted the proliferation of ESCC, which was detected using the xCELLigence RTCA DP system, while the knockdown of LINC00958 inhibited the proliferation of ESCC (Fig 2C and 2D).	('proliferation', 'CPA', (196, 209))	('LINC00958', 'Gene', '100506305', (46, 55))	('knockdown', 'Var', (159, 168))	('LINC00958', 'Gene', (172, 181))	('proliferation', 'CPA', (69, 82))	('ESCC', 'CPA', (86, 90))	('LINC00958', 'Gene', (46, 55))	('inhibited', 'NegReg', (182, 191))	('LINC00958', 'Gene', '100506305', (172, 181))	('promoted', 'PosReg', (56, 64))
846537	34003875	The knockdown of LINC00958 caused a significant increase in the number of cells in the G1 phase and a significant decrease in the number of cells in the S phase (Fig 2H and 2I).	('LINC00958', 'Gene', (17, 26))	('LINC00958', 'Gene', '100506305', (17, 26))	('decrease', 'NegReg', (114, 122))	('knockdown', 'Var', (4, 13))	('increase', 'PosReg', (48, 56))
846541	34003875	The knockdown of LINC00958 significantly inhibited the migration ability of ESCC, while the overexpression of LINC00958 significantly promoted the migration ability (Fig 3A-3C).	('LINC00958', 'Gene', (17, 26))	('LINC00958', 'Gene', '100506305', (110, 119))	('migration ability', 'CPA', (147, 164))	('ESCC', 'CPA', (76, 80))	('promoted', 'PosReg', (134, 142))	('LINC00958', 'Gene', (110, 119))	('migration ability', 'CPA', (55, 72))	('inhibited', 'NegReg', (41, 50))	('LINC00958', 'Gene', '100506305', (17, 26))	('knockdown', 'Var', (4, 13))
846543	34003875	After knockdown of LINC00958, the invasion ability of the EC109 cells was significantly reduced (Fig 3D).	('invasion ability of the EC109 cells', 'CPA', (34, 69))	('EC109', 'CellLine', 'CVCL:6898', (58, 63))	('LINC00958', 'Gene', '100506305', (19, 28))	('LINC00958', 'Gene', (19, 28))	('knockdown', 'Var', (6, 15))	('reduced', 'NegReg', (88, 95))
846548	34003875	To further study the function of LINC00958, we used the ENCORI website to predict the relationship between LINC00958 and miR-510-5p (Fig 4A).	('LINC00958', 'Gene', '100506305', (107, 116))	('LINC00958', 'Gene', '100506305', (33, 42))	('miR-510-5p', 'Chemical', '-', (121, 131))	('LINC00958', 'Gene', (107, 116))	('miR-510-5p', 'Var', (121, 131))	('LINC00958', 'Gene', (33, 42))
846549	34003875	A dual luciferase reporter gene experiment was used to verify that the miR-510-5p mimics significantly inhibited the luciferase activity of the PmirGLO-LINC00958 plasmid, but had no effect on the PmirGLO-NC plasmid (Fig 4B).	('activity', 'MPA', (128, 136))	('LINC00958', 'Gene', (152, 161))	('inhibited', 'NegReg', (103, 112))	('miR-510-5p', 'Chemical', '-', (71, 81))	('luciferase', 'Enzyme', (117, 127))	('miR-510-5p mimics', 'Var', (71, 88))	('LINC00958', 'Gene', '100506305', (152, 161))
846550	34003875	Subsequently, we used the TargetScan website to predict the downstream mRNA of miR-510-5p, and we focused on SPOCK1.	('miR-510-5p', 'Chemical', '-', (79, 89))	('SPOCK1', 'Gene', (109, 115))	('SPOCK1', 'Gene', '6695', (109, 115))	('miR-510-5p', 'Var', (79, 89))
846555	34003875	Compared with the control group, miR-510-5p significantly inhibited the expression of SPOCK1 (Fig 4H and 4I).	('SPOCK1', 'Gene', '6695', (86, 92))	('expression', 'MPA', (72, 82))	('miR-510-5p', 'Chemical', '-', (33, 43))	('miR-510-5p', 'Var', (33, 43))	('inhibited', 'NegReg', (58, 67))	('SPOCK1', 'Gene', (86, 92))
846569	34003875	To verify the function of LINC00958 in ESCC, we predicted that there was a targeting relationship between LINC00958 and miR-510-5p using the ENCORI website (S1 Fig).	('LINC00958', 'Gene', '100506305', (26, 35))	('LINC00958', 'Gene', '100506305', (106, 115))	('miR-510-5p', 'Chemical', '-', (120, 130))	('LINC00958', 'Gene', (106, 115))	('LINC00958', 'Gene', (26, 35))	('miR-510-5p', 'Var', (120, 130))
846570	34003875	Studies have reported that miR-510-5p acts as a tumour suppressor in renal cell carcinoma and, thus, inhibits cell proliferation and migration, and promotes cell apoptosis.	('miR-510-5p', 'Chemical', '-', (27, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('miR-510-5p', 'Var', (27, 37))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (69, 89))	('cell apoptosis', 'CPA', (157, 171))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('inhibits', 'NegReg', (101, 109))	('tumour', 'Disease', (48, 54))	('promotes', 'PosReg', (148, 156))	('renal cell carcinoma', 'Disease', (69, 89))
846571	34003875	It can be speculated that miR-510-5p may act as a tumour suppressor in ESCC and play a similar role to that in renal cell carcinoma.	('miR-510-5p', 'Var', (26, 36))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('tumour', 'Disease', (50, 56))	('ESCC', 'Disease', (71, 75))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (111, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('miR-510-5p', 'Chemical', '-', (26, 36))	('renal cell carcinoma', 'Disease', (111, 131))
846573	34003875	Through the TargetScan website, we predicted that there was a targeting relationship between miR-510-5p and SPOCK1.	('miR-510-5p', 'Chemical', '-', (93, 103))	('SPOCK1', 'Gene', '6695', (108, 114))	('miR-510-5p', 'Var', (93, 103))	('SPOCK1', 'Gene', (108, 114))
846574	34003875	Our experimental results showed that miR-510-5p is the upstream miRNA of SPOCK1.	('SPOCK1', 'Gene', (73, 79))	('miR-510-5p', 'Var', (37, 47))	('miR-510-5p', 'Chemical', '-', (37, 47))	('SPOCK1', 'Gene', '6695', (73, 79))
846581	34003875	reported that silencing of SPOCK1 by small interfering RNA inhibited ESCC cells migration and invasion Therefore, we suggested that LINC00958 might regulate the expression of SPOCK1 by its sponging of miR-510-5p, and involve proliferation, migration, invasion and EMT of ESCC.	('SPOCK1', 'Gene', '6695', (27, 33))	('invasion', 'CPA', (94, 102))	('silencing', 'Var', (14, 23))	('EMT', 'CPA', (264, 267))	('LINC00958', 'Gene', '100506305', (132, 141))	('expression', 'MPA', (161, 171))	('inhibited', 'NegReg', (59, 68))	('ESCC cells migration', 'CPA', (69, 89))	('ESCC', 'Disease', (271, 275))	('LINC00958', 'Gene', (132, 141))	('invasion', 'CPA', (251, 259))	('SPOCK1', 'Gene', (175, 181))	('proliferation', 'CPA', (225, 238))	('miR-510-5p', 'Chemical', '-', (201, 211))	('SPOCK1', 'Gene', '6695', (175, 181))	('SPOCK1', 'Gene', (27, 33))	('migration', 'CPA', (240, 249))	('regulate', 'Reg', (148, 156))
846594	34003875	Given the growing body of evidence implicating long noncoding RNAs in cancer development, this manuscript is of interest to the field of esophageal biology.	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('long noncoding RNAs', 'Var', (47, 66))
846595	34003875	Major concern: The data are too preliminary to support the central conclusion of this manuscript - that LINC00958-mediated 'sponging' of miR-510-5p results in elevated SPOCK1 expression, driving ESCC development.	('LINC00958', 'Gene', '100506305', (104, 113))	('expression', 'MPA', (175, 185))	('miR-510-5p', 'Var', (137, 147))	('elevated', 'PosReg', (159, 167))	('LINC00958', 'Gene', (104, 113))	('ESCC development', 'CPA', (195, 211))	('SPOCK1', 'Gene', (168, 174))	('driving', 'PosReg', (187, 194))	('SPOCK1', 'Gene', '6695', (168, 174))	('miR-510-5p', 'Chemical', '-', (137, 147))
846598	34003875	Does SPOCK1 overexpression rescue the oncogenic effects (growth, invasion, EMT) of LINC00958 silencing?	('silencing', 'Var', (93, 102))	('LINC00958', 'Gene', (83, 92))	('oncogenic effects', 'MPA', (38, 55))	('SPOCK1', 'Gene', (5, 11))	('SPOCK1', 'Gene', '6695', (5, 11))	('LINC00958', 'Gene', '100506305', (83, 92))	('invasion', 'CPA', (65, 73))
846600	34003875	The following questions need to be addressed in order to conclude that LINC00958 "sponging" of miR-510-5p is resulting in the SPOCK1-mediated oncogenic effects described in this manuscript: 1.	('LINC00958', 'Gene', '100506305', (71, 80))	('SPOCK1', 'Gene', (126, 132))	('oncogenic effects', 'CPA', (142, 159))	('SPOCK1', 'Gene', '6695', (126, 132))	('LINC00958', 'Gene', (71, 80))	('miR-510-5p', 'Chemical', '-', (95, 105))	('miR-510-5p', 'Var', (95, 105))
846601	34003875	Does overexpression of miR-510-5p reduce the oncogenic effects (growth, invasion, EMT) of LINC00958 overexpression?	('miR-510-5p', 'Var', (23, 33))	('LINC00958', 'Gene', '100506305', (90, 99))	('oncogenic effects', 'MPA', (45, 62))	('reduce', 'NegReg', (34, 40))	('LINC00958', 'Gene', (90, 99))	('miR-510-5p', 'Chemical', '-', (23, 33))	('invasion', 'CPA', (72, 80))
846602	34003875	Does miR-510-5p loss-of-function rescue the oncogenic effects (growth, invasion, EMT) of LINC00958 silencing?	('LINC00958', 'Gene', (89, 98))	('invasion', 'CPA', (71, 79))	('LINC00958', 'Gene', '100506305', (89, 98))	('loss-of-function', 'NegReg', (16, 32))	('silencing', 'Var', (99, 108))	('miR-510-5p', 'Chemical', '-', (5, 15))
846603	34003875	Additionally, more evidence must be given to conclude that miR-510-5p and LINC00958 interact.	('interact', 'Reg', (84, 92))	('miR-510-5p', 'Chemical', '-', (59, 69))	('LINC00958', 'Gene', '100506305', (74, 83))	('miR-510-5p', 'Var', (59, 69))	('LINC00958', 'Gene', (74, 83))
846610	34003875	Figure 4: More discussion is required to explain why miR-510-5p and SPOCK1 were evaluated in this manuscript.	('miR-510-5p', 'Var', (53, 63))	('miR-510-5p', 'Chemical', '-', (53, 63))	('SPOCK1', 'Gene', (68, 74))	('SPOCK1', 'Gene', '6695', (68, 74))
846618	34003875	The authors demonstrated a little effect on the ESCC cell proliferation by overexpression or knockdown of LINC00958 (Figure 2C-D) within 3 days.	('knockdown', 'Var', (93, 102))	('LINC00958', 'Gene', (106, 115))	('overexpression', 'PosReg', (75, 89))	('LINC00958', 'Gene', '100506305', (106, 115))	('ESCC', 'Disease', (48, 52))
846630	34003875	Then, we have predicted the competitive binding relationship between LINC00958 and miR-510-5p through the ENCORI website (Fig 4A).	('LINC00958', 'Gene', (69, 78))	('miR-510-5p', 'Chemical', '-', (83, 93))	('miR-510-5p', 'Var', (83, 93))	('LINC00958', 'Gene', '100506305', (69, 78))	('binding', 'Interaction', (40, 47))
846633	34003875	(CircRNA SCARB1 Promotes Renal Cell Carcinoma Progression Via Mir- 510-5p/SDC3 Axis) have reported that miR-510-5p acts as a tumor suppressor in renal cell carcinoma, inhibiting cell proliferation and migration, and promoting cell apoptosis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cell proliferation', 'CPA', (178, 196))	('miR-510-5p', 'Chemical', '-', (104, 114))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (145, 165))	('miR-510-5p', 'Var', (104, 114))	('Promotes Renal Cell Carcinoma', 'Disease', (16, 45))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (25, 45))	('SDC3', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('SCARB1', 'Gene', (9, 15))	('promoting', 'PosReg', (216, 225))	('inhibiting', 'NegReg', (167, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('Carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('renal cell carcinoma', 'Disease', (145, 165))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (145, 165))	('SDC3', 'Gene', '9672', (74, 78))	('SCARB1', 'Gene', '949', (9, 15))	('Promotes Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (16, 45))	('Mir- 510', 'Gene', '574515', (62, 70))	('Mir- 510', 'Gene', (62, 70))	('cell apoptosis', 'CPA', (226, 240))	('tumor', 'Disease', (125, 130))
846635	34003875	It can be speculated that miR-510-5p may act as a tumor suppressor in ESCC and play a similar role to that in renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('miR-510-5p', 'Var', (26, 36))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (110, 130))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('ESCC', 'Disease', (70, 74))	('miR-510-5p', 'Chemical', '-', (26, 36))	('renal cell carcinoma', 'Disease', (110, 130))
846636	34003875	Through the Target Scan website, we predicted the targeting relationship between miR-510-5p and SPOCK1, and the experimental results also showed that miR-510-5p was the upstream miRNA of SPOCK1.	('SPOCK1', 'Gene', '6695', (96, 102))	('miR-510-5p', 'Var', (150, 160))	('SPOCK1', 'Gene', (187, 193))	('SPOCK1', 'Gene', '6695', (187, 193))	('miR-510-5p', 'Chemical', '-', (81, 91))	('SPOCK1', 'Gene', (96, 102))	('miR-510-5p', 'Chemical', '-', (150, 160))
846644	34003875	The title is now changed to "LINC00958 upregulates SPOCK1 expression to promote the development of oesophageal squamous cell carcinoma by sponging miR-510-5p".	('SPOCK1', 'Gene', '6695', (51, 57))	('miR-510-5p', 'Chemical', '-', (147, 157))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('LINC00958', 'Gene', '100506305', (29, 38))	('expression', 'MPA', (58, 68))	('sponging', 'Var', (138, 146))	('LINC00958', 'Gene', (29, 38))	('promote', 'PosReg', (72, 79))	('upregulates', 'PosReg', (39, 50))	('SPOCK1', 'Gene', (51, 57))	('oesophageal squamous cell carcinoma', 'Disease', (99, 134))
846649	34003875	[Does SPOCK1 overexpression rescue the oncogenic effects (growth, invasion, EMT) of LINC00958 silencing?]	('SPOCK1', 'Gene', '6695', (6, 12))	('silencing', 'Var', (94, 103))	('LINC00958', 'Gene', '100506305', (84, 93))	('LINC00958', 'Gene', (84, 93))	('SPOCK1', 'Gene', (6, 12))	('invasion', 'CPA', (66, 74))
846650	34003875	Changes in the expression of LINC00958 will lead to changes in the expression of SPOCK1, which has been verified by western blot experiment (Fig 4D and E).	('LINC00958', 'Gene', '100506305', (29, 38))	('SPOCK1', 'Gene', (81, 87))	('LINC00958', 'Gene', (29, 38))	('Changes', 'Var', (0, 7))	('SPOCK1', 'Gene', '6695', (81, 87))	('expression', 'MPA', (67, 77))	('changes', 'Reg', (52, 59))
846659	34003875	According to our experimental results, overexpression of LINC00958 will promote the growth, migration, invasion and EMT of esophageal squamous cell carcinoma cells, while knocking down LINC00958 will get the opposite result (Page 12, lines 243-259).	('overexpression', 'PosReg', (39, 53))	('LINC00958', 'Gene', '100506305', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('invasion', 'CPA', (103, 111))	('esophageal squamous cell carcinoma', 'Disease', (123, 157))	('growth', 'CPA', (84, 90))	('promote', 'PosReg', (72, 79))	('migration', 'CPA', (92, 101))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (123, 157))	('LINC00958', 'Gene', '100506305', (185, 194))	('LINC00958', 'Gene', (57, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('knocking down', 'Var', (171, 184))	('LINC00958', 'Gene', (185, 194))	('EMT', 'CPA', (116, 119))
846661	34003875	Therefore, the overexpression of miR-510-5p can reduce the oncogenic effect of LINC00958 through the competitive binding of LINC00958.	('LINC00958', 'Gene', (79, 88))	('LINC00958', 'Gene', '100506305', (124, 133))	('overexpression', 'PosReg', (15, 29))	('LINC00958', 'Gene', (124, 133))	('miR-510-5p', 'Chemical', '-', (33, 43))	('competitive binding', 'Interaction', (101, 120))	('oncogenic effect', 'CPA', (59, 75))	('reduce', 'NegReg', (48, 54))	('miR-510-5p', 'Var', (33, 43))	('LINC00958', 'Gene', '100506305', (79, 88))
846662	34003875	[Does miR-510-5p loss-of-function rescue the oncogenic effects (growth, invasion, EMT) of LINC00958 silencing?]	('LINC00958', 'Gene', '100506305', (90, 99))	('miR-510-5p', 'Chemical', '-', (6, 16))	('loss-of-function', 'NegReg', (17, 33))	('silencing', 'Var', (100, 109))	('LINC00958', 'Gene', (90, 99))	('invasion', 'CPA', (72, 80))
846663	34003875	(MicroRNA library screening identifies growth-suppressive microRNAs that regulate genes involved in cell cycle progression and apoptosis) have been identified that miR-510-5p has tumor suppressor function and can inhibit cell growth.	('cell growth', 'CPA', (221, 232))	('miR-510-5p', 'Var', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('inhibit', 'NegReg', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('miR-510-5p', 'Chemical', '-', (164, 174))	('tumor', 'Disease', (179, 184))
846665	34003875	Theoretically, when the function of miR-510-5p was lost, it could no longer combine with LINC00958 competitively.	('combine', 'Interaction', (76, 83))	('LINC00958', 'Gene', (89, 98))	('LINC00958', 'Gene', '100506305', (89, 98))	('miR-510-5p', 'Chemical', '-', (36, 46))	('miR-510-5p', 'Var', (36, 46))
846669	34003875	We paid attention to miR-510-5p that had an active relationship with LINC00958 (Figure 4A).	('miR-510-5p', 'Var', (21, 31))	('miR-510-5p', 'Chemical', '-', (21, 31))	('LINC00958', 'Gene', (69, 78))	('LINC00958', 'Gene', '100506305', (69, 78))
846670	34003875	After that, the dual luciferase experiment was used to verify that miR-510-5p mimics significantly inhibited the luciferase activity of PmirGLO-LINC00958, but had no effect on PmirGLO-NC (Fig 4B), indicating that miR-510-5p and LINC00958 indeed have an interaction relationship.	('miR-510-5p', 'Chemical', '-', (213, 223))	('inhibited', 'NegReg', (99, 108))	('activity', 'MPA', (124, 132))	('LINC00958', 'Gene', '100506305', (228, 237))	('luciferase', 'Enzyme', (113, 123))	('miR-510-5p', 'Chemical', '-', (67, 77))	('LINC00958', 'Gene', (228, 237))	('LINC00958', 'Gene', '100506305', (144, 153))	('miR-510-5p', 'Var', (67, 77))	('LINC00958', 'Gene', (144, 153))
846689	34003875	We focus on miR-510-5p, and have predicted the competitive binding relationship between LINC00958 and miR-510-5p through the ENCORI website (Fig 4A).We used TargetScan to predict the downstream mRNA of miR-510-5p, and we focused on SPOCK1.	('miR-510-5p', 'Chemical', '-', (202, 212))	('SPOCK1', 'Gene', (232, 238))	('LINC00958', 'Gene', '100506305', (88, 97))	('miR-510-5p', 'Var', (202, 212))	('SPOCK1', 'Gene', '6695', (232, 238))	('miR-510-5p', 'Chemical', '-', (12, 22))	('LINC00958', 'Gene', (88, 97))	('miR-510-5p', 'Chemical', '-', (102, 112))
846693	34003875	Compared with the control group, miR-510-5p significantly inhibited the expression of SPOCK1 (Fig 4H and 4I), so miR-510-5p and SPOCK1 were evaluated in our manuscript.	('SPOCK1', 'Gene', '6695', (128, 134))	('SPOCK1', 'Gene', '6695', (86, 92))	('expression', 'MPA', (72, 82))	('miR-510-5p', 'Chemical', '-', (113, 123))	('miR-510-5p', 'Chemical', '-', (33, 43))	('miR-510-5p', 'Var', (33, 43))	('SPOCK1', 'Gene', (128, 134))	('inhibited', 'NegReg', (58, 67))	('SPOCK1', 'Gene', (86, 92))
846694	34003875	In addition, we will conduct more specific experiments to explain the related functions of miR-510-5p and SPOCK1.	('SPOCK1', 'Gene', '6695', (106, 112))	('SPOCK1', 'Gene', (106, 112))	('miR-510-5p', 'Var', (91, 101))	('miR-510-5p', 'Chemical', '-', (91, 101))
846702	34003875	[The authors demonstrated a little effect on the ESCC cell proliferation by overexpression or knockdown of LINC00958 (Figure 2C-D) within 3 days.	('knockdown', 'Var', (94, 103))	('LINC00958', 'Gene', '100506305', (107, 116))	('LINC00958', 'Gene', (107, 116))	('ESCC', 'Disease', (49, 53))	('overexpression', 'PosReg', (76, 90))
846713	34003875	The authors would be required to demonstrate that SPOCK1 knockdown or overexpression rescue the phenotypes observed as result of LINC00958 knockdown or overexpression.	('overexpression', 'PosReg', (152, 166))	('LINC00958', 'Gene', '100506305', (129, 138))	('knockdown', 'Var', (139, 148))	('SPOCK1', 'Gene', (50, 56))	('SPOCK1', 'Gene', '6695', (50, 56))	('knockdown', 'Var', (57, 66))	('LINC00958', 'Gene', (129, 138))
846716	34003875	However, more work is needed to conclude that the observed decrease in migration following LINC00958 modulation is specifically by the EMT pathway.	('migration', 'CPA', (71, 80))	('LINC00958', 'Gene', '100506305', (91, 100))	('modulation', 'Var', (101, 111))	('decrease', 'NegReg', (59, 67))	('LINC00958', 'Gene', (91, 100))
846719	34003875	Given the growing interest in the tumor promoting role for long noncoding RNAs in ESCC, this manuscript is of interest to the field.	('tumor', 'Disease', (34, 39))	('ESCC', 'Disease', (82, 86))	('long noncoding RNAs', 'Var', (59, 78))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
846723	34003875	While the authors argue that changes in SPOCK1 have been well-studied in ESCC and are associated with proliferation and EMT, this evidence likely does not extend to the small changes in SPOCK1 expression observed during LINC00958 over or underexpression.	('LINC00958', 'Gene', (220, 229))	('changes', 'Var', (29, 36))	('EMT', 'CPA', (120, 123))	('SPOCK1', 'Gene', '6695', (186, 192))	('associated', 'Reg', (86, 96))	('SPOCK1', 'Gene', (40, 46))	('SPOCK1', 'Gene', '6695', (40, 46))	('LINC00958', 'Gene', '100506305', (220, 229))	('ESCC', 'Disease', (73, 77))	('SPOCK1', 'Gene', (186, 192))
846724	34003875	The authors need to address this discrepancy, ideally by determining if SPOCK1 knockdown or overexpression rescue the phenotypes observed by LINC00958 knockdown or overexpression.	('SPOCK1', 'Gene', '6695', (72, 78))	('LINC00958', 'Gene', (141, 150))	('knockdown', 'Var', (79, 88))	('LINC00958', 'Gene', '100506305', (141, 150))	('SPOCK1', 'Gene', (72, 78))	('knockdown', 'Var', (151, 160))
846753	34003875	The authors need to address this discrepancy, ideally by determining if SPOCK1 knockdown or overexpression rescue the phenotypes observed by LINC00958 knockdown or overexpression.]	('SPOCK1', 'Gene', '6695', (72, 78))	('LINC00958', 'Gene', (141, 150))	('knockdown', 'Var', (79, 88))	('LINC00958', 'Gene', '100506305', (141, 150))	('SPOCK1', 'Gene', (72, 78))	('knockdown', 'Var', (151, 160))
846767	34003875	10 May 2021  PONE-D-20-41067R2  LINC00958 promotes proliferation, migration, invasion, and Epithelial-Mesenchymal Transition of oesophageal squamous cell carcinoma cells  Dear Dr. Wang: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('Epithelial-Mesenchymal Transition', 'CPA', (91, 124))	('migration', 'CPA', (66, 75))	('invasion', 'CPA', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('proliferation', 'CPA', (51, 64))	('promotes', 'PosReg', (42, 50))	('oesophageal squamous cell carcinoma', 'Disease', (128, 163))	('LINC00958', 'Gene', '100506305', (32, 41))	('LINC00958', 'Gene', (32, 41))	('PONE-D-20-41067R2', 'Var', (13, 30))	('PONE-D-20-41067', 'Chemical', '-', (13, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 163))
846789	33462372	Interestingly, FAP is expressed in the stroma of more than 90% of human cancers and has an important role in tumor progression, with high FAP tumor expression being associated with a poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('high', 'Var', (133, 137))	('tumor', 'Disease', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('FAP tumor', 'Disease', 'MESH:C567782', (138, 147))	('human', 'Species', '9606', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('FAP tumor', 'Disease', (138, 147))	('tumor', 'Disease', (109, 114))
846807	33462372	In the TE4 cells alone group, tumor growth could be suppressed by 5-FU compared with control treatment (39.0% reduction, day 28, P < 0.05) (Fig.	('TE4', 'Chemical', '-', (7, 10))	('5-FU', 'Var', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('suppressed', 'NegReg', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('5-FU', 'Chemical', '-', (66, 70))
846811	33462372	The migration assay showed that the number of migrated cancer cells was increased in each cancer cell line for tumor cells stimulated with CM from CAFs (CM/CAFTE4 or CM/CAFOE19) compared with control tumor cells, whereas migration was not upregulated in cancer cells stimulated with normal fibroblasts (CM/NF) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Disease', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Disease', (200, 205))	('CM/CAFOE19', 'Var', (166, 176))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('migration', 'CPA', (4, 13))	('cancer', 'Disease', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('CAFs', 'Var', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('tumor', 'Disease', (111, 116))	('CAFTE4', 'Chemical', '-', (156, 162))	('CM from CAFs', 'Var', (139, 151))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('increased', 'PosReg', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('CAFOE19', 'Chemical', '-', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (90, 96))
846814	33462372	2) The spheroid formation assay showed that cancer cells could make larger spheroids under stimulation with CAFs than under control treatment, demonstrating that spheroid formation was enhanced by CM/CAF, and the effects were strong under conditions of direct contact between cancer cells and CAFs (TE4DC and OE19DC) (Fig.	('spheroid formation', 'CPA', (162, 180))	('cancer', 'Disease', (276, 282))	('TE4', 'Chemical', '-', (299, 302))	('enhanced', 'PosReg', (185, 193))	('CM/CAF', 'Var', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
846816	33462372	First, we observed morphological changes in cancer cells, demonstrating that the population of tumor cells that had fewer cell junctions and elongated pseudopodia was increased in CAF-treated cells compared with untreated control cells.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('increased', 'PosReg', (167, 176))	('CAF-treated', 'Var', (180, 191))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cell junctions', 'CPA', (122, 136))	('tumor', 'Disease', (95, 100))
846819	33462372	The populations of CD44- and CD133-, which are considered markers of cancer stem cells, positive cells were analyzed by flow cytometry.	('CD44-', 'Var', (19, 24))	('CD133-', 'Var', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
846826	33462372	In brief, tumor cells were stimulated with CM from CAFs (CM/CAFTE4, OE19) continuously until measurement (labeled TE4CM/CAF or OE19CM/CAF).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('TE4CM/CAF', 'Gene', (114, 123))	('OE19CM/CAF', 'Var', (127, 137))	('TE4CM/CAF', 'Gene', '104272', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('CAFTE4', 'Chemical', '-', (60, 66))
846828	33462372	Then, this CM stimulation was stopped, and the medium was changed back to normal medium (TE4R or OE19R) to eliminate CAF effects (Fig.	('TE4R', 'Var', (89, 93))	('OE19R', 'Var', (97, 102))	('TE4', 'Chemical', '-', (89, 92))
846829	33462372	Although TE4CM/CAF and OE19CM/CAF cells acquired resistance to 5-FU, as in the other experiments, the acquired therapeutic resistance was diminished once stimulation with CM/CAFs was eliminated, as demonstrated in the TE4R and OE19R groups (Fig.	('OE19R', 'Var', (227, 232))	('OE19CM/CAF', 'Var', (23, 33))	('TE4CM/CAF', 'Gene', (9, 18))	('5-FU', 'Chemical', '-', (63, 67))	('TE4', 'Chemical', '-', (9, 12))	('resistance to 5-FU', 'MPA', (49, 67))	('TE4R', 'Var', (218, 222))	('diminished', 'NegReg', (138, 148))	('TE4', 'Chemical', '-', (218, 221))	('TE4CM/CAF', 'Gene', '104272', (9, 18))
846835	33462372	Based on these results, we next further confirmed whether FAP-IR700 binds to FAP-expressing cells and evaluated the effect of NIR-PIT on those cells.	('FAP-IR700', 'Var', (58, 67))	('IR700', 'Chemical', '-', (62, 67))	('binds', 'Interaction', (68, 73))
846838	33462372	Most of the CAFs educated by either TE4 or OE19 cells exhibited cell disruption (CAFTE4: 98.7% reduction, P < 0.01, CAFOE19: 98.7%, P < 0.01) by FAP-targeted NIR-PIT.	('OE19', 'Var', (43, 47))	('CAFOE19', 'Chemical', '-', (116, 123))	('cell disruption', 'CPA', (64, 79))	('TE4', 'Var', (36, 39))	('reduction', 'NegReg', (95, 104))	('TE4', 'Chemical', '-', (36, 39))	('TE4', 'Chemical', '-', (84, 87))	('CAFTE4', 'Chemical', '-', (81, 87))
846841	33462372	In addition, even in the coculture model in vitro, only CAFs seemed to be damaged by NIR-PIT, which caused cell death.	('NIR-PIT', 'Var', (85, 92))	('death', 'Disease', 'MESH:D003643', (112, 117))	('death', 'Disease', (112, 117))
846847	33462372	6b, 5-FU: 13.3% reduction, combination of 5-FU and NIR-PIT: 70.9% reduction, day 28, P < 0.01), indicating that elimination of CAFs contributed to the recovery of drug sensitivity and led to tumor suppression.	('elimination', 'Var', (112, 123))	('drug sensitivity', 'Phenotype', 'HP:0020174', (163, 179))	('drug sensitivity', 'MPA', (163, 179))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('recovery', 'MPA', (151, 159))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('5-FU', 'Chemical', '-', (4, 8))	('5-FU', 'Chemical', '-', (42, 46))
846862	33462372	Based on our previous reports, our review on day 21 showed a clear difference in tumor reduction at 21 days between NIR-PIT alone and NIR-PIT with 5-FU: 42.5% reduction and 71.4% reduction, respectively, although we did not compare two groups in this research.	('tumor reduction', 'Disease', 'MESH:D007022', (81, 96))	('tumor reduction', 'Disease', (81, 96))	('NIR-PIT', 'Var', (134, 141))	('5-FU', 'Chemical', '-', (147, 151))	('reduction', 'NegReg', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
846874	33462372	Furthermore, CAFs secrete extracellular matrix (ECM) components, such as collagen, proteogrican and vascular endothelial growth factor (VEGF); thus, the presence of CAFs causes angiogenesis, which is required for abundant stroma and tumor growth.	('causes', 'Reg', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('CAFs', 'Gene', (165, 169))	('tumor', 'Disease', (233, 238))	('VEGF', 'Gene', '22339', (136, 140))	('angiogenesis', 'CPA', (177, 189))	('vascular endothelial growth factor', 'Gene', (100, 134))	('presence', 'Var', (153, 161))	('vascular endothelial growth factor', 'Gene', '22339', (100, 134))	('VEGF', 'Gene', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
846876	33462372	Third, in addition to those reasons, it has been reported that NIR-PIT targeting cancer cells induces perivascular cell death, resulting in massive leakage of nanoparticles into the tumor beds.	('tumor', 'Disease', (182, 187))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('death', 'Disease', 'MESH:D003643', (120, 125))	('death', 'Disease', (120, 125))	('cancer', 'Disease', (81, 87))	('NIR-PIT', 'Var', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('leakage of nanoparticles into the', 'MPA', (148, 181))
846896	33462372	After 24 h, the medium was replaced with DMEM containing 2% FBS or CM/TE4 or CM/OE19, and the cells were incubated for 2 days.	('TE4', 'Chemical', '-', (70, 73))	('CM/TE4', 'Var', (67, 73))	('CM/OE19', 'Var', (77, 84))	('DMEM', 'Chemical', '-', (41, 45))
846899	33462372	After 24 h, the medium was replaced with DMEM containing 2% FBS (control) or CM from activated FEF3 cells (CM/CAFTE4 or CM/CAFOE19); these tumor cells were termed TE4CM/CAF or OE19CM/CAF.	('OE19CM/CAF', 'Var', (176, 186))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('TE4CM/CAF', 'Gene', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('CAFTE4', 'Chemical', '-', (110, 116))	('TE4CM/CAF', 'Gene', '104272', (163, 172))	('CAFOE19', 'Chemical', '-', (123, 130))	('DMEM', 'Chemical', '-', (41, 45))
846902	33462372	Tumor cells were stimulated for 4 days with CM/CAFTE4 or CM/CAFOE19 (TE4CM or OE19CM) or cocultured with tumor cells and fibroblasts (TE4DC or OE19DC).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TE4', 'Chemical', '-', (134, 137))	('TE4', 'Chemical', '-', (69, 72))	('CAFOE19', 'Chemical', '-', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('TE4DC', 'Var', (134, 139))	('CM/CAFTE4', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('TE4CM', 'Var', (69, 74))	('OE19DC', 'Var', (143, 149))	('TE4', 'Chemical', '-', (50, 53))	('CAFTE4', 'Chemical', '-', (47, 53))	('tumor', 'Disease', (105, 110))	('OE19CM', 'Var', (78, 84))
846907	33462372	TE4 and OE19 cells were plated in 96-well microplates (TE4: 3 x 103/well, OE19: 5 x 103/well) and incubated (at 37  C with 5% CO2) for 24 h. Then, the medium was changed to DMEM supplemented with 2% FBS (control), CM from CAFs (CM/CAFTE4 or CM/CAFOE19) or normal FEF3 cells (CM/NF), and the cells were cultured for 2 days.	('TE4', 'Chemical', '-', (0, 3))	('TE4', 'Chemical', '-', (234, 237))	('CAFOE19', 'Chemical', '-', (244, 251))	('CM/CAFOE19', 'Var', (241, 251))	('TE4', 'Chemical', '-', (55, 58))	('CM/CAFTE4', 'Var', (228, 237))	('CO2', 'Chemical', 'MESH:D002245', (126, 129))	('DMEM', 'Chemical', '-', (173, 177))	('CAFTE4', 'Chemical', '-', (231, 237))
846908	33462372	The tumor cells cultured with CM/NF were termed TE4CM/NF or OE19CM/NF.	('tumor', 'Disease', (4, 9))	('TE4', 'Chemical', '-', (48, 51))	('OE19CM/NF', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('TE4CM/NF', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
846911	33462372	In the migration assay, tumor cells (1 x 105) were seeded in the upper compartment in 500 muL of serum-free DMEM or CM from CAFs (CM/CAFTE4 or CM/CAFOE19) or FEF3 cells (CM/NF).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('CM/CAFOE19', 'Var', (143, 153))	('tumor', 'Disease', (24, 29))	('DMEM', 'Chemical', '-', (108, 112))	('CAFOE19', 'Chemical', '-', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('CAFTE4', 'Chemical', '-', (133, 139))
846915	33462372	Then, the medium was changed to normal medium (control) or CM from CAFs (CM/CAFTE4 or CM/CAFOE19), and the cells were cultured for 2 days.	('CAFTE4', 'Chemical', '-', (76, 82))	('CM/CAFTE4', 'Var', (73, 82))	('CM/CAFOE19', 'Var', (86, 96))	('CAFOE19', 'Chemical', '-', (89, 96))
846918	33462372	Tumor cells were stimulated for 4 days with CM/CAFTE4 or CM/CAFOE19 (TE4CM/CAF or OE19CM/CAF) or cocultured with fibroblasts (TE4DC or OE19DC).	('TE4CM/CAF', 'Gene', (69, 78))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TE4', 'Chemical', '-', (126, 129))	('TE4', 'Chemical', '-', (69, 72))	('CAFOE19', 'Chemical', '-', (60, 67))	('TE4DC', 'Var', (126, 131))	('CM/CAFTE4', 'Var', (44, 53))	('TE4CM/CAF', 'Gene', '104272', (69, 78))	('OE19CM/CAF', 'Var', (82, 92))	('TE4', 'Chemical', '-', (50, 53))	('CAFTE4', 'Chemical', '-', (47, 53))	('OE19DC', 'Var', (135, 141))
846937	33462372	Tumor cells (TE4: 1 x 104/well, OE19: 6 x 103/well) were plated (in 96-well microplates) and stimulated with CM from CAFs (CM/CAFTE4 or CM/CAFOE19) or normal medium for 2 days.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CM/CAFTE4', 'Var', (123, 132))	('CAFOE19', 'Chemical', '-', (139, 146))	('TE4', 'Chemical', '-', (129, 132))	('CAFTE4', 'Chemical', '-', (126, 132))	('CM/CAFOE19', 'Var', (136, 146))	('TE4', 'Chemical', '-', (13, 16))
846970	33462372	Administrative, technical, or material support (i.e., reporting or organizing data and constructing databases): R.K., H.K., K.N., H.T., S.K., H.K., T.F.	('K.N.', 'Var', (124, 128))	('H.T', 'Disease', 'MESH:D000848', (130, 133))	('S.K.', 'Var', (136, 140))	('H.K.', 'Var', (118, 122))	('H.K.', 'Var', (142, 146))	('H.T', 'Disease', (130, 133))	('R.K.', 'Var', (112, 116))
846971	33462372	Study supervision: K.N., S.K., H.T., S.K., H.K., T.F.	('H.K.', 'Var', (43, 47))	('S.K.', 'Var', (37, 41))	('H.T', 'Disease', 'MESH:D000848', (31, 34))	('H.T', 'Disease', (31, 34))
846982	32296343	Although these Paneth cell alterations are frequently associated with chronic inflammation, the molecular mechanism and significance of Paneth cell-related pathologies are poorly understood.	('inflammation', 'Disease', 'MESH:D007249', (78, 90))	('inflammation', 'Disease', (78, 90))	('associated', 'Reg', (54, 64))	('alterations', 'Var', (27, 38))
846997	32296343	Additionally, during repair and regeneration of damaged epithelium in IBD patients, there might be an increased chance of mutation accumulation (cyclic hit model, described in later paragraphs), and the metaplastic Paneth cells may contribute to accelerated epithelial tumorigenesis by providing stem cell growth factor to tumor cells.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('IBD', 'Phenotype', 'HP:0002037', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('stem cell growth factor', 'CPA', (296, 319))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('accelerated', 'PosReg', (246, 257))	('mutation', 'Var', (122, 130))	('tumor', 'Disease', (323, 328))	('patients', 'Species', '9606', (74, 82))	('IBD', 'Disease', (70, 73))	('tumor', 'Disease', (269, 274))	('IBD', 'Disease', 'MESH:D015212', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (323, 328))
847013	32296343	This continuous process of paligenosis increases the risk of accumulation of mutations leading to emergence of a neoplastic or dysplastic clone.	('dysplastic', 'Disease', 'MESH:D004416', (127, 137))	('mutations', 'Var', (77, 86))	('dysplastic', 'Disease', (127, 137))
847022	32296343	However, other studies showed that eradication of H. pylori somewhat reduced the IM.	('reduced', 'NegReg', (69, 76))	('H. pylori', 'Species', '210', (50, 59))	('H. pylori', 'Disease', (50, 59))	('eradication', 'Var', (35, 46))
847025	32296343	However, these changes may also indirectly alter the gastric colonization of H. pylori or other bacterial species.	('H. pylori', 'Disease', (77, 86))	('gastric colonization', 'CPA', (53, 73))	('changes', 'Var', (15, 22))	('alter', 'Reg', (43, 48))	('H. pylori', 'Species', '210', (77, 86))
847075	31548877	Univariate and multivariate analysis also revealed XIAP as an independent prognostic factor for overall survival in ESCC patients.	('ESCC', 'Disease', (116, 120))	('patients', 'Species', '9606', (121, 129))	('ESCC', 'Disease', 'MESH:D018307', (116, 120))	('XIAP', 'Var', (51, 55))
847076	31548877	In both EC9706 and TE13 cell lines, knockdown of XIAP decreased the migration of cancer cells by inhibiting EMT process through regulating the TGF-beta signaling pathway, pinpointing a regulatory role of XIAP in migratory process upon TGF-beta activation.	('XIAP', 'Gene', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('TGF-beta', 'Gene', '7040', (235, 243))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('knockdown', 'Var', (36, 45))	('TGF-beta', 'Gene', (235, 243))	('decreased', 'NegReg', (54, 63))	('TGF-beta', 'Gene', '7040', (143, 151))	('EMT process', 'CPA', (108, 119))	('regulating', 'Reg', (128, 138))	('TGF-beta', 'Gene', (143, 151))	('inhibiting', 'NegReg', (97, 107))
847101	31548877	The primary antibodies used in our study including XIAP (1:1000, NO.14334, CST, USA), E-cadherin (1:2000, NO.ab53226 Abcam, USA), N-cadherin (1:1000, NO.ab18203, Abcam, USA), Vimentin (1:1000, NO.ab92547, Abcam, USA), TGF-beta (1:1000, NO.3711s, CST, USA), GAPDH (1:5000, NO.HRP-60004, Proteintech, USA).	('Vimentin', 'Gene', '7431', (175, 183))	('GAPDH', 'Gene', '2597', (257, 262))	('CST', 'Gene', '106478911', (246, 249))	('TGF-beta', 'Gene', '7040', (218, 226))	('Vimentin', 'Gene', (175, 183))	('N-cadherin', 'Gene', (130, 140))	('CST', 'Gene', (75, 78))	('GAPDH', 'Gene', (257, 262))	('1:1000', 'Var', (185, 191))	('N-cadherin', 'Gene', '1000', (130, 140))	('TGF-beta', 'Gene', (218, 226))	('CST', 'Gene', (246, 249))	('CST', 'Gene', '106478911', (75, 78))	('1:1000', 'Var', (142, 148))	('1:1000', 'Var', (228, 234))	('1:2000', 'Var', (98, 104))	('NO.ab53226', 'Var', (106, 116))	('E-cadherin', 'Gene', (86, 96))	('E-cadherin', 'Gene', '999', (86, 96))
847105	31548877	The primary antibodies were E-cadherin (1:500, NO.ab53226, Abcam, USA), N-cadherin (1:200, NO.ab18203, Abcam, USA), Vimentin (1:200, NO.ab92547, Abcam, USA).	('1:500', 'Var', (40, 45))	('Vimentin', 'Gene', '7431', (116, 124))	('NO.ab18203', 'Var', (91, 101))	('1:200', 'Var', (126, 131))	('NO.ab53226', 'Var', (47, 57))	('N-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', (28, 38))	('Vimentin', 'Gene', (116, 124))	('E-cadherin', 'Gene', '999', (28, 38))	('N-cadherin', 'Gene', '1000', (72, 82))	('1:200', 'Var', (84, 89))
847112	31548877	Mice at age of 6 weeks were randomly divided into two groups, EC9706 (sh-Ctrl) and EC9706 (sh-XIAP) were injected into nude mice via an I.V.	('nude mice', 'Species', '10090', (119, 128))	('EC9706', 'Var', (62, 68))	('EC9706', 'Var', (83, 89))	('Mice', 'Species', '10090', (0, 4))
847119	31548877	Kaplan-Meier analysis demonstrated that patients with high expression of XIAP exhibited worse overall survival (OS) compared with the low expression group (p = 0.004, Fig.	('XIAP', 'Gene', (73, 77))	('high expression', 'Var', (54, 69))	('overall survival', 'MPA', (94, 110))	('patients', 'Species', '9606', (40, 48))	('worse', 'NegReg', (88, 93))
847123	31548877	This finding suggested that XIAP knockdown could effectively inhibit the migration ability of ESCC cells.	('inhibit', 'NegReg', (61, 68))	('knockdown', 'Var', (33, 42))	('ESCC', 'Disease', 'MESH:D018307', (94, 98))	('ESCC', 'Disease', (94, 98))
847124	31548877	We have demonstrated that XIAP knockdown inhibited the migration of ESCC cells.	('ESCC', 'Disease', (68, 72))	('inhibited', 'NegReg', (41, 50))	('XIAP', 'Gene', (26, 30))	('ESCC', 'Disease', 'MESH:D018307', (68, 72))	('knockdown', 'Var', (31, 40))
847127	31548877	3a, b, epithelial marker (E-cadherin) was remarkably increased while the mesenchymal markers (N-cadherin and Vimentin) were decreased in sh-XIAP groups by immunofluorescence assay and also confirmed by qRT-PCR and Western blotting.	('epithelial marker', 'CPA', (7, 24))	('E-cadherin', 'Gene', (26, 36))	('Vimentin', 'Gene', (109, 117))	('decreased', 'NegReg', (124, 133))	('N-cadherin', 'Gene', (94, 104))	('mesenchymal markers', 'CPA', (73, 92))	('E-cadherin', 'Gene', '999', (26, 36))	('increased', 'PosReg', (53, 62))	('Vimentin', 'Gene', '7431', (109, 117))	('sh-XIAP', 'Var', (137, 144))	('N-cadherin', 'Gene', '1000', (94, 104))
847128	31548877	3c, d, XIAP knockdown in ESCC cells led to up-regulate E-Cadherin and down-regulate N-Cadherin and Vimentin.	('E-Cadherin', 'Gene', '999', (55, 65))	('up-regulate', 'PosReg', (43, 54))	('ESCC', 'Disease', 'MESH:D018307', (25, 29))	('Vimentin', 'Gene', '7431', (99, 107))	('knockdown', 'Var', (12, 21))	('ESCC', 'Disease', (25, 29))	('down-regulate', 'NegReg', (70, 83))	('E-Cadherin', 'Gene', (55, 65))	('N-Cadherin', 'Gene', (84, 94))	('Vimentin', 'Gene', (99, 107))	('N-Cadherin', 'Gene', '1000', (84, 94))
847129	31548877	The number of lung metastatic tumors in mice injected with EC9706 (sh-Ctrl) cells was remarkably increased than sh-XIAP group (Fig.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('EC9706', 'Var', (59, 65))	('increased', 'PosReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mice', 'Species', '10090', (40, 44))	('lung metastatic tumors', 'Disease', 'MESH:D008175', (14, 36))	('lung metastatic tumors', 'Disease', (14, 36))
847131	31548877	XIAP knockdown led to up-regulate E-Cadherin and down-regulate N-Cadherin and Vimentin.	('XIAP', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('E-Cadherin', 'Gene', (34, 44))	('N-Cadherin', 'Gene', (63, 73))	('E-Cadherin', 'Gene', '999', (34, 44))	('Vimentin', 'Gene', (78, 86))	('N-Cadherin', 'Gene', '1000', (63, 73))	('down-regulate', 'NegReg', (49, 62))	('up-regulate', 'PosReg', (22, 33))	('Vimentin', 'Gene', '7431', (78, 86))
847136	31548877	The number of cells treated with exogenous TGF-beta exhibited significantly increased compared with sh-XIAP groups (Fig.	('increased', 'PosReg', (76, 85))	('exogenous', 'Var', (33, 42))	('TGF-beta', 'Gene', (43, 51))	('TGF-beta', 'Gene', '7040', (43, 51))
847139	31548877	These results demonstrated that XIAP knockdown suppressed EMT of ESCC cells depending on TGF-beta signaling.	('suppressed', 'NegReg', (47, 57))	('ESCC', 'Disease', 'MESH:D018307', (65, 69))	('knockdown', 'Var', (37, 46))	('EMT of', 'CPA', (58, 64))	('XIAP', 'Gene', (32, 36))	('ESCC', 'Disease', (65, 69))	('TGF-beta', 'Gene', '7040', (89, 97))	('TGF-beta', 'Gene', (89, 97))
847149	31548877	Kaplan-Meier analysis indicated that ESCC patients with high XIAP expression in general had worse prognosis than those with low XIAP expression.	('ESCC', 'Disease', 'MESH:D018307', (37, 41))	('patients', 'Species', '9606', (42, 50))	('high XIAP expression', 'Var', (56, 76))	('ESCC', 'Disease', (37, 41))
847150	31548877	Univariate and multivariate Cox regression analysis indicated that high XIAP expression was an independent risk factor for the prognosis of ESCC patients.	('patients', 'Species', '9606', (145, 153))	('ESCC', 'Disease', 'MESH:D018307', (140, 144))	('expression', 'MPA', (77, 87))	('high', 'Var', (67, 71))	('ESCC', 'Disease', (140, 144))	('XIAP', 'Gene', (72, 76))
847156	31548877	In response to a Wnt signal, XIAP was recruited to mono-ubiquitinates TLE and liberated TCF to form transcription complexes with beta-catenin to active Wnt signal which was a key step in activate cell migration.	('TLE', 'Disease', (70, 73))	('beta-catenin', 'Gene', (129, 141))	('TCF', 'Gene', '3172', (88, 91))	('TCF', 'Gene', (88, 91))	('mono-ubiquitinates', 'Var', (51, 69))	('beta-catenin', 'Gene', '1499', (129, 141))	('TLE', 'Disease', 'MESH:D004833', (70, 73))
847158	31548877	The results showed that XIAP knockdown could suppress the ESCC migration compared with control group.	('suppress', 'NegReg', (45, 53))	('knockdown', 'Var', (29, 38))	('ESCC', 'Disease', 'MESH:D018307', (58, 62))	('ESCC', 'Disease', (58, 62))	('XIAP', 'Gene', (24, 28))
847160	31548877	Knockdown of XIAP could change the expression of several typical EMT markers, including up-regulation epithelial marker (E-cadherin) and down-regulation of mesenchymal markers (N-cadherin and Vimentin).	('Vimentin', 'Gene', '7431', (192, 200))	('N-cadherin', 'Gene', '1000', (177, 187))	('change', 'Reg', (24, 30))	('Knockdown', 'Var', (0, 9))	('E-cadherin', 'Gene', '999', (121, 131))	('mesenchymal', 'CPA', (156, 167))	('up-regulation', 'PosReg', (88, 101))	('expression', 'MPA', (35, 45))	('down-regulation', 'NegReg', (137, 152))	('E-cadherin', 'Gene', (121, 131))	('Vimentin', 'Gene', (192, 200))	('XIAP', 'Gene', (13, 17))	('N-cadherin', 'Gene', (177, 187))
847161	31548877	We also found that XIAP could promote lung metastasis and EMT of ESCC cells in vivo nude mice.	('promote', 'PosReg', (30, 37))	('XIAP', 'Var', (19, 23))	('ESCC', 'Disease', 'MESH:D018307', (65, 69))	('nude mice', 'Species', '10090', (84, 93))	('lung metastasis', 'CPA', (38, 53))	('ESCC', 'Disease', (65, 69))
847168	31548877	In conclusion, the present study revealed that XIAP significantly correlated with a poor prognosis of ESCC.	('ESCC', 'Disease', (102, 106))	('ESCC', 'Disease', 'MESH:D018307', (102, 106))	('XIAP', 'Var', (47, 51))
847187	31235994	In doing so, this study seeks to better understand how PPIs could alter, via gut microbiota imbalance, human homeostasis.	('human', 'Species', '9606', (103, 108))	('human homeostasis', 'MPA', (103, 120))	('imbalance', 'Phenotype', 'HP:0002172', (92, 101))	('alter', 'Reg', (66, 71))	('PPIs', 'Var', (55, 59))
847202	31235994	Moreover, the presence of Fusobacterium nucleatum (F. nucleatum) has been described in esophageal cancers and has been associated with a poor prognosis, suggesting its potential role as a prognostic biomarker.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('presence', 'Var', (14, 22))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('esophageal cancers', 'Disease', (87, 105))	('F. nucleatum', 'Species', '851', (51, 63))	('esophageal cancers', 'Disease', 'MESH:D004938', (87, 105))	('Fusobacterium nucleatum', 'Species', '851', (26, 49))	('Fusobacterium nucleatum', 'Var', (26, 49))	('described', 'Reg', (74, 83))
847203	31235994	Finally, esophageal samples of BE with high-grade dysplasia and EAC show a decreased microbiota diversity and a relative abundance of Lactobacillales that, through their capability to acidify the microenvironment and to produce harmful substances such as hydrogen peroxide, might contribute to the development of these diseases.	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (255, 272))	('produce', 'MPA', (220, 227))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('contribute', 'Reg', (280, 290))	('Lactobacillales', 'Gene', (134, 149))	('microbiota diversity', 'CPA', (85, 105))	('dysplasia', 'Disease', (50, 59))	('dysplasia', 'Disease', 'MESH:D004476', (50, 59))	('high-grade', 'Var', (39, 49))	('acidify', 'MPA', (184, 191))	('EAC', 'Disease', (64, 67))	('BE', 'Phenotype', 'HP:0100580', (31, 33))	('decreased', 'NegReg', (75, 84))
847211	31235994	Moreover, high gastric pH values can give rise to a different bacterial balance characterized by a significant increase in oral bacteria, such as Pepto-streptococcus stomatis, Streptococcus anginosus, Parvimonas micra, Slackia exigua and Dialister pneumosintes.	('increase', 'PosReg', (111, 119))	('Pepto-streptococcus stomatis', 'Disease', (146, 174))	('Dialister pneumosintes', 'Disease', (238, 260))	('Slackia exigua', 'Species', '84109', (219, 233))	('Streptococcus anginosus', 'Disease', (176, 199))	('streptococcus', 'Species', '1328', (152, 165))	('Dialister pneumosintes', 'Species', '39950', (238, 260))	('Slackia exigua', 'Disease', (219, 233))	('Parvimonas micra', 'Disease', (201, 217))	('oral', 'Disease', (123, 127))	('bacterial', 'MPA', (62, 71))	('Parvimonas micra', 'Species', '33033', (201, 217))	('high', 'Var', (10, 14))	('Streptococcus anginosus', 'Species', '1328', (176, 199))
847231	31235994	PPI-induced dysbiosis may represent a risk factor for hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP) in cirrhotic patients.	('bacterial peritonitis', 'Disease', 'MESH:D010534', (98, 119))	('encephalopathy', 'Phenotype', 'HP:0001298', (62, 76))	('patients', 'Species', '9606', (139, 147))	('PPI-induced', 'Var', (0, 11))	('peritonitis', 'Phenotype', 'HP:0002586', (108, 119))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (54, 76))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (54, 76))	('hepatic encephalopathy', 'Disease', (54, 76))	('bacterial peritonitis', 'Disease', (98, 119))	('dysbiosis', 'Disease', (12, 21))	('dysbiosis', 'Disease', 'MESH:D064806', (12, 21))	('HE', 'Phenotype', 'HP:0002480', (78, 80))
847234	31235994	It is noteworthy that some of the microbial changes caused by PPIs are the same as the alterations already present in patients with cirrhosis and especially in patients with decompensated cirrhosis including the relative increase of potentially pathogenic bacteria such as Staphylococcaeae, Enterobacteriaceae and Enterococcaceae.	('PPIs', 'Var', (62, 66))	('patients', 'Species', '9606', (160, 168))	('cirrhosis', 'Disease', 'MESH:D005355', (132, 141))	('Enterococcaceae', 'Disease', (314, 329))	('cirrhosis', 'Phenotype', 'HP:0001394', (188, 197))	('Staphylococcaeae', 'Disease', (273, 289))	('increase', 'PosReg', (221, 229))	('cirrhosis', 'Disease', (132, 141))	('cirrhosis', 'Disease', 'MESH:D005355', (188, 197))	('Enterobacteriaceae', 'Enzyme', (291, 309))	('patients', 'Species', '9606', (118, 126))	('cirrhosis', 'Phenotype', 'HP:0001394', (132, 141))	('cirrhosis', 'Disease', (188, 197))
847238	31235994	PPIs have also been reported to exacerbate the mucosal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) in the distal portion of the small bowel to the ligament of Treitz, which stands in contrast to the protective effects of PPIs on NSAIDs-induced upper GI mucosal injury.	('upper GI mucosal injury', 'Disease', (264, 287))	('mucosal damage', 'Disease', 'MESH:D009059', (47, 61))	('exacerbate', 'PosReg', (32, 42))	('upper GI mucosal injury', 'Disease', 'MESH:D052016', (264, 287))	('PPIs', 'Var', (0, 4))	('mucosal damage', 'Disease', (47, 61))
847242	31235994	Moreover, PPIs augmented the expression of bacteria with beta-glucuronidases activity, and this microbial imbalance could promote the spread of NSAIDs into enterohepatic circulation, increasing bile cytotoxicity and subsequently causing ulcerative lesions.	('increasing', 'PosReg', (183, 193))	('spread', 'MPA', (134, 140))	('ulcer', 'Disease', (237, 242))	('ulcer', 'Disease', 'MESH:D014456', (237, 242))	('beta-glucuronidases', 'Enzyme', (57, 76))	('cytotoxicity', 'Disease', (199, 211))	('promote', 'PosReg', (122, 129))	('augmented', 'PosReg', (15, 24))	('imbalance', 'Phenotype', 'HP:0002172', (106, 115))	('activity', 'MPA', (77, 85))	('causing', 'Reg', (229, 236))	('expression', 'MPA', (29, 39))	('cytotoxicity', 'Disease', 'MESH:D064420', (199, 211))	('PPIs', 'Var', (10, 14))
847247	31235994	Therefore, it is reasonable to assume that PPI-driven dysbiosis significantly impacts host health.	('PPI-driven', 'Var', (43, 53))	('impacts', 'Reg', (78, 85))	('dysbiosis', 'Disease', (54, 63))	('host health', 'CPA', (86, 97))	('dysbiosis', 'Disease', 'MESH:D064806', (54, 63))
847248	31235994	PPIs can influence the onset of enteric infections, resulting in an increased risk of Clostridium difficile infection (CDI), as well as Salmonella, Campylobacter and diarrheagenic Escherichia coli (E. coli).	('enteric infections', 'Disease', 'MESH:D004751', (32, 50))	('diarrhea', 'Disease', 'MESH:D003967', (166, 174))	('influence', 'Reg', (9, 18))	('E. coli', 'Species', '562', (198, 205))	('Campylobacter', 'Species', '199', (148, 161))	('CDI', 'Phenotype', 'HP:0032167', (119, 122))	('infection', 'Disease', (40, 49))	('Escherichia coli', 'Species', '562', (180, 196))	('infection', 'Disease', 'MESH:D007239', (40, 49))	('Clostridium difficile', 'Species', '1496', (86, 107))	('CD', 'Phenotype', 'HP:0100280', (119, 121))	('diarrhea', 'Phenotype', 'HP:0002014', (166, 174))	('PPIs', 'Var', (0, 4))	('Campylobacter', 'Disease', (148, 161))	('Salmonella', 'Disease', (136, 146))	('CD', 'Disease', 'MESH:D006223', (119, 121))	('enteric infections', 'Disease', (32, 50))	('infection', 'Disease', (108, 117))	('infection', 'Disease', 'MESH:D007239', (108, 117))	('diarrhea', 'Disease', (166, 174))	('Clostridium difficile infection', 'Phenotype', 'HP:0032167', (86, 117))
847249	31235994	Even if not fully clarified, it has been hypothesized that, in CDI, a reduction in alpha diversity and a decrease in the abundance of bacteria of the Ruminococcoceae associated with an increase in the Enterobacteriaceae, Enterococcoceae and Lactobacillaceae families observed during long-term PPI treatment could facilitate the onset of infection.	('increase', 'PosReg', (185, 193))	('reduction', 'NegReg', (70, 79))	('abundance', 'MPA', (121, 130))	('CDI', 'Phenotype', 'HP:0032167', (63, 66))	('Enterobacteriaceae', 'Enzyme', (201, 219))	('infection', 'Disease', (337, 346))	('alpha diversity', 'MPA', (83, 98))	('Enterococcoceae', 'Enzyme', (221, 236))	('CD', 'Disease', 'MESH:D006223', (63, 65))	('infection', 'Disease', 'MESH:D007239', (337, 346))	('CD', 'Phenotype', 'HP:0100280', (63, 65))	('PPI', 'Var', (293, 296))	('decrease', 'NegReg', (105, 113))
847259	31235994	In the context of dysbiosis, PPIs may lead to short-term flare ups in the course of IBDs.	('PPIs', 'Var', (29, 33))	('dysbiosis', 'Disease', (18, 27))	('dysbiosis', 'Disease', 'MESH:D064806', (18, 27))	('IBD', 'Phenotype', 'HP:0002037', (84, 87))	('lead to', 'Reg', (38, 45))	('flare ups', 'MPA', (57, 66))	('IBDs', 'Disease', (84, 88))
847261	31235994	Moreover, the expansion of Proteobacteria could facilitate a mucosal immune response in genetically predisposed individuals, leading to the development and continuation of chronic intestinal inflammation.	('leading to', 'Reg', (125, 135))	('facilitate', 'PosReg', (48, 58))	('mucosal immune response', 'CPA', (61, 84))	('expansion', 'Var', (14, 23))	('intestinal inflammation', 'Disease', 'MESH:D007249', (180, 203))	('Proteobacteria', 'Protein', (27, 41))	('intestinal inflammation', 'Disease', (180, 203))
847268	31235994	The net result of these changes is the creation of a pro-inflammatory milieu for tumor growth, favored by the FapA-mediated suppression of T cells' cytotoxic activity.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('changes', 'Var', (24, 31))	('tumor', 'Disease', (81, 86))	('pro-inflammatory', 'MPA', (53, 69))
847281	30073448	Higher 25(OH)D was associated with lower overall cancer mortality (HR=0.76, 95% CI 0.67-0.85 for highest vs. lowest quintile, p-trend <0.0001).	('25(OH)D', 'Var', (7, 14))	('25(OH)D', 'Chemical', 'MESH:C101470', (7, 14))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('lower', 'NegReg', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
847282	30073448	Higher 25(OH)D was related to lower mortality from the following site-specific malignancies: prostate (HR=0.74, 95% CI 0.55-1.01, p-trend=0.005), kidney (HR=0.59, 95% CI 0.35-0.98, p-trend=0.28), and melanoma (HR=0.39, 95% CI 0.20-0.78, p-trend=0.01), but increased mortality from lung cancer (HR=1.28, 95% CI 1.02-1.61, p-trend=0.19).	('prostate', 'Disease', (93, 101))	('lower', 'NegReg', (30, 35))	('25(OH)D', 'Var', (7, 14))	('lung cancer', 'Disease', (281, 292))	('25(OH)D', 'Chemical', 'MESH:C101470', (7, 14))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (281, 292))	('melanoma', 'Disease', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('malignancies', 'Disease', (79, 91))	('lung cancer', 'Disease', 'MESH:D008175', (281, 292))	('kidney', 'Disease', (146, 152))
847285	30073448	Vitamin D has been associated with improved overall cancer survival in several prospective studies, but not all, and although low vitamin D status has been observed in cancer patients after diagnosis, fewer studies have examined prospectively measured vitamin D and subsequent site-specific cancer mortality outcomes.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('improved', 'PosReg', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('low vitamin D', 'Phenotype', 'HP:0100512', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('patients', 'Species', '9606', (175, 183))	('Vitamin', 'Var', (0, 7))	('vitamin D', 'Chemical', 'MESH:D014807', (252, 261))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('vitamin D', 'Chemical', 'MESH:D014807', (130, 139))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))
847286	30073448	We have previously shown that 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, was associated with improved prostate cancer, but not lung cancer, survival.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('25-hydroxyvitamin D', 'Chemical', 'MESH:D002112', (30, 49))	('vitamin D', 'Chemical', 'MESH:D014807', (87, 96))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('25(OH)D', 'Chemical', 'MESH:C101470', (51, 58))	('prostate cancer', 'Disease', (134, 149))	('prostate cancer', 'Phenotype', 'HP:0012125', (134, 149))	('improved', 'PosReg', (125, 133))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (134, 149))	('vitamin D', 'Chemical', 'MESH:D014807', (40, 49))	('25-hydroxyvitamin', 'Var', (30, 47))
847287	30073448	The present study was undertaken to examine whether prospectively measured 25(OH)D, years in advance of cancer diagnoses, is related to overall and site-specific cancer survival in a cohort of male smokers.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('related', 'Reg', (125, 132))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('25(OH)D', 'Var', (75, 82))	('cancer', 'Disease', (104, 110))	('25(OH)D', 'Chemical', 'MESH:C101470', (75, 82))
847293	30073448	Cancer cases were drawn from previous nested case-control studies of circulating 25(OH)D and cancer risk within the ATBC Study.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('circulating 25(OH)D', 'Var', (69, 88))	('25(OH)D', 'Chemical', 'MESH:C101470', (81, 88))
847330	30073448	Higher circulating 25(OH)D years prior to cancer diagnosis was associated with lower cancer mortality (HR=0.76, 95% CI 0.67-0.85 for highest vs. lowest quintile, p-trend <0.0001, Table 2; Kaplan-Meier survival plot of vitamin D quintiles shown in Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('lower', 'NegReg', (79, 84))	('cancer', 'Disease', (85, 91))	('vitamin D', 'Chemical', 'MESH:D014807', (218, 227))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('25(OH)D', 'Chemical', 'MESH:C101470', (19, 26))	('25(OH)D', 'Var', (19, 26))
847335	30073448	By contrast, higher 25(OH)D was associated with poorer lung and esophageal cancer survival (albeit, significant only for lung cancer, Table 2).	('lung and esophageal cancer', 'Disease', 'MESH:D008175', (55, 81))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('25(OH)D', 'Chemical', 'MESH:C101470', (20, 27))	('25(OH)D', 'Var', (20, 27))	('poorer', 'NegReg', (48, 54))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
847339	30073448	The reduced prostate cancer mortality for high vitamin D status was limited to stages 1-2 (HR=0.49, 95% CI 0.25-0.96, p-trend 0.03) vs. stages 3-4 disease (HR=0.95, 95% CI 0.66-1.39, p-trend=0.60), while the elevated lung cancer mortality was more apparent for stage 3-4 (HR=1.74, 95% CI 1.18-2.56, p-trend 0.03) vs. stage 1-2 disease (HR=1.19, 95% CI 0.66-2.13, p-trend 0.59), though neither interaction test was significant (p>0.63).	('prostate cancer', 'Disease', (12, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('reduced', 'NegReg', (4, 11))	('reduced prostate', 'Phenotype', 'HP:0008687', (4, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('high vitamin D', 'Phenotype', 'HP:0100512', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('prostate cancer', 'Disease', 'MESH:D011471', (12, 27))	('elevated lung cancer', 'Disease', (208, 228))	('elevated lung cancer', 'Disease', 'MESH:D008175', (208, 228))	('vitamin D', 'Chemical', 'MESH:D014807', (47, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (12, 27))	('high', 'Var', (42, 46))
847344	30073448	Prior studies examining cancer survival in relation to post-diagnostic (and sometimes post-treatment) vitamin D status have indicated that patients with higher 25(OH)D blood concentrations have improved survival, including for breast, colorectal, head and neck, hematological, kidney, liver, lung, ovarian, prostate, pancreatic, skin (melanoma) and stomach cancers.	('survival', 'MPA', (203, 211))	('cancer', 'Disease', (24, 30))	('25(OH)D', 'Var', (160, 167))	('liver', 'Disease', (285, 290))	('ovarian', 'Disease', (298, 305))	('melanoma', 'Phenotype', 'HP:0002861', (335, 343))	('men', 'Species', '9606', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('kidney', 'Disease', (277, 283))	('colorectal', 'Disease', 'MESH:D015179', (235, 245))	('breast', 'Disease', (227, 233))	('hematological', 'Disease', (262, 275))	('cancers', 'Phenotype', 'HP:0002664', (357, 364))	('cancer', 'Disease', (357, 363))	('pancreatic, skin (melanoma) and stomach cancers', 'Disease', 'MESH:C563985', (317, 364))	('prostate', 'Disease', (307, 315))	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('patients', 'Species', '9606', (139, 147))	('lung', 'Disease', (292, 296))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('higher 25(OH)D', 'Var', (153, 167))	('stomach cancers', 'Phenotype', 'HP:0012126', (349, 364))	('vitamin D', 'Chemical', 'MESH:D014807', (102, 111))	('ovarian', 'Disease', 'MESH:D010049', (298, 305))	('colorectal', 'Disease', (235, 245))	('cancer', 'Disease', 'MESH:D009369', (357, 363))	('improved', 'PosReg', (194, 202))	('25(OH)D', 'Chemical', 'MESH:C101470', (160, 167))
847348	30073448	Vitamin D supplementation has been associated with increased cancer survival in a meta-analysis of a few trials, although risk estimates in the individual studies were not significant.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('increased', 'PosReg', (51, 60))	('cancer', 'Disease', (61, 67))	('men', 'Species', '9606', (16, 19))	('Vitamin', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('supplementation', 'Var', (10, 25))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))
847350	30073448	We observed that higher prospectively-measured 25(OH)D was associated with improved survival after a diagnosis of prostate cancer, kidney cancer, and melanoma.	('improved', 'PosReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('25(OH)D', 'Chemical', 'MESH:C101470', (47, 54))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('kidney cancer', 'Disease', 'MESH:D007680', (131, 144))	('survival', 'MPA', (84, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('kidney cancer', 'Phenotype', 'HP:0009726', (131, 144))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('kidney cancer', 'Disease', (131, 144))	('25(OH)D', 'Var', (47, 54))	('prostate cancer', 'Disease', (114, 129))
847352	30073448	By contrast, data from five cohorts within the Breast and Prostate Cancer Cohort Consortium showed no 25(OH)D-survival association, and the NHANES III study found non-significant decreased prostate cancer survival for men with higher 25(OH)D status.	('decreased prostate cancer', 'Disease', (179, 204))	('decreased prostate', 'Phenotype', 'HP:0008687', (179, 197))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('25(OH)D status', 'Var', (234, 248))	('25(OH)D', 'Chemical', 'MESH:C101470', (102, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (189, 204))	('25(OH)D', 'Chemical', 'MESH:C101470', (234, 241))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Breast and Prostate Cancer', 'Disease', 'MESH:D001943', (47, 73))	('men', 'Species', '9606', (218, 221))	('decreased prostate cancer', 'Disease', 'MESH:D011471', (179, 204))
847357	30073448	NHANES III found no vitamin D association with non-Hodgkin lymphoma or leukemia survival, but indicated non-significantly increased mortality for digestive cancers (including pancreas, esophagus, stomach and liver cancers combined) in men with higher pre-diagnostic 25(OH)D (RR= 1.6).	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('liver cancers', 'Disease', 'MESH:D006528', (208, 221))	('non-Hodgkin lymphoma', 'Disease', (47, 67))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (47, 67))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (47, 67))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('liver cancers', 'Phenotype', 'HP:0002896', (208, 221))	('25(OH)D', 'Chemical', 'MESH:C101470', (266, 273))	('leukemia', 'Disease', 'MESH:D007938', (71, 79))	('leukemia', 'Disease', (71, 79))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('liver cancer', 'Phenotype', 'HP:0002896', (208, 220))	('25(OH)D', 'Var', (266, 273))	('liver cancers', 'Disease', (208, 221))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('pancreas', 'Disease', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('men', 'Species', '9606', (235, 238))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (51, 67))	('stomach', 'Disease', (196, 203))	('esophagus', 'Disease', (185, 194))	('vitamin D', 'Chemical', 'MESH:D014807', (20, 29))
847358	30073448	Several studies have observed improved colorectal cancer survival with higher vitamin D status, although a pooled analysis showed no association.	('higher', 'Var', (71, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('higher vitamin D status', 'Phenotype', 'HP:0100512', (71, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('vitamin D', 'Chemical', 'MESH:D014807', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('colorectal cancer', 'Disease', (39, 56))	('improved', 'PosReg', (30, 38))
847359	30073448	Vitamin D was directly associated with lung cancer mortality in the present analysis, strengthening our earlier finding based on shorter follow-up, of a non-significant 20% elevated mortality.	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lung cancer', 'Disease', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('Vitamin', 'Var', (0, 7))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))	('associated', 'Reg', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
847363	30073448	Observational studies of vitamin D status and cancer incidence suggest that increased circulating 25(OH)D is associated with lower colorectal cancer risk and higher prostate cancer risk, with inconsistent data for other organ sites.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('higher', 'PosReg', (158, 164))	('increased', 'PosReg', (76, 85))	('cancer', 'Disease', (174, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (142, 148))	('vitamin D', 'Chemical', 'MESH:D014807', (25, 34))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('25(OH)D', 'Chemical', 'MESH:C101470', (98, 105))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('prostate cancer', 'Disease', (165, 180))	('lower', 'NegReg', (125, 130))	('colorectal cancer', 'Disease', (131, 148))	('25(OH)D', 'Var', (98, 105))
847364	30073448	A recent Mendelian randomization analysis found no association between a vitamin D genetic score and risk of seven cancers (colorectal, breast, prostate, ovarian, lung, and pancreatic cancers and neuroblastoma).	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (173, 191))	('colorectal, breast, prostate, ovarian, lung', 'Disease', 'MESH:D010051', (124, 167))	('ran', 'Gene', (19, 22))	('ran', 'Gene', '5901', (19, 22))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('vitamin D', 'Chemical', 'MESH:D014807', (73, 82))	('cancers', 'Disease', (184, 191))	('pancreatic cancers', 'Disease', (173, 191))	('vitamin D', 'Gene', (73, 82))	('genetic score', 'Var', (83, 96))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('pancreatic cancers', 'Disease', 'MESH:D010190', (173, 191))	('neuroblastoma', 'Disease', (196, 209))	('neuroblastoma', 'Phenotype', 'HP:0003006', (196, 209))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (173, 190))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('Men', 'Species', '9606', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('neuroblastoma', 'Disease', 'MESH:D009447', (196, 209))
847525	29259386	Endoscopic examination with normal white light (GIF-H290Z and UM-3R-3-20 MHz; Olympus, Tokyo, Japan) in our hospital revealed a brownish submucosal tumor, located 25 cm from the incisor of the middle esophagus (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('submucosal tumor', 'Disease', (137, 153))	('GIF-H290Z', 'Var', (48, 57))	('H290Z', 'CellLine', 'CVCL:A555', (52, 57))	('submucosal tumor', 'Disease', 'MESH:C563509', (137, 153))
847543	29259386	The depth of penetration of the wall was pT1b-SM2, 1800 mum from the muscularis mucosa; both the horizontal margins and vertical stump were negative, and lymphovascular invasion was not observed with D2-40 staining.	('vertical stump', 'Disease', 'MESH:D009437', (120, 134))	('vertical stump', 'Disease', (120, 134))	('pT1b-SM2', 'Chemical', '-', (41, 49))	('pT1b-SM2', 'Var', (41, 49))
847615	27737660	Based on these findings, the patient was diagnosed with T3N0M0, stage IIA (according to the Union for International Cancer Control TNM classification of malignant tumors, 7th edition) ESCC.	('patient', 'Species', '9606', (29, 36))	('malignant tumors', 'Disease', (153, 169))	('SCC', 'Gene', (185, 188))	('malignant tumors', 'Disease', 'MESH:D018198', (153, 169))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TNM', 'Gene', '10178', (131, 134))	('SCC', 'Gene', '6317', (185, 188))	('T3N0M0', 'Var', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('TNM', 'Gene', (131, 134))
847635	27737660	An excess amount of aberrant production causes an inflammatory response such as fever and positive CRP, a kind of leukemoid reaction (leukocytosis >50,000 leukocytes/muL), and paraneoplastic syndrome in clinical oncology.	('muL', 'Gene', (166, 169))	('causes', 'Reg', (40, 46))	('fever', 'Disease', (80, 85))	('fever', 'Phenotype', 'HP:0001945', (80, 85))	('leukemoid reaction', 'Disease', (114, 132))	('oncology', 'Phenotype', 'HP:0002664', (212, 220))	('CRP', 'Gene', (99, 102))	('leukocytosis', 'Disease', 'MESH:D007964', (134, 146))	('leukocytosis', 'Phenotype', 'HP:0001974', (134, 146))	('inflammatory response', 'MPA', (50, 71))	('muL', 'Gene', '4591', (166, 169))	('paraneoplastic syndrome', 'Disease', (176, 199))	('leukemoid reaction', 'Disease', 'MESH:D007955', (114, 132))	('CRP', 'Gene', '1401', (99, 102))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (176, 199))	('leukocytosis', 'Disease', (134, 146))	('aberrant production', 'Var', (20, 39))	('fever', 'Disease', 'MESH:D005334', (80, 85))
847656	25154680	Inhibition of mitogen-activated protein kinase pathway can induce upregulation of human leukocyte antigen class I without PD-L1-upregulation in contrast to interferon-gamma treatment Recently, we reported that human leukocyte antigen (HLA) class I expression is predominantly regulated by the mitogen-activated protein kinase (MAPK) pathway as one of the oncogenic regulations of HLA class I expression.	('upregulation', 'PosReg', (66, 78))	('interferon-gamma', 'Gene', '3458', (156, 172))	('leukocyte antigen ', 'Gene', (216, 234))	('interferon-gamma', 'Gene', (156, 172))	('PD-L1', 'Gene', (122, 127))	('human', 'Species', '9606', (210, 215))	('Inhibition', 'Var', (0, 10))	('leukocyte antigen ', 'Gene', '3105', (216, 234))	('leukocyte antigen ', 'Gene', (88, 106))	('PD-L1', 'Gene', '29126', (122, 127))	('leukocyte antigen ', 'Gene', '3105', (88, 106))	('human', 'Species', '9606', (82, 87))
847662	25154680	In conclusion, in addition to the original anti-proliferative activity, MAPK inhibitors may work toward the enhancement of T-cell-mediated anti-tumor immunity through the upregulation of HLA class I without the upregulation of PD-L1.	('tumor', 'Disease', (144, 149))	('enhancement', 'PosReg', (108, 119))	('inhibitors', 'Var', (77, 87))	('upregulation', 'PosReg', (171, 183))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('MAPK', 'Gene', (72, 76))	('HLA class I', 'Protein', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
847665	25154680	Recently, we showed that HLA class I expression is predominantly regulated by the ras/mitogen-activated protein kinase (MAPK) pathway in gastric and esophageal cancer as one of the oncogenic regulations of HLA class I expression, and the inhibition of the MAPK pathway with specific inhibitors leads to the upregulation of HLA class I expression on tumors.	('tumors', 'Disease', (349, 355))	('tumors', 'Disease', 'MESH:D009369', (349, 355))	('expression', 'MPA', (335, 345))	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('gastric and esophageal cancer', 'Disease', 'MESH:D013274', (137, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('HLA class I', 'Gene', (323, 334))	('inhibition', 'Var', (238, 248))	('upregulation', 'PosReg', (307, 319))
847666	25154680	Since it has been shown that upregulation of the MAPK pathway occurs in the majority of tumors, owing to oncogenic activating mutations in KRAS, NRAS, and BRAF, manipulation of the MAPK pathway is a promising strategy for cancer treatment.	('BRAF', 'Gene', (155, 159))	('NRAS', 'Gene', (145, 149))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (222, 228))	('upregulation', 'PosReg', (29, 41))	('KRAS', 'Gene', (139, 143))	('NRAS', 'Gene', '4893', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('KRAS', 'Gene', '3845', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mutations', 'Var', (126, 135))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('BRAF', 'Gene', '673', (155, 159))	('MAPK pathway', 'Pathway', (49, 61))
847670	25154680	In fact, it has been shown that PD-L1 expression on tumors inhibits the effector phase of CTL function through anergy or the apoptosis of T cells, and blockade of PD-L1 can augment the tumor-specific CTL response in vitro.	('tumor', 'Disease', (185, 190))	('PD-L1', 'Gene', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('PD-L1', 'Gene', (32, 37))	('inhibits', 'NegReg', (59, 67))	('tumor', 'Disease', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('apoptosis of T cells', 'CPA', (125, 145))	('tumors', 'Disease', (52, 58))	('blockade', 'Var', (151, 159))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('augment', 'PosReg', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('effector phase of CTL function', 'CPA', (72, 102))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
847675	25154680	ESCC lines, KYSE30, KYSE50, KYSE70, and KYSE110, gastric cancer cell lines, MKN7, MKN45, MKN74, NUGC-3, and OCUM-1, and a breast cancer cell line, MRK-nu-1, were purchased from the Japanese Collection of Research Bioresources Cell Bank (Osaka, Japan).	('MRK', 'CellLine', 'CVCL:W334', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('KYSE50', 'Var', (20, 26))	('KYSE70', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gastric cancer', 'Disease', (49, 63))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))	('MKN74', 'Chemical', '-', (89, 94))
847681	25154680	Tumor cells were cultured in a 12-well plate and exposed to various concentrations of IFN-gamma with or without the MAPK signal inhibitors, PD98059 (Cell Signalling Technology, Danvers, MA, USA), UO126 (Cell Signalling Technology), and PD0325901 (Cayman Chemical, Ann Arbor, MI, USA).	('PD0325901', 'Var', (236, 245))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PD98059', 'Var', (140, 147))	('IFN-gamma', 'Gene', '3458', (86, 95))	('IFN-gamma', 'Gene', (86, 95))	('PD0325901', 'Chemical', 'MESH:C506614', (236, 245))	('UO126', 'Chemical', 'MESH:C113580', (196, 201))	('PD98059', 'Chemical', 'MESH:C093973', (140, 147))
847684	25154680	Under doses of MAPK inhibitors used in the present study, percentages of dying cells treated with MAPK inhibitors accounted for <8%, when analyzed by Annexin-V and 7-AAD staining.	('MAPK', 'Gene', (98, 102))	('7-AAD', 'Chemical', 'MESH:C025942', (164, 169))	('Annexin-V', 'Gene', (150, 159))	('inhibitors', 'Var', (20, 30))	('inhibitors', 'Var', (103, 113))	('Annexin-V', 'Gene', '308', (150, 159))	('MAPK', 'Gene', (15, 19))
847692	25154680	The following antibodies were used for staining: Annexin V-FITC (Becton Dickinson, San Jose, CA, USA), 7-AAD (Becton Dickinson), anti-human HLA-ABC (clone: W6/32)-FITC and -PE (eBioscience, Santa Clara, CA, USA), anti-human HLA-A2 (clone: BB7.2)-PE (Becton Dickinson), anti-human HLA-A24 (clone: 22E1)-PE (Medical & Biological Laboratories, Nagoya, Japan), and anti-human CD274 (B7-H1) (clone: MIH1)-PE (eBioscience).	('and', 'Var', (357, 360))	('HLA-A', 'Gene', (140, 145))	('HLA-A', 'Gene', '3105', (224, 229))	('B7-H1', 'Gene', '29126', (379, 384))	('human', 'Species', '9606', (366, 371))	('7-AAD', 'Chemical', 'MESH:C025942', (103, 108))	('human', 'Species', '9606', (134, 139))	('HLA-A', 'Gene', '3105', (140, 145))	('MIH1', 'Gene', (394, 398))	('HLA-A', 'Gene', (280, 285))	('Annexin V', 'Gene', '308', (49, 58))	('CD274', 'Gene', '29126', (372, 377))	('B7-H1', 'Gene', (379, 384))	('Annexin V', 'Gene', (49, 58))	('HLA-A', 'Gene', (224, 229))	('MIH1', 'Gene', '837', (394, 398))	('human', 'Species', '9606', (218, 223))	('CD274', 'Gene', (372, 377))	('human', 'Species', '9606', (274, 279))	('HLA-A', 'Gene', '3105', (280, 285))
847714	25154680	We could further confirm the upregulation of HLA class I expression by inhibition of the MAPK pathway with PD98059 (optimal dose, 50 muM) in several different types of cancer (n = 26), such as breast, pancreas, lung, and liver cancer cells (Fig.1a).	('inhibition', 'NegReg', (71, 81))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('PD98059', 'Chemical', 'MESH:C093973', (107, 114))	('expression', 'MPA', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('HLA class I', 'Protein', (45, 56))	('PD98059', 'Var', (107, 114))	('pancreas', 'Disease', (201, 209))	('MAPK pathway', 'Pathway', (89, 101))	('upregulation', 'PosReg', (29, 41))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('breast', 'Disease', (193, 199))	('liver cancer', 'Disease', 'MESH:D006528', (221, 233))	('lung', 'Disease', (211, 215))	('cancer', 'Disease', (227, 233))	('muM', 'Gene', '56925', (133, 136))	('muM', 'Gene', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('liver cancer', 'Phenotype', 'HP:0002896', (221, 233))	('liver cancer', 'Disease', (221, 233))
847716	25154680	S1a), tumor cells were treated with optimal doses of several different MAPK inhibitions, PD98059 (50 muM), UO0126 (2 muM), and PD0325901 (1 muM).	('muM', 'Gene', '56925', (140, 143))	('PD98059', 'Chemical', 'MESH:C093973', (89, 96))	('UO0126', 'Chemical', '-', (107, 113))	('UO0126', 'Var', (107, 113))	('muM', 'Gene', (140, 143))	('muM', 'Gene', '56925', (117, 120))	('PD0325901', 'Var', (127, 136))	('muM', 'Gene', '56925', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('muM', 'Gene', (117, 120))	('PD0325901', 'Chemical', 'MESH:C506614', (127, 136))	('muM', 'Gene', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('MAPK', 'Gene', (71, 75))
847717	25154680	MAPK inhibitors can significantly induce the upregulation of total HLA class I (W6/32), HLA-A02, and HLA-A24 in all cell lines tested (Fig.1a,b and Supplemental Fig.	('HLA-A', 'Gene', (88, 93))	('MAPK', 'Gene', (0, 4))	('inhibitors', 'Var', (5, 15))	('HLA class I', 'Protein', (67, 78))	('HLA-A', 'Gene', '3105', (101, 106))	('upregulation', 'PosReg', (45, 57))	('HLA-A', 'Gene', (101, 106))	('HLA-A', 'Gene', '3105', (88, 93))
847725	25154680	Also, the combination of IFN-gamma and PD98059 led to the most marked additive effects after 48 h and 0.5 ng/mL of IFN-gamma (Suppl.	('IFN-gamma', 'Gene', '3458', (25, 34))	('IFN-gamma', 'Gene', (25, 34))	('PD98059', 'Chemical', 'MESH:C093973', (39, 46))	('IFN-gamma', 'Gene', '3458', (115, 124))	('IFN-gamma', 'Gene', (115, 124))	('PD98059', 'Var', (39, 46))
847728	25154680	Of note, the combination of PD98059 with IFN-gamma had additive effects on the upregulation of HLA class I expression in 19 out of 26 tumor cells tested (Suppl.	('IFN-gamma', 'Gene', '3458', (41, 50))	('IFN-gamma', 'Gene', (41, 50))	('PD98059', 'Var', (28, 35))	('expression', 'MPA', (107, 117))	('combination', 'Interaction', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('PD98059', 'Chemical', 'MESH:C093973', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('upregulation', 'PosReg', (79, 91))	('HLA class I', 'Protein', (95, 106))	('tumor', 'Disease', (134, 139))
847730	25154680	When treated with a combination of IFN-gamma with different MAPK inhibitors, UO126 and PD0325901 (Fig.3b), the same additive effects were confirmed in the upregulation of HLA-class I, HLA-A02, and HLA-A24.	('HLA-A', 'Gene', (184, 189))	('HLA-A', 'Gene', '3105', (197, 202))	('UO126', 'Chemical', 'MESH:C113580', (77, 82))	('HLA-A', 'Gene', (197, 202))	('IFN-gamma', 'Gene', '3458', (35, 44))	('IFN-gamma', 'Gene', (35, 44))	('PD0325901', 'Var', (87, 96))	('HLA-A', 'Gene', '3105', (184, 189))	('HLA-class I', 'Protein', (171, 182))	('upregulation', 'PosReg', (155, 167))	('PD0325901', 'Chemical', 'MESH:C506614', (87, 96))
847731	25154680	Based on the effect of HLA class I induced by IFN-gamma and/or PD98059 (Suppl.	('PD98059', 'Chemical', 'MESH:C093973', (63, 70))	('IFN-gamma', 'Gene', '3458', (46, 55))	('IFN-gamma', 'Gene', (46, 55))	('PD98059', 'Var', (63, 70))
847732	25154680	S3a), we classified the 26 cell lines tested into three categories: additive effects of PD98059 with IFN-gamma (n = 19), upregulation by IFN-gamma but not by PD98059 (n = 4, TE-4, SNU-449, MKN45, and OCUM1), and no upregulation by either PD98059 or IFN-gamma (n = 3, KYSE70, KYSE110, and MKN74) (Fig.4).	('PD98059', 'Var', (88, 95))	('SNU-449', 'CellLine', 'CVCL:0454', (180, 187))	('MKN74', 'Chemical', '-', (288, 293))	('upregulation', 'PosReg', (121, 133))	('IFN-gamma', 'Gene', '3458', (101, 110))	('IFN-gamma', 'Gene', (101, 110))	('PD98059', 'Chemical', 'MESH:C093973', (158, 165))	('PD98059', 'Chemical', 'MESH:C093973', (88, 95))	('IFN-gamma', 'Gene', '3458', (249, 258))	('IFN-gamma', 'Gene', (249, 258))	('IFN-gamma', 'Gene', '3458', (137, 146))	('IFN-gamma', 'Gene', (137, 146))	('PD98059', 'Chemical', 'MESH:C093973', (238, 245))
847733	25154680	There was no cell line showing the upregulation of HLA class I by PD98059 but not by IFN-gamma.	('PD98059', 'Var', (66, 73))	('HLA class I', 'Protein', (51, 62))	('PD98059', 'Chemical', 'MESH:C093973', (66, 73))	('IFN-gamma', 'Gene', '3458', (85, 94))	('IFN-gamma', 'Gene', (85, 94))	('upregulation', 'PosReg', (35, 47))
847735	25154680	In 18 out of 19 cell lines with the additive effect of MAPK inhibitors with IFN-gamma, both phospho-STAT1/JAK2 activation and inhibition of phospho-Erk were seen independently, as noted in the representative Western blot for NUGC3 and OE19 (Fig.4); when cells were treated with IFN-gamma, there was no alteration of p-Erk expression and, in turn, there was no activation of phospho-STAT1 or phospho-JAK2 when treated with MAPK inhibitors.	('IFN-gamma', 'Gene', '3458', (278, 287))	('IFN-gamma', 'Gene', (278, 287))	('STAT1', 'Gene', '6772', (100, 105))	('STAT1', 'Gene', (382, 387))	('JAK2', 'Gene', (106, 110))	('JAK2', 'Gene', (399, 403))	('STAT1', 'Gene', '6772', (382, 387))	('Erk', 'Gene', (318, 321))	('Erk', 'Gene', '5594', (318, 321))	('IFN-gamma', 'Gene', '3458', (76, 85))	('IFN-gamma', 'Gene', (76, 85))	('expression', 'MPA', (322, 332))	('JAK2', 'Gene', '3717', (106, 110))	('OE19', 'CellLine', 'CVCL:1622', (235, 239))	('Erk', 'Gene', (148, 151))	('inhibitors', 'Var', (60, 70))	('STAT1', 'Gene', (100, 105))	('Erk', 'Gene', '5594', (148, 151))	('JAK2', 'Gene', '3717', (399, 403))
847736	25154680	Of interest, only MKN7 out of the 19 cell lines with the additive effect of MAPK inhibitors with IFN-gamma showed that the MAPK inhibitor, PD98059 induced the upregulation of phospho-STAT1 (Suppl.	('PD98059', 'Chemical', 'MESH:C093973', (139, 146))	('IFN-gamma', 'Gene', (97, 106))	('IFN-gamma', 'Gene', '3458', (97, 106))	('STAT1', 'Gene', (183, 188))	('STAT1', 'Gene', '6772', (183, 188))	('PD98059', 'Var', (139, 146))	('upregulation', 'PosReg', (159, 171))
847738	25154680	The observation only seen in MKN7 suggests that PD98059 treatment may partially act through the JAK-STAT pathway in MKN7.	('PD98059', 'Var', (48, 55))	('PD98059', 'Chemical', 'MESH:C093973', (48, 55))	('JAK-STAT pathway', 'Pathway', (96, 112))	('MKN7', 'Disease', (116, 120))
847740	25154680	Of note, among the 26 tumor cell lines tested, there were three IFN-gamma-resistant cell lines in terms of the upregulation of HLA class I, KYSE70, KYSE110, and MKN74 (Suppl.	('KYSE110', 'Var', (148, 155))	('upregulation', 'PosReg', (111, 123))	('HLA class I', 'Protein', (127, 138))	('KYSE70', 'Var', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('MKN74', 'Var', (161, 166))	('IFN-gamma', 'Gene', '3458', (64, 73))	('IFN-gamma', 'Gene', (64, 73))	('MKN74', 'Chemical', '-', (161, 166))
847742	25154680	Furthermore, among seven PD98089-resistant cell lines, there were two patterns of MAPK-signaling molecules (Fig.4): one showed no inhibition of p-Erk in spite of treatment with MAPK inhibitors (MKN45), and the other showed clear inhibition of p-Erk with MAPK inhibitors (MKN74, OCUM-1 and KYSE70).	('PD98089', 'Chemical', '-', (25, 32))	('MKN74', 'Var', (271, 276))	('Erk', 'Gene', (146, 149))	('inhibition', 'NegReg', (229, 239))	('MKN74', 'Chemical', '-', (271, 276))	('Erk', 'Gene', (245, 248))	('Erk', 'Gene', '5594', (146, 149))	('Erk', 'Gene', '5594', (245, 248))
847743	25154680	To investigate the functional consequence of upregulated HLA class I on immune recognition, we examined antigen-specific CTL responses of tumor targets treated with IFN-gamma and/or PD98059.	('PD98059', 'Var', (182, 189))	('tumor', 'Disease', (138, 143))	('upregulated', 'PosReg', (45, 56))	('PD98059', 'Chemical', 'MESH:C093973', (182, 189))	('upregulated HLA class I', 'Phenotype', 'HP:0002853', (45, 68))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('IFN-gamma', 'Gene', '3458', (165, 174))	('IFN-gamma', 'Gene', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
847747	25154680	S5b), were pre-treated with IFN-gamma and/or PD98059 and subjected to ELISPOT and cytotoxic assays.	('PD98059', 'Var', (45, 52))	('IFN-gamma', 'Gene', '3458', (28, 37))	('IFN-gamma', 'Gene', (28, 37))	('PD98059', 'Chemical', 'MESH:C093973', (45, 52))
847748	25154680	Of importance, an ELISPOT assay showed marked upregulation of CTL reactivity when treated with PD98059, while CTL reactivity was completely lost when treated with IFN-gamma (Fig.5a).	('upregulation', 'PosReg', (46, 58))	('PD98059', 'Chemical', 'MESH:C093973', (95, 102))	('IFN-gamma', 'Gene', '3458', (163, 172))	('IFN-gamma', 'Gene', (163, 172))	('CTL reactivity', 'MPA', (62, 76))	('PD98059', 'Var', (95, 102))
847749	25154680	Similarly in a cytotoxic assay, PD98059-pre-treated MKN7 showed much higher susceptibility to the CTL clone compared to the control target, while IFN-gamma-pre-treated MKN7 showed lower susceptibility to the CTL clone compared to the control target (Fig.5b).	('PD98059-pre-treated', 'Var', (32, 51))	('IFN-gamma', 'Gene', '3458', (146, 155))	('IFN-gamma', 'Gene', (146, 155))	('susceptibility', 'MPA', (76, 90))	('higher', 'PosReg', (69, 75))	('PD98059', 'Chemical', 'MESH:C093973', (32, 39))	('CTL clone', 'CPA', (98, 107))
847750	25154680	These results indicate there was a markedly contrasting phenomenon in terms of CTL reactivity between IFN-gamma and PD98059 treatment, in spite of the upregulation of HLA class I in both treatments.	('HLA class I', 'Protein', (167, 178))	('IFN-gamma', 'Gene', '3458', (102, 111))	('PD98059', 'Var', (116, 123))	('PD98059', 'Chemical', 'MESH:C093973', (116, 123))	('CTL reactivity', 'MPA', (79, 93))	('upregulation', 'PosReg', (151, 163))	('IFN-gamma', 'Gene', (102, 111))
847755	25154680	In contrast, there was no significant alteration or only a slight increase of PD-L1 expression when treated with MAPK inhibitors, PD98059, UO126, and PD0325901 (Fig.6a).	('PD98059', 'Chemical', 'MESH:C093973', (130, 137))	('UO126', 'Chemical', 'MESH:C113580', (139, 144))	('PD0325901', 'Var', (150, 159))	('PD-L1', 'Gene', (78, 83))	('PD0325901', 'Chemical', 'MESH:C506614', (150, 159))	('expression', 'MPA', (84, 94))	('PD98059', 'Var', (130, 137))	('UO126', 'Var', (139, 144))
847761	25154680	In the present study, we further expanded this observation to a more general phenomenon, showing that the inhibition of MAPK can upregulate HLA class I expression in a panel of human solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (183, 195))	('MAPK', 'Gene', (120, 124))	('HLA class I', 'Protein', (140, 151))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('inhibition', 'Var', (106, 116))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('solid tumors', 'Disease', (183, 195))	('upregulate', 'PosReg', (129, 139))	('human', 'Species', '9606', (177, 182))	('upregulate HLA class I', 'Phenotype', 'HP:0002853', (129, 151))	('expression', 'MPA', (152, 162))
847762	25154680	Of note, we showed for the first time that MAPK inhibitors act on the upregulation of HLA class I expression through a distinct pathway different from IFN-gamma, in which MAPK inhibitors did not stimulate the JAK/STAT pathway.	('IFN-gamma', 'Gene', '3458', (151, 160))	('IFN-gamma', 'Gene', (151, 160))	('upregulation', 'PosReg', (70, 82))	('expression', 'MPA', (98, 108))	('HLA class I', 'Protein', (86, 97))	('inhibitors', 'Var', (48, 58))	('MAPK', 'Gene', (43, 47))
847763	25154680	The observation is based on two facts: there was an additive effect in the upregulation of HLA class I when treated with the combination of MAPK inhibitors with IFN-gamma, and there was no overlapping activation in major signal transduction molecules in most cases when treated with either IFN-gamma or MAPK inhibitors.	('MAPK', 'Gene', (140, 144))	('upregulation', 'PosReg', (75, 87))	('IFN-gamma', 'Gene', '3458', (161, 170))	('inhibitors', 'Var', (145, 155))	('HLA class I', 'Protein', (91, 102))	('IFN-gamma', 'Gene', (161, 170))	('IFN-gamma', 'Gene', '3458', (290, 299))	('IFN-gamma', 'Gene', (290, 299))
847784	25154680	Our findings suggest that MAPK inhibitors may enhance T-cell mediated anti-tumor immunity through the upregulation of HLA class I without any upregulation of PD-L1.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('HLA class I', 'Protein', (118, 129))	('upregulation', 'PosReg', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('enhance', 'PosReg', (46, 53))	('inhibitors', 'Var', (31, 41))	('tumor', 'Disease', (75, 80))	('MAPK', 'Gene', (26, 30))
847785	25154680	Taken together, manipulation of the MAPK signaling pathway may positively act on anti-tumor T-cell immunity, in addition to direct anti-proliferative activity on tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('manipulation', 'Var', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (162, 167))	('act', 'Reg', (74, 77))	('MAPK', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
847832	25680671	A similar dichotomy exists for gastric cancer; case-control studies have associated red meat with gastric cancer, whereas cohort studies have not.	('red meat', 'Var', (84, 92))	('gastric cancer', 'Disease', (98, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (31, 45))	('gastric cancer', 'Disease', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
847886	25680671	In fact, there was some evidence that vitamin D was associated with increased risk of upper GI cancer in some subgroups.	('vitamin D', 'Chemical', 'MESH:D014807', (38, 47))	('GI cancer', 'Phenotype', 'HP:0007378', (92, 101))	('upper GI cancer', 'Disease', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('vitamin', 'Var', (38, 45))	('upper GI cancer', 'Disease', 'MESH:D009369', (86, 101))
847893	25680671	Thirty of the case-control studies found that pickled vegetables significantly increased risk for gastric cancer, and 1 found that it significantly reduced risk.	('increased risk for gastric cancer', 'Phenotype', 'HP:0006753', (79, 112))	('pickled vegetables', 'Var', (46, 64))	('reduced', 'NegReg', (148, 155))	('gastric cancer', 'Disease', (98, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
847928	25680671	Many people of East Asian ancestry have polymorphisms that affect metabolism of ethanol, commonly known as the flushing response.163 Individuals with a single copy of a specific polymorphism in ALDH2 develop symptoms after consumption of ethanol, so they eliminate it from their diet.	('symptoms', 'MPA', (208, 216))	('eliminate', 'NegReg', (255, 264))	('flushing', 'Disease', 'MESH:D005483', (111, 119))	('single copy', 'Var', (152, 163))	('ethanol', 'Chemical', 'MESH:D000431', (238, 245))	('ethanol', 'Chemical', 'MESH:D000431', (80, 87))	('people', 'Species', '9606', (5, 11))	('develop', 'PosReg', (200, 207))	('flushing', 'Phenotype', 'HP:0031284', (111, 119))	('ALDH2', 'Gene', '217', (194, 199))	('polymorphism', 'Var', (178, 190))	('flushing', 'Disease', (111, 119))	('ALDH2', 'Gene', (194, 199))
847931	25680671	An analysis from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) found no association between total alcoholic beverage consumption, even high doses (7 drinks/day) and esophageal adenocarcinoma.161 In most studies, adenocarcinomas of the stomach appear not to be associated with alcoholic beverage consumption, but there is some evidence for an adverse effect in subjects with genetic polymorphisms that alter metabolism of ethanol, similar to the effects of ALDH2 variants on esophageal cancer risk, although the current level of evidence is modest.165, 166 Heavier consumption of alcohol has been causally linked to cancers of colorectum, but with a more modest magnitude than for other types of GI cancers, such as esophageal squamous cell carcinoma.	('cancers', 'Disease', 'MESH:D009369', (633, 640))	('esophageal squamous cell carcinoma', 'Disease', (733, 767))	('modest.165', 'Var', (558, 568))	('ALDH2', 'Gene', '217', (474, 479))	('cancers', 'Phenotype', 'HP:0002664', (716, 723))	('alcohol', 'Chemical', 'MESH:D000438', (294, 301))	('cancers', 'Disease', (716, 723))	('cancer', 'Phenotype', 'HP:0002664', (716, 722))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('adenocarcinomas of the stomach', 'Phenotype', 'HP:0006753', (230, 260))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (744, 767))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (733, 767))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (35, 60))	('cancers', 'Phenotype', 'HP:0002664', (633, 640))	('GI cancers', 'Disease', (713, 723))	('cancers', 'Disease', (633, 640))	('cancers', 'Disease', 'MESH:D009369', (716, 723))	('alcohol', 'Chemical', 'MESH:D000438', (116, 123))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (35, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('esophageal cancer', 'Disease', 'MESH:D004938', (492, 509))	('ALDH2', 'Gene', (474, 479))	('ethanol', 'Chemical', 'MESH:D000431', (439, 446))	('cancer', 'Phenotype', 'HP:0002664', (633, 639))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('Esophageal Adenocarcinoma', 'Disease', (35, 60))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (183, 208))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (183, 208))	('esophageal cancer', 'Disease', (492, 509))	('adenocarcinomas', 'Disease', 'MESH:D000230', (230, 245))	('adenocarcinomas', 'Disease', (230, 245))	('GI cancer', 'Phenotype', 'HP:0007378', (713, 722))	('linked', 'Reg', (623, 629))	('alcohol', 'Chemical', 'MESH:D000438', (597, 604))	('carcinomas', 'Phenotype', 'HP:0030731', (235, 245))	('GI cancers', 'Disease', 'MESH:D009369', (713, 723))	('cancer', 'Phenotype', 'HP:0002664', (503, 509))	('carcinoma', 'Phenotype', 'HP:0030731', (758, 767))	('esophageal adenocarcinoma', 'Disease', (183, 208))
847941	25680671	Trials can be helpful, but are not always possible, and negative results do not always quell the perception that modulating intake of certain foods or nutrients will lower risk for GI malignancies.	('GI malignancies', 'Disease', 'MESH:D009369', (181, 196))	('lower', 'NegReg', (166, 171))	('modulating', 'Var', (113, 123))	('GI malignancies', 'Disease', (181, 196))
847953	25609981	Patients with LMR <=2.93 had a significantly worse 5-year CSS than patients with LMR >2.93 (21.2% versus 59.3%, P<0.001).	('LMR', 'Chemical', '-', (81, 84))	('CSS', 'CPA', (58, 61))	('patients', 'Species', '9606', (67, 75))	('LMR', 'Chemical', '-', (14, 17))	('worse', 'NegReg', (45, 50))	('Patients', 'Species', '9606', (0, 8))	('LMR <=2.93', 'Var', (14, 24))	('CSS', 'Chemical', '-', (58, 61))
847954	25609981	For subgroup analysis, the predictive value of LMR was also significant in patients with T1-2 cancer (P=0.003), T3-4a (P<0.001), and patients with (P=0.044) or without (P<0.001) nodal metastasis.	('T1-2 cancer', 'Disease', (89, 100))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (75, 83))	('T1-2 cancer', 'Disease', 'MESH:D009369', (89, 100))	('T3-4a', 'Disease', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('LMR', 'Var', (47, 50))	('LMR', 'Chemical', '-', (47, 50))
847956	25609981	In multivariate analysis, LMR was a significant predictive factor of CSS (P=0.010).	('LMR', 'Var', (26, 29))	('CSS', 'Disease', (69, 72))	('LMR', 'Chemical', '-', (26, 29))	('CSS', 'Chemical', '-', (69, 72))
847966	25609981	Recently studies demonstrated that LMR is associated with prognosis in several cancers, such as hematological malignancy, colon cancer, and lung cancer.	('hematological malignancy', 'Disease', 'MESH:D019337', (96, 120))	('lung cancer', 'Disease', (140, 151))	('cancers', 'Disease', (79, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('LMR', 'Var', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('associated', 'Reg', (42, 52))	('LMR', 'Chemical', '-', (35, 38))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('hematological malignancy', 'Phenotype', 'HP:0004377', (96, 120))	('hematological malignancy', 'Disease', (96, 120))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('colon cancer', 'Disease', (122, 134))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
847988	25609981	Our study showed that LMR was associated with tumor length (P=0.033), depth of invasion (P=0.015), nodal metastasis (P=0.007), ALC (P<0.001), and AMC (P<0.001) (Table 2).	('ALC', 'Disease', (127, 130))	('ALC', 'Chemical', '-', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('depth of invasion', 'CPA', (70, 87))	('LMR', 'Var', (22, 25))	('AMC', 'Disease', (146, 149))	('AMC', 'Chemical', '-', (146, 149))	('nodal metastasis', 'CPA', (99, 115))	('LMR', 'Chemical', '-', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
847989	25609981	Patients with LMR <=2.93 had a significantly worse 5-year CSS than patients with LMR >2.93 (21.2% versus 59.3%, P<0.001) (Figure 4A).	('LMR', 'Chemical', '-', (81, 84))	('CSS', 'CPA', (58, 61))	('patients', 'Species', '9606', (67, 75))	('LMR', 'Chemical', '-', (14, 17))	('worse', 'NegReg', (45, 50))	('Patients', 'Species', '9606', (0, 8))	('LMR <=2.93', 'Var', (14, 24))	('CSS', 'Chemical', '-', (58, 61))
847994	25609981	Then multivariate Cox proportional hazards model demonstrated that LMR was an independent prognostic factor in patients with ESCC (Table 3).	('SCC', 'Gene', '6317', (126, 129))	('patients', 'Species', '9606', (111, 119))	('LMR', 'Var', (67, 70))	('LMR', 'Chemical', '-', (67, 70))	('SCC', 'Gene', (126, 129))
847995	25609981	LMR >2.93 had a hazard ratio of 0.60 (95% confidence interval: 0.407-0.885, P=0.010) for CSS (Table 3).	('LMR', 'Chemical', '-', (0, 3))	('CSS', 'Chemical', '-', (89, 92))	('LMR >2.93', 'Var', (0, 9))	('CSS', 'Disease', (89, 92))
847997	25609981	Our study showed that LMR is associated with tumor progression and can be considered as an independent predictive marker of prognosis in patients with ESCC.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('LMR', 'Var', (22, 25))	('patients', 'Species', '9606', (137, 145))	('SCC', 'Gene', (152, 155))	('SCC', 'Gene', '6317', (152, 155))	('associated', 'Reg', (29, 39))	('LMR', 'Chemical', '-', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
848006	25609981	Our study showed that LMR was associated with tumor length (P=0.033), depth of invasion (P=0.015), and nodal metastasis (P=0.015).	('nodal metastasis', 'CPA', (103, 119))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('depth of invasion', 'CPA', (70, 87))	('LMR', 'Var', (22, 25))	('LMR', 'Chemical', '-', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
848010	25609981	Our study showed that patients with LMR <=2.93 had a significantly worse 5-years CSS than patients with LMR >2.93.	('LMR <=2.93', 'Var', (36, 46))	('patients', 'Species', '9606', (22, 30))	('LMR', 'Chemical', '-', (104, 107))	('CSS', 'Chemical', '-', (81, 84))	('CSS', 'CPA', (81, 84))	('LMR', 'Chemical', '-', (36, 39))	('patients', 'Species', '9606', (90, 98))	('worse', 'NegReg', (67, 72))
848011	25609981	In multivariate analysis, LMR was a significant predictive factor of CSS.	('LMR', 'Var', (26, 29))	('CSS', 'Disease', (69, 72))	('LMR', 'Chemical', '-', (26, 29))	('CSS', 'Chemical', '-', (69, 72))
848013	25609981	In our study, the predictive value of LMR was also significant in patients with T1-2 cancer (P=0.003), T3-4a (P<0.001), and patients with (P=0.044) or without (P<0.001) nodal metastasis.	('T3-4a', 'Disease', (103, 108))	('LMR', 'Var', (38, 41))	('LMR', 'Chemical', '-', (38, 41))	('T1-2 cancer', 'Disease', (80, 91))	('T1-2 cancer', 'Disease', 'MESH:D009369', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('patients', 'Species', '9606', (124, 132))	('patients', 'Species', '9606', (66, 74))
848015	25609981	From the database of 348 patients with ESCC, our results clearly demonstrated that LMR can serve as an independent predictor of long-term survival for ESCC patients.	('patients', 'Species', '9606', (156, 164))	('SCC', 'Gene', '6317', (40, 43))	('LMR', 'Var', (83, 86))	('LMR', 'Chemical', '-', (83, 86))	('SCC', 'Gene', (152, 155))	('patients', 'Species', '9606', (25, 33))	('SCC', 'Gene', '6317', (152, 155))	('SCC', 'Gene', (40, 43))
848016	25609981	In conclusion, our study showed that LMR is associated with tumor progression and can be considered as an independent marker of prognosis in patients with ESCC.	('associated', 'Reg', (44, 54))	('LMR', 'Chemical', '-', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('SCC', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('LMR', 'Var', (37, 40))	('tumor', 'Disease', (60, 65))	('SCC', 'Gene', '6317', (156, 159))	('patients', 'Species', '9606', (141, 149))
848028	23761828	Almost half of human miRNAs are localized in tumor-associated genetic or fragile regions, including amplification, loss of heterozygosity, fragile and oncogene or anti-oncogene breakpoint regions.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('human', 'Species', '9606', (15, 20))	('tumor', 'Disease', (45, 50))	('loss of heterozygosity', 'Var', (115, 137))	('amplification', 'Disease', (100, 113))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
848053	23761828	Zhang et al concluded, based on the comparison between 209 EC and 140 control samples, that seven serum miRNAs (miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a and miR-127-3p) were significantly upregulated in the sera of esophageal squamous cell carcinoma patients compared with control individuals.	('miR-223', 'Gene', '407008', (148, 155))	('miR-10a', 'Gene', (112, 119))	('miR-22', 'Gene', '407004', (148, 154))	('miR-22', 'Gene', (148, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (239, 262))	('miR-127-3p', 'Gene', '100302165', (170, 180))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (228, 262))	('miR-100', 'Gene', (129, 136))	('miR-22', 'Gene', '407004', (121, 127))	('miR-127-3p', 'Gene', (170, 180))	('miR-22', 'Gene', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('upregulated', 'PosReg', (201, 212))	('miR-100', 'Gene', '406892', (129, 136))	('miR-223', 'Gene', (148, 155))	('miR-10a', 'Gene', '406902', (112, 119))	('133a', 'Chemical', '-', (161, 165))	('esophageal squamous cell carcinoma', 'Disease', (228, 262))	('miR-148b', 'Gene', '442892', (138, 146))	('miR-148b', 'Gene', (138, 146))	('patients', 'Species', '9606', (263, 271))	('miR-133a', 'Var', (157, 165))
848054	23761828	This study also showed that the EC tissues exhibited upregulated miR-100 and miR-133a compared with normal tissues.	('miR-100', 'Gene', (65, 72))	('miR-133a', 'Var', (77, 85))	('133a', 'Chemical', '-', (81, 85))	('miR-100', 'Gene', '406892', (65, 72))	('upregulated', 'PosReg', (53, 64))
848059	23408147	The abnormal expression of DAPK was highly correlated with the invasiveness and lymphatic metastasis of the cancer.	('abnormal', 'Var', (4, 12))	('metastasis of the cancer', 'Disease', 'MESH:D009362', (90, 114))	('expression', 'MPA', (13, 23))	('metastasis of the cancer', 'Disease', (90, 114))	('DAPK', 'Gene', (27, 31))	('correlated', 'Reg', (43, 53))	('DAPK', 'Gene', '1612', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('invasiveness', 'CPA', (63, 75))
848060	23408147	The abnormal expression of E-cadherin was highly correlated with the differentiation and lymphatic metastasis of the cancer.	('correlated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('abnormal', 'Var', (4, 12))	('differentiation', 'CPA', (69, 84))	('expression', 'MPA', (13, 23))	('metastasis of the cancer', 'Disease', 'MESH:D009362', (99, 123))	('metastasis of the cancer', 'Disease', (99, 123))	('E-cadherin', 'Gene', (27, 37))	('E-cadherin', 'Gene', '999', (27, 37))
848071	23408147	Mutation of the residue eradicates the apoptotic effect of DAPK.	('DAPK', 'Gene', (59, 63))	('DAPK', 'Gene', '1612', (59, 63))	('Mutation', 'Var', (0, 8))	('eradicates', 'NegReg', (24, 34))	('apoptotic effect', 'CPA', (39, 55))
848133	23408147	The results also indicate that the abnormal DAPK gene expression is closely correlated with the invasion depth of esophageal squamous cell carcinoma and lymph node metastasis, which suggests that the abnormal expression of DAPK may be an indicator of prognosis.	('expression', 'MPA', (54, 64))	('DAPK', 'Gene', (44, 48))	('invasion depth', 'CPA', (96, 110))	('DAPK', 'Gene', '1612', (44, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('lymph node metastasis', 'CPA', (153, 174))	('abnormal', 'Var', (35, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('DAPK', 'Gene', (223, 227))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (114, 148))	('DAPK', 'Gene', '1612', (223, 227))	('esophageal squamous cell carcinoma', 'Disease', (114, 148))	('correlated', 'Reg', (76, 86))
848149	19435811	EGR-1 knockdown also caused a marked induction in IkappaBalpha expression, an effect also observed in GRObeta RNA interference-expressing WHCO1 cells, because EGR-1 lies downstream of GRO/CXCR2 signaling.	('GRObeta', 'Gene', '2919', (102, 109))	('induction', 'PosReg', (37, 46))	('GRObeta', 'Gene', (102, 109))	('IkappaBalpha', 'Gene', '4792', (50, 62))	('expression', 'MPA', (63, 73))	('IkappaBalpha', 'Gene', (50, 62))	('EGR-1', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))
848150	19435811	Immunohistochemical analysis indicated that p65 is elevated in 78% (n = 61) of esophageal tumor sections analyzed.	('esophageal tumor', 'Disease', 'MESH:D004941', (79, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('esophageal tumor', 'Disease', (79, 95))	('esophageal tumor', 'Phenotype', 'HP:0100751', (79, 95))	('elevated', 'PosReg', (51, 59))	('p65', 'Var', (44, 47))
848151	19435811	Moreover, nuclear factor-kappaB inhibition with either sodium salicylate or p65 RNA interference led to a significant reduction in GROalpha and GRObeta expression.	('GROalpha and GRObeta', 'Gene', '2919', (131, 151))	('inhibition', 'NegReg', (32, 42))	('reduction', 'NegReg', (118, 127))	('p65 RNA interference', 'Var', (76, 96))	('nuclear factor-kappaB', 'Protein', (10, 31))	('sodium salicylate', 'Chemical', 'MESH:D012980', (55, 72))	('expression', 'MPA', (152, 162))
848159	19435811	Blockade of the GRO/CXCR2 signaling loop using either an antagonist of CXCR2 (SB225002) or knockdown of GRObeta significantly reduced the proliferation of esophageal cancer cells in culture.	('SB225002', 'Chemical', 'MESH:C112019', (78, 86))	('GRObeta', 'Gene', '2919', (104, 111))	('GRObeta', 'Gene', (104, 111))	('proliferation', 'CPA', (138, 151))	('esophageal cancer', 'Disease', (155, 172))	('knockdown', 'Var', (91, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('reduced', 'NegReg', (126, 133))
848163	19435811	Moreover, the factors responsible for the decreased proliferation of esophageal cancer cells in response to blockade of GRO/CXCR2 signaling remain unknown.	('proliferation', 'CPA', (52, 65))	('decreased', 'NegReg', (42, 51))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('blockade', 'Var', (108, 116))
848179	19435811	Because sequence analysis showed a potential EGR-1 binding site in the promoter region of genes encoding cyclin-dependent kinase (CDK) 4 and p27Kip1, key regulators of cell cycle, we hence determined the potential role of EGR-1 in the transcriptional regulation of CDK4 and p27Kip1 in esophageal cancer cells.	('EGR-1', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('esophageal cancer', 'Disease', (285, 302))	('cyclin-dependent kinase (CDK) 4', 'Gene', '1019', (105, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (285, 302))	('p27Kip1', 'Var', (274, 281))
848180	19435811	Because our previous studies showed that depletion of GRObeta in the medium of WHCO1 cells resulted in a significant reduction of EGR-1 mRNA levels, the levels of EGR-1 and p27Kip1 in GRObeta RNAi-expressing and GROalpha RNAi-expressing WHCO1 clones (generated in previous study) were also determined.	('reduction', 'NegReg', (117, 126))	('GROalpha', 'Gene', '2919', (212, 220))	('WHCO1', 'Gene', (79, 84))	('GROalpha', 'Gene', (212, 220))	('p27Kip1', 'Var', (173, 180))	('GRObeta', 'Gene', '2919', (184, 191))	('mRNA levels', 'MPA', (136, 147))	('GRObeta', 'Gene', (184, 191))	('GRObeta', 'Gene', '2919', (54, 61))	('GRObeta', 'Gene', (54, 61))	('EGR-1', 'Gene', (130, 135))	('depletion', 'MPA', (41, 50))
848182	19435811	Consistent with the results obtained in EGR-1 RNAi clone, the p27Kip1 levels were also strongly elevated in GRObeta RNAi-expressing and GROalpha RNAi-expressing WHCO1 cells in which a 50% reduction in proliferation was observed in the GRObeta knockdown clone (observed previously in ref.	('GROalpha', 'Gene', (136, 144))	('GROalpha', 'Gene', '2919', (136, 144))	('GRObeta', 'Gene', '2919', (108, 115))	('GRObeta', 'Gene', (108, 115))	('p27Kip1', 'Var', (62, 69))	('elevated', 'PosReg', (96, 104))	('GRObeta', 'Gene', '2919', (235, 242))	('GRObeta', 'Gene', (235, 242))
848208	19435811	Furthermore, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed a 40% reduction (P < 0.05) in proliferation of the p65 knockdown cells only after day 7 (Fig.	('reduction', 'NegReg', (97, 106))	('knockdown', 'Var', (146, 155))	('3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (15, 75))	('proliferation', 'CPA', (121, 134))	('p65', 'Gene', (142, 145))
848218	19435811	The reduction in GROalpha and GRObeta expression in esophageal cancer cells treated with either sodium salicylate or p65 RNAi suggests a key role for NF-kappaB in maintaining the GRO/CXCR2 autocrine loop that facilitates cellular proliferation in esophageal tumorigenesis.	('esophageal tumor', 'Disease', 'MESH:D004941', (247, 263))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('facilitates', 'PosReg', (209, 220))	('cellular proliferation', 'CPA', (221, 243))	('NF-kappaB', 'Gene', '4790', (150, 159))	('esophageal tumor', 'Disease', (247, 263))	('expression', 'MPA', (38, 48))	('NF-kappaB', 'Gene', (150, 159))	('GROalpha and GRObeta', 'Gene', '2919', (17, 37))	('esophageal cancer', 'Disease', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('esophageal tumor', 'Phenotype', 'HP:0100751', (247, 263))	('p65 RNAi', 'Var', (117, 125))	('sodium salicylate', 'Chemical', 'MESH:D012980', (96, 113))	('reduction', 'NegReg', (4, 13))	('GRO/CXCR2 autocrine loop', 'MPA', (179, 203))
848242	19435811	Four esophageal cancer cell lines, WHCO1, WHCO5, WHCO6, and KYSE 450 (obtained commercially from Deutsche Sammlung von Mikroorganismen und Zellkulturen), originally established from surgical specimens of primary esophageal squamous cell carcinomas and WHCO1 cells expressing EGR-1 RNAi, EGR-1 sister control, p65 RNAi, and control RNAi were cultured at 37 C in a humidified atmosphere of 5% CO2 and 95% air in DMEM containing 10% FCS.	('carcinomas', 'Phenotype', 'HP:0030731', (237, 247))	('EGR-1', 'Gene', (275, 280))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:C562729', (212, 247))	('esophageal squamous cell carcinomas', 'Disease', (212, 247))	('CO2', 'Chemical', 'MESH:D002245', (391, 394))	('esophageal cancer', 'Disease', (5, 22))	('p65 RNAi', 'Var', (309, 317))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (223, 247))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))	('esophageal cancer', 'Disease', 'MESH:D004938', (5, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
848272	31864387	The mechanism of CPP enhances the activity of TRAIL was analyzed by western blot, dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assay.	('TRAIL', 'CPA', (46, 51))	('activity', 'MPA', (34, 42))	('enhances', 'PosReg', (21, 29))	('CPP', 'Var', (17, 20))	('CPP', 'Chemical', '-', (17, 20))
848274	31864387	In our studies, we found that CPP alone or in combination with TRAIL could inhibit the proliferation of ESCC cells and induce apoptosis, and we certificated that combination of two agents exert synergized functions.	('proliferation', 'CPA', (87, 100))	('inhibit', 'NegReg', (75, 82))	('CPP', 'Var', (30, 33))	('apoptosis', 'CPA', (126, 135))	('CPP', 'Chemical', '-', (30, 33))	('induce', 'Reg', (119, 125))
848277	31864387	We also showed that CPP reduced the expression of Survivin by inhibiting the activity of Wnt/beta-catenin pathway.	('Survivin', 'Protein', (50, 58))	('reduced', 'NegReg', (24, 31))	('Wnt/beta-catenin pathway', 'Pathway', (89, 113))	('inhibiting', 'NegReg', (62, 72))	('activity', 'MPA', (77, 85))	('CPP', 'Var', (20, 23))	('expression', 'MPA', (36, 46))	('CPP', 'Chemical', '-', (20, 23))
848282	31864387	ESCC is the major histological type of esophageal cancer in Asia, and studies have shown that about 59-93% of ESCC patients have a TP53 mutation in genomic and 23% of ESCC patients shared deregulation of Wnt/beta-catenin activity.	('patients', 'Species', '9606', (115, 123))	('mutation', 'Var', (136, 144))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('esophageal cancer', 'Disease', (39, 56))	('ESCC', 'Disease', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('patients', 'Species', '9606', (172, 180))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))
848286	31864387	Though TP53 mutation occur at a high rate and could be a potential target for ESCC, targeting TP53 mutation has been unsuccessful so far.	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutation', 'Var', (12, 20))
848294	31864387	To date, some mechanisms by which cancer cells developed resistance to TRAIL have been elucidated, including the dysfunction of DR4 or DR5, defects in FADD and the overexpression of anti-apoptotic proteins such as c-FLIP, Bcl-2 and Survivin.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('FADD', 'Gene', (151, 155))	('c-FLIP', 'Gene', (214, 220))	('Bcl-2', 'Gene', '596', (222, 227))	('overexpression', 'PosReg', (164, 178))	('as c', 'Gene', (211, 215))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('DR5', 'Gene', '8795', (135, 138))	('dysfunction', 'Var', (113, 124))	('FADD', 'Gene', '8772', (151, 155))	('Survivin', 'Protein', (232, 240))	('c-FLIP', 'Gene', '8837', (214, 220))	('DR5', 'Gene', (135, 138))	('DR4', 'Gene', (128, 131))	('as c', 'Gene', '29108', (211, 215))	('Bcl-2', 'Gene', (222, 227))	('cancer', 'Disease', (34, 40))	('defects', 'Var', (140, 147))	('DR4', 'Gene', '8797', (128, 131))
848298	31864387	Recent studies have shown that CPP can inhibit the proliferation and promote the apoptosis in several cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibit', 'NegReg', (39, 46))	('apoptosis', 'CPA', (81, 90))	('proliferation', 'CPA', (51, 64))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('promote', 'PosReg', (69, 76))	('CPP', 'Var', (31, 34))	('CPP', 'Chemical', '-', (31, 34))
848303	31864387	Notably, we firstly identified FoxP3 as one of the important transcription factor of DRs in the ESCC, and revealed that suppression of FoxP3 expression is the essential molecular mechanisms for CPP to increase DRs Expression.	('DRs Expression', 'MPA', (210, 224))	('FoxP3', 'Gene', '50943', (31, 36))	('increase', 'PosReg', (201, 209))	('FoxP3', 'Gene', '50943', (135, 140))	('CPP', 'Chemical', '-', (194, 197))	('FoxP3', 'Gene', (31, 36))	('FoxP3', 'Gene', (135, 140))	('suppression', 'Var', (120, 131))
848351	31864387	To survey the activity of CPP on esophageal cancer cell lines, we firstly investigated the effect of CPP on the viability of 8 ESCC cell lines: Eca-109, YES-2, TE-1, KYSE-30, KYSE-150, KYSE-180, KYSE-410 and KYSE-510.	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('KYSE-510', 'CellLine', 'CVCL:1354', (208, 216))	('YES-2', 'Gene', '7526', (153, 158))	('CPP', 'Chemical', '-', (101, 104))	('KYSE-510', 'Var', (208, 216))	('esophageal cancer', 'Disease', (33, 50))	('KYSE-180', 'Var', (185, 193))	('KYSE-150', 'Var', (175, 183))	('CPP', 'Chemical', '-', (26, 29))	('KYSE-410', 'Var', (195, 203))	('YES-2', 'Gene', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
848357	31864387	The Q values of YES-2, KYSE-150 and KYSE-510 cells were higher than that in other cell lines (Fig.	('YES-2', 'Gene', (16, 21))	('Q values', 'MPA', (4, 12))	('KYSE-510', 'CellLine', 'CVCL:1354', (36, 44))	('KYSE-510', 'Var', (36, 44))	('KYSE-150', 'Var', (23, 31))	('YES-2', 'Gene', '7526', (16, 21))	('higher', 'PosReg', (56, 62))
848362	31864387	Similarly, the result of TUNEL assay showed that the number of TUNEL-positive staining of YES-2, KYSE-150 and KYSE-510 ESCC cells treated with CPP (100 ng/ml) and TRAIL (1 mug/ml) were all much higher than cells treated with CPP or TRAIL alone (Fig.	('higher', 'PosReg', (194, 200))	('YES-2', 'Gene', '7526', (90, 95))	('KYSE-510', 'Var', (110, 118))	('CPP', 'Chemical', '-', (225, 228))	('KYSE-510 ESCC', 'CellLine', 'CVCL:1354', (110, 123))	('YES-2', 'Gene', (90, 95))	('CPP', 'Chemical', '-', (143, 146))
848375	31864387	To determine how CPP potentiates TRAIL-induced apoptosis, we investigated the effect CPP on the protein levels of DR4 and DR5.	('DR4', 'Gene', (114, 117))	('DR5', 'Gene', '8795', (122, 125))	('CPP', 'Var', (17, 20))	('CPP', 'Chemical', '-', (85, 88))	('CPP', 'Chemical', '-', (17, 20))	('DR5', 'Gene', (122, 125))	('DR4', 'Gene', '8797', (114, 117))
848380	31864387	Firstly, DR4 and DR5 mRNA levels in ESCC cell lines were detected after treatment with different concentrations of CPP (0, 50, 100 or 200 ng/ml) for 24 h. The results showed that CPP enhanced the expression of DR4 and DR5 genes in a dose-dependent manner (Fig.	('DR5', 'Gene', '8795', (17, 20))	('CPP', 'Chemical', '-', (179, 182))	('DR4', 'Gene', (9, 12))	('expression', 'MPA', (196, 206))	('CPP', 'Chemical', '-', (115, 118))	('enhanced', 'PosReg', (183, 191))	('DR5', 'Gene', (218, 221))	('DR4', 'Gene', '8797', (210, 213))	('DR4', 'Gene', (210, 213))	('DR5', 'Gene', '8795', (218, 221))	('CPP', 'Var', (179, 182))	('DR5', 'Gene', (17, 20))	('DR4', 'Gene', '8797', (9, 12))
848383	31864387	Due to the elevated expression levels of DR4 and DR5 mRNA in ESCC cells after treated with CPP, we hypothesized that CPP played an essential role in upregulating DR4 and DR5 by affecting the transcription factors.	('CPP', 'Var', (117, 120))	('DR5', 'Gene', (49, 52))	('affecting', 'Reg', (177, 186))	('DR4', 'Gene', (162, 165))	('CPP', 'Chemical', '-', (117, 120))	('DR5', 'Gene', '8795', (49, 52))	('transcription factors', 'MPA', (191, 212))	('CPP', 'Chemical', '-', (91, 94))	('DR4', 'Gene', '8797', (41, 44))	('DR5', 'Gene', (170, 173))	('DR5', 'Gene', '8795', (170, 173))	('DR4', 'Gene', (41, 44))	('elevated', 'PosReg', (11, 19))	('upregulating', 'PosReg', (149, 161))	('expression levels', 'MPA', (20, 37))	('DR4', 'Gene', '8797', (162, 165))
848406	31864387	Luciferase reporter gene assays were conducted using DR gene promoters containing wild FoxP3 binding site or mutant FoxP3 binding site.	('FoxP3', 'Gene', (116, 121))	('FoxP3', 'Gene', '50943', (87, 92))	('FoxP3', 'Gene', (87, 92))	('mutant', 'Var', (109, 115))	('FoxP3', 'Gene', '50943', (116, 121))
848420	31864387	To further verify whether CPP reduces the expression of Survivin through affecting the Wnt/beta-catenin pathway, the mRNA levels of Survivin, c-Myc, and cyclin D1, which are all target genes regulated by the Wnt/beta-catenin pathway, were detected in the YES-2 and KYSE-150 cells in rescue experiments.	('YES-2', 'Gene', '7526', (255, 260))	('cyclin D1', 'Gene', '595', (153, 162))	('expression', 'MPA', (42, 52))	('cyclin D1', 'Gene', (153, 162))	('c-Myc', 'Gene', (142, 147))	('CPP', 'Var', (26, 29))	('affecting', 'Reg', (73, 82))	('YES-2', 'Gene', (255, 260))	('CPP', 'Chemical', '-', (26, 29))	('Wnt/beta-catenin pathway', 'Pathway', (87, 111))	('reduces', 'NegReg', (30, 37))	('Survivin', 'Protein', (56, 64))	('c-Myc', 'Gene', '4609', (142, 147))
848427	31864387	As demonstrated in our study, the reduction of tumor growth was much more significant in mice treated with the combination of CPP and AAV-TRAIL than AAV-TRAIL (1 x 1010 Gps) or CPP (0.09 mg per mouse) alone.	('combination', 'Interaction', (111, 122))	('CPP', 'Chemical', '-', (177, 180))	('mice', 'Species', '10090', (89, 93))	('AAV-TRAIL', 'Var', (134, 143))	('mouse', 'Species', '10090', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('AAV', 'Species', '272636', (134, 137))	('reduction', 'NegReg', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CPP', 'Chemical', '-', (126, 129))	('AAV', 'Species', '272636', (149, 152))	('tumor', 'Disease', (47, 52))
848449	31864387	In addition to upregulating the expression of DR4/5, CPP also downregulates the expression of Survivin, which further enhances TRAIL-induced apoptosis of cells.	('enhances', 'PosReg', (118, 126))	('Survivin', 'Protein', (94, 102))	('DR4', 'Gene', '8797', (46, 49))	('DR4', 'Gene', (46, 49))	('TRAIL-induced apoptosis of cells', 'CPA', (127, 159))	('CPP', 'Var', (53, 56))	('CPP', 'Chemical', '-', (53, 56))	('downregulates', 'NegReg', (62, 75))	('expression', 'MPA', (80, 90))	('expression', 'MPA', (32, 42))	('upregulating', 'PosReg', (15, 27))
848460	31864387	In addition, CPP also reduces Survivin through downregulating the p-beta-catenin in nucleus.	('p-beta-catenin in nucleus', 'MPA', (66, 91))	('Survivin', 'Protein', (30, 38))	('CPP', 'Var', (13, 16))	('downregulating', 'NegReg', (47, 61))	('reduces', 'NegReg', (22, 29))	('CPP', 'Chemical', '-', (13, 16))
848463	31864387	Additionally, although the mutation of TP53 is considered to be a key factor in the development of ESCC, we have not found that the expression of DR4 and DR5 was related to the mutation of TP53 in this study, neither did we investigate whether TP53 was one of targets of CPP.	('DR4', 'Gene', '8797', (146, 149))	('mutation', 'Var', (177, 185))	('DR4', 'Gene', (146, 149))	('TP53', 'Gene', '7157', (189, 193))	('TP53', 'Gene', (244, 248))	('TP53', 'Gene', (189, 193))	('ESCC', 'Disease', (99, 103))	('mutation', 'Var', (27, 35))	('DR5', 'Gene', (154, 157))	('TP53', 'Gene', '7157', (39, 43))	('CPP', 'Chemical', '-', (271, 274))	('DR5', 'Gene', '8795', (154, 157))	('TP53', 'Gene', (39, 43))	('TP53', 'Gene', '7157', (244, 248))
848467	31864387	On the other hand, CPP could inhibit the activity of Wnt/beta-catenin pathway by affecting the nuclear localization of beta-catenin in ESCC cells, thus inhibiting the transcription of Survivin, and inducing apoptosis of cancer cell.	('Survivin', 'Protein', (184, 192))	('affecting', 'Reg', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('transcription', 'MPA', (167, 180))	('Wnt/beta-catenin pathway', 'Pathway', (53, 77))	('CPP', 'Var', (19, 22))	('inhibit', 'NegReg', (29, 36))	('beta-catenin', 'Protein', (119, 131))	('CPP', 'Chemical', '-', (19, 22))	('nuclear localization', 'MPA', (95, 115))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('inducing', 'Reg', (198, 206))	('cancer', 'Disease', (220, 226))	('inhibiting', 'NegReg', (152, 162))	('activity', 'MPA', (41, 49))
848468	31864387	Therefore, CPP can enhance the sensitivity of ESCC cells to apoptosis induced by TRAIL in vitro and in vivo.	('sensitivity', 'MPA', (31, 42))	('enhance', 'PosReg', (19, 26))	('CPP', 'Var', (11, 14))	('CPP', 'Chemical', '-', (11, 14))
848675	28095814	A previous report suggested that enlargement of the irradiation field increased the risk of aspiration pneumonia.	('enlargement', 'Var', (33, 44))	('aspiration', 'Phenotype', 'HP:0002835', (92, 102))	('aspiration pneumonia', 'Disease', (92, 112))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (92, 112))	('pneumonia', 'Phenotype', 'HP:0002090', (103, 112))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (92, 112))
848730	27799791	Chinese race was associated with a better OS in patients with ESCC (P=0.001).	('ESCC', 'Disease', (62, 66))	('patients', 'Species', '9606', (48, 56))	('OS', 'Chemical', '-', (42, 44))	('Chinese race', 'Var', (0, 12))
848731	27799791	Caucasian race was associated with a better OS in patients with EAC (P=0.006) (Table S1).	('patients', 'Species', '9606', (50, 58))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('Caucasian race', 'Var', (0, 14))	('OS', 'Chemical', '-', (44, 46))	('EAC', 'Disease', (64, 67))	('better', 'PosReg', (37, 43))
848733	27799791	Chinese race was independently associated with a better OS in patients with ESCC compared to Caucasian patients (hazard ratio [HR] =1.330; 95% confidence interval [CI] =1.159-1.527, P<0.001).	('OS', 'Chemical', '-', (56, 58))	('Chinese race', 'Var', (0, 12))	('better', 'PosReg', (49, 55))	('patients', 'Species', '9606', (103, 111))	('ESCC', 'Disease', (76, 80))	('patients', 'Species', '9606', (62, 70))
848746	27799791	In this study, the survival rate of patients undergoing CDS was higher than their counterparts who did not.	('survival', 'CPA', (19, 27))	('patients', 'Species', '9606', (36, 44))	('higher', 'PosReg', (64, 70))	('CDS', 'Var', (56, 59))	('CDS', 'Chemical', '-', (56, 59))
848791	23972096	There was evidence of perineural invasion, desmoplasmin mild peritumoral, mild intra and peritumoral lymphocytic response, ulceration, and the rate of four mitoses per 10 fields.	('desmoplasmin', 'Var', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (93, 98))	('perineural invasion', 'CPA', (22, 41))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('ulceration', 'CPA', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
848846	23972096	In a series of ten patients with primary malignant melanoma of the esophagus studied by Langer et al., the mutation of c-KIT, among others was detected in two by molecular analysis, and in all by immunohistochemistry .	('patients', 'Species', '9606', (19, 27))	('malignant melanoma', 'Phenotype', 'HP:0002861', (41, 59))	('primary malignant melanoma of the esophagus', 'Disease', 'MESH:D008545', (33, 76))	('c-KIT', 'Gene', '3815', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('mutation', 'Var', (107, 115))	('primary malignant melanoma of the esophagus', 'Disease', (33, 76))	('c-KIT', 'Gene', (119, 124))
848942	22016580	Moreover, studies suggest that the presence of biliary salts and pancreatic juices may worsen the lesion.	('presence', 'Var', (35, 43))	('pancreatic', 'Disease', (65, 75))	('biliary salts', 'MPA', (47, 60))	('lesion', 'MPA', (98, 104))	('worsen', 'PosReg', (87, 93))	('pancreatic', 'Disease', 'MESH:D010195', (65, 75))
849011	33686969	It is well known that the absence of adenomatous polyps colis (Apc), an inhibitor of WNT signaling, can lead to primary precursor lesion for colon carcinoma in humans.	('adenomatous polyps colis', 'Disease', (37, 61))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (37, 55))	('humans', 'Species', '9606', (160, 166))	('absence', 'Var', (26, 33))	('colon carcinoma', 'Disease', (141, 156))	('lead', 'Reg', (104, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('adenomatous polyps colis', 'Disease', 'MESH:D018256', (37, 61))	('colon carcinoma', 'Disease', 'MESH:D003110', (141, 156))
849012	33686969	With a germline nonsense mutation in the tumor suppressor gene of Apc, Apcmin/+ mice model is a classical model for studying intestinal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('intestinal tumor', 'Disease', (125, 141))	('germline nonsense mutation', 'Var', (7, 33))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (136, 141))	('intestinal tumor', 'Disease', 'MESH:D007414', (125, 141))
849026	33686969	COX-2 inhibitors can prevent tumorigenesis by reducing cyclooxygenase activity, decreasing prostaglandin levels and influencing apoptosis.	('decreasing', 'NegReg', (80, 90))	('prostaglandin', 'Chemical', 'MESH:D011453', (91, 104))	('influencing', 'Reg', (116, 127))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('decreasing prostaglandin levels', 'Phenotype', 'HP:0003566', (80, 111))	('tumor', 'Disease', (29, 34))	('inhibitors', 'Var', (6, 16))	('COX-2', 'Gene', '19225', (0, 5))	('reducing', 'NegReg', (46, 54))	('COX-2', 'Gene', (0, 5))	('apoptosis', 'CPA', (128, 137))	('prostaglandin levels', 'MPA', (91, 111))	('cyclooxygenase activity', 'MPA', (55, 78))
849050	33686969	The tumor size was classified into three types based on the tumor diameter: small size (< 1 mm), middle size (1-3 mm), and large size (> 3mm).	('tumor', 'Disease', (4, 9))	('< 1 mm', 'Var', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('1-3 mm', 'Var', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (60, 65))
849101	33686969	Retinoblastoma inactivation increases the secretion of the chemoattractant CCL2, which promotes tumor angiogenesis and recruitment of tumor-associated macrophages and myeloid-derived suppressor cells into the tumor microenvironment in several tumor types including sarcoma and breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('increases', 'PosReg', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (243, 248))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('Retinoblastoma', 'Disease', 'MESH:D012175', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('Retinoblastoma', 'Disease', (0, 14))	('CCL2', 'Gene', (75, 79))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('secretion', 'MPA', (42, 51))	('promotes', 'PosReg', (87, 95))	('sarcoma and breast cancer', 'Disease', 'MESH:D001943', (265, 290))	('inactivation', 'Var', (15, 27))	('CCL2', 'Gene', '20296', (75, 79))
849105	33686969	It is shown that the expression of CXCL1, CXCL2, CXCL3, and CXCL8 is increased in CPT-11-R LoVo colon cancer cells.	('CXCL8', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('increased', 'PosReg', (69, 78))	('expression', 'MPA', (21, 31))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('LoVo', 'CellLine', 'CVCL:0399', (91, 95))	('CXCL8', 'Gene', '3576', (60, 65))	('colon cancer', 'Disease', (96, 108))	('CPT-11-R', 'Var', (82, 90))
849118	33686969	CXCR2 is important in the immunoregulation of pancreatic cancer and inhibition of CXCR2 can reduce metastasis and improve response to gemcitabine and anti-PD1.	('CXCR2', 'Gene', (82, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (46, 63))	('reduce', 'NegReg', (92, 98))	('inhibition', 'Var', (68, 78))	('pancreatic cancer', 'Disease', (46, 63))	('response to gemcitabine', 'MPA', (122, 145))	('pancreatic cancer', 'Disease', 'MESH:D010190', (46, 63))	('improve', 'PosReg', (114, 121))	('metastasis', 'CPA', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))
849119	33686969	Moreover, a single copy (heterozygote) deletion of the CXCR2 gene is sufficient to synergize with low-dose sulindac treatment in suppressing Apc min-induced intestinal polyposis.	('intestinal polyposis', 'Disease', (157, 177))	('intestinal polyposis', 'Phenotype', 'HP:0200008', (157, 177))	('intestinal polyposis', 'Disease', 'MESH:D044483', (157, 177))	('suppressing', 'NegReg', (129, 140))	('deletion', 'Var', (39, 47))	('CXCR2', 'Gene', (55, 60))	('sulindac', 'Chemical', 'MESH:D013467', (107, 115))
849134	33686969	In conclusion, our results have indicated that Zinc deficiency accelerates colon tumorigenesis by activating pro-inflammatory mediators.	('Zinc deficiency', 'Var', (47, 62))	('Zinc deficiency', 'Phenotype', 'HP:0031831', (47, 62))	('colon tumor', 'Phenotype', 'HP:0100273', (75, 86))	('activating', 'Reg', (98, 108))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('accelerates', 'PosReg', (63, 74))	('colon tumorigenesis', 'Disease', 'MESH:D063646', (75, 94))	('colon tumorigenesis', 'Disease', (75, 94))
849139	33686969	The composition of zinc deficiency (ZD) (TD.85419) and zinc sufficiency diet (ZS) (TD.85420) were identical except for the Zn content, which was approximately 0.5 - 1.5 ppm and approximately 50.5 - 51.5 ppm, respectively.	('zinc deficiency', 'Phenotype', 'HP:0031831', (19, 34))	('ZD', 'Phenotype', 'HP:0031831', (36, 38))	('TD.85420', 'Var', (83, 91))	('zinc deficiency', 'Disease', (19, 34))	('TD.85419', 'Var', (41, 49))	('ZD', 'Chemical', '-', (36, 38))	('zinc deficiency', 'Disease', 'MESH:C564286', (19, 34))	('Zn', 'Chemical', 'MESH:D015032', (123, 125))
849168	33686969	After incubating with anti-CXCR2 (1:1000; ab217314, Abcam, USA) and anti-COX-2 (1:1000; ab23672, Abcam, USA) antibodies overnight in a 4  C refrigerator, the membrane was transferred to the secondary antibody (1:5000; Cell Signaling Technology) incubating for 1 hour.	('1:1000; ab23672', 'Var', (80, 95))	('1:1000', 'Var', (34, 40))	('COX-2', 'Gene', '19225', (73, 78))	('COX-2', 'Gene', (73, 78))
849214	32064448	Genetic analysis was positive for KRAS mutations in codons 12, 13, 61, 117, and 146 of known pathologic significance in pancreatic adenocarcinoma.	('KRAS', 'Gene', '3845', (34, 38))	('pancreatic adenocarcinoma', 'Disease', (120, 145))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (120, 145))	('positive', 'Reg', (21, 29))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (120, 145))	('mutations', 'Var', (39, 48))	('KRAS', 'Gene', (34, 38))
849265	29695636	The role of AKT in ESCC was studied using immuno- histochemical analysis of a tumor microarray, the effect of AKT knockdown on cell growth, and treatment of cells with MK-2206, an AKT inhibitor.	('men', 'Species', '9606', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('knockdown', 'Var', (114, 123))	('AKT', 'Gene', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('MK-2206', 'Chemical', 'MESH:C548887', (168, 175))
849267	29695636	It inhibited growth of KYSE70, KYSE410 and KYSE450 esophageal cancer cells in a time- and concentration-dependent manner.	('KYSE450', 'Var', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancer', 'Disease', (51, 68))	('inhibited', 'NegReg', (3, 12))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('KYSE410', 'Var', (31, 38))	('growth', 'CPA', (13, 19))
849299	29695636	Cells were seeded (6x103 cells/well for KYSE70; 2.5x103 cells/well for KYSE410; 2x103 cells/well for KYSE450) in 96-well plates and incubated for 24 h and then treated with different amounts of oridonin or vehicle.	('oridonin', 'Chemical', 'MESH:C011959', (194, 202))	('KYSE70', 'Var', (40, 46))	('KYSE410', 'Var', (71, 78))
849336	29695636	After antigen unmasking, the sections were blocked with 5% goat serum and incubated at 4 C overnight with antibodies to detect Ki-67, phosphorylated AKT (Ser473), mTOR (Ser2448) or GSK-3beta (Ser9).	('Ser2448', 'Chemical', '-', (169, 176))	('Ki-67', 'Gene', (127, 132))	('mTOR', 'Gene', '2475', (163, 167))	('mTOR', 'Gene', (163, 167))	('Ser473', 'Var', (154, 160))	('goat', 'Species', '9925', (59, 63))	('Ser2448', 'Var', (169, 176))	('Ser9', 'Chemical', '-', (192, 196))	('Ser473', 'Chemical', '-', (154, 160))	('GSK-3beta', 'Gene', '2932', (181, 190))	('GSK-3beta', 'Gene', (181, 190))	('AKT', 'Pathway', (149, 152))
849342	29695636	We also evaluated the effects of treatment of ESCC cells with an AKT inhibitor or knock-down of AKT (Fig.	('AKT', 'Pathway', (65, 68))	('knock-down', 'Var', (82, 92))	('AKT', 'Pathway', (96, 99))	('men', 'Species', '9606', (38, 41))
849343	29695636	The results revealed that treatment with the AKT inhibitor, MK-2206, significantly decreased the growth of KYSE70, KYSE410 or KYSE450 cells (Fig.	('men', 'Species', '9606', (31, 34))	('KYSE450', 'Var', (126, 133))	('decreased', 'NegReg', (83, 92))	('MK-2206', 'Chemical', 'MESH:C548887', (60, 67))	('MK-2206', 'Var', (60, 67))	('growth', 'MPA', (97, 103))	('KYSE410', 'Var', (115, 122))
849346	29695636	First, we performed an in vitro kinase assay with immunoprecipitated AKT in the presence of 5 or 10 muM oridonin and results indicated that the phosphorylation of GSK-3alpha/beta (Ser21/9), an AKT substrate, was decreased by treatment with oridonin compared to an untreated control (Fig.	('decreased', 'NegReg', (212, 221))	('phosphorylation', 'MPA', (144, 159))	('oridonin', 'Var', (240, 248))	('men', 'Species', '9606', (230, 233))	('oridonin', 'Chemical', 'MESH:C011959', (240, 248))	('oridonin', 'Chemical', 'MESH:C011959', (104, 112))	('muM', 'Gene', '56925', (100, 103))	('GSK-3alpha', 'Gene', (163, 173))	('muM', 'Gene', (100, 103))	('Ser21', 'Chemical', '-', (180, 185))	('GSK-3alpha', 'Gene', '2931', (163, 173))
849352	29695636	The docking model predicted that oridonin formed two hydrogen bonds each at Asp292 or Lys277/Asp293 in the backbone of AKT1 (Fig.	('AKT1', 'Gene', (119, 123))	('hydrogen', 'Chemical', 'MESH:D006859', (53, 61))	('Asp293', 'Chemical', '-', (93, 99))	('Asp292', 'Chemical', '-', (76, 82))	('oridonin', 'Chemical', 'MESH:C011959', (33, 41))	('Lys277/Asp293', 'Var', (86, 99))	('AKT1', 'Gene', '207', (119, 123))	('Lys277', 'Chemical', '-', (86, 92))
849358	29695636	Treatment of KYSE70, KYSE410 and KYSE450 ESCC cells with oridonin (5, 10 or 20 muM) significantly inhibited growth in a time-dependent manner compared to a DMSO control (Fig.	('inhibited', 'NegReg', (98, 107))	('muM', 'Gene', '56925', (79, 82))	('DMSO', 'Chemical', 'MESH:D004121', (156, 160))	('KYSE70', 'Var', (13, 19))	('KYSE410', 'Var', (21, 28))	('muM', 'Gene', (79, 82))	('oridonin', 'Chemical', 'MESH:C011959', (57, 65))	('men', 'Species', '9606', (5, 8))	('KYSE450', 'Var', (33, 40))	('growth', 'MPA', (108, 114))
849361	29695636	After knock-down of AKT1 and AKT2 in ESCC cells (Fig.	('AKT1', 'Gene', '207', (20, 24))	('AKT1', 'Gene', (20, 24))	('AKT2', 'Gene', (29, 33))	('knock-down', 'Var', (6, 16))	('AKT2', 'Gene', '208', (29, 33))
849367	29695636	Oridonin (10 or 20 muM) caused significant G2/M phase cell cycle arrest in KYSE70, KYSE410 and KYSE450 cells (Fig.	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('muM', 'Gene', (19, 22))	('KYSE70', 'Var', (75, 81))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('arrest', 'Disease', (65, 71))	('Oridonin', 'Chemical', 'MESH:C011959', (0, 8))	('muM', 'Gene', '56925', (19, 22))	('KYSE410', 'Var', (83, 90))	('KYSE450', 'Var', (95, 102))
849375	29695636	Treatment of KYSE70, KYSE410 or KYSE450 ESCC cells with oridonin had no effect on the expression of phosphorylated AKT or total AKT but decreased the levels of phosphorylated GSK-3beta (Ser9) and phosphorylated mTOR (Ser2448) compared to untreated controls (Fig.	('GSK-3beta', 'Gene', '2932', (175, 184))	('Ser9', 'Chemical', '-', (186, 190))	('oridonin', 'Chemical', 'MESH:C011959', (56, 64))	('mTOR', 'Gene', '2475', (211, 215))	('mTOR', 'Gene', (211, 215))	('KYSE70', 'Var', (13, 19))	('KYSE410', 'Var', (21, 28))	('Ser2448', 'Chemical', '-', (217, 224))	('KYSE450', 'Var', (32, 39))	('men', 'Species', '9606', (5, 8))	('levels', 'MPA', (150, 156))	('GSK-3beta', 'Gene', (175, 184))	('decreased', 'NegReg', (136, 145))
849377	29695636	Furthermore, KYSE70, KYSE410 or KYSE450 ESCC cells transfected with an NF-kappaB-luciferase plasmid and then treated with oridonin showed significant inhibition of luciferase reporter gene activity (Fig.	('oridonin', 'Chemical', 'MESH:C011959', (122, 130))	('NF-kappaB', 'Gene', (71, 80))	('NF-kappaB', 'Gene', '4790', (71, 80))	('KYSE70', 'Var', (13, 19))	('inhibition', 'NegReg', (150, 160))	('KYSE410', 'Var', (21, 28))	('KYSE450', 'Var', (32, 39))	('luciferase reporter gene', 'Enzyme', (164, 188))	('activity', 'MPA', (189, 197))
849381	29695636	The results revealed that growth of KYSE450 and KYSE410 cells was synergistically or additively inhibited by co-treatment with oridonin and 5-FU (Fig.	('men', 'Species', '9606', (117, 120))	('inhibited', 'NegReg', (96, 105))	('5-FU', 'Chemical', '-', (140, 144))	('growth', 'CPA', (26, 32))	('oridonin', 'Chemical', 'MESH:C011959', (127, 135))	('KYSE410', 'Var', (48, 55))
849385	29695636	Colony number formation was also substantially decreased after co-treatment with oridonin and 5-FU (Fig.	('5-FU', 'Var', (94, 98))	('men', 'Species', '9606', (71, 74))	('oridonin', 'Chemical', 'MESH:C011959', (81, 89))	('Colony number formation', 'CPA', (0, 23))	('5-FU', 'Chemical', '-', (94, 98))	('decreased', 'NegReg', (47, 56))
849409	29695636	Our MTT and soft agar assay results also revealed that oridonin significantly inhibited growth of KYSE70, KYSE410 and KYSE450 ESCC cell lines (Fig.	('oridonin', 'Chemical', 'MESH:C011959', (55, 63))	('inhibited', 'NegReg', (78, 87))	('agar', 'Chemical', 'MESH:D000362', (17, 21))	('KYSE410', 'Var', (106, 113))	('growth', 'CPA', (88, 94))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('KYSE450', 'Var', (118, 125))
849468	31293338	Regarding the biomarker value of pre-therapeutic PET in surgically treated esophageal cancer, Fukunaga et al reported that a high SUV of the tumor before surgery had a poorer prognosis compared with those with low FDG uptake in esophageal cancer patients who received curative surgery without neoadjuvant therapy in 1998.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('patients', 'Species', '9606', (246, 254))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (141, 146))	('FDG', 'Chemical', 'MESH:D019788', (214, 217))	('esophageal cancer', 'Disease', (228, 245))	('esophageal cancer', 'Disease', (75, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (228, 245))	('high', 'Var', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
849501	30487696	Furthermore, it has also been hypothesized that freezing results in vascular injury by causing stasis in blood flow.	('freezing', 'Var', (48, 56))	('vascular injury', 'Disease', 'MESH:D057772', (68, 83))	('causing', 'Reg', (87, 94))	('results in', 'Reg', (57, 67))	('stasis in blood flow', 'MPA', (95, 115))	('vascular injury', 'Disease', (68, 83))
414297	30487696	CE-D rate was significantly lower (67%) in those with ultra-long BE compared with those with < 8 cm (100%, P = 0.02).	('lower', 'NegReg', (28, 33))	('CE-D', 'CPA', (0, 4))	('CE-D', 'Chemical', '-', (0, 4))	('ultra-long BE', 'Var', (54, 67))	('BE', 'Phenotype', 'HP:0100580', (65, 67))
849576	30487696	Patients who underwent RFA had a threefold higher odd of having CE-IM than those who underwent cryotherapy [odds ratio (OR) = 2.9, 95% confidence interval (CI): 1.4-6.0, P = 0.004], but CE-D were similar between the two groups (OR = 1.7, 95%CI: 0.66-4.30, P = 0.28).	('CE-IM', 'Chemical', '-', (64, 69))	('Patients', 'Species', '9606', (0, 8))	('RFA', 'Var', (23, 26))	('CE-IM', 'Disease', (64, 69))	('CE-D', 'Chemical', '-', (186, 190))
849713	29114599	In our study, VMAT did not increase the risk of radiation pneumonitis, pulmonary fibrosis, or pleural effusion compared with ssIMRT.	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (71, 89))	('pneumonitis', 'Disease', 'MESH:D011014', (58, 69))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (71, 89))	('pulmonary fibrosis', 'Disease', (71, 89))	('pleural effusion', 'Disease', 'MESH:D010996', (94, 110))	('pleural effusion', 'Disease', (94, 110))	('pleural effusion', 'Phenotype', 'HP:0002202', (94, 110))	('pneumonitis', 'Disease', (58, 69))	('VMAT', 'Var', (14, 18))
849811	28279422	Current cancer clinical trials are examining inhibitors of IGF-1.	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('inhibitors', 'Var', (45, 55))	('IGF-1', 'Gene', '3479', (59, 64))	('IGF-1', 'Gene', (59, 64))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
849838	28279422	Several recent studies suggest there are improved cancer outcomes in those on cholesterol-lowering agents; these are discussed later.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('improved', 'PosReg', (41, 49))	('cholesterol', 'Chemical', 'MESH:D002784', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cholesterol-lowering', 'Var', (78, 98))
849845	28279422	Nitrosamines, produced from nitrates and added to processed meat for conservation, are genotoxic substances that can act directly on DNA, causing point mutations, deletions, and insertions.	('insertions', 'Var', (178, 188))	('Nitrosamines', 'Chemical', 'MESH:D009602', (0, 12))	('causing', 'Reg', (138, 145))	('nitrates', 'Chemical', 'MESH:D009566', (28, 36))	('point mutations', 'Var', (146, 161))	('deletions', 'Var', (163, 172))
849847	28279422	In animal species as well as in human case-control studies, nitrosamines have been associated with gastric cancer and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('nitrosamines', 'Var', (60, 72))	('nitrosamines', 'Chemical', 'MESH:D009602', (60, 72))	('gastric cancer', 'Disease', (99, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('associated', 'Reg', (83, 93))	('human', 'Species', '9606', (32, 37))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))
849852	28279422	Polyphenols seem to affect several metabolic pathways, including mitogen-activated protein kinases, phosphatidylinositol 3-kinases, IGF-1, nuclear factor kappaB, and reactive oxygen species, leading to reductions in both cardiovascular disease and cancer.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('Polyphenols', 'Var', (0, 11))	('IGF-1', 'Gene', '3479', (132, 137))	('metabolic pathways', 'Pathway', (35, 53))	('IGF-1', 'Gene', (132, 137))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (166, 189))	('cardiovascular disease', 'Disease', 'MESH:D002318', (221, 243))	('Polyphenols', 'Chemical', 'MESH:D059808', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cardiovascular disease', 'Disease', (221, 243))	('phosphatidylinositol 3-kinases', 'MPA', (100, 130))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (221, 243))	('affect', 'Reg', (20, 26))	('nuclear', 'MPA', (139, 146))	('reductions', 'NegReg', (202, 212))	('reactive oxygen species', 'MPA', (166, 189))	('mitogen-activated protein kinases', 'Pathway', (65, 98))
849855	28279422	Based on several previously published articles, there is an increased risk of cardiovascular disease associated with high content of saturated fats, red meat, sugar, and processed food.	('cardiovascular disease', 'Phenotype', 'HP:0001626', (78, 100))	('cardiovascular disease', 'Disease', 'MESH:D002318', (78, 100))	('cardiovascular disease', 'Disease', (78, 100))	('fats', 'Gene', (143, 147))	('sugar', 'Chemical', 'MESH:D000073893', (159, 164))	('high', 'Var', (117, 121))	('fats', 'Gene', '118611', (143, 147))	('saturated fat', 'Chemical', 'MESH:D008055', (133, 146))
849859	28279422	Exercise can also have a favorable effect on improving cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Exercise', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('improving', 'PosReg', (45, 54))	('cancer', 'Disease', (55, 61))
849861	28279422	Exercise seems to decrease not only primary incidence of cancer but also recurrence in cancer survivors.	('recurrence', 'CPA', (73, 83))	('cancer', 'Disease', (87, 93))	('primary incidence', 'CPA', (36, 53))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('Exercise', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('decrease', 'NegReg', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
849863	28279422	Exercise has also been associated with a decrease in cancer mortality.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('decrease', 'NegReg', (41, 49))	('Exercise', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
849873	28279422	Thus the overall effect of exercise is a reduction in circulating sex and metabolic hormones, a decrease in insulin, decrease in leptin, and a decrease in inflammatory markers (CRP, tumor necrosis factor, and IL-6), several of which are known to be carcinogenic.	('CRP', 'Gene', '1401', (177, 180))	('insulin', 'Gene', (108, 115))	('decrease', 'NegReg', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('carcinogenic', 'Disease', (249, 261))	('necrosis', 'Disease', 'MESH:D009336', (188, 196))	('IL-6', 'Gene', '3569', (209, 213))	('carcinogenic', 'Disease', 'MESH:D063646', (249, 261))	('necrosis', 'Disease', (188, 196))	('CRP', 'Gene', (177, 180))	('leptin', 'Gene', '3952', (129, 135))	('decrease', 'NegReg', (96, 104))	('leptin', 'Gene', (129, 135))	('IL-6', 'Gene', (209, 213))	('exercise', 'Var', (27, 35))	('insulin', 'Gene', '3630', (108, 115))	('reduction', 'NegReg', (41, 50))	('tumor', 'Disease', (182, 187))	('decrease', 'NegReg', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
849886	28279422	In the large European Prospective Investigation into Cancer and Nutrition (EPIC) study of 23,153 individuals ages 35 to 65 years, researchers examined whether those who adhered to lifestyle events of a BMI less than 30 kg/m2, no tobacco use, exercise greater than 3.5 h/wk, and a healthy diet had improvements in chronic disease outcomes.	('Cancer', 'Disease', 'MESH:D009369', (53, 59))	('chronic disease', 'Disease', (313, 328))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('chronic disease', 'Disease', 'MESH:D002908', (313, 328))	('less than 30', 'Var', (206, 218))	('improvements', 'PosReg', (297, 309))	('men', 'Species', '9606', (304, 307))	('Cancer', 'Disease', (53, 59))	('tobacco', 'Species', '4097', (229, 236))
849887	28279422	After a mean follow-up of 7.8 years, adherence to all 4 lifestyles events compared with 0 lifestyle events resulted in decreases in chronic disease (adjusted HR 0.22), diabetes (adjusted HR 0.07), myocardial infarction (adjusted HR 0.19), stroke (adjusted HR 0.50), and cancer (adjusted HR 0.64).	('stroke', 'Phenotype', 'HP:0001297', (239, 245))	('diabetes', 'Disease', (168, 176))	('stroke', 'Disease', (239, 245))	('myocardial infarction', 'Phenotype', 'HP:0001658', (197, 218))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('diabetes', 'Disease', 'MESH:D003920', (168, 176))	('decreases in chronic disease', 'Disease', (119, 147))	('stroke', 'Disease', 'MESH:D020521', (239, 245))	('myocardial infarction', 'Disease', 'MESH:D009203', (197, 218))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('decreases in chronic disease', 'Disease', 'MESH:D002908', (119, 147))	('myocardial infarction', 'Disease', (197, 218))	('adherence', 'Var', (37, 46))
849889	28279422	Adhering to 6 of the 7 health metrics resulted in a 51% lower incidence of cancer, after adjusting for age, gender, race, and ARIC study site.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('lower', 'NegReg', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Adhering', 'Var', (0, 8))
849893	28279422	Although small studies have suggested a possible increase in cancer risk with the use of insulin analogs, a significant amount of data suggests metformin may actually reduce cancer risk.	('insulin', 'Gene', (89, 96))	('reduce', 'NegReg', (167, 173))	('metformin', 'Var', (144, 153))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('insulin', 'Gene', '3630', (89, 96))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('metformin', 'Chemical', 'MESH:D008687', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
849895	28279422	Mechanistically, metformin activates adenosine monophosphate-activated protein kinase in hepatocytes.	('adenosine', 'Enzyme', (37, 46))	('metformin', 'Var', (17, 26))	('metformin', 'Chemical', 'MESH:D008687', (17, 26))	('activates', 'PosReg', (27, 36))
849897	28279422	Currently, there are ongoing studies looking at metformin and cancer in prostate cancer, colorectal cancer, breast cancer, nonsmall cell lung cancer, bladder cancer, ovarian, and endometrial cancers (NCT02360618, NCT02115464, NCT02285855, NCT01340300, NCT02122185, NCT02065687, and NCT01243385).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', (81, 87))	('endometrial cancers', 'Disease', 'MESH:D016889', (179, 198))	('endometrial cancers', 'Disease', (179, 198))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('NCT01243385', 'Var', (282, 293))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('endometrial cancer', 'Phenotype', 'HP:0012114', (179, 197))	('NCT02065687', 'Var', (265, 276))	('cancer', 'Disease', (191, 197))	('prostate cancer', 'Disease', 'MESH:D011471', (72, 87))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('NCT02122185', 'Var', (252, 263))	('NCT02360618', 'Var', (200, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('colorectal cancer', 'Disease', (89, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (72, 87))	('bladder cancer', 'Disease', 'MESH:D001749', (150, 164))	('bladder cancer', 'Disease', (150, 164))	('cancer', 'Disease', (158, 164))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (123, 148))	('cancer', 'Disease', (62, 68))	('prostate cancer', 'Disease', (72, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('NCT02285855', 'Var', (226, 237))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('cancer', 'Disease', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('NCT02115464', 'Var', (213, 224))	('metformin', 'Chemical', 'MESH:D008687', (48, 57))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('cancer', 'Disease', (100, 106))	('breast cancer', 'Disease', (108, 121))	('NCT01340300', 'Var', (239, 250))	('cancer', 'Disease', (115, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('nonsmall cell lung cancer', 'Disease', (123, 148))	('ovarian', 'Disease', (166, 173))	('ovarian', 'Disease', 'MESH:D010051', (166, 173))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
849899	28279422	In animal models, furosemide and hydrochlorothiazide use results in a marginal increase in renal cell carcinoma and adrenal adenomatous growths.	('increase', 'PosReg', (79, 87))	('adrenal adenomatous growths', 'Disease', 'MESH:D011125', (116, 143))	('hydrochlorothiazide', 'Var', (33, 52))	('renal cell carcinoma', 'Disease', (91, 111))	('hydrochlorothiazide', 'Chemical', 'MESH:D006852', (33, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('adrenal adenomatous growths', 'Disease', (116, 143))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (91, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('furosemide', 'Chemical', 'MESH:D005665', (18, 28))
849907	28279422	Inhibitors of hydroxymethylglutaryl coenzyme A reductase (HMGCR), otherwise known as statins, are well known to cause a reduction in cardiovascular mortality.	('hydroxymethylglutaryl coenzyme A reductase', 'Gene', '3156', (14, 56))	('HMGCR', 'Gene', (58, 63))	('Inhibitors', 'Var', (0, 10))	('reduction', 'NegReg', (120, 129))	('HMGCR', 'Gene', '3156', (58, 63))	('hydroxymethylglutaryl coenzyme A reductase', 'Gene', (14, 56))	('cardiovascular', 'Disease', (133, 147))
849933	27843412	Overexpression of A613T and G462T variants of DNA polymerase beta weakens chemotherapy sensitivity in esophageal cancer cell lines Human DNA polymerase beta (polbeta) is a small monomeric protein that is essential for short-patch base excision repair.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('weakens', 'NegReg', (66, 73))	('A613T', 'Mutation', 'rs764290273', (18, 23))	('DNA polymerase beta', 'Gene', '5423', (137, 156))	('polbeta', 'Gene', '5423', (158, 165))	('DNA polymerase beta', 'Gene', (46, 65))	('G462T', 'Mutation', 'c.462G>T', (28, 33))	('chemotherapy', 'MPA', (74, 86))	('polbeta', 'Gene', (158, 165))	('esophageal cancer', 'Disease', (102, 119))	('Human', 'Species', '9606', (131, 136))	('G462T', 'Var', (28, 33))	('DNA polymerase beta', 'Gene', (137, 156))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('A613T', 'Var', (18, 23))	('DNA polymerase beta', 'Gene', '5423', (46, 65))
849937	27843412	There are 229 patients with the polbeta mutation, 18 patients with A613T mutation, 12 patients with G462T mutation among 538 ECs.	('A613T mutation', 'Var', (67, 81))	('polbeta', 'Gene', '5423', (32, 39))	('polbeta', 'Gene', (32, 39))	('patients', 'Species', '9606', (53, 61))	('A613T', 'Mutation', 'rs764290273', (67, 72))	('G462T', 'Mutation', 'c.462G>T', (100, 105))	('patients', 'Species', '9606', (14, 22))	('G462T', 'Var', (100, 105))	('patients', 'Species', '9606', (86, 94))
849938	27843412	Analysis results of survival time showed that EC patients with A613T, G462T mutation had a shorter survival than the others (P < 0.05).	('G462T', 'Var', (70, 75))	('G462T', 'Mutation', 'c.462G>T', (70, 75))	('A613T', 'Mutation', 'rs764290273', (63, 68))	('patients', 'Species', '9606', (49, 57))	('survival', 'MPA', (99, 107))	('shorter', 'NegReg', (91, 98))	('A613T', 'Var', (63, 68))
849939	27843412	CCK-8 and flow cytometry assays results showed the A613T, G462T EC9706 cells were less sensitive than WT cells to 5-FU and cisplatin (P < 0.05).	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('G462T', 'SUBSTITUTION', 'None', (58, 63))	('A613T', 'Var', (51, 56))	('less', 'NegReg', (82, 86))	('G462T', 'Var', (58, 63))	('sensitive', 'MPA', (87, 96))	('5-FU', 'Chemical', 'MESH:D005472', (114, 118))	('A613T', 'Mutation', 'rs764290273', (51, 56))
849940	27843412	Experiments results in vivo showed that the tumor sizes of A613T and G462T group were larger than WT and polbeta-/- groups (P < 0.05).	('larger', 'PosReg', (86, 92))	('polbeta', 'Gene', '5423', (105, 112))	('polbeta', 'Gene', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('G462T', 'Mutation', 'c.462G>T', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('G462T', 'Var', (69, 74))	('A613T', 'Mutation', 'rs764290273', (59, 64))	('A613T', 'Var', (59, 64))	('tumor', 'Disease', (44, 49))
849941	27843412	In this study, we discovered A to T point mutation at nucleotide 613 (A613T) and G to T point mutation at nucleotide 462 (G462T) in the polbeta gene through 538 EC patients cohort study.	('G462T', 'Mutation', 'c.462G>T', (122, 127))	('polbeta', 'Gene', '5423', (136, 143))	('polbeta', 'Gene', (136, 143))	('G462T', 'Var', (122, 127))	('patients', 'Species', '9606', (164, 172))	('A613T', 'Mutation', 'rs764290273', (70, 75))
849942	27843412	A613T and G462T variant of DNA polymerase beta weaken chemotherapy sensitivity of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('weaken', 'NegReg', (47, 53))	('A613T', 'Mutation', 'rs764290273', (0, 5))	('G462T', 'Mutation', 'c.462G>T', (10, 15))	('DNA polymerase beta', 'Gene', '5423', (27, 46))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('chemotherapy sensitivity', 'CPA', (54, 78))	('G462T', 'Var', (10, 15))	('esophageal cancer', 'Disease', (82, 99))	('A613T', 'Var', (0, 5))	('DNA polymerase beta', 'Gene', (27, 46))
849945	27843412	Through nonhomologous end joining, polbeta participates in the repair of DNA double-strand break.	('repair', 'MPA', (63, 69))	('DNA', 'Var', (73, 76))	('participates', 'Reg', (43, 55))	('polbeta', 'Gene', '5423', (35, 42))	('polbeta', 'Gene', (35, 42))
849946	27843412	30% of the tumors were reported to have a polbeta mutation.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('polbeta', 'Gene', '5423', (42, 49))	('polbeta', 'Gene', (42, 49))	('mutation', 'Var', (50, 58))
849948	27843412	Mutations polbeta gene had been reported in a variety of cancers.	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('Mutations', 'Var', (0, 9))	('reported', 'Reg', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('polbeta', 'Gene', '5423', (10, 17))	('polbeta', 'Gene', (10, 17))
849950	27843412	Some research results showed that polbeta gene mutation is exited in EC tissues.	('polbeta', 'Gene', '5423', (34, 41))	('mutation', 'Var', (47, 55))	('polbeta', 'Gene', (34, 41))
849952	27843412	In this study, we analyze the relationship between polbeta mutation and chemotherapy in ECs.	('mutation', 'Var', (59, 67))	('polbeta', 'Gene', '5423', (51, 58))	('polbeta', 'Gene', (51, 58))	('ECs', 'Disease', (88, 91))
849957	27843412	Full-length wild-type, A613T and G462T mutation polbeta were amplified by PCR.	('G462T', 'Var', (33, 38))	('polbeta', 'Gene', (48, 55))	('A613T', 'Mutation', 'rs764290273', (23, 28))	('A613T', 'Var', (23, 28))	('polbeta', 'Gene', '5423', (48, 55))	('G462T', 'Mutation', 'c.462G>T', (33, 38))
849958	27843412	These fragments were cloned into the lentiviral vector (LV5) to expression LV5-WT, LV5-A613T and LV5-G462T.	('G462T', 'Mutation', 'c.462G>T', (101, 106))	('LV5-G462T', 'Var', (97, 106))	('A613T', 'Mutation', 'rs764290273', (87, 92))	('LV5-A613T', 'Var', (83, 92))
849964	27843412	The cells were divided into four groups: wild-type EC9706 cells (WT), G462T mutation EC9706 cells (G462T), A613T mutation EC9706 cells (A613T) and polbeta null EC9706 cells (polbeta-/-).	('EC9706', 'CellLine', 'CVCL:E307', (122, 128))	('G462T', 'Mutation', 'c.462G>T', (99, 104))	('polbeta-/-)', 'Gene', '5423', (174, 185))	('polbeta-/-', 'Gene', (174, 184))	('A613T', 'Mutation', 'rs764290273', (136, 141))	('polbeta', 'Gene', '5423', (174, 181))	('A613T mutation', 'Var', (107, 121))	('polbeta', 'Gene', (174, 181))	('EC9706', 'CellLine', 'CVCL:E307', (51, 57))	('polbeta', 'Gene', (147, 154))	('G462T', 'Mutation', 'c.462G>T', (70, 75))	('polbeta', 'Gene', '5423', (147, 154))	('A613T', 'Mutation', 'rs764290273', (107, 112))	('EC9706', 'CellLine', 'CVCL:E307', (160, 166))	('G462T mutation', 'Var', (70, 84))	('EC9706', 'CellLine', 'CVCL:E307', (85, 91))
849974	27843412	To confirm the effect of A613T and G462T mutation on chemotherapy, CCK-8 assay was performed in the four groups of EC9706 cells (WT, A613T, G462T, and polbeta-/-).	('A613T', 'Var', (25, 30))	('G462T', 'Mutation', 'c.462G>T', (140, 145))	('A613T', 'Mutation', 'rs764290273', (133, 138))	('G462T', 'Var', (140, 145))	('EC9706', 'CellLine', 'CVCL:E307', (115, 121))	('polbeta-/-', 'Gene', (151, 161))	('A613T', 'Var', (133, 138))	('G462T', 'Mutation', 'c.462G>T', (35, 40))	('polbeta-/-)', 'Gene', '5423', (151, 162))	('A613T', 'Mutation', 'rs764290273', (25, 30))	('G462T', 'Var', (35, 40))
849977	27843412	The four groups of EC9706 cells (WT, A613T, G462T and polbeta-/-) were incubated overnight in complete medium.	('EC9706', 'CellLine', 'CVCL:E307', (19, 25))	('A613T', 'Mutation', 'rs764290273', (37, 42))	('G462T', 'Mutation', 'c.462G>T', (44, 49))	('G462T', 'Var', (44, 49))	('polbeta-/-)', 'Gene', '5423', (54, 65))	('A613T', 'Var', (37, 42))	('polbeta-/-', 'Gene', (54, 64))
849980	27843412	Transfected with lentivirus of four groups cells (WT, A613T, G462T, and polbeta-/-) (1 x 107) were subcutaneously inoculated into 6-week-old female BALB/c nude mice at the dorsal flank.	('nude mice', 'Species', '10090', (155, 164))	('G462T', 'Mutation', 'c.462G>T', (61, 66))	('G462T', 'Var', (61, 66))	('A613T', 'Mutation', 'rs764290273', (54, 59))	('polbeta-/-', 'Gene', (72, 82))	('A613T', 'Var', (54, 59))	('polbeta-/-)', 'Gene', '5423', (72, 83))
849988	27843412	The mutations of polbeta were detected by PCR and DNA sequencing.	('mutations', 'Var', (4, 13))	('polbeta', 'Gene', '5423', (17, 24))	('polbeta', 'Gene', (17, 24))
849989	27843412	There are 229 (42.57%) patients with the polbeta mutation (Table 2), 18 (3.35%) patients with A613T mutation, 12 (2.23%) patients with G462T mutation among 538 ECs (Fig.	('G462T', 'Var', (135, 140))	('G462T', 'Mutation', 'c.462G>T', (135, 140))	('patients', 'Species', '9606', (80, 88))	('A613T', 'Var', (94, 99))	('patients', 'Species', '9606', (23, 31))	('polbeta', 'Gene', '5423', (41, 48))	('polbeta', 'Gene', (41, 48))	('patients', 'Species', '9606', (121, 129))	('A613T', 'Mutation', 'rs764290273', (94, 99))
849990	27843412	A613T mutation takes in 7.86% of 229 polbeta mutations, and G462T takes in 5.24% of 229 polbeta mutations.	('G462T', 'Mutation', 'c.462G>T', (60, 65))	('polbeta', 'Gene', '5423', (88, 95))	('polbeta', 'Gene', (88, 95))	('G462T', 'Var', (60, 65))	('polbeta', 'Gene', '5423', (37, 44))	('A613T', 'Mutation', 'rs764290273', (0, 5))	('polbeta', 'Gene', (37, 44))	('A613T', 'Var', (0, 5))
849991	27843412	The corresponding changes in amino acids of A613T and G462T mutations and their location in polbeta protein are presented in Table 2.	('G462T', 'Mutation', 'c.462G>T', (54, 59))	('A613T', 'Mutation', 'rs764290273', (44, 49))	('G462T', 'Var', (54, 59))	('polbeta', 'Gene', (92, 99))	('polbeta', 'Gene', '5423', (92, 99))	('A613T', 'Var', (44, 49))
849992	27843412	We analyzed the different survival time among patients with A613T, G462T mutation and others by Kaplan-Meier method.	('G462T', 'Mutation', 'c.462G>T', (67, 72))	('patients', 'Species', '9606', (46, 54))	('G462T mutation', 'Var', (67, 81))	('A613T', 'Mutation', 'rs764290273', (60, 65))	('A613T', 'Var', (60, 65))
849993	27843412	We used the Kaplan-Meier to analyze the difference in survival time between the patients with A613T mutation and wild type, the patients with A613T mutation and others (all patients except A613T mutation), the patients with A613T mutation and patients with other mutations (all patients with mutations except A613T mutation), based on follow-up visits of EC patients.	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (173, 181))	('patients', 'Species', '9606', (243, 251))	('A613T', 'Mutation', 'rs764290273', (224, 229))	('A613T mutation', 'Var', (224, 238))	('A613T mutation', 'Var', (94, 108))	('A613T', 'Mutation', 'rs764290273', (309, 314))	('A613T', 'Mutation', 'rs764290273', (189, 194))	('patients', 'Species', '9606', (210, 218))	('patients', 'Species', '9606', (278, 286))	('patients', 'Species', '9606', (128, 136))	('A613T mutation', 'Var', (142, 156))	('A613T', 'Mutation', 'rs764290273', (142, 147))	('patients', 'Species', '9606', (358, 366))	('A613T', 'Mutation', 'rs764290273', (94, 99))
849997	27843412	Analysis results show that EC patients with A613T or G462T mutation had a shorter survival than the others (P < 0.05, Fig.	('shorter', 'NegReg', (74, 81))	('G462T', 'Var', (53, 58))	('survival', 'CPA', (82, 90))	('A613T', 'Mutation', 'rs764290273', (44, 49))	('patients', 'Species', '9606', (30, 38))	('A613T', 'Var', (44, 49))	('G462T', 'Mutation', 'c.462G>T', (53, 58))
849998	27843412	The expression levels of polbeta mRNA and protein of patients samples and four groups cells (polbeta-/-, WT, A613Tand G462T) were detected by qRT-PCR and western blot assays.	('polbeta', 'Gene', '5423', (93, 100))	('patients', 'Species', '9606', (53, 61))	('expression', 'MPA', (4, 14))	('A613T', 'Mutation', 'rs764290273', (109, 114))	('polbeta', 'Gene', '5423', (25, 32))	('A613Tand G462T', 'Var', (109, 123))	('polbeta', 'Gene', (25, 32))	('polbeta', 'Gene', (93, 100))	('G462T', 'Mutation', 'c.462G>T', (118, 123))
850001	27843412	The polbeta protein expression levels of adjacent non-tumor tissues of A613T mutation patients (A1-A3), G462T mutation patients (A4-A5), tumor tissues of A613T mutation patients (T1-T3, match to A1-A3) and polbeta-/-, WT, A613T cell lines are presented in Fig.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('A613T', 'Mutation', 'rs764290273', (154, 159))	('A613T', 'Gene', (71, 76))	('patients', 'Species', '9606', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('polbeta', 'Gene', '5423', (206, 213))	('polbeta', 'Gene', (4, 11))	('G462T mutation', 'Var', (104, 118))	('tumor', 'Disease', (137, 142))	('A613T', 'Mutation', 'rs764290273', (222, 227))	('A613T mutation', 'Var', (154, 168))	('A613T', 'Mutation', 'rs764290273', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('patients', 'Species', '9606', (169, 177))	('patients', 'Species', '9606', (119, 127))	('polbeta', 'Gene', (206, 213))	('polbeta', 'Gene', '5423', (4, 11))	('G462T', 'Mutation', 'c.462G>T', (104, 109))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
850003	27843412	The polbeta protein expression levels of tumor tissues of G462T mutation patients (T4-T6, match to A4-A5) and G462T cell line are presented in Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('G462T', 'Mutation', 'c.462G>T', (58, 63))	('G462T', 'Var', (58, 63))	('polbeta', 'Gene', '5423', (4, 11))	('polbeta', 'Gene', (4, 11))	('G462T', 'Mutation', 'c.462G>T', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('patients', 'Species', '9606', (73, 81))
850006	27843412	polbeta protein expression levels of WT, A613T, and G462T cell lines were significantly higher than that of adjacent non-tumor tissues (P < 0.05), and had no significant difference with tumor tissues.	('higher', 'PosReg', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('A613T', 'Var', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (186, 191))	('polbeta', 'Gene', '5423', (0, 7))	('polbeta', 'Gene', (0, 7))	('G462T', 'Mutation', 'c.462G>T', (52, 57))	('A613T', 'Mutation', 'rs764290273', (41, 46))	('G462T', 'Var', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
850007	27843412	In order to further study the relationship between polbeta mutation and resistance to chemotherapy in ECs, we performed CCK-8 assay on four group cells for proliferation inhibition effect of 5-FU and cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (200, 209))	('inhibition', 'NegReg', (170, 180))	('mutation', 'Var', (59, 67))	('polbeta', 'Gene', '5423', (51, 58))	('5-FU', 'Chemical', 'MESH:D005472', (191, 195))	('polbeta', 'Gene', (51, 58))
850008	27843412	The A613T, G462T cells were less sensitive than WT cells to 5-FU and cisplatin (P < 0.05; Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('G462T', 'Mutation', 'c.462G>T', (11, 16))	('A613T', 'Mutation', 'rs764290273', (4, 9))	('G462T', 'Var', (11, 16))	('A613T', 'Var', (4, 9))	('5-FU', 'Chemical', 'MESH:D005472', (60, 64))
850009	27843412	The results were in agreement with the clinical observation, that A613T and G462T mutations patients have less chemotherapy sensitivity and short survival time, indicated that A613T, G462T mutation are associated with poor response to chemotherapy of ECs.	('G462T', 'Var', (183, 188))	('A613T', 'Var', (176, 181))	('G462T', 'Mutation', 'c.462G>T', (183, 188))	('A613T', 'Mutation', 'rs764290273', (66, 71))	('patients', 'Species', '9606', (92, 100))	('G462T mutations', 'Var', (76, 91))	('ECs', 'Disease', (251, 254))	('less', 'NegReg', (106, 110))	('G462T', 'Mutation', 'c.462G>T', (76, 81))	('chemotherapy sensitivity', 'MPA', (111, 135))	('A613T', 'Mutation', 'rs764290273', (176, 181))	('A613T', 'Var', (66, 71))
850010	27843412	Our flow cytometry results indicated that the apoptosis levels of the A613T and G462T groups with 5-FU and cisplatin were weaken compared to the polbeta-/- and WT groups with5-FU and cisplatin (P < 0.05; Fig.	('5-FU', 'Chemical', 'MESH:D005472', (98, 102))	('A613T', 'Var', (70, 75))	('G462T', 'Var', (80, 85))	('5-FU', 'Chemical', 'MESH:D005472', (174, 178))	('weaken', 'NegReg', (122, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (183, 192))	('G462T', 'Mutation', 'c.462G>T', (80, 85))	('A613T', 'Mutation', 'rs764290273', (70, 75))	('polbeta', 'Gene', '5423', (145, 152))	('polbeta', 'Gene', (145, 152))	('apoptosis levels', 'MPA', (46, 62))
850011	27843412	We conclude that A613T and G462T mutations weaken the apoptosis effect of chemotherapeutics in EC9706 cells.	('EC9706', 'CellLine', 'CVCL:E307', (95, 101))	('weaken', 'NegReg', (43, 49))	('G462T', 'Mutation', 'c.462G>T', (27, 32))	('A613T', 'Mutation', 'rs764290273', (17, 22))	('G462T', 'Var', (27, 32))	('A613T', 'Var', (17, 22))	('apoptosis effect of chemotherapeutics', 'CPA', (54, 91))
850012	27843412	Experiments in vivo further confirmed the relationship between A613T, G462T mutation and poor response to chemotherapeutics.	('G462T', 'Mutation', 'c.462G>T', (70, 75))	('G462T', 'Var', (70, 75))	('A613T', 'Mutation', 'rs764290273', (63, 68))	('A613T', 'Var', (63, 68))
850013	27843412	The tumor sizes of A613T and G462T group were larger than WT and polbeta-/- groups (P < 0.05; Fig.	('tumor', 'Disease', (4, 9))	('G462T', 'Var', (29, 34))	('A613T', 'Mutation', 'rs764290273', (19, 24))	('larger', 'PosReg', (46, 52))	('A613T', 'Var', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('polbeta', 'Gene', '5423', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('polbeta', 'Gene', (65, 72))	('G462T', 'Mutation', 'c.462G>T', (29, 34))
850014	27843412	These results indicated that A613T, G462T mutation weaken the inhibition proliferation of chemotherapeutics in vivo.	('G462T', 'Mutation', 'c.462G>T', (36, 41))	('A613T', 'Mutation', 'rs764290273', (29, 34))	('G462T', 'Var', (36, 41))	('A613T', 'Var', (29, 34))	('weaken', 'NegReg', (51, 57))
850021	27843412	The present study presents the A613T, G462T mutation of polbeta gene in EC patients.	('polbeta', 'Gene', '5423', (56, 63))	('polbeta', 'Gene', (56, 63))	('A613T', 'Var', (31, 36))	('patients', 'Species', '9606', (75, 83))	('G462T', 'Mutation', 'c.462G>T', (38, 43))	('G462T', 'Var', (38, 43))	('A613T', 'Mutation', 'rs764290273', (31, 36))
850022	27843412	The A613T, G462T mutations were associated with chemotherapy for EC.	('associated', 'Reg', (32, 42))	('G462T', 'Mutation', 'c.462G>T', (11, 16))	('A613T', 'Mutation', 'rs764290273', (4, 9))	('G462T', 'Var', (11, 16))	('A613T', 'Var', (4, 9))
850024	27843412	To detect the incidence of A613T, G462T mutation in EC, we established a cohort of 538 EC patients.	('G462T', 'Mutation', 'c.462G>T', (34, 39))	('G462T', 'Var', (34, 39))	('A613T', 'Mutation', 'rs764290273', (27, 32))	('patients', 'Species', '9606', (90, 98))	('A613T', 'Var', (27, 32))
850026	27843412	Among 229 polbeta mutation cases, A613T point mutation was detected in 18 patients (7.86%) and G462T point mutation was detected in 12 patients (5.24%).	('patients', 'Species', '9606', (135, 143))	('G462T', 'Mutation', 'c.462G>T', (95, 100))	('patients', 'Species', '9606', (74, 82))	('A613T', 'Mutation', 'rs764290273', (34, 39))	('polbeta', 'Gene', '5423', (10, 17))	('G462T point', 'Var', (95, 106))	('A613T point mutation', 'Var', (34, 54))	('polbeta', 'Gene', (10, 17))
850027	27843412	The patients with A613T, G462T mutation had shorter survival time than the others.	('A613T', 'Mutation', 'rs764290273', (18, 23))	('survival time', 'CPA', (52, 65))	('G462T', 'Var', (25, 30))	('G462T', 'Mutation', 'c.462G>T', (25, 30))	('patients', 'Species', '9606', (4, 12))	('shorter', 'NegReg', (44, 51))	('A613T', 'Var', (18, 23))
850028	27843412	The results of CCK-8, flow cytometry and in vivo tumor growth assays indicated that polbeta-/- group cells are more sensitive than wild-type to 5-FU and cisplatin, and A613T, G462T mutation weaken the sensitivity of cells to 5-FU and cisplatin.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('polbeta', 'Gene', '5423', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('polbeta', 'Gene', (84, 91))	('5-FU', 'Chemical', 'MESH:D005472', (144, 148))	('G462T', 'Mutation', 'c.462G>T', (175, 180))	('sensitive', 'MPA', (116, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('tumor', 'Disease', (49, 54))	('G462T', 'Var', (175, 180))	('sensitivity', 'MPA', (201, 212))	('A613T', 'Mutation', 'rs764290273', (168, 173))	('5-FU', 'Chemical', 'MESH:D005472', (225, 229))	('A613T', 'Var', (168, 173))	('weaken', 'NegReg', (190, 196))
850030	27843412	That means polbeta participates in the repair of DNA double-strand break.	('polbeta', 'Gene', '5423', (11, 18))	('participates', 'Reg', (19, 31))	('polbeta', 'Gene', (11, 18))	('DNA', 'Var', (49, 52))
850031	27843412	The A613T and G462T mutation may change some functions of polbeta.	('functions', 'MPA', (45, 54))	('A613T', 'Var', (4, 9))	('G462T', 'Mutation', 'c.462G>T', (14, 19))	('polbeta', 'Gene', '5423', (58, 65))	('A613T', 'Mutation', 'rs764290273', (4, 9))	('polbeta', 'Gene', (58, 65))	('G462T', 'Var', (14, 19))	('change', 'Reg', (33, 39))
850032	27843412	Our clinical and experimental data indicate that A613T, G462T mutation has a tumor-promoting property, and in comparison to the wild-type polbeta gene in EC, it may shorten survival of EC patients.	('polbeta', 'Gene', '5423', (138, 145))	('A613T', 'Var', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('shorten', 'NegReg', (165, 172))	('patients', 'Species', '9606', (188, 196))	('G462T', 'Mutation', 'c.462G>T', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('G462T', 'Var', (56, 61))	('tumor', 'Disease', (77, 82))	('A613T', 'Mutation', 'rs764290273', (49, 54))	('survival', 'CPA', (173, 181))	('polbeta', 'Gene', (138, 145))
850033	27843412	This study confirms that the A613T, G462T mutation of polbeta desensitize EC patients to chemotherapy.	('G462T', 'Mutation', 'c.462G>T', (36, 41))	('A613T', 'Mutation', 'rs764290273', (29, 34))	('polbeta', 'Gene', '5423', (54, 61))	('desensitize', 'NegReg', (62, 73))	('G462T', 'Var', (36, 41))	('polbeta', 'Gene', (54, 61))	('A613T', 'Var', (29, 34))	('patients', 'Species', '9606', (77, 85))
850034	27843412	Thus, the A613T, G462T mutation polbeta gene may be clinically useful for EC patients to predicting the responsiveness to chemotherapy.	('polbeta', 'Gene', '5423', (32, 39))	('polbeta', 'Gene', (32, 39))	('G462T', 'Mutation', 'c.462G>T', (17, 22))	('patients', 'Species', '9606', (77, 85))	('G462T', 'Var', (17, 22))	('A613T', 'Mutation', 'rs764290273', (10, 15))	('A613T', 'Var', (10, 15))
850065	27390601	The proposed mechanisms of MALAT1 action include alternative splicing control and gene expression regulation.	('MALAT1', 'Gene', '378938', (27, 33))	('MALAT1', 'Gene', (27, 33))	('alternative splicing', 'Var', (49, 69))
850078	27390601	Genetic studies also identified an ESCC susceptibility SNP rs920778 which locates within the HOTAIR intronic enhancer region.	('ESCC susceptibility', 'Disease', (35, 54))	('rs920778', 'Var', (59, 67))	('rs920778', 'Mutation', 'rs920778', (59, 67))
850079	27390601	This allelic regulation of rs920778 on HOTAIR expression and ESCC risk clearly demonstrates the vital role of HOTAIR in ESCC progression.	('rs920778', 'Var', (27, 35))	('ESCC', 'Disease', (61, 65))	('ESCC', 'Disease', (120, 124))	('rs920778', 'Mutation', 'rs920778', (27, 35))
850084	27390601	ESCC cells with knockdown of linc-POU3F3 formed xenograft tumors more slowly in mice than control ESCC cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('knockdown', 'Var', (16, 25))	('linc-POU3F3', 'Gene', '100506421', (29, 40))	('linc-POU3F3', 'Gene', (29, 40))	('mice', 'Species', '10090', (80, 84))	('slowly', 'NegReg', (70, 76))
850086	27390601	TUG1 is known to bind the methylated and un-methylated Prc2 together with lncRNAs MALAT1/NEAT2, which works as a scaffold to mediate gene activation programs.	('MALAT1', 'Gene', (82, 88))	('methylated', 'Var', (26, 36))	('ncRNA', 'Gene', (75, 80))	('TUG1', 'Gene', (0, 4))	('NEAT2', 'Gene', '378938', (89, 94))	('Prc2', 'Gene', (55, 59))	('ncRNA', 'Gene', '220202', (75, 80))	('NEAT2', 'Gene', (89, 94))	('bind', 'Interaction', (17, 21))	('MALAT1', 'Gene', '378938', (82, 88))	('TUG1', 'Gene', '55000', (0, 4))
850092	27390601	Silencing via siRNA block of TUG1 inhibits proliferation, migration, and cell cycle in ESCC cells.	('inhibits', 'NegReg', (34, 42))	('TUG1', 'Gene', '55000', (29, 33))	('ESCC', 'Disease', (87, 91))	('cell cycle', 'CPA', (73, 83))	('TUG1', 'Gene', (29, 33))	('proliferation', 'CPA', (43, 56))	('Silencing', 'Var', (0, 9))	('migration', 'CPA', (58, 67))
850101	27390601	Silencing of miR-449a expression leads to the release of E2F1, which forms a positive feedback loop and continues to promote gastric cancer cell proliferation.	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('release', 'MPA', (46, 53))	('miR-449a', 'Gene', '554213', (13, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('E2F1', 'Gene', '1869', (57, 61))	('E2F1', 'Gene', (57, 61))	('promote', 'PosReg', (117, 124))	('miR-449a', 'Gene', (13, 21))	('Silencing', 'Var', (0, 9))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
850102	27390601	In ESCC, inhibition of ANRIL was found to promote the expression of p15 (INK4b) and transforming growth factor beta1 (TGFbeta1), and block of ANRIL in ESCC cell lines reduces cellular proliferation.	('expression', 'MPA', (54, 64))	('ANRIL', 'Gene', (142, 147))	('reduces', 'NegReg', (167, 174))	('p15', 'Gene', (68, 71))	('ANRIL', 'Gene', (23, 28))	('p15', 'Gene', '1030', (68, 71))	('cellular proliferation', 'CPA', (175, 197))	('INK4b', 'Gene', (73, 78))	('ANRIL', 'Gene', '100048912', (142, 147))	('promote', 'PosReg', (42, 49))	('transforming growth factor beta1', 'Gene', (84, 116))	('INK4b', 'Gene', '1030', (73, 78))	('ANRIL', 'Gene', '100048912', (23, 28))	('TGFbeta1', 'Gene', '7040', (118, 126))	('transforming growth factor beta1', 'Gene', '7040', (84, 116))	('TGFbeta1', 'Gene', (118, 126))	('block', 'Var', (133, 138))
850107	27390601	Furthermore, they showed that blocking SOX2OT significantly altered the cell cycle, and SOX2OT was reduced upon the neural differentiation in NT2 Cell Line.	('blocking', 'Var', (30, 38))	('cell cycle', 'CPA', (72, 82))	('SOX2OT', 'Gene', '347689', (88, 94))	('SOX2OT', 'Gene', '347689', (39, 45))	('SOX2OT', 'Gene', (88, 94))	('altered', 'Reg', (60, 67))	('SOX2OT', 'Gene', (39, 45))	('reduced', 'NegReg', (99, 106))	('NT2', 'CellLine', 'CVCL:7006', (142, 145))
850115	27390601	Inhibition of MALAT-1 affected multiple cellular functions such as apoptosis, migration/invasion, colony formation and cell cycle arrest.	('MALAT-1', 'Gene', (14, 21))	('cell cycle arrest', 'CPA', (119, 136))	('apoptosis', 'CPA', (67, 76))	('affected', 'Reg', (22, 30))	('migration/invasion', 'CPA', (78, 96))	('colony formation', 'CPA', (98, 114))	('Inhibition', 'Var', (0, 10))	('MALAT-1', 'Gene', '378938', (14, 21))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (119, 136))
850118	27390601	Specifically, high HOTAIR expression was significantly associated with TNM stage in esophageal carcinoma.	('TNM', 'Gene', (71, 74))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (84, 104))	('associated', 'Reg', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('TNM', 'Gene', '10178', (71, 74))	('high HOTAIR', 'Var', (14, 25))	('esophageal carcinoma', 'Disease', (84, 104))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (84, 104))
850124	27390601	recently found that among patients treated with preoperative chemo-radiotherapy followed by surgical resection, the pathological complete response rate was significantly higher in patient groups with high LOC285194 expression, than patient groups with low LOC285194 expression.	('patient', 'Species', '9606', (26, 33))	('pathological complete response', 'CPA', (116, 146))	('higher', 'PosReg', (170, 176))	('high LOC285194', 'Var', (200, 214))	('patients', 'Species', '9606', (26, 34))	('patient', 'Species', '9606', (232, 239))	('patient', 'Species', '9606', (180, 187))
850130	27390601	Inhibition of PlncRNA-1 led to blocking of proliferation and induction of apoptosis in CaP cell lines LNCaP and LNCaP-AI.	('apoptosis', 'CPA', (74, 83))	('LNCaP', 'CellLine', 'CVCL:0395', (112, 117))	('PlncRNA-1', 'Gene', '100506428', (14, 23))	('LNCaP', 'CellLine', 'CVCL:0395', (102, 107))	('Inhibition', 'Var', (0, 10))	('proliferation', 'CPA', (43, 56))	('PlncRNA-1', 'Gene', (14, 23))	('induction', 'Reg', (61, 70))	('blocking', 'NegReg', (31, 39))
850135	27390601	SiRNAs, antisense oligonucleotides (ASOs) as well as ribozymes or deoxyribozymes, can be designed to silence endogenous lncRNAs.	('ncRNA', 'Gene', '220202', (121, 126))	('oligonucleotides', 'Chemical', 'MESH:D009841', (18, 34))	('antisense', 'Var', (8, 17))	('ASOs', 'Chemical', 'MESH:D016376', (36, 40))	('SiRNAs', 'MPA', (0, 6))	('silence', 'NegReg', (101, 108))	('ncRNA', 'Gene', (121, 126))
850139	27390601	In a MALAT1 knockout lung tumor model, Diederichs and co-workers demonstrated that blocking MALAT1 with antisense oligonucleotides prevented metastasis formation after tumor implantation.	('lung tumor', 'Phenotype', 'HP:0100526', (21, 31))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('MALAT1', 'Gene', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('MALAT1', 'Gene', '378938', (92, 98))	('prevented', 'NegReg', (131, 140))	('lung tumor', 'Disease', (21, 31))	('tumor', 'Disease', (26, 31))	('MALAT1', 'Gene', '378938', (5, 11))	('lung tumor', 'Disease', 'MESH:D008175', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('MALAT1', 'Gene', (92, 98))	('oligonucleotides', 'Chemical', 'MESH:D009841', (114, 130))	('antisense', 'Var', (104, 113))
850140	27390601	Thus, targeting MALAT1 provides a promising therapeutic approach to prevent cancer metastasis.	('cancer metastasis', 'Disease', (76, 93))	('MALAT1', 'Gene', '378938', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('targeting', 'Var', (6, 15))	('cancer metastasis', 'Disease', 'MESH:D009362', (76, 93))	('MALAT1', 'Gene', (16, 22))
850205	25009653	Histone deacetylase 1 (HDAC1)/metastasis-associated gene (MTA1) complexes inhibit p53 acetylation and thus, inhibit p53-induced apoptosis.	('Histone deacetylase 1', 'Gene', '297893', (0, 21))	('inhibit', 'NegReg', (74, 81))	('inhibit', 'NegReg', (108, 115))	('p53', 'Protein', (82, 85))	('Histone deacetylase 1', 'Gene', (0, 21))	('p53-induced apoptosis', 'CPA', (116, 137))	('acetylation', 'MPA', (86, 97))	('MTA1', 'Gene', (58, 62))	('complexes', 'Var', (64, 73))	('HDAC1', 'Gene', (23, 28))
850216	25009653	Diet and lifestyle alterations in the Western world have been associated with an increased prevalence of obesity and hiatal hernias, which are known risk factors for GERD and esophageal cancer.	('esophageal cancer', 'Disease', (175, 192))	('obesity', 'Disease', 'MESH:D009765', (105, 112))	('hernias', 'Phenotype', 'HP:0100790', (124, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('hiatal hernias', 'Disease', (117, 131))	('obesity', 'Disease', (105, 112))	('rat', 'Species', '10116', (23, 26))	('hiatal hernias', 'Disease', 'MESH:D006551', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('hiatal hernias', 'Phenotype', 'HP:0002036', (117, 131))	('alterations', 'Var', (19, 30))	('GERD', 'Disease', (166, 170))	('obesity', 'Phenotype', 'HP:0001513', (105, 112))
850272	25009653	Numerous molecular alterations leading to the development of esophageal carcinoma have been reported.	('esophageal carcinoma', 'Disease', (61, 81))	('leading', 'Reg', (31, 38))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (61, 81))	('rat', 'Species', '10116', (23, 26))	('alterations', 'Var', (19, 30))
850277	25009653	DeltaNp63alpha, an N-terminally truncated form, which functions as a key ESCC cell survival factor, associates with HDAC1 and HDAC2 to form an active transcriptional repressor complex that may be targeted to provide a therapeutic advantage.	('associates', 'Interaction', (100, 110))	('HDAC2', 'Gene', (126, 131))	('HDAC1', 'Gene', (116, 121))	('DeltaNp63alpha', 'Var', (0, 14))	('HDAC2', 'Gene', '84577', (126, 131))
850295	25009653	Previous studies have determined that the HDAC1/MTA1 complexes deacetylate the p53 protein and attenuate the transactivation function of p53 in human carcinoma, thereby inhibiting p53-induced apoptosis.	('attenuate', 'NegReg', (95, 104))	('human', 'Species', '9606', (144, 149))	('deacetylate', 'NegReg', (63, 74))	('p53-induced apoptosis', 'CPA', (180, 201))	('transactivation function', 'MPA', (109, 133))	('protein', 'Protein', (83, 90))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('p53 protein', 'Protein', (79, 90))	('p53', 'Protein', (137, 140))	('complexes', 'Var', (53, 62))	('inhibiting', 'NegReg', (169, 179))	('carcinoma', 'Disease', (150, 159))
850307	25009653	In rats with BM and EADC, the deletion and translocation of chromosome 7 and 11, and overexpression of important peptide mediators are considered to be significant in carcinogenesis, including hypoxia-inducible factor (HIF) 1alpha, cyclin dependent kinase 4, vascular endothelial growth factor, polo-like kinase and the epidermal growth factor receptor.	('overexpression', 'PosReg', (85, 99))	('epidermal growth factor receptor', 'Gene', (320, 352))	('carcinogenesis', 'Disease', (167, 181))	('cyclin dependent kinase 4', 'Gene', '94201', (232, 257))	('epidermal growth factor receptor', 'Gene', '24329', (320, 352))	('rats', 'Species', '10116', (3, 7))	('deletion', 'Var', (30, 38))	('hypoxia-inducible factor (HIF) 1alpha', 'Gene', '29560', (193, 230))	('cyclin dependent kinase 4', 'Gene', (232, 257))	('translocation', 'Var', (43, 56))	('carcinogenesis', 'Disease', 'MESH:D063646', (167, 181))
850322	25009653	The HDAC inhibitors have been shown to be potent inducers of growth arrest, differentiation and/or apoptotic cell death of transformed cells and, as a result, are currently receiving considerable attention as antitumor agents.	('tumor', 'Disease', (213, 218))	('inducers', 'PosReg', (49, 57))	('HDAC', 'Gene', '9734', (4, 8))	('growth arrest', 'Disease', (61, 74))	('apoptotic cell death', 'CPA', (99, 119))	('differentiation', 'CPA', (76, 91))	('growth arrest', 'Disease', 'MESH:D006323', (61, 74))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('growth arrest', 'Phenotype', 'HP:0001510', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('inhibitors', 'Var', (9, 19))	('HDAC', 'Gene', (4, 8))
850323	25009653	In addition, the HDAC inhibitors have been reported to disrupt the cell cycle in the G2 phase, allowing cells to prematurely enter the M phase, as well as to interfere directly with the mitotic spindle checkpoint.	('mitotic spindle checkpoint', 'CPA', (186, 212))	('inhibitors', 'Var', (22, 32))	('interfere', 'Reg', (158, 167))	('disrupt', 'NegReg', (55, 62))	('cell cycle', 'CPA', (67, 77))	('HDAC', 'Gene', (17, 21))	('HDAC', 'Gene', '9734', (17, 21))
850347	24885858	Furthermore, NPRA deficiency can substantially protect C57BL/6 mice from lung, skin, and ovarian cancers.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('NPRA', 'Gene', (13, 17))	('ovarian cancers', 'Phenotype', 'HP:0100615', (89, 104))	('ovarian cancers', 'Disease', (89, 104))	('lung', 'Disease', (73, 77))	('mice', 'Species', '10090', (63, 67))	('ovarian cancers', 'Disease', 'MESH:D010051', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('deficiency', 'Var', (18, 28))	('skin', 'Disease', (79, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (89, 103))
850369	24885858	Membranes were blocked for 90 min with a 5% milk solution prepared in PBS, followed by incubation overnight at 4 C with the primary NPRA antibodies (1:500, SC-16867, Santa Cruz, CA, USA) and beta-actin antibodies (1:200, BS0061R, bioss, Beijing, China).	('1:200', 'Var', (214, 219))	('beta-actin', 'Gene', '728378', (191, 201))	('beta-actin', 'Gene', (191, 201))	('NPRA', 'Gene', (132, 136))	('1:500', 'Var', (149, 154))	('PBS', 'Chemical', 'MESH:D007854', (70, 73))	('SC-16867', 'Var', (156, 164))
850400	24885858	So they suggested that reduced NPRA signaling can activate MMP and is involved in NF-kb signaling activation, which leads to the development of cardiac hypertrophy, myocardial fibrosis, and congestive heart failure.	('myocardial fibrosis', 'Disease', (165, 184))	('congestive heart failure', 'Disease', 'MESH:D006333', (190, 214))	('congestive heart failure', 'Disease', (190, 214))	('congestive heart failure', 'Phenotype', 'HP:0001635', (190, 214))	('NPRA signaling', 'MPA', (31, 45))	('cardiac hypertrophy', 'Disease', (144, 163))	('myocardial fibrosis', 'Phenotype', 'HP:0001685', (165, 184))	('myocardial fibrosis', 'Disease', 'MESH:D005355', (165, 184))	('MMP', 'CPA', (59, 62))	('activate', 'PosReg', (50, 58))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (144, 163))	('reduced', 'Var', (23, 30))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (144, 163))	('leads to', 'Reg', (116, 124))
850408	24391993	MspI and Ile462Val Polymorphisms in CYP1A1 and Overall Cancer Risk: A Meta-Analysis Cytochrome P450 1A1 (CYP1A1) is a member of the CYP1 family, which is a key enzyme in the metabolism of many endogenous substrates and exogenous carcinogens.	('CYP', 'Gene', '9360', (105, 108))	('CYP', 'Gene', (105, 108))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('CYP', 'Gene', '9360', (36, 39))	('Cytochrome P450 1A1', 'Gene', (84, 103))	('CYP1A1', 'Gene', (105, 111))	('CYP1A1', 'Gene', (36, 42))	('Cytochrome P450 1A1', 'Gene', '1543', (84, 103))	('CYP1A1', 'Gene', '1543', (105, 111))	('CYP1A1', 'Gene', '1543', (36, 42))	('CYP', 'Gene', '9360', (132, 135))	('CYP', 'Gene', (132, 135))	('Ile462Val', 'Chemical', '-', (9, 18))	('Polymorphisms', 'Var', (19, 32))	('CYP', 'Gene', (36, 39))
850410	24391993	Overall, a significant elevated risk of cancer was associated with CYP1A1 MspI and Ile462Val polymorphisms for all genetic models studied.	('Ile462Val', 'Var', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('CYP1A1', 'Gene', (67, 73))	('Ile462Val', 'Chemical', '-', (83, 92))	('cancer', 'Disease', (40, 46))	('CYP1A1', 'Gene', '1543', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
850411	24391993	Further stratified analysis by cancer types revealed that the MspI polymorphism may increase the risk of lung cancer and cervical cancer whereas the Ile462Val polymorphism may contribute to a higher risk of lung cancer, leukemia, esophageal carcinoma, and prostate cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('esophageal carcinoma', 'Disease', (230, 250))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('Ile462Val', 'Chemical', '-', (149, 158))	('prostate cancer', 'Disease', 'MESH:D011471', (256, 271))	('prostate cancer', 'Phenotype', 'HP:0012125', (256, 271))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('leukemia', 'Phenotype', 'HP:0001909', (220, 228))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('prostate cancer', 'Disease', (256, 271))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (230, 250))	('increase', 'PosReg', (84, 92))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('polymorphism', 'Var', (67, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('leukemia', 'Disease', 'MESH:D007938', (220, 228))	('leukemia', 'Disease', (220, 228))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Ile462Val', 'Var', (149, 158))	('cancer', 'Disease', (212, 218))	('cervical cancer', 'Disease', 'MESH:D002583', (121, 136))	('cervical cancer', 'Disease', (121, 136))	('lung cancer', 'Disease', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('MspI polymorphism', 'Var', (62, 79))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (230, 250))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', (265, 271))	('lung cancer', 'Disease', (207, 218))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
850412	24391993	In the subgroup analysis by ethnicity, obvious associations were found in the Asian population for the MspI polymorphism while an increased risk of cancer was observed in Asians and Caucasians for the Ile462Val polymorphism.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('MspI', 'Gene', (103, 107))	('polymorphism', 'Var', (108, 120))	('Ile462Val', 'Var', (201, 210))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Ile462Val', 'Chemical', '-', (201, 210))	('associations', 'Interaction', (47, 59))
850413	24391993	The results of this meta-analysis suggest that CYP1A1 MspI and Ile462Val polymorphisms contribute to increased cancer susceptibility among Asians.	('Ile462Val polymorphisms', 'Var', (63, 86))	('increased', 'PosReg', (101, 110))	('Ile462Val', 'Chemical', '-', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CYP1A1', 'Gene', (47, 53))	('polymorphisms', 'Var', (73, 86))	('CYP1A1', 'Gene', '1543', (47, 53))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
850417	24391993	To date, many important single nucleotide polymorphisms (SNPs) have been identified in CYP genes, and such polymorphisms within these genes may play an important role in determining individual susceptibility to many cancers.	('single nucleotide polymorphisms', 'Var', (24, 55))	('role', 'Reg', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('play', 'Reg', (144, 148))	('polymorphisms', 'Var', (107, 120))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('CYP', 'Gene', '9360', (87, 90))	('CYP', 'Gene', (87, 90))	('determining', 'Reg', (170, 181))
850424	24391993	Such variations in genes encoding these enzymes could alter their expression and function, potentially influenced the balance between metabolic activation and detoxification of toxicants, leading to individual susceptibilities to cancer.	('variations', 'Var', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('alter', 'Reg', (54, 59))	('function', 'MPA', (81, 89))	('detoxification of toxicants', 'MPA', (159, 186))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('susceptibilities', 'Reg', (210, 226))	('expression', 'MPA', (66, 76))	('cancer', 'Disease', (230, 236))	('leading to', 'Reg', (188, 198))	('balance between metabolic activation', 'MPA', (118, 154))	('influenced', 'Reg', (103, 113))
850425	24391993	Specifically, a T-to-C mutation in the non-coding 3'-flanking region has been reported to cause the creation a new MspI restriction site (MspI polymorphism m1, T6235C, rs4646903).	('rs4646903', 'Var', (168, 177))	('rs4646903', 'Mutation', 'rs4646903', (168, 177))	('cause', 'Reg', (90, 95))	('T6235C', 'Mutation', 'rs4646903', (160, 166))	('T6235C', 'Var', (160, 166))
850426	24391993	Another CYP1A1 polymorphism is a G-to-A transition (A4889G) in exon 7, resulting in the replacement of isoleucine (Ile) by valine (Val), which is a heme-binding site (Ile462Val polymorphism m2, A4889G, rs1048943).	('Ile462Val', 'Chemical', '-', (167, 176))	('heme', 'Chemical', 'MESH:D006418', (148, 152))	('isoleucine', 'MPA', (103, 113))	('Ile', 'Chemical', 'MESH:D007532', (167, 170))	('CYP1A1', 'Gene', (8, 14))	('Val', 'Chemical', 'MESH:D014633', (131, 134))	('Val', 'Chemical', 'MESH:D014633', (173, 176))	('rs1048943', 'Var', (202, 211))	('rs1048943', 'Mutation', 'rs1048943', (202, 211))	('CYP1A1', 'Gene', '1543', (8, 14))	('A4889G', 'Mutation', 'rs1048943', (52, 58))	('A4889G', 'Var', (194, 200))	('valine', 'Chemical', 'MESH:D014633', (123, 129))	('Ile', 'Chemical', 'MESH:D007532', (115, 118))	('A4889G', 'Mutation', 'rs1048943', (194, 200))	('isoleucine', 'Chemical', 'MESH:D007532', (103, 113))
850427	24391993	To date, a number of meta-analyses have been performed to explore the association between the MspI and Ile462Val polymorphisms of CYP1A1 and various cancers including prostate, ovarian, breast, lung, and colorectal cancer and leukemia, to name a few that occur in different ethnic populations.	('association', 'Interaction', (70, 81))	('prostate', 'Disease', (167, 175))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('polymorphisms', 'Var', (113, 126))	('breast', 'Disease', (186, 192))	('ovarian', 'Disease', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancers', 'Disease', (149, 156))	('Ile462Val polymorphisms', 'Var', (103, 126))	('leukemia', 'Phenotype', 'HP:0001909', (226, 234))	('colorectal cancer', 'Disease', 'MESH:D015179', (204, 221))	('CYP1A1', 'Gene', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colorectal cancer', 'Disease', (204, 221))	('leukemia', 'Disease', (226, 234))	('leukemia', 'Disease', 'MESH:D007938', (226, 234))	('Ile462Val', 'Chemical', '-', (103, 112))	('lung', 'Disease', (194, 198))	('CYP1A1', 'Gene', '1543', (130, 136))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
850429	24391993	In the past twenty years, many molecular epidemiological studies have been conducted to investigate the association between CYP1A1 polymorphisms and cancer risk in humans.	('cancer', 'Disease', (149, 155))	('CYP1A1', 'Gene', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('CYP1A1', 'Gene', '1543', (124, 130))	('polymorphisms', 'Var', (131, 144))	('humans', 'Species', '9606', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
850430	24391993	Hence, we performed a meta-analysis of all eligible studies to derive a more precise estimation of the relationship between the MspI and Ile462Val polymorphisms of CYP1A1 and an overall cancer risk.	('Ile462Val', 'Chemical', '-', (137, 146))	('CYP1A1', 'Gene', '1543', (164, 170))	('polymorphisms', 'Var', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('Ile462Val polymorphisms', 'Var', (137, 160))	('CYP1A1', 'Gene', (164, 170))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
850431	24391993	All papers regarding the association between CYP1A1 polymorphisms and cancer risk published up to December 31, 2012 were identified through comprehensive searches using the PubMed database with the following terms and keywords: ''cytochrome P450 1A1", ''CYP1A1'' and ''polymorphism'', ''variation'', ''mutation'' and these terms were also paired with ''cancer'', ''tumor'' and ''carcinoma''.	("''carcinoma''", 'Disease', 'MESH:D002277', (377, 390))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('CYP1A1', 'Gene', '1543', (254, 260))	('cytochrome P450 1A1"', 'Gene', (230, 250))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('cytochrome P450 1A1"', 'Gene', '1543', (230, 250))	('cancer', 'Disease', (70, 76))	('CYP1A1', 'Gene', (45, 51))	("''cancer", 'Disease', (351, 359))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	("variation''", 'Var', (287, 298))	("''cancer", 'Disease', 'MESH:D009369', (351, 359))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (365, 370))	("''carcinoma''", 'Disease', (377, 390))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('CYP1A1', 'Gene', '1543', (45, 51))	("mutation''", 'Var', (302, 312))	('cancer', 'Disease', (353, 359))	('CYP1A1', 'Gene', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))
850433	24391993	For inclusion, the studies must have met the following criteria: (a) having information on the evaluation of the CYP1A1 polymorphism and cancer risk, (b) using a case-control design, and (c) containing complete information about all genotype frequencies.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('CYP1A1', 'Gene', (113, 119))	('polymorphism', 'Var', (120, 132))	('CYP1A1', 'Gene', '1543', (113, 119))
850436	24391993	OR (odds ratios) and their 95% CIs (confidence intervals) were used to determine the strength of association between CYP1A1 MspI and Ile462Val polymorphisms and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CYP1A1', 'Gene', '1543', (117, 123))	('polymorphisms', 'Var', (143, 156))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('Ile462Val polymorphisms', 'Var', (133, 156))	('cancer', 'Disease', (161, 167))	('CYP1A1', 'Gene', (117, 123))	('Ile462Val', 'Chemical', '-', (133, 142))
850437	24391993	The risks (ORs) of cancer associated with CYP1A1 MspI and Ile462Val polymorphisms were estimated for each study.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('Ile462Val', 'Var', (58, 67))	('CYP1A1', 'Gene', '1543', (42, 48))	('cancer', 'Disease', (19, 25))	('Ile462Val', 'Chemical', '-', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('CYP1A1', 'Gene', (42, 48))
850446	24391993	The relationship between the MspI polymorphism and the risk of different kinds of cancer is summarized in Table S1 .	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('polymorphism', 'Var', (34, 46))	('MspI', 'Gene', (29, 33))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
850447	24391993	Overall, a significantly elevated risk of cancer was associated with the CYP1A1 C/C polymorphism for the allele contrast (C vs. T: OR = 1.15 CI = 1.09-1.22), the additive genetic model (C/C vs. T/T: OR = 1.33 CI = 1.17-1.51; C/C vs. C/T: OR = 1.14 CI = 1.03-1.27), the recessive genetic model (C/C vs. C/T+T/T: OR = 1.24 CI = 1.11-1.39) and the dominant genetic model(C/C + C/T vs. T/T: OR = 1.17 CI = 1.10-1.24).	('CYP1A1', 'Gene', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('C/C + C/T', 'Var', (368, 377))	('C/C vs. C/T+T/T', 'Var', (294, 309))	('CYP1A1', 'Gene', '1543', (73, 79))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
850448	24391993	In the subgroup analysis by ethnicity, the results indicated that individuals with C/C genotype had a significantly higher cancer risk among Asians (C/C vs. T/T: OR = 1.45, CI = 1.24-1.69; C/C vs. C/T: OR = 1.17, CI = 1.04-1.32; recessive model: OR = 1.30, CI = 1.14-1.49; dominant model: OR = 1.26, CI = 1.13-1.39).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('higher', 'PosReg', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('C/C', 'Var', (83, 86))
850449	24391993	In the stratified analysis by cancer types, significant associations were found for lung cancer (C/C vs. T/T: OR = 1.43, CI = 1.16-1.78; dominant model: OR = 1.21, CI = 1.10-1.32; recessive model: OR = 1.32, CI = 1.07-1.62), cervical cancer (C/C vs. T/T: OR = 3.12, CI = 1.39-6.99; C/C vs. C/T: OR = 1.79, CI = 1.11-2.88; recessive model: OR = 2.48, CI = 1.41-4.36).	('lung cancer', 'Disease', (84, 95))	('C/C vs. C/T: OR', 'Var', (282, 297))	('cervical cancer', 'Disease', 'MESH:D002583', (225, 240))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cervical cancer', 'Disease', (225, 240))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
850451	24391993	Overall, a significantly increased risk of cancer was associated with the CYP1A1 G/G polymorphism for the allele contrast (G vs. A: OR = 1.18 CI = 1.12-1.25), the additive genetic model (G/G vs. A/A: OR =1.52 CI = 1.34-1.72; G/G vs. G/A: OR = 1.28 CI = 1.17-1.39), the recessive genetic model (G/G vs. G/A+A/A: OR = 1.42 CI = 1.27-1.60) and the dominant genetic model (G/G + G/A vs. A/A: OR = 1.18 CI = 1.11-1.26).	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('G/G + G/A', 'Var', (369, 378))	('G/G vs. G/A+A/A', 'Var', (294, 309))	('CYP1A1', 'Gene', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('CYP1A1', 'Gene', '1543', (74, 80))
850453	24391993	Take the CYP1A1 Ile462Val genotype for example, there was significant heterogeneity for allele contrast (G vs. A: P <0.001), the additive genetic model comparison (G/G vs. G/A: P <0.001 and G/G vs. A/A: P <0.001), the dominant model comparison (G/G+G/A vs. A/A: P <0.001), and the recessive model comparison (G/G vs. G/A+A/A: P <0.001).	('G/G+G/A', 'Var', (245, 252))	('CYP1A1', 'Gene', (9, 15))	('G/G', 'Var', (164, 167))	('G/G', 'Var', (309, 312))	('CYP1A1', 'Gene', '1543', (9, 15))	('G/G', 'Var', (190, 193))	('Ile462Val', 'Chemical', '-', (16, 25))
850462	24391993	Such changes can be precursors to malignancy.	('changes', 'Var', (5, 12))	('malignancy', 'Disease', (34, 44))	('malignancy', 'Disease', 'MESH:D009369', (34, 44))
850463	24391993	CYP1A1 is a critical CYPP450 and studies suggest that a CYP1A1 polymorphism may be a risk factor for several malignancies even in the face of its role in detoxification of environmental carcinogens and metabolic activation of dietary compounds that protect against cancer.	('malignancies', 'Disease', 'MESH:D009369', (109, 121))	('CYP1A1', 'Gene', (56, 62))	('polymorphism', 'Var', (63, 75))	('malignancies', 'Disease', (109, 121))	('CYP1A1', 'Gene', '1543', (0, 6))	('CYP1A1', 'Gene', '1543', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('CYP', 'Gene', '9360', (21, 24))	('CYP', 'Gene', (21, 24))	('CYP', 'Gene', '9360', (0, 3))	('CYP', 'Gene', (0, 3))	('risk factor', 'Reg', (85, 96))	('CYP', 'Gene', '9360', (56, 59))	('CYP', 'Gene', (56, 59))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('CYP1A1', 'Gene', (0, 6))
850465	24391993	Previous studies about CYP1A1 polymorphisms and cancer risk have been inconclusive.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('polymorphisms', 'Var', (30, 43))	('CYP1A1', 'Gene', (23, 29))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('CYP1A1', 'Gene', '1543', (23, 29))
850466	24391993	To the best of our knowledge, this is the first meta-analysis to evaluate the relationship between CYP1A1 polymorphisms and overall cancer risk.	('cancer', 'Disease', (132, 138))	('polymorphisms', 'Var', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('CYP1A1', 'Gene', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('CYP1A1', 'Gene', '1543', (99, 105))
850468	24391993	Our results indicated that the MspI polymorphism C/C genotype was associated with an increased risk of cancers, especially for lung and cervical cancer among Asians and mixed populations, whereas the Ile462Val polymorphism G/G genotype was associated with an increased risk of lung cancer, leukemia, esophageal carcinoma, and prostate cancer among Caucasians and Asians.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('Ile462Val', 'Var', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (300, 320))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('C/C', 'Var', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('lung cancer', 'Disease', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('esophageal carcinoma', 'Disease', (300, 320))	('prostate cancer', 'Disease', 'MESH:D011471', (326, 341))	('leukemia', 'Phenotype', 'HP:0001909', (290, 298))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))	('prostate cancer', 'Phenotype', 'HP:0012125', (326, 341))	('MspI', 'Gene', (31, 35))	('prostate cancer', 'Disease', (326, 341))	('polymorphism C/C', 'Var', (36, 52))	('lung cancer', 'Disease', 'MESH:D008175', (277, 288))	('Ile462Val', 'Chemical', '-', (200, 209))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (300, 320))	('leukemia', 'Disease', 'MESH:D007938', (290, 298))	('leukemia', 'Disease', (290, 298))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('lung and cervical cancer', 'Disease', 'MESH:D008175', (127, 151))
850470	24391993	We found that CYP1A1 MspI and Ile462Val polymorphisms correlated with increased lung cancer susceptibility.	('increased lung cancer', 'Disease', 'MESH:D008175', (70, 91))	('CYP1A1', 'Gene', (14, 20))	('Ile462Val', 'Chemical', '-', (30, 39))	('polymorphisms', 'Var', (40, 53))	('CYP1A1', 'Gene', '1543', (14, 20))	('increased lung cancer', 'Disease', (70, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('Ile462Val polymorphisms', 'Var', (30, 53))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
850471	24391993	Also, the MspI polymorphism C/C genotype is associated with an increased risk of cervical cancer.	('polymorphism C/C genotype', 'Var', (15, 40))	('cervical cancer', 'Disease', 'MESH:D002583', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cervical cancer', 'Disease', (81, 96))	('MspI', 'Gene', (10, 14))
850472	24391993	Interestingly, Gutman and co-workers reported that the CYP1A1 MspI C/C polymorphism is unlikely to be a major risk factor for cervical cancer which is contrary to our data from the meta-analysis.	('MspI C/C', 'Gene', (62, 70))	('CYP1A1', 'Gene', (55, 61))	('CYP1A1', 'Gene', '1543', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cervical cancer', 'Disease', (126, 141))	('cervical cancer', 'Disease', 'MESH:D002583', (126, 141))	('polymorphism', 'Var', (71, 83))
850473	24391993	Both researchers reported that the Ile462Val G/G polymorphism is not associated with an increased risk of esophageal carcinoma and prostate cancer but our data indicate that this G/G polymorphism may affect susceptibility to these very kinds of cancer.	('affect', 'Reg', (200, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('G/G', 'Var', (179, 182))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (106, 126))	('Ile462Val', 'Var', (35, 44))	('cancer', 'Disease', (245, 251))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('Ile462Val', 'SUBSTITUTION', 'None', (35, 44))	('esophageal carcinoma and prostate cancer', 'Disease', 'MESH:D011471', (106, 146))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
850476	24391993	In the subgroup analysis by ethnicity, the MspI C/C polymorphism was found to confer an increased cancer risk among Asians and mixed population but not Caucasians or Africans.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('polymorphism', 'Var', (52, 64))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('MspI C/C', 'Gene', (43, 51))
850477	24391993	For the Ile462Val G/G polymorphism, statistically significantly elevated cancer risks were observed in Asians and Caucasians but not in Africans or in mixed descendant populations.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('elevated', 'PosReg', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Ile462Val', 'Var', (8, 17))	('Ile462Val', 'SUBSTITUTION', 'None', (8, 17))
850483	24391993	In conclusion, although significant heterogeneity from included studies existed, our meta-analysis provided evidence to support an association between the CYP1A1 MspI and Ile462Val polymorphisms and increased cancer risk.	('CYP1A1', 'Gene', (155, 161))	('Ile462Val', 'Chemical', '-', (171, 180))	('CYP1A1', 'Gene', '1543', (155, 161))	('polymorphisms', 'Var', (181, 194))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (209, 215))	('Ile462Val polymorphisms', 'Var', (171, 194))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
850536	20633283	The average CI for Pgtv (0.706 +- 0.056) and PTV (0.707 +- 0.029) in IMRT plans with mMLC, were significantly better than those in plans with sMLC (for Pgtv 0.677 +- 0.086 and for PTV 0.699 +- 0.029), respectively (p < 0.05).	('0.707 +- 0.029', 'Var', (50, 64))	('mMLC', 'Gene', '170790', (85, 89))	('PTV', 'Chemical', '-', (45, 48))	('better', 'PosReg', (110, 116))	('PTV', 'Chemical', '-', (180, 183))	('MLC', 'Gene', '170790', (143, 146))	('MLC', 'Gene', (143, 146))	('MLC', 'Gene', '170790', (86, 89))	('MLC', 'Gene', (86, 89))	('mMLC', 'Gene', (85, 89))
850539	20633283	Although the differences of the V5 and V30 between the two series were not statistically significant, the IMRT plans with the mMLC had clearly advantages in the differences of the V10 (33.2 +- 6.5 vs 34.0 +- 6.7, p < 0.01), V20 (16.0 +- 4.6 vs 16.6 +- 4.7, p < 0.01), MLD (866.2 +- 174.1 vs 887.9 +- 172.1, p < 0.01) and gEUD (938.6 +- 175.2 vs 956.8 +- 171.0, p < 0.02) respectively, compared with those with the sMLC.	('mMLC', 'Gene', '170790', (126, 130))	('MLD', 'Disease', (268, 271))	('MLD', 'Disease', 'MESH:D007966', (268, 271))	('mMLC', 'Gene', (126, 130))	('V10', 'Var', (180, 183))	('MLC', 'Gene', '170790', (127, 130))	('MLC', 'Gene', (127, 130))	('advantages', 'PosReg', (143, 153))	('V20', 'MPA', (224, 227))	('MLC', 'Gene', '170790', (415, 418))	('MLC', 'Gene', (415, 418))
850554	20633283	The mean dose reductions for D17 and D35 for the rectum were 20.0% and 18.3%, respectively, compared with the plans with the sMLC.	('D35', 'Var', (37, 40))	('D17', 'Var', (29, 32))	('MLC', 'Gene', '170790', (126, 129))	('MLC', 'Gene', (126, 129))	('reductions', 'NegReg', (14, 24))
850573	33420370	Bioinformatics analysis revealed that PLOD1 is associated with the progression of GBM, particularly the most malignant mesenchymal subtype (MES).	('MES', 'Chemical', '-', (140, 143))	('PLOD1', 'Var', (38, 43))	('GBM', 'Disease', (82, 85))	('associated with', 'Reg', (47, 62))
850574	33420370	Moreover, in the TCGA and CGGA datasets, the mean survival time of patients with high PLOD1 expression was significantly shorter than that of patients with low expression.	('patients', 'Species', '9606', (67, 75))	('high PLOD1 expression', 'Var', (81, 102))	('shorter', 'NegReg', (121, 128))	('patients', 'Species', '9606', (142, 150))	('survival time', 'CPA', (50, 63))
850576	33420370	PLOD1 also enhanced tumor viability, proliferation, migration, and promoted MES transition while inhibited apoptosis.	('migration', 'CPA', (52, 61))	('promoted', 'PosReg', (67, 75))	('MES transition', 'CPA', (76, 90))	('PLOD1', 'Var', (0, 5))	('MES', 'Chemical', '-', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('enhanced', 'PosReg', (11, 19))	('proliferation', 'CPA', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('inhibited', 'NegReg', (97, 106))	('apoptosis', 'CPA', (107, 116))	('tumor', 'Disease', (20, 25))
850577	33420370	Tumor xenograft results also indicated that PLOD1 overexpression significantly promotes malignant behavior of tumors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('malignant behavior of tumors', 'Disease', (88, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('PLOD1', 'Gene', (44, 49))	('promotes', 'PosReg', (79, 87))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('malignant behavior of tumors', 'Disease', 'MESH:D009369', (88, 116))	('overexpression', 'Var', (50, 64))
850587	33420370	Collagen is an important component that constitutes the extracellular matrix (ECM) of tumors, and cross-linking of collagen in ECM enhances the hardness of tumor tissue and promotes proliferation, migration, invasion, and adhesion of tumor cells.	('tumor', 'Disease', (234, 239))	('enhances', 'PosReg', (131, 139))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', (156, 161))	('hardness of tumor', 'Disease', (144, 161))	('adhesion', 'CPA', (222, 230))	('promotes', 'PosReg', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('proliferation', 'CPA', (182, 195))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Disease', (86, 92))	('migration', 'CPA', (197, 206))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('collagen', 'Protein', (115, 123))	('invasion', 'CPA', (208, 216))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('hardness of tumor', 'Disease', 'MESH:D018804', (144, 161))	('cross-linking', 'Var', (98, 111))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
850588	33420370	Mutations and overexpression of PLOD promote the occurrence and metastasis of multiple malignancies.	('PLOD', 'Gene', '5351', (32, 36))	('promote', 'PosReg', (37, 44))	('malignancies', 'Disease', (87, 99))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('PLOD', 'Gene', (32, 36))	('Mutations', 'Var', (0, 9))	('metastasis', 'CPA', (64, 74))	('occurrence', 'CPA', (49, 59))	('overexpression', 'PosReg', (14, 28))
850592	33420370	Mutations or overexpression of PLOD1 were also detected in esophageal squamous cell carcinoma, gastric cancer, and colorectal cancer and associated with shorter patient survival.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patient', 'Species', '9606', (161, 168))	('esophageal squamous cell carcinoma', 'Disease', (59, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('shorter', 'NegReg', (153, 160))	('gastric cancer', 'Disease', (95, 109))	('Mutations', 'Var', (0, 9))	('overexpression', 'PosReg', (13, 27))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('detected', 'Reg', (47, 55))	('colorectal cancer', 'Disease', (115, 132))	('PLOD1', 'Gene', (31, 36))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (59, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))
850594	33420370	Further GSEA analysis revealed that PLOD1 is strongly associated with the nuclear factor-kappaB (NF-kappaB) signaling pathway.	('nuclear factor-kappaB', 'Gene', '4790', (74, 95))	('PLOD1', 'Var', (36, 41))	('GSEA', 'Chemical', '-', (8, 12))	('NF-kappaB', 'Gene', '4790', (97, 106))	('nuclear factor-kappaB', 'Gene', (74, 95))	('associated', 'Reg', (54, 64))	('NF-kappaB', 'Gene', (97, 106))
850605	33420370	In addition, we performed Kaplan-Meier survival analysis for the prognostic significance of PLOD1 expression in patients with GBM, and the average survival time of patients with high PLOD1 expression was significantly lower in the CGGA dataset than in patients with low expression (Fig.	('survival', 'CPA', (147, 155))	('patients', 'Species', '9606', (252, 260))	('high PLOD1 expression', 'Var', (178, 199))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (164, 172))	('lower', 'NegReg', (218, 223))
850607	33420370	In addition, we performed Kaplan-Meier survival analysis on patients (qPCR quantification, Cutoff: median), and the results showed that the median survival of mesenchymal patients with higher PLOD1 expression was significantly lower than that of patients with low expression, while there was no survival significance in another three subtypes (Fig.	('mesenchymal patients', 'CPA', (159, 179))	('patients', 'Species', '9606', (246, 254))	('patients', 'Species', '9606', (60, 68))	('lower', 'NegReg', (227, 232))	('PLOD1', 'Gene', (192, 197))	('patients', 'Species', '9606', (171, 179))	('higher', 'Var', (185, 191))	('expression', 'MPA', (198, 208))
850610	33420370	By flow analysis, three strains of PN03-GSC, PN04-GSC, and PN09-GSC were positive for CD133, a proneural marker, by more than 80%, and three strains of MES02-GSC, MES06-GSC, and MES13-GSC were positive for CD44, a mesenchymal marker, by more than 80% (Supplementary Fig.	('CD133', 'Gene', (86, 91))	('MES02', 'Chemical', '-', (152, 157))	('CD133', 'Gene', '8842', (86, 91))	('PN09-GSC', 'Var', (59, 67))	('MES', 'Chemical', '-', (163, 166))	('MES', 'Chemical', '-', (152, 155))	('positive', 'Reg', (73, 81))	('CD44', 'Gene', (206, 210))	('MES', 'Chemical', '-', (178, 181))	('PN04-GSC', 'Var', (45, 53))	('MES06', 'Chemical', '-', (163, 168))	('PN03-GSC', 'Var', (35, 43))
850611	33420370	Immunofluorescence staining confirmed the presence of CD133+, CD44+, and nestin+ expression in isolated neurospheres (Supplementary Fig.	('nestin', 'Gene', (73, 79))	('CD44+', 'Var', (62, 67))	('CD133', 'Gene', (54, 59))	('CD133', 'Gene', '8842', (54, 59))	('nestin', 'Gene', '10763', (73, 79))
850616	33420370	To investigate the role of PLOD1 in GSCs proliferation and tumor promotion, Crispr-Cas9-mediated PLOD1 knockout was performed and mesenchymal GSCs MES02-GSC and MES06-GSC was transfected to knockout PLOD1.	('tumor', 'Disease', (59, 64))	('PLOD1', 'Gene', (97, 102))	('MES06', 'Chemical', '-', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('MES02', 'Chemical', '-', (147, 152))	('knockout', 'Var', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
850617	33420370	Western blotting and qPCR were used to confirm the efficiency of PLOD1 knockout in MES02-GSC and MES06-GSC (Fig.	('PLOD1', 'Gene', (65, 70))	('MES02', 'Chemical', '-', (83, 88))	('knockout', 'Var', (71, 79))	('MES06', 'Chemical', '-', (97, 102))
850618	33420370	First, we used the MTS assays to detect the proliferation activity of tumor cells after PLOD1 knockout, and the absorbance values were significantly lower than those of the control group (Fig.	('knockout', 'Var', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('PLOD1', 'Gene', (88, 93))	('tumor', 'Disease', (70, 75))	('proliferation activity', 'CPA', (44, 66))	('lower', 'NegReg', (149, 154))	('absorbance values', 'MPA', (112, 129))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
850620	33420370	2e, f, where tumor cells' invading ability was significantly inhibited after PLOD1 knockout compared to the control group (Fig.	('tumor', 'Disease', (13, 18))	('inhibited', 'NegReg', (61, 70))	('PLOD1', 'Gene', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('knockout', 'Var', (83, 91))
850621	33420370	In addition, we used TUNEL assays to detect the effect of PLOD1 knockout on apoptosis in GSCs and showed that PLOD1 knockout significantly promoted apoptosis in tumor cells (Fig.	('promoted', 'PosReg', (139, 147))	('knockout', 'Var', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('apoptosis', 'CPA', (148, 157))	('tumor', 'Disease', (161, 166))	('PLOD1', 'Gene', (110, 115))
850622	33420370	The extreme limiting dilution assays also showed a reduction in tumor formation after PLOD1 knockout (Fig.	('reduction', 'NegReg', (51, 60))	('tumor', 'Disease', (64, 69))	('knockout', 'Var', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PLOD1', 'Gene', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
850623	33420370	Finally, we again performed western blotting and found that the expressions of the mesenchymal marker genes CD44 and YKL40 were significantly reduced after PLOD1 knockout in MES02-GSC and MES06-GSC (Fig.	('YKL40', 'Gene', '1116', (117, 122))	('CD44', 'Gene', (108, 112))	('expressions', 'MPA', (64, 75))	('PLOD1', 'Gene', (156, 161))	('reduced', 'NegReg', (142, 149))	('MES06', 'Chemical', '-', (188, 193))	('MES02', 'Chemical', '-', (174, 179))	('YKL40', 'Gene', (117, 122))	('knockout', 'Var', (162, 170))
850624	33420370	The above results indicated that PLOD1 knockout inhibits glioma cell proliferation, invasion, and MES transition of glioma and induces its apoptosis.	('PLOD1', 'Gene', (33, 38))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('invasion', 'CPA', (84, 92))	('inhibits', 'NegReg', (48, 56))	('knockout', 'Var', (39, 47))	('induces', 'Reg', (127, 134))	('glioma', 'Disease', (57, 63))	('glioma', 'Disease', (116, 122))	('MES transition', 'CPA', (98, 112))	('MES', 'Chemical', '-', (98, 101))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('apoptosis', 'CPA', (139, 148))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
850631	33420370	The results showed a significant NF-kappaB signaling pathway enrichment in the higher PLOD1 expression group (Fig.	('NF-kappaB', 'Gene', '4790', (33, 42))	('higher PLOD1 expression', 'Var', (79, 102))	('NF-kappaB', 'Gene', (33, 42))	('enrichment', 'Reg', (61, 71))
850633	33420370	The results showed the expression levels of p-P65, p-IkappaBalpha, and p-IKKalpha/beta were significantly downregulated after PLOD1 knockout (Fig.	('downregulated', 'NegReg', (106, 119))	('IKKalpha/beta', 'Gene', (73, 86))	('IKKalpha/beta', 'Gene', '1147', (73, 86))	('PLOD1', 'Gene', (126, 131))	('P65', 'Gene', '5970', (46, 49))	('P65', 'Gene', (46, 49))	('expression levels', 'MPA', (23, 40))	('p-IkappaBalpha', 'Var', (51, 65))
850635	33420370	Luciferase reporter assays demonstrated that PLOD1 knockout decreased the luciferase activity of pGL3-wt in MES02-GSC and MES06-GSC, but not in pGL3-mt (Fig.	('decreased', 'NegReg', (60, 69))	('PLOD1', 'Gene', (45, 50))	('MES02', 'Chemical', '-', (108, 113))	('MES06', 'Chemical', '-', (122, 127))	('luciferase', 'Enzyme', (74, 84))	('knockout', 'Var', (51, 59))	('activity', 'MPA', (85, 93))
850637	33420370	The above evidence proves that PLOD1 can modulate the NF-kappaB signaling pathway in GSCs.	('NF-kappaB', 'Gene', (54, 63))	('GSCs', 'Disease', (85, 89))	('NF-kappaB', 'Gene', '4790', (54, 63))	('modulate', 'Reg', (41, 49))	('PLOD1', 'Var', (31, 36))
850638	33420370	To further verify whether PLOD1 promotes malignant progression in GSCs through the NF-kappaB signaling pathway, we treated PN03-GSC, PN04-GSC cell lines after PLOD1 overexpression with JSH-23, an inhibitor of the NF-kappaB signaling pathway, and the blocking effect of NF-kappaB signaling pathway was confirmed by western blotting as lower expression levels of downstream molecules (Fig.	('NF-kappaB', 'Gene', '4790', (269, 278))	('expression levels of downstream molecules', 'MPA', (340, 381))	('NF-kappaB', 'Gene', '4790', (213, 222))	('PLOD1', 'Var', (26, 31))	('NF-kappaB', 'Gene', '4790', (83, 92))	('JSH-23', 'Chemical', 'MESH:C549066', (185, 191))	('malignant progression', 'CPA', (41, 62))	('NF-kappaB', 'Gene', (213, 222))	('lower', 'NegReg', (334, 339))	('NF-kappaB', 'Gene', (83, 92))	('NF-kappaB', 'Gene', (269, 278))
850649	33420370	We performed the luciferase reporter gene assays and found that PLOD1-wt transfected MES02-GSC and MES06-GSC had significantly enhanced luciferase activity under hypoxia (Fig.	('enhanced', 'PosReg', (127, 135))	('MES06', 'Chemical', '-', (99, 104))	('MES06-GSC', 'Var', (99, 108))	('hypoxia', 'Disease', 'MESH:D000860', (162, 169))	('luciferase', 'Enzyme', (136, 146))	('MES02', 'Chemical', '-', (85, 90))	('hypoxia', 'Disease', (162, 169))	('activity', 'MPA', (147, 155))
850664	33420370	Finally, to determine whether PLOD1 can regulate tumorigenesis and MES transition of GSCs in vivo, we injected PLOD1 knockout, overexpression, and control GSCs in situ into the brains of nude mice.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('nude mice', 'Species', '10090', (187, 196))	('tumor', 'Disease', (49, 54))	('MES', 'Chemical', '-', (67, 70))	('PLOD1', 'Gene', (111, 116))	('knockout', 'Var', (117, 125))
850665	33420370	We found that PLOD1 knockout significantly inhibited intracranial tumor growth in MES02-GSC compared with controls (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('intracranial tumor', 'Disease', 'MESH:D001932', (53, 71))	('inhibited', 'NegReg', (43, 52))	('intracranial tumor', 'Disease', (53, 71))	('MES02', 'Chemical', '-', (82, 87))	('PLOD1', 'Gene', (14, 19))	('knockout', 'Var', (20, 28))
850667	33420370	We further performed H&E staining and immunohistochemical staining of tumorigenic tissues, and the intensity and expression levels of PLOD1, CD44, ki-67, and p-P65 were clearly lower in the PLOD1 knockout group than in the control group.	('and expression', 'MPA', (109, 123))	('the', 'MPA', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('and', 'Var', (154, 157))	('H&E', 'Chemical', '-', (21, 24))	('ki-67', 'Gene', (147, 152))	('tumor', 'Disease', (70, 75))	('the PLOD1', 'Var', (186, 195))	('ki-67', 'Gene', '17345', (147, 152))	('clearly', 'NegReg', (169, 176))	('P65', 'Gene', '5970', (160, 163))	('P65', 'Gene', (160, 163))
850668	33420370	The above results show that PLOD1 can promote tumorigenesis, MES transition, and enhance malignant behaviors in nude mice.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('malignant behaviors', 'CPA', (89, 108))	('tumor', 'Disease', (46, 51))	('nude mice', 'Species', '10090', (112, 121))	('MES transition', 'CPA', (61, 75))	('PLOD1', 'Var', (28, 33))	('promote', 'PosReg', (38, 45))	('MES', 'Chemical', '-', (61, 64))	('enhance', 'PosReg', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
850669	33420370	In conclusion, we demonstrate the possible mechanism by which PLOD1 regulates the behavior of GSCs in terms of genesis, proliferation, anti-apoptosis, and MES transition through a model diagram (Fig.	('proliferation', 'CPA', (120, 133))	('genesis', 'CPA', (111, 118))	('MES', 'Chemical', '-', (155, 158))	('regulates', 'Reg', (68, 77))	('MES transition', 'CPA', (155, 169))	('anti-apoptosis', 'CPA', (135, 149))	('behavior', 'MPA', (82, 90))	('PLOD1', 'Var', (62, 67))
850673	33420370	PLOD1 was overexpression in mesenchymal and IDH wild-type GBM and was strongly associated with poor prognosis.	('associated', 'Reg', (79, 89))	('PLOD1', 'Var', (0, 5))	('IDH', 'Gene', (44, 47))	('overexpression', 'PosReg', (10, 24))	('IDH', 'Gene', '3417', (44, 47))
850675	33420370	Moreover, Kaplan-Meier survival analysis showed that in mesenchymal GBM, patients with high PLOD1 expression had shorter median survival times than patients with low PLOD1 expression.	('patients', 'Species', '9606', (148, 156))	('mesenchymal GBM', 'Disease', (56, 71))	('median survival', 'MPA', (121, 136))	('high PLOD1 expression', 'Var', (87, 108))	('shorter', 'NegReg', (113, 120))	('patients', 'Species', '9606', (73, 81))
850676	33420370	The proneural and mesenchymal subtypes are more clinically consistent in their respective subtypes, with the proneural subtype GBM exhibiting a higher proportion of IDH1 mutations and showing a favorable prognosis.	('mutations', 'Var', (170, 179))	('IDH1', 'Gene', '3417', (165, 169))	('IDH1', 'Gene', (165, 169))
850679	33420370	Besides, PLOD1 is also significantly overexpression in a wide range of malignancies, including esophageal squamous cell carcinoma, gastric cancer, and colorectal cancer, and is significantly associated with poor patient outcomes.	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('overexpression', 'PosReg', (37, 51))	('esophageal squamous cell carcinoma', 'Disease', (95, 129))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('malignancies', 'Disease', (71, 83))	('patient', 'Species', '9606', (212, 219))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('colorectal cancer', 'Disease', (151, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PLOD1', 'Var', (9, 14))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (95, 129))	('associated', 'Reg', (191, 201))	('colorectal cancer', 'Disease', 'MESH:D015179', (151, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('gastric cancer', 'Disease', (131, 145))
850684	33420370	Moreover, our study has confirmed that PLOD1 can upregulate collagen I expression, which suggests that PLOD1 may regulate collagen cross-linking and deposition, participate in ECM, and further affect the course of GBM disease.	('GBM disease', 'Disease', (214, 225))	('collagen cross-linking', 'MPA', (122, 144))	('regulate', 'Reg', (113, 121))	('deposition', 'MPA', (149, 159))	('PLOD1', 'Var', (39, 44))	('affect', 'Reg', (193, 199))	('ECM', 'Disease', (176, 179))	('collagen I', 'Gene', (60, 70))	('GBM disease', 'Disease', 'MESH:D005910', (214, 225))	('upregulate', 'PosReg', (49, 59))	('participate', 'Reg', (161, 172))	('PLOD1', 'Var', (103, 108))
850690	33420370	Moreover, since PLOD1 can directly bind to IkappaBalpha according to the CoIP, it suggested that PLOD1 may activate the NF-kappaB signaling pathway through binding IkappaBalpha to induce phosphorylation of IkappaBalpha, but this requires further research of validation.	('NF-kappaB', 'Gene', '4790', (120, 129))	('IkappaBalpha', 'Protein', (164, 176))	('IkappaBalpha', 'Protein', (206, 218))	('NF-kappaB', 'Gene', (120, 129))	('induce', 'PosReg', (180, 186))	('activate', 'PosReg', (107, 115))	('phosphorylation', 'MPA', (187, 202))	('binding', 'Interaction', (156, 163))	('PLOD1', 'Var', (97, 102))
850693	33420370	We further performed rescue assays and found that NF-kB inhibitors treatment effectively inhibited glioma proliferation, invasion, migration, MES transition, and other malignant behaviors, resulting in the disappearance of all promoting effects caused by PLOD1 overexpression.	('PLOD1', 'Gene', (255, 260))	('migration', 'CPA', (131, 140))	('promoting effects', 'MPA', (227, 244))	('MES', 'Chemical', '-', (142, 145))	('inhibited', 'NegReg', (89, 98))	('MES transition', 'CPA', (142, 156))	('malignant behaviors', 'CPA', (168, 187))	('NF-kB', 'Protein', (50, 55))	('glioma', 'Disease', (99, 105))	('inhibitors', 'Var', (56, 66))	('disappearance', 'NegReg', (206, 219))	('overexpression', 'PosReg', (261, 275))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('invasion', 'CPA', (121, 129))
850703	33420370	In conclusion, we found that PLOD1 is closely associated with the occurrence, development, and poor prognosis of GBM, especially in mesenchymal GBM, and that PLOD1 regulates GSCs proliferation, invasion, MES transition, and other malignant behaviors through the NF-kappaB signaling pathway.	('GSCs proliferation', 'CPA', (174, 192))	('invasion', 'CPA', (194, 202))	('malignant behaviors', 'CPA', (230, 249))	('associated', 'Reg', (46, 56))	('regulates', 'Reg', (164, 173))	('NF-kappaB', 'Gene', '4790', (262, 271))	('MES transition', 'CPA', (204, 218))	('PLOD1', 'Var', (158, 163))	('MES', 'Chemical', '-', (204, 207))	('GBM', 'Disease', (113, 116))	('NF-kappaB', 'Gene', (262, 271))
850723	33420370	The primary antibodies against PLOD1 (Sigma-Aldrich), CD133 (1:1000, #ab222782, Abcam), CD44 (Abcam), nestin+ (1:500, #ab18102, Abcam), GFAP (1:1000, #ab4674, Abcam), and beta III tubulin (1:1000, #ab7751, Abcam) were the same as described above.	('beta III tubulin', 'Protein', (171, 187))	('CD44', 'Gene', (88, 92))	('GFAP', 'Gene', (136, 140))	('#ab222782', 'Var', (69, 78))	('GFAP', 'Gene', '2670', (136, 140))	('nestin', 'Gene', '10763', (102, 108))	('CD133', 'Gene', (54, 59))	('CD133', 'Gene', '8842', (54, 59))	('nestin', 'Gene', (102, 108))
850725	33420370	Briefly, tissue samples were paraffin-embedded, cut into 4-mum sections, and examined by using a combination of anti-PLOD1 (Sigma-Aldrich), CD44, YKL40, Ki-67, and p-P65 (Abcam) for primary antibody labeling.	('anti-PLOD1', 'Var', (112, 122))	('YKL40', 'Gene', '1116', (146, 151))	('Ki-67', 'Gene', '17345', (153, 158))	('CD44', 'Var', (140, 144))	('paraffin', 'Chemical', 'MESH:D010232', (29, 37))	('Ki-67', 'Gene', (153, 158))	('P65', 'Gene', '5970', (166, 169))	('P65', 'Gene', (166, 169))	('YKL40', 'Gene', (146, 151))
850740	33628589	RECQL4 depletion induced G0/G1 phase arrest and cellular senescence.	('arrest', 'Disease', 'MESH:D006323', (37, 43))	('cellular senescence', 'CPA', (48, 67))	('depletion', 'Var', (7, 16))	('arrest', 'Disease', (37, 43))
850747	33628589	Mutation of RECQL4 causes Rothmund-Thomson syndrome (OMIM 268400), an autosomal recessive disorder that is characterized by abnormalities in the skin and skeleton, juvenile cataracts, premature aging, and a predisposition to neoplasia.	('abnormalities in the skin', 'Phenotype', 'HP:0000951', (124, 149))	('neoplasia', 'Disease', (225, 234))	('causes', 'Reg', (19, 25))	('Mutation', 'Var', (0, 8))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (70, 98))	('cataracts', 'Disease', 'MESH:D002386', (173, 182))	('neoplasia', 'Disease', 'MESH:D009369', (225, 234))	('Rothmund-Thomson syndrome', 'Disease', (26, 51))	('cataracts', 'Disease', (173, 182))	('neoplasia', 'Phenotype', 'HP:0002664', (225, 234))	('RECQL4', 'Gene', (12, 18))	('juvenile cataracts', 'Phenotype', 'HP:0001118', (164, 182))	('autosomal recessive disorder', 'Disease', (70, 98))	('cataracts', 'Phenotype', 'HP:0000518', (173, 182))	('Rothmund-Thomson syndrome', 'Disease', 'MESH:D011038', (26, 51))
850751	33628589	Moreover, depletion of RECQL4 in cancer cells has been shown to significantly reduce cell proliferation and cell invasion potential, promote apoptosis, and impair tumorgenicity in tumor-bearing mice.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cell proliferation', 'CPA', (85, 103))	('cancer', 'Disease', (33, 39))	('reduce', 'NegReg', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('promote', 'PosReg', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mice', 'Species', '10090', (194, 198))	('tumor', 'Disease', (180, 185))	('depletion', 'Var', (10, 19))	('cell invasion potential', 'CPA', (108, 131))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', (163, 168))	('impair', 'NegReg', (156, 162))	('apoptosis', 'CPA', (141, 150))	('RECQL4', 'Gene', (23, 29))
850757	33628589	RECQL4 depletion induced reactive oxygen species and DNA damage in ESCC cells, which was accompanied by cell cycle arrest and cell senescence.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('RECQL4', 'Gene', (0, 6))	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('reactive oxygen species', 'MPA', (25, 48))	('DNA damage', 'MPA', (53, 63))	('arrest', 'Disease', (115, 121))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (25, 48))	('depletion', 'Var', (7, 16))	('cell senescence', 'CPA', (126, 141))
850780	33628589	Antibodies to RECQL4 (1:1,000), p-ATM (1:1,000), ATM (1:1,000), p-ATR (1:1,000), ATR (1:1,000), p-CHK1 (1:1,000), CHK1 (1:1,000), p-CHK2 (1:1,000), CHK2 (1:1,000), gamma-H2AX (1:1,000), p-p65 (1:1,000), P65 (1:1,000), p-ERK1/2 (1:1,000), ERK1/2 (1:1,000), p-AKT (1:1,000), and AKT (1:1,000) were purchased from Cell Signaling Technology (Danvers, MA, USA); anti-E-cadherin (1:1,000), anti-BAX (1:1,000), anti-Bcl-2 (1:1,000), anti-p21 (1:1,000), and anti-GAPDH (1:10,000) were from Proteintech (Wuhan, China); anti-CHK1 (1:200) was from Santa Cruz Biotechnology (Santa Cruz, CA, USA); and anti-vimentin (1:500), anti-cyclin D (1:500), anti-cyclin E (1:500), and anti-c-myc (1:500) were from Affinity Biosciences (Changzhou, Jiangsu, China).	('CHK1', 'Gene', (98, 102))	('CHK2', 'Gene', '11200', (148, 152))	('H2AX', 'Gene', (170, 174))	('P65', 'Gene', '5970', (203, 206))	('P65', 'Gene', (203, 206))	('c-myc', 'Gene', (667, 672))	('GAPDH', 'Gene', (455, 460))	('BAX', 'Gene', '581', (389, 392))	('ATM', 'Gene', (34, 37))	('BAX', 'Gene', (389, 392))	('ATR', 'Gene', '545', (66, 69))	('ATM', 'Gene', (49, 52))	('p65', 'Gene', '5970', (188, 191))	('CHK1', 'Gene', (114, 118))	('Bcl-2', 'Gene', (409, 414))	('AKT', 'Gene', (277, 280))	('ERK', 'Gene', '5594', (238, 241))	('E-cadherin', 'Gene', (362, 372))	('ATR', 'Gene', '545', (81, 84))	('H2AX', 'Gene', '3014', (170, 174))	('E-cadherin', 'Gene', '999', (362, 372))	('CHK1', 'Gene', (515, 519))	('CHK1', 'Gene', '1111', (98, 102))	('Bcl-2', 'Gene', '596', (409, 414))	('ERK', 'Gene', (238, 241))	('1:500', 'Var', (604, 609))	('AKT', 'Gene', (258, 261))	('c-myc', 'Gene', '4609', (667, 672))	('CHK1', 'Gene', '1111', (114, 118))	('AKT', 'Gene', '207', (277, 280))	('ATR', 'Gene', (66, 69))	('CHK2', 'Gene', (148, 152))	('ERK', 'Gene', '5594', (220, 223))	('CHK2', 'Gene', (132, 136))	('vimentin', 'Gene', '7431', (594, 602))	('CHK1', 'Gene', '1111', (515, 519))	('ATM', 'Gene', '472', (34, 37))	('vimentin', 'Gene', (594, 602))	('ATR', 'Gene', (81, 84))	('ATM', 'Gene', '472', (49, 52))	('p65', 'Gene', (188, 191))	('GAPDH', 'Gene', '2597', (455, 460))	('p21', 'Gene', (431, 434))	('AKT', 'Gene', '207', (258, 261))	('ERK', 'Gene', (220, 223))	('p21', 'Gene', '644914', (431, 434))	('CHK2', 'Gene', '11200', (132, 136))
850822	33628589	Kaplan-Meier survival analyses showed that ESCC patients with higher RECQL4 expression had no significantly shorter overall survival time than those patients with lower RECQL4 expression (P = 0.19) (Figure 1D).	('patients', 'Species', '9606', (149, 157))	('ESCC', 'Disease', (43, 47))	('RECQL4', 'Gene', (69, 75))	('shorter', 'NegReg', (108, 115))	('higher', 'PosReg', (62, 68))	('patients', 'Species', '9606', (48, 56))	('expression', 'Var', (76, 86))
850823	33628589	Taken together, the results showed that the expression of RECQL4 was upregulated during the clinical progression of ESCC, indicating that the expression of RECQL4 may have induced the progression of ESCC cancer.	('expression', 'Var', (142, 152))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('expression', 'MPA', (44, 54))	('ESCC', 'Disease', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('upregulated', 'PosReg', (69, 80))	('induced', 'Reg', (172, 179))	('RECQL4', 'Gene', (156, 162))	('RECQL4', 'Gene', (58, 64))
850824	33628589	To investigate whether RECQL4 played a role in the biological behavior of ESCC cells, we first determined the mRNA and protein levels of RECQL4 in 5 ESCC cell lines, KYSE30, TE-1, KYSE150, KYSE450, and KYSE410, using qRT-PCR and Western blot assays.	('TE', 'Chemical', 'MESH:D013691', (174, 176))	('KYSE410', 'CellLine', 'CVCL:1352', (202, 209))	('mRNA', 'MPA', (110, 114))	('RECQL4', 'Gene', (137, 143))	('KYSE30', 'Var', (166, 172))
850825	33628589	RECQL4 expression was higher in KYSE30 and TE-1 cells, and lower in the other three cell lines (Figure 2A, 2B).	('higher', 'PosReg', (22, 28))	('RECQL4', 'Gene', (0, 6))	('lower', 'NegReg', (59, 64))	('expression', 'MPA', (7, 17))	('TE', 'Chemical', 'MESH:D013691', (43, 45))	('KYSE30', 'Var', (32, 38))
850827	33628589	A considerable reduction of RECQL4 was achieved in KYSE30 shRNA-RECQL4 and TE-1 shRNA-RECQL4 cells in the presence of doxycycline (+Dox) (Figure 2C).	('doxycycline', 'Chemical', 'MESH:D004318', (118, 129))	('reduction', 'NegReg', (15, 24))	('Dox', 'Chemical', 'MESH:D004318', (132, 135))	('KYSE30', 'Var', (51, 57))	('TE', 'Chemical', 'MESH:D013691', (75, 77))
850828	33628589	The colony formation and EdU incorporation assays demonstrated that RECQL4 knockdown inhibited colony formation (Figure 2D) and the proliferation (Figure 2E) of ESCC cells.	('inhibited', 'NegReg', (85, 94))	('colony formation', 'CPA', (95, 111))	('proliferation', 'CPA', (132, 145))	('knockdown', 'Var', (75, 84))	('EdU', 'Chemical', '-', (25, 28))	('RECQL4', 'Gene', (68, 74))
850831	33628589	RECQL4 knockdown was induced by 1.2 mg/mL of doxycycline administered in 5% sucrose-containing drinking water.	('RECQL4', 'Gene', (0, 6))	('induced', 'Reg', (21, 28))	('sucrose', 'Chemical', 'MESH:D013395', (76, 83))	('knockdown', 'Var', (7, 16))	('doxycycline', 'Chemical', 'MESH:D004318', (45, 56))	('water', 'Chemical', 'MESH:D014867', (104, 109))
850832	33628589	The growth of tumors formed by RECQL4 knockdown cells was slower than that of the control cells at all time points analyzed (Figure 2F).	('growth', 'CPA', (4, 10))	('RECQL4', 'Gene', (31, 37))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('slower', 'NegReg', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('knockdown', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
850833	33628589	The average size and weight of tumors formed by RECQL4 knockdown cancer cells at the final experimental endpoint was significantly reduced (Figure 2G, 2H).	('knockdown', 'Var', (55, 64))	('RECQL4', 'Gene', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('reduced', 'NegReg', (131, 138))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
850834	33628589	To assess the effect of increased expression of RECQL4 on ESCC cells, we next established stable RECQL4-overexpressing ESCC cells, KYSE150-RECQL4, and KYSE410-RECQL4.	('KYSE410', 'CellLine', 'CVCL:1352', (151, 158))	('RECQL4-overexpressing', 'Gene', (97, 118))	('KYSE410-RECQL4', 'Var', (151, 165))
850835	33628589	Western blot analysis confirmed the significantly increased RECQL4 expression in KYSE150-RECQL4 and KYSE410-RECQL4 cells when compared to control cells (Figure 3A).	('RECQL4', 'Gene', (60, 66))	('KYSE410', 'CellLine', 'CVCL:1352', (100, 107))	('increased', 'PosReg', (50, 59))	('KYSE150-RECQL4', 'Var', (81, 95))	('expression', 'MPA', (67, 77))
850836	33628589	Both the KYSE150-RECQL4 and KYSE410-RECQL4 cells displayed a significant proliferation advantage over the respective control cells, as revealed by the colony formation and EdU incorporation assays (P < 0.05; Figures 3B, 3C), confirming that RECQL4 promoted cell proliferation.	('proliferation advantage', 'CPA', (73, 96))	('KYSE410', 'CellLine', 'CVCL:1352', (28, 35))	('KYSE150-RECQL4', 'Var', (9, 23))	('cell proliferation', 'CPA', (257, 275))	('KYSE410-RECQL4', 'Var', (28, 42))	('promoted', 'PosReg', (248, 256))	('EdU', 'Chemical', '-', (172, 175))
850838	33628589	Silencing of RECQL4 caused more cells to arrest in the G1 phase and fewer cells to enter S and G2 phases, when examined at 72 h after transfection, indicating G1/G0 arrest (Figure 4B).	('arrest', 'Disease', 'MESH:D006323', (165, 171))	('arrest', 'Disease', (165, 171))	('arrest', 'Disease', (41, 47))	('Silencing', 'Var', (0, 9))	('arrest', 'Disease', 'MESH:D006323', (41, 47))	('RECQL4', 'Gene', (13, 19))
850840	33628589	We therefore measured SA-beta-gal activity, as a marker of senescence, in RECQL4 knockdown and control cells.	('knockdown', 'Var', (81, 90))	('SA-beta-gal', 'Protein', (22, 33))	('SA-beta-gal', 'Chemical', '-', (22, 33))
850843	33628589	However, knockdown of RECQL4 had no significant impact on apoptosis in both KYSE30 and TE-1 cells (Supplementary Figures S1 and 4D).	('RECQL4', 'Gene', (22, 28))	('knockdown', 'Var', (9, 18))	('apoptosis', 'CPA', (58, 67))	('TE', 'Chemical', 'MESH:D013691', (87, 89))
850849	33628589	As shown in Figure 6A, RECQL4 knockdown for 72 h led to an increase in the generation of ROS in both cell lines tested.	('ROS', 'Chemical', 'MESH:D017382', (89, 92))	('ROS', 'MPA', (89, 92))	('generation', 'MPA', (75, 85))	('knockdown', 'Var', (30, 39))	('increase', 'PosReg', (59, 67))
850855	33628589	Surprisingly, RECQL4 depletion resulted in a significant reduction in the phosphorylation of ATM and ATR, markers for their activation (Figure 7E).	('ATM', 'Gene', '472', (93, 96))	('reduction', 'NegReg', (57, 66))	('phosphorylation of', 'MPA', (74, 92))	('depletion', 'Var', (21, 30))	('ATM', 'Gene', (93, 96))	('ATR', 'Gene', '545', (101, 104))	('ATR', 'Gene', (101, 104))
850857	33628589	Given that EMT-related genes are downstream targets of NF-kappaB signaling, and ATM is the upstream kinase of the NF-kB pathway, we hypothesized that the impaired ATM activation due to RECQL4 depletion may lead to decreased phosphorylation of p65, a NF-kappaB subunit.	('ATM', 'Gene', (80, 83))	('ATM', 'Gene', '472', (163, 166))	('p65', 'Gene', (243, 246))	('NF-kappaB', 'Gene', (250, 259))	('activation', 'PosReg', (167, 177))	('depletion', 'Var', (192, 201))	('ATM', 'Gene', '472', (80, 83))	('phosphorylation', 'MPA', (224, 239))	('NF-kappaB', 'Gene', '4790', (55, 64))	('p65', 'Gene', '5970', (243, 246))	('decreased', 'NegReg', (214, 223))	('ATM', 'Gene', (163, 166))	('NF-kappaB', 'Gene', (55, 64))	('NF-kappaB', 'Gene', '4790', (250, 259))
850862	33628589	In primary tumors, high RECQL4 expression was positively associated with tumor differentiation, depth of invasion, and lymph node metastasis.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('high', 'Var', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('primary tumors', 'Disease', (3, 17))	('RECQL4', 'Gene', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('depth of invasion', 'CPA', (96, 113))	('tumor', 'Disease', (11, 16))	('lymph node metastasis', 'CPA', (119, 140))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('primary tumors', 'Disease', 'MESH:D001932', (3, 17))	('tumor', 'Disease', (73, 78))	('expression', 'MPA', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('associated', 'Reg', (57, 67))
850863	33628589	Mechanistically, RECQL4 depletion led to increased ROS production and DNA damage accumulation.	('increased', 'PosReg', (41, 50))	('DNA damage', 'MPA', (70, 80))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('depletion', 'Var', (24, 33))	('ROS production', 'MPA', (51, 65))	('increased ROS production', 'Phenotype', 'HP:0025464', (41, 65))	('accumulation', 'PosReg', (81, 93))
850864	33628589	Overexpression of RECQL4 due to gene amplification has been reported to be associated with tumor progression of many human malignant cancers.	('associated with', 'Reg', (75, 90))	('Overexpression', 'PosReg', (0, 14))	('human', 'Species', '9606', (117, 122))	('RECQL4', 'Gene', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('malignant cancers', 'Disease', (123, 140))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('gene amplification', 'Var', (32, 50))	('tumor', 'Disease', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('malignant cancers', 'Disease', 'MESH:D009369', (123, 140))
850869	33628589	Most notably, RECQL4 knockdown in metastatic prostate cancer cells drastically reduced their cell invasiveness in vitro and tumorigenicity in vivo.	('reduced', 'NegReg', (79, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (45, 60))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (45, 60))	('tumor', 'Disease', (124, 129))	('RECQL4', 'Gene', (14, 20))	('prostate cancer', 'Disease', (45, 60))	('knockdown', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cell invasiveness in vitro', 'CPA', (93, 119))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
850870	33628589	Increased oxidative stress and DNA damage caused by RECQL4 depletion could drive cellular senescence and thereby inhibit tumor progression.	('cellular senescence', 'CPA', (81, 100))	('drive', 'PosReg', (75, 80))	('RECQL4', 'Gene', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('oxidative stress', 'Phenotype', 'HP:0025464', (10, 26))	('tumor', 'Disease', (121, 126))	('inhibit', 'NegReg', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('depletion', 'Var', (59, 68))	('Increased', 'PosReg', (0, 9))	('oxidative stress', 'MPA', (10, 26))	('DNA damage', 'MPA', (31, 41))
850875	33628589	When the activations of ATM, ATR, CHK1, CHK2, NF-kappaB, AKT, and ERK were analyzed by Western blot analyses, we surprisingly found that knockdown of RECQL4 significantly reduced the phosphorylation of all these kinases.	('NF-kappaB', 'Gene', (46, 55))	('ATM', 'Gene', '472', (24, 27))	('ATR', 'Gene', '545', (29, 32))	('ATR', 'Gene', (29, 32))	('CHK1', 'Gene', (34, 38))	('CHK2', 'Gene', '11200', (40, 44))	('AKT', 'Gene', '207', (57, 60))	('knockdown', 'Var', (137, 146))	('reduced', 'NegReg', (171, 178))	('ATM', 'Gene', (24, 27))	('NF-kappaB', 'Gene', '4790', (46, 55))	('CHK1', 'Gene', '1111', (34, 38))	('ERK', 'Gene', '5594', (66, 69))	('RECQL4', 'Gene', (150, 156))	('phosphorylation', 'MPA', (183, 198))	('AKT', 'Gene', (57, 60))	('ERK', 'Gene', (66, 69))	('CHK2', 'Gene', (40, 44))
850992	30569149	Furthermore, overexpression of miR-21 (mimic) could significantly decrease the gene level of RASA1.	('RASA1', 'Gene', (93, 98))	('miR-21', 'Var', (31, 37))	('overexpression', 'PosReg', (13, 27))	('decrease', 'NegReg', (66, 74))	('gene level', 'MPA', (79, 89))	('miR-21', 'Chemical', '-', (31, 37))	('RASA1', 'Gene', '5921', (93, 98))
850993	30569149	Conversely, downregulation of miR-21 (inhibitor) significantly increased the gene level of RASA1, while downregulation of RASA1 (siRASA1) markedly increased the gene expression of miR-21.	('miR-21', 'Chemical', '-', (180, 186))	('RASA1', 'Gene', '5921', (131, 136))	('increased', 'PosReg', (63, 72))	('increased', 'PosReg', (147, 156))	('RASA1', 'Gene', (131, 136))	('RASA1', 'Gene', (122, 127))	('RASA1', 'Gene', '5921', (91, 96))	('gene expression', 'MPA', (161, 176))	('RASA1', 'Gene', (91, 96))	('RASA1', 'Gene', '5921', (122, 127))	('downregulation', 'Var', (12, 26))	('gene level', 'MPA', (77, 87))	('miR-21', 'Chemical', '-', (30, 36))	('downregulation', 'NegReg', (104, 118))	('miR-21', 'Gene', (30, 36))
851032	30569149	The 293T cells (2x104) were cultured in 24-well plates and transfected with 50 nM miR-21 mimics, 100 nM inhibitor or NC, 0.5 microg of psi-CHECK-2 luciferase reporter vector that contained the wild-type or mutant 3'UTR of RASA1 or empty plasmid.	('EC', 'Phenotype', 'HP:0011459', (141, 143))	('293T', 'CellLine', 'CVCL:0063', (4, 8))	('mutant', 'Var', (206, 212))	('RASA1', 'Gene', '5921', (222, 227))	('RASA1', 'Gene', (222, 227))	('miR-21', 'Chemical', '-', (82, 88))
851046	30569149	The cell colonies assay revealed that the cell colony formation rate was significantly decreased in the miR-21 inhibitor group compared with the inhibitor NC group, while the rate was significantly increased in the miR-21 mimic group compared with the mimic NC group (P<0.05) (Fig.	('decreased', 'NegReg', (87, 96))	('increased', 'PosReg', (198, 207))	('miR-21', 'Gene', (104, 110))	('miR-21', 'Chemical', '-', (215, 221))	('inhibitor', 'Var', (111, 120))	('miR-21', 'Chemical', '-', (104, 110))	('cell colony formation rate', 'CPA', (42, 68))
851053	30569149	The vector with mutated or wild-type RASA1 was constructed and used for the luciferase reporter assay (Fig.	('RASA1', 'Gene', (37, 42))	('RASA1', 'Gene', '5921', (37, 42))	('mutated', 'Var', (16, 23))
851058	30569149	The gene level of RASA1 was significantly increased when the Eca-109 cells were transfected with the miR-21 inhibitor compared with the inhibitor NC (P<0.05).	('gene level', 'MPA', (4, 14))	('increased', 'PosReg', (42, 51))	('miR-21', 'Chemical', '-', (101, 107))	('inhibitor', 'Var', (108, 117))	('RASA1', 'Gene', '5921', (18, 23))	('miR-21', 'Gene', (101, 107))	('RASA1', 'Gene', (18, 23))
851060	30569149	The expression of miR-21 was significantly increased in the group of cells which were transfected with siRASA1 when compared with the siNC group (P<0.05) (Fig.	('miR-21', 'Chemical', '-', (18, 24))	('transfected', 'Var', (86, 97))	('RASA1', 'Gene', '5921', (105, 110))	('expression', 'MPA', (4, 14))	('siNC', 'Chemical', 'MESH:C052464', (134, 138))	('miR-21', 'Gene', (18, 24))	('RASA1', 'Gene', (105, 110))	('increased', 'PosReg', (43, 52))
851086	30569149	Conversely, downregulated miR-21 significantly increased the RASA1 gene expression.	('downregulated', 'Var', (12, 25))	('miR-21', 'Chemical', '-', (26, 32))	('RASA1', 'Gene', '5921', (61, 66))	('expression', 'MPA', (72, 82))	('increased', 'PosReg', (47, 56))	('RASA1', 'Gene', (61, 66))	('miR-21', 'Gene', (26, 32))
851105	30373221	Tumor volumes were markedly reduced by cetuximab in TE-8 tumor (92.5 +- 5.9%), but TE-4 tumors were refractory to cetuximab treatment.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('reduced', 'NegReg', (28, 35))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cetuximab', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cetuximab', 'Chemical', 'MESH:D000068818', (114, 123))	('cetuximab', 'Chemical', 'MESH:D000068818', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (88, 93))	('Tumor volumes', 'CPA', (0, 13))
851116	30373221	Because ESCC patients with high EGFR expression have shown a higher response rate on EGFR-targeting regimen, such as tyrosine kinase inhibitor and anti-EGFR monoclonal antibody, than those with low or moderate EGFR expression, EGFR could be a proper molecular target for diagnosis and targeted therapy.	('ESCC', 'Disease', (8, 12))	('higher', 'PosReg', (61, 67))	('patients', 'Species', '9606', (13, 21))	('tyrosine kinase inhibitor', 'MPA', (117, 142))	('high', 'Var', (27, 31))	('response', 'MPA', (68, 76))	('EGFR', 'Gene', (32, 36))
851129	30373221	We evaluated the in vitro and in vivo feasibility of 64Cu-PCTA-cetuximab, an immuno-PET imaging biomarker, in EGFR-expressing ESCC tumor models.	('ESCC tumor', 'Disease', (126, 136))	('PET', 'Gene', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('ESCC tumor', 'Disease', 'MESH:D004938', (126, 136))	('64Cu-PCTA-cetuximab', 'Var', (53, 72))	('PET', 'Gene', '22095', (84, 87))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (53, 72))
851132	30373221	A431 (human epidermoid carcinoma) and U87-MG (human glioblastoma) were purchased from American Type Culture Collection (Manassas, WV, USA) and maintained in Dulbecco's Modified Eagle's medium.	('human', 'Species', '9606', (6, 11))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('U87-MG', 'CellLine', 'CVCL:0022', (38, 44))	('A431', 'CellLine', 'CVCL:0037', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('U87-MG', 'Var', (38, 44))	('human', 'Species', '9606', (46, 51))	('epidermoid carcinoma', 'Disease', 'MESH:D002294', (12, 32))	('glioblastoma', 'Disease', (52, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('epidermoid carcinoma', 'Disease', (12, 32))
851174	30373221	These results indicated that binding of 64Cu-PCTA-cetuximab represented the level of EGFR expression on the cells.	('64Cu-PCTA-cetuximab', 'Var', (40, 59))	('binding', 'Interaction', (29, 36))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (40, 59))
851176	30373221	Cetuximab-induced cell growth inhibition was found in high-EGFR-expressing TE-8 cells, while it was minimal in low-EGFR-expressing TE-4 (Figure 3).	('cell growth inhibition', 'CPA', (18, 40))	('high-EGFR-expressing', 'Var', (54, 74))	('Cetuximab-induced', 'Gene', (0, 17))	('Cetuximab', 'Chemical', 'MESH:D000068818', (0, 9))
851179	30373221	In the isotype group, the growth rate of TE-4 tumors was faster than that of TE-8 tumors.	('TE-4', 'Var', (41, 45))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('faster', 'PosReg', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Disease', (46, 52))	('growth rate', 'CPA', (26, 37))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
851186	30373221	64Cu-PCTA-cetxuximab had favorable immunoreactive fraction of 0.972, and its radio immunoconjugate showed good in vitro serum stability (above 90%).	('immunoreactive fraction', 'MPA', (35, 58))	('64Cu-PCTA-cetxuximab', 'Chemical', '-', (0, 20))	('64Cu-PCTA-cetxuximab', 'Var', (0, 20))
851189	30373221	PET images clearly showed the uptake of 64Cu-PCTA-cetuximab in TE-4 and TE-8 tumors at 48 h after injection (Figure 5a,b).	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('PET', 'Gene', '22095', (0, 3))	('uptake', 'MPA', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('PET', 'Gene', (0, 3))	('64Cu-PCTA-cetuximab', 'Var', (40, 59))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (40, 59))
851190	30373221	The SUV of 64Cu-cetuximab before treatment was 2.5-fold higher in TE-8 (4.6 +- 0.7) than TE-4 tumors (1.8 +- 0.3).	('64Cu-cetuximab', 'Chemical', '-', (11, 25))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('SUV', 'MPA', (4, 7))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('TE-8', 'Var', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('higher', 'PosReg', (56, 62))
851221	30373221	Thus, we postulated that changes in 18F-FDG uptake could indicate modulation of EGFR function.	('18F-FDG', 'Chemical', '-', (36, 43))	('18F-FDG uptake', 'MPA', (36, 50))	('EGFR', 'Protein', (80, 84))	('modulation', 'Reg', (66, 76))	('changes', 'Var', (25, 32))
851233	30373221	In western blot assay, TE-4 cell is HER2 expressing cell line (data not shown) and pAkt expression level in TE-4 tumor slightly increased with cetuximab treatment compared to isotype treatment (Figure 7b,e).	('tumor', 'Disease', (113, 118))	('HER2', 'Gene', (36, 40))	('Akt', 'Gene', '11651', (84, 87))	('increased', 'PosReg', (128, 137))	('Akt', 'Gene', (84, 87))	('HER2', 'Gene', '13866', (36, 40))	('cetuximab', 'Var', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cetuximab', 'Chemical', 'MESH:D000068818', (143, 152))
851234	30373221	Therefore, aberrant HER2 signaling could be used to activate a bypass signaling pathway in TE-4 tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('HER2', 'Gene', '13866', (20, 24))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('aberrant', 'Var', (11, 19))	('activate', 'PosReg', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('bypass signaling pathway', 'Pathway', (63, 87))	('HER2', 'Gene', (20, 24))
851238	30373221	Inhibition of HER2 may play a potential role in antiproliferation of tumor, and inhibition of EGFR and combination therapy with TKIs could be useful in EGFR- or HER2-overexpressing ESCC.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('HER2', 'Gene', '13866', (161, 165))	('HER2', 'Gene', '13866', (14, 18))	('tumor', 'Disease', (69, 74))	('EGFR', 'Gene', (94, 98))	('ESCC', 'Disease', (181, 185))	('HER2', 'Gene', (161, 165))	('inhibition', 'Var', (80, 90))	('HER2', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
851239	30373221	First, because two ESCC cell line model was used, expanded preclinical and clinical research are required in various ESCC animal models and clinical patients with tumors expressing varying level of EGFR to validate the association between 64Cu-PCTA-cetuximab accumulation in tumor lesion and prognosis after cetuximab immunotherapy and to establish PET signal cutoff value for target selection as imaging biomarker.	('PET', 'Gene', '22095', (349, 352))	('association', 'Interaction', (219, 230))	('patients', 'Species', '9606', (149, 157))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (239, 258))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('PET', 'Gene', (349, 352))	('cetuximab', 'Chemical', 'MESH:D000068818', (249, 258))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('cetuximab', 'Chemical', 'MESH:D000068818', (308, 317))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('64Cu-PCTA-cetuximab', 'Var', (239, 258))	('tumor lesion', 'Disease', (275, 287))	('tumor lesion', 'Disease', 'MESH:D051437', (275, 287))
851255	29374572	Immunohistochemical assessment of the GATA-3+ and T-bet+ cells may help distinguish patients with EoE/PPI-REE from GERD and aid in assessment of treatment response.	('T-bet', 'Gene', '30009', (50, 55))	('EoE', 'Phenotype', 'HP:0410151', (98, 101))	('patients', 'Species', '9606', (84, 92))	('aid', 'Reg', (124, 127))	('GATA-3', 'Gene', (38, 44))	('T-bet', 'Gene', (50, 55))	('PPI-REE', 'Chemical', '-', (102, 109))	('EoE/PPI-REE', 'Var', (98, 109))	('GATA-3', 'Gene', '2625', (38, 44))
851266	29374572	Given its role in Th2-associated inflammation, we hypothesized that GATA-3 expression would be increased in EoE and PPI-REE and that the ratio of GATA-3/T-bet expression would differentiate these individuals from subjects with GERD.	('GATA-3', 'Gene', (68, 74))	('T-bet', 'Gene', '30009', (153, 158))	('differentiate', 'Reg', (176, 189))	('T-bet', 'Gene', (153, 158))	('GATA-3', 'Gene', '2625', (68, 74))	('inflammation', 'Disease', 'MESH:D007249', (33, 45))	('GATA-3', 'Gene', '2625', (146, 152))	('GATA-3', 'Gene', (146, 152))	('inflammation', 'Disease', (33, 45))	('PPI-REE', 'Chemical', '-', (116, 123))	('EoE', 'Phenotype', 'HP:0410151', (108, 111))	('increased', 'PosReg', (95, 104))	('expression', 'MPA', (75, 85))	('PPI-REE', 'Var', (116, 123))
851269	29374572	All subjects with EoE and PPI-REE demonstrated histologic resolution of esophageal eosinophilia (<15 eos/hpf) after 6-8 weeks of treatment, respectively.	('PPI-REE', 'Chemical', '-', (26, 33))	('esophageal eosinophilia', 'Disease', (72, 95))	('EoE', 'Phenotype', 'HP:0410151', (18, 21))	('PPI-REE', 'Var', (26, 33))	('eosinophilia', 'Phenotype', 'HP:0001880', (83, 95))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (72, 95))
851285	29374572	Our observations corroborate earlier findings suggesting that EoE and PPI-REE share a common pathophysiology and that PPI, topical corticosteroids and dietary elimination each result in decreased GATA-3 expression.	('GATA-3', 'Gene', '2625', (196, 202))	('GATA-3', 'Gene', (196, 202))	('expression', 'MPA', (203, 213))	('steroids', 'Chemical', 'MESH:D013256', (138, 146))	('EoE', 'Disease', (62, 65))	('EoE', 'Phenotype', 'HP:0410151', (62, 65))	('decreased', 'NegReg', (186, 195))	('PPI-REE', 'Chemical', '-', (70, 77))	('PPI', 'Var', (118, 121))
851319	29303995	A point mutation in the aldehyde dehydrogenase 2 gene has randomized millions of alcohol consumers to markedly increased local ACH exposure via saliva and gastric juice, which is associated with a manifold risk for upper GI tract cancers.	('increased', 'PosReg', (111, 120))	('alcohol', 'Chemical', 'MESH:D000438', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('upper GI tract cancers', 'Disease', 'MESH:D004067', (215, 237))	('ACH', 'Chemical', 'MESH:D000079', (127, 130))	('GI tract cancer', 'Phenotype', 'HP:0007378', (221, 236))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('aldehyde dehydrogenase 2', 'Gene', '217', (24, 48))	('upper GI tract cancers', 'Disease', (215, 237))	('point mutation', 'Var', (2, 16))	('local ACH exposure', 'MPA', (121, 139))	('aldehyde dehydrogenase 2', 'Gene', (24, 48))
851325	29303995	However, even smoking cessation and moderation of alcohol consumption are associated with a marked decrease in local ACH exposure and cancer risk, especially among established risk groups.	('ACH', 'Chemical', 'MESH:D000079', (117, 120))	('moderation', 'Var', (36, 46))	('alcohol', 'Chemical', 'MESH:D000438', (50, 57))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('decrease', 'NegReg', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('local ACH exposure', 'MPA', (111, 129))
851333	29303995	A point mutation in the aldehyde dehydrogenase 2 (ALDH2) gene results in deficient activity of the main ACH-metabolizing mitochondrial enzyme (ALDH2) and proves conclusively the causal relationship between local ACH exposure and upper GI tract cancers (Table 1).	('activity', 'MPA', (83, 91))	('ACH', 'Chemical', 'MESH:D000079', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('upper GI tract cancers', 'Disease', 'MESH:D004067', (229, 251))	('ALDH2', 'Gene', (50, 55))	('deficient', 'NegReg', (73, 82))	('aldehyde dehydrogenase 2', 'Gene', '217', (24, 48))	('point mutation', 'Var', (2, 16))	('upper GI tract cancers', 'Disease', (229, 251))	('ALDH2', 'Gene', (143, 148))	('GI tract cancer', 'Phenotype', 'HP:0007378', (235, 250))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('aldehyde dehydrogenase 2', 'Gene', (24, 48))	('ACH', 'Chemical', 'MESH:D000079', (212, 215))
851341	29303995	ACH is electrophilic and genotoxic, alters DNA repair, and induces oxidative stress.	('alters', 'Reg', (36, 42))	('DNA repair', 'MPA', (43, 53))	('oxidative stress', 'MPA', (67, 83))	('induces', 'Reg', (59, 66))	('ACH', 'Var', (0, 3))	('ACH', 'Chemical', 'MESH:D000079', (0, 3))	('oxidative stress', 'Phenotype', 'HP:0025464', (67, 83))
851342	29303995	When administered in relatively high concentrations in vitro, ACH causes DNA-protein crosslinks, DNA-strand breaks, DNA adducts, sister chromatid exchanges, chromosomal aberrations, and micronuclei in eukaryotic cells.	('micronuclei', 'CPA', (186, 197))	('DNA-protein', 'CPA', (73, 84))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (157, 180))	('causes', 'Reg', (66, 72))	('ACH', 'Var', (62, 65))	('chromosomal aberrations', 'CPA', (157, 180))	('ACH', 'Chemical', 'MESH:D000079', (62, 65))	('DNA-strand breaks', 'CPA', (97, 114))	('sister chromatid exchanges', 'CPA', (129, 155))	('crosslinks', 'Interaction', (85, 95))
851343	29303995	In a study using pig liver DNA, ACH concentrations ranging from 100 to 500 microM in the presence of polyamines resulted in an exponential increase of mutagenic ACH-DNA adduct (1,N2-propanodeoxyguanosine) formation.	('1,N2-propanodeoxyguanosine', 'Chemical', 'MESH:C060934', (177, 203))	('polyamines', 'Var', (101, 111))	('pig', 'Species', '9823', (17, 20))	('ACH', 'Chemical', 'MESH:D000079', (32, 35))	('increase', 'PosReg', (139, 147))	('ACH', 'Chemical', 'MESH:D000079', (161, 164))	('polyamines', 'Chemical', 'MESH:D011073', (101, 111))
851368	29303995	A single point mutation in ALDH2 gene results in deficient activity of the main ACH metabolizing low KM mitochondrial enzyme (ALDH2).	('single point mutation', 'Var', (2, 23))	('activity', 'MPA', (59, 67))	('ACH', 'Chemical', 'MESH:D000079', (80, 83))	('ALDH2', 'Gene', (126, 131))	('deficient', 'NegReg', (49, 58))	('ALDH2', 'Gene', (27, 32))
851383	29303995	On the basis of the alcohol elimination rate (7 g/h), the increased exposure time to salivary ACH caused by the deficient ALDH2 enzyme is 283 min in moderate drinkers and 660 min in heavy drinkers.	('deficient', 'Var', (112, 121))	('alcohol', 'Chemical', 'MESH:D000438', (20, 27))	('ALDH2', 'Gene', (122, 127))	('ACH', 'Chemical', 'MESH:D000079', (94, 97))
851386	29303995	The oropharyngeal cancer risk of ALDH2-deficient alcohol drinkers compared with that of ALDH2-active individuals thus appears to have a dose-dependent correlation with the additional local ACH exposure caused by the deficient ALDH2 enzyme.	('ACH', 'Chemical', 'MESH:D000079', (189, 192))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (4, 24))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (49, 65))	('deficient', 'Var', (216, 225))	('oropharyngeal cancer', 'Disease', (4, 24))	('ALDH2', 'Gene', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('ALDH2-deficient alcohol drinkers', 'Disease', (33, 65))	('ALDH2-deficient alcohol drinkers', 'Disease', 'MESH:D000437', (33, 65))
851475	29303995	In the presence of alcohol, the intragastric ACH production in patients with hypochlorhydria or achlorhydric stomach secondary either to atrophic gastritis or the use of acid suppressive drugs is increased to mutagenic levels.	('achlorhydric', 'Var', (96, 108))	('increased', 'PosReg', (196, 205))	('alcohol', 'Chemical', 'MESH:D000438', (19, 26))	('hypochlorhydria', 'Disease', 'MESH:D000126', (77, 92))	('intragastric ACH production', 'MPA', (32, 59))	('atrophic gastritis', 'Disease', (137, 155))	('gastritis', 'Phenotype', 'HP:0005263', (146, 155))	('patients', 'Species', '9606', (63, 71))	('atrophic gastritis', 'Disease', 'MESH:D005757', (137, 155))	('ACH', 'Chemical', 'MESH:D000079', (45, 48))	('hypochlorhydria', 'Disease', (77, 92))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (137, 155))
851484	29303995	In addition, gene polymorphisms have an effect on the activities of enzymes that metabolize ethanol and ACH.	('ACH', 'Chemical', 'MESH:D000079', (104, 107))	('ethanol', 'Chemical', 'MESH:D000431', (92, 99))	('polymorphisms', 'Var', (18, 31))	('activities', 'MPA', (54, 64))	('effect', 'Reg', (40, 46))	('enzymes', 'Enzyme', (68, 75))
851491	29303995	Sixty minutes after a moderate dose (0.5 g/kg) of alcohol, three Asian ALDH2-deficient volunteers (heterozygous for the mutant ALDH2*2 allele) had markedly elevated ACH levels (3.9-75.0 microM) in their sterile parotid gland saliva.	('elevated', 'PosReg', (156, 164))	('ACH', 'Chemical', 'MESH:D000079', (165, 168))	('alcohol', 'Chemical', 'MESH:D000438', (50, 57))	('ALDH2*2', 'Gene', (127, 134))	('ACH levels', 'MPA', (165, 175))	('parotid gland saliva', 'Disease', 'MESH:D010309', (211, 231))	('ALDH2-deficient volunteers', 'Disease', (71, 97))	('ALDH2-deficient volunteers', 'Disease', 'MESH:D007153', (71, 97))	('parotid gland saliva', 'Disease', (211, 231))	('mutant', 'Var', (120, 126))
851537	29303995	In the worst case-scenario, however, three yogurts (450 mL)/day with a particularly high ACH concentration (17.4 mg/L) would result in ACH exposure close to that of five cigarettes daily (Table 2).	('result in', 'Reg', (125, 134))	('ACH exposure', 'MPA', (135, 147))	('17.4', 'Var', (108, 112))	('ACH', 'Chemical', 'MESH:D000079', (135, 138))	('ACH', 'Chemical', 'MESH:D000079', (89, 92))
851586	29303995	A point mutation in the ALDH2 gene provides a unique human cancer model for local ACH exposure, the kind of which is not available for any other of the group 1 human carcinogens.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ALDH2', 'Gene', (24, 29))	('point mutation', 'Var', (2, 16))	('human', 'Species', '9606', (53, 58))	('ACH', 'Chemical', 'MESH:D000079', (82, 85))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('human', 'Species', '9606', (160, 165))
851700	28086818	The areas under the sROC curve in the per-patient analysis were 0.9559 for Lugol chromoendoscopy and 0.9611 for NBI, demonstrating good accuracy of the methods with no significant difference between them.	('patient', 'Species', '9606', (42, 49))	('Lugol', 'Chemical', 'MESH:C010389', (75, 80))	('0.9611', 'Var', (101, 107))	('Lugol chromoendoscopy', 'Disease', (75, 96))
851701	28086818	In the per-lesion analysis, these areas were 0.9685 for Lugol chromoendoscopy and 0.9587 for NBI.	('0.9587', 'Var', (82, 88))	('Lugol chromoendoscopy', 'Disease', (56, 77))	('Lugol', 'Chemical', 'MESH:C010389', (56, 61))
851723	27042219	Of these three treatments, induction radiation has gradually been rejected, as it increases perioperative complications and mortality without improving survival, whereas induction CRT and induction CT are presently thought to improve survival in EC patients.7 Induction therapy is associated with its own toxic and side effects, however, and could also increase postoperative complications and mortality.	('postoperative complications', 'CPA', (362, 389))	('Induction therapy', 'Var', (260, 277))	('patients', 'Species', '9606', (249, 257))	('increase', 'PosReg', (353, 361))	('mortality', 'CPA', (394, 403))	('men', 'Species', '9606', (20, 23))
851747	27042219	All five clinical trials (with a total of 678 patients) offered perioperative mortality data; four of these studies demonstrated that patients who received induction CRT plus surgery tended to suffer higher perioperative mortality compared with those who received induction CT alone plus surgery.	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (134, 142))	('induction', 'Var', (156, 165))	('higher', 'PosReg', (200, 206))	('perioperative mortality', 'CPA', (207, 230))
851750	27042219	Four of the five clinical trials (with a total of 559 cases) offered postoperative complication data; three studies reported that patients who received induction CRT plus surgery tended to suffer from higher postoperative complication rates compared with those who received induction CT alone plus surgery; however, only one study showed statistical significance.	('postoperative complication', 'CPA', (208, 234))	('patients', 'Species', '9606', (130, 138))	('induction', 'Var', (152, 161))	('higher', 'PosReg', (201, 207))
851767	27042219	The present meta analysis synthesized the results of five clinical trials with a total of 678 patients; we found that induction CRT improved the OS of EC patients compared with induction CT alone (HR 0.73, 95% CI 0.61-0.89; P = 0.002) and the pCR rate was higher in the induction CRT group (RR 6.48, 95% CI 3.36-12.49; P < 0.001).	('higher', 'PosReg', (256, 262))	('patients', 'Species', '9606', (94, 102))	('induction CRT', 'Var', (118, 131))	('patients', 'Species', '9606', (154, 162))	('improved', 'PosReg', (132, 140))
851777	25344912	Inhibition of the PI3K/AKT pathway with specific inhibitors, wortmannin and LY294002, significantly reduced Bcl-xL expression, induced caspase-3-dependent apoptosis, and repressed cell proliferation and tumor growth in vitro and in vivo without obvious toxic effects.	('wortmannin', 'Chemical', 'MESH:D000077191', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('caspase-3', 'Gene', (135, 144))	('repressed cell proliferation', 'CPA', (170, 198))	('reduced', 'NegReg', (100, 107))	('AKT', 'Gene', '207', (23, 26))	('LY294002', 'Var', (76, 84))	('Bcl-xL', 'Gene', '598', (108, 114))	('caspase-3', 'Gene', '836', (135, 144))	('AKT', 'Gene', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('Bcl-xL', 'Gene', (108, 114))	('LY294002', 'Chemical', 'MESH:C085911', (76, 84))	('induced', 'PosReg', (127, 134))
851779	25344912	Inactivation of PI3K/AKT pathway markedly increased the sensitivity and even reversed acquired resistance of esophageal cancer cells to chemotherapeutic drugs in vitro.	('increased', 'PosReg', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('reversed', 'NegReg', (77, 85))	('acquired', 'MPA', (86, 94))	('AKT', 'Gene', '207', (21, 24))	('sensitivity', 'MPA', (56, 67))	('esophageal cancer', 'Disease', (109, 126))	('Inactivation', 'Var', (0, 12))	('AKT', 'Gene', (21, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
851799	25344912	Two specific inhibitors, wortmannin and LY294002, were used in this study to block the PI3K/AKT signaling pathway.	('LY294002', 'Chemical', 'MESH:C085911', (40, 48))	('wortmannin', 'Chemical', 'MESH:D000077191', (25, 35))	('AKT', 'Gene', '207', (92, 95))	('LY294002', 'Var', (40, 48))	('AKT', 'Gene', (92, 95))
851803	25344912	We also found that wortmannin and LY294002 significantly increased the percentage of sub-G1 esophageal cancer cell population, whereas addition of Z-DEVD-FMK, a caspase-3 inhibitor, markedly abrogated these effects (Figure 2C).	('caspase-3', 'Gene', '836', (161, 170))	('LY294002', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('wortmannin', 'Chemical', 'MESH:D000077191', (19, 29))	('Z-DEVD-FMK', 'Chemical', 'MESH:C110772', (147, 157))	('LY294002', 'Chemical', 'MESH:C085911', (34, 42))	('esophageal cancer', 'Disease', (92, 109))	('increased', 'PosReg', (57, 66))	('caspase-3', 'Gene', (161, 170))	('G1 esophageal cancer', 'Phenotype', 'HP:0011459', (89, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
851804	25344912	These data indicated that wortmannin and LY294002 exerted dose-dependent inhibitory effects on the PI3K/AKT pathway and pro-apoptotic proteins, therefore inducing caspase-3-dependent apoptosis in esophageal cancer cells.	('wortmannin', 'Chemical', 'MESH:D000077191', (26, 36))	('esophageal cancer', 'Disease', (196, 213))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('caspase-3', 'Gene', (163, 172))	('AKT', 'Gene', (104, 107))	('caspase-3', 'Gene', '836', (163, 172))	('AKT', 'Gene', '207', (104, 107))	('LY294002', 'Chemical', 'MESH:C085911', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('inducing', 'PosReg', (154, 162))	('inhibitory effects', 'MPA', (73, 91))	('LY294002', 'Var', (41, 49))
851805	25344912	The esophageal cancer cell lines KYSE150, HKESC-1, KYSE270, and T.Tn were exposed to different concentrations of wortmannin or LY294002, and the results from MTT and colony-formation assays showed that blockade of PI3K/AKT pathway inhibited proliferation (Figure 3) and colony-formation ability (Figure 4) of esophageal cancer cells, suggesting that specific inhibitors of PI3K may have antitumor effects.	('esophageal cancer', 'Disease', (309, 326))	('tumor', 'Disease', (391, 396))	('AKT', 'Gene', (219, 222))	('MTT', 'Chemical', 'MESH:C070243', (158, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('wortmannin', 'Chemical', 'MESH:D000077191', (113, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (309, 326))	('proliferation', 'CPA', (241, 254))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('LY294002', 'Chemical', 'MESH:C085911', (127, 135))	('colony-formation ability', 'CPA', (270, 294))	('blockade', 'Var', (202, 210))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('AKT', 'Gene', '207', (219, 222))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('esophageal cancer', 'Disease', (4, 21))	('inhibited', 'NegReg', (231, 240))
851807	25344912	As shown in Figure 5A, treatment with wortmannin for 19 days caused a significant dose-dependent suppression of tumor volume, with decreases of 59.2% and 77.3% for KYSE150 and KYSE270 tumors, respectively, in the groups receiving 0.6 mg/kg wortmannin treatment.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('suppression', 'NegReg', (97, 108))	('wortmannin', 'Chemical', 'MESH:D000077191', (38, 48))	('tumors', 'Disease', (184, 190))	('decreases', 'NegReg', (131, 140))	('tumor', 'Disease', (184, 189))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('KYSE150', 'Var', (164, 171))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('wortmannin', 'Chemical', 'MESH:D000077191', (240, 250))	('tumor', 'Disease', (112, 117))
851818	25344912	The results showed that although 5-FU, wortmannin, or LY294002 alone at the dosages used had no or only slight effects on the proliferation of KYSE150FR and KYSE410FR cells, combining 5-FU with wortmannin or LY294002 significantly reverted the resistance and lowered the proliferation rate (Figure 7B).	('proliferation rate', 'CPA', (271, 289))	('lowered', 'NegReg', (259, 266))	('wortmannin', 'Chemical', 'MESH:D000077191', (39, 49))	('LY294002', 'Chemical', 'MESH:C085911', (54, 62))	('LY294002', 'Chemical', 'MESH:C085911', (208, 216))	('resistance', 'CPA', (244, 254))	('LY294002', 'Var', (208, 216))	('LY294002', 'Var', (54, 62))	('reverted', 'PosReg', (231, 239))	('wortmannin', 'Chemical', 'MESH:D000077191', (194, 204))	('5-FU', 'Chemical', 'MESH:D005472', (184, 188))	('5-FU', 'Chemical', 'MESH:D005472', (33, 37))
851819	25344912	Furthermore, the FR cell lines which were resistant to 5-FU-induced apoptosis were rendered apoptotic by the addition of wortmannin or LY294002, as evidenced by the increase in sub-G1 population and cleaved caspase-3 expression (Figure 7C-D).	('increase', 'PosReg', (165, 173))	('sub-G1 population', 'CPA', (177, 194))	('caspase-3', 'Gene', (207, 216))	('LY294002', 'Var', (135, 143))	('wortmannin', 'Chemical', 'MESH:D000077191', (121, 131))	('5-FU', 'Chemical', 'MESH:D005472', (55, 59))	('caspase-3', 'Gene', '836', (207, 216))	('LY294002', 'Chemical', 'MESH:C085911', (135, 143))
851820	25344912	More importantly, our in vivo experiments showed that the resistance of KYSE410FR tumor xenografts to 5-FU treatment in nude mice was markedly abrogated by wortmannin treatment (Figure 7E).	('wortmannin', 'Chemical', 'MESH:D000077191', (156, 166))	('5-FU', 'Chemical', 'MESH:D005472', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('nude mice', 'Species', '10090', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('KYSE410FR', 'Var', (72, 81))	('resistance', 'MPA', (58, 68))	('tumor', 'Disease', (82, 87))	('abrogated', 'NegReg', (143, 152))
851822	25344912	PI3K is a lipid kinase that generates second messenger lipid phosphatidylinositol (3-5)-triphosphate (PIP3), which recruits and activates a number of proteins including AKT.	('PI3K', 'Var', (0, 4))	('recruits', 'PosReg', (115, 123))	('activates', 'PosReg', (128, 137))	('phosphatidylinositol (3-5)-triphosphate', 'Chemical', '-', (61, 100))	('PIP3', 'Chemical', '-', (102, 106))	('lipid', 'Chemical', 'MESH:D008055', (10, 15))	('AKT', 'Gene', (169, 172))	('lipid', 'Chemical', 'MESH:D008055', (55, 60))	('proteins', 'Protein', (150, 158))	('AKT', 'Gene', '207', (169, 172))
851825	25344912	In esophageal cancer, the association of genetic variants of AKT with chemoradiotherapy response and survival has been reported.	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('AKT', 'Gene', '207', (61, 64))	('genetic variants', 'Var', (41, 57))	('AKT', 'Gene', (61, 64))	('association', 'Interaction', (26, 37))
851829	25344912	More importantly, the data from phase I clinical trial suggested that treatment of the cancer patients with PI3K inhibitors was associated with prolonged stable disease, and phase II trials are in progress.	('cancer', 'Disease', (87, 93))	('patients', 'Species', '9606', (94, 102))	('inhibitors', 'Var', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('PI3K', 'Gene', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
851831	25344912	Our in vitro and in vivo results showed that specific inhibitors of PI3K/AKT inhibited proliferation and promoted apoptosis of esophageal cancer cells in a dose-dependent manner (Figures 2-5), thus indicating the therapeutic potential of targeting PI3K/AKT in esophageal cancer treatment.	('promoted', 'PosReg', (105, 113))	('apoptosis', 'CPA', (114, 123))	('esophageal cancer', 'Disease', (127, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (260, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('proliferation', 'CPA', (87, 100))	('inhibitors', 'Var', (54, 64))	('inhibited', 'NegReg', (77, 86))	('AKT', 'Gene', (73, 76))	('AKT', 'Gene', '207', (253, 256))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('AKT', 'Gene', (253, 256))	('AKT', 'Gene', '207', (73, 76))	('esophageal cancer', 'Disease', (260, 277))
851832	25344912	Chemotherapy is now widely used in clinical cancer treatment but development of chemoresistance can compromise treatment or even result in recurrence of the disease.	('result in', 'Reg', (129, 138))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('compromise', 'NegReg', (100, 110))	('chemoresistance', 'Var', (80, 95))	('treatment', 'CPA', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
851835	25344912	Several in vitro studies have shown that inhibition of PI3K/AKT pathway can sensitize a variety of other types of cancer cells to chemotherapeutic drugs, but the effects of specific inhibitors of PI3K/AKT on esophageal cancer chemoresistance have not been reported.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('AKT', 'Gene', '207', (201, 204))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('sensitize', 'Reg', (76, 85))	('AKT', 'Gene', '207', (60, 63))	('AKT', 'Gene', (201, 204))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('inhibition', 'Var', (41, 51))	('esophageal cancer', 'Disease', (208, 225))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (219, 225))	('AKT', 'Gene', (60, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('cancer', 'Disease', (114, 120))
851836	25344912	Our current findings showed for the first time that wortmannin and LY294002 significantly enhanced the sensitivity of parental esophageal cancer cells and chemoresistant sublines to chemotherapeutic drugs not only in vitro, but also in xenografted animal models (Figures 6-7), which strongly suggest that combining PI3K/AKT inhibitors and conventional chemotherapeutic drugs may be a potentially useful therapeutic strategy in treating esophageal cancer patients, particularly as upfront therapy before tumors have a chance to develop chemoresistance.	('cancer', 'Phenotype', 'HP:0002664', (447, 453))	('esophageal cancer', 'Disease', (436, 453))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('LY294002', 'Var', (67, 75))	('enhanced', 'PosReg', (90, 98))	('tumors', 'Phenotype', 'HP:0002664', (503, 509))	('AKT', 'Gene', (320, 323))	('parental esophageal cancer', 'Disease', 'MESH:D004938', (118, 144))	('LY294002', 'Chemical', 'MESH:C085911', (67, 75))	('wortmannin', 'Chemical', 'MESH:D000077191', (52, 62))	('sensitivity', 'MPA', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (503, 508))	('tumors', 'Disease', (503, 509))	('patients', 'Species', '9606', (454, 462))	('parental esophageal cancer', 'Disease', (118, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (436, 453))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('tumors', 'Disease', 'MESH:D009369', (503, 509))	('AKT', 'Gene', '207', (320, 323))
851838	25344912	Taken together, we have demonstrated the significance of PI3K/AKT pathway in malignant progression of esophageal cancer, and have provided the first evidence that PI3K/AKT inhibitors can increase the sensitivity and even reverse acquired resistance of esophageal cancer cells to chemotherapeutic drugs.	('esophageal cancer', 'Disease', 'MESH:D004938', (252, 269))	('acquired resistance', 'CPA', (229, 248))	('AKT', 'Gene', (62, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('increase', 'PosReg', (187, 195))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('malignant progression', 'CPA', (77, 98))	('sensitivity', 'MPA', (200, 211))	('reverse', 'NegReg', (221, 228))	('AKT', 'Gene', '207', (168, 171))	('inhibitors', 'Var', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('AKT', 'Gene', '207', (62, 65))	('esophageal cancer', 'Disease', (252, 269))	('esophageal cancer', 'Disease', (102, 119))	('AKT', 'Gene', (168, 171))
851839	25344912	Genetic mutations in the PI3K/AKT pathway are common in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('AKT', 'Gene', '207', (30, 33))	('human', 'Species', '9606', (56, 61))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Genetic mutations', 'Var', (0, 17))	('AKT', 'Gene', (30, 33))
851840	25344912	A recent study showed that patients with gynecologic and breast cancer that have PIK3CA mutations are more responsive to treatment with PI3K/AKT/mTOR inhibitors than patients without mutations.	('breast cancer', 'Disease', (57, 70))	('PIK3CA', 'Gene', (81, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('gynecologic', 'Disease', (41, 52))	('PIK3CA', 'Gene', '5290', (81, 87))	('AKT', 'Gene', (141, 144))	('mTOR', 'Gene', (145, 149))	('mutations', 'Var', (88, 97))	('mTOR', 'Gene', '2475', (145, 149))	('patients', 'Species', '9606', (166, 174))	('patients', 'Species', '9606', (27, 35))	('AKT', 'Gene', '207', (141, 144))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('responsive', 'MPA', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
851841	25344912	The effects of PI3K/AKT inhibitors on esophageal cancer with genetic variations in the PI3K/AKT pathway warrant further investigation.	('AKT', 'Gene', (20, 23))	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('AKT', 'Gene', '207', (92, 95))	('genetic variations', 'Var', (61, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('AKT', 'Gene', '207', (20, 23))	('AKT', 'Gene', (92, 95))
851870	21347561	For example, patients with Lynch syndrome have germline mismatch repair gene mutations, and develop colorectal cancer at an earlier age than sporadic cases.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('Lynch syndrome', 'Disease', 'MESH:D003123', (27, 41))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('patients', 'Species', '9606', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('germline mismatch repair gene mutations', 'Var', (47, 86))	('colorectal cancer', 'Disease', (100, 117))	('mutations', 'Var', (77, 86))	('develop', 'PosReg', (92, 99))	('Lynch syndrome', 'Disease', (27, 41))
851871	21347561	Hereditary breast cancer can have germline BRCA1/BRCA2 mutations, and affected individuals develop breast cancer at earlier ages.	('BRCA1', 'Gene', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('mutations', 'Var', (55, 64))	('breast cancer', 'Disease', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('BRCA2', 'Gene', '675', (49, 54))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('Hereditary breast cancer', 'Disease', 'MESH:D001943', (0, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('BRCA1', 'Gene', '672', (43, 48))	('Hereditary breast cancer', 'Disease', (0, 24))	('BRCA2', 'Gene', (49, 54))
851893	21347561	A smaller proportion of FBE probands as compared to non-FBE probands had a history of high-grade dysplasia (HGD) or EAC, either at diagnosis or developed during follow-up (34.3 vs. 60.7%, p = 0.002).	('dysplasia', 'Disease', (97, 106))	('dysplasia', 'Disease', 'MESH:D004476', (97, 106))	('FBE', 'Var', (24, 27))	('EAC', 'Phenotype', 'HP:0011459', (116, 119))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('EAC', 'Disease', (116, 119))	('BE', 'Phenotype', 'HP:0100580', (25, 27))
851930	19138993	To test the hypothesis that adverse alleles in miRNA-related genes may increase the risk for esophageal cancer, we assessed the associations between esophageal cancer risk and 41 potentially functional single-nucleotide polymorphisms (SNPs) in 26 miRNA-related genes in a case-control study of 346 Caucasian esophageal-cancer patients (85.5% with esophageal adenocarcinoma) and 346 frequencymatched (age, gender, and ethnicity) controls.	('esophageal cancer', 'Disease', (93, 110))	('esophageal cancer', 'Disease', (149, 166))	('increase', 'PosReg', (71, 79))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (347, 372))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (347, 372))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('adverse alleles', 'Var', (28, 43))	('associations', 'Interaction', (128, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (363, 372))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('single-nucleotide polymorphisms', 'Var', (202, 233))	('esophageal adenocarcinoma', 'Disease', (347, 372))	('miRNA-related', 'Gene', (47, 60))	('esophageal-cancer', 'Disease', 'MESH:D004938', (308, 325))	('miRNA-related genes', 'Gene', (247, 266))	('patients', 'Species', '9606', (326, 334))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (149, 166))	('esophageal-cancer', 'Disease', (308, 325))
851932	19138993	The most notable finding was that the SNP rs6505162, which is located in the pre-mir423 region, was associated with a per-allele odds ratio of 0.64 (95% confidence interval [CI], 0.51-0.80; P for trend < 0.0001).	('rs6505162', 'Mutation', 'rs6505162', (42, 51))	('rs6505162', 'Var', (42, 51))	('mir423', 'Gene', '494335', (81, 87))	('mir423', 'Gene', (81, 87))
851933	19138993	A common haplotype of the GEMIN4 gene was associated with a significantly reduced risk of esophageal cancer (odds ratio = 0.65; 95% CI, 0.42-0.99).	('haplotype', 'Var', (9, 18))	('GEMIN4', 'Gene', (26, 32))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('GEMIN4', 'Gene', '50628', (26, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('reduced', 'NegReg', (74, 81))
851935	19138993	The present study provides the first evidence that miRNAs may affect esophageal cancer risk in general and that specific genetic variants in miRNA-related genes may affect esophageal cancer risk individually and jointly.	('affect', 'Reg', (165, 171))	('affect', 'Reg', (62, 68))	('miRNA-related genes', 'Gene', (141, 160))	('esophageal cancer', 'Disease', (172, 189))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (172, 189))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('variants', 'Var', (129, 137))
851948	19138993	We recently published the first study showing that single nucleotide polymorphisms (SNPs) in miRNA biogenesis genes and miRNA genes were associated with the risk of bladder cancer individually and jointly.	('single nucleotide polymorphisms', 'Var', (51, 82))	('associated with', 'Reg', (137, 152))	('miRNA genes', 'Gene', (120, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (165, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('bladder cancer', 'Disease', 'MESH:D001749', (165, 179))	('bladder cancer', 'Disease', (165, 179))	('miRNA biogenesis genes', 'Gene', (93, 115))
851949	19138993	In the current study, we hypothesized that these genetic variants might also modulate the risk of esophageal cancer.	('modulate', 'Reg', (77, 85))	('esophageal cancer', 'Disease', (98, 115))	('genetic variants', 'Var', (49, 65))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
851950	19138993	To test this hypothesis, we selected 41 potentially functional polymorphisms, including 24 SNPs in 11 miRNA processing genes, seven SNPs in seven pre-miRNAs genes along with 10 SNPs in eight pri-miRNAs genes, and evaluated their individual and joint associations with esophageal cancer in a case-control study.	('esophageal cancer', 'Disease', (268, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('SNPs', 'Var', (91, 95))	('polymorphisms', 'Var', (63, 76))	('miRNA processing genes', 'Gene', (102, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (268, 285))	('associations', 'Interaction', (250, 262))
851966	19138993	Among the 41 SNPs, two SNPs (rs10719 in DROSHA and rs17276588 in Let7f-2) showed significant departure from HWE and were excluded from further analyses (data not shown).	('rs17276588', 'Var', (51, 61))	('DROSHA', 'Gene', '29102', (40, 46))	('rs10719', 'Mutation', 'rs10719', (29, 36))	('DROSHA', 'Gene', (40, 46))	('rs17276588', 'Mutation', 'rs17276588', (51, 61))	('rs10719', 'Var', (29, 36))	('Let7f-2', 'Gene', '406889', (65, 72))	('Let7f-2', 'Gene', (65, 72))
851973	19138993	Among them, additive model was the best-fitting model for two SNPs (rs6505162 in mir423 and rs5745925 in mir631), dominant model was the best-fitting model for one SNP (rs213210 in mir219-1), and recessive model was the best-fitting model for four SNPs (rs11614913 in mir196a-2, rs14035 in RAN, rs531564 in mir124-1, and rs11077 in XPO5).	('RAN', 'Gene', '5901', (290, 293))	('rs14035', 'Mutation', 'rs14035', (279, 286))	('XPO5', 'Gene', (332, 336))	('mir124-1', 'Gene', '406907', (307, 315))	('mir423', 'Gene', '494335', (81, 87))	('mir219-1', 'Gene', (181, 189))	('rs11614913', 'Var', (254, 264))	('rs11077', 'Var', (321, 328))	('rs11614913', 'Mutation', 'rs11614913', (254, 264))	('RAN', 'Gene', (290, 293))	('rs531564', 'Mutation', 'rs531564', (295, 303))	('rs6505162', 'Mutation', 'rs6505162', (68, 77))	('mir219-1', 'Gene', '407002', (181, 189))	('mir196a-2', 'Gene', (268, 277))	('rs11077', 'Mutation', 'rs11077', (321, 328))	('XPO5', 'Gene', '57510', (332, 336))	('rs5745925', 'Mutation', 'rs5745925', (92, 101))	('rs14035', 'Var', (279, 286))	('rs6505162', 'Var', (68, 77))	('mir196a-2', 'Gene', '406973', (268, 277))	('rs531564', 'Var', (295, 303))	('mir423', 'Gene', (81, 87))	('rs213210', 'Mutation', 'rs213210', (169, 177))	('mir124-1', 'Gene', (307, 315))	('mir631', 'Gene', '693216', (105, 111))	('mir631', 'Gene', (105, 111))
851974	19138993	The most significant association was a SNP (rs6505162) in the pre-miRNA region of mir423 that showed a significantly reduced esophageal cancer risk in an additive genetic model (per-allele OR = 0.64, P for trend < 0.0001) (Table 2).	('reduced', 'NegReg', (117, 124))	('esophageal cancer', 'Disease', (125, 142))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('mir423', 'Gene', (82, 88))	('mir423', 'Gene', '494335', (82, 88))	('rs6505162', 'Mutation', 'rs6505162', (44, 53))	('rs6505162', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
851975	19138993	Compared with the homozygous wild-type genotype of rs6505162, individuals with the heterozygous and homozygous variant genotype had a significantly reduced esophageal cancer risk with an OR of 0.58 (95% CI, 0.41-0.82) and 0.43 (95% CI, 0.27-0.68), respectively (data not shown).	('variant', 'Var', (111, 118))	('rs6505162', 'Mutation', 'rs6505162', (51, 60))	('reduced', 'NegReg', (148, 155))	('rs6505162', 'Var', (51, 60))	('esophageal cancer', 'Disease', (156, 173))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
851976	19138993	The protective effect of mir423 rs6505162 remained significant among male (P for trend < 0.0001); for subjects <= 64 years old (P for trend < 0.001), but not for subjects > 64 years old; for both never smokers (P for trend = 0.001) and ever smokers (P for trend = 0.013) (Table 3).	('rs6505162', 'Var', (32, 41))	('mir423', 'Gene', '494335', (25, 31))	('mir423', 'Gene', (25, 31))	('rs6505162', 'Mutation', 'rs6505162', (32, 41))
851977	19138993	The protective effect of mir423 rs6505162 were over twice among subjects <= 64 years old than that among subjects > 64 years old.	('rs6505162', 'Var', (32, 41))	('mir423', 'Gene', '494335', (25, 31))	('mir423', 'Gene', (25, 31))	('rs6505162', 'Mutation', 'rs6505162', (32, 41))
851978	19138993	Mir196a-2 rs11614913 showed approximately twice the risk of esophageal cancer among never smokers than ever smokers (OR = 2.52 and P = 0.006 for never smokers, OR = 1.41 and P = 0.166 for ever smokers).	('Mir196a-2', 'Gene', (0, 9))	('rs11614913', 'Var', (10, 20))	('Mir196a-2', 'Gene', '406973', (0, 9))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs11614913', 'Mutation', 'rs11614913', (10, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
851979	19138993	The interactions between mir423 rs6505162 and age group were significant (P = 0.019), while the interactions between mir196a-2 rs11614913 and smoking did not reach statistical significance (P = 0.18).	('mir423', 'Gene', '494335', (25, 31))	('mir196a-2', 'Gene', (117, 126))	('mir196a-2', 'Gene', '406973', (117, 126))	('interactions', 'Interaction', (4, 16))	('rs6505162', 'Mutation', 'rs6505162', (32, 41))	('rs11614913', 'Mutation', 'rs11614913', (127, 137))	('rs6505162', 'Var', (32, 41))	('mir423', 'Gene', (25, 31))
851980	19138993	To further assess the cumulative effects of miRNA-related genetic variants on esophageal cancer risk, we performed an unfavorable genotype analysis using the eleven SNPs that showed at least a borderline significant association with esophageal cancer risk (P-value for best fitting model < 0.10).	('esophageal cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('esophageal cancer', 'Disease', 'MESH:D004938', (233, 250))	('variants', 'Var', (66, 74))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
851981	19138993	They were rs11077 (MM), rs14035 (MM), rs197414 (WW+WM), rs11614913 (MM), rs6505162 (WW), rs5745925 (WW+WM), rs7372209 (WW+WM), rs16827546 (WW+WM), rs531564 (MM), rs107822 (WW+WM), and rs213210 (WW+WM) (WW: homozygous wild-types, WM: heterozygotes, MM: homozygous variants).	('rs107822', 'Mutation', 'rs107822', (162, 170))	('rs197414', 'Mutation', 'rs197414', (38, 46))	('rs107822', 'Var', (162, 170))	('rs5745925', 'Mutation', 'rs5745925', (89, 98))	('rs14035', 'Mutation', 'rs14035', (24, 31))	('rs11614913', 'Var', (56, 66))	('rs5745925', 'Var', (89, 98))	('rs531564', 'Var', (147, 155))	('rs11614913', 'Mutation', 'rs11614913', (56, 66))	('rs6505162', 'Mutation', 'rs6505162', (73, 82))	('rs11077', 'Var', (10, 17))	('rs7372209', 'Var', (108, 117))	('rs6505162', 'Var', (73, 82))	('rs213210', 'Mutation', 'rs213210', (184, 192))	('rs14035', 'Var', (24, 31))	('rs16827546', 'Mutation', 'rs16827546', (127, 137))	('rs531564', 'Mutation', 'rs531564', (147, 155))	('rs16827546', 'Var', (127, 137))	('rs7372209', 'Mutation', 'rs7372209', (108, 117))	('rs11077', 'Mutation', 'rs11077', (10, 17))	('rs197414', 'Var', (38, 46))
851985	19138993	The only common haplotype showing significant association with esophageal cancer risk was a haplotype of the GEMIN4 gene (WWWWMWW, W: wild-type allele, M: variant allele), in the order of rs910924, rs2740348, rs7813, rs910925, rs3744741, rs1062923, and rs4968104.	('rs910925', 'Mutation', 'rs910925', (217, 225))	('rs910925', 'Var', (217, 225))	('rs4968104', 'Mutation', 'rs4968104', (253, 262))	('rs1062923', 'Mutation', 'rs1062923', (238, 247))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('GEMIN4', 'Gene', '50628', (109, 115))	('association', 'Reg', (46, 57))	('rs2740348', 'Mutation', 'rs2740348', (198, 207))	('rs3744741', 'Var', (227, 236))	('rs7813', 'Mutation', 'rs7813', (209, 215))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('rs3744741', 'Mutation', 'rs3744741', (227, 236))	('rs1062923', 'Var', (238, 247))	('esophageal cancer', 'Disease', (63, 80))	('rs4968104', 'Var', (253, 262))	('GEMIN4', 'Gene', (109, 115))	('rs7813', 'Var', (209, 215))	('rs910924', 'Mutation', 'rs910924', (188, 196))	('rs2740348', 'Var', (198, 207))	('rs910924', 'Var', (188, 196))
851988	19138993	The most notable finding was a SNP in the pre-mir423 region that was associated with reduced esophageal cancer risk and with a significant gene-dosage effect.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('mir423', 'Gene', (46, 52))	('mir423', 'Gene', '494335', (46, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('reduced', 'NegReg', (85, 92))	('SNP in', 'Var', (31, 37))
851989	19138993	We further demonstrated the haplotypic and cumulative effects of multiple genetic variants on risk prediction, highlighting the importance of using a pathway-based polygenic approach in genetic association studies of complex human diseases like cancer.	('variants', 'Var', (82, 90))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (245, 251))	('effects', 'Reg', (54, 61))	('human', 'Species', '9606', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
851990	19138993	The roles played by genetic variants of the miRNA-harboring regions in tumorigenesis have only been evaluated in a few studies with mixed results.	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('variants', 'Var', (28, 36))
851991	19138993	Consistent with the latter observation, we recently reported that genetic variants in both miRNA processing pathway genes and miRNA genes might affect bladder cancer susceptibility both individually and jointly.	('bladder cancer', 'Disease', (151, 165))	('miRNA processing pathway genes', 'Gene', (91, 121))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('miRNA genes', 'Gene', (126, 137))	('genetic variants', 'Var', (66, 82))	('affect', 'Reg', (144, 150))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))
851992	19138993	In the current study, we found that these variants were also associated with the development of esophageal cancer.	('associated with', 'Reg', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('variants', 'Var', (42, 50))	('esophageal cancer', 'Disease', (96, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))
851997	19138993	Nonetheless, it remained to be determined whether the genetic variants identified in our studies modulate esophageal cancer risk through their influences on the functions or expressions of their host genes with further functional assessment through in vitro and in vivo experiments.	('modulate', 'Reg', (97, 105))	('expressions', 'MPA', (174, 185))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('influences', 'Reg', (143, 153))	('variants', 'Var', (62, 70))	('esophageal cancer', 'Disease', (106, 123))	('functions', 'MPA', (161, 170))
851999	19138993	The polymorphism in the pre-mir423 remained significant after adjusting for multiple comparisons at FDR 5% level, suggesting that this result was unlikely due to chance.	('mir423', 'Gene', (28, 34))	('polymorphism', 'Var', (4, 16))	('mir423', 'Gene', '494335', (28, 34))
852004	19138993	A polymorphism in the pre-mir196a-2 gene was associated with a 1.7-fold increased risk in our study.	('polymorphism', 'Var', (2, 14))	('mir196a-2', 'Gene', (26, 35))	('mir196a-2', 'Gene', '406973', (26, 35))
852006	19138993	We also found a polymorphism in the pre-mir631 gene that was associated with a significantly increased esophageal cancer risk.	('esophageal cancer', 'Disease', (103, 120))	('polymorphism', 'Var', (16, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mir631', 'Gene', (40, 46))	('associated', 'Reg', (61, 71))	('mir631', 'Gene', '693216', (40, 46))
852009	19138993	In this study, we also found two significant SNPs in the miRNA processing pathway genes that were associated with an increased esophageal cancer risk (one in XPO5 and the other in RAN).	('esophageal cancer', 'Disease', (127, 144))	('RAN', 'Gene', (180, 183))	('RAN', 'Gene', '5901', (180, 183))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('SNPs', 'Var', (45, 49))	('miRNA processing pathway', 'Pathway', (57, 81))	('XPO5', 'Gene', (158, 162))	('XPO5', 'Gene', '57510', (158, 162))	('associated', 'Reg', (98, 108))
852012	19138993	Knocking down XPO5 expression using RNA interference led to decreased miRNA levels.	('decreased', 'NegReg', (60, 69))	('Knocking down', 'Var', (0, 13))	('miRNA levels', 'MPA', (70, 82))	('XPO5', 'Gene', (14, 18))	('XPO5', 'Gene', '57510', (14, 18))
852020	19138993	HOXA7 and HOXC8 have been demonstrated in vitro as the targets of mir196.	('mir196', 'Var', (66, 72))	('HOXC8', 'Gene', '3224', (10, 15))	('HOXC8', 'Gene', (10, 15))	('HOXA7', 'Gene', (0, 5))	('HOXA7', 'Gene', '3204', (0, 5))
852021	19138993	2005 showed that the expression levels of HOXC7 and HOXA8 were associated with esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('expression levels', 'MPA', (21, 38))	('associated', 'Reg', (63, 73))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('HOXA8', 'Gene', (52, 57))	('HOXC7', 'Var', (42, 47))	('HOXC7', 'CellLine', 'CVCL:J486', (42, 47))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))
852028	19138993	These findings highlighted the importance of taking a multigenic approach in pathway-based association studies to identify signatures of genetic variations as predictors of cancer risk.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('variations', 'Var', (145, 155))
852031	19138993	The only difference between this haplotype and the most common GEMIN4 haplotype (that contained the wild-type allele in all the SNPs) was that this haplotype contained the variant allele of rs3744741.	('rs3744741', 'Var', (190, 199))	('GEMIN4', 'Gene', (63, 69))	('rs3744741', 'Mutation', 'rs3744741', (190, 199))	('GEMIN4', 'Gene', '50628', (63, 69))
852032	19138993	Since rs3744741 did not show a significant finding in the single SNP analysis, there may be potential interaction effects between the several GEMIN4 SNPs in the modulation of esophageal cancer risk.	('esophageal cancer', 'Disease', (175, 192))	('GEMIN4', 'Gene', (142, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('rs3744741', 'Var', (6, 15))	('GEMIN4', 'Gene', '50628', (142, 148))	('rs3744741', 'Mutation', 'rs3744741', (6, 15))	('interaction', 'Interaction', (102, 113))
852035	19138993	The rs3744741 SNP is an nsSNP that leads to an Arg to Gln amino acid change in the exon 2 of GEMIN4.	('GEMIN4', 'Gene', (93, 99))	('nsSNP', 'Chemical', '-', (24, 29))	('Arg to Gln amino acid change', 'MPA', (47, 75))	('rs3744741', 'Mutation', 'rs3744741', (4, 13))	('Gln amino acid', 'Chemical', '-', (54, 68))	('GEMIN4', 'Gene', '50628', (93, 99))	('rs3744741 SNP', 'Var', (4, 17))	('Arg', 'Chemical', 'MESH:D001120', (47, 50))
852038	19138993	Our results suggest that certain polymorphisms in miRNA-related genes may impact the etiology of esophageal cancer individually, interactively, and jointly.	('polymorphisms', 'Var', (33, 46))	('impact', 'Reg', (74, 80))	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('miRNA-related genes', 'Gene', (50, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('etiology', 'MPA', (85, 93))
852040	33819921	Stromal tumor infiltrating lymphocytes (sTIL) and certain single nucleotide polymorphisms (SNPs) have been found to be predictive of patient survival.	('single nucleotide polymorphisms', 'Var', (58, 89))	('patient', 'Species', '9606', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('Stromal tumor', 'Disease', (0, 13))	('Stromal tumor', 'Disease', 'MESH:D036821', (0, 13))
852045	33819921	A multivariable analysis revealed that sTIL, rs1801131, rs25487, and rs8030672 were independent prognostic markers for ESCC patients.	('rs8030672', 'Var', (69, 78))	('ESCC', 'Disease', (119, 123))	('rs1801131', 'Mutation', 'rs1801131', (45, 54))	('rs25487', 'Var', (56, 63))	('rs1801131', 'Var', (45, 54))	('rs25487', 'Mutation', 'rs25487', (56, 63))	('patients', 'Species', '9606', (124, 132))	('rs8030672', 'Mutation', 'rs8030672', (69, 78))
852058	33819921	Both the risk of developing ESCC and patient prognosis may be influenced by genetic variations, (e.g., polymorphisms), which are involved in many cellular pathways, including cell proliferation, DNA repair, apoptosis, and the immune response.	('involved', 'Reg', (129, 137))	('patient', 'Species', '9606', (37, 44))	('polymorphisms', 'Var', (103, 116))	('influenced', 'Reg', (62, 72))	('ESCC', 'Disease', (28, 32))
852068	33819921	Patients with rs1799930 genotype A/A had the highest percentage of sTIL among all the SNPs.	('rs1799930', 'Mutation', 'rs1799930', (14, 23))	('sTIL', 'Disease', (67, 71))	('rs1799930 genotype', 'Var', (14, 32))	('Patients', 'Species', '9606', (0, 8))
852069	33819921	The percentage of sTIL in patients with the rs1800682 genotype T/C was significantly higher than that of patients carrying the genotypes T/T and C/C (P < 0.01).	('patients', 'Species', '9606', (105, 113))	('rs1800682', 'Mutation', 'rs1800682', (44, 53))	('higher', 'PosReg', (85, 91))	('sTIL', 'Disease', (18, 22))	('patients', 'Species', '9606', (26, 34))	('rs1800682', 'Var', (44, 53))
852070	33819921	The rs2234767 genotype G/A was significantly higher than that of patients carrying A/A.	('higher', 'PosReg', (45, 51))	('patients', 'Species', '9606', (65, 73))	('rs2234767', 'Mutation', 'rs2234767', (4, 13))	('rs2234767', 'Var', (4, 13))
852071	33819921	Similarly, for the rs1312200, rs2051428 and rs3762894 polymorphisms, heterozygous patients had a higher percentage of sTIL than the homozygous patients (Supplementary Figure 1).	('higher', 'PosReg', (97, 103))	('rs1312200', 'Mutation', 'rs1312200', (19, 28))	('rs3762894', 'Var', (44, 53))	('patients', 'Species', '9606', (82, 90))	('sTIL', 'Disease', (118, 122))	('rs2051428', 'Var', (30, 39))	('rs3762894', 'Mutation', 'rs3762894', (44, 53))	('patients', 'Species', '9606', (143, 151))	('rs2051428', 'Mutation', 'rs2051428', (30, 39))	('rs1312200', 'Var', (19, 28))
852075	33819921	Patients with rs1801131 C/C had a higher risk of death than those with A/A (Adjusted HR (aHR) = 1.869; 95% CI = 1.183 - 2.954; P = 0.007) and the results changed little after adjusting for staging information (aHR = 1.947; 95% CI = 1.098 - 3.453; P = 0.023) (Supplementary Table 2).	('rs1801131 C/C', 'Var', (14, 27))	('rs1801131', 'Mutation', 'rs1801131', (14, 23))	('Patients', 'Species', '9606', (0, 8))	('death', 'Disease', 'MESH:D003643', (49, 54))	('death', 'Disease', (49, 54))
852076	33819921	Patients with the rs8030672 T/T genotype had a higher risk of death than those carrying the T/A genotype (aHR = 1.545; 95% CI = 1.045 - 2.284, P = 0.029).	('death', 'Disease', 'MESH:D003643', (62, 67))	('Patients', 'Species', '9606', (0, 8))	('rs8030672 T/T', 'Var', (18, 31))	('death', 'Disease', (62, 67))	('rs8030672', 'Mutation', 'rs8030672', (18, 27))
852077	33819921	Patients carrying the rs25487 G/G genotype exhibited better survival compared with the A/A genotype (aHR = 0.619; 95% CI = 0.424 - 0.906; P = 0.014).	('survival', 'CPA', (60, 68))	('rs25487', 'Mutation', 'rs25487', (22, 29))	('rs25487 G/G', 'Var', (22, 33))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (53, 59))
852078	33819921	The percentage of sTIL among the rs994771, rs2234767, and rs1800682 genotypes also significantly differed (Table 3), however, this significance was lost after adjusting for sTIL, age, gender, grade of differentiation, first-line treatment method, and BMI.	('rs2234767', 'Mutation', 'rs2234767', (43, 52))	('rs2234767', 'Var', (43, 52))	('sTIL', 'Disease', (18, 22))	('rs994771', 'Var', (33, 41))	('rs1800682', 'Mutation', 'rs1800682', (58, 67))	('differed', 'Reg', (97, 105))	('rs994771', 'Mutation', 'rs994771', (33, 41))	('rs1800682', 'Var', (58, 67))
852079	33819921	We further combined the FAS/ACTA2 rs2234767 A/A+G/G and rs1800682 C/C+T/C genotypes, which exhibited a similar prognostic risk.	('ACTA2', 'Gene', '59', (28, 33))	('rs2234767', 'Mutation', 'rs2234767', (34, 43))	('C+T', 'Disease', (68, 71))	('C+T', 'Disease', 'MESH:C537418', (68, 71))	('rs1800682', 'Mutation', 'rs1800682', (56, 65))	('rs2234767 A/A+G/G', 'Var', (34, 51))	('ACTA2', 'Gene', (28, 33))
852080	33819921	For DFS, patients with the rs2234767 G/A and rs1800682 C/C+T/C genotypes had a decreased risk of disease progression, compared with those carrying the rs2234767 A/A+G/G (P < 0.001) and rs1800682 T/T genotypes (P = 0.012) (Figure 1).	('patients', 'Species', '9606', (9, 17))	('decreased', 'NegReg', (79, 88))	('disease progression', 'CPA', (97, 116))	('rs1800682', 'Mutation', 'rs1800682', (185, 194))	('rs2234767 G/A', 'Var', (27, 40))	('C+T', 'Disease', 'MESH:C537418', (57, 60))	('rs2234767', 'Mutation', 'rs2234767', (151, 160))	('rs1800682', 'Mutation', 'rs1800682', (45, 54))	('rs2234767', 'Mutation', 'rs2234767', (27, 36))	('C+T', 'Disease', (57, 60))
852084	33819921	Notably, SNP rs2234767 and rs1800682 on gene FAS/ACTA2 were found to be significantly associated with both the percentage of sTIL and patient prognosis.	('ACTA2', 'Gene', '59', (49, 54))	('sTIL', 'Disease', (125, 129))	('SNP rs2234767', 'Var', (9, 22))	('associated', 'Reg', (86, 96))	('rs2234767', 'Mutation', 'rs2234767', (13, 22))	('rs1800682', 'Mutation', 'rs1800682', (27, 36))	('rs1800682', 'Var', (27, 36))	('patient', 'Species', '9606', (134, 141))	('ACTA2', 'Gene', (49, 54))
852087	33819921	found that the FAS rs1800682 T/C polymorphism may affect the survival of early NSCLC, and that the survival rate of patients with the C/C genotypes was significantly lower than those with the T/T genotype.	('rs1800682', 'Mutation', 'rs1800682', (19, 28))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('patients', 'Species', '9606', (116, 124))	('FAS rs1800682', 'Gene', (15, 28))	('affect', 'Reg', (50, 56))	('survival', 'MPA', (61, 69))	('C/C', 'Var', (134, 137))	('lower', 'NegReg', (166, 171))	('survival', 'MPA', (99, 107))	('NSCLC', 'Disease', (79, 84))
852089	33819921	found a significant association between the FAS rs2234767 G/A genotype (P = 0.040; HR = 0.451; CI = 0.496 - 1.188) with DFS in the univariate Cox regression and a similar case was reported in China.	('rs2234767 G/A', 'Var', (48, 61))	('FAS', 'Gene', (44, 47))	('rs2234767', 'Mutation', 'rs2234767', (48, 57))	('DFS', 'Disease', (120, 123))
852090	33819921	showed that FAS rs2234767 G/A were found to be associated with a decreased risk of cancer.	('rs2234767', 'Mutation', 'rs2234767', (16, 25))	('decreased', 'NegReg', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('rs2234767 G/A', 'Var', (16, 29))	('cancer', 'Disease', (83, 89))
852091	33819921	More importantly, we are the first to show that rs1800682 and rs2234767 were also associated with the percentage of sTIL in ESCC.	('associated', 'Reg', (82, 92))	('rs1800682', 'Mutation', 'rs1800682', (48, 57))	('rs2234767', 'Mutation', 'rs2234767', (62, 71))	('sTIL', 'Disease', (116, 120))	('rs1800682', 'Var', (48, 57))	('rs2234767', 'Var', (62, 71))	('ESCC', 'Disease', (124, 128))
852092	33819921	Rs2234767 and rs1800682 are only significantly associated with patient survival in univariable analyses, whereas the multi-variable analysis was not significant after adjusting for sTIL, age, sex, first-line treatment method, and BMI.	('Rs2234767', 'Var', (0, 9))	('patient survival', 'CPA', (63, 79))	('rs1800682', 'Mutation', 'rs1800682', (14, 23))	('Rs2234767', 'Mutation', 'Rs2234767', (0, 9))	('patient', 'Species', '9606', (63, 70))	('rs1800682', 'Var', (14, 23))	('associated', 'Reg', (47, 57))
852093	33819921	This implies that the two SNPs are potential confounders or the genetic variation of the gene FAS affect patient survival via sTIL.	('patient', 'Species', '9606', (105, 112))	('FAS', 'Gene', (94, 97))	('sTIL', 'MPA', (126, 130))	('genetic variation', 'Var', (64, 81))	('patient survival', 'CPA', (105, 121))	('affect', 'Reg', (98, 104))
852096	33819921	It has been found that SNPs in the promoter regions of the FAS and FASL genes are associated with the differential expression of these two genes.	('associated', 'Reg', (82, 92))	('FASL', 'Gene', (67, 71))	('SNPs', 'Var', (23, 27))	('expression', 'MPA', (115, 125))	('FASL', 'Gene', '356', (67, 71))	('FAS', 'Gene', (59, 62))
852097	33819921	The FAS rs2234767 and rs1800682 polymorphisms have been shown to reduce promoter activity and downregulate FAS gene expression by disrupting the SP1 and STAT1 transcription factor binding sites.	('promoter activity', 'MPA', (72, 89))	('downregulate', 'NegReg', (94, 106))	('expression', 'MPA', (116, 126))	('rs2234767', 'Var', (8, 17))	('rs1800682', 'Mutation', 'rs1800682', (22, 31))	('disrupting', 'NegReg', (130, 140))	('FAS gene', 'Gene', (107, 115))	('rs1800682', 'Var', (22, 31))	('STAT1', 'Gene', (153, 158))	('reduce', 'NegReg', (65, 71))	('SP1', 'MPA', (145, 148))	('STAT1', 'Gene', '6772', (153, 158))	('rs2234767', 'Mutation', 'rs2234767', (8, 17))	('FAS', 'Gene', (4, 7))
852098	33819921	In addition, these SNPs have been reported to be involved in the development of esophageal cancer, lung cancer, and breast cancer, for which apoptosis plays a key pathogenic role.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('SNPs', 'Var', (19, 23))	('lung cancer', 'Disease', (99, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (80, 97))	('involved', 'Reg', (49, 57))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
852100	33819921	It is possible that individuals carrying genotype T/T of rs8030672 in gene ANP32A may be more susceptible to alterations in the state of gene modifications or DNA damage related to autoimmune regulation, when stimulated by certain carcinogen exposures such as acetaldehyde and nicotine.	('ANP32A', 'Gene', (75, 81))	('acetaldehyde', 'Chemical', 'MESH:D000079', (260, 272))	('rs8030672', 'Mutation', 'rs8030672', (57, 66))	('nicotine', 'Chemical', 'MESH:D009538', (277, 285))	('rs8030672', 'Var', (57, 66))	('ANP32A', 'Gene', '8125', (75, 81))	('susceptible', 'Reg', (94, 105))
852127	31700061	The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (59, 64))	('ESCC', 'Disease', (116, 120))	('patients', 'Species', '9606', (102, 110))	('PDC', 'Gene', (26, 29))	('PDC', 'Gene', '5132', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
852128	31700061	Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening.	('PDC', 'Gene', (56, 59))	('mutations', 'Var', (15, 24))	('PDC', 'Gene', '5132', (56, 59))
852130	31700061	Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.	('patient', 'Species', '9606', (14, 21))	('ESCC', 'Gene', (117, 121))	('mutations', 'Var', (104, 113))	('drug sensitivity', 'Phenotype', 'HP:0020174', (60, 76))
852134	31700061	Many known agents associated with driven gene mutations were re-confirmed such as gefitinib and the EGFR (epidermal growth factor receptor) mutation, and some relationships, which have not been reported before, were also discovered.	('EGFR', 'Gene', '1956', (100, 104))	('mutations', 'Var', (46, 55))	('EGFR', 'Gene', (100, 104))	('mutation', 'Var', (140, 148))	('epidermal growth factor receptor', 'Gene', '1956', (106, 138))	('gefitinib', 'Chemical', 'MESH:C419708', (82, 91))	('epidermal growth factor receptor', 'Gene', (106, 138))
852136	31700061	Commercial cell lines are limited and might lose their original tumor characteristics due to repeated passaging, which results in genetic variation and divergence from the original tumor.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (181, 186))	('lose', 'NegReg', (44, 48))	('results in', 'Reg', (119, 129))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('genetic variation', 'Var', (130, 147))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
852146	31700061	Although uncovering of the genomic landscape and functional study of these mutant cancer genes have deepened our understanding of the mechanism of ESCC occurrence and development, further exploration and validation of these genes as potential therapeutic biomarkers of drug sensitivity for ESCC are largely lacking.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ESCC', 'Disease', (147, 151))	('mutant', 'Var', (75, 81))	('drug sensitivity', 'Phenotype', 'HP:0020174', (269, 285))
852147	31700061	In this study, only targeted deep sequencing focused on tumor-related genes was an effective approach to identifying genomic variants associated with cancer tumorigenesis in a large cohort of ESCC and their PDCs.	('tumor', 'Disease', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PDC', 'Gene', (207, 210))	('tumor', 'Disease', (56, 61))	('ESCC', 'Disease', (192, 196))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('variants', 'Var', (125, 133))	('cancer', 'Disease', (150, 156))	('PDC', 'Gene', '5132', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
852156	31700061	Among all genes with copy number alterations, CCND1 (42%), MCL1 (38%), FGF4 (35%), FGF3 (35%), SOX2 (34%), FGF19 (34%), and CDKN1B (30%) were frequently amplified, while MST1R (30%), CDKN2A (26%), and CDKN2B (13%) were recurrently deleted (Fig.	('FGF4', 'Gene', (71, 75))	('FGF3', 'Gene', '2248', (83, 87))	('CDKN1B', 'Gene', (124, 130))	('MCL1', 'Gene', (59, 63))	('MCL1', 'Gene', '4170', (59, 63))	('FGF19', 'Gene', '9965', (107, 112))	('CCND1', 'Gene', '595', (46, 51))	('FGF4', 'Gene', '2249', (71, 75))	('FGF19', 'Gene', (107, 112))	('CDKN2A', 'Gene', (183, 189))	('CCND1', 'Gene', (46, 51))	('CDKN1B', 'Gene', '1027', (124, 130))	('amplified', 'PosReg', (153, 162))	('SOX2', 'Gene', (95, 99))	('MST1R', 'Gene', '4486', (170, 175))	('SOX2', 'Gene', '6657', (95, 99))	('CDKN2B', 'Gene', (201, 207))	('copy number alterations', 'Var', (21, 44))	('MST1R', 'Gene', (170, 175))	('FGF3', 'Gene', (83, 87))
852158	31700061	We found that PIK3CA amplification and JUN neutral were significantly associated with poorer disease-free survival (DFS, p = 0.036 and 0.043, log-rank test) and OS (OS, p = 0.023 and 0.018, log-rank test) (Supplementary Fig.	('JUN neutral', 'MPA', (39, 50))	('PIK3CA', 'Gene', '5290', (14, 20))	('Su', 'Chemical', 'MESH:C035067', (206, 208))	('poorer', 'NegReg', (86, 92))	('disease-free survival', 'CPA', (93, 114))	('PIK3CA', 'Gene', (14, 20))	('amplification', 'Var', (21, 34))
852160	31700061	ESCC patients with NOTCH2 mutations had a significantly shortened OS in comparison to those without NOTCH2 mutations (p = 0.034, log-rank test, Supplementary Fig.	('NOTCH2', 'Gene', '4853', (19, 25))	('patients', 'Species', '9606', (5, 13))	('Su', 'Chemical', 'MESH:C035067', (144, 146))	('NOTCH2', 'Gene', (100, 106))	('shortened', 'NegReg', (56, 65))	('mutations', 'Var', (26, 35))	('ESCC', 'Disease', (0, 4))	('NOTCH2', 'Gene', (19, 25))	('NOTCH2', 'Gene', '4853', (100, 106))
852161	31700061	In addition, we found that ACVR2A amplification was associated with poorer DFS (p = 0.038, log-rank test, Supplementary Fig.	('poorer', 'NegReg', (68, 74))	('ACVR2A', 'Gene', '92', (27, 33))	('Su', 'Chemical', 'MESH:C035067', (106, 108))	('amplification', 'Var', (34, 47))	('ACVR2A', 'Gene', (27, 33))	('DFS', 'MPA', (75, 78))
852164	31700061	We succeeded in deriving eight ESCC PDCs (ZEC043, ZEC056, ZEC061, ZEC118, ZEC127, ZEC145, ZEC157, and ZEC166) from the 123 ESCC patient tissues available, with a 6.5% success rate of establishing ESCC PDCs (Supplementary Data 6).	('PDC', 'Gene', (201, 204))	('ZEC043', 'Var', (42, 48))	('PDC', 'Gene', (36, 39))	('ZEC061', 'Var', (58, 64))	('ZEC056', 'Var', (50, 56))	('ZEC118', 'Var', (66, 72))	('PDC', 'Gene', '5132', (201, 204))	('ZEC145', 'Var', (82, 88))	('PDC', 'Gene', '5132', (36, 39))	('ZEC127', 'Chemical', 'MESH:C078661', (74, 80))	('patient', 'Species', '9606', (128, 135))	('Su', 'Chemical', 'MESH:C035067', (207, 209))	('ZEC166', 'Var', (102, 108))	('ZEC157', 'Var', (90, 96))	('ZEC127', 'Var', (74, 80))
852173	31700061	For example, the eight PDCs harbored the single-nucleotide variant (SNV)/indel overlapping genes found in the 161 ESCC patients (recurrence >=5%), including AR, ARID1A, CDKN2A, EP300, KMT2D, LRP1B, NF1, NOTCH1, SPTA1, and TP53 (Supplementary Fig.	('KMT2D', 'Gene', (184, 189))	('PDC', 'Gene', (23, 26))	('single-nucleotide', 'Var', (41, 58))	('NF1', 'Gene', '4763', (198, 201))	('SPTA1', 'Gene', '6708', (211, 216))	('NF1', 'Gene', (198, 201))	('ARID1A', 'Gene', (161, 167))	('LRP1B', 'Gene', '53353', (191, 196))	('NOTCH1', 'Gene', (203, 209))	('TP53', 'Gene', '7157', (222, 226))	('SPTA1', 'Gene', (211, 216))	('Su', 'Chemical', 'MESH:C035067', (228, 230))	('EP300', 'Gene', '2033', (177, 182))	('KMT2D', 'Gene', '8085', (184, 189))	('ESCC', 'Disease', (114, 118))	('ARID1A', 'Gene', '8289', (161, 167))	('NOTCH1', 'Gene', '4851', (203, 209))	('PDC', 'Gene', '5132', (23, 26))	('EP300', 'Gene', (177, 182))	('patients', 'Species', '9606', (119, 127))	('TP53', 'Gene', (222, 226))	('LRP1B', 'Gene', (191, 196))
852178	31700061	To study the associations between the mutated genes and drug sensitivity across the ESCC PDCs, we used an analysis incorporating the ratio and significance of IC50s between mutated PDCs and non-mutated ones.	('50s', 'Species', '1214577', (161, 164))	('drug sensitivity', 'Phenotype', 'HP:0020174', (56, 72))	('PDC', 'Gene', '5132', (181, 184))	('mutated', 'Var', (173, 180))	('PDC', 'Gene', (89, 92))	('PDC', 'Gene', (181, 184))	('PDC', 'Gene', '5132', (89, 92))
852183	31700061	To further validate potential CDK4/6 inhibitor sensitivity conferred by CNVs of CDKN2A and CDKN2B, two CDK4/6 inhibitors, palbociclib (PD-0332991) and ribociclib (LEE011), approved for clinical breast cancer use, were used to perform an analysis on the sensitivity of eight PDCs.	('clinical', 'Species', '191496', (185, 193))	('breast cancer', 'Disease', (194, 207))	('CNVs', 'Var', (72, 76))	('PDC', 'Gene', (274, 277))	('CDKN2B', 'Gene', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PDC', 'Gene', '5132', (274, 277))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('PD-0332991', 'Chemical', 'MESH:C500026', (135, 145))	('CDKN2A', 'Gene', (80, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
852185	31700061	Due to intratumoral heterogeneity of tumor tissue and clonal enrichment of PDCs, some PDCs were not completely concordant with corresponding tumor tissue in detecting the CNVs of CDKN2A and CDKN2B (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (12, 17))	('CDKN2B', 'Gene', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('PDC', 'Gene', '5132', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('PDC', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('PDC', 'Gene', '5132', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CNVs', 'Var', (171, 175))	('CDKN2A', 'Gene', (179, 185))	('PDC', 'Gene', (86, 89))
852195	31700061	The data suggest that the potential biomarker of CDK4/6 inhibitors could be validated in ESCC PDCs rather than commercial cell lines.	('PDC', 'Gene', (94, 97))	('PDC', 'Gene', '5132', (94, 97))	('inhibitors', 'Var', (56, 66))	('CDK4/6', 'Protein', (49, 55))
852199	31700061	In addition, the result of ZEC166 (CDKN2A/2B wild-type) was a similar trend to the result of ZEC118 (Supplementary Fig.	('Su', 'Chemical', 'MESH:C035067', (101, 103))	('CDKN2A/2B', 'Gene', '1029', (35, 44))	('ZEC166', 'Var', (27, 33))	('CDKN2A/2B', 'Gene', (35, 44))
852204	31700061	Interestingly, the expression levels of TP53 non-synonymous mutations and CHEK1 loss were significantly different between the mutated group and the non-mutated group (p = 0.0002 and p = 0.0399, Wilcoxon's test) (Supplementary Data 17).	('loss', 'NegReg', (80, 84))	('Su', 'Chemical', 'MESH:C035067', (212, 214))	('different', 'Reg', (104, 113))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('CHEK1', 'Gene', '1111', (74, 79))	('expression levels', 'MPA', (19, 36))	('CHEK1', 'Gene', (74, 79))	('mutated', 'Var', (126, 133))
852215	31700061	However, in PDCX-ZEC166 models with wild-type CDKN2A and CDKN2B, the tumors still progressed in both palbociclib treatment groups (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CDKN2A', 'Gene', (46, 52))	('CDKN2B', 'Var', (57, 63))	('progressed', 'PosReg', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('PDCX-ZEC166', 'Chemical', 'MESH:C055293', (12, 23))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))
852228	31700061	In addition, using targeted deep sequencing, we confirmed that the PDX-Z16062301 model had CDKN2A and CDKN2B loss.	('CDKN2A', 'Gene', (91, 97))	('PDX-Z16062301', 'Var', (67, 80))	('loss', 'NegReg', (109, 113))	('CDKN2B', 'Gene', (102, 108))	('PDX-Z16062301', 'Chemical', 'MESH:C113421', (67, 80))
852240	31700061	For example, V600E BRAF melanoma but not colorectal cancers were sensitive to BRAF-targeting vemurafenib.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('V600E', 'Var', (13, 18))	('BRAF', 'Gene', '673', (19, 23))	('BRAF melanoma', 'Disease', 'MESH:D008545', (19, 32))	('BRAF', 'Gene', '673', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('colorectal cancers', 'Disease', 'MESH:D015179', (41, 59))	('BRAF melanoma', 'Disease', (19, 32))	('BRAF', 'Gene', (19, 23))	('BRAF', 'Gene', (78, 82))	('vemurafenib', 'Chemical', 'MESH:C551177', (93, 104))	('colorectal cancers', 'Disease', (41, 59))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('V600E', 'Mutation', 'p.V600E', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
852241	31700061	showed that KRAS mutations correlate significantly with sensitivity to navitoclax among colorectal cancer cell lines (CCLs), but not among all CCLs.	('colorectal cancer', 'Disease', (88, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('KRAS', 'Gene', (12, 16))	('KRAS', 'Gene', '3845', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('sensitivity to navitoclax', 'MPA', (56, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('mutations', 'Var', (17, 26))
852258	31700061	Our discovery of MM-102-KMT2D mutation associations may fill this gap and shed light on MLL1 inhibitor as a promising epigenetic treatment for ESCC patients.	('patients', 'Species', '9606', (148, 156))	('mutation', 'Var', (30, 38))	('ESCC', 'Disease', (143, 147))	('MLL1', 'Gene', (88, 92))	('KMT2D', 'Gene', '8085', (24, 29))	('associations', 'Interaction', (39, 51))	('KMT2D', 'Gene', (24, 29))	('MLL1', 'Gene', '4297', (88, 92))
852281	31700061	Variant calls meeting the following criteria were advanced to further analysis: (1) the minimum coverage in tumors is 30; (2) the maximum mutation frequency in normal samples is <=0.03; (3) the minimum mutation frequency difference between normal and tumor is >=0.05; (4) the maximum strand bias is <=0.9; and (5) the minimum support reads of mutation is >=5.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (251, 256))	('mutation', 'Var', (343, 351))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
852289	31700061	Nineteen STR loci (TH01, D12S391, D7S820, CSF1PO, FGA, D5S818, D2S1338, D21S11, D18S51, TPOX, vWA, D8S1179, D3S1358, D13S317, D6S1043, D16S539, Penta E, D19S433, and Penta D) and amelogenin were amplified by PCR and analyzed using an Applied Biosystems 3730xl DNA Analyzer (Applied Biosystems Inc., Foster City, CA, USA).	('D2S1338', 'Var', (63, 70))	('D3S1358', 'Var', (108, 115))	('D6S1043', 'Var', (126, 133))	('FGA', 'Gene', (50, 53))	('D19S433', 'Var', (153, 160))	('D16S539', 'Var', (135, 142))	('D13S317', 'Chemical', 'MESH:C000597538', (117, 124))	('D7S820', 'Var', (34, 40))	('D12S391', 'Var', (25, 32))	('D21S11', 'Var', (72, 78))	('D18S51', 'Var', (80, 86))	('D5S818', 'Var', (55, 61))	('FGA', 'Gene', '2243', (50, 53))	('D13S317', 'Var', (117, 124))	('D8S1179', 'Var', (99, 106))
852378	31461487	Hospitalization days (ALOS) at the ICU were also higher in the EVT group (on average 7.69, median: 8) than in the SEMS group (on average 4.66, median: 3) (p = 0.164).	('EVT', 'Var', (63, 66))	('EVT', 'Chemical', '-', (63, 66))	('ALOS', 'Chemical', '-', (22, 26))	('Hospitalization days', 'MPA', (0, 20))	('higher', 'PosReg', (49, 55))
852402	31461487	In the current G-DRG system two codes exist: G35Z (`complex vacuum treatment for diseases and disorders of the digestive system; cost-weight: 11.518) or I98Z (`complex vacuum treatment for diseases and disorders at musculoskeletal system and connective tissue`; cost-weight: 7.816).	('disorders of the digestive system', 'Phenotype', 'HP:0025031', (94, 127))	('G35Z', 'Var', (45, 49))	('diseases and disorders at musculoskeletal system', 'Disease', 'MESH:D009140', (189, 237))	('I98Z', 'Var', (153, 157))
852413	30569129	MicroRNA-206 exerts anti-oncogenic functions in esophageal squamous cell carcinoma by suppressing the c-Met/AKT/mTOR pathway Increasing evidence suggests that the dysregulation of microRNAs (miRNAs) has an important role in the progression of human cancer, including ESCC.	('human', 'Species', '9606', (243, 248))	('ESCC', 'Disease', (267, 271))	('cancer', 'Disease', (249, 255))	('dysregulation', 'Var', (163, 176))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('AKT', 'Gene', (108, 111))	('esophageal squamous cell carcinoma', 'Disease', (48, 82))	('MicroRNA-206', 'Gene', '406989', (0, 12))	('mTOR', 'Gene', (112, 116))	('miR', 'Gene', '220972', (191, 194))	('c-Met', 'Gene', '4233', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('mTOR', 'Gene', '2475', (112, 116))	('MicroRNA-206', 'Gene', (0, 12))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('AKT', 'Gene', '207', (108, 111))	('miR', 'Gene', (191, 194))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (48, 82))	('suppressing', 'NegReg', (86, 97))	('c-Met', 'Gene', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
852418	30569129	CCK-8 and flow cytometry assays demonstrated that ectopic miR-206 expression inhibited ESCC cell proliferation and induced cell apoptosis.	('miR-206', 'Gene', (58, 65))	('ectopic', 'Var', (50, 57))	('inhibited', 'NegReg', (77, 86))	('miR-206', 'Gene', '406989', (58, 65))	('cell apoptosis', 'CPA', (123, 137))	('ESCC', 'Disease', (87, 91))	('induced', 'Reg', (115, 122))
852507	30569129	The expression of c-Met at the protein level was significantly downregulated following overexpression of miR-206, whereas it was upregulated following knockdown of miR-206 in Eca109 and KYSE410 ESCC cells (Fig.	('c-Met', 'Gene', (18, 23))	('c-Met', 'Gene', '4233', (18, 23))	('miR-206', 'Gene', (164, 171))	('upregulated', 'PosReg', (129, 140))	('miR-206', 'Gene', '406989', (105, 112))	('expression', 'MPA', (4, 14))	('miR-206', 'Gene', '406989', (164, 171))	('downregulated', 'NegReg', (63, 76))	('KYSE410', 'CellLine', 'CVCL:1352', (186, 193))	('overexpression', 'PosReg', (87, 101))	('miR-206', 'Gene', (105, 112))	('knockdown', 'Var', (151, 160))
852541	30569129	Another study from Liu et al reported that using LY294002, a PI3K specific inhibitor, significantly inhibits ESCC cell proliferation and migration.	('LY294002', 'Chemical', 'MESH:C085911', (49, 57))	('LY294002', 'Var', (49, 57))	('inhibits', 'NegReg', (100, 108))	('ESCC', 'Disease', (109, 113))
852584	28491289	Another trial compared neoadjuvant chemotherapy with chemoradiotherapy in resectable cancer of the esophagus and gastric cardia patients (n = 181 with 73% EAC), and although chemoradiation resulted in a higher pCR rate (28% versus 9%), higher R0 resection rate (87% versus 74%), and a lower rate of lymph nodal metastases (35% versus 62%), there was no OS benefit (3-year OS: 49% versus 47%; P = 0.77) .	('chemoradiation', 'Var', (174, 188))	('higher', 'PosReg', (236, 242))	('cancer of the esophagus', 'Phenotype', 'HP:0100751', (85, 108))	('lymph nodal metastases', 'Disease', 'MESH:D009362', (299, 321))	('lower rate of lymph nodal metastases', 'Phenotype', 'HP:0002732', (285, 321))	('pCR rate', 'CPA', (210, 218))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('higher', 'PosReg', (203, 209))	('cancer', 'Disease', (85, 91))	('gastric cardia', 'Disease', (113, 127))	('gastric cardia', 'Disease', 'MESH:D004938', (113, 127))	('R0 resection rate', 'CPA', (243, 260))	('patients', 'Species', '9606', (128, 136))	('lymph nodal metastases', 'Disease', (299, 321))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('EAC', 'Chemical', 'MESH:C000430', (155, 158))
852604	28491289	Mutations in TP53, CDKN2A, ARID1A, and SMAD4 were common in EAC.	('TP53', 'Gene', (13, 17))	('SMAD4', 'Gene', (39, 44))	('CDKN2A', 'Gene', (19, 25))	('EAC', 'Chemical', 'MESH:C000430', (60, 63))	('EAC', 'Disease', (60, 63))	('common', 'Reg', (50, 56))	('ARID1A', 'Gene', '8289', (27, 33))	('ARID1A', 'Gene', (27, 33))	('CDKN2A', 'Gene', '1029', (19, 25))	('Mutations', 'Var', (0, 9))	('SMAD4', 'Gene', '4089', (39, 44))	('TP53', 'Gene', '7157', (13, 17))
852605	28491289	Amplifications in ERBB2, VEGFA, GATA4, and GATA6 were common in EAC.	('VEGFA', 'Gene', (25, 30))	('GATA6', 'Gene', (43, 48))	('GATA6', 'Gene', '2627', (43, 48))	('GATA4', 'Gene', '2626', (32, 37))	('EAC', 'Chemical', 'MESH:C000430', (64, 67))	('common', 'Reg', (54, 60))	('GATA4', 'Gene', (32, 37))	('ERBB2', 'Gene', '2064', (18, 23))	('Amplifications', 'Var', (0, 14))	('VEGFA', 'Gene', '7422', (25, 30))	('ERBB2', 'Gene', (18, 23))	('EAC', 'Disease', (64, 67))
852606	28491289	A positive result for microsatellite instability or Epstein-Barr virus was rare in EAC.	('EAC', 'Chemical', 'MESH:C000430', (83, 86))	('microsatellite', 'Var', (22, 36))	('Epstein-Barr virus', 'Disease', (52, 70))	('Epstein-Barr virus', 'Species', '10376', (52, 70))
852608	28491289	Compared with gastric cancer, EAC had more frequent CpG hyper-methylation phenotype, VEGFA and MYC amplifications and mutation of SMARCA4, deletion of tumor suppressor RUNX1, FHIT, and WWOX, and lower APC pathway activation .	('EAC', 'Chemical', 'MESH:C000430', (30, 33))	('lower', 'NegReg', (195, 200))	('VEGFA', 'Gene', '7422', (85, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (14, 28))	('APC pathway', 'Pathway', (201, 212))	('FHIT', 'Gene', '2272', (175, 179))	('SMARCA4', 'Gene', '6597', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('WWOX', 'Gene', '51741', (185, 189))	('gastric cancer', 'Disease', (14, 28))	('CpG hyper-methylation', 'MPA', (52, 73))	('EAC', 'Disease', (30, 33))	('mutation', 'Var', (118, 126))	('RUNX1', 'Gene', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('SMARCA4', 'Gene', (130, 137))	('VEGFA', 'Gene', (85, 90))	('RUNX1', 'Gene', '861', (168, 173))	('gastric cancer', 'Disease', 'MESH:D013274', (14, 28))	('deletion', 'Var', (139, 147))	('FHIT', 'Gene', (175, 179))	('tumor', 'Disease', (151, 156))	('WWOX', 'Gene', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
852610	28491289	ESCC had significantly mutated genes, such as TP53, NFE2L2, MLL2, ZNF750, NOTCH1, and TGFBR2, and specific somatic copy number alterations, such as amplifications of SOX2, TERT, FGFR1, MDM2, and NKX2-1 and deletion of RB1.	('RB1', 'Gene', '5925', (218, 221))	('NOTCH1', 'Gene', '4851', (74, 80))	('NFE2L2', 'Gene', '4780', (52, 58))	('deletion', 'Var', (206, 214))	('MLL2', 'Gene', '9757', (60, 64))	('TP53', 'Gene', '7157', (46, 50))	('MDM2', 'Gene', (185, 189))	('TERT', 'Gene', (172, 176))	('NFE2L2', 'Gene', (52, 58))	('FGFR1', 'Gene', '2260', (178, 183))	('TERT', 'Gene', '7015', (172, 176))	('TGFBR2', 'Gene', '7048', (86, 92))	('ZNF750', 'Gene', '79755', (66, 72))	('SOX2', 'Gene', '6657', (166, 170))	('SOX2', 'Gene', (166, 170))	('MDM2', 'Gene', '4193', (185, 189))	('ZNF750', 'Gene', (66, 72))	('MLL2', 'Gene', (60, 64))	('RB1', 'Gene', (218, 221))	('amplifications', 'Var', (148, 162))	('NKX2-1', 'Gene', '7080', (195, 201))	('TGFBR2', 'Gene', (86, 92))	('FGFR1', 'Gene', (178, 183))	('NOTCH1', 'Gene', (74, 80))	('TP53', 'Gene', (46, 50))	('NKX2-1', 'Gene', (195, 201))
852611	28491289	Compared with EAC, inactivation of CDKN2A, amplification of CCND1 and TP63/SOX2, and alterations of histone-modifying factors were more common in ESCC; conversely, ERBB2 alterations were rare, suggesting that molecular targeting can differ between EAC and ESCC .	('TP63', 'Gene', (70, 74))	('TP63', 'Gene', '8626', (70, 74))	('CDKN2A', 'Gene', '1029', (35, 41))	('EAC', 'Chemical', 'MESH:C000430', (14, 17))	('ERBB2', 'Gene', '2064', (164, 169))	('CCND1', 'Gene', (60, 65))	('ERBB2', 'Gene', (164, 169))	('CCND1', 'Gene', '595', (60, 65))	('histone-modifying factors', 'MPA', (100, 125))	('SOX2', 'Gene', (75, 79))	('alterations', 'Var', (85, 96))	('EAC', 'Chemical', 'MESH:C000430', (248, 251))	('inactivation', 'Var', (19, 31))	('common', 'Reg', (136, 142))	('CDKN2A', 'Gene', (35, 41))	('ESCC', 'Disease', (146, 150))	('SOX2', 'Gene', '6657', (75, 79))
852612	28491289	reported whole-genome sequencing in 129 EAC samples and classified EAC into three groups: C>A/T dominant (29%), DNA damage repair (DDR) impaired (18%), and mutagenic (53%) .	('EAC', 'Chemical', 'MESH:C000430', (67, 70))	('C>A/T', 'Var', (90, 95))	('EAC', 'Chemical', 'MESH:C000430', (40, 43))	('DNA damage', 'MPA', (112, 122))	('mutagenic', 'Var', (156, 165))	('impaired', 'NegReg', (136, 144))
852613	28491289	The report recommends that, in some patients, the combination of anti-ERBB2 and anti-MET inhibition might prove useful.	('ERBB2', 'Gene', (70, 75))	('anti-MET', 'Var', (80, 88))	('ERBB2', 'Gene', '2064', (70, 75))	('patients', 'Species', '9606', (36, 44))
852614	28491289	In the presence of DDR impairment, inhibition by poly ADP ribose polymerase (PARP) inhibitor in combination with DNA-damaging agent might prove useful.	('poly ADP ribose polymerase', 'Gene', (49, 75))	('PARP', 'Gene', (77, 81))	('DDR', 'Disease', (19, 22))	('PARP', 'Gene', '142', (77, 81))	('impairment', 'Var', (23, 33))	('poly ADP ribose polymerase', 'Gene', '142', (49, 75))
852616	28491289	Therefore, tumors that have high mutation load may be amenable to immune-checkpoint inhibitors .	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('mutation load', 'Var', (33, 46))
852617	28491289	For instance, 3'-untranslated region polymorphisms of thymidylate synthase may predict a response to 5-fluorouracil (5-FU)-based chemoradiation .	('polymorphisms', 'Var', (37, 50))	('predict', 'Reg', (79, 86))	('thymidylate synthase', 'Gene', (54, 74))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (101, 115))	('thymidylate synthase', 'Gene', '7298', (54, 74))	('5-FU', 'Chemical', 'MESH:D005472', (117, 121))	('response', 'MPA', (89, 97))
852618	28491289	Overexpression of excision repair cross-complementation group 1 may be associated with chemoradiation response, especially with platinum agent .	('associated', 'Reg', (71, 81))	('chemoradiation response', 'CPA', (87, 110))	('Overexpression', 'Var', (0, 14))	('platinum', 'Chemical', 'MESH:D010984', (128, 136))
852622	28491289	In colorectal cancer, during treatment, mutation or copy number status in ctDNA can be dynamically monitored , .	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('copy number status', 'Var', (52, 70))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
852625	19813066	We use a stable lentiviral shRNA model to demonstrate that ERBB2 suppression in upper gastrointestinal adenocarcinomas with documented ERBB2 amplification effectively decreases ERBB2 protein levels and decreases cell viability.	('amplification', 'Var', (141, 154))	('ERBB2', 'Gene', (177, 182))	('upper gastrointestinal adenocarcinomas', 'Disease', (80, 118))	('cell viability', 'CPA', (212, 226))	('decreases', 'NegReg', (202, 211))	('ERBB2', 'Gene', '2064', (177, 182))	('suppression', 'NegReg', (65, 76))	('ERBB2', 'Gene', (59, 64))	('ERBB2', 'Gene', '2064', (59, 64))	('ERBB2', 'Gene', '2064', (135, 140))	('upper gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (80, 118))	('decreases', 'NegReg', (167, 176))	('ERBB2', 'Gene', (135, 140))
852630	19813066	ERBB2 knockdown significantly decreased cell viability in cell lines with high ERBB2 levels.	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB2', 'Gene', (0, 5))	('ERBB2', 'Gene', (79, 84))	('ERBB2', 'Gene', '2064', (79, 84))	('knockdown', 'Var', (6, 15))	('cell viability', 'CPA', (40, 54))	('decreased', 'NegReg', (30, 39))
852633	19813066	ERBB2 knockdown significantly decreases tumor growth in vivo.	('decreases', 'NegReg', (30, 39))	('ERBB2', 'Gene', '2064', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('ERBB2', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('tumor', 'Disease', (40, 45))
852641	19813066	Of these proto-oncogenes, ERBB2 is amplified in a much higher proportion of samples.	('ERBB2', 'Gene', (26, 31))	('ERBB2', 'Gene', '2064', (26, 31))	('amplified', 'Var', (35, 44))
852646	19813066	However, when ERBB2 is overexpressed as the result of a gene amplification event, it is hypothesized that the receptor homodimerizes.	('gene', 'Var', (56, 60))	('overexpressed', 'PosReg', (23, 36))	('ERBB2', 'Gene', (14, 19))	('ERBB2', 'Gene', '2064', (14, 19))
852650	19813066	Given these inherent limitations of siRNA, we proceeded to evaluate of ERBB2 knockdown on upper gastrointestinal adenocarcinomas using a stable transfection model, via lentiviral ERBB2 shRNA vectors.	('upper gastrointestinal adenocarcinomas', 'Disease', (90, 128))	('ERBB2', 'Gene', '2064', (71, 76))	('ERBB2', 'Gene', (71, 76))	('ERBB2', 'Gene', '2064', (179, 184))	('ERBB2', 'Gene', (179, 184))	('knockdown', 'Var', (77, 86))	('upper gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (90, 128))
852651	19813066	The purpose of this study was to generate a stable transfection model in order to analyze the effect of ERBB2 knockdown on (1) cell viability in upper gastrointestinal adenocarcinoma cell lines with different levels of ERBB2 expression, and (2) tumor growth in an in vivo model.	('knockdown', 'Var', (110, 119))	('upper gastrointestinal adenocarcinoma', 'Disease', 'MESH:D004067', (145, 182))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('upper gastrointestinal adenocarcinoma', 'Disease', (145, 182))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('ERBB2', 'Gene', (219, 224))	('ERBB2', 'Gene', '2064', (219, 224))	('ERBB2', 'Gene', '2064', (104, 109))	('tumor', 'Disease', (245, 250))	('ERBB2', 'Gene', (104, 109))
852652	19813066	We believe that in cell lines with ERBB2 amplification there will be a more significant increase in cell death, correlating with our previous siRNA work.	('increase', 'PosReg', (88, 96))	('cell death', 'CPA', (100, 110))	('amplification', 'Var', (41, 54))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))
852654	19813066	We show that ERBB2 knockdown via lentiviral shRNA vectors in upper gastrointestinal (GI) adenocarcinoma cell lines significantly decreases cell viability in the cell lines known to have ERBB2 amplification.	('knockdown', 'Var', (19, 28))	('ERBB2', 'Gene', '2064', (13, 18))	('upper gastrointestinal (GI) adenocarcinoma', 'Disease', 'MESH:D005767', (61, 103))	('ERBB2', 'Gene', (13, 18))	('cell viability', 'CPA', (139, 153))	('decreases', 'NegReg', (129, 138))	('ERBB2', 'Gene', '2064', (186, 191))	('ERBB2', 'Gene', (186, 191))
852662	19813066	The referenced names as for the ERBB2 shRNA are V2LHS_17669, V2LHS_17671, and V2LHS_17672.	('ERBB2', 'Gene', (32, 37))	('ERBB2', 'Gene', '2064', (32, 37))	('V2LHS_17671', 'Var', (61, 72))	('V2LHS_17669', 'Var', (48, 59))	('V2LHS_17672', 'Var', (78, 89))
852716	19813066	When evaluated in vivo, we find that treating the cell line with the highest level of ERBB2 amplification with shRNA, tumor growth is significantly slower and less than in tumors of cells treated with a nonsilencing control shRNA.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('less', 'NegReg', (159, 163))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Disease', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', (118, 123))	('ERBB2', 'Gene', '2064', (86, 91))	('ERBB2', 'Gene', (86, 91))	('slower', 'NegReg', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
852719	19813066	As seen in these breast cancer models, ERBB2 amplification is documented in 25-40% of tumors evaluated.	('ERBB2', 'Gene', '2064', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('breast cancer', 'Disease', (17, 30))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('amplification', 'Var', (45, 58))	('ERBB2', 'Gene', (39, 44))
852735	26980572	MicroRNA-203 suppresses gastric cancer growth by targeting PIBF1/Akt signaling MicroRNAs (miRNAs) have been proved involved in many tumorigenic behaviors including tumor growth.	('PIBF1', 'Gene', '10464', (59, 64))	('tumor', 'Disease', (164, 169))	('Akt', 'Gene', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('PIBF1', 'Gene', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('suppresses', 'NegReg', (13, 23))	('miR', 'Gene', '735281', (90, 93))	('tumor', 'Disease', (132, 137))	('gastric cancer', 'Disease', (24, 38))	('Akt', 'Gene', '207', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('MicroRNA-203', 'Var', (0, 12))	('miR', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
852738	26980572	Overexpression of miR-203 or knockdown of its target progesterone immunomodulatory binding factor 1 (PIBF1) inhibited GC growth in vitro and in vivo, while miR-203 knockdown promoted GC proliferation.	('progesterone immunomodulatory binding factor 1', 'Gene', '10464', (53, 99))	('miR-203', 'Gene', (18, 25))	('GC proliferation', 'CPA', (183, 199))	('miR-203', 'Gene', (156, 163))	('GC', 'Phenotype', 'HP:0012126', (183, 185))	('promoted', 'PosReg', (174, 182))	('PIBF1', 'Gene', '10464', (101, 106))	('GC', 'Phenotype', 'HP:0012126', (118, 120))	('GC growth', 'CPA', (118, 127))	('progesterone immunomodulatory binding factor 1', 'Gene', (53, 99))	('knockdown', 'Var', (164, 173))	('PIBF1', 'Gene', (101, 106))	('inhibited', 'NegReg', (108, 117))
852751	26980572	In the present study, our studies demonstrated that decreased expression of miR-203 predicted poor prognosis and recurrence in GC patients and miR-203 overexpression or knockdown of its target PIBF1 inhibited cell proliferation and the colony formation of GC cells by inhibition of Akt signaling.	('cell proliferation', 'CPA', (209, 227))	('inhibition', 'NegReg', (268, 278))	('GC', 'Phenotype', 'HP:0012126', (127, 129))	('miR-203', 'Gene', (76, 83))	('colony formation of GC cells', 'CPA', (236, 264))	('poor prognosis', 'CPA', (94, 108))	('knockdown', 'Var', (169, 178))	('Akt', 'Gene', (282, 285))	('expression', 'MPA', (62, 72))	('inhibited', 'NegReg', (199, 208))	('recurrence', 'CPA', (113, 123))	('patients', 'Species', '9606', (130, 138))	('miR-203', 'Gene', (143, 150))	('Akt', 'Gene', '207', (282, 285))	('PIBF1', 'Gene', (193, 198))	('overexpression', 'Var', (151, 165))	('decreased', 'NegReg', (52, 61))	('PIBF1', 'Gene', '10464', (193, 198))	('GC', 'Phenotype', 'HP:0012126', (256, 258))
852780	26980572	Briefly, GC cells transfected with miR-203 or PIBF1 shRNA were incubated in 96-well-plates at a density of 1 x 105 cells per well with DMEM medium supplemented with 10 % FBS.	('FBS', 'Disease', 'MESH:D005198', (170, 173))	('FBS', 'Disease', (170, 173))	('DMEM medium', 'Chemical', '-', (135, 146))	('PIBF1', 'Gene', '10464', (46, 51))	('GC', 'Phenotype', 'HP:0012126', (9, 11))	('PIBF1', 'Gene', (46, 51))	('miR-203', 'Var', (35, 42))
852796	26980572	These data suggested that aberrant expression of miR-203 was a frequent event in human GC tissues.	('GC', 'Phenotype', 'HP:0012126', (87, 89))	('human', 'Species', '9606', (81, 86))	('aberrant', 'Var', (26, 34))	('miR-203', 'Gene', (49, 56))
852799	26980572	As shown in Table 1, the results indicated that miR-203 expression was significantly associated with tumor size (P = 0.006), but did not correlate with age, sex, vascular invasion and pathological stage in GC patients (P > 0.05).	('miR-203', 'Var', (48, 55))	('GC', 'Phenotype', 'HP:0012126', (206, 208))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('associated', 'Reg', (85, 95))	('patients', 'Species', '9606', (209, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
852811	26980572	Moreover, we found that miR-203 knockdown promoted cell growth (Additional file 3: Figure S1A), but exerted no effect on cell colony formation (Additional file 3: Figure S1B) in MKN-28 and MGC-803 cells with high miR-203 expression.	('cell growth', 'CPA', (51, 62))	('MGC-803', 'CellLine', 'CVCL:5334', (189, 196))	('promoted', 'PosReg', (42, 50))	('knockdown', 'Var', (32, 41))	('GC', 'Phenotype', 'HP:0012126', (190, 192))	('miR-203', 'Gene', (213, 220))	('cell colony formation', 'CPA', (121, 142))	('miR-203', 'Gene', (24, 31))
852813	26980572	The results showed that miR-203 knockdown upregulated the protein expression of PIBF1and p-Akt, but had no effect on the expression of Akt, EGFR and STAT3 in MKN-28 and MGC-803 cells (Additional file 3: Figure S1C).	('Akt', 'Gene', '207', (135, 138))	('Akt', 'Gene', '207', (91, 94))	('STAT3', 'Gene', '6774', (149, 154))	('EGFR', 'Gene', (140, 144))	('MGC-803', 'CellLine', 'CVCL:5334', (169, 176))	('STAT3', 'Gene', (149, 154))	('protein expression', 'MPA', (58, 76))	('Akt', 'Gene', (91, 94))	('knockdown', 'Var', (32, 41))	('Akt', 'Gene', (135, 138))	('PIBF1', 'Gene', '10464', (80, 85))	('upregulated', 'PosReg', (42, 53))	('GC', 'Phenotype', 'HP:0012126', (170, 172))	('PIBF1', 'Gene', (80, 85))	('EGFR', 'Gene', '1956', (140, 144))	('miR-203', 'Gene', (24, 31))
852817	26980572	To further confirm whether miR-203 could directly bind to the 3' UTR of PIBF1, the WT 3' UTR or the mutant 3' UTR target sequences (Fig.	('bind', 'Interaction', (50, 54))	('mutant', 'Var', (100, 106))	('PIBF1', 'Gene', '10464', (72, 77))	('PIBF1', 'Gene', (72, 77))	('miR-203', 'Gene', (27, 34))
852822	26980572	Moreover, PIBF1 knockdown significantly reduced the cells proliferation (Fig.	('PIBF1', 'Gene', '10464', (10, 15))	('PIBF1', 'Gene', (10, 15))	('knockdown', 'Var', (16, 25))	('reduced', 'NegReg', (40, 47))	('cells proliferation', 'CPA', (52, 71))
852827	26980572	The results showed that miR-203 downregulated the protein expression of p-Akt by inhibition of the PIBF1 expression, but had no effect on the expression of Akt, EGFR and STAT3 (Fig.	('Akt', 'Gene', '207', (74, 77))	('downregulated', 'NegReg', (32, 45))	('EGFR', 'Gene', (161, 165))	('STAT3', 'Gene', '6774', (170, 175))	('PIBF1', 'Gene', (99, 104))	('Akt', 'Gene', (156, 159))	('Akt', 'Gene', '207', (156, 159))	('inhibition', 'NegReg', (81, 91))	('STAT3', 'Gene', (170, 175))	('Akt', 'Gene', (74, 77))	('EGFR', 'Gene', '1956', (161, 165))	('protein expression', 'MPA', (50, 68))	('expression', 'MPA', (105, 115))	('PIBF1', 'Gene', '10464', (99, 104))	('miR-203', 'Var', (24, 31))
852832	26980572	When the tumors were harvested, the average weight and volumes of the tumors in miR-203 group were significantly smaller than those in si-NC group (**P < 0.01, Fig.	('smaller', 'NegReg', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('miR-203', 'Var', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
852844	26980572	Some studies indicate that miR-203 overexpression suppresses cell growth and metastasis via targeting different genes in different tumor tissues, such as targeting TBK1 in Osteosarcoma, ADAM9 and long non-coding RNA HULC in hepatocellular carcinoma, Rap1A in prostate cancer, Ran and miR-21 in esophageal cancer.	('hepatocellular carcinoma', 'Disease', (224, 248))	('Ran', 'Gene', '5901', (276, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('Rap1A', 'Gene', '5906', (250, 255))	('prostate cancer', 'Disease', (259, 274))	('targeting', 'Var', (154, 163))	('tumor', 'Disease', (131, 136))	('HULC', 'Gene', (216, 220))	('Ran', 'Gene', (276, 279))	('miR-203', 'Gene', (27, 34))	('miR-21', 'Gene', (284, 290))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (172, 184))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('suppresses', 'NegReg', (50, 60))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (224, 248))	('esophageal cancer', 'Disease', 'MESH:D004938', (294, 311))	('HULC', 'Gene', '728655', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Rap1A', 'Gene', (250, 255))	('esophageal cancer', 'Disease', (294, 311))	('TBK1', 'Gene', '29110', (164, 168))	('Osteosarcoma', 'Disease', (172, 184))	('Osteosarcoma', 'Disease', 'MESH:D012516', (172, 184))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (224, 248))	('TBK1', 'Gene', (164, 168))	('ADAM9', 'Gene', '8754', (186, 191))	('miR-21', 'Gene', '406991', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('ADAM9', 'Gene', (186, 191))	('prostate cancer', 'Disease', 'MESH:D011471', (259, 274))	('prostate cancer', 'Phenotype', 'HP:0012125', (259, 274))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
852845	26980572	However, few studies show that miR-203 may function as the carcinogenic factor via enhancing cell proliferation, migration and invasion by degrading SIK1 in pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('SIK1 in pancreatic cancer', 'Disease', (149, 174))	('degrading', 'NegReg', (139, 148))	('enhancing', 'PosReg', (83, 92))	('invasion', 'CPA', (127, 135))	('cell proliferation', 'CPA', (93, 111))	('SIK1 in pancreatic cancer', 'Disease', 'MESH:D010190', (149, 174))	('carcinogenic', 'Disease', 'MESH:D063646', (59, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (157, 174))	('carcinogenic', 'Disease', (59, 71))	('migration', 'CPA', (113, 122))	('miR-203', 'Var', (31, 38))
852846	26980572	In the present study, we further evaluated the functions and targeted genes of miR-203 in GC cells and found that miR-203 overexpression inhibited cell proliferation and colony formation, while its knockdown promoted cell proliferation in GC cells, indicating miR-203 as a tumor suppressor in GC.	('miR-203', 'Gene', (114, 121))	('promoted', 'PosReg', (208, 216))	('cell proliferation', 'CPA', (217, 235))	('colony formation', 'CPA', (170, 186))	('inhibited', 'NegReg', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('knockdown', 'Var', (198, 207))	('cell proliferation', 'CPA', (147, 165))	('overexpression', 'PosReg', (122, 136))	('GC', 'Phenotype', 'HP:0012126', (90, 92))	('GC', 'Phenotype', 'HP:0012126', (293, 295))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('GC', 'Phenotype', 'HP:0012126', (239, 241))
852849	26980572	Our studies showed knockdown of PIBF1 reduced cell proliferation and colony formation, and PIBF1 was predicted to be a direct target of miR-203 by bioinformatics analysis and was validated by western blotting in GC cells.	('PIBF1', 'Gene', (32, 37))	('PIBF1', 'Gene', (91, 96))	('GC', 'Phenotype', 'HP:0012126', (212, 214))	('reduced', 'NegReg', (38, 45))	('knockdown', 'Var', (19, 28))	('PIBF1', 'Gene', '10464', (32, 37))	('PIBF1', 'Gene', '10464', (91, 96))	('cell proliferation', 'CPA', (46, 64))	('colony formation', 'CPA', (69, 85))
852851	26980572	We found that miR-203 exerted targeted inhibition of PIBF1 expression and downregulated its downstream p-Akt, its knockdown upregulated the expression of PIBF1 and p-Akt, and the restoration of PIBF1 abrogated the anti-proliferative effects of miR-203 in GC cells, suggesting that miR-203 might inhibit GC proliferation via targeting PIBF1/Akt signaling.	('miR-203', 'Var', (14, 21))	('GC', 'Phenotype', 'HP:0012126', (255, 257))	('inhibition', 'NegReg', (39, 49))	('Akt', 'Gene', (166, 169))	('PIBF1', 'Gene', '10464', (334, 339))	('GC', 'Phenotype', 'HP:0012126', (303, 305))	('expression', 'MPA', (59, 69))	('inhibit', 'NegReg', (295, 302))	('upregulated', 'PosReg', (124, 135))	('Akt', 'Gene', '207', (166, 169))	('Akt', 'Gene', (340, 343))	('PIBF1', 'Gene', (53, 58))	('GC proliferation', 'CPA', (303, 319))	('Akt', 'Gene', '207', (340, 343))	('PIBF1', 'Gene', '10464', (53, 58))	('PIBF1', 'Gene', (194, 199))	('PIBF1', 'Gene', (154, 159))	('knockdown', 'Var', (114, 123))	('Akt', 'Gene', (105, 108))	('PIBF1', 'Gene', '10464', (194, 199))	('PIBF1', 'Gene', '10464', (154, 159))	('Akt', 'Gene', '207', (105, 108))	('anti-proliferative effects', 'CPA', (214, 240))	('expression', 'MPA', (140, 150))	('abrogated', 'NegReg', (200, 209))	('PIBF1', 'Gene', (334, 339))	('downregulated', 'NegReg', (74, 87))
852936	24558329	E7 binds to and degrades Rb, releasing E2F, leading to p16INK4A overexpression, hereafter denoted as p16, which is associated with superior clinical outcome.	('p16INK4A', 'Gene', '1029', (55, 63))	('degrades', 'NegReg', (16, 24))	('leading to', 'Reg', (44, 54))	('overexpression', 'PosReg', (64, 78))	('p16INK4A', 'Gene', (55, 63))	('E2F', 'Var', (39, 42))
852959	24558329	Integration of HPV results in higher expression of the oncoproteins E6/E7, thereby abrogating the p53 and Rb protein functions, promoting genomic rearrangements; rearranged DNA is theoretically more sensitive to radiation and chemotherapy, providing an explanation for the indication of higher survival rates for patients with HPV-positive tumors.	('higher', 'PosReg', (287, 293))	('functions', 'MPA', (117, 126))	('higher', 'PosReg', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('Rb protein', 'Protein', (106, 116))	('E6/E7', 'Gene', '25479186', (68, 73))	('E6/E7', 'Gene', (68, 73))	('promoting', 'PosReg', (128, 137))	('HPV', 'Gene', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('rearranged', 'Var', (162, 172))	('expression', 'MPA', (37, 47))	('genomic rearrangements', 'CPA', (138, 160))	('abrogating', 'NegReg', (83, 93))
852962	22040862	TP53 mutations, human papilloma virus DNA and inflammation markers in esophageal squamous cell carcinoma from the Rift Valley, a high-incidence area in Kenya Squamous Cell Carcinoma of Esophagus is one of the most common malignancies in both men and women in eastern and south-eastern Africa.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('inflammation', 'Disease', (46, 58))	('TP53', 'Gene', '7157', (0, 4))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('papilloma', 'Phenotype', 'HP:0012740', (22, 31))	('Carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('Carcinoma of Esophagus', 'Phenotype', 'HP:0011459', (172, 194))	('malignancies', 'Disease', (221, 233))	('human papilloma virus', 'Species', '10566', (16, 37))	('mutations', 'Var', (5, 14))	('men', 'Species', '9606', (252, 255))	('Squamous Cell Carcinoma', 'Disease', (158, 181))	('esophageal squamous cell carcinoma', 'Disease', (70, 104))	('inflammation', 'Disease', 'MESH:D007249', (46, 58))	('TP53', 'Gene', (0, 4))	('women', 'Species', '9606', (250, 255))	('men', 'Species', '9606', (242, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))
852965	22040862	We have analyzed TP53 mutations, the presence of human papilloma virus (HPV) DNA and expression of inflammation markers Cyclooxygenase 2 (Cox-2) and Nitrotyrosine (NTyR) in 28 cases (13 males and 15 females) of archived ESCC tissues collected at the Moi Teaching and Referral Hospital in Eldoret, Kenya.	('papilloma', 'Phenotype', 'HP:0012740', (55, 64))	('inflammation', 'Disease', 'MESH:D007249', (99, 111))	('HPV', 'Species', '10566', (72, 75))	('inflammation', 'Disease', (99, 111))	('Nitrotyrosine', 'Chemical', 'MESH:C002744', (149, 162))	('human papilloma virus', 'Species', '10566', (49, 70))	('mutations', 'Var', (22, 31))	('NTyR', 'Chemical', 'MESH:C002744', (164, 168))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
852971	22040862	Low prevalence of TP53 mutation compared with other intermediate or high incidence areas of the world highlights this hypothesis.	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))
852979	22040862	In South Africa (Transkei region), molecular studies have reported a low prevalence of mutations in exons 5 to 8 of the TP53 tumor suppressor gene (17%), well below the world average (40%) and the high prevalence observed in high incidence areas of China (70%) or Northern Iran (90%) (Abedi-Ardekani et al, not published).	('mutations in', 'Var', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
852985	22040862	We have analysed TP53 mutations in exons 5 to 8, presence of high risk types of HPV, and Immunohistochemical (IHC) expression of two markers associated with inflammation damage (NTyR, a direct marker of protein damage by nitric oxide over expressed in ESCC linked with inflammation, and inflammatory response (Cox-2, which is often elevated in ESCC from various high-incidence areas,).	('inflammation', 'Disease', (269, 281))	('nitric oxide', 'Chemical', 'MESH:D009569', (221, 233))	('TP53', 'Gene', (17, 21))	('inflammation', 'Disease', 'MESH:D007249', (157, 169))	('HPV', 'Species', '10566', (80, 83))	('mutations', 'Var', (22, 31))	('inflammation', 'Disease', (157, 169))	('TP53', 'Gene', '7157', (17, 21))	('inflammation', 'Disease', 'MESH:D007249', (269, 281))	('NTyR', 'Chemical', 'MESH:C002744', (178, 182))
852991	22040862	TP53 mutations in exons 5-8 were analyzed using the IARC reference protocol http://www-p53.iarc.fr/Download/TP53_DirectSequencing_IARC.pdf.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (108, 112))	('p53', 'Gene', (87, 90))	('TP53', 'Gene', (108, 112))	('p53', 'Gene', '7157', (87, 90))	('mutations', 'Var', (5, 14))
852999	22040862	The characteristics of the 28 patients analyzed for both TP53 mutations and HPV DNA are summarized in Table 1.	('HPV', 'Species', '10566', (76, 79))	('patients', 'Species', '9606', (30, 38))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
853006	22040862	TP53 mutations (Table 2) were detected in 11 of 28 patients (39.3%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (51, 59))	('mutations', 'Var', (5, 14))
853007	22040862	None of these mutations occurred at common TP53 mutation hotspots as reported in the IARC TP53 database.	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (14, 23))
853011	22040862	Among 11 cases with TP53 mutations, IHC analysis was possible on 6 and 5 had moderate or strong p53 expression scores.	('mutations', 'Var', (25, 34))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('TP53', 'Gene', (20, 24))	('TP53', 'Gene', '7157', (20, 24))
853015	22040862	However, from a molecular viewpoint, ESCC from Rift Valley appears different from those high incidence areas in the prevalence of TP53 mutations.	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('mutations', 'Var', (135, 144))
853016	22040862	We report a prevalence of TP53 mutation of 39%, far below the high prevalence reported in high incidence areas of China (50-75%), Northern Iran (90%) (Abedi-Ardekani et al., not published) or Western France (Normandy, 76%).	('TP53', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('TP53', 'Gene', '7157', (26, 30))
853017	22040862	Remarkably, a low prevalence of TP53 mutations has also been reported in Transkei.	('mutations', 'Var', (37, 46))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))
853018	22040862	Furthermore, the mutations identified, both in the present study and in Transkei, differ from the average mutation patterns of most cancers which are dominated by transition mutations at "hotspot" codons within CpG sites.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (17, 26))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
853020	22040862	Low prevalence of TP53 mutations suggested that other molecular events may take place in ESCC from the Rift Valley.	('mutations', 'Var', (23, 32))	('ESCC', 'Disease', (89, 93))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))
853028	22040862	In particular, the low prevalence of TP53 mutation, also observed in ESCC from South Africa, suggests that some other mechanism of p53 inactivation may take place in these cancers.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('p53', 'Gene', (131, 134))	('TP53', 'Gene', '7157', (37, 41))	('p53', 'Gene', '7157', (131, 134))	('mutation', 'Var', (42, 50))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('ESCC', 'Disease', (69, 73))	('cancers', 'Disease', (172, 179))	('TP53', 'Gene', (37, 41))
853036	21129375	We investigated whether peginterferon decreases the incidence of HCC in the HALT-C cohort over a longer post-treatment follow-up period.	('decreases', 'NegReg', (38, 47))	('peginterferon', 'Var', (24, 37))	('HCC', 'Gene', (65, 68))	('peginterferon', 'Chemical', '-', (24, 37))	('HCC', 'Gene', '619501', (65, 68))
853040	21129375	There was a significantly lower incidence of HCC among patients given peginterferon therapy who had cirrhosis, but not fibrosis, based on analysis of baseline biopsy samples.	('fibrosis', 'Disease', 'MESH:D005355', (119, 127))	('fibrosis', 'Disease', (119, 127))	('cirrhosis', 'Disease', (100, 109))	('HCC', 'Gene', (45, 48))	('peginterferon', 'Var', (70, 83))	('patients', 'Species', '9606', (55, 63))	('HCC', 'Gene', '619501', (45, 48))	('cirrhosis', 'Phenotype', 'HP:0001394', (100, 109))	('cirrhosis', 'Disease', 'MESH:D005355', (100, 109))	('lower', 'NegReg', (26, 31))	('peginterferon', 'Chemical', '-', (70, 83))
853092	21129375	The cumulative incidence of HCC at 3, 5 and 7 years in the peginterferon group was 2.6%, 5.1%, and 7.8%, and, in the untreated control group, 4.0%, 11.1%, and 24.2%, respectively (log-rank test, P = 0.009).	('HCC', 'Gene', '619501', (28, 31))	('peginterferon', 'Chemical', '-', (59, 72))	('peginterferon', 'Var', (59, 72))	('HCC', 'Gene', (28, 31))
853096	21129375	In noncirrhotics, the cumulative incidence of HCC at 3, 5 and 7 years in the peginterferon group was 2.1%, 6.4%, and 8.3% and in the control group, 1.4%, 2.9%, and 6.8%, respectively; the incidence of HCC in the two treatment groups was similar throughout the duration of the study (Figure 1B).	('peginterferon', 'Var', (77, 90))	('HCC', 'Gene', '619501', (46, 49))	('peginterferon', 'Chemical', '-', (77, 90))	('HCC', 'Gene', (201, 204))	('HCC', 'Gene', (46, 49))	('HCC', 'Gene', '619501', (201, 204))
853109	21129375	Patients who received peginterferon for >=2 years had a significantly lower incidence of HCC compared to those who were treated for <2 years (HR 0.36, 95% CI 0.16-0.82, P = 0.02) (Table 3); however, this difference was observed only in the patients with cirrhosis at baseline (HR 0.10, 95% CI 0.03-0.44, P = 0.002).	('HCC', 'Gene', (89, 92))	('peginterferon', 'Var', (22, 35))	('cirrhosis', 'Disease', (254, 263))	('peginterferon', 'Chemical', '-', (22, 35))	('HCC', 'Gene', '619501', (89, 92))	('cirrhosis', 'Phenotype', 'HP:0001394', (254, 263))	('lower', 'NegReg', (70, 75))	('cirrhosis', 'Disease', 'MESH:D005355', (254, 263))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (240, 248))
853113	21129375	To determine whether the effect of peginterferon on prevention of HCC was related to its effect in decreasing hepatic inflammation, we analyzed 426 patients in the peginterferon group and 416 in the control group who had repeat liver biopsies at 1.5 years.	('decreasing hepatic inflammation', 'Phenotype', 'HP:0001410', (99, 130))	('patients', 'Species', '9606', (148, 156))	('peginterferon', 'Chemical', '-', (35, 48))	('hepatic inflammation', 'Disease', (110, 130))	('hepatic inflammation', 'Disease', 'MESH:D007249', (110, 130))	('decreasing', 'NegReg', (99, 109))	('HCC', 'Gene', (66, 69))	('peginterferon', 'Var', (164, 177))	('HCC', 'Gene', '619501', (66, 69))	('peginterferon', 'Chemical', '-', (164, 177))	('hepatic inflammation', 'Phenotype', 'HP:0012115', (110, 130))
853135	21129375	First, among patients randomized to receive peginterferon, multivariate analysis showed that those who stopped treatment before 2 years did not have a reduction in the risk of HCC after adjusting for laboratory markers of advanced liver disease.	('peginterferon', 'Var', (44, 57))	('liver disease', 'Phenotype', 'HP:0001392', (231, 244))	('patients', 'Species', '9606', (13, 21))	('liver disease', 'Disease', (231, 244))	('peginterferon', 'Chemical', '-', (44, 57))	('HCC', 'Gene', (176, 179))	('liver disease', 'Disease', 'MESH:D008107', (231, 244))	('reduction', 'NegReg', (151, 160))	('HCC', 'Gene', '619501', (176, 179))
853137	21129375	Third, in a regression analysis of factors associated with the development of HCC, including treatment assignment, peginterferon therapy was associated with an approximate 50% reduction in the incidence of HCC over a median of 6.1 year observation period among patients with cirrhosis at baseline even when adjusted for other risk factors including age, race, smoking history, and laboratory tests associated with advanced liver disease.	('patients', 'Species', '9606', (261, 269))	('HCC', 'Gene', (78, 81))	('reduction', 'NegReg', (176, 185))	('peginterferon', 'Chemical', '-', (115, 128))	('liver disease', 'Phenotype', 'HP:0001392', (423, 436))	('liver disease', 'Disease', (423, 436))	('cirrhosis', 'Disease', (275, 284))	('HCC', 'Gene', '619501', (78, 81))	('HCC', 'Gene', (206, 209))	('liver disease', 'Disease', 'MESH:D008107', (423, 436))	('peginterferon therapy', 'Var', (115, 136))	('cirrhosis', 'Phenotype', 'HP:0001394', (275, 284))	('HCC', 'Gene', '619501', (206, 209))	('cirrhosis', 'Disease', 'MESH:D005355', (275, 284))
853157	21129375	If, indeed, peginterferon prevented HCC, several years would have been required to detect this effect.	('prevented', 'NegReg', (26, 35))	('HCC', 'Gene', '619501', (36, 39))	('peginterferon', 'Chemical', '-', (12, 25))	('HCC', 'Gene', (36, 39))	('peginterferon', 'Var', (12, 25))
853187	33416035	Compared with the control group, overexpression of miR-1269 promoted cell proliferation, migration, and invasion, while knockdown of miR-1269 inhibited cell proliferation, migration, and invasion.	('invasion', 'CPA', (187, 195))	('miR-1269', 'Gene', '100302177', (51, 59))	('miR-1269', 'Gene', (51, 59))	('promoted', 'PosReg', (60, 68))	('invasion', 'CPA', (104, 112))	('knockdown', 'Var', (120, 129))	('cell proliferation', 'CPA', (69, 87))	('miR-1269', 'Gene', '100302177', (133, 141))	('cell proliferation', 'CPA', (152, 170))	('inhibited', 'NegReg', (142, 151))	('migration', 'CPA', (89, 98))	('miR-1269', 'Gene', (133, 141))	('migration', 'CPA', (172, 181))
853197	33416035	It has been reported that the abnormal expression of microRNAs (miRNAs) is associated with cancer development and plays an important role in ESCC.	('abnormal', 'Var', (30, 38))	('microRNAs', 'Protein', (53, 62))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('role', 'Reg', (133, 137))	('expression', 'MPA', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (75, 85))	('ESCC', 'Disease', (141, 145))
853289	32901882	The targeting of KIAA0101 by miR-216a-5p was verified by dual-luciferase reporter assays.	('miR-216a-5p', 'Var', (29, 40))	('miR-216a-5p', 'Chemical', '-', (29, 40))	('KIAA0101', 'Gene', (17, 25))
853291	32901882	miR-216a-5p was lowly expressed and inversely correlated with KIAA0101 protein expression in ESCC tissues and cell lines.	('expression', 'MPA', (79, 89))	('miR-216a-5p', 'Var', (0, 11))	('KIAA0101', 'Gene', (62, 70))	('correlated', 'Reg', (46, 56))	('protein', 'Protein', (71, 78))	('miR-216a-5p', 'Chemical', '-', (0, 11))
853292	32901882	Lower miR-216a-5p expression was associated with worse prognosis in patients with ESCC.	('ESCC', 'Disease', (82, 86))	('miR-216a-5p', 'Var', (6, 17))	('patients', 'Species', '9606', (68, 76))	('Lower', 'NegReg', (0, 5))	('miR-216a-5p', 'Chemical', '-', (6, 17))
853293	32901882	miR-216a-5p negatively regulated KIAA0101 expression by directly targeting the 3'-untranslated region of the KIAA0101 mRNA.	('expression', 'MPA', (42, 52))	('miR-216a-5p', 'Var', (0, 11))	('miR-216a-5p', 'Chemical', '-', (0, 11))	('targeting', 'Reg', (65, 74))	('negatively', 'NegReg', (12, 22))	('KIAA0101', 'Gene', (33, 41))
853295	32901882	Meanwhile, KIAA0101 promoted ESCC migration and invasion, and its overexpression abolished the antitumor effects of miR-216a-5p mimics.	('tumor', 'Disease', (99, 104))	('KIAA0101', 'Var', (11, 19))	('promoted', 'PosReg', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('miR-216a-5p', 'Chemical', '-', (116, 127))	('invasion', 'CPA', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('ESCC migration', 'CPA', (29, 43))	('abolished', 'NegReg', (81, 90))
853296	32901882	As a tumor suppressor, miR-216a-5p targets KIAA0101 to inhibit the proliferation, migration, and invasion of ESCC.	('miR-216a-5p', 'Var', (23, 34))	('ESCC', 'Disease', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('migration', 'CPA', (82, 91))	('proliferation', 'CPA', (67, 80))	('miR-216a-5p', 'Chemical', '-', (23, 34))	('tumor', 'Disease', (5, 10))	('invasion', 'CPA', (97, 105))	('inhibit', 'NegReg', (55, 62))
853301	32901882	KIAA0101 (also referred to as NS5ATP9 or Paf15) is involved in multiple biological activities, including DNA repair, cell proliferation, cell cycle progression, and cell migration.	('cell cycle progression', 'CPA', (137, 159))	('Paf15', 'Gene', (41, 46))	('cell migration', 'CPA', (165, 179))	('KIAA0101', 'Var', (0, 8))	('NS5ATP9', 'Gene', '9768', (30, 37))	('cell proliferation', 'CPA', (117, 135))	('NS5ATP9', 'Gene', (30, 37))	('involved', 'Reg', (51, 59))	('Paf15', 'Gene', '9768', (41, 46))
853304	32901882	The overexpression of KIAA0101 was also found to enhance ESCC cell proliferation and to upregulate the expression of cyclins A and B, thus leading to a reduced percentage of cells in the G1 phase.	('cyclins A and B', 'Gene', '890', (117, 132))	('upregulate', 'PosReg', (88, 98))	('expression', 'MPA', (103, 113))	('enhance', 'PosReg', (49, 56))	('reduced', 'NegReg', (152, 159))	('ESCC cell proliferation', 'CPA', (57, 80))	('KIAA0101', 'Var', (22, 30))
853306	32901882	For example, miR-216a is significantly upregulated in hepatocellular carcinoma and was found to induce epithelial-mesenchymal transition (EMT) by suppressing the expression of PTEN, SMAD7, and TSLC1, thus contributing to carcinogenesis and recurrence.	('upregulated', 'PosReg', (39, 50))	('carcinogenesis', 'Disease', (221, 235))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 78))	('TSLC1', 'Gene', '23705', (193, 198))	('SMAD7', 'Gene', '4092', (182, 187))	('carcinogenesis', 'Disease', 'MESH:D063646', (221, 235))	('induce', 'PosReg', (96, 102))	('hepatocellular carcinoma', 'Disease', (54, 78))	('suppressing', 'NegReg', (146, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('PTEN', 'Gene', (176, 180))	('contributing', 'Reg', (205, 217))	('epithelial-mesenchymal transition', 'CPA', (103, 136))	('TSLC1', 'Gene', (193, 198))	('miR-216a', 'Var', (13, 21))	('PTEN', 'Gene', '5728', (176, 180))	('SMAD7', 'Gene', (182, 187))	('expression', 'MPA', (162, 172))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (54, 78))
853307	32901882	On the other hand, miR-216a displays a low expression in non-small cell lung cancer (NSCLC) and could inhibit the cell activity of NSCLC by directly targeting eIF4B and ZEB1.	('miR-216a', 'Var', (19, 27))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('ZEB1', 'Gene', '6935', (169, 173))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('inhibit', 'NegReg', (102, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', (131, 136))	('low', 'NegReg', (39, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('ZEB1', 'Gene', (169, 173))	('targeting', 'Reg', (149, 158))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('eIF4B', 'Gene', '1975', (159, 164))	('lung cancer', 'Disease', (72, 83))	('expression', 'MPA', (43, 53))	('eIF4B', 'Gene', (159, 164))
853308	32901882	In addition, KIAA0101 enhanced resistance to cisplatin by upregulating cell mitosis.	('KIAA0101', 'Var', (13, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('upregulating', 'PosReg', (58, 70))	('cell mitosis', 'CPA', (71, 83))	('enhanced', 'PosReg', (22, 30))	('resistance to cisplatin', 'MPA', (31, 54))
853310	32901882	In the present study, we evaluated the expression level of miR-216a-5p in clinical specimens of ESCC and human ESCC cell lines and observed that lower expression of miR-216a-5p was associated with malignancy in comparison with the control tissues or cells.	('miR-216a-5p', 'Chemical', '-', (165, 176))	('miR-216a-5p', 'Var', (165, 176))	('expression', 'MPA', (151, 161))	('lower', 'NegReg', (145, 150))	('malignancy', 'Disease', 'MESH:D009369', (197, 207))	('human', 'Species', '9606', (105, 110))	('malignancy', 'Disease', (197, 207))	('miR-216a-5p', 'Chemical', '-', (59, 70))
853312	32901882	KIAA0101 was confirmed to be a downstream target of miR-216a-5p, and the in vitro experimental results demonstrated that miR-216a-5p inhibited tumor proliferation, migration, and invasion by directly decreasing the expression of KIAA0101 in ESCC.	('decreasing', 'NegReg', (200, 210))	('miR-216a-5p', 'Chemical', '-', (121, 132))	('migration', 'CPA', (164, 173))	('tumor', 'Disease', (143, 148))	('miR-216a-5p', 'Var', (121, 132))	('miR-216a-5p', 'Chemical', '-', (52, 63))	('inhibited', 'NegReg', (133, 142))	('invasion', 'CPA', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('KIAA0101', 'Gene', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('expression', 'MPA', (215, 225))
853313	32901882	Our study demonstrated a critical role of the miR216a-5p/KIAA0101 axis in the progression of ESCC.	('216a', 'Chemical', '-', (49, 53))	('ESCC', 'Disease', (93, 97))	('miR216a-5p/KIAA0101', 'Var', (46, 65))
853322	32901882	EC9706, EC109, KYSE150, KYSE450, TE1, and TE10 cells were cultured in RPMI-1640 medium (HyClone; GE Healthcare) containing 10% fetal bovine serum (FSB; HyClone; GE Healthcare) and 1% penicillin/streptomycin (Sigma-Aldrich; Merck KGaA).	('EC9706', 'Var', (0, 6))	('streptomycin', 'Chemical', 'MESH:D013307', (194, 206))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('KYSE150', 'Var', (15, 22))	('penicillin', 'Chemical', 'MESH:D010406', (183, 193))	('RPMI-1640 medium', 'Chemical', '-', (70, 86))
853332	32901882	The relative expression of miR-216a-5p was normalized against U6, while that of KIAA0101 was normalized to beta-actin, both using the 2-DeltaDeltaCq method.	('miR-216a-5p', 'Var', (27, 38))	('beta-actin', 'Gene', '728378', (107, 117))	('DeltaCq', 'Chemical', '-', (141, 148))	('beta-actin', 'Gene', (107, 117))	('miR-216a-5p', 'Chemical', '-', (27, 38))
853342	32901882	Following the manual of Gene Tailor Site-Directed Mutagenesis System (Invitrogen; Thermo Fisher Scientific, Inc.), the construct with mutations in the miR-216a-5p seed sequence (the sequence of TGAGATT at 357-363 bp was mutated to TCACAAT) was produced by the mutagenic oligonucleotide primers (forward: 5'-GTTGTATTTCACAATTGCTTAGATTGTTGTAC-3' and reverse: 5'-CTAAGCAATTGTGAAATACAACATACTTGTAA-3').	('miR-216a-5p', 'Chemical', '-', (151, 162))	('miR-216a-5p', 'Gene', (151, 162))	('mutations', 'Var', (134, 143))
853343	32901882	EC9706 and TE1 cells were co-transfected with 30 ng of pmiR-RB-KIAA0101 3'-UTR or their mutant constructs, 50 ng luciferase reporter, and 10 ng Renilla luciferase reporter using Lipofectamine 2000.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (178, 196))	('mutant', 'Var', (88, 94))	('pmiR-RB-KIAA0101', 'Gene', (55, 71))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))
853348	32901882	A total of 1x105 EC9706 or TE1 cells were seeded in the upper chambers.	('TE1 cells', 'CPA', (27, 36))	('EC9706', 'CellLine', 'CVCL:E307', (17, 23))	('EC9706', 'Var', (17, 23))
853354	32901882	To explore the potential roles of miR-216a-5p in the pathogenesis and chemoresistance of ESCC, we first evaluated the binding site of miR-216a-5p to the 3'UTR of KIAA0101.	('ESCC', 'Disease', (89, 93))	('miR-216a-5p', 'Chemical', '-', (134, 145))	('binding', 'Interaction', (118, 125))	('miR-216a-5p', 'Chemical', '-', (34, 45))	('miR-216a-5p', 'Var', (134, 145))
853355	32901882	We found that miR-216a-5p could bind the 3'UTR of KIAA0101 (Fig.	('miR-216a-5p', 'Var', (14, 25))	('bind', 'Interaction', (32, 36))	('miR-216a-5p', 'Chemical', '-', (14, 25))
853358	32901882	RT-qPCR analysis demonstrated that compared with the adjacent normal tissues, the tumor tissues had significantly lower expression of miR-216a-5p (Fig.	('expression', 'MPA', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('miR-216a-5p', 'Chemical', '-', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lower', 'NegReg', (114, 119))	('tumor', 'Disease', (82, 87))	('miR-216a-5p', 'Var', (134, 145))
853361	32901882	The miR-216a-5p expression levels in ESCC were not correlated with sex, age, pTNM stage, or preoperative CEA levels, but were correlated with histology (P=0.022), tumor depth (P=0.006), and lymph node metastasis (P=0.018; Table I).	('miR-216a-5p', 'Chemical', '-', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('miR-216a-5p', 'Var', (4, 15))	('lymph node metastasis', 'CPA', (190, 211))	('ESCC', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CEA', 'Gene', (105, 108))	('correlated', 'Reg', (126, 136))	('CEA', 'Gene', '1084', (105, 108))	('tumor', 'Disease', (163, 168))
853362	32901882	In addition, the Cox regression analysis (Table II) revealed that the lymph node metastasis (P=0.001), pTNM stage (P<0.001), and miR-216a-5p levels (P<0.001) were independent risk factors for shorter overall survival in patients with ESCC.	('shorter', 'NegReg', (192, 199))	('overall survival', 'MPA', (200, 216))	('ESCC', 'Disease', (234, 238))	('miR-216a-5p', 'Chemical', '-', (129, 140))	('miR-216a-5p levels', 'Var', (129, 147))	('patients', 'Species', '9606', (220, 228))
853363	32901882	Furthermore, patients with ESCC and lower miR-216a-5p expression displayed reduced DFS (P<0.0001; Fig.	('lower', 'NegReg', (36, 41))	('miR-216a-5p', 'Chemical', '-', (42, 53))	('miR-216a-5p expression', 'Var', (42, 64))	('patients', 'Species', '9606', (13, 21))	('reduced', 'NegReg', (75, 82))	('ESCC', 'Disease', (27, 31))	('DFS', 'MPA', (83, 86))
853369	32901882	To ascertain whether miR-216a-5p functionally affects KIAA0101 expression, miR-216a-5p was overexpressed and knocked down by transfecting the ESCC cell lines EC9706 and TE1 with the miR-216a-5p mimics and miR-216a-5p inhibitor.	('EC9706', 'CellLine', 'CVCL:E307', (158, 164))	('affects', 'Reg', (46, 53))	('miR-216a-5p', 'Chemical', '-', (205, 216))	('knocked', 'Var', (109, 116))	('expression', 'MPA', (63, 73))	('miR-216a-5p', 'Chemical', '-', (75, 86))	('miR-216a-5p', 'Gene', (75, 86))	('miR-216a-5p', 'Chemical', '-', (182, 193))	('miR-216a-5p', 'Chemical', '-', (21, 32))
853376	32901882	Therefore, this finding revealed that miR-216a-5p could reduce the expression of KIAA0101 protein by directly binding to the 3'UTR of KIAA0101 and possible translation suppression.	('miR-216a-5p', 'Var', (38, 49))	('translation', 'MPA', (156, 167))	('protein', 'Protein', (90, 97))	('binding', 'Interaction', (110, 117))	('reduce', 'NegReg', (56, 62))	('miR-216a-5p', 'Chemical', '-', (38, 49))	('expression', 'MPA', (67, 77))	('KIAA0101', 'Gene', (81, 89))
853380	32901882	Overexpression of miR-216a-5p significantly suppressed the ESCC invasion and reduced the ESCC migration.	('suppressed', 'NegReg', (44, 54))	('ESCC migration', 'CPA', (89, 103))	('miR-216a-5p', 'Chemical', '-', (18, 29))	('ESCC invasion', 'CPA', (59, 72))	('miR-216a-5p', 'Var', (18, 29))	('reduced', 'NegReg', (77, 84))
853381	32901882	In contrast, the migration and invasion of ESCC cells increased when endogenous miR-216a-5p was inhibited (Fig.	('migration', 'CPA', (17, 26))	('miR-216a-5p', 'Chemical', '-', (80, 91))	('increased', 'PosReg', (54, 63))	('miR-216a-5p', 'Var', (80, 91))	('inhibited', 'NegReg', (96, 105))	('invasion of ESCC cells', 'CPA', (31, 53))
853384	32901882	5D) also demonstrated that KIAA0101 ectopic expression significantly attenuated the anti-proliferative effects of miR-216a-5p.	('miR-216a-5p', 'Chemical', '-', (114, 125))	('anti-proliferative effects', 'CPA', (84, 110))	('attenuated', 'NegReg', (69, 79))	('ectopic expression', 'Var', (36, 54))	('miR-216a-5p', 'Var', (114, 125))
853385	32901882	Meanwhile, additionally forced KIAA0101 expression in ESCC cells restored the migration and invasion inhibition induced by overexpression of miR-216a-5p (Fig.	('miR-216a-5p', 'Chemical', '-', (141, 152))	('miR-216a-5p', 'Var', (141, 152))	('restored', 'PosReg', (65, 73))	('invasion inhibition', 'CPA', (92, 111))	('migration', 'CPA', (78, 87))
853387	32901882	Collectively, overexpression of miR-216a-5p can inhibit the in vitro proliferation, migration, and invasion of ESCC cells through targeting the oncogene KIAA0101.	('in vitro proliferation', 'CPA', (60, 82))	('migration', 'CPA', (84, 93))	('miR-216a-5p', 'Chemical', '-', (32, 43))	('invasion', 'CPA', (99, 107))	('miR-216a-5p', 'Var', (32, 43))	('overexpression', 'PosReg', (14, 28))	('ESCC', 'Disease', (111, 115))	('inhibit', 'NegReg', (48, 55))
853390	32901882	In the present study, we identified that miR-216a-5p expression was significantly downregulated in primary human ESCC specimens and cell lines, and demonstrated an inverse correlation with KIAA0101 expression.	('downregulated', 'NegReg', (82, 95))	('miR-216a-5p', 'Var', (41, 52))	('human', 'Species', '9606', (107, 112))	('expression', 'MPA', (53, 63))	('miR-216a-5p', 'Chemical', '-', (41, 52))
853392	32901882	KIAA0101 was validated to be a direct downstream target of miR-216a-5p, and its expression in ESCC cells was regulated by miR-216a-5p at the translational level.	('miR-216a-5p', 'Var', (122, 133))	('miR-216a-5p', 'Var', (59, 70))	('regulated', 'Reg', (109, 118))	('expression', 'MPA', (80, 90))	('miR-216a-5p', 'Chemical', '-', (122, 133))	('miR-216a-5p', 'Chemical', '-', (59, 70))
853394	32901882	Our data demonstrated that the miR-216a-5p/KIAA0101 axis contributes to the progression of ESCC, and represents a valuable prognosis marker and therapeutic target for patients with ESCC.	('patients', 'Species', '9606', (167, 175))	('ESCC', 'Disease', (91, 95))	('miR-216a-5p/KIAA0101', 'Var', (31, 51))	('miR-216a-5p', 'Chemical', '-', (31, 42))
853396	32901882	In addition, KIAA0101 was found to enhance resistance to cisplatin by upregulating cell mitosis.	('cell mitosis', 'CPA', (83, 95))	('KIAA0101', 'Var', (13, 21))	('enhance', 'PosReg', (35, 42))	('upregulating', 'PosReg', (70, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('resistance to cisplatin', 'MPA', (43, 66))
853397	32901882	Herein we identified miR-216a-5p as an upstream regulator of KIAA0101 that was inversely correlated with KIAA0101.	('miR-216a-5p', 'Var', (21, 32))	('miR-216a-5p', 'Chemical', '-', (21, 32))	('KIAA0101', 'Gene', (61, 69))
853398	32901882	Consistent with the previous results, lower levels of miR-216a-5p in ESCC specimens corresponded to a higher level of KIAA0101 and less favorable prognosis for patients with ESCC.	('patients', 'Species', '9606', (160, 168))	('lower', 'NegReg', (38, 43))	('KIAA0101', 'MPA', (118, 126))	('ESCC', 'Disease', (174, 178))	('higher', 'PosReg', (102, 108))	('miR-216a-5p', 'Chemical', '-', (54, 65))	('ESCC', 'Disease', (69, 73))	('miR-216a-5p', 'Var', (54, 65))
853399	32901882	Our findings suggest that by repressing KIAA0101 protein, miR-216a-5p plays an essential role in suppressing the proliferation and metastasis of ESCC.	('miR-216a-5p', 'Var', (58, 69))	('protein', 'Protein', (49, 56))	('suppressing', 'NegReg', (97, 108))	('miR-216a-5p', 'Chemical', '-', (58, 69))	('ESCC', 'Disease', (145, 149))
853400	32901882	Evidence reveals that the abnormal expression of miR-216a is involved in tumorigenesis and cancer progression, but the specific role of miR-216a seems to be cell type-dependent.	('miR-216a', 'Gene', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('involved', 'Reg', (61, 69))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('expression', 'MPA', (35, 45))	('tumor', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('abnormal', 'Var', (26, 34))
853401	32901882	miR-216a has a low expression in NSCLC specimens and could inhibit cell activity of NSCLC, which was in accordance with observations in oral squamous cell carcinoma.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('expression', 'MPA', (19, 29))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('NSCLC', 'Disease', (84, 89))	('oral squamous cell carcinoma', 'Disease', (136, 164))	('NSCLC', 'Disease', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('inhibit', 'NegReg', (59, 66))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('miR-216a', 'Var', (0, 8))	('cell', 'CPA', (67, 71))
853402	32901882	In addition, Wang et al identified that miR-216a negatively regulated the progression of pancreatic cancer by direct interaction with JAK2.	('negatively regulated', 'NegReg', (49, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('progression', 'CPA', (74, 85))	('interaction', 'Interaction', (117, 128))	('JAK2', 'Gene', '3717', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('miR-216a', 'Var', (40, 48))	('JAK2', 'Gene', (134, 138))	('pancreatic cancer', 'Disease', (89, 106))
853404	32901882	Nevertheless, miR-216a was also found to demonstrate a tumor-promoting role, and its expression affected the therapeutic effects of anticancer treatments.	('expression', 'MPA', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('miR-216a', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('affected', 'Reg', (96, 104))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', (136, 142))	('therapeutic effects', 'CPA', (109, 128))
853408	32901882	Link et al found that decreased expression of fecal miR-216a could be used as a non-invasive miRNA biomarker for pancreatic cancer.	('miR-216a', 'Gene', (52, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('pancreatic cancer', 'Disease', (113, 130))	('fecal', 'Var', (46, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('expression', 'MPA', (32, 42))	('decreased', 'NegReg', (22, 31))
853410	32901882	In the present study, miR-216a-5p had lower expression in ESCC specimens and cell lines than in the normal control tissues and cells.	('expression', 'MPA', (44, 54))	('lower', 'NegReg', (38, 43))	('miR-216a-5p', 'Chemical', '-', (22, 33))	('miR-216a-5p', 'Var', (22, 33))	('ESCC', 'Disease', (58, 62))
853412	32901882	In addition, tectonic family member 1 (TCTN1) was proven to be another downstream target of miR-216a-5p in ESCC, and the restoration of TCTN expression reversed the effects of miR-216a-5p on cell proliferation and apoptosis.	('apoptosis', 'CPA', (214, 223))	('tectonic family member 1', 'Gene', '79600', (13, 37))	('restoration', 'Var', (121, 132))	('miR-216a-5p', 'Chemical', '-', (176, 187))	('miR-216a-5p', 'Chemical', '-', (92, 103))	('tectonic family member 1', 'Gene', (13, 37))	('TCTN1', 'Gene', (39, 44))	('ESCC', 'Disease', (107, 111))	('cell proliferation', 'CPA', (191, 209))	('TCTN', 'Gene', (136, 140))	('TCTN1', 'Gene', '79600', (39, 44))	('miR-216a-5p', 'Var', (92, 103))
853413	32901882	Therefore, further investigation of potential targets of miR-216a-5p is needed to fully elucidate the functions of miR-216a-5p in ESCC pathogenesis.	('ESCC', 'Disease', (130, 134))	('miR-216a-5p', 'Var', (115, 126))	('miR-216a-5p', 'Chemical', '-', (115, 126))	('miR-216a-5p', 'Chemical', '-', (57, 68))
853414	32901882	Its major strength is its novelty; to the best of our knowledge, this is the first report to unveil the critical role of the miR-216a-5p/KIAA0101 axis in ESCC pathogenesis.	('miR-216a-5p', 'Chemical', '-', (125, 136))	('ESCC', 'Disease', (154, 158))	('miR-216a-5p/KIAA0101', 'Var', (125, 145))
853418	32901882	Finally, miR-216a-5p has targets other than KIAA0101, and it is possible to modulate the expression of miR-216a-5p affecting ESCC proliferation through proteins other than KIAA0101.	('modulate', 'Reg', (76, 84))	('miR-216a-5p', 'Chemical', '-', (103, 114))	('miR-216a-5p', 'Chemical', '-', (9, 20))	('miR-216a-5p', 'Var', (103, 114))	('affecting', 'Reg', (115, 124))	('ESCC', 'Disease', (125, 129))
853419	32901882	In summary, this is the first report that reveals the targeting effect of miR-216a-5p on KIAA0101 expression in ESCC.	('miR-216a-5p', 'Chemical', '-', (74, 85))	('miR-216a-5p', 'Var', (74, 85))	('ESCC', 'Disease', (112, 116))
853420	32901882	Our results demonstrated the antitumor effects of miR-216a-5p and oncogenic effects of KIAA0101 in ESCC cells in terms of regulating cell proliferation, cell cycle progression, migration, and invasion.	('cell proliferation', 'CPA', (133, 151))	('regulating', 'Reg', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('KIAA0101', 'Gene', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('invasion', 'CPA', (192, 200))	('migration', 'CPA', (177, 186))	('ESCC', 'Disease', (99, 103))	('cell cycle progression', 'CPA', (153, 175))	('miR-216a-5p', 'Chemical', '-', (50, 61))	('tumor', 'Disease', (33, 38))	('miR-216a-5p', 'Var', (50, 61))
853434	32883946	In addition, patients with high predictive scores showed significantly longer overall and relapse-free survival across multiple centers (P < 0.05).	('longer', 'PosReg', (71, 77))	('patients', 'Species', '9606', (13, 21))	('overall', 'CPA', (78, 85))	('high', 'Var', (27, 31))	('relapse-free survival', 'CPA', (90, 111))
853467	32883946	Finally, a survival analysis in the external validation cohort also confirmed that, in patients with a high discriminate score, the OS was significantly longer than that in patients with low discriminate scores (Fig.	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (173, 181))	('longer', 'PosReg', (153, 159))	('high', 'Var', (103, 107))
853486	32883946	We found that high expression PAI-1 was enriched in pCRs and associated with improved survival.	('PAI-1', 'Gene', (30, 35))	('survival', 'MPA', (86, 94))	('PAI-1', 'Gene', '5054', (30, 35))	('high expression', 'Var', (14, 29))	('pCRs', 'Disease', (52, 56))	('improved', 'PosReg', (77, 85))
853490	32883946	Interestingly, a recently study pointed out that knocking out MMP12 caused the accumulation of macrophages in the TME, indicating that knocking out MMP12 may enhance chemoradiotherapy resistance in a macrophage-mediated way.	('knocking out', 'Var', (49, 61))	('enhance', 'PosReg', (158, 165))	('MMP12', 'Gene', (62, 67))	('knocking out', 'Var', (135, 147))	('MMP12', 'Gene', (148, 153))	('accumulation', 'PosReg', (79, 91))	('chemoradiotherapy resistance', 'CPA', (166, 194))	('MMP12', 'Gene', '4321', (62, 67))	('MMP12', 'Gene', '4321', (148, 153))
853498	32883946	What's more, EPS8 knockdown was related to increased chemosensitivity in several different cancer cell lines.	('knockdown', 'Var', (18, 27))	('chemosensitivity', 'MPA', (53, 69))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('EPS8', 'Gene', '2059', (13, 17))	('increased', 'PosReg', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('EPS8', 'Gene', (13, 17))
853530	31725046	MicroRNA-107 inhibits proliferation and invasion of laryngeal squamous cell carcinoma cells by targeting CACNA2D1 in vitro Our previous studies have confirmed that alpha2delta1 has the potential to function as a cancer stem cell marker, and CACNA2D1 is the coding gene of alpha2delta1.	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 85))	('invasion', 'CPA', (40, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('squamous cell carcinoma', 'Disease', (62, 85))	('CACNA2D1', 'Gene', (105, 113))	('targeting', 'Var', (95, 104))	('CACNA2D1', 'Gene', '781', (105, 113))	('cancer', 'Disease', (212, 218))	('MicroRNA-107', 'Gene', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('CACNA2D1', 'Gene', '781', (241, 249))	('proliferation', 'CPA', (22, 35))	('CACNA2D1', 'Gene', (241, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('inhibits', 'NegReg', (13, 21))	('MicroRNA-107', 'Gene', '406901', (0, 12))
853536	31725046	Moreover, the expression of CACNA2D1 and alpha2delta1 protein were significantly decreased in TU212 and TU686 cells transfected with microRNA-107 expression vectors (P < 0.05), and proliferation, clone formation, migration, and invasion of these cells were also reduced.	('proliferation', 'CPA', (181, 194))	('decreased', 'NegReg', (81, 90))	('clone formation', 'CPA', (196, 211))	('expression vectors', 'Species', '29278', (146, 164))	('reduced', 'NegReg', (262, 269))	('expression', 'Species', '29278', (14, 24))	('TU686', 'CellLine', 'CVCL:6985', (104, 109))	('TU212', 'CellLine', 'CVCL:Z025', (94, 99))	('expression', 'MPA', (14, 24))	('expression', 'Species', '29278', (146, 156))	('alpha2delta1 protein', 'Protein', (41, 61))	('TU686', 'Var', (104, 109))	('CACNA2D1', 'Gene', (28, 36))	('invasion of', 'CPA', (228, 239))	('migration', 'CPA', (213, 222))
853545	31725046	The role of miRNAs in cancer has been extensively studied, and dysregulated miRNAs are frequently detected in cancer tissues and cells, which act as oncogenes or tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancer', 'Disease', (110, 116))	('dysregulated', 'Var', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', (162, 167))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
853550	31725046	The expression levels of CACNA2D1 were decreased by miR-107.	('expression levels', 'MPA', (4, 21))	('expression', 'Species', '29278', (4, 14))	('miR-107', 'Var', (52, 59))	('CACNA2D1', 'Gene', (25, 33))	('decreased', 'NegReg', (39, 48))
853591	31725046	The vectors with wild-type 3'-UTR (100 ng) or mutated 3'-UTR (100 ng) were cotransfected with agomiR-107, agomir NC, antagomiR-107, or antagomir NC into TU686 cells in a 96-well plate.	('agomiR-107', 'Chemical', '-', (94, 104))	('mutated', 'Var', (46, 53))	('TU686', 'CellLine', 'CVCL:6985', (153, 158))	('antagomir NC', 'Var', (135, 147))	('antagomiR-107', 'Var', (117, 130))	('agomiR-107', 'Chemical', '-', (120, 130))	('antagomiR-107', 'Chemical', '-', (117, 130))
853593	31725046	Immunofluorescence and Western blot (WB) results indicated that alpha2delta1 was highly expressed in LSCC tissues compared with adjacent normal tissues (P < 0.05; Fig.	('LSCC', 'Disease', 'MESH:D002294', (101, 105))	('alpha2delta1', 'Var', (64, 76))	('LSCC', 'Disease', (101, 105))
853598	31725046	Compared with the control group, the expression levels of CACNA2D1 mRNA and protein (alpha2delta1) in the agomiR-107 group were significantly reduced (Fig.	('agomiR-107', 'Var', (106, 116))	('reduced', 'NegReg', (142, 149))	('agomiR-107', 'Chemical', '-', (106, 116))	('expression levels', 'MPA', (37, 54))	('expression', 'Species', '29278', (37, 47))	('CACNA2D1', 'Gene', (58, 66))
853599	31725046	2c-f), while CACNA2D1 mRNA and alpha2delta1 protein expressions were significantly increased in the antagomiR-107 group (Fig.	('increased', 'PosReg', (83, 92))	('expression', 'Species', '29278', (52, 62))	('CACNA2D1', 'Gene', (13, 21))	('antagomiR-107', 'Var', (100, 113))	('alpha2delta1 protein', 'Protein', (31, 51))	('antagomiR-107', 'Chemical', '-', (100, 113))
853601	31725046	TargetScanHuman 7.1 suggested that there are two putative miR-107 binding sites in the 3'-UTR conserved regions of CACNA2D1 (site A: 202-209; site B: 902-908), and the reporter gene expression vectors containing the CACNA2D1 wild type or mutant 3'-UTR were cloned downstream of the luciferase gene (Fig.	('Human', 'Species', '9606', (10, 15))	('mutant', 'Var', (238, 244))	('expression vectors', 'Species', '29278', (182, 200))	('miR-107', 'Gene', (58, 65))
853605	31725046	In the meantime, antagomiR-107 was able to enhance the luciferase activity at both binding sites (both P < 0.05).	('activity', 'MPA', (66, 74))	('antagomiR-107', 'Chemical', '-', (17, 30))	('antagomiR-107', 'Var', (17, 30))	('luciferase', 'Enzyme', (55, 65))	('enhance', 'PosReg', (43, 50))
853606	31725046	To determine the role of miR-107 in LSCC cell proliferation, we performed MTT assays in TU212 and TU686 cells, and transfected agomiR-107, antagomiR-107, and corresponding NC into these two cell lines.	('antagomiR-107', 'Chemical', '-', (139, 152))	('TU212', 'CellLine', 'CVCL:Z025', (88, 93))	('MTT', 'Chemical', 'MESH:C070243', (74, 77))	('agomiR-107', 'Chemical', '-', (142, 152))	('LSCC', 'Disease', 'MESH:D002294', (36, 40))	('agomiR-107', 'Chemical', '-', (127, 137))	('TU686', 'CellLine', 'CVCL:6985', (98, 103))	('agomiR-107', 'Var', (127, 137))	('LSCC', 'Disease', (36, 40))	('antagomiR-107', 'Var', (139, 152))
853614	31725046	These results suggest that miR-107 can significantly inhibit the migration and invasion of LSCC cells.	('miR-107', 'Var', (27, 34))	('inhibit', 'NegReg', (53, 60))	('LSCC', 'Disease', (91, 95))	('LSCC', 'Disease', 'MESH:D002294', (91, 95))
853616	31725046	The results suggested that the number of clones in the two LSCC cell lines in the agomiR-107 group was significantly lower than that in the control group (P < 0.05; Fig.	('agomiR-107', 'Chemical', '-', (82, 92))	('LSCC cell lines', 'Disease', 'MESH:D002294', (59, 74))	('lower', 'NegReg', (117, 122))	('agomiR-107', 'Var', (82, 92))	('LSCC cell lines', 'Disease', (59, 74))
853618	31725046	This means that miR-107 is able to inhibit clonal formation of LSCC cells.	('clonal formation of', 'CPA', (43, 62))	('miR-107', 'Var', (16, 23))	('LSCC', 'Disease', (63, 67))	('inhibit', 'NegReg', (35, 42))	('LSCC', 'Disease', 'MESH:D002294', (63, 67))
853623	31725046	confirmed that alpha2delta1 plays the role of a marker for liver cancer and lung cancer tumor initiation cells.	('liver cancer', 'Phenotype', 'HP:0002896', (59, 71))	('liver cancer', 'Disease', 'MESH:D006528', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('liver cancer', 'Disease', (59, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('lung cancer tumor', 'Disease', (76, 93))	('alpha2delta1', 'Var', (15, 27))	('lung cancer tumor', 'Disease', 'MESH:D008175', (76, 93))
853624	31725046	Based on this research, our team initially confirmed that the voltage-gated calcium channel subunit alpha2delta1 has the potential to function as a marker of LSCC stem cells, and the alpha2delta1 subunit promotes the progression of LSCC.	('LSCC', 'Disease', (232, 236))	('voltage-gated calcium channel subunit alpha2delta1', 'Gene', (62, 112))	('voltage-gated calcium channel subunit alpha2delta1', 'Gene', '781', (62, 112))	('progression', 'CPA', (217, 228))	('LSCC', 'Disease', (158, 162))	('alpha2delta1', 'Var', (183, 195))	('LSCC', 'Disease', 'MESH:D002294', (232, 236))	('LSCC', 'Disease', 'MESH:D002294', (158, 162))	('promotes', 'PosReg', (204, 212))
853631	31725046	This is consistent with our findings in the LSCC tissue, suggesting that alpha2delta1 may be involved in the key steps in the pathogenesis and progression of LSCC.	('LSCC', 'Disease', (44, 48))	('LSCC', 'Disease', (158, 162))	('involved', 'Reg', (93, 101))	('alpha2delta1', 'Var', (73, 85))	('LSCC', 'Disease', 'MESH:D002294', (44, 48))	('LSCC', 'Disease', 'MESH:D002294', (158, 162))
853632	31725046	Various tumor studies have shown that miRNAs can regulate cancer stem cells and affect the characteristics of cancer cells.	('cancer', 'Disease', (110, 116))	('affect', 'Reg', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('regulate', 'Reg', (49, 57))	('tumor', 'Disease', (8, 13))	('miRNAs', 'Var', (38, 44))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
853645	31725046	Therefore, these experimental results suggest that miR-107 is inversely related to the level of CACNA2D1, and miR-107 may have an effect in inhibiting the progression of LSCC.	('inhibiting', 'NegReg', (140, 150))	('LSCC', 'Disease', 'MESH:D002294', (170, 174))	('miR-107', 'Var', (110, 117))	('progression', 'CPA', (155, 166))	('LSCC', 'Disease', (170, 174))
853648	31725046	Knockdown of miR-107 was closely related to a significant surge in CACNA2D1 expression levels.	('Knockdown', 'Var', (0, 9))	('CACNA2D1', 'Gene', (67, 75))	('expression levels', 'MPA', (76, 93))	('expression', 'Species', '29278', (76, 86))	('surge', 'PosReg', (58, 63))	('miR-107', 'Gene', (13, 20))
853649	31725046	In the biological function study, we found that overexpression of miR-107 not only reduces the expression level of the CACNA2D1 gene, but it also curbs the expression level of CACNA2D1 protein (alpha2delta1).	('miR-107', 'Var', (66, 73))	('CACNA2D1', 'Protein', (176, 184))	('expression', 'Species', '29278', (52, 62))	('expression level', 'MPA', (156, 172))	('reduces', 'NegReg', (83, 90))	('CACNA2D1 gene', 'Gene', (119, 132))	('expression level', 'MPA', (95, 111))	('expression', 'Species', '29278', (156, 166))	('curbs', 'NegReg', (146, 151))	('overexpression', 'PosReg', (48, 62))	('expression', 'Species', '29278', (95, 105))
853650	31725046	After knocking down miR-107, the expression levels of the CACNA2D1 gene and alpha2delta1 were increased.	('increased', 'PosReg', (94, 103))	('expression', 'Species', '29278', (33, 43))	('expression levels', 'MPA', (33, 50))	('CACNA2D1', 'Gene', (58, 66))	('miR-107', 'Gene', (20, 27))	('knocking down', 'Var', (6, 19))
853652	31725046	In contrast, knockdown of miR-107 promoted proliferation, migration, invasion, and colony formation of LSCC cells.	('LSCC', 'Disease', (103, 107))	('promoted', 'PosReg', (34, 42))	('miR-107', 'Gene', (26, 33))	('invasion', 'CPA', (69, 77))	('proliferation', 'CPA', (43, 56))	('knockdown', 'Var', (13, 22))	('colony formation', 'CPA', (83, 99))	('migration', 'CPA', (58, 67))	('LSCC', 'Disease', 'MESH:D002294', (103, 107))
853654	31725046	In addition, we also found that low expression of miR-107 and/or high expression of CACNA2D1 are associated with poor prognosis in patients with LSCC.	('low', 'NegReg', (32, 35))	('high expression', 'MPA', (65, 80))	('patients', 'Species', '9606', (131, 139))	('CACNA2D1', 'Gene', (84, 92))	('LSCC', 'Disease', 'MESH:D002294', (145, 149))	('expression', 'Species', '29278', (70, 80))	('miR-107', 'Var', (50, 57))	('expression', 'Species', '29278', (36, 46))	('LSCC', 'Disease', (145, 149))
853695	30519177	Due to this, per discussions, the patient's findings such as nodules in the subcutaneous areas of the face, within the base of the tongue, neck muscles, paraspinal and iliopsoas musculature were deemed to be more likely metastasis from the EC primary.	('nodules', 'Var', (61, 68))	('patient', 'Species', '9606', (34, 41))	('EC primary', 'Disease', (240, 250))	('metastasis', 'CPA', (220, 230))
853718	29494516	The other ncRNA species are less studied, either due to their recent discovery, such as stable intronic sequence RNA (sisRNA), YRNA, miRNA-offset RNAs (moRNA), telomerase RNA component (TERC), natural antisense transcript (NAT), transcribed ultraconserved regions (T-UCR), and pseudogene transcript, or because they are still largely seen as non-coding transcripts with no relevance to pathogenesis.	('ncRNA', 'Gene', '54719', (10, 15))	('TERC', 'Gene', '7012', (186, 190))	('ncRNA', 'Gene', (10, 15))	('moR', 'Gene', (152, 155))	('moR', 'Gene', '4988', (152, 155))	('pseudogene transcript', 'Var', (277, 298))	('TERC', 'Gene', (186, 190))
853724	29494516	Squamous cell carcinoma is related to NOTCH1, PIK3CA and PTEN mutations, while esophageal cancer is related to high rates of KRAS mutations and HER2 amplification.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('esophageal cancer', 'Disease', (79, 96))	('PIK3CA', 'Gene', '5290', (46, 52))	('KRAS', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('KRAS', 'Gene', '3845', (125, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('Squamous cell carcinoma', 'Disease', (0, 23))	('PTEN', 'Gene', (57, 61))	('HER2', 'Gene', (144, 148))	('PTEN', 'Gene', '5728', (57, 61))	('NOTCH1', 'Gene', '4851', (38, 44))	('NOTCH1', 'Gene', (38, 44))	('HER2', 'Gene', '2064', (144, 148))	('mutations', 'Var', (62, 71))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 23))	('PIK3CA', 'Gene', (46, 52))
853742	29494516	They can be sources of endogenous siRNA and miRNA, can sponge miRNAs or regulate gene expression through epigenetic modifications.	('gene', 'Gene', (81, 85))	('epigenetic modifications', 'Var', (105, 129))	('regulate', 'Reg', (72, 80))	('expression', 'Species', '29278', (86, 96))
853756	29494516	In H9 and HeLa cells, it was discovered that the sisRNA ci-ankrd52 can bind to the Pol II and stimulate the transcription of their own gene of origin.	('bind', 'Interaction', (71, 75))	('transcription', 'MPA', (108, 121))	('ci-ankrd52', 'Var', (56, 66))	('stimulate', 'PosReg', (94, 103))	('HeLa', 'CellLine', 'CVCL:0030', (10, 14))	('Pol II', 'Protein', (83, 89))
853767	29494516	In primary cell culture of macrophage from C57BL/6 J mice and THP.1 monocytes, RNY1 or RNY3 was related with the apoptosis activation through the cleavage of caspase-3 and NFkB signaling pathway.	('RNY3', 'Gene', '19874', (87, 91))	('apoptosis', 'CPA', (113, 122))	('RNY1', 'Var', (79, 83))	('caspase-3', 'Gene', '12367', (158, 167))	('NFkB signaling pathway', 'Pathway', (172, 194))	('RNY3', 'Gene', (87, 91))	('activation', 'PosReg', (123, 133))	('caspase-3', 'Gene', (158, 167))	('cleavage', 'MPA', (146, 154))	('mice', 'Species', '10090', (53, 57))	('THP.1', 'CellLine', 'CVCL:0006', (62, 67))
853821	29494516	At the tRNA 5' end, cleavage is catalyzed by the ubiquitous endoribonuclease RNase P, and tRNA 3' end cleavage is specific for RNase P. The cleaved fragments, that have poly-U repeats at the 3' end, are categorized as tRF-1.	('poly-U repeats', 'Var', (169, 183))	('tRF-1', 'Gene', '7013', (218, 223))	('tRF-1', 'Gene', (218, 223))
853822	29494516	The Dicer enzyme may further process the mature tRNA1 by a cut in the T loop and generate the tRF-3.	('tRNA1', 'Protein', (48, 53))	('cut', 'Var', (59, 62))	('tRF-3', 'Gene', (94, 99))	('tRF-3', 'Gene', '387332', (94, 99))	('T loop', 'Protein', (70, 76))
853829	29494516	Because of their length, pseudogene RNA are sometimes regarded as lncRNAs.	('ncRNA', 'Gene', '54719', (67, 72))	('pseudogene', 'Var', (25, 35))	('ncRNA', 'Gene', (67, 72))
853845	29494516	The down-regulated T-UCRs, i.e., uc.214+, uc.328+, uc.329+ and uc.356+, and up-regulated T-UCRs, i.e., uc.202-, uc.223-, and uc.269-, were found to be associated with the carcinogenesis of this malignancy through tissue microarray analysis.	('carcinogenesis', 'Disease', 'MESH:D063646', (171, 185))	('uc.214+', 'Var', (33, 40))	('uc.202-', 'Var', (103, 110))	('carcinogenesis', 'Disease', (171, 185))	('uc.269-', 'Var', (125, 132))	('up-regulated', 'PosReg', (76, 88))	('malignancy', 'Disease', 'MESH:D009369', (194, 204))	('uc.223-', 'Var', (112, 119))	('down-regulated', 'NegReg', (4, 18))	('uc.328+', 'Var', (42, 49))	('malignancy', 'Disease', (194, 204))	('uc.329+', 'Var', (51, 58))	('uc.356+', 'Var', (63, 70))
853847	29494516	The pseudogene transcripts are dysregulated in the head and neck malignancies (Figure 3 and Table 2), suggesting that they can become valuable diagnostic, prognostic or even therapeutic markers.	('pseudogene', 'Var', (4, 14))	('neck malignancies', 'Disease', 'MESH:D009369', (60, 77))	('neck malignancies', 'Disease', (60, 77))	('head and neck malignancies', 'Phenotype', 'HP:0012288', (51, 77))
853863	29029429	And we investigated the biological pathways that are activated in Twist1-high ESCC using The Cancer Genome Atlas (TCGA) data.	('Twist1-high', 'Var', (66, 77))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (93, 112))	('high ESCC', 'Phenotype', 'HP:0003565', (73, 82))	('Cancer Genome Atlas', 'Disease', (93, 112))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))
853867	29029429	Depletion of Twist1 in ex vivo cultured ESCC CAFs induced significant decrease in migration, invasion, colony formation, sphere formation, and contractibility of ESCC cancer cells compared to control CAFs.	('Twist1', 'Gene', (13, 19))	('sphere formation', 'CPA', (121, 137))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('CAF', 'Gene', '8850', (200, 203))	('CAF', 'Gene', '8850', (45, 48))	('cancer', 'Disease', (167, 173))	('migration', 'CPA', (82, 91))	('Depletion', 'Var', (0, 9))	('CAF', 'Gene', (200, 203))	('CAF', 'Gene', (45, 48))	('invasion', 'CPA', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('decrease', 'NegReg', (70, 78))	('colony formation', 'CPA', (103, 119))	('contractibility', 'CPA', (143, 158))
853894	29029429	In addition, patients with ESCC showing expression of all 5 CAF markers (Twsit1, FSP1, SMA, Tenascin C, PDGFRa) showed significantly reduced OS and DFS rate than other patients (Supplementary Figure 1).	('Tenascin C', 'Gene', (92, 102))	('PDGFRa', 'Gene', (104, 110))	('CAF', 'Gene', (60, 63))	('FSP1', 'Gene', (81, 85))	('expression', 'Var', (40, 50))	('Twsit1', 'Gene', (73, 79))	('FSP1', 'Gene', '6275', (81, 85))	('SMA', 'Gene', (87, 90))	('CAF', 'Gene', '8850', (60, 63))	('patients', 'Species', '9606', (13, 21))	('Tenascin C', 'Gene', '3371', (92, 102))	('patients', 'Species', '9606', (168, 176))	('reduced', 'NegReg', (133, 140))	('PDGFRa', 'Gene', '5156', (104, 110))
853900	29029429	Moreover, we found that the gene signature of breast cancer-stroma-derived prognosis prediction was also marginally upregulated in Twist1-high ESCC (NES = 1.57, FDR q-val = 0.054).	('breast cancer-stroma', 'Disease', 'MESH:D001943', (46, 66))	('high ESCC', 'Phenotype', 'HP:0003565', (138, 147))	('breast cancer-stroma', 'Disease', (46, 66))	('upregulated', 'PosReg', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Twist1-high ESCC', 'Var', (131, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
853903	29029429	Next, we studied whether Twist1 induces the expressions of various CAF markers in esophageal normal fibroblasts and CAFs.	('CAF', 'Gene', (67, 70))	('expressions', 'MPA', (44, 55))	('CAF', 'Gene', (116, 119))	('CAF', 'Gene', '8850', (67, 70))	('CAF', 'Gene', '8850', (116, 119))	('Twist1', 'Var', (25, 31))	('induces', 'Reg', (32, 39))
853907	29029429	As a result, Twist1 increased the expressions of CAF markers including FAPa, PDGFRa.	('increased', 'PosReg', (20, 29))	('expressions', 'MPA', (34, 45))	('FAPa', 'Gene', (71, 75))	('PDGFRa', 'Gene', '5156', (77, 83))	('PDGFRa', 'Gene', (77, 83))	('Twist1', 'Var', (13, 19))	('CAF', 'Gene', (49, 52))	('CAF', 'Gene', '8850', (49, 52))
853914	29029429	On the other hand, shRNA-mediated depletion of Twist1 in esophageal CAFs reduced tumor-promoting ability of CAFs.	('CAF', 'Gene', '8850', (108, 111))	('esophageal CAFs reduced tumor', 'Disease', (57, 86))	('CAF', 'Gene', (68, 71))	('depletion', 'Var', (34, 43))	('CAF', 'Gene', '8850', (68, 71))	('Twist1', 'Gene', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CAF', 'Gene', (108, 111))	('esophageal CAFs reduced tumor', 'Disease', 'MESH:D004938', (57, 86))
853927	29029429	In addition, several highly aggressive cancer-specific histologic parameters such as, endolymphatic tumor emboli, micropapillary pattern, and tumor budding were observed only in TE11+ENF8-Twist1 xenografts not in TE11+ENF8-GFP or TE11 only xenografts (Figure 9D).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Disease', (39, 45))	('TE11+ENF8-Twist1', 'Var', (178, 194))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('micropapillary pattern', 'CPA', (114, 136))	('endolymphatic tumor', 'Phenotype', 'HP:0030393', (86, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('endolymphatic tumor', 'Disease', (86, 105))	('endolymphatic tumor', 'Disease', 'MESH:D018159', (86, 105))
853930	29029429	In addition, the simultaneous expression of Twist1 and other CAF markers was strongly associated with adverse clinical outcome.	('expression', 'Var', (30, 40))	('associated with', 'Reg', (86, 101))	('CAF', 'Gene', (61, 64))	('CAF', 'Gene', '8850', (61, 64))	('Twist1', 'Gene', (44, 50))
853945	29029429	On the other hand, co-expression of Twist1 and CAF markers was strongly correlated with nodal metastasis and unfavorable clinical outcomes.	('co-expression', 'Var', (19, 32))	('correlated', 'Reg', (72, 82))	('nodal metastasis', 'Disease', 'MESH:D009362', (88, 104))	('CAF', 'Gene', (47, 50))	('Twist1', 'Gene', (36, 42))	('CAF', 'Gene', '8850', (47, 50))	('nodal metastasis', 'Disease', (88, 104))
853950	29029429	The current study uncovered a function of Twist1 in tumor-stromal cell communication, demonstrated that Twist1 could be a useful prognostic marker, and indicated that high Twist1 expression correlated with poor prognosis in ESCC, making Twist1 a solid candidate as a potent therapeutic target for ESCC.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Twist1', 'Gene', (172, 178))	('Twist1', 'Gene', (42, 48))	('expression', 'MPA', (179, 189))	('tumor', 'Disease', (52, 57))	('high', 'Var', (167, 171))	('ESCC', 'Disease', (224, 228))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('function', 'Reg', (30, 38))
853963	29029429	The gene sets used for GSEA were as follows: HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION(M5930), MISHRA_CARCINOMA_ASSOCIATED_FIBROBLAST_UP (M18292), HALLMARK_ANGIOGENESIS (M5944), HALLMARK_HYPOXIA (M5891), \FINAK_BREAST_CANCER_SDPP_SIGNATURE (M12461), \MESODERM_DEVELOPMENT(M15421).	('ASSOCIATED', 'Disease', (113, 123))	('M12461', 'Var', (242, 248))	('M5944', 'Var', (171, 176))	('M5930', 'Var', (88, 93))	('ASSOCIATED', 'Disease', 'MESH:D000072716', (113, 123))	('M18292', 'Var', (139, 145))	('GSEA', 'Chemical', '-', (23, 27))	('\\MESODERM_DEVELOPMENT', 'CPA', (251, 272))	('M15421', 'Var', (273, 279))
853969	29029429	Fibroblast cells were collected from the supernatant by centrifugation at 800 rpm for 8 min, washed twice with PBS, and cultured in D/F12 media supplemented with 10% FBS and 1% antibiotics.	('D/F12', 'Var', (132, 137))	('FBS', 'Disease', (166, 169))	('D/F12', 'SUBSTITUTION', 'None', (132, 137))	('FBS', 'Disease', 'MESH:D005198', (166, 169))	('PBS', 'Chemical', 'MESH:D007854', (111, 114))
853970	29029429	NF (#8, #12) and CAF (#8, #12) were seeded in 10 cm dishes, and after overnight attachment and growth, cells were washed twice with PBS and grown in serum-free D/F12 media.	('CAF', 'Gene', (17, 20))	('D/F12', 'Var', (160, 165))	('D/F12', 'SUBSTITUTION', 'None', (160, 165))	('CAF', 'Gene', '8850', (17, 20))	('PBS', 'Chemical', 'MESH:D007854', (132, 135))
853983	33529461	BAP1 mutations are early and rare events in esophageal carcinoma, but the involvement of BAP1 in progression of esophageal carcinoma is unclear.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (44, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('BAP1', 'Gene', (0, 4))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('esophageal carcinoma', 'Disease', (44, 64))	('esophageal carcinoma', 'Disease', (112, 132))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (44, 64))
853984	33529461	Here, we report that cell proliferation and migration were significantly enhanced in esophageal carcinoma ECA109 cells overexpressing BAP1, while they were diminished upon BAP1 knockdown.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('esophageal carcinoma', 'Disease', (85, 105))	('BAP1', 'Gene', (134, 138))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (85, 105))	('cell proliferation', 'CPA', (21, 39))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (85, 105))	('overexpressing', 'Var', (119, 133))	('enhanced', 'PosReg', (73, 81))
854000	33529461	Deletions, loss of heterozygosity, missense mutations, and large rearrangements in the BAP1 gene locus have been found in lung and sporadic breast tumors and lung cancer cell lines [7].	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('lung cancer', 'Disease', (158, 169))	('breast tumors', 'Phenotype', 'HP:0100013', (140, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('loss of heterozygosity', 'Var', (11, 33))	('BAP1', 'Gene', (87, 91))	('rearrangements', 'Var', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('found', 'Reg', (113, 118))	('sporadic breast tumors', 'Disease', (131, 153))	('missense mutations', 'Var', (35, 53))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('lung', 'Disease', (122, 126))	('Deletions', 'Var', (0, 9))	('sporadic breast tumors', 'Disease', 'MESH:D001943', (131, 153))
854019	33529461	Antibodies against BAP1 (ab245391, 1 : 2000), KLF5 (ab137676, 1 : 1000), CyclinD1 (ab134175, 1 : 10 000), and FGF-BP1 (ab215353, 1 : 500) were provided by Abcam (Cambridge, UK).	('ab245391', 'Var', (25, 33))	('ab215353', 'Var', (119, 127))	('FGF-BP1', 'Gene', '9982', (110, 117))	('CyclinD1', 'Gene', '595', (73, 81))	('FGF-BP1', 'Gene', (110, 117))	('KLF5', 'Gene', (46, 50))	('KLF5', 'Gene', '688', (46, 50))	('CyclinD1', 'Gene', (73, 81))
854026	33529461	As expected, the expression of KLF5 was enhanced in the BAP1 overexpression system compared with that in the control (Fig.	('overexpression system', 'Var', (61, 82))	('KLF5', 'Gene', (31, 35))	('expression', 'MPA', (17, 27))	('KLF5', 'Gene', '688', (31, 35))	('BAP1', 'Gene', (56, 60))	('enhanced', 'PosReg', (40, 48))
854027	33529461	KLF5 mRNA levels were also significantly reduced in ECA109 cells transfected with siRNA-BAP1 compared with those in the NC group (Fig.	('reduced', 'NegReg', (41, 48))	('siRNA-BAP1', 'Var', (82, 92))	('KLF5', 'Gene', (0, 4))	('KLF5', 'Gene', '688', (0, 4))
854028	33529461	Interestingly, we found that the expression of downstream genes, KLF5, CyclinD1, and FGF-BP1, was positively regulated by the expression of KLF5.	('FGF-BP1', 'Gene', (85, 92))	('KLF5', 'Gene', (65, 69))	('KLF5', 'Gene', '688', (65, 69))	('KLF5', 'Gene', '688', (140, 144))	('regulated', 'Reg', (109, 118))	('CyclinD1', 'Gene', (71, 79))	('expression', 'Var', (126, 136))	('expression', 'MPA', (33, 43))	('FGF-BP1', 'Gene', '9982', (85, 92))	('CyclinD1', 'Gene', '595', (71, 79))	('KLF5', 'Gene', (140, 144))
854037	33529461	first reported a meta-relationship between BAP1 deletion and the diagnoses and prognoses of various cancer types, and confirmed that BAP1 is a marker of poor prognosis in diverse cancer types, including uveal melanoma, renal cell carcinoma, cholangiocarcinoma, non-small cell lung cancer, and colorectal cancer [12].	('BAP1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (261, 287))	('cancer', 'Disease', (304, 310))	('colorectal cancer', 'Phenotype', 'HP:0003003', (293, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('renal cell carcinoma', 'Disease', (219, 239))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('deletion', 'Var', (48, 56))	('lung cancer', 'Disease', (276, 287))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('uveal melanoma', 'Phenotype', 'HP:0007716', (203, 217))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (219, 239))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (265, 287))	('cholangiocarcinoma', 'Disease', (241, 259))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('uveal melanoma', 'Disease', (203, 217))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('colorectal cancer', 'Disease', 'MESH:D015179', (293, 310))	('lung cancer', 'Disease', 'MESH:D008175', (276, 287))	('cancer', 'Disease', (100, 106))	('colorectal cancer', 'Disease', (293, 310))	('lung cancer', 'Phenotype', 'HP:0100526', (276, 287))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (219, 239))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (281, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Disease', (179, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (203, 217))
854038	33529461	Inactivating BAP1 mutants were found in two patients with uveal melanoma by exon capture and large-scale sequencing, and BAP1 mutants were also found in 25 (45%) of 55 additional cases of uveal melanoma [13].	('BAP1', 'Gene', (13, 17))	('patients', 'Species', '9606', (44, 52))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('mutants', 'Var', (18, 25))	('BAP1', 'Gene', (121, 125))	('Inactivating', 'Var', (0, 12))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (188, 202))	('found', 'Reg', (144, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (188, 202))	('uveal melanoma', 'Disease', (188, 202))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('uveal melanoma', 'Disease', (58, 72))	('found', 'Reg', (31, 36))	('mutants', 'Var', (126, 133))
854039	33529461	suggested that the deletion of BAP1 is a diagnostic marker of mesothelioma in effusion cytology [14].	('mesothelioma in effusion', 'Disease', 'MESH:D008654', (62, 86))	('mesothelioma in effusion', 'Disease', (62, 86))	('BAP1', 'Gene', (31, 35))	('deletion', 'Var', (19, 27))
854041	33529461	BAP1 mutations have been reported as early and rare events in esophageal cancer [15].	('BAP1', 'Gene', (0, 4))	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (5, 14))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))
854045	33529461	Proliferation and migration of ECA109 cells were significantly inhibited by BAP1 knockdown, which is consistent with the results reported by Qin et al.	('Qin', 'Gene', (141, 144))	('migration', 'CPA', (18, 27))	('knockdown', 'Var', (81, 90))	('Qin', 'Gene', '2290', (141, 144))	('BAP1', 'Gene', (76, 80))	('inhibited', 'NegReg', (63, 72))
854047	33529461	Both mRNA expression and protein expression of KLF5 increased significantly in the BAP1 overexpression system, whereas the expression was impaired in the BAP1 knockdown system.	('increased', 'PosReg', (52, 61))	('mRNA expression', 'MPA', (5, 20))	('BAP1', 'Gene', (83, 87))	('protein expression', 'MPA', (25, 43))	('overexpression', 'Var', (88, 102))	('KLF5', 'Gene', (47, 51))	('KLF5', 'Gene', '688', (47, 51))
854087	21075347	Cdx2 is also phosphorylated at serine 281 by cyclin-dependent kinase 2 (Cdk2) and shunted toward the proteosome for degradation.	('Cdk2', 'Gene', '1017', (72, 76))	('shunted', 'MPA', (82, 89))	('cyclin-dependent kinase 2', 'Gene', '1017', (45, 70))	('Cdk2', 'Gene', (72, 76))	('serine', 'Chemical', 'MESH:D012694', (31, 37))	('serine 281', 'Var', (31, 41))	('cyclin-dependent kinase 2', 'Gene', (45, 70))
854106	21075347	Foxa3-Cre mice were bred with Cdx2 loxP mice to disrupt the Cdx2 gene prior to development of the intestinal epithelium.	('Foxa3', 'Gene', (0, 5))	('disrupt', 'Var', (48, 55))	('Cdx2 gene', 'Gene', (60, 69))	('mice', 'Species', '10090', (10, 14))	('Foxa3', 'Gene', '15377', (0, 5))	('mice', 'Species', '10090', (40, 44))
854107	21075347	Loss of Cdx2 in this context results in the replacement of normal simple columnar intestinal cells with a stratified squamous epithelium in the proximal intestine, consisting of keratinocytes due to aberrant expression of esophageal transcription factors including Sox2.	('rat', 'Species', '10116', (108, 111))	('rat', 'Species', '10116', (180, 183))	('Sox2', 'Gene', (265, 269))	('Cdx2', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('Sox2', 'Gene', '6657', (265, 269))
854117	21075347	This association with neoplasia remains incompletely explained, but current hypotheses suggest that the cellular environment that provokes IM also likely induces mutations within metaplastic cells.	('mutations', 'Var', (162, 171))	('induces', 'Reg', (154, 161))	('neoplasia', 'Disease', (22, 31))	('neoplasia', 'Phenotype', 'HP:0002664', (22, 31))	('neoplasia', 'Disease', 'MESH:D009369', (22, 31))
854118	21075347	It is these genetic mutations, though not obvious histologically in the benign-appearing IM, that contribute to transformation and neoplasia of these tissues.	('neoplasia', 'Disease', (131, 140))	('genetic mutations', 'Var', (12, 29))	('neoplasia', 'Disease', 'MESH:D009369', (131, 140))	('contribute to', 'Reg', (98, 111))	('neoplasia', 'Phenotype', 'HP:0002664', (131, 140))	('transformation', 'CPA', (112, 126))
854130	21075347	However, some (but not all) human studies suggest the Type III GIM has the highest risk for progression to gastric adenocarcinoma.	('human', 'Species', '9606', (28, 33))	('gastric adenocarcinoma', 'Disease', (107, 129))	('Type III', 'Var', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (107, 129))
854149	21075347	However, the presence of BE has been implicated as an important risk factor for esophageal adenocarcinoma (EAC) (Figure 6).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (80, 105))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (80, 105))	('presence', 'Var', (13, 21))	('esophageal adenocarcinoma', 'Disease', (80, 105))
854191	21075347	VacA induces vacuolization of the epithelium and subsequently apoptosis, contributing to the formation of gastric ulcers.	('vacuolization', 'MPA', (13, 26))	('gastric ulcers', 'Disease', 'MESH:D013276', (106, 120))	('gastric ulcers', 'Disease', (106, 120))	('apoptosis', 'CPA', (62, 71))	('contributing to', 'Reg', (73, 88))	('gastric ulcers', 'Phenotype', 'HP:0002592', (106, 120))	('VacA', 'Var', (0, 4))
854196	21075347	This results in dysregulated tyrosine phosphatase activity within the cell and may potentiate a tissue response to the infection and inflammation as a result of H. pylori infection.	('infection', 'Disease', (171, 180))	('infection', 'Disease', 'MESH:D007239', (171, 180))	('H. pylori', 'Species', '210', (161, 170))	('H. pylori', 'Disease', (161, 170))	('infection', 'Disease', (119, 128))	('dysregulated', 'Var', (16, 28))	('inflammation', 'Disease', 'MESH:D007249', (133, 145))	('infection', 'Disease', 'MESH:D007239', (119, 128))	('H. pylori infection', 'Phenotype', 'HP:0005202', (161, 180))	('inflammation', 'Disease', (133, 145))	('results', 'Reg', (5, 12))	('tyrosine phosphatase activity', 'MPA', (29, 58))	('potentiate', 'PosReg', (83, 93))
854210	21075347	DNA nucleotides are very stable chemically, but free-radicals can induce DNA single and double-stranded breaks as well as modifications of purine and pyrimidine bases.	('modifications', 'MPA', (122, 135))	('purine', 'Chemical', 'MESH:C030985', (139, 145))	('pyrimidine', 'Chemical', 'MESH:C030986', (150, 160))	('induce', 'Reg', (66, 72))	('free-radicals', 'Var', (48, 61))
854213	21075347	If not excised prior to DNA replication, the 8-nitroguanine will induce a G to T point mutation.	('8-nitroguanine', 'Chemical', 'MESH:C095838', (45, 59))	('8-nitroguanine', 'Var', (45, 59))	('induce', 'Reg', (65, 71))
854214	21075347	This type of mutation, when occurring within gene coding regions, can lead to missense and nonsense mutations that activate oncogenes like Ras, or inactivate tumor suppressors like p53.	('p53', 'Gene', (181, 184))	('mutations', 'Var', (100, 109))	('oncogenes', 'Gene', (124, 133))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutation', 'Var', (13, 21))	('inactivate', 'NegReg', (147, 157))	('activate', 'PosReg', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Ras', 'Protein', (139, 142))	('missense', 'Var', (78, 86))	('lead', 'Reg', (70, 74))
854240	21075347	All of these findings show that aberrant expression of CDX2 is consistently observed in GIM and in a subset of gastric carcinomas, and indirectly implies that CDX2 expression may promote the intestinal differentiation characteristic of GIM.	('CDX2', 'Gene', (159, 163))	('CDX2', 'Gene', '1045', (55, 59))	('expression', 'MPA', (41, 51))	('GIM', 'Disease', (88, 91))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (111, 128))	('CDX2', 'Gene', '1045', (159, 163))	('promote', 'PosReg', (179, 186))	('intestinal differentiation', 'CPA', (191, 217))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('gastric carcinomas', 'Disease', (111, 129))	('CDX2', 'Gene', (55, 59))	('aberrant', 'Var', (32, 40))	('gastric carcinomas', 'Disease', 'MESH:D013274', (111, 129))	('observed', 'Reg', (76, 84))
854241	21075347	In addition to this clinical association of Cdx expression with GIM, the ectopic expression of Cdx1 and Cdx2 has been shown to cause gastric intestinal metaplasia experimentally.	('Cdx', 'Gene', (95, 98))	('ectopic expression', 'Var', (73, 91))	('cause', 'Reg', (127, 132))	('Cdx', 'Gene', (104, 107))	('Cdx', 'Gene', '12590', (104, 107))	('gastric intestinal metaplasia', 'Disease', (133, 162))	('Cdx', 'Gene', '12590', (44, 47))	('Cdx', 'Gene', '12590', (95, 98))	('gastric intestinal metaplasia', 'Disease', 'MESH:D013274', (133, 162))	('Cdx', 'Gene', (44, 47))
854242	21075347	Several transgenic mouse models have been reported in which ectopic Cdx1 or Cdx2 expression was directed to gastric epithelium.	('Cdx1', 'Gene', (68, 72))	('ectopic', 'Var', (60, 67))	('transgenic', 'Species', '10090', (8, 18))	('Cdx2', 'Gene', (76, 80))	('mouse', 'Species', '10090', (19, 24))
854245	21075347	Moreover, in Foxa 3/Cdx2 transgenic mice, the intestinal-type goblet cells produced sulfated mucins, which is consistent with a type III GIM.	('mucin', 'Gene', '100508689', (93, 98))	('sulfated', 'MPA', (84, 92))	('Foxa 3', 'Gene', '15377', (13, 19))	('mucin', 'Gene', (93, 98))	('transgenic mice', 'Species', '10090', (25, 40))	('Foxa 3', 'Gene', (13, 19))	('transgenic', 'Var', (25, 35))
854257	21075347	Mutations in p53 and APC genes were identified in many of the tumors to explain the nuclear localization of these factors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('APC', 'Disease', 'MESH:D011125', (21, 24))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('APC', 'Disease', (21, 24))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))
854258	21075347	As a proof of the proposed model, crossing the H+/K+-ATPase /Cdx2 mice with transgenic mouse lines that harbored mutations in the p53 or APC genes led to accelerated gastric tumorigenesis by 30 weeks of age.	('tumor', 'Disease', (174, 179))	('transgenic', 'Species', '10090', (76, 86))	('APC', 'Disease', 'MESH:D011125', (137, 140))	('mouse', 'Species', '10090', (87, 92))	('H+/K+-ATPase', 'Gene', (47, 59))	('rat', 'Species', '10116', (160, 163))	('accelerated', 'PosReg', (154, 165))	('APC', 'Disease', (137, 140))	('mice', 'Species', '10090', (66, 70))	('H+/K+-ATPase', 'Gene', '11945', (47, 59))	('mutations', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('p53', 'Gene', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
854260	21075347	Despite these limitations, together these findings suggest ectopic Cdx1 or Cdx2 expression in gastric epithelium is sufficient to induce gastric intestinal metaplasia and adenocarcinoma in murine model systems.	('induce', 'PosReg', (130, 136))	('Cdx1', 'Gene', (67, 71))	('ectopic', 'Var', (59, 66))	('gastric intestinal metaplasia and adenocarcinoma', 'Disease', 'MESH:D013274', (137, 185))	('murine', 'Species', '10090', (189, 195))	('Cdx2', 'Gene', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
854265	21075347	Of interest, BMP4 has an important role in promoting differentiation of intestinal epithelial cells, and mutations in members of this pathway have been associated with juvenile polyposis syndrome, which is a hamartomatous syndrome of the intestine and colon.	('BMP4', 'Gene', (13, 17))	('hamartomatous syndrome', 'Disease', 'MESH:C563621', (208, 230))	('juvenile polyposis syndrome', 'Disease', (168, 195))	('hamartomatous syndrome of the intestine and colon', 'Phenotype', 'HP:0004390', (208, 257))	('mutations', 'Var', (105, 114))	('BMP4', 'Gene', '652', (13, 17))	('juvenile polyposis syndrome', 'Phenotype', 'HP:0004784', (168, 195))	('associated', 'Reg', (152, 162))	('hamartomatous syndrome', 'Disease', (208, 230))	('juvenile polyposis syndrome', 'Disease', 'MESH:C537702', (168, 195))
854276	21075347	Whether loss of SOX2 in GIM is an etiologic cause for ectopic CDX2 gene expression will need to be clarified in future studies.	('CDX2', 'Gene', '1045', (62, 66))	('expression', 'MPA', (72, 82))	('SOX2', 'Gene', '6657', (16, 20))	('SOX2', 'Gene', (16, 20))	('loss', 'Var', (8, 12))	('ectopic', 'MPA', (54, 61))	('CDX2', 'Gene', (62, 66))
854321	21075347	Since inactivating p53 mutations are acquired late in Barrett's esophagus, HET-1A cells may therefore not be an ideal cell line in which to study CDX2-mediated intestinalization.	('CDX2', 'Gene', '1045', (146, 150))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (54, 73))	('mutations', 'Var', (23, 32))	('p53', 'Gene', (19, 22))	('inactivating', 'Var', (6, 18))	('CDX2', 'Gene', (146, 150))
854323	21075347	EPC-hTERT cells are immortalized only by ectopic expression of human telomerase protein (hTERT).	('hTERT', 'Gene', (4, 9))	('human', 'Species', '9606', (63, 68))	('hTERT', 'Gene', (89, 94))	('hTERT', 'Gene', '7015', (89, 94))	('ectopic expression', 'Var', (41, 59))	('hTERT', 'Gene', '7015', (4, 9))	('EPC-hTERT', 'CellLine', 'CVCL:4361', (0, 9))
854358	21075347	Treatment of explant cultures of normal human esophagi with all-trans retinoic acid induces ulceration and sloughing of the stratified epithelial cells with concomitant proliferation of submucosal glands.	('rat', 'Species', '10116', (176, 179))	('all-trans', 'Var', (60, 69))	('sloughing', 'CPA', (107, 116))	('ulceration', 'CPA', (92, 102))	('rat', 'Species', '10116', (126, 129))	('rat', 'Species', '10116', (96, 99))	('retinoic acid', 'Chemical', 'MESH:D014212', (70, 83))	('human', 'Species', '9606', (40, 45))
854386	21075347	Also among the genes whose expression is regulated by methylation in BE are CDX1 and CDX2.	('methylation', 'Var', (54, 65))	('CDX1', 'Gene', (76, 80))	('CDX2', 'Gene', (85, 89))	('CDX2', 'Gene', '1045', (85, 89))	('CDX1', 'Gene', '1044', (76, 80))
854387	21075347	However, unlike p16INK4 and other tumor suppressor genes, the CDX1 and CDX2 genes appear to be demethylated in BE cells compared to normal squamous esophagus.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('CDX1', 'Gene', (62, 66))	('CDX2', 'Gene', (71, 75))	('CDX1', 'Gene', '1044', (62, 66))	('p16INK4', 'Gene', '1029', (16, 23))	('p16INK4', 'Gene', (16, 23))	('CDX2', 'Gene', '1045', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('demethylated', 'Var', (95, 107))
854393	21075347	In human biopsy specimens of normal esophagus, EAC, and esophageal squamous cell carcinomas (ESCC), the CDX2 gene was demethylated only in the EAC tissues.	('CDX2', 'Gene', '1045', (104, 108))	('human', 'Species', '9606', (3, 8))	('esophageal squamous cell carcinomas', 'Disease', (56, 91))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (56, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('demethylated', 'Var', (118, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('CDX2', 'Gene', (104, 108))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (67, 91))
854415	29416812	Based on the similarity between Siewert I GEJ cancer and esophageal cancer, Siewert III GEJ cancer and gastric cancer, the treatment for Siewert I and III type cancers mirror those for esophageal and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (208, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('esophageal', 'Disease', 'MESH:D004941', (57, 67))	('cancer', 'Disease', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('III type cancers', 'Disease', 'MESH:D009369', (151, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancer', 'Disease', (160, 166))	('Siewert III GEJ', 'Var', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', (46, 52))	('esophageal', 'Disease', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('esophageal cancer', 'Disease', (57, 74))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal', 'Disease', (57, 67))	('gastric cancer', 'Disease', (200, 214))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('III type cancers', 'Disease', (151, 167))	('gastric cancer', 'Disease', (103, 117))	('cancer', 'Disease', (68, 74))	('esophageal', 'Disease', 'MESH:D004941', (185, 195))
854444	29416812	Seer histology stage was divided into 4 subtypes (reginal, localized, distant and unstaged), and we found that among all these four subtypes, RLNs were significantly associated with OS (Figure 7) and CSS (Figure 8) (P < 0.05).	('CSS', 'Disease', (200, 203))	('CSS', 'Chemical', '-', (200, 203))	('RLNs', 'Var', (142, 146))	('associated', 'Reg', (166, 176))	('OS', 'Chemical', '-', (182, 184))
854472	29416812	In conclusion, RLNs was an independent prognostic factor for Siewert type II GEJ cancer patients and patients can achieve better overall and cancer-specific survival with 21 or more LNs dissected.	('better', 'PosReg', (122, 128))	('patients', 'Species', '9606', (101, 109))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('Siewert type II GEJ cancer', 'Disease', 'MESH:D007619', (61, 87))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Siewert type II GEJ cancer', 'Disease', (61, 87))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (141, 147))	('RLNs', 'Var', (15, 19))
854488	28267808	The most suitable method of digestive tract reconstruction after esophagectomy for esophageal cancer is the anastomosis of the esophageal remnant with the stomach, as this ensures a reliable blood supply.	('esophageal remnant', 'Phenotype', 'HP:0100628', (127, 145))	('esophageal cancer', 'Disease', (83, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('anastomosis', 'Var', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))
854508	28267808	compared the rates of anastomotic leakage between patients who had undergone esophagogastric anastomosis with hand suturing vs. stapling, and found that the incidence of anastomotic leakage was lower after stapling than after hand suturing.	('patients', 'Species', '9606', (50, 58))	('stapling', 'Var', (206, 214))	('esophagogastric anastomosis', 'Phenotype', 'HP:0100628', (77, 104))	('anastomotic leakage', 'MPA', (170, 189))	('anastomotic leakage', 'MPA', (22, 41))	('lower', 'NegReg', (194, 199))
854513	27026921	Association between OGG1 Ser326Cys polymorphism and risk of upper aero-digestive tract and gastrointestinal cancers: a meta-analysis Cancers of the upper aero-digestive and gastrointestinal tract are one of the major causes of mortality around the world.	('Ser326Cys', 'Var', (25, 34))	('gastrointestinal tract', 'Disease', (173, 195))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (91, 115))	('Cancers', 'Disease', (133, 140))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('gastrointestinal cancers', 'Disease', (91, 115))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (173, 195))	('Cancers', 'Disease', 'MESH:D009369', (133, 140))	('Cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('OGG1', 'Gene', (20, 24))	('Association', 'Interaction', (0, 11))	('OGG1', 'Gene', '4968', (20, 24))	('Ser326Cys', 'SUBSTITUTION', 'None', (25, 34))
854515	27026921	Polymorphisms in the nucleotide sequence of DNA repair genes are often reported to be associated with an increased risk for different cancers.	('DNA repair genes', 'Gene', (44, 60))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('Polymorphisms', 'Var', (0, 13))	('cancers', 'Disease', (134, 141))	('associated', 'Reg', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
854517	27026921	Several studies report that the OGG1 Ser326Cys polymorphism increases the risk for cancers of the upper aero-digestive and gastrointestinal tract.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('OGG1', 'Gene', (32, 36))	('Ser326Cys', 'Var', (37, 46))	('OGG1', 'Gene', '4968', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Ser326Cys', 'SUBSTITUTION', 'None', (37, 46))	('gastrointestinal tract', 'Disease', (123, 145))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (123, 145))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('increases', 'PosReg', (60, 69))	('cancers', 'Disease', (83, 90))
854518	27026921	A meta-analysis to assess the role of OGG1 Ser326Cys polymorphism in the cancers of the upper aero-digestive and gastrointestinal tract was therefore undertaken in order to resolve this ambiguity.	('cancers', 'Disease', (73, 80))	('Ser326Cys', 'Var', (43, 52))	('gastrointestinal tract', 'Disease', (113, 135))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Ser326Cys', 'SUBSTITUTION', 'None', (43, 52))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('OGG1', 'Gene', (38, 42))	('OGG1', 'Gene', '4968', (38, 42))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (113, 135))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
854519	27026921	Our study reveals an association between OGG1 Ser326Cys polymorphism and cancer susceptibility of the upper aero-digestive and gastrointestinal tract (CG + GG vs CC; odds ratio, OR 1.22; 95 % CI 1.05-1.41; GG vs CG + CC; OR 1.36; 95 % CI 1.09-1.70; GG vs CC; OR 1.46; 95 % CI 1.12-1.92).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Ser326Cys', 'Var', (46, 55))	('OGG1', 'Gene', '4968', (41, 45))	('polymorphism', 'Var', (56, 68))	('Ser326Cys', 'SUBSTITUTION', 'None', (46, 55))	('CG', 'Chemical', 'MESH:C028505', (212, 214))	('CG', 'Chemical', 'MESH:C028505', (151, 153))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('gastrointestinal tract', 'Disease', (127, 149))	('OGG1', 'Gene', (41, 45))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (127, 149))
854520	27026921	Subgroup analysis based on cancer types and ethnicity also revealed the association of OGG1 Ser326Cys polymorphism to the risk for upper aero-digestive and gastrointestinal tract cancers among both the Asian and the Caucasian populations.	('polymorphism', 'Var', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('upper aero-digestive', 'Disease', (131, 151))	('gastrointestinal tract cancers', 'Disease', (156, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('association', 'Interaction', (72, 83))	('Ser326Cys', 'SUBSTITUTION', 'None', (92, 101))	('Ser326Cys', 'Var', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('OGG1', 'Gene', '4968', (87, 91))	('OGG1', 'Gene', (87, 91))	('cancer', 'Disease', (179, 185))	('gastrointestinal tract cancers', 'Disease', 'MESH:D004067', (156, 186))
854521	27026921	No risk was however observed for smoking habits and OGG1 Ser326Cys polymorphism.	('Ser326Cys', 'Var', (57, 66))	('OGG1', 'Gene', '4968', (52, 56))	('OGG1', 'Gene', (52, 56))	('Ser326Cys', 'SUBSTITUTION', 'None', (57, 66))
854522	27026921	In conclusion, OGG1 Ser326Cys polymorphism may be associated with the increased risk for aero-digestive tract and gastro-intestinal cancers in both Asian and Caucasian populations.	('gastro-intestinal cancers', 'Disease', (114, 139))	('OGG1', 'Gene', (15, 19))	('OGG1', 'Gene', '4968', (15, 19))	('Ser326Cys', 'SUBSTITUTION', 'None', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('aero-digestive tract', 'Disease', (89, 109))	('Ser326Cys', 'Var', (20, 29))	('associated', 'Reg', (50, 60))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('gastro-intestinal cancers', 'Disease', 'MESH:D007414', (114, 139))
854527	27026921	Most cancers primarily involve the dysregulation of three classes of genes viz., (proto) oncogenes, tumor suppressor genes and DNA repair genes.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('tumor', 'Disease', (100, 105))	('cancers', 'Disease', (5, 12))	('involve', 'Reg', (23, 30))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('dysregulation', 'Var', (35, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
854533	27026921	Tobacco smoke contains various carcinogens among which benzo[a]pyrene induces 8-oxoG formation in animal tissue.	('benzo[a]pyrene', 'Var', (55, 69))	('induces', 'Reg', (70, 77))	('carcinogens', 'Disease', 'MESH:D063646', (31, 42))	('Tobacco', 'Species', '4097', (0, 7))	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (55, 69))	('8-oxoG formation', 'MPA', (78, 94))	('8-oxoG', 'Chemical', 'MESH:C453560', (78, 84))	('carcinogens', 'Disease', (31, 42))
854539	27026921	It removes the 8-oxoG lesion by slicing the glycosydic bond between the modified base and the sugar moiety, leaving an abasic apurinic/apyrimidinic (AP) site in DNA (Zhou et al.).	('slicing', 'Var', (32, 39))	('leaving', 'Reg', (108, 115))	('abasic', 'MPA', (119, 125))	('8-oxoG', 'Chemical', 'MESH:C453560', (15, 21))	('sugar', 'Chemical', 'MESH:D000073893', (94, 99))
854540	27026921	There are at least 20 validated sequence variants of OGG1 gene, of which the most studied functional polymorphism is an amino acid substitution of serine (Ser) with cysteine (Cys) (Ser326Cys) resulting from a C to G transversion at position 1245 in exon 7 of the OGG1 gene (Bravard et al.).	('Cys', 'Chemical', 'MESH:D003545', (187, 190))	('Ser', 'Chemical', 'MESH:D012694', (155, 158))	('OGG1', 'Gene', (263, 267))	('Ser', 'Chemical', 'MESH:D012694', (181, 184))	('OGG1', 'Gene', (53, 57))	('OGG1', 'Gene', '4968', (53, 57))	('C to G transversion at position 1245', 'Mutation', 'rs1052133', (209, 245))	('OGG1', 'Gene', '4968', (263, 267))	('serine', 'Chemical', 'MESH:D012694', (147, 153))	('Ser326Cys', 'Var', (181, 190))	('Cys', 'Chemical', 'MESH:D003545', (175, 178))	('amino acid substitution', 'Var', (120, 143))	('Ser326Cys', 'SUBSTITUTION', 'None', (181, 190))	('cysteine', 'Chemical', 'MESH:D003545', (165, 173))
854542	27026921	In most of these studies the Ser326Cys polymorphism was found to increase the risk for different cancers such as head and neck cancer, colorectal cancer and gall bladder cancer (Kumar et al.	('increase', 'PosReg', (65, 73))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('cancers', 'Disease', (97, 104))	('Ser326Cys', 'SUBSTITUTION', 'None', (29, 38))	('Ser326Cys', 'Var', (29, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (162, 176))	('head and neck cancer', 'Disease', 'MESH:D006258', (113, 133))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('gall bladder cancer', 'Disease', (157, 176))	('head and neck cancer', 'Phenotype', 'HP:0012288', (113, 133))	('colorectal cancer', 'Disease', (135, 152))	('gall bladder cancer', 'Disease', 'MESH:D005706', (157, 176))
854543	27026921	However, some recent studies have also reported no association of Ser326Cys polymorphism with the increased risk for cancer (Gorgens et al.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('Ser326Cys', 'SUBSTITUTION', 'None', (66, 75))	('Ser326Cys', 'Var', (66, 75))
854544	27026921	It has also been reported that individuals with the homozygous recessive allele of OGG1 (Cys326Cys) and a 50 % increase in vegetable and fruit intake are at 50 % decreased risk of developing lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('increase', 'PosReg', (111, 119))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('Cys326Cys', 'Chemical', '-', (89, 98))	('decreased', 'NegReg', (162, 171))	('OGG1', 'Gene', (83, 87))	('Cys326Cys', 'Var', (89, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('OGG1', 'Gene', '4968', (83, 87))	('lung cancer', 'Disease', (191, 202))
854545	27026921	This study has therefore been undertaken in order to resolve the ambiguity regarding the association between OGG1 Ser326Cys polymorphism and susceptibility to upper aero-digestive tract and gastrointestinal cancers.	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('gastrointestinal cancers', 'Disease', (190, 214))	('Ser326Cys', 'Var', (114, 123))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (190, 214))	('OGG1', 'Gene', (109, 113))	('upper aero-digestive tract', 'Disease', (159, 185))	('Ser326Cys', 'SUBSTITUTION', 'None', (114, 123))	('OGG1', 'Gene', '4968', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))
854546	27026921	Research articles relevant to the study were searched through the search engines "PubMed", "OMIM" and "Google Scholar" using search terms like "OGG1, hOGG1", "polymorphism, alleles, Ser326Cys, variants", "cancer, gastric cancer, colorectal cancer, head and neck cancer, oral cancer, aero-digestive tract cancer, pharyngeal cancer, pancreatic cancer, gallbladder cancer, cancer of digestive tract, esophageal cancer.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('hOGG1', 'Gene', (150, 155))	('cancer', 'Disease', (342, 348))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('cancer', 'Disease', (304, 310))	('colorectal cancer', 'Phenotype', 'HP:0003003', (229, 246))	('gastric cancer', 'Disease', (213, 227))	('pancreatic cancer', 'Disease', 'MESH:D010190', (331, 348))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (240, 246))	('tract cancer', 'Disease', 'MESH:D014571', (298, 310))	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('colorectal cancer', 'Disease', 'MESH:D015179', (229, 246))	('pancreatic cancer', 'Disease', (331, 348))	('cancer', 'Disease', 'MESH:D009369', (408, 414))	('gallbladder cancer', 'Disease', (350, 368))	('gastric cancer', 'Disease', 'MESH:D013274', (213, 227))	('Ser326Cys', 'SUBSTITUTION', 'None', (182, 191))	('Ser326Cys', 'Var', (182, 191))	('cancer', 'Disease', (262, 268))	('colorectal cancer', 'Disease', (229, 246))	('tract cancer', 'Disease', (298, 310))	('pharyngeal cancer', 'Disease', 'MESH:D010610', (312, 329))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('pharyngeal cancer', 'Disease', (312, 329))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('cancer', 'Disease', (221, 227))	('polymorphism', 'Var', (159, 171))	('cancer', 'Disease', (205, 211))	('head and neck cancer', 'Phenotype', 'HP:0012288', (248, 268))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (312, 329))	('cancer', 'Disease', (370, 376))	('OGG1', 'Gene', (151, 155))	('OGG1', 'Gene', '4968', (151, 155))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('OGG1', 'Gene', (144, 148))	('OGG1', 'Gene', '4968', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('esophageal cancer', 'Disease', 'MESH:D004938', (397, 414))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('oral cancer', 'Disease', 'MESH:D009062', (270, 281))	('cancer', 'Disease', (275, 281))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (331, 348))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (288, 310))	('gastric cancer', 'Phenotype', 'HP:0012126', (213, 227))	('oral cancer', 'Disease', (270, 281))	('variants', 'Disease', (193, 201))	('cancer', 'Disease', (323, 329))	('cancer', 'Disease', (362, 368))	('cancer of digestive tract', 'Phenotype', 'HP:0007378', (370, 395))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('esophageal cancer', 'Disease', (397, 414))	('bladder cancer', 'Phenotype', 'HP:0009725', (354, 368))	('cancer', 'Disease', (408, 414))	('gallbladder cancer', 'Disease', 'MESH:D005706', (350, 368))	('hOGG1', 'Gene', '4968', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('head and neck cancer', 'Disease', 'MESH:D006258', (248, 268))
854547	27026921	Articles for the meta-analysis were selected if they met the following criteria: (1) Studies not prior to 2007 (2) case-control study related to the risk of OGG1 Ser326Cys polymorphism (3) articles written in English (4) studies in which full information about genotype distributions are reported (5) Studies in which genotype distribution of control populations are in accordance with Hardy-Weinberg Equilibrium (P > 0.05) (6) only original research articles excluding reviews, letters and case reports.	('Ser326Cys', 'SUBSTITUTION', 'None', (162, 171))	('Ser326Cys', 'Var', (162, 171))	('OGG1', 'Gene', '4968', (157, 161))	('OGG1', 'Gene', (157, 161))
854550	27026921	In a preliminary search, we identified 58 research articles related to OGG1 Ser326Cys polymorphism and the risk of head and neck, oral, pancreatic, gallbladder, colorectal and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('Ser326Cys', 'Var', (76, 85))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (161, 191))	('OGG1', 'Gene', (71, 75))	('Ser326Cys', 'SUBSTITUTION', 'None', (76, 85))	('pancreatic', 'Disease', 'MESH:D010195', (136, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('OGG1', 'Gene', '4968', (71, 75))	('gallbladder', 'Disease', (148, 159))	('oral', 'Disease', (130, 134))	('pancreatic', 'Disease', (136, 146))	('gastric cancers', 'Phenotype', 'HP:0012126', (176, 191))
854551	27026921	The meta-analysis suggests that there was significant risk for all the three models of OGG1 Ser326Cys polymorphism (for dominant model CG + GG vs CC; odds ratio, OR 1.22; 95 % CI 1.05-1.41, recessive model GG vs CG + CC; OR 1.36; 95 % CI 1.09-1.70, homozygote comparison GG vs CC; OR 1.46; 95 % CI 1.12-1.92) (Fig.	('risk', 'Reg', (54, 58))	('CG', 'Chemical', 'MESH:C028505', (212, 214))	('Ser326Cys', 'SUBSTITUTION', 'None', (92, 101))	('Ser326Cys', 'Var', (92, 101))	('CG', 'Chemical', 'MESH:C028505', (135, 137))	('OGG1', 'Gene', '4968', (87, 91))	('OGG1', 'Gene', (87, 91))
854552	27026921	Furthermore we have stratified the studies based on ethnicity to determine the role of OGG1 Ser326Cys polymorphism in the risk for cancer among different ethnic groups (Table 2).	('cancer', 'Disease', (131, 137))	('OGG1', 'Gene', (87, 91))	('Ser326Cys', 'SUBSTITUTION', 'None', (92, 101))	('Ser326Cys', 'Var', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('OGG1', 'Gene', '4968', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
854553	27026921	The frequency of Ser/Cys and Cys/Cys genotype was slightly higher among cancer cases (0.37 and 0.06) than among the controls (0.35 and 0.05) for the Caucasian population.	('Ser', 'Chemical', 'MESH:D012694', (17, 20))	('Ser/Cys', 'Var', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cys', 'Chemical', 'MESH:D003545', (29, 32))	('Cys', 'Chemical', 'MESH:D003545', (33, 36))	('Cys/Cys', 'Var', (29, 36))	('higher', 'PosReg', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Cys', 'Chemical', 'MESH:D003545', (21, 24))	('cancer', 'Disease', (72, 78))
854555	27026921	Results suggest that the polymorphism was a risk for cancer among both the Asian (CG + GG vs CC; OR 1.21; 95 % CI 0.93-1.56, GG vs CG + CC; OR 1.40; 95 % CI 1.09-1.80, GG vs CC; OR 1.56; 95 % CI 1.15-2.11) and the Caucasian (CG + GG vs CC; OR 1.22; 95 % CI 1.01-1.48, GG vs CG + CC; OR 1.29; 95 % CI 0.95-1.76, GG vs CC; OR 1.40; 95 % CI 0.97-2.03) populations for all the three models.	('polymorphism', 'Var', (25, 37))	('risk', 'Reg', (44, 48))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('CG', 'Chemical', 'MESH:C028505', (131, 133))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CG', 'Chemical', 'MESH:C028505', (225, 227))	('CG', 'Chemical', 'MESH:C028505', (82, 84))	('CG', 'Chemical', 'MESH:C028505', (274, 276))
854558	27026921	Data pertaining to the habit of smoking was available only for a few of the included studies and the genotypes of OGG1 Ser326Cys stratified on the basis of smoking habit was also available only for cancer cases and not for the controls.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('OGG1', 'Gene', (114, 118))	('OGG1', 'Gene', '4968', (114, 118))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Ser326Cys', 'SUBSTITUTION', 'None', (119, 128))	('Ser326Cys', 'Var', (119, 128))
854559	27026921	We therefore conducted a meta-analysis with only 6 studies in order to determine the association of the polymorphism with the occurrence of GI and UADT cancers in patients who smoked compared to those who did not smoke.	('GI', 'Disease', 'MESH:D005767', (140, 142))	('patients', 'Species', '9606', (163, 171))	('polymorphism', 'Var', (104, 116))	('UADT cancers', 'Disease', 'MESH:D006258', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('association', 'Interaction', (85, 96))	('UADT cancers', 'Disease', (147, 159))
854565	27026921	Similarly, increased risk was also observed for colorectal cancer for all the models (CG + GG vs CC; OR 1.29; 95 % CI 0.9-1.84, GG vs CG + CC; OR 1.34; 95 % CI 1.05-1.71, GG vs CC; OR 1.38; 95 % CI 1.08-1.77).	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('CG + GG', 'Var', (86, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))	('colorectal cancer', 'Disease', (48, 65))	('CG', 'Chemical', 'MESH:C028505', (86, 88))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('GG vs CG + CC', 'Var', (128, 141))	('CG', 'Chemical', 'MESH:C028505', (134, 136))
854568	27026921	In this study significant heterogeneity was observed for all the models of OGG1 Ser326Cys polymorphism (CG + GG vs CC; P < 0.0001, I2 = 69.1 %, GG vs CG + CC; P = 0.0248, I2 = 44.4 %, CC vs GG; P = 0.0019, I2 = 57.1 %) and subsequently the random effect model was selected.	('CG', 'Chemical', 'MESH:C028505', (150, 152))	('Ser326Cys', 'SUBSTITUTION', 'None', (80, 89))	('Ser326Cys', 'Var', (80, 89))	('CG', 'Chemical', 'MESH:C028505', (104, 106))	('OGG1', 'Gene', (75, 79))	('OGG1', 'Gene', '4968', (75, 79))
854572	27026921	Although many polymorphisms have been reported in OGG1, the C/G polymorphism at the 326 codon of exon 7 which results in an amino acid substitution from serine to cysteine is of great importance as it has been linked to the increased risk for different cancers.	('OGG1', 'Gene', (50, 54))	('OGG1', 'Gene', '4968', (50, 54))	('linked', 'Reg', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('amino', 'Var', (124, 129))	('cancers', 'Disease', (253, 260))	('cysteine', 'Chemical', 'MESH:D003545', (163, 171))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('C/G polymorphism at', 'Var', (60, 79))	('serine', 'Chemical', 'MESH:D012694', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('results in', 'Reg', (110, 120))
854573	27026921	In few studies, the OGG1 protein encoded by the 326Ser variant is found to have more DNA repair activity than that coded by the 326Cys variant indicating the role of this polymorphism in carcinogenesis (Elahi et al.).	('carcinogenesis', 'Disease', (187, 201))	('Cys', 'Chemical', 'MESH:D003545', (131, 134))	('326Ser', 'Var', (48, 54))	('DNA repair activity', 'MPA', (85, 104))	('OGG1', 'Gene', (20, 24))	('carcinogenesis', 'Disease', 'MESH:D063646', (187, 201))	('326Ser', 'Chemical', '-', (48, 54))	('OGG1', 'Gene', '4968', (20, 24))	('more', 'PosReg', (80, 84))
854574	27026921	Previous studies including several meta-analyses pertaining to the role of OGG1 Ser326Cys polymorphism with the risk for different cancers were found to be ambiguous.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('Ser326Cys', 'SUBSTITUTION', 'None', (80, 89))	('Ser326Cys', 'Var', (80, 89))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('OGG1', 'Gene', (75, 79))	('OGG1', 'Gene', '4968', (75, 79))
854575	27026921	did not find any association between OGG1 polymorphism and the risk for pancreatic cancer, colorectal cancer and gastric cancer respectively.	('polymorphism', 'Var', (42, 54))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('OGG1', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pancreatic cancer', 'Disease', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Disease', (113, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('OGG1', 'Gene', '4968', (37, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
854576	27026921	reported that the OGG1 polymorphism was significantly associated with increased risk for colorectal cancer in Caucasian population.	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('OGG1', 'Gene', '4968', (18, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('polymorphism', 'Var', (23, 35))	('OGG1', 'Gene', (18, 22))	('associated', 'Reg', (54, 64))
854578	27026921	In an effort to resolve this ambiguity, we have performed a meta-analysis to determine the role of OGG1 Ser326Cys polymorphism on the risk for UADT cancer and GI cancer which includes different independent case control studies on head and neck cancer, gastric cancer, colorectal cancer, pancreatic cancer, gallbladder cancer and esophageal cancer.	('gallbladder cancer', 'Disease', (306, 324))	('colorectal cancer', 'Phenotype', 'HP:0003003', (268, 285))	('UADT cancer', 'Disease', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('head and neck cancer', 'Disease', 'MESH:D006258', (230, 250))	('Ser326Cys', 'SUBSTITUTION', 'None', (104, 113))	('Ser326Cys', 'Var', (104, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (329, 346))	('polymorphism', 'Var', (114, 126))	('gastric cancer', 'Disease', (252, 266))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('OGG1', 'Gene', (99, 103))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (287, 304))	('bladder cancer', 'Phenotype', 'HP:0009725', (310, 324))	('GI cancer', 'Disease', (159, 168))	('OGG1', 'Gene', '4968', (99, 103))	('esophageal cancer', 'Disease', (329, 346))	('colorectal cancer', 'Disease', 'MESH:D015179', (268, 285))	('gallbladder cancer', 'Disease', 'MESH:D005706', (306, 324))	('UADT cancer', 'Disease', 'MESH:D006258', (143, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (252, 266))	('colorectal cancer', 'Disease', (268, 285))	('pancreatic cancer', 'Disease', 'MESH:D010190', (287, 304))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('GI cancer', 'Disease', 'MESH:D009369', (159, 168))	('GI cancer', 'Phenotype', 'HP:0007378', (159, 168))	('head and neck cancer', 'Phenotype', 'HP:0012288', (230, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('pancreatic cancer', 'Disease', (287, 304))	('gastric cancer', 'Phenotype', 'HP:0012126', (252, 266))
854579	27026921	Our study has revealed a significant association of OGG1 polymorphism with UADT and GI cancer risk.	('GI cancer', 'Disease', 'MESH:D009369', (84, 93))	('UADT', 'Disease', (75, 79))	('UADT', 'Chemical', '-', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('OGG1', 'Gene', (52, 56))	('GI cancer', 'Phenotype', 'HP:0007378', (84, 93))	('polymorphism', 'Var', (57, 69))	('GI cancer', 'Disease', (84, 93))	('OGG1', 'Gene', '4968', (52, 56))
854580	27026921	For all the three models (CG + GG vs CC, GG vs CG + CC and GG vs CC) we observe a significant risk, clearly indicating the role of the mutant G allele in increasing the risk for UADT and GI cancers.	('CG', 'Chemical', 'MESH:C028505', (47, 49))	('GI cancers', 'Disease', (187, 197))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('increasing', 'PosReg', (154, 164))	('GI cancers', 'Disease', 'MESH:D009369', (187, 197))	('CG + GG vs CC', 'Var', (26, 39))	('mutant', 'Var', (135, 141))	('GI cancer', 'Phenotype', 'HP:0007378', (187, 196))	('UADT', 'Disease', (178, 182))	('GG vs CC', 'Var', (59, 67))	('UADT', 'Chemical', '-', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('CG', 'Chemical', 'MESH:C028505', (26, 28))
854581	27026921	Stratified analysis based on ethnicity reveals that the OGG1 polymorphism increases the risk for cancer in both Asian and Caucasian populations.	('OGG1', 'Gene', (56, 60))	('OGG1', 'Gene', '4968', (56, 60))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('increases', 'PosReg', (74, 83))	('polymorphism', 'Var', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
854584	27026921	However, our study revealed no association between the habit of smoking and OGG1 Ser326Cys polymorphism.	('OGG1', 'Gene', (76, 80))	('Ser326Cys', 'SUBSTITUTION', 'None', (81, 90))	('Ser326Cys', 'Var', (81, 90))	('OGG1', 'Gene', '4968', (76, 80))
854585	27026921	Our study based on the risk for different types of cancers and OGG1 polymorphism showed highly significant risk for both the head and neck and colorectal cancers which was in accordance with Su et al.	('colorectal cancers', 'Disease', 'MESH:D015179', (143, 161))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('colorectal cancers', 'Disease', (143, 161))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('OGG1', 'Gene', (63, 67))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('polymorphism', 'Var', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('risk', 'Reg', (107, 111))	('OGG1', 'Gene', '4968', (63, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))
854587	27026921	On further stratifying our study into GI and UADT cancers it was observed that individuals with G allele are at an increased risk for both the type of cancer.	('GI', 'Disease', 'MESH:D005767', (38, 40))	('G allele', 'Var', (96, 104))	('UADT cancers', 'Disease', (45, 57))	('type of cancer', 'Disease', (143, 157))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('UADT cancers', 'Disease', 'MESH:D006258', (45, 57))	('type of cancer', 'Disease', 'MESH:D009369', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
854592	27026921	In conclusion, our meta-analysis provides evidence that the OGG1 Ser326Cys polymorphism may be associated with an increased risk for UADT and GI cancers in both Asian and Caucasian populations.	('GI cancer', 'Phenotype', 'HP:0007378', (142, 151))	('GI cancers', 'Disease', (142, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('OGG1', 'Gene', (60, 64))	('UADT', 'Disease', (133, 137))	('UADT', 'Chemical', '-', (133, 137))	('GI cancers', 'Disease', 'MESH:D009369', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('OGG1', 'Gene', '4968', (60, 64))	('associated', 'Reg', (95, 105))	('Ser326Cys', 'Var', (65, 74))	('Ser326Cys', 'SUBSTITUTION', 'None', (65, 74))
854617	25184776	The mechanical anastomosis increased the absolute risk of anastomotic stricture in 3% (CI 95% 0,00 a 0,06; p<0,0002 e I=70%), needing to treat 33 patients to obtain this harm (Figure 2).	('anastomotic stricture', 'Disease', (58, 79))	('patients', 'Species', '9606', (146, 154))	('mechanical', 'Var', (4, 14))
854625	25184776	So, stapled generated less blood loss when compared with hand-sewn (Figure 2).	('blood loss', 'Disease', (27, 37))	('blood loss', 'Disease', 'MESH:D006473', (27, 37))	('stapled', 'Var', (4, 11))	('less', 'NegReg', (22, 26))
854654	25358597	Inhibition of ERK1/2 enhanced the antitumor activity of CP.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('ERK1/2', 'Gene', (14, 20))	('enhanced', 'PosReg', (21, 29))	('ERK1/2', 'Gene', '5595;5594', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Inhibition', 'Var', (0, 10))
854655	25358597	Furthermore, CP was a more powerful agonist for IGF-1R down-regulation than IGF-1, and dysregulation of beta-arrestin1 and GRKs affected this down-regulation.	('GRKs', 'Gene', '2870', (123, 127))	('beta-arrestin1', 'Gene', '408', (104, 118))	('dysregulation', 'Var', (87, 100))	('beta-arrestin1', 'Gene', (104, 118))	('IGF-1', 'Gene', (48, 53))	('IGF-1', 'Gene', '3479', (48, 53))	('GRKs', 'Gene', (123, 127))	('IGF-1', 'Gene', '3479', (76, 81))	('down-regulation', 'NegReg', (55, 70))	('IGF-1', 'Gene', (76, 81))
854662	25358597	Elevations of serum IGF-I and/or IGF binding protein 3 (IGFBP3) not only increase the risk of developing several cancers, but also correlate with cancer patients' worse survival.	('cancer', 'Disease', (146, 152))	('IGFBP3', 'Gene', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancer', 'Disease', (113, 119))	('cancers', 'Disease', (113, 120))	('IGF binding protein 3', 'Gene', '3486', (33, 54))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Elevations of serum IGF-I', 'Phenotype', 'HP:0030269', (0, 25))	('IGFBP3', 'Gene', '3486', (56, 62))	('Elevations', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('IGF-I', 'Gene', (20, 25))	('increase', 'PosReg', (73, 81))	('patients', 'Species', '9606', (153, 161))	('IGF-I', 'Gene', '3479', (20, 25))	('IGF binding protein 3', 'Gene', (33, 54))
854715	25358597	Treatment with MG132 could reverse the CP induced IGF-1R down-regulation greatly, and the NH4Cl could also reverse the down-regulation effect partially (Figure 4c), suggesting that the degradation of IGF-1R induced by CP was mainly through the proteasome pathway.	('IGF-1R', 'Gene', (200, 206))	('degradation', 'MPA', (185, 196))	('down-regulation', 'NegReg', (57, 72))	('IGF-1R', 'Gene', (50, 56))	('NH4Cl', 'Chemical', 'MESH:D000643', (90, 95))	('MG132', 'Var', (15, 20))	('MG132', 'Chemical', 'MESH:C072553', (15, 20))
854735	25358597	Inhibition of ERK1/2 made the cells more sensitive to CP treatment, especially for the TE-1 cells, which exhibited high basal ERK1/2 activation and were initially not so sensitive to CP treatment (Figure 5e).	('ERK1/2', 'Gene', (14, 20))	('ERK1/2', 'Gene', '5595;5594', (14, 20))	('TE-1', 'CellLine', 'CVCL:1759', (87, 91))	('Inhibition', 'Var', (0, 10))	('sensitive', 'MPA', (41, 50))	('ERK1/2', 'Gene', (126, 132))	('ERK1/2', 'Gene', '5595;5594', (126, 132))
854759	25358597	One important humanized IgG2 antibody Figitumumab (CP751871, CP), not only has good antitumor activity, also has a good pharmacokinetic distribution.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CP751871', 'Var', (51, 59))	('human', 'Species', '9606', (14, 19))	('Figitumumab', 'Chemical', 'MESH:C525021', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
854785	25358597	Addition of U0126 made the cells more sensitive to CP treatment especially in TE-1 cells, which were initially more resistant to CP treatment.	('sensitive', 'MPA', (38, 47))	('TE-1', 'CellLine', 'CVCL:1759', (78, 82))	('U0126', 'Var', (12, 17))	('U0126', 'Chemical', 'MESH:C113580', (12, 17))
854801	25358597	Antibodies for IGF-1R, phosphor-IGF-1R (Tyr 1135), phosphor-ERK1/2(Thr202/Tyr204) and phosphor-Akt (S473) were from Cell Signaling Technology (Danvers, USA).	('Tyr204', 'Chemical', '-', (74, 80))	('Akt', 'Gene', '207', (95, 98))	('IGF-1R', 'Gene', (15, 21))	('Akt', 'Gene', (95, 98))	('Tyr', 'Chemical', 'MESH:D014443', (40, 43))	('Tyr', 'Chemical', 'MESH:D014443', (74, 77))	('ERK1/2', 'Gene', (60, 66))	('Tyr 1135', 'Var', (40, 48))	('Thr202', 'Chemical', '-', (67, 73))	('ERK1/2', 'Gene', '5595;5594', (60, 66))
854856	32869704	Deactivating the regulatory signaling pathway of interleukin-6/signal transduction and activation of transcription 3 and neutralizing deoxycholic acid may be novel targets for improving the clinical efficacy of esophageal adenocarcinoma therapy.	('improving', 'PosReg', (176, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('activation', 'PosReg', (87, 97))	('interleukin-6', 'Gene', '3569', (49, 62))	('adenocarcinoma', 'Disease', 'MESH:D000230', (222, 236))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (211, 236))	('deoxycholic acid', 'MPA', (134, 150))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (134, 150))	('neutralizing', 'Var', (121, 133))	('interleukin-6', 'Gene', (49, 62))	('transcription', 'Gene', (101, 114))	('regulatory signaling pathway', 'Pathway', (17, 45))	('Deactivating', 'NegReg', (0, 12))	('adenocarcinoma', 'Disease', (222, 236))
854868	32869704	Huo et al  treated BE cell lines with DCA and ursodeoxycholic acid (UDCA) and found that DCA caused oxidative stress reaction and subsequent cell DNA damage, while hydrophobic UDCA did not damage the cell DNA.	('DCA', 'Var', (89, 92))	('oxidative stress reaction', 'MPA', (100, 125))	('DCA', 'Chemical', 'MESH:D003840', (38, 41))	('DCA', 'Chemical', 'MESH:D003840', (69, 72))	('cell DNA', 'CPA', (141, 149))	('BE', 'Phenotype', 'HP:0100580', (19, 21))	('oxidative stress', 'Phenotype', 'HP:0025464', (100, 116))	('UDCA', 'Chemical', 'MESH:D014580', (176, 180))	('DCA', 'Chemical', 'MESH:D003840', (177, 180))	('ursodeoxycholic acid', 'Chemical', 'MESH:D014580', (46, 66))	('UDCA', 'Chemical', 'MESH:D014580', (68, 72))	('DCA', 'Chemical', 'MESH:D003840', (89, 92))
854871	32869704	Although DCA was shown to have a certain malignant induction effect on esophageal cells, the specific mechanism by which DCA induces the malignant transformation process of esophageal squamous epithelial cells to form BE and EAC remains unclear.	('BE', 'Phenotype', 'HP:0100580', (218, 220))	('DCA', 'Chemical', 'MESH:D003840', (121, 124))	('malignant transformation process', 'CPA', (137, 169))	('DCA', 'Var', (121, 124))	('induces', 'Reg', (125, 132))	('DCA', 'Chemical', 'MESH:D003840', (9, 12))	('squamous epithelia', 'Phenotype', 'HP:0002860', (184, 202))	('EAC', 'Phenotype', 'HP:0011459', (225, 228))
854872	32869704	It is speculated that DCA induces the malignant transformation of EAC through the activation of stem cell-associated gene expression.	('induces', 'Reg', (26, 33))	('malignant transformation', 'CPA', (38, 62))	('stem cell-associated gene expression', 'Gene', (96, 132))	('activation', 'PosReg', (82, 92))	('EAC', 'Phenotype', 'HP:0011459', (66, 69))	('DCA', 'Var', (22, 25))	('DCA', 'Chemical', 'MESH:D003840', (22, 25))	('EAC', 'Disease', (66, 69))
854879	32869704	In liver cancer, it has also been found that inhibition of OCT4 can reduce both tumor resistance to chemotherapy drugs and the stemness of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (3, 15))	('liver cancer', 'Disease', 'MESH:D006528', (3, 15))	('stemness of tumor', 'Disease', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('liver cancer', 'Disease', (3, 15))	('tumor', 'Disease', (80, 85))	('reduce', 'NegReg', (68, 74))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('stemness of tumor', 'Disease', 'MESH:D020295', (127, 144))	('inhibition', 'Var', (45, 55))	('OCT4', 'Protein', (59, 63))
854885	32869704	Studies have found that KLF4 can be activated by bile acids and KLF4 can increase the transcriptional activity of MUC2 and CDX2, indicating the potential role of KLF4 in the development of BE.	('BE', 'Phenotype', 'HP:0100580', (189, 191))	('increase', 'PosReg', (73, 81))	('transcriptional activity', 'MPA', (86, 110))	('CDX2', 'Gene', (123, 127))	('bile acids', 'Chemical', 'MESH:D001647', (49, 59))	('CDX2', 'Gene', '1045', (123, 127))	('MUC2', 'Gene', (114, 118))	('MUC2', 'Gene', '4583', (114, 118))	('KLF4', 'Var', (64, 68))
854892	32869704	In Nanog+ cancer stem cells, IGF2 and IGF receptors are upregulated, while silencing Nanog inhibits IGF1 receptor expression.	('Nanog', 'Gene', (3, 8))	('IGF2', 'Gene', '3481', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('upregulated', 'PosReg', (56, 67))	('IGF1', 'Gene', (100, 104))	('IGF2', 'Gene', (29, 33))	('Nanog', 'Gene', '79923', (85, 90))	('silencing', 'Var', (75, 84))	('expression', 'MPA', (114, 124))	('Nanog', 'Gene', '79923', (3, 8))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('inhibits', 'NegReg', (91, 99))	('IGF receptors', 'Protein', (38, 51))	('cancer', 'Disease', (10, 16))	('Nanog', 'Gene', (85, 90))
854909	32869704	However, the knockout of HIF-1alpha eliminated the proliferation of anoxia-mediated glioma stem cells.	('eliminated', 'NegReg', (36, 46))	('glioma', 'Disease', (84, 90))	('knockout', 'Var', (13, 21))	('proliferation', 'CPA', (51, 64))	('HIF-1alpha', 'Gene', '3091', (25, 35))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('rat', 'Species', '10116', (58, 61))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('HIF-1alpha', 'Gene', (25, 35))
854930	32869704	This study aimed to explore whether DCA can affect the expression of reprogramming factors KLF4, OCT4, and Nanog and whether it can induce the malignant transformation of EAC cells into EAC stem cells.	('Nanog', 'Gene', (107, 112))	('EAC', 'Phenotype', 'HP:0011459', (171, 174))	('OCT4', 'Gene', (97, 101))	('induce', 'Reg', (132, 138))	('expression', 'MPA', (55, 65))	('DCA', 'Var', (36, 39))	('DCA', 'Chemical', 'MESH:D003840', (36, 39))	('Nanog', 'Gene', '79923', (107, 112))	('EAC', 'Disease', (171, 174))	('affect', 'Reg', (44, 50))	('malignant transformation', 'CPA', (143, 167))	('EAC', 'Phenotype', 'HP:0011459', (186, 189))
854954	32869704	The rabbit primary antibodies used were STAT3 (Proteintech), pSTAT3 (Tyr705; ABclonal), KLF4 (Proteintech), OCT4 (Proteintech), and beta-actin (Proteintech).	('Tyr705', 'Chemical', '-', (69, 75))	('Tyr705', 'Var', (69, 75))	('beta-actin', 'Gene', '728378', (132, 142))	('beta-actin', 'Gene', (132, 142))
854958	32869704	After STAT3 silencing in OE33, the relative mRNA expressions of OCT4, HIF-1alpha, and Nanog decreased (P < .01), but the relative expression of CD44 increased (P < .05).	('expression', 'MPA', (130, 140))	('Nanog', 'Gene', (86, 91))	('Nanog', 'Gene', '79923', (86, 91))	('HIF-1alpha', 'Gene', (70, 80))	('CD44', 'Gene', '960', (144, 148))	('STAT3 silencing', 'Var', (6, 21))	('OE33', 'Gene', (25, 29))	('OCT4', 'Protein', (64, 68))	('CD44', 'Gene', (144, 148))	('mRNA expressions', 'MPA', (44, 60))	('HIF-1alpha', 'Gene', '3091', (70, 80))	('decreased', 'NegReg', (92, 101))
854959	32869704	After the knockdown of STAT3, Bcl-xL gene expression in the HEEC and OE33 cell lines were reduced by 31% (P < .01) and 29% (P < 0.05), respectively, showing significant differences (Figure 1).	('reduced', 'NegReg', (90, 97))	('Bcl-xL', 'Gene', (30, 36))	('STAT3', 'Gene', (23, 28))	('knockdown', 'Var', (10, 19))	('Bcl-xL', 'Gene', '598', (30, 36))
854979	32869704	Western blot analysis showed that KLF4, OCT4, and Bcl-xL protein expression were also significantly decreased after silencing STAT3 (Figure 7A-C).	('Bcl-xL', 'Gene', (50, 56))	('decreased', 'NegReg', (100, 109))	('Bcl-xL', 'Gene', '598', (50, 56))	('OCT4', 'MPA', (40, 44))	('silencing', 'Var', (116, 125))	('KLF4', 'MPA', (34, 38))	('STAT3', 'Gene', (126, 131))
854982	32869704	Furthermore, after STAT3 silencing, the mRNA expression of the antiapoptotic Bcl-xL gene was reduced to 29% of that of the negative control group, with a statistical difference (P < .05; Figure 6A), indicating that STAT3 was an upstream regulator of Bcl-xL and had an enhancing effect on the expression of Bcl-xL.	('silencing', 'Var', (25, 34))	('Bcl-xL', 'Gene', (77, 83))	('mRNA expression', 'MPA', (40, 55))	('Bcl-xL', 'Gene', '598', (306, 312))	('reduced', 'NegReg', (93, 100))	('enhancing', 'PosReg', (268, 277))	('expression', 'MPA', (292, 302))	('STAT3', 'Gene', (19, 24))	('Bcl-xL', 'Gene', (306, 312))	('Bcl-xL', 'Gene', '598', (250, 256))	('Bcl-xL', 'Gene', '598', (77, 83))	('Bcl-xL', 'Gene', (250, 256))
854997	32869704	The source of CSCs might derive from the transformation of adult stem cells, mutations of adult cells, the activation of proto-oncogenes, or from the dedifferentiation of tumor cells expressing stem cell-related genes.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mutations', 'Var', (77, 86))	('proto-oncogenes', 'Gene', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
854999	32869704	Similarly, normal tissue cells induced with the expression of stem cells markers would dedifferentiate into pluripotent stem cells under certain condition and finally promote the transformation to tumor cells.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('promote', 'PosReg', (167, 174))	('dedifferentiate', 'CPA', (87, 102))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('expression', 'Var', (48, 58))	('tumor', 'Disease', (197, 202))	('transformation', 'CPA', (179, 193))
855012	32869704	Therefore, silencing STAT3 could inhibit the expression of stem cell-related genes, and that silencing STAT3 might be one of the important factors for inhibiting the acquisition of stemness in EAC cell lines and reducing its malignant progression, proliferation, recurrence, metastasis, and radiotherapy/chemotherapy resistance.	('silencing', 'Var', (11, 20))	('recurrence', 'CPA', (263, 273))	('reducing', 'NegReg', (212, 220))	('silencing', 'Var', (93, 102))	('metastasis', 'CPA', (275, 285))	('malignant progression', 'CPA', (225, 246))	('STAT3', 'Gene', (103, 108))	('proliferation', 'CPA', (248, 261))	('inhibit', 'NegReg', (33, 40))	('radiotherapy/chemotherapy resistance', 'CPA', (291, 327))	('acquisition', 'CPA', (166, 177))	('expression', 'MPA', (45, 55))	('inhibiting', 'NegReg', (151, 161))	('rat', 'Species', '10116', (255, 258))	('EAC', 'Phenotype', 'HP:0011459', (193, 196))	('stem cell-related genes', 'Gene', (59, 82))
855018	32869704	Zaanan et al  showed that STAT3 promoted the apoptotic resistance induced by KRAS mutation by upregulating Bcl-xL expression.	('promoted', 'PosReg', (32, 40))	('mutation', 'Var', (82, 90))	('Bcl-xL', 'Gene', '598', (107, 113))	('Bcl-xL', 'Gene', (107, 113))	('KRAS', 'Gene', (77, 81))	('apoptotic resistance', 'CPA', (45, 65))	('KRAS', 'Gene', '3845', (77, 81))	('upregulating', 'PosReg', (94, 106))
855040	32869704	To date, the source of CSCs in vivo has not been determined, which may be transformed from the activation of stem cells or progenitor proto-oncogene mutations, or the dedifferentiation of tumor cells to drive the formation of CSCs.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mutations', 'Var', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
855053	32869704	Studies have shown that utilization of the STAT3 inhibitor WP1066 can inhibit the expression of OCT4 in iPSCs.	('WP1066', 'Chemical', 'MESH:C519885', (59, 65))	('expression', 'MPA', (82, 92))	('WP1066', 'Var', (59, 65))	('inhibit', 'NegReg', (70, 77))	('OCT4', 'Protein', (96, 100))
855055	32869704	After transfection with an STAT3 active mutant, pancreatic cancer cells expressed the stem cell marker OCT4.	('pancreatic cancer', 'Disease', (48, 65))	('pancreatic cancer', 'Disease', 'MESH:D010190', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (48, 65))	('mutant', 'Var', (40, 46))	('OCT4', 'Protein', (103, 107))
855059	32869704	In colorectal cancer, gastric cancer, esophageal squamous cell carcinoma, lung cancer, prostate cancer, and bladder cancer, low expression of KLF4 can promote excessive cell proliferation and malignant transformation, supporting the role of KLF4 as a tumor suppressor gene.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (38, 72))	('tumor', 'Disease', (251, 256))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('colorectal cancer', 'Disease', (3, 20))	('KLF4', 'Gene', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('low expression', 'Var', (124, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', (22, 36))	('promote', 'PosReg', (151, 158))	('rat', 'Species', '10116', (181, 184))	('malignant transformation', 'CPA', (192, 216))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (22, 36))	('esophageal squamous cell carcinoma', 'Disease', (38, 72))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('prostate cancer', 'Disease', (87, 102))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('lung cancer', 'Disease', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('gastric cancer', 'Phenotype', 'HP:0012126', (22, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
855063	32869704	Yu et al  found that KLF4 is necessary to maintain the stemness of breast cancer stem cells, and the clearance of KLF4 reduces the ability of tumor formation.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('clearance', 'Var', (101, 110))	('KLF4', 'Gene', (114, 118))	('tumor', 'Disease', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('stemness of breast cancer', 'Disease', (55, 80))	('stemness of breast cancer', 'Disease', 'MESH:D001943', (55, 80))	('reduces', 'NegReg', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
855070	32869704	Research has shown that the use of the STAT3 inhibitor WP1066 can inhibit KLF4 expression in iPSCs, suggesting that STAT3 is crucial in maintaining the pluripotency of iPSCs.	('expression', 'MPA', (79, 89))	('pluripotency of iPSCs', 'Disease', (152, 173))	('WP1066', 'Chemical', 'MESH:C519885', (55, 61))	('pluripotency of iPSCs', 'Disease', 'None', (152, 173))	('WP1066', 'Var', (55, 61))	('inhibit', 'NegReg', (66, 73))	('KLF4', 'Protein', (74, 78))
855078	32869704	In the small intestine, expression of OCT4 causes dysplasia and expansion of progenitor cells.	('OCT4', 'Gene', (38, 42))	('dysplasia', 'Disease', 'MESH:C536170', (50, 59))	('dysplasia', 'Disease', (50, 59))	('expression', 'Var', (24, 34))	('expansion of progenitor cells', 'CPA', (64, 93))	('causes', 'Reg', (43, 49))
855079	32869704	Knocking out the OCT4 gene in human and mouse cell lines can reduce CSC subsets.	('human', 'Species', '9606', (30, 35))	('reduce', 'NegReg', (61, 67))	('OCT4 gene', 'Gene', (17, 26))	('CSC', 'Disease', (68, 71))	('mouse', 'Species', '10090', (40, 45))	('Knocking out', 'Var', (0, 12))
855080	32869704	Studies have reported that SOX2 can maintain the key signaling cascade of tumorigenesis and that tumor cells silenced by SOX2 have a decreased expression of c-MYC, Wnt1, and Notch1, which reduces the ability of immune-deficient nude mice to be transplanted with tumors.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('Wnt1', 'Gene', '22408', (164, 168))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('tumor', 'Disease', (74, 79))	('key signaling cascade', 'MPA', (49, 70))	('SOX2', 'Gene', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MYC', 'Gene', (159, 162))	('tumors', 'Disease', (262, 268))	('tumor', 'Disease', (97, 102))	('Notch1', 'Gene', (174, 180))	('decreased', 'NegReg', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('expression', 'MPA', (143, 153))	('nude mice', 'Species', '10090', (228, 237))	('tumor', 'Disease', (262, 267))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Wnt1', 'Gene', (164, 168))	('MYC', 'Gene', '4609', (159, 162))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('silenced', 'Var', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('reduces', 'NegReg', (188, 195))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))
855082	32869704	Knocking out bm-1 in CD133+ laryngeal cancer cells resulted in decreased cell growth, clonal formation, cell invasion ability, and inhibition of tumorigenesis ability in vivo.	('cell growth', 'CPA', (73, 84))	('CD133', 'Gene', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('CD133', 'Gene', '8842', (21, 26))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (28, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('decreased', 'NegReg', (63, 72))	('tumor', 'Disease', (145, 150))	('bm-1', 'Gene', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('Knocking out', 'Var', (0, 12))	('cancer', 'Disease', (38, 44))	('cell invasion ability', 'CPA', (104, 125))	('clonal formation', 'CPA', (86, 102))	('inhibition', 'NegReg', (131, 141))
855094	32869704	The inflammation caused by deoxycholic acid increases cellular reactive oxygen species that are associated with the increase of circccRNA of miR-21 and miR-21, which are directly regulated by the transcription factor (NF-kappaB), and the activated NF-kappaB pathway could also produce antiapoptotic protein Bcl-2, making DNA-damaged cells resistant to apoptosis.	('miR-21', 'Gene', (141, 147))	('NF-kappaB', 'Gene', '4790', (248, 257))	('inflammation', 'Disease', 'MESH:D007249', (4, 16))	('circccRNA', 'MPA', (128, 137))	('increases', 'PosReg', (44, 53))	('Bcl-2', 'Gene', (307, 312))	('cellular reactive oxygen species', 'MPA', (54, 86))	('increase', 'PosReg', (116, 124))	('inflammation', 'Disease', (4, 16))	('miR-21', 'Gene', '406991', (152, 158))	('Bcl-2', 'Gene', '596', (307, 312))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (27, 43))	('deoxycholic acid', 'Var', (27, 43))	('miR-21', 'Gene', '406991', (141, 147))	('reactive oxygen', 'Chemical', '-', (63, 78))	('NF-kappaB', 'Gene', (218, 227))	('miR-21', 'Gene', (152, 158))	('NF-kappaB', 'Gene', (248, 257))	('NF-kappaB', 'Gene', '4790', (218, 227))
855098	32869704	In the case of the relationship between STAT3 and antiapoptotic protein Bcl-xL, studies have found that PVN can upregulate the expression of antiapoptotic proteins Bcl-xL and Bcl-2 by inhibiting JAK2/STAT3 activation.	('Bcl-xL', 'Gene', '598', (164, 170))	('expression', 'MPA', (127, 137))	('Bcl-xL', 'Gene', '598', (72, 78))	('upregulate', 'PosReg', (112, 122))	('JAK2', 'Gene', '3717', (195, 199))	('Bcl-xL', 'Gene', (164, 170))	('JAK2', 'Gene', (195, 199))	('PVN', 'Var', (104, 107))	('Bcl-xL', 'Gene', (72, 78))	('inhibiting', 'NegReg', (184, 194))	('Bcl-2', 'Gene', (175, 180))	('Bcl-2', 'Gene', '596', (175, 180))
855107	32869704	On the other hand, DCA activates the IL-6/STAT3 pathway to upregulate the antiapoptosis protein Bcl-xL, increasing the antiapoptosis ability of EAC cells, which inhibits programed cell death, improves their survival rate, and worsens the malignancy of EAC.	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('IL-6', 'Gene', '3569', (37, 41))	('malignancy', 'Disease', (238, 248))	('EAC', 'Phenotype', 'HP:0011459', (252, 255))	('DCA', 'Chemical', 'MESH:D003840', (19, 22))	('IL-6', 'Gene', (37, 41))	('worsens', 'NegReg', (226, 233))	('Bcl-xL', 'Gene', (96, 102))	('EAC', 'Disease', (252, 255))	('Bcl-xL', 'Gene', '598', (96, 102))	('improves', 'PosReg', (192, 200))	('survival rate', 'CPA', (207, 220))	('DCA', 'Var', (19, 22))	('programed cell death', 'CPA', (170, 190))	('upregulate', 'PosReg', (59, 69))	('inhibits', 'NegReg', (161, 169))	('antiapoptosis ability', 'MPA', (119, 140))	('malignancy', 'Disease', 'MESH:D009369', (238, 248))	('rat', 'Species', '10116', (216, 219))	('increasing', 'PosReg', (104, 114))
855108	32869704	Thus, targeting STAT3 inhibition may improve the clinical treatment of EAC to limit the survival of tumor cells and promote tumor cell death.	('inhibition', 'Var', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (100, 105))	('EAC', 'Disease', (71, 74))	('tumor', 'Disease', (124, 129))	('promote', 'PosReg', (116, 123))	('STAT3', 'Gene', (16, 21))	('tumor cell death', 'Disease', 'MESH:D003643', (124, 140))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('limit', 'NegReg', (78, 83))	('tumor cell death', 'Disease', (124, 140))
855110	32869704	Deoxycholic acid was shown to have a malignant induction effect, activating the IL-6/STAT3 pathway, and promoting the upregulation of KLF4, OCT4, Nanog, Bcl-xL, and other genes.	('Deoxycholic acid', 'Chemical', 'MESH:D003840', (0, 16))	('KLF4', 'Protein', (134, 138))	('IL-6', 'Gene', (80, 84))	('promoting', 'PosReg', (104, 113))	('genes', 'Gene', (171, 176))	('Nanog', 'Gene', (146, 151))	('Deoxycholic', 'Var', (0, 11))	('upregulation', 'PosReg', (118, 130))	('activating', 'PosReg', (65, 75))	('IL-6', 'Gene', '3569', (80, 84))	('Bcl-xL', 'Gene', '598', (153, 159))	('Bcl-xL', 'Gene', (153, 159))	('Nanog', 'Gene', '79923', (146, 151))	('OCT4', 'Gene', (140, 144))
855146	32492647	described that 47.4% of papilloma lesions were associated with the high-risk HPV serotype 16.	('papilloma lesions', 'Disease', 'MESH:D010212', (24, 41))	('serotype 16', 'Var', (81, 92))	('HPV', 'Gene', (77, 80))	('papilloma', 'Phenotype', 'HP:0012740', (24, 33))	('papilloma lesions', 'Disease', (24, 41))	('associated', 'Reg', (47, 57))
855192	32411711	Primary antibodies used were specific for CD8 (Ventana 790-4460 clone sp57, Roche, Switzerland), PD-1 (Ventana 760-4895, Roche, Switzerland), and PD-L1 (Ventana SP263 assay, Roche, Switzerland).	('Ventana', 'Var', (103, 110))	('CD8', 'Gene', (42, 45))	('PD-1', 'Gene', (97, 101))	('PD-1', 'Gene', '5133', (97, 101))	('Ventana', 'Var', (47, 54))	('CD8', 'Gene', '925', (42, 45))
855200	32411711	Chi-square, Fisher's exact, Mann-Whitney-Wilcoxon, Kruskal-Wallis, and Jonckheere-Terpstra tests were used to determine the association of CD8, PD-1, and PD-L1 positivity and clinical-pathological features.	('CD8', 'Gene', (139, 142))	('CD8', 'Gene', '925', (139, 142))	('PD-L1', 'Gene', (154, 159))	('PD-1', 'Gene', (144, 148))	('association', 'Interaction', (124, 135))	('PD-1', 'Gene', '5133', (144, 148))	('positivity', 'Var', (160, 170))
855231	32411711	In a cohort of Western patients, PD-L1 expression was reported to be associated with a favorable clinical course.	('patients', 'Species', '9606', (23, 31))	('PD-L1', 'Gene', (33, 38))	('expression', 'Var', (39, 49))
855372	31043159	It is supposed that NGT placement could lead to sensory disorders, such as sensory deficits or desensitization in the laryngopharyngeal structures.	('sensory deficits', 'Phenotype', 'HP:0003474', (75, 91))	('desensitization', 'Disease', (95, 110))	('placement', 'Var', (24, 33))	('lead to', 'Reg', (40, 47))	('sensory disorders', 'Disease', 'MESH:D015417', (48, 65))	('sensory deficits', 'Disease', (75, 91))	('NGT', 'Phenotype', 'HP:0040288', (20, 23))	('sensory disorders', 'Disease', (48, 65))	('NGT', 'Var', (20, 23))	('sensory deficits', 'Disease', 'MESH:D015417', (75, 91))
855445	31086666	In Group A, 5-year OS of patients with R0 resections was significantly higher (72.93%) than in the R1 subgroup (6.25%, P<001).	('higher', 'PosReg', (71, 77))	('R0 resections', 'Var', (39, 52))	('patients', 'Species', '9606', (25, 33))	('OS', 'Chemical', '-', (19, 21))
855476	31086666	However, in the NCCN guidelines, the standard treatment of SCC staged as T1b-T4a, N0-N+ or M0 is preoperative chemoradiation followed by esophagectomy.	('SCC', 'Gene', (59, 62))	('T1b-T4a', 'Var', (73, 80))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('SCC', 'Gene', '6317', (59, 62))	('N0-N+', 'Var', (82, 87))
855609	30131072	The chromosome 11q13.3 amplification associated lymph node metastasis is driven by miR-548k through modulating tumor microenvironment The prognosis for esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis (LNM) is still dismal.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('patients', 'Species', '9606', (194, 202))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (152, 186))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('modulating', 'Reg', (100, 110))	('amplification', 'Var', (23, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('tumor', 'Disease', (111, 116))	('miR', 'Gene', '220972', (83, 86))	('esophageal squamous cell carcinoma', 'Disease', (152, 186))	('miR', 'Gene', (83, 86))
855612	30131072	In the pooled cohort of 314 ESCC patients, we found 76 significant focused regions including 43 amplifications and 33 deletions.	('ESCC', 'Disease', (28, 32))	('deletions', 'Var', (118, 127))	('amplifications', 'Var', (96, 110))	('patients', 'Species', '9606', (33, 41))
855625	30131072	Importantly, disrupting the conversation of tumor cells and LECs by interferring RNA or neutralizing antibodies to VEGFC or VEGFR3, has been shown to reduce the rate of lymph node metastasis in vitro and in vivo.	('VEGFR3', 'Gene', '2324', (124, 130))	('neutralizing', 'Var', (88, 100))	('disrupting', 'NegReg', (13, 23))	('lymph node metastasis', 'CPA', (169, 190))	('reduce', 'NegReg', (150, 156))	('VEGFC', 'Gene', '7424', (115, 120))	('VEGFC', 'Gene', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('VEGFR3', 'Gene', (124, 130))	('tumor', 'Disease', (44, 49))	('reduce the rate of lymph node metastasis', 'Phenotype', 'HP:0002732', (150, 190))
855633	30131072	Given that one miRNA could target different mRNAs to exert diverse functions, it is reasonable to speculated that miR-548k may act as a molecular driver of 11q13.3 amplicon associated with LNM.	('LNM', 'Disease', (189, 192))	('11q13.3', 'Gene', (156, 163))	('amplicon', 'Var', (164, 172))	('miR-548k', 'Gene', '100313770', (114, 122))	('miR-548k', 'Gene', (114, 122))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', (114, 117))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
855658	30131072	Serial 4.0 mum sections were taken and analyzed by IHC with anti-LYVE-1 (Abcam) and anti-GFP (Santa Cruz) antibodies.	('LYVE-1', 'Gene', '10894', (65, 71))	('anti-GFP', 'Var', (84, 92))	('LYVE-1', 'Gene', (65, 71))
855668	30131072	Given the fact that each miRNA can regulate hundreds of mRNAs to mediate diverse biological functions, dysregulation of miRNAs are intimately related to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (120, 123))	('miR', 'Gene', '220972', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('miR', 'Gene', (25, 28))	('tumor', 'Disease', (153, 158))	('dysregulation', 'Var', (103, 116))	('related', 'Reg', (142, 149))
855702	30131072	As expected, all the foot-pad xenograft tumors expressed GFP (Additional file 2: Figure S4c) and the lymph nodes in tumors formed from miR-548k high expression cells displayed more GFP-positive tumor cells than tumors formed from control cells (Fig.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('xenograft tumors', 'Disease', (30, 46))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('miR-548k', 'Gene', (135, 143))	('tumors', 'Disease', (40, 46))	('xenograft tumors', 'Disease', 'MESH:D009369', (30, 46))	('high expression', 'Var', (144, 159))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('GFP', 'Protein', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('miR-548k', 'Gene', '100313770', (135, 143))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Disease', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (40, 45))	('tumors', 'Disease', (211, 217))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
855721	30131072	Quantitative real time PCR assays confirmed that ADAMTS1 was remarkably downregulated upon miR-548k overexpression in KYSE30 and KYSE510 (Fig.	('KYSE510', 'Var', (129, 136))	('ADAMTS1', 'Gene', '9510', (49, 56))	('ADAMTS1', 'Gene', (49, 56))	('miR-548k', 'Gene', '100313770', (91, 99))	('downregulated', 'NegReg', (72, 85))	('overexpression', 'PosReg', (100, 114))	('KYSE30', 'Var', (118, 124))	('miR-548k', 'Gene', (91, 99))
855729	30131072	Interestingly, ectopic expression of ADAMTS1 could reduce the abilities of miR-548k on migration and tube formation in HDLECs (Fig.	('ectopic expression', 'Var', (15, 33))	('miR-548k', 'Gene', (75, 83))	('ADAMTS1', 'Gene', (37, 44))	('abilities', 'MPA', (62, 71))	('reduce', 'NegReg', (51, 57))	('ADAMTS1', 'Gene', '9510', (37, 44))	('miR-548k', 'Gene', '100313770', (75, 83))
855730	30131072	Consistently, the condition media of ADAMTS1 knockdown cells induced more rapidly and more tube formation in HDLECs than the control media, while media from silencing ADAMTS1 and simultaneously inhibiting miR-548k cells attenuated these abilities compared to miR-548k inhibition along in KYSE150 cells (Additional file 2: Figure S7 and Additional file 2: Figure S8a, b).	('ADAMTS1', 'Gene', '9510', (37, 44))	('KYSE150', 'CellLine', 'CVCL:1348', (288, 295))	('attenuated', 'NegReg', (220, 230))	('miR-548k', 'Gene', '100313770', (259, 267))	('tube formation in HDLECs', 'CPA', (91, 115))	('ADAMTS1', 'Gene', (167, 174))	('ADAMTS1', 'Gene', (37, 44))	('silencing', 'Var', (157, 166))	('more', 'PosReg', (86, 90))	('miR-548k', 'Gene', '100313770', (205, 213))	('inhibiting', 'NegReg', (194, 204))	('ADAMTS1', 'Gene', '9510', (167, 174))	('miR-548k', 'Gene', (205, 213))	('knockdown', 'Var', (45, 54))	('miR-548k', 'Gene', (259, 267))
855734	30131072	Maybe due to the suppression effect of miR-548k on ADAMTS1, the ADMATS1/VEGFC protein complex was less in miR-548k overexpression cells than the control cells (Fig.	('miR-548k', 'Gene', '100313770', (106, 114))	('VEGFC', 'Gene', '7424', (72, 77))	('ADAMTS1', 'Gene', '9510', (51, 58))	('overexpression', 'Var', (115, 129))	('VEGFC', 'Gene', (72, 77))	('miR-548k', 'Gene', (106, 114))	('less', 'NegReg', (98, 102))	('ADAMTS1', 'Gene', (51, 58))	('miR-548k', 'Gene', '100313770', (39, 47))	('miR-548k', 'Gene', (39, 47))
855758	30131072	In tumor xenograft formed from miR-548k overexpression cells, EGFR and phosphorylation of Akt were consistently higher than that in control counterparts (Additional file 2: Figure S9).	('phosphorylation', 'MPA', (71, 86))	('tumor', 'Disease', (3, 8))	('Akt', 'Gene', (90, 93))	('higher', 'PosReg', (112, 118))	('EGFR', 'Gene', '1956', (62, 66))	('miR-548k', 'Gene', '100313770', (31, 39))	('miR-548k', 'Gene', (31, 39))	('EGFR', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('overexpression', 'Var', (40, 54))	('Akt', 'Gene', '207', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
855760	30131072	The data shown that ectopic expression of KLF10 coding sequence (CDS) region could compromise the phenotypes of miR-548k overexpression, which including reducing cell proliferation, migration and invasion (Fig.	('miR-548k', 'Gene', '100313770', (112, 120))	('migration', 'CPA', (182, 191))	('miR-548k', 'Gene', (112, 120))	('invasion', 'CPA', (196, 204))	('cell proliferation', 'CPA', (162, 180))	('KLF10', 'Gene', (42, 47))	('ectopic expression', 'Var', (20, 38))	('reducing', 'NegReg', (153, 161))	('KLF10', 'Gene', '7071', (42, 47))
855761	30131072	Consistently, knockdown KLF10 increased the cellular mobility in KYSE150 cells, while silencing KLF10 and simultaneously inhibiting miR-548k attenuated the ability of migration and invasion compared to miR-548k inhibition along in KYSE150 cells (Additional file 2: Figure S10a, b).	('KYSE150', 'CellLine', 'CVCL:1348', (231, 238))	('KLF10', 'Gene', '7071', (96, 101))	('silencing', 'Var', (86, 95))	('KYSE150', 'CellLine', 'CVCL:1348', (65, 72))	('attenuated', 'NegReg', (141, 151))	('miR-548k', 'Gene', (202, 210))	('miR-548k', 'Gene', '100313770', (202, 210))	('cellular mobility', 'CPA', (44, 61))	('KLF10', 'Gene', (24, 29))	('inhibiting', 'NegReg', (121, 131))	('miR-548k', 'Gene', (132, 140))	('KLF10', 'Gene', (96, 101))	('knockdown', 'Var', (14, 23))	('increased', 'PosReg', (30, 39))	('miR-548k', 'Gene', '100313770', (132, 140))	('KLF10', 'Gene', '7071', (24, 29))
855788	30131072	Amplification of the 11q13.3 region is one of the most common aberrations in multiple human cancers including ESCC and has been implicated with tumor malignancy.	('Amplification', 'Var', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('human', 'Species', '9606', (86, 91))	('tumor malignancy', 'Disease', 'MESH:D018198', (144, 160))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('ESCC', 'Disease', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor malignancy', 'Disease', (144, 160))	('implicated', 'Reg', (128, 138))
855907	28429196	High expression of PD1 is associated with advanced tumor stage and lymph node involvement, but not with survival.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('High', 'Var', (0, 4))	('lymph node involvement', 'CPA', (67, 89))	('tumor', 'Disease', (51, 56))	('PD1', 'Gene', (19, 22))	('associated', 'Reg', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
855946	28429196	Clinicopathologic findings were evaluated for tumors containing PD1+ TILs versus those without (<5%) PD1+ TILs (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PD1+ TILs', 'Var', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
855954	28429196	In the univariate analyses, the patients with PD1+ (>5%) cancer cells showed a significantly lower OS than the patients in whom PD1 was not detectable on cancer cells (respective 1-, 5-, and 10-year survival rates of 74.6, 43.5, and 33.9% vs. 91.1, 68.8, and 48.1%; log-rank 0.047; Table 3).	('PD1+', 'Var', (46, 50))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('lower', 'NegReg', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('OS', 'Chemical', '-', (99, 101))	('patients', 'Species', '9606', (111, 119))
855956	28429196	In terms of DFS, the cancer PD1+ and TIL PD1+ patients both demonstrated a significantly reduced DFS (5-year DFS of 71.3 vs. 41.6%; log-rank 0.008 and 73.3 vs. 41.9%; log-rank 0.008, respectively; Table 3).	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('patients', 'Species', '9606', (46, 54))	('cancer', 'Disease', (21, 27))	('reduced', 'NegReg', (89, 96))	('DFS', 'MPA', (97, 100))	('PD1+', 'Var', (28, 32))
855966	28429196	Importantly, we found that the presence of both PD1+ TILs and PD1+ cancer cells within the TME significantly correlated with tumor recurrence.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cancer', 'Disease', (67, 73))	('PD1+', 'Gene', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('PD1+', 'Var', (48, 52))	('correlated with', 'Reg', (109, 124))
855994	25760075	The patients with high-expression of TACC3 had a significantly poor prognosis compared to those of low-expression (p = 0.017), especially in the patients at stages I-II (p = 0.028).	('high-expression', 'Var', (18, 33))	('patients', 'Species', '9606', (145, 153))	('TACC3', 'Gene', '10460', (37, 42))	('patients', 'Species', '9606', (4, 12))	('TACC3', 'Gene', (37, 42))
856000	25760075	The allelic losses at chromosomes 3p, 5q, 9p, 9q, 13q, 17p, 17q and 18q, as well as mutations of p53 (missense), Rb (deletions), cyclin D1 (amplifications) and c-myc (amplifications) were commonly found in esophageal cancer.	('c-myc', 'Gene', (160, 165))	('p53', 'Gene', (97, 100))	('esophageal cancer', 'Disease', (206, 223))	('cyclin D1', 'Gene', '595', (129, 138))	('losses', 'NegReg', (12, 18))	('p53', 'Gene', '7157', (97, 100))	('cyclin D1', 'Gene', (129, 138))	('mutations', 'Var', (84, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (206, 223))	('c-myc', 'Gene', '4609', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
856005	25760075	It is reported that TACC3 is a promising cancer chemotherapy target and knockdown of TACC3 may efficiently improve the chemosensitivity of cancer cells by modulating a premature senescence program.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TACC3', 'Gene', (85, 90))	('TACC3', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('TACC3', 'Gene', '10460', (20, 25))	('premature senescence program', 'MPA', (168, 196))	('modulating', 'Reg', (155, 165))	('cancer', 'Disease', (41, 47))	('improve', 'PosReg', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('knockdown', 'Var', (72, 81))	('TACC3', 'Gene', '10460', (85, 90))	('cancer', 'Disease', (139, 145))
856007	25760075	TACC3 deficiency has been demonstrated to link with a high rate of p53-mediated apoptosis and suppression of EMT phenotype through the activation of PI3K/Akt and ERK signaling pathways.	('activation', 'PosReg', (135, 145))	('suppression', 'NegReg', (94, 105))	('Akt', 'Gene', '207', (154, 157))	('ERK', 'Gene', (162, 165))	('TACC3', 'Gene', (0, 5))	('p53', 'Gene', (67, 70))	('deficiency', 'Var', (6, 16))	('p53', 'Gene', '7157', (67, 70))	('Akt', 'Gene', (154, 157))	('TACC3', 'Gene', '10460', (0, 5))	('EMT phenotype', 'CPA', (109, 122))	('ERK', 'Gene', '5594', (162, 165))
856013	25760075	In addition, functional studies were performed to identify knockdown of TACC3 could inhibit the proliferation, colony formation ability and epithelial mesenchymal transition (EMT) in ESCC cells.	('epithelial mesenchymal transition', 'CPA', (140, 173))	('TACC3', 'Gene', '10460', (72, 77))	('inhibit', 'NegReg', (84, 91))	('TACC3', 'Gene', (72, 77))	('knockdown', 'Var', (59, 68))	('colony formation ability', 'CPA', (111, 135))
856016	25760075	To investigate the TACC3 expression in ESCC, qRT-PCR and western blotting were performed in both an immortalized normal human esophageal epithelial cell line, NE3, and a panel of ESCC cell lines including Eca-109, EC18, HKESC1, KYSE30, KYSE140, KYSE150, KYSE410, and KYSE510, respectively.	('HKESC1', 'CellLine', 'CVCL:D568', (220, 226))	('human', 'Species', '9606', (120, 125))	('KYSE510', 'Var', (267, 274))	('KYSE410', 'CellLine', 'CVCL:1352', (254, 261))	('KYSE150', 'Var', (245, 252))	('TACC3', 'Gene', '10460', (19, 24))	('KYSE410', 'Var', (254, 261))	('TACC3', 'Gene', (19, 24))
856042	25760075	To investigate the potential roles of TACC3 in ESCC tumorigenesis, we knocked down TACC3 in HKESC1 and KYSE410 cells with two siRNA duplexes.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TACC3', 'Gene', '10460', (38, 43))	('TACC3', 'Gene', '10460', (83, 88))	('tumor', 'Disease', (52, 57))	('TACC3', 'Gene', (38, 43))	('TACC3', 'Gene', (83, 88))	('ESCC', 'Disease', (47, 51))	('KYSE410', 'CellLine', 'CVCL:1352', (103, 110))	('HKESC1', 'CellLine', 'CVCL:D568', (92, 98))	('knocked', 'Var', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
856046	25760075	In addition, knock-down of TACC3 in HKESC1 and KYSE410 cells resulted in dramatically decreases both in the size and the number of colonies to grow in soft agar (Figure 5C).	('knock-down', 'Var', (13, 23))	('TACC3', 'Gene', '10460', (27, 32))	('TACC3', 'Gene', (27, 32))	('decreases', 'NegReg', (86, 95))	('HKESC1', 'CellLine', 'CVCL:D568', (36, 42))	('KYSE410', 'CellLine', 'CVCL:1352', (47, 54))
856057	25760075	It has been suspected that deregulation of TACC3 may be associated with the development of various types of human cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('deregulation', 'Var', (27, 39))	('associated', 'Reg', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (108, 113))	('TACC3', 'Gene', '10460', (43, 48))	('TACC3', 'Gene', (43, 48))	('cancer', 'Disease', (114, 120))
856072	25760075	suggested TACC3-depleted cells arrested in G (1) through a cellular senescence program and the onset of senescence following TACC3 knockdown was remarkably accelerated in the presence of paclitaxel concentrations.	('knockdown', 'Var', (131, 140))	('accelerated', 'PosReg', (156, 167))	('TACC3', 'Gene', '10460', (10, 15))	('TACC3', 'Gene', (10, 15))	('paclitaxel', 'Chemical', 'MESH:D017239', (187, 197))	('TACC3', 'Gene', '10460', (125, 130))	('TACC3', 'Gene', (125, 130))	('cellular senescence program', 'CPA', (59, 86))
856074	25760075	Additionally, it has been reported that high expression of TACC3 conferred cellular sensitization to radiation.	('TACC3', 'Gene', '10460', (59, 64))	('sensitization to radiation', 'Phenotype', 'HP:0011133', (84, 110))	('high expression', 'Var', (40, 55))	('TACC3', 'Gene', (59, 64))	('cellular', 'CPA', (75, 83))
856086	25760075	In summary, we observed the highly expressed TACC3 in ESCC and knockdown TACC3 contributed decreases in cell proliferation, colony formation ability and EMT of ESCC cells, and demonstrated that ESCC patients expressing high levels of TACC3 exhibit a substantially lower 5-year overall survival rate than TACC3-low expression patients.	('TACC3', 'Gene', '10460', (234, 239))	('overall survival rate', 'CPA', (277, 298))	('patients', 'Species', '9606', (325, 333))	('TACC3', 'Gene', (234, 239))	('TACC3', 'Gene', '10460', (45, 50))	('lower', 'NegReg', (264, 269))	('TACC3', 'Gene', (45, 50))	('cell proliferation', 'CPA', (104, 122))	('TACC3', 'Gene', (304, 309))	('colony formation ability', 'CPA', (124, 148))	('EMT', 'CPA', (153, 156))	('TACC3', 'Gene', '10460', (73, 78))	('TACC3', 'Gene', (73, 78))	('high', 'Var', (219, 223))	('TACC3', 'Gene', '10460', (304, 309))	('patients', 'Species', '9606', (199, 207))	('decreases', 'NegReg', (91, 100))	('knockdown', 'Var', (63, 72))
856097	25760075	The ESCC cell lines EC18, HKESC1, KYSE30, KYSE140, KYSE150, KYSE410, and KYSE510 were kindly provided by Professor Xin-Yuan Guan (Department of Clinical Oncology, The University of Hong Kong).	('Oncology', 'Phenotype', 'HP:0002664', (153, 161))	('KYSE410', 'Var', (60, 67))	('HKESC1', 'CellLine', 'CVCL:D568', (26, 32))	('Xin', 'Gene', '165904', (115, 118))	('Xin', 'Gene', (115, 118))	('KYSE510', 'Var', (73, 80))	('KYSE410', 'CellLine', 'CVCL:1352', (60, 67))	('KYSE150', 'Var', (51, 58))
856122	24281182	The silencing of DLEC1 can be modulated by epigenetic modifications, such as DNA hypermethylation and histone hypoacetylation.	('histone', 'MPA', (102, 109))	('DLEC1', 'Gene', (17, 22))	('DLEC1', 'Gene', '9940', (17, 22))	('silencing', 'MPA', (4, 13))	('DNA hypermethylation', 'Var', (77, 97))	('modulated', 'Reg', (30, 39))	('hypermethylation', 'Var', (81, 97))
856123	24281182	In the case of HCC, hepatitis B virus X protein (HBx) has been implicated in methylation of target promoters resulting in the down-regulation of tumor suppressor genes, which in turn contributes to the development of HCC.	('HCC', 'Phenotype', 'HP:0001402', (217, 220))	('methylation', 'Var', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('HCC', 'Gene', '619501', (15, 18))	('HCC', 'Phenotype', 'HP:0001402', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('HBx', 'Gene', '944566', (49, 52))	('HCC', 'Gene', (217, 220))	('tumor', 'Disease', (145, 150))	('HBx', 'Gene', (49, 52))	('hepatitis B virus X', 'Disease', (20, 39))	('contributes', 'Reg', (183, 194))	('HCC', 'Gene', '619501', (217, 220))	('down-regulation', 'NegReg', (126, 141))	('HCC', 'Gene', (15, 18))	('hepatitis B virus X', 'Disease', 'MESH:D006509', (20, 39))	('hepatitis', 'Phenotype', 'HP:0012115', (20, 29))
856125	24281182	In particular, HBx genotype A was found to decrease DNA methylation of the DLEC1 promoter.	('decrease', 'NegReg', (43, 51))	('genotype A', 'Var', (19, 29))	('DLEC1', 'Gene', (75, 80))	('HBx', 'Gene', '944566', (15, 18))	('DNA methylation', 'MPA', (52, 67))	('DLEC1', 'Gene', '9940', (75, 80))	('HBx', 'Gene', (15, 18))
856126	24281182	Our results have provided new insights on the impact of HBx in HCC development by epigenetic modifications.	('epigenetic modifications', 'Var', (82, 106))	('HCC', 'Gene', (63, 66))	('HCC', 'Phenotype', 'HP:0001402', (63, 66))	('HBx', 'Gene', '944566', (56, 59))	('HBx', 'Gene', (56, 59))	('HCC', 'Gene', '619501', (63, 66))
856128	24281182	These include chromosomal deletions as well as mutations in tumor suppressor genes (TSGs).	('TSG', 'Gene', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mutations', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('chromosomal deletions', 'Var', (14, 35))	('TSG', 'Gene', '57045', (84, 87))	('tumor', 'Disease', (60, 65))
856129	24281182	Recently, epigenetic modifications have been suggested in HCC development, involving both DNA methylation and histone acetylation status.	('histone acetylation', 'MPA', (110, 129))	('HCC', 'Gene', (58, 61))	('epigenetic modifications', 'Var', (10, 34))	('HCC', 'Gene', '619501', (58, 61))	('HCC', 'Phenotype', 'HP:0001402', (58, 61))
856130	24281182	DNA hypermethylation has been linked to the down-regulation of several TSGs including RASSF1A, p16INK14, E-cadherin, GSTP1 and DLEC1.	('DLEC1', 'Gene', (127, 132))	('RASSF1A', 'Gene', (86, 93))	('DLEC1', 'Gene', '9940', (127, 132))	('down-regulation', 'NegReg', (44, 59))	('E-cadherin', 'Gene', (105, 115))	('GSTP1', 'Gene', (117, 122))	('E-cadherin', 'Gene', '999', (105, 115))	('TSG', 'Gene', (71, 74))	('RASSF1A', 'Gene', '11186', (86, 93))	('GSTP1', 'Gene', '2950', (117, 122))	('TSG', 'Gene', '57045', (71, 74))	('p16INK14', 'Gene', (95, 103))	('hypermethylation', 'Var', (4, 20))
856132	24281182	On the other hand, histone acetylation affects the lysine residues at the N terminus of histone proteins resulting in the removal of positive charges, thus reducing the affinity between histones and DNA.	('lysine', 'Chemical', 'MESH:D008239', (51, 57))	('histones', 'Protein', (186, 194))	('removal of positive charges', 'MPA', (122, 149))	('histone', 'Var', (19, 26))	('DNA', 'Protein', (199, 202))	('affects', 'Reg', (39, 46))	('affinity between', 'Interaction', (169, 185))	('acetylation', 'MPA', (27, 38))	('reducing', 'NegReg', (156, 164))
856136	24281182	HBV has been implicated in epigenetic modifications leading to HCC.	('leading', 'Reg', (52, 59))	('HCC', 'Gene', '619501', (63, 66))	('HBV', 'Gene', (0, 3))	('HCC', 'Gene', (63, 66))	('HCC', 'Phenotype', 'HP:0001402', (63, 66))	('epigenetic', 'Var', (27, 37))
856139	24281182	For example, the expression of E-cadherin and p16INK14 can be repressed upon the activation of DNMT1 by HBx.	('activation', 'PosReg', (81, 91))	('DNMT1', 'Gene', (95, 100))	('HBx', 'Gene', '944566', (104, 107))	('DNMT1', 'Gene', '1786', (95, 100))	('HBx', 'Gene', (104, 107))	('p16INK14', 'Var', (46, 54))	('E-cadherin', 'Gene', (31, 41))	('E-cadherin', 'Gene', '999', (31, 41))
856142	24281182	Further molecular characterization of HBV genotypes in epigenetic modifications should provide us with helpful information on the underlying mechanisms of genotype-specific HCC development.	('HCC', 'Phenotype', 'HP:0001402', (173, 176))	('HBV', 'Gene', (38, 41))	('epigenetic modifications', 'Var', (55, 79))	('HCC', 'Gene', (173, 176))	('HCC', 'Gene', '619501', (173, 176))
856145	24281182	Our results provide new insights on the impact of HBx in HCC development by epigenetic modifications.	('HBx', 'Gene', (50, 53))	('HCC', 'Gene', (57, 60))	('HCC', 'Gene', '619501', (57, 60))	('HCC', 'Phenotype', 'HP:0001402', (57, 60))	('epigenetic modifications', 'Var', (76, 100))	('HBx', 'Gene', '944566', (50, 53))
856147	24281182	The silencing of DLEC1 is associated with DNA methylation, as well as histone acetylation.	('DLEC1', 'Gene', (17, 22))	('DLEC1', 'Gene', '9940', (17, 22))	('DNA methylation', 'MPA', (42, 57))	('histone acetylation', 'MPA', (70, 89))	('associated', 'Reg', (26, 36))	('silencing', 'Var', (4, 13))
856149	24281182	In the case of HCC associated with HBV infection, epigenetic modifications may well implicate viral proteins including HBx, which has been linked to the silencing of tumor suppressor genes and development of HCC.	('implicate', 'Reg', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('HCC', 'Gene', '619501', (15, 18))	('HBx', 'Gene', (119, 122))	('HCC', 'Gene', '619501', (208, 211))	('linked', 'Reg', (139, 145))	('HCC', 'Phenotype', 'HP:0001402', (208, 211))	('HCC', 'Phenotype', 'HP:0001402', (15, 18))	('silencing', 'Var', (153, 162))	('tumor', 'Disease', (166, 171))	('epigenetic', 'Var', (50, 60))	('HBV infection', 'Disease', (35, 48))	('HCC', 'Gene', (208, 211))	('HCC', 'Gene', (15, 18))	('HBV infection', 'Disease', 'MESH:D006509', (35, 48))	('HBx', 'Gene', '944566', (119, 122))
856157	24281182	Combined with our findings in Huh7 cells, our results indicated that DLEC1 was significantly methylated in HCC-derived cell lines.	('HCC', 'Gene', '619501', (107, 110))	('HCC', 'Phenotype', 'HP:0001402', (107, 110))	('Huh7', 'Gene', '284424', (30, 34))	('DLEC1', 'Gene', (69, 74))	('DLEC1', 'Gene', '9940', (69, 74))	('HCC', 'Gene', (107, 110))	('methylated', 'Var', (93, 103))	('Huh7', 'Gene', (30, 34))
856163	24281182	As shown in Figure 1C, DLEC1 expression was upregulated in both types of cells incubated with 5-Aza-dC compared with those without any incubation with 5-Aza-dC.	('5-Aza-dC', 'Var', (94, 102))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (94, 102))	('upregulated', 'PosReg', (44, 55))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (151, 159))	('DLEC1', 'Gene', (23, 28))	('DLEC1', 'Gene', '9940', (23, 28))	('expression', 'MPA', (29, 39))
856172	24281182	Interestingly, the increase of DLEC1 expression after the incubation of cells with TSA (Figure 2B) was more significant than that in cells incubated with 5-Aza-dC (Figure 1C).	('DLEC1', 'Gene', (31, 36))	('DLEC1', 'Gene', '9940', (31, 36))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (154, 162))	('increase', 'PosReg', (19, 27))	('TSA', 'Chemical', 'MESH:C012589', (83, 86))	('expression', 'MPA', (37, 47))	('TSA', 'Var', (83, 86))
856176	24281182	Results of methylation analysis by BGS shown in Figure 3A indicated that the methylation of DLEC1 promoter was lower in HepG2.2.15 (46.49%) than that in HepG2 (89.47%, Figure 1A).	('HepG2.2.15', 'CellLine', 'CVCL:L855', (120, 130))	('BGS', 'Disease', (35, 38))	('HepG2', 'CellLine', 'CVCL:0027', (153, 158))	('BGS', 'Disease', 'MESH:C536788', (35, 38))	('HepG2', 'CellLine', 'CVCL:0027', (120, 125))	('lower', 'NegReg', (111, 116))	('DLEC1', 'Gene', (92, 97))	('methylation', 'MPA', (77, 88))	('HepG2.2.15', 'Var', (120, 130))	('DLEC1', 'Gene', '9940', (92, 97))
856178	24281182	In addition, the acetylation level of histones H3 and H4 was found to be higher in HepG2.2.15 (lanes 3 and 5, Figure 3B) compared with that in HepG2 (lanes 3 and 5, Figure 2A).	('HepG2.2.15', 'Var', (83, 93))	('HepG2.2.15', 'CellLine', 'CVCL:L855', (83, 93))	('HepG2', 'CellLine', 'CVCL:0027', (143, 148))	('histones H3', 'Protein', (38, 49))	('HepG2', 'CellLine', 'CVCL:0027', (83, 88))	('acetylation level', 'MPA', (17, 34))	('higher', 'PosReg', (73, 79))
856179	24281182	The level of acetylation of histone 3 was further increased after HepG2.2.15 cells were incubated with TSA (lane 4, Figure 3B).	('HepG2.2.15', 'Var', (66, 76))	('HepG2.2.15', 'CellLine', 'CVCL:L855', (66, 76))	('increased', 'PosReg', (50, 59))	('TSA', 'Chemical', 'MESH:C012589', (103, 106))	('acetylation', 'MPA', (13, 24))
856193	24281182	The biological significance of demethylation/acetylation of DLEC1 and its up-regulation HBx may be of particular interest.	('HBx', 'Gene', (88, 91))	('demethylation/acetylation', 'Var', (31, 56))	('up-regulation', 'PosReg', (74, 87))	('DLEC1', 'Gene', '9940', (60, 65))	('DLEC1', 'Gene', (60, 65))	('HBx', 'Gene', '944566', (88, 91))
856199	24281182	For example, for SOCS-1, which is silenced by hypermethylation in HCC and shows growth-suppression activity, its CpG island hypermethylation has been found to be inversely associated with HBV infection status.	('HBV infection status', 'Disease', 'MESH:D006509', (188, 208))	('hypermethylation', 'Var', (124, 140))	('HCC', 'Gene', (66, 69))	('associated', 'Reg', (172, 182))	('SOCS-1', 'Gene', (17, 23))	('hypermethylation', 'Var', (46, 62))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('HCC', 'Gene', '619501', (66, 69))	('SOCS-1', 'Gene', '8651', (17, 23))	('HBV infection status', 'Disease', (188, 208))
856208	24281182	Compared with the input control, the acetylated histone H4 (Figure 5B, panel 2) was increased to a different extent in Huh7 transfected by HBx of various genotypes, especially in HBx A (Figure 5B, panel 2, lane 2), compared with that in cells transfected with pXJ40 (lane 1).	('HBx', 'Gene', (139, 142))	('Huh7', 'Gene', '284424', (119, 123))	('acetylated', 'MPA', (37, 47))	('HBx', 'Gene', '944566', (179, 182))	('transfected', 'Var', (124, 135))	('HBx', 'Gene', (179, 182))	('increased', 'PosReg', (84, 93))	('HBx', 'Gene', '944566', (139, 142))	('Huh7', 'Gene', (119, 123))
856211	24281182	Our results therefore indicate that the DLEC1 expression is modulated by epigenetic modifications, which are influenced by HBx in a genotype specific manner.	('DLEC1', 'Gene', '9940', (40, 45))	('HBx', 'Gene', '944566', (123, 126))	('HBx', 'Gene', (123, 126))	('modulated', 'Reg', (60, 69))	('epigenetic modifications', 'Var', (73, 97))	('influenced', 'Reg', (109, 119))	('DLEC1', 'Gene', (40, 45))	('expression', 'MPA', (46, 56))
856212	24281182	Among the four genotypes of HBx, HBx A showed significant correlation between epigenetic analyses and DLEC1 expression.	('HBx', 'Gene', (33, 36))	('HBx', 'Gene', '944566', (28, 31))	('HBx', 'Gene', '944566', (33, 36))	('expression', 'MPA', (108, 118))	('HBx', 'Gene', (28, 31))	('epigenetic', 'Var', (78, 88))	('DLEC1', 'Gene', '9940', (102, 107))	('DLEC1', 'Gene', (102, 107))
856215	24281182	Our findings indicate that the HBV genotype D repressed DLEC1 in HepG2.2.15 independently of the epigenetic alterations in its promoter (part 2.2).	('epigenetic', 'Var', (97, 107))	('DLEC1', 'Gene', (56, 61))	('DLEC1', 'Gene', '9940', (56, 61))	('HepG2.2.15', 'CellLine', 'CVCL:L855', (65, 75))	('HBV genotype D', 'Species', '489483', (31, 45))
856220	24281182	In addition to its role in interacting with cytoskeletal proteins, further investigation should shed new light on the role of this proline-rich region in HBx-mediated epigenetic alterations.	('epigenetic', 'Var', (167, 177))	('proline', 'Chemical', 'MESH:D011392', (131, 138))	('HBx', 'Gene', '944566', (154, 157))	('HBx', 'Gene', (154, 157))
856224	24281182	The sequence variations among different genotypes of HBx may as well affect the interaction of HBx with DNMT3A and lead to genotype specific effects on DLEC1 expression.	('HBx', 'Gene', (53, 56))	('HBx', 'Gene', (95, 98))	('affect', 'Reg', (69, 75))	('effects', 'Reg', (141, 148))	('expression', 'MPA', (158, 168))	('interaction', 'Interaction', (80, 91))	('DLEC1', 'Gene', (152, 157))	('DLEC1', 'Gene', '9940', (152, 157))	('sequence variations', 'Var', (4, 23))	('DNMT3A', 'Gene', (104, 110))	('DNMT3A', 'Gene', '1788', (104, 110))	('HBx', 'Gene', '944566', (53, 56))	('HBx', 'Gene', '944566', (95, 98))	('lead to', 'Reg', (115, 122))
856231	24281182	Total RNA of the cells transfected with pXJ40 vector or plasmids containing HBx or treated by 5-Aza-dC or TSA was isolated using RNeasy Mini kit (QIAGEN).	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (94, 102))	('TSA', 'Chemical', 'MESH:C012589', (106, 109))	('pXJ40', 'Var', (40, 45))	('HBx', 'Gene', '944566', (76, 79))	('HBx', 'Gene', (76, 79))
856260	24281182	In conclusion, we have established a cell system to investigate the effects of epigenetic modifications on expression of target genes, in particular DLEC1, which is silenced in human cancers including HCC.	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('cancers', 'Disease', (183, 190))	('HCC', 'Phenotype', 'HP:0001402', (201, 204))	('epigenetic modifications', 'Var', (79, 103))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('DLEC1', 'Gene', (149, 154))	('HCC', 'Gene', (201, 204))	('DLEC1', 'Gene', '9940', (149, 154))	('human', 'Species', '9606', (177, 182))	('HCC', 'Gene', '619501', (201, 204))
856359	21979112	Patients who underwent an esophagectomy between 1993 and 2010 were divided into three groups according to their BMI: normal weight (<25 kg/m2), overweight (25-30 kg/m2) or obese (>=30 kg/m2).	('<25 kg/m2', 'Var', (132, 141))	('25-30 kg/m2', 'Var', (156, 167))	('overweight', 'Phenotype', 'HP:0025502', (144, 154))	('obese', 'Disease', 'MESH:D009765', (172, 177))	('Patients', 'Species', '9606', (0, 8))	('obese', 'Disease', (172, 177))
856376	21979112	Patients were divided into three groups according to their BMI: normal weight (<25 kg/m2), overweight (25-30 kg/m2), or obese (>=30 kg/m2).	('25-30 kg/m2', 'Var', (103, 114))	('overweight', 'Phenotype', 'HP:0025502', (91, 101))	('obese', 'Disease', 'MESH:D009765', (120, 125))	('obese', 'Disease', (120, 125))	('Patients', 'Species', '9606', (0, 8))
856384	21979112	Grading of complications was performed according to the most severe complication in each patient by a panel of four contributing authors (R.B., S.L., M.v.B.H., and O.B.).	('patient', 'Species', '9606', (89, 96))	('S.L.', 'Var', (144, 148))	('M.v.B.H.', 'Var', (150, 158))
856409	21979112	It has also been speculated that anastomotic leakage in patients with a high BMI is due to a compromised vascularity of the conduit because of an increased tension on the conduit in the thoracic compartment.	('patients', 'Species', '9606', (56, 64))	('increased', 'PosReg', (146, 155))	('tension', 'MPA', (156, 163))	('anastomotic leakage', 'Disease', (33, 52))	('high', 'Var', (72, 76))
856478	31125107	Most of the individuals from the NCGG (2586 of 2670) were older than 60 years, and approximately half of them (1469 of 2670) were diagnosed as having dementia.	('diagnosed', 'Reg', (130, 139))	('dementia', 'Phenotype', 'HP:0000726', (150, 158))	('dementia', 'Disease', (150, 158))	('dementia', 'Disease', 'MESH:D003704', (150, 158))	('1469 of 2670', 'Var', (111, 123))
856483	31125107	The EC index was calculated as follows: (0.961037)*miR-8073+(-0.962054)*miR-6794-5p+(1.31647)*miR-3196+(-1.0132)*miR-6820-5p+(0.657628)*miR-744-5p+(-0.406723)*miR-6799-5p-9.799262.	('miR-6820', 'Gene', (113, 121))	('miR-6799', 'Gene', (159, 167))	('miR-6799', 'Gene', '102465479', (159, 167))	('miR-6794', 'Gene', (72, 80))	('miR-6820', 'Gene', '102465492', (113, 121))	('EC', 'Chemical', '-', (4, 6))	('miR-744', 'Gene', (136, 143))	('miR-8073', 'Gene', '102465872', (51, 59))	('miR-8073', 'Gene', (51, 59))	('miR-6794', 'Gene', '102466196', (72, 80))	('miR-3196', 'Gene', '100423014', (94, 102))	('miR-744', 'Gene', '100126313', (136, 143))	('0.961037', 'Var', (41, 49))	('miR-3196', 'Gene', (94, 102))
856493	31125107	The results showed that 7 miRNAs (miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a, and miR-127-3p) were significantly upregulated in the serum of patients with ESCC compared with the control patients (the AUC for the 7 miRNAs ranged from 0.817 to 0.949).	('miR-127-3p', 'Gene', (93, 103))	('miR-100', 'Gene', (51, 58))	('patients', 'Species', '9606', (197, 205))	('miR-22', 'Gene', '407004', (43, 49))	('miR-22', 'Gene', (43, 49))	('upregulated', 'PosReg', (124, 135))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('miR-223', 'Gene', (70, 77))	('miR-100', 'Gene', '406892', (51, 58))	('miR-10a', 'Gene', '406902', (34, 41))	('SCC', 'Gene', '6317', (167, 170))	('miR-148b', 'Gene', '442892', (60, 68))	('miR-148b', 'Gene', (60, 68))	('miR-133a', 'Var', (79, 87))	('miR-223', 'Gene', '407008', (70, 77))	('patients', 'Species', '9606', (152, 160))	('SCC', 'Gene', (167, 170))	('miR-22', 'Gene', '407004', (70, 76))	('miR-22', 'Gene', (70, 76))	('miR-127-3p', 'Gene', '100302165', (93, 103))	('miR-10a', 'Gene', (34, 41))
856593	31096448	Immunotherapy is a new field in the treatment of esophageal cancer, and many trials have reported that PD-1 and PD-L1 inhibitors can benefit patients alone more than traditional platinum-based chemotherapy.	('inhibitors', 'Var', (118, 128))	('esophageal cancer', 'Disease', (49, 66))	('PD-L1', 'Gene', (112, 117))	('PD-1', 'Gene', (103, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('PD-1', 'Gene', '5133', (103, 107))	('PD-L1', 'Gene', '29126', (112, 117))	('platinum', 'Chemical', 'MESH:D010984', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('patients', 'Species', '9606', (141, 149))
856626	30988074	Cells were cultivated in RPMI-1640 medium (Gibco, Thermo Fisher Scientific, Waltham, MA, U.S.A.) supplemented with 10% fetal bovine serum (FBS) (Thermo Fisher Scientific), streptomycin (100 U/ml) (Thermo Fisher Scientific), and penicillin (100 U/ml) (Thermo Fisher Scientific) at 37 C with an atmosphere of 5% CO2.	('FBS', 'Disease', 'MESH:D005198', (139, 142))	('streptomycin', 'Chemical', 'MESH:D013307', (172, 184))	('penicillin', 'Chemical', 'MESH:D010406', (228, 238))	('CO2', 'Chemical', '-', (310, 313))	('bovine', 'Species', '9913', (125, 131))	('FBS', 'Disease', (139, 142))	('100 U/ml', 'Var', (240, 248))	('RPMI-1640 medium', 'Chemical', '-', (25, 41))
856643	30988074	Similarly, the 3'-UTR regions of LASP1 containing potential binding sites and their mutants were also inserted into pmirGLO luciferase vector.	('mutants', 'Var', (84, 91))	('LASP1', 'Gene', '3927', (33, 38))	('binding', 'Interaction', (60, 67))	('LASP1', 'Gene', (33, 38))
856644	30988074	The obtained wild-type and mutant plasmids were cotransfected with miRNA mimic or miRNA NC using Lipofectamine 2000 (Invitrogen) as described in manual.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (97, 115))	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))	('mutant', 'Var', (27, 33))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))
856658	30988074	As shown in Figure 2B,C, cell viabilities of Eca-109 and KYSE-150 were obviously repressed by 46% and 53%, respectively, after the transfection of specific siRNA.	('cell viabilities', 'CPA', (25, 41))	('transfection', 'Var', (131, 143))	('KYSE-150', 'CellLine', 'CVCL:1348', (57, 65))	('repressed', 'NegReg', (81, 90))
856660	30988074	Besides, Transwell assay showed that hsa_circ_0004370 knockdown obviously inhibited cell invasion of Eca-109 and KYSE-150 by 55% and 47%, respectively (Figure 2E).	('inhibited', 'NegReg', (74, 83))	('knockdown', 'Var', (54, 63))	('cell invasion of Eca-109', 'CPA', (84, 108))	('KYSE-150', 'CellLine', 'CVCL:1348', (113, 121))	('cir', 'Gene', (41, 44))	('cir', 'Gene', '9541', (41, 44))
856667	30988074	RIP assay showed that anti-Ago2 antibodies obviously enriched hsa_circ_0004370 and miRNA-1294 than the IgG group in both cells (Figure 3E,F), further confirming the relationship between the two RNA molecules.	('antibodies', 'Var', (32, 42))	('Ago2', 'Gene', (27, 31))	('enriched', 'Reg', (53, 61))	('cir', 'Gene', (66, 69))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('Ago2', 'Gene', '27161', (27, 31))	('cir', 'Gene', '9541', (66, 69))
856679	30988074	Western blotting showed similar changes in the protein level of LASP1 in both cells after transfection of these molecules (Figure 4K,L).	('changes', 'Reg', (32, 39))	('LASP1', 'Gene', '3927', (64, 69))	('LASP1', 'Gene', (64, 69))	('transfection', 'Var', (90, 102))	('protein level', 'MPA', (47, 60))
856688	30988074	Many circRNAs have been identified and their aberrant expression has been proved to involve in the progression of bladder cancer, breast cancer, lung cancer, pancreatic ductal cancer, and cholangiocarcinoma as tumor suppressor or promoter.	('bladder cancer', 'Disease', 'MESH:D001749', (114, 128))	('bladder cancer', 'Disease', (114, 128))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (188, 206))	('involve', 'Reg', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('aberrant expression', 'Var', (45, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('cir', 'Gene', '9541', (5, 8))	('lung cancer', 'Disease', (145, 156))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('pancreatic ductal cancer', 'Disease', (158, 182))	('breast cancer', 'Disease', (130, 143))	('pancreatic ductal cancer', 'Disease', 'MESH:D010190', (158, 182))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cir', 'Gene', (5, 8))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (188, 206))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cholangiocarcinoma', 'Disease', (188, 206))
856691	30988074	Further, hsa_circ_0004370 knockdown obviously decreased cell proliferation and migration and promoted cell apoptosis.	('cell apoptosis', 'CPA', (102, 116))	('cir', 'Gene', (13, 16))	('knockdown', 'Var', (26, 35))	('cell proliferation', 'CPA', (56, 74))	('decreased', 'NegReg', (46, 55))	('cir', 'Gene', '9541', (13, 16))	('promoted', 'PosReg', (93, 101))
856704	30988074	Dysregulation of protein expression via different mechanisms plays a key role in the development of cancer.	('protein', 'Protein', (17, 24))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
856967	26960365	According to the International Association of Cancer Registries (IACR) and NCCR requirements of cancer registration data, our data evaluation was as follows: 74.43% MV%, 1.21% DCO%, 0.70 M/I, 0.23% O and U% [Table 2].	('Cancer', 'Disease', (46, 52))	('men', 'Species', '9606', (87, 90))	('Cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('0.70', 'Var', (182, 186))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
857055	26504871	This endoscopic mucosal resection was performed for removal of nodularity as well as for deeper tissue resection of the carcinoma in situ.	('carcinoma', 'Disease', (120, 129))	('carcinoma', 'Disease', 'MESH:D002277', (120, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('nodularity', 'Var', (63, 73))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (120, 137))
857078	20217248	In those who had nodal metastases, the median survival of patients with ypV0 and ypV+ were 21.2 months and 17.4 months respectively (P = .37).	('ypV0', 'Var', (72, 76))	('nodal metastases', 'Disease', 'MESH:D009362', (17, 33))	('ypV+', 'Var', (81, 85))	('patients', 'Species', '9606', (58, 66))	('nodal metastases', 'Disease', (17, 33))
857106	20217248	The percentage of viable residual tumor was designated as a continuous variable and also categorized into 4 groups as a measure of the extent of chemoradiation response: ypV0, no viable cell; ypV1, 1%-33% viable tumor; ypV2, 34%-66% viable tumor; and ypV3, 67%-100% viable tumor, according to the Guidelines of Japanese Society for Esophageal Disease.	('ypV1', 'Var', (192, 196))	('ypV0', 'Var', (170, 174))	('Esophageal Disease', 'Disease', 'MESH:D004935', (332, 350))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('ypV2', 'Var', (219, 223))	('tumor', 'Disease', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('Esophageal Disease', 'Disease', (332, 350))	('ypV3', 'Var', (251, 255))
857159	20217248	It is important to note that in our patients who had ypN0 disease, ypV0 patients survived longer than those who had ypV+ disease.	('patients', 'Species', '9606', (36, 44))	('ypN0', 'Var', (53, 57))	('survived', 'CPA', (81, 89))	('ypV0', 'Disease', (67, 71))	('patients', 'Species', '9606', (72, 80))
857199	32337608	Pathological examination of a specimen identified pT1bN0M0 pStage IA gastric cancer (tub1).	('pStage IA gastric cancer', 'Disease', 'MESH:D013274', (59, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('pT1bN0M0', 'Var', (50, 58))	('pStage IA gastric cancer', 'Disease', (59, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
857253	32201667	Three alleles were identified: arginine/arginine, arginine/histidine, and histidine/histidine.	('arginine', 'Chemical', 'MESH:D001120', (40, 48))	('histidine', 'Chemical', 'MESH:D006639', (84, 93))	('arginine', 'Chemical', 'MESH:D001120', (31, 39))	('histidine', 'Chemical', 'MESH:D006639', (74, 83))	('arginine/histidine', 'Var', (50, 68))	('arginine/arginine', 'Var', (31, 48))	('histidine', 'Chemical', 'MESH:D006639', (59, 68))	('histidine/histidine', 'Var', (74, 93))	('arginine', 'Chemical', 'MESH:D001120', (50, 58))
857254	32201667	The risk of developing esophageal cancer was higher in Taiwanese men with the arginine/histidine allele than in those with the two homozygous alleles.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('arginine', 'Chemical', 'MESH:D001120', (78, 86))	('men', 'Species', '9606', (65, 68))	('arginine/histidine', 'Var', (78, 96))	('esophageal cancer', 'Disease', (23, 40))	('histidine', 'Chemical', 'MESH:D006639', (87, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (23, 40))
857255	32201667	In addition to showing that genetics are involved in the development of esophageal cancer, these findings suggest that detection of the arginine/histidine allele may be a marker for early-stage esophageal cancer.	('histidine', 'Chemical', 'MESH:D006639', (145, 154))	('arginine', 'Chemical', 'MESH:D001120', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('arginine/histidine', 'Var', (136, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('esophageal cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('men', 'Species', '9606', (64, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))
857289	32201667	A study assessing the correlation between alcohol drinking and the development of EADC in Taiwanese women found that ethanol could potentially affect the esophageal mucosa and that alcohol-associated toxicity or oxidative damage could penetrate the mucosal layer, causing damage to that layer.	('EADC', 'Disease', (82, 86))	('toxicity', 'Disease', 'MESH:D064420', (200, 208))	('esophageal mucosa', 'Disease', 'MESH:D004941', (154, 171))	('ethanol', 'Chemical', 'MESH:D000431', (117, 124))	('women', 'Species', '9606', (100, 105))	('oxidative damage', 'Var', (212, 228))	('EADC', 'Phenotype', 'HP:0011459', (82, 86))	('penetrate', 'Reg', (235, 244))	('causing damage', 'Reg', (264, 278))	('men', 'Species', '9606', (102, 105))	('EADC', 'Disease', 'MESH:D004938', (82, 86))	('alcohol', 'Chemical', 'MESH:D000438', (181, 188))	('alcohol', 'Chemical', 'MESH:D000438', (42, 49))	('men', 'Species', '9606', (74, 77))	('alcohol drinking', 'Phenotype', 'HP:0030955', (42, 58))	('affect', 'Reg', (143, 149))	('esophageal mucosa', 'Disease', (154, 171))	('toxicity', 'Disease', (200, 208))
857298	32201667	Individuals with the STAT1A1 arginine/histidine allele are at greater risk factor for esophageal cancer than those with the arginine/arginine and histidine/histidine alleles, with men in Taiwan being more likely to carry the arginine/histidine allele than women.	('arginine', 'Chemical', 'MESH:D001120', (29, 37))	('men', 'Species', '9606', (258, 261))	('arginine', 'Chemical', 'MESH:D001120', (133, 141))	('histidine', 'Chemical', 'MESH:D006639', (156, 165))	('arginine/histidine', 'Var', (29, 47))	('arginine', 'Chemical', 'MESH:D001120', (225, 233))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('women', 'Species', '9606', (256, 261))	('men', 'Species', '9606', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('arginine', 'Chemical', 'MESH:D001120', (124, 132))	('histidine', 'Chemical', 'MESH:D006639', (234, 243))	('histidine', 'Chemical', 'MESH:D006639', (38, 47))	('STAT1A1 arginine/histidine', 'Var', (21, 47))	('histidine', 'Chemical', 'MESH:D006639', (146, 155))
857313	27100431	The complicaion rate was lower in the EVT group (0/7, 0.0%) than that in the E-SEMS group (6/11, 54.5%) with statistically significant difference (P = 0.042).	('EVT', 'Var', (38, 41))	('complicaion rate', 'CPA', (4, 20))	('EVT', 'Chemical', '-', (38, 41))	('lower', 'NegReg', (25, 30))
857351	27100431	The clinical success rate was higher in the EVT group (7/7, 100.0%) than that in the E-SEMS group (7/11, 63.6%), but there was no significant difference (P = 0.351).	('EVT', 'Chemical', '-', (44, 47))	('higher', 'PosReg', (30, 36))	('clinical success rate', 'CPA', (4, 25))	('EVT', 'Var', (44, 47))
857353	27100431	However, the complication rate was lower in the EVT group (0/7, 0.0%) than that in the E-SEMS group (6/11, 54.5%) with statistically significant difference (P = 0.042).	('EVT', 'Var', (48, 51))	('lower', 'NegReg', (35, 40))	('complication rate', 'CPA', (13, 30))	('EVT', 'Chemical', '-', (48, 51))
857371	27100431	The overall closure rate was significantly higher in the EVT group (84.4%) compared with the Stent group (53.8%).	('EVT', 'Var', (57, 60))	('closure rate', 'CPA', (12, 24))	('EVT', 'Chemical', '-', (57, 60))	('higher', 'PosReg', (43, 49))
857398	27042104	Fascin-1 (FSCN1) was identified as one of the targets of miR-429 and knockdown of FSCN1 mimics the function of miR-429 overexpression.	('FSCN1', 'Gene', (82, 87))	('FSCN1', 'Gene', (10, 15))	('FSCN1', 'Gene', '6624', (10, 15))	('Fascin-1', 'Gene', (0, 8))	('Fascin-1', 'Gene', '6624', (0, 8))	('FSCN1', 'Gene', '6624', (82, 87))	('knockdown', 'Var', (69, 78))
857402	27042104	Currently, molecular profiling of GC has suggested that genetic alterations, chromosomal instability, and Helicobacter pylori infections are correlated with GC development and progression.	('correlated', 'Reg', (141, 151))	('Helicobacter pylori infections', 'Disease', (106, 136))	('genetic alterations', 'Var', (56, 75))	('Helicobacter pylori', 'Species', '210', (106, 125))	('Helicobacter pylori infections', 'Phenotype', 'HP:0005202', (106, 136))	('GC', 'Phenotype', 'HP:0012126', (34, 36))	('GC', 'Phenotype', 'HP:0012126', (157, 159))	('chromosomal instability', 'Phenotype', 'HP:0040012', (77, 100))
857404	27042104	MiRNAs have been implicated in the development of acute myeloid leukemia, breast cancer, non-small-cell lung carcinoma, hepatocellular carcinoma, colon cancer, GC, and other cancers.	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (89, 118))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (50, 72))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('GC', 'Phenotype', 'HP:0012126', (160, 162))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (56, 72))	('colon cancer', 'Disease', 'MESH:D015179', (146, 158))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (50, 72))	('hepatocellular carcinoma', 'Disease', (120, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('implicated', 'Reg', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('non-small-cell lung carcinoma', 'Disease', (89, 118))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (89, 118))	('colon cancer', 'Disease', (146, 158))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (120, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (120, 144))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (93, 118))	('breast cancer', 'Disease', (74, 87))	('MiRNAs', 'Var', (0, 6))	('acute myeloid leukemia', 'Disease', (50, 72))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))
857411	27042104	Furthermore, we identified and validated fascin-1 (FSCN1) as one of the targets of miR-429, which suggests that miR-429 participates in cancer cell biology by regulating FSCN1 expression.	('fascin-1', 'Gene', '6624', (41, 49))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('FSCN1', 'Gene', '6624', (51, 56))	('FSCN1', 'Gene', '6624', (170, 175))	('expression', 'MPA', (176, 186))	('cancer', 'Disease', (136, 142))	('participates', 'Reg', (120, 132))	('regulating', 'Reg', (159, 169))	('fascin-1', 'Gene', (41, 49))	('FSCN1', 'Gene', (170, 175))	('FSCN1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('miR-429', 'Var', (112, 119))
857420	27042104	FSCN1-3'UTR-psiCHECK2-MUT carried the mutated sequence in the complementary site for the seed region of miR-429 and was generated based on FSCN1-3'UTR-psiCHECK 2-WT by site-specific mutagenesis (Transgene, Beijing, People's Republic of China), which mutated CAGTATT to AGTGCGA.	('FSCN1', 'Gene', (0, 5))	('FSCN1', 'Gene', '6624', (0, 5))	("People's Republic", 'Disease', 'MESH:D006212', (215, 232))	('GC', 'Phenotype', 'HP:0012126', (272, 274))	('mutated', 'Var', (250, 257))	("People's Republic", 'Disease', (215, 232))	('FSCN1', 'Gene', (139, 144))	('FSCN1', 'Gene', '6624', (139, 144))
857426	27042104	A total of 1.2x105 transfected cells were plated into 6-well plates, and DNA synthesis was assessed with a Cell-Light  EdU Apollo 488 In Vitro Imaging Kit (C10310-3, RiboBio, Guangzhou, People's Republic of China).	("People's Republic", 'Disease', (186, 203))	('DNA synthesis', 'MPA', (73, 86))	("People's Republic", 'Disease', 'MESH:D006212', (186, 203))	('C10310-3', 'Var', (156, 164))
857455	27042104	Given that the expression of miR-429 is downregulated in GC, we then determined whether miR-429 functions as a tumor suppressor.	('miR-429', 'Gene', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('downregulated', 'NegReg', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('expression', 'MPA', (15, 25))	('GC', 'Phenotype', 'HP:0012126', (57, 59))	('miR-429', 'Var', (88, 95))
857457	27042104	The capacity of colony formation was also evaluated on SGC-7901 cells expressing miR-429 mimics, and the results showed that miR-429 significantly reduced the cells' proliferation (Figure 1D).	('miR-429', 'Var', (125, 132))	('SGC-7901', 'CellLine', 'CVCL:0520', (55, 63))	('reduced', 'NegReg', (147, 154))	('GC', 'Phenotype', 'HP:0012126', (56, 58))
857458	27042104	Nude mice injected with SGC-7901/miR-429-LV cells showed a significant reduction in tumor size and weight as compared with those of NC (P<0.01) (Figure 2A-C).	('SGC-7901', 'CellLine', 'CVCL:0520', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Nude mice', 'Species', '10090', (0, 9))	('GC', 'Phenotype', 'HP:0012126', (25, 27))	('reduction', 'NegReg', (71, 80))	('SGC-7901/miR-429-LV cells', 'Var', (24, 49))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))
857459	27042104	Therefore, predicted targets associated with tumor progression were analyzed (Figure S2) and further validated by examining their expression at the mRNA level upon the transfection of miR-429 in SGC7901 cells.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('GC', 'Phenotype', 'HP:0012126', (196, 198))	('SGC7901', 'CellLine', 'CVCL:0520', (195, 202))	('tumor', 'Disease', (45, 50))	('miR-429', 'Var', (184, 191))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
857460	27042104	Among these six candidates, the level of FSCN1 was suppressed by miR-429 (Figure 3A) and the potential 3'UTR binding site of FSCN1 of miR-429 is shown in Figure 3B.	('miR-429', 'Var', (65, 72))	('FSCN1', 'Gene', (41, 46))	('FSCN1', 'Gene', (125, 130))	('FSCN1', 'Gene', '6624', (41, 46))	('suppressed', 'NegReg', (51, 61))	('FSCN1', 'Gene', '6624', (125, 130))	('level', 'MPA', (32, 37))
857462	27042104	As shown in Figure 3C, the miR-429 mimics the reduced renilla luciferase activity of the wild-type plasmid (wt FSCN1 3'UTR) which resulted in the increase of relative LUC (Fluc/Rluc)% (P<0.05) but not the mutant plasmid (mut FSCN1 3'UTR).	('renilla luciferase', 'Enzyme', (54, 72))	('increase', 'PosReg', (146, 154))	('activity', 'MPA', (73, 81))	('miR-429', 'Var', (27, 34))	('FSCN1', 'Gene', (111, 116))	('FSCN1', 'Gene', '6624', (111, 116))	('reduced', 'NegReg', (46, 53))	('FSCN1', 'Gene', (225, 230))	('FSCN1', 'Gene', '6624', (225, 230))
857463	27042104	Moreover, the expression level of FSCN1 protein in the cells overexpressing miR-429 mimics was dramatically lower than that of NC miRNA (Figure 3D).	('miR-429', 'Gene', (76, 83))	('FSCN1', 'Gene', '6624', (34, 39))	('expression level', 'MPA', (14, 30))	('FSCN1', 'Gene', (34, 39))	('lower', 'NegReg', (108, 113))	('protein', 'Protein', (40, 47))	('mimics', 'Var', (84, 90))
857464	27042104	These findings suggest that miR-429 directly targets FSCN1 expression by binding to the 3'UTR region of FSCN1.	('miR-429', 'Var', (28, 35))	('binding', 'Interaction', (73, 80))	('expression', 'MPA', (59, 69))	('FSCN1', 'Gene', (104, 109))	('FSCN1', 'Gene', '6624', (104, 109))	('FSCN1', 'Gene', (53, 58))	('FSCN1', 'Gene', '6624', (53, 58))	('targets', 'Reg', (45, 52))
857465	27042104	To further study the role of FSCN1 in GC development, we investigated whether RNA interference knockdown of FSCN1 could recapitulate the oncogenic effects of miR-429 in SGC-7901 cells.	('GC', 'Phenotype', 'HP:0012126', (38, 40))	('RNA interference', 'MPA', (78, 94))	('FSCN1', 'Gene', '6624', (108, 113))	('knockdown', 'Var', (95, 104))	('FSCN1', 'Gene', (108, 113))	('SGC-7901', 'CellLine', 'CVCL:0520', (169, 177))	('GC', 'Phenotype', 'HP:0012126', (170, 172))	('FSCN1', 'Gene', (29, 34))	('FSCN1', 'Gene', '6624', (29, 34))
857466	27042104	As shown in Figure 4A-C, FSCN1 knockdown, similar to the transfection of miR-429, significantly reduced cell proliferation and slowed cell cycle progression in SGC-7901 cells.	('GC', 'Phenotype', 'HP:0012126', (161, 163))	('FSCN1', 'Gene', '6624', (25, 30))	('cell proliferation', 'CPA', (104, 122))	('slowed', 'NegReg', (127, 133))	('FSCN1', 'Gene', (25, 30))	('SGC-7901', 'CellLine', 'CVCL:0520', (160, 168))	('cell cycle progression', 'CPA', (134, 156))	('knockdown', 'Var', (31, 40))	('reduced', 'NegReg', (96, 103))
857477	27042104	For example, miR-429 inhibits expression of the transcriptional repressors ZEB1 in breast cancer and oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (101, 129))	('miR-429', 'Var', (13, 20))	('inhibits', 'NegReg', (21, 29))	('expression', 'MPA', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('ZEB1', 'Gene', '6935', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('ZEB1', 'Gene', (75, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))
857480	27042104	miR-429 also modulates the expression of c-myc in human gastric carcinoma cells.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (56, 73))	('miR-429', 'Var', (0, 7))	('modulates', 'Reg', (13, 22))	('c-myc', 'Gene', '4609', (41, 46))	('expression', 'MPA', (27, 37))	('c-myc', 'Gene', (41, 46))	('gastric carcinoma', 'Disease', 'MESH:D013274', (56, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('human', 'Species', '9606', (50, 55))	('gastric carcinoma', 'Disease', (56, 73))
857484	27042104	To elucidate the underlying molecular mechanisms of miR-429 in cancer cell proliferation, the public TCGA data, gene-level summarized RNA-seq data sets, DESeq, and TargetScan were used.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('miR-429', 'Var', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('DESeq', 'Chemical', '-', (153, 158))
857487	27042104	Then we demonstrated that the knockdown of FSCN1 mimics the effects of miR-429 overexpression that leads to the growth defect in GC cells.	('FSCN1', 'Gene', (43, 48))	('growth', 'MPA', (112, 118))	('knockdown', 'Var', (30, 39))	('FSCN1', 'Gene', '6624', (43, 48))	('GC', 'Phenotype', 'HP:0012126', (129, 131))
857493	27042104	In particular, the knockdown of FSCN1 expression reduced the proliferation and metastasis of GC cells and the higher expression of FSCN1 is correlated with more advanced cancer stages and inversely with survival rates in gastric adenocarcinomas.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('gastric adenocarcinomas', 'Disease', (221, 244))	('proliferation', 'CPA', (61, 74))	('cancer', 'Disease', (170, 176))	('reduced', 'NegReg', (49, 56))	('knockdown', 'Var', (19, 28))	('expression', 'MPA', (117, 127))	('FSCN1', 'Gene', '6624', (32, 37))	('FSCN1', 'Gene', (131, 136))	('FSCN1', 'Gene', '6624', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('GC', 'Phenotype', 'HP:0012126', (93, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('FSCN1', 'Gene', (32, 37))	('higher', 'PosReg', (110, 116))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (221, 244))	('metastasis of GC cells', 'CPA', (79, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (234, 244))
857496	27042104	So, we speculate that miR-429 may contribute to the inhibition of GC via directly targeting FSCN1 and that miR-429 may serve as a useful biomarker for earlier diagnosis and prognosis of GC.	('inhibition', 'NegReg', (52, 62))	('GC', 'Phenotype', 'HP:0012126', (66, 68))	('GC', 'Phenotype', 'HP:0012126', (186, 188))	('miR-429', 'Var', (107, 114))	('miR-429', 'Var', (22, 29))	('FSCN1', 'Gene', (92, 97))	('FSCN1', 'Gene', '6624', (92, 97))
857612	25133115	Ingestion of acids usually causes superficial coagulation necrosis, in which formation of thrombi within the vessels and bundling of connective tissue lead to the formation of scar tissue.	('scar', 'Phenotype', 'HP:0100699', (176, 180))	('causes', 'Reg', (27, 33))	('lead to', 'Reg', (151, 158))	('Ingestion', 'Var', (0, 9))	('coagulation necrosis', 'Disease', 'MESH:D009336', (46, 66))	('coagulation necrosis', 'Disease', (46, 66))	('coagulation necrosis', 'Phenotype', 'HP:0010885', (46, 66))
857721	20416464	The following codes were used to identify sites of interest: lip (000-009), tongue (019-024, 028-029), gum (030-031, 039), floor of mouth (040-041, 048-049), palate (050-052, 058-059), other parts of mouth (060-062, 068-069), tonsil (090-091, 098-099), oropharynx (100-104, 108-109), nasopharynx (110-113, 118-119), pyriform sinus (129), hypopharynx (130-132, 138-139), and larynx (320-323, 328-329).	('060-062', 'Var', (207, 214))	('050-052', 'Var', (166, 173))	('040-041', 'Var', (139, 146))	('lip', 'Gene', (61, 64))	('palate', 'Disease', (158, 164))	('floor of mouth', 'Phenotype', 'HP:0410012', (123, 137))	('090-091, 098-099', 'Var', (234, 250))	('lip', 'Gene', '23049', (61, 64))	('100-104', 'Var', (265, 272))	('130-132', 'Var', (351, 358))	('palate', 'Disease', 'MESH:D002972', (158, 164))
857723	20416464	The ICD-O-3 classification system was used to identify patients with squamous cell histology (8050-8052, 8070-8076, 8078, 8082-8084).	('8050-8052', 'Var', (94, 103))	('8070-8076', 'Var', (105, 114))	('squamous cell histology', 'Disease', (69, 92))	('8078', 'Var', (116, 120))	('patients', 'Species', '9606', (55, 63))
857771	22543216	Seventy-two patients who had previously received conventionally fractionated radiation therapy to the thorax were treated with SABR (50 Gy in 4 fractions) for recurrent disease or secondary parenchymal lung cancer (T <4 cm, N0, M0, or Mx).	('T <4 cm', 'Var', (215, 222))	('patients', 'Species', '9606', (12, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('secondary parenchymal lung cancer', 'Disease', 'MESH:D008175', (180, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('SABR', 'Chemical', '-', (127, 131))	('recurrent disease', 'Disease', (159, 176))	('secondary parenchymal lung cancer', 'Disease', (180, 213))
857775	22543216	Multivariate analysis revealed that ECOG PS scores of 2-3 before SABR (P=.009), FEV1 <=65% before SABR (P=.012), V20 >=30% of the composite plan (P=.021), and an initial PTV in the bilateral mediastinum (P=.025) were all associated with RP.	('SABR', 'Chemical', '-', (65, 69))	('V20 >=30%', 'Var', (113, 122))	('associated', 'Reg', (221, 231))	('PTV', 'Chemical', '-', (170, 173))	('FEV1', 'Phenotype', 'HP:0032342', (80, 84))	('SABR', 'Chemical', '-', (98, 102))	('FEV1 <=65%', 'Var', (80, 90))
857793	22543216	Each patient had an isolated pulmonary lesion <4 cm in diameter and N0M0 or N0Mx disease.	('pulmonary lesion', 'Disease', 'MESH:D008171', (29, 45))	('N0M0', 'Var', (68, 72))	('patient', 'Species', '9606', (5, 12))	('N0Mx disease', 'Var', (76, 88))	('pulmonary lesion', 'Disease', (29, 45))
857809	22543216	Continuous variables such as forced expiratory volume in 1 second (FEV1), interval between previous conventional RT and SABR, V10-V40, and mean lung dose (MLD) from all 3 sets of plans were dichotomized according to the sample median and then analyzed as nominal categoric variables.	('FEV1', 'Phenotype', 'HP:0032342', (67, 71))	('V10-V40', 'Var', (126, 133))	('forced expiratory volume in 1 second', 'Phenotype', 'HP:0032342', (29, 65))	('MLD', 'Disease', 'MESH:D007966', (155, 158))	('SABR', 'Chemical', '-', (120, 124))	('MLD', 'Disease', (155, 158))
857825	22543216	The patient with grade 5 RP had had a significant history of chronic infectious pulmonary disease in the 6 years before SABR, including fungal pneumonia, chronic bronchiectasis, and mycobacterial infection.	('fungal pneumonia', 'Disease', (136, 152))	('chronic bronchiectasis', 'Disease', 'MESH:D001987', (154, 176))	('bronchiectasis', 'Phenotype', 'HP:0002110', (162, 176))	('chronic bronchiectasis', 'Phenotype', 'HP:0004469', (154, 176))	('patient', 'Species', '9606', (4, 11))	('mycobacterial infection', 'Phenotype', 'HP:0011274', (182, 205))	('mycobacterial infection', 'Disease', 'MESH:D009165', (182, 205))	('infectious pulmonary disease', 'Disease', (69, 97))	('grade 5 RP', 'Var', (17, 27))	('fungal pneumonia', 'Disease', 'MESH:D011014', (136, 152))	('infectious pulmonary disease', 'Disease', 'MESH:D008171', (69, 97))	('infectious pulmonary disease', 'Phenotype', 'HP:0006532', (69, 97))	('chronic bronchiectasis', 'Disease', (154, 176))	('pneumonia', 'Phenotype', 'HP:0002090', (143, 152))	('SABR', 'Chemical', '-', (120, 124))	('mycobacterial infection', 'Disease', (182, 205))
857828	22543216	Univariate analysis of patient characteristics (Table 2) and dosimetric factors (Table 3) revealed that pre-SABR ECOG PS, FEV1, previous PTV location (unilateral vs bilateral), the V10 and MLD of the previous plans, and the V10-V40 and MLD of the composite plans were significantly associated with the incidence of grade 3-5 RP (P<.05).	('SABR', 'Chemical', '-', (108, 112))	('MLD', 'Disease', (236, 239))	('MLD', 'Disease', 'MESH:D007966', (236, 239))	('V10-V40', 'Var', (224, 231))	('PTV', 'Chemical', '-', (137, 140))	('FEV1', 'Phenotype', 'HP:0032342', (122, 126))	('associated', 'Reg', (282, 292))	('grade 3-5 RP', 'Disease', (315, 327))	('MLD', 'Disease', 'MESH:D007966', (189, 192))	('MLD', 'Disease', (189, 192))	('V10', 'Var', (181, 184))	('patient', 'Species', '9606', (23, 30))
857829	22543216	The interval between previous conventional RT and SABR, the V30 and V40 of the previous RT plans, and the V10-V40 and MLD of the SABR plans tended to associate with grade 3-5 RP, but these apparent associations were not statistically significant.	('MLD', 'Disease', 'MESH:D007966', (118, 121))	('MLD', 'Disease', (118, 121))	('V10-V40', 'Var', (106, 113))	('V40', 'Var', (68, 71))	('SABR', 'Chemical', '-', (50, 54))	('grade 3-5 RP', 'Disease', (165, 177))	('associate', 'Reg', (150, 159))	('SABR', 'Chemical', '-', (129, 133))	('V30', 'Var', (60, 63))
857830	22543216	In that analysis, having a pre-SABR ECOG PS 2-3 (P=.008), a pre-SABR FEV1 <=65% (P=.012), a V20 >=30% in the composite plan (P=.020), and previous bilateral mediastinal PTV (P=.024) were associated with grade 3-5 RP.	('SABR', 'Chemical', '-', (31, 35))	('V20 >=30%', 'Var', (92, 101))	('PTV', 'Chemical', '-', (169, 172))	('SABR', 'Chemical', '-', (64, 68))	('FEV1', 'Phenotype', 'HP:0032342', (69, 73))	('grade 3-5 RP', 'Disease', (203, 215))
857849	22543216	Of the 36 patients whose interval between RT and SABR was >=21 months, 16 had a history of COPD, 21 had FEV1 <=65% (median value), 28 had a PTV that included the bilateral mediastinum, and 11 had a V20 >=39% (75th percentile value) in their composite plans.	('SABR', 'Chemical', '-', (49, 53))	('V20 >=39%', 'Var', (198, 207))	('PTV', 'Chemical', '-', (140, 143))	('COPD', 'Disease', (91, 95))	('FEV1', 'Phenotype', 'HP:0032342', (104, 108))	('patients', 'Species', '9606', (10, 18))	('COPD', 'Phenotype', 'HP:0006510', (91, 95))
857865	22543216	Some dosimetric data from the previous RT plans (eg, V20 and V30) were not related to RP risk, but V10 and MLD were.	('MLD', 'Disease', (107, 110))	('V20', 'Var', (53, 56))	('V10', 'Var', (99, 102))	('MLD', 'Disease', 'MESH:D007966', (107, 110))	('V30', 'Var', (61, 64))
857866	22543216	We did find that the dosimetric data from the composite plans were more predictive than were those from the previous RT or the SABR plans; in composite plans, both V10-V40 and MLD were related to severe RP, but only a V20 >= 30% in the composite plan was significant in multivariate analysis.	('MLD', 'Disease', (176, 179))	('V10-V40', 'Var', (164, 171))	('severe RP', 'Disease', (196, 205))	('related', 'Reg', (185, 192))	('SABR', 'Chemical', '-', (127, 131))	('MLD', 'Disease', 'MESH:D007966', (176, 179))
857913	19833119	In recent years, argon (-186 C) and nitrous oxide (-89.5 C), which had limited use as cryogenic agents in the past, came into common use in apparatus as pressurized gases, cooling by the Joule-Thomson (J-T) effect.	('nitrous oxide', 'Chemical', 'MESH:D009609', (36, 49))	('-89.5', 'Var', (51, 56))	('-186 C', 'Var', (24, 30))	('rat', 'Species', '10116', (144, 147))	('argon', 'Chemical', 'MESH:D001128', (17, 22))
858052	19833119	Esophageal injury following cryoablation in the pulmonary veins may occur, but is not likely to be transmural.	('cryoablation', 'Var', (28, 40))	('Esophageal injury', 'Disease', 'MESH:D004941', (0, 17))	('Esophageal injury', 'Disease', (0, 17))
858075	19833119	In similar experiments, Tatsutani et al., working with cultured arterial cells and smooth muscle cells, found that the smooth muscle cells were susceptible to freeze-induced apoptosis in the range of -5 to -15 C, which led to the conclusion that endovascular cryotherapy might limit neointimal formation and thereby reduce the incidence of restenosis.	('limit', 'NegReg', (277, 282))	('cryotherapy', 'Var', (259, 270))	('reduce', 'NegReg', (316, 322))	('restenosis', 'Disease', 'MESH:D023903', (340, 350))	('restenosis', 'Disease', (340, 350))	('neointimal formation', 'CPA', (283, 303))
858144	19833119	reported that cryotherapy of the peripheral retina in rabbits resulted in elongation of the eye.	('elongation of the eye', 'CPA', (74, 95))	('cryotherapy', 'Var', (14, 25))	('rabbits', 'Species', '9986', (54, 61))
858152	19833119	investigated the morphological changes of urinary bladder cryoablation in pigs and produced a controllable transmural necrosis with single and repeated cycles.	('pigs', 'Species', '9823', (74, 78))	('necrosis', 'Disease', (118, 126))	('cycle', 'Gene', (152, 157))	('urinary bladder', 'Disease', (42, 57))	('cycle', 'Gene', '25729', (152, 157))	('necrosis', 'Disease', 'MESH:D009336', (118, 126))	('cryoablation', 'Var', (58, 70))
858204	19833119	used TNF-alpha as an adjunctive agent and demonstrated that the use of TNF-alpha enhanced cell death by activation of both apoptotic and inflammatory pathways.	('activation', 'PosReg', (104, 114))	('enhanced', 'PosReg', (81, 89))	('TNF-alpha', 'Gene', '21926', (5, 14))	('use', 'Var', (64, 67))	('TNF-alpha', 'Gene', '21926', (71, 80))	('TNF-alpha', 'Gene', (5, 14))	('inflammatory pathways', 'Pathway', (137, 158))	('TNF-alpha', 'Gene', (71, 80))	('rat', 'Species', '10116', (49, 52))	('cell death', 'CPA', (90, 100))
858244	33054425	mEHT has comparable benefits as those obtained with other types of HT, improving local control and survival rates in several types of tumors, such as cervical, brain, and pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', (134, 140))	('cervical', 'Disease', (150, 158))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('HT', 'Phenotype', 'HP:0001945', (2, 4))	('improving', 'PosReg', (71, 80))	('HT', 'Phenotype', 'HP:0001945', (67, 69))	('brain', 'Disease', (160, 165))	('survival', 'CPA', (99, 107))	('mEHT', 'Chemical', '-', (0, 4))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (171, 188))	('mEHT', 'Var', (0, 4))	('local control', 'CPA', (81, 94))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('pancreatic cancer', 'Disease', (171, 188))	('pancreatic cancer', 'Disease', 'MESH:D010190', (171, 188))
858265	33054425	The disease control (DC) rate increases from 66% to 92% after mEHT.	('disease control', 'Disease', (4, 19))	('mEHT', 'Var', (62, 66))	('mEHT', 'Chemical', '-', (62, 66))	('HT', 'Phenotype', 'HP:0001945', (64, 66))
858333	33054425	CRT + HT, when compared with CRT alone, improves both OS and DC in esophageal cancer with low toxicity.	('improves', 'PosReg', (40, 48))	('low toxicity', 'Disease', (90, 102))	('low toxicity', 'Disease', 'MESH:D009800', (90, 102))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('HT', 'Phenotype', 'HP:0001945', (6, 8))	('CRT', 'Var', (0, 3))
858387	32185826	Therefore, these results demonstrate hsa_circ_0012563 is consistently expressed in both ESCC tumor tissues and ESCC cell.	('ESCC', 'Disease', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('hsa_circ_0012563', 'Var', (37, 53))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
858389	32185826	The results revealed that si-hsa_circ_0012563 transfection promoted ESCC cell apoptosis (Figure 2D) and induced G1 arrest (Figure 2E) compared with si-NC transfection.	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('arrest', 'Disease', (115, 121))	('ESCC cell apoptosis', 'CPA', (68, 87))	('promoted', 'PosReg', (59, 67))	('induced', 'Reg', (104, 111))	('si-hsa_circ_0012563', 'Var', (26, 45))
858390	32185826	Therefore, hsa_circ_0012563 exerts a tumor-promotive function in ESCC.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('hsa_circ_0012563', 'Var', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('ESCC', 'Disease', (65, 69))
858395	32185826	The RT-qPCR and Western blot indicated that knockdown of hsa_circ_0012563 could promote expression of XRCC1, E-cadherin and inhibit N-cadherin expression, and downregulation of XRCC1 restores E-cadherin and N-cadherin expression of transfected si-hsa_circ_0012563 TE-1 cell (Figure 4C and D), suggested that hsa_circ_0012563 activated EMT pathway by inhibiting XRCC1 expression in ESCC cell.	('XRCC1', 'Gene', (102, 107))	('E-cadherin', 'Gene', (109, 119))	('E-cadherin', 'Gene', '999', (109, 119))	('XRCC1', 'Gene', '7515', (177, 182))	('N-cadherin', 'Gene', (132, 142))	('N-cadherin', 'Gene', '1000', (132, 142))	('expression', 'MPA', (367, 377))	('XRCC1', 'Gene', '7515', (102, 107))	('inhibit', 'NegReg', (124, 131))	('XRCC1', 'Gene', (361, 366))	('promote', 'PosReg', (80, 87))	('inhibiting', 'NegReg', (350, 360))	('E-cadherin', 'Gene', (192, 202))	('E-cadherin', 'Gene', '999', (192, 202))	('N-cadherin', 'Gene', (207, 217))	('EMT pathway', 'Pathway', (335, 346))	('XRCC1', 'Gene', (177, 182))	('N-cadherin', 'Gene', '1000', (207, 217))	('XRCC1', 'Gene', '7515', (361, 366))	('activated', 'PosReg', (325, 334))	('downregulation', 'NegReg', (159, 173))	('hsa_circ_0012563', 'Var', (308, 324))
858397	32185826	Thus, hsa_circ_0012563 promoted cell migration and invasion by regulating XRCC1/EMT pathway.	('XRCC1', 'Gene', (74, 79))	('hsa_circ_0012563', 'Var', (6, 22))	('promoted', 'PosReg', (23, 31))	('regulating', 'Reg', (63, 73))	('XRCC1', 'Gene', '7515', (74, 79))	('cell migration', 'CPA', (32, 46))	('invasion', 'CPA', (51, 59))
858405	32185826	For instance, hsa_circ_0001649 is a potential novel biomarker for hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('hepatocellular carcinoma', 'Disease', (66, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('hsa_circ_0001649', 'Var', (14, 30))
858415	32185826	Thus, hsa_circ_0012563 promotes migration and invasion of ESCC via regulating XRCC1/EMT pathway.	('regulating', 'Reg', (67, 77))	('XRCC1', 'Gene', (78, 83))	('hsa_circ_0012563', 'Var', (6, 22))	('promotes', 'PosReg', (23, 31))	('XRCC1', 'Gene', '7515', (78, 83))	('migration', 'CPA', (32, 41))	('invasion', 'CPA', (46, 54))
858416	32185826	In summary, hsa_circ_0012563 is upregulated in ESCC tumor tissues and cells, and its expression is associated to tumor pathogenesis and metastatic.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (113, 118))	('expression', 'MPA', (85, 95))	('tumor', 'Disease', (52, 57))	('ESCC', 'Disease', (47, 51))	('hsa_circ_0012563', 'Var', (12, 28))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('associated', 'Reg', (99, 109))	('upregulated', 'PosReg', (32, 43))
858417	32185826	Further, hsa_circ_0012563 promotes migration and invasion of ESCC via regulating XRCC1/EMT pathway.	('migration', 'CPA', (35, 44))	('XRCC1', 'Gene', (81, 86))	('promotes', 'PosReg', (26, 34))	('ESCC', 'Disease', (61, 65))	('invasion', 'CPA', (49, 57))	('regulating', 'Reg', (70, 80))	('hsa_circ_0012563', 'Var', (9, 25))	('XRCC1', 'Gene', '7515', (81, 86))
858433	32581314	MetS is closely linked to cancer, as it increases cancer risk and cancer-related mortality.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('MetS', 'Var', (0, 4))	('cancer', 'Disease', (26, 32))	('mortality', 'Disease', 'MESH:D003643', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mortality', 'Disease', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('increases', 'PosReg', (40, 49))	('cancer', 'Disease', (66, 72))
858477	32581314	MetS was associated with 9%, 27%, and 11% higher risk of developing oral, laryngeal, and esophageal cancers, respectively.	('esophageal cancers', 'Disease', (89, 107))	('MetS', 'Var', (0, 4))	('esophageal cancers', 'Disease', 'MESH:D004938', (89, 107))	('oral', 'Disease', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('laryngeal', 'Disease', (74, 83))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))
858521	32581314	Oral, laryngeal, and esophageal cancers were defined as C00-C06, C32.0-32.9, and C15.0-C15.9, respectively.	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('esophageal cancers', 'Disease', (21, 39))	('Oral', 'Disease', (0, 4))	('esophageal cancers', 'Disease', 'MESH:D004938', (21, 39))	('laryngeal', 'Disease', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('C15.0-C15.9', 'Var', (81, 92))
858527	32581314	The measured BP was classified as normal SBP < 120 mmHg and DBP < 80 mmHg), prehypertension (SBP 120-139 mmHg or DBP 80-89 mmHg), or hypertension (SBP >= 140 mmHg or DBP >= 90 mmHg).	('hypertension', 'Disease', (133, 145))	('hypertension', 'Disease', 'MESH:D006973', (79, 91))	('hypertension', 'Phenotype', 'HP:0000822', (133, 145))	('hypertension', 'Disease', (79, 91))	('SBP 120-139 mmHg', 'Var', (93, 109))	('hypertension', 'Disease', 'MESH:D006973', (133, 145))	('hypertension', 'Phenotype', 'HP:0000822', (79, 91))
858536	32581314	According to this institution, patients with MetS should have three or more of the following five components: abdominal obesity (>= 90 cm for men and >= 85 cm for women), elevated blood pressure (systolic >= 130 and/or diastolic >= 85 mmHg), hyperglycemia (fasting plasma glucose >= 5.6 mmol/L (>= 100 mg/dL)), hypertriglyceridemia (triglycerides >= 1.7 mmol/L (>= 150 mg/dL)), and low HDL-cholesterol levels (1.0 mmol/L (< 40 mg/dL) for men and 1.3 mmol/L (< 50 mg/dL) for women).	('triglyceride', 'Chemical', 'MESH:D014280', (333, 345))	('elevated', 'PosReg', (171, 179))	('abdominal obesity', 'Disease', 'MESH:D056128', (110, 127))	('low', 'NegReg', (382, 385))	('cholesterol', 'Chemical', 'MESH:D002784', (390, 401))	('obesity', 'Phenotype', 'HP:0001513', (120, 127))	('hyperglycemia', 'Disease', (242, 255))	('men', 'Species', '9606', (476, 479))	('men', 'Species', '9606', (438, 441))	('women', 'Species', '9606', (474, 479))	('blood pressure', 'MPA', (180, 194))	('abdominal obesity', 'Phenotype', 'HP:0012743', (110, 127))	('hyperglycemia', 'Disease', 'MESH:D006943', (242, 255))	('>=', 'Var', (129, 131))	('hypertriglyceridemia', 'Disease', (311, 331))	('HDL-cholesterol levels', 'MPA', (386, 408))	('hypertriglyceridemia', 'Disease', 'MESH:D015228', (311, 331))	('men', 'Species', '9606', (142, 145))	('triglyceride', 'Chemical', 'MESH:D014280', (316, 328))	('low HDL-cholesterol', 'Phenotype', 'HP:0003233', (382, 401))	('elevated blood pressure', 'Phenotype', 'HP:0032263', (171, 194))	('men', 'Species', '9606', (165, 168))	('glucose', 'Chemical', 'MESH:D005947', (272, 279))	('women', 'Species', '9606', (163, 168))	('patients', 'Species', '9606', (31, 39))	('hyperglycemia', 'Phenotype', 'HP:0003074', (242, 255))	('abdominal obesity', 'Disease', (110, 127))	('hypertriglyceridemia', 'Phenotype', 'HP:0002155', (311, 331))
858548	30758105	We also found ANXA10 promoted the cell growth of ESCC cell lines via the phosphorylation of Akt and Erk1/2 pathways in vitro.	('Erk1/2', 'Gene', '5595;5594', (100, 106))	('ESCC', 'Disease', 'MESH:C562729', (49, 53))	('Akt', 'Gene', '207', (92, 95))	('promoted', 'PosReg', (21, 29))	('Erk1/2', 'Gene', (100, 106))	('cell growth', 'CPA', (34, 45))	('ESCC', 'Disease', (49, 53))	('Akt', 'Gene', (92, 95))	('phosphorylation', 'MPA', (73, 88))	('ANXA10', 'Var', (14, 20))
858554	30758105	The protein CD163 and CD204 have been used as markers of M2 macrophages.10, 11 TAMs induce angiogenesis in the tumor microenvironment, suppress antitumor immunity and directly stimulate tumor cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (186, 191))	('CD163', 'Gene', '9332', (12, 17))	('macrophages.10', 'Var', (60, 74))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('CD204', 'Gene', '4481', (22, 27))	('CD204', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CD163', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('suppress', 'NegReg', (135, 143))	('tumor', 'Disease', (111, 116))	('induce', 'PosReg', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('angiogenesis', 'CPA', (91, 103))	('TAM', 'Gene', (79, 82))	('tumor', 'Disease', (148, 153))	('TAM', 'Gene', '8205', (79, 82))	('stimulate', 'PosReg', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
858569	30758105	The primers were as follows: CYP1A1 (Hs01054797_g1), DHRS3 (Hs00191073_m1), ANXA10 (Hs01105012_m1), KLK6 (Hs00160519_m1), CYP1B1 (Hs02382916_s1), AMTN (Hs00418384_m1), IGFL1 (Hs01651089_g1) and GAPDH (Hs02786624_g1).	('DHRS3', 'Gene', (53, 58))	('IGFL1', 'Gene', '374918', (168, 173))	('Hs01105012_m1', 'Var', (84, 97))	('KLK6', 'Gene', '5653', (100, 104))	('GAPDH', 'Gene', (194, 199))	('AMTN', 'Gene', (146, 150))	('KLK6', 'Gene', (100, 104))	('CYP1A1', 'Gene', (29, 35))	('Hs02382916_s1', 'Var', (130, 143))	('Hs00418384_m1', 'Var', (152, 165))	('AMTN', 'Gene', '401138', (146, 150))	('DHRS3', 'Gene', '9249', (53, 58))	('CYP1B1', 'Gene', '1545', (122, 128))	('Hs01651089_g1', 'Var', (175, 188))	('CYP1B1', 'Gene', (122, 128))	('Hs00191073_m1', 'Var', (60, 73))	('Hs00160519_m1', 'Var', (106, 119))	('CYP1A1', 'Gene', '1543', (29, 35))	('Hs01054797_g1', 'Var', (37, 50))	('GAPDH', 'Gene', '2597', (194, 199))	('Hs02786624_g1', 'Var', (201, 214))	('IGFL1', 'Gene', (168, 173))
858575	30758105	The tissue sections were then incubated with anti-ANXA10 rabbit polyclonal antibody (1:200, NBP190156SS, Novus Biologicals, Littleton, CO, USA), anti-CYB1B1 rabbit polyclonal antibody (1:50, sc-32882, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and anti-KLK6 mouse monoclonal antibody (1:50, sc-374564, Santa Cruz) at 4 C in a moist chamber overnight.	('NBP190156SS', 'Chemical', 'MESH:C000592574', (92, 103))	('rabbit', 'Species', '9986', (57, 63))	('mouse', 'Species', '10090', (262, 267))	('CO', 'Chemical', 'MESH:D002245', (135, 137))	('1:200', 'Var', (85, 90))	('KLK6', 'Gene', '5653', (257, 261))	('KLK6', 'Gene', (257, 261))	('rabbit', 'Species', '9986', (157, 163))	('sc-374564', 'Chemical', 'MESH:D012538', (295, 304))
858592	30758105	We also observed that a high number of infiltrating CD68+ (P = 0.046) or CD204+ (P = 0.006) macrophages was significantly correlated with high expressions of ANXA10 in cancer cells (Table 2).	('CD204', 'Gene', (73, 78))	('CD68', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('CD68', 'Gene', '968', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('ANXA10', 'Gene', (158, 164))	('cancer', 'Disease', (168, 174))	('correlated', 'Reg', (122, 132))	('high', 'Var', (138, 142))	('CD204', 'Gene', '4481', (73, 78))
858593	30758105	The disease-free survival of the patients with a high expression of ANXA10 was significantly shorter compared to that of the patients with low ANXA10 by log-rank test (P = 0.0216) (Fig.	('patients', 'Species', '9606', (33, 41))	('disease-free survival', 'CPA', (4, 25))	('shorter', 'NegReg', (93, 100))	('high', 'Var', (49, 53))	('ANXA10', 'Gene', (68, 74))	('patients', 'Species', '9606', (125, 133))
858594	30758105	The overall survival of the patients and cancer-related survival was not significantly different between the low and high ANXA10 expression groups (Fig.	('high', 'Var', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('expression', 'MPA', (129, 139))	('ANXA10', 'Protein', (122, 128))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (28, 36))
858598	30758105	ANXA10 knockdown significantly inhibited the growth of both of these ESCC cell lines (Fig.	('ESCC', 'Disease', 'MESH:C562729', (69, 73))	('growth', 'MPA', (45, 51))	('ESCC', 'Disease', (69, 73))	('inhibited', 'NegReg', (31, 40))	('ANXA10', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))
858599	30758105	ANXA10 knockdown suppressed the phosphorylation status of p-Akt (Ser473 and Thr308) and p-Erk1/2 (Thr202/Tyr204) and inhibit the growth of the ESCC cell lines (Fig.	('Thr308', 'Var', (76, 82))	('Erk1/2', 'Gene', '5595;5594', (90, 96))	('Akt', 'Gene', '207', (60, 63))	('Ser', 'Chemical', 'MESH:C530429', (65, 68))	('ESCC', 'Disease', (143, 147))	('suppressed', 'NegReg', (17, 27))	('Thr202/Tyr204', 'Var', (98, 111))	('Akt', 'Gene', (60, 63))	('Thr308', 'Chemical', 'MESH:C015596', (76, 82))	('Erk1/2', 'Gene', (90, 96))	('phosphorylation status', 'MPA', (32, 54))	('ANXA10', 'Gene', (0, 6))	('ESCC', 'Disease', 'MESH:C562729', (143, 147))	('growth', 'CPA', (129, 135))	('inhibit', 'NegReg', (117, 124))	('knockdown', 'Var', (7, 16))
858601	30758105	ANXA10 overexpression increased the phosphorylation status of p-Akt (Ser473 and Thr308) and p-Erk1/2 (Thr202/Tyr204) and increased the growth induction of the ESCC cells (Fig.	('Thr308', 'Chemical', 'MESH:C015596', (80, 86))	('increased', 'PosReg', (121, 130))	('Akt', 'Gene', '207', (64, 67))	('Ser', 'Chemical', 'MESH:C530429', (69, 72))	('Erk1/2', 'Gene', '5595;5594', (94, 100))	('increased', 'PosReg', (22, 31))	('Ser473', 'Var', (69, 75))	('phosphorylation status', 'MPA', (36, 58))	('Akt', 'Gene', (64, 67))	('Thr202/Tyr204', 'Var', (102, 115))	('Erk1/2', 'Gene', (94, 100))	('ESCC', 'Disease', 'MESH:C562729', (159, 163))	('ANXA10', 'Gene', (0, 6))	('growth induction', 'CPA', (135, 151))	('Thr308', 'Var', (80, 86))	('ESCC', 'Disease', (159, 163))
858617	30758105	The results showed that ANXA10 knockdown significantly decreased cell growth by inhibiting Akt and Erk1/2 signaling pathways.	('Erk1/2', 'Gene', (99, 105))	('cell growth', 'CPA', (65, 76))	('Akt', 'Gene', '207', (91, 94))	('Erk1/2', 'Gene', '5595;5594', (99, 105))	('Akt', 'Gene', (91, 94))	('decreased', 'NegReg', (55, 64))	('inhibiting', 'NegReg', (80, 90))	('ANXA10', 'Gene', (24, 30))	('knockdown', 'Var', (31, 40))
858618	30758105	We also introduced ANXA10 expression vector into ESCC cells with a low expression of ANXA10 and we observed that ANXA10 significantly increased cell growth by activating Akt and Erk1/2 signaling pathways.	('Erk1/2', 'Gene', '5595;5594', (178, 184))	('ESCC', 'Disease', 'MESH:C562729', (49, 53))	('ANXA10', 'Var', (113, 119))	('Erk1/2', 'Gene', (178, 184))	('Akt', 'Gene', (170, 173))	('activating', 'PosReg', (159, 169))	('cell growth', 'CPA', (144, 155))	('ESCC', 'Disease', (49, 53))	('increased', 'PosReg', (134, 143))	('Akt', 'Gene', '207', (170, 173))
858619	30758105	Our results are the first to indicate that ANXA10 might play an important role in the growth of ESCCs by activating both the Akt andErk1/2 signaling pathways.	('ANXA10', 'Var', (43, 49))	('Akt', 'Gene', (125, 128))	('ESCCs', 'Disease', 'MESH:C562729', (96, 101))	('Erk1/2', 'Gene', '5595;5594', (132, 138))	('Erk1/2', 'Gene', (132, 138))	('ESCCs', 'Disease', (96, 101))	('activating', 'PosReg', (105, 115))	('Akt', 'Gene', '207', (125, 128))
858665	31533757	Patients with high dose (>=60Gy) or radiotherapy combined with chemotherapy were more likely to have grade 3 toxicity.	('Patients', 'Species', '9606', (0, 8))	('toxicity', 'Disease', 'MESH:D064420', (109, 117))	('radiotherapy', 'Var', (36, 48))	('toxicity', 'Disease', (109, 117))
858711	29569125	Trimodality therapy was associated with improved 5-year OS in low-risk patients (p = 0.003), whereas it showed no significant survival benefit in high-risk patients (p = 0.302).	('patients', 'Species', '9606', (156, 164))	('OS', 'Chemical', '-', (56, 58))	('Trimodality', 'Var', (0, 11))	('patients', 'Species', '9606', (71, 79))	('improved', 'PosReg', (40, 48))
858819	15447788	A published meta-analysis using updated individual patient data on 1147 patients from five trials detected a hazard ratio for death of 0.89 (95% CI, 0.78 to 1.01; p = 0.062) for preoperative radiotherapy compared with surgery alone.	('radiotherapy', 'Var', (191, 203))	('preoperative', 'Var', (178, 190))	('patient', 'Species', '9606', (72, 79))	('patient', 'Species', '9606', (51, 58))	('patients', 'Species', '9606', (72, 80))
858895	27775562	While new cancer incidence is expected to rise by 70% by the year 2034, approximately 35% of cancer deaths are attributed to the five leading behavioral and dietary risks: high body mass index (BMI), low fruit and vegetable intake, lack of physical activity, tobacco use (primarily smoking) and harmful alcohol use.	('harmful alcohol', 'Phenotype', 'HP:0030955', (295, 310))	('cancer', 'Disease', (93, 99))	('low', 'NegReg', (200, 203))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer deaths', 'Disease', 'MESH:D003643', (93, 106))	('tobacco', 'Species', '4097', (259, 266))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('alcohol', 'Chemical', 'MESH:D000438', (303, 310))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('high body mass index', 'Phenotype', 'HP:0031418', (172, 192))	('high', 'Var', (172, 176))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer deaths', 'Disease', (93, 106))	('cancer', 'Disease', (10, 16))
858908	27775562	Genomic changes such as point mutations, gene deletion and amplification and chromosomal rearrangements, all mark initiation, subsequently committing the cell to an irreversible status.	('gene deletion', 'Var', (41, 54))	('point mutations', 'Var', (24, 39))	('chromosomal', 'CPA', (77, 88))	('amplification', 'Var', (59, 72))	('men', 'Species', '9606', (98, 101))
858921	27775562	Oxidative stress causes damage to tissues and elicits an immune response that induces inflammation in an attempt of the body to rectify the inflicted damage.	('induces', 'Reg', (78, 85))	('inflammation', 'Disease', (86, 98))	('Oxidative', 'Var', (0, 9))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('elicits', 'Reg', (46, 53))	('inflammation', 'Disease', 'MESH:D007249', (86, 98))
858931	27775562	Interestingly, work with preclinical models, demonstrated that inhibition of autophagy can restore chemosensitivity and enhance tumor cell death thus improving response to therapy.	('rat', 'Species', '10116', (52, 55))	('tumor', 'Disease', (128, 133))	('enhance', 'PosReg', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('response', 'MPA', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('improving', 'PosReg', (150, 159))	('autophagy', 'CPA', (77, 86))	('inhibition', 'Var', (63, 73))	('chemosensitivity', 'CPA', (99, 115))	('restore', 'PosReg', (91, 98))
858935	27775562	Although inherited genetic mutations do not necessarily lead to cancer development, cancer risk is increased, as the probability is significantly higher.	('higher', 'PosReg', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('genetic mutations', 'Var', (19, 36))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('men', 'Species', '9606', (78, 81))	('lead', 'Reg', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
858937	27775562	Examples of chemical carcinogens are asbestos and benzene, and they are associated with an increased risk of cancer primarily of the lungs.	('benzene', 'Var', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('associated', 'Reg', (72, 82))	('cancer', 'Disease', (109, 115))	('cancer primarily of the lungs', 'Phenotype', 'HP:0100526', (109, 138))	('asbestos', 'Chemical', 'MESH:D001194', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('benzene', 'Chemical', 'MESH:D001554', (50, 57))
858984	27775562	A variety of phytochemicals such as indole-3-carbinol, curcuminoids and epigallocatechin-3-gallate (EGCG) (as well as black raspberries as a whole fruit) have been shown to suppress Akt activation thus leading to cancer suppression signaling.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('leading to', 'Reg', (202, 212))	('epigallocatechin-3-gallate', 'Var', (72, 98))	('suppress', 'NegReg', (173, 181))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (72, 98))	('Akt', 'Gene', '207', (182, 185))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('EGCG', 'Chemical', 'MESH:C045651', (100, 104))	('activation', 'MPA', (186, 196))	('indole-3-carbinol', 'Chemical', 'MESH:C016517', (36, 53))	('cancer', 'Disease', (213, 219))	('Akt', 'Gene', (182, 185))	('curcuminoids', 'Chemical', '-', (55, 67))
859002	27775562	Cell adhesion proteins such as beta-catenin, ICAM-1 and VCAM-1 are attenuated by berries, while cellular invasion is also inhibited through the repression of MMP and u-PA by anthocyanins commonly found in berries.	('ICAM-1', 'Gene', '3383', (45, 51))	('u-PA', 'Gene', '5328', (166, 170))	('MMP', 'Gene', (158, 161))	('berries', 'Var', (81, 88))	('VCAM-1', 'Gene', (56, 62))	('inhibited', 'NegReg', (122, 131))	('ICAM-1', 'Gene', (45, 51))	('Cell adhesion proteins', 'Protein', (0, 22))	('anthocyanins', 'Chemical', 'MESH:D000872', (174, 186))	('VCAM-1', 'Gene', '7412', (56, 62))	('attenuated', 'NegReg', (67, 77))	('repression', 'NegReg', (144, 154))	('u-PA', 'Gene', (166, 170))	('cellular invasion', 'CPA', (96, 113))	('beta-catenin', 'Protein', (31, 43))
859006	27775562	More specifically, polyphenols have been shown to inhibit strongly phase-I detoxifying enzyme CYP1A1 while inducing phase-II detoxifying enzymes GST and NADPH quinone oxidoreductase (NQO) in mouse epidermal cells.	('quinone oxidoreductase', 'Gene', (159, 181))	('phase-I detoxifying', 'MPA', (67, 86))	('polyphenols', 'Chemical', 'MESH:D059808', (19, 30))	('polyphenols', 'Var', (19, 30))	('inducing', 'PosReg', (107, 115))	('inhibit', 'NegReg', (50, 57))	('CYP1A1', 'Enzyme', (94, 100))	('quinone oxidoreductase', 'Gene', '1429', (159, 181))	('mouse', 'Species', '10090', (191, 196))	('GST', 'MPA', (145, 148))	('phase-II detoxifying', 'MPA', (116, 136))	('NADPH', 'MPA', (153, 158))
859007	27775562	Furthermore, other modes of berry activity via certain bioactive compounds they contain involve modulation of miRNA expression profiles, DNA methylation and histone modifications, all of which can lead to the inhibition of cancer cell growth, induction of apoptosis, reversal of epithelial-mesenchymal transition, or improvement of conventional cancer therapeutics' efficacy.	('miRNA expression profiles', 'MPA', (110, 135))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('men', 'Species', '9606', (324, 327))	('improvement', 'PosReg', (317, 328))	('apoptosis', 'CPA', (256, 265))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('DNA', 'MPA', (137, 140))	('epithelial-mesenchymal transition', 'CPA', (279, 312))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('histone', 'Protein', (157, 164))	('inhibition', 'NegReg', (209, 219))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('modulation', 'Reg', (96, 106))	('cancer', 'Disease', (223, 229))	('modifications', 'Var', (165, 178))	('induction', 'Reg', (243, 252))	('cancer', 'Disease', (345, 351))
859008	27775562	Epigenetic alterations such as inhibition of histone deacetylases (HDACs), miRNAs and modification of the CpG methylation of cancer-related genes may indeed be key mechanisms by which berries reduce cancer risk, especially when taking into account the significantly lower concentrations of bioactive compounds in human blood compared to in vitro testing.	('berries', 'Var', (184, 191))	('inhibition', 'NegReg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('rat', 'Species', '10116', (15, 18))	('human', 'Species', '9606', (313, 318))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('reduce', 'NegReg', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('histone', 'Protein', (45, 52))	('cancer', 'Disease', (199, 205))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('modification', 'Var', (86, 98))	('rat', 'Species', '10116', (279, 282))
859009	27775562	A plausible explanation for their activity in humans, even at markedly lower concentrations, could be that these compounds exert their biological activities through epigenetic modulation.	('activity', 'MPA', (34, 42))	('humans', 'Species', '9606', (46, 52))	('rat', 'Species', '10116', (84, 87))	('epigenetic modulation', 'Var', (165, 186))
859010	27775562	There is growing interest in dietary compounds that confer favorable epigenetic modulation against chronic diseases such as cancer.	('cancer', 'Disease', (124, 130))	('epigenetic', 'Var', (69, 79))	('chronic diseases', 'Disease', 'MESH:D002908', (99, 115))	('chronic diseases', 'Disease', (99, 115))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
859016	27775562	More interestingly, prolonged incubation of HT29 cells with AE02 resulted in significantly induced apoptosis via the activation of caspase-3, DNA fragmentation, and cleavage of poly(ADP ribose) polymerase.	('men', 'Species', '9606', (150, 153))	('AE02', 'Chemical', '-', (60, 64))	('poly(ADP ribose) polymerase', 'Gene', '142', (177, 204))	('caspase-3', 'Gene', (131, 140))	('DNA fragmentation', 'CPA', (142, 159))	('apoptosis', 'CPA', (99, 108))	('caspase-3', 'Gene', '836', (131, 140))	('cleavage', 'MPA', (165, 173))	('HT29 cells', 'CellLine', 'CVCL:0320', (44, 54))	('poly(ADP ribose) polymerase', 'Gene', (177, 204))	('induced', 'PosReg', (91, 98))	('activation', 'PosReg', (117, 127))	('AE02', 'Var', (60, 64))
859055	27775562	Intestinal tumor formation and cell proliferation was inhibited after a 12-week consumption of a Western-style diet supplemented with 10% (wt/wt) freeze-dried black raspberries in Apc1638+/- and Muc2-/- mice, both models of human colorectal cancer, although via distinct mechanisms.	('inhibited', 'NegReg', (54, 63))	('Muc2', 'Gene', '17831', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('colorectal cancer', 'Disease', (230, 247))	('Apc1638+/-', 'Var', (180, 190))	('tumor', 'Disease', (11, 16))	('mice', 'Species', '10090', (203, 207))	('cell proliferation', 'CPA', (31, 49))	('rat', 'Species', '10116', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('human', 'Species', '9606', (224, 229))	('rectal cancer', 'Phenotype', 'HP:0100743', (234, 247))	('Muc2', 'Gene', (195, 199))	('colorectal cancer', 'Disease', 'MESH:D015179', (230, 247))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('men', 'Species', '9606', (122, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (230, 247))
859056	27775562	Tumor incidence and multiplicity was reduced by 45% and 60%, respectively in the Apc1638+/- mouse, and by 50% in the Muc2-/- mouse.	('Muc2', 'Gene', (117, 121))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Muc2', 'Gene', '17831', (117, 121))	('mouse', 'Species', '10090', (125, 130))	('Tumor incidence', 'CPA', (0, 15))	('mouse', 'Species', '10090', (92, 97))	('reduced', 'NegReg', (37, 44))	('Apc1638+/-', 'Var', (81, 91))	('multiplicity', 'CPA', (20, 32))
859059	27775562	In the Apc1638+/- mouse, beta-catenin was markedly reduced, while its downstream effectors, c-Myc and cyclin D1 were slightly reduced, along a positive, but non-significant modulation of several inflammatory markers (COX-2, TNF-alpha, IL-6, IL-10 and IL-1).	('reduced', 'NegReg', (126, 133))	('Apc1638+/-', 'Var', (7, 17))	('reduced', 'NegReg', (51, 58))	('beta-catenin', 'MPA', (25, 37))	('mouse', 'Species', '10090', (18, 23))	('Myc', 'Gene', '4609', (94, 97))	('cyclin D1', 'MPA', (102, 111))	('TNF-alpha', 'MPA', (224, 233))	('Myc', 'Gene', (94, 97))	('COX-2', 'Gene', (217, 222))	('COX-2', 'Gene', '5743', (217, 222))
859062	27775562	Among the affected metabolites, putrescine and linolenate, are associated with colorectal cancer in humans.	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('putrescine', 'MPA', (32, 42))	('associated', 'Reg', (63, 73))	('linolenate', 'Var', (47, 57))	('colorectal cancer', 'Disease', (79, 96))	('rectal cancer', 'Phenotype', 'HP:0100743', (83, 96))	('linolenate', 'Chemical', 'MESH:D017962', (47, 57))	('putrescine', 'Chemical', 'MESH:D011700', (32, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('humans', 'Species', '9606', (100, 106))
859080	27775562	The black raspberry treatment modified positively genetic and epigenetic markers measured in colorectal adenocarcinomas and adjacent normal tissues, as observed by modified gene expression of beta-catenin and E-cadherin downstream of the Wnt pathway, and demethylation of SFRP2 and WIF, tumor suppressor genes upstream of the Wnt pathway.	('E-cadherin', 'Protein', (209, 219))	('WIF', 'Gene', (282, 285))	('colorectal adenocarcinomas', 'Disease', (93, 119))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('SFRP2', 'Gene', (272, 277))	('men', 'Species', '9606', (25, 28))	('beta-catenin', 'Protein', (192, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (93, 119))	('black raspberry', 'Species', '75079', (4, 19))	('tumor', 'Disease', (287, 292))	('modified', 'Reg', (30, 38))	('demethylation', 'Var', (255, 268))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('gene expression', 'MPA', (173, 188))	('modified', 'Reg', (164, 172))
859081	27775562	Aberrant signaling of Wnt/beta-catenin pathway occurs in about 85% of sporadic colorectal cancers and is mainly attributed to Apc gene mutations.	('Wnt/beta-catenin pathway', 'Pathway', (22, 46))	('colorectal cancers', 'Disease', 'MESH:D015179', (79, 97))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('attributed', 'Reg', (112, 122))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('mutations', 'Var', (135, 144))	('colorectal cancers', 'Disease', (79, 97))	('rectal cancer', 'Phenotype', 'HP:0100743', (83, 96))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('signaling', 'MPA', (9, 18))	('sporadic', 'Disease', (70, 78))
859090	27775562	Similarly, in thirty healthy volunteers (16 women, 14 men, age 20-60 years) the blackcurrant extract (672 mg/d for two weeks) elicited a positive modulation of gut microbiota by enhancing growth of lactobacilli and bifidobacteria (beneficial microflora), while lowering fecal pH, bacteroides and clostridia and inhibiting beta-glucuronidase.	('inhibiting', 'NegReg', (311, 321))	('clostridia', 'Disease', 'None', (296, 306))	('beta-glucuronidase', 'Gene', (322, 340))	('fecal pH', 'MPA', (270, 278))	('bacteroides', 'MPA', (280, 291))	('672', 'Var', (102, 105))	('lactobacilli', 'Protein', (198, 210))	('clostridia', 'Disease', (296, 306))	('enhancing', 'PosReg', (178, 187))	('growth', 'MPA', (188, 194))	('women', 'Species', '9606', (44, 49))	('men', 'Species', '9606', (46, 49))	('lowering', 'NegReg', (261, 269))	('men', 'Species', '9606', (54, 57))	('beta-glucuronidase', 'Gene', '2990', (322, 340))	('lowering fecal pH', 'Phenotype', 'HP:0032490', (261, 278))	('bifidobacteria', 'CPA', (215, 229))
859169	27775562	These pathways are responsible for the modulation of different cellular processes, showing certain common signaling events such as arrest of cell cycle by increasing levels of cyclin-dependent kinase inhibitor proteins (CDIs) and inhibition of cyclins, induction of apoptosis via cytochrome c release, activation of caspases and down- or up-regulation of Bcl-2 family members, inhibition of survival/proliferation signals (Akt, MAPK, NF-kappaB) and inflammation (COX-2, TNF, IL secretion), as well as suppression of key proteins that are critically involved in angiogenesis and metastasis.	('COX-2', 'Gene', '5743', (463, 468))	('key proteins', 'Protein', (516, 528))	('inflammation', 'Disease', 'MESH:D007249', (449, 461))	('Bcl-2', 'Gene', (355, 360))	('survival/proliferation', 'CPA', (391, 413))	('NF-kappaB', 'Protein', (434, 443))	('caspases', 'Gene', (316, 324))	('caspases', 'Gene', '841;842;9360', (316, 324))	('TNF', 'Gene', (470, 473))	('proteins', 'Protein', (520, 528))	('cytochrome c', 'Gene', (280, 292))	('Bcl-2', 'Gene', '596', (355, 360))	('inflammation', 'Disease', (449, 461))	('increasing', 'PosReg', (155, 165))	('activation', 'PosReg', (302, 312))	('apoptosis', 'CPA', (266, 275))	('TNF', 'Gene', '7124', (470, 473))	('inhibition', 'Var', (230, 240))	('COX-2', 'Gene', (463, 468))	('inhibition', 'NegReg', (377, 387))	('Akt', 'Gene', (423, 426))	('rat', 'Species', '10116', (407, 410))	('down-', 'NegReg', (329, 334))	('up-regulation', 'PosReg', (338, 351))	('Akt', 'Gene', '207', (423, 426))	('cytochrome c', 'Gene', '54205', (280, 292))	('suppression', 'NegReg', (501, 512))
859191	27826618	However, several recent preclinical and clinical studies have demonstrated that irradiation induces an increase in invasiveness and metastatic potential of several cancer cell types, including glioma, colon, breast, and lung cancer.	('increase', 'PosReg', (103, 111))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('metastatic potential', 'CPA', (132, 152))	('glioma', 'Disease', (193, 199))	('cancer', 'Disease', (225, 231))	('invasiveness', 'CPA', (115, 127))	('lung cancer', 'Disease', (220, 231))	('irradiation', 'Var', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('breast', 'Disease', (208, 214))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('colon', 'Disease', (201, 206))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
859198	27826618	Irradiation can cause many cellular effects, including apoptosis, senescence, and genomic instability, that may lead to cancer cell death.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer cell death', 'Disease', 'MESH:D003643', (120, 137))	('lead to', 'Reg', (112, 119))	('Irradiation', 'Var', (0, 11))	('apoptosis', 'CPA', (55, 64))	('cancer cell death', 'Disease', (120, 137))	('genomic instability', 'CPA', (82, 101))	('senescence', 'CPA', (66, 76))
859202	27826618	HDAC inhibitors induce cell cycle arrest, differentiation, and apoptosis in vitro and in vivo.	('HDAC', 'Gene', (0, 4))	('differentiation', 'CPA', (42, 57))	('HDAC', 'Gene', '9734', (0, 4))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (23, 40))	('inhibitors', 'Var', (5, 15))	('apoptosis', 'CPA', (63, 72))	('cell cycle arrest', 'CPA', (23, 40))
859247	27826618	We used primary antibodies against the following proteins: E-cadherin (1:500), vimentin (1:500), beta-catenin (1:1,000), TGF-beta1 (1:1,000), Smad2 (1:200), Smad3 (1:200), phosphorylated-Smad2 (p-Smad2) (1:200), p-Smad3 (1:200), Twist (1:200), Snail (1:200), Slug (1:200), pro-MMP-2 (1:200), pro-MMP-7 (1:200), pro-MMP-9 (1:200), and HIF-1alpha (1:500).	('Smad2', 'Gene', (187, 192))	('beta-catenin', 'Gene', (97, 109))	('MMP-7', 'Gene', (296, 301))	('beta-catenin', 'Gene', '1499', (97, 109))	('Smad2', 'Gene', '4087', (142, 147))	('Smad3', 'Gene', '4088', (214, 219))	('MMP-9', 'Gene', '4318', (315, 320))	('MMP-9', 'Gene', (315, 320))	('MMP-2', 'Gene', (277, 282))	('Smad3', 'Gene', '4088', (157, 162))	('Smad3', 'Gene', (214, 219))	('Smad3', 'Gene', (157, 162))	('Snail', 'Gene', '6615', (244, 249))	('E-cadherin', 'Gene', (59, 69))	('E-cadherin', 'Gene', '999', (59, 69))	('Smad2', 'Gene', (142, 147))	('MMP-7', 'Gene', '4316', (296, 301))	('Slug', 'Gene', (259, 263))	('HIF-1alpha', 'Gene', '3091', (334, 344))	('vimentin', 'Gene', (79, 87))	('vimentin', 'Gene', '7431', (79, 87))	('Smad2', 'Gene', '4087', (196, 201))	('1:200', 'Var', (265, 270))	('Smad2', 'Gene', '4087', (187, 192))	('HIF-1alpha', 'Gene', (334, 344))	('MMP-2', 'Gene', '4313', (277, 282))	('Snail', 'Gene', (244, 249))	('Slug', 'Gene', '6591', (259, 263))	('Smad2', 'Gene', (196, 201))	('1:200', 'Var', (303, 308))
859328	27826618	As shown in this study, VPA can also suppress radiation-induced EMT, leading to inhibition of invasion and metastasis, and reducing resistance to further chemoradiotherapy.	('reducing', 'NegReg', (123, 131))	('resistance to further chemoradiotherapy', 'CPA', (132, 171))	('radiation-induced EMT', 'CPA', (46, 67))	('inhibition', 'NegReg', (80, 90))	('VPA', 'Chemical', 'MESH:D014635', (24, 27))	('suppress', 'NegReg', (37, 45))	('VPA', 'Var', (24, 27))
859357	26657507	The three-scale genome-wide association studies of Chinese Han populations identified a new susceptibility locus related to ESCC in the phospholipase C epsilon 1 (PLCE1), a member of the phospholipase family.	('PLCE1', 'Gene', (163, 168))	('PLCE1', 'Gene', '51196', (163, 168))	('ESCC', 'Var', (124, 128))	('phospholipase C epsilon 1', 'Gene', '51196', (136, 161))	('phospholipase C epsilon 1', 'Gene', (136, 161))
859360	26657507	In our previous study, we found that the genetic variants of PLCE1 are candidate makers for ESCC susceptibility of the Kazakh population.	('PLCE1', 'Gene', '51196', (61, 66))	('ESCC', 'Disease', (92, 96))	('PLCE1', 'Gene', (61, 66))	('variants', 'Var', (49, 57))
859361	26657507	And these linkage disequilibrium variants may influence ESCC risk individually and jointly by promoting the mRNA and protein expression levels of PLCE1.	('influence', 'Reg', (46, 55))	('ESCC', 'Disease', (56, 60))	('PLCE1', 'Gene', '51196', (146, 151))	('si', 'Chemical', 'MESH:D012825', (131, 133))	('promoting', 'PosReg', (94, 103))	('variants', 'Var', (33, 41))	('PLCE1', 'Gene', (146, 151))
859362	26657507	We also confirmed that the heterozygote of PLCE1 rs2274223 increase susceptibility to HPV infection in Kazakh patients with esophageal carcinoma.	('rs2274223', 'Mutation', 'rs2274223', (49, 58))	('rs2274223', 'Var', (49, 58))	('HPV infection', 'Disease', 'MESH:D030361', (86, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('susceptibility', 'Reg', (68, 82))	('esophageal carcinoma', 'Disease', (124, 144))	('PLCE1', 'Gene', (43, 48))	('PLCE1', 'Gene', '51196', (43, 48))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (124, 144))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (124, 144))	('HPV infection', 'Disease', (86, 99))	('patients', 'Species', '9606', (110, 118))
859373	26657507	In ESCC, the aberrant expressions level of miRNAs, such as miR-27a, miR-9, miR-335, and miR-183, regulate tumor cell growth, apoptosis, migration, and invasion by targeting proteins involved in these cellular pathways.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('miR-27a', 'Gene', '407018', (59, 66))	('miR-335', 'Gene', (75, 82))	('proteins', 'Protein', (173, 181))	('apoptosis', 'CPA', (125, 134))	('targeting', 'Reg', (163, 172))	('tumor', 'Disease', (106, 111))	('miR-183', 'Gene', '406959', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('miR-27a', 'Gene', (59, 66))	('miR-183', 'Gene', (88, 95))	('invasion', 'CPA', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('miR-335', 'Gene', '442904', (75, 82))	('regulate', 'Reg', (97, 105))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('si', 'Chemical', 'MESH:D012825', (131, 133))	('miR-9', 'Var', (68, 73))	('migration', 'CPA', (136, 145))
859388	26657507	The results showed that the mean mRNA level of PLCE1 was threefold higher in ESCC samples than that in the corresponding normal esophageal epithelial tissues (0.006556 +- 0.0015 vs. 0.002051 +- 0.0007, P = 0.0108, Figure 1D).	('higher', 'PosReg', (67, 73))	('ESCC', 'Disease', (77, 81))	('PLCE1', 'Gene', (47, 52))	('PLCE1', 'Gene', '51196', (47, 52))	('mRNA level', 'MPA', (33, 43))	('0.006556 +- 0.0015', 'Var', (159, 177))
859389	26657507	Kaplan-Meier survival analysis also revealed that the overall survival rate was significantly lower in patients with high PLCE1 expression than that in patients with low PLCE1 expression (log-rank test, chi2 = 6.749, P < 0.001, Figure 1E and 1F).	('expression', 'Var', (128, 138))	('PLCE1', 'Gene', (170, 175))	('PLCE1', 'Gene', '51196', (170, 175))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('PLCE1', 'Gene', '51196', (122, 127))	('lower', 'NegReg', (94, 99))	('PLCE1', 'Gene', (122, 127))	('si', 'Chemical', 'MESH:D012825', (182, 184))	('high', 'Var', (117, 121))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (152, 160))	('si', 'Chemical', 'MESH:D012825', (80, 82))
859390	26657507	Moreover, multivariate survival analysis using Cox's proportional hazards model showed a close correlation between high PLCE1 protein expression and clinical prognosis (HR = 8.435, 95% CI = 1.875 to 37.983, P = 0.005, Supplementary Table 2).	('high', 'Var', (115, 119))	('Cox', 'Gene', '1351', (47, 50))	('protein', 'Protein', (126, 133))	('expression', 'MPA', (134, 144))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('Cox', 'Gene', (47, 50))	('PLCE1', 'Gene', (120, 125))	('PLCE1', 'Gene', '51196', (120, 125))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('si', 'Chemical', 'MESH:D012825', (42, 44))
859394	26657507	The PLCE1 protein levels were successfully reduced through transfection of specific siRNA against PLCE1 (Figure 2A-2C).	('protein', 'Protein', (10, 17))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('PLCE1', 'Gene', (98, 103))	('PLCE1', 'Gene', (4, 9))	('transfection', 'Var', (59, 71))	('PLCE1', 'Gene', '51196', (98, 103))	('PLCE1', 'Gene', '51196', (4, 9))	('reduced', 'NegReg', (43, 50))
859395	26657507	The proliferation rate of Eca109 and EC9706 cells decreased in si-PLCE1-transfected cells compared with that in the respective controls (Figure 2D and 2E).	('PLCE1', 'Gene', (66, 71))	('PLCE1', 'Gene', '51196', (66, 71))	('EC9706', 'Var', (37, 43))	('EC9706', 'CellLine', 'CVCL:E307', (37, 43))	('decreased', 'NegReg', (50, 59))	('proliferation rate', 'CPA', (4, 22))	('si', 'Chemical', 'MESH:D012825', (63, 65))
859399	26657507	Western blot analysis showed that PLCE1 inhibition increased the levels of the apoptosis-related protein p53, Bax, cleaved PARP, caspase3, and cleaved caspase3 but decreased the level of Bcl-2 (Figure 3D).	('PARP', 'Gene', '1302', (123, 127))	('caspase3', 'Gene', '836', (151, 159))	('p53', 'Gene', (105, 108))	('PARP', 'Gene', (123, 127))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('Bcl-2', 'Gene', (187, 192))	('caspase3', 'Gene', (129, 137))	('levels of', 'MPA', (65, 74))	('Bax', 'Gene', (110, 113))	('inhibition', 'Var', (40, 50))	('increased', 'PosReg', (51, 60))	('Bcl-2', 'Gene', '596', (187, 192))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('Bax', 'Gene', '581', (110, 113))	('PLCE1', 'Gene', (34, 39))	('caspase3', 'Gene', (151, 159))	('PLCE1', 'Gene', '51196', (34, 39))	('caspase3', 'Gene', '836', (129, 137))	('decreased', 'NegReg', (164, 173))	('p53', 'Gene', '7157', (105, 108))
859401	26657507	The tumor cell migration and invasion assay indicated that si-PLCE1 transfection reduced the invasion and migration capability of Eca109 and EC9706 cell lines.	('tumor', 'Disease', (4, 9))	('PLCE1', 'Gene', '51196', (62, 67))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('transfection', 'Var', (68, 80))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('EC9706', 'CellLine', 'CVCL:E307', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('reduced', 'NegReg', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('PLCE1', 'Gene', (62, 67))
859405	26657507	After knocked down of PLCE1, E-cadherin expression was significantly upregulated, whereas vimentin expression was significantly downregulated in the two cell lines compared with that in the control siRNA groups (Figure 4E and 4F).	('expression', 'MPA', (40, 50))	('expression', 'MPA', (99, 109))	('vimentin', 'Gene', '7431', (90, 98))	('E-cadherin', 'Gene', (29, 39))	('E-cadherin', 'Gene', '999', (29, 39))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('vimentin', 'Gene', (90, 98))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('knocked down', 'Var', (6, 18))	('si', 'Chemical', 'MESH:D012825', (198, 200))	('PLCE1', 'Gene', (22, 27))	('PLCE1', 'Gene', '51196', (22, 27))	('upregulated', 'PosReg', (69, 80))	('downregulated', 'NegReg', (128, 141))	('si', 'Chemical', 'MESH:D012825', (55, 57))
859408	26657507	Examination of cell morphology indicated that PLCE1 knockdown induced morphological changes in Eca109 cells (Figure 4G).	('morphological changes', 'CPA', (70, 91))	('PLCE1', 'Gene', '51196', (46, 51))	('knockdown', 'Var', (52, 61))	('PLCE1', 'Gene', (46, 51))
859409	26657507	Furthermore, the use of phalloidin-TRITC (F-actin) to monitor cytoskeleton dynamics in Eca109 cells showed that PLCE1 knockdown inhibited the formation of lamellipodia and filopodia compared with that in control cells (Figure 4G).	('knockdown', 'Var', (118, 127))	('PLCE1', 'Gene', (112, 117))	('phalloidin-TRITC', 'Chemical', '-', (24, 40))	('PLCE1', 'Gene', '51196', (112, 117))	('inhibited', 'NegReg', (128, 137))
859413	26657507	As such, we investigated the effect of PLCE1 knockdown in ESCC cells on TNFalpha-mediated NF-kappaB activation and apoptotic induction.	('PLCE1', 'Gene', (39, 44))	('PLCE1', 'Gene', '51196', (39, 44))	('TNFalpha', 'Gene', (72, 80))	('NF-kappaB', 'Gene', '4790', (90, 99))	('TNFalpha', 'Gene', '7124', (72, 80))	('NF-kappaB', 'Gene', (90, 99))	('knockdown', 'Var', (45, 54))
859417	26657507	Response of ESCC cells to apoptosis induced by cytokines following PLCE1 knockdown indicated that PLCE1 inhibition may sensitize the cells to apoptosis induced by chemotherapeutic agents.	('inhibition', 'NegReg', (104, 114))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('PLCE1', 'Gene', (67, 72))	('PLCE1', 'Gene', (98, 103))	('PLCE1', 'Gene', '51196', (67, 72))	('sensitize', 'Reg', (119, 128))	('PLCE1', 'Gene', '51196', (98, 103))	('apoptosis', 'CPA', (142, 151))	('knockdown', 'Var', (73, 82))
859418	26657507	We also determined the effect of PLCE1 knockdown on the survival of cancer cells given with Paclitaxel and 5-FU, which are chemotherapeutic drugs commonly used for clinical treatment of ESCC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PLCE1', 'Gene', (33, 38))	('knockdown', 'Var', (39, 48))	('PLCE1', 'Gene', '51196', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('5-FU', 'Chemical', 'MESH:D005472', (107, 111))	('cancer', 'Disease', (68, 74))	('Paclitaxel', 'Chemical', 'MESH:D017239', (92, 102))
859419	26657507	PLCE1 knockdown induced Eca109 cells to be sensitive to paclitaxel-induced cell death (Figure 5E and 5F).	('paclitaxel', 'Chemical', 'MESH:D017239', (56, 66))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('PLCE1', 'Gene', '51196', (0, 5))	('PLCE1', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))
859421	26657507	These findings indicate that PLCE1 knockdown promoted apoptosis induced by TNFalpha, TRAIL, paclitaxel, and 5-FU; hence, overexpressing PLCE1 contributed to the resistance of ESCC cells to chemotherapy.	('apoptosis', 'CPA', (54, 63))	('TNFalpha', 'Gene', (75, 83))	('knockdown', 'Var', (35, 44))	('si', 'Chemical', 'MESH:D012825', (131, 133))	('PLCE1', 'Gene', (29, 34))	('TRAIL', 'Gene', (85, 90))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('TNFalpha', 'Gene', '7124', (75, 83))	('PLCE1', 'Gene', '51196', (29, 34))	('5-FU', 'Chemical', 'MESH:D005472', (108, 112))	('paclitaxel', 'Chemical', 'MESH:D017239', (92, 102))	('promoted', 'PosReg', (45, 53))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('PLCE1', 'Gene', (136, 141))	('PLCE1', 'Gene', '51196', (136, 141))	('TRAIL', 'Gene', '8743', (85, 90))
859436	26657507	miR-145 expression levels increased in Eca109 cells transfected with miR-145 mimic (Figure 6E, lower panel) but decreased in TE-1 cells transfected miR-145 inhibitor (Figure 6F, lower panel).	('si', 'Chemical', 'MESH:D012825', (14, 16))	('miR-145', 'Gene', (148, 155))	('miR-145', 'Gene', '406937', (69, 76))	('mimic', 'Var', (77, 82))	('miR-145', 'Gene', '406937', (148, 155))	('TE-1', 'CellLine', 'CVCL:1759', (125, 129))	('increased', 'PosReg', (26, 35))	('expression levels', 'MPA', (8, 25))	('miR-145', 'Gene', (0, 7))	('decreased', 'NegReg', (112, 121))	('miR-145', 'Gene', (69, 76))	('miR-145', 'Gene', '406937', (0, 7))
859458	26657507	As shown in Figure 7H, Eca109 cell lines transfected with miR-145 mimic inhibited the formation of lamelipodia and filopodia compared with those transfected with miR-145 inhibitor.	('miR-145', 'Gene', (162, 169))	('miR-145', 'Gene', '406937', (162, 169))	('mimic', 'Var', (66, 71))	('miR-145', 'Gene', (58, 65))	('inhibited', 'NegReg', (72, 81))	('miR-145', 'Gene', '406937', (58, 65))
859460	26657507	We also examined whether PLCE1 knockdown by siRNA can potentiate the antitumor effects of miR-145.	('miR-145', 'Gene', (90, 97))	('potentiate', 'PosReg', (54, 64))	('miR-145', 'Gene', '406937', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PLCE1', 'Gene', '51196', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('PLCE1', 'Gene', (25, 30))	('knockdown', 'Var', (31, 40))
859463	26657507	MiRNAs have expression patterns that are opposite to those of their targets.	('expression', 'MPA', (12, 22))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('MiRNAs', 'Var', (0, 6))	('si', 'Chemical', 'MESH:D012825', (18, 20))
859480	26657507	Our previous study showed that PLCE1 may serve as a candidate marker for ESCC susceptibility in the Kazakh population; linkage disequilibrium variants may also influence ESCC risk individually and jointly by promoting mRNA and protein expression of PLCE1.	('influence', 'Reg', (160, 169))	('PLCE1', 'Gene', '51196', (31, 36))	('variants', 'Var', (142, 150))	('PLCE1', 'Gene', (249, 254))	('PLCE1', 'Gene', '51196', (249, 254))	('promoting', 'PosReg', (208, 217))	('PLCE1', 'Gene', (31, 36))	('si', 'Chemical', 'MESH:D012825', (241, 243))	('ESCC', 'Disease', (170, 174))
859481	26657507	Moreover, the heterozygote of PLCE1 rs2274223 increases susceptibility to HPV infection in Kazakh patients with esophageal carcinoma.	('HPV infection', 'Disease', (74, 87))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('susceptibility', 'MPA', (56, 70))	('PLCE1', 'Gene', (30, 35))	('patients', 'Species', '9606', (98, 106))	('rs2274223', 'Mutation', 'rs2274223', (36, 45))	('rs2274223', 'Var', (36, 45))	('HPV infection', 'Disease', 'MESH:D030361', (74, 87))	('PLCE1', 'Gene', '51196', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('esophageal carcinoma', 'Disease', (112, 132))
859491	26657507	The present study provides the first evidence that miR-145 functions as a tumor suppressor by regulating aberrant PLCE1 activity in ESCC.	('PLCE1', 'Gene', (114, 119))	('PLCE1', 'Gene', '51196', (114, 119))	('aberrant', 'Var', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('miR-145', 'Gene', (51, 58))	('activity', 'MPA', (120, 128))	('ESCC', 'Disease', (132, 136))	('miR-145', 'Gene', '406937', (51, 58))	('regulating', 'Reg', (94, 104))
859499	26657507	In the present study, PLCE1 knockdown reduced cell growth/proliferation and increased the frequency of apoptotic esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('reduced', 'NegReg', (38, 45))	('increased', 'PosReg', (76, 85))	('PLCE1', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('PLCE1', 'Gene', '51196', (22, 27))	('knockdown', 'Var', (28, 37))	('esophageal cancer', 'Disease', (113, 130))	('cell growth/proliferation', 'CPA', (46, 71))
859500	26657507	Similarly, PLCE1 knockdown in bladder cancer reduces proliferating cell nuclear antigen and cyclin D1 in the bladder tumor xenograft, leading to significant inhibition of cell proliferation and cell cycle arrest.	('si', 'Chemical', 'MESH:D012825', (145, 147))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (194, 211))	('bladder tumor', 'Disease', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('bladder tumor', 'Disease', 'MESH:D001749', (109, 122))	('proliferating cell nuclear antigen', 'MPA', (53, 87))	('inhibition', 'NegReg', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('cyclin D1', 'Gene', (92, 101))	('cell cycle arrest', 'CPA', (194, 211))	('knockdown', 'Var', (17, 26))	('PLCE1', 'Gene', (11, 16))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))	('PLCE1', 'Gene', '51196', (11, 16))	('cell proliferation', 'CPA', (171, 189))	('cyclin D1', 'Gene', '595', (92, 101))	('reduces', 'NegReg', (45, 52))	('bladder tumor', 'Phenotype', 'HP:0009725', (109, 122))
859502	26657507	Total p53 was markedly upregulated in PLCE1-silenced ESCC cells compared with that in the control group, similar to those reported by Yun Li et al.. We further found that the inhibited expression of PLCE1 significantly enhanced cleaved PARP and cleaved caspase3 expression, which is a crucial executioner of cell apoptosis, but disrupted the balance of the Bcl-2 family members by reducing Bcl-2 expression and increasing Bax expression.	('Bcl-2', 'Gene', (357, 362))	('disrupted', 'NegReg', (328, 337))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('Bax', 'Gene', (422, 425))	('increasing', 'PosReg', (411, 421))	('si', 'Chemical', 'MESH:D012825', (319, 321))	('Bcl-2', 'Gene', '596', (390, 395))	('PLCE1', 'Gene', (38, 43))	('caspase3', 'Gene', '836', (253, 261))	('Bcl-2', 'Gene', '596', (357, 362))	('PLCE1', 'Gene', '51196', (38, 43))	('PARP', 'Gene', (236, 240))	('Bax', 'Gene', '581', (422, 425))	('reducing', 'NegReg', (381, 389))	('si', 'Chemical', 'MESH:D012825', (191, 193))	('expression', 'MPA', (262, 272))	('expression', 'Var', (185, 195))	('p53', 'Gene', '7157', (6, 9))	('inhibited', 'NegReg', (175, 184))	('si', 'Chemical', 'MESH:D012825', (205, 207))	('balance', 'MPA', (342, 349))	('si', 'Chemical', 'MESH:D012825', (402, 404))	('p53', 'Gene', (6, 9))	('si', 'Chemical', 'MESH:D012825', (268, 270))	('si', 'Chemical', 'MESH:D012825', (417, 419))	('enhanced', 'PosReg', (219, 227))	('expression', 'MPA', (426, 436))	('caspase3', 'Gene', (253, 261))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('Bcl-2', 'Gene', (390, 395))	('PLCE1', 'Gene', (199, 204))	('si', 'Chemical', 'MESH:D012825', (432, 434))	('PLCE1', 'Gene', '51196', (199, 204))	('PARP', 'Gene', '1302', (236, 240))
859505	26657507	These results indicate that PLCE1 silencing partially activated apoptosis by regulating the p53-Bax/Bcl-2-caspase3 mediated pro-apoptotic signaling pathway.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('activated', 'PosReg', (54, 63))	('caspase3', 'Gene', '836', (106, 114))	('si', 'Chemical', 'MESH:D012825', (138, 140))	('Bcl-2', 'Gene', (100, 105))	('Bcl-2', 'Gene', '596', (100, 105))	('Bax', 'Gene', '581', (96, 99))	('apoptosis', 'CPA', (64, 73))	('p53', 'Gene', (92, 95))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('Bax', 'Gene', (96, 99))	('caspase3', 'Gene', (106, 114))	('p53', 'Gene', '7157', (92, 95))	('silencing', 'Var', (34, 43))	('PLCE1', 'Gene', (28, 33))	('PLCE1', 'Gene', '51196', (28, 33))
859506	26657507	This study also reveals that PLCE1 knockdown enhanced cell apoptosis induced by TNFalpha, TRAIL, PTX, and 5-FU, suggesting that overexpressing PLCE1 contributed to the resistance of ESCC cells to chemotherapy.	('knockdown', 'Var', (35, 44))	('si', 'Chemical', 'MESH:D012825', (138, 140))	('PLCE1', 'Gene', (29, 34))	('5-FU', 'Chemical', 'MESH:D005472', (106, 110))	('si', 'Chemical', 'MESH:D012825', (170, 172))	('cell apoptosis', 'CPA', (54, 68))	('PTX', 'Chemical', '-', (97, 100))	('enhanced', 'PosReg', (45, 53))	('PLCE1', 'Gene', '51196', (29, 34))	('TRAIL', 'Gene', '8743', (90, 95))	('TNFalpha', 'Gene', (80, 88))	('TRAIL', 'Gene', (90, 95))	('PLCE1', 'Gene', '51196', (143, 148))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('PLCE1', 'Gene', (143, 148))	('TNFalpha', 'Gene', '7124', (80, 88))
859510	26657507	PLCE1 silencing may also downregulate MMP and BCL2 gene expression, thereby reducing the invasiveness of bladder cancer cells.	('si', 'Chemical', 'MESH:D012825', (62, 64))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('invasiveness of bladder cancer', 'Disease', 'MESH:D001749', (89, 119))	('invasiveness of bladder cancer', 'Disease', (89, 119))	('BCL2', 'Gene', '596', (46, 50))	('downregulate', 'NegReg', (25, 37))	('expression', 'MPA', (56, 66))	('PLCE1', 'Gene', (0, 5))	('reducing', 'NegReg', (76, 84))	('PLCE1', 'Gene', '51196', (0, 5))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('silencing', 'Var', (6, 15))	('BCL2', 'Gene', (46, 50))
859518	26657507	PLCE1 overexpression in esophageal cancer cells is caused by multiple factors, including genetic variants of PLCE1, as shown in our previous report, and miRNA regulation, as revealed in the present study.	('esophageal cancer', 'Disease', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('miRNA regulation', 'MPA', (153, 169))	('PLCE1', 'Gene', (109, 114))	('variants', 'Var', (97, 105))	('esophageal cancer', 'Disease', 'MESH:D004938', (24, 41))	('PLCE1', 'Gene', '51196', (109, 114))	('PLCE1', 'Gene', (0, 5))	('overexpression', 'PosReg', (6, 20))	('PLCE1', 'Gene', '51196', (0, 5))
859521	26657507	showed that the PLCE1 variant rs2274223 enhances PLCE1 mRNA and protein expression in esophageal cancer tissues and ESCC cell lines.	('PLCE1', 'Gene', '51196', (49, 54))	('enhances', 'PosReg', (40, 48))	('esophageal cancer', 'Disease', (86, 103))	('PLCE1', 'Gene', (16, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('PLCE1', 'Gene', '51196', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('rs2274223', 'Mutation', 'rs2274223', (30, 39))	('rs2274223', 'Var', (30, 39))	('PLCE1', 'Gene', (49, 54))
859530	26657507	found that miR-145 downregulation is mediated by DNA methylation and p53 mutation pathways.	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('miR-145', 'Gene', (11, 18))	('miR-145', 'Gene', '406937', (11, 18))	('downregulation', 'NegReg', (19, 33))	('DNA', 'Var', (49, 52))
859532	26657507	MiR-145, which is located in chromosome 5q32-33, exhibits frequent deletion in esophageal cancer, as detected through comparative genomic hybridization, and may harbor many tumor suppressor genes.	('esophageal cancer', 'Disease', (79, 96))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('deletion', 'Var', (67, 75))	('MiR-145', 'Gene', (0, 7))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('MiR-145', 'Gene', '406937', (0, 7))
859554	26657507	In conclusion, high PLCE1 expression levels are correlated with poor prognosis of patients with ESCC, and this molecule functions as an oncogene in ESCC tumorigenesis.	('high', 'Var', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('patients', 'Species', '9606', (82, 90))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('PLCE1', 'Gene', '51196', (20, 25))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('ESCC', 'Disease', (96, 100))	('PLCE1', 'Gene', (20, 25))	('ESCC', 'Disease', (148, 152))	('expression levels', 'MPA', (26, 43))
859596	26657507	The cells were incubated with anti-PLCE1 (Sigma; 1:50 dilution) and anti-F-actin (Abcom; 1:10 dilution) in 5% bovine serum albumin at 4 C overnight.	('PLCE1', 'Gene', '51196', (35, 40))	('bovine', 'Species', '9913', (110, 116))	('anti-F-actin', 'Var', (68, 80))	('PLCE1', 'Gene', (35, 40))
859599	26657507	ESCC cells were maintained in DMEM; cells at 70-90% confluence in 96-well plates were allowed to settle for 16 h, and then co-transfected with 200 ng of pMIR vectors (Promega), which harbored PLCE1 3'-UTR wild-type or mutant constructs and 10 ng of the Renilla luciferase vector with Lipofectamine  2000 Reagent (Invitrogen) according to the recommendation of the manufacturer.	('mutant', 'Var', (218, 224))	('DMEM', 'Chemical', '-', (30, 34))	('PLCE1', 'Gene', (192, 197))	('PLCE1', 'Gene', '51196', (192, 197))
859790	20446296	The MASCOT search engine was used to search the UniProt protein database, and search results were filtered with ProteinParser according to the following parameters: 1 missed cleavage allowed from tryptic digestion, +- 0.03 m/z tolerance for precursors, +2 and +3 charges, oxidation of methionine (variable modification), ion score >= 30, expect <= 0.1, accept only bold red queries, and a minimum peptide mass of 600.00 Da.	('expect <=', 'Var', (338, 347))	('+- 0.03', 'Var', (215, 222))	('ion score >= 30', 'Var', (321, 336))	('oxidation', 'Var', (272, 281))	('methionine', 'Chemical', 'MESH:D008715', (285, 295))
859843	33234735	Its fusion with MAD1L1 might contribute to tumorigenesis, cancer stem cell like properties and therapeutic resistance.	('contribute', 'Reg', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('fusion', 'Var', (4, 10))	('MAD1L1', 'Gene', '8379', (16, 22))	('MAD1L1', 'Gene', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('therapeutic resistance', 'CPA', (95, 117))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Disease', (58, 64))	('tumor', 'Disease', (43, 48))
859844	33234735	STMN1 functions as a critical element of regulating microtubule dynamics, which is necessary in the final stage of cell division, and its mutation may lead to uncontrolled cell proliferation.	('STMN1', 'Gene', (0, 5))	('uncontrolled cell proliferation', 'CPA', (159, 190))	('microtubule dynamics', 'MPA', (52, 72))	('lead to', 'Reg', (151, 158))	('mutation', 'Var', (138, 146))	('STMN1', 'Gene', '3925', (0, 5))
859856	33234735	The CLDN9 gene was changed in 2.75% of cases, displaying diverse alterations; 1.65% had amplification and 0.55% had deep mutations in GFPT1; The HMMR gene contained one deep deletion sample and one truncating mutation sample; RARS and STMN1 had 0.55% amplification and 0.55% missense mutations, respectively (Figure 4).	('CLDN9', 'Gene', (4, 9))	('GFPT1', 'Gene', '2673', (134, 139))	('CLDN9', 'Gene', '9080', (4, 9))	('missense mutations', 'Var', (275, 293))	('HMMR', 'Gene', '3161', (145, 149))	('RARS', 'Gene', (226, 230))	('STMN1', 'Gene', '3925', (235, 240))	('STMN1', 'Gene', (235, 240))	('GFPT1', 'Gene', (134, 139))	('HMMR', 'Gene', (145, 149))	('RARS', 'Gene', '5917', (226, 230))
859860	33234735	The joint risk score of the five genes was calculated by substituting the coefficient into the formula to evaluate the prognosis as follows: risk score = (0.1340 x expression of CLDN9) + (0.0347 x expression of GFPT1) + (-0.1031 x expression of HMMR) + (0.0969 xexpression of RARS) + (0.0590 x expression of STMN1).	('HMMR', 'Gene', (245, 249))	('GFPT1', 'Gene', '2673', (211, 216))	('CLDN9', 'Gene', (178, 183))	('RARS', 'Gene', (276, 280))	('CLDN9', 'Gene', '9080', (178, 183))	('RARS', 'Gene', '5917', (276, 280))	('0.1340 x', 'Var', (155, 163))	('GFPT1', 'Gene', (211, 216))	('STMN1', 'Gene', (308, 313))	('HMMR', 'Gene', '3161', (245, 249))	('STMN1', 'Gene', '3925', (308, 313))
859871	33234735	For instance, expression of the glycolytic enzyme PKM2 is positively associated with obesity in EAC patients, overexpression of uncoupling protein-2 (UCP2) abrogated cigarette smoking condensate and deoxycholic acid mediated increases in lactate and ATP production in EAC; these links may provide novel strategies for EAC therapy.	('EAC', 'Phenotype', 'HP:0011459', (318, 321))	('obesity', 'Disease', 'MESH:D009765', (85, 92))	('increases', 'PosReg', (225, 234))	('patients', 'Species', '9606', (100, 108))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (199, 215))	('ATP', 'Chemical', 'MESH:D000255', (250, 253))	('abrogated', 'NegReg', (156, 165))	('lactate', 'MPA', (238, 245))	('UCP2', 'Gene', (150, 154))	('obesity', 'Phenotype', 'HP:0001513', (85, 92))	('EAC', 'Phenotype', 'HP:0011459', (268, 271))	('uncoupling protein-2', 'Gene', (128, 148))	('uncoupling protein-2', 'Gene', '7351', (128, 148))	('associated', 'Reg', (69, 79))	('PKM2', 'Gene', (50, 54))	('PKM2', 'Gene', '5315', (50, 54))	('overexpression', 'Var', (110, 124))	('UCP2', 'Gene', '7351', (150, 154))	('EAC', 'Phenotype', 'HP:0011459', (96, 99))	('obesity', 'Disease', (85, 92))	('ATP production', 'MPA', (250, 264))	('lactate', 'Chemical', 'MESH:D019344', (238, 245))
859907	33121507	The AUC of Rad-score was 0.812 (95% CI 0.742-0.869, p < 0.001) in the training set and 0.744 (95% CI 0.632-0.851, p = 0.003) in the validation set.	('Rad', 'Gene', '6236', (11, 14))	('0.744', 'Var', (87, 92))	('Rad', 'Gene', (11, 14))
859916	33121507	However, the effect of CCRT remained poor, as more than a half of patients treated with standard-dose CCRT were eventually developed recurrence or distant metastases and succumbed to this disease.	('developed', 'PosReg', (123, 132))	('CR', 'Chemical', '-', (103, 105))	('CR', 'Chemical', '-', (24, 26))	('CCRT', 'Var', (102, 106))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('recurrence', 'CPA', (133, 143))	('patients', 'Species', '9606', (66, 74))	('metastases', 'Disease', (155, 165))
860001	30854104	Overexpression of TAF1L Promotes Cell Proliferation, Migration and Invasion in Esophageal Squamous Cell Carcinoma Currently, it reported that TAF1L gene mutation is found in a number of carcinomas, but its pathophysiological function has not been well studied.	('Invasion', 'CPA', (67, 75))	('TAF1L', 'Gene', '138474', (142, 147))	('TAF1L', 'Gene', (18, 23))	('Promotes', 'PosReg', (24, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('TAF1L', 'Gene', (142, 147))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('Migration', 'CPA', (53, 62))	('carcinomas', 'Disease', 'MESH:D002277', (186, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('Esophageal Squamous Cell Carcinoma', 'Disease', (79, 113))	('carcinomas', 'Disease', (186, 196))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (79, 113))	('Carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('Cell Proliferation', 'CPA', (33, 51))	('mutation', 'Var', (153, 161))	('TAF1L', 'Gene', '138474', (18, 23))
860006	30854104	Furthermore, the proliferation, migration and invasion of ESCC cells were inhibited after TAF1L gene silencing.	('inhibited', 'NegReg', (74, 83))	('TAF1L', 'Gene', '138474', (90, 95))	('gene silencing', 'Var', (96, 110))	('TAF1L', 'Gene', (90, 95))	('migration', 'CPA', (32, 41))	('invasion of', 'CPA', (46, 57))
860017	30854104	However, when the expression of p27Kip1 was reduced as a consequence of knocking down TAF1, those tested cells became more resistance to apoptosis.	('more', 'PosReg', (118, 122))	('TAF1', 'Gene', (86, 90))	('TAF1', 'Gene', '6872', (86, 90))	('knocking down', 'Var', (72, 85))	('expression', 'MPA', (18, 28))	('reduced', 'NegReg', (44, 51))	('p27Kip1', 'Gene', '1027', (32, 39))	('resistance to apoptosis', 'CPA', (123, 146))	('p27Kip1', 'Gene', (32, 39))
860042	30854104	As primary antibodies TAF1L (1:1000), p-Akt (Thr308, 1:1000), Akt (1:1000), p53 (1:1000), c-Myc (1:1000) and GAPDH (1:1000) were applied, and incubated at 4 C, overnight.	('c-Myc', 'Gene', '4609', (90, 95))	('p53', 'Gene', (76, 79))	('Akt', 'Gene', '207', (40, 43))	('p53', 'Gene', '7157', (76, 79))	('Thr308', 'Chemical', '-', (45, 51))	('Akt', 'Gene', '207', (62, 65))	('c-Myc', 'Gene', (90, 95))	('TAF1L', 'Gene', '138474', (22, 27))	('Akt', 'Gene', (40, 43))	('1:1000', 'Var', (67, 73))	('TAF1L', 'Gene', (22, 27))	('Akt', 'Gene', (62, 65))
860064	30854104	Expression levels of TAF1L protein were also increased 1.67 and 1.93 times in KYSE150 cells and KYSE180 cells, respectively.	('protein', 'Protein', (27, 34))	('increased', 'PosReg', (45, 54))	('TAF1L', 'Gene', (21, 26))	('Expression levels', 'MPA', (0, 17))	('KYSE180', 'CellLine', 'CVCL:1349', (96, 103))	('KYSE180', 'Var', (96, 103))	('KYSE150', 'CellLine', 'CVCL:1348', (78, 85))	('TAF1L', 'Gene', '138474', (21, 26))
860083	30854104	Oh, et al reported that TAF1L has frame shift mutations in gastric and colorectal cancers due to the mononucleotide repeats.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('frame shift mutations', 'Var', (34, 55))	('TAF1L', 'Gene', '138474', (24, 29))	('gastric', 'Disease', (59, 66))	('TAF1L', 'Gene', (24, 29))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('colorectal cancers', 'Disease', 'MESH:D015179', (71, 89))	('mononucleotide repeats', 'Var', (101, 123))	('mononucleotide', 'Chemical', '-', (101, 115))	('colorectal cancers', 'Disease', (71, 89))
860084	30854104	Glaser, et al found that a variant of TAF1L in lymphatic endothelial cells was derived from lymphatic malformations, using whole exome sequencing.	('lymphatic malformations', 'Phenotype', 'HP:0100763', (92, 115))	('TAF1L', 'Gene', '138474', (38, 43))	('TAF1L', 'Gene', (38, 43))	('malformations', 'Disease', 'MESH:D000014', (102, 115))	('variant', 'Var', (27, 34))	('malformations', 'Disease', (102, 115))
860085	30854104	Based on the references, mentioned SNP mutation sites (rs10971047, rs10758145, rs10971046 and rs199701622) were examined by sequencing and analyzing in this study.	('rs199701622', 'Var', (94, 105))	('rs10758145', 'Mutation', 'rs10758145', (67, 77))	('rs10971047', 'Var', (55, 65))	('rs10971046', 'Var', (79, 89))	('rs10758145', 'Var', (67, 77))	('rs10971046', 'Mutation', 'rs10971046', (79, 89))	('rs10971047', 'Mutation', 'rs10971047', (55, 65))	('rs199701622', 'Mutation', 'rs199701622', (94, 105))
860092	30854104	As for ESCC, phosphorylated Akt phosphorylation was reported to be elevated in tumor tissues compared with paired normal tissues, and genetic variations of Akt might predict increased recurrence risk after chemoradiotherapy.	('Akt', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('elevated', 'PosReg', (67, 75))	('Akt', 'Gene', (156, 159))	('predict', 'Reg', (166, 173))	('genetic variations', 'Var', (134, 152))	('Akt', 'Gene', '207', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Akt', 'Gene', '207', (156, 159))	('recurrence', 'CPA', (184, 194))
860093	30854104	Results obtained in this study identified that blocking TAF1L gene could reduce expressive level of downstream phosphorylated Akt, suggesting that TAF1L may have potential roles in the malignant proliferation and metastasis of ESCC cells.	('expressive level of downstream phosphorylated', 'MPA', (80, 125))	('TAF1L', 'Gene', '138474', (56, 61))	('blocking', 'Var', (47, 55))	('TAF1L', 'Gene', (147, 152))	('Akt', 'Gene', '207', (126, 129))	('TAF1L', 'Gene', (56, 61))	('metastasis', 'CPA', (213, 223))	('roles', 'Reg', (172, 177))	('TAF1L', 'Gene', '138474', (147, 152))	('reduce', 'NegReg', (73, 79))	('ESCC', 'Disease', (227, 231))	('Akt', 'Gene', (126, 129))	('malignant proliferation', 'CPA', (185, 208))
860094	30854104	p53, as a tumor suppressor gene, can derive many mutations in more than 50% of malignancies, and promote tumorigenesis via repressing downstream target genes.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', (10, 15))	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('malignancies', 'Disease', (79, 91))	('repressing', 'NegReg', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', (105, 110))	('promote', 'PosReg', (97, 104))
860205	30352542	Thariat et al carried out a cohort study of 880 patients with T1-4, N1-3 squamous cell carcinoma of the oropharynx, larynx, or hypopharynx treated with chemoradiation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('hypopharynx', 'Disease', (127, 138))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('squamous cell carcinoma', 'Disease', (73, 96))	('patients', 'Species', '9606', (48, 56))	('hypopharynx', 'Disease', 'None', (127, 138))	('T1-4', 'Var', (62, 66))
860256	30002748	A total of 3 postoperative complications included gastric perforation and positivity of resection line (following EMR/ESD) and recurrent bleeding.	('positivity', 'Var', (74, 84))	('gastric perforation', 'Disease', (50, 69))	('resection', 'Gene', (88, 97))	('recurrent', 'CPA', (127, 136))	('bleeding', 'Disease', 'MESH:D006470', (137, 145))	('bleeding', 'Disease', (137, 145))
860286	30002748	We are more likely to perform non-selective IOG in esophageal or gastric intramural tumors, esophageal diverticula (middle and lower esophagus), re-do fundoplications and early-stage gastric and esophageal tumors.	('esophageal diverticula', 'Disease', 'MESH:D004936', (92, 114))	('esophageal diverticula', 'Phenotype', 'HP:0100628', (92, 114))	('esophageal diverticula', 'Disease', (92, 114))	('fundoplications', 'Disease', (151, 166))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('gastric intramural tumors', 'Disease', (65, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('gastric intramural tumors', 'Disease', 'MESH:D013274', (65, 90))	('esophageal tumors', 'Disease', 'MESH:D004938', (195, 212))	('non-selective', 'Var', (30, 43))	('esophageal', 'Disease', (51, 61))	('esophageal tumors', 'Phenotype', 'HP:0100751', (195, 212))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('esophageal tumors', 'Disease', (195, 212))
860316	30002748	In the minority of surgical therapies, endoscopic therapy can be used (clipping of small ulcers, ligation of the esophageal component of gastroesophageal varices type GOV 1 and 2) usually as an adjunct to surgical therapy.	('ligation', 'Var', (97, 105))	('esophageal component of gastroesophageal', 'Disease', 'MESH:D004941', (113, 153))	('gastroesophageal varices', 'Phenotype', 'HP:0002040', (137, 161))	('ulcers', 'Disease', 'MESH:D014456', (89, 95))	('esophageal component of gastroesophageal', 'Disease', (113, 153))	('ulcers', 'Disease', (89, 95))
860321	30002748	In duodenal tumors, a meaningful indication of IOG remains in D1-D4 early tumors and polyps feasible for endoscopic or partial surgical resection in order to navigate surgery.	('duodenal tumors', 'Disease', (3, 18))	('polyps', 'Disease', (85, 91))	('duodenal tumors', 'Disease', 'MESH:D004382', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('polyps', 'Disease', 'MESH:D011127', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('D1-D4', 'Var', (62, 67))	('duodenal tumors', 'Phenotype', 'HP:0006771', (3, 18))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Disease', (74, 80))
860339	29088777	Overexpression of CHD1L is associated with poor survival and aggressive tumor biology in esophageal carcinoma Esophageal carcinoma (EC) is a malignancy with high metastatic potential.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('esophageal carcinoma', 'Disease', (89, 109))	('aggressive tumor', 'Disease', (61, 77))	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('CHD1L', 'Gene', (18, 23))	('Esophageal carcinoma', 'Disease', (110, 130))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (89, 109))	('malignancy', 'Disease', (141, 151))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (110, 130))	('CHD1L', 'Gene', '9557', (18, 23))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (89, 109))	('Overexpression', 'Var', (0, 14))	('aggressive tumor', 'Disease', 'MESH:D001523', (61, 77))
860346	29088777	In addition, positive CHD1L expression was strongly related to advanced clinical stage (P<0.01), and lymph node metastasis (P<0.01) of EC.	('CHD1L', 'Gene', (22, 27))	('lymph node metastasis', 'CPA', (101, 122))	('positive', 'Var', (13, 21))	('CHD1L', 'Gene', '9557', (22, 27))	('expression', 'MPA', (28, 38))	('related', 'Reg', (52, 59))
860347	29088777	The Kaplan-Meier curve indicated that high expression of CHD1L may result in poor prognosis of EC patients (P<0.01), and multivariate analysis showed that CHD1L overexpression was an independent predictor of overall survival.	('CHD1L', 'Gene', '9557', (57, 62))	('poor', 'NegReg', (77, 81))	('high', 'Var', (38, 42))	('patients', 'Species', '9606', (98, 106))	('CHD1L', 'Gene', (155, 160))	('CHD1L', 'Gene', '9557', (155, 160))	('expression', 'MPA', (43, 53))	('CHD1L', 'Gene', (57, 62))
860351	29088777	Like other solid tumors, the development of EC often involves the acquisition of genetic alterations and corresponding changes in protein expression that modify normal growth control and survival pathways.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('changes', 'Reg', (119, 126))	('modify', 'Reg', (154, 160))	('normal growth control', 'MPA', (161, 182))	('genetic alterations', 'Var', (81, 100))	('solid tumors', 'Disease', (11, 23))	('survival', 'CPA', (187, 195))	('protein', 'Protein', (130, 137))	('solid tumors', 'Disease', 'MESH:D009369', (11, 23))
860364	29088777	Overexpression of CHD1L in EC was significantly associated with clinical stage (P=0.003) and lymph node metastasis (P<0.01).	('associated', 'Reg', (48, 58))	('CHD1L', 'Gene', (18, 23))	('CHD1L', 'Gene', '9557', (18, 23))	('Overexpression', 'Var', (0, 14))	('clinical stage', 'CPA', (64, 78))	('lymph node metastasis', 'CPA', (93, 114))
860367	29088777	A significantly shorter median overall survival was observed in patients with a high expression of CHD1L compared to patients with a low expression of CHD1L (35.2 vs. 40.6 months, P<0.01; Table 2, Figure 1C).	('CHD1L', 'Gene', (99, 104))	('patients', 'Species', '9606', (64, 72))	('CHD1L', 'Gene', '9557', (99, 104))	('CHD1L', 'Gene', (151, 156))	('CHD1L', 'Gene', '9557', (151, 156))	('shorter', 'NegReg', (16, 23))	('patients', 'Species', '9606', (117, 125))	('high expression', 'Var', (80, 95))	('overall survival', 'MPA', (31, 47))
860371	29088777	To study the biological effects of CHD1L, we transfected CHD1L siRNA and control-siRNA into EC cells to knock down endogenous CHD1L.	('CHD1L', 'Gene', '9557', (57, 62))	('CHD1L', 'Gene', (126, 131))	('CHD1L', 'Gene', '9557', (126, 131))	('knock down', 'Var', (104, 114))	('CHD1L', 'Gene', (35, 40))	('CHD1L', 'Gene', '9557', (35, 40))	('CHD1L', 'Gene', (57, 62))
860376	29088777	Therefore, we supposed that knocking down the expression of CHD1L would prevent the process of migration.	('CHD1L', 'Gene', '9557', (60, 65))	('CHD1L', 'Gene', (60, 65))	('knocking down', 'Var', (28, 41))	('prevent', 'NegReg', (72, 79))
860377	29088777	In the wound healing assay, the migration rate of the CHD1L-siRNA4 group was slower than that in the control group, indicating that the migration ability of the siRNA4 group was decreased by knocking down the expression of CHD1L compared to the control group.	('CHD1L', 'Gene', (54, 59))	('expression', 'MPA', (209, 219))	('decreased', 'NegReg', (178, 187))	('CHD1L', 'Gene', '9557', (54, 59))	('migration ability', 'CPA', (136, 153))	('CHD1L', 'Gene', (223, 228))	('CHD1L', 'Gene', '9557', (223, 228))	('knocking down', 'Var', (191, 204))
860386	29088777	In addition, amplification of CHD1L has been observed in various solid tumors, including breast cancer, colorectal cancer, bladder cancer, nasopharyngeal cancer, and HCC.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('nasopharyngeal cancer', 'Disease', (139, 160))	('breast cancer', 'Disease', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('amplification', 'Var', (13, 26))	('HCC', 'Disease', (166, 169))	('CHD1L', 'Gene', (30, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (139, 160))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('HCC', 'Phenotype', 'HP:0001402', (166, 169))	('CHD1L', 'Gene', '9557', (30, 35))	('observed', 'Reg', (45, 53))	('colorectal cancer', 'Disease', (104, 121))	('solid tumors', 'Disease', (65, 77))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (139, 160))	('solid tumors', 'Disease', 'MESH:D009369', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Disease', 'MESH:D001749', (123, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('bladder cancer', 'Disease', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
860402	29088777	The inhibition of apoptosis is one of the major mechanisms in cancer development and ultimately extends cell survival, allowing for the accumulation of genetic instability and mutations.	('mutations', 'Var', (176, 185))	('accumulation', 'PosReg', (136, 148))	('extends', 'PosReg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cell survival', 'CPA', (104, 117))	('apoptosis', 'CPA', (18, 27))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('inhibition', 'NegReg', (4, 14))	('genetic instability', 'MPA', (152, 171))
860443	28036265	One recent study described that aberrant spatial distribution of integrin alpha6 correlates with the poor outcome of ESCC patients.	('ESCC', 'Disease', (117, 121))	('integrin alpha6', 'Protein', (65, 80))	('patients', 'Species', '9606', (122, 130))	('aberrant spatial', 'Var', (32, 48))
860456	28036265	In order to study how integrin alpha6 promoted metastasis of ESCC cells, we then assessed the expression of p-Akt (T308) and p-FAK (Y397 and Y925) in 30-D cells transfected with siRNAs against integrin alpha6 under adherent condition (48 hr) or chemotaxis condition (1 hr); however, no detectable changes were observed in these three phosphorylated proteins (Figure 3A).	('T308', 'Chemical', '-', (115, 119))	('Akt', 'Gene', (110, 113))	('Y925', 'Var', (141, 145))	('T308', 'Var', (115, 119))	('FAK', 'Gene', (127, 130))	('FAK', 'Gene', '5747', (127, 130))	('metastasis', 'CPA', (47, 57))	('promoted', 'PosReg', (38, 46))	('Akt', 'Gene', '207', (110, 113))	('Y397', 'Var', (132, 136))
860469	28036265	Moreover, we cloned the presumed binding site of miR-92b from 3'-UTR of integrin alpha6 into the downstream of luciferase in pISO plasmid (ITGA6-3'UTR), and then mutated the binding site (ITGA6-3'UTR-mut) (Figure 4E).	('ITGA6', 'Gene', '3655', (188, 193))	('mutated', 'Var', (162, 169))	('miR-92b', 'Gene', '693235', (49, 56))	('ITGA6', 'Gene', (188, 193))	('miR-92b', 'Gene', (49, 56))	('binding', 'Interaction', (33, 40))	('ITGA6', 'Gene', '3655', (139, 144))	('ITGA6', 'Gene', (139, 144))
860478	28036265	Mechanistically, loss of integrin alpha6 reduces the activated Akt (T308) under the suspended condition, and suppression of Akt activation using LY294002 and Wortmannin hampers the motility capacity of ESCC cells.	('Wortmannin', 'Chemical', 'MESH:D000077191', (158, 168))	('hampers', 'NegReg', (169, 176))	('LY294002', 'Chemical', 'MESH:C085911', (145, 153))	('motility capacity of ESCC cells', 'CPA', (181, 212))	('Akt', 'Gene', (124, 127))	('reduces', 'NegReg', (41, 48))	('T308', 'Chemical', '-', (68, 72))	('suppression', 'NegReg', (109, 120))	('Akt', 'Gene', '207', (63, 66))	('activated', 'Protein', (53, 62))	('Akt', 'Gene', '207', (124, 127))	('loss', 'Var', (17, 21))	('integrin alpha6', 'Protein', (25, 40))	('Akt', 'Gene', (63, 66))
860483	28036265	However, the exact function of integrin alpha6 has not been fully clarified in this study; thereby, it is not clear that absence of integrin alpha6 inhibits formation of overt metastases through either disabling the initiation of proliferation or hampering the rapid growth of colonized ESCC cells.	('disabling', 'NegReg', (202, 211))	('initiation of proliferation', 'CPA', (216, 243))	('metastases', 'Disease', 'MESH:D009362', (176, 186))	('inhibits', 'NegReg', (148, 156))	('rapid growth of colonized ESCC cells', 'CPA', (261, 297))	('metastases', 'Disease', (176, 186))	('absence', 'Var', (121, 128))	('hampering', 'NegReg', (247, 256))
860491	28036265	For example, miR-92b overexpression or integrin alphaV deletion hampered the pulmonary arrest of ESCC cells, whereas knockdown of integrin alpha6 did not affect this process (Figure 2E).	('overexpression', 'PosReg', (21, 35))	('pulmonary arrest', 'Disease', (77, 93))	('miR-92b', 'Gene', (13, 20))	('deletion', 'Var', (55, 63))	('miR-92b', 'Gene', '693235', (13, 20))	('pulmonary arrest', 'Disease', 'MESH:D006323', (77, 93))	('hampered', 'NegReg', (64, 72))	('integrin', 'Gene', (39, 47))
860495	28036265	Akt pathway is crucial for viability, proliferation and motility of ESCC cells; loss of integrin alpha6 deactivates Akt of the malignant esophageal cells in suspension.	('loss', 'Var', (80, 84))	('Akt', 'Gene', '207', (116, 119))	('Akt', 'Gene', '207', (0, 3))	('integrin alpha6', 'Protein', (88, 103))	('deactivates', 'NegReg', (104, 115))	('Akt', 'Gene', (116, 119))	('Akt', 'Gene', (0, 3))
860502	28036265	Akt inhibitors, LY294002 and Wortmannin, were purchased from Cell Signaling Technology (Danvers, MA, USA) and the cells were pre-treated for 4 hr before the transwell assay.	('LY294002', 'Chemical', 'MESH:C085911', (16, 24))	('Akt', 'Gene', '207', (0, 3))	('Wortmannin', 'Chemical', 'MESH:D000077191', (29, 39))	('LY294002', 'Var', (16, 24))	('Akt', 'Gene', (0, 3))
860514	28036265	Luciferase activity was detected using Dual-Luciferase Reporter Assay (Promega, WI, USA) 24 hr after the pISO plasmids containing wild type or mutated binding site of miR-92b were transfected with miR-92b mimic, inhibitor or scramble oligos respectively into cells.	('miR-92b', 'Gene', (197, 204))	('activity', 'MPA', (11, 19))	('miR-92b', 'Gene', (167, 174))	('miR-92b', 'Gene', '693235', (197, 204))	('miR-92b', 'Gene', '693235', (167, 174))	('mutated', 'Var', (143, 150))
860515	28036265	In order to knockdown the expression of integrin alpha6, three siRNAs against this integrin and scramble oligo were ordered from Integrated DNA Technologies (IA, USA).	('expression', 'MPA', (26, 36))	('IA', 'Disease', 'MESH:C536041', (158, 160))	('knockdown', 'Var', (12, 21))
860548	28103500	The definitive diagnosis was of a pT1bN0M0 p-stage IA (UICC, 7th edition) basaloid squamous cell carcinoma of the esophagus.	('pT1bN0M0', 'Var', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('squamous cell carcinoma of the esophagus', 'Disease', (83, 123))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (83, 123))
860611	27958342	To investigate the chemopreventive potential and anticancer action of vitamin D, we conducted a longitudinal, observational study of supplementation with vitamin D for improving poor clinical outcomes in EC patients.	('vitamin D', 'Chemical', 'MESH:D014807', (154, 163))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('vitamin D', 'Chemical', 'MESH:D014807', (70, 79))	('supplementation', 'Var', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('improving', 'PosReg', (168, 177))	('poor clinical outcomes', 'MPA', (178, 200))
860628	27958342	However, vitamin D supplementation was only associated with DFS (p = 0.035; HR 0.611; 95% CI 0.386-0.966) but not related to OS (p = 0.308; HR 0.795; 95% CI 0.511-1.237).	('DFS', 'Disease', (60, 63))	('OS', 'Chemical', '-', (125, 127))	('vitamin D', 'Chemical', 'MESH:D014807', (9, 18))	('associated', 'Interaction', (44, 54))	('supplementation', 'Var', (19, 34))
860646	27958342	In addition to the influence of vitamin D on cancer risk, numerous reports showed that vitamin D sufficiency could improve survival in lung cancer, breast cancer, prostate cancer and follicular lymphoma.	('prostate cancer', 'Disease', (163, 178))	('lymphoma', 'Phenotype', 'HP:0002665', (194, 202))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('follicular lymphoma', 'Disease', (183, 202))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('lung cancer', 'Disease', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('vitamin D sufficiency', 'Phenotype', 'HP:0100512', (87, 108))	('survival', 'CPA', (123, 131))	('vitamin D', 'Chemical', 'MESH:D014807', (87, 96))	('sufficiency', 'Var', (97, 108))	('cancer', 'Disease', (140, 146))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('vitamin D', 'Chemical', 'MESH:D014807', (32, 41))	('improve', 'PosReg', (115, 122))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (155, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('prostate cancer', 'Disease', 'MESH:D011471', (163, 178))	('follicular lymphoma', 'Disease', 'MESH:D008224', (183, 202))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))
860649	27958342	They also reported that vitamin D supplementation in patients with nonmetastatic HER2+ breast cancer was associated with improved DFS but not related to OS.	('vitamin D', 'Chemical', 'MESH:D014807', (24, 33))	('patients', 'Species', '9606', (53, 61))	('vitamin', 'Gene', (24, 31))	('improved', 'PosReg', (121, 129))	('DFS', 'MPA', (130, 133))	('OS', 'Chemical', '-', (153, 155))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('HER2', 'Gene', (81, 85))	('supplementation', 'Var', (34, 49))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('HER2', 'Gene', '2064', (81, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
860822	26622818	DFS (chi2=8.277, P=0.0040), and OS (chi2=8.203, P=0.0042) curves were also affected by the P53/Cox-2 co-expression status, with a two-year OS of 75.0% for the double-positive group compared with 85.6% for the other groups, and a DFS of 63.9% in double-positive patients compared with 82.8% in the other groups (Fig.	('P53', 'Gene', (91, 94))	('P53', 'Gene', '7157', (91, 94))	('affected', 'Reg', (75, 83))	('Cox-2', 'Gene', '4513', (95, 100))	('Cox-2', 'Gene', (95, 100))	('patients', 'Species', '9606', (261, 269))	('double-positive', 'Var', (245, 260))
860833	26622818	However, mtp53 acts as a proto-oncogene by promoting the occurrence and development of tumor cells.	('men', 'Species', '9606', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('occurrence', 'CPA', (57, 67))	('mtp53', 'Var', (9, 14))	('tumor', 'Disease', (87, 92))	('promoting', 'PosReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
860835	26622818	However, when cells become damaged or mutated by various factors, P53 expression increases significantly.	('mutated', 'Var', (38, 45))	('P53', 'Gene', (66, 69))	('expression', 'MPA', (70, 80))	('P53', 'Gene', '7157', (66, 69))	('increases', 'PosReg', (81, 90))
860836	26622818	Mtp53, instead of inhibiting tumor cell proliferation, promotes cell proliferation and eventually alters the cellular phenotype in a malignant manner.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cell proliferation', 'CPA', (64, 82))	('alters', 'Reg', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('promotes', 'PosReg', (55, 63))	('tumor', 'Disease', (29, 34))	('inhibiting', 'NegReg', (18, 28))	('Mtp53', 'Var', (0, 5))
860837	26622818	Previous studies have demonstrated that the P53 gene mutation is associated with poor prognosis in various types of cancer, including colon, breast, lung, gastric and esophageal cancer.	('colon', 'Disease', (134, 139))	('P53', 'Gene', (44, 47))	('mutation', 'Var', (53, 61))	('breast', 'Disease', (141, 147))	('esophageal cancer', 'Disease', 'MESH:D004938', (167, 184))	('P53', 'Gene', '7157', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (116, 122))	('gastric', 'Disease', 'MESH:D013274', (155, 162))	('gastric', 'Disease', (155, 162))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (178, 184))	('lung', 'Disease', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal cancer', 'Disease', (167, 184))
860838	26622818	Overexpression of P53 in esophageal tumor cells increases their potential to invade tissue and blood vessels, and promotes the local recurrence and metastasis of esophageal cancer, leading the progression towards late pathological staging and poor prognosis.	('local recurrence', 'CPA', (127, 143))	('increases', 'PosReg', (48, 57))	('metastasis of esophageal cancer', 'Disease', (148, 179))	('esophageal tumor', 'Disease', 'MESH:D004938', (25, 41))	('esophageal tumor', 'Disease', (25, 41))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (148, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('late pathological staging', 'CPA', (213, 238))	('P53', 'Gene', (18, 21))	('Overexpression', 'Var', (0, 14))	('promotes', 'PosReg', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('P53', 'Gene', '7157', (18, 21))	('esophageal tumor', 'Phenotype', 'HP:0100751', (25, 41))
860870	26622818	Mutations in the P53 gene are induced by various factors and lead to a loss of P53 tumor cell growth-inhibiting functions.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('P53', 'Gene', (17, 20))	('P53', 'Gene', '7157', (17, 20))	('Mutations', 'Var', (0, 9))	('P53', 'Gene', (79, 82))	('loss', 'NegReg', (71, 75))	('P53', 'Gene', '7157', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
860871	26622818	Mutated P53 promotes tumor cell proliferation, inhibits apoptosis and promotes the occurrence and development of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('P53', 'Gene', '7157', (8, 11))	('tumor', 'Disease', (21, 26))	('development', 'CPA', (98, 109))	('promotes', 'PosReg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('men', 'Species', '9606', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('promotes', 'PosReg', (12, 20))	('P53', 'Gene', (8, 11))	('apoptosis', 'CPA', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('Mutated', 'Var', (0, 7))	('esophageal cancer', 'Disease', (113, 130))	('inhibits', 'NegReg', (47, 55))
860875	26622818	Song et al noted that blocking Cox-2 expression using small interfering RNA reinforced P53 transcriptional activity.	('Cox-2', 'Gene', (31, 36))	('reinforced', 'PosReg', (76, 86))	('transcriptional activity', 'MPA', (91, 115))	('P53', 'Gene', (87, 90))	('Cox-2', 'Gene', '4513', (31, 36))	('P53', 'Gene', '7157', (87, 90))	('small interfering', 'Var', (54, 71))
860883	26622818	In addition, mutated P53 proteins may coexist with Cox-2 in the same cells and could synergize to inhibit cell apoptosis, thereby enhancing the malignant behavior of tumors and resulting in a significantly poorer prognosis.	('Cox-2', 'Gene', '4513', (51, 56))	('Cox-2', 'Gene', (51, 56))	('enhancing', 'PosReg', (130, 139))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('poorer', 'NegReg', (206, 212))	('cell apoptosis', 'CPA', (106, 120))	('P53', 'Gene', (21, 24))	('inhibit', 'NegReg', (98, 105))	('P53', 'Gene', '7157', (21, 24))	('prognosis', 'CPA', (213, 222))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('mutated', 'Var', (13, 20))	('proteins', 'Protein', (25, 33))
860890	26622818	P53 and Cox-2 co-expression was associated with increased malignant behavior of tumors and predicted a poor prognosis.	('increased', 'PosReg', (48, 57))	('Cox-2', 'Gene', '4513', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('Cox-2', 'Gene', (8, 13))	('co-expression', 'Var', (14, 27))	('P53', 'Gene', (0, 3))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('P53', 'Gene', '7157', (0, 3))
860903	25009644	The inhibition of mTOR by Rap was found to effectively inhibit the proliferation, survival and radiation-induced DNA damage repair of the Eca109 cells following irradiation, as well as promoting radiation-induced apoptosis, thereby increasing the radiosensitivity of the esophageal carcinoma Eca109 cells.	('radiosensitivity', 'CPA', (247, 263))	('increasing', 'PosReg', (232, 242))	('esophageal carcinoma', 'Disease', (271, 291))	('mTOR', 'Gene', (18, 22))	('mTOR', 'Gene', '2475', (18, 22))	('survival', 'CPA', (82, 90))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (271, 291))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (271, 291))	('Rap', 'Gene', (26, 29))	('inhibition', 'Var', (4, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('proliferation', 'CPA', (67, 80))	('radiation-induced DNA', 'CPA', (95, 116))	('radiation-induced apoptosis', 'CPA', (195, 222))	('promoting', 'PosReg', (185, 194))	('inhibit', 'NegReg', (55, 62))	('Rap', 'Gene', '74370', (26, 29))
860907	25009644	In addition, it has been shown that mTOR is important for the oncogenic transformation induced specifically by PI3K and Akt, components of a pathway that has also been indicated to be involved in tumorigenesis, which is becoming an important target for cancer treatment.	('tumor', 'Disease', (196, 201))	('oncogenic transformation', 'CPA', (62, 86))	('mTOR', 'Gene', (36, 40))	('Akt', 'Gene', '207', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('mTOR', 'Gene', '2475', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('PI3K', 'Var', (111, 115))	('cancer', 'Disease', (253, 259))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('Akt', 'Gene', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
860917	25009644	However, whether mTOR inhibition enhances radiation-induced DNA damage in esophageal carcinoma cells remains unclear.	('inhibition', 'Var', (22, 32))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (74, 94))	('enhances', 'PosReg', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('esophageal carcinoma', 'Disease', (74, 94))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (74, 94))	('radiation-induced DNA damage', 'MPA', (42, 70))
860974	25009644	Two repair pathways have been identified: DNA non-homologous end-joining (NHEJ) involving DNA-protein kinases, including Ku70, Ku80 and DNA-PKcs; and homologous recombination involving the ataxia telangiectasia mutated protein.	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (189, 210))	('Ku80', 'Gene', '7520', (127, 131))	('telangiectasia', 'Phenotype', 'HP:0001009', (196, 210))	('Ku70', 'Gene', (121, 125))	('DNA-PKcs', 'Gene', '5591', (136, 144))	('ataxia', 'Phenotype', 'HP:0001251', (189, 195))	('ataxia telangiectasia', 'Disease', (189, 210))	('homologous recombination', 'Var', (150, 174))	('Ku80', 'Gene', (127, 131))	('DNA-PKcs', 'Gene', (136, 144))	('Ku70', 'Gene', '2547', (121, 125))
860987	25009644	It is possible that the combination of mTOR inhibition and radiation may improve the efficacy of tumor radiotherapy via a dual mechanism that promotes radiation-induced tumor cell cytotoxicity and inhibits tumor angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('inhibition', 'Var', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (206, 211))	('cytotoxicity', 'Disease', 'MESH:D064420', (180, 192))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (97, 102))	('mTOR', 'Gene', (39, 43))	('inhibits', 'NegReg', (197, 205))	('mTOR', 'Gene', '2475', (39, 43))	('tumor', 'Disease', (169, 174))	('promotes', 'PosReg', (142, 150))	('improve', 'PosReg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('cytotoxicity', 'Disease', (180, 192))
860988	25009644	Therefore, whether mTOR inhibition enhances the radiosensitivity of esophageal carcinoma in vivo also requires further study.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (68, 88))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (68, 88))	('radiosensitivity', 'MPA', (48, 64))	('mTOR', 'Gene', '2475', (19, 23))	('mTOR', 'Gene', (19, 23))	('inhibition', 'Var', (24, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('enhances', 'PosReg', (35, 43))	('esophageal carcinoma', 'Disease', (68, 88))
860992	22582080	In addition, microRNAs have been associated with cancer progression and outcome.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('associated', 'Reg', (33, 43))	('microRNAs', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
860997	22582080	Possible mechanisms of altered microRNA expression include defective microRNA processing or post-transcriptional regulation, germ-line or somatic mutation and epigenetic changes such as methylation.	('methylation', 'Var', (186, 197))	('expression', 'Species', '29278', (40, 50))	('microRNA processing', 'MPA', (69, 88))	('defective', 'NegReg', (59, 68))	('altered', 'Reg', (23, 30))	('microRNA expression', 'MPA', (31, 50))	('post-transcriptional regulation', 'MPA', (92, 123))
861002	22582080	Various techniques have enabled researchers to measure microRNA levels and determine how alterations in their expression level are associated with particular phenotypes and how they can be clinically utilized.	('expression level', 'MPA', (110, 126))	('microRNA levels', 'MPA', (55, 70))	('alterations', 'Var', (89, 100))	('expression', 'Species', '29278', (110, 120))
861012	22582080	On the other hand, changes in microRNA expression may be a downstream effect of potent oncogenes or tumor suppressors in the carcinogenesis process, such as the modulation of miR-34 by p53 in pancreatic cancer.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('modulation', 'Var', (161, 171))	('p53', 'Gene', (185, 188))	('p53', 'Gene', '7157', (185, 188))	('changes', 'Reg', (19, 26))	('tumor', 'Disease', (100, 105))	('microRNA expression', 'MPA', (30, 49))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (192, 209))	('miR-34', 'Gene', (175, 181))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('miR-34', 'Gene', '407040', (175, 181))	('expression', 'Species', '29278', (39, 49))	('carcinogenesis', 'Disease', (125, 139))	('pancreatic cancer', 'Disease', 'MESH:D010190', (192, 209))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('pancreatic cancer', 'Disease', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
861016	22582080	Recent reports have shown that loss p53 can lead to reduced expression of miR-143 and miR-145, a signaling network that targets the oncogene c-Myc and affect colon cancer growth.	('miR', 'Gene', (74, 77))	('expression', 'MPA', (60, 70))	('affect', 'Reg', (151, 157))	('Myc', 'Gene', '4609', (143, 146))	('miR', 'Gene', '220972', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('reduced', 'NegReg', (52, 59))	('loss', 'Var', (31, 35))	('p53', 'Gene', (36, 39))	('Myc', 'Gene', (143, 146))	('p53', 'Gene', '7157', (36, 39))	('miR', 'Gene', (86, 89))	('miR', 'Gene', '220972', (86, 89))	('colon cancer', 'Phenotype', 'HP:0003003', (158, 170))	('colon cancer', 'Disease', 'MESH:D015179', (158, 170))	('expression', 'Species', '29278', (60, 70))	('colon cancer', 'Disease', (158, 170))
861032	22582080	It has been suggested that loss of p53 and inflammatory stimuli induce miR-21.	('induce', 'Reg', (64, 70))	('loss', 'Var', (27, 31))	('p53', 'Gene', '7157', (35, 38))	('p53', 'Gene', (35, 38))	('miR-21', 'Gene', (71, 77))
861035	22582080	MiR-34, for example, plays tumor suppressive roles including the induction of senescence, apoptosis and cell cycle arrest and is frequently downregulated in gastroenteroIogical cancers through transcriptional degregulation and chromosomal instability.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('downregulated', 'NegReg', (140, 153))	('chromosomal instability', 'Var', (227, 250))	('tumor', 'Disease', (27, 32))	('MiR-34', 'Gene', (0, 6))	('gastroenteroIogical cancers', 'Disease', 'MESH:D009369', (157, 184))	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('chromosomal instability', 'Phenotype', 'HP:0040012', (227, 250))	('arrest', 'Disease', (115, 121))	('senescence', 'CPA', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('apoptosis', 'CPA', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('MiR-34', 'Gene', '407040', (0, 6))	('gastroenteroIogical cancers', 'Disease', (157, 184))
861036	22582080	In fact, the expression of mir-34b and mir-34c is downregulated through promoter methylation in colon cancer.	('mir', 'Gene', '220972', (39, 42))	('expression', 'Species', '29278', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('expression', 'MPA', (13, 23))	('promoter methylation', 'Var', (72, 92))	('mir', 'Gene', '220972', (27, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('mir', 'Gene', (39, 42))	('mir', 'Gene', (27, 30))	('downregulated', 'NegReg', (50, 63))	('colon cancer', 'Disease', (96, 108))
861077	22582080	In addition, locked-nucleic-acid antisense oligonucleotides (LNAs) have been designed to increase stability and have the benefits of being highly aqueous with reduced toxicity in-vivo.	('toxicity', 'Disease', 'MESH:D064420', (167, 175))	('toxicity', 'Disease', (167, 175))	('oligonucleotides', 'Chemical', 'MESH:D009841', (43, 59))	('locked-nucleic-acid', 'Var', (13, 32))	('stability', 'MPA', (98, 107))	('increase', 'PosReg', (89, 97))
861087	22582080	Several microRNAs have been introduced to cells via this methodology, including miR-34, miR-15, miR-16 and let-7.	('miR', 'Gene', (88, 91))	('miR', 'Gene', '220972', (80, 83))	('miR', 'Gene', (80, 83))	('miR-34', 'Gene', (80, 86))	('miR-34', 'Gene', '407040', (80, 86))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('let-7', 'Var', (107, 112))	('miR', 'Gene', '220972', (88, 91))
861116	18619919	Progression to cancer occurred in 15% of PDT-treated subjects, as compared with 29% of subjects receiving acid suppression alone.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('PDT-treated', 'Var', (41, 52))
861179	18619919	Esophageal stricture develops in 23-27% of patients following porfimer sodium PDT for HGD or IMC, and may require multiple endoscopic dilations for palliation.	('Esophageal stricture', 'Phenotype', 'HP:0002043', (0, 20))	('patients', 'Species', '9606', (43, 51))	('Esophageal stricture', 'Disease', (0, 20))	('porfimer', 'Var', (62, 70))
861182	18619919	Alternatively, in a prospective study of HGD patients receiving PDT, 15% developed cancer over 5-year follow-up.	('PDT', 'Var', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('developed', 'Reg', (73, 82))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
861191	18619919	Variability in performance or interpretation of histopathologic, endoscopic, or imaging findings may impact accuracy of pre-treatment cancer stage.	('impact', 'Reg', (101, 107))	('Variability', 'Var', (0, 11))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
861290	32060757	In principle, D2 lymphadenectomy is indicated for cN+ or >= cT2 tumors and a D1 or D1+ for cT1N0 tumors.	('cN+', 'Var', (50, 53))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cT2', 'Gene', (60, 63))	('cT2', 'Gene', '386757', (60, 63))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
861313	32060757	In case of PPG, the hepatic branch should be preserved to maintain the pyloric function (CQ2).	('PPG', 'Var', (11, 14))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('PPG', 'Chemical', '-', (11, 14))	('pyloric function', 'MPA', (71, 87))
861338	32060757	In addition, when more than one histological type is found in a tumor, all histological types are to be recorded in the order of quantitative predominance, e.g., tub2 > tub1.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('tub2 > tub1', 'Var', (162, 173))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
861359	32060757	When cancer is with ulcerative findings (UL1), the resection is still classified as eCuraA when all of the following conditions are fulfilled: en bloc resection, tumor size <= 3 cm, histologically differentiated type-dominant, pT1a, HM0, VM0, Ly0, V0.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('T1a', 'Gene', '10630', (228, 231))	('<= 3', 'Var', (173, 177))	('T1a', 'Gene', (228, 231))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Disease', (162, 167))	('pT1', 'Gene', (227, 230))	('cancer', 'Disease', (5, 11))	('VM0', 'Var', (238, 241))	('C', 'Chemical', 'MESH:D002244', (85, 86))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('HM0', 'Var', (233, 236))	('Ly0', 'Var', (243, 246))	('ulcer', 'Disease', 'MESH:D014456', (20, 25))	('ulcer', 'Disease', (20, 25))	('pT1', 'Gene', '58492', (227, 230))
861360	32060757	The resection is classified as endoscopic curability B (eCuraB) for histologically undifferentiated type-dominant when all of the following conditions are fulfilled: UL0, en bloc resection, pT1a, HM0, VM0, Ly0, V0, tumor size <= 2 cm.	('Ly0', 'Var', (206, 209))	('T1a', 'Gene', (191, 194))	('pT1', 'Gene', '58492', (190, 193))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('T1a', 'Gene', '10630', (191, 194))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('VM0', 'Var', (201, 204))	('pT1', 'Gene', (190, 193))	('tumor', 'Disease', (215, 220))	('HM0', 'Var', (196, 199))
861371	32060757	When the lesion is differentiated type of <= 3 cm and either UL1or pT1b1 (SM1), size of the residual mucosal lesion should be reassessed by endoscopy.	('pT1', 'Gene', '58492', (67, 70))	('pT1', 'Gene', (67, 70))	('UL1or', 'Var', (61, 66))	('SM1', 'Gene', '7911', (74, 77))	('SM1', 'Gene', (74, 77))
861419	32060757	The definition of HER2 positive in the ToGA trial had been either IHC3+ or FISH positive.	('IHC3+', 'Var', (66, 71))	('HER2', 'Gene', '2064', (18, 22))	('C', 'Chemical', 'MESH:D002244', (68, 69))	('HER2', 'Gene', (18, 22))
861465	32060757	CQ3 Is proximal gastrectomy recommended for cT1N0 tumor in the upper-third stomach when EMR or ESD is not indicated?	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cT1N0', 'Var', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('tumor', 'Disease', (50, 55))
861480	32060757	CQ10 Is staging laparoscopy recommended to decide the treatment plan for gastric cancer?	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('CQ10', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('gastric cancer', 'Disease', (73, 87))
861485	32060757	CQ12 Is Helicobacter pylori eradication after endoscopic resection recommended for a Helicobacter pylori-positive gastric cancer patient?	('gastric cancer', 'Disease', (114, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('Helicobacter pylori', 'Species', '210', (8, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('CQ12', 'Var', (0, 4))	('Helicobacter pylori', 'Species', '210', (85, 104))	('patient', 'Species', '9606', (129, 136))
861489	32060757	CQ14 Are the taxanes recommended for the first-line treatment of AGC?	('AGC', 'Disease', (65, 68))	('C', 'Chemical', 'MESH:D002244', (67, 68))	('taxanes', 'Chemical', 'MESH:D043823', (13, 20))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('CQ14', 'Var', (0, 4))
861495	32060757	CQ17 Is administration of trastuzumab beyond progression recommended in the second-line treatment of HER2-positive AGC?	('CQ17', 'Var', (0, 4))	('HER2', 'Gene', (101, 105))	('C', 'Chemical', 'MESH:D002244', (117, 118))	('HER2', 'Gene', '2064', (101, 105))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('trastuzumab', 'Chemical', 'MESH:D000068878', (26, 37))
861503	32060757	CQ21 Is chemotherapy recommended for patients with impaired oral intake or massive ascites due to extensive peritoneal disease?	('impaired oral intake', 'Disease', (51, 71))	('patients', 'Species', '9606', (37, 45))	('CQ21', 'Var', (0, 4))	('ascites', 'Disease', (83, 90))	('ascites', 'Phenotype', 'HP:0001541', (83, 90))	('ascites', 'Disease', 'MESH:D001201', (83, 90))	('impaired oral intake', 'Disease', 'MESH:D000855', (51, 71))	('C', 'Chemical', 'MESH:D002244', (0, 1))
861513	32060757	CQ25 Is postoperative adjuvant chemotherapy recommended for Stage IV gastric cancer after R0 resection?	('gastric cancer', 'Disease', (69, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('CQ25', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('C', 'Chemical', 'MESH:D002244', (0, 1))
861515	32060757	CQ26 Is neoadjuvant chemotherapy recommended for resectable advanced gastric cancer?	('gastric cancer', 'Disease', (69, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('CQ26', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('C', 'Chemical', 'MESH:D002244', (0, 1))
861521	30006931	With sub-optimal detection sensitivity of existing imaging techniques, we propose a methylation signature which identifies patients with LNM with greater accuracy.	('patients', 'Species', '9606', (123, 131))	('LNM', 'Disease', (137, 140))	('methylation', 'Var', (84, 95))
861525	30006931	In conclusion, our novel methylation signature is a powerful biomarker that identifies LNM status robustly and is also associated with worse prognosis in ESCC patients.	('methylation', 'Var', (25, 36))	('patients', 'Species', '9606', (159, 167))	('ESCC', 'Disease', (154, 158))	('associated', 'Reg', (119, 129))
861536	30006931	Epigenetic alterations are recognized as key contributors to cancer initiation and progression .	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
861556	30006931	Using stringent criterion of at least 20% hyper or hypo methylation in LNM (+) vs. LNM (-) patients, we identified 22 hyper-methylated and 1 hypo-methylated probe (depicted by red and blue dots respectively in Figure 1B).	('hyper-methylated', 'Var', (118, 134))	('patients', 'Species', '9606', (91, 99))	('hypo methylation', 'Var', (51, 67))	('hyper', 'Var', (42, 47))
861564	30006931	Two probes were at the 3' UTR (cg20693607-EPHB3 and cg24505892-LBX1) while two of the remaining probes were located near long intergenic non-coding (LINC) RNA (cg22352818-LOC105373496 and cg21530266-LINC01391).	('LBX1', 'Gene', '10660', (63, 67))	('EPHB3', 'Gene', '2049', (42, 47))	('LINC01391', 'Gene', (199, 208))	('LINC01391', 'Gene', '103344930', (199, 208))	('cg22352818-LOC105373496', 'Var', (160, 183))	('EPHB3', 'Gene', (42, 47))	('LBX1', 'Gene', (63, 67))
861565	30006931	Overall, we observed that three out of the ten methylated probes were associated with homeobox family of genes (EVX1, LBX1 and HOXB8).	('methylated probes', 'Var', (47, 64))	('EVX1', 'Gene', (112, 116))	('LBX1', 'Gene', (118, 122))	('LBX1', 'Gene', '10660', (118, 122))	('EVX1', 'Gene', '2128', (112, 116))	('associated', 'Reg', (70, 80))	('HOXB8', 'Gene', '3218', (127, 132))	('HOXB8', 'Gene', (127, 132))
861589	31892989	Upon silencing HIF-1alpha by siRNA, the invasion and migration ability of ESCC cells were significantly inhibited, which could be restored by the overexpression of SP1.	('HIF-1alpha', 'Protein', (15, 25))	('silencing', 'Var', (5, 14))	('inhibited', 'NegReg', (104, 113))	('rat', 'Species', '10116', (56, 59))
861606	31892989	This study showed that the HIF-1alpha protein level was higher in cancer tissues than in adjacent normal tissues, and the expression of HIF-1alpha was correlated with tumor metastasis, recurrence and poor prognosis in patients with esophageal cancer.	('tumor metastasis', 'Disease', (167, 183))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('expression', 'Var', (122, 132))	('correlated with', 'Reg', (151, 166))	('cancer', 'Disease', (243, 249))	('recurrence', 'CPA', (185, 195))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('higher', 'PosReg', (56, 62))	('tumor metastasis', 'Disease', 'MESH:D009362', (167, 183))	('esophageal cancer', 'Disease', (232, 249))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('HIF-1alpha', 'Gene', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('HIF-1alpha protein level', 'MPA', (27, 51))	('cancer', 'Disease', (66, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (232, 249))
861631	31892989	After washed with Tris buffered saline Tween-20 buffer (TBST; pH 7.5; 10 mM Tris, 150 mM NaCl and 0.1% Tween 20) for 10 min x 3 times, PVDF membrane was blocked in 5% skim milk for 1 hour, then incubated overnight at 4  C with primary antibodies (anti-beta-ACTIN, anti-HIF-1alpha or anti-SP1; 1:1000, CST, USA).	('anti-HIF-1alpha', 'Var', (264, 279))	('Tris', 'Chemical', '-', (18, 22))	('anti-SP1; 1:1000', 'Var', (283, 299))	('CST', 'Gene', '106478911', (301, 304))	('Tris buffered saline Tween-20 buffer', 'Chemical', '-', (18, 54))	('NaCl', 'Chemical', 'MESH:D012965', (89, 93))	('Tris', 'Chemical', '-', (76, 80))	('beta-ACTIN', 'Gene', (252, 262))	('Tween 20', 'Chemical', 'MESH:D011136', (103, 111))	('PVDF', 'Chemical', 'MESH:C024865', (135, 139))	('TBST', 'Chemical', '-', (56, 60))	('CST', 'Gene', (301, 304))	('beta-ACTIN', 'Gene', '728378', (252, 262))
861648	31892989	Kaplan-Meier analysis showed that compared to those with lower HIF-1alpha expression, the patients with higher HIF-1alpha expression have higher rates of early metastasis and recurrence (estimated 3-year recurrence rate70.83% vs 45.46%, Figure 1b) and lower survival (estimated 5-years survival rate 8.15% vs20.25%, Figure 1c).	('HIF-1alpha', 'Var', (111, 121))	('recurrence', 'CPA', (175, 185))	('rat', 'Species', '10116', (215, 218))	('early metastasis', 'CPA', (154, 170))	('rat', 'Species', '10116', (295, 298))	('higher', 'PosReg', (104, 110))	('higher', 'PosReg', (138, 144))	('patients', 'Species', '9606', (90, 98))	('rat', 'Species', '10116', (145, 148))	('survival', 'MPA', (258, 266))	('lower', 'NegReg', (252, 257))
861662	31892989	As shown in Table 2, high expression level of SP1 was significantly associated with tumor metastasis and recurrence (Table 2).	('tumor metastasis', 'Disease', 'MESH:D009362', (84, 100))	('tumor metastasis', 'Disease', (84, 100))	('associated', 'Reg', (68, 78))	('SP1', 'Gene', (46, 49))	('recurrence', 'CPA', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('high', 'Var', (21, 25))
861668	31892989	Patients with high expression of both HIF-1alpha and SP1 were more likely to have tumor metastasis (Table 4).	('tumor metastasis', 'Disease', 'MESH:D009362', (82, 98))	('tumor metastasis', 'Disease', (82, 98))	('SP1', 'Gene', (53, 56))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('high expression', 'Var', (14, 29))	('HIF-1alpha', 'Protein', (38, 48))
861669	31892989	Kaplan-Meier analysis estimated that patients with high expression of both HIF-1alpha and SP1 had a higher 3-year recurrence rate of 75.0% (Figure 4h), and lower 5-year survival rate of 12.11% (Figure 4i), compared with the others.	('SP1', 'Gene', (90, 93))	('rat', 'Species', '10116', (125, 128))	('patients', 'Species', '9606', (37, 45))	('HIF-1alpha', 'Gene', (75, 85))	('higher', 'PosReg', (100, 106))	('high expression', 'Var', (51, 66))	('rat', 'Species', '10116', (178, 181))	('5-year survival', 'CPA', (162, 177))	('lower', 'NegReg', (156, 161))	('recurrence', 'CPA', (114, 124))
861681	31892989	T.Kurokawa et al showed that high expression of HIF-1alpha was positively correlated with tumor metastasis and poor prognosis in patients with ESCC.	('high', 'Var', (29, 33))	('patients', 'Species', '9606', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ESCC', 'Disease', (143, 147))	('tumor metastasis', 'Disease', 'MESH:D009362', (90, 106))	('tumor metastasis', 'Disease', (90, 106))	('correlated', 'Reg', (74, 84))	('HIF-1alpha', 'Protein', (48, 58))
861687	31892989	In this study, we found that SP1 is highly expressed in ESCC, and accelerates tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (78, 94))	('tumor metastasis', 'Disease', (78, 94))	('rat', 'Species', '10116', (72, 75))	('SP1', 'Var', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('accelerates', 'PosReg', (66, 77))
861795	30766610	These results further demonstrated that knockdown of CCNA2 could strengthen the anti-tumor effects of miR-219-5p in ESCC cells.	('tumor', 'Disease', (85, 90))	('miR', 'Gene', '220972', (102, 105))	('CCNA2', 'Gene', '890', (53, 58))	('miR', 'Gene', (102, 105))	('ESCC', 'Disease', (116, 120))	('knockdown', 'Var', (40, 49))	('CCNA2', 'Gene', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('strengthen', 'PosReg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
861811	30766610	The effect of miR-219-5p on ESCC cell behavior could be potentiated by silencing CCNA2.	('CCNA2', 'Gene', '890', (81, 86))	('silencing', 'Var', (71, 80))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('CCNA2', 'Gene', (81, 86))	('ESCC', 'Disease', (28, 32))
861819	30766610	High CCNA2 immunopositivity is associated with tumor development and poor survival rate of ESCC patients.	('survival', 'CPA', (74, 82))	('CCNA2', 'Gene', '890', (5, 10))	('High', 'Var', (0, 4))	('ESCC', 'Disease', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('CCNA2', 'Gene', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('patients', 'Species', '9606', (96, 104))	('poor', 'NegReg', (69, 73))	('tumor', 'Disease', (47, 52))
861820	30766610	Our study demonstrated that knockdown of CCNA2 imitated cell cycle arrest at G2/M phase, induced by overexpression of miR-219-5p.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('CCNA2', 'Gene', (41, 46))	('cell cycle arrest at G2/M phase', 'CPA', (56, 87))	('miR', 'Gene', '220972', (118, 121))	('knockdown', 'Var', (28, 37))	('CCNA2', 'Gene', '890', (41, 46))	('miR', 'Gene', (118, 121))	('overexpression', 'PosReg', (100, 114))
861835	29315304	Patients with PTFE-TIPS were at significantly lower risk for variceal re-bleeding than patients with bare metal stents (14% vs. 37%, OR:0.259; p<0.001) and had less need for stent revision (21% vs. 37%; p = 0.024).	('variceal re-bleeding', 'MPA', (61, 81))	('PTFE-TIPS', 'Var', (14, 23))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (46, 51))	('patients', 'Species', '9606', (87, 95))	('PTFE', 'Chemical', '-', (14, 18))
861836	29315304	Patients with PTFE stent grafts showed lower mortality than patients with bare stents after 1 year (19% vs. 31%, p = 0.020) and 2 years (29% vs. 40%; p = 0.041) after TIPS implantation.	('PTFE', 'Var', (14, 18))	('patients', 'Species', '9606', (60, 68))	('Patients', 'Species', '9606', (0, 8))	('PTFE', 'Chemical', '-', (14, 18))	('lower', 'NegReg', (39, 44))	('mortality', 'MPA', (45, 54))
861881	29315304	While MELD-Na scores were similar between groups, MELD was significantly higher in patients who received bare stents as compared to patients who received ePTFE stents (median 12.7 vs. 11.2 points, p = 0.001), as were its components creatinine (median 0.97 mg/dl vs. 0.87 mg/dl, p<0.001) and INR (1.42 vs. 1.30, p = 0.004), but not bilirubin (median 1.55 vs. 1.35 mg/dl, p = 0.191).	('INR', 'MPA', (291, 294))	('ePTFE stents', 'Chemical', '-', (154, 166))	('MELD', 'MPA', (50, 54))	('creatinine', 'MPA', (232, 242))	('bare stents', 'Var', (105, 116))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (132, 140))	('higher', 'PosReg', (73, 79))
861882	29315304	Of note, significantly more patients in the ePTFE group than in the bare stent group received NSBB prophylaxis prior to TIPS implantation (ePTFE: 27% vs. bare metal: 11%; p = 0.001).	('NSBB prophylaxis', 'Disease', (94, 110))	('ePTFE', 'Chemical', '-', (44, 49))	('ePTFE', 'Var', (44, 49))	('patients', 'Species', '9606', (28, 36))	('ePTFE', 'Chemical', '-', (139, 144))
861883	29315304	A total of 67 patients (23%) had at least one re-bleeding episode following TIPS-implantation, which occurred significantly less often in patients with ePTFE stents (n = 23, 14%) than in patients with bare stents (n = 44, 37%) (p<0.001 on log-rank analysis).	('patients', 'Species', '9606', (187, 195))	('bleeding episode', 'Phenotype', 'HP:0001892', (49, 65))	('ePTFE stents', 'Var', (152, 164))	('ePTFE stents', 'Chemical', '-', (152, 164))	('patients', 'Species', '9606', (14, 22))	('less', 'NegReg', (124, 128))	('patients', 'Species', '9606', (138, 146))
861905	29315304	Patients treated with ePTFE stents also showed significantly lower in-hospital and 1-year mortality in univariate analysis than patients receiving bare metal stents.	('lower', 'NegReg', (61, 66))	('ePTFE stents', 'Chemical', '-', (22, 34))	('Patients', 'Species', '9606', (0, 8))	('ePTFE stents', 'Var', (22, 34))	('patients', 'Species', '9606', (128, 136))
861907	29315304	The MELD score was higher in patients with bare metal stents, while more ePTFE patients had been treated with standard of care NSBB plus EBL prior to TIPS implantation.	('patients', 'Species', '9606', (29, 37))	('higher', 'PosReg', (19, 25))	('bare metal', 'Var', (43, 53))	('patients', 'Species', '9606', (79, 87))	('ePTFE', 'Chemical', '-', (73, 78))	('MELD score', 'MPA', (4, 14))
861911	29315304	A survival benefit for TIPS was also not confirmed in the competing risk analysis that still demonstrated a significantly lower risk of re-bleeding with ePTFE TIPS (see S2 Fig).	('ePTFE', 'Gene', (153, 158))	('lower', 'NegReg', (122, 127))	('ePTFE', 'Chemical', '-', (153, 158))	('TIPS', 'Var', (159, 163))
862017	26384302	The proliferation and tumorigenicity of ESCC cells were dramatically induced by SOX9 overexpression but were inhibited by SOX9 knockdown both in vitro and in vivo.	('ESCC', 'Disease', (40, 44))	('proliferation', 'CPA', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('inhibited', 'NegReg', (109, 118))	('induced', 'PosReg', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('SOX9', 'Gene', (80, 84))	('tumor', 'Disease', (22, 27))	('overexpression', 'Var', (85, 99))
862026	26384302	Mutation or abnormal expression of the SOX9 gene contributes to many diseases, such as campomelic dysplasia and autosomal sex reversal.	('campomelic dysplasia', 'Disease', 'MESH:D055036', (87, 107))	('campomelic dysplasia', 'Disease', (87, 107))	('sex reversal', 'Phenotype', 'HP:0012245', (122, 134))	('Mutation', 'Var', (0, 8))	('autosomal sex reversal', 'Disease', (112, 134))	('contributes', 'Reg', (49, 60))	('abnormal expression', 'Var', (12, 31))	('SOX9', 'Gene', (39, 43))
862041	26384302	There were significantly more bromodeoxyuridine (BrdU)-positive cells among SOX9-transduced KYSE30 and KYSE140 cells, whereas the control cells displayed lower BrdU incorporation rates (Figure 3D).	('KYSE30', 'Var', (92, 98))	('bromodeoxyuridine', 'Chemical', 'MESH:D001973', (30, 47))	('more', 'PosReg', (25, 29))	('KYSE140', 'Var', (103, 110))	('BrdU', 'Chemical', 'MESH:D001973', (49, 53))	('BrdU', 'Chemical', 'MESH:D001973', (160, 164))	('SOX9-transduced KYSE30', 'Var', (76, 98))
862043	26384302	Furthermore, silencing SOX9 in ESCC cells dramatically decreased the percentages of BrdU-positive cells as compared to the control cells (Figure 4D).	('BrdU', 'Chemical', 'MESH:D001973', (84, 88))	('BrdU-positive cells', 'CPA', (84, 103))	('decreased', 'NegReg', (55, 64))	('SOX9', 'Gene', (23, 27))	('silencing', 'Var', (13, 22))
862046	26384302	As shown in Figure 5A-5C, the tumors formed by SOX9-transduced ESCC cells were larger and heavier than the vector control tumors, whereas tumors formed by SOX9-silenced cells were smaller and lighter than the tumors formed by the control cells.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('SOX9-transduced', 'Var', (47, 62))	('tumors', 'Disease', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('ESCC', 'Disease', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', (209, 215))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('heavier', 'PosReg', (90, 97))	('tumors', 'Disease', (138, 144))
862052	26384302	Moreover, the expression of phosphorylated Akt (p-Akt), the upstream regulator of p21Cip1, p27Kip1, and cyclin D1, was dramatically elevated in SOX9-transduced cells but reduced in SOX9-silenced cells (Figure 6B).	('cyclin D1', 'Gene', '595', (104, 113))	('p21Cip1', 'Gene', '1026', (82, 89))	('elevated', 'PosReg', (132, 140))	('Akt', 'Gene', '207', (50, 53))	('cyclin D1', 'Gene', (104, 113))	('Akt', 'Gene', '207', (43, 46))	('Akt', 'Gene', (50, 53))	('Akt', 'Gene', (43, 46))	('expression', 'MPA', (14, 24))	('p27Kip1', 'Gene', (91, 98))	('p27Kip1', 'Gene', '1027', (91, 98))	('p21Cip1', 'Gene', (82, 89))	('SOX9-transduced', 'Var', (144, 159))
862053	26384302	Overexpressing SOX9 dramatically increased the levels of phosphorylated forkhead box O (FOXO) 1 (p-FOXO1) and FOXO3 (p-FOXO3), the downstream factors of Akt (Figure 6B), but silencing SOX9 decreased them.	('forkhead box O (FOXO) 1', 'Gene', (72, 95))	('FOXO3', 'Gene', '2309', (110, 115))	('p-FOXO3', 'Gene', '2309', (117, 124))	('forkhead box O (FOXO) 1', 'Gene', '2308', (72, 95))	('Akt', 'Gene', '207', (153, 156))	('FOXO1', 'Gene', '2308', (99, 104))	('silencing', 'Var', (174, 183))	('FOXO3', 'Gene', (119, 124))	('FOXO1', 'Gene', (99, 104))	('Akt', 'Gene', (153, 156))	('p-FOXO3', 'Gene', (117, 124))	('increased', 'PosReg', (33, 42))	('levels', 'MPA', (47, 53))	('SOX9', 'Gene', (15, 19))	('phosphorylated', 'MPA', (57, 71))	('FOXO3', 'Gene', '2309', (119, 124))	('FOXO3', 'Gene', (110, 115))
862055	26384302	Furthermore, we found that overexpression of SOX9 promoted the proliferation and tumorigenicity of ESCC cells both in vitro and in vivo but that knockdown of SOX9 inhibited it.	('promoted', 'PosReg', (50, 58))	('proliferation', 'CPA', (63, 76))	('knockdown', 'Var', (145, 154))	('SOX9', 'Gene', (45, 49))	('ESCC', 'Disease', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('overexpression', 'PosReg', (27, 41))	('tumor', 'Disease', (81, 86))
862072	26384302	Furthermore, knockdown of SOX9 expression reduces the invasiveness and metastasis of colon cancer cells.	('reduces', 'NegReg', (42, 49))	('metastasis of colon cancer', 'Disease', (71, 97))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('metastasis of colon cancer', 'Disease', 'MESH:D009362', (71, 97))	('knockdown', 'Var', (13, 22))	('SOX9', 'Gene', (26, 30))
862077	26384302	The cause of SOX9 deregulation in cancer is another issue of interest.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('deregulation', 'Var', (18, 30))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('SOX9', 'Gene', (13, 17))
862081	26384302	The ESCC cell lines, purchased from Bogoo Co. (Shanghai, China), including EC18, KYSE30, KYSE140, KYSE180, KYSE410, KYSE510, KYSE 520, 108Ca, TE-1, ECa109, EC18 and HKESC1 were grown in DMEM medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Invitrogen) and 100 mug/ml penicillin, and 100 mug/ml streptomycin (Invitrogen) at 37 C in a humidified atmosphere containing 5% CO2.	('KYSE30', 'Var', (81, 87))	('HKESC1', 'CellLine', 'CVCL:D568', (165, 171))	('KYSE510', 'Var', (116, 123))	('bovine', 'Species', '9913', (258, 264))	('CO2', 'Gene', '717', (401, 404))	('KYSE180', 'Var', (98, 105))	('CO2', 'Gene', (401, 404))	('KYSE140', 'Var', (89, 96))	('KYSE410', 'Var', (107, 114))
862095	26384302	The membrane was probed with anti-SOX9 (56KD) mouse monoclonal antibody (1:500; #ab76997, Abcam, Cambridge, MA, USA), anti-p-Akt(#4056), anti-Akt(#9272), anti-p21(#2947), anti-p27(#3686), anti-CyclinD1(#2922), anti-p-FOXO1(#9461), anti-FOXO1(#9454), anti-p-FOXO3(#9465) or anti-FOXO3(#2472) (Cell Signaling, Danvers, MA, USA).	('Akt', 'Gene', (142, 145))	('p21', 'Gene', (159, 162))	('mouse', 'Species', '10090', (46, 51))	('FOXO3', 'Gene', (278, 283))	('Akt', 'Gene', '207', (142, 145))	('FOXO3', 'Gene', '2309', (257, 262))	('p-FOXO3', 'Gene', '2309', (255, 262))	('Akt', 'Gene', (125, 128))	('FOXO1', 'Gene', '2308', (236, 241))	('Akt', 'Gene', '207', (125, 128))	('FOXO3', 'Gene', '2309', (278, 283))	('p21', 'Gene', '1026', (159, 162))	('FOXO1', 'Gene', (236, 241))	('#2922', 'Var', (202, 207))	('anti-CyclinD1(#2922', 'Var', (188, 207))	('FOXO1', 'Gene', '2308', (217, 222))	('p-FOXO3', 'Gene', (255, 262))	('FOXO1', 'Gene', (217, 222))	('p27', 'Gene', '5715', (176, 179))	('p27', 'Gene', (176, 179))	('FOXO3', 'Gene', (257, 262))
862100	26384302	Tumor cell proportions were scored as follows: 0 (no positive tumor cells); 1 (< 10% positive tumor cells); 2 (10-35% positive tumor cells); 3 (35-75% positive tumor cells), or 4 (> 75% positive tumor cells).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('35-75', 'Var', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', (94, 99))	('10-35', 'Var', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
862150	24808953	For example, minor erosion of the inner lamina of thyroid cartilage is notoriously difficult to diagnose with a high level of accuracy, yet the presence of this may upstage a small glottic cancer from T1 to T3.	('thyroid cartilage', 'Disease', (50, 67))	('thyroid cartilage', 'Disease', 'MESH:D002357', (50, 67))	('glottic cancer', 'Disease', 'MESH:C563636', (181, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('upstage', 'PosReg', (165, 172))	('presence', 'Var', (144, 152))	('glottic cancer', 'Disease', (181, 195))
862180	24808953	For example, resection of one arytenoid cartilage during supracricoid laryngectomy has been shown to lead to increased risk of aspiration pneumonia, longer time to decannulation of tracheostomy tube, and poorer voice.	('voice', 'MPA', (211, 216))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (127, 147))	('arytenoid cartilage', 'Disease', (30, 49))	('arytenoid cartilage', 'Disease', 'MESH:D002357', (30, 49))	('aspiration', 'Phenotype', 'HP:0002835', (127, 137))	('increased risk of aspiration pneumonia', 'Phenotype', 'HP:0002100', (109, 147))	('tracheostomy tube', 'Disease', 'MESH:D009436', (181, 198))	('pneumonia', 'Phenotype', 'HP:0002090', (138, 147))	('aspiration pneumonia', 'Disease', (127, 147))	('tracheostomy tube', 'Disease', (181, 198))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (127, 147))	('resection', 'Var', (13, 22))
862281	33592421	PDT can cause intense inflammation in tissues adjacent to the tumor.	('cause', 'Reg', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PDT', 'Var', (0, 3))	('tumor', 'Disease', (62, 67))	('inflammation', 'Disease', 'MESH:D007249', (22, 34))	('inflammation', 'Disease', (22, 34))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
862291	33592421	Therefore, PDT can cause intense inflammation in tissues adjacent to the tumor.	('cause', 'Reg', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PDT', 'Var', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('inflammation', 'Disease', 'MESH:D007249', (33, 45))	('tumor', 'Disease', (73, 78))	('inflammation', 'Disease', (33, 45))
862348	33592421	PDT can cause intense inflammation beyond the esophageal tissue around the tumor regardless of the depth of the tumor.	('cause', 'Reg', (8, 13))	('PDT', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('inflammation', 'Disease', 'MESH:D007249', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (112, 117))	('inflammation', 'Disease', (22, 34))	('tumor', 'Disease', (75, 80))
862430	32456707	Preoperative squamous cell carcinoma antigen and albumin serum levels predict the survival of patients with stage T1-3N0M0 esophageal squamous cell carcinoma: a retrospective observational study This study aimed to explore the significance of preoperative levels of squamous cell carcinoma antigen (SCC-Ag) and albumin on the cancer-specific survival (CSS) of patients with stage T1-3N0M0 in esophageal squamous cell cancer (ESCC).	('albumin', 'Gene', '213', (311, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('SCC', 'Gene', (426, 429))	('SCC', 'Gene', (299, 302))	('esophageal squamous cell carcinoma', 'Disease', (123, 157))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (392, 423))	('albumin', 'Gene', '213', (49, 56))	('squamous cell carcinoma', 'Disease', (266, 289))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('cancer', 'Disease', 'MESH:D009369', (417, 423))	('patients', 'Species', '9606', (94, 102))	('CSS', 'Chemical', '-', (352, 355))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (403, 423))	('cancer', 'Disease', (326, 332))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (13, 36))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('esophageal squamous cell cancer', 'Disease', (392, 423))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (123, 157))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('albumin', 'Gene', (311, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('albumin', 'Gene', (49, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('patients', 'Species', '9606', (360, 368))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 36))	('Preoperative squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 36))	('Preoperative squamous cell carcinoma', 'Disease', (0, 36))	('cancer', 'Disease', (417, 423))	('stage T1-3N0M0', 'Var', (374, 388))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('SCC', 'Gene', '6317', (426, 429))	('SCC', 'Gene', '6317', (299, 302))	('cancer', 'Phenotype', 'HP:0002664', (417, 423))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (266, 289))
862439	32456707	Patients with ESCC with low albumin level had a worse CSS than those with high albumin level (HR, 0.540; 95% CI, 0.348-0.838; P = 0.006).	('high albumin', 'Phenotype', 'HP:0012117', (74, 86))	('CSS', 'MPA', (54, 57))	('albumin', 'Gene', '213', (28, 35))	('albumin', 'Gene', '213', (79, 86))	('low albumin', 'Phenotype', 'HP:0003073', (24, 35))	('albumin', 'Gene', (28, 35))	('Patients', 'Species', '9606', (0, 8))	('albumin', 'Gene', (79, 86))	('SCC', 'Gene', (15, 18))	('CSS', 'Chemical', '-', (54, 57))	('low', 'Var', (24, 27))	('SCC', 'Gene', '6317', (15, 18))
862440	32456707	Patients with both high SCC-Ag and low albumin levels had worse 5-year CSS than patients with low SCC-Ag and high albumin levels (P < 0.05).	('patients', 'Species', '9606', (80, 88))	('worse', 'NegReg', (58, 63))	('SCC', 'Gene', (24, 27))	('SCC', 'Gene', '6317', (98, 101))	('Patients', 'Species', '9606', (0, 8))	('SCC', 'Gene', '6317', (24, 27))	('CSS', 'Chemical', '-', (71, 74))	('low albumin', 'Phenotype', 'HP:0003073', (35, 46))	('high albumin', 'Phenotype', 'HP:0012117', (109, 121))	('albumin', 'Gene', (114, 121))	('albumin', 'Gene', '213', (114, 121))	('low', 'Var', (35, 38))	('CSS', 'CPA', (71, 74))	('albumin', 'Gene', (39, 46))	('albumin', 'Gene', '213', (39, 46))	('SCC', 'Gene', (98, 101))
862450	32456707	With regard to ESCC, existing literatures identified high SCC-Ag level as a predictor of poor prognosis.	('SCC', 'Gene', (58, 61))	('high', 'Var', (53, 57))	('SCC', 'Gene', '6317', (58, 61))	('SCC', 'Gene', (16, 19))	('SCC', 'Gene', '6317', (16, 19))
862452	32456707	They found that patients with high SCC-Ag level had worse survival (P < 0.05).	('SCC', 'Gene', (35, 38))	('patients', 'Species', '9606', (16, 24))	('worse', 'NegReg', (52, 57))	('high', 'Var', (30, 34))	('SCC', 'Gene', '6317', (35, 38))	('survival', 'MPA', (58, 66))
862488	32456707	The 1-, 3-, and 5-year CSS rates in patients with low albumin level were lower than those with high albumin level (1-year CSS, 67.0% vs 85.0%; 3-year CSS, 51.0% vs. 72.0%; 5-year CSS, 51.0% vs. 67.0%).	('patients', 'Species', '9606', (36, 44))	('low', 'Var', (50, 53))	('albumin', 'Gene', '213', (54, 61))	('albumin', 'Gene', (100, 107))	('albumin', 'Gene', '213', (100, 107))	('low albumin', 'Phenotype', 'HP:0003073', (50, 61))	('CSS', 'Chemical', '-', (150, 153))	('high albumin', 'Phenotype', 'HP:0012117', (95, 107))	('CSS', 'Chemical', '-', (23, 26))	('lower', 'NegReg', (73, 78))	('CSS', 'Chemical', '-', (122, 125))	('CSS', 'Chemical', '-', (179, 182))	('CSS', 'CPA', (23, 26))	('albumin', 'Gene', (54, 61))
862497	32456707	The results showed that patients with low albumin and high SCC-Ag levels had the worst 5-year CSS than patients in the two other groups (Fig.	('SCC', 'Gene', (59, 62))	('CSS', 'Chemical', '-', (94, 97))	('high', 'Var', (54, 58))	('low albumin', 'Phenotype', 'HP:0003073', (38, 49))	('albumin', 'Gene', '213', (42, 49))	('CSS', 'CPA', (94, 97))	('SCC', 'Gene', '6317', (59, 62))	('albumin', 'Gene', (42, 49))	('low', 'NegReg', (38, 41))	('worst', 'NegReg', (81, 86))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (103, 111))
862513	32456707	Similarly, we illustrated that patients with albumin level > 39.8 g/L had more survival advantage than patients with albumin level <= 39.8 g/L.	('survival advantage', 'CPA', (79, 97))	('albumin', 'Gene', (45, 52))	('> 39.8 g/L', 'Var', (59, 69))	('albumin', 'Gene', '213', (45, 52))	('albumin', 'Gene', (117, 124))	('albumin', 'Gene', '213', (117, 124))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (103, 111))
862526	32456707	In addition, patients with low albumin and high SCC-Ag levels had worst 5-year CSS than other patients.	('CSS', 'Chemical', '-', (79, 82))	('patients', 'Species', '9606', (94, 102))	('worst', 'NegReg', (66, 71))	('high', 'Var', (43, 47))	('albumin', 'Gene', (31, 38))	('CSS', 'CPA', (79, 82))	('SCC', 'Gene', (48, 51))	('albumin', 'Gene', '213', (31, 38))	('low', 'NegReg', (27, 30))	('patients', 'Species', '9606', (13, 21))	('low albumin', 'Phenotype', 'HP:0003073', (27, 38))	('SCC', 'Gene', '6317', (48, 51))
862538	31616746	This is important because type 2B vWD itself can be associated with thrombocytopenia, thus limiting the use of desmopressin which is frequently used in the common forms of vWD.	('vWD', 'Gene', '7450', (172, 175))	('thrombocytopenia', 'Disease', (68, 84))	('vWD', 'Gene', '7450', (34, 37))	('vWD', 'Gene', (172, 175))	('vWD', 'Gene', (34, 37))	('associated', 'Reg', (52, 62))	('limiting', 'NegReg', (91, 99))	('thrombocytopenia', 'Disease', 'MESH:D013921', (68, 84))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (68, 84))	('type 2B', 'Var', (26, 33))	('use', 'MPA', (104, 107))
862541	31616746	In 2005, she was diagnosed with type 2B vWD from a de novo mutation (c.3946G>A [p.V1316M]) after developing an epidural hematoma from mild head trauma.	('c.3946G>A', 'Mutation', 'c.3946G>A', (69, 78))	('c.3946G>A', 'Var', (69, 78))	('mild head', 'Phenotype', 'HP:0040196', (134, 143))	('hematoma', 'Disease', 'MESH:D006406', (120, 128))	('head trauma', 'Disease', 'MESH:D006259', (139, 150))	('epidural hematoma', 'Phenotype', 'HP:0100310', (111, 128))	('p.V1316M', 'Mutation', 'p.V1316M', (80, 88))	('hematoma', 'Disease', (120, 128))	('vWD', 'Gene', '7450', (40, 43))	('head trauma', 'Disease', (139, 150))	('vWD', 'Gene', (40, 43))
862564	31616746	The 2B subtype accounts for ~5% of patients with vWD and is characterized by a gain of function mutation that has spontaneous binding of vWF to GP1balpha receptors on platelets which allows for increased clearance of the larger von Willebrand multimers and platelets leading to resulting thrombocytopenia.	('vWF', 'Gene', (137, 140))	('thrombocytopenia', 'Disease', (288, 304))	('binding', 'Interaction', (126, 133))	('vWF', 'Gene', '7450', (137, 140))	('vWD', 'Gene', '7450', (49, 52))	('vWD', 'Gene', (49, 52))	('mutation', 'Var', (96, 104))	('thrombocytopenia', 'Disease', 'MESH:D013921', (288, 304))	('von Willebrand', 'Disease', 'MESH:D014842', (228, 242))	('increased', 'PosReg', (194, 203))	('GP1balpha', 'Protein', (144, 153))	('gain of function', 'PosReg', (79, 95))	('patients', 'Species', '9606', (35, 43))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (288, 304))	('clearance', 'MPA', (204, 213))	('von Willebrand', 'Disease', (228, 242))
862611	30111361	In brief, the inclusion criteria were as follows: Patients diagnosed with ESCC using histology via esophagogastroduodenoscopy; <=70 years old; Eastern Cooperative Oncology Group scoring (ECOG) <=2; clinical stage of TanyNanyM0 or M1 with supraclavicular lymph node metastasis; sufficient pretreatment assessment available to define the clinical stage and to assess the adaptation for treatment (including surgery, chemotherapy and radiotherapy); treated initially with CRT followed with or without AC; no prior salvage surgery performed; and sufficient follow-up data available for short-term treatment response and survival assessment.	('<=2', 'Var', (193, 196))	('supraclavicular lymph node metastasis', 'Disease', (238, 275))	('ESCC', 'Disease', (74, 78))	('Patients', 'Species', '9606', (50, 58))	('CR', 'Gene', '799', (469, 471))	('Oncology', 'Phenotype', 'HP:0002664', (163, 171))	('supraclavicular lymph node metastasis', 'Disease', 'MESH:D009362', (238, 275))
862667	30111361	Tam et al..... reported that AC in TMT improved the OS in patients with PR to neoadjuvant CRT, but not in complete responders and non-responders.	('OS', 'Chemical', '-', (52, 54))	('TMT', 'Gene', (35, 38))	('AC in', 'Var', (29, 34))	('TMT', 'Gene', '25823', (35, 38))	('patients', 'Species', '9606', (58, 66))	('improved', 'PosReg', (39, 47))	('CR', 'Gene', '799', (90, 92))
862708	27905171	Group 3 had the largest complement of patients, with component categories being cT2N0M0G3, cT3N1-2M0, and cT4aN0-2M0.	('cT2', 'Gene', (80, 83))	('cT2', 'Gene', '30848', (80, 83))	('patients', 'Species', '9606', (38, 46))	('cT3', 'Gene', '285782', (91, 94))	('cT3', 'Gene', (91, 94))	('cT4aN0-2M0', 'Var', (106, 116))
862709	27905171	cT4aN3M0 and cM1 cancer comprised group 4.	('cT4aN3M0', 'Var', (0, 8))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
862715	27905171	Group 4 had the largest complement of patients and consisted of cT2N0M0G3, cT2N1M0, cT3N0M0, and cT4aN0-1M0 cancers.	('cT4aN0-1M0', 'Var', (97, 107))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cT3', 'Gene', '285782', (84, 87))	('patients', 'Species', '9606', (38, 46))	('cT2', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cT2', 'Gene', '30848', (75, 78))	('cT2', 'Gene', (64, 67))	('cT3', 'Gene', (84, 87))	('cT2', 'Gene', '30848', (64, 67))	('cancers', 'Disease', (108, 115))
862718	27905171	There were too few cT1-2N2, cT4aN2M0, cT4bN0-2, and cTanyN3M0 adenocarcinomas to be grouped.	('cT1-2', 'Gene', (19, 24))	('cT4aN2M0', 'Var', (28, 36))	('adenocarcinomas', 'Disease', 'MESH:D000230', (62, 77))	('cT1-2', 'Gene', '266740', (19, 24))	('adenocarcinomas', 'Disease', (62, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cT4bN0-2', 'Var', (38, 46))	('cTanyN3M0', 'Var', (52, 61))
862723	27905171	Group 3 comprised cT3N1-2M0 and cT4N0-2M0.	('cT4N0-2M0', 'Var', (32, 41))	('cT3', 'Gene', '285782', (18, 21))	('cT3', 'Gene', (18, 21))
862728	27905171	Group 4 comprised cT2N1M0, cT3N0M0, and cT4aN0-1M0 cancers.	('cT2', 'Gene', (18, 21))	('cT2', 'Gene', '30848', (18, 21))	('cT3', 'Gene', (27, 30))	('cT4aN0-1M0', 'Var', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cT3', 'Gene', '285782', (27, 30))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
862740	27905171	cStage IVA comprised the most locally advanced cancers, including cT1-4aN2M0, cT4bN0-2M0, and cTany N3M0.	('advanced cancers', 'Disease', 'MESH:D006223', (38, 54))	('cT1', 'Gene', (66, 69))	('IVA', 'Disease', (7, 10))	('IVA', 'Disease', 'MESH:C538167', (7, 10))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cT4bN0-2M0', 'Var', (78, 88))	('cT1', 'Gene', '1489', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cTany', 'Disease', (94, 99))	('advanced cancers', 'Disease', (38, 54))
862745	27905171	Stage I and II SCCs include T1-2N1M0 and T3N0M0 cancers, which are advanced-stage (cStage III) adenocarcinomas; cT1N0-1M0 is cStage I, and cT2N0-1M0 plus cT3N0M0 is cStage II.	('adenocarcinomas', 'Disease', (95, 110))	('cancers', 'Disease', (48, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('cT1', 'Gene', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cT1', 'Gene', '1489', (112, 115))	('T3N0M0', 'Var', (41, 47))	('cT2', 'Gene', (139, 142))	('cT3', 'Gene', '285782', (154, 157))	('SCC', 'Gene', (15, 18))	('cT2', 'Gene', '30848', (139, 142))	('SCC', 'Gene', '6317', (15, 18))	('cT3', 'Gene', (154, 157))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('adenocarcinomas', 'Disease', 'MESH:D000230', (95, 110))
862767	27905171	cN+ was shown to be a high-risk finding for adenocarcinoma and should accordingly direct treatment decisions and crude prognostication.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('adenocarcinoma', 'Disease', (44, 58))	('direct', 'Reg', (82, 88))	('cN+', 'Var', (0, 3))	('adenocarcinoma', 'Disease', 'MESH:D000230', (44, 58))
862770	27905171	The identification of G3 in T1-2N0M0 adenocarcinoma and T2N0M0 SCC is a high-risk finding and should be used in decision-making and prognostication for these patients.	('adenocarcinoma', 'Disease', (37, 51))	('adenocarcinoma', 'Disease', 'MESH:D000230', (37, 51))	('SCC', 'Gene', (63, 66))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('T2N0M0', 'Var', (56, 62))	('SCC', 'Gene', '6317', (63, 66))	('T1-2N0M0', 'Var', (28, 36))	('patients', 'Species', '9606', (158, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
862798	28185291	These alterations cause increased production and release of numerous cytokines, chemokines and polypeptide growth factors that result in the recruitment of bone marrow-derived and circulating fibrocytes and in the phenotypic conversion of quiescent tissue fibroblasts, and of epithelial and endothelial cells into activated myofibroblasts, the cells ultimately responsible for the fibroproliferative vasculopathy and progressive tissue fibrosis.	('alterations', 'Var', (6, 17))	('rat', 'Species', '10116', (393, 396))	('production', 'MPA', (34, 44))	('fibrosis', 'Disease', 'MESH:D005355', (436, 444))	('fibrosis', 'Disease', (436, 444))	('vasculopathy', 'Disease', 'MESH:D020144', (400, 412))	('release', 'MPA', (49, 56))	('rat', 'Species', '10116', (10, 13))	('vasculopathy', 'Disease', (400, 412))	('increased', 'PosReg', (24, 33))
862799	28185291	These alterations also result in chemokine and cytokine-mediated attraction of specific inflammatory cellular elements from the bloodstream and bone marrow to the affected tissues and in the activation of resident tissue macrophages resulting in the establishment of a chronic inflammatory process.	('alterations', 'Var', (6, 17))	('attraction', 'CPA', (65, 75))	('activation', 'PosReg', (191, 201))	('result in', 'Reg', (23, 32))	('rat', 'Species', '10116', (10, 13))	('chronic inflammatory process', 'CPA', (269, 297))
862811	28185291	This was evidenced by the demonstration that SScIgGs caused specific attenuation of the simultaneous rat colonic contractile response and release of acetylcholine induced by electric field stimulation.	('SScIgGs', 'Var', (45, 52))	('rat', 'Species', '10116', (101, 104))	('rat', 'Species', '10116', (33, 36))	('acetylcholine', 'Chemical', 'MESH:D000109', (149, 162))	('release of acetylcholine', 'MPA', (138, 162))	('attenuation', 'NegReg', (69, 80))
862812	28185291	SScIgGs were also found to abrogate the M3-R agonist-induced contractile response of rat colonic smooth muscle in a dose dependent manner.	('SScIgGs', 'Var', (0, 7))	('M3-R', 'Gene', '12671', (40, 44))	('rat', 'Species', '10116', (85, 88))	('abrogate', 'NegReg', (27, 35))	('M3-R', 'Gene', (40, 44))
862818	28185291	Recent studies have shown that alterations in CMI are important participants in GIT involvement in SSc.	('SSc', 'Disease', (99, 102))	('alterations', 'Var', (31, 42))	('participants', 'Species', '9606', (64, 76))	('rat', 'Species', '10116', (35, 38))	('CMI', 'Gene', (46, 49))
862858	28185291	GERD is also associated with higher prevalence and rapid progression of interstitial lung disease, most likely caused by repeated micro-aspiration of gastric contents into the lungs.	('interstitial lung disease', 'Phenotype', 'HP:0006530', (72, 97))	('interstitial lung disease', 'Disease', 'MESH:D017563', (72, 97))	('interstitial lung disease', 'Disease', (72, 97))	('GERD', 'Var', (0, 4))	('aspiration', 'Phenotype', 'HP:0002835', (136, 146))	('rat', 'Species', '10116', (140, 143))	('lung disease', 'Phenotype', 'HP:0002088', (85, 97))
862918	28185291	Owing to the autoimmune nature of SSc, some patients may harbor anti-liver kidney microsomal antibodies (Anti-LKM) or anti-smooth muscle antibodies (Anti-SMA) in the absence of liver disease.	('patients', 'Species', '9606', (44, 52))	('SSc', 'Disease', (34, 37))	('liver disease', 'Phenotype', 'HP:0001392', (177, 190))	('anti-liver kidney microsomal antibodies', 'Protein', (64, 103))	('liver disease', 'Disease', (177, 190))	('anti-smooth', 'Var', (118, 129))	('liver disease', 'Disease', 'MESH:D008107', (177, 190))
862938	28185291	Autoantibody mediated dysmotility offers a new avenue for further research into the pathogenesis and treatment of gastrointestinal SSc.	('dysmotility', 'Disease', (22, 33))	('gastrointestinal SSc', 'Disease', (114, 134))	('dysmotility', 'Disease', 'MESH:D015154', (22, 33))	('Autoantibody', 'Var', (0, 12))	('gastrointestinal SSc', 'Disease', 'MESH:D005767', (114, 134))
863024	25750543	These results indicate that nimotuzumab can inhibit key cancer survival mechanisms, the EGFR signaling pathway, and DNA repair and thereby reverse acquired radioresistance in KYSE-150R cell line.	('DNA repair', 'MPA', (116, 126))	('inhibit', 'NegReg', (44, 51))	('nimotuzumab', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('reverse', 'NegReg', (139, 146))	('EGFR', 'Gene', '1956', (88, 92))	('nimotuzumab', 'Chemical', 'MESH:C501466', (28, 39))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('EGFR', 'Gene', (88, 92))
863035	25750543	High EGFR expression is correlated with poor OS and disease-free survival in esophageal cancer patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (95, 103))	('expression', 'MPA', (10, 20))	('disease-free survival', 'CPA', (52, 73))	('EGFR', 'Gene', '1956', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EGFR', 'Gene', (5, 9))	('esophageal cancer', 'Disease', (77, 94))
863038	25750543	Therefore, inhibition of EGFR activity and signaling became an effective strategy to increase tumor radiosensitivity in RT.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('EGFR', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('inhibition', 'Var', (11, 21))	('tumor radiosensitivity', 'Phenotype', 'HP:0010997', (94, 116))	('increase tumor radiosensitivity', 'Phenotype', 'HP:0010997', (85, 116))	('increase', 'PosReg', (85, 93))	('EGFR', 'Gene', '1956', (25, 29))
863046	25750543	Using a radiation-resistant human esophageal carcinoma cell line, KYSE-150R, we have studied the capacity of nimotuzumab to reverse radiation resistance and involved molecular mechanisms, and demonstrated that nimotuzumab can significantly reduce radioresistance in esophageal cancer cells, suggesting a potential clinical application in RT for esophageal caner.	('esophageal cancer', 'Disease', 'MESH:D004938', (266, 283))	('nimotuzumab', 'Chemical', 'MESH:C501466', (109, 120))	('esophageal carcinoma', 'Disease', (34, 54))	('nimotuzumab', 'Var', (210, 221))	('human', 'Species', '9606', (28, 33))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (34, 54))	('radioresistance', 'CPA', (247, 262))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (34, 54))	('reduce', 'NegReg', (240, 246))	('nimotuzumab', 'Chemical', 'MESH:C501466', (210, 221))	('esophageal cancer', 'Disease', (266, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
863050	25750543	Cells (4x103 cells per well) were cultured in 96-well plates for 24 hours, then incubated with different concentrations of nimotuzumab (250-4,000 nM) and cisplatin (5-80 muM) for another 72 hours.	('nimotuzumab', 'Chemical', 'MESH:C501466', (123, 134))	('muM', 'Gene', '56925', (170, 173))	('250-4,000', 'Var', (136, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('muM', 'Gene', (170, 173))
863062	25750543	Anti-EGFR, antiphospho-EGFR (S1981), antiphospho-AKT (S473), and anti-AKT and antiphospho-ERK1/2 and anti-ERK1/2 antibodies were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA).	('ERK1/2', 'Gene', (106, 112))	('ERK1/2', 'Gene', '5595;5594', (106, 112))	('AKT', 'Gene', '207', (70, 73))	('AKT', 'Gene', (49, 52))	('ERK1/2', 'Gene', (90, 96))	('ERK1/2', 'Gene', '5595;5594', (90, 96))	('AKT', 'Gene', (70, 73))	('EGFR', 'Gene', '1956', (5, 9))	('S473', 'Var', (54, 58))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (5, 9))	('AKT', 'Gene', '207', (49, 52))	('EGFR', 'Gene', (23, 27))	('S1981', 'Var', (29, 34))
863076	25750543	Interestingly, we found that nimotuzumab can also increase radiosensitivity of the parental KYSE-150 cell.	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (50, 75))	('nimotuzumab', 'Chemical', 'MESH:C501466', (29, 40))	('increase', 'PosReg', (50, 58))	('nimotuzumab', 'Var', (29, 40))	('radiosensitivity', 'CPA', (59, 75))
863082	25750543	There was no difference in the average numbers of gamma-H2AX foci at 4 hours after IR between the KYSE-150R cells treated by the combined nimotuzumab/radiation and the cells treated with radiation/IgG.	('nimotuzumab/radiation', 'Var', (138, 159))	('H2AX', 'Gene', (56, 60))	('nimotuzumab', 'Chemical', 'MESH:C501466', (138, 149))	('H2AX', 'Gene', '3014', (56, 60))
863103	25750543	As compared with the previous report on the effects of cetuximab, we further focused on the EGFR signaling pathway and DNA repair in terms of neutralization of the EGFR in esophageal cancer cells.	('EGFR', 'Gene', (164, 168))	('neutralization', 'Var', (142, 156))	('esophageal cancer', 'Disease', (172, 189))	('cetuximab', 'Chemical', 'MESH:D000068818', (55, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '1956', (164, 168))
863111	25750543	It is known that radiation-induced phosphorylation of the EGFR activates the Ras/Raf/ERK (MAPK) and the PI3K-Akt signaling pathways, which can protect cells from radiation-induced cell death but promote cell survival and proliferation.	('EGFR', 'Gene', '1956', (58, 62))	('Raf', 'Gene', (81, 84))	('Akt', 'Gene', '207', (109, 112))	('cell survival', 'CPA', (203, 216))	('EGFR', 'Gene', (58, 62))	('ERK', 'Gene', '5594', (85, 88))	('proliferation', 'CPA', (221, 234))	('ERK', 'Gene', (85, 88))	('promote', 'PosReg', (195, 202))	('Akt', 'Gene', (109, 112))	('Raf', 'Gene', '22882', (81, 84))	('phosphorylation', 'Var', (35, 50))	('activates', 'PosReg', (63, 72))
863118	25750543	Previous studies have demonstrated that blockade of EGFR signaling can inhibit cellular DNA repair.	('blockade', 'Var', (40, 48))	('cellular DNA repair', 'CPA', (79, 98))	('EGFR', 'Gene', '1956', (52, 56))	('inhibit', 'NegReg', (71, 78))	('EGFR', 'Gene', (52, 56))
863119	25750543	Golding et al found that blocking EGFR signaling impaired the formation of both p-(T2609) DNA-PKcs and p-(S1981) ATM foci.	('T2609', 'CellLine', 'CVCL:AR10', (83, 88))	('EGFR', 'Gene', (34, 38))	('ATM', 'Gene', (113, 116))	('DNA-PKcs', 'Gene', (90, 98))	('formation', 'MPA', (62, 71))	('ATM', 'Gene', '472', (113, 116))	('p-(S1981', 'Var', (103, 111))	('impaired', 'NegReg', (49, 57))	('EGFR', 'Gene', '1956', (34, 38))	('DNA-PKcs', 'Gene', '5591', (90, 98))
863129	25750543	Rad51 is important for DSB repair through HR, and inhibition of Rad51 increases radiosensitivity.	('Rad51', 'Gene', '5888', (0, 5))	('inhibition', 'Var', (50, 60))	('Rad51', 'Gene', '5888', (64, 69))	('increases', 'PosReg', (70, 79))	('Rad51', 'Gene', (64, 69))	('radiosensitivity', 'CPA', (80, 96))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (70, 96))	('Rad51', 'Gene', (0, 5))
863140	25436102	At four months following treatment with pioglitazone or metformin there was a significant reduction in body weight(p<=0.04), serum aspartate aminotransferase (p<0.01), ALT (p<0.01), alkaline phosphatase (p<0.01), cholesterol (p<0.01), low density lipoprotein (p<0.01), fasting plasma glucose (p<0.01), homeostasis model assessment-insulin resistance (p<0.01) and liver fat content (p<0.01) and a significant increase in serum high density lipoprotein (p<0.01).	('reduction in body weight', 'Phenotype', 'HP:0004325', (90, 114))	('ALT', 'MPA', (168, 171))	('glucose', 'Chemical', 'MESH:D005947', (284, 291))	('insulin', 'Gene', (331, 338))	('fasting plasma glucose', 'MPA', (269, 291))	('pioglitazone', 'Chemical', 'MESH:D000077205', (40, 52))	('insulin resistance', 'Phenotype', 'HP:0000855', (331, 349))	('pioglitazone', 'Var', (40, 52))	('increase', 'PosReg', (408, 416))	('low density lipoprotein', 'MPA', (235, 258))	('cholesterol', 'MPA', (213, 224))	('reduction', 'NegReg', (90, 99))	('increase in serum high density lipoprotein', 'Phenotype', 'HP:0012184', (408, 450))	('serum aspartate aminotransferase', 'MPA', (125, 157))	('metformin', 'Chemical', 'MESH:D008687', (56, 65))	('insulin', 'Gene', '3630', (331, 338))	('liver fat content', 'MPA', (363, 380))	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (125, 157))	('serum high density lipoprotein', 'MPA', (420, 450))	('alkaline phosphatase', 'MPA', (182, 202))	('body', 'CPA', (103, 107))
863173	25436102	Although additional studies are required to further characterise FSPs, modulation of FSP activity may represent a novel therapeutic target in diarrhoea predominant IBS by reducing colonic hypersensitivity.	('reducing', 'NegReg', (171, 179))	('diarrhoea predominant IBS', 'Disease', 'MESH:D043183', (142, 167))	('diarrhoea predominant IBS', 'Disease', (142, 167))	('modulation', 'Var', (71, 81))	('hypersensitivity', 'Disease', 'MESH:D004342', (188, 204))	('FSP', 'Protein', (85, 88))	('hypersensitivity', 'Disease', (188, 204))	('diarrhoea', 'Phenotype', 'HP:0002014', (142, 151))
863322	30425090	Identifying patients with alterations in the MET pathway (including MET amplification) has been proposed as a method to identify cancer subtypes that may be dependent on MET signaling and sensitive to MET inhibition.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('patients', 'Species', '9606', (12, 20))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('alterations', 'Var', (26, 37))	('MET pathway', 'Pathway', (45, 56))
863344	30425090	Patients with complete response (CR), partial response (PR), or stable disease (SD), and without DLTs, resumed treatment on day 36 and continued until disease progression, withdrawal of consent, or intolerable toxicity.	('complete', 'Disease', (14, 22))	('toxicity', 'Disease', 'MESH:D064420', (210, 218))	('stable disease', 'Disease', (64, 78))	('toxicity', 'Disease', (210, 218))	('partial', 'Var', (38, 45))	('Patients', 'Species', '9606', (0, 8))
863385	30425090	Nine patients (8.1%) exhibited absolute heart rate-corrected QT interval (Fridericia's formula; QTcF) >480-500 msec, and 5 (4.5%) exhibited QTcF >500 msec.	('>480-500', 'Var', (102, 110))	('patients', 'Species', '9606', (5, 13))	('QTcF', 'Disease', (140, 144))	('QTcF', 'Disease', (96, 100))	('QTcF', 'Disease', 'None', (140, 144))	('QTcF', 'Disease', 'None', (96, 100))	('heart rate-corrected QT interval', 'MPA', (40, 72))
863392	30425090	Among patients who received AMG 337 200 mg once daily, mean trough concentration (Ctrough) was 416 ng/mL on day 1; this corresponds to a mean unbound Ctrough of 312 ng/mL, a concentration that is approximately 10-fold higher than the unbound concentration (27 nmol/L) associated with a 90% inhibition of MET signaling in the TPR-MET mouse tumor model.	('AMG 337 200', 'Var', (28, 39))	('tumor', 'Disease', (339, 344))	('TPR', 'Gene', '7175', (325, 328))	('mouse', 'Species', '10090', (333, 338))	('inhibition', 'NegReg', (290, 300))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('MET signaling', 'MPA', (304, 317))	('patients', 'Species', '9606', (6, 14))	('AMG 337', 'Chemical', 'MESH:C000609912', (28, 35))	('TPR', 'Gene', (325, 328))
863398	30425090	The CR occurred in a 63-year-old man with stage IV MET-amplified (FISH ratio, 25.0) distal esophageal adenocarcinoma who was treated on the 200-mg once-daily dosing schedule (dose reduced to 150 mg once daily after 35 weeks).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (91, 116))	('esophageal adenocarcinoma', 'Disease', (91, 116))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (91, 116))	('MET-amplified', 'Var', (51, 64))
863405	30425090	Among the 19 patients with MET-amplified tumors who did not achieve a CR/PR, 9 achieved SD, 3 had progressive disease, and 7 had unknown best tumor response.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (142, 147))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('MET-amplified', 'Var', (27, 40))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
863410	30425090	AMG 337 blocks MET signaling and inhibits growth of MET-dependent cancer cell lines, including gastric cancers.	('gastric cancers', 'Disease', (95, 110))	('growth', 'CPA', (42, 48))	('gastric cancers', 'Disease', 'MESH:D013274', (95, 110))	('gastric cancers', 'Phenotype', 'HP:0012126', (95, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('MET signaling', 'Pathway', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('AMG', 'Var', (0, 3))	('AMG 337', 'Chemical', 'MESH:C000609912', (0, 7))	('blocks', 'NegReg', (8, 14))	('inhibits', 'NegReg', (33, 41))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (66, 72))
863412	30425090	AMG 337 was associated with a dose-dependent increase in headache incidence, possibly due to its potent inhibition of adenosine transporters (refs.	('inhibition', 'NegReg', (104, 114))	('headache', 'Phenotype', 'HP:0002315', (57, 65))	('headache', 'Disease', 'MESH:D006261', (57, 65))	('adenosine', 'Chemical', 'MESH:D000241', (118, 127))	('AMG 337', 'Var', (0, 7))	('AMG 337', 'Chemical', 'MESH:C000609912', (0, 7))	('headache', 'Disease', (57, 65))	('adenosine transporters', 'MPA', (118, 140))	('increase', 'PosReg', (45, 53))
863414	30425090	Consistent with other MET inhibitors, low-grade peripheral edema occurred in 24% of patients who received AMG 337; however, no grade >=3 peripheral edema was observed.	('edema', 'Phenotype', 'HP:0000969', (148, 153))	('peripheral edema', 'Disease', 'MESH:D004487', (137, 153))	('patients', 'Species', '9606', (84, 92))	('peripheral edema', 'Disease', (137, 153))	('peripheral edema', 'Phenotype', 'HP:0012398', (48, 64))	('AMG', 'Var', (106, 109))	('AMG 337', 'Chemical', 'MESH:C000609912', (106, 113))	('peripheral edema', 'Disease', 'MESH:D004487', (48, 64))	('peripheral edema', 'Disease', (48, 64))	('edema', 'Phenotype', 'HP:0000969', (59, 64))	('peripheral edema', 'Phenotype', 'HP:0012398', (137, 153))
863419	30425090	Preclinical studies showed that AMG 337 inhibits the phosphorylation of MET and downstream effectors in various MET-amplified cancer cell lines, blocking MET-dependent cell proliferation and inducing apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('AMG 337', 'Var', (32, 39))	('MET-dependent', 'MPA', (154, 167))	('AMG 337', 'Chemical', 'MESH:C000609912', (32, 39))	('blocking', 'NegReg', (145, 153))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('inducing', 'Reg', (191, 199))	('inhibits', 'NegReg', (40, 48))	('apoptosis', 'CPA', (200, 209))	('phosphorylation', 'MPA', (53, 68))
863422	30425090	Within the esophagogastric cancers, the subgroup of MET-amplified patients has a reportedly worse prognosis; thus, the response and disease control rates in this subgroup are particularly intriguing.	('gastric cancers', 'Disease', 'MESH:D013274', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('gastric cancers', 'Disease', (19, 34))	('gastric cancers', 'Phenotype', 'HP:0012126', (19, 34))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('MET-amplified', 'Var', (52, 65))	('patients', 'Species', '9606', (66, 74))
863427	30425090	In this study, although evidence of durable clinical responses with 200- or 300-mg once-daily doses of AMG 337 was demonstrated in patients with refractory MET-amplified GEJ/gastric/esophageal tumors and other tumor types, we concluded that the presence of MET amplification alone was not sufficient to predict response across the wide range of doses tested.	('patients', 'Species', '9606', (131, 139))	('MET-amplified', 'Var', (156, 169))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('AMG 337', 'Gene', (103, 110))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (210, 215))	('esophageal tumors', 'Disease', 'MESH:D004938', (182, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('esophageal tumors', 'Phenotype', 'HP:0100751', (182, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('esophageal tumors', 'Disease', (182, 199))	('AMG 337', 'Chemical', 'MESH:C000609912', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
863429	30425090	Despite failure of several MET pathway inhibitors to produce a significant response in patients with MET amplification, some small-molecule MET inhibitors have shown activity in patients with highly MET-amplified tumors.	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Disease', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('activity', 'MPA', (166, 174))	('patients', 'Species', '9606', (178, 186))	('MET amplification', 'Var', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('patients', 'Species', '9606', (87, 95))
863434	30425090	High-level MET amplification, defined as a MET/CEP7 ratio of at least 5, correlates to higher MET protein levels, poorer patient prognosis, and absence of other oncogenic driver mutations.	('MET', 'Var', (11, 14))	('MET protein levels', 'MPA', (94, 112))	('patient', 'Species', '9606', (121, 128))	('higher', 'PosReg', (87, 93))
863441	30425090	AMG 337 produced meaningful responses in patients with MET-amplified tumors, most notably in a subset of patients with GEJ/gastric/esophageal tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('MET-amplified', 'Var', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('esophageal tumors', 'Disease', (131, 148))	('patients', 'Species', '9606', (105, 113))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('AMG 337', 'Chemical', 'MESH:C000609912', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('AMG', 'Gene', (0, 3))	('esophageal tumors', 'Disease', 'MESH:D004938', (131, 148))	('esophageal tumors', 'Phenotype', 'HP:0100751', (131, 148))
863442	30425090	Although durable responses were observed in some MET-amplified tumors, many did not respond, indicating the complexity of the MET signaling pathway and likely requirement of combination strategies.	('MET-amplified', 'Var', (49, 62))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
863444	30425090	A phase II study of AMG 337 in patients with MET-amplified GEJ/gastric/esophageal adenocarcinoma or other MET-amplified solid tumors has been conducted and is reported separately.	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('esophageal adenocarcinoma', 'Disease', (71, 96))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (71, 96))	('patients', 'Species', '9606', (31, 39))	('AMG 337', 'Chemical', 'MESH:C000609912', (20, 27))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (71, 96))	('MET-amplified', 'Var', (45, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
863448	30425090	Patients with alterations in the MET pathway may have tumors that are dependent on MET signaling and therefore sensitive to MET inhibition.	('alterations', 'Var', (14, 25))	('MET signaling', 'MPA', (83, 96))	('MET pathway', 'Pathway', (33, 44))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
863450	30425090	The study included dose escalation in patients with advanced solid tumors followed by dose expansion in patients with select MET-amplified tumors.	('MET-amplified', 'Var', (125, 138))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('patients', 'Species', '9606', (38, 46))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', (67, 73))
863512	30116837	The post-PET/CT cohort also underwent marginally more open and close laparotomies for undetected distant metastases (n = 27, 12.1%) compared with the pre-PET/CT cohort (n = 30, 11%, p = 0.698).	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('post-PET/CT', 'Var', (4, 15))	('metastases', 'Disease', (105, 115))
863523	30116837	This is the first study and propensity score analysis to demonstrate a positive significant correlation between the introduction of PET/CT into an EC staging algorithm and a reduction in cancer recurrence, with a commensurate increase in durations of survival, irrespective of stage, in patients undergoing potentially curative surgery.	('durations', 'MPA', (238, 247))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('patients', 'Species', '9606', (287, 295))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('introduction', 'Var', (116, 128))	('PET/CT', 'Gene', (132, 138))	('reduction', 'NegReg', (174, 183))	('increase', 'PosReg', (226, 234))
863527	30116837	Consequently, the hypothesis addressed, namely that introduction of PET/CT into the routine EC staging algorithm was associated with improved OS after potentially curative surgery, was proven correct.	('improved', 'PosReg', (133, 141))	('OS', 'Chemical', '-', (142, 144))	('PET/CT', 'Var', (68, 74))
863544	30116837	The findings of this study have shown that the introduction of PET/CT into the global patient assessment process changed the risk profile of over one in ten patients, reduced global recurrence by one-quarter, and improved median survival by a full year.	('global recurrence', 'MPA', (175, 192))	('improved', 'PosReg', (213, 221))	('patient', 'Species', '9606', (157, 164))	('median survival', 'MPA', (222, 237))	('patients', 'Species', '9606', (157, 165))	('patient', 'Species', '9606', (86, 93))	('PET/CT', 'Var', (63, 69))	('changed', 'Reg', (113, 120))	('risk profile', 'MPA', (125, 137))	('reduced', 'NegReg', (167, 174))
863553	22112482	With new SNP based technology and larger cohort studies with greater sample sizes, there is promise to achieve better biomarkers for EA risk stratification and early detection for clinical use because genome-wide measures of chromosome instability and 17pLOH have shown promise in all prospective studies.	('EA', 'Phenotype', 'HP:0011459', (133, 135))	('chromosome instability', 'CPA', (225, 247))	('17pLOH', 'Var', (252, 258))	('rat', 'Species', '10116', (143, 146))	('chromosome instability', 'Phenotype', 'HP:0040012', (225, 247))
863579	22112482	Recent studies reporting DNA sequences of several cancer genomes, including colon, breast, pancreas and glioblastoma, have revealed many more mutations than were expected, affecting multiple steps in multiple biological pathway.	('mutations', 'Var', (142, 151))	('cancer', 'Disease', (50, 56))	('pancreas and glioblastoma', 'Disease', 'MESH:D005909', (91, 116))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('breast', 'Disease', (83, 89))	('affecting', 'Reg', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('colon', 'Disease', (76, 81))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))
863632	22112482	In BE, spatial relationships among clonal genetic abnormalities have been evaluated at the scales of individual crypts, biopsies and the BE segment, Spatial data at the level of biopsies and the BE segment led to the hypothesis that CDKN2A abnormalities (LOH, methylation, mutation) were early events in BE that preceded TP53 abnormalities (LOH, mutation), and then DNA content tetraploidy and aneuploidy.	('genetic abnormalities', 'Disease', 'MESH:D030342', (42, 63))	('CDKN2A', 'Gene', (233, 239))	('BE', 'Phenotype', 'HP:0100580', (304, 306))	('CDKN2A', 'Gene', '1029', (233, 239))	('genetic abnormalities', 'Disease', (42, 63))	('TP53', 'Gene', '7157', (321, 325))	('BE', 'Phenotype', 'HP:0100580', (137, 139))	('tetraploidy and aneuploidy', 'Disease', 'MESH:D057891', (378, 404))	('BE', 'Phenotype', 'HP:0100580', (195, 197))	('BE', 'Phenotype', 'HP:0100580', (3, 5))	('abnormalities', 'Var', (240, 253))	('TP53', 'Gene', (321, 325))
863638	22112482	In a separate cohort study of 322 patients with BE, DNA content tetraploidy (4N fractions > 6%) and aneuploidy were highly predictive of progression from BE to EA.	('rat', 'Species', '10116', (9, 12))	('aneuploidy', 'Disease', (100, 110))	('aneuploidy', 'Disease', 'MESH:D000782', (100, 110))	('tetraploidy', 'Var', (64, 75))	('patients', 'Species', '9606', (34, 42))	('BE', 'Phenotype', 'HP:0100580', (154, 156))	('EA', 'Phenotype', 'HP:0011459', (160, 162))	('BE', 'Phenotype', 'HP:0100580', (48, 50))
863639	22112482	The five year cumulative incidence of EA in patients who had normal flow cytometric results at the baseline endoscopy was only 5% compared to 62% for those with DNA content tetraploidy and 41% with aneuploidy.	('EA', 'Phenotype', 'HP:0011459', (38, 40))	('patients', 'Species', '9606', (44, 52))	('aneuploidy', 'Disease', (198, 208))	('tetraploidy', 'Var', (173, 184))	('aneuploidy', 'Disease', 'MESH:D000782', (198, 208))
863640	22112482	In patients without HGD, the five-year cumulative EA incidence was 28% in those with either DNA content tetraploidy or aneuploidy compared with 0% in those whose baseline flow cytometric results were normal.	('EA', 'Phenotype', 'HP:0011459', (50, 52))	('tetraploidy', 'Var', (104, 115))	('DNA', 'Protein', (92, 95))	('aneuploidy', 'Disease', 'MESH:D000782', (119, 129))	('patients', 'Species', '9606', (3, 11))	('aneuploidy', 'Disease', (119, 129))	('HGD', 'Gene', '3081', (20, 23))	('HGD', 'Gene', (20, 23))
863643	22112482	The five-year cumulative incidences of EA were 75% in patients with both aneuploidy greater than 2.7N and elevated 4N fractions compared to 5.2% in those with neither.	('aneuploidy', 'Disease', (73, 83))	('patients', 'Species', '9606', (54, 62))	('4N fractions', 'MPA', (115, 127))	('greater than 2.7N', 'Var', (84, 101))	('elevated', 'PosReg', (106, 114))	('aneuploidy', 'Disease', 'MESH:D000782', (73, 83))	('EA', 'Phenotype', 'HP:0011459', (39, 41))
863645	22112482	Patients with 17p LOH were also at increased risk of progression to DNA content tetraploid (RR=6.1) or aneuploid (RR=7.5) cell populations compared to those with two 17p alleles at the baseline endoscopy.	('Patients', 'Species', '9606', (0, 8))	('17p LOH', 'Var', (14, 21))	('aneuploid', 'Var', (103, 112))
863652	22112482	The study was based on biomarkers that had been evaluated spatially in BE and included the chromosome instability biomarkers 9p LOH, 17p LOH and DNA content abnormalities (tetraploidy and aneuploidy) as well as the gene specific biomarkers TP53 mutation and CDKN2A mutation and methylation.	('chromosome instability', 'Phenotype', 'HP:0040012', (91, 113))	('TP53', 'Gene', '7157', (240, 244))	('TP53', 'Gene', (240, 244))	('BE', 'Phenotype', 'HP:0100580', (71, 73))	('mutation', 'Var', (265, 273))	('CDKN2A', 'Gene', (258, 264))	('methylation', 'Var', (278, 289))	('tetraploidy and aneuploidy', 'Disease', 'MESH:D057891', (172, 198))	('CDKN2A', 'Gene', '1029', (258, 264))	('mutation', 'Var', (245, 253))
863653	22112482	At 10 years, all biomarkers except CDKN2A methylation and mutation contributed significantly to risk in univariate analysis.	('mutation', 'Var', (58, 66))	('methylation', 'Var', (42, 53))	('CDKN2A', 'Gene', '1029', (35, 41))	('CDKN2A', 'Gene', (35, 41))
863654	22112482	The chromosome instability panel of 9p LOH, 17p LOH and DNA content abnormalities (tetraploidy, aneuploidy) was the best predictor of EA among the biomarkers evaluated in the study (RR=38.7; 95% CI = 10.8-138.5; p<0.001) (Figure 2A).	('aneuploidy', 'Disease', (96, 106))	('chromosome instability', 'Phenotype', 'HP:0040012', (4, 26))	('aneuploidy', 'Disease', 'MESH:D000782', (96, 106))	('abnormalities', 'Var', (68, 81))	('EA', 'Phenotype', 'HP:0011459', (134, 136))
863665	22112482	A recent BAC array study reported that copy number provided a robust assessment of DNA content flow cytometric aneuploidy in 174 samples from a cohort of 98 patients with BE or EA.	('copy', 'Var', (39, 43))	('aneuploidy', 'Disease', (111, 121))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('patients', 'Species', '9606', (157, 165))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))	('DNA', 'MPA', (83, 86))	('EA', 'Phenotype', 'HP:0011459', (177, 179))
863666	22112482	In this study, the vast majority of flow cytometric DNA content diploid samples (141/155; 91%) had less than 180 BAC alterations, compared to 0/19 aneuploid samples.	('flow', 'Gene', (36, 40))	('diploid', 'Var', (64, 71))	('DNA content', 'Gene', (52, 63))	('rat', 'Species', '10116', (121, 124))
863670	22112482	In summary, a large body of research from many laboratories has provided evidence that chromosomal instability leading to copy gain, loss, LOH and DNA content abnormalities is associated with progression from BE to EA.	('chromosomal instability', 'Var', (87, 110))	('associated', 'Reg', (176, 186))	('chromosomal instability', 'Phenotype', 'HP:0040012', (87, 110))	('LOH', 'MPA', (139, 142))	('copy gain', 'Var', (122, 131))	('DNA content', 'MPA', (147, 158))	('BE', 'Phenotype', 'HP:0100580', (209, 211))	('EA', 'Phenotype', 'HP:0011459', (215, 217))	('loss', 'MPA', (133, 137))	('rat', 'Species', '10116', (51, 54))
863673	22112482	Bleomycin sensitive patients were found to be at increased risk of progression to aneuploidy (adjusted hazard ratio, 3.71; 95% CI 1.44-9.53) and nonsignificantly greater risk of cancer (adjusted hazard ratio, 1.63; 95% CI 0.71-3.75).	('rat', 'Species', '10116', (110, 113))	('Bleomycin', 'Chemical', 'MESH:D001761', (0, 9))	('aneuploidy', 'Disease', 'MESH:D000782', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Bleomycin', 'Var', (0, 9))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('patients', 'Species', '9606', (20, 28))	('rat', 'Species', '10116', (202, 205))	('aneuploidy', 'Disease', (82, 92))
863675	22112482	This study supports the hypothesis that sensitivity to mutagens increases the risk of neoplastic progression in persons with Barrett's esophagus, particularly those with 17p LOH including the TP53 locus.	('neoplastic progression', 'CPA', (86, 108))	('persons', 'Species', '9606', (112, 119))	("Barrett's esophagus", 'Disease', (125, 144))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (125, 144))	('sensitivity', 'Var', (40, 51))	('TP53', 'Gene', '7157', (192, 196))	('TP53', 'Gene', (192, 196))
863685	22112482	In patients with zero, one, two or three chromosome instability biomarkers (9p LOH, 17p LOH, DNA content abnormality), there was a significant trend towards EA risk reduction in NSAID users compared to nonusers (p=0.01).	('DNA content', 'MPA', (93, 104))	('EA', 'Phenotype', 'HP:0011459', (157, 159))	('chromosome instability', 'Phenotype', 'HP:0040012', (41, 63))	('patients', 'Species', '9606', (3, 11))	('reduction', 'NegReg', (165, 174))	('9p LOH', 'Var', (76, 82))
863687	22112482	Inhibition of COX-2 has also been reported to decrease the incidence of EA in an animal model of BE.	('BE', 'Phenotype', 'HP:0100580', (97, 99))	('EA', 'Phenotype', 'HP:0011459', (72, 74))	('Inhibition', 'Var', (0, 10))	('COX-2', 'Gene', '4513', (14, 19))	('decrease', 'NegReg', (46, 54))	('COX-2', 'Gene', (14, 19))
863688	22112482	have recently proposed a model of epigenetic progression in neoplasia.	('neoplasia', 'Disease', 'MESH:D009369', (60, 69))	('pig', 'Species', '9823', (35, 38))	('neoplasia', 'Disease', (60, 69))	('epigenetic', 'Var', (34, 44))	('neoplasia', 'Phenotype', 'HP:0002664', (60, 69))
863690	22112482	Continued epigenetic and genetic plasticity then drive further neoplastic progression.	('epigenetic', 'Var', (10, 20))	('drive', 'Reg', (49, 54))	('pig', 'Species', '9823', (11, 14))	('neoplastic progression', 'CPA', (63, 85))
863691	22112482	There has been recent interest in epigenetic mechanisms, especially DNA methylation, in BE and EA, and the promoter regions of about four dozen genes have been evaluated using a candidate gene approach imported from other cancers.	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('pig', 'Species', '9823', (35, 38))	('cancers', 'Disease', (222, 229))	('BE', 'Phenotype', 'HP:0100580', (88, 90))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('DNA methylation', 'Var', (68, 83))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('EA', 'Phenotype', 'HP:0011459', (95, 97))
863694	22112482	ESR1 methylation was found in inflammatory reflux esophagitis and all subsequent stages whereas APC and CDKN2A methylation were found in BE metaplasia, dysplasia and carcinoma.	('CDKN2A', 'Gene', '1029', (104, 110))	('inflammatory reflux', 'Phenotype', 'HP:0002020', (30, 49))	('ESR1', 'Gene', (0, 4))	('methylation', 'Var', (5, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('inflammatory reflux esophagitis', 'Disease', 'MESH:D005764', (30, 61))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('inflammatory reflux esophagitis', 'Disease', (30, 61))	('esophagitis', 'Phenotype', 'HP:0100633', (50, 61))	('metaplasia, dysplasia and carcinoma', 'Disease', 'MESH:D008679', (140, 175))	('APC', 'Disease', (96, 99))	('ESR1', 'Gene', '2099', (0, 4))	('found', 'Reg', (21, 26))	('CDKN2A', 'Gene', (104, 110))	('BE', 'Phenotype', 'HP:0100580', (137, 139))
863695	22112482	The authors concluded that when hypermethylation of APC, CDKN2A, and ESR1 occurs, it is usually found in a large contiguous field, suggesting either a concerted methylation change associated with metaplasia or a clonal expansion of cells with abnormal hypermethylation.	('methylation', 'MPA', (161, 172))	('CDKN2A', 'Gene', (57, 63))	('ESR1', 'Gene', (69, 73))	('CDKN2A', 'Gene', '1029', (57, 63))	('hypermethylation', 'Var', (32, 48))	('APC', 'Disease', 'MESH:D011125', (52, 55))	('metaplasia', 'Disease', 'MESH:D008679', (196, 206))	('ESR1', 'Gene', '2099', (69, 73))	('APC', 'Disease', (52, 55))	('metaplasia', 'Disease', (196, 206))
863696	22112482	examined the spatial distribution of CDKN2A abnormalities, including methylation, mutation and 9p LOH, in endoscopic biopsies and concluded that both genetic and epigenetic changes were consistent with clonal expansions in the BE segment.	('CDKN2A', 'Gene', (37, 43))	('methylation', 'MPA', (69, 80))	('mutation', 'Var', (82, 90))	('CDKN2A', 'Gene', '1029', (37, 43))	('pig', 'Species', '9823', (163, 166))	('BE', 'Phenotype', 'HP:0100580', (227, 229))
863704	22112482	A recent study of the human colon cancer methylome using unbiased array-based relative methylation analysis reported that most methylation changes were not in promoters or CpG islands, but rather in sequences up to 2kb distant, termed "CpG island shores."	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('changes', 'Var', (139, 146))	('methylation changes', 'Var', (127, 146))	('colon cancer', 'Phenotype', 'HP:0003003', (28, 40))	('colon cancer', 'Disease', 'MESH:D015179', (28, 40))	('human', 'Species', '9606', (22, 27))	('rat', 'Species', '10116', (189, 192))	('colon cancer', 'Disease', (28, 40))
863705	22112482	There was significant overlap between locations of cancer methylation related changes and tissue specific methylation changes, consistent with the epigenetic progenitor model of cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('changes', 'Reg', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('methylation', 'Var', (58, 69))	('cancer', 'Disease', (178, 184))	('pig', 'Species', '9823', (148, 151))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
863712	22112482	They reported that patients whose biopsies were cyclin D1 positive were at significantly increased risk of progression to EA compared to those whose biopsies were negative (OR = 6.85; 95% CI = 1.57-29.91).	('cyclin D1', 'Gene', (48, 57))	('patients', 'Species', '9606', (19, 27))	('biopsies', 'Var', (34, 42))	('cyclin D1', 'Gene', '595', (48, 57))	('EA', 'Phenotype', 'HP:0011459', (122, 124))
863715	22112482	They assessed TP53, cyclin D1, COX-2, and beta-catenin immunostaining and reported that TP53 positive staining was associated with an increased risk of progression (OR = 11.7; 95% CI= 1.93-71.4), but that the sensitivity was too low as a single biomarker to guide endoscopic surveillance.	('TP53', 'Gene', '7157', (14, 18))	('beta-catenin', 'Gene', (42, 54))	('TP53', 'Gene', (14, 18))	('beta-catenin', 'Gene', '1499', (42, 54))	('TP53', 'Gene', '7157', (88, 92))	('cyclin D1', 'Gene', '595', (20, 29))	('positive staining', 'Var', (93, 110))	('cyclin D1', 'Gene', (20, 29))	('TP53', 'Gene', (88, 92))	('COX-2', 'Gene', '4513', (31, 36))	('COX-2', 'Gene', (31, 36))
863730	22112482	Diploid S and 4N fractions were significantly higher in biopsies with TP53 mutation and LOH, and biallelic inactivation of TP53 was highly associated with elevated 4N fractions, which has been previously associated with progression to EA.	('4N fractions', 'MPA', (164, 176))	('biallelic inactivation', 'Var', (97, 119))	('higher', 'PosReg', (46, 52))	('TP53', 'Gene', '7157', (70, 74))	('mutation', 'Var', (75, 83))	('TP53', 'Gene', (70, 74))	('associated', 'Reg', (204, 214))	('TP53', 'Gene', '7157', (123, 127))	('elevated', 'PosReg', (155, 163))	('EA', 'Phenotype', 'HP:0011459', (235, 237))	('LOH', 'Var', (88, 91))	('TP53', 'Gene', (123, 127))
863736	22112482	Subsequent studies evaluated non-random LOH, including 5q, 9p, 13q, 17p, and 18q, DNA content abnormalities, CDKN2A mutation and methylation, and TP53 mutation in endoscopic biopsies and esophagectomy specimens.	('TP53', 'Gene', '7157', (146, 150))	('methylation', 'Var', (129, 140))	('mutation', 'Var', (116, 124))	('CDKN2A', 'Gene', (109, 115))	('TP53', 'Gene', (146, 150))	('mutation', 'Var', (151, 159))	('CDKN2A', 'Gene', '1029', (109, 115))
863737	22112482	These studies performed at the biopsy and BE segment spatial scales reported evidence of clonal heterogeneity and clonal expansions involving large regions of the esophageal mucosa with 9p LOH, 17p LOH and DNA content abnormalities occurring in the premalignant BE surrounding EAs.	('EA', 'Phenotype', 'HP:0011459', (277, 279))	('BE', 'Phenotype', 'HP:0100580', (262, 264))	('expansions', 'Var', (121, 131))	('esophageal mucosa', 'Disease', (163, 180))	('DNA content', 'Gene', (206, 217))	('esophageal mucosa', 'Disease', 'MESH:D004941', (163, 180))	('EAs', 'Chemical', '-', (277, 280))	('BE', 'Phenotype', 'HP:0100580', (42, 44))
863738	22112482	In this study of 211 persons with BE, CDKN2A mutation and methylation, 9p LOH, TP53 mutations and 17p LOH were all highly selected as evidenced by their association with clonal expansions.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('persons', 'Species', '9606', (21, 28))	('mutations', 'Var', (84, 93))	('methylation', 'Var', (58, 69))	('mutation', 'Var', (45, 53))	('CDKN2A', 'Gene', (38, 44))	('BE', 'Phenotype', 'HP:0100580', (34, 36))	('CDKN2A', 'Gene', '1029', (38, 44))
863739	22112482	For example, 92% of microsatellite shifts that expanded could be explained as hitchhikers ("passengers") on selected CDKN2A abnormalities.	('shifts', 'Var', (35, 41))	('microsatellite', 'MPA', (20, 34))	('CDKN2A', 'Gene', '1029', (117, 123))	('CDKN2A', 'Gene', (117, 123))
863744	22112482	These results suggest that the combination of clonal expansion and genetic instability interact to promote progression from BE to EA and likely integrates assessment of increased population size with mutation rate.	('rat', 'Species', '10116', (149, 152))	('genetic instability', 'Var', (67, 86))	('promote', 'PosReg', (99, 106))	('rat', 'Species', '10116', (209, 212))	('EA', 'Phenotype', 'HP:0011459', (130, 132))	('clonal expansion', 'Var', (46, 62))	('BE', 'Phenotype', 'HP:0100580', (124, 126))
863746	22112482	For example, it is unknown whether a clonal expansion that homogenizes a cell population as is seen in some CDKN2A expansions in BE or accumulation of clonal diversity as suggested with emergence of multiple aneuploid populations in BE  is more predictive of progression to cancer.	('CDKN2A', 'Gene', '1029', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Disease', (274, 280))	('expansions', 'Var', (115, 125))	('BE', 'Phenotype', 'HP:0100580', (129, 131))	('BE', 'Phenotype', 'HP:0100580', (233, 235))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('CDKN2A', 'Gene', (108, 114))
863751	22112482	Diversity, as assessed by Shannon Index, was higher in biopsies with TP53 LOH than in those without, indicating that TP53 LOH is also associated with increased cellular diversity.	('cellular diversity', 'CPA', (160, 178))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (69, 73))	('TP53', 'Gene', (117, 121))	('increased', 'PosReg', (150, 159))	('higher', 'PosReg', (45, 51))	('Diversity', 'MPA', (0, 9))	('LOH', 'Var', (74, 77))
863752	22112482	The investigators dissected individual crypts from BE segments and evaluated them for LOH involving APC (5q), p16 (9p) and TP53 (17p) using microsatellite polymorphisms as well as p16 and TP53 point mutations.	('p16', 'Gene', '1029', (110, 113))	('p16', 'Gene', '1029', (180, 183))	('APC', 'Disease', 'MESH:D011125', (100, 103))	('APC', 'Disease', (100, 103))	('p16', 'Gene', (110, 113))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', '7157', (188, 192))	('TP53', 'Gene', (188, 192))	('p16', 'Gene', (180, 183))	('BE', 'Phenotype', 'HP:0100580', (51, 53))	('point mutations', 'Var', (193, 208))	('TP53', 'Gene', (123, 127))
863762	22935382	Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient's ESCC tissues.	('mutations', 'Var', (21, 30))	('B-raf', 'Gene', (47, 52))	('EGFR', 'Gene', (34, 38))	('SCC', 'CellLine', 'CVCL:1R13', (143, 146))	('patient', 'Species', '9606', (132, 139))	('PIK3CA', 'Gene', (57, 63))
863766	22935382	A second HER-2 positive (IHC 2+) model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363.	('PIK3CA', 'Gene', (64, 70))	('EC039', 'CellLine', 'CVCL:9048', (40, 45))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (233, 244))	('mutation', 'Var', (71, 79))	('activation', 'PosReg', (98, 108))	('AZD5363', 'Chemical', 'MESH:C575618', (263, 270))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (161, 172))	('AKT signaling pathway', 'Pathway', (116, 137))
863768	22935382	This study demonstrates Trastuzumab-induced tumor regressions in HER-2 positive tumors, and highlights PIK3CA mutation as a potential resistance mechanism to Trastuzumab treatment in pre-clinical patient-derived EC xenograft models.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('regressions', 'NegReg', (50, 61))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (158, 169))	('patient', 'Species', '9606', (196, 203))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (80, 85))	('PIK3CA', 'Gene', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('HER-2', 'Protein', (65, 70))	('mutation', 'Var', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
863782	22935382	Results from early clinical trials demonstrated a correlation between HER-2 expression and gene amplification with Trastuzumab therapeutic efficacy in patients with esophageal adenocarcinomas.	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (165, 191))	('patients', 'Species', '9606', (151, 159))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))	('gene amplification', 'Var', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('HER-2', 'Protein', (70, 75))	('esophageal adenocarcinomas', 'Disease', (165, 191))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (115, 126))
863800	22935382	After three consecutive mouse-to-mouse passages, the xenograft was considered to be stabilized and was submitted to the process of model characterization, including histopathologic analysis, HER-2 expression by FISH and IHC assays, and mutation detection for EGFR, K-ras, B-raf and PIK3CA genes.	('mouse', 'Species', '10090', (24, 29))	('mutation', 'Var', (236, 244))	('K-ras', 'Protein', (265, 270))	('PIK3CA', 'Gene', (282, 288))	('B-raf', 'Gene', (272, 277))	('mouse', 'Species', '10090', (33, 38))	('EGFR', 'Gene', (259, 263))
863832	22935382	2971) from DAKO Biotechnology, and mTor (No 2972), AKT (No 9272), p44/42 MAP Kinase (No 9102), S6 (No 2317), 4EBP1 (No 9452) and p-AKT-Ser 473 (M3628), Phospho-p44/42-MAPK-Thr202/Tyr 204 (No 4370), p-S6-Ser 240/244 (No 2215), p-4EBP1-Thr 70 (No 9455), and anti-GAPDH were purchased from CST Biotechnology.	('M3628', 'Var', (144, 149))	('p-S6-Ser 240/244', 'Var', (198, 214))	('GAPDH', 'Gene', '2597', (261, 266))	('mTor', 'Gene', (35, 39))	('Thr202/Tyr', 'Var', (172, 182))	('p-AKT-Ser', 'Var', (129, 138))	('GAPDH', 'Gene', (261, 266))	('4EBP1', 'Gene', '1978', (228, 233))	('DAKO', 'Chemical', '-', (11, 15))	('No 9102', 'Var', (85, 92))	('4EBP1', 'Gene', '1978', (109, 114))	('4EBP1', 'Gene', (228, 233))	('mTor', 'Gene', '2475', (35, 39))	('4EBP1', 'Gene', (109, 114))	('Thr202/Tyr', 'SUBSTITUTION', 'None', (172, 182))
863848	22935382	Following Hoffman' HER-2 score criteria (12), two PDECX mouse models (EC039 and EC044) were scored as moderately positive for HER-2 membrane staining (2+), the remaining models (EC004, 016 and 054) were negative for HER-2 staining (Figure 2).	('HER-2 membrane', 'Protein', (126, 140))	('mouse', 'Species', '10090', (56, 61))	('EC039', 'CellLine', 'CVCL:9048', (70, 75))	('positive', 'Reg', (113, 121))	('EC044', 'Var', (80, 85))
863849	22935382	However, models EC039 and EC044 showed increased gene copy numbers, with average copy numbers of 3.90 and 3.92, respectively.	('EC044', 'Var', (26, 31))	('gene copy numbers', 'MPA', (49, 66))	('increased', 'PosReg', (39, 48))	('EC039', 'Var', (16, 21))	('EC039', 'CellLine', 'CVCL:9048', (16, 21))
863855	22935382	To explore potential Trastuzumab resistance mechanisms in model EC039, we screened for mutations in a panel of genes (EGFR, K-ras, B-raf and PIK3CA) across all 5 PDECX models and their corresponding patient EC tissues.	('K-ras', 'Gene', (124, 129))	('EC039', 'CellLine', 'CVCL:9048', (64, 69))	('screened', 'Reg', (74, 82))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (21, 32))	('patient', 'Species', '9606', (199, 206))	('EGFR', 'Gene', (118, 122))	('B-raf', 'Gene', (131, 136))	('mutations', 'Var', (87, 96))
863856	22935382	Interestingly, PIK3CA G1624A (E542K) mutation was identified within exon 9 of the PIK3CA gene helical domain in both EC039 model and the corresponding patient's EC tissue.	('G1624A (E542K', 'Var', (22, 35))	('E542K', 'Mutation', 'rs121913273', (30, 35))	('G1624A', 'Mutation', 'rs121913273', (22, 28))	('PIK3CA', 'Gene', (82, 88))	('patient', 'Species', '9606', (151, 158))	('EC039', 'CellLine', 'CVCL:9048', (117, 122))
863859	22935382	Significant increases in the protein levels of AKT and pAKT were observed in model EC039 compared to model EC044 (p<0.0004).	('protein levels', 'MPA', (29, 43))	('EC039', 'Var', (83, 88))	('EC039', 'CellLine', 'CVCL:9048', (83, 88))	('increases', 'PosReg', (12, 21))	('AKT', 'Protein', (47, 50))
863860	22935382	Our data clearly demonstrate AKT pathway activation as a consequence of PIK3CA mutation in model EC039, compared with the PIK3CA wild type model EC044.	('AKT pathway', 'Pathway', (29, 40))	('PIK3CA', 'Gene', (72, 78))	('EC039', 'CellLine', 'CVCL:9048', (97, 102))	('mutation', 'Var', (79, 87))	('activation', 'PosReg', (41, 51))
863861	22935382	To further test our hypothesis that PIK3CA mutation was responsible for the resistance to Trastuzumab therapy in a HER-2 positive esophageal PDECX model, we performed an anti-tumor efficacy combination study using Trastuzumab and the small molecule AKT inhibitor, AZD5363.	('AZD5363', 'Chemical', 'MESH:C575618', (264, 271))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (214, 225))	('tumor', 'Disease', (175, 180))	('mutation', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (90, 101))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('PIK3CA', 'Gene', (36, 42))
863870	22935382	Esophageal carcinoma represents another disease with a high frequency of tumor HER-2 expression and gene amplification.	('Esophageal carcinoma', 'Disease', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('gene amplification', 'Var', (100, 118))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (0, 20))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
863872	22935382	In addition, the predominant histological subtype of esophageal carcinoma differs between Eastern and Western countries, and adenocarcinoma has been shown to exhibit higher rates of HER-2 protein expression positivity and gene amplification compared to squamous cell carcinoma.	('higher', 'PosReg', (166, 172))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (53, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (125, 139))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (253, 276))	('HER-2 protein', 'Protein', (182, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('adenocarcinoma', 'Disease', (125, 139))	('gene', 'MPA', (222, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (253, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('positivity', 'Var', (207, 217))	('esophageal carcinoma', 'Disease', (53, 73))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (53, 73))	('squamous cell carcinoma', 'Disease', (253, 276))
863885	22935382	In clinical studies of metastatic colon cancer, patients with wild type K-ras, B-raf and PIK3CA genes gain benefit from cetuximab therapy, whilst lung cancer patients with mutations in exons 19 and 21 of the EGFR gene benefit from Iressa or Tarceva therapy.	('colon cancer', 'Disease', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('Tarceva', 'Chemical', 'MESH:D000069347', (241, 248))	('gain benefit', 'PosReg', (102, 114))	('PIK3CA genes', 'Gene', (89, 101))	('B-raf', 'Gene', (79, 84))	('cetuximab', 'Chemical', 'MESH:D000068818', (120, 129))	('mutations in exons 19', 'Var', (172, 193))	('colon cancer', 'Phenotype', 'HP:0003003', (34, 46))	('colon cancer', 'Disease', 'MESH:D015179', (34, 46))	('lung cancer', 'Disease', (146, 157))	('EGFR', 'Gene', (208, 212))	('patients', 'Species', '9606', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('patients', 'Species', '9606', (48, 56))
863886	22935382	Furthermore, mutations in ESCC patients have been recently reported; 16% of ESCC patients (5/30 cases) harbor K-ras gene mutations, 14% of ESCC patients (7/50 cases) contain EGFR mutation, and 2.2-11.8% of ESCC patients have gene mutations in exon 9 of the PIK3CA gene.	('EGFR', 'Gene', (174, 178))	('gene mutations in', 'Var', (225, 242))	('mutations', 'Var', (121, 130))	('patients', 'Species', '9606', (211, 219))	('PIK3CA', 'Gene', (257, 263))	('mutation', 'Var', (179, 187))	('patients', 'Species', '9606', (81, 89))	('SCC', 'CellLine', 'CVCL:1R13', (207, 210))	('SCC', 'CellLine', 'CVCL:1R13', (77, 80))	('patients', 'Species', '9606', (144, 152))	('K-ras gene', 'Protein', (110, 120))	('patients', 'Species', '9606', (31, 39))	('SCC', 'CellLine', 'CVCL:1R13', (140, 143))	('ESCC', 'Disease', (76, 80))	('SCC', 'CellLine', 'CVCL:1R13', (27, 30))
863888	22935382	After screening for EGFR, K-ras, B-raf and PIK3CA gene mutations in the 5 PDECX mouse models and their corresponding primary tumors, we found that model EC039 (and the corresponding patient tissue) had a helical domain mutation (G1624A, E542K) in exon 9 of the PIK3CA gene (Figure 4 and Table 1).	('G1624A', 'Var', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('E542K', 'Mutation', 'rs121913273', (237, 242))	('PIK3CA', 'Gene', (261, 267))	('tumors', 'Disease', (125, 131))	('patient', 'Species', '9606', (182, 189))	('mouse', 'Species', '10090', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('EC039', 'CellLine', 'CVCL:9048', (153, 158))	('E542K', 'Var', (237, 242))	('G1624A', 'Mutation', 'rs121913273', (229, 235))	('PIK3CA', 'Gene', (43, 49))
863890	22935382	PIK3CA activating mutations have been reported to associate with shorter time to progression (TTP) in Trastuzumab-treated breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('Trastuzumab-treated breast cancer', 'Disease', 'MESH:D001943', (102, 135))	('shorter', 'NegReg', (65, 72))	('PIK3CA', 'Gene', (0, 6))	('Trastuzumab-treated breast cancer', 'Disease', (102, 135))	('time to progression', 'MPA', (73, 92))	('mutations', 'Var', (18, 27))
863892	22935382	Mutations in exon 9 and 20 of the PIK3CA gene have been observed in 8% to 40% of breast cancers.	('PIK3CA', 'Gene', (34, 40))	('breast cancers', 'Disease', 'MESH:D001943', (81, 95))	('observed', 'Reg', (56, 64))	('breast cancers', 'Disease', (81, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('Mutations in', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))
863893	22935382	Furthermore, an association between PIK3CA mutation and resistance to Trastuzumab therapy in HER-2-amplified breast cancer cell lines has also been reported.	('breast cancer', 'Disease', (109, 122))	('mutation', 'Var', (43, 51))	('association', 'Reg', (16, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('resistance to Trastuzumab therapy', 'MPA', (56, 89))	('PIK3CA', 'Gene', (36, 42))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
863894	22935382	have also suggested that oncogenic mutations of PIK3CA may render breast cancers more resistant to treatment with Trastuzumab, and Eichhorn et al.	('breast cancers', 'Phenotype', 'HP:0003002', (66, 80))	('PIK3CA', 'Gene', (48, 54))	('resistant', 'MPA', (86, 95))	('breast cancers', 'Disease', 'MESH:D001943', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancers', 'Disease', (66, 80))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (114, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('mutations', 'Var', (35, 44))
863895	22935382	have further shown that mutational activation of PIK3CA can similarly render cells more resistant to the recently approved anti-HER2 agent Lapatinib.	('mutational', 'Var', (24, 34))	('HER2', 'Gene', (128, 132))	('HER2', 'Gene', '2064', (128, 132))	('resistant to', 'MPA', (88, 100))	('Lapatinib', 'Chemical', 'MESH:D000077341', (139, 148))	('PIK3CA', 'Gene', (49, 55))	('activation', 'PosReg', (35, 45))
863896	22935382	In this situation however, Lapatinib resistance caused by the dominant activating mutations in PIK3CA can be effectively reversed by treatment with the PI3K/mTOR inhibitor, NVP-BEZ235.	('PIK3CA', 'Gene', (95, 101))	('Lapatinib', 'Chemical', 'MESH:D000077341', (27, 36))	('activating', 'PosReg', (71, 81))	('Lapatinib resistance', 'MPA', (27, 47))	('mutations', 'Var', (82, 91))	('mTOR', 'Gene', (157, 161))	('mTOR', 'Gene', '2475', (157, 161))
863897	22935382	Moreover, the AKT inhibitor AZD5363 increases the efficacy of lapatinib and/or trastuzumab in xenografts derived from HER2+ breast cancer cell lines harboring PIK3CA mutation.	('AZD5363', 'Var', (28, 35))	('efficacy', 'MPA', (50, 58))	('lapatinib', 'Chemical', 'MESH:D000077341', (62, 71))	('HER2', 'Gene', (118, 122))	('AZD5363', 'Chemical', 'MESH:C575618', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('trastuzumab', 'Chemical', 'MESH:D000068878', (79, 90))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('HER2', 'Gene', '2064', (118, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('PIK3CA', 'Gene', (159, 165))	('increases', 'PosReg', (36, 45))	('mutation', 'Var', (166, 174))
863898	22935382	In our study, we observed strong AKT pathway activation in the PIK3CA mutation model EC039 (Figure 5A) compared to wild type model EC044, suggesting that activated AKT pathway signaling likely contributes to Trastuzumab resistance in our efficacy study.	('Trastuzumab', 'Chemical', 'MESH:D000068878', (208, 219))	('EC039', 'CellLine', 'CVCL:9048', (85, 90))	('AKT pathway', 'Pathway', (33, 44))	('PIK3CA', 'Gene', (63, 69))	('mutation', 'Var', (70, 78))	('activation', 'PosReg', (45, 55))
863899	22935382	To our knowledge, we are the first to describe a PIK3CA gene mutation which causes resistance to Trastuzumab therapy in a preclinical PDECX mouse model, and which can be partly resensitised using a combination of Trastuzumab and AKT inhibitor (Figure 5B).	('mouse', 'Species', '10090', (140, 145))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (213, 224))	('mutation', 'Var', (61, 69))	('PIK3CA', 'Gene', (49, 55))	('causes', 'Reg', (76, 82))	('resistance to Trastuzumab therapy', 'MPA', (83, 116))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (97, 108))
863902	22935382	Our results demonstrate that a non-amplified, HER-2 IHC 2+ model responds completely to Trastuzumab targeted therapy, and importantly, that PIK3CA gene mutation negatively associates with Trastuzumab anti-tumor efficacy in a xenograft model of ESCC.	('PIK3CA', 'Gene', (140, 146))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (188, 199))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('associates with', 'Reg', (172, 187))	('SCC', 'CellLine', 'CVCL:1R13', (245, 248))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('ESCC', 'Disease', (244, 248))	('mutation', 'Var', (152, 160))	('negatively', 'NegReg', (161, 171))
863904	22935382	Taken together, this study illustrates that Trastuzumab can induce regression in a HER-2 positive tumor, and that PIK3CA mutation (in a HER-2 positive background) may be a potential resistance mechanism to Trastuzumab treatment in pre-clinical patient-derived EC xenograft models.	('Trastuzumab', 'Chemical', 'MESH:D000068878', (44, 55))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('patient', 'Species', '9606', (244, 251))	('regression', 'CPA', (67, 77))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (206, 217))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutation', 'Var', (121, 129))	('PIK3CA', 'Gene', (114, 120))	('HER-2', 'Protein', (83, 88))
863908	22935382	The authors also thank Dr. Barry R. Davies and Dr. Derek Yu provided the AKT inhibitor AZD5363 for combination efficacy study in animal tumor model.	('AZD5363', 'Var', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('AZD5363', 'Chemical', 'MESH:C575618', (87, 94))
863918	33613616	Current clinical oncology applications have been complementary to genomic mutation analysis to improve precision medicine: (1) prediction of response and resistance to various therapies, especially targeted therapy and immunotherapy; (2) assessment and monitoring of therapy efficacy; (3) prediction of invasive cancer cell behavior and prognosis; (4) measurement of circulating tumor cells.	('mutation', 'Var', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (379, 384))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('oncology', 'Phenotype', 'HP:0002664', (17, 25))	('tumor', 'Disease', (379, 384))	('invasive cancer', 'Disease', (303, 318))	('invasive cancer', 'Disease', 'MESH:D009362', (303, 318))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
863930	33613616	The availability of Next Generation Sequencing (NGS) techniques has enabled identifying tumor-driving gene mutations in many histologies of cancer.	('mutations', 'Var', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', (88, 93))
863931	33613616	FDA approval was recently obtained for the use of the PI3K inhibitor drug alpelisib in breast cancer patients with a PIK3CA mutation, based on the results of the SOLAR-1 trial.	('patients', 'Species', '9606', (101, 109))	('drug alpelisib in breast cancer', 'Disease', 'MESH:D001943', (69, 100))	('PIK3CA', 'Gene', (117, 123))	('drug alpelisib in breast cancer', 'Disease', (69, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PIK3CA', 'Gene', '5290', (117, 123))	('mutation', 'Var', (124, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('AR', 'Gene', '367', (165, 167))
863932	33613616	Other mutations may be clinically used independent of FDA approval, for example activating mutations in the ESR1 gene coding for the estrogen receptor and associated with resistance to hormonal therapy.	('ESR1', 'Gene', '2099', (108, 112))	('activating mutations', 'Var', (80, 100))	('associated', 'Reg', (155, 165))	('ESR1', 'Gene', (108, 112))	('estrogen receptor', 'Gene', (133, 150))	('estrogen receptor', 'Gene', '2099', (133, 150))
863933	33613616	An important factor, partially explaining this disappointing result, is that the cancer cell phenotype is determined not only by genomic mutations, but also by epigenetic dysregulations and by interactions with cells in the tumor microenvironment, e.g., fibroblasts and a variety of immune cells.	('genomic mutations', 'Var', (129, 146))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('epigenetic dysregulations', 'Var', (160, 185))	('tumor', 'Disease', (224, 229))	('determined', 'Reg', (106, 116))	('interactions', 'Interaction', (193, 205))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
863958	33613616	Our findings have shown that STP analysis of a cancer tissue sample may assist in functionally characterizing a gene mutation; for example, an unknown mutation in a gene encoding a signaling protein is more likely to be a functional mutation if the corresponding pathway was found active (Figure 3).	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (47, 53))	('mutation', 'Var', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
863961	33613616	Wnt pathway activity scores were normal in the reference (WT), increased in loss-of-function APC-mutated ovary cancer and in gain-of-function CTNNB1 Asp32Tyr mutated breast cancer, and normal in non-functionally mutated CTNNB1 Asp665Glu breast cancer (Figure 3).	('ovary cancer', 'Phenotype', 'HP:0100615', (105, 117))	('CTNNB1', 'Gene', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('loss-of-function', 'NegReg', (76, 92))	('breast cancer', 'Disease', (166, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('gain-of-function', 'PosReg', (125, 141))	('Asp32Tyr mutated', 'Var', (149, 165))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('breast cancer', 'Disease', (237, 250))	('APC', 'Disease', 'MESH:D011125', (93, 96))	('APC', 'Disease', (93, 96))	('ovary cancer', 'Disease', (105, 117))	('Asp665Glu', 'Mutation', 'rs77750814', (227, 236))	('CTNNB1', 'Gene', '1499', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Asp665Glu', 'Var', (227, 236))	('CTNNB1', 'Gene', '1499', (220, 226))	('increased', 'PosReg', (63, 72))	('ovary cancer', 'Disease', 'MESH:D010051', (105, 117))	('Asp32Tyr', 'Mutation', 'rs28931588', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('Wnt pathway', 'Pathway', (0, 11))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('CTNNB1', 'Gene', (142, 148))
863986	33613616	The PI3K pathway is a major growth factor pathway, sometimes called a "survival" pathway, and the frequent pathway activity can be caused by for example mutations in the PIK3CA gene or amplification of the HER2 gene.	('PIK3CA', 'Gene', '5290', (170, 176))	('caused', 'Reg', (131, 137))	('mutations', 'Var', (153, 162))	('activity', 'MPA', (115, 123))	('HER2', 'Gene', (206, 210))	('PI3K pathway', 'Pathway', (4, 16))	('HER2', 'Gene', '2064', (206, 210))	('amplification', 'Var', (185, 198))	('PIK3CA', 'Gene', (170, 176))
863990	33613616	In breast cancer and colon cancer, high TGFbeta pathway activity was associated with worse prognosis.	('TGFbeta', 'Gene', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('activity', 'MPA', (56, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('TGFbeta', 'Gene', '7039', (40, 47))	('colon cancer', 'Disease', 'MESH:D015179', (21, 33))	('high', 'Var', (35, 39))	('colon cancer', 'Disease', (21, 33))
864016	33613616	This is illustrated in Figure 5 in which anti-EGFR inhibitors (cetuximab, gefitinib, and afatinib) had been used to treat breast cancer cells containing mutations in genes coding for proteins that play a direct or indirect role (through crosstalk between pathways) in the PI3K pathway.	('PI3K pathway', 'Pathway', (272, 284))	('cetuximab', 'Chemical', 'MESH:D000068818', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('afatinib', 'Chemical', 'MESH:D000077716', (89, 97))	('mutations', 'Var', (153, 162))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', (46, 50))	('gefitinib', 'Chemical', 'MESH:D000077156', (74, 83))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
864020	33613616	Only minor inhibitory effects were observed in HRAS- and PIK3CA-mutant cells because these mutations are located downstream of the TKI drug targets and therefore confer resistance.	('PIK3CA', 'Gene', '5290', (57, 63))	('resistance', 'MPA', (169, 179))	('HRAS-', 'Gene', (47, 52))	('confer', 'Reg', (162, 168))	('mutations', 'Var', (91, 100))	('PIK3CA', 'Gene', (57, 63))
864040	31431383	Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity TH-302 combined with RT enhances tumor growth delay in esophageal cancer models.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('enhances', 'PosReg', (125, 133))	('carcinomas', 'Disease', 'MESH:D009369', (35, 45))	('toxicity', 'Disease', (92, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('Evofosfamide', 'Chemical', 'MESH:C552526', (0, 12))	('carcinomas', 'Disease', (35, 45))	('TH-302', 'Chemical', 'MESH:C552526', (101, 107))	('esophageal cancer', 'Disease', (156, 173))	('TH-302', 'Var', (101, 107))	('tumor growth delay', 'Disease', 'MESH:D006130', (134, 152))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (24, 45))	('growth delay', 'Phenotype', 'HP:0001510', (140, 152))	('tumor growth delay', 'Disease', (134, 152))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('toxicity', 'Disease', 'MESH:D064420', (92, 100))
864049	31431383	The combination treatment of TH-302 with radiotherapy resulted in significant tumor growth delay in OE19 (P = 0.02) and OE21 (P = 0.03) carcinomas, compared to radiotherapy only.	('OE19', 'Disease', (100, 104))	('TH-302', 'Chemical', 'MESH:C552526', (29, 35))	('tumor growth delay', 'Disease', 'MESH:D006130', (78, 96))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('carcinomas', 'Disease', 'MESH:D009369', (136, 146))	('tumor growth delay', 'Disease', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('carcinomas', 'Disease', (136, 146))	('OE21', 'Var', (120, 124))	('growth delay', 'Phenotype', 'HP:0001510', (84, 96))
864071	31431383	In the present study, we therefore assessed in vivo whether TH-302 can sensitize esophageal carcinomas to RT and if this combination therapy results in increased short-term and/or long-term normal tissue toxicity using a gut mucosa and a lung fibrosis model, sensitive to acute and late radiation injury respectively.	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (81, 102))	('lung fibrosis', 'Disease', 'MESH:D005355', (238, 251))	('radiation injury', 'Disease', (287, 303))	('increased', 'PosReg', (152, 161))	('sensitize', 'Reg', (71, 80))	('carcinomas', 'Disease', 'MESH:D009369', (92, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('toxicity', 'Disease', 'MESH:D064420', (204, 212))	('lung fibrosis', 'Disease', (238, 251))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('carcinomas', 'Disease', (92, 102))	('TH-302', 'Chemical', 'MESH:C552526', (60, 66))	('TH-302', 'Var', (60, 66))	('toxicity', 'Disease', (204, 212))	('radiation injury', 'Disease', 'MESH:D011832', (287, 303))	('lung fibrosis', 'Phenotype', 'HP:0002206', (238, 251))
864096	31431383	1B) increased by TH-302 monotherapy (12.4 +- 4.5  days to 14.5 +- 3.8 and 17.1 +- 4.0 to 27.0 +- 14.9 days for OE19 and OE21 respectively).	('TH-302', 'Chemical', 'MESH:C552526', (17, 23))	('OE21', 'Var', (120, 124))	('OE19', 'Var', (111, 115))
864101	31431383	This assay also showed that TH-302 was only activated under anoxic conditions and that the combination of RT and TH-302 resulted in the lowest cell viability (Suppl Fig.	('cell viability', 'CPA', (143, 157))	('combination', 'Interaction', (91, 102))	('lowest', 'NegReg', (136, 142))	('TH-302', 'Chemical', 'MESH:C552526', (113, 119))	('TH-302', 'Var', (113, 119))	('TH-302', 'Chemical', 'MESH:C552526', (28, 34))
864105	31431383	The combination of TH-302 and RT resulted in a small reduction in citrulline concentration compared to RT alone (P < 0.05), whereas there was no additional effect of TH-302 on crypt survival and mucosal surface area.	('citrulline', 'Chemical', 'MESH:D002956', (66, 76))	('citrulline concentration', 'MPA', (66, 90))	('TH-302', 'Chemical', 'MESH:C552526', (166, 172))	('TH-302', 'Chemical', 'MESH:C552526', (19, 25))	('reduction', 'NegReg', (53, 62))	('TH-302', 'Var', (19, 25))
864113	31431383	For all parameters and all three groups, the combination of TH-302 and RT did not increase intestinal damage compared to radiotherapy alone.	('intestinal damage', 'Disease', 'MESH:D007410', (91, 108))	('intestinal damage', 'Disease', (91, 108))	('TH-302', 'Chemical', 'MESH:C552526', (60, 66))	('TH-302', 'Var', (60, 66))
864123	31431383	In addition, we showed little or no additional toxicity when supplementing TH-302 to RT on the gut (short-term) and lung (long-term).	('TH-302', 'Chemical', 'MESH:C552526', (75, 81))	('toxicity', 'Disease', 'MESH:D064420', (47, 55))	('TH-302', 'Var', (75, 81))	('toxicity', 'Disease', (47, 55))
864124	31431383	Although the OE19 model was more resistant to therapy (to RT, TH-302 monotherapy and the combination) than OE21, both models showed an increased time to reach four times start volume (T4xSV) upon TH-302 combination with RT in vivo.	('TH-302', 'Chemical', 'MESH:C552526', (62, 68))	('time', 'MPA', (145, 149))	('increased', 'PosReg', (135, 144))	('combination', 'Interaction', (203, 214))	('TH-302', 'Chemical', 'MESH:C552526', (196, 202))	('TH-302', 'Var', (196, 202))
864136	31431383	TH-302 did not increase radiation-induced toxicity on the long term, as assessed by changes in CT density of partially irradiated lungs representing fibrosis.	('TH-302', 'Var', (0, 6))	('CT density', 'MPA', (95, 105))	('changes', 'Reg', (84, 91))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('toxicity', 'Disease', (42, 50))	('fibrosis', 'Disease', 'MESH:D005355', (149, 157))	('fibrosis', 'Disease', (149, 157))	('TH-302', 'Chemical', 'MESH:C552526', (0, 6))
864141	31431383	Here we show a favorable tumor growth inhibition by the combination of TH-302 and RT over RT alone in two esophageal cancer models, expressed as an enhancement ratio (ER) of 1.38 (average of the two models).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('enhancement', 'PosReg', (148, 159))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (25, 30))	('TH-302', 'Chemical', 'MESH:C552526', (71, 77))	('TH-302', 'Var', (71, 77))	('esophageal cancer', 'Disease', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
864157	31431383	Possibly, higher dosing schedules can be used when combining TH-302 with RT leading to improved therapeutic benefit.	('therapeutic', 'MPA', (96, 107))	('TH-302', 'Chemical', 'MESH:C552526', (61, 67))	('improved', 'PosReg', (87, 95))	('TH-302', 'Var', (61, 67))
864158	31431383	In conclusion, we show that the combination of TH-302 and RT influences therapeutic efficacy to a different extent in two esophageal cancer models, with only minor effect on radiation-induced normal tissue toxicity.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('toxicity', 'Disease', 'MESH:D064420', (206, 214))	('toxicity', 'Disease', (206, 214))	('TH-302', 'Chemical', 'MESH:C552526', (47, 53))	('TH-302', 'Var', (47, 53))	('therapeutic efficacy', 'CPA', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('influences', 'Reg', (61, 71))
864246	28163045	The multivariate-adjusted HR of metabolic syndrome was significant in male patients with TNM stage I or II (HR = 1.59; 95% CI: 1.05-2.41; P = 0.029) and positive regional LNM (N1-N3) (HR = 1.42; 95% CI: 1.10-1.83; P = 0.008) after adjusting for age, smoking and drinking, while no significance was noticed in females.	('patients', 'Species', '9606', (75, 83))	('positive regional LNM', 'Var', (153, 174))	('metabolic syndrome', 'Disease', 'MESH:D008659', (32, 50))	('TNM', 'Disease', (89, 92))	('metabolic syndrome', 'Disease', (32, 50))
864290	27410681	Lack of Correlation between Aberrant p16, RAR-beta2, TIMP3, ERCC1, and BRCA1 Protein Expression and Promoter Methylation in Squamous Cell Carcinoma Accompanying Candida albicans-Induced Inflammation Hyperplastic candidiasis is characterized by thickening of the mucosal epithelia with Candida albicans infection with occasional progression to squamous cell carcinoma (SCC).	('Squamous Cell Carcinoma', 'Disease', (124, 147))	('Candida albicans infection', 'Disease', 'MESH:C536777', (285, 311))	('Hyperplastic candidiasis', 'Disease', 'MESH:D002177', (199, 223))	('SCC', 'Gene', '6317', (368, 371))	('p16', 'Gene', '1029', (37, 40))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (343, 366))	('ERCC1', 'Gene', (60, 65))	('SCC', 'Gene', (368, 371))	('Candida albicans', 'Species', '5476', (161, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('Candida albicans infection', 'Disease', (285, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (357, 366))	('squamous cell carcinoma', 'Disease', (343, 366))	('Hyperplastic candidiasis', 'Disease', (199, 223))	('mucosal epithelia', 'Disease', (262, 279))	('BRCA1', 'Gene', '672', (71, 76))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (124, 147))	('Candida albicans', 'Species', '5476', (285, 301))	('Inflammation Hyperplastic candidiasis', 'Phenotype', 'HP:0005411', (186, 223))	('BRCA1', 'Gene', (71, 76))	('TIMP3', 'Gene', '7078', (53, 58))	('TIMP3', 'Gene', (53, 58))	('SCC', 'Phenotype', 'HP:0002860', (368, 371))	('Aberrant', 'Var', (28, 36))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (343, 366))	('mucosal epithelia', 'Disease', 'MESH:D052016', (262, 279))	('ERCC1', 'Gene', '2067', (60, 65))	('p16', 'Gene', (37, 40))
864293	27410681	In the present study, we investigate whether impaired DNA methylation and associated protein expression of tumor suppressor and DNA repair genes are involved in the SCC carcinogenesis process using this hyperplastic candidiasis model.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('SCC carcinogenesis', 'Disease', (165, 183))	('tumor', 'Disease', (107, 112))	('SCC carcinogenesis', 'Disease', 'MESH:D063646', (165, 183))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('impaired', 'Var', (45, 53))	('hyperplastic candidiasis', 'Phenotype', 'HP:0005411', (203, 227))	('involved', 'Reg', (149, 157))	('hyperplastic candidiasis', 'Disease', (203, 227))	('protein expression', 'MPA', (85, 103))	('hyperplastic candidiasis', 'Disease', 'MESH:D002177', (203, 227))
864299	27410681	These results suggest that aberrant p16, RAR-beta2, TIMP3, ERCC1, and BRCA1 expression might occur that is inconsistent with the respective gene promoter methylation status, and that this overexpression might serve to promote the inflammatory carcinogenesis caused by C. albicans infection.	('ERCC1', 'Gene', (59, 64))	('inflammatory carcinogenesis', 'Disease', 'MESH:D063646', (230, 257))	('aberrant', 'Var', (27, 35))	('promote', 'PosReg', (218, 225))	('BRCA1', 'Gene', '672', (70, 75))	('ERCC1', 'Gene', '2067', (59, 64))	('overexpression', 'PosReg', (188, 202))	('BRCA1', 'Gene', (70, 75))	('inflammatory carcinogenesis', 'Disease', (230, 257))	('infection', 'Disease', (280, 289))	('infection', 'Disease', 'MESH:D007239', (280, 289))	('RAR-beta2', 'Gene', (41, 50))	('p16', 'Gene', (36, 39))	('C. albicans', 'Species', '5476', (268, 279))
864313	27410681	Epigenetic changes such as nucleotide and histone modifications play a significant role in tumorigenesis in addition to genetic changes such as mutation and deletion.	('nucleotide', 'Var', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('deletion', 'Var', (157, 165))	('mutation', 'Var', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('histone', 'Protein', (42, 49))	('tumor', 'Disease', (91, 96))
864314	27410681	In oral SCC and gastric cancer, abnormal epigenetic changes are reportedly observed from the early stages of the multistep carcinogenesis process, which induce genetic abnormalities owing to the accumulation of a large number of epigenetic alterations.	('multistep carcinogenesis', 'Disease', (113, 137))	('multistep carcinogenesis', 'Disease', 'MESH:D063646', (113, 137))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('gastric cancer', 'Disease', (16, 30))	('epigenetic alterations', 'Var', (229, 251))	('gastric cancer', 'Disease', 'MESH:D013274', (16, 30))	('rat', 'Species', '10116', (244, 247))	('SCC', 'Gene', (8, 11))	('SCC', 'Phenotype', 'HP:0002860', (8, 11))	('induce', 'Reg', (153, 159))	('genetic abnormalities', 'Disease', 'MESH:D030342', (160, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (16, 30))	('SCC', 'Gene', '6317', (8, 11))	('genetic abnormalities', 'Disease', (160, 181))
864315	27410681	The most commonly researched epigenetic mechanism in carcinogenesis studies is DNA methylation.	('carcinogenesis', 'Disease', 'MESH:D063646', (53, 67))	('DNA methylation', 'Var', (79, 94))	('methylation', 'Var', (83, 94))	('carcinogenesis', 'Disease', (53, 67))
864316	27410681	In SCC occurring in the esophagus, oral cavity, and lung, the DNA methylation of many tumor suppressor genes (p16, p15, CADM1, TIMP3, RAR-beta2, RASSF1A, DAPK1, and SOCS-3) and DNA repair genes (ERCC1, BRCA1, XRCC1, and MLH1) suppresses their protein expression and induces abnormal cell cycle and proliferative signaling leading to the accumulation of mutations.	('proliferative signaling', 'MPA', (298, 321))	('ERCC1', 'Gene', (195, 200))	('SCC', 'Gene', '6317', (3, 6))	('MLH1', 'Gene', (220, 224))	('suppresses', 'NegReg', (226, 236))	('SCC', 'Gene', (3, 6))	('protein expression', 'MPA', (243, 261))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('BRCA1', 'Gene', '672', (202, 207))	('BRCA1', 'Gene', (202, 207))	('MLH1', 'Gene', '4292', (220, 224))	('induces', 'Reg', (266, 273))	('rat', 'Species', '10116', (305, 308))	('abnormal cell cycle', 'Phenotype', 'HP:0011018', (274, 293))	('XRCC1', 'Gene', (209, 214))	('cell cycle', 'CPA', (283, 293))	('SCC', 'Phenotype', 'HP:0002860', (3, 6))	('ERCC1', 'Gene', '2067', (195, 200))	('tumor', 'Disease', (86, 91))	('mutations', 'Var', (353, 362))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
864319	27410681	In this study, we investigated the association of aberrant DNA methylation and protein expression of tumor suppressor and DNA repair genes with the process of multistep carcinogenesis using our animal model for hyperplastic candidiasis and determined the potential role such changes might play in the mechanism underlying SCC.	('hyperplastic candidiasis', 'Disease', 'MESH:D002177', (211, 235))	('hyperplastic candidiasis', 'Phenotype', 'HP:0005411', (211, 235))	('SCC', 'Gene', '6317', (322, 325))	('hyperplastic candidiasis', 'Disease', (211, 235))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('association', 'Interaction', (35, 46))	('multistep carcinogenesis', 'Disease', (159, 183))	('multistep carcinogenesis', 'Disease', 'MESH:D063646', (159, 183))	('aberrant', 'Var', (50, 58))	('SCC', 'Gene', (322, 325))	('SCC', 'Phenotype', 'HP:0002860', (322, 325))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
864357	27410681	The frequency of rats showing RAR-beta2 promoter methylation was 0% in normal epithelia and gradually increased in hyperplasia (27%) and hyperplasia adjacent to SCC (83%) but was rapidly lost in SCC (0%) (Fig 4A).	('rats', 'Species', '10116', (17, 21))	('SCC', 'Gene', (161, 164))	('SCC', 'Gene', (195, 198))	('hyperplasia', 'Disease', 'MESH:D006965', (137, 148))	('SCC', 'Phenotype', 'HP:0002860', (161, 164))	('SCC', 'Phenotype', 'HP:0002860', (195, 198))	('hyperplasia', 'Disease', (115, 126))	('epithelia', 'Disease', (78, 87))	('epithelia', 'Disease', 'None', (78, 87))	('SCC', 'Gene', '6317', (161, 164))	('SCC', 'Gene', '6317', (195, 198))	('RAR-beta2', 'Gene', (30, 39))	('hyperplasia', 'Disease', (137, 148))	('methylation', 'Var', (49, 60))	('increased', 'PosReg', (102, 111))	('hyperplasia', 'Disease', 'MESH:D006965', (115, 126))
864369	27410681	Hypermethylation of the p16 gene promoter is reported in many tumors such as oral, esophageal, and lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lung squamous cell carcinoma', 'Disease', (99, 127))	('reported', 'Reg', (45, 53))	('tumors', 'Disease', (62, 68))	('Hypermethylation', 'Var', (0, 16))	('oral', 'Disease', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('p16', 'Gene', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal', 'Disease', (83, 93))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (99, 127))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 127))
864372	27410681	p16 protein overexpression reportedly occurs in cancer owing to mutation of the CDKN2A gene or feedback control caused by loss of the Rb gene.	('overexpression', 'PosReg', (12, 26))	('protein', 'Protein', (4, 11))	('mutation', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('feedback', 'MPA', (95, 103))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('loss', 'NegReg', (122, 126))	('CDKN2A', 'Gene', (80, 86))	('p16 protein', 'Protein', (0, 11))
864373	27410681	In C. albicans-induced chronic inflammation-associated cancer, it is probable that p16 protein overexpression might be caused by alternative pathways such as CDKN2A gene mutation or loss of the Rb gene irrespective of p16 promoter hypermethylation.	('loss', 'NegReg', (182, 186))	('inflammation', 'Disease', (31, 43))	('protein', 'Protein', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('overexpression', 'PosReg', (95, 109))	('CDKN2A', 'Gene', (158, 164))	('C. albicans', 'Species', '5476', (3, 14))	('p16', 'Gene', (83, 86))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('inflammation', 'Disease', 'MESH:D007249', (31, 43))	('cancer', 'Disease', (55, 61))	('mutation', 'Var', (170, 178))
864375	27410681	TIMP3 promoter methylation is observed in many tumors such as esophageal, gastric, and thyroid cancer, and causes loss of TIMP3 protein expression.	('methylation', 'Var', (15, 26))	('tumors', 'Disease', (47, 53))	('expression', 'MPA', (136, 146))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('gastric', 'Disease', (74, 81))	('thyroid cancer', 'Disease', 'MESH:D013964', (87, 101))	('loss', 'NegReg', (114, 118))	('protein', 'Protein', (128, 135))	('TIMP3', 'Gene', (122, 127))	('esophageal', 'Disease', (62, 72))	('TIMP3', 'Gene', (0, 5))	('observed', 'Reg', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('thyroid cancer', 'Phenotype', 'HP:0002890', (87, 101))	('thyroid cancer', 'Disease', (87, 101))
864376	27410681	However, the down-regulation of TIMP3 protein not resulting from TIMP3 promoter hypermethylation has also been reported in pancreatic adenocarcinoma; this phenomenon is also known to be associated with microRNA and the loss of heterozygosity.	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (123, 148))	('pancreatic adenocarcinoma', 'Disease', (123, 148))	('TIMP3', 'Gene', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (123, 148))	('hypermethylation', 'Var', (80, 96))	('down-regulation', 'NegReg', (13, 28))	('TIMP3', 'Gene', (65, 70))
864380	27410681	RAR-beta2 reportedly leads to the inhibition of cell growth and induction of apoptosis and its gene and mRNA expression disappears because of methylation of the DNA promoter region in SCC and dysplasia of the esophagus and oral mucosa.	('disappears', 'NegReg', (120, 130))	('cell growth', 'CPA', (48, 59))	('dysplasia of the esophagus', 'Disease', 'MESH:D004938', (192, 218))	('apoptosis', 'CPA', (77, 86))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('RAR-beta2', 'Gene', (0, 9))	('SCC', 'Gene', (184, 187))	('dysplasia of the esophagus', 'Disease', (192, 218))	('inhibition', 'NegReg', (34, 44))	('gene', 'MPA', (95, 99))	('methylation', 'Var', (142, 153))	('mRNA expression', 'MPA', (104, 119))	('SCC', 'Gene', '6317', (184, 187))
864390	27410681	In this study, since its protein expression disappeared upon hyperplasia irrespective of promoter methylation, the underlying causative factor might involve gene mutation, degradation of the proteins by ROS, or epigenetic change other than promoter methylation.	('ROS', 'Chemical', '-', (203, 206))	('protein', 'Protein', (25, 32))	('disappeared', 'NegReg', (44, 55))	('hyperplasia', 'Disease', (61, 72))	('ROS', 'Protein', (203, 206))	('proteins', 'Protein', (191, 199))	('epigenetic change', 'Var', (211, 228))	('hyperplasia', 'Disease', 'MESH:D006965', (61, 72))	('degradation', 'MPA', (172, 183))
864392	27410681	Our findings suggest that an abnormality in the promoter region might enhance ERCC1 protein expression in C. albicans-induced cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('enhance', 'PosReg', (70, 77))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('C. albicans', 'Species', '5476', (106, 117))	('abnormality', 'Var', (29, 40))	('ERCC1', 'Gene', '2067', (78, 83))	('ERCC1', 'Gene', (78, 83))	('expression', 'MPA', (92, 102))
864394	27410681	Gene mutation and loss of protein expression reportedly exist in breast and ovarian cancer and the loss and dysfunction of the BRCA1 protein induced by BRCA1 promoter hypermethylation have been identified in breast and ovarian cancer.	('protein', 'Protein', (133, 140))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (65, 90))	('loss', 'NegReg', (18, 22))	('BRCA1', 'Gene', '672', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('BRCA1', 'Gene', '672', (152, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (219, 233))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('BRCA1', 'Gene', (127, 132))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (208, 233))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('dysfunction', 'MPA', (108, 119))	('loss', 'NegReg', (99, 103))	('promoter hypermethylation', 'Var', (158, 183))	('protein', 'Protein', (26, 33))	('BRCA1', 'Gene', (152, 157))
864397	27410681	It is likely that BRCA1 inactivation might be related to the early stage of neoplastic transformation irrespective of promoter methylation status.	('inactivation', 'Var', (24, 36))	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1', 'Gene', (18, 23))	('related', 'Reg', (46, 53))
864414	27410681	The present results suggest that aberrant protein expression of p16, RAR-beta2, TIMP3, BRCA1, and ERCC1 might occur regardless of promoter methylation and might promote the process of inflammatory carcinogenesis caused by C. albicans infection.	('TIMP3', 'Gene', (80, 85))	('infection', 'Disease', (234, 243))	('p16', 'Gene', (64, 67))	('inflammatory carcinogenesis', 'Disease', 'MESH:D063646', (184, 211))	('infection', 'Disease', 'MESH:D007239', (234, 243))	('protein', 'Protein', (42, 49))	('BRCA1', 'Gene', '672', (87, 92))	('C. albicans', 'Species', '5476', (222, 233))	('promote', 'PosReg', (161, 168))	('BRCA1', 'Gene', (87, 92))	('inflammatory carcinogenesis', 'Disease', (184, 211))	('aberrant', 'Var', (33, 41))	('ERCC1', 'Gene', '2067', (98, 103))	('RAR-beta2', 'Gene', (69, 78))	('ERCC1', 'Gene', (98, 103))
864529	31091245	We found that Rk3 was able to significantly repress cell proliferation and colony formation in both Eca109 and KYSE150 cells in vitro.	('cell proliferation', 'CPA', (52, 70))	('colony formation', 'CPA', (75, 91))	('KYSE150', 'CellLine', 'CVCL:1348', (111, 118))	('repress', 'NegReg', (44, 51))	('Rk3', 'Var', (14, 17))
864530	31091245	In the KYSE150 xenograft model, Rk3 obviously inhibited tumor growth and exhibited little toxicity in organs.	('KYSE150', 'CellLine', 'CVCL:1348', (7, 14))	('Rk3', 'Var', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('toxicity', 'Disease', 'MESH:D064420', (90, 98))	('toxicity', 'Disease', (90, 98))	('inhibited', 'NegReg', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
864533	31091245	Further studies indicated that pretreatment with the Akt inhibitor GSK690693 or the mTOR inhibitor rapamycin promoted Rk3-induced apoptosis and autophagy, demonstrating that the PI3K/Akt/mTOR pathway is related to Rk3-induced apoptosis and autophagy.	('Akt', 'Gene', '207', (53, 56))	('promoted', 'PosReg', (109, 117))	('Akt', 'Gene', (183, 186))	('Rk3-induced', 'Gene', (118, 129))	('mTOR', 'Gene', '2475', (187, 191))	('mTOR', 'Gene', (187, 191))	('GSK690693', 'Var', (67, 76))	('mTOR', 'Gene', '2475', (84, 88))	('rapamycin', 'Chemical', 'MESH:D020123', (99, 108))	('mTOR', 'Gene', (84, 88))	('GSK690693', 'Chemical', 'MESH:C528328', (67, 76))	('Akt', 'Gene', (53, 56))	('Akt', 'Gene', '207', (183, 186))	('autophagy', 'CPA', (144, 153))
864534	31091245	In conclusion, the present study is the first to clarify that Rk3 can inhibit Eca109 and KYSE150 cell proliferation through activating apoptosis and autophagy by blocking the PI3K/Akt/mTOR pathway, suggesting that Rk3 may be a promising antitumor agent for esophageal cancer.	('apoptosis', 'CPA', (135, 144))	('mTOR', 'Gene', '2475', (184, 188))	('tumor', 'Disease', (241, 246))	('esophageal cancer', 'Disease', (257, 274))	('mTOR', 'Gene', (184, 188))	('Akt', 'Gene', (180, 183))	('blocking', 'NegReg', (162, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (257, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('autophagy', 'CPA', (149, 158))	('activating', 'PosReg', (124, 134))	('Rk3', 'Var', (62, 65))	('inhibit', 'NegReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('Akt', 'Gene', '207', (180, 183))	('KYSE150', 'CellLine', 'CVCL:1348', (89, 96))
864553	31091245	Primary antibodies against GAPDH (Cat# 10494-1-AP), Bad (Cat# 10435-1-AP), Bax (Cat# 50599-2-Ig), Bcl-2 (Cat# 12789-1-AP), caspase-9 (Cat# 10380-1-AP), Atg5 (Cat# 10181-2-AP), Beclin1 (Cat# 11306-1-AP), CDK4 (Cat# 11026-1-AP), p53 (Cat# 10442-1-AP) and p21 (Cat# 10355-1-AP) were purchased from Proteintech Group Inc. (Chicago, USA).	('p53', 'Gene', (227, 230))	('Bax', 'Gene', (75, 78))	('Beclin1', 'Gene', '8678', (176, 183))	('caspase-9', 'Gene', '842', (123, 132))	('p53', 'Gene', '7157', (227, 230))	('Atg5', 'Gene', '9474', (152, 156))	('Bax', 'Gene', '581', (75, 78))	('p21', 'Gene', '1026', (253, 256))	('Bcl-2', 'Gene', (98, 103))	('Beclin1', 'Gene', (176, 183))	('Atg5', 'Gene', (152, 156))	('p21', 'Gene', (253, 256))	('Cat# 11306-1-AP', 'Var', (185, 200))	('caspase-9', 'Gene', (123, 132))	('Cat# 10355-1-AP', 'Var', (258, 273))	('CDK4', 'Gene', (203, 207))	('CDK4', 'Gene', '1019', (203, 207))	('Bcl-2', 'Gene', '596', (98, 103))
864554	31091245	Antibodies against cleaved PARP (Cat# ab2317), cytochrome-c (Cat# ab18738), mTOR (Cat# ab2732), p-mTOR (Cat# ab109268) and LC3B (Cat# ab51520) were purchased from Abcam (Cambridge, UK).	('Cat# ab109268', 'Var', (104, 117))	('PARP', 'Gene', '1302', (27, 31))	('cytochrome-c', 'Gene', (47, 59))	('mTOR', 'Gene', (76, 80))	('mTOR', 'Gene', '2475', (76, 80))	('Cat# ab18738', 'Var', (61, 73))	('PARP', 'Gene', (27, 31))	('LC3B', 'Gene', '81631', (123, 127))	('Cat# ab2317', 'Var', (33, 44))	('mTOR', 'Gene', '2475', (98, 102))	('Cat# ab51520', 'Var', (129, 141))	('Cat# ab2732', 'Var', (82, 93))	('mTOR', 'Gene', (98, 102))	('cytochrome-c', 'Gene', '54205', (47, 59))	('LC3B', 'Gene', (123, 127))
864555	31091245	Primary antibodies against SQSTM1/P62 (Cat# 5114), cleaved caspase-3 (Cat# 9664), cyclinD1 (Cat# 2922), Akt (Cat# 9272) and p-Akt (Cat# 4058) were purchased from Cell Signaling Technology (Danvers, USA).	('caspase-3', 'Gene', '836', (59, 68))	('Akt', 'Gene', (104, 107))	('Akt', 'Gene', '207', (104, 107))	('Akt', 'Gene', '207', (126, 129))	('SQSTM1', 'Gene', '8878', (27, 33))	('Cat# 9664', 'Var', (70, 79))	('cyclinD1', 'Gene', (82, 90))	('P62', 'Gene', (34, 37))	('Cat# 2922', 'Var', (92, 101))	('caspase-3', 'Gene', (59, 68))	('Cat# 5114', 'Var', (39, 48))	('P62', 'Gene', '8878', (34, 37))	('Cat# 9272', 'Var', (109, 118))	('SQSTM1', 'Gene', (27, 33))	('Akt', 'Gene', (126, 129))	('cyclinD1', 'Gene', '595', (82, 90))
864577	31091245	Tumor tissues were immunostained with cleaved caspase-3 (1:100), LC3B (1:100), p-AKT (1:50) and p-mTOR (1:50).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('caspase-3', 'Gene', (46, 55))	('AKT', 'Gene', '207', (81, 84))	('LC3B', 'Gene', (65, 69))	('1:100', 'Var', (71, 76))	('caspase-3', 'Gene', '836', (46, 55))	('AKT', 'Gene', (81, 84))	('mTOR', 'Gene', '2475', (98, 102))	('mTOR', 'Gene', (98, 102))	('LC3B', 'Gene', '81631', (65, 69))
864588	31091245	As shown in Fig 1B, treatment with varying concentrations of Rk3 (0-250 muM) for 24 h or 48 h decreased the viability of both Eca109 and KYSE150 cells in a dose- and time-dependent manner.	('KYSE150', 'CellLine', 'CVCL:1348', (137, 144))	('muM', 'Gene', '56925', (72, 75))	('Rk3', 'Var', (61, 64))	('viability', 'CPA', (108, 117))	('decreased', 'NegReg', (94, 103))	('muM', 'Gene', (72, 75))
864594	31091245	Mice in the 20 and 40 mg/kg Rk3 and cis-platinum groups exhibited smaller tumor volumes than those in the solvent group, with inhibition rates of 32.6 +- 6.3%, 66.2 +- 8.4% and 72.8 +- 7.1%, respectively (Fig 1E).	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('smaller', 'NegReg', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cis-platinum', 'Chemical', 'MESH:D002945', (36, 48))	('tumor', 'Disease', (74, 79))	('Mice', 'Species', '10090', (0, 4))	('Rk3', 'Var', (28, 31))
864602	31091245	As shown in Fig 2A, after treatment with 200 muM Rk3, the proportion of Eca109 cells in G1 phase increased from 37.79% to 74.12%, the number of cells in S phase decreased from 43.07% to 12.43%, and the ratio of cells in G2 phase was essentially the same.	('increased', 'PosReg', (97, 106))	('decreased', 'NegReg', (161, 170))	('muM', 'Gene', '56925', (45, 48))	('muM', 'Gene', (45, 48))	('Rk3', 'Var', (49, 52))
864603	31091245	Similarly, in contrast to the control, treatment with 200 muM Rk3 resulted in an obvious increase (30.05%) in the population of KYSE150 cells in G1 phase and a marked decrease (18.07%) in S phase, the percentage of cells in G2 phase was essentially the same.	('muM', 'Gene', '56925', (58, 61))	('S phase', 'CPA', (188, 195))	('KYSE150', 'Var', (128, 135))	('muM', 'Gene', (58, 61))	('decrease', 'NegReg', (167, 175))	('KYSE150', 'CellLine', 'CVCL:1348', (128, 135))	('Rk3', 'Var', (62, 65))	('increase', 'PosReg', (89, 97))
864604	31091245	The results displayed that Rk3 dramatically upregulated the expression of p53 and p21, but downregulated the levels of cyclin D1 and CDK4 in a dose-dependent manner in both Eca109 and KYSE150 cells (Fig 2B).	('expression', 'MPA', (60, 70))	('downregulated', 'NegReg', (91, 104))	('cyclin D1', 'Gene', '595', (119, 128))	('upregulated', 'PosReg', (44, 55))	('CDK4', 'Gene', (133, 137))	('p21', 'Gene', '1026', (82, 85))	('p53', 'Gene', (74, 77))	('Rk3', 'Var', (27, 30))	('KYSE150', 'CellLine', 'CVCL:1348', (184, 191))	('levels', 'MPA', (109, 115))	('CDK4', 'Gene', '1019', (133, 137))	('p53', 'Gene', '7157', (74, 77))	('p21', 'Gene', (82, 85))	('cyclin D1', 'Gene', (119, 128))
864605	31091245	Taken together, those findings suggest that Rk3 triggers cell cycle arrest by influencing the levels of proteins involved in the G1 transition.	('arrest', 'Disease', (68, 74))	('levels of proteins involved', 'MPA', (94, 121))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('Rk3', 'Var', (44, 47))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (57, 74))	('influencing', 'Reg', (78, 89))	('triggers', 'Reg', (48, 56))
864611	31091245	As shown in Fig 3D, Bax, cleaved caspase-3, cleaved caspase-9, cytochrome C and cleaved PARP levels were increased after treatment with Rk3, whereas Bad and Bcl-2 levels were reduced in a dose-dependent manner in both Eca109 and KYSE150 cells, indicating that Rk3 activated apoptosis in esophageal cancer cells.	('cytochrome C', 'Gene', '54205', (63, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (287, 304))	('Bax', 'Gene', '581', (20, 23))	('caspase-3', 'Gene', (33, 42))	('Bcl-2', 'Gene', '596', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('Rk3', 'Var', (136, 139))	('Bax', 'Gene', (20, 23))	('cytochrome C', 'Gene', (63, 75))	('Bcl-2', 'Gene', (157, 162))	('caspase-3', 'Gene', '836', (33, 42))	('increased', 'PosReg', (105, 114))	('caspase-9', 'Gene', '842', (52, 61))	('PARP', 'Gene', '1302', (88, 92))	('KYSE150', 'CellLine', 'CVCL:1348', (229, 236))	('esophageal cancer', 'Disease', (287, 304))	('caspase-9', 'Gene', (52, 61))	('PARP', 'Gene', (88, 92))
864612	31091245	Immunohistochemistry staining of tumor tissue showed that the area positive for cleaved caspase-3 was larger in the Rk3 group than in the control group (Fig 3E).	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('caspase-3', 'Gene', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Rk3', 'Var', (116, 119))	('tumor', 'Disease', (33, 38))	('caspase-3', 'Gene', '836', (88, 97))	('larger', 'PosReg', (102, 108))
864616	31091245	Immunohistochemical staining of tumor tissue showed that the LC3-II-positive area was larger in the Rk3 group than in the control group (Fig 4C).	('LC3', 'Gene', '84557', (61, 64))	('larger', 'PosReg', (86, 92))	('LC3', 'Gene', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Rk3', 'Var', (100, 103))	('tumor', 'Disease', (32, 37))
864619	31091245	The MTT results demonstrated that 3-MA could partially block the inhibitory effect of Rk3 on Eca109 and KYSE150 cell viability, revealing that the autophagy induced by Rk3 was pro-death (Fig 4D).	('autophagy', 'CPA', (147, 156))	('3-MA', 'Chemical', 'MESH:C025946', (34, 38))	('pro-death', 'CPA', (176, 185))	('KYSE150', 'CellLine', 'CVCL:1348', (104, 111))	('Rk3', 'Var', (168, 171))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))
864622	31091245	The results showed that Rk3 significantly downregulated the levels of phosphorylated PI3K, Akt and mTOR in a dose-dependent manner but did not change the expression of PI3K, Akt or mTOR in either Eca109 or KYSE150 cells (Fig 5A), suggesting that Rk3 blocked the PI3K/Akt/mTOR pathway.	('mTOR', 'Gene', '2475', (181, 185))	('Akt', 'Gene', '207', (91, 94))	('Akt', 'Gene', '207', (267, 270))	('KYSE150', 'CellLine', 'CVCL:1348', (206, 213))	('phosphorylated', 'MPA', (70, 84))	('downregulated', 'NegReg', (42, 55))	('Akt', 'Gene', (91, 94))	('Akt', 'Gene', '207', (174, 177))	('mTOR', 'Gene', '2475', (271, 275))	('Akt', 'Gene', (267, 270))	('levels', 'MPA', (60, 66))	('Rk3', 'Var', (24, 27))	('Akt', 'Gene', (174, 177))	('mTOR', 'Gene', (271, 275))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', (99, 103))	('mTOR', 'Gene', (181, 185))
864623	31091245	Immunohistochemical staining of tumor tissue showed that the area positive for p-Akt and p-mTOR was smaller in the Rk3 group than in the control group (Fig 5B).	('Rk3', 'Var', (115, 118))	('Akt', 'Gene', '207', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Akt', 'Gene', (81, 84))	('smaller', 'NegReg', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mTOR', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (91, 95))	('tumor', 'Disease', (32, 37))
864624	31091245	Next, to verify whether Rk3 can induce apoptosis and autophagy through the PI3K/Akt/mTOR pathway, we exposed the cells to GSK690693 (an Akt inhibitor) or rapamycin (a mTOR inhibitor) before treatment with Rk3.	('Akt', 'Gene', '207', (80, 83))	('apoptosis', 'CPA', (39, 48))	('Akt', 'Gene', (80, 83))	('mTOR', 'Gene', '2475', (84, 88))	('Akt', 'Gene', '207', (136, 139))	('mTOR', 'Gene', (84, 88))	('autophagy', 'CPA', (53, 62))	('mTOR', 'Gene', '2475', (167, 171))	('rapamycin', 'Chemical', 'MESH:D020123', (154, 163))	('induce', 'Reg', (32, 38))	('mTOR', 'Gene', (167, 171))	('Akt', 'Gene', (136, 139))	('Rk3', 'Var', (24, 27))	('GSK690693', 'Chemical', 'MESH:C528328', (122, 131))
864625	31091245	Notably, the MTT results showed that the ability of Rk3 to inhibit Eca109 cell growth was further enhanced by both GSK690693 and rapamycin (Fig 6A).	('enhanced', 'PosReg', (98, 106))	('GSK690693', 'Var', (115, 124))	('MTT', 'Chemical', 'MESH:C070243', (13, 16))	('GSK690693', 'Chemical', 'MESH:C528328', (115, 124))	('rapamycin', 'Chemical', 'MESH:D020123', (129, 138))	('Rk3', 'Gene', (52, 55))	('inhibit', 'NegReg', (59, 66))	('Eca109 cell growth', 'CPA', (67, 85))
864626	31091245	Moreover, western blot analysis revealed that pretreatment with GSK690693 blocked the phosphorylation of Akt and mTOR and activated apoptosis and autophagy in Eca109 cells (Fig 6B).	('apoptosis', 'CPA', (132, 141))	('Akt', 'Gene', '207', (105, 108))	('autophagy', 'CPA', (146, 155))	('activated', 'PosReg', (122, 131))	('Akt', 'Gene', (105, 108))	('phosphorylation', 'CPA', (86, 101))	('blocked', 'NegReg', (74, 81))	('mTOR', 'Gene', (113, 117))	('mTOR', 'Gene', '2475', (113, 117))	('GSK690693', 'Var', (64, 73))	('GSK690693', 'Chemical', 'MESH:C528328', (64, 73))
864628	31091245	These data show that Rk3 can induce apoptosis and autophagy in esophageal cancer cells through regulation of the PI3K/Akt/mTOR pathway.	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('apoptosis', 'CPA', (36, 45))	('Akt', 'Gene', (118, 121))	('autophagy', 'CPA', (50, 59))	('Rk3', 'Var', (21, 24))	('mTOR', 'Gene', (122, 126))	('mTOR', 'Gene', '2475', (122, 126))	('induce', 'PosReg', (29, 35))	('Akt', 'Gene', '207', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
864636	31091245	In particular, the inhibition rate in the 40 mg/kg Rk3 group was 66.2%, and there was no significant difference compared with the cis-platinum group (72.8%).	('inhibition', 'NegReg', (19, 29))	('Rk3', 'Var', (51, 54))	('cis-platinum', 'Chemical', 'MESH:D002945', (130, 142))
864646	31091245	Our findings showed that Rk3 upregulated the protein levels of p21 and p53 but downregulated cyclinD1 and CDK4 protein expression in esophageal cancer cells, indicating that Rk3 induced G1 arrest in esophageal cells.	('protein levels', 'MPA', (45, 59))	('arrest', 'Disease', 'MESH:D006323', (189, 195))	('upregulated', 'PosReg', (29, 40))	('cyclinD1', 'Gene', (93, 101))	('p21', 'Gene', (63, 66))	('arrest', 'Disease', (189, 195))	('downregulated', 'NegReg', (79, 92))	('CDK4', 'Gene', (106, 110))	('p53', 'Gene', (71, 74))	('cyclinD1', 'Gene', '595', (93, 101))	('p53', 'Gene', '7157', (71, 74))	('Rk3', 'Var', (25, 28))	('CDK4', 'Gene', '1019', (106, 110))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('p21', 'Gene', '1026', (63, 66))
864648	31091245	The ginsenosides Rg3, Rh2, Rg5, Rk1 and Rh4 have been proved to trigger apoptosis in multiple types of cancer cells.	('Rh4', 'Gene', (40, 43))	('Rg3', 'Var', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Rh4', 'Gene', '6007', (40, 43))	('ginsenosides', 'Chemical', 'MESH:D036145', (4, 16))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('Rh2', 'Gene', (22, 25))	('apoptosis', 'CPA', (72, 81))	('Rg5', 'Gene', (27, 30))	('cancer', 'Disease', (103, 109))	('Rh2', 'Gene', '6005', (22, 25))	('trigger', 'PosReg', (64, 71))	('Rk1', 'Gene', (32, 35))
864658	31091245	Further experiments showed that 3-MA weakened the inhibitory effect of Rk3 on esophageal cells, suggesting that Rk3 induced-autophagy likely contributes to cell death.	('3-MA', 'Chemical', 'MESH:C025946', (32, 36))	('Rk3', 'Var', (112, 115))	('inhibitory effect', 'MPA', (50, 67))
864665	31091245	The results showed that the suppression of p-Akt with GSK690693 dramatically increased Bax, cleaved caspase-9, cleaved caspase-3 and LC3-II levels and reduced Bad and p-mTOR levels in Eca109 cells.	('LC3', 'Gene', (133, 136))	('Akt', 'Gene', (45, 48))	('caspase-9', 'Gene', (100, 109))	('reduced', 'NegReg', (151, 158))	('caspase-3', 'Gene', '836', (119, 128))	('suppression', 'NegReg', (28, 39))	('GSK690693', 'Chemical', 'MESH:C528328', (54, 63))	('GSK690693', 'Var', (54, 63))	('mTOR', 'Gene', '2475', (169, 173))	('Bax', 'Gene', '581', (87, 90))	('mTOR', 'Gene', (169, 173))	('Akt', 'Gene', '207', (45, 48))	('caspase-9', 'Gene', '842', (100, 109))	('caspase-3', 'Gene', (119, 128))	('increased', 'PosReg', (77, 86))	('LC3', 'Gene', '84557', (133, 136))	('Bax', 'Gene', (87, 90))
864670	31091245	Moreover, we discovered that Rk3 contemporaneously induced apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway in esophageal cancer cells.	('autophagy', 'CPA', (73, 82))	('Akt', 'Gene', (107, 110))	('esophageal cancer', 'Disease', (127, 144))	('mTOR', 'Gene', '2475', (111, 115))	('Rk3', 'Var', (29, 32))	('mTOR', 'Gene', (111, 115))	('induced', 'PosReg', (51, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('apoptosis', 'CPA', (59, 68))	('suppressing', 'NegReg', (86, 97))	('Akt', 'Gene', '207', (107, 110))
864682	30484962	In subgroup analyses, the presence of LVI significantly decreased overall survival in pN0, pN2, and pN3 stage patients.	('overall survival', 'MPA', (66, 82))	('pN2', 'Gene', '351', (91, 94))	('pN3', 'Gene', '6336', (100, 103))	('pN3', 'Gene', (100, 103))	('pN0', 'Disease', (86, 89))	('patients', 'Species', '9606', (110, 118))	('decreased', 'NegReg', (56, 65))	('LVI', 'Chemical', '-', (38, 41))	('pN2', 'Gene', (91, 94))	('presence', 'Var', (26, 34))	('LVI', 'Disease', (38, 41))
864692	30484962	The selection criteria included: (i) pathologically confirmed ESCC; (ii) transthoracic esophagectomy with three-field lymphadenectomy had been performed; (iii) pathological T status of T1, T2, T3, or T4a; (iv) microscopically complete resection of the tumor (R0); and (v) aged >= 18 and <= 75 years.	('ESCC', 'Disease', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('T4a', 'Var', (200, 203))	('tumor', 'Disease', (252, 257))
864749	29930979	This study defines immune-associated factors supportive of esophageal adenocarcinoma cell growth through small interfering RNA screening and pathologic and functional studies.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (59, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('esophageal adenocarcinoma', 'Disease', (59, 84))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (59, 84))	('small interfering', 'Var', (105, 122))
864756	29930979	The most prevalent mutations or copy number variations have been reported in presently nonactionable tumor-suppressor genes such as TP53, ELMO1, CDKN2A, SMAD4, and ARID1A, rather than driver oncogenes, and also prominently are observed in the precancerous metaplastic tissues of EAC and non-EAC patients.	('prevalent', 'Reg', (9, 18))	('ARID1A', 'Gene', '8289', (164, 170))	('TP53', 'Gene', (132, 136))	('SMAD4', 'Gene', '4089', (153, 158))	('EAC', 'Disease', (279, 282))	('CDKN2A', 'Gene', (145, 151))	('cancer', 'Disease', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('CDKN2A', 'Gene', '1029', (145, 151))	('EAC', 'Phenotype', 'HP:0011459', (291, 294))	('TP53', 'Gene', '7157', (132, 136))	('ELMO1', 'Gene', '9844', (138, 143))	('SMAD4', 'Gene', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('ELMO1', 'Gene', (138, 143))	('copy number variations', 'Var', (32, 54))	('ARID1A', 'Gene', (164, 170))	('tumor', 'Disease', (101, 106))	('mutations', 'Var', (19, 28))	('patients', 'Species', '9606', (295, 303))	('EAC', 'Phenotype', 'HP:0011459', (279, 282))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
864757	29930979	Common amplifications have been reported in KRAS (21%), ERBB2/HER2 (19%), and EGFR (16%), and deletions in SMAD4 and CDKN2A.	('HER2', 'Gene', '2064', (62, 66))	('KRAS', 'Gene', '3845', (44, 48))	('SMAD4', 'Gene', '4089', (107, 112))	('RA', 'Phenotype', 'HP:0001370', (45, 47))	('KRAS', 'Gene', (44, 48))	('ERBB2', 'Gene', '2064', (56, 61))	('deletions', 'Var', (94, 103))	('CDKN2A', 'Gene', (117, 123))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (78, 82))	('ERBB2', 'Gene', (56, 61))	('HER2', 'Gene', (62, 66))	('SMAD4', 'Gene', (107, 112))	('CDKN2A', 'Gene', '1029', (117, 123))
864806	29930979	Previous publications from our laboratory showed that silencing of the GATA6 transcription factor resulted in significant EAC cell growth arrest and apoptosis.	('apoptosis', 'CPA', (149, 158))	('growth arrest', 'Phenotype', 'HP:0001510', (131, 144))	('GATA6', 'Gene', (71, 76))	('silencing', 'Var', (54, 63))	('EAC', 'Phenotype', 'HP:0011459', (122, 125))	('GATA6', 'Gene', '2627', (71, 76))	('growth arrest', 'Disease', (131, 144))	('growth arrest', 'Disease', 'MESH:D006323', (131, 144))
864811	29930979	The observed viability data derived from the siRNA screen was distributed normally, permitting the use of standard Z score and robust Z score cut-off values of Z < -1.645, resulting in 299 and 252 gene transcript-targeting siRNA pools, respectively, that significantly affected EAC cell viability (Figure 1A-D).	('tin', 'Chemical', 'MESH:D014001', (177, 180))	('EAC', 'Disease', (278, 281))	('tin', 'Chemical', 'MESH:D014001', (218, 221))	('EAC', 'Phenotype', 'HP:0011459', (278, 281))	('Z < -1.645', 'Var', (160, 170))	('tin', 'Chemical', 'MESH:D014001', (90, 93))	('affected', 'Reg', (269, 277))
864816	29930979	Amplifications associated with GTF2H4, GUCA1B, ABCC10, RUNX2, TREM2, POLH, and FRS3, whose silencing reduced the viability of EAC cells in screening data, were specific to EAC rather than ESCC (Figure 2A), significantly higher in gastroesophageal junctions than gastric carcinomas (Figure 2B), and were all co-encoded at chromosome 6p21.1.	('TREM2', 'Gene', '54209', (62, 67))	('higher', 'Reg', (220, 226))	('GUCA1B', 'Gene', '2979', (39, 45))	('gastroesophageal junctions than gastric carcinomas', 'Disease', (230, 280))	('GTF2H4', 'Gene', '2968', (31, 37))	('EAC', 'Phenotype', 'HP:0011459', (126, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('EAC', 'Phenotype', 'HP:0011459', (172, 175))	('Amplifications', 'Var', (0, 14))	('carcinomas', 'Phenotype', 'HP:0030731', (270, 280))	('gastroesophageal junctions than gastric carcinomas', 'Disease', 'MESH:D013274', (230, 280))	('ABCC10', 'Gene', (47, 53))	('GUCA1B', 'Gene', (39, 45))	('FRS3', 'Gene', (79, 83))	('RUNX2', 'Gene', (55, 60))	('silencing', 'Var', (91, 100))	('ABCC10', 'Gene', '89845', (47, 53))	('RUNX2', 'Gene', '860', (55, 60))	('reduced', 'NegReg', (101, 108))	('GTF2H4', 'Gene', (31, 37))	('TREM2', 'Gene', (62, 67))	('FRS3', 'Gene', '10817', (79, 83))
864838	29930979	Similarly LIF and C1QA, but not TREM2, expression was associated with poor outcome in gastric adenocarcinoma (www.kmplot.com).	('TREM2', 'Gene', (32, 37))	('LIF', 'Gene', (10, 13))	('expression', 'Var', (39, 49))	('LIF', 'Gene', '3976', (10, 13))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (86, 108))	('C1QA', 'Gene', (18, 22))	('gastric adenocarcinoma', 'Disease', (86, 108))	('C1QA', 'Gene', '712', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('TREM2', 'Gene', '54209', (32, 37))
864847	29930979	Silencing of LIF in multiple EAC cell lines resulted in significantly reduced levels of target mRNA (Figure 6A), secreted LIF protein (Figure 6B), and reduced cell viability in multiple EAC cell lines (Figure 6C), as suggested from siRNA screening data.	('LIF', 'Gene', (13, 16))	('LIF', 'Gene', '3976', (13, 16))	('LIF', 'Gene', '3976', (122, 125))	('reduced', 'NegReg', (70, 77))	('reduced', 'NegReg', (151, 158))	('EAC', 'Phenotype', 'HP:0011459', (29, 32))	('LIF', 'Gene', (122, 125))	('cell viability', 'CPA', (159, 173))	('levels', 'MPA', (78, 84))	('Silencing', 'Var', (0, 9))	('EAC', 'Phenotype', 'HP:0011459', (186, 189))
864851	29930979	Thus, silencing LIF overproduction by EAC cells allows the STAT3 pathway to once again become responsive to exogenous IL6 or LIF.	('LIF', 'Gene', '3976', (125, 128))	('EAC', 'Phenotype', 'HP:0011459', (38, 41))	('LIF', 'Gene', (16, 19))	('LIF', 'Gene', (125, 128))	('LIF', 'Gene', '3976', (16, 19))	('silencing', 'Var', (6, 15))	('STAT3 pathway', 'Pathway', (59, 72))	('overproduction', 'PosReg', (20, 34))	('responsive', 'MPA', (94, 104))
864855	29930979	During validation of LIF silencing, reduced levels of C1QA mRNA were observed in LIF-silenced EAC cells (Figure 6I), consistent with the reported STAT3 regulation of C1q production in macrophages.	('silencing', 'Var', (25, 34))	('LIF', 'Gene', '3976', (21, 24))	('C1q', 'Gene', '712', (166, 169))	('EAC', 'Phenotype', 'HP:0011459', (94, 97))	('LIF', 'Gene', (21, 24))	('C1q', 'Gene', (166, 169))	('levels', 'MPA', (44, 50))	('reduced', 'NegReg', (36, 43))	('LIF', 'Gene', '3976', (81, 84))	('LIF', 'Gene', (81, 84))	('C1QA', 'Gene', (54, 58))	('C1QA', 'Gene', '712', (54, 58))
864860	29930979	Post screen verification experiments showed that inhibition of C1QA by siRNA-mediated silencing results in reduced cell growth of the CP-D cell line.	('silencing', 'Var', (86, 95))	('reduced', 'NegReg', (107, 114))	('CP-D', 'Gene', (134, 138))	('C1QA', 'Gene', (63, 67))	('C1QA', 'Gene', '712', (63, 67))	('CP-D', 'Gene', '1362', (134, 138))	('inhibition', 'NegReg', (49, 59))
864878	29930979	Because LIF, C1q, and TREM2 signaling were prominent in the regulation of EAC cell survival/growth, we examined the ability of fostamatanib R406 to target the JAK/STAT and SYK/AKT pathways and induce growth arrest or apoptosis in EAC cells.	('EAC', 'Phenotype', 'HP:0011459', (74, 77))	('TREM2', 'Gene', (22, 27))	('growth arrest', 'Phenotype', 'HP:0001510', (200, 213))	('R406', 'Var', (140, 144))	('SYK', 'Gene', (172, 175))	('LIF', 'Gene', (8, 11))	('apoptosis', 'CPA', (217, 226))	('LIF', 'Gene', '3976', (8, 11))	('SYK', 'Gene', '6850', (172, 175))	('C1q', 'Gene', '712', (13, 16))	('EAC', 'Phenotype', 'HP:0011459', (230, 233))	('induce', 'Reg', (193, 199))	('TREM2', 'Gene', '54209', (22, 27))	('C1q', 'Gene', (13, 16))	('fostamatanib', 'Chemical', '-', (127, 139))	('growth arrest', 'Disease', 'MESH:D006323', (200, 213))	('growth arrest', 'Disease', (200, 213))
864879	29930979	Furthermore, significant levels of apoptosis (18.7% +- 1.7 sub-G0/G1 or R6; P < .001), as defined by 7-AAD/bromodeoxyuridine staining, were observed in SKGT4 cells treated with 12.5 mumol/L R406 by comparison with vehicle control (3.8% +- 0.87 sub-G0/G1 or R6) in addition to increased growth arrest (31.5% +- 2.3 G0/G1; P < .001) at 24 hours (Figure 8C and D).	('R406', 'Var', (190, 194))	('growth arrest', 'Phenotype', 'HP:0001510', (286, 299))	('bromodeoxyuridine', 'Chemical', 'MESH:D001973', (107, 124))	('increased', 'PosReg', (276, 285))	('growth arrest', 'Disease', (286, 299))	('growth arrest', 'Disease', 'MESH:D006323', (286, 299))
864880	29930979	These findings were replicated in EAC cell lines known to form robust tumors in nude mice, OE33 cells, and FLO-1 cells over a range of R406 concentrations and measuring cell proliferation and apoptosis at 24 hours (Figure 8E).	('nude mice', 'Species', '10090', (80, 89))	('R406', 'Var', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('EAC', 'Phenotype', 'HP:0011459', (34, 37))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
864883	29930979	Over the first 30 days after engraftment, treatment with 80 mg/kg R788 significantly suppressed tumor growth, however, some evidence of refractory growth pattern in response to the fostamatinib R788 inhibitor was observed at day 33 (Figure 8F).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('fostamatinib', 'Chemical', 'MESH:C523665', (181, 193))	('suppressed', 'NegReg', (85, 95))	('tumor', 'Disease', (96, 101))	('R788', 'Var', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
864887	29930979	The data suggest that the low-grade epithelial inflammation induced by a stressor in conjunction with tumor-suppressor loss (p53 mutation) results in a macrophage mimicry by tumor cells.	('tumor', 'Disease', (174, 179))	('results in', 'Reg', (139, 149))	('epithelial inflammation', 'Disease', 'MESH:D007249', (36, 59))	('mutation', 'Var', (129, 137))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('epithelial inflammation', 'Disease', (36, 59))
864898	29930979	Thus, the significant association between genes sustaining EAC growth in siRNA screening data and their expression from Chr6p21.1 supports the hypothesis that alterations at this locus also may contribute to oncogenesis through enhanced proliferative rates in addition to that mediated by alterations to VEGFA levels and angiogenic pathways.	('VEGFA', 'Gene', '7422', (304, 309))	('oncogenesis', 'CPA', (208, 219))	('alterations', 'Var', (159, 170))	('VEGFA', 'Gene', (304, 309))	('EAC', 'Phenotype', 'HP:0011459', (59, 62))	('proliferative rates', 'CPA', (237, 256))	('enhanced', 'PosReg', (228, 236))
864900	29930979	Gene amplification events that were defined at Chr8q24.3 and Chr20q13.33 were not cancer-type-specific and occurred at similar frequencies in either EAC or ESCC.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('occurred', 'Reg', (107, 115))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Chr20q13.33', 'Var', (61, 72))	('ESCC', 'Disease', (156, 160))	('EAC', 'Phenotype', 'HP:0011459', (149, 152))	('EAC', 'Disease', (149, 152))
864903	29930979	In our study, neither silencing of IL6 expression nor anti-IL6 blocking affected EAC cell growth or survival in human cell lines.	('EAC', 'Phenotype', 'HP:0011459', (81, 84))	('EAC', 'Disease', (81, 84))	('IL6', 'Gene', (35, 38))	('silencing', 'Var', (22, 31))	('human', 'Species', '9606', (112, 117))
864904	29930979	However, silencing of the IL6 family member, LIF, resulted in significantly reduced EAC cell proliferation, pSTAT3 and IL6 levels in SKGT4 EAC cells that could be rescued through treatment with exogenous recombinant LIF.	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('LIF', 'Gene', (216, 219))	('silencing', 'Var', (9, 18))	('LIF', 'Gene', '3976', (216, 219))	('LIF', 'Gene', (45, 48))	('LIF', 'Gene', '3976', (45, 48))	('reduced', 'NegReg', (76, 83))	('EAC cell proliferation', 'CPA', (84, 106))	('EAC', 'Phenotype', 'HP:0011459', (139, 142))
864905	29930979	Critically, silencing LIF expression also resulted in reduced C1QA levels, showing an interdependency between these pathways.	('silencing', 'Var', (12, 21))	('C1QA', 'Gene', (62, 66))	('C1QA', 'Gene', '712', (62, 66))	('reduced', 'NegReg', (54, 61))	('LIF', 'Gene', (22, 25))	('LIF', 'Gene', '3976', (22, 25))
864910	29930979	Silencing of the complement C1q binding protein (C1QBP or GC1QR), which normally binds to the globular heads of C1q protein, thus inhibiting C1 activation, has been observed to result in reduced lamellipodia formation and consequently reduced cell migration and invasion of cancer cells in a number of studies.	('C1q', 'Gene', (112, 115))	('Silencing', 'Var', (0, 9))	('C1QBP', 'Gene', '708', (49, 54))	('cell migration', 'CPA', (243, 257))	('inhibiting', 'NegReg', (130, 140))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('C1q', 'Gene', '712', (112, 115))	('GC1QR', 'Gene', '708', (58, 63))	('lamellipodia formation', 'CPA', (195, 217))	('C1q', 'Gene', (28, 31))	('activation', 'MPA', (144, 154))	('C1QBP', 'Gene', (49, 54))	('tin', 'Chemical', 'MESH:D014001', (136, 139))	('cancer', 'Disease', (274, 280))	('reduced', 'NegReg', (187, 194))	('reduced', 'NegReg', (235, 242))	('C1q', 'Gene', '712', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('GC1QR', 'Gene', (58, 63))
864911	29930979	However, silencing C1QBP was not observed as a significant regulator of EAC cell growth in our screening data.	('silencing', 'Var', (9, 18))	('EAC', 'Phenotype', 'HP:0011459', (72, 75))	('C1QBP', 'Gene', (19, 24))	('C1QBP', 'Gene', '708', (19, 24))
864917	29930979	However, recent reports have indicated that silencing TREM2 in glioma cells may result in cell death and thus provide a rational therapeutic target.	('result in', 'Reg', (80, 89))	('TREM2', 'Gene', (54, 59))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('silencing', 'Var', (44, 53))	('TREM2', 'Gene', '54209', (54, 59))	('cell death', 'CPA', (90, 100))	('glioma', 'Disease', (63, 69))
864927	29930979	Thus, the use of R788/fostamatinib for the treatment of EAC, as suggested by this report, may mediate therapeutic effects through JAK/STAT and SYK, key pathways in the inflammatory promotion of EAC and the regulation of EAC cell proliferation and survival as defined in this study.	('EAC', 'Disease', (56, 59))	('survival', 'CPA', (247, 255))	('SYK', 'Gene', (143, 146))	('EAC', 'Phenotype', 'HP:0011459', (220, 223))	('EAC', 'Disease', (194, 197))	('JAK/STAT', 'Gene', (130, 138))	('SYK', 'Gene', '6850', (143, 146))	('R788/fostamatinib', 'Var', (17, 34))	('EAC', 'Phenotype', 'HP:0011459', (56, 59))	('EAC', 'Phenotype', 'HP:0011459', (194, 197))	('fostamatinib', 'Chemical', 'MESH:C523665', (22, 34))
864931	27703488	Incidence of adverse events was significantly lower or higher in PKM and PPV arm (n = 23) or PPV and chemotherapy arm (n = 16) as compared to that of the counter arm (n = 11 or 18), respectively.	('PKM', 'Var', (65, 68))	('PPV', 'Chemical', '-', (73, 76))	('PPV', 'Chemical', '-', (93, 96))	('lower', 'NegReg', (46, 51))	('higher', 'PosReg', (55, 61))
864944	27703488	However, JTT neither affected CTL responses specific to the vaccine antigens nor prolonged overall survival, although it prevented the deterioration of patients' conditions.	('CTL', 'MPA', (30, 33))	('patients', 'Species', '9606', (152, 160))	('JTT', 'Var', (9, 12))
864948	27703488	The other inclusion criteria were as follows: an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of first visit; positive status for the human leukocyte antigen- (HLA-) A2, HLA-A24, or HLA-A3 supertypes (A3, A11, A31, or A33) or the HLA-A26 type; life expectancy of at least 12 weeks; and adequate hematologic, hepatic, and renal function.	('A3', 'Var', (239, 241))	('A33', 'Gene', '10223', (256, 259))	('A31', 'Var', (248, 251))	('A33', 'Gene', (256, 259))	('A11', 'Gene', (243, 246))	('human', 'Species', '9606', (172, 177))	('A11', 'Gene', '8248', (243, 246))	('Oncology', 'Phenotype', 'HP:0002664', (69, 77))	('EC', 'Chemical', '-', (85, 87))
864984	27703488	Under this definition, 23 patients received PKM and PPV (termed as PKM and PPV arm), whereas the remaining 11 patients (9 patients without any KM and 2 patients with JTT alone) did not receive PKM but received PPV (termed as PPV without PKM arm).	('PPV', 'Chemical', '-', (210, 213))	('PPV', 'Chemical', '-', (52, 55))	('PPV', 'Var', (52, 55))	('PKM', 'Var', (44, 47))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (122, 130))	('PPV', 'Chemical', '-', (225, 228))	('PPV', 'Chemical', '-', (75, 78))	('patients', 'Species', '9606', (152, 160))	('patients', 'Species', '9606', (110, 118))
864988	27703488	The most frequently reported adverse events in PKM and PPV arm were dermatologic reactions at the injection sites (61%), hypoalbuminemia (30%), lymphopenia (30%), and anorexia (26%).	('lymphopenia', 'Disease', 'MESH:D008231', (144, 155))	('anorexia', 'Phenotype', 'HP:0002039', (167, 175))	('PPV', 'Chemical', '-', (55, 58))	('dermatologic reactions', 'Phenotype', 'HP:0011123', (68, 90))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (121, 136))	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (121, 136))	('lymphopenia', 'Disease', (144, 155))	('PPV', 'Var', (55, 58))	('hypoalbuminemia', 'Disease', (121, 136))	('anorexia', 'Disease', 'MESH:D000855', (167, 175))	('PKM', 'Var', (47, 50))	('lymphopenia', 'Phenotype', 'HP:0001888', (144, 155))	('anorexia', 'Disease', (167, 175))	('dermatologic reactions', 'Disease', (68, 90))
864991	27703488	Therefore, after removing the PPV-related skin reactions, the mean incidence of adverse events per patient in the PKM and PPV arm was significantly lower than that in PPV without PKM arm (2.5 versus 4.7, P = 0.048).	('PPV', 'Chemical', '-', (122, 125))	('patient', 'Species', '9606', (99, 106))	('PPV', 'Chemical', '-', (167, 170))	('PPV', 'Var', (122, 125))	('skin reactions', 'Phenotype', 'HP:0011123', (42, 56))	('lower', 'NegReg', (148, 153))	('PPV', 'Chemical', '-', (30, 33))	('adverse events', 'MPA', (80, 94))
864994	27703488	The percentage of SAE (8 of 71; 11.3%) among all the adverse events in PKM and PPV arm was significantly lower (P = 0.02) than that (16 of 59, 27.1%) in PPV without PKM arm.	('lower', 'NegReg', (105, 110))	('PPV', 'Chemical', '-', (79, 82))	('PKM', 'Var', (71, 74))	('PPV arm', 'Var', (79, 86))	('PPV', 'Chemical', '-', (153, 156))	('SAE', 'Chemical', '-', (18, 21))
865016	27703488	These results suggested that PKM, but not chemotherapy, significantly prolonged the OS of aEC patients under PPV.	('patients', 'Species', '9606', (94, 102))	('PKM', 'Var', (29, 32))	('prolonged', 'PosReg', (70, 79))	('EC', 'Chemical', '-', (91, 93))	('PPV', 'Chemical', '-', (109, 112))	('aEC', 'Disease', (90, 93))
865031	27703488	All these results suggest that PKM was not only safe but further decreased disease-related adverse events, whereas the chemotherapy induced lymphopenia as expected.	('decreased', 'NegReg', (65, 74))	('disease-related', 'Disease', (75, 90))	('lymphopenia', 'Disease', (140, 151))	('lymphopenia', 'Disease', 'MESH:D008231', (140, 151))	('lymphopenia', 'Phenotype', 'HP:0001888', (140, 151))	('PKM', 'Var', (31, 34))
865043	27703488	This study showed that PKM, but not chemotherapy, significantly prolonged the OS of aEC patients under PPV.	('prolonged', 'PosReg', (64, 73))	('aEC', 'Disease', (84, 87))	('patients', 'Species', '9606', (88, 96))	('PPV', 'Chemical', '-', (103, 106))	('PKM', 'Var', (23, 26))	('EC', 'Chemical', '-', (85, 87))
865107	26039424	The purpose of this study was to examine the associations between genetic variants of various cancer-related genes and the risk of ESCC.	('associations', 'Interaction', (45, 57))	('ESCC', 'Disease', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('genetic variants', 'Var', (66, 82))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
865108	26039424	In this study, we first examined the association between 18 potentially disruptive genetic variants of 17 genes, including alcohol dehydrogenase 4 (ADH4) and checkpoint kinase 2 (CHEK2), and ESCC risk in a Hangzhou population of 617 patients matched with 534 controls.	('association', 'Interaction', (37, 48))	('CHEK2', 'Gene', (179, 184))	('alcohol dehydrogenase 4', 'Gene', (123, 146))	('ADH4', 'Gene', '127', (148, 152))	('disruptive', 'NegReg', (72, 82))	('checkpoint kinase 2', 'Gene', (158, 177))	('variants', 'Var', (91, 99))	('patients', 'Species', '9606', (233, 241))	('ADH4', 'Gene', (148, 152))	('alcohol dehydrogenase 4', 'Gene', '127', (123, 146))	('CHEK2', 'Gene', '11200', (179, 184))	('ESCC', 'Disease', (191, 195))	('checkpoint kinase 2', 'Gene', '11200', (158, 177))
865111	26039424	A significantly increased risk of developing ESCC was revealed in subjects with the AA genotype of rs3805322 (ADH4) compared with those with the AG or GG genotype by unconditional univariate logistic regression analysis.	('rs3805322', 'Var', (99, 108))	('ADH4', 'Gene', '127', (110, 114))	('rs3805322', 'Mutation', 'rs3805322', (99, 108))	('ESCC', 'Disease', (45, 49))	('ADH4', 'Gene', (110, 114))
865112	26039424	Using a dominant model, the CC genotype of rs4822983 (CHEK2) had a marginally significant protective effect compared to the CT and TT genotypes.	('CHEK2', 'Gene', (54, 59))	('rs4822983', 'Mutation', 'rs4822983', (43, 52))	('rs4822983', 'Var', (43, 52))	('CHEK2', 'Gene', '11200', (54, 59))
865113	26039424	The association of ESCC risk with these two SNPs (rs3805322 and rs4822983) was further validated in a Jinan case-control set.	('rs3805322', 'Mutation', 'rs3805322', (50, 59))	('ESCC', 'Disease', (19, 23))	('rs4822983', 'Mutation', 'rs4822983', (64, 73))	('rs4822983', 'Var', (64, 73))	('rs3805322', 'Var', (50, 59))
865114	26039424	Individuals with the ADH4 rs3805322 AA or AG genotype had ORs of 1.10 (95% CI = 0.81-1.49, P < 0.001) or 1.86 (95% CI = 1.33-2.59, P = 0.559), respectively, for developing ESCC compared with individuals with the GG genotype.	('ADH4', 'Gene', '127', (21, 25))	('rs3805322', 'Mutation', 'rs3805322', (26, 35))	('ADH4', 'Gene', (21, 25))	('rs3805322 AA', 'Var', (26, 38))	('ESCC', 'Disease', (172, 176))
865115	26039424	CHEK2 rs4822983 CC carriers showed a marginally significantly decreased ESCC risk compared with those carrying the CT and TT genotypes in the validation set (95% CI = 0.61-1.01, P = 0.064).	('CHEK2', 'Gene', (0, 5))	('decreased', 'NegReg', (62, 71))	('rs4822983 CC', 'Var', (6, 18))	('rs4822983', 'Mutation', 'rs4822983', (6, 15))	('CHEK2', 'Gene', '11200', (0, 5))	('decreased ESCC', 'Phenotype', 'HP:0025022', (62, 76))	('ESCC', 'Disease', (72, 76))
865116	26039424	In conclusion, this current study provides substantial evidence that genetic polymorphisms of rs3805322 in the ADH4 gene may be associated with an increased risk of developing ESCC in two Chinese Han populations.	('ESCC', 'Disease', (176, 180))	('ADH4', 'Gene', '127', (111, 115))	('rs3805322', 'Var', (94, 103))	('associated', 'Reg', (128, 138))	('ADH4', 'Gene', (111, 115))	('rs3805322', 'Mutation', 'rs3805322', (94, 103))
865122	26039424	Single nucleotide polymorphisms (SNPs) in genes such as checkpoint kinase 2 (CHEK2) and nei endonuclease VIII-like 2 (NEIL2), which contribute to inter-individual diversity in DNA repair capacity, may play a significant role in modifying EC risk.	('checkpoint kinase 2', 'Gene', (56, 75))	('NEIL2', 'Gene', (118, 123))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('nei endonuclease VIII-like 2', 'Gene', '252969', (88, 116))	('NEIL2', 'Gene', '252969', (118, 123))	('modifying', 'Reg', (228, 237))	('checkpoint kinase 2', 'Gene', '11200', (56, 75))	('nei endonuclease VIII-like 2', 'Gene', (88, 116))	('CHEK2', 'Gene', '11200', (77, 82))	('CHEK2', 'Gene', (77, 82))
865124	26039424	Genetic variants of mucin 1 (MUC1) and S100 calcium binding protein A14 (S100A14) have been reported to be associated with ESCC.	('S100 calcium binding protein A14', 'Gene', '57402', (39, 71))	('MUC1', 'Gene', (29, 33))	('S100 calcium binding protein A14', 'Gene', (39, 71))	('S100A14', 'Gene', (73, 80))	('associated', 'Reg', (107, 117))	('MUC1', 'Gene', '4582', (29, 33))	('mucin 1', 'Gene', '4582', (20, 27))	('ESCC', 'Disease', (123, 127))	('S100A14', 'Gene', '57402', (73, 80))	('variants', 'Var', (8, 16))	('mucin 1', 'Gene', (20, 27))
865134	26039424	The genotyping of rs3805322 (ADH4) and rs4822983 (CHEK2) in the Jinan case-control set was performed using TaqMan assays on an ABI 7900 system (Applied Biosystems, Foster City, CA) according to the manufacturer's instructions.	('ADH4', 'Gene', (29, 33))	('CHEK2', 'Gene', (50, 55))	('rs4822983', 'Mutation', 'rs4822983', (39, 48))	('rs3805322', 'Var', (18, 27))	('rs4822983', 'Var', (39, 48))	('ADH4', 'Gene', '127', (29, 33))	('CHEK2', 'Gene', '11200', (50, 55))	('rs3805322', 'Mutation', 'rs3805322', (18, 27))
865137	26039424	These two case-control sets were used to detect associations between five ADH1B-ADH1C-ADH7 cluster SNPs and the risk of ESCC.	('ADH7', 'Gene', (86, 90))	('ADH1C', 'Gene', '126', (80, 85))	('ADH1B', 'Gene', '125', (74, 79))	('associations', 'Interaction', (48, 60))	('SNPs', 'Var', (99, 103))	('ADH1C', 'Gene', (80, 85))	('ADH7', 'Gene', '131', (86, 90))	('ADH1B', 'Gene', (74, 79))
865140	26039424	In addition, the P values of the HWE tests for rs3805322 (ADH4) and rs4822983 (CHEK2) in the controls of the Jinan set were 0.495 and 0.873, respectively.	('CHEK2', 'Gene', '11200', (79, 84))	('CHEK2', 'Gene', (79, 84))	('ADH4', 'Gene', '127', (58, 62))	('rs3805322', 'Mutation', 'rs3805322', (47, 56))	('rs4822983', 'Mutation', 'rs4822983', (68, 77))	('rs4822983', 'Var', (68, 77))	('ADH4', 'Gene', (58, 62))	('rs3805322', 'Var', (47, 56))
865141	26039424	We genotyped 18 selected SNPs in 17 genes for all 617 ESCC patients and 534 control subjects in the discovery arm (Hangzhou).	('ESCC', 'Disease', (54, 58))	('patients', 'Species', '9606', (59, 67))	('SNPs', 'Var', (25, 29))
865142	26039424	The genotype frequencies of rs3805322 (ADH4) polymorphisms were significantly different between cases and controls (P < 0.001, Table 2).	('rs3805322', 'Mutation', 'rs3805322', (28, 37))	('ADH4', 'Gene', (39, 43))	('rs3805322', 'Var', (28, 37))	('ADH4', 'Gene', '127', (39, 43))
865144	26039424	Unconditional univariate logistic regression analysis revealed a significantly increased risk of developing ESCC in subjects with the AA genotype for rs3805322 (ADH4) compared with those with the AG (OR 1.19, 95% CI 0.89-1.61) or GG (OR 2.16, 95% CI 1.56-3.00) genotypes.	('rs3805322', 'Mutation', 'rs3805322', (150, 159))	('ADH4', 'Gene', (161, 165))	('ESCC', 'Disease', (108, 112))	('ADH4', 'Gene', '127', (161, 165))	('rs3805322', 'Var', (150, 159))
865146	26039424	Similar results were observed for the two SNPs (rs3805322 and rs4822983) by multivariate logistic regression analysis, which was adjusted for environmental factors such as smoking and drinking (Table 3).	('rs3805322', 'Mutation', 'rs3805322', (48, 57))	('rs4822983', 'Mutation', 'rs4822983', (62, 71))	('rs3805322', 'Var', (48, 57))	('rs4822983', 'Var', (62, 71))
865147	26039424	The association of ESCC risk with these two SNPs (rs3805322 and rs4822983) was further validated in an independent case-control set (Jinan).	('rs3805322', 'Mutation', 'rs3805322', (50, 59))	('ESCC', 'Disease', (19, 23))	('rs4822983', 'Mutation', 'rs4822983', (64, 73))	('rs4822983', 'Var', (64, 73))	('rs3805322', 'Var', (50, 59))
865148	26039424	Individuals with the ADH4 rs3805322 AA or AG genotypes had ORs of 1.10 (95% CI = 0.81-1.49, P < 0.001) or 1.86 (95% CI = 1.33-2.59, P = 0.559), respectively, for developing ESCC compared with those with the GG genotype.	('ADH4', 'Gene', '127', (21, 25))	('ESCC', 'Disease', (173, 177))	('rs3805322', 'Mutation', 'rs3805322', (26, 35))	('ADH4', 'Gene', (21, 25))	('rs3805322 AA', 'Var', (26, 38))
865149	26039424	CHEK2 rs4822983 CC carriers showed a marginally significantly decreased ESCC risk compared with those harboring the CT and TT genotypes in the Jinan population (95% CI = 0.61-1.01, P = 0.064) (Table 3).	('CHEK2', 'Gene', (0, 5))	('decreased', 'NegReg', (62, 71))	('rs4822983 CC', 'Var', (6, 18))	('rs4822983', 'Mutation', 'rs4822983', (6, 15))	('CHEK2', 'Gene', '11200', (0, 5))	('decreased ESCC', 'Phenotype', 'HP:0025022', (62, 76))	('ESCC', 'Disease', (72, 76))
865151	26039424	Interestingly, we found no significant association between the ADH4 rs3805322 genotypes and ESCC risk among the subgroups of either smokers or non-smokers (Table 4).	('rs3805322', 'Var', (68, 77))	('ESCC', 'Disease', (92, 96))	('ADH4', 'Gene', '127', (63, 67))	('rs3805322', 'Mutation', 'rs3805322', (68, 77))	('ADH4', 'Gene', (63, 67))
865152	26039424	There was a significant association between ADH4 rs3805322 genotype and ESCC risk among alcohol drinkers (OR 2.59, 95% CI 1.76-3.84).	('rs3805322', 'Mutation', 'rs3805322', (49, 58))	('ADH4', 'Gene', (44, 48))	('alcohol', 'Chemical', 'MESH:D000438', (88, 95))	('rs3805322', 'Var', (49, 58))	('ADH4', 'Gene', '127', (44, 48))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (88, 104))	('ESCC', 'Disease', (72, 76))
865153	26039424	However, there was no statistically significant association between the CHEK2 rs4822983 genotype and ESCC risk.	('CHEK2', 'Gene', '11200', (72, 77))	('rs4822983', 'Mutation', 'rs4822983', (78, 87))	('rs4822983', 'Var', (78, 87))	('CHEK2', 'Gene', (72, 77))	('ESCC', 'Disease', (101, 105))
865154	26039424	In addition, the gene-environment interactions between the two SNPs (ADH4 rs3805322 and CHEK2 rs4822983) and smoking or drinking were evaluated using SPSS.	('rs4822983', 'Var', (94, 103))	('rs3805322', 'Mutation', 'rs3805322', (74, 83))	('ADH4', 'Gene', '127', (69, 73))	('rs3805322', 'Var', (74, 83))	('ADH4', 'Gene', (69, 73))	('CHEK2', 'Gene', (88, 93))	('CHEK2', 'Gene', '11200', (88, 93))	('rs4822983', 'Mutation', 'rs4822983', (94, 103))
865159	26039424	The association between EC and polymorphisms in some of these ADH genes, including rs1229984 (ADH1B), rs698 (ADH1C), rs17028973 (ADH7), and rs671 (ALDH2), has been investigated.	('ADH', 'Gene', (129, 132))	('rs698', 'Var', (102, 107))	('rs1229984', 'Var', (83, 92))	('ALDH2', 'Gene', (147, 152))	('rs17028973', 'Mutation', 'rs17028973', (117, 127))	('ADH', 'Gene', '124;125;126;127;131;128;130;130;131', (129, 132))	('ADH', 'Gene', (62, 65))	('ADH', 'Gene', (94, 97))	('rs671', 'Var', (140, 145))	('ADH1C', 'Gene', (109, 114))	('ADH1B', 'Gene', '125', (94, 99))	('rs17028973', 'Var', (117, 127))	('ADH', 'Gene', (109, 112))	('rs671', 'Mutation', 'rs671', (140, 145))	('rs1229984', 'Mutation', 'rs1229984', (83, 92))	('ALDH2', 'Gene', '217', (147, 152))	('rs698', 'Mutation', 'rs698', (102, 107))	('ADH7', 'Gene', (129, 133))	('ADH', 'Gene', '124;125;126;127;131;128;130;130;131', (62, 65))	('ADH1C', 'Gene', '126', (109, 114))	('ADH1B', 'Gene', (94, 99))	('ADH', 'Gene', '124;125;126;127;131;128;130;130;131', (94, 97))	('ADH7', 'Gene', '131', (129, 133))	('ADH', 'Gene', '124;125;126;127;131;128;130;130;131', (109, 112))
865160	26039424	In our study, we examined the association between 18 selected SNPs in 17 cancer-related genes and the risk of developing ESCC in a two Chinese populations.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SNPs', 'Var', (62, 66))	('ESCC', 'Disease', (121, 125))
865161	26039424	We found that patients with the AA genotype of rs3805322 (ADH4) had a significantly increased risk of developing ESCC compared with those with the AG or GG genotypes in our discovery dataset.	('ESCC', 'Disease', (113, 117))	('ADH4', 'Gene', '127', (58, 62))	('rs3805322', 'Mutation', 'rs3805322', (47, 56))	('ADH4', 'Gene', (58, 62))	('patients', 'Species', '9606', (14, 22))	('rs3805322', 'Var', (47, 56))
865163	26039424	determined that compared with other genotypes, the GG genotype of ADH4 rs3805322 was associated with an increased risk of upper aerodigestive tract cancer in per-allele, dominant, and recessive models.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('rs3805322', 'Mutation', 'rs3805322', (71, 80))	('ADH4', 'Gene', '127', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('ADH4', 'Gene', (66, 70))	('rs3805322', 'Var', (71, 80))
865168	26039424	In the current study, we observed that the CC genotype of CHEK2 rs4822983 showed a marginally significantly decreased ESCC risk compared with the CT and TT genotypes.	('ESCC', 'Disease', (118, 122))	('decreased ESCC', 'Phenotype', 'HP:0025022', (108, 122))	('CHEK2', 'Gene', (58, 63))	('rs4822983', 'Mutation', 'rs4822983', (64, 73))	('rs4822983', 'Var', (64, 73))	('decreased', 'NegReg', (108, 117))	('CHEK2', 'Gene', '11200', (58, 63))
865169	26039424	However, there was no interaction between the two polymorphisms (ADH4 rs3805322 and CHEK2 rs4822983) and drinking and smoking in terms of ESCC susceptibility.	('rs3805322', 'Mutation', 'rs3805322', (70, 79))	('ADH4', 'Gene', '127', (65, 69))	('rs3805322', 'Var', (70, 79))	('CHEK2', 'Gene', '11200', (84, 89))	('ADH4', 'Gene', (65, 69))	('CHEK2', 'Gene', (84, 89))	('rs4822983', 'Mutation', 'rs4822983', (90, 99))	('ESCC', 'Disease', (138, 142))	('rs4822983', 'Var', (90, 99))
865170	26039424	The current study provides substantial evidence that genetic polymorphisms of rs3805322 in the ADH4 gene may be associated with an increased risk of developing ESCC in two Chinese Han populations.	('ESCC', 'Disease', (160, 164))	('rs3805322', 'Mutation', 'rs3805322', (78, 87))	('ADH4', 'Gene', (95, 99))	('rs3805322', 'Var', (78, 87))	('associated', 'Reg', (112, 122))	('ADH4', 'Gene', '127', (95, 99))
865171	26039424	Polymorphisms in ADH4 rs3805322 influence susceptibility to ESCC in different genetic models of allele-dose effects and recessive effects.	('rs3805322', 'Var', (22, 31))	('susceptibility', 'MPA', (42, 56))	('ESCC', 'Disease', (60, 64))	('rs3805322', 'Mutation', 'rs3805322', (22, 31))	('ADH4', 'Gene', (17, 21))	('ADH4', 'Gene', '127', (17, 21))
865210	24886219	Once returned in the surgical ward, the mean daily request of diazepam, lormetazepam, and lorazepam was 0.069 (95% CI: 0.032-0.106), 0.021 (95% CI 0.002-0.040), and 0.269 (95% CI 0.186-0.351) doses, respectively.	('lorazepam', 'Chemical', 'MESH:D008140', (90, 99))	('lormetazepam', 'Chemical', 'MESH:C023842', (72, 84))	('0.069', 'Var', (104, 109))	('0.021', 'Var', (133, 138))	('diazepam', 'Chemical', 'MESH:D003975', (62, 70))
865264	23967217	Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples.	('miR-133b', 'Gene', (78, 86))	('miR-196a', 'Chemical', '-', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('expressional', 'MPA', (12, 24))	('miR-196a', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('miR-196a', 'Var', (104, 112))	('miR-133b', 'Gene', '442890', (78, 86))	('miR-196a', 'Chemical', '-', (126, 134))
865268	23967217	Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.	('miR-196a', 'Chemical', '-', (42, 50))	('laryngeal cancer', 'Disease', 'MESH:D007822', (99, 115))	('laryngeal cancer', 'Disease', (99, 115))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (99, 115))	('miR-196a', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
865281	23967217	In recent years, there has been a considerable interest in understanding the role of miRNAs in disease processes and their dysregulation is believed to promote the malignant behavior of tumors.	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('dysregulation', 'Var', (123, 136))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumors', 'Disease', (186, 192))	('promote', 'PosReg', (152, 159))
865282	23967217	The links between the aberrant expression of miRNAs and the pathogenesis of several cancer types are documented.	('aberrant expression', 'Var', (22, 41))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('miRNAs', 'Gene', (45, 51))
865304	23967217	Samples analyzed include 2 laryngeal cancers (T416, 66 y.o.	('laryngeal cancers', 'Disease', (27, 44))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (27, 43))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('T416', 'Var', (46, 50))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (27, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('laryngeal cancers', 'Disease', 'MESH:D007822', (27, 44))
865305	23967217	male, T3N2c) as advanced cancer samples and 3 laryngeal papillomas (T421, 33 y.o.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('laryngeal papillomas', 'Disease', (46, 66))	('laryngeal papillomas', 'Disease', 'MESH:C535297', (46, 66))	('papillomas', 'Phenotype', 'HP:0012740', (56, 66))	('T3N2c', 'Var', (6, 11))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
865326	23967217	Efficacy of treatment on both tumors and their locoregional lymph node metastasis was examined in each of the following 2 groups: Group 1, miR-196a inhibitor; Group 2, inhibitor negative control (control).	('tumors', 'Disease', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('miR-196a inhibitor', 'Var', (139, 157))	('miR-196a', 'Chemical', '-', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
865337	23967217	The results showed that 5 miRNAs (miR-130b-5p (formerly designated as miR-130b*), miR-196a, miR-455-3p, miR-455-5p, and miR-801) or 2 miRNAs (miR-133b and miR-145) were significantly up-regulated or down-regulated, respectively in laryngeal cancers (Figure 1A).	('miR-455-3p', 'Chemical', '-', (92, 102))	('down-regulated', 'NegReg', (199, 213))	('miR-133b', 'Gene', '442890', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('miR-801', 'Var', (120, 127))	('miR-130b', 'Gene', '406920', (34, 42))	('miR-145', 'Gene', '406937', (155, 162))	('miR-130b', 'Gene', (34, 42))	('miR-455-5p', 'Var', (104, 114))	('miR-455-3p', 'Var', (92, 102))	('laryngeal cancers', 'Disease', (231, 248))	('miR-145', 'Gene', (155, 162))	('laryngeal cancers', 'Disease', 'MESH:D007822', (231, 248))	('miR-196a', 'Var', (82, 90))	('miR-133b', 'Gene', (142, 150))	('miR-196a', 'Chemical', '-', (82, 90))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (231, 247))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (231, 248))	('up-regulated', 'PosReg', (183, 195))	('miR-130b', 'Gene', '406920', (70, 78))	('miR-130b', 'Gene', (70, 78))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))
865343	23967217	Thus, qRT-PCR analysis was performed on residual 4 miRNAs (i.e., miR-130b-5p, miR-196a, miR-455-5p, and miR-133b).	('miR-130b', 'Gene', (65, 73))	('miR-133b', 'Gene', '442890', (104, 112))	('miR-455-5p', 'Var', (88, 98))	('miR-196a', 'Var', (78, 86))	('miR-133b', 'Gene', (104, 112))	('miR-196a', 'Chemical', '-', (78, 86))	('miR-130b', 'Gene', '406920', (65, 73))
865347	23967217	Furthermore, expression levels of miR-196a and miR-455-5p were significantly higher in cancer tissues when compared with neighboring controls (miR-196a, p = 0.0460; miR-455-5p, p = 0.0286) (Figure 2A), while expression level of miR-133b was significantly lower in cancer samples compared with controls (p = 0.0274) (Figure 2B).	('cancer', 'Disease', (87, 93))	('expression levels', 'MPA', (13, 30))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('miR-196a', 'Chemical', '-', (34, 42))	('higher', 'PosReg', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('miR-196a', 'Var', (34, 42))	('miR-455-5p', 'Var', (47, 57))	('miR-133b', 'Gene', '442890', (228, 236))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('miR-196a', 'Chemical', '-', (143, 151))	('cancer', 'Disease', (264, 270))	('miR-133b', 'Gene', (228, 236))
865348	23967217	Thus, of these 4 miRNAs, 3 miRNAs (i.e., miR-196a, miR-455-5p and miR-133b) showed significantly different expression levels in cancer tissues when compared with their matched control tissues and further quantification of miRNAs was performed using 48 laryngeal samples.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('miR-196a', 'Chemical', '-', (41, 49))	('expression levels', 'MPA', (107, 124))	('cancer', 'Disease', (128, 134))	('miR-133b', 'Gene', '442890', (66, 74))	('miR-196a', 'Var', (41, 49))	('different', 'Reg', (97, 106))	('miR-133b', 'Gene', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('miR-455-5p', 'Var', (51, 61))
865350	23967217	When 48 samples were studied, the expression level of miR-455-5p was significantly higher in cancers compared with adjacent noncancerous counterparts and benign laryngeal tissues (p = 0.0113).	('cancer', 'Disease', (93, 99))	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('miR-455-5p', 'Var', (54, 64))	('cancer', 'Disease', (127, 133))	('higher', 'PosReg', (83, 89))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('expression level', 'MPA', (34, 50))
865351	23967217	Furthermore, expression level of miR-196a was clearly higher in cancer tissues compared with noncancerous other tissues (adjacent noncancerous counterparts and benign laryngeal tissues, p = 0.0003; dysplasias, p = 0.0040) (Figure 3A).	('dysplasias', 'Disease', (198, 208))	('higher', 'PosReg', (54, 60))	('miR-196a', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (133, 139))	('dysplasias', 'Disease', 'MESH:D004476', (198, 208))	('miR-196a', 'Chemical', '-', (33, 41))	('expression level', 'MPA', (13, 29))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
865353	23967217	Therefore, to further explore the significance of miR-196a as a promising biomarker for laryngeal cancer, qRT-PCR analysis of miR-196a was performed on 84 histologically verified samples (15 noncancerous counterparts, 24 benign diseases, 18 dysplasias, 27 laryngeal cancers) and 7 HNSCC cell lines.	('miR-196a', 'Var', (126, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (281, 286))	('cancer', 'Disease', (98, 104))	('dysplasias', 'Disease', (241, 251))	('miR-196a', 'Chemical', '-', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('laryngeal cancer', 'Disease', 'MESH:D007822', (256, 272))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (256, 272))	('benign diseases', 'Disease', (221, 236))	('laryngeal cancers', 'Disease', (256, 273))	('laryngeal cancer', 'Disease', 'MESH:D007822', (88, 104))	('laryngeal cancers', 'Disease', 'MESH:D007822', (256, 273))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('laryngeal cancer', 'Disease', (88, 104))	('miR-196a', 'Chemical', '-', (50, 58))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (88, 104))	('dysplasias', 'Disease', 'MESH:D004476', (241, 251))	('cancer', 'Disease', (194, 200))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancer', 'Disease', (266, 272))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (256, 273))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))
865354	23967217	The study showed that increasing tendency of miR-196a expression level was observed when cancer samples were compared with noncancerous counterparts, benign tissues, or dysplasias (Figure 4A).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('miR-196a', 'Chemical', '-', (45, 53))	('dysplasias', 'Disease', (169, 179))	('expression level', 'MPA', (54, 70))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('miR-196a', 'Var', (45, 53))	('dysplasias', 'Disease', 'MESH:D004476', (169, 179))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
865357	23967217	Together with these findings, miR-196a could be a favorable marker for laryngeal cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('laryngeal cancer', 'Disease', 'MESH:D007822', (71, 87))	('miR-196a', 'Var', (30, 38))	('laryngeal cancer', 'Disease', (71, 87))	('miR-196a', 'Chemical', '-', (30, 38))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (71, 87))
865358	23967217	Such variations are primarily caused by a shift of cleavage sites when mature miRNAs are processed by Drosha and Dicer, but are also introduced by terminal nucleotide additions or internal RNA editing.	('variations', 'Var', (5, 15))	('introduced', 'Reg', (133, 143))	('cleavage sites', 'MPA', (51, 65))	('Drosha', 'Gene', (102, 108))	('internal RNA', 'Var', (180, 192))	('shift', 'Reg', (42, 47))	('Dicer', 'Gene', '23405', (113, 118))	('Dicer', 'Gene', (113, 118))	('caused', 'Reg', (30, 36))	('Drosha', 'Gene', '29102', (102, 108))
865363	23967217	Among a series of miR-196a isomiRs detected in each sample, the most abundant ones in cancer samples were nearly equal to the canonical sequence deposited in miRBase entry (MIMAT0000226, 5'- uagguaguuucauguuguuggg -3'), while those in non-cancer samples were shorter at both ends with 1-2 nucleotides (Figure 5B).	('miR-196a', 'Chemical', '-', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('non-cancer', 'Disease', (235, 245))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('non-cancer', 'Disease', 'MESH:D009369', (235, 245))	('miR-196a', 'Gene', (18, 26))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('MIMAT0000226', 'Var', (173, 185))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Disease', (86, 92))
865367	23967217	The result showed that the expression of miR-196a was evident in laryngeal cancer, but was under detection levels in the adjacent normal counterpart (Figure 6).	('laryngeal cancer', 'Disease', (65, 81))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (65, 81))	('miR-196a', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('laryngeal cancer', 'Disease', 'MESH:D007822', (65, 81))	('miR-196a', 'Chemical', '-', (41, 49))
865369	23967217	Together with the result that miR-196a is highly expressed in laryngeal cancer cell line JHU-011 cells (Figure 4A), these findings raised the possibility that cancer cells secrete miR-196a transferable or functional in stromal cells.	('cancer', 'Disease', (159, 165))	('laryngeal cancer', 'Disease', (62, 78))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (62, 78))	('miR-196a', 'Chemical', '-', (180, 188))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('JHU-011', 'CellLine', 'CVCL:5986', (89, 96))	('laryngeal cancer', 'Disease', 'MESH:D007822', (62, 78))	('miR-196a', 'Chemical', '-', (30, 38))	('miR-196a', 'Var', (180, 188))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (72, 78))
865370	23967217	Next, to explore the physiological significance of miR-196a expression in laryngeal cancer, we first examined whether miR-196a is beneficial to the propagation of laryngeal cancer cells.	('miR-196a', 'Chemical', '-', (51, 59))	('laryngeal cancer', 'Disease', (163, 179))	('propagation', 'CPA', (148, 159))	('laryngeal cancer', 'Disease', 'MESH:D007822', (74, 90))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (163, 179))	('miR-196a', 'Chemical', '-', (118, 126))	('laryngeal cancer', 'Disease', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (74, 90))	('miR-196a', 'Var', (118, 126))	('laryngeal cancer', 'Disease', 'MESH:D007822', (163, 179))
865372	23967217	Significant suppression of cell proliferation was observed by miR-196a inhibitor compared with control (miR-196a inhibitor, 22.67+-3.06x104/ml; control, 44.33+-6.66x104/ml; p = 0.0069) (Figure 7A).	('miR-196a', 'Chemical', '-', (62, 70))	('miR-196a', 'Chemical', '-', (104, 112))	('cell proliferation', 'CPA', (27, 45))	('suppression', 'NegReg', (12, 23))	('rat', 'Species', '10116', (39, 42))	('miR-196a inhibitor', 'Var', (62, 80))
865376	23967217	The study showed that relative number of live cells or that of dead cells were significantly suppressed (control, 1+-0.019; miR-196a inhibitor, 0.584+-0.029; p = 0.0022) or enhanced (control, 1+-0.025; miR-196a inhibitor, 1.692+-0.059; p = 0.0015), respectively, in the miR-196a inhibitor treatment group compared with control group (Figure 7B).	('miR-196a', 'Chemical', '-', (124, 132))	('miR-196a inhibitor', 'Var', (270, 288))	('miR-196a', 'Chemical', '-', (270, 278))	('relative number', 'CPA', (22, 37))	('suppressed', 'NegReg', (93, 103))	('enhanced', 'PosReg', (173, 181))	('miR-196a', 'Chemical', '-', (202, 210))
865387	23967217	Recent reports revealed that manipulation of tumor-specific miRNAs could suppress cell invasion, cell migration, and to reduce the anchorage-independent growth in vitro, and suppress metastasis in vivo.	('suppress', 'NegReg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('manipulation', 'Var', (29, 41))	('reduce', 'NegReg', (120, 126))	('rat', 'Species', '10116', (105, 108))	('metastasis', 'CPA', (183, 193))	('tumor', 'Disease', (45, 50))	('suppress', 'NegReg', (174, 182))	('cell migration', 'CPA', (97, 111))	('cell invasion', 'CPA', (82, 95))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('anchorage-independent growth', 'CPA', (131, 159))
865388	23967217	Several known mechanisms to explain the tumor suppressive role by miRNAs modifications are epigenetic aberration by targeting the DNA methyltransferases, regulation of the epidermal growth factor receptor expression, and regulation of tumor angiogenesis.	('epidermal growth factor receptor', 'Gene', (172, 204))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('targeting', 'Reg', (116, 125))	('modifications', 'Var', (73, 86))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('epidermal growth factor receptor', 'Gene', '1956', (172, 204))	('tumor', 'Disease', (235, 240))	('rat', 'Species', '10116', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('miRNAs', 'Var', (66, 72))	('DNA methyltransferases', 'Enzyme', (130, 152))
865389	23967217	Moreover, it has been suggested that specific miRNAs may have crucial roles in the initiation and/or progression of human cancers through their effects on various molecular pathways.	('effects', 'Reg', (144, 151))	('miRNAs', 'Var', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('molecular pathways', 'Pathway', (163, 181))	('human', 'Species', '9606', (116, 121))
865394	23967217	Down-regulation of miRNAs in cancers may be achieved through mutation or by epigenetic silencing or the miRNA, resulting in loss of tissue-specific miRNA synthesis and overexpression of oncogenes which normally function as tumor suppressors.	('loss', 'NegReg', (124, 128))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('mutation', 'Var', (61, 69))	('oncogenes', 'CPA', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))	('Down-regulation', 'NegReg', (0, 15))	('epigenetic silencing', 'Var', (76, 96))	('tissue-specific miRNA synthesis', 'MPA', (132, 163))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('overexpression', 'PosReg', (168, 182))
865399	23967217	MYCN, FOS, YES, FLY, cyclins D2 and L1, MAP3K3 and MAPK4K4 were reported to be potential oncogenic targets of miR-145.	('FOS', 'Gene', '3772082', (6, 9))	('miR-145', 'Gene', '406937', (110, 117))	('FOS', 'Gene', (6, 9))	('MAPK4K4', 'Var', (51, 58))	('MAP3K3', 'Gene', '4215', (40, 46))	('miR-145', 'Gene', (110, 117))	('MAP3K3', 'Gene', (40, 46))
865403	23967217	While miR-130b-5p, miR-455-3p, miR-455-5p, and miR-801 were up-regulated in laryngeal cancer in our study, much less study has been performed on these miRNAs before.	('miR-130b', 'Gene', (6, 14))	('miR-455-5p', 'Var', (31, 41))	('miR-801', 'Var', (47, 54))	('laryngeal cancer', 'Disease', (76, 92))	('miR-455-3p', 'Chemical', '-', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (76, 92))	('miR-455-3p', 'Var', (19, 29))	('up-regulated', 'PosReg', (60, 72))	('miR-130b', 'Gene', '406920', (6, 14))	('laryngeal cancer', 'Disease', 'MESH:D007822', (76, 92))
865406	23967217	One known target of miR-455-3p is TTK (also known as MPS1) protein kinase which regulates mitotic spindle formation and cell proliferation  .	('cell proliferation', 'CPA', (120, 138))	('mitotic spindle formation', 'CPA', (90, 115))	('rat', 'Species', '10116', (132, 135))	('MPS1', 'Gene', (53, 57))	('TTK', 'Gene', '7272', (34, 37))	('miR-455-3p', 'Chemical', '-', (20, 30))	('miR-455-3p', 'Var', (20, 30))	('regulates', 'Reg', (80, 89))	('TTK', 'Gene', (34, 37))	('MPS1', 'Gene', '7272', (53, 57))
865407	23967217	TTK kinase is differentially expressed in lung, esophageal and breast cancer, and mutation of TTK kinase induces the failure of the spindle checkpoint and aberrant mitosis of cells.	('spindle checkpoint', 'CPA', (132, 150))	('induces', 'Reg', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutation', 'Var', (82, 90))	('TTK', 'Gene', (94, 97))	('lung', 'Disease', (42, 46))	('esophageal', 'Disease', (48, 58))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('TTK', 'Gene', '7272', (0, 3))	('TTK', 'Gene', '7272', (94, 97))	('breast cancer', 'Disease', (63, 76))	('mitosis', 'Disease', (164, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('mitosis', 'Disease', 'None', (164, 171))	('esophageal', 'Disease', 'MESH:D004941', (48, 58))	('TTK', 'Gene', (0, 3))	('failure', 'CPA', (117, 124))
865411	23967217	Notably, compared with pre-cancerous dysplasias, miR-196a expression was significantly higher in early T1a cancer in our study, suggesting the potential of miR-196a to be a very supportive or crucial tumor marker especially for early laryngeal cancer with frequent difficulty with pathological diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('expression', 'MPA', (58, 68))	('crucial tumor', 'Disease', 'MESH:D009369', (192, 205))	('laryngeal cancer', 'Disease', 'MESH:D007822', (234, 250))	('miR-196a', 'Var', (156, 164))	('higher', 'PosReg', (87, 93))	('laryngeal cancer', 'Disease', (234, 250))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (234, 250))	('miR-196a', 'Chemical', '-', (156, 164))	('crucial tumor', 'Disease', (192, 205))	('cancerous dysplasias', 'Disease', 'MESH:D009369', (27, 47))	('T1a cancer', 'Disease', (103, 113))	('cancerous dysplasias', 'Disease', (27, 47))	('T1a cancer', 'Disease', 'MESH:D009369', (103, 113))	('miR-196a', 'Gene', (49, 57))	('miR-196a', 'Chemical', '-', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))
865413	23967217	Another previous report proved that miR-196a promoted cell proliferation, anchorage-independent growth and suppressed apoptosis by targeting annexin A1.	('apoptosis', 'CPA', (118, 127))	('cell proliferation', 'CPA', (54, 72))	('miR-196a', 'Var', (36, 44))	('anchorage-independent growth', 'CPA', (74, 102))	('miR-196a', 'Chemical', '-', (36, 44))	('promoted', 'PosReg', (45, 53))	('suppressed', 'NegReg', (107, 117))	('annexin A1', 'Gene', (141, 151))	('annexin A1', 'Gene', '301', (141, 151))	('targeting', 'Reg', (131, 140))	('rat', 'Species', '10116', (66, 69))
865414	23967217	Furthermore, high levels of miR-196a activates the AKT signaling pathway and promotes cancer cell detachment, migration, invasion, but does not impact on proliferation or apoptosis in the colorectal cancer cell line.	('miR-196a', 'Chemical', '-', (28, 36))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('promotes', 'PosReg', (77, 85))	('migration', 'CPA', (110, 119))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rat', 'Species', '10116', (113, 116))	('activates', 'PosReg', (37, 46))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('rat', 'Species', '10116', (161, 164))	('miR-196a', 'Var', (28, 36))	('AKT signaling pathway', 'Pathway', (51, 72))	('invasion', 'CPA', (121, 129))	('cancer', 'Disease', (199, 205))	('cancer', 'Disease', (86, 92))
865416	23967217	Furthermore, the role of miR-196a as one of the regulators of the ETS transcription factor ERG known as an adverse prognostic factor for acute leukemia has been also reported.	('miR-196a', 'Chemical', '-', (25, 33))	('acute leukemia', 'Disease', 'MESH:D015470', (137, 151))	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('miR-196a', 'Var', (25, 33))	('acute leukemia', 'Phenotype', 'HP:0002488', (137, 151))	('ERG', 'Gene', '2078', (91, 94))	('ERG', 'Gene', (91, 94))	('acute leukemia', 'Disease', (137, 151))
865418	23967217	Although further study is necessary to examine biological significance including the downstream targets of miR-196a in laryngeal cancer, there may be a mechanism through HOX gene deregulation to promote laryngeal cancer.	('deregulation', 'Var', (179, 191))	('laryngeal cancer', 'Disease', (203, 219))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (203, 219))	('miR-196a', 'Chemical', '-', (107, 115))	('laryngeal cancer', 'Disease', 'MESH:D007822', (119, 135))	('promote', 'PosReg', (195, 202))	('laryngeal cancer', 'Disease', 'MESH:D007822', (203, 219))	('miR-196a', 'Gene', (107, 115))	('laryngeal cancer', 'Disease', (119, 135))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (119, 135))
865421	23967217	In the current release of miRBase, both miR-196a-5p and -3p arm sequences are annotated in mir-196a-2 precursor, while miR-196a-5p but not -3p sequence is annotated in mir-196a-1 precursor.	('mir-196a-2', 'Gene', '406973', (91, 101))	('miR-196a-5p', 'Var', (40, 51))	('mir-196a-1', 'Gene', '406972', (168, 178))	('miR-196a', 'Chemical', '-', (40, 48))	('miR-196a', 'Chemical', '-', (119, 127))	('mir-196a-1', 'Gene', (168, 178))	('mir-196a-2', 'Gene', (91, 101))
865422	23967217	According to our deep sequencing data, mir-196a-1 precursor is as well responsible for expressing unannotated miR-196a-3p sequence that is slightly different from that of mir-196a-2 precursor origin.	('mir-196a-2', 'Gene', (171, 181))	('miR-196a', 'Chemical', '-', (110, 118))	('mir-196a-2', 'Gene', '406973', (171, 181))	('mir-196a-1', 'Gene', (39, 49))	('miR-196a-3p', 'Var', (110, 121))	('mir-196a-1', 'Gene', '406972', (39, 49))
865425	23967217	In contrast, non-cancer tissues revealed low expression level of miR-196a in a form shorter than miRBase information.	('miR-196a', 'Chemical', '-', (65, 73))	('miR-196a', 'Var', (65, 73))	('non-cancer', 'Disease', (13, 23))	('non-cancer', 'Disease', 'MESH:D009369', (13, 23))	('expression level', 'MPA', (45, 61))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
865431	23967217	Actually, our preliminary data revealed that miR-196a could be detected in a serum sample obtained from advanced cancer patients (data not shown).	('miR-196a', 'Chemical', '-', (45, 53))	('detected', 'Reg', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('miR-196a', 'Var', (45, 53))	('cancer', 'Disease', (113, 119))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
865432	23967217	Our findings suggested that miR-196a could be a potential tumor marker in the FFPE tissue sample of laryngeal cancer.	('miR-196a', 'Chemical', '-', (28, 36))	('laryngeal cancer', 'Disease', (100, 116))	('tumor', 'Disease', (58, 63))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (100, 116))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('laryngeal cancer', 'Disease', 'MESH:D007822', (100, 116))	('miR-196a', 'Var', (28, 36))
865439	23967217	Thus, our laryngeal cancer xenograft data demonstrate, as a whole, that miR-196a is sufficient to strongly enhance laryngeal cancer growth (even if we are not providing the precise biological mechanisms behind this dramatic effect) and, consequently, that the inhibition of miR-196a is necessary, and in fact effective, to reduce the in vivo growth of this tumor.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (10, 26))	('tumor', 'Disease', (357, 362))	('laryngeal cancer', 'Disease', (115, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('miR-196a', 'Chemical', '-', (72, 80))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (115, 131))	('miR-196a', 'Chemical', '-', (274, 282))	('enhance', 'PosReg', (107, 114))	('laryngeal cancer', 'Disease', 'MESH:D007822', (10, 26))	('tumor', 'Disease', 'MESH:D009369', (357, 362))	('rat', 'Species', '10116', (49, 52))	('miR-196a', 'Var', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('laryngeal cancer', 'Disease', 'MESH:D007822', (115, 131))	('laryngeal cancer', 'Disease', (10, 26))
865480	33854048	Consistently, knockdown of THAP9-AS1 inhibited xenograft tumor growth in vivo.	('inhibited', 'NegReg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (27, 36))	('THAP9-AS1', 'Gene', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', (57, 62))
865483	33854048	Moreover, the anti-tumor property induced by THAP9-AS1 knockdown was significantly impaired due to miR-133b downregulation or SOX4 overexpression.	('knockdown', 'Var', (55, 64))	('miR-133b', 'Gene', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('THAP9-AS1', 'Gene', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (45, 54))	('downregulation', 'NegReg', (108, 122))	('SOX4', 'Gene', (126, 130))	('tumor', 'Disease', (19, 24))	('overexpression', 'PosReg', (131, 145))	('miR-133b', 'Gene', '442890', (99, 107))	('impaired', 'NegReg', (83, 91))	('SOX4', 'Gene', '6659', (126, 130))
865490	33854048	A multitude of evidence identifies lncRNAs as tumor suppressors or drivers via influencing various cellular processes important for normal development and physiology, highlighting their great potential in cancer diagnosis, prognosis, and therapy.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('influencing', 'Reg', (79, 90))	('cancer', 'Disease', (205, 211))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cellular', 'CPA', (99, 107))	('lncRNAs', 'Var', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
865501	33854048	Functionally, silencing of THAP9-AS1 suppressed ESCC cell proliferation, migration, and invasion in vitro and reduced tumor growth in vivo.	('migration', 'CPA', (73, 82))	('silencing', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('reduced', 'NegReg', (110, 117))	('invasion', 'CPA', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (27, 36))	('THAP9-AS1', 'Gene', (27, 36))	('tumor', 'Disease', (118, 123))	('ESCC', 'Disease', (48, 52))	('suppressed', 'NegReg', (37, 47))
865581	33854048	As demonstrated by CCK-8 and clonogenic assays, silencing of THAP9-AS1 resulted in significant suppression of cell proliferation and colony-forming capability (Fig.	('THAP9-AS1', 'Gene', (61, 70))	('silencing', 'Var', (48, 57))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (61, 70))	('colony-forming capability', 'CPA', (133, 158))	('suppression', 'NegReg', (95, 106))	('cell proliferation', 'CPA', (110, 128))
865584	33854048	Wound healing assays manifested that depletion of THAP9-AS1 lowered cell motility (Fig.	('depletion', 'Var', (37, 46))	('cell motility', 'CPA', (68, 81))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (50, 59))	('THAP9-AS1', 'Gene', (50, 59))	('lowered', 'NegReg', (60, 67))
865587	33854048	In order to unearth the action mechanism by which THAPH-AS1 facilitates ESCC progression, we firstly made a prediction of the subcellular location of THAP9-AS1 with an online tool lncLocator (http://www.csbio.sjtu.edu.cn/bioinf/lncLocator/).	('THAP9-AS1', 'Gene', '100499177;79725;5729', (150, 159))	('THAPH-AS1', 'Var', (50, 59))	('facilitates', 'PosReg', (60, 71))	('ESCC', 'Disease', (72, 76))	('THAP9-AS1', 'Gene', (150, 159))
865598	33854048	There are two binding sites on THAP9-AS1 (500-507 and 6024-6031) for miR-133b (Fig.	('miR-133b', 'Gene', '442890', (69, 77))	('500-507', 'Var', (42, 49))	('miR-133b', 'Gene', (69, 77))	('THAP9-AS1', 'Gene', (31, 40))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (31, 40))	('6024-6031', 'Var', (54, 63))
865611	33854048	As for metastatic potential, the suppression of cell motility caused by THAP9-AS1 silencing was effectively eliminated due to the decrease of miR-133b expression (Fig.	('miR-133b', 'Gene', '442890', (142, 150))	('decrease', 'NegReg', (130, 138))	('miR-133b', 'Gene', (142, 150))	('cell motility', 'CPA', (48, 61))	('expression', 'MPA', (151, 161))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (72, 81))	('silencing', 'Var', (82, 91))	('THAP9-AS1', 'Gene', (72, 81))	('eliminated', 'NegReg', (108, 118))
865620	33854048	To confirm the binding between miR-133b and SOX4, luciferase reporter vectors possessing either wild type or mutant SOX4-3'UTR, in which there existed the binding sequences of miR-133b or corresponding mutant sequences, were constructed (Fig.	('miR-133b', 'Gene', '442890', (31, 39))	('miR-133b', 'Gene', (31, 39))	('miR-133b', 'Gene', '442890', (176, 184))	('SOX4', 'Gene', (44, 48))	('SOX4', 'Gene', '6659', (44, 48))	('SOX4', 'Gene', (116, 120))	('miR-133b', 'Gene', (176, 184))	('SOX4', 'Gene', '6659', (116, 120))	('mutant', 'Var', (109, 115))
865623	33854048	Moreover, western blot assays showed that miR-133b mimics resulted in a significant decrease of SOX4 protein level in both Eca-109 and KYSE-30 cells (Fig.	('decrease', 'NegReg', (84, 92))	('miR-133b', 'Gene', '442890', (42, 50))	('SOX4', 'Gene', '6659', (96, 100))	('miR-133b', 'Gene', (42, 50))	('mimics', 'Var', (51, 57))	('KYSE-30', 'CellLine', 'CVCL:1351', (135, 142))	('SOX4', 'Gene', (96, 100))
865625	33854048	And more notably, knockdown of THAP9-AS1 also repressed the protein expression of SOX4, while this effect was obviously countervailed by miR-133b inhibitor (Fig.	('miR-133b', 'Gene', (137, 145))	('knockdown', 'Var', (18, 27))	('repressed', 'PosReg', (46, 55))	('THAP9-AS1', 'Gene', (31, 40))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (31, 40))	('SOX4', 'Gene', (82, 86))	('SOX4', 'Gene', '6659', (82, 86))	('miR-133b', 'Gene', '442890', (137, 145))	('protein expression', 'MPA', (60, 78))
865631	33854048	Moreover, the lowered proliferation ability conferred by THAP9-AS1 knockdown was effectively restored by SOX4 overexpression (Fig.	('knockdown', 'Var', (67, 76))	('SOX4', 'Gene', (105, 109))	('SOX4', 'Gene', '6659', (105, 109))	('lowered', 'NegReg', (14, 21))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (57, 66))	('THAP9-AS1', 'Gene', (57, 66))	('proliferation ability', 'CPA', (22, 43))
865634	33854048	Similarly, the suppression of cell migration and invasion induced by THAP9-AS1 depletion was greatly disrupted due to the increase of SOX4 expression (Fig.	('SOX4', 'Gene', '6659', (134, 138))	('THAP9-AS1', 'Gene', (69, 78))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (69, 78))	('depletion', 'Var', (79, 88))	('SOX4', 'Gene', (134, 138))	('expression', 'MPA', (139, 149))	('suppression', 'NegReg', (15, 26))	('disrupted', 'NegReg', (101, 110))	('increase', 'PosReg', (122, 130))
865635	33854048	Taken together, THAPP9-AS1 facilitated ESCC progression in vitro via modulating SOX4 expression.	('expression', 'MPA', (85, 95))	('ESCC', 'Disease', (39, 43))	('SOX4', 'Gene', (80, 84))	('SOX4', 'Gene', '6659', (80, 84))	('THAPP9-AS1', 'Var', (16, 26))	('modulating', 'Reg', (69, 79))	('facilitated', 'PosReg', (27, 38))
865638	33854048	Moreover, THAP-AS1 expression was suppressed by SOX4 knockdown, while was enhanced due to SOX4 overexpression (Fig.	('expression', 'MPA', (19, 29))	('SOX4', 'Gene', (90, 94))	('SOX4', 'Gene', '6659', (90, 94))	('SOX4', 'Gene', '6659', (48, 52))	('THAP-AS1', 'Gene', (10, 18))	('suppressed', 'NegReg', (34, 44))	('knockdown', 'Var', (53, 62))	('enhanced', 'PosReg', (74, 82))	('SOX4', 'Gene', (48, 52))
865640	33854048	The results manifested the SOX4 occupancy at the P2 site (-769 ~ -760) rather than the P1 site (-835 ~ -826) on the THAP9-AS1 promoter (Fig.	('THAP9-AS1', 'Gene', '100499177;79725;5729', (116, 125))	('-769 ~ -760', 'Var', (58, 69))	('THAP9-AS1', 'Gene', (116, 125))	('SOX4', 'Gene', (27, 31))	('SOX4', 'Gene', '6659', (27, 31))
865644	33854048	The results revealed that knockdown of THAP9-AS1 significantly lowered tumor growth and tumor weight (Fig.	('THAP9-AS1', 'Gene', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('lowered', 'NegReg', (63, 70))	('knockdown', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (88, 93))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (39, 48))
865645	33854048	IHC analysis found a decrease of Ki-67 and PCNA expression in xenograft tumor tissues with THAP9-AS1 knockdown compared to the sh-NC group (Fig.	('THAP9-AS1', 'Gene', '100499177;79725;5729', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('THAP9-AS1', 'Gene', (91, 100))	('PCNA', 'Gene', (43, 47))	('tumor', 'Disease', (72, 77))	('decrease', 'NegReg', (21, 29))	('Ki-67', 'Protein', (33, 38))	('PCNA', 'Gene', '5111', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('knockdown', 'Var', (101, 110))
865650	33854048	A growing body of researches illuminates that aberrant expression of lncRNAs plays a crucial role in different physiological and pathological processes of human cancers.	('lncRNAs', 'Gene', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('human', 'Species', '9606', (155, 160))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('aberrant expression', 'Var', (46, 65))
865656	33854048	Moreover, high THAP9-AS1 expression was positively correlated to tumor size, TNM stage, lymph node metastasis, and poor prognosis of ESCC patients.	('patients', 'Species', '9606', (138, 146))	('tumor', 'Disease', (65, 70))	('TNM', 'Gene', (77, 80))	('lymph node metastasis', 'CPA', (88, 109))	('ESCC', 'Disease', (133, 137))	('expression', 'MPA', (25, 35))	('TNM', 'Gene', '10178', (77, 80))	('high', 'Var', (10, 14))	('THAP9-AS1', 'Gene', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('correlated', 'Reg', (51, 61))
865657	33854048	Functionally, silencing of THAP9-AS1 resulted in a suppression of cell proliferation, migration, and invasion, while induced apoptosis.	('silencing', 'Var', (14, 23))	('migration', 'CPA', (86, 95))	('suppression', 'NegReg', (51, 62))	('cell proliferation', 'CPA', (66, 84))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (27, 36))	('THAP9-AS1', 'Gene', (27, 36))	('induced', 'Reg', (117, 124))	('invasion', 'CPA', (101, 109))
865662	33854048	Moreover, knockdown of THAP9-AS1 decreased cell proliferation and colony-forming capacity in vitro and inhibited tumor growth in vivo.	('tumor', 'Disease', (113, 118))	('inhibited', 'NegReg', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cell proliferation', 'CPA', (43, 61))	('colony-forming capacity', 'CPA', (66, 89))	('decreased', 'NegReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('knockdown', 'Var', (10, 19))	('THAP9-AS1', 'Gene', (23, 32))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (23, 32))
865664	33854048	Our study, for the first time, demonstrated the dysregulation of THAP9-AS1 in ESCC and its stimulative effects on cell growth and metastasis.	('THAP9-AS1', 'Gene', (65, 74))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (65, 74))	('ESCC', 'Disease', (78, 82))	('dysregulation', 'Var', (48, 61))
865675	33854048	On this basis, we herein further explored whether miR-133b was responsible for the inhibition of THAP9-AS1 knockdown on ESCC cell malignant phenotypes by rescue experiments.	('knockdown', 'Var', (107, 116))	('ESCC', 'Disease', (120, 124))	('THAP9-AS1', 'Gene', (97, 106))	('miR-133b', 'Gene', '442890', (50, 58))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (97, 106))	('miR-133b', 'Gene', (50, 58))
865676	33854048	As a result, the suppressive effects of THAP9-AS1 silencing on cell proliferation, migration, and invasion were partly abolished by the miR-133b inhibitor.	('abolished', 'NegReg', (119, 128))	('THAP9-AS1', 'Gene', (40, 49))	('miR-133b', 'Gene', (136, 144))	('invasion', 'CPA', (98, 106))	('silencing', 'Var', (50, 59))	('cell proliferation', 'CPA', (63, 81))	('suppressive', 'NegReg', (17, 28))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (40, 49))	('migration', 'CPA', (83, 92))	('miR-133b', 'Gene', '442890', (136, 144))
865684	33854048	found that SOX4 was upregulated, and knockdown of SOX4 inhibited cell proliferation and enhanced doxorubicin-induced cell senescence.	('SOX4', 'Gene', (11, 15))	('SOX4', 'Gene', '6659', (11, 15))	('doxorubicin-induced cell senescence', 'MPA', (97, 132))	('SOX4', 'Gene', (50, 54))	('SOX4', 'Gene', '6659', (50, 54))	('knockdown', 'Var', (37, 46))	('upregulated', 'PosReg', (20, 31))	('cell proliferation', 'CPA', (65, 83))	('doxorubicin', 'Chemical', 'MESH:D004317', (97, 108))	('enhanced', 'PosReg', (88, 96))	('inhibited', 'NegReg', (55, 64))
865693	33854048	Functionally, depletion of THAP9-AS1 suppresses cell proliferation, migration, and invasion in vitro and lowers tumor growth in vivo.	('suppresses', 'NegReg', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('THAP9-AS1', 'Gene', '100499177;79725;5729', (27, 36))	('cell proliferation', 'CPA', (48, 66))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('depletion', 'Var', (14, 23))	('THAP9-AS1', 'Gene', (27, 36))	('invasion', 'CPA', (83, 91))	('tumor', 'Disease', (112, 117))	('lowers', 'NegReg', (105, 111))	('migration', 'CPA', (68, 77))
865788	31355925	Furthermore, F. nucleatum-positive patients had significantly shorter esophageal cancer survival, suggesting a potential role as a prognostic biomarker for esophageal cancer, which has also been seen for colorectal cancer.	('shorter', 'NegReg', (62, 69))	('esophageal cancer', 'Disease', (70, 87))	('colorectal cancer', 'Disease', 'MESH:D015179', (204, 221))	('F. nucleatum', 'Species', '851', (13, 25))	('F. nucleatum-positive', 'Var', (13, 34))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('esophageal cancer', 'Disease', (156, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('patients', 'Species', '9606', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('colorectal cancer', 'Disease', (204, 221))
865806	31355925	However, H. pylori seropositivity is associated with increased risks for GCA in China and Iran, but not in other countries, such as the US, Finland, Sweden and Norway, which suggests that H. pylori may have a distinct association with GCA in China and Iran, perhaps through interactions with other microbiota.	('pylori seropositivity', 'Phenotype', 'HP:0005202', (12, 33))	('GCA', 'Disease', (73, 76))	('H. pylori', 'Species', '210', (188, 197))	('GCA', 'Disease', (235, 238))	('H. pylori', 'Species', '210', (9, 18))	('seropositivity', 'Var', (19, 33))
865898	32280773	We believe that LIM inhibits body movements in a different manner from sedation in patients with poor sedation.	('patients', 'Species', '9606', (83, 91))	('LIM', 'Var', (16, 19))	('body movements', 'CPA', (29, 43))	('inhibits', 'NegReg', (20, 28))
865972	32111930	We found that the incidence of squamous esophageal cancer in males in Taiwan continuously increased with a CIR30-84 of 0.0146% (2008~2010) to 0.0165% (2013-2014) (Table 2).	('squamous esophageal cancer', 'Disease', 'MESH:D004938', (31, 57))	('squamous esophageal cancer', 'Disease', (31, 57))	('0.0165%', 'Var', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
866010	32111930	Esophageal cancer included ICD-10-CM codes: C153, C154, C155, C158, C159, and ICD-O-3 morphology code: 8050/03~8089/3(squamous cell carcinoma), 8140/3(adenocarcinoma), and others.	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('C153', 'Var', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('C154', 'Var', (50, 54))	('8140/3', 'Var', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('C158', 'Var', (62, 66))	('8050/03~8089/3', 'Var', (103, 117))	('squamous cell carcinoma', 'Disease', (118, 141))	('adenocarcinoma', 'Disease', (151, 165))	('C159', 'Var', (68, 72))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 141))	('Esophageal cancer', 'Disease', (0, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (151, 165))	('C155', 'Var', (56, 60))
866046	30563114	The metastization process of epithelial malignant neoplasia involves the acquisition of invasive potential by the primary tumor, through genetic and epigenetic alterations, followed by an expansive growth and invasion through the basement membrane.	('epigenetic alterations', 'Var', (149, 171))	('genetic', 'Var', (137, 144))	('epithelial malignant neoplasia', 'Phenotype', 'HP:0031492', (29, 59))	('metastization', 'CPA', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('invasion', 'CPA', (209, 217))	('neoplasia', 'Phenotype', 'HP:0002664', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('invasive potential', 'CPA', (88, 106))	('epithelial malignant neoplasia', 'Disease', 'MESH:D002277', (29, 59))	('epithelial malignant neoplasia', 'Disease', (29, 59))	('tumor', 'Disease', (122, 127))	('expansive growth', 'CPA', (188, 204))	('men', 'Species', '9606', (234, 237))
866055	30563114	Numerous miRNAs have been implicated in cancer initiation, progression and dissemination, either supporting or countering cancer development.	('miRNAs', 'Var', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer initiation', 'Disease', 'MESH:D009369', (40, 57))	('cancer', 'Disease', (40, 46))	('implicated', 'Reg', (26, 36))	('cancer initiation', 'Disease', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('men', 'Species', '9606', (136, 139))
866073	30563114	In agreement, HeLa cells transfected with miR-21 mimics showed increased phosphorylation of the Ras downstream targets protein kinase B (Akt) and extracellular signal-regulated kinases (Erk).	('protein kinase B', 'Pathway', (119, 135))	('increased', 'PosReg', (63, 72))	('miR-21', 'Gene', (42, 48))	('men', 'Species', '9606', (8, 11))	('Akt', 'Gene', '207', (137, 140))	('Erk', 'Gene', (186, 189))	('extracellular signal-regulated kinases', 'Gene', '5594', (146, 184))	('mimics', 'Var', (49, 55))	('extracellular signal-regulated kinases', 'Gene', (146, 184))	('miR-21', 'Gene', '406991', (42, 48))	('Akt', 'Gene', (137, 140))	('phosphorylation', 'MPA', (73, 88))	('Erk', 'Gene', '5594', (186, 189))	('HeLa', 'CellLine', 'CVCL:0030', (14, 18))
866090	30563114	Suppression of miR-375 increases the expression of specificity protein 1 (SP1) and consequently promotes cell proliferation, migration and invasion in vitro.	('invasion', 'CPA', (139, 147))	('migration', 'CPA', (125, 134))	('miR-375', 'Gene', '494324', (15, 22))	('specificity protein 1', 'Gene', '6667', (51, 72))	('Suppression', 'Var', (0, 11))	('promotes', 'PosReg', (96, 104))	('SP1', 'Gene', (74, 77))	('miR-375', 'Gene', (15, 22))	('specificity protein 1', 'Gene', (51, 72))	('expression', 'MPA', (37, 47))	('increases', 'PosReg', (23, 32))	('cell proliferation', 'CPA', (105, 123))
866093	30563114	MALAT1 is a long non-coding RNA (lncRNA) upregulated in cervical cancer whose knockdown significantly reduces cell growth rate and invasion and increased cell apoptosis and the expression of miR-124.	('reduces', 'NegReg', (102, 109))	('cell growth rate', 'CPA', (110, 126))	('invasion', 'CPA', (131, 139))	('MALAT1', 'Gene', '378938', (0, 6))	('knockdown', 'Var', (78, 87))	('MALAT1', 'Gene', (0, 6))	('cell apoptosis', 'CPA', (154, 168))	('upregulated', 'PosReg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cervical cancer', 'Disease', (56, 71))	('miR-124', 'Gene', (191, 198))	('expression', 'MPA', (177, 187))	('increased', 'PosReg', (144, 153))	('cervical cancer', 'Disease', 'MESH:D002583', (56, 71))
866094	30563114	Growth factor receptor bound protein 2 (GRB2) was identified as a target of miR-124 and its knockdown significantly reduced cell invasion and increased apoptosis.	('increased', 'PosReg', (142, 151))	('Growth factor receptor bound protein 2', 'Gene', (0, 38))	('GRB2', 'Gene', (40, 44))	('knockdown', 'Var', (92, 101))	('cell invasion', 'CPA', (124, 137))	('GRB2', 'Gene', '2885', (40, 44))	('Growth factor receptor bound protein 2', 'Gene', '2885', (0, 38))	('miR-124', 'Gene', (76, 83))	('reduced', 'NegReg', (116, 123))	('apoptosis', 'CPA', (152, 161))
866104	30563114	The knockdown of GALNT7 in cervical cancer cell lines inhibited cell proliferation, migration, and invasion.	('inhibited', 'NegReg', (54, 63))	('cell proliferation', 'CPA', (64, 82))	('GALNT7', 'Gene', (17, 23))	('migration', 'CPA', (84, 93))	('GALNT7', 'Gene', '51809', (17, 23))	('invasion', 'CPA', (99, 107))	('cervical cancer', 'Disease', (27, 42))	('cervical cancer', 'Disease', 'MESH:D002583', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('knockdown', 'Var', (4, 13))
866114	30563114	Increased expression of miR-20b is also promoted by HPV E6.	('miR-20b', 'Gene', (24, 31))	('promoted', 'PosReg', (40, 48))	('expression', 'MPA', (10, 20))	('HPV', 'Species', '10566', (52, 55))	('Increased', 'PosReg', (0, 9))	('miR-20b', 'Gene', '574032', (24, 31))	('HPV E6', 'Var', (52, 58))
866133	30563114	Among those miRNAs dysregulated in HPV-positive tumors, only miR-16 and miR-19b-1 have been previously associated with cell invasion in ovarian and cervical cancers but their role in HPV-related vulvar cancer remains to be clarified.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('miRNAs', 'Var', (12, 18))	('vulvar cancer', 'Disease', 'MESH:D014846', (195, 208))	('HPV-positive tumors', 'Disease', (35, 54))	('miR-16', 'Var', (61, 67))	('vulvar cancer', 'Phenotype', 'HP:0030416', (195, 208))	('HPV', 'Species', '10566', (35, 38))	('ovarian and cervical cancers', 'Disease', 'MESH:D010051', (136, 164))	('dysregulated', 'Var', (19, 31))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (35, 54))	('miR-19b-1', 'Var', (72, 81))	('HPV', 'Species', '10566', (183, 186))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('associated with', 'Reg', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cell invasion', 'CPA', (119, 132))	('vulvar cancer', 'Disease', (195, 208))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
866158	30563114	Specifically, a set of miRNAs, namely miR-151, miR-152, miR-324-5p, miR-361 and miR-492 is significantly associated with distant metastases in HPV-derived oropharyngeal carcinoma.	('HPV', 'Species', '10566', (143, 146))	('miR-324-5p', 'Var', (56, 66))	('oropharyngeal carcinoma', 'Disease', (155, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('miR-152', 'Var', (47, 54))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (155, 178))	('metastases', 'Disease', (129, 139))	('miR-492', 'Var', (80, 87))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (155, 178))	('miR-361', 'Var', (68, 75))	('metastases', 'Disease', 'MESH:D009362', (129, 139))	('miR-151', 'Var', (38, 45))	('associated with', 'Reg', (105, 120))
866160	30563114	Myosin 1B (MYO1B) is targeted by miR-363, and siRNA knockdown of MYO1B expression reduces migration in cell lines of HNC.	('HNC', 'Phenotype', 'HP:0012288', (117, 120))	('MYO1B', 'Gene', '4430', (11, 16))	('MYO1B', 'Gene', (11, 16))	('reduces', 'NegReg', (82, 89))	('miR-363', 'Gene', '574031', (33, 40))	('Myosin 1B', 'Gene', (0, 9))	('migration', 'CPA', (90, 99))	('miR-363', 'Gene', (33, 40))	('knockdown', 'Var', (52, 61))	('MYO1B', 'Gene', '4430', (65, 70))	('Myosin 1B', 'Gene', '4430', (0, 9))	('MYO1B', 'Gene', (65, 70))
866164	30563114	In this study, miR-34a expression inhibited tumor cell proliferation and colony formation by downregulating E2F transcription factor 3 (E2F3) and survivin.	('colony formation', 'CPA', (73, 89))	('E2F transcription factor 3', 'Gene', (108, 134))	('survivin', 'Protein', (146, 154))	('downregulating', 'NegReg', (93, 107))	('inhibited', 'NegReg', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('expression', 'Var', (23, 33))	('miR-34a', 'Gene', '407040', (15, 22))	('E2F transcription factor 3', 'Gene', '1871', (108, 134))	('miR-34a', 'Gene', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('E2F3', 'Gene', (136, 140))	('tumor', 'Disease', (44, 49))	('E2F3', 'Gene', '1871', (136, 140))
866165	30563114	Additionally, miR-34a transfection inhibited cell migration and tumor angiogenesis by downregulating VEGFA.	('miR-34a', 'Gene', '407040', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('miR-34a', 'Gene', (14, 21))	('tumor', 'Disease', (64, 69))	('downregulating', 'NegReg', (86, 100))	('transfection', 'Var', (22, 34))	('cell migration', 'CPA', (45, 59))	('VEGFA', 'Gene', (101, 106))	('inhibited', 'NegReg', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('VEGFA', 'Gene', '7422', (101, 106))
866166	30563114	The expression of miR-20a was also found to be significantly elevated in oral HNC, and the silencing of HPV16 E7 in Cal27 cells induced miR-20a downregulation.	('miR-20a', 'Gene', (136, 143))	('miR-20a', 'Gene', '406982', (136, 143))	('expression', 'MPA', (4, 14))	('elevated', 'PosReg', (61, 69))	('downregulation', 'NegReg', (144, 158))	('miR-20a', 'Gene', (18, 25))	('Cal27', 'CellLine', 'CVCL:1107', (116, 121))	('miR-20a', 'Gene', '406982', (18, 25))	('HNC', 'Phenotype', 'HP:0012288', (78, 81))	('silencing', 'Var', (91, 100))	('HPV16 E7', 'Gene', (104, 112))	('oral HNC', 'Disease', (73, 81))	('HPV16', 'Species', '333760', (104, 109))
866171	30563114	Overall, dysregulated expression of miRNAs is associated with tumor cell migration, invasion and metastization in HNC, but most studies do not report HPV status, thereby limiting the conclusions that may be drawn concerning the relationship between HPV and miRNAs in this setting.	('HNC', 'Phenotype', 'HP:0012288', (114, 117))	('invasion', 'CPA', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('miRNAs', 'Gene', (36, 42))	('HNC', 'Disease', (114, 117))	('tumor', 'Disease', (62, 67))	('dysregulated', 'Var', (9, 21))	('metastization', 'CPA', (97, 110))	('associated with', 'Reg', (46, 61))	('HPV', 'Species', '10566', (150, 153))	('HPV', 'Species', '10566', (249, 252))	('expression', 'MPA', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
866178	30563114	The authors also suggested that miR-203 hypermethylation could be a potential biomarker for HPV16-positive ESCC and that targeted delivery of this miRNA may serve as a preventive or therapeutic approach for ESSC.	('miR-203', 'Gene', (32, 39))	('HPV16', 'Species', '333760', (92, 97))	('miR-203', 'Gene', '406986', (32, 39))	('ESSC', 'Disease', (207, 211))	('hypermethylation', 'Var', (40, 56))	('HPV16-positive', 'Gene', (92, 106))	('ESCC', 'Disease', (107, 111))
866184	30563114	High expression of MTA-1 was also associated with a poor clinical outcome, tumor recurrence and a poor therapeutic response.	('associated', 'Reg', (34, 44))	('High', 'Var', (0, 4))	('MTA-1', 'Gene', '9112', (19, 24))	('therapeutic response', 'CPA', (103, 123))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('MTA-1', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
866253	25598323	We also performed additional analyses by grouping individuals into predefined well-established categories of BMI (18.5-<25 for normalweight, 25-<30 for overweight, and >=30kg/m2 for obese).	('overweight', 'Phenotype', 'HP:0025502', (152, 162))	('18.5-<25', 'Var', (114, 122))	('25-<30', 'Var', (141, 147))	('obese', 'Disease', 'MESH:D009765', (182, 187))	('obese', 'Disease', (182, 187))	('>=30kg/m2', 'Var', (168, 177))
866323	30317074	For example, EAC shows a molecular profile similar to the so-called chromosomal instable subtype of gastric cancer (characterized by a TP53 mutation and in up to 20% by an ERBB2 amplification), but the absence of Epstein-Barr virus-related tumors and the rarity of microsatellite instability were highlighted, two important subtypes described earlier in gastric carcinoma.	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('mutation', 'Var', (140, 148))	('tumors', 'Disease', (240, 246))	('Epstein-Barr virus', 'Species', '10376', (213, 231))	('gastric carcinoma', 'Disease', 'MESH:D013274', (354, 371))	('TP53', 'Gene', '7157', (135, 139))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('gastric carcinoma', 'Disease', (354, 371))	('gastric cancer', 'Disease', (100, 114))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (354, 371))	('EAC', 'Gene', '1540', (13, 16))	('EAC', 'Gene', (13, 16))	('ERBB2', 'Gene', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (362, 371))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ERBB2', 'Gene', '2064', (172, 177))	('TP53', 'Gene', (135, 139))
866324	30317074	Furthermore, EACs characteristically show a high content of copy number variations (CNVs) leading to chromosomal instability (the so-called genomic catastrophe in EAC) and squamous cell carcinomas showing molecular similarities to non-HPV-related head-neck carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (257, 267))	('leading to', 'Reg', (90, 100))	('EAC', 'Gene', '1540', (163, 166))	('head-neck carcinomas', 'Disease', (247, 267))	('EAC', 'Gene', (163, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (172, 196))	('head-neck carcinomas', 'Disease', 'MESH:D006258', (247, 267))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('EAC', 'Gene', '1540', (13, 16))	('copy number variations', 'Var', (60, 82))	('squamous cell carcinomas', 'Disease', (172, 196))	('EAC', 'Gene', (13, 16))	('chromosomal instability', 'Phenotype', 'HP:0040012', (101, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('chromosomal', 'MPA', (101, 112))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (172, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
866325	30317074	On the other hand, according to the patient cohort analyzed by the The Cancer Genome Atlas (TCGA), about 17% of esophageal carcinomas have a biallelic intact TP53 gene [9 out of 96 analyzed squamous cell carcinomas (9.3%) and 23 out of 89 analyzed adenocarcinomas (25.8%)].	('TP53', 'Gene', (158, 162))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (190, 214))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (71, 90))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (190, 214))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('Cancer Genome Atlas', 'Disease', (71, 90))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (112, 133))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (112, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('squamous cell carcinomas', 'Disease', (190, 214))	('esophageal carcinomas', 'Disease', (112, 133))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TP53', 'Gene', '7157', (158, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('adenocarcinomas', 'Disease', 'MESH:D000230', (248, 263))	('adenocarcinomas', 'Disease', (248, 263))	('carcinomas', 'Phenotype', 'HP:0030731', (253, 263))	('patient', 'Species', '9606', (36, 43))	('biallelic intact', 'Var', (141, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))
866327	30317074	Likely, a functional loss of TP53 exists in all of the TP53 nonmutated tumors mediated by pathway alterations located up- or downstream of TP53.	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (139, 143))	('tumors', 'Disease', (71, 77))	('TP53', 'Gene', (139, 143))	('TP53', 'Gene', (29, 33))	('TP53', 'Gene', '7157', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('up-', 'PosReg', (118, 121))	('nonmutated', 'Var', (60, 70))	('pathway', 'Pathway', (90, 97))	('alterations', 'Var', (98, 109))	('loss', 'NegReg', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
866331	30317074	Survival analysis of TP53-wild-type and mutant patients as well as comparative analysis of somatic copy number alterations was performed through analysis workflows on the Cancer Systems Biology Database.	('TP53', 'Gene', (21, 25))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('patients', 'Species', '9606', (47, 55))	('mutant', 'Var', (40, 46))	('TP53', 'Gene', '7157', (21, 25))
866341	30317074	Score 0 was interpreted as a mutation of TP53 hindering the formation of TP53 protein.	('TP53', 'Gene', '7157', (41, 45))	('mutation', 'Var', (29, 37))	('TP53', 'Gene', (41, 45))	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('formation of', 'MPA', (60, 72))	('hindering', 'NegReg', (46, 55))
866344	30317074	Score 2 was strong staining of >=30% of tumor cells or moderate staining of >=70% and was interpreted as a TP53 mutation hinders a functionally active TP53 protein.	('hinders', 'NegReg', (121, 128))	('TP53', 'Gene', (151, 155))	('mutation', 'Var', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('functionally active', 'MPA', (131, 150))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('TP53', 'Gene', '7157', (151, 155))
866347	30317074	Cases were only further evaluated if control tissue nuclei displayed one or two clearly distinct signals of each color (MDM2 green, centromere chromosome 12 orange).	('MDM2', 'Gene', '4193', (120, 124))	('MDM2', 'Gene', (120, 124))	('centromere', 'Var', (132, 142))
866356	30317074	Thirty-two of these have a biallelic intact TP53 gene [9 out of 96 analyzed squamous cell carcinomas (9.3%) and 23 out of 89 analyzed adenocarcinomas (25.8%)].	('adenocarcinomas', 'Disease', (134, 149))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (76, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (76, 100))	('TP53', 'Gene', '7157', (44, 48))	('squamous cell carcinomas', 'Disease', (76, 100))	('TP53', 'Gene', (44, 48))	('adenocarcinomas', 'Disease', 'MESH:D000230', (134, 149))	('biallelic', 'Var', (27, 36))
866357	30317074	In order to judge the effect of TP53 on the number and size of genomic CNVs, we summed up the overall size of all CNVs in base pairs for amplifications with CN > =3 and deletions with CN < =1 in each tumor.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('CN > =3', 'Var', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('TP53', 'Gene', '7157', (32, 36))	('tumor', 'Disease', (200, 205))	('TP53', 'Gene', (32, 36))	('deletions', 'Var', (169, 178))
866360	30317074	When CNVs are compared in more detail, TP53-wild-type tumors mainly show amplifications in the regions of chromosomes 12p13.3, 12q15, and 17q21.1 and deletions in 5q12.1, 7q36.6, and 9p21.3 as well as single-gene deletions in the loci of 4q22.1, 16q23.1, 20p12.1, and 21q22.12 (Figure 1; Supplementary Table 1, online).	('deletions', 'Var', (150, 159))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('amplifications', 'Var', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TP53', 'Gene', '7157', (39, 43))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('5q12.1', 'Gene', (163, 169))	('TP53', 'Gene', (39, 43))
866361	30317074	A comparative analysis of gene expression using RNA-Seq data revealed that 2272 genes were differentially expressed between the TP53-wild-type and the mutant patients at a cutoff of 1.5 for absolute linear fold enrichment and .01 for significance level.	('differentially', 'Reg', (91, 105))	('mutant', 'Var', (151, 157))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('patients', 'Species', '9606', (158, 166))
866367	30317074	There are only 5 TP53-wild-type patients which carried somatic mutations and copy number aberrations, and none of the patients carried more than one somatic mutation and more than one somatic copy number alteration in the TP53 pathway.	('patients', 'Species', '9606', (32, 40))	('copy number aberrations', 'Var', (77, 100))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (222, 226))	('TP53', 'Gene', '7157', (222, 226))	('patients', 'Species', '9606', (118, 126))	('TP53', 'Gene', (17, 21))
866376	30317074	There was no survival difference between patients with TP53-wild-type tumors and those with TP53 mutations.	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('tumors', 'Disease', (70, 76))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))
866379	30317074	There were 20 cases with high-level amplification of MDM2 according to the evaluation criteria (5.6%) and 237 tumors without elevated MDM2 signals (94.4%).	('MDM2', 'Gene', '4193', (53, 57))	('MDM2', 'Gene', (53, 57))	('MDM2', 'Gene', '4193', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('MDM2', 'Gene', (134, 138))	('amplification', 'Var', (36, 49))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))
866385	30317074	Twenty-one of these TP53-wild-type tumors did not bear any further mutations; 6 tumors showed mutations in PTEN (2x), KRAS, KEAP1 (2x), and PIK3CA (compare Table 3).	('PIK3CA', 'Gene', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('KRAS', 'Gene', (118, 122))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Disease', (80, 86))	('PTEN', 'Gene', (107, 111))	('TP53', 'Gene', (20, 24))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('PTEN', 'Gene', '5728', (107, 111))	('mutations', 'Var', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('PIK3CA', 'Gene', '5290', (140, 146))	('TP53', 'Gene', '7157', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('KEAP1', 'Gene', '9817', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (35, 41))	('KRAS', 'Gene', '3845', (118, 122))	('KEAP1', 'Gene', (124, 129))
866386	30317074	Twelve tumors showed a TP53 mutation of which 10 (83.3%) resulted in a truncated protein and 2 (16.7%) in a nonfunctional protein.	('resulted in', 'Reg', (57, 68))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('mutation', 'Var', (28, 36))	('truncated protein', 'MPA', (71, 88))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('nonfunctional protein', 'MPA', (108, 129))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
866387	30317074	Ten out of 12 TP53 mutated cases did not show any further mutations (considering our 12-gene panel), one case demonstrated additional activating BRAF (exon 15; V600E) as well as KEAP1 gene mutation, and one case showed an additional activating KRAS mutation (compare Table 3).	('KEAP1', 'Gene', '9817', (178, 183))	('KRAS', 'Gene', '3845', (244, 248))	('TP53', 'Gene', (14, 18))	('BRAF', 'Gene', (145, 149))	('TP53', 'Gene', '7157', (14, 18))	('V600E', 'Mutation', 'rs113488022', (160, 165))	('KEAP1', 'Gene', (178, 183))	('V600E', 'Var', (160, 165))	('BRAF', 'Gene', '673', (145, 149))	('activating', 'PosReg', (134, 144))	('KRAS', 'Gene', (244, 248))
866390	30317074	The number and size of somatic CNVs (amplifications and deletions) in cancer can serve as an indicator for its genetic integrity.	('deletions', 'Var', (56, 65))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))
866393	30317074	TP53-wild-type tumors mainly show amplifications in the regions of chromosomes 12p13.3, 12q15, and 17q21.1 and deletions in 5q12.1, 7q36.6, and 9p21.3 as well as single-gene deletions in the loci of 4q22.1, 16q23.1, 20p12.1, and 21q22.12.	('tumors', 'Disease', (15, 21))	('TP53', 'Gene', '7157', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('deletions', 'Var', (111, 120))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
866401	30317074	PTPRR encodes for a receptor-type tyrosine phosphatase and inhibits the MAP kinase pathway via epigenetic silencing.	('PTPRR', 'Gene', '5801', (0, 5))	('inhibits', 'NegReg', (59, 67))	('MAP kinase pathway', 'Pathway', (72, 90))	('epigenetic silencing', 'Var', (95, 115))	('PTPRR', 'Gene', (0, 5))
866404	30317074	Co-deletions of the 9p21 loci are well-known genomic alterations mainly due to the loss of the important tumor suppressor gene CDK2NA and deletions of genes for different interferons, which can be linked to reduced survival and inflammatory reaction in melanoma.	('CDK2', 'Gene', (127, 131))	('CDK2', 'Gene', '1017', (127, 131))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('Co-deletions', 'Var', (0, 12))	('melanoma', 'Disease', (253, 261))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('melanoma', 'Disease', 'MESH:D008545', (253, 261))	('reduced', 'NegReg', (207, 214))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('deletions', 'Var', (138, 147))	('tumor', 'Disease', (105, 110))	('loss', 'NegReg', (83, 87))
866411	30317074	Mutations in the TSC2 gene cause diseases like tuberous sclerosis or lymphangioleiomyomatosis.	('lymphangioleiomyomatosis', 'Disease', 'MESH:D018192', (69, 93))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (47, 65))	('tuberous sclerosis', 'Disease', (47, 65))	('lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (69, 93))	('cause', 'Reg', (27, 32))	('Mutations', 'Var', (0, 9))	('TSC2', 'Gene', '7249', (17, 21))	('lymphangioleiomyomatosis', 'Disease', (69, 93))	('TSC2', 'Gene', (17, 21))
866412	30317074	Mutated TSC2 can cause a dysregulation of signaling including an activation of RHEB.	('dysregulation of signaling', 'MPA', (25, 51))	('RHEB', 'Gene', (79, 83))	('cause', 'Reg', (17, 22))	('RHEB', 'Gene', '6009', (79, 83))	('TSC2', 'Gene', '7249', (8, 12))	('TSC2', 'Gene', (8, 12))	('Mutated', 'Var', (0, 7))	('activation', 'PosReg', (65, 75))
866423	30317074	Copy number elevation is one important reason for an increase of MDM2 expression.	('Copy number elevation', 'Var', (0, 21))	('increase', 'PosReg', (53, 61))	('expression', 'MPA', (70, 80))	('MDM2', 'Gene', '4193', (65, 69))	('MDM2', 'Gene', (65, 69))
866426	30317074	Using parallel sequencing, in our patient cohort, we found gene alterations in PIK3CA, KEAP1, KRAS, and PTEN in the group of TP53-nonmutated tumors, indicating that the AKT-mTOR pathway via activating PIK3CA mutations or inactivating PTEN mutations is important for these tumors.	('PIK3CA', 'Gene', '5290', (201, 207))	('KRAS', 'Gene', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (208, 217))	('mutations', 'Var', (239, 248))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('TP53', 'Gene', (125, 129))	('mTOR', 'Gene', '2475', (173, 177))	('activating', 'PosReg', (190, 200))	('patient', 'Species', '9606', (34, 41))	('PTEN', 'Gene', (234, 238))	('inactivating', 'NegReg', (221, 233))	('KEAP1', 'Gene', '9817', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('KEAP1', 'Gene', (87, 92))	('PIK3CA', 'Gene', (201, 207))	('PTEN', 'Gene', (104, 108))	('PIK3CA', 'Gene', '5290', (79, 85))	('PTEN', 'Gene', '5728', (234, 238))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('TP53', 'Gene', '7157', (125, 129))	('AKT', 'Gene', (169, 172))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('PTEN', 'Gene', '5728', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', (272, 278))	('PIK3CA', 'Gene', (79, 85))	('mTOR', 'Gene', (173, 177))	('KRAS', 'Gene', '3845', (94, 98))	('alterations', 'Reg', (64, 75))	('AKT', 'Gene', '207', (169, 172))
866427	30317074	We found an activation of the RAS-RAF-ERK pathway (including simultaneously activating mutations in BRAF and KRAS) in the TP53-mutated group (compare Table 3).	('TP53', 'Gene', (122, 126))	('activation', 'PosReg', (12, 22))	('activating', 'PosReg', (76, 86))	('mutations', 'Var', (87, 96))	('KRAS', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (100, 104))	('KRAS', 'Gene', '3845', (109, 113))	('BRAF', 'Gene', (100, 104))	('TP53', 'Gene', '7157', (122, 126))	('ERK', 'Gene', (38, 41))	('ERK', 'Gene', '5595;5594;5595', (38, 41))
866428	30317074	Interestingly, the TP53 mutation status in esophageal carcinoma did not correlate with survival in our cohort as well as in the TCGA patient cohort (See Fig.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (43, 63))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (43, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('patient', 'Species', '9606', (133, 140))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('mutation', 'Var', (24, 32))	('esophageal carcinoma', 'Disease', (43, 63))
866448	30317074	The most relevant downregulated miRNAs in comparison to the TP53-mutated tumors are the miRNA-488 and miRNA-4423.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('miRNA-4423', 'Var', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('downregulated', 'NegReg', (18, 31))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('miRNA-488', 'Var', (88, 97))	('TP53', 'Gene', '7157', (60, 64))	('tumors', 'Disease', (73, 79))	('TP53', 'Gene', (60, 64))	('miRNA-488', 'Chemical', '-', (88, 97))
866449	30317074	miRNA-488 is known to suppress cell migration and cell proliferation which was most recently described for non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('non-small cell lung cancer', 'Disease', (107, 133))	('miRNA-488', 'Chemical', '-', (0, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('cell migration', 'CPA', (31, 45))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (107, 133))	('suppress', 'NegReg', (22, 30))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (107, 133))	('miRNA-488', 'Var', (0, 9))	('cell proliferation', 'CPA', (50, 68))
866450	30317074	In addition, miRNA-488 has been shown to be a tumor suppressor that acts via targeting eIF3a.	('miRNA-488', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('eIF3a', 'Gene', '8669', (87, 92))	('miRNA-488', 'Chemical', '-', (13, 22))	('tumor', 'Disease', (46, 51))	('eIF3a', 'Gene', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
866452	30317074	miRNA-4423 was found to be important in the airway epithelial cell differentiation and is likely to be important in lung carcinogenesis.	('lung carcinogenesis', 'Disease', 'MESH:D063646', (116, 135))	('important', 'Reg', (103, 112))	('important', 'Reg', (27, 36))	('miRNA-4423', 'Var', (0, 10))	('lung carcinogenesis', 'Disease', (116, 135))	('airway epithelial cell differentiation', 'CPA', (44, 82))
866466	29416759	It's found that deregulated expression of ncRNAs have an important roles in the process of tumorigenesis.	('ncRNAs', 'Gene', (42, 48))	('deregulated', 'Var', (16, 27))	('expression', 'MPA', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
866469	29416759	Moreover, it's reported that SNHG1 may contribute to the aggravation of hepatocellular carcinoma through the inhibition of miR-195.	('miR-195', 'Gene', '406971', (123, 130))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('SNHG1', 'Var', (29, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('hepatocellular carcinoma', 'Disease', (72, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('inhibition', 'NegReg', (109, 119))	('miR-195', 'Gene', (123, 130))
866498	29416759	We then constructed luciferase reporter vectors containing the SNHG1 wild type (WT) or mutations at the putative miR-145 binding sites (MUT) (Figure 3A).	('miR-145', 'Gene', '406937', (113, 120))	('SNHG1', 'Gene', (63, 68))	('mutations', 'Var', (87, 96))	('miR-145', 'Gene', (113, 120))
866499	29416759	LOVO cells were transfected with miR-145 in combination with either SNHG1 wild type (SNHG1-WT Luc) or SNHG1 mutated (SNHG1-MUT Luc) luciferase reporter vectors.	('miR-145', 'Gene', (33, 40))	('mutated', 'Var', (108, 115))	('miR-145', 'Gene', '406937', (33, 40))	('SNHG1', 'Gene', (102, 107))
866507	29416759	Previous studies showed that p70S6k and E2F3 were two main targets of miR-145.	('miR-145', 'Gene', (70, 77))	('p70S6k', 'Var', (29, 35))	('miR-145', 'Gene', '406937', (70, 77))	('E2F3', 'Var', (40, 44))
866512	29416759	As shown in Figure 4C, miR-145 suppressed the expression of p70S6k and E2F3; however, this suppression effect was compromised by overexpression of SNHG1 in LOVO cells.	('p70S6k', 'Var', (60, 66))	('miR-145', 'Gene', (23, 30))	('miR-145', 'Gene', '406937', (23, 30))	('E2F3', 'Gene', (71, 75))	('suppressed', 'NegReg', (31, 41))	('expression', 'MPA', (46, 56))
866513	29416759	Similarly, the luciferase assay also indicated that the suppression effect of miR-145 on p70S6k and E2F3 were rescued by SNHG1 (*, p<0.05, Figure 4D).	('miR-145', 'Gene', (78, 85))	('miR-145', 'Gene', '406937', (78, 85))	('p70S6k', 'Var', (89, 95))	('E2F3', 'Var', (100, 104))
866514	29416759	Moreover, co-expression of SNHG1 with either p70S6k or E2F3 was analyzed through querying open database ChIPBase v2.0 in TCGA colorectal cancer datasets.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('SNHG1', 'Gene', (27, 32))	('colorectal cancer', 'Disease', (126, 143))	('p70S6k', 'Var', (45, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('E2F3', 'Var', (55, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
866515	29416759	The results showed that SNHG1 was positively correlated with target genes of miR-145 in colorectal cancers (SNHG1 and p70S6k: r: 0.353, p= 3.57E -11; E2F3: r: 0.582, p= 1.86E -31; Figure 4E).	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('miR-145', 'Gene', (77, 84))	('miR-145', 'Gene', '406937', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('p70S6k', 'Var', (118, 124))	('colorectal cancers', 'Disease', 'MESH:D015179', (88, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancers', 'Disease', (88, 106))
866518	29416759	As shown in Supplementary Figure 1, in comparison with vector control, SNHG1 enhanced the cell proliferation in HCT116 parental cells (*, p<0.05; Supplementary Figure 1A).	('SNHG1', 'Var', (71, 76))	('HCT116', 'CellLine', 'CVCL:0291', (112, 118))	('enhanced', 'PosReg', (77, 85))	('cell proliferation in HCT116 parental cells', 'CPA', (90, 133))
866519	29416759	However, the effect of SNHG1 on cell proliferation was attenuated in HCT116 Dicer-/- cells (Supplementary Figure 1B).	('HCT116', 'Var', (69, 75))	('attenuated', 'NegReg', (55, 65))	('HCT116', 'CellLine', 'CVCL:0291', (69, 75))	('SNHG1', 'Gene', (23, 28))	('cell proliferation', 'CPA', (32, 50))
866520	29416759	Similarly, as compared with vector control, the average change in p70S6K or E2F3 expression was less significant in HCT116 Dicer-/- cells.	('HCT116', 'CellLine', 'CVCL:0291', (116, 122))	('E2F3', 'Gene', (76, 80))	('HCT116', 'Var', (116, 122))	('p70S6K', 'Gene', (66, 72))	('p70S6K', 'Gene', '6198', (66, 72))
866522	29416759	These results supported the notion that the SNHG1 requires mature miRNAs for its function towards p70S6K or E2F3.	('p70S6K', 'Gene', (98, 104))	('miR', 'Gene', (66, 69))	('p70S6K', 'Gene', '6198', (98, 104))	('miR', 'Gene', '220972', (66, 69))	('E2F3', 'Var', (108, 112))
866527	29416759	After knockdown of SNHG1, cell growth were inhibited; however, this cell growth suppression effect conferred by loss of SNHG1 could be rescued by inhibition of endogenous miR-145 in colorectal cancer cells (*, p<0.05, Figure 5C).	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('inhibition', 'NegReg', (146, 156))	('colorectal cancer', 'Disease', (182, 199))	('miR-145', 'Gene', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cell growth suppression', 'CPA', (68, 91))	('loss', 'Var', (112, 116))	('miR-145', 'Gene', '406937', (171, 178))	('SNHG1', 'Gene', (120, 125))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))
866535	29416759	It's also found that SNHG1 could promote cancer progression via inhibition of miR-101-3p and activation of Wnt/beta-catenin signaling pathway in lung cancer.	('activation', 'PosReg', (93, 103))	('promote', 'PosReg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('beta-catenin', 'Gene', (111, 123))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('3p', 'Chemical', '-', (86, 88))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('inhibition', 'NegReg', (64, 74))	('cancer', 'Disease', (150, 156))	('lung cancer', 'Disease', (145, 156))	('beta-catenin', 'Gene', '1499', (111, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('SNHG1', 'Var', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
866542	29416759	For example, epigenetically regulated miR-145 suppresses colon cancer invasion and metastasis by targeting LASP1.	('suppresses', 'NegReg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('LASP1', 'Gene', '3927', (107, 112))	('epigenetically regulated', 'Var', (13, 37))	('colon cancer', 'Disease', (57, 69))	('targeting', 'Reg', (97, 106))	('LASP1', 'Gene', (107, 112))	('miR-145', 'Gene', (38, 45))	('miR-145', 'Gene', '406937', (38, 45))
866563	29416759	Briefly, lentiviral plasmids expressing SNHG1 or SNHG1-shRNAs were co-transfected with pHelper plasmids in 293T cells.	('SNHG1-shRNAs', 'Var', (49, 61))	('293T', 'CellLine', 'CVCL:0063', (107, 111))	('SNHG1', 'Var', (40, 45))
866566	29416759	Cells were co-transfected with synthetic miR-145, the wild-type or mutant SNHG1 luciferase reporter vector (SNHG1-WT Luc or SNHG1-MUT Luc) and pRL vector coding for the Renilla luciferase (Promega, Madison, WI, USA), and Cells were then cultured for 24 hours.	('Renilla luciferase', 'Disease', (169, 187))	('SNHG1', 'Gene', (74, 79))	('Renilla luciferase', 'Disease', 'None', (169, 187))	('miR-145', 'Gene', (41, 48))	('mutant', 'Var', (67, 73))	('miR-145', 'Gene', '406937', (41, 48))
866573	29416759	The co-expression analysis of SNHG1 and miR-145 (p70S6K or E2F3) were performed using ChIPBase v2.0 databse.	('miR-145', 'Gene', (40, 47))	('miR-145', 'Gene', '406937', (40, 47))	('p70S6K', 'Gene', (49, 55))	('E2F3', 'Var', (59, 63))	('SNHG1', 'Gene', (30, 35))	('p70S6K', 'Gene', '6198', (49, 55))
866593	28881819	Small molecule inhibitors of Aurora A cause defects in centrosome separation with the formation of multiple centrosomes.	('defects', 'NegReg', (44, 51))	('Aurora A', 'Gene', '6790', (29, 37))	('centrosome separation', 'CPA', (55, 76))	('inhibitors', 'Var', (15, 25))	('Aurora A', 'Gene', (29, 37))
866602	28881819	Currently, several Aurora kinase inhibitors have entered into clinical trials and include AZD1152, MLN8237, VX-680.	('MLN8237', 'Chemical', 'MESH:C550258', (99, 106))	('MLN8237', 'Var', (99, 106))	('VX-680', 'Var', (108, 114))	('AZD1152', 'Var', (90, 97))	('AZD1152', 'Chemical', 'MESH:C520647', (90, 97))	('VX-680', 'Chemical', 'MESH:C484810', (108, 114))
866607	28881819	Results showed that esophageal cancer cell growth was inhibited after knocking down Aurora A or B expression.	('inhibited', 'NegReg', (54, 63))	('esophageal cancer', 'Disease', (20, 37))	('Aurora A', 'Gene', (84, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('knocking down', 'Var', (70, 83))	('Aurora A', 'Gene', '6790', (84, 92))
866612	28881819	The scientific literature indicates that high levels of Aurora A kinase are associated with advanced clinical stage and poor prognosis in several cancers.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('high levels', 'Var', (41, 52))	('Aurora A', 'Gene', '6790', (56, 64))	('associated', 'Reg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Aurora A', 'Gene', (56, 64))
866617	28881819	Next, the KYSE450, KYSE510 and KYSE30 esophageal cancer cell lines and normal Het-1A esophageal cells were treated with different concentrations of APIO-EE-9 and colony formation was assessed.	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('KYSE30', 'Var', (31, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('APIO-EE-9', 'Chemical', '-', (148, 157))	('KYSE510', 'Var', (19, 26))
866618	28881819	Results demonstrated that APIO-EE-9 dramatically inhibited colony formation (Figure 1C) and decreased viability (Figure 1D) in a dose-dependent manner, but it had little effect on the proliferation of normal cells (Supplementary Figure 1B).	('viability', 'CPA', (102, 111))	('APIO-EE-9', 'Chemical', '-', (26, 35))	('decreased', 'NegReg', (92, 101))	('APIO-EE-9', 'Var', (26, 35))	('colony formation', 'CPA', (59, 75))	('inhibited', 'NegReg', (49, 58))
866621	28881819	Furthermore, KYSE450, KYSE510, and KYSE30 esophageal cancer cells treated with the compound exhibited substantial up-regulation of apoptosis-associated proteins, including cleaved-PARP, cleaved caspase 3 and pro-apoptotic Bax whereas anti-apoptotic Bcl-2 expression was decreased (Figure 2B).	('KYSE510', 'Var', (22, 29))	('esophageal cancer', 'Disease', (42, 59))	('apoptosis-associated proteins', 'Protein', (131, 160))	('cleaved', 'MPA', (186, 193))	('up-regulation', 'PosReg', (114, 127))	('Bax', 'Gene', (222, 225))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('pro-apoptotic', 'CPA', (208, 221))	('Bcl-2', 'Gene', (249, 254))	('PARP', 'Gene', '1302', (180, 184))	('Bcl-2', 'Gene', '596', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PARP', 'Gene', (180, 184))	('Bax', 'Gene', '581', (222, 225))
866633	28881819	Immunofluorescence results revealed that APIO-EE-9 does indeed induce multi-nucleation and multi-centrosome formation in KYSE450 cells (Figure 3D, Supplementary Figure 1C).	('APIO-EE-9', 'Var', (41, 50))	('induce', 'Reg', (63, 69))	('multi-nucleation', 'CPA', (70, 86))	('multi-centrosome formation', 'CPA', (91, 117))	('APIO-EE-9', 'Chemical', '-', (41, 50))
866643	28881819	We confirmed that active Aurora A or B kinase binds with APIO-EE-9-Sepharose 4B beads, but not with Sepharose 4B beads alone (Figure 4E, 4F).	('Sepharose 4B', 'Chemical', 'MESH:D012685', (100, 112))	('B kinase', 'Enzyme', (37, 45))	('binds', 'Interaction', (46, 51))	('Aurora A', 'Gene', (25, 33))	('APIO-EE-9-Sepharose', 'Var', (57, 76))	('Sepharose 4B', 'Chemical', 'MESH:D012685', (67, 79))	('Aurora A', 'Gene', '6790', (25, 33))
866647	28881819	Because Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that knocking down Aurora A or B expression would produce an antitumor effect against esophageal cancer cells.	('esophageal cancer', 'Disease', (220, 237))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Aurora A', 'Gene', '6790', (8, 16))	('Aurora A and B', 'Gene', '6790;9212', (8, 22))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('Aurora A', 'Gene', '6790', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('Aurora A', 'Gene', (8, 16))	('Aurora A', 'Gene', (153, 161))	('esophageal cancer', 'Disease', 'MESH:D004938', (220, 237))	('knocking down', 'Var', (139, 152))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cell division', 'CPA', (45, 58))
866648	28881819	First, the efficiency of short hairpin RNA (shRNA) knockdown in KYSE450 and KYSE510 esophageal cancer cells was examined and results showed that the expression of Aurora A or B was obviously decreased after shRNA transfection (Figures 5A, 6A).	('transfection', 'Var', (213, 225))	('Aurora A', 'Gene', '6790', (163, 171))	('expression', 'MPA', (149, 159))	('esophageal cancer', 'Disease', (84, 101))	('decreased', 'NegReg', (191, 200))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Aurora A', 'Gene', (163, 171))
866649	28881819	Moreover, colony formation (Figures 5B, 6B, Supplementary Figure 1D) and cell growth (Figures 5C, 6C) were dramatically inhibited in the shRNA-Aurora A- (Figure 5B, 5C) or shRNA-Aurora B- (Figure 6B, 6C) transfected groups compared with the negative control (mock-transfected groups).	('Aurora A', 'Gene', '6790', (143, 151))	('cell growth', 'CPA', (73, 84))	('Aurora B', 'Gene', '9212', (178, 186))	('Supplementary Figure 1D', 'Disease', (44, 67))	('Aurora B', 'Gene', (178, 186))	('Aurora A', 'Gene', (143, 151))	('inhibited', 'NegReg', (120, 129))	('transfected', 'Var', (204, 215))	('Supplementary Figure 1D', 'Disease', 'MESH:D017034', (44, 67))	('colony formation', 'CPA', (10, 26))
866651	28881819	Apoptosis was increased in KYSE450 and KYSE510 esophageal cancer cells after Aurora A (Figure 5D) or B (Figure 6D) protein expression was attenuated by shRNA transfection.	('KYSE510', 'Var', (39, 46))	('increased', 'PosReg', (14, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Aurora A', 'Gene', (77, 85))	('KYSE450', 'Var', (27, 34))	('protein', 'Protein', (115, 122))	('Apoptosis', 'CPA', (0, 9))	('esophageal cancer', 'Disease', (47, 64))	('Aurora A', 'Gene', '6790', (77, 85))
866653	28881819	In addition, knocking down Aurora A or B also inhibited phosphorylation of histone H3 (Ser10) in esophageal cancer cells (Figures 5F, 6F).	('knocking down', 'Var', (13, 26))	('Aurora A', 'Gene', '6790', (27, 35))	('histone H3', 'Protein', (75, 85))	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Aurora A', 'Gene', (27, 35))	('H3', 'Chemical', 'MESH:C012616', (83, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('phosphorylation', 'MPA', (56, 71))	('inhibited', 'NegReg', (46, 55))	('Ser10', 'Chemical', '-', (87, 92))
866654	28881819	Overall, these data showed that Aurora A and B play a critical role in KYSE450 and KYSE510 esophageal cancer cell growth.	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('esophageal cancer', 'Disease', (91, 108))	('Aurora A and B', 'Gene', '6790;9212', (32, 46))	('KYSE510', 'Var', (83, 90))	('KYSE450', 'Var', (71, 78))
866656	28881819	Athymic nude mice were injected with KYSE450 cells expressing knock down Aurora A or B.	('nude mice', 'Species', '10090', (8, 17))	('knock down', 'Var', (62, 72))	('Aurora A', 'Gene', '6790', (73, 81))	('Aurora A', 'Gene', (73, 81))
866657	28881819	Results showed that knocking down Aurora A or Aurora B expression suppressed KYSE450-xenograft tumor growth (Figure 7A).	('Aurora A', 'Gene', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('suppressed', 'NegReg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Aurora A', 'Gene', '6790', (34, 42))	('Aurora B', 'Gene', (46, 54))	('Aurora B', 'Gene', '9212', (46, 54))	('tumor', 'Disease', (95, 100))	('knocking down', 'Var', (20, 33))
866660	28881819	Data showed that Aurora A or B expression level was obviously decreased after shRNA transfection.	('Aurora A', 'Gene', (17, 25))	('Aurora A', 'Gene', '6790', (17, 25))	('transfection', 'Var', (84, 96))	('decreased', 'NegReg', (62, 71))
866661	28881819	Ki-67 and phosphorylation of histone H3 were dramatically inhibited and Bax protein expression was significantly increased in the shRNA groups compared with the Mock group (Figure 7C).	('histone H3', 'Protein', (29, 39))	('H3', 'Chemical', 'MESH:C012616', (37, 39))	('phosphorylation', 'MPA', (10, 25))	('Bax', 'Gene', '581', (72, 75))	('Ki-67', 'MPA', (0, 5))	('increased', 'PosReg', (113, 122))	('inhibited', 'NegReg', (58, 67))	('shRNA', 'Var', (130, 135))	('Bax', 'Gene', (72, 75))
866683	28881819	Aurora B deregulation leads to progression through anaphase despite the presence of misaligned chromosomes.	('leads to', 'Reg', (22, 30))	('Aurora B', 'Gene', (0, 8))	('anaphase', 'CPA', (51, 59))	('Aurora B', 'Gene', '9212', (0, 8))	('deregulation', 'Var', (9, 21))
866684	28881819	In addition, amplification of Aurora A was detected in 27 of 29 (93.1%) esophageal cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('Aurora A', 'Gene', (30, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))	('amplification', 'Var', (13, 26))	('detected', 'Reg', (43, 51))	('Aurora A', 'Gene', '6790', (30, 38))
866685	28881819	These data reveal that gene amplification might be a major cause of Aurora A overexpression in esophageal cancer.	('Aurora A overexpression in esophageal cancer', 'Disease', 'MESH:D004938', (68, 112))	('cause', 'Reg', (59, 64))	('Aurora A overexpression in esophageal cancer', 'Disease', (68, 112))	('gene amplification', 'Var', (23, 41))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
866696	28881819	For example, MLN8237 is presently undergoing Phase I and Phase II clinical trials administered solely or in combination with other agents as a cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('MLN8237', 'Var', (13, 20))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
866700	28881819	Our data showed that APIO-EE-9 significantly decreased esophageal cancer cell growth (Figure 1B, 1D) and induced apoptosis (Figure 2A), but did not have any effect on normal esophageal Het-1A cells.	('apoptosis', 'CPA', (113, 122))	('induced', 'Reg', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (55, 72))	('decreased', 'NegReg', (45, 54))	('APIO-EE-9', 'Chemical', '-', (21, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('APIO-EE-9', 'Var', (21, 30))
866713	28881819	KYSE450, KYSE30 and KYSE510 human esophageal cancer cell lines, normal Het-1A esophageal cells, and 293T cells were purchased from American Type Culture Collection (ATCC; Manassas, VA).	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('human', 'Species', '9606', (28, 33))	('293T', 'CellLine', 'CVCL:0063', (100, 104))	('KYSE510', 'Var', (20, 27))	('KYSE30', 'Var', (9, 15))
866715	28881819	The KYSE450, KYSE30, KYSE510 cell lines were cultured in RPMI 1640 medium/10% FBS and the 293T cell line was cultured in DMEM/10% FBS.	('RPMI', 'Chemical', '-', (57, 61))	('FBS', 'Disease', 'MESH:D005198', (78, 81))	('KYSE510', 'Var', (21, 28))	('KYSE30', 'Var', (13, 19))	('FBS', 'Disease', 'MESH:D005198', (130, 133))	('DMEM', 'Chemical', '-', (121, 125))	('293T', 'CellLine', 'CVCL:0063', (90, 94))	('FBS', 'Disease', (78, 81))	('FBS', 'Disease', (130, 133))
866763	23642906	However, the most convincing biological and preclinical evidence has been observed in BCC with a high frequency of mutations in PTCH1 or SMO, making BCC uniquely sensitive to SHH inhibitors.	('SMO', 'Gene', (137, 140))	('mutations', 'Var', (115, 124))	('PTCH1', 'Gene', '5727', (128, 133))	('SHH', 'Gene', '6469', (175, 178))	('sensitive', 'Reg', (162, 171))	('SMO', 'Gene', '6608', (137, 140))	('PTCH1', 'Gene', (128, 133))	('BCC', 'Phenotype', 'HP:0002671', (86, 89))	('SHH', 'Gene', (175, 178))	('BCC', 'Phenotype', 'HP:0002671', (149, 152))
866785	23642906	Early in phase 1 trials, BMS-936558, an anti-PD1 monoclonal antibody, showed promising efficacy with objective responses in 28% of patients with metastatic melanoma, 27% of patients with renal cell carcinoma, and 18% of patients with non-small cell lung cancer (NSCLC).	('renal cell carcinoma', 'Disease', (187, 207))	('NSCLC', 'Disease', (262, 267))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (187, 207))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('patients', 'Species', '9606', (220, 228))	('NSCLC', 'Phenotype', 'HP:0030358', (262, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (249, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('PD1', 'Gene', (45, 48))	('BMS-936558', 'Var', (25, 35))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (234, 260))	('patients', 'Species', '9606', (173, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('patients', 'Species', '9606', (131, 139))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (238, 260))	('melanoma', 'Disease', (156, 164))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (187, 207))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (234, 260))	('PD1', 'Gene', '5133', (45, 48))	('NSCLC', 'Disease', 'MESH:D002289', (262, 267))	('non-small cell lung cancer', 'Disease', (234, 260))
866792	23642906	Among 991 randomly assigned patients with HER2-positive advanced breast cancer, the median PFS was 9.6 months with T-DM1 vs. 6.4 months with lapatinib plus capeci-tabine.	('HER2', 'Gene', '2064', (42, 46))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('lapatinib', 'Chemical', 'MESH:D000077341', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('capeci-tabine', 'Chemical', 'MESH:D000069287', (156, 169))	('T-DM1', 'Var', (115, 120))	('T-DM1', 'Chemical', 'MESH:C550911', (115, 120))	('patients', 'Species', '9606', (28, 36))	('HER2', 'Gene', (42, 46))
866793	23642906	The objective response rate was also higher for T-DM1 (43.6% vs. 30.8% ).	('T-DM1', 'Var', (48, 53))	('objective response', 'CPA', (4, 22))	('higher', 'PosReg', (37, 43))	('T-DM1', 'Chemical', 'MESH:C550911', (48, 53))
866812	23642906	FGFR inhibitors have begun to show encouraging clinical outcomes in cancer, including durable partial responses.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('FGFR', 'Gene', (0, 4))	('inhibitors', 'Var', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))
866813	23642906	These include the need to (1) better understand the predictive value of eight genetic alterations in FGFR, including copy number gains, activating mutations, and chromosomal translocations; (2) strategize and incorporate FGFR inhibitors into existing treatment regimens, such as EGFR inhibitor treatment in lung cancer and anti-VEGF therapy in renal cancer, to overcome or prevent FGFR-mediated recurrence or resistance; and (3) match isoform-specific FGFR inhibitors to tumor types exhibiting distinct, isoform-specific mechanisms of FGFR activation, e.g., FGFR1 amplification in breast cancer, FGFR2 amplification in gastric cancer, FGFR2 mutation in endometrial cancer, or FGFR3 mutation in bladder cancer.	('gastric cancer', 'Disease', (619, 633))	('bladder cancer', 'Disease', (694, 708))	('mutation', 'Var', (641, 649))	('bladder cancer', 'Phenotype', 'HP:0009725', (694, 708))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('VEGF', 'Gene', '7422', (328, 332))	('EGFR', 'Gene', (279, 283))	('gastric cancer', 'Disease', 'MESH:D013274', (619, 633))	('tumor', 'Disease', (471, 476))	('renal cancer', 'Disease', (344, 356))	('cancer', 'Phenotype', 'HP:0002664', (588, 594))	('renal cancer', 'Phenotype', 'HP:0009726', (344, 356))	('cancer', 'Phenotype', 'HP:0002664', (627, 633))	('VEGF', 'Gene', (328, 332))	('lung cancer', 'Disease', (307, 318))	('FGFR2', 'Gene', (635, 640))	('tumor', 'Disease', 'MESH:D009369', (471, 476))	('FGFR1', 'Gene', '2260', (558, 563))	('FGFR3', 'Gene', (676, 681))	('endometrial cancer', 'Phenotype', 'HP:0012114', (653, 671))	('FGFR2', 'Gene', (596, 601))	('renal cancer', 'Disease', 'MESH:D007680', (344, 356))	('breast cancer', 'Phenotype', 'HP:0003002', (581, 594))	('gastric cancer', 'Phenotype', 'HP:0012126', (619, 633))	('cancer', 'Phenotype', 'HP:0002664', (665, 671))	('FGFR2', 'Gene', '2263', (635, 640))	('FGFR3', 'Gene', '2261', (676, 681))	('amplification', 'Var', (602, 615))	('tumor', 'Phenotype', 'HP:0002664', (471, 476))	('mutation', 'Var', (682, 690))	('endometrial cancer', 'Disease', (653, 671))	('EGFR', 'Gene', '1956', (279, 283))	('amplification', 'Var', (564, 577))	('lung cancer', 'Disease', 'MESH:D008175', (307, 318))	('endometrial cancer', 'Disease', 'MESH:D016889', (653, 671))	('breast cancer', 'Disease', 'MESH:D001943', (581, 594))	('FGFR2', 'Gene', '2263', (596, 601))	('breast cancer', 'Disease', (581, 594))	('lung cancer', 'Phenotype', 'HP:0100526', (307, 318))	('FGFR1', 'Gene', (558, 563))	('bladder cancer', 'Disease', 'MESH:D001749', (694, 708))
866815	23642906	Several MET pathway inhibitors are currently being studied, including (1) antibodies that compete and block the binding of HGF to MET, i.e., rilotumumab (AMG 102, Amgen) and ficlatuzumab (AV-299, AVEO); (2) antibodies that bind to MET, resulting in its degradation and subsequently to its inactivation, i.e., onartuzumab (MetMab, Roche); (3) selective MET receptor kinase inhibitors, e.g., tivantinib (ARQ 197, ArQule); and (4) nonselective MET kinase inhibitors, e.g., crizotinib (Xalkori, Pfizer; approved for ALK-positive NSCLC due to its ALK inhibitory activity), cabozantinib (XL 184, Cometriq, Exelixis; approved for medullary thyroid cancer), and foretinib (Glaxo-SmithKline).	('tivantinib', 'Chemical', 'MESH:C551661', (390, 400))	('inactivation', 'MPA', (289, 301))	('HGF', 'Gene', (123, 126))	('cabozantinib', 'Chemical', 'MESH:C558660', (568, 580))	('NSCLC', 'Phenotype', 'HP:0030358', (525, 530))	('degradation', 'MPA', (253, 264))	('thyroid cancer', 'Disease', 'MESH:D013964', (633, 647))	('ALK', 'Gene', '238', (512, 515))	('thyroid cancer', 'Phenotype', 'HP:0002890', (633, 647))	('rilotumumab', 'Chemical', 'MESH:C524459', (141, 152))	('ficlatuzumab', 'Chemical', 'MESH:C583360', (174, 186))	('ALK', 'Gene', '238', (542, 545))	('ALK', 'Gene', (512, 515))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (623, 647))	('antibodies', 'Var', (207, 217))	('ALK', 'Gene', (542, 545))	('onartuzumab', 'Chemical', 'MESH:C584058', (309, 320))	('crizotinib', 'Chemical', 'MESH:D000077547', (470, 480))	('cancer', 'Phenotype', 'HP:0002664', (641, 647))	('NSCLC', 'Disease', 'MESH:D002289', (525, 530))	('crizotinib', 'Gene', (470, 480))	('HGF', 'Gene', '3082', (123, 126))	('thyroid cancer', 'Disease', (633, 647))	('AR', 'Gene', '367', (402, 404))	('NSCLC', 'Disease', (525, 530))
866828	23642906	In addition to mTOR and CDK inhibitors, PI3K and AKT inhibitors are also ideal candidates to combine with hormone treatments in breast or prostate cancers.	('AKT', 'Gene', (49, 52))	('breast or prostate cancers', 'Disease', 'MESH:D011471', (128, 154))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('mTOR', 'Gene', (15, 19))	('mTOR', 'Gene', '2475', (15, 19))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('prostate cancers', 'Phenotype', 'HP:0012125', (138, 154))	('AKT', 'Gene', '207', (49, 52))	('PI3K', 'Var', (40, 44))	('combine', 'Interaction', (93, 100))	('breast or prostate cancers', 'Disease', (128, 154))
866829	23642906	The approval of vemurafenib (Zelboraf), a BRAF inhibitor developed by Roche/Plexxikon, transformed the treatment of patients with melanoma harboring BRAF V600E mutations.	('BRAF', 'Gene', '673', (42, 46))	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('V600E mutations', 'Var', (154, 169))	('patients', 'Species', '9606', (116, 124))	('V600E', 'Mutation', 'rs113488022', (154, 159))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('vemurafenib', 'Chemical', 'MESH:D000077484', (16, 27))	('melanoma', 'Disease', (130, 138))	('BRAF', 'Gene', (42, 46))	('Zelboraf', 'Chemical', 'MESH:D000077484', (29, 37))
866861	22114677	The Effect of hOGG1 Ser326Cys Polymorphism on Cancer Risk: Evidence from a Meta-Analysis Human oxoguanine glycosylase 1 (hOGG1) in base excision repair (BER) pathway plays a vital role in DNA repair.	('hOGG1', 'Gene', '4968', (14, 19))	('Human', 'Species', '9606', (89, 94))	('hOGG1', 'Gene', '4968', (121, 126))	('hOGG1', 'Gene', (14, 19))	('Ser326Cys', 'Var', (20, 29))	('Ser326Cys', 'SUBSTITUTION', 'None', (20, 29))	('hOGG1', 'Gene', (121, 126))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
866862	22114677	Numerous epidemiological studies have evaluated the association between hOGG1 Ser326Cys polymorphism and the risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('hOGG1', 'Gene', '4968', (72, 77))	('Ser326Cys', 'Var', (78, 87))	('Ser326Cys', 'SUBSTITUTION', 'None', (78, 87))	('association', 'Interaction', (52, 63))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('hOGG1', 'Gene', (72, 77))	('cancer', 'Disease', (117, 123))
866863	22114677	A comprehensive search was conducted to identify the eligible studies of hOGG1 Ser326Cys polymorphism and cancer risk.	('hOGG1', 'Gene', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('hOGG1', 'Gene', '4968', (73, 78))	('cancer', 'Disease', (106, 112))	('Ser326Cys', 'SUBSTITUTION', 'None', (79, 88))	('Ser326Cys', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
866864	22114677	We found that the hOGG1 Ser326Cys polymorphism was significantly associated with overall cancer risk (Cys/Cys vs. Ser/Ser: OR = 1.19, 95%CI = 1.09-1.30, P<0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.16, 95%CI = 1.08-1.26, P<0.001).	('associated', 'Reg', (65, 75))	('cancer', 'Disease', (89, 95))	('Ser326Cys', 'Var', (24, 33))	('Ser326Cys', 'SUBSTITUTION', 'None', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Ser', 'Chemical', 'MESH:D012694', (178, 181))	('Cys', 'Chemical', 'MESH:D003545', (162, 165))	('Ser', 'Chemical', 'MESH:D012694', (114, 117))	('Ser', 'Chemical', 'MESH:D012694', (186, 189))	('Cys', 'Chemical', 'MESH:D003545', (106, 109))	('hOGG1', 'Gene', '4968', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Cys', 'Chemical', 'MESH:D003545', (174, 177))	('hOGG1', 'Gene', (18, 23))	('Ser', 'Chemical', 'MESH:D012694', (182, 185))	('Ser', 'Chemical', 'MESH:D012694', (24, 27))	('Cys', 'Chemical', 'MESH:D003545', (166, 169))	('Cys', 'Chemical', 'MESH:D003545', (30, 33))	('Ser', 'Chemical', 'MESH:D012694', (118, 121))	('Cys', 'Chemical', 'MESH:D003545', (102, 105))
866865	22114677	Moreover, in subgroup analyses by cancer types, the stronger significant association between hOGG1 Ser326Cys polymorphism and lung cancer risk was found (Cys/Cys vs. Ser/Ser: OR = 1.29, 95%CI = 1.16-1.44, P<0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.22, 95%CI = 1.12-1.33, P<0.001).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('hOGG1', 'Gene', '4968', (93, 98))	('Cys', 'Chemical', 'MESH:D003545', (154, 157))	('Cys/Cys', 'Var', (214, 221))	('hOGG1', 'Gene', (93, 98))	('Cys', 'Chemical', 'MESH:D003545', (226, 229))	('Ser', 'Chemical', 'MESH:D012694', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('Ser', 'Chemical', 'MESH:D012694', (234, 237))	('Cys', 'Chemical', 'MESH:D003545', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('lung cancer', 'Disease', (126, 137))	('Cys', 'Chemical', 'MESH:D003545', (218, 221))	('Ser', 'Chemical', 'MESH:D012694', (170, 173))	('Ser', 'Chemical', 'MESH:D012694', (238, 241))	('Cys', 'Chemical', 'MESH:D003545', (158, 161))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('cancer', 'Disease', (131, 137))	('Ser', 'Chemical', 'MESH:D012694', (230, 233))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cys', 'Chemical', 'MESH:D003545', (214, 217))	('Ser326Cys', 'Var', (99, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('Ser', 'Chemical', 'MESH:D012694', (166, 169))	('cancer', 'Disease', (34, 40))	('Ser326Cys', 'SUBSTITUTION', 'None', (99, 108))
866866	22114677	The significant effects of hOGG1 Ser326Cys polymorphism on colorectal, breast, bladder, prostate, esophageal, and gastric cancer were not detected.	('gastric cancer', 'Disease', (114, 128))	('hOGG1', 'Gene', '4968', (27, 32))	('Ser326Cys', 'Var', (33, 42))	('prostate', 'Disease', (88, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('Ser326Cys', 'SUBSTITUTION', 'None', (33, 42))	('colorectal', 'Disease', 'MESH:D015179', (59, 69))	('esophageal', 'Disease', 'MESH:D004941', (98, 108))	('breast', 'Disease', (71, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('hOGG1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('esophageal', 'Disease', (98, 108))	('colorectal', 'Disease', (59, 69))	('bladder', 'Disease', (79, 86))
866867	22114677	In addition, in subgroup analyses by ethnicities, we found that the hOGG1 Ser326Cys polymorphism was associated with overall cancer risk in Asians (Cys/Cys vs. Ser/Ser: OR = 1.21, 95%CI = 1.10-1.33, P<0.001).	('Ser', 'Chemical', 'MESH:D012694', (164, 167))	('Ser', 'Chemical', 'MESH:D012694', (74, 77))	('Cys', 'Chemical', 'MESH:D003545', (148, 151))	('Cys', 'Chemical', 'MESH:D003545', (152, 155))	('Cys', 'Chemical', 'MESH:D003545', (80, 83))	('Ser326Cys', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('hOGG1', 'Gene', (68, 73))	('Ser326Cys', 'SUBSTITUTION', 'None', (74, 83))	('associated', 'Reg', (101, 111))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('Ser', 'Chemical', 'MESH:D012694', (160, 163))	('hOGG1', 'Gene', '4968', (68, 73))
866870	22114677	DNA damage, if it is not repaired, could lead to apoptosis or mutation, which may cause induction of carcinogenesis.	('carcinogenesis', 'Disease', (101, 115))	('mutation', 'Var', (62, 70))	('lead to', 'Reg', (41, 48))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))	('apoptosis', 'CPA', (49, 58))
866873	22114677	The presence of 8-OH-dG in DNA is thought to be a major cause of G:C to T:A transversion, because 8-OH-dG could direct the incorporation of adenine as well as cytosine opposite the lesion.	('direct', 'Reg', (112, 118))	('incorporation', 'MPA', (123, 136))	('cytosine', 'MPA', (159, 167))	('8-OH-dG', 'Var', (98, 105))	('8-OH-dG', 'Chemical', 'MESH:C067134', (98, 105))	('cytosine', 'Chemical', 'MESH:D003596', (159, 167))	('adenine', 'Chemical', 'MESH:D000225', (140, 147))	('G:C', 'Disease', (65, 68))	('8-OH-dG', 'Chemical', 'MESH:C067134', (16, 23))
866878	22114677	Genetic variations in hOGG1 gene are increasingly studied for an elevated cancer risk because of the critical roles in stabilizing genome integrity.	('hOGG1', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('Genetic variations', 'Var', (0, 18))	('hOGG1', 'Gene', '4968', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
866879	22114677	The hOGG1 gene has codon 326 polymorphism (Ser326Cys, rs1052133), and Cys326 has lower ability to prevent mutagenesis by 8-OH-dG than Ser326 in human cells in vivo.	('lower', 'NegReg', (81, 86))	('human', 'Species', '9606', (144, 149))	('Ser326Cys', 'Var', (43, 52))	('hOGG1', 'Gene', (4, 9))	('rs1052133', 'Mutation', 'rs1052133', (54, 63))	('prevent mutagenesis', 'MPA', (98, 117))	('Ser326Cys', 'SUBSTITUTION', 'None', (43, 52))	('Cys326', 'Var', (70, 76))	('Ser326', 'Chemical', '-', (43, 49))	('Cys326', 'Chemical', '-', (70, 76))	('8-OH-dG', 'Chemical', 'MESH:C067134', (121, 128))	('Ser326', 'Chemical', '-', (134, 140))	('hOGG1', 'Gene', '4968', (4, 9))
866880	22114677	So far, there were so many reports about the association of hOGG1 Ser326Cys polymorphism with risk of different cancers, including breast, prostate, pancreatic, bladder, gallbladder, gastric, colorectal, esophageal, lung, cervical cancers, and so on.	('lung', 'Disease', (216, 220))	('pancreatic', 'Disease', (149, 159))	('esophageal', 'Disease', (204, 214))	('colorectal', 'Disease', (192, 202))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('association', 'Interaction', (45, 56))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', (231, 238))	('breast', 'Disease', (131, 137))	('polymorphism', 'Var', (76, 88))	('gastric', 'Disease', (183, 190))	('cancers', 'Disease', (112, 119))	('gallbladder', 'Disease', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('hOGG1', 'Gene', '4968', (60, 65))	('cervical cancers', 'Disease', (222, 238))	('esophageal', 'Disease', 'MESH:D004941', (204, 214))	('hOGG1', 'Gene', (60, 65))	('colorectal', 'Disease', 'MESH:D015179', (192, 202))	('cervical cancers', 'Disease', 'MESH:D002583', (222, 238))	('bladder', 'Disease', (161, 168))	('pancreatic', 'Disease', 'MESH:D010195', (149, 159))	('prostate', 'Disease', (139, 147))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('Ser326Cys', 'SUBSTITUTION', 'None', (66, 75))	('Ser326Cys', 'Var', (66, 75))
866881	22114677	One study showed that the hOGG1 Ser326Cys polymorphism was associated with an increased risk of colorectal cancer (odds ratio: 2.3; 95% confidence interval: 1.1-5.0), the risk being higher in younger individuals.	('hOGG1', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('Ser326Cys', 'SUBSTITUTION', 'None', (32, 41))	('Ser326Cys', 'Var', (32, 41))	('colorectal cancer', 'Disease', (96, 113))	('hOGG1', 'Gene', '4968', (26, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
866882	22114677	Canbay et al found that hOGG1 Ser326Cys polymorphism might be associated with increased risk of colorectal cancer in a Turkish population.	('hOGG1', 'Gene', '4968', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('hOGG1', 'Gene', (24, 29))	('Ser326Cys', 'Var', (30, 39))	('colorectal cancer', 'Disease', (96, 113))	('Ser326Cys', 'SUBSTITUTION', 'None', (30, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
866883	22114677	However, other studies did not show the significant association between the Ser326Cys polymorphism and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('Ser326Cys', 'Var', (76, 85))	('Ser326Cys', 'SUBSTITUTION', 'None', (76, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('colorectal cancer', 'Disease', (103, 120))
866884	22114677	Numerous studies and systematic approaches examined the role of the Ser326Cys polymorphism in lung cancer susceptibility.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('Ser326Cys', 'SUBSTITUTION', 'None', (68, 77))	('Ser326Cys', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
866886	22114677	Some studies indicated that the Ser326Cys polymorphism was not associated with breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('associated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('Ser326Cys', 'SUBSTITUTION', 'None', (32, 41))	('Ser326Cys', 'Var', (32, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))
866887	22114677	However, Sangrajrang et al found that Thai women with variant allele of hOGG1 were likely to have an increased susceptibility to breast cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('variant', 'Var', (54, 61))	('hOGG1', 'Gene', '4968', (72, 77))	('women', 'Species', '9606', (43, 48))	('hOGG1', 'Gene', (72, 77))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
866888	22114677	In addition, Chen et al found that hOGG1 Ser326Cys polymorphism was associated with prostate cancer risk whereas Nock et al did not find the significant association in the total study population.	('associated', 'Reg', (68, 78))	('prostate cancer', 'Disease', (84, 99))	('hOGG1', 'Gene', '4968', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('hOGG1', 'Gene', (35, 40))	('Ser326Cys', 'SUBSTITUTION', 'None', (41, 50))	('Ser326Cys', 'Var', (41, 50))
866889	22114677	On the whole, the results about the association between hOGG1 Ser326Cys polymorphism and cancer risk were conflicting and inconclusive.	('Ser326Cys', 'SUBSTITUTION', 'None', (62, 71))	('hOGG1', 'Gene', '4968', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('association', 'Interaction', (36, 47))	('hOGG1', 'Gene', (56, 61))	('Ser326Cys', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
866890	22114677	PubMed (1956 to 30 July 2011) and Embase (1947 to 30 July 2011) database search was performed using following search terms: "oxoguanine glycosylase 1, hOGG1 or OGG1", "polymorphism or variant", and "cancer, neoplasm or tumor".	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('OGG1"', 'Gene', '4968', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('OGG1"', 'Gene', (160, 165))	('polymorphism', 'Var', (168, 180))	('neoplasm or tumor', 'Disease', (207, 224))	('hOGG1', 'Gene', '4968', (151, 156))	('variant', 'Var', (184, 191))	('neoplasm or tumor', 'Disease', 'MESH:D009369', (207, 224))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('neoplasm', 'Phenotype', 'HP:0002664', (207, 215))	('cancer', 'Disease', (199, 205))	('hOGG1', 'Gene', (151, 156))
866891	22114677	Studies included in this meta-analysis should meet the following criteria: (a) evaluation the association of hOGG1 Ser326Cys polymorphism and cancer risk published in English language, (b) use a case-control design, (c) contain available genotype frequency, and (d) the distribution of genotypes in the controls was consistent with Hardy-Weinberg equilibrium (HWE).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('Ser326Cys', 'SUBSTITUTION', 'None', (115, 124))	('Ser326Cys', 'Var', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('hOGG1', 'Gene', (109, 114))	('association', 'Interaction', (94, 105))	('Hardy-Weinberg equilibrium', 'Disease', (332, 358))	('hOGG1', 'Gene', '4968', (109, 114))	('cancer', 'Disease', (142, 148))
866895	22114677	The strength of the association between hOGG1 Ser326Cys polymorphism and cancer risk was measured by odds ratios (ORs) with 95% confidence intervals (CIs).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Ser326Cys', 'Var', (46, 55))	('hOGG1', 'Gene', (40, 45))	('Ser326Cys', 'SUBSTITUTION', 'None', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('hOGG1', 'Gene', '4968', (40, 45))
866898	22114677	For control group of each study, the allelic frequency was calculated, and the observed genotype frequencies of the hOGG1 Ser326Cys polymorphism were assessed for Hardy-Weinberg equilibrium (HWE) by using the Pearson chi-square test; P<0.05 was considered significant.	('Hardy-Weinberg equilibrium', 'Disease', (163, 189))	('hOGG1', 'Gene', (116, 121))	('Ser326Cys', 'SUBSTITUTION', 'None', (122, 131))	('Ser326Cys', 'Var', (122, 131))	('hOGG1', 'Gene', '4968', (116, 121))
866899	22114677	For cancer susceptibility related to hOGG1 Ser326Cys polymorphism, articles were retrieved based on the search criteria.	('hOGG1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Ser326Cys', 'Var', (43, 52))	('Ser326Cys', 'SUBSTITUTION', 'None', (43, 52))	('hOGG1', 'Gene', '4968', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))
866906	22114677	We carried out a meta-analysis of the hOGG1 Ser326Cys polymorphism overall, and in subgroups according to cancer types and ethnic groups under various genetic models (Table S2).	('hOGG1', 'Gene', '4968', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('hOGG1', 'Gene', (38, 43))	('Ser326Cys', 'Var', (44, 53))	('cancer', 'Disease', (106, 112))	('Ser326Cys', 'SUBSTITUTION', 'None', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
866907	22114677	Overall, we found that the hOGG1 Ser326Cys polymorphism was significantly associated with the risk of cancer (Cys/Cys vs. Ser/Ser: OR = 1.19, 95%CI = 1.09-1.30, P<0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.16, 95%CI = 1.08-1.26, P<0.001; Table S2, Figure S2).	('Ser', 'Chemical', 'MESH:D012694', (126, 129))	('Ser326Cys', 'Var', (33, 42))	('Ser326Cys', 'SUBSTITUTION', 'None', (33, 42))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Cys', 'Chemical', 'MESH:D003545', (114, 117))	('Cys', 'Chemical', 'MESH:D003545', (170, 173))	('Ser', 'Chemical', 'MESH:D012694', (194, 197))	('Ser', 'Chemical', 'MESH:D012694', (186, 189))	('Ser', 'Chemical', 'MESH:D012694', (122, 125))	('hOGG1', 'Gene', '4968', (27, 32))	('cancer', 'Disease', (102, 108))	('Cys', 'Chemical', 'MESH:D003545', (182, 185))	('Cys', 'Chemical', 'MESH:D003545', (174, 177))	('hOGG1', 'Gene', (27, 32))	('Ser', 'Chemical', 'MESH:D012694', (33, 36))	('Cys', 'Chemical', 'MESH:D003545', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Cys', 'Chemical', 'MESH:D003545', (39, 42))	('Ser', 'Chemical', 'MESH:D012694', (190, 193))	('associated', 'Reg', (74, 84))
866908	22114677	In subgroup analyses by cancer types, we found that the hOGG1 Ser326Cys polymorphism was significantly associated with lung cancer (Cys/Cys vs. Ser/Ser: OR = 1.29, 95%CI = 1.16-1.44, P<0.001; Cys/Cys vs. Cys/ Ser+Ser/Ser: OR = 1.22, 95%CI = 1.12-1.33, P<0.001; Table S2, Figure 2), but not with colorectal, breast, bladder, prostate, and gastric cancer.	('lung cancer', 'Disease', (119, 130))	('Cys', 'Chemical', 'MESH:D003545', (132, 135))	('associated', 'Reg', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('Cys', 'Chemical', 'MESH:D003545', (204, 207))	('gastric cancer', 'Phenotype', 'HP:0012126', (338, 352))	('Ser', 'Chemical', 'MESH:D012694', (148, 151))	('colorectal', 'Disease', (295, 305))	('cancer', 'Disease', (24, 30))	('Cys', 'Chemical', 'MESH:D003545', (68, 71))	('Ser', 'Chemical', 'MESH:D012694', (209, 212))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('Cys', 'Chemical', 'MESH:D003545', (196, 199))	('Cys', 'Chemical', 'MESH:D003545', (192, 195))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('Ser326Cys', 'Var', (62, 71))	('gastric cancer', 'Disease', (338, 352))	('Ser326Cys', 'SUBSTITUTION', 'None', (62, 71))	('colorectal', 'Disease', 'MESH:D015179', (295, 305))	('cancer', 'Disease', (346, 352))	('Ser', 'Chemical', 'MESH:D012694', (217, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('Cys', 'Chemical', 'MESH:D003545', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('Ser', 'Chemical', 'MESH:D012694', (213, 216))	('cancer', 'Disease', (124, 130))	('Ser', 'Chemical', 'MESH:D012694', (62, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (338, 352))	('Ser', 'Chemical', 'MESH:D012694', (144, 147))	('hOGG1', 'Gene', '4968', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('hOGG1', 'Gene', (56, 61))
866909	22114677	In addition, we found that the hOGG1 Ser326Cys polymorphism was significantly associated with the risk of head and neck cancer (Cys/Cys vs. Ser/Ser: OR = 1.71, 95%CI = 1.05-2.78, P = 0.03).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('associated', 'Reg', (78, 88))	('Ser', 'Chemical', 'MESH:D012694', (140, 143))	('Cys', 'Chemical', 'MESH:D003545', (128, 131))	('head and neck cancer', 'Phenotype', 'HP:0012288', (106, 126))	('Ser', 'Chemical', 'MESH:D012694', (144, 147))	('hOGG1', 'Gene', '4968', (31, 36))	('Ser326Cys', 'Var', (37, 46))	('Cys', 'Chemical', 'MESH:D003545', (132, 135))	('Cys', 'Chemical', 'MESH:D003545', (43, 46))	('Ser326Cys', 'SUBSTITUTION', 'None', (37, 46))	('head and neck cancer', 'Disease', 'MESH:D006258', (106, 126))	('Ser', 'Chemical', 'MESH:D012694', (37, 40))	('hOGG1', 'Gene', (31, 36))
866910	22114677	In subgroup analyses by ethnicities, we found that the hOGG1 Ser326Cys polymorphism was associated with overall cancer risk in Asian population (Cys/Cys vs. Ser/Ser: OR = 1.21, 95%CI = 1.10-1.33, P<0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.14, 95%CI = 1.03-1.26, P = 0.004; Cys/Cys+Cys/Ser vs. Ser/Ser: OR = 1.12, 95%CI = 1.05-1.19, P<0.001; Table S2).	('Cys', 'Chemical', 'MESH:D003545', (67, 70))	('cancer', 'Disease', (112, 118))	('Ser', 'Chemical', 'MESH:D012694', (299, 302))	('hOGG1', 'Gene', '4968', (55, 60))	('Cys', 'Chemical', 'MESH:D003545', (283, 286))	('Cys', 'Chemical', 'MESH:D003545', (209, 212))	('Ser', 'Chemical', 'MESH:D012694', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Cys', 'Chemical', 'MESH:D003545', (145, 148))	('hOGG1', 'Gene', (55, 60))	('Ser', 'Chemical', 'MESH:D012694', (225, 228))	('Cys', 'Chemical', 'MESH:D003545', (217, 220))	('Cys', 'Chemical', 'MESH:D003545', (279, 282))	('Ser', 'Chemical', 'MESH:D012694', (161, 164))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Ser326Cys', 'Var', (61, 70))	('Ser326Cys', 'SUBSTITUTION', 'None', (61, 70))	('Ser', 'Chemical', 'MESH:D012694', (287, 290))	('Cys', 'Chemical', 'MESH:D003545', (149, 152))	('Ser', 'Chemical', 'MESH:D012694', (295, 298))	('Cys', 'Chemical', 'MESH:D003545', (205, 208))	('Cys/Cys+Cys/Ser', 'Var', (275, 290))	('Ser', 'Chemical', 'MESH:D012694', (221, 224))	('Ser', 'Chemical', 'MESH:D012694', (229, 232))	('associated', 'Reg', (88, 98))	('Cys', 'Chemical', 'MESH:D003545', (275, 278))	('Ser', 'Chemical', 'MESH:D012694', (157, 160))
866911	22114677	In subgroup analyses by age, we found that the hOGG1 Ser326Cys polymorphism was associated with overall cancer risk among cancer cases (<60 years) and cancer cases (>=60 years), respectively (Table S3).	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('hOGG1', 'Gene', (47, 52))	('cancer', 'Disease', (122, 128))	('Ser326Cys', 'Var', (53, 62))	('Ser326Cys', 'SUBSTITUTION', 'None', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('associated', 'Reg', (80, 90))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('hOGG1', 'Gene', '4968', (47, 52))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
866912	22114677	In addition, in subgroup analyses by sex, we found that the Ser326Cys polymorphism was not associated with overall cancer risk among women and men, respectively (Table S3).	('cancer', 'Disease', (115, 121))	('women', 'Species', '9606', (133, 138))	('men', 'Species', '9606', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Ser326Cys', 'Var', (60, 69))	('Ser326Cys', 'SUBSTITUTION', 'None', (60, 69))	('men', 'Species', '9606', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
866913	22114677	When the data were analyzed in subgroups of subjects stratified by ethnicities, we found that the hOGG1 Ser326Cys polymorphism was significantly associated with overall cancer risk among Asians (Cys/Cys vs. Ser/Ser: OR = 1.21, 95%CI = 1.10-1.33, P<0.001; Table S2).	('Cys', 'Chemical', 'MESH:D003545', (110, 113))	('Ser326Cys', 'SUBSTITUTION', 'None', (104, 113))	('Ser326Cys', 'Var', (104, 113))	('cancer', 'Disease', (169, 175))	('hOGG1', 'Gene', (98, 103))	('Ser', 'Chemical', 'MESH:D012694', (104, 107))	('associated', 'Reg', (145, 155))	('Ser', 'Chemical', 'MESH:D012694', (207, 210))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Ser', 'Chemical', 'MESH:D012694', (211, 214))	('hOGG1', 'Gene', '4968', (98, 103))	('Cys', 'Chemical', 'MESH:D003545', (199, 202))	('Cys', 'Chemical', 'MESH:D003545', (195, 198))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
866914	22114677	The results of logistic regression analyses showed joint effects between Asians and hOGG1 Ser326Cys polymorphism (P<0.01).	('Ser326Cys', 'SUBSTITUTION', 'None', (90, 99))	('Ser326Cys', 'Var', (90, 99))	('hOGG1', 'Gene', '4968', (84, 89))	('joint', 'Interaction', (51, 56))	('hOGG1', 'Gene', (84, 89))
866916	22114677	In stratified analyses by cancer types, we did not find the significant heterogeneity for lung cancer under two genetic models (Cys/Cys vs. Ser/Ser: P heterogeneity = 0.40; Cys/Cys vs. Cys/ Ser+Ser/Ser: P heterogeneity = 0.40).	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('Cys', 'Chemical', 'MESH:D003545', (132, 135))	('Cys/Cys', 'Var', (173, 180))	('cancer', 'Disease', (26, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Ser', 'Chemical', 'MESH:D012694', (140, 143))	('Cys', 'Chemical', 'MESH:D003545', (177, 180))	('cancer', 'Disease', (95, 101))	('Ser', 'Chemical', 'MESH:D012694', (194, 197))	('Cys', 'Chemical', 'MESH:D003545', (185, 188))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Cys', 'Chemical', 'MESH:D003545', (128, 131))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('lung cancer', 'Disease', (90, 101))	('Cys', 'Chemical', 'MESH:D003545', (173, 176))	('Ser', 'Chemical', 'MESH:D012694', (144, 147))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('Ser', 'Chemical', 'MESH:D012694', (190, 193))	('Ser', 'Chemical', 'MESH:D012694', (198, 201))
866918	22114677	Egger's test further provided statistical evidence of funnel plot symmetry (Cys/Cys vs. Ser/Ser: P = 0.28; Cys/Ser vs. Ser/Ser: P = 0.57; Cys/Cys vs. Cys/Ser+Ser/Ser: P = 0.20; Cys/Cys+Cys/Ser vs. Ser/Ser: P = 0.21).	('Ser', 'Chemical', 'MESH:D012694', (189, 192))	('Cys/Cys+Cys/Ser', 'Var', (177, 192))	('Ser', 'Chemical', 'MESH:D012694', (154, 157))	('Ser', 'Chemical', 'MESH:D012694', (92, 95))	('Ser', 'Chemical', 'MESH:D012694', (123, 126))	('Cys', 'Chemical', 'MESH:D003545', (107, 110))	('Cys', 'Chemical', 'MESH:D003545', (138, 141))	('Cys', 'Chemical', 'MESH:D003545', (76, 79))	('Cys', 'Chemical', 'MESH:D003545', (177, 180))	('Ser', 'Chemical', 'MESH:D012694', (201, 204))	('Ser', 'Chemical', 'MESH:D012694', (162, 165))	('Cys', 'Chemical', 'MESH:D003545', (185, 188))	('Cys/Cys', 'Var', (138, 145))	('Cys', 'Chemical', 'MESH:D003545', (150, 153))	('Ser', 'Chemical', 'MESH:D012694', (88, 91))	('Ser', 'Chemical', 'MESH:D012694', (119, 122))	('Ser', 'Chemical', 'MESH:D012694', (158, 161))	('Cys', 'Chemical', 'MESH:D003545', (142, 145))	('Cys', 'Chemical', 'MESH:D003545', (80, 83))	('Ser', 'Chemical', 'MESH:D012694', (197, 200))	('Ser', 'Chemical', 'MESH:D012694', (111, 114))	('Cys', 'Chemical', 'MESH:D003545', (181, 184))
866920	22114677	Previous conclusions of numerous studies on the association between the hOGG1 Ser326Cys polymorphism and cancer risk remain conflicting and contradictory.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('hOGG1', 'Gene', '4968', (72, 77))	('Ser326Cys', 'Var', (78, 87))	('Ser326Cys', 'SUBSTITUTION', 'None', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hOGG1', 'Gene', (72, 77))
866921	22114677	The conflicting results are possibly because of a small effect of the Ser326Cys polymorphism on cancer risk or the relatively low statistical power of published studies.	('Ser326Cys', 'Var', (70, 79))	('Ser326Cys', 'SUBSTITUTION', 'None', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
866922	22114677	The present meta-analysis, including 31,297 cancer cases and 39,033 controls, explored the relationship between the Ser326Cys polymorphism and overall cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Ser326Cys', 'SUBSTITUTION', 'None', (116, 125))	('Ser326Cys', 'Var', (116, 125))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
866923	22114677	In the meta-analysis, we found that the hOGG1 Ser326Cys polymorphism was significantly associated with overall cancer risk.	('Ser326Cys', 'Var', (46, 55))	('hOGG1', 'Gene', (40, 45))	('Ser326Cys', 'SUBSTITUTION', 'None', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (87, 97))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('hOGG1', 'Gene', '4968', (40, 45))
866924	22114677	In subgroup analyses by cancer types, the significant association between the hOGG1 Ser326Cys polymorphism and lung cancer risk was further detected.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('hOGG1', 'Gene', (78, 83))	('Ser326Cys', 'Var', (84, 93))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('Ser326Cys', 'SUBSTITUTION', 'None', (84, 93))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('hOGG1', 'Gene', '4968', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
866925	22114677	In addition, in subgroup analyses by ethnicities, we found that the hOGG1 Ser326Cys polymorphism was significantly associated with overall cancer risk in Asian population.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('Ser326Cys', 'Var', (74, 83))	('hOGG1', 'Gene', '4968', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('hOGG1', 'Gene', (68, 73))	('Ser326Cys', 'SUBSTITUTION', 'None', (74, 83))	('polymorphism', 'Var', (84, 96))	('associated with', 'Reg', (115, 130))	('cancer', 'Disease', (139, 145))
866926	22114677	However, sensitivity analyses suggested that the significant association between the Ser326Cys polymorphism and overall cancer risk among Caucasians lacked convincing evidence.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('Ser326Cys', 'Var', (85, 94))	('Ser326Cys', 'SUBSTITUTION', 'None', (85, 94))
866929	22114677	With respect to the important roles of hOGG1 in DNA repair, it is biologically plausible that hOGG1 Ser326Cys polymorphism may modulate the risk of cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('polymorphism', 'Var', (110, 122))	('hOGG1', 'Gene', (39, 44))	('Ser326Cys', 'SUBSTITUTION', 'None', (100, 109))	('hOGG1', 'Gene', '4968', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('modulate', 'Reg', (127, 135))	('hOGG1', 'Gene', '4968', (39, 44))	('hOGG1', 'Gene', (94, 99))	('Ser326Cys', 'Var', (100, 109))
866931	22114677	We did not find that hOGG1 Ser326Cys polymorphism was significantly associated with cancer risk in Caucasian population and other cancer types including breast, prostate, pancreatic, bladder, gallbladder, gastric, colorectal, and esophageal cancer, suggesting the influence of the genetic variant may be masked by the presence of other as-yet unidentified causal genes involved in carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('Ser326Cys', 'SUBSTITUTION', 'None', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('pancreatic', 'Disease', (171, 181))	('carcinogenesis', 'Disease', 'MESH:D063646', (381, 395))	('hOGG1', 'Gene', '4968', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('colorectal', 'Disease', (214, 224))	('hOGG1', 'Gene', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('gallbladder', 'Disease', (192, 203))	('cancer', 'Disease', (84, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (230, 247))	('breast', 'Disease', (153, 159))	('gastric', 'Disease', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('esophageal cancer', 'Disease', (230, 247))	('bladder', 'Disease', (183, 190))	('colorectal', 'Disease', 'MESH:D015179', (214, 224))	('associated', 'Reg', (68, 78))	('pancreatic', 'Disease', 'MESH:D010195', (171, 181))	('cancer', 'Disease', (130, 136))	('prostate', 'Disease', (161, 169))	('cancer', 'Disease', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('carcinogenesis', 'Disease', (381, 395))	('Ser326Cys', 'Var', (27, 36))
866932	22114677	In addition, we found that the frequency of the 326Cys allele was 47.07% among Asian controls, which was significantly higher than that of Caucasian controls (23.62%, P<0.001), which may also affect the roles of hOGG1 Ser326Cys polymorphism on cancer risk in Asians and Caucasians.	('326Cys', 'Chemical', '-', (221, 227))	('Ser326Cys', 'Var', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('hOGG1', 'Gene', (212, 217))	('Ser326Cys', 'SUBSTITUTION', 'None', (218, 227))	('326Cys', 'Chemical', '-', (48, 54))	('affect', 'Reg', (192, 198))	('hOGG1', 'Gene', '4968', (212, 217))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
866934	22114677	In summary, this meta-analysis provided evidence of the association between hOGG1 Ser326Cys polymorphism and cancer risk, supporting the hypothesis that hOGG1 Ser326Cys polymorphism might be a low-penetrant susceptibility marker of lung cancer.	('Ser326Cys', 'Var', (159, 168))	('Ser326Cys', 'SUBSTITUTION', 'None', (159, 168))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('hOGG1', 'Gene', (76, 81))	('Ser326Cys', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', (109, 115))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('Ser326Cys', 'SUBSTITUTION', 'None', (82, 91))	('hOGG1', 'Gene', '4968', (76, 81))	('association', 'Interaction', (56, 67))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('hOGG1', 'Gene', '4968', (153, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (237, 243))	('lung cancer', 'Disease', (232, 243))	('hOGG1', 'Gene', (153, 158))
866935	22114677	Moreover, sophisticated gene-gene interaction should be considered in future analysis, which would lead a better, comprehensive understanding of the association between hOGG1 Ser326Cys polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('hOGG1', 'Gene', (169, 174))	('association', 'Interaction', (149, 160))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('hOGG1', 'Gene', '4968', (169, 174))	('Ser326Cys', 'Var', (175, 184))	('cancer', 'Disease', (202, 208))	('Ser326Cys', 'SUBSTITUTION', 'None', (175, 184))
866951	21994879	In terms of the clinical staging of cirrhosis, 22 patients were graded Child-Pugh class A, 18 class B, and 3 class C. The etiologies of LC were hepatitis B surface antigen (HBsAg) positivity in 4 patients, antibody to hepatitis C virus (anti-HCV) in 16 patients, alcoholic liver disease in 8 patients, sarcoidosis in 1 patient, and unknown in 2 patients.	('patient', 'Species', '9606', (319, 326))	('patients', 'Species', '9606', (253, 261))	('positivity', 'Var', (180, 190))	('patients', 'Species', '9606', (196, 204))	('sarcoidosis', 'Disease', (302, 313))	('patients', 'Species', '9606', (292, 300))	('hepatitis', 'Species', '11103', (218, 227))	('antibody to hepatitis C virus', 'Disease', (206, 235))	('alcoholic liver disease', 'Disease', 'MESH:D008108', (263, 286))	('hepatitis', 'Phenotype', 'HP:0012115', (144, 153))	('LC', 'Phenotype', 'HP:0001394', (136, 138))	('liver disease', 'Phenotype', 'HP:0001392', (273, 286))	('patient', 'Species', '9606', (292, 299))	('patients', 'Species', '9606', (345, 353))	('antibody to hepatitis C virus', 'Phenotype', 'HP:0410371', (206, 235))	('patient', 'Species', '9606', (253, 260))	('hepatitis', 'Species', '11103', (144, 153))	('patients', 'Species', '9606', (50, 58))	('alcoholic liver disease', 'Disease', (263, 286))	('cirrhosis', 'Disease', 'MESH:D005355', (36, 45))	('patient', 'Species', '9606', (196, 203))	('antibody to hepatitis C virus', 'Disease', 'MESH:D006526', (206, 235))	('Child', 'Species', '9606', (71, 76))	('sarcoidosis', 'Disease', 'MESH:D012507', (302, 313))	('cirrhosis', 'Phenotype', 'HP:0001394', (36, 45))	('anti-HCV', 'Phenotype', 'HP:0410371', (237, 245))	('hepatitis', 'Phenotype', 'HP:0012115', (218, 227))	('cirrhosis', 'Disease', (36, 45))	('patient', 'Species', '9606', (345, 352))	('patient', 'Species', '9606', (50, 57))
866984	21994879	EIS has been reported to be successful in controlling duodenal variceal bleeding but there have been reports of cases of rebleeding of duodenal varices after EIS.	('bleeding', 'Disease', (72, 80))	('EIS', 'Var', (158, 161))	('duodenal', 'Disease', (135, 143))	('bleeding', 'Disease', 'MESH:D006470', (123, 131))	('bleeding', 'Disease', (123, 131))	('bleeding', 'Disease', 'MESH:D006470', (72, 80))
866999	21994879	Adhesions tend to bring the parietal surface of the viscera in contact with the abdominal wall, and portal hypertension results in the formation of varices below the intestinal mucosa.	('Adhesions', 'Var', (0, 9))	('hypertension', 'Phenotype', 'HP:0000822', (107, 119))	('portal', 'Var', (100, 106))	('hypertension', 'Disease', 'MESH:D006973', (107, 119))	('results in', 'Reg', (120, 130))	('Adhesions tend', 'Phenotype', 'HP:0100550', (0, 14))	('portal hypertension', 'Phenotype', 'HP:0001409', (100, 119))	('hypertension', 'Disease', (107, 119))
867049	21532508	There is evidence from laboratory studies and some clinical trials that inhibition of COX-2 activity may enhance the cytotoxicity of chemotherapy agents and radiation therapy.	('activity', 'MPA', (92, 100))	('COX-2', 'Gene', (86, 91))	('COX-2', 'Gene', '5743', (86, 91))	('cytotoxicity', 'Disease', 'MESH:D064420', (117, 129))	('inhibition', 'Var', (72, 82))	('enhance', 'PosReg', (105, 112))	('cytotoxicity', 'Disease', (117, 129))
867053	21532508	Patients were considered eligible if their clinical stage was T2-T3/N0, T1-T3/ N1, or T1-T3/M1a-M1b (lymph).	('Patients', 'Species', '9606', (0, 8))	('T1-T3/M1a-M1b', 'Var', (86, 99))	('T1-T3/', 'Disease', (72, 78))	('T2-T3/N0', 'Disease', (62, 70))
867128	21532508	Despite evidence that chemotherapeutic agents including taxanes are potent inducers of COX-2 and that abrogation of COX-2 activity may potentially enhance their cytotoxicity, trials examining the efficacy of COX-2 inhibitors administered in conjunction with chemotherapy or chemoradiotherapy have yielded mixed and mostly disappointing results.	('COX-2', 'Gene', (87, 92))	('COX-2', 'Gene', '5743', (87, 92))	('taxanes', 'Chemical', 'MESH:D043823', (56, 63))	('enhance', 'PosReg', (147, 154))	('COX-2', 'Gene', (208, 213))	('cytotoxicity', 'Disease', (161, 173))	('COX-2', 'Gene', '5743', (208, 213))	('abrogation', 'Var', (102, 112))	('COX-2', 'Gene', (116, 121))	('cytotoxicity', 'Disease', 'MESH:D064420', (161, 173))	('COX-2', 'Gene', '5743', (116, 121))	('inducers', 'PosReg', (75, 83))	('activity', 'MPA', (122, 130))
867135	21532508	Importantly, patients with tumors lacking COX-2 expression who received celecoxib had significantly worse survivals than those with COX-2-negative tumors who were not treated with celecoxib.	('COX-2', 'Gene', '5743', (42, 47))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('celecoxib', 'Var', (72, 81))	('survivals', 'MPA', (106, 115))	('worse', 'NegReg', (100, 105))	('COX-2', 'Gene', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('lacking', 'NegReg', (34, 41))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('celecoxib', 'Chemical', 'MESH:D000068579', (72, 81))	('COX-2', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Disease', (27, 33))	('COX-2', 'Gene', '5743', (132, 137))	('celecoxib', 'Chemical', 'MESH:D000068579', (180, 189))
867152	31369196	Furthermore, our in vivo results showed that overexpression of miR-145 or silencing of lncRNA PVT1 resulted in decreased tumor growth in nude mice.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('nude mice', 'Species', '10090', (137, 146))	('decreased tumor', 'Disease', (111, 126))	('decreased tumor', 'Disease', 'None', (111, 126))	('silencing', 'Var', (74, 83))	('lncRNA PVT1', 'Gene', (87, 98))	('miR-145', 'Gene', (63, 70))	('overexpression', 'PosReg', (45, 59))
867162	31369196	In a study prior to this current one, miR-145 promoted glioma cell apoptosis by suppressing BNIP3, which led to the inactivation of Notch signaling pathway (Du et al., 2017).	('glioma', 'Disease', (55, 61))	('promoted', 'PosReg', (46, 54))	('inactivation', 'NegReg', (116, 128))	('BNIP3', 'Gene', (92, 97))	('BNIP3', 'Gene', '664', (92, 97))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('suppressing', 'NegReg', (80, 91))	('miR-145', 'Var', (38, 45))	('Notch signaling pathway', 'Pathway', (132, 155))
867229	31369196	Subsequent results in relation to the correlation between lncRNA PVT1 expression and DFS and OS analyzed by the Kaplan-Meier method showed that OS and DFS of patients with high lncRNA PVT1 expression were significantly lower than those with low lncRNA PVT1 expression.	('expression', 'MPA', (189, 199))	('patients', 'Species', '9606', (158, 166))	('high lncRNA', 'Var', (172, 183))	('lower', 'NegReg', (219, 224))
867247	31369196	In comparison with the blank group and the NC group, tumor volume and weight of nude mice were decreased in the miR-145 mimic and si-FSCN1 groups (P < 0.05), increased in the miR-145 inhibitor group (P < 0.05), and exhibited no obvious difference in the miR-145 inhibitor + si-FSCN1 group (P > 0.05).	('decreased', 'NegReg', (95, 104))	('nude mice', 'Species', '10090', (80, 89))	('si-FSCN1', 'Var', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('miR-145', 'Gene', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('increased', 'PosReg', (158, 167))
867253	31369196	Expression of FSCN1, Bcl-2, CD147, VEGFR2, and MTA1 was down-regulated and that of Bax was up-regulated upon treatment of silencing lncRNA PVT1 or overexpressed miR-145.	('Bcl-2', 'Gene', (21, 26))	('MTA1', 'Gene', (47, 51))	('FSCN1', 'Gene', (14, 19))	('Bax', 'Gene', '581', (83, 86))	('CD147', 'Gene', '682', (28, 33))	('Bcl-2', 'Gene', '596', (21, 26))	('down-regulated', 'NegReg', (56, 70))	('up-regulated', 'PosReg', (91, 103))	('VEGFR2', 'Gene', (35, 41))	('miR-145', 'Gene', (161, 168))	('CD147', 'Gene', (28, 33))	('MTA1', 'Gene', '9112', (47, 51))	('silencing', 'Var', (122, 131))	('lncRNA PVT1', 'Gene', (132, 143))	('Bax', 'Gene', (83, 86))
867255	31369196	Silencing VEGFR2 could promote cell development and angiogenesis in mouse models of pancreatic ductal adenocarcinoma, and up-regulation of miR-200 leads to decreased VEGFR2 (Sureban et al., 2013).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('angiogenesis', 'CPA', (52, 64))	('miR', 'Gene', '220972', (139, 142))	('miR', 'Gene', (139, 142))	('mouse', 'Species', '10090', (68, 73))	('VEGFR2', 'MPA', (166, 172))	('promote', 'PosReg', (23, 30))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (84, 116))	('pancreatic ductal adenocarcinoma', 'Disease', (84, 116))	('VEGFR2', 'Gene', (10, 16))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (84, 116))	('decreased', 'NegReg', (156, 165))	('up-regulation', 'PosReg', (122, 135))	('cell development', 'CPA', (31, 47))	('Silencing', 'Var', (0, 9))
867258	31369196	In a prior study, overexpressed miR-145 was found to suppress non-small-cell lung cancer cell growth, migration, and invasion, partially by suppressing FSCN1 expression (Zhang and Lin, 2015).	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('overexpressed', 'Var', (18, 31))	('suppressing', 'NegReg', (140, 151))	('miR-145', 'Var', (32, 39))	('non-small-cell lung cancer', 'Disease', (62, 88))	('expression', 'MPA', (158, 168))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (62, 88))	('suppress', 'NegReg', (53, 61))	('FSCN1', 'Gene', (152, 157))	('invasion', 'CPA', (117, 125))
867259	31369196	indicated that aberrant expression of miR-145 dampens migration and invasion of colorectal cancer cells (Chang et al., 2017).	('aberrant expression', 'Var', (15, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('invasion', 'CPA', (68, 76))	('dampens', 'NegReg', (46, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('migration', 'CPA', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('miR-145', 'Gene', (38, 45))
867263	31369196	lncRNA PVT1 functions as a tumor promoter in cancer development whose knockdown has the capacity to expressively reduce viability, migration, invasion, and enhanced apoptosis of cervical cancer cells (Ping et al., 2018).	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('knockdown', 'Var', (70, 79))	('migration', 'CPA', (131, 140))	('cancer', 'Disease', (187, 193))	('tumor', 'Disease', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('reduce', 'NegReg', (113, 119))	('apoptosis', 'CPA', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('enhanced', 'PosReg', (156, 164))	('cancer', 'Disease', (45, 51))	('invasion', 'CPA', (142, 150))	('viability', 'CPA', (120, 129))
867265	31369196	Similarly, it was validated that the silencing lncRNA CASC9 can help to suppress migration and invasion of EC cells in vitro (Pan et al., 2016).	('suppress', 'NegReg', (72, 80))	('silencing', 'Var', (37, 46))	('CASC9', 'Gene', '101805492', (54, 59))	('CASC9', 'Gene', (54, 59))	('EC', 'Phenotype', 'HP:0011459', (107, 109))
867266	31369196	Consequently, this study demonstrated that silencing of lncRNA PVT1 can promote the expression of miR-145, and thus, it can function as a tumor suppressor in EC cells through down-regulating FSCN1 (Fig.	('tumor', 'Disease', (138, 143))	('EC', 'Phenotype', 'HP:0011459', (158, 160))	('silencing', 'Var', (43, 52))	('promote', 'PosReg', (72, 79))	('miR-145', 'Gene', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('down-regulating', 'NegReg', (175, 190))	('lncRNA PVT1', 'Gene', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('FSCN1', 'Gene', (191, 196))	('expression', 'MPA', (84, 94))
867321	30902421	ARPKD participants with either splenomegaly or low platelets had a higher median age than those without signs of portal hypertension.	('splenomegaly', 'Disease', 'MESH:D013163', (31, 43))	('hypertension', 'Disease', 'MESH:D006973', (120, 132))	('ARPKD', 'Gene', (0, 5))	('low', 'Var', (47, 50))	('participants', 'Species', '9606', (6, 18))	('hypertension', 'Disease', (120, 132))	('portal hypertension', 'Phenotype', 'HP:0001409', (113, 132))	('splenomegaly', 'Phenotype', 'HP:0001744', (31, 43))	('hypertension', 'Phenotype', 'HP:0000822', (120, 132))	('splenomegaly', 'Disease', (31, 43))	('ARPKD', 'Gene', '5314', (0, 5))
867323	30902421	All participants with low platelets had splenomegaly, and were defined as having "definitive" portal hypertension (n=9).	('portal hypertension', 'Phenotype', 'HP:0001409', (94, 113))	('splenomegaly', 'Disease', (40, 52))	('low', 'Var', (22, 25))	('platelets', 'Gene', (26, 35))	('participants', 'Species', '9606', (4, 16))	('hypertension', 'Disease', 'MESH:D006973', (101, 113))	('splenomegaly', 'Phenotype', 'HP:0001744', (40, 52))	('splenomegaly', 'Disease', 'MESH:D013163', (40, 52))	('hypertension', 'Disease', (101, 113))	('hypertension', 'Phenotype', 'HP:0000822', (101, 113))
867326	30902421	both splenomegaly and low platelets, n=9) had a higher median age and lower WBC count than those without portal hypertension (n=11) (median age 7.7 vs. 1.9 years, p=0.03; WBC 4.4 vs. 11.0 x103/muL, p=0.01).	('hypertension', 'Disease', 'MESH:D006973', (112, 124))	('hypertension', 'Disease', (112, 124))	('splenomegaly', 'Disease', (5, 17))	('lower WBC count', 'Phenotype', 'HP:0020060', (70, 85))	('portal hypertension', 'Phenotype', 'HP:0001409', (105, 124))	('hypertension', 'Phenotype', 'HP:0000822', (112, 124))	('WBC count', 'MPA', (76, 85))	('lower', 'NegReg', (70, 75))	('muL', 'Gene', '4591', (193, 196))	('low platelets', 'Var', (22, 35))	('splenomegaly', 'Disease', 'MESH:D013163', (5, 17))	('splenomegaly', 'Phenotype', 'HP:0001744', (5, 17))	('muL', 'Gene', (193, 196))
867344	30902421	ARPKD participants with low platelets had significantly higher median liver and spleen stiffness than those without low platelets.	('low', 'Var', (24, 27))	('ARPKD', 'Gene', (0, 5))	('participants', 'Species', '9606', (6, 18))	('higher', 'PosReg', (56, 62))	('ARPKD', 'Gene', '5314', (0, 5))
867364	30902421	Within the ARPKD group, participants with either splenomegaly or low platelets had significantly higher liver and spleen stiffness than those without these clinical signs of portal hypertension.	('higher', 'PosReg', (97, 103))	('ARPKD', 'Gene', '5314', (11, 16))	('hypertension', 'Disease', 'MESH:D006973', (181, 193))	('splenomegaly', 'Disease', 'MESH:D013163', (49, 61))	('splenomegaly', 'Phenotype', 'HP:0001744', (49, 61))	('participants', 'Species', '9606', (24, 36))	('hypertension', 'Disease', (181, 193))	('portal hypertension', 'Phenotype', 'HP:0001409', (174, 193))	('hypertension', 'Phenotype', 'HP:0000822', (181, 193))	('ARPKD', 'Gene', (11, 16))	('splenomegaly', 'Disease', (49, 61))	('low', 'Var', (65, 68))
867365	30902421	Overall, median liver and spleen stiffness measurements were higher in ARPKD participants with low platelets compared with those with splenomegaly, suggesting that low platelets are sign of more advanced portal hypertension.	('portal hypertension', 'Phenotype', 'HP:0001409', (204, 223))	('hypertension', 'Phenotype', 'HP:0000822', (211, 223))	('splenomegaly', 'Disease', 'MESH:D013163', (134, 146))	('splenomegaly', 'Phenotype', 'HP:0001744', (134, 146))	('low', 'Var', (95, 98))	('ARPKD', 'Gene', (71, 76))	('higher', 'PosReg', (61, 67))	('participants', 'Species', '9606', (77, 89))	('splenomegaly', 'Disease', (134, 146))	('ARPKD', 'Gene', '5314', (71, 76))	('hypertension', 'Disease', 'MESH:D006973', (211, 223))	('hypertension', 'Disease', (211, 223))
867511	30439645	found that miRNA-103 and miRNA-107 inhibit the translation of cofilin.	('miRNA-103', 'Var', (11, 20))	('cofilin', 'Gene', '1072', (62, 69))	('translation', 'MPA', (47, 58))	('cofilin', 'Gene', (62, 69))	('inhibit', 'NegReg', (35, 42))	('miRNA-107', 'Var', (25, 34))
867515	30439645	A recent study also showed that miRNA-23, miRNA-24, and miRNA-27 contained underlying therapeutic factors in ischemic heart and vascular disorders disease.	('ischemic heart', 'Disease', (109, 123))	('vascular disorders disease', 'Disease', (128, 154))	('ischemic heart', 'Disease', 'MESH:D003324', (109, 123))	('miRNA-24', 'Var', (42, 50))	('miRNA-27', 'Var', (56, 64))	('vascular disorders disease', 'Disease', 'MESH:D000783', (128, 154))	('miRNA-23', 'Var', (32, 40))
867525	30439645	As shown in Figures 1 and 2, RFMDA achieved an AUC of 0.8891, which is higher than AUCs of 0.8781 (HGIMDA), 0.8749 (MCMDA), 0.8624 (MaxFlow), 0.8426 (RLSMDA), 0.8366 (HDMP), and 0.8030 (WBSMDA) in global LOOCV.	('0.8426', 'Var', (142, 148))	('0.8624', 'Var', (124, 130))	('WBSMDA', 'Chemical', '-', (186, 192))	('0.8366', 'Var', (159, 165))	('0.8030', 'Var', (178, 184))	('0.8749', 'Var', (108, 114))
867526	30439645	Besides, in local LOOCV, HGIMDA, MCMDA, MaxFlow, RLSMDA, HDMP, WBSMDA, MIDP, MiRAI, and RWRMDA obtained AUCs of 0.8077, 0.7718, 0.7774, 0.6953, 0.7702, 0.8031, 0.8196, 0.6299, and 0.7891, respectively.	('0.7702', 'Var', (144, 150))	('0.7718', 'Var', (120, 126))	('0.8196', 'Var', (160, 166))	('WBSMDA', 'Chemical', '-', (63, 69))	('0.6953', 'Var', (136, 142))	('0.6299', 'Var', (168, 174))	('0.7891', 'Var', (180, 186))	('0.8077', 'Var', (112, 118))	('0.7774', 'Var', (128, 134))	('0.8031', 'Var', (152, 158))
867527	30439645	The average AUC of 0.8818 under 100 cross-validation is still higher than the average AUCs of 0.8767 (MCMDA), 0.8579 (MaxFlow), 0.8569 (RLSMDA), 0.8342 (HDMP), and 0.8185 (WBSMDA).	('0.8818', 'Var', (19, 25))	('0.8569', 'Var', (128, 134))	('WBSMDA', 'Chemical', '-', (172, 178))	('0.8579', 'Var', (110, 116))
867535	30439645	For example, the methylation ratios of miRNA-34a, miRNA-34b/c, and miRNA-129-2 are 66.67%, 40.74%, and 96.30%, respectively, in esophageal squamous cell carcinoma, which are obviously higher than those in non-tumor tissues.	('methylation', 'MPA', (17, 28))	('tumor', 'Disease', (209, 214))	('miRNA-34b', 'Gene', (50, 59))	('miRNA-34a', 'Gene', (39, 48))	('miRNA-34b', 'Gene', '407041', (50, 59))	('miRNA-34a', 'Gene', '407040', (39, 48))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (128, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('miRNA-129-2', 'Var', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('higher', 'PosReg', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('esophageal squamous cell carcinoma', 'Disease', (128, 162))
867645	28392898	Aberrant expression of PRDXs has been shown in different types of cancer.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('expression', 'MPA', (9, 19))	('PRDXs', 'Gene', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))	('shown', 'Reg', (38, 43))
867688	27540571	Previous reports noted that EUS is more sensitive for the detection of regional lymph node metastases of esophageal cancer than CT. By the addition of EUS, the diagnostic power for staging before chemoradiotherapy or radiotherapy will increase.	('metastases of esophageal cancer', 'Disease', (91, 122))	('EUS', 'Gene', (151, 154))	('addition', 'Var', (139, 147))	('increase', 'PosReg', (235, 243))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('metastases of esophageal cancer', 'Disease', 'MESH:D009362', (91, 122))
867703	27559535	Codes 8140-8389 were used to define adenomas and adenocarcinomas; codes 8050-8089 for squamous cell neoplasms; and all other remaining codes as other histology.	('adenomas', 'Disease', 'MESH:D000236', (36, 44))	('adenomas', 'Disease', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('squamous cell neoplasms', 'Disease', 'MESH:D002294', (86, 109))	('adenocarcinomas', 'Disease', (49, 64))	('codes 8050-8089', 'Var', (66, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('neoplasms', 'Phenotype', 'HP:0002664', (100, 109))	('squamous cell neoplasms', 'Disease', (86, 109))
867727	26687301	Our previous study showed that EpCAM aptamer SYL3C could specifically bind to EpCAM antigen in intestinal tissue, thus holding diagnostic value for colorectal cancer.	('EpCAM', 'Gene', (31, 36))	('bind', 'Interaction', (70, 74))	('diagnostic', 'Reg', (127, 137))	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('EpCAM', 'Gene', (78, 83))	('colorectal cancer', 'Disease', (148, 165))	('EpCAM', 'Gene', '4072', (31, 36))	('SYL3C', 'Var', (45, 50))	('EpCAM', 'Gene', '4072', (78, 83))
867730	26687301	However, sixty cases each, both ESCC and EACA, equally showed 98% overexpression of EpCAM by SYL3C, while all 20 cases of metastasis appeared as 100% overexpressed.	('EpCAM', 'Gene', '4072', (84, 89))	('overexpression', 'PosReg', (66, 80))	('SYL3C', 'Var', (93, 98))	('EpCAM', 'Gene', (84, 89))
867780	26687301	We noticed that normal epithelial tissues from the same cancer patient with overexpressed EpCAM were negative for SYL3C staining and that cancer tissue showed strong positive staining of SYL3C, while the random sequence was negative for EpCAM expression.	('EpCAM', 'Gene', (237, 242))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('EpCAM', 'Gene', (90, 95))	('EpCAM', 'Gene', '4072', (237, 242))	('overexpressed', 'PosReg', (76, 89))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('EpCAM', 'Gene', '4072', (90, 95))	('patient', 'Species', '9606', (63, 70))	('negative', 'NegReg', (101, 109))	('cancer', 'Disease', (56, 62))	('SYL3C', 'Var', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
867811	26383589	They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1.	('CRTC1', 'Gene', (88, 93))	('CRTC1', 'Gene', '23373', (88, 93))	('BARX1', 'Gene', '56033', (106, 111))	('FOXP1', 'Gene', '27086', (95, 100))	('FOXP1', 'Gene', (95, 100))	('variants', 'Var', (56, 64))	('significant association', 'Reg', (28, 51))	('BARX1', 'Gene', (106, 111))
867813	26383589	We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk.	('EAC', 'Disease', (152, 155))	('FOXP1', 'Gene', '27086', (38, 43))	('confer', 'Reg', (145, 151))	('variants', 'Var', (121, 129))	('BARX1', 'Gene', (45, 50))	('BARX1', 'Gene', '56033', (45, 50))	('FOXP1', 'Gene', (38, 43))	('FOXF1', 'Gene', '2294', (56, 61))	('EAC', 'Phenotype', 'HP:0011459', (152, 155))	('FOXF1', 'Gene', (56, 61))
867814	26383589	In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P < 10-5) although not genome-wide significantly associated with the BEACON GWAS.	('XRCC2', 'Gene', '7516', (61, 66))	('XRCC2', 'Gene', (61, 66))	('GATA6', 'Gene', (71, 76))	('GATA6', 'Gene', '2627', (71, 76))	('EAC', 'Phenotype', 'HP:0011459', (167, 170))	('variants', 'Var', (37, 45))	('P < 10-5', 'Gene', (97, 105))	('associated', 'Reg', (146, 156))	('association', 'Interaction', (22, 33))	('P < 10-5', 'Gene', '4790', (97, 105))
867816	26383589	Eighty-seven single nucleotide polymorphisms (SNPs) showed disease association with P < 10-4 and were followed up in 874 EAC and 759 Barrett's esophagus cases (total of 1633 cases) as well as 6911 controls from the United Kingdom (replication sample).	('EAC', 'Disease', (121, 124))	("Barrett's esophagus", 'Disease', (133, 152))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (133, 152))	('EAC', 'Phenotype', 'HP:0011459', (121, 124))	('P < 10-4', 'Gene', (84, 92))	('single nucleotide polymorphisms', 'Var', (13, 44))	('P < 10-4', 'Gene', '4820', (84, 92))
867818	26383589	The second locus concerns chromosome 9q22 and the most significant associated marker, rs11789015, is located in intron 3 of the gene homeobox protein BarH-like 1b (BARX1), which encodes a transcription factor important in esophageal differentiation.	('rs11789015', 'Var', (86, 96))	('BARX1', 'Gene', '56033', (164, 169))	('BARX1', 'Gene', (164, 169))	('rs11789015', 'Mutation', 'rs11789015', (86, 96))
867823	26383589	In total, they identified three additional association signals (at rs1490865, rs3111601, and rs2178146) pointing to a complex genetic risk architecture at 16q24.	('rs2178146', 'Mutation', 'rs2178146', (93, 102))	('rs2178146', 'Var', (93, 102))	('rs3111601', 'Mutation', 'rs3111601', (78, 87))	('rs3111601', 'Var', (78, 87))	('rs1490865', 'Mutation', 'rs1490865', (67, 76))
867824	26383589	The association of the originally reported risk conferring SNP, rs9936833, was thereby explained by all four SNP markers that showed association in the stepwise conditional analysis.	('rs9936833', 'Mutation', 'rs9936833', (64, 73))	('association', 'Interaction', (133, 144))	('rs9936833', 'Var', (64, 73))
867830	26383589	The most significant EAC association in our sample was found for rs2687201 followed by rs9837992 (P1-d.f.	('rs9837992', 'Mutation', 'rs9837992', (87, 96))	('rs2687201', 'Mutation', 'rs2687201', (65, 74))	('EAC', 'Phenotype', 'HP:0011459', (21, 24))	('rs2687201', 'Var', (65, 74))	('rs9837992', 'Var', (87, 96))	('EAC', 'Disease', (21, 24))
867833	26383589	SNP rs11789015 is located in intron 3 of BARX1 on chromosome 9q22 and was genome-wide significantly associated with the BEACON sample.	('rs11789015', 'Mutation', 'rs11789015', (4, 14))	('BARX1', 'Gene', (41, 46))	('associated', 'Reg', (100, 110))	('BARX1', 'Gene', '56033', (41, 46))	('EAC', 'Phenotype', 'HP:0011459', (121, 124))	('SNP', 'Var', (0, 3))
867834	26383589	In addition, rs9936833, which was genome-wide significantly associated with the Barrett's esophagus GWAS and is located near FOXF1 on chromosome 16q24, was EAC associated (P1-d.f.	('rs9936833', 'Var', (13, 22))	('FOXF1', 'Gene', (125, 130))	('esophagus GWAS', 'Disease', (90, 104))	('rs9936833', 'Mutation', 'rs9936833', (13, 22))	('FOXF1', 'Gene', '2294', (125, 130))	('EAC', 'Phenotype', 'HP:0011459', (156, 159))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (80, 99))	('associated', 'Reg', (60, 70))
867836	26383589	In addition, rs4800353 near the gene GATA-binding protein 6 (GATA6) was EAC associated with our sample (P1-d.f.	('GATA-binding protein 6', 'Gene', '2627', (37, 59))	('GATA6', 'Gene', '2627', (61, 66))	('GATA6', 'Gene', (61, 66))	('GATA-binding protein 6', 'Gene', (37, 59))	('associated', 'Reg', (76, 86))	('EAC', 'Phenotype', 'HP:0011459', (72, 75))	('rs4800353', 'Var', (13, 22))	('rs4800353', 'Mutation', 'rs4800353', (13, 22))
867840	26383589	Of all 88 included variants, we found the most significantly EAC-associated SNPs at FOXP1, which were also genome-wide significantly associated with EAC/Barrett's esophagus in the BEACON study.	('FOXP1', 'Gene', (84, 89))	('EAC', 'Phenotype', 'HP:0011459', (61, 64))	("EAC/Barrett's esophagus", 'Disease', (149, 172))	('EAC-associated', 'Disease', (61, 75))	('EAC', 'Phenotype', 'HP:0011459', (181, 184))	('EAC', 'Phenotype', 'HP:0011459', (149, 152))	('FOXP1', 'Gene', '27086', (84, 89))	('SNPs', 'Var', (76, 80))	('variants', 'Var', (19, 27))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (153, 172))	('associated', 'Reg', (133, 143))
867841	26383589	Although our findings do not withstand a Bonferroni correction, they confirm that genetic variability at FOXP1 confers risk to EAC.	('risk', 'Reg', (119, 123))	('EAC', 'Phenotype', 'HP:0011459', (127, 130))	('FOXP1', 'Gene', (105, 110))	('genetic variability', 'Var', (82, 101))	('EAC', 'Disease', (127, 130))	('FOXP1', 'Gene', '27086', (105, 110))
867842	26383589	When one-sided tested, variants at BARX1 and FOXF1 showed disease association.	('BARX1', 'Gene', (35, 40))	('FOXF1', 'Gene', '2294', (45, 50))	('BARX1', 'Gene', '56033', (35, 40))	('disease association', 'Reg', (58, 77))	('variants', 'Var', (23, 31))	('FOXF1', 'Gene', (45, 50))
867843	26383589	However, given that rs3950627, which was the strongest associated SNP at FOXF1 in the BEACON study showed no significant EAC association in our sample (P = 0.121, Table S1), we did not perform a conditional analysis at this locus, as has been done by BEACON.	('rs3950627', 'Var', (20, 29))	('FOXF1', 'Gene', (73, 78))	('FOXF1', 'Gene', '2294', (73, 78))	('EAC', 'Phenotype', 'HP:0011459', (87, 90))	('rs3950627', 'Mutation', 'rs3950627', (20, 29))	('EAC', 'Phenotype', 'HP:0011459', (121, 124))	('EAC', 'Phenotype', 'HP:0011459', (252, 255))
867844	26383589	Furthermore, of all previously reported risk loci we do not find association evidence for CRTC1 (P = 0.349 for rs10419226, Table S1), which was the strongest disease associated variant in the BEACON study.	('EAC', 'Phenotype', 'HP:0011459', (193, 196))	('rs10419226', 'Var', (111, 121))	('CRTC1', 'Gene', (90, 95))	('rs10419226', 'Mutation', 'rs10419226', (111, 121))	('CRTC1', 'Gene', '23373', (90, 95))
867850	26383589	In addition, rs4800353 near GATA6 showed disease association in the BEACON study with P = 2.69 x 10-7 .	('EAC', 'Phenotype', 'HP:0011459', (69, 72))	('GATA6', 'Gene', (28, 33))	('GATA6', 'Gene', '2627', (28, 33))	('rs4800353', 'Var', (13, 22))	('rs4800353', 'Mutation', 'rs4800353', (13, 22))	('disease association', 'Reg', (41, 60))
867854	26383589	In conclusion, we provide supportive evidence that genetic variants at FOXP1, BARX1, and FOXF1 confer risk for the development of EAC.	('FOXF1', 'Gene', '2294', (89, 94))	('risk', 'Reg', (102, 106))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('FOXP1', 'Gene', (71, 76))	('genetic variants', 'Var', (51, 67))	('FOXF1', 'Gene', (89, 94))	('EAC', 'Disease', (130, 133))	('BARX1', 'Gene', (78, 83))	('FOXP1', 'Gene', '27086', (71, 76))	('BARX1', 'Gene', '56033', (78, 83))
867855	26383589	In addition, we found association with variants near XRCC2 and GATA6 that were strongly disease associated with the BEACON GWAS, although this was not genome-wide significant.	('XRCC2', 'Gene', (53, 58))	('GATA6', 'Gene', (63, 68))	('GATA6', 'Gene', '2627', (63, 68))	('association', 'Interaction', (22, 33))	('EAC', 'Phenotype', 'HP:0011459', (117, 120))	('variants', 'Var', (39, 47))	('XRCC2', 'Gene', '7516', (53, 58))
867882	25957861	It is believed that in predisposed individuals, GERD can lead to erosive esophagitis, and after an aberrant healing process a metaplastic, specialized intestinal epithelium (Barrett's esophagus).	('esophagitis', 'Disease', (73, 84))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (174, 193))	('lead to', 'Reg', (57, 64))	('esophagitis', 'Phenotype', 'HP:0100633', (73, 84))	('esophagitis', 'Disease', 'MESH:D004941', (73, 84))	('GERD', 'Var', (48, 52))
867888	25957861	Alcohol use is also a strong risk factor for esophageal squamous cell carcinoma, but has not proven to be a consistent risk factor for EAC.	('risk', 'Reg', (29, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (45, 79))	('Alcohol use', 'Var', (0, 11))	('Alcohol use', 'Phenotype', 'HP:0030955', (0, 11))	('esophageal squamous cell carcinoma', 'Disease', (45, 79))	('EAC', 'Phenotype', 'HP:0011459', (135, 138))
867901	25957861	A polymorphism in the gene encoding IGF1 is associated with Barrett's esophagus, and a polymorphism in the gene encoding the IGF1 receptor modifies the effect of obesity on the risk for Barrett's esophagus and EAC.	('obesity', 'Disease', (162, 169))	('associated', 'Reg', (44, 54))	("Barrett's esophagus", 'Disease', (186, 205))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (186, 205))	("Barrett's esophagus", 'Disease', (60, 79))	('modifies', 'Reg', (139, 147))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (60, 79))	('IGF1', 'Gene', '3479', (125, 129))	('obesity', 'Disease', 'MESH:D009765', (162, 169))	('EAC', 'Phenotype', 'HP:0011459', (210, 213))	('obesity', 'Phenotype', 'HP:0001513', (162, 169))	('IGF1', 'Gene', '3479', (36, 40))	('polymorphism', 'Var', (2, 14))	('IGF1', 'Gene', (125, 129))	('EAC', 'Disease', (210, 213))	('polymorphism in', 'Var', (87, 102))	('IGF1', 'Gene', (36, 40))
867902	25957861	A polymorphism in the gene encoding IGF2 is also associated with EAC, perhaps more so among smokers.	('associated', 'Reg', (49, 59))	('IGF2', 'Gene', (36, 40))	('EAC', 'Phenotype', 'HP:0011459', (65, 68))	('polymorphism', 'Var', (2, 14))	('EAC', 'Disease', (65, 68))	('IGF2', 'Gene', '3481', (36, 40))
867976	25957861	EUS may be particularly inaccurate if strictures prevent passage of the echoendoscope to the full extent of the tumor.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('strictures', 'Var', (38, 48))	('passage', 'MPA', (57, 64))	('tumor', 'Disease', (112, 117))
867987	25957861	Bronchoscopy should be considered to assess invasion and, in the event of fistula formation, stent the bronchus.	('fistula', 'Disease', (74, 81))	('stent the bronchus', 'Phenotype', 'HP:0001642', (93, 111))	('stent', 'Var', (93, 98))	('fistula', 'Disease', 'MESH:D005402', (74, 81))
868042	25957861	Palliative tumor debulking of more advanced lesions, via resection, thermal therapies, cryotherapy, and/or photodynamic therapy, have all been described, and can improve quality of life, and in some instances, forestall stent placement.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('quality of life', 'CPA', (170, 185))	('cryotherapy', 'Var', (87, 98))	('men', 'Species', '9606', (231, 234))	('Palliative tumor', 'Disease', (0, 16))	('improve', 'PosReg', (162, 169))	('Palliative tumor', 'Disease', 'MESH:D009369', (0, 16))	('thermal therapies', 'Var', (68, 85))
868077	22797822	Non-Hispanic black (NHB) had significantly higher overall GI-cancer related mortality compared to non-Hispanic white (NHW, adjusted hazard ratio, aHR: 2.31, 95 % CI 1.57-3.38, p < 0.001).	('aHR', 'Gene', (146, 149))	('aHR', 'Gene', '196', (146, 149))	('GI-cancer', 'Disease', (58, 67))	('higher', 'PosReg', (43, 49))	('Non-Hispanic black', 'Var', (0, 18))	('GI-cancer', 'Disease', 'MESH:D009369', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('GI-cancer', 'Phenotype', 'HP:0007378', (58, 67))
868078	22797822	Subgroup analyses by sex demonstrated higher mortality from gastric, colorectal and primary liver cancer related mortality in NHB men compared to NHW men.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('liver cancer', 'Phenotype', 'HP:0002896', (92, 104))	('NHB', 'Var', (126, 129))	('higher', 'PosReg', (38, 44))	('men', 'Species', '9606', (150, 153))	('gastric', 'Disease', (60, 67))	('colorectal and primary liver cancer', 'Disease', 'MESH:D015179', (69, 104))	('men', 'Species', '9606', (130, 133))
868079	22797822	Esophageal and pancreatic cancer mortalities were higher in NHB women compared to NHW women.	('Esophageal', 'Disease', (0, 10))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (15, 32))	('higher', 'PosReg', (50, 56))	('NHB', 'Var', (60, 63))	('women', 'Species', '9606', (64, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (15, 32))	('pancreatic cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('women', 'Species', '9606', (86, 91))
868080	22797822	Overall GI cancer-related mortality is significantly higher among NHB compared to NHW in the US population.	('higher', 'PosReg', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('GI cancer', 'Disease', 'MESH:D009369', (8, 17))	('GI cancer', 'Phenotype', 'HP:0007378', (8, 17))	('NHB', 'Var', (66, 69))	('GI cancer', 'Disease', (8, 17))
868104	22797822	The overall GI cancers-related mortality (UCODE_113, 21-25) was calculated using combined mortality from malignant neoplasm of esophagus (ICD-10 C15), stomach (ICD-10 C16), colon, rectum and anus (ICD-10 C18-C21), liver (ICD-10 C22) and pancreas (ICD-10 C25).	('stomach', 'Disease', (151, 158))	('GI cancers', 'Disease', (12, 22))	('ICD-10 C18-C21', 'Var', (197, 211))	('GI cancer', 'Phenotype', 'HP:0007378', (12, 21))	('malignant neoplasm of esophagus', 'Disease', 'MESH:D004938', (105, 136))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('GI cancers', 'Disease', 'MESH:D009369', (12, 22))	('neoplasm of esophagus', 'Phenotype', 'HP:0100751', (115, 136))	('pancreas', 'Disease', (237, 245))	('neoplasm', 'Phenotype', 'HP:0002664', (115, 123))	('ICD-10 C22', 'Var', (221, 231))	('pancreas', 'Disease', 'MESH:D010190', (237, 245))	('malignant neoplasm of esophagus', 'Disease', (105, 136))	('colon', 'Disease', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
868121	22797822	Independent risk factors for mortality included non-Hispanic black (aHR 6.98, 95 % CI 1.70-28.63), smoking (aHR 4.16, 95 % CI 1.76-9.80), and excessive alcohol use (aHR 8.55, 95 % CI 2.23-32.75).	('aHR', 'Gene', '196', (165, 168))	('aHR', 'Gene', '196', (108, 111))	('non-Hispanic', 'Var', (48, 60))	('aHR', 'Gene', (68, 71))	('alcohol use', 'Phenotype', 'HP:0030955', (152, 163))	('aHR', 'Gene', (165, 168))	('aHR', 'Gene', '196', (68, 71))	('aHR', 'Gene', (108, 111))	('alcohol', 'Chemical', 'MESH:D000438', (152, 159))
868122	22797822	Stratified analysis by sex did not show any racial difference in mortality in males; however, non-His-panic blacks had significantly higher risk of esophageal cancer-related mortality than that of non-Hispanic white females (aHR 7.05, 95 % CI 1.59-31.29) (Tables 3, 4 and 5).	('aHR', 'Gene', (225, 228))	('non-His-panic blacks', 'Var', (94, 114))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('esophageal cancer', 'Disease', (148, 165))	('aHR', 'Gene', '196', (225, 228))	('higher', 'PosReg', (133, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('-panic', 'Phenotype', 'HP:0000739', (101, 107))
868127	22797822	However, analysis of the male population showed non-Hispanic black ethnicity as an independent risk factor for primary liver cancer-related mortality (aHR 5.17, 95 % CI 1.71-15.63; Tables 4 and 5).	('liver cancer', 'Disease', (119, 131))	('non-Hispanic black ethnicity', 'Var', (48, 76))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('liver cancer', 'Phenotype', 'HP:0002896', (119, 131))	('aHR', 'Gene', (151, 154))	('aHR', 'Gene', '196', (151, 154))	('liver cancer', 'Disease', 'MESH:D006528', (119, 131))
868142	22797822	More importantly, significant epigenetic differences in between racial groups may account for the differences seen in tumor initiation, progression, aggressiveness, and outcome of these cancers.	('aggressiveness', 'Phenotype', 'HP:0000718', (149, 163))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('tumor initiation', 'Disease', 'MESH:D009369', (118, 134))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('account', 'Reg', (82, 89))	('aggressiveness', 'Disease', 'MESH:D001523', (149, 163))	('tumor initiation', 'Disease', (118, 134))	('epigenetic differences', 'Var', (30, 52))	('aggressiveness', 'Disease', (149, 163))
868344	31031851	Although the treatment design was inconsistent, an increase in the median OS in patients treated with nimotuzumab (11.9 vs 6.5 months) and an increase of the 1-year survival rate (54.0% vs 21.9%) were observed.	('increase', 'PosReg', (51, 59))	('nimotuzumab', 'Var', (102, 113))	('increase', 'PosReg', (142, 150))	('patients', 'Species', '9606', (80, 88))	('nimotuzumab', 'Chemical', 'MESH:C501466', (102, 113))	('OS', 'Chemical', '-', (74, 76))
868394	30631751	Indeed, E2F modulates the expression of a broad variety of genes implied in cell cycle S1 phase and mitosis.	('expression', 'MPA', (26, 36))	('mitosis', 'Disease', 'None', (100, 107))	('E2F', 'Var', (8, 11))	('modulates', 'Reg', (12, 21))	('mitosis', 'Disease', (100, 107))
868401	30631751	In solid tumors, an hyperactivation of the CCND-CDK4/6 activity can occur through: (1) increased activity of upstream mitogenic signaling pathways; (2) aberrant activity of the components of the pathway or their regulators.	('increased', 'PosReg', (87, 96))	('hyperactivation', 'PosReg', (20, 35))	('activity', 'MPA', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('activity', 'MPA', (97, 105))	('solid tumors', 'Disease', (3, 15))	('upstream mitogenic signaling pathways', 'Pathway', (109, 146))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('aberrant', 'Var', (152, 160))	('CCND-CDK4/6', 'Gene', (43, 54))	('solid tumors', 'Disease', 'MESH:D009369', (3, 15))
868402	30631751	This latter may depend on various molecular mechanisms, i.e., point mutations, translocations or amplification of CDK4/6, amplification of D-type cyclins, deletions that cause the loss of p16INK4A or pRb expression, epigenetic modifications and downregulation of microRNAs (miRNAs) that target CDK4/6.	('CDK4/6', 'Gene', (114, 120))	('epigenetic modifications', 'Var', (216, 240))	('pRb', 'Gene', (200, 203))	('cyclin', 'Gene', (146, 152))	('loss', 'NegReg', (180, 184))	('p16INK4A', 'Gene', (188, 196))	('point mutations', 'Var', (62, 77))	('pRb', 'Gene', '5925', (200, 203))	('deletions', 'Var', (155, 164))	('p16INK4A', 'Gene', '1029', (188, 196))	('expression', 'MPA', (204, 214))	('downregulation', 'NegReg', (245, 259))	('cyclin', 'Gene', '5111', (146, 152))
868403	30631751	Alterations of the expression of CCND-CDK4/6-INK4-Rb pathway components or of their direct regulators result in cell cycle progression and cell proliferation and represent a key mechanism of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('INK4', 'Gene', (45, 49))	('INK4', 'Gene', '1029', (45, 49))	('Alterations', 'Var', (0, 11))	('result in', 'Reg', (102, 111))	('cell proliferation', 'CPA', (139, 157))	('cell cycle progression', 'CPA', (112, 134))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('rat', 'Species', '10116', (151, 154))	('rat', 'Species', '10116', (4, 7))
868404	30631751	The solid tumors for which the CCND-CDK4/6-INK4-Rb pathway is more frequently deregulated through direct genetic, epigenetic or transcriptional modifications are breast, head and neck, lung, pancreatic, ovarian and bladder cancer, melanoma, endometrial carcinoma, liposarcoma, neuroblastoma, and malignant rabdoid tumors.	('liposarcoma', 'Disease', 'MESH:D008080', (264, 275))	('INK4', 'Gene', (43, 47))	('lung', 'Disease', (185, 189))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('malignant rabdoid tumors', 'Disease', (296, 320))	('epigenetic', 'Var', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('solid tumors', 'Disease', (4, 16))	('endometrial carcinoma', 'Disease', (241, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('neuroblastoma', 'Disease', (277, 290))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('liposarcoma', 'Disease', (264, 275))	('neuroblastoma', 'Phenotype', 'HP:0003006', (277, 290))	('bladder cancer', 'Phenotype', 'HP:0009725', (215, 229))	('malignant rabdoid tumors', 'Disease', 'MESH:D018198', (296, 320))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('neuroblastoma', 'Disease', 'MESH:D009447', (277, 290))	('sarcoma', 'Phenotype', 'HP:0100242', (268, 275))	('breast', 'Disease', (162, 168))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (241, 262))	('solid tumors', 'Disease', 'MESH:D009369', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('INK4', 'Gene', '1029', (43, 47))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (241, 262))	('liposarcoma', 'Phenotype', 'HP:0012034', (264, 275))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('deregulated', 'Reg', (78, 89))	('pancreatic, ovarian and bladder cancer', 'Disease', 'MESH:D001749', (191, 229))
868425	30631751	As previously reported, the CCND-CDK4/6-INK4-Rb pathway is frequently deregulated through direct genetic, epigenetic or transcriptional modifications in a broad variety of neoplasms.	('deregulated', 'Reg', (70, 81))	('neoplasms', 'Disease', 'MESH:D009369', (172, 181))	('neoplasms', 'Disease', (172, 181))	('transcriptional modifications', 'Var', (120, 149))	('neoplasms', 'Phenotype', 'HP:0002664', (172, 181))	('epigenetic', 'Var', (106, 116))	('INK4', 'Gene', '1029', (40, 44))	('INK4', 'Gene', (40, 44))
868438	30631751	Another study demonstrated that palbociclib may inhibit cellular growth and induce senescence in liposarcoma cell lines and mice xenografts and in sarcoma cell lines.	('palbociclib', 'Var', (32, 43))	('senescence', 'CPA', (83, 93))	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('liposarcoma cell lines', 'Disease', 'MESH:D008080', (97, 119))	('sarcoma', 'Disease', (147, 154))	('liposarcoma', 'Phenotype', 'HP:0012034', (97, 108))	('sarcoma', 'Disease', (101, 108))	('liposarcoma cell lines', 'Disease', (97, 119))	('mice', 'Species', '10090', (124, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('induce', 'Reg', (76, 82))	('rat', 'Species', '10116', (21, 24))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('palbociclib', 'Chemical', 'MESH:C500026', (32, 43))	('cellular growth', 'CPA', (56, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('inhibit', 'NegReg', (48, 55))
868445	30631751	In preclinical models, ribociclib also showed some activity in melanomas with activating mutations of BRAF or NRAS.	('activity', 'MPA', (51, 59))	('activating', 'PosReg', (78, 88))	('NRAS', 'Gene', '4893', (110, 114))	('BRAF', 'Gene', '673', (102, 106))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('BRAF', 'Gene', (102, 106))	('melanomas', 'Disease', (63, 72))	('mutations', 'Var', (89, 98))	('NRAS', 'Gene', (110, 114))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))
868450	30631751	Furthermore, abemaciclib yielded tumor growth regression in a vemurafenib-resistant model, and induced apoptotic cell death in a concentration-dependent manner, suggesting that this drug might be a viable therapeutic option to overcome MAPK-mediated resistance to B-RAF inhibitors in B-RAF V600E melanoma.	('B-RAF', 'Gene', '673', (284, 289))	('melanoma', 'Disease', (296, 304))	('abemaciclib', 'Chemical', 'MESH:C000590451', (13, 24))	('melanoma', 'Disease', 'MESH:D008545', (296, 304))	('vemurafenib', 'Chemical', 'MESH:D000077484', (62, 73))	('regression', 'NegReg', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('V600E', 'Var', (290, 295))	('B-RAF', 'Gene', (284, 289))	('B-RAF', 'Gene', '673', (264, 269))	('V600E', 'Mutation', 'rs113488022', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('rat', 'Species', '10116', (136, 139))	('tumor', 'Disease', (33, 38))	('B-RAF', 'Gene', (264, 269))	('apoptotic cell death', 'CPA', (103, 123))	('melanoma', 'Phenotype', 'HP:0002861', (296, 304))
868464	30631751	The most frequent G3/4 ADRs were neutropenia (50%), leukopenia (47%), thrombocytopenia (30%), lymphopenia (27%), and anemia (17%).	('neutropenia', 'Phenotype', 'HP:0001875', (33, 44))	('leukopenia', 'Disease', (52, 62))	('neutropenia', 'Disease', 'MESH:D009503', (33, 44))	('thrombocytopenia', 'Disease', 'MESH:D013921', (70, 86))	('lymphopenia', 'Phenotype', 'HP:0001888', (94, 105))	('anemia', 'Phenotype', 'HP:0001903', (117, 123))	('leukopenia', 'Disease', 'MESH:D007970', (52, 62))	('lymphopenia', 'Disease', 'MESH:D008231', (94, 105))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (70, 86))	('neutropenia', 'Disease', (33, 44))	('thrombocytopenia', 'Disease', (70, 86))	('G3/4', 'Var', (18, 22))	('leukopenia', 'Phenotype', 'HP:0001882', (52, 62))	('anemia', 'Disease', (117, 123))	('lymphopenia', 'Disease', (94, 105))	('anemia', 'Disease', 'MESH:D000740', (117, 123))
868467	30631751	G3/4 ADRs were primarily hematologic and included neutropenia (33%), without neutropenic fever.	('neutropenic fever', 'Disease', (77, 94))	('G3/4', 'Var', (0, 4))	('neutropenia', 'Disease', (50, 61))	('included', 'Reg', (41, 49))	('fever', 'Phenotype', 'HP:0001945', (89, 94))	('ADRs', 'Disease', (5, 9))	('neutropenic fever', 'Disease', 'MESH:D005334', (77, 94))	('neutropenia', 'Disease', 'MESH:D009503', (50, 61))	('neutropenia', 'Phenotype', 'HP:0001875', (50, 61))
868472	30631751	Single agent palbociclib was also not effective in advanced gastric and esophageal tumors, even if the patients had been selected for Rb expression and despite 19/38 tumors showed amplification of CCND1.	('amplification', 'Var', (180, 193))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('esophageal tumors', 'Phenotype', 'HP:0100751', (72, 89))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('CCND1', 'Gene', (197, 202))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal tumors', 'Disease', 'MESH:D004938', (72, 89))	('patients', 'Species', '9606', (103, 111))	('CCND1', 'Gene', '595', (197, 202))	('gastric', 'Disease', 'MESH:D013274', (60, 67))	('gastric', 'Disease', (60, 67))	('tumors', 'Disease', (166, 172))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('esophageal tumors', 'Disease', (72, 89))	('palbociclib', 'Chemical', 'MESH:C500026', (13, 24))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
868492	30631751	More specifically, single agent palbociclib will be studied in the context of a sub-study that includes all patients that harbored genetic alterations involving cell-cycle genes.	('cell-cycle genes', 'Gene', (161, 177))	('genetic alterations', 'Var', (131, 150))	('rat', 'Species', '10116', (143, 146))	('palbociclib', 'Chemical', 'MESH:C500026', (32, 43))	('patients', 'Species', '9606', (108, 116))
868501	30631751	The NCT01037790 phase II clinical trial is studying activity, safety and tolerability of single agent palbociclib in preatreated refractory solid tumors, including metastatic colorectal cancer that harbors the Kras or BRAF mutation, metastatic breast cancer, advanced or metastatic esophageal and/or gastric cancer, cisplatin-refractory, unresectable germ cell tumors and any tumor type if tissue tests positive for CCND1 amplification, CDK4/6 mutation, CCND2 amplification or any other functional alteration at the G1/S checkpoint.	('advanced', 'Disease', (259, 267))	('CDK4/6', 'Gene', (437, 443))	('rat', 'Species', '10116', (502, 505))	('CCND1', 'Gene', '595', (416, 421))	('tumor', 'Disease', (376, 381))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (361, 366))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('germ cell tumors', 'Phenotype', 'HP:0100728', (351, 367))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('gastric cancer', 'Disease', (300, 314))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('CCND1', 'Gene', (416, 421))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('solid tumors', 'Disease', (140, 152))	('breast cancer', 'Disease', 'MESH:D001943', (244, 257))	('colorectal cancer', 'Disease', (175, 192))	('breast cancer', 'Disease', (244, 257))	('esophageal', 'Disease', (282, 292))	('tumors', 'Phenotype', 'HP:0002664', (361, 367))	('CCND2', 'Gene', (454, 459))	('gastric cancer', 'Disease', 'MESH:D013274', (300, 314))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('CCND2', 'Gene', '894', (454, 459))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('mutation', 'Var', (223, 231))	('tumors', 'Disease', (361, 367))	('solid tumors', 'Disease', 'MESH:D009369', (140, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('amplification', 'Var', (422, 435))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('Kras', 'Gene', '3845', (210, 214))	('esophageal', 'Disease', 'MESH:D004941', (282, 292))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('BRAF', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (218, 222))	('mutation', 'Var', (444, 452))	('gastric cancer', 'Phenotype', 'HP:0012126', (300, 314))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('unresectable germ cell', 'Phenotype', 'HP:0012862', (338, 360))	('tumors', 'Disease', 'MESH:D009369', (361, 367))	('Kras', 'Gene', (210, 214))	('tumors', 'Disease', (146, 152))	('palbociclib', 'Chemical', 'MESH:C500026', (102, 113))	('positive', 'Reg', (403, 411))
868504	30631751	Finally, a single arm phase II trial (NCT03454919) in acral melanoma bearing alterations in cell cycle pathways, including CDK4 amplification and/or CCND1 amplification and/or P16 (CDKN2A) loss, is going to start but not yet recruiting patients.	('acral melanoma', 'Disease', 'MESH:D008545', (54, 68))	('P16', 'Gene', '1029', (176, 179))	('acral melanoma', 'Phenotype', 'HP:0012060', (54, 68))	('CDK4', 'Gene', (123, 127))	('alterations', 'Reg', (77, 88))	('P16', 'Gene', (176, 179))	('CDKN2A', 'Gene', '1029', (181, 187))	('amplification', 'Var', (155, 168))	('patients', 'Species', '9606', (236, 244))	('CDK4', 'Gene', '1019', (123, 127))	('acral melanoma', 'Disease', (54, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('CCND1', 'Gene', '595', (149, 154))	('cell cycle pathways', 'Pathway', (92, 111))	('amplification', 'Var', (128, 141))	('CCND1', 'Gene', (149, 154))	('rat', 'Species', '10116', (81, 84))	('CDKN2A', 'Gene', (181, 187))	('loss', 'NegReg', (189, 193))
868531	30631751	Among those 49 patients, 19 were affected by KRAS wildtype tumors, 26 by KRAS mutant tumors and 4 with unknown KRAS status.	('KRAS', 'Gene', '3845', (45, 49))	('patients', 'Species', '9606', (15, 23))	('KRAS', 'Gene', (73, 77))	('affected', 'Reg', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('KRAS', 'Gene', (111, 115))	('KRAS', 'Gene', '3845', (73, 77))	('KRAS', 'Gene', '3845', (111, 115))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('mutant', 'Var', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('KRAS', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (85, 91))
868548	30631751	Tumors must be pRb wild type and carry inactivation of CDKN2A/B or C in the tumor by homozygous deletion.	('CDKN2A/B', 'Gene', (55, 63))	('pRb', 'Gene', '5925', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('pRb', 'Gene', (15, 18))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('inactivation', 'Var', (39, 51))	('CDKN2A/B', 'Gene', '1029;1030', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
868559	30631751	Another phase II trial in (NCT03356223) patients with locally advanced/metastatic head and neck cancer is currently evaluating abemaciclib monotherapy after failure of platinum and cetuximab or anti-EGFR-based therapy, but only in tumors harboring a homozygous deletion of CDKN2A, and/or amplification of CCND1 and/or of CDK6.	('CDKN2A', 'Gene', (273, 279))	('CDK6', 'Gene', (321, 325))	('CCND1', 'Gene', (305, 310))	('deletion', 'Var', (261, 269))	('tumors', 'Disease', (231, 237))	('cetuximab', 'Chemical', 'MESH:D000068818', (181, 190))	('amplification', 'Var', (288, 301))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CDKN2A', 'Gene', '1029', (273, 279))	('neck cancer', 'Disease', 'MESH:D006258', (91, 102))	('neck cancer', 'Disease', (91, 102))	('head and neck cancer', 'Phenotype', 'HP:0012288', (82, 102))	('platinum', 'Chemical', 'MESH:D010984', (168, 176))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('abemaciclib', 'Chemical', 'MESH:C000590451', (127, 138))	('CCND1', 'Gene', '595', (305, 310))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('patients', 'Species', '9606', (40, 48))	('CDK6', 'Gene', '1021', (321, 325))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))
868561	30631751	Finally, the NCT03310879 phase II study is testing abemaciclib in patients with solid tumors of non-breast origin harboring genetic alterations in genes encoding D-type Cyclins or amplification of CDK4/6 without therapeutic alternative.	('amplification', 'Var', (180, 193))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Cyclin', 'Gene', (169, 175))	('genetic alterations', 'Var', (124, 143))	('solid tumors', 'Disease', 'MESH:D009369', (80, 92))	('CDK4/6', 'Gene', (197, 203))	('abemaciclib', 'Chemical', 'MESH:C000590451', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('rat', 'Species', '10116', (136, 139))	('Cyclin', 'Gene', '5111', (169, 175))	('solid tumors', 'Disease', (80, 92))	('patients', 'Species', '9606', (66, 74))
868569	30631751	Laboratory evidences suggest that markers of intrinsic resistance might be the pRb loss and subsequent increase in p16INK4A, deregulation of cyclin E expression, E2F family members amplification and TP53 mutations.	('deregulation', 'MPA', (125, 137))	('increase', 'PosReg', (103, 111))	('E2F family', 'Gene', (162, 172))	('TP53', 'Gene', (199, 203))	('cyclin', 'Gene', (141, 147))	('mutations', 'Var', (204, 213))	('p16INK4A', 'Gene', '1029', (115, 123))	('p16INK4A', 'Gene', (115, 123))	('cyclin', 'Gene', '5111', (141, 147))	('amplification', 'Var', (181, 194))	('rat', 'Species', '10116', (4, 7))	('pRb', 'Gene', '5925', (79, 82))	('loss', 'NegReg', (83, 87))	('TP53', 'Gene', '7157', (199, 203))	('pRb', 'Gene', (79, 82))
868570	30631751	showed for the first time in human patients that acquired mutations leading to functional loss of pRb encoding gene (RB1) might emerge under treatment with palbociclib and ribociclib, maybe due to selective pressure from the CDK4/6i and might potentially confer therapeutic resistance.	('mutations', 'Var', (58, 67))	('loss', 'NegReg', (90, 94))	('RB1', 'Gene', (117, 120))	('pRb', 'Gene', (98, 101))	('palbociclib', 'Chemical', 'MESH:C500026', (156, 167))	('RB1', 'Gene', '5925', (117, 120))	('pRb', 'Gene', '5925', (98, 101))	('human', 'Species', '9606', (29, 34))	('patients', 'Species', '9606', (35, 43))
868588	30279559	Despite of that, ionizing radiation could induce mutations in oncogenes such as Minor Allele Frequency (MAF), tumor suppressor genes such as p53, or DNA repair genes such as Asynchronous Transfer Mode (ATM).	('p53', 'Gene', (141, 144))	('mutations', 'Var', (49, 58))	('induce', 'Reg', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('p53', 'Gene', '301300', (141, 144))	('oncogenes', 'Gene', (62, 71))	('Minor', 'MPA', (80, 85))
868589	30279559	Ionizing radiation could also lead to the mutation of genes that are involved in intercellular interaction and inflammation, and enhance the migration and invasion of esophageal epithelial cells via stromal-derived hepatocyte growth factors.	('lead to', 'Reg', (30, 37))	('migration', 'CPA', (141, 150))	('inflammation', 'Disease', 'MESH:D007249', (111, 123))	('inflammation', 'Disease', (111, 123))	('genes', 'Gene', (54, 59))	('Ionizing radiation', 'Disease', 'MESH:D004194', (0, 18))	('Ionizing radiation', 'Disease', (0, 18))	('mutation', 'Var', (42, 50))	('invasion', 'CPA', (155, 163))	('rat', 'Species', '10116', (144, 147))	('enhance', 'PosReg', (129, 136))
868624	30279559	The differentially expressed miRNAs were involved in many cellular processes, such as cell proliferation, cell migration, and lipid metabolism.	('miRNAs', 'Var', (29, 35))	('lipid', 'Chemical', 'MESH:D008055', (126, 131))	('rat', 'Species', '10116', (114, 117))	('involved', 'Reg', (41, 49))	('rat', 'Species', '10116', (98, 101))	('cell proliferation', 'CPA', (86, 104))	('differentially', 'Reg', (4, 18))	('cell migration', 'CPA', (106, 120))
868629	30279559	In particular, the steroid metabolism gene CYP2D polymorphism is associated with clinical late toxicity in patients treated with conformal radiotherapy.	('CYP2D', 'Gene', (43, 48))	('polymorphism', 'Var', (49, 61))	('associated with', 'Reg', (65, 80))	('CYP2D', 'Gene', '1564', (43, 48))	('steroid', 'Chemical', 'MESH:D013256', (19, 26))	('patients', 'Species', '9606', (107, 115))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('toxicity', 'Disease', (95, 103))
868649	29516570	Zhang et al12 found that esophageal squamous cell carcinoma KYSE450 cells transfected with antisense SLP-2 show decreased cell growth, proliferation, tumorigenicity, and cell adhesion.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (25, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('KYSE450', 'CellLine', 'CVCL:1353', (60, 67))	('SLP-2', 'Gene', (101, 106))	('antisense', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cell adhesion', 'CPA', (170, 183))	('esophageal squamous cell carcinoma', 'Disease', (25, 59))	('proliferation', 'CPA', (135, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SLP-2', 'Gene', '30968', (101, 106))	('cell growth', 'CPA', (122, 133))	('decreased', 'NegReg', (112, 121))	('tumor', 'Disease', (150, 155))
868668	29516570	Transfected HELA or SIHA cells treated with IC50 of cisplatin for 6 hours were collected and washed twice with ice-cold PBS and resuspended in 1x binding buffer before incubation with annexin V-FITC according to the manufacturer's protocol (Bestbio, Shanghai, China).	('SIHA', 'Disease', 'None', (20, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('annexin V', 'Gene', (184, 193))	('annexin V', 'Gene', '308', (184, 193))	('HELA', 'CellLine', 'CVCL:0030', (12, 16))	('IC50', 'Var', (44, 48))	('SIHA', 'Disease', (20, 24))
868671	29516570	Transfected or infected HELA or SIHA cells treated with IC50 of cisplatin for 6 hours were stained with Rhod-2 dye according to the manufacturer's protocol (GENMED, USA), and fluorescent enzyme was used to determine the relative fluorescence units.	('HELA', 'CellLine', 'CVCL:0030', (24, 28))	('SIHA', 'Disease', (32, 36))	('IC50', 'Var', (56, 60))	('SIHA', 'Disease', 'None', (32, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))
868674	29516570	Transfected HELA or SIHA cells treated with IC50 of cisplatin for 6 hours were incubated with JC-1 staining liquid for 20 minutes at 37 C, washed three times with JC-1 staining buffer and examined under flow cytometry (Becton Dickinson).	('SIHA', 'Disease', 'None', (20, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('IC50', 'Var', (44, 48))	('HELA', 'CellLine', 'CVCL:0030', (12, 16))	('SIHA', 'Disease', (20, 24))	('JC-1', 'Chemical', 'MESH:C068624', (163, 167))	('JC-1', 'Chemical', 'MESH:C068624', (94, 98))
868679	29516570	Transfected or infected HELA or SIHA cells treated with IC50 of cisplatin for 8 hours were lysed for 30 minutes with lysis buffer (Bestbio).	('HELA', 'CellLine', 'CVCL:0030', (24, 28))	('SIHA', 'Disease', (32, 36))	('IC50', 'Var', (56, 60))	('SIHA', 'Disease', 'None', (32, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))
868680	29516570	Transfected or infected HELA or SIHA cells treated with IC50 of cisplatin or cells treated with different concentrations of cisplatin for 24 hours were lysed for 30 minutes with lysis buffer (KeyGEN BioTECH) to obtain total protein.	('HELA', 'CellLine', 'CVCL:0030', (24, 28))	('SIHA', 'Disease', (32, 36))	('IC50', 'Var', (56, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('SIHA', 'Disease', 'None', (32, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))
868696	29516570	We found that annexin V+/PI- cells (early apoptosis) were more frequently detected in siSLP-2 transfected cells than in control cells (Figure 3B,C,b,c).	('SLP-2', 'Gene', '30968', (88, 93))	('annexin V', 'Gene', (14, 23))	('transfected', 'Var', (94, 105))	('SLP-2', 'Gene', (88, 93))	('annexin V', 'Gene', '308', (14, 23))
868709	29516570	As shown in Figure 6(A,B,a,b), MEK1/2 inhibition by U0126 decreased the levels of p-MEK1/2 and p-ERK1/2.	('levels', 'MPA', (72, 78))	('U0126', 'Chemical', 'MESH:C113580', (52, 57))	('decreased', 'NegReg', (58, 67))	('MEK1/2', 'Enzyme', (31, 37))	('inhibition', 'NegReg', (38, 48))	('U0126', 'Var', (52, 57))	('p-ERK', 'Gene', (95, 100))	('p-ERK', 'Gene', '9451', (95, 100))
868711	29516570	We found that changes in p-MEK1/2 and p-ERK1/2 had little effect on SLP-2 levels in cisplatin-induced apoptosis (Figure 6C,D,c,d).	('SLP-2', 'Gene', (68, 73))	('p-ERK', 'Gene', (38, 43))	('SLP-2', 'Gene', '30968', (68, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('p-MEK1/2', 'Var', (25, 33))	('p-ERK', 'Gene', '9451', (38, 43))
868714	29516570	To further investigate the effect of SLP-2 on MEK/ERK signaling and the mitochondrial apoptosis pathway, increasing cisplatin concentrations (0, 0.5x IC50, 1x IC50, 1.5x IC50, and 2x IC50) were used to treat HELA and SIHA cells for 24 hours to measure protein levels of SLP-2, p-MEK1/2, p-ERK1/2, Bax, Bcl-2, caspase 9, cleaved caspase-9, caspase-3, cleaved caspase-3, PARP, and cleaved PARP.	('Bcl-2', 'Gene', '596', (302, 307))	('PARP', 'Gene', (387, 391))	('ERK', 'Gene', '5594', (50, 53))	('caspase-3', 'Gene', '836', (358, 367))	('p-ERK', 'Gene', '9451', (287, 292))	('cleaved', 'MPA', (350, 357))	('HELA', 'CellLine', 'CVCL:0030', (208, 212))	('MEK', 'Gene', (46, 49))	('p-ERK', 'Gene', (287, 292))	('caspase-9', 'Gene', '842', (328, 337))	('ERK', 'Gene', (289, 292))	('caspase-3', 'Gene', (358, 367))	('ERK', 'Gene', (50, 53))	('PARP', 'Gene', '142', (369, 373))	('caspase 9', 'Gene', (309, 318))	('SLP-2', 'Gene', (270, 275))	('PARP', 'Gene', (369, 373))	('SIHA', 'Disease', 'None', (217, 221))	('caspase-3', 'Gene', '836', (339, 348))	('MEK', 'Gene', '5609', (279, 282))	('cleaved', 'Var', (379, 386))	('caspase-9', 'Gene', (328, 337))	('SLP-2', 'Gene', (37, 42))	('caspase 9', 'Gene', '842', (309, 318))	('caspase-3', 'Gene', (339, 348))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('SIHA', 'Disease', (217, 221))	('cleaved', 'MPA', (320, 327))	('SLP-2', 'Gene', '30968', (270, 275))	('Bcl-2', 'Gene', (302, 307))	('Bax', 'Gene', (297, 300))	('ERK', 'Gene', '5594', (289, 292))	('MEK', 'Gene', (279, 282))	('Bax', 'Gene', '581', (297, 300))	('PARP', 'Gene', '142', (387, 391))	('MEK', 'Gene', '5609', (46, 49))	('SLP-2', 'Gene', '30968', (37, 42))
868717	29516570	Cisplatin at 2x IC50 concentration also increased the protein levels of p-MEK1/2 and p-ERK1/2, and decreased the ratio of Bax/Bcl-2, cleaved caspase-9/caspase-9, cleaved caspase-3/caspase-3, and cleaved PARP/PARP compared to cells incubated with 1x IC50 of cisplatin (Figure 7).	('decreased', 'NegReg', (99, 108))	('ratio', 'MPA', (113, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (257, 266))	('Bax', 'Gene', (122, 125))	('PARP', 'Gene', '142', (203, 207))	('Bcl-2', 'Gene', '596', (126, 131))	('caspase-9', 'Gene', (151, 160))	('caspase-9', 'Gene', (141, 150))	('Bax', 'Gene', '581', (122, 125))	('PARP', 'Gene', (203, 207))	('protein levels', 'MPA', (54, 68))	('caspase-3', 'Gene', '836', (180, 189))	('caspase-3', 'Gene', (180, 189))	('PARP', 'Gene', '142', (208, 212))	('caspase-3', 'Gene', '836', (170, 179))	('cleaved', 'MPA', (195, 202))	('p-ERK', 'Gene', '9451', (85, 90))	('p-ERK', 'Gene', (85, 90))	('PARP', 'Gene', (208, 212))	('caspase-3', 'Gene', (170, 179))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('caspase-9', 'Gene', '842', (151, 160))	('caspase-9', 'Gene', '842', (141, 150))	('increased', 'PosReg', (40, 49))	('Cisplatin', 'Var', (0, 9))	('Bcl-2', 'Gene', (126, 131))
868741	29190988	Survival data showed that high Ezrin expression is associated with poor prognosis in gastric, colorectal and esophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('high', 'Var', (26, 30))	('colorectal and esophageal cancers', 'Disease', 'MESH:D015179', (94, 127))	('Ezrin', 'Gene', '7430', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('Ezrin', 'Gene', (31, 36))	('expression', 'MPA', (37, 47))	('gastric', 'Disease', (85, 92))
868760	29190988	First, the pooled data of 6 studies showed that high Ezrin expression was significantly associated with tumor grade in gastric cancer (OR = 2.32, 95% CI = 1.53-3.52, P = 0.000).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('gastric cancer', 'Disease', (119, 133))	('expression', 'MPA', (59, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('Ezrin', 'Gene', '7430', (53, 58))	('associated', 'Reg', (88, 98))	('high', 'Var', (48, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('Ezrin', 'Gene', (53, 58))
868761	29190988	Second, the pooled data from 4 studies showed that high Ezrin expression was significantly associated with the TNM stage of gastric cancer (OR = 4.69, 95% CI = 1.38-15.89, P = 0.013), but the heterogeneity among these 4 studies was significant (I2 = 90.6%, P = 0.000) (Figure 3A).	('gastric cancer', 'Disease', (124, 138))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('Ezrin', 'Gene', '7430', (56, 61))	('expression', 'MPA', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('TNM', 'Gene', '10178', (111, 114))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('Ezrin', 'Gene', (56, 61))	('high', 'Var', (51, 55))	('TNM', 'Gene', (111, 114))	('associated with', 'Reg', (91, 106))
868762	29190988	Third, the pooled data from 6 studies showed that high Ezrin expression was significantly associated with lymph node metastasis in gastric cancer (OR = 3.96, 95% CI = 1.47-10.70, P = 0.007), with significant heterogeneity among studies (I2 = 85.0%, P = 0.000) (Figure 4A).	('high', 'Var', (50, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('Ezrin', 'Gene', '7430', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'MPA', (61, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('associated with', 'Reg', (90, 105))	('lymph node metastasis', 'CPA', (106, 127))	('Ezrin', 'Gene', (55, 60))	('gastric cancer', 'Disease', (131, 145))
868763	29190988	In addition, the pooled data of 3 studies showed that high Ezrin expression was not associated with distant metastasis in gastric cancer (OR = 3.41, 95% CI = 0.43-27.23, P = 0.247).	('high', 'Var', (54, 58))	('Ezrin', 'Gene', (59, 64))	('gastric cancer', 'Disease', (122, 136))	('expression', 'MPA', (65, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('Ezrin', 'Gene', '7430', (59, 64))	('distant metastasis', 'CPA', (100, 118))
868768	29190988	First, the pooled data of 5 studies showed that high Ezrin expression was significantly associated with tumor grade in colorectal cancer (OR = 3.94, 95% CI = 2.10-7.38, P = 0.000), where no significant heterogeneity among studies was observed (I2 = 0.0%, P = 0.446) (Figure 2B).	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('colorectal cancer', 'Disease', (119, 136))	('tumor', 'Disease', (104, 109))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Ezrin', 'Gene', '7430', (53, 58))	('high', 'Var', (48, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('associated with', 'Reg', (88, 103))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('Ezrin', 'Gene', (53, 58))
868769	29190988	Second, the pooled data of 4 studies showed significant association between high Ezrin expression and the TNM stage of colorectal cancer (OR = 5.66, 95% CI = 1.41-22.67, P = 0.014).	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('TNM', 'Gene', '10178', (106, 109))	('Ezrin', 'Gene', (81, 86))	('colorectal cancer', 'Disease', (119, 136))	('TNM', 'Gene', (106, 109))	('expression', 'MPA', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Ezrin', 'Gene', '7430', (81, 86))	('high', 'Var', (76, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))
868770	29190988	Third, the combined data of 3 studies showed that high Ezrin expression was significantly associated with lymph node metastasis in colorectal cancer (OR = 9.52, 95% CI = 3.93-23.02, P = 0.000), with no significant heterogeneity among studies observed (I2 = 0.0%, P = 0.902) (Figure 4B).	('Ezrin', 'Gene', '7430', (55, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('expression', 'MPA', (61, 71))	('associated with', 'Reg', (90, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('lymph', 'Disease', (106, 111))	('Ezrin', 'Gene', (55, 60))	('colorectal cancer', 'Disease', (131, 148))	('high', 'Var', (50, 54))
868771	29190988	Also, the pooled data of 3 studies showed that high Ezrin expression was significantly associated with distant metastasis in colorectal cancer (OR = 3.06, 95% CI = 1.77-5.31, P = 0.000), where no significant heterogeneity among studies was noted (I2 = 0.0%, P = 0.530) (Figure 5B).	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('Ezrin', 'Gene', '7430', (52, 57))	('expression', 'MPA', (58, 68))	('high', 'Var', (47, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('associated with', 'Reg', (87, 102))	('Ezrin', 'Gene', (52, 57))	('colorectal cancer', 'Disease', (125, 142))	('distant metastasis', 'CPA', (103, 121))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
868776	29190988	The pooled data of 4 studies showed significant association between high Ezrin expression and lymph node metastasis in esophageal cancer (OR = 2.07, 95% CI = 1.00-4.28, P = 0.050).	('lymph node metastasis', 'CPA', (94, 115))	('expression', 'MPA', (79, 89))	('high', 'Var', (68, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('Ezrin', 'Gene', '7430', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Ezrin', 'Gene', (73, 78))	('esophageal cancer', 'Disease', (119, 136))
868780	29190988	The pooled data of two studies showed that high Ezrin expression was significantly associated with overall survival (OS) for gastric cancer (HR = 1.88, 95% CI = 1.33-2.66, P = 0.000), and no significant heterogeneity was observed (I2 = 0.0%, P = 0.446) (Table 2).	('expression', 'MPA', (54, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('Ezrin', 'Gene', '7430', (48, 53))	('high', 'Var', (43, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('overall survival', 'MPA', (99, 115))	('Ezrin', 'Gene', (48, 53))	('associated with', 'Reg', (83, 98))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
868782	29190988	Significant association was also observed between high Ezrin expression and OS in esophageal cancer (HR = 1.49, 95% CI = 1.17-1.89, P = 0.001), with no significant heterogeneity noted (I2 = 0.0%, P = 0.914) (Table 2).	('high', 'Var', (50, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('Ezrin', 'Gene', '7430', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Ezrin', 'Gene', (55, 60))	('esophageal cancer', 'Disease', (82, 99))	('expression', 'MPA', (61, 71))
868797	29190988	Our results showed significant association between high Ezrin expression and multiple clinical parameters including tumor grade, TNM stage and lymph node metastasis in gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('Ezrin', 'Gene', '7430', (56, 61))	('TNM', 'Gene', (129, 132))	('expression', 'MPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('lymph node metastasis', 'CPA', (143, 164))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Ezrin', 'Gene', (56, 61))	('high', 'Var', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('TNM', 'Gene', '10178', (129, 132))	('gastric cancer', 'Disease', (168, 182))	('tumor', 'Disease', (116, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (168, 182))
868798	29190988	We also found that high Ezrin expression was significantly associated with OS in gastric cancer.	('Ezrin', 'Gene', '7430', (24, 29))	('expression', 'MPA', (30, 40))	('high', 'Var', (19, 23))	('associated with', 'Reg', (59, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('Ezrin', 'Gene', (24, 29))	('gastric cancer', 'Disease', (81, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
868800	29190988	Meta-analysis of 7 studies on colorectal cancer showed significant association between high Ezrin expression and tumor grade, TNM stage, lymph node involvement and distant metastasis.	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('colorectal cancer', 'Disease', (30, 47))	('TNM', 'Gene', '10178', (126, 129))	('expression', 'MPA', (98, 108))	('TNM', 'Gene', (126, 129))	('high', 'Var', (87, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (30, 47))	('lymph node involvement', 'CPA', (137, 159))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('Ezrin', 'Gene', '7430', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('distant metastasis', 'CPA', (164, 182))	('colorectal cancer', 'Phenotype', 'HP:0003003', (30, 47))	('Ezrin', 'Gene', (92, 97))
868804	29190988	But pooled data on esophageal cancer showed significant association between high Ezrin expression and lymph node metastasis.	('Ezrin', 'Gene', (81, 86))	('lymph node metastasis', 'CPA', (102, 123))	('expression', 'MPA', (87, 97))	('esophageal cancer', 'Disease', (19, 36))	('Ezrin', 'Gene', '7430', (81, 86))	('high', 'Var', (76, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
868822	29190988	Furthermore, high Ezrin expression is associated with poor prognosis according to the pooled data of OS and DFS in gastric/colorectal/esophageal cancers.	('colorectal/esophageal cancers', 'Disease', (123, 152))	('Ezrin', 'Gene', '7430', (18, 23))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('colorectal/esophageal cancers', 'Disease', 'MESH:D015179', (123, 152))	('Ezrin', 'Gene', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
868843	29046713	The differential expression of the tumor suppressor protein p53 is one of the commonest abnormality in several cancer types, including EC, and its mutation is mainly related to cell invasion and metastasis, as well as being related to advanced stages of the disease.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('related', 'Reg', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mutation', 'Var', (147, 155))	('expression', 'MPA', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (35, 40))	('p53', 'Gene', (60, 63))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('p53', 'Gene', '7157', (60, 63))	('cancer', 'Disease', (111, 117))	('metastasis', 'CPA', (195, 205))	('related', 'Reg', (224, 231))	('cell invasion', 'CPA', (177, 190))
868844	29046713	These mutations can lead to an increase in expression of p53, which accumulates in the nuclei and can be detected by immunohistochemistry (IHC) methods.	('p53', 'Gene', '7157', (57, 60))	('accumulates', 'PosReg', (68, 79))	('p53', 'Gene', (57, 60))	('expression', 'MPA', (43, 53))	('mutations', 'Var', (6, 15))	('increase', 'PosReg', (31, 39))
868846	29046713	Similarly, high p16 expression supposedly correlates with favorable prognosis in esophageal squamous cell carcinoma as well, although data are still limited and variable.	('esophageal squamous cell carcinoma', 'Disease', (81, 115))	('expression', 'MPA', (20, 30))	('high', 'Var', (11, 15))	('p16', 'Gene', '1029', (16, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (81, 115))	('p16', 'Gene', (16, 19))
868886	29046713	(1993) reported that HPV positive patients have worse survival than those HPV negative with overexpression of p53 in EC patients.	('HPV', 'Species', '10566', (21, 24))	('p53', 'Gene', (110, 113))	('HPV', 'Gene', (21, 24))	('overexpression', 'PosReg', (92, 106))	('worse', 'NegReg', (48, 53))	('p53', 'Gene', '7157', (110, 113))	('positive', 'Var', (25, 33))	('HPV', 'Species', '10566', (74, 77))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (120, 128))	('survival', 'CPA', (54, 62))
868890	29046713	Currently, there are several studies trying to correlate the expression of p53 protein and mutations in the p53 gene with survival of patients carrying EC, and the results are widely variable.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('patients', 'Species', '9606', (134, 142))	('p53', 'Gene', (75, 78))	('mutations', 'Var', (91, 100))	('p53', 'Gene', '7157', (75, 78))
868891	29046713	(2014) found that high p53 expression was associated with a poor survival rate in ESCC patients; and Han et al.	('ESCC', 'Disease', (82, 86))	('poor', 'NegReg', (60, 64))	('expression', 'MPA', (27, 37))	('high', 'Var', (18, 22))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('patients', 'Species', '9606', (87, 95))
868895	29046713	Furthermore, significant associations were also found between high expression of p53 and poor prognosis by Shang et al.	('high expression', 'Var', (62, 77))	('poor prognosis', 'CPA', (89, 103))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))
868899	29046713	Furthermore, a p53 research group study demonstrated that, for EC, p53 immunohistochemistry does not correlate with response to chemotherapy, curative resection rate, or prognosis, whereas data from p53 mutation analyses are more consistent concerning the association of p53 mutation and poor survival .	('p53', 'Gene', '7157', (271, 274))	('p53', 'Gene', (199, 202))	('p53', 'Gene', '7157', (199, 202))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('p53', 'Gene', (15, 18))	('mutation', 'Var', (275, 283))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', (271, 274))
868906	29046713	HPV status did not statistically correlated to survival rates, despite the clear tendency of positive HPV cases to be more aggressive than the HPV negative, in opposition to HPV significance in oropharyngeal cancers.	('aggressive', 'CPA', (123, 133))	('HPV', 'Species', '10566', (143, 146))	('oropharyngeal cancers', 'Disease', 'MESH:D009959', (194, 215))	('HPV', 'Species', '10566', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('positive', 'Var', (93, 101))	('HPV', 'Species', '10566', (174, 177))	('HPV', 'Species', '10566', (102, 105))	('oropharyngeal cancers', 'Disease', (194, 215))	('HPV', 'Gene', (102, 105))
868927	28931046	Locally advanced esophageal carcinoma (LAEC) comprises those tumours that invade through the muscular layer and involve other adjacent structures or lymph nodes (T3-4N0 and T1-4aN1, M0).	('esophageal carcinoma', 'Disease', (17, 37))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (17, 37))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (17, 37))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('tumours', 'Disease', (61, 68))	('T3-4N0', 'Var', (162, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('T1-4aN1', 'Var', (173, 180))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
868981	28931046	Our cohort comprised 21 patients (21%) with T4 staging at diagnosis and 88% cN+, conferring a more aggressive disease according to the TNM classification 7th Edition AJCC.	('aggressive disease', 'Disease', (99, 117))	('aggressive disease', 'Disease', 'MESH:D001523', (99, 117))	('cN+', 'Var', (76, 79))	('patients', 'Species', '9606', (24, 32))
868983	28931046	cN+ downstaging was achieved in 61% of patients, thus ypN+ resulted as an independent prognostic factor for recurrence disease and low survival in the multivariate Cox Regression analysis, consistent with previous reports.	('recurrence', 'Disease', (108, 118))	('ypN+', 'Var', (54, 58))	('patients', 'Species', '9606', (39, 47))	('low survival', 'NegReg', (131, 143))
868995	28931046	The attempt to establish molecular subtypes based on genetic and molecular alterations tries to find potential predictive and prognostic biomarkers in order to investigate the role of tailored therapies to improve the current treatment.. Amplification of ERBB2, which encodes for the HER2 protein is present almost in 7 to 34% of esophagogastric ADC.	('esophagogastric ADC', 'Disease', (330, 349))	('HER2', 'Gene', (284, 288))	('HER2', 'Gene', '2064', (284, 288))	('ERBB2', 'Gene', (255, 260))	('ERBB2', 'Gene', '2064', (255, 260))	('Amplification', 'Var', (238, 251))
869075	27853077	It has recently been reported that some cases have a mutation in epidermal growth factor receptor (EGFR, 15.7-28.1%), Kirsten rat sarcoma viral oncogene homolog (KRAS, 3.1-27.2%), MET (22%) and other genes.	('EGFR', 'Gene', (99, 103))	('KRAS', 'Gene', (162, 166))	('mutation', 'Var', (53, 61))	('sarcoma', 'Disease', 'MESH:D012509', (130, 137))	('KRAS', 'Gene', '24525', (162, 166))	('epidermal growth factor receptor', 'Gene', '24329', (65, 97))	('epidermal growth factor receptor', 'Gene', (65, 97))	('sarcoma', 'Disease', (130, 137))	('MET', 'Gene', (180, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('rat', 'Species', '10116', (126, 129))
869076	27853077	The effectiveness of inhibitors for those molecules has not yet been established, though Zou and colleagues reported that a pulmonary pleomorphic carcinoma patient with EGFR mutation showed a good response to erlotinib treatment.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('erlotinib', 'Chemical', 'MESH:D000069347', (209, 218))	('mutation', 'Var', (174, 182))	('pulmonary pleomorphic carcinoma', 'Disease', 'MESH:D008228', (124, 155))	('EGFR', 'Gene', (169, 173))	('pulmonary pleomorphic carcinoma', 'Disease', (124, 155))	('patient', 'Species', '9606', (156, 163))
869096	26899563	Furthermore, we found that both proliferation and tumorigenicity of ESCC cells were significantly induced by suprabasin overexpression, but inhibited by suprabasin knock-down.	('overexpression', 'Var', (120, 134))	('suprabasin', 'Protein', (109, 119))	('inhibited', 'NegReg', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('proliferation', 'CPA', (32, 45))	('induced', 'PosReg', (98, 105))	('tumor', 'Disease', (50, 55))
869106	26899563	Furthermore, suprabasin is also found to be upregulated in tumor endothelial cells (TEC) compared with normal endothelial cells, and silencing inhibited both TEC migration and tube formation.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tube formation', 'CPA', (176, 190))	('upregulated', 'PosReg', (44, 55))	('inhibited', 'NegReg', (143, 152))	('suprabasin', 'Gene', (13, 23))	('silencing', 'Var', (133, 142))	('TEC migration', 'CPA', (158, 171))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
869126	26899563	To examine the effect of suprabasin on ESCC cell tumorigenicity, an anchorage-independent growth assay was performed and showed that suprabasin-transduced ESCC cells formed a larger number and larger colonies than control cells, while suprabasin inhibition had the opposite effect (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('larger', 'PosReg', (193, 199))	('tumor', 'Disease', (49, 54))	('suprabasin-transduced', 'Var', (133, 154))	('larger', 'PosReg', (175, 181))	('ESCC', 'Disease', (155, 159))
869135	26899563	In addition, target genes downstream of the Wnt/beta-catenin signaling pathway including AXIN2, CTLA4, CCND1, FGFs, FRA1, ITF2, MMP7, JUN, LEF1, MYC and TCF1 were dramatically upregulated in cells overexpressing suprabasin and downregulated in silenced cells (Fig.	('AXIN2', 'Gene', (89, 94))	('MYC', 'Gene', (145, 148))	('FRA1', 'Gene', '8061', (116, 120))	('CTLA4', 'Gene', (96, 101))	('JUN', 'Gene', (134, 137))	('MMP7', 'Gene', (128, 132))	('FGFs', 'Gene', (110, 114))	('LEF1', 'Gene', (139, 143))	('beta-catenin', 'Gene', (48, 60))	('CCND1', 'Gene', '595', (103, 108))	('overexpressing', 'PosReg', (197, 211))	('beta-catenin', 'Gene', '1499', (48, 60))	('MYC', 'Gene', '4609', (145, 148))	('TCF1', 'Gene', '6932', (153, 157))	('CCND1', 'Gene', (103, 108))	('AXIN2', 'Gene', '8313', (89, 94))	('ITF2', 'Gene', '6925', (122, 126))	('FRA1', 'Gene', (116, 120))	('LEF1', 'Gene', '51176', (139, 143))	('TCF1', 'Gene', (153, 157))	('MMP7', 'Gene', '4316', (128, 132))	('upregulated', 'PosReg', (176, 187))	('CTLA4', 'Gene', '1493', (96, 101))	('suprabasin', 'Var', (212, 222))	('ITF2', 'Gene', (122, 126))
869137	26899563	However, overexpression of suprabasin dramatically reduced, but downregulation of suprabasin increased, expression of phosphorylated beta-catenin (phospho S33 +- S37).	('beta-catenin', 'Gene', '1499', (133, 145))	('phospho S33 +- S37', 'Var', (147, 165))	('increased', 'PosReg', (93, 102))	('downregulation', 'NegReg', (64, 78))	('expression', 'MPA', (104, 114))	('beta-catenin', 'Gene', (133, 145))	('suprabasin', 'Gene', (82, 92))
869154	26899563	Our study also found that the tumors formed by suprabasin-overexpressing ESCC cells exhibited increased percentages of microvascular density (MVD) whereas the tumors formed by suprabasin-silenced tumors displayed decreased MVD, indicating a potential function of suprabasin on ESCC angiogenesis (Supplementary Fig.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (196, 202))	('increased', 'PosReg', (94, 103))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('suprabasin-overexpressing', 'Var', (47, 72))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('microvascular density', 'MPA', (119, 140))	('ESCC', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
869160	26899563	Suprabasin knock-down inhibited TEC migration and tube formation capability.	('inhibited', 'NegReg', (22, 31))	('Suprabasin', 'Gene', '374897', (0, 10))	('knock-down', 'Var', (11, 21))	('TEC migration', 'CPA', (32, 45))	('Suprabasin', 'Gene', (0, 10))	('tube formation capability', 'CPA', (50, 75))
869163	26899563	We also found that overexpressing suprabasin leads to promotion of ESCC cell proliferation and tumorigenesis, both in vitro and in vivo, indicating an important oncogenic function in ESCC development.	('overexpressing', 'Var', (19, 33))	('promotion', 'PosReg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ESCC cell proliferation', 'CPA', (67, 90))	('tumor', 'Disease', (95, 100))
869167	26899563	found that suprabasin is hypomethylated in salivary adenoid cystic carcinoma and suprabasin transcription is significantly upregulated induced by 5-aza-2'-deoxycytidine.	('salivary adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (43, 76))	("5-aza-2'-deoxycytidine", 'Var', (146, 168))	('upregulated', 'PosReg', (123, 134))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (146, 168))	('suprabasin', 'Gene', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('salivary adenoid cystic carcinoma', 'Disease', (43, 76))	('transcription', 'MPA', (92, 105))
869169	26899563	Moreover, amplification of the 19q13 chromosomal locus was found to be associated with clinicopathological parameters and patient survival.	('patient', 'Species', '9606', (122, 129))	('19q13', 'Gene', (31, 36))	('amplification', 'Var', (10, 23))	('associated', 'Reg', (71, 81))
869170	26899563	The ESCC cell lines, including KYSE30, KYSE140, KYSE180, KYSE410, KYSE510, KYSE 520, ECa109, 108Ca, TE-1, EC18 and HKESC1 were grown in DMEM medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Invitrogen) and 100 mug/ml penicillin, and 100 mug/ml streptomycin (Invitrogen) at 37  C in a humidified atmosphere containing 5% CO2.	('CO2', 'Chemical', '-', (352, 355))	('HKESC1', 'CellLine', 'CVCL:D568', (115, 121))	('KYSE510', 'Var', (66, 73))	('KYSE410', 'Var', (57, 64))	('KYSE30', 'Var', (31, 37))	('KYSE 520', 'Var', (75, 83))	('DMEM medium', 'Chemical', '-', (136, 147))	('bovine', 'Species', '9913', (208, 214))	('KYSE180', 'CellLine', 'CVCL:1349', (48, 55))	('KYSE140', 'Var', (39, 46))	('KYSE180', 'Var', (48, 55))
835788	26899563	Tumor cell proportions were scored as follows: 0 (no positive tumor cells); 1 (<10% positive tumor cells); 2 (10-35% positive tumor cells); 3 (35-75% positive tumor cells) and 4 (>75% positive tumor cells).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('35-75', 'Var', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (93, 98))	('10-35', 'Var', (110, 115))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', (126, 131))
869197	26899563	100 ng of reporter plasmids containing wild-type (CCTTTGATC; TOPflash) or mutated (CCTTTGGCC; FOPflash) T cell factor (TCF)/LEF DNA binding sites (Upstate Biotechnology, Lake Placid, NY, USA) plus 10 ng pRL-TK Renilla luciferase normalization control (Promega) were cotransfected using Lipofectamine 2000 (Invitrogen).	('T cell factor', 'Gene', (104, 117))	('T cell factor', 'Gene', '3172', (104, 117))	('FOPflash', 'Disease', (94, 102))	('mutated', 'Var', (74, 81))	('FOPflash', 'Disease', 'None', (94, 102))	('TCF', 'Gene', (119, 122))	('TCF', 'Gene', '3172', (119, 122))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (286, 304))
869200	26899563	Overexpression of Suprabasin is Associated with Proliferation and Tumorigenicity of Esophageal Squamous Cell Carcinoma.	('Proliferation', 'CPA', (48, 61))	('Esophageal Squamous Cell Carcinoma', 'Disease', (84, 118))	('Tumorigenicity', 'CPA', (66, 80))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (84, 118))	('Carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Associated', 'Reg', (32, 42))	('Suprabasin', 'Gene', (18, 28))	('Overexpression', 'Var', (0, 14))	('Suprabasin', 'Gene', '374897', (18, 28))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (95, 118))
869203	26764421	ctDNA can be distinguished from non-tumor DNA by the presence of tumor-specific mutations and copy number variations, and also by aberrant DNA methylation, with both DNA sequence and methylation changes corresponding to those found in the tumor.	('DNA methylation', 'MPA', (139, 154))	('tumor', 'Disease', (65, 70))	('copy number variations', 'Var', (94, 116))	('mutations', 'Var', (80, 89))	('variations', 'Var', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ctDNA', 'Disease', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
869204	26764421	Aberrant methylation of specific promoter regions can be a very consistent feature of cancer, in contrast to mutations, which typically occur at a wide range of sites.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('methylation', 'MPA', (9, 20))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
869206	26764421	Genomics is anticipated to bring major improvements in the treatment of cancer patients.	('Genomics', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('patients', 'Species', '9606', (79, 87))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
869211	26764421	ctDNA can be distinguished from circulating DNA from healthy cells by the presence of genomic aberrations that correspond to those found in the tumor, such as tumor-specific mutations or methylation.	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('mutations', 'Var', (174, 183))	('methylation', 'Var', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
869212	26764421	The feasibility of using tumor-specific mutations in ctDNA to monitor the response to therapy has been demonstrated in colorectal, breast, ovarian and lung cancers; however, the highly individual nature of tumor DNA mutations makes this a very labor intensive approach.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (25, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('ctDNA', 'Gene', (53, 58))	('very labor', 'Disease', 'MESH:D048949', (239, 249))	('mutations', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancers', 'Phenotype', 'HP:0100526', (151, 163))	('colorectal, breast, ovarian and lung cancers', 'Disease', 'MESH:D001943', (119, 163))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('very labor', 'Disease', (239, 249))
869213	26764421	For example, inadequate nutrition levels around early pregnancy decrease methylation of the insulin-like growth factor 2 gene, while exposure to benzene is associated with genome-wide hypomethylation and gene promoter hypermethylation in a pattern overlapping with acute myeloid leukemia, a cancer linked to this pollutant.	('insulin-like growth factor 2', 'Gene', (92, 120))	('decrease', 'NegReg', (64, 72))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (265, 287))	('leukemia', 'Phenotype', 'HP:0001909', (279, 287))	('cancer', 'Disease', (291, 297))	('methylation', 'MPA', (73, 84))	('insulin-like growth factor 2', 'Gene', '3481', (92, 120))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('early pregnancy', 'Phenotype', 'HP:0001622', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (271, 287))	('benzene', 'Chemical', 'MESH:D001554', (145, 152))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (265, 287))	('hypomethylation', 'Var', (184, 199))	('acute myeloid leukemia', 'Disease', (265, 287))
869215	26764421	Methylation changes are a common feature of different cancer types, and occur early in cancer development, typically repressing the expression of tumor suppressor genes.	('cancer', 'Disease', (87, 93))	('repressing', 'NegReg', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (54, 60))	('Methylation changes', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('expression', 'MPA', (132, 142))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
869216	26764421	Aberrant DNA methylation may offer a more consistent and hence broadly applicable marker of tumor DNA in blood than mutations.	('Aberrant', 'Var', (0, 8))	('methylation', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('DNA', 'Protein', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
869217	26764421	For example, GSTP1 is methylated in >90% of prostate cancers, STRATIFIN is methylated in 96% of breast cancers and HOXA9 and EN1 are methylated in 95 and 80% of ovarian tumors respectively.	('prostate cancers', 'Phenotype', 'HP:0012125', (44, 60))	('prostate cancers', 'Disease', (44, 60))	('GSTP1', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('methylated', 'Var', (22, 32))	('ovarian tumors', 'Disease', (161, 175))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('ovarian tumors', 'Disease', 'MESH:D010051', (161, 175))	('EN1', 'Gene', '2019', (125, 128))	('breast cancers', 'Disease', 'MESH:D001943', (96, 110))	('breast cancers', 'Disease', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('prostate cancers', 'Disease', 'MESH:D011471', (44, 60))	('HOXA9', 'Gene', (115, 120))	('STRATIFIN', 'Gene', (62, 71))	('EN1', 'Gene', (125, 128))	('STRATIFIN', 'Gene', '2810', (62, 71))	('breast cancers', 'Phenotype', 'HP:0003002', (96, 110))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('HOXA9', 'Gene', '3205', (115, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('GSTP1', 'Gene', '2950', (13, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))	('ovarian tumors', 'Phenotype', 'HP:0100615', (161, 175))
869225	26764421	One approach to determining whether tumor-derived DNA sequences are present is to assay circulating DNA for the presence of tumor-specific mutations.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mutations', 'Var', (139, 148))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
869230	26764421	A list of tumor-specific methylated sequences that have been shown to decrease in patient blood following surgery is presented in Table 1, and selected examples are discussed below.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('patient', 'Species', '9606', (82, 89))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('methylated sequences', 'Var', (25, 45))	('in patient blood', 'MPA', (79, 95))	('decrease', 'NegReg', (70, 78))
869231	26764421	CDKN2A methylation is common in liver cancer and has been reported in 73% of hepatocellular carcinoma tumors.	('CDKN2A', 'Gene', '1029', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('reported', 'Reg', (58, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('hepatocellular carcinoma tumors', 'Disease', (77, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (77, 101))	('methylation', 'Var', (7, 18))	('liver cancer', 'Phenotype', 'HP:0002896', (32, 44))	('liver cancer', 'Disease', 'MESH:D006528', (32, 44))	('hepatocellular carcinoma tumors', 'Disease', 'MESH:D006528', (77, 108))	('common', 'Reg', (22, 28))	('liver cancer', 'Disease', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('CDKN2A', 'Gene', (0, 6))
869232	26764421	A study by found methylated CDKN2A in the pre-surgery plasma of 31% of liver cancer patients, with a median methylation index (methylated circulating CDKN2A/total circulating CDKN2A) of 35%.	('liver cancer', 'Disease', (71, 83))	('patients', 'Species', '9606', (84, 92))	('methylated', 'Var', (17, 27))	('CDKN2A', 'Gene', (150, 156))	('CDKN2A', 'Gene', (175, 181))	('methylation', 'MPA', (108, 119))	('CDKN2A', 'Gene', '1029', (150, 156))	('CDKN2A', 'Gene', (28, 34))	('CDKN2A', 'Gene', '1029', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CDKN2A', 'Gene', '1029', (28, 34))	('liver cancer', 'Phenotype', 'HP:0002896', (71, 83))	('liver cancer', 'Disease', 'MESH:D006528', (71, 83))
869234	26764421	APC methylation has been detected in the tumors of 44-68% of patients with esophageal cancer, and is indicative of poor patient outcome.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('patient', 'Species', '9606', (61, 68))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('APC', 'Gene', (0, 3))	('patient', 'Species', '9606', (120, 127))	('patients', 'Species', '9606', (61, 69))	('tumors', 'Disease', (41, 47))	('methylation', 'Var', (4, 15))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('APC', 'Gene', '324', (0, 3))	('esophageal cancer', 'Disease', (75, 92))	('detected', 'Reg', (25, 33))
869236	26764421	Consistent with previous reports, APC was methylated in 46% of pre-operative patient samples.	('APC', 'Gene', (34, 37))	('APC', 'Gene', '324', (34, 37))	('patient', 'Species', '9606', (77, 84))	('methylated', 'Var', (42, 52))
869237	26764421	Pre-operative methylated APC together with methylated DAPK predicted shorter overall survival, possibly by reflecting higher tumor burden at diagnosis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('APC', 'Gene', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('shorter', 'NegReg', (69, 76))	('tumor', 'Disease', (125, 130))	('APC', 'Gene', '324', (25, 28))	('overall survival', 'MPA', (77, 93))	('methylated', 'Var', (14, 24))	('DAPK', 'Gene', (54, 58))	('DAPK', 'Gene', '1612', (54, 58))
869238	26764421	Detection of methylated APC in serum from blood collected 10 days following the operation was significantly associated with the presence of apparent residual tumor after surgery; however, impact on survival was not assessed.	('tumor', 'Disease', (158, 163))	('methylated', 'Var', (13, 23))	('APC', 'Gene', (24, 27))	('associated', 'Reg', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('APC', 'Gene', '324', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
869239	26764421	used a 56 gene panel assay (MethDet-56) to identify methylated sequences in the plasma of breast cancer patients that decrease following surgery and tamoxifen treatment.	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tamoxifen', 'Chemical', 'MESH:D013629', (149, 158))	('breast cancer', 'Disease', (90, 103))	('decrease', 'NegReg', (118, 126))	('methylated sequences', 'Var', (52, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('patients', 'Species', '9606', (104, 112))
869240	26764421	Twenty patients with ER-positive breast cancer had plasma collected prior to and after surgery, and three genes (RARb2, MSH2 and ESR1B promoter) were found to be methylated in significantly more pre-surgery samples than post-surgery samples.	('more', 'PosReg', (190, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('MSH2', 'Gene', (120, 124))	('patients', 'Species', '9606', (7, 15))	('ESR1', 'Gene', '2099', (129, 133))	('MSH2', 'Gene', '4436', (120, 124))	('methylated', 'Var', (162, 172))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('ESR1', 'Gene', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
869242	26764421	RUNX3 has been reported to be a tumor suppressor gene in gastric cancer, with promoter hypermethylation contributing to tumorigenesis.	('RUNX3', 'Gene', '864', (0, 5))	('gastric cancer', 'Disease', (57, 71))	('contributing', 'Reg', (104, 116))	('promoter hypermethylation', 'Var', (78, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (32, 37))	('RUNX3', 'Gene', (0, 5))	('tumor', 'Disease', (120, 125))
869243	26764421	identified RUNX3 promoter methylation in 91% of gastric cancers and in 29% of patient serum samples.	('methylation', 'Var', (26, 37))	('patient', 'Species', '9606', (78, 85))	('RUNX3', 'Gene', '864', (11, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('RUNX3', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('gastric cancers', 'Disease', (48, 63))	('gastric cancers', 'Disease', 'MESH:D013274', (48, 63))	('gastric cancers', 'Phenotype', 'HP:0012126', (48, 63))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
869245	26764421	The post-operative median methylation index for RUNX3 was 12-fold lower than the pre-operative median methylation index, and serum RUNX3 methylation was found to be a more sensitive indicator of cancer recurrence than CEA.	('RUNX3', 'Gene', (48, 53))	('methylation', 'Var', (137, 148))	('RUNX3', 'Gene', '864', (48, 53))	('RUNX3', 'Gene', '864', (131, 136))	('cancer', 'Disease', (195, 201))	('lower', 'NegReg', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('RUNX3', 'Gene', (131, 136))	('CEA', 'Gene', (218, 221))	('CEA', 'Gene', '1048', (218, 221))	('methylation index', 'MPA', (26, 43))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
869252	26764421	Several studies report the use of tumor-specific mutations to measure ctDNA dynamics at multiple time points during treatment.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
869253	26764421	For example, used mutations in tumor DNA identified via sequencing of FFPE samples to assay ctDNA and track patient response to chemotherapy during breast cancer treatment.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (31, 36))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('patient', 'Species', '9606', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('mutations', 'Var', (18, 27))
869257	26764421	The presence of methylated GSTP1 DNA in plasma has been used to track the response of prostate cancer patients to chemotherapy.	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('patients', 'Species', '9606', (102, 110))	('GSTP1', 'Gene', (27, 32))	('prostate cancer', 'Disease', (86, 101))	('GSTP1', 'Gene', '2950', (27, 32))	('methylated', 'Var', (16, 26))
869260	26764421	The level of methylated GSTP1 in plasma was a better predictor of overall survival than PSA.	('methylated', 'Var', (13, 23))	('GSTP1', 'Gene', (24, 29))	('overall survival', 'CPA', (66, 82))	('PSA', 'Gene', '354', (88, 91))	('PSA', 'Gene', (88, 91))	('GSTP1', 'Gene', '2950', (24, 29))
869265	26764421	Methylated serum RASSF1 is also an indicator of response to tamoxifen treatment in breast cancer.	('Methylated', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tamoxifen', 'Chemical', 'MESH:D013629', (60, 69))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('RASSF1', 'Gene', '11186', (17, 23))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('RASSF1', 'Gene', (17, 23))
869269	26764421	Conversely, detectable serum methylated RASSF1 after 1 year of adjuvant tamoxifen treatment was an independent predictor of poor recurrence-free (RR 5.1, 95% CI 1.3-19.8) and overall survival (RR 6.9, 95% CI 1.9-25.9).	('recurrence-free', 'CPA', (129, 144))	('RASSF1', 'Gene', '11186', (40, 46))	('RASSF1', 'Gene', (40, 46))	('methylated', 'Var', (29, 39))	('tamoxifen', 'Chemical', 'MESH:D013629', (72, 81))	('poor', 'NegReg', (124, 128))	('overall survival', 'CPA', (175, 191))
869272	26764421	In a separate study, a high level of pre-treatment methylated serum STRATIFIN in serum has been reported to be associated with sensitivity to cisplatin-plus-gemcitabine treatment in non-small cell lung cancer patients; however, the study did not report on changes in methylation in response to treatment.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (186, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('gemcitabine', 'Chemical', 'MESH:C056507', (157, 168))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (182, 208))	('associated', 'Reg', (111, 121))	('methylated', 'Var', (51, 61))	('patients', 'Species', '9606', (209, 217))	('STRATIFIN', 'Gene', (68, 77))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (182, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))	('STRATIFIN', 'Gene', '2810', (68, 77))	('non-small cell lung cancer', 'Disease', (182, 208))
869275	26764421	At the single gene level, the frequency of BRCA1 methylation was significantly correlated with response to chemotherapy.	('BRCA1', 'Gene', (43, 48))	('response to chemotherapy', 'CPA', (95, 119))	('BRCA1', 'Gene', '672', (43, 48))	('methylation', 'Var', (49, 60))	('correlated', 'Reg', (79, 89))
869276	26764421	RASSF1A and RARB2 methylation have been observed to be indicative of treatment response in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('RASSF1A', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('RASSF1A', 'Gene', '11186', (0, 7))	('RARB2', 'Gene', (12, 17))	('methylation', 'Var', (18, 29))	('lung cancer', 'Disease', (91, 102))
869280	26764421	Methylated SHOX2 was first tested as a plasma marker for lung cancer diagnosis and showed promising results with 60% sensitivity (95% CI: 53-67%) and 90% specificity (95% CI: 84-94%).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('SHOX2', 'Gene', (11, 16))	('SHOX2', 'Gene', '6474', (11, 16))	('Methylated', 'Var', (0, 10))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
869288	26764421	An increase in circulating methylated RASSF1A or APC1 at the 24 h time point was shown to be associated with chemosensitivity and complete or partial response, while no change in the two markers following treatment was associated with stable or progressive disease.	('RASSF1A', 'Gene', (38, 45))	('APC1', 'Gene', (49, 53))	('methylated', 'Var', (27, 37))	('APC1', 'Gene', '29957', (49, 53))	('chemosensitivity', 'Disease', (109, 125))	('RASSF1A', 'Gene', '11186', (38, 45))	('increase', 'PosReg', (3, 11))
869292	26764421	Methylation can facilitate tumor progression by silencing genes that directly regulate cell growth and metastatic potential, and it can also reflect tumor subtype, which is in turn linked to prognosis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cell growth', 'CPA', (87, 98))	('linked', 'Reg', (181, 187))	('metastatic potential', 'CPA', (103, 123))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (27, 32))	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('reflect', 'Reg', (141, 148))	('genes', 'Gene', (58, 63))	('tumor', 'Disease', (149, 154))	('facilitate', 'PosReg', (16, 26))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('silencing', 'NegReg', (48, 57))
869294	26764421	Examples of prognostic methylated genes in serum or plasma include TIMP3, XAF1, ABPA2, SOX17 and RARb2.	('methylated', 'Var', (23, 33))	('SOX17', 'Gene', (87, 92))	('XAF1', 'Gene', '54739', (74, 78))	('TIMP3', 'Gene', (67, 72))	('TIMP3', 'Gene', '7078', (67, 72))	('XAF1', 'Gene', (74, 78))	('SOX17', 'Gene', '64321', (87, 92))	('ABPA2', 'Gene', (80, 85))	('RARb2', 'Gene', (97, 102))
869295	26764421	A list of genes, separated by tumor type, for which methylation in plasma or serum has been shown to be prognostic in cancer is presented in Table 3.	('tumor', 'Disease', (30, 35))	('cancer', 'Disease', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('methylation', 'Var', (52, 63))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
869297	26764421	SOX17 plays a tumor suppressor role by regulating the WNT signaling pathway, and inhibition of SOX17 promotes tumorigenesis.	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('inhibition', 'Var', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('SOX17', 'Gene', '64321', (95, 100))	('SOX17', 'Gene', '64321', (0, 5))	('WNT signaling pathway', 'Pathway', (54, 75))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('promotes', 'PosReg', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('SOX17', 'Gene', (0, 5))	('SOX17', 'Gene', (95, 100))
869298	26764421	SOX17 methylation in tumor tissue is associated with poor prognosis in breast and esophageal cancer.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('SOX17', 'Gene', '64321', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('methylation', 'Var', (6, 17))	('breast and esophageal cancer', 'Disease', 'MESH:D004938', (71, 99))	('SOX17', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
869300	26764421	used plasma samples from 60 breast cancer patients to show that SOX17 methylation was associated with TNM stage, but was also an independent prognostic factor in multivariate analysis.	('TNM', 'Gene', '10178', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('associated', 'Reg', (86, 96))	('TNM', 'Gene', (102, 105))	('SOX17', 'Gene', '64321', (64, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('methylation', 'Var', (70, 81))	('patients', 'Species', '9606', (42, 50))	('SOX17', 'Gene', (64, 69))
869301	26764421	showed that in a cohort of 73 patients with gastric cancer, serum SOX17 methylation was correlated with tumor differentiation and overall survival.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('correlated', 'Reg', (88, 98))	('SOX17', 'Gene', (66, 71))	('tumor', 'Disease', (104, 109))	('gastric cancer', 'Disease', (44, 58))	('methylation', 'Var', (72, 83))	('patients', 'Species', '9606', (30, 38))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('SOX17', 'Gene', '64321', (66, 71))	('overall survival', 'CPA', (130, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
869303	26764421	In tumors, methylation of RARb2 has been consistently shown to be associated with poor prognosis, and has been linked to poor outcome in colorectal cancer, breast cancer and lung cancer.	('lung cancer', 'Disease', (174, 185))	('colorectal cancer', 'Disease', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('RARb2', 'Gene', (26, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('breast cancer', 'Disease', (156, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('methylation', 'Var', (11, 22))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('linked to', 'Reg', (111, 120))	('tumors', 'Disease', (3, 9))	('associated', 'Reg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
869304	26764421	The results obtained in tumor tissue are reflected in ctDNA, and methylated RARb2 in plasma or serum has been shown to be associated with worse patient outcomes in breast cancer, lung cancer and mesothelioma.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mesothelioma', 'Disease', (195, 207))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))	('tumor', 'Disease', (24, 29))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('associated with', 'Reg', (122, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('patient', 'Species', '9606', (144, 151))	('methylated', 'Var', (65, 75))	('breast cancer', 'Disease', (164, 177))	('mesothelioma', 'Disease', 'MESH:D008654', (195, 207))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('RARb2', 'Gene', (76, 81))
869305	26764421	TIMP3 inhibits endothelial cell migration, thus limiting angiogenesis in tumors and methylation of the gene promoter is a known mechanism of carcinogenesis.	('limiting', 'NegReg', (48, 56))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('methylation', 'Var', (84, 95))	('inhibits', 'NegReg', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('angiogenesis', 'CPA', (57, 69))	('TIMP3', 'Gene', (0, 5))	('carcinogenesis', 'Disease', 'MESH:D063646', (141, 155))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('TIMP3', 'Gene', '7078', (0, 5))	('tumors', 'Disease', (73, 79))	('endothelial cell migration', 'CPA', (15, 41))	('carcinogenesis', 'Disease', (141, 155))
869306	26764421	In a study of 92 patients newly diagnosed with gastric cancer, detection of methylated TIMP3 promoter sequence in the serum was an independent predictor of poor disease-free survival (DFS).	('poor', 'NegReg', (156, 160))	('gastric cancer', 'Disease', (47, 61))	('disease-free survival', 'CPA', (161, 182))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('methylated', 'Var', (76, 86))	('patients', 'Species', '9606', (17, 25))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('TIMP3', 'Gene', (87, 92))	('TIMP3', 'Gene', '7078', (87, 92))
869309	26764421	A study by Ling et al showed that XAF1 tumor methylation in gastric cancer is linked to decreased survival, with a median DFS of 23.4 months in patients with methylated XAF1, in contrast to a median DFS of 39.6 months in patients with unmethylated XAF1.	('XAF1', 'Gene', '54739', (248, 252))	('patients', 'Species', '9606', (221, 229))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('XAF1', 'Gene', '54739', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('survival', 'MPA', (98, 106))	('decreased', 'NegReg', (88, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('methylated', 'Var', (158, 168))	('Ling', 'Species', '163112', (11, 15))	('XAF1', 'Gene', (34, 38))	('XAF1', 'Gene', (248, 252))	('XAF1', 'Gene', (169, 173))	('gastric cancer', 'Disease', (60, 74))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('patients', 'Species', '9606', (144, 152))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('XAF1', 'Gene', '54739', (34, 38))
869310	26764421	Correspondingly, patients positive for serum XAF1 methylation had significantly lower DFS than patients negative for serum XAF1 methylation.	('patients', 'Species', '9606', (95, 103))	('serum', 'Var', (39, 44))	('DFS', 'MPA', (86, 89))	('lower', 'NegReg', (80, 85))	('patients', 'Species', '9606', (17, 25))	('XAF1', 'Gene', '54739', (123, 127))	('XAF1', 'Gene', (123, 127))	('XAF1', 'Gene', '54739', (45, 49))	('XAF1', 'Gene', (45, 49))	('methylation', 'Var', (50, 61))
869311	26764421	While promoter methylation silencing of tumor suppressor genes can directly confer a more aggressive tumor phenotype, broad methylation differences at hundreds of gene promoters can be reflective of different tumor subtypes, each with different prognosis.	('tumor', 'Disease', (209, 214))	('more', 'PosReg', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (101, 106))	('aggressive tumor', 'Disease', 'MESH:D001523', (90, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('aggressive tumor', 'Disease', (90, 106))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('promoter methylation', 'Var', (6, 26))
869313	26764421	It follows that the presence of a methylated sequence in blood could be indicative of tumor subtype, and hence prognosis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('methylated sequence', 'Var', (34, 53))	('tumor', 'Disease', (86, 91))	('indicative', 'Reg', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
869319	26764421	Hence, detection of target methylated sequences in serum or plasma can be indicative of aggressive phenotype and/or large volume of tumor, both of which correlate with poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('methylated sequences', 'Var', (27, 47))
869320	26764421	It is not always clear whether increased detection of particular circulating methylated genes in patients with poor outcomes reflects the impact of gene methylation on tumor biology, or simply increased ctDNA due to high tumor burden.	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('increased', 'PosReg', (193, 202))	('ctDNA', 'Disease', (203, 208))	('methylation', 'Var', (153, 164))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('patients', 'Species', '9606', (97, 105))
869327	26764421	One biomarker under development is methylated SHOX2, which has shown promise in blood-based diagnosis of lung cancer, and has more recently been investigated as marker of early response to treatment in lung cancer patients.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('patients', 'Species', '9606', (214, 222))	('lung cancer', 'Disease', (202, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('methylated', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('SHOX2', 'Gene', '6474', (46, 51))	('SHOX2', 'Gene', (46, 51))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))	('lung cancer', 'Disease', (105, 116))
869336	26764421	Thus the abundance of tumor-specific methylated sequences in blood may provide a direct indication of the effect of drug treatment on the tumor.	('methylated sequences', 'Var', (37, 57))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
869343	26764421	Methylated GSTP1 in plasma was a better predictor of overall survival than PSA in prostate cancer patients.	('prostate cancer', 'Disease', 'MESH:D011471', (82, 97))	('GSTP1', 'Gene', (11, 16))	('prostate cancer', 'Disease', (82, 97))	('patients', 'Species', '9606', (98, 106))	('PSA', 'Gene', '354', (75, 78))	('PSA', 'Gene', (75, 78))	('overall', 'MPA', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Methylated', 'Var', (0, 10))	('GSTP1', 'Gene', '2950', (11, 16))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))
869351	24353609	Previous studies regarding the association of folate intake and Methylenetetrahydrofolate reductase C677T polymorphism with ESCC was conflicting.	('C677T', 'Var', (100, 105))	('C677T', 'Mutation', 'rs1801133', (100, 105))	('ESCC', 'Disease', (124, 128))	('association', 'Interaction', (31, 42))
869352	24353609	We conducted a meta-analysis to investigate the association of MTHFR C677T and folate intake with esophageal cancer risk.	('C677T', 'SUBSTITUTION', 'None', (69, 74))	('MTHFR', 'Gene', '4524', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('association', 'Interaction', (48, 59))	('C677T', 'Var', (69, 74))	('MTHFR', 'Gene', (63, 68))	('esophageal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
869353	24353609	The quality of studies were evaluated by predefined scale, and The association of polymorphisms of MTHFR C677T and folate intake and ESCC risk was estimated by Odds ratio (ORs) with 95% confidence intervals (CIs).	('C677T', 'Var', (105, 110))	('ESCC', 'Disease', (133, 137))	('MTHFR', 'Gene', (99, 104))	('C677T', 'SUBSTITUTION', 'None', (105, 110))	('association', 'Interaction', (67, 78))
869354	24353609	Conclusions: Our meta-analysis indicated the folate intake and MTHFR 677CT/TT are associated with the risk of ESCC, and folate showed a significant interaction with polymorphism of MTHFR C677T.	('C677T', 'Var', (187, 192))	('associated', 'Reg', (82, 92))	('C677T', 'SUBSTITUTION', 'None', (187, 192))	('ESCC', 'Disease', (110, 114))	('MTHFR 677CT/TT', 'Var', (63, 77))
869359	24353609	Deficiency of folate could induce defective DNA repair and chromosomal fragile site expression, leading to chromosomal breaks and micronucleus formation.	('DNA repair', 'CPA', (44, 54))	('chromosomal breaks', 'CPA', (107, 125))	('micronucleus formation', 'CPA', (130, 152))	('defective', 'NegReg', (34, 43))	('chromosomal fragile site', 'Phenotype', 'HP:0040012', (59, 83))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (107, 125))	('chromosomal fragile', 'Disease', (59, 78))	('chromosomal fragile', 'Disease', 'MESH:D002873', (59, 78))	('Deficiency of folate', 'Phenotype', 'HP:0100507', (0, 20))	('Deficiency', 'Var', (0, 10))
869360	24353609	Methylenetetrahydrofolate reductase (MTHFR) C677T in the gene encoding the MTHFR enzyme, which converts dietary folate to its active cofactor in Hcy catabolism, has been studies as candidate genetic risk factor for esophageal cancer.	('MTHFR', 'Gene', (75, 80))	('C677T', 'Var', (44, 49))	('esophageal cancer', 'Disease', (215, 232))	('C677T', 'SUBSTITUTION', 'None', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
869362	24353609	Therefore, we conducted a systematic review to investigate the association of MTHFR C677T and folate intake with esophageal cancer risk by reducing random error and obtaining precise estimates for some potential genetic associations.	('C677T', 'Var', (84, 89))	('C677T', 'SUBSTITUTION', 'None', (84, 89))	('MTHFR', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal cancer', 'Disease', (113, 130))
869364	24353609	The eligible criteria for including studies were (1) a case-control study reporting an association between MTHFR C677T polymorphisms and ESCC; (2) original study and an available genotype or allele frequency of MTHFR C677T genotypes for estimating an odds ratio (OR) with a 95% confidence interval (CI).	('polymorphisms', 'Var', (119, 132))	('C677T', 'Var', (113, 118))	('ESCC', 'Disease', (137, 141))	('C677T', 'Var', (217, 222))	('association', 'Interaction', (87, 98))	('C677T', 'SUBSTITUTION', 'None', (113, 118))	('C677T', 'SUBSTITUTION', 'None', (217, 222))
869366	24353609	From those studies which werefinally selected, we extracted the following data: first author's name, year of publication, country of origin, numbers of cases and controls, genotype frequencies of MTHFR C677T.	('MTHFR', 'Gene', (196, 201))	('C677T', 'Var', (202, 207))	('C677T', 'SUBSTITUTION', 'None', (202, 207))
869367	24353609	The association of polymorphisms of MTHFR C677T and folate intake and ESCC risk was estimated by Odds ratio (ORs) with 95% confidence intervals (CIs).	('association', 'Interaction', (4, 15))	('MTHFR', 'Gene', (36, 41))	('C677T', 'Var', (42, 47))	('ESCC', 'Disease', (70, 74))	('C677T', 'SUBSTITUTION', 'None', (42, 47))
869368	24353609	These results indicated folate had a significant interaction with MTHFR C677T.	('C677T', 'Var', (72, 77))	('C677T', 'SUBSTITUTION', 'None', (72, 77))	('MTHFR', 'Gene', (66, 71))	('interaction', 'Interaction', (49, 60))
869369	24353609	Many epidemiologic studies which investigated the role of folate intake and MTHFR C677T for EC risk provided inconsistent results.	('C677T', 'Var', (82, 87))	('C677T', 'SUBSTITUTION', 'None', (82, 87))	('MTHFR', 'Gene', (76, 81))
869370	24353609	Therefore, we conducted an updated meta-analysis by critically reviewing 19 individual case-control studies on MTHFR C677T and folate intake with esophageal cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('C677T', 'SUBSTITUTION', 'None', (117, 122))	('esophageal cancer', 'Disease', (146, 163))	('C677T', 'Var', (117, 122))	('MTHFR', 'Gene', (111, 116))
869372	24353609	Our study showed that high intake of folate had a protective factor for esophageal cancer, and folate showed a significant interaction with polymorphism of MTHFR C677T.	('C677T', 'SUBSTITUTION', 'None', (162, 167))	('high intake of folate', 'Phenotype', 'HP:0032164', (22, 43))	('MTHFR', 'Gene', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('C677T', 'Var', (162, 167))	('polymorphism', 'Var', (140, 152))
869375	24353609	The MTHFR gene is high polymorphic in the general population, the mutation of most common functional variant of 677C to T. This polymorphism results in an alanine to valine substitution, leading to a reduction in enzyme activity.35 The role of MTHFR in the folate metabolism decides the interaction between folate and polymorphisms of MTHFR, which was proved by our meta-analysis.	('variant', 'Var', (101, 108))	('reduction', 'NegReg', (200, 209))	('alanine', 'Chemical', 'MESH:D000409', (155, 162))	('valine', 'Chemical', 'MESH:D014633', (166, 172))	('enzyme activity.35', 'MPA', (213, 231))	('mutation', 'Var', (66, 74))	('alanine', 'MPA', (155, 162))
869376	24353609	In conclusion, our meta-analysis has indicated the folate intake and MTHFR 677CT/TT are associated with the risk of ESCC, and folate showed a significant interaction with polymorphism of MTHFR C677T.	('C677T', 'Var', (193, 198))	('ESCC', 'Disease', (116, 120))	('C677T', 'SUBSTITUTION', 'None', (193, 198))	('MTHFR', 'Gene', (69, 74))	('associated', 'Reg', (88, 98))
869380	19258542	Moreover, antisense RAR-beta2 cDNA induced COX-2 expression in TE-3 cells.	('RAR-beta', 'Gene', '5915', (20, 28))	('COX-2', 'Gene', (43, 48))	('expression', 'MPA', (49, 59))	('induced', 'Reg', (35, 42))	('RAR-beta', 'Gene', (20, 28))	('antisense', 'Var', (10, 19))
869381	19258542	Furthermore, when COX-2 expression is first blocked by using antisense COX-2 expression vector, the effect of RAR-beta2 is diminished in these tumor cells.	('tumor', 'Disease', (143, 148))	('diminished', 'NegReg', (123, 133))	('RAR-beta', 'Gene', '5915', (110, 118))	('antisense', 'Var', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('RAR-beta', 'Gene', (110, 118))
869391	19258542	In addition, the apparent immortality of cultures isolated from oral dysplastic lesions was associated with the loss of RAR-beta2, p16, and mutated p53 expression and with increased levels of telomerase reverse transcriptase mRNA, but only the loss of RAR-beta2 and of p16 was responsible for the immortalization of the cultures.	('RAR-beta', 'Gene', '5915', (120, 128))	('oral dysplastic lesions', 'Disease', 'OMIM:155600', (64, 87))	('p16', 'Gene', '1029', (269, 272))	('increased', 'PosReg', (172, 181))	('p53', 'Gene', (148, 151))	('RAR-beta', 'Gene', (252, 260))	('levels', 'MPA', (182, 188))	('p16', 'Gene', '1029', (131, 134))	('p53', 'Gene', '7157', (148, 151))	('RAR-beta', 'Gene', (120, 128))	('loss', 'NegReg', (112, 116))	('p16', 'Gene', (269, 272))	('RAR-beta', 'Gene', '5915', (252, 260))	('oral dysplastic lesions', 'Disease', (64, 87))	('expression', 'MPA', (152, 162))	('telomerase reverse transcriptase mRNA', 'MPA', (192, 229))	('p16', 'Gene', (131, 134))	('mutated', 'Var', (140, 147))
869393	19258542	Indeed, the restoration of RAR-beta2 expression inhibited the growth of various cancers, induced tumor cells to undergo apoptosis, and suppressed cancer development in vitro and in vivo (for reviews, see refs.).	('cancer', 'Disease', (146, 152))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('induced', 'Reg', (89, 96))	('restoration', 'Var', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('suppressed', 'NegReg', (135, 145))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (97, 102))	('RAR-beta', 'Gene', '5915', (27, 35))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancers', 'Disease', (80, 87))	('inhibited', 'NegReg', (48, 57))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('expression', 'MPA', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('RAR-beta', 'Gene', (27, 35))
869401	19258542	The expression of exogenous RAR-beta2 cDNA or knockdown of RAR-beta2 expression was measured by Northern and Western blotting (see ref.).	('RAR-beta', 'Gene', '5915', (59, 67))	('RAR-beta', 'Gene', '5915', (28, 36))	('knockdown', 'Var', (46, 55))	('RAR-beta', 'Gene', (59, 67))	('RAR-beta', 'Gene', (28, 36))
869405	19258542	The antibodies used were anti-RAR-beta (Santa Cruz Biotechnology, Inc.), anti-COX-2 (BD Transduction Laboratories), and anti-beta-actin (Sigma-Aldrich).	('RAR-beta', 'Gene', (30, 38))	('beta-actin', 'Gene', '728378', (125, 135))	('anti-COX-2', 'Var', (73, 83))	('beta-actin', 'Gene', (125, 135))	('RAR-beta', 'Gene', '5915', (30, 38))
869414	19258542	Esophageal cancer cell lines TE-1, TE-8, HCE-4, and SKGT-4 were grown in monolayer overnight and transiently transfected with either pCMS/enhanced green fluorescent protein (EGFP; BD Clontech) plus pRC/CMV vector or pCMS/EGFP plus pRC/CMV/RAR-beta2 by using Lipofectamine 2000.	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('RAR-beta', 'Gene', (239, 247))	('pCMS/enhanced', 'Var', (133, 146))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (258, 276))	('Esophageal cancer', 'Disease', (0, 17))	('RAR-beta', 'Gene', '5915', (239, 247))
869418	19258542	The percentage of control of cell proliferation was calculated from the following equation: % control = NT/NV x 100, where NT and NV are the numbers of Ki67-positive cells in GFP-positive cells of COX-2 antisense- transfected or RAR-beta2-transfected and vector control cultures, respectively.	('COX-2', 'Gene', (197, 202))	('RAR-beta', 'Gene', (229, 237))	('RAR-beta', 'Gene', '5915', (229, 237))	('antisense-', 'Var', (203, 213))
869431	19258542	Moreover, after we introduced antisense RAR-beta2 cDNA into TE-3 cells that express high level of RAR-beta2 but low level of COX-2 (see refs.	('RAR-beta', 'Gene', (40, 48))	('RAR-beta', 'Gene', (98, 106))	('antisense', 'Var', (30, 39))	('RAR-beta', 'Gene', '5915', (40, 48))	('RAR-beta', 'Gene', '5915', (98, 106))
869432	19258542	), COX-2 expression was up-regulated in the antisense RAR-beta2 stable sublines (Fig.	('RAR-beta', 'Gene', (54, 62))	('expression', 'MPA', (9, 19))	('antisense', 'Var', (44, 53))	('RAR-beta', 'Gene', '5915', (54, 62))	('COX-2', 'Gene', (3, 8))	('up-regulated', 'PosReg', (24, 36))
869436	19258542	Furthermore, we did additional experiments to block COX-2 expression in these esophageal cancer cell lines using transient transfection of a COX-2 antisense expression vector, and 2 days later, we transfected a RAR-beta2 expression vector into these cells.	('COX-2', 'Gene', (141, 146))	('RAR-beta', 'Gene', (211, 219))	('antisense', 'Var', (147, 156))	('RAR-beta', 'Gene', '5915', (211, 219))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
869447	19258542	Indeed, our experiments found that a low dose of NS398 (12.5 micromol/L) itself does not have much antitumor activity, but it can additively increase the effect of ATRA in inhibiting growth of some of esophageal cancer cells (Fig.	('NS398', 'Chemical', 'MESH:C080955', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('increase', 'PosReg', (141, 149))	('tumor', 'Disease', (103, 108))	('NS398', 'Var', (49, 54))	('inhibiting', 'NegReg', (172, 182))	('esophageal cancer', 'Disease', (201, 218))	('ATRA', 'Chemical', '-', (164, 168))	('growth', 'CPA', (183, 189))	('esophageal cancer', 'Disease', 'MESH:D004938', (201, 218))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
869450	19258542	However, knockdown of RAR-beta2 expression up-regulated COX-2 expression in RAR-beta2-positive esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('knockdown', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('expression', 'MPA', (62, 72))	('RAR-beta', 'Gene', (22, 30))	('RAR-beta', 'Gene', '5915', (76, 84))	('RAR-beta', 'Gene', '5915', (22, 30))	('up-regulated', 'PosReg', (43, 55))	('esophageal cancer', 'Disease', (95, 112))	('RAR-beta', 'Gene', (76, 84))	('COX-2', 'Gene', (56, 61))
869451	19258542	Furthermore, combination of COX-2 inhibitor, NS398, with RA can additively increase their antitumor effects in some of esophageal cancer cell lines.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('NS398', 'Var', (45, 50))	('combination', 'Interaction', (13, 24))	('tumor', 'Disease', (94, 99))	('NS398', 'Chemical', 'MESH:C080955', (45, 50))	('RA', 'Chemical', 'MESH:D011883', (57, 59))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('increase', 'PosReg', (75, 83))	('esophageal cancer', 'Disease', (119, 136))
869454	19258542	For examples, an earlier study showed that lung cancer cell lines H157 and Calu-1 expressing transfected RAR-beta2 exhibited the decreased tumorigenicity in nude mice and these tumor cells expressed COX-2 protein.	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('RAR-beta', 'Gene', (105, 113))	('H157', 'CellLine', 'CVCL:2458', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('nude mice', 'Species', '10090', (157, 166))	('transfected', 'Var', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('RAR-beta', 'Gene', '5915', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('decreased', 'NegReg', (129, 138))
869462	19258542	Indeed, our previous studies showed that induction of RAR-beta2 can suppress COX-2 expression in esophageal cancer cells and the current study showed that RA can inhibit COX-2 expression in patients with oral premalignant lesions.	('RA', 'Chemical', 'MESH:D011883', (155, 157))	('oral premalignant lesions', 'Disease', 'MESH:D020820', (204, 229))	('inhibit', 'NegReg', (162, 169))	('patients', 'Species', '9606', (190, 198))	('RAR-beta', 'Gene', (54, 62))	('induction', 'Var', (41, 50))	('esophageal cancer', 'Disease', (97, 114))	('COX-2', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('COX-2', 'Enzyme', (170, 175))	('expression', 'MPA', (176, 186))	('RA', 'Chemical', 'MESH:D011883', (54, 56))	('RAR-beta', 'Gene', '5915', (54, 62))	('suppress', 'NegReg', (68, 76))	('expression', 'MPA', (83, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('oral premalignant lesions', 'Disease', (204, 229))
869494	22570818	Invasion of these structures produces symptoms of airway insufficiency, dysphagia, and hemoptysis and may increase morbidity by about 5 times or more.	('dysphagia', 'Disease', (72, 81))	('airway insufficiency', 'Disease', (50, 70))	('Invasion', 'Var', (0, 8))	('airway insufficiency', 'Phenotype', 'HP:0002093', (50, 70))	('morbidity', 'MPA', (115, 124))	('dysphagia', 'Phenotype', 'HP:0002015', (72, 81))	('hemoptysis', 'Disease', 'MESH:D006469', (87, 97))	('airway insufficiency', 'Disease', 'MESH:D000309', (50, 70))	('dysphagia', 'Disease', 'MESH:D003680', (72, 81))	('hemoptysis', 'Phenotype', 'HP:0002105', (87, 97))	('hemoptysis', 'Disease', (87, 97))
869605	30925028	We conducted a series of studies in Linxian of ESCC cases using a variety of different HPV assessment measures, including a prediagnostic serological HPV antibody test, cytological HPV DNA test, PCR assay in tissue samples, and serological E6/E7 antibody test, but found no consistent evidence of the role of HPV in the etiology of ESCC.38, 39, 40 These null results were consistent with results from a large international consortium project on serologic analyses of HPV L1 and E6/E7 and ESCC, which found only 0.3% of the total ESCC cases were positive for HPV 16 E6 and E7.41 Thus, the current evidence indicates that HPV does not play a significant role in the etiology of ESCC, and the number of ESCC cases caused by this virus, if any, is limited.	('HPV', 'Species', '10566', (467, 470))	('HPV', 'Species', '10566', (309, 312))	('HPV', 'Species', '10566', (181, 184))	('HPV 16', 'Species', '333760', (558, 564))	('HPV', 'Species', '10566', (558, 561))	('men', 'Species', '9606', (97, 100))	('HPV', 'Species', '10566', (87, 90))	('ESCC', 'Disease', (676, 680))	('ESCC', 'Disease', (700, 704))	('HPV', 'Species', '10566', (620, 623))	('E7.41', 'Var', (572, 577))	('HPV', 'Species', '10566', (150, 153))
869667	30643386	In recent decades, SC/B6 has been clinically applied as an adjuvant therapy for malignancies and has been beneficial for advanced DSN patients in several trials.	('SC/B6', 'Var', (19, 24))	('patients', 'Species', '9606', (134, 142))	('advanced DSN', 'Disease', (121, 133))	('malignancies', 'Disease', 'MESH:D009369', (80, 92))	('SC', 'Chemical', '-', (19, 21))	('malignancies', 'Disease', (80, 92))
869671	30643386	These results indicated that intravenous infusion of SC/B6 improved the curative effects of CMT for advanced DSNs.	('DSNs', 'Phenotype', 'HP:0007378', (109, 113))	('improved', 'PosReg', (59, 67))	('advanced DSNs', 'Disease', (100, 113))	('SC/B6', 'Var', (53, 58))	('curative effects', 'CPA', (72, 88))	('SC', 'Chemical', '-', (53, 55))
869676	30643386	Moreover, our subgroup analysis showed that SC/B6 combined with XELOX/capecitabine was more effective for DSN treatment.	('DSN', 'Disease', (106, 109))	('capecitabine', 'Chemical', 'MESH:D000069287', (70, 82))	('SC/B6', 'Var', (44, 49))	('XELOX', 'Chemical', 'MESH:C519688', (64, 69))	('SC', 'Chemical', '-', (44, 46))
869682	30643386	In summary, this meta-analysis indicated that SC/B6 and CMT combined therapy was effective in treating advanced DSNs.	('SC/B6', 'Var', (46, 51))	('DSNs', 'Phenotype', 'HP:0007378', (112, 116))	('advanced DSNs', 'Disease', (103, 116))	('SC', 'Chemical', '-', (46, 48))
869683	30643386	Intravenous infusion of SC/B6 not only greatly improved the therapeutic effects of CMT but also effectively alleviated the toxicity and most of the side effects associated with chemotherapy.	('improved', 'PosReg', (47, 55))	('toxicity', 'Disease', (123, 131))	('alleviated', 'NegReg', (108, 118))	('SC', 'Chemical', '-', (24, 26))	('therapeutic', 'MPA', (60, 71))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))	('SC/B6', 'Var', (24, 29))
869684	30643386	Therefore, SC/B6 has potential for development as a new adjuvant therapy for the treatment of DSN.	('SC/B6', 'Var', (11, 16))	('DSN', 'Disease', (94, 97))	('SC', 'Chemical', '-', (11, 13))
869795	28260921	SIX1 depletion inhibited cell growth, invasion, and colony formation, whereas its overexpression facilitated in vivo and in vitro cell growth, invasion, and colony formation.	('inhibited', 'NegReg', (15, 24))	('depletion', 'Var', (5, 14))	('invasion', 'CPA', (143, 151))	('SIX1', 'Gene', (0, 4))	('overexpression facilitated', 'PosReg', (82, 108))	('invasion', 'CPA', (38, 46))	('colony formation', 'CPA', (157, 173))	('SIX1', 'Gene', '6495', (0, 4))	('cell growth', 'CPA', (25, 36))	('colony formation', 'CPA', (52, 68))
869796	28260921	The apoptosis rate induced by X-ray irradiation was substantially increased by SIX1 knockdown in Eca-109 cells.	('increased', 'PosReg', (66, 75))	('knockdown', 'Var', (84, 93))	('SIX1', 'Gene', (79, 83))	('SIX1', 'Gene', '6495', (79, 83))	('apoptosis rate', 'CPA', (4, 18))
869798	28260921	Western blot analysis showed that SIX1 depletion downregulated cyclin E, matrix metalloproteinase-2 (MMP-2), Bcl-2 expression and upregulated Bim expression.	('matrix metalloproteinase-2', 'Gene', (73, 99))	('upregulated', 'PosReg', (130, 141))	('depletion', 'Var', (39, 48))	('matrix metalloproteinase-2', 'Gene', '4313', (73, 99))	('MMP-2', 'Gene', '4313', (101, 106))	('cyclin E', 'Protein', (63, 71))	('SIX1', 'Gene', (34, 38))	('Bim', 'Gene', (142, 145))	('expression', 'MPA', (115, 125))	('MMP-2', 'Gene', (101, 106))	('downregulated', 'NegReg', (49, 62))	('SIX1', 'Gene', '6495', (34, 38))	('Bim', 'Gene', '10018', (142, 145))	('Bcl-2', 'Gene', (109, 114))	('Bcl-2', 'Gene', '596', (109, 114))
869849	28260921	Selection of stable TE-1-SIX1 cell line was accomplished with G418 (Sigma-Aldrich Co.) at a concentration of 0.3 mg/mL.	('TE-1', 'CellLine', 'CVCL:1759', (20, 24))	('SIX1', 'Gene', (25, 29))	('G418', 'Chemical', 'MESH:C010680', (62, 66))	('SIX1', 'Gene', '6495', (25, 29))	('G418', 'Var', (62, 66))
869871	28260921	MTT demonstrated that SIX1 transfection facilitated the cell proliferation rate in TE-1 cell line, while its siRNA blocked proliferation in Eca-109 cell line (Figure 3A).	('blocked', 'NegReg', (115, 122))	('SIX1', 'Gene', (22, 26))	('facilitated', 'PosReg', (40, 51))	('SIX1', 'Gene', '6495', (22, 26))	('cell proliferation rate', 'CPA', (56, 79))	('transfection', 'Var', (27, 39))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('TE-1', 'CellLine', 'CVCL:1759', (83, 87))
869884	28260921	The results showed that SIX1 transfection upregulated cyclin E and MMP-2 expression, while SIX1 depletion showed the opposite effects (Figure 4B).	('SIX1', 'Gene', '6495', (91, 95))	('SIX1', 'Gene', (91, 95))	('MMP-2', 'Gene', '4313', (67, 72))	('SIX1', 'Gene', '6495', (24, 28))	('SIX1', 'Gene', (24, 28))	('cyclin E', 'Protein', (54, 62))	('expression', 'MPA', (73, 83))	('upregulated', 'PosReg', (42, 53))	('MMP-2', 'Gene', (67, 72))	('transfection', 'Var', (29, 41))
869893	28260921	As shown in Figure 5A, inhibition of ERK signaling blocked the role of SIX1 on MMP-2 production.	('SIX1', 'Gene', (71, 75))	('MMP-2', 'Gene', (79, 84))	('inhibition', 'Var', (23, 33))	('SIX1', 'Gene', '6495', (71, 75))	('ERK', 'Gene', '5594', (37, 40))	('ERK', 'Gene', (37, 40))	('MMP-2', 'Gene', '4313', (79, 84))	('blocked', 'NegReg', (51, 58))
869922	28260921	Targeting SIX1 might be a novel strategy to improve therapeutic effects in ESCC patients.	('patients', 'Species', '9606', (80, 88))	('ESCC', 'Disease', (75, 79))	('SIX1', 'Gene', (10, 14))	('SIX1', 'Gene', '6495', (10, 14))	('Targeting', 'Var', (0, 9))
869961	25967554	The majority of migrations are often asymptomatic but they can cause hazardous issues like tracheoesophageal fistula formation, bleeding, obstruction and perforation.	('bleeding', 'Disease', (128, 136))	('obstruction', 'Disease', (138, 149))	('perforation', 'Disease', (154, 165))	('cause', 'Reg', (63, 68))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (91, 116))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (91, 116))	('bleeding', 'Disease', 'MESH:D006470', (128, 136))	('obstruction', 'Disease', 'MESH:D000402', (138, 149))	('tracheoesophageal fistula', 'Disease', (91, 116))	('migrations', 'Var', (16, 26))
869994	25337902	Single Nucleotide Polymorphisms of One-Carbon Metabolism and Cancers of the Esophagus, Stomach, and Liver in a Chinese Population One-carbon metabolism (folate metabolism) is considered important in carcinogenesis because of its involvement in DNA synthesis and biological methylation reactions.	('Cancers of the Esophagus', 'Phenotype', 'HP:0100751', (61, 85))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Carbon', 'Chemical', 'MESH:D002244', (39, 45))	('Cancers of the Esophagus', 'Disease', (61, 85))	('involvement', 'Reg', (229, 240))	('One-carbon', 'Chemical', '-', (130, 140))	('carcinogenesis', 'Disease', 'MESH:D063646', (199, 213))	('Single Nucleotide Polymorphisms', 'Var', (0, 31))	('Cancers', 'Phenotype', 'HP:0002664', (61, 68))	('carcinogenesis', 'Disease', (199, 213))	('Cancers of the Esophagus', 'Disease', 'MESH:D004938', (61, 85))	('folate', 'Chemical', '-', (153, 159))
869995	25337902	We investigated the associations of single nucleotide polymorphisms (SNPs) in folate metabolic pathway and the risk of three GI cancers in a population-based case-control study in Taixing City, China, with 218 esophageal cancer cases, 206 stomach cancer cases, 204 liver cancer cases, and 415 healthy population controls.	('associations', 'Interaction', (20, 32))	('GI cancer', 'Phenotype', 'HP:0007378', (125, 134))	('liver cancer', 'Disease', 'MESH:D006528', (265, 277))	('stomach cancer', 'Disease', 'MESH:D013274', (239, 253))	('stomach cancer', 'Phenotype', 'HP:0012126', (239, 253))	('single nucleotide polymorphisms', 'Var', (36, 67))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('liver cancer', 'Phenotype', 'HP:0002896', (265, 277))	('liver cancer', 'Disease', (265, 277))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('esophageal cancer', 'Disease', 'MESH:D004938', (210, 227))	('folate metabolic pathway', 'Pathway', (78, 102))	('GI cancers', 'Disease', (125, 135))	('esophageal cancer', 'Disease', (210, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('stomach cancer', 'Disease', (239, 253))	('GI cancers', 'Disease', 'MESH:D009369', (125, 135))	('folate', 'Chemical', '-', (78, 84))	('investigated', 'Reg', (3, 15))
869999	25337902	After shrinkage and adjusting for potential confounding factors, we found positive associations between MTHFR rs1801133 and stomach cancer (any T versus C/C, SB odds-ratio [SBOR]: 1.79, 95% posterior limits: 1.18, 2.71) and liver cancer (SBOR: 1.51, 95% posterior limits: 0.98, 2.32).	('stomach cancer', 'Disease', 'MESH:D013274', (124, 138))	('rs1801133', 'Mutation', 'rs1801133', (110, 119))	('liver cancer', 'Phenotype', 'HP:0002896', (224, 236))	('stomach cancer', 'Phenotype', 'HP:0012126', (124, 138))	('SB', 'Chemical', '-', (238, 240))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('liver cancer', 'Disease', 'MESH:D006528', (224, 236))	('SB', 'Chemical', '-', (173, 175))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('liver cancer', 'Disease', (224, 236))	('stomach cancer', 'Disease', (124, 138))	('MTHFR', 'Gene', '4524', (104, 109))	('SB', 'Chemical', '-', (158, 160))	('rs1801133', 'Var', (110, 119))	('MTHFR', 'Gene', (104, 109))
870000	25337902	There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94).	('DNMT1', 'Gene', (41, 46))	('DNMT1', 'Gene', '1786', (41, 46))	('rs2228612', 'Mutation', 'rs2228612', (47, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('inverse', 'NegReg', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rs2228612', 'Var', (47, 56))	('SB', 'Chemical', '-', (98, 100))	('esophageal cancer', 'Disease', (61, 78))
870002	25337902	Among non-alcohol drinkers, the variant allele (allele G) of these two SNPs was inversely associated with the risk of these cancers; while a positive association was observed among ever-alcohol drinkers.	('variant', 'Var', (32, 39))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (10, 26))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (186, 202))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('alcohol', 'Chemical', 'MESH:D000438', (10, 17))	('inversely', 'NegReg', (80, 89))	('cancers', 'Disease', (124, 131))	('alcohol', 'Chemical', 'MESH:D000438', (186, 193))
870003	25337902	Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver.	('cancers of the esophagus', 'Disease', (103, 127))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('carbon', 'Chemical', 'MESH:D002244', (62, 68))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (103, 127))	('associated', 'Reg', (87, 97))	('stomach', 'Disease', (129, 136))	('genetic polymorphisms', 'Var', (25, 46))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('liver', 'Disease', (142, 147))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (103, 127))
870004	25337902	Heterogeneity across alcohol consumption status of the associations between MTR/MTRR polymorphisms and these cancers indicates potential interactions between alcohol drinking and one-carbon metabolic pathway.	('interactions', 'Interaction', (137, 149))	('MTRR', 'Gene', (80, 84))	('associations', 'Interaction', (55, 67))	('polymorphisms', 'Var', (85, 98))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('one-carbon metabolic pathway', 'Pathway', (179, 207))	('alcohol', 'Chemical', 'MESH:D000438', (158, 165))	('MTRR', 'Gene', '4552', (80, 84))	('cancers', 'Disease', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('alcohol drinking', 'Phenotype', 'HP:0030955', (158, 174))	('alcohol', 'Chemical', 'MESH:D000438', (21, 28))	('carbon', 'Chemical', 'MESH:D002244', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
870009	25337902	Continued research regarding the involvement of single nucleotide polymorphisms (SNPs) in the etiology of these three upper GI cancers has been fruitful.	('upper GI cancers', 'Disease', (118, 134))	('single nucleotide polymorphisms', 'Var', (48, 79))	('GI cancer', 'Phenotype', 'HP:0007378', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('upper GI cancers', 'Disease', 'MESH:D009369', (118, 134))
870011	25337902	Neoplasms may develop when this pathway is disregulated by the depletion of micronutrients or through the incorporation of polymorphisms.	('Neoplasms', 'Phenotype', 'HP:0002664', (0, 9))	('incorporation', 'Reg', (106, 119))	('depletion of micronutrients', 'MPA', (63, 90))	('polymorphisms', 'Var', (123, 136))	('develop', 'Reg', (14, 21))	('Neoplasms', 'Disease', 'MESH:D009369', (0, 9))	('Neoplasms', 'Disease', (0, 9))
870017	25337902	Animal studies provided some evidence for an effect of low folate levels in oxidative stress, DNA methylation, and hepatocarcinogenesis; while high folate intake can increase global DNA methylation and reduce gastric cancer risk.	('global DNA methylation', 'MPA', (175, 197))	('increase', 'PosReg', (166, 174))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (115, 135))	('low folate levels', 'Phenotype', 'HP:0100507', (55, 72))	('high folate intake', 'Phenotype', 'HP:0032164', (143, 161))	('oxidative', 'MPA', (76, 85))	('gastric cancer', 'Disease', (209, 223))	('reduce', 'NegReg', (202, 208))	('high folate', 'Var', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('gastric cancer', 'Disease', 'MESH:D013274', (209, 223))	('folate', 'Chemical', '-', (59, 65))	('oxidative stress', 'Phenotype', 'HP:0025464', (76, 92))	('hepatocarcinogenesis', 'Disease', (115, 135))	('folate', 'Chemical', '-', (148, 154))	('reduce gastric cancer', 'Phenotype', 'HP:0006753', (202, 223))	('gastric cancer', 'Phenotype', 'HP:0012126', (209, 223))
870018	25337902	Epidemiologic studies have suggested that genetic polymorphisms of genes in one-carbon metabolic pathway might modulate the risk of esophageal and gastric cancer.	('modulate', 'Reg', (111, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('one-carbon metabolic pathway', 'Pathway', (76, 104))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('carbon', 'Chemical', 'MESH:D002244', (80, 86))	('gastric cancer', 'Disease', (147, 161))	('esophageal', 'Disease', (132, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('genetic polymorphisms', 'Var', (42, 63))
870019	25337902	Therefore, considering the importance of one-carbon metabolism in upper GI cancer development, we examined the associations between eight SNPs in genes in one-carbon metabolic pathway and cancers of the esophagus, stomach, and liver in a Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('carbon', 'Chemical', 'MESH:D002244', (45, 51))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('associations', 'Interaction', (111, 123))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (188, 212))	('carbon', 'Chemical', 'MESH:D002244', (159, 165))	('liver', 'Disease', (227, 232))	('upper GI cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancers of the esophagus', 'Disease', (188, 212))	('stomach', 'Disease', (214, 221))	('SNPs', 'Var', (138, 142))	('upper GI cancer', 'Disease', 'MESH:D009369', (66, 81))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (188, 212))	('GI cancer', 'Phenotype', 'HP:0007378', (72, 81))
870035	25337902	We selected eight SNPs from MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes, based on the following criteria: 1) SNPs which are functional or potentially functional (SNPs located in the coding, 3'-, and 5'-untranslated regions); 2) SNPs previously reported to be associated with upper GI cancers; and 3) SNPs with minor allele frequency of at least 5% in the National Center for Biotechnology Information SNP database.	('SNPs', 'Var', (225, 229))	('MTHFR', 'Gene', '4524', (28, 33))	('DNMT1', 'Gene', (46, 51))	('DNMT1', 'Gene', '1786', (46, 51))	('MTRR', 'Gene', (40, 44))	('MTRR', 'Gene', '4552', (40, 44))	('ALDH2', 'Gene', (57, 62))	('MTR', 'Gene', (35, 38))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('MTHFR', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('upper GI cancers', 'Disease', 'MESH:D009369', (272, 288))	('associated', 'Reg', (256, 266))	('upper GI cancers', 'Disease', (272, 288))	('ALDH2', 'Gene', '217', (57, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (278, 287))
870038	25337902	Models included age-matched categories, sex, residency (urban/rural), education (illiteracy/primary school/higher than middle school), body mass index (BMI, continuous), smoking pack-years (continuous), alcohol consumption frequency (never/occasionally/often/everyday), H. pylori infection (stomach cancer; negative/positive), HBsAg status (liver cancer; negative/positive) and plasma AFB1-albumin adduct levels in quintiles (liver cancer; estimated quintile: <222.7, 222.7-344.2, 344.2-442.6, 442.6-588.5, and >588.5 fmol/mg).	('liver cancer', 'Phenotype', 'HP:0002896', (426, 438))	('cancer', 'Phenotype', 'HP:0002664', (432, 438))	('liver cancer', 'Disease', (426, 438))	('222.7-344.2', 'Var', (468, 479))	('442.6-588.5', 'Var', (494, 505))	('H. pylori', 'Species', '210', (270, 279))	('pylori infection', 'Disease', 'MESH:D016481', (273, 289))	('AFB1', 'Chemical', 'MESH:D016604', (385, 389))	('stomach cancer', 'Disease', 'MESH:D013274', (291, 305))	('stomach cancer', 'Phenotype', 'HP:0012126', (291, 305))	('plasma AFB1-albumin adduct levels', 'MPA', (378, 411))	('>588.5 fmol/mg', 'Var', (511, 525))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('pylori infection', 'Disease', (273, 289))	('liver cancer', 'Disease', 'MESH:D006528', (341, 353))	('alcohol', 'Chemical', 'MESH:D000438', (203, 210))	('H. pylori infection', 'Phenotype', 'HP:0005202', (270, 289))	('liver cancer', 'Disease', 'MESH:D006528', (426, 438))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('liver cancer', 'Phenotype', 'HP:0002896', (341, 353))	('344.2-442.6', 'Var', (481, 492))	('liver cancer', 'Disease', (341, 353))	('stomach cancer', 'Disease', (291, 305))
870054	25337902	Genotype distributions among controls appeared compatible with Hardy-Weinberg equilibrium, except possibly for DNMT1 rs2228612, which had P = 0.010, below the traditional alpha level of 0.05, but larger than the Bonferroni-adjusted alpha level of 0.05/8 = 0.006 (testing all eight SNPs).	('DNMT1', 'Gene', '1786', (111, 116))	('DNMT1', 'Gene', (111, 116))	('rs2228612', 'Mutation', 'rs2228612', (117, 126))	('rs2228612', 'Var', (117, 126))
870056	25337902	We have previously reported positive associations of the T allele of MTHFR rs1801133 with stomach and liver cancer.	('liver cancer', 'Disease', 'MESH:D006528', (102, 114))	('stomach', 'Disease', (90, 97))	('MTHFR', 'Gene', '4524', (69, 74))	('liver cancer', 'Disease', (102, 114))	('rs1801133', 'Var', (75, 84))	('positive', 'PosReg', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('rs1801133', 'Mutation', 'rs1801133', (75, 84))	('MTHFR', 'Gene', (69, 74))	('liver cancer', 'Phenotype', 'HP:0002896', (102, 114))
870058	25337902	In stratified SB analyses, the association between MTHFR rs1801133 and stomach cancer appeared stronger among individuals who had lower plasma folate levels, higher plasma vitamin B12 or tHcy levels, and among smokers (Figure 1).	('SB', 'Chemical', '-', (14, 16))	('stomach cancer', 'Disease', 'MESH:D013274', (71, 85))	('higher', 'PosReg', (158, 164))	('tHcy levels', 'MPA', (187, 198))	('stomach cancer', 'Phenotype', 'HP:0012126', (71, 85))	('lower', 'NegReg', (130, 135))	('stronger', 'PosReg', (95, 103))	('rs1801133', 'Mutation', 'rs1801133', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('folate', 'Chemical', '-', (143, 149))	('MTHFR', 'Gene', '4524', (51, 56))	('plasma folate levels', 'MPA', (136, 156))	('stomach cancer', 'Disease', (71, 85))	('tHcy', 'Chemical', '-', (187, 191))	('vitamin B12', 'Chemical', 'MESH:D014805', (172, 183))	('lower plasma folate levels', 'Phenotype', 'HP:0100507', (130, 156))	('rs1801133', 'Var', (57, 66))	('plasma vitamin B12', 'MPA', (165, 183))	('MTHFR', 'Gene', (51, 56))
870059	25337902	There was no clear association of MTHFR rs1801133 with esophageal cancer (Table 2 and Tables S1, S2, S3, S4, S5).	('MTHFR', 'Gene', '4524', (34, 39))	('rs1801133', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal cancer', 'Disease', (55, 72))	('rs1801133', 'Mutation', 'rs1801133', (40, 49))	('MTHFR', 'Gene', (34, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))
870060	25337902	While there was no clear overall association between SNPs in MTR and MTRR and any cancer in main effect analyses (Table 2), heterogeneity of association was suggested in stratified analyses on alcohol consumption, including associations of MTR rs1805087 with liver cancer (homogeneity P = 0.021), and MTRR rs1801394 with both esophageal (homogeneity P = 0.005) and stomach cancer (homogeneity P = 0.004).	('stomach cancer', 'Disease', 'MESH:D013274', (365, 379))	('MTRR', 'Gene', (301, 305))	('stomach cancer', 'Phenotype', 'HP:0012126', (365, 379))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancer', 'Disease', (82, 88))	('liver cancer', 'Phenotype', 'HP:0002896', (259, 271))	('MTRR', 'Gene', (69, 73))	('liver cancer', 'Disease', (259, 271))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('associations', 'Interaction', (224, 236))	('cancer', 'Disease', (373, 379))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('rs1805087', 'Var', (244, 253))	('MTR', 'Gene', (240, 243))	('stomach cancer', 'Disease', (365, 379))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('rs1801394', 'Mutation', 'rs1801394', (306, 315))	('rs1801394', 'Var', (306, 315))	('esophageal', 'Disease', (326, 336))	('alcohol', 'Chemical', 'MESH:D000438', (193, 200))	('rs1805087', 'Mutation', 'rs1805087', (244, 253))	('MTRR', 'Gene', '4552', (301, 305))	('cancer', 'Disease', 'MESH:D009369', (373, 379))	('liver cancer', 'Disease', 'MESH:D006528', (259, 271))	('cancer', 'Disease', (265, 271))	('MTRR', 'Gene', '4552', (69, 73))
870061	25337902	While G allele carriers of MTR rs1805087 were inversely associated with liver cancer among non-drinkers (SBOR: 0.57, 95% posterior limits: 0.31, 1.04), they were positively associated with liver cancer among drinkers (SBOR: 1.48, 95% posterior limits: 0.85, 2.57) (Figure 1).	('inversely', 'NegReg', (46, 55))	('liver cancer', 'Phenotype', 'HP:0002896', (189, 201))	('liver cancer', 'Disease', 'MESH:D006528', (189, 201))	('MTR', 'Gene', (27, 30))	('SB', 'Chemical', '-', (218, 220))	('liver cancer', 'Phenotype', 'HP:0002896', (72, 84))	('liver cancer', 'Disease', 'MESH:D006528', (72, 84))	('SB', 'Chemical', '-', (105, 107))	('rs1805087', 'Var', (31, 40))	('liver cancer', 'Disease', (72, 84))	('associated with', 'Reg', (173, 188))	('liver cancer', 'Disease', (189, 201))	('rs1805087', 'Mutation', 'rs1805087', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
870062	25337902	Similarly, G allele carriers of MTRR rs1801394 were inversely associated with esophageal and stomach cancer among non-drinkers (SBOR: 0.59, 95% posterior limits: 0.37, 0.94 for esophageal cancer; SBOR: 0.49, 95% posterior limits: 0.30, 0.79 for stomach cancer) but positively associated with cancer among drinkers (SBOR: 1.56, 95% posterior limits: 0.95, 2.56 for esophageal cancer; SBOR: 1.39, 95% posterior limits: 0.83, 2.32 for stomach cancer) (Figure 1).	('esophageal cancer', 'Disease', (364, 381))	('stomach cancer', 'Disease', 'MESH:D013274', (245, 259))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('stomach cancer', 'Phenotype', 'HP:0012126', (245, 259))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('stomach cancer', 'Disease', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('SB', 'Chemical', '-', (383, 385))	('associated', 'Reg', (62, 72))	('stomach cancer', 'Disease', (432, 446))	('cancer', 'Disease', (292, 298))	('cancer', 'Disease', 'MESH:D009369', (440, 446))	('rs1801394', 'Mutation', 'rs1801394', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('rs1801394', 'Var', (37, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('SB', 'Chemical', '-', (128, 130))	('stomach cancer', 'Disease', 'MESH:D013274', (93, 107))	('MTRR', 'Gene', '4552', (32, 36))	('esophageal and stomach cancer', 'Disease', 'MESH:D013274', (78, 107))	('stomach cancer', 'Phenotype', 'HP:0012126', (93, 107))	('cancer', 'Disease', (253, 259))	('stomach cancer', 'Disease', (245, 259))	('cancer', 'Disease', (188, 194))	('esophageal cancer', 'Disease', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('stomach cancer', 'Disease', 'MESH:D013274', (432, 446))	('stomach cancer', 'Phenotype', 'HP:0012126', (432, 446))	('MTRR', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (101, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (364, 381))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('SB', 'Chemical', '-', (315, 317))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (440, 446))	('SB', 'Chemical', '-', (196, 198))	('cancer', 'Disease', (375, 381))
870063	25337902	For DNMT1 polymorphism, rs2228612 was inversely associated with esophageal cancer in the dominant genetic model (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94) (Table 2).	('SB', 'Chemical', '-', (131, 133))	('associated', 'Reg', (48, 58))	('esophageal cancer', 'Disease', (64, 81))	('rs2228612', 'Mutation', 'rs2228612', (24, 33))	('inversely', 'NegReg', (38, 47))	('DNMT1', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('DNMT1', 'Gene', '1786', (4, 9))	('rs2228612', 'Var', (24, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
870064	25337902	Among three ALDH2 SNPs, rs671 was associated with esophageal cancer in the recessive genetic model (A/A versus any G, SBOR: 1.76, 95% posterior limits: 0.96, 3.24).	('ALDH2', 'Gene', (12, 17))	('associated with', 'Reg', (34, 49))	('rs671', 'Var', (24, 29))	('SB', 'Chemical', '-', (118, 120))	('rs671', 'Mutation', 'rs671', (24, 29))	('esophageal cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ALDH2', 'Gene', '217', (12, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
870065	25337902	In stratified adjusted analyses, ALDH2 rs671 appeared associated with esophageal cancer among individuals with lower plasma folate levels (A/A versus any G, SBOR: 2.12, 95% posterior limits: 1.01, 4.44) (Figure 1).	('rs671', 'Mutation', 'rs671', (39, 44))	('ALDH2', 'Gene', (33, 38))	('esophageal cancer', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('rs671', 'Var', (39, 44))	('lower', 'NegReg', (111, 116))	('SB', 'Chemical', '-', (157, 159))	('plasma folate levels', 'MPA', (117, 137))	('ALDH2', 'Gene', '217', (33, 38))	('folate', 'Chemical', '-', (124, 130))	('lower plasma folate levels', 'Phenotype', 'HP:0100507', (111, 137))	('associated with', 'Reg', (54, 69))
870066	25337902	The ALDH2 rs2238151 appeared inversely associated with liver cancer when comparing T allele carriers to those with the C/C genotype (age and sex-adjusted SBOR: 0.47, 95% posterior limits: 0.24, 0.92).	('inversely', 'NegReg', (29, 38))	('ALDH2', 'Gene', '217', (4, 9))	('liver cancer', 'Phenotype', 'HP:0002896', (55, 67))	('liver cancer', 'Disease', 'MESH:D006528', (55, 67))	('ALDH2', 'Gene', (4, 9))	('rs2238151', 'Mutation', 'rs2238151', (10, 19))	('liver cancer', 'Disease', (55, 67))	('associated', 'Reg', (39, 49))	('SB', 'Chemical', '-', (154, 156))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('rs2238151', 'Var', (10, 19))
870067	25337902	While we did not find associations between ALDH2 rs886205 and cancer susceptibility in main effect analyses, stratum-specific SBOR suggested that ALDH2 rs886205 was positively associated with stomach cancer among participants with higher plasma vitamin B12 levels (SBOR: 1.87, 95% posterior limits: 1.09, 3.20) (Figure 1).	('rs886205', 'Mutation', 'rs886205', (49, 57))	('ALDH2', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('rs886205', 'Mutation', 'rs886205', (152, 160))	('SB', 'Chemical', '-', (265, 267))	('ALDH2', 'Gene', '217', (146, 151))	('associated with', 'Reg', (176, 191))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('ALDH2', 'Gene', '217', (43, 48))	('rs886205', 'Var', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('stomach cancer', 'Disease', (192, 206))	('SB', 'Chemical', '-', (126, 128))	('vitamin B12', 'Chemical', 'MESH:D014805', (245, 256))	('participants', 'Species', '9606', (213, 225))	('stomach cancer', 'Phenotype', 'HP:0012126', (192, 206))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('stomach cancer', 'Disease', 'MESH:D013274', (192, 206))	('ALDH2', 'Gene', (146, 151))	('cancer', 'Disease', (200, 206))
870070	25337902	We examined the associations between eight SNPs in genes involved in the one-carbon metabolic pathway and susceptibility of esophageal, stomach, and liver cancers in a Chinese population.	('SNPs', 'Var', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('stomach', 'Disease', (136, 143))	('liver cancer', 'Phenotype', 'HP:0002896', (149, 161))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('liver cancers', 'Phenotype', 'HP:0002896', (149, 162))	('liver cancers', 'Disease', (149, 162))	('liver cancers', 'Disease', 'MESH:D006528', (149, 162))	('esophageal', 'Disease', (124, 134))	('carbon', 'Chemical', 'MESH:D002244', (77, 83))
870071	25337902	After applying SB shrinkage methods and controlling for potential confounders, we observed that any T genotype of MTHFR rs1801133 was positively associated with both stomach and liver cancer.	('liver cancer', 'Disease', 'MESH:D006528', (178, 190))	('liver cancer', 'Disease', (178, 190))	('stomach', 'Disease', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('rs1801133', 'Var', (120, 129))	('associated', 'Reg', (145, 155))	('MTHFR', 'Gene', '4524', (114, 119))	('SB', 'Chemical', '-', (15, 17))	('rs1801133', 'Mutation', 'rs1801133', (120, 129))	('liver cancer', 'Phenotype', 'HP:0002896', (178, 190))	('MTHFR', 'Gene', (114, 119))
870072	25337902	We also found an inverse association between the variant G allele of DNMT1 rs2228612 and esophageal cancer.	('rs2228612', 'Mutation', 'rs2228612', (75, 84))	('esophageal cancer', 'Disease', (89, 106))	('DNMT1', 'Gene', '1786', (69, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('inverse', 'NegReg', (17, 24))	('rs2228612', 'Var', (75, 84))	('DNMT1', 'Gene', (69, 74))
870073	25337902	In addition, our study suggested potential OR variations across strata of alcohol consumption, including associations of MTRR rs1801394 with esophageal and stomach cancer, and MTR rs1805087 with liver cancer.	('liver cancer', 'Phenotype', 'HP:0002896', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('rs1801394', 'Var', (126, 135))	('rs1801394', 'Mutation', 'rs1801394', (126, 135))	('liver cancer', 'Disease', 'MESH:D006528', (195, 207))	('alcohol', 'Chemical', 'MESH:D000438', (74, 81))	('liver cancer', 'Disease', (195, 207))	('stomach cancer', 'Phenotype', 'HP:0012126', (156, 170))	('MTR', 'Var', (176, 179))	('associations', 'Interaction', (105, 117))	('rs1805087', 'Var', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('rs1805087', 'Mutation', 'rs1805087', (180, 189))	('MTRR', 'Gene', (121, 125))	('esophageal and stomach cancer', 'Disease', 'MESH:D013274', (141, 170))	('MTRR', 'Gene', '4552', (121, 125))
870077	25337902	The MTHFR C677T (rs1801133) polymorphism, which results in an alanine to valine substitution, leads to reduced MTHFR enzyme activity, decreased 5-methylTHF and an accumulation of 5,10-methyleneTHF in red blood cells.	('valine', 'Chemical', 'MESH:D014633', (73, 79))	('5,10-methyleneTHF', 'Chemical', 'MESH:C013123', (179, 196))	('5-methylTHF', 'Chemical', 'MESH:C005984', (144, 155))	('5-methylTHF', 'MPA', (144, 155))	('MTHFR', 'Gene', (111, 116))	('alanine', 'MPA', (62, 69))	('MTHFR', 'Gene', '4524', (4, 9))	('rs1801133', 'Mutation', 'rs1801133', (17, 26))	('C677T (rs1801133', 'Var', (10, 26))	('decreased', 'NegReg', (134, 143))	('alanine', 'Chemical', 'MESH:D000409', (62, 69))	('reduced', 'NegReg', (103, 110))	('activity', 'MPA', (124, 132))	('results', 'Reg', (48, 55))	('MTHFR', 'Gene', (4, 9))	('C677T', 'Mutation', 'rs1801133', (10, 15))	('accumulation', 'PosReg', (163, 175))	('MTHFR', 'Gene', '4524', (111, 116))	('rs1801133', 'Var', (17, 26))
870080	25337902	Although evidence in support of these hypotheses is weak and inconsistent, an in vitro study suggested that the effect of MTHFR rs1801133 on DNA stability and methylation is site-specific and may depend on folate availability.	('MTHFR', 'Gene', '4524', (122, 127))	('rs1801133', 'Mutation', 'rs1801133', (128, 137))	('rs1801133', 'Var', (128, 137))	('methylation', 'MPA', (159, 170))	('folate', 'Chemical', '-', (206, 212))	('MTHFR', 'Gene', (122, 127))	('DNA stability', 'MPA', (141, 154))
870081	25337902	When folate supply is adequate or high, the T allele of MTHFR is associated with increased genomic DNA methylation in colon cancer cells, but decreased DNA methylation in breast cancer cells.	('folate', 'Chemical', '-', (5, 11))	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('DNA methylation', 'MPA', (152, 167))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('T allele', 'Var', (44, 52))	('breast cancer', 'Disease', (171, 184))	('colon cancer', 'Disease', (118, 130))	('MTHFR', 'Gene', '4524', (56, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('decreased', 'NegReg', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('MTHFR', 'Gene', (56, 61))	('increased', 'PosReg', (81, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (118, 130))	('colon cancer', 'Disease', 'MESH:D015179', (118, 130))
870084	25337902	This site-specific difference may partly explain the difference in cancer risk associated with the MTHFR rs1801133 polymorphism.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('MTHFR', 'Gene', '4524', (99, 104))	('cancer', 'Disease', (67, 73))	('rs1801133', 'Var', (105, 114))	('MTHFR', 'Gene', (99, 104))	('rs1801133', 'Mutation', 'rs1801133', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
870085	25337902	In epidemiologic studies, the T allele appears to decrease the risk of colorectal and breast cancers, but increase the risk of cancers of the esophagus, stomach, liver, bladder, cervix uteri, and lung.	('bladder', 'Disease', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers of the esophagus', 'Phenotype', 'HP:0100751', (127, 151))	('breast cancers', 'Phenotype', 'HP:0003002', (86, 100))	('T allele', 'Var', (30, 38))	('stomach', 'Disease', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('colorectal and breast cancers', 'Disease', 'MESH:D015179', (71, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('liver', 'Disease', (162, 167))	('cancers of the esophagus', 'Disease', (127, 151))	('cancers of the esophagus', 'Disease', 'MESH:D004938', (127, 151))	('increase', 'PosReg', (106, 114))	('cervix uteri', 'Phenotype', 'HP:0000139', (178, 190))	('cervix uteri', 'Disease', (178, 190))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('decrease', 'NegReg', (50, 58))
870086	25337902	In the present analysis using SB shrinkage, we confirmed our previous findings of positive associations between the T allele of MTHFR rs1801133 and cancers of the stomach and liver in this Taixing population, implying that the disturbance of DNA methylation resulting from this variant plays a major role in stomach and liver carcinogenesis.	('liver carcinogenesis', 'Disease', (320, 340))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('MTHFR', 'Gene', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('rs1801133', 'Var', (134, 143))	('cancers of the stomach', 'Disease', 'MESH:D013274', (148, 170))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (320, 340))	('cancers of the stomach', 'Disease', (148, 170))	('rs1801133', 'Mutation', 'rs1801133', (134, 143))	('SB', 'Chemical', '-', (30, 32))	('MTHFR', 'Gene', '4524', (128, 133))	('cancers of the stomach', 'Phenotype', 'HP:0006753', (148, 170))
870088	25337902	reported a larger association between MTHFR rs1801133 and stomach cancer among study populations without folic acid fortification (OR: 1.60, 95% CI: 1.36-1.88), as compared to those with fortification (OR: 1.15, 95% CI: 0.81-1.63), which is similar to our finding of a stronger association among individuals with lower plasma folate levels.	('stomach cancer', 'Disease', (58, 72))	('MTHFR', 'Gene', '4524', (38, 43))	('folate', 'Chemical', '-', (326, 332))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('rs1801133', 'Mutation', 'rs1801133', (44, 53))	('rs1801133', 'Var', (44, 53))	('MTHFR', 'Gene', (38, 43))	('lower plasma folate levels', 'Phenotype', 'HP:0100507', (313, 339))	('stomach cancer', 'Disease', 'MESH:D013274', (58, 72))	('stomach cancer', 'Phenotype', 'HP:0012126', (58, 72))	('folic acid', 'Chemical', 'MESH:D005492', (105, 115))
870089	25337902	For esophageal cancer, our data suggested an increased risk among MTHFR rs1801133 T allele carriers (any T vs. C/C, SBOR: 1.25, 95% posterior limits: 0.85, 1.84), which is consistent with findings from a meta-analysis of 19 studies (C/T versus C/C, OR: 1.47, 95% CI: 1.32-1.63; T/T versus C/C, OR: 1.69, 95% CI: 1.49-1.91).	('esophageal cancer', 'Disease', 'MESH:D004938', (4, 21))	('MTHFR', 'Gene', '4524', (66, 71))	('SB', 'Chemical', '-', (116, 118))	('rs1801133', 'Var', (72, 81))	('MTHFR', 'Gene', (66, 71))	('esophageal cancer', 'Disease', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('rs1801133', 'Mutation', 'rs1801133', (72, 81))
870092	25337902	MTR A2756G (rs1805087), a common SNP leading to the substitution of aspartic acid with glycine, has been largely studied.	('MTR A2756G (rs1805087', 'Var', (0, 21))	('A2756G', 'Mutation', 'rs1805087', (4, 10))	('glycine', 'Chemical', 'MESH:D005998', (87, 94))	('aspartic acid', 'Chemical', 'MESH:D001224', (68, 81))	('rs1805087', 'Var', (12, 21))	('rs1805087', 'Mutation', 'rs1805087', (12, 21))
870095	25337902	Two common polymorphisms, MTRR A66G (rs1801394, converts isoleucine to methionine) and C524T (rs1532268, changes serine to leucine), have been indicated to regenerate MTR less efficiently.	('rs1801394', 'Var', (37, 46))	('methionine', 'Chemical', 'MESH:D008715', (71, 81))	('serine', 'Chemical', 'MESH:D012694', (113, 119))	('leucine', 'Chemical', 'MESH:D007930', (123, 130))	('A66G', 'Mutation', 'rs1801394', (31, 35))	('changes', 'Reg', (105, 112))	('rs1532268', 'Var', (94, 103))	('MTRR', 'Gene', (26, 30))	('MTRR', 'Gene', '4552', (26, 30))	('C524T', 'Mutation', 'rs1532268', (87, 92))	('isoleucine', 'Chemical', 'MESH:D007532', (57, 67))	('leucine', 'Chemical', 'MESH:D007930', (60, 67))	('rs1801394', 'Mutation', 'rs1801394', (37, 46))	('rs1532268', 'Mutation', 'rs1532268', (94, 103))
870096	25337902	G allele carriers of MTRR rs1801394 have been associated with increased risk for hepatocellular carcinoma (HCC).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('rs1801394', 'Var', (26, 35))	('rs1801394', 'Mutation', 'rs1801394', (26, 35))	('hepatocellular carcinoma', 'Disease', (81, 105))	('MTRR', 'Gene', (21, 25))	('associated', 'Reg', (46, 56))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))	('MTRR', 'Gene', '4552', (21, 25))	('increased risk for hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (62, 105))
870098	25337902	Most studies that have investigated MTRR rs1532268 reported no associations with colorectal, gastric, breast, and lung cancer.	('breast', 'Disease', (102, 108))	('rs1532268', 'Var', (41, 50))	('colorectal', 'Disease', 'MESH:D015179', (81, 91))	('MTRR', 'Gene', (36, 40))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('associations', 'Interaction', (63, 75))	('MTRR', 'Gene', '4552', (36, 40))	('gastric', 'Disease', (93, 100))	('colorectal', 'Disease', (81, 91))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('rs1532268', 'Mutation', 'rs1532268', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
870099	25337902	Our study observed odds-ratio variation of the associations between these MTR/MTRR polymorphisms and upper GI cancers across alcohol consumption, even after conservative SB shrinkage.	('GI cancer', 'Phenotype', 'HP:0007378', (107, 116))	('MTRR', 'Gene', (78, 82))	('upper GI cancers across alcohol consumption', 'Disease', (101, 144))	('SB', 'Chemical', '-', (170, 172))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('polymorphisms', 'Var', (83, 96))	('MTRR', 'Gene', '4552', (78, 82))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('upper GI cancers across alcohol consumption', 'Disease', 'MESH:D000437', (101, 144))	('associations', 'Interaction', (47, 59))
870102	25337902	Matsuo et al., observed a similar OR variation: G/G genotype carriers of MTR rs1805087 showed higher colorectal cancer risk among alcohol drinkers and lower risk among non-drinkers.	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('alcohol', 'Chemical', 'MESH:D000438', (130, 137))	('rs1805087', 'Mutation', 'rs1805087', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('MTR', 'Gene', (73, 76))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (130, 146))	('colorectal cancer', 'Disease', (101, 118))	('rs1805087', 'Var', (77, 86))	('higher', 'PosReg', (94, 100))
870103	25337902	Although the functional effect of MTR/MTRR polymorphisms has not been established, our results are biologically plausible as alcohol can disrupt one-carbon metabolism by inhibiting folate absorption, suppressing SAM synthesis, and impairing DNA methylation.	('SAM synthesis', 'MPA', (212, 225))	('SAM', 'Chemical', 'MESH:D012436', (212, 215))	('folate absorption', 'MPA', (181, 198))	('DNA methylation', 'MPA', (241, 256))	('folate', 'Chemical', '-', (181, 187))	('impairing', 'NegReg', (231, 240))	('one-carbon metabolism', 'MPA', (145, 166))	('carbon', 'Chemical', 'MESH:D002244', (149, 155))	('alcohol', 'Var', (125, 132))	('suppressing', 'NegReg', (200, 211))	('MTRR', 'Gene', (38, 42))	('MTRR', 'Gene', '4552', (38, 42))	('disrupt', 'NegReg', (137, 144))	('inhibiting', 'NegReg', (170, 180))	('alcohol', 'Chemical', 'MESH:D000438', (125, 132))
870104	25337902	Alcohol can also cause inhibition of methionine synthase activity.	('methionine synthase', 'Gene', '4548', (37, 56))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('inhibition', 'NegReg', (23, 33))	('methionine synthase', 'Gene', (37, 56))	('Alcohol', 'Var', (0, 7))
870105	25337902	Therefore, it is possible that the variant allele of these two MTR/MTRR polymorphisms is protective for the upper GI cancers under the environment without alcohol exposures.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('GI cancer', 'Phenotype', 'HP:0007378', (114, 123))	('MTRR', 'Gene', (67, 71))	('MTRR', 'Gene', '4552', (67, 71))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('alcohol', 'Chemical', 'MESH:D000438', (155, 162))	('variant', 'Var', (35, 42))	('upper GI cancers', 'Disease', 'MESH:D009369', (108, 124))	('upper GI cancers', 'Disease', (108, 124))
870109	25337902	The ALDH2 rs671 A allele (slow type) has been associated with increased risk of head and neck cancer, as well as esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('head and neck cancer', 'Disease', 'MESH:D006258', (80, 100))	('ALDH2', 'Gene', '217', (4, 9))	('rs671', 'Mutation', 'rs671', (10, 15))	('rs671 A', 'Var', (10, 17))	('ALDH2', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('head and neck cancer', 'Phenotype', 'HP:0012288', (80, 100))	('esophageal cancer', 'Disease', (113, 130))
870110	25337902	Consistent with previous findings, we observed a positive association between the A/A genotype and esophageal cancer in this study, and further reported a stronger association among individuals with lower plasma folate levels.	('plasma folate levels', 'MPA', (205, 225))	('lower', 'NegReg', (199, 204))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('lower plasma folate levels', 'Phenotype', 'HP:0100507', (199, 225))	('folate', 'Chemical', '-', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('positive', 'PosReg', (49, 57))	('A/A', 'Var', (82, 85))	('esophageal cancer', 'Disease', (99, 116))
870112	25337902	It is possible that the deleterious effect associated with rs671 polymorphism is more prominent under the condition of lower folate supply.	('rs671', 'Var', (59, 64))	('lower', 'NegReg', (119, 124))	('rs671', 'Mutation', 'rs671', (59, 64))	('lower folate supply', 'Phenotype', 'HP:0100507', (119, 138))	('folate', 'Chemical', '-', (125, 131))
870113	25337902	Another common variation in the ALDH2 gene: rs886205 with a G to A substitution in the promoter region:has been suggested to be functional.	('ALDH2', 'Gene', (32, 37))	('ALDH2', 'Gene', '217', (32, 37))	('rs886205', 'Var', (44, 52))	('rs886205', 'Mutation', 'rs886205', (44, 52))
870115	25337902	The G allele of rs886205 was reported to be associated with increased risk of ESCC but not with stomach and colorectal cancer.	('ESCC', 'Disease', (78, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('rs886205', 'Var', (16, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('rs886205', 'Mutation', 'rs886205', (16, 24))	('colorectal cancer', 'Disease', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
870117	25337902	We observed a positive association between the A allele of rs886205 and stomach cancer among those with higher plasma vitamin B12 levels.	('stomach cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('vitamin B12', 'Chemical', 'MESH:D014805', (118, 129))	('stomach cancer', 'Disease', (72, 86))	('rs886205', 'Var', (59, 67))	('stomach cancer', 'Disease', 'MESH:D013274', (72, 86))	('rs886205', 'Mutation', 'rs886205', (59, 67))
870118	25337902	Although ALDH2 rs886205 is suggested to be a functional polymorphism in hepatoma cells, further functionality studies are warranted.	('ALDH2', 'Gene', (9, 14))	('rs886205', 'Var', (15, 23))	('hepatoma', 'Disease', (72, 80))	('hepatoma', 'Disease', 'MESH:D006528', (72, 80))	('rs886205', 'Mutation', 'rs886205', (15, 23))	('ALDH2', 'Gene', '217', (9, 14))
870125	25337902	Using these methods, in this Chinese population, several polymorphisms in the one-carbon metabolic pathway appear to be associated with esophageal, stomach, and liver cancer, with heterogeneity across strata of alcohol consumption for the odds ratios relating MTR/MTRR polymorphisms to these cancers, suggesting potential interactions between alcohol drinking and genes of the one-carbon metabolic pathway.	('associated', 'Reg', (120, 130))	('carbon', 'Chemical', 'MESH:D002244', (381, 387))	('stomach', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('polymorphisms', 'Var', (57, 70))	('liver cancer', 'Disease', 'MESH:D006528', (161, 173))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('cancers', 'Disease', (292, 299))	('alcohol', 'Chemical', 'MESH:D000438', (211, 218))	('liver cancer', 'Phenotype', 'HP:0002896', (161, 173))	('one-carbon metabolic pathway', 'Pathway', (78, 106))	('MTRR', 'Gene', '4552', (264, 268))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('liver cancer', 'Disease', (161, 173))	('MTRR', 'Gene', (264, 268))	('esophageal', 'Disease', (136, 146))	('carbon', 'Chemical', 'MESH:D002244', (82, 88))	('alcohol', 'Chemical', 'MESH:D000438', (343, 350))	('alcohol drinking', 'Phenotype', 'HP:0030955', (343, 359))	('cancers', 'Disease', 'MESH:D009369', (292, 299))	('interactions', 'Interaction', (322, 334))
870128	24820515	To evaluate the effect p21, p53, TP53BP1 and p73 single nucleotide polymorphisms (SNPs) on the risk of ESCC, we conducted a hospital based case-control study.	('TP53BP1', 'Gene', '7158', (33, 40))	('TP53BP1', 'Gene', (33, 40))	('p21', 'Gene', '1026', (23, 26))	('ESCC', 'Disease', (103, 107))	('p73 single nucleotide polymorphisms', 'Var', (45, 80))	('p21', 'Gene', (23, 26))	('p53', 'Var', (28, 31))
870130	24820515	When the p73 rs1801173 CC homozygote genotype was used as the reference group, the CT genotype was associated with a significantly increased risk of ESCC.	('ESCC', 'Disease', (149, 153))	('rs1801173', 'Mutation', 'rs1801173', (13, 22))	('p73 rs1801173 CC', 'Var', (9, 25))
870132	24820515	p21 rs3176352 G>C and p73 rs1801173 C>T SNPs are associated with increased risk of ESCC.	('p21', 'Gene', (0, 3))	('rs3176352', 'Mutation', 'rs3176352', (4, 13))	('p73 rs1801173 C>T', 'Var', (22, 39))	('ESCC', 'Disease', (83, 87))	('p21', 'Gene', '1026', (0, 3))	('rs1801173', 'Mutation', 'rs1801173', (26, 35))
870136	24820515	A well-studied p53 polymorphism, Arg72Pro (rs1042522 C/G; R/P) has been reported to have functional significance.	('Arg72Pro', 'SUBSTITUTION', 'None', (33, 41))	('Arg72Pro', 'Var', (33, 41))	('rs1042522', 'Mutation', 'rs1042522', (43, 52))	('p53', 'Gene', (15, 18))
870137	24820515	Polymorphism p53 rs1042522 G>C has been associated with risk of numerous kinds of cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('rs1042522 G>C', 'Var', (17, 30))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('p53', 'Gene', (13, 16))	('rs1042522', 'Mutation', 'rs1042522', (17, 26))	('associated', 'Reg', (40, 50))
870140	24820515	Cell cycle arrest at the G1-S phase restriction point is mediated through p21 up-regulation induced by p53, and the associated G1 cyclins-cdk2 complexes inhibition.	('G1 cyclins-cdk2 complexes', 'Protein', (127, 152))	('inhibition', 'NegReg', (153, 163))	('up-regulation', 'PosReg', (78, 91))	('p21', 'Gene', '1026', (74, 77))	('p21', 'Gene', (74, 77))	('Cell cycle arrest', 'Phenotype', 'HP:0011018', (0, 17))	('p53', 'Var', (103, 106))
870147	24820515	p73 is located at 1p36.33, mapping to a region that is often deleted in cancers.	('p73', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
870148	24820515	p73 activates transcription of p21- and p53-responsive genes, which participate in cell cycle control, DNA repair, apoptosis and inhibits cell growth in a p53-like manner by inducing apoptosis or G1 cell cycle arrest.	('p21', 'Gene', '1026', (31, 34))	('p73', 'Var', (0, 3))	('cell growth', 'CPA', (138, 149))	('p21', 'Gene', (31, 34))	('G1 cell cycle arrest', 'CPA', (196, 216))	('transcription', 'MPA', (14, 27))	('apoptosis', 'CPA', (183, 192))	('p53-responsive genes', 'Gene', (40, 60))	('activates', 'PosReg', (4, 13))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (199, 216))	('inhibits', 'NegReg', (129, 137))	('inducing', 'NegReg', (174, 182))
870149	24820515	This suggests that p73 has tumor-suppressor functions.	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('p73', 'Var', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
870151	24820515	Genetic variations in the p53 pathway genes, such as p21, p53, TP53BP1 and p73, may contribute to the development of ESCC.	('contribute to', 'Reg', (84, 97))	('p53', 'Gene', (26, 29))	('p21', 'Gene', '1026', (53, 56))	('p73', 'Var', (75, 78))	('p21', 'Gene', (53, 56))	('ESCC', 'Disease', (117, 121))	('p53', 'Gene', (58, 61))	('TP53BP1', 'Gene', '7158', (63, 70))	('TP53BP1', 'Gene', (63, 70))
870152	24820515	In a hospital-based case-control study, we performed genotyping analyses of eight functional p21, p53, TP53BP1 and p73 SNPs in 629 ESCC cases and 686 controls in a Chinese population.	('TP53BP1', 'Gene', (103, 110))	('p21', 'Gene', '1026', (93, 96))	('p21', 'Gene', (93, 96))	('p53', 'Var', (98, 101))	('TP53BP1', 'Gene', '7158', (103, 110))	('p73 SNPs', 'Var', (115, 123))	('ESCC', 'Disease', (131, 135))
870162	24820515	Using the chi 2 test, between the cases and controls, the distributions of demographic characteristics, selected variables, and genotypes of the p21, p53, TP53BP1 and p73 variants differences were evaluated.	('p21', 'Gene', '1026', (145, 148))	('p21', 'Gene', (145, 148))	('p73 variants', 'Var', (167, 179))	('TP53BP1', 'Gene', (155, 162))	('TP53BP1', 'Gene', '7158', (155, 162))
870167	24820515	When the p73 rs1801173 CC homozygote genotype was used as the reference group, the CT genotype was associated with a significantly increased risk for ESCC (CT vs. CC: adjusted OR = 1.39, 95% CI = 1.10-1.76, p = 0.006); the TT genotype was not associated with the risk of ESCC.	('ESCC', 'Disease', (150, 154))	('rs1801173', 'Mutation', 'rs1801173', (13, 22))	('p73 rs1801173 CC', 'Var', (9, 25))
870168	24820515	In the dominant model, the p73 rs1801173 CT/TT variants were associated with a significantly increased risk for ESCC (CT/TT vs. CC: adjusted OR = 1.37, 95% CI = 1.10-1.72, p = 0.006), compared with the p73 rs1801173 CC genotype.	('p73 rs1801173', 'Var', (27, 40))	('ESCC', 'Disease', (112, 116))	('rs1801173', 'Mutation', 'rs1801173', (31, 40))	('rs1801173', 'Mutation', 'rs1801173', (206, 215))
870169	24820515	In the recessive model, when the p73 rs1801173 CC/CT genotypes were used as the reference group, the TT homozygote genotype was not associated with the risk of ESCC (Table 3).	('p73 rs1801173 CC/CT', 'Var', (33, 52))	('rs1801173', 'Mutation', 'rs1801173', (37, 46))	('ESCC', 'Disease', (160, 164))
870172	24820515	Logistic regression analyses revealed that the p21 rs2395655 G>A, p21 rs1059234 C>T, p21 rs762623 C>A and p53 rs1042522 G>C polymorphisms were not associated with the risk of ESCC (Table 2).	('rs1042522', 'Mutation', 'rs1042522', (110, 119))	('p21', 'Gene', (66, 69))	('rs762623 C>A', 'Var', (89, 101))	('rs2395655', 'Mutation', 'rs2395655', (51, 60))	('rs1042522 G>C', 'Var', (110, 123))	('ESCC', 'Disease', (175, 179))	('p21', 'Gene', '1026', (85, 88))	('rs1059234 C>T', 'Var', (70, 83))	('rs762623', 'Mutation', 'rs762623', (89, 97))	('p21', 'Gene', '1026', (47, 50))	('rs2395655 G>A', 'Var', (51, 64))	('rs1059234', 'Mutation', 'rs1059234', (70, 79))	('p21', 'Gene', (85, 88))	('p21', 'Gene', (47, 50))	('p21', 'Gene', '1026', (66, 69))
870173	24820515	After the Bonferroni correction (number of mutiple test  = 32), for p21 rs3176352 G>C, the adjusted p = 0.096 for CC vs. GG, adjusted p = 0.0192 for CC vs. GG/GC.	('rs3176352', 'Mutation', 'rs3176352', (72, 81))	('p21', 'Gene', (68, 71))	('rs3176352 G>C', 'Var', (72, 85))	('p21', 'Gene', '1026', (68, 71))
870175	24820515	When the p21 rs3176352 CC genotype and p73 rs1801173 CT/TT genotypes were considered as risk variant genotypes.	('rs3176352', 'Mutation', 'rs3176352', (13, 22))	('p21', 'Gene', '1026', (9, 12))	('p21', 'Gene', (9, 12))	('rs1801173', 'Mutation', 'rs1801173', (43, 52))	('p73 rs1801173', 'Var', (39, 52))
870176	24820515	To evaluate the effects of p21 rs3176352 G>C genotypes on ESCC risk according to different age, sex, smoking and alcohol drinking status; we performed the stratification analyses.	('p21', 'Gene', (27, 30))	('alcohol drinking', 'Phenotype', 'HP:0030955', (113, 129))	('rs3176352 G>C', 'Var', (31, 44))	('rs3176352', 'Mutation', 'rs3176352', (31, 40))	('alcohol', 'Chemical', 'MESH:D000438', (113, 120))	('ESCC', 'Disease', (58, 62))	('p21', 'Gene', '1026', (27, 30))
870178	24820515	A significantly decreased risk of ESCC associated with the p73 rs1801173 C>T polymorphism was evident among older patients, female patients and patients who never drinking or smoking (Table S2).	('patients', 'Species', '9606', (131, 139))	('rs1801173', 'Mutation', 'rs1801173', (63, 72))	('patients', 'Species', '9606', (144, 152))	('ESCC', 'Disease', (34, 38))	('patients', 'Species', '9606', (114, 122))	('p73 rs1801173 C>T', 'Var', (59, 76))	('decreased', 'NegReg', (16, 25))
870179	24820515	In this hospital-based case-control study of ESCC, we found that the p21 rs3176352 CC and p73 rs1801173 CT/TT genotypes were associated with increased risk of ESCC; positive results were also observed in genotype combination analysis.	('p21', 'Gene', (69, 72))	('ESCC', 'Disease', (159, 163))	('rs3176352', 'Mutation', 'rs3176352', (73, 82))	('rs1801173', 'Mutation', 'rs1801173', (94, 103))	('p73 rs1801173', 'Var', (90, 103))	('p21', 'Gene', '1026', (69, 72))
870180	24820515	To the best of our knowledge, this is the first positive association of p21 rs3176352 G/C and p73 rs1801173 C/T polymorphisms with ESCC risk.	('p21', 'Gene', '1026', (72, 75))	('p73 rs1801173 C/T', 'Var', (94, 111))	('p21', 'Gene', (72, 75))	('rs3176352', 'Mutation', 'rs3176352', (76, 85))	('rs1801173', 'Mutation', 'rs1801173', (98, 107))	('ESCC', 'Disease', (131, 135))
870187	24820515	demonstrated that p21 rs3176352 G/C polymorphism appeared to be in linkage disequilibrium with Ser31Arg in a Korean population.	('p21', 'Gene', '1026', (18, 21))	('p21', 'Gene', (18, 21))	('Ser31Arg', 'SUBSTITUTION', 'None', (95, 103))	('rs3176352', 'Mutation', 'rs3176352', (22, 31))	('Ser31Arg', 'Var', (95, 103))
870190	24820515	A case-control study from northeastern Iran, with 126 cases and 100 controls, was carried out to detect associations of p21 polymorphisms (rs1801270 and rs1059234) with ESCC risk.	('ESCC', 'Disease', (169, 173))	('rs1059234', 'Var', (153, 162))	('associations', 'Interaction', (104, 116))	('rs1801270', 'Mutation', 'rs1801270', (139, 148))	('rs1801270', 'Var', (139, 148))	('p21', 'Gene', '1026', (120, 123))	('p21', 'Gene', (120, 123))	('rs1059234', 'Mutation', 'rs1059234', (153, 162))
870193	24820515	p73 rs1801173 C/T polymorphism merits further functional study to elucidate the etiology of this SNP and ESCC.	('ESCC', 'Disease', (105, 109))	('p73 rs1801173 C/T', 'Var', (0, 17))	('SNP', 'Disease', (97, 100))	('rs1801173', 'Mutation', 'rs1801173', (4, 13))
870199	24820515	In conclusion, our study provides strong evidence that p21 rs3176352 G/C and p73 rs1801173 C/T polymorphisms may contribute to ESCC risk.	('rs1801173', 'Mutation', 'rs1801173', (81, 90))	('rs3176352 G/C', 'Var', (59, 72))	('rs3176352', 'Mutation', 'rs3176352', (59, 68))	('ESCC', 'Disease', (127, 131))	('contribute', 'Reg', (113, 123))	('p21', 'Gene', (55, 58))	('p73 rs1801173 C/T', 'Var', (77, 94))	('p21', 'Gene', '1026', (55, 58))
870208	23722120	Dysregulation of the cell cycle machinery is a fundamental hallmark of cancer progression and the cell programmers of proliferation, differentiation, senescence and apoptosis are intimately linked to the cell cycle regulatory machinery.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (71, 77))	('men', 'Species', '9606', (52, 55))	('Dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (0, 31))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
870283	23722120	The present study showed that the cells in carcinoma with aberrant nuclear localization of cyclin B1 not only pushes on cell from G2-M mitosis phase but also demonstrate lack of cell differentiation into next stratum.	('G2-M mitosis', 'Disease', 'MESH:C566367', (130, 142))	('nuclear localization', 'MPA', (67, 87))	('carcinoma', 'Disease', 'MESH:D002277', (43, 52))	('aberrant', 'Var', (58, 66))	('G2-M mitosis', 'Disease', (130, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('pushes', 'PosReg', (110, 116))	('carcinoma', 'Disease', (43, 52))	('cyclin B1', 'Gene', (91, 100))	('cyclin B1', 'Gene', '891', (91, 100))
870289	23677165	MicroRNAs modulate cell commitment, and are also reportedly dysregulated in Barrett's carcinogenesis.	('MicroRNAs', 'Var', (0, 9))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (76, 100))	('cell commitment', 'CPA', (19, 34))	('modulate', 'Reg', (10, 18))	("Barrett's carcinogenesis", 'Disease', (76, 100))
870350	23677165	Several studies have focused on miRNA dysregulation in Barrett's carcinogenesis and specific miRNA expression signatures have been associated with cancer progression, whereas the molecular profiling of BE-related metaplastic changes had never been investigated.	('miR', 'Gene', (32, 35))	('miR', 'Gene', '22877', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('miR', 'Gene', '22877', (32, 35))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (55, 79))	('associated', 'Reg', (131, 141))	('dysregulation', 'Var', (38, 51))	("Barrett's carcinogenesis", 'Disease', (55, 79))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('miR', 'Gene', (93, 96))	('BE', 'Phenotype', 'HP:0100580', (202, 204))
870411	21523221	Point mutations thus induced may activate specific oncogenes and initiate the development of oral cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('oncogenes', 'Protein', (51, 60))	('oral cancer', 'Disease', 'MESH:D009062', (93, 104))	('Point mutations', 'Var', (0, 15))	('initiate', 'PosReg', (65, 73))	('oral cancer', 'Disease', (93, 104))	('activate', 'PosReg', (33, 41))
870445	21523221	These findings have implications not only on the potential for tissue invasion by the organism, but on the potential to enhance the invasion of genetically altered epithelial cells, first by reducing keratinocyte cohesion and then by assisting their passage through the basement membrane.	('enhance', 'PosReg', (120, 127))	('genetically', 'Var', (144, 155))	('assisting', 'PosReg', (234, 243))	('passage through the basement membrane', 'CPA', (250, 287))	('keratinocyte cohesion', 'CPA', (200, 221))	('rat', 'Species', '10116', (202, 205))	('reducing', 'NegReg', (191, 199))	('invasion', 'CPA', (132, 140))
870455	21523221	It responds to signals from the toll-like receptor (TLR)-My88 signaling pathway, which is activated after tissue damage and microbial infection and can also be turned on as a result of genetic alterations in tumor cells.	('result', 'Reg', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('rat', 'Species', '10116', (197, 200))	('genetic', 'Var', (185, 192))	('microbial infection', 'Disease', 'MESH:D015163', (124, 143))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('microbial infection', 'Disease', (124, 143))
870489	31870427	We hypothesize that nonplacement of a cervical drainage tube leads to a noninferior postoperative anastomotic leakage rate, duration to oral intake, hospital stay, and less analgesic use compared with placement of a cervical drainage tube, which is the current standard of care.	('postoperative anastomotic leakage', 'Disease', (84, 117))	('analgesic use', 'MPA', (173, 186))	('nonplacement', 'Var', (20, 32))	('hospital stay', 'MPA', (149, 162))	('duration', 'MPA', (124, 132))	('postoperative anastomotic leakage', 'Disease', 'MESH:D057868', (84, 117))
870533	31870427	In the current study, we hypothesize that nonplacement of a cervical drainage tube will lead to a noninferior postoperative anastomotic leakage rate.	('nonplacement', 'Var', (42, 54))	('postoperative anastomotic leakage', 'Disease', 'MESH:D057868', (110, 143))	('postoperative anastomotic leakage', 'Disease', (110, 143))	('lead to', 'Reg', (88, 95))
870671	30596334	The concentration of urinary 1-OHPG was four times higher in people who consumed greater than 1000 mL of mate per day, when compared to those who drank less than 100 mL per day.	('1-OHPG', 'Chemical', '-', (29, 35))	('concentration', 'MPA', (4, 17))	('mate', 'Gene', (105, 109))	('greater than 1000 mL', 'Var', (81, 101))	('mate', 'Gene', '107758984', (105, 109))	('people', 'Species', '9606', (61, 67))	('rat', 'Species', '10116', (11, 14))	('higher', 'PosReg', (51, 57))	('urinary', 'MPA', (21, 28))
870683	30596334	Exposure to B[a]P produces P53 signature mutations in humans.	('mutations', 'Var', (41, 50))	('humans', 'Species', '9606', (54, 60))	('P53', 'Gene', (27, 30))	('B[a]P', 'Chemical', 'MESH:D001564', (12, 17))	('P53', 'Gene', '7157', (27, 30))
870814	32611448	Esophagectomy with extended lymph node dissection is recommend as the primary treatment for pT1b esophageal squamous cell carcinoma (ESCC) because of the high incidence of lymph node metastasis.	('pT1b', 'Var', (92, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (97, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('esophageal squamous cell carcinoma', 'Disease', (97, 131))
870841	32611448	According to the current National Comprehensive Cancer Network (NCCN) guidelines of esophageal and gastric cancer, esophagectomy is the primary treatment option for pathological T1b ESCC.	('T1b', 'Var', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gastric cancer', 'Disease', (99, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('Cancer', 'Disease', (48, 54))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))
870891	32611448	Previous studies have confirmed that the tumor invasion within the submucosa can be well controlled by radiotherapy, and so for the residual lesions in the lateral resection margin after ESD, subsequent adjuvant chemoradiotherapy or surgery is sufficient to obtain local radical treatment.	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('lesions', 'Var', (141, 148))
870903	31957793	The additional analysis interrogating extended haplotypes (integrated haplotype score) showed robust concordance of the detected signatures, contributing to fine-mapping of the genes, and provided allelic directional insights into selection pressure (e.g., positive selection for ADH1B-Arg48His and HLA-DPB1*04:01).	('Arg48His', 'SUBSTITUTION', 'None', (286, 294))	('HLA-DPB1', 'Gene', '3115', (299, 307))	('ADH1B', 'Gene', (280, 285))	('ADH1B', 'Gene', '125', (280, 285))	('HLA-DPB1', 'Gene', (299, 307))	('Arg48His', 'Var', (286, 294))
870910	31957793	Then, a variety of frameworks have been introduced 1) to enhance statistical power by interrogating extended haplotypes (integrated haplotype score [iHS; ] and cross-population extended haplotype homozygosity), 2) to fine-map the variants responsible for the selective sweeps (composite of multiple signals), 3) to assign functional annotations to selection signatures (site frequency spectra), and 4) to expand the time phases corresponding to the selection from older ages to very recent ages (singleton density score [SDS; ]).	('SDS', 'Chemical', 'MESH:D012967', (521, 524))	('enhance', 'PosReg', (57, 64))	('variants', 'Var', (230, 238))
870933	31957793	The lead SNP allele within the MHC region rs6930052-T with iHS z-score = 8.04 was in tight linkage disequilibrium (LD) with the HLA-DPB1*04:01 allele (r2 = 0.88), on which strong recent positive selection acted locally within the Japanese archipelago.	('rs6930052-T', 'Var', (42, 53))	('HLA-DPB1', 'Gene', (128, 136))	('rs6930052', 'Mutation', 'rs6930052', (42, 51))	('HLA-DPB1', 'Gene', '3115', (128, 136))
870935	31957793	In the ADH cluster locus, we also observed nominally significant positive selection pressure at the well-known functional missense variant of ADH1B, which is associated with lower alcohol consumption, as well (rs1229984-A [Arg48His], PiHS = 7.1 x 10-4 with iHS z-score = 3.39, r2 = 0.34 with rs1442493 in Japanese).	('Arg48His', 'SUBSTITUTION', 'None', (223, 231))	('lower', 'NegReg', (174, 179))	('rs1229984', 'Mutation', 'rs1229984', (210, 219))	('ADH', 'Gene', (7, 10))	('ADH', 'Gene', '10327', (7, 10))	('rs1442493', 'Mutation', 'rs1442493', (292, 301))	('alcohol consumption', 'MPA', (180, 199))	('Arg48His', 'Var', (223, 231))	('ADH1B', 'Gene', (142, 147))	('ADH', 'Gene', (142, 145))	('ADH', 'Gene', '10327', (142, 145))	('ADH1B', 'Gene', '125', (142, 147))	('alcohol', 'Chemical', 'MESH:D000438', (180, 187))	('rs1442493', 'Var', (292, 301))
870945	31957793	Thus, we conducted a phenome-wide enrichment analysis of the ASMC and iHS selection signatures on the lead variants that were associated with human complex traits in Japanese satisfying the genome-wide significance threshold (P < 5.0 x 10-8).	('associated with', 'Reg', (126, 141))	('human', 'Species', '9606', (142, 147))	('variants', 'Var', (107, 115))	('ASMC', 'Chemical', '-', (61, 65))
870946	31957793	We curated the 2,190 Japanese trait-associated variants of the 105 phenotypes which consist of 35 diseases and 70 quantitative measurements classified into 14 categories (anthropometric [n = 2], behavior [n = 4], blood pressure [n = 4], echocardiographic [n = 4], electrolyte [n = 5], hematological [n = 13], kidney function [n = 4], liver function [n = 6], metabolic [n = 6], other biochemical [n = 7], pharmacogenetics [n = 2], protein [n = 5], reproductive aging [n = 4], and skin pigmentation [n = 4]).	('variants', 'Var', (47, 55))	('skin pigmentation', 'Phenotype', 'HP:0000953', (479, 496))	('skin pigmentation', 'Disease', (479, 496))	('skin pigmentation', 'Disease', 'MESH:D010859', (479, 496))
870949	31957793	These results were mostly driven by strong selection signatures at the functional missense SNPs involved in alcohol metabolism (Arg47His at ADH1B and Glu504Lys at ALDH2), which are specifically observed in east Asian populations due to population-specific positive selection pressure.	('ALDH2', 'Gene', (163, 168))	('Glu504Lys', 'Var', (150, 159))	('ADH1B', 'Gene', (140, 145))	('Glu504Lys', 'SUBSTITUTION', 'None', (150, 159))	('Arg47His', 'SUBSTITUTION', 'None', (128, 136))	('ADH1B', 'Gene', '125', (140, 145))	('ALDH2', 'Gene', '217', (163, 168))	('alcohol', 'Chemical', 'MESH:D000438', (108, 115))	('Arg47His', 'Var', (128, 136))
870963	31957793	Additional analysis using iHS showed robustness of the analytic results, contributing to the fine-mapping of the genes responsible for selection drive, and provided allelic directional insights (e.g., positive selection for ADH1B-Arg48His and HLA-DPB1*04:01).	('HLA-DPB1', 'Gene', (243, 251))	('Arg48His', 'Var', (230, 238))	('HLA-DPB1', 'Gene', '3115', (243, 251))	('ADH1B', 'Gene', (224, 229))	('Arg48His', 'SUBSTITUTION', 'None', (230, 238))	('ADH1B', 'Gene', '125', (224, 229))
870970	31957793	In addition to alcohol-related phenotypes, associations of these loci with human behaviors have been recently reported (e.g., risk-taking behaviors and assortative mating at ADH1B rs1229984).	('alcohol', 'Chemical', 'MESH:D000438', (15, 22))	('risk-taking', 'Phenotype', 'HP:0031472', (126, 137))	('rs1229984', 'Var', (180, 189))	('ADH1B', 'Gene', (174, 179))	('rs1229984', 'Mutation', 'rs1229984', (180, 189))	('assortative mating', 'CPA', (152, 170))	('associations', 'Interaction', (43, 55))	('ADH1B', 'Gene', '125', (174, 179))	('human', 'Species', '9606', (75, 80))
870972	31957793	Recent large-scale studies in Japanese reported contribution of the ADH1B and ALDH2 functional variants on dietary consumptions of wider ranges of traditional foods and beverages, as well as all-cause mortality rates.	('ALDH2', 'Gene', (78, 83))	('ADH1B', 'Gene', (68, 73))	('ADH1B', 'Gene', '125', (68, 73))	('variants', 'Var', (95, 103))	('ALDH2', 'Gene', '217', (78, 83))
870983	31957793	Since genome-wide DRCT statistics are known to follow a gamma distribution, we fitted the single null gamma distribution of the DRCT statistics in our data set based on maximum likelihood estimate by conservatively excluding those in the previously known variants with significant selection signatures in the Japanese or Asian populations (+-5 Mb of the MHC region or ALDH2, or +-500 kb of the other detected loci).	('ALDH2', 'Gene', '217', (368, 373))	('ALDH2', 'Gene', (368, 373))	('MHC region', 'Gene', (354, 364))	('+-5 Mb', 'Var', (340, 346))
870991	31957793	As suggested previously, we did not include the genes in the MHC region for the pathway analysis, considering complex LD structure of the variants and pivotal functional roles of the human leukocyte antigen (HLA) genes.	('human', 'Species', '9606', (183, 188))	('variants', 'Var', (138, 146))	('HLA', 'Gene', (208, 211))
871007	31888532	Recent studies revealed that the aberrant activation of various signaling pathways, such as PIK3CA and NOTCH1 pathways promote the development of ESCC and contribute to several processes of ESCC, such as metastasis and proliferation.	('ESCC', 'Disease', (190, 194))	('proliferation', 'CPA', (219, 232))	('metastasis', 'CPA', (204, 214))	('PIK3CA', 'Gene', '5290', (92, 98))	('promote', 'PosReg', (119, 126))	('development', 'CPA', (131, 142))	('activation', 'PosReg', (42, 52))	('NOTCH1', 'Gene', '4851', (103, 109))	('NOTCH1', 'Gene', (103, 109))	('aberrant', 'Var', (33, 41))	('ESCC', 'Disease', (146, 150))	('PIK3CA', 'Gene', (92, 98))	('contribute', 'Reg', (155, 165))
871012	31888532	The following antibodies for western blotting analysis were purchased from Cell Signaling Technology: anti-Stat3 (#9139), anti-p-Stat3 (#9145), anti-Src (#2109), anti-p-Src (#12432), anti-Erk (#4696), anti-p-Erk (#4370), anti-GSK3beta (#5676), and anti-p-GSK3beta (#9327) antibodies.	('#9145', 'Var', (136, 141))	('#4696', 'Var', (193, 198))	('Stat3', 'Gene', '6774', (107, 112))	('Erk', 'Gene', '5594', (188, 191))	('#9139', 'Var', (114, 119))	('Stat3', 'Gene', '6774', (129, 134))	('#12432', 'Var', (174, 180))	('Erk', 'Gene', (208, 211))	('Stat3', 'Gene', (129, 134))	('#4370', 'Var', (213, 218))	('#9327', 'Var', (265, 270))	('Erk', 'Gene', (188, 191))	('Erk', 'Gene', '5594', (208, 211))	('#2109', 'Var', (154, 159))	('Stat3', 'Gene', (107, 112))	('#5676', 'Var', (236, 241))
871035	31888532	The recombinant TOPK (Signalchem, T14-10G-10) and purified GST-tagged TOPK protein (> 90%) were captured by the anti-GST antibody on the CM5 chip.	('GST', 'Gene', (59, 62))	('T14-10G', 'Var', (34, 41))	('GST', 'Gene', (117, 120))	('T14-10G', 'SUBSTITUTION', 'None', (34, 41))	('GST', 'Gene', '373156', (59, 62))	('GST', 'Gene', '373156', (117, 120))
871062	31888532	The effect of TOPK knockdown in the KYSE510 cells on the signal transduction pathways was evaluated using the human phospho-kinase array.	('TOPK', 'Gene', (14, 18))	('knockdown', 'Var', (19, 28))	('human', 'Species', '9606', (110, 115))
871064	31888532	The phosphorylation levels of Src Y419, GSK3alphabeta kinase S21/S9, and ERK1/2 T202/Y204 in the shTOPK#1-transfected KYSE510 cells decreased to 0.71, 0.65, and 0.81, respectively, whereas those in the shTOPK#2-transfected cells decreased to 0.65, 0.66, and 0.79, respectively (Fig.	('T202/Y204', 'Var', (80, 89))	('Src Y419', 'Var', (30, 38))	('ERK1/2', 'Gene', (73, 79))	('ERK1/2', 'Gene', '5595;5594', (73, 79))	('phosphorylation levels', 'MPA', (4, 26))	('decreased', 'NegReg', (132, 141))
871065	31888532	The western blotting analysis revealed that the phosphorylation of STAT3 Y705, GSK3beta S21, Src Y419, and ERK1/2 T202/Y204 was strongly inhibited upon TOPK knockdown in the KYSE510 and KYSE30 cells (Fig.	('T202/Y204', 'Var', (114, 123))	('ERK1/2', 'Gene', (107, 113))	('Y705', 'Var', (73, 77))	('inhibited', 'NegReg', (137, 146))	('ERK1/2', 'Gene', '5595;5594', (107, 113))	('STAT3', 'Gene', '6774', (67, 72))	('phosphorylation', 'MPA', (48, 63))	('STAT3', 'Gene', (67, 72))	('knockdown', 'Var', (157, 166))	('TOPK', 'Gene', (152, 156))
871066	31888532	Next, the KYSE510 and KYSE30 cells were treated with different doses of HI-TOPK-032 for 24 h. The western blotting analysis revealed that HI-TOPK-032 dose-dependently inhibited the p-TOPK, STAT3, Src/GSK3beta, and ERK signaling pathways (Fig.	('inhibited', 'NegReg', (167, 176))	('HI-TOPK-032', 'Var', (138, 149))	('STAT3', 'Gene', (189, 194))	('STAT3', 'Gene', '6774', (189, 194))	('Src/GSK3beta', 'Pathway', (196, 208))	('p-TOPK', 'Pathway', (181, 187))	('ERK signaling pathways', 'Pathway', (214, 236))
871074	31888532	Immunofluorescence analysis indicated that TOPK knockdown induced the expression of gamma-catenin in the KYSE510 and KYSE30 cells (Fig.	('induced', 'PosReg', (58, 65))	('TOPK', 'Gene', (43, 47))	('gamma-catenin', 'Gene', '16480', (84, 97))	('expression', 'MPA', (70, 80))	('gamma-catenin', 'Gene', (84, 97))	('knockdown', 'Var', (48, 57))
871077	31888532	Treating the athymic nude xenograft mouse model with HI-TOPK-032 suppressed lung metastasis without affecting the bodyweight in vivo (Fig.	('mouse', 'Species', '10090', (36, 41))	('HI-TOPK-032', 'Var', (53, 64))	('lung metastasis', 'CPA', (76, 91))	('suppressed', 'NegReg', (65, 75))
871082	31888532	Several studies have revealed a correlation between TOPK expression and poor prognosis in numerous cancers, such as leukemia, breast cancer, ovarian cancer, cervical cancer, lung cancer, colon cancer, and oral cancer.	('lung cancer', 'Disease', (174, 185))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('correlation', 'Reg', (32, 43))	('cancer', 'Disease', (193, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (141, 155))	('TOPK', 'Gene', (52, 56))	('ovarian cancer', 'Disease', (141, 155))	('colon cancer', 'Disease', (187, 199))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('breast cancer', 'Disease', (126, 139))	('numerous cancers', 'Disease', 'MESH:D009369', (90, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('leukemia', 'Phenotype', 'HP:0001909', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (166, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('expression', 'Var', (57, 67))	('oral cancer', 'Disease', 'MESH:D009369', (205, 216))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (141, 155))	('colon cancer', 'Phenotype', 'HP:0003003', (187, 199))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('leukemia', 'Disease', 'MESH:D007938', (116, 124))	('numerous cancers', 'Disease', (90, 106))	('leukemia', 'Disease', (116, 124))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Disease', (99, 105))	('colon cancer', 'Disease', 'MESH:D015179', (187, 199))	('oral cancer', 'Disease', (205, 216))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancer', 'Disease', (179, 185))
871085	31888532	Various studies indicated that the abnormal expression of TOPK in many cancers triggered aberrant activation of different signaling pathways, such as the ERK1/2, p38, c-Jun, and NF (nuclear factor)-kappaB signaling pathways.	('c-Jun', 'Gene', '3725', (167, 172))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('signaling pathways', 'Pathway', (122, 140))	('abnormal', 'Var', (35, 43))	('activation', 'PosReg', (98, 108))	('cancers', 'Disease', (71, 78))	('p38', 'Gene', (162, 165))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('c-Jun', 'Gene', (167, 172))	('TOPK', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ERK1/2', 'Gene', '5595;5594', (154, 160))	('ERK1/2', 'Gene', (154, 160))	('p38', 'Gene', '5594', (162, 165))
871090	31888532	Moreover, some studies demonstrated that Src-mediated Y216 GSK-3beta phosphorylation and activation increased prostate cancer cell motility, proliferation, micrometastasis, and progression.	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('micrometastasis', 'CPA', (156, 171))	('activation increased', 'PosReg', (89, 109))	('proliferation', 'CPA', (141, 154))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('phosphorylation', 'CPA', (69, 84))	('prostate cancer', 'Disease', (110, 125))	('GSK-3beta', 'Gene', '2931', (59, 68))	('GSK-3beta', 'Gene', (59, 68))	('Y216', 'Var', (54, 58))	('progression', 'CPA', (177, 188))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
871092	31888532	In this study, TOPK knockdown decreased the phosphorylation levels of Src, GSK3beta, STAT3, and ERK proteins in the ESCC tissues.	('ERK proteins', 'Protein', (96, 108))	('phosphorylation levels', 'MPA', (44, 66))	('Src', 'Protein', (70, 73))	('STAT3', 'Gene', '6774', (85, 90))	('STAT3', 'Gene', (85, 90))	('knockdown', 'Var', (20, 29))	('GSK3beta', 'Protein', (75, 83))	('decreased', 'NegReg', (30, 39))	('TOPK', 'Gene', (15, 19))
871104	31888532	Therefore, this suggested that downregulating TOPK may increase and stabilize gamma-catenin and subsequently decrease the cell adhesion and motility.	('decrease', 'NegReg', (109, 117))	('TOPK', 'Gene', (46, 50))	('increase', 'PosReg', (55, 63))	('gamma-catenin', 'Gene', '16480', (78, 91))	('gamma-catenin', 'Gene', (78, 91))	('stabilize', 'MPA', (68, 77))	('downregulating', 'Var', (31, 45))
871107	31888532	The silencing of gamma-catenin but not desmoplakin is reported to activate the p38-dependent keratin filament collapse and cell dissociation.	('p38', 'Gene', (79, 82))	('gamma-catenin', 'Gene', (17, 30))	('cell dissociation', 'CPA', (123, 140))	('activate', 'PosReg', (66, 74))	('p38', 'Gene', '5594', (79, 82))	('gamma-catenin', 'Gene', '16480', (17, 30))	('silencing', 'Var', (4, 13))
871109	31888532	Recent studies demonstrated that gamma-catenin knockout cells exhibited enhanced activation of Src signal pathways and that gamma-catenin regulated cell motility through distinct Src and Rho GTPase-dependent pathways.	('Src', 'Pathway', (179, 182))	('gamma-catenin', 'Gene', '16480', (33, 46))	('enhanced activation', 'PosReg', (72, 91))	('knockout', 'Var', (47, 55))	('gamma-catenin', 'Gene', (124, 137))	('cell motility', 'CPA', (148, 161))	('gamma-catenin', 'Gene', (33, 46))	('gamma-catenin', 'Gene', '16480', (124, 137))	('Src signal pathways', 'Pathway', (95, 114))
871111	31888532	8): TOPK binds gamma-catenin and the deregulated gamma-catenin activates the Src/GSK3beta/STAT3 signaling pathway.	('STAT3', 'Gene', '6774', (90, 95))	('gamma-catenin', 'Gene', '16480', (49, 62))	('deregulated', 'Var', (37, 48))	('STAT3', 'Gene', (90, 95))	('gamma-catenin', 'Gene', '16480', (15, 28))	('gamma-catenin', 'Gene', (49, 62))	('gamma-catenin', 'Gene', (15, 28))	('activates', 'PosReg', (63, 72))
871112	31888532	Interestingly, the TOPK inhibitor, HI-TOPK-032 also inhibits the ESCC cell metastasis through the same Src/GSK3beta/STAT3 signaling pathway.	('HI-TOPK-032', 'Var', (35, 46))	('STAT3', 'Gene', '6774', (116, 121))	('inhibits', 'NegReg', (52, 60))	('ESCC', 'Disease', (65, 69))	('STAT3', 'Gene', (116, 121))
871136	27391361	The present study aimed to investigate whether there is a correlation of LAPTM4B gene polymorphism with prognosis in colorectal and esophageal cancer patients after surgical resection.	('LAPTM4B', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('polymorphism', 'Var', (86, 98))	('LAPTM4B', 'Gene', '55353', (73, 80))	('patients', 'Species', '9606', (150, 158))	('colorectal and esophageal cancer', 'Disease', 'MESH:D015179', (117, 149))
871149	27391361	The association of LAPTM4B gene polymorphism with overall survival (OS) was analyzed using Kaplan-Meier curves and log-rank test.	('overall survival', 'MPA', (50, 66))	('polymorphism', 'Var', (32, 44))	('LAPTM4B', 'Gene', (19, 26))	('LAPTM4B', 'Gene', '55353', (19, 26))
871155	27391361	Among 167 colon cancer cases, the LAPTM4B genotypes: *1/1, *1/2 and *2/2 frequencies were 44.6%, 42.3% and 13.1%, respectively.	('*2/2', 'Var', (68, 72))	('LAPTM4B', 'Gene', '55353', (34, 41))	('colon cancer', 'Phenotype', 'HP:0003003', (10, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('colon cancer', 'Disease', 'MESH:D015179', (10, 22))	('LAPTM4B', 'Gene', (34, 41))	('colon cancer', 'Disease', (10, 22))
871175	27391361	In the present study, we revealed an independent prognostic role of LAPTM4B gene polymorphism in colon cancer patients who received surgical resection, but not in rectal and esophageal cancers.	('colon cancer', 'Disease', 'MESH:D015179', (97, 109))	('esophageal cancers', 'Disease', 'MESH:D004938', (174, 192))	('esophageal cancers', 'Disease', (174, 192))	('LAPTM4B', 'Gene', '55353', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('colon cancer', 'Disease', (97, 109))	('LAPTM4B', 'Gene', (68, 75))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('colon cancer', 'Phenotype', 'HP:0003003', (97, 109))	('polymorphism', 'Var', (81, 93))	('patients', 'Species', '9606', (110, 118))
871259	24476518	An additional minor concern is that patients who receive fluorescein will have yellow skin, eyes, and urine for several hours after the procedure.	('fluorescein', 'Var', (57, 68))	('patients', 'Species', '9606', (36, 44))	('fluorescein', 'Chemical', 'MESH:D019793', (57, 68))	('yellow skin', 'Phenotype', 'HP:0000952', (79, 90))	('yellow', 'Disease', (79, 85))
871340	24476518	Changes of basement membrane shape and density are usually associated with invasion of malignant cells and changes in the stroma are thought to be important in the development and progression of neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (195, 204))	('invasion of malignant cells', 'CPA', (75, 102))	('associated', 'Reg', (59, 69))	('neoplasia', 'Disease', (195, 204))	('Changes', 'Var', (0, 7))	('neoplasia', 'Disease', 'MESH:D009369', (195, 204))
871357	19789312	Our multi-center-based results highlight miRNAs involved in major histological types of esophageal carcinoma and uncover significant associations with prognosis.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (88, 108))	('involved', 'Reg', (48, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('miRNAs', 'Var', (41, 47))	('esophageal carcinoma', 'Disease', (88, 108))	('associations', 'Interaction', (133, 145))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (88, 108))
871366	19789312	In addition, miRNAs are often located in fragile sites or cancer-associated genomic regions.	('fragile sites', 'Disease', 'MESH:C565001', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('miRNAs', 'Var', (13, 19))	('cancer', 'Disease', (58, 64))	('fragile sites', 'Disease', (41, 54))
871372	19789312	In this study, we utilized four independent clinical centers to confirm and find novel miRNAs involved in the pathogenesis of human esophageal cancers and Barrett's , and to explore their utility as predictors of prognosis.	('miRNAs', 'Var', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (126, 131))	('Barrett', 'Disease', (155, 162))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('esophageal cancers', 'Disease', (132, 150))	('esophageal cancers', 'Disease', 'MESH:D004938', (132, 150))	('involved', 'Reg', (94, 102))
871404	19789312	Elevated expression of miR-21, miR-223, mir-192, mir-194, and reduced expression of miR-203 in ADC cancerous compared to adjacent non-cancerous tissue was confirmed in training and validation set samples, including those from the UMD and Canada cohorts (Figure 2A).	('miR-203', 'Gene', (84, 91))	('Elevated', 'PosReg', (0, 8))	('expression', 'MPA', (9, 19))	('miR-21', 'Gene', (23, 29))	('miR-223', 'Gene', (31, 38))	('miR-203', 'Gene', '406986', (84, 91))	('cancerous', 'Disease', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancerous', 'Disease', 'MESH:D009369', (134, 143))	('reduced', 'NegReg', (62, 69))	('expression', 'MPA', (70, 80))	('miR-223', 'Gene', '407008', (31, 38))	('mir-194', 'Var', (49, 56))	('mir-192', 'Gene', '406967', (40, 47))	('miR-21', 'Gene', '406991', (23, 29))	('cancerous', 'Disease', (134, 143))	('mir-192', 'Gene', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancerous', 'Disease', 'MESH:D009369', (99, 108))
871408	19789312	This association was not confirmed in the Canada cohort (mir-192 Barrett's:non-Barrett's fold change: 0.41, pval = 0.17; mir-194 Barrett's:non-Barrett's fold change: 0.46, pval = 0.22).	('mir-192', 'Gene', '406967', (57, 64))	('mir-194', 'Var', (121, 128))	('mir-192', 'Gene', (57, 64))
871425	19789312	Kaplan-Meier analysis revealed a statistically significant association between high expression of miR-21 in non-cancerous tissue (HR = 4.23; 95% CI = 1.68 - 10.61) and worse prognosis (Figure 3B, Table 2, Supplemental Table 8).	('miR-21', 'Gene', (98, 104))	('significant association', 'Reg', (47, 70))	('cancerous', 'Disease', (112, 121))	('high', 'Var', (79, 83))	('miR-21', 'Gene', '406991', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancerous', 'Disease', 'MESH:D009369', (112, 121))
871426	19789312	Elevated levels of miR-155 (HR = 2.69; 95% CI = 1.12 - 6.46), miR-146b (HR = 2.4; 95% CI = 1.03 - 5.56), and miR-181b (HR = 2.76; 95% CI = 1.15 - 6.62) in non-cancerous tissue showed a borderline significant association with worse prognosis.	('miR-181b', 'Var', (109, 117))	('cancerous', 'Disease', (159, 168))	('miR-155', 'Gene', (19, 26))	('miR-146b', 'Gene', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('miR-146b', 'Gene', '574447', (62, 70))	('miR-155', 'Gene', '406947', (19, 26))	('cancerous', 'Disease', 'MESH:D009369', (159, 168))
871438	19789312	Furthermore, increased expression of miR-194, miR-192, miR-223 and reduced expression of miR-203 are observed in ADC patients from two independent clinical centers while decreased expression of miR-375 is detected in SCC patients from three clinical centers.	('ADC', 'Disease', (113, 116))	('patients', 'Species', '9606', (221, 229))	('miR-192', 'Gene', (46, 53))	('miR-192', 'Gene', '406967', (46, 53))	('SCC', 'Gene', (217, 220))	('miR-375', 'Gene', '494324', (194, 201))	('miR-194', 'Var', (37, 44))	('miR-203', 'Gene', (89, 96))	('increased', 'PosReg', (13, 22))	('miR-223', 'Gene', (55, 62))	('reduced', 'NegReg', (67, 74))	('miR-203', 'Gene', '406986', (89, 96))	('miR-375', 'Gene', (194, 201))	('SCC', 'Gene', '6317', (217, 220))	('miR-223', 'Gene', '407008', (55, 62))	('patients', 'Species', '9606', (117, 125))	('expression', 'MPA', (75, 85))	('expression', 'MPA', (23, 33))
871454	19789312	A direct association between JAK2 and PI3-kinase upon glycine-extended gastrin stimulation has been shown in Barrett's associated ADC cells.	('extended gastrin', 'Phenotype', 'HP:0500167', (62, 78))	('gastrin', 'Gene', (71, 78))	('ADC', 'Disease', (130, 133))	('JAK2', 'Gene', (29, 33))	('PI3-kinase', 'Var', (38, 48))	('glycine', 'Chemical', 'MESH:D005998', (54, 61))	('gastrin', 'Gene', '2520', (71, 78))	('Barrett', 'Disease', (109, 116))	('JAK2', 'Gene', '3717', (29, 33))
871456	19789312	In concordance with our observations, a recent study based on a cohort of 7 patients reported that miR-21 is over-expressed in ADC, miR-143 is under-expressed in ADC, and miR-194 is over-expressed in Barrett's .	('miR-143', 'Gene', (132, 139))	('patients', 'Species', '9606', (76, 84))	('over-expressed', 'PosReg', (182, 196))	('miR-194', 'Var', (171, 178))	('ADC', 'Disease', (127, 130))	('under-expressed', 'NegReg', (143, 158))	('Barrett', 'Disease', (200, 207))	('miR-21', 'Gene', '406991', (99, 105))	('miR-143', 'Gene', '406935', (132, 139))	('miR-21', 'Gene', (99, 105))	('over-expressed', 'PosReg', (109, 123))
871469	19789312	In Barrett's associated ADC patients, high levels of mir-375, which targets genes associated with tumor cell proliferation, in the cancerous tissue was associated with worse prognosis.	('high levels', 'Var', (38, 49))	('mir-375', 'Gene', (53, 60))	('cancerous', 'Disease', (131, 140))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('ADC', 'Disease', (24, 27))	('cancerous', 'Disease', 'MESH:D009369', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('patients', 'Species', '9606', (28, 36))
871561	20066945	Following esophagectomy for Barrett's esophagus with high-grade dysplasia, older patients were more likely to report diminished physical function and performance at work, compared with the national standard.	('physical function', 'CPA', (128, 145))	('high-grade', 'Var', (53, 63))	('patients', 'Species', '9606', (81, 89))	('performance at work', 'CPA', (150, 169))	('diminished', 'NegReg', (117, 127))	("Barrett's esophagus", 'Disease', (28, 47))	('dysplasia', 'Disease', (64, 73))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (28, 47))	('dysplasia', 'Disease', 'MESH:D004476', (64, 73))
871594	19903854	One of the clones encoded the a.a. 378-440 of mouse AEG-1 which was designated as the 'lung homing domain' of the protein.	('encoded', 'Reg', (18, 25))	('AEG-1', 'Gene', (52, 57))	('a.a. 378-440', 'Var', (30, 42))	('mouse', 'Species', '10090', (46, 51))
871598	19903854	This location is especially significant since amplification of 8q22 has been demonstrated in a number of malignancies such as malignant glioma, hepatocellular carcinoma (HCC) and breast cancer and indeed genomic amplification of AEG-1 has been identified in HCC and breast cancer patients.	('malignancies', 'Disease', (105, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (144, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('hepatocellular carcinoma', 'Disease', (144, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('demonstrated', 'Reg', (77, 89))	('malignant glioma', 'Disease', 'MESH:D005910', (126, 142))	('malignant glioma', 'Disease', (126, 142))	('patients', 'Species', '9606', (280, 288))	('breast cancer', 'Phenotype', 'HP:0003002', (266, 279))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('rat', 'Species', '10116', (84, 87))	('breast cancer', 'Disease', (179, 192))	('AEG-1', 'Gene', (229, 234))	('HCC', 'Disease', (258, 261))	('breast cancer', 'Disease', 'MESH:D001943', (266, 279))	('HCC', 'Phenotype', 'HP:0001402', (258, 261))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('breast cancer', 'Disease', (266, 279))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (144, 168))	('amplification', 'Var', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('8q22', 'Gene', (63, 67))	('HCC', 'Phenotype', 'HP:0001402', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))
871613	19903854	In a separate study analyzing 170 breast cancer patients, 47% showed moderate to high level of AEG-1 expression and AEG-1 expression was significantly associated with a higher risk of metastasis indicating that AEG-1 might be a prognostic factor for this disease.	('AEG-1 expression', 'Var', (116, 132))	('rat', 'Species', '10116', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('metastasis', 'CPA', (184, 194))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('associated', 'Reg', (151, 161))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('expression', 'MPA', (101, 111))	('AEG-1', 'Protein', (95, 100))	('patients', 'Species', '9606', (48, 56))	('rat', 'Species', '10116', (73, 76))
871627	19903854	Overexpression of AEG-1 resulted in increased proliferation of human liver and esophageal cancer, malignant glioma, neuroblastoma and melanoma cells (manuscript in preparation).	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('proliferation', 'CPA', (46, 59))	('Overexpression', 'Var', (0, 14))	('human', 'Species', '9606', (63, 68))	('AEG-1', 'Gene', (18, 23))	('melanoma cells', 'Disease', 'MESH:D008545', (134, 148))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('increased', 'PosReg', (36, 45))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('neuroblastoma', 'Disease', (116, 129))	('rat', 'Species', '10116', (53, 56))	('neuroblastoma', 'Phenotype', 'HP:0003006', (116, 129))	('rat', 'Species', '10116', (169, 172))	('esophageal cancer', 'Disease', (79, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (116, 129))	('malignant glioma', 'Disease', 'MESH:D005910', (98, 114))	('malignant glioma', 'Disease', (98, 114))	('melanoma cells', 'Disease', (134, 148))
871629	19903854	As a corollary, knockdown of AEG-1 inhibited proliferation of human prostate cancer, neuroblastoma and melanoma cells and induced apoptosis in prostate cancer and neuroblastoma cells.	('neuroblastoma', 'Disease', 'MESH:D009447', (163, 176))	('induced', 'Reg', (122, 129))	('prostate cancer', 'Disease', (68, 83))	('melanoma cells', 'Disease', 'MESH:D008545', (103, 117))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('inhibited', 'NegReg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('prostate cancer', 'Disease', 'MESH:D011471', (143, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (143, 158))	('proliferation', 'CPA', (45, 58))	('human', 'Species', '9606', (62, 67))	('neuroblastoma', 'Disease', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma cells', 'Disease', (103, 117))	('neuroblastoma', 'Phenotype', 'HP:0003006', (85, 98))	('rat', 'Species', '10116', (52, 55))	('neuroblastoma', 'Disease', (163, 176))	('apoptosis in prostate cancer', 'Disease', (130, 158))	('neuroblastoma', 'Disease', 'MESH:D009447', (85, 98))	('knockdown', 'Var', (16, 25))	('neuroblastoma', 'Phenotype', 'HP:0003006', (163, 176))	('apoptosis in prostate cancer', 'Disease', 'MESH:D011471', (130, 158))	('AEG-1', 'Gene', (29, 34))	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))
871630	19903854	AEG-1 knockdown also inhibited invasion of human prostate cancer, neuroblastoma, malignant glioma and melanoma cell lines (unpublished data).	('neuroblastoma', 'Disease', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('neuroblastoma', 'Phenotype', 'HP:0003006', (66, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('invasion', 'CPA', (31, 39))	('malignant glioma', 'Disease', (81, 97))	('inhibited', 'NegReg', (21, 30))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('malignant glioma', 'Disease', 'MESH:D005910', (81, 97))	('knockdown', 'Var', (6, 15))	('neuroblastoma', 'Disease', 'MESH:D009447', (66, 79))	('prostate cancer', 'Disease', (49, 64))	('human', 'Species', '9606', (43, 48))	('AEG-1', 'Gene', (0, 5))
871631	19903854	Interestingly, neither overexpression nor inhibition altered any of these in vitro properties of human breast cancer cells, although our recent studies document that overexpression of AEG-1 does increase proliferation and invasion of human breast cancer cells and knockdown of AEG-1 reverses these effects (manuscript in preparation).	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('invasion', 'CPA', (222, 230))	('human', 'Species', '9606', (234, 239))	('rat', 'Species', '10116', (211, 214))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('breast cancer', 'Disease', (240, 253))	('human', 'Species', '9606', (97, 102))	('proliferation', 'CPA', (204, 217))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('rat', 'Species', '10116', (326, 329))	('breast cancer', 'Disease', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('AEG-1', 'Gene', (184, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('knockdown', 'Var', (264, 273))	('increase', 'PosReg', (195, 203))
871647	19903854	IL-8, an NF-kappaB downstream gene, positively regulated angiogenesis and metastasis and inhibition of NF-kappaB abrogated AEG-1-induced augmentation of soft agar growth and Matrigel invasion by HeLa cells.	('NF-kappaB', 'Gene', (9, 18))	('Matrigel invasion', 'CPA', (174, 191))	('inhibition', 'Var', (89, 99))	('angiogenesis', 'CPA', (57, 69))	('NF-kappaB', 'Gene', '4790', (103, 112))	('metastasis', 'CPA', (74, 84))	('IL-8', 'Gene', '3576', (0, 4))	('HeLa', 'CellLine', 'CVCL:0030', (195, 199))	('AEG-1-induced', 'Gene', (123, 136))	('IL-8', 'Gene', (0, 4))	('NF-kappaB', 'Gene', (103, 112))	('abrogated', 'NegReg', (113, 122))	('augmentation of soft agar growth', 'Disease', (137, 169))	('NF-kappaB', 'Gene', '4790', (9, 18))	('augmentation of soft agar growth', 'Disease', 'MESH:D006130', (137, 169))
871653	19903854	On the other hand, AEG-1 itself activated NF-kappaB and inhibition of AEG-1 prevented LPS-induced production of proinflammatory cytokines, such as TNF-alpha and PGE2.	('TNF-alpha', 'Gene', '7124', (147, 156))	('PGE2', 'Chemical', 'MESH:D015232', (161, 165))	('LPS', 'Chemical', 'MESH:D008070', (86, 89))	('activated', 'PosReg', (32, 41))	('LPS-induced', 'Disease', (86, 97))	('AEG-1', 'Gene', (70, 75))	('TNF-alpha', 'Gene', (147, 156))	('NF-kappaB', 'Gene', '4790', (42, 51))	('production of proinflammatory cytokines', 'MPA', (98, 137))	('prevented', 'NegReg', (76, 85))	('inhibition', 'Var', (56, 66))	('NF-kappaB', 'Gene', (42, 51))
871656	19903854	Ha-ras activates the PI3K/Akt pathway that leads to binding of the transcription factor c-Myc to the E-box element in the promoter region of AEG-1 and induces AEG-1 transcription.	('induces', 'PosReg', (151, 158))	('Akt', 'Gene', '207', (26, 29))	('PI3', 'Gene', '5266', (21, 24))	('AEG-1', 'Gene', (159, 164))	('c-Myc', 'Gene', '4609', (88, 93))	('AEG-1', 'Gene', (141, 146))	('binding', 'Interaction', (52, 59))	('Akt', 'Gene', (26, 29))	('Ha-ras', 'Var', (0, 6))	('c-Myc', 'Gene', (88, 93))	('PI3', 'Gene', (21, 24))
871658	19903854	While c-Myc induces AEG-1 transcription, AEG-1 also induces c-Myc expression and in neuroblastoma cells it induces N-Myc expression thereby amplifying the tumorigenic effect.	('transcription', 'MPA', (26, 39))	('expression', 'MPA', (121, 131))	('tumor', 'Disease', (155, 160))	('expression', 'MPA', (66, 76))	('c-Myc', 'Gene', '4609', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('c-Myc', 'Gene', (6, 11))	('amplifying', 'PosReg', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('neuroblastoma', 'Disease', (84, 97))	('induces', 'Reg', (107, 114))	('neuroblastoma', 'Phenotype', 'HP:0003006', (84, 97))	('induces', 'Reg', (52, 59))	('c-Myc', 'Gene', '4609', (6, 11))	('AEG-1', 'Protein', (20, 25))	('N-Myc', 'Gene', (115, 120))	('N-Myc', 'Gene', '4613', (115, 120))	('AEG-1', 'Var', (41, 46))	('neuroblastoma', 'Disease', 'MESH:D009447', (84, 97))	('c-Myc', 'Gene', (60, 65))
871660	19903854	Inhibition of AEG-1 in prostate cancer cells downregulates Akt activation and leads to upregulation of forkhead box (FOXO)3a activity and p27 resulting in apoptosis.	('Akt', 'Gene', (59, 62))	('AEG-1', 'Gene', (14, 19))	('activity', 'MPA', (125, 133))	('prostate cancer', 'Disease', (23, 38))	('FOXO', 'Gene', '2309', (117, 121))	('FOXO', 'Gene', (117, 121))	('p27', 'Gene', '3429', (138, 141))	('p27', 'Gene', (138, 141))	('Akt', 'Gene', '207', (59, 62))	('Inhibition', 'Var', (0, 10))	('downregulates', 'NegReg', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (23, 38))	('apoptosis', 'CPA', (155, 164))	('prostate cancer', 'Phenotype', 'HP:0012125', (23, 38))	('activation', 'PosReg', (63, 73))	('upregulation', 'PosReg', (87, 99))
871674	19903854	Additionally, AEG-1 induces the 5-FU catabolizing enzyme Dihydropyrimidine dehydrogenase (DPYD).	('AEG-1', 'Var', (14, 19))	('Dihydropyrimidine dehydrogenase', 'Gene', (57, 88))	('DPYD', 'Gene', (90, 94))	('DPYD', 'Gene', '1806', (90, 94))	('induces', 'Reg', (20, 27))	('Dihydropyrimidine dehydrogenase', 'Gene', '1806', (57, 88))	('5-FU', 'Chemical', 'MESH:D005472', (32, 36))
871679	19903854	Loss of BCCIP impairs G1/S checkpoint activation following DNA damage and in conjunction with BRCA2, BCCIP plays a role in homologous recombination repair of DNA damage and contributes to maintenance of chromosome stability.	('chromosome stability', 'CPA', (203, 223))	('BCCIP', 'Gene', (101, 106))	('contributes', 'Reg', (173, 184))	('BRCA2', 'Gene', (94, 99))	('G1/S checkpoint activation', 'MPA', (22, 48))	('BCCIP', 'Gene', (8, 13))	('BCCIP', 'Gene', '56647', (101, 106))	('impairs', 'NegReg', (14, 21))	('BRCA2', 'Gene', '675', (94, 99))	('BCCIP', 'Gene', '56647', (8, 13))	('Loss', 'Var', (0, 4))
871696	19903854	One important question is whether AEG-1 only promotes metastasis, as suggested by two studies in breast cancer, or does it also regulate crucial events earlier in the carcinogenic process, such as immortalization, transformation and increased proliferation as suggested by multiple studies in other cancer indications as well as using immortal normal cells?	('promotes', 'PosReg', (45, 53))	('transformation', 'CPA', (214, 228))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('metastasis', 'CPA', (54, 64))	('AEG-1', 'Var', (34, 39))	('carcinogenic process', 'Disease', (167, 187))	('increased proliferation', 'CPA', (233, 256))	('carcinogenic process', 'Disease', 'MESH:D009385', (167, 187))	('rat', 'Species', '10116', (250, 253))	('immortalization', 'CPA', (197, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('regulate', 'Reg', (128, 136))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Disease', (97, 110))
871707	18831746	Similarity of aberrant DNA methylation in Barrett's esophagus and esophageal adenocarcinoma Barrett's esophagus (BE) is the metaplastic replacement of squamous with columnar epithelium in the esophagus, as a result of reflux.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (66, 91))	("Barrett's esophagus", 'Disease', (92, 111))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (92, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('aberrant', 'Var', (14, 22))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (42, 61))	('BE', 'Phenotype', 'HP:0100580', (113, 115))	('DNA', 'Protein', (23, 26))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (66, 91))	('esophageal adenocarcinoma', 'Disease', (66, 91))
871709	18831746	Methylation of CpG dinucleotides of normally unmethylated genes is associated with silencing of their expression, and is common in EAC.	('common', 'Reg', (121, 127))	('silencing', 'MPA', (83, 92))	('EAC', 'Disease', (131, 134))	('expression', 'MPA', (102, 112))	('Methylation', 'Var', (0, 11))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (15, 31))	('dinucleotides', 'Chemical', 'MESH:D015226', (19, 32))	('EAC', 'Phenotype', 'HP:0011459', (131, 134))
871715	18831746	This is also the first report of gene silencing by methylation of ID4 in BE or EAC.	('BE', 'Phenotype', 'HP:0100580', (73, 75))	('gene', 'MPA', (33, 37))	('methylation', 'Var', (51, 62))	('EAC', 'Phenotype', 'HP:0011459', (79, 82))	('ID4', 'Gene', (66, 69))	('ID4', 'Gene', '3400', (66, 69))
871723	18831746	Abnormalities in CDKN2A, seen in BE metaplastic tissue, followed by altered TP53 expression, generally reported in dysplastic tissue, have been associated with the transition from BE to EAC.	('associated with', 'Reg', (144, 159))	('BE', 'Phenotype', 'HP:0100580', (33, 35))	('TP53', 'Gene', '7157', (76, 80))	('dysplastic', 'Disease', 'MESH:D004416', (115, 125))	('dysplastic', 'Disease', (115, 125))	('CDKN2A', 'Gene', (17, 23))	('TP53', 'Gene', (76, 80))	('CDKN2A', 'Gene', '1029', (17, 23))	('EAC', 'Phenotype', 'HP:0011459', (186, 189))	('altered', 'Var', (68, 75))	('expression', 'MPA', (81, 91))	('BE', 'Phenotype', 'HP:0100580', (180, 182))
871724	18831746	Alterations in the expression of many other genes have also been described at different stages of the progression to cancer.	('expression', 'MPA', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('described', 'Reg', (65, 74))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
871726	18831746	However, aberrant methylation of normally unmethylated CpG islands is a common cause of altered gene expression in cancer.	('cancer', 'Disease', (115, 121))	('altered gene expression', 'MPA', (88, 111))	('methylation', 'MPA', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cause', 'Reg', (79, 84))	('aberrant', 'Var', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
871731	18831746	Treatment with aza-dC reduced methylation and significantly increased the expression of all methylated genes except TMEFF2, which was undetected in either cell line.	('aza-dC', 'Var', (15, 21))	('expression', 'MPA', (74, 84))	('TMEFF2', 'Gene', (116, 122))	('aza-dC', 'Chemical', 'MESH:D000077209', (15, 21))	('TMEFF2', 'Gene', '23671', (116, 122))	('reduced', 'NegReg', (22, 29))	('methylation', 'MPA', (30, 41))	('increased', 'PosReg', (60, 69))
871733	18831746	Following treatment with aza-dC, transcript levels were not significantly increased for any unmethylated genes, except for APC in OE33.	('APC', 'Disease', 'MESH:D011125', (123, 126))	('APC', 'Disease', (123, 126))	('transcript levels', 'MPA', (33, 50))	('aza-dC', 'Chemical', 'MESH:D000077209', (25, 31))	('aza-dC', 'Var', (25, 31))
871734	18831746	The results in Figure 2 show the methylation frequency, the percentage of samples that had any extent of methylation, for each of the nine genes, in squamous tissues from either patients with no known history of BE (S), or patients with BE (S-BE) or patients with adenocarcinoma (S-EAC), in metaplastic Barrett's from patients with BE but no dysplasia or adenocarcinoma (BE), in high grade dysplastic Barrett's from patients with adenocarcinoma (D-EAC), and in adenocarcinoma (EAC).	('adenocarcinoma', 'Disease', 'MESH:D000230', (430, 444))	('adenocarcinoma', 'Disease', (355, 369))	('BE', 'Phenotype', 'HP:0100580', (243, 245))	('dysplasia or adenocarcinoma', 'Disease', 'MESH:D000230', (342, 369))	('adenocarcinoma', 'Disease', 'MESH:D000230', (461, 475))	('patients', 'Species', '9606', (178, 186))	('dysplasia or adenocarcinoma', 'Disease', (342, 369))	('adenocarcinoma', 'Disease', 'MESH:D000230', (355, 369))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('patients', 'Species', '9606', (250, 258))	('adenocarcinoma', 'Disease', (264, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (466, 475))	('carcinoma', 'Phenotype', 'HP:0030731', (435, 444))	('EAC', 'Phenotype', 'HP:0011459', (282, 285))	('patients', 'Species', '9606', (416, 424))	('BE', 'Phenotype', 'HP:0100580', (237, 239))	('methylation', 'Var', (105, 116))	('EAC', 'Phenotype', 'HP:0011459', (448, 451))	("dysplastic Barrett's", 'Disease', 'MESH:D001471', (390, 410))	('patients', 'Species', '9606', (318, 326))	('dysplastic Barrett', 'Disease', (390, 408))	('D-EAC', 'Chemical', '-', (446, 451))	('adenocarcinoma', 'Disease', (430, 444))	('adenocarcinoma', 'Disease', (461, 475))	('EAC', 'Phenotype', 'HP:0011459', (477, 480))	('BE', 'Phenotype', 'HP:0100580', (332, 334))	('adenocarcinoma', 'Disease', 'MESH:D000230', (264, 278))	('BE', 'Phenotype', 'HP:0100580', (371, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (360, 369))	('patients', 'Species', '9606', (223, 231))	('BE', 'Phenotype', 'HP:0100580', (212, 214))
871736	18831746	For all nine genes the methylation frequency in BE and D-EAC was significantly higher than each of the squamous tissues (S, S-BE and S-EAC) with the exception of CDKN2A (no difference between BE or D-EAC and S or S-BE), RBP1 (BE vs S-BE and D-EAC vs S or S-BE) and SFRP1 (D-EAC vs S-EAC).	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('higher', 'PosReg', (79, 85))	('EAC', 'Phenotype', 'HP:0011459', (135, 138))	('BE', 'Phenotype', 'HP:0100580', (226, 228))	('D-EAC', 'Var', (55, 60))	('D-EAC', 'Chemical', '-', (198, 203))	('methylation', 'MPA', (23, 34))	('CDKN2A', 'Gene', (162, 168))	('SFRP1', 'Gene', '6422', (265, 270))	('D-EAC', 'Chemical', '-', (55, 60))	('BE', 'Phenotype', 'HP:0100580', (192, 194))	('BE', 'Phenotype', 'HP:0100580', (48, 50))	('EAC', 'Phenotype', 'HP:0011459', (274, 277))	('EAC', 'Phenotype', 'HP:0011459', (243, 246))	('CDKN2A', 'Gene', '1029', (162, 168))	('BE', 'Phenotype', 'HP:0100580', (126, 128))	('BE', 'Phenotype', 'HP:0100580', (215, 217))	('RBP1', 'Gene', '5947', (220, 224))	('RBP1', 'Gene', (220, 224))	('D-EAC', 'Chemical', '-', (272, 277))	('SFRP1', 'Gene', (265, 270))	('D-EAC', 'Chemical', '-', (241, 246))	('EAC', 'Phenotype', 'HP:0011459', (200, 203))
871742	18831746	Significantly more genes were methylated in specimens of BE, D-EAC and EAC, compared to any of the squamous tissues (P < 0.01 for each comparison).	('methylated', 'Var', (30, 40))	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('D-EAC', 'Chemical', '-', (61, 66))	('BE', 'Phenotype', 'HP:0100580', (57, 59))	('EAC', 'Disease', (71, 74))	('D-EAC', 'Var', (61, 66))	('EAC', 'Phenotype', 'HP:0011459', (63, 66))	('more', 'PosReg', (14, 18))
871749	18831746	There was significantly less expression of MGMT in methylated tumors compared to unmethylated tumors (Figure.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('methylated', 'Var', (51, 61))	('MGMT', 'Gene', '4255', (43, 47))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('MGMT', 'Gene', (43, 47))	('less', 'NegReg', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('expression', 'MPA', (29, 39))
871750	18831746	Furthermore, the expression of MGMT did not differ between unmethylated squamous and unmethylated tumor tissues, suggesting that the observed reduction in EAC was primarily due to methylation, not phenotypic differences.	('reduction', 'NegReg', (142, 151))	('EAC', 'Gene', (155, 158))	('MGMT', 'Gene', '4255', (31, 35))	('MGMT', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('EAC', 'Phenotype', 'HP:0011459', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('methylation', 'Var', (180, 191))
871751	18831746	Methylation is an important mechanism for the silencing of genes in the development of cancer.	('cancer', 'Disease', (87, 93))	('silencing', 'NegReg', (46, 55))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
871755	18831746	This suggests that methylation of these genes can occur early in the development of Barrett's metaplasia, and for only some of these genes does the extent of methylation increases during the progression to cancer.	('methylation', 'Var', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (206, 212))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (84, 104))	("Barrett's metaplasia", 'Disease', (84, 104))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
871760	18831746	For these three genes we have shown using cell lines established from other cancers that methylation of the regions we amplified are associated with gene silencing (unpublished observations).	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('gene', 'MPA', (149, 153))	('methylation', 'Var', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
871761	18831746	In our EAC tissues only methylation of MGMT was associated with a significant reduction in mRNA expression.	('mRNA expression', 'MPA', (91, 106))	('reduction', 'NegReg', (78, 87))	('methylation', 'Var', (24, 35))	('EAC', 'Phenotype', 'HP:0011459', (7, 10))	('MGMT', 'Gene', (39, 43))	('MGMT', 'Gene', '4255', (39, 43))
871762	18831746	The lack of a significant difference in gene expression for the other genes may be due to methylation of only one allele, or the presence of unmethylated cells in the tissue, such as clonal variants of the tumor, or stromal or infiltrating cells.	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('methylation', 'Var', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))
871765	18831746	It is accepted that BE is a pre-malignant condition, which over time, as a result of the accumulation of multiple genetic and epigenetic modifications, can progress through dysplasia to EAC in a percentage of patients.	('progress', 'Reg', (156, 164))	('dysplasia', 'Disease', (173, 182))	('epigenetic modifications', 'Var', (126, 150))	('EAC', 'Disease', (186, 189))	('patients', 'Species', '9606', (209, 217))	('BE', 'Phenotype', 'HP:0100580', (20, 22))	('dysplasia', 'Disease', 'MESH:D004476', (173, 182))	('EAC', 'Phenotype', 'HP:0011459', (186, 189))
871771	18831746	They also reported four genes, CDKN2A, ESR1 and MYOD1 and CALCA as unmethylated in these BE patients, and methylated in the cancers.	('MYOD1', 'Gene', (48, 53))	('MYOD1', 'Gene', '4654', (48, 53))	('methylated', 'Var', (106, 116))	('patients', 'Species', '9606', (92, 100))	('ESR1', 'Gene', '2099', (39, 43))	('CALCA', 'Gene', '796', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BE', 'Phenotype', 'HP:0100580', (89, 91))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('CDKN2A', 'Gene', (31, 37))	('CALCA', 'Gene', (58, 63))	('cancers', 'Disease', (124, 131))	('ESR1', 'Gene', (39, 43))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('CDKN2A', 'Gene', '1029', (31, 37))
871776	18831746	Of the nine genes which we studied, only methylation of CDKN2A and RUNX3 appeared to increase in frequency in the progression from BE to cancer, and only six of the nine genes increased in the extent of methylation.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('RUNX3', 'Gene', '864', (67, 72))	('BE', 'Phenotype', 'HP:0100580', (131, 133))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('methylation', 'Var', (41, 52))	('cancer', 'Disease', (137, 143))	('RUNX3', 'Gene', (67, 72))	('CDKN2A', 'Gene', (56, 62))	('increase', 'PosReg', (85, 93))	('CDKN2A', 'Gene', '1029', (56, 62))
871777	18831746	The underlying mechanisms that cause aberrant DNA methylation in Barrett's metaplasia and cancer are unknown.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (65, 85))	("Barrett's metaplasia", 'Disease', (65, 85))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('aberrant', 'Var', (37, 45))
871778	18831746	Our study confirms that aberrant methylation of multiple genes is an early event, and mostly occurs independently of dysplasia or EAC.	('dysplasia', 'Disease', (117, 126))	('dysplasia', 'Disease', 'MESH:D004476', (117, 126))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('EAC', 'Disease', (130, 133))	('aberrant methylation', 'Var', (24, 44))
871781	18831746	This is the first report of ID4 methylation in BE or EAC.	('ID4', 'Gene', '3400', (28, 31))	('methylation', 'Var', (32, 43))	('EAC', 'Phenotype', 'HP:0011459', (53, 56))	('BE', 'Phenotype', 'HP:0100580', (47, 49))	('ID4', 'Gene', (28, 31))
871785	18831746	Methylation of ID4 has been reported in and associated with the silencing of gene transcription and loss of protein expression in lymphoma, and gastric, colorectal and breast carcinoma.	('lymphoma', 'Disease', (130, 138))	('gastric', 'Disease', (144, 151))	('Methylation', 'Var', (0, 11))	('ID4', 'Gene', (15, 18))	('lymphoma', 'Disease', 'MESH:D008223', (130, 138))	('ID4', 'Gene', '3400', (15, 18))	('lymphoma', 'Phenotype', 'HP:0002665', (130, 138))	('protein expression', 'MPA', (108, 126))	('silencing', 'NegReg', (64, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('gene transcription', 'MPA', (77, 95))	('breast carcinoma', 'Phenotype', 'HP:0003002', (168, 184))	('loss', 'NegReg', (100, 104))	('colorectal and breast carcinoma', 'Disease', 'MESH:D015179', (153, 184))
871786	18831746	Methylation of ID4 correlated with increased risk of lymph node metastasis in T1 stage breast cancer, and histopathological tumor grade and poorer prognosis in colorectal carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Methylation', 'Var', (0, 11))	('ID4', 'Gene', (15, 18))	('tumor', 'Disease', (124, 129))	('lymph node metastasis', 'CPA', (53, 74))	('colorectal carcinoma', 'Disease', (160, 180))	('ID4', 'Gene', '3400', (15, 18))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
871787	18831746	Our findings that ID4 is frequently methylated in BE and EAC but not in the normal squamous mucosa and that demethylation of cancer cell lines significantly increases expression, suggests loss of ID4 expression is important in the neoplastic progression of BE, supporting its role as a tumor suppressor.	('demethylation', 'Var', (108, 121))	('ID4', 'Gene', '3400', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('EAC', 'Phenotype', 'HP:0011459', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('BE', 'Phenotype', 'HP:0100580', (50, 52))	('BE', 'Phenotype', 'HP:0100580', (257, 259))	('ID4', 'Gene', (196, 199))	('cancer', 'Disease', (125, 131))	('loss', 'Var', (188, 192))	('increases', 'PosReg', (157, 166))	('ID4', 'Gene', '3400', (196, 199))	('expression', 'MPA', (167, 177))	('ID4', 'Gene', (18, 21))
871790	18831746	Genomic loss, chromosomal gains and amplifications, mutations, and aneuploidy are observed in BE, and loss of heterozygosity of CDKN2A is reported in 47 - 75% of patients with BE, in the absence of dysplasia or EAC.	('mutations', 'Var', (52, 61))	('absence of dysplasia', 'Disease', (187, 207))	('patients', 'Species', '9606', (162, 170))	('BE', 'Phenotype', 'HP:0100580', (94, 96))	('CDKN2A', 'Gene', '1029', (128, 134))	('aneuploidy', 'Disease', (67, 77))	('BE', 'Phenotype', 'HP:0100580', (176, 178))	('loss', 'NegReg', (8, 12))	('absence of dysplasia', 'Disease', 'MESH:D004832', (187, 207))	('amplifications', 'MPA', (36, 50))	('chromosomal gains', 'Disease', (14, 31))	('loss', 'NegReg', (102, 106))	('chromosomal gains', 'Disease', 'MESH:D015430', (14, 31))	('aneuploidy', 'Disease', 'MESH:D000782', (67, 77))	('CDKN2A', 'Gene', (128, 134))	('EAC', 'Phenotype', 'HP:0011459', (211, 214))
871792	18831746	Mutations in CDKN2A have been reported in up to 7% of patients with metaplasia, but most reports suggest that mutations are absent in BE from patients without dysplasia or EAC.	('reported', 'Reg', (30, 38))	('dysplasia', 'Disease', (159, 168))	('patients', 'Species', '9606', (54, 62))	('to 7', 'Species', '1214577', (45, 49))	('CDKN2A', 'Gene', (13, 19))	('BE', 'Phenotype', 'HP:0100580', (134, 136))	('metaplasia', 'Disease', 'MESH:D008679', (68, 78))	('dysplasia', 'Disease', 'MESH:D004476', (159, 168))	('Mutations', 'Var', (0, 9))	('EAC', 'Phenotype', 'HP:0011459', (172, 175))	('CDKN2A', 'Gene', '1029', (13, 19))	('metaplasia', 'Disease', (68, 78))	('patients', 'Species', '9606', (142, 150))
871793	18831746	In this study of methylation in esophageal disease we have measured little methylation in any esophageal squamous epithelium, but in BE tissues there was significant methylation which for all but two of the nine genes examined did not increase in frequency in the progression from BE to EAC.	('esophageal disease', 'Disease', 'MESH:D004935', (32, 50))	('EAC', 'Phenotype', 'HP:0011459', (287, 290))	('BE', 'Phenotype', 'HP:0100580', (133, 135))	('esophageal disease', 'Disease', (32, 50))	('EAC', 'Disease', (287, 290))	('BE', 'Phenotype', 'HP:0100580', (281, 283))	('methylation', 'Var', (166, 177))
871795	18831746	Together these findings confirm that BE is a precancerous tissue, and that aberrant promoter methylation occurs early in metaplasia before histological evidence of progression towards cancer, and that metaplastic BE is nearly as abnormal epigenetically as EAC.	('cancer', 'Disease', (184, 190))	('aberrant', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('BE', 'Phenotype', 'HP:0100580', (37, 39))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('promoter methylation', 'MPA', (84, 104))	('EAC', 'Phenotype', 'HP:0011459', (256, 259))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('metaplasia', 'Disease', 'MESH:D008679', (121, 131))	('BE', 'Phenotype', 'HP:0100580', (213, 215))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('metaplasia', 'Disease', (121, 131))
871873	33318305	For example, a very recent study reported that the expression level of ADAMTS9-AS2 is lower in esophageal cancer tissues and over-expressing it can suppress the development of esophageal cancer via inducing CDHS promoter methylation.	('CDHS promoter methylation', 'MPA', (207, 232))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('suppress', 'NegReg', (148, 156))	('esophageal cancer', 'Disease', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('ADAMTS9', 'Gene', (71, 78))	('lower', 'NegReg', (86, 91))	('development', 'CPA', (161, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (176, 193))	('inducing', 'PosReg', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('over-expressing', 'Var', (125, 140))	('esophageal cancer', 'Disease', (95, 112))	('ADAMTS9', 'Gene', '56999', (71, 78))	('expression level', 'MPA', (51, 67))
872199	24210755	Patients with pathCR often have a longer survival and have a lower rate distant relapse than those who have <pathCR.	('lower', 'NegReg', (61, 66))	('distant relapse', 'CPA', (72, 87))	('longer', 'PosReg', (34, 40))	('Patients', 'Species', '9606', (0, 8))	('pathCR', 'Var', (14, 20))
872208	24210755	In breast carcinomas, high ALDH-1 activity identified tumorigenic cell fraction that could recapitulate the heterogeneity of the parental tumor.	('activity', 'MPA', (34, 42))	('tumor', 'Disease', (138, 143))	('breast carcinomas', 'Disease', 'MESH:D001943', (3, 20))	('high', 'Var', (22, 26))	('breast carcinomas', 'Disease', (3, 20))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('ALDH-1', 'Gene', (27, 33))	('breast carcinomas', 'Phenotype', 'HP:0003002', (3, 20))	('tumor', 'Disease', (54, 59))	('parental tumor', 'Disease', 'MESH:D063129', (129, 143))	('parental tumor', 'Disease', (129, 143))
872243	24210755	(Figure 3) For overall survival, the Martingale residual plot suggested a linear relationship between ALDH-1 LIs and the risk of death.	('death', 'Disease', 'MESH:D003643', (129, 134))	('death', 'Disease', (129, 134))	('LIs', 'Var', (109, 112))	('ALDH-1', 'Gene', (102, 108))
872253	24210755	Our results on EC cells suggest that high ALDH-1 LIs are associated with therapy resistance, aggressive phenotype (higher proliferative rate) in tumor spheres, and overexpression of resistance conferring genes (Shh, YAP1, Shh, Gal-3, and Hes-1).	('YAP1', 'Gene', (216, 220))	('YAP1', 'Gene', '10413', (216, 220))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('high', 'Var', (37, 41))	('Shh', 'Gene', (211, 214))	('therapy resistance', 'CPA', (73, 91))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Hes-1', 'Gene', (238, 243))	('Shh', 'Gene', (222, 225))	('tumor', 'Disease', (145, 150))	('Gal-3', 'Gene', (227, 232))	('ALDH-1', 'Gene', (42, 48))	('overexpression', 'PosReg', (164, 178))	('Gal-3', 'Gene', '3958', (227, 232))	('Shh', 'Gene', '6469', (211, 214))	('Hes-1', 'Gene', '3280', (238, 243))	('Shh', 'Gene', '6469', (222, 225))	('associated', 'Reg', (57, 67))
872391	24570884	Generally, the literature does not support endoscopic treatment because of LNM rates of at least 8% for sm1 and 15% for sm2 and sm3.	('sm2', 'Gene', (120, 123))	('sm1', 'Var', (104, 107))	('sm3', 'Chemical', '-', (128, 131))	('sm2', 'Gene', '53366', (120, 123))
872415	18598945	Mutations in Fbx4 inhibit phosphorylation-dependent dimerization of the SCFFbx4 ligase and contribute to cyclin D1 overexpression in human cancer SCFFbx4 was recently identified as the E3 ligase for cyclin D1.	('inhibit', 'NegReg', (18, 25))	('Fbx4', 'Gene', (13, 17))	('Fbx4', 'Gene', '26272', (75, 79))	('cyclin D1', 'Gene', (105, 114))	('cyclin D1', 'Gene', (199, 208))	('overexpression', 'PosReg', (115, 129))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('Fbx4', 'Gene', (149, 153))	('contribute', 'Reg', (91, 101))	('cyclin D1', 'Gene', '595', (105, 114))	('Mutations', 'Var', (0, 9))	('cyclin D1', 'Gene', '595', (199, 208))	('human', 'Species', '9606', (133, 138))	('phosphorylation-dependent dimerization', 'MPA', (26, 64))	('Fbx4', 'Gene', (75, 79))	('Fbx4', 'Gene', '26272', (13, 17))	('cancer', 'Disease', (139, 145))	('Fbx4', 'Gene', '26272', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))
872418	18598945	The importance of this regulatory pathway for normal cell growth is emphasized by the prevalence of mutations in Fbx4 in human cancer that impair dimerization.	('mutations', 'Var', (100, 109))	('dimerization', 'MPA', (146, 158))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Fbx4', 'Gene', (113, 117))	('impair', 'NegReg', (139, 145))	('human', 'Species', '9606', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('val', 'Chemical', 'MESH:D014633', (89, 92))
872419	18598945	Collectively, this data reveals that inactivation of the cyclin D1 E3 ligase will likely contribute to cyclin D1 overexpression in a significant fraction of human cancer.	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('expression', 'Species', '29278', (117, 127))	('human', 'Species', '9606', (157, 162))	('overexpression', 'PosReg', (113, 127))	('contribute', 'Reg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cyclin D1', 'MPA', (103, 112))	('cancer', 'Disease', (163, 169))	('inactivation', 'Var', (37, 49))	('cyclin D1 E3 ligase', 'Enzyme', (57, 76))
872422	18598945	In summary, our study establishes Fbx4 as a tumor suppressor in human cancer, function of which is abrogated by a unique category of mutations that target E3 ligase activity.	('activity', 'MPA', (165, 173))	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutations', 'Var', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Fbx4', 'Gene', (34, 38))	('E3 ligase', 'Protein', (155, 164))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))	('tumor', 'Disease', (44, 49))
872429	18598945	Overexpression was thought initially to result from chromosomal translocations or gene amplification.	('gene amplification', 'Var', (82, 100))	('result', 'Reg', (40, 46))	('chromosomal translocations', 'Var', (52, 78))	('expression', 'Species', '29278', (4, 14))
872430	18598945	Because the frequency of cyclin D1 overexpression exceeds the frequency of such large chromosomal alterations, it was proposed that alterations in turnover of cyclin D1 protein might also contribute to aberrant cyclin D1 levels.	('turnover', 'MPA', (147, 155))	('alterations', 'Var', (132, 143))	('contribute', 'Reg', (188, 198))	('expression', 'Species', '29278', (39, 49))	('cyclin D1 levels', 'MPA', (211, 227))
872437	18598945	Mutation of this serine residue to alanine attenuates dimerization of Fbx4 and significantly impairs cyclin D1 ubiquitination and proteolysis.	('alanine', 'Chemical', 'MESH:D000409', (35, 42))	('serine', 'Chemical', 'MESH:D012694', (17, 23))	('Mutation', 'Var', (0, 8))	('proteolysis', 'MPA', (130, 141))	('dimerization', 'MPA', (54, 66))	('attenuates', 'NegReg', (43, 53))	('impairs', 'NegReg', (93, 100))	('Fbx4', 'Gene', (70, 74))	('cyclin D1 ubiquitination', 'MPA', (101, 125))
872440	18598945	Finally, we demonstrate that inhibition of SCFFbx4/alphaB-crystallin ligase activity leads to accumulation of cyclin D1 in the nuclei and promotes cellular transformation.	('activity', 'MPA', (76, 84))	('alphaB-crystallin', 'Gene', '12955', (51, 68))	('cyclin D1', 'Protein', (110, 119))	('promotes', 'PosReg', (138, 146))	('accumulation', 'PosReg', (94, 106))	('cellular transformation', 'CPA', (147, 170))	('alphaB-crystallin', 'Gene', (51, 68))	('inhibition', 'Var', (29, 39))
872442	18598945	While neither the F-box nor the C-terminal regions were required, removal of the N-terminal 50 amino acids of Fbx4 abrogated dimerization (Fig.	('abrogated', 'NegReg', (115, 124))	('dimerization', 'MPA', (125, 137))	('removal', 'Var', (66, 73))	('val', 'Chemical', 'MESH:D014633', (70, 73))	('Fbx4', 'Gene', (110, 114))
872444	18598945	Mutation of leucine/isoleucine residues, within Fbx4 (Fig.	('Mutation', 'Var', (0, 8))	('Fbx4', 'Gene', (48, 52))	('leucine', 'Chemical', 'MESH:D007930', (12, 19))	('isoleucine', 'Chemical', 'MESH:D007532', (20, 30))	('leucine', 'Chemical', 'MESH:D007930', (23, 30))
872445	18598945	S1B), that are spatially conserved with leucines that contribute to dimerization of Fbw7, defined leucine 23 as essential for Fbx4 dimerization (Fig.	('leucine 23', 'Var', (98, 108))	('dimerization', 'MPA', (68, 80))	('leucine', 'Chemical', 'MESH:D007930', (40, 47))	('Fbw7', 'Gene', (84, 88))	('leucine', 'Chemical', 'MESH:D007930', (98, 105))	('Fbw7', 'Gene', '55294', (84, 88))
872446	18598945	As with dimerization defective Fbw7, Fbx4 mutants retained their capacity to associate with cyclin D1 (Fig.	('mutants', 'Var', (42, 49))	('capacity', 'MPA', (65, 73))	('associate', 'Interaction', (77, 86))	('Fbx4', 'Gene', (37, 41))	('Fbw7', 'Gene', '55294', (31, 35))	('Fbw7', 'Gene', (31, 35))	('cyclin D1', 'Protein', (92, 101))
872448	18598945	Serine 12 of Fbx4 is a predicted proline-directed phosphorylation motif.	('Serine', 'Chemical', 'MESH:D012694', (0, 6))	('proline', 'Chemical', 'MESH:D011392', (33, 40))	('Fbx4', 'Gene', (13, 17))	('Serine 12', 'Var', (0, 9))
872450	18598945	We therefore generated both non-phosphorylatable (S12A) and phosphomimetic (S12E) mutations in Fbx4 as well as a P13A mutant to address whether a proline directed kinase targeted this site; all mutants were then assessed for dimerization potential.	('S12A', 'SUBSTITUTION', 'None', (50, 54))	('S12A', 'Var', (50, 54))	('Fbx4', 'Gene', (95, 99))	('S12E', 'Mutation', 'p.S12E', (76, 80))	('mutations', 'Var', (82, 91))	('proline', 'Chemical', 'MESH:D011392', (146, 153))	('S12E', 'Var', (76, 80))	('P13A', 'Mutation', 'p.P13A', (113, 117))
872451	18598945	We next reconstituted murine NIH3T3 cell lines wherein endogenous Fbx4 had been stably knocked down, with either wild type (human) Fbx4 or the serine 12 mutants of Fbx4 followed by G418 selection to establish stable cell lines.	('murine', 'Species', '10090', (22, 28))	('serine 12 mutants', 'Var', (143, 160))	('human', 'Species', '9606', (124, 129))	('NIH3T3', 'CellLine', 'CVCL:0594', (29, 35))	('Fbx4', 'Gene', (164, 168))	('serine 12', 'Chemical', '-', (143, 152))	('Fbx4', 'Gene', (66, 70))	('knocked down', 'NegReg', (87, 99))
872452	18598945	We previously demonstrated that Fbx4 knockdown results in overexpression of endogenous cyclin D1 (Fig.	('endogenous cyclin D1', 'MPA', (76, 96))	('Fbx4', 'Gene', (32, 36))	('expression', 'Species', '29278', (62, 72))	('knockdown', 'Var', (37, 46))	('overexpression', 'PosReg', (58, 72))
872453	18598945	Reconstitution of cells with either wild type Fbx4 or Fbx4S12E resulted in a reduction of cyclin D1 to levels comparable to parental NIH3T3, while Fbx4S12A had reduced activity.	('cyclin D1', 'MPA', (90, 99))	('NIH3T3', 'CellLine', 'CVCL:0594', (133, 139))	('Fbx4', 'Gene', (46, 50))	('reduction', 'NegReg', (77, 86))	('Fbx4S12E', 'Var', (54, 62))
872455	18598945	To assess the contribution of serine-12 to Fbx4-dependent ubiquitination activity, we purified wild type or mutant SCF Fbx4 ligases from NIH3T3 stable cell lines by anti-Flag affinity purification (Fig.	('serine-12', 'Chemical', '-', (30, 39))	('Fbx4', 'Gene', (119, 123))	('mutant', 'Var', (108, 114))	('NIH3T3', 'CellLine', 'CVCL:0594', (137, 143))	('SCF Fbx4', 'Gene', (115, 123))
872456	18598945	Thus, disruption of serine 12 leads to decreased dimerization of Fbx4 and decreased ubiquitination of cyclin D1.	('serine 12', 'Chemical', '-', (20, 29))	('ubiquitination', 'MPA', (84, 98))	('disruption', 'Var', (6, 16))	('decreased', 'NegReg', (74, 83))	('Fbx4', 'Gene', (65, 69))	('decreased', 'NegReg', (39, 48))	('dimerization', 'MPA', (49, 61))
872460	18598945	To test this premise, NIH-3T3 cells were synchronized by serum starvation; following mitogen triggered cell cycle reentry, p-S12 of Fbx4 was assessed at 0, 6, 16 and 20h using our phospho-specific antibody.	('NIH-3T3', 'CellLine', 'CVCL:0594', (22, 29))	('p-S12', 'Var', (123, 128))	('Fbx4', 'Gene', (132, 136))
872469	18598945	Additionally, while GSK3beta efficiently phosphorylated S12, GSK3alpha did not exhibit detectable activity toward this residue in Fbx4 (Fig.	('GSK3alpha', 'Gene', (61, 70))	('S12', 'Var', (56, 59))	('GSK3alpha', 'Gene', '2931', (61, 70))	('GSK3beta', 'Gene', (20, 28))	('GSK3beta', 'Gene', '2932', (20, 28))
872472	18598945	Both LiCl and SB216763 reduced pS12 while roscovitine did not (Fig.	('roscovitine', 'Chemical', 'MESH:D000077546', (42, 53))	('pS12', 'MPA', (31, 35))	('reduced', 'NegReg', (23, 30))	('SB216763', 'Var', (14, 22))	('LiCl', 'Chemical', 'MESH:D018021', (5, 9))	('SB216763', 'Chemical', 'MESH:C417521', (14, 22))
872475	18598945	Expression of kinase-dead GSK3beta efficiently inhibited phosphorylation in a dose-dependent manner and when total Fbx4 was immunoprecipitated from cells, kinase-dead GSK3beta stably associated with Fbx4 (Fig.	('GSK3beta', 'Gene', '2932', (26, 34))	('inhibited', 'NegReg', (47, 56))	('kinase-dead', 'Var', (155, 166))	('Expression', 'Species', '29278', (0, 10))	('GSK3beta', 'Gene', (167, 175))	('GSK3beta', 'Gene', (26, 34))	('phosphorylation', 'MPA', (57, 72))	('associated', 'Interaction', (183, 193))	('GSK3beta', 'Gene', '2932', (167, 175))
872486	18598945	Inhibition of GSK3beta activity through overexpression of RasV12 or GSK3beta knockdown resulted in an inhibition of S12 phosphorylation and decreased Fbx4 dimerization (Fig.	('decreased', 'NegReg', (140, 149))	('GSK3beta', 'Gene', (14, 22))	('RasV12', 'Gene', (58, 64))	('Fbx4 dimerization', 'MPA', (150, 167))	('GSK3beta', 'Gene', '2932', (14, 22))	('overexpression', 'PosReg', (40, 54))	('knockdown', 'Var', (77, 86))	('GSK3beta', 'Gene', (68, 76))	('inhibition', 'NegReg', (102, 112))	('S12', 'Protein', (116, 119))	('GSK3beta', 'Gene', '2932', (68, 76))	('expression', 'Species', '29278', (44, 54))
872488	18598945	In cells with high Akt activity (Fig 3E, TE8 and T47D) there was no detectable S12 phosphorylation.	('S12 phosphorylation', 'MPA', (79, 98))	('T47D', 'CellLine', 'CVCL:0553', (49, 53))	('T47D', 'Var', (49, 53))	('Akt', 'Protein', (19, 22))	('activity', 'MPA', (23, 31))
872491	18598945	Consistent with increased Akt activity down regulating ligase phosphorylation (and thus activity), cyclin D1 levels were also increased in tumors with high Akt activity.	('down regulating', 'NegReg', (39, 54))	('cyclin D1 levels', 'MPA', (99, 115))	('Akt', 'Protein', (26, 29))	('high', 'Var', (151, 155))	('activity', 'MPA', (88, 96))	('activity', 'MPA', (160, 168))	('increased', 'PosReg', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('ligase phosphorylation', 'MPA', (55, 77))	('increased', 'PosReg', (126, 135))	('activity', 'MPA', (30, 38))
872492	18598945	Finally, we assessed the ability of phosphorylation deficient or phosphomimetic Fbx4 mutants to rescue cyclin D1 turnover in NIH3T3 cells wherein endogenous Fbx4 is knocked down.	('Fbx4', 'Gene', (80, 84))	('rescue', 'PosReg', (96, 102))	('NIH3T3', 'CellLine', 'CVCL:0594', (125, 131))	('cyclin D1 turnover', 'MPA', (103, 121))	('mutants', 'Var', (85, 92))
872494	18598945	Strikingly, the Fbx4S12A mutant was not able to restore normal kinetics of cyclin D1 turnover while Fbx4S12E was proficient in restoring the rate cyclin D1 proteolysis (Fig.	('cyclin D1 turnover', 'MPA', (75, 93))	('S12E', 'Mutation', 'p.S12E', (104, 108))	('Fbx4S12A', 'Var', (16, 24))	('Fbx4S12E', 'Var', (100, 108))	('rate cyclin D1 proteolysis', 'MPA', (141, 167))
872496	18598945	Indeed knock down of either Fbx4 or alphaB-crystallin in mouse fibroblasts facilitated growth of cells in soft agar, a characteristic of neoplastic transformation (Fig.	('alphaB-crystallin', 'Gene', (36, 53))	('facilitated', 'PosReg', (75, 86))	('agar', 'Chemical', 'MESH:D000362', (111, 115))	('Fbx4', 'Gene', (28, 32))	('alphaB-crystallin', 'Gene', '12955', (36, 53))	('mouse', 'Species', '10090', (57, 62))	('knock down', 'Var', (7, 17))	('growth of cells in soft agar', 'CPA', (87, 115))
872497	18598945	In contrast, knockdown of Fbx4 in cyclin D1 null fibroblasts failed to induce growth in soft agar (Fig.	('Fbx4', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('agar', 'Chemical', 'MESH:D000362', (93, 97))
872503	18598945	Past work has provided evidence that accumulation of cyclin D1-dependent kinase in the nucleus during S-phase disrupts temporal control of DNA replication through stabilization of Cdt1 that in turn induces DNA re-replication and genomic instability.	('temporal control', 'MPA', (119, 135))	('Cdt1', 'Gene', '81620', (180, 184))	('DNA re-replication', 'MPA', (206, 224))	('disrupts', 'NegReg', (110, 118))	('genomic instability', 'CPA', (229, 248))	('Cdt1', 'Gene', (180, 184))	('leu', 'Chemical', 'MESH:D007930', (90, 93))	('accumulation', 'PosReg', (37, 49))	('stabilization', 'Var', (163, 176))	('induces', 'Reg', (198, 205))
872506	18598945	The differences in nuclear accumulation in Fbx4 versus alphaB-crystallin knockdown likely reflect knockdown efficiency, as our degree of Fbx4 knockdown is routinely 60% while alphaB-crystallin is reduced to undetectable levels (Fig.	('alphaB-crystallin', 'Gene', '12955', (55, 72))	('Fbx4', 'Gene', (137, 141))	('alphaB-crystallin', 'Gene', (55, 72))	('alphaB-crystallin', 'Gene', (175, 192))	('alphaB-crystallin', 'Gene', '12955', (175, 192))	('knockdown', 'Var', (142, 151))
872507	18598945	As expected with the nuclear accumulation of cyclin D1, Cdt1 was overexpressed following knockdown of either Fbx4 or alphaB-crystallin (Fig.	('alphaB-crystallin', 'Gene', '12955', (117, 134))	('overexpressed', 'PosReg', (65, 78))	('Fbx4', 'Gene', (109, 113))	('Cdt1', 'Gene', '81620', (56, 60))	('Cdt1', 'Gene', (56, 60))	('knockdown', 'Var', (89, 98))	('alphaB-crystallin', 'Gene', (117, 134))
872509	18598945	We therefore assessed primary esophageal cancers, which are known to frequently overexpress cyclin D1; for mutations in Fbx4 and alphaB crystallin.	('esophageal cancers', 'Disease', (30, 48))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (107, 116))	('esophageal cancers', 'Disease', 'MESH:D004938', (30, 48))	('Fbx4', 'Gene', (120, 124))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('alphaB crystallin', 'Protein', (129, 146))
872511	18598945	We identified and verified hemizygous, missense mutations in 14% of the primary tumors (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('primary tumors', 'Disease', (72, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('primary tumors', 'Disease', 'MESH:D009369', (72, 86))	('missense mutations', 'Var', (39, 57))
872512	18598945	No mutations were identified in alphaB crystallin and cyclin D1 was wild type in tumors harboring inactivating Fbx4 mutations.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('mutations', 'Var', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Fbx4', 'Gene', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
872513	18598945	Mutations that impair phosphorylation (S12L; P13S) and indirectly influence dimerization along with mutations that target critical residue within the dimerization motif (L23Q) were detected.	('P13S', 'Var', (45, 49))	('L23Q', 'Var', (170, 174))	('dimerization', 'MPA', (76, 88))	('P13S', 'SUBSTITUTION', 'None', (45, 49))	('L23Q', 'Mutation', 'p.L23Q', (170, 174))	('influence', 'Reg', (66, 75))	('S12L', 'Mutation', 'p.S12L', (39, 43))	('impair', 'NegReg', (15, 21))	('phosphorylation', 'MPA', (22, 37))
872514	18598945	In addition, a proline to threonine mutation was identified at residue 76 within the F-box (P76T); P76T impairs binding to Skp1 (Fig.	('P76T', 'Mutation', 'p.P76T', (92, 96))	('binding', 'Interaction', (112, 119))	('P76T', 'Mutation', 'p.P76T', (99, 103))	('P76T', 'Var', (99, 103))	('impairs', 'NegReg', (104, 111))	('threonine', 'Chemical', 'MESH:D013912', (26, 35))	('Skp1', 'Gene', '6500', (123, 127))	('proline', 'Chemical', 'MESH:D011392', (15, 22))	('Skp1', 'Gene', (123, 127))
872515	18598945	Mutations in this domain, like S12L, impair Fbx4-dependent regulation of cyclin D1 degradation (Fig.	('regulation of cyclin D1 degradation', 'MPA', (59, 94))	('Fbx4-dependent', 'Gene', (44, 58))	('S12L', 'Mutation', 'p.S12L', (31, 35))	('Mutations', 'Var', (0, 9))	('impair', 'NegReg', (37, 43))
872516	18598945	Immunohistochemical analysis revealed overexpression of cyclin D1 and TRF1 in Fbx4 mutant tumors consistent with a substrate-ligase relationship (Fig.	('expression', 'Species', '29278', (42, 52))	('mutant', 'Var', (83, 89))	('Fbx4', 'Gene', (78, 82))	('cyclin D1', 'Protein', (56, 65))	('TRF1', 'Gene', '7013', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('TRF1', 'Gene', (70, 74))	('tumors', 'Disease', (90, 96))	('overexpression', 'PosReg', (38, 52))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))
872521	18598945	NIH3T3 fibroblasts were transfected with wtFbx4 with or without Fbx4 mutants.	('Fbx4', 'Gene', (64, 68))	('NIH3T3', 'CellLine', 'CVCL:0594', (0, 6))	('mutants', 'Var', (69, 76))
872523	18598945	S6F, compare lanes 1-2), while co-expression of Fbx4-S8R, S12L or P13SFbx4 (transfected in 1:1 ratio relative to wtFbx4) attenuated Fbx4-dependent cyclin D1 loss (Fig.	('attenuated', 'NegReg', (121, 131))	('Fbx4-dependent cyclin D1', 'MPA', (132, 156))	('S12L', 'Mutation', 'p.S12L', (58, 62))	('P13SFbx4', 'Var', (66, 74))	('Fbx4-S8R', 'Var', (48, 56))	('S12L', 'Var', (58, 62))	('loss', 'NegReg', (157, 161))	('expression', 'Species', '29278', (34, 44))
872524	18598945	We next assessed the ability of wtFbx4 or Fbx4 mutants, S8R, S12A and L23A, restore normal growth characteristics of Fbx4 knockdown fibroblasts.	('growth', 'MPA', (91, 97))	('S12A', 'Var', (61, 65))	('S12A', 'SUBSTITUTION', 'None', (61, 65))	('Fbx4', 'Gene', (42, 46))	('restore', 'PosReg', (76, 83))	('L23A', 'Mutation', 'p.L23A', (70, 74))	('mutants', 'Var', (47, 54))
872527	18598945	Re-expression of wtFbx4 significantly reduced the number of colonies, while ligase defective Fbx4 mutants did not exhibit significant activity (Fig.	('expression', 'Species', '29278', (3, 13))	('mutants', 'Var', (98, 105))	('Fbx4', 'Gene', (93, 97))	('reduced', 'NegReg', (38, 45))
872528	18598945	Altogether, we provide the evidence that cancer derived Fbx4 mutations that target GSK3beta phosphorylation site in Fbx4 and affect its dimerization have reduced activity toward cyclin D1.	('GSK3beta', 'Gene', '2932', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('affect', 'Reg', (125, 131))	('Fbx4', 'Gene', (116, 120))	('activity toward cyclin D1', 'MPA', (162, 187))	('mutations', 'Var', (61, 70))	('cancer', 'Disease', (41, 47))	('dimerization', 'MPA', (136, 148))	('reduced', 'NegReg', (154, 161))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('Fbx4', 'Gene', (56, 60))	('GSK3beta', 'Gene', (83, 91))
872529	18598945	The mechanism, by which these mutations contribute to the tumor formation in vivo is a subject of the great interest for future studies.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('contribute', 'Reg', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (30, 39))
872534	18598945	Of equal importance, analysis of human esophageal cancer, where cyclin D1 overexpression is a common event, revealed mutations in Fbx4 that directly abrogate Fbx4 dimerization or inhibit binding to core SCF components (Skp1).	('mutations', 'Var', (117, 126))	('Skp1', 'Gene', '6500', (219, 223))	('abrogate', 'NegReg', (149, 157))	('Skp1', 'Gene', (219, 223))	('Fbx4 dimerization', 'MPA', (158, 175))	('Fbx4', 'Gene', (130, 134))	('human', 'Species', '9606', (33, 38))	('binding', 'Interaction', (187, 194))	('esophageal cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('inhibit', 'NegReg', (179, 186))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))	('expression', 'Species', '29278', (78, 88))
872536	18598945	Skp2 levels are determined in part through E2F-dependent transcription.	('Skp2', 'Gene', '6502', (0, 4))	('Skp2', 'Gene', (0, 4))	('E2F-dependent', 'Var', (43, 56))
872540	18598945	We have defined leucine/isoleucine residues (leu-23/28; iso-27) in Fbx4 that are essential for homo-dimerization.	('leucine', 'Chemical', 'MESH:D007930', (27, 34))	('isoleucine', 'Chemical', 'MESH:D007532', (24, 34))	('Fbx4', 'Gene', (67, 71))	('leu', 'Chemical', 'MESH:D007930', (27, 30))	('leucine', 'Chemical', 'MESH:D007930', (16, 23))	('leu', 'Chemical', 'MESH:D007930', (45, 48))	('leu-23/28;', 'Var', (45, 55))	('leu', 'Chemical', 'MESH:D007930', (16, 19))
872541	18598945	The spatial organization of these residues is conserved spatially with leu-246 and val-251, which contribute to the dimerization of Fbw7.	('leu', 'Chemical', 'MESH:D007930', (71, 74))	('contribute', 'Reg', (98, 108))	('Fbw7', 'Gene', (132, 136))	('val', 'Chemical', 'MESH:D014633', (83, 86))	('Fbw7', 'Gene', '55294', (132, 136))	('dimerization', 'MPA', (116, 128))	('val-251', 'Var', (83, 90))	('leu-246', 'Var', (71, 78))
872542	18598945	What distinguishes Fbx4 is the role of serine-12/proline-13, which acts as a phospho-acceptor residue for GSK3beta.	('Fbx4', 'Gene', (19, 23))	('GSK3beta', 'Gene', (106, 114))	('serine-12/proline', 'SUBSTITUTION', 'None', (39, 56))	('serine-12/proline', 'Var', (39, 56))	('GSK3beta', 'Gene', '2932', (106, 114))
872544	18598945	The significance of this is highlighted by mutations of serine 12 and proline 13 in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('serine 12', 'Protein', (56, 65))	('proline', 'Chemical', 'MESH:D011392', (70, 77))	('mutations', 'Var', (43, 52))	('human', 'Species', '9606', (84, 89))	('serine 12', 'Chemical', '-', (56, 65))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
872546	18598945	The nuclear deregulation of cyclin D1/CDK4 activity disrupts temporal regulation of DNA replication by directly impairing proteolysis of the replication licensing factor Cdt1.	('temporal regulation', 'MPA', (61, 80))	('impairing', 'NegReg', (112, 121))	('deregulation', 'Var', (12, 24))	('DNA replication', 'MPA', (84, 99))	('Cdt1', 'Gene', '81620', (170, 174))	('disrupts', 'NegReg', (52, 60))	('proteolysis', 'MPA', (122, 133))	('activity', 'MPA', (43, 51))	('Cdt1', 'Gene', (170, 174))	('CDK4', 'Gene', '1019', (38, 42))	('CDK4', 'Gene', (38, 42))
872547	18598945	If nuclear overexpression of cyclin D1 is in fact the oncogenic event, why does loss of components of the D1 E3 ligase promote neoplastic growth?	('promote', 'PosReg', (119, 126))	('expression', 'Species', '29278', (15, 25))	('loss', 'Var', (80, 84))	('neoplastic growth', 'CPA', (127, 144))
872548	18598945	Critically, impaired Fbx4 or alphaB-crystallin, also promotes nuclear accumulation of cyclin D1 and a consequent stabilization of Cdt1, a direct consequence of nuclear cyclin D1/CDK4.	('nuclear accumulation', 'MPA', (62, 82))	('alphaB-crystallin', 'Gene', (29, 46))	('Cdt1', 'Gene', (130, 134))	('promotes', 'PosReg', (53, 61))	('cyclin D1', 'Protein', (86, 95))	('stabilization', 'MPA', (113, 126))	('Fbx4', 'Gene', (21, 25))	('alphaB-crystallin', 'Gene', '12955', (29, 46))	('Cdt1', 'Gene', '81620', (130, 134))	('CDK4', 'Gene', '1019', (178, 182))	('CDK4', 'Gene', (178, 182))	('impaired', 'Var', (12, 20))
872549	18598945	The significance of Fbx4 activity for cell homeostasis is emphasized by the relative frequency of mutations that impair its biochemical activity in human cancer.	('biochemical activity', 'MPA', (124, 144))	('cancer', 'Disease', (154, 160))	('human', 'Species', '9606', (148, 153))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('Fbx4', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
872550	18598945	We identified 16 mutations in 116 esophageal tumors screened.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('esophageal tumors', 'Disease', 'MESH:D004938', (34, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('esophageal tumors', 'Disease', (34, 51))	('esophageal tumors', 'Phenotype', 'HP:0100751', (34, 51))	('mutations', 'Var', (17, 26))
872551	18598945	Alternatively, our data reveals that co-expression of mutants with wild type Fbx4 can attenuate Fbx4 mediated cyclin D1 turnover.	('Fbx4 mediated cyclin D1 turnover', 'MPA', (96, 128))	('Fbx4', 'Gene', (77, 81))	('attenuate', 'NegReg', (86, 95))	('mutants', 'Var', (54, 61))	('expression', 'Species', '29278', (40, 50))
872552	18598945	This result is expected in the case of the P76 mutation, which disrupts Skp1 binding resulting in a dominant negative allele similar to those generated through deletion of the F-box.	('deletion', 'Var', (160, 168))	('disrupts', 'NegReg', (63, 71))	('Skp1', 'Gene', '6500', (72, 76))	('Skp1', 'Gene', (72, 76))	('negative', 'NegReg', (109, 117))	('binding', 'Interaction', (77, 84))	('P76', 'Gene', (43, 46))	('P76', 'Gene', '196463', (43, 46))
872553	18598945	Given that the other mutations disrupt oligomerization rather than Skp1-Cul-Rbx1 recruitment, the dominant negative activity may reflect titration of these ligase components into inactive complexes.	('mutations', 'Var', (21, 30))	('oligomerization', 'MPA', (39, 54))	('Rbx1', 'Gene', (76, 80))	('Rbx1', 'Gene', '9978', (76, 80))	('Skp1', 'Gene', '6500', (67, 71))	('activity', 'MPA', (116, 124))	('Skp1', 'Gene', (67, 71))	('disrupt', 'Reg', (31, 38))
872554	18598945	In all tumor specimen that harbor Fbx4 mutations, cyclin D1 protein levels were elevated and accumulated in the nuclei.	('elevated', 'PosReg', (80, 88))	('accumulated', 'PosReg', (93, 104))	('tumor', 'Disease', (7, 12))	('mutations', 'Var', (39, 48))	('cyclin D1 protein levels', 'MPA', (50, 74))	('Fbx4', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
872555	18598945	It also underscores the importance of Fbx4 dimerization for ligase activity, since the disruption of dimerization is observed in human esophageal cancer, in contrast to Fbw7 where all identified mutations directly impair substrate binding.	('dimerization', 'MPA', (101, 113))	('substrate binding', 'Interaction', (221, 238))	('esophageal cancer', 'Disease', (135, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('mutations', 'Var', (195, 204))	('Fbw7', 'Gene', (169, 173))	('impair', 'NegReg', (214, 220))	('human', 'Species', '9606', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Fbw7', 'Gene', '55294', (169, 173))
872560	18598945	Human Fbx4 Myc-tagged vector was generated using PCR of human Fbx4 with primers designed for directional cloning into pCS2-MT plasmid (in frame with 6 Myc tags at the N-terminus of Fbx4).	('Human', 'Species', '9606', (0, 5))	('PCR', 'Var', (49, 52))	('Fbx4', 'Gene', (62, 66))	('human', 'Species', '9606', (56, 61))
872572	18598945	NIH3T3 derived stable cell lines expressing wild type Fbx4 and S12 mutants were used to purify Fbx4 SCF complexes.	('S12', 'Gene', (63, 66))	('NIH3T3', 'CellLine', 'CVCL:0594', (0, 6))	('Fbx4', 'Gene', (54, 58))	('mutants', 'Var', (67, 74))
872580	29253542	Epigenetic changes, including aberrant promoter DNA methylation, are common events in both cancer initiation and progression.	('Epi', 'Gene', '7035', (0, 3))	('aberrant', 'Var', (30, 38))	('cancer initiation', 'Disease', 'MESH:D009369', (91, 108))	('Epi', 'Gene', (0, 3))	('cancer initiation', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
872582	29253542	In this article, we will provide an update and current clinical perspectives for DNA methylation alterations in patients with colorectal, gastric, pancreatic, liver and esophageal cancers, and discuss their potential role as cancer biomarkers.	('methylation', 'Var', (85, 96))	('liver and esophageal cancers', 'Disease', 'MESH:D006528', (159, 187))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('alterations', 'Reg', (97, 108))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('gastric', 'Disease', (138, 145))	('cancer', 'Disease', (225, 231))	('patients', 'Species', '9606', (112, 120))	('colorectal', 'Disease', (126, 136))	('DNA', 'Gene', (81, 84))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('pancreatic', 'Disease', (147, 157))	('cancer', 'Disease', (180, 186))
872593	29253542	The most commonly studied epigenetic alteration in cancer, including in GI cancer, is aberrant DNA methylation.	('aberrant DNA methylation', 'Var', (86, 110))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('GI cancer', 'Disease', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('GI cancer', 'Disease', 'MESH:D009369', (72, 81))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('GI cancer', 'Phenotype', 'HP:0007378', (72, 81))
872596	29253542	However, in cancer cells, these islands are frequently targeted for hypermethylation-an alteration that causes transcriptional repression of the associated gene, including tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('tumor', 'Disease', (172, 177))	('hypermethylation-an', 'Var', (68, 87))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
872597	29253542	Gene silencing by promoter hypermethylation occurs in the majority of cancer types, and occurs more frequently compared to genetic mutations.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (70, 76))	('promoter hypermethylation', 'Var', (18, 43))	('Gene silencing', 'NegReg', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
872598	29253542	Since aberrant promoter DNA methylation may additionally be detected in various bodily fluids, including bile, feces, and blood, such markers are gaining a lot of attention as potential noninvasive cancer biomarkers for the early detection, prognosis and for predicting the treatment outcomes.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('aberrant', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('promoter DNA', 'Protein', (15, 27))
872603	29253542	In the colon, epigenetic alterations have been observed also in aberrant crypt foci and in the pre-malignant adenomas, highlighting the clinical potential of exploiting aberrant promoter methylation for the early detection of colorectal adenomas and cancers.	('adenomas', 'Disease', (237, 245))	('cancers', 'Disease', 'MESH:D009369', (250, 257))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('adenomas', 'Disease', 'MESH:D000236', (109, 117))	('colorectal adenomas', 'Disease', 'MESH:D015179', (226, 245))	('cancers', 'Disease', (250, 257))	('adenomas', 'Disease', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('aberrant', 'Var', (169, 177))	('adenomas', 'Disease', 'MESH:D000236', (237, 245))	('epigenetic alterations', 'Var', (14, 36))	('colorectal adenomas', 'Disease', (226, 245))
872617	29253542	Colonocytes from tumors are constantly shed into the lumen, and identification of aberrant methylation in fecal samples represents a good source for cancer specific detection of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Disease', (149, 155))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('colorectal cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('aberrant methylation', 'Var', (82, 102))	('rectal cancer', 'Phenotype', 'HP:0100743', (182, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancer', 'Disease', (189, 195))
872618	29253542	Aberrant methylation of VIM was included in the first commercial fecal test for colorectal cancer detection (ColoSure, LabCorp).	('rectal cancer', 'Phenotype', 'HP:0100743', (84, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('VIM', 'Gene', '7431', (24, 27))	('Aberrant methylation', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('VIM', 'Gene', (24, 27))
872620	29253542	The FDA approved Cologuard (Exact Sciences) evaluates methylation of BMP3 and NDRG4, mutant KRAS, beta-actin and hemoglobin.	('NDRG4', 'Gene', '65009', (78, 83))	('NDRG4', 'Gene', (78, 83))	('beta-actin', 'Protein', (98, 108))	('BMP3', 'Gene', '651', (69, 73))	('KRAS', 'Gene', (92, 96))	('BMP3', 'Gene', (69, 73))	('KRAS', 'Gene', '3845', (92, 96))	('methylation', 'MPA', (54, 65))	('mutant', 'Var', (85, 91))
872622	29253542	Importantly, the sensitivity for advanced precancerous lesions was higher for Cologuard compared to FIT alone.	('sensitivity', 'MPA', (17, 28))	('higher', 'PosReg', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('FIT', 'Chemical', '-', (100, 103))	('Cologuard', 'Var', (78, 87))	('precancerous lesions', 'Disease', 'MESH:D011230', (42, 62))	('precancerous lesions', 'Disease', (42, 62))
872627	29253542	Abnormal CpG island methylation is a source for prognostic and predictive information.	('Abnormal CpG island', 'Disease', 'MESH:D007340', (0, 19))	('methylation', 'Var', (20, 31))	('Abnormal CpG island', 'Disease', (0, 19))
872629	29253542	Although it has been suggested that CIMP confers improved survival, most studies report that CIMP is associated with a worse prognosis, including two recent meta-analyses.	('improved', 'PosReg', (49, 57))	('survival', 'MPA', (58, 66))	('CIMP', 'Chemical', '-', (36, 40))	('CIMP', 'Var', (36, 40))	('CIMP', 'Chemical', '-', (93, 97))
872630	29253542	Additionally, a recent study, analyzing more than 1000 tumor samples, found that CIMP was associated with inferior survival, both across all patients and specifically within patients with MSS and MSS BRAF mutated tumors.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('BRAF', 'Gene', (200, 204))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('CIMP', 'Var', (81, 85))	('survival', 'MPA', (115, 123))	('inferior', 'NegReg', (106, 114))	('mutated', 'Var', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('patients', 'Species', '9606', (141, 149))	('tumors', 'Disease', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MSS', 'Gene', (196, 199))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', (55, 60))	('patients', 'Species', '9606', (174, 182))	('CIMP', 'Chemical', '-', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('BRAF', 'Gene', '673', (200, 204))
872632	29253542	Some studies have shown that patients with CIMP positive colorectal cancers display better survival when treated with 5-FU based adjuvant chemotherapy in addition to surgery, or that these patients may have a survival benefit when treated with irinotecan in addition to 5-FU.	('survival', 'CPA', (91, 99))	('patients', 'Species', '9606', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('colorectal cancers', 'Disease', (57, 75))	('CIMP positive', 'Var', (43, 56))	('rectal cancer', 'Phenotype', 'HP:0100743', (61, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('CIMP', 'Chemical', '-', (43, 47))	('better', 'PosReg', (84, 90))	('patients', 'Species', '9606', (189, 197))	('colorectal cancers', 'Disease', 'MESH:D015179', (57, 75))	('5-FU', 'Chemical', 'MESH:D005472', (118, 122))	('irinotecan', 'Chemical', 'MESH:D000077146', (244, 254))	('5-FU', 'Chemical', 'MESH:D005472', (270, 274))
872634	29253542	It has furthermore been reported that patients with CIMP positive tumors experienced a worse survival when treated with chemotherapy compared to surgery alone.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CIMP', 'Chemical', '-', (52, 56))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('CIMP positive', 'Var', (52, 65))	('patients', 'Species', '9606', (38, 46))
872635	29253542	reported that patients with IGFBP methylation had an improved disease free survival (DFS), and further that stage II and III patients with high levels of IGFBP3 methylation did not seem to benefit from adjuvant 5-FU-based chemotherapy.	('disease free survival', 'CPA', (62, 83))	('patients', 'Species', '9606', (14, 22))	('methylation', 'Var', (34, 45))	('IGFBP', 'Gene', (28, 33))	('IGFBP3', 'Gene', '3486', (154, 160))	('5-FU', 'Chemical', 'MESH:D005472', (211, 215))	('improved', 'PosReg', (53, 61))	('IGFBP3', 'Gene', (154, 160))	('patients', 'Species', '9606', (125, 133))
872636	29253542	Methylation of HPP1 in blood has also, in addition to being associated with worse survival, been suggested as a potential marker for the identification of patients who have likely not benefitted from a combination chemotherapy with bevacizumab.	('HPP1', 'Gene', '780897', (15, 19))	('bevacizumab', 'Chemical', 'MESH:D000068258', (232, 243))	('Methylation', 'Var', (0, 11))	('HPP1', 'Gene', (15, 19))	('patients', 'Species', '9606', (155, 163))	('associated', 'Reg', (60, 70))
872637	29253542	Furthermore, patients with MSI tumors, normally caused by epigenetic silencing of MLH1, have been shown to have either no benefit or to have increased mortality when treated with 5-FU.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('5-FU', 'Chemical', 'MESH:D005472', (179, 183))	('epigenetic silencing', 'Var', (58, 78))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('increased', 'PosReg', (141, 150))	('MLH1', 'Gene', '4292', (82, 86))	('patients', 'Species', '9606', (13, 21))	('MLH1', 'Gene', (82, 86))	('MSI tumors', 'Disease', (27, 37))	('mortality', 'Disease', 'MESH:D003643', (151, 160))	('mortality', 'Disease', (151, 160))	('MSI tumors', 'Disease', 'MESH:D009369', (27, 37))
872638	29253542	observed a strong association between TFAP2E methylation and lack of response towards 5-FU based chemotherapy, by analyzing four independent patient cohorts with primary rectal cancer and metastatic colorectal cancers.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('colorectal cancer', 'Phenotype', 'HP:0003003', (199, 216))	('colorectal cancers', 'Disease', 'MESH:D015179', (199, 217))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('colorectal cancers', 'Disease', (199, 217))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('patient', 'Species', '9606', (141, 148))	('rectal cancer', 'Phenotype', 'HP:0100743', (203, 216))	('rectal cancer', 'Phenotype', 'HP:0100743', (170, 183))	('methylation', 'Var', (45, 56))	('TFAP2E', 'Gene', '339488', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('5-FU', 'Chemical', 'MESH:D005472', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (210, 216))	('TFAP2E', 'Gene', (38, 44))
872639	29253542	For instance, a significantly higher proportion of patients with WNT5A methylation responded to 5-FU-based chemotherapy compared to patients with an unmethylated promoter.	('methylation', 'Var', (71, 82))	('higher', 'PosReg', (30, 36))	('responded to 5-FU-based chemotherapy', 'MPA', (83, 119))	('WNT5A', 'Gene', '7474', (65, 70))	('5-FU', 'Chemical', 'MESH:D005472', (96, 100))	('patients', 'Species', '9606', (51, 59))	('patients', 'Species', '9606', (132, 140))	('WNT5A', 'Gene', (65, 70))
872651	29253542	As is the case in colorectal cancer, promoter DNA methylation of several tumor suppressor genes have been identified in premalignant stages of gastric carcinomas, highlighting their suitability as biomarkers for early cancer detection.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('colorectal cancer', 'Disease', (18, 35))	('identified', 'Reg', (106, 116))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('gastric carcinomas', 'Disease', 'MESH:D013274', (143, 161))	('gastric carcinomas', 'Disease', (143, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (151, 161))	('cancer', 'Disease', (29, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('rectal cancer', 'Phenotype', 'HP:0100743', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('promoter DNA methylation', 'Var', (37, 61))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))
872652	29253542	A number of hypermethylated genes with potential for early detection have been identified in blood specimens from gastric cancer patients (reviewed in).	('gastric cancer', 'Disease', (114, 128))	('hypermethylated', 'Var', (12, 27))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('patients', 'Species', '9606', (129, 137))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
872654	29253542	Since this initial study, methylation of CDH1 and CDKN2A have been confirmed as potential biomarkers for gastric cancer detection in blood samples.	('methylation', 'Var', (26, 37))	('CDKN2A', 'Gene', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CDH1', 'Gene', '999', (41, 45))	('CDKN2A', 'Gene', '1029', (50, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))	('gastric cancer', 'Disease', (105, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (105, 119))	('CDH1', 'Gene', (41, 45))
872657	29253542	Gastric washes represent an alternative source for detecting aberrant DNA methylation is gastric cancer.	('gastric cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('aberrant DNA methylation', 'Var', (61, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))
872659	29253542	Recently, it was reported that BARHL2 methylation in gastric washes had promising potential for detection of gastric cancer with significantly higher methylation frequency in the 128 analyzed cancer samples compared to the 32 control samples.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('methylation', 'Var', (38, 49))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('cancer', 'Disease', (192, 198))	('higher', 'PosReg', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('BARHL2', 'Gene', (31, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('cancer', 'Disease', (117, 123))	('methylation', 'MPA', (150, 161))	('BARHL2', 'Gene', '343472', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
872661	29253542	Furthermore, promoter methylation of BARHL2 in exosomal DNA from gastric juice could discriminate between cancer (n = 20) and controls (n = 10) with a sensitivity and specificity of 90% and 100%, respectively.	('BARHL2', 'Gene', (37, 43))	('BARHL2', 'Gene', '343472', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('promoter methylation', 'Var', (13, 33))	('discriminate', 'Reg', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
872666	29253542	Promoter hypermethylation of several genes have been reported to be associated with worse prognosis in gastric cancer (Table 2 and reviewed in).	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('associated', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric cancer', 'Disease', (103, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('Promoter hypermethylation', 'Var', (0, 25))
872668	29253542	Combining the two cohorts, 55% of the cancer patients displayed BCL6 B promoter methylation.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('BCL6 B', 'Gene', '255877', (64, 70))	('methylation', 'Var', (80, 91))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('patients', 'Species', '9606', (45, 53))	('BCL6 B', 'Gene', (64, 70))	('cancer', 'Disease', (38, 44))
872671	29253542	Methylation of either BNIP3 or DAPK was shown to confer a significantly poorer OS and PFS in a study including 80 tissue samples from gastric cancer patients.	('BNIP3', 'Gene', (22, 27))	('patients', 'Species', '9606', (149, 157))	('BNIP3', 'Gene', '664', (22, 27))	('Methylation', 'Var', (0, 11))	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('poorer', 'NegReg', (72, 78))	('PFS', 'CPA', (86, 89))	('DAPK', 'Gene', (31, 35))	('DAPK', 'Gene', '1612', (31, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))
872672	29253542	Methylation was additionally predictive of lower response to 5-FU based chemotherapy.	('Methylation', 'Var', (0, 11))	('response', 'MPA', (49, 57))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('lower', 'NegReg', (43, 48))
872673	29253542	noted that methylation of DAPK together with TMS1was associated with poor prognosis, and also lower response towards 5-FU among patients with recurrent disease.	('DAPK', 'Gene', (26, 30))	('DAPK', 'Gene', '1612', (26, 30))	('TMS1', 'Gene', (45, 49))	('TMS1', 'Gene', '10955', (45, 49))	('5-FU', 'Chemical', 'MESH:D005472', (117, 121))	('methylation', 'Var', (11, 22))	('response towards 5-FU', 'MPA', (100, 121))	('associated', 'Reg', (53, 63))	('lower', 'NegReg', (94, 99))	('patients', 'Species', '9606', (128, 136))
872674	29253542	Recently, it was reported that methylation of NDRG4 was predictive for poor prognosis among Chinese gastric cancer patients.	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('patients', 'Species', '9606', (115, 123))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('methylation', 'Var', (31, 42))	('NDRG4', 'Gene', '65009', (46, 51))	('NDRG4', 'Gene', (46, 51))	('gastric cancer', 'Disease', (100, 114))
872675	29253542	Validation in the TCGA data which included 357 gastric patients, did however, imply an improved prognosis for patients with NDRG4 promoter methylation, suggesting that different ethnicities, therapies, and methylation detection methods could influence both the methylation frequencies and survival.	('influence', 'Reg', (242, 251))	('improved', 'PosReg', (87, 95))	('promoter methylation', 'Var', (130, 150))	('patients', 'Species', '9606', (55, 63))	('NDRG4', 'Gene', '65009', (124, 129))	('NDRG4', 'Gene', (124, 129))	('patients', 'Species', '9606', (110, 118))	('methylation', 'Var', (139, 150))
872676	29253542	Additional examples of methylated genes that confer improved prognosis include BMP4 methylation, which also caused sensitization to cisplatin, IGF2 methylation, and methylation of MLH1.	('methylated', 'Var', (23, 33))	('methylation', 'Var', (84, 95))	('IGF2', 'Gene', '3481', (143, 147))	('MLH1', 'Gene', '4292', (180, 184))	('sensitization', 'MPA', (115, 128))	('improved', 'PosReg', (52, 60))	('methylation', 'Var', (165, 176))	('caused', 'Reg', (108, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('BMP4', 'Gene', (79, 83))	('IGF2', 'Gene', (143, 147))	('methylation', 'Var', (148, 159))	('MLH1', 'Gene', (180, 184))	('BMP4', 'Gene', '652', (79, 83))
872678	29253542	Methylation of CDH1, both in preoperative peritoneal washes, serum, and tissue samples has for instance been reported to be significantly associated with worse survival.	('Methylation', 'Var', (0, 11))	('associated', 'Reg', (138, 148))	('CDH1', 'Gene', (15, 19))	('CDH1', 'Gene', '999', (15, 19))	('worse', 'NegReg', (154, 159))
872679	29253542	In addition to showing that XAF1 was frequently methylated in a cancer-specific manner, in the serum from gastric cancer patients, Ling et al.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('XAF1', 'Gene', '54739', (28, 32))	('XAF1', 'Gene', (28, 32))	('methylated', 'Var', (48, 58))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('Ling', 'Species', '163112', (131, 135))	('gastric cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('patients', 'Species', '9606', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (114, 120))
872680	29253542	reported that patients with XAF1 promoter methylation had significantly poorer survival compared to those with an unmethylated promoter.	('XAF1', 'Gene', '54739', (28, 32))	('XAF1', 'Gene', (28, 32))	('promoter methylation', 'Var', (33, 53))	('poorer', 'NegReg', (72, 78))	('patients', 'Species', '9606', (14, 22))	('survival', 'MPA', (79, 87))
872681	29253542	XAF1 methylation in sera was additionally associated with tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('methylation', 'Var', (5, 16))	('associated with', 'Reg', (42, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('XAF1', 'Gene', '54739', (0, 4))	('XAF1', 'Gene', (0, 4))
872682	29253542	Methylation of RPRM was reported to predict both poor survival among patients with advanced gastric cancer, and poor response towards 5-FU and cisplatin.	('response', 'MPA', (117, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('5-FU', 'Chemical', 'MESH:D005472', (134, 138))	('Methylation', 'Var', (0, 11))	('gastric cancer', 'Disease', (92, 106))	('RPRM', 'Gene', (15, 19))	('RPRM', 'Gene', '56475', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('predict', 'Reg', (36, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('poor', 'NegReg', (49, 53))	('patients', 'Species', '9606', (69, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))
872685	29253542	CDKN2A, and found that methylation of this gene, in addition to MGMT, RASSF2 and FLNc, was associated with poor survival, both across all samples and when only tumors without residual disease were included.	('RASSF2', 'Gene', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('CDKN2A', 'Gene', '1029', (0, 6))	('methylation', 'Var', (23, 34))	('FLNc', 'Gene', '2318', (81, 85))	('FLNc', 'Gene', (81, 85))	('MGMT', 'Gene', '4255', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('MGMT', 'Gene', (64, 68))	('CDKN2A', 'Gene', (0, 6))	('tumors', 'Disease', (160, 166))	('RASSF2', 'Gene', '9770', (70, 76))	('poor', 'NegReg', (107, 111))	('associated with', 'Reg', (91, 106))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
872686	29253542	Methylation of CDKN2A has further been reported to be significantly associated with improved survival in patients treated with 5-FU.	('5-FU', 'Chemical', 'MESH:D005472', (127, 131))	('survival', 'MPA', (93, 101))	('patients', 'Species', '9606', (105, 113))	('CDKN2A', 'Gene', (15, 21))	('Methylation', 'Var', (0, 11))	('CDKN2A', 'Gene', '1029', (15, 21))	('improved', 'PosReg', (84, 92))
872698	29253542	These researches further found significantly higher incidences of hypermethylation in tissues from patients with dysplasia or cancer, compared to patients with no further progression of their disease, confirming that abnormal DNA methylation represents a clinical tool in stratifying Barrett's esophagus patients at risk of developing cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	("Barrett's esophagus", 'Disease', (284, 303))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('patients', 'Species', '9606', (304, 312))	('abnormal', 'Var', (217, 225))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (284, 303))	('dysplasia', 'Disease', 'MESH:C536170', (113, 122))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('patients', 'Species', '9606', (99, 107))	('dysplasia', 'Disease', (113, 122))	('higher', 'PosReg', (45, 51))	('patients', 'Species', '9606', (146, 154))
872707	29253542	The frequency of methylation increased through intraepithelial neoplasia to advanced ESCC; hence most likely contributing to the pathogenesis of this malignancy.	('malignancy', 'Disease', (150, 160))	('neoplasia', 'Phenotype', 'HP:0002664', (63, 72))	('neoplasia', 'Disease', 'MESH:D009369', (63, 72))	('methylation', 'Var', (17, 28))	('ESCC', 'Disease', (85, 89))	('increased', 'PosReg', (29, 38))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (47, 72))	('malignancy', 'Disease', 'MESH:D009369', (150, 160))	('neoplasia', 'Disease', (63, 72))
872708	29253542	The genes with the highest methylation frequencies in ESCC cases were MGMT (80%) and SFRP1 (64%).	('MGMT', 'Gene', (70, 74))	('ESCC', 'Disease', (54, 58))	('SFRP1', 'Gene', (85, 90))	('MGMT', 'Gene', '4255', (70, 74))	('methylation', 'Var', (27, 38))	('SFRP1', 'Gene', '6422', (85, 90))
872712	29253542	Of these, TFF1 was methylated both in ESCC and surrounding tissue in contrast to healthy esophageal mucosa, suggesting that it could be an early event and potential biomarker for ESCC.	('methylated', 'Var', (19, 29))	('TFF1', 'Gene', (10, 14))	('TFF1', 'Gene', '7031', (10, 14))	('ESCC', 'Disease', (179, 183))
872715	29253542	Furthermore, CDKN2A methylation has been found in 23% (7/31) of ESCC patients harboring a methylated primary tumor.	('found', 'Reg', (41, 46))	('ESCC', 'Disease', (64, 68))	('CDKN2A', 'Gene', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('methylation', 'Var', (20, 31))	('CDKN2A', 'Gene', '1029', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Disease', (109, 114))
872717	29253542	Zhai and coworkers used methylation arrays to identify hundreds of differentially methylated loci between cell-free circulating DNA from a limited number of EAC and Barrett's esophagus patients.	('differentially', 'Var', (67, 81))	('EAC', 'Phenotype', 'HP:0011459', (157, 160))	("Barrett's esophagus", 'Disease', (165, 184))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (165, 184))	('patients', 'Species', '9606', (185, 193))	('EAC', 'Disease', (157, 160))
872720	29253542	In ESCCs, FHIT has been analyzed in a larger cohort (n = 257), and aberrant promoter methylation was significantly associated with a poor prognosis for early stage (I &II) cancers (multivariate HR = 5.81, P = 0.009).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('FHIT', 'Gene', '2272', (10, 14))	('FHIT', 'Gene', (10, 14))	('associated', 'Reg', (115, 125))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('aberrant promoter methylation', 'Var', (67, 96))
872721	29253542	Finally, in a recent study CDO1 methylation was suggested as an independent prognostic factor for ESCC patients (multivariate HR = 2.00, P = 0.03) based on analyses of 169 cancer samples.	('methylation', 'Var', (32, 43))	('CDO1', 'Gene', '1036', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('CDO1', 'Gene', (27, 31))	('ESCC', 'Disease', (98, 102))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('patients', 'Species', '9606', (103, 111))
872732	29253542	Methylation of >=2 of the fives genes CCND2, TFPI2, PENK, NPTX2, and FOXE1 has been shown to distinguish between patients with cancer (n = 11) and individuals without neoplasia (n = 64), including chronic pancreatitis, with high sensitivity (82%) and specificity (100%).	('pancreatitis', 'Phenotype', 'HP:0001733', (205, 217))	('neoplasia', 'Disease', (167, 176))	('TFPI2', 'Gene', (45, 50))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (197, 217))	('Methylation', 'Var', (0, 11))	('cancer', 'Disease', (127, 133))	('neoplasia', 'Phenotype', 'HP:0002664', (167, 176))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (113, 121))	('FOXE1', 'Gene', (69, 74))	('TFPI2', 'Gene', '7980', (45, 50))	('chronic pancreatitis', 'Disease', (197, 217))	('CCND2', 'Gene', (38, 43))	('PENK', 'Gene', (52, 56))	('CCND2', 'Gene', '894', (38, 43))	('distinguish', 'Reg', (93, 104))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (197, 217))	('PENK', 'Gene', '5179', (52, 56))	('NPTX2', 'Gene', '4885', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('FOXE1', 'Gene', '2304', (69, 74))	('NPTX2', 'Gene', (58, 63))	('neoplasia', 'Disease', 'MESH:D009369', (167, 176))
872738	29253542	Several additional aberrantly methylated genes have been identified in pancreatic juice from cancer patients, including NPTX2 (67%), SARP2 (46%), and CLDN5 (42%), PENK (67%) and CDKN2A (11%), and APC (71%).	('CLDN5', 'Gene', '7122', (150, 155))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('SARP2', 'Gene', '6422', (133, 138))	('PENK', 'Gene', (163, 167))	('NPTX2', 'Gene', '4885', (120, 125))	('APC', 'Disease', 'MESH:D011125', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('APC', 'Disease', (196, 199))	('CDKN2A', 'Gene', (178, 184))	('PENK', 'Gene', '5179', (163, 167))	('patients', 'Species', '9606', (100, 108))	('NPTX2', 'Gene', (120, 125))	('CDKN2A', 'Gene', '1029', (178, 184))	('aberrantly methylated genes', 'Var', (19, 46))	('SARP2', 'Gene', (133, 138))	('CLDN5', 'Gene', (150, 155))
872739	29253542	Genes aberrantly methylated in cell free DNA in plasma represent another potential source for non-invasive pancreatic cancer detection.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('invasive pancreatic cancer', 'Disease', 'MESH:D010190', (98, 124))	('aberrantly methylated', 'Var', (6, 27))	('invasive pancreatic cancer', 'Disease', (98, 124))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))
872740	29253542	By analyzing patients with PDAC (n = 95), and non-malignant controls (chronic pancreatitis, n = 97, and healthy controls, n = 27), a diagnostic prediction model was generated, including age > 65, and promoter methylation of BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2.	('patients', 'Species', '9606', (13, 21))	('SFRP2', 'Gene', '6423', (275, 280))	('pancreatitis', 'Phenotype', 'HP:0001733', (78, 90))	('TFPI2', 'Gene', '7980', (253, 258))	('APC', 'Disease', 'MESH:D011125', (260, 263))	('PDAC', 'Chemical', '-', (27, 31))	('BMP3', 'Gene', '651', (224, 228))	('SFRP1', 'Gene', '6422', (265, 270))	('APC', 'Disease', (260, 263))	('SFRP2', 'Gene', (275, 280))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (70, 90))	('BNC1', 'Gene', '646', (239, 243))	('RASSF1A', 'Gene', '11186', (230, 237))	('BNC1', 'Gene', (239, 243))	('TFPI2', 'Gene', (253, 258))	('RASSF1A', 'Gene', (230, 237))	('promoter methylation', 'Var', (200, 220))	('chronic pancreatitis', 'Disease', (70, 90))	('BMP3', 'Gene', (224, 228))	('SFRP1', 'Gene', (265, 270))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (70, 90))
872742	29253542	By analyzing 42 serum samples from patients with pancreatic cancer and 26 samples from healthy controls, methylation of BNC1 and ADAMS1 could detect cancer with a sensitivity of 79% and 48%, respectively.	('pancreatic cancer', 'Disease', (49, 66))	('cancer', 'Disease', (149, 155))	('methylation', 'Var', (105, 116))	('pancreatic cancer', 'Disease', 'MESH:D010190', (49, 66))	('BNC1', 'Gene', '646', (120, 124))	('detect', 'Reg', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('ADAMS1', 'Gene', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (60, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('patients', 'Species', '9606', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('BNC1', 'Gene', (120, 124))
872745	29253542	Furthermore, the combination of ADAMTS1 and BNC1 methylation showed superior sensitivity compared with CA19-9.	('ADAMTS1', 'Gene', (32, 39))	('CA19-9', 'Chemical', 'MESH:C086528', (103, 109))	('superior', 'PosReg', (68, 76))	('ADAMTS1', 'Gene', '9510', (32, 39))	('combination', 'Interaction', (17, 28))	('methylation', 'Var', (49, 60))	('BNC1', 'Gene', '646', (44, 48))	('BNC1', 'Gene', (44, 48))	('sensitivity', 'MPA', (77, 88))
872748	29253542	Finally, aberrant methylation for pancreatic cancer detection has also been observed in brush samples.	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('methylation', 'MPA', (18, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('aberrant', 'Var', (9, 17))	('pancreatic cancer', 'Disease', (34, 51))
872752	29253542	In a study analyzing promoter methylation in whole-blood samples from 30 pancreatic cancer patients, methylation of the two genes TNFRSF10C and ACIN1 was found to be significantly associated with shorter OS (P = 0.023 and P = 0.012, respectively).	('patients', 'Species', '9606', (91, 99))	('pancreatic cancer', 'Disease', (73, 90))	('ACIN1', 'Gene', '22985', (144, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('associated', 'Reg', (180, 190))	('TNFRSF10C', 'Gene', (130, 139))	('TNFRSF10C', 'Gene', '8794', (130, 139))	('shorter OS', 'Disease', (196, 206))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ACIN1', 'Gene', (144, 149))	('methylation', 'Var', (101, 112))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
872756	29253542	It has been further shown that patients with hypermethylated MUC1 and MUC4 had significantly improved survival compared to patients with hypomethylated promoters.	('MUC4', 'Gene', '4585', (70, 74))	('improved', 'PosReg', (93, 101))	('patients', 'Species', '9606', (123, 131))	('MUC4', 'Gene', (70, 74))	('MUC1', 'Gene', (61, 65))	('MUC1', 'Gene', '4582', (61, 65))	('patients', 'Species', '9606', (31, 39))	('hypermethylated', 'Var', (45, 60))	('survival', 'MPA', (102, 110))
872761	29253542	The finding was validated in 12 pancreatic cancer cell lines treated with gemcitabine, suggesting that hypermethylation of the two genes may sensitize patients to this type of drug treatment.	('gemcitabine', 'Chemical', 'MESH:C056507', (74, 85))	('hypermethylation', 'Var', (103, 119))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (32, 49))	('patients', 'Species', '9606', (151, 159))	('pancreatic cancer', 'Disease', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('pancreatic cancer', 'Disease', 'MESH:D010190', (32, 49))	('sensitize', 'Reg', (141, 150))
872765	29253542	Although some epigenetic biomarkers have been reported for pancreatic cancer detection, including CD1D, their accuracy is not optimal, underscoring that more research is needed.	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('pancreatic cancer', 'Disease', (59, 76))	('epigenetic', 'Var', (14, 24))	('CD1D', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CD1D', 'Gene', '912', (98, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))
872768	29253542	Most liver cancers (~85%) occur in Asia, and can largely be explained by the continent's high rate of chronic infections with hepatitis B- (HBV) and C- viruses (HCV), which are known risk factors for HCC and CCA.	('hepatitis', 'Phenotype', 'HP:0012115', (126, 135))	('HCC', 'Gene', '619501', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CCA', 'Disease', (208, 211))	('infections', 'Disease', (110, 120))	('HCC', 'Phenotype', 'HP:0001402', (200, 203))	('C- viruses', 'Var', (149, 159))	('chronic infections', 'Phenotype', 'HP:0031035', (102, 120))	('hepatitis B', 'Disease', 'MESH:D006509', (126, 137))	('hepatitis B', 'Disease', (126, 137))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('CCA', 'Phenotype', 'HP:0030153', (208, 211))	('liver cancers', 'Phenotype', 'HP:0002896', (5, 18))	('liver cancers', 'Disease', 'MESH:D006528', (5, 18))	('HCC', 'Gene', (200, 203))	('liver cancer', 'Phenotype', 'HP:0002896', (5, 17))	('infections', 'Disease', 'MESH:D007239', (110, 120))	('liver cancers', 'Disease', (5, 18))
872775	29253542	Aberrant DNA methylation has been observed both in patients with PSC and in CCA precursor lesions (biliary intraepithelial neoplasia; BiIN), emphasizing the suitability of such markers for early detection of CCA.	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (107, 132))	('Aberrant', 'Var', (0, 8))	('CCA', 'Disease', (76, 79))	('PSC', 'Gene', '100653366', (65, 68))	('biliary intraepithelial neoplasia', 'Disease', (99, 132))	('PSC', 'Gene', (65, 68))	('DNA', 'Protein', (9, 12))	('CCA', 'Phenotype', 'HP:0030153', (76, 79))	('patients', 'Species', '9606', (51, 59))	('CCA', 'Phenotype', 'HP:0030153', (208, 211))	('biliary intraepithelial neoplasia', 'Disease', 'MESH:D019048', (99, 132))	('neoplasia', 'Phenotype', 'HP:0002664', (123, 132))
872776	29253542	As previously mentioned (section 5.1), the methylation levels of TFPI2, NPTX2 and CCND2 could detect biliary tract cancers (n = 10) from biliary brush samples with a sensitivity of 80% and a specificity of 86% compared to patients with benign liver conditions.	('NPTX2', 'Gene', (72, 77))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('CCND2', 'Gene', (82, 87))	('methylation', 'Var', (43, 54))	('patients', 'Species', '9606', (222, 230))	('TFPI2', 'Gene', (65, 70))	('detect', 'Reg', (94, 100))	('TFPI2', 'Gene', '7980', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('NPTX2', 'Gene', '4885', (72, 77))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (101, 121))	('biliary tract cancers', 'Disease', 'MESH:D001661', (101, 122))	('biliary tract cancers', 'Disease', (101, 122))	('CCND2', 'Gene', '894', (82, 87))
872782	29253542	reported that methylation of the marker panel CCND2, CDH13, GRIN2B, RUNX3, and TWIST1 achieved 70% sensitivity in a training set (n = 20), 74% sensitivity in the first validation set (n = 33), and 83% sensitivity in the second validation set (n = 24), with 100% specificity for all sets (total n = 48).	('CCND2', 'Gene', (46, 51))	('RUNX3', 'Gene', '864', (68, 73))	('GRIN2B', 'Gene', (60, 66))	('TWIST1', 'Gene', (79, 85))	('CDH13', 'Gene', (53, 58))	('CCND2', 'Gene', '894', (46, 51))	('CDH13', 'Gene', '1012', (53, 58))	('TWIST1', 'Gene', '7291', (79, 85))	('methylation', 'Var', (14, 25))	('GRIN2B', 'Gene', '2904', (60, 66))	('RUNX3', 'Gene', (68, 73))
872783	29253542	Finally, promoter hypermethylation of SHOX2 and SEPT9 was shown to display a sensitivity of 45% and a specificity of 99% when analyzed in plasma from 20 CCA patients and 100 controls.	('promoter hypermethylation', 'Var', (9, 34))	('CCA', 'Disease', (153, 156))	('SEPT9', 'Gene', '10801', (48, 53))	('SHOX2', 'Gene', (38, 43))	('patients', 'Species', '9606', (157, 165))	('SHOX2', 'Gene', '6474', (38, 43))	('SEPT9', 'Gene', (48, 53))	('CCA', 'Phenotype', 'HP:0030153', (153, 156))
872785	29253542	In addition to CDKN2A, several genes, mainly in tissue specimens but also in blood samples, were found to be frequently methylated in HCC (reviewed in).	('methylated', 'Var', (120, 130))	('CDKN2A', 'Gene', (15, 21))	('HCC', 'Gene', (134, 137))	('CDKN2A', 'Gene', '1029', (15, 21))	('HCC', 'Gene', '619501', (134, 137))	('HCC', 'Phenotype', 'HP:0001402', (134, 137))
872794	29253542	By analyzing 79 patients with CCA, Lee and colleagues found that methylation of APC, CDKN2A and TIMP3 was significantly associated with worse OS in univariate analyses.	('associated', 'Reg', (120, 130))	('APC', 'Disease', (80, 83))	('patients', 'Species', '9606', (16, 24))	('CDKN2A', 'Gene', (85, 91))	('CDKN2A', 'Gene', '1029', (85, 91))	('CCA', 'Disease', (30, 33))	('CCA', 'Phenotype', 'HP:0030153', (30, 33))	('methylation', 'Var', (65, 76))	('TIMP3', 'Gene', (96, 101))	('APC', 'Disease', 'MESH:D011125', (80, 83))	('TIMP3', 'Gene', '7078', (96, 101))	('worse OS', 'Disease', (136, 144))
872795	29253542	Methylation of DAPK was in another study shown to be an interdependent predictor of poor survival while analyzing 37 patients with biliary tract carcinomas (multivariate HR = 8.71, P = 0.024).	('biliary tract carcinomas', 'Disease', (131, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('Methylation', 'Var', (0, 11))	('patients', 'Species', '9606', (117, 125))	('biliary tract carcinomas', 'Disease', 'MESH:D001661', (131, 155))	('DAPK', 'Gene', (15, 19))	('DAPK', 'Gene', '1612', (15, 19))
872797	29253542	Single genes have also been proposed to have prognostic value, including methylation of RASSF1 in plasma (n = 72), which was shown to be an independent prognostic factor for OS (multivariate HR = 3.26, P = 0.003).	('methylation', 'Var', (73, 84))	('RASSF1', 'Gene', '11186', (88, 94))	('RASSF1', 'Gene', (88, 94))
872798	29253542	Similarly, hypomethylation of S100A8 was significantly associated with both worse OS (multivariate HR = 1.71, P < 0.05) and PFS (multivariate HR = 1.77, P < 0.05), analyzing 52 HCC tissue samples.	('HCC', 'Gene', '619501', (177, 180))	('PFS', 'Disease', (124, 127))	('S100A8', 'Gene', (30, 36))	('HCC', 'Phenotype', 'HP:0001402', (177, 180))	('hypomethylation', 'Var', (11, 26))	('associated', 'Reg', (55, 65))	('S100A8', 'Gene', '6279', (30, 36))	('worse OS', 'Disease', (76, 84))	('HCC', 'Gene', (177, 180))
872799	29253542	Finally, SOCS3 methylation was recently reported to predict treatment response and prognosis in 246 HCC patients receiving transarterial chemoembolization (TACE) treatment (multivariate HR = 3.44, P < 0.001).	('methylation', 'Var', (15, 26))	('predict', 'Reg', (52, 59))	('HCC', 'Gene', (100, 103))	('SOCS3', 'Gene', '9021', (9, 14))	('patients', 'Species', '9606', (104, 112))	('HCC', 'Gene', '619501', (100, 103))	('SOCS3', 'Gene', (9, 14))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))
872803	29253542	Although bile and biliary brush samples are interesting sources for detection of epigenetic biomarkers, the potential risk of pancreatitis during collection of such material underscore the need for non-invasive analyses.	('pancreatitis', 'Disease', 'MESH:D010195', (126, 138))	('epigenetic', 'Var', (81, 91))	('pancreatitis', 'Disease', (126, 138))	('pancreatitis', 'Phenotype', 'HP:0001733', (126, 138))
872810	29253542	1, several genes are hypermethylated in more than one GI cancer type, including the Epi ProColon SEPT9, which has also been reported by Epigenomics themselves.	('GI cancer', 'Disease', 'MESH:D009369', (54, 63))	('Epi', 'Gene', '7035', (136, 139))	('Epi', 'Gene', (136, 139))	('GI cancer', 'Phenotype', 'HP:0007378', (54, 63))	('hypermethylated', 'Var', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('SEPT9', 'Gene', '10801', (97, 102))	('GI cancer', 'Disease', (54, 63))	('Epi', 'Gene', '7035', (84, 87))	('SEPT9', 'Gene', (97, 102))	('Epi', 'Gene', (84, 87))
872815	29253542	Such changes may in the future play a major role in GI cancer detection, for determining prognosis and for predicting response to specific treatments.	('changes', 'Var', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('GI cancer', 'Disease', (52, 61))	('GI cancer', 'Disease', 'MESH:D009369', (52, 61))	('GI cancer', 'Phenotype', 'HP:0007378', (52, 61))
872817	32012470	MicroRNA-153-3p regulates cell proliferation and cisplatin resistance via Nrf-2 in esophageal squamous cell carcinoma Our recent studies have indicated that miR-153-3p is downregulated in the esophageal squamous cell carcinoma (ESCC) cell lines and tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('ESCC', 'Disease', (228, 232))	('Nrf-2', 'Gene', (74, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('downregulated', 'NegReg', (171, 184))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('esophageal squamous cell carcinoma', 'Disease', (83, 117))	('esophageal squamous cell carcinoma', 'Disease', (192, 226))	('miR-153-3p', 'Chemical', '-', (157, 167))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (192, 226))	('Nrf-2', 'Gene', '4780', (74, 79))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (83, 117))	('ESCC', 'Disease', 'MESH:C562729', (228, 232))	('miR-153-3p', 'Var', (157, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
872818	32012470	Upregulation of miR-153-3p was found to inhibit migration and invasion of ESCC cells.	('Upregulation', 'PosReg', (0, 12))	('miR-153-3p', 'Chemical', '-', (16, 26))	('inhibit', 'NegReg', (40, 47))	('ESCC', 'Disease', (74, 78))	('miR-153-3p', 'Var', (16, 26))	('ESCC', 'Disease', 'MESH:C562729', (74, 78))
872820	32012470	In this study, we explored whether and how miR-153-3p regulates the proliferation and confers cisplatin resistance in ESCC by targeting the Nrf-2 protein.	('ESCC', 'Disease', (118, 122))	('proliferation', 'MPA', (68, 81))	('miR-153-3p', 'Chemical', '-', (43, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('targeting', 'Reg', (126, 135))	('miR-153-3p', 'Var', (43, 53))	('Nrf-2', 'Gene', (140, 145))	('cisplatin resistance', 'MPA', (94, 114))	('protein', 'Protein', (146, 153))	('ESCC', 'Disease', 'MESH:C562729', (118, 122))	('Nrf-2', 'Gene', '4780', (140, 145))	('regulates', 'Reg', (54, 63))
872822	32012470	A dual-luciferase reporter assay was performed on Eca109 cells cotransfected with the wild-type/mutant 3'UTR sequences of Nrf-2 and control or microRNA-153-3p mimics.	('3p', 'Chemical', '-', (156, 158))	('wild-type/mutant', 'Var', (86, 102))	('Nrf-2', 'Gene', '4780', (122, 127))	('Nrf-2', 'Gene', (122, 127))
872824	32012470	MiR-153-3p significantly suppressed cell proliferation and increased the sensitivity of Eca-109 cells to cisplatin.	('sensitivity', 'MPA', (73, 84))	('suppressed', 'NegReg', (25, 35))	('MiR-153-3p', 'Chemical', '-', (0, 10))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('increased', 'PosReg', (59, 68))	('MiR-153-3p', 'Var', (0, 10))	('cell proliferation', 'CPA', (36, 54))
872825	32012470	MiR-153-3p showed a negative correlation with Nrf-2 in human esophageal carcinoma tissues.	('esophageal carcinoma', 'Disease', (61, 81))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (61, 81))	('negative', 'NegReg', (20, 28))	('Nrf-2', 'Gene', '4780', (46, 51))	('human', 'Species', '9606', (55, 60))	('MiR-153-3p', 'Chemical', '-', (0, 10))	('MiR-153-3p', 'Var', (0, 10))	('Nrf-2', 'Gene', (46, 51))
872826	32012470	MiR-153-3p suppressed the expression of Nrf-2 via binding to its 3'-UTR region.	('expression', 'MPA', (26, 36))	('suppressed', 'NegReg', (11, 21))	('MiR-153-3p', 'Chemical', '-', (0, 10))	('Nrf-2', 'Gene', (40, 45))	('Nrf-2', 'Gene', '4780', (40, 45))	('binding', 'Interaction', (50, 57))	('MiR-153-3p', 'Var', (0, 10))
872827	32012470	Furthermore, inhibition of Nrf-2 also decreased cell proliferation and increased the sensitivity of Eca109 cells to cisplatin.	('decreased', 'NegReg', (38, 47))	('inhibition', 'Var', (13, 23))	('cell proliferation', 'CPA', (48, 66))	('increased', 'PosReg', (71, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('Nrf-2', 'Gene', (27, 32))	('sensitivity', 'MPA', (85, 96))	('Nrf-2', 'Gene', '4780', (27, 32))
872828	32012470	High expression of Nrf-2 in human ESCC samples was associated with poor overall survival of ESCC patients.	('ESCC', 'Disease', 'MESH:C562729', (34, 38))	('ESCC', 'Disease', (92, 96))	('High', 'Var', (0, 4))	('overall', 'MPA', (72, 79))	('Nrf-2', 'Gene', (19, 24))	('human', 'Species', '9606', (28, 33))	('poor', 'NegReg', (67, 71))	('Nrf-2', 'Gene', '4780', (19, 24))	('ESCC', 'Disease', (34, 38))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))	('patients', 'Species', '9606', (97, 105))
872829	32012470	MiR-153-3p inhibits cell proliferation and confers cisplatin resistance by downregulating Nrf-2 expression in Eca-109 cells.	('Nrf-2', 'Gene', (90, 95))	('cell proliferation', 'CPA', (20, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('Nrf-2', 'Gene', '4780', (90, 95))	('inhibits', 'NegReg', (11, 19))	('expression', 'MPA', (96, 106))	('cisplatin resistance', 'MPA', (51, 71))	('MiR-153-3p', 'Chemical', '-', (0, 10))	('downregulating', 'NegReg', (75, 89))	('confers', 'PosReg', (43, 50))	('MiR-153-3p', 'Var', (0, 10))
872835	32012470	Upregulation of miR-153 has been shown to inhibit the migration and invasion of ESCC cells, both in vitro and in vivo.2 Some studies have found that miR-153-3p can inhibit the proliferation and invasive growth of breast cancer and osteosarcoma cells.9, 10 These findings indicate that miR-153-3p can act as a tumor suppressor and may serve as a potential target for the treatment of malignant tumors.	('miR-153-3p', 'Var', (285, 295))	('miR-153', 'Chemical', '-', (16, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('tumor', 'Disease', (393, 398))	('osteosarcoma', 'Phenotype', 'HP:0002669', (231, 243))	('miR-153', 'Chemical', '-', (285, 292))	('miR-153', 'Chemical', '-', (149, 156))	('tumor', 'Disease', 'MESH:D009369', (393, 398))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Disease', (213, 226))	('tumors', 'Phenotype', 'HP:0002664', (393, 399))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('tumor', 'Disease', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (393, 398))	('osteosarcoma', 'Disease', (231, 243))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('miR-153-3p', 'Chemical', '-', (285, 295))	('miR-153-3p', 'Chemical', '-', (149, 159))	('osteosarcoma', 'Disease', 'MESH:D012516', (231, 243))	('ESCC', 'Disease', (80, 84))	('malignant tumors', 'Disease', (383, 399))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('malignant tumors', 'Disease', 'MESH:D009369', (383, 399))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
872836	32012470	However, whether miR-153-3p regulates the proliferation of ESCC cells and confers sensitivity to cisplatin chemotherapy remains unclear.	('ESCC', 'Disease', 'MESH:C562729', (59, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('regulates', 'Reg', (28, 37))	('miR-153-3p', 'Chemical', '-', (17, 27))	('ESCC', 'Disease', (59, 63))	('miR-153-3p', 'Var', (17, 27))
872839	32012470	Nrf-2 was shown to improve the sensitivity of lung cancer cell line A549 to cisplatin.13 In addition, miR-153-3p has been shown to regulate Nrf-2 expression by controlling the redox homeostasis in SH-SY5Y cells.14 In another study, inhibiting miR-153-3p was shown to protect against paraquat-induced dopaminergic neurotoxicity via targeting Nrf-2 in the central nervous system.15 These studies indicate that Nrf-2 may be a potential target of miR-153-3p in ESCC, and may play a critical role in tumor cell proliferation and cisplatin resistance in ESCC.	('miR-153-3p', 'Chemical', '-', (243, 253))	('Nrf-2', 'Gene', '4780', (341, 346))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Nrf-2', 'Gene', (408, 413))	('ESCC', 'Disease', (457, 461))	('lung cancer', 'Disease', (46, 57))	('ESCC', 'Disease', 'MESH:C562729', (548, 552))	('Nrf-2', 'Gene', '4780', (0, 5))	('tumor', 'Disease', (495, 500))	('Nrf-2', 'Gene', (0, 5))	('Nrf-2', 'Gene', '4780', (140, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (524, 533))	('Nrf-2', 'Gene', (341, 346))	('tumor', 'Disease', 'MESH:D009369', (495, 500))	('ESCC', 'Disease', (548, 552))	('miR-153-3p', 'Chemical', '-', (443, 453))	('role', 'Reg', (487, 491))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (197, 204))	('Nrf-2', 'Gene', '4780', (408, 413))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (495, 500))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('dopaminergic neurotoxicity', 'Disease', (300, 326))	('miR-153-3p', 'Chemical', '-', (102, 112))	('ESCC', 'Disease', 'MESH:C562729', (457, 461))	('dopaminergic neurotoxicity', 'Disease', 'MESH:D020258', (300, 326))	('Nrf-2', 'Gene', (140, 145))	('cisplatin', 'MPA', (524, 533))	('miR-153-3p', 'Var', (443, 453))	('play', 'Reg', (471, 475))
872840	32012470	In this study, we explored whether miR-153-3p regulated the proliferation of ESCC cells and conferred cisplatin resistance via targeting the Nrf-2 protein.	('protein', 'Protein', (147, 154))	('miR-153-3p', 'Var', (35, 45))	('regulated', 'Reg', (46, 55))	('Nrf-2', 'Gene', (141, 146))	('cisplatin resistance', 'MPA', (102, 122))	('Nrf-2', 'Gene', '4780', (141, 146))	('ESCC', 'Disease', (77, 81))	('targeting', 'Reg', (127, 136))	('conferred', 'Reg', (92, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('proliferation', 'CPA', (60, 73))	('miR-153-3p', 'Chemical', '-', (35, 45))	('ESCC', 'Disease', 'MESH:C562729', (77, 81))
872853	32012470	Transfection of miR-153-p mimic, NC mimics, Nrf-2 siRNA and NC siRNA were carried out using Lipofectamine 2000 reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions.	('Lipofectamine 2000 reagent', 'Chemical', '-', (92, 118))	('miR-153-p mimic', 'Var', (16, 31))	('Nrf-2', 'Gene', (44, 49))	('miR-153-p', 'Chemical', '-', (16, 25))	('Nrf-2', 'Gene', '4780', (44, 49))
872867	32012470	Luciferase reporter assay was performed to confirm whether miR-153-3p interacted with Nrf-2 mRNA.	('interacted', 'Interaction', (70, 80))	('Nrf-2', 'Gene', '4780', (86, 91))	('miR-153-3p', 'Chemical', '-', (59, 69))	('Nrf-2', 'Gene', (86, 91))	('miR-153-3p', 'Var', (59, 69))
872872	32012470	Post transfection for 48 hours, the expression level of miR-153-3p in Eca109 cells was significantly increased compared to NC mimics control (Fig 1a).	('expression level', 'MPA', (36, 52))	('miR-153-3p', 'Chemical', '-', (56, 66))	('miR-153-3p', 'Var', (56, 66))	('increased', 'PosReg', (101, 110))
872873	32012470	Upregulation of miR-153-3p significantly suppressed cell viability and colony formation by Eca-109 cells, which suggested that miR-153-3p can suppress proliferation of ESCC cells (Fig 1b-d; P < 0.05).	('miR-153-3p', 'Chemical', '-', (16, 26))	('proliferation', 'CPA', (151, 164))	('cell viability', 'CPA', (52, 66))	('ESCC', 'Disease', 'MESH:C562729', (168, 172))	('suppressed', 'NegReg', (41, 51))	('colony formation', 'CPA', (71, 87))	('miR-153-3p', 'Chemical', '-', (127, 137))	('ESCC', 'Disease', (168, 172))	('miR-153-3p', 'Var', (127, 137))	('suppress', 'NegReg', (142, 150))
872874	32012470	To confirm the effect of miR-153-3p on proliferation of ESCC cells, the expression levels of proliferation-related proteins, Cyclin D1 and Survivin, were also measured by western blotting.	('ESCC', 'Disease', (56, 60))	('Cyclin D1', 'Gene', (125, 134))	('ESCC', 'Disease', 'MESH:C562729', (56, 60))	('expression', 'MPA', (72, 82))	('miR-153-3p', 'Chemical', '-', (25, 35))	('miR-153-3p', 'Var', (25, 35))	('Cyclin D1', 'Gene', '595', (125, 134))
872875	32012470	The results showed that the expression levels of Cyclin D1 and Survivin were significantly decreased in cells with miR-153-3p mimics transfection (Fig 1e; P < 0.05).	('miR-153-3p mimics transfection', 'Var', (115, 145))	('Cyclin D1', 'Gene', (49, 58))	('expression levels', 'MPA', (28, 45))	('Survivin', 'Protein', (63, 71))	('Cyclin D1', 'Gene', '595', (49, 58))	('decreased', 'NegReg', (91, 100))	('miR-153-3p', 'Chemical', '-', (115, 125))
872876	32012470	These results suggested that miR-153-3p suppressed the proliferation of human ESCC cells and acts as a tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('ESCC', 'Disease', (78, 82))	('suppressed', 'NegReg', (40, 50))	('tumor', 'Disease', (103, 108))	('proliferation', 'CPA', (55, 68))	('miR-153-3p', 'Var', (29, 39))	('human', 'Species', '9606', (72, 77))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('miR-153-3p', 'Chemical', '-', (29, 39))
872879	32012470	However, irrespective of the concentration of cisplatin, the cell viability with miR-153-3p mimic was significantly lower than that with NC mimic (Fig 2a).	('lower', 'NegReg', (116, 121))	('miR-153-3p mimic', 'Var', (81, 97))	('miR-153-3p', 'Chemical', '-', (81, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('cell viability', 'CPA', (61, 75))
872880	32012470	The IC50 of cisplatin in Eca-109 cells with miR-153-3p mimics was lower than that of the control cells (Fig 2b).	('IC50', 'MPA', (4, 8))	('miR-153-3p', 'Chemical', '-', (44, 54))	('lower', 'NegReg', (66, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (12, 21))	('miR-153-3p mimics', 'Var', (44, 61))
872881	32012470	Thus, miR-153-3p increased the chemosensitivity of ESCC.	('increased', 'PosReg', (17, 26))	('ESCC', 'Disease', 'MESH:C562729', (51, 55))	('ESCC', 'Disease', (51, 55))	('chemosensitivity', 'MPA', (31, 47))	('miR-153-3p', 'Chemical', '-', (6, 16))	('miR-153-3p', 'Var', (6, 16))
872883	32012470	Low concentration of cisplatin also significantly increased the expression of cleaved caspase-3 in Eca-109 cells transfected with miR-153-3p mimics as compared to cells transfected with NC mimics (Fig 2e).	('miR-153-3p mimics', 'Var', (130, 147))	('caspase-3', 'Gene', (86, 95))	('expression', 'MPA', (64, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('miR-153-3p', 'Chemical', '-', (130, 140))	('increased', 'PosReg', (50, 59))	('caspase-3', 'Gene', '836', (86, 95))	('cleaved', 'MPA', (78, 85))
872884	32012470	Thus, our results indicate that upregulation of miR-153-3p significantly increased the sensitivity of ESCC to cisplatin, which suggests that loss of mir-153-3p leads to cisplatin resistance in ESCC.	('3p', 'Chemical', '-', (157, 159))	('ESCC', 'Disease', (193, 197))	('increased', 'PosReg', (73, 82))	('3p', 'Chemical', '-', (56, 58))	('upregulation', 'PosReg', (32, 44))	('ESCC', 'Disease', (102, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('loss', 'Var', (141, 145))	('ESCC', 'Disease', 'MESH:C562729', (193, 197))	('sensitivity', 'MPA', (87, 98))	('mir-153-3p', 'Gene', (149, 159))	('cisplatin resistance', 'MPA', (169, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('miR-153-3p', 'Chemical', '-', (48, 58))	('leads to', 'Reg', (160, 168))	('ESCC', 'Disease', 'MESH:C562729', (102, 106))
872885	32012470	To explore whether miR-153-3p regulates cell proliferation via targeting Nrf-2 protein, we measured the correlation between miR-153-3p and Nrf-2 in 25 pairs of fresh ESCC and adjacent normal esophageal epithelial samples.	('Nrf-2', 'Gene', (73, 78))	('miR-153-3p', 'Var', (124, 134))	('miR-153-3p', 'Chemical', '-', (19, 29))	('Nrf-2', 'Gene', (139, 144))	('Nrf-2', 'Gene', '4780', (73, 78))	('Nrf-2', 'Gene', '4780', (139, 144))	('ESCC', 'Disease', 'MESH:C562729', (166, 170))	('ESCC', 'Disease', (166, 170))	('miR-153-3p', 'Chemical', '-', (124, 134))
872886	32012470	The expression level of miR-153-3p in ESCC tissues showed a negative correlation with the expression level of Nrf-2 mRNA (Fig 3a).	('negative', 'NegReg', (60, 68))	('ESCC', 'Disease', 'MESH:C562729', (38, 42))	('Nrf-2', 'Gene', (110, 115))	('Nrf-2', 'Gene', '4780', (110, 115))	('expression', 'MPA', (4, 14))	('ESCC', 'Disease', (38, 42))	('miR-153-3p', 'Chemical', '-', (24, 34))	('miR-153-3p', 'Var', (24, 34))	('expression level', 'MPA', (90, 106))
872887	32012470	We found that upregulation of miR-153-3p due to transfection with mimics inhibited the expression of Nrf-2 in Eca109 cells in vitro (Fig 3b).	('Nrf-2', 'Gene', (101, 106))	('miR-153-3p', 'Chemical', '-', (30, 40))	('Nrf-2', 'Gene', '4780', (101, 106))	('expression', 'MPA', (87, 97))	('inhibited', 'NegReg', (73, 82))	('miR-153-3p', 'Var', (30, 40))	('transfection', 'Var', (48, 60))	('upregulation', 'PosReg', (14, 26))
872888	32012470	To verify whether miR-153-3p targets Nrf-2 directly, we performed the luciferase reporter assay and found that miR-153-3p could directly bind to Nrf-2 mRNA at the 3'-UTR region and inhibit its expression (Fig 3c).	('miR-153-3p', 'Var', (111, 121))	('Nrf-2', 'Gene', (145, 150))	('Nrf-2', 'Gene', '4780', (145, 150))	('inhibit', 'NegReg', (181, 188))	('Nrf-2', 'Gene', (37, 42))	('Nrf-2', 'Gene', '4780', (37, 42))	('bind', 'Interaction', (137, 141))	('miR-153-3p', 'Chemical', '-', (18, 28))	('expression', 'MPA', (193, 203))	('miR-153-3p', 'Chemical', '-', (111, 121))	('mRNA', 'Protein', (151, 155))
872889	32012470	Subsequently, we mutated the Nrf2 mRNA 3'-UTR which was the binding site of miR-153-3p and found that the relative luciferase activity did not downregulate it.	('Nrf2', 'Gene', (29, 33))	('luciferase', 'Enzyme', (115, 125))	('Nrf2', 'Gene', '4780', (29, 33))	('miR-153-3p', 'Chemical', '-', (76, 86))	('activity', 'MPA', (126, 134))	('mutated', 'Var', (17, 24))
872890	32012470	These results confirmed that miR-153-3p downregulated Nrf-2 expression by directly binding to Nrf2 mRNA 3'-UTR region.	('expression', 'MPA', (60, 70))	('downregulated', 'NegReg', (40, 53))	('Nrf-2', 'Gene', (54, 59))	('binding', 'Interaction', (83, 90))	('miR-153-3p', 'Var', (29, 39))	('Nrf2', 'Gene', '4780', (94, 98))	('Nrf-2', 'Gene', '4780', (54, 59))	('Nrf2', 'Gene', (94, 98))	('miR-153-3p', 'Chemical', '-', (29, 39))
872893	32012470	Inhibition of Nrf-2 also decreased colony formation by Eca109 cells (Fig 3e,f).	('Nrf-2', 'Gene', '4780', (14, 19))	('decreased', 'NegReg', (25, 34))	('Inhibition', 'Var', (0, 10))	('Nrf-2', 'Gene', (14, 19))	('colony formation', 'CPA', (35, 51))
872895	32012470	Thus, miR-153-3p inhibited cell proliferation by downregulating Nrf-2 expression.	('downregulating', 'NegReg', (49, 63))	('cell proliferation', 'CPA', (27, 45))	('inhibited', 'NegReg', (17, 26))	('expression', 'MPA', (70, 80))	('Nrf-2', 'Gene', (64, 69))	('miR-153-3p', 'Chemical', '-', (6, 16))	('Nrf-2', 'Gene', '4780', (64, 69))	('miR-153-3p', 'Var', (6, 16))
872897	32012470	The viability of control Eca109 cells decreased over a range of cisplatin concentrations (from 4-32 mug/mL), while inhibition of Nrf-2 significantly increased the chemosensitivity of ESCC to cisplatin (from 1-32 mug/mL) (Fig 4a).	('decreased', 'NegReg', (38, 47))	('chemosensitivity', 'MPA', (163, 179))	('increased', 'PosReg', (149, 158))	('ESCC', 'Disease', 'MESH:C562729', (183, 187))	('Nrf-2', 'Gene', (129, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (191, 200))	('Nrf-2', 'Gene', '4780', (129, 134))	('inhibition', 'Var', (115, 125))	('ESCC', 'Disease', (183, 187))	('viability', 'MPA', (4, 13))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))
872901	32012470	Therefore, our results suggested that inhibition of Nrf-2 significantly increased the sensitivity of ESCC cells to cisplatin.	('Nrf-2', 'Gene', (52, 57))	('increased', 'PosReg', (72, 81))	('Nrf-2', 'Gene', '4780', (52, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('sensitivity', 'MPA', (86, 97))	('ESCC', 'Disease', 'MESH:C562729', (101, 105))	('inhibition', 'Var', (38, 48))	('ESCC', 'Disease', (101, 105))
872911	32012470	miR-153-3p inhibited proliferation, migration, and invasion of acute lymphoblastic leukemia cells by suppressing inhibitor of growth protein 2 expression.25 In addition to regulating tumor cell infiltration and metastasis, miR-153-3p has also been shown to regulate chemosensitivity of cancer cells.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (63, 91))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('acute lymphoblastic leukemia', 'Disease', (63, 91))	('miR-153-3p', 'Var', (223, 233))	('regulate', 'Reg', (257, 265))	('chemosensitivity', 'CPA', (266, 282))	('tumor', 'Disease', (183, 188))	('miR-153-3p', 'Chemical', '-', (0, 10))	('miR-153-3p', 'Chemical', '-', (223, 233))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (63, 91))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (69, 91))	('cancer', 'Disease', (286, 292))
872912	32012470	MiR-153-3p has been reported to overcome the resistance of lung cancer cells to gefitinib by downregulating ABCE1.26 Our recent studies have shown that MiR-153-3p inhibits the migration and invasion of ESCC cells whereas miR-153 antagomir promotes migration and invasion of normal esophageal epithelial cells.3 Therefore, whether miR-153-3p regulates the proliferation of ESCC cells and confers sensitivity to cisplatin chemotherapy is not clear.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('ABCE1', 'Gene', '6059', (108, 113))	('gefitinib', 'Chemical', 'MESH:D000077156', (80, 89))	('ESCC', 'Disease', (202, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('miR-153-3p', 'Var', (330, 340))	('ABCE1', 'Gene', (108, 113))	('MiR-153-3p', 'Chemical', '-', (152, 162))	('miR-153', 'Chemical', '-', (221, 228))	('ESCC', 'Disease', 'MESH:C562729', (372, 376))	('MiR-153-3p', 'Chemical', '-', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('miR-153', 'Chemical', '-', (330, 337))	('lung cancer', 'Disease', (59, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (410, 419))	('regulates', 'Reg', (341, 350))	('ESCC', 'Disease', (372, 376))	('ESCC', 'Disease', 'MESH:C562729', (202, 206))	('miR-153-3p', 'Chemical', '-', (330, 340))
872913	32012470	In the present study, we found that miR-153-3p suppressed the proliferation of human ESCC cells and Eca109 cells.	('suppressed', 'NegReg', (47, 57))	('human', 'Species', '9606', (79, 84))	('Eca109 cells', 'CPA', (100, 112))	('proliferation', 'CPA', (62, 75))	('miR-153-3p', 'Chemical', '-', (36, 46))	('ESCC', 'Disease', (85, 89))	('miR-153-3p', 'Var', (36, 46))	('ESCC', 'Disease', 'MESH:C562729', (85, 89))
872914	32012470	Upregulation of miR-153-3p significantly increased the sensitivity of ESCC cells to cisplatin; this suggests that miR-153-3p also plays a critical role in overcoming cisplatin resistance in ESCC.	('ESCC', 'Disease', (190, 194))	('miR-153-3p', 'Chemical', '-', (16, 26))	('miR-153-3p', 'Var', (114, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('sensitivity', 'MPA', (55, 66))	('overcoming', 'PosReg', (155, 165))	('ESCC', 'Disease', 'MESH:C562729', (70, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('ESCC', 'Disease', 'MESH:C562729', (190, 194))	('cisplatin resistance', 'MPA', (166, 186))	('ESCC', 'Disease', (70, 74))	('miR-153-3p', 'Chemical', '-', (114, 124))
872917	32012470	found that Nrf-2 played an important role in the resistance of head and neck squamous cell carcinoma cells to cisplatin.30 In the present study, we observed a negative correlation between the expressions of miR-153-3p and Nrf-2 in human esophageal carcinoma tissues.	('esophageal carcinoma', 'Disease', (237, 257))	('Nrf-2', 'Gene', '4780', (11, 16))	('miR-153-3p', 'Chemical', '-', (207, 217))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (72, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (237, 257))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (237, 257))	('miR-153-3p', 'Var', (207, 217))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('Nrf-2', 'Gene', (222, 227))	('neck squamous cell carcinoma', 'Disease', (72, 100))	('negative', 'NegReg', (159, 167))	('Nrf-2', 'Gene', '4780', (222, 227))	('human', 'Species', '9606', (231, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (63, 100))	('Nrf-2', 'Gene', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
872918	32012470	Furthermore, miR-153-3p suppressed the expression of Nrf-2 via binding to its 3'-UTR region in Eca109 cells.	('Nrf-2', 'Gene', (53, 58))	('binding', 'Interaction', (63, 70))	('miR-153-3p', 'Chemical', '-', (13, 23))	('suppressed', 'NegReg', (24, 34))	('Nrf-2', 'Gene', '4780', (53, 58))	('expression', 'MPA', (39, 49))	('miR-153-3p', 'Var', (13, 23))
872919	32012470	The results suggested that miR-153-3p inhibited the proliferation of Eca-109 cells probably by downregulating the expression of Nrf-2.	('proliferation', 'CPA', (52, 65))	('Nrf-2', 'Gene', (128, 133))	('Nrf-2', 'Gene', '4780', (128, 133))	('inhibited', 'NegReg', (38, 47))	('miR-153-3p', 'Chemical', '-', (27, 37))	('expression', 'MPA', (114, 124))	('miR-153-3p', 'Var', (27, 37))	('downregulating', 'NegReg', (95, 109))
872921	32012470	In this study, we found that inhibition of Nrf-2 also decreased cell proliferation and colony formation by Eca109 cells.	('colony formation by Eca109 cells', 'CPA', (87, 119))	('cell proliferation', 'CPA', (64, 82))	('Nrf-2', 'Gene', (43, 48))	('decreased', 'NegReg', (54, 63))	('Nrf-2', 'Gene', '4780', (43, 48))	('inhibition', 'Var', (29, 39))
872922	32012470	Furthermore, inhibition of Nrf-2 significantly increased the sensitivity of ESCC cells to cisplatin, which suggests that Nrf-2 may play a critical role in cisplatin resistance in ESCC.	('ESCC', 'Disease', 'MESH:C562729', (179, 183))	('Nrf-2', 'Gene', '4780', (121, 126))	('Nrf-2', 'Gene', (27, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('Nrf-2', 'Gene', '4780', (27, 32))	('inhibition', 'Var', (13, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('ESCC', 'Disease', (179, 183))	('ESCC', 'Disease', 'MESH:C562729', (76, 80))	('increased', 'PosReg', (47, 56))	('ESCC', 'Disease', (76, 80))	('sensitivity', 'MPA', (61, 72))	('Nrf-2', 'Gene', (121, 126))
872923	32012470	The results further confirm that miR-153-3p inhibits proliferation of Eca-109 cells and confers cisplatin resistance probably by downregulating Nrf-2 expression.	('confers', 'Reg', (88, 95))	('Nrf-2', 'Gene', '4780', (144, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('expression', 'MPA', (150, 160))	('miR-153-3p', 'Chemical', '-', (33, 43))	('miR-153-3p', 'Var', (33, 43))	('cisplatin resistance', 'MPA', (96, 116))	('proliferation', 'CPA', (53, 66))	('Nrf-2', 'Gene', (144, 149))	('inhibits', 'NegReg', (44, 52))	('downregulating', 'NegReg', (129, 143))
872927	32012470	In summary, our data demonstrated that miR-153-3p acts as a tumor suppressor by inhibiting the proliferation of EC109 cells and enhances their sensitivity to cisplatin.	('sensitivity to cisplatin', 'MPA', (143, 167))	('miR-153-3p', 'Chemical', '-', (39, 49))	('miR-153-3p', 'Var', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('EC109', 'CellLine', 'CVCL:6898', (112, 117))	('inhibiting', 'NegReg', (80, 90))	('proliferation', 'CPA', (95, 108))	('tumor', 'Disease', (60, 65))	('enhances', 'PosReg', (128, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))
872928	32012470	MiR-153-3p inhibits cell proliferation and reverses cisplatin resistance probably by downregulating Nrf-2 expression in Eca-109 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('downregulating', 'NegReg', (85, 99))	('cell proliferation', 'CPA', (20, 38))	('Nrf-2', 'Gene', '4780', (100, 105))	('expression', 'MPA', (106, 116))	('inhibits', 'NegReg', (11, 19))	('cisplatin resistance', 'MPA', (52, 72))	('MiR-153-3p', 'Chemical', '-', (0, 10))	('reverses', 'NegReg', (43, 51))	('Nrf-2', 'Gene', (100, 105))	('MiR-153-3p', 'Var', (0, 10))
872952	30305083	Poor scores in QoL assessed at 6 months after esophageal cancer surgery were associated with an increased risk of death.	('QoL', 'Gene', (15, 18))	('Poor scores', 'Var', (0, 11))	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('death', 'Disease', 'MESH:D003643', (114, 119))	('death', 'Disease', (114, 119))	('associated', 'Reg', (77, 87))
873098	26886613	The PER score was identified as an independent predictor of tumor recurrence (hazard ratio [HR] 2.1; P < 0.001) and OS (HR 2.2; P < 0.001).	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('PER score', 'Var', (4, 13))	('OS', 'Chemical', '-', (116, 118))	('tumor', 'Disease', (60, 65))
873326	26101523	Leakage may result in spill of gastrointestinal contents, followed by the development of fistula, wound infection, abscess, mediastinitis, empyema, and sepsis.	('sepsis', 'Disease', 'MESH:D018805', (152, 158))	('abscess', 'Disease', (115, 122))	('abscess', 'Phenotype', 'HP:0025615', (115, 122))	('empyema', 'Disease', 'MESH:D004653', (139, 146))	('empyema', 'Disease', (139, 146))	('result in', 'Reg', (12, 21))	('fistula', 'Disease', 'MESH:D005402', (89, 96))	('infection', 'Disease', (104, 113))	('sepsis', 'Phenotype', 'HP:0100806', (152, 158))	('mediastinitis', 'Disease', 'MESH:D008480', (124, 137))	('gastrointestinal contents', 'MPA', (31, 56))	('Leakage', 'Var', (0, 7))	('infection', 'Disease', 'MESH:D007239', (104, 113))	('mediastinitis', 'Disease', (124, 137))	('spill', 'Disease', (22, 27))	('sepsis', 'Disease', (152, 158))	('fistula', 'Disease', (89, 96))
873348	25691934	Rate of transfection in KYSE30 was also between 40 to 50%, using the pSilencer-Brg1shRNA (1:1 ratio).	('transfection', 'Var', (8, 20))	('Brg1', 'Gene', '6597', (79, 83))	('Brg1', 'Gene', (79, 83))
873358	25691934	It has been shown that genetic and epigenetic alterations, which are regulated via the chromatin remodeling enzymes are common feature of tumors with advanced stages.	('genetic', 'Var', (23, 30))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('epigenetic alterations', 'Var', (35, 57))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
873362	25691934	Therefore, Brg1 aberrant expression in advanced stages of tumor may has an important role in progression and metastasis.	('Brg1', 'Gene', '6597', (11, 15))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('metastasis', 'CPA', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Brg1', 'Gene', (11, 15))	('progression', 'CPA', (93, 104))	('aberrant expression', 'Var', (16, 35))
873389	25691934	Level of Brg1 mRNA expression in KYSE30 was compared with normal esophageal tissue of patients with ESCC.	('patients', 'Species', '9606', (86, 94))	('Brg1', 'Gene', '6597', (9, 13))	('Brg1', 'Gene', (9, 13))	('KYSE30', 'Var', (33, 39))
873396	25691934	In advanced stages of tumor, aberration of epigenetic and chromatin remodeling enzymes is an important cause in deregulation of downstream genes that are responsible for the overexpression of MMP enzymes, which leads to the tumor migration, invasion, and metastasis.	('metastasis', 'CPA', (255, 265))	('MMP', 'Gene', (192, 195))	('MMP', 'Gene', '4313;4318', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('deregulation', 'MPA', (112, 124))	('cause', 'Reg', (103, 108))	('tumor', 'Disease', (22, 27))	('aberration', 'Var', (29, 39))	('invasion', 'CPA', (241, 249))	('leads to', 'Reg', (211, 219))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
873404	25691934	Therefore, modulation of MMPs expression with Brg1 is associated with invasion and metastasis in some of cancers such as melanoma and glioma.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('melanoma', 'Disease', (121, 129))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('modulation', 'Var', (11, 21))	('Brg1', 'Gene', (46, 50))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('expression', 'Protein', (30, 40))	('glioma', 'Disease', (134, 140))	('associated with', 'Reg', (54, 69))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('metastasis', 'CPA', (83, 93))	('Brg1', 'Gene', '6597', (46, 50))	('MMPs', 'Gene', (25, 29))	('MMPs', 'Gene', '4313;4318', (25, 29))	('invasion', 'CPA', (70, 78))
873410	25691934	For further evaluation of Brg1 in ESCC, we knockdown expression of Brg1 mRNA to shed the light on its function in biology of ESCC.	('Brg1', 'Gene', (67, 71))	('knockdown', 'Var', (43, 52))	('Brg1', 'Gene', '6597', (67, 71))	('Brg1', 'Gene', (26, 30))	('Brg1', 'Gene', '6597', (26, 30))
873411	25691934	Therefore, Brg1 overexpression in KYSE30 can be a common reason for overexpression of MMPs genes during the ESCC metastasis and it can be introduced as a novel target for the therapeutic approaches.	('Brg1', 'Gene', '6597', (11, 15))	('overexpression', 'PosReg', (16, 30))	('KYSE30', 'Var', (34, 40))	('overexpression', 'PosReg', (68, 82))	('MMPs', 'Gene', '4313;4318', (86, 90))	('Brg1', 'Gene', (11, 15))	('MMPs', 'Gene', (86, 90))
873431	23724052	The aberrant miRNA expression has been highlighted in the initiation and progression of several cancers including UGCs.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('aberrant', 'Var', (4, 12))	('UGCs', 'Disease', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
873478	23724052	A considerable body of evidence highlights the aberrant miRNA expression as a key player in the development and progression of gastrointestinal cancers.	('aberrant', 'Var', (47, 55))	('gastrointestinal cancers', 'Disease', (127, 151))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (127, 151))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
873566	31748640	Radiation-induced gastrointestinal toxicity was more pronounced and mouse survival (7 days vs. 15 days, p = 0.0001) was inferior in the ultra-high dose rate arm compared to conventional dose rate arm.	('mouse', 'Species', '10090', (68, 73))	('gastrointestinal toxicity', 'Disease', (18, 43))	('ultra-high dose', 'Var', (136, 151))	('inferior', 'NegReg', (120, 128))	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (18, 43))	('mouse survival', 'CPA', (68, 82))
873591	31748640	On day 24 post-irradiation, CD3 cell counts recovered to 50% of baseline levels with ultra-high dose rate RT compared to 100% recovery for conventional dose rate RT.	('CD3', 'Gene', (28, 31))	('CD3', 'Gene', '12501', (28, 31))	('ultra-high dose rate', 'Var', (85, 105))	('recovered', 'PosReg', (44, 53))
873596	31748640	As with cardiac irradiation, ultra-high dose rate RT depleted circulating CD3, CD4, CD8, and CD19 cells to a similar extent as conventional dose rate RT, as shown in Fig.	('depleted', 'NegReg', (53, 61))	('CD19', 'Gene', (93, 97))	('CD3', 'Gene', '12501', (74, 77))	('CD19', 'Gene', '12478', (93, 97))	('CD4', 'Gene', (79, 82))	('CD4', 'Gene', '12504', (79, 82))	('ultra-high dose rate', 'Var', (29, 49))	('CD3', 'Gene', (74, 77))
873690	31583026	It is now generally accepted that Gas6 activates Axl, Tyro3, and MERTK and that protein S activates MERTK and Tyro3.	('Gas6', 'Var', (34, 38))	('MERTK', 'CPA', (65, 70))	('Tyro3', 'Gene', (54, 59))	('Tyro3', 'Gene', '7301', (110, 115))	('activates', 'PosReg', (39, 48))	('Tyro3', 'Gene', '7301', (54, 59))	('Axl', 'MPA', (49, 52))	('Tyro3', 'Gene', (110, 115))
873700	31583026	Specifically regarding the area of coagulation, Gas6 seems to stimulate hemostasis playing a complementary role in platelet function, and it has been proposed as a biomarker for the diagnosis of pulmonary embolism.	('Gas6', 'Var', (48, 52))	('pulmonary embolism', 'Disease', (195, 213))	('pulmonary embolism', 'Disease', 'MESH:D011655', (195, 213))	('stimulate', 'PosReg', (62, 71))	('hemostasis', 'MPA', (72, 82))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (195, 213))
873707	31583026	On the contrary, defects in TAM signaling have been associated with numerous autoimmune diseases and degenerative diseases, since an impaired clearance of apoptotic bodies and an inappropriate inflammatory response are considered critical for the deranged immune response observed in these conditions.	('degenerative diseases', 'Disease', (101, 122))	('deranged immune response', 'Phenotype', 'HP:0002958', (247, 271))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (77, 96))	('associated', 'Reg', (52, 62))	('degenerative diseases', 'Disease', 'MESH:D019636', (101, 122))	('clearance of apoptotic bodies', 'MPA', (142, 171))	('impaired', 'NegReg', (133, 141))	('autoimmune diseases', 'Disease', 'MESH:D001327', (77, 96))	('defects', 'Var', (17, 24))	('autoimmune diseases', 'Disease', (77, 96))
873714	31583026	In this context, Gas6 exerts an antiapoptotic effect on both HSCs and HSCs/MFBs, acting as a survival factor, probably supporting transient HSC/MFB accumulation during liver healing.	('HSC', 'Gene', '2523', (70, 73))	('MFB', 'Chemical', 'MESH:C032355', (144, 147))	('HSC', 'Gene', (61, 64))	('HSC', 'Gene', '2523', (61, 64))	('HSC', 'Gene', (140, 143))	('MFB', 'Chemical', 'MESH:C032355', (75, 78))	('HSC', 'Gene', '2523', (140, 143))	('antiapoptotic effect', 'MPA', (32, 52))	('Gas6', 'Var', (17, 21))	('HSC', 'Gene', (70, 73))
873718	31583026	So Gas6 deficiency, by limiting cytokine/chemokine release, prevents hepatocyte proliferation, macrophage infiltration in liver necrotic areas (which, in turn, is mediated by a direct chemotactic effect of Gas6), and accumulation of myofibroblasts in healing areas.	('liver necrotic areas', 'Disease', (122, 142))	('cytokine/chemokine release', 'MPA', (32, 58))	('prevents', 'NegReg', (60, 68))	('accumulation', 'PosReg', (217, 229))	('liver necrotic areas', 'Disease', 'MESH:D008113', (122, 142))	('deficiency', 'Var', (8, 18))	('hepatocyte proliferation', 'CPA', (69, 93))	('macrophage infiltration', 'CPA', (95, 118))	('Gas6', 'Gene', (3, 7))
873722	31583026	I/R induced early hepatic AKT phosphorylation in wild-type but not in Gas6-/- mice, whereas hepatic IL-1beta and TNF mRNA levels (e.g., lipopolysaccharide- (LPS-) induced cytokines) were higher in Gas6-/- mice compared to wild-type mice.	('mice', 'Species', '10090', (232, 236))	('hepatic AKT phosphorylation', 'MPA', (18, 45))	('IL-1beta', 'Gene', '16176', (100, 108))	('TNF', 'Gene', '21926', (113, 116))	('lipopolysaccharide-', 'MPA', (136, 155))	('Gas6-/-', 'Var', (197, 204))	('IL-1beta', 'Gene', (100, 108))	('TNF', 'Gene', (113, 116))	('mice', 'Species', '10090', (205, 209))	('hepatic', 'MPA', (92, 99))	('mice', 'Species', '10090', (78, 82))	('higher', 'PosReg', (187, 193))	('PS', 'Chemical', 'MESH:D010718', (158, 160))
873723	31583026	In line with the in vivo data, in vitro studies indicated that Gas6 induced AKT phosphorylation in primary mouse hepatocytes protecting them from hypoxia-induced cell death, while Gas6 diminished IL-1beta and TNF in murine macrophages.	('AKT', 'Pathway', (76, 79))	('hypoxia', 'Disease', 'MESH:D000860', (146, 153))	('murine', 'Species', '10090', (216, 222))	('Gas6', 'Var', (63, 67))	('IL-1beta', 'Gene', '16176', (196, 204))	('mouse', 'Species', '10090', (107, 112))	('TNF', 'Gene', '21926', (209, 212))	('Gas6', 'Var', (180, 184))	('diminished', 'NegReg', (185, 195))	('IL-1beta', 'Gene', (196, 204))	('TNF', 'Gene', (209, 212))	('hypoxia', 'Disease', (146, 153))
873743	31583026	According to the two-hit model of NAFLD, steatosis is the first hit that increases hepatocyte vulnerability to any secondary insult eliciting an inflammatory response, but most probably, both events are tightly interconnected since fat accumulation per se induces oxidative injury and inflammatory cytokine synthesis.	('inflammatory cytokine synthesis', 'MPA', (285, 316))	('oxidative injury', 'Disease', 'MESH:D028361', (264, 280))	('increases', 'PosReg', (73, 82))	('steatosis', 'Phenotype', 'HP:0001397', (41, 50))	('steatosis', 'Disease', (41, 50))	('NAFLD', 'Disease', (34, 39))	('steatosis', 'Disease', 'MESH:D005234', (41, 50))	('fat', 'Var', (232, 235))	('NAFLD', 'Disease', 'MESH:D065626', (34, 39))	('oxidative injury', 'Disease', (264, 280))	('hepatocyte vulnerability', 'MPA', (83, 107))	('induces', 'Reg', (256, 263))
873745	31583026	To address the role of Gas6 in NAFLD and in the progression to liver fibrosis, an animal model was studied, e.g., Gas6 KO mice fed with a choline-deficient ethionine-supplemented diet (CDE) or receiving a CCl4 treatment.	('mice', 'Species', '10090', (122, 126))	('ethionine', 'Chemical', 'MESH:D005001', (156, 165))	('liver fibrosis', 'Disease', 'MESH:D008103', (63, 77))	('choline', 'Chemical', 'MESH:D002794', (138, 145))	('NAFLD', 'Disease', (31, 36))	('Gas6', 'Var', (114, 118))	('liver fibrosis', 'Phenotype', 'HP:0001395', (63, 77))	('deficient ethionine', 'Phenotype', 'HP:0003658', (146, 165))	('liver fibrosis', 'Disease', (63, 77))	('NAFLD', 'Disease', 'MESH:D065626', (31, 36))
873748	31583026	Gas6 deficiency moreover reduced CDE-induced fibrogenesis and hepatic myofibroblast activation, decreased expression of TGF-beta and collagen type 1 mRNAs, and increased Axl protein levels.	('TGF-beta', 'Gene', (120, 128))	('reduced', 'NegReg', (25, 32))	('deficiency', 'Var', (5, 15))	('decreased', 'NegReg', (96, 105))	('increased', 'PosReg', (160, 169))	('collagen type 1 mRNAs', 'MPA', (133, 154))	('expression', 'MPA', (106, 116))	('hepatic myofibroblast activation', 'CPA', (62, 94))	('CDE-induced', 'Disease', (33, 44))	('TGF-beta', 'Gene', '7040', (120, 128))	('Axl protein levels', 'MPA', (170, 188))	('Gas6', 'Gene', (0, 4))
873763	31583026	While Gas6 reduced LPS-induced gene expression, Axl inhibition did not affect it.	('Gas6', 'Var', (6, 10))	('PS', 'Chemical', 'MESH:D010718', (20, 22))	('reduced', 'NegReg', (11, 18))	('LPS-induced gene', 'Gene', (19, 35))
873766	31583026	Taken together, these data seem to suggest that sAxl levels are an early marker of NASH that correlates with disease development and, at least in experimental NASH models, that therapeutic inhibition of Axl can diminish liver fibrosis by blocking HSC activation and reducing hepatic inflammation, possibly due to Gas6 hepatoprotective action.	('NASH', 'Disease', 'MESH:D065626', (83, 87))	('diminish', 'NegReg', (211, 219))	('Axl', 'Protein', (203, 206))	('hepatic inflammation', 'Disease', (275, 295))	('liver fibrosis', 'Disease', 'MESH:D008103', (220, 234))	('hepatic inflammation', 'Disease', 'MESH:D007249', (275, 295))	('NASH', 'Disease', (83, 87))	('activation', 'MPA', (251, 261))	('blocking', 'NegReg', (238, 246))	('NASH', 'Disease', 'MESH:D065626', (159, 163))	('HSC', 'Gene', (247, 250))	('liver fibrosis', 'Phenotype', 'HP:0001395', (220, 234))	('diminish liver fibrosis', 'Phenotype', 'HP:0001410', (211, 234))	('HSC', 'Gene', '2523', (247, 250))	('reducing', 'NegReg', (266, 274))	('NASH', 'Disease', (159, 163))	('inhibition', 'Var', (189, 199))	('hepatic inflammation', 'Phenotype', 'HP:0012115', (275, 295))	('liver fibrosis', 'Disease', (220, 234))
873768	31583026	Therefore, MERTK and its variants could act as central players in the control of apoptosis, immune response, HSC activation, and steatosis modulation, e.g., all factors involved in the pathogenesis of NAFLD and its fibrotic progression to steatohepatitis and cirrhosis.	('variants', 'Var', (25, 33))	('NAFLD', 'Disease', 'MESH:D065626', (201, 206))	('HSC', 'Gene', (109, 112))	('HSC', 'Gene', '2523', (109, 112))	('hepatitis', 'Phenotype', 'HP:0012115', (245, 254))	('steatohepatitis and cirrhosis', 'Disease', 'MESH:D005234', (239, 268))	('steatosis', 'Phenotype', 'HP:0001397', (129, 138))	('steatosis', 'Disease', 'MESH:D005234', (129, 138))	('cirrhosis', 'Phenotype', 'HP:0001394', (259, 268))	('steatosis', 'Disease', (129, 138))	('NAFLD', 'Disease', (201, 206))
873769	31583026	Based on a genome-wide study in patients with CHC which, amongst several susceptibility loci for severity and progression of liver fibrosis, identified as the strongest one the homozygosity for rs4374383 G>A single nucleotide polymorphism, a non-coding variant in the MERTK gene, an in vivo and in vitro study was conducted on NAFLD.	('MERTK', 'Gene', (268, 273))	('NAFLD', 'Disease', 'MESH:D065626', (327, 332))	('liver fibrosis', 'Disease', 'MESH:D008103', (125, 139))	('patients', 'Species', '9606', (32, 40))	('CHC', 'Disease', 'MESH:D019698', (46, 49))	('rs4374383 G>A', 'Var', (194, 207))	('rs4374383', 'Mutation', 'rs4374383', (194, 203))	('CHC', 'Disease', (46, 49))	('liver fibrosis', 'Phenotype', 'HP:0001395', (125, 139))	('NAFLD', 'Disease', (327, 332))	('liver fibrosis', 'Disease', (125, 139))
873774	31583026	MERTK was overexpressed in the liver of NAFLD patients with F2-F4 fibrosis, mainly in HSCs and macrophages (but not in hepatocytes).	('NAFLD', 'Disease', (40, 45))	('overexpressed', 'PosReg', (10, 23))	('patients', 'Species', '9606', (46, 54))	('NAFLD', 'Disease', 'MESH:D065626', (40, 45))	('HSC', 'Gene', (86, 89))	('fibrosis', 'Disease', (66, 74))	('fibrosis', 'Disease', 'MESH:D005355', (66, 74))	('MERTK', 'Gene', (0, 5))	('HSC', 'Gene', '2523', (86, 89))	('F2-F4', 'Var', (60, 65))
873791	31583026	More in detail, a genetic predisposition with regard to an accelerated fibrosis (demonstrated by liver histology and/or transient elastography) has been reported for what concerns the aforementioned rs4374383 G>A single nucleotide polymorphism.	('rs4374383 G>A single nucleotide polymorphism', 'Var', (199, 243))	('rs4374383', 'Mutation', 'rs4374383', (199, 208))	('fibrosis', 'Disease', 'MESH:D005355', (71, 79))	('fibrosis', 'Disease', (71, 79))
873792	31583026	As shown in other diseases, it is likely that patients carrying the GG/GA genotypes have a significantly higher hepatic MERTK expression, although the underlying mechanism is unknown.	('higher', 'PosReg', (105, 111))	('hepatic MERTK expression', 'MPA', (112, 136))	('patients', 'Species', '9606', (46, 54))	('GG/GA', 'Var', (68, 73))
873793	31583026	It has to be noted that, although the rs4374383 SNP is not located in a regulatory MERTK region, a high number of SNPs are in high linkage disequilibrium (LD) with it.	('linkage', 'Interaction', (131, 138))	('rs4374383', 'Var', (38, 47))	('rs4374383', 'Mutation', 'rs4374383', (38, 47))
873794	31583026	This issue was investigated by Cavalli et al., who suggested that rs6726639A allele, in high LD with rs4374383 (r2 = 0.94), could promote the binding of interferon regulatory factor 1 (IRF1) to this region and serve to activate or repress the expression of a high number of genes involved in the immune response.	('promote', 'PosReg', (130, 137))	('rs4374383', 'Var', (101, 110))	('expression', 'MPA', (243, 253))	('interferon regulatory factor 1', 'Gene', '3659', (153, 183))	('activate', 'PosReg', (219, 227))	('rs6726639', 'Mutation', 'rs6726639', (66, 75))	('IRF1', 'Gene', '3659', (185, 189))	('IRF1', 'Gene', (185, 189))	('binding', 'Interaction', (142, 149))	('rs6726639A', 'Var', (66, 76))	('repress', 'NegReg', (231, 238))	('interferon regulatory factor 1', 'Gene', (153, 183))	('rs4374383', 'Mutation', 'rs4374383', (101, 110))
873796	31583026	So, in genetic association studies, the two SNPs (rs4374383 and rs6726639) may be interchangeable for predicting liver fibrosis progression.	('rs4374383', 'Mutation', 'rs4374383', (50, 59))	('liver fibrosis', 'Disease', (113, 127))	('rs4374383', 'Var', (50, 59))	('liver fibrosis', 'Phenotype', 'HP:0001395', (113, 127))	('rs6726639', 'Var', (64, 73))	('liver fibrosis', 'Disease', 'MESH:D008103', (113, 127))	('rs6726639', 'Mutation', 'rs6726639', (64, 73))
873810	31583026	The pathophysiological rationale of Gas6/Axl deleterious role probably consists in its capacity to activate HSCs and modulate hepatocyte differentiation, as suggested by a preliminary study which demonstrated that in HCC cancer cell lines Gas6/Axl can enhance cell invasiveness through transcriptional activation of Slug which induces epithelial to mesenchymal transition (EMT).	('modulate', 'Reg', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('enhance', 'PosReg', (252, 259))	('HSC', 'Gene', (108, 111))	('HSC', 'Gene', '2523', (108, 111))	('HCC', 'Disease', 'MESH:D006528', (217, 220))	('Slug', 'Gene', (316, 320))	('activation', 'PosReg', (302, 312))	('cancer', 'Disease', (221, 227))	('activate', 'PosReg', (99, 107))	('Gas6/Axl', 'Var', (239, 247))	('transcriptional', 'Var', (286, 301))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cell invasiveness', 'CPA', (260, 277))	('Slug', 'Gene', '6591', (316, 320))	('epithelial to mesenchymal transition', 'CPA', (335, 371))	('HCC', 'Disease', (217, 220))	('induces', 'Reg', (327, 334))	('HCC', 'Phenotype', 'HP:0001402', (217, 220))
873833	31583026	In the same study, neoplastic patients, compared with controls, had also a significant increase in MERTK-expressing circulating monocytes (and in Gas6, as previously mentioned).	('Gas6', 'MPA', (146, 150))	('patients', 'Species', '9606', (30, 38))	('neoplastic', 'Var', (19, 29))	('increase', 'PosReg', (87, 95))
873834	31583026	Inhibition of MERTK signaling restored their proinflammatory capabilities, thereby identifying a possible novel immunotherapeutic target in HCC.	('restored', 'PosReg', (30, 38))	('proinflammatory capabilities', 'MPA', (45, 73))	('HCC', 'Disease', 'MESH:D006528', (140, 143))	('Inhibition', 'Var', (0, 10))	('HCC', 'Disease', (140, 143))	('HCC', 'Phenotype', 'HP:0001402', (140, 143))
873838	31583026	group that proposed there might be a switch predisposing liver fibrosis, cirrhosis, or even HCC development, where even in the event of a cleavage of Axl, the inhibitory Axl shedding mechanism is circumvented due to the presence of abundant nonshedded Axl receptors that will overcome the loss of proteolytically cleaved Axl.	('Axl receptors', 'Protein', (252, 265))	('liver fibrosis', 'Disease', (57, 71))	('cirrhosis', 'Disease', (73, 82))	('cleavage', 'Var', (138, 146))	('HCC', 'Disease', 'MESH:D006528', (92, 95))	('liver fibrosis', 'Disease', 'MESH:D008103', (57, 71))	('HCC', 'Disease', (92, 95))	('liver fibrosis', 'Phenotype', 'HP:0001395', (57, 71))	('cirrhosis', 'Phenotype', 'HP:0001394', (73, 82))	('HCC', 'Phenotype', 'HP:0001402', (92, 95))	('cirrhosis', 'Disease', 'MESH:D005355', (73, 82))
873864	31583026	For example, future research should verify if MERTK inhibition or MERTK KO mice display reduced fibrosis, as already observed in Axl KO mice or after pharmacological Axl inhibition.	('mice', 'Species', '10090', (136, 140))	('mice', 'Species', '10090', (75, 79))	('MERTK', 'Gene', (46, 51))	('fibrosis', 'Disease', 'MESH:D005355', (96, 104))	('fibrosis', 'Disease', (96, 104))	('MERTK KO', 'Var', (66, 74))	('reduced', 'NegReg', (88, 95))
873869	30047470	The combination of the DTX-DCM and AZD8186-DCM showed a highly efficacious and synergistic anti-tumor effect and decreased hematotoxicity.	('AZD8186-DCM', 'Var', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('decreased hematotoxicity', 'Disease', (113, 137))	('decreased hematotoxicity', 'Disease', 'MESH:D012021', (113, 137))	('DTX', 'Chemical', 'MESH:C067311', (23, 26))
873870	30047470	A pro-apoptotic protein, Bax was significantly upregulated in ESCC cells treated with combination therapy compared to that with monotherapy.	('combination therapy', 'Var', (86, 105))	('Bax', 'Gene', '581', (25, 28))	('ESCC', 'Disease', 'MESH:C562729', (62, 66))	('upregulated', 'PosReg', (47, 58))	('Bax', 'Gene', (25, 28))	('ESCC', 'Disease', (62, 66))
873877	30047470	Dysregulation of PI3K has been identified in several solid tumors, such as breast cancer, prostate cancer, including esophageal cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('esophageal cancer', 'Disease', (117, 134))	('Dysregulation', 'Var', (0, 13))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('PI3', 'Gene', '5266', (17, 20))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('prostate cancer', 'Disease', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PI3', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('identified', 'Reg', (31, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('breast cancer', 'Disease', (75, 88))	('tumors', 'Disease', (59, 65))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
873880	30047470	AZD8186, a novel small-molecule inhibitor of PI3Kbeta and PI3Kdelta inhibits the growth of tumor cells, regulating signaling through the PI3K/AKT signaling pathway.	('PI3Kbeta', 'Gene', (45, 53))	('PI3', 'Gene', '5266', (137, 140))	('AKT', 'Gene', (142, 145))	('PI3Kdelta', 'Gene', '5293', (58, 67))	('PI3', 'Gene', (58, 61))	('tumor', 'Disease', (91, 96))	('PI3Kbeta', 'Gene', '5291', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('PI3', 'Gene', (137, 140))	('AKT', 'Gene', '207', (142, 145))	('inhibits', 'NegReg', (68, 76))	('AZD8186', 'Var', (0, 7))	('PI3Kdelta', 'Gene', (58, 67))	('PI3', 'Gene', '5266', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('PI3', 'Gene', '5266', (58, 61))	('signaling', 'MPA', (115, 124))	('regulating', 'Reg', (104, 114))	('PI3', 'Gene', (45, 48))
873889	30047470	Our study firstly demonstrated the synergistic effects in vitro and in vivo of AZD8186 and DTX within nano-formulations against ESCC and greatly reduced hematotoxicity.	('reduced hematotoxicity', 'Disease', 'MESH:D006987', (145, 167))	('AZD8186', 'Var', (79, 86))	('ESCC', 'Disease', 'MESH:C562729', (128, 132))	('reduced hematotoxicity', 'Disease', (145, 167))	('ESCC', 'Disease', (128, 132))	('DTX', 'Chemical', 'MESH:C067311', (91, 94))
873913	30047470	For cell uptake study, KYSE70 cells were seeded in eight-well tissue culture chamber slides (BD Biosciences, Bedford, MA, USA) and were incubated with 50 mug/ml DID, DID-DCMs, DID-AZD8186-DCMs or DID-DTX-DCMs for 4 hours.	('BD Biosciences', 'Disease', (93, 107))	('DID-DCMs', 'Var', (166, 174))	('DID-DTX-DCMs', 'Var', (196, 208))	('DID-AZD8186-DCMs', 'Var', (176, 192))	('DTX', 'Chemical', 'MESH:C067311', (200, 203))	('BD Biosciences', 'Disease', 'MESH:D001528', (93, 107))
873914	30047470	Annexin V and propidium iodide (PI) double staining (Pharmingen, San Diego, CA, USA) were used to evaluate the KYSE70 cell apoptosis treated with free DTX, AZD8186, DTX-DCMs, and AZD8186-DCMs.	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('DTX', 'Chemical', 'MESH:C067311', (151, 154))	('DTX', 'Chemical', 'MESH:C067311', (165, 168))	('AZD8186-DCMs', 'Var', (179, 191))	('AZD8186', 'Var', (156, 163))	('propidium iodide', 'Chemical', 'MESH:D011419', (14, 30))	('DTX-DCMs', 'Var', (165, 173))
873915	30047470	Cells were treated with various concentrations (3mug/ml, 30mug/ml) of free DTX, free AZD8186, DTX-DCMs, and AZD8186-DCMs for 24h respectively.	('AZD8186', 'Var', (85, 92))	('AZD8186-DCMs', 'Var', (108, 120))	('DTX', 'Chemical', 'MESH:C067311', (75, 78))	('DTX', 'Chemical', 'MESH:C067311', (94, 97))
873922	30047470	Xenograft model was established by injecting 7x106 KYSE70 esophageal cancer cells in a 100muL of a mixture of PBS and Matrigel (1:1 v/v) subcutaneously into the left flank of nude mice (Harland).	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('7x106 KYSE70', 'Var', (45, 57))	('nude mice', 'Species', '10090', (175, 184))
873924	30047470	At different time points post-injection of DiD-AZD8186- DCMs (DiD 50 mg/kg; AZD8186 10 mg/kg), The mice were then scanned with Kodak multimodal imaging system IS2000MM with an excitation bandpass filter at 625nm and an emission at 700nm.	('AZD8186', 'Var', (76, 83))	('DiD-AZD8186- DCMs', 'Var', (43, 60))	('mice', 'Species', '10090', (99, 103))
873946	30047470	The drug loading efficiency of AZD8186 and DTX was 85.2% and 82.4%, respectively, based the HPLC measurements.	('DTX', 'Chemical', 'MESH:C067311', (43, 46))	('AZD8186', 'Var', (31, 38))	('drug loading', 'MPA', (4, 16))
873950	30047470	Both free and DCM-AZD8186 effectively caused a dose-dependent loss in cell viability due to induction of cell apoptosis (including increases of early (Annexin+/PI-) and late (Annexin+/PI+) apoptosis) and G1 arrest (increased G1 % compared to control) (Fig 3 A,B,C & Fig S1).	('loss', 'NegReg', (62, 66))	('DCM-AZD8186', 'Var', (14, 25))	('cell apoptosis', 'CPA', (105, 119))	('increases', 'PosReg', (131, 140))	('cell viability', 'CPA', (70, 84))	('arrest', 'Disease', 'MESH:D006323', (207, 213))	('increased', 'PosReg', (215, 224))	('arrest', 'Disease', (207, 213))
873953	30047470	Combining with the finding in Fig 2B, these results indicated that AZD8186-DCMs and DTX-DCMs could be uptake by the cells and released to function as anti-cancer agents comparable with their free formulations.	('AZD8186-DCMs', 'Var', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (155, 161))	('DTX', 'Chemical', 'MESH:C067311', (84, 87))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
873958	30047470	We demonstrated that AZD8186-DCM and DTX-DCM showed a better synergistic effect at the 1:1 and 2:1 ratios.	('synergistic effect', 'MPA', (61, 79))	('AZD8186-DCM', 'Var', (21, 32))	('DTX', 'Chemical', 'MESH:C067311', (37, 40))
873959	30047470	Based on this study, the synergistic effects of AZD8186-DCMs and DTX-DCMs in esophageal cancers were demonstrated.	('esophageal cancers', 'Disease', (77, 95))	('esophageal cancers', 'Disease', 'MESH:D004938', (77, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('DTX', 'Chemical', 'MESH:C067311', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('AZD8186-DCMs', 'Var', (48, 60))
873966	30047470	All organs and tumors were harvested for ex vivo imaging which then showed that DiD-AZD8186-DCMs preferentially accumulated at the tumor sites.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('preferentially', 'PosReg', (97, 111))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', (131, 136))	('DiD-AZD8186-DCMs', 'Var', (80, 96))	('tumor', 'Disease', (15, 20))	('accumulated', 'PosReg', (112, 123))	('tumors', 'Disease', (15, 21))
873968	30047470	For the in vivo antitumor efficacy studies, KYSE70 xenograft-bearing nude mice were treated with PBS, free AZD8186, AZD8186-DCMs, free DTX, DTX-DCMs, or AZD8186-DCMs + DTX-DCMs.	('AZD8186-DCMs', 'Var', (153, 165))	('DTX', 'Chemical', 'MESH:C067311', (140, 143))	('DTX', 'Chemical', 'MESH:C067311', (168, 171))	('AZD8186-DCMs', 'Var', (116, 128))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('AZD8186', 'Var', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('DTX', 'Chemical', 'MESH:C067311', (135, 138))	('nude mice', 'Species', '10090', (69, 78))	('tumor', 'Disease', (20, 25))
873970	30047470	Compared to PBS control, free DTX and AZD8186 displayed mild inhibition effects on tumor growth, while AZD8186-DCMs and DTX-DCMs showed moderate inhibition effects (Fig 5B&C).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('DTX', 'Chemical', 'MESH:C067311', (120, 123))	('tumor', 'Disease', (83, 88))	('inhibition', 'NegReg', (61, 71))	('AZD8186-DCMs', 'Var', (103, 115))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('DTX', 'Chemical', 'MESH:C067311', (30, 33))
873972	30047470	Moreover, the combination of AZD8186-DCMs and DTX-DCMs demonstrated the most potency in inhibition of ESCC tumor growth than mono-therapy in both formulations (Fig 5B and C).	('AZD8186-DCMs', 'Var', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('inhibition', 'NegReg', (88, 98))	('ESCC', 'Disease', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('DTX', 'Chemical', 'MESH:C067311', (46, 49))	('ESCC', 'Disease', 'MESH:C562729', (102, 106))
873973	30047470	Collectively, this study demonstrated that AZD8186 in combination with docetaxel may result in tumor regression or stasis in esophageal cancer.	('docetaxel', 'Chemical', 'MESH:C067311', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('AZD8186', 'Var', (43, 50))	('esophageal cancer', 'Disease', (125, 142))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('stasis', 'CPA', (115, 121))	('tumor', 'Disease', (95, 100))
873979	30047470	This result strongly suggested that DCM could significantly decrease bone marrow suppression (inhibition of both RBC and WBC) induced by DTX.	('decrease', 'NegReg', (60, 68))	('inhibition', 'NegReg', (94, 104))	('DTX', 'Chemical', 'MESH:C067311', (137, 140))	('RBC', 'CPA', (113, 116))	('DCM', 'Var', (36, 39))	('bone marrow suppression', 'Disease', (69, 92))	('bone marrow suppression', 'Disease', 'MESH:D001855', (69, 92))	('decrease bone marrow', 'Phenotype', 'HP:0005528', (60, 80))
873982	30047470	We further elucidated the molecular mechanism for the synergistic anti-tumor efficacy of DTX-DCM and AZD8186-DCM in ESCC cells.	('DTX', 'Chemical', 'MESH:C067311', (89, 92))	('AZD8186-DCM', 'Var', (101, 112))	('ESCC', 'Disease', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('ESCC', 'Disease', 'MESH:C562729', (116, 120))
873983	30047470	AZD8186 is an isoform-specific small-molecule PI3K inhibitor and could block PI3K/Akt signaling pathway.	('AZD8186', 'Var', (0, 7))	('PI3', 'Gene', (46, 49))	('Akt', 'Gene', '207', (82, 85))	('PI3', 'Gene', (77, 80))	('Akt', 'Gene', (82, 85))	('block', 'NegReg', (71, 76))	('PI3', 'Gene', '5266', (46, 49))	('PI3', 'Gene', '5266', (77, 80))
873984	30047470	As expected, both free AZD8186 and AZD8186-DCM significantly diminished phosphorylation of both PI3K and Akt (p<0.05).	('AZD8186-DCM', 'Var', (35, 46))	('Akt', 'Gene', '207', (105, 108))	('diminished', 'NegReg', (61, 71))	('Akt', 'Gene', (105, 108))	('phosphorylation', 'MPA', (72, 87))	('PI3', 'Gene', '5266', (96, 99))	('AZD8186', 'Var', (23, 30))	('PI3', 'Gene', (96, 99))
873987	30047470	Upregulation of Bax and decrease of Bcl-2 expression, along with increase p53 resulted in cell apoptosis (Fig 3 and 6) upon AZD8186 and AZD8186-DCM treatments.	('Upregulation', 'PosReg', (0, 12))	('increase', 'PosReg', (65, 73))	('Bax', 'Gene', (16, 19))	('AZD8186', 'Var', (124, 131))	('expression', 'MPA', (42, 52))	('p53', 'Gene', (74, 77))	('AZD8186-DCM', 'Var', (136, 147))	('Bcl-2', 'Gene', (36, 41))	('decrease', 'NegReg', (24, 32))	('Bcl-2', 'Gene', '596', (36, 41))	('Bax', 'Gene', '581', (16, 19))	('p53', 'Gene', '7157', (74, 77))	('cell apoptosis', 'CPA', (90, 104))
873996	30047470	Our study successfully demonstrated the combination of AZD8186-DCM and DTX-DCM could synergistically eliminate ESCC in vitro and in vivo.	('AZD8186-DCM', 'Var', (55, 66))	('eliminate', 'NegReg', (101, 110))	('ESCC', 'Disease', 'MESH:C562729', (111, 115))	('DTX', 'Chemical', 'MESH:C067311', (71, 74))	('ESCC', 'Disease', (111, 115))
874000	30047470	Our study demonstrated that high expression of PI3K of the esophageal cancer cells might be associated with tumor progression, and high expression of PI3K predicted poorer survival of esophageal cancer patients (Fig 1).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('esophageal cancer', 'Disease', (59, 76))	('poorer', 'NegReg', (165, 171))	('PI3', 'Gene', '5266', (47, 50))	('PI3', 'Gene', '5266', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('PI3', 'Gene', (150, 153))	('tumor', 'Disease', (108, 113))	('esophageal cancer', 'Disease', (184, 201))	('survival', 'CPA', (172, 180))	('patients', 'Species', '9606', (202, 210))	('PI3', 'Gene', (47, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('associated', 'Reg', (92, 102))	('high', 'Var', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
874004	30047470	For example, UNBS5162, C-X-C motif chemokine ligand antagonist, was found to inhibited ESCC cell proliferation, invasion, and migration via the PI3K/Akt pathway.	('UNBS5162', 'Var', (13, 21))	('Akt', 'Gene', (149, 152))	('ESCC', 'Disease', 'MESH:C562729', (87, 91))	('inhibited', 'NegReg', (77, 86))	('invasion', 'CPA', (112, 120))	('PI3', 'Gene', '5266', (144, 147))	('ESCC', 'Disease', (87, 91))	('Akt', 'Gene', '207', (149, 152))	('UNBS5162', 'Chemical', 'MESH:C531082', (13, 21))	('PI3', 'Gene', (144, 147))	('migration', 'CPA', (126, 135))
874006	30047470	This is the first study showed the combination of AZD8186 and DTX could effectively control ESCC growth in a mouse xenograft model (Fig 5).	('control', 'PosReg', (84, 91))	('DTX', 'Chemical', 'MESH:C067311', (62, 65))	('ESCC', 'Disease', (92, 96))	('AZD8186', 'Var', (50, 57))	('ESCC', 'Disease', 'MESH:C562729', (92, 96))	('mouse', 'Species', '10090', (109, 114))
874008	30047470	Nevertheless, with the aid of targeted delivery technology, DCM formulated AZD8186 and DTX could significantly control the tumor growth, and this is presumably due to the effects of more drugs had been delivered to the cancer sites based on the biodistribution results (Fig 5A).	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('DTX', 'Chemical', 'MESH:C067311', (87, 90))	('AZD8186', 'Var', (75, 82))	('cancer', 'Disease', (219, 225))	('control', 'PosReg', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
874014	30047470	The mechanism of cell apoptosis induced by AZD8186 and DTX was widely studied, while DCM formulation did not alter their anti-cancer mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('DTX', 'Chemical', 'MESH:C067311', (55, 58))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('AZD8186', 'Var', (43, 50))
874015	30047470	Our findings are in concordance with other reports that AZD8186 inhibits PI3K-dependent activation of AKT and induces tumor suppressor gene p53 up-regulation in KYSE70 cells leading to tumor cell apoptosis (Fig 6).	('tumor', 'Disease', (185, 190))	('PI3', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('up-regulation', 'PosReg', (144, 157))	('induces', 'PosReg', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('AZD8186', 'Var', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', (118, 123))	('PI3', 'Gene', '5266', (73, 76))	('AKT', 'Gene', '207', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('inhibits', 'NegReg', (64, 72))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('AKT', 'Gene', (102, 105))
874017	30047470	The combination of AZD8186-DCMs and DTX-DCMs only significantly enhanced Bax expression comparing to monotherapy and was considered as one of the major mechanisms contributing to superior anti-cancer effects (Fig 6).	('Bax', 'Gene', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('AZD8186-DCMs', 'Var', (19, 31))	('cancer', 'Disease', (193, 199))	('Bax', 'Gene', '581', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('DTX', 'Chemical', 'MESH:C067311', (36, 39))	('superior', 'PosReg', (179, 187))	('enhanced', 'PosReg', (64, 72))
874036	30514256	When esophageal cancer occurs with funnel chest, the narrow working space in the mediastinum caused by funnel chest makes it difficult to perform intrathoracic surgery, which is necessary for treatment.	('funnel chest', 'Phenotype', 'HP:0000767', (35, 47))	('funnel chest', 'Phenotype', 'HP:0000767', (103, 115))	('esophageal cancer', 'Disease', (5, 22))	('funnel chest', 'Var', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (5, 22))
874122	29970894	The levels of cell surface marker proteins in the DPSC group were significantly higher than those in the other two groups (Fig.	('levels of cell surface marker proteins', 'MPA', (4, 42))	('DPSC', 'Var', (50, 54))	('higher', 'PosReg', (80, 86))	('DPSC', 'Chemical', '-', (50, 54))
874123	29970894	The MODs of the AOIs of four cell surface markers (CD71, CK14, integrin alpha6, and PCNA) in the DPSC group were significantly higher than those in the other two groups (Fig.	('CK14', 'Gene', '287701', (57, 61))	('PCNA', 'Gene', '25737', (84, 88))	('PCNA', 'Gene', (84, 88))	('CD71', 'Gene', (51, 55))	('DPSC', 'Chemical', '-', (97, 101))	('integrin alpha6', 'Gene', (63, 78))	('integrin alpha6', 'Gene', '114517', (63, 78))	('CK14', 'Gene', (57, 61))	('AOI', 'Disease', 'MESH:C535396', (16, 19))	('AOI', 'Disease', (16, 19))	('DPSC', 'Var', (97, 101))	('higher', 'PosReg', (127, 133))
874125	29970894	The mean epithelial thickness was significantly increased in the DPSC group (62.35 +- 1.99 mum) relative to the control group (27.11 +- 2.92 mum) and the sham-operated group (25.71 +- 1.90 mum; Fig.	('DPSC', 'Chemical', '-', (65, 69))	('epithelial thickness', 'CPA', (9, 29))	('increased', 'PosReg', (48, 57))	('rat', 'Species', '10116', (162, 165))	('DPSC', 'Var', (65, 69))
874126	29970894	The IL-1beta, IL-8, and TNF-alpha levels in the DPSC group were not significantly different from those in the sham-operated group (P > 0.05).	('DPSC', 'Chemical', '-', (48, 52))	('rat', 'Species', '10116', (118, 121))	('TNF-alpha', 'Gene', (24, 33))	('IL-1beta', 'Gene', (4, 12))	('DPSC', 'Var', (48, 52))	('IL-1beta', 'Gene', '24494', (4, 12))	('TNF-alpha', 'Gene', '24835', (24, 33))
874131	29970894	The recuperative extrema of food intake in the DPSC group was significantly higher than that in the control group (P < 0.0001; Fig.	('DPSC', 'Var', (47, 51))	('DPSC', 'Chemical', '-', (47, 51))	('higher', 'PosReg', (76, 82))	('rat', 'Species', '10116', (10, 13))	('extrema of food intake', 'Disease', 'MESH:D000080146', (17, 39))	('extrema of food intake', 'Disease', (17, 39))
874139	29970894	In the present study, most of the expanded DPSCs expressed CD90 and CD29, whereas few expressed CD45 and CD34.	('CD29', 'Var', (68, 72))	('CD90', 'Gene', (59, 63))	('CD45', 'Gene', '24699', (96, 100))	('CD34', 'Gene', (105, 109))	('DPSCs', 'Chemical', '-', (43, 48))	('CD34', 'Gene', '305081', (105, 109))	('CD90', 'Gene', '24832', (59, 63))	('CD45', 'Gene', (96, 100))
874151	29970894	In this model, which was induced by 125I seeds in vivo, the lumen of the esophagus was first irradiated, and the mucosa developed congestion, edema, inflammatory effusion, and exfoliation; meanwhile, inflammatory cytokines, including TNF-alpha, IL-1beta, and IL-8, were released.	('TNF-alpha', 'Gene', (234, 243))	('inflammatory effusion', 'Disease', 'MESH:D010996', (149, 170))	('edema', 'Disease', 'MESH:D004487', (142, 147))	('edema', 'Phenotype', 'HP:0000969', (142, 147))	('inflammatory effusion', 'Disease', (149, 170))	('IL-1beta', 'Gene', '24494', (245, 253))	('edema', 'Disease', (142, 147))	('TNF-alpha', 'Gene', '24835', (234, 243))	('exfoliation', 'CPA', (176, 187))	('IL-1beta', 'Gene', (245, 253))	('125I', 'Var', (36, 40))
874161	29970894	The food intake of the DPSC group was significantly increased compared with the control group beginning on the sixth day.	('DPSC', 'Var', (23, 27))	('DPSC', 'Chemical', '-', (23, 27))	('increased', 'PosReg', (52, 61))	('food intake', 'CPA', (4, 15))
874163	29970894	In addition, the degree of inflammation was significantly relieved in the DPSC group, as evidenced by the TNF-alpha, IL-1beta, and IL-8 levels.	('TNF-alpha', 'Gene', (106, 115))	('relieved', 'NegReg', (58, 66))	('IL-1beta', 'Gene', '24494', (117, 125))	('DPSC', 'Chemical', '-', (74, 78))	('TNF-alpha', 'Gene', '24835', (106, 115))	('inflammation', 'Disease', 'MESH:D007249', (27, 39))	('inflammation', 'Disease', (27, 39))	('IL-1beta', 'Gene', (117, 125))	('DPSC', 'Var', (74, 78))
874172	29970894	In the present study, the WB and immunohistochemical analyses revealed significantly higher expression levels of cell surface markers, including PCNA, CD71, integrin alpha6, and CK14, in the DPSC-treated group than those in the control and sham-operated groups.	('CK14', 'Gene', (178, 182))	('integrin alpha6', 'Gene', (157, 172))	('higher', 'PosReg', (85, 91))	('integrin alpha6', 'Gene', '114517', (157, 172))	('DPSC', 'Chemical', '-', (191, 195))	('DPSC-treated', 'Var', (191, 203))	('CK14', 'Gene', '287701', (178, 182))	('expression levels', 'MPA', (92, 109))	('rat', 'Species', '10116', (248, 251))	('PCNA', 'Gene', '25737', (145, 149))	('PCNA', 'Gene', (145, 149))	('CD71', 'Gene', (151, 155))
874180	29970894	Based on their regenerative performance, DPSCs heal tissue damage and improve the esophageal function following acute radioactive esophageal injury in rats.	('rats', 'Species', '10116', (151, 155))	('esophageal', 'MPA', (82, 92))	('improve', 'PosReg', (70, 77))	('rat', 'Species', '10116', (21, 24))	('esophageal injury', 'Disease', (130, 147))	('rat', 'Species', '10116', (151, 154))	('esophageal injury', 'Disease', 'MESH:D004941', (130, 147))	('DPSCs', 'Var', (41, 46))	('DPSCs', 'Chemical', '-', (41, 46))
874282	29868478	Treatment with HMGB1 inhibitors prolonged the survival of malignant mesothelioma xenograft mice.	('malignant mesothelioma', 'Disease', (58, 80))	('mice', 'Species', '10090', (91, 95))	('prolonged', 'PosReg', (32, 41))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (58, 80))	('inhibitors', 'Var', (21, 31))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (58, 80))	('survival', 'CPA', (46, 54))	('HMGB1', 'Gene', (15, 20))
874286	29868478	Aberrant expression of KRT7 in budding cancer cells represents a modification of the epithelial phenotype (epithelial-epithelial transition) which may be linked to gains in motility and invasive potential.	('KRT7', 'Gene', (23, 27))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('invasive potential', 'CPA', (186, 204))	('modification', 'Reg', (65, 77))	('expression', 'MPA', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('gains in motility', 'Disease', (164, 181))	('gains in motility', 'Disease', 'MESH:D015430', (164, 181))	('KRT7', 'Gene', '3855', (23, 27))
874295	29868478	PRMT1 is the main enzyme that mediates the methylation of histone H4, a specific tag for epigenetic transcriptional activation.	('methylation', 'Var', (43, 54))	('PRMT1', 'Gene', (0, 5))	('histone H4', 'Gene', (58, 68))	('histone H4', 'Gene', '8294', (58, 68))	('PRMT1', 'Gene', '3276', (0, 5))
874298	29868478	Knockdown of PRMT1 in three NSCLC cell lines was associated with a significant suppression of cell growth.	('suppression', 'NegReg', (79, 90))	('NSCLC', 'Disease', (28, 33))	('PRMT1', 'Gene', '3276', (13, 18))	('Knockdown', 'Var', (0, 9))	('PRMT1', 'Gene', (13, 18))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('cell growth', 'CPA', (94, 105))
874301	29868478	Significant correlation was found between high expression and S100P and shorter overall survival (OS) and increased drug resistance in gastric and ovarian cancer.	('drug resistance', 'CPA', (116, 131))	('drug resistance', 'Phenotype', 'HP:0020174', (116, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('S100P', 'Gene', (62, 67))	('shorter', 'NegReg', (72, 79))	('overall survival', 'MPA', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('high expression', 'Var', (42, 57))	('gastric and ovarian cancer', 'Disease', 'MESH:D013274', (135, 161))	('increased', 'PosReg', (106, 115))	('S100P', 'Gene', '6286', (62, 67))
874307	29868478	Knockdown of ANXA1 was found to block the intake of chemotherapy, leading to anticancer drug resistance.	('ANXA1', 'Gene', '301', (13, 18))	('drug resistance', 'Phenotype', 'HP:0020174', (88, 103))	('Knockdown', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('leading to', 'Reg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ANXA1', 'Gene', (13, 18))	('intake of chemotherapy', 'MPA', (42, 64))
874313	29868478	On the other hand, patients with high CRNN gene expression were more likely to achieve a pathologic complete response to neoadjuvant chemoradiotherapy.	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (19, 27))	('CRNN', 'Gene', (38, 42))	('CRNN', 'Gene', '49860', (38, 42))
874322	29868478	And on the other hand, a high S100A8 expression was found to be a favorable prognostic factor for the survival of oropharyngeal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('S100A8', 'Gene', (30, 36))	('squamous cell carcinoma', 'Disease', (128, 151))	('S100A8', 'Gene', '6279', (30, 36))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('high', 'Var', (25, 29))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (114, 151))	('expression', 'MPA', (37, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
874343	29868478	Inhibiting LGALS3BP could presumably stimulate the adaptive immune system against EAC tissue while also increasing sensitivity to cisplatin.	('stimulate', 'PosReg', (37, 46))	('LGALS3BP', 'Gene', '3959', (11, 19))	('adaptive immune system', 'CPA', (51, 73))	('Inhibiting', 'Var', (0, 10))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('sensitivity to cisplatin', 'MPA', (115, 139))	('LGALS3BP', 'Gene', (11, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('increasing', 'PosReg', (104, 114))
874369	29743817	Analysis of the role of rs2031920 and rs3813867 polymorphisms within the cytochrome P450 2E1 gene in the risk of squamous cell carcinoma To explore the genetic effect of rs2031920 and rs3813867 polymorphisms within the cytochrome P450 2E1 (CYP2E1) gene on the risk of squamous cell carcinoma (SCC), a meta-analysis was performed.	('rs3813867', 'Mutation', 'rs3813867', (38, 47))	('rs2031920', 'Mutation', 'rs2031920', (170, 179))	('squamous cell carcinoma', 'Disease', (268, 291))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 136))	('cytochrome P450 2E1', 'Gene', '1571', (219, 238))	('cytochrome P450 2E1', 'Gene', (219, 238))	('rs3813867', 'Var', (184, 193))	('SCC', 'Phenotype', 'HP:0002860', (293, 296))	('CYP2E1', 'Gene', '1571', (240, 246))	('squamous cell carcinoma', 'Disease', (113, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('rs2031920', 'Mutation', 'rs2031920', (24, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (268, 291))	('rs3813867', 'Mutation', 'rs3813867', (184, 193))	('rs2031920', 'Var', (170, 179))	('SCC', 'Gene', '6317', (293, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('rs3813867', 'Var', (38, 47))	('cytochrome P450 2E1', 'Gene', '1571', (73, 92))	('CYP2E1', 'Gene', (240, 246))	('SCC', 'Gene', (293, 296))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (268, 291))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('cytochrome P450 2E1', 'Gene', (73, 92))	('rs2031920', 'Var', (24, 33))
874370	29743817	With regard to the rs2031920 C/T polymorphism, in comparison to controls, a reduced risk in cases of esophageal squamous cell carcinoma (ESCC) was detected for the models of allele T vs. allele C [P = 0.025, odds ratio (OR) = 0.67], carrier T vs. carrier C (P = 0.014, OR = 0.70), TT vs. CC (P = 0.029, OR = 0.65), CT vs. CC (P = 0.040, OR = 0.56), CT + TT vs. CC (P = 0.035, OR = 0.58).	('SCC', 'Gene', (138, 141))	('rs2031920 C/T', 'Var', (19, 32))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (101, 135))	('rs2031920', 'Mutation', 'rs2031920', (19, 28))	('CT + TT vs.', 'Var', (349, 360))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('SCC', 'Gene', '6317', (138, 141))	('reduced', 'NegReg', (76, 83))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('esophageal squamous cell carcinoma', 'Disease', (101, 135))
874371	29743817	Similarly, a decreased SCC risk was observed for the rs3813867 G/C polymorphism in the allele, carrier, homozygote, dominant, and recessive models of overall SCC meta-analysis and "ESCC" subgroup analysis (all P < 0.05, OR < 1) and in all genetic models of "Asian" and "population-based control (PB)" subgroup analysis (all P < 0.05, OR < 1).	('SCC', 'Gene', (182, 185))	('SCC', 'Phenotype', 'HP:0002860', (182, 185))	('decreased', 'NegReg', (13, 22))	('SCC', 'Gene', '6317', (23, 26))	('PB', 'Chemical', '-', (296, 298))	('SCC', 'Gene', '6317', (158, 161))	('SCC', 'Phenotype', 'HP:0002860', (158, 161))	('SCC', 'Gene', '6317', (182, 185))	('rs3813867 G/C', 'Var', (53, 66))	('rs3813867', 'Mutation', 'rs3813867', (53, 62))	('SCC', 'Gene', (23, 26))	('SCC', 'Phenotype', 'HP:0002860', (23, 26))	('SCC', 'Gene', (158, 161))
874372	29743817	Additionally, for the rs2031920/rs3813867 haplotype, a decreased SCC risk was also detected in the overall SCC meta-analysis under the allele, carrier, homozygote and dominant model (all P < 0.05, OR < 1) and the subgroup analysis of "PB" under the allele, carrier, and dominant models (all P < 0.05, OR < 1).	('SCC', 'Gene', (65, 68))	('PB', 'Chemical', '-', (235, 237))	('SCC', 'Gene', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('decreased', 'NegReg', (55, 64))	('rs2031920', 'Mutation', 'rs2031920', (22, 31))	('SCC', 'Gene', '6317', (107, 110))	('rs3813867', 'Mutation', 'rs3813867', (32, 41))	('rs2031920/rs3813867', 'Var', (22, 41))
874373	29743817	Our meta-analysis supports the "T" allele carrier of the CYP2E1 rs2031920 C/T polymorphism and "C" allele carrier of the rs3813867 G/C polymorphism as protective factors for ESCC patients, especially in Asian populations.	('SCC', 'Gene', (175, 178))	('SCC', 'Phenotype', 'HP:0002860', (175, 178))	('rs3813867', 'Mutation', 'rs3813867', (121, 130))	('rs2031920 C/T', 'Var', (64, 77))	('CYP2E1', 'Gene', '1571', (57, 63))	('SCC', 'Gene', '6317', (175, 178))	('CYP2E1', 'Gene', (57, 63))	('patients', 'Species', '9606', (179, 187))	('rs2031920', 'Mutation', 'rs2031920', (64, 73))
874376	29743817	Polymorphic variants, existing in the functional genes of the cytochrome P450 system, are associated with the pathogenesis of several clinical cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cytochrome P450', 'Gene', '4051', (62, 77))	('associated', 'Reg', (90, 100))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('cytochrome P450', 'Gene', (62, 77))	('Polymorphic variants', 'Var', (0, 20))
874377	29743817	For example, rs2031920 C/T with an RsaI restriction enzyme site and rs3813867 C/T with a PstI restriction enzyme site are two common single nucleotide polymorphisms (SNP) within the 5'-flanking regions of the CYP2E1 gene.	('CYP2E1', 'Gene', (209, 215))	('PstI', 'Gene', '6690', (89, 93))	('rs3813867', 'Mutation', 'rs3813867', (68, 77))	('rs2031920 C/T', 'Var', (13, 26))	('CYP2E1', 'Gene', '1571', (209, 215))	('PstI', 'Gene', (89, 93))	('rs3813867 C/T', 'Var', (68, 81))	('rs2031920', 'Mutation', 'rs2031920', (13, 22))
874378	29743817	Three genotypes of c1/c1, c1/c2, c2/c2 were generated; rs2031920 and rs3813867 were in close linkage disequilibrium.	('rs3813867', 'Mutation', 'rs3813867', (69, 78))	('rs3813867', 'Var', (69, 78))	('rs2031920', 'Var', (55, 64))	('rs2031920', 'Mutation', 'rs2031920', (55, 64))	('c1/c1, c1/c2, c2/c2', 'Gene', '6966;717', (19, 38))
874379	29743817	Furthermore, CYP2E1 polymorphisms were reported to be linked to several cancers, such as nasopharyngeal carcinoma, urinary cancers and head and neck carcinoma, particularly in Asian populations.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('urinary cancers', 'Disease', 'MESH:D001749', (115, 130))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (135, 158))	('CYP2E1', 'Gene', (13, 19))	('nasopharyngeal carcinoma', 'Disease', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('urinary cancers', 'Disease', (115, 130))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('linked', 'Reg', (54, 60))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (89, 113))	('polymorphisms', 'Var', (20, 33))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('neck carcinoma', 'Disease', (144, 158))	('CYP2E1', 'Gene', '1571', (13, 19))	('neck carcinoma', 'Disease', 'MESH:D006258', (144, 158))	('cancers', 'Disease', (123, 130))
874382	29743817	Living habits (e.g., smoking, drinking), viral infection [e.g., human papillomavirus (HPV)], immune system, and polymorphic variants with many genes may be related to the risk of different SCC diseases.	('human papillomavirus', 'Species', '10566', (64, 84))	('related', 'Reg', (156, 163))	('HPV', 'Disease', 'MESH:D030361', (86, 89))	('SCC diseases', 'Disease', (189, 201))	('SCC', 'Phenotype', 'HP:0002860', (189, 192))	('viral infection', 'Disease', (41, 56))	('HPV', 'Disease', (86, 89))	('human papillomavirus', 'Disease', (64, 84))	('SCC diseases', 'Disease', 'MESH:D004194', (189, 201))	('polymorphic variants', 'Var', (112, 132))	('viral infection', 'Disease', 'MESH:D001102', (41, 56))
874383	29743817	Previously, we conducted an updated meta-analysis to explore the impact of MDM2 (MDM2 Proto-Oncogene) polymorphisms on SCC susceptibility and found that the GG genotype of MDM2 rs2279744 polymorphism may be associated with an increased risk of esophageal SCC in Asian populations.	('SCC', 'Gene', (255, 258))	('SCC', 'Gene', '6317', (119, 122))	('esophageal SCC', 'Disease', (244, 258))	('SCC', 'Phenotype', 'HP:0002860', (255, 258))	('SCC', 'Gene', '6317', (255, 258))	('rs2279744', 'Mutation', 'rs2279744', (177, 186))	('MDM2', 'Gene', '4193', (75, 79))	('MDM2', 'Gene', (75, 79))	('MDM2', 'Gene', (81, 85))	('MDM2', 'Gene', '4193', (81, 85))	('esophageal SCC', 'Disease', 'MESH:D004941', (244, 258))	('rs2279744', 'Var', (177, 186))	('MDM2', 'Gene', '4193', (172, 176))	('MDM2', 'Gene', (172, 176))	('SCC', 'Gene', (119, 122))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
874384	29743817	We observed a different conclusion regarding the role of rs2031920 and rs3813867 polymorphisms within the CYP2E1 gene in the risk of SCC.	('CYP2E1', 'Gene', (106, 112))	('SCC', 'Gene', '6317', (133, 136))	('rs2031920', 'Mutation', 'rs2031920', (57, 66))	('rs3813867', 'Mutation', 'rs3813867', (71, 80))	('CYP2E1', 'Gene', '1571', (106, 112))	('rs2031920', 'Var', (57, 66))	('rs3813867', 'Var', (71, 80))	('SCC', 'Gene', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))
874385	29743817	Thus, we are very interested in investigating the role of the rs2031920 and rs3813867 polymorphisms within the CYP2E1 gene in the susceptibility to SCC, considering the lack of publications of specific meta-analyses.	('rs2031920', 'Var', (62, 71))	('rs2031920', 'Mutation', 'rs2031920', (62, 71))	('CYP2E1', 'Gene', (111, 117))	('rs3813867', 'Mutation', 'rs3813867', (76, 85))	('SCC', 'Gene', (148, 151))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('rs3813867', 'Var', (76, 85))	('CYP2E1', 'Gene', '1571', (111, 117))	('SCC', 'Gene', '6317', (148, 151))
874390	29743817	A meta-analysis of rs2031920 and SCC risk was conducted on the allele model (allele T vs. allele C), carrier model (carrier T vs. carrier C), homozygote model (TT vs. CC), heterozygote model (CT vs. CC), dominant model (CT + TT vs. CC), and recessive model (TT vs. CC + CT).	('SCC', 'Gene', '6317', (33, 36))	('rs2031920', 'Mutation', 'rs2031920', (19, 28))	('rs2031920', 'Var', (19, 28))	('SCC', 'Gene', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))
874393	29743817	As shown in Table 2, in comparison with controls, a reduced ESCC risk was observed in the models of allele T vs. allele C (P = 0.025, OR = 0.67), carrier T vs. carrier C (P = 0.014, OR = 0.70), TT vs. CC (P = 0.029, OR = 0.65), CT vs. CC (P = 0.040, OR = 0.56), CT + TT vs. CC (P = 0.035, OR = 0.58), but not TT vs. CC + CT (P = 0.770).	('CT + TT vs. CC', 'Var', (262, 276))	('carrier T vs.', 'Var', (146, 159))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('SCC', 'Gene', '6317', (61, 64))	('reduced', 'NegReg', (52, 59))	('SCC', 'Gene', (61, 64))
874395	29743817	The "T" allele carrier of the rs2031920 polymorphism within the CYP2E1 gene seems to be linked to ESCC risk.	('SCC', 'Gene', '6317', (99, 102))	('CYP2E1', 'Gene', '1571', (64, 70))	('linked', 'Reg', (88, 94))	('rs2031920', 'Var', (30, 39))	('rs2031920', 'Mutation', 'rs2031920', (30, 39))	('SCC', 'Gene', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('CYP2E1', 'Gene', (64, 70))
874396	29743817	We also conducted the overall and subgroup meta-analysis of rs3813867 and SCC risk under the allele (10 case-control studies), carrier (10 case-control studies), homozygote (6 case-control studies), heterozygote (10 case-control studies), dominant (11 case-control studies), and recessive (6 case-control studies) models.	('rs3813867', 'Var', (60, 69))	('SCC', 'Gene', (74, 77))	('rs3813867', 'Mutation', 'rs3813867', (60, 69))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('SCC', 'Gene', '6317', (74, 77))
874397	29743817	The positive results regarding the association between CYP2E1 rs3813867 and SCC risk were detected in the overall SCC meta-analysis and subgroup analysis of "ESCC" and "Y" (P value of Hardy-Weinberg equilibrium > 0.05) under all genetic models (Table 3, all P < 0.05, OR < 1), only apart from the heterozygote model (P = 0.150).	('rs3813867', 'Mutation', 'rs3813867', (62, 71))	('SCC', 'Gene', (114, 117))	('SCC', 'Gene', (159, 162))	('SCC', 'Gene', (76, 79))	('rs3813867', 'Var', (62, 71))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('CYP2E1', 'Gene', (55, 61))	('association', 'Interaction', (35, 46))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('SCC', 'Gene', '6317', (159, 162))	('SCC', 'Gene', '6317', (76, 79))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('CYP2E1', 'Gene', '1571', (55, 61))
874400	29743817	The "C" allele carrier of CYP2E1 rs3813867 polymorphism may be associated with the risk of SCC, especially the ESCC cases in Asian populations.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('SCC', 'Gene', '6317', (91, 94))	('SCC', 'Gene', '6317', (112, 115))	('CYP2E1', 'Gene', '1571', (26, 32))	('associated', 'Reg', (63, 73))	('rs3813867', 'Mutation', 'rs3813867', (33, 42))	('SCC', 'Gene', (91, 94))	('rs3813867', 'Var', (33, 42))	('CYP2E1', 'Gene', (26, 32))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('SCC', 'Gene', (112, 115))
874401	29743817	The results of overall and subgroup meta-analysis of the rs2031920/rs3813867 haplotype and SCC risk under the allele (five case-control studies), carrier (five studies), homozygote (three studies), heterozygote (five studies), dominant (seven studies), and recessive (three studies) models are shown in Table 4.	('rs2031920', 'Mutation', 'rs2031920', (57, 66))	('SCC', 'Gene', (91, 94))	('rs3813867', 'Mutation', 'rs3813867', (67, 76))	('rs2031920/rs3813867', 'Var', (57, 76))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('SCC', 'Gene', '6317', (91, 94))
874403	29743817	These results suggested a potential link between the c1/c2 or c2/c2 of rs2031920/rs3813867 haplotype and SCC risk, which still requires more case-control studies.	('link', 'Reg', (36, 40))	('c1/c2', 'Gene', '6966', (53, 58))	('rs2031920', 'Mutation', 'rs2031920', (71, 80))	('c1/c2', 'Gene', (53, 58))	('SCC', 'Gene', (105, 108))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('rs2031920/rs3813867', 'Var', (71, 90))	('rs3813867', 'Mutation', 'rs3813867', (81, 90))	('SCC', 'Gene', '6317', (105, 108))
874405	29743817	The fixed model was used for the allele, carrier, homozygote and recessive models of rs3813867 (Table 5, all I2 < 50.0%, P value of heterogeneity > 0.05); and the allele, carrier, homozygote, dominant, and recessive models of the rs2031920/rs3813867 haplotype (Table 5, all I2 < 50.0%, P value of heterogeneity > 0.05).	('rs3813867', 'Var', (85, 94))	('rs3813867', 'Mutation', 'rs3813867', (240, 249))	('rs2031920/rs3813867', 'Var', (230, 249))	('rs2031920', 'Mutation', 'rs2031920', (230, 239))	('rs3813867', 'Mutation', 'rs3813867', (85, 94))
874407	29743817	Figures 2b and 3b show the Egger's publication bias plot of rs2031920 and rs3813867 under the allele model, respectively.	('rs2031920', 'Mutation', 'rs2031920', (60, 69))	('rs3813867', 'Mutation', 'rs3813867', (74, 83))	('rs3813867', 'Var', (74, 83))	('rs2031920', 'Var', (60, 69))
874410	29743817	CYP2E1 rs2031920 was related to the risk of ESCC in a high-incidence region (Kashmir, India).	('rs2031920', 'Var', (7, 16))	('SCC', 'Gene', (45, 48))	('CYP2E1', 'Gene', (0, 6))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('SCC', 'Gene', '6317', (45, 48))	('CYP2E1', 'Gene', '1571', (0, 6))	('rs2031920', 'Mutation', 'rs2031920', (7, 16))
874411	29743817	We did not observe published meta-analyses specific for the genetic relationship between CYP2E1 rs2031920, rs3813867 SNP and ESCC risk.	('rs2031920', 'Var', (96, 105))	('rs2031920', 'Mutation', 'rs2031920', (96, 105))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('SCC', 'Gene', '6317', (126, 129))	('rs3813867', 'Mutation', 'rs3813867', (107, 116))	('rs3813867 SNP', 'Var', (107, 120))	('CYP2E1', 'Gene', '1571', (89, 95))	('CYP2E1', 'Gene', (89, 95))	('SCC', 'Gene', (126, 129))
874412	29743817	In this study, we provide evidence that the "T" allele carrier of the rs2031920 polymorphism and the "C" allele carrier of the CYP2E1 rs3813867 polymorphism may be associated with a decreased risk of ESCC, especially in Asian populations because most of the included case-control studies were from China or India.	('decreased', 'NegReg', (182, 191))	('CYP2E1', 'Gene', (127, 133))	('rs2031920', 'Var', (70, 79))	('SCC', 'Gene', (201, 204))	('rs2031920', 'Mutation', 'rs2031920', (70, 79))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('SCC', 'Gene', '6317', (201, 204))	('rs3813867', 'Mutation', 'rs3813867', (134, 143))	('CYP2E1', 'Gene', '1571', (127, 133))	('rs3813867', 'Var', (134, 143))
874413	29743817	selected 21 case-control studies for a meta-analysis in 2010 and investigated the potential effect of CYP2E1 rs2031920 and rs3813867 in the risk of head and neck cancer; they found that the homozygote genotype of CYP2E1 rs2031920/rs3813867 may be linked to the risk of head and neck cancer, especially in Asian populations.	('CYP2E1', 'Gene', (213, 219))	('rs2031920/rs3813867', 'Var', (220, 239))	('CYP2E1', 'Gene', (102, 108))	('rs2031920', 'Mutation', 'rs2031920', (220, 229))	('neck cancer', 'Disease', 'MESH:D006258', (278, 289))	('neck cancer', 'Disease', (278, 289))	('head and neck cancer', 'Phenotype', 'HP:0012288', (269, 289))	('head and neck cancer', 'Phenotype', 'HP:0012288', (148, 168))	('rs3813867', 'Mutation', 'rs3813867', (123, 132))	('CYP2E1', 'Gene', '1571', (213, 219))	('CYP2E1', 'Gene', '1571', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('neck cancer', 'Disease', 'MESH:D006258', (157, 168))	('rs2031920', 'Mutation', 'rs2031920', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('rs3813867', 'Mutation', 'rs3813867', (230, 239))	('linked', 'Reg', (247, 253))	('neck cancer', 'Disease', (157, 168))
874414	29743817	performed another meta-analysis containing 43 case-control studies in 2016 and reported a positive association between CYP2E1 rs2031920/rs3813867 and head and neck cancer risk under the homozygote model.	('neck cancer', 'Disease', (159, 170))	('CYP2E1', 'Gene', (119, 125))	('rs2031920/rs3813867', 'Var', (126, 145))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('CYP2E1', 'Gene', '1571', (119, 125))	('positive', 'PosReg', (90, 98))	('rs3813867', 'Mutation', 'rs3813867', (136, 145))	('head and neck cancer', 'Phenotype', 'HP:0012288', (150, 170))	('rs2031920', 'Mutation', 'rs2031920', (126, 135))	('neck cancer', 'Disease', 'MESH:D006258', (159, 170))
874416	29743817	In our meta-analysis, we failed to observe the statistical relationship between CYP2E1 rs2031920 SNP, rs3813867 SNP, rs2031920/rs3813867 haplotype and HNSCC risk.	('rs3813867', 'Mutation', 'rs3813867', (127, 136))	('rs2031920/rs3813867', 'Var', (117, 136))	('rs3813867 SNP', 'Var', (102, 115))	('SCC', 'Gene', '6317', (153, 156))	('rs2031920', 'Mutation', 'rs2031920', (87, 96))	('rs2031920', 'Mutation', 'rs2031920', (117, 126))	('rs2031920 SNP', 'Var', (87, 100))	('CYP2E1', 'Gene', (80, 86))	('SCC', 'Gene', (153, 156))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('rs3813867', 'Mutation', 'rs3813867', (102, 111))	('CYP2E1', 'Gene', '1571', (80, 86))
874417	29743817	selected 17 case-control studies with 2639 cases and 3450 controls for a meta-analysis of the association between CYP2E1 rs3813867 and the risk of lung cancer in the Chinese population in 2014, and showed a potential link between the "C" allele carriers of CYP2E1 rs3813867 and a decreased risk of lung cancer.	('CYP2E1', 'Gene', '1571', (114, 120))	('CYP2E1', 'Gene', (257, 263))	('rs3813867', 'Mutation', 'rs3813867', (121, 130))	('lung cancer', 'Disease', (298, 309))	('rs3813867', 'Mutation', 'rs3813867', (264, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (298, 309))	('lung cancer', 'Disease', (147, 158))	('rs3813867', 'Var', (121, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('CYP2E1', 'Gene', (114, 120))	('rs3813867', 'Var', (264, 273))	('association', 'Interaction', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('decreased', 'NegReg', (280, 289))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', 'MESH:D008175', (298, 309))	('CYP2E1', 'Gene', '1571', (257, 263))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
874418	29743817	In our meta-analysis, very limited data were included after our strict selection; thus, no statistical evidence regarding the role of CYP2E1 rs3813867 in LSCC risk was provided.	('rs3813867', 'Mutation', 'rs3813867', (141, 150))	('SCC', 'Gene', (155, 158))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('CYP2E1', 'Gene', '1571', (134, 140))	('rs3813867', 'Var', (141, 150))	('SCC', 'Gene', '6317', (155, 158))	('CYP2E1', 'Gene', (134, 140))
874419	29743817	However, we enrolled five case-control studies in our subgroup analysis of "LSCC" for CYP2E1 rs2031920 and found a negative genetic relationship, which was partly in line with the previous data from LSCC subgroup analysis.	('CYP2E1', 'Gene', '1571', (86, 92))	('SCC', 'Gene', '6317', (200, 203))	('CYP2E1', 'Gene', (86, 92))	('rs2031920', 'Var', (93, 102))	('rs2031920', 'Mutation', 'rs2031920', (93, 102))	('SCC', 'Gene', (77, 80))	('SCC', 'Gene', (200, 203))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('negative', 'NegReg', (115, 123))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))	('SCC', 'Gene', '6317', (77, 80))
874420	29743817	The close linkage disequilibrium between rs2031920 and rs3813867 for the CYP2E1 gene was reported.	('CYP2E1', 'Gene', '1571', (73, 79))	('rs2031920', 'Var', (41, 50))	('rs2031920', 'Mutation', 'rs2031920', (41, 50))	('rs3813867', 'Mutation', 'rs3813867', (55, 64))	('CYP2E1', 'Gene', (73, 79))	('rs3813867', 'Var', (55, 64))
874422	29743817	Thus, we performed a meta-analysis of rs2031920 and rs3813867, respectively; then, we analyzed the role of the rs2031920/rs3813867 haplotype based on the available data.	('rs3813867', 'Mutation', 'rs3813867', (121, 130))	('rs2031920', 'Mutation', 'rs2031920', (111, 120))	('rs3813867', 'Mutation', 'rs3813867', (52, 61))	('rs3813867', 'Var', (52, 61))	('rs2031920/rs3813867', 'Var', (111, 130))	('rs2031920', 'Var', (38, 47))	('rs2031920', 'Mutation', 'rs2031920', (38, 47))
874425	29743817	Only one case-control study was included in the "cervical SCC" subgroup analysis of rs2031920 under the allele, carrier, homozygote, heterozygote, and recessive models.	('SCC', 'Gene', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('SCC', 'Gene', '6317', (58, 61))	('rs2031920', 'Mutation', 'rs2031920', (84, 93))	('rs2031920', 'Var', (84, 93))
874426	29743817	Only one case-control study was enrolled in the "lung SCC" subgroup analysis of rs3813867 under all genetic models.	('SCC', 'Gene', '6317', (54, 57))	('rs3813867', 'Mutation', 'rs3813867', (80, 89))	('rs3813867', 'Var', (80, 89))	('SCC', 'Gene', (54, 57))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))
874427	29743817	Only two studies were enrolled in the "ESCC" subgroup analysis of the rs2031920/rs3813867 haplotype.	('SCC', 'Gene', '6317', (40, 43))	('rs2031920/rs3813867', 'Var', (70, 89))	('rs2031920', 'Mutation', 'rs2031920', (70, 79))	('rs3813867', 'Mutation', 'rs3813867', (80, 89))	('SCC', 'Gene', (40, 43))	('SCC', 'Phenotype', 'HP:0002860', (40, 43))
874428	29743817	In this study, we focused on the genetic role of two polymorphisms within the CYP2E1 gene in our meta-analysis, and we still cannot rule out the potential genetic effect of other CYP2E1 polymorphisms (e.g., rs6413432 T/A) and the variant combination between CYP2E1 and other related genes (e.g., MDM2).	('rs6413432', 'Mutation', 'rs6413432', (207, 216))	('CYP2E1', 'Gene', (258, 264))	('CYP2E1', 'Gene', (179, 185))	('CYP2E1', 'Gene', '1571', (78, 84))	('MDM2', 'Gene', '4193', (296, 300))	('rs6413432 T/A', 'Var', (207, 220))	('MDM2', 'Gene', (296, 300))	('CYP2E1', 'Gene', '1571', (258, 264))	('CYP2E1', 'Gene', '1571', (179, 185))	('CYP2E1', 'Gene', (78, 84))
874438	29743817	In conclusion, our meta-analysis data demonstrated that the CYP2E1 rs2031920 and rs3813867 polymorphisms may be associated with the risk of ESCC.	('rs3813867', 'Var', (81, 90))	('SCC', 'Gene', (141, 144))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('CYP2E1', 'Gene', '1571', (60, 66))	('SCC', 'Gene', '6317', (141, 144))	('rs2031920', 'Var', (67, 76))	('rs2031920', 'Mutation', 'rs2031920', (67, 76))	('CYP2E1', 'Gene', (60, 66))	('associated', 'Reg', (112, 122))	('rs3813867', 'Mutation', 'rs3813867', (81, 90))
874440	28538690	Dysregulation of miRNA Expression in Cancer Associated Fibroblasts (CAFs) and Its Consequences on the Tumor Microenvironment The tumor microenvironment, including cancer-associated fibroblasts (CAF), has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('CAF', 'Gene', '8850', (68, 71))	('tumor', 'Disease', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('Tumor', 'Phenotype', 'HP:0002664', (102, 107))	('CAF', 'Gene', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('CAF', 'Gene', '8850', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('CAF', 'Gene', (194, 197))	('tumor', 'Disease', (255, 260))	('esp', 'Gene', (308, 311))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('miRNA', 'Protein', (17, 22))	('cancer', 'Disease', (163, 169))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))	('esp', 'Gene', '148713', (308, 311))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (320, 326))
874441	28538690	Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations.	('CAF', 'Gene', '8850', (62, 65))	('epigenetic regulations', 'Var', (112, 134))	('CAF', 'Gene', (62, 65))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
874444	28538690	In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment.	('deregulated', 'Var', (12, 23))	('soluble factors', 'MPA', (169, 184))	('extracellular', 'MPA', (113, 126))	('affect', 'Reg', (29, 35))	('G-protein signaling', 'MPA', (206, 225))	('EMT', 'Gene', (149, 152))	('cell cycle', 'CPA', (241, 251))	('EMT', 'Gene', '3702', (149, 152))	('miR', 'Gene', '220972', (24, 27))	('apoptosis', 'CPA', (227, 236))	('cytoskeleton', 'MPA', (135, 147))	('miR', 'Gene', (24, 27))	('intracellular functional complexes', 'MPA', (44, 78))
874446	28538690	Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('epigenetic communication', 'Var', (13, 37))	('CAF', 'Gene', '8850', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('CAF', 'Gene', (46, 49))	('cancer', 'Disease', (55, 61))
874453	28538690	As one key event CAF activation appears to induce alternative production and secretion of extracellular matrix (ECM) proteins resulting in ECM remodeling and cancer cell invasion.	('activation', 'Var', (21, 31))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('CAF', 'Gene', (17, 20))	('cancer', 'Disease', (158, 164))	('secretion of', 'MPA', (77, 89))	('ECM', 'MPA', (139, 142))	('production', 'MPA', (62, 72))	('CAF', 'Gene', '8850', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
874459	28538690	Their target genes are known to affect cell differentiation, adhesion, migration, proliferation, secretion and cell-cell interaction, among others.	('rat', 'Species', '10116', (74, 77))	('affect', 'Reg', (32, 38))	('migration', 'CPA', (71, 80))	('genes', 'Var', (13, 18))	('rat', 'Species', '10116', (89, 92))	('secretion', 'MPA', (97, 106))	('cell differentiation', 'CPA', (39, 59))	('proliferation', 'CPA', (82, 95))	('cell-cell interaction', 'CPA', (111, 132))	('adhesion', 'CPA', (61, 69))
874509	28538690	Deregulation of miRs in fibroblasts in general appears to induce as major effects smooth muscle alpha-actin (alpha-SMA) upregulation and modulated secretion of cytokines including: increased IL-6 and CXCL12, activation of the TGF-beta and inhibition of various signaling pathways, such as the PI3K-AKT pathways.	('TGF-beta', 'Gene', (226, 234))	('IL-6', 'Gene', (191, 195))	('activation', 'PosReg', (208, 218))	('CXCL12', 'Gene', (200, 206))	('Deregulation', 'Var', (0, 12))	('increased', 'PosReg', (181, 190))	('IL-6', 'Gene', '3569', (191, 195))	('increased IL-6', 'Phenotype', 'HP:0030783', (181, 195))	('AKT', 'Gene', '207', (298, 301))	('modulated', 'Reg', (137, 146))	('inhibition', 'NegReg', (239, 249))	('miR', 'Gene', '220972', (16, 19))	('CXCL12', 'Gene', '6387', (200, 206))	('TGF-beta', 'Gene', '7040', (226, 234))	('upregulation', 'PosReg', (120, 132))	('secretion of cytokines', 'MPA', (147, 169))	('AKT', 'Gene', (298, 301))	('miR', 'Gene', (16, 19))
874515	28538690	MiR-146b inhibition is sufficient to transactivate NFs into CAFs, which promote EMT transition in breast cancer cells in a paracrine manner.	('inhibition', 'NegReg', (9, 19))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('CAF', 'Gene', (60, 63))	('breast cancer', 'Disease', (98, 111))	('CAF', 'Gene', '8850', (60, 63))	('promote', 'PosReg', (72, 79))	('EMT', 'Gene', (80, 83))	('EMT', 'Gene', '3702', (80, 83))	('MiR-146b', 'Gene', '574447', (0, 8))	('NFs', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('transactivate', 'Var', (37, 50))	('MiR-146b', 'Gene', (0, 8))
874521	28538690	CAF exosomes and NF exosomes transfected with miRs-21, -378e, and -143 promoted the stemness and EMT phenotype of breast cancer cells.	('miR', 'Gene', (46, 49))	('stemness', 'Disease', 'MESH:D020295', (84, 92))	('stemness', 'Disease', (84, 92))	('promoted', 'PosReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('EMT', 'Gene', (97, 100))	('EMT', 'Gene', '3702', (97, 100))	('miR', 'Gene', '220972', (46, 49))	('CAF', 'Gene', (0, 3))	('CAF', 'Gene', '8850', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))	('and -143', 'Var', (62, 70))
874547	28538690	Downregulated miR-101 appears to increase CAF-promoted vascular mimicry formation in vitro and in vivo.	('Downregulated', 'Var', (0, 13))	('vascular mimicry formation', 'CPA', (55, 81))	('increase', 'PosReg', (33, 41))	('CAF', 'Gene', (42, 45))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('CAF', 'Gene', '8850', (42, 45))
874563	28538690	In fibroblasts with amplification of miR-92 expression an enhanced invasive capacity of breast cancer cells was reported.	('miR-92', 'Gene', (37, 43))	('miR-92', 'Gene', '407047', (37, 43))	('enhanced', 'PosReg', (58, 66))	('amplification', 'Var', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
874631	28538690	In summary, deregulated miRs affect various intracellular functional complexes, but also formation and composition of the extracellular microenvironment.	('deregulated', 'Var', (12, 23))	('affect', 'Reg', (29, 35))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('intracellular functional complexes', 'MPA', (44, 78))
874632	28538690	Furthermore, epigenetic communication between CAFs and cancer cells, for example via extracellular microvesicles, may confer to cancer specific functional readouts (Figure 2).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('epigenetic communication', 'Var', (13, 37))	('CAF', 'Gene', '8850', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('functional readouts', 'MPA', (144, 163))	('CAF', 'Gene', (46, 49))	('cancer', 'Disease', (55, 61))	('cancer', 'Disease', (128, 134))
874650	28362001	Examples of this include the relaxation of the gastric sphincter following exposure to lipopolysaccharide being associated with increased reflux, and the association of certain microbial species with the expression of genes involved in the innate immune response in the esophagus.	('increased reflux', 'Phenotype', 'HP:0002020', (128, 144))	('association', 'Interaction', (154, 165))	('reflux', 'MPA', (138, 144))	('gastric sphincter', 'Disease', (47, 64))	('increased', 'PosReg', (128, 137))	('lipopolysaccharide', 'Var', (87, 105))	('relaxation', 'MPA', (29, 39))	('gastric sphincter', 'Disease', 'MESH:D013274', (47, 64))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (87, 105))
874653	28362001	HFD fed rats gained more weight than controls, and at the end of the experiment (16 weeks of diet), HFD fed rats were significantly heavier than control fed rats (Delta Body Weight: Control: 487.7 +- 17.8 g; HFD: 593.6 +- 14.8 g; P = 0.0014; Fig.	('rats', 'Species', '10116', (157, 161))	('rats', 'Species', '10116', (108, 112))	('heavier', 'PosReg', (132, 139))	('rats', 'Species', '10116', (8, 12))	('HFD', 'Var', (100, 103))
874654	28362001	Consistently, total fat and percentage fat relative to body weight were both significantly higher in HFD fed rats as compared to control fed rats (Fig.	('percentage fat', 'MPA', (28, 42))	('higher', 'PosReg', (91, 97))	('total fat', 'MPA', (14, 23))	('HFD', 'Var', (101, 104))	('rats', 'Species', '10116', (141, 145))	('rats', 'Species', '10116', (109, 113))
874657	28362001	An insulin tolerance test conducted at 15 weeks of diet showed an increased AUC (P = 0.061) in HFD fed rats as compared to control fed rats (Fig.	('increased', 'PosReg', (66, 75))	('AUC', 'MPA', (76, 79))	('rats', 'Species', '10116', (103, 107))	('HFD', 'Var', (95, 98))	('rats', 'Species', '10116', (135, 139))
874669	28362001	Clostridium sensu stricto (OTU244) was found to be significantly more abundant in HFD fed rats as compared to control fed rats in both the upper and lower esophagus (Fig.	('rats', 'Species', '10116', (122, 126))	('Clostridium', 'Species', '1054297', (0, 11))	('more', 'PosReg', (65, 69))	('rats', 'Species', '10116', (90, 94))	('HFD', 'Var', (82, 85))
874679	28362001	In support of this, the percentage relative abundance of Fusobacterium was higher in HFD-fed compared to control-fed rats (CU: 3.52%, CL: 2.56%, HFU: 6.31%, HFL: 4.22%).	('Fusobacterium', 'Species', '856', (57, 70))	('HFD-fed', 'Var', (85, 92))	('higher', 'PosReg', (75, 81))	('HFL', 'CellLine', 'CVCL:0298', (157, 160))	('CU', 'Chemical', 'MESH:D003300', (123, 125))	('rats', 'Species', '10116', (117, 121))
874683	28362001	On the other hand, ten pathways were significantly different in the lower esophagus of HFD fed rats as compared to the lower esophagus of control fed rats (Fig.	('rats', 'Species', '10116', (150, 154))	('HFD fed', 'Var', (87, 94))	('different', 'Reg', (51, 60))	('rats', 'Species', '10116', (95, 99))
874696	28362001	As expected, HFD fed rats gained significantly more weight than those on control diet, and the weight gain corresponded to significantly higher levels of body fat.	('weight gain', 'Disease', 'MESH:D015430', (95, 106))	('more', 'PosReg', (47, 51))	('rats', 'Species', '10116', (21, 25))	('higher', 'PosReg', (137, 143))	('weight gain', 'Phenotype', 'HP:0004324', (95, 106))	('weight gain', 'Disease', (95, 106))	('levels of body fat', 'MPA', (144, 162))	('HFD', 'Var', (13, 16))	('weight', 'MPA', (52, 58))	('gained', 'PosReg', (26, 32))
874697	28362001	Further, HFD fed rats had higher fasting glucose levels, reduced glucose tolerance and increased insulin resistance compared to control fed rats at 14-15 weeks of diet.	('rats', 'Species', '10116', (17, 21))	('increased', 'PosReg', (87, 96))	('insulin resistance', 'Phenotype', 'HP:0000855', (97, 115))	('higher', 'PosReg', (26, 32))	('rats', 'Species', '10116', (140, 144))	('insulin resistance', 'CPA', (97, 115))	('HFD', 'Var', (9, 12))	('reduced glucose tolerance', 'Phenotype', 'HP:0040270', (57, 82))	('glucose', 'MPA', (65, 72))	('reduced', 'NegReg', (57, 64))	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('glucose', 'Chemical', 'MESH:D005947', (65, 72))
874796	31860979	The first cause of aggravation is that TEVAR does not treat the esophageal defect, which is a source of infection, and thus increases the risk of rehemorrhage, mediastinitis, sepsis, and death, with a poor long-term prognosis.	('sepsis', 'Phenotype', 'HP:0100806', (175, 181))	('sepsis', 'Disease', (175, 181))	('esophageal defect', 'Disease', 'MESH:D004941', (64, 81))	('sepsis', 'Disease', 'MESH:D018805', (175, 181))	('esophageal defect', 'Disease', (64, 81))	('increases', 'PosReg', (124, 133))	('hemorrhage', 'Disease', (148, 158))	('infection', 'Disease', (104, 113))	('not', 'NegReg', (50, 53))	('hemorrhage', 'Disease', 'MESH:D006470', (148, 158))	('infection', 'Disease', 'MESH:D007239', (104, 113))	('death', 'Disease', 'MESH:D003643', (187, 192))	('TEVAR', 'Phenotype', 'HP:0012727', (39, 44))	('death', 'Disease', (187, 192))	('mediastinitis', 'Disease', (160, 173))	('TEVAR', 'Var', (39, 44))
874919	31185636	In addition to previously observed elevation of IL-7 at the systemic level in CRC, also esophageal cancer was associated with the oversecretion of IL-7.	('IL-7', 'Gene', (147, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('IL-7', 'Gene', (48, 52))	('oversecretion', 'Var', (130, 143))	('associated', 'Reg', (110, 120))	('CRC', 'Phenotype', 'HP:0003003', (78, 81))	('IL-7', 'Gene', '3574', (147, 151))	('esophageal cancer', 'Disease', (88, 105))	('elevation', 'PosReg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('IL-7', 'Gene', '3574', (48, 52))
874965	31185636	This finding might be interpreted in the favor of beneficial role attributed to IL-7 and imply that the loss of IL-7 in the immediate environment of the tumor may facilitate cancer progression.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('loss', 'Var', (104, 108))	('IL-7', 'Gene', '3574', (80, 84))	('facilitate', 'PosReg', (163, 173))	('IL-7', 'Gene', (80, 84))	('cancer', 'Disease', (174, 180))	('tumor', 'Disease', (153, 158))	('IL-7', 'Gene', '3574', (112, 116))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('IL-7', 'Gene', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
874985	29306203	For the three patients given PLDR for bulky tumor, all of them achieved partial remission 1 month after the PLDR, and one patient achieved complete response at the fourth month.	('patient', 'Species', '9606', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('patient', 'Species', '9606', (14, 21))	('PLDR', 'Var', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Disease', (44, 49))	('partial remission', 'NegReg', (72, 89))
874995	29306203	In a murine orthotopic model of glioblastoma, Marples' group found that PLDR was more efficacious than the standard fractionated treatment.	('glioblastoma', 'Phenotype', 'HP:0012174', (32, 44))	('glioblastoma', 'Disease', (32, 44))	('murine', 'Species', '10090', (5, 11))	('PLDR', 'Var', (72, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (32, 44))
874999	29306203	The preclinical study demonstrated that the combination of PLDR and temozolomide was associated with increased vascularization and fewer degenerating neurons compared with standard fractionated treatment plus temozolomide.	('temozolomide', 'Chemical', 'MESH:D000077204', (68, 80))	('fewer', 'NegReg', (131, 136))	('temozolomide', 'Chemical', 'MESH:D000077204', (209, 221))	('increased', 'PosReg', (101, 110))	('temozolomide', 'Gene', (68, 80))	('vascularization', 'CPA', (111, 126))	('PLDR', 'Var', (59, 63))	('degenerating neurons', 'CPA', (137, 157))	('combination', 'Var', (44, 55))
875000	29306203	For the head and neck squamous cell carcinoma murine models, Marples' group also found that the PLDR group exerted fewer tumor hypoxia compared to the conventional radiotherapy group.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (8, 45))	('neck squamous cell carcinoma', 'Disease', (17, 45))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (17, 45))	('fewer', 'NegReg', (115, 120))	('murine', 'Species', '10090', (46, 52))	('tumor hypoxia', 'Disease', 'MESH:D000860', (121, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('tumor hypoxia', 'Disease', (121, 134))	('PLDR', 'Var', (96, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))
875002	29306203	PLDR caused less vascular damage, and the preserved vascular network could improve tumor oxygenation and could explain the improved therapeutic effect.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('vascular damage', 'Disease', 'MESH:D000783', (17, 32))	('tumor', 'Disease', (83, 88))	('PLDR', 'Var', (0, 4))	('vascular damage', 'Disease', (17, 32))	('improve', 'PosReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
875317	22170739	Aberrantly methylated PKP1 in the progression of Barrett's esophagus to esophageal adenocarcinoma The aberrant DNA methylation of tumor suppressor genes occurs frequently in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) and likely affects the initiation and progression of BE to EAC.	('PKP1', 'Gene', '5317', (22, 26))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (72, 97))	('EAC', 'Phenotype', 'HP:0011459', (294, 297))	('aberrant DNA', 'Var', (102, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('PKP1', 'Gene', (22, 26))	('EAC', 'Phenotype', 'HP:0011459', (230, 233))	('tumor', 'Disease', (130, 135))	('esophageal adenocarcinoma', 'Disease', (72, 97))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('EAC', 'Gene', '1540', (294, 297))	('BE', 'Phenotype', 'HP:0100580', (288, 290))	('EAC', 'Gene', (294, 297))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (203, 228))	('EAC', 'Gene', '1540', (230, 233))	('EAC', 'Gene', (230, 233))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (203, 228))	("Barrett's esophagus", 'Disease', (174, 193))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (49, 68))	('esophageal adenocarcinoma', 'Disease', (203, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('affects', 'Reg', (246, 253))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (174, 193))	('BE', 'Phenotype', 'HP:0100580', (195, 197))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (72, 97))
875318	22170739	In the present study we discovered PKP1 as a novel methylated gene in EAC and then investigated the role of loss of PKP1, a constituent of the desmosome complex found in stratified epithelial layers, on the behavior of Barrett's esophagus and esophageal adenocarcinoma cells.	('PKP1', 'Gene', (35, 39))	('EAC', 'Gene', '1540', (70, 73))	('EAC', 'Gene', (70, 73))	('loss', 'Var', (108, 112))	('esophageal adenocarcinoma', 'Disease', (243, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (243, 268))	('PKP1', 'Gene', (116, 120))	('epithelia', 'Disease', 'None', (181, 190))	('epithelia', 'Disease', (181, 190))	('PKP1', 'Gene', '5317', (35, 39))	('rat', 'Species', '10116', (172, 175))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (243, 268))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (219, 238))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))	('PKP1', 'Gene', '5317', (116, 120))
875319	22170739	Using primary esophageal tissue samples, we determined that PKP1 was rarely methylated in normal squamous esophagus (5/55; 9.1%) and BE (5/39; 12.8%) and more frequently methylated in Barrett's esophagus with high-grade dysplasia (HGD) or EAC (20/60; 33.3%; p<0.05).	("Barrett's esophagus", 'Disease', (184, 203))	('dysplasia', 'Disease', 'MESH:D004476', (220, 229))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (184, 203))	('HGD', 'Gene', '3081', (231, 234))	('EAC', 'Phenotype', 'HP:0011459', (239, 242))	('EAC', 'Gene', '1540', (239, 242))	('PKP1', 'Gene', (60, 64))	('HGD', 'Gene', (231, 234))	('EAC', 'Gene', (239, 242))	('BE', 'Phenotype', 'HP:0100580', (133, 135))	('dysplasia', 'Disease', (220, 229))	('methylated', 'Var', (170, 180))	('PKP1', 'Gene', '5317', (60, 64))
875322	22170739	Thus, PKP1 loss secondary to promoter methylation, as well as other mechanisms, may promote the progression of BE to EAC in a subset of patients via decreased desmosome assembly and increased cell motility.	('increased', 'PosReg', (182, 191))	('EAC', 'Gene', (117, 120))	('promote', 'PosReg', (84, 91))	('BE', 'Phenotype', 'HP:0100580', (111, 113))	('cell motility', 'CPA', (192, 205))	('promoter methylation', 'Var', (29, 49))	('desmosome assembly', 'MPA', (159, 177))	('patients', 'Species', '9606', (136, 144))	('PKP1 loss', 'Disease', (6, 15))	('PKP1 loss', 'Disease', 'MESH:D015431', (6, 15))	('decreased', 'NegReg', (149, 158))	('EAC', 'Phenotype', 'HP:0011459', (117, 120))	('EAC', 'Gene', '1540', (117, 120))
875325	22170739	In addition, epigenetic modifications of numerous genes, in the form of DNA hypermethylation with subsequent gene silencing, have been demonstrated to occur frequently in BE and EAC.	('epigenetic modifications', 'Var', (13, 37))	('BE', 'Phenotype', 'HP:0100580', (171, 173))	('silencing', 'NegReg', (114, 123))	('EAC', 'Phenotype', 'HP:0011459', (178, 181))	('EAC', 'Gene', '1540', (178, 181))	('EAC', 'Gene', (178, 181))	('rat', 'Species', '10116', (142, 145))	('DNA', 'MPA', (72, 75))
875326	22170739	A subset of these aberrantly methylated tumor suppressor genes are predicted to play an important role in the pathogenesis of BE and/or EAC.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('EAC', 'Phenotype', 'HP:0011459', (136, 139))	('BE', 'Phenotype', 'HP:0100580', (126, 128))	('BE and/or', 'Disease', (126, 135))	('EAC', 'Gene', '1540', (136, 139))	('tumor', 'Disease', (40, 45))	('aberrantly methylated', 'Var', (18, 39))	('EAC', 'Gene', (136, 139))	('play', 'Reg', (80, 84))
875327	22170739	Furthermore, some of these methylated genes might be useful prognostic markers as they appear to precede and thus predict the progression of BE to EAC.	('EAC', 'Phenotype', 'HP:0011459', (147, 150))	('methylated', 'Var', (27, 37))	('EAC', 'Gene', '1540', (147, 150))	('EAC', 'Gene', (147, 150))	('BE', 'Phenotype', 'HP:0100580', (141, 143))
875330	22170739	Others have shown that in BE specimens obtained from patients who progressed to cancer or high grade dysplasia, APC, TIMP3, and TERT were frequently methylated, whereas in BE tissue obtained from patients who did not progress, methylation of these genes was uncommon.	('APC', 'Disease', 'MESH:D011125', (112, 115))	('dysplasia', 'Disease', (101, 110))	('APC', 'Disease', (112, 115))	('patients', 'Species', '9606', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('dysplasia', 'Disease', 'MESH:D004476', (101, 110))	('patients', 'Species', '9606', (196, 204))	('methylated', 'Var', (149, 159))	('BE', 'Phenotype', 'HP:0100580', (26, 28))	('TERT', 'Gene', (128, 132))	('BE', 'Phenotype', 'HP:0100580', (172, 174))	('TERT', 'Gene', '7015', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('TIMP3', 'Gene', '7078', (117, 122))	('TIMP3', 'Gene', (117, 122))	('cancer', 'Disease', (80, 86))
875338	22170739	Defects in desmosome-mediated cell-cell adhesion can lead to tissue fragility syndromes, affecting the skin and the heart, as well as to defects in embryological development.	('fragility syndrome', 'Disease', 'MESH:D005600', (68, 86))	('lead to', 'Reg', (53, 60))	('fragility syndrome', 'Disease', (68, 86))	('Defects', 'Var', (0, 7))	('embryological development', 'CPA', (148, 173))	('defects', 'NegReg', (137, 144))	('desmosome-mediated', 'Protein', (11, 29))
875346	22170739	We have now identified hypermethylated PKP1 in a subset of cases of EAC and provide evidence that reduced levels of PKP1 seen in BE result in increased cell motility, which would be predicted to favor the progression of BE to EAC.	('PKP1', 'Gene', '5317', (39, 43))	('increased', 'PosReg', (142, 151))	('PKP1', 'Gene', (39, 43))	('hypermethylated', 'Var', (23, 38))	('EAC', 'Phenotype', 'HP:0011459', (68, 71))	('PKP1', 'Gene', (116, 120))	('EAC', 'Phenotype', 'HP:0011459', (226, 229))	('EAC', 'Gene', '1540', (68, 71))	('BE', 'Phenotype', 'HP:0100580', (129, 131))	('EAC', 'Gene', '1540', (226, 229))	('EAC', 'Gene', (68, 71))	('cell motility', 'CPA', (152, 165))	('reduced', 'NegReg', (98, 105))	('EAC', 'Gene', (226, 229))	('levels', 'MPA', (106, 112))	('favor', 'PosReg', (195, 200))	('BE', 'Phenotype', 'HP:0100580', (220, 222))	('PKP1', 'Gene', '5317', (116, 120))
875362	22170739	The optimal annealing temperature for the PKP1 methyl- and unmethyl-specific primers (64 C) was determined using DNA samples that were known to carry unmethylated or methylated PKP1.	('PKP1', 'Gene', (177, 181))	('PKP1', 'Gene', '5317', (42, 46))	('rat', 'Species', '10116', (27, 30))	('methylated', 'Var', (166, 176))	('PKP1', 'Gene', (42, 46))	('PKP1', 'Gene', '5317', (177, 181))
875385	22170739	We used methylation-specific PCR (MSP) to assess for methylated PKP1 in BE and EAC cases (Figure 1).	('EAC', 'Gene', (79, 82))	('BE', 'Phenotype', 'HP:0100580', (72, 74))	('PKP1', 'Gene', (64, 68))	('EAC', 'Gene', '1540', (79, 82))	('EAC', 'Phenotype', 'HP:0011459', (79, 82))	('PKP1', 'Gene', '5317', (64, 68))	('methylated', 'Var', (53, 63))
875386	22170739	PKP1 was more frequently methylated in cases of Barrett's esophagus with high-grade dysplasia (HGD) and esophageal adenocarcinoma (33.3%, N=20/60) when compared to Barrett's esophagus (12.8%, N=5/39) and to normal squamous esophagus (9.1%, N=5/55) cases (p<0.05 for both normal and BE versus HGD/EAC) (Table 1).	('EAC', 'Gene', (296, 299))	('methylated', 'Var', (25, 35))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (164, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('HGD', 'Gene', '3081', (95, 98))	("Barrett's esophagus", 'Disease', (48, 67))	('HGD', 'Gene', '3081', (292, 295))	('PKP1', 'Gene', '5317', (0, 4))	('EAC', 'Phenotype', 'HP:0011459', (296, 299))	('HGD', 'Gene', (95, 98))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (48, 67))	('PKP1', 'Gene', (0, 4))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (104, 129))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (104, 129))	('HGD', 'Gene', (292, 295))	('dysplasia', 'Disease', (84, 93))	('esophageal adenocarcinoma', 'Disease', (104, 129))	('dysplasia', 'Disease', 'MESH:D004476', (84, 93))	('EAC', 'Gene', '1540', (296, 299))	('BE', 'Phenotype', 'HP:0100580', (282, 284))
875390	22170739	The esophageal adenocarcinoma cell line OE33, which carries methylated PKP1 (Table 1) has a low level of PKP1 expression (Figure 2).	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('PKP1', 'Gene', (105, 109))	('PKP1', 'Gene', (71, 75))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (4, 29))	('expression', 'MPA', (110, 120))	('esophageal adenocarcinoma', 'Disease', (4, 29))	('PKP1', 'Gene', '5317', (105, 109))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (4, 29))	('PKP1', 'Gene', '5317', (71, 75))	('methylated', 'Var', (60, 70))
875391	22170739	Following treatment with 5muM 5-aza-2' deoxycytidine, PKP1 expression increased ~5.4 fold, consistent with the effect of methylation of PKP1 leading to its transcriptional repression.	('muM', 'Gene', (26, 29))	('transcriptional repression', 'MPA', (156, 182))	('increased', 'PosReg', (70, 79))	('PKP1', 'Gene', (54, 58))	('PKP1', 'Gene', (136, 140))	('expression', 'MPA', (59, 69))	('methylation', 'Var', (121, 132))	('muM', 'Gene', '56925', (26, 29))	('5-aza', 'Chemical', 'MESH:D001374', (30, 35))	('PKP1', 'Gene', '5317', (54, 58))	('PKP1', 'Gene', '5317', (136, 140))
875394	22170739	We then compared PKP1 mRNA expression between the EAC cases with methylated and unmethylated PKP1.	('PKP1', 'Gene', '5317', (17, 21))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))	('compared', 'Reg', (8, 16))	('EAC', 'Gene', '1540', (50, 53))	('PKP1', 'Gene', (17, 21))	('EAC', 'Gene', (50, 53))	('methylated', 'Var', (65, 75))	('PKP1', 'Gene', '5317', (93, 97))	('PKP1', 'Gene', (93, 97))
875396	22170739	Using this cutoff, 2/8 (25%) of EAC cases with methylated PKP1 were expressors, and 8/11 (73%) of EAC cases with unmethylated PKP1 were expressors.	('methylated', 'Var', (47, 57))	('PKP1', 'Gene', '5317', (126, 130))	('EAC', 'Phenotype', 'HP:0011459', (98, 101))	('EAC', 'Gene', '1540', (32, 35))	('PKP1', 'Gene', '5317', (58, 62))	('EAC', 'Gene', '1540', (98, 101))	('EAC', 'Gene', (32, 35))	('PKP1', 'Gene', (126, 130))	('EAC', 'Gene', (98, 101))	('PKP1', 'Gene', (58, 62))	('EAC', 'Phenotype', 'HP:0011459', (32, 35))
875402	22170739	Following siRNA knockdown we noted an adequate reduction in PKP1 mRNA expression, in the range of 33-69% versus non-targeting siRNA control treatment (Supplemental Figure 3).	('PKP1', 'Gene', (60, 64))	('reduction', 'NegReg', (47, 56))	('knockdown', 'Var', (16, 25))	('siRNA', 'Gene', (10, 15))	('PKP1', 'Gene', '5317', (60, 64))
875406	22170739	Similarly, knockdown of PKP1 in CP-D cells resulted in a 16.3-fold increase in cell motility (1.5 +/-0.7 control cells vs. 24.5 +/-3.5 PKP1 knock-down cells).	('PKP1', 'Gene', '5317', (24, 28))	('PKP1', 'Gene', (135, 139))	('cell motility', 'CPA', (79, 92))	('increase', 'PosReg', (67, 75))	('PKP1', 'Gene', '5317', (135, 139))	('PKP1', 'Gene', (24, 28))	('knockdown', 'Var', (11, 20))
875414	22170739	We first evaluated the methylation status of PKP1 in a collection of human esophageal biopsy specimens using methylation-specific PCR (MSP) and found that PKP1 was methylated in significantly more of the combined high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) cases than normal esophagus and Barrett's esophagus cases.	('more', 'PosReg', (192, 196))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (308, 327))	('PKP1', 'Gene', '5317', (155, 159))	('HGD', 'Gene', (235, 238))	('EAC', 'Gene', '1540', (271, 274))	('EAC', 'Gene', (271, 274))	('dysplasia', 'Disease', (224, 233))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (244, 269))	('dysplasia', 'Disease', 'MESH:D004476', (224, 233))	('PKP1', 'Gene', (155, 159))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (244, 269))	('esophageal adenocarcinoma', 'Disease', (244, 269))	('methylated', 'Var', (164, 174))	('human', 'Species', '9606', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('PKP1', 'Gene', '5317', (45, 49))	('EAC', 'Phenotype', 'HP:0011459', (271, 274))	('HGD', 'Gene', '3081', (235, 238))	('PKP1', 'Gene', (45, 49))
875415	22170739	These results suggest that the aberrant methylation of PKP1 occurs late in the BE-EAC progression sequence in a subset of esophageal cancer patients and may influence the malignant transformation of BE to EAC.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('EAC', 'Gene', '1540', (205, 208))	('BE', 'Phenotype', 'HP:0100580', (79, 81))	('EAC', 'Phenotype', 'HP:0011459', (205, 208))	('aberrant', 'Var', (31, 39))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('BE', 'Phenotype', 'HP:0100580', (199, 201))	('influence', 'Reg', (157, 166))	('PKP1', 'Gene', '5317', (55, 59))	('EAC', 'Gene', (205, 208))	('EAC', 'Gene', '1540', (82, 85))	('EAC', 'Gene', (82, 85))	('patients', 'Species', '9606', (140, 148))	('methylation', 'MPA', (40, 51))	('PKP1', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('malignant transformation', 'CPA', (171, 195))
875416	22170739	In order to demonstrate the effect of methylation on PKP1 expression, we treated the OE33 esophageal adenocarcinoma cell line, which carries methylated PKP1, with the demethylating agent 5-aza-deoxycytidine and found a 5.4-fold increase in expression following treatment, providing evidence that methylation of PKP1 can suppress its expression.	('PKP1', 'Gene', (152, 156))	('expression', 'MPA', (333, 343))	('5-aza-deoxycytidine', 'Chemical', 'MESH:D000077209', (187, 206))	('esophageal adenocarcinoma', 'Disease', (90, 115))	('suppress', 'NegReg', (320, 328))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (90, 115))	('PKP1', 'Gene', (53, 57))	('rat', 'Species', '10116', (19, 22))	('increase', 'PosReg', (228, 236))	('PKP1', 'Gene', '5317', (152, 156))	('expression', 'MPA', (240, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('PKP1', 'Gene', (311, 315))	('methylation', 'Var', (296, 307))	('PKP1', 'Gene', '5317', (53, 57))	('PKP1', 'Gene', '5317', (311, 315))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (90, 115))
875418	22170739	When we compared PKP1 expression in the EAC cases with methylated PKP1 to cases with unmethylated PKP1, there was no statistically significant difference between these groups.	('PKP1', 'Gene', '5317', (17, 21))	('PKP1', 'Gene', '5317', (98, 102))	('EAC', 'Phenotype', 'HP:0011459', (40, 43))	('EAC', 'Gene', '1540', (40, 43))	('PKP1', 'Gene', '5317', (66, 70))	('EAC', 'Gene', (40, 43))	('PKP1', 'Gene', (17, 21))	('PKP1', 'Gene', (98, 102))	('methylated', 'Var', (55, 65))	('PKP1', 'Gene', (66, 70))	('expression', 'MPA', (22, 32))
875426	22170739	They concluded that hypermethylation in only these distinct promoter sites accounted for the reduced MT3 expression they noted in the cancer cases.	('hypermethylation', 'Var', (20, 36))	('reduced', 'NegReg', (93, 100))	('cancer', 'Disease', (134, 140))	('MT3', 'Gene', '4504', (101, 104))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('MT3', 'Gene', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
875427	22170739	We also found that PKP1 expression in the non-dysplastic Barrett's esophagus cases was reduced compared to normal squamous esophagus even though only approximately 13% of cases had methylated PKP1, suggesting there are additional mechanisms responsible for the reduction of PKP1 levels in the majority of the BE cases.	("non-dysplastic Barrett's esophagus", 'Disease', (42, 76))	('PKP1', 'Gene', '5317', (192, 196))	('BE', 'Phenotype', 'HP:0100580', (309, 311))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (57, 76))	('expression', 'MPA', (24, 34))	('methylated', 'Var', (181, 191))	('PKP1', 'Gene', (19, 23))	('reduced', 'NegReg', (87, 94))	('PKP1', 'Gene', (274, 278))	('PKP1', 'Gene', (192, 196))	("non-dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (42, 76))	('PKP1', 'Gene', '5317', (19, 23))	('PKP1', 'Gene', '5317', (274, 278))
875432	22170739	In a similar fashion, it is possible that PKP1 methylation, which occurs in a subset of EAC cases, serves to 'reinforce' the silencing of PKP1 that occurs secondary to other mechanisms in BE.	('PKP1', 'Gene', (138, 142))	('EAC', 'Phenotype', 'HP:0011459', (88, 91))	('EAC', 'Gene', '1540', (88, 91))	('PKP1', 'Gene', '5317', (138, 142))	('methylation', 'Var', (47, 58))	('EAC', 'Gene', (88, 91))	('silencing', 'MPA', (125, 134))	('PKP1', 'Gene', '5317', (42, 46))	('BE', 'Phenotype', 'HP:0100580', (188, 190))	('PKP1', 'Gene', (42, 46))	("'reinforce'", 'PosReg', (109, 120))
875434	22170739	We propose that the process of esophageal carcinogenesis is the cumulative effect of both reduced PKP1 expression plus additional genetic and/or epigenetic alterations.	('epigenetic alterations', 'Var', (145, 167))	('PKP1', 'Gene', '5317', (98, 102))	('reduced', 'NegReg', (90, 97))	('rat', 'Species', '10116', (160, 163))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (31, 56))	('expression', 'MPA', (103, 113))	('esophageal carcinogenesis', 'Disease', (31, 56))	('PKP1', 'Gene', (98, 102))
875435	22170739	In light of PKP1's role as a critical component of the desmosome complex and in cell-cell adhesion, we next assessed the effect of PKP1 silencing on cell motility in BE.	('PKP1', 'Gene', (131, 135))	('PKP1', 'Gene', (12, 16))	('BE', 'Phenotype', 'HP:0100580', (166, 168))	('PKP1', 'Gene', '5317', (131, 135))	('silencing', 'Var', (136, 145))	('PKP1', 'Gene', '5317', (12, 16))
875437	22170739	Given PKP1's role in the organization and integrity of the desmosome complex, we hypothesized that altered levels of PKP1 might affect cell migration in Barrett's esophagus cell lines.	('altered', 'Var', (99, 106))	('affect', 'Reg', (128, 134))	('PKP1', 'Gene', '5317', (6, 10))	('PKP1', 'Gene', '5317', (117, 121))	('rat', 'Species', '10116', (143, 146))	('cell migration', 'CPA', (135, 149))	('PKP1', 'Gene', (6, 10))	('PKP1', 'Gene', (117, 121))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (153, 172))
875438	22170739	We found that PKP1 knock-down in both the CP-A and CP-D Barrett's esophagus cells resulted in significantly increased cell migration.	('PKP1', 'Gene', '5317', (14, 18))	('increased', 'PosReg', (108, 117))	('cell migration', 'CPA', (118, 132))	('PKP1', 'Gene', (14, 18))	('rat', 'Species', '10116', (126, 129))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (56, 75))	('knock-down', 'Var', (19, 29))
875439	22170739	These studies highlight the importance of PKP1 in cell-cell interactions and cell movement in cell lines, and as such reduced levels of PKP1 could be a mechanism of BE progression through decreasing cell adhesion and enhancing cell motility.	('levels', 'Var', (126, 132))	('cell adhesion', 'CPA', (199, 212))	('reduced', 'NegReg', (118, 125))	('enhancing', 'PosReg', (217, 226))	('PKP1', 'Gene', (136, 140))	('cell motility', 'CPA', (227, 240))	('PKP1', 'Gene', '5317', (42, 46))	('decreasing', 'NegReg', (188, 198))	('BE', 'Phenotype', 'HP:0100580', (165, 167))	('PKP1', 'Gene', (42, 46))	('PKP1', 'Gene', '5317', (136, 140))
875443	22170739	In oropharyngeal tumors, cytoplasmic localization of PKP1 has been associated with local recurrence, and alterations in expression of cadherin and catenin complexes have been described previously in Barrett's esophagus.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('cadherin', 'Protein', (134, 142))	('oropharyngeal tumors', 'Phenotype', 'HP:0100638', (3, 23))	('expression', 'MPA', (120, 130))	('cytoplasmic localization', 'Var', (25, 49))	('PKP1', 'Gene', (53, 57))	("Barrett's esophagus", 'Disease', (199, 218))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (199, 218))	('oropharyngeal tumors', 'Disease', 'MESH:D009959', (3, 23))	('alterations', 'Var', (105, 116))	('rat', 'Species', '10116', (109, 112))	('associated', 'Reg', (67, 77))	('PKP1', 'Gene', '5317', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('oropharyngeal tumors', 'Disease', (3, 23))	('local recurrence', 'Disease', (83, 99))
875445	22170739	Our results suggest that a similar mechanism occurs during the transformation from normal squamous esophagus to BE to EAC, where the loss of PKP1 at cell-cell junctions leads to disordered desmosome assembly and ensuing increased cell motility.	('PKP1', 'Gene', (141, 145))	('desmosome assembly', 'MPA', (189, 207))	('increased', 'PosReg', (220, 229))	('EAC', 'Gene', '1540', (118, 121))	('EAC', 'Gene', (118, 121))	('cell motility', 'CPA', (230, 243))	('disordered', 'Disease', 'MESH:D030342', (178, 188))	('BE', 'Phenotype', 'HP:0100580', (112, 114))	('PKP1', 'Gene', '5317', (141, 145))	('loss', 'Var', (133, 137))	('EAC', 'Phenotype', 'HP:0011459', (118, 121))	('disordered', 'Disease', (178, 188))
875446	22170739	Aberrant methylation of PKP1 occurs in a subset of BE and EAC cases and there are presumably additional mechanisms responsible for reducing PKP1 expression, and for modifying its subcellular location, in the remainder of cases.	('subcellular location', 'MPA', (179, 199))	('PKP1', 'Gene', '5317', (140, 144))	('PKP1', 'Gene', '5317', (24, 28))	('Aberrant', 'Var', (0, 8))	('BE', 'Phenotype', 'HP:0100580', (51, 53))	('EAC', 'Phenotype', 'HP:0011459', (58, 61))	('expression', 'MPA', (145, 155))	('EAC', 'Gene', '1540', (58, 61))	('reducing', 'NegReg', (131, 139))	('methylation', 'MPA', (9, 20))	('PKP1', 'Gene', (140, 144))	('PKP1', 'Gene', (24, 28))	('modifying', 'Reg', (165, 174))	('EAC', 'Gene', (58, 61))
875496	22280838	Using IPA, CRISP databases we identified a subset of 10 tumor dysregulated genes (AURKA , CDC2 , PDGFRA , PDGFA , IL8RB , NPR3 , NR3C2 , ODC1 , PRKCA , SOAT1 ) where therapeutic agents exist (MLN8054, flavopiridol, becaplermin, cilostazol, SB-265610, nesiritide, fludrocortisones acetate, eflornithine, L-threo-safingol, pactimibe; respectively) that act as inhibitors or agonists to the tumor dysregulated genes and are in clinical use or trial for other diseases.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('AURKA', 'Gene', '6790', (82, 87))	('ODC1', 'Gene', '4953', (137, 141))	('SOAT1', 'Gene', '6646', (152, 157))	('AURKA', 'Gene', (82, 87))	('PRKCA', 'Gene', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (388, 393))	('NR3C2', 'Gene', (129, 134))	('ODC1', 'Gene', (137, 141))	('SOAT1', 'Gene', (152, 157))	('IL8RB', 'Gene', (114, 119))	('PDGFA', 'Gene', (106, 111))	('eflornithine', 'Chemical', 'MESH:D000518', (289, 301))	('tumor', 'Disease', (56, 61))	('NPR3', 'Gene', '4883', (122, 126))	('CDC2', 'Gene', (90, 94))	('PRKCA', 'Gene', '5578', (144, 149))	('CDC2', 'Gene', '983', (90, 94))	('IL8RB', 'Gene', '3579', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (388, 393))	('NR3C2', 'Gene', '4306', (129, 134))	('NPR3', 'Gene', (122, 126))	('PDGFRA', 'Gene', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (388, 393))	('clinical', 'Species', '191496', (424, 432))	('PDGFA', 'Gene', '5154', (106, 111))	('PDGFRA', 'Gene', '5156', (97, 103))	('MLN8054', 'Var', (192, 199))
875547	22280838	However, IMP3 expression has been correlated with increased tumor aggressiveness and reduced overall survival in pituitary tumors.	('expression', 'Var', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('overall', 'MPA', (93, 100))	('increased tumor aggressiveness', 'Disease', (50, 80))	('IMP3', 'Gene', '55272', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('pituitary tumors', 'Disease', 'MESH:D010911', (113, 129))	('aggressiveness', 'Phenotype', 'HP:0000718', (66, 80))	('increased tumor aggressiveness', 'Disease', 'MESH:D009369', (50, 80))	('reduced', 'NegReg', (85, 92))	('IMP3', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('pituitary tumors', 'Disease', (113, 129))
875554	22280838	The G2M DNA Damage Checkpoint Regulation pathway acts to recognize damaged DNA and stop cell cycle progression at the G2/M transition, and defective G2/M checkpoints may increase cytotoxicity of chemotherapy.	('increase', 'PosReg', (170, 178))	('cytotoxicity', 'Disease', (179, 191))	('cell cycle progression', 'CPA', (88, 110))	('G2/M', 'Gene', (149, 153))	('defective', 'Var', (139, 148))	('cytotoxicity', 'Disease', 'MESH:D064420', (179, 191))	('stop', 'NegReg', (83, 87))
875564	22280838	ISG15 is associated with the FGF Signaling pathway and involved in protein metabolism and modification and has been associated at the protein and transcriptomic levels in oral cancer and was once associated with ESCC, suggesting that inhibition of ISG15 may be beneficial in treatment.	('oral cancer', 'Disease', 'MESH:D009062', (171, 182))	('ISG15', 'Gene', (0, 5))	('ISG15', 'Gene', '9636', (248, 253))	('associated', 'Reg', (196, 206))	('ESCC', 'Disease', (212, 216))	('ISG15', 'Gene', (248, 253))	('involved', 'Reg', (55, 63))	('oral cancer', 'Disease', (171, 182))	('FGF Signaling pathway', 'Pathway', (29, 50))	('associated', 'Reg', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('inhibition', 'Var', (234, 244))	('ISG15', 'Gene', '9636', (0, 5))	('associated', 'Reg', (116, 126))
875600	18775083	External compression of the left atrium was previously reported to provoke atrial fibrillation.	('atrial fibrillation', 'Disease', 'MESH:D001281', (75, 94))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (75, 94))	('External', 'Var', (0, 8))	('atrial fibrillation', 'Disease', (75, 94))
875673	16620378	According to epidemiological studies, HPV 16 is the most prevalent HPV type in cervical cancer, followed by HPV 18, 45, 31, and 33, in descending order.	('HPV', 'Species', '10566', (38, 41))	('HPV', 'Species', '10566', (108, 111))	('HPV type in cervical cancer', 'Disease', 'MESH:D030361', (67, 94))	('HPV 16', 'Var', (38, 44))	('HPV type in cervical cancer', 'Disease', (67, 94))	('HPV', 'Species', '10566', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HPV 16', 'Species', '333760', (38, 44))
875675	16620378	In patients with tonsil cancer, the presence of HPV in the tumors correlates with better survival.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('HPV', 'Species', '10566', (48, 51))	('better', 'PosReg', (82, 88))	('presence', 'Var', (36, 44))	('tumors', 'Disease', (59, 65))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('patients', 'Species', '9606', (3, 11))	('tonsil cancer', 'Phenotype', 'HP:0011110', (17, 30))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
875725	16620378	Amplification of HPV 16 DNA was detected in 16% of the patients and no other HPV type was detected.	('Amplification', 'Var', (0, 13))	('HPV 16', 'Gene', (17, 23))	('HPV', 'Species', '10566', (77, 80))	('HPV 16', 'Species', '333760', (17, 23))	('patients', 'Species', '9606', (55, 63))	('HPV', 'Species', '10566', (17, 20))
875734	16620378	According to earlier studies, HPV 16 is the most common type of HPV associated with head and neck malignancies, while other high-risk HPV types are rare.	('HPV', 'Species', '10566', (64, 67))	('associated', 'Reg', (68, 78))	('HPV 16', 'Var', (30, 36))	('malignancies', 'Disease', (98, 110))	('HPV 16', 'Species', '333760', (30, 36))	('HPV', 'Species', '10566', (30, 33))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('HPV', 'Species', '10566', (134, 137))
875748	16620378	However, for patients having a HPV 16 viral load > 1.0 viral genome per cell, an indication of higher survival rate was found in comparison with patients having a HPV 16 viral load < 1.0 viral genome per cell (Figure 2).	('survival rate', 'CPA', (102, 115))	('patients', 'Species', '9606', (145, 153))	('> 1.0', 'Var', (49, 54))	('patients', 'Species', '9606', (13, 21))	('higher', 'PosReg', (95, 101))	('HPV 16', 'Gene', (31, 37))	('HPV 16', 'Species', '333760', (31, 37))	('HPV 16', 'Species', '333760', (163, 169))
875753	16620378	Integration of HPV result in higher expression of the oncoproteins E6/E7, thereby abrogating the p53 and Rb protein functions, promoting genomic rearrangements and development of cervical carcinoma.	('higher', 'PosReg', (29, 35))	('promoting', 'PosReg', (127, 136))	('Integration', 'Var', (0, 11))	('cervical carcinoma', 'Disease', (179, 197))	('p53', 'Gene', (97, 100))	('E6/E7', 'Gene', '25479186', (67, 72))	('E6/E7', 'Gene', (67, 72))	('cervical carcinoma', 'Disease', 'MESH:D002575', (179, 197))	('p53', 'Gene', '7157', (97, 100))	('abrogating', 'NegReg', (82, 92))	('genomic rearrangements', 'CPA', (137, 159))	('HPV', 'Species', '10566', (15, 18))	('HPV', 'Gene', (15, 18))	('functions', 'MPA', (116, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('expression', 'MPA', (36, 46))
875754	16620378	Rearranged DNA is theoretically more sensitive to radiation, providing an explanation for the indication of a higher survival rate for patients with HPV positive tumors.	('patients', 'Species', '9606', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('HPV positive tumors', 'Disease', (149, 168))	('HPV positive tumors', 'Disease', 'MESH:D030361', (149, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('higher', 'PosReg', (110, 116))	('Rearranged', 'Var', (0, 10))
875756	16620378	In vitro studies report that cisplatin sensitivity is increased in HPV 16 transfected ovarian cancer cells, in accordance with results from the present study.	('HPV 16', 'Gene', (67, 73))	('ovarian cancer', 'Disease', (86, 100))	('HPV 16', 'Species', '333760', (67, 73))	('increased', 'PosReg', (54, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))	('transfected', 'Var', (74, 85))	('cisplatin sensitivity', 'MPA', (29, 50))
875777	31664951	Consistently, NKCC1 was found to have higher expression in more poorly differentiated esophageal squamous-cell carcinoma (SCC) cases and depletion of NKCC1 inhibited cell proliferation.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('depletion', 'Var', (137, 146))	('NKCC1', 'Gene', (150, 155))	('SCC', 'Disease', (122, 125))	('NKCC1', 'Gene', (14, 19))	('NKCC1', 'Gene', '6558', (150, 155))	('cell proliferation', 'CPA', (166, 184))	('squamous-cell carcinoma', 'Disease', 'MESH:D002294', (97, 120))	('expression', 'MPA', (45, 55))	('squamous-cell carcinoma', 'Disease', (97, 120))	('higher', 'PosReg', (38, 44))	('NKCC1', 'Gene', '6558', (14, 19))	('SCC', 'Disease', 'MESH:D002294', (122, 125))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('inhibited', 'NegReg', (156, 165))
875782	31664951	A cohort of newly diagnosed esophageal and gastric cancer patients was ascertained from English cancer registries between 1998 and 2013 using International Classification of Disease (ICD) codes C15 and C16, respectively.	('C16', 'Var', (202, 205))	('C15', 'Gene', '51316', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('C16', 'Chemical', 'MESH:C477640', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('C15', 'Gene', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('gastric cancer', 'Phenotype', 'HP:0012126', (43, 57))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', (96, 102))	('esophageal and gastric cancer', 'Disease', 'MESH:D013274', (28, 57))
875785	31664951	Deaths from esophageal or gastric cancer were identified up to September 2015 based upon the underlying cause of death (from the ONS mortality data) using ICD codes C15, C16 and C26.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('C15', 'Gene', (165, 168))	('gastric cancer', 'Phenotype', 'HP:0012126', (26, 40))	('gastric cancer', 'Disease', (26, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (26, 40))	('C15', 'Gene', '51316', (165, 168))	('C26', 'Var', (178, 181))	('C16', 'Var', (170, 173))	('C16', 'Chemical', 'MESH:C477640', (170, 173))	('esophageal', 'Disease', (12, 22))
875833	31664951	Preclinical studies have recently shown that inhibition of the NKCC1 could slow cancer cell deterioration by influencing cancer cell growth and metastasis, and furosemide could reduce cell growth in poorly differentiated gastric adenocarcinoma cells.	('furosemide', 'Chemical', 'MESH:D005665', (160, 170))	('cell growth', 'CPA', (184, 195))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (221, 243))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('NKCC1', 'Gene', (63, 68))	('slow', 'NegReg', (75, 79))	('NKCC1', 'Gene', '6558', (63, 68))	('inhibition', 'Var', (45, 55))	('gastric adenocarcinoma', 'Disease', (221, 243))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('poorly differentiated', 'CPA', (199, 220))	('influencing', 'Reg', (109, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('cancer', 'Disease', (121, 127))	('reduce', 'NegReg', (177, 183))	('cancer', 'Disease', (80, 86))
875941	28600510	The reported prevalence of HER2 discordance between primary tumors and corresponding metastases varies, hampering uniform patient selection for HER2 targeted therapy.	('primary tumor', 'Disease', (52, 65))	('patient', 'Species', '9606', (122, 129))	('primary tumor', 'Disease', 'MESH:D009369', (52, 65))	('discordance', 'Var', (32, 43))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('metastases', 'Disease', (85, 95))	('HER2', 'Gene', (144, 148))	('HER2', 'Gene', '2064', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('HER2', 'Gene', '2064', (144, 148))	('HER2', 'Gene', (27, 31))	('metastases', 'Disease', 'MESH:D009362', (85, 95))	('tumors', 'Disease', (60, 66))
875961	28600510	Considering the selection of eligible patients for trastuzumab treatment, it is important to notice that the ToGA trial included patients with either HER2 IHC 3+ scores and/or amplification of the HER2/neu gene by fluorescence in-situ hybridization (FISH).	('patients', 'Species', '9606', (129, 137))	('HER2/neu', 'Gene', '2064', (197, 205))	('HER2', 'Gene', (197, 201))	('trastuzumab', 'Chemical', 'MESH:D000068878', (51, 62))	('HER2', 'Gene', '2064', (197, 201))	('HER2/neu', 'Gene', (197, 205))	('HER2', 'Gene', (150, 154))	('patients', 'Species', '9606', (38, 46))	('HER2', 'Gene', '2064', (150, 154))	('amplification', 'Var', (176, 189))
875964	28600510	Those IHC 2+ tumors showing amplification of the HER2/neu gene (HER2:CEP17 ratio of 2.0, or when using a single probe >6.0 copies) are likewise confirmed HER2 positive cases and patients may be treated with trastuzumab.	('HER2/neu', 'Gene', (49, 57))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('patients', 'Species', '9606', (178, 186))	('HER2', 'Gene', (64, 68))	('HER2', 'Gene', '2064', (64, 68))	('trastuzumab', 'Chemical', 'MESH:D000068878', (207, 218))	('HER2', 'Gene', (154, 158))	('HER2', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HER2/neu', 'Gene', '2064', (49, 57))	('HER2', 'Gene', '2064', (154, 158))	('HER2', 'Gene', '2064', (49, 53))	('amplification', 'Var', (28, 41))
875967	28600510	with HER2 positivity defined as IHC score 3+ or IHC score 2+ with an amplification of the HER2/neu gene by in situ hybridization (ISH).	('HER2', 'Gene', (90, 94))	('HER2', 'Gene', (5, 9))	('HER2/neu', 'Gene', (90, 98))	('HER2', 'Gene', '2064', (90, 94))	('HER2', 'Gene', '2064', (5, 9))	('amplification', 'Var', (69, 82))	('HER2/neu', 'Gene', '2064', (90, 98))
875968	28600510	The broad definitions include IHC scores 2+ and 3+ marked HER2 positive (irrespective of ISH) or amplification of the HER2/neu gene without IHC analysis.	('amplification', 'Var', (97, 110))	('HER2/neu', 'Gene', (118, 126))	('HER2', 'Gene', (118, 122))	('HER2', 'Gene', '2064', (118, 122))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (58, 62))	('HER2/neu', 'Gene', '2064', (118, 126))
875989	28600510	The discordance rate between sub-groups showed no significant differences: method of HER2 detection (IHC3+ or IHC2+ and additional ISH), location (esophageal, GEJ/stomach), type of metastasis (locoregional lymph node or distant), timing of metastasis (synchronous or metachronous), sampling type (resection specimen or biopsy and resection specimen), received (neo)adjuvant therapy (yes, no or not reported), ethnicity (Asian or Western) and study design (retro- or prospective) (Table 4).	('IHC2+', 'Var', (110, 115))	('HER2', 'Gene', (85, 89))	('HER2', 'Gene', '2064', (85, 89))
876008	28600510	Therefore, for now, we advocate that patients with HER2 positivity according to the strict criteria in either primary tumor or metastasis should be offered HER2 targeted therapy.	('HER2', 'Gene', (156, 160))	('HER2', 'Gene', '2064', (156, 160))	('patients', 'Species', '9606', (37, 45))	('positivity', 'Var', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('primary tumor', 'Disease', (110, 123))	('HER2', 'Gene', (51, 55))	('primary tumor', 'Disease', 'MESH:D009369', (110, 123))	('HER2', 'Gene', '2064', (51, 55))
876024	28600510	Random-effect single-arm meta-analyses were performed in R version 3.2.3. applying the strict method of HER2 assessment on the following subgroups: gastric, GEJ or esophageal cancer, the prevalence of negative conversion or positive conversion, type of metastasis (regional, distant and synchronous or metachronous).	('esophageal cancer', 'Disease', (164, 181))	('esophageal cancer', 'Disease', 'MESH:D004938', (164, 181))	('positive', 'Var', (224, 232))	('GEJ', 'Disease', (157, 160))	('HER2', 'Gene', (104, 108))	('gastric', 'Disease', (148, 155))	('negative conversion', 'Var', (201, 220))	('HER2', 'Gene', '2064', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
876036	28028531	We used a single-channel upper gastrointestinal endoscope (GIF Q260J; Olympus, Tokyo, Japan), with an electrosurgical unit (ICC-200; ERBE, Tubingen, Germany) and electrosurgical knife (Dual knife KD-650 L/IT knife nano KD-612; Olympus, Tokyo, Japan).	('Q260J', 'SUBSTITUTION', 'None', (63, 68))	('Q260J', 'Var', (63, 68))	('upper gastrointestinal endoscope', 'Disease', (25, 57))	('upper gastrointestinal endoscope', 'Disease', 'MESH:D005767', (25, 57))
876143	24810640	Our group has shown that vaccination with Ad.E7 prevents the growth of another E7-expressing lung adenocarcinoma cell line, TC1.	('growth', 'MPA', (61, 67))	('lung adenocarcinoma', 'Disease', (93, 112))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (93, 112))	('Ad.E7', 'Var', (42, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('prevents', 'NegReg', (48, 56))	('TC1', 'CellLine', 'CVCL:1F93', (124, 127))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
876144	24810640	First, we confirmed that Ad.E7 vaccination could generate E7-specific CD8+ T cells.	('rat', 'Species', '10116', (53, 56))	('E7-specific', 'Var', (58, 69))	('Ad.E7', 'Var', (25, 30))
876145	24810640	Briefly, we vaccinated naive non tumor-bearing mice with Ad.E7 (n= 8) or Ad.LacZ (n=9) both 10 and 3 days prior to injecting AKR-E7 cells into the GE junction.	('Ad.E7', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Ad.LacZ', 'Var', (73, 80))	('tumor', 'Disease', (33, 38))	('mice', 'Species', '10090', (47, 51))
876146	24810640	Of note, at the time of tumor cell implantation, a mouse from each group was euthanized to confirm the presence of E7 epitope-specific CD8+ T cells using tetramer staining techniques.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('mouse', 'Species', '10090', (51, 56))	('E7 epitope-specific', 'Var', (115, 134))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
876147	24810640	As shown in Figure 3a, the Ad.E7-vaccinated animal generated more E7-specific CD8+ T cells than the Ad.LacZ control animal.	('Ad.E7-vaccinated', 'Var', (27, 43))	('rat', 'Species', '10116', (55, 58))	('E7-specific CD8+', 'MPA', (66, 82))
876150	24810640	We appreciated growth in 14% (1/7) of tumors in the mice randomized to Ad.E7 vaccination compared to 75% (6/8) in mice randomized to control vaccination protocols (p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mice', 'Species', '10090', (52, 56))	('Ad.E7 vaccination', 'Var', (71, 88))	('vaccination', 'Var', (77, 88))	('mice', 'Species', '10090', (114, 118))
876157	24810640	Thus, these results demonstrate that Ad.E7 vaccination generates tumor antigen-specific (E7-specific) CD8+ T cells with significant in vivo anti-tumor cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (151, 163))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cytotoxicity', 'Disease', (151, 163))	('tumor', 'Disease', (145, 150))	('rat', 'Species', '10116', (27, 30))	('rat', 'Species', '10116', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Ad.E7', 'Var', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
876161	24810640	Five days after tumor-injection, animals were randomized to receive administration of 1x1010 viral particles of either Ad.E7 (n=14) or Ad.LacZ (n=14) in the flank.	('rat', 'Species', '10116', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('Ad.E7', 'Var', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('Ad.LacZ', 'Var', (135, 142))
876164	24810640	By Day 14, we appreciated significant reduction in tumor growth in mice randomized to the Ad.E7 immunotherapy protocol compared to Ad.LacZ (control) (164 mg vs. 324 mg, respectively; p<0.05) (Figure 4a).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('Ad.E7', 'Var', (90, 95))	('reduction', 'NegReg', (38, 47))	('mice', 'Species', '10090', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
876165	24810640	As shown in the Kaplan Meier survival analysis in Figure 4b, animals who received Ad.E7 immunotherapy demonstrated significantly prolonged survival compared to Ad.LacZ-vaccinated animals.	('rat', 'Species', '10116', (109, 112))	('prolonged', 'PosReg', (129, 138))	('survival', 'CPA', (139, 147))	('Ad.E7 immunotherapy', 'Var', (82, 101))
876167	24810640	Thus, these results demonstrate that Ad.E7 vaccination, when employed as an immunotherapy in the treatment of esophageal cancer, has the potential to significantly reduce the rate of tumor growth and improve survival.	('improve', 'PosReg', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('Ad.E7 vaccination', 'Var', (37, 54))	('reduce', 'NegReg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('esophageal cancer', 'Disease', (110, 127))	('rat', 'Species', '10116', (27, 30))	('tumor', 'Disease', (183, 188))	('rat', 'Species', '10116', (175, 178))	('vaccination', 'Var', (43, 54))	('survival', 'CPA', (208, 216))
876169	24810640	Our group has shown that the reduction in TC1 flank tumor growth associated with Ad.E7 vaccination is the direct result of the induction of cytotoxic CD8+ T cells that secrete IFNgamma.	('IFNgamma', 'Gene', (176, 184))	('IFNgamma', 'Gene', '15978', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('reduction', 'NegReg', (29, 38))	('flank tumor', 'Disease', (46, 57))	('vaccination', 'Var', (87, 98))	('Ad.E7', 'Gene', (81, 86))	('TC1', 'CellLine', 'CVCL:1F93', (42, 45))	('flank tumor', 'Disease', 'MESH:D021501', (46, 57))
876170	24810640	To investigate if a similar mechanism was responsible for the reduction in tumor growth associated with our orthotopic esophageal cancer model, we analyzed tumors isolated from Ad.E7 and Ad.LacZ-treated tumor-bearing animals.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumors', 'Disease', (156, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('reduction', 'NegReg', (62, 71))	('Ad.E7', 'Var', (177, 182))	('tumor', 'Disease', (75, 80))	('esophageal cancer', 'Disease', (119, 136))
876172	24810640	Tumor-bearing animals were vaccinated with Ad.E7 (n=7) or Ad.LacZ (n=7) on Day 5 post tumor-injection and received a booster on Day 10.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Ad.LacZ', 'Var', (58, 65))	('Ad.E7', 'Var', (43, 48))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
876174	24810640	As shown in Figure 5, vaccination of AKR-E7 tumor-bearing animals with Ad.E7 resulted in a significant increase in tumor-associated CD8+ T cells compared to Ad.LacZ (control) (19% vs. 5.1%, respectively; p<0.05) (top panels of Figure 5a and 5b).	('Ad.E7', 'Var', (71, 76))	('increase', 'PosReg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
876176	24810640	Furthermore, when primed with PMA and ionomycin, a higher percentage of the intratumoral CD8+ T cells from the Ad.E7-vaccinated animals secreted IFNgamma (23.6% vs. 16.3%, respectively; p<0.05).	('IFNgamma', 'Gene', '15978', (145, 153))	('PMA', 'Chemical', 'MESH:D013755', (30, 33))	('Ad.E7-vaccinated', 'Var', (111, 127))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('rat', 'Species', '10116', (79, 82))	('ionomycin', 'Chemical', 'MESH:D015759', (38, 47))	('secreted', 'MPA', (136, 144))	('tumor', 'Disease', (81, 86))	('IFNgamma', 'Gene', (145, 153))
876177	24810640	Thus, these results suggest that the mechanism by which Ad.E7 vaccination limits the rate of orthotopic AKR-E7 tumor growth is dependent on the induction of antigen-specific CD8+ T cells which demonstrate increased tumor infiltration and IFNgamma production.	('rat', 'Species', '10116', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('IFNgamma', 'Gene', '15978', (238, 246))	('rat', 'Species', '10116', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('rat', 'Species', '10116', (85, 88))	('increased', 'PosReg', (205, 214))	('limits', 'NegReg', (74, 80))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('Ad.E7', 'Var', (56, 61))	('tumor', 'Disease', (215, 220))	('IFNgamma', 'Gene', (238, 246))
876187	24810640	An alternative model has utilized genetically engineered mice with p53 mutations.	('mice', 'Species', '10090', (57, 61))	('mutations', 'Var', (71, 80))	('p53', 'Gene', '22060', (67, 70))	('p53', 'Gene', (67, 70))
876211	24810640	Within this NSCLC model, our group was able to show that Ad.E7 vaccination significantly inhibited the growth of small tumors by inducing an antigen-specific, functionally active CD8+ T cell population.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('small tumors', 'Disease', (113, 125))	('small tumors', 'Disease', 'MESH:D058405', (113, 125))	('Ad.E7', 'Var', (57, 62))	('inhibited', 'NegReg', (89, 98))	('NSCLC', 'Disease', (12, 17))	('inducing', 'PosReg', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('growth', 'MPA', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
876214	24810640	More importantly, Ad.E7 vaccination significantly reduced the rate of established tumor growth and prolonged overall survival (Figures 4-5).	('Ad.E7 vaccination', 'Var', (18, 35))	('prolonged', 'PosReg', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('overall survival', 'CPA', (109, 125))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('reduced', 'NegReg', (50, 57))	('rat', 'Species', '10116', (62, 65))	('tumor', 'Disease', (82, 87))
876216	24810640	Experiments are currently underway to determine if augmentation with chemotherapy or COX-2 inhibitors may enhance the anti-tumor response and further limit tumor growth and prolong survival.	('limit', 'NegReg', (150, 155))	('enhance', 'PosReg', (106, 113))	('inhibitors', 'Var', (91, 101))	('tumor', 'Disease', (123, 128))	('COX-2', 'Gene', '17709', (85, 90))	('prolong', 'PosReg', (173, 180))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('survival', 'CPA', (181, 189))	('COX-2', 'Gene', (85, 90))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
876230	26339650	Aberrant hERG1 expression may be exploited either for early diagnosis (especially in those cancers where it is expressed in the initial steps of tumor progression) or for therapy purposes.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('hERG1', 'Gene', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancers', 'Disease', (91, 98))	('hERG1', 'Gene', '3757', (9, 14))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
876231	26339650	Indeed, hERG1 blockage impairs tumor cell growth both in vitro and in vivo in preclinical mouse model.	('blockage', 'Var', (14, 22))	('impairs tumor', 'Disease', 'MESH:D015417', (23, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('impairs tumor', 'Disease', (23, 36))	('mouse', 'Species', '10090', (90, 95))	('hERG1', 'Gene', '3757', (8, 13))	('hERG1', 'Gene', (8, 13))	('clinical', 'Species', '191496', (81, 89))
876265	26339650	More recently, it was shown that hERG1 hyperstimulation in SKBR3 and MDA-MB-231 cells might induce cell senescence.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (69, 79))	('hERG1', 'Gene', '3757', (33, 38))	('hERG1', 'Gene', (33, 38))	('cell senescence', 'CPA', (99, 114))	('SKBR3', 'CellLine', 'CVCL:0033', (59, 64))	('induce', 'Reg', (92, 98))	('hyperstimulation', 'Var', (39, 55))
876300	26339650	Even more interestingly, by treating xenografted cancers with a combination of hERG1 blockers and Bevacizumab the effect was greater than that obtained with single-agent treatment.	('hERG1', 'Gene', '3757', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('combination', 'Interaction', (64, 75))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (98, 109))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('hERG1', 'Gene', (79, 84))	('cancers', 'Disease', (49, 56))	('blockers', 'Var', (85, 93))
876312	26339650	The molecular sequence from adenoma to invasive cancer is well established, with the identification of misexpression and mutation of several genes (including rare inherited syndromes).	('invasive cancer', 'Disease', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('invasive cancer', 'Disease', 'MESH:D009362', (39, 54))	('adenoma', 'Disease', 'MESH:D000236', (28, 35))	('adenoma', 'Disease', (28, 35))	('mutation', 'Var', (121, 129))
876316	26339650	In CRC cell lines, a correlation between invasive phenotype and high hERG1 levels of expression has been shown and proliferation assays demonstrated that treating the cells with a specific hERG1 blocker (E4031) reduced tumor growth.	('hERG1', 'Gene', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('hERG1', 'Gene', '3757', (69, 74))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('hERG1', 'Gene', (69, 74))	('tumor', 'Disease', (219, 224))	('E4031', 'Var', (204, 209))	('reduced', 'NegReg', (211, 218))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('hERG1', 'Gene', '3757', (189, 194))
876325	26339650	Moreover, hERG1 presence associated with Glut-1 absence represents an independent negative prognostic factor in TNM I and II colorectal adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('hERG1', 'Gene', '3757', (10, 15))	('TNM', 'Gene', '10178', (112, 115))	('Glut-1', 'Gene', (41, 47))	('TNM', 'Gene', (112, 115))	('Glut-1', 'Gene', '6513', (41, 47))	('presence', 'Var', (16, 24))	('absence', 'NegReg', (48, 55))	('II colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (122, 151))	('II colorectal adenocarcinomas', 'Disease', (122, 151))	('hERG1', 'Gene', (10, 15))	('negative', 'NegReg', (82, 90))
876339	26339650	Moreover, blocking hERG1 in PDAC cells reduces cell growth and migration and we demonstrated that PDAC patients with high hERG1 expression had a worse prognosis.	('hERG1', 'Gene', '3757', (122, 127))	('blocking', 'Var', (10, 18))	('hERG1', 'Gene', '3757', (19, 24))	('hERG1', 'Gene', (19, 24))	('patients', 'Species', '9606', (103, 111))	('expression', 'MPA', (128, 138))	('hERG1', 'Gene', (122, 127))	('high', 'PosReg', (117, 121))	('reduces', 'NegReg', (39, 46))
876353	26339650	Among epigenetic aberrations that might be used as biomarkers, the best characterized is BRCA1 hypermethylation which leads to the absence of mRNA and protein and correlates with poor outcome.	('BRCA1', 'Gene', '672', (89, 94))	('BRCA1', 'Gene', (89, 94))	('absence', 'NegReg', (131, 138))	('hypermethylation', 'Var', (95, 111))
876359	26339650	Those results, although obtained in a small set of OC samples, might indicate that that loss of hERG1 expression by methylation could represent a potential prognostic marker.	('hERG1', 'Gene', (96, 101))	('expression', 'MPA', (102, 112))	('methylation', 'Var', (116, 127))	('hERG1', 'Gene', '3757', (96, 101))	('loss', 'NegReg', (88, 92))	('OC', 'Phenotype', 'HP:0100615', (51, 53))
876412	23370365	EUS stages at enrollment were T3N1 (29 pts), T3N0 (4 pts), T2N1 (6 pts), and T4N0 (1 pts).	('T2N1', 'Var', (59, 63))	('pts', 'Species', '9606', (67, 70))	('pts', 'Species', '9606', (39, 42))	('pts', 'Species', '9606', (53, 56))	('pts', 'Species', '9606', (85, 88))	('T3N0', 'Var', (45, 49))	('T4N0', 'Var', (77, 81))	('T3N1', 'Disease', (30, 34))
876434	23370365	Previously untreated patients with locally advanced, surgically resectable cancer of the esophagus or gastroesophageal (GE) junction, clinical stage II-III (T2-4N0M0, T1-4N1M0) with histologic or cytologic evidence of adenocarcinoma or squamous cell carcinoma confirmed by the Department of Pathology at Dartmouth-Hitchcock Medical Center were eligible.	('T1-4N1M0', 'Var', (167, 175))	('cancer of the esophagus or gastroesophageal', 'Disease', (75, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (236, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('cancer of the esophagus or gastroesophageal', 'Disease', 'MESH:D004938', (75, 118))	('patients', 'Species', '9606', (21, 29))	('cancer of the esophagus', 'Phenotype', 'HP:0100751', (75, 98))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('adenocarcinoma or squamous cell carcinoma', 'Disease', 'MESH:D002294', (218, 259))	('T2-4N0M0', 'Var', (157, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('adenocarcinoma or squamous cell carcinoma', 'Disease', (218, 259))
876472	23370365	Clinical stages at enrollment were T3N1 (N=29, 72.5%), T2N1 (N=6, 15%), T3N0 (N=4 10%), and T4N0 (N=1, 2.5%) with disease involving the distal esophagus (N=12, 30%), the distal esophagus and the GE junction (N=19, 47.5%), or both these areas and the cardia of the stomach (N=8, 20%).	('cardia of the stomach', 'Disease', 'MESH:D004938', (250, 271))	('T4N0', 'Var', (92, 96))	('T3N0', 'Var', (72, 76))	('cardia of the stomach', 'Disease', (250, 271))
876499	23370365	We found that 11 patients (30.6%, 95% confidence interval 15.5% - 45.6%) who had pCR or MRD had a median survival of 86.6 months, compared to a median survival of 19.1 months for 25 patients who had a greater extend of residual disease.	('pCR', 'Var', (81, 84))	('MRD', 'Var', (88, 91))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (182, 190))
876545	31383552	In addition, the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathway is implicated in the modulation of human cancers by miR-134.	('cancers', 'Disease', (159, 166))	('ERK', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('miR-134', 'Var', (170, 177))	('human', 'Species', '9606', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('implicated', 'Reg', (121, 131))	('ERK', 'Gene', '5594', (94, 97))
876547	31383552	We found that miR-134 could restrain the cancer cell proliferation, migration, invasion, and tumour metastasis of ESCC through its regulation on PLXNA1-mediated MAPK signalling pathway.	('miR-134', 'Var', (14, 21))	('tumour metastasis', 'Disease', 'MESH:D009362', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('ESCC', 'Disease', (114, 118))	('restrain', 'NegReg', (28, 36))	('regulation', 'Reg', (131, 141))	('tumour metastasis', 'Disease', (93, 110))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', (41, 47))	('invasion', 'CPA', (79, 87))	('PLXNA1-mediated MAPK signalling pathway', 'Pathway', (145, 184))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('migration', 'CPA', (68, 77))
876558	31383552	In particular, PLXNA1 has been demonstrated to accelerate the progression of lung cancer.	('accelerate', 'PosReg', (47, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('progression', 'CPA', (62, 73))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('PLXNA1', 'Var', (15, 21))	('lung cancer', 'Disease', (77, 88))
876579	31383552	When the cell density reached 70% - 80%, cells were treated with miR-134 mimic, miR-134 inhibitor, siRNA targeting PLXNA1 (si-PLXNA1) alone, or SB203580 (a p38MAPK inhibitor), LY3214996 (a ERK inhibitor), SP600125 (a JNK inhibitor) in the presence of si-PLXNA1, with dimethylsulfoxide (DMSO) in the presence of si-PLXNA1 as control (the final concentration of inhibitors was 10 nM, respectively) according to the instructions of lipofectamine 2000 (11668-019, Invitrogen, Carlsbad, CA, USA).	('SP600125', 'Chemical', 'MESH:C432165', (205, 213))	('SP600125', 'Var', (205, 213))	('JNK', 'Gene', '5599', (217, 220))	('SB203580', 'Chemical', 'MESH:C093642', (144, 152))	('LY3214996', 'Var', (176, 185))	('p38', 'Gene', (156, 159))	('SB203580', 'Var', (144, 152))	('LY3214996', 'Chemical', '-', (176, 185))	('si-PLXNA1', 'Var', (251, 260))	('p38', 'Gene', '5594', (156, 159))	('ERK', 'Gene', '5594', (189, 192))	('JNK', 'Gene', (217, 220))	('DMSO', 'Chemical', 'MESH:D004121', (286, 290))	('ERK', 'Gene', (189, 192))
876585	31383552	Afterwards, the membrane was incubated with the following primary antibodies at 4  overnight: ERK (1: 1000, ab196883), JNK (1: 1000, ab4821), p38 (1: 1000, ab170099), BAX (1: 2000, ab32503), Bcl-2 (1: 1000, ab32124), p-ERK (1: 200, ab214362), p-JNK (1: 1000, ab124956) and p-p38 (1: 1000, ab4822).	('p-ERK', 'Gene', (217, 222))	('JNK', 'Gene', (119, 122))	('Bcl-2', 'Gene', '596', (191, 196))	('p38', 'Gene', '5594', (142, 145))	('JNK', 'Gene', '5599', (119, 122))	('ERK', 'Gene', (219, 222))	('JNK', 'Gene', (245, 248))	('BAX', 'Gene', '581', (167, 170))	('BAX', 'Gene', (167, 170))	('JNK', 'Gene', '5599', (245, 248))	('1: 1000', 'Var', (198, 205))	('p38', 'Gene', '5594', (275, 278))	('ERK', 'Gene', '5594', (94, 97))	('1: 1000', 'Var', (250, 257))	('ERK', 'Gene', (94, 97))	('p38', 'Gene', (142, 145))	('1: 1000', 'Var', (280, 287))	('Bcl-2', 'Gene', (191, 196))	('ERK', 'Gene', '5594', (219, 222))	('ab32503', 'Var', (181, 188))	('p-ERK', 'Gene', '9451', (217, 222))	('p38', 'Gene', (275, 278))
876614	31383552	The expression of BAX was elevated when the cells were transfected with miR-134 mimic, si-PLXNA1, or co-transfected with miR-134 mimic plus si-PLXNA1, while that of Bcl-2 was reduced (p < .05).	('si-PLXNA1', 'Var', (87, 96))	('expression', 'MPA', (4, 14))	('elevated', 'PosReg', (26, 34))	('BAX', 'Gene', (18, 21))	('BAX', 'Gene', '581', (18, 21))	('Bcl-2', 'Gene', (165, 170))	('Bcl-2', 'Gene', '596', (165, 170))	('miR-134', 'Gene', (72, 79))
876616	31383552	The mRNA and protein expression levels of PLXNA1 as well as the ratios of p-ERK/ERK, p-JNK/JNK and p-p38/p38 were significantly increased in the cells transfected with miR-134 inhibitor, but decreased in the cells transfected with miR-134 mimic, si-PLXNA1, or co-transfected with miR-134 mimic plus si-PLXNA1 (all p < .05).	('p-JNK/JNK', 'Gene', (85, 94))	('ERK', 'Gene', '5594', (80, 83))	('ERK', 'Gene', (76, 79))	('p38', 'Gene', (101, 104))	('ERK', 'Gene', (80, 83))	('increased', 'PosReg', (128, 137))	('p-JNK/JNK', 'Gene', '5599', (85, 94))	('inhibitor', 'Var', (176, 185))	('p-ERK', 'Gene', '9451', (74, 79))	('p-ERK', 'Gene', (74, 79))	('p38', 'Gene', (105, 108))	('miR-134', 'Var', (168, 175))	('p38', 'Gene', '5594', (101, 104))	('p38', 'Gene', '5594', (105, 108))	('ERK', 'Gene', '5594', (76, 79))
876617	31383552	The regulatory effects of miR-134 on ESCC cell proliferation, cell cycle, and apoptosis in ESCC cells expressing miR-134 and in those with the absence of miR-134 or PLXNA1 were each determined by CCK-8 assay, PI staining, and Annexin V/PI double-staining assay, respectively.	('apoptosis', 'CPA', (78, 87))	('Annexin V', 'Gene', (226, 235))	('cell cycle', 'CPA', (62, 72))	('miR-134', 'Var', (113, 120))	('Annexin V', 'Gene', '308', (226, 235))
876618	31383552	8a-d) as compared with DMSO treatment in the presence of si-PLXNA1, SB203580, LY3214996, and SP600125 in the presence of si-PLXNA1 treatments exerted an inhibitory effect on cell proliferation, migration and invasion, but a promotive effect on cell apoptosis (p < .05).	('invasion', 'CPA', (208, 216))	('si-PLXNA1', 'Var', (57, 66))	('cell proliferation', 'CPA', (174, 192))	('SB203580', 'Chemical', 'MESH:C093642', (68, 76))	('DMSO', 'Chemical', 'MESH:D004121', (23, 27))	('SP600125', 'Var', (93, 101))	('LY3214996', 'Chemical', '-', (78, 87))	('cell apoptosis', 'CPA', (244, 258))	('SP600125', 'Chemical', 'MESH:C432165', (93, 101))
876619	31383552	8f, g) showed that Bcl-2 expression decreased and BAX expression was elevated after treatment with SB203580, LY3214996, and SP600125 in the presence of si-PLXNA1 versus that after co-treatment of si-PLXNA1 and DMSO (p < .05).	('expression', 'MPA', (54, 64))	('SP600125', 'Var', (124, 132))	('expression', 'MPA', (25, 35))	('SB203580', 'Chemical', 'MESH:C093642', (99, 107))	('Bcl-2', 'Gene', '596', (19, 24))	('SB203580', 'Var', (99, 107))	('Bcl-2', 'Gene', (19, 24))	('BAX', 'Gene', '581', (50, 53))	('DMSO', 'Chemical', 'MESH:D004121', (210, 214))	('si-PLXNA1', 'Var', (152, 161))	('decreased', 'NegReg', (36, 45))	('SP600125', 'Chemical', 'MESH:C432165', (124, 132))	('elevated', 'PosReg', (69, 77))	('BAX', 'Gene', (50, 53))	('LY3214996', 'Chemical', '-', (109, 118))	('LY3214996', 'Var', (109, 118))
876624	31383552	The tumour weight, tumour volume, and MLD were significantly decreased in the mice injected with cells transfected with miR-134 mimic or si-PLXNA1 or both, since the 12th day (all p < .05).	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('tumour weight', 'Disease', 'MESH:D015431', (4, 17))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour weight', 'Disease', (4, 17))	('tumour', 'Disease', (19, 25))	('mice', 'Species', '10090', (78, 82))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('MLD', 'Disease', 'MESH:D007966', (38, 41))	('tumour', 'Disease', (4, 10))	('decreased', 'NegReg', (61, 70))	('miR-134', 'Gene', (120, 127))	('MLD', 'Disease', (38, 41))	('si-PLXNA1', 'Var', (137, 146))
876625	31383552	The tumour growth rate and volume were the lowest in the mice injected with cells co-transfected with miR-134 mimic and si-PLXNA1 (p < .01).	('mice', 'Species', '10090', (57, 61))	('lowest', 'NegReg', (43, 49))	('tumour growth', 'Disease', (4, 17))	('si-PLXNA1', 'Var', (120, 129))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour growth', 'Disease', 'MESH:D006130', (4, 17))	('miR-134', 'Gene', (102, 109))
876629	31383552	Only a few lymphatic vessels were found in strip shape in the mice injected with cells transfected with miR-134 mimic or si-PLXNA1 or both, and the MLD of these lymphatic vessels in these groups (8.68 +- 2.13, 9.75 +- 1.40, and 6.13 +- 1.18 respectively) was significantly lower than that in the mice injected with non-transfected cells or cells transfected with empty plasmid (p < .05).	('miR-134', 'Gene', (104, 111))	('MLD', 'Disease', (148, 151))	('mice', 'Species', '10090', (296, 300))	('mice', 'Species', '10090', (62, 66))	('si-PLXNA1', 'Var', (121, 130))	('lower', 'NegReg', (273, 278))	('MLD', 'Disease', 'MESH:D007966', (148, 151))
876630	31383552	However, the injection of miR-134 inhibitor-transfected cells resulted in more dilated lymphatic vessels in tumour tissues, some cancer cells in lymphatic vessels, and a higher MLD (16.79 +- 2.97) than those in the mice injected with non-transfected cells or cells transfected with empty plasmid (p < .05).	('tumour', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('more', 'PosReg', (74, 78))	('MLD', 'Disease', (177, 180))	('higher', 'PosReg', (170, 176))	('MLD', 'Disease', 'MESH:D007966', (177, 180))	('dilated lymphatic vessels in', 'CPA', (79, 107))	('miR-134', 'Gene', (26, 33))	('inhibitor-transfected', 'Var', (34, 55))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('mice', 'Species', '10090', (215, 219))	('tumour', 'Disease', 'MESH:D009369', (108, 114))
876637	31383552	It has also been found that miR-134 can impede gastric cancer cell proliferation by downregulating GOLPH3.	('miR-134', 'Var', (28, 35))	('gastric cancer', 'Disease', (47, 61))	('GOLPH3', 'Gene', '64083', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('downregulating', 'NegReg', (84, 98))	('impede', 'NegReg', (40, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('GOLPH3', 'Gene', (99, 105))
876638	31383552	In a similar finding, it has been demonstrated that PLXNA1 functions as a tumour promoter in prostate cancer.	('prostate cancer', 'Disease', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('PLXNA1', 'Var', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
876639	31383552	PLXNA1 knockdown is shown to reduce the proliferation-marker genes at the mRNA level and downregulate cell proliferation in Lewis lung carcinoma (LLC) cells.	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('Lewis lung carcinoma', 'Disease', (124, 144))	('PLXNA1', 'Gene', (0, 6))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (124, 144))	('downregulate', 'NegReg', (89, 101))	('knockdown', 'Var', (7, 16))	('reduce', 'NegReg', (29, 35))	('cell proliferation', 'CPA', (102, 120))
876648	31383552	In this study, the level of BAX was found increased, while the level of Bcl-2 was noted as decreased after miR-134 overexpression, suggesting that miR-134 potentially induces the apoptosis of ESCC cells.	('increased', 'PosReg', (42, 51))	('induces', 'Reg', (167, 174))	('Bcl-2', 'Gene', (72, 77))	('Bcl-2', 'Gene', '596', (72, 77))	('apoptosis', 'CPA', (179, 188))	('BAX', 'Gene', (28, 31))	('BAX', 'Gene', '581', (28, 31))	('miR-134', 'Var', (147, 154))	('level', 'MPA', (19, 24))
876649	31383552	Hence, it is reasonable to conclude that upregulation of miR-134 suppresses tumour metastasis and induces cell apoptosis, thus preventing the progression of ESCC by downregulation of PLXNA1, In this study, miR-134 was further demonstrated to inhibit the expression of MAPK signalling pathway-related proteins via downregulating PLXNA1.	('miR-134', 'Var', (206, 213))	('tumour metastasis', 'Disease', 'MESH:D009362', (76, 93))	('inhibit', 'NegReg', (242, 249))	('PLXNA1', 'Gene', (328, 334))	('downregulating', 'NegReg', (313, 327))	('induces', 'Reg', (98, 105))	('MAPK signalling pathway-related', 'Pathway', (268, 299))	('cell apoptosis', 'CPA', (106, 120))	('expression', 'MPA', (254, 264))	('ESCC', 'Disease', (157, 161))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour metastasis', 'Disease', (76, 93))	('suppresses', 'NegReg', (65, 75))	('upregulation', 'PosReg', (41, 53))
876653	31383552	In agreement with our findings, miR-134 suppressed proliferation and EMT of renal cell carcinoma cells by downregulating the MAPK/ERK signalling pathway.	('suppressed', 'NegReg', (40, 50))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('miR-134', 'Var', (32, 39))	('ERK', 'Gene', '5594', (130, 133))	('proliferation', 'CPA', (51, 64))	('EMT of renal cell carcinoma', 'Disease', 'MESH:C538614', (69, 96))	('ERK', 'Gene', (130, 133))	('EMT of renal cell carcinoma', 'Disease', (69, 96))	('downregulating', 'NegReg', (106, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
876656	29675925	Pathway abnormalities enhance the reactive oxygen species scavenging ability of cancer cells; thus the pathway is involved in carcinogenesis and resistance to chemoradiotherapy (CRT).	('reactive oxygen species scavenging', 'MPA', (34, 68))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('abnormalities', 'Var', (8, 21))	('carcinogenesis', 'Disease', (126, 140))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (34, 57))	('involved', 'Reg', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('enhance', 'PosReg', (22, 29))	('cancer', 'Disease', (80, 86))
876663	29675925	As a core transcription factor, Nrf2 is bound to Keap1 in cytoplasm and degrades in a proteasome-dependent manner under homeostatic conditions.19 Oxidative stress results in conformational change of the Keap1-Nrf2 complex, allowing Nrf2 to be translocated into the nucleus and activating the transcription of target antioxidant and redox genes.20, 21, 22, 23 Aberrant signaling via the Keap1-Nrf2 pathway frequently occurs in cancer cells, leading to the over-activation of Nrf2 and elevation of ROS scavenging ability, facilitating the initiation and development of malignant cells that produce ROS during rapid proliferation.24, 25, 26, 27, 28, 29, 30 On the other hand, ROS are also indispensable for the therapeutic effect of platinum complexes, fluorouracil, and X-ray, which means that Nrf2 over-activation could also help cancer cells survive chemotherapy and irradiation and subsequently relapse.9, 11, 12, 13, 14, 26, 31  The promoting role of aberrant Keap1-Nrf2 signaling in carcinogenesis and therapy resistance has been well demonstrated in vivo and animal models;7, 13, 17, 25, 29, 31, 32 however, relevant clinical studies remain inadequate.	('aberrant', 'Var', (953, 961))	('cancer', 'Disease', (829, 835))	('promoting', 'PosReg', (935, 944))	('cancer', 'Phenotype', 'HP:0002664', (426, 432))	('carcinogenesis', 'Disease', 'MESH:D063646', (986, 1000))	('platinum', 'Chemical', 'MESH:D010984', (730, 738))	('cancer', 'Phenotype', 'HP:0002664', (829, 835))	('ROS', 'Chemical', 'MESH:D017382', (673, 676))	('cancer', 'Disease', (426, 432))	('ROS', 'Chemical', 'MESH:D017382', (596, 599))	('cancer', 'Disease', 'MESH:D009369', (426, 432))	('Oxidative stress', 'Phenotype', 'HP:0025464', (146, 162))	('elevation of ROS scavenging ability', 'Phenotype', 'HP:0025464', (483, 518))	('therapy resistance', 'CPA', (1005, 1023))	('carcinogenesis', 'Disease', (986, 1000))	('ROS', 'Chemical', 'MESH:D017382', (496, 499))	('cancer', 'Disease', 'MESH:D009369', (829, 835))
876695	29675925	The promoting role of aberrant Keap1-Nrf2 signaling in carcinogenesis was proven in a clinical setting.	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('aberrant', 'Var', (22, 30))	('Keap1-Nrf2', 'Gene', (31, 41))	('carcinogenesis', 'Disease', (55, 69))
876698	28937022	Mutation of tumor suppressor gene p53 is observed in many gastrointestinal malignancies including ESCC.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('Mutation', 'Var', (0, 8))	('ESCC', 'Disease', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('observed', 'Reg', (41, 49))	('gastrointestinal malignancies', 'Disease', (58, 87))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (58, 87))	('tumor', 'Disease', (12, 17))
876699	28937022	The immunohistochemical protein expression of mutant p53 has been proposed as a potential tool to evaluate the biological behavior of ESCC.	('mutant', 'Var', (46, 52))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))
876720	28937022	Deregulation of the cell cycle leads to tumorigenesis.	('cell cycle', 'CPA', (20, 30))	('Deregulation', 'Var', (0, 12))	('leads to', 'Reg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
876721	28937022	Genetic and epigenetic changes affecting cell cycle regulating genes are the major events during carcinogenesis.	('carcinogenesis', 'Disease', (97, 111))	('Genetic', 'Var', (0, 7))	('cell cycle regulating genes', 'Gene', (41, 68))	('epigenetic changes', 'Var', (12, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (97, 111))
876723	28937022	Genetic and epigenetic alterations in this pathway lead to inactivation of these genes, thus leading to uncontrolled proliferation of damaged DNA, which turns into cancer formation.	('leading to', 'Reg', (93, 103))	('inactivation', 'NegReg', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('turns into', 'Reg', (153, 163))	('uncontrolled proliferation', 'MPA', (104, 130))	('epigenetic alterations', 'Var', (12, 34))	('lead to', 'Reg', (51, 58))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))
876725	28937022	It is well known that these mutations can lead to an increase in expression of p53, which accumulates in nuclei and can be detected by immunohistochemistry (IHC) methods.	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', (79, 82))	('increase', 'PosReg', (53, 61))	('expression', 'MPA', (65, 75))	('mutations', 'Var', (28, 37))
876743	28937022	The IHC staining of mutant (MT) p53 was assessed according to the Immunoreactive Score (IRS) [Table 1a and b], which is based on the percentage of positive cells and the staining intensity.	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('mutant', 'Var', (20, 26))
876761	28937022	On Kaplan-Meier survival analysis, patients with p53 high expression had significantly shorter overall survival than those patients with low p53 expression (log-rank P < 0.0001) [Chart 1].	('p53', 'Gene', (49, 52))	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('p53', 'Gene', '7157', (49, 52))	('patients', 'Species', '9606', (123, 131))	('shorter', 'NegReg', (87, 94))	('overall survival', 'MPA', (95, 111))	('patients', 'Species', '9606', (35, 43))	('high expression', 'Var', (53, 68))
876762	28937022	At 12th month of follow-up, 67.89% (CI 0.75-0.97) of patients with p53 high-expression group survived and 91.43% (CI 0.53-0.76) of patients with p53 low-expression group survived.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (53, 61))	('high-expression', 'Var', (71, 86))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('p53', 'Gene', '7157', (67, 70))	('p53', 'Gene', (67, 70))
876763	28937022	Multivariate analysis by Cox regression model further shows that high p53 expression was an independent predictor of overall poorer survival [heart rate (HR) = 5.5; 95% CI 4.1-13.51, P = 0.005].	('expression', 'MPA', (74, 84))	('p53', 'Gene', (70, 73))	('Cox', 'Gene', '1351', (25, 28))	('poorer', 'NegReg', (125, 131))	('Cox', 'Gene', (25, 28))	('p53', 'Gene', '7157', (70, 73))	('high', 'Var', (65, 69))
876768	28937022	Mutation in p53 results in the loss of its ability to induce cell death leading to uncontrolled cell growth, which promotes tumorigenesis.	('cell death', 'CPA', (61, 71))	('loss', 'NegReg', (31, 35))	('uncontrolled', 'MPA', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('ability', 'MPA', (43, 50))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', (124, 129))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('promotes', 'PosReg', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
876769	28937022	Normally p53 gene is not detected immunohistochemically, but when mutated p53 becomes stabilized and has an increased half-life; thus it accumulates in the cell nucleus and can be detected immunohistochemically using monoclonal antibodies.	('mutated', 'Var', (66, 73))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('half-life', 'MPA', (118, 127))	('accumulates', 'PosReg', (137, 148))	('p53', 'Gene', (74, 77))	('p53', 'Gene', '7157', (74, 77))
876770	28937022	Mutations of p53 gene have been observed in many malignancies and are found in ~30-50% of lung, colorectal, head and neck, and ovarian cancers, and in ~5% of leukemia, sarcoma, melanoma, testicular cancer, and cervical cancer patients.	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('observed', 'Reg', (32, 40))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('ovarian cancers', 'Disease', (127, 142))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('lung', 'Disease', (90, 94))	('ovarian cancers', 'Disease', 'MESH:D010051', (127, 142))	('testicular cancer', 'Disease', (187, 204))	('malignancies', 'Disease', (49, 61))	('colorectal', 'Disease', (96, 106))	('testicular cancer', 'Phenotype', 'HP:0010788', (187, 204))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('patients', 'Species', '9606', (226, 234))	('p53', 'Gene', '7157', (13, 16))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('leukemia', 'Disease', (158, 166))	('ovarian cancers', 'Phenotype', 'HP:0100615', (127, 142))	('leukemia', 'Disease', 'MESH:D007938', (158, 166))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('cervical cancer', 'Disease', 'MESH:D002583', (210, 225))	('p53', 'Gene', (13, 16))	('cervical cancer', 'Disease', (210, 225))	('found', 'Reg', (70, 75))	('sarcoma', 'Disease', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('testicular cancer', 'Disease', 'MESH:D013736', (187, 204))
876773	28937022	p53 protein accumulation not only represents mutated p53 gene but also represents effect of other genes on its expression, so expression of p53 needs to be assessed separately for survival prediction.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('protein', 'Protein', (4, 11))	('p53', 'Gene', (53, 56))	('accumulation', 'PosReg', (12, 24))	('p53', 'Gene', '7157', (53, 56))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('mutated', 'Var', (45, 52))
876776	28937022	Previous studies showed 41-87% of p53 positivity in ESCC patients.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('positivity', 'Var', (38, 48))	('patients', 'Species', '9606', (57, 65))	('ESCC', 'Disease', (52, 56))
876790	28937022	In our study Kaplan-Meier analysis demonstrated that patients with high p53 expression show significantly poor survival than patients with low p53 expression.	('high', 'Var', (67, 71))	('p53', 'Gene', '7157', (143, 146))	('patients', 'Species', '9606', (53, 61))	('p53', 'Gene', (72, 75))	('poor', 'NegReg', (106, 110))	('p53', 'Gene', '7157', (72, 75))	('survival', 'CPA', (111, 119))	('p53', 'Gene', (143, 146))	('patients', 'Species', '9606', (125, 133))
876984	25743945	Variations of gastric corpus microbiota are associated with early esophageal squamous cell carcinoma and squamous dysplasia Observational studies revealed a relationship between changes in gastric mucosa and risk of esophageal squamous cell carcinoma (ESCC) which suggested a possible role for gastric microbiota in ESCC carcinogenesis.	('associated', 'Reg', (44, 54))	('carcinogenesis', 'Disease', 'MESH:D063646', (321, 335))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('squamous dysplasia', 'Disease', (105, 123))	('esophageal squamous cell carcinoma', 'Disease', (216, 250))	('carcinogenesis', 'Disease', (321, 335))	('biota', 'Species', '131567', (307, 312))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (66, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('squamous dysplasia', 'Disease', 'MESH:D002294', (105, 123))	('changes', 'Var', (178, 185))	('Variations', 'Var', (0, 10))	('esophageal squamous cell carcinoma', 'Disease', (66, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (105, 123))	('biota', 'Species', '131567', (34, 39))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (216, 250))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (227, 250))
877015	25743945	In an animal study, presence of members of Clostridiales altered the pathogenicity of H. pylori by recruitment of CD4 T-cells to the gastric mucosa which suggests a possible impact of microbial composition on gastritis outcome.	('gastritis', 'Disease', 'MESH:D005756', (209, 218))	('gastritis', 'Phenotype', 'HP:0005263', (209, 218))	('CD4 T-cells', 'CPA', (114, 125))	('pathogenicity', 'MPA', (69, 82))	('gastritis', 'Disease', (209, 218))	('H. pylori', 'Species', '210', (86, 95))	('H. pylori', 'Disease', (86, 95))	('altered', 'Reg', (57, 64))	('presence', 'Var', (20, 28))	('recruitment', 'PosReg', (99, 110))
877080	19959682	Eligible cases were classified under specific ICD-O codes (C00, C01, C02, C03, C04, C05, C06, C09, C10, C12, C13, C14.0, C14.8, C15.0, C15.3, C15.4, C15.5, C15.8, C15.9, and C32), including cancer of the oral cavity, pharynx (excluding nasopharynx), larynx and esophagus.	('C04', 'Var', (79, 82))	('C15.9', 'CellLine', 'CVCL:0H97', (163, 168))	('C15.9', 'Var', (163, 168))	('C03', 'Var', (74, 77))	('cancer', 'Disease', (190, 196))	('C12', 'Var', (104, 107))	('C15.8', 'Var', (156, 161))	('C14.0', 'Var', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('C13', 'Var', (109, 112))	('esophagus', 'Disease', (261, 270))	('C15.3', 'Var', (135, 140))	('C01', 'CellLine', 'CVCL:E303', (64, 67))	('C05', 'Var', (84, 87))	('C01', 'Var', (64, 67))	('C14.8', 'Var', (121, 126))	('C00', 'Var', (59, 62))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('C02', 'Var', (69, 72))	('C06', 'Var', (89, 92))	('C10', 'Var', (99, 102))	('larynx', 'Disease', (250, 256))	('cancer of the oral', 'Phenotype', 'HP:0100649', (190, 208))	('C09', 'Var', (94, 97))	('C15.0', 'Var', (128, 133))	('C15.4', 'Var', (142, 147))	('C15.5', 'Var', (149, 154))
877153	24608110	Polymorphisms in the Insulin-Like Growth Factor Axis Are Associated with Gastrointestinal Cancer Numerous factors influence the development of gastrointestinal (GI) cancer.	('influence', 'Reg', (114, 123))	('Gastrointestinal Cancer', 'Disease', 'MESH:D004067', (73, 96))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Growth Factor Axis', 'Disease', 'MESH:C566610', (34, 52))	('Polymorphisms', 'Var', (0, 13))	('men', 'Species', '9606', (135, 138))	('Gastrointestinal Cancer', 'Disease', (73, 96))	('Growth Factor Axis', 'Disease', (34, 52))	('Insulin', 'Gene', '3630', (21, 28))	('Gastrointestinal Cancer', 'Phenotype', 'HP:0007378', (73, 96))	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Associated', 'Reg', (57, 67))	('Insulin', 'Gene', (21, 28))	('gastrointestinal (GI) cancer', 'Disease', 'MESH:D004067', (143, 171))
877156	24608110	Here, the prevalence of the single nucleotide polymorphisms (SNPs) rs6214 in the IGF type I (IGF-I) gene and rs6898743 in the growth hormone receptor (GHR) gene in patients with GI cancer and controls was studied.	('growth hormone receptor', 'Gene', (126, 149))	('GHR', 'Gene', (151, 154))	('GHR', 'Gene', '2690', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('growth hormone receptor', 'Gene', '2690', (126, 149))	('GI cancer', 'Disease', (178, 187))	('GI cancer', 'Phenotype', 'HP:0007378', (178, 187))	('IGF type I (IGF-I', 'Gene', '3479', (81, 98))	('GI cancer', 'Disease', 'MESH:D009369', (178, 187))	('rs6214', 'Mutation', 'rs6214', (67, 73))	('rs6898743', 'Mutation', 'rs6898743', (109, 118))	('patients', 'Species', '9606', (164, 172))	('rs6898743', 'Var', (109, 118))	('rs6214', 'Var', (67, 73))
877157	24608110	In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC), 475 with esophageal cancer (EC) and 544 with colorectal cancer (CRC) and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction.	('colorectal cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('rs6898743', 'Var', (267, 276))	('patients', 'Species', '9606', (91, 99))	('GI cancer', 'Disease', 'MESH:D009369', (67, 76))	('GI cancer', 'Phenotype', 'HP:0007378', (67, 76))	('rs6898743', 'Mutation', 'rs6898743', (267, 276))	('patients', 'Species', '9606', (77, 85))	('head and neck cancer', 'Phenotype', 'HP:0012288', (105, 125))	('rs6214', 'Mutation', 'rs6214', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('rs6214', 'Var', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (142, 159))	('HNC', 'Phenotype', 'HP:0012288', (127, 130))	('esophageal cancer', 'Disease', (142, 159))	('head and neck cancer', 'Disease', 'MESH:D006258', (105, 125))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('CRC', 'Phenotype', 'HP:0003003', (197, 200))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))	('GI cancer', 'Disease', (67, 76))
877159	24608110	Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05), using the most common genotypes GG as reference.	('rs6898743', 'Mutation', 'rs6898743', (51, 60))	('rs6214', 'Var', (40, 46))	('rs6898743', 'Var', (51, 60))	('GI cancer', 'Disease', 'MESH:D009369', (12, 21))	('GI cancer', 'Phenotype', 'HP:0007378', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('GI cancer', 'Disease', (12, 21))	('rs6214', 'Mutation', 'rs6214', (40, 46))
877161	24608110	Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26-0.86) for ESCC.	('rs6898743', 'Var', (15, 24))	('ESCC', 'Disease', (70, 74))	('rs6898743', 'Mutation', 'rs6898743', (15, 24))
877162	24608110	The A allele of SNP rs6214 in the IGF-I gene was associated with EAC, and with HNC in women.	('rs6214', 'Mutation', 'rs6214', (20, 26))	('HNC', 'Disease', (79, 82))	('associated', 'Reg', (49, 59))	('IGF-I', 'Gene', '3479', (34, 39))	('EAC', 'Phenotype', 'HP:0011459', (65, 68))	('IGF-I', 'Gene', (34, 39))	('women', 'Species', '9606', (86, 91))	('HNC', 'Phenotype', 'HP:0012288', (79, 82))	('EAC', 'Disease', (65, 68))	('SNP rs6214', 'Var', (16, 26))
877163	24608110	The GC genotype of rs6898743 in the GHR gene was negatively associated with ESCC.	('negatively', 'NegReg', (49, 59))	('rs6898743', 'Mutation', 'rs6898743', (19, 28))	('GHR', 'Gene', (36, 39))	('rs6898743', 'Var', (19, 28))	('GHR', 'Gene', '2690', (36, 39))	('ESCC', 'Disease', (76, 80))
877170	24608110	In addition, risk modulating genetic factors with low penetrance, such as numerous single nucleotide polymorphisms (SNPs), may be involved in the development of GI cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('involved', 'Reg', (130, 138))	('GI cancer', 'Disease', (161, 170))	('single nucleotide polymorphisms', 'Var', (83, 114))	('men', 'Species', '9606', (153, 156))	('GI cancer', 'Disease', 'MESH:D009369', (161, 170))	('GI cancer', 'Phenotype', 'HP:0007378', (161, 170))
877191	24608110	analyzed 102 SNPs in the IGF axis and characterized three genetic variants that appeared to be associated with esophageal adenocarcinoma: rs6214 in the IGF-I gene, rs6898743 in the GHR gene and a CA-repeat in the promoter region (5'-UTR) of the IGF-I gene, the latter variant however being very rare.	('rs6898743', 'Var', (164, 173))	('esophageal adenocarcinoma', 'Disease', (111, 136))	('IGF-I', 'Gene', (152, 157))	('GHR', 'Gene', '2690', (181, 184))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (111, 136))	('GHR', 'Gene', (181, 184))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (111, 136))	('IGF-I', 'Gene', (245, 250))	('rs6214', 'Mutation', 'rs6214', (138, 144))	('IGF-I', 'Gene', '3479', (152, 157))	('IGF-I', 'Gene', '3479', (245, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('associated', 'Reg', (95, 105))	('rs6214', 'Var', (138, 144))	('rs6898743', 'Mutation', 'rs6898743', (164, 173))
877192	24608110	The association between the SNPs rs6214 and rs6898743 and other GI cancers was not investigated yet.	('rs6898743', 'Var', (44, 53))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('GI cancers', 'Disease', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('GI cancer', 'Phenotype', 'HP:0007378', (64, 73))	('rs6214', 'Mutation', 'rs6214', (33, 39))	('rs6898743', 'Mutation', 'rs6898743', (44, 53))	('SNPs', 'Var', (28, 32))	('GI cancers', 'Disease', 'MESH:D009369', (64, 74))	('rs6214', 'Var', (33, 39))
877195	24608110	The SNP rs6898743 (c.71-26648G>C) is an intronic SNP in the GHR gene, localized on chromosome 5.	('c.71-26648G>C', 'Mutation', 'rs6898743', (19, 32))	('GHR', 'Gene', '2690', (60, 63))	('rs6898743', 'Mutation', 'rs6898743', (8, 17))	('GHR', 'Gene', (60, 63))	('c.71-26648G>C', 'Var', (19, 32))
877196	24608110	In this study, the prevalence of the SNPs rs6214 and rs6898743 in patients with GI cancer and controls were investigated in a Dutch population.	('GI cancer', 'Disease', 'MESH:D009369', (80, 89))	('GI cancer', 'Phenotype', 'HP:0007378', (80, 89))	('rs6214', 'Mutation', 'rs6214', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rs6898743', 'Mutation', 'rs6898743', (53, 62))	('rs6214', 'Var', (42, 48))	('GI cancer', 'Disease', (80, 89))	('rs6898743', 'Var', (53, 62))	('patients', 'Species', '9606', (66, 74))
877211	24608110	The rs6214 and rs6898743 polymorphisms were established by means of real-time polymerase chain reaction (RT-PCR) techniques.	('rs6898743', 'Var', (15, 24))	('rs6214', 'Mutation', 'rs6214', (4, 10))	('rs6214', 'Var', (4, 10))	('rs6898743', 'Mutation', 'rs6898743', (15, 24))
877218	24608110	The genotype distribution for SNPs rs6214 and rs6898743 in patients with GI cancer and controls are presented in Table 3.	('rs6898743', 'Mutation', 'rs6898743', (46, 55))	('SNPs', 'Gene', (30, 34))	('rs6214', 'Mutation', 'rs6214', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('GI cancer', 'Disease', (73, 82))	('rs6898743', 'Var', (46, 55))	('patients', 'Species', '9606', (59, 67))	('rs6214', 'Var', (35, 41))	('GI cancer', 'Phenotype', 'HP:0007378', (73, 82))	('GI cancer', 'Disease', 'MESH:D009369', (73, 82))
877219	24608110	For the SNPs rs6214 and rs6898743, the distribution of the genotypes in the overall GI cancer patient group, in the GI cancer sub-groups as well as in the control groups did not deviate from the Hardy-Weinberg equilibrium (all p-values >0.05), except for the ESCC patient sub-group, which showed a p-value of 0.003 for SNP rs6898743.	('rs6898743', 'Mutation', 'rs6898743', (323, 332))	('rs6898743', 'Var', (24, 33))	('SNPs rs6214', 'Var', (8, 19))	('rs6214', 'Mutation', 'rs6214', (13, 19))	('GI cancer', 'Disease', 'MESH:D009369', (84, 93))	('GI cancer', 'Disease', 'MESH:D009369', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('GI cancer', 'Phenotype', 'HP:0007378', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('GI cancer', 'Phenotype', 'HP:0007378', (116, 125))	('patient', 'Species', '9606', (94, 101))	('patient', 'Species', '9606', (264, 271))	('rs6898743', 'Mutation', 'rs6898743', (24, 33))	('GI cancer', 'Disease', (84, 93))	('SNP', 'Var', (319, 322))	('GI cancer', 'Disease', (116, 125))
877220	24608110	For both SNPs, no associations with GI cancer were seen (ORs between 1.01 and 1.20, p-values >0.05), except for a significant over-expression of the GA genotype of rs6214 in female patients (OR 1.38, 95% CI 1.01-1.87).	('GI cancer', 'Disease', (36, 45))	('over-expression', 'PosReg', (126, 141))	('rs6214', 'Mutation', 'rs6214', (164, 170))	('GI cancer', 'Disease', 'MESH:D009369', (36, 45))	('rs6214', 'Var', (164, 170))	('patients', 'Species', '9606', (181, 189))	('GI cancer', 'Phenotype', 'HP:0007378', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
877221	24608110	Table 4 summarizes the genotype distribution and the ORs (95% CI) for SNPs rs6214 and rs6898743 per cancer subtype.	('SNPs', 'Gene', (70, 74))	('rs6898743', 'Mutation', 'rs6898743', (86, 95))	('rs6214', 'Var', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rs6898743', 'Var', (86, 95))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('rs6214', 'Mutation', 'rs6214', (75, 81))
877224	24608110	Analyzed according to gender, genotype AA of rs6214 in men showed an even higher OR of 1.68 (95% CI, 1.09-2.59) with a p-value of 0.019.	('rs6214', 'Mutation', 'rs6214', (45, 51))	('rs6214', 'Var', (45, 51))	('men', 'Species', '9606', (55, 58))	('higher', 'PosReg', (74, 80))
877227	24608110	The ORs calculated for the rs6214 and rs6898743 genotypes, per histological subtype of EC are shown in Table 5.	('rs6214', 'Var', (27, 33))	('rs6898743', 'Mutation', 'rs6898743', (38, 47))	('rs6898743', 'Var', (38, 47))	('rs6214', 'Mutation', 'rs6214', (27, 33))
877228	24608110	An OR of 1.45 (95% CI, 1.04-2.01) was found for GA heterozygotes of rs6214 in EAC (p-value = 0.028), whereas homozygotes for the variant allele AA showed an OR of 1.71 (95% CI, 1.10-2.68; p-value = 0.018).	('EAC', 'Gene', (78, 81))	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('rs6214', 'Mutation', 'rs6214', (68, 74))	('rs6214', 'Var', (68, 74))
877231	24608110	For SNP rs6898743, an inverse association with ESCC was noticed for genotypes GC (OR 0.47, 95% CI, 0.26-0.86) with a p-value of 0.014.	('rs6898743', 'Mutation', 'rs6898743', (8, 17))	('ESCC', 'Disease', (47, 51))	('inverse', 'NegReg', (22, 29))	('SNP rs6898743', 'Var', (4, 17))
877234	24608110	This population-based case-control study was performed to investigate the role of the IGF associated SNPs rs6214 and rs6898743 in the development of gastrointestinal cancer.	('men', 'Species', '9606', (141, 144))	('rs6214', 'Mutation', 'rs6214', (106, 112))	('rs6898743', 'Mutation', 'rs6898743', (117, 126))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (149, 172))	('rs6898743', 'Var', (117, 126))	('rs6214', 'Var', (106, 112))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (149, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('gastrointestinal cancer', 'Disease', (149, 172))	('SNPs', 'Gene', (101, 105))
877235	24608110	The SNPs rs6214 and rs6898743 were not found associated with GI cancer, however in GI cancer subgroups, some interesting associations were noticed.	('GI cancer', 'Disease', (61, 70))	('rs6898743', 'Var', (20, 29))	('GI cancer', 'Phenotype', 'HP:0007378', (83, 92))	('associations', 'Interaction', (121, 133))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('GI cancer', 'Disease', (83, 92))	('GI cancer', 'Disease', 'MESH:D009369', (61, 70))	('rs6214', 'Mutation', 'rs6214', (9, 15))	('GI cancer', 'Phenotype', 'HP:0007378', (61, 70))	('GI cancer', 'Disease', 'MESH:D009369', (83, 92))	('rs6214', 'Var', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('rs6898743', 'Mutation', 'rs6898743', (20, 29))
877236	24608110	Genotype AA of rs6214 in the IGF-I gene was associated with EC, but this risk modifying effect of the rs6214 A allele was mainly the result of an association with the histological subgroup of EAC; individuals bearing the GA or AA genotypes showed relative risks of 1.45 and 1.71, respectively.	('associated', 'Reg', (44, 54))	('IGF-I', 'Gene', (29, 34))	('rs6214', 'Mutation', 'rs6214', (102, 108))	('rs6214', 'Var', (15, 21))	('EAC', 'Phenotype', 'HP:0011459', (192, 195))	('rs6214', 'Var', (102, 108))	('EAC', 'Disease', (192, 195))	('association', 'Interaction', (146, 157))	('rs6214', 'Mutation', 'rs6214', (15, 21))	('IGF-I', 'Gene', '3479', (29, 34))
877237	24608110	The SNP rs6214 has been investigated in several previous studies on GI cancer risk.	('GI cancer', 'Disease', (68, 77))	('GI cancer', 'Disease', 'MESH:D009369', (68, 77))	('rs6214', 'Mutation', 'rs6214', (8, 14))	('GI cancer', 'Phenotype', 'HP:0007378', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs6214', 'Var', (8, 14))
877239	24608110	reported a significant decreased risk of Barrett's esophagus (BE) for the AA genotype of rs6214 in an Irish study population (OR = 0.43, 95% CI 0.24-0.75).	('rs6214', 'Mutation', 'rs6214', (89, 95))	('rs6214', 'Var', (89, 95))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (41, 60))	("Barrett's esophagus", 'Disease', (41, 60))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (41, 60))	('decreased', 'NegReg', (23, 32))	('BE', 'Phenotype', 'HP:0100580', (62, 64))
877241	24608110	Therefore it is surprising that we found a significant inverse association with EAC for the rs6214 GA and AA genotypes.	('rs6214', 'Var', (92, 98))	('EAC', 'Disease', (80, 83))	('inverse', 'NegReg', (55, 62))	('rs6214', 'Mutation', 'rs6214', (92, 98))	('EAC', 'Phenotype', 'HP:0011459', (80, 83))
877245	24608110	The role of the genetic variant of rs6214 in pancreatic cancer in a Japanese population was assessed by Nakao et al..	('pancreatic cancer', 'Disease', (45, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('rs6214', 'Mutation', 'rs6214', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('rs6214', 'Var', (35, 41))
877246	24608110	Using AA as the reference genotype, no association was found between rs6214 and pancreatic cancer in the overall analysis, whereas 20 years old carriers of the GA and GG genotypes with a BMI >=25 kg/m2 showed an increased risk for pancreatic cancer.	('rs6214', 'Mutation', 'rs6214', (69, 75))	('pancreatic cancer', 'Disease', (80, 97))	('pancreatic cancer', 'Disease', (231, 248))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('pancreatic cancer', 'Disease', 'MESH:D010190', (231, 248))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rs6214', 'Var', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (231, 248))
877248	24608110	High plasma levels of IGF-I were suggested to be a risk for various cancers, including CRC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('High', 'Var', (0, 4))	('IGF-I', 'Gene', (22, 27))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('CRC', 'Phenotype', 'HP:0003003', (87, 90))	('risk', 'Reg', (51, 55))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('IGF-I', 'Gene', '3479', (22, 27))
877249	24608110	investigated the role of the rs6214 SNP on the circulating IGF-I levels in Caucasians.	('IGF-I', 'Gene', '3479', (59, 64))	('circulating IGF-I', 'Phenotype', 'HP:0030269', (47, 64))	('rs6214', 'Mutation', 'rs6214', (29, 35))	('IGF-I', 'Gene', (59, 64))	('rs6214', 'Var', (29, 35))
877252	24608110	Some interesting gender related differences were found; in women, genotype GA of SNP rs6214 was significantly associated with GI- and HNC, whereas homozygosity for the variant C allele of rs6898743 was inversely associated with HNC.	('rs6214', 'Mutation', 'rs6214', (85, 91))	('HNC', 'Phenotype', 'HP:0012288', (228, 231))	('rs6214', 'Var', (85, 91))	('GI-', 'Disease', (126, 129))	('HNC', 'Disease', (228, 231))	('associated', 'Reg', (110, 120))	('SNP', 'Gene', (81, 84))	('HNC', 'Phenotype', 'HP:0012288', (134, 137))	('women', 'Species', '9606', (59, 64))	('rs6898743', 'Mutation', 'rs6898743', (188, 197))	('HNC', 'Disease', (134, 137))
877264	24608110	In conclusion, the A allele of SNP rs6214 of the IGF-I gene is associated with esophageal cancer.	('IGF-I', 'Gene', (49, 54))	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (63, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('rs6214', 'Mutation', 'rs6214', (35, 41))	('IGF-I', 'Gene', '3479', (49, 54))	('SNP rs6214', 'Var', (31, 41))
877266	24608110	Furthermore, women with the A allele of SNP rs6214 may have an increased risk for developing GI cancer, more in particular HNC.	('HNC', 'Disease', (123, 126))	('rs6214', 'Mutation', 'rs6214', (44, 50))	('SNP rs6214', 'Var', (40, 50))	('GI cancer', 'Phenotype', 'HP:0007378', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('GI cancer', 'Disease', (93, 102))	('women', 'Species', '9606', (13, 18))	('HNC', 'Phenotype', 'HP:0012288', (123, 126))	('GI cancer', 'Disease', 'MESH:D009369', (93, 102))
877277	19307989	If Rag-/- mice are instead reconstituted with naive CD4+25- T cells expressing a mutated TGF-Beta receptor, induction of Foxp3+ Treg in Pan02 bearing mice is blocked.	('mice', 'Species', '10090', (150, 154))	('TGF-Beta', 'Gene', '7040', (89, 97))	('mice', 'Species', '10090', (10, 14))	('CD4', 'Gene', (52, 55))	('mutated', 'Var', (81, 88))	('CD4', 'Gene', '12504', (52, 55))	('TGF-Beta', 'Gene', (89, 97))	('Treg', 'Chemical', '-', (128, 132))
877301	19307989	What these findings at least suggest is that selective depletion of certain Treg subtypes may be a more efficient and possibly effective way of overcoming Treg suppression in cancer patients.	('overcoming', 'NegReg', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Treg', 'Chemical', '-', (76, 80))	('Treg', 'MPA', (155, 159))	('patients', 'Species', '9606', (182, 190))	('depletion', 'NegReg', (55, 64))	('selective', 'Var', (45, 54))	('Treg', 'Chemical', '-', (155, 159))
877306	19307989	When tumor bearing mice are reconstituted with naive T cells expressing a mutated TGF-Beta receptor II (dnTGF-BetaRII) these naive T cells do not undergo conversion despite the systemically elevated presence of TGF-Beta.	('TGF-Beta', 'Gene', '7040', (82, 90))	('TGF-Beta receptor II', 'Gene', (82, 102))	('TGF-Beta receptor II', 'Gene', '21813', (82, 102))	('TGF-Beta', 'Gene', (211, 219))	('TGF-Beta', 'Gene', '7040', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('TGF-Beta', 'Gene', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('TGF-Beta', 'Gene', (106, 114))	('mutated', 'Var', (74, 81))	('tumor', 'Disease', (5, 10))	('TGF-Beta', 'Gene', '7040', (211, 219))	('mice', 'Species', '10090', (19, 23))
877332	19307989	TaqMan  Universal PCR Master Mix and TaqMan  Primer with non-fluorescent quencher probes for Foxp3 (Cat # Mm 00475156) and HPRT (Cat # Mm00446968) were purchased from Applied Biosystems.	('Cat # Mm 00475156', 'Var', (100, 117))	('Foxp3', 'Gene', (93, 98))	('HPRT', 'Gene', (123, 127))	('HPRT', 'Gene', '15452', (123, 127))	('Cat # Mm00446968', 'Var', (129, 145))
877377	19307989	Serum levels of TGF-Beta in Pan02 mice were significantly elevated above levels measured in non-tumor bearing mice (Fig.	('Serum levels', 'MPA', (0, 12))	('mice', 'Species', '10090', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Pan02', 'Var', (28, 33))	('tumor', 'Disease', (96, 101))	('TGF-Beta', 'Gene', (16, 24))	('mice', 'Species', '10090', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('elevated', 'PosReg', (58, 66))	('TGF-Beta', 'Gene', '7040', (16, 24))
877383	19307989	Staining for Foxp3 in Pan02 tumors demonstrated a high number of Foxp3+ cells within the Pan02 tumors (Fig.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('Foxp3+', 'Var', (65, 71))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('rat', 'Species', '10116', (42, 45))
877400	19307989	By contrast, CD4+CD25- reconstituted mice challenged with Pan02 had marked upregulation of Foxp3 expression within the TDLN compared to those challenged with ES02.	('CD4', 'Gene', '12504', (13, 16))	('expression', 'MPA', (97, 107))	('Pan02', 'Var', (58, 63))	('upregulation', 'PosReg', (75, 87))	('Foxp3', 'Gene', (91, 96))	('CD4', 'Gene', (13, 16))	('mice', 'Species', '10090', (37, 41))
877417	19307989	Mice expressing a dominant negative TGF-Beta receptor II (dnTGF-BetaRII) transgene have a mutation that prevents downstream signaling via the receptor and renders T cells insensate to TGF-Beta .	('TGF-Beta', 'Gene', (36, 44))	('TGF-Beta', 'Gene', (184, 192))	('prevents', 'NegReg', (104, 112))	('TGF-Beta', 'Gene', '7040', (184, 192))	('TGF-Beta', 'Gene', (60, 68))	('Mice', 'Species', '10090', (0, 4))	('downstream signaling', 'MPA', (113, 133))	('TGF-Beta', 'Gene', '7040', (36, 44))	('mutation', 'Var', (90, 98))	('TGF-Beta receptor II', 'Gene', (36, 56))	('TGF-Beta receptor II', 'Gene', '21813', (36, 56))	('TGF-Beta', 'Gene', '7040', (60, 68))
877423	19307989	By contrast, if the transgenic line of mice themselves were challenged with tumor versus the wildtype controls, the transgenic mice had statistically less tumor burden than their wildtype controls (Fig.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mice', 'Species', '10090', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (155, 160))	('less', 'NegReg', (150, 154))	('transgenic mice', 'Species', '10090', (116, 131))	('transgenic', 'Var', (116, 126))	('mice', 'Species', '10090', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
877428	19307989	This is because non-selective neutralization of both nTreg and iTreg puts the host at risk of developing autoimmunity;.	('Treg', 'Chemical', '-', (54, 58))	('Treg', 'Chemical', '-', (64, 68))	('autoimmunity', 'Disease', (105, 117))	('neutralization', 'Var', (30, 44))	('autoimmunity', 'Disease', 'MESH:D001327', (105, 117))	('nTreg', 'Protein', (53, 58))	('autoimmunity', 'Phenotype', 'HP:0002960', (105, 117))
877444	19307989	In the adoptive transfer model naive T cells were only converted in Treg while in the presence Pan02 and not Eso2.	('Pan02', 'Var', (95, 100))	('Treg', 'Chemical', '-', (68, 72))	('Treg', 'CPA', (68, 72))	('Eso2', 'Chemical', '-', (109, 113))
877456	19307989	To further address this limitation, we chose to then investigate whether neutralization of TGF-Beta made by our Pan02 tumor blocked conversion of naive T cells into Treg in our adoptive transfer model.	('neutralization', 'Var', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('TGF-Beta', 'Gene', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Treg', 'Chemical', '-', (165, 169))	('tumor', 'Disease', (118, 123))	('blocked', 'NegReg', (124, 131))	('TGF-Beta', 'Gene', '7040', (91, 99))
877462	19307989	The observation that antibody neutralization of TGF-Beta blocks tumor induced conversion of naive T cells into Treg suggests that TGF-Beta receptor signaling plays an important role.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TGF-Beta', 'Gene', '7040', (130, 138))	('TGF-Beta blocks tumor', 'Disease', (48, 69))	('TGF-Beta', 'Gene', '7040', (48, 56))	('neutralization', 'Var', (30, 44))	('TGF-Beta', 'Gene', (130, 138))	('TGF-Beta blocks tumor', 'Disease', 'MESH:D007340', (48, 69))	('Treg', 'Chemical', '-', (111, 115))	('antibody neutralization', 'Var', (21, 44))	('TGF-Beta', 'Gene', (48, 56))
877463	19307989	To test this hypothesis we again utilized our adoptive transfer model but instead reconstituted them with naive T cells expressing a mutated TGF-Beta receptor.	('TGF-Beta', 'Gene', '7040', (141, 149))	('mutated', 'Var', (133, 140))	('TGF-Beta', 'Gene', (141, 149))
877470	19307989	This observation mirrors what is found in the literature, where these transgenics have been shown to be resistant to tumor challenge and have enhanced anti-tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (117, 122))	('rat', 'Species', '10116', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('enhanced', 'PosReg', (142, 150))	('transgenics', 'Var', (70, 81))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
877474	19307989	For future directions with targeted immunotherapy this would be important to know, since inhibiting only one of the three mechanisms potentially would result in suboptimal blockade of Treg mediated tumor immunosuppression and an infective anti-tumor response.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('Treg', 'Chemical', '-', (184, 188))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('inhibiting', 'Var', (89, 99))
877478	19307989	They too, utilized antibody directed neutralization of TGF-beta to demonstrate blockade of tumor induced Treg conversion.	('TGF-beta', 'Gene', (55, 63))	('Treg', 'Chemical', '-', (105, 109))	('rat', 'Species', '10116', (74, 77))	('neutralization', 'Var', (37, 51))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TGF-beta', 'Gene', '21803', (55, 63))	('tumor', 'Disease', (91, 96))
877479	19307989	They show that mice receiving 1D11 had reduced tumor burden and number of CD4+CD25+ T cells within isolated lung metastases.	('CD4', 'Gene', '12504', (74, 77))	('lung metastases', 'Disease', (108, 123))	('lung metastases', 'Disease', 'MESH:D009362', (108, 123))	('1D11', 'Var', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('reduced', 'NegReg', (39, 46))	('CD4', 'Gene', (74, 77))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', (47, 52))
877480	19307989	Based on these findings they comment that TGF-Beta neutralization "abolished the conversion" of naive T cells into Treg.	('neutralization', 'Var', (51, 65))	('Treg', 'Chemical', '-', (115, 119))	('TGF-Beta', 'Gene', '7040', (42, 50))	('conversion', 'CPA', (81, 91))	('TGF-Beta', 'Gene', (42, 50))
877484	19307989	We show in an immunodeficient Rag-/- model replete with ex vivo isolated naive T cells that Treg are induced by the presence of TGF-Beta secreting tumor cells and that indeed neutralization of TGF-Beta results in blockade of this induction.	('TGF-Beta secreting tumor', 'Disease', 'MESH:D007340', (128, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('TGF-Beta', 'Gene', (193, 201))	('Treg', 'Chemical', '-', (92, 96))	('Treg', 'CPA', (92, 96))	('neutralization', 'Var', (175, 189))	('TGF-Beta', 'Gene', '7040', (128, 136))	('TGF-Beta', 'Gene', '7040', (193, 201))	('TGF-Beta', 'Gene', (128, 136))	('TGF-Beta secreting tumor', 'Disease', (128, 152))
877593	22888256	Myotomy at the narrow EGJ has a higher risk either of mucosal damage or laceration of the longitudinal muscle.	('Myotomy', 'Var', (0, 7))	('laceration', 'CPA', (72, 82))	('mucosal damage', 'Disease', (54, 68))	('mucosal damage', 'Disease', 'MESH:D009059', (54, 68))
877671	20028503	High H3K27me3 expression was associated with poor locoregional progression-free survival (LPFS) (P = 0.010) in ESCC.	('H3K27me3', 'Gene', (5, 13))	('High', 'Var', (0, 4))	('locoregional progression-free survival', 'CPA', (50, 88))	('expression', 'MPA', (14, 24))	('PF', 'Chemical', 'MESH:C002997', (91, 93))	('H3K27me3', 'Gene', '126961', (5, 13))	('poor', 'NegReg', (45, 49))	('ESCC', 'Disease', (111, 115))
877680	20028503	It is known that epigenetic changes, including DNA methylation and covalent histone modification, are involved in tumorigenesis and tumor progression of human cancers.	('cancers', 'Disease', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('covalent histone modification', 'MPA', (67, 96))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('involved', 'Reg', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('DNA', 'MPA', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('epigenetic changes', 'Var', (17, 35))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (132, 137))	('human', 'Species', '9606', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
877681	20028503	One of the most important mechanisms is that many cancer-related genes are silenced by the enhancer of zeste homolog 2 (EZH2), which can specially trimethylate lysine 27 on histone H3 (H3K27) of the target gene promoters.	('enhancer of zeste homolog 2', 'Gene', (91, 118))	('trimethylate', 'Chemical', '-', (147, 159))	('EZH2', 'Gene', (120, 124))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('H3', 'Gene', '126961', (181, 183))	('lysine', 'Chemical', 'MESH:D008239', (160, 166))	('H3', 'Gene', '126961', (185, 187))	('enhancer of zeste homolog 2', 'Gene', '2146', (91, 118))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('silenced', 'NegReg', (75, 83))	('trimethylate', 'Var', (147, 159))	('EZH2', 'Gene', '2146', (120, 124))
877736	20028503	In the 53 ESCC cases with high EZH2 expression, an average of 55.0% of the ESCC cells stained positively with H3K27me3 antibody, a percentage of cancer cells that was significantly larger than that (43.3%) in the remaining 45 cancers with a low expression of EZH2 (P = 0.036, Fig.	('cancer', 'Disease', (145, 151))	('high', 'Var', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('H3K27me3', 'Gene', (110, 118))	('stained', 'Reg', (86, 93))	('ESCC', 'Disease', (75, 79))	('H3K27me3', 'Gene', '126961', (110, 118))	('expression', 'Var', (36, 46))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('ESCC', 'Disease', (10, 14))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('EZH2', 'Gene', '2146', (31, 35))	('EZH2', 'Gene', (31, 35))	('EZH2', 'Gene', '2146', (259, 263))	('EZH2', 'Gene', (259, 263))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('cancer', 'Disease', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
877759	20028503	Since methylation of H3K27 mediated by EZH2 has been implicated in the aggressive phenotype of cancer cells through repression of a panel of tumor suppression genes, the loss of function of these genes, in turn, locks stem/precursor cells into abnormal clonal expansion which begins a process of neoplastic initiation.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('locks', 'Reg', (212, 217))	('implicated', 'Reg', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('H3', 'Gene', '126961', (21, 23))	('neoplastic initiation', 'Disease', 'MESH:D007319', (296, 317))	('repression', 'NegReg', (116, 126))	('tumor', 'Disease', (141, 146))	('cancer', 'Disease', (95, 101))	('methylation', 'Var', (6, 17))	('loss of function', 'NegReg', (170, 186))	('EZH2', 'Gene', (39, 43))	('EZH2', 'Gene', '2146', (39, 43))	('neoplastic initiation', 'Disease', (296, 317))
877761	20028503	Moreover, an imbalance of H3K27 methylation owing to overexpression of EZH2 has been implicated in metastatic prostate and aggressive breast cancers, in which a highly significant overlap between PRC2- and H3K27me3-occupied genes was observed.	('EZH2', 'Gene', (71, 75))	('H3K27me3', 'Gene', '126961', (206, 214))	('methylation', 'Var', (32, 43))	('H3', 'Gene', '126961', (26, 28))	('imbalance', 'Phenotype', 'HP:0002172', (13, 22))	('overexpression', 'PosReg', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('H3', 'Gene', '126961', (206, 208))	('aggressive breast cancers', 'Disease', (123, 148))	('implicated', 'Reg', (85, 95))	('H3K27me3', 'Gene', (206, 214))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('aggressive breast cancers', 'Disease', 'MESH:D001943', (123, 148))	('breast cancers', 'Phenotype', 'HP:0003002', (134, 148))	('EZH2', 'Gene', '2146', (71, 75))	('metastatic prostate', 'Disease', (99, 118))
877765	20028503	Considering that the mechanism by which EZH2-mediated H3K27 methylation leads to gene silencing may vary among gene targets and among organisms, discrepancies in different studies may arise.	('gene silencing', 'MPA', (81, 95))	('methylation', 'Var', (60, 71))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('H3', 'Gene', '126961', (54, 56))
877817	33402129	Only lymph-vascular space invasion (OR = 3.632, 95% CI 1.499-8.797; P = 0.004) and tumor length (OR = 1.208, 95% CI 1.019-1.431; P = 0.029) were identified as independent predictors of skipping regional lymph node metastasis by multivariable analysis of these risk factors obtained from univariate analysis (Table 2).	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('skipping', 'Var', (185, 193))
877833	33402129	If we find that the predictive metastasis risk of continuous or skipping regional lymph nodes is high, then extended systematic nodal dissection must be performed to avoid omitting positive lymph nodes.	('metastasis', 'CPA', (31, 41))	('skipping', 'Var', (64, 72))	('nodal', 'Gene', '4838', (128, 133))	('nodal', 'Gene', (128, 133))
877834	33402129	If we find that the predictive metastasis risk of continuous and skipping regional lymph nodes is low and that of regional lymph nodes is high, then we can only perform systemic regional lymph node dissection corresponding to the position of the esophageal tumor.	('tumor', 'Disease', (257, 262))	('skipping', 'Var', (65, 73))	('esophageal tumor', 'Phenotype', 'HP:0100751', (246, 262))	('age', 'Gene', (251, 254))	('age', 'Gene', '5973', (251, 254))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
877835	33402129	If we find that the predictive metastasis risk of continuous and skipping regional lymph nodes is low and that of regional lymph nodes is also low, we can only perform regional lymph node sampling corresponding to the position of the esophageal tumor.	('metastasis', 'CPA', (31, 41))	('age', 'Gene', (239, 242))	('skipping', 'Var', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('age', 'Gene', '5973', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Disease', (245, 250))	('esophageal tumor', 'Phenotype', 'HP:0100751', (234, 250))
877852	31976023	Cancer that satisfies two conditions (a collaborative staging (CS) Schema V0204+entry of "EsophagusGEJunction" and a primary site entry of "Cardia, NOS") is classified as Siewert type II cancer.	('V0204+entry', 'Var', (74, 85))	('Cardia', 'Disease', (140, 146))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('Cardia', 'Disease', 'MESH:D004938', (140, 146))	('V0204', 'Chemical', 'MESH:D014639', (74, 79))
877854	31976023	The tumor site and the tumor morphology were both part of the CS Schema v0204+entry of "EsophagusGEJunction" and primary site-labeled entry of "C16.0-Cardia, NOS".	('CS Schema', 'Disease', (62, 71))	('CS Schema', 'Disease', 'MESH:D006223', (62, 71))	('v0204+entry', 'Var', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
877932	30108204	Anticoagulation was associated with a 3.33-fold higher of recanalization rate, and a lower recurrent thrombosis rate, while patients with and without anticoagulation experienced a similar rate of major bleeding episodes.	('bleeding episode', 'Phenotype', 'HP:0001892', (202, 218))	('recanalization', 'MPA', (58, 72))	('bleeding episodes', 'Phenotype', 'HP:0001892', (202, 219))	('lower', 'NegReg', (85, 90))	('Anticoagulation', 'Var', (0, 15))	('thrombosis', 'Disease', (101, 111))	('higher', 'PosReg', (48, 54))	('bleeding episode', 'Disease', 'MESH:D006470', (202, 218))	('bleeding episode', 'Disease', (202, 218))	('thrombosis', 'Disease', 'MESH:D013927', (101, 111))	('recurrent thrombosis', 'Phenotype', 'HP:0004419', (91, 111))	('patients', 'Species', '9606', (124, 132))
877966	30108204	The analysis started with the following variables: age, male sex, Asian ethnicity, personal history of venous thromboembolism, incidentally detected SVT, gastrointestinal bleeding at onset, ascites, esophageal varices, PVT, solid cancer, anemia (hemoglobin <=10 g/dL), creatinine >1.5 mg/dL, Child-Pugh class, MELD score, and anticoagulant treatment (defined as the use of anticoagulation medication begun during the acute phase).	('ascites', 'Disease', 'MESH:D001201', (190, 197))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (154, 179))	('solid cancer', 'Disease', (224, 236))	('thromboembolism', 'Phenotype', 'HP:0001907', (110, 125))	('SVT', 'Phenotype', 'HP:0030247', (149, 152))	('creatinine', 'Chemical', 'MESH:D003404', (269, 279))	('venous thromboembolism', 'Disease', (103, 125))	('SVT', 'Disease', (149, 152))	('anemia', 'Phenotype', 'HP:0001903', (238, 244))	('venous thromboembolism', 'Disease', 'MESH:D054556', (103, 125))	('ascites', 'Phenotype', 'HP:0001541', (190, 197))	('anemia', 'Disease', (238, 244))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (154, 179))	('MELD', 'Disease', (310, 314))	('solid cancer', 'Disease', 'MESH:D009369', (224, 236))	('gastrointestinal bleeding', 'Disease', (154, 179))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('creatinine', 'Disease', (269, 279))	('MELD', 'Disease', 'None', (310, 314))	('>1.5', 'Var', (280, 284))	('ascites', 'Disease', (190, 197))	('PVT', 'Phenotype', 'HP:0030242', (219, 222))	('anemia', 'Disease', 'MESH:D000740', (238, 244))	('Child', 'Species', '9606', (292, 297))	('esophageal varices', 'Phenotype', 'HP:0002040', (199, 217))	('PVT', 'Disease', (219, 222))	('esophageal varices', 'Disease', (199, 217))
878017	30108204	In two other cohorts, resolution of thrombosis was shown to reduce the pressure on esophageal varices and to correlate with fewer bleeding episodes from esophageal varices, and it correlated independently with fewer decompensations in cirrhotics prophylactically treated in a randomized controlled trial to prevent PVT.	('esophageal varices', 'Phenotype', 'HP:0002040', (153, 171))	('fewer', 'NegReg', (124, 129))	('reduce', 'NegReg', (60, 66))	('fewer', 'NegReg', (210, 215))	('PVT', 'Phenotype', 'HP:0030242', (315, 318))	('decompensations', 'Disease', (216, 231))	('PVT', 'Disease', (315, 318))	('bleeding episode', 'Disease', 'MESH:D006470', (130, 146))	('thrombosis', 'Disease', (36, 46))	('resolution', 'Var', (22, 32))	('esophageal varices', 'Phenotype', 'HP:0002040', (83, 101))	('bleeding episodes', 'Phenotype', 'HP:0001892', (130, 147))	('bleeding episode', 'Disease', (130, 146))	('bleeding episode', 'Phenotype', 'HP:0001892', (130, 146))	('pressure on esophageal varices', 'MPA', (71, 101))	('thrombosis', 'Disease', 'MESH:D013927', (36, 46))
878045	28147340	Higher rate of SCLN metastasis was associated with upper tumor location, metastasis involving seven or more nodes, and positive recurrent laryngeal nerve node status.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('metastasis', 'Var', (73, 83))	('SCLN', 'Chemical', '-', (15, 19))	('SCLN metastasis', 'Disease', (15, 30))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
878069	28147340	When SCLNs were considered as distant nodes, the long-term survival of cases with M1 status was similar to that of cases with N2 status (P = 0.788) but better than that of cases with N3 status (P = 0.041) (Figure 1A).	('better', 'PosReg', (152, 158))	('M1 status', 'Var', (82, 91))	('SCLN', 'Chemical', '-', (5, 9))
878073	28147340	As shown in Table 4, the AIC value for the modified version was smaller than that for the current version, indicating that the modified version yields a better prognostic stratification; the c-index value was larger for the modified version than for the current version (P = 0.0092), indicating that it is more informative regarding patient outcome.	('patient', 'Species', '9606', (333, 340))	('larger', 'PosReg', (209, 215))	('modified', 'Var', (127, 135))	('c-index', 'MPA', (191, 198))
878083	28147340	As indicated by many studies, the outcomes of ESCC are not simply impacted by SCLN status but are primarily determined by the number of involved nodes including SCLNs; survival is commonly found to be worse in patients with SCLN metastasis, not simply because of the SCLN metastasis, but because of the number of involved nodes.	('SCLN', 'Chemical', '-', (224, 228))	('SCLN metastasis', 'Var', (224, 239))	('survival', 'MPA', (168, 176))	('SCLN', 'Chemical', '-', (78, 82))	('worse', 'NegReg', (201, 206))	('patients', 'Species', '9606', (210, 218))	('SCLN', 'Chemical', '-', (267, 271))	('SCLN', 'Chemical', '-', (161, 165))
878111	28147340	All patients with pathologically confirmed ESCC who fit the following inclusion criteria were included in the analysis: (1) received transthoracic esophagectomy and three-field lymphadenectomy; (2) pathological T status of T1, T2, T3, or T4a; (3) pathological lymph nodal metastasis (including SCLN metastasis); (3) without visceral metastasis; (4) microscopically complete resection (R0); (5) resection was not preceded by chemotherapy, radiotherapy, or other anti-cancer treatment; and (6) the records contained complete basic clinicopathological information.	('cancer', 'Disease', 'MESH:D009369', (466, 472))	('pathological', 'Var', (198, 210))	('cancer', 'Disease', (466, 472))	('ESCC', 'Disease', (43, 47))	('T4a', 'Var', (238, 241))	('visceral metastasis', 'Disease', (324, 343))	('SCLN', 'Chemical', '-', (294, 298))	('visceral metastasis', 'Disease', 'MESH:D009362', (324, 343))	('patients', 'Species', '9606', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (466, 472))
878132	28002789	In this study, using a novel in vitro isogenic model of radioresistant EAC, we demonstrate that radioresistant EAC cells have enhanced tumorigenicity in vivo, increased expression of CSC-associated markers and enhanced holoclone forming ability.	('EAC', 'Phenotype', 'HP:0011459', (111, 114))	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('enhanced', 'PosReg', (126, 134))	('enhanced', 'PosReg', (210, 218))	('increased', 'PosReg', (159, 168))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('radioresistant', 'Var', (96, 110))	('expression', 'MPA', (169, 179))	('holoclone forming ability', 'CPA', (219, 244))
878152	28002789	Increasing evidence suggests that the pro-tumorigenic properties of CSCs may result from epigenetic and post-transcriptional alterations, which alter multiple signalling pathways.	('result from', 'Reg', (77, 88))	('tumor', 'Disease', (42, 47))	('post-transcriptional alterations', 'Var', (104, 136))	('alter', 'Reg', (144, 149))	('epigenetic', 'Var', (89, 99))	('CSCs', 'Disease', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
878163	28002789	To investigate the tumorigenicity of this novel isogenic model in vivo, OE33 P and OE33 R cells were transplanted subcutaneously into the flank of immunocompromised NOD SCID mice.	('SCID', 'Disease', 'MESH:D053632', (169, 173))	('SCID', 'Disease', (169, 173))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('N', 'Chemical', 'MESH:D009584', (165, 166))	('tumor', 'Disease', (19, 24))	('OE33 R', 'Var', (83, 89))
878165	28002789	OE33 R cells demonstrated higher tumorigenic potential; this manifested as higher graft success rates and corresponded to shorter latency and larger tumor volumes with respect to time, when compared to OE33 P cells (Figure 1A and 1B).	('shorter', 'NegReg', (122, 129))	('higher', 'PosReg', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('larger', 'PosReg', (142, 148))	('higher', 'PosReg', (75, 81))	('latency', 'CPA', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', (33, 38))	('OE33 R', 'Var', (0, 6))	('graft success rates', 'CPA', (82, 101))
878166	28002789	OE33 R cells produced palpable tumors in all animals transplanted (n=3) by day 30 post transplantation.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('OE33 R cells', 'Var', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))
878167	28002789	By day 78 post transplantation, OE33 R cells had produced tumors with an average diameter of 9.8 mm.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('OE33 R', 'Var', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))
878168	28002789	In contrast, OE33 P cells produced a palpable tumor in only one of the 3 transplanted animals, which at day 78 post transplantation had reached an average tumor diameter of 1 mm.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (155, 160))	('OE33 P cells', 'Var', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
878169	28002789	Therefore, this may suggest that the enhanced tumorigenicity demonstrated by OE33 R cells is due to alterations in the biology of the population of cells, or a subpopulation of cells, such as CSCs, which have the ability to drive tumor growth, rather than alterations in specific gene/protein drivers of oncogenesis.	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('OE33 R', 'Var', (77, 83))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('enhanced', 'PosReg', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
878170	28002789	To investigate if the enhanced tumorigenicity demonstrated by OE33 R cells in vivo may indeed be due to an enriched CSC population, we assessed several 'stemness' properties in OE33 R and OE33 P cells.	('OE33 R', 'Var', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('OE33', 'Var', (188, 192))	('tumor', 'Disease', (31, 36))	('OE33', 'Var', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('enhanced', 'PosReg', (22, 30))
878172	28002789	Expression of both ALDH1 and beta-catenin was significantly increased in OE33 R cells, when compared to OE33 P (Figure 2A and Figure 2B), suggesting an enrichment of CSCs in the OE33 R cell line.	('Expression', 'MPA', (0, 10))	('ALDH1', 'Gene', (19, 24))	('beta-catenin', 'Gene', (29, 41))	('ALDH1', 'Gene', '216', (19, 24))	('beta-catenin', 'Gene', '1499', (29, 41))	('increased', 'PosReg', (60, 69))	('OE33 R', 'Var', (73, 79))
878173	28002789	Together, these data suggest that OE33 R cells are enriched for CSCs, which may be an important feature underlying their enhanced tumorigenicity in vivo and resistance to X-ray radiation in vitro.	('OE33 R', 'Var', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('enhanced', 'PosReg', (121, 129))	('CSCs', 'Disease', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
878175	28002789	Supporting the alterations at mRNA level, radioresistant OE33 R had a significantly higher percentage of ALDH+ve cells (49%), when compared to radiosensitive OE33 P (32%) (Figure 3A and 3B), again suggesting that OE33 R cells are enriched for CSCs.	('ALDH+ve cells', 'CPA', (105, 118))	('N', 'Chemical', 'MESH:D009584', (32, 33))	('OE33 R', 'Var', (57, 63))	('higher', 'PosReg', (84, 90))
878181	28002789	Taken together, these data suggest that enrichment of ALDH+ve CSCs is associated with resistance to X-ray radiation and cisplatin in EAC cells.	('ALDH+ve', 'Var', (54, 61))	('EAC', 'Phenotype', 'HP:0011459', (133, 136))	('associated', 'Reg', (70, 80))	('resistance', 'CPA', (86, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
878207	28002789	This supports two recent studies in prostate and head and neck cancer, which demonstrated that cells with high ALDH activity have enhanced resistance to radiation and maintain their tumorigenic properties, when compared to ALDH-ve cells.	('enhanced', 'PosReg', (130, 138))	('tumor', 'Disease', (182, 187))	('head and neck cancer', 'Phenotype', 'HP:0012288', (49, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('high', 'Var', (106, 110))	('resistance to radiation', 'MPA', (139, 162))	('activity', 'MPA', (116, 124))	('neck cancer', 'Disease', 'MESH:D006258', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('neck cancer', 'Disease', (58, 69))	('ALDH', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
878208	28002789	Furthermore, a recent study by Ajani and colleagues demonstrated that high ALDH1 expression in pre-treatment EAC biopsies is associated with subsequent resistance to neoadjuvant CRT and is increased in vitro in chemoresistant EAC cells.	('resistance to neoadjuvant CRT', 'MPA', (152, 181))	('EAC', 'Phenotype', 'HP:0011459', (109, 112))	('EAC', 'Phenotype', 'HP:0011459', (226, 229))	('ALDH1', 'Gene', (75, 80))	('associated with', 'Reg', (125, 140))	('high', 'Var', (70, 74))	('ALDH1', 'Gene', '216', (75, 80))	('expression', 'MPA', (81, 91))
878211	28002789	Supporting this, 8 miRNAs were demonstrated to be significantly altered between ALDH+ve and ALDH-ve populations from OE33 R, suggesting a role for miRNAs in the enhanced radioresistance of the OE33 R ALDH+ve population.	('enhanced', 'PosReg', (161, 169))	('OE33 R', 'Var', (193, 199))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('N', 'Chemical', 'MESH:D009584', (150, 151))	('radioresistance', 'CPA', (170, 185))
878226	28002789	Moreover, several studies have highlighted a role for mutations and genomic rearrangements in the pathogenesis of EAC, with both losses and gains at 13q highlighted, suggesting that genomic alterations may provide a mechanism for the decreased miR-17-5p expression demonstrated here in tumors of poorly responding patients.	('miR-17-5p', 'Gene', '406952', (244, 253))	('EAC', 'Disease', (114, 117))	('patients', 'Species', '9606', (314, 322))	('decreased', 'NegReg', (234, 243))	('miR-17-5p', 'Gene', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('mutations', 'Var', (54, 63))	('expression', 'MPA', (254, 264))	('tumors', 'Disease', (286, 292))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('EAC', 'Phenotype', 'HP:0011459', (114, 117))
878232	28002789	It is now well established that the immune system plays an important role in the tumor response to radiation, with radiation therapy augmenting the anti-tumor immune response.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('radiation therapy', 'Var', (115, 132))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('augmenting', 'PosReg', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
878244	28002789	Mice were subcutaneously injected, above the right hind-limb, with 1 x 103 cells (either OE33 P or OE33 R) in a 100 mul volume of 20% high concentration Matrigel (Corning) and 80% Ham's F12 media (Lonza).	('OE33 P', 'Var', (89, 95))	('OE33 R', 'Var', (99, 105))	('Mice', 'Species', '10090', (0, 4))
878248	28002789	Growth of OE33 R tumors was terminated at 78 days post-injection, whilst OE33 P tumor growth was terminated at 108 days post-injection, coinciding with the maximum mean tumor diameter limit.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mum', 'Gene', '56925', (160, 163))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mum', 'Gene', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (80, 85))	('OE33', 'Var', (10, 14))	('P tumor', 'Disease', (78, 85))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('P tumor', 'Disease', 'MESH:C000656865', (78, 85))
878288	26943393	The pathological diagnosis according to the Japanese classification of esophageal cancer was MtLt, 47 mm, 0-IIa + IIb, pT1a-MM, ie(+), INF-b, ly3, v0, pN4(4a), pIM1, M0, and pstage IVa.	('MtLt', 'Var', (93, 97))	('pstage IVa', 'Disease', 'MESH:C536467', (174, 184))	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('pIM1', 'Gene', (160, 164))	('pIM1', 'Gene', '5292', (160, 164))	('esophageal cancer', 'Disease', (71, 88))	('pstage IVa', 'Disease', (174, 184))	('ly3', 'Var', (142, 145))
878305	26943393	The patient was diagnosed with a superficial, esophageal squamous cell carcinoma in the middle and lower thoracic esophagus with intramural metastasis and perigastric and distant lymph node metastases, and was classified as having cT1bN4M0IM1 stage IVa according to the Japanese classification of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (297, 314))	('metastases', 'Disease', (190, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('cT1bN4M0IM1', 'Var', (231, 242))	('patient', 'Species', '9606', (4, 11))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (46, 80))	('metastases', 'Disease', 'MESH:D009362', (190, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('esophageal cancer', 'Disease', (297, 314))	('esophageal squamous cell carcinoma', 'Disease', (46, 80))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))
878318	26943393	Therefore, the pathological diagnosis was MtLt, 47 mm, 0-IIa + IIb, pT1a-MM, ie(+), INF-b, ly3, v0, pN4(4a), pIM1, M0, and pstage IVa.	('pIM1', 'Gene', (109, 113))	('pT1a-MM', 'Var', (68, 75))	('pIM1', 'Gene', '5292', (109, 113))	('pstage IVa', 'Disease', (123, 133))	('pstage IVa', 'Disease', 'MESH:C536467', (123, 133))
878399	26507424	While they primarily used carboplatin (56%) and paclitaxel (55%) for induction chemotherapy, our patients were more likely to receive cisplatin and 5-FU with a concurrent 5-6 weeks of induction radiation.	('5-FU', 'Var', (148, 152))	('cisplatin', 'Var', (134, 143))	('5-FU', 'Chemical', 'MESH:D005472', (148, 152))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('carboplatin', 'Chemical', 'MESH:D016190', (26, 37))	('patients', 'Species', '9606', (97, 105))
878462	25924824	The TNM classification of these 41 patients was as follows; 2, 0, 25 and 14 patients were cT1, T2, T3 and T4 tumors respectively, 13 and 28 cases were cN0 and N1 respectively, 28 and 13 cases were cM0 and M1 respectively and 1, 9, 15 and 16 cases were cStage I, II, III and IV, respectively.	('patients', 'Species', '9606', (76, 84))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('cN0', 'Var', (151, 154))	('cT1', 'Gene', (90, 93))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('patients', 'Species', '9606', (35, 43))	('cT1', 'Gene', '1489', (90, 93))	('tumors', 'Disease', (109, 115))
878697	31895837	Additionally, impaired hepatic function as indicated by elevated serum aspartate aminotransferase (AST) (175.0 U/L, normal range 1-40 U/L), alanine aminotransferase (ALT) (56.0 U/L, normal range 1-40 U/L), alkaline phosphatase (ALP) (248 U/L, normal range 15-140 U/L), gamma-glutamyl transpeptidase (GGT) (103 U/L, normal range 5-60 U/L), and lactic dehydrogenase (LDH) (1692 U/L, normal range 15-210 U/L).	('ALP', 'Gene', (228, 231))	('gamma-glutamyl transpeptidase', 'Gene', '102724197', (269, 298))	('1692 U/L', 'Var', (371, 379))	('impaired hepatic function', 'Phenotype', 'HP:0001410', (14, 39))	('aspartate aminotransferase', 'Gene', '26503', (71, 97))	('alanine aminotransferase', 'Gene', (140, 164))	('alanine aminotransferase', 'Gene', '2875', (140, 164))	('alkaline phosphatase', 'Gene', (206, 226))	('aspartate aminotransferase', 'Gene', (71, 97))	('alkaline phosphatase', 'Gene', '250', (206, 226))	('impaired hepatic function', 'Disease', 'MESH:D008107', (14, 39))	('lactic', 'MPA', (343, 349))	('gamma-glutamyl transpeptidase', 'Gene', (269, 298))	('AST', 'Gene', '26503', (99, 102))	('elevated serum aspartate', 'Phenotype', 'HP:0500159', (56, 80))	('elevated', 'PosReg', (56, 64))	('impaired hepatic function', 'Disease', (14, 39))	('elevated serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (56, 97))	('ALP', 'Gene', '250', (228, 231))	('AST', 'Gene', (99, 102))
878723	31895837	A meta-analysis of randomized controlled trials reveals the significant efficacy and safety of VEGFR-2 inhibitors in metastatic gastric and GEJ cancer patients.	('VEGFR-2', 'Gene', (95, 102))	('gastric and GEJ cancer', 'Disease', 'MESH:D013274', (128, 150))	('patients', 'Species', '9606', (151, 159))	('inhibitors', 'Var', (103, 113))	('VEGFR-2', 'Gene', '3791', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
878857	31125642	It is noteworthy that the squamous epithelium contains relatively common mutations in some genes including NOTCH1 and TP53 in the normal esophagus.	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('NOTCH1', 'Gene', '4851', (107, 113))	('NOTCH1', 'Gene', (107, 113))	('mutations', 'Var', (73, 82))
878859	31125642	New evidence showed that two SNPs, including rs7447927 and rs1642764, which are located in TMEM173 and ATP1B2 genes, respectively, achieved genome-wide significance after joint analysis of three genome-wide association studies of ESCC; additionally, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved a genome-wide significance in the two populations associating with the highest risk for ESSC.	('TMEM173', 'Gene', '340061', (91, 98))	('ATP1B2', 'Gene', (103, 109))	('rs35597309', 'Var', (297, 307))	('rs1642764', 'Var', (59, 68))	('rs7447927', 'Var', (45, 54))	('ATP1B2', 'Gene', '482', (103, 109))	('rs7447927', 'Mutation', 'rs7447927', (45, 54))	('rs35597309', 'Mutation', 'rs35597309', (297, 307))	('ESSC', 'Disease', (406, 410))	('rs1642764', 'Mutation', 'rs1642764', (59, 68))	('TMEM173', 'Gene', (91, 98))
878860	31125642	In addition, the rs1154402C>G in intron-1 of the ADH5 gene substantially reduces the expression levels of ADH1A.	('expression levels', 'MPA', (85, 102))	('ADH5', 'Gene', '128', (49, 53))	('reduces', 'NegReg', (73, 80))	('rs1154402C>G', 'DBSNP_MENTION', 'None', (17, 29))	('rs1154402C>G', 'Var', (17, 29))	('ADH1A', 'Gene', '124', (106, 111))	('ADH1A', 'Gene', (106, 111))	('ADH5', 'Gene', (49, 53))
878861	31125642	The suppressive effects caused by rs1154402 in ADH5 and another SNP (rs11066015 in ALDH2) can substantially increase the risk of ESCC.	('rs11066015', 'Mutation', 'rs11066015', (69, 79))	('ESCC', 'Disease', (129, 133))	('ALDH2', 'Gene', '217', (83, 88))	('ADH5', 'Gene', (47, 51))	('rs1154402', 'Mutation', 'rs1154402', (34, 43))	('rs11066015', 'Var', (69, 79))	('ADH5', 'Gene', '128', (47, 51))	('ALDH2', 'Gene', (83, 88))	('rs1154402', 'Var', (34, 43))	('suppressive effects', 'NegReg', (4, 23))
878863	31125642	The study also showed that low levels of all-trans-retinoic acid in the serum of individuals with the rs138478634-GA genotype as compared to the rs138478634-GG genotype in the CYP26B1 gene.	('levels', 'MPA', (31, 37))	('CYP26B1', 'Gene', (176, 183))	('rs138478634-GA', 'Var', (102, 116))	('rs138478634', 'Mutation', 'rs138478634', (102, 113))	('low', 'NegReg', (27, 30))	('CYP26B1', 'Gene', '56603', (176, 183))	('rs138478634', 'Mutation', 'rs138478634', (145, 156))	('all-trans-retinoic acid', 'MPA', (41, 64))	('all-trans-retinoic acid', 'Chemical', 'MESH:D014212', (41, 64))
878864	31125642	EAC pathogenesis has also been associated with decreased estrogen exposure, single-nucleotide polymorphisms in cancer-related genes and obesity.	('single-nucleotide polymorphisms', 'Var', (76, 107))	('obesity', 'Disease', 'MESH:D009765', (136, 143))	('estrogen exposure', 'MPA', (57, 74))	('obesity', 'Disease', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('EAC', 'Disease', (0, 3))	('obesity', 'Phenotype', 'HP:0001513', (136, 143))	('decreased', 'NegReg', (47, 56))
878865	31125642	In addition, EAC progression can be further influenced by helicobacter pylori infection, gene methylation, and ectopic expression of some genes, such as GATA6 and CDK6.	('CDK6', 'Gene', '1021', (163, 167))	('infection', 'Disease', 'MESH:D007239', (78, 87))	('GATA6', 'Gene', '2627', (153, 158))	('GATA6', 'Gene', (153, 158))	('EAC', 'Phenotype', 'HP:0011459', (13, 16))	('helicobacter pylori', 'Species', '210', (58, 77))	('influenced', 'Reg', (44, 54))	('ectopic expression', 'MPA', (111, 129))	('EAC', 'Disease', (13, 16))	('helicobacter pylori infection', 'Phenotype', 'HP:0005202', (58, 87))	('methylation', 'Var', (94, 105))	('helicobacter pylori', 'Disease', (58, 77))	('CDK6', 'Gene', (163, 167))	('infection', 'Disease', (78, 87))
878867	31125642	One of these models suggests that mutation in the Trp63 gene is associated with intestine-like metaplasia of squamous epithelium.	('associated', 'Reg', (64, 74))	('Trp63', 'Gene', (50, 55))	('intestine-like metaplasia of squamous epithelium', 'Disease', (80, 128))	('mutation', 'Var', (34, 42))	('Trp63', 'Chemical', '-', (50, 55))
878890	31125642	For example, judged from Table 2 and Table 3, autoantibodies against Trp53, Peroxiredoxin VI, and lncRNA POU3F3 were found in patients with ESCC, but not EAC.	('EAC', 'Phenotype', 'HP:0011459', (154, 157))	('Trp53', 'Gene', (69, 74))	('Peroxiredoxin VI', 'Enzyme', (76, 92))	('POU3F3', 'Gene', (105, 111))	('ESCC', 'Disease', (140, 144))	('POU3F3', 'Gene', '5455', (105, 111))	('Trp53', 'Gene', '7157', (69, 74))	('autoantibodies', 'Var', (46, 60))	('patients', 'Species', '9606', (126, 134))	('found', 'Reg', (117, 122))
878895	31125642	For instance, the APC gene becomes abnormally methylated and is detected in the plasma DNA in patients with EAC, suggesting that the hypermethylation status of APC is an indicator of aggressive disease in patients with EC.	('APC', 'Disease', (160, 163))	('aggressive disease', 'Disease', (183, 201))	('patients', 'Species', '9606', (205, 213))	('patients', 'Species', '9606', (94, 102))	('aggressive disease', 'Disease', 'MESH:D001523', (183, 201))	('APC', 'Disease', 'MESH:D011125', (18, 21))	('APC', 'Disease', (18, 21))	('EAC', 'Phenotype', 'HP:0011459', (108, 111))	('APC', 'Disease', 'MESH:D011125', (160, 163))	('hypermethylation', 'Var', (133, 149))
878907	30578781	Genomic instability and hyper-mutability are central hallmarks of cancer development.	('Genomic instability', 'CPA', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('hyper-mutability', 'Var', (24, 40))	('cancer', 'Disease', (66, 72))
878910	30578781	To date, several, functionally important, key MMR protein heterodimers have been described: MSH2 protein forms a heterodimer with either MSH6 (MutSalpha) or MSH3 (MutSbeta) and MLH1 pairing with PMS2 (MutLalpha), MLH2 (MutLbeta) or MLH3 (MutLgamma) - all of which are responsible for repairing single nucleotide or INDEL mismatches.	('MSH6', 'Gene', '2956', (137, 141))	('INDEL mismatches', 'Var', (315, 331))	('MLH3', 'Gene', (232, 236))	('PMS2', 'Gene', (195, 199))	('MSH2', 'Gene', (92, 96))	('MSH2', 'Gene', '4436', (92, 96))	('MLH1', 'Gene', (177, 181))	('MLH3', 'Gene', '27030', (232, 236))	('PMS2', 'Gene', '5395', (195, 199))	('MLH1', 'Gene', '4292', (177, 181))	('MLH2', 'Gene', '5378', (213, 217))	('MSH3', 'Gene', (157, 161))	('MLH2', 'Gene', (213, 217))	('MSH6', 'Gene', (137, 141))	('single nucleotide', 'Var', (294, 311))	('MSH3', 'Gene', '4437', (157, 161))
878913	30578781	The MMR deficiency resulting from germline mutations or epigenetic alterations (gene inactivation by promoter methylation) in any of the MMR genes (MLH1, MSH2, MSH6, and PMS2), as well as deletions in the EPCAM gene (which leads to constitutional repression of MSH2 gene expression through promoter methylation) is the principle cause of Lynch syndrome (LS) and its variants (Muir- Torre or Turcot's syndromes).	('LS', 'Disease', 'MESH:D003123', (354, 356))	('MSH2', 'Gene', '4436', (154, 158))	('deletions', 'Var', (188, 197))	('MLH1', 'Gene', (148, 152))	('Lynch syndrome', 'Disease', (338, 352))	('EPCAM', 'Gene', (205, 210))	('PMS2', 'Gene', (170, 174))	('MSH2', 'Gene', (261, 265))	('MMR deficiency', 'Disease', 'MESH:C536928', (4, 18))	('MLH1', 'Gene', '4292', (148, 152))	('MMR deficiency', 'Disease', (4, 18))	('Lynch syndrome', 'Disease', 'MESH:D003123', (338, 352))	('MSH6', 'Gene', '2956', (160, 164))	('MMR', 'Gene', (137, 140))	('MSH2', 'Gene', '4436', (261, 265))	('cause', 'Reg', (329, 334))	('MSH2', 'Gene', (154, 158))	('MSH6', 'Gene', (160, 164))	('EPCAM', 'Gene', '4072', (205, 210))	('mutations', 'Var', (43, 52))	('PMS2', 'Gene', '5395', (170, 174))
878915	30578781	Homozygous germline mutations in any of the four aforementioned MMR genes can cause a constitutional MMR deficiency syndrome, which is one of the most aggressive, highly penetrant childhood cancer predisposition syndromes.	('cancer', 'Disease', (190, 196))	('cause', 'Reg', (78, 83))	('MMR deficiency', 'Disease', (101, 115))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('MMR', 'Gene', (64, 67))	('Homozygous', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('MMR deficiency', 'Disease', 'MESH:C536928', (101, 115))
878916	30578781	In addition, LS also can result from mosaic germline MLH1 epimutations.	('MLH1', 'Gene', (53, 57))	('MLH1', 'Gene', '4292', (53, 57))	('epimutations', 'Var', (58, 70))	('LS', 'Disease', 'MESH:D003123', (13, 15))	('result from', 'Reg', (25, 36))	('mosaic germline', 'Var', (37, 52))
878917	30578781	In contrast, bi-allelic MLH1 promoter methylation is primarily the key somatic event responsible for the loss of MLH1 expression in ~75-80% of sporadic cancers with MSI.	('MLH1', 'Gene', '4292', (113, 117))	('MLH1', 'Gene', (113, 117))	('methylation', 'Var', (38, 49))	('sporadic cancers', 'Disease', 'MESH:D009369', (143, 159))	('loss', 'NegReg', (105, 109))	('sporadic cancers', 'Disease', (143, 159))	('MLH1', 'Gene', '4292', (24, 28))	('MLH1', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('expression', 'MPA', (118, 128))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
878921	30578781	A classical hallmark feature of the MSI-H CRCs is a prominent lymphocytic infiltrate, which correlates with a higher neoantigen load (resulting from the somatic mutations that produce more immunogenic peptides), as well as with a higher expression of various immune checkpoint molecules [PD-1, programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA4), LAG-3, and IDO].	('neoantigen load', 'MPA', (117, 132))	('higher', 'PosReg', (230, 236))	('programmed death-ligand 1', 'Gene', (294, 319))	('cytotoxic T-lymphocyte antigen 4', 'Gene', (329, 361))	('higher', 'PosReg', (110, 116))	('CTLA4', 'Gene', (363, 368))	('IDO', 'Gene', (382, 385))	('[PD-1', 'Gene', (287, 292))	('LAG-3', 'Gene', '3902', (371, 376))	('cytotoxic T-lymphocyte antigen 4', 'Gene', '1493', (329, 361))	('programmed death-ligand 1', 'Gene', '29126', (294, 319))	('CRC', 'Disease', (42, 45))	('expression', 'MPA', (237, 247))	('IDO', 'Gene', '3620', (382, 385))	('MSI-H', 'Var', (36, 41))	('PD-L1', 'Gene', (321, 326))	('CRC', 'Disease', 'MESH:D015179', (42, 45))	('LAG-3', 'Gene', (371, 376))	('mutations', 'Var', (161, 170))	('CTLA4', 'Gene', '1493', (363, 368))
878962	30578781	Despite the fact that exploratory analysis obtained from GI cancers with viral-associations did not observe any clear correlation between infection status and therapeutic benefit from anti-PD-1 therapy, one can speculate that epitopes derived from viral open reading frames could potentially act as immunogenic neoantigens promoting T-cell tumor infiltration.	('epitopes', 'Var', (226, 234))	('GI cancers', 'Disease', (57, 67))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('promoting', 'PosReg', (323, 332))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('GI cancers', 'Disease', 'MESH:D005770', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (340, 345))
878973	30578781	Besides, there is an approximately 1.3% rate of CRC harboring POLE exonuclease domain mutations and even a small percentage of POLE-mutated MSI-H tumors with high and extremely high TML, respectively.	('domain mutations', 'Var', (79, 95))	('CRC', 'Disease', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('CRC', 'Disease', 'MESH:D015179', (48, 51))	('tumor', 'Disease', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('MSI-H', 'Gene', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
878980	30578781	Along with JAK1/2 and IFNgamma-receptor 1 mutations, similar alterations have been observed in melanoma, NSCLC, and CRC and deemed to be as genetic drivers of primary or acquired resistance to ICI therapy, reflecting their role as a mechanism of adaptive resistance against T-cell tumor infiltration.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('CRC', 'Disease', 'MESH:D015179', (116, 119))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('ICI', 'Chemical', '-', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('CRC', 'Disease', (116, 119))	('NSCLC', 'Disease', (105, 110))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', (281, 286))	('JAK1/2 and IFNgamma-receptor 1', 'Gene', '3459;3716;3717', (11, 41))
878998	30578781	Furthermore, it was recently demonstrated that inactivation of the MMR system in CRC cells, either by genomic editing or through pharmacological manipulations, resulted in improved immune surveillance and enabled tumor regression.	('tumor', 'Disease', (213, 218))	('inactivation', 'Var', (47, 59))	('immune surveillance', 'CPA', (181, 200))	('improved', 'PosReg', (172, 180))	('CRC', 'Disease', (81, 84))	('enabled', 'PosReg', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('CRC', 'Disease', 'MESH:D015179', (81, 84))
879000	30578781	Similarly, in mouse pancreatic cancer models, the blockade of FAK, as well as dual inhibition with an anti-PD-1 antibody, led to tumor size reduction and prolonged survival in mice through modulation of the TME.	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('blockade', 'Var', (50, 58))	('mouse', 'Species', '10090', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('prolonged', 'PosReg', (154, 163))	('TME', 'MPA', (207, 210))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('survival', 'CPA', (164, 172))	('FAK', 'Gene', '14083', (62, 65))	('mice', 'Species', '10090', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('FAK', 'Gene', (62, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('modulation', 'Reg', (189, 199))	('reduction', 'NegReg', (140, 149))	('tumor', 'Disease', (129, 134))	('pancreatic cancer', 'Disease', (20, 37))
879002	30578781	Lastly, mouse ovarian cancer models demonstrated that the ARID1A deficiency compromises MMR, promoting additional mutation burden, and hence potentiating the antitumor immunity, which subsequently can be unleashed by an anti-PD-L1 drug.	('ovarian cancer', 'Disease', (14, 28))	('potentiating', 'PosReg', (141, 153))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('promoting', 'PosReg', (93, 102))	('mutation burden', 'MPA', (114, 129))	('ARID1A', 'Gene', (58, 64))	('tumor', 'Disease', (162, 167))	('ARID1A', 'Gene', '93760', (58, 64))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('MMR', 'Protein', (88, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (14, 28))	('deficiency', 'Var', (65, 75))	('mouse', 'Species', '10090', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('compromises', 'NegReg', (76, 87))
879003	30578781	These findings could have a potential application to several GI malignancies with known inactivating mutations in ARID1A (HCC, CRC, esophageal and pancreatic adenocarcinomas, SBA, ampullary carcinoma, and cholangiocarcinoma).	('pancreatic adenocarcinomas', 'Disease', (147, 173))	('CRC', 'Disease', 'MESH:D015179', (127, 130))	('SBA', 'Disease', (175, 178))	('ARID1A', 'Gene', (114, 120))	('ARID1A', 'Gene', '93760', (114, 120))	('ampullary carcinoma', 'Disease', 'MESH:D002277', (180, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('HCC', 'Disease', 'MESH:D006528', (122, 125))	('inactivating mutations', 'Var', (88, 110))	('esophageal', 'Disease', (132, 142))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010195', (147, 173))	('ampullary carcinoma', 'Disease', (180, 199))	('CRC', 'Disease', (127, 130))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (205, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (147, 173))	('HCC', 'Disease', (122, 125))	('cholangiocarcinoma', 'Disease', (205, 223))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (205, 223))
879007	30578781	Despite the fact that MMR-deficiency is clearly associated with clinical benefit in a bunch of cases, the molecular mechanisms underlying therapeutic response and resistance to ICIs remain unclear in the majority of cases.	('ICI', 'Chemical', '-', (177, 180))	('MMR-deficiency', 'Gene', (22, 36))	('MMR-deficiency', 'Var', (22, 36))
879025	30606157	The overall survival rates of patients with SPC were lower than those for patients without SPC, especially those with SPC in the esophagus or lungs.	('patients', 'Species', '9606', (74, 82))	('SPC', 'Var', (44, 47))	('lower', 'NegReg', (53, 58))	('patients', 'Species', '9606', (30, 38))
879038	30606157	This record includes information about patients' sex, age at diagnosis, sequential order of cancer incidence, histological type of cancer, and cancer site categorized according to the third edition of the International Classification of Diseases for Oncology (ICD-O-3), such as mouth/pharynx (C00-14), esophagus (C15), larynx (C32), and lung (C33, C34).	('patients', 'Species', '9606', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mouth', 'Disease', (278, 283))	('type of cancer', 'Disease', 'MESH:D009369', (123, 137))	('mouth', 'Disease', 'MESH:D009059', (278, 283))	('C15', 'Gene', '51316', (313, 316))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('C32', 'Gene', (327, 330))	('larynx', 'Disease', (319, 325))	('esophagus', 'Disease', (302, 311))	('C15', 'Gene', (313, 316))	('cancer', 'Disease', (143, 149))	('C32', 'Gene', '51192', (327, 330))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', (92, 98))	('C00-14', 'Var', (293, 299))	('C33', 'Gene', (343, 346))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (131, 137))	('type of cancer', 'Disease', (123, 137))	('Oncology', 'Phenotype', 'HP:0002664', (250, 258))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung', 'Disease', (337, 341))	('C33', 'Gene', '3732', (343, 346))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
879111	29872701	Aberrant accumulation of polyamines is associated with various pathological consequences, including cancer.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('polyamines', 'Chemical', 'MESH:D011073', (25, 35))	('accumulation', 'PosReg', (9, 21))	('associated', 'Reg', (39, 49))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('polyamines', 'Protein', (25, 35))
879129	29872701	Our results showed that knocking down ODC expression with shODC significantly increased total apoptosis of both KYSE450 and KYSE510 cell lines (Fig.	('knocking down', 'Var', (24, 37))	('ODC', 'Gene', (38, 41))	('increased', 'PosReg', (78, 87))	('apoptosis', 'CPA', (94, 103))	('KYSE510', 'CellLine', 'CVCL:1354', (124, 131))
879137	29872701	Our data showed that shMock-infected KYSE450 cells formed markedly larger xenograft tumors in nude mice compared to the shODC-infected groups (p < 0.01, Fig.	('nude mice', 'Species', '10090', (94, 103))	('xenograft tumors', 'Disease', (74, 90))	('larger', 'PosReg', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('shMock-infected', 'Var', (21, 36))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('xenograft tumors', 'Disease', 'MESH:D009369', (74, 90))
879140	29872701	These results confirmed that inhibiting ODC expression in ESCC cells suppresses proliferation and induces apoptosis, leading to attenuation of ESCC tumorigenesis.	('attenuation', 'NegReg', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('induces', 'Reg', (98, 105))	('proliferation', 'CPA', (80, 93))	('tumor', 'Disease', (148, 153))	('apoptosis', 'CPA', (106, 115))	('ODC expression', 'Protein', (40, 54))	('ESCC', 'Disease', (143, 147))	('inhibiting', 'Var', (29, 39))	('suppresses', 'NegReg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('rat', 'Species', '10116', (87, 90))
879146	29872701	Western blot analysis showed that DFMO induced an increased expression of Bax, p53, p21, p27, phosphorylation of CDK1 (Tyr15), cleavage of caspase 3 and PARP and suppressed expression of PCNA, Bcl-2 and cyclin B1.	('expression', 'MPA', (60, 70))	('Tyr15', 'Chemical', '-', (119, 124))	('PCNA', 'Gene', '5111', (187, 191))	('Bax', 'Gene', (74, 77))	('p21', 'Gene', '1026', (84, 87))	('DFMO', 'Chemical', 'MESH:D000518', (34, 38))	('DFMO', 'Var', (34, 38))	('p53', 'Gene', '7157', (79, 82))	('CDK1', 'Gene', '983', (113, 117))	('cyclin B1', 'Gene', '891', (203, 212))	('cyclin B1', 'Gene', (203, 212))	('CDK1', 'Gene', (113, 117))	('increased', 'PosReg', (50, 59))	('caspase 3', 'Protein', (139, 148))	('phosphorylation', 'MPA', (94, 109))	('p53', 'Gene', (79, 82))	('PARP', 'Gene', '142', (153, 157))	('cleavage', 'MPA', (127, 135))	('Bcl-2', 'Gene', (193, 198))	('PCNA', 'Gene', (187, 191))	('p21', 'Gene', (84, 87))	('expression', 'MPA', (173, 183))	('suppressed', 'NegReg', (162, 172))	('PARP', 'Gene', (153, 157))	('p27', 'Gene', '3429', (89, 92))	('p27', 'Gene', (89, 92))	('Bcl-2', 'Gene', '596', (193, 198))
879151	29872701	Results indicated that over 33 days of treatment, DFMO had no effect on mouse body weight compared with the vehicle-treated group.	('mouse', 'Species', '10090', (72, 77))	('DFMO', 'Chemical', 'MESH:D000518', (50, 54))	('mouse body weight', 'CPA', (72, 89))	('DFMO', 'Var', (50, 54))
879168	29872701	Studies focusing on transgenic mouse models have shown an essential role of polyamines in the early promotion of tumorigenesis.	('tumor', 'Disease', (113, 118))	('mouse', 'Species', '10090', (31, 36))	('polyamines', 'Chemical', 'MESH:D011073', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('transgenic', 'Species', '10090', (20, 30))	('polyamines', 'Var', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
879171	29872701	Our data showed that when ODC expression in ESCC cells was knocked down, both proliferation and anchorage-independent growth of ESCC cells were significantly suppressed (Fig.	('suppressed', 'NegReg', (158, 168))	('rat', 'Species', '10116', (85, 88))	('anchorage-independent growth', 'CPA', (96, 124))	('knocked', 'Var', (59, 66))	('ODC expression', 'Protein', (26, 40))
879174	29872701	reported that polyamine depletion prevented apoptosis of rat intestinal epithelial cells by decreasing caspase 3 and 9 activities, as well as the translocation of Bax to mitochondria, thus diminishing cytochrome c release.	('diminishing', 'NegReg', (189, 200))	('decreasing', 'NegReg', (92, 102))	('polyamine depletion', 'Var', (14, 33))	('cytochrome c', 'Gene', (201, 213))	('polyamine', 'Chemical', 'MESH:D011073', (14, 23))	('depletion', 'Var', (24, 33))	('cytochrome c', 'Gene', '54205', (201, 213))	('caspase', 'Protein', (103, 110))	('rat', 'Species', '10116', (57, 60))	('diminishing cytochrome c', 'Phenotype', 'HP:0003514', (189, 213))	('translocation', 'MPA', (146, 159))	('activities', 'MPA', (119, 129))
879180	29872701	The homodimerization of Bcl-2 leads to anti-apoptosis signaling and Bax can heterodimerize with Bcl-2 to induce apoptosis.	('induce', 'PosReg', (105, 111))	('Bcl-2', 'Gene', (96, 101))	('heterodimerize', 'Var', (76, 90))	('Bcl-2', 'Gene', '596', (96, 101))	('apoptosis', 'CPA', (112, 121))	('homodimerization', 'MPA', (4, 20))	('anti-apoptosis signaling', 'MPA', (39, 63))	('Bcl-2', 'Gene', (24, 29))	('Bcl-2', 'Gene', '596', (24, 29))
879188	29872701	ODC activity displays two peaks during the entire cell cycle process, one associated with the G1/S transition and the other associated with the S/G2 and G2/M phases, suggesting that polyamines also play key roles in cell cycle progression.	('polyamines', 'Chemical', 'MESH:D011073', (182, 192))	('G1/S', 'Disease', (94, 98))	('S/G2', 'Var', (144, 148))	('S/G2', 'SUBSTITUTION', 'None', (144, 148))	('associated', 'Reg', (74, 84))
879190	29872701	Other effects, including arrest at the S or G2/M phase, have been reported in different cell lines, suggesting that polyamine depletion affects the cell cycle in a cell-type specific manner.	('affects', 'Reg', (136, 143))	('polyamine', 'Chemical', 'MESH:D011073', (116, 125))	('cell cycle', 'CPA', (148, 158))	('polyamine', 'Var', (116, 125))
879194	29872701	Our results showed that polyamine depletion increased the expression of wildtype p53, which in turn directly down-regulated the transcription of cyclin B1 mRNA and inactivated the CDK1/cyclin B1 complex by phosphorylation of CDK1.	('CDK1', 'Gene', (180, 184))	('expression', 'MPA', (58, 68))	('p53', 'Gene', (81, 84))	('transcription', 'MPA', (128, 141))	('CDK1', 'Gene', '983', (225, 229))	('CDK1', 'Gene', (225, 229))	('polyamine', 'Chemical', 'MESH:D011073', (24, 33))	('phosphorylation', 'MPA', (206, 221))	('depletion', 'Var', (34, 43))	('increased', 'PosReg', (44, 53))	('cyclin B1', 'Gene', '891', (185, 194))	('cyclin B1', 'Gene', (185, 194))	('down-regulated', 'NegReg', (109, 123))	('cyclin B1', 'Gene', '891', (145, 154))	('cyclin B1', 'Gene', (145, 154))	('polyamine depletion', 'Var', (24, 43))	('inactivated', 'NegReg', (164, 175))	('p53', 'Gene', '7157', (81, 84))	('CDK1', 'Gene', '983', (180, 184))
879202	29872701	However, DFMO is generally cytostatic in mammalian cells, causing a reduction in the rate of proliferation in the absence of cell death.	('mammalian', 'Species', '9606', (41, 50))	('rate', 'MPA', (85, 89))	('rat', 'Species', '10116', (85, 88))	('DFMO', 'Chemical', 'MESH:D000518', (9, 13))	('DFMO', 'Var', (9, 13))	('reduction', 'NegReg', (68, 77))	('rat', 'Species', '10116', (100, 103))
879211	29872701	Moreover, IHC results reconfirmed that DFMO not only suppressed proliferation, but also induced apoptosis in ESCC cells, leading to the inhibition of ESCC progression.	('induced', 'Reg', (88, 95))	('rat', 'Species', '10116', (71, 74))	('inhibition', 'NegReg', (136, 146))	('ESCC', 'Disease', (150, 154))	('apoptosis', 'CPA', (96, 105))	('proliferation', 'CPA', (64, 77))	('DFMO', 'Var', (39, 43))	('DFMO', 'Chemical', 'MESH:D000518', (39, 43))	('suppressed', 'NegReg', (53, 63))
879214	29872701	Our study also demonstrated that polyamine depletion not only suppressed proliferation, but also induced apoptosis of ESCC cells.	('induced', 'Reg', (97, 104))	('polyamine depletion', 'Var', (33, 52))	('apoptosis', 'CPA', (105, 114))	('proliferation', 'CPA', (73, 86))	('rat', 'Species', '10116', (80, 83))	('rat', 'Species', '10116', (22, 25))	('suppressed', 'NegReg', (62, 72))	('polyamine', 'Chemical', 'MESH:D011073', (33, 42))
879225	29872701	5625), phosphorylated ERKs (T202/Y204; Catalog No.	('ERKs', 'Gene', '5595;5594;5595', (22, 26))	('ERKs', 'Gene', (22, 26))	('T202/Y204;', 'Var', (28, 38))
879228	29872701	2524), phosphorylated CDK1 (Tyr15; Catalog No.	('CDK1', 'Gene', (22, 26))	('Tyr15', 'Chemical', '-', (28, 33))	('Tyr15;', 'Var', (28, 34))	('CDK1', 'Gene', '983', (22, 26))
879232	29872701	Human ESCC cell lines (KYSE450, KYSE510) and the human embryonic kidney cell line (HEK293T) were purchased from American Type Culture Collection (ATCC; Manassas, VA).	('Human', 'Species', '9606', (0, 5))	('KYSE510', 'CellLine', 'CVCL:1354', (32, 39))	('embryonic kidney', 'Disease', (55, 71))	('human', 'Species', '9606', (49, 54))	('embryonic kidney', 'Disease', 'MESH:D007674', (55, 71))	('KYSE510', 'Var', (32, 39))	('HEK293T', 'CellLine', 'CVCL:0063', (83, 90))
879303	29187878	Furthermore, UHRF1 depletion induced cell cycle arrest at the G2/M phase, accompanied by activation of Wee1 and DNA damage response pathway.	('DNA damage response pathway', 'Pathway', (112, 139))	('depletion', 'Var', (19, 28))	('Wee1', 'Gene', (103, 107))	('cell cycle arrest at the G2/M phase', 'CPA', (37, 72))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (37, 54))	('UHRF1', 'Gene', (13, 18))	('Wee1', 'Gene', '7465', (103, 107))	('activation', 'PosReg', (89, 99))
879307	29187878	Epigenetic alterations such as DNA methylation, histone modification, and loss of genome imprinting play a crucial role in ESCC tumorigenesis, along with genetic changes.	('DNA methylation', 'Var', (31, 46))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('ESCC', 'Disease', (123, 127))	('loss', 'NegReg', (74, 78))	('histone modification', 'Var', (48, 68))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
879308	29187878	DNA hypermethylation within the gene promoter region of tumor suppressor genes (TSGs) usually leads to transcriptional repression.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('leads to', 'Reg', (94, 102))	('transcriptional repression', 'MPA', (103, 129))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('hypermethylation', 'Var', (4, 20))
879309	29187878	Many TSGs, such as CDKN2A, CDKN2B, RASSF1 and RARB, have been reported to be frequently silenced by promoter hypermethylation in ESCC.	('RASSF1', 'Gene', (35, 41))	('CDKN2B', 'Gene', '1030', (27, 33))	('ESCC', 'Gene', (129, 133))	('CDKN2A', 'Gene', (19, 25))	('RARB', 'Gene', (46, 50))	('silenced', 'NegReg', (88, 96))	('CDKN2A', 'Gene', '1029', (19, 25))	('RARB', 'Gene', '5915', (46, 50))	('promoter hypermethylation', 'Var', (100, 125))	('RASSF1', 'Gene', '11186', (35, 41))	('CDKN2B', 'Gene', (27, 33))
879313	29187878	Furthermore, UHRF1 depletion inhibits cell proliferation and migration, and induces cell cycle arrest and apoptosis through DNA demethylation, suggesting that UHRF1 can be a useful therapy target of cancers.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cell proliferation', 'CPA', (38, 56))	('depletion', 'Var', (19, 28))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('apoptosis', 'CPA', (106, 115))	('UHRF1', 'Gene', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('inhibits', 'NegReg', (29, 37))	('DNA demethylation', 'MPA', (124, 141))	('cell cycle arrest', 'CPA', (84, 101))	('induces', 'Reg', (76, 83))	('cancers', 'Disease', (199, 206))
879328	29187878	The clones with stable knockdown of UHRF1 were identified and verified using qRT-PCR and Western blotting.	('UHRF1', 'Gene', (36, 41))	('knockdown', 'Var', (23, 32))	('C', 'Chemical', 'MESH:D002244', (82, 83))
879364	29187878	In a univariate analysis, Kaplan-Meier curves showed that patients with negative UHRF1 expression survived significantly longer than patients with positive UHRF1 expression (P=0.003, Fig 1C and Table S1).	('expression', 'Var', (87, 97))	('UHRF1', 'Gene', (81, 86))	('patients', 'Species', '9606', (133, 141))	('longer', 'PosReg', (121, 127))	('negative', 'NegReg', (72, 80))	('patients', 'Species', '9606', (58, 66))	('C', 'Chemical', 'MESH:D002244', (188, 189))
879365	29187878	The mean survival time of patients with negative UHRF1 expression was 33.2+-4.9 months, but it decreased to 17.0+-3.4 months in patients with positive UHRF1 expression.	('patients', 'Species', '9606', (26, 34))	('negative', 'NegReg', (40, 48))	('UHRF1', 'Gene', (49, 54))	('patients', 'Species', '9606', (128, 136))	('expression', 'Var', (55, 65))
879367	29187878	Multivariate analysis revealed that positive UHRF1 expression (HR=2.161, 95%CI=1.219-3.833, P=0.008, Table 2) was independent prognostic factors for poor prognosis in ESCC along with tumor stage (HR=1.772, 95%CI=1.004-3.128, P=0.049).	('C', 'Chemical', 'MESH:D002244', (170, 171))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('C', 'Chemical', 'MESH:D002244', (76, 77))	('ESCC', 'Disease', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('C', 'Chemical', 'MESH:D002244', (169, 170))	('tumor', 'Disease', (183, 188))	('UHRF1', 'Gene', (45, 50))	('positive', 'Var', (36, 44))	('C', 'Chemical', 'MESH:D002244', (209, 210))
879368	29187878	Then, the ECA109 and TE-1 cell lines were chosen for transfection with lenti-shUHRF1 or shNC containing GFP because of their relatively high UHRF1 expression.	('expression', 'MPA', (147, 157))	('C', 'Chemical', 'MESH:D002244', (91, 92))	('UHRF1', 'Gene', (141, 146))	('lenti-shUHRF1', 'Var', (71, 84))	('C', 'Chemical', 'MESH:D002244', (11, 12))
879370	29187878	The results showed that the mRNA and protein levels of UHRF1 were significantly downregulated in lenti-shUHRF1 transfected cells (shUHRF1 group) compared with lenti-shNC transfected cells (shNC group) and untransfected cells (Blank group) (Fig 2C and 2D).	('C', 'Chemical', 'MESH:D002244', (168, 169))	('lenti-shUHRF1 transfected cells', 'Var', (97, 128))	('C', 'Chemical', 'MESH:D002244', (245, 246))	('downregulated', 'NegReg', (80, 93))	('UHRF1', 'Gene', (55, 60))	('C', 'Chemical', 'MESH:D002244', (192, 193))
879371	29187878	UHRF1 plays an important role in maintaining DNA methylation, UHRF1 alteration can affect the global DNA methylation levels in human, mouse and zebrafish cells, but the role in ESCC cells remains unclear.	('zebrafish', 'Species', '7955', (144, 153))	('affect', 'Reg', (83, 89))	('human', 'Species', '9606', (127, 132))	('alteration', 'Var', (68, 78))	('global DNA methylation levels', 'MPA', (94, 123))	('UHRF1', 'Gene', (62, 67))	('mouse', 'Species', '10090', (134, 139))
879373	29187878	Previous studies have shown that the proliferation of cancer cells was inhibited by UHRF1 knockdown.	('knockdown', 'Var', (90, 99))	('inhibited', 'NegReg', (71, 80))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('UHRF1', 'Gene', (84, 89))
879374	29187878	The results showed that growth of ECA109 and TE-1 cells was inhibited after knockdown of UHRF1 with shUHRF1 (P<0.01, Fig 3A).	('shUHRF1', 'Gene', (100, 107))	('knockdown', 'Var', (76, 85))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('UHRF1', 'Gene', (89, 94))	('inhibited', 'NegReg', (60, 69))	('growth', 'CPA', (24, 30))
879375	29187878	To determine whether depletion of UHRF1 induced apoptosis in ESCC cells, flow cytometry (FCM) was used to detect the apoptotic changes in transfected cells.	('C', 'Chemical', 'MESH:D002244', (90, 91))	('UHRF1', 'Gene', (34, 39))	('depletion', 'Var', (21, 30))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('C', 'Chemical', 'MESH:D002244', (63, 64))
879377	29187878	Then, Western blotting results showed that depletion of UHRF1 significantly increased the activity of caspase-3 and caspase-7 in ESCC cells (Fig 4B).	('caspase-7', 'Gene', '840', (116, 125))	('activity', 'MPA', (90, 98))	('depletion', 'Var', (43, 52))	('increased', 'PosReg', (76, 85))	('caspase-3', 'Gene', (102, 111))	('UHRF1', 'Gene', (56, 61))	('caspase-3', 'Gene', '836', (102, 111))	('caspase-7', 'Gene', (116, 125))
879380	29187878	The results showed that the proportion of cells in G2/M phase increased after UHRF1 knockdown in ECA109 and TE-1 cells (P<0.01, Fig 5A), while there was no significant change in the number of cells in G1 phase.	('increased', 'PosReg', (62, 71))	('UHRF1', 'Gene', (78, 83))	('G2/M phase', 'CPA', (51, 61))	('knockdown', 'Var', (84, 93))	('C', 'Chemical', 'MESH:D002244', (98, 99))
879381	29187878	In addition, the percentage of cells in S phase decreased after knockdown of UHRF1 in ECA109 cells but not TE-1 cells.	('C', 'Chemical', 'MESH:D002244', (87, 88))	('UHRF1', 'Gene', (77, 82))	('decreased', 'NegReg', (48, 57))	('cells in S phase', 'CPA', (31, 47))	('knockdown', 'Var', (64, 73))
879383	29187878	Western blotting showed that phosphorylation of CDC2Tyr15, the inactivated state of CDC2, increased in cells depleted of UHRF1, while expression of Cyclin B1 decreased (Fig 5B).	('Cyclin B1', 'Gene', '891', (148, 157))	('increased', 'PosReg', (90, 99))	('CDC2', 'Gene', (48, 52))	('CDC2', 'Gene', '983', (48, 52))	('Cyclin B1', 'Gene', (148, 157))	('depleted', 'Var', (109, 117))	('UHRF1', 'Gene', (121, 126))	('CDC2', 'Gene', '983', (84, 88))	('CDC2', 'Gene', (84, 88))	('phosphorylation', 'MPA', (29, 44))
879384	29187878	As cells approach the G2/M boundary, the inhibitory phosphorylation of CDC2 at Tyr15 is primarily catalyzed by Wee1.	('Tyr15', 'Chemical', '-', (79, 84))	('Wee1', 'Gene', (111, 115))	('Tyr15', 'Var', (79, 84))	('Wee1', 'Gene', '7465', (111, 115))	('inhibitory phosphorylation', 'MPA', (41, 67))	('CDC2', 'Gene', '983', (71, 75))	('CDC2', 'Gene', (71, 75))
879387	29187878	Surprisingly, phosphorylation of Wee1 at Ser642, the activated state of Wee1, was enhanced in cells depleted of UHRF1, while total Wee1 remained constant.	('enhanced', 'PosReg', (82, 90))	('UHRF1', 'Gene', (112, 117))	('depleted', 'Var', (100, 108))	('Wee1', 'Gene', (72, 76))	('Wee1', 'Gene', (131, 135))	('phosphorylation', 'MPA', (14, 29))	('Ser642', 'Var', (41, 47))	('Wee1', 'Gene', (33, 37))	('Wee1', 'Gene', '7465', (72, 76))	('Wee1', 'Gene', '7465', (131, 135))	('Wee1', 'Gene', '7465', (33, 37))	('Ser642', 'Chemical', '-', (41, 47))
879389	29187878	The results showed that inhibition of Wee1 induced activation of the Cyclin B1/CDC2 complex and subsequently catalyzed mitosis, indicated by enhanced phosphorylation of histone H3Ser10 (Fig 5C).	('catalyzed mitosis', 'Disease', 'None', (109, 126))	('phosphorylation', 'MPA', (150, 165))	('Wee1', 'Gene', '7465', (38, 42))	('Wee1', 'Gene', (38, 42))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('Cyclin B1', 'Gene', (69, 78))	('CDC2', 'Gene', '983', (79, 83))	('CDC2', 'Gene', (79, 83))	('activation', 'PosReg', (51, 61))	('C', 'Chemical', 'MESH:D002244', (191, 192))	('inhibition', 'Var', (24, 34))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('enhanced', 'PosReg', (141, 149))	('catalyzed mitosis', 'Disease', (109, 126))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('histone H3Ser10', 'Protein', (169, 184))	('Cyclin B1', 'Gene', '891', (69, 78))
879390	29187878	These results suggested that UHRF1 depletion induced cell cycle arrest at the G2/M transition was correlated with activation of Wee1.	('activation', 'PosReg', (114, 124))	('Wee1', 'Gene', (128, 132))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (53, 70))	('Wee1', 'Gene', '7465', (128, 132))	('cell cycle arrest at the G2/M transition', 'CPA', (53, 93))	('depletion', 'Var', (35, 44))	('UHRF1', 'Gene', (29, 34))
879391	29187878	In response to DNA damage, Wee1 can be phosphorylated by pCHK1Ser345, resulting in maintenance of phosphorylation of CDC2 at Tyr15 and hence G2 delay.	('phosphorylation', 'MPA', (98, 113))	('Wee1', 'Gene', '7465', (27, 31))	('CDC2', 'Gene', '983', (117, 121))	('CDC2', 'Gene', (117, 121))	('Tyr15', 'Chemical', '-', (125, 130))	('CHK1', 'Gene', (58, 62))	('Tyr15', 'Var', (125, 130))	('CHK1', 'Gene', '1111', (58, 62))	('Wee1', 'Gene', (27, 31))
879393	29187878	To understand whether knockdown of UHRF1 induced DNA damage, we measured pH2AXSer139 content in ESCC cells by immunofluorescence firstly.	('knockdown', 'Var', (22, 31))	('UHRF1', 'Gene', (35, 40))	('pH2AXSer139', 'Chemical', '-', (73, 84))
879394	29187878	As shown in Fig 6A and Fig 6B, cells depleted of UHRF1 showed a higher percentage of cells positive for pH2AXSer139 compared to control cells (P<0.01).	('UHRF1', 'Gene', (49, 54))	('pH2AXSer139', 'Chemical', '-', (104, 115))	('pH2AXSer139', 'Var', (104, 115))
879400	29187878	Moreover, the multivariate survival analysis showed, for the first time, that positive UHRF1 expression was an independent prognostic factor for ESCC patients.	('positive', 'Var', (78, 86))	('patients', 'Species', '9606', (150, 158))	('expression', 'MPA', (93, 103))	('UHRF1', 'Gene', (87, 92))	('ESCC', 'Disease', (145, 149))
879403	29187878	1) Because UHRF1 plays an important role in maintaining DNA methylation by recognizing hemimethylated CpG sites during DNA replication and subsequently recruiting DNMT1, depletion of UHRF1 could directly cause a failure to write the DNA methylome.	('UHRF1', 'Gene', (183, 188))	('failure', 'MPA', (212, 219))	('DNMT1', 'Gene', (163, 168))	('DNMT1', 'Gene', '1786', (163, 168))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('cause', 'Reg', (204, 209))	('depletion', 'Var', (170, 179))
879408	29187878	A previous study reported that transfection of colorectal cancer cells with lenti-shUHRF1 induced cell cycle arrest in G0/G1 phase.	('cell cycle arrest in G0/G1 phase', 'CPA', (98, 130))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('lenti-shUHRF1', 'Var', (76, 89))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))
879409	29187878	In the present study, knockdown of UHRF1 in ESCC cells induced cell cycle arrest at G2/M phase, accompanied by inactivation of the Cyclin B1/CDC2 complex.	('Cyclin B1', 'Gene', '891', (131, 140))	('inactivation', 'NegReg', (111, 123))	('cell cycle arrest at G2/M phase', 'CPA', (63, 94))	('knockdown', 'Var', (22, 31))	('Cyclin B1', 'Gene', (131, 140))	('CDC2', 'Gene', (141, 145))	('CDC2', 'Gene', '983', (141, 145))	('UHRF1', 'Gene', (35, 40))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))
879414	29187878	Altogether, these results support the finding that UHRF1 depletion caused cell cycle arrest at the G2/M transition through Wee1 activation in ESCC cells.	('activation', 'PosReg', (128, 138))	('Wee1', 'Gene', '7465', (123, 127))	('UHRF1', 'Gene', (51, 56))	('depletion', 'Var', (57, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('cell cycle arrest at the G2/M transition', 'CPA', (74, 114))	('Wee1', 'Gene', (123, 127))
879417	29187878	The DNA damage response is primarily accomplished by phosphorylation of CHK1 and CHK2, leading to their activation and further transmission of the checkpoint signal.	('CHK1', 'Gene', '1111', (72, 76))	('activation', 'PosReg', (104, 114))	('phosphorylation', 'Var', (53, 68))	('CHK2', 'Gene', (81, 85))	('CHK1', 'Gene', (72, 76))	('transmission of the checkpoint signal', 'MPA', (127, 164))	('CHK2', 'Gene', '11200', (81, 85))
879418	29187878	In our study, both immunofluorescence and western blotting showed that UHRF1 knockdown caused phosphorylation of H2AX at Ser139, suggesting that DNA damage occurred.	('UHRF1', 'Gene', (71, 76))	('H2AX', 'Gene', '3014', (113, 117))	('knockdown', 'Var', (77, 86))	('H2AX', 'Gene', (113, 117))	('phosphorylation', 'MPA', (94, 109))	('Ser139', 'Chemical', '-', (121, 127))
879419	29187878	In addition, UHRF1 depletion induced the DNA damage response through phosphorylation of CHK1 and CHK2 and subsequent activation of Wee1.	('CHK2', 'Gene', '11200', (97, 101))	('depletion', 'Var', (19, 28))	('CHK1', 'Gene', (88, 92))	('induced', 'Reg', (29, 36))	('CHK1', 'Gene', '1111', (88, 92))	('UHRF1', 'Gene', (13, 18))	('Wee1', 'Gene', (131, 135))	('Wee1', 'Gene', '7465', (131, 135))	('DNA damage response', 'MPA', (41, 60))	('phosphorylation', 'MPA', (69, 84))	('activation', 'PosReg', (117, 127))	('CHK2', 'Gene', (97, 101))
879421	29187878	However, p53Ser15 remained constant in cells depleted of UHRF1, indicating that the cell cycle arrest and apoptosis induced by UHRF1 knockdown in ESCC cells may not be p53 dependent.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('apoptosis', 'CPA', (106, 115))	('p53', 'Gene', '7157', (168, 171))	('p53', 'Gene', (9, 12))	('knockdown', 'Var', (133, 142))	('p53', 'Gene', '7157', (9, 12))	('UHRF1', 'Gene', (127, 132))	('cell cycle arrest', 'CPA', (84, 101))	('p53', 'Gene', (168, 171))
879423	29187878	This effect was similar, in part, to a previous study that reported that UHRF1 depletion caused DNA damage and activated CHK2-CDC25.	('CHK2', 'Gene', '11200', (121, 125))	('CDC25', 'Gene', '995', (126, 131))	('CDC25', 'Gene', (126, 131))	('depletion', 'Var', (79, 88))	('CHK2', 'Gene', (121, 125))	('DNA damage', 'MPA', (96, 106))	('caused', 'Reg', (89, 95))	('UHRF1', 'Gene', (73, 78))	('activated', 'PosReg', (111, 120))
879424	29187878	In colorectal cancer cells, loss of DNA methylation was also observed to result in genomic instability, DNA damage, activation of the DNA damage checkpoint and subsequent G2 phase arrest.	('DNA damage', 'MPA', (104, 114))	('methylation', 'Var', (40, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('DNA', 'MPA', (134, 137))	('genomic instability', 'CPA', (83, 102))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('activation', 'PosReg', (116, 126))	('G2 phase arrest', 'CPA', (171, 186))	('DNA', 'Gene', (36, 39))	('colorectal cancer', 'Disease', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('result in', 'Reg', (73, 82))	('loss', 'NegReg', (28, 32))
879425	29187878	In conclusion, our study showed that positive UHRF1 expression was an independent prognostic factor of ESCC patients.	('positive', 'Var', (37, 45))	('patients', 'Species', '9606', (108, 116))	('expression', 'MPA', (52, 62))	('ESCC patients', 'Disease', (103, 116))	('UHRF1', 'Gene', (46, 51))
879440	24530603	Furthermore, height also is associated with increased risk of all-cancer mortality.	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('height', 'Var', (13, 19))	('cancer', 'Disease', (66, 72))
879441	24530603	Although height is an independent risk factor and prognostic factor for cancers of the colorectum, breast, endometrium, prostate, ovary, and melanoma, studies have reported an inverse association between height and gastric cancer and with cancers of the head and neck.	('ovary', 'Disease', (130, 135))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('endometrium', 'Disease', (107, 118))	('gastric cancer', 'Disease', (215, 229))	('prostate', 'Disease', (120, 128))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('height', 'Var', (204, 210))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancers', 'Disease', (239, 246))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (215, 229))	('breast', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (215, 229))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('inverse', 'NegReg', (176, 183))	('cancers of the head and neck', 'Phenotype', 'HP:0012288', (239, 267))	('cancers', 'Disease', 'MESH:D009369', (239, 246))
879452	24530603	A recent genome-wide association study for height conducted by the Genetic Investigation of ANthropometric Traits (GIANT) consortium identified 697 independent SNPs associated with height at genome-wide significance (P < 5 x 10-8) (Wood AR et al, unpublished data, 2013).	('SNPs', 'Var', (160, 164))	('height', 'Disease', (181, 187))	('associated', 'Reg', (165, 175))	('GIANT', 'Disease', (115, 120))	('GIANT', 'Disease', 'MESH:D005870', (115, 120))
879467	24530603	Greater height is associated with increased risk of all cancers combined and with risk of death from cancer.	('cancers', 'Disease', (56, 63))	('Greater height', 'Phenotype', 'HP:0000098', (0, 14))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('death', 'Disease', 'MESH:D003643', (90, 95))	('death', 'Disease', (90, 95))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('Greater height', 'Var', (0, 14))
879499	33322542	Substitution of this cysteine residue by a serine results in a catalytically inactive form (PTPN13-C/S).	('Substitution', 'Var', (0, 12))	('cysteine', 'Chemical', 'MESH:D003545', (21, 29))	('serine', 'Chemical', 'MESH:D012694', (43, 49))	('catalytically inactive form', 'MPA', (63, 90))
879510	33322542	Many cancer cell lines develop resistance to FAS-induced apoptosis by acquiring mutations in the FAS gene or by regulating FAS availability at the cell surface.	('regulating', 'Reg', (112, 122))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('FAS', 'Gene', (97, 100))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
879515	33322542	They also established that transfection of HCT15 cells with siRNAs against DLG1 increases FAS-induced cell death.	('DLG1', 'Gene', (75, 79))	('DLG1', 'Gene', '1739', (75, 79))	('increases', 'PosReg', (80, 89))	('HCT15', 'CellLine', 'CVCL:0292', (43, 48))	('FAS-induced cell death', 'CPA', (90, 112))	('siRNAs', 'Var', (60, 66))
879518	33322542	Conversely, FAS surface expression is upregulated after transfection of TIG3 bladder carcinoma cells with PTPN13 dominant negative mutants or after PTPN13 silencing by siRNA.	('silencing', 'NegReg', (155, 164))	('TIG3', 'Gene', (72, 76))	('bladder carcinoma', 'Disease', (77, 94))	('negative', 'NegReg', (122, 130))	('PTPN13', 'Gene', (106, 112))	('TIG3', 'Gene', '5920', (72, 76))	('upregulated', 'PosReg', (38, 49))	('mutants', 'Var', (131, 138))	('FAS surface expression', 'MPA', (12, 34))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (77, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('bladder carcinoma', 'Disease', 'MESH:D001749', (77, 94))
879519	33322542	In line with these findings, PTPN13 overexpression in Capan-1 pancreatic carcinoma cells negatively regulate FAS-mediated apoptosis, and PTPN13 silencing by siRNA in SW480 colorectal cancer cells increases FAS/FasL-mediated apoptosis.	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('pancreatic carcinoma', 'Disease', (62, 82))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (62, 82))	('FasL', 'Gene', (210, 214))	('increases', 'PosReg', (196, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('PTPN13', 'Gene', (137, 143))	('silencing', 'Var', (144, 153))	('FasL', 'Gene', '356', (210, 214))	('regulate', 'Reg', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('FAS-mediated apoptosis', 'CPA', (109, 131))	('colorectal cancer', 'Disease', (172, 189))	('Capan-1', 'CellLine', 'CVCL:0237', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('SW480', 'CellLine', 'CVCL:0546', (166, 171))	('negatively', 'NegReg', (89, 99))	('rectal cancer', 'Phenotype', 'HP:0100743', (176, 189))
879521	33322542	Interestingly, another study reported that PTPN13 can dephosphorylate and inhibit c-Abl, suggesting a possible retro-control of ABL activity that is lost in the case of the BCR/ABL translocation.	('activity', 'MPA', (132, 140))	('c-Abl', 'Gene', (82, 87))	('inhibit', 'NegReg', (74, 81))	('PTPN13', 'Var', (43, 49))	('c-Abl', 'Gene', '25', (82, 87))	('dephosphorylate', 'MPA', (54, 69))
879523	33322542	BCR/ABL overexpression leads to a decrease in tyrosine phosphorylation of GSK3beta (an APC partner) and in serine phosphorylation of beta-catenin (a GSK3 substrate), and consequently to increased beta-catenin transcriptional activity.	('beta-catenin', 'Gene', '1499', (133, 145))	('beta-catenin', 'Gene', '1499', (196, 208))	('tyrosine', 'Chemical', 'MESH:D014443', (46, 54))	('transcriptional activity', 'MPA', (209, 233))	('GSK3beta', 'Gene', (74, 82))	('increased', 'PosReg', (186, 195))	('decrease', 'NegReg', (34, 42))	('APC', 'Phenotype', 'HP:0005227', (87, 90))	('serine', 'Chemical', 'MESH:D012694', (107, 113))	('BCR/ABL', 'Gene', (0, 7))	('GSK3beta', 'Gene', '2931', (74, 82))	('APC', 'Disease', 'MESH:D011125', (87, 90))	('overexpression', 'Var', (8, 22))	('beta-catenin', 'Gene', (133, 145))	('tyrosine phosphorylation', 'MPA', (46, 70))	('serine phosphorylation', 'MPA', (107, 129))	('APC', 'Disease', (87, 90))	('beta-catenin', 'Gene', (196, 208))
879532	33322542	In the pancreatic adenocarcinoma A818-6 cell line, anti-FAS antibodies induce apoptosis in cells grown in 2D- or 3D-polarized cell cultures, independently of PTPN13 and FAS colocalization.	('apoptosis', 'CPA', (78, 87))	('antibodies', 'Var', (60, 70))	('pancreatic adenocarcinoma', 'Disease', (7, 32))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (7, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('anti-FAS', 'Protein', (51, 59))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (7, 32))	('induce', 'Reg', (71, 77))
879541	33322542	Moreover, ephrinB1/ERBB2 complex formation is promoted by expression of a constitutively active oncogenic mutant of ERBB2.	('ERBB2', 'Gene', '2064', (19, 24))	('promoted', 'PosReg', (46, 54))	('mutant', 'Var', (106, 112))	('ERBB2', 'Gene', (19, 24))	('ERBB2', 'Gene', '2064', (116, 121))	('expression', 'MPA', (58, 68))	('ERBB2', 'Gene', (116, 121))	('complex', 'Interaction', (25, 32))
879542	33322542	Signaling by this complex is activated by SRC and is increased by transfection of the catalytically inactive PTPN13-C/S variant.	('activated', 'PosReg', (29, 38))	('PTPN13-C/S', 'Gene', (109, 119))	('increased', 'PosReg', (53, 62))	('variant', 'Var', (120, 127))	('SRC', 'Gene', '6714', (42, 45))	('Signaling', 'MPA', (0, 9))	('SRC', 'Gene', (42, 45))
879546	33322542	Transfection of HEK293 cells with the PTPN13-C/S mutant increases ephrinB1 phosphorylation, its association with ERBB1, and ERK1/2 phosphorylation.	('ERBB1', 'Gene', '1956', (113, 118))	('increases', 'PosReg', (56, 65))	('PTPN13-C/S', 'Var', (38, 48))	('ephrinB1', 'Protein', (66, 74))	('ERK1/2', 'Gene', (124, 130))	('ERBB1', 'Gene', (113, 118))	('association', 'Interaction', (96, 107))	('ERK1/2', 'Gene', '5595;5594', (124, 130))	('phosphorylation', 'MPA', (131, 146))	('phosphorylation', 'MPA', (75, 90))	('HEK293', 'CellLine', 'CVCL:0045', (16, 22))
879548	33322542	In vivo, in a mouse model of HPV-positive head and neck squamous cancer (HNSCC), tumor growth was reduced (p < 0.001) and survival was improved (p < 0.001) in mice injected with HNSCC cells transfected with ephrinB1 shRNA compared with cells transfected wild-type ephrinB1.	('squamous cancer', 'Phenotype', 'HP:0002860', (56, 71))	('ephrinB1 shRNA', 'Var', (207, 221))	('mouse', 'Species', '10090', (14, 19))	('survival', 'CPA', (122, 130))	('neck squamous cancer', 'Disease', 'MESH:D006258', (51, 71))	('mice', 'Species', '10090', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('improved', 'PosReg', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('neck squamous cancer', 'Disease', (51, 71))	('reduced', 'NegReg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
879561	33322542	in a high-grade serous ovarian carcinoma (HGSOC) cell line (OV-90), in which PTPN13 transfection decreased the levels of IkappaBalpha phosphorylated at Y42 and of nuclear NF-kappaB, in contrast to transfection with PTPN13 siRNA.	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (16, 40))	('PTPN13', 'Gene', (77, 83))	('NF-kappaB', 'Gene', '4790', (171, 180))	('IkappaBalpha', 'Gene', '4792', (121, 133))	('levels', 'MPA', (111, 117))	('IkappaBalpha', 'Gene', (121, 133))	('NF-kappaB', 'Gene', (171, 180))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (23, 40))	('decreased', 'NegReg', (97, 106))	('serous ovarian carcinoma', 'Disease', (16, 40))	('transfection', 'Var', (84, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('OV-90', 'CellLine', 'CVCL:3768', (60, 65))
879562	33322542	By using a siRNA against PTPN13 in combination with an inhibitor of IkappaBalpha phosphorylation or an IkappaBalpha mutant (Y42A), they confirmed that PTPN13 exerts its tumor suppressive effect by dephosphorylating IkappaBalpha at Tyr42.	('IkappaBalpha', 'Gene', '4792', (103, 115))	('dephosphorylating', 'MPA', (197, 214))	('IkappaBalpha', 'Gene', (103, 115))	('PTPN13', 'Var', (151, 157))	('IkappaBalpha', 'Gene', '4792', (215, 227))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('Y42A', 'Mutation', 'p.Y42A', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Tyr42', 'Chemical', '-', (231, 236))	('IkappaBalpha', 'Gene', '4792', (68, 80))	('tumor', 'Disease', (169, 174))	('IkappaBalpha', 'Gene', (68, 80))	('IkappaBalpha', 'Gene', (215, 227))
879567	33322542	Although inhibition of miRNA-200c, which targets PTPN13, is associated with EMT, an in vivo study found no significant association between downregulation of the miRNA-200 family, PTPN13 expression, and colorectal cancer metastatic potential.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('miRNA-200c', 'Gene', (23, 33))	('colorectal cancer', 'Disease', (202, 219))	('rectal cancer', 'Phenotype', 'HP:0100743', (206, 219))	('PTPN13', 'Gene', (179, 185))	('PTPN13', 'Gene', (49, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))	('EMT', 'Disease', (76, 79))	('inhibition', 'Var', (9, 19))	('downregulation', 'NegReg', (139, 153))
879571	33322542	showing that PTPN13 stabilizes beta-catenin in megakaryocytes, found that inhibition of PTPN13 or beta-catenin in vivo increases HSC adhesion to their niche.	('increases', 'PosReg', (119, 128))	('inhibition', 'Var', (74, 84))	('beta-catenin', 'Gene', (31, 43))	('beta-catenin', 'Gene', '1499', (31, 43))	('HSC adhesion to their niche', 'CPA', (129, 156))	('beta-catenin', 'Gene', (98, 110))	('PTPN13', 'Gene', (88, 94))	('beta-catenin', 'Gene', '1499', (98, 110))
879601	33322542	The authors then reported a drastic decrease in cell survival after transfection of the PTPN13-C/S mutant in Ewing sarcoma cells.	('Ewing sarcoma', 'Disease', (109, 122))	('cell survival', 'CPA', (48, 61))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (109, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (109, 122))	('mutant', 'Var', (99, 105))	('PTPN13-C/S', 'Gene', (88, 98))	('decrease', 'NegReg', (36, 44))
879609	33322542	found that the PTPN13 promoter is methylated in 60% of 47 diffuse large B cell lymphoma samples, compared with 6.3% of 16 non-tumor tissue samples.	('PTPN13', 'Gene', (15, 21))	('methylated', 'Var', (34, 44))	('lymphoma', 'Disease', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('lymphoma', 'Disease', 'MESH:D008223', (79, 87))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (72, 87))	('lymphoma', 'Phenotype', 'HP:0002665', (79, 87))	('large B cell', 'Phenotype', 'HP:0005404', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('6.3', 'Gene', '55558', (111, 114))	('6.3', 'Gene', (111, 114))	('tumor', 'Disease', (126, 131))
879611	33322542	Specifically, it was methylated in 56% of 16 esophageal adenocarcinoma samples, and this was associated with decreased mRNA levels in 75% of cases.	('decreased', 'NegReg', (109, 118))	('methylated', 'Var', (21, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('adenocarcinoma', 'Disease', (56, 70))	('mRNA levels', 'MPA', (119, 130))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (45, 70))
879614	33322542	In tumor samples, miR30-e is decreased in bladder, breast, and rectal cancer, while it is overexpressed in salivary gland cancer and pulmonary adenocarcinoma.	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 157))	('salivary gland cancer', 'Disease', (107, 128))	('miR30-e', 'Var', (18, 25))	('rectal cancer', 'Phenotype', 'HP:0100743', (63, 76))	('pulmonary adenocarcinoma', 'Disease', (133, 157))	('tumor', 'Disease', (3, 8))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('overexpressed', 'PosReg', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('salivary gland cancer', 'Disease', 'MESH:D012468', (107, 128))	('cancer', 'Disease', (70, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast', 'Disease', (51, 57))	('decreased', 'NegReg', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('bladder', 'Disease', (42, 49))	('salivary gland cancer', 'Phenotype', 'HP:0100684', (107, 128))	('cancer', 'Disease', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (133, 157))
879616	33322542	They also showed that PTPN13 is a direct target of miR30-e. Tumor growth is promoted in mice xenografted with A549 cells transfected with miR30-e compared with cells transfected with vector alone.	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('miR30-e', 'Var', (138, 145))	('Tumor growth', 'CPA', (60, 72))	('promoted', 'PosReg', (76, 84))	('mice', 'Species', '10090', (88, 92))	('Tumor', 'Phenotype', 'HP:0002664', (60, 65))
879620	33322542	Indeed, miR-26a overexpression leads to wild-type PTPN13 protein level reduction, but has no effect on the expression of a PTPN13 variant harboring a mutation in the putative miR-26a binding site.	('miR-26a', 'Gene', '407015', (175, 182))	('miR-26a', 'Gene', (175, 182))	('mutation', 'Var', (150, 158))	('PTPN13', 'Gene', (123, 129))	('variant', 'Var', (130, 137))	('reduction', 'NegReg', (71, 80))	('PTPN13 protein level', 'MPA', (50, 70))	('miR-26a', 'Gene', '407015', (8, 15))	('miR-26a', 'Gene', (8, 15))
879621	33322542	In the SPCA-1 lung adenocarcinoma cell line, siRNA-mediated PTPN13 knockdown mimics the effect of miR26-a, promoting phosphorylation of SRC, Akt, and ERK, supporting miR26a oncogenic role in bronchial adenocarcinoma.	('lung adenocarcinoma', 'Disease', (14, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (201, 215))	('PTPN13', 'Gene', (60, 66))	('miR26a', 'Gene', '407015', (166, 172))	('SRC', 'Gene', '6714', (136, 139))	('SPCA-1', 'Gene', (7, 13))	('Akt', 'Gene', '207', (141, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (14, 33))	('promoting', 'PosReg', (107, 116))	('ERK', 'Gene', '5594', (150, 153))	('knockdown', 'Var', (67, 76))	('phosphorylation', 'MPA', (117, 132))	('SRC', 'Gene', (136, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('adenocarcinoma', 'Disease', (19, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('SPCA-1', 'Gene', '27032', (7, 13))	('miR26a', 'Gene', (166, 172))	('ERK', 'Gene', (150, 153))	('adenocarcinoma', 'Disease', (201, 215))	('miR26-a', 'Gene', (98, 105))	('miR26-a', 'Gene', '407015', (98, 105))	('adenocarcinoma', 'Disease', 'MESH:D000230', (19, 33))	('Akt', 'Gene', (141, 144))
879622	33322542	The miR-200 family contains five subtypes (miR-200a/b/c, miR-141, and miR-429), and is involved in maintaining the epithelial phenotype.	('miR-200a/b', 'Gene', '406983', (43, 53))	('miR-141', 'Var', (57, 64))	('miR-429', 'Gene', '554210', (70, 77))	('miR-200', 'Gene', (4, 11))	('miR-200', 'Chemical', '-', (4, 11))	('epithelial', 'MPA', (115, 125))	('miR-429', 'Gene', (70, 77))	('miR-200a/b', 'Gene', (43, 53))	('miR-200', 'Chemical', '-', (43, 50))
879629	33322542	However, two studies only on HGSOC, the most frequent ovarian cancer subtype, highlighted a correlation between high PTPN13 protein and mRNA expression and better prognosis in 97 and 58 HGSOC samples, respectively (p = 0.042 and p = 0.03).	('ovarian cancer', 'Disease', 'MESH:D010051', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mRNA expression', 'MPA', (136, 151))	('ovarian cancer', 'Disease', (54, 68))	('high', 'Var', (112, 116))	('PTPN13', 'Gene', (117, 123))	('ovarian cancer', 'Phenotype', 'HP:0100615', (54, 68))
879631	33322542	In breast cancer (n = 291 samples), we showed that high PTPN13 expression, measured by RT/PCR, is associated with better prognosis (p = 0.01 and RR = 0.48 in multivariate analysis).	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('expression', 'MPA', (63, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('PTPN13', 'Gene', (56, 62))	('high', 'Var', (51, 55))
879643	33322542	Overall, PTPN13 expression is linked to less aggressive tumors and better patient survival.	('patient', 'Species', '9606', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('expression', 'Var', (16, 26))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('aggressive tumors', 'Disease', 'MESH:D001523', (45, 62))	('PTPN13', 'Gene', (9, 15))	('better', 'PosReg', (67, 73))	('aggressive tumors', 'Disease', (45, 62))
879650	33322542	In line with these data, inhibition of the PTPN13/FAS interaction with the SLV peptide in PTPN13-overexpressing CD133+ colon cancer stem cells increases their sensitivity to oxaliplatin, restoring FAS-induced apoptosis.	('increases', 'PosReg', (143, 152))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('sensitivity to oxaliplatin', 'MPA', (159, 185))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colon cancer', 'Disease', 'MESH:D015179', (119, 131))	('PTPN13-overexpressing', 'Gene', (90, 111))	('restoring', 'PosReg', (187, 196))	('colon cancer', 'Disease', (119, 131))	('CD133', 'Gene', (112, 117))	('inhibition', 'Var', (25, 35))	('CD133', 'Gene', '8842', (112, 117))	('interaction', 'Interaction', (54, 65))	('FAS-induced apoptosis', 'CPA', (197, 218))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (174, 185))
879652	33322542	On the other hand, in NSCLC cell lines (SPCA1 and PC-9), PTPN13 increases the sensitivity to an anti-EGFR TKI (gefitinib).	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('PC-9', 'Gene', '255738', (50, 54))	('gefitinib', 'Chemical', 'MESH:D000077156', (111, 120))	('SPCA1', 'Gene', '27032', (40, 45))	('SPCA1', 'Gene', (40, 45))	('PC-9', 'Gene', (50, 54))	('PTPN13', 'Var', (57, 63))	('NSCLC', 'Disease', (22, 27))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('increases', 'PosReg', (64, 73))
879662	33322542	A recent study demonstrated PTPN13 involvement in cisplatin sensitivity of HNSCC cell lines (WSU-HN6 and CAL-27) where cancer-derived IgG inhibition upregulates PTPN13, resulting in the inhibition of the SRC/PKD1/AKT pathway.	('upregulates', 'PosReg', (149, 160))	('inhibition', 'NegReg', (186, 196))	('SRC', 'Gene', '6714', (204, 207))	('PKD1', 'Gene', '5310', (208, 212))	('SRC', 'Gene', (204, 207))	('PKD1', 'Gene', (208, 212))	('AKT', 'Gene', (213, 216))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('PTPN13', 'Gene', (161, 167))	('cancer', 'Disease', (119, 125))	('PTPN13', 'Gene', (28, 34))	('AKT', 'Gene', '207', (213, 216))	('inhibition', 'Var', (138, 148))	('IgG', 'Protein', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
879665	33322542	Similarly, PTPN13 LOH has been reported in 67% of HGSOC, and PTPN13 bi-allelic loss in 26% of NSCLC samples.	('PTPN13', 'Gene', (61, 67))	('NSCLC', 'Disease', (94, 99))	('PTPN13', 'Gene', (11, 17))	('LOH', 'Var', (18, 21))	('HGSOC', 'Disease', (50, 55))	('bi-allelic', 'Var', (68, 78))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))
879666	33322542	The Y2081D Tyr2081Asp (T > G), rs989902 (rs for SNP reference), in exon 39, near the PTPN13 phosphatase domain, is associated with colorectal cancer in Polish patients (relative risk compared to the "wild-type" genotype: 2.087), and with HNSCC in American patients (Odds Ratio, OR, =1.26).	('rectal cancer', 'Phenotype', 'HP:0100743', (135, 148))	('Tyr2081Asp', 'SUBSTITUTION', 'None', (11, 21))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (256, 264))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('Y2081D', 'Var', (4, 10))	('Tyr2081Asp', 'Var', (11, 21))	('rs989902', 'Mutation', 'rs989902', (31, 39))	('Y2081D', 'SUBSTITUTION', 'None', (4, 10))	('colorectal cancer', 'Disease', (131, 148))	('patients', 'Species', '9606', (159, 167))	('associated with', 'Reg', (115, 130))	('rs989902', 'Var', (31, 39))
879668	33322542	In breast cancer, this meta-analysis found a protective role for this SNP (OR = 0.63), as well as a Chinese study on the C/A and G/C genotypes of this SNP (OR = 0.63 and OR= 0.66).	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('G/C', 'Var', (129, 132))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('C/A', 'Var', (121, 124))
879669	33322542	The I1522M Ile1522Met (A > G), rs2230600, in exon 29 within the third PTPN13 PDZ domain, has been associated with HNSCC occurrence (OR = 1.89).	('Ile1522Met', 'Chemical', '-', (11, 21))	('rs2230600', 'Var', (31, 40))	('HNSCC', 'Disease', (114, 119))	('rs2230600', 'Mutation', 'rs2230600', (31, 40))	('I1522M', 'Mutation', 'rs2230600', (4, 10))	('associated', 'Reg', (98, 108))
879672	33322542	Conversely, the E2455D and Y2260WX SNPs in the catalytic domain of PTPN13 that have been identified in colorectal cancer induce a loss of 50 to almost 100%, respectively, of the phosphatase activity.	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('phosphatase activity', 'MPA', (178, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('Y2260WX', 'Var', (27, 34))	('E2455D', 'Var', (16, 22))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('loss', 'NegReg', (130, 134))	('E2455D', 'Mutation', 'rs753760213', (16, 22))	('rectal cancer', 'Phenotype', 'HP:0100743', (107, 120))	('PTPN13', 'Gene', (67, 73))
879673	33322542	In addition, the nonsense Tyr1758*** (T > A) and missense Glu745Gln mutations have been found in hepatitis B virus-induced HCC samples, and the L1424P false-sense mutation, which is located in a protein-interacting PDZ domain (genomic position 87687597), may affect PTPN13 function.	('PTPN13', 'Gene', (266, 272))	('L1424P', 'Mutation', 'rs749353184', (144, 150))	('hepatitis B virus', 'Species', '10407', (97, 114))	('missense', 'Var', (49, 57))	('hepatitis', 'Phenotype', 'HP:0012115', (97, 106))	('Glu745Gln', 'Mutation', 'p.E745Q', (58, 67))	('hepatitis B virus-induced HCC', 'Disease', (97, 126))	('affect', 'Reg', (259, 265))	('found', 'Reg', (88, 93))	('Glu745Gln', 'Var', (58, 67))	('HCC', 'Phenotype', 'HP:0001402', (123, 126))	('Tyr1758', 'Chemical', '-', (26, 33))	('function', 'MPA', (273, 281))	('L1424P', 'Var', (144, 150))
879674	33322542	Around 6% of TCGA gastric cancer samples harbor PTPN13 mutations that have been associated with poor prognosis.	('gastric cancer', 'Disease', (18, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('mutations', 'Var', (55, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('PTPN13', 'Gene', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('harbor', 'Reg', (41, 47))
879675	33322542	In 262 patients with familial lung cancer, a non-synonymous PTPN13 exon variant (rs115836094) at 4q21.3-28.3 could be involved in carcinogenesis.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('rs115836094', 'Var', (81, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('PTPN13', 'Gene', (60, 66))	('familial lung cancer', 'Disease', (21, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('carcinogenesis', 'Disease', (130, 144))	('rs115836094', 'Mutation', 'rs115836094', (81, 92))	('involved', 'Reg', (118, 126))	('patients', 'Species', '9606', (7, 15))	('familial lung cancer', 'Disease', 'MESH:D008175', (21, 41))
879676	33322542	Moreover, 8% of NSCLC samples harbored false-sense PTPN13 mutations with unknown functions (e.g., A808C leading to N270H in exon 7, and G1925A, leading to R482Q in exon 10).	('R482Q', 'Var', (155, 160))	('N270H', 'Var', (115, 120))	('N270H', 'Mutation', 'rs1275026116', (115, 120))	('A808C', 'Mutation', 'rs1275026116', (98, 103))	('G1925A', 'Var', (136, 142))	('PTPN13', 'Gene', (51, 57))	('A808C', 'Var', (98, 103))	('NSCLC', 'Disease', (16, 21))	('G1925A', 'Mutation', 'c.1925G>A', (136, 142))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('R482Q', 'Mutation', 'rs781154444', (155, 160))
879678	33322542	Overall, approximately 7-8% of lung cancer and 20% of HPV-negative HNSCC samples harbor PTPN13 mutations.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('harbor', 'Reg', (81, 87))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('PTPN13', 'Gene', (88, 94))
879679	33322542	A mutational analysis of data from a tyrosine phosphatome-wide study of 157 CRC samples showed that PTPN13 is the second most commonly mutated phosphatase in these cancers (n = 15 tumors with a mutation; 9% of the entire sample).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mutated', 'Var', (135, 142))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', (180, 186))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('tyrosine', 'Chemical', 'MESH:D014443', (37, 45))	('PTPN13', 'Gene', (100, 106))
879680	33322542	Nevertheless, all analyzed mutations have an inhibitory effect on PTPN13 activity, and their presence appears to be associated with poor prognosis in lung cancer (p = 0.02) and possibly in gastric cancer.	('mutations', 'Var', (27, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('lung cancer', 'Disease', (150, 161))	('activity', 'MPA', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('PTPN13', 'Gene', (66, 72))	('gastric cancer', 'Disease', (189, 203))	('gastric cancer', 'Disease', 'MESH:D013274', (189, 203))
879689	32411602	Studies that investigated the prognostic significance of generalized, CD8+, CD4+, FoxP3+, CD3+, and CD45O+ TILs in ESCC patients were included.	('CD3+', 'Var', (90, 94))	('ESCC', 'Disease', (115, 119))	('CD4', 'Gene', (100, 103))	('CD45', 'Gene', '5788', (100, 104))	('CD4', 'Gene', (76, 79))	('CD4', 'Gene', '920', (100, 103))	('FoxP3', 'Gene', '50943', (82, 87))	('patients', 'Species', '9606', (120, 128))	('CD8', 'Gene', (70, 73))	('CD4', 'Gene', '920', (76, 79))	('CD8', 'Gene', '925', (70, 73))	('FoxP3', 'Gene', (82, 87))	('CD45', 'Gene', (100, 104))
879691	32411602	The pan-tumor, intra-tumor and peri-tumor CD8+ TILs had a favorable effect on OS, with univariate-related HRs of 0.733 (0.555-0.968), 0.797 (0.660-0.962), and 0.776 (0.635-0.948), respectively.	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('0.797', 'Var', (134, 139))	('CD8', 'Gene', '925', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('CD8', 'Gene', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
879694	32411602	Our meta-analysis confirms the prognostic efficacy of generalized TILs and CD8+ TILs in esophageal squamous cell carcinoma (ESCC) patients.	('esophageal squamous cell carcinoma', 'Disease', (88, 122))	('CD8', 'Gene', '925', (75, 78))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (88, 122))	('patients', 'Species', '9606', (130, 138))	('generalized TILs', 'Var', (54, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('CD8', 'Gene', (75, 78))
879716	32411602	For time-to-event data, HRs were used to evaluate the risk of progression or death for patients with high-level TILs vs. low-level TILs.	('death', 'Disease', 'MESH:D003643', (77, 82))	('death', 'Disease', (77, 82))	('high-level TILs', 'Var', (101, 116))	('patients', 'Species', '9606', (87, 95))	('TILs', 'Var', (112, 116))
879748	32411602	For instance, when clinical stage, tumor grade, and follow-up time were taken into account, TILs can improve outcome prediction even more significantly.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('TILs', 'Var', (92, 96))	('improve', 'PosReg', (101, 108))	('outcome prediction', 'MPA', (109, 127))
879766	32411602	However, previous findings demonstrated that high FoxP3+ Tregs density was associated with a significant lower OS rate in melanomas and hepatocellular carcinoma.	('lower', 'NegReg', (105, 110))	('melanomas and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (122, 160))	('Tregs', 'Chemical', '-', (57, 62))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('high', 'Var', (45, 49))	('FoxP3', 'Gene', '50943', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (136, 160))	('FoxP3', 'Gene', (50, 55))
879769	32411602	In this meta-analysis, we investigated the prognostic value of CD3+ TILs, which are generally considered to be a positive predictor of prognosis for ESCC patients.	('ESCC', 'Disease', (149, 153))	('CD3+ TILs', 'Var', (63, 72))	('patients', 'Species', '9606', (154, 162))
879773	32411602	Therefore, detecting intraepithelial infiltration of CD3+ TILs is a comparatively specific method for predicting tumor prognosis.	('tumor', 'Disease', (113, 118))	('CD3+', 'Var', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
879807	30763622	PEGylated peptide to TIP1 is a novel targeting agent that binds specifically to various cancers in vivo Targeted molecular imaging allows specific visualization and monitoring of tumors.	('TIP1', 'Gene', (21, 25))	('PEGylated', 'Var', (0, 9))	('tumors', 'Disease', (179, 185))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('cancers', 'Disease', (88, 95))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('TIP1', 'Gene', '76281', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))
879869	30763622	LS601-NHS ester was dissolved in DMF and added to the PEG solution.	('LS601-NHS', 'Var', (0, 9))	('LS601-NHS ester', 'Chemical', '-', (0, 15))	('PEG', 'Gene', (54, 57))	('PEG', 'Gene', '5047', (54, 57))	('DMF', 'Chemical', '-', (33, 36))
879872	30763622	LS601-NHS ester was dissolved in DMSO and added to the PEG solution.	('DMSO', 'Chemical', 'MESH:D004121', (33, 37))	('LS601-NHS', 'Var', (0, 9))	('PEG', 'Gene', '5047', (55, 58))	('LS601-NHS ester', 'Chemical', '-', (0, 15))	('PEG', 'Gene', (55, 58))
879906	30763622	The TIP1 residues involved in interacting with HVGGSSV are Lys 20, Glu 25, Asn 26, Leu 27, Ile 28, Leu 29, Gly 30, Phe 31, Lys 95, Thr 98, Lys 99, Arg 100.	('Lys', 'Chemical', 'MESH:D008239', (59, 62))	('Thr 98', 'Var', (131, 137))	('Lys', 'Chemical', 'MESH:D008239', (139, 142))	('Leu', 'Chemical', 'MESH:D007930', (99, 102))	('Gly 30', 'Var', (107, 113))	('Glu', 'Var', (67, 70))	('Lys 20', 'Var', (59, 65))	('Leu', 'Chemical', 'MESH:D007930', (83, 86))	('Lys 95', 'Var', (123, 129))	('Arg 100', 'Var', (147, 154))	('Phe 31', 'Var', (115, 121))	('Thr', 'Chemical', 'MESH:D013912', (131, 134))	('Leu 29', 'Var', (99, 105))	('Glu', 'Chemical', 'MESH:D018698', (67, 70))	('Asn', 'Chemical', 'MESH:D001216', (75, 78))	('Gly', 'Chemical', 'MESH:D005998', (107, 110))	('Lys 99', 'Var', (139, 145))	('Ile', 'Chemical', 'MESH:D007532', (91, 94))	('Leu 27', 'Var', (83, 89))	('Ile 28', 'Var', (91, 97))	('Phe', 'Chemical', 'MESH:D010649', (115, 118))	('Lys', 'Chemical', 'MESH:D008239', (123, 126))	('Arg', 'Chemical', 'MESH:D001120', (147, 150))
879908	30763622	The third and fourth glycine of HVGGSSV interacts with Leu 27 and Arg 100 respectively.	('glycine', 'Chemical', 'MESH:D005998', (21, 28))	('HVGGSSV', 'Gene', (32, 39))	('Leu', 'Chemical', 'MESH:D007930', (55, 58))	('Leu 27', 'Var', (55, 61))	('interacts', 'Reg', (40, 49))	('Arg', 'Protein', (66, 69))	('Arg', 'Chemical', 'MESH:D001120', (66, 69))
879911	30763622	The overall interaction of the peptide with the protein is stabilized by hydrophobic interactions with Ile 28, Leu 29, Gly 30, Phe 31, Lys 95.	('Ile 28', 'Var', (103, 109))	('Phe', 'Chemical', 'MESH:D010649', (127, 130))	('Gly', 'Chemical', 'MESH:D005998', (119, 122))	('protein', 'Protein', (48, 55))	('hydrophobic interactions', 'MPA', (73, 97))	('Leu', 'Chemical', 'MESH:D007930', (111, 114))	('Lys', 'Chemical', 'MESH:D008239', (135, 138))	('interaction', 'Interaction', (12, 23))	('Ile', 'Chemical', 'MESH:D007532', (103, 106))	('Phe 31', 'Var', (127, 133))	('Gly 30', 'Var', (119, 125))	('stabilized', 'Reg', (59, 69))	('Lys 95', 'Var', (135, 141))	('Leu 29', 'Var', (111, 117))
879915	30763622	We also found whole cell expression of TIP1 in D54, HT3, OE33 and A549, which also enhanced at 24h and 48h post radiation (Supplementary Figure 2C).	('OE33', 'Var', (57, 61))	('HT3', 'Gene', (52, 55))	('enhanced', 'PosReg', (83, 91))	('expression', 'MPA', (25, 35))	('A549', 'Var', (66, 70))	('TIP1', 'Gene', (39, 43))	('HT3', 'Gene', '109523', (52, 55))
879917	30763622	Cancer cells D54, HT3, OE33, and A549 were incubated with HVGGSSV peptide, or scrambled peptide conjugated with FITC.	('HVGGSSV peptide', 'Var', (58, 73))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('FITC', 'Chemical', 'MESH:D016650', (112, 116))	('HT3', 'Gene', '109523', (18, 21))	('HT3', 'Gene', (18, 21))
879918	30763622	We found uptake of HVGGSSV peptide in D54, HT3, OE33, and A549 and there was little or no uptake of the scrambled peptide (Fig.	('HVGGSSV peptide', 'Var', (19, 34))	('HT3', 'Gene', (43, 46))	('HT3', 'Gene', '109523', (43, 46))	('uptake', 'MPA', (9, 15))
879942	30763622	We found very low or negligible binding of 111In-labeled PEG-DTPA-control in both HT3 (Fig.	('HT3', 'Gene', '109523', (82, 85))	('HT3', 'Gene', (82, 85))	('binding', 'Interaction', (32, 39))	('PEG-DTPA-control', 'Var', (57, 73))	('111In', 'Chemical', 'MESH:C000615551', (43, 48))
879967	30763622	To overcome this, we conjugated the HVGGSSV peptide to a 40kDa PEG to enhance its circulation time and extravasation to the tumors.	('PEG', 'Gene', '5047', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('enhance', 'PosReg', (70, 77))	('circulation time', 'MPA', (82, 98))	('tumors', 'Disease', (124, 130))	('extravasation', 'MPA', (103, 116))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('PEG', 'Gene', (63, 66))	('HVGGSSV', 'Var', (36, 43))
879968	30763622	40kDa PEG was chosen based on our NIR study with different sizes of PEG since we found the most accumulation of 40kDa in the mouse tumors.	('40kDa', 'Var', (112, 117))	('accumulation', 'PosReg', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('mouse', 'Species', '10090', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('PEG', 'Gene', (68, 71))	('PEG', 'Gene', '5047', (68, 71))	('PEG', 'Gene', (6, 9))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('PEG', 'Gene', '5047', (6, 9))
880104	29541406	NFkB hyperactivation causes invasion of esophageal squamous cell carcinoma with EGFR overexpression and p120-catenin down-regulation Four out of five patients diagnosed with esophageal squamous cell carcinoma (ESCC) will die within five years.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (174, 208))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (40, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('esophageal squamous cell carcinoma', 'Disease', (40, 74))	('overexpression', 'PosReg', (85, 99))	('esophageal squamous cell carcinoma', 'Disease', (174, 208))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('patients', 'Species', '9606', (150, 158))	('hyperactivation', 'Var', (5, 20))	('NFkB', 'Gene', (0, 4))	('p120-catenin', 'Gene', (104, 116))	('down-regulation', 'NegReg', (117, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('invasion', 'Disease', (28, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('p120-catenin', 'Gene', '1500', (104, 116))
880162	29541406	Together, these data demonstrate that inhibition of NFkB 1) does not affect EPC1-C epithelium in 3D cultures, 2) does not affect the cell counts of EPC1-PE cells, and 3) results in inhibition of EPC1-PE invasion in Matrigel and 3D cultures.	('NFkB 1', 'Gene', '4790', (52, 58))	('EPC1', 'Gene', '80314', (195, 199))	('EPC1', 'Gene', (195, 199))	('NFkB 1', 'Gene', (52, 58))	('inhibition', 'NegReg', (181, 191))	('inhibition', 'Var', (38, 48))	('EPC1', 'Gene', '80314', (148, 152))	('EPC1', 'Gene', '80314', (76, 80))	('EPC1', 'Gene', (148, 152))	('EPC1', 'Gene', (76, 80))
880213	29541406	Figure 6C and 6D demonstrate inhibition of pNFkB expression levels through pharmacologic treatment of TE10-C and TE10-PE cells.	('expression levels', 'MPA', (49, 66))	('inhibition', 'NegReg', (29, 39))	('TE10-PE', 'Var', (113, 120))	('pNFkB', 'Gene', (43, 48))	('TE10-PE', 'Chemical', '-', (113, 120))	('TE10-C', 'Var', (102, 108))
880246	29541406	We believe we have laid the groundwork for identifying a subset of ESCC patients (with p120ctn down-regulation and EGFR overexpression together) that may respond to more targeted therapy as a result of the modification of these two genes.	('p120ctn', 'Gene', '1500', (87, 94))	('ESCC', 'Disease', (67, 71))	('overexpression', 'PosReg', (120, 134))	('EGFR', 'Gene', '1956', (115, 119))	('down-regulation', 'NegReg', (95, 110))	('modification', 'Var', (206, 218))	('EGFR', 'Gene', (115, 119))	('p120ctn', 'Gene', (87, 94))	('patients', 'Species', '9606', (72, 80))
880251	29541406	It is hyperactivated downstream of these genetic alterations through increased activity of RhoA GTPase and Rho-kinase.	('activity', 'MPA', (79, 87))	('genetic alterations', 'Var', (41, 60))	('alterations', 'Var', (49, 60))	('increased', 'PosReg', (69, 78))	('Rho-kinase', 'Enzyme', (107, 117))	('GTP', 'Chemical', 'MESH:D006160', (96, 99))	('RhoA', 'Gene', (91, 95))	('RhoA', 'Gene', '387', (91, 95))	('hyperactivated', 'PosReg', (6, 20))
880279	29541406	Inhibition of NFkB was performed using NFkB Activation Inhibitor II, JSH-23 (#481408) at a concentration of 10 muM for 2 hours or BAY 11-7085 (#196872) at a concentration of 10 muM for 2 hours.	('#481408', 'Var', (77, 84))	('NFkB', 'Gene', (39, 43))	('JSH-23', 'Chemical', 'MESH:C549066', (69, 75))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (130, 141))	('#196872', 'Var', (143, 150))
880344	28969099	The first model of circRNAs synthesis is intron-pairing-driven circularization, termed "direct back-splicing" (Figure 1A).	('cir', 'Gene', (19, 22))	('cir', 'Gene', '9541', (19, 22))	('intron-pairing-driven', 'Var', (41, 62))	('cir', 'Gene', (63, 66))	('cir', 'Gene', '9541', (63, 66))
880347	28969099	Notably, it has been reported that in humans the bordering introns of circRNAs are highly enriched in ALU repeats, which contain RCMs.	('cir', 'Gene', (70, 73))	('ALU repeats', 'Var', (102, 113))	('cir', 'Gene', '9541', (70, 73))	('humans', 'Species', '9606', (38, 44))
880351	28969099	This leads to the generation of either exon circRNAs (ecircRNAs) or exon-intron circRNAs (EIciRNAs).	('exon-intron', 'MPA', (68, 79))	('cir', 'Gene', '9541', (55, 58))	('cir', 'Gene', (44, 47))	('cir', 'Gene', (80, 83))	('cir', 'Gene', '9541', (80, 83))	('cir', 'Gene', '9541', (44, 47))	('cir', 'Gene', (55, 58))	('leads to', 'Reg', (5, 13))	('exon', 'Var', (39, 43))
880377	28969099	In both cell lines transfected with empty vector (control of cir-ITCH plasmid), luciferase activity was significantly decreased, in a concentration dependent manner, by a miR-7 or miR-214 mimic.	('-ITCH', 'Phenotype', 'HP:0000989', (64, 69))	('miR-214', 'Gene', (180, 187))	('miR-7', 'Var', (171, 176))	('ITCH', 'Gene', '83737', (65, 69))	('ITCH', 'Phenotype', 'HP:0000989', (65, 69))	('cir', 'Gene', (61, 64))	('activity', 'MPA', (91, 99))	('ITCH', 'Gene', (65, 69))	('miR-214', 'Gene', '406996', (180, 187))	('decreased', 'NegReg', (118, 127))	('cir', 'Gene', '9541', (61, 64))	('luciferase', 'Enzyme', (80, 90))
880398	28969099	Following the knockdown of hsa_circ_0001649 with siRNA, there was an increase in the expression level of the pro-metastatic matrix metalloproteinases (MPPs), MMP9, MMP10 and MMP13.	('MMP9', 'Gene', (158, 162))	('cir', 'Gene', '9541', (31, 34))	('increase', 'PosReg', (69, 77))	('MMP9', 'Gene', '4318', (158, 162))	('MMP10', 'Gene', (164, 169))	('MMP10', 'Gene', '4319', (164, 169))	('MMP13', 'Gene', (174, 179))	('cir', 'Gene', (31, 34))	('knockdown', 'Var', (14, 23))	('MMP13', 'Gene', '4322', (174, 179))	('expression level', 'MPA', (85, 101))
880406	28969099	When ciRS-7 is knocked-down, there is a significant inhibition of HCC cell proliferation and invasion, which is likely due to the release of miR-7.	('knocked-down', 'Var', (15, 27))	('ciRS-7', 'Gene', (5, 11))	('HCC cell proliferation', 'CPA', (66, 88))	('ciRS-7', 'Gene', '103611090', (5, 11))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('invasion', 'CPA', (93, 101))	('inhibition', 'NegReg', (52, 62))
880411	28969099	Consequently, the ectopic expression of circPVT1 may reduce the antineoplastic effects of miR-125b and E2F2.	('reduce', 'NegReg', (53, 59))	('ectopic expression', 'Var', (18, 36))	('E2F2', 'Gene', '1870', (103, 107))	('cir', 'Gene', (40, 43))	('cir', 'Gene', '9541', (40, 43))	('antineoplastic effects', 'CPA', (64, 86))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))	('E2F2', 'Gene', (103, 107))
880427	28969099	In a study of the CRC cell lines, HCT116 and SW480, sponge activity of cir-ITCH was demonstrated towards miR-7, miR-20a, and miR-214.	('ITCH', 'Gene', '83737', (75, 79))	('miR-20a', 'Gene', (112, 119))	('miR-7', 'Var', (105, 110))	('cir', 'Gene', (71, 74))	('miR-20a', 'Gene', '406982', (112, 119))	('miR-214', 'Gene', (125, 132))	('ITCH', 'Gene', (75, 79))	('HCT116', 'CellLine', 'CVCL:0291', (34, 40))	('sponge activity', 'MPA', (52, 67))	('CRC', 'Phenotype', 'HP:0003003', (18, 21))	('miR-214', 'Gene', '406996', (125, 132))	('cir', 'Gene', '9541', (71, 74))	('SW480', 'CellLine', 'CVCL:0546', (45, 50))	('ITCH', 'Phenotype', 'HP:0000989', (75, 79))	('-ITCH', 'Phenotype', 'HP:0000989', (74, 79))
880429	28969099	It has also been reported that the ectopic expression of cir-ITCH inhibits the expression of c-myc and cyclin D1, which are target genes of the Wnt/beta-catenin signaling pathway.	('ITCH', 'Gene', '83737', (61, 65))	('expression', 'MPA', (79, 89))	('ITCH', 'Gene', (61, 65))	('beta-catenin', 'Gene', (148, 160))	('cir', 'Gene', (57, 60))	('inhibits', 'NegReg', (66, 74))	('c-myc', 'Gene', (93, 98))	('c-myc', 'Gene', '4609', (93, 98))	('beta-catenin', 'Gene', '1499', (148, 160))	('cir', 'Gene', '9541', (57, 60))	('cyclin D1', 'Gene', (103, 112))	('cyclin D1', 'Gene', '595', (103, 112))	('ITCH', 'Phenotype', 'HP:0000989', (61, 65))	('-ITCH', 'Phenotype', 'HP:0000989', (60, 65))	('ectopic expression', 'Var', (35, 53))
880438	28969099	Moreover, knockdown of hsa_circ_001569 in SW620 and LOVO cells has been shown to reverse invasive abilities.	('SW620', 'CellLine', 'CVCL:0547', (42, 47))	('invasive abilities', 'CPA', (89, 107))	('cir', 'Gene', (27, 30))	('reverse', 'NegReg', (81, 88))	('knockdown', 'Var', (10, 19))	('cir', 'Gene', '9541', (27, 30))
880443	28969099	A knockdown of circ-BANP using siRNA was also shown to reduce proliferation and colony formation of the CRC cell lines, HCT116 and HT29.	('BANP', 'Gene', (20, 24))	('colony formation', 'CPA', (80, 96))	('cir', 'Gene', (15, 18))	('HCT116', 'CellLine', 'CVCL:0291', (120, 126))	('knockdown', 'Var', (2, 11))	('proliferation', 'CPA', (62, 75))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('cir', 'Gene', '9541', (15, 18))	('reduce', 'NegReg', (55, 61))	('BANP', 'Gene', '54971', (20, 24))
880463	28969099	These results implicated the abnormally expressed circRNAs in the development of radiation resistance in the esophageal cancer cells.	('implicated', 'Reg', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('abnormally expressed', 'Var', (29, 49))	('men', 'Species', '9606', (73, 76))	('cir', 'Gene', (50, 53))	('cir', 'Gene', '9541', (50, 53))	('radiation resistance', 'CPA', (81, 101))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
880465	28969099	Moreover, siRNA mediated silencing of hsa_circ_0067934 suppressed ESCC cell proliferation, migration and cell cycle progression.	('silencing', 'Var', (25, 34))	('migration', 'CPA', (91, 100))	('suppressed', 'NegReg', (55, 65))	('cell cycle progression', 'CPA', (105, 127))	('ESCC', 'Disease', (66, 70))	('cir', 'Gene', (42, 45))	('cir', 'Gene', '9541', (42, 45))
880469	28969099	The authors also identified that cir-ITCH acts as a sponge of miR-7, miR-17, and miR-214, thereby up-regulated the target gene ITCH, which negatively regulates the Wnt/beta-catenin pathway via targeting dishevelled (Dvl) protein.	('miR-17', 'Gene', (69, 75))	('ITCH', 'Gene', (127, 131))	('negatively', 'NegReg', (139, 149))	('cir', 'Gene', '9541', (33, 36))	('miR-7', 'Var', (62, 67))	('ITCH', 'Phenotype', 'HP:0000989', (37, 41))	('miR-214', 'Gene', '406996', (81, 88))	('beta-catenin', 'Gene', (168, 180))	('-ITCH', 'Phenotype', 'HP:0000989', (36, 41))	('Dvl', 'Gene', (216, 219))	('cir', 'Gene', (33, 36))	('beta-catenin', 'Gene', '1499', (168, 180))	('ITCH', 'Gene', '83737', (127, 131))	('ITCH', 'Gene', (37, 41))	('miR-214', 'Gene', (81, 88))	('dishevelled', 'Gene', (203, 214))	('miR-17', 'Gene', '406952', (69, 75))	('up-regulated', 'PosReg', (98, 110))	('dishevelled', 'Gene', '8215', (203, 214))	('ITCH', 'Phenotype', 'HP:0000989', (127, 131))	('regulates', 'Reg', (150, 159))	('Dvl', 'Gene', '8215', (216, 219))	('ITCH', 'Gene', '83737', (37, 41))
880473	28969099	While DCIS is generally considered to be highly curable, some women with DCIS will develop life-threatening invasive breast cancer, infiltrating ductal cancer (IDC), but the determinants of this progression remains largely unknown.	('DCIS', 'Phenotype', 'HP:0030075', (6, 10))	('develop', 'PosReg', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('invasive breast cancer', 'Disease', (108, 130))	('ductal cancer', 'Disease', 'MESH:D009369', (145, 158))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('DCIS', 'Var', (73, 77))	('ductal cancer', 'Disease', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('women', 'Species', '9606', (62, 67))	('invasive breast cancer', 'Disease', 'MESH:D001943', (108, 130))
880517	28969099	Silencing of cZNF292 expression was reported to inhibit glioma cell proliferation and halt cell cycle progression in U87MG and U251 cells via inactivation of the Wnt/beta-catenin signaling pathway.	('glioma', 'Disease', (56, 62))	('beta-catenin', 'Gene', (166, 178))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('inactivation', 'NegReg', (142, 154))	('halt', 'NegReg', (86, 90))	('beta-catenin', 'Gene', '1499', (166, 178))	('cell cycle progression', 'CPA', (91, 113))	('cZNF292', 'Gene', (13, 20))	('Silencing', 'Var', (0, 9))	('U87MG', 'CellLine', 'CVCL:0022', (117, 122))	('U251', 'CellLine', 'CVCL:0021', (127, 131))	('inhibit', 'NegReg', (48, 55))
880533	28969099	Functional analysis found that a knockdown of circRNA_100290 could induce G1/S arrest in SCC9 cell lines, and this significantly inhibited cell proliferation.	('inhibited', 'NegReg', (129, 138))	('S arrest', 'Disease', (77, 85))	('cir', 'Gene', (46, 49))	('cir', 'Gene', '9541', (46, 49))	('knockdown', 'Var', (33, 42))	('S arrest', 'Disease', 'MESH:D006323', (77, 85))	('cell proliferation', 'CPA', (139, 157))	('induce', 'Reg', (67, 73))	('SCC9', 'CellLine', 'CVCL:1685', (89, 93))
880553	28969099	Previous studies have shown how miR expression can be regulated through mechanisms, such as DNA copy number variations, epigenetics, transcription factors and other mechanisms in cancer.	('miR', 'Gene', (32, 35))	('epigenetics', 'Var', (120, 131))	('regulated', 'Reg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))	('expression', 'MPA', (36, 46))	('miR', 'Gene', '220972', (32, 35))
880659	28367248	There were two different concurrent chemotherapy regimens for neoadjuvant treatment: 1. two cycles of cisplatin (25 mg/m2, d 1-4 and d 22-25) and NVB (25 mg/m2, d1, d8, d22, d29) concurrently with 40 Gy radiation, which was given in 20 fractions over 4 weeks; and 2. weekly cisplatin (25 mg/m2, d 1, d 8, d 15, and d 22) and docetaxel (25 mg/m2, d 1, d 8, d 15, and d 22) concurrently with 40 Gy radiation, which was administered in 20 fractions over 4 weeks.	('25 mg/m2', 'Var', (336, 344))	('25 mg/m2', 'Var', (285, 293))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('docetaxel', 'Chemical', 'MESH:D000077143', (325, 334))	('cisplatin', 'Chemical', 'MESH:D002945', (274, 283))
880728	28367248	The results in the current study suggested that potentially curable ESCC patients who received NCT followed by surgery achieved a superior 3-year OS compared with those receiving surgery alone (estimated OS of 68.7 months in the NCT + surgery group, 52.7 months in the surgery group, p=0.000 using the log-rank test), which is consistent with the previous published data from the CROSS trial.	('ESCC', 'Disease', (68, 72))	('OS', 'Chemical', '-', (204, 206))	('OS', 'Chemical', '-', (146, 148))	('OS', 'Chemical', '-', (382, 384))	('patients', 'Species', '9606', (73, 81))	('NCT', 'Var', (95, 98))
880738	28367248	NCCN guidelines recommend that ESCC patients with T1BN+, T2-T4aN0N+ receive NCT + surgery as radical treatment, but definitive CCRT should be administered to patients who are diagnosed with cervical primaries or who decline surgery.	('patients', 'Species', '9606', (36, 44))	('T1BN+', 'Var', (50, 55))	('CRT', 'Gene', '799', (128, 131))	('T2-T4aN0N+', 'Var', (57, 67))	('CRT', 'Gene', (128, 131))	('patients', 'Species', '9606', (158, 166))
880765	28298808	Based on a cutoff value of 0.319, the sensitivity and specificity of autoantibodies against Ezrin for diagnosis of ESCC were 27.5% and 95.9%, respectively.	('ESCC', 'Disease', (115, 119))	('autoantibodies', 'Var', (69, 83))	('Ezrin', 'Gene', '7430', (92, 97))	('Ezrin', 'Gene', (92, 97))
880766	28298808	Compared with normal controls, the positive rate of autoantibodies against Ezrin was significantly elevated in patients with early-stage ESCC (P < 0.0001).	('autoantibodies', 'Var', (52, 66))	('Ezrin', 'Gene', (75, 80))	('elevated', 'PosReg', (99, 107))	('early-stage ESCC', 'Disease', (125, 141))	('Ezrin', 'Gene', '7430', (75, 80))	('patients', 'Species', '9606', (111, 119))
880768	28298808	Our study indicates that the presence of autoantibodies against Ezrin is significantly associated with ESCC.	('autoantibodies', 'Var', (41, 55))	('presence', 'Var', (29, 37))	('Ezrin', 'Gene', (64, 69))	('associated', 'Reg', (87, 97))	('ESCC', 'Disease', (103, 107))	('Ezrin', 'Gene', '7430', (64, 69))
880782	28298808	identified autoantibodies to Ezrin as early diagnostic biomarker in pancreatic cancer.	('autoantibodies', 'Var', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('Ezrin', 'Gene', '7430', (29, 34))	('pancreatic cancer', 'Disease', (68, 85))	('Ezrin', 'Gene', (29, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))
880822	28298808	In recent years, autoantibodies to TAAs have drawn increasing scientific interest owing to their promising value of clinical application in terms of the early detection of cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('TAAs', 'Protein', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('autoantibodies', 'Var', (17, 31))
880827	28298808	We here measured autoantibodies against Ezrin in sera of patients with early-stage ESCC and normal controls resulting in 27.8% sensitivity with a robust specificity of 95.9%.	('measured', 'Reg', (8, 16))	('Ezrin', 'Gene', (40, 45))	('patients', 'Species', '9606', (57, 65))	('ESCC', 'Disease', (83, 87))	('Ezrin', 'Gene', '7430', (40, 45))	('autoantibodies', 'Var', (17, 31))
880835	28298808	In conclusion, to date this study is the first to assess the diagnostic value of serum autoantibodies against Ezrin in ESCC, indicating that the presence of autoantibodies against Ezrin is significantly associated with ESCC and may be of clinical value for ESCC.	('presence', 'Var', (145, 153))	('associated with', 'Reg', (203, 218))	('Ezrin', 'Gene', '7430', (110, 115))	('Ezrin', 'Gene', '7430', (180, 185))	('ESCC', 'Disease', (257, 261))	('ESCC', 'Disease', (219, 223))	('Ezrin', 'Gene', (180, 185))	('autoantibodies', 'Var', (157, 171))	('Ezrin', 'Gene', (110, 115))
880836	28298808	Moreover, our results reveal that autoantibody against Ezrin combined with other specific autoantibodies in esophageal cancer may shed light on a promising way to develop a highly sensitive test for early diagnosis of ESCC in the future.	('ESCC', 'Disease', (218, 222))	('Ezrin', 'Gene', '7430', (55, 60))	('esophageal cancer', 'Disease', (108, 125))	('autoantibody', 'Var', (34, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('Ezrin', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
880838	28099114	Previously we described mtDNA copy number depletion across many solid tumor types (Reznik et al., 2016).	('copy number depletion', 'Var', (30, 51))	('solid tumor', 'Disease', (64, 75))	('solid tumor', 'Disease', 'MESH:D009369', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
880858	28099114	In, we observed widespread mtDNA copy number depletion in tumors compared to matched adjacent normal tissue in a number of solid tumor types.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('copy number depletion', 'Var', (33, 54))	('solid tumor', 'Disease', (123, 134))	('solid tumor', 'Disease', 'MESH:D009369', (123, 134))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mtDNA', 'Gene', (27, 32))
880863	28099114	We also observed that LUAD (lung adenocarcinoma), which we found to be the only cancer type with increased mtDNA copy number in, had lower expression of 6/13 mtRNAs, suggesting that any increase in mtDNA copy number in LUAD was compensated for at the transcriptional level.	('mtDNA', 'Gene', (107, 112))	('lung adenocarcinoma', 'Disease', (28, 47))	('mtRNAs', 'Protein', (158, 164))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (28, 47))	('copy number', 'Var', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('expression', 'MPA', (139, 149))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('lower', 'NegReg', (133, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('LUAD', 'Disease', (22, 26))	('cancer', 'Disease', (80, 86))
880868	28099114	Two recent publications have highlighted the role that mtDNA mutations have in the development of one substype of chromophobes, eosinophilic chromophobe renal cell carcinomas.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (153, 174))	('eosinophilic chromophobe renal cell carcinomas', 'Disease', (128, 174))	('mtDNA', 'Gene', (55, 60))	('mutations', 'Var', (61, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (153, 173))	('eosinophilic chromophobe renal cell carcinomas', 'Disease', 'MESH:C538614', (128, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
880870	28099114	This phenotype arises from two critical dysfunctions: somatic mtDNA mutations that render mitochondrial OXPHOS non-functional, and defective mitophagy that prevents clearance of dysfunctional mitochondria.	('mtDNA', 'Gene', (62, 67))	('mitophagy', 'CPA', (141, 150))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (178, 204))	('mitochondrial OXPHOS non-functional', 'MPA', (90, 125))	('mutations', 'Var', (68, 77))	('dysfunctional mitochondria', 'Disease', (178, 204))	('prevents', 'NegReg', (156, 164))
880877	28099114	Among these, papillary renal cell carcinoma (KIRP), esophageal carcinoma (ESCA), and thyroid cancer (THCA) showed an association between high mtRNA expression and increased age.	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (13, 43))	('mtRNA', 'Protein', (142, 147))	('esophageal carcinoma', 'Disease', (52, 72))	('high', 'Var', (137, 141))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (13, 43))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (52, 72))	('papillary renal cell carcinoma', 'Disease', (13, 43))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (23, 43))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (52, 72))	('thyroid cancer', 'Disease', (85, 99))	('thyroid cancer', 'Phenotype', 'HP:0002890', (85, 99))	('expression', 'MPA', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('thyroid cancer', 'Disease', 'MESH:D013964', (85, 99))
880886	28099114	Of the seven cancer types with mtDNA depletion in tumors relative to normal tissue, five (all but esophageal and head and neck) showed positive correlation between mtDNA copy number and expression.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mtDNA', 'Gene', (31, 36))	('positive correlation', 'Reg', (135, 155))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('expression', 'MPA', (186, 196))	('mtDNA', 'Gene', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('copy number', 'Var', (170, 181))
880891	28099114	Upon closer examination of samples from KICH (Figure 4:figure supplement 3), we found that tumor and normal samples had strong but distinct patterns of correlation between mtDNA copy number and mtRNA levels.	('mtRNA levels', 'MPA', (194, 206))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('copy number', 'Var', (178, 189))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('correlation', 'Interaction', (152, 163))	('tumor', 'Disease', (91, 96))	('mtDNA', 'Gene', (172, 177))
880894	28099114	Given that many KICH tumors harbor mtDNA mutations, these observations suggest that compensation for such mitochondrial dysfunction in KICH may be via transcriptional mechanisms, rather than changes to mtDNA ploidy.	('mutations', 'Var', (41, 50))	('mitochondrial dysfunction', 'Disease', (106, 131))	('mtDNA', 'Gene', (35, 40))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (106, 131))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (106, 131))	('KICH tumors', 'Disease', (16, 27))	('KICH tumors', 'Disease', 'MESH:D009369', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
880908	28099114	While changes in mtDNA copy number and mtRNA expression cannot be used as surrogates for changes in respiratory flux, several of the cancer types examined here are driven by genetic changes affecting mitochondrial respiration, suggesting that changes in mtRNA levels may reflect bona fide changes in respiration.	('driven by', 'Reg', (164, 173))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('changes', 'Var', (182, 189))	('mitochondrial respiration', 'MPA', (200, 225))	('affecting', 'Reg', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
880909	28099114	For example, clear-cell renal cell carcinomas are driven by homozygous loss of VHL, which leads to activation of hypoxia inducible factor (HIF), and subsequently increased transcription of glycolytic enzymes.	('VHL', 'Gene', '7428', (79, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (24, 44))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('increased', 'PosReg', (162, 171))	('transcription', 'MPA', (172, 185))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('hypoxia', 'Disease', (113, 120))	('activation', 'PosReg', (99, 109))	('clear-cell renal cell carcinomas', 'Disease', 'MESH:C538614', (13, 45))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (24, 45))	('clear-cell renal cell carcinomas', 'Disease', (13, 45))	('loss', 'Var', (71, 75))	('VHL', 'Gene', (79, 82))	('glycolytic enzymes', 'Enzyme', (189, 207))
880925	28099114	Prior studies of mitochondrial-nuclear (mitonuclear) protein imbalance in C. elegans claimed that it promotes longevity via activation of the mitochondrial unfolded protein response (UPRMT), a transcriptional response preserving mitochondrial function in the face of stress.	('activation', 'PosReg', (124, 134))	('mitochondrial unfolded protein response', 'MPA', (142, 181))	('imbalance', 'Var', (61, 70))	('longevity', 'CPA', (110, 119))	('imbalance', 'Phenotype', 'HP:0002172', (61, 70))	('promotes', 'PosReg', (101, 109))	('C. elegans', 'Species', '6239', (74, 84))
880926	28099114	If cancer cells indeed have substantial changes in mtDNA copy number and transcription (and mtDNA mutations), then activation of the mammalian UPR may be critical in supporting their proliferation in the face of increased mitochondrial stress.	('mtDNA', 'Gene', (51, 56))	('changes', 'Reg', (40, 47))	('transcription', 'MPA', (73, 86))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (98, 107))	('mammalian', 'Species', '9606', (133, 142))	('cancer', 'Disease', (3, 9))	('mtDNA', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
880952	28099114	Several recent studies based on the TCGA specimens have revealed that mitochondria DNAs are altered in cancers, including mtDNA mutations as well as copy number changes.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('copy number changes', 'Var', (149, 168))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (128, 137))	('mtDNA', 'Disease', (122, 127))	('mitochondria DNAs', 'MPA', (70, 87))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('altered', 'Reg', (92, 99))	('cancers', 'Disease', (103, 110))
880977	28099114	We are unable to perform in vivo or in vitro experiments to measure how suppression of mtRNAs affects respiratory flux and proliferation/malignancy.	('malignancy', 'Disease', (137, 147))	('mtRNAs', 'Gene', (87, 93))	('suppression', 'Var', (72, 83))	('affects', 'Reg', (94, 101))	('respiratory flux', 'MPA', (102, 118))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
880980	28099114	In both of these cancer types, we propose that changes in mtRNA are an adaptive response to "driver" genetic mutations and upstream changes in cell signaling.	('mtRNA', 'Gene', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('changes', 'Var', (47, 54))	('cancer', 'Disease', (17, 23))	('mutations', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
880981	28099114	For example, VHL inactivation in KIRC leads to activation of HIF which upregulates glycolytic genes and suppresses OXPHOS gene expression.	('suppresses', 'NegReg', (104, 114))	('inactivation', 'Var', (17, 29))	('glycolytic genes', 'MPA', (83, 99))	('upregulates', 'PosReg', (71, 82))	('activation', 'PosReg', (47, 57))	('VHL', 'Gene', (13, 16))	('OXPHOS gene expression', 'MPA', (115, 137))	('VHL', 'Gene', '7428', (13, 16))
881086	20865331	However, our observation is not novel because a survival advantage in patients with high BMI has been repeatedly described for renal cancer and sporadically reported for esophagogastric cancers.	('renal cancer', 'Disease', (127, 139))	('patients', 'Species', '9606', (70, 78))	('high', 'Var', (84, 88))	('renal cancer', 'Phenotype', 'HP:0009726', (127, 139))	('advantage', 'PosReg', (57, 66))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('renal cancer', 'Disease', 'MESH:D007680', (127, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (178, 192))	('esophagogastric cancers', 'Disease', (170, 193))	('BMI', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('esophagogastric cancers', 'Disease', 'MESH:C537006', (170, 193))
881087	20865331	found that in their series of 7925 patients operated on for gastric cancer, BMI >= 25 was associated with improved OS (81.5 vs. 71.3%, P = 0.001) and disease- specific survival (84.0 vs. 76.7%, P = 0.001).	('improved', 'PosReg', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('gastric cancer', 'Disease', (60, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('patients', 'Species', '9606', (35, 43))	('BMI >= 25', 'Var', (76, 85))	('disease- specific survival', 'CPA', (150, 176))
881093	20865331	In conclusion, our data confirm that carefully selected patients with high BMI can safely undergo esophageal resection without compromising rates of R0 resections and number of collected lymph nodes.	('esophageal resection', 'Disease', (98, 118))	('patients', 'Species', '9606', (56, 64))	('high BMI', 'Var', (70, 78))
881155	25097689	Nonetheless, according to some studies, the acid suppressing effect of PPI may on the contrary enhance the development of intestinal metaplasia and cellular proliferation in duodenogastroesophageal reflux leading to malignization of Barrett's mucosa.	('Barrett', 'Disease', (233, 240))	('PPI', 'Var', (71, 74))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (181, 204))	('gastroesophageal reflux', 'Disease', (181, 204))	('intestinal metaplasia', 'Disease', (122, 143))	('cellular proliferation', 'CPA', (148, 170))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (122, 143))	('acid suppressing', 'MPA', (44, 60))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (181, 204))	('esophageal reflux', 'Phenotype', 'HP:0002020', (187, 204))	('development', 'CPA', (107, 118))	('enhance', 'PosReg', (95, 102))	('malignization', 'MPA', (216, 229))
881221	23319416	However, when we limited our analyses to those who had started opium use at least one year prior to diagnosis, opium still showed a strong increased risk, with adjusted ORs (95% CIs) of 2.9 (1.1-7.5), 2.8 (1.4-5.6), and 2.9 (1.7-4.8) for noncardia, cardia, and all gastric adenocarcinomas, respectively.	('noncardia, cardia', 'Disease', 'MESH:D004938', (238, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('opium', 'Var', (111, 116))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (265, 288))	('gastric adenocarcinomas', 'Disease', (265, 288))
881235	23319416	In vitro studies have shown that pyrolysed opium dross shows mutagenic activity in Salmonella typhimurium strains TA98 and TA100 .	('pyrolysed', 'Var', (33, 42))	('Salmonella typhimurium', 'Species', '90371', (83, 105))	('mutagenic activity', 'MPA', (61, 79))
881290	23234272	Subjects with esophageal cancer and any other cancer (ICD-9 140-208 and A-code A08x-A14x) identified by the index year were excluded.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('esophageal cancer', 'Disease', (14, 31))	('cancer', 'Disease', (46, 52))	('A08x-A14x', 'Var', (79, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('ICD', 'Disease', 'OMIM:252500', (54, 57))	('ICD', 'Disease', (54, 57))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (25, 31))
881293	23234272	They were alcoholism (ICD-9 codes 303, 305.00, 305.01, 305.02, 305.03, and V11.3 and A-code A215), tobacco use disorders (ICD-9 codes 305.1X), periodontal disease (523.8 and 523.9X), HPV infection (079.4), hyperlipidemia (272.0, 272.1, 272.2, 272.3 and 272.4), Barrett's esophagus (530.85), esophageal ulcer (530.2), esophageal reflux (530.81, 530.11) and esophageal burn (947.2).	('hyperlipidemia', 'Phenotype', 'HP:0003077', (206, 220))	('periodontal disease', 'Disease', (143, 162))	('esophageal reflux', 'Disease', (317, 334))	('ICD', 'Disease', (22, 25))	('esophageal reflux', 'Disease', 'MESH:D005764', (317, 334))	('esophageal burn', 'Disease', (356, 371))	('tobacco', 'Species', '4097', (99, 106))	('ICD', 'Disease', 'OMIM:252500', (22, 25))	('HPV infection', 'Disease', 'MESH:D030361', (183, 196))	('periodontal disease', 'Phenotype', 'HP:0000704', (143, 162))	('alcoholism', 'Phenotype', 'HP:0030955', (10, 20))	('tobacco use disorders', 'Disease', (99, 120))	('HPV infection', 'Disease', (183, 196))	('esophageal ulcer', 'Disease', (291, 307))	('alcoholism', 'Disease', (10, 20))	('periodontal disease', 'Disease', 'MESH:D010510', (143, 162))	('hyperlipidemia', 'Disease', (206, 220))	("Barrett's esophagus", 'Disease', (261, 280))	('alcoholism', 'Disease', 'MESH:D000437', (10, 20))	('esophageal ulcer', 'Disease', 'MESH:D014456', (291, 307))	('ICD', 'Disease', (122, 125))	('hyperlipidemia', 'Disease', 'MESH:D006949', (206, 220))	('esophageal reflux', 'Phenotype', 'HP:0002020', (317, 334))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (261, 280))	('530.81', 'Var', (336, 342))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (261, 280))	('ICD', 'Disease', 'OMIM:252500', (122, 125))	('esophageal ulcer', 'Phenotype', 'HP:0004791', (291, 307))
881329	23234272	have also reported that long term pharmacological gastric acid suppression is associated with the risk of oesophageal and gastric adenocarcinoma.	('gastric adenocarcinoma', 'Disease', (122, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('pharmacological', 'Var', (34, 49))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (122, 144))	('gastric acid suppression', 'Phenotype', 'HP:0002578', (50, 74))	('oesophageal', 'Disease', (106, 117))
881395	21734885	In this setting, they did not find a significant correlation between a positive CTC count and lung or liver metastases but the presence of >=2 CTCs per 7.5 ml of blood had a significant correlation with serosal dissemination (pleural or peritoneal).	('pleural', 'Disease', 'MESH:D010995', (226, 233))	('correlation with', 'Reg', (186, 202))	('serosal dissemination', 'Disease', (203, 224))	('serosal dissemination', 'Disease', 'MESH:D012700', (203, 224))	('liver metastases', 'Disease', 'MESH:D009362', (102, 118))	('pleural', 'Disease', (226, 233))	('presence', 'Var', (127, 135))	('liver metastases', 'Disease', (102, 118))
881400	32885893	Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large-Scale Data to Inform Therapeutic Directions We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('solid tumors', 'Disease', 'MESH:D009369', (213, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('solid tumors', 'Disease', (213, 225))	('Cyclin', 'Gene', '5111', (0, 6))	('cyclin', 'Gene', '5111', (154, 160))	('cyclin', 'Gene', (154, 160))	('alterations', 'Var', (190, 201))	('Tumors', 'Disease', (56, 62))	('Tumors', 'Disease', 'MESH:D009369', (56, 62))	('Tumors', 'Phenotype', 'HP:0002664', (56, 62))	('interactive gene pathway', 'Pathway', (165, 189))	('Cyclin', 'Gene', (0, 6))
881402	32885893	Alterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies.	('malignancies', 'Disease', (82, 94))	('Alterations', 'Var', (0, 11))	('cyclin', 'Gene', '5111', (28, 34))	('cyclin', 'Gene', (28, 34))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))	('occurred', 'Reg', (63, 71))
881405	32885893	Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors).	('sarcomas', 'Disease', 'MESH:D012509', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('kidney cancer', 'Phenotype', 'HP:0009726', (195, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('kidney cancer', 'Disease', (195, 208))	('cancer', 'Disease', (82, 88))	('sarcomas', 'Disease', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (229, 254))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('CDK4', 'Gene', (98, 102))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('amplification', 'Var', (58, 71))	('mutations', 'Var', (182, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('CCND2', 'Gene', (134, 139))	('testicular cancer', 'Phenotype', 'HP:0010788', (143, 160))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('SMARCB1', 'Gene', '6598', (174, 181))	('malignant rhabdoid tumors', 'Disease', (229, 254))	('CDK4', 'Gene', '1019', (98, 102))	('SMARCB1', 'Gene', (174, 181))	('CCND2', 'Gene', '894', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('kidney cancer', 'Disease', 'MESH:D007680', (195, 208))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('breast cancer', 'Disease', (75, 88))	('alterations', 'Var', (103, 114))	('CCND1', 'Gene', '595', (52, 57))	('cancer', 'Disease', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Disease', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('CCND1', 'Gene', (52, 57))
881406	32885893	Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples.	('CCNE1', 'Gene', '898', (40, 45))	('CCNE1', 'Gene', (40, 45))	('Alterations', 'Var', (0, 11))	('RB1', 'Gene', (32, 35))	('RB1', 'Gene', '5925', (32, 35))
881408	32885893	AR and cyclin activating/sensitizing alterations in prostate cancer co-occurred more frequently (vs. AR alterations and wild-type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild-type activating/sensitizing alterations).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('AR', 'Gene', '367', (101, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('cyclin', 'Gene', '5111', (7, 13))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('alterations', 'Var', (37, 48))	('prostate cancer', 'Disease', (52, 67))	('ESR1', 'Gene', '2099', (201, 205))	('ESR1', 'Gene', (201, 205))	('ESR1', 'Gene', '2099', (328, 332))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cyclin', 'Gene', (7, 13))	('cyclin', 'Gene', '5111', (337, 343))	('cyclin', 'Gene', '5111', (130, 136))	('ESR1', 'Gene', (328, 332))	('cancer', 'Disease', (61, 67))	('cyclin', 'Gene', '5111', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cyclin', 'Gene', (337, 343))	('AR', 'Gene', '367', (0, 2))	('breast', 'Disease', (255, 261))	('cyclin', 'Gene', (130, 136))	('cancer', 'Disease', (296, 302))	('cyclin', 'Gene', (210, 216))
881410	32885893	Cyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology.	('genomic abnormalities', 'Var', (15, 36))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (65, 70))	('Cyclin', 'Gene', '5111', (0, 6))	('solid tumors', 'Disease', (59, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('human', 'Species', '9606', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('solid tumors', 'Disease', 'MESH:D009369', (59, 71))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Cyclin', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
881411	32885893	This article identifies molecular alterations in genes involved in the cyclin activation/sensitizing pathways and reports coexisting resistance and hormone pathway alterations in 190,247 diverse solid tumors that underwent next-generation sequencing.	('cyclin', 'Gene', (71, 77))	('solid tumors', 'Disease', (195, 207))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('solid tumors', 'Disease', 'MESH:D009369', (195, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('alterations', 'Var', (34, 45))	('cyclin', 'Gene', '5111', (71, 77))
881417	32885893	Alterations in cyclins and their CDKs, as well as inactivating mutations in RB1, could lead to increased E2F activity and higher S-phase fraction in tumor cells [4].	('E2F activity', 'MPA', (105, 117))	('cyclin', 'Gene', '5111', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('RB1', 'Gene', (76, 79))	('S-phase fraction', 'MPA', (129, 145))	('Alterations', 'Var', (0, 11))	('higher', 'PosReg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cyclin', 'Gene', (15, 21))	('tumor', 'Disease', (149, 154))	('RB1', 'Gene', '5925', (76, 79))	('inactivating mutations', 'Var', (50, 72))	('CDKs', 'Gene', '983;1017;1019;1021', (33, 37))	('increased', 'PosReg', (95, 104))	('CDKs', 'Gene', (33, 37))
881418	32885893	Various factors are responsible for upregulation of this axis, including CCND gene amplification [5], cyclin D overexpression [6], CDK4/6 mutation/amplification [7], and loss of negative regulators of the complex, such as CDKN2A and CDKN2B [8].	('CDK4/6', 'Gene', (131, 137))	('CDKN2A', 'Gene', (222, 228))	('amplification', 'Var', (83, 96))	('upregulation', 'PosReg', (36, 48))	('loss', 'NegReg', (170, 174))	('CDKN2B', 'Gene', '1030', (233, 239))	('cyclin', 'Gene', '5111', (102, 108))	('CDKN2A', 'Gene', '1029', (222, 228))	('CDKN2B', 'Gene', (233, 239))	('CDK4/6', 'Gene', '1019;1021', (131, 137))	('mutation/amplification', 'Var', (138, 160))	('cyclin', 'Gene', (102, 108))	('overexpression', 'PosReg', (111, 125))	('CCND gene', 'Gene', (73, 82))
881421	32885893	Indeed, inhibitors of CDK4/6 were clinically tested in patients with HR+ breast cancer and led to consistent benefit when administered with aromatase inhibitors [10, 11, 12].	('HR+ breast cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CDK4/6', 'Gene', (22, 28))	('HR+ breast cancer', 'Disease', 'MESH:D001943', (69, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('patients', 'Species', '9606', (55, 63))	('CDK4/6', 'Gene', '1019;1021', (22, 28))	('benefit', 'PosReg', (109, 116))	('inhibitors', 'Var', (8, 18))
881426	32885893	As previously demonstrated, many solid tumors harbor genetic alterations in cyclin pathway genes, including CCN amplifications and CDKN2A and CDK4/6 aberrations [5, 17, 18, 19].	('CDK4/6', 'Gene', (142, 148))	('cyclin', 'Gene', (76, 82))	('CCN', 'Gene', (108, 111))	('CDKN2A', 'Gene', '1029', (131, 137))	('solid tumors', 'Disease', 'MESH:D009369', (33, 45))	('genetic alterations', 'Var', (53, 72))	('aberrations', 'Var', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('CDK4/6', 'Gene', '1019;1021', (142, 148))	('cyclin', 'Gene', '5111', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('CDKN2A', 'Gene', (131, 137))	('solid tumors', 'Disease', (33, 45))
881435	32885893	Genomic alterations of interest were classified either as activators of the cyclin pathway (eight genes, including CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], and SMARCB1) or as related to potential resistance pathways related to CDK4/6 inhibition (RB1 and CCNE1).	('CDKN2B', 'Gene', '1030', (176, 182))	('CCND2', 'Gene', '894', (162, 167))	('CDK4/6', 'Gene', (277, 283))	('CDK4', 'Gene', '1019', (277, 281))	('amplification', 'Var', (140, 153))	('SMARCB1', 'Gene', '6598', (210, 217))	('SMARCB1', 'Gene', (210, 217))	('CDK6', 'Gene', '1021', (135, 139))	('CDK4', 'Gene', (115, 119))	('CCND3', 'Gene', (169, 174))	('cyclin', 'Gene', '5111', (76, 82))	('CDK6', 'Gene', (135, 139))	('CDK4/6', 'Gene', '1019;1021', (277, 283))	('CDKN2A', 'Gene', (191, 197))	('CCNE1', 'Gene', (304, 309))	('RB1', 'Gene', (296, 299))	('CDK4', 'Gene', '1019', (115, 119))	('alterations', 'Var', (8, 19))	('amplification', 'Var', (120, 133))	('CDKN2B', 'Gene', (176, 182))	('CCND3', 'Gene', '896', (169, 174))	('CCNE1', 'Gene', '898', (304, 309))	('cyclin', 'Gene', (76, 82))	('CDKN2A', 'Gene', '1029', (191, 197))	('RB1', 'Gene', '5925', (296, 299))	('CDK4', 'Gene', (277, 281))	('CCND1', 'Gene', '595', (155, 160))	('activators', 'PosReg', (58, 68))	('CCND1', 'Gene', (155, 160))	('CCND2', 'Gene', (162, 167))
881438	32885893	Co-occurrence analysis was performing matching cyclin pathway genomic alterations with three different subsets of genomic alterations (resistance pathway, cyclin-related, and ESR1/AR).	('alterations', 'Var', (70, 81))	('ESR1', 'Gene', (175, 179))	('resistance pathway', 'Pathway', (135, 153))	('cyclin', 'Gene', '5111', (47, 53))	('cyclin', 'Gene', (47, 53))	('ESR1', 'Gene', '2099', (175, 179))	('cyclin', 'Gene', '5111', (155, 161))	('cyclin', 'Gene', (155, 161))	('AR', 'Gene', '367', (180, 182))
881439	32885893	Alterations in any cyclin pathway activating/sensitizing genes (supplemental online Table 1) were found in 24% of the 190,247 tumors analyzed (Fig.	('cyclin', 'Gene', '5111', (19, 25))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('Alterations', 'Var', (0, 11))	('cyclin', 'Gene', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
881442	32885893	Overall, 89% of cases presented a single genomic alteration in one of the eight activating/sensitizing genes selected as part of the cyclin pathway (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1).	('CDK6', 'Gene', '1021', (169, 173))	('CDKN2B', 'Gene', '1030', (210, 216))	('CCND2', 'Gene', '894', (196, 201))	('CDK4', 'Gene', (149, 153))	('CDK6', 'Gene', (169, 173))	('cyclin', 'Gene', '5111', (133, 139))	('CDKN2A', 'Gene', (225, 231))	('CDK4', 'Gene', '1019', (149, 153))	('amplification', 'Var', (154, 167))	('CCND3', 'Gene', '896', (203, 208))	('SMARCB1', 'Gene', (240, 247))	('SMARCB1', 'Gene', '6598', (240, 247))	('CCND1', 'Gene', '595', (189, 194))	('CDKN2A', 'Gene', '1029', (225, 231))	('cyclin', 'Gene', (133, 139))	('CCND1', 'Gene', (189, 194))	('CDKN2B', 'Gene', (210, 216))	('amplification', 'Var', (174, 187))	('CCND2', 'Gene', (196, 201))	('CCND3', 'Gene', (203, 208))
881443	32885893	Alterations in two cyclin pathway activating/sensitizing genes occurred in 20% cases, and 1% of cases had more than two co-occurring alterations.	('cyclin', 'Gene', '5111', (19, 25))	('Alterations', 'Var', (0, 11))	('cyclin', 'Gene', (19, 25))
881445	32885893	Different types of alterations were identified in the eight cyclin pathway activating/sensitizing genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1) (supplemental online Table 2).	('amplification', 'Var', (110, 123))	('CCND1', 'Gene', '595', (145, 150))	('CCND2', 'Gene', (152, 157))	('CDKN2A', 'Gene', '1029', (181, 187))	('CCND1', 'Gene', (145, 150))	('CDKN2B', 'Gene', (166, 172))	('CDK4', 'Gene', (105, 109))	('CCND2', 'Gene', '894', (152, 157))	('alterations', 'Var', (19, 30))	('CDK6', 'Gene', '1021', (125, 129))	('CCND3', 'Gene', (159, 164))	('cyclin', 'Gene', '5111', (60, 66))	('SMARCB1', 'Gene', (196, 203))	('CDK4', 'Gene', '1019', (105, 109))	('CDKN2B', 'Gene', '1030', (166, 172))	('CDK6', 'Gene', (125, 129))	('cyclin', 'Gene', (60, 66))	('SMARCB1', 'Gene', '6598', (196, 203))	('CDKN2A', 'Gene', (181, 187))	('CCND3', 'Gene', '896', (159, 164))
881446	32885893	Copy number changes were the sole type of alteration detected in CDK4, CDK6, and CCND1 genes (all amplifications).	('CDK6', 'Gene', (71, 75))	('CDK6', 'Gene', '1021', (71, 75))	('Copy number changes', 'Var', (0, 19))	('CCND1', 'Gene', (81, 86))	('CDK4', 'Gene', (65, 69))	('CCND1', 'Gene', '595', (81, 86))	('CDK4', 'Gene', '1019', (65, 69))
881447	32885893	CDKN2A was uniformly affected by gene loss, whereas 1% of CDKN2B alterations were rearrangements.	('alterations', 'Var', (65, 76))	('rearrangements', 'Var', (82, 96))	('gene', 'Var', (33, 37))	('CDKN2A', 'Gene', (0, 6))	('CDKN2B', 'Gene', (58, 64))	('loss', 'NegReg', (38, 42))	('CDKN2B', 'Gene', '1030', (58, 64))	('CDKN2A', 'Gene', '1029', (0, 6))
881448	32885893	In fact, seven of the eight cyclin genes presented mostly (or exclusively) with copy number changes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss]).	('CDKN2A', 'Gene', (177, 183))	('CDK4', 'Gene', '1019', (101, 105))	('CCND3', 'Gene', (155, 160))	('CDK4', 'Gene', (101, 105))	('CCND2', 'Gene', '894', (148, 153))	('CDKN2A', 'Gene', '1029', (177, 183))	('CDKN2B', 'Gene', (162, 168))	('CDKN2B', 'Gene', '1030', (162, 168))	('CCND1', 'Gene', '595', (141, 146))	('cyclin', 'Gene', '5111', (28, 34))	('amplification', 'Var', (126, 139))	('CDK6', 'Gene', (121, 125))	('CCND3', 'Gene', '896', (155, 160))	('CDK6', 'Gene', '1021', (121, 125))	('cyclin', 'Gene', (28, 34))	('CCND1', 'Gene', (141, 146))	('CCND2', 'Gene', (148, 153))
881449	32885893	A single nucleotide change was the predominant SMARCB1 alteration (73% of cases of altered SMARCB1).	('SMARCB1', 'Gene', '6598', (91, 98))	('SMARCB1', 'Gene', (91, 98))	('SMARCB1', 'Gene', '6598', (47, 54))	('SMARCB1', 'Gene', (47, 54))	('single nucleotide change', 'Var', (2, 26))
881451	32885893	Of the other genes included in this analysis, RB1 (67% of cases altered RB1), ESR1 (79%), CDKN1A (95%), and CDKN1B (82%) presented more frequently with single nucleotide changes.	('single nucleotide changes', 'Var', (152, 177))	('RB1', 'Gene', (72, 75))	('CDKN1B', 'Gene', '1027', (108, 114))	('RB1', 'Gene', (46, 49))	('ESR1', 'Gene', '2099', (78, 82))	('CDKN1B', 'Gene', (108, 114))	('RB1', 'Gene', '5925', (72, 75))	('RB1', 'Gene', '5925', (46, 49))	('CDKN1A', 'Gene', '1026', (90, 96))	('CDKN1A', 'Gene', (90, 96))	('altered', 'Reg', (64, 71))	('ESR1', 'Gene', (78, 82))
881452	32885893	CDKN2C and AR presented more frequently with copy number changes (54% and 59% of cases with alterations, respectively).	('CDKN2C', 'Gene', '1031', (0, 6))	('copy number changes', 'Var', (45, 64))	('AR', 'Gene', '367', (11, 13))	('CDKN2C', 'Gene', (0, 6))
881455	32885893	Gliomas (54% of tumors had cyclin activating/sensitizing pathway alterations) and urothelial carcinoma (41%) were the histologies that most frequently harbored alterations; adenoid cystic (7%) and small cell carcinoma (6%) were the least commonly altered.	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Gliomas', 'Disease', (0, 7))	('tumors', 'Disease', (16, 22))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (197, 217))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('small cell carcinoma', 'Disease', (197, 217))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('alterations', 'Var', (160, 171))	('cyclin', 'Gene', '5111', (27, 33))	('small cell carcinoma', 'Disease', 'MESH:D018288', (197, 217))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (82, 102))	('alterations', 'Reg', (65, 76))	('adenoid cystic', 'Disease', (173, 187))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('urothelial carcinoma', 'Disease', (82, 102))	('cyclin', 'Gene', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
881457	32885893	CDKN2A and CDKN2B deletions were the most frequent cyclin activating/sensitizing alterations across histologies, with similar frequencies between both genes in each histology (Fig.	('cyclin', 'Gene', (51, 57))	('deletions', 'Var', (18, 27))	('CDKN2B', 'Gene', '1030', (11, 17))	('CDKN2A', 'Gene', (0, 6))	('cyclin', 'Gene', '5111', (51, 57))	('CDKN2B', 'Gene', (11, 17))	('CDKN2A', 'Gene', '1029', (0, 6))
881459	32885893	Alteration frequencies of note by histology include a high frequency of CCND1 amplification in urothelial carcinoma (12.3%) and squamous cell carcinoma (13%), a high frequency of CDK4 alterations in sarcomas (10.4%), and a relatively high proportion of CCND2 alterations in germ cell tumors (16.3%, compared with 1.5% in the overall population).	('sarcomas', 'Phenotype', 'HP:0100242', (199, 207))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('urothelial carcinoma', 'Disease', (95, 115))	('amplification', 'Reg', (78, 91))	('sarcomas', 'Disease', (199, 207))	('CDK4', 'Gene', (179, 183))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('CCND1', 'Gene', '595', (72, 77))	('alterations', 'Reg', (259, 270))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('CDK4', 'Gene', '1019', (179, 183))	('CCND1', 'Gene', (72, 77))	('tumors', 'Disease', (284, 290))	('CCND2', 'Gene', (253, 258))	('squamous cell carcinoma', 'Disease', (128, 151))	('alterations', 'Var', (184, 195))	('CCND2', 'Gene', '894', (253, 258))	('germ cell tumors', 'Phenotype', 'HP:0100728', (274, 290))	('tumors', 'Disease', 'MESH:D009369', (284, 290))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (95, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('sarcomas', 'Disease', 'MESH:D012509', (199, 207))
881462	32885893	Cyclin gene alterations were less frequently detected in cervical (5.2%), colorectal (7.8%), uterine (8.3%), and prostate (9.7%) cancers.	('cervical', 'Disease', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('prostate', 'Disease', (113, 121))	('alterations', 'Var', (12, 23))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('Cyclin', 'Gene', '5111', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('colorectal', 'Disease', (74, 84))	('cancers', 'Disease', (129, 136))	('Cyclin', 'Gene', (0, 6))	('uterine', 'Disease', (93, 100))
881464	32885893	Breast cancer was the leading tumor for CCND1 amplification (17.3% of cases vs. 4.8% overall for all tumors), soft tissue sarcomas for CDK4 alterations (12% vs. 3% overall), esophageal cancer for CDK6 alterations (8.6% vs. 1.5% overall), testicular cancers typically presented CCND2 alterations (23.4% vs. 1.5% overall), bone tumors a high frequency of CCND3 alterations (6.2% vs. 1.4% overall), and, finally, kidney cancers a relevant frequency of SMARCB1 alterations (3% vs. 0.7% overall).	('kidney cancers', 'Disease', (410, 424))	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('SMARCB1', 'Gene', '6598', (449, 456))	('CDK4', 'Gene', '1019', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('testicular cancers', 'Disease', 'MESH:D013736', (238, 256))	('cancer', 'Disease', (249, 255))	('SMARCB1', 'Gene', (449, 456))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('testicular cancers', 'Phenotype', 'HP:0010788', (238, 256))	('CCND3', 'Gene', (353, 358))	('bone tumors', 'Disease', (321, 332))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Disease', (185, 191))	('kidney cancers', 'Phenotype', 'HP:0009726', (410, 424))	('cancer', 'Disease', 'MESH:D009369', (417, 423))	('testicular cancers', 'Disease', (238, 256))	('bone tumors', 'Phenotype', 'HP:0010622', (321, 332))	('tumors', 'Disease', (326, 332))	('alterations', 'Var', (201, 212))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('CDK6', 'Gene', '1021', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Disease', (7, 13))	('tumor', 'Disease', (326, 331))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('bone tumors', 'Disease', 'MESH:D001859', (321, 332))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('CCND1', 'Gene', '595', (40, 45))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (110, 129))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (110, 130))	('kidney cancers', 'Disease', 'MESH:D007680', (410, 424))	('CCND2', 'Gene', (277, 282))	('CDK6', 'Gene', (196, 200))	('tumors', 'Disease', 'MESH:D009369', (326, 332))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('alterations', 'Var', (359, 370))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('CCND1', 'Gene', (40, 45))	('CCND3', 'Gene', '896', (353, 358))	('CCND2', 'Gene', '894', (277, 282))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('sarcomas', 'Disease', 'MESH:D012509', (122, 130))	('sarcomas', 'Phenotype', 'HP:0100242', (122, 130))	('tumors', 'Disease', (101, 107))	('cancers', 'Phenotype', 'HP:0002664', (417, 424))	('cancer', 'Disease', (417, 423))	('CDK4', 'Gene', (135, 139))	('testicular cancer', 'Phenotype', 'HP:0010788', (238, 255))	('sarcomas', 'Disease', (122, 130))	('alterations', 'Var', (283, 294))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('cancer', 'Phenotype', 'HP:0002664', (417, 423))	('kidney cancer', 'Phenotype', 'HP:0009726', (410, 423))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))	('alterations', 'Var', (140, 151))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('Breast cancer', 'Disease', (0, 13))	('tumor', 'Disease', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
881466	32885893	Bladder (41%) and esophageal (45.5%) squamous cell carcinomas and malignant peripheral nerve sheath tumors (46.4%) harbored CDKN2A alterations.	('CDKN2A', 'Gene', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (66, 106))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (37, 61))	('CDKN2A', 'Gene', '1029', (124, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('malignant peripheral nerve sheath tumors', 'Disease', (66, 106))	('alterations', 'Var', (131, 142))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (66, 106))	('harbored', 'Reg', (115, 123))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (37, 61))	('squamous cell carcinomas', 'Disease', (37, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
881467	32885893	Breast neuroendocrine carcinoma presented a high frequency of CCND1 amplification (26.3%).	('Breast neuroendocrine carcinoma', 'Disease', (0, 31))	('CCND1', 'Gene', '595', (62, 67))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (7, 31))	('Breast neuroendocrine carcinoma', 'Disease', 'MESH:D001943', (0, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('amplification', 'Var', (68, 81))	('CCND1', 'Gene', (62, 67))
881468	32885893	Overall, 38.1% of heart sarcomas had CDK4 alterations, and 14.1% had CCND3 alterations.	('heart sarcomas', 'Disease', (18, 32))	('alterations', 'Var', (42, 53))	('heart sarcomas', 'Disease', 'MESH:D012509', (18, 32))	('CDK4', 'Gene', (37, 41))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('CDK4', 'Gene', '1019', (37, 41))	('CCND3', 'Gene', '896', (69, 74))	('heart sarcomas', 'Phenotype', 'HP:0031350', (18, 32))	('CCND3', 'Gene', (69, 74))
881469	32885893	Finally, although SMARCB1 alterations are rare in the overall population (0.7%), some rare tumors presented high frequencies of alterations in this gene, including brain rhabdoid tumor (88.4%), kidney rhabdoid tumor (90%), kidney medullary carcinoma (41.3%), epithelioid sarcoma (56%), and extrarenal rhabdoid tumor (63.6%).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (301, 315))	('carcinoma', 'Disease', (240, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (271, 278))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('brain rhabdoid tumor', 'Disease', 'MESH:D018335', (164, 184))	('kidney rhabdoid tumor', 'Disease', 'MESH:D018335', (194, 215))	('rhabdoid tumor', 'Disease', (301, 315))	('kidney rhabdoid tumor', 'Disease', (194, 215))	('carcinoma', 'Disease', 'MESH:D009369', (240, 249))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (170, 184))	('brain rhabdoid tumor', 'Disease', (164, 184))	('SMARCB1', 'Gene', '6598', (18, 25))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('SMARCB1', 'Gene', (18, 25))	('alterations', 'Var', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('sarcoma', 'Disease', 'MESH:D012509', (271, 278))	('tumors', 'Disease', (91, 97))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (201, 215))	('sarcoma', 'Disease', (271, 278))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))
881470	32885893	We analyzed genomic alterations in RB1 and CCNE1 because they may promote resistance to cyclin inhibitors.	('cyclin', 'Gene', '5111', (88, 94))	('alterations', 'Var', (20, 31))	('CCNE1', 'Gene', '898', (43, 48))	('CCNE1', 'Gene', (43, 48))	('RB1', 'Gene', (35, 38))	('cyclin', 'Gene', (88, 94))	('RB1', 'Gene', '5925', (35, 38))	('promote', 'PosReg', (66, 73))
881471	32885893	Overall, RB1 alterations were detected in 7.2% of samples; CCNE1, in 3.6% (supplemental online Figs.	('CCNE1', 'Gene', '898', (59, 64))	('CCNE1', 'Gene', (59, 64))	('RB1', 'Gene', (9, 12))	('alterations', 'Var', (13, 24))	('RB1', 'Gene', '5925', (9, 12))
881472	32885893	Tumors presenting a high frequency of RB1 alterations included bladder cancer (20.9%), nonmelanoma skin cancer (17.9%), soft tissue sarcomas (14.6%), and bone tumors (11.8%).	('nonmelanoma skin cancer', 'Disease', 'MESH:D012878', (87, 110))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('skin cancer', 'Phenotype', 'HP:0008069', (99, 110))	('bone tumors', 'Disease', (154, 165))	('RB1', 'Gene', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('bone tumors', 'Phenotype', 'HP:0010622', (154, 165))	('sarcomas', 'Disease', 'MESH:D012509', (132, 140))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (120, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (132, 140))	('Tumors', 'Disease', (0, 6))	('sarcomas', 'Disease', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (120, 140))	('bone tumors', 'Disease', 'MESH:D001859', (154, 165))	('bladder cancer', 'Disease', (63, 77))	('nonmelanoma skin cancer', 'Disease', (87, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (63, 77))	('alterations', 'Var', (42, 53))	('RB1', 'Gene', '5925', (38, 41))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))
881473	32885893	In the case of CCNE1, alterations were frequent in ovarian (12.7%), esophageal (10.3%), and uterine cancers (9%).	('CCNE1', 'Gene', (15, 20))	('esophageal', 'Disease', (68, 78))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('ovarian', 'Disease', 'MESH:D010049', (51, 58))	('ovarian', 'Disease', (51, 58))	('frequent', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('uterine cancers', 'Phenotype', 'HP:0010784', (92, 107))	('alterations', 'Var', (22, 33))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('CCNE1', 'Gene', '898', (15, 20))	('cancers', 'Disease', (100, 107))
881480	32885893	In comparison with other histologies, a higher frequency of CDKN1A alterations was found in urothelial carcinomas (3.5%), CDKN1B in neuroendocrine cancers (3.1%), and CDKN2C in gliomas (2.5%).	('CDKN2C', 'Gene', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('CDKN1A', 'Gene', (60, 66))	('gliomas', 'Disease', (177, 184))	('neuroendocrine cancers', 'Disease', (132, 154))	('alterations', 'Var', (67, 78))	('CDKN1B', 'Gene', '1027', (122, 128))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('CDKN1A', 'Gene', '1026', (60, 66))	('neuroendocrine cancers', 'Disease', 'MESH:D009369', (132, 154))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (92, 113))	('CDKN2C', 'Gene', '1031', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('CDKN1B', 'Gene', (122, 128))	('urothelial carcinomas', 'Disease', (92, 113))
881483	32885893	For all tumors, there is a slightly higher likelihood of co-occurrence between alterations in cyclin-related genes (SMAD3, CDKN1A, CDKN1B, CDKN2C) and activating/sensitizing genes of the cyclin pathway (OR, 1.11; p < .001) (vs. an alteration in a cyclin-related gene in the presence of wild-type activating/sensitizing cyclin genes) (Fig.	('SMAD3', 'Gene', (116, 121))	('CDKN1A', 'Gene', (123, 129))	('CDKN1B', 'Gene', (131, 137))	('CDKN2C', 'Gene', '1031', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cyclin', 'Gene', (319, 325))	('CDKN1A', 'Gene', '1026', (123, 129))	('tumors', 'Disease', (8, 14))	('cyclin', 'Gene', (247, 253))	('cyclin', 'Gene', '5111', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('cyclin', 'Gene', '5111', (187, 193))	('CDKN1B', 'Gene', '1027', (131, 137))	('cyclin', 'Gene', (94, 100))	('SMAD3', 'Gene', '4088', (116, 121))	('CDKN2C', 'Gene', (139, 145))	('alterations', 'Var', (79, 90))	('cyclin', 'Gene', (187, 193))	('cyclin', 'Gene', '5111', (247, 253))	('cyclin', 'Gene', '5111', (319, 325))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
881488	32885893	Higher frequencies of alterations were noted in breast (11% of breast cancers had an ESR1 alteration) and uterine cancers (3.6%).	('ESR1', 'Gene', (85, 89))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('breast', 'Disease', (48, 54))	('cancers', 'Disease', (114, 121))	('uterine cancers', 'Phenotype', 'HP:0010784', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancers', 'Phenotype', 'HP:0003002', (63, 77))	('ESR1', 'Gene', '2099', (85, 89))	('alterations', 'Var', (22, 33))	('breast cancers', 'Disease', 'MESH:D001943', (63, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('breast cancers', 'Disease', (63, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancers', 'Disease', (70, 77))
881499	32885893	The frequency of alterations of cyclin genes varied by disease, being highest in brain tumors (47%), esophagogastric cancers (40%), and mesotheliomas (38%), and by histopathology, with highest frequencies in gliomas (54%) and urothelial cancers (41%).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('urothelial cancers', 'Disease', (226, 244))	('gliomas', 'Phenotype', 'HP:0009733', (208, 215))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('mesotheliomas', 'Disease', (136, 149))	('cyclin', 'Gene', (32, 38))	('brain tumors', 'Disease', 'MESH:D001932', (81, 93))	('brain tumors', 'Phenotype', 'HP:0030692', (81, 93))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (237, 244))	('alterations', 'Var', (17, 28))	('mesotheliomas', 'Disease', 'MESH:D008654', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('urothelial cancers', 'Disease', 'MESH:D014523', (226, 244))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('highest', 'Reg', (70, 77))	('gliomas', 'Disease', (208, 215))	('brain tumors', 'Disease', (81, 93))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', (117, 124))	('gliomas', 'Disease', 'MESH:D005910', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('cyclin', 'Gene', '5111', (32, 38))
881500	32885893	A previous report from our group using a similar genomic analysis, albeit with only 4,864 patients, similarly revealed frequent cyclin gene alterations across cancers [18], as did data on cBioPortal (http://www.cbioportal.org) and other prior smaller series [5, 17].	('cancers', 'Disease', (159, 166))	('cyclin', 'Gene', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('alterations', 'Var', (140, 151))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('cyclin', 'Gene', '5111', (128, 134))	('patients', 'Species', '9606', (90, 98))
881501	32885893	Unique to this study, SMARCB1 alterations were analyzed as part of the cyclin pathway.	('SMARCB1', 'Gene', '6598', (22, 29))	('cyclin', 'Gene', (71, 77))	('SMARCB1', 'Gene', (22, 29))	('alterations', 'Var', (30, 41))	('cyclin', 'Gene', '5111', (71, 77))
881503	32885893	Overall, we detected alterations in this gene in 0.7% of patients, whereas Memorial Sloan Kettering-Integrated mutation profiling of actionable cancer targets (MSK-IMPACT) demonstrated an alteration frequency of 1.3% (n = 10,945) [26].	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('patients', 'Species', '9606', (57, 65))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('alterations', 'Var', (21, 32))
881504	32885893	Mutations in SMARCB1 were first described in malignant rhabdoid tumors [27].	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('malignant rhabdoid tumors', 'Disease', (45, 70))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (45, 70))	('Mutations', 'Var', (0, 9))	('described', 'Reg', (32, 41))	('SMARCB1', 'Gene', '6598', (13, 20))	('SMARCB1', 'Gene', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
881505	32885893	We demonstrated a high frequency of SMARCB1 alterations in tumors with a rhabdoid component (supplemental online Table 3), including brain teratoid rhabdoid tumor (88.4% with alterations), kidney malignant rhabdoid tumor (90%), and extrarenal rhabdoid tumors (63.6%).	('SMARCB1', 'Gene', '6598', (36, 43))	('SMARCB1', 'Gene', (36, 43))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('alterations', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('rhabdoid tumors', 'Disease', (243, 258))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (243, 258))	('brain teratoid rhabdoid tumor', 'Disease', 'MESH:C000597569', (133, 162))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (252, 258))	('kidney malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (189, 220))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('brain teratoid rhabdoid tumor', 'Disease', (133, 162))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('alterations', 'Var', (175, 186))	('kidney malignant rhabdoid tumor', 'Disease', (189, 220))	('tumors', 'Disease', (59, 65))
881506	32885893	SMARCB1 inactivation was previously also demonstrated as a characteristic hallmark of renal medullary carcinomas in four cases [28].	('hallmark of renal medullary carcinomas', 'Disease', (74, 112))	('inactivation', 'Var', (8, 20))	('SMARCB1', 'Gene', '6598', (0, 7))	('hallmark of renal medullary carcinomas', 'Disease', 'MESH:D018276', (74, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('SMARCB1', 'Gene', (0, 7))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('renal medullary carcinomas', 'Phenotype', 'HP:0008659', (86, 112))
881508	32885893	Although quite uncommon, SMARCB1 alterations can be detected in a variety of other tumors based on our analysis, especially those neoplasms with a mesenchymal component.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('neoplasms', 'Phenotype', 'HP:0002664', (130, 139))	('detected', 'Reg', (52, 60))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('alterations', 'Var', (33, 44))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('SMARCB1', 'Gene', '6598', (25, 32))	('SMARCB1', 'Gene', (25, 32))	('neoplasms', 'Disease', 'MESH:D009369', (130, 139))	('neoplasms', 'Disease', (130, 139))
881510	32885893	CCND2 may be deregulated in testicular germ cell tumors [31], and we demonstrated a high frequency of alterations in CCND2 (mainly amplifications) in germ cell tumors of different origins (23.4% vs. 1.5% overall).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('germ cell tumors', 'Phenotype', 'HP:0100728', (39, 55))	('alterations', 'Var', (102, 113))	('CCND2', 'Gene', '894', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('germ cell tumors', 'Phenotype', 'HP:0100728', (150, 166))	('CCND2', 'Gene', '894', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('CCND2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('CCND2', 'Gene', (117, 122))	('tumors', 'Disease', (160, 166))	('deregulated', 'Reg', (13, 24))	('testicular', 'Disease', (28, 38))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
881511	32885893	About 8.6% of esophageal cancers harbor alterations in CDK6 in our series, which may identify a possible subset of these patients who are resistant to radiotherapy and may be candidates for therapeutic effects of CDK4/6 inhibition [32, 33].	('CDK4/6', 'Gene', '1019;1021', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('alterations', 'Var', (40, 51))	('CDK4/6', 'Gene', (213, 219))	('esophageal cancers', 'Disease', (14, 32))	('CDK6', 'Gene', (55, 59))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('CDK6', 'Gene', '1021', (55, 59))	('esophageal cancers', 'Disease', 'MESH:D004938', (14, 32))	('patients', 'Species', '9606', (121, 129))
881514	32885893	Regarding the cyclin pathway, soft tissue sarcomas were enriched for CDK4 alterations (12% vs. 3% overall), especially heart sarcomas (38.1% tumors presented alterations); conversely, bone tumors had a high frequency of CCND3 alterations (6.2% vs. 1.4% overall).	('CCND3', 'Gene', (220, 225))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('heart sarcomas', 'Phenotype', 'HP:0031350', (119, 133))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('alterations', 'Var', (226, 237))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('CDK4', 'Gene', '1019', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('sarcomas', 'Disease', 'MESH:D012509', (125, 133))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('sarcomas', 'Phenotype', 'HP:0100242', (125, 133))	('CCND3', 'Gene', '896', (220, 225))	('sarcomas', 'Disease', (125, 133))	('cyclin', 'Gene', '5111', (14, 20))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (30, 49))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (189, 195))	('alterations', 'Reg', (74, 85))	('bone tumors', 'Disease', (184, 195))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (30, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('heart sarcomas', 'Disease', 'MESH:D012509', (119, 133))	('bone tumors', 'Phenotype', 'HP:0010622', (184, 195))	('cyclin', 'Gene', (14, 20))	('sarcomas', 'Disease', 'MESH:D012509', (42, 50))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('sarcomas', 'Disease', (42, 50))	('heart sarcomas', 'Disease', (119, 133))	('bone tumors', 'Disease', 'MESH:D001859', (184, 195))	('CDK4', 'Gene', (69, 73))
881518	32885893	For other solid tumors, a phase II basket trial with ribociclib included heavily pretreated patients with advanced cancer and a cyclin genomic alteration (either CDK4/6 mutation or amplification, CCND1/3 amplification, or CDKN2A mutation or loss).	('CCND1/3', 'Gene', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('solid tumors', 'Disease', 'MESH:D009369', (10, 22))	('CDK4/6', 'Gene', '1019;1021', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cyclin', 'Gene', (128, 134))	('amplification', 'Reg', (204, 217))	('patients', 'Species', '9606', (92, 100))	('loss', 'NegReg', (241, 245))	('mutation', 'Var', (169, 177))	('CDKN2A', 'Gene', (222, 228))	('solid tumors', 'Disease', (10, 22))	('CCND1/3', 'Gene', '595;896', (196, 203))	('mutation', 'Var', (229, 237))	('cancer', 'Disease', (115, 121))	('CDK4/6', 'Gene', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('CDKN2A', 'Gene', '1029', (222, 228))	('amplification', 'Var', (181, 194))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('cyclin', 'Gene', '5111', (128, 134))
881520	32885893	A prospective trial with palbociclib in patients with pancreatic or biliary cancers with CDKN2A loss or mutation (prevalence in our series of 25.3% and 22%, respectively) also failed to demonstrate activity [21].	('pancreatic or biliary cancers', 'Disease', (54, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('palbociclib', 'Chemical', 'MESH:C500026', (25, 36))	('patients', 'Species', '9606', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CDKN2A', 'Gene', (89, 95))	('mutation', 'Var', (104, 112))	('CDKN2A', 'Gene', '1029', (89, 95))	('pancreatic or biliary cancers', 'Disease', 'MESH:D010190', (54, 83))	('loss', 'NegReg', (96, 100))
881524	32885893	Interestingly, we report a co-occurrence of AR and cyclin gene alterations, which could identify a subset of patients with more intense resistance to next-generation antiandrogens.	('cyclin', 'Gene', (51, 57))	('alterations', 'Var', (63, 74))	('patients', 'Species', '9606', (109, 117))	('AR', 'Gene', '367', (44, 46))	('cyclin', 'Gene', '5111', (51, 57))
881526	32885893	It is also noteworthy that, for the first time, we report a significant co-occurrence of ESR1 mutations with cyclin pathway alterations for breast cancer (OR, 1.63; p < .001).	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('ESR1', 'Gene', (89, 93))	('alterations', 'Reg', (124, 135))	('cyclin', 'Gene', '5111', (109, 115))	('breast cancer', 'Disease', (140, 153))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('cyclin', 'Gene', (109, 115))	('ESR1', 'Gene', '2099', (89, 93))
881529	32885893	Rb1 inactivating mutations may confer resistance to cyclin inhibition and may also emerge during therapy with palbociclib [45].	('inactivating mutations', 'Var', (4, 26))	('Rb1', 'Gene', '5925', (0, 3))	('palbociclib', 'Chemical', 'MESH:C500026', (110, 121))	('cyclin', 'Gene', '5111', (52, 58))	('Rb1', 'Gene', (0, 3))	('cyclin', 'Gene', (52, 58))
881530	32885893	High CCNE1 mRNA expression was also associated with resistance to this drug [40].	('High', 'Var', (0, 4))	('mRNA expression', 'MPA', (11, 26))	('associated', 'Reg', (36, 46))	('resistance to this drug', 'MPA', (52, 75))	('CCNE1', 'Gene', '898', (5, 10))	('CCNE1', 'Gene', (5, 10))
881538	32885893	The cyclin pathway regulation can also be affected by epigenetic modulation or noncoding genomic alterations [49].	('epigenetic modulation', 'Var', (54, 75))	('affected', 'Reg', (42, 50))	('regulation', 'MPA', (19, 29))	('cyclin', 'Gene', '5111', (4, 10))	('cyclin', 'Gene', (4, 10))
881540	32885893	Our analysis shows that alterations in cyclin pathway activating/sensitizing genes occurred in 24% of 190,247 tumors.	('cyclin', 'Gene', '5111', (39, 45))	('alterations', 'Var', (24, 35))	('cyclin', 'Gene', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))
881556	32052383	Exercise is also emerging as a potential coadjuvant treatment; when combined with cyclophosphamide, exercise delays murine breast tumor growth versus chemotherapy alone, and similar findings have been reported for exercise combined with anthracyclines.	('exercise', 'Var', (100, 108))	('breast tumor', 'Phenotype', 'HP:0100013', (123, 135))	('murine', 'Species', '10090', (116, 122))	('breast tumor', 'Disease', 'MESH:D001943', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('exercise delays', 'Phenotype', 'HP:0003546', (100, 115))	('men', 'Species', '9606', (57, 60))	('anthracyclines', 'Chemical', 'MESH:D018943', (237, 251))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (82, 98))	('breast tumor', 'Disease', (123, 135))	('delays', 'NegReg', (109, 115))
881569	32052383	In this respect, exercise may promote a shift toward a more "normalized" tumor microenvironment by improving intratumoral perfusion/vascularization, at least in orthotopic murine models of human BC and prostate cancer and in xenografts of different tumors (melanoma, pancreas).	('prostate cancer', 'Disease', 'MESH:D011471', (202, 217))	('prostate cancer', 'Phenotype', 'HP:0012125', (202, 217))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('rat', 'Species', '10116', (112, 115))	('tumor', 'Disease', (249, 254))	('prostate cancer', 'Disease', (202, 217))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('improving', 'PosReg', (99, 108))	('tumor', 'Disease', (114, 119))	('murine', 'Species', '10090', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('human', 'Species', '9606', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', (73, 78))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('melanoma', 'Disease', (257, 265))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('BC', 'Phenotype', 'HP:0003002', (195, 197))	('men', 'Species', '9606', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('exercise', 'Var', (17, 25))	('tumors', 'Disease', (249, 255))
881570	32052383	Exercise might also attenuate the development of metastases.	('attenuate', 'NegReg', (20, 29))	('metastases', 'Disease', 'MESH:D009362', (49, 59))	('Exercise', 'Var', (0, 8))	('men', 'Species', '9606', (41, 44))	('metastases', 'Disease', (49, 59))
881577	32052383	One major potential "anticancer" effect of exercise lies in an enhancement of immune function.	('enhancement', 'PosReg', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('men', 'Species', '9606', (70, 73))	('enhancement of immune function', 'Phenotype', 'HP:0002721', (63, 93))	('exercise', 'Var', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('immune function', 'CPA', (78, 93))	('cancer', 'Disease', (25, 31))
881600	32052383	Regarding the amount of PA required to obtain maximum benefit, a cohort of more than 40,000 men in the USA (The Health Professionals Follow-up Study) showed that aerobic PA seems to be more beneficial and that overall PA is more relevant than the intensity of PA.	('aerobic', 'Var', (162, 169))	('beneficial', 'PosReg', (190, 200))	('men', 'Species', '9606', (92, 95))
881651	32052383	BC mortality was reduced in patients who achieved 18.7 or more MET-hours/week, and no association was found between PA and BC recurrence.	('MET-hours/week', 'Var', (63, 77))	('mortality', 'Disease', 'MESH:D003643', (3, 12))	('BC', 'Phenotype', 'HP:0003002', (123, 125))	('BC', 'Phenotype', 'HP:0003002', (0, 2))	('mortality', 'Disease', (3, 12))	('patients', 'Species', '9606', (28, 36))	('reduced', 'NegReg', (17, 24))
881675	32052383	Different reviews have shown that exercise improves fitness capacity and might reduce some cancer-related side effects, such as fatigue.	('fitness', 'Disease', (52, 59))	('fatigue', 'Disease', 'MESH:D005221', (128, 135))	('fitness', 'Disease', 'MESH:D012640', (52, 59))	('cancer', 'Disease', (91, 97))	('improves', 'PosReg', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('fatigue', 'Disease', (128, 135))	('reduce', 'NegReg', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('fatigue', 'Phenotype', 'HP:0012378', (128, 135))	('exercise', 'Var', (34, 42))
881734	32269846	Follow-up endoscopy showed more frequent reflux esophagitis cases in the CEG group than in the SPADE group (30% vs. 15.3%, P=0.19).	('CEG', 'Chemical', '-', (73, 76))	('esophagitis', 'Phenotype', 'HP:0100633', (48, 59))	('reflux esophagitis', 'Disease', 'MESH:D005764', (41, 59))	('reflux esophagitis', 'Disease', (41, 59))	('CEG', 'Var', (73, 76))
881735	32269846	Similarly, bile reflux (26.7% vs. 7.7%, P=0.08) and residual food (P=0.01) cases occurred more frequently in the CEG group than in the SPADE group.	('bile reflux', 'Disease', (11, 22))	('CEG', 'Chemical', '-', (113, 116))	('residual food', 'MPA', (52, 65))	('CEG', 'Var', (113, 116))
881743	32269846	The main issues are reflux, stricture, surveillance of remnant stomach, technical complexity, cost, operative time, and other morbidities; a major issue is a reflux, which is caused by loss of the food-containing function of the fundus, transition of a newly formed esophagogastric junction (EGJ) above the diaphragm like a sliding hiatal hernia, and loss of the angle of His.	('hiatal hernia', 'Phenotype', 'HP:0002036', (332, 345))	('hernia', 'Phenotype', 'HP:0100790', (339, 345))	('loss', 'Var', (351, 355))	('His', 'Chemical', 'MESH:D006639', (372, 375))	('reflux', 'Disease', (158, 164))	('hiatal hernia', 'Disease', 'MESH:D006551', (332, 345))	('loss', 'NegReg', (185, 189))	('hiatal hernia', 'Disease', (332, 345))
881745	32269846	This technique enabled anastomosis creation in the abdominal cavity as well as an artificial angle of His and pseudo-fornix and duplication of 2-3 cm of esophagogastric walls in the anastomosis that could have sphincter function because of distal peristaltic muscles.	('His', 'Chemical', 'MESH:D006639', (102, 105))	('anastomosis creation', 'Disease', 'MESH:C563598', (23, 43))	('duplication of 2-3 cm', 'Phenotype', 'HP:0004691', (128, 149))	('anastomosis creation', 'Disease', (23, 43))	('duplication', 'Var', (128, 139))
881766	32269846	Follow-up EGD showed frequent reflux esophagitis cases in the CEG group than in the SPADE group (30% vs. 15.3%, P=0.19).	('CEG', 'Chemical', '-', (62, 65))	('CEG', 'Var', (62, 65))	('reflux esophagitis', 'Disease', (30, 48))	('reflux esophagitis', 'Disease', 'MESH:D005764', (30, 48))	('esophagitis', 'Phenotype', 'HP:0100633', (37, 48))
881767	32269846	Similarly, the mean bile reflux grade was higher (26.7% vs. 7.7%, P=0.08) in the CEG group than in the SPADE group, as was the residual food grade (P=0.01).	('residual food grade', 'MPA', (127, 146))	('bile reflux grade', 'MPA', (20, 37))	('higher', 'PosReg', (42, 48))	('CEG', 'Chemical', '-', (81, 84))	('CEG', 'Var', (81, 84))
881772	32269846	The advantages of the SPADE operation are derived from physiological factors including the loss of fundus function, creation of a new sliding EGJ above the diaphragm, and loss of the angle of His, all of which are significant physiological changes contributing to the high prevalence and severity of reflux symptoms after a CEG anastomosis.	('CEG', 'Chemical', '-', (324, 327))	('His', 'Chemical', 'MESH:D006639', (192, 195))	('reflux symptoms', 'Disease', (300, 315))	('reflux symptoms', 'Phenotype', 'HP:0002020', (300, 315))	('loss', 'NegReg', (91, 95))	('loss', 'Var', (171, 175))
881830	31095082	One cohort study observed that strenuous activity was inversely and significantly associated with reduced breast cancer risk, particularly in certain molecular subtypes.	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('strenuous activity', 'Var', (31, 49))	('reduced', 'NegReg', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
881883	31095082	The project found that engaging in 10 or more MET-hours per week was associated with a 27 percent reduction in all-cause mortality (hazard ratio (HR)=0.73; 95% CI: 0.66-0.82) and a 25 percent reduction in breast cancer-specific mortality (HR=0.75; 95% CI: 0.65-0.85).	('mortality', 'Disease', (121, 130))	('mortality', 'Disease', (228, 237))	('reduction', 'NegReg', (98, 107))	('all-cause', 'CPA', (111, 120))	('mortality', 'Disease', 'MESH:D003643', (121, 130))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('reduction', 'NegReg', (192, 201))	('MET-hours per week', 'Var', (46, 64))	('breast cancer', 'Disease', (205, 218))	('mortality', 'Disease', 'MESH:D003643', (228, 237))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
881895	31095082	A review of the papers included in the systematic reviews indicates that highest versus lowest levels of total, recreational, non-sedentary occupational, and vigorous physical activity, as well as greater MET-hours per week or greater numbers of hours per week, were statistically significantly related to reduced risk for all-cause mortality.	('mortality', 'Disease', 'MESH:D003643', (333, 342))	('reduced', 'NegReg', (306, 313))	('MET-hours per week', 'Var', (205, 223))	('mortality', 'Disease', (333, 342))	('all-cause', 'Disease', (323, 332))
881900	31095082	We found strong evidence that physical activity reduces the risk of cancers of the breast, colon, endometrium, bladder, stomach, esophagus (adenocarcinoma) and kidney and moderate evidence for an association with lung cancer risk, with 10 to 20% reductions in relative risks.	('bladder', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('lung cancer', 'Disease', (213, 224))	('endometrium', 'Disease', (98, 109))	('kidney', 'Disease', (160, 166))	('colon', 'Disease', (91, 96))	('adenocarcinoma', 'Disease', (140, 154))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('lung cancer', 'Disease', 'MESH:D008175', (213, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('breast', 'Disease', (83, 89))	('reduces', 'NegReg', (48, 55))	('stomach', 'Disease', (120, 127))	('cancers of the breast', 'Phenotype', 'HP:0100013', (68, 89))	('physical activity', 'Var', (30, 47))	('reductions', 'NegReg', (246, 256))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('esophagus', 'Disease', (129, 138))
881970	31041568	For example, fucoidan (from F. vesiculosus) inhibits HepG2 cell viability and induces apoptosis.	('induces', 'Reg', (78, 85))	('HepG2 cell viability', 'CPA', (53, 73))	('HepG2', 'CellLine', 'CVCL:0027', (53, 58))	('F. vesiculosus', 'Species', '49266', (28, 42))	('fucoidan', 'Var', (13, 21))	('inhibits', 'NegReg', (44, 52))	('fucoidan', 'Chemical', 'MESH:C007789', (13, 21))	('apoptosis', 'CPA', (86, 95))
881998	31041568	Induction of unbalanced ROS in cancer cells via therapeutic approaches, such as chemotherapy and radiotherapy, may trigger ROS-mediated cell death mechanisms.	('ROS', 'Chemical', 'MESH:D017382', (123, 126))	('ROS-mediated', 'CPA', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('unbalanced', 'Var', (13, 23))	('ROS', 'Chemical', 'MESH:D017382', (24, 27))	('ROS', 'Protein', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('trigger', 'Reg', (115, 122))
882001	31041568	It reported that significantly enhanced generation of superoxide and NO from fucoidan treatment in Leishmania donovani-infected BALB/c mice in vivo, one of the mechanisms is fucoidan can induce Th1 cytokines and NO generation in infected macrophages.	('enhanced', 'PosReg', (31, 39))	('Th1', 'Gene', '57314', (194, 197))	('induce', 'PosReg', (187, 193))	('superoxide', 'Chemical', 'MESH:D013481', (54, 64))	('generation of superoxide', 'MPA', (40, 64))	('rat', 'Species', '10116', (219, 222))	('mice', 'Species', '10090', (135, 139))	('rat', 'Species', '10116', (44, 47))	('fucoidan', 'Var', (174, 182))	('Leishmania donovani-infected BALB', 'Disease', (99, 132))	('Th1', 'Gene', (194, 197))	('fucoidan', 'Chemical', 'MESH:C007789', (77, 85))	('fucoidan', 'Chemical', 'MESH:C007789', (174, 182))	('Leishmania donovani-infected BALB', 'Disease', 'MESH:D007896', (99, 132))
882021	31041568	For example, fucoidan induces G1 arrest of cell cycle progression in human bladder cancer EJ cells associated with down-regulation of cyclin D1, cyclin E, and cyclin-dependent-kinases (Cdks) in a concentration-dependent manner.	('cyclin', 'Gene', (145, 151))	('Cdks', 'Gene', '23552', (185, 189))	('cyclin', 'Gene', '5111', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('fucoidan', 'Chemical', 'MESH:C007789', (13, 21))	('cyclin', 'Gene', (159, 165))	('cyclin', 'Gene', (134, 140))	('cyclin D1', 'Gene', (134, 143))	('cell cycle progression', 'CPA', (43, 65))	('EJ', 'CellLine', 'CVCL:7039', (90, 92))	('G1 arrest', 'CPA', (30, 39))	('human', 'Species', '9606', (69, 74))	('cyclin D1', 'Gene', '595', (134, 143))	('cyclin', 'Gene', '5111', (145, 151))	('fucoidan', 'Var', (13, 21))	('rat', 'Species', '10116', (203, 206))	('down-regulation', 'NegReg', (115, 130))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('Cdks', 'Gene', (185, 189))	('cyclin', 'Gene', '5111', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
882023	31041568	Fucoidan-induced G1 phase arrest is caused by the activity of the p16INK4a-Rb and p14Arf-p53 pathways.	('p14Arf', 'Gene', (82, 88))	('G1 phase arrest', 'CPA', (17, 32))	('Fucoidan', 'Chemical', 'MESH:C007789', (0, 8))	('caused by', 'Reg', (36, 45))	('activity', 'MPA', (50, 58))	('p53', 'Gene', (89, 92))	('p14Arf', 'Gene', '1029', (82, 88))	('p16INK4a-Rb', 'Var', (66, 77))	('p53', 'Gene', '7157', (89, 92))
882049	31041568	The PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK pathways control the translation of HIF-1alpha, and HIF-1alpha activates VEGFs, u-PA, and MMP-2 and -9 to promote tumor metastasis.	('mammalian target of rapamycin', 'Gene', '2475', (13, 42))	('HIF-1alpha', 'Var', (110, 120))	('tumor metastasis', 'Disease', 'MESH:D009362', (172, 188))	('mTOR', 'Gene', '2475', (44, 48))	('PI3', 'Gene', (4, 7))	('mammalian target of rapamycin', 'Gene', (13, 42))	('tumor metastasis', 'Disease', (172, 188))	('VEGFs', 'Protein', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('ERK', 'Gene', '5594', (54, 57))	('promote', 'PosReg', (164, 171))	('MMP-2 and -9', 'Gene', '4313;4318', (148, 160))	('u-PA', 'Gene', (138, 142))	('activates', 'PosReg', (121, 130))	('Akt', 'Gene', (9, 12))	('ERK', 'Gene', (54, 57))	('mTOR', 'Gene', (44, 48))	('PI3', 'Gene', '5266', (4, 7))	('u-PA', 'Gene', '5328', (138, 142))	('Akt', 'Gene', '207', (9, 12))
882054	31041568	Fucoidan inhibits the growth and migration of human bladder cancer cells; specifically, it inhibits cell growth via p21WAF1-mediated G1-phase cell-cycle arrest by activation of AKT.	('cell growth', 'CPA', (100, 111))	('G1-phase cell-cycle arrest', 'CPA', (133, 159))	('p21WAF1-mediated', 'Var', (116, 132))	('activation', 'PosReg', (163, 173))	('AKT', 'Gene', '207', (177, 180))	('Fucoidan', 'Chemical', 'MESH:C007789', (0, 8))	('rat', 'Species', '10116', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('AKT', 'Gene', (177, 180))	('human', 'Species', '9606', (46, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('inhibits', 'NegReg', (9, 17))	('inhibits', 'NegReg', (91, 99))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))
882080	31041568	The immune-prevention effects of fucoidan on cancer demonstrate that fucoidan (from F. vesiculosus) enhances immune responses in immune cells including natural killer (NK) cells and macrophages.	('fucoidan', 'Chemical', 'MESH:C007789', (69, 77))	('fucoidan', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('immune', 'MPA', (109, 115))	('F. vesiculosus', 'Species', '49266', (84, 98))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('enhances', 'PosReg', (100, 108))	('rat', 'Species', '10116', (59, 62))	('fucoidan', 'Chemical', 'MESH:C007789', (33, 41))	('cancer', 'Disease', (45, 51))
882101	31041568	Several studies have reported that fucoidan and its combinations can induce apoptosis in a variety of cancers.	('fucoidan', 'Chemical', 'MESH:C007789', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('combinations', 'Var', (52, 64))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('induce', 'PosReg', (69, 75))	('cancers', 'Disease', (102, 109))	('apoptosis', 'CPA', (76, 85))
882139	31041568	The current findings indicate that fucoidan has potential as a therapeutic intervention for controlling breast cancer or other cancers and that manipulation of the proteasomal ubiquitin-dependent degradation of proteins in relation to the TGFR/Smad/Snail, Slug, and Twist/EMT axes should be a beneficial strategy for cancer patients.	('Slug', 'Gene', (256, 260))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('proteins', 'Protein', (211, 219))	('breast cancer', 'Disease', (104, 117))	('manipulation', 'Var', (144, 156))	('cancer', 'Disease', (111, 117))	('Snail', 'Gene', (249, 254))	('patients', 'Species', '9606', (324, 332))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('proteasomal ubiquitin-dependent degradation of', 'MPA', (164, 210))	('cancer', 'Disease', (127, 133))	('cancers', 'Disease', (127, 134))	('Slug', 'Gene', '6591', (256, 260))	('cancer', 'Disease', (317, 323))	('fucoidan', 'Chemical', 'MESH:C007789', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('rat', 'Species', '10116', (306, 309))	('Snail', 'Gene', '6615', (249, 254))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
882145	31041568	TGFRs play important roles in the regulation of proliferation and progression, and high TGFRI expression in lung cancer specimens is associated with a worse prognosis.	('TGFRI', 'Gene', (88, 93))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('expression', 'MPA', (94, 104))	('high', 'Var', (83, 87))	('rat', 'Species', '10116', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('associated', 'Reg', (133, 143))
882150	31041568	Mechanistically, fucoidan promotes the conjugation of Smurf2 and Smad7 with TGFRs, resulting in TGFRs degradation; however, Smurf2-shRNA abolishes fucoidan-enhanced UPP-mediated TGFRs degradation.	('TGFRs degradation', 'MPA', (96, 113))	('Smurf2-shRNA', 'Var', (124, 136))	('abolishes', 'NegReg', (137, 146))	('fucoidan', 'Chemical', 'MESH:C007789', (147, 155))	('fucoidan', 'Chemical', 'MESH:C007789', (17, 25))	('conjugation', 'Interaction', (39, 50))
882173	31041568	Moreover, Toll-like receptor 4 (TLR4) knockdown attenuates fucoidan-induced ROS and CHOP expression.	('Toll-like receptor 4', 'Gene', '7099', (10, 30))	('fucoidan', 'Chemical', 'MESH:C007789', (59, 67))	('attenuates', 'NegReg', (48, 58))	('CHOP expression', 'MPA', (84, 99))	('TLR4', 'Gene', '7099', (32, 36))	('Toll-like receptor 4', 'Gene', (10, 30))	('TLR4', 'Gene', (32, 36))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('knockdown', 'Var', (38, 47))	('fucoidan-induced ROS', 'MPA', (59, 79))
882361	28536606	We confirmed that VEGF-A is a target for miR-126.	('VEGF-A', 'Gene', '7422', (18, 24))	('VEGF-A', 'Gene', (18, 24))	('miR-126', 'Var', (41, 48))
882363	28536606	The results showed that miR-126 could inhibit esophageal cancer cell proliferation in vitro.	('esophageal cancer', 'Disease', (46, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (46, 63))	('miR-126', 'Var', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('inhibit', 'NegReg', (38, 45))
882373	28536606	However, in some cases, miR-126 supports cancer progression via promotion of blood vessel formation.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('blood vessel formation', 'CPA', (77, 99))	('miR-126', 'Var', (24, 31))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('promotion', 'PosReg', (64, 73))
882394	28536606	1 x 107 cells stably transfected with LV-miR-126, LV-anti-miR-126 and lenti-miR-NC were injected subcutaneously into the right foreleg armpit of three groups of 18-26 g male BALB/c nude mice (8 mice/group) to establish a cancer model.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('LV-miR-126', 'Var', (38, 48))	('cancer', 'Disease', (221, 227))	('mice', 'Species', '10090', (194, 198))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('mice', 'Species', '10090', (186, 190))	('nude mice', 'Species', '10090', (181, 190))	('LV-anti-miR-126', 'Var', (50, 65))
882411	28536606	To find direct targets of miR-126, luciferase activity was measured by the co-transfection of the VEGF-A wild-type 3'-UTR with miR-126.	('VEGF-A', 'Gene', (98, 104))	('miR-126', 'Var', (127, 134))	('activity', 'MPA', (46, 54))	('luciferase', 'Enzyme', (35, 45))	('VEGF-A', 'Gene', '7422', (98, 104))
882412	28536606	The miRNA decreased luciferase activity, whereas this effect was completely ablated by deletion of the miR-126-binding site in the VEGF-A 3'-UTR (Fig.	('activity', 'MPA', (31, 39))	('miR-126-binding', 'Gene', (103, 118))	('decreased', 'NegReg', (10, 19))	('ablated', 'NegReg', (76, 83))	('VEGF-A', 'Gene', (131, 137))	('luciferase', 'Enzyme', (20, 30))	('VEGF-A', 'Gene', '7422', (131, 137))	('deletion', 'Var', (87, 95))
882416	28536606	These results demonstrate that overexpression of miR-126 could inhibit VEGF-A expression.	('expression', 'MPA', (78, 88))	('inhibit', 'NegReg', (63, 70))	('VEGF-A', 'Gene', '7422', (71, 77))	('miR-126', 'Var', (49, 56))	('VEGF-A', 'Gene', (71, 77))	('overexpression', 'PosReg', (31, 45))
882419	28536606	These results suggest that miR-126 could inhibit VEGF-A expression and then inhibit esophageal cancer cell proliferation in vitro.	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('inhibit', 'NegReg', (76, 83))	('VEGF-A', 'Gene', '7422', (49, 55))	('VEGF-A', 'Gene', (49, 55))	('expression', 'MPA', (56, 66))	('esophageal cancer', 'Disease', (84, 101))	('inhibit', 'NegReg', (41, 48))	('miR-126', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
882420	28536606	To figure out whether changes in miR-126 expression could influence the growth of tumorsin vivo, three groups of nude mice were inoculated with OE33 cells that had been stably transfected with recombinant lentivirus miR-126 (LV-miR-126), anti-miR-126 inhibitor (LV-anti-miR-126) and lentivirus miR negative control (LV-miR-NC).	('tumors', 'Disease', (82, 88))	('growth', 'CPA', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('changes', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('nude mice', 'Species', '10090', (113, 122))	('influence', 'Reg', (58, 67))
882423	28536606	The average tumor weight of mice inoculated with lenti-miR-126-transfected OE33 cells was significantly lower on day 42 (p < 0.01) than that for mice inoculated with anti-miR-126 transfected OE33 cells and the miR-NC negative control group.	('lenti-miR-126-transfected', 'Var', (49, 74))	('mice', 'Species', '10090', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lower', 'NegReg', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Disease', (12, 17))
882424	28536606	These results revealed that miR-126 could inhibit esophageal cancer growth by downregulating VEGF-A expression.	('miR-126', 'Var', (28, 35))	('inhibit', 'NegReg', (42, 49))	('expression', 'MPA', (100, 110))	('VEGF-A', 'Gene', '7422', (93, 99))	('esophageal cancer', 'Disease', (50, 67))	('VEGF-A', 'Gene', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('downregulating', 'NegReg', (78, 92))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
882425	28536606	It has been demonstrated that abnormal expression of miR-126 correlates with human tumorigenesis and that miR-126 has roles in cancers of the gastrointestinal tract, genital tracts, breasts, thyroid, lungs and some other tissues and organs.	('expression', 'MPA', (39, 49))	('abnormal', 'Var', (30, 38))	('roles', 'Reg', (118, 123))	('breasts', 'Disease', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancers of the gastrointestinal tract', 'Disease', (127, 164))	('tumor', 'Disease', (83, 88))	('miR-126', 'Gene', (106, 113))	('cancers of the gastrointestinal tract', 'Disease', 'MESH:D004067', (127, 164))	('genital tracts', 'Disease', (166, 180))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('lungs', 'Disease', (200, 205))	('thyroid', 'Disease', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('miR-126', 'Gene', (53, 60))	('human', 'Species', '9606', (77, 82))
882432	28536606	Crawford discovered that miR-126 can suppress lung cancer invasion by directly targeting CRK, and Liu reported that miR-126 suppresses the expression of VEGF-A, inhibiting cancer cell growth.	('suppresses', 'NegReg', (124, 134))	('CRK', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('VEGF-A', 'Gene', (153, 159))	('suppress', 'NegReg', (37, 45))	('miR-126', 'Var', (116, 123))	('inhibiting', 'NegReg', (161, 171))	('VEGF-A', 'Gene', '7422', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('expression', 'MPA', (139, 149))	('cancer', 'Disease', (172, 178))	('CRK', 'Gene', '1398', (89, 92))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
882440	28536606	reported that when miR-126 in the esophageal cancer tissues was compared with its levels in matched normal tissues using miRNA microarrays, it was found to be reduced.	('miR-126', 'Var', (19, 26))	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
882448	28536606	These results suggest that miR-126 as a possible negative regulatory role in VEGF-A expression.	('VEGF-A', 'Gene', (77, 83))	('negative regulatory', 'NegReg', (49, 68))	('miR-126', 'Var', (27, 34))	('expression', 'MPA', (84, 94))	('VEGF-A', 'Gene', '7422', (77, 83))
882453	28536606	Based on luciferase activity assays, we found that VEGF-A is a direct target of miR-126and confirmed that miR-126 negatively regulates VEGF-A expression in overexpressed miR-126 esophageal cancer cells from the lines JH-EsoAd1, OE19 and OE33.	('esophageal cancer', 'Disease', (178, 195))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('negatively', 'NegReg', (114, 124))	('VEGF-A', 'Gene', '7422', (51, 57))	('VEGF-A', 'Gene', '7422', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('miR-126', 'Var', (106, 113))	('overexpressed', 'PosReg', (156, 169))	('VEGF-A', 'Gene', (51, 57))	('VEGF-A', 'Gene', (135, 141))	('expression', 'MPA', (142, 152))	('regulates', 'Reg', (125, 134))	('miR-126', 'Gene', (170, 177))
882455	28536606	More importantly, ectopic expression of miR-126 in nude mouse inhibited tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ectopic expression', 'Var', (18, 36))	('tumor', 'Disease', (72, 77))	('mouse', 'Species', '10090', (56, 61))	('inhibited', 'NegReg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('miR-126', 'Gene', (40, 47))
882458	28536606	In conclusion, miR-126 was naturally complementary to the VEGF-A 3'-UTR and could downregulate overexpression of VEGF-A in esophageal cancer cells, thus inhibiting the esophageal cancer growth.	('VEGF-A', 'Gene', '7422', (113, 119))	('esophageal cancer', 'Disease', (123, 140))	('esophageal cancer', 'Disease', (168, 185))	('VEGF-A', 'Gene', (113, 119))	('VEGF-A', 'Gene', '7422', (58, 64))	('downregulate', 'NegReg', (82, 94))	('miR-126', 'Var', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('VEGF-A', 'Gene', (58, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('overexpression', 'MPA', (95, 109))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('inhibiting', 'NegReg', (153, 163))
882546	25847432	While non-EAC esophagectomy cases also had more ductal metaplasia (4.3%) than was found in the control group (3.5%, p-value 0.001), there was not a significant difference from HGD/EAC group (12.7%, p-value 0.19); these results are presented in Table 2.	('non-EAC', 'Var', (6, 13))	('ductal metaplasia', 'Disease', (48, 65))	('esophagectomy', 'Disease', (14, 27))	('ductal metaplasia', 'Disease', 'MESH:D008679', (48, 65))
882552	25847432	In some patients with BE, ESMG ducts and overlying metaplastic epithelia have been described as sharing a common mutation in the tumor suppressor gene p16, suggesting an association between the underlying ESMG ducts and overlying BE.	('mutation', 'Var', (113, 121))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('p16', 'Gene', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('association', 'Interaction', (170, 181))	('p16', 'Gene', '1029', (151, 154))	('patients', 'Species', '9606', (8, 16))
882553	25847432	In addition, when mitochondrial mutations in the cytochrome C oxidase gene were used to map the clonal origins of neoplastic esophageal epithelial cells, a common mitochondrial gene mutation was also found in both the submucosa and the surface epithelium.	('mutation', 'Var', (182, 190))	('neoplastic esophageal', 'Disease', 'MESH:D004938', (114, 135))	('neoplastic esophageal', 'Disease', (114, 135))
882582	25659582	ROS are required for cells undergoing EMT while excessive ROS may induce cell death or senescence; however, little is known as to how cellular antioxidant capabilities may be regulated during EMT.	('senescence', 'CPA', (87, 97))	('ROS', 'Var', (58, 61))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('excessive ROS', 'Var', (48, 61))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('induce', 'Reg', (66, 72))	('cell death', 'CPA', (73, 83))
882592	25659582	During the early stages of carcinogenesis, oncogene-induced ROS may promote EMT in premalignant epithelial cells to negate oncogene-induced senescence, serving as a fail-safe mechanism to prevent malignant transformation .	('oncogene-induced', 'Var', (43, 59))	('ROS', 'Gene', (60, 63))	('promote', 'PosReg', (68, 75))	('carcinogenesis', 'Disease', 'MESH:D063646', (27, 41))	('negate', 'NegReg', (116, 122))	('EMT in premalignant epithelial cells', 'CPA', (76, 112))	('carcinogenesis', 'Disease', (27, 41))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))
882627	25659582	Examination of E-cadherin and N-cadherin expression patterns validated the epithelial and mesenchymal characteristics of EPC2T CD44L and CD44H cells, respectively (Figure 2A).	('EPC2T', 'Var', (121, 126))	('N-cadherin', 'Gene', (30, 40))	('E-cadherin', 'Gene', (15, 25))	('CD44', 'Gene', '960', (137, 141))	('E-cadherin', 'Gene', '999', (15, 25))	('CD44', 'Gene', '960', (127, 131))	('N-cadherin', 'Gene', '1000', (30, 40))	('CD44', 'Gene', (137, 141))	('CD44', 'Gene', (127, 131))	('EPC2T', 'CellLine', 'CVCL:4361', (121, 126))
882628	25659582	Moreover, in addition to upregulation of the EMT-associated transcription factors ZEB1 and ZEB2, EPC2T CD44H cells showed significantly elevated expression of SOD2 as well as GPX1 and catalase (Fig.	('GPX1', 'Gene', (175, 179))	('ZEB2', 'Gene', '9839', (91, 95))	('EPC2T', 'Var', (97, 102))	('SOD2', 'Gene', (159, 163))	('ZEB2', 'Gene', (91, 95))	('ZEB1', 'Gene', '6935', (82, 86))	('expression', 'MPA', (145, 155))	('catalase', 'Gene', (184, 192))	('elevated', 'PosReg', (136, 144))	('ZEB1', 'Gene', (82, 86))	('CD44', 'Gene', '960', (103, 107))	('catalase', 'Gene', '847', (184, 192))	('EPC2T', 'CellLine', 'CVCL:4361', (97, 102))	('CD44', 'Gene', (103, 107))	('upregulation', 'PosReg', (25, 37))
882636	25659582	Activation of NF-kappaB in EPC2T CD44H cells was corroborated by increased NF-kappaB p65Ser536 phosphorylation level and basal NF-kappaB reporter activity (Fig.	('increased', 'PosReg', (65, 74))	('CD44', 'Gene', (33, 37))	('NF-kappaB', 'Gene', '4790', (127, 136))	('NF-kappaB', 'Gene', (75, 84))	('NF-kappaB', 'Gene', '4790', (14, 23))	('NF-kappaB', 'Gene', (14, 23))	('EPC2T', 'CellLine', 'CVCL:4361', (27, 32))	('NF-kappaB', 'Gene', (127, 136))	('p65Ser536', 'Var', (85, 94))	('CD44', 'Gene', '960', (33, 37))	('NF-kappaB', 'Gene', '4790', (75, 84))
882637	25659582	To test the involvement of NF-kappaB in SOD2 expression, we performed NF-kappaB knock down by RNAi directed against NF-kappaB p65.	('knock', 'Var', (80, 85))	('NF-kappaB', 'Gene', '4790', (116, 125))	('NF-kappaB', 'Gene', (116, 125))	('NF-kappaB', 'Gene', '4790', (27, 36))	('NF-kappaB', 'Gene', '4790', (70, 79))	('NF-kappaB', 'Gene', (27, 36))	('NF-kappaB', 'Gene', (70, 79))
882639	25659582	Of note, NF-kappaB knockdown did not affect the expression of E-cadherin and N-cadherin in CD44L and CD44H cells (data not shown).	('NF-kappaB', 'Gene', (9, 18))	('CD44', 'Gene', (101, 105))	('CD44', 'Gene', '960', (101, 105))	('knockdown', 'Var', (19, 28))	('CD44', 'Gene', '960', (91, 95))	('N-cadherin', 'Gene', '1000', (77, 87))	('CD44', 'Gene', (91, 95))	('E-cadherin', 'Gene', (62, 72))	('NF-kappaB', 'Gene', '4790', (9, 18))	('N-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (62, 72))
882645	25659582	Moreover, NF-kappaB knockdown reduced pSODLUC-3340 and P7/pGL3 reporter activities in CD44H, but not CD44L cells (Figure 3F), indicating that the NF-kappaB may also indirectly influence SOD2 transcription activity in CD44H cells.	('CD44', 'Gene', (86, 90))	('CD44', 'Gene', (101, 105))	('pGL3', 'Gene', (58, 62))	('CD44', 'Gene', '960', (101, 105))	('NF-kappaB', 'Gene', '4790', (10, 19))	('pGL3', 'Gene', '6391', (58, 62))	('pSODLUC-3340', 'MPA', (38, 50))	('NF-kappaB', 'Gene', '4790', (146, 155))	('SOD2', 'Gene', (186, 190))	('CD44', 'Gene', '960', (217, 221))	('CD44', 'Gene', '960', (86, 90))	('reduced', 'NegReg', (30, 37))	('NF-kappaB', 'Gene', (10, 19))	('influence', 'Reg', (176, 185))	('knockdown', 'Var', (20, 29))	('CD44', 'Gene', (217, 221))	('NF-kappaB', 'Gene', (146, 155))
882649	25659582	NF-kappaB knockdown did not affect ZEB1 or ZEB2 expression (Figure 3E), suggesting that ZEBs are not directly regulated by NF-kappaB in CD44H cells.	('ZEB1', 'Gene', '6935', (35, 39))	('ZEB2', 'Gene', '9839', (43, 47))	('ZEB1', 'Gene', (35, 39))	('NF-kappaB', 'Gene', '4790', (0, 9))	('NF-kappaB', 'Gene', '4790', (123, 132))	('NF-kappaB', 'Gene', (0, 9))	('ZEB2', 'Gene', (43, 47))	('CD44', 'Gene', (136, 140))	('CD44', 'Gene', '960', (136, 140))	('NF-kappaB', 'Gene', (123, 132))	('knockdown', 'Var', (10, 19))
882650	25659582	Interestingly, however, knockdown of ZEB2, but not ZEB1, resulted in attenuation of SOD2 expression in EPC2T CD44H cells (Fig.	('CD44', 'Gene', '960', (109, 113))	('ZEB2', 'Gene', '9839', (37, 41))	('expression', 'MPA', (89, 99))	('CD44', 'Gene', (109, 113))	('ZEB2', 'Gene', (37, 41))	('SOD2', 'Gene', (84, 88))	('EPC2T', 'CellLine', 'CVCL:4361', (103, 108))	('ZEB1', 'Gene', (51, 55))	('attenuation', 'NegReg', (69, 80))	('ZEB1', 'Gene', '6935', (51, 55))	('knockdown', 'Var', (24, 33))
882657	25659582	SOD2 knockdown raised basal ROS level significantly in CD44L cells (Fig.	('knockdown', 'Var', (5, 14))	('ROS', 'Chemical', 'MESH:D017382', (28, 31))	('raised', 'PosReg', (15, 21))	('basal ROS level', 'MPA', (22, 37))	('CD44', 'Gene', '960', (55, 59))	('CD44', 'Gene', (55, 59))	('SOD2', 'Gene', (0, 4))
882659	25659582	Moreover, SOD2 knockdown made EPC2T CD44L cells prone to ROS induction upon exposure to H2O2, hypoxia or TGF-beta (Figure 5E), indicating that cells expressing lower SOD2 may be more susceptible to oxidative stress.	('SOD2', 'Gene', (10, 14))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('oxidative stress', 'Phenotype', 'HP:0025464', (198, 214))	('knockdown', 'Var', (15, 24))	('EPC2T', 'CellLine', 'CVCL:4361', (30, 35))	('CD44', 'Gene', (36, 40))	('ROS induction', 'MPA', (57, 70))	('TGF-beta', 'Gene', '7040', (105, 113))	('prone', 'PosReg', (48, 53))	('TGF-beta', 'Gene', (105, 113))	('hypoxia', 'Disease', 'MESH:D000860', (94, 101))	('H2O2', 'Chemical', 'MESH:D006861', (88, 92))	('EPC2T', 'Var', (30, 35))	('hypoxia', 'Disease', (94, 101))	('CD44', 'Gene', '960', (36, 40))
882664	25659582	We first asked how SOD2 knockdown may alter the cell distribution within EPC2T where CD44L cells represent the majority of cells.	('CD44', 'Gene', '960', (85, 89))	('cell distribution', 'MPA', (48, 65))	('EPC2T', 'Gene', (73, 78))	('CD44', 'Gene', (85, 89))	('alter', 'Reg', (38, 43))	('knockdown', 'Var', (24, 33))	('EPC2T', 'CellLine', 'CVCL:4361', (73, 78))
882665	25659582	When SOD2 was knocked down by transient transfection, the percentage of CD44H cells was increased within 4 days after siRNA was transfected into the cells (Fig.	('CD44', 'Gene', (72, 76))	('increased', 'PosReg', (88, 97))	('SOD2', 'Gene', (5, 9))	('knocked down', 'Var', (14, 26))	('CD44', 'Gene', '960', (72, 76))
882672	25659582	These "transitioning" cells, designated CD44T, which are induced along with CD44H cells in response to SOD2 knockdown in EPC2T cells (Supplemental Figure S4), have the potential to provide further insight into the dynamic role of SOD2 in EMT and cell fate decisions in response to environmental cues.	('knockdown', 'Var', (108, 117))	('CD44', 'Gene', (40, 44))	('CD44', 'Gene', (76, 80))	('SOD2', 'Gene', (103, 107))	('CD44', 'Gene', '960', (40, 44))	('EPC2T', 'CellLine', 'CVCL:4361', (121, 126))	('CD44', 'Gene', '960', (76, 80))
882680	25659582	Glutathione may be upregulated in the reduced state to exert antioxidant activities in cancer stem cells expressing variant isoforms of CD44 ; however, to date no functional relationship has been established between SOD2 and CD44 despite their potential roles in the redox regulation and malignant properties of cancer cells.	('cancer', 'Disease', (87, 93))	('upregulated', 'PosReg', (19, 30))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('Glutathione', 'Chemical', 'MESH:D005978', (0, 11))	('CD44', 'Gene', (225, 229))	('CD44', 'Gene', '960', (136, 140))	('CD44', 'Gene', (136, 140))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('variant', 'Var', (116, 123))	('cancer', 'Disease', (312, 318))	('antioxidant', 'MPA', (61, 72))	('CD44', 'Gene', '960', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
882682	25659582	EGFR overexpression and p53 mutation).	('p53', 'Gene', (24, 27))	('EGFR', 'Gene', (0, 4))	('p53', 'Gene', '7157', (24, 27))	('overexpression', 'PosReg', (5, 19))	('mutation', 'Var', (28, 36))	('EGFR', 'Gene', '1956', (0, 4))
882689	25659582	NF-kappaB knockdown, however, affected neither ZEB1 nor ZEB2 in EPC2T (Figure 3E), implying a cell-type specific role of NF-kappaB that is independent of regulation of cadherin expression.	('cadherin', 'Gene', '999;1009;1000', (168, 176))	('NF-kappaB', 'Gene', '4790', (0, 9))	('NF-kappaB', 'Gene', (0, 9))	('ZEB1', 'Gene', (47, 51))	('NF-kappaB', 'Gene', '4790', (121, 130))	('EPC2T', 'CellLine', 'CVCL:4361', (64, 69))	('ZEB1', 'Gene', '6935', (47, 51))	('ZEB2', 'Gene', '9839', (56, 60))	('NF-kappaB', 'Gene', (121, 130))	('cadherin', 'Gene', (168, 176))	('knockdown', 'Var', (10, 19))	('ZEB2', 'Gene', (56, 60))
882691	25659582	Interestingly, NF-kappaB knockdown suppressed P7/pGL3 reporter activity sharply in CD44H cells although this construct lacks a known NF-kappaB binding site unlike the I2E-P7/pGL3 construct, suggesting that CD44H cells may have not only a higher NF-kB activity but an increased dependence upon NF-kappaB for SOD2 expression.	('higher', 'PosReg', (238, 244))	('NF-kappaB', 'Gene', (15, 24))	('pGL3', 'Gene', (49, 53))	('NF-kappaB', 'Gene', (133, 142))	('CD44', 'Gene', '960', (206, 210))	('pGL3', 'Gene', '6391', (49, 53))	('CD44', 'Gene', (206, 210))	('NF-kB', 'Enzyme', (245, 250))	('activity', 'MPA', (251, 259))	('NF-kappaB', 'Gene', '4790', (15, 24))	('NF-kappaB', 'Gene', '4790', (133, 142))	('NF-kappaB', 'Gene', (293, 302))	('NF-kappaB', 'Gene', '4790', (293, 302))	('pGL3', 'Gene', (174, 178))	('knockdown', 'Var', (25, 34))	('pGL3', 'Gene', '6391', (174, 178))	('CD44', 'Gene', '960', (83, 87))	('suppressed', 'NegReg', (35, 45))	('CD44', 'Gene', (83, 87))
882692	25659582	Moreover, ZEB2 knockdown had a similar impact upon all constructs (Figure 4C), indicating that ZEB2 may target common cis-elements within the proximal GC-rich basal promoter region (-210 to +24) shared by all constructs even though there is no consensus ZEB binding site within this region.	('-210 to +24', 'Var', (182, 193))	('ZEB2', 'Gene', '9839', (95, 99))	('ZEB2', 'Gene', '9839', (10, 14))	('ZEB2', 'Gene', (95, 99))	('ZEB2', 'Gene', (10, 14))
882726	25659582	RNA isolation, cDNA synthesis and real-time RT-PCR were performed using TaqMan  Gene Expression Assays (Applied Biosystems) for SOD2 (Hs00167309_m1), Catalase (Hs00156308_m1), GPX2 (Hs00702173_s1), GPX7 (Hs00210410_m1), CDH1 (Hs00170423_m1), CDH2 (Hs00983062_m1), ZEB1 (Hs00232783_m1), ZEB2 (Hs00207691_m1) as described .	('ZEB2', 'Gene', (286, 290))	('CDH2', 'Gene', (242, 246))	('GPX2', 'Gene', (176, 180))	('CDH1', 'Gene', '999', (220, 224))	('Hs00702173_s1', 'Var', (182, 195))	('ZEB2', 'Gene', '9839', (286, 290))	('ZEB1', 'Gene', '6935', (264, 268))	('CDH1', 'Gene', (220, 224))	('CDH2', 'Gene', '1000', (242, 246))	('GPX7', 'Gene', '2882', (198, 202))	('Hs00210410_m1', 'Var', (204, 217))	('Hs00170423_m1', 'Var', (226, 239))	('GPX7', 'Gene', (198, 202))	('Hs00232783_m1', 'Var', (270, 283))	('Hs00156308_m1', 'Var', (160, 173))	('Hs00983062_m1', 'Var', (248, 261))	('GPX2', 'Gene', '2877', (176, 180))	('ZEB1', 'Gene', (264, 268))	('Hs00207691_m1', 'Var', (292, 305))	('Hs00167309_m1', 'Var', (134, 147))
882728	25659582	SYBR green was also used to quantitate mRNA for NF-kappaB p65, IL6 and IL8 with paired forward and reverse primers NF-kappaB p65-F (5'-CTCCGCGGGCAGCAT-3') and NF-kappaB p65-R (5'-TCCTGTGTAGCCATTGATCTTGA T-3'); IL-6-F (5'-GCAGAAAAAGGCAAAGAATC-3') and IL-6-R (5'-CTACATTTGCCGAAGAGC-3'); and IL-8-F (5'-CACCGGAAGGAACCATCTCA-3') and IL-8-R (5'-TGGCAAAACTGCACCTT CACA-3').	('IL-8-F', 'Var', (289, 295))	('SYBR green', 'Chemical', '-', (0, 10))	('IL8', 'Gene', (71, 74))	('IL6', 'Gene', '3569', (63, 66))	('IL-6-R', 'Gene', (250, 256))	('NF-kappaB', 'Gene', '4790', (48, 57))	('IL8', 'Gene', '3576', (71, 74))	('IL6', 'Gene', (63, 66))	('NF-kappaB', 'Gene', '4790', (159, 168))	('NF-kappaB', 'Gene', '4790', (115, 124))	('NF-kappaB', 'Gene', (48, 57))	('IL-6-R', 'Gene', '3570', (250, 256))	('NF-kappaB', 'Gene', (115, 124))	('NF-kappaB', 'Gene', (159, 168))
882838	32104079	Deletion of miR146a by antagomiR (complementary sequence of miR-146a that cut off binding miR146a to 3' UTR COX-2) or existence of mutation in 3'-UTR COX2 upregulated COX2 and subsequently prostaglandin that control cell proliferation.	('miR146a', 'Gene', (90, 97))	('miR', 'Gene', '29116', (12, 15))	('miR', 'Gene', '29116', (29, 32))	('miR', 'Gene', '29116', (60, 63))	('COX2', 'Gene', '4513', (167, 171))	('COX2', 'Gene', (150, 154))	('upregulated', 'PosReg', (155, 166))	('miR146a', 'Gene', '406938', (12, 19))	('miR', 'Gene', (12, 15))	('mutation', 'Var', (131, 139))	('miR', 'Gene', '29116', (90, 93))	('miR', 'Gene', (29, 32))	('miR', 'Gene', (60, 63))	('miR146a', 'Gene', '406938', (90, 97))	('men', 'Species', '9606', (40, 43))	('COX2', 'Gene', '4513', (150, 154))	('miR', 'Gene', (90, 93))	('Deletion', 'Var', (0, 8))	('miR-146a', 'Gene', (60, 68))	('COX-2', 'Gene', (108, 113))	("3'-UTR", 'Gene', (143, 149))	('miR-146a', 'Gene', '406938', (60, 68))	('miR146a', 'Gene', (12, 19))	('prostaglandin', 'Chemical', 'MESH:D011453', (189, 202))	('COX2', 'Gene', (167, 171))	('COX-2', 'Gene', '5743', (108, 113))
882839	32104079	Polymorphism in 3'-UTR COX2 may delete the miR-binding site and upregulatesCOX2 expression.	('Polymorphism', 'Var', (0, 12))	('miR', 'Gene', (43, 46))	('COX2', 'Gene', (23, 27))	('delete', 'NegReg', (32, 38))	('COX2', 'Gene', (75, 79))	('COX2', 'Gene', '4513', (23, 27))	('miR', 'Gene', '29116', (43, 46))	('COX2', 'Gene', '4513', (75, 79))	('expression', 'MPA', (80, 90))
882840	32104079	In this study, we assessed miR-146-a and COX-2 expression level in the patients with ESCC who 44% had 8473 SNP in 3'-UTR COX2.	('8473 SNP', 'Var', (102, 110))	('COX-2', 'Gene', (41, 46))	('miR-146-a', 'Gene', '406938', (27, 36))	('COX-2', 'Gene', '5743', (41, 46))	('patients', 'Species', '9606', (71, 79))	('ESCC', 'Disease', (85, 89))	('miR-146-a', 'Gene', (27, 36))	('expression level', 'MPA', (47, 63))	('COX2', 'Gene', (121, 125))	('ESCC', 'Disease', 'MESH:C562729', (85, 89))	('COX2', 'Gene', '4513', (121, 125))
882859	32104079	In our work, 44% of the patients had 8473 T>C polymorphism in 3'-UTR COX2 and miR146a expression was lower in patients with 8473 TC (heterozygote) and CC (mutant) genotypes than TT wild type genotype (Table 2).	('miR146a', 'Gene', '406938', (78, 85))	('patients', 'Species', '9606', (24, 32))	('expression', 'MPA', (86, 96))	('lower', 'NegReg', (101, 106))	('miR146a', 'Gene', (78, 85))	('COX2', 'Gene', (69, 73))	('8473 T>C', 'Mutation', 'rs5275', (37, 45))	('COX2', 'Gene', '4513', (69, 73))	('patients', 'Species', '9606', (110, 118))	('8473 T>C polymorphism', 'Var', (37, 58))
882872	32104079	Kaplan-Meier curve revealed that individuals with high expression of miR146a had a worse overall survival (OS) rather than who have miR146a low expression.	('high expression', 'Var', (50, 65))	('miR146a', 'Gene', (69, 76))	('miR146a', 'Gene', (132, 139))	('miR146a', 'Gene', '406938', (69, 76))	('miR146a', 'Gene', '406938', (132, 139))	('overall survival', 'MPA', (89, 105))
882878	32104079	Survival analysis based on COX2 expression showed patients with low expression COX2 had 8 months shorter life span than high expression (P-value= 0.125) (Table 7, Figure 7).	('patients', 'Species', '9606', (50, 58))	('low expression', 'Var', (64, 78))	('life span', 'CPA', (105, 114))	('COX2', 'Gene', (27, 31))	('COX2', 'Gene', (79, 83))	('shorter', 'NegReg', (97, 104))	('COX2', 'Gene', '4513', (27, 31))	('COX2', 'Gene', '4513', (79, 83))
882885	32104079	This may be described by having a +8473 (TC/CC) SNP (into 3'-UTR COX2) in 44% of the samples, based on our previous project.	('COX2', 'Gene', '4513', (65, 69))	('+8473 (TC/CC', 'Var', (34, 46))	('COX2', 'Gene', (65, 69))
882887	32104079	However, the mutation in 3'-UTR COX2 disrupts the miR-binding site somehow prevents the regulatory effect of miR146a on COX2.	('COX2', 'Gene', (32, 36))	('miR', 'Gene', (50, 53))	('miR', 'Gene', (109, 112))	('COX2', 'Gene', '4513', (32, 36))	('mutation', 'Var', (13, 21))	('prevents', 'NegReg', (75, 83))	('miR', 'Gene', '29116', (50, 53))	('COX2', 'Gene', (120, 124))	('COX2', 'Gene', '4513', (120, 124))	('miR', 'Gene', '29116', (109, 112))	('miR146a', 'Gene', (109, 116))	('disrupts', 'NegReg', (37, 45))	('miR146a', 'Gene', '406938', (109, 116))
882896	32104079	In our study, the Kaplan-Meier curve demonstrated a worse overall survival (OS) for individuals with high expression of miR-146a so they had 7 months shorter life span rather than patients with low expression miR146a that our results are reversed to Wang et al.	('overall survival', 'MPA', (58, 74))	('miR146a', 'Gene', '406938', (209, 216))	('miR-146a', 'Gene', (120, 128))	('worse', 'NegReg', (52, 57))	('patients', 'Species', '9606', (180, 188))	('miR146a', 'Gene', (209, 216))	('shorter', 'NegReg', (150, 157))	('miR-146a', 'Gene', '406938', (120, 128))	('high expression', 'Var', (101, 116))
882910	30940778	Silencing RPN2 effectively inhibited cell proliferation of esophageal cancer cells in vitro and in vivo.	('esophageal cancer', 'Disease', (59, 76))	('cell proliferation of', 'CPA', (37, 58))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('RPN2', 'Gene', (10, 14))	('inhibited', 'NegReg', (27, 36))	('Silencing', 'Var', (0, 9))
882926	30940778	Moreover, RPN2 silencing showed anti-tumor effect on esophageal cancer, while RPN1 knockdown showed no significant effect on esophageal cancer cells.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('RPN1', 'Gene', (78, 82))	('esophageal cancer', 'Disease', (125, 142))	('silencing', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('RPN2', 'Gene', (10, 14))	('esophageal cancer', 'Disease', (53, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('RPN1', 'Gene', '6184', (78, 82))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
882956	30940778	Proteins were then detected with anti-RPN2 (Ab186117; dilution 1:1000), anti-E-cadherin (Ab15148; dilution 1:800), anti-matrix metalloproteinase (MMP-2) (Ab37150; dilution 1:1200), anti-proliferating cell nuclear antigen (PCNA) (Ab18197; dilution 1:800), anti-Snail (Ab53519; dilution 1:800), anti-phosphorylation-Smad2/3 (p-Smad2/3, Ab202445, dilution 1:1000), and Smad2/3 (Ab202445; dilution 1:1000).	('Ab18197; dilution 1:800', 'Var', (229, 252))	('Snail', 'Gene', (260, 265))	('Ab53519; dilution 1:800', 'Var', (267, 290))	('PCNA', 'Gene', (222, 226))	('Ab202445; dilution', 'Var', (375, 393))	('anti-proliferating cell nuclear antigen', 'Gene', (181, 220))	('Snail', 'Gene', '6615', (260, 265))	('E-cadherin', 'Gene', (77, 87))	('MMP-2', 'Gene', (146, 151))	('E-cadherin', 'Gene', '999', (77, 87))	('Ab37150;', 'Var', (154, 162))	('PCNA', 'Gene', '5111', (222, 226))	('anti-proliferating cell nuclear antigen', 'Gene', '5111', (181, 220))	('MMP-2', 'Gene', '4313', (146, 151))
882964	30940778	As expected, the expression of RPN2 was increased significantly in CP-D and CP-C cells compared with Het-1A cells (P<0.001, Figure 1E,F).	('expression', 'MPA', (17, 27))	('CP-D', 'Disease', (67, 71))	('increased', 'PosReg', (40, 49))	('CP-C', 'Var', (76, 80))	('RPN2', 'Gene', (31, 35))	('CP-C', 'Chemical', 'MESH:C015101', (76, 80))
882970	30940778	The tumor-suppressive effect of silencing RPN2 was also studied using in vivo xenograft experiments.	('tumor', 'Disease', (4, 9))	('silencing', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('RPN2', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
882975	30940778	Furthermore, RPN2 knockdown dramatically reduced the tumor size and weight (P<0.001, Figure 2E).	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('RPN2', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
882976	30940778	The protein expression of RPN2 and E-cadherin was then identified by Western blot, and the results showed that E-cadherin expression was decreased significantly in xenografted tumors with shRPN2 transfection compared with that in shNC groups (P<0.001, Figure 2F).	('E-cadherin', 'Gene', '999', (35, 45))	('E-cadherin', 'Gene', (111, 121))	('E-cadherin', 'Gene', '999', (111, 121))	('expression', 'MPA', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', (176, 182))	('transfection', 'Var', (195, 207))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('shRPN2', 'Gene', (188, 194))	('decreased', 'NegReg', (137, 146))	('E-cadherin', 'Gene', (35, 45))
882979	30940778	As shown in Figure 3A, cell migration of esophageal cancer cells was significantly suppressed by siRNP2 treatment compared with siNC treatment (P<0.01).	('siRNP2', 'Gene', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('siRNP2', 'Chemical', '-', (97, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('treatment', 'Var', (104, 113))	('cell migration of', 'CPA', (23, 40))	('suppressed', 'NegReg', (83, 93))	('siNC', 'Chemical', 'MESH:C052464', (128, 132))	('esophageal cancer', 'Disease', (41, 58))
882980	30940778	For CP-D cells, cell invasion rate was decreased to 23.41 +- 3.14% following siRNP2 transfection (Figure 3B).	('cell invasion rate', 'CPA', (16, 34))	('siRNP2', 'Gene', (77, 83))	('siRNP2', 'Chemical', '-', (77, 83))	('decreased', 'NegReg', (39, 48))	('transfection', 'Var', (84, 96))
882981	30940778	Similarly, cell invasion rate of CP-C cells transfected with siRPN2 was decreased to 18.67 +- 2.47% (Figure 3B).	('CP-C', 'Chemical', 'MESH:C015101', (33, 37))	('decreased', 'NegReg', (72, 81))	('cell invasion rate', 'CPA', (11, 29))	('transfected', 'Var', (44, 55))	('siRPN2', 'Gene', (61, 67))
882982	30940778	The results reveal that RPN2 knockdown might attenuate tumor metastasis in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('knockdown', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('attenuate', 'NegReg', (45, 54))	('tumor metastasis', 'Disease', 'MESH:D009362', (55, 71))	('tumor metastasis', 'Disease', (55, 71))	('RPN2', 'Gene', (24, 28))	('esophageal cancer', 'Disease', (75, 92))
882989	30940778	reported that RPN2 silencing induced apoptosis of breast cancer cells in the presence of docetaxel, in vitro and in vivo.	('apoptosis', 'CPA', (37, 46))	('silencing', 'Var', (19, 28))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('RPN2', 'Gene', (14, 18))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('docetaxel', 'Chemical', 'MESH:D000077143', (89, 98))
882991	30940778	demonstrated that siRNA-RPN2 could dramatically suppress the invasion and migration of human nasopharyngeal carcinoma cells through AKT/PI3K signaling.	('suppress', 'NegReg', (48, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('AKT', 'Gene', '207', (132, 135))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (93, 117))	('human', 'Species', '9606', (87, 92))	('nasopharyngeal carcinoma', 'Disease', (93, 117))	('AKT', 'Gene', (132, 135))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (93, 117))	('siRNA-RPN2', 'Var', (18, 28))
882997	30940778	Abnormal expression of oncogene often gives rise to over-proliferation during the development and metastasis of esophageal carcinomas.	('metastasis of esophageal carcinomas', 'Disease', (98, 133))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('Abnormal expression', 'Var', (0, 19))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (112, 133))	('gives rise to', 'Reg', (38, 51))	('metastasis of esophageal carcinomas', 'Disease', 'MESH:D009362', (98, 133))	('oncogene', 'Gene', (23, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('over-proliferation', 'MPA', (52, 70))
882998	30940778	In the present study, we found that knockdown of RPN2 effectively inhibited cell proliferation of esophageal cancer cells.	('knockdown', 'Var', (36, 45))	('RPN2', 'Gene', (49, 53))	('esophageal cancer', 'Disease', (98, 115))	('inhibited', 'NegReg', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cell proliferation of', 'CPA', (76, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
883015	30940778	In summary, we report that elevated RPN2 expression was seen in esophageal cancer and that RPN2 could promote cell proliferation, migration, and invasion of esophageal cancer cells.	('RPN2', 'Var', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('RPN2', 'Gene', (36, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('expression', 'MPA', (41, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('promote', 'PosReg', (102, 109))	('elevated', 'PosReg', (27, 35))	('cell proliferation', 'CPA', (110, 128))	('migration', 'CPA', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('invasion', 'CPA', (145, 153))	('esophageal cancer', 'Disease', (157, 174))
883016	30940778	We also confirmed the anti-tumorigenic effects of silencing RPN2 expression in esophageal cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('RPN2', 'Gene', (60, 64))	('tumor', 'Disease', (27, 32))	('silencing', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
883095	30866690	Of note, during the study period, the cumulative incidence of H&N cancer was significantly higher among non-CHM users as compared with CHM users (Figure 2).	('CHM', 'Disease', 'MESH:D015794', (135, 138))	('CHM', 'Disease', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('H&N cancer', 'Disease', 'MESH:D009369', (62, 72))	('H&N cancer', 'Disease', (62, 72))	('significantly', 'PosReg', (77, 90))	('CHM', 'Disease', 'MESH:D015794', (108, 111))	('CHM', 'Disease', (108, 111))	('among', 'Var', (98, 103))
883142	30866690	It has been demonstrated that Liu-Jun-Zi-Tang exhibited both anti-inflammatory and antioxidative protective effects on mice exposed to cigarette smoke through enhanced activities of antioxidant enzymes and by attenuating the levels of lipid oxidative production through inhibiting phosphorylation of IkappaB-alpha and NF-kappaB.	('antioxidant', 'Enzyme', (182, 193))	('IkappaB-alpha', 'Gene', '18035', (300, 313))	('mice', 'Species', '10090', (119, 123))	('activities', 'MPA', (168, 178))	('inhibiting', 'NegReg', (270, 280))	('N', 'Chemical', 'MESH:D009584', (318, 319))	('IkappaB-alpha', 'Gene', (300, 313))	('phosphorylation', 'MPA', (281, 296))	('enhanced', 'PosReg', (159, 167))	('Liu-Jun-Zi-Tang', 'Var', (30, 45))	('NF-kappaB', 'Protein', (318, 327))	('attenuating', 'NegReg', (209, 220))	('anti-inflammatory', 'CPA', (61, 78))	('levels of lipid oxidative production', 'MPA', (225, 261))	('antioxidative protective', 'CPA', (83, 107))
883143	30866690	Additionally, Liu-Jun-Zi-Tang has been shown to regulate insulin secretion and ameliorate metabolic syndromes, which are beneficial for the prevention of SPC initiation.	('Liu-Jun-Zi-Tang', 'Var', (14, 29))	('insulin secretion', 'Disease', (57, 74))	('SPC', 'Disease', (154, 157))	('metabolic syndromes', 'MPA', (90, 109))	('ameliorate', 'PosReg', (79, 89))	('regulate', 'Reg', (48, 56))	('insulin secretion', 'Disease', 'MESH:D007333', (57, 74))
883154	30866690	Notably, Bu-Zhong-Yi-Qi-Tang has been shown to relieve cancer-related fatigue by enhancing interleukin-18 to induce cell-mediated immunity and improve the host's defensive capabilities.	('fatigue', 'Disease', (70, 77))	('cell-mediated immunity', 'CPA', (116, 138))	('enhancing', 'PosReg', (81, 90))	('fatigue', 'Phenotype', 'HP:0012378', (70, 77))	('interleukin-18', 'Gene', '3606', (91, 105))	('improve', 'PosReg', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Bu-Zhong-Yi-Qi-Tang', 'Var', (9, 28))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('interleukin-18', 'Gene', (91, 105))	('defensive capabilities', 'CPA', (162, 184))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('fatigue', 'Disease', 'MESH:D005221', (70, 77))	('induce', 'PosReg', (109, 115))	('cancer', 'Disease', (55, 61))
883199	29784063	Two ESCC microarray datasets (GSE53624 and GSE53622) generated using the Agilent-038314 CBC Homo sapiens lncRNA + mRNA microarray V2.0 (http://www.genomics.agilent.com/) were selected.	('GSE53622', 'Var', (43, 51))	('Homo sapiens', 'Species', '9606', (92, 104))	('GSE53624', 'Var', (30, 38))
883227	29784063	This analysis demonstrated that the survival-related PCG-lncRNA set in GSE63624 was reduced to three independent principal components PC1, PC2, and PC3, accounting for 99% of the variance of the component space (Fig.	('PC3', 'Gene', (148, 151))	('PC2', 'Gene', '3854', (139, 142))	('PC1', 'Gene', '5167', (134, 137))	('PC3', 'Gene', '10120', (148, 151))	('PC2', 'Gene', (139, 142))	('GSE63624', 'Var', (71, 79))	('PC1', 'Gene', (134, 137))
883237	29784063	Higher expression levels of BEX2 and LINC01800 were associated with longer OS (univariable Cox regression coefficient < 0).	('Cox', 'Gene', (91, 94))	('LINC01800', 'Var', (37, 46))	('BEX2', 'Gene', (28, 32))	('LINC01800', 'Chemical', '-', (37, 46))	('expression', 'MPA', (7, 17))	('OS', 'Chemical', '-', (75, 77))	('longer OS', 'Disease', (68, 77))	('BEX2', 'Gene', '84707', (28, 32))	('Cox', 'Gene', '1351', (91, 94))
883248	29784063	To further investigate the potential biological roles of the three markers, a coexpression network comprising SEMA3A, BEX2, and LINC01800 was constructed by computing Pearson correlation coefficients of the GSE53624 and GSE53622 datasets (Fig.	('GSE53624', 'Var', (207, 215))	('SEMA3A', 'Gene', '10371', (110, 116))	('LINC01800', 'Chemical', '-', (128, 137))	('BEX2', 'Gene', (118, 122))	('SEMA3A', 'Gene', (110, 116))	('GSE53622', 'Gene', (220, 228))	('BEX2', 'Gene', '84707', (118, 122))
883259	29784063	After error testing and pruning, the final tree comprising LINC01800, SEMA3A, and BEX2 achieved the best size, lowest misclassification rate, and smallest complexity parameter.	('SEMA3A', 'Gene', '10371', (70, 76))	('BEX2', 'Gene', '84707', (82, 86))	('LINC01800', 'Var', (59, 68))	('SEMA3A', 'Gene', (70, 76))	('BEX2', 'Gene', (82, 86))	('LINC01800', 'Chemical', '-', (59, 68))
883285	28744596	In particular, low LMR, low NLR, and high PLR are each known to be strong predictors of postoperative survival in several types of cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('low LMR', 'Var', (15, 22))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('low', 'Var', (24, 27))
883313	28744596	For the PLR, the AUC and cutoff level for predicting CSS were 0.65 and 147, respectively, with a sensitivity of 59.6% and a specificity of 68.4%.	('CSS', 'Disease', (53, 56))	('0.65', 'Var', (62, 66))	('CSS', 'Chemical', '-', (53, 56))
883316	28744596	The potential prognostic factors for esophageal cancer were as follows: age (<70 vs. >=70 years); sex; TNM pathologic stage (I and II vs. III); tumor size (<3 cm vs. >=3 cm); operation time (<600 min vs. >=600 min); intraoperative blood loss (<500 mL vs. >=500 mL); LMR (<4 vs. >=4); NLR (<1.6 vs. >=1.6); PLR (<147 vs. >=147); serum SCC antigen level (<1.5 ng/ml vs. >=1.5 ng/ml); and IRB score (2 or 3 vs. 0 or 1).	('tumor', 'Disease', (144, 149))	('<147', 'Var', (311, 315))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('TNM', 'Gene', '10178', (103, 106))	('SCC', 'Gene', (334, 337))	('SCC', 'Phenotype', 'HP:0002860', (334, 337))	('intraoperative blood loss', 'Disease', (216, 241))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (216, 241))	('SCC', 'Gene', '6317', (334, 337))	('esophageal cancer', 'Disease', (37, 54))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('TNM', 'Gene', (103, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
883321	28744596	It was notable that the LMR significantly correlated with more advanced TNM pathologic stages, while the NLR and PLR did not.	('TNM', 'Gene', '10178', (72, 75))	('TNM', 'Gene', (72, 75))	('LMR', 'Var', (24, 27))	('correlated', 'Reg', (42, 52))
883333	28744596	Among non-elderly patients, univariate analyses showed that the TNM pStage (p < 0.0001), tumor size (p = 0.001), LMR (p = 0.0045), PLR (p = 0.0439), and IRB score (p = 0.0021) were significantly associated with a worse prognosis (Table 6).	('TNM', 'Gene', (64, 67))	('PLR', 'Var', (131, 134))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('TNM', 'Gene', '10178', (64, 67))
883357	28744596	We suggested that low LMR, low NLR, or high PLR independently predicts disease recurrence and shorter survival in esophageal SCC patients.	('high', 'Var', (39, 43))	('patients', 'Species', '9606', (129, 137))	('shorter', 'NegReg', (94, 101))	('disease', 'Disease', (71, 78))	('SCC', 'Gene', (125, 128))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('low', 'Var', (27, 30))	('SCC', 'Gene', '6317', (125, 128))	('low LMR', 'Var', (18, 25))
883403	28809342	The reaction between 3PS* and 1PS leads to PS anion and cation radicals, PS-  and PS+ , respectively.	('cation radicals', 'MPA', (56, 71))	('PS anion', 'Chemical', '-', (43, 51))	('PS anion', 'MPA', (43, 51))	('PS', 'Chemical', 'MESH:D010758', (73, 75))	('leads to', 'Reg', (34, 42))	('PS', 'Chemical', 'MESH:D010758', (43, 45))	('PS+', 'Chemical', 'MESH:D010758', (82, 85))	('PS', 'Chemical', 'MESH:D010758', (22, 24))	('PS', 'Chemical', 'MESH:D010758', (82, 84))	('3PS*', 'Var', (21, 25))	('PS', 'Chemical', 'MESH:D010758', (31, 33))
883406	28809342	O2-  formation from 3PS*, however, competes with the production of singlet oxygen (type II).	('O2-', 'Chemical', '-', (0, 3))	('singlet oxygen', 'Chemical', 'MESH:D026082', (67, 81))	('3PS*', 'Var', (20, 24))	('O2-  formation', 'MPA', (0, 14))	('PS', 'Chemical', 'MESH:D010758', (21, 23))
883408	28809342	The subsequent steps include reduction of Fe3+ by O2- , and Fe2+ reaction with hydrogen peroxide to form a hydroxyl radical.	('reduction', 'MPA', (29, 38))	('Fe2+', 'Var', (60, 64))	('O2-', 'Chemical', '-', (50, 53))	('hydroxyl radical', 'Chemical', 'MESH:D017665', (107, 123))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (79, 96))
883452	28809342	m-THPP, however, caused skin phototoxicity, but not as severely as the ortho isomer.	('m-THPP', 'Var', (0, 6))	('toxicity', 'Disease', 'MESH:D064420', (34, 42))	('m-THPP', 'Chemical', '-', (0, 6))	('toxicity', 'Disease', (34, 42))
883454	28809342	TPPS4 exhibited lower photochemical efficiency than meso-substituted porphyrins containing fewer sulfonate groups.	('photochemical efficiency', 'MPA', (22, 46))	('TPPS4', 'Var', (0, 5))	('sulfonate', 'Chemical', '-', (97, 106))	('TPPS4', 'Chemical', '-', (0, 5))	('lower', 'NegReg', (16, 21))	('meso-substituted porphyrins', 'Chemical', '-', (52, 79))
883458	28809342	The final step in heme formation by enzyme ferrochelatase is a rate-limiting step, and excess ALA accumulates PpIX in the mitochondria before it slowly transforms into heme.	('heme', 'Chemical', 'MESH:D006418', (168, 172))	('ferrochelatase', 'Gene', (43, 57))	('PpIX', 'Var', (110, 114))	('PpIX', 'Chemical', 'MESH:C028025', (110, 114))	('heme', 'Chemical', 'MESH:D006418', (18, 22))	('ALA', 'Chemical', 'MESH:C000614854', (94, 97))	('ferrochelatase', 'Gene', '2235', (43, 57))
883467	28809342	Phase II trials are underway for treatment of cervical intraepithelial neoplasia (NCT01256424), and Phase II/III trials are ongoing for genital erosive lichen planus (NCT01282515).	('NCT01256424', 'Var', (82, 93))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (46, 80))	('cervical intraepithelial neoplasia', 'Disease', 'MESH:D018290', (46, 80))	('cervical intraepithelial neoplasia', 'Disease', (46, 80))	('neoplasia', 'Phenotype', 'HP:0002664', (71, 80))	('NCT01282515', 'Var', (167, 178))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (55, 80))	('genital erosive lichen planus', 'Disease', (136, 165))
883488	28809342	HPPH is currently in Phase II trials for lung cancer (NCT00528775) and esophageal cancer at precancerous or early stage conditions (NCT00281736), in Phase I trials for treating dysplasia, carcinoma of the oral cavity, carcinoma of the oropharynx (NCT01140178), and head and neck cancer (NCT00670397), and in phase I/II trials involving Barrett's esophagus (NCT01236443).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (82, 88))	('carcinoma', 'Disease', 'MESH:D002277', (188, 197))	('cancer', 'Disease', (279, 285))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('HPPH', 'Chemical', '-', (0, 4))	('carcinoma', 'Disease', 'MESH:D002277', (218, 227))	('head and neck cancer', 'Phenotype', 'HP:0012288', (265, 285))	('cancer', 'Disease', (95, 101))	('dysplasia', 'Disease', (177, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('NCT00281736', 'Var', (132, 143))	('dysplasia', 'Disease', 'MESH:D004476', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('NCT00528775', 'Var', (54, 65))	('cancer', 'Disease', (46, 52))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (336, 355))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('head and neck cancer', 'Disease', 'MESH:D006258', (265, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('carcinoma', 'Disease', (188, 197))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('lung cancer', 'Disease', (41, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('carcinoma of the oral', 'Phenotype', 'HP:0100649', (188, 209))	('esophageal cancer', 'Disease', (71, 88))	('carcinoma', 'Disease', (218, 227))
883525	28809342	This cyanine sensitizer has been evaluated for PDT in preclinical and in vitro models for treatment of leukemia and neuroblastoma where it produced considerable cellular damage.	('PDT', 'Var', (47, 50))	('neuroblastoma', 'Disease', 'MESH:D009447', (116, 129))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('neuroblastoma', 'Disease', (116, 129))	('leukemia', 'Disease', 'MESH:D007938', (103, 111))	('leukemia', 'Disease', (103, 111))	('cyanine', 'Chemical', 'MESH:C009469', (5, 12))	('neuroblastoma', 'Phenotype', 'HP:0003006', (116, 129))	('D', 'Species', '9606', (48, 49))
883562	28465643	PIK3CA gene mutations in Northwest Chinese esophageal squamous cell carcinoma To evaluate PIK3CA gene mutational status in Northwest Chinese esophageal squamous cell carcinoma (ESCC) patients, and examine the associations of PIK3CA gene mutations with clinicopathological characteristics and clinical outcome.	('esophageal squamous cell carcinoma', 'Disease', (43, 77))	('PIK3CA', 'Gene', (225, 231))	('associations', 'Interaction', (209, 221))	('PIK3CA', 'Gene', '5290', (225, 231))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (141, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('mutations', 'Var', (12, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('PIK3CA', 'Gene', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('PIK3CA', 'Gene', (90, 96))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (43, 77))	('PIK3CA', 'Gene', '5290', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))	('PIK3CA', 'Gene', '5290', (90, 96))	('patients', 'Species', '9606', (183, 191))
883564	28465643	Pyrosequencing was applied to investigate mutations in exons 9 and 20 of PIK3CA gene in 210 Northwest Chinese ESCCs.	('PIK3CA', 'Gene', '5290', (73, 79))	('mutations', 'Var', (42, 51))	('PIK3CA', 'Gene', (73, 79))
883566	28465643	PIK3CA gene mutations in exon 9 were detected in 48 cases (22.9%) of a non-biased database of 210 curatively resected Northwest Chinese ESCCs.	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', '5290', (0, 6))	('detected', 'Reg', (37, 45))	('PIK3CA', 'Gene', (0, 6))
883567	28465643	PIK3CA gene mutations were not associated with sex, tobacco use, alcohol use, tumor location, stage, or local recurrence.	('alcohol use', 'Phenotype', 'HP:0030955', (65, 76))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (31, 41))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PIK3CA', 'Gene', '5290', (0, 6))	('tobacco', 'Species', '4097', (52, 59))	('alcohol', 'Chemical', 'MESH:D000438', (65, 72))	('tumor', 'Disease', (78, 83))
883568	28465643	When compared with wild-type PIK3CA gene cases, patients with PIK3CA gene mutations in exons 9 experienced significantly better disease-free survival and overall survival rates.	('overall survival', 'CPA', (154, 170))	('PIK3CA', 'Gene', (62, 68))	('mutations in', 'Var', (74, 86))	('better', 'PosReg', (121, 127))	('disease-free survival', 'CPA', (128, 149))	('PIK3CA', 'Gene', '5290', (62, 68))	('PIK3CA', 'Gene', (29, 35))	('patients', 'Species', '9606', (48, 56))	('PIK3CA', 'Gene', '5290', (29, 35))
883569	28465643	The results of this study suggest that PIK3CA gene mutations could act as a prognostic biomarker in Northwest Chinese ESCC patients.	('PIK3CA', 'Gene', (39, 45))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (123, 131))	('PIK3CA', 'Gene', '5290', (39, 45))
883570	28465643	Core tip: PIK3CA gene mutations have been associated with various prognoses in patients with different cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('associated', 'Reg', (42, 52))	('PIK3CA', 'Gene', (10, 16))	('patients', 'Species', '9606', (79, 87))	('mutations', 'Var', (22, 31))	('PIK3CA', 'Gene', '5290', (10, 16))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
883571	28465643	However, no large-scale study has examined the prognostic impact of PIK3CA gene mutations in Northwest Chinese esophageal squamous cell carcinoma (ESCC).	('PIK3CA', 'Gene', (68, 74))	('mutations', 'Var', (80, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (111, 145))	('PIK3CA', 'Gene', '5290', (68, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('esophageal squamous cell carcinoma', 'Disease', (111, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
883573	28465643	It was found that PIK3CA gene mutations in Northwest Chinese ESCC are associated with favorable prognoses.	('PIK3CA', 'Gene', (18, 24))	('mutations', 'Var', (30, 39))	('PIK3CA', 'Gene', '5290', (18, 24))
883574	28465643	It has been suggested that PIK3CA gene mutational status can have a potential role as a prognostic biomarker for ESCC.	('mutational status', 'Var', (39, 56))	('ESCC', 'Disease', (113, 117))	('PIK3CA', 'Gene', '5290', (27, 33))	('PIK3CA', 'Gene', (27, 33))
883576	28465643	As one of the most commonly diagnosed cancers among men in China, the estimated number of new cases of esophageal cancer was 291238 in 2011, while the numbers of deaths was 218957 in the same year; by 2015, these numbers had increased to 477900 and 375000, respectively.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('esophageal cancer', 'Disease', (103, 120))	('men', 'Species', '9606', (52, 55))	('deaths', 'Disease', 'MESH:D003643', (162, 168))	('deaths', 'Disease', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('291238', 'Var', (125, 131))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))
883581	28465643	The mutant PIK3CA gene stimulates the AKT pathway and promotes cell growth and invasion in various types of human cancer (Samuels, 2004 #620; Samuels, 2005 #638), including lung, breast, gastric, and colon.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('AKT', 'Gene', (38, 41))	('mutant', 'Var', (4, 10))	('stimulates', 'PosReg', (23, 33))	('breast', 'Disease', (179, 185))	('cancer', 'Disease', (114, 120))	('PIK3CA', 'Gene', (11, 17))	('AKT', 'Gene', '207', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (108, 113))	('PIK3CA', 'Gene', '5290', (11, 17))	('gastric', 'Disease', (187, 194))	('lung', 'Disease', (173, 177))	('invasion', 'CPA', (79, 87))	('colon', 'Disease', (200, 205))	('cell growth', 'CPA', (63, 74))	('promotes', 'PosReg', (54, 62))
883582	28465643	PIK3CA gene mutations have also been detected in Japanese and Korean ESCCs.	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))
883585	28465643	We therefore quantified PIK3CA gene mutations in 210 samples of curatively resected ESCCs using pyrosequencing, and examined the prognostic significance of PIK3CA gene mutations in Northwest Chinese ESCC patients.	('patients', 'Species', '9606', (204, 212))	('PIK3CA', 'Gene', (24, 30))	('PIK3CA', 'Gene', '5290', (156, 162))	('mutations', 'Var', (36, 45))	('PIK3CA', 'Gene', '5290', (24, 30))	('PIK3CA', 'Gene', (156, 162))
883594	28465643	Two sets of primers (Table 1) were used for the detection of any mutation points in exons 9 and 20 of the PIK3CA gene.	('PIK3CA', 'Gene', (106, 112))	('mutation points', 'Var', (65, 80))	('PIK3CA', 'Gene', '5290', (106, 112))
883599	28465643	The association between PIK3CA gene mutations and clinicopathological variables were performed using the chi2-test or Fisher's exact probability test.	('PIK3CA', 'Gene', '5290', (24, 30))	('mutations', 'Var', (36, 45))	('PIK3CA', 'Gene', (24, 30))
883601	28465643	In this study, PIK3CA gene mutations were only observed in exon 9 in 48 (22.9%) of 210 Northwest Chinese ESCC samples.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', '5290', (15, 21))	('PIK3CA', 'Gene', (15, 21))
883602	28465643	The most common mutation of PIK3CA exon 9 was the c.1634A>C (p.E545A) mutation, which was present in 35 tumors, followed by c.1633G>A (p.E545K) in 13 tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('c.1634A>C', 'Var', (50, 59))	('PIK3CA', 'Gene', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('c.1633G>A', 'Var', (124, 133))	('p.E545A', 'Mutation', 'rs121913274', (61, 68))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('c.1634A>C', 'Mutation', 'rs121913274', (50, 59))	('PIK3CA', 'Gene', '5290', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('c.1633G>A', 'Mutation', 'rs104886003', (124, 133))	('p.E545K', 'Mutation', 'rs104886003', (135, 142))
883603	28465643	We examined whether the influence of PIK3CA gene mutations on cancer-specific survival was modified by any of the evaluated clinical, pathologic, or epidemiologic variables of the ESCCs.	('PIK3CA', 'Gene', '5290', (37, 43))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('modified', 'Reg', (91, 99))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('PIK3CA', 'Gene', (37, 43))
883604	28465643	As a result, we found that PIK3CA gene mutations were not significantly associated with any of the evaluated characteristics of ESCCs, namely sex (male vs female), tobacco use (yes vs no), alcohol use (yes vs no), tumor location (upper, middle vs lower thoracic), preoperative treatment (yes vs no), lymph node metastasis (yes vs no), or local recurrence (yes vs no) (all P > 0.01; Table 3).	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tobacco', 'Species', '4097', (164, 171))	('alcohol use', 'Phenotype', 'HP:0030955', (189, 200))	('associated', 'Reg', (72, 82))	('PIK3CA', 'Gene', (27, 33))	('mutations', 'Var', (39, 48))	('local recurrence', 'CPA', (338, 354))	('men', 'Species', '9606', (282, 285))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (214, 219))	('PIK3CA', 'Gene', '5290', (27, 33))	('alcohol', 'Chemical', 'MESH:D000438', (189, 196))	('ESCCs', 'Disease', (128, 133))
883608	28465643	In the Kaplan-Meier analysis, patients with PIK3CA gene mutations experienced significantly longer disease-free survival (log rank P = 0.0094), cancer-specific survival (log rank P = 0.0059), and overall survival (log rank P = 0.0066) rates than those with the wild-type PIK3CA gene (Figure 1).	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (56, 65))	('disease-free survival', 'CPA', (99, 120))	('PIK3CA', 'Gene', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PIK3CA', 'Gene', '5290', (44, 50))	('cancer', 'Disease', (144, 150))	('patients', 'Species', '9606', (30, 38))	('PIK3CA', 'Gene', '5290', (271, 277))	('overall survival', 'CPA', (196, 212))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('longer', 'PosReg', (92, 98))
883611	28465643	PIK3CA gene mutations and the subsequent activation of the PI3K/AKT pathway are considered to play a crucial role in cancer cell signaling pathways downstream of growth factors, cytokines, and other cellular stimuli in human neoplasm.	('human', 'Species', '9606', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (12, 21))	('neoplasm', 'Disease', (225, 233))	('AKT', 'Gene', '207', (64, 67))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('neoplasm', 'Disease', 'MESH:D009369', (225, 233))	('neoplasm', 'Phenotype', 'HP:0002664', (225, 233))	('activation', 'PosReg', (41, 51))	('cancer', 'Disease', (117, 123))	('AKT', 'Gene', (64, 67))
883612	28465643	We therefore conducted this study to examine the prognostic impact of PIK3CA gene mutations among 210 Northwest Chinese patients with curatively resected ESCC.	('PIK3CA', 'Gene', (70, 76))	('mutations', 'Var', (82, 91))	('PIK3CA', 'Gene', '5290', (70, 76))	('patients', 'Species', '9606', (120, 128))
883613	28465643	In this study, we identified PIK3CA gene mutations in 48 out of 210 (22.9%) Northwest Chinese patients with curatively resected ESCC, which is a rate similar to that previously observed in ESCC (21%), colorectal cancer (32%), and breast cancer (25%-40%), but slightly higher than that for gastric cancers (4.3%) and brain tumors (5%).	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('brain tumors', 'Disease', (316, 328))	('breast cancer', 'Disease', (230, 243))	('gastric cancers', 'Disease', 'MESH:D013274', (289, 304))	('tumors', 'Phenotype', 'HP:0002664', (322, 328))	('gastric cancers', 'Phenotype', 'HP:0012126', (289, 304))	('gastric cancers', 'Disease', (289, 304))	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (94, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (201, 218))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('ESCC', 'Disease', (128, 132))	('PIK3CA', 'Gene', '5290', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('brain tumors', 'Disease', 'MESH:D001932', (316, 328))	('brain tumors', 'Phenotype', 'HP:0030692', (316, 328))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('colorectal cancer', 'Disease', 'MESH:D015179', (201, 218))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('ESCC', 'Disease', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('PIK3CA', 'Gene', (29, 35))	('colorectal cancer', 'Disease', (201, 218))
883616	28465643	When identifying PIK3CA gene mutations, other researchers typically use direct sequencing rather than the pyrosequencing used in the current study, which is a reliable high-throughput method that could be used as an alternative method for genotyping mutation studies.	('PIK3CA', 'Gene', (17, 23))	('mutations', 'Var', (29, 38))	('PIK3CA', 'Gene', '5290', (17, 23))
883618	28465643	Additionally, pyrosequencing has been shown to be more sensitive than regular sequencing in detecting EGFR and KRAS mutations in lung cancer patients.	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('KRAS', 'Gene', (111, 115))	('KRAS', 'Gene', '3845', (111, 115))	('mutations', 'Var', (116, 125))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('patients', 'Species', '9606', (141, 149))
883621	28465643	Previous studies examining the relationship between PIK3CA gene mutations and prognosis in human cancers have yielded variable results and showed that PIK3CA gene mutational status is not associated with ESCC patient survival, although it does denote a better prognosis in breast cancer and ovarian cancer.	('better', 'PosReg', (253, 259))	('mutational', 'Var', (163, 173))	('ovarian cancer', 'Disease', (291, 305))	('PIK3CA', 'Gene', (52, 58))	('human cancers', 'Disease', 'MESH:D009369', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('ovarian cancer', 'Phenotype', 'HP:0100615', (291, 305))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('PIK3CA', 'Gene', '5290', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('PIK3CA', 'Gene', '5290', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('breast cancer', 'Disease', (273, 286))	('ovarian cancer', 'Disease', 'MESH:D010051', (291, 305))	('patient', 'Species', '9606', (209, 216))	('PIK3CA', 'Gene', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('human cancers', 'Disease', (91, 104))
883623	28465643	We conducted this study to explore the prognostic impact of PIK3CA gene mutations among 210 Northwest Chinese patients with curatively resected ESCC.	('mutations', 'Var', (72, 81))	('PIK3CA', 'Gene', '5290', (60, 66))	('patients', 'Species', '9606', (110, 118))	('PIK3CA', 'Gene', (60, 66))
883624	28465643	It was revealed that PIK3CA gene mutations were associated with a favorable prognosis among patients with curatively resected ESCC, suggesting PIK3CA gene mutational status may be a prognostic biomarker for Northwest Chinese ESCC patients that can be used to identify the clinical outcome of patients with curatively resected ESCC, which is consistent with its roles in Japanese ESCC patients.	('PIK3CA', 'Gene', (143, 149))	('PIK3CA', 'Gene', (21, 27))	('ESCC', 'Disease', (326, 330))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (384, 392))	('PIK3CA', 'Gene', '5290', (143, 149))	('PIK3CA', 'Gene', '5290', (21, 27))	('patients', 'Species', '9606', (292, 300))
883625	28465643	Nonetheless, our findings regarding the correlation between PIK3CA mutations and favorable prognosis in esophageal cancer requires further confirmation by future independent studies using much larger non-biased cohorts of ESCCs.	('PIK3CA', 'Gene', (60, 66))	('PIK3CA', 'Gene', '5290', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (67, 76))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))
883626	28465643	In summary, this study suggests that PIK3CA gene mutations are associated with a favorable clinical outcome in operational resected ESCC, which supports the PIK3CA gene's role as a prognostic biomarker for ESCC.	('PIK3CA', 'Gene', '5290', (37, 43))	('mutations', 'Var', (49, 58))	('associated', 'Reg', (63, 73))	('PIK3CA', 'Gene', (157, 163))	('PIK3CA', 'Gene', '5290', (157, 163))	('PIK3CA', 'Gene', (37, 43))
883627	28465643	Our data correlates with that of previous studies suggesting that the acquisition of PIK3CA gene mutations may be an important molecular event in the etiology of a wide range of tumor types and highlights the potential broad applicability that the PIK3CA gene may have in the clinical outcome of human cancers.	('mutations', 'Var', (97, 106))	('human cancers', 'Disease', (296, 309))	('tumor', 'Disease', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('PIK3CA', 'Gene', '5290', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('PIK3CA', 'Gene', (248, 254))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('human cancers', 'Disease', 'MESH:D009369', (296, 309))	('PIK3CA', 'Gene', '5290', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('PIK3CA', 'Gene', (85, 91))
883628	28465643	Future studies are needed to confirm this association and clarify the exact molecular mechanisms by which PIK3CA gene mutations affects human cancer behavior.	('human', 'Species', '9606', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('PIK3CA', 'Gene', (106, 112))	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PIK3CA', 'Gene', '5290', (106, 112))	('affects', 'Reg', (128, 135))	('cancer', 'Disease', (142, 148))
883632	28465643	High frequencies of somatic mutations conferring oncogenic potential have been found in the PIK3CA gene, which is associated with poor prognosis in patients with colorectal or lung cancer.	('patients', 'Species', '9606', (148, 156))	('PIK3CA', 'Gene', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PIK3CA', 'Gene', '5290', (92, 98))	('oncogenic potential', 'MPA', (49, 68))	('colorectal or lung cancer', 'Disease', (162, 187))	('associated', 'Reg', (114, 124))	('colorectal or lung cancer', 'Disease', 'MESH:D015179', (162, 187))	('mutations', 'Var', (28, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
883633	28465643	In contrast, a relationship between PIK3CA gene mutations and favorable prognoses has been shown in breast cancer.	('PIK3CA', 'Gene', '5290', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('PIK3CA', 'Gene', (36, 42))	('mutations', 'Var', (48, 57))
883635	28465643	The frequency of PIK3CA gene mutation in ESCC varied from 0% to 21%, which could likely introduce some bias in the statistical analyses of their clinical significance.	('mutation', 'Var', (29, 37))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))
883636	28465643	More than 80% of PIK3CA gene mutations detected were localized in exons 9 and 20 (helical and kinase domain), with three "hot-spot" mutations: E542K, E545K, and H1047R.	('E542K', 'Mutation', 'rs121913273', (143, 148))	('E545K', 'Mutation', 'rs104886003', (150, 155))	('H1047R', 'Mutation', 'rs121913279', (161, 167))	('E545K', 'Var', (150, 155))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('H1047R', 'Var', (161, 167))	('E542K', 'Var', (143, 148))
883637	28465643	A recent report correlated with previous studies suggesting that the acquisition of PIK3CA mutations may be an important molecular event in the etiology of ESCC, and that mutations are associated with their clinical outcome.	('PIK3CA', 'Gene', '5290', (84, 90))	('associated', 'Reg', (185, 195))	('mutations', 'Var', (91, 100))	('PIK3CA', 'Gene', (84, 90))	('mutations', 'Var', (171, 180))	('ESCC', 'Disease', (156, 160))
883638	28465643	This is, by far, one of the largest studies on the prognostic role of PIK3CA gene mutations in Northwest Chinese ESCC to date, and it shows that PIK3CA gene mutations in ESCC are associated with a favorable prognoses.	('PIK3CA', 'Gene', (70, 76))	('mutations', 'Var', (157, 166))	('PIK3CA', 'Gene', (145, 151))	('PIK3CA', 'Gene', '5290', (145, 151))	('PIK3CA', 'Gene', '5290', (70, 76))
883639	28465643	It has been suggested that PIK3CA gene mutational status can have a potential role as a prognostic biomarker for ESCC patients.	('ESCC', 'Disease', (113, 117))	('PIK3CA', 'Gene', (27, 33))	('mutational status', 'Var', (39, 56))	('PIK3CA', 'Gene', '5290', (27, 33))	('patients', 'Species', '9606', (118, 126))
883640	28465643	PIK3CA gene mutations are associated with a favorable clinical outcome in operational resected Northwest Chinese ESCC patients, thereby suggesting that the acquisition of PIK3CA gene mutations may be an important molecular event in the etiology of a wide range of tumor types and highlighting the potential broad applicability that PIK3CA gene may have in the clinical outcome of human cancers.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('PIK3CA', 'Gene', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (386, 393))	('tumor', 'Disease', (264, 269))	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', (332, 338))	('PIK3CA', 'Gene', '5290', (171, 177))	('human cancers', 'Disease', 'MESH:D009369', (380, 393))	('PIK3CA', 'Gene', '5290', (332, 338))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('human cancers', 'Disease', (380, 393))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('patients', 'Species', '9606', (118, 126))
883643	28465643	The authors examined the associations of PIK3CA gene mutations with clinicopathological characteristics and clinical outcome in esophageal squamous cell carcinoma patients in Northwest China.	('associations', 'Interaction', (25, 37))	('patients', 'Species', '9606', (163, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (128, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('PIK3CA', 'Gene', (41, 47))	('mutations', 'Var', (53, 62))	('PIK3CA', 'Gene', '5290', (41, 47))	('esophageal squamous cell carcinoma', 'Disease', (128, 162))
883644	28465643	The study suggests that PIK3CA gene mutations are associated with a favorable clinical outcome in esophageal squamous cell cancer and that in the future the evaluation of PIK3CA gene mutations may be potentially applied as a prognostic marker.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PIK3CA', 'Gene', (171, 177))	('PIK3CA', 'Gene', (24, 30))	('PIK3CA', 'Gene', '5290', (171, 177))	('mutations', 'Var', (36, 45))	('esophageal squamous cell cancer', 'Disease', (98, 129))	('PIK3CA', 'Gene', '5290', (24, 30))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (109, 129))	('associated', 'Reg', (50, 60))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (98, 129))
883772	25071900	A first GWAS report demonstrated that variants at two loci were associated with disease risk; chromosome 6p21 (OR, 1.21; 95% CI, 1.13 to 1.28), within the major histocompatibility complex locus, and chromosome 16q24 (OR, 1.14; 95% CI, 1.10 to 1.19), in close proximity to FOXF1 gene, which is implicated in esophageal development and structure.	('associated', 'Reg', (64, 74))	('variants', 'Var', (38, 46))	('FOXF1', 'Gene', '2294', (272, 277))	('disease', 'Disease', (80, 87))	('men', 'Species', '9606', (325, 328))	('FOXF1', 'Gene', (272, 277))
883773	25071900	Three new association loci were identified; 19p13 within CRTC1, whose activation has been associated with oncogenic activity, 9q22 within BARX1, which encodes a transcription factor involved in esophageal specification and 3p14 near the transcription factor FOXP1, which regulates esophageal development.	('CRTC1', 'Gene', (57, 62))	('BARX1', 'Gene', (138, 143))	('men', 'Species', '9606', (299, 302))	('FOXP1', 'Gene', '27086', (258, 263))	('CRTC1', 'Gene', '23373', (57, 62))	('p14', 'Gene', (224, 227))	('BARX1', 'Gene', '56033', (138, 143))	('FOXP1', 'Gene', (258, 263))	('p14', 'Gene', '1029', (224, 227))	('9q22', 'Var', (126, 130))
883782	25071900	In addition, acquired deregulation of HOX genes during adulthood has been linked to carcinogenesis.	('carcinogenesis', 'Disease', (84, 98))	('HOX genes', 'Gene', (38, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))	('linked', 'Reg', (74, 80))	('deregulation', 'Var', (22, 34))
883787	25071900	In addition, oxidative DNA damage in BE causes telomerase activation and telomere instability, which are known to result in mutation of cancer-related genes and promotion of cancer.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('telomere instability', 'CPA', (73, 93))	('telomerase', 'CPA', (47, 57))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (136, 142))	('mutation', 'Var', (124, 132))	('activation', 'PosReg', (58, 68))	('oxidative', 'Var', (13, 22))	('promotion', 'PosReg', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
883794	25071900	Wu and collaborators showed that the lncRNA AFAP1-AS1 is hypo-methylated and overexpressed in BE and EAC and its silencing in vitro inhibited invasion and promoted apoptosis.	('inhibited', 'NegReg', (132, 141))	('AFAP1', 'Gene', '60312', (44, 49))	('AS1', 'Gene', '5729', (50, 53))	('AFAP1', 'Gene', (44, 49))	('AS1', 'Gene', (50, 53))	('apoptosis', 'CPA', (164, 173))	('promoted', 'PosReg', (155, 163))	('silencing', 'Var', (113, 122))	('invasion', 'CPA', (142, 150))
883805	25071900	The large Northern Irish population study has also found that the presence of intestinal metaplasia (IM) was associated with a hazard ratio for progression to cancer of 3.54 (95% CI, 2.09 to 6.00).	('cancer', 'Disease', (159, 165))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (78, 99))	('presence', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('intestinal metaplasia', 'Disease', (78, 99))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
883813	25071900	Gain or more rarely loss of individual chromosomes (aneuploidy) or duplication of the entire genome (tetraploidy) are common events in EAC and can precede the development of cancer or even dysplasia (Fig.	('dysplasia', 'Disease', 'MESH:D004476', (189, 198))	('aneuploidy', 'Disease', (52, 62))	('EAC', 'Disease', (135, 138))	('Gain', 'PosReg', (0, 4))	('cancer', 'Disease', (174, 180))	('men', 'Species', '9606', (166, 169))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('aneuploidy', 'Disease', 'MESH:D000782', (52, 62))	('loss', 'NegReg', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('duplication', 'Var', (67, 78))	('dysplasia', 'Disease', (189, 198))
883815	25071900	In particular loss of heterozygosity at tumor suppressor genes, such as p16 and p53, have been linked to acquisition of dysplasia in BE.	('p16', 'Gene', '1029', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('p53', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('loss of heterozygosity', 'Var', (14, 36))	('dysplasia', 'Disease', (120, 129))	('p53', 'Gene', '7157', (80, 83))	('p16', 'Gene', (72, 75))	('linked', 'Reg', (95, 101))	('tumor', 'Disease', (40, 45))	('dysplasia', 'Disease', 'MESH:D004476', (120, 129))
883820	25071900	In a follow-up study three biomarkers (abnormal DNA content, p53 LOH, and p16 LOH) were evaluated as a panel in a cohort of 243 patients, and a step-wise increase in the cancer progression risk was found with increasing number of positive biomarkers.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('p16', 'Gene', (74, 77))	('p53', 'Gene', (61, 64))	('cancer', 'Disease', (170, 176))	('p16', 'Gene', '1029', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('abnormal', 'Var', (39, 47))	('p53', 'Gene', '7157', (61, 64))	('increase', 'PosReg', (154, 162))	('patients', 'Species', '9606', (128, 136))
883829	25071900	The same group used FISH to detect copy changes of cancer-related genes, such as c-myc, EGFR, and 20q13 locus, which were found to be amplified in up to 14% and 50% of cases with HGD and EAC, respectively.	('20q13 locus', 'Gene', (98, 109))	('EAC', 'Disease', (187, 190))	('copy changes', 'Var', (35, 47))	('c-myc', 'Gene', '4609', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('EGFR', 'Gene', '1956', (88, 92))	('HGD', 'Disease', (179, 182))	('cancer', 'Disease', (51, 57))	('EGFR', 'Gene', (88, 92))	('c-myc', 'Gene', (81, 86))
883832	25071900	Mutation in the tumor suppressor gene p53 is the most recurrent genetic hit in EAC.	('p53', 'Gene', '7157', (38, 41))	('p53', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('Mutation', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('EAC', 'Disease', (79, 82))
883833	25071900	p53 function is associated with G1 arrest during cell cycle and apoptosis; as a result, mutation of the p53 gene will adversely affect control of cell proliferation and impair activation of apoptosis, promoting carcinogenesis.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (104, 107))	('mutation', 'Var', (88, 96))	('affect', 'Reg', (128, 134))	('carcinogenesis', 'Disease', (211, 225))	('p53', 'Gene', '7157', (104, 107))	('promoting', 'PosReg', (201, 210))	('control of cell proliferation', 'CPA', (135, 164))	('impair', 'NegReg', (169, 175))	('activation', 'CPA', (176, 186))	('carcinogenesis', 'Disease', 'MESH:D063646', (211, 225))	('apoptosis', 'CPA', (190, 199))
883834	25071900	Mutation of p53 leads to either stabilization of an inactive product or complete absence of the protein.	('protein', 'Protein', (96, 103))	('absence', 'NegReg', (81, 88))	('stabilization', 'MPA', (32, 45))	('Mutation', 'Var', (0, 8))	('inactive product', 'MPA', (52, 68))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))
883835	25071900	A case-control study by Murray and coworkers found that abnormal p53 protein expression was associated with progression to EAC at follow-up, with an OR of 11.7 (95% CI, 1.93 to 71.7).	('associated with', 'Reg', (92, 107))	('expression', 'MPA', (77, 87))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('protein', 'Protein', (69, 76))	('EAC', 'Disease', (123, 126))	('abnormal', 'Var', (56, 64))
883840	25071900	Promoter hypermethylation can lead to silencing of gene expression and cancer and has been shown to be associated with widespread epigenetic changes involving global DNA hypomethylation and targeted hypermethylation of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('lead to', 'Reg', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('global DNA', 'MPA', (159, 169))	('silencing', 'MPA', (38, 47))	('tumor', 'Disease', (219, 224))	('cancer', 'Disease', (71, 77))	('associated', 'Reg', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('Promoter hypermethylation', 'Var', (0, 25))
883844	25071900	Hypermethylation of p16 and APC was also found to associate with dysplasia at a biopsy level and correlate with cancer risk at a patient level, with an OR for combined HGD/EAC of 14.97 (95% CI, 1.7-inf) when both genes were methylated.	('dysplasia', 'Disease', (65, 74))	('dysplasia', 'Disease', 'MESH:D004476', (65, 74))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Hypermethylation', 'Var', (0, 16))	('p16', 'Gene', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('APC', 'Disease', 'MESH:D011125', (28, 31))	('p16', 'Gene', '1029', (20, 23))	('correlate', 'Reg', (97, 106))	('associate with', 'Reg', (50, 64))	('APC', 'Disease', (28, 31))	('patient', 'Species', '9606', (129, 136))
883900	25071900	This study found that AFI positivity correlated with molecular abnormalities of the Barrett's tissue and even if that area was not dysplastic on a focal biopsy there was a very high correlation between the molecular read-out from these areas and the overall dysplasia status of the patient.	('molecular abnormalities', 'MPA', (53, 76))	('dysplasia', 'Disease', (258, 267))	('dysplasia', 'Disease', 'MESH:D004476', (258, 267))	('correlated', 'Reg', (37, 47))	('dysplastic', 'Disease', (131, 141))	('patient', 'Species', '9606', (282, 289))	('dysplastic', 'Disease', 'MESH:D004416', (131, 141))	('AFI', 'Gene', (22, 25))	('positivity', 'Var', (26, 36))
883913	25071900	Only very recently GWAS studies have started to provide the first insights into the genetic variants that predispose to the development of BE and EAC, but we are still far from being able to draw a risk profile based on the inherited genetic factors.	('men', 'Species', '9606', (131, 134))	('variants', 'Var', (92, 100))	('EAC', 'Disease', (146, 149))
884016	30619753	Single Nucleotide Polymorphisms in PLCE1 for Cancer Risk of Different Types: A Meta-Analysis Background: Recent studies have investigated the relationships between PLCE1 polymorphisms and cancer susceptibility.	('PLCE1', 'Gene', '51196', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Single Nucleotide Polymorphisms', 'Var', (0, 31))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('Cancer', 'Disease', (45, 51))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('PLCE1', 'Gene', (164, 169))	('cancer', 'Disease', (188, 194))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('polymorphisms', 'Var', (170, 183))	('relationships', 'Interaction', (142, 155))	('PLCE1', 'Gene', '51196', (164, 169))	('PLCE1', 'Gene', (35, 40))
884017	30619753	Objectives: In the current study, we conducted a meta-analysis to more accurately evaluate the relationships between PLCE1 (rs2274223, rs3765524, rs753724, rs11187842, and rs7922612) single nucleotide polymorphisms (SNPs) and risk for different types of cancer.	('rs2274223', 'Mutation', 'rs2274223', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('rs2274223', 'Var', (124, 133))	('rs3765524', 'Mutation', 'rs3765524', (135, 144))	('PLCE1', 'Gene', (117, 122))	('rs753724', 'Mutation', 'rs753724', (146, 154))	('rs753724', 'Var', (146, 154))	('rs11187842', 'Var', (156, 166))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('single nucleotide polymorphisms', 'Var', (183, 214))	('rs11187842', 'Mutation', 'rs11187842', (156, 166))	('cancer', 'Disease', (254, 260))	('rs3765524', 'Var', (135, 144))	('rs7922612', 'Mutation', 'rs7922612', (172, 181))	('PLCE1', 'Gene', '51196', (117, 122))
884018	30619753	The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate relationships between the PLCE1 polymorphisms and cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('polymorphisms', 'Var', (119, 132))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('PLCE1', 'Gene', (113, 118))	('cancer', 'Disease', (137, 143))	('PLCE1', 'Gene', '51196', (113, 118))	('relationships', 'Interaction', (87, 100))
884019	30619753	Results: Results of the meta-analysis demonstrated that the rs2274223 polymorphism showed a significant correlation with increased overall cancer susceptibility (AG vs. AA: OR 1.168, 95% CI 1.084-1.259; GG vs. AA: OR 1.351, 95% CI 1.163-1.570; AG+GG vs. AA: OR 1.193, 95% CI 1.103-1.290; GG vs. AA+AG: OR 1.262, 95% CI 1.102-1.446; G vs. A: OR 1.163, 95% CI 1.089-1.242).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('increased', 'PosReg', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs2274223', 'Mutation', 'rs2274223', (60, 69))	('rs2274223', 'Var', (60, 69))	('cancer', 'Disease', (139, 145))
884020	30619753	Results of subgroup analysis showed that the rs2274223 polymorphism was associated with higher risk for esophageal cancer and gastric cancer relative to colorectal cancer and head and neck cancer.	('rs2274223', 'Var', (45, 54))	('head and neck cancer', 'Phenotype', 'HP:0012288', (175, 195))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('gastric cancer', 'Disease', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('head and neck cancer', 'Disease', 'MESH:D006258', (175, 195))	('esophageal cancer', 'Disease', (104, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('rs2274223', 'Mutation', 'rs2274223', (45, 54))	('colorectal cancer', 'Disease', (153, 170))
884021	30619753	In addition, the rs2274223 polymorphism was found to be associated with increased cancer risk, especially among the subgroups comprising Asians, studies with population-based controls, studies employing the TaqMan genotyping method, and studies consistent with Hardy-Weinberg equilibrium (HWE).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('increased', 'PosReg', (72, 81))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('rs2274223', 'Mutation', 'rs2274223', (17, 26))	('rs2274223', 'Var', (17, 26))
884022	30619753	The association between the rs3765524 polymorphism and reduced overall cancer risk was detected in one specific genetic model (CT vs. CC: OR 0.681, 95% CI 0.523-0.886).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('reduced', 'NegReg', (55, 62))	('cancer', 'Disease', (71, 77))	('rs3765524', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs3765524', 'Mutation', 'rs3765524', (28, 37))
884023	30619753	Results of subgroup analysis showed that the rs3765524 polymorphism was associated with cancer risk in a specific genetic model among the subgroups of colorectal cancer, esophageal cancer, Asians, studies with population-based controls, and studies consistent with HWE.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('cancer', 'Disease', (162, 168))	('associated', 'Reg', (72, 82))	('esophageal cancer', 'Disease', (170, 187))	('colorectal cancer', 'Disease', (151, 168))	('rs3765524', 'Var', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (151, 168))	('esophageal cancer', 'Disease', 'MESH:D004938', (170, 187))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (181, 187))	('rs3765524', 'Mutation', 'rs3765524', (45, 54))
884024	30619753	However, relationships among the PLCE1 rs753724, rs11187842, and rs7922612 polymorphisms and tumor risk were not identified.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('rs11187842', 'Var', (49, 59))	('PLCE1', 'Gene', (33, 38))	('PLCE1', 'Gene', '51196', (33, 38))	('rs11187842', 'Mutation', 'rs11187842', (49, 59))	('tumor', 'Disease', (93, 98))	('rs7922612', 'Var', (65, 74))	('rs753724', 'Mutation', 'rs753724', (39, 47))	('rs753724', 'Var', (39, 47))	('rs7922612', 'Mutation', 'rs7922612', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
884025	30619753	Conclusions: Results of the current meta-analysis suggested that PLCE1 (rs2274223, rs3765524) polymorphisms are associated with cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('rs2274223', 'Mutation', 'rs2274223', (72, 81))	('rs3765524', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PLCE1', 'Gene', (65, 70))	('PLCE1', 'Gene', '51196', (65, 70))	('associated', 'Reg', (112, 122))	('rs3765524', 'Mutation', 'rs3765524', (83, 92))	('rs2274223', 'Var', (72, 81))	('cancer', 'Disease', (128, 134))
884031	30619753	In the last few decades, extensive experimental and epidemiological findings demonstrated the close association between genetic alterations and tumor risk.	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('genetic alterations', 'Var', (120, 139))
884032	30619753	Single nucleotide polymorphisms (SNPs), the most common form of gene alteration in the human genome, refers to single-nucleotide variations with distribution frequencies that are >1% in the population.	('human', 'Species', '9606', (87, 92))	('single-nucleotide variations', 'Var', (111, 139))	('Single nucleotide polymorphisms', 'Var', (0, 31))
884035	30619753	Since then, multiple researchers investigated the relationship between PLCE1 polymorphisms and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('polymorphisms', 'Var', (77, 90))	('PLCE1', 'Gene', (71, 76))	('cancer', 'Disease', (95, 101))	('PLCE1', 'Gene', '51196', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
884036	30619753	explored the association between PLCE1 polymorphisms and risk for esophageal squamous cell carcinoma.	('association', 'Interaction', (13, 24))	('polymorphisms', 'Var', (39, 52))	('PLCE1', 'Gene', (33, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (66, 100))	('PLCE1', 'Gene', '51196', (33, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('esophageal squamous cell carcinoma', 'Disease', (66, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))
884037	30619753	Li, Zhang and other authors investigated the relationship between PLCE1 polymorphisms and colorectal cancer risk.	('PLCE1', 'Gene', (66, 71))	('PLCE1', 'Gene', '51196', (66, 71))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('polymorphisms', 'Var', (72, 85))	('colorectal cancer', 'Disease', (90, 107))
884038	30619753	Yuan, Malik and other authors investigated the association between PLCE1 polymorphisms and gastric carcinoma risk.	('gastric carcinoma', 'Disease', (91, 108))	('PLCE1', 'Gene', (67, 72))	('PLCE1', 'Gene', '51196', (67, 72))	('polymorphisms', 'Var', (73, 86))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (91, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('gastric carcinoma', 'Disease', 'MESH:D013274', (91, 108))
884039	30619753	Sharma and other authors showed that PLCE1 polymorphisms were associated with susceptibility to developing gall bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('polymorphisms', 'Var', (43, 56))	('gall bladder cancer', 'Disease', (107, 126))	('associated', 'Reg', (62, 72))	('PLCE1', 'Gene', (37, 42))	('gall bladder cancer', 'Disease', 'MESH:D005706', (107, 126))	('PLCE1', 'Gene', '51196', (37, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))
884040	30619753	Among all studies that investigated PLCE1 polymorphisms and cancer susceptibility, the SNPs rs2274223, rs3765524, rs753724, rs11187842, and rs7922612 were five of the most extensively studied polymorphic loci.	('rs11187842', 'Mutation', 'rs11187842', (124, 134))	('rs7922612', 'Var', (140, 149))	('rs753724', 'Var', (114, 122))	('rs11187842', 'Var', (124, 134))	('rs2274223', 'Var', (92, 101))	('PLCE1', 'Gene', (36, 41))	('rs753724', 'Mutation', 'rs753724', (114, 122))	('cancer', 'Disease', (60, 66))	('rs3765524', 'Var', (103, 112))	('PLCE1', 'Gene', '51196', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('rs2274223', 'Mutation', 'rs2274223', (92, 101))	('rs7922612', 'Mutation', 'rs7922612', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('rs3765524', 'Mutation', 'rs3765524', (103, 112))
884041	30619753	In addition, the latest meta-analysis on the relationship between the rs2274223 polymorphism and the overall cancer risk was published in 2015.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('rs2274223', 'Var', (70, 79))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('rs2274223', 'Mutation', 'rs2274223', (70, 79))
884042	30619753	Furthermore, to the best of our knowledge, no studies conducted meta-analysis of the association of rs3765524, rs753724, rs11187842, and rs7922612 polymorphisms with overall cancer risk.	('rs7922612', 'Var', (137, 146))	('rs3765524', 'Mutation', 'rs3765524', (100, 109))	('rs11187842', 'Var', (121, 131))	('rs11187842', 'Mutation', 'rs11187842', (121, 131))	('rs753724', 'Var', (111, 119))	('cancer', 'Disease', (174, 180))	('rs753724', 'Mutation', 'rs753724', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('rs7922612', 'Mutation', 'rs7922612', (137, 146))	('rs3765524', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('association', 'Interaction', (85, 96))
884043	30619753	Therefore, in the present study, we summarized all currently qualified case-control studies to obtain a more accurate understanding of the relationship between the PLCE1 polymorphism rs2274223 and overall cancer risk [ studies were added to the current meta-analysis from the meta-analysis published in 2015 ].	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('rs2274223', 'Mutation', 'rs2274223', (183, 192))	('cancer', 'Disease', (205, 211))	('rs2274223', 'Var', (183, 192))	('PLCE1', 'Gene', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('PLCE1', 'Gene', '51196', (164, 169))
884044	30619753	And we firstly performed a meta-analysis of the association between the rs3765524, rs753724, rs11187842, and rs7922612 polymorphisms and cancer risk in the overall population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('rs753724', 'Var', (83, 91))	('rs3765524', 'Mutation', 'rs3765524', (72, 81))	('rs7922612', 'Var', (109, 118))	('rs753724', 'Mutation', 'rs753724', (83, 91))	('rs11187842', 'Var', (93, 103))	('association', 'Interaction', (48, 59))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('rs11187842', 'Mutation', 'rs11187842', (93, 103))	('rs3765524', 'Var', (72, 81))	('rs7922612', 'Mutation', 'rs7922612', (109, 118))	('cancer', 'Disease', (137, 143))
884045	30619753	The search queries comprised a combination of the Medical Subject Headings (MeSH) and the following keywords: (rs2274223 OR rs3765524 OR rs753724 OR rs11187842 OR rs7922612) OR (PLCE1 OR PLCE OR PPLC OR NPHS3) and (cancer OR tumor OR carcinoma OR neoplasm OR malignancy).	('rs3765524', 'Mutation', 'rs3765524', (124, 133))	('PLCE', 'Gene', (187, 191))	('tumor', 'Disease', (225, 230))	('PPLC', 'Gene', (195, 199))	('carcinoma OR neoplasm OR malignancy', 'Disease', 'MESH:D009369', (234, 269))	('rs753724', 'Var', (137, 145))	('PLCE', 'Gene', '51196', (178, 182))	('rs7922612', 'Var', (163, 172))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('cancer', 'Disease', (215, 221))	('rs7922612', 'Mutation', 'rs7922612', (163, 172))	('rs11187842', 'Mutation', 'rs11187842', (149, 159))	('rs3765524', 'Var', (124, 133))	('PPLC', 'Gene', '51196', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('PLCE', 'Gene', (178, 182))	('rs753724', 'Mutation', 'rs753724', (137, 145))	('neoplasm', 'Phenotype', 'HP:0002664', (247, 255))	('rs2274223', 'Mutation', 'rs2274223', (111, 120))	('rs2274223', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('rs11187842', 'Var', (149, 159))	('PLCE1', 'Gene', (178, 183))	('PLCE1', 'Gene', '51196', (178, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('carcinoma OR neoplasm OR malignancy', 'Disease', (234, 269))	('PLCE', 'Gene', '51196', (187, 191))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('NPHS3', 'Gene', '51196', (203, 208))	('NPHS3', 'Gene', (203, 208))
884046	30619753	The inclusion criteria for qualified literatures were as follows: (a) The studies evaluated the associations between PLCE1 polymorphisms (rs2274223 or rs3765524 or rs753724 or rs11187842 or rs7922612) and cancer risk.	('rs3765524', 'Mutation', 'rs3765524', (151, 160))	('rs2274223', 'Mutation', 'rs2274223', (138, 147))	('rs2274223', 'Var', (138, 147))	('rs753724', 'Var', (164, 172))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('rs7922612', 'Mutation', 'rs7922612', (190, 199))	('rs11187842', 'Mutation', 'rs11187842', (176, 186))	('cancer', 'Disease', (205, 211))	('rs11187842', 'Var', (176, 186))	('rs753724', 'Mutation', 'rs753724', (164, 172))	('PLCE1', 'Gene', '51196', (117, 122))	('rs3765524', 'Var', (151, 160))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('PLCE1', 'Gene', (117, 122))	('rs7922612', 'Var', (190, 199))	('associations', 'Interaction', (96, 108))
884047	30619753	Exclusion criteria of qualified literatures were as follows: (a) Articles did not estimate the relationships between the PLCE1 (rs2274223, rs3765524, rs753724, rs11187842, or rs7922612) polymorphisms and cancer susceptibility.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('rs753724', 'Mutation', 'rs753724', (150, 158))	('PLCE1', 'Gene', '51196', (121, 126))	('rs7922612', 'Var', (175, 184))	('rs2274223', 'Mutation', 'rs2274223', (128, 137))	('rs3765524', 'Mutation', 'rs3765524', (139, 148))	('rs2274223', 'Var', (128, 137))	('rs7922612', 'Mutation', 'rs7922612', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('rs11187842', 'Mutation', 'rs11187842', (160, 170))	('rs3765524', 'Var', (139, 148))	('rs11187842', 'Var', (160, 170))	('rs753724', 'Var', (150, 158))	('PLCE1', 'Gene', (121, 126))
884050	30619753	The pooled ORs with 95% CIs were used to evaluate relationships between the PLCE1 polymorphisms (rs2274223, rs3765524, rs753724, rs11187842, and rs7922612) and cancer susceptibility.	('rs2274223', 'Mutation', 'rs2274223', (97, 106))	('PLCE1', 'Gene', (76, 81))	('rs2274223', 'Var', (97, 106))	('rs7922612', 'Mutation', 'rs7922612', (145, 154))	('PLCE1', 'Gene', '51196', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('rs3765524', 'Mutation', 'rs3765524', (108, 117))	('rs753724', 'Mutation', 'rs753724', (119, 127))	('rs3765524', 'Var', (108, 117))	('rs11187842', 'Var', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rs11187842', 'Mutation', 'rs11187842', (129, 139))	('rs7922612', 'Var', (145, 154))	('rs753724', 'Var', (119, 127))
884051	30619753	The rs2274223, rs3765524, rs753724, and rs11187842, rs7922612 polymorphisms were involved in 35, eight, four, four, and three studies, respectively.	('rs753724', 'Mutation', 'rs753724', (26, 34))	('rs753724', 'Var', (26, 34))	('rs7922612', 'Mutation', 'rs7922612', (52, 61))	('rs2274223', 'Mutation', 'rs2274223', (4, 13))	('involved', 'Reg', (81, 89))	('rs3765524', 'Mutation', 'rs3765524', (15, 24))	('rs7922612', 'Var', (52, 61))	('rs11187842', 'Mutation', 'rs11187842', (40, 50))	('rs11187842', 'Var', (40, 50))	('rs3765524', 'Var', (15, 24))	('rs2274223', 'Var', (4, 13))
884053	30619753	A total of 35 qualified case-control studies were included in this meta-analysis, which assessed the relationship between the PLCE1 rs2274223 polymorphism and cancer susceptibility.	('cancer', 'Disease', (159, 165))	('rs2274223', 'Mutation', 'rs2274223', (132, 141))	('rs2274223', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('PLCE1', 'Gene', (126, 131))	('PLCE1', 'Gene', '51196', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
884054	30619753	Results of the meta-analysis of the relationship between the PLCE1 rs2274223 polymorphism and cancer risk are shown in Table 2 and Figure 2.	('rs2274223', 'Mutation', 'rs2274223', (67, 76))	('rs2274223', 'Var', (67, 76))	('PLCE1', 'Gene', (61, 66))	('PLCE1', 'Gene', '51196', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
884055	30619753	Results showed a correlation between the rs2274223 polymorphism with significantly increased overall cancer susceptibility in all genetic models [AG vs. AA: OR 1.168, 95% CI 1.084-1.259 (P < 0.001); GG vs. AA: OR 1.351, 95% CI 1.163-1.570 (P < 0.001); AG+GG vs. AA: OR 1.193, 95% CI 1.103-1.290 (P < 0.001); GG vs. AA+AG: OR 1.262, 95% CI 1.102-1.446 (P = 0.001); G vs. A: OR 1.163, 95% CI 1.089-1.242 (P < 0.001)].	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('rs2274223', 'Var', (41, 50))	('increased', 'PosReg', (83, 92))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('rs2274223', 'Mutation', 'rs2274223', (41, 50))
884057	30619753	Results according to the cancer type indicated that the rs2274223 polymorphism was associated with a higher risk of gastric cancer in four genetic models [GG vs. AA: OR 1.317, 95% CI 1.041-1.667 (P = 0.022); AG+GG vs. AA: OR 1.163, 95% CI 1.002-1.350 (P = 0.047); GG vs. AA+AG: OR 1.271, 95% CI 1.114-1.449 (P < 0.001); G vs. A: OR 1.144, 95% CI 1.018-1.286 (P = 0.023)].	('rs2274223', 'Var', (56, 65))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('gastric cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (116, 130))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('gastric cancer', 'Phenotype', 'HP:0012126', (116, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('rs2274223', 'Mutation', 'rs2274223', (56, 65))
884058	30619753	Meanwhile, the rs2274223 polymorphism was related to a significantly increased risk of esophageal cancer in all genetic models [AG vs. AA: OR 1.247, 95% CI 1.157-1.344 (P < 0.001); GG vs. AA: OR 1.542, 95% CI 1.247-1.907 (P < 0.001); AG+GG vs. AA: OR 1.266, 95% CI 1.133-1.415 (P < 0.001); GG vs. AA+AG: OR 1.356, 95% CI 1.192-1.544 (P < 0.001); G vs. A: OR 1.226, 95% CI 1.112-1.351 (P < 0.001)].	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs2274223', 'Mutation', 'rs2274223', (15, 24))	('rs2274223', 'Var', (15, 24))	('esophageal cancer', 'Disease', (87, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))
884059	30619753	However, we found no statistically significant associations between the rs2274223 polymorphism and risks of head and neck cancer and colorectal cancer.	('rs2274223', 'Mutation', 'rs2274223', (72, 81))	('colorectal cancer', 'Disease', (133, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (133, 150))	('head and neck cancer', 'Phenotype', 'HP:0012288', (108, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('head and neck cancer', 'Disease', 'MESH:D006258', (108, 128))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('rs2274223', 'Var', (72, 81))
884060	30619753	The results of subgroup analyses according to ethnicity indicated that the rs2274223 polymorphism increased cancer susceptibility in Asians [AG vs. AA: OR 1.221, 95% CI 1.102-1.352 (P < 0.001); GG vs. AA: OR 1.665, 95% CI 1.381-2.006 (P < 0.001); AG+GG vs. AA: OR 1.270, 95% CI 1.142-1.412 (P < 0.001); GG vs. AA+AG: OR 1.465, 95% CI 1.316-1.632 (P < 0.001); G vs. A: OR 1.251, 95% CI 1.145-1.366 (P < 0.001)].	('rs2274223', 'Mutation', 'rs2274223', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('rs2274223', 'Var', (75, 84))	('increased', 'PosReg', (98, 107))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
884061	30619753	However, the association between rs2274223 polymorphism and cancer risk was not identified in Caucasians.	('rs2274223', 'Mutation', 'rs2274223', (33, 42))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('rs2274223', 'Var', (33, 42))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
884062	30619753	The results of subgroup analyses based on the source of control showed that the rs2274223 polymorphism was associated with significantly increased risk of tumor in hospital-based subgroup [AG vs. AA: OR 1.188, 95% CI 1.106-1.277 (P < 0.001); GG vs. AA: OR 1.289, 95% CI 1.009-1.647 (P = 0.042); AG+GG vs. AA: OR 1.206, 95% CI 1.126-1.291 (P < 0.001); G vs. A: OR 1.150, 95% CI 1.050-1.259 (P = 0.003)].	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('rs2274223', 'Mutation', 'rs2274223', (80, 89))	('rs2274223', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))
884063	30619753	Meanwhile, the statistically significant relationship between the rs2274223 polymorphism and cancer susceptibility was also detected in the population-based subgroup [AG vs. AA: OR 1.169, 95% CI 1.028-1.329 (P = 0.017); GG vs. AA: OR 1.448, 95% CI 1.184-1.770 (P < 0.001); AG+GG vs. AA: OR 1.203, 95% CI 1.054-1.373 (P = 0.006); GG vs. AA+AG: OR 1.352, 95% CI 1.205-1.516 (P < 0.001); G vs. A: OR 1.184, 95% CI 1.066-1.316 (P = 0.002)].	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rs2274223', 'Mutation', 'rs2274223', (66, 75))	('rs2274223', 'Var', (66, 75))
884064	30619753	The results of subgroup analyses based on genotyping methods indicated that rs2274223 polymorphism might increase tumor risk in all genetic models in TaqMan subgroup.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('rs2274223', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('increase', 'PosReg', (105, 113))	('tumor', 'Disease', (114, 119))	('TaqMan', 'Disease', (150, 156))	('rs2274223', 'Mutation', 'rs2274223', (76, 85))
884065	30619753	In addition, the rs2274223 polymorphism was related to a significantly higher risk of tumor in three genetic models in the PCR subgroup [AG vs. AA: OR 1.278, 95% CI 1.163-1.405 (P < 0.001); AG+GG vs. AA: OR 1.290, 95% CI 1.178-1.412 (P < 0.001); G vs. A: OR 1.183, 95% CI 1.041-1.344 (P = 0.010)].	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('rs2274223', 'Mutation', 'rs2274223', (17, 26))	('rs2274223', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
884066	30619753	However, the rs2274223 polymorphism was associated with tumor risk in a few genetic models in MassArray subgroup and other subgroup.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('rs2274223', 'Var', (13, 22))	('tumor', 'Disease', (56, 61))	('associated', 'Reg', (40, 50))	('rs2274223', 'Mutation', 'rs2274223', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
884067	30619753	After removing this study, the statistically significant association between rs2274223 polymorphism and cancer risk still existed [AG vs. AA: OR 1.169, 95% CI 1.083-1.262 (P < 0.001); GG vs. AA: OR 1.341, 95% CI 1.158-1.554 (P < 0.001); AG+GG vs. AA: OR 1.190, 95% CI 1.098-1.288 (P < 0.001); GG vs. AA+AG: OR 1.254, 95% CI 1.098-1.432 (P = 0.001); G vs. A: OR 1.157, 95% CI 1.083-1.236 (P < 0.001)].	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs2274223', 'Mutation', 'rs2274223', (77, 86))	('rs2274223', 'Var', (77, 86))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
884068	30619753	There were eight qualified case-control studies in this meta-analysis, which assessed the relationship between the PLCE1 rs3765524 polymorphism and cancer susceptibility.	('cancer', 'Disease', (148, 154))	('rs3765524', 'Mutation', 'rs3765524', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('PLCE1', 'Gene', (115, 120))	('PLCE1', 'Gene', '51196', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('rs3765524', 'Var', (121, 130))
884069	30619753	The results of meta-analysis on the relationship between the PLCE1 rs3765524 polymorphism and cancer risk are summarized in Table 3 and Figure 3.	('rs3765524', 'Var', (67, 76))	('PLCE1', 'Gene', (61, 66))	('PLCE1', 'Gene', '51196', (61, 66))	('rs3765524', 'Mutation', 'rs3765524', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
884070	30619753	The association between the rs3765524 polymorphism and overall cancer risk was identified in one genetic model [CT vs. CC: OR 0.681, 95% CI 0.523-0.886 (P = 0.004)].	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('rs3765524', 'Var', (28, 37))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('rs3765524', 'Mutation', 'rs3765524', (28, 37))
884071	30619753	The results of subgroup analyses based on cancer type showed that the rs3765524 polymorphism was associated with risk of esophageal cancer in two genetic models [CT vs. CC: OR 0.611, 95% CI 0.515-0.726 (P < 0.001); T vs. C: OR 1.154, 95% CI 1.014-1.313 (P = 0.029)].	('cancer', 'Disease', (132, 138))	('rs3765524', 'Mutation', 'rs3765524', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('rs3765524', 'Var', (70, 79))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
884072	30619753	In addition, the rs3765524 polymorphism was associated with colorectal cancer susceptibility in the specific genetic models [TT vs. CC: OR 0.431, 95% CI 0.229-0.811 (P = 0.009); TT vs. CT+CC: OR 0.429, 95% CI 0.232-0.794 (P = 0.007)].	('associated', 'Reg', (44, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('rs3765524', 'Var', (17, 26))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colorectal cancer', 'Disease', (60, 77))	('rs3765524', 'Mutation', 'rs3765524', (17, 26))
884073	30619753	However, the observed relationship between rs3765524 polymorphism and risk of gastric cancer was not statistically significant.	('rs3765524', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs3765524', 'Mutation', 'rs3765524', (43, 52))	('gastric cancer', 'Disease', (78, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
884074	30619753	Subgroup analyses according to ethnicity identified an association between the rs3765524 polymorphism and cancer risk in Asians [CT vs. CC: OR 0.579, 95% CI 0.492-0.680 (P < 0.001)].	('rs3765524', 'Mutation', 'rs3765524', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('rs3765524', 'Var', (79, 88))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
884075	30619753	The results of stratified analyses based on the source of controls showed that the CT genotype of rs3765524 decreased cancer susceptibility in the population-based subgroup relative to CC genotype [CT vs. CC: OR 0.568, 95% CI 0.371-0.870 (P = 0.009)].	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('decreased', 'NegReg', (108, 117))	('rs3765524', 'Mutation', 'rs3765524', (98, 107))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('rs3765524', 'Var', (98, 107))
884076	30619753	The results of subgroup analyses based on genotyping method indicated that the rs3765524 polymorphism is not associated with tumor risk in each subgroup.	('rs3765524', 'Mutation', 'rs3765524', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('rs3765524', 'Var', (79, 88))	('tumor', 'Disease', (125, 130))
884077	30619753	In the subgroup whose genotype frequencies among controls was consistent with HWE, the rs3765524 polymorphism was associated with cancer risk in only one genetic model [CT vs. CC: OR 0.594, 95% CI 0.511-0.691 (P < 0.001)].	('rs3765524', 'Mutation', 'rs3765524', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('rs3765524', 'Var', (87, 96))	('associated', 'Reg', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
884078	30619753	The rs753724, rs11187842, and rs7922612 polymorphisms were involved in four, four, and three case-control studies, respectively.	('rs753724', 'Var', (4, 12))	('rs7922612', 'Var', (30, 39))	('rs753724', 'Mutation', 'rs753724', (4, 12))	('rs11187842', 'Var', (14, 24))	('rs11187842', 'Mutation', 'rs11187842', (14, 24))	('involved', 'Reg', (59, 67))	('rs7922612', 'Mutation', 'rs7922612', (30, 39))
884079	30619753	The results of meta-analysis on the association between PLCE1 (rs753724, rs11187842, and rs7922612) polymorphisms and cancer risk are summarized in Table 4 and Figure S1.	('cancer', 'Disease', (118, 124))	('rs753724', 'Var', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('rs7922612', 'Mutation', 'rs7922612', (89, 98))	('rs7922612', 'Var', (89, 98))	('rs753724', 'Mutation', 'rs753724', (63, 71))	('rs11187842', 'Var', (73, 83))	('rs11187842', 'Mutation', 'rs11187842', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('association', 'Interaction', (36, 47))	('PLCE1', 'Gene', (56, 61))	('PLCE1', 'Gene', '51196', (56, 61))
884080	30619753	Results indicated no significant relationship between the PLCE1 rs753724, rs11187842, and rs7922612 polymorphisms and cancer risk.	('cancer', 'Disease', (118, 124))	('rs753724', 'Mutation', 'rs753724', (64, 72))	('rs7922612', 'Mutation', 'rs7922612', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs11187842', 'Mutation', 'rs11187842', (74, 84))	('rs7922612', 'Var', (90, 99))	('rs753724', 'Var', (64, 72))	('rs11187842', 'Var', (74, 84))	('PLCE1', 'Gene', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('PLCE1', 'Gene', '51196', (58, 63))
884086	30619753	However, identifying the source of heterogeneity for rs3765524, rs753724, rs11187842, and rs7922612 was difficult based on stratified analyses.	('rs753724', 'Mutation', 'rs753724', (64, 72))	('rs7922612', 'Mutation', 'rs7922612', (90, 99))	('rs3765524', 'Mutation', 'rs3765524', (53, 62))	('rs11187842', 'Mutation', 'rs11187842', (74, 84))	('rs7922612', 'Var', (90, 99))	('rs753724', 'Var', (64, 72))	('rs11187842', 'Var', (74, 84))	('rs3765524', 'Var', (53, 62))
884087	30619753	As the effects of genetic mutations on cancer continued to be revealed, many authors have focused on the associations between SNPs and cancer susceptibility.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('associations', 'Interaction', (105, 117))	('SNPs', 'Disease', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
884093	30619753	Likewise, several meta-analyses assessed the association between PLCE1 polymorphisms and cancer risk.	('polymorphisms', 'Var', (71, 84))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('assessed', 'Reg', (32, 40))	('PLCE1', 'Gene', (65, 70))	('PLCE1', 'Gene', '51196', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
884094	30619753	However, most of these studies focused on the relationship between PLCE1 polymorphisms and digestive tract cancer rather than the overall tumor risk.	('digestive tract cancer', 'Phenotype', 'HP:0007378', (91, 113))	('focused', 'Reg', (31, 38))	('tumor', 'Disease', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PLCE1', 'Gene', (67, 72))	('tract cancer', 'Disease', 'MESH:D014571', (101, 113))	('PLCE1', 'Gene', '51196', (67, 72))	('polymorphisms', 'Var', (73, 86))	('tract cancer', 'Disease', (101, 113))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
884095	30619753	Our current findings showed that the rs2274223 polymorphism was associated with overall tumor susceptibility in five genetic models, consistent with the results reported by Xue et al..	('associated', 'Reg', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('rs2274223', 'Mutation', 'rs2274223', (37, 46))	('rs2274223', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
884096	30619753	However, the current results were slightly different from those reported by Umar, in which the rs2274223 polymorphism showed no significant association with overall cancer susceptibility in one specific genetic model (GG vs. AG+AA).	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('rs2274223', 'Mutation', 'rs2274223', (95, 104))	('rs2274223', 'Var', (95, 104))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
884097	30619753	Further stratified analysis revealed that the rs2274223 polymorphism was associated with gastric cancer and esophageal cancer susceptibility, but not with other types of cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (170, 176))	('rs2274223', 'Mutation', 'rs2274223', (46, 55))	('rs2274223', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('esophageal cancer', 'Disease', (108, 125))	('associated', 'Reg', (73, 83))	('gastric cancer', 'Disease', (89, 103))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
884098	30619753	The above findings were consistent with those reported by Umar, but slightly different from the findings of Xue et al., which suggested that rs2274223 polymorphism was not associated with susceptibility to gastric cancer.	('rs2274223', 'Mutation', 'rs2274223', (141, 150))	('rs2274223', 'Var', (141, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (188, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('gastric cancer', 'Disease', (206, 220))	('gastric cancer', 'Disease', 'MESH:D013274', (206, 220))
884100	30619753	Moreover, the results of the stratified analysis indicated that the rs2274223 polymorphism was associated with cancer susceptibility in Asians but not in Caucasians, consistent with the findings of Umar et al..	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rs2274223', 'Mutation', 'rs2274223', (68, 77))	('rs2274223', 'Var', (68, 77))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('associated', 'Reg', (95, 105))
884101	30619753	Results of subgroup analysis according to the source of controls identified a relationship between rs2274223 polymorphism and tumor risk regardless of whether controls were obtained from a hospital or a population and were also consistent with the findings of Umar et al.. For rs3765524, the results of the present meta-analysis showed that the association between the rs3765524 polymorphism and overall cancer risk was identified in only one genetic model (CT vs. CC).	('cancer', 'Disease', 'MESH:D009369', (404, 410))	('rs3765524', 'Mutation', 'rs3765524', (369, 378))	('cancer', 'Disease', (404, 410))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('rs2274223', 'Mutation', 'rs2274223', (99, 108))	('rs3765524', 'Mutation', 'rs3765524', (277, 286))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('rs3765524', 'Var', (369, 378))	('tumor', 'Disease', (126, 131))
884102	30619753	The results of stratified analysis indicated that the rs3765524 polymorphism was associated with colorectal cancer and esophageal cancer susceptibility but not with the other types of cancer.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('rs3765524', 'Mutation', 'rs3765524', (54, 63))	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colorectal cancer', 'Disease', (97, 114))	('rs3765524', 'Var', (54, 63))	('associated', 'Reg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (108, 114))	('esophageal cancer', 'Disease', (119, 136))
884103	30619753	The above findings were distinct from those of Mocellin et al., which identified an association between the rs3765524 polymorphism and gastric cancer susceptibility.	('gastric cancer', 'Disease', (135, 149))	('association', 'Interaction', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('rs3765524', 'Mutation', 'rs3765524', (108, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('rs3765524', 'Var', (108, 117))
884104	30619753	Finally, our results of both the total cancer analysis or subgroup analysis indicated that the rs753724, rs11187842, and rs7922612 polymorphisms were not related to tumor risk.	('rs7922612', 'Mutation', 'rs7922612', (121, 130))	('rs753724', 'Mutation', 'rs753724', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('rs753724', 'Var', (95, 103))	('rs11187842', 'Var', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('rs11187842', 'Mutation', 'rs11187842', (105, 115))	('rs7922612', 'Var', (121, 130))	('tumor', 'Disease', (165, 170))
884105	30619753	First, relatively few qualified studies were included for investigating rs753724, rs11187842, and rs7922612, and some subgroups included in the stratified analysis had low sample sizes, which might have affected statistical results.	('rs7922612', 'Var', (98, 107))	('rs753724', 'Var', (72, 80))	('rs7922612', 'Mutation', 'rs7922612', (98, 107))	('rs753724', 'Mutation', 'rs753724', (72, 80))	('affected', 'Reg', (203, 211))	('rs11187842', 'Mutation', 'rs11187842', (82, 92))	('rs11187842', 'Var', (82, 92))
884107	30619753	Our findings indicated that the PLCE1 rs2274223 polymorphism is significantly associated with cancer susceptibility in the overall population.	('associated', 'Reg', (78, 88))	('PLCE1', 'Gene', (32, 37))	('PLCE1', 'Gene', '51196', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rs2274223', 'Mutation', 'rs2274223', (38, 47))	('rs2274223', 'Var', (38, 47))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
884108	30619753	On the other hand, the PLCE1 rs753724, rs11187842, and rs7922612 polymorphisms showed no significant associations with cancer risk.	('rs7922612', 'Mutation', 'rs7922612', (55, 64))	('PLCE1', 'Gene', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('PLCE1', 'Gene', '51196', (23, 28))	('rs11187842', 'Var', (39, 49))	('cancer', 'Disease', (119, 125))	('rs11187842', 'Mutation', 'rs11187842', (39, 49))	('rs753724', 'Var', (29, 37))	('rs753724', 'Mutation', 'rs753724', (29, 37))	('rs7922612', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
884109	30619753	In addition, the results suggested that the PLCE1 rs3765524 polymorphism is associated with overall cancer risk under the heterozygote model (CT vs. CC).	('rs3765524', 'Mutation', 'rs3765524', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PLCE1', 'Gene', (44, 49))	('associated', 'Reg', (76, 86))	('PLCE1', 'Gene', '51196', (44, 49))	('rs3765524', 'Var', (50, 59))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
884139	28836965	The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and A codes were used to define liver cancer (155, 155.0, 155.1, A095).	('liver cancer', 'Disease', 'MESH:D006528', (127, 139))	('liver cancer', 'Disease', (127, 139))	('155', 'Var', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('liver cancer', 'Phenotype', 'HP:0002896', (127, 139))
884143	28836965	The ICD-9-CM and A codes were used to define liver cirrhosis (571.5, 571.6, and 571.2), hepatitis B virus (HBV) (070.20-070.23, 070.30-070.33, V0261, and A046), hepatitis C virus (HCV) (070.41, 070.44, 070.51, 070.54, V0262, and A046), esophageal varices with bleeding (456.0 and 456.20), ascites (789.5), stroke (430-437), chronic kidney disease (CKD) (585), and hemodialysis (V451).	('stroke', 'Disease', 'MESH:D020521', (306, 312))	('kidney disease', 'Phenotype', 'HP:0000112', (332, 346))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (324, 346))	('hepatitis B virus', 'Species', '10407', (88, 105))	('stroke', 'Disease', (306, 312))	('liver cirrhosis', 'Disease', (45, 60))	('hepatitis', 'Phenotype', 'HP:0012115', (88, 97))	('bleeding', 'Disease', (260, 268))	('ascites', 'Disease', (289, 296))	('hepatitis B virus', 'Disease', (88, 105))	('esophageal varices', 'Phenotype', 'HP:0002040', (236, 254))	('HCV', 'Species', '11103', (180, 183))	('esophageal varices', 'Disease', (236, 254))	('ascites', 'Disease', 'MESH:D001201', (289, 296))	('HBV', 'Species', '10407', (107, 110))	('chronic kidney disease', 'Disease', (324, 346))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (45, 60))	('CKD', 'Disease', (348, 351))	('V0262', 'CellLine', 'CVCL:8V62', (218, 223))	('ascites', 'Phenotype', 'HP:0001541', (289, 296))	('V0261', 'CellLine', 'CVCL:8V61', (143, 148))	('CKD', 'Phenotype', 'HP:0012622', (348, 351))	('V0262', 'Var', (218, 223))	('liver cirrhosis', 'Disease', 'MESH:D008103', (45, 60))	('070.41', 'Var', (186, 192))	('bleeding', 'Disease', 'MESH:D006470', (260, 268))	('CKD', 'Disease', 'MESH:D012080', (348, 351))	('A046', 'Var', (229, 233))	('hepatitis C virus', 'Species', '11103', (161, 178))	('stroke', 'Phenotype', 'HP:0001297', (306, 312))	('chronic kidney disease', 'Disease', 'MESH:D051436', (324, 346))	('hepatitis C virus', 'Disease', (161, 178))	('cirrhosis', 'Phenotype', 'HP:0001394', (51, 60))	('hepatitis', 'Phenotype', 'HP:0012115', (161, 170))	('hemodialysis', 'Disease', (364, 376))
884144	28836965	To increase validity, those who had at least 3 diagnoses of diabetes (ICD-9-CM: 250 and A code A181) and at least 3 diagnoses of hypertension (ICD-9-CM: 401-405 and A code A26) for either outpatient or inpatient care within 365 calendar days were considered to have a diagnosis of diabetes or hypertension.	('diabetes', 'Disease', (281, 289))	('code A181', 'Var', (90, 99))	('diabetes', 'Disease', 'MESH:D003920', (60, 68))	('diabetes', 'Disease', 'MESH:D003920', (281, 289))	('hypertension', 'Disease', (129, 141))	('hypertension', 'Disease', 'MESH:D006973', (293, 305))	('outpatient', 'Species', '9606', (188, 198))	('hypertension', 'Phenotype', 'HP:0000822', (129, 141))	('diabetes', 'Disease', (60, 68))	('hypertension', 'Disease', 'MESH:D006973', (129, 141))	('ICD-9-CM', 'Var', (70, 78))	('hypertension', 'Disease', (293, 305))	('hypertension', 'Phenotype', 'HP:0000822', (293, 305))
884221	27910227	Whether the dysphagia is actually the result of esophageal cancer or aberrant subclavian artery is difficult to determine.	('dysphagia', 'Disease', 'MESH:D003680', (12, 21))	('esophageal cancer', 'Disease', (48, 65))	('aberrant subclavian artery', 'Phenotype', 'HP:0031014', (69, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (48, 65))	('aberrant', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('dysphagia', 'Disease', (12, 21))	('dysphagia', 'Phenotype', 'HP:0002015', (12, 21))
884364	25636830	If the patient's case meets the indications for ESD, this combination treatment should be actively considered because performing ESD before CRT improves the local control rate, and doing so can decrease the number of cardiac toxicities due to a radiation-dose reduction relative to CRT alone.	('CRT', 'Gene', '45841', (140, 143))	('CRT', 'Gene', (140, 143))	('patient', 'Species', '9606', (7, 14))	('cardiac toxicities', 'Disease', 'MESH:D066126', (217, 235))	('ESD', 'Var', (129, 132))	('CRT', 'Gene', '45841', (282, 285))	('improves', 'PosReg', (144, 152))	('CRT', 'Gene', (282, 285))	('local control', 'CPA', (157, 170))	('cardiac toxicities', 'Disease', (217, 235))	('decrease', 'NegReg', (194, 202))
884393	19134212	In the present study, we investigated the expression of p75NTR in esophageal squamous cell carcinoma (ESCC) and explored the biological properties of p75NTR+ cells.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (66, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('esophageal squamous cell carcinoma', 'Disease', (66, 100))	('p75NTR', 'Var', (56, 62))
884396	19134212	The expression of Bmi-1, which is associated with self-renewal of stem cells, was significantly higher in p75NTR+ cells.	('expression', 'MPA', (4, 14))	('Bmi-1', 'Gene', '648', (18, 23))	('Bmi-1', 'Gene', (18, 23))	('higher', 'PosReg', (96, 102))	('p75NTR+ cells', 'Var', (106, 119))
884398	19134212	The expression of CTR1, which is associated with cisplatin (DDP)-resistance, was significantly decreased in p75NTR+ cells.	('decreased', 'NegReg', (95, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('expression', 'MPA', (4, 14))	('DDP', 'Gene', '1678', (60, 63))	('p75NTR+', 'Var', (108, 115))	('CTR1', 'Gene', (18, 22))	('DDP', 'Gene', (60, 63))
884399	19134212	Expression levels of differentiation markers, such as involucrin, cytokeratin 13, beta1-integrin and beta4-integrin, were lower in p75NTR+ cells.	('lower', 'NegReg', (122, 127))	('involucrin', 'Gene', (54, 64))	('beta1-integrin', 'Gene', (82, 96))	('cytokeratin 13', 'Gene', (66, 80))	('Expression levels', 'MPA', (0, 17))	('involucrin', 'Gene', '3713', (54, 64))	('beta4-integrin', 'MPA', (101, 115))	('cytokeratin 13', 'Gene', '3860', (66, 80))	('beta1-integrin', 'Gene', '3688', (82, 96))	('p75NTR+', 'Var', (131, 138))
884401	19134212	Furthermore, p75NTR+ cells were found to be more resistant to DDP and exhibited lower 64copper accumulation than p75NTR- cells.	('DDP', 'Gene', (62, 65))	('resistant', 'MPA', (49, 58))	('copper', 'Chemical', 'MESH:D003300', (88, 94))	('DDP', 'Gene', '1678', (62, 65))	('p75NTR+', 'Var', (13, 20))	('lower', 'NegReg', (80, 85))	('64copper accumulation', 'MPA', (86, 107))
884402	19134212	Our results demonstrated that p75NTR+ cells possess some characteristics of CSCs, namely, self-renewal and chemotherapy resistance.	('CSCs', 'Disease', (76, 80))	('p75NTR+', 'Var', (30, 37))	('rat', 'Species', '10116', (19, 22))	('chemotherapy resistance', 'CPA', (107, 130))	('self-renewal', 'CPA', (90, 102))
884410	19134212	Low-affinity neurotrophin receptor (p75NTR), a member of tumor necrosis factor superfamily, has been shown to paradoxically mediate neuronal survival and differentiation or apoptotic cell death, depending on the environment of the cells.	('tumor necrosis', 'Disease', (57, 71))	('neurotrophin', 'Gene', '627', (13, 25))	('p75NTR', 'Var', (36, 42))	('neuronal survival', 'CPA', (132, 149))	('mediate', 'Reg', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor necrosis', 'Disease', 'MESH:D009336', (57, 71))	('differentiation', 'CPA', (154, 169))	('neurotrophin', 'Gene', (13, 25))	('apoptotic cell death', 'CPA', (173, 193))
884411	19134212	Okumura et al reported that p75NTR+ esophageal epithelial cells were stem cells due to their capacity of proliferation, self-renewal and multidirectional differentiation.	('self-renewal', 'CPA', (120, 132))	('p75NTR+', 'Var', (28, 35))	('rat', 'Species', '10116', (112, 115))	('multidirectional differentiation', 'CPA', (137, 169))
884413	19134212	In the present study, we found that p75NTR+ esophageal squamous cell carcinomas (ESCC) cells exhibited properties of CSCs in terms of self-renewal and chemotherapy resistance.	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('chemotherapy resistance', 'CPA', (151, 174))	('p75NTR+', 'Var', (36, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('self-renewal', 'CPA', (134, 146))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (55, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('esophageal squamous cell carcinomas', 'Disease', (44, 79))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (44, 79))
884421	19134212	The samples were divided into two groups according to the percentage of p75NTR staining-positive cells, tumors were classified as positive if >10% tumor cells were stained and negative if <= 10% tumor cells were stained.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (104, 109))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('p75NTR', 'Var', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
884431	19134212	Fluorescence-activated cell sorting (FACS) of p75NTR+and p75NTR- cells was performed on a Cytomation MoFlo cytometer (DakoCytomation Corporation, Denmark).	('rat', 'Species', '10116', (138, 141))	('p75NTR+and', 'Var', (46, 56))	('p75NTR-', 'Var', (57, 64))
884446	19134212	Furthermore, cell mixture composed of 10% p75NTR+ Eca109-eGFP and 90% p75NTR- Eca109 cells were cultured for 2 days and then exposed to 0.5 and 1 mug/ml DDP for 4 days respectively.	('p75NTR+', 'Var', (42, 49))	('DDP', 'Gene', (153, 156))	('DDP', 'Gene', '1678', (153, 156))
884451	19134212	Various numbers of p75NTR+ and p75NTR- Eca109 cells were suspended in 200 mul serum-free DMEM or in 200 mul serum-free DMEM/Matrigel (1:1), and injected subcutaneously into NOD/SCID mice.	('NOD', 'Gene', '1822', (173, 176))	('DMEM', 'Chemical', '-', (89, 93))	('p75NTR+', 'Var', (19, 26))	('SCID', 'Disease', 'MESH:D053632', (177, 181))	('p75NTR- Eca109', 'Var', (31, 45))	('SCID', 'Disease', (177, 181))	('mice', 'Species', '10090', (182, 186))	('NOD', 'Gene', (173, 176))	('DMEM', 'Chemical', '-', (119, 123))
884458	19134212	Parallel sections from WDC and MDC showed that p75NTR+ cells were located at some distance from the terminally differentiated cells stained brightly for involucrin, and generally absent in the zones immediately surrounding the involucrin+ cells.	('involucrin', 'Gene', '3713', (153, 163))	('p75NTR+', 'Var', (47, 54))	('involucrin', 'Gene', (227, 237))	('involucrin', 'Gene', '3713', (227, 237))	('involucrin', 'Gene', (153, 163))
884459	19134212	In PDC, there were few cells positive for involucrin, most of the cells were stained very brightly for p75NTR.	('involucrin', 'Gene', (42, 52))	('PDC', 'Disease', (3, 6))	('p75NTR', 'Var', (103, 109))	('involucrin', 'Gene', '3713', (42, 52))
884460	19134212	In addition, p75NTR and p63 had similar tissue distribution both in NEE and in ESCC specimens (Figure 1B).	('NEE', 'Disease', (68, 71))	('p63', 'Gene', (24, 27))	('p75NTR', 'Var', (13, 19))	('p63', 'Gene', '8626', (24, 27))	('ESCC', 'Disease', (79, 83))
884461	19134212	p75NTR expression correlated with age (P = 0.008), tumor diameter (P = 0.004) and pathological grade (P = 0.001).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('p75NTR expression', 'Var', (0, 17))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
884462	19134212	There was no significant correlation between p75NTR expression and other factors such as gender, ki-67 index, necrosis, distant metastasis and paraesophageal lymph node metastasis.	('necrosis', 'Disease', (110, 118))	('necrosis', 'Disease', 'MESH:D009336', (110, 118))	('p75NTR', 'Var', (45, 51))	('paraesophageal lymph node metastasis', 'Disease', (143, 179))	('paraesophageal lymph node metastasis', 'Disease', 'MESH:D009362', (143, 179))
884464	19134212	The cells derived from p75NTR+ cells contained both p75NTR+ and p75NTR- cells, whereas those from p75NTR- cells generated only p75NTR- cells.	('rat', 'Species', '10116', (116, 119))	('p75NTR-', 'Var', (64, 71))	('p75NTR+', 'Var', (52, 59))	('p75NTR+', 'Var', (23, 30))
884467	19134212	In addition, p75NTR+ cells expressed lower levels of markers of differentiation such as involucrin, cytokeratin 13, beta1-integrin and beta4-integrin than p75NTR- cells.	('beta1-integrin', 'Gene', (116, 130))	('involucrin', 'Gene', (88, 98))	('involucrin', 'Gene', '3713', (88, 98))	('beta4-integrin', 'MPA', (135, 149))	('p75NTR+', 'Var', (13, 20))	('cytokeratin 13', 'Gene', (100, 114))	('lower', 'NegReg', (37, 42))	('beta1-integrin', 'Gene', '3688', (116, 130))	('cytokeratin 13', 'Gene', '3860', (100, 114))	('levels of', 'MPA', (43, 52))
884473	19134212	Cell viability was measured by MTT assay 4 days after subjecting p75NTR+ and p75NTR- cells to DDP.	('DDP', 'Gene', '1678', (94, 97))	('MTT', 'Chemical', 'MESH:C070243', (31, 34))	('Cell viability', 'CPA', (0, 14))	('p75NTR+', 'Var', (65, 72))	('DDP', 'Gene', (94, 97))
884475	19134212	It was demonstrated that DDP induced significant enrichment of p75NTR+ cells and their percentage increased from 9.4% to 48.1% and 86.2%, respectively (Figure 5B).	('DDP', 'Gene', (25, 28))	('DDP', 'Gene', '1678', (25, 28))	('rat', 'Species', '10116', (14, 17))	('p75NTR+', 'Var', (63, 70))
884480	19134212	The results showed that at least 2 x 103 p75NTR+ cells or p75NTR- cells were needed to generate tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('rat', 'Species', '10116', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('p75NTR-', 'Var', (58, 65))
884481	19134212	When transplanted cells were suspended in DMEM/Matrigel, the result showed that the lowest number of p75NTR+ and p75NTR- cells to generate tumors was 500 and 2 x 103, respectively (Table 2).	('p75NTR+', 'Var', (101, 108))	('DMEM', 'Chemical', '-', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('p75NTR-', 'Var', (113, 120))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('rat', 'Species', '10116', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
884482	19134212	Although statistical analysis showed that positive rate of p75NTR was not associated with lower pathological grade, histopathological analysis indicated that the number and distribution of p75NTR+ cells altered depending on the degree of anaplasia in ESCC.	('altered', 'Reg', (203, 210))	('anaplasia', 'Disease', 'MESH:D000708', (238, 247))	('ESCC', 'Disease', (251, 255))	('p75NTR+', 'Var', (189, 196))	('anaplasia', 'Disease', (238, 247))	('rat', 'Species', '10116', (51, 54))
884485	19134212	These results suggested that p75NTR was expressed in cells that were proliferating or capable of proliferating.	('rat', 'Species', '10116', (76, 79))	('proliferating', 'CPA', (97, 110))	('rat', 'Species', '10116', (104, 107))	('p75NTR', 'Var', (29, 35))
884486	19134212	Furthermore, the distribution of p75NTR in ESCC was similar to that of p63, a marker identified in keratinocyte stem cells.	('p75NTR', 'Var', (33, 39))	('rat', 'Species', '10116', (101, 104))	('p63', 'Gene', '8626', (71, 74))	('p63', 'Gene', (71, 74))
884488	19134212	In the present study, our results revealed that p75NTR+ cells could generate both p75NTR+ and p75NTR- progenies, but p75NTR- cells could generate only p75NTR- cells, suggesting a p75NTR-associated cell hierarchy may exist in ESCC.	('p75NTR+', 'Var', (48, 55))	('rat', 'Species', '10116', (141, 144))	('ESCC', 'Disease', (225, 229))	('rat', 'Species', '10116', (72, 75))
884489	19134212	p75NTR+ cells could be propagated undifferentiatedly cells in serum-free medium and differentiate into involucrin+ and cytokeratin 13+ cells under differentiating conditions.	('cytokeratin 13', 'Gene', (119, 133))	('cytokeratin 13', 'Gene', '3860', (119, 133))	('p75NTR+', 'Var', (0, 7))	('involucrin', 'Gene', '3713', (103, 113))	('involucrin', 'Gene', (103, 113))
884498	19134212	Meanwhile, the result of MTT assay showed that p75NTR+ cells were more resistant to DDP than p75NTR- cells in all 4 esophageal carcinoma cell lines.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (116, 136))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (116, 136))	('p75NTR+', 'Var', (47, 54))	('MTT', 'Chemical', 'MESH:C070243', (25, 28))	('DDP', 'Gene', '1678', (84, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('DDP', 'Gene', (84, 87))	('esophageal carcinoma', 'Disease', (116, 136))
884499	19134212	Furthermore, the result of the enrichment assay offered the direct evidence that p75NTR+ cells were more resistant to DDP since p75NTR+ and p75NTR- cells were cocultured in the same condition.	('DDP', 'Gene', (118, 121))	('DDP', 'Gene', '1678', (118, 121))	('p75NTR+', 'Var', (81, 88))
884500	19134212	Finally, we injected 102 to 105 p75NTR+ and p75NTR-cells isolated from Eca109 into NOD/SCID mice to determine whether p75NTR+ cells possess higher tumorigenicity in immunocompromised mice than p75NTR- cells.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('NOD', 'Gene', (83, 86))	('higher', 'PosReg', (140, 146))	('mice', 'Species', '10090', (183, 187))	('SCID', 'Disease', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('SCID', 'Disease', 'MESH:D053632', (87, 91))	('p75NTR+', 'Var', (118, 125))	('mice', 'Species', '10090', (92, 96))	('NOD', 'Gene', '1822', (83, 86))
884502	19134212	The results confirmed the tumorigenicity of p75NTR+ cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('p75NTR+', 'Var', (44, 51))
884503	19134212	Although p75NTR- cells also exhibited some tumorigenic potential, this may be due to the meta-topical implantation of cells into a more permissive environment (e.g.	('p75NTR- cells', 'Var', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (43, 48))
884505	19134212	(2) p75NTR+ cells isolated from ESCC cell lines were able to generate both p75NTR+ and p75NTR- cells, to form spheres in serum-free medium supplemented with growth factors, and to differentiate into mature esophageal squamous epithelial cells.	('differentiate', 'Reg', (180, 193))	('p75NTR- cells', 'Var', (87, 100))	('p75NTR+', 'Var', (75, 82))	('rat', 'Species', '10116', (65, 68))
884507	19134212	Our results demonstrated that p75NTR+ cells possessed some characteristics of CSCs, namely, self-renewal and chemotherapy resistance.	('self-renewal', 'CPA', (92, 104))	('p75NTR+', 'Var', (30, 37))	('rat', 'Species', '10116', (19, 22))	('CSCs', 'Disease', (78, 82))	('chemotherapy resistance', 'CPA', (109, 132))
884531	33688259	For example, administration of 2 cycles of cisplatin with 5-FU, a previously most commonly used regimen, prior to surgery improved resection rate of R0 (60% vs 54%, P<0.0001) and 5-year survival rate (23% vs 17%, P = 0.03) compared with surgery alone in OEO2 study.	('resection rate', 'CPA', (131, 145))	('cisplatin', 'Var', (43, 52))	('5-year survival', 'CPA', (179, 194))	('5-FU', 'Chemical', 'MESH:D005472', (58, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('improved', 'PosReg', (122, 130))
884534	33688259	Furthermore, a recent study demonstrated that preoperative regimen of cisplatin, 5-FU and paclitaxel improved the pCR rate by 24.1%, R0 resection rate was 82.5%, and the perioperative mortality rate was only 1.9%.	('5-FU', 'Chemical', 'MESH:D005472', (81, 85))	('mortality', 'Disease', (184, 193))	('paclitaxel', 'Chemical', 'MESH:D017239', (90, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('pCR', 'Disease', (114, 117))	('improved', 'PosReg', (101, 109))	('R0 resection', 'CPA', (133, 145))	('mortality', 'Disease', 'MESH:D003643', (184, 193))	('cisplatin', 'Var', (70, 79))
884606	33572115	The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma Inhibition of the protein neddylation process by the small-molecule inhibitor MLN4924 has been recently indicated as a promising direction for cancer treatment.	('MMP9', 'Gene', '4318', (61, 65))	('p', 'Gene', '23436', (88, 89))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('Inflammation', 'Disease', (40, 52))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('Inflammation', 'Disease', 'MESH:D007249', (40, 52))	('cancer', 'Disease', (263, 269))	('p', 'Gene', '23436', (239, 240))	('MLN4924', 'Chemical', 'MESH:C539933', (198, 205))	('p', 'Gene', '23436', (158, 159))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (96, 119))	('p', 'Gene', '23436', (138, 139))	('MLN4924', 'Var', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('Carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('p', 'Gene', '23436', (73, 74))	('MMP9', 'Gene', (61, 65))	('Squamous Cell Carcinoma', 'Disease', (96, 119))
884607	33572115	However, the knowledge of all biological consequences of MLN4924 for cancer cells is still incomplete.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('MLN4924', 'Chemical', 'MESH:C539933', (57, 64))	('p', 'Gene', '23436', (96, 97))	('MLN4924', 'Var', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
884608	33572115	Here, we report that MLN4924 inhibits tumor necrosis factor-alpha (TNF-alpha)-induced matrix metalloproteinase 9 (MMP9)-driven cell migration.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor necrosis factor-alpha', 'Gene', (38, 65))	('tumor necrosis factor-alpha', 'Gene', '7124', (38, 65))	('matrix metalloproteinase 9', 'Gene', '4318', (86, 112))	('p', 'Gene', '23436', (11, 12))	('p', 'Gene', '23436', (62, 63))	('MLN4924', 'Chemical', 'MESH:C539933', (21, 28))	('inhibits', 'NegReg', (29, 37))	('p', 'Gene', '23436', (100, 101))	('TNF-alpha', 'Gene', '7124', (67, 76))	('p', 'Gene', '23436', (73, 74))	('matrix metalloproteinase 9', 'Gene', (86, 112))	('TNF-alpha', 'Gene', (67, 76))	('MLN4924', 'Var', (21, 28))
884609	33572115	Using real-time polymerase chain reaction (PCR) and gelatin zymography, we found that MLN4924 inhibited expression and activity of MMP9 at the messenger RNA (mRNA) and protein levels in both resting cells and cells stimulated with TNF-alpha, and this inhibition was closely related to impaired cell migration.	('MLN4924', 'Var', (86, 93))	('cell migration', 'CPA', (294, 308))	('p', 'Gene', '23436', (16, 17))	('p', 'Gene', '23436', (287, 288))	('p', 'Gene', '23436', (106, 107))	('p', 'Gene', '23436', (168, 169))	('TNF-alpha', 'Gene', '7124', (231, 240))	('MMP9', 'Gene', (131, 135))	('p', 'Gene', '23436', (237, 238))	('TNF-alpha', 'Gene', (231, 240))	('MLN4924', 'Chemical', 'MESH:C539933', (86, 93))	('activity', 'MPA', (119, 127))	('p', 'Gene', '23436', (67, 68))	('inhibited', 'NegReg', (94, 103))
884610	33572115	We also revealed that MLN4924, similar to TNF-alpha, induced phosphorylation of inhibitor of nuclear factor kappa B-alpha (IkappaB-alpha).	('TNF-alpha', 'Gene', '7124', (42, 51))	('induced', 'Reg', (53, 60))	('p', 'Gene', '23436', (61, 62))	('IkappaB-alpha', 'Gene', '4792', (123, 136))	('p', 'Gene', '23436', (133, 134))	('TNF-alpha', 'Gene', (42, 51))	('MLN4924', 'Chemical', 'MESH:C539933', (22, 29))	('p', 'Gene', '23436', (126, 127))	('p', 'Gene', '23436', (127, 128))	('p', 'Gene', '23436', (118, 119))	('p', 'Gene', '23436', (48, 49))	('MLN4924', 'Var', (22, 29))	('p', 'Gene', '23436', (111, 112))	('p', 'Gene', '23436', (65, 66))	('p', 'Gene', '23436', (110, 111))	('nuclear factor kappa B', 'Gene', '4790', (93, 115))	('nuclear factor kappa B', 'Gene', (93, 115))	('IkappaB-alpha', 'Gene', (123, 136))
884611	33572115	However, contrary to TNF-alpha, MLN4924 did not induce IkappaB-alpha degradation in treated cells.	('TNF-alpha', 'Gene', (21, 30))	('MLN4924', 'Chemical', 'MESH:C539933', (32, 39))	('IkappaB-alpha', 'Gene', (55, 68))	('MLN4924', 'Var', (32, 39))	('IkappaB-alpha', 'Gene', '4792', (55, 68))	('TNF-alpha', 'Gene', '7124', (21, 30))
884612	33572115	In coimmunoprecipitation experiments, nuclear IkappaB-alpha which formed complexes with nuclear factor kappa B p65 subunit (NFkappaB/p65) was found to be highly phosphorylated at Ser32 in the cells treated with MLN4924, but not in the cells treated with TNF-alpha alone.	('p', 'Gene', '23436', (161, 162))	('p', 'Gene', '23436', (106, 107))	('p', 'Gene', '23436', (11, 12))	('p', 'Gene', '23436', (27, 28))	('p', 'Gene', '23436', (105, 106))	('p', 'Gene', '23436', (50, 51))	('MLN4924', 'Chemical', 'MESH:C539933', (211, 218))	('p', 'Gene', '23436', (129, 130))	('p', 'Gene', '23436', (49, 50))	('p', 'Gene', '23436', (111, 112))	('p', 'Gene', '23436', (56, 57))	('p', 'Gene', '23436', (128, 129))	('p', 'Gene', '23436', (16, 17))	('p', 'Gene', '23436', (165, 166))	('nuclear factor kappa B p65 subunit (NFkappaB/p65', 'Gene', '5970', (88, 136))	('IkappaB-alpha', 'Gene', (46, 59))	('IkappaB-alpha', 'Gene', '4792', (46, 59))	('TNF-alpha', 'Gene', '7124', (254, 263))	('TNF-alpha', 'Gene', (254, 263))	('p', 'Gene', '23436', (260, 261))	('p', 'Gene', '23436', (133, 134))	('Ser32', 'Chemical', '-', (179, 184))	('MLN4924', 'Var', (211, 218))	('p', 'Gene', '23436', (76, 77))
884613	33572115	Moreover, in the presence of MLN4924, nuclear NFkappaB/p65 complexes were found to be enriched in c-Jun and cyclin dependent kinase inhibitor 1 A (CDKN1A/p21) proteins.	('p', 'Gene', '23436', (159, 160))	('cyclin dependent kinase inhibitor 1 A', 'Gene', (108, 145))	('p', 'Gene', '23436', (50, 51))	('p', 'Gene', '23436', (154, 155))	('cyclin dependent kinase inhibitor 1 A', 'Gene', '1026', (108, 145))	('c-Jun', 'MPA', (98, 103))	('MLN4924', 'Chemical', 'MESH:C539933', (29, 36))	('p21', 'Gene', '1026', (154, 157))	('CDKN1A', 'Gene', (147, 153))	('p', 'Gene', '23436', (117, 118))	('p', 'Gene', '23436', (17, 18))	('p', 'Gene', '23436', (62, 63))	('p', 'Gene', '23436', (55, 56))	('enriched', 'PosReg', (86, 94))	('MLN4924', 'Var', (29, 36))	('CDKN1A', 'Gene', '1026', (147, 153))	('p21', 'Gene', (154, 157))	('p', 'Gene', '23436', (51, 52))
884615	33572115	Taken together, our findings identified MLN4924 as a suppressor of TNF-alpha-induced MMP9-driven cell migration in esophageal squamous cell carcinoma (ESCC), likely acting by affecting the nuclear ubiquitin-proteasome system that governs NFkappaB/p65 complex formation and its DNA binding activity in regard to the MMP9 promoter, suggesting that inhibition of neddylation might be a new therapeutic strategy to prevent invasion/metastasis in ESCC patients.	('p', 'Gene', '23436', (242, 243))	('p', 'Gene', '23436', (243, 244))	('p', 'Gene', '23436', (447, 448))	('p', 'Gene', '23436', (320, 321))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (115, 149))	('p', 'Gene', '23436', (247, 248))	('p', 'Gene', '23436', (254, 255))	('TNF-alpha', 'Gene', '7124', (67, 76))	('MLN4924', 'Var', (40, 47))	('p', 'Gene', '23436', (56, 57))	('p', 'Gene', '23436', (73, 74))	('TNF-alpha', 'Gene', (67, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('p', 'Gene', '23436', (207, 208))	('p', 'Gene', '23436', (411, 412))	('p', 'Gene', '23436', (55, 56))	('cell migration', 'CPA', (97, 111))	('patients', 'Species', '9606', (447, 455))	('p', 'Gene', '23436', (118, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('affecting', 'Reg', (175, 184))	('MLN4924', 'Chemical', 'MESH:C539933', (40, 47))	('p', 'Gene', '23436', (392, 393))	('esophageal squamous cell carcinoma', 'Disease', (115, 149))
884630	33572115	It is obvious that NFkappaB is an essential transcription factor for TNF-alpha-dependent MMP9 expression and the inhibition of NFkappaB activity significantly reduces MMP9 secretion.	('p', 'Gene', '23436', (132, 133))	('TNF-alpha', 'Gene', '7124', (69, 78))	('MMP9', 'Gene', (89, 93))	('p', 'Gene', '23436', (75, 76))	('TNF-alpha', 'Gene', (69, 78))	('activity', 'MPA', (136, 144))	('MMP9 secretion', 'MPA', (167, 181))	('NFkappaB', 'Gene', '4790', (19, 27))	('p', 'Gene', '23436', (81, 82))	('inhibition', 'Var', (113, 123))	('p', 'Gene', '23436', (24, 25))	('reduces', 'NegReg', (159, 166))	('p', 'Gene', '23436', (96, 97))	('p', 'Gene', '23436', (23, 24))	('NFkappaB', 'Gene', (19, 27))	('NFkappaB', 'Gene', '4790', (127, 135))	('NFkappaB', 'Gene', (127, 135))	('p', 'Gene', '23436', (52, 53))	('p', 'Gene', '23436', (131, 132))
884634	33572115	Although the cullin family members are the best-known and studied neddylation targets, other non-cullin proteins including various transcription factors such as tumor protein 53 (TP53), tumor protein 73 (TP73) and E2F have been recently shown to be tagged with NEDD8 and dysregulation of the neddylation appears to be one of the hallmarks of cancers.	('tumor protein 53', 'Gene', '7157', (161, 177))	('p', 'Gene', '23436', (305, 306))	('tumor', 'Disease', (186, 191))	('NEDD8', 'Gene', '4738', (261, 266))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('tumor', 'Disease', (161, 166))	('TP53', 'Gene', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('p', 'Gene', '23436', (167, 168))	('cullin', 'Gene', (97, 103))	('dysregulation', 'Var', (271, 284))	('cancers', 'Phenotype', 'HP:0002664', (342, 349))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('TP73', 'Gene', '7161', (204, 208))	('p', 'Gene', '23436', (192, 193))	('NEDD8', 'Gene', (261, 266))	('p', 'Gene', '23436', (104, 105))	('hallmarks of cancers', 'Disease', (329, 349))	('cullin', 'Gene', '143384', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('hallmarks of cancers', 'Disease', 'MESH:D009369', (329, 349))	('TP73', 'Gene', (204, 208))	('cullin', 'Gene', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('TP53', 'Gene', '7157', (179, 183))	('cullin', 'Gene', '143384', (13, 19))	('p', 'Gene', '23436', (306, 307))	('tumor protein 53', 'Gene', (161, 177))	('E2F', 'Gene', (214, 217))	('p', 'Gene', '23436', (139, 140))
884635	33572115	A decade ago, a highly selective small-molecule inhibitor of NAE, MLN4924 (also known as pevonedistat), was developed to interrupt the growth of tumor cells through the inhibition of CRL-dependent protein degradation, resulting in accumulation of intracellular suppressors of signaling pathways.	('NAE', 'Chemical', '-', (61, 64))	('intracellular', 'MPA', (247, 260))	('MLN4924', 'Var', (66, 73))	('pevonedistat', 'Chemical', 'MESH:C539933', (89, 101))	('p', 'Gene', '23436', (264, 265))	('p', 'Gene', '23436', (114, 115))	('p', 'Gene', '23436', (263, 264))	('p', 'Gene', '23436', (89, 90))	('tumor', 'Disease', (145, 150))	('MLN4924', 'Chemical', 'MESH:C539933', (66, 73))	('p', 'Gene', '23436', (286, 287))	('accumulation', 'PosReg', (231, 243))	('p', 'Gene', '23436', (128, 129))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('p', 'Gene', '23436', (189, 190))	('CRL', 'Gene', (183, 186))	('p', 'Gene', '23436', (197, 198))	('inhibition', 'NegReg', (169, 179))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CRL', 'Gene', '133396', (183, 186))
884636	33572115	Because MLN4924 could affect the cell cycle, DNA replication, DNA damage response and cell motility, it has been recognized as a promising anticancer agent, and is undergoing phase I or phase II clinical testing for several hematological and solid tumors.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('MLN4924', 'Chemical', 'MESH:C539933', (8, 15))	('p', 'Gene', '23436', (76, 77))	('p', 'Gene', '23436', (175, 176))	('p', 'Gene', '23436', (129, 130))	('MLN4924', 'Var', (8, 15))	('tumors', 'Disease', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('cell motility', 'CPA', (86, 99))	('affect', 'Reg', (22, 28))	('cancer', 'Disease', (143, 149))	('p', 'Gene', '23436', (186, 187))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cell cycle', 'CPA', (33, 43))	('p', 'Gene', '23436', (51, 52))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
884637	33572115	Although in many studies MLN4924 was shown to indirectly block NFkappaB activation, the exact mechanism of action of MLN4924 in the regulation of NFkappaB-dependent gene expression is still not fully elucidated.	('MLN4924', 'Var', (25, 32))	('p', 'Gene', '23436', (157, 158))	('MLN4924', 'Var', (117, 124))	('p', 'Gene', '23436', (150, 151))	('activation', 'MPA', (72, 82))	('p', 'Gene', '23436', (68, 69))	('p', 'Gene', '23436', (172, 173))	('NFkappaB', 'Gene', (63, 71))	('p', 'Gene', '23436', (151, 152))	('NFkappaB', 'Gene', '4790', (63, 71))	('MLN4924', 'Chemical', 'MESH:C539933', (117, 124))	('MLN4924', 'Chemical', 'MESH:C539933', (25, 32))	('block', 'NegReg', (57, 62))	('NFkappaB', 'Gene', '4790', (146, 154))	('NFkappaB', 'Gene', (146, 154))	('p', 'Gene', '23436', (67, 68))
884638	33572115	The aim of this study was to investigate the effects of MLN4924 on TNF-alpha-induced expression and secretion of MMP9 in human esophageal squamous cancer cells and to shed some light on the mechanism underlying these processes.	('p', 'Gene', '23436', (130, 131))	('effects', 'Reg', (45, 52))	('squamous cancer', 'Disease', 'MESH:D002294', (138, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('MLN4924', 'Var', (56, 63))	('squamous cancer', 'Disease', (138, 153))	('p', 'Gene', '23436', (217, 218))	('human', 'Species', '9606', (121, 126))	('p', 'Gene', '23436', (87, 88))	('TNF-alpha', 'Gene', '7124', (67, 76))	('secretion', 'MPA', (100, 109))	('p', 'Gene', '23436', (73, 74))	('TNF-alpha', 'Gene', (67, 76))	('squamous cancer', 'Phenotype', 'HP:0002860', (138, 153))	('MLN4924', 'Chemical', 'MESH:C539933', (56, 63))
884639	33572115	We revealed that MLN4924 totally blocks interactions between NFkappaB and the MMP9 gene promoter likely by disruption of the stoichiometric balance within components of the NFkappaB complex.	('NFkappaB', 'Gene', (173, 181))	('p', 'Gene', '23436', (88, 89))	('p', 'Gene', '23436', (177, 178))	('NFkappaB', 'Gene', (61, 69))	('NFkappaB', 'Gene', '4790', (173, 181))	('p', 'Gene', '23436', (112, 113))	('NFkappaB', 'Gene', '4790', (61, 69))	('MMP9 gene', 'Gene', (78, 87))	('interactions', 'Interaction', (40, 52))	('p', 'Gene', '23436', (185, 186))	('p', 'Gene', '23436', (158, 159))	('p', 'Gene', '23436', (178, 179))	('MLN4924', 'Chemical', 'MESH:C539933', (17, 24))	('p', 'Gene', '23436', (66, 67))	('stoichiometric balance', 'MPA', (125, 147))	('p', 'Gene', '23436', (65, 66))	('MLN4924', 'Var', (17, 24))	('blocks', 'NegReg', (33, 39))
884644	33572115	The pre-treatment of ESCC cells with MLN4924 inhibited TNF-alpha-induced secretion of MMP9 in both KYSE70 and KYSE150 cells.	('p', 'Gene', '23436', (61, 62))	('secretion of MMP9', 'MPA', (73, 90))	('MLN4924', 'Chemical', 'MESH:C539933', (37, 44))	('TNF-alpha', 'Gene', '7124', (55, 64))	('p', 'Gene', '23436', (4, 5))	('KYSE150', 'CellLine', 'CVCL:1348', (110, 117))	('TNF-alpha', 'Gene', (55, 64))	('MLN4924', 'Var', (37, 44))	('inhibited', 'NegReg', (45, 54))
884645	33572115	In gelatin zymograms, activity of MMP9 in the conditioned medium was undetectable even at MLN4924 concentration as low as 0.2 microM.	('activity', 'MPA', (22, 30))	('undetectable', 'NegReg', (69, 81))	('MLN4924', 'Var', (90, 97))	('MLN4924', 'Chemical', 'MESH:C539933', (90, 97))
884646	33572115	The inhibitory effect of MLN4924 on MMP9 expression was verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR).	('p', 'Gene', '23436', (43, 44))	('MLN4924', 'Var', (25, 32))	('p', 'Gene', '23436', (113, 114))	('MMP9', 'Gene', (36, 40))	('MLN4924', 'Chemical', 'MESH:C539933', (25, 32))	('p', 'Gene', '23436', (84, 85))
884647	33572115	As shown in Figure 1B, in the cells treated with MLN4924 alone, a meaningful reduction of the MMP9 mRNA level (fold change = 0.7 and 0.4 in KYSE70 and KYSE150, respectively) to below the basal level found in control untreated cells (p < 0.05) was observed.	('MLN4924', 'Var', (49, 56))	('KYSE150', 'CellLine', 'CVCL:1348', (151, 158))	('reduction', 'NegReg', (77, 86))	('p', 'Gene', '23436', (233, 234))	('MMP9 mRNA level', 'MPA', (94, 109))	('p', 'Gene', '23436', (163, 164))	('MLN4924', 'Chemical', 'MESH:C539933', (49, 56))	('KYSE150', 'Var', (151, 158))	('KYSE70', 'MPA', (140, 146))
884648	33572115	In the cells treated with TNF-alpha combined with MLN4924, the mRNA level of MMP9 was similar to that observed in untreated cells and remarkably lower as compared with the cells stimulated with TNF-alpha alone.	('p', 'Gene', '23436', (32, 33))	('p', 'Gene', '23436', (157, 158))	('mRNA level of MMP9', 'MPA', (63, 81))	('MLN4924', 'Chemical', 'MESH:C539933', (50, 57))	('TNF-alpha', 'Gene', '7124', (194, 203))	('MLN4924', 'Var', (50, 57))	('lower', 'NegReg', (145, 150))	('TNF-alpha', 'Gene', '7124', (26, 35))	('TNF-alpha', 'Gene', (194, 203))	('p', 'Gene', '23436', (200, 201))	('TNF-alpha', 'Gene', (26, 35))
884650	33572115	To determine the role of MLN4924 in modulating the availability of transcriptional regulators of the MMP9 gene promoter, the levels of NFkappaB/p65, SP1, c-Jun and CDKN1A/p21 proteins were analyzed by Western blotting in KYSE150 cells.	('p21', 'Gene', (171, 174))	('MLN4924', 'Var', (25, 32))	('p', 'Gene', '23436', (75, 76))	('p', 'Gene', '23436', (171, 172))	('CDKN1A', 'Gene', '1026', (164, 170))	('p', 'Gene', '23436', (144, 145))	('p', 'Gene', '23436', (175, 176))	('p', 'Gene', '23436', (140, 141))	('CDKN1A', 'Gene', (164, 170))	('KYSE150', 'CellLine', 'CVCL:1348', (221, 228))	('p', 'Gene', '23436', (111, 112))	('MLN4924', 'Chemical', 'MESH:C539933', (25, 32))	('p21', 'Gene', '1026', (171, 174))	('p', 'Gene', '23436', (139, 140))
884651	33572115	We observed a significant increase in levels of c-Jun and CDKN1A/p21 in a dose- and time-dependent manner in the cells treated with MLN4924 as compared with non-stimulated cells or those stimulated with TNF-alpha alone (Figure 1A, Figure 2 and Figure S1).	('MLN4924', 'Chemical', 'MESH:C539933', (132, 139))	('p', 'Gene', '23436', (91, 92))	('TNF-alpha', 'Gene', '7124', (203, 212))	('p21', 'Gene', '1026', (65, 68))	('increase', 'PosReg', (26, 34))	('p21', 'Gene', (65, 68))	('TNF-alpha', 'Gene', (203, 212))	('MLN4924', 'Var', (132, 139))	('p', 'Gene', '23436', (209, 210))	('CDKN1A', 'Gene', (58, 64))	('p', 'Gene', '23436', (146, 147))	('CDKN1A', 'Gene', '1026', (58, 64))	('p', 'Gene', '23436', (65, 66))	('c-Jun', 'MPA', (48, 53))	('levels', 'MPA', (38, 44))
884652	33572115	These data provide evidence that MLN4924 selectively inhibits MMP9 activity in ESCC cells and confirm the presence of alterations in the composition of MMP9-associated transcriptional regulators under the treatment with MLN4924.	('MLN4924', 'Var', (220, 227))	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('alterations', 'Reg', (118, 129))	('p', 'Gene', '23436', (106, 107))	('p', 'Gene', '23436', (140, 141))	('p', 'Gene', '23436', (11, 12))	('activity', 'MPA', (67, 75))	('MLN4924', 'Var', (33, 40))	('MLN4924', 'Chemical', 'MESH:C539933', (220, 227))	('p', 'Gene', '23436', (176, 177))	('inhibits', 'NegReg', (53, 61))	('MMP9', 'Enzyme', (62, 66))
884656	33572115	In the presence of MLN4924, the pro-migratory activity of TNF-alpha on esophageal squamous cancer cells was significantly reduced (p < 0.005).	('p', 'Gene', '23436', (32, 33))	('p', 'Gene', '23436', (74, 75))	('TNF-alpha', 'Gene', '7124', (58, 67))	('TNF-alpha', 'Gene', (58, 67))	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('p', 'Gene', '23436', (64, 65))	('squamous cancer', 'Phenotype', 'HP:0002860', (82, 97))	('MLN4924', 'Var', (19, 26))	('reduced', 'NegReg', (122, 129))	('p', 'Gene', '23436', (7, 8))	('squamous cancer', 'Disease', 'MESH:D002294', (82, 97))	('p', 'Gene', '23436', (131, 132))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('squamous cancer', 'Disease', (82, 97))
884657	33572115	Motility of the cells treated with TNF-alpha in combination with MLN4924 was significantly lower even when compared with untreated control cells (p < 0.05).	('lower', 'NegReg', (91, 96))	('MLN4924', 'Var', (65, 72))	('TNF-alpha', 'Gene', '7124', (35, 44))	('Motility', 'CPA', (0, 8))	('TNF-alpha', 'Gene', (35, 44))	('p', 'Gene', '23436', (41, 42))	('p', 'Gene', '23436', (146, 147))	('MLN4924', 'Chemical', 'MESH:C539933', (65, 72))	('p', 'Gene', '23436', (110, 111))
884658	33572115	The ratio of artificial wound closure in the culture treated with MLN4924 only was found to be the lowest of all and this effect was statistically significant at both 24 h and 48 h as compared with other cells (Figure 1D).	('artificial wound closure', 'CPA', (13, 37))	('lowest', 'NegReg', (99, 105))	('MLN4924 only', 'Var', (66, 78))	('MLN4924', 'Chemical', 'MESH:C539933', (66, 73))	('p', 'Gene', '23436', (187, 188))
884659	33572115	As we observed, the treatment of ESCC cells with MLN4924 with a range of concentrations up to 1 muM did not result in changes in cell viability within 24 h. Cell growth decreased by 50% in both KYSE70 and KYSE150 after 48 h of treatment with MLN4924, but not with TNF-alpha (Figure S2).	('TNF-alpha', 'Gene', '7124', (264, 273))	('p', 'Gene', '23436', (270, 271))	('MLN4924', 'Chemical', 'MESH:C539933', (242, 249))	('p', 'Gene', '23436', (89, 90))	('KYSE150', 'Var', (205, 212))	('MLN4924', 'Var', (242, 249))	('TNF-alpha', 'Gene', (264, 273))	('Cell growth', 'CPA', (157, 168))	('KYSE150', 'CellLine', 'CVCL:1348', (205, 212))	('decreased', 'NegReg', (169, 178))	('MLN4924', 'Chemical', 'MESH:C539933', (49, 56))	('KYSE70', 'Var', (194, 200))
884660	33572115	However, only the treatment of ESCC cells with MLN4924 at the concentration >= 25 muM led to cell apoptosis confirmed by alterations in cell morphology and cleavage of PARP1 (proteins including poly(ADP-ribose) polymerase-1) in an 89 kDa fragment (Figure S3).	('p', 'Gene', '23436', (211, 212))	('poly(ADP-ribose) polymerase-1', 'Gene', (194, 223))	('p', 'Gene', '23436', (194, 195))	('p', 'Gene', '23436', (99, 100))	('p', 'Gene', '23436', (144, 145))	('p', 'Gene', '23436', (175, 176))	('MLN4924', 'Chemical', 'MESH:C539933', (47, 54))	('PARP1', 'Gene', '142', (168, 173))	('poly(ADP-ribose) polymerase-1', 'Gene', '142', (194, 223))	('p', 'Gene', '23436', (101, 102))	('MLN4924', 'Var', (47, 54))	('cleavage', 'MPA', (156, 164))	('alterations', 'Reg', (121, 132))	('PARP1', 'Gene', (168, 173))
884661	33572115	These data confirm that MLN4924 may inhibit migration of ESCC cells independently of apoptosis.	('p', 'Gene', '23436', (88, 89))	('MLN4924', 'Var', (24, 31))	('ESCC', 'Disease', (57, 61))	('inhibit', 'NegReg', (36, 43))	('p', 'Gene', '23436', (86, 87))	('p', 'Gene', '23436', (72, 73))	('migration', 'CPA', (44, 53))	('MLN4924', 'Chemical', 'MESH:C539933', (24, 31))
884663	33572115	In this study, we used a membrane-based antibody array to evaluate relative levels of 45 selected NFkappaB pathway proteins in the cells exposed to MLN4924 or TNF-alpha (Figure S4).	('p', 'Gene', '23436', (102, 103))	('MLN4924', 'Chemical', 'MESH:C539933', (148, 155))	('p', 'Gene', '23436', (165, 166))	('NFkappaB', 'Gene', (98, 106))	('TNF-alpha', 'Gene', '7124', (159, 168))	('NFkappaB', 'Gene', '4790', (98, 106))	('MLN4924', 'Var', (148, 155))	('p', 'Gene', '23436', (103, 104))	('p', 'Gene', '23436', (107, 108))	('TNF-alpha', 'Gene', (159, 168))	('p', 'Gene', '23436', (115, 116))	('p', 'Gene', '23436', (139, 140))
884664	33572115	The level of phosphorylation of p53 (Ser46), NFkappaB/p65 (Ser529), STAT1 (Tyr701) and STAT2 (Tyr689) was determined and normalized to total proteins (Figure 2A).	('STAT1', 'Gene', (68, 73))	('Ser46', 'Var', (37, 42))	('Ser529', 'Chemical', '-', (59, 65))	('Tyr689', 'Var', (94, 100))	('p53', 'Gene', '7157', (32, 35))	('p', 'Gene', '23436', (50, 51))	('STAT1', 'Gene', '6772', (68, 73))	('Ser529', 'Var', (59, 65))	('STAT2', 'Gene', '6773', (87, 92))	('p53', 'Gene', (32, 35))	('p', 'Gene', '23436', (17, 18))	('p', 'Gene', '23436', (49, 50))	('STAT2', 'Gene', (87, 92))	('p', 'Gene', '23436', (32, 33))	('p', 'Gene', '23436', (141, 142))	('Ser46', 'Chemical', '-', (37, 42))	('p', 'Gene', '23436', (54, 55))	('p', 'Gene', '23436', (13, 14))	('Tyr689', 'Chemical', '-', (94, 100))	('Tyr701', 'Chemical', '-', (75, 81))	('Tyr701', 'Var', (75, 81))
884665	33572115	The treatment with MLN4924 and TNF-alpha, either separately or in combination, resulted in a 1.1-fold, 1.6-fold and 2.4-fold increase, respectively, in NFkappaB/p65 (Ser529) phosphorylation and a 1.3-fold, 1.6-fold and 1.7-fold increase, respectively, in STAT2 (Tyr689) phosphorylation as compared with the untreated controls.	('TNF-alpha', 'Gene', '7124', (31, 40))	('p', 'Gene', '23436', (274, 275))	('p', 'Gene', '23436', (161, 162))	('TNF-alpha', 'Gene', (31, 40))	('p', 'Gene', '23436', (178, 179))	('MLN4924', 'Var', (19, 26))	('p', 'Gene', '23436', (241, 242))	('p', 'Gene', '23436', (51, 52))	('increase', 'PosReg', (125, 133))	('increase', 'PosReg', (228, 236))	('STAT2', 'Gene', '6773', (255, 260))	('STAT2', 'Gene', (255, 260))	('p', 'Gene', '23436', (270, 271))	('p', 'Gene', '23436', (157, 158))	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('p', 'Gene', '23436', (174, 175))	('p', 'Gene', '23436', (292, 293))	('Ser529', 'Chemical', '-', (166, 172))	('p', 'Gene', '23436', (37, 38))	('Tyr689', 'Chemical', '-', (262, 268))	('p', 'Gene', '23436', (138, 139))	('p', 'Gene', '23436', (156, 157))
884666	33572115	On the other hand, the phosphorylation level of STAT1 (Tyr701) was found to be decreased with a fold change = 0.6 under MLN4924 treatment.	('STAT1', 'Gene', (48, 53))	('decreased', 'NegReg', (79, 88))	('STAT1', 'Gene', '6772', (48, 53))	('Tyr701', 'Chemical', '-', (55, 61))	('Tyr701', 'Var', (55, 61))	('MLN4924', 'Chemical', 'MESH:C539933', (120, 127))	('p', 'Gene', '23436', (27, 28))	('MLN4924', 'Var', (120, 127))	('p', 'Gene', '23436', (23, 24))
884668	33572115	Of the other proteins, NFkappaB inhibitors, IkappaB-alpha and IkappaB-epsilon, and two IkappaB kinases, IKK1 and IKK2, were downregulated in the TNF-alpha-stimulated cells with a fold change = 0.5 and 0.7, respectively, but they remained unchanged in the presence of MLN4924 when compared with untreated control cells (Figure 2B).	('NFkappaB', 'Gene', (23, 31))	('p', 'Gene', '23436', (91, 92))	('p', 'Gene', '23436', (209, 210))	('p', 'Gene', '23436', (90, 91))	('p', 'Gene', '23436', (27, 28))	('p', 'Gene', '23436', (66, 67))	('IkappaB-alpha', 'Gene', (44, 57))	('IKK2', 'Gene', '3551', (113, 117))	('IkappaB-alpha', 'Gene', '4792', (44, 57))	('MLN4924', 'Chemical', 'MESH:C539933', (267, 274))	('p', 'Gene', '23436', (48, 49))	('p', 'Gene', '23436', (255, 256))	('p', 'Gene', '23436', (65, 66))	('p', 'Gene', '23436', (47, 48))	('p', 'Gene', '23436', (71, 72))	('TNF-alpha', 'Gene', '7124', (145, 154))	('downregulated', 'NegReg', (124, 137))	('IKK2', 'Gene', (113, 117))	('p', 'Gene', '23436', (151, 152))	('TNF-alpha', 'Gene', (145, 154))	('p', 'Gene', '23436', (283, 284))	('IKK1', 'Gene', '1147', (104, 108))	('NFkappaB', 'Gene', '4790', (23, 31))	('p', 'Gene', '23436', (54, 55))	('IKK1', 'Gene', (104, 108))	('p', 'Gene', '23436', (13, 14))	('p', 'Gene', '23436', (28, 29))	('MLN4924', 'Var', (267, 274))
884672	33572115	Unlike the classical IkappaB-alpha phosphorylation/degradation process induced by TNF-alpha, the MLN4924-related phosphorylation of IkappaB-alpha at Ser32 occurred over one hour and increased in a time-dependent manner (Figure 2D).	('increased', 'PosReg', (182, 191))	('IkappaB-alpha', 'Gene', (21, 34))	('IkappaB-alpha', 'Gene', '4792', (21, 34))	('IkappaB-alpha', 'Gene', (132, 145))	('p', 'Gene', '23436', (35, 36))	('IkappaB-alpha', 'Gene', '4792', (132, 145))	('p', 'Gene', '23436', (88, 89))	('p', 'Gene', '23436', (113, 114))	('p', 'Gene', '23436', (136, 137))	('p', 'Gene', '23436', (24, 25))	('p', 'Gene', '23436', (63, 64))	('p', 'Gene', '23436', (142, 143))	('TNF-alpha', 'Gene', '7124', (82, 91))	('p', 'Gene', '23436', (25, 26))	('TNF-alpha', 'Gene', (82, 91))	('p', 'Gene', '23436', (135, 136))	('p', 'Gene', '23436', (39, 40))	('p', 'Gene', '23436', (117, 118))	('p', 'Gene', '23436', (31, 32))	('MLN4924-related', 'Var', (97, 112))	('p', 'Gene', '23436', (204, 205))	('MLN4924', 'Chemical', 'MESH:C539933', (97, 104))	('Ser32', 'Chemical', '-', (149, 154))
884675	33572115	The increase in total c-Jun under MLN4924 was found to be positively correlated with the phosphorylation level at Ser73.	('MLN4924', 'Var', (34, 41))	('p', 'Gene', '23436', (89, 90))	('Ser73', 'Chemical', '-', (114, 119))	('p', 'Gene', '23436', (58, 59))	('p', 'Gene', '23436', (93, 94))	('MLN4924', 'Chemical', 'MESH:C539933', (34, 41))	('increase', 'PosReg', (4, 12))
884676	33572115	Treatment of ESCC cells with varying concentrations of MLN4924 up to 5.0 microM within 48 h did not lead to changes in total NFkappaB/p65 and SP1 levels (Figure S5).	('p', 'Gene', '23436', (130, 131))	('p', 'Gene', '23436', (134, 135))	('MLN4924', 'Var', (55, 62))	('p', 'Gene', '23436', (64, 65))	('p', 'Gene', '23436', (129, 130))	('SP1 levels', 'MPA', (142, 152))	('MLN4924', 'Chemical', 'MESH:C539933', (55, 62))
884677	33572115	These data indicate that MLN4924 by itself upregulates phosphorylation of both IkappaB-alpha and NFkappaB/p65, as well as c-Jun, in a time- and dose-dependent manner in ESCC cells, suggesting its ability to activate NFkappaB signaling.	('p', 'Gene', '23436', (82, 83))	('p', 'Gene', '23436', (44, 45))	('p', 'Gene', '23436', (106, 107))	('MLN4924', 'Var', (25, 32))	('p', 'Gene', '23436', (89, 90))	('NFkappaB', 'Gene', '4790', (216, 224))	('p', 'Gene', '23436', (221, 222))	('NFkappaB', 'Gene', '4790', (97, 105))	('p', 'Gene', '23436', (102, 103))	('IkappaB-alpha', 'Gene', (79, 92))	('IkappaB-alpha', 'Gene', '4792', (79, 92))	('NFkappaB', 'Gene', (216, 224))	('c-Jun', 'MPA', (122, 127))	('p', 'Gene', '23436', (151, 152))	('activate', 'PosReg', (207, 215))	('p', 'Gene', '23436', (55, 56))	('MLN4924', 'Chemical', 'MESH:C539933', (25, 32))	('NFkappaB', 'Gene', (97, 105))	('p', 'Gene', '23436', (101, 102))	('p', 'Gene', '23436', (59, 60))	('p', 'Gene', '23436', (83, 84))	('p', 'Gene', '23436', (220, 221))
884678	33572115	To analyze the effects of MLN4924 and TNF-alpha on intracellular localization of phosphorylated forms of NFkappaB/p65 (Ser536) and IkappaB-alpha (Ser32), cytoplasmic and nuclear fractions were separated.	('TNF-alpha', 'Gene', (38, 47))	('p', 'Gene', '23436', (44, 45))	('Ser536', 'Chemical', '-', (119, 125))	('IkappaB-alpha', 'Gene', (131, 144))	('MLN4924', 'Var', (26, 33))	('IkappaB-alpha', 'Gene', '4792', (131, 144))	('p', 'Gene', '23436', (114, 115))	('p', 'Gene', '23436', (81, 82))	('p', 'Gene', '23436', (135, 136))	('p', 'Gene', '23436', (134, 135))	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('p', 'Gene', '23436', (158, 159))	('p', 'Gene', '23436', (110, 111))	('p', 'Gene', '23436', (141, 142))	('p', 'Gene', '23436', (109, 110))	('p', 'Gene', '23436', (85, 86))	('p', 'Gene', '23436', (195, 196))	('Ser536', 'Var', (119, 125))	('Ser32', 'Chemical', '-', (146, 151))	('TNF-alpha', 'Gene', '7124', (38, 47))
884680	33572115	In the presence of MLN4924, the level of nuclear phospho-NFkappaB/p65 was slightly lowered as compared with that of control untreated cells.	('p', 'Gene', '23436', (61, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('p', 'Gene', '23436', (62, 63))	('lowered', 'NegReg', (83, 90))	('MLN4924', 'Var', (19, 26))	('p', 'Gene', '23436', (7, 8))	('p', 'Gene', '23436', (97, 98))	('p', 'Gene', '23436', (49, 50))	('p', 'Gene', '23436', (66, 67))	('p', 'Gene', '23436', (53, 54))
884681	33572115	However, a significantly increased phospho-NFkappaB/p65 level was found in nuclei of the cells treated with TNF-alpha alone, as well as in combination with MLN4924.	('p', 'Gene', '23436', (47, 48))	('MLN4924', 'Chemical', 'MESH:C539933', (156, 163))	('increased', 'PosReg', (25, 34))	('TNF-alpha', 'Gene', '7124', (108, 117))	('TNF-alpha', 'Gene', (108, 117))	('p', 'Gene', '23436', (48, 49))	('p', 'Gene', '23436', (35, 36))	('MLN4924', 'Var', (156, 163))	('p', 'Gene', '23436', (52, 53))	('p', 'Gene', '23436', (114, 115))	('p', 'Gene', '23436', (39, 40))
884682	33572115	Contrary to NFkappaB/p65, the levels of nuclear phospho-IkappaB-alpha were found to be remarkably upregulated in the cells treated with MLN4924 but only slightly increased in the cells treated with TNF-alpha only as compared to untreated controls.	('p', 'Gene', '23436', (16, 17))	('p', 'Gene', '23436', (99, 100))	('p', 'Gene', '23436', (60, 61))	('MLN4924', 'Chemical', 'MESH:C539933', (136, 143))	('IkappaB-alpha', 'Gene', (56, 69))	('p', 'Gene', '23436', (59, 60))	('p', 'Gene', '23436', (21, 22))	('p', 'Gene', '23436', (219, 220))	('TNF-alpha', 'Gene', '7124', (198, 207))	('p', 'Gene', '23436', (17, 18))	('p', 'Gene', '23436', (48, 49))	('MLN4924', 'Var', (136, 143))	('IkappaB-alpha', 'Gene', '4792', (56, 69))	('p', 'Gene', '23436', (66, 67))	('TNF-alpha', 'Gene', (198, 207))	('p', 'Gene', '23436', (52, 53))	('p', 'Gene', '23436', (204, 205))
884684	33572115	Interestingly, we found dramatically lowered levels of total IkappaB-alpha in the cells treated with both MLN4924 and TNF-alpha in relation to untreated controls (Figure 3A).	('levels', 'MPA', (45, 51))	('lowered', 'NegReg', (37, 44))	('IkappaB-alpha', 'Gene', '4792', (61, 74))	('TNF-alpha', 'Gene', '7124', (118, 127))	('MLN4924', 'Chemical', 'MESH:C539933', (106, 113))	('TNF-alpha', 'Gene', (118, 127))	('MLN4924', 'Var', (106, 113))	('IkappaB-alpha', 'Gene', (61, 74))
884685	33572115	The changes in the localization of phosphorylated NFkappaB/p65 at Ser536 in ESCC cells treated with MLN4924 and TNF-alpha applied separately or in combination were also investigated by immunocytochemistry.	('p', 'Gene', '23436', (132, 133))	('p', 'Gene', '23436', (54, 55))	('MLN4924', 'Var', (100, 107))	('MLN4924', 'Chemical', 'MESH:C539933', (100, 107))	('p', 'Gene', '23436', (59, 60))	('p', 'Gene', '23436', (123, 124))	('Ser536', 'Var', (66, 72))	('Ser536', 'Chemical', '-', (66, 72))	('p', 'Gene', '23436', (35, 36))	('p', 'Gene', '23436', (55, 56))	('TNF-alpha', 'Gene', '7124', (112, 121))	('p', 'Gene', '23436', (118, 119))	('p', 'Gene', '23436', (124, 125))	('TNF-alpha', 'Gene', (112, 121))	('p', 'Gene', '23436', (39, 40))
884687	33572115	However, the phospho-NFkappaB/p65-related fluorescence could also be observed in nuclei of many MLN4924-treated cells.	('p', 'Gene', '23436', (26, 27))	('fluorescence', 'MPA', (42, 54))	('p', 'Gene', '23436', (30, 31))	('p', 'Gene', '23436', (13, 14))	('p', 'Gene', '23436', (25, 26))	('p', 'Gene', '23436', (17, 18))	('MLN4924', 'Chemical', 'MESH:C539933', (96, 103))	('observed', 'Reg', (69, 77))	('MLN4924-treated', 'Var', (96, 111))
884689	33572115	Taken together, our findings show that MLN4924 treatment significantly impairs the passage of phosphorylated forms of NFkappaB/p65 from the cytosol into the nucleus and simultaneously increases nuclear levels of phospho-IkappaB-alpha.	('IkappaB-alpha', 'Gene', '4792', (220, 233))	('p', 'Gene', '23436', (98, 99))	('p', 'Gene', '23436', (230, 231))	('p', 'Gene', '23436', (122, 123))	('MLN4924', 'Chemical', 'MESH:C539933', (39, 46))	('increases', 'PosReg', (184, 193))	('IkappaB-alpha', 'Gene', (220, 233))	('p', 'Gene', '23436', (123, 124))	('p', 'Gene', '23436', (127, 128))	('p', 'Gene', '23436', (83, 84))	('p', 'Gene', '23436', (223, 224))	('p', 'Gene', '23436', (212, 213))	('p', 'Gene', '23436', (224, 225))	('MLN4924', 'Var', (39, 46))	('p', 'Gene', '23436', (216, 217))	('p', 'Gene', '23436', (73, 74))	('p', 'Gene', '23436', (94, 95))
884690	33572115	To investigate the ability of NFkappaB/p65 to form nuclear complexes with its protein partners, coimmunoprecipitation studies were performed on the nuclear fractions of cells treated with MLN4924 or TNF-alpha using the anti-NFkappaB/p65 antibody.	('p', 'Gene', '23436', (205, 206))	('p', 'Gene', '23436', (228, 229))	('p', 'Gene', '23436', (78, 79))	('TNF-alpha', 'Gene', (199, 208))	('p', 'Gene', '23436', (109, 110))	('p', 'Gene', '23436', (34, 35))	('MLN4924', 'Chemical', 'MESH:C539933', (188, 195))	('p', 'Gene', '23436', (233, 234))	('p', 'Gene', '23436', (62, 63))	('p', 'Gene', '23436', (35, 36))	('p', 'Gene', '23436', (86, 87))	('p', 'Gene', '23436', (131, 132))	('p', 'Gene', '23436', (229, 230))	('p', 'Gene', '23436', (104, 105))	('MLN4924', 'Var', (188, 195))	('p', 'Gene', '23436', (39, 40))	('TNF-alpha', 'Gene', '7124', (199, 208))
884692	33572115	However, the presence of MLN4924 resulted in a considerably increased signal of phospho-IkappaB-alpha (Ser32) as well as of c-Jun/phospho-c-Jun (Ser73) with NFkappaB when compared with the cells treated with TNF-alpha alone or untreated controls.	('p', 'Gene', '23436', (130, 131))	('p', 'Gene', '23436', (91, 92))	('p', 'Gene', '23436', (98, 99))	('NFkappaB', 'Gene', (157, 165))	('p', 'Gene', '23436', (161, 162))	('MLN4924', 'Var', (25, 32))	('IkappaB-alpha', 'Gene', (88, 101))	('Ser32', 'Chemical', '-', (103, 108))	('p', 'Gene', '23436', (214, 215))	('p', 'Gene', '23436', (80, 81))	('increased', 'PosReg', (60, 69))	('IkappaB-alpha', 'Gene', '4792', (88, 101))	('p', 'Gene', '23436', (134, 135))	('TNF-alpha', 'Gene', '7124', (208, 217))	('p', 'Gene', '23436', (174, 175))	('MLN4924', 'Chemical', 'MESH:C539933', (25, 32))	('TNF-alpha', 'Gene', (208, 217))	('p', 'Gene', '23436', (84, 85))	('p', 'Gene', '23436', (92, 93))	('NFkappaB', 'Gene', '4790', (157, 165))	('p', 'Gene', '23436', (13, 14))	('Ser73', 'Chemical', '-', (145, 150))	('p', 'Gene', '23436', (162, 163))
884695	33572115	These data confirm that the composition of NFkappaB nuclear complexes is significantly impaired in the presence of MLN4924, resulting in excessive levels of phosphorylated forms of IkappaB-alpha and c-Jun.	('p', 'Gene', '23436', (161, 162))	('p', 'Gene', '23436', (185, 186))	('MLN4924', 'Var', (115, 122))	('excessive', 'PosReg', (137, 146))	('p', 'Gene', '23436', (184, 185))	('NFkappaB', 'Gene', '4790', (43, 51))	('p', 'Gene', '23436', (89, 90))	('p', 'Gene', '23436', (63, 64))	('p', 'Gene', '23436', (103, 104))	('p', 'Gene', '23436', (48, 49))	('p', 'Gene', '23436', (191, 192))	('NFkappaB', 'Gene', (43, 51))	('p', 'Gene', '23436', (47, 48))	('p', 'Gene', '23436', (157, 158))	('MLN4924', 'Chemical', 'MESH:C539933', (115, 122))	('p', 'Gene', '23436', (31, 32))	('IkappaB-alpha', 'Gene', (181, 194))	('IkappaB-alpha', 'Gene', '4792', (181, 194))	('c-Jun', 'MPA', (199, 204))
884696	33572115	Additionally, CDKN1A/p21 protein was identified in NFkappaB/p65-containing complexes in the cells treated with MLN4924.	('p21', 'Gene', (21, 24))	('MLN4924', 'Chemical', 'MESH:C539933', (111, 118))	('p', 'Gene', '23436', (78, 79))	('p', 'Gene', '23436', (60, 61))	('MLN4924', 'Var', (111, 118))	('p', 'Gene', '23436', (56, 57))	('p', 'Gene', '23436', (21, 22))	('p', 'Gene', '23436', (25, 26))	('p', 'Gene', '23436', (55, 56))	('p21', 'Gene', '1026', (21, 24))	('CDKN1A', 'Gene', (14, 20))	('CDKN1A', 'Gene', '1026', (14, 20))
884698	33572115	To determine the inhibitory effect of MLN4924 on the binding ability of NFkappaB to the MMP9 promoter, the chromatin immunoprecipitation quantitative real-time PCR (ChIP-qPCR) assay was performed using an antibody directed against NFkappaB.	('p', 'Gene', '23436', (236, 237))	('NFkappaB', 'Gene', '4790', (231, 239))	('MLN4924', 'Var', (38, 45))	('p', 'Gene', '23436', (235, 236))	('p', 'Gene', '23436', (77, 78))	('p', 'Gene', '23436', (123, 124))	('p', 'Gene', '23436', (93, 94))	('p', 'Gene', '23436', (186, 187))	('p', 'Gene', '23436', (128, 129))	('NFkappaB', 'Gene', (72, 80))	('p', 'Gene', '23436', (76, 77))	('binding', 'Interaction', (53, 60))	('MLN4924', 'Chemical', 'MESH:C539933', (38, 45))	('NFkappaB', 'Gene', '4790', (72, 80))	('NFkappaB', 'Gene', (231, 239))
884700	33572115	Contrary to non-treated controls or TNF-alpha-treated cells, in MLN4924-treated cells, binding of NFkappaB to the MMP9 promoter was inhibited.	('inhibited', 'NegReg', (132, 141))	('p', 'Gene', '23436', (102, 103))	('NFkappaB', 'Gene', (98, 106))	('p', 'Gene', '23436', (119, 120))	('MLN4924-treated', 'Var', (64, 79))	('NFkappaB', 'Gene', '4790', (98, 106))	('binding', 'Interaction', (87, 94))	('p', 'Gene', '23436', (103, 104))	('p', 'Gene', '23436', (42, 43))	('MLN4924', 'Chemical', 'MESH:C539933', (64, 71))	('TNF-alpha', 'Gene', '7124', (36, 45))	('TNF-alpha', 'Gene', (36, 45))
884701	33572115	In the presence of MLN4924, the specific ChIP reaction with an NFkappaB/p65 antibody yielded results similar to those of the non-specific antibody control (fold enrichment = 1.13 +- 0.66), while use of this antibody in the cells untreated or treated with TNF-alpha resulted in 1.7 +- 0.04- and 4.5 +- 0.45-fold enrichment of the DNA template, respectively (Figure 4C).	('p', 'Gene', '23436', (130, 131))	('p', 'Gene', '23436', (346, 347))	('TNF-alpha', 'Gene', '7124', (255, 264))	('p', 'Gene', '23436', (336, 337))	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('TNF-alpha', 'Gene', (255, 264))	('p', 'Gene', '23436', (68, 69))	('MLN4924', 'Var', (19, 26))	('p', 'Gene', '23436', (7, 8))	('p', 'Gene', '23436', (261, 262))	('p', 'Gene', '23436', (72, 73))	('p', 'Gene', '23436', (33, 34))	('p', 'Gene', '23436', (67, 68))
884702	33572115	Taken together, these data confirm that MLN4924 treatment results in a loss of interactions between NFkappaB/p65 and the MMP9 gene promoter.	('p', 'Gene', '23436', (105, 106))	('MMP9 gene', 'Gene', (121, 130))	('p', 'Gene', '23436', (109, 110))	('interactions', 'Interaction', (79, 91))	('MLN4924', 'Chemical', 'MESH:C539933', (40, 47))	('loss', 'NegReg', (71, 75))	('MLN4924', 'Var', (40, 47))	('p', 'Gene', '23436', (131, 132))	('p', 'Gene', '23436', (104, 105))
884708	33572115	It was consistent with a study on MMP9-deficient mice showing that the loss of MMP9-cell surface interactions dramatically decreases tumor cell motility and invasiveness.	('decreases', 'NegReg', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mice', 'Species', '10090', (49, 53))	('tumor', 'Disease', (133, 138))	('invasiveness', 'CPA', (157, 169))	('loss', 'Var', (71, 75))	('MMP9-cell surface interactions', 'Protein', (79, 109))
884711	33572115	In the presence of MLN4924, TNF-alpha-induced MMP9 expression was totally abrogated while expression of other metalloproteinases, such as MMP2 or MMP14, was not affected at neither the mRNA or protein level.	('p', 'Gene', '23436', (92, 93))	('TNF-alpha', 'Gene', (28, 37))	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('p', 'Gene', '23436', (34, 35))	('MMP2', 'Gene', (138, 142))	('p', 'Gene', '23436', (117, 118))	('MMP9', 'Gene', (46, 50))	('MLN4924', 'Var', (19, 26))	('abrogated', 'NegReg', (74, 83))	('MMP14', 'Gene', '4323', (146, 151))	('p', 'Gene', '23436', (7, 8))	('MMP2', 'Gene', '4313', (138, 142))	('TNF-alpha', 'Gene', '7124', (28, 37))	('MMP14', 'Gene', (146, 151))	('p', 'Gene', '23436', (53, 54))	('p', 'Gene', '23436', (193, 194))
884713	33572115	that MLN4924 significantly inhibits gastric cancer cell migration by repressing MMP9 but not MMP2 gene transcription.	('inhibits', 'NegReg', (27, 35))	('p', 'Gene', '23436', (71, 72))	('gastric cancer', 'Disease', (36, 50))	('MLN4924', 'Chemical', 'MESH:C539933', (5, 12))	('MMP9', 'Gene', (80, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('MMP2', 'Gene', (93, 97))	('MLN4924', 'Var', (5, 12))	('p', 'Gene', '23436', (111, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('MMP2', 'Gene', '4313', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
884715	33572115	Blocking NAE-dependent neddylation of cullin and consequently CRL-mediated protein ubiquitination by MLN4924 results in the loss of proteostasis due to the accumulation of CRL's substrates.	('p', 'Gene', '23436', (132, 133))	('NAE', 'Chemical', '-', (9, 12))	('p', 'Gene', '23436', (75, 76))	('CRL', 'Gene', (62, 65))	('substrates', 'MPA', (178, 188))	('p', 'Gene', '23436', (15, 16))	('MLN4924', 'Chemical', 'MESH:C539933', (101, 108))	('CRL', 'Gene', (172, 175))	('loss of proteostasis', 'Disease', (124, 144))	('MLN4924', 'Var', (101, 108))	('loss of proteostasis', 'Disease', 'MESH:D057165', (124, 144))	('CRL', 'Gene', '133396', (172, 175))	('CRL', 'Gene', '133396', (62, 65))	('cullin', 'Gene', (38, 44))	('cullin', 'Gene', '143384', (38, 44))	('accumulation', 'PosReg', (156, 168))	('neddylation', 'MPA', (23, 34))
884718	33572115	Hence, insufficient ubiquitination and consequently inadequate degradation of IkappaB-alpha in the presence of MLN4924 significantly impairs activation of NFkappaB and NFkappaB-dependent gene expression.	('p', 'Gene', '23436', (82, 83))	('MLN4924', 'Chemical', 'MESH:C539933', (111, 118))	('degradation', 'MPA', (63, 74))	('insufficient', 'NegReg', (7, 19))	('p', 'Gene', '23436', (99, 100))	('NFkappaB', 'Gene', (155, 163))	('activation', 'MPA', (141, 151))	('p', 'Gene', '23436', (88, 89))	('p', 'Gene', '23436', (81, 82))	('p', 'Gene', '23436', (159, 160))	('p', 'Gene', '23436', (135, 136))	('p', 'Gene', '23436', (160, 161))	('MLN4924', 'Var', (111, 118))	('NFkappaB', 'Gene', '4790', (168, 176))	('IkappaB-alpha', 'Gene', (78, 91))	('p', 'Gene', '23436', (173, 174))	('IkappaB-alpha', 'Gene', '4792', (78, 91))	('ubiquitination', 'MPA', (20, 34))	('p', 'Gene', '23436', (179, 180))	('p', 'Gene', '23436', (172, 173))	('NFkappaB', 'Gene', (168, 176))	('NFkappaB', 'Gene', '4790', (155, 163))	('p', 'Gene', '23436', (194, 195))
884719	33572115	In this study we found that MLN4924 significantly increased levels of phosphorylated IkappaB-alpha at Ser32 in a dose- and time-dependent manner.	('p', 'Gene', '23436', (74, 75))	('IkappaB-alpha', 'Gene', '4792', (85, 98))	('p', 'Gene', '23436', (88, 89))	('p', 'Gene', '23436', (95, 96))	('p', 'Gene', '23436', (130, 131))	('MLN4924', 'Var', (28, 35))	('p', 'Gene', '23436', (89, 90))	('increased', 'PosReg', (50, 59))	('Ser32', 'Chemical', '-', (102, 107))	('p', 'Gene', '23436', (70, 71))	('IkappaB-alpha', 'Gene', (85, 98))	('MLN4924', 'Chemical', 'MESH:C539933', (28, 35))
884721	33572115	This effect characterized the cells treated with MLN4924 alone as well as in combination with TNF-alpha; however, it seemed independent of TNF-alpha.	('MLN4924', 'Var', (49, 56))	('TNF-alpha', 'Gene', '7124', (94, 103))	('TNF-alpha', 'Gene', '7124', (139, 148))	('TNF-alpha', 'Gene', (94, 103))	('TNF-alpha', 'Gene', (139, 148))	('p', 'Gene', '23436', (100, 101))	('p', 'Gene', '23436', (145, 146))	('MLN4924', 'Chemical', 'MESH:C539933', (49, 56))	('p', 'Gene', '23436', (128, 129))
884723	33572115	Interestingly, MLN4924-dependent upregulation of phospho-IkappaB-alpha occurred together with increasing levels of phospho-NFkappaB/p65 (Ser536) and phospho-NFkappaB/p65 (Ser529) at unchanged concentrations of the total NFkappaB/p65 protein.	('p', 'Gene', '23436', (132, 133))	('p', 'Gene', '23436', (60, 61))	('p', 'Gene', '23436', (161, 162))	('p', 'Gene', '23436', (34, 35))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('p', 'Gene', '23436', (233, 234))	('p', 'Gene', '23436', (153, 154))	('increasing', 'PosReg', (94, 104))	('p', 'Gene', '23436', (25, 26))	('IkappaB-alpha', 'Gene', (57, 70))	('p', 'Gene', '23436', (224, 225))	('p', 'Gene', '23436', (49, 50))	('p', 'Gene', '23436', (166, 167))	('p', 'Gene', '23436', (229, 230))	('IkappaB-alpha', 'Gene', '4792', (57, 70))	('p', 'Gene', '23436', (128, 129))	('p', 'Gene', '23436', (119, 120))	('p', 'Gene', '23436', (127, 128))	('Ser536', 'Var', (137, 143))	('Ser529', 'Chemical', '-', (171, 177))	('p', 'Gene', '23436', (149, 150))	('p', 'Gene', '23436', (53, 54))	('p', 'Gene', '23436', (61, 62))	('Ser536', 'Chemical', '-', (137, 143))	('p', 'Gene', '23436', (162, 163))	('p', 'Gene', '23436', (115, 116))	('p', 'Gene', '23436', (225, 226))	('p', 'Gene', '23436', (67, 68))
884724	33572115	While elevated levels of phosphorylated forms of IkappaB-alpha may result from the impairment of proteasome-mediated degradation in the CRL-dependent pathway, the presence of increased phospho-NFkappaB/p65 levels under MLN4924 is ambiguous.	('p', 'Gene', '23436', (185, 186))	('CRL', 'Gene', '133396', (136, 139))	('p', 'Gene', '23436', (202, 203))	('MLN4924', 'Chemical', 'MESH:C539933', (219, 226))	('p', 'Gene', '23436', (97, 98))	('levels', 'MPA', (15, 21))	('p', 'Gene', '23436', (142, 143))	('p', 'Gene', '23436', (25, 26))	('p', 'Gene', '23436', (198, 199))	('p', 'Gene', '23436', (150, 151))	('IkappaB-alpha', 'Gene', (49, 62))	('p', 'Gene', '23436', (189, 190))	('IkappaB-alpha', 'Gene', '4792', (49, 62))	('increased', 'PosReg', (175, 184))	('p', 'Gene', '23436', (29, 30))	('p', 'Gene', '23436', (53, 54))	('MLN4924', 'Var', (219, 226))	('p', 'Gene', '23436', (197, 198))	('p', 'Gene', '23436', (85, 86))	('CRL', 'Gene', (136, 139))	('p', 'Gene', '23436', (59, 60))	('elevated', 'PosReg', (6, 14))	('p', 'Gene', '23436', (52, 53))	('p', 'Gene', '23436', (163, 164))
884727	33572115	They found that neddylation of NEMO/IKKgamma by the RING E3 ligase TRIM40 attenuates NFkappaB activity and prevents inflammation-associated carcinogenesis in gastrointestinal epithelial cells.	('NFkappaB', 'Gene', '4790', (85, 93))	('carcinogenesis', 'Disease', (140, 154))	('inflammation', 'Disease', 'MESH:D007249', (116, 128))	('p', 'Gene', '23436', (90, 91))	('neddylation', 'Var', (16, 27))	('IKKgamma', 'Gene', (36, 44))	('p', 'Gene', '23436', (176, 177))	('TRIM40', 'Gene', '135644', (67, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('p', 'Gene', '23436', (89, 90))	('NFkappaB', 'Gene', (85, 93))	('IKKgamma', 'Gene', '8517', (36, 44))	('NEMO', 'Gene', '8517', (31, 35))	('inflammation', 'Disease', (116, 128))	('attenuates', 'NegReg', (74, 84))	('activity', 'MPA', (94, 102))	('TRIM40', 'Gene', (67, 73))	('NEMO', 'Gene', (31, 35))	('p', 'Gene', '23436', (107, 108))
884730	33572115	Hence, inhibition of BCA3 neddylation could enable NFkappaB/p65 transcription and activation.	('BCA3', 'Gene', '56672', (21, 25))	('activation', 'MPA', (82, 92))	('p', 'Gene', '23436', (60, 61))	('inhibition', 'Var', (7, 17))	('p', 'Gene', '23436', (55, 56))	('p', 'Gene', '23436', (72, 73))	('enable', 'PosReg', (44, 50))	('p', 'Gene', '23436', (56, 57))	('BCA3', 'Gene', (21, 25))
884734	33572115	Although MLN4924 induced phosphorylation of NFkappaB by itself, it did not lead to translocation and accumulation of NFkappaB in the nucleus like TNF-alpha did.	('p', 'Gene', '23436', (152, 153))	('NFkappaB', 'Gene', '4790', (44, 52))	('p', 'Gene', '23436', (29, 30))	('NFkappaB', 'Gene', (44, 52))	('MLN4924', 'Chemical', 'MESH:C539933', (9, 16))	('TNF-alpha', 'Gene', '7124', (146, 155))	('p', 'Gene', '23436', (122, 123))	('TNF-alpha', 'Gene', (146, 155))	('MLN4924', 'Var', (9, 16))	('p', 'Gene', '23436', (25, 26))	('p', 'Gene', '23436', (48, 49))	('p', 'Gene', '23436', (121, 122))	('p', 'Gene', '23436', (49, 50))	('NFkappaB', 'Gene', '4790', (117, 125))	('NFkappaB', 'Gene', (117, 125))
884735	33572115	However, TNF-alpha-induced nuclear translocation of the phosphorylated form of NFkappaB was found to be impaired in the presence of MLN4924.	('MLN4924', 'Chemical', 'MESH:C539933', (132, 139))	('p', 'Gene', '23436', (60, 61))	('TNF-alpha', 'Gene', '7124', (9, 18))	('nuclear translocation', 'MPA', (27, 48))	('MLN4924', 'Var', (132, 139))	('p', 'Gene', '23436', (120, 121))	('p', 'Gene', '23436', (106, 107))	('p', 'Gene', '23436', (83, 84))	('NFkappaB', 'Gene', '4790', (79, 87))	('NFkappaB', 'Gene', (79, 87))	('TNF-alpha', 'Gene', (9, 18))	('p', 'Gene', '23436', (56, 57))	('p', 'Gene', '23436', (15, 16))	('p', 'Gene', '23436', (84, 85))
884736	33572115	On the other hand, as we observed, the total level of nuclear NFkappaB in the cells treated with MLN4924 was not different from others.	('NFkappaB', 'Gene', '4790', (62, 70))	('MLN4924', 'Chemical', 'MESH:C539933', (97, 104))	('NFkappaB', 'Gene', (62, 70))	('MLN4924', 'Var', (97, 104))
884739	33572115	However, contrary to untreated or TNF-alpha-treated cells, MLN4924-related immune complexes were found to be rich in highly phosphorylated IkappaB-alpha and c-Jun and additionally in CDKN1A/p21.	('c-Jun', 'MPA', (157, 162))	('IkappaB-alpha', 'Gene', (139, 152))	('IkappaB-alpha', 'Gene', '4792', (139, 152))	('rich', 'PosReg', (109, 113))	('p', 'Gene', '23436', (142, 143))	('MLN4924-related', 'Var', (59, 74))	('p21', 'Gene', (190, 193))	('MLN4924', 'Chemical', 'MESH:C539933', (59, 66))	('TNF-alpha', 'Gene', '7124', (34, 43))	('CDKN1A', 'Gene', (183, 189))	('p', 'Gene', '23436', (128, 129))	('p', 'Gene', '23436', (190, 191))	('CDKN1A', 'Gene', '1026', (183, 189))	('TNF-alpha', 'Gene', (34, 43))	('p', 'Gene', '23436', (40, 41))	('p', 'Gene', '23436', (143, 144))	('p', 'Gene', '23436', (149, 150))	('p', 'Gene', '23436', (85, 86))	('p21', 'Gene', '1026', (190, 193))	('p', 'Gene', '23436', (124, 125))
884742	33572115	As previously indicated, AP1/c-Jun and CDKN1A/p21 are proteins that are primarily degraded through the ubiquitin-proteasome pathway and abnormally accumulated in cells under the treatment with MLN4924.	('p', 'Gene', '23436', (46, 47))	('AP1', 'Gene', '3725', (25, 28))	('CDKN1A', 'Gene', '1026', (39, 45))	('CDKN1A', 'Gene', (39, 45))	('MLN4924', 'Chemical', 'MESH:C539933', (193, 200))	('p', 'Gene', '23436', (54, 55))	('AP1', 'Gene', (25, 28))	('p', 'Gene', '23436', (113, 114))	('p21', 'Gene', '1026', (46, 49))	('p', 'Gene', '23436', (3, 4))	('MLN4924', 'Var', (193, 200))	('p21', 'Gene', (46, 49))	('p', 'Gene', '23436', (72, 73))	('p', 'Gene', '23436', (124, 125))	('accumulated', 'PosReg', (147, 158))	('degraded', 'NegReg', (82, 90))
884743	33572115	We found that MLN4924 also caused a time- and dose-dependent increase in levels of these two proteins in ESCC cells.	('MLN4924', 'Var', (14, 21))	('p', 'Gene', '23436', (93, 94))	('increase', 'PosReg', (61, 69))	('p', 'Gene', '23436', (53, 54))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))
884748	33572115	However, increasing levels of CDKN1A/p21 in the presence of MLN4924 did not correlate with MMP9 expression and activity.	('p', 'Gene', '23436', (98, 99))	('CDKN1A', 'Gene', (30, 36))	('MLN4924', 'Chemical', 'MESH:C539933', (60, 67))	('p21', 'Gene', '1026', (37, 40))	('CDKN1A', 'Gene', '1026', (30, 36))	('p', 'Gene', '23436', (48, 49))	('MLN4924', 'Var', (60, 67))	('p21', 'Gene', (37, 40))	('p', 'Gene', '23436', (37, 38))
884755	33572115	For instance, phosphorylation at Ser63 and Ser73 increases the DNA-binding capacity of c-Jun.	('Ser63', 'Chemical', '-', (33, 38))	('Ser73', 'Var', (43, 48))	('p', 'Gene', '23436', (77, 78))	('increases', 'PosReg', (49, 58))	('p', 'Gene', '23436', (14, 15))	('p', 'Gene', '23436', (18, 19))	('Ser73', 'Chemical', '-', (43, 48))	('DNA-binding', 'Interaction', (63, 74))
884757	33572115	Since NFkappaB/p65-c-Jun-IkappaB-alpha-SP1 complexes were formed in all the cells, both untreated controls and TNF-alpha- or MLN4924-treated cells, we assume that the NFkappaB/p65 transcriptional activation in the presence of MLN4924 was blocked by the overload of nuclear NFkappaB/p65 complexes with highly phosphorylated IkappaB and AP1/c-Jun forms which prevent NFkappaB/p65:DNA interaction.	('MLN4924', 'Var', (226, 233))	('p', 'Gene', '23436', (312, 313))	('p', 'Gene', '23436', (10, 11))	('p', 'Gene', '23436', (11, 12))	('p', 'Gene', '23436', (327, 328))	('p', 'Gene', '23436', (35, 36))	('p', 'Gene', '23436', (176, 177))	('p', 'Gene', '23436', (289, 290))	('MLN4924', 'Chemical', 'MESH:C539933', (125, 132))	('p', 'Gene', '23436', (326, 327))	('p', 'Gene', '23436', (374, 375))	('p', 'Gene', '23436', (278, 279))	('MLN4924', 'Chemical', 'MESH:C539933', (226, 233))	('p', 'Gene', '23436', (15, 16))	('p', 'Gene', '23436', (214, 215))	('p', 'Gene', '23436', (308, 309))	('IkappaB-alpha', 'Gene', (25, 38))	('p', 'Gene', '23436', (277, 278))	('IkappaB-alpha', 'Gene', '4792', (25, 38))	('p', 'Gene', '23436', (117, 118))	('p', 'Gene', '23436', (357, 358))	('p', 'Gene', '23436', (29, 30))	('AP1', 'Gene', '3725', (335, 338))	('p', 'Gene', '23436', (46, 47))	('AP1', 'Gene', (335, 338))	('p', 'Gene', '23436', (171, 172))	('TNF-alpha', 'Gene', '7124', (111, 120))	('p', 'Gene', '23436', (370, 371))	('p', 'Gene', '23436', (188, 189))	('TNF-alpha', 'Gene', (111, 120))	('p', 'Gene', '23436', (172, 173))	('p', 'Gene', '23436', (28, 29))	('p', 'Gene', '23436', (282, 283))	('p', 'Gene', '23436', (369, 370))
884758	33572115	Our results indicate that MLN4924 may impair not only the cytoplasmic, but also the nuclear UPS activity.	('p', 'Gene', '23436', (40, 41))	('nuclear UPS activity', 'CPA', (84, 104))	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('p', 'Gene', '23436', (62, 63))	('MLN4924', 'Var', (26, 33))
884762	33572115	On the other hand, it is known that in addition to the inhibitory effects of neddylation, MLN4924 also shows neddylation-independent activities.	('MLN4924', 'Chemical', 'MESH:C539933', (90, 97))	('MLN4924', 'Var', (90, 97))	('p', 'Gene', '23436', (125, 126))	('activities', 'MPA', (133, 143))
884763	33572115	observed that knockdown of NEDD8 did not mimic MLN4924 in activating JNK signaling in human head and neck squamous cell carcinoma (HNSCC) cell lines.	('HNSCC', 'CellLine', 'CVCL:5985', (131, 136))	('JNK', 'Gene', '5599', (69, 72))	('human', 'Species', '9606', (86, 91))	('MLN4924', 'Chemical', 'MESH:C539933', (47, 54))	('NEDD8', 'Gene', '4738', (27, 32))	('neck squamous cell carcinoma', 'Disease', (101, 129))	('NEDD8', 'Gene', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (101, 129))	('MLN4924', 'Var', (47, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('JNK', 'Gene', (69, 72))
884764	33572115	MLN4924 was found to trigger epidermal growth factor receptor (EGFR) dimerization and activate EGFR downstream signaling pathways such as RAS/RAF/MEK/ERK and PI3K/AKT1/mTOR promoting tumor sphere formation and inducing wound healing in mouse models.	('mTOR', 'Gene', '56717', (168, 172))	('AKT1', 'Gene', '11651', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('activate', 'PosReg', (86, 94))	('p', 'Gene', '23436', (121, 122))	('p', 'Gene', '23436', (57, 58))	('inducing', 'NegReg', (210, 218))	('MEK', 'Gene', '17242', (146, 149))	('epidermal growth factor receptor', 'Gene', (29, 61))	('dimerization', 'MPA', (69, 81))	('mouse', 'Species', '10090', (236, 241))	('p', 'Gene', '23436', (190, 191))	('mTOR', 'Gene', (168, 172))	('MLN4924', 'Var', (0, 7))	('wound healing', 'CPA', (219, 232))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '13649', (63, 67))	('ERK', 'Gene', '13844', (150, 153))	('MEK', 'Gene', (146, 149))	('ERK', 'Gene', (150, 153))	('tumor', 'Disease', (183, 188))	('AKT1', 'Gene', (163, 167))	('p', 'Gene', '23436', (173, 174))	('EGFR', 'Gene', (95, 99))	('EGFR', 'Gene', '13649', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('p', 'Gene', '23436', (30, 31))	('epidermal growth factor receptor', 'Gene', '13649', (29, 61))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('trigger', 'PosReg', (21, 28))
884766	33572115	These pro-survival neddylation-independent activities of MLN4924 may indicate that MLN4924 can also serve as a stimulator of certain cells.	('MLN4924', 'Var', (83, 90))	('p', 'Gene', '23436', (6, 7))	('MLN4924', 'Chemical', 'MESH:C539933', (57, 64))	('p', 'Gene', '23436', (35, 36))	('activities', 'MPA', (43, 53))	('MLN4924', 'Var', (57, 64))	('MLN4924', 'Chemical', 'MESH:C539933', (83, 90))
884776	33572115	Effects of MLN4924 and TNF-alpha on cell viability were determined using Trevigen's TACS MTT Cell Proliferation Assay (R&D Systems, Minneapolis, MN, USA, 4890-050-K) according to the manufacturer's instructions.	('MLN4924', 'Var', (11, 18))	('MTT', 'Chemical', 'MESH:C070243', (89, 92))	('TNF-alpha', 'Gene', '7124', (23, 32))	('MN', 'CellLine', 'CVCL:U508', (145, 147))	('p', 'Gene', '23436', (138, 139))	('MLN4924', 'Chemical', 'MESH:C539933', (11, 18))	('p', 'Gene', '23436', (29, 30))	('TNF-alpha', 'Gene', (23, 32))
884792	33572115	KYSE150 cells after 24-h starvation were treated with MLN4924 and TNF-alpha alone or in combination for 1 h and then processed according to the manufacturer's protocol.	('KYSE150', 'CellLine', 'CVCL:1348', (0, 7))	('MLN4924', 'Chemical', 'MESH:C539933', (54, 61))	('TNF-alpha', 'Gene', '7124', (66, 75))	('TNF-alpha', 'Gene', (66, 75))	('p', 'Gene', '23436', (117, 118))	('MLN4924', 'Var', (54, 61))	('p', 'Gene', '23436', (72, 73))	('p', 'Gene', '23436', (159, 160))
884796	33572115	Chromatin immunoprecipitation of NFkappaB binding with the promoter of the MMP9 gene was performed using chromatin prepared from 107 KYSE150 cells treated with MLN4924 (1 microM) or TNF-alpha (30 ng/mL) for 24 h and 1 h, respectively.	('TNF-alpha', 'Gene', (182, 191))	('KYSE150', 'CellLine', 'CVCL:1348', (133, 140))	('p', 'Gene', '23436', (89, 90))	('MLN4924', 'Var', (160, 167))	('p', 'Gene', '23436', (224, 225))	('p', 'Gene', '23436', (16, 17))	('NFkappaB', 'Gene', '4790', (33, 41))	('binding', 'Interaction', (42, 49))	('p', 'Gene', '23436', (38, 39))	('p', 'Gene', '23436', (118, 119))	('MMP9', 'Gene', (75, 79))	('p', 'Gene', '23436', (37, 38))	('NFkappaB', 'Gene', (33, 41))	('MLN4924', 'Chemical', 'MESH:C539933', (160, 167))	('p', 'Gene', '23436', (59, 60))	('p', 'Gene', '23436', (188, 189))	('p', 'Gene', '23436', (21, 22))	('p', 'Gene', '23436', (115, 116))	('TNF-alpha', 'Gene', '7124', (182, 191))
884819	33572115	The cells were then treated with 1 microM MLN4924 alone or in combination with 30 ng/mL of TNF-alpha in a serum-free medium.	('TNF-alpha', 'Gene', (91, 100))	('TNF-alpha', 'Gene', '7124', (91, 100))	('MLN4924', 'Var', (42, 49))	('MLN4924', 'Chemical', 'MESH:C539933', (42, 49))
884824	33572115	Hence, this report was aimed at providing more detailed information on a mechanism by which MLN4924 prevents MMP9 expression.	('p', 'Gene', '23436', (32, 33))	('p', 'Gene', '23436', (116, 117))	('p', 'Gene', '23436', (14, 15))	('MLN4924', 'Chemical', 'MESH:C539933', (92, 99))	('p', 'Gene', '23436', (100, 101))	('MMP9', 'Gene', (109, 113))	('MLN4924', 'Var', (92, 99))
884825	33572115	We found that in the presence of MLN4924 interactions between NFkappaB and the MMP9 gene promoter are totally blocked.	('MMP9', 'Gene', (79, 83))	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('interactions', 'Interaction', (41, 53))	('p', 'Gene', '23436', (89, 90))	('p', 'Gene', '23436', (21, 22))	('MLN4924', 'Var', (33, 40))	('NFkappaB', 'Gene', (62, 70))	('p', 'Gene', '23436', (66, 67))	('NFkappaB', 'Gene', '4790', (62, 70))	('blocked', 'NegReg', (110, 117))	('p', 'Gene', '23436', (67, 68))
884829	33572115	The following are available online at , Figure S1: Effect of MLN4924 pretreatment on CDKN1A/p21 and c-Jun protein level in cells treated with TNF-alpha in different concentrations; Figure S2: Effect of MLN4924 and TNF-alpha on cell viability in KYSE70 and KYSE150 cells.	('TNF-alpha', 'Gene', '7124', (142, 151))	('p', 'Gene', '23436', (148, 149))	('p', 'Gene', '23436', (92, 93))	('KYSE150', 'CellLine', 'CVCL:1348', (256, 263))	('CDKN1A', 'Gene', (85, 91))	('p', 'Gene', '23436', (106, 107))	('TNF-alpha', 'Gene', '7124', (214, 223))	('CDKN1A', 'Gene', '1026', (85, 91))	('TNF-alpha', 'Gene', (142, 151))	('MLN4924', 'Chemical', 'MESH:C539933', (61, 68))	('p', 'Gene', '23436', (220, 221))	('MLN4924', 'Chemical', 'MESH:C539933', (202, 209))	('p', 'Gene', '23436', (69, 70))	('p21', 'Gene', '1026', (92, 95))	('Effect', 'Reg', (192, 198))	('TNF-alpha', 'Gene', (214, 223))	('p21', 'Gene', (92, 95))	('MLN4924', 'Var', (202, 209))
884830	33572115	; Figure S3: PARP1 cleavage in response to MLN4924 in ESCC cells.	('cleavage', 'MPA', (19, 27))	('PARP1', 'Gene', (13, 18))	('p', 'Gene', '23436', (34, 35))	('MLN4924', 'Chemical', 'MESH:C539933', (43, 50))	('PARP1', 'Gene', '142', (13, 18))	('MLN4924', 'Var', (43, 50))
884832	33572115	; Figure S5: A dose-dependent effect of MLN4924 on the signaling pathways mediating MMP9 gene expression in KYSE70 cells.	('p', 'Gene', '23436', (22, 23))	('MLN4924', 'Chemical', 'MESH:C539933', (40, 47))	('MMP9 gene', 'Gene', (84, 93))	('p', 'Gene', '23436', (96, 97))	('MLN4924', 'Var', (40, 47))	('p', 'Gene', '23436', (65, 66))
884875	32708343	Previous trials have shown that, when associated with classical biopsy, WATS leads to an increase in the detection of intestinal metaplasia and dysplasia.	('intestinal metaplasia and dysplasia', 'Disease', 'MESH:D008679', (118, 153))	('WATS', 'Var', (72, 76))	('WATS', 'Chemical', '-', (72, 76))	('increase', 'PosReg', (89, 97))
884887	32708343	A multicenter US trial on one thousand patients reported that VLE improved the neoplasia diagnostic yield in BE by 55%.	('patients', 'Species', '9606', (39, 47))	('neoplasia', 'Disease', 'MESH:D009369', (79, 88))	('neoplasia', 'Phenotype', 'HP:0002664', (79, 88))	('improved', 'PosReg', (66, 74))	('VLE', 'Var', (62, 65))	('neoplasia', 'Disease', (79, 88))
884960	30323623	While the aberrant expression of RDGN is involved in the proliferation, apoptosis, angiogenesis, and metastasis of tumors via interacting with different cytokine-related signals, such as CXCL8, IL-6, TGF-beta, FGF, and VEGF, in a cell- or tissue-dependent manner.	('VEGF', 'Gene', (219, 223))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('metastasis of tumors', 'Disease', (101, 121))	('involved', 'Reg', (41, 49))	('VEGF', 'Gene', '7422', (219, 223))	('aberrant expression', 'Var', (10, 29))	('CXCL8', 'Gene', '3576', (187, 192))	('CXCL8', 'Gene', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('RDGN', 'Gene', (33, 37))	('apoptosis', 'CPA', (72, 81))	('interacting', 'Interaction', (126, 137))	('angiogenesis', 'CPA', (83, 95))	('metastasis of tumors', 'Disease', 'MESH:D009362', (101, 121))
884964	30323623	However, the dysregulation of those cytokines results in diseases ranging from autoimmune disorders to cancers.	('autoimmune disorders to cancers', 'Disease', (79, 110))	('results in', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('dysregulation', 'Var', (13, 26))	('diseases', 'Disease', (57, 65))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (79, 99))	('autoimmune disorders to cancers', 'Disease', 'MESH:D001327', (79, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
884970	30323623	RDGN is a critical signal in tissue specification and organogenesis, the aberrant of this network is related to various diseases ranging from congenital anomaly (development defect) and cancers.	('congenital anomaly', 'Disease', 'MESH:D000013', (142, 160))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('aberrant', 'Var', (73, 81))	('congenital anomaly', 'Disease', (142, 160))	('related', 'Reg', (101, 108))
884975	30323623	While the abnormal expression of DACH1 leads to various diseases, including bilateral cystic renal dysplasia, chronic kidney disease, familial young-onset diabetes, prediabetes, and cardiovascular diseases.	('DACH1', 'Gene', '1602', (33, 38))	('cardiovascular diseases', 'Disease', (182, 205))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (110, 132))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (182, 205))	('diabetes', 'Disease', 'MESH:D003920', (155, 163))	('renal dysplasia', 'Phenotype', 'HP:0000110', (93, 108))	('kidney disease', 'Phenotype', 'HP:0000112', (118, 132))	('cystic renal dysplasia', 'Disease', (86, 108))	('diabetes', 'Disease', (168, 176))	('cystic renal dysplasia', 'Disease', 'MESH:D052177', (86, 108))	('prediabetes', 'Disease', (165, 176))	('leads to', 'Reg', (39, 47))	('chronic kidney disease', 'Disease', (110, 132))	('diabetes', 'Disease', (155, 163))	('prediabetes', 'Disease', 'MESH:D011236', (165, 176))	('cystic renal dysplasia', 'Phenotype', 'HP:0000800', (86, 108))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (182, 205))	('DACH1', 'Gene', (33, 38))	('diabetes', 'Disease', 'MESH:D003920', (168, 176))	('abnormal expression', 'Var', (10, 29))	('chronic kidney disease', 'Disease', 'MESH:D051436', (110, 132))
884997	30323623	Besides, DACH1 controlled liver cell growth by reactivating TGF-beta signaling; thus, the loss of DACH1 expression in hepatocellular carcinoma impeded the antiproliferative function of TGF-beta and stimulated tumor growth.	('DACH1', 'Gene', '1602', (9, 14))	('DACH1', 'Gene', (98, 103))	('tumor', 'Disease', (209, 214))	('DACH1', 'Gene', '1602', (98, 103))	('stimulated', 'PosReg', (198, 208))	('loss', 'Var', (90, 94))	('impeded', 'NegReg', (143, 150))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (118, 142))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (118, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('antiproliferative function', 'CPA', (155, 181))	('hepatocellular carcinoma', 'Disease', (118, 142))	('TGF-beta signaling', 'MPA', (60, 78))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('DACH1', 'Gene', (9, 14))
884999	30323623	Silencing of DACH1 caused by methylation in part contributed to the esophageal carcinogenesis by hampering TGF-beta.	('methylation', 'Var', (29, 40))	('contributed', 'Reg', (49, 60))	('esophageal carcinogenesis', 'Disease', (68, 93))	('hampering', 'NegReg', (97, 106))	('DACH1', 'Gene', (13, 18))	('Silencing', 'NegReg', (0, 9))	('DACH1', 'Gene', '1602', (13, 18))	('TGF-beta', 'Protein', (107, 115))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (68, 93))
885007	30323623	Furthermore, deletion of Eya2 in MCF7 mammary carcinoma cells blocked SIX1-mediated tumor progression via TGF-beta signaling.	('mammary carcinoma', 'Phenotype', 'HP:0003002', (38, 55))	('SIX1-mediated tumor', 'Disease', (70, 89))	('carcinoma', 'Disease', 'MESH:D002277', (46, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('MCF7', 'CellLine', 'CVCL:0031', (33, 37))	('deletion', 'Var', (13, 21))	('SIX1-mediated tumor', 'Disease', 'MESH:C567355', (70, 89))	('TGF-beta signaling', 'MPA', (106, 124))	('carcinoma', 'Disease', (46, 55))	('Eya2', 'Gene', '2139', (25, 29))	('blocked', 'NegReg', (62, 69))	('Eya2', 'Gene', (25, 29))
885012	30323623	Whereas, knock down of CXCR4-CXCL12 signaling could impair DACH1-induced endothelial expression and migration both in vitro and in vivo (Table 1).	('knock down', 'Var', (9, 19))	('impair', 'NegReg', (52, 58))	('CXCL12', 'Gene', (29, 35))	('CXCR4', 'Gene', (23, 28))	('DACH1', 'Gene', (59, 64))	('DACH1', 'Gene', '1602', (59, 64))	('CXCL12', 'Gene', '6387', (29, 35))	('CXCR4', 'Gene', '7852', (23, 28))
885018	30323623	Moreover, knockdown of DACH1 expression blocked the effect of metformin on myeloid-derived suppressor cells' (MDSCs) chemotaxis (Table 1).	('blocked', 'NegReg', (40, 47))	('DACH1', 'Gene', '1602', (23, 28))	("myeloid-derived suppressor cells'", 'CPA', (75, 108))	('metformin', 'Chemical', 'MESH:D008687', (62, 71))	('knockdown', 'Var', (10, 19))	('DACH1', 'Gene', (23, 28))
885035	30323623	Aberrant expression of IL-6 is correlated with high tumor burden, such as advanced stage and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Aberrant', 'Var', (0, 8))	('IL-6', 'Gene', (23, 27))	('expression', 'MPA', (9, 19))	('high tumor', 'Disease', (47, 57))	('high tumor', 'Disease', 'MESH:D009369', (47, 57))	('correlated', 'Reg', (31, 41))
885043	30323623	At the meantime, exogenous bFGF rescues stemness and tum-origenicity of the U87 cells with high expression of DACH1, suggesting that loss of DACH1 increases the number of CSC through transcriptional activation of bFGF.	('increases', 'PosReg', (147, 156))	('stemness', 'Disease', 'MESH:D020295', (40, 48))	('stemness', 'Disease', (40, 48))	('tum-origenicity', 'CPA', (53, 68))	('bFGF', 'Gene', '2247', (27, 31))	('DACH1', 'Gene', '1602', (110, 115))	('bFGF', 'Gene', '2247', (213, 217))	('bFGF', 'Gene', (213, 217))	('bFGF', 'Gene', (27, 31))	('activation', 'PosReg', (199, 209))	('U87', 'CellLine', 'CVCL:0022', (76, 79))	('DACH1', 'Gene', (110, 115))	('DACH1', 'Gene', (141, 146))	('loss', 'Var', (133, 137))	('DACH1', 'Gene', '1602', (141, 146))
885052	30323623	SIX1 augmented the TGF-beta-activated SMAD2/3 and then assisted with the SMAD pathway to modulate VEGF-C expression.	('SMAD2/3', 'Gene', (38, 45))	('SIX1', 'Var', (0, 4))	('TGF-beta-activated', 'Enzyme', (19, 37))	('SMAD pathway', 'Pathway', (73, 85))	('modulate', 'Reg', (89, 97))	('SMAD2/3', 'Gene', '4087;4088', (38, 45))	('augmented', 'PosReg', (5, 14))	('VEGF-C', 'Gene', (98, 104))
885059	30323623	High mRNA expression of SIX1 was found to be related with late stage and worse prognosis of ovarian carcinoma (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('High', 'Var', (0, 4))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (92, 109))	('mRNA expression', 'MPA', (5, 20))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (92, 109))	('ovarian carcinoma', 'Disease', (92, 109))	('SIX1', 'Gene', (24, 28))	('related', 'Reg', (45, 52))
885060	30323623	In terms of mechanism, SIX1 prevented ovarian carcinoma cells from TRAIL-mediated cell death and contributed to the tumorigenesis and distant metastasis of ovarian carcinoma via conferring resistance to apoptosis-related process of tumor cells.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (156, 173))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('TRAIL', 'Gene', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (232, 237))	('metastasis of ovarian carcinoma', 'Disease', 'MESH:D009362', (142, 173))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('prevented', 'NegReg', (28, 37))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (38, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (156, 173))	('ovarian carcinoma', 'Disease', (38, 55))	('metastasis of ovarian carcinoma', 'Disease', (142, 173))	('resistance', 'CPA', (189, 199))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (38, 55))	('TRAIL', 'Gene', '8743', (67, 72))	('tumor', 'Disease', (116, 121))	('SIX1', 'Var', (23, 27))
885069	30323623	While another member of RDGN, SIX1 facilitates tumor progression by stimulating cytokines' secretion and activating the pathways triggered by cytokine factors.	('SIX1', 'Var', (30, 34))	('stimulating', 'PosReg', (68, 79))	('pathways', 'Pathway', (120, 128))	('facilitates', 'PosReg', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('activating', 'Reg', (105, 115))	("cytokines' secretion", 'MPA', (80, 100))	('tumor', 'Disease', (47, 52))
885094	28977894	Therefore, we investigated a new approach to lymph node (LN)-survival analysis by using pre-/post-NAC CT in pN0 esophageal cancer.	('NAC', 'Chemical', '-', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('pN0 esophageal cancer', 'Phenotype', 'HP:0011459', (108, 129))	('pN0', 'Var', (108, 111))	('esophageal cancer', 'Disease', (112, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
885100	28977894	The size and number of lymph node on pre-/post-NAC CT were reliable and important prognostic factors in patients with pN0 esophageal cancer.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('pN0', 'Var', (118, 121))	('pN0 esophageal cancer', 'Phenotype', 'HP:0011459', (118, 139))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('NAC', 'Chemical', '-', (47, 50))
885105	28977894	Although the N classification is the most important prognostic factor in esophageal cancer because patients without lymph node involvement have a better prognosis than those with nodal involvement, we find that these patients presented different survival benefit after NAC downstaging occurrence in clinical follow-up.	('benefit', 'PosReg', (255, 262))	('NAC', 'Var', (269, 272))	('esophageal cancer', 'Disease', (73, 90))	('NAC', 'Chemical', '-', (269, 272))	('men', 'Species', '9606', (192, 195))	('survival', 'MPA', (246, 254))	('patients', 'Species', '9606', (99, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('nodal', 'Gene', (179, 184))	('patients', 'Species', '9606', (217, 225))	('downstaging', 'NegReg', (273, 284))	('nodal', 'Gene', '4838', (179, 184))	('men', 'Species', '9606', (134, 137))
885125	28977894	Multivariate survival analysis, including all statistically significant prognostic factors mentioned in univariate analysis (p value less than or equal to 0.05), was performed to determine the independent prognostic factors for pN0 esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('men', 'Species', '9606', (91, 94))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (232, 266))	('pN0', 'Var', (228, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('esophageal squamous cell carcinoma', 'Disease', (232, 266))
885131	28977894	Patients in pN0a group (n=50, median survival time not reached) survived longer (Figure 2).	('longer', 'PosReg', (73, 79))	('pN0a', 'Var', (12, 16))	('Patients', 'Species', '9606', (0, 8))
885145	28977894	On the other hand, some hazards of lymphadenopathy recurrence were involved in N0b group, which made their survival time similar to patients with pN1 staging.	('pN1', 'Gene', (146, 149))	('N0b', 'Var', (79, 82))	('lymphadenopathy', 'Disease', (35, 50))	('lymphadenopathy', 'Disease', 'MESH:D008206', (35, 50))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (35, 50))	('pN1', 'Gene', '5270', (146, 149))	('patients', 'Species', '9606', (132, 140))
885147	28977894	We also compared the OS of pN0b patients with that of pN1 patients in the same study population (Figure 2).	('pN1', 'Gene', '5270', (54, 57))	('OS', 'Chemical', '-', (21, 23))	('patients', 'Species', '9606', (32, 40))	('pN0b', 'Var', (27, 31))	('pN1', 'Gene', (54, 57))	('patients', 'Species', '9606', (58, 66))
885184	28977894	In conclusion, the size and number of lymph node measured on pre-/post-NAC is a reliable and important prognostic factor in patients with pN0 esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (142, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('pN0', 'Var', (138, 141))	('esophageal squamous cell carcinoma', 'Disease', (142, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('NAC', 'Chemical', '-', (71, 74))	('patients', 'Species', '9606', (124, 132))
885305	28578693	CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest Cell cycle dysregulation is common in human malignancies, and CDK4/6 inhibitors targeting cell cycle have potential antitumor activity.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('tumor', 'Disease', (282, 287))	('human', 'Species', '9606', (200, 205))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (61, 95))	('tumor', 'Disease', (43, 48))	('CDK4/6', 'Gene', (0, 6))	('Cell cycle dysregulation', 'Phenotype', 'HP:0011018', (162, 186))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('inhibiting', 'NegReg', (99, 109))	('inhibitor-SHR6390', 'Var', (7, 24))	('malignancies', 'Disease', 'MESH:D009369', (206, 218))	('CDK4/6', 'Gene', '1019;1021', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('malignancies', 'Disease', (206, 218))	('G1 cell cycle arrest Cell cycle', 'CPA', (141, 172))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('phosphorylated', 'MPA', (110, 124))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('inducing', 'Reg', (132, 140))	('esophageal squamous cell carcinoma', 'Disease', (61, 95))	('CDK4/6', 'Gene', (224, 230))
885306	28578693	SHR6390 is a novel small molecule inhibitor specifically targeting the CDK4/6 pathway.	('SHR6390', 'Var', (0, 7))	('SHR6390', 'Chemical', '-', (0, 7))	('CDK4/6 pathway', 'Pathway', (71, 85))
885311	28578693	SHR6390 could suppress cell proliferation in vitro cell lines and inhibit tumor growth in vivo PDX models with different drug susceptibility.	('suppress', 'NegReg', (14, 22))	('cell proliferation in vitro cell lines', 'CPA', (23, 61))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('inhibit', 'NegReg', (66, 73))	('SHR6390', 'Var', (0, 7))	('SHR6390', 'Chemical', '-', (0, 7))
885312	28578693	The effective treatment of SHR6390 induced the inhibition of phosphorylated Rb and cell cycle arrest at G1 phase both in cell lines and in xenografts.	('SHR6390', 'Chemical', '-', (27, 34))	('cell cycle arrest at G1 phase', 'CPA', (83, 112))	('inhibition', 'NegReg', (47, 57))	('phosphorylated', 'MPA', (61, 75))	('Rb', 'Chemical', 'MESH:D012413', (76, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('SHR6390', 'Var', (27, 34))
885315	28578693	CDK4/6 inhibitor-SHR6390 exerted potential antitumor activity against ESCC cell lines and xenografts, and evaluation of CDK6 and Cyclin D1 expressions might be helpful to select patients beneficial from SHR6390, which provided evidences for future clinical trials.	('SHR6390', 'Chemical', '-', (203, 210))	('inhibitor-SHR6390', 'Var', (7, 24))	('CDK6', 'Gene', (120, 124))	('Cyclin D1', 'Gene', '595', (129, 138))	('CDK6', 'Gene', '1021', (120, 124))	('patients', 'Species', '9606', (178, 186))	('Cyclin D1', 'Gene', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ESCC', 'Disease', (70, 74))	('tumor', 'Disease', (47, 52))	('SHR6390', 'Chemical', '-', (17, 24))
885318	28578693	Cell cycle dysregulation indicated by abnormal expressions and variations (mutations, amplifications, and deletions) were noted to occur frequently in human malignancies.	('expressions', 'MPA', (47, 58))	('malignancies', 'Disease', 'MESH:D009369', (157, 169))	('deletions', 'Var', (106, 115))	('human', 'Species', '9606', (151, 156))	('Cell cycle dysregulation', 'CPA', (0, 24))	('Cell cycle dysregulation', 'Phenotype', 'HP:0011018', (0, 24))	('malignancies', 'Disease', (157, 169))	('abnormal expressions', 'Phenotype', 'HP:0100022', (38, 58))
885321	28578693	Phosphorylation of Rb reduces the inhibitory control of the transcription factor E2F, which enables the cell to pass through the G1 restriction point into S-phase.	('Phosphorylation', 'Var', (0, 15))	('Rb', 'Chemical', 'MESH:D012413', (19, 21))	('reduces', 'NegReg', (22, 29))	('inhibitory control', 'MPA', (34, 52))
885322	28578693	Deregulation of the Cyclin D1-CDK4/6-Rb pathway triggered loss of cell-cycle control, one of the hallmark of cancer inducing carcinogenesis.	('cell-cycle control', 'CPA', (66, 84))	('Rb', 'Chemical', 'MESH:D012413', (37, 39))	('loss', 'NegReg', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('Cyclin D1', 'Gene', '595', (20, 29))	('carcinogenesis', 'Disease', (125, 139))	('Cyclin D1', 'Gene', (20, 29))
885326	28578693	Genomic characterization has demonstrated that ESCC harbour amplification of CDK6 and Cyclin D1, deletion of p16, and mutations of Rb, which are important regulators of cell cycle.	('CDK6', 'Gene', (77, 81))	('p16', 'Gene', (109, 112))	('Cyclin D1', 'Gene', (86, 95))	('amplification', 'Var', (60, 73))	('CDK6', 'Gene', '1021', (77, 81))	('mutations', 'Var', (118, 127))	('Cyclin D1', 'Gene', '595', (86, 95))	('p16', 'Gene', '1029', (109, 112))	('Rb', 'Chemical', 'MESH:D012413', (131, 133))	('deletion', 'Var', (97, 105))
885327	28578693	Here, we aimed to evaluate the anti-tumor activity of SHR6390, which is an orally bioavailable, small molecule CDK4/6 inhibitor, in ESCC in vitro cell lines and in vivo PDXs models.	('SHR6390', 'Var', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('SHR6390', 'Chemical', '-', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('ESCC', 'Disease', (132, 136))	('tumor', 'Disease', (36, 41))
885328	28578693	Moreover, we investigated the possible mechanisms of SHR6390 and the effects of SHR6390 combined with paclitaxel (PTX) or cisplatin (CDDP).	('SHR6390', 'Var', (80, 87))	('SHR6390', 'Var', (53, 60))	('SHR6390', 'Chemical', '-', (80, 87))	('SHR6390', 'Chemical', '-', (53, 60))	('CDDP', 'Chemical', '-', (133, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('paclitaxel', 'Chemical', 'MESH:D017239', (102, 112))	('PTX', 'Chemical', 'MESH:D017239', (114, 117))
885341	28578693	Antibodies used were against: CDK6 (sc-177) (Santa Cruz Biotechnology, Santa Cruz, CA, USA); Rb(#9313S), pRb(#9307S), CDK4(#12790), Cyclin D1 (#2978) (Cell Signaling Technology, Boston, MA, USA); beta-actin (#014M4759) (Sigma-Aldrich, USA).	('Cyclin D1', 'Gene', '595', (132, 141))	('CDK4', 'Gene', (118, 122))	('#9313S', 'Var', (96, 102))	('Cyclin D1', 'Gene', (132, 141))	('CDK4', 'Gene', '1019', (118, 122))	('pRb', 'Gene', '5925', (105, 108))	('CDK6', 'Gene', (30, 34))	('Rb', 'Chemical', 'MESH:D012413', (106, 108))	('pRb', 'Gene', (105, 108))	('CDK6', 'Gene', '1021', (30, 34))	('beta-actin', 'Gene', '728378', (196, 206))	('beta-actin', 'Gene', (196, 206))	('Rb', 'Chemical', 'MESH:D012413', (93, 95))	('#014M4759', 'Var', (208, 217))	('#2978', 'Var', (143, 148))
885348	28578693	When tumors was about 150-200 mm3, mice were randomized into six groups (5-6 per group) and treated with saline; SHR6390 (150 mg/kg weekly, oral gavage); PTX (3 mg/kg twice weekly, ip); or CDDP (3 mg/kg twice weekly, ip); SHR6390 and CDDP or PTX (see previous doses).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('PTX', 'Chemical', 'MESH:D017239', (242, 245))	('PTX', 'Chemical', 'MESH:D017239', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('SHR6390', 'Var', (222, 229))	('SHR6390', 'Chemical', '-', (113, 120))	('mice', 'Species', '10090', (35, 39))	('CDDP', 'Chemical', '-', (234, 238))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('SHR6390', 'Chemical', '-', (222, 229))	('saline', 'Chemical', 'MESH:D012965', (105, 111))	('CDDP', 'Chemical', '-', (189, 193))
885355	28578693	1a, SHR6390 inhibited cell proliferation in a dose-dependent manner, with Eca 109 being the relative sensitive one and Eca 9706 being the relative resistant one (Fig.	('inhibited', 'NegReg', (12, 21))	('SHR6390', 'Chemical', '-', (4, 11))	('SHR6390', 'Var', (4, 11))	('Eca 9706', 'CellLine', 'CVCL:E307', (119, 127))	('cell proliferation', 'CPA', (22, 40))
885357	28578693	The growth of tumors treated with SHR6390 alone was significantly suppressed both in Eca 109 and Eca 9706 xenografts compared to the control groups (Fig.	('growth', 'CPA', (4, 10))	('SHR6390', 'Chemical', '-', (34, 41))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Eca 9706', 'CellLine', 'CVCL:E307', (97, 105))	('suppressed', 'NegReg', (66, 76))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('SHR6390', 'Var', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
885359	28578693	Thus, SHR6390 restricts proliferation in ESCC cell lines and xenografts.	('restricts', 'NegReg', (14, 23))	('SHR6390', 'Var', (6, 13))	('proliferation', 'CPA', (24, 37))	('SHR6390', 'Chemical', '-', (6, 13))
885365	28578693	Thus, SHR6390 inhibited proliferation of ESCC in vitro cell lines and tumor growth in vivo with various suppressions.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('proliferation', 'CPA', (24, 37))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('inhibited', 'NegReg', (14, 23))	('SHR6390', 'Var', (6, 13))	('SHR6390', 'Chemical', '-', (6, 13))
885367	28578693	2a, SHR6390 reduced Rb phosphorylation in Eca 109 and KYSE-510 cell lines.	('reduced', 'NegReg', (12, 19))	('SHR6390', 'Var', (4, 11))	('Rb', 'Chemical', 'MESH:D012413', (20, 22))	('SHR6390', 'Chemical', '-', (4, 11))
885369	28578693	The in vitro results showed that pRb was significantly suppressed by effective treatment of SHR6390 in ESCC, which were also validated in vivo xenografts.	('SHR6390', 'Var', (92, 99))	('pRb', 'Gene', '5925', (33, 36))	('pRb', 'Gene', (33, 36))	('suppressed', 'NegReg', (55, 65))	('SHR6390', 'Chemical', '-', (92, 99))	('ESCC', 'Gene', (103, 107))
885371	28578693	Consistent with in vitro results, SHR6390 reduced Rb phosphorylation in six PDXs models, and the decrease degree of pRb had some correlation with antitumor activity (Fig.	('reduced', 'NegReg', (42, 49))	('SHR6390', 'Chemical', '-', (34, 41))	('Rb', 'Chemical', 'MESH:D012413', (50, 52))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('Rb', 'Chemical', 'MESH:D012413', (117, 119))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('pRb', 'Gene', '5925', (116, 119))	('SHR6390', 'Var', (34, 41))	('pRb', 'Gene', (116, 119))	('tumor', 'Disease', (150, 155))
885373	28578693	To explore the potential mechanisms responsible for the inhibitory effect of SHR6390 in ESCC, cell cycle and cell apoptosis analyses were conducted in ESCC cell lines.	('SHR6390', 'Var', (77, 84))	('SHR6390', 'Chemical', '-', (77, 84))	('ESCC', 'Disease', (88, 92))
885374	28578693	Here we explored that SHR6390 treatment led to significant increases of G1 arrest and decreases in the S-phase fraction in Eca 109 and KYSE-510 cells, which was not found in Eca 9706 cells (Fig.	('S-phase fraction', 'MPA', (103, 119))	('Eca 9706', 'CellLine', 'CVCL:E307', (174, 182))	('SHR6390', 'Var', (22, 29))	('decreases', 'NegReg', (86, 95))	('SHR6390', 'Chemical', '-', (22, 29))	('G1 arrest', 'CPA', (72, 81))	('increases', 'PosReg', (59, 68))
885377	28578693	However, cell apoptosis was not induced by treatment with SHR6390 in Eca 109 and Eca 9706 cell lines (Additional file 1: Figure S1), which means SHR6390 inhibited ESCC cell proliferations mainly through cell cycle arrest.	('SHR6390', 'Var', (145, 152))	('ESCC', 'Disease', (163, 167))	('SHR6390', 'Chemical', '-', (145, 152))	('Eca 9706', 'CellLine', 'CVCL:E307', (81, 89))	('cell cycle arrest', 'CPA', (203, 220))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (203, 220))	('SHR6390', 'Chemical', '-', (58, 65))	('inhibited', 'NegReg', (153, 162))
885378	28578693	Our results demonstrated clear potential of SHR6390 in ESCC.	('SHR6390', 'Var', (44, 51))	('SHR6390', 'Chemical', '-', (44, 51))	('ESCC', 'Disease', (55, 59))
885382	28578693	SHR6390 also enhanced chemotherapy responses in Eca 109 xenograft, though combination therapy did not cause significantly changes compared to SHR6390 single therapy (Fig.	('enhanced', 'PosReg', (13, 21))	('SHR6390', 'Chemical', '-', (142, 149))	('chemotherapy responses', 'CPA', (22, 44))	('SHR6390', 'Var', (0, 7))	('SHR6390', 'Chemical', '-', (0, 7))
885383	28578693	Our results suggested that SHR6390 could enhance the chemotherapy sensitivity of ESCC in vivo, especially in cells which showed relative lower sensitivity of SHR6390 single, which will be validated in future studies.	('chemotherapy sensitivity', 'MPA', (53, 77))	('SHR6390', 'Chemical', '-', (27, 34))	('enhance', 'PosReg', (41, 48))	('ESCC', 'Gene', (81, 85))	('SHR6390', 'Chemical', '-', (158, 165))	('SHR6390', 'Var', (27, 34))
885387	28578693	These results suggested that, combined with PTX or CDDP, SHR6390 produced better synergy by regulating molecules in the cell cycle pathways.	('regulating', 'Reg', (92, 102))	('PTX', 'Chemical', 'MESH:D017239', (44, 47))	('synergy', 'MPA', (81, 88))	('SHR6390', 'Var', (57, 64))	('molecules', 'MPA', (103, 112))	('SHR6390', 'Chemical', '-', (57, 64))	('CDDP', 'Chemical', '-', (51, 55))	('cell cycle pathways', 'Pathway', (120, 139))
885388	28578693	Our results demonstrated clear potential for SHR6390 single treatment or combined with chemotherapy in ESCC.	('ESCC', 'Disease', (103, 107))	('SHR6390', 'Var', (45, 52))	('SHR6390', 'Chemical', '-', (45, 52))
885403	28578693	Given the presence of highly mutation loads in Cyclin D1-CDK4/6-Rb signalling pathway-related molecules of ESCC, we investigated the effect of CDK4/6 inhibitor SHR6390 in our study.	('Rb', 'Chemical', 'MESH:D012413', (64, 66))	('Cyclin D1', 'Gene', '595', (47, 56))	('Cyclin D1', 'Gene', (47, 56))	('SHR6390', 'Chemical', '-', (160, 167))	('mutation loads', 'Var', (29, 43))
885404	28578693	Treatment of SHR6390 suppressed cell proliferation and tumor growth in ESCC cell lines and xenografts by inhibiting levels of pRb and effectively arrested the cell cycle at the G1 phase with the expression levels of p53 and p21 were upregulated.	('inhibiting', 'NegReg', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('p21', 'Gene', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('p21', 'Gene', '644914', (224, 227))	('suppressed', 'NegReg', (21, 31))	('upregulated', 'PosReg', (233, 244))	('tumor', 'Disease', (55, 60))	('levels', 'MPA', (116, 122))	('p53', 'Gene', '7157', (216, 219))	('pRb', 'Gene', '5925', (126, 129))	('arrested', 'NegReg', (146, 154))	('SHR6390', 'Var', (13, 20))	('pRb', 'Gene', (126, 129))	('SHR6390', 'Chemical', '-', (13, 20))	('cell proliferation', 'CPA', (32, 50))	('p53', 'Gene', (216, 219))	('cell cycle at the G1 phase', 'CPA', (159, 185))
885409	28578693	On the other hand, SHR6390 treatment failed to induce significant apoptosis in Eca 109 cells, dedicating that SHR6390 inhibited tumor growth mainly through arresting cell cycle at G1 phase.	('inhibited', 'NegReg', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('arresting', 'NegReg', (156, 165))	('SHR6390', 'Chemical', '-', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cell cycle at G1 phase', 'CPA', (166, 188))	('SHR6390', 'Chemical', '-', (19, 26))	('tumor', 'Disease', (128, 133))	('SHR6390', 'Var', (110, 117))
885411	28578693	It has been reported that CDDP could induce DNA damage-mediated cytotoxicity in cells that are arrested in the G1 phase.	('DNA', 'CPA', (44, 47))	('cytotoxicity', 'Disease', (64, 76))	('CDDP', 'Var', (26, 30))	('cytotoxicity', 'Disease', 'MESH:D064420', (64, 76))	('induce', 'Reg', (37, 43))	('CDDP', 'Chemical', '-', (26, 30))
885412	28578693	Thus, SHR6390 mediated G1 accumulation of cells may sensitize them to CDDP.	('sensitize', 'Reg', (52, 61))	('SHR6390', 'Var', (6, 13))	('SHR6390', 'Chemical', '-', (6, 13))	('CDDP', 'Chemical', '-', (70, 74))
885414	28578693	Modeling studies indicate that combinations of effective cytostatic and cytotoxic drugs should increase cure rates by delaying drug resistance and preventing tumor growth between treatments with cytotoxic agents.	('cure rates', 'CPA', (104, 114))	('tumor', 'Disease', (158, 163))	('drug resistance', 'Phenotype', 'HP:0020174', (127, 142))	('combinations', 'Var', (31, 43))	('increase', 'PosReg', (95, 103))	('drug resistance', 'MPA', (127, 142))	('delaying', 'NegReg', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('preventing', 'NegReg', (147, 157))
885419	28578693	Preclinical studies have defined a series of biomarkers that respond to CDK4/6 inhibitors, of which the Cyclin D1-CDK4/6-Rb pathway has been the best one till now.	('CDK4/6', 'Gene', (72, 78))	('Cyclin D1', 'Gene', (104, 113))	('inhibitors', 'Var', (79, 89))	('Rb', 'Chemical', 'MESH:D012413', (121, 123))	('Cyclin D1', 'Gene', '595', (104, 113))
885420	28578693	Alterations in the expression of genes that related to the cell cycle are important in determining drug sensitivity to anticancer agents.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('expression', 'MPA', (19, 29))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('drug sensitivity', 'Phenotype', 'HP:0020174', (99, 115))	('cancer', 'Disease', (123, 129))
885421	28578693	We therefore sought to validate biomarkers that predict in vitro response to SHR6390 in cell cycle signaling.	('SHR6390', 'Var', (77, 84))	('SHR6390', 'Chemical', '-', (77, 84))	('cell', 'MPA', (88, 92))
885423	28578693	reported that knockdown of CDK6 restored CDK4/6 inhibitor sensitivity, while enforced overexpression of CDK6 was sufficient to mediate drug resistance in breast cell lines.	('drug resistance', 'MPA', (135, 150))	('mediate', 'Reg', (127, 134))	('CDK6', 'Gene', (27, 31))	('CDK6', 'Gene', '1021', (27, 31))	('CDK6', 'Gene', (104, 108))	('CDK6', 'Gene', '1021', (104, 108))	('CDK4/6 inhibitor sensitivity', 'MPA', (41, 69))	('drug resistance', 'Phenotype', 'HP:0020174', (135, 150))	('knockdown', 'Var', (14, 23))	('restored', 'PosReg', (32, 40))
885425	28578693	Meanwhile, our results showed that higher expression of Cyclin D1 was correlated with SHR6390 higher sensitivity.	('Cyclin D1', 'Gene', (56, 65))	('SHR6390', 'Chemical', '-', (86, 93))	('expression', 'MPA', (42, 52))	('SHR6390', 'Var', (86, 93))	('Cyclin D1', 'Gene', '595', (56, 65))	('higher', 'PosReg', (35, 41))
885432	28578693	In conclusion, our findings support further clinical evaluation of SHR6390 as a single agent or in combination with chemotherapy in ESCC patients.	('SHR6390', 'Chemical', '-', (67, 74))	('ESCC', 'Disease', (132, 136))	('patients', 'Species', '9606', (137, 145))	('SHR6390', 'Var', (67, 74))
885433	28578693	Moreover, the assessment of CDK6 and Cyclin D1 expressions may help to identify the patient subgroup most likely to benefit from treatment with SHR6390.	('SHR6390', 'Chemical', '-', (144, 151))	('Cyclin D1', 'Gene', '595', (37, 46))	('Cyclin D1', 'Gene', (37, 46))	('SHR6390', 'Var', (144, 151))	('CDK6', 'Gene', (28, 32))	('CDK6', 'Gene', '1021', (28, 32))	('patient', 'Species', '9606', (84, 91))
885486	18516262	Heliobacter pylori, in contrast to obesity and hiatal hernia, may affect the risk of BE by physiologic rather than anatomic means; H. pylori can decrease gastric acidity through activity of urease.	('hiatal hernia', 'Phenotype', 'HP:0002036', (47, 60))	('pylori', 'Species', '210', (134, 140))	('obesity', 'Disease', (35, 42))	('gastric acidity', 'Disease', (154, 169))	('rat', 'Species', '10116', (103, 106))	('obesity', 'Disease', 'MESH:D009765', (35, 42))	('affect', 'Reg', (66, 72))	('pylori', 'Species', '210', (12, 18))	('urease', 'Enzyme', (190, 196))	('hiatal hernia', 'Disease', 'MESH:D006551', (47, 60))	('H. pylori', 'Species', '210', (131, 140))	('activity', 'MPA', (178, 186))	('decrease', 'NegReg', (145, 153))	('hiatal hernia', 'Disease', (47, 60))	('hernia', 'Phenotype', 'HP:0100790', (54, 60))	('H. pylori', 'Var', (131, 140))	('decrease gastric acidity', 'Phenotype', 'HP:0002578', (145, 169))	('obesity', 'Phenotype', 'HP:0001513', (35, 42))	('gastric acidity', 'Disease', 'MESH:D005764', (154, 169))	('BE', 'Phenotype', 'HP:0100580', (85, 87))
885487	18516262	The fact that H. pylori may be protective against BE is a contrast to its well established status as a risk factor for peptic ulcer disease (PUD) and gastritis, and indeed eradication of H. pylori for PUD may increase risk of BE.	('gastritis', 'Disease', 'MESH:D005756', (150, 159))	('gastritis', 'Phenotype', 'HP:0005263', (150, 159))	('eradication', 'Var', (172, 183))	('H. pylori', 'Species', '210', (187, 196))	('H. pylori', 'Species', '210', (14, 23))	('BE', 'Phenotype', 'HP:0100580', (50, 52))	('peptic ulcer', 'Phenotype', 'HP:0004398', (119, 131))	('gastritis', 'Disease', (150, 159))	('peptic ulcer disease', 'Disease', 'MESH:D010437', (119, 139))	('H. pylori', 'Gene', (187, 196))	('peptic ulcer disease', 'Disease', (119, 139))	('BE', 'Phenotype', 'HP:0100580', (226, 228))
885516	18516262	Case control studies suggest a protective effect of NSAIDs for the development of BE and the progression to dysplasia and/or carcinoma.	('dysplasia', 'Disease', (108, 117))	('carcinoma', 'Disease', 'MESH:D002277', (125, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinoma', 'Disease', (125, 134))	('dysplasia', 'Disease', 'MESH:D004476', (108, 117))	('BE', 'Phenotype', 'HP:0100580', (82, 84))	('NSAIDs', 'Var', (52, 58))
885524	18516262	As discussed in the section on treatment, premalignant diagnosis of BE substantially improves survival of subsequent cancer, as cancer is caught early due to surveillance measures.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BE', 'Phenotype', 'HP:0100580', (68, 70))	('improves', 'PosReg', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('premalignant diagnosis', 'Var', (42, 64))	('cancer', 'Disease', (117, 123))	('survival', 'CPA', (94, 102))	('cancer', 'Disease', (128, 134))
885533	18516262	Available data demonstrate that even twice-daily PPI administration allows for periods of significant nocturnal gastric acidity with pH < 4.0 in the majority of patients, despite good control of symptoms in most.	('pH <', 'MPA', (133, 137))	('rat', 'Species', '10116', (22, 25))	('rat', 'Species', '10116', (61, 64))	('patients', 'Species', '9606', (161, 169))	('PPI', 'Var', (49, 52))	('nocturnal gastric acidity', 'Disease', 'MESH:D005764', (102, 127))	('nocturnal gastric acidity', 'Disease', (102, 127))
885536	18516262	second, control of reflux symptoms on PPIs does not indicate adequate control of acid reflux into the esophagus: 62% of BE patients treated with esomeprazole had pathologic esophageal acidity, particularly at night, despite control of symptoms.	('acid reflux', 'Phenotype', 'HP:0002020', (81, 92))	('patients', 'Species', '9606', (123, 131))	('BE', 'Phenotype', 'HP:0100580', (120, 122))	('esophageal acidity', 'Disease', 'MESH:D004941', (173, 191))	('pathologic', 'Var', (162, 172))	('esophageal acidity', 'Disease', (173, 191))	('esomeprazole', 'Chemical', 'MESH:D064098', (145, 157))	('reflux symptoms', 'Phenotype', 'HP:0002020', (19, 34))
885545	18516262	Limited clinical data suggests that PPI might prevent progression of metaplastic tissue towards dysplasia and/or cancer.	('prevent', 'NegReg', (46, 53))	('dysplasia', 'Disease', (96, 105))	('PPI', 'Var', (36, 39))	('progression', 'CPA', (54, 65))	('dysplasia', 'Disease', 'MESH:D004476', (96, 105))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
885576	18516262	Reasons to manage a high grade dysplasia patient with observation include the highly variable risk (18%-60%) of progression to esophageal cancer, the very high morbidity and mortality of esophagectomy (up to 15% in low volume centers), and the risk of masking progression to cancer through ablation of the superficial esophageal epithelium.	('cancer', 'Disease', (138, 144))	('esophageal cancer', 'Disease', (127, 144))	('cancer', 'Disease', (275, 281))	('dysplasia', 'Disease', 'MESH:D004476', (31, 40))	('ablation', 'Var', (290, 298))	('esophagectomy', 'Disease', (187, 200))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('patient', 'Species', '9606', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('dysplasia', 'Disease', (31, 40))
885603	18516262	As an example, of 322 Barrett's patients studied by a combination of histology and flow cytometric analysis for abnormal chromosomal number (aneuploidy or 4N), 247 had baseline histology that was either negative, indefinite, or showed low-grade dysplasia.	('abnormal chromosomal number', 'Var', (112, 139))	('aneuploidy', 'Disease', (141, 151))	('patients', 'Species', '9606', (32, 40))	('low-grade dysplasia', 'Disease', 'MESH:D008228', (235, 254))	('aneuploidy', 'Disease', 'MESH:D000782', (141, 151))	('low-grade dysplasia', 'Disease', (235, 254))
885688	32697782	Genome wide association studies have emphasized that GERD is a polygenic disease, and have shown an association between multiple GERD single nucleotide polymorphisms (SNPs) and the development of BE and EAC.	('GERD', 'Disease', (53, 57))	('association', 'Interaction', (100, 111))	('polygenic disease', 'Disease', (63, 80))	('EAC', 'Phenotype', 'HP:0011459', (203, 206))	('GERD', 'Gene', (129, 133))	('BE', 'Phenotype', 'HP:0100580', (196, 198))	('polygenic disease', 'Disease', 'MESH:D003141', (63, 80))	('single nucleotide polymorphisms', 'Var', (134, 165))
885691	32697782	While further exploration of associations between risk loci for tonsillectomy, GERD, BE and EAC are needed, another study suggested that functional polymorphisms in the immune-related gene for human beta defensin (DEFB1) were associated with increased susceptibility to adeno-tonsillar hypertrophy.	('tonsillar hypertrophy', 'Phenotype', 'HP:0030812', (276, 297))	('tonsillar hypertrophy', 'Disease', (276, 297))	('DEFB1', 'Gene', '1672', (214, 219))	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('DEFB1', 'Gene', (214, 219))	('polymorphisms', 'Var', (148, 161))	('BE', 'Phenotype', 'HP:0100580', (85, 87))	('tonsillar hypertrophy', 'Disease', 'MESH:D006984', (276, 297))	('human', 'Species', '9606', (193, 198))
885759	29115925	The tumor suppressor gene CDH1 germline mutation (encoding E-cadherin) is deemed to be the most common molecular event in HDGC.	('tumor', 'Disease', (4, 9))	('HDGC', 'Disease', (122, 126))	('GC', 'Phenotype', 'HP:0012126', (124, 126))	('germline', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CDH1', 'Gene', (26, 30))	('E-cadherin', 'Gene', (59, 69))	('E-cadherin', 'Gene', '999', (59, 69))	('CDH1', 'Gene', '999', (26, 30))
885760	29115925	Recent publications have named other closely related mutations in gastric cancer with hereditary background: CTNNA1, BRCA2, ATM, MUC1, PSCA and PLCE1.	('ATM', 'Gene', (124, 127))	('BRCA2', 'Gene', (117, 122))	('BRCA2', 'Gene', '675', (117, 122))	('ATM', 'Gene', '472', (124, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('MUC1', 'Gene', (129, 133))	('MUC1', 'Gene', '4582', (129, 133))	('mutations', 'Var', (53, 62))	('PSCA', 'Gene', '8000', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('PLCE1', 'Gene', (144, 149))	('CTNNA1', 'Gene', (109, 115))	('PSCA', 'Gene', (135, 139))	('gastric cancer', 'Disease', (66, 80))	('CTNNA1', 'Gene', '1495', (109, 115))	('PLCE1', 'Gene', '51196', (144, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
885785	29115925	Consequently, SNPs rs2294008 C > T in prostate stem cell antigen (PSCA) gene were found in the current study using next-generation sequencing (NGS).	('rs2294008', 'Mutation', 'rs2294008', (19, 28))	('PSCA', 'Gene', '8000', (66, 70))	('SNPs rs2294008 C > T', 'Var', (14, 34))	('PSCA', 'Gene', (66, 70))
885791	29115925	rs2294008 C > T polymorphism is the most extensively studied SNP in this gene and it has been shown to be significantly closely associated with increased overall cancer risk, especially for gastric cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('increased', 'PosReg', (144, 153))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (198, 204))	('rs2294008', 'Mutation', 'rs2294008', (0, 9))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('rs2294008 C > T', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('associated', 'Reg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('gastric cancer', 'Disease', (190, 204))
885792	29115925	The mechanism and physiological function are not fully understood, in vitro experiments have demonstrated that the PSCA rs2294008T might decrease the transcriptional activity of the host gene by recruiting transcription factor Yin Yang 1 (YY1) to its promoter and eventually predispose gastric epithelial cells to GC development.	('Yin Yang 1', 'Gene', (227, 237))	('gastric epithelial cells', 'CPA', (286, 310))	('predispose', 'Reg', (275, 285))	('rs2294008', 'Mutation', 'rs2294008', (120, 129))	('decrease', 'NegReg', (137, 145))	('recruiting', 'PosReg', (195, 205))	('YY1', 'Gene', (239, 242))	('PSCA', 'Gene', '8000', (115, 119))	('GC development', 'CPA', (314, 328))	('GC', 'Phenotype', 'HP:0012126', (314, 316))	('Yin Yang 1', 'Gene', '7528', (227, 237))	('PSCA', 'Gene', (115, 119))	('transcriptional activity', 'MPA', (150, 174))	('rs2294008T', 'Var', (120, 130))
885809	26786590	The results indicated that high selenium exposure had a protective effect on cancer risk (pooled OR = 0.78; 95%CI: 0.73-0.83).	('selenium', 'Chemical', 'MESH:D012643', (32, 40))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('high', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
885844	26786590	The result of the pooled analysis showed that high selenium exposure had a protective efficacy on cancer at the highest compared with the lowest category (pooled OR = 0.78; 95%CI: 0.73-0.83), with obvious heterogeneity (Q = 423.52; P = 0.000; I2 % = 73.3) and publication bias (Begger's test zc = 2.55, P = 0.011; Egger's test t = -2.61, P = 0.010).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('high', 'Var', (46, 50))	('publication bias', 'Disease', (260, 276))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('publication bias', 'Disease', 'MESH:D065309', (260, 276))	('cancer', 'Disease', (98, 104))	('selenium', 'Chemical', 'MESH:D012643', (51, 59))
885847	26786590	The pooled result from 58 independent estimates showed that high serum/plasma selenium had a effect on cancer prevention at the highest compared with the lowest category (pooled OR = 0.75, 95%CI: 0.69-0.82, Fig.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('high', 'Var', (60, 64))	('selenium', 'Chemical', 'MESH:D012643', (78, 86))	('high serum/plasma selenium', 'Phenotype', 'HP:0031903', (60, 86))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
885854	26786590	The result showed that high toenail selenium decreased cancer risk (pooled OR = 0.74, 95%CI: 0.62-0.87, as shown in Fig.	('high toenail', 'Var', (23, 35))	('decreased cancer', 'Disease', 'MESH:D009369', (45, 61))	('selenium', 'Chemical', 'MESH:D012643', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('decreased cancer', 'Disease', (45, 61))
885882	26786590	S5) 26 estimates from 25 studies described the association between selenium and risk of prostate cancer.	('prostate cancer', 'Disease', (88, 103))	('selenium', 'Chemical', 'MESH:D012643', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('selenium', 'Var', (67, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('association', 'Interaction', (47, 58))
885886	26786590	The result of linear dose-response analysis presented that plasma/serum selenium was associated with prostate cancer risk per 10 ug/L increases (pooled OR = 0.97, 95%CI: 0.95-0.99; Q = 19.5, P = 0.003).	('selenium', 'Chemical', 'MESH:D012643', (72, 80))	('prostate cancer', 'Disease', (101, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))	('increases', 'PosReg', (134, 143))	('plasma/serum', 'Var', (59, 71))	('associated', 'Reg', (85, 95))
885908	26786590	study showed a gender-specific relation between toenail selenium and bladder cancer that high toenail selenium had a protective effect on female bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (69, 83))	('bladder cancer', 'Disease', (69, 83))	('selenium', 'Chemical', 'MESH:D012643', (56, 64))	('high toenail', 'Var', (89, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('selenium', 'Chemical', 'MESH:D012643', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('bladder cancer', 'Disease', (145, 159))
885933	26786590	meta-analysis which included seven studies showed a protective effect of selenium on colorectal adenomas (OR = 0.67; 95%CI: 0.55-81).	('colorectal adenomas', 'Disease', 'MESH:D015179', (85, 104))	('selenium', 'Var', (73, 81))	('colorectal adenomas', 'Disease', (85, 104))	('selenium', 'Chemical', 'MESH:D012643', (73, 81))
885937	26786590	According to prostate cancer, we find a protective effect of high selenium exposure for prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))	('prostate cancer', 'Disease', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('high', 'Var', (61, 65))	('prostate cancer', 'Disease', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (13, 28))	('selenium', 'Chemical', 'MESH:D012643', (66, 74))
886029	24649241	JARID1B knockdown resulted in the suppression of esophageal cancer cell growth, sphere formation and invasion ability and was associated with loss of epithelial marker expression.	('epithelial marker expression', 'MPA', (150, 178))	('sphere formation', 'CPA', (80, 96))	('loss', 'NegReg', (142, 146))	('esophageal cancer', 'Disease', (49, 66))	('knockdown', 'Var', (8, 17))	('JARID1B', 'Gene', (0, 7))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('invasion ability', 'CPA', (101, 117))	('suppression', 'NegReg', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
886037	24649241	A previous study suggested that the genetic and epigenetic alterations, which constrain tumor suppressor genes and activate oncogenes, are involved in the initiation, progression and development of carcinogenesis in the esophagus, which is asssociated with exposure to environmental carcinogens.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('carcinogenesis', 'Disease', (198, 212))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (198, 212))	('involved', 'Reg', (139, 147))	('epigenetic alterations', 'Var', (48, 70))
886038	24649241	Specifically, animal model analogies of environmental carcinogenesis in humans indicated that alterations in the expression of microRNAs, such as miR-31 and miR-21, characterized epithelial tumor progression in the esophagus.	('expression', 'MPA', (113, 123))	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('miR-31', 'Gene', '407035', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('alterations', 'Var', (94, 105))	('miR-21', 'Gene', (157, 163))	('carcinogenesis', 'Disease', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('epithelial tumor', 'Phenotype', 'HP:0031492', (179, 195))	('characterized', 'Reg', (165, 178))	('tumor', 'Disease', (190, 195))	('miR-31', 'Gene', (146, 152))	('miR-21', 'Gene', '406991', (157, 163))	('humans', 'Species', '9606', (72, 78))
886040	24649241	Although epigenetic regulation is eventually involved in tumor development in the esophagus, few molecular biomarkers have been translated to widespread clinical practice.	('epigenetic regulation', 'Var', (9, 30))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('involved', 'Reg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
886041	24649241	Epigenetic studies have shown that the aberrant DNA methylation of tumor suppressor genes is involved in esophageal cancer, as well as in adenocarcinoma, squamous cell carcinoma and Barrett's esophagus.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (138, 152))	('aberrant DNA methylation', 'Var', (39, 63))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (182, 201))	('involved', 'Reg', (93, 101))	('esophageal cancer', 'Disease', (105, 122))	("Barrett's esophagus", 'Disease', (182, 201))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (182, 201))	('adenocarcinoma', 'Disease', (138, 152))	('tumor', 'Disease', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('squamous cell carcinoma', 'Disease', (154, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 177))
886046	24649241	JARID1B knockdown ultimately inhibited melanoma cell growth.	('inhibited', 'NegReg', (29, 38))	('knockdown', 'Var', (8, 17))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('JARID1B', 'Gene', (0, 7))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))
886047	24649241	In this study, we investigated the effects of JARID1B knockdown on squamous cell carcinoma of the esophagus using lentiviral transfer of small hairpin (sh) RNA molecules for inhibition.	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (81, 107))	('knockdown', 'Var', (54, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('squamous cell carcinoma of the esophagus', 'Disease', (67, 107))	('JARID1B', 'Gene', (46, 53))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (67, 107))
886048	24649241	Our findings are compatible with the hypothesis that, similar to genetic alterations, epigenetic aberrations including histone modifications significantly contribute to tumor initiation and progression in gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', (205, 229))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (205, 229))	('tumor initiation', 'Disease', 'MESH:D009369', (169, 185))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor initiation', 'Disease', (169, 185))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('histone', 'MPA', (119, 126))	('epigenetic aberrations', 'Var', (86, 108))	('contribute', 'Reg', (155, 165))
886051	24649241	For shRNA-mediated knockdown of endogenous JARID1B, lentiviruses were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA).	('JARID1B', 'Gene', (43, 50))	('knockdown', 'Var', (19, 28))	('B, lentiviruses', 'Species', '11656', (49, 64))
886059	24649241	A total of 102 or 103 cells (JARID1B knockdown TE4 cells and control TE4 cells), mixed with BD matrigel (Becton Dickinson) at a 1:1 ratio, were injected subcutaneously into NOD/SCID mice.	('SCID', 'Disease', (177, 181))	('knockdown', 'Var', (37, 46))	('mice', 'Species', '10090', (182, 186))	('SCID', 'Disease', 'MESH:D053632', (177, 181))
886062	24649241	These results indicated that JARID1B knockdown suppressed esophageal tumor cell growth.	('JARID1B', 'Gene', (29, 36))	('suppressed', 'NegReg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('knockdown', 'Var', (37, 46))	('esophageal tumor', 'Disease', 'MESH:D004938', (58, 74))	('esophageal tumor', 'Disease', (58, 74))	('esophageal tumor', 'Phenotype', 'HP:0100751', (58, 74))
886066	24649241	Thus, these results indicated that JARID1B knockdown reduced tumor cell growth and invasion via the induction of a network of EMT-related genes.	('EMT-related', 'Gene', (126, 137))	('knockdown', 'Var', (43, 52))	('induction', 'Reg', (100, 109))	('JARID1B', 'Gene', (35, 42))	('reduced', 'NegReg', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('invasion', 'CPA', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
886069	24649241	Thus, these results suggest that JARID1B knockdown reduced the self-renewal activity of esophageal cancer cells.	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('JARID1B', 'Gene', (33, 40))	('reduced', 'NegReg', (51, 58))	('esophageal cancer', 'Disease', (88, 105))	('knockdown', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
886071	24649241	When 102 JARID1B knockdown TE4 or TE8 cells were inoculated subcutaneously into mice, tumorigenicity was reduced as observed on days 30 and 37 (representative data shown in Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('reduced', 'NegReg', (105, 112))	('mice', 'Species', '10090', (80, 84))	('knockdown', 'Var', (17, 26))	('JARID1B', 'Gene', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
886072	24649241	Consistent with this possibility, observations on day 45 indicated that even initially-JARID1B knockdown vector-treated cells exhibited tumorigenicity.	('initially-JARID1B', 'Gene', (77, 94))	('initially-JARID1B', 'Var', (77, 94))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
886075	24649241	Dysregulation of these activities are hallmarks of cancer through genetic and epigenetic alterations.	('Dysregulation', 'Var', (0, 13))	('genetic', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('epigenetic alterations', 'Var', (78, 100))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (51, 57))	('activities', 'MPA', (23, 33))
886076	24649241	It was recently observed that Jarid1a/b-mediated demethylation of histone H3K4 contributed to silencing retinoblastoma target genes in senescent cells, presumably through closing the chromatin in which the silencing of retinoblastoma trigger genes was involved.	('Jarid1a', 'Gene', '214899', (30, 37))	('silencing', 'NegReg', (94, 103))	('retinoblastoma', 'Disease', 'MESH:D012175', (104, 118))	('retinoblastoma', 'Disease', (104, 118))	('retinoblastoma', 'Disease', 'MESH:D012175', (219, 233))	('H3K4', 'Protein', (74, 78))	('retinoblastoma', 'Phenotype', 'HP:0009919', (219, 233))	('histone H3K4', 'Protein', (66, 78))	('retinoblastoma', 'Phenotype', 'HP:0009919', (104, 118))	('closing', 'NegReg', (171, 178))	('demethylation', 'Var', (49, 62))	('Jarid1a', 'Gene', (30, 37))	('retinoblastoma', 'Disease', (219, 233))
886078	24649241	The results of the present study indicated that JARID1B knockdown (i.e., inhibition of H3K4 demethylation) resulted in the suppression of tumor cell growth in vitro and in vivo.	('tumor', 'Disease', (138, 143))	('inhibition', 'NegReg', (73, 83))	('JARID1B', 'Gene', (48, 55))	('H3K4', 'Protein', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('suppression', 'NegReg', (123, 134))	('knockdown', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
886084	24649241	Therapeutic approaches for esophageal cancer include conventional treatments, such as surgical removal and chemoradiation treatment as well as gene therapy strategies, such as the introduction of the tumor suppressor p16/INK4A, expression of IL-2, IL-6 and GM-CSF gene products, and the transduction of the herpes simplex virus-thymidine kinase gene.	('p16', 'Gene', '12578', (217, 220))	('IL-2', 'Gene', '16183', (242, 246))	('herpes simplex', 'Phenotype', 'HP:0012302', (307, 321))	('INK4A', 'Gene', '12578', (221, 226))	('IL-2', 'Gene', (242, 246))	('transduction', 'Var', (287, 299))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))	('tumor', 'Disease', (200, 205))	('p16', 'Gene', (217, 220))	('GM-CSF', 'Gene', '12981', (257, 263))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('esophageal cancer', 'Disease', (27, 44))	('GM-CSF', 'Gene', (257, 263))	('IL-6', 'Gene', (248, 252))	('INK4A', 'Gene', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('IL-6', 'Gene', '16193', (248, 252))	('herpes simplex virus-thymidine kinase gene', 'Gene', (307, 349))
886085	24649241	To achieve continuous knockdown of JARID1B, options include antisense oligonucleotides or low molecular therapeutic pharmacology.	('knockdown', 'Var', (22, 31))	('oligonucleotides', 'Chemical', 'MESH:D009841', (70, 86))	('antisense', 'Var', (60, 69))	('JARID1B', 'Gene', (35, 42))
886146	33729331	Histopathological tissue damage score for fibrosis development was lower in cordycepin-treated rats than in prednisolone-treated rats.	('cordycepin-treated', 'Var', (76, 94))	('rats', 'Species', '10116', (95, 99))	('prednisolone', 'Chemical', 'MESH:D011239', (108, 120))	('fibrosis', 'Disease', 'MESH:D005355', (42, 50))	('fibrosis', 'Disease', (42, 50))	('cordycepin', 'Chemical', 'MESH:C058120', (76, 86))	('rats', 'Species', '10116', (129, 133))	('lower', 'NegReg', (67, 72))
886148	33729331	Stenosis index of cordycepin group was comparable with those of sham group, but significantly lower than the control group (p < 0.05).	('Stenosis', 'Disease', (0, 8))	('Stenosis', 'Disease', 'MESH:D003251', (0, 8))	('lower', 'NegReg', (94, 99))	('cordycepin', 'Chemical', 'MESH:C058120', (18, 28))	('cordycepin', 'Var', (18, 28))
886174	33729331	Cordycepin has been shown to attenuate age-related oxidative stress and enhance antioxidant capacity in rats.	('antioxidant capacity', 'MPA', (80, 100))	('enhance', 'PosReg', (72, 79))	('rats', 'Species', '10116', (104, 108))	('oxidative stress', 'Phenotype', 'HP:0025464', (51, 67))	('Cordycepin', 'Chemical', 'MESH:C058120', (0, 10))	('attenuate', 'NegReg', (29, 38))	('Cordycepin', 'Var', (0, 10))
886188	33729331	Stenosis index of the cordycepin group was comparable with those of sham group, but significantly lower than the control group, suggesting that the cordycepin produced a significant increase in the esophageal diameter and restored the normal deglutition.	('increase', 'PosReg', (182, 190))	('restored', 'PosReg', (222, 230))	('Stenosis', 'Disease', (0, 8))	('normal deglutition', 'MPA', (235, 253))	('esophageal diameter', 'MPA', (198, 217))	('Stenosis', 'Disease', 'MESH:D003251', (0, 8))	('cordycepin', 'Chemical', 'MESH:C058120', (148, 158))	('cordycepin', 'Var', (148, 158))	('cordycepin', 'Chemical', 'MESH:C058120', (22, 32))
886231	32793454	Stent-induced A stent may cause pressure necrosis, inflammation, and fibrosis of the esophageal mucosa.	('cause', 'Reg', (26, 31))	('inflammation', 'Disease', (51, 63))	('pressure necrosis', 'Phenotype', 'HP:0010885', (32, 49))	('pressure', 'CPA', (32, 40))	('fibrosis', 'Disease', 'MESH:D005355', (69, 77))	('fibrosis', 'Disease', (69, 77))	('necrosis', 'Disease', 'MESH:D009336', (41, 49))	('inflammation', 'Disease', 'MESH:D007249', (51, 63))	('Stent-induced', 'Var', (0, 13))	('necrosis', 'Disease', (41, 49))
886241	32793454	A connection of the esophagus with the trachea or bronchus results in constant cough and sputum, with the same pathophysiology as aspiration pneumonia.	('pneumonia', 'Phenotype', 'HP:0002090', (141, 150))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (130, 150))	('cough', 'Disease', 'MESH:D003371', (79, 84))	('cough', 'Phenotype', 'HP:0012735', (79, 84))	('aspiration', 'Phenotype', 'HP:0002835', (130, 140))	('connection', 'Var', (2, 12))	('aspiration pneumonia', 'Disease', (130, 150))	('cough', 'Disease', (79, 84))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (130, 150))	('results in', 'Reg', (59, 69))	('sputum', 'Disease', (89, 95))
886356	31360073	Collectively, this summary strongly suggests that targeting aberrant YAP/TAZ activation is a promising strategy for the suppression of squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('YAP/TAZ', 'Protein', (69, 76))	('rat', 'Species', '10116', (105, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('squamous cell carcinoma', 'Disease', (135, 158))	('aberrant', 'Var', (60, 68))
886365	31360073	On the contrary, aberrantly high activity of YAP/TAZ promotes cell overgrowth and tumor formation.	('promotes', 'PosReg', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('activity', 'MPA', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cell overgrowth', 'CPA', (62, 77))	('YAP/TAZ', 'Gene', (45, 52))	('tumor', 'Disease', (82, 87))	('aberrantly high', 'Var', (17, 32))	('overgrowth', 'Phenotype', 'HP:0001548', (67, 77))
886371	31360073	Upon inactivation of the Hippo pathway, dephosphorylated YAP/TAZ translocates to the nucleus and binds to the transcription factor TEAD to induce expression of the genes involved in cell proliferation, anti-apoptosis, and epithelial-mesenchymal cell transformation (Figure 1).	('Hippo', 'Gene', '37247', (25, 30))	('anti-apoptosis', 'CPA', (202, 216))	('rat', 'Species', '10116', (194, 197))	('cell proliferation', 'CPA', (182, 200))	('binds', 'Interaction', (97, 102))	('Hippo', 'Gene', (25, 30))	('epithelial-mesenchymal cell transformation', 'CPA', (222, 264))	('induce', 'PosReg', (139, 145))	('inactivation', 'Var', (5, 17))	('expression', 'MPA', (146, 156))
886384	31360073	A previous study demonstrated that the WW domain specifically recognizes the PpxY (P is proline, x is any amino acid and y is tyrosine) motifs, thereby controlling the localization and activity of YAP/TAZ.	('activity', 'MPA', (185, 193))	('controlling', 'Reg', (152, 163))	('localization', 'MPA', (168, 180))	('proline', 'Chemical', 'MESH:D011392', (88, 95))	('PpxY', 'Var', (77, 81))	('tyrosine', 'Chemical', 'MESH:D014443', (126, 134))	('rat', 'Species', '10116', (24, 27))
886389	31360073	On the contrary, mutant YAP gene knockout mice showed marked epidermis shrinkage and delayed wound healing.	('YAP', 'Gene', (24, 27))	('mice', 'Species', '10090', (42, 46))	('wound healing', 'CPA', (93, 106))	('delayed wound healing', 'Phenotype', 'HP:0001058', (85, 106))	('epidermis shrinkage', 'CPA', (61, 80))	('mutant', 'Var', (17, 23))	('delayed', 'NegReg', (85, 92))
886412	31360073	For melanoma, recent papers described high expression of TAZ/YAP promoted its progression associated with stimulation of low-density lipoprotein receptor-related protein 1 (LRP1) and affects the postoperative survival of patients.	('patients', 'Species', '9606', (221, 229))	('low-density lipoprotein receptor-related protein 1', 'Gene', '4035', (121, 171))	('LRP1', 'Gene', '4035', (173, 177))	('progression', 'CPA', (78, 89))	('TAZ/YAP', 'Gene', (57, 64))	('stimulation', 'PosReg', (106, 117))	('postoperative survival', 'CPA', (195, 217))	('high expression', 'Var', (38, 53))	('promoted', 'PosReg', (65, 73))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('LRP1', 'Gene', (173, 177))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('rat', 'Species', '10116', (202, 205))	('affects', 'Reg', (183, 190))	('melanoma', 'Disease', (4, 12))	('low-density lipoprotein receptor-related protein 1', 'Gene', (121, 171))
886438	31360073	An experiment by Wang et al showed that the level of nuclear YAP/TAZ in fibroblasts associated with perineural invasion was higher than those in the stroma of normal mucosa, suggesting that the transcription programs mediated by YAP/TAZ in the fibroblasts may contribute to perineural invasion in HNSCC.	('SCC', 'Gene', (299, 302))	('contribute', 'Reg', (260, 270))	('YAP/TAZ', 'Var', (229, 236))	('SCC', 'Phenotype', 'HP:0002860', (299, 302))	('SCC', 'Gene', '6317', (299, 302))	('perineural invasion', 'CPA', (274, 293))	('HNSCC', 'Phenotype', 'HP:0012288', (297, 302))
886439	31360073	Interestingly, a recent study reported that upregulation of a circular RNA, circPVT1 together with TP53 mutation resulted in increased proliferation of HNSCC cell lines through the formation of mut-p53/YAP/TEAD complex.	('TP53', 'Gene', (99, 103))	('SCC', 'Gene', '6317', (154, 157))	('increased', 'PosReg', (125, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (152, 157))	('upregulation', 'PosReg', (44, 56))	('proliferation', 'CPA', (135, 148))	('mutation', 'Var', (104, 112))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('TP53', 'Gene', '7157', (99, 103))	('SCC', 'Gene', (154, 157))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))	('rat', 'Species', '10116', (142, 145))
886442	31360073	Recent research showed the expression level of YAP was higher in OSCC tissues than that in adjacent normal tissues and YAP could drive the transcription of bcl-2 and c-myc genes subsequently leading to OSCC cell proliferation and resistance to apoptosis.	('drive', 'PosReg', (129, 134))	('resistance to apoptosis', 'CPA', (230, 253))	('SCC', 'Gene', (66, 69))	('SCC', 'Gene', (203, 206))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('leading to', 'Reg', (191, 201))	('SCC', 'Gene', '6317', (66, 69))	('SCC', 'Gene', '6317', (203, 206))	('c-myc', 'Gene', (166, 171))	('YAP', 'Var', (119, 122))	('bcl-2', 'Gene', '596', (156, 161))	('c-myc', 'Gene', '4609', (166, 171))	('SCC', 'Phenotype', 'HP:0002860', (203, 206))	('transcription', 'MPA', (139, 152))	('rat', 'Species', '10116', (219, 222))	('expression level', 'MPA', (27, 43))	('bcl-2', 'Gene', (156, 161))
886454	31360073	It was reported that viral GPCR inhibited the Hippo pathway kinases Lats1/2 through Gq/11 and G12/13, which resulted in the activation of YAP/TAZ.	('activation', 'PosReg', (124, 134))	('GPCR', 'Gene', '10663', (27, 31))	('Hippo', 'Gene', '37247', (46, 51))	('inhibited', 'NegReg', (32, 41))	('GPCR', 'Gene', (27, 31))	('Hippo', 'Gene', (46, 51))	('YAP/TAZ', 'Disease', (138, 145))	('Lats1/2', 'Enzyme', (68, 75))	('G12/13', 'Var', (94, 100))
886513	30961474	Although TE-1 cells were treated with increasing doses of Bortezomib (0, 50, 150, 450 nM), G2/M arrest was only observed with the highest concentration (450 nM; Figure 2A).	('M arrest', 'Disease', 'MESH:D006323', (94, 102))	('M arrest', 'Disease', (94, 102))	('Bortezomib', 'Chemical', 'MESH:D000069286', (58, 68))	('450 nM', 'Var', (153, 159))	('TE-1', 'CellLine', 'CVCL:1759', (9, 13))
886543	30961474	HDAC6 inhibitors exhibit antiproliferative and proapoptotic activities.	('HDAC6', 'Gene', '10013', (0, 5))	('proapoptotic activities', 'CPA', (47, 70))	('HDAC6', 'Gene', (0, 5))	('antiproliferative', 'CPA', (25, 42))	('inhibitors', 'Var', (6, 16))
886549	27723755	Among this widespread allele-specific expression, we identify germline polymorphisms that are associated with response to cancer therapies.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('germline', 'Var', (62, 70))	('associated with', 'Reg', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
886550	27723755	We further leverage this integrative data to uncover expressed mutations in several known cancer genes as well as a recurrent mutation in the motor domain of KIF3B that significantly affects kinesin-microtubule interactions.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('kinesin-microtubule interactions', 'MPA', (191, 223))	('KIF3B', 'Gene', (158, 163))	('cancer', 'Disease', (90, 96))	('mutation in', 'Var', (126, 137))	('KIF3B', 'Gene', '9371', (158, 163))	('affects', 'Reg', (183, 190))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
886551	27723755	In cancer, for example, roughly a third of the somatic single-nucleotide variants (SNVs) that fall within coding regions can also be observed in the RNA, providing a biologic filter for candidate driver mutations.	('single-nucleotide variants', 'Var', (55, 81))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('fall', 'Phenotype', 'HP:0002527', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
886559	27723755	The tumor genome was sequenced to an average coverage of 38x and displayed a skewed coverage distribution indicative of large-scale copy-number alterations (Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('copy-number alterations', 'Var', (132, 155))
886560	27723755	Comparing the Simul-seq tumor genome with a DNA-seq paired normal genome revealed a highly aneuploid genomic landscape, with somatic evidence for 142 structural variants and 9 expressed gene fusions as well as 15,607 SNVs and 2,904 indels (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('variants', 'Var', (161, 169))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('SNVs', 'Var', (217, 221))
886562	27723755	Given the high levels of LOH-induced allele-specific expression (ASE) in the tumor, we hypothesized that damaging germline variants in tumor suppressor genes might be specifically expressed in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('ASE', 'Chemical', '-', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (197, 202))	('variants', 'Var', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
886564	27723755	In addition to representing potential driver mutations, these expressed protein-altering mutations are also possible neoantigens from which patient-specific immunotherapies may be derived.	('patient', 'Species', '9606', (140, 147))	('protein-altering', 'Protein', (72, 88))	('mutations', 'Var', (89, 98))
886565	27723755	Notably, three Cosmic Cancer census genes (TP53, ATM and ESWR1) were found to harbor expressed somatic missense mutations.	('Cosmic Cancer', 'Disease', 'MESH:D009369', (15, 28))	('ATM', 'Gene', '472', (49, 52))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('missense mutations', 'Var', (103, 121))	('Cosmic Cancer', 'Disease', (15, 28))	('ATM', 'Gene', (49, 52))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('ESWR1', 'Gene', (57, 62))
886566	27723755	While ESWR1 is typically a constituent of an oncogenic fusion protein, and the R45W mutation in the ATM serine/threonine kinase tumor suppressor is not yet characterized, the Y220C mutation is a known TP53 hotspot that decreases protein stability.	('R45W', 'Var', (79, 83))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('ATM', 'Gene', '472', (100, 103))	('R45W', 'Mutation', 'rs3218684', (79, 83))	('decreases', 'NegReg', (219, 228))	('TP53', 'Gene', '7157', (201, 205))	('Y220C', 'Mutation', 'rs121912666', (175, 180))	('Y220C', 'Var', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TP53', 'Gene', (201, 205))	('protein stability', 'MPA', (229, 246))	('ATM', 'Gene', (100, 103))
886568	27723755	Interestingly, this patient also exhibited ASE for common germline polymorphisms in the epidermal growth factor receptor gene (EGFR, rs2227983) as well as the cyclin D1 gene (CCND1, rs9344) (Supplementary Table 6), polymorphisms that are associated with response to chemotherapeutic treatments.	('cyclin D1', 'Gene', (159, 168))	('ASE', 'Chemical', '-', (43, 46))	('epidermal growth factor receptor', 'Gene', '1956', (88, 120))	('rs2227983', 'Var', (133, 142))	('rs9344', 'Var', (182, 188))	('rs9344', 'Mutation', 'rs9344', (182, 188))	('rs2227983', 'Mutation', 'rs2227983', (133, 142))	('patient', 'Species', '9606', (20, 27))	('CCND1', 'Gene', (175, 180))	('EGFR', 'Gene', (127, 131))	('EGFR', 'Gene', '1956', (127, 131))	('epidermal growth factor receptor', 'Gene', (88, 120))	('CCND1', 'Gene', '595', (175, 180))	('cyclin D1', 'Gene', '595', (159, 168))
886569	27723755	In addition to discovering clinically relevant alterations in known cancer genes, we observed an expressed arginine-to-tryptophan mutation in KIF3B (R293W), a type II kinesin motor protein.	('KIF3B', 'Gene', '9371', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('R293W', 'Var', (149, 154))	('arginine-to-tryptophan', 'MPA', (107, 129))	('R293W', 'SUBSTITUTION', 'None', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('KIF3B', 'Gene', (142, 147))	('arginine', 'Chemical', 'MESH:D001120', (107, 115))	('cancer', 'Disease', (68, 74))	('tryptophan', 'Chemical', 'MESH:D014364', (119, 129))
886571	27723755	KIF3B has been linked to the intracellular trafficking of several tumor suppressor genes, and biochemical data have shown that substitution of specific arginine and lysine residues within the kinesin motor domain negatively impacts kinesin-microtubule association.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('KIF3B', 'Gene', (0, 5))	('tumor', 'Disease', (66, 71))	('substitution', 'Var', (127, 139))	('KIF3B', 'Gene', '9371', (0, 5))	('negatively impacts', 'NegReg', (213, 231))	('lysine', 'Chemical', 'MESH:D008239', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('arginine', 'Chemical', 'MESH:D001120', (152, 160))	('kinesin-microtubule association', 'MPA', (232, 263))
886573	27723755	Overall, KIF3B harbored verified nonsynonymous mutations in ~6% of the tumor samples, and the R293W mutation was observed in a second independent patient (Fig.	('KIF3B', 'Gene', '9371', (9, 14))	('R293W', 'Var', (94, 99))	('nonsynonymous', 'MPA', (33, 46))	('R293W', 'SUBSTITUTION', 'None', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('KIF3B', 'Gene', (9, 14))	('patient', 'Species', '9606', (146, 153))	('tumor', 'Disease', (71, 76))
886574	27723755	To investigate the functional consequences of this recurrent R293W mutation, we purified recombinant wild-type and mutant KIF3B motor domains (Supplementary Fig.	('KIF3B', 'Gene', (122, 127))	('mutant', 'Var', (115, 121))	('R293W', 'Var', (61, 66))	('KIF3B', 'Gene', '9371', (122, 127))	('R293W', 'SUBSTITUTION', 'None', (61, 66))
886575	27723755	When compared with the wild-type domain, the mutant motor domain displayed a significantly reduced rate of ATP hydrolysis upon incubation with various concentrations of microtubules, suggesting that the R293W mutation abrogates kinesin-microtubule binding (Fig.	('kinesin-microtubule binding', 'MPA', (228, 255))	('abrogates', 'NegReg', (218, 227))	('reduced', 'NegReg', (91, 98))	('ATP', 'Chemical', 'MESH:D000255', (107, 110))	('R293W', 'Var', (203, 208))	('R293W', 'SUBSTITUTION', 'None', (203, 208))
886578	27723755	Applying Simul-seq to laser-capture-microdissected tumor tissue revealed a highly aneuploid somatic landscape, including a recurrent R293W mutation in KIF3B that dramatically reduced kinesin-microtubule interaction.	('reduced', 'NegReg', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('R293W', 'Var', (133, 138))	('kinesin-microtubule interaction', 'MPA', (183, 214))	('tumor', 'Disease', (51, 56))	('KIF3B', 'Gene', (151, 156))	('R293W', 'SUBSTITUTION', 'None', (133, 138))	('KIF3B', 'Gene', '9371', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
886580	27723755	Intriguingly, overexpression of C-terminal truncations of KIF3B-induced aneuploidy in NIH3T3 cells.	('C-terminal truncations', 'Var', (32, 54))	('aneuploidy', 'Disease', (72, 82))	('NIH3T3', 'CellLine', 'CVCL:0594', (86, 92))	('KIF3B', 'Gene', (58, 63))	('aneuploidy', 'Disease', 'MESH:D000782', (72, 82))	('KIF3B', 'Gene', '9371', (58, 63))	('overexpression', 'PosReg', (14, 28))
886582	27723755	Together, our findings suggest that additional experiments are warranted to delineate specific functional roles for KIF3B mutation in esophageal tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('KIF3B', 'Gene', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutation', 'Var', (122, 130))	('tumor', 'Disease', (145, 150))	('KIF3B', 'Gene', '9371', (116, 121))
886583	27723755	In addition to the novel KIF3B mutation, we also identified a number of clinically relevant variants in this EAC patient sample.	('KIF3B', 'Gene', '9371', (25, 30))	('patient', 'Species', '9606', (113, 120))	('EAC', 'Phenotype', 'HP:0011459', (109, 112))	('mutation', 'Var', (31, 39))	('KIF3B', 'Gene', (25, 30))	('variants', 'Var', (92, 100))
886584	27723755	We observed a known TP53 hotspot mutation (Y220C) that destabilizes the TP53 protein at body temperatures and is also a target of several small molecules designed to restore TP53 function in tumors.	('TP53', 'Gene', '7157', (174, 178))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('Y220C', 'Mutation', 'rs121912666', (43, 48))	('TP53', 'Gene', (20, 24))	('TP53', 'Gene', (174, 178))	('TP53', 'Gene', '7157', (72, 76))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('Y220C', 'Var', (43, 48))	('TP53', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('TP53', 'Gene', '7157', (20, 24))	('destabilizes', 'NegReg', (55, 67))
886585	27723755	TP53 inactivation followed by whole-genome duplication and chromosomal catastrophe is a frequent trajectory for EAC development and is consistent with our observations for this tumor.	('TP53', 'Gene', '7157', (0, 4))	('chromosomal catastrophe', 'Phenotype', 'HP:0040012', (59, 82))	('TP53', 'Gene', (0, 4))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('EAC', 'Disease', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('inactivation', 'Var', (5, 17))	('tumor', 'Disease', (177, 182))
886586	27723755	Among the widespread LOH induced by this genomic instability, we detected ASE for germline variants with pharmacogenomic links to the efficacy of cancer therapies used in EAC.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('ASE', 'Chemical', '-', (74, 77))	('EAC', 'Phenotype', 'HP:0011459', (171, 174))	('variants', 'Var', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
886587	27723755	The EGFR polymorphism (rs2227983) observed in this patient is associated with increased survival of colorectal cancer patients treated with Cetuximab, perhaps via attenuation of EGFR pathway signaling.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('EGFR', 'Gene', '1956', (178, 182))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('EGFR', 'Gene', (4, 8))	('rs2227983', 'Var', (23, 32))	('EGFR', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rs2227983', 'Mutation', 'rs2227983', (23, 32))	('colorectal cancer', 'Disease', (100, 117))	('survival', 'MPA', (88, 96))	('increased', 'PosReg', (78, 87))	('patient', 'Species', '9606', (51, 58))	('Cetuximab', 'Chemical', 'MESH:D000068818', (140, 149))	('patient', 'Species', '9606', (118, 125))	('patients', 'Species', '9606', (118, 126))	('attenuation', 'NegReg', (163, 174))	('EGFR', 'Gene', '1956', (4, 8))
886588	27723755	In contrast, the patient harbored a second variant in CCND1 (rs9344) that is inversely correlated with overall survival in colorectal cancer patients treated with Cetuximab.	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('rs9344', 'Var', (61, 67))	('Cetuximab', 'Chemical', 'MESH:D000068818', (163, 172))	('rs9344', 'Mutation', 'rs9344', (61, 67))	('patient', 'Species', '9606', (17, 24))	('colorectal cancer', 'Disease', (123, 140))	('patient', 'Species', '9606', (141, 148))	('CCND1', 'Gene', (54, 59))	('correlated with', 'Reg', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('CCND1', 'Gene', '595', (54, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))	('patients', 'Species', '9606', (141, 149))
886624	27723755	Using these criteria, three variants in KIF3B were identified and subsequently validated using pyrophosphate sequencing (see Supplementary Fig.	('pyrophosphate', 'Chemical', 'MESH:C107241', (95, 108))	('KIF3B', 'Gene', (40, 45))	('KIF3B', 'Gene', '9371', (40, 45))	('variants', 'Var', (28, 36))
886625	27723755	A single tumor-normal pair (00-18224-A2) displayed a substantially higher number of variant calls yet a lower number of uniquely mapped reads, suggesting that these samples harbored increased rates of PCR errors induced by low-quality genomic DNA.	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('variant calls', 'Var', (84, 97))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))
886627	27723755	The PCR products were digested with NdeI/XhoI restriction enzymes and cloned into NdeI/XhoI-digested pET28a backbone, tagging the KIF3B motor domains on the N terminus.	('KIF3B', 'Gene', '9371', (130, 135))	('tagging', 'Var', (118, 125))	('KIF3B', 'Gene', (130, 135))
886667	28039448	PD-L1 has a much broader tissue distribution than PD-L2.	('PD-L2', 'Gene', (50, 55))	('PD-L1', 'Var', (0, 5))	('PD-L2', 'Gene', '80380', (50, 55))
886671	28039448	With this expression pattern, PD-L1 is adaptively induced as a consequence of the presence of tumor antigen-specific T cells, and these cancer cells expressed PD-L1 and turned off the specific cytotoxic immune response, which contributes to immune evasion and facilitates tumor growth.	('facilitates', 'PosReg', (260, 271))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (272, 277))	('turned off', 'NegReg', (169, 179))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('PD-L1', 'Gene', (30, 35))	('tumor', 'Disease', (94, 99))	('immune evasion', 'MPA', (241, 255))	('cancer', 'Disease', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('PD-L1', 'Var', (159, 164))	('specific cytotoxic immune', 'MPA', (184, 209))
886673	28039448	Chen et al recently suggested PD-L1 expression is a favorable indicator for ESCC prognosis, while other researchers found that PD-L1-positive ESCC patients had significantly poorer prognosis than the negative patients.	('PD-L1 expression', 'Var', (30, 46))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (209, 217))	('ESCC', 'Disease', (142, 146))	('ESCC', 'Disease', (76, 80))
886701	28039448	We found in ESCC patients with earlier stage (stage I-II or lymph node-negative), PD-L1 expression was associated with a significant better prognosis, while a lack of association between PD-L1 expression and outcome in patients with later stage (stage III-IV or lymph node-positive).	('expression', 'Var', (88, 98))	('PD-L1', 'Gene', (82, 87))	('ESCC', 'Disease', (12, 16))	('better', 'PosReg', (133, 139))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (219, 227))
886703	28039448	For example, the prognostic impact of defective DNA mismatch repair (dMMR) appears to be stronger in earlier stage colorectal cancer (CRC) (stage II) than in later CRC (lymph node-positive or stage III).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('defective DNA', 'Var', (38, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('colorectal cancer', 'Disease', (115, 132))
886711	28039448	For example, in breast cancer, cytoplasmic expression of PD-L1 was associated with improved patient survival for breast cancer-specific death, however, stromal expression fell short of significance for breast cancer-specific death.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (16, 29))	('patient', 'Species', '9606', (92, 99))	('improved', 'PosReg', (83, 91))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('PD-L1', 'Gene', (57, 62))	('breast cancer', 'Disease', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cytoplasmic expression', 'Var', (31, 53))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
886716	28039448	PD-L1 expression was associated with a better outcome in earlier stage of ESCC, which has also been observed in NSCLC, pulmonary lymphoepithelioma-like carcinoma,colorectal cancer, breast cancer, and melanoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('ESCC', 'Disease', (74, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('breast cancer', 'Disease', (181, 194))	('melanoma', 'Disease', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('PD-L1', 'Gene', (0, 5))	('pulmonary lymphoepithelioma-like carcinoma,colorectal cancer', 'Disease', 'MESH:D015179', (119, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('NSCLC', 'Disease', (112, 117))	('expression', 'Var', (6, 16))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
886740	28133631	The pathogenesis of dysmotility is related to a progression of myopathy, neuropathy and fibrosis leading to abnormalities in compliance and contractility of the GI tract wall.	('fibrosis', 'Disease', (88, 96))	('dysmotility', 'Disease', (20, 31))	('neuropathy', 'Disease', (73, 83))	('contractility', 'CPA', (140, 153))	('compliance', 'MPA', (125, 135))	('myopathy', 'Phenotype', 'HP:0003198', (63, 71))	('abnormalities', 'Var', (108, 121))	('dysmotility', 'Disease', 'MESH:D015154', (20, 31))	('myopathy', 'Disease', (63, 71))	('neuropathy', 'Disease', 'MESH:D009422', (73, 83))	('neuropathy', 'Phenotype', 'HP:0009830', (73, 83))	('fibrosis', 'Disease', 'MESH:D005355', (88, 96))	('myopathy', 'Disease', 'MESH:D009135', (63, 71))
886757	28133631	Prospective studies have reported abnormalities on esophageal manometry in about 70-75% of SSc patients.	('SSc', 'Disease', (91, 94))	('patients', 'Species', '9606', (95, 103))	('abnormalities', 'Var', (34, 47))	('esophageal manometry', 'MPA', (51, 71))
886805	28133631	While most forms of GI involvement in SSc are evenly distributed between disease types, vascular mucosal lesions were significantly associated with lcSSc, digital ulcers, higher score of nailfold videocapillaroscopy, and anti-centromere antibody.	('higher score', 'PosReg', (171, 183))	('ulcers', 'Disease', (163, 169))	('digital ulcers', 'Phenotype', 'HP:0031917', (155, 169))	('ulcers', 'Disease', 'MESH:D014456', (163, 169))	('vascular mucosal lesions', 'Disease', 'MESH:D009059', (88, 112))	('anti-centromere antibody', 'Phenotype', 'HP:0030873', (221, 245))	('associated', 'Reg', (132, 142))	('lcSSc', 'Disease', (148, 153))	('vascular mucosal lesions', 'Disease', (88, 112))	('anti-centromere', 'Var', (221, 236))
886848	28133631	Also, PPI and antibiotics are frequently reported to cause diarrhea.	('cause', 'Reg', (53, 58))	('diarrhea', 'Phenotype', 'HP:0002014', (59, 67))	('diarrhea', 'Disease', 'MESH:D003967', (59, 67))	('diarrhea', 'Disease', (59, 67))	('PPI', 'Var', (6, 9))
886972	27471400	Shitara et al conducted a retrospective study in a Japanese population and found that smoking history strongly predicted poor prognosis in ESCC patients; 364 cases were included in this study and the results showed that heavy smoking increased the mortality risk to 1.73 (95% CI =1.12-2.68, P=0.013) compared with nonsmokers.	('patients', 'Species', '9606', (144, 152))	('heavy smoking', 'Var', (220, 233))	('ESCC', 'Disease', (139, 143))
886993	27471400	p53 mutation was reported to be more common in heavy smokers.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('common', 'Reg', (37, 43))	('mutation', 'Var', (4, 12))
886995	27471400	Coupled with genetic alterations in acetaldehyde elimination modulated by alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), tumors develop and spread aggressively, resulting in younger age at diagnosis of ESCC.	('acetaldehyde', 'Chemical', 'MESH:D000079', (36, 48))	('alcohol dehydrogenase 1B', 'Gene', (74, 98))	('aldehyde dehydrogenase 2', 'Gene', (111, 135))	('spread', 'CPA', (164, 170))	('ALDH2', 'Gene', '217', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ESCC', 'Disease', (226, 230))	('acetaldehyde', 'MPA', (36, 48))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('ADH1B', 'Gene', (100, 105))	('ALDH2', 'Gene', (137, 142))	('alcohol dehydrogenase 1B', 'Gene', '125', (74, 98))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('aldehyde dehydrogenase 2', 'Gene', '217', (111, 135))	('genetic alterations', 'Var', (13, 32))	('ADH1B', 'Gene', '125', (100, 105))
886997	27471400	Furthermore, alcohol drinking was found to be associated with larger tumor size (>3 cm) at baseline.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('alcohol', 'Chemical', 'MESH:D000438', (13, 20))	('alcohol drinking', 'Phenotype', 'HP:0030955', (13, 29))	('alcohol drinking', 'Var', (13, 29))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
887053	27066454	The deformable registration-based contour propagation has been shown to expedite the tumor contouring and texture quantification processes while not compromising the predictive ability of the textures.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('deformable', 'Var', (4, 14))	('expedite', 'PosReg', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('texture quantification', 'CPA', (106, 128))
887064	27066454	The MTV30%, MTV40%, MTV50%, and MTV60% on pretreatment PET images had median value of 28, 19, 12, and 7 cm3, respectively.	('MTV60%', 'Var', (32, 38))	('MTV30%', 'Var', (4, 10))	('MTV50', 'Chemical', '-', (20, 25))	('MTV50%', 'Var', (20, 26))	('MTV40', 'Chemical', '-', (12, 17))	('MTV60', 'Chemical', '-', (32, 37))	('MTV40%', 'Var', (12, 18))
887065	27066454	The median posttreatment MTV30%, MTV40%, MTV50%, and MTV60% was 26, 14, 8, and 4 cm3, respectively.	('MTV60%', 'Var', (53, 59))	('MTV30%', 'Var', (25, 31))	('MTV40', 'Chemical', '-', (33, 38))	('MTV50%', 'Var', (41, 47))	('MTV50', 'Chemical', '-', (41, 46))	('MTV60', 'Chemical', '-', (53, 58))	('MTV40%', 'Var', (33, 39))
887069	27066454	Figure 5 demonstrated that median DeltaEntropy, DeltaHigh-gray-run emphasis, DeltaShort-run high-gray-run emphasis, and DeltaHigh-gray-zone emphasis significantly discriminated patients with poor and good survival (log-rank test p < 0.02).	('patients', 'Species', '9606', (177, 185))	('discriminated', 'Reg', (163, 176))	('DeltaHigh-gray-run', 'Var', (48, 66))	('DeltaHigh-gray-zone', 'Var', (120, 139))
887071	27066454	However, c-index indicated that the performance of DeltaHigh-gray-run emphasis, DeltaShort-run high-gray-run emphasis, and DeltaHigh-gray-zone emphasis were moderately related to the patients' overall survival (c-index = 0.61-0.62, p = 0.06-0.08).	('DeltaShort-run', 'Var', (80, 94))	('DeltaHigh-gray-zone', 'Var', (123, 142))	('DeltaHigh-gray-run emphasis', 'Var', (51, 78))	('related', 'Reg', (168, 175))	('patients', 'Species', '9606', (183, 191))
887181	26484300	Currently, [18F]FDGPET is widely used for cancer diagnosis and staging work-up, and its use for detecting double primary cancer may possibly have increased.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('[18F]FDGPET', 'Var', (11, 22))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
887249	22174720	Cancers arising in the context of S. japonicum infection tend to occur in young patients, with 57% of S. japonicum-associated cancers being found in the 21-40-year-old range, as compared to 39% of nonschistosomal-associated colon cancers.	('patients', 'Species', '9606', (80, 88))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('colon cancer', 'Phenotype', 'HP:0003003', (224, 236))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('S. japonicum-associated', 'Var', (102, 125))	('colon cancers', 'Disease', 'MESH:D015179', (224, 237))	('S. japonicum', 'Species', '6182', (102, 114))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancers', 'Disease', (230, 237))	('colon cancers', 'Disease', (224, 237))	('infection', 'Disease', (47, 56))	('infection', 'Disease', 'MESH:D007239', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('cancers', 'Disease', (126, 133))	('S. japonicum', 'Species', '6182', (34, 46))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('colon cancers', 'Phenotype', 'HP:0003003', (224, 237))
887251	22174720	Cancers associated with S. japonicum tended to be more often well differentiated than controls (91.6% of schistosomal-associated colorectal cancers were well differentiated, as compared to 69.1% of nonschistosomal-associated cancers), while control cases were more frequently associated with adenomatous polyps.	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('cancers', 'Disease', (225, 232))	('adenomatous polyps', 'Disease', (292, 310))	('S. japonicum', 'Species', '6182', (24, 36))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (292, 310))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('colorectal cancers', 'Disease', 'MESH:D015179', (129, 147))	('rectal cancer', 'Phenotype', 'HP:0100743', (133, 146))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('adenomatous polyps', 'Disease', 'MESH:D018256', (292, 310))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('S. japonicum', 'Var', (24, 36))	('colorectal cancers', 'Disease', (129, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
887252	22174720	It was also noted in this study that cancers associated with S. japonicum tended to occur in younger patients (mean 40.3 years) than in nonschistosomal-associated cancers (mean 46.3), although no statistical significance was given.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('patients', 'Species', '9606', (101, 109))	('cancers', 'Disease', (163, 170))	('S. japonicum', 'Species', '6182', (61, 73))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('S. japonicum', 'Var', (61, 73))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancers', 'Disease', 'MESH:D009369', (163, 170))
887259	22174720	Two studies have reported an increased risk of hepatocellular carcinoma in mice infected with S. japonicum (reviewed in), but no similar animal model of S. japonicum driven colorectal carcinoma has been reported.	('S. japonicum', 'Species', '6182', (94, 106))	('S. japonicum', 'Var', (94, 106))	('S. japonicum', 'Species', '6182', (153, 165))	('colorectal carcinoma', 'Disease', (173, 193))	('mice', 'Species', '10090', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (173, 193))	('increased risk of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (29, 71))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (47, 71))	('hepatocellular carcinoma', 'Disease', (47, 71))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (47, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
887265	22174720	Another study attempted to identify characteristic mutations in p53 in schistosomal and nonschistosomal-associated rectal cancers.	('schistosomal', 'Disease', (71, 83))	('rectal cancer', 'Phenotype', 'HP:0100743', (115, 128))	('mutations', 'Var', (51, 60))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('rectal cancers', 'Disease', 'MESH:D012004', (115, 129))	('p53', 'Gene', (64, 67))	('rectal cancers', 'Disease', (115, 129))	('p53', 'Gene', '7157', (64, 67))
887266	22174720	In this study, twenty-two cases of rectal cancer with evidence of S. japonicum and twenty-two nonschistosomal rectal cancers were subjected to single strand conformational polymorphism testing for p53 mutations and subsequent sequencing.	('rectal cancer', 'Phenotype', 'HP:0100743', (110, 123))	('mutations', 'Var', (201, 210))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('p53', 'Gene', (197, 200))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('p53', 'Gene', '7157', (197, 200))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Disease', (117, 123))	('S. japonicum', 'Species', '6182', (66, 78))	('rectal cancer', 'Phenotype', 'HP:0100743', (35, 48))	('rectal cancers', 'Disease', 'MESH:D012004', (110, 124))	('rectal cancers', 'Disease', (110, 124))
887267	22174720	In schistosomal rectal cancers, thirteen p53 mutations were identified in ten cases, most of which were found to be base-pair substitutions, while thirteen mutations were found in nine nonschistosomal rectal cancers.	('rectal cancers', 'Disease', 'MESH:D012004', (16, 30))	('mutations', 'Var', (45, 54))	('p53', 'Gene', '7157', (41, 44))	('rectal cancers', 'Disease', (16, 30))	('rectal cancers', 'Disease', 'MESH:D012004', (201, 215))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('rectal cancers', 'Disease', (201, 215))	('rectal cancer', 'Phenotype', 'HP:0100743', (16, 29))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('rectal cancer', 'Phenotype', 'HP:0100743', (201, 214))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('base-pair substitutions', 'Var', (116, 139))	('p53', 'Gene', (41, 44))
887268	22174720	A higher proportion of base-pair substitutions were found at CpG dinucleotides in S. japonicum-associated rectal cancers as compared to nonschistosomal rectal cancers, although this difference did not reach statistical significance.	('rectal cancers', 'Disease', 'MESH:D012004', (152, 166))	('rectal cancers', 'Disease', (152, 166))	('S. japonicum', 'Species', '6182', (82, 94))	('dinucleotides', 'Chemical', 'MESH:D015226', (65, 78))	('rectal cancers', 'Disease', 'MESH:D012004', (106, 120))	('rectal cancer', 'Phenotype', 'HP:0100743', (106, 119))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('rectal cancers', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('rectal cancer', 'Phenotype', 'HP:0100743', (152, 165))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('base-pair substitutions', 'Var', (23, 46))
887270	22174720	In summary, the pathogenesis of S. japonicum-associated colorectal cancers may have some similarities to those seen arising in the setting of inflammatory bowel disease, but much remains unknown.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('rectal cancer', 'Phenotype', 'HP:0100743', (60, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (142, 168))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (142, 168))	('S. japonicum-associated', 'Var', (32, 55))	('colorectal cancers', 'Disease', 'MESH:D015179', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('inflammatory bowel disease', 'Disease', (142, 168))	('colorectal cancers', 'Disease', (56, 74))	('S. japonicum', 'Species', '6182', (32, 44))
887279	22174720	Since this monograph was published, only a handful of additional studies have been published on this topic, although at least one additional case control study published in 2005 did find epidemiological evidence again implicating S. japonicum as a causative agent in colorectal carcinoma.	('S. japonicum', 'Species', '6182', (230, 242))	('colorectal carcinoma', 'Disease', (267, 287))	('S. japonicum', 'Var', (230, 242))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (267, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))
887306	22174720	The authors speculated that p53 alterations may act as an inciting event in schistosomal-associated neoplasia.	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (28, 31))	('neoplasia', 'Disease', 'MESH:D009369', (100, 109))	('neoplasia', 'Phenotype', 'HP:0002664', (100, 109))	('alterations', 'Var', (32, 43))	('neoplasia', 'Disease', (100, 109))
887310	22174720	S. mansoni ova were also more frequent among patients whose tumors showed KRAS mutations, although this was seen only in a small number of patients (80% [4 of 5] of patients with KRAS mutations had S. mansoni ova versus 31% of the 42 patients with no evidence of KRAS mutations, P = 0.05).	('KRAS', 'Gene', '3845', (179, 183))	('S. mansoni ova', 'CPA', (198, 212))	('mutations', 'Var', (184, 193))	('S. mansoni', 'Species', '6183', (0, 10))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (165, 173))	('KRAS', 'Gene', (179, 183))	('KRAS', 'Gene', '3845', (74, 78))	('S. mansoni ova', 'Disease', (0, 14))	('mutations', 'Var', (79, 88))	('KRAS', 'Gene', (74, 78))	('patients', 'Species', '9606', (234, 242))	('KRAS', 'Gene', '3845', (263, 267))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('patients', 'Species', '9606', (139, 147))	('KRAS', 'Gene', (263, 267))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (60, 66))	('S. mansoni', 'Species', '6183', (198, 208))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
887353	34032716	High GNL3L expression was associated with pathologic type and poor differentiation.	('poor differentiation', 'CPA', (62, 82))	('High', 'Var', (0, 4))	('GNL3L', 'Gene', '54552', (5, 10))	('expression', 'MPA', (11, 21))	('GNL3L', 'Gene', (5, 10))	('associated', 'Reg', (26, 36))
887354	34032716	Patients with high GNL3L expression had shorter overall survival (OS) than those with low GNL3L expression.	('GNL3L', 'Gene', '54552', (19, 24))	('overall survival', 'MPA', (48, 64))	('GNL3L', 'Gene', (90, 95))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (40, 47))	('GNL3L', 'Gene', (19, 24))	('GNL3L', 'Gene', '54552', (90, 95))
887377	34032716	High GNL3L expression was associated with ulcerative type, poor differentiation, and worse prognosis.	('High', 'Var', (0, 4))	('GNL3L', 'Gene', '54552', (5, 10))	('expression', 'MPA', (11, 21))	('ulcerative type', 'Disease', (42, 57))	('GNL3L', 'Gene', (5, 10))	('poor differentiation', 'CPA', (59, 79))	('associated', 'Reg', (26, 36))
887407	34032716	As shown in Table 1, high GNL3L expression was significantly associated with clinicopathological variables including pathologic type (P = .020) and poor differentiation (P = .007).	('poor differentiation', 'CPA', (148, 168))	('GNL3L', 'Gene', '54552', (26, 31))	('high', 'Var', (21, 25))	('associated', 'Reg', (61, 71))	('expression', 'MPA', (32, 42))	('GNL3L', 'Gene', (26, 31))
887412	34032716	As shown in Figure 3, high GNL3L expression demonstrated significant correlation with poor OS in patients with esophageal cancer (P = .008).	('age', 'Gene', (116, 119))	('high', 'Var', (22, 26))	('cancer', 'Disease', (122, 128))	('GNL3L', 'Gene', (27, 32))	('poor OS', 'Disease', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('age', 'Gene', '5973', (116, 119))	('expression', 'MPA', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('GNL3L', 'Gene', '54552', (27, 32))	('patients', 'Species', '9606', (97, 105))
887416	34032716	The results demonstrated that patients with high GNL3L expression had shorter progression-free survival (PFS) and OS than those with low GNL3L expression (P < .05).	('high', 'Var', (44, 48))	('GNL3L', 'Gene', (137, 142))	('shorter', 'NegReg', (70, 77))	('GNL3L', 'Gene', '54552', (137, 142))	('GNL3L', 'Gene', (49, 54))	('patients', 'Species', '9606', (30, 38))	('progression-free survival', 'CPA', (78, 103))	('GNL3L', 'Gene', '54552', (49, 54))
887425	34032716	High GNL3L expression was an independent risk factor for an unfavorable OS in patients with esophageal cancer.	('age', 'Gene', '5973', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('High', 'Var', (0, 4))	('GNL3L', 'Gene', '54552', (5, 10))	('patients', 'Species', '9606', (78, 86))	('age', 'Gene', (97, 100))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('GNL3L', 'Gene', (5, 10))
887432	34032716	A recent study by Kannathasan et al revealed that high GNL3L expression was associated with chemoresistance.	('high', 'Var', (50, 54))	('chemoresistance', 'CPA', (92, 107))	('associated', 'Reg', (76, 86))	('GNL3L', 'Gene', (55, 60))	('GNL3L', 'Gene', '54552', (55, 60))	('expression', 'MPA', (61, 71))
887436	34032716	Therefore, high GNL3L expression may not influence the chemoresistance of esophageal cancer, but confer a more aggressive phenotype to esophageal cancer than low GNL3L expression.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('GNL3L', 'Gene', '54552', (16, 21))	('age', 'Gene', (140, 143))	('age', 'Gene', '5973', (140, 143))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('GNL3L', 'Gene', (162, 167))	('cancer', 'Disease', (85, 91))	('age', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('high', 'Var', (11, 15))	('GNL3L', 'Gene', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('GNL3L', 'Gene', '54552', (162, 167))	('age', 'Gene', '5973', (79, 82))
887437	34032716	These may explain at least partly why patients with high GNL3L expression had poor prognosis.	('high', 'Var', (52, 56))	('GNL3L', 'Gene', '54552', (57, 62))	('GNL3L', 'Gene', (57, 62))	('patients', 'Species', '9606', (38, 46))
887443	34032716	Therefore, cancer cells with high GNL3L expression might be more likely to have a stem cell phenotype.	('high', 'Var', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('GNL3L', 'Gene', (34, 39))	('stem cell phenotype', 'CPA', (82, 101))	('GNL3L', 'Gene', '54552', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
887444	34032716	High GNL3L expression could confer higher proliferation capacity, chemoresistance, invasiveness, and metastasis to cancer cells.	('invasiveness', 'CPA', (83, 95))	('cancer', 'Disease', (115, 121))	('High', 'Var', (0, 4))	('GNL3L', 'Gene', '54552', (5, 10))	('expression', 'MPA', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('GNL3L', 'Gene', (5, 10))	('chemoresistance', 'CPA', (66, 81))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('higher', 'PosReg', (35, 41))
887445	34032716	Although we did not observe an association between GNL3L expression and drug response, there was a significant difference in OS between patients with low and high GNL3L expression.	('low', 'NegReg', (150, 153))	('high', 'Var', (158, 162))	('GNL3L', 'Gene', (51, 56))	('patients', 'Species', '9606', (136, 144))	('GNL3L', 'Gene', (163, 168))	('GNL3L', 'Gene', '54552', (51, 56))	('GNL3L', 'Gene', '54552', (163, 168))
887448	34032716	Our findings provide the first evidence that high GNL3L expression is closely related to an unfavorable prognosis.	('GNL3L', 'Gene', (50, 55))	('GNL3L', 'Gene', '54552', (50, 55))	('related', 'Reg', (78, 85))	('expression', 'MPA', (56, 66))	('high', 'Var', (45, 49))
887456	32985648	MiR-25-3p was proved to be a biomarker for the diagnosis and treatment of many cancers.	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('MiR-25-3p', 'Var', (0, 9))	('MiR-25-3p', 'Chemical', '-', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
887464	32985648	MiR-25-3p targeted PTEN and inhibited the expression of PTEN.	('targeted', 'Reg', (10, 18))	('PTEN', 'Gene', (56, 60))	('expression', 'MPA', (42, 52))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (56, 60))	('PTEN', 'Gene', '5728', (19, 23))	('MiR-25-3p', 'Var', (0, 9))	('inhibited', 'NegReg', (28, 37))	('MiR-25-3p', 'Chemical', '-', (0, 9))
887465	32985648	MiR-25-3p mimic increased the viability, migration, invasion and the expressions of Bcl-2, and inhibited the apoptosis and the expression of Bax and cleaved caspase-3 in EC cells.	('viability', 'CPA', (30, 39))	('migration', 'CPA', (41, 50))	('MiR-25-3p mimic', 'Var', (0, 15))	('caspase-3', 'Gene', '836', (157, 166))	('expression', 'MPA', (127, 137))	('Bax', 'Gene', '581', (141, 144))	('apoptosis', 'CPA', (109, 118))	('inhibited', 'NegReg', (95, 104))	('Bcl-2', 'Gene', (84, 89))	('expressions', 'MPA', (69, 80))	('Bcl-2', 'Gene', '596', (84, 89))	('increased', 'PosReg', (16, 25))	('MiR-25-3p', 'Chemical', '-', (0, 9))	('caspase-3', 'Gene', (157, 166))	('invasion', 'CPA', (52, 60))	('Bax', 'Gene', (141, 144))
887466	32985648	MiR-25-3p mimic also enhanced the expressions of p-PI3K and p-AKT and the ratios of p-PI3K/PI3K and p-AKT/AKT in EC cells.	('AKT', 'Gene', (106, 109))	('AKT', 'Gene', (62, 65))	('expressions', 'MPA', (34, 45))	('enhanced', 'PosReg', (21, 29))	('PI3', 'Gene', (91, 94))	('PI3', 'Gene', '5266', (51, 54))	('MiR-25-3p', 'Var', (0, 9))	('PI3', 'Gene', '5266', (86, 89))	('AKT', 'Gene', '207', (102, 105))	('MiR-25-3p', 'Chemical', '-', (0, 9))	('AKT', 'Gene', '207', (106, 109))	('AKT', 'Gene', '207', (62, 65))	('PI3', 'Gene', (86, 89))	('PI3', 'Gene', '5266', (91, 94))	('PI3', 'Gene', (51, 54))	('AKT', 'Gene', (102, 105))
887467	32985648	PTEN overexpression not only had an opposite effect of miR-25-3p mimic, but also reversed the effect of miR-25-3p mimic on EC cells.	('miR-25-3p', 'Chemical', '-', (104, 113))	('miR-25-3p', 'Chemical', '-', (55, 64))	('miR-25-3p', 'Var', (55, 64))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
887468	32985648	Conclusion: MiR-25-3p targeted PTEN to promote the migration and invasion, and inhibit apoptosis of EC cells via the PI3K/AKT pathway, which might provide a new therapeutic target for EC treatment.	('inhibit', 'NegReg', (79, 86))	('PTEN', 'Gene', (31, 35))	('PI3', 'Gene', (117, 120))	('PTEN', 'Gene', '5728', (31, 35))	('promote', 'PosReg', (39, 46))	('MiR-25-3p', 'Var', (12, 21))	('MiR-25-3p', 'Chemical', '-', (12, 21))	('migration', 'CPA', (51, 60))	('apoptosis', 'CPA', (87, 96))	('PI3', 'Gene', '5266', (117, 120))	('AKT', 'Gene', '207', (122, 125))	('invasion', 'CPA', (65, 73))	('AKT', 'Gene', (122, 125))
887473	32985648	Like other cancers, the occurrence and progression of EC are closely related to the abnormal expressions of multiple genes, such as oncogenes, tumor-suppressor, and growth-related genes.	('abnormal expressions', 'Phenotype', 'HP:0100022', (84, 104))	('tumor', 'Disease', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('expressions', 'MPA', (93, 104))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('abnormal', 'Var', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('related', 'Reg', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
887475	32985648	More and more evidence has shown that abnormal expressions of miRNAs are highly related to the occurrence and progression of various diseases and cancers, including EC.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('abnormal', 'Var', (38, 46))	('related to', 'Reg', (80, 90))	('miRNAs', 'Protein', (62, 68))	('abnormal expressions', 'Phenotype', 'HP:0100022', (38, 58))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
887478	32985648	In addition, miR-25-3p was proved to be a biomarker for the diagnosis and treatment of many cancers and able to regulate the biological functions of various cells.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('miR-25-3p', 'Var', (13, 22))	('regulate', 'Reg', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('biological functions', 'CPA', (125, 145))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('miR-25-3p', 'Chemical', '-', (13, 22))
887479	32985648	Besides, miR-25-3p could enhance the proliferation and migration of glioma cells, impair tumorigenesis of gastric cancer and regulate the migration of gastric cancer cells, and promote the pre-metastatic niche formation of colorectal cancer.	('promote', 'PosReg', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('miR-25-3p', 'Chemical', '-', (9, 18))	('pre-metastatic niche formation', 'CPA', (189, 219))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('gastric cancer', 'Disease', (151, 165))	('glioma', 'Disease', (68, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('colorectal cancer', 'Disease', 'MESH:D015179', (223, 240))	('regulate', 'Reg', (125, 133))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('migration', 'CPA', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('colorectal cancer', 'Disease', (223, 240))	('proliferation', 'CPA', (37, 50))	('miR-25-3p', 'Var', (9, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('tumor', 'Disease', (89, 94))	('migration', 'CPA', (138, 147))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('gastric cancer', 'Disease', (106, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('enhance', 'PosReg', (25, 32))	('impair', 'NegReg', (82, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (223, 240))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
887480	32985648	miR-25-3p regulates cancer cell processes by targeting genes or regulatory signaling pathways.	('regulatory signaling pathways', 'Pathway', (64, 93))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('miR-25-3p', 'Var', (0, 9))	('genes', 'Pathway', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('regulates', 'Reg', (10, 19))	('cancer', 'Disease', (20, 26))	('targeting', 'Reg', (45, 54))	('miR-25-3p', 'Chemical', '-', (0, 9))
887486	32985648	Moreover, miR-25-3p promoted the viability, migration and invasion, and inhibited the apoptosis via targeting PTEN by regulating PI3K/AKT signaling pathway in EC cells.	('PTEN', 'Gene', '5728', (110, 114))	('AKT', 'Gene', (134, 137))	('PI3', 'Gene', '5266', (129, 132))	('miR-25-3p', 'Chemical', '-', (10, 19))	('miR-25-3p', 'Var', (10, 19))	('PI3', 'Gene', (129, 132))	('promoted', 'PosReg', (20, 28))	('invasion', 'CPA', (58, 66))	('AKT', 'Gene', '207', (134, 137))	('viability', 'CPA', (33, 42))	('inhibited', 'NegReg', (72, 81))	('migration', 'CPA', (44, 53))	('regulating', 'Reg', (118, 128))	('apoptosis', 'CPA', (86, 95))	('PTEN', 'Gene', (110, 114))
887497	32985648	Finally, the mixed liquid was added into the cells of each well, and 1.8 ml of medium was then added into the cells and cultured for an additional 48 h. The fragments of PTEN wild-type (PTEN-WT) (5'-AGTTCTAGAAATTTTGTGCAATA-3') and PTEN mutant (PTEN-MUT) (5'-AGTTCTAGAAATTTTTACACGCA-3') binding sites for miR-25-3p were inserted into pmirGLO luciferase Vectors (E1330, Promega, CA, U.S.A.).	('PTEN', 'Gene', '5728', (244, 248))	('PTEN', 'Gene', (170, 174))	('PTEN', 'Gene', '5728', (170, 174))	('PTEN', 'Gene', (186, 190))	('PTEN', 'Gene', (231, 235))	('PTEN', 'Gene', '5728', (186, 190))	('PTEN', 'Gene', '5728', (231, 235))	('mutant', 'Var', (236, 242))	('miR-25-3p', 'Chemical', '-', (304, 313))	('PTEN', 'Gene', (244, 248))
887522	32985648	Next, the membranes were incubated with 5% skimmed milk for 2 h at normal atmospheric temperature, and then incubated with the following primary antibodies: Bax (1:1000, 20kD, #5023, CST, CA, U.S.A.), Bcl-2 (1:1000, 26kD, #4223, CST), cleaved Caspase-3 (1:1000, 17kD, #9661, CST), PTEN (1:1000, 54kD, #9188, CST), p-PI3K (1:1000, 85kD, #4228, CST), PI3K (1:1000, 85kD, #4292, CST), p-AKT (1:1000, 60kD, #9271, CST), AKT (1:1000, 60kD, #4691, CST), and GAPDH (1:1000, 37kD, #5174, CST).	('CST', 'Gene', (442, 445))	('CST', 'Gene', '106478911', (183, 186))	('CST', 'Gene', (376, 379))	('Caspase-3', 'Gene', '836', (243, 252))	('PI3', 'Gene', '5266', (349, 352))	('CST', 'Gene', (343, 346))	('CST', 'Gene', '106478911', (229, 232))	('PI3', 'Gene', '5266', (316, 319))	('CST', 'Gene', (183, 186))	('1:1000', 'Var', (421, 427))	('CST', 'Gene', '106478911', (308, 311))	('GAPDH', 'Gene', '2597', (452, 457))	('AKT', 'Gene', (384, 387))	('PTEN', 'Gene', (281, 285))	('CST', 'Gene', '106478911', (275, 278))	('AKT', 'Gene', (416, 419))	('1:1000', 'Var', (355, 361))	('Bcl-2', 'Gene', (201, 206))	('Bax', 'Gene', (157, 160))	('CST', 'Gene', '106478911', (410, 413))	('CST', 'Gene', '106478911', (480, 483))	('PI3', 'Gene', (349, 352))	('CST', 'Gene', '106478911', (442, 445))	('1:1000', 'Var', (322, 328))	('1:1000', 'Var', (459, 465))	('GAPDH', 'Gene', (452, 457))	('Caspase-3', 'Gene', (243, 252))	('CST', 'Gene', (229, 232))	('PI3', 'Gene', (316, 319))	('CST', 'Gene', (308, 311))	('PTEN', 'Gene', '5728', (281, 285))	('Bax', 'Gene', '581', (157, 160))	('CST', 'Gene', '106478911', (376, 379))	('CST', 'Gene', (275, 278))	('AKT', 'Gene', '207', (384, 387))	('Bcl-2', 'Gene', '596', (201, 206))	('CST', 'Gene', '106478911', (343, 346))	('AKT', 'Gene', '207', (416, 419))	('CST', 'Gene', (410, 413))	('CST', 'Gene', (480, 483))
887525	32985648	Considering that the expression of miR-25-3p in Eca-109 and OE19 cells was higher than in other cells, these two cell lines were chosen for later use.	('higher', 'PosReg', (75, 81))	('Eca', 'Chemical', '-', (48, 51))	('miR-25-3p', 'Chemical', '-', (35, 44))	('OE19', 'CellLine', 'CVCL:1622', (60, 64))	('expression', 'MPA', (21, 31))	('miR-25-3p', 'Var', (35, 44))
887526	32985648	After we transfected miR-25-3p mimic into Eca-109 and OE19 cells, the transcription level of miR-25-3p was obviously increased as compared with the MC groups (P<0.001; Figure 1C,D).	('miR-25-3p', 'Chemical', '-', (21, 30))	('increased', 'PosReg', (117, 126))	('Eca', 'Chemical', '-', (42, 45))	('miR-25-3p', 'Chemical', '-', (93, 102))	('OE19', 'CellLine', 'CVCL:1622', (54, 58))	('miR-25-3p', 'Var', (93, 102))	('transcription level', 'MPA', (70, 89))	('miR-25-3p mimic', 'Var', (21, 36))
887527	32985648	Then we detected the effects of miR-25-3p on the viability of these two cells (Figure 1E,F), and the results indicated that miR-25-3p mimic significantly increased the viability of Eca-109 and OE19 cells after culture for 48 and 72 h as compared with the MC group (P<0.05).	('miR-25-3p mimic', 'Var', (124, 139))	('Eca', 'Chemical', '-', (181, 184))	('OE19', 'CellLine', 'CVCL:1622', (193, 197))	('miR-25-3p', 'Chemical', '-', (124, 133))	('viability', 'CPA', (168, 177))	('Eca-109', 'CPA', (181, 188))	('increased', 'PosReg', (154, 163))	('miR-25-3p', 'Chemical', '-', (32, 41))
887528	32985648	Then we detected the effects of miR-25-3p on the apoptosis of Eca-109 and OE19 cells, and the results indicated that miR-25-3p mimic significantly decreased the relative apoptosis rates of Eca-109 and OE19 cells as compared with the MC group (P<0.001; Figure 2A-D).	('Eca', 'Chemical', '-', (62, 65))	('OE19', 'CellLine', 'CVCL:1622', (74, 78))	('miR-25-3p', 'Chemical', '-', (117, 126))	('Eca', 'Chemical', '-', (189, 192))	('decreased', 'NegReg', (147, 156))	('miR-25-3p', 'Var', (117, 126))	('apoptosis rates', 'CPA', (170, 185))	('miR-25-3p', 'Chemical', '-', (32, 41))	('OE19', 'CellLine', 'CVCL:1622', (201, 205))
887530	32985648	The results exhibited that miR-25-3p mimic inhibited the protein expressions of Bax and Cleaved caspase-3 and up-regulated the expression of Bcl-2 in Eca-109 and OE19 cells as compared with the MC group (P<0.001; Figure 2E,F,I,J).	('caspase-3', 'Gene', (96, 105))	('Cleaved', 'MPA', (88, 95))	('Bax', 'Gene', (80, 83))	('up-regulated', 'PosReg', (110, 122))	('Bcl-2', 'Gene', '596', (141, 146))	('miR-25-3p', 'Chemical', '-', (27, 36))	('expression', 'MPA', (127, 137))	('inhibited', 'NegReg', (43, 52))	('Bcl-2', 'Gene', (141, 146))	('caspase-3', 'Gene', '836', (96, 105))	('miR-25-3p', 'Var', (27, 36))	('Bax', 'Gene', '581', (80, 83))	('protein expressions', 'MPA', (57, 76))	('Eca', 'Chemical', '-', (150, 153))	('OE19', 'CellLine', 'CVCL:1622', (162, 166))
887531	32985648	The result also showed that miR-25-3p mimic promoted the mRNA expression of Bcl-2, but inhibited Bax mRNA expression (P<0.001; Figure 2G,H).	('mRNA expression', 'MPA', (57, 72))	('miR-25-3p', 'Chemical', '-', (28, 37))	('promoted', 'PosReg', (44, 52))	('Bcl-2', 'Gene', (76, 81))	('Bcl-2', 'Gene', '596', (76, 81))	('miR-25-3p', 'Var', (28, 37))	('Bax', 'Gene', '581', (97, 100))	('inhibited', 'NegReg', (87, 96))	('Bax', 'Gene', (97, 100))
887532	32985648	In addition, we detected the changes of migration and invasion of Eca-109 and OE19 cells after transfection of miR-25-3p mimic.	('invasion', 'CPA', (54, 62))	('Eca', 'Chemical', '-', (66, 69))	('OE19', 'CellLine', 'CVCL:1622', (78, 82))	('miR-25-3p mimic', 'Var', (111, 126))	('miR-25-3p', 'Chemical', '-', (111, 120))	('migration', 'CPA', (40, 49))
887533	32985648	As shown in Figure 3, the relative migration and invasion rates of Eca-109 and OE19 cells were both significantly increased by miR-25-3p mimic (P<0.001), which indicated that miR-25-3p could enhance the migration and invasion abilities of Eca-109 and OE19 cells.	('invasion abilities', 'CPA', (217, 235))	('miR-25-3p', 'Chemical', '-', (175, 184))	('miR-25-3p', 'Var', (175, 184))	('increased', 'PosReg', (114, 123))	('Eca', 'Chemical', '-', (67, 70))	('miR-25-3p mimic', 'Var', (127, 142))	('OE19', 'CellLine', 'CVCL:1622', (251, 255))	('invasion rates', 'CPA', (49, 63))	('OE19', 'CellLine', 'CVCL:1622', (79, 83))	('enhance', 'PosReg', (191, 198))	('Eca', 'Chemical', '-', (239, 242))	('miR-25-3p', 'Chemical', '-', (127, 136))
887534	32985648	The analysis results of Targetscan7.2 predicted that PTEN was a target of miR-25-3p owing that miR-25-3p contained sequences complementary to PTEN-WT (Figure 4A).	('PTEN', 'Gene', (142, 146))	('PTEN', 'Gene', '5728', (142, 146))	('miR-25-3p', 'Chemical', '-', (74, 83))	('PTEN', 'Gene', (53, 57))	('PTEN', 'Gene', '5728', (53, 57))	('miR-25-3p', 'Chemical', '-', (95, 104))	('miR-25-3p', 'Var', (95, 104))
887537	32985648	In addition, the mRNA expression of PTEN in these two cells was up-regulated by PTEN overexpression and down-regulated by miR-25-3p mimic as compared with the NC group, and the inhibitory effect of miR-25-3p on PTEN expression was reversed by PTEN overexpression (P<0.01; Figure 4H,I).	('PTEN', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (80, 84))	('PTEN', 'Gene', (211, 215))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', (243, 247))	('PTEN', 'Gene', '5728', (211, 215))	('mRNA expression', 'MPA', (17, 32))	('down-regulated', 'NegReg', (104, 118))	('PTEN', 'Gene', '5728', (36, 40))	('PTEN', 'Gene', '5728', (243, 247))	('up-regulated', 'PosReg', (64, 76))	('miR-25-3p', 'Chemical', '-', (198, 207))	('miR-25-3p', 'Chemical', '-', (122, 131))	('overexpression', 'Var', (85, 99))
887545	32985648	Then we revealed that miR-25-3p targeted PTEN and that miR-25-3p mimic increased the viability, migration and invasion and inhibited the apoptosis of EC cells while enhancing the activation of the PI3K/AKT pathway.	('viability', 'CPA', (85, 94))	('migration', 'CPA', (96, 105))	('AKT', 'Gene', (202, 205))	('apoptosis', 'CPA', (137, 146))	('enhancing', 'PosReg', (165, 174))	('miR-25-3p', 'Chemical', '-', (55, 64))	('PI3', 'Gene', (197, 200))	('miR-25-3p', 'Chemical', '-', (22, 31))	('inhibited', 'NegReg', (123, 132))	('AKT', 'Gene', '207', (202, 205))	('increased', 'PosReg', (71, 80))	('miR-25-3p', 'Var', (55, 64))	('PTEN', 'Gene', (41, 45))	('invasion', 'CPA', (110, 118))	('PTEN', 'Gene', '5728', (41, 45))	('miR-25-3p', 'Var', (22, 31))	('PI3', 'Gene', '5266', (197, 200))
887548	32985648	Recently, more and more evidence has confirmed that abnormal expressions of miRNAs are closely associated with the occurrence and progression of different kinds of cancers and most of these abnormally expressed miRNAs could be used as biomarkers for the diagnosis and therapy of many cancers.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (284, 291))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('cancers', 'Disease', (284, 291))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('abnormal', 'Var', (52, 60))	('cancers', 'Disease', (164, 171))	('miRNAs', 'Protein', (76, 82))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('abnormal expressions', 'Phenotype', 'HP:0100022', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('associated', 'Reg', (95, 105))
887553	32985648	In the present study, we not only found that miR-25-3p was up-regulated in the blood of EC patients and cells but also revealed that miR-25-3p had the ability to promote the migration and invasion and inhibited the apoptosis of EC cells, which indicated that miR-25-3p played a crucial role in the progression of EC, though the potential mechanism still needs further investigation.	('inhibited', 'NegReg', (201, 210))	('up-regulated', 'PosReg', (59, 71))	('patients', 'Species', '9606', (91, 99))	('apoptosis', 'CPA', (215, 224))	('miR-25-3p', 'Chemical', '-', (45, 54))	('invasion', 'CPA', (188, 196))	('miR-25-3p', 'Chemical', '-', (259, 268))	('migration', 'CPA', (174, 183))	('miR-25-3p', 'Gene', (45, 54))	('promote', 'PosReg', (162, 169))	('miR-25-3p', 'Chemical', '-', (133, 142))	('miR-25-3p', 'Var', (133, 142))
887555	32985648	For instance, BTG2 was targeted by miR-25-3p to promote the proliferation of breast cancer; FBXW7 and DKK3 could be targeted by miR-25-3p to enhance the proliferation and migration of glioma cancer cells.	('DKK3', 'Gene', (102, 106))	('enhance', 'PosReg', (141, 148))	('miR-25-3p', 'Chemical', '-', (35, 44))	('BTG2', 'Gene', '7832', (14, 18))	('DKK3', 'Gene', '27122', (102, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('glioma cancer', 'Disease', 'MESH:D009369', (184, 197))	('miR-25-3p', 'Chemical', '-', (128, 137))	('migration', 'CPA', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('proliferation', 'CPA', (60, 73))	('promote', 'PosReg', (48, 55))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('FBXW7', 'Gene', (92, 97))	('breast cancer', 'Disease', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('miR-25-3p', 'Var', (128, 137))	('glioma cancer', 'Disease', (184, 197))	('proliferation', 'CPA', (153, 166))	('BTG2', 'Gene', (14, 18))	('FBXW7', 'Gene', '55294', (92, 97))
887556	32985648	In the present study, we further found that PTEN was targeted by miR-25-3p in EC cells.	('miR-25-3p', 'Chemical', '-', (65, 74))	('miR-25-3p', 'Var', (65, 74))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('targeted', 'Reg', (53, 61))
887562	32985648	It's also well known that the activity of PTEN antagonizes the PI3K/AKT pathway to suppress cancer cell survival, which means that deficient PTEN expression leads to the PI3K/AKT pathway activation, thereby enhancing cell anti-apoptosis.	('PI3', 'Gene', '5266', (170, 173))	('PTEN', 'Gene', (141, 145))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('activation', 'PosReg', (187, 197))	('enhancing', 'PosReg', (207, 216))	('PTEN', 'Gene', '5728', (141, 145))	('PI3', 'Gene', (170, 173))	('PI3', 'Gene', '5266', (63, 66))	('cell anti-apoptosis', 'CPA', (217, 236))	('AKT', 'Gene', '207', (175, 178))	('deficient', 'Var', (131, 140))	('AKT', 'Gene', (68, 71))	('PTEN', 'Gene', (42, 46))	('cancer', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PI3', 'Gene', (63, 66))	('PTEN', 'Gene', '5728', (42, 46))	('AKT', 'Gene', '207', (68, 71))	('suppress', 'NegReg', (83, 91))	('AKT', 'Gene', (175, 178))
887564	32985648	In conclusion, this research revealed that miR-25-3p enhanced the migration, invasion and suppressed the apoptosis of EC cells through PTEN-mediated PI3K/AKT pathway, which indicated that miR-25-3p might be a target for EC treatment.	('enhanced', 'PosReg', (53, 61))	('migration', 'CPA', (66, 75))	('apoptosis', 'CPA', (105, 114))	('AKT', 'Gene', '207', (154, 157))	('PTEN', 'Gene', (135, 139))	('miR-25-3p', 'Chemical', '-', (43, 52))	('invasion', 'CPA', (77, 85))	('PTEN', 'Gene', '5728', (135, 139))	('AKT', 'Gene', (154, 157))	('PI3', 'Gene', '5266', (149, 152))	('suppressed', 'NegReg', (90, 100))	('miR-25-3p', 'Var', (43, 52))	('miR-25-3p', 'Chemical', '-', (188, 197))	('PI3', 'Gene', (149, 152))
887565	32985648	Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved: All authors The study had been reviewed and approved by the Ethics Committee of Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute (Z20180522S) and all patients had signed informed consent and agreed that their blood would be used for clinical research.	('Cancer', 'Disease', (311, 317))	('Cancer', 'Disease', 'MESH:D009369', (311, 317))	('Cancer', 'Phenotype', 'HP:0002664', (311, 317))	('Cancer', 'Phenotype', 'HP:0002664', (257, 263))	('Cancer', 'Disease', (257, 263))	('patients', 'Species', '9606', (360, 368))	('Z20180522S', 'Var', (340, 350))	('Cancer', 'Disease', 'MESH:D009369', (257, 263))	('Z20180522S', 'SUBSTITUTION', 'None', (340, 350))
887590	32231541	The patient is diagnosed with stage IIB, cT1bN1 esophageal adenocarcinoma and undergoes neoadjuvant chemoradiation with carboplatin/Taxol then surgical resection with the IVOR-Lewis approach.	('Taxol', 'Chemical', 'MESH:D017239', (132, 137))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (48, 73))	('carboplatin', 'Chemical', 'MESH:D016190', (120, 131))	('patient', 'Species', '9606', (4, 11))	('cT1bN1', 'Var', (41, 47))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (48, 73))	('esophageal adenocarcinoma', 'Disease', (48, 73))
887591	32231541	A potential molecular relationship may exist between a genetic variant underlying a specific subtype of HHT and esophageal cancer pathogenesis.	('variant', 'Var', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('HHT', 'Disease', (104, 107))	('esophageal cancer', 'Disease', (112, 129))	('HHT', 'Disease', 'MESH:D013683', (104, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
887592	32231541	Namely, HHT subtype 1 is associated with pathological variants of ENG which encodes a transformation growth factor beta (TGF-beta) superfamily auxiliary receptor.	('associated', 'Reg', (25, 35))	('ENG', 'Gene', (66, 69))	('HHT', 'Disease', (8, 11))	('variants', 'Var', (54, 62))	('HHT', 'Disease', 'MESH:D013683', (8, 11))	('ENG', 'Gene', '2022', (66, 69))
887596	32231541	Our patient, as part of his previous diagnostic evaluation of HHT, underwent genetic testing, which revealed a genetic variant in ENG.	('ENG', 'Gene', (130, 133))	('HHT', 'Disease', (62, 65))	('genetic variant', 'Var', (111, 126))	('patient', 'Species', '9606', (4, 11))	('revealed', 'Reg', (100, 108))	('HHT', 'Disease', 'MESH:D013683', (62, 65))	('ENG', 'Gene', '2022', (130, 133))
887597	32231541	It is difficult to ascertain if and whether the underlying genetic variant was associated with the onset of esophageal cancer in this relatively young patient, given that he did have risk factors including male sex, obesity, and cigarette smoking.	('obesity', 'Phenotype', 'HP:0001513', (216, 223))	('associated', 'Reg', (79, 89))	('variant', 'Var', (67, 74))	('esophageal cancer', 'Disease', (108, 125))	('patient', 'Species', '9606', (151, 158))	('obesity', 'Disease', 'MESH:D009765', (216, 223))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('obesity', 'Disease', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
887611	32231541	The lessons of this case are the following: (1) screening guidelines and indications for complications in HHT patients are established but many aspects are controversial; (2) certain genetic variants associated with HHT may also be involved in esophageal cancer pathogenesis; and (3) despite its reputation as an aggressive cancer with poor treatment response, locally advanced esophageal cancer can have pCR with surprising frequency.	('HHT', 'Disease', (106, 109))	('aggressive cancer', 'Disease', 'MESH:D009369', (313, 330))	('aggressive cancer', 'Disease', (313, 330))	('involved', 'Reg', (232, 240))	('HHT', 'Disease', (216, 219))	('esophageal cancer', 'Disease', (244, 261))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('esophageal cancer', 'Disease', 'MESH:D004938', (378, 395))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('HHT', 'Disease', 'MESH:D013683', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('HHT', 'Disease', 'MESH:D013683', (216, 219))	('variants', 'Var', (191, 199))	('patients', 'Species', '9606', (110, 118))	('esophageal cancer', 'Disease', (378, 395))
887612	32231541	This case describes the diagnosis of a locally advanced esophageal cancer in a relatively young patient with a variant gene suspected to be involved in esophageal cancer pathogenesis.	('esophageal cancer', 'Disease', (56, 73))	('esophageal cancer', 'Disease', (152, 169))	('patient', 'Species', '9606', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('variant gene', 'Var', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))
887616	31897226	Here, we found that miR-26b is upregulated in ESCC cell lines with cisplatin treatment, and it relies on the expression of E2F1 because E2F1 directly binds to the promoter of the miR-26b gene, thus activating the transcriptional activity of miR-26b.	('miR-26b', 'Gene', '407017', (241, 248))	('ESCC', 'Disease', (46, 50))	('transcriptional activity', 'MPA', (213, 237))	('E2F1', 'Var', (136, 140))	('ESCC', 'Disease', 'MESH:C562729', (46, 50))	('upregulated', 'PosReg', (31, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('activating', 'PosReg', (198, 208))	('miR-26b', 'Gene', (20, 27))	('miR-26b', 'Gene', (179, 186))	('binds', 'Interaction', (150, 155))	('miR-26b', 'Gene', (241, 248))	('miR-26b', 'Gene', '407017', (20, 27))	('miR-26b', 'Gene', '407017', (179, 186))
887620	31897226	A nude mouse xenograft model of cisplatin treatment showed that the tumor volume was increased in the Si-E2F1 group compared with that in the group with cisplatin treatment alone.	('tumor', 'Disease', (68, 73))	('mouse', 'Species', '10090', (7, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('increased', 'PosReg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Si-E2F1', 'Var', (102, 109))	('Si', 'Chemical', 'MESH:D012825', (102, 104))
887622	31897226	In conclusion, our results indicate that E2F1 promotes the chemosensitization to cisplatin in ESCC.	('E2F1', 'Var', (41, 45))	('ESCC', 'Disease', 'MESH:C562729', (94, 98))	('promotes', 'PosReg', (46, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('chemosensitization to cisplatin', 'MPA', (59, 90))	('ESCC', 'Disease', (94, 98))
887640	31897226	We found that E2F1 enhances the sensitivity of ESCC cells to cisplatin by regulating miR-26b and the cellular DNA damage response.	('regulating', 'Reg', (74, 84))	('enhances', 'PosReg', (19, 27))	('ESCC', 'Disease', (47, 51))	('cellular DNA damage response', 'MPA', (101, 129))	('miR-26b', 'Gene', (85, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('E2F1', 'Var', (14, 18))	('miR-26b', 'Gene', '407017', (85, 92))	('sensitivity', 'MPA', (32, 43))	('ESCC', 'Disease', 'MESH:C562729', (47, 51))
887650	31897226	The pMIR-RB-3UTR-WT and pMIR-ATM-3UTR-WT plasmids contained the 3`UTR segment of the RB gene (NM_000321.2) and ATM gene (NM_000051), respectively, as well as the putative miR-26b binding site.	('NM_000051', 'Var', (121, 130))	('ATM', 'Gene', (111, 114))	('ATM', 'Gene', (29, 32))	('ATM', 'Gene', '472', (111, 114))	('miR-26b', 'Gene', (171, 178))	('ATM', 'Gene', '472', (29, 32))	('miR-26b', 'Gene', '407017', (171, 178))	('NM_000321.2', 'Var', (94, 105))
887659	31897226	For the reporter assay to detect the binding site of miR-26b in the 3`UTR region of RB and ATM, the pMIR vector (pMIR-RB-3UTR-WT/MUT, pMIR-ATM-3UTR-WT/MUT) was mixed with mimics (miR-26b or negative control) and pRL-Tk, followed by co-transfection using Lipofectamine 2000 according to the manufacturer's instructions.	('ATM', 'Gene', (139, 142))	('ATM', 'Gene', (91, 94))	('miR-26b', 'Gene', '407017', (53, 60))	('miR-26b', 'Gene', (53, 60))	('ATM', 'Gene', '472', (91, 94))	('ATM', 'Gene', '472', (139, 142))	('pMIR-RB-3UTR-WT/MUT', 'Var', (113, 132))	('miR-26b', 'Gene', (179, 186))	('miR-26b', 'Gene', '407017', (179, 186))
887667	31897226	The collected 2 x 106 cells (EC109-NC, EC109-siE2F1) were mixed in 50% Matrigel (BD Biosciences) and were injected subcutaneously into approximately 4-week-old nude BALB/c mice.	('EC109-siE2F1', 'Var', (39, 51))	('BD Biosciences', 'Disease', 'MESH:D001528', (81, 95))	('EC109', 'CellLine', 'CVCL:6898', (29, 34))	('mice', 'Species', '10090', (172, 176))	('EC109', 'CellLine', 'CVCL:6898', (39, 44))	('BD Biosciences', 'Disease', (81, 95))
887671	31897226	The membranes were then incubated with the following primary antibodies at 4 C overnight: anti-ATM (Epitomics; 1549-1), anti-RB (CST; 9309), anti-E2F1 (Upstate; 05-379), anti-GAPDH (KC5G5; Kangchen Bio-Tech).	('ATM', 'Gene', (95, 98))	('GAPDH', 'Gene', (175, 180))	('anti-E2F1', 'Var', (141, 150))	('ATM', 'Gene', '472', (95, 98))	('GAPDH', 'Gene', '2597', (175, 180))
887690	31897226	Thus, E2F1 may promote the transcriptional activity of miR-26b by binding to the site 3.	('promote', 'PosReg', (15, 22))	('miR-26b', 'Gene', '407017', (55, 62))	('transcriptional activity', 'MPA', (27, 51))	('binding', 'Interaction', (66, 73))	('E2F1', 'Var', (6, 10))	('miR-26b', 'Gene', (55, 62))
887696	31897226	By contrast, miR-26b background expression of EC9706 was highest in our collected ESCC cell lines, so loss-of-function assays were performed.	('ESCC', 'Disease', (82, 86))	('EC9706', 'Var', (46, 52))	('miR-26b', 'Gene', (13, 20))	('expression', 'MPA', (32, 42))	('miR-26b', 'Gene', '407017', (13, 20))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))	('EC9706', 'CellLine', 'CVCL:E307', (46, 52))
887712	31897226	To further investigate whether E2F1 could affect the chemosensitization of cisplatin in vivo, the cell model of Si-E2F1 EC109 and normal controls were constructed using lentiviruses.	('affect', 'Reg', (42, 48))	('chemosensitization of cisplatin', 'MPA', (53, 84))	('Si-E2F1 EC109', 'CellLine', 'CVCL:3166', (112, 125))	('Si-E2F1', 'Var', (112, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('E2F1', 'Var', (31, 35))
887714	31897226	However, the tumor volumes of the cisplatin with Si-E2F1 group were higher than those of the cisplatin group.	('tumor', 'Disease', (13, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('Si-E2F1', 'Var', (49, 56))	('Si', 'Chemical', 'MESH:D012825', (49, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('higher', 'PosReg', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
887715	31897226	Thus, our study suggested that E2F1 may promote the chemosensitization of cisplatin in EC109 cells.	('chemosensitization of cisplatin', 'MPA', (52, 83))	('promote', 'PosReg', (40, 47))	('EC109', 'CellLine', 'CVCL:6898', (87, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('E2F1', 'Var', (31, 35))
887730	31897226	We found that E2F1 increased the chemosensitization of cisplatin in EC109 cells in our present study.	('chemosensitization of cisplatin', 'MPA', (33, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('increased', 'PosReg', (19, 28))	('E2F1', 'Var', (14, 18))	('EC109', 'CellLine', 'CVCL:6898', (68, 73))
887731	31897226	In addition, the cell viability of the cisplatin with siE2F1 group was significantly higher than that of the cisplatin group, indicating that the chemosensitization of cisplatin relies on the expression of E2F1.	('siE2F1', 'Var', (54, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (168, 177))	('cell viability', 'CPA', (17, 31))	('higher', 'PosReg', (85, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))
887738	31897226	So, E2F1 increased the chemosensitization of cisplatin likely through the G1/S arrest effect of miR-26b.	('miR-26b', 'Gene', '407017', (96, 103))	('S arrest', 'Disease', (77, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('increased', 'PosReg', (9, 18))	('E2F1', 'Var', (4, 8))	('chemosensitization of cisplatin', 'MPA', (23, 54))	('miR-26b', 'Gene', (96, 103))	('S arrest', 'Disease', 'MESH:D018455', (77, 85))
887741	31897226	It has been reported that ATM participates in the cisplatin-induced DNA damage response, and activation of ATM induces activation of cell cycle checkpoints and DNA repair responses.	('DNA repair', 'MPA', (160, 170))	('ATM', 'Gene', (26, 29))	('ATM', 'Gene', '472', (107, 110))	('cisplatin-induced DNA damage response', 'MPA', (50, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('activation', 'Var', (93, 103))	('cell cycle checkpoints', 'CPA', (133, 155))	('activation', 'PosReg', (119, 129))	('ATM', 'Gene', '472', (26, 29))	('ATM', 'Gene', (107, 110))
887742	31897226	Moreover, previous studies also found that E2F1 can enhances the ATM expression level through enhancing ATM promoter activity.	('ATM', 'Gene', '472', (65, 68))	('ATM', 'Gene', '472', (104, 107))	('E2F1', 'Var', (43, 47))	('ATM', 'Gene', (104, 107))	('enhancing', 'PosReg', (94, 103))	('ATM', 'Gene', (65, 68))	('enhances', 'PosReg', (52, 60))
887746	31897226	ATM deficiency sensitizes the cells to cisplatin-induced apoptosis.	('sensitizes', 'Reg', (15, 25))	('deficiency', 'Var', (4, 14))	('ATM', 'Gene', (0, 3))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('ATM', 'Gene', '472', (0, 3))
887749	31897226	Deregulation of the Rb-E2F1 pathway often occurs in most cancers involving mutations or epigenetic events, cell cycle progression and apoptosis induction in response to DNA damage through its capacity to activate p53/p73 death pathways.	('apoptosis', 'CPA', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('p53', 'Gene', '7157', (213, 216))	('activate', 'PosReg', (204, 212))	('death', 'Disease', (221, 226))	('cell cycle progression', 'CPA', (107, 129))	('epigenetic events', 'Var', (88, 105))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('Rb', 'Chemical', 'MESH:D012413', (20, 22))	('cancers', 'Disease', (57, 64))	('p53', 'Gene', (213, 216))	('p73', 'Gene', '7161', (217, 220))	('p73', 'Gene', (217, 220))	('Deregulation', 'MPA', (0, 12))	('death', 'Disease', 'MESH:D003643', (221, 226))	('Rb-E2F1 pathway', 'Pathway', (20, 35))	('occurs', 'Reg', (42, 48))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('mutations', 'Var', (75, 84))
887750	31897226	E2F1 activates ATM using a mechanism initiated by DNA damage, and E2F1 also directly enhances ATM through enhancing its promoter activity.	('ATM', 'Gene', (15, 18))	('enhancing', 'PosReg', (106, 115))	('ATM', 'Gene', '472', (94, 97))	('activates', 'PosReg', (5, 14))	('ATM', 'Gene', '472', (15, 18))	('promoter activity', 'MPA', (120, 137))	('E2F1', 'Var', (0, 4))	('enhances', 'PosReg', (85, 93))	('E2F1', 'Var', (66, 70))	('ATM', 'Gene', (94, 97))
887751	31897226	E2F1 affects the ATM signaling pathway, which induces Chk2 and p53 phosphorylation and is involved in cell apoptosis.	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('Chk2', 'Gene', '11200', (54, 58))	('affects', 'Reg', (5, 12))	('Chk2', 'Gene', (54, 58))	('induces', 'PosReg', (46, 53))	('ATM', 'Gene', (17, 20))	('E2F1', 'Var', (0, 4))	('involved', 'Reg', (90, 98))	('phosphorylation', 'MPA', (67, 82))	('ATM', 'Gene', '472', (17, 20))
887755	31897226	Notably, the effect of E2F1 increased chemosensitization of cisplatin may be cell specific.	('increased', 'PosReg', (28, 37))	('chemosensitization of cisplatin', 'MPA', (38, 69))	('E2F1', 'Var', (23, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
887756	31897226	Some studies suggested that E2F1 is associated with malignant phenotypes in some cancers.	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('E2F1', 'Var', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('associated', 'Reg', (36, 46))
887757	31897226	In human tumor cells, overexpressed E2F1 is involved in multidrug resistance; E2F1 increases the activity of the MDR1 promoter, resulted in higher P-gp levels.	('increases', 'PosReg', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('E2F1', 'Var', (78, 82))	('P-gp', 'Gene', '283871', (147, 151))	('human', 'Species', '9606', (3, 8))	('MDR1', 'Gene', '5243', (113, 117))	('activity', 'MPA', (97, 105))	('higher', 'PosReg', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('P-gp', 'Gene', (147, 151))	('tumor', 'Disease', (9, 14))	('MDR1', 'Gene', (113, 117))
887758	31897226	In our study, the chemosensitization of cisplatin relies on E2F1 in ESCC.	('ESCC', 'Disease', (68, 72))	('E2F1', 'Var', (60, 64))	('ESCC', 'Disease', 'MESH:C562729', (68, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))
887762	31897226	In conclusion, E2F1 increases the chemosensitization of cisplatin in ESCC, and the effect may be due to the upregulation of its target gene miR-26b.	('E2F1', 'Var', (15, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('ESCC', 'Disease', 'MESH:C562729', (69, 73))	('miR-26b', 'Gene', (140, 147))	('chemosensitization of cisplatin', 'MPA', (34, 65))	('ESCC', 'Disease', (69, 73))	('miR-26b', 'Gene', '407017', (140, 147))	('upregulation', 'PosReg', (108, 120))	('increases', 'PosReg', (20, 29))
887765	31340866	First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors Transient CD4+ T cell depletion led to the proliferation of tumor-specific CD8+ T cells in the draining lymph node and increased infiltration of PD-1+CD8+ T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice.	('CD8', 'Gene', (209, 212))	('CD4', 'Gene', (144, 147))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('human', 'Species', '9606', (9, 14))	('tumor', 'Disease', (306, 311))	('CD4+ T cell depletion', 'Phenotype', 'HP:0005407', (144, 165))	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('CD8', 'Gene', '925', (284, 287))	('tumor', 'Disease', (360, 365))	('tumors', 'Disease', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('infiltration', 'CPA', (263, 275))	('PD-1', 'Gene', (279, 283))	('human', 'Species', '9606', (56, 61))	('PD-1', 'Gene', '5133', (279, 283))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('tumor', 'Disease', (343, 348))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('CD8', 'Gene', '925', (209, 212))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('patients', 'Species', '9606', (98, 106))	('IT1208', 'Var', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('CD4', 'Gene', '920', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('CD8', 'Gene', (284, 287))	('mice', 'Species', '10090', (374, 378))	('tumor', 'Disease', (127, 132))	('CD4', 'Gene', '920', (144, 147))	('increased', 'PosReg', (253, 262))	('CD4', 'Gene', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
887766	31340866	This is a first-in-human study of IT1208, a defucosylated humanized anti-CD4 monoclonal antibody, engineered to exert potent antibody-dependent cellular cytotoxicity.	('human', 'Species', '9606', (58, 63))	('cytotoxicity', 'Disease', 'MESH:D064420', (153, 165))	('IT1208', 'Chemical', '-', (34, 40))	('human', 'Species', '9606', (19, 24))	('IT1208', 'Var', (34, 40))	('cytotoxicity', 'Disease', (153, 165))
887767	31340866	Patients with advanced solid tumors were treated with intravenous IT1208 at doses of 0.1 or 1.0 mg/kg.	('IT1208', 'Var', (66, 72))	('solid tumors', 'Disease', 'MESH:D009369', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('solid tumors', 'Disease', (23, 35))	('IT1208', 'Chemical', '-', (66, 72))
887771	31340866	Decreased CD4+ T cells in peripheral blood due to IT1208 were observed in all patients and especially in those receiving two administrations of 1.0 mg/kg.	('IT1208', 'Chemical', '-', (50, 56))	('Decreased CD4+ T cells', 'Phenotype', 'HP:0005407', (0, 22))	('Decreased', 'NegReg', (0, 9))	('Decreased CD4+ T', 'Phenotype', 'HP:0005407', (0, 16))	('patients', 'Species', '9606', (78, 86))	('IT1208', 'Var', (50, 56))	('CD4+ T cells', 'MPA', (10, 22))
887774	31340866	Moreover, transcriptomic profiling of the liver metastasis of the patient revealed upregulation of the expression of interferon-stimulated genes, T cell activation-related genes, and antigen presentation-related genes after IT1208 administration.	('IT1208', 'Var', (224, 230))	('upregulation', 'PosReg', (83, 95))	('expression', 'MPA', (103, 113))	('T cell activation-related genes', 'Gene', (146, 177))	('patient', 'Species', '9606', (66, 73))	('IT1208', 'Chemical', '-', (224, 230))
887776	31340866	IT1208 monotherapy successfully depleted CD4+ T cells with a manageable safety profile and encouraging preliminary efficacy signals, which warrants further investigations, especially in combination with immune checkpoint inhibitors.	('CD4+', 'Protein', (41, 45))	('IT1208', 'Chemical', '-', (0, 6))	('depleted', 'NegReg', (32, 40))	('IT1208', 'Var', (0, 6))
887780	31340866	Several reports suggested that depletion of CD4+ cells, including Tregs, Th2 cells, and a subpopulation of MDSCs and pDCs, results in strong antitumor effects in mouse models due to the enhancement of cytotoxic T-lymphocyte responses.	('depletion', 'MPA', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('enhancement', 'PosReg', (186, 197))	('Th2', 'Chemical', '-', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mouse', 'Species', '10090', (162, 167))	('tumor', 'Disease', (145, 150))	('cytotoxic T-lymphocyte responses', 'CPA', (201, 233))	('CD4+', 'Var', (44, 48))
887781	31340866	Previously, we showed that administration of the anti-CD4 mAb had strong antitumor effects superior to those elicited by CD25+ Treg depletion or other immune checkpoint mAbs in B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, which were completely reversed by CD8+ cell depletion.	('Lewis lung carcinoma subcutaneous tumor', 'Disease', 'MESH:D018827', (198, 237))	('CD8', 'Gene', '925', (280, 283))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('B16F10', 'CellLine', 'CVCL:0159', (177, 183))	('Lewis lung carcinoma subcutaneous tumor', 'Disease', (198, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('anti-CD4', 'Var', (49, 57))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (219, 237))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', (77, 82))	('CD8', 'Gene', (280, 283))
887784	31340866	Further, combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival.	('PD-1', 'Gene', (99, 103))	('anti-CD4', 'Var', (40, 48))	('suppressed', 'NegReg', (140, 150))	('PD-1', 'Gene', '5133', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('prolonged', 'PosReg', (176, 185))	('survival', 'CPA', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
887785	31340866	IT1208 (IDAC Theranostics, Inc., Tokyo, Japan US8399621) is a humanized anti-CD4 immunoglobulin G1 mAb with a defucosylated Fc region, which markedly enhances antibody-dependent cellular cytotoxicity (ADCC).	('cytotoxicity', 'Disease', 'MESH:D064420', (187, 199))	('human', 'Species', '9606', (62, 67))	('enhances', 'PosReg', (150, 158))	('US8399621', 'Var', (46, 55))	('IT1208', 'Chemical', '-', (0, 6))	('cytotoxicity', 'Disease', (187, 199))	('IT1208', 'Var', (0, 6))
887786	31340866	The present study is a first-in-human, phase I, open-label, dose-escalation study conducted to assess the safety, pharmacokinetics, pharmacodynamics, and immunological mechanisms of action of IT1208 when administered as monotherapy to patients with advanced solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('patients', 'Species', '9606', (235, 243))	('solid tumors', 'Disease', (258, 270))	('IT1208', 'Chemical', '-', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('human', 'Species', '9606', (32, 37))	('IT1208', 'Var', (192, 198))	('solid tumors', 'Disease', 'MESH:D009369', (258, 270))
887789	31340866	Exploratory biomarker analysis included histological and transcriptomic analyses of the tumor to assess cellular and molecular effects of IT1208.	('IT1208', 'Chemical', '-', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('IT1208', 'Var', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
887792	31340866	Patients who had previously received immune checkpoint inhibitors such as anti-PD1 or anti-PD-L1 mAb were eligible if the treatment had been discontinued at least 4 weeks prior to study.	('Patients', 'Species', '9606', (0, 8))	('PD1', 'Gene', (79, 82))	('PD1', 'Gene', '5133', (79, 82))	('anti-PD-L1', 'Var', (86, 96))
887797	31340866	The first patient in each cohort was treated with one dose of IT1208 on day 1, and other patients received two doses of IT1208 on days 1 and 8 followed by safety and efficacy assessment until disease progression or the development of intolerable toxicity.	('toxicity', 'Disease', (246, 254))	('patient', 'Species', '9606', (89, 96))	('IT1208', 'Chemical', '-', (120, 126))	('patient', 'Species', '9606', (10, 17))	('IT1208', 'Chemical', '-', (62, 68))	('patients', 'Species', '9606', (89, 97))	('IT1208', 'Var', (62, 68))	('toxicity', 'Disease', 'MESH:D064420', (246, 254))
887799	31340866	DLTs were defined as any of the following toxicities judged to be caused due to IT1208: grade 4 neutropenia; grade 4 thrombocytopenia or thrombocytopenia requiring transfusions; grade >= 3 febrile neutropenia; uncontrollable nonhematologic toxicity of grade >= 3 despite maximal supportive care, excluding manageable grade 3 infusion-related reactions; and toxicities that required treatment delay of >=3 days or discontinuation of the planned day 8 infusion.	('caused', 'Reg', (66, 72))	('toxicity', 'Disease', (240, 248))	('toxicities', 'Disease', 'MESH:D064420', (42, 52))	('thrombocytopenia', 'Disease', 'MESH:D013921', (137, 153))	('neutropenia', 'Disease', 'MESH:D009503', (197, 208))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (137, 153))	('neutropenia', 'Phenotype', 'HP:0001875', (197, 208))	('toxicities', 'Disease', (42, 52))	('thrombocytopenia', 'Disease', (117, 133))	('neutropenia', 'Disease', (96, 107))	('IT1208', 'Var', (80, 86))	('DLTs', 'Disease', (0, 4))	('grade', 'Disease', (178, 183))	('toxicities', 'Disease', 'MESH:D064420', (357, 367))	('toxicities', 'Disease', (357, 367))	('thrombocytopenia', 'Disease', 'MESH:D013921', (117, 133))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (117, 133))	('thrombocytopenia', 'Disease', (137, 153))	('toxicity', 'Disease', 'MESH:D064420', (240, 248))	('neutropenia', 'Disease', (197, 208))	('neutropenia', 'Disease', 'MESH:D009503', (96, 107))	('neutropenia', 'Phenotype', 'HP:0001875', (96, 107))	('IT1208', 'Chemical', '-', (80, 86))
887818	31340866	Patients receiving 0.1 mg/kg were associated with grade 1 infusion-related reactions with the primary symptom of fever (Additional file 3: Table S1).	('fever', 'Disease', 'MESH:D005334', (113, 118))	('fever', 'Disease', (113, 118))	('Patients', 'Species', '9606', (0, 8))	('fever', 'Phenotype', 'HP:0001945', (113, 118))	('0.1 mg/kg', 'Var', (19, 28))	('grade', 'Disease', (50, 55))
887821	31340866	All symptoms recovered after transient interruption of IT1208 administration, and the remaining IT1208 administrations were completed within a day in all patients.	('IT1208', 'Var', (55, 61))	('symptoms', 'MPA', (4, 12))	('patients', 'Species', '9606', (154, 162))	('IT1208', 'Chemical', '-', (96, 102))	('IT1208', 'Chemical', '-', (55, 61))
887824	31340866	The maximum plasma concentration (Cmax) of IT1208 at a dose of 0.1 mg/kg after one or two administrations was 0.255 +- 0.0838 mug/mL (average +- standard deviation) and decreased to less than the detection threshold (0.03 mug/mL) at 4 h after the end of infusion (Additional file 4: Figure S2).	('IT1208', 'Var', (43, 49))	('IT1208', 'Chemical', '-', (43, 49))	('decreased', 'NegReg', (169, 178))
887828	31340866	Decreased CD4+ T-cell counts in PBMCs due to IT1208 were observed in all patients, especially in patients receiving two administrations of 1.0 mg/kg, who experienced a reduction of CD4+ T cell count from a median 395/muL at baseline to 3.5/muL at nadir (Fig.	('IT1208', 'Var', (45, 51))	('CD4+ T-cell counts', 'MPA', (10, 28))	('CD4+ T cell count', 'MPA', (181, 198))	('Decreased', 'NegReg', (0, 9))	('Decreased CD4+ T', 'Phenotype', 'HP:0005407', (0, 16))	('IT1208', 'Chemical', '-', (45, 51))	('reduction of CD4+ T cell', 'Phenotype', 'HP:0005407', (168, 192))	('patients', 'Species', '9606', (73, 81))	('reduction', 'NegReg', (168, 177))	('patients', 'Species', '9606', (97, 105))
887829	31340866	CD8+ T cell counts were also decreased immediately after IT1208 administration but then increased until day 29 and surpassed baseline counts in most patients, which resulted in remarkably decreased CD4/8 ratios.	('decreased', 'NegReg', (188, 197))	('patients', 'Species', '9606', (149, 157))	('IT1208', 'Chemical', '-', (57, 63))	('CD8', 'Gene', (0, 3))	('CD4/8 ratios', 'MPA', (198, 210))	('IT1208', 'Var', (57, 63))	('CD8', 'Gene', '925', (0, 3))
887831	31340866	NK cell counts were also decreased immediately after IT1208 administration but increased subsequently.	('IT1208', 'Chemical', '-', (53, 59))	('IT1208', 'Var', (53, 59))	('decreased', 'NegReg', (25, 34))	('NK cell counts', 'CPA', (0, 14))
887835	31340866	Moreover, following the decrease in eTregs, the population of CD45RAhiCCR7- effector CD8+ T cells tended to increase in later phases (Fig.	('eTregs', 'Chemical', '-', (36, 42))	('increase', 'PosReg', (108, 116))	('CD45RAhiCCR7-', 'Var', (62, 75))	('CD8', 'Gene', (85, 88))	('CD8', 'Gene', '925', (85, 88))
887844	31340866	The density of CD3+CD4+ T cells in the tumor decreased in six of seven patients receiving 1.0 mg/kg IT1208 (Fig.	('IT1208', 'Var', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('patients', 'Species', '9606', (71, 79))	('decreased', 'NegReg', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('density', 'MPA', (4, 11))	('IT1208', 'Chemical', '-', (100, 106))
887845	31340866	4c and Additional file 8: Table S2), while case 10 with PR showed a dramatic increase in the density of both CD3+CD8+ and CD3+CD4+ T cells in the tumor area (Fig.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('CD8', 'Gene', (113, 116))	('CD8', 'Gene', '925', (113, 116))	('tumor', 'Disease', (146, 151))	('increase', 'PosReg', (77, 85))	('CD3+CD4+ T', 'Var', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
887846	31340866	Moreover, the density of Ki67+-activated T cells also increased after IT1208 administration in case 10 (Fig.	('IT1208', 'Var', (70, 76))	('IT1208', 'Chemical', '-', (70, 76))	('increased', 'PosReg', (54, 63))
887847	31340866	We also evaluated CD204+ CD4+ macrophages and found no significant change in the CD204+ CD4+ area in the tumor of patients receiving two doses of 1.0 mg/kg IT1208 (Additional file 9: Figure S6).	('IT1208', 'Chemical', '-', (156, 162))	('IT1208', 'Var', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Disease', (105, 110))
887853	31340866	Sum total frequency of overlapping clones in the blood CD8+ T cells tended to increase after IT1208 administration, particularly in patients receiving 1.0 mg/kg (Fig.	('IT1208', 'Chemical', '-', (93, 99))	('IT1208', 'Var', (93, 99))	('increase', 'PosReg', (78, 86))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))	('patients', 'Species', '9606', (132, 140))
887855	31340866	We evaluated the mode of action, tolerated dose, and pharmacokinetics of IT1208 as an anti-CD4 depleting mAb in patients with advanced solid tumors.	('anti-CD4', 'MPA', (86, 94))	('solid tumors', 'Disease', 'MESH:D009369', (135, 147))	('IT1208', 'Var', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('patients', 'Species', '9606', (112, 120))	('solid tumors', 'Disease', (135, 147))	('IT1208', 'Chemical', '-', (73, 79))
887861	31340866	This patient also showed increasing Ki67+ CD4+ and CD8+ T cells along with the upregulation of antitumor gene expression localized to the tumor after IT1208 administration.	('tumor', 'Disease', (99, 104))	('patient', 'Species', '9606', (5, 12))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Ki67+', 'Var', (36, 41))	('IT1208', 'Chemical', '-', (150, 156))	('CD8', 'Gene', (51, 54))	('increasing', 'PosReg', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CD8', 'Gene', '925', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('upregulation', 'PosReg', (79, 91))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
887866	31340866	TCR repertoire analyses revealed that IT1208 not only reduced the number of CD4+ T cells but also altered the repertoire (or antigen reactivity) dose dependently.	('antigen reactivity', 'MPA', (125, 143))	('repertoire', 'MPA', (110, 120))	('TCR', 'Gene', '6962', (0, 3))	('CD4+ T cells', 'CPA', (76, 88))	('reduced', 'NegReg', (54, 61))	('IT1208', 'Chemical', '-', (38, 44))	('TCR', 'Gene', (0, 3))	('altered', 'Reg', (98, 105))	('IT1208', 'Var', (38, 44))
887870	31340866	Considering that both tumor-blood overlapping clones and MHC class I gene expression increased in the IT1208 responders (Cases 3 and 10), the increase of tumor-blood overlapping CD8+ TCR clones and MHC class I gene expression may reflect the mode of action of CD4 depletion and may be a response marker to IT1208 treatment.	('increase', 'PosReg', (142, 150))	('CD8', 'Gene', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('MHC class I gene', 'Gene', (57, 73))	('increased', 'PosReg', (85, 94))	('tumor', 'Disease', (154, 159))	('expression', 'MPA', (74, 84))	('TCR', 'Gene', (183, 186))	('MHC class I gene', 'Gene', (198, 214))	('IT1208', 'Chemical', '-', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('IT1208', 'Chemical', '-', (306, 312))	('expression', 'MPA', (215, 225))	('CD8', 'Gene', '925', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (22, 27))	('TCR', 'Gene', '6962', (183, 186))	('IT1208', 'Var', (102, 108))
887872	31340866	The decrease in eTregs and increase in effector CD8+ T cells might form a rationale for combinations of IT1208 with additional therapies such as anti-PD-1 or PD-L1 inhibitors.	('eTregs', 'Chemical', '-', (16, 22))	('eTregs', 'CPA', (16, 22))	('IT1208', 'Var', (104, 110))	('PD-1', 'Gene', (150, 154))	('PD-1', 'Gene', '5133', (150, 154))	('decrease', 'NegReg', (4, 12))	('CD8', 'Gene', (48, 51))	('IT1208', 'Chemical', '-', (104, 110))	('CD8', 'Gene', '925', (48, 51))	('increase', 'PosReg', (27, 35))	('combinations', 'Interaction', (88, 100))
887877	31340866	However, we should take caution because the depletion of CD4+ T cells decreases humoral immune responses to inexperienced virus infection, such as seasonal influenza infection and so on.	('virus infection', 'Disease', 'MESH:D015658', (122, 137))	('seasonal influenza infection', 'Disease', (147, 175))	('depletion of CD4+ T cells', 'Phenotype', 'HP:0005407', (44, 69))	('depletion', 'Var', (44, 53))	('decreases', 'NegReg', (70, 79))	('T cells decreases', 'Phenotype', 'HP:0005403', (62, 79))	('seasonal influenza infection', 'Disease', 'MESH:D007251', (147, 175))	('virus infection', 'Disease', (122, 137))	('decreases humoral immune', 'Phenotype', 'HP:0005368', (70, 94))
887881	31340866	We have shown that IT1208 monotherapy successfully depleted CD4+ T cells with a manageable safety profile and encouraging preliminary efficacy signals, which warrants further investigations, especially in combinations with immune checkpoint inhibitors.	('CD4+ T cells', 'CPA', (60, 72))	('IT1208', 'Chemical', '-', (19, 25))	('depleted', 'NegReg', (51, 59))	('IT1208', 'Var', (19, 25))
888001	29098187	In another study, pharmacological inhibition of CB1 led to decreased amount of refeeding in rats after food deprivation, highlighting CB1 receptor's role in appetite regulation.	('rats', 'Species', '10116', (92, 96))	('decreased', 'NegReg', (59, 68))	('CB1', 'Gene', (48, 51))	('amount of refeeding', 'MPA', (69, 88))	('pharmacological', 'Var', (18, 33))
888003	29098187	It was also suggested to play a role in hyperphagia after antagonism of CB1 with an inhibitor led to decreased food intake in rats fed a WD for 60 days.	('food intake', 'CPA', (111, 122))	('rats', 'Species', '10116', (126, 130))	('antagonism', 'Var', (58, 68))	('hyperphagia', 'Phenotype', 'HP:0002591', (40, 51))	('decreased', 'NegReg', (101, 110))	('CB1', 'Gene', (72, 75))	('WD', 'Disease', 'MESH:D006527', (137, 139))	('hyperphagia', 'Disease', (40, 51))	('hyperphagia', 'Disease', 'MESH:D006963', (40, 51))
888018	29098187	CB1 receptor activation has been shown to decrease spontaneous swallows in human and animal studies.	('activation', 'Var', (13, 23))	('human', 'Species', '9606', (75, 80))	('spontaneous swallows', 'Phenotype', 'HP:0002015', (51, 71))	('decrease', 'NegReg', (42, 50))	('spontaneous swallows', 'CPA', (51, 71))	('CB1 receptor', 'Protein', (0, 12))
888023	29098187	The only study in humans to date found administration of the combination CB1/CB2 agonist Delta9-THC resulted in a significant reduction in the number of swallows wherein high doses (20 mg) led to a reduction in spontaneous swallows by 50%.	('spontaneous swallows', 'MPA', (211, 231))	('humans', 'Species', '9606', (18, 24))	('reduction', 'NegReg', (198, 207))	('Delta9-THC', 'Var', (89, 99))	('rat', 'Species', '10116', (47, 50))	('CB1/CB2', 'Gene', (73, 80))	('reduction', 'NegReg', (126, 135))	('Delta9-THC', 'Chemical', 'MESH:D013759', (89, 99))	('spontaneous swallows', 'Phenotype', 'HP:0002015', (211, 231))
888026	29098187	Administration of Delta9-THC decreased basal lower esophageal sphincter (LES) pressure in a nondose-dependent manner, with onset occurring 45 min after meal ingestion, maximal effect around 100 min, followed by slow recovery.	('rat', 'Species', '10116', (8, 11))	('esophageal sphincter', 'Disease', (51, 71))	('Delta9-THC', 'Chemical', 'MESH:D013759', (18, 28))	('esophageal sphincter', 'Disease', 'MESH:D009122', (51, 71))	('decreased', 'NegReg', (29, 38))	('Delta9-THC', 'Var', (18, 28))
888047	29098187	Other studies have suggested that using Delta9-THC inhibits gastric insufflation-induced LES relaxations in the decerebrate ferret, highlighting the need for further clarification of the relationship between gastric stimulation and TLESRs.	('gastric insufflation', 'Disease', 'MESH:D013274', (60, 80))	('inhibits', 'NegReg', (51, 59))	('TLESRs', 'Chemical', '-', (232, 238))	('Delta9-THC', 'Var', (40, 50))	('rat', 'Species', '10116', (119, 122))	('ferret', 'Species', '9669', (124, 130))	('Delta9-THC', 'Chemical', 'MESH:D013759', (40, 50))	('gastric insufflation', 'Disease', (60, 80))
888052	29098187	demonstrated decreased rate of TLESRs in healthy volunteers who received 10 and 20 mg of Delta9-THC on three occasions a week apart.	('decreased', 'NegReg', (13, 22))	('rat', 'Species', '10116', (23, 26))	('Delta9-THC', 'Var', (89, 99))	('TLESRs', 'Disease', (31, 37))	('rat', 'Species', '10116', (7, 10))	('Delta9-THC', 'Chemical', 'MESH:D013759', (89, 99))	('TLESRs', 'Chemical', '-', (31, 37))
888053	29098187	Delta(9)-THC significantly reduced the number of TLESRs and caused a nonsignificant reduction of acid reflux episodes in the first postprandial hour.	('TLESRs', 'MPA', (49, 55))	('reduced', 'NegReg', (27, 34))	('acid reflux episodes', 'MPA', (97, 117))	('reduction', 'NegReg', (84, 93))	('Delta(9)-THC', 'Var', (0, 12))	('acid reflux', 'Phenotype', 'HP:0002020', (97, 108))	('Delta(9)-THC', 'Chemical', 'MESH:D013759', (0, 12))	('TLESRs', 'Chemical', '-', (49, 55))
888054	29098187	In addition, lower esophageal sphincter pressure and swallowing were significantly reduced by Delta(9)-THC.	('Delta(9)-THC', 'Chemical', 'MESH:D013759', (94, 106))	('reduced', 'NegReg', (83, 90))	('esophageal sphincter pressure', 'Disease', (19, 48))	('sphincter pressure', 'Phenotype', 'HP:0002839', (30, 48))	('Delta(9)-THC', 'Var', (94, 106))	('esophageal sphincter pressure', 'Disease', 'MESH:D009122', (19, 48))	('swallowing', 'CPA', (53, 63))
888055	29098187	However, in the high dose of Delta9-THC (20 mg) group, central activity led to increased nausea and vomiting.	('increased', 'PosReg', (79, 88))	('nausea', 'Phenotype', 'HP:0002018', (89, 95))	('nausea', 'Disease', (89, 95))	('nausea', 'Disease', 'MESH:D009325', (89, 95))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (89, 108))	('vomiting', 'Phenotype', 'HP:0002013', (100, 108))	('Delta9-THC', 'Chemical', 'MESH:D013759', (29, 39))	('vomiting', 'Disease', (100, 108))	('vomiting', 'Disease', 'MESH:D014839', (100, 108))	('central activity', 'MPA', (55, 71))	('Delta9-THC', 'Var', (29, 39))
888116	27119071	investigated the presence of EGFR mutations in 19 esophageal cancer cell lines and primary tumors by PCR and DNA sequencing targeting exons 18, 19, 20 and 21.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('primary tumors', 'Disease', (83, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))	('primary tumors', 'Disease', 'MESH:D009369', (83, 97))	('EGFR', 'Gene', '1956', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('esophageal cancer', 'Disease', (50, 67))	('EGFR', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (34, 43))
888117	27119071	One of the 50 patients had an EGFR mutation in codon 719, resulting in an amino acid substitution from glycine to aspartic acid.	('EGFR', 'Gene', (30, 34))	('amino', 'Var', (74, 79))	('glycine', 'Chemical', 'MESH:D005998', (103, 110))	('mutation', 'Var', (35, 43))	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', '1956', (30, 34))	('aspartic acid', 'Chemical', 'MESH:D001224', (114, 127))
888125	27119071	The primary results suggested that the sensitivity and specificity for diagnosing severe dysplasia or adenocarcinoma are 88 and 100 %, respectively, by detecting HER2, c-myc, 20q13.2, and aneuploidy (Pacha et al.).	('HER2', 'Gene', '2064', (162, 166))	('dysplasia or adenocarcinoma', 'Disease', 'MESH:D000230', (89, 116))	('HER2', 'Gene', (162, 166))	('c-myc', 'Gene', '4609', (168, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('aneuploidy', 'Disease', 'MESH:D000782', (188, 198))	('c-myc', 'Gene', (168, 173))	('20q13.2', 'Var', (175, 182))	('dysplasia or adenocarcinoma', 'Disease', (89, 116))	('aneuploidy', 'Disease', (188, 198))	('detecting', 'Reg', (152, 161))
888138	27119071	For example, in the diagnosis of low-grade dysplasia, three pathological scientists agreed that the expression of p53 protein immunohistochemical abnormalities may be considered a major risk of disease progression (Skacel et al.).	('abnormalities', 'Var', (146, 159))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('dysplasia', 'Disease', (43, 52))	('protein', 'Protein', (118, 125))	('expression', 'Var', (100, 110))	('dysplasia', 'Disease', 'MESH:D004476', (43, 52))
888149	27119071	Antibodies against tumor-associated antigen (TAA), which is present in the serum of patients with various types of cancers, can be used as a biomarker for early diagnosis of EC.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('Antibodies', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('patients', 'Species', '9606', (84, 92))	('cancers', 'Disease', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('EC', 'Phenotype', 'HP:0011459', (174, 176))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))
888154	27119071	Anti-p53 induced by mutant p53 protein in serum is one of the most frequently tested antibodies.	('p53', 'Gene', '7157', (27, 30))	('protein', 'Protein', (31, 38))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '7157', (5, 8))	('mutant', 'Var', (20, 26))	('p53', 'Gene', (27, 30))
888159	27119071	Based on the current evidence, they concluded that serum p53 antibody has a potential diagnostic value for EC.	('EC', 'Phenotype', 'HP:0011459', (107, 109))	('serum', 'Var', (51, 56))	('p53', 'Gene', '7157', (57, 60))	('p53', 'Gene', (57, 60))
888162	27119071	found that four antibodies (i.e., SURF1, HOOK2, LOC146223, and AGENCOURT_7565913) are highly specific for esophageal cancer, compared with breast cancer, gastric cancer, colorectal cancer.	('HOOK2', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('SURF1', 'Gene', (34, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (170, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('esophageal cancer', 'Disease', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('gastric cancer', 'Disease', (154, 168))	('HOOK2', 'Gene', '29911', (41, 46))	('breast cancer', 'Disease', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('SURF1', 'Gene', '6834', (34, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (170, 187))	('LOC146223', 'Var', (48, 57))	('gastric cancer', 'Disease', 'MESH:D013274', (154, 168))	('colorectal cancer', 'Disease', (170, 187))
888193	27119071	reported that miR-106b-25 can inhibit the expression of target genes p21 and Bim and promote the transformation from Barrett to EAC.	('Bim', 'Gene', '10018', (77, 80))	('miR-106b-25', 'Var', (14, 25))	('inhibit', 'NegReg', (30, 37))	('promote', 'PosReg', (85, 92))	('expression', 'MPA', (42, 52))	('Barrett', 'Disease', (117, 124))	('p21', 'Gene', (69, 72))	('p21', 'Gene', '644914', (69, 72))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('transformation', 'MPA', (97, 111))	('Bim', 'Gene', (77, 80))
888195	27119071	reported that the tumor invasion in the low GNG7 [guanine nucleotide binding protein (G protein), gamma 7] expression group is higher than that in the high expression group; moreover, the survival rate is low, and GNG7 expression is regulated by miR-328.	('low', 'NegReg', (205, 208))	('guanine nucleotide binding protein (G protein), gamma 7', 'Gene', '2788', (50, 105))	('GNG7', 'Gene', (214, 218))	('tumor', 'Disease', (18, 23))	('GNG7', 'Gene', (44, 48))	('low', 'Var', (40, 43))	('miR-328', 'Gene', (246, 253))	('GNG7', 'Gene', '2788', (44, 48))	('higher', 'PosReg', (127, 133))	('GNG7', 'Gene', '2788', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('miR-328', 'Gene', '442901', (246, 253))	('survival rate', 'CPA', (188, 201))
888212	25709466	PSCA rs2294008 C > T polymorphism contributes to gastric and bladder cancer risk Previous studies suggested genetic variations in PSCA (prostate stem cell antigen) may confer the susceptibility of cancer.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('rs2294008', 'DBSNP_MENTION', 'None', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('PSCA', 'Gene', (130, 134))	('gastric', 'Disease', (49, 56))	('rs2294008', 'Var', (5, 14))	('PSCA', 'Gene', '8000', (130, 134))	('prostate stem cell antigen', 'Gene', '8000', (136, 162))	('prostate stem cell antigen', 'Gene', (136, 162))	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('PSCA', 'Gene', (0, 4))	('cancer', 'Disease', (197, 203))	('bladder cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))	('cancer', 'Disease', (69, 75))	('variations', 'Var', (116, 126))	('PSCA', 'Gene', '8000', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))
888213	25709466	Many case-control studies have reported the relationship between PSCA rs2294008 C > T polymorphism and cancer, especially gastric cancer and bladder cancer.	('rs2294008', 'DBSNP_MENTION', 'None', (70, 79))	('cancer', 'Disease', (103, 109))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rs2294008', 'Var', (70, 79))	('PSCA', 'Gene', (65, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))	('PSCA', 'Gene', '8000', (65, 69))	('bladder cancer', 'Disease', (141, 155))	('cancer', 'Disease', (149, 155))	('especially gastric cancer', 'Disease', 'MESH:D013274', (111, 136))	('especially gastric cancer', 'Disease', (111, 136))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
888214	25709466	This meta-analysis is aimed at evaluating the association of rs2294008 polymorphism with cancer risk.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('rs2294008', 'DBSNP_MENTION', 'None', (61, 70))	('cancer', 'Disease', (89, 95))	('association', 'Interaction', (46, 57))	('rs2294008', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
888216	25709466	The results showed that the rs2294008 polymorphism was associated with increased cancer risk in any genetic model (T vs C, OR: 1.18, 95% CI: 1.08-1.28; TT vs CC, OR: 1.36, 95% CI: 1.14-1.62; TC vs CC, OR: 1.29, 95% CI: 1.17-1.44; TT + TC vs CC, OR: 1.32, 95% CI: 1.18-1.49; TT vs TC + CC, OR: 1.15, 95% CI: 1.02-1.30).	('TC', 'Chemical', 'MESH:D013667', (280, 282))	('rs2294008', 'Var', (28, 37))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('TC', 'Chemical', 'MESH:D013667', (235, 237))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('rs2294008', 'DBSNP_MENTION', 'None', (28, 37))	('TC', 'Chemical', 'MESH:D013667', (191, 193))
888217	25709466	In stratified analysis by cancer type, we found that the T allele had a significant high risk of gastric and bladder cancer, but not in other cancers.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Disease', (142, 149))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('T allele', 'Var', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('gastric and bladder cancer', 'Disease', 'MESH:D001749', (97, 123))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancer', 'Disease', (142, 148))
888219	25709466	Our study suggested that the PSCA rs2294008 C > T polymorphism is a risk factor for cancer, especially in gastric and bladder cancer.	('PSCA', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (84, 90))	('gastric and bladder cancer', 'Disease', 'MESH:D001749', (106, 132))	('cancer', 'Disease', (126, 132))	('PSCA', 'Gene', '8000', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (118, 132))	('rs2294008', 'DBSNP_MENTION', 'None', (34, 43))	('rs2294008', 'Var', (34, 43))
888228	25709466	The most extensively studied single nucleotide polymorphism (SNP) in PSCA is rs2294008 C > T. Although in vitro experiments have revealed that the variant rs2294008T could reduce the transcriptional activity of an upstream fragment of PSCA, its mechanism and physiological function are still unknown.	('PSCA', 'Gene', (235, 239))	('PSCA', 'Gene', '8000', (69, 73))	('rs2294008', 'Var', (155, 164))	('transcriptional activity', 'MPA', (183, 207))	('PSCA', 'Gene', (69, 73))	('reduce', 'NegReg', (172, 178))	('rs2294008', 'DBSNP_MENTION', 'None', (77, 86))	('PSCA', 'Gene', '8000', (235, 239))	('rs2294008', 'Var', (77, 86))	('rs2294008', 'DBSNP_MENTION', 'None', (155, 164))
888229	25709466	Previously, genome-wide association studies (GWAS) have found that the rs2294008 polymorphism in PSCA is significantly associated with gastric and bladder cancers.	('gastric and bladder cancer', 'Disease', 'MESH:D001749', (135, 161))	('bladder cancers', 'Phenotype', 'HP:0009725', (147, 162))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('bladder cancers', 'Disease', 'MESH:D001749', (147, 162))	('rs2294008', 'DBSNP_MENTION', 'None', (71, 80))	('PSCA', 'Gene', '8000', (97, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (147, 161))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('PSCA', 'Gene', (97, 101))	('bladder cancers', 'Disease', (147, 162))	('rs2294008', 'Var', (71, 80))	('associated', 'Reg', (119, 129))
888230	25709466	Although several studies have described the relationship between the rs2294008 polymorphism and other cancers, the sample sizes of these studies were small.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs2294008', 'Var', (69, 78))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('rs2294008', 'DBSNP_MENTION', 'None', (69, 78))
888231	25709466	More recently, five meta-analyses have assessed the relationship between the polymorphism of PSCA rs2294008 C > T and the susceptibility to gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('PSCA', 'Gene', '8000', (93, 97))	('susceptibility to gastric cancer', 'Phenotype', 'HP:0006753', (122, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('rs2294008', 'DBSNP_MENTION', 'None', (98, 107))	('gastric cancer', 'Disease', (140, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('rs2294008', 'Var', (98, 107))	('PSCA', 'Gene', (93, 97))
888232	25709466	Furthermore, there is a lack of evidence of a relationship between the rs2294008 polymorphism and cancer overall.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs2294008', 'DBSNP_MENTION', 'None', (71, 80))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('rs2294008', 'Var', (71, 80))
888233	25709466	Additionally, the genetic variant of rs2294008 may be correlated with cancer risk in different cancer type and/or ethnicity.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('rs2294008', 'DBSNP_MENTION', 'None', (37, 46))	('correlated', 'Reg', (54, 64))	('rs2294008', 'Var', (37, 46))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
888234	25709466	Herein, we carried out a meta-analysis to derive a more precise evaluation on the relationship between the rs2294008 polymorphism and cancer risk.	('rs2294008', 'DBSNP_MENTION', 'None', (107, 116))	('rs2294008', 'Var', (107, 116))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
888235	25709466	We searched the databases of PubMed, ISI Web of Knowledge, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) for related articles with the keywords: "PSCA/Prostate stem cell antigen", "rs2294008", "single nucleotide polymorphism/SNP/variation/genotype", and "cancer/carcinoma/tumor/neoplasm".	('carcinoma/tumor', 'Disease', 'MESH:D009369', (277, 292))	('rs2294008', 'Var', (196, 205))	('Prostate stem cell antigen', 'Gene', (166, 192))	('PSCA', 'Gene', (161, 165))	('neoplasm', 'Disease', (293, 301))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('rs2294008', 'DBSNP_MENTION', 'None', (196, 205))	('neoplasm', 'Phenotype', 'HP:0002664', (293, 301))	('carcinoma/tumor', 'Disease', (277, 292))	('PSCA', 'Gene', '8000', (161, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('neoplasm', 'Disease', 'MESH:D009369', (293, 301))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('Prostate stem cell antigen', 'Gene', '8000', (166, 192))
888236	25709466	The following criteria were used to select the eligible literature for this meta-analysis: 1) original papers investigating the associations between PSCA (rs2294008) polymorphisms and cancer risk; 2) case-control studies; and 3) full-text published articles and included detailed genotyping data.	('cancer', 'Disease', (184, 190))	('rs2294008', 'Var', (155, 164))	('associations', 'Interaction', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('PSCA', 'Gene', '8000', (149, 153))	('polymorphisms', 'Var', (166, 179))	('PSCA', 'Gene', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('rs2294008', 'DBSNP_MENTION', 'None', (155, 164))
888239	25709466	The associations between the PSCA (rs2294008) polymorphism and cancer risk were measured by the odds ratio (OR) with 95% confidence intervals (CIs) according to allele contrast (T vs C), homozygote (TT vs CC), heterozygote (TC vs CC), recessive (TT vs CC + TC), and dominant (CC vs TC + TT) models.	('PSCA', 'Gene', (29, 33))	('rs2294008', 'Var', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('PSCA', 'Gene', '8000', (29, 33))	('TC', 'Chemical', 'MESH:D013667', (257, 259))	('TC', 'Chemical', 'MESH:D013667', (282, 284))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('TC', 'Chemical', 'MESH:D013667', (224, 226))	('cancer', 'Disease', (63, 69))	('associations', 'Interaction', (4, 16))	('rs2294008', 'DBSNP_MENTION', 'None', (35, 44))
888247	25709466	The rs2294008 polymorphism was associated with gastric cancer risk in four genetic models (T vs C, OR: 1.26, 95% CI: 1.10-1.45, P=0.001; TT vs CC, OR: 1.51, 95% CI: 1.10-2.08, P=0.01; TC vs CC, OR: 1.39, 95% CI: 1.19-1.63, P<0.0001; TT + TC vs CC, OR: 1.44, 95% CI: 1.19-1.74, P=0.0002).	('rs2294008', 'Var', (4, 13))	('gastric cancer', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('associated', 'Reg', (31, 41))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('rs2294008', 'DBSNP_MENTION', 'None', (4, 13))	('TC', 'Chemical', 'MESH:D013667', (184, 186))	('TC', 'Chemical', 'MESH:D013667', (238, 240))
888248	25709466	However, the recessive model showed that there was no association between rs2294008 and gastric cancer (OR: 1.22, 95% CI: 0.99-1.49, P=0.06).	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('rs2294008', 'DBSNP_MENTION', 'None', (74, 83))	('rs2294008', 'Var', (74, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))
888249	25709466	Five studies with 12,397 cases and 19,237 controls were used to evaluate the relationship between the rs2294008 polymorphism and bladder cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('bladder cancer', 'Disease', (129, 143))	('rs2294008', 'DBSNP_MENTION', 'None', (102, 111))	('rs2294008', 'Var', (102, 111))
888250	25709466	As shown in Table 3 and Figure 2, there was a significant association between rs2294008 and bladder cancer risk in all genetic models (T vs C, OR: 1.13, 95% CI: 1.06-1.21, P=0.0005; TT vs CC, OR: 1.28, 95% CI: 1.20-1.37, P<0.00001; TC vs CC, OR: 1.23, 95% CI: 1.17-1.30, P<0.00001; TT +TC vs CC, OR: 1.25, 95% CI: 1.19-1.31, P<0.00001; TT vs TC + CC, OR: 1.13, 95% CI: 1.07-1.20, P<0.0001).	('TC', 'Chemical', 'MESH:D013667', (232, 234))	('TC', 'Chemical', 'MESH:D013667', (342, 344))	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('bladder cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rs2294008', 'DBSNP_MENTION', 'None', (78, 87))	('rs2294008', 'Var', (78, 87))	('TC', 'Chemical', 'MESH:D013667', (286, 288))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))
888251	25709466	In the stratified analysis by ethnicity, pooled analysis of Asians showed that the T allele of the PSCA rs2294008 polymorphism was associated with increased cancer risk under all genetic models except for the recessive model (T vs C, OR: 1.19, 95% CI: 1.05-1.35, P=0.007, Figure 3; TT vs CC, OR: 1.37, 95% CI: 1.03-1.82, P=0.03; TC vs CC, OR: 1.36, 95% CI: 1.18-1.57, P<0.0001; TT + TC vs CC, OR: 1.38, 95% CI: 1.17-1.62, P=0.0001).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('rs2294008', 'DBSNP_MENTION', 'None', (104, 113))	('TC', 'Chemical', 'MESH:D013667', (329, 331))	('PSCA', 'Gene', (99, 103))	('rs2294008', 'Var', (104, 113))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('PSCA', 'Gene', '8000', (99, 103))	('TC', 'Chemical', 'MESH:D013667', (383, 385))
888252	25709466	PSCA rs2294008 showed a significant association among Caucasians based on three models (T vs C, OR: 1.15, 95% CI: 1.04-1.26, P=0.004, Figure 3; TT vs CC, OR: 1.32, 95% CI: 1.10-1.59, P=0.003; TT vs TC + CC, OR: 1.15, 95% CI: 1.09-1.22, P<0.00001).	('TC', 'Chemical', 'MESH:D013667', (198, 200))	('PSCA', 'Gene', (0, 4))	('rs2294008', 'DBSNP_MENTION', 'None', (5, 14))	('rs2294008', 'Var', (5, 14))	('PSCA', 'Gene', '8000', (0, 4))
888261	25709466	The findings of our meta-analysis may demonstrate that rs2294008 acts as an effect modifier in the development of different cancers.	('rs2294008', 'DBSNP_MENTION', 'None', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rs2294008', 'Var', (55, 64))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
888262	25709466	This comprehensive meta-analysis, involving 26 studies from 24 articles with 30,050 multiple cancer cases and 51,671 controls, showed that the rs2294008 polymorphism is significantly associated with overall cancer risk based on all genetic models.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('rs2294008', 'DBSNP_MENTION', 'None', (143, 152))	('associated with', 'Reg', (183, 198))	('rs2294008', 'Var', (143, 152))
888263	25709466	Further stratified analyses by cancer type revealed that the polymorphism was associated with an increased risk for gastric and bladder cancer; no association was found with other cancers in all genetic models.	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('gastric and bladder cancer', 'Disease', 'MESH:D001749', (116, 142))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('cancer', 'Disease', (31, 37))	('polymorphism', 'Var', (61, 73))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
888264	25709466	Studies from Dai et al and Lochhead et al indicated that the variant rs2294008C may have a protective role in esophageal cancer, but large well-designed studies are warranted to confirm this conclusion.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal cancer', 'Disease', (110, 127))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('rs2294008C', 'Var', (69, 79))
888265	25709466	The stratified analysis by ethnicity showed that the rs2294008 polymorphism was associated with an increased risk of cancer in both Asians and Caucasians.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rs2294008', 'DBSNP_MENTION', 'None', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('rs2294008', 'Var', (53, 62))	('cancer', 'Disease', (117, 123))
888267	25709466	Larger scale multicenter studies based on Africans are warranted to further validate the association between the rs2294008 polymorphism and cancer risk.	('rs2294008', 'Var', (113, 122))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('rs2294008', 'DBSNP_MENTION', 'None', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
888268	25709466	So far, there have been five meta-analyses that have investigated the role of the PSCA rs2294008 polymorphism in gastric cancer risk.	('rs2294008', 'Var', (87, 96))	('PSCA', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('PSCA', 'Gene', '8000', (82, 86))	('rs2294008', 'DBSNP_MENTION', 'None', (87, 96))
888269	25709466	All of them had the same finding that the rs2294008 polymorphism is associated with increased risk of gastric cancer.	('rs2294008', 'Var', (42, 51))	('gastric cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (84, 116))	('rs2294008', 'DBSNP_MENTION', 'None', (42, 51))
888270	25709466	Significantly increased risks were found for rs2294008 both among Asians and Caucasians in three articles, which is congruous with our results.	('increased', 'PosReg', (14, 23))	('rs2294008', 'Var', (45, 54))	('rs2294008', 'DBSNP_MENTION', 'None', (45, 54))
888272	25709466	Their last search update was on August 2013, and in total, they identified 16 studies, including 18,820 gastric cases and 35,756 controls for the rs2294008 polymorphism.	('gastric', 'Disease', (104, 111))	('rs2294008', 'Var', (146, 155))	('rs2294008', 'DBSNP_MENTION', 'None', (146, 155))
888275	25709466	This meta-analysis provided evidence on the overall cancer risk of rs2294008 and contained the newest data and largest sample size on the relationship between rs2294008 and cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (173, 179))	('rs2294008', 'DBSNP_MENTION', 'None', (159, 168))	('rs2294008', 'Var', (67, 76))	('rs2294008', 'DBSNP_MENTION', 'None', (67, 76))	('rs2294008', 'Var', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
888276	25709466	Although the pooled analysis was performed to show the association between rs2294008 and cancer risk, some limitations still inevitably exist in this meta-analysis.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('association', 'Interaction', (55, 66))	('cancer', 'Disease', (89, 95))	('rs2294008', 'DBSNP_MENTION', 'None', (75, 84))	('rs2294008', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
888279	25709466	Hence, the final OR was largely contributed by the ORs of gastric or bladder cancer; more evidence is needed to prove whether the rs2294008 polymorphism is association with cancer overall.	('gastric or bladder cancer', 'Disease', 'MESH:D001749', (58, 83))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('association', 'Reg', (156, 167))	('gastric or bladder cancer', 'Disease', (58, 83))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (69, 83))	('rs2294008', 'DBSNP_MENTION', 'None', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rs2294008', 'Var', (130, 139))
888283	25709466	In conclusion, the present meta-analysis demonstrated that the PSCA rs2294008 C > T polymorphism is a risk factor for cancer in both Asians and Caucasians.	('rs2294008', 'Var', (68, 77))	('cancer', 'Disease', (118, 124))	('PSCA', 'Gene', '8000', (63, 67))	('risk', 'Reg', (102, 106))	('PSCA', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs2294008', 'DBSNP_MENTION', 'None', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
888285	25709466	Further large case-control studies are needed to assess the relationship between rs2294008 and other cancer types.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('rs2294008', 'DBSNP_MENTION', 'None', (81, 90))	('rs2294008', 'Var', (81, 90))
888293	25360410	Barium esophagography revealed an approximately 6 cm arc filling defect, local mucosal damages and wall stiffness, irregularities in lower thoracic esophagus (Fig.	('irregularities', 'Var', (115, 129))	('wall stiffness', 'CPA', (99, 113))	('Barium', 'Chemical', 'MESH:D001464', (0, 6))
888295	25360410	Clinical staging of the double cancer was stage II (T3N0M0) in esophageal cancer and stage IB (T2N0M0) in gastric cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('esophageal cancer', 'Disease', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('cancer', 'Disease', (74, 80))	('gastric cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('T2N0M0', 'Var', (95, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (114, 120))
888351	23678319	Aspiration of the corrosive substance may cause endotracheal or bronchial necrosis with mediastinitis, often leading to fatal outcome.	('endotracheal', 'Disease', (48, 60))	('mediastinitis', 'Disease', 'MESH:D008480', (88, 101))	('mediastinitis', 'Disease', (88, 101))	('Aspiration', 'Var', (0, 10))	('cause', 'Reg', (42, 47))	('bronchial necrosis', 'Disease', 'MESH:D001982', (64, 82))	('Aspiration', 'Phenotype', 'HP:0002835', (0, 10))	('bronchial necrosis', 'Disease', (64, 82))
888364	23678319	Stenosis of antrum and pyloris - onset of symptoms of full stomach, nausea, vomiting and weight loss suggest gastric obstruction.	('gastric obstruction', 'Disease', 'MESH:D013274', (109, 128))	('full stomach', 'Disease', (54, 66))	('Stenosis', 'Var', (0, 8))	('nausea', 'Disease', (68, 74))	('full stomach', 'Phenotype', 'HP:0005207', (54, 66))	('gastric obstruction', 'Disease', (109, 128))	('weight loss', 'Disease', (89, 100))	('nausea', 'Phenotype', 'HP:0002018', (68, 74))	('weight loss', 'Phenotype', 'HP:0001824', (89, 100))	('nausea', 'Disease', 'MESH:D009325', (68, 74))	('vomiting', 'Phenotype', 'HP:0002013', (76, 84))	('weight loss', 'Disease', 'MESH:D015431', (89, 100))	('vomiting', 'Disease', (76, 84))	('vomiting', 'Disease', 'MESH:D014839', (76, 84))	('gastric obstruction', 'Phenotype', 'HP:0004796', (109, 128))
888457	22174193	We fitted age and sex adjusted models (data not shown) for comparison to fully adjusted models that included total energy intake (daily kilocalories), antacid, aspirin and non-steroidal anti-inflammatory drug use (yes/no during the past 12 months), marital status (yes/no), diabetes (yes/no), ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, and Asian/Pacific Islander/Native American), cigarette smoking (never smokers, former smokers who smoked <=20 cigarettes/day, former smokers who smoked >20 cigarettes/day, current smokers who smoke <=20 cigarettes/day and current smokers who smoke >20 cigarettes/day), education (high school graduate or less, post high school training or some college training, college graduate, and postgraduate education), vigorous physical activity (never, rarely, 1-3 times/month, 1-2 times/week, 3-4 times/week, 5 or more times per week), usual activity throughout the day (sit all day, sit much of the day/walk some times, stand/walk often/no lifting, lift/carry light loads and carry heavy loads), alcohol consumption (none, >0-0.5, >0.5-1, >1-2, >2-4, >4 drinks per day), red and white meat intake (grams per day), and fruit and vegetable intakes (both pyramid servings per day).	('>0.5-1', 'Var', (1078, 1084))	('>1-2', 'Var', (1086, 1090))	('alcohol consumption', 'CPA', (1043, 1062))	('steroid', 'Chemical', 'MESH:D013256', (176, 183))	('diabetes', 'Disease', (274, 282))	('red', 'CPA', (1118, 1121))	('diabetes', 'Disease', 'MESH:D003920', (274, 282))
888466	22174193	WHR was associated with gastric cardia adenocarcinoma in the age and sex adjusted model (fourth quartile versus the referent; HR (95% CI) 1.57 (1.08-2.28), P for trend = 0.01), but was attenuated after multivariate adjustment (HR (95% CI) 1.37 (0.92-2.05), P for trend = 0.08).	('men', 'Species', '9606', (221, 224))	('associated', 'Reg', (8, 18))	('WHR', 'Var', (0, 3))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (24, 53))	('gastric cardia adenocarcinoma', 'Disease', (24, 53))
888469	22174193	WHR was also associated with gastric non-cardia adenocarcinoma in the age and sex adjusted model (fourth quartile versus the referent; HR (95% CI) 1.58 (1.05-2.37), P for trend = 0.02), and was marginally attenuated after multivariate adjustment (HR (95% CI) 1.56 (0.94-2.59), P for trend = 0.05).	('gastric non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (29, 62))	('men', 'Species', '9606', (241, 244))	('gastric non-cardia adenocarcinoma', 'Disease', (29, 62))	('associated', 'Reg', (13, 23))	('WHR', 'Var', (0, 3))
888475	22174193	A positive association for WHR was also seen for risk of gastric cardia adenocarcinoma in patients with normal BMI (HR (95% CI) 1.64 (1.06-2.53)), yet it was not present in overweight patients (HR (95% CI) 1.04 (0.80-1.34)), or in unstratified analysis (HR (95% CI) 1.16 (0.93-1.44)).	('patients', 'Species', '9606', (184, 192))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (57, 86))	('normal', 'Var', (104, 110))	('gastric cardia adenocarcinoma', 'Disease', (57, 86))	('patients', 'Species', '9606', (90, 98))	('overweight', 'Phenotype', 'HP:0025502', (173, 183))
888505	22174193	Also, in a recent study and editorial, it was suggested that intra-abdominal fat is associated with an increased risk of erosive esophagitis in both males and females, independent of GERD.	('esophagitis', 'Disease', 'MESH:D004941', (129, 140))	('GERD', 'Disease', 'MESH:D005764', (183, 187))	('GERD', 'Disease', (183, 187))	('esophagitis', 'Phenotype', 'HP:0100633', (129, 140))	('esophagitis', 'Disease', (129, 140))	('intra-abdominal fat', 'Var', (61, 80))
888531	22174193	Waist circumference was also related to increased risk of gastric cardia adenocarcinoma, but no association with WHR was observed.	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (58, 87))	('gastric cardia adenocarcinoma', 'Disease', (58, 87))	('Waist circumference', 'Var', (0, 19))
888551	22796132	For this multi-center, double-blind, placebo controlled phase II clinical trial, we hypothesized that a PPI plus higher dose aspirin would be more effective for downregulating PGE2 than either a PPI alone or a PPI plus lower dose aspirin in BE patients.	('downregulating', 'NegReg', (161, 175))	('aspirin', 'Chemical', 'MESH:D001241', (230, 237))	('PGE2', 'Chemical', 'MESH:D015232', (176, 180))	('PPI', 'Var', (104, 107))	('patients', 'Species', '9606', (244, 252))	('aspirin', 'Chemical', 'MESH:D001241', (125, 132))	('PGE2', 'Gene', (176, 180))
888599	22796132	Within the randomized cohort, 6 participants were not evaluable for the analyses of PGE2 analyses due to sample-related issues (e.g., improper temperature, lost or delayed samples), leaving 114 evaluable participants for the primary endpoint.	('leaving', 'Reg', (182, 189))	('PGE2', 'Gene', (84, 88))	('participants', 'Species', '9606', (204, 216))	('PGE2', 'Chemical', 'MESH:D015232', (84, 88))	('participants', 'Species', '9606', (32, 44))	('improper', 'Var', (134, 142))
888617	22796132	Higher dose aspirin + PPI was also associated with a significant decrease in the percent change in PGE2 values (secondary endpoint) compared to aspirin placebo + PPI (p < 0.0001) (Table 3 and Figure 3).	('PGE2', 'Chemical', 'MESH:D015232', (99, 103))	('PGE2 values', 'MPA', (99, 110))	('aspirin', 'Chemical', 'MESH:D001241', (144, 151))	('aspirin + PPI', 'Var', (12, 25))	('decrease', 'NegReg', (65, 73))	('aspirin', 'Chemical', 'MESH:D001241', (12, 19))
888641	22796132	While observational studies suggest that PPI therapy is associated with a decreased risk for the development of high-grade dysplasia and adenocarcinoma, the chemopreventive potential of PPIs, by suppressing acid and bile salt reflux, appears to be marginal when used as monotherapy.	('dysplasia and adenocarcinoma', 'Disease', 'MESH:D000230', (123, 151))	('bile salt', 'Chemical', 'MESH:D001647', (216, 225))	('suppressing', 'NegReg', (195, 206))	('PPI', 'Var', (41, 44))	('decreased', 'NegReg', (74, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
888643	22796132	Unfortunately, selective COX-2 inhibitors have been shown to increase the risk of thrombotic cardiovascular events making their widespread use for cancer chemoprevention problematic.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('thrombotic cardiovascular events', 'Disease', 'MESH:D002318', (82, 114))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('thrombotic cardiovascular events', 'Disease', (82, 114))	('cancer', 'Disease', (147, 153))	('inhibitors', 'Var', (31, 41))	('COX-2', 'Gene', '4513', (25, 30))	('COX-2', 'Gene', (25, 30))	('cardiovascular events', 'Phenotype', 'HP:0001626', (93, 114))
888646	22796132	In addition, PPIs may make aspirin a more useful and safer chemopreventive agent by minimizing aspirin-induced mucosal injury.	('aspirin', 'Chemical', 'MESH:D001241', (95, 102))	('mucosal injury', 'Disease', (111, 125))	('aspirin', 'Chemical', 'MESH:D001241', (27, 34))	('PPIs', 'Var', (13, 17))	('mucosal injury', 'Disease', 'MESH:D052016', (111, 125))	('minimizing', 'NegReg', (84, 94))
888665	22796132	The findings that carcinogenic bile salts in pH dependent manner upregulate PGE2 biosynthesis along with increased expression of key regulators of PGE2 by DNA damage and by aberrant p53 expression further support that the effect of genetic or epigenetic gains or losses that promote neoplasia could be inferred through a mechanistically relevant composite biochemical readout such as PGE2 synthesis.	('PGE2', 'Chemical', 'MESH:D015232', (147, 151))	('biosynthesis', 'MPA', (81, 93))	('PGE2', 'Chemical', 'MESH:D015232', (76, 80))	('p53', 'Gene', '7157', (182, 185))	('PGE2', 'Gene', (76, 80))	('PGE2', 'Chemical', 'MESH:D015232', (384, 388))	('losses', 'NegReg', (263, 269))	('carcinogenic', 'Disease', (18, 30))	('neoplasia', 'Disease', 'MESH:D009369', (283, 292))	('p53', 'Gene', (182, 185))	('bile salts', 'Chemical', 'MESH:D001647', (31, 41))	('neoplasia', 'Disease', (283, 292))	('promote', 'PosReg', (275, 282))	('carcinogenic', 'Disease', 'MESH:D063646', (18, 30))	('increased', 'PosReg', (105, 114))	('aberrant', 'Var', (173, 181))	('genetic', 'Var', (232, 239))	('epigenetic gains', 'Var', (243, 259))	('expression', 'MPA', (115, 125))	('neoplasia', 'Phenotype', 'HP:0002664', (283, 292))	('expression', 'MPA', (186, 196))	('upregulate', 'PosReg', (65, 75))
888686	20944134	However, activating mutations in SFKs are rarely found in human carcinomas suggesting that impaired negative regulatory mechanisms likely account for the increased kinase activity .	('SFK', 'Gene', (33, 36))	('carcinomas', 'Disease', (64, 74))	('human', 'Species', '9606', (58, 63))	('kinase', 'MPA', (164, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('SFK', 'Gene', '2534;14360;6714', (33, 36))	('increased', 'PosReg', (154, 163))	('carcinomas', 'Disease', 'MESH:D002277', (64, 74))	('mutations', 'Var', (20, 29))
888691	20944134	More recent studies with K14-Fyn Y528F/K14-Srcasm mice show that raising Srcasm levels can inhibit skin SCC formation through a mechanism that involves p53 and Notch 1 .	('inhibit', 'NegReg', (91, 98))	('SCC', 'Gene', '6317', (104, 107))	('p53', 'Gene', (152, 155))	('SCC', 'Gene', (104, 107))	('Y528F', 'Var', (33, 38))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('Y528F', 'SUBSTITUTION', 'None', (33, 38))	('Srcasm', 'MPA', (73, 79))	('skin', 'Disease', (99, 103))	('K14-Fyn', 'Var', (25, 32))	('mice', 'Species', '10090', (50, 54))	('p53', 'Gene', '22060', (152, 155))
888737	33448310	miR-93-5p regulates the occurrence and development of esophageal carcinoma epithelial cells by targeting TGFbetaR2 Emerging studies have indicated that the dysregulation of microRNAs (miRNAs or miRs) plays a vital role in the development and metastasis of tumors.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (54, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('metastasis of tumors', 'Disease', (242, 262))	('miR-93', 'Gene', '407051', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('miR-93', 'Gene', (0, 6))	('TGFbetaR2', 'Gene', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('esophageal carcinoma', 'Disease', (54, 74))	('metastasis of tumors', 'Disease', 'MESH:D009362', (242, 262))	('dysregulation', 'Var', (156, 169))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (54, 74))
888745	33448310	Some studies have demonstrated the abnormally high expression of miR-93-5p in liver, breast and lung cancer, and it is able to promote cell proliferation and migration by binding to various target genes.	('binding', 'Interaction', (171, 178))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('liver', 'Disease', (78, 83))	('promote', 'PosReg', (127, 134))	('lung cancer', 'Disease', (96, 107))	('miR-93-5p', 'Var', (65, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('expression', 'MPA', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cell proliferation', 'CPA', (135, 153))	('breast', 'Disease', (85, 91))
888746	33448310	Moreover, it has been reported that miR-93-5p may be a potential biomarker for the detection of the presence of cancer.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('miR-93-5p', 'Var', (36, 45))	('cancer', 'Disease', (112, 118))
888776	33448310	2B, the viability of the EC9706 cells in the miR-93-5p mimic group was significantly increased by comparison with that in the NC mimic group (P<0.05).	('EC9706', 'CellLine', 'CVCL:E307', (25, 31))	('EC', 'Phenotype', 'HP:0011459', (25, 27))	('increased', 'PosReg', (85, 94))	('miR-93-5p mimic', 'Var', (45, 60))
888778	33448310	The results revealed that the migration rate of the EC9706 cells in miR-93-5p mimic group was significantly increased relative to that in the NC mimic group (P<0.05).	('increased', 'PosReg', (108, 117))	('EC9706', 'CellLine', 'CVCL:E307', (52, 58))	('migration rate', 'CPA', (30, 44))	('EC', 'Phenotype', 'HP:0011459', (52, 54))	('miR-93-5p mimic', 'Var', (68, 83))
888780	33448310	3D) of the EC9706 transfected with miR-93-5p inhibitor were significantly decreased compared with those in the control group.	('EC9706 transfected', 'Var', (11, 29))	('EC9706', 'CellLine', 'CVCL:E307', (11, 17))	('EC', 'Phenotype', 'HP:0011459', (11, 13))	('decreased', 'NegReg', (74, 83))	('miR-93-5p', 'Var', (35, 44))
888784	33448310	To confirm whether TGFbetaR2 can reverse the effects of miR-93-5p on the proliferation, migration and invasion of EC cells, EC9706 cells were transfected with miR-93-5p mimic + oe-NC, NC mimic + oe-NC, miR-93-5p mimic + oe-TGFbetaR2, respectively.	('miR-93-5p mimic + oe-TGFbetaR2', 'Var', (202, 232))	('invasion', 'CPA', (102, 110))	('miR-93-5p mimic + oe-NC', 'Var', (159, 182))	('EC9706', 'CellLine', 'CVCL:E307', (124, 130))	('migration', 'CPA', (88, 97))	('EC', 'Phenotype', 'HP:0011459', (124, 126))	('EC', 'Phenotype', 'HP:0011459', (114, 116))
888788	33448310	miR-93-5p is located in the intron of the MCM7 gene and is a part of the cluster containing two other miRNAs (miR-25 and miR-106b).	('MCM7', 'Gene', (42, 46))	('miR-93-5p', 'Var', (0, 9))	('miR-106b', 'Gene', (121, 129))	('MCM7', 'Gene', '4176', (42, 46))	('miR-25', 'Gene', '407014', (110, 116))	('miR-106b', 'Gene', '406900', (121, 129))	('miR-25', 'Gene', (110, 116))
888789	33448310	The present study found that miR-93-5p was highly expressed in EC cells, which was consistent with previous findings on breast cancer, gastric cancer, prostate cancer and colorectal cancer.	('gastric cancer', 'Disease', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal cancer', 'Disease', (171, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('colorectal cancer', 'Disease', 'MESH:D015179', (171, 188))	('prostate cancer', 'Disease', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('EC', 'Phenotype', 'HP:0011459', (63, 65))	('miR-93-5p', 'Var', (29, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))
888790	33448310	Studies have reported that tje knockdown of miR-93-5p inhibits cell proliferation, migration and invasion in gastric cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('miR-93-5p', 'Var', (44, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('cell proliferation', 'CPA', (63, 81))	('inhibits', 'NegReg', (54, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('invasion', 'CPA', (97, 105))	('migration', 'CPA', (83, 92))
888792	33448310	It has been demonstrated that TGFbetaR2 is the major target of miR-93-5p in nasopharyngeal carcinoma invasion.	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (76, 100))	('miR-93-5p', 'Var', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('TGFbetaR2', 'Gene', (30, 39))	('carcinoma invasion', 'Disease', 'MESH:D009361', (91, 109))	('carcinoma invasion', 'Disease', (91, 109))
888914	28979713	Additionally, in early-stage esophageal cancer, cryotherapy has been shown to eliminate mucosal cancer in 75%, including as rescue therapy in patients who have failed other modalities.	('mucosal cancer', 'Disease', 'MESH:D009062', (88, 102))	('cryotherapy', 'Var', (48, 59))	('mucosal cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('esophageal cancer', 'Disease', (29, 46))	('eliminate', 'NegReg', (78, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (29, 46))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
888933	24065387	Rad51 expression affects both chemo- and radiosensitivity in many cancers; however, its role in ESCC is unclear.	('radiosensitivity', 'CPA', (41, 57))	('Rad51', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('affects', 'Reg', (17, 24))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('ESCC', 'Disease', (96, 100))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('expression', 'Var', (6, 16))
888943	24065387	NACRT for esophageal cancer may also increase the risk of perioperative complications.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('esophageal cancer', 'Disease', (10, 27))	('esophageal cancer', 'Disease', 'MESH:D004938', (10, 27))	('NACRT', 'Var', (0, 5))	('NACRT', 'Chemical', '-', (0, 5))
888945	24065387	One predictive factor for chemoradiotherapy response in a variety of human cancers is Rad51.	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('Rad51', 'Var', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
888977	24065387	Overexpression of Rad51 has been observed in several cancers and may be involved in either the initiation or the progression of tumorigenesis.	('Rad51', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('observed', 'Reg', (33, 41))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('involved', 'Reg', (72, 80))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (128, 133))
888979	24065387	Overexpression of Rad51 has been reported to correlate with histological grading of sporadic invasive ductal breast cancer, and is more frequently observed in advanced prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (168, 183))	('Rad51', 'Gene', (18, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('prostate cancer', 'Disease', (168, 183))	('observed', 'Reg', (147, 155))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
888981	24065387	In this study, high expression of Rad51 was associated with lymph node metastases in cases of esophageal cancer in which the patients had not undergone NACRT.	('patients', 'Species', '9606', (125, 133))	('high expression', 'Var', (15, 30))	('metastases', 'Disease', (71, 81))	('esophageal cancer', 'Disease', (94, 111))	('NACRT', 'Chemical', '-', (152, 157))	('associated with', 'Reg', (44, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('metastases', 'Disease', 'MESH:D009362', (71, 81))	('Rad51', 'Gene', (34, 39))
888988	24065387	In our study, some population bias was observed between the groups with and without NACRT; the NACRT group included more advanced cases of ESCC than the group without NACRT.	('NACRT', 'Chemical', '-', (95, 100))	('NACRT', 'Chemical', '-', (84, 89))	('NACRT', 'Var', (95, 100))	('NACRT', 'Chemical', '-', (167, 172))	('ESCC', 'Disease', (139, 143))
889002	24065387	Radiation and CDDP inhibits cellular growth by inducing DNA DSBs.	('DNA DSBs', 'Disease', (56, 64))	('CDDP', 'Chemical', 'MESH:D002945', (14, 18))	('Radiation', 'Disease', (0, 9))	('DSBs', 'Chemical', '-', (60, 64))	('CDDP', 'Var', (14, 18))	('cellular growth', 'CPA', (28, 43))	('inhibits', 'NegReg', (19, 27))	('inducing', 'Reg', (47, 55))	('Radiation', 'Disease', 'MESH:D004194', (0, 9))
889007	24065387	On the other hand, 5-FU, an antimetabolic drug, exerts its antitumor effects through suppression of both DNA and RNA synthesis, pathways separate from CDDP or radiation.	('tumor', 'Disease', (63, 68))	('CDDP', 'Chemical', 'MESH:D002945', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('5-FU', 'Var', (19, 23))	('suppression', 'NegReg', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('5-FU', 'Chemical', 'MESH:D005472', (19, 23))
889042	24324347	The rate of cancer detection using DWIBS is superior to that using FDG-PET.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('DWIBS', 'Var', (35, 40))	('DWIBS', 'Chemical', '-', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
889075	23249675	The tumor length adversely affected OS, with the 5-year rate being 93.5%, 82.0%, 68.6%, 67.9%, 55.3% and 41.1%, respectively for tumor lengths of less than 10 mm, 10 to 20 mm, 20 to 30 mm, 30 to 40 mm, 40 to 50 mm, and greater than 50 mm (P< 0.001).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('OS', 'Chemical', '-', (36, 38))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (129, 134))	('less than 10 mm', 'Var', (146, 161))
889204	32681567	In multivariate analysis, cNLR at week 4(P = .026) and week 5(P = .025) during radiotherapy were significantly associated with OS, along with BMI, tumor stage, tumor length, tumor location, and grade of adverse events.	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('BMI', 'Disease', (142, 145))	('tumor', 'Disease', (147, 152))	('cNLR', 'Var', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('associated with', 'Reg', (111, 126))	('tumor', 'Disease', (160, 165))
889253	32681567	Additionally, patients who received CCRT had a higher BMI than patients who received RT alone (P = .044).	('higher', 'PosReg', (47, 53))	('BMI', 'MPA', (54, 57))	('patients', 'Species', '9606', (63, 71))	('patients', 'Species', '9606', (14, 22))	('CCRT', 'Var', (36, 40))
889282	32681567	42 ,  43  Previous studies have suggested that baseline LMR, another indicator of inflammation and immune status, is a prognostic factor in nasopharyngeal carcinoma, 44  gastric cancer, 45  and hepatocellular carcinoma.	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (140, 164))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('LMR', 'Var', (56, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('carcinoma', 'Disease', 'MESH:D009369', (209, 218))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (194, 218))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('carcinoma', 'Disease', (155, 164))	('hepatocellular carcinoma', 'Disease', (194, 218))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (194, 218))	('carcinoma', 'Disease', 'MESH:D009369', (155, 164))	('inflammation', 'Disease', (82, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('gastric cancer', 'Disease', (170, 184))	('carcinoma', 'Disease', (209, 218))
889286	32681567	This may be due to several reasons: (a) the removal of tumor cells by chemotherapy leads to a stronger inflammatory response; and (b) chemotherapy has a certain radiosensitization effect, leading to an increased inflammatory response.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('increased', 'PosReg', (202, 211))	('inflammatory response', 'CPA', (103, 124))	('increased inflammatory response', 'Phenotype', 'HP:0012649', (202, 233))	('chemotherapy', 'Var', (134, 146))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('inflammatory response', 'CPA', (212, 233))	('stronger', 'PosReg', (94, 102))
889304	32855364	The KM plotter revealed high KIAA0101 expression to be associated with worse overall survival in HCC (HR=2.09, p=4.1e-05); this prognostic power was stronger for male than female, early-stage than advanced-stage, and Asian than Caucasian patients.	('HCC', 'Disease', (97, 100))	('KIAA0101', 'Gene', '9768', (29, 37))	('HCC', 'Phenotype', 'HP:0001402', (97, 100))	('expression', 'MPA', (38, 48))	('KIAA0101', 'Gene', (29, 37))	('overall survival', 'MPA', (77, 93))	('high', 'Var', (24, 28))	('stronger', 'Reg', (149, 157))	('worse', 'NegReg', (71, 76))	('patients', 'Species', '9606', (238, 246))
889308	32855364	Alternative splicing analysis indicated higher expression of variant 1 and variant 2 in HCC and no significant differences in exon usage of KIAA0101 between cancer and normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('higher', 'PosReg', (40, 46))	('KIAA0101', 'Gene', (140, 148))	('variant', 'Var', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('KIAA0101', 'Gene', '9768', (140, 148))	('HCC', 'Phenotype', 'HP:0001402', (88, 91))	('cancer', 'Disease', (157, 163))	('expression', 'MPA', (47, 57))
889325	32855364	The CCLE database offers a large dataset of gene expression and copy number variation (CNV) in cancer cell lines.	('copy number variation', 'Var', (64, 85))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('CCLE', 'Chemical', '-', (4, 8))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
889328	32855364	The copy number of KIAA0101 approximately correlated positively with KIAA0101 expression, but the strength of the correlation varied in different cancer cell lines (Figure 1C and 1D).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('expression', 'MPA', (78, 88))	('positively', 'PosReg', (53, 63))	('KIAA0101', 'Gene', '9768', (19, 27))	('KIAA0101', 'Gene', (69, 77))	('KIAA0101', 'Gene', '9768', (69, 77))	('copy number', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('KIAA0101', 'Gene', (19, 27))
889343	32855364	According to the Chen liver dataset, HCV-positive HCC had the highest level of KIAA0101, followed by HBV-positive HCC and no-value samples (Figure 3E).	('HCC', 'Phenotype', 'HP:0001402', (114, 117))	('KIAA0101', 'Gene', (79, 87))	('HCC', 'Phenotype', 'HP:0001402', (50, 53))	('KIAA0101', 'Gene', '9768', (79, 87))	('HCV-positive', 'Var', (37, 49))	('HCV', 'Species', '11103', (37, 40))
889351	32855364	Patients with higher mRNA KIAA0101 expression had shorter OS than those with lower expression in both early (HR=2.34 p=0.00074) (Figure 4D) and advanced (HR=1.93, p=0.031) (Figure 4E) stages.	('KIAA0101', 'Gene', (26, 34))	('KIAA0101', 'Gene', '9768', (26, 34))	('expression', 'MPA', (35, 45))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (50, 57))	('mRNA', 'Var', (21, 25))	('higher', 'PosReg', (14, 20))
889352	32855364	Additionally, the prognostic effect of high mRNA expression of KIAA0101 tended to be stronger for early-stage HCC patients.	('HCC', 'Phenotype', 'HP:0001402', (110, 113))	('high', 'Var', (39, 43))	('KIAA0101', 'Gene', (63, 71))	('stronger', 'PosReg', (85, 93))	('KIAA0101', 'Gene', '9768', (63, 71))	('patients', 'Species', '9606', (114, 122))	('early-stage HCC', 'Disease', (98, 113))
889391	32855364	For example, the OS of patients harboring high KIAA0101 mRNA expression was significantly reduced, which was consistent with the conclusion of previous studies.	('mRNA expression', 'MPA', (56, 71))	('reduced', 'NegReg', (90, 97))	('patients', 'Species', '9606', (23, 31))	('KIAA0101', 'Gene', '9768', (47, 55))	('high', 'Var', (42, 46))	('KIAA0101', 'Gene', (47, 55))
889393	32855364	Regarding tumor stage, a study conducted by Yuan et al reported that HCC patients with KIAA0101 overexpression were two times more likely to have advanced-stage disease than those with normal expression, as confirmed in Abdelgawad's study.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('overexpression', 'Var', (96, 110))	('HCC', 'Phenotype', 'HP:0001402', (69, 72))	('tumor', 'Disease', (10, 15))	('advanced-stage disease', 'CPA', (146, 168))	('KIAA0101', 'Gene', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('patients', 'Species', '9606', (73, 81))	('KIAA0101', 'Gene', '9768', (87, 95))
889411	32855364	NS5A encodes a 477-aa phosphoprotein harboring differently phosphorylated forms of 56 and 58 kDa in size with modified serine residues, which is likely to have interaction with various cellular proteins and involved in modulation of cellular signaling pathways, cell growth and pathogenesis of HCV.	('cellular signaling pathways', 'Pathway', (233, 260))	('serine', 'Chemical', 'MESH:D012694', (119, 125))	('HCV', 'Disease', (294, 297))	('modulation', 'Reg', (219, 229))	('cellular', 'Protein', (185, 193))	('involved', 'Reg', (207, 215))	('interaction', 'Interaction', (160, 171))	('serine', 'Protein', (119, 125))	('modified', 'Var', (110, 118))	('NS5A', 'Gene', (0, 4))	('HCV', 'Species', '11103', (294, 297))
889416	32855364	Nevertheless, opposite findings were reported by Wang Q et al, who revealed that overexpression of NS5ATP9 suppressed Bel7402 cell proliferation, while RNAi-mediated knockdown of NS5ATP9 enhanced HepG2 cell growth.	('knockdown', 'Var', (166, 175))	('NS5ATP9', 'Gene', (99, 106))	('Bel7402', 'CellLine', 'CVCL:5492', (118, 125))	('suppressed', 'NegReg', (107, 117))	('enhanced', 'PosReg', (187, 195))	('HepG2', 'CellLine', 'CVCL:0027', (196, 201))	('HepG2 cell growth', 'CPA', (196, 213))	('Bel7402', 'MPA', (118, 125))
889417	32855364	In cases of HCV NS5A expression, suppressed proliferation of HepG2 cells may be reversed by RNAi-mediated targeting of NS5ATP9, indicating that NS5ATP9 might function as an anti-proliferative gene to be involved in inhibiting HCV NS5A-mediated cell growth through the MEK/ERK signaling pathway.	('HCV', 'Species', '11103', (226, 229))	('ERK', 'Gene', '5594', (272, 275))	('HepG2', 'CellLine', 'CVCL:0027', (61, 66))	('MEK', 'Gene', (268, 271))	('HCV', 'Species', '11103', (12, 15))	('MEK', 'Gene', '5609', (268, 271))	('NS5A', 'Gene', (16, 20))	('NS5ATP9', 'Var', (144, 151))	('ERK', 'Gene', (272, 275))	('inhibiting', 'NegReg', (215, 225))
889431	32855364	On the contrary, the conversion of endogenous LC3-I to LC3-II was not increased by NS5A in HepG2 cells after NS5ATP9 silencing.	('LC3', 'Gene', '84557', (55, 58))	('silencing', 'Var', (117, 126))	('HepG2', 'CellLine', 'CVCL:0027', (91, 96))	('LC3', 'Gene', (55, 58))	('LC3', 'Gene', '84557', (46, 49))	('LC3', 'Gene', (46, 49))
889438	32855364	It has been reported that variant 1 of KIAA0101 is overexpressed in HCC tissue but that variant 2-encoded proteins are upregulated in adjacent tissues.	('upregulated', 'PosReg', (119, 130))	('KIAA0101', 'Gene', '9768', (39, 47))	('proteins', 'Protein', (106, 114))	('variant', 'Var', (26, 33))	('overexpressed', 'PosReg', (51, 64))	('HCC', 'Phenotype', 'HP:0001402', (68, 71))	('KIAA0101', 'Gene', (39, 47))
889472	32489659	Additionally, risk factors such as; smoking, alcohol abuse, obesity, gastroesophageal reflux disease, viral infection, poverty, esophageal achalasia and genetic and epigenetic factors contribute chiefly to the onset of EC.	('contribute', 'Reg', (184, 194))	('EC', 'Disease', 'MESH:D005955', (219, 221))	('alcohol abuse', 'Disease', (45, 58))	('obesity', 'Disease', 'MESH:D009765', (60, 67))	('achalasia', 'Disease', (139, 148))	('viral infection', 'Disease', 'MESH:D001102', (102, 117))	('viral infection', 'Disease', (102, 117))	('achalasia', 'Disease', 'MESH:D004931', (139, 148))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (69, 100))	('obesity', 'Disease', (60, 67))	('alcohol abuse', 'Disease', 'MESH:D000437', (45, 58))	('achalasia', 'Phenotype', 'HP:0002571', (139, 148))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (69, 92))	('alcohol abuse', 'Phenotype', 'HP:0030955', (45, 58))	('obesity', 'Phenotype', 'HP:0001513', (60, 67))	('epigenetic factors', 'Var', (165, 183))	('poverty', 'Disease', (119, 126))	('gastroesophageal reflux disease', 'Disease', (69, 100))
889491	32489659	Interestingly single nucleotide polymorphism of IL-10 (-819 T/T) is associated with greater incidence of PP and decreased levels of postoperative IL-10.	('IL-10', 'Gene', '3586', (48, 53))	('single nucleotide polymorphism', 'Var', (14, 44))	('-819 T/T', 'Var', (55, 63))	('IL-10', 'Gene', '3586', (146, 151))	('IL-10', 'Gene', (48, 53))	('decreased', 'NegReg', (112, 121))	('IL-10', 'Gene', (146, 151))
889493	32489659	Geriatric patients presenting malnutrition and reduced skeletal muscle mass (measured by psoas muscle index) have higher risk of acquiring PP, and may reduce overall survival rate.	('reduced skeletal muscle mass', 'Phenotype', 'HP:0003199', (47, 75))	('malnutrition', 'Var', (30, 42))	('malnutrition', 'Phenotype', 'HP:0004395', (30, 42))	('reduce', 'NegReg', (151, 157))	('patients', 'Species', '9606', (10, 18))	('reduced', 'NegReg', (47, 54))	('skeletal muscle mass', 'CPA', (55, 75))
889524	32489659	Surgical trauma like stretch, compression or thermal shock to laryngeal nerve can lead to nerve palsy relatively up to 60%.	('lead to', 'Reg', (82, 89))	('palsy', 'Disease', (96, 101))	('shock', 'Phenotype', 'HP:0031273', (53, 58))	('trauma', 'Disease', (9, 15))	('palsy', 'Disease', 'MESH:D010243', (96, 101))	('nerve', 'Disease', (90, 95))	('trauma', 'Disease', 'MESH:D014947', (9, 15))	('thermal shock', 'Var', (45, 58))
889540	32489659	A survey of practice pattern by thoracic surgeon reported that chemoprophylaxis with low-dose unfractionated heparin or low-molecular-weight heparin before esophagectomy is essential for DVT.	('heparin', 'Chemical', 'MESH:D006493', (109, 116))	('DVT', 'Disease', (187, 190))	('heparin', 'Chemical', 'MESH:D006493', (141, 148))	('DVT', 'Disease', 'OMIM:612862', (187, 190))	('low-molecular-weight', 'Var', (120, 140))	('DVT', 'Phenotype', 'HP:0002625', (187, 190))
889545	32489659	However, transthoracic approach in advanced-age patients with the history of cardiopulmonary diseases increases the risk of the development of AF, adding to days of hospitalization and other complications.	('AF', 'Disease', 'MESH:D001281', (143, 145))	('cardiopulmonary diseases increases', 'Disease', 'MESH:D006323', (77, 111))	('adding', 'Reg', (147, 153))	('cardiopulmonary diseases increases', 'Disease', (77, 111))	('AF', 'Phenotype', 'HP:0005110', (143, 145))	('patients', 'Species', '9606', (48, 56))	('transthoracic', 'Var', (9, 22))	('days', 'MPA', (157, 161))
889547	32489659	Preoperative usage of calcium channel blockers, angiotensin converting enzyme inhibitors and blockers of angiotensin receptor can reduce the risk of AF, leading to decrease in overall survival rate and subsequent mortality.	('AF', 'Phenotype', 'HP:0005110', (149, 151))	('reduce', 'NegReg', (130, 136))	('blockers', 'Var', (93, 101))	('calcium', 'Chemical', 'MESH:D002118', (22, 29))	('mortality', 'Disease', 'MESH:D003643', (213, 222))	('AF', 'Disease', 'MESH:D001281', (149, 151))	('decrease', 'NegReg', (164, 172))	('angiotensin converting enzyme', 'Gene', (48, 77))	('overall survival rate', 'CPA', (176, 197))	('angiotensin', 'Protein', (105, 116))	('mortality', 'Disease', (213, 222))	('angiotensin converting enzyme', 'Gene', '1636', (48, 77))
889554	32489659	Emergency esophagectomy in response to perforation of esophagus followed by chemoradiotherapy is also characterized with the increased incidence of acute renal failure.	('renal failure', 'Phenotype', 'HP:0000083', (154, 167))	('acute renal failure', 'Phenotype', 'HP:0001919', (148, 167))	('acute renal failure', 'Disease', (148, 167))	('perforation', 'Var', (39, 50))	('acute renal failure', 'Disease', 'MESH:D058186', (148, 167))	('Emergency esophagectomy', 'Disease', (0, 23))
889568	30934003	Investigation of somatic single nucleotide variations in human endogenous retrovirus elements and their potential association with cancer Human endogenous retroviruses (HERVs) have been investigated for potential links with human cancer.	('cancer', 'Disease', (131, 137))	('human endogenous retrovirus', 'Species', '11827', (57, 84))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('HERVs', 'Species', '206037', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('links', 'Interaction', (213, 218))	('single nucleotide variations', 'Var', (25, 53))	('human', 'Species', '9606', (224, 229))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('Human endogenous retroviruses', 'Species', '206037', (138, 167))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('human', 'Species', '9606', (57, 62))
889573	30934003	In an effort to identify mutations that effect survival, all nsSNVs were further evaluated and it was found that kidney cancer patients with mutation C2270G in ZNF99 have a significantly lower survival rate (hazard ratio = 2.6) compared to those without it.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('kidney cancer', 'Phenotype', 'HP:0009726', (113, 126))	('C2270G', 'Mutation', 'rs774052255', (150, 156))	('survival', 'MPA', (193, 201))	('kidney cancer', 'Disease', (113, 126))	('ZNF99', 'Gene', (160, 165))	('ZNF99', 'Gene', '7652', (160, 165))	('patients', 'Species', '9606', (127, 135))	('lower', 'NegReg', (187, 192))	('kidney cancer', 'Disease', 'MESH:D007680', (113, 126))	('C2270G', 'Var', (150, 156))
889577	30934003	This study provides a list of mutational hotspots in HERVs, which could potentially be used as biomarkers and therapeutic targets.	('mutational', 'Var', (30, 40))	('HERVs', 'Species', '206037', (53, 58))	('HERVs', 'Gene', (53, 58))
889579	30934003	Over the course of time, most ERVs in the human genome have been severely damaged in their original genetic structure due to the accumulation of mutations, insertions, deletions and translocations that have spliced out the original coding region of proviral genes between two flanking LTRs.	('ERVs', 'Gene', (30, 34))	('human', 'Species', '9606', (42, 47))	('mutations', 'Var', (145, 154))	('damaged', 'NegReg', (74, 81))	('deletions', 'Var', (168, 177))	('insertions', 'Var', (156, 166))	('translocations', 'Var', (182, 196))
889594	30934003	For example, a mutation found in a HERV LTR leads to the activation of syncytin-1 encoded by HERV-W Env with high expression in bladder carcinoma.	('mutation', 'Var', (15, 23))	('HERV-W', 'Species', '87786', (93, 99))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (128, 145))	('activation', 'PosReg', (57, 67))	('bladder carcinoma', 'Disease', 'MESH:D001749', (128, 145))	('Env', 'Gene', (100, 103))	('bladder carcinoma', 'Disease', (128, 145))	('syncytin-1', 'Gene', '30816', (71, 81))	('syncytin-1', 'Gene', (71, 81))	('expression', 'MPA', (114, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('HERV', 'Species', '11827', (93, 97))	('HERV', 'Species', '11827', (35, 39))	('Env', 'Gene', '30816', (100, 103))
889595	30934003	It has been proposed that somatic mutations are associated with aberrant activation of stem cell-associated retroviruses (SCAR) and with stem cell-like phenotypes of cancer cells, clinical intractability of human malignancies, and increased likelihood of therapy failure and death from cancer.	('SCAR', 'Phenotype', 'HP:0100699', (122, 126))	('activation', 'PosReg', (73, 83))	('cancer', 'Disease', (166, 172))	('SCAR', 'Gene', (122, 126))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('malignancies', 'Disease', 'MESH:D009369', (213, 225))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('failure', 'Disease', 'MESH:D017093', (263, 270))	('malignancies', 'Disease', (213, 225))	('death', 'Disease', 'MESH:D003643', (275, 280))	('death', 'Disease', (275, 280))	('SCAR', 'Gene', '6191', (122, 126))	('human', 'Species', '9606', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('failure', 'Disease', (263, 270))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', (286, 292))
889597	30934003	In this study, we have analyzed such datasets to explore pan-cancer mutations in HERV elements.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('HERV', 'Species', '11827', (81, 85))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (68, 77))	('HERV elements', 'Protein', (81, 94))
889598	30934003	Although, it has been shown in several studies that such pan-cancer analysis can help identify patterns of driver mutations, to the best of our knowledge no such study has been performed on HERV elements.	('HERV', 'Species', '11827', (190, 194))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (114, 123))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
889599	30934003	This study explores correlations between HERV elements and cancers by identifying somatic mutation hotspots in the human genome, followed by a detailed review of functional annotations available for these genomic regions.	('mutation', 'Var', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('HERV', 'Species', '11827', (41, 45))	('human', 'Species', '9606', (115, 120))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))
889638	30934003	Of these 167,561 mutations, 135,032, or 80.8% were found within HERV Gamma-retrovirus/Epsilon-retrovirus-related (GE) retroviruses.	('HERV Gamma-retrovirus/Epsilon-retrovirus-related', 'Protein', (64, 112))	('HERV', 'Species', '11827', (64, 68))	('mutations', 'Var', (17, 26))
889656	30934003	The relationship between nsSNVs in the protein coding region HERV elements and multiple cancer types is shown in Fig 2.	('multiple cancer', 'Disease', 'MESH:D009369', (79, 94))	('HERV', 'Species', '11827', (61, 65))	('nsSNVs in', 'Var', (25, 34))	('HERV elements', 'Gene', (61, 74))	('multiple cancer', 'Disease', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
889657	30934003	It can be seen from Table 2 that 81.3% of the nsSNVs are from Gamma-retrovirus/Epsilon-retrovirus-related (GE) non-canonical HERV elements (HERV-W/LTR17/HERV17, HERV-9/LTR12 and HERV-IP10F/LTR10F).	('HERV', 'Species', '11827', (161, 165))	('HERV-W/LTR17/HERV17', 'Var', (140, 159))	('HERV', 'Species', '11827', (140, 144))	('HERV-W', 'Species', '87786', (140, 146))	('HERV', 'Species', '11827', (178, 182))	('HERV', 'Species', '11827', (125, 129))	('HERV-IP10F/LTR10F', 'Var', (178, 195))	('HERV', 'Species', '11827', (153, 157))	('HERV-9/LTR12', 'Var', (161, 173))
889659	30934003	The top three cancer types:skin cancer, lung cancer, and colon cancer:are associated with mutated sites in HERV-W/LTR17/HERV17.	('HERV-W/LTR17/HERV17', 'Gene', (107, 126))	('skin cancer', 'Disease', (27, 38))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('HERV-W', 'Species', '87786', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('mutated sites', 'Var', (90, 103))	('HERV', 'Species', '11827', (120, 124))	('cancer', 'Disease', (32, 38))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('skin cancer', 'Phenotype', 'HP:0008069', (27, 38))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (63, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('skin cancer', 'Disease', 'MESH:D012878', (27, 38))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('HERV', 'Species', '11827', (107, 111))	('colon cancer', 'Disease', (57, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('lung cancer', 'Disease', (40, 51))	('associated', 'Reg', (74, 84))
889660	30934003	The proportion of mutations in HERV-W/LTR17/HERV17 was 50.6% (249/492).	('HERV', 'Species', '11827', (44, 48))	('HERV', 'Species', '11827', (31, 35))	('HERV-W', 'Species', '87786', (31, 37))	('HERV-W/LTR17/HERV17', 'Gene', (31, 50))	('mutations', 'Var', (18, 27))
889662	30934003	The proportion of mutations in (MaLR/MST) was 18.7% (92/492).	('MST', 'Disease', (37, 40))	('MST', 'Disease', 'MESH:C563551', (37, 40))	('mutations', 'Var', (18, 27))
889663	30934003	This set of MaLR/MST mutations is found in many cancer types including skin cancer, thyroid cancer, and lung cancer.	('skin cancer', 'Disease', 'MESH:D012878', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('MST', 'Disease', 'MESH:C563551', (17, 20))	('cancer', 'Disease', (48, 54))	('found', 'Reg', (34, 39))	('thyroid cancer', 'Disease', 'MESH:D013964', (84, 98))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('thyroid cancer', 'Phenotype', 'HP:0002890', (84, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('skin cancer', 'Disease', (71, 82))	('MST', 'Disease', (17, 20))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('skin cancer', 'Phenotype', 'HP:0008069', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (76, 82))	('mutations', 'Var', (21, 30))	('thyroid cancer', 'Disease', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('lung cancer', 'Disease', (104, 115))
889664	30934003	SNVs in the human chromosomal non-coding region of HERV elements could also lead to carcinogenesis if they impact regulatory regions or protein binding sites.	('carcinogenesis', 'Disease', (84, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))	('regulatory regions', 'MPA', (114, 132))	('HERV', 'Species', '11827', (51, 55))	('HERV', 'Gene', (51, 55))	('impact', 'Reg', (107, 113))	('human', 'Species', '9606', (12, 17))	('protein', 'Protein', (136, 143))	('SNVs', 'Var', (0, 4))	('lead to', 'Reg', (76, 83))
889670	30934003	Fig 3 shows the distribution of SNVs in 357 canonical and 431 non-canonical HERV elements that map to protein non-coding regions.	('HERV', 'Species', '11827', (76, 80))	('HERV elements', 'Protein', (76, 89))	('SNVs', 'Var', (32, 36))
889673	30934003	HML-3/HERV-K9I/MER9 is the most affected non-canonical Alpha-retrovirus/Beta-retrovirus-related (AB) HERVs.	('HERV-K', 'Species', '45617', (6, 12))	('HERVs', 'Species', '206037', (101, 106))	('affected', 'Reg', (32, 40))	('HML-3/HERV-K9I/MER9', 'Var', (0, 19))
889686	30934003	In the gene TNN, cancer-associated nsSNVs within HERV elements were found to likely impact amino acid post-translational modification (PTM) sites that led to phosphorylation gain or loss.	('nsSNVs', 'Var', (35, 41))	('impact', 'Reg', (84, 90))	('loss', 'NegReg', (182, 186))	('TNN', 'Gene', '63923', (12, 15))	('phosphorylation', 'MPA', (158, 173))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('HERV', 'Species', '11827', (49, 53))	('cancer', 'Disease', (17, 23))	('TNN', 'Gene', (12, 15))	('gain', 'Disease', (174, 178))	('gain', 'Disease', 'MESH:D015430', (174, 178))	('amino acid post-translational modification', 'MPA', (91, 133))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
889687	30934003	In KIR2DL1, mutations were found to likely impact multiple functions such as phosphorylation, glycosylation, and ligand binding site.	('glycosylation', 'MPA', (94, 107))	('phosphorylation', 'MPA', (77, 92))	('ligand', 'MPA', (113, 119))	('impact', 'Reg', (43, 49))	('KIR2DL1', 'Gene', '3802', (3, 10))	('mutations', 'Var', (12, 21))	('KIR2DL1', 'Gene', (3, 10))
889694	30934003	After extracting metadata and clinical data for patients for these 22 nsSNVs, we found one SNV in ZNF99 to be associated closely with patient survival rate, as shown in Fig 5.	('SNV', 'Var', (91, 94))	('patient survival rate', 'CPA', (134, 155))	('associated', 'Reg', (110, 120))	('patient', 'Species', '9606', (48, 55))	('ZNF99', 'Gene', (98, 103))	('ZNF99', 'Gene', '7652', (98, 103))	('patients', 'Species', '9606', (48, 56))	('patient', 'Species', '9606', (134, 141))
889695	30934003	As shown in Fig 5, patients with this nsSNV in ZNF99 at amino acid position 757 (A to G modification) have a lower survival rate than the patients without this variation.	('lower', 'NegReg', (109, 114))	('patients', 'Species', '9606', (19, 27))	('nsSNV', 'Var', (38, 43))	('survival', 'MPA', (115, 123))	('ZNF99', 'Gene', (47, 52))	('ZNF99', 'Gene', '7652', (47, 52))	('patients', 'Species', '9606', (138, 146))
889697	30934003	Additionally, the kidney cancer patients with this key mutation in ZNF99 have a significant decrease in survival rate (Hazard ratio = 2.642; p = 0.05).	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('decrease', 'NegReg', (92, 100))	('kidney cancer', 'Phenotype', 'HP:0009726', (18, 31))	('kidney cancer', 'Disease', 'MESH:D007680', (18, 31))	('kidney cancer', 'Disease', (18, 31))	('survival rate', 'CPA', (104, 117))	('ZNF99', 'Gene', (67, 72))	('ZNF99', 'Gene', '7652', (67, 72))	('mutation', 'Var', (55, 63))
889700	30934003	We found that 62,575 variants occur in both HERV elements and in at least one DNA functional element (Fig 6).	('variants', 'Var', (21, 29))	('occur', 'Reg', (30, 35))	('HERV elements', 'Protein', (44, 57))	('HERV', 'Species', '11827', (44, 48))
889704	30934003	Fig 7 shows that, HERV mutations in lncRNAs are found in multiple cancers, especially, skin and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('lncRNAs', 'Gene', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('multiple cancers', 'Disease', (57, 73))	('mutations', 'Var', (23, 32))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('HERV', 'Species', '11827', (18, 22))	('found', 'Reg', (48, 53))	('HERV', 'Gene', (18, 22))	('multiple cancers', 'Disease', 'MESH:D009369', (57, 73))	('skin', 'Disease', (87, 91))
889705	30934003	Additionally, HERV mutation hotspots in introns are from at least 10 cancer types.	('mutation', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('HERV', 'Species', '11827', (14, 18))	('HERV', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
889706	30934003	HERV mutations in TFBS is primarily found in skin cancer and breast cancer; especially, the non-canonical Gamma-retrovirus/Epsilon-retrovirus-related (GE) HERV in the TFBS.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('skin cancer', 'Phenotype', 'HP:0008069', (45, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('HERV', 'Species', '11827', (0, 4))	('skin cancer', 'Disease', (45, 56))	('found', 'Reg', (36, 41))	('mutations', 'Var', (5, 14))	('TFBS', 'Chemical', '-', (167, 171))	('HERV', 'Gene', (0, 4))	('TFBS', 'Gene', (18, 22))	('skin cancer', 'Disease', 'MESH:D012878', (45, 56))	('HERV', 'Species', '11827', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('TFBS', 'Chemical', '-', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
889712	30934003	have suggested that the mutation hotspot located on the 3'-LTR of HERV-W element may have a regulatory role and might be involved in the activation of neighboring genes and its abnormal expression.	('HERV-W element', 'Gene', (66, 80))	('regulatory role', 'MPA', (92, 107))	('involved', 'Reg', (121, 129))	('activation', 'PosReg', (137, 147))	('mutation', 'Var', (24, 32))	('expression', 'MPA', (186, 196))	('HERV-W', 'Species', '87786', (66, 72))
889721	30934003	Importantly, patients with the alteration of amino acid position 757 (A to G modification) in ZNF99 have a lower survival rate than the patients without this variation as shown in Fig 5.	('alteration of amino acid position 757', 'Var', (31, 68))	('ZNF99', 'Gene', (94, 99))	('ZNF99', 'Gene', '7652', (94, 99))	('patients', 'Species', '9606', (13, 21))	('lower', 'NegReg', (107, 112))	('survival', 'MPA', (113, 121))	('patients', 'Species', '9606', (136, 144))
889722	30934003	Overall, our data indicated over-representative SNVs (hotspots) strengthen the relationship between these four possible HERV-involved genes and multiple cancer types.	('SNVs', 'Var', (48, 52))	('multiple cancer', 'Disease', (144, 159))	('HERV', 'Species', '11827', (120, 124))	('strengthen', 'PosReg', (64, 74))	('HERV-involved genes', 'Gene', (120, 139))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('multiple cancer', 'Disease', 'MESH:D009369', (144, 159))	('relationship', 'Interaction', (79, 91))
889728	30934003	Further research supports DNA functional elements such as lncRNAs could be involved in carcinogenesis because mutations are located in the DNA functional region.	('mutations', 'Var', (110, 119))	('carcinogenesis', 'Disease', (87, 101))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))
889733	30934003	This was the first report that an intronic mutation was related to the development of cancer.	('intronic mutation', 'Var', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('related', 'Reg', (56, 63))	('cancer', 'Disease', (86, 92))
889734	30934003	Moreover, copy number variants of the TFBS which is involved in a proliferation effector-gene and an apoptosis effector-gene are highly associated with melanoma and breast cancer.	('associated', 'Reg', (136, 146))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('copy number variants', 'Var', (10, 30))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('TFBS', 'Gene', (38, 42))	('TFBS', 'Chemical', '-', (38, 42))
889740	30934003	This study has identified mutational hotspots in HERVs and attempts to rank HERVs which might be associated with cancer.	('HERVs', 'Species', '206037', (49, 54))	('HERVs', 'Gene', (49, 54))	('HERVs', 'Species', '206037', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('mutational', 'Var', (26, 36))	('associated', 'Reg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
889741	30934003	Although, survival analysis is performed with one mutation, it is clear that there can be other mutations in HERVs which can have a profound impact on cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('HERVs', 'Gene', (109, 114))	('impact', 'Reg', (141, 147))	('HERVs', 'Species', '206037', (109, 114))	('mutations', 'Var', (96, 105))
889746	30934003	We showed that kidney cancer patients with the specific amino acid mutation A757G in ZNF99 within the HERV-W/LTR17/HERV17 element had a lower survival rate based on a survival analysis.	('survival', 'MPA', (142, 150))	('lower', 'NegReg', (136, 141))	('patients', 'Species', '9606', (29, 37))	('ZNF99', 'Gene', '7652', (85, 90))	('HERV', 'Species', '11827', (102, 106))	('HERV-W', 'Species', '87786', (102, 108))	('A757G', 'Mutation', 'rs760712933', (76, 81))	('kidney cancer', 'Phenotype', 'HP:0009726', (15, 28))	('A757G', 'Var', (76, 81))	('kidney cancer', 'Disease', 'MESH:D007680', (15, 28))	('ZNF99', 'Gene', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('HERV', 'Species', '11827', (115, 119))	('kidney cancer', 'Disease', (15, 28))
889806	30841909	Some of the major steps in desmoplasia are cross-linking of collagens, fiber elongation and fiber realignment, which are associated with poor survival in cancer patients.	('fiber elongation', 'CPA', (71, 87))	('cross-linking', 'Var', (43, 56))	('collagens', 'Protein', (60, 69))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('desmoplasia', 'Disease', 'None', (27, 38))	('patients', 'Species', '9606', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('desmoplasia', 'Disease', (27, 38))
889809	30841909	ECM proteins secreted and modulated by CAFs further recruit other cell types such as immune cells, which promote tumor progression.	('tumor', 'Disease', (113, 118))	('promote', 'PosReg', (105, 112))	('recruit', 'PosReg', (52, 59))	('CAF', 'Gene', (39, 42))	('modulated', 'Var', (26, 35))	('CAF', 'Gene', '8850', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
889813	30841909	In one study, it has been shown that when the stromal content was reduced by deleting the sonic hedgehog protein in a pancreas cancer mouse model, the mice had more aggressive tumors as compared to control mice.	('reduced', 'NegReg', (66, 73))	('pancreas cancer', 'Disease', (118, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('more', 'PosReg', (160, 164))	('mice', 'Species', '10090', (151, 155))	('pancreas cancer', 'Disease', 'MESH:D010190', (118, 133))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('deleting', 'Var', (77, 85))	('mice', 'Species', '10090', (206, 210))	('pancreas cancer', 'Phenotype', 'HP:0002894', (118, 133))	('sonic hedgehog protein', 'Gene', '20423', (90, 112))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('mouse', 'Species', '10090', (134, 139))	('aggressive tumors', 'Disease', 'MESH:D001523', (165, 182))	('sonic hedgehog protein', 'Gene', (90, 112))	('aggressive tumors', 'Disease', (165, 182))
889814	30841909	This was supported by similar findings, showing that the depletion of CAFs in mice led to much more aggressive tumors.	('CAF', 'Gene', '8850', (70, 73))	('depletion', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('aggressive tumors', 'Disease', (100, 117))	('more', 'PosReg', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('CAF', 'Gene', (70, 73))	('mice', 'Species', '10090', (78, 82))	('aggressive tumors', 'Disease', 'MESH:D001523', (100, 117))
889836	30841909	However, a few studies have shown that type II collagen can affect cell behavior and that the type II collagen fragment PIIBNP can inhibit osteoclast survival and induce cell death in tumor cells.	('PIIBNP', 'Var', (120, 126))	('cell behavior', 'CPA', (67, 80))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('inhibit', 'NegReg', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('induce', 'Reg', (163, 169))	('tumor', 'Disease', (184, 189))	('osteoclast survival', 'CPA', (139, 158))	('affect', 'Reg', (60, 66))	('cell death', 'CPA', (170, 180))
889859	30841909	In addition, endotrophin is highly upregulated in cisplatin resistant breast tumor cells, and inhibition of endotrophin lead to cisplatin sensitivity in a breast tumor mouse model.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('breast tumor', 'Disease', (155, 167))	('breast tumor', 'Disease', 'MESH:D001943', (70, 82))	('mouse', 'Species', '10090', (168, 173))	('endotrophin', 'Gene', (13, 24))	('breast tumor', 'Phenotype', 'HP:0100013', (70, 82))	('lead to', 'Reg', (120, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('breast tumor', 'Disease', (70, 82))	('breast tumor', 'Phenotype', 'HP:0100013', (155, 167))	('upregulated', 'PosReg', (35, 46))	('cisplatin sensitivity', 'MPA', (128, 149))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('endotrophin', 'Gene', (108, 119))	('inhibition', 'Var', (94, 104))	('breast tumor', 'Disease', 'MESH:D001943', (155, 167))
889879	30841909	In esophageal cancer a-SMA and FSP-1 positive staining correlates with larger tumor size, advanced T-stage and shorter survival.	('a-SMA', 'Gene', '58', (21, 26))	('positive staining', 'Var', (37, 54))	('esophageal cancer', 'Disease', (3, 20))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('FSP-1', 'Gene', '6275', (31, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('shorter', 'NegReg', (111, 118))	('tumor', 'Disease', (78, 83))	('a-SMA', 'Gene', (21, 26))	('FSP-1', 'Gene', (31, 36))
889893	30841909	Interestingly, the ratio of formation and degradation markers of collagen III has shown to be capable of predicting pancreas patients most likely to respond to the hyaluronan targeting drug PEGPH20 (pegvorhyaluronidase alfa).	('pancreas', 'Disease', (116, 124))	('PEGPH20', 'Var', (190, 197))	('hyaluronan', 'Chemical', 'MESH:D006820', (164, 174))	('respond', 'MPA', (149, 156))	('pancreas', 'Disease', 'MESH:D010190', (116, 124))	('patients', 'Species', '9606', (125, 133))
889922	28902370	Furthermore, enforced Let-7 sensitized the stem cells to chemotherapies in a Wnt pathway inhibition-dependent manner, contributing to Let-7 sensitization of chemotherapeutic response.	('sensitization', 'Reg', (140, 153))	('Let-7', 'Chemical', '-', (22, 27))	('chemotherapeutic', 'CPA', (157, 173))	('Let-7', 'Var', (134, 139))	('Let-7', 'Gene', (22, 27))	('Let-7', 'Chemical', '-', (134, 139))
889978	28902370	Let-7 family of miRNAs includes of Let-7a/b/c/d/e/f/g/I and miRNA-98, and Let-7b was selected as the candidate for its stably inhibitive function after we deeply explored their roles in multiple malignancies.	('Let-7b', 'Gene', (74, 80))	('Let-7', 'Chemical', '-', (35, 40))	('malignancies', 'Disease', 'MESH:D009369', (195, 207))	('Let-7', 'Chemical', '-', (74, 79))	('Let-7a/b/c/d/e/f/g/I', 'Var', (35, 55))	('Let-7b', 'Gene', '406884', (74, 80))	('malignancies', 'Disease', (195, 207))	('Let-7', 'Chemical', '-', (0, 5))
890020	26129866	We observed genome-wide significant associations for rs10074991 in PRKAA1 at 5p13.1 for cardia (p = 2.77x10-12) and noncardia cancers (p = 3.95x10-21) with per allele OR (95% CI) for the combined endpoint of 0.80 (0.77-0.83).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cardia', 'Disease', 'MESH:D004938', (119, 125))	('PRKAA1', 'Gene', (67, 73))	('cardia', 'Disease', 'MESH:D004938', (88, 94))	('cardia', 'Disease', (88, 94))	('noncardia cancers', 'Disease', 'MESH:D009369', (116, 133))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('rs10074991', 'Mutation', 'rs10074991', (53, 63))	('cardia', 'Disease', (119, 125))	('associations', 'Reg', (36, 48))	('noncardia cancers', 'Disease', (116, 133))	('rs10074991', 'Var', (53, 63))
890021	26129866	At 6p21.1, rs2294693 near UNC5CL was significantly associated with gastric noncardia cancer risk (p = 2.50 x10-8), with OR (95% CI) of 1.18 (1.12-1.26), but there was only a nominal association for cardia cancer (p = 1.47x10-2).	('cardia cancer', 'Disease', 'MESH:D004938', (78, 91))	('cardia cancer', 'Disease', 'MESH:D004938', (198, 211))	('rs2294693', 'Mutation', 'rs2294693', (11, 20))	('gastric noncardia cancer', 'Disease', (67, 91))	('associated with', 'Reg', (51, 66))	('rs2294693', 'Var', (11, 20))	('cardia cancer', 'Disease', (198, 211))	('gastric noncardia cancer', 'Disease', 'MESH:D013274', (67, 91))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
890022	26129866	We also confirmed a previously reported association for rs4072037 in MUC1 with p = 6.59x10-8 for total GC and similar estimates for cardia and noncardia cancers.	('rs4072037', 'Var', (56, 65))	('rs4072037', 'Mutation', 'rs4072037', (56, 65))	('cardia and noncardia cancers', 'Disease', 'MESH:D004938', (132, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('MUC1', 'Gene', (69, 73))
890030	26129866	Recently, we published a genome-wide association study that examined the associations between common genetic variants and risk of gastric adenocarcinoma and esophageal squamous cell carcinoma (ESCC) risk in ethnic Chinese subjects.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (130, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('gastric adenocarcinoma', 'Disease', (130, 152))	('esophageal squamous cell carcinoma', 'Disease', (157, 191))	('variants', 'Var', (109, 117))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (157, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))
890031	26129866	We reported that the strongest association for gastric cardia adenocarcinoma and ESCC were SNPs in a locus on chromosome 10q23 in the PLCE1 gene, but these SNPs showed no association with gastric noncardia adenocarcinoma.	('gastric noncardia adenocarcinoma', 'Disease', (188, 220))	('ESCC', 'Disease', (81, 85))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (47, 76))	('SNPs', 'Var', (91, 95))	('PLCE1', 'Gene', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('gastric cardia adenocarcinoma', 'Disease', (47, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('gastric noncardia adenocarcinoma', 'Disease', 'MESH:D013274', (188, 220))
890034	26129866	A GWAS of gastric adenocarcinoma from Japan reported significant associations for SNPs in prostate stem cell antigen (PSCA) and for SNPs at 1q22 which were associated with gastric adenocarcinomas of diffuse but not intestinal histologic type, which are subtypes of adenocarcinoma defined in the Lauren histologic classification system.	('adenocarcinoma', 'Disease', 'MESH:D000230', (18, 32))	('diffuse but not intestinal', 'Disease', (199, 225))	('SNPs at', 'Var', (132, 139))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (10, 32))	('gastric adenocarcinoma', 'Disease', (10, 32))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (172, 195))	('SNPs', 'Var', (82, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (172, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('gastric adenocarcinomas', 'Disease', (172, 195))	('adenocarcinoma', 'Disease', (265, 279))	('associated', 'Reg', (156, 166))	('adenocarcinoma', 'Disease', (18, 32))	('adenocarcinoma', 'Disease', (180, 194))	('adenocarcinoma', 'Disease', 'MESH:D000230', (265, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('adenocarcinoma', 'Disease', 'MESH:D000230', (180, 194))
890036	26129866	A GWAS of noncardia gastric adenocarcinoma from China reported significant associations with SNPs at 5p13.1 and 3q13.31 with the strongest associations at rs13361707 and rs9841504, respectively.	('rs9841504', 'Mutation', 'rs9841504', (170, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('noncardia gastric adenocarcinoma', 'Disease', 'MESH:D013274', (10, 42))	('rs13361707', 'Mutation', 'rs13361707', (155, 165))	('associations', 'Interaction', (139, 151))	('noncardia gastric adenocarcinoma', 'Disease', (10, 42))	('rs13361707', 'Var', (155, 165))	('rs9841504', 'Var', (170, 179))
890044	26129866	For the assays that failed to design, LD surrogates rs6717108, rs6768588, rs61364777, and rs10881372 were used for the originally selected SNPs rs11884368, rs2035265, rs3935714, and rs12403232, respectively.	('rs11884368', 'Var', (144, 154))	('rs2035265', 'Var', (156, 165))	('rs6717108', 'Mutation', 'rs6717108', (52, 61))	('rs11884368', 'Mutation', 'rs11884368', (144, 154))	('rs10881372', 'Mutation', 'rs10881372', (90, 100))	('rs2035265', 'Mutation', 'rs2035265', (156, 165))	('rs6717108', 'Var', (52, 61))	('rs3935714', 'Mutation', 'rs3935714', (167, 176))	('rs61364777', 'Mutation', 'rs61364777', (74, 84))	('rs10881372', 'Var', (90, 100))	('rs12403232', 'Var', (182, 192))	('rs12403232', 'Mutation', 'rs12403232', (182, 192))	('rs6768588', 'Mutation', 'rs6768588', (63, 72))	('rs61364777', 'Var', (74, 84))	('rs3935714', 'Var', (167, 176))
890054	26129866	The 29 SNPs (Supplementary Table 2) included 12 SNPs with the lowest p-values each for cardia and noncardia, and four additional SNPs with the lowest p-values for total gastric cancer, plus rs4072037 near MUC1 because it appeared to be strongly associated with gastric cancer risk in many previous candidate gene studies.	('gastric cancer', 'Disease', (169, 183))	('MUC1', 'Gene', (205, 209))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (261, 275))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('rs4072037', 'Var', (190, 199))	('rs4072037', 'Mutation', 'rs4072037', (190, 199))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('total gastric cancer', 'Phenotype', 'HP:0006753', (163, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('associated with', 'Reg', (245, 260))	('gastric cancer', 'Disease', (261, 275))	('cardia and noncardia', 'Disease', 'MESH:D004938', (87, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (261, 275))
890059	26129866	At 6p21.1, rs2294693 we observed nominal associations with each gastric cancer subsite, but the association was genome-wide significant for only noncardia cancer risk (p = 2.50 x10-8), with OR (95% CI) of 1.18 (1.12-1.26).	('associations', 'Interaction', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rs2294693', 'Mutation', 'rs2294693', (11, 20))	('gastric cancer', 'Disease', (64, 78))	('only noncardia cancer', 'Disease', 'MESH:D009369', (140, 161))	('rs2294693', 'Var', (11, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('only noncardia cancer', 'Disease', (140, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))
890061	26129866	rs2294693 is an intronic SNP in UNC5CL (unc-5 homolog C (C. elegans)-like) (Figure 1b).	('rs2294693', 'Mutation', 'rs2294693', (0, 9))	('UNC5CL', 'Gene', (32, 38))	('C. elegans', 'Species', '6239', (57, 67))	('rs2294693', 'Var', (0, 9))
890063	26129866	The exonic SNP rs4072037, in MUC1 at 1q22, showed a similar OR (95% CI) for cardia and noncardia gastric cancer and a combined per allele OR (95% CI) of 0.76 (0.69-0.84), p = 6.59 x 10-8 (Figure 1c).	('MUC1', 'Gene', (29, 33))	('rs4072037', 'Var', (15, 24))	('rs4072037', 'Mutation', 'rs4072037', (15, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cardia and noncardia gastric cancer', 'Disease', 'MESH:D013274', (76, 111))
890066	26129866	Similarly, rs12922317 at 16p13.13 replicated in the Beijing set, but not in the other two studies (combined p = 2.62 x 10-6, Supplemental Table 3) In Table 3, we present results from our stage 1 GWAS data, without attempted replication, for six SNPs at four loci that were gleaned from previously published gastric cancer GWAS and two SNPs from a GWAS for Helicobacter pylori seropositivity.	('pylori seropositivity', 'Phenotype', 'HP:0005202', (369, 390))	('Helicobacter pylori', 'Species', '210', (356, 375))	('gastric cancer', 'Disease', (307, 321))	('gastric cancer', 'Disease', 'MESH:D013274', (307, 321))	('Helicobacter pylori seropositivity', 'Phenotype', 'HP:0005202', (356, 390))	('gastric cancer', 'Phenotype', 'HP:0012126', (307, 321))	('rs12922317', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('rs12922317', 'Mutation', 'rs12922317', (11, 21))
890067	26129866	Notably, we confirm prior independent GWAS reports of an association between multiple SNPs in PSCA at 8q24.3 and risk of noncardia gastric cancer, but find no evidence for an association with cardia cancer.	('cardia cancer', 'Disease', (192, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('noncardia gastric cancer', 'Disease', (121, 145))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (121, 145))	('cardia cancer', 'Disease', 'MESH:D004938', (192, 205))	('multiple SNPs', 'Var', (77, 90))	('PSCA', 'Gene', (94, 98))
890068	26129866	reported a novel association for rs9841504 in ZBTB20 with noncardia gastric cancer, but we saw no evidence of that association in our data.	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (58, 82))	('rs9841504', 'Mutation', 'rs9841504', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('rs9841504', 'Var', (33, 42))	('ZBTB20', 'Gene', (46, 52))	('noncardia gastric cancer', 'Disease', (58, 82))
890071	26129866	We also looked up the association for two SNPs reported to be associated with Helicobacter pylori seropositivity in Europeans, without regard to development of gastric cancer, because H. pylori is an important cause of gastric adenocarcinoma.	('Helicobacter pylori seropositivity', 'Phenotype', 'HP:0005202', (78, 112))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('H. pylori', 'Var', (184, 193))	('gastric cancer', 'Disease', (160, 174))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (91, 112))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (219, 241))	('gastric cancer', 'Disease', 'MESH:D013274', (160, 174))	('gastric adenocarcinoma', 'Disease', (219, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('H. pylori', 'Species', '210', (184, 193))	('gastric cancer', 'Phenotype', 'HP:0012126', (160, 174))	('cause', 'Reg', (210, 215))	('Helicobacter pylori', 'Species', '210', (78, 97))
890072	26129866	We found one locus (rs368433) to be nearly monomorphic in our population and no evidence for an association with gastric cancer risk at the other locus (rs10004195).	('rs368433', 'Var', (20, 28))	('rs10004195', 'Var', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('rs368433', 'Mutation', 'rs368433', (20, 28))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('rs10004195', 'Mutation', 'rs10004195', (153, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))
890074	26129866	One SNP, rs10074991 in PRKAA1 at 5p13.1, reached genome-wide significance for both cardia- and noncardia gastric cancers, while rs2294693 at 6p21.1 showed genome-wide significance for only noncardia gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (199, 213))	('noncardia gastric cancer', 'Disease', (189, 213))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (189, 213))	('cardia- and noncardia gastric cancers', 'Disease', 'MESH:D013274', (83, 120))	('gastric cancers', 'Phenotype', 'HP:0012126', (105, 120))	('rs10074991', 'Var', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('rs10074991', 'Mutation', 'rs10074991', (9, 19))	('rs2294693', 'Mutation', 'rs2294693', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('PRKAA1', 'Gene', (23, 29))	('rs2294693', 'Var', (128, 137))	('noncardia gastric cancer', 'Disease', (95, 119))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (95, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))
890075	26129866	An intronic SNP in PRKAA1, rs13361707, was recently reported to be associated with risk of noncardia but not cardia gastric cancer.	('cardia gastric cancer', 'Disease', 'MESH:D013274', (109, 130))	('rs13361707', 'Mutation', 'rs13361707', (27, 37))	('cardia', 'Disease', 'MESH:D004938', (94, 100))	('cardia', 'Disease', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cardia', 'Disease', 'MESH:D004938', (109, 115))	('cardia', 'Disease', (109, 115))	('associated', 'Reg', (67, 77))	('cardia gastric cancer', 'Disease', (109, 130))	('PRKAA1', 'Gene', (19, 25))	('rs13361707', 'Var', (27, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (116, 130))
890076	26129866	Here we found significant associations with ORs of similar magnitude for both gastric cancer subsites for rs10074991, a SNP in perfect LD with rs13361707.	('rs13361707', 'Mutation', 'rs13361707', (143, 153))	('rs10074991', 'Mutation', 'rs10074991', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs10074991', 'Var', (106, 116))	('gastric cancer', 'Disease', (78, 92))	('rs13361707', 'Var', (143, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))	('associations', 'Interaction', (26, 38))
890080	26129866	Supplementary table 6 provides additional biological information on rs10074991 and SNPs in linkage disequilibrium with it showing numerous potential changes in altered binding motifs.	('rs10074991', 'Var', (68, 78))	('binding', 'Interaction', (168, 175))	('altered', 'Reg', (160, 167))	('changes', 'Reg', (149, 156))	('rs10074991', 'Mutation', 'rs10074991', (68, 78))
890081	26129866	An association between rs2294693 at 6p21.1 and risk of noncardia gastric cancer reached genome-wide significance, but not for gastric cardia cancer alone or the combined endpoint.	('rs2294693', 'Var', (23, 32))	('noncardia gastric cancer', 'Disease', (55, 79))	('gastric cardia cancer', 'Disease', 'MESH:D013274', (126, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (55, 79))	('gastric cardia cancer', 'Disease', (126, 147))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rs2294693', 'Mutation', 'rs2294693', (23, 32))
890083	26129866	Two SNPs, rs10484761 and rs2494938, are 200 kb and 500 kb telomeric to rs2294693, respectively, and have been associated with esophageal squamous cell carcinoma and noncardia gastric cancer in Chinese populations.	('noncardia gastric cancer', 'Disease', (165, 189))	('rs2294693', 'Var', (71, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))	('rs10484761', 'Var', (10, 20))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (165, 189))	('esophageal squamous cell carcinoma', 'Disease', (126, 160))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('associated', 'Reg', (110, 120))	('rs10484761', 'Mutation', 'rs10484761', (10, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (126, 160))	('rs2494938', 'Mutation', 'rs2494938', (25, 34))	('rs2294693', 'Mutation', 'rs2294693', (71, 80))	('rs2494938', 'Var', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
890084	26129866	However, the pairwise r-squared values for these three SNPs were low (<=0.015), and rs2494938 is not associated with gastric cancer risk in our GWAS data (Table 3).	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('rs2494938', 'Mutation', 'rs2494938', (84, 93))	('rs2494938', 'Var', (84, 93))	('gastric cancer', 'Disease', (117, 131))	('associated', 'Reg', (101, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))
890085	26129866	rs2294693 and SNPs in high LD with it (Supplementary Table 6), including a synonymous change in the coding sequence, lead to alterations in numerous protein binding and other motifs, but there is only limited evidence for alterations predicted to alter gene regulation.	('rs2294693', 'Mutation', 'rs2294693', (0, 9))	('rs2294693', 'Var', (0, 9))	('alterations', 'Reg', (125, 136))	('protein', 'Protein', (149, 156))	('motifs', 'MPA', (175, 181))
890086	26129866	We previously reported a borderline significant association for rs4072037 (MUC1) for total gastric cancer using a subset of the current data.	('rs4072037', 'Mutation', 'rs4072037', (64, 73))	('gastric cancer', 'Disease', (91, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (91, 105))	('total gastric cancer', 'Phenotype', 'HP:0006753', (85, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('rs4072037', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
890087	26129866	Our original published findings for rs4072037 included about 2240 gastric cancer cases, while the total here includes about 3146 cases.	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('rs4072037', 'Var', (36, 45))	('rs4072037', 'Mutation', 'rs4072037', (36, 45))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
890088	26129866	reported that rs4072037 was associated with both diffuse type gastric cancer (OR 1.66, 95% CI 1.44-1.93) and intestinal type gastric cancer (1.23, 1.02-1.48).	('rs4072037', 'Mutation', 'rs4072037', (14, 23))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('associated', 'Reg', (28, 38))	('type gastric cancer', 'Disease', 'MESH:D013274', (57, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('type gastric cancer', 'Disease', 'MESH:D013274', (120, 139))	('type gastric cancer', 'Disease', (57, 76))	('intestinal type gastric cancer', 'Disease', 'MESH:D013274', (109, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('intestinal type gastric cancer', 'Disease', (109, 139))	('rs4072037', 'Var', (14, 23))
890091	26129866	rs4072037 seems to be functionally important because it altered transcriptional regulation and determined splice variants in MUC1.	('determined', 'Reg', (95, 105))	('MUC1', 'Gene', (125, 129))	('transcriptional regulation', 'MPA', (64, 90))	('altered', 'Reg', (56, 63))	('rs4072037', 'Var', (0, 9))	('rs4072037', 'Mutation', 'rs4072037', (0, 9))	('splice variants', 'MPA', (106, 121))
890092	26129866	Using our GWAS data, we observed significant associations between variants at 8q24.3 (PSCA) and risk of noncardia gastric cancer, which has been reported in several prior publications (Table 3).	('noncardia gastric cancer', 'Disease', (104, 128))	('variants', 'Var', (66, 74))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (104, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
890093	26129866	also showed evidence for an association between rs2285947 at 7p15.3 and noncardia gastric cancer risk.	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('noncardia gastric cancer', 'Disease', (72, 96))	('rs2285947', 'Var', (48, 57))	('noncardia gastric cancer', 'Disease', 'MESH:D013274', (72, 96))	('rs2285947', 'Mutation', 'rs2285947', (48, 57))
890094	26129866	This SNP does not appear on our array so we examined a proxy, rs976516 (r2 = 0.85) and found further evidence for an association with noncardia and cardia cancer, with p-value (9.42 x 10-3) for total gastric cancer.	('gastric cancer', 'Disease', (200, 214))	('total gastric cancer', 'Phenotype', 'HP:0006753', (194, 214))	('rs976516', 'Var', (62, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('association', 'Interaction', (117, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('noncardia and cardia cancer', 'Disease', 'MESH:D004938', (134, 161))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('rs976516', 'Mutation', 'rs976516', (62, 70))
890097	26129866	Our overall results showed that rs10074991 was associated with risk of gastric cardia adenocarcinoma (p = 7.36 x 10-12) despite little evidence for an association in our GWAS subjects (p = 1.27 x 10-2).	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (71, 100))	('gastric cardia adenocarcinoma', 'Disease', (71, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('rs10074991', 'Mutation', 'rs10074991', (32, 42))	('rs10074991', 'Var', (32, 42))
890098	26129866	Finally, when added to the known consistent differences between cardia and noncardia gastric cancer for the associations in common variants for PSCA and PLCE1, our results suggest that the clearest picture of the association of common genetic variants with gastric cancer in the future will come from studies that include both gastric cancer sub-locations studied independently whenever possible.	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('association', 'Interaction', (213, 224))	('gastric cancer', 'Disease', (327, 341))	('gastric cancer', 'Phenotype', 'HP:0012126', (257, 271))	('gastric cancer', 'Disease', 'MESH:D013274', (327, 341))	('gastric cancer', 'Disease', (85, 99))	('cardia and noncardia gastric cancer', 'Disease', 'MESH:D013274', (64, 99))	('PSCA', 'Gene', (144, 148))	('variants', 'Var', (131, 139))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('gastric cancer', 'Phenotype', 'HP:0012126', (327, 341))	('gastric cancer', 'Disease', (257, 271))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (257, 271))	('variants', 'Var', (243, 251))
890101	26129866	In summary, our replication study found associations with variants in PRKAA1 and MUC1 for cardia and noncardia gastric cancers.	('gastric cancers', 'Phenotype', 'HP:0012126', (111, 126))	('PRKAA1', 'Gene', (70, 76))	('variants', 'Var', (58, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('MUC1', 'Gene', (81, 85))	('associations', 'Reg', (40, 52))	('cardia and noncardia gastric cancers', 'Disease', 'MESH:D013274', (90, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
890102	26129866	ESCC Esophageal squamous cell carcinoma NCI National Cancer Institute There are almost one million new cases of gastric cancer each year and Eastern Asia has the highest rates of any geographic region Several previous GWAS studies of gastric cancer in subjects of East Asian ethnicities have reported a modest number of associations for common single nucleotide polymorphisms These studies have reported that many SNPs have different results when analyzed by location of the tumor within the stomach - cardia versus noncardia Using a GWAS with subjects of Asian ethnicity and more than 1000 cases from each sub-location within the stomach, we found that rs10074991 in PRKAA1 at 5p13.1 showed genome-wide significant associations for cardia and noncardia cancers, with the finding for cardia being novel.	('tumor', 'Disease', 'MESH:D009369', (475, 480))	('gastric cancer', 'Disease', 'MESH:D013274', (234, 248))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('cardia', 'Disease', (502, 508))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (5, 39))	('rs10074991', 'Mutation', 'rs10074991', (654, 664))	('cardia', 'Disease', 'MESH:D004938', (733, 739))	('cardia and noncardia cancers', 'Disease', 'MESH:D004938', (733, 761))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (475, 480))	('cardia', 'Disease', (784, 790))	('gastric cancer', 'Phenotype', 'HP:0012126', (234, 248))	('cancers', 'Phenotype', 'HP:0002664', (754, 761))	('cardia', 'Disease', 'MESH:D004938', (519, 525))	('cardia', 'Disease', 'MESH:D004938', (747, 753))	('cardia versus noncardia', 'Disease', (502, 525))	('rs10074991', 'Var', (654, 664))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('cancer', 'Phenotype', 'HP:0002664', (754, 760))	('cardia', 'Disease', 'MESH:D004938', (502, 508))	('PRKAA1', 'Gene', (668, 674))	('cardia', 'Disease', (733, 739))	('cardia versus noncardia', 'Disease', 'MESH:D004938', (502, 525))	('Esophageal squamous cell carcinoma', 'Disease', (5, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('gastric cancer', 'Disease', (234, 248))	('associations', 'Reg', (716, 728))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor within the stomach', 'Phenotype', 'HP:0006753', (475, 499))	('cardia', 'Disease', 'MESH:D004938', (784, 790))	('cardia', 'Disease', (519, 525))	('gastric cancer', 'Disease', (112, 126))	('tumor', 'Disease', (475, 480))	('cardia', 'Disease', (747, 753))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('Cancer', 'Disease', (53, 59))
890103	26129866	Furthermore, we observed that rs2294693 near UNC5CL at 6p212.1 was genome-wide significant for gastric noncardia cancer.	('gastric noncardia cancer', 'Disease', 'MESH:D013274', (95, 119))	('rs2294693', 'Var', (30, 39))	('gastric noncardia cancer', 'Disease', (95, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('significant', 'Reg', (79, 90))	('rs2294693', 'Mutation', 'rs2294693', (30, 39))
890104	26129866	A SNP in MUC1 (rs4072037) showed near genome-wide significance, with similar associations for cardia and noncardia tumors Three SNPs in PSCA previously reported to be associated with gastric noncardia cancer showed subsite specific findings with some evidence for an association in the noncardia, but no association for cardia cancer.	('cardia cancer', 'Disease', 'MESH:D004938', (194, 207))	('cardia', 'Disease', 'MESH:D004938', (108, 114))	('cardia', 'Disease', 'MESH:D004938', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('gastric noncardia cancer', 'Disease', 'MESH:D013274', (183, 207))	('noncardia tumors', 'Disease', 'MESH:D009369', (105, 121))	('cardia cancer', 'Disease', 'MESH:D004938', (320, 333))	('cardia', 'Disease', 'MESH:D004938', (320, 326))	('cardia', 'Disease', 'MESH:D004938', (289, 295))	('cardia', 'Disease', (94, 100))	('cardia cancer', 'Disease', (320, 333))	('gastric noncardia cancer', 'Disease', (183, 207))	('rs4072037', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('cardia and noncardia', 'Disease', 'MESH:D004938', (94, 114))	('noncardia tumors', 'Disease', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cardia', 'Disease', (194, 200))	('cardia', 'Disease', (108, 114))	('cardia', 'Disease', (289, 295))	('cardia', 'Disease', (320, 326))	('cardia', 'Disease', 'MESH:D004938', (94, 100))	('rs4072037', 'Mutation', 'rs4072037', (15, 24))	('associated', 'Reg', (167, 177))
890111	27564102	Treatment with irbesartan or AT1R-RNAi knockdown but not treatment with PD123319 significantly decreased the level of angiotensin II-induced ESCC cell proliferation.	('decreased', 'NegReg', (95, 104))	('men', 'Species', '9606', (62, 65))	('irbesartan', 'Chemical', 'MESH:D000077405', (15, 25))	('angiotensin II', 'Gene', (118, 132))	('knockdown', 'Var', (39, 48))	('AT1R-RNAi', 'Gene', (29, 38))	('men', 'Species', '9606', (5, 8))	('PD123319', 'Chemical', 'MESH:C073402', (72, 80))	('angiotensin II', 'Gene', '183', (118, 132))	('ESCC', 'Disease', (141, 145))
890112	27564102	Angiotensin II also caused mTOR activation in a dose-dependent manner, and everolimus or mTOR-RNAi knockdown significantly suppressed the level of angiotensin II-induced ESCC cell proliferation.	('mTOR', 'MPA', (27, 31))	('activation', 'PosReg', (32, 42))	('suppressed', 'NegReg', (123, 133))	('mTOR-RNAi', 'Gene', (89, 98))	('everolimus', 'Chemical', 'MESH:D000068338', (75, 85))	('angiotensin II', 'Gene', '183', (147, 161))	('knockdown', 'Var', (99, 108))	('Angiotensin II', 'Gene', (0, 14))	('angiotensin II', 'Gene', (147, 161))	('Angiotensin II', 'Gene', '183', (0, 14))	('ESCC', 'Disease', (170, 174))
890121	27564102	AT1R and AT2R have been detected in several types of cancers, and some have been reported to be associated with patients' prognosis.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('detected', 'Reg', (24, 32))	('AT2R', 'Gene', (9, 13))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('associated', 'Reg', (96, 106))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('AT2R', 'Gene', '186', (9, 13))	('AT1R', 'Var', (0, 4))
890134	27564102	AT2R overexpression was significantly associated with high pathologic T classification (T3+4; P=0.016) and AT1R overexpression (P=0.001).	('AT2R', 'Gene', (0, 4))	('high pathologic T classification', 'CPA', (54, 86))	('AT1R', 'Var', (107, 111))	('AT2R', 'Gene', '186', (0, 4))
890138	27564102	The AT1R antagonists significantly decreased the level of angiotensin II-induced ESCC cell proliferation (P<0.05, Figure 3B), whereas the AT2R antagonist had no effect (P>0.05, Figure 3B).	('AT2R', 'Gene', (138, 142))	('AT1R', 'Gene', (4, 8))	('AT2R', 'Gene', '186', (138, 142))	('ESCC', 'Disease', (81, 85))	('antagonists', 'Var', (9, 20))	('decreased', 'NegReg', (35, 44))	('angiotensin II', 'Gene', '183', (58, 72))	('angiotensin II', 'Gene', (58, 72))
890145	27564102	The knockdown of endogenous AT1R in CE81T/VGH or CE48T/VGH cells led to a significant decrease of angiotensin II-induced ESCC cell proliferation, colony formation, and BrdU incorporation (P<0.05, Figure 3D and 3E and Supplementary Figure S1B and S1C).	('angiotensin II', 'Gene', '183', (98, 112))	('CE81T/VGH', 'Var', (36, 45))	('colony formation', 'CPA', (146, 162))	('CE48T/VGH', 'Var', (49, 58))	('men', 'Species', '9606', (223, 226))	('AT1R', 'Gene', (28, 32))	('angiotensin II', 'Gene', (98, 112))	('ESCC cell proliferation', 'CPA', (121, 144))	('BrdU', 'Chemical', 'MESH:D001973', (168, 172))	('decrease', 'NegReg', (86, 94))	('BrdU incorporation', 'CPA', (168, 186))
890146	27564102	Additionally, we also demonstrated that CE81T/VGH treated with irbesartan caused a dramatic reduction of angiotensin II-induced colony formation and BrdU incorporation (Figure 3F).	('BrdU incorporation', 'CPA', (149, 167))	('CE81T/VGH', 'Var', (40, 49))	('angiotensin II', 'Gene', '183', (105, 119))	('reduction', 'NegReg', (92, 101))	('angiotensin II', 'Gene', (105, 119))	('BrdU', 'Chemical', 'MESH:D001973', (149, 153))	('irbesartan', 'Chemical', 'MESH:D000077405', (63, 73))
890153	27564102	Additionally, Western blotting analyses also showed that angiotensin II stimulated p-mTOR expression in CE81T/VGH and CE48T/VGH cells in a dose-dependent manner (Figure 4A).	('angiotensin II', 'Gene', '183', (57, 71))	('stimulated', 'PosReg', (72, 82))	('CE48T/VGH', 'Var', (118, 127))	('angiotensin II', 'Gene', (57, 71))	('expression', 'MPA', (90, 100))	('CE81T/VGH', 'Var', (104, 113))	('p-mTOR', 'Protein', (83, 89))
890154	27564102	CE81T/VGH and CE48T/VGH cells were treated with everolimus (an mTOR inhibitor) prior to the angiotensin II treatment, and everolimus significantly decreased the level of angiotensin II-induced ESCC cell proliferation, colony formation, and BrdU incorporation (Figure 4B).	('men', 'Species', '9606', (112, 115))	('everolimus', 'Var', (122, 132))	('angiotensin II', 'Gene', (170, 184))	('decreased', 'NegReg', (147, 156))	('angiotensin II', 'Gene', (92, 106))	('colony formation', 'CPA', (218, 234))	('BrdU', 'Chemical', 'MESH:D001973', (240, 244))	('BrdU incorporation', 'CPA', (240, 258))	('everolimus', 'Chemical', 'MESH:D000068338', (122, 132))	('CE48T/VGH', 'Var', (14, 23))	('angiotensin II', 'Gene', '183', (170, 184))	('ESCC cell proliferation', 'CPA', (193, 216))	('angiotensin II', 'Gene', '183', (92, 106))	('everolimus', 'Chemical', 'MESH:D000068338', (48, 58))
890156	27564102	To further confirm the role of mTOR activation in angiotensin II-induced ESCC cell proliferation, siRNA was used to reduce endogenous mTOR expression in CE81T/VGH and CE48T/VGH cells.	('reduce', 'NegReg', (116, 122))	('angiotensin II', 'Gene', '183', (50, 64))	('angiotensin II', 'Gene', (50, 64))	('endogenous mTOR expression', 'MPA', (123, 149))	('CE48T/VGH', 'Var', (167, 176))	('CE81T/VGH', 'Var', (153, 162))
890157	27564102	The endogenous protein expression levels of mTOR in CE81T/VGH or CE48T/VGH cells transfected with siRNAs targeting mTOR were significantly reduced (Figure 4C and Supplementary Figure S2B).	('CE81T/VGH', 'Var', (52, 61))	('reduced', 'NegReg', (139, 146))	('siRNAs targeting', 'Var', (98, 114))	('endogenous protein expression levels', 'MPA', (4, 40))	('men', 'Species', '9606', (168, 171))
890158	27564102	The knockdown of endogenous mTOR in CE81T/VGH and CE48T/VGH cells led to a significant decrease in the angiotensin II-induced ESCC cell proliferative effect (P<0.05; Figure 4C and Supplementary Figure S2B).	('angiotensin II', 'Gene', (103, 117))	('CE81T/VGH', 'Var', (36, 45))	('CE48T/VGH', 'Var', (50, 59))	('men', 'Species', '9606', (186, 189))	('angiotensin II', 'Gene', '183', (103, 117))	('decrease', 'NegReg', (87, 95))	('ESCC cell proliferative effect', 'CPA', (126, 156))
890159	27564102	Additionally, the knockdown of endogenous AT1R in CE81T/VGH and CE48T/VGH cells also led to a decrease in the p-mTOR levels measured by Western blotting (Figure 4D and Supplementary Figure S2C).	('knockdown', 'Var', (18, 27))	('AT1R', 'Gene', (42, 46))	('p-mTOR levels', 'MPA', (110, 123))	('CE48T/VGH', 'Var', (64, 73))	('Western blotting', 'MPA', (136, 152))	('men', 'Species', '9606', (174, 177))	('CE81T/VGH', 'Var', (50, 59))	('decrease', 'NegReg', (94, 102))
890164	27564102	As shown in Figure 5A, angiotensin II significantly promoted CE81T/VGH xenograft tumor growth compared to a vehicle control group.	('CE81T/VGH', 'Var', (61, 70))	('angiotensin II', 'Gene', '183', (23, 37))	('angiotensin II', 'Gene', (23, 37))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('promoted', 'PosReg', (52, 60))	('tumor', 'Disease', (81, 86))
890209	27564102	For AT1R and AT2R, incubation without the primary antibody was used as a negative control, while normal adrenal gland was used as a positive control.	('AT2R', 'Gene', '186', (13, 17))	('AT1R', 'Var', (4, 8))	('AT2R', 'Gene', (13, 17))
890213	27564102	The AT1R or AT2R overexpression was defined as the presence of at least staining in  35% of tumor cells.	('AT1R', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('AT2R', 'Gene', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('AT2R', 'Gene', '186', (12, 16))	('overexpression', 'PosReg', (17, 31))	('tumor', 'Disease', (92, 97))
890216	27564102	We used the Taq-Man probe to detect the expression levels of AT1R and AT2R, following the manufacturer's instructions.	('Man', 'Species', '9606', (16, 19))	('AT1R', 'Var', (61, 65))	('AT2R', 'Gene', (70, 74))	('AT2R', 'Gene', '186', (70, 74))
890221	27564102	The CE81T/VGH and CE48T/VGH ESCC cell lines were obtained from the Bioresource Collection and Research Center (BCRC), and cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal calf serum, 2 mmol/L glutamine, 100 U/mL penicillin, and 100 mug/mL streptomycin.	('DMEM', 'Chemical', '-', (168, 172))	('CE81T/VGH', 'Var', (4, 13))	('streptomycin', 'Chemical', 'MESH:D013307', (270, 282))	('calf', 'Species', '9913', (202, 206))	('penicillin', 'Chemical', 'MESH:D010406', (243, 253))	('men', 'Species', '9606', (180, 183))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (134, 166))	('glutamine', 'Chemical', 'MESH:D005973', (223, 232))	('CE48T/VGH', 'Var', (18, 27))
479382	27564102	Dysplasia was defined as loss of polarity in the epithelial cells, nuclear pleomorphism and hyperchromasia, abnormal single cell keratinization (dyskeratosis), and increased or abnormal mitoses.	('polarity', 'MPA', (33, 41))	('dyskeratosis', 'Disease', (145, 157))	('hyperchromasia', 'Disease', (92, 106))	('hyperchromasia', 'Disease', 'None', (92, 106))	('dyskeratosis', 'Disease', 'MESH:D019871', (145, 157))	('nuclear pleomorphism', 'Var', (67, 87))	('loss', 'NegReg', (25, 29))	('Dysplasia', 'Disease', (0, 9))	('Dysplasia', 'Disease', 'MESH:D004476', (0, 9))
890273	27574454	Current research has indicated that PN expression is upregulated in cells that highly expressed both epidermal growth factor receptor (EGFR) and mutant p53 compared to control cells that highly expressed EGFR or mutant p53 alone.	('epidermal growth factor receptor', 'Gene', '1956', (101, 133))	('p53', 'Gene', '7157', (219, 222))	('mutant', 'Var', (145, 151))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (152, 155))	('EGFR', 'Gene', '1956', (135, 139))	('EGFR', 'Gene', '1956', (204, 208))	('epidermal growth factor receptor', 'Gene', (101, 133))	('EGFR', 'Gene', (135, 139))	('EGFR', 'Gene', (204, 208))	('upregulated', 'PosReg', (53, 64))	('p53', 'Gene', (219, 222))
890274	27574454	Meanwhile, PN protein expression in in vitro cells was decreased by inhibiting EGFR or restoring wild-type p53 signaling, suggesting that PN expression was modulated mechanistically by activating EGFR signaling and p53 mutation.	('EGFR', 'Gene', (196, 200))	('PN protein', 'Protein', (11, 21))	('restoring', 'PosReg', (87, 96))	('EGFR', 'Gene', '1956', (79, 83))	('inhibiting', 'NegReg', (68, 78))	('EGFR', 'Gene', (79, 83))	('activating', 'PosReg', (185, 195))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('p53', 'Gene', (215, 218))	('mutation', 'Var', (219, 227))	('p53', 'Gene', '7157', (215, 218))	('decreased', 'NegReg', (55, 64))	('EGFR', 'Gene', '1956', (196, 200))
890301	27574454	Grading of tumor cells' staining intensity was as follows: negative, 0; light yellow, 1; brownish-yellow, 2; and brown, 3.	('brownish-yellow', 'Var', (89, 104))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('negative', 'NegReg', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
890328	27574454	According to the Kaplan-Meier analysis, disease-free survival (DFS) in patients with high expression of PN was shorter than that in patients with low expression of PN, with DFS time of 18.77+-2.45 months and 44.40+-3.80 months, respectively (P=0.000; Figure 4A).	('disease-free survival', 'CPA', (40, 61))	('high expression', 'Var', (85, 100))	('patients', 'Species', '9606', (71, 79))	('shorter', 'NegReg', (111, 118))	('patients', 'Species', '9606', (132, 140))
890329	27574454	Moreover, the overall survival (OS) in patients with high expression of PN was also worse than that in the patients with low expression of PN, with the OS time of 29.19+-2.53 months and 53.69+-2.72 months, respectively (P=0.000; Figure 4B).	('patients', 'Species', '9606', (39, 47))	('overall', 'MPA', (14, 21))	('worse', 'NegReg', (84, 89))	('high expression', 'Var', (53, 68))	('patients', 'Species', '9606', (107, 115))
890331	27574454	DFS and OS in patients with high expression of EGFR were shorter than those in the patients with low expression of EGFR (20.50+-2.12 months vs 46.52+-4.58 months and 31.80+-2.22 months vs 54.11+-3.61 months, respectively; both P<0.05; Figure 4C and D).	('DFS', 'CPA', (0, 3))	('EGFR', 'Gene', '1956', (115, 119))	('EGFR', 'Gene', (115, 119))	('high expression', 'Var', (28, 43))	('EGFR', 'Gene', '1956', (47, 51))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', (47, 51))	('shorter', 'NegReg', (57, 64))
890334	27574454	Compared with PN or EGFR single marker, the coexpression of PN and EGFR dedicated worse prognosis, which might stratify patients more accurately (both P<0.05; Figure 5A and B).	('coexpression', 'Var', (44, 56))	('EGFR', 'Gene', (20, 24))	('patients', 'Species', '9606', (120, 128))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('EGFR', 'Gene', '1956', (20, 24))
890352	27574454	Preexisting literature showed that an abnormal expression of EGFR was closely related to clinicopathological features such as differentiation, lymphatic metastasis, and stage.	('differentiation', 'CPA', (126, 141))	('abnormal', 'Var', (38, 46))	('related', 'Reg', (78, 85))	('EGFR', 'Gene', (61, 65))	('EGFR', 'Gene', '1956', (61, 65))	('expression', 'MPA', (47, 57))	('lymphatic metastasis', 'CPA', (143, 163))
890360	27574454	Interestingly, the risk of death for patients with low expression of two biomarkers and high expression of single biomarker was 0.243 times and 0.503 times, respectively, than that for patients with high expression of two biomarkers.	('high expression', 'Var', (88, 103))	('patients', 'Species', '9606', (37, 45))	('death', 'Disease', 'MESH:D003643', (27, 32))	('low', 'NegReg', (51, 54))	('death', 'Disease', (27, 32))	('patients', 'Species', '9606', (185, 193))
890447	27011160	showed that the nerve injury rate in MIE-cervical anastomosis was significant higher with compared with MIE-intrathoracic anastomosis (8% vs. 1%).	('cervical anastomosis', 'Phenotype', 'HP:0002949', (41, 61))	('nerve injury', 'Disease', (16, 28))	('MIE', 'Chemical', '-', (104, 107))	('nerve injury', 'Disease', 'MESH:D000080902', (16, 28))	('higher', 'PosReg', (78, 84))	('MIE-intrathoracic anastomosis', 'Disease', 'MESH:D006045', (104, 133))	('MIE-intrathoracic anastomosis', 'Disease', (104, 133))	('MIE', 'Chemical', '-', (37, 40))	('MIE-cervical', 'Var', (37, 49))
890450	27011160	In particular, pulmonary complications are significantly lower with MIE.	('pulmonary complications', 'Phenotype', 'HP:0006532', (15, 38))	('pulmonary complications', 'Disease', (15, 38))	('pulmonary complications', 'Disease', 'MESH:D008171', (15, 38))	('MIE', 'Chemical', '-', (68, 71))	('MIE', 'Var', (68, 71))	('lower', 'NegReg', (57, 62))
890463	25404787	Thus, the dysregulation of the biogenesis and function of miRNAs is often associated with human diseases, especially malignancies.	('biogenesis', 'MPA', (31, 41))	('dysregulation', 'Var', (10, 23))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('function', 'MPA', (46, 54))	('miRNAs', 'Gene', (58, 64))	('malignancies', 'Disease', (117, 129))	('associated', 'Reg', (74, 84))
890468	25404787	The search strategy was "microRNA-375 OR miR-375" AND "tumor OR neoplasm OR cancer OR carcinoma."	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('microRNA-375', 'Gene', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('microRNA-375', 'Gene', '494324', (25, 37))	('neoplasm', 'Disease', (64, 72))	('neoplasm', 'Phenotype', 'HP:0002664', (64, 72))	('miR-375', 'Var', (41, 48))	('neoplasm', 'Disease', 'MESH:D009369', (64, 72))
890476	25404787	In hepatocellular carcinoma, the restoration of miR-375 in cancer cells decreased cell proliferation, clonogenicity, migration, and invasion and induced G1 arrest and apoptosis.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('migration', 'CPA', (117, 126))	('cell proliferation', 'CPA', (82, 100))	('miR-375', 'Gene', (48, 55))	('decreased', 'NegReg', (72, 81))	('apoptosis', 'CPA', (167, 176))	('arrest', 'Disease', 'MESH:D006323', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('restoration', 'Var', (33, 44))	('induced', 'Reg', (145, 152))	('arrest', 'Disease', (156, 162))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('clonogenicity', 'CPA', (102, 115))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('invasion', 'CPA', (132, 140))
890480	25404787	Similarly, in esophageal squamous cell carcinoma miR-375 was confirmed to inhibit cell proliferation, colony formation, and metastasis in vitro and in vivo.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (14, 48))	('metastasis', 'CPA', (124, 134))	('cell proliferation', 'CPA', (82, 100))	('inhibit', 'NegReg', (74, 81))	('colony formation', 'CPA', (102, 118))	('esophageal squamous cell carcinoma', 'Disease', (14, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('miR-375', 'Var', (49, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))
890544	32276266	An increasing number of studies have shown that genistein is involved in inducing cancer cell apoptosis, inhibiting cell proliferation, suppressing angiogenesis and inhibiting colorectal cancer metastasis.	('suppressing', 'NegReg', (136, 147))	('inhibiting', 'NegReg', (105, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('genistein', 'Var', (48, 57))	('cancer', 'Disease', (187, 193))	('inducing', 'PosReg', (73, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('genistein', 'Chemical', 'MESH:D019833', (48, 57))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('inhibiting', 'NegReg', (165, 175))	('colorectal cancer', 'Disease', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('angiogenesis', 'CPA', (148, 160))	('cell proliferation', 'CPA', (116, 134))
890577	32276266	To uncover the mechanism through which genistein affects cyclical distribution and apoptosis in esophageal cancer cells, we tested the expression levels and phosphorylation levels of JAK1, JAK2, STAT1 and STAT3 in Eca-109 cells.	('STAT1', 'Gene', '6772', (195, 200))	('STAT3', 'Gene', '6774', (205, 210))	('JAK1', 'Var', (183, 187))	('esophageal cancer', 'Disease', (96, 113))	('Eca', 'Chemical', '-', (214, 217))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('STAT3', 'Gene', (205, 210))	('JAK2', 'Gene', '3717', (189, 193))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('affects', 'Reg', (49, 56))	('expression', 'MPA', (135, 145))	('cyclical distribution', 'MPA', (57, 78))	('JAK2', 'Gene', (189, 193))	('genistein', 'Chemical', 'MESH:D019833', (39, 48))	('tested', 'Reg', (124, 130))	('STAT1', 'Gene', (195, 200))
890578	32276266	In Figure 5, compared with un-treated cells, the phosphorylation levels of JAK1, JAK2 and STAT3 were significantly decreased after genistein treatment, but not those of STAT1 (Figure 5A-5C).	('STAT3', 'Gene', '6774', (90, 95))	('JAK2', 'Gene', '3717', (81, 85))	('JAK1', 'MPA', (75, 79))	('STAT3', 'Gene', (90, 95))	('genistein', 'Var', (131, 140))	('decreased', 'NegReg', (115, 124))	('STAT1', 'Gene', (169, 174))	('genistein', 'Chemical', 'MESH:D019833', (131, 140))	('JAK2', 'Gene', (81, 85))	('STAT1', 'Gene', '6772', (169, 174))	('phosphorylation levels', 'MPA', (49, 71))
890585	32276266	The JAK1 pathway inhibitor GLPG0634 (16 nM) and the Akt pathway inhibitor MK-2206 (32 nM) were selected for subsequent experiments following CCK-8 assays (Figure 6A).	('MK-2206', 'Chemical', 'MESH:C548887', (74, 81))	('GLPG0634', 'Chemical', 'MESH:C584571', (27, 35))	('GLPG0634', 'Var', (27, 35))	('JAK1 pathway', 'Pathway', (4, 16))
890586	32276266	The results show that when Eca-109 cells were co-treated using genistein (4 muM) and the JAK1 pathway inhibitor GLPG0634 (16 nM) or the Akt pathway inhibitor MK-2206 (32 nM), cell proliferation was significantly down-regulated (Figure 6B), while cell apoptosis (Figure 6C) and ROS levels (Figure 6D) were markedly increased, and cell cycle was arrested in the G0/G1 phase (Figure 6E), compared with Eca-109 cells treated with genistein alone.	('cell cycle', 'CPA', (329, 339))	('arrest', 'Disease', 'MESH:D006323', (344, 350))	('Akt pathway', 'Pathway', (136, 147))	('genistein', 'Chemical', 'MESH:D019833', (426, 435))	('muM', 'Gene', '56925', (76, 79))	('ROS levels', 'MPA', (277, 287))	('muM', 'Gene', (76, 79))	('cell proliferation', 'CPA', (175, 193))	('increased', 'PosReg', (314, 323))	('GLPG0634', 'Chemical', 'MESH:C584571', (112, 120))	('MK-2206', 'Chemical', 'MESH:C548887', (158, 165))	('MK-2206', 'Var', (158, 165))	('Eca', 'Chemical', '-', (27, 30))	('ROS', 'Chemical', 'MESH:D017382', (277, 280))	('cell apoptosis', 'CPA', (246, 260))	('down-regulated', 'NegReg', (212, 226))	('genistein', 'Chemical', 'MESH:D019833', (63, 72))	('arrest', 'Disease', (344, 350))	('Eca', 'Chemical', '-', (399, 402))
890587	32276266	Furthermore, genistein plus the JAK1 pathway inhibitor GLPG0634 and the Akt pathway inhibitor MK-2206 produced substantial decreases in cell viability and facilitated ROS production compared with Eca-109 cells co-treated with genistein and GLPG0634 or genistein and MK-2206, respectively (Supplementary Figure 2).	('genistein', 'Chemical', 'MESH:D019833', (226, 235))	('ROS production', 'MPA', (167, 181))	('decreases', 'NegReg', (123, 132))	('Eca', 'Chemical', '-', (196, 199))	('MK-2206', 'Chemical', 'MESH:C548887', (94, 101))	('GLPG0634', 'Chemical', 'MESH:C584571', (240, 248))	('Akt', 'Pathway', (72, 75))	('MK-2206', 'Var', (94, 101))	('genistein', 'Chemical', 'MESH:D019833', (252, 261))	('genistein', 'Chemical', 'MESH:D019833', (13, 22))	('MK-2206', 'Chemical', 'MESH:C548887', (266, 273))	('facilitated', 'PosReg', (155, 166))	('GLPG0634', 'Chemical', 'MESH:C584571', (55, 63))	('GLPG0634', 'Var', (55, 63))	('cell viability', 'CPA', (136, 150))	('ROS', 'Chemical', 'MESH:D017382', (167, 170))
890590	32276266	However, genistein in combination with the JAK1 pathway inhibitor GLPG0634 or the Akt pathway inhibitor MK-2206 had an enhanced inhibitory effect on STAT3 and MDM2 phosphorylation in Eca-109 cells in comparison with EsC cells subjected to genistein treatment alone (Figure 6G and 6H, P<0.05).	('inhibitory effect', 'MPA', (128, 145))	('GLPG0634', 'Var', (66, 74))	('MDM2', 'Gene', (159, 163))	('STAT3', 'Gene', '6774', (149, 154))	('GLPG0634', 'Chemical', 'MESH:C584571', (66, 74))	('MK-2206', 'Chemical', 'MESH:C548887', (104, 111))	('STAT3', 'Gene', (149, 154))	('EsC', 'Phenotype', 'HP:0011459', (216, 219))	('Eca', 'Chemical', '-', (183, 186))	('genistein', 'Chemical', 'MESH:D019833', (9, 18))	('genistein', 'Chemical', 'MESH:D019833', (239, 248))	('enhanced', 'PosReg', (119, 127))	('MDM2', 'Gene', '4193', (159, 163))
890592	32276266	Co-treatment with genistein and the JAK1 pathway inhibitor GLPG0634 (1 mg/kg) or the Akt pathway inhibitor MK-2206 (1 mg/kg) had an enhanced inhibitory effect on tumor growth in comparison with matched control groups (Figure 6I-6L, P<0.01).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('genistein', 'Chemical', 'MESH:D019833', (18, 27))	('tumor', 'Disease', (162, 167))	('MK-2206', 'Chemical', 'MESH:C548887', (107, 114))	('Akt pathway', 'Pathway', (85, 96))	('inhibitory', 'NegReg', (141, 151))	('enhanced', 'PosReg', (132, 140))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('GLPG0634', 'Chemical', 'MESH:C584571', (59, 67))	('GLPG0634', 'Var', (59, 67))
890600	32276266	In conclusion, the inhibition of EGFR suppressed downstream pathways (the JAK1/2/-STAT3 and AKT/MDM2 signaling axis), causing the up-regulation of P53 expression and the down-regulation of cell cycle-related gene expression, thereby arresting cell cycle at the G0/G1 phase and promoting cell apoptosis in EsC cells.	('cell cycle', 'CPA', (243, 253))	('EsC', 'Phenotype', 'HP:0011459', (305, 308))	('cell apoptosis', 'CPA', (287, 301))	('inhibition', 'Var', (19, 29))	('suppressed', 'NegReg', (38, 48))	('MDM2', 'Gene', (96, 100))	('EGFR', 'Gene', (33, 37))	('AKT', 'Gene', (92, 95))	('arrest', 'Disease', (233, 239))	('expression', 'MPA', (213, 223))	('P53', 'Gene', (147, 150))	('expression', 'MPA', (151, 161))	('MDM2', 'Gene', '4193', (96, 100))	('STAT3', 'Gene', (82, 87))	('JAK1/2', 'Gene', '3716;3717', (74, 80))	('JAK1/2', 'Gene', (74, 80))	('down-regulation', 'NegReg', (170, 185))	('EGFR', 'Gene', '1956', (33, 37))	('AKT', 'Gene', '207', (92, 95))	('STAT3', 'Gene', '6774', (82, 87))	('downstream pathways', 'Pathway', (49, 68))	('up-regulation', 'PosReg', (130, 143))	('promoting', 'PosReg', (277, 286))	('P53', 'Gene', '7157', (147, 150))	('cell cycle-related gene', 'Gene', (189, 212))	('arrest', 'Disease', 'MESH:D006323', (233, 239))
890626	32276266	This positive feedback effect may be more significant in esophageal cancer with high EGFR expression.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('EGFR', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('esophageal cancer', 'Disease', (57, 74))	('EGFR', 'Gene', '1956', (85, 89))	('high', 'Var', (80, 84))
890767	28429247	There are multiple plausible mechanisms whereby EoE patients benefit from PPI-induced acid suppression: first, acid suppression as well as antiinflammatory effects of PPIs might decrease acid injury-related cytokines, pain, and esophageal permeability.	('acid', 'MPA', (111, 115))	('esophageal permeability', 'MPA', (228, 251))	('decrease', 'NegReg', (178, 186))	('pain', 'Phenotype', 'HP:0012531', (218, 222))	('acid injury-related cytokines', 'MPA', (187, 216))	('PPIs', 'Var', (167, 171))	('pain', 'Disease', 'MESH:D010146', (218, 222))	('pain', 'Disease', (218, 222))	('EoE', 'Phenotype', 'HP:0410151', (48, 51))	('patients', 'Species', '9606', (52, 60))
890768	28429247	Second, PPIs can inhibit Th2 cytokine-induced eotaxin-3 secretion in esophageal epithelial cells, potentially reducing eosinophil recruitment.	('eotaxin-3', 'Gene', (46, 55))	('PPIs', 'Var', (8, 12))	('reducing', 'NegReg', (110, 118))	('inhibit', 'NegReg', (17, 24))	('eotaxin-3', 'Gene', '10344', (46, 55))	('eosinophil recruitment', 'MPA', (119, 141))
890776	28429247	Eradication of H. pylori can not only accelerate ulcer healing, but also reduce the recurrence of ulcers and the risk of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('H. pylori', 'Species', '210', (15, 24))	('recurrence of', 'CPA', (84, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('accelerate', 'PosReg', (38, 48))	('ulcer healing', 'Disease', (49, 62))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))	('accelerate ulcer healing', 'Phenotype', 'HP:0001058', (38, 62))	('Eradication', 'Var', (0, 11))	('H. pylori', 'Gene', (15, 24))	('gastric cancer', 'Disease', (121, 135))	('ulcers', 'Disease', 'MESH:D014456', (98, 104))	('reduce', 'NegReg', (73, 79))	('ulcer healing', 'Disease', 'MESH:D014456', (49, 62))	('ulcers', 'Disease', (98, 104))
890777	28429247	A multicenter, open-label, randomized controlled clinical trial containing 544 patients with early gastric cancer indicated that prophylactic eradication of H. pylori prevented the development of metachronous gastric carcinoma.	('H. pylori', 'Species', '210', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gastric cancer', 'Disease', (99, 113))	('eradication', 'Var', (142, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('metachronous gastric carcinoma', 'Disease', 'MESH:D016609', (196, 226))	('patients', 'Species', '9606', (79, 87))	('H. pylori', 'Gene', (157, 166))	('metachronous gastric carcinoma', 'Disease', (196, 226))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (209, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('prevented', 'NegReg', (167, 176))
890794	28429247	suggests that H. pylori eradication rates are not affected by host CYP2C19 polymorphisms.	('polymorphisms', 'Var', (75, 88))	('H. pylori', 'Species', '210', (14, 23))	('CYP2C19', 'Gene', '1557', (67, 74))	('H. pylori', 'Disease', (14, 23))	('eradication', 'MPA', (24, 35))	('CYP2C19', 'Gene', (67, 74))
890806	28429247	Exposure to PPIs resulted in a strong induction of heme oxygenase-1 (HO-1) mRNA and protein expression, leading to increased activity of this enzyme.	('HO-1', 'Gene', (69, 73))	('increased', 'PosReg', (115, 124))	('induction', 'PosReg', (38, 47))	('activity', 'MPA', (125, 133))	('heme oxygenase-1', 'Gene', '3162', (51, 67))	('HO-1', 'Gene', '3162', (69, 73))	('PPIs', 'Var', (12, 16))	('heme oxygenase-1', 'Gene', (51, 67))
890809	28429247	A possible reason for the treatment of coughs or other respiratory or gastrointestinal complaints caused by gastroesophageal reflux (GER) is that PPIs can decrease the production of proinflammatory cytokines such as IL-6, IL-8 and TNF-alpha in cultured airway epithelial cells.	('PPIs', 'Var', (146, 150))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (108, 131))	('IL-8', 'Gene', '3576', (222, 226))	('GER', 'Phenotype', 'HP:0002020', (133, 136))	('coughs', 'Disease', (39, 45))	('gastroesophageal reflux', 'Disease', (108, 131))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (108, 131))	('IL-8', 'Gene', (222, 226))	('TNF-alpha', 'Gene', '7124', (231, 240))	('IL-6', 'Gene', (216, 220))	('decrease', 'NegReg', (155, 163))	('gastrointestinal complaints', 'Phenotype', 'HP:0002027', (70, 97))	('TNF-alpha', 'Gene', (231, 240))	('coughs', 'Phenotype', 'HP:0012735', (39, 45))	('IL-6', 'Gene', '3569', (216, 220))	('production of proinflammatory cytokines', 'MPA', (168, 207))
890823	28429247	showed that PPIs combined with vinblastine could increase the sensitivity to vinblastinein, a pre-B acute lymphoblastic leukemia (ALL) cell line, and dose-dependently inhibit proliferation of tumor B cells, even used alone.	('vinblastine', 'Chemical', 'MESH:D014747', (31, 42))	('increase', 'PosReg', (49, 57))	('tumor', 'Disease', (192, 197))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (100, 128))	('ALL', 'Phenotype', 'HP:0006721', (130, 133))	('PPIs', 'Var', (12, 16))	('vinblastine', 'Chemical', 'MESH:D014747', (77, 88))	('acute lymphoblastic leukemia', 'Disease', (100, 128))	('inhibit', 'NegReg', (167, 174))	('vinblastinein', 'Chemical', '-', (77, 90))	('sensitivity to vinblastinein', 'MPA', (62, 90))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (106, 128))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (100, 128))	('B acute lymphoblastic leukemia', 'Phenotype', 'HP:0004812', (98, 128))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('proliferation', 'CPA', (175, 188))
890824	28429247	Another experiment also revealed that treating human gastric cancer cells with PPIs significantly attenuated cell viability in a time- and dose-dependent manner.	('gastric cancer', 'Disease', (53, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('attenuated', 'NegReg', (98, 108))	('human', 'Species', '9606', (47, 52))	('PPIs', 'Var', (79, 83))	('cell viability', 'CPA', (109, 123))
890830	28429247	The proposed mechanism was that PPIs combined with aspirin may eliminate acid and bile salt reflux or block the activation of gastrin-cholecystekinin (CCK)-cyclooxygenase-2 (COX-2)-mediated pro-carcinogenic signal pathways and regulate PGE2 production.	('PGE2 production', 'MPA', (236, 251))	('bile salt', 'Chemical', 'MESH:D001647', (82, 91))	('PPIs', 'Var', (32, 36))	('cyclooxygenase-2', 'Gene', '5743', (156, 172))	('cyclooxygenase-2', 'Gene', (156, 172))	('aspirin', 'Chemical', 'MESH:D001241', (51, 58))	('gastrin', 'Gene', (126, 133))	('gastrin', 'Gene', '25320', (126, 133))	('block', 'NegReg', (102, 107))	('regulate', 'Reg', (227, 235))	('eliminate', 'NegReg', (63, 72))	('PGE2', 'Chemical', 'MESH:D015232', (236, 240))
890843	28429247	The most probable mechanism of the antitumor effects of PPIs could be explained by inhibiting the acidic microenvironment in cancer.	('acidic microenvironment', 'MPA', (98, 121))	('PPIs', 'Var', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('iron', 'Chemical', 'MESH:D007501', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('inhibiting', 'NegReg', (83, 93))	('tumor', 'Disease', (39, 44))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
890844	28429247	PPIs remarkably disturb the acidic microenvironment and inhibit phosphorylation of the extracellular signal, which regulates kinase 1/2 (ERK1/2), Akt/Src kinases and pyruvate kinase M2 (PKM2), which might also contribute to the induction of apoptosis in cancer cells.	('Src', 'Gene', (150, 153))	('disturb', 'Reg', (16, 23))	('cancer', 'Disease', (254, 260))	('regulates', 'Reg', (115, 124))	('ERK1/2', 'Gene', (137, 143))	('pyruvate kinase M2', 'Gene', (166, 184))	('inhibit', 'NegReg', (56, 63))	('Src', 'Gene', '6714', (150, 153))	('ERK1/2', 'Gene', '5595;5594', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('pyruvate kinase M2', 'Gene', '5315', (166, 184))	('contribute', 'Reg', (210, 220))	('Akt', 'Gene', (146, 149))	('acidic microenvironment', 'MPA', (28, 51))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('PKM2', 'Gene', (186, 190))	('PKM2', 'Gene', '5315', (186, 190))	('PPIs', 'Var', (0, 4))	('phosphorylation of the extracellular signal', 'MPA', (64, 107))	('Akt', 'Gene', '207', (146, 149))	('iron', 'Chemical', 'MESH:D007501', (43, 47))
890852	28429247	Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and p38 MAPK were reported to be associated with PPI-induced ROS accumulation.	('p38', 'Var', (64, 67))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('associated', 'Reg', (93, 103))	('ROS accumulation', 'MPA', (121, 137))	('Nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (0, 33))
890856	28429247	A study containing 1420 patients showed that inhibiting TOPK could benefit 30-40% patients with metastatic colorectal cancer.	('inhibiting', 'Var', (45, 55))	('patients', 'Species', '9606', (82, 90))	('TOPK', 'Gene', '55872', (56, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TOPK', 'Gene', (56, 60))	('colorectal cancer', 'Disease', (107, 124))	('patients', 'Species', '9606', (24, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))
890865	28429247	A systematic review of eight observational studies found that the overall risk of pneumonia (either community or hospital acquired) was higher among people using PPIs (OR 1.27; 95% CI 1.11-1.46).	('PPIs', 'Var', (162, 166))	('people', 'Species', '9606', (149, 155))	('pneumonia', 'Phenotype', 'HP:0002090', (82, 91))	('pneumonia', 'Disease', (82, 91))	('pneumonia', 'Disease', 'MESH:D011014', (82, 91))
890869	28429247	Another infection associated with PPI therapy is Clostridium difficile infection (CDI), which is a common cause of nosocomial diarrhea, leading to a high risk of morbidity and mortality.	('nosocomial diarrhea', 'Disease', 'MESH:D003967', (115, 134))	('diarrhea', 'Phenotype', 'HP:0002014', (126, 134))	('Clostridium difficile infection', 'Disease', 'MESH:D003015', (49, 80))	('Clostridium difficile infection', 'Disease', (49, 80))	('nosocomial diarrhea', 'Disease', (115, 134))	('CDI', 'Phenotype', 'HP:0032167', (82, 85))	('infection', 'Disease', (8, 17))	('PPI therapy', 'Var', (34, 45))	('infection', 'Disease', 'MESH:D007239', (8, 17))	('infection', 'Disease', (71, 80))	('Clostridium difficile infection', 'Phenotype', 'HP:0032167', (49, 80))	('infection', 'Disease', 'MESH:D007239', (71, 80))
890876	28429247	A meta-analysis of nine studies reported a statistically significant effect of PPI therapy on the risk of developing hypomagnesemia (OR 1.76; 95% CI 1.08-2.92) in 2015.	('hypomagnesemia', 'Phenotype', 'HP:0002917', (117, 131))	('hypomagnesemia', 'Disease', (117, 131))	('hypomagnesemia', 'Disease', 'MESH:C537153', (117, 131))	('PPI therapy', 'Var', (79, 90))
890882	28429247	Previous studies discovered that patients with PPI-induced hypomagnesemia also have low fractional excretion of magnesium in the urine, which suggests an extra-renal cause for this electrolyte abnormality.	('PPI-induced', 'Var', (47, 58))	('low', 'NegReg', (84, 87))	('patients', 'Species', '9606', (33, 41))	('hypomagnesemia', 'Disease', 'MESH:C537153', (59, 73))	('magnesium', 'Chemical', 'MESH:D008274', (112, 121))	('electrolyte abnormality', 'Phenotype', 'HP:0003111', (181, 204))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (59, 73))	('hypomagnesemia', 'Disease', (59, 73))	('fractional excretion of magnesium in the urine', 'MPA', (88, 134))
890885	28429247	Many clinical studies have shown a correlation between PPIs and osteoporosis or osteoporosis-related fractures, and PPI therapy increases the risk of osteoporosis-related fractures significantly.	('osteoporosis', 'Phenotype', 'HP:0000939', (80, 92))	('osteoporosis', 'Disease', (150, 162))	('fractures', 'Disease', (171, 180))	('fractures', 'Disease', 'MESH:D050723', (101, 110))	('osteoporosis', 'Phenotype', 'HP:0000939', (64, 76))	('PPIs', 'Disease', (55, 59))	('PPI', 'Var', (116, 119))	('osteoporosis', 'Phenotype', 'HP:0000939', (150, 162))	('increases', 'PosReg', (128, 137))	('correlation', 'Interaction', (35, 46))	('osteoporosis', 'Disease', 'MESH:D010024', (80, 92))	('fractures', 'Disease', 'MESH:D050723', (171, 180))	('osteoporosis', 'Disease', (80, 92))	('fractures', 'Disease', (101, 110))	('osteoporosis', 'Disease', 'MESH:D010024', (64, 76))	('osteoporosis', 'Disease', (64, 76))	('osteoporosis', 'Disease', 'MESH:D010024', (150, 162))
890886	28429247	conducted a nested case-control study to evaluate the correlation between long-term use of high-dose PPIs and hip fracture, and the results showed that the adjusted odds ratio (AOR) for hip fracture associated with PPI therapy (more than 1 year) was 1.44.	('PPI', 'Var', (215, 218))	('hip fracture', 'Disease', 'MESH:D006620', (186, 198))	('hip fracture', 'Disease', (110, 122))	('hip fracture', 'Disease', (186, 198))	('hip fracture', 'Disease', 'MESH:D006620', (110, 122))
890888	28429247	A prospective randomized study recruited 26 patients aged between 55 and 85 (PPI group, n = 13; revaprazan group, n = 13) and showed that PPIs might directly alter the bone metabolism after an 8-week therapy in elderly patients.	('PPIs', 'Var', (138, 142))	('patients', 'Species', '9606', (44, 52))	('alter', 'Reg', (158, 163))	('patients', 'Species', '9606', (219, 227))	('bone metabolism', 'MPA', (168, 183))	('revaprazan', 'Chemical', 'MESH:C108798', (96, 106))
890892	28429247	According to clinical studies, hypochlorhydria caused by PPI therapy leads to a decrease in calcium absorption in the small intestine and then lower blood calcium.	('lower blood calcium', 'Phenotype', 'HP:0002901', (143, 162))	('lower', 'NegReg', (143, 148))	('PPI therapy', 'Var', (57, 68))	('hypochlorhydria', 'Disease', (31, 46))	('calcium', 'Chemical', 'MESH:D002118', (92, 99))	('calcium', 'Chemical', 'MESH:D002118', (155, 162))	('calcium absorption in the small intestine', 'MPA', (92, 133))	('blood calcium', 'MPA', (149, 162))	('hypochlorhydria', 'Disease', 'MESH:D000126', (31, 46))	('decrease', 'NegReg', (80, 88))
890894	28429247	Second, PPIs could inhibit the V-ATPase of osteoclasts in the same way that PPIs inhibit gastric H+/K+-ATPase, having a direct deleterious effect on bone cells, with the possibility of decreased bone turnover.	('decreased bone turnover', 'Disease', 'MESH:D001859', (185, 208))	('PPIs', 'Var', (76, 80))	('inhibit', 'NegReg', (19, 26))	('inhibit', 'NegReg', (81, 88))	('gastric H+/K+-ATPase', 'MPA', (89, 109))	('V-ATPase', 'Protein', (31, 39))	('decreased bone turnover', 'Disease', (185, 208))
890902	28429247	PPI-induced AIN may relate to an immunologic reaction, as indicated by the relatively common appearance of extrarenal manifestations of hypersensitivity.	('AIN', 'Disease', (12, 15))	('PPI-induced', 'Var', (0, 11))	('hypersensitivity', 'Disease', 'MESH:D004342', (136, 152))	('AIN', 'Phenotype', 'HP:0004729', (12, 15))	('hypersensitivity', 'Disease', (136, 152))
890908	28429247	Inhibition of intracellular Ca2+ outflow may cause intracellular calcium overload, causing a series of cell death.	('intracellular calcium overload', 'Phenotype', 'HP:0003575', (51, 81))	('Ca2+', 'Chemical', 'MESH:D000069285', (28, 32))	('causing', 'Reg', (83, 90))	('intracellular calcium overload', 'MPA', (51, 81))	('Inhibition', 'Var', (0, 10))	('cause', 'Reg', (45, 50))	('intracellular Ca2+ outflow', 'MPA', (14, 40))	('calcium', 'Chemical', 'MESH:D002118', (65, 72))
890912	28429247	Another possible reason is that PPIs inhibit the enzymatic activity of dimethylarginine dimethyl aminohydrolase (DDAH), which is responsible for clearing 80% of asymmetric dimethylarginine (ADMA).	('ADMA', 'Chemical', 'MESH:C018524', (190, 194))	('dimethylarginine', 'Chemical', 'MESH:C487735', (71, 87))	('dimethylarginine dimethyl aminohydrolase', 'Gene', (71, 111))	('DDAH', 'Gene', (113, 117))	('PPIs', 'Var', (32, 36))	('enzymatic activity', 'MPA', (49, 67))	('DDAH', 'Gene', '23576', (113, 117))	('inhibit', 'NegReg', (37, 44))	('dimethylarginine', 'Chemical', 'MESH:C487735', (172, 188))	('dimethylarginine dimethyl aminohydrolase', 'Gene', '23576', (71, 111))
890913	28429247	A recent pre-clinical study found that PPIs increased the ADMA levels in human endothelial cells and in mice by about 20-30%.	('mice', 'Species', '10090', (104, 108))	('human', 'Species', '9606', (73, 78))	('PPIs', 'Var', (39, 43))	('increased', 'PosReg', (44, 53))	('ADMA', 'Chemical', 'MESH:C018524', (58, 62))	('ADMA levels', 'MPA', (58, 69))
890924	28429247	There is evidence suggesting that PPIs may decrease methotrexate clearance and elevate the serum concentration, eventually increasing the toxicity.	('decrease', 'NegReg', (43, 51))	('methotrexate', 'Chemical', 'MESH:D008727', (52, 64))	('toxicity', 'Disease', 'MESH:D064420', (138, 146))	('increasing', 'PosReg', (123, 133))	('elevate', 'PosReg', (79, 86))	('methotrexate clearance', 'MPA', (52, 74))	('toxicity', 'Disease', (138, 146))	('PPIs', 'Var', (34, 38))	('serum concentration', 'MPA', (91, 110))
891085	27689360	It was reported that TRIM24 could activate estrogen-dependent genes associated with cellular proliferation and tumor development in breast cancer, and was negatively correlated with survival of this disease.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('activate', 'PosReg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('negatively', 'NegReg', (155, 165))	('cellular proliferation', 'CPA', (84, 106))	('TRIM24', 'Var', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', (111, 116))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('estrogen-dependent genes', 'Gene', (43, 67))
891087	27689360	However, some other studies show that mice with deletion of TRIM24 are predisposed to spontaneous hepatocarcinogenesis with the increased oncogenic activity of RARalpha, demonstrating that TRIM24 gene functions as a tumor suppressor while RARalpha as an oncogene in the development and progression of liver cancer.	('tumor', 'Disease', (216, 221))	('liver cancer', 'Disease', (301, 313))	('hepatocarcinogenesis', 'Disease', (98, 118))	('mice', 'Species', '10090', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('predisposed', 'Reg', (71, 82))	('TRIM24', 'Gene', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (98, 118))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('deletion', 'Var', (48, 56))	('liver cancer', 'Phenotype', 'HP:0002896', (301, 313))	('liver cancer', 'Disease', 'MESH:D006528', (301, 313))
891108	27689360	The results demonstrate that 71.6% (78/109) of patients with low TRIM24 expression have lymph node metastasis (LNM) while only 28.4% (31/109) of patients with high expression have LNM (P=0.024, Table 1); 71.4% (70/98) of ones with low expression have pathological tumour-node-metastasis stage (pTNM stage) III while only 28.6% (28/98) of ones with high expression have pTNM stage III (P=0.046, Table 1), suggesting that TRIM24 may inhibit ESCC progression.	('patients', 'Species', '9606', (145, 153))	('TNM', 'Gene', '10178', (370, 373))	('tumour-node-metastasis', 'Disease', 'MESH:D009362', (264, 286))	('tumour-node-metastasis', 'Disease', (264, 286))	('inhibit', 'NegReg', (431, 438))	('low', 'NegReg', (61, 64))	('SCC', 'Gene', (440, 443))	('ES', 'Chemical', 'MESH:D004540', (439, 441))	('patients', 'Species', '9606', (47, 55))	('TNM', 'Gene', (370, 373))	('TNM', 'Gene', (295, 298))	('expression', 'MPA', (72, 82))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('SCC', 'Gene', '6317', (440, 443))	('TRIM24', 'Var', (420, 426))	('TNM', 'Gene', '10178', (295, 298))	('TRIM24', 'Gene', (65, 71))
891109	27689360	Moreover, patients with low expression have more postoperative relapse and metastasis than those with high expression (72.4% [97/134] vs 27.6% [37/134], P=0.001, Table 1), implying that TRIM24 may suppress ESCC development and metastasis.	('postoperative', 'CPA', (49, 62))	('suppress', 'NegReg', (197, 205))	('ES', 'Chemical', 'MESH:D004540', (206, 208))	('SCC', 'Gene', (207, 210))	('TRIM24', 'Var', (186, 192))	('patients', 'Species', '9606', (10, 18))	('SCC', 'Gene', '6317', (207, 210))
891111	27689360	As expected, Kaplan-Meier survival analysis shows that patients with high TRIM24 expression have significantly better overall survival (OS) and disease-free survival (DFS) than those with low expression (P<0.001, P<0.001, respectively; Fig.	('overall survival', 'CPA', (118, 134))	('disease-free survival', 'CPA', (144, 165))	('better', 'PosReg', (111, 117))	('TRIM24', 'Protein', (74, 80))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (55, 63))
891112	27689360	Survival analysis also display that 5-year OS and 5-year DFS of patients with high TRIM24 level are 64.4% and 57.2%, compared with 35.8% and 28.9% of those with low level, respectively, which hint that TRIM24 is a tumor suppressor in ESCC patients.	('TRIM24', 'Gene', (83, 89))	('high', 'Var', (78, 82))	('SCC', 'Gene', '6317', (235, 238))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('patients', 'Species', '9606', (239, 247))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('ES', 'Chemical', 'MESH:D004540', (234, 236))	('tumor', 'Disease', (214, 219))	('hint', 'Gene', '3094', (192, 196))	('SCC', 'Gene', (235, 238))	('hint', 'Gene', (192, 196))
891117	27689360	As presented in Table 2, TRIM24 expression is identified as an independent survival predictor for OS (HR, 0.519; 95%CI, 0.341-0.788; P=0.002) and DFS (HR, 0.584; 95%CI, 0.397-0.861; P=0.007), and pTNM staging system is another independent prognostic factor.	('TRIM24 expression', 'Var', (25, 42))	('TNM', 'Gene', (197, 200))	('TNM', 'Gene', '10178', (197, 200))	('DFS', 'Disease', (146, 149))
891126	27689360	Since the above result shows that TRIM24 can provide additional prognostic information, we hypothesized that TRIM24 will improve the prediction of survival in ESCC patients when it is combined with pTNM staging system.	('TRIM24', 'Var', (109, 115))	('TNM', 'Gene', '10178', (199, 202))	('ES', 'Chemical', 'MESH:D004540', (159, 161))	('survival', 'Disease', (147, 155))	('TNM', 'Gene', (199, 202))	('SCC', 'Gene', (160, 163))	('improve', 'PosReg', (121, 128))	('patients', 'Species', '9606', (164, 172))	('SCC', 'Gene', '6317', (160, 163))
891135	27689360	These results suggest that TRIM24 can significantly improve postoperative prognostic prediction for ESCC patients in the combined risk model.	('patients', 'Species', '9606', (105, 113))	('TRIM24', 'Var', (27, 33))	('SCC', 'Gene', (101, 104))	('improve', 'PosReg', (52, 59))	('ES', 'Chemical', 'MESH:D004540', (100, 102))	('SCC', 'Gene', '6317', (101, 104))	('postoperative', 'MPA', (60, 73))
891136	27689360	In this study, our findings indicate that TRIM24 functions as a tumor suppressor in ESCC, which is conflicting with some reports on other cancers.	('ES', 'Chemical', 'MESH:D004540', (84, 86))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('SCC', 'Gene', '6317', (85, 88))	('TRIM24', 'Var', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('SCC', 'Gene', (85, 88))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
891137	27689360	However, in transgenic mice models, TRIM24 is demonstrated as a tumor suppressor and can suppress liver carcinogenesis via interacting with RARalpha.	('TRIM24', 'Var', (36, 42))	('tumor', 'Disease', (64, 69))	('transgenic mice', 'Species', '10090', (12, 27))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (98, 118))	('interacting', 'Interaction', (123, 134))	('liver carcinogenesis', 'Disease', (98, 118))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('suppress', 'NegReg', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
891146	27689360	In the current study, immunohistochemical staining shows that TRIM24 protein is predominantly localized in the nuclei of ESCC cells and NECT cells, suggesting that it may be involved in the transcriptional process, which is in accordance with other reports.	('SCC', 'Gene', (122, 125))	('involved', 'Reg', (174, 182))	('SCC', 'Gene', '6317', (122, 125))	('TRIM24', 'Var', (62, 68))	('ES', 'Chemical', 'MESH:D004540', (121, 123))
891148	27689360	More important, our study shows that lower expression level of TRIM24 protein is associated with more lymph node metastasis, advanced pTNM stage and postoperative recurrence/metastasis, signifying that TRIM24 protein mainly functions as tumor suppressor in early development of ESCC and loss of TRIM24 protein may result in the progression of ESCC.	('TNM', 'Gene', (135, 138))	('tumor', 'Disease', (237, 242))	('SCC', 'Gene', (279, 282))	('ES', 'Chemical', 'MESH:D004540', (343, 345))	('result in', 'Reg', (314, 323))	('SCC', 'Gene', '6317', (344, 347))	('SCC', 'Gene', (344, 347))	('SCC', 'Gene', '6317', (279, 282))	('lymph node metastasis', 'CPA', (102, 123))	('ES', 'Chemical', 'MESH:D004540', (278, 280))	('expression level', 'MPA', (43, 59))	('TNM', 'Gene', '10178', (135, 138))	('loss', 'Var', (287, 291))	('lower', 'NegReg', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('TRIM24', 'Gene', (63, 69))
891149	27689360	Furthermore, survival analysis reveals that patients with decreased level of TRIM24 have a poor survival rate and that TRIM24 is an independent prognostic factor in ESCC.	('patients', 'Species', '9606', (44, 52))	('TRIM24', 'Var', (119, 125))	('decreased', 'NegReg', (58, 67))	('TRIM24', 'Gene', (77, 83))	('survival rate', 'CPA', (96, 109))	('SCC', 'Gene', (166, 169))	('ES', 'Chemical', 'MESH:D004540', (165, 167))	('poor', 'NegReg', (91, 95))	('SCC', 'Gene', '6317', (166, 169))
891153	27689360	An earlier study defined TRIM24 as an E3-ubiquitin ligase that could degrade p53 protein, and loss of TRIM24/bonus would result in increased p53 expression and p53-dependent apoptosis in Drosophila and p53-postive MCF7 human breast cancer cells.	('human', 'Species', '9606', (219, 224))	('increased', 'PosReg', (131, 140))	('p53-dependent apoptosis', 'CPA', (160, 183))	('TRIM24/bonus', 'Gene', (102, 114))	('MCF7', 'CellLine', 'CVCL:0031', (214, 218))	('loss', 'Var', (94, 98))	('Drosophila', 'Species', '7227', (187, 197))	('expression', 'MPA', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('degrade', 'NegReg', (69, 76))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', (225, 238))	('p53', 'Protein', (141, 144))	('p53 protein', 'Protein', (77, 88))
891155	27689360	Importantly, in a mouse model with cre-mediated excision of exon 4 of TRIM24 (TRIM24dlE4/dlE4), Khetchoumian K et al found that deficiency of TRIM24 may lead to continuous hepatocytes proliferation, spontaneous hepatocarcino-genesis, and increased susceptibility to chemically induced HCC.	('TRIM24', 'Gene', (142, 148))	('hepatocarcino-genesis', 'Disease', 'MESH:D006938', (211, 232))	('mouse', 'Species', '10090', (18, 23))	('continuous', 'CPA', (161, 171))	('chemically induced HCC', 'Disease', (266, 288))	('deficiency', 'Var', (128, 138))	('lead to', 'Reg', (153, 160))	('hepatocarcino-genesis', 'Disease', (211, 232))
891158	27689360	Mechanically, TRIM24 inhibits RARalpha dependent transcription to negatively regulate IFN/ STAT signaling pathway in the hepatocarcinogenesis of mice.	('inhibits', 'NegReg', (21, 29))	('negatively regulate', 'NegReg', (66, 85))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (121, 141))	('RARalpha', 'Protein', (30, 38))	('hepatocarcinogenesis', 'Disease', (121, 141))	('TRIM24', 'Var', (14, 20))	('mice', 'Species', '10090', (145, 149))	('IFN/ STAT signaling pathway', 'Pathway', (86, 113))
891208	26297437	TOPFlash activity was elevated following Dkk1 silencing in CP-A but not in OE33 cells.	('Dkk1', 'Gene', '22943', (41, 45))	('CP-A', 'Gene', '1357', (59, 63))	('Dkk1', 'Gene', (41, 45))	('silencing', 'Var', (46, 55))	('CP-A', 'Gene', (59, 63))	('elevated', 'PosReg', (22, 30))	('TOPFlash activity', 'MPA', (0, 17))
891308	26297437	Furthermore, following Dkk1 siRNA-mediated gene knockdown in resting CP-A cells (over 75% knockdown), a significant increase in TOPflash activity was observed (Figure 6B).	('Dkk1', 'Gene', (23, 27))	('TOPflash', 'CPA', (128, 136))	('CP-A', 'Gene', '1357', (69, 73))	('CP-A', 'Gene', (69, 73))	('increase', 'PosReg', (116, 124))	('Dkk1', 'Gene', '22943', (23, 27))	('knockdown', 'Var', (48, 57))
891318	26297437	Therefore, we analyzed next the levels of beta-catenin signaling in OE33 cells following Dkk1 gene silencing (Figure 7C).	('Dkk1', 'Gene', '22943', (89, 93))	('beta-catenin', 'Gene', (42, 54))	('beta-catenin', 'Gene', '1499', (42, 54))	('Dkk1', 'Gene', (89, 93))	('gene silencing', 'Var', (94, 108))
891319	26297437	As shown by luciferase assay and real-time PCR, the Dkk1 knockdown had no effect on the baseline TOPflash activity in OE33 (Figure 7D), suggesting the inability of Dkk1 to autoregulate the levels of beta-catenin signaling in OE33 cells as it did in CP-A cells.	('Dkk1', 'Gene', '22943', (164, 168))	('beta-catenin', 'Gene', '1499', (199, 211))	('Dkk1', 'Gene', '22943', (52, 56))	('Dkk1', 'Gene', (164, 168))	('knockdown', 'Var', (57, 66))	('TOPflash activity', 'MPA', (97, 114))	('Dkk1', 'Gene', (52, 56))	('CP-A', 'Gene', '1357', (249, 253))	('CP-A', 'Gene', (249, 253))	('beta-catenin', 'Gene', (199, 211))
891325	26297437	Reversely, Dkk1 knockdown increased TOPflash activity and AXIN2 gene expression in these cells, underlying the Dkk1-mediated suppression of Wnt axis.	('activity', 'MPA', (45, 53))	('Wnt axis', 'Pathway', (140, 148))	('Dkk1', 'Gene', '22943', (11, 15))	('AXIN2', 'Gene', (58, 63))	('suppression', 'NegReg', (125, 136))	('AXIN2', 'Gene', '8313', (58, 63))	('knockdown', 'Var', (16, 25))	('expression', 'MPA', (69, 79))	('Dkk1', 'Gene', '22943', (111, 115))	('Dkk1', 'Gene', (11, 15))	('increased', 'PosReg', (26, 35))	('Dkk1', 'Gene', (111, 115))	('TOPflash', 'Protein', (36, 44))
891327	26297437	However, contrary to CP-A cells, Dkk1 knockdown in OE33 cells did not alter TOPflash activity, underscoring the possible inability of Dkk1 to suppress Wnt axis in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('CP-A', 'Gene', '1357', (21, 25))	('Wnt axis', 'Pathway', (151, 159))	('CP-A', 'Gene', (21, 25))	('Dkk1', 'Gene', (134, 138))	('TOPflash activity', 'MPA', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Dkk1', 'Gene', '22943', (33, 37))	('knockdown', 'Var', (38, 47))	('cancer', 'Disease', (163, 169))	('Dkk1', 'Gene', '22943', (134, 138))	('Dkk1', 'Gene', (33, 37))
891337	26297437	Thus, using a specific antibody detecting the dephosphorylated (Ser 37002FThr 41) ABC, we verified higher beta-catenin activity in BE compared with squamous mucosa.	('beta-catenin', 'Gene', '1499', (106, 118))	('BE', 'Phenotype', 'HP:0100580', (131, 133))	('higher', 'PosReg', (99, 105))	('Ser 37002FThr 41', 'Var', (64, 80))	('Ser', 'Chemical', 'MESH:D012694', (64, 67))	('beta-catenin', 'Gene', (106, 118))
891349	26297437	In line with this notion, differential expression of Wnt ligands has already been suggested in squamous epithelium, whereas the reflux-associated expression of the Wnt-antagonist Dkk1 may prevent canonical Wnt signaling as a response to constitutive increase of Wnt signals during reflux esophagitis.	('expression', 'Var', (146, 156))	('prevent', 'NegReg', (188, 195))	('canonical Wnt signaling', 'MPA', (196, 219))	('Dkk1', 'Gene', (179, 183))	('reflux esophagitis', 'Disease', (281, 299))	('reflux esophagitis', 'Disease', 'MESH:D005764', (281, 299))	('esophagitis', 'Phenotype', 'HP:0100633', (288, 299))	('Dkk1', 'Gene', '22943', (179, 183))
891353	26297437	The increased signaling activation of beta-catenin by Wnt3a was blocked by Dkk1, whereas Dkk1 knockdown in CP-A cells resulted in increased beta-catenin transcriptional activity along with a higher sensitization of the cells to Wnt3a.	('higher', 'PosReg', (191, 197))	('knockdown', 'Var', (94, 103))	('CP-A', 'Gene', '1357', (107, 111))	('Dkk1', 'Gene', '22943', (89, 93))	('increased', 'PosReg', (130, 139))	('beta-catenin', 'Gene', (38, 50))	('Dkk1', 'Gene', (75, 79))	('beta-catenin', 'Gene', '1499', (38, 50))	('Wnt3a', 'Gene', '89780', (228, 233))	('Wnt3a', 'Gene', '89780', (54, 59))	('beta-catenin', 'Gene', (140, 152))	('Wnt3a', 'Gene', (228, 233))	('Wnt3a', 'Gene', (54, 59))	('beta-catenin', 'Gene', '1499', (140, 152))	('Dkk1', 'Gene', (89, 93))	('sensitization', 'MPA', (198, 211))	('CP-A', 'Gene', (107, 111))	('signaling activation', 'MPA', (14, 34))	('Dkk1', 'Gene', '22943', (75, 79))
891362	26297437	BMP4 signaling was reduced in a mouse model following deletion of Wnt ligands, suggesting that Wnt signaling may be positioned upstream of BMP pathway in specifying the columnar differentiation.	('BMP', 'Gene', (0, 3))	('deletion', 'Var', (54, 62))	('BMP', 'Gene', '649', (139, 142))	('columnar differentiation', 'CPA', (169, 193))	('BMP', 'Gene', (139, 142))	('reduced', 'NegReg', (19, 26))	('mouse', 'Species', '10090', (32, 37))	('BMP', 'Gene', '649', (0, 3))
891370	26297437	In an effort to elucidate this activation, changes, such as increased expression of Wnt2 ligand or epigenetic loss of the Wnt inhibitory factor 1 and secreted frizzled receptor proteins negative regulators, have already been reported in EAC.	('Wnt inhibitory factor 1', 'Gene', (122, 145))	('Wnt2', 'Gene', (84, 88))	('EAC', 'Phenotype', 'HP:0011459', (237, 240))	('Wnt inhibitory factor 1', 'Gene', '11197', (122, 145))	('expression', 'MPA', (70, 80))	('epigenetic', 'Var', (99, 109))	('EAC', 'Disease', (237, 240))	('Wnt2', 'Gene', '7472', (84, 88))	('increased', 'PosReg', (60, 69))
891372	26297437	Interestingly, loss-of-function mutations in APC, beta-catenin, or Axin, which have been associated with high beta-catenin activity , are not frequently detected in BE or EAC.	('beta-catenin', 'Gene', (110, 122))	('beta-catenin', 'Gene', '1499', (50, 62))	('EAC', 'Phenotype', 'HP:0011459', (171, 174))	('APC', 'Phenotype', 'HP:0005227', (45, 48))	('beta-catenin', 'Gene', '1499', (110, 122))	('beta-catenin', 'Gene', (50, 62))	('Axin', 'Gene', '8312', (67, 71))	('mutations', 'Var', (32, 41))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (45, 48))	('loss-of-function', 'NegReg', (15, 31))	('Axin', 'Gene', (67, 71))	('BE', 'Phenotype', 'HP:0100580', (165, 167))
891394	25344056	Although ENI might delay cervical nodes progression in elective field; it could not decrease the incidence of these failures.	('delay', 'NegReg', (19, 24))	('ENI', 'Chemical', '-', (9, 12))	('ENI', 'Var', (9, 12))	('cervical nodes progression', 'CPA', (25, 51))
891465	25344056	also showed ENI was effective for preventing regional nodal failure.	('ENI', 'Chemical', '-', (12, 15))	('nodal failure', 'Disease', (54, 67))	('nodal failure', 'Disease', 'MESH:D013611', (54, 67))	('ENI', 'Var', (12, 15))
891606	23247578	In general, these results should serve to reassure patients and their physicians that, in most cases, RFA induces a durable complete eradication of dysplasia and intestinal metaplasia.	('eradication of dysplasia', 'Disease', 'MESH:D004476', (133, 157))	('eradication of dysplasia', 'Disease', (133, 157))	('dysplasia and intestinal metaplasia', 'Disease', 'MESH:D008679', (148, 183))	('patients', 'Species', '9606', (51, 59))	('RFA', 'Var', (102, 105))
891678	19415697	This review provides a brief overview of current data documenting various mechanisms underlying aberrant cyclin D1 regulation in human cancers and their impact on neoplastic transformation.	('impact', 'Reg', (153, 159))	('regulation', 'MPA', (115, 125))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('neoplastic transformation', 'CPA', (163, 188))	('cancers', 'Disease', (135, 142))	('aberrant', 'Var', (96, 104))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('human', 'Species', '9606', (129, 134))	('cyclin D1', 'Protein', (105, 114))
891705	19415697	Genomic alterations leading to aberrant cyclin D1 expression have been the subject of intensive investigation in a variety of tumors because of their predicted role for dysregulation of cyclin D1 abundance.	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('aberrant', 'Var', (31, 39))	('cyclin D1', 'Gene', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('expression', 'MPA', (50, 60))
891706	19415697	Chromosomal translocation is a common genetic mechanism of pathogenesis of B-cell lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('Chromosomal translocation', 'Var', (0, 25))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (75, 90))	('B-cell lymphoma', 'Disease', (75, 90))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (75, 90))	('cell lymphoma', 'Phenotype', 'HP:0012191', (77, 90))
891709	19415697	The chromosomal translocation t(6;14)(p21.1;q32.3) is a rare but recurrent event in multiple myeloma.	('t(6;14)(p21.1;q32.3', 'Var', (30, 49))	('t(6;14)(p21.1;q32.3)', 'STRUCTURAL_ABNORMALITY', 'None', (30, 50))	('multiple myeloma', 'Disease', 'MESH:D009101', (84, 100))	('multiple myeloma', 'Phenotype', 'HP:0006775', (84, 100))	('multiple myeloma', 'Disease', (84, 100))
891710	19415697	In addition to multiple myeloma, the t(6;14)(p21.1;q32.3) translocation and an accompanying overexpression of cyclin D3 has been observed in several histologic subtypes of mature B-cell malignancies.	('cyclin D3', 'Gene', (110, 119))	('overexpression', 'PosReg', (92, 106))	('multiple myeloma', 'Phenotype', 'HP:0006775', (15, 31))	('multiple myeloma', 'Disease', 'MESH:D009101', (15, 31))	('multiple myeloma', 'Disease', (15, 31))	('t(6;14)(p21.1', 'Var', (37, 50))	('cyclin D3', 'Gene', '896', (110, 119))	('t(6;14)(p21.1;q32.3)', 'STRUCTURAL_ABNORMALITY', 'None', (37, 57))
891712	19415697	Gene amplifications that encompass the cyclin D1 locus have also been observed in a number of cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cyclin D1', 'Gene', (39, 48))	('Gene amplifications', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('observed', 'Reg', (70, 78))	('cancers', 'Disease', (94, 101))
891713	19415697	Cyclin D1 overexpression resulting from amplification of 11q13 has been reported in various tumor types such as head and neck carcinoma, pituitary tumor, esophageal squamous cell carcinoma, and breast cancer.	('esophageal squamous cell carcinoma', 'Disease', (154, 188))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (112, 135))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Cyclin D1', 'Gene', '595', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Cyclin D1', 'Gene', (0, 9))	('amplification of', 'Var', (40, 56))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('pituitary tumor', 'Disease', 'MESH:D010911', (137, 152))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (154, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('pituitary tumor', 'Disease', (137, 152))	('11q13', 'Gene', (57, 62))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('overexpression', 'PosReg', (10, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('neck carcinoma', 'Disease', (121, 135))	('breast cancer', 'Disease', (194, 207))	('neck carcinoma', 'Disease', 'MESH:D006258', (121, 135))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (92, 97))
891714	19415697	Among more than 100 polymorphisms identified in cyclin D1, G/A870 polymorphism has gained the most attention due to its potential contribution to cyclin D1 alternative splicing.	('G/A870', 'Var', (59, 65))	('G/A870', 'Mutation', 'rs9344', (59, 65))	('cyclin D1 alternative splicing', 'MPA', (146, 176))	('contribution', 'Reg', (130, 142))
891716	19415697	Recently, it has been shown that truncations in 3' untranslated region (UTR) of CCND1 mRNA in MCL cell lines eliminate miR-16-1 binding sites in the 3' UTR, resulting in escape of the CCND1 transcripts from miR-16-1-mediated down-regulation.	('CCND1', 'Gene', (184, 189))	('miR-16-1', 'Gene', (207, 215))	('CCND1', 'Gene', (80, 85))	('miR-16-1', 'Gene', '406950', (207, 215))	('down-regulation', 'NegReg', (225, 240))	('truncations', 'Var', (33, 44))	('miR-16-1', 'Gene', (119, 127))	('CCND1', 'Gene', '595', (80, 85))	('eliminate', 'NegReg', (109, 118))	('CCND1', 'Gene', '595', (184, 189))	('binding', 'Interaction', (128, 135))	('transcripts', 'MPA', (190, 201))	('miR-16-1', 'Gene', '406950', (119, 127))	('escape', 'MPA', (170, 176))
891718	19415697	As a key regulator of G1 reentry and progression, cyclin D1 turnover is subject to a tight regulation by a defined mechanism involving GSK3beta-mediated phosphorylation of Thr286, nuclear export by CRM1, and subsequent ubiquitylation by SCFFbx4/alphaB-crystallin ligase targeting the cyclin D1 to the 26S proteasome (Figure 1A).	('Thr286', 'Chemical', '-', (172, 178))	('CRM1', 'Gene', '7514', (198, 202))	('GSK3beta', 'Gene', (135, 143))	('nuclear export', 'MPA', (180, 194))	('GSK3beta', 'Gene', '2932', (135, 143))	('CRM1', 'Gene', (198, 202))	('ubiquitylation', 'MPA', (219, 233))	('Thr286', 'Var', (172, 178))
891720	19415697	Consistent with this notion, mutations targeting the nuclear export or proteolysis of cyclin D1 have been well documented in human cancers while mutations directed at the Thr286 seem to be rare.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cyclin D1', 'Gene', (86, 95))	('cancers', 'Disease', (131, 138))	('proteolysis', 'MPA', (71, 82))	('mutations', 'Var', (29, 38))	('human', 'Species', '9606', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('nuclear export', 'MPA', (53, 67))	('Thr286', 'Chemical', '-', (171, 177))
891721	19415697	For example, several mutations that impair phosphorylation-dependent nuclear export of cyclin D1 have been identified in esophageal carcinoma and esophageal cancer-derived cell lines.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('esophageal cancer', 'Disease', (146, 163))	('cyclin', 'Protein', (87, 93))	('phosphorylation-dependent nuclear export', 'MPA', (43, 83))	('esophageal carcinoma', 'Disease', (121, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (121, 141))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (121, 141))	('impair', 'NegReg', (36, 42))	('mutations', 'Var', (21, 30))
891722	19415697	Similarly, cyclin D1 gene in endometrial cancer also possesses mutations or deletions that are expected to affect the phosphorylation of Thr286 and CRM1 binding.	('mutations', 'Var', (63, 72))	('CRM1', 'Gene', '7514', (148, 152))	('affect', 'Reg', (107, 113))	('CRM1', 'Gene', (148, 152))	('Thr286', 'Chemical', '-', (137, 143))	('cyclin D1', 'Gene', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('endometrial cancer', 'Disease', (29, 47))	('binding', 'Interaction', (153, 160))	('Thr286', 'Protein', (137, 143))	('endometrial cancer', 'Phenotype', 'HP:0012114', (29, 47))	('phosphorylation', 'MPA', (118, 133))	('deletions', 'Var', (76, 85))	('endometrial cancer', 'Disease', 'MESH:D016889', (29, 47))
891723	19415697	In addition to these mutations, we recently discovered that esophageal tumors have a number of mutations targeting the E3 ligase for cyclin D1 proteolysis so that the tumors can maintain high levels of cyclin D1 due to the decreased proteolysis efficiency.	('esophageal tumors', 'Phenotype', 'HP:0100751', (60, 77))	('E3 ligase', 'Enzyme', (119, 128))	('esophageal tumors', 'Disease', (60, 77))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('decreased proteolysis efficiency', 'Disease', 'MESH:D012021', (223, 255))	('cyclin D1', 'MPA', (202, 211))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (71, 77))	('decreased proteolysis efficiency', 'Disease', (223, 255))	('tumors', 'Disease', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('esophageal tumors', 'Disease', 'MESH:D004938', (60, 77))
891724	19415697	These mutations occur in Fbx4 that is a substrate specificity factor for cyclin D1 in the SCF ligase, and affect the ligase activity by impairing its dimerization or interaction with other E3 ligase component.	('E3 ligase', 'Enzyme', (189, 198))	('SCF', 'Gene', '4254', (90, 93))	('ligase', 'Enzyme', (117, 123))	('activity', 'MPA', (124, 132))	('interaction', 'Interaction', (166, 177))	('SCF', 'Gene', (90, 93))	('Fbx4', 'Gene', (25, 29))	('impairing', 'NegReg', (136, 145))	('dimerization', 'MPA', (150, 162))	('affect', 'Reg', (106, 112))	('mutations', 'Var', (6, 15))
891725	19415697	Along with the identification of cyclin D1b splice variant in human cancer, mutations targeting cyclin D1 nuclear export and proteolysis suggest that perturbed protein turnover and consequent accumulation of nuclear cyclin D1 may be more prevailing in cancers than previously thought.	('nuclear cyclin', 'MPA', (208, 222))	('cyclin D1', 'Gene', (96, 105))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('mutations', 'Var', (76, 85))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Disease', (252, 259))	('cancer', 'Disease', (252, 258))	('human', 'Species', '9606', (62, 67))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('protein turnover', 'MPA', (160, 176))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', (68, 74))	('nuclear export', 'MPA', (106, 120))	('accumulation', 'PosReg', (192, 204))	('perturbed', 'Var', (150, 159))
891736	19415697	Furthermore, transgenic mice that over-express the identical mutant cyclin D1 driven by MMTV promoter (MMTV-D1T286A) developed mammary adenocarcinoma with a shorter latency relative to mice over-expressing the wild-type cyclin D1 (MMTV-D1).	('MMTV', 'Species', '11757', (103, 107))	('adenocarcinoma', 'Disease', 'MESH:D000230', (135, 149))	('mice', 'Species', '10090', (24, 28))	('over-express', 'PosReg', (34, 46))	('developed', 'PosReg', (117, 126))	('mice', 'Species', '10090', (185, 189))	('MMTV', 'Species', '11757', (231, 235))	('MMTV', 'Species', '11757', (88, 92))	('mutant', 'Var', (61, 67))	('adenocarcinoma', 'Disease', (135, 149))	('transgenic mice', 'Species', '10090', (13, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cyclin D1', 'Gene', (68, 77))
891738	19415697	The experimental data described above stem from use of cyclin D1 mutants that are refractory to both CRM1-dependent nuclear export and Fbx4- and ubiquitin-dependent turnover.	('cyclin D1', 'Gene', (55, 64))	('CRM1', 'Gene', '7514', (101, 105))	('CRM1', 'Gene', (101, 105))	('mutants', 'Var', (65, 72))
891739	19415697	While such mutations have been observed in human cancers, they appear at low frequency (<3%).	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('human', 'Species', '9606', (43, 48))
891743	19415697	This hypothesis is supported by the observations that overexpression of p16 INK4a or p15INK4b suppresses Ras-induced transformation in vitro.	('p15INK4b', 'Gene', '1030', (85, 93))	('p15INK4b', 'Gene', (85, 93))	('Ras-induced transformation', 'CPA', (105, 131))	('suppresses', 'NegReg', (94, 104))	('p16 INK4a', 'Var', (72, 81))
891744	19415697	Moreover, expression of p16 INK4a blocks ErbB2-induced mammary tumor development in mice.	('tumor', 'Disease', (63, 68))	('blocks', 'NegReg', (34, 40))	('ErbB2', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('p16 INK4a', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('ErbB2', 'Gene', '13866', (41, 46))	('mice', 'Species', '10090', (84, 88))
891749	19415697	Nuclear accumulation of catalytically active mutant cyclin D1/CDK4 complex stabilizes Cdt1, an origin-licensing factor that is normally degraded during S phase to prevent reloading of the replicative MCM helicase.	('mutant', 'Var', (45, 51))	('Cdt1', 'Gene', '81620', (86, 90))	('Cdt1', 'Gene', (86, 90))	('reloading', 'MPA', (171, 180))	('Nuclear accumulation', 'MPA', (0, 20))
891752	19415697	Although the precise mechanism of this transcriptional regulation remains to be uncovered, the kinase-inactive mutant of CDK4 was shown to abrogate the nuclear cyclin D1-induced Cdt1 stabilization by relieving the transcriptional repression of Cul4A and Cul4B, suggesting that nuclear cyclin D1 induces DNA re-replication during S phase through its associated CDK4 activity.	('induces', 'PosReg', (295, 302))	('stabilization', 'MPA', (183, 196))	('Cdt1', 'Gene', '81620', (178, 182))	('DNA re-replication', 'CPA', (303, 321))	('abrogate', 'NegReg', (139, 147))	('Cdt1', 'Gene', (178, 182))	('mutant', 'Var', (111, 117))	('transcriptional', 'MPA', (214, 229))	('activity', 'MPA', (365, 373))	('nuclear', 'Var', (277, 284))	('Cul4B', 'Gene', '8450', (254, 259))	('Cul4A', 'Gene', '8451', (244, 249))	('Cul4B', 'Gene', (254, 259))	('Cul4A', 'Gene', (244, 249))	('CDK4', 'Gene', (121, 125))
891754	19415697	All these observations suggest that nuclear retention of active cyclin D1/CDK complex may be a critical determinant to elicit the oncogenicity of cyclin D1 in addition to its prevalent overexpression in cancers.	('oncogenicity', 'MPA', (130, 142))	('elicit', 'Reg', (119, 125))	('cyclin', 'Var', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('nuclear', 'MPA', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
891760	19415697	Treatment of MCL cells that express predominantly cyclin D1a isoform (full-length cyclin D1) with a small molecule CDK4/6 inhibitor PD0332991 efficiently suppresses RB phosphorylation and cell proliferation at nanomolar concentrations.	('cell proliferation', 'CPA', (188, 206))	('CDK4/6', 'Gene', (115, 121))	('suppresses', 'NegReg', (154, 164))	('PD0332991', 'Chemical', 'MESH:C500026', (132, 141))	('CDK4/6', 'Gene', '1019;1021', (115, 121))	('RB', 'Chemical', 'MESH:D012413', (165, 167))	('PD0332991', 'Var', (132, 141))
891761	19415697	While there are no inhibitors that target cyclin D1 directly so far, alternative therapeutic strategies targeting cyclin D1 turnover may be postulated, such as modulation of GSK3beta activity especially when nuclear retention of cyclin D1 is considered to be a causative factor for initial oncogenic events.	('GSK3beta', 'Gene', (174, 182))	('modulation', 'Var', (160, 170))	('GSK3beta', 'Gene', '2932', (174, 182))
891763	19415697	Would such an approach only be useful in the subset of tumors harboring mutations in cyclin D1 or Fbx4?	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Fbx4', 'Gene', (98, 102))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('cyclin D1', 'Gene', (85, 94))
891767	19415697	Additional work using mice wherein endogenous CDK4 was deleted via homologous recombination also reported resistance to mammary tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CDK4', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('deleted', 'Var', (55, 62))	('tumor', 'Disease', (128, 133))	('mice', 'Species', '10090', (22, 26))
891768	33289209	p21-activated kinase 4 promotes the progression of esophageal squamous cell carcinoma by targeting LASP1 Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors of the digestive tract in humans.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 85))	('humans', 'Species', '9606', (216, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('targeting', 'Var', (89, 98))	('LASP1', 'Gene', (99, 104))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (51, 85))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('tumors of the digestive tract', 'Phenotype', 'HP:0007378', (183, 212))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('squamous cell carcinoma', 'Disease', (116, 139))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('esophageal squamous cell carcinoma', 'Disease', (51, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('malignant tumors', 'Disease', (173, 189))	('malignant tumors', 'Disease', 'MESH:D009369', (173, 189))
891769	33289209	To further investigate the role of PAK4 in ESCC, cell viability assays, anchorage-independent cell growth assays, wound healing assays, cellular invasion assays, in vivo xenograft mouse models, and metastasis assays were conducted, and the results showed that PAK4 can significantly facilitate ESCC proliferation and metastasis in vitro and in vivo.	('ESCC proliferation', 'CPA', (294, 312))	('metastasis', 'CPA', (317, 327))	('PAK4', 'Var', (260, 264))	('mouse', 'Species', '10090', (180, 185))	('facilitate', 'PosReg', (283, 293))
891773	33289209	The etiology of ESCC is complex, and it has been found that alcohol consumption, tobacco use, hot food consumption, deficiency of selenium, zinc, or vitamin E, and high exposure to polycystic aromatic hydrocarbons are risk factors for ESCC.	('selenium', 'Protein', (130, 138))	('ESCC', 'Disease', (235, 239))	('alcohol', 'Chemical', 'MESH:D000438', (60, 67))	('deficiency', 'Var', (116, 126))	('tobacco', 'Species', '4097', (81, 88))	('ESCC', 'Disease', (16, 20))	('selenium', 'Chemical', 'MESH:D012643', (130, 138))	('polycystic aromatic hydrocarbons', 'Chemical', '-', (181, 213))	('vitamin E', 'Chemical', 'MESH:D014810', (149, 158))
891785	33289209	Taken together, these results suggest that PAK4 can promote ESCC through LASP1 and that PAK4 may be a potential target for the treatment of ESCC patients in the clinic.	('patients', 'Species', '9606', (145, 153))	('ESCC', 'Disease', (60, 64))	('LASP1', 'Gene', (73, 78))	('promote', 'PosReg', (52, 59))	('PAK4', 'Var', (43, 47))
891788	33289209	Antibodies to detect total AKT, phosphorylated AKT (Ser473), total ERK1/2, phosphorylated ERK1/2 (Thr202/Tyr204), total mTOR, phosphorylated mTOR (Ser2448), E-cadherin, N-cadherin, Vimentin, and Snail were purchased from Cell Signaling Technology, Inc. (Cell Signaling Technology).	('Ser473', 'Chemical', '-', (52, 58))	('mTOR', 'Gene', '2475', (141, 145))	('ERK1/2', 'Gene', (90, 96))	('ERK1/2', 'Gene', '5595;5594', (90, 96))	('Snail', 'Gene', (195, 200))	('E-cadherin', 'Gene', (157, 167))	('E-cadherin', 'Gene', '999', (157, 167))	('AKT', 'Gene', (47, 50))	('Vimentin', 'Gene', '7431', (181, 189))	('N-cadherin', 'Gene', (169, 179))	('mTOR', 'Gene', (120, 124))	('N-cadherin', 'Gene', '1000', (169, 179))	('Vimentin', 'Gene', (181, 189))	('AKT', 'Gene', (27, 30))	('Snail', 'Gene', '6615', (195, 200))	('AKT', 'Gene', '207', (47, 50))	('Ser2448', 'Chemical', '-', (147, 154))	('mTOR', 'Gene', '2475', (120, 124))	('Tyr204', 'Chemical', '-', (105, 111))	('Ser2448', 'Var', (147, 154))	('mTOR', 'Gene', (141, 145))	('Thr202', 'Chemical', '-', (98, 104))	('AKT', 'Gene', '207', (27, 30))	('ERK1/2', 'Gene', (67, 73))	('ERK1/2', 'Gene', '5595;5594', (67, 73))
891833	33289209	Moreover, we also detected the expression levels of PAK4 and p-PAK4 in different ESCC cell lines, and the results showed that PAK4 and p-PAK4 were highly expressed in most ESCC cell lines compared with SHEE, a human normal esophageal epithelial cell line (Figure 1F,G).	('PAK4', 'Var', (126, 130))	('p-PAK4', 'Var', (135, 141))	('human', 'Species', '9606', (210, 215))	('ESCC', 'Disease', (172, 176))	('HE', 'Chemical', 'MESH:D006371', (203, 205))
891840	33289209	The overexpression efficiency was assessed by Western blot analysis, and the results showed that the expression of PAK4 in both KYSE30 and KYSE150 cells was significantly higher than that in control cells that expressed the empty pcDNA.3.1-3xFlag vector (Figure 3A).	('higher', 'PosReg', (171, 177))	('expression', 'MPA', (101, 111))	('KYSE150', 'CellLine', 'CVCL:1348', (139, 146))	('KYSE30', 'Var', (128, 134))	('PAK4', 'Gene', (115, 119))
891841	33289209	As expected, overexpression of PAK4 significantly promoted the cell growth and colony formation in KYSE30 and KYSE150 cells compared with those in control cells (Figure 3B,C), and the rate of cell migration and the number of invading cells also increased in both KYSE30 and KYSE150 overexpressing cells compared with control cells (Figure 3D,E).	('cell migration', 'CPA', (192, 206))	('promoted', 'PosReg', (50, 58))	('increased', 'PosReg', (245, 254))	('KYSE150', 'CellLine', 'CVCL:1348', (110, 117))	('number of invading cells', 'CPA', (215, 239))	('colony formation', 'CPA', (79, 95))	('KYSE150', 'CellLine', 'CVCL:1348', (274, 281))	('KYSE30', 'Var', (263, 269))	('PAK4', 'Gene', (31, 35))	('cell growth', 'CPA', (63, 74))	('overexpression', 'Var', (13, 27))
891846	33289209	To further determine whether PAK4 can directly interact with LASP1, HEK293T cells were transiently transfected with pc-DNA3.1-3xFlag-pak4 and pc-DNA3.1-HA-lasp1.	('lasp1', 'Gene', (155, 160))	('HEK293T', 'CellLine', 'CVCL:0063', (68, 75))	('lasp1', 'Gene', '3927', (155, 160))	('pc-DNA3.1-3xFlag-pak4', 'Var', (116, 137))
891849	33289209	27  To further verify whether PAK4 is involved in the regulation of these two pathways in ESCC, immunoblot analysis of p-ERK1/2 (Thr202/Tyr204), p-AKT (Ser473), and p-mTOR (Ser2448), and total ERKs, AKT, mTOR was performed; the results showed that the expression levels of p-ERK, p-AKT, and p-mTOR were decreased after knocking down PAK4 (Figure 5A), whereas the expression levels were upregulated followed by PAK4 overexpression (Figure 5B), which indicated that PAK4 regulated the proliferation of ESCC cells by participating in ERK and AKT signaling pathways.	('ERK1/2', 'Gene', (121, 127))	('AKT', 'Gene', (199, 202))	('PAK4', 'Var', (464, 468))	('ERK1/2', 'Gene', '5595;5594', (121, 127))	('decreased', 'NegReg', (303, 312))	('mTOR', 'Gene', '2475', (204, 208))	('proliferation', 'CPA', (483, 496))	('ERK', 'Gene', '5594', (121, 124))	('knocking down', 'Var', (319, 332))	('Ser2448', 'Chemical', '-', (173, 180))	('ERK', 'Gene', (193, 196))	('regulated', 'Reg', (469, 478))	('ERK', 'Gene', '5594', (531, 534))	('AKT', 'Gene', '207', (539, 542))	('mTOR', 'Gene', (167, 171))	('AKT', 'Gene', '207', (199, 202))	('expression levels', 'MPA', (252, 269))	('AKT', 'Gene', (147, 150))	('ERK', 'Gene', (121, 124))	('ESCC', 'Disease', (500, 504))	('mTOR', 'Gene', (293, 297))	('ERK', 'Gene', (531, 534))	('Ser473', 'Chemical', '-', (152, 158))	('AKT', 'Gene', (282, 285))	('mTOR', 'Gene', '2475', (167, 171))	('PAK4', 'Gene', (333, 337))	('ERK', 'Gene', '5594', (275, 278))	('participating', 'Reg', (514, 527))	('Thr202', 'Chemical', '-', (129, 135))	('Tyr204', 'Chemical', '-', (136, 142))	('mTOR', 'Gene', '2475', (293, 297))	('mTOR', 'Gene', (204, 208))	('AKT', 'Gene', '207', (147, 150))	('AKT', 'Gene', (539, 542))	('AKT', 'Gene', '207', (282, 285))	('ERK', 'Gene', (275, 278))	('ERK', 'Gene', '5594', (193, 196))
891853	33289209	The results showed that after knocking down PAK4, the expression level of E-cadherin was increased, and the expression level of N-cadherin was decreased (Figure 5A), while after overexpression of PAK4, the expression of E-cadherin was decreased and the expression of N-cadherin was increased (Figure 5B), which indicated that PAK4 was involved in the EMT process of ESCC cells.	('increased', 'PosReg', (282, 291))	('expression level', 'MPA', (108, 124))	('expression', 'MPA', (253, 263))	('decreased', 'NegReg', (143, 152))	('PAK4', 'Gene', (44, 48))	('expression', 'MPA', (206, 216))	('E-cadherin', 'Gene', (74, 84))	('expression level', 'MPA', (54, 70))	('E-cadherin', 'Gene', '999', (74, 84))	('N-cadherin', 'Gene', (128, 138))	('decreased', 'NegReg', (235, 244))	('N-cadherin', 'Gene', (267, 277))	('increased', 'PosReg', (89, 98))	('E-cadherin', 'Gene', (220, 230))	('E-cadherin', 'Gene', '999', (220, 230))	('knocking down', 'Var', (30, 43))	('N-cadherin', 'Gene', '1000', (267, 277))	('N-cadherin', 'Gene', '1000', (128, 138))
891855	33289209	The results showed that downregulation of LASP1 could weaken the upregulation of p-ERK, p-AKT, N-cadherin, Vimentin, and Snail caused by PAK4 overexpression (Figure 5C).	('overexpression', 'PosReg', (142, 156))	('ERK', 'Gene', (83, 86))	('N-cadherin', 'Gene', '1000', (95, 105))	('Vimentin', 'Gene', (107, 115))	('AKT', 'Gene', (90, 93))	('weaken', 'NegReg', (54, 60))	('LASP1', 'Gene', (42, 47))	('Vimentin', 'Gene', '7431', (107, 115))	('downregulation', 'NegReg', (24, 38))	('Snail', 'Gene', '6615', (121, 126))	('Snail', 'Gene', (121, 126))	('AKT', 'Gene', '207', (90, 93))	('upregulation', 'PosReg', (65, 77))	('ERK', 'Gene', '5594', (83, 86))	('PAK4', 'Var', (137, 141))	('N-cadherin', 'Gene', (95, 105))
891859	33289209	The average tumor weights in the EC109-shpak4-1 and EC109-shpak4-2 groups were 0.04 g and 0.09 g, respectively, compared with a weight of 0.15 g in the control group (Figure 6C).	('EC109-shpak4-2', 'Var', (52, 66))	('EC109-shpak4-1', 'Var', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
891860	33289209	These results indicated that knockdown of PAK4 can inhibit tumor growth in vivo.	('tumor', 'Disease', (59, 64))	('knockdown', 'Var', (29, 38))	('PAK4', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('inhibit', 'NegReg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
891861	33289209	Taken with the results that PAK4 regulates the proliferation of ESCC cells by participating in ERK and AKT signaling pathways (Figure 5A,B), to determine whether the tumor inhibition effect was associated with EGFR and EMT signaling pathways, tumor extracts from each group were prepared for immunohistochemistry (IHC) analysis.	('regulates', 'Reg', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('AKT', 'Gene', '207', (103, 106))	('ERK', 'Gene', '5594', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('EGFR', 'Gene', (210, 214))	('ERK', 'Gene', (95, 98))	('AKT', 'Gene', (103, 106))	('tumor', 'Disease', (166, 171))	('PAK4', 'Var', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('EGFR', 'Gene', '1956', (210, 214))	('participating', 'Reg', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
891862	33289209	Ki67 expression served as a marker of tumor proliferation and the expression of Ki67 was considerably decreased in the EC109-shpak4 groups, suggesting that a reduction in PAK4 expression led to an inhibition of tumor proliferation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('Ki67', 'Gene', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('inhibition', 'NegReg', (197, 207))	('expression', 'MPA', (66, 76))	('EC109-shpak4', 'Var', (119, 131))	('PAK4', 'Gene', (171, 175))	('reduction', 'NegReg', (158, 167))	('expression', 'MPA', (176, 186))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('decreased', 'NegReg', (102, 111))
891863	33289209	IHC staining results showed that the expression of p-ERK1/2 (Thr202/Tyr204) was substantially decreased and the expression of E-cadherin was significantly increased in the EC109-shpak4 groups compared with the control group (Figure 6D).	('EC109-shpak4', 'Var', (172, 184))	('increased', 'PosReg', (155, 164))	('Tyr204', 'Chemical', '-', (68, 74))	('Thr202', 'Chemical', '-', (61, 67))	('E-cadherin', 'Gene', (126, 136))	('decreased', 'NegReg', (94, 103))	('E-cadherin', 'Gene', '999', (126, 136))	('ERK1/2', 'Gene', (53, 59))	('ERK1/2', 'Gene', '5595;5594', (53, 59))	('expression', 'MPA', (37, 47))	('expression', 'MPA', (112, 122))
891864	33289209	These results confirmed that the tumor inhibition caused by PAK4 deletion is related to EGFR and EMT signaling pathways in ESCC.	('PAK4', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('EMT', 'CPA', (97, 100))	('ESCC', 'Disease', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('EGFR', 'Gene', '1956', (88, 92))	('tumor', 'Disease', (33, 38))	('deletion', 'Var', (65, 73))	('EGFR', 'Gene', (88, 92))
891865	33289209	To further confirm whether PAK4 can promote ESCC metastasis, KYSE30 cells stably expressing empty vector and Flag-pak4 were injected into SCID mice via the tail vein.	('ESCC', 'Disease', (44, 48))	('Flag-pak4', 'Var', (109, 118))	('SCID', 'Disease', (138, 142))	('SCID', 'Disease', 'MESH:D053632', (138, 142))	('mice', 'Species', '10090', (143, 147))
891867	33289209	The results showed that the mice injected with Flag-pak4 KYSE30 cells exhibited more metastatic nodules in the lungs and livers than the control group (Figure 6E,F).	('Flag-pak4 KYSE30 cells', 'Var', (47, 69))	('metastatic nodules in the lungs', 'CPA', (85, 116))	('mice', 'Species', '10090', (28, 32))	('more', 'PosReg', (80, 84))
891878	33289209	LASP1 is overexpressed in metastatic breast and ovarian cancer, and knockdown of LASP1 in metastatic breast cancer and ovarian cancer cell lines has a strong inhibitory effect on their migration and proliferation.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('ovarian cancer', 'Disease', 'MESH:D010051', (119, 133))	('LASP1', 'Gene', (81, 86))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (37, 62))	('inhibitory effect', 'NegReg', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('knockdown', 'Var', (68, 77))	('ovarian cancer', 'Disease', (119, 133))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('ovarian cancer', 'Disease', (48, 62))
891880	33289209	45  In addition, renal cell carcinoma patients with high expression of LASP1 have a poor prognosis.	('LASP1', 'Gene', (71, 76))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (17, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('renal cell carcinoma', 'Disease', (17, 37))	('patients', 'Species', '9606', (38, 46))	('high expression', 'Var', (52, 67))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (17, 37))
891881	33289209	46  Studies also show that LASP1 is related to the secretion of matrix metalloproteinases (MMP), 47  LASP1 goes deep into the cell layer through a structure similar to pseudopods, enhances the secretion of MMP in the extracellular matrix (ECM), and promotes the invasion of tumor cells.	('enhances', 'PosReg', (180, 188))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('MMP', 'Protein', (206, 209))	('LASP1', 'Var', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('promotes', 'PosReg', (249, 257))	('secretion', 'MPA', (193, 202))
891972	32143307	Furthermore, skipping of lymph nodes showed a strong association with the occurrence of a tumor recurrence (OR 3.702, 95% CI 1.297-10.571; p = 0.014).	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('skipping of lymph nodes', 'Phenotype', 'HP:0002732', (13, 36))	('skipping', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
891984	32143307	Interestingly, a significantly higher ratio of micrometastatic positive lymph nodes in BNMM positive patients as compared to BNMM negative patients was seen.	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (139, 147))	('positive', 'Var', (92, 100))	('micrometastatic positive lymph nodes', 'CPA', (47, 83))	('higher', 'PosReg', (31, 37))	('BNMM', 'Gene', (87, 91))
892021	32143307	Especially, the occurrence of lymph node micrometastases with a skipping of the anatomical node chain is associated with earlier disease related death and recurrence.	('metastases', 'Disease', (46, 56))	('lymph', 'Disease', (30, 35))	('death', 'Disease', 'MESH:D003643', (145, 150))	('metastases', 'Disease', 'MESH:D009362', (46, 56))	('skipping', 'Var', (64, 72))	('death', 'Disease', (145, 150))
892050	31413282	Blood leukocytes on POD 0-2 were higher in patients of the MPR-group compared to the ILE-group.	('higher', 'PosReg', (33, 39))	('patients', 'Species', '9606', (43, 51))	('MPR-group', 'Var', (59, 68))	('Blood leukocytes on POD 0-2', 'MPA', (0, 27))	('ILE', 'Chemical', '-', (85, 88))
892067	31413282	However, the previously reported pulmonary complication rates, especially for pneumonia (up to 6%) and ARDS (approximately 4% in the early phase after anatomic lung resection) are considerably lower after MPR compared with ILE, although - as shown in the present study - the rate of preexisting chronic pulmonary diseases is obviously higher in MPR patients.	('MPR', 'Var', (205, 208))	('ARDS', 'Phenotype', 'HP:0011948', (103, 107))	('pneumonia', 'Phenotype', 'HP:0002090', (78, 87))	('patients', 'Species', '9606', (349, 357))	('ILE', 'Chemical', '-', (223, 226))	('pulmonary diseases', 'Disease', (303, 321))	('pneumonia', 'Disease', (78, 87))	('pneumonia', 'Disease', 'MESH:D011014', (78, 87))	('ARDS', 'Disease', (103, 107))	('pulmonary diseases', 'Disease', 'MESH:D008171', (303, 321))	('pulmonary complication', 'CPA', (33, 55))	('lower', 'NegReg', (193, 198))
892071	31413282	was herein applied in a slightly modified version with regard to the current "International Guidelines for the Management of Severe Sepsis and Septic Shock 2012" by using a body temperature >=38.0  C or <=36.0  C. This resulted in a high sensitivity of the scoring system for retrospective assessment of pneumonia in our patient cohort and a slightly higher rate of postoperative pneumonia of ILE and MPR patients (39.8% and 20.4%, respectively) than those reported in the recent literature.	('Severe Sepsis and Septic Shock 2012', 'Disease', 'MESH:D012772', (125, 160))	('postoperative pneumonia', 'Disease', (366, 389))	('Shock', 'Phenotype', 'HP:0031273', (150, 155))	('pneumonia', 'Phenotype', 'HP:0002090', (304, 313))	('Sepsis', 'Phenotype', 'HP:0100806', (132, 138))	('ILE', 'Chemical', '-', (393, 396))	('patient', 'Species', '9606', (405, 412))	('patients', 'Species', '9606', (405, 413))	('pneumonia', 'Phenotype', 'HP:0002090', (380, 389))	('pneumonia', 'Disease', (304, 313))	('pneumonia', 'Disease', 'MESH:D011014', (304, 313))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (366, 389))	('>=38.0', 'Var', (190, 196))	('pneumonia', 'Disease', (380, 389))	('pneumonia', 'Disease', 'MESH:D011014', (380, 389))	('Septic Shock', 'Phenotype', 'HP:0100806', (143, 155))	('patient', 'Species', '9606', (321, 328))
892105	31413282	Especially after transhiatal esophagectomy, the rate of pulmonary complications is lower compared with the transthoracic approach.	('pulmonary complications', 'Disease', 'MESH:D008171', (56, 79))	('lower', 'NegReg', (83, 88))	('pulmonary complications', 'Phenotype', 'HP:0006532', (56, 79))	('transhiatal', 'Var', (17, 28))	('pulmonary complications', 'Disease', (56, 79))
892109	31413282	During ILE, surgeons usually transect the vagus nerve at the level, where the azygos vein joins the vena cava, which results in extensive or even complete vagal denervation of the lung.	('ILE', 'Chemical', '-', (7, 10))	('transect', 'Var', (29, 37))	('vagal denervation', 'Phenotype', 'HP:0002886', (155, 172))	('vagal', 'MPA', (155, 160))	('denervation', 'NegReg', (161, 172))	('results in', 'Reg', (117, 127))
892113	31413282	We hypothesize, that a classical ILE with high thoracic esophageal resection margins and mediastinal lymph node dissection even leads to parasympathetic and sensory denervation of trachea, bronchi and pulmonary vasculature (especially pulmonary arteries) by vagotomy, the consecutive dysbalance of the autonomic nervous system innervating pulmonary structures would result in a higher sympathetic drive and thus may impair respiratory function and gas exchange widely analogous to the situation of neurogenic pulmonary edema.	('edema', 'Phenotype', 'HP:0000969', (519, 524))	('neurogenic pulmonary edema', 'Disease', 'MESH:D011654', (498, 524))	('sympathetic drive', 'MPA', (385, 402))	('impair', 'NegReg', (416, 422))	('higher', 'PosReg', (378, 384))	('denervation', 'NegReg', (165, 176))	('gas exchange', 'MPA', (448, 460))	('impair respiratory function', 'Phenotype', 'HP:0002093', (416, 443))	('ILE', 'Chemical', '-', (33, 36))	('respiratory function', 'MPA', (423, 443))	('neurogenic pulmonary edema', 'Disease', (498, 524))	('parasympathetic', 'MPA', (137, 152))	('pulmonary edema', 'Phenotype', 'HP:0100598', (509, 524))	('dysbalance', 'Var', (284, 294))
892298	28195186	Our results suggest that NLR is an independent prognostic indicator for patients with ESCC undergoing dCRT and changes in NLR level with treatment may indicate therapeutic benefit.	('dCRT', 'Gene', '45841', (102, 106))	('changes', 'Var', (111, 118))	('dCRT', 'Gene', (102, 106))	('NLR', 'MPA', (122, 125))	('patients', 'Species', '9606', (72, 80))
892348	28195186	High NLR at baseline was significantly associated with worse ECOG PS (p = 0.033), larger tumor size (p < 0.001), distant lymph node metastasis (p < 0.001), advanced TNM stage (p < 0.001), and low response rate to dCRT (p < 0.001, Table 2).	('ECOG', 'MPA', (61, 65))	('High', 'Var', (0, 4))	('distant lymph node metastasis', 'CPA', (113, 142))	('dCRT', 'Gene', (213, 217))	('worse', 'NegReg', (55, 60))	('dCRT', 'Gene', '45841', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('NLR', 'Gene', (5, 8))
892352	28195186	However, there was no significant difference in dCRT response between post-treatment NLR >= 5 or <5 (52 vs 58%, p = 0.256, Table 3).	('dCRT', 'Gene', (48, 52))	('dCRT', 'Gene', '45841', (48, 52))	('>= 5', 'Var', (89, 93))
892357	28195186	Results of univariate analysis indicated that ECOG PS (>=2), tumor length (>=5), lymph node metastasis (positive), tumor stage (III/IV), dCRT response (SD + PD), SCCA level (>=1.5), and baseline NLR radio (>=5) were significantly correlated with decreased PFS or OS (p < 0.05, Table 4).	('dCRT', 'Gene', (137, 141))	('NLR radio', 'MPA', (195, 204))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('PD', 'Disease', 'MESH:D010300', (157, 159))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('ECOG', 'Var', (46, 50))	('SCCA level', 'MPA', (162, 172))	('decreased PFS or OS', 'Disease', 'MESH:C567932', (246, 265))	('SD', 'Chemical', '-', (152, 154))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('decreased PFS or OS', 'Disease', (246, 265))	('tumor', 'Disease', (61, 66))	('dCRT', 'Gene', '45841', (137, 141))
892368	28195186	Moreover, our results also showed that patients with normalised post-treatment NLR (at 4 weeks after treatment) had a better PFS and OS than those with sustained high NLR.	('PF', 'Chemical', 'MESH:C002997', (125, 127))	('patients', 'Species', '9606', (39, 47))	('normalised', 'Var', (53, 63))	('NLR', 'Gene', (79, 82))
892418	15533252	The NCCTG trial employed two modifications to the Minnie Pearl Regimen in an attempt to mitigate toxicity: 1) carboplatin dosing was reduced from AUC = 6 to AUC = 4 in the first 10 patients with the possibility of dose escalation thereafter; 2) amifostine 500 mg subcutaneously to be given before radiation, as prompted by data from Koukourakis and others as well as by other subsequent reports.	('carboplatin dosing', 'MPA', (110, 128))	('amifostine', 'Var', (245, 255))	('amifostine', 'Chemical', 'MESH:D004999', (245, 255))	('NCCTG', 'Chemical', '-', (4, 9))	('carboplatin', 'Chemical', 'MESH:D016190', (110, 121))	('patients', 'Species', '9606', (181, 189))	('toxicity', 'Disease', 'MESH:D064420', (97, 105))	('toxicity', 'Disease', (97, 105))	('reduced', 'NegReg', (133, 140))
892423	15533252	Eligibility criteria consisted of the following: 1) age >= 18 years; 2) histologic or cytologic evidence of squamous cell carcinoma or adenocarcinoma of the esophagus; 3) surgically resectable tumor, as deemed by a surgeon; 4) Eastern Cooperative Oncology Group (ECOG) performance score of 0-2; 5) anticipated life expectancy of >= 12 weeks; 7) the laboratory parameters < 14 days prior to registration of absolute neutrophil count >= 1.5 x 109/L, platelet count >= 100 x 109/L, total bilirubin <= 1.5 times the upper limit of normal, serum creatinine <= 1.5 times the upper limit of normal, asparatate aminotransferase <= three times the upper limit of normal.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('total bilirubin', 'MPA', (479, 494))	('tumor', 'Disease', (193, 198))	('adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (135, 166))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('Oncology', 'Phenotype', 'HP:0002664', (247, 255))	('>= 100 x', 'Var', (463, 471))	('squamous cell carcinoma', 'Disease', (108, 131))	('platelet', 'MPA', (448, 456))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('serum creatinine', 'MPA', (535, 551))	('asparatate', 'MPA', (592, 602))	('adenocarcinoma of the esophagus', 'Disease', (135, 166))
892480	27088889	Further study revealed that B7-H4 silenced cells also showed reduction in interleukin-6 (IL-6) secretion, signal transducer and activator of transcription 3 (STAT3) activation, and p-STAT3 translocation from cytoplasm to nucleus.	('signal transducer and activator of transcription 3', 'Gene', '20848', (106, 156))	('p-STAT3 translocation from cytoplasm', 'MPA', (181, 217))	('secretion', 'MPA', (95, 104))	('B7-H4', 'Var', (28, 33))	('reduction', 'NegReg', (61, 70))	('interleukin-6', 'Gene', '16193', (74, 87))	('activation', 'PosReg', (165, 175))	('interleukin-6', 'Gene', (74, 87))
892481	27088889	Moreover, B7-H4 depletion inhibited the IL-6 secretion of control cells but not JAK2/STAT3 inhibitor FLLL32-treated cells.	('FLLL32', 'Chemical', 'MESH:C548902', (101, 107))	('JAK2', 'Gene', (80, 84))	('inhibited', 'NegReg', (26, 35))	('B7-H4', 'Var', (10, 15))	('depletion', 'Var', (16, 25))	('IL-6 secretion', 'MPA', (40, 54))	('JAK2', 'Gene', '3717', (80, 84))
892488	27088889	In addition to the traditional B7-1 and B7-2 family members, other B7 family members have been discovered, including B7-H1,8 B7-H2,9 B7-H3,10 B7-H4,11 B7-DC,12 and B7-H6.13 In 2003, B7-H4 was identified by three different laboratories simultaneously and was designated three different names, B7-H4,11 B7s1,14 and B7x.15 Previous studies observed that B7-H4 mRNA is broadly expressed in human peripheral tissues whereas B7-H4 protein expression was confined only to some tumor tissues, such as lung,16 ovarian,17 prostate,18 melanoma,19 stomach,20 breast,21 kidney,22 and esophagus.23 It has been proved that B7-H4 plays an important role in regulating adaptive immune response by inhibiting the proliferation, activation, and cytokine production of T cells, and host innate immune response by suppressing growth of neutrophil progenitors.24 In addition, Cheng et al.25 found that B7-H4-deficient mice showed lower ovarian tumorigenicity and Qian et al.26 reported that B7-H4 knocked down pancreatic cells showed lower proliferation and higher apoptosis.	('B7-H6', 'Gene', (164, 169))	('lower', 'NegReg', (1012, 1017))	('B7-DC', 'Gene', (151, 156))	('B7-H3', 'Gene', '80381', (133, 138))	('B7-H1', 'Gene', '29126', (117, 122))	('pancreatic', 'Disease', 'MESH:D010195', (988, 998))	('melanoma', 'Disease', (524, 532))	('tumor', 'Disease', (470, 475))	('higher', 'PosReg', (1036, 1042))	('B7-H2', 'Gene', (125, 130))	('knocked down', 'NegReg', (975, 987))	('pancreatic', 'Disease', (988, 998))	('tumor', 'Disease', 'MESH:D009369', (470, 475))	('tumor', 'Disease', (922, 927))	('lower ovarian tumorigenicity', 'Disease', (908, 936))	('B7s1', 'Gene', '79679', (301, 305))	('B7s1', 'Gene', (301, 305))	('B7-H3', 'Gene', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (922, 927))	('B7-H1', 'Gene', (117, 122))	('lower ovarian tumorigenicity', 'Disease', 'MESH:D002471', (908, 936))	('apoptosis', 'CPA', (1043, 1052))	('B7-H4', 'Var', (969, 974))	('melanoma', 'Disease', 'MESH:D008545', (524, 532))	('tumor', 'Phenotype', 'HP:0002664', (470, 475))	('mice', 'Species', '10090', (896, 900))	('B7-1 and B7-2 family members', 'Gene', '941', (31, 59))	('tumor', 'Phenotype', 'HP:0002664', (922, 927))	('B7-H6', 'Gene', '374383', (164, 169))	('human', 'Species', '9606', (386, 391))	('B7-H2', 'Gene', '23308', (125, 130))	('B7-DC', 'Gene', '80380', (151, 156))
892489	27088889	It was suggested that B7-H4, as an important tumor marker, was able to promote cancer cell proliferation and tumorigenesis independently of lymphocytes.	('promote', 'PosReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('B7-H4', 'Var', (22, 27))	('tumor', 'Disease', (109, 114))
892504	27088889	The Western blot analysis was carried out as described previously.31 The transfer times were: 30 min for GAPDH, TATA-binding protein (TBP), Bcl-2, BAX, and Survivin; 1 h for B7-H4, STAT3, and p-STAT3; and 2 h for JAK2 and p-JAK2.	('TBP', 'Gene', (134, 137))	('TBP', 'Gene', '6908', (134, 137))	('B7-H4', 'Var', (174, 179))	('JAK2', 'Gene', '3717', (224, 228))	('p-STAT3', 'Var', (192, 199))	('JAK2', 'Gene', '3717', (213, 217))	('TATA-binding protein', 'Gene', (112, 132))	('TATA-binding protein', 'Gene', '6908', (112, 132))	('GAPDH', 'Gene', '2597', (105, 110))	('Survivin', 'Gene', '11799', (156, 164))	('JAK2', 'Gene', (224, 228))	('JAK2', 'Gene', (213, 217))	('Survivin', 'Gene', (156, 164))	('GAPDH', 'Gene', (105, 110))
892522	27088889	As shown in Figure 3(c), B7-H4 silence downregulated p-JAK2 expression in Eca109 (P < 0.01), TE1 (P < 0.05), and TE13 (P < 0.01), cells although the total JAK2 expression was not obviously influenced.	('expression', 'MPA', (60, 70))	('JAK2', 'Gene', '3717', (55, 59))	('B7-H4', 'Var', (25, 30))	('JAK2', 'Gene', '3717', (155, 159))	('JAK2', 'Gene', (55, 59))	('JAK2', 'Gene', (155, 159))	('downregulated', 'NegReg', (39, 52))
892523	27088889	In contrast, compared with FLLL32 and control shRNA-treated cells, IL-6 secretion in Eca109, TE1, and TE13 cells pretreated with B7-H4 shRNA and FLLL32 was not significantly affected (Fig.	('IL-6 secretion', 'MPA', (67, 81))	('B7-H4', 'Var', (129, 134))	('FLLL32', 'Chemical', 'MESH:C548902', (145, 151))	('FLLL32', 'Chemical', 'MESH:C548902', (27, 33))
892524	27088889	These data suggested that B7-H4 silence inhibited IL-6 secretion in control cells but not JAK2/STAT3 blocked cells.	('B7-H4', 'Var', (26, 31))	('JAK2', 'Gene', (90, 94))	('inhibited', 'NegReg', (40, 49))	('IL-6 secretion', 'MPA', (50, 64))	('JAK2', 'Gene', '3717', (90, 94))
892525	27088889	JAK2/STAT3 activation is necessary for B7-H4 facilitating IL-6 secretion.	('JAK2', 'Gene', '3717', (0, 4))	('JAK2', 'Gene', (0, 4))	('B7-H4', 'Var', (39, 44))
892526	27088889	As Figure 5(b) shows, B7-H4 depletion inhibited p-JAK2 and p-STAT3 expression of control cells.	('JAK2', 'Gene', (50, 54))	('inhibited', 'NegReg', (38, 47))	('B7-H4 depletion', 'Var', (22, 37))	('JAK2', 'Gene', '3717', (50, 54))	('p-STAT3 expression', 'MPA', (59, 77))
892527	27088889	B7-H4 silence also markedly suppressed p-STAT3 expression in Eca109, TE1, and TE13 cells pretreated with tocilizumab (all P < 0.05).	('silence', 'Var', (6, 13))	('p-STAT3 expression', 'MPA', (39, 57))	('suppressed', 'NegReg', (28, 38))	('B7-H4', 'Gene', (0, 5))	('tocilizumab', 'Chemical', 'MESH:C502936', (105, 116))
892529	27088889	B7-H4 knocked down inhibited p-JAK2 expression to some extent in Eca109 cells cultured with tocilizumab.	('inhibited', 'NegReg', (19, 28))	('knocked down', 'Var', (6, 18))	('B7-H4', 'Gene', (0, 5))	('JAK2', 'Gene', '3717', (31, 35))	('tocilizumab', 'Chemical', 'MESH:C502936', (92, 103))	('JAK2', 'Gene', (31, 35))	('expression', 'MPA', (36, 46))
892532	27088889	However, compared with cells pretreated with B7-H4 shRNA, cell proliferation rates and colony numbers of Eca109, TE1, and TE13 cells pretreated with B7-H4 shRNA and tocilizumab were not obviously affected.	('colony numbers', 'CPA', (87, 101))	('tocilizumab', 'Chemical', 'MESH:C502936', (165, 176))	('B7-H4', 'Var', (149, 154))	('cell proliferation rates', 'CPA', (58, 82))
892538	27088889	B7-H4 silence dampened IL-6 secretion through JAK2/STAT3 pathway inactivation which accounted for ESCC cell proliferation inhibition as well as apoptosis induction.	('silence', 'Var', (6, 13))	('JAK2', 'Gene', (46, 50))	('inactivation', 'NegReg', (65, 77))	('IL-6 secretion', 'MPA', (23, 37))	('apoptosis', 'CPA', (144, 153))	('inhibition', 'NegReg', (122, 132))	('B7-H4', 'Gene', (0, 5))	('dampened', 'NegReg', (14, 22))	('JAK2', 'Gene', '3717', (46, 50))
892540	27088889	All these data suggested that B7-H4 promoted ESCC cell growth and tumorigenesis through IL-6/STAT3 positive loopback signal pathway activation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('B7-H4', 'Var', (30, 35))	('tumor', 'Disease', (66, 71))	('ESCC', 'Disease', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('promoted', 'PosReg', (36, 44))
892544	27088889	In our study, we found that B7-H4 promoted IL-6 through JAK2/STAT3 activation.	('IL-6', 'MPA', (43, 47))	('JAK2', 'Gene', (56, 60))	('B7-H4', 'Var', (28, 33))	('promoted', 'PosReg', (34, 42))	('JAK2', 'Gene', '3717', (56, 60))
892545	27088889	Interleukin-6 upregulation played an important part in B7-H4 facilitating ESCC cell growth and tumorigenesis.	('ESCC', 'Disease', (74, 78))	('tumor', 'Disease', (95, 100))	('facilitating', 'PosReg', (61, 73))	('B7-H4', 'Var', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('upregulation', 'PosReg', (14, 26))
892563	32085654	Mice lacking even a single VEGF-A allele exhibit impaired development of early vasculature and die at E11-E12.	('development of early vasculature', 'CPA', (58, 90))	('men', 'Species', '9606', (65, 68))	('E11-E12', 'Var', (102, 109))	('VEGF-A', 'Gene', (27, 33))	('Mice', 'Species', '10090', (0, 4))	('impaired', 'NegReg', (49, 57))
892597	32085654	As expected, VEGF-A overexpression frequently correlates not only with enhanced cancer invasiveness, but also with a high risk of tumor recurrence and unfavorable prognosis.	('enhanced', 'PosReg', (71, 79))	('overexpression', 'Var', (20, 34))	('cancer invasiveness', 'Disease', 'MESH:D009362', (80, 99))	('cancer invasiveness', 'Disease', (80, 99))	('VEGF-A', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
892598	32085654	On this basis, inhibition of the VEGF-A/VEGFRs signaling represents a widely used approach for cancer treatment through the use of the anti-VEGF-A and anti-VEGFR-2 monoclonal antibodies (mAbs) bevacizumab and ramucirumab, respectively; the chimeric molecule ziv-aflibercept; or a number of multi-targeted small-molecule TK inhibitors.	('bevacizumab', 'Chemical', 'MESH:D000068258', (193, 204))	('men', 'Species', '9606', (107, 110))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('ramucirumab', 'Chemical', 'MESH:C543333', (209, 220))	('VEGFR', 'Gene', (156, 161))	('anti-VEGF-A', 'Var', (135, 146))	('VEGFR', 'Gene', (40, 45))	('cancer', 'Disease', (95, 101))	(')', 'Gene', '7424', (191, 192))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('VEGFR', 'Gene', '3791', (156, 161))	('VEGFR', 'Gene', '3791', (40, 45))
892603	32085654	In regard to VEGF-B, ectopic expression of the growth factor in pancreatic beta-cells of transgenic mice prevented the formation of neuroendocrine tumors likely displacing VEGF-A or PlGF from VEGFR-1.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('displacing', 'NegReg', (161, 171))	('prevented', 'NegReg', (105, 114))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('formation', 'CPA', (119, 128))	('pancreatic', 'Disease', 'MESH:D010195', (64, 74))	('transgenic mice', 'Species', '10090', (89, 104))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (132, 153))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (132, 153))	('pancreatic', 'Disease', (64, 74))	('ectopic expression', 'Var', (21, 39))	('neuroendocrine tumors', 'Disease', (132, 153))
892616	32085654	The anti-VEGF-A bevacizumab is the standard regimen for advanced/metastatic non-squamous NSCLC in the first-line setting, in combination with platinum-based chemotherapy.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('platinum', 'Chemical', 'MESH:D010984', (142, 150))	('men', 'Species', '9606', (48, 51))	('bevacizumab', 'Chemical', 'MESH:D000068258', (16, 27))	('SCLC', 'Phenotype', 'HP:0030357', (90, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('NSCLC', 'Disease', (89, 94))	('anti-VEGF-A', 'Var', (4, 15))
892619	32085654	NSCLC is often associated with a hypoxic environment leading to HIF-1alpha overexpression, and HIF-1alpha knockdown in the NCI-H157 lung carcinoma cell line has been shown to reduce VEGF-A expression and cell invasiveness.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('HIF-1alpha', 'Gene', '3091', (95, 105))	('men', 'Species', '9606', (48, 51))	('overexpression', 'PosReg', (75, 89))	('HIF-1alpha', 'Gene', '3091', (64, 74))	('reduce', 'NegReg', (175, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('expression', 'MPA', (189, 199))	('knockdown', 'Var', (106, 115))	('VEGF-A', 'Protein', (182, 188))	('HIF-1alpha', 'Gene', (95, 105))	('NCI-H157 lung carcinoma', 'Disease', (123, 146))	('NCI-H157 lung carcinoma', 'Disease', 'MESH:D008175', (123, 146))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('HIF-1alpha', 'Gene', (64, 74))	('cell invasiveness', 'CPA', (204, 221))	('NSCLC', 'Disease', (0, 5))
892626	32085654	The sVEGFR-1-i13 splice variant was reported to increase during treatment with antiangiogenic therapies and to contribute to the progression of squamous lung carcinoma.	('splice variant', 'Var', (17, 31))	('men', 'Species', '9606', (69, 72))	('squamous lung carcinoma', 'Disease', (144, 167))	('sVEGFR-1-i13', 'Gene', (4, 16))	('squamous lung carcinoma', 'Phenotype', 'HP:0030359', (144, 167))	('squamous lung carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('contribute', 'Reg', (111, 121))	('increase', 'PosReg', (48, 56))
892627	32085654	In fact, besides acting as inhibitor of angiogenesis, this sVEGFR-1 variant is a component of the ECM that binds to the alpha5beta1 integrin and stimulates the adhesion and migration of endothelial cells.	('binds', 'Interaction', (107, 112))	('rat', 'Species', '10116', (176, 179))	('sVEGFR-1', 'Gene', (59, 67))	('variant', 'Var', (68, 75))	('adhesion', 'CPA', (160, 168))	('beta1 integrin', 'Gene', '3688', (126, 140))	('stimulates', 'PosReg', (145, 155))	('beta1 integrin', 'Gene', (126, 140))
892637	32085654	Furthermore, the VEGFR-1 relevance to NSCLC aggressiveness was confirmed by the observation that patients with squamous cell carcinoma and high VEGF-B expression showed poorer survival compared to those with low VEGF-B expression.	('NSCLC', 'Disease', (38, 43))	('aggressiveness', 'Disease', 'MESH:D001523', (44, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('aggressiveness', 'Disease', (44, 58))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('survival', 'MPA', (176, 184))	('aggressiveness', 'Phenotype', 'HP:0000718', (44, 58))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 134))	('VEGF-B', 'Gene', (144, 150))	('squamous cell carcinoma', 'Disease', (111, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('poorer', 'NegReg', (169, 175))	('SCLC', 'Phenotype', 'HP:0030357', (39, 43))	('high', 'Var', (139, 143))	('patients', 'Species', '9606', (97, 105))
892651	32085654	Nevertheless, after metastatic nodule formation, VEGFR-1 blockade led to a decrease of BMDCs infiltration inside and around the metastatic nodules.	('decrease', 'NegReg', (75, 83))	('blockade', 'Var', (57, 65))	('VEGFR-1', 'Gene', (49, 56))	('rat', 'Species', '10116', (99, 102))	('BMDCs infiltration', 'CPA', (87, 105))
892656	32085654	Hepatocellular carcinoma is a hypervascularized cancer type, and dysregulation of several angiogenic pathways, including those activated by the VEGF family members, has been involved in the development and progression of this tumor.	('involved', 'Reg', (174, 182))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (0, 24))	('VEGF', 'Gene', '7422', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('dysregulation', 'Var', (65, 78))	('men', 'Species', '9606', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('hypervascularized cancer', 'Disease', 'MESH:D009369', (30, 54))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('hypervascularized cancer', 'Disease', (30, 54))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('VEGF', 'Gene', (144, 148))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))	('angiogenic pathways', 'Pathway', (90, 109))	('tumor', 'Disease', (226, 231))
892663	32085654	PlGF blockade resulted in normalization of tumor-associated vessels, reduced tumor nodule formation in the liver, and increased animal survival.	('blockade', 'Var', (5, 13))	('reduced', 'NegReg', (69, 76))	('animal survival', 'CPA', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('increased', 'PosReg', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PlGF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (77, 82))	('normalization', 'NegReg', (26, 39))
892664	32085654	Similar findings were obtained in chemically-induced hepatocellular and cholangiocarcinoma in vivo models, where treatment with the 5D11D4 mAb decreased tumor burden and infiltration by protumoral M2 cells.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (189, 194))	('rat', 'Species', '10116', (176, 179))	('decreased', 'NegReg', (143, 152))	('cholangiocarcinoma', 'Disease', (72, 90))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))	('men', 'Species', '9606', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('tumoral', 'Disease', (189, 196))	('tumoral', 'Disease', 'MESH:D009369', (189, 196))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('5D11D4', 'Var', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('hepatocellular', 'Disease', (53, 67))
892673	32085654	Consistently, patients with high PlGF and miR-19a levels in the tumor showed a shorter overall survival (OS) than patients with low expression.	('tumor', 'Disease', (64, 69))	('miR-19a', 'Gene', (42, 49))	(')', 'Gene', '7424', (107, 108))	('shorter', 'NegReg', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('miR-19a', 'Gene', '406979', (42, 49))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('overall survival', 'MPA', (87, 103))
892676	32085654	In fact, blockade of VEGFR-1 by the MF-1 mAb in syngeneic murine RCC models induced 31% reduction in the growth of liver metastases, whereas blockade of VEGFR-2 had minimal effects.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('blockade', 'Var', (9, 17))	('reduction', 'NegReg', (88, 97))	('VEGFR-1', 'Gene', (21, 28))	('MF-1', 'Gene', (36, 40))	('liver metastases', 'Disease', (115, 131))	('murine', 'Species', '10090', (58, 64))	('MF-1', 'Gene', '17300', (36, 40))	('liver metastases', 'Disease', 'MESH:D009362', (115, 131))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
892677	32085654	In the case of metastases from colon carcinoma, only the neutralization of both VEGFR-1 and VEGFR-2 was able to decrease the size of liver metastasis.	('liver metastasis', 'Disease', (133, 149))	('VEGFR-2', 'Gene', (92, 99))	('metastases', 'Disease', (15, 25))	('decrease', 'NegReg', (112, 120))	('neutralization', 'Var', (57, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('colon carcinoma', 'Disease', 'MESH:D015179', (31, 46))	('metastases', 'Disease', 'MESH:D009362', (15, 25))	('size of liver', 'Phenotype', 'HP:0002240', (125, 138))	('colon carcinoma', 'Disease', (31, 46))	('VEGFR-1', 'Gene', (80, 87))	('liver metastasis', 'Disease', 'MESH:D009362', (133, 149))
892686	32085654	The ccRCC is characterized by mutations or epigenetic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which are considered to play a key role in VEGF-A overexpression.	('epigenetic inactivation', 'Var', (43, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (74, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ccRCC', 'Disease', (4, 9))	('ccRCC', 'Disease', 'MESH:C538614', (4, 9))	('mutations', 'Var', (30, 39))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))
892689	32085654	Thus, in the presence of low expression or dysfunctional VHL, the HIF-1alpha accumulates and activates a number of hypoxia-driven genes, including VEGF-A.	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('dysfunctional', 'Var', (43, 56))	('activates', 'PosReg', (93, 102))	('HIF-1alpha', 'Gene', (66, 76))	('low expression', 'Var', (25, 39))	('accumulates', 'PosReg', (77, 88))	('VHL', 'Gene', (57, 60))	('HIF-1alpha', 'Gene', '3091', (66, 76))	('VHL', 'Gene', '7428', (57, 60))	('hypoxia', 'Disease', (115, 122))
892690	32085654	Several single nucleotide polymorphisms identified in the VEGF gene have been reported to be associated with RCC risk, tumor growth, and metastases.	('VEGF', 'Gene', (58, 62))	('tumor', 'Disease', (119, 124))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('VEGF', 'Gene', '7422', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('associated', 'Reg', (93, 103))	('RCC', 'Disease', (109, 112))	('single nucleotide polymorphisms', 'Var', (8, 39))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('metastases', 'Disease', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
892691	32085654	In particular, two meta-analysis studies indicated that the VEGF -2578C/A, +936C/T, and +405G/C polymorphisms correlated with elevated risk of RCC, especially in the Asian populations.	('VEGF', 'Gene', '7422', (60, 64))	('+405G/C', 'Mutation', 'rs2010963', (88, 95))	('VEGF', 'Gene', (60, 64))	('-2578C/A', 'Mutation', 'rs699947', (65, 73))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('+936C/T', 'Mutation', 'rs3025039', (75, 82))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('+405G/C', 'Var', (88, 95))
892706	32085654	However, PlGF neutralization by the TB403 mAb did not inhibit the growth of sunitinib-resistant ccRCC xenografts, which did not express VEGFR-1.	('TB403', 'Var', (36, 41))	('TB', 'Chemical', 'MESH:D013725', (36, 38))	('inhibit', 'NegReg', (54, 61))	('sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ccRCC', 'Disease', (96, 101))	('ccRCC', 'Disease', 'MESH:C538614', (96, 101))
892713	32085654	demonstrated that VEGFR-1 overexpression increases in vitro and in vivo glioma growth via modulation of the Sonic Hedgehog Homolog (SHH) signaling pathway.	('glioma', 'Disease', (72, 78))	('increases', 'PosReg', (41, 50))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('VEGFR-1', 'Gene', (18, 25))	('rat', 'Species', '10116', (7, 10))	('overexpression', 'Var', (26, 40))	('Sonic Hedgehog Homolog', 'Gene', '6469', (108, 130))	('Sonic Hedgehog Homolog', 'Gene', (108, 130))	('modulation', 'Reg', (90, 100))
892716	32085654	In vitro treatment with the anti-VEGFR-1 D16F7 mAb markedly inhibited receptor autophosphorylation and ERK1/2 activation and reduced glioblastoma cell invasive behavior.	('glioblastoma', 'Disease', (133, 145))	('anti-VEGFR-1', 'Gene', (28, 40))	('men', 'Species', '9606', (14, 17))	('ERK1/2', 'Gene', (103, 109))	('ERK1/2', 'Gene', '5595;5594', (103, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('receptor autophosphorylation', 'MPA', (70, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('reduced', 'NegReg', (125, 132))	('inhibited', 'NegReg', (60, 69))	('activation', 'MPA', (110, 120))	('D16F7', 'Var', (41, 46))	('D16F7', 'Chemical', 'MESH:C000627505', (41, 46))
892717	32085654	In vivo studies in glioblastoma murine models indicated that D16F7 was well-tolerated and confirmed its promising therapeutic potential, as the mAb induced a decrease in glioma growth and angiogenesis, as well as an increase in mice survival.	('glioblastoma', 'Disease', (19, 31))	('D16F7', 'Var', (61, 66))	('decrease in glioma growth', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (19, 31))	('rat', 'Species', '10116', (80, 83))	('D16F7', 'Chemical', 'MESH:C000627505', (61, 66))	('murine', 'Species', '10090', (32, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('angiogenesis', 'CPA', (188, 200))	('decrease in glioma growth', 'Disease', 'MESH:D005910', (158, 183))	('mice survival', 'CPA', (228, 241))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('increase', 'PosReg', (216, 224))	('mice', 'Species', '10090', (228, 232))
892718	32085654	In particular, the efficacy of D16F7 mAb was tested in heterotopic (intramuscular) and orthotopic (intracranial) models using rat C6 glioma sublines, transfected to overexpress VEGFR-1.	('C6 glioma sublines', 'Disease', 'MESH:C567307', (130, 148))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('overexpress', 'PosReg', (165, 176))	(')', 'Gene', '7424', (111, 112))	('rat', 'Species', '10116', (126, 129))	('tested', 'Reg', (45, 51))	('C6 glioma sublines', 'Disease', (130, 148))	('D16F7', 'Var', (31, 36))	('VEGFR-1', 'Gene', (177, 184))	(')', 'Gene', '7424', (81, 82))	('D16F7', 'Chemical', 'MESH:C000627505', (31, 36))
892719	32085654	In the heterotopic intramuscular model, treatment with D16F7 reduced tumor growth and in the orthotopic intracranial model the mAb increased animal survival by 40% and 65% at 10 and 20 mg/kg, respectively, with a remarkable percentage (46%) of long-term survivors at the higher dose.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('increased', 'PosReg', (131, 140))	('men', 'Species', '9606', (45, 48))	('animal survival', 'CPA', (141, 156))	('tumor', 'Disease', (69, 74))	('D16F7', 'Chemical', 'MESH:C000627505', (55, 60))	('D16F7', 'Var', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('reduced', 'NegReg', (61, 68))	(')', 'Gene', '7424', (239, 240))
892720	32085654	Additionally, immunohistochemical analysis of tumor sections from D16F7-treated animals showed a higher number of apoptotic cells and fewer blood vessels compared to untreated mice.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('apoptotic cells', 'CPA', (114, 129))	('mice', 'Species', '10090', (176, 180))	('fewer', 'NegReg', (134, 139))	('D16F7', 'Chemical', 'MESH:C000627505', (66, 71))	('D16F7-treated', 'Var', (66, 79))	('blood vessels', 'CPA', (140, 153))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
892742	32085654	Treatment of human (CR-Mel) and murine (B16F10) melanoma cells with the anti-VEGFR-1 D16F7 mAb strongly down-modulated the migration triggered by PlGF.	('human', 'Species', '9606', (13, 18))	('melanoma cells', 'Disease', 'MESH:D008545', (48, 62))	('murine', 'Species', '10090', (32, 38))	('anti-VEGFR-1', 'Var', (72, 84))	(')', 'Gene', '7424', (26, 27))	('D16F7', 'Chemical', 'MESH:C000627505', (85, 90))	(')', 'Gene', '7424', (46, 47))	('men', 'Species', '9606', (5, 8))	('rat', 'Species', '10116', (126, 129))	('down-modulated', 'NegReg', (104, 118))	('melanoma cells', 'Disease', (48, 62))	('migration', 'CPA', (123, 132))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
892743	32085654	Moreover, D16F7 inhibited vasculogenic mimicry (i.e., the formation of tube-like structures, resembling blood vessels) by melanoma cells in response to VEGF-A.	('inhibited', 'NegReg', (16, 25))	(')', 'Gene', '7424', (117, 118))	('D16F7', 'Var', (10, 15))	('melanoma cells', 'Disease', 'MESH:D008545', (122, 136))	('melanoma cells', 'Disease', (122, 136))	('vasculogenic mimicry', 'CPA', (26, 46))	('D16F7', 'Chemical', 'MESH:C000627505', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('formation of tube-like structures', 'CPA', (58, 91))
892744	32085654	In vivo studies performed in a syngeneic murine melanoma model (B16F10 cells injected in B6D2F1 mice) confirmed the efficacy of VEGFR-1 blockade by D16F7 and the good tolerability of the treatment.	('melanoma', 'Disease', (48, 56))	('blockade', 'NegReg', (136, 144))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('murine', 'Species', '10090', (41, 47))	('VEGFR-1', 'Gene', (128, 135))	('men', 'Species', '9606', (192, 195))	('D16F7', 'Var', (148, 153))	('D16F7', 'Chemical', 'MESH:C000627505', (148, 153))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
892746	32085654	Furthermore, immunohistochemical analysis of melanoma sections from D16F7-treated animals showed a reduction of tumor infiltration by monocytes/macrophages and a marked decrease of bone invasion by melanoma cells.	('rat', 'Species', '10116', (124, 127))	('decrease', 'NegReg', (169, 177))	('melanoma cells', 'Disease', 'MESH:D008545', (198, 212))	('melanoma cells', 'Disease', (198, 212))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('D16F7-treated', 'Var', (68, 81))	('reduction', 'NegReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('D16F7', 'Chemical', 'MESH:C000627505', (68, 73))	('tumor', 'Disease', (112, 117))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
892748	32085654	In fact, the expression of VEGFR-1 in melanoma cells resistant to the BRAFi vemurafenib was higher than in their BRAFi-sensitive counterparts, whereas the transient silencing of VEGFR-1 in resistant cells increased BRAFi sensitivity and in susceptible cells delayed resistance development.	('BRAF', 'Gene', (215, 219))	('VEGFR-1', 'Gene', (178, 185))	('delayed', 'NegReg', (258, 265))	('VEGFR-1', 'Gene', (27, 34))	('increased', 'PosReg', (205, 214))	('BRAFi vemurafenib', 'Chemical', '-', (70, 87))	('silencing', 'Var', (165, 174))	('higher', 'PosReg', (92, 98))	('melanoma cells', 'Disease', 'MESH:D008545', (38, 52))	('BRAF', 'Gene', '673', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BRAF', 'Gene', (70, 74))	('men', 'Species', '9606', (284, 287))	('BRAF', 'Gene', '673', (113, 117))	('BRAF', 'Gene', (113, 117))	('expression', 'MPA', (13, 23))	('melanoma cells', 'Disease', (38, 52))	('resistance development', 'CPA', (266, 288))	('BRAF', 'Gene', '673', (215, 219))
892749	32085654	Furthermore, vemurafenib-resistant melanoma cells expressing VEGFR-1 showed a higher invasive behavior, compared to melanoma cells susceptible to the BRAFi.	('vemurafenib', 'Chemical', 'MESH:D000077484', (13, 24))	('VEGFR-1', 'Var', (61, 68))	('higher', 'PosReg', (78, 84))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('melanoma cells', 'Disease', (116, 130))	('melanoma cells', 'Disease', 'MESH:D008545', (116, 130))	('invasive behavior', 'CPA', (85, 102))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma cells', 'Disease', 'MESH:D008545', (35, 49))	('melanoma cells', 'Disease', (35, 49))
892750	32085654	Accordingly, treatment with D16F7 markedly reduced ECM invasion by resistant cells in response to VEGF-A and PlGF, suggesting that VEGFR-1 blockade in combination with the BRAFi might delay the acquisition of a resistance phenotype.	('resistance phenotype', 'CPA', (211, 231))	('men', 'Species', '9606', (18, 21))	('D16F7', 'Var', (28, 33))	('delay', 'NegReg', (184, 189))	('ECM invasion', 'CPA', (51, 63))	('D16F7', 'Chemical', 'MESH:C000627505', (28, 33))	('BRAF', 'Gene', '673', (172, 176))	('reduced', 'NegReg', (43, 50))	('VEGFR-1', 'Gene', (131, 138))	('BRAF', 'Gene', (172, 176))
892753	32085654	Indeed, PlGF silencing or inhibition of NF-kappaB restored melanoma cell sensitivity to the chemotherapeutic agent Finally, VEGF-B transcript levels in the tumor measured in a large cohort of melanoma patients inversely correlated with survival.	('patients', 'Species', '9606', (201, 209))	('PlGF', 'Gene', (8, 12))	('transcript levels', 'MPA', (131, 148))	('NF-kappaB', 'Gene', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('inhibition', 'NegReg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('tumor', 'Disease', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('VEGF-B', 'Gene', (124, 130))	('restored', 'PosReg', (50, 58))	('correlated', 'Reg', (220, 230))	('silencing', 'Var', (13, 22))
892764	32085654	Moreover, a meta-analysis study performed in a Chinese population reported a link between VEGF-A gene polymorphisms (VEGF +936C/T and -634 G/C) and the risk of developing osteosarcoma.	('+936C/T', 'Mutation', 'rs3025039', (122, 129))	('VEGF', 'Gene', (117, 121))	('osteosarcoma', 'Phenotype', 'HP:0002669', (171, 183))	('VEGF', 'Gene', (90, 94))	('osteosarcoma', 'Disease', 'MESH:D012516', (171, 183))	('-634 G/C', 'Var', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('VEGF', 'Gene', '7422', (117, 121))	('-634 G/C', 'SUBSTITUTION', 'None', (134, 142))	('VEGF', 'Gene', '7422', (90, 94))	('osteosarcoma', 'Disease', (171, 183))
892766	32085654	Indeed, HIF-1alpha and VEGF-A knockdown decreased the invasive potential of Saos-2 and U2-OS osteosarcoma cell lines.	('VEGF-A', 'Gene', (23, 29))	('HIF-1alpha', 'Gene', '3091', (8, 18))	('HIF-1alpha', 'Gene', (8, 18))	('osteosarcoma', 'Phenotype', 'HP:0002669', (93, 105))	('invasive potential of Saos-2', 'CPA', (54, 82))	('osteosarcoma', 'Disease', (93, 105))	('osteosarcoma', 'Disease', 'MESH:D012516', (93, 105))	('knockdown', 'Var', (30, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('decreased', 'NegReg', (40, 49))
892773	32085654	Consistently with the in vitro data, tumors originated from high-VEGFR-1 K7M3 cells produced more VEGF-A than low-VEGFR-1 cells.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('high-VEGFR-1 K7M3', 'Var', (60, 77))	('K7M3', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('VEGF-A', 'MPA', (98, 104))
892797	32085654	Increased levels of PlGF were reported in obesity-associated pancreatic cancer patients and ablation of the VEGFR-1 signaling in pancreatic ductal adenocarcinoma murine models prevented obesity-induced tumor progression.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('ablation', 'Var', (92, 100))	('obesity', 'Phenotype', 'HP:0001513', (42, 49))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (129, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('obesity', 'Disease', (186, 193))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic ductal adenocarcinoma', 'Disease', (129, 161))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('obesity', 'Disease', (42, 49))	('pancreatic cancer', 'Disease', (61, 78))	('obesity', 'Disease', 'MESH:D009765', (186, 193))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (129, 161))	('obesity', 'Disease', 'MESH:D009765', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('murine', 'Species', '10090', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('prevented', 'NegReg', (176, 185))	('VEGFR-1', 'Gene', (108, 115))	('patients', 'Species', '9606', (79, 87))	('obesity', 'Phenotype', 'HP:0001513', (186, 193))
892814	32085654	Patients with VEGF-A overexpression have a significantly increased risk (2-fold) of disease progression, with the development of distant metastases and shorter OS.	('metastases', 'Disease', 'MESH:D009362', (137, 147))	(')', 'Gene', '7424', (79, 80))	('overexpression', 'Var', (21, 35))	('men', 'Species', '9606', (121, 124))	('Patients', 'Species', '9606', (0, 8))	('disease', 'Disease', (84, 91))	('VEGF-A', 'Gene', (14, 20))	('metastases', 'Disease', (137, 147))
892816	32085654	Furthermore, a clinical study enrolling 334 patients with advanced esophageal squamous cell carcinoma revealed that the genetic polymorphism rs2010963 in VEGF-A gene independently correlated with worse OS, although this genotype was not associated with high pretreatment VEGF-A levels in the serum.	('patients', 'Species', '9606', (44, 52))	('VEGF-A', 'Gene', (154, 160))	('rs2010963', 'Mutation', 'rs2010963', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (67, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('rs2010963', 'Var', (141, 150))	('men', 'Species', '9606', (266, 269))	('worse OS', 'Disease', (196, 204))	('correlated with', 'Reg', (180, 195))	('esophageal squamous cell carcinoma', 'Disease', (67, 101))
892859	32085654	Overexpression of CSE also increased the levels of MMP2 and MMP9 in early metastatic breast cancer cells, allowing the degradation of the ECM and consequently the entering of tumor cells into the blood circulation.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('tumor', 'Disease', (175, 180))	('MMP2', 'Gene', (51, 55))	('increased', 'PosReg', (27, 36))	('breast cancer', 'Disease', (85, 98))	('entering', 'MPA', (163, 171))	('CSE', 'Gene', '1491', (18, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('MMP2', 'Gene', '4313', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('degradation', 'MPA', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MMP9', 'Var', (60, 64))	('CSE', 'Gene', (18, 21))	('allowing', 'Reg', (106, 114))
892865	32085654	The addition of the anti-VEGFR-1 KM1732 mAb and a VEGFR-1 trap (sFlt-1-Fc) to CD34+ cultures, pretreated with the MDA-MB-231-conditioned medium or PlGF, prevented the generation of CD11b+ cells with sprouting-inducing ability.	('CD11b', 'Gene', (181, 186))	('CD34', 'Gene', (78, 82))	('CD34', 'Gene', '947', (78, 82))	('Flt-1', 'Gene', '2321', (65, 70))	('rat', 'Species', '10116', (171, 174))	(')', 'Gene', '7424', (73, 74))	('prevented', 'NegReg', (153, 162))	('Flt-1', 'Gene', (65, 70))	('CD11b', 'Gene', '3684', (181, 186))	('anti-VEGFR-1', 'Var', (20, 32))
892866	32085654	Furthermore, CD11b+ cells induced a significant angiogenic response in the murine corneal angiogenesis in vivo assay and PlGF silencing reduced the proangiogenic activity of circulating CD11b+ myelomonocytic cells in a breast cancer murine model.	('CD11b', 'Gene', (13, 18))	('corneal angiogenesis', 'Phenotype', 'HP:0011496', (82, 102))	('CD11b', 'Gene', '3684', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('murine', 'Species', '10090', (75, 81))	('CD11b', 'Gene', (186, 191))	('breast cancer', 'Disease', (219, 232))	('angiogenic response', 'CPA', (48, 67))	('murine', 'Species', '10090', (233, 239))	('CD11b', 'Gene', '3684', (186, 191))	('reduced', 'NegReg', (136, 143))	('silencing', 'Var', (126, 135))	('proangiogenic activity', 'CPA', (148, 170))	('PlGF', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
892870	32085654	Furthermore, while obesity promoted IL-6 and MMP9 expression in tumors, deletion of VEGFR-1 TK domain decreased the expression of these pro-M2 markers only in obese mice.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('mice', 'Species', '10090', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('expression', 'MPA', (50, 60))	('deletion', 'Var', (72, 80))	('tumors', 'Disease', (64, 70))	('obese', 'Disease', (159, 164))	('IL-6', 'Gene', (36, 40))	('obesity', 'Disease', (19, 26))	('obese', 'Disease', 'MESH:D009765', (159, 164))	('decreased', 'NegReg', (102, 111))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('obesity', 'Disease', 'MESH:D009765', (19, 26))	('IL-6', 'Gene', '16193', (36, 40))	('promoted', 'PosReg', (27, 35))	('expression', 'MPA', (116, 126))	('MMP9', 'Protein', (45, 49))	('VEGFR-1', 'Gene', (84, 91))	('obesity', 'Phenotype', 'HP:0001513', (19, 26))
892871	32085654	PlGF was identified as the VEGFR-1 ligand responsible for such effects since its plasma levels were elevated in diet-induced obese mice, and its deletion induced similar effects to those observed in VEGFR-1-TK-null obese mice.	('obese', 'Disease', (125, 130))	('obese', 'Disease', 'MESH:D009765', (215, 220))	('obese', 'Disease', (215, 220))	('mice', 'Species', '10090', (221, 225))	('PlGF', 'Gene', (0, 4))	('plasma levels', 'MPA', (81, 94))	('obese', 'Disease', 'MESH:D009765', (125, 130))	('mice', 'Species', '10090', (131, 135))	('elevated', 'PosReg', (100, 108))	('deletion', 'Var', (145, 153))
892879	32085654	Also ZEB2 expression, a transcription factor with a crucial role in EMT, strongly correlated with PlGF levels in ovarian cancer tissues: PlGF overexpression significantly increased ZEB2 levels and cell invasiveness, conversely PlGF depletion was associated with a decline of ZEB2 levels and cell invasiveness.	('cell invasiveness', 'CPA', (291, 308))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('cell invasiveness', 'CPA', (197, 214))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('ZEB2', 'Gene', '9839', (181, 185))	('PlGF', 'Gene', (137, 141))	('ZEB2', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ZEB2', 'Gene', '9839', (275, 279))	('overexpression', 'Var', (142, 156))	('ZEB2', 'Gene', (181, 185))	('ovarian cancer', 'Disease', (113, 127))	('ZEB2', 'Gene', (275, 279))	('ZEB2', 'Gene', '9839', (5, 9))	('increased', 'PosReg', (171, 180))
892882	32085654	Mice transplanted with human ovarian adenocarcinoma SKOV3 cells transfected with pLV-sFLT1 or exogenously (intraperitoneally) treated with recombinant sVEGFR-1, confirmed the antitumor effect of sVEGFR-1 also in vivo, in terms of reduced tumor size compared to control animals.	('reduced', 'NegReg', (230, 237))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (29, 51))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('sVEGFR-1', 'Var', (195, 203))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (29, 51))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('ovarian adenocarcinoma', 'Disease', (29, 51))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	(')', 'Gene', '7424', (124, 125))	('tumor', 'Disease', (238, 243))	('Mice', 'Species', '10090', (0, 4))	('human', 'Species', '9606', (23, 28))	('SKOV3', 'CellLine', 'CVCL:0532;0.04086655203281981', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('tumor', 'Disease', (179, 184))
892884	32085654	VEGFR-1 as well VEGFR-2 expression levels in biopsy specimens have been recognized as prognostic factors for patients with cervical cancer: high VEGFR-1 expression was linked to distant metastases, together with poor OS and PFS, whereas high VEGFR-2 expression correlated with increased tumor size and reduced OS.	('metastases', 'Disease', (186, 196))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('cervical cancer', 'Disease', (123, 138))	('high', 'Var', (140, 144))	('cervical cancer', 'Disease', 'MESH:D002583', (123, 138))	('metastases', 'Disease', 'MESH:D009362', (186, 196))	('VEGFR-1', 'Gene', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('increased', 'PosReg', (277, 286))	('tumor', 'Disease', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('men', 'Species', '9606', (57, 60))	('linked to', 'Reg', (168, 177))
892886	32085654	On the other hand, a recent study reported that patients with high serum levels of both VEGF-A and VEGFR-2 presented bulky tumors, pelvic lymph node involvement, parametrial infiltration, and significantly lower OS than patients with low VEGF-A and VEGFR-2 expression.	('VEGFR-2', 'Gene', (99, 106))	('parametrial infiltration', 'CPA', (162, 186))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('rat', 'Species', '10116', (180, 183))	('pelvic lymph node involvement', 'CPA', (131, 160))	('men', 'Species', '9606', (156, 159))	('lower', 'NegReg', (206, 211))	('serum levels', 'MPA', (67, 79))	('patients', 'Species', '9606', (220, 228))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))	('VEGF-A', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
892890	32085654	Deregulation of cellular energetic metabolism has been recognized as another feature of cancer, aimed at increasing the production of lactate, whose efflux in the ECM induces angiogenesis.	('cellular energetic metabolism', 'MPA', (16, 45))	('cancer', 'Disease', (88, 94))	('increasing', 'PosReg', (105, 115))	('induces', 'Reg', (167, 174))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Deregulation', 'Var', (0, 12))	('lactate', 'Chemical', 'MESH:D019344', (134, 141))	('angiogenesis', 'CPA', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('efflux', 'MPA', (149, 155))	('production of lactate', 'MPA', (120, 141))
892912	32085654	Consistently, ectopic VEGF-A expression decreased miR-130b level and abrogated its antiangiogenic effect, thus promoting the angiogenic response.	('abrogated', 'NegReg', (69, 78))	('antiangiogenic effect', 'CPA', (83, 104))	('promoting', 'PosReg', (111, 120))	('miR-130b', 'Gene', '406920', (50, 58))	('miR-130b', 'Gene', (50, 58))	('ectopic', 'Var', (14, 21))	('angiogenic response', 'CPA', (125, 144))	('decreased', 'NegReg', (40, 49))	('VEGF-A', 'Gene', (22, 28))
892935	32085654	Thus, the authors suggested that blockade of VEGFR-1 by a selective therapeutic agent might counteract leukemia cell movement within the bone marrow, delaying the extra-medullary tumor growth.	('blockade', 'Var', (33, 41))	('men', 'Species', '9606', (121, 124))	('delaying', 'NegReg', (150, 158))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('leukemia', 'Disease', 'MESH:D007938', (103, 111))	('VEGFR-1', 'Gene', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('leukemia', 'Disease', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
892941	32085654	Other approved agents that are endowed with antiangiogenic effects but do not directly target the VEGFRs or their ligands include (i) the mammalian target of rapamycin (mTOR) inhibitors temsirolimus (approved for RCC and mantle cell lymphoma) and everolimus (approved for advanced kidney and breast cancers, subependymal giant cell astrocytoma, pancreatic neuroendocrine tumors, neuroendocrine tumors of gastrointestinal or lung origin), and the (ii) the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide and pomalidomide, approved for the treatment of multiple myeloma (lenalidomide also for relapsed or refractory mantle cell lymphoma and myelodysplastic syndromes with deletion of the long arm of chromosome 5).	('men', 'Species', '9606', (552, 555))	('multiple myeloma', 'Phenotype', 'HP:0006775', (560, 576))	('breast cancers', 'Phenotype', 'HP:0003002', (292, 306))	(')', 'Gene', '7424', (484, 485))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (356, 377))	('subependymal giant cell astrocytoma', 'Disease', (308, 343))	('pancreatic neuroendocrine tumors', 'Disease', (345, 377))	('cell lymphoma', 'Phenotype', 'HP:0012191', (228, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('lymphoma', 'Phenotype', 'HP:0002665', (233, 241))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (379, 400))	('mantle cell lymphoma', 'Disease', (623, 643))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (623, 643))	('multiple myeloma', 'Disease', 'MESH:D009101', (560, 576))	('tumors', 'Phenotype', 'HP:0002664', (394, 400))	('subependymal giant cell astrocytoma', 'Phenotype', 'HP:0009718', (308, 343))	('myelodysplastic syndromes', 'Disease', (648, 673))	('tumors', 'Phenotype', 'HP:0002664', (371, 377))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (648, 673))	('cell lymphoma', 'Phenotype', 'HP:0012191', (630, 643))	('lymphoma', 'Phenotype', 'HP:0002665', (635, 643))	(')', 'Gene', '7424', (173, 174))	('subependymal giant cell astrocytoma', 'Disease', 'MESH:D001254', (308, 343))	('mammalian target of rapamycin', 'Gene', '2475', (138, 167))	(')', 'Gene', '7424', (435, 436))	('everolimus', 'Chemical', 'MESH:D000068338', (247, 257))	('VEGFR', 'Gene', '3791', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('multiple myeloma', 'Disease', (560, 576))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (648, 673))	('deletion', 'Var', (679, 687))	('VEGFR', 'Gene', (98, 103))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (221, 241))	(')', 'Gene', '7424', (719, 720))	(')', 'Gene', '7424', (132, 133))	('mammalian target of rapamycin', 'Gene', (138, 167))	('mantle cell lymphoma', 'Disease', (221, 241))	(')', 'Gene', '7424', (449, 450))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('astrocytoma', 'Phenotype', 'HP:0009592', (332, 343))	(')', 'Gene', '7424', (241, 242))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancers', 'Disease', 'MESH:D001943', (292, 306))	('breast cancers', 'Disease', (292, 306))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('neuroendocrine tumors of gastrointestinal', 'Disease', (379, 420))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (345, 377))	('tumors of gastrointestinal', 'Phenotype', 'HP:0007378', (394, 420))	('neuroendocrine tumors of gastrointestinal', 'Disease', 'MESH:D018358', (379, 420))
892945	32085654	Most of these mAbs prevent the interaction of VEGFR-1 ligands with the receptor (competitive inhibitors), whereas only D16F7 blocks receptor signal transduction without inhibiting ligand binding (non-competitive inhibitor).	('prevent', 'NegReg', (19, 26))	('D16F7', 'Var', (119, 124))	('interaction', 'Interaction', (31, 42))	(')', 'Gene', '7424', (103, 104))	('D16F7', 'Chemical', 'MESH:C000627505', (119, 124))	(')', 'Gene', '7424', (221, 222))	('receptor signal transduction', 'MPA', (132, 160))	('blocks', 'NegReg', (125, 131))	('VEGFR-1', 'Gene', (46, 53))
892948	32085654	This mAb has shown antitumor activity in human breast carcinoma xenograft models (i.e., DU4475, MDA-MB-231, and MDA-MB-435).	('DU4475', 'Var', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('breast carcinoma xenograft', 'Disease', (47, 73))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('human', 'Species', '9606', (41, 46))	('breast carcinoma xenograft', 'Disease', 'MESH:D001943', (47, 73))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('breast carcinoma', 'Phenotype', 'HP:0003002', (47, 63))	('tumor', 'Disease', (23, 28))	('DU4475', 'CellLine', 'CVCL:1183;-0.001036928386686134', (88, 94))
892950	32085654	Moreover, immunohistochemical analysis of tumor xenografts collected from treated mice showed an increase of tumor cell apoptosis and a decrease in MAPK and AKT activation and cell proliferation; (ii) The murine anti-human VEGFR-1 D16F7 mAb (mouse IgG1), which has a novel mechanism of action, as it interacts with a receptor site distinct from that involved in VEGF-A or PlGF binding and downregulates the signaling through the membrane receptor without affecting ligand binding.	(')', 'Gene', '7424', (199, 200))	('human', 'Species', '9606', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (42, 47))	('murine', 'Species', '10090', (205, 211))	('rat', 'Species', '10116', (188, 191))	('signaling through the membrane receptor', 'MPA', (407, 446))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	(')', 'Gene', '7424', (252, 253))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('D16F7', 'Var', (231, 236))	('mice', 'Species', '10090', (82, 86))	('MAPK', 'Pathway', (148, 152))	('mouse', 'Species', '10090', (242, 247))	('downregulates', 'NegReg', (389, 402))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('interacts', 'Interaction', (300, 309))	('D16F7', 'Chemical', 'MESH:C000627505', (231, 236))	('decrease', 'NegReg', (136, 144))	('tumor', 'Disease', (109, 114))
892952	32085654	Moreover, D16F7 leaves unaffected the sVEGFR-1 decoy function, as it neither affects sVEGFR-1 interaction with its ligands nor hampers the sVEGFR-1/VEGFR-2 inhibitory heterodimer formation.	('interaction', 'Interaction', (94, 105))	('D16F7', 'Var', (10, 15))	('D16F7', 'Chemical', 'MESH:C000627505', (10, 15))	('hampers', 'NegReg', (127, 134))	('sVEGFR-1/VEGFR-2 inhibitory heterodimer formation', 'MPA', (139, 188))
892953	32085654	D16F7 has shown antitumor efficacy in preclinical in vivo models against highly aggressive tumor types, such as glioblastoma and melanoma (see also Section 2.4 and Section 2.5).	('tumor', 'Disease', (91, 96))	('D16F7', 'Var', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('D16F7', 'Chemical', 'MESH:C000627505', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('aggressive tumor', 'Disease', 'MESH:D001523', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('aggressive tumor', 'Disease', (80, 96))	('glioblastoma and melanoma', 'Disease', 'MESH:D005909', (112, 137))	('tumor', 'Disease', (20, 25))	(')', 'Gene', '7424', (175, 176))
892954	32085654	Its ability to recognize not only the human form of the VEGFR-1 but also the murine receptor has allowed the analysis of the effects of VEGFR-1 inhibition on tumor-associated microenvironment; (iii) The anti-human VEGFR-1 KM1730 and KM1732 mAbs (mouse IgG1), which recognize different epitopes of the second Ig-like domain.	(')', 'Gene', '7424', (256, 257))	('tumor', 'Disease', (158, 163))	('human', 'Species', '9606', (38, 43))	('murine', 'Species', '10090', (77, 83))	('KM1732', 'Var', (233, 239))	('men', 'Species', '9606', (187, 190))	('mouse', 'Species', '10090', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	(')', 'Gene', '7424', (197, 198))	('human', 'Species', '9606', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('KM1730', 'Var', (222, 228))
892956	32085654	Moreover, treatment with KM1732 mAb of primary cell cultures derived from bone marrow samples collected from patients with AML resulted in significant inhibition of cell growth.	('KM1732 mAb', 'Var', (25, 35))	('patients', 'Species', '9606', (109, 117))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('men', 'Species', '9606', (15, 18))	('AML', 'Phenotype', 'HP:0004808', (123, 126))	('AML', 'Disease', (123, 126))	('inhibition', 'NegReg', (151, 161))	('cell growth', 'CPA', (165, 176))
892963	32085654	The anti-PlGF mAb 5D11D4 is directed against the murine PlGF of which inhibits the interaction with VEGFR-1 and with NRP-1.	('VEGFR-1', 'Protein', (100, 107))	('interaction', 'Interaction', (83, 94))	('inhibits', 'NegReg', (70, 78))	('5D11D4', 'Var', (18, 24))	('murine', 'Species', '10090', (49, 55))
892964	32085654	The 5D11D4 mAb inhibited tumor growth and metastasis formation in melanoma, cholangiocarcinoma, pancreatic, hepatocellular, and colon cancer in vivo models.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('melanoma', 'Disease', (66, 74))	('cholangiocarcinoma', 'Disease', (76, 94))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (76, 94))	('hepatocellular', 'Disease', (108, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('5D11D4', 'Var', (4, 10))	('pancreatic', 'Disease', 'MESH:D010195', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('tumor', 'Disease', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('pancreatic', 'Disease', (96, 106))	('inhibited', 'NegReg', (15, 24))	('colon cancer', 'Disease', (128, 140))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (76, 94))
892981	32085654	AEE788 is instead a dual inhibitor of epidermal growth factor and VEGF receptors and is currently under investigation in patients with recurrent glioblastoma, as single agent or in combination with everolimus.	('VEGF', 'Gene', (66, 70))	('AEE788', 'Var', (0, 6))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('everolimus', 'Chemical', 'MESH:D000068338', (198, 208))	('AEE788', 'Chemical', 'MESH:C489254', (0, 6))	('VEGF', 'Gene', '7422', (66, 70))	('glioblastoma', 'Disease', (145, 157))	('epidermal growth factor', 'Protein', (38, 61))	('patients', 'Species', '9606', (121, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))
892983	32085654	A total of thirty-two trials can be found in  where lucitanib is tested for solid tumors, breast cancer, NSCLC, SCLC, gastroesophageal reflux disease, and functional dyspepsia, with two of them including tumors with genetic alterations of the FGF receptor.	('gastroesophageal reflux disease', 'Disease', (118, 149))	('tumors', 'Disease', (82, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (118, 149))	('SCLC', 'Disease', 'MESH:D055752', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('genetic alterations', 'Var', (216, 235))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('rat', 'Species', '10116', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('SCLC', 'Disease', 'MESH:D055752', (112, 116))	('SCLC', 'Disease', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('solid tumors', 'Disease', (76, 88))	('dyspepsia', 'Phenotype', 'HP:0410281', (166, 175))	('tumors', 'Disease', (204, 210))	('SCLC', 'Phenotype', 'HP:0030357', (106, 110))	('FGF receptor', 'Gene', (243, 255))	('SCLC', 'Disease', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('functional dyspepsia', 'Disease', 'MESH:D004415', (155, 175))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (118, 141))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('functional dyspepsia', 'Disease', (155, 175))	('breast cancer', 'Disease', (90, 103))	('lucitanib', 'Chemical', 'MESH:C000595232', (52, 61))	('NSCLC', 'Disease', (105, 110))	('tested', 'Reg', (65, 71))
892991	32085654	Inhibition of VEGF-A and its signaling through VEGFR-2, a receptor also involved in physiological angiogenesis, causes important adverse effects such as hypertension, proteinuria, bleeding, thromboembolism, delay in wound healing, and gastrointestinal perforation.	('bleeding', 'Disease', (180, 188))	('gastrointestinal', 'Disease', (235, 251))	('thromboembolism', 'Disease', 'MESH:D013923', (190, 205))	('thromboembolism', 'Phenotype', 'HP:0001907', (190, 205))	('VEGFR-2', 'Gene', (47, 54))	('hypertension', 'Disease', 'MESH:D006973', (153, 165))	('delay', 'CPA', (207, 212))	('proteinuria', 'Disease', (167, 178))	('hypertension', 'Disease', (153, 165))	('proteinuria', 'Disease', 'MESH:D011507', (167, 178))	('Inhibition', 'Var', (0, 10))	('rat', 'Species', '10116', (257, 260))	('thromboembolism', 'Disease', (190, 205))	('bleeding', 'Disease', 'MESH:D006470', (180, 188))	('proteinuria', 'Phenotype', 'HP:0000093', (167, 178))	('wound healing', 'CPA', (216, 229))	('hypertension', 'Phenotype', 'HP:0000822', (153, 165))	('VEGF-A', 'Gene', (14, 20))	('delay in wound healing', 'Phenotype', 'HP:0001058', (207, 229))
892994	32085654	Conversely, the neutralization of VEGFR-1 specific ligands, i.e., VEGF-B and PlGF, and the selective blockade of VEGFR-1 activation, represents a promising strategy to specifically counteract tumor-associated angiogenesis as well as malignant processes not directly related to new blood vessels formation.	('tumor', 'Disease', (192, 197))	('neutralization', 'Var', (16, 30))	('VEGFR-1', 'Gene', (34, 41))	('rat', 'Species', '10116', (158, 161))	('VEGF-B', 'Gene', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('VEGFR-1', 'Gene', (113, 120))
892995	32085654	Indeed, inhibition of VEGFR-1 signaling also reduces tumor cell survival and invasiveness, counteracts the mobilization of myeloid progenitors and prevents tumor infiltration by M2 protumoral macrophages.	('VEGFR-1', 'Gene', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumoral', 'Disease', 'MESH:D009369', (184, 191))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('reduces', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (184, 189))	('invasiveness', 'CPA', (77, 89))	('prevents', 'NegReg', (147, 155))	('rat', 'Species', '10116', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (53, 58))	('inhibition', 'Var', (8, 18))	('tumoral', 'Disease', (184, 191))
892996	32085654	In this context, the D16F7 mAb is a promising tool to specifically and non-competitively interfere with VEGFR-1 signaling in the tumor.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('interfere', 'NegReg', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('D16F7', 'Chemical', 'MESH:C000627505', (21, 26))	('D16F7', 'Var', (21, 26))	('tumor', 'Disease', (129, 134))	('VEGFR-1 signaling', 'MPA', (104, 121))
892997	32085654	Conversely, other experimental mAbs designed to inhibit human VEGFR-1 signaling, like IMC-18F1/icrucumab, KM1730, or KM1732, possess a competitive mechanism of action, by inhibiting VEGF-A, VEGF-B, or PlGF binding to VEGFR-1.	('men', 'Species', '9606', (24, 27))	('PlGF', 'Protein', (201, 205))	('inhibiting', 'NegReg', (171, 181))	('binding', 'Interaction', (206, 213))	('icrucumab', 'Chemical', 'MESH:C000626257', (95, 104))	('IMC-18F1', 'Chemical', 'MESH:C548516', (86, 94))	('KM1730', 'Var', (106, 112))	('human', 'Species', '9606', (56, 61))	('VEGF-A', 'Protein', (182, 188))	('KM1732', 'Var', (117, 123))	('VEGF-B', 'Protein', (190, 196))	('inhibit', 'NegReg', (48, 55))
892998	32085654	Competitive VEGFR-1 inhibitors, by antagonizing ligand binding, may increase in the ECM the free VEGF-A available for VEGFR-2 activation and this may reduce the overall efficacy of the treatment.	('free VEGF-A', 'MPA', (92, 103))	('ligand binding', 'Interaction', (48, 62))	('reduce', 'NegReg', (150, 156))	('inhibitors', 'Var', (20, 30))	('antagonizing', 'Reg', (35, 47))	('men', 'Species', '9606', (190, 193))	('increase', 'PosReg', (68, 76))	('ECM', 'MPA', (84, 87))	('VEGFR-1', 'Gene', (12, 19))	('efficacy of the treatment', 'CPA', (169, 194))
893000	32085654	D16F7 mAb efficacy in monotherapy has already been demonstrated in in vivo preclinical models of highly aggressive tumors, showing significant inhibition of glioblastoma and melanoma growth, invasiveness and migration, impairment of endothelial cells chemotaxis and tumor-associated angiogenesis, as well as reduced myeloid progenitor mobilization and tumor infiltration by monocytes/macrophages.	('impairment', 'NegReg', (219, 229))	('aggressive tumors', 'Disease', 'MESH:D001523', (104, 121))	('tumor', 'Disease', (115, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('men', 'Species', '9606', (225, 228))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('tumor', 'Disease', (266, 271))	('inhibition', 'NegReg', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('invasiveness', 'CPA', (191, 203))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('melanoma growth', 'Disease', 'MESH:D008545', (174, 189))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', (352, 357))	('myeloid progenitor mobilization', 'CPA', (316, 347))	('rat', 'Species', '10116', (364, 367))	('glioblastoma and melanoma', 'Disease', 'MESH:D005909', (157, 182))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('endothelial cells chemotaxis', 'CPA', (233, 261))	('rat', 'Species', '10116', (211, 214))	('D16F7', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('rat', 'Species', '10116', (58, 61))	('reduced', 'NegReg', (308, 315))	('melanoma growth', 'Disease', (174, 189))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('aggressive tumors', 'Disease', (104, 121))	('D16F7', 'Chemical', 'MESH:C000627505', (0, 5))	('migration', 'CPA', (208, 217))
893010	32102317	Positive-VM was strongly associated with poor OS (hazard ratio = 0.50; 95% confidence interval: 0.38-0.64), which remained consistent following the subgroup analysis of the studies.	('poor OS', 'Disease', (41, 48))	('OS', 'Chemical', '-', (46, 48))	('Positive-VM', 'Var', (0, 11))
893068	32102317	All the studies showed that positive-VM immunoreactivity is associated with a decreased probability of overall survival, so that patients with positive-VM were more likely to die compared with negative-VM patients.	('positive-VM immunoreactivity', 'Var', (28, 56))	('overall survival', 'CPA', (103, 119))	('patients', 'Species', '9606', (205, 213))	('positive-VM', 'Var', (143, 154))	('patients', 'Species', '9606', (129, 137))	('die', 'CPA', (175, 178))	('decreased', 'NegReg', (78, 87))
893076	32102317	Indeed, our findings are in agreement with previous meta-analysis reports that have shown the association between VM positivity with decreased probability of patients' survival in different cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('positivity', 'Var', (117, 127))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('patients', 'Species', '9606', (158, 166))	('decreased', 'NegReg', (133, 142))
893079	32102317	In the same direction, another recent meta-analysis showed that positive VM was a reliable indicator of poor prognosis in digestive cancer patients.	('positive VM', 'Var', (64, 75))	('cancer', 'Disease', (132, 138))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
893192	28849204	Comprehensive bioinformatics analysis of the mRNA profile of PLCE1 knockdown in esophageal squamous cell carcinoma The authors previously reported that Phospholipase C epsilon 1 (PLCE1) exacerbated esophageal squamous cell carcinoma (ESCC), however, the underlying mechanism remains to be fully elucidated.	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('knockdown', 'Var', (67, 76))	('exacerbated', 'PosReg', (186, 197))	('PLCE1', 'Gene', (61, 66))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (80, 114))	('PLCE1', 'Gene', '51196', (61, 66))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (198, 232))	('Phospholipase C epsilon 1', 'Gene', '51196', (152, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (209, 232))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('PLCE1', 'Gene', (179, 184))	('PLCE1', 'Gene', '51196', (179, 184))	('Phospholipase C epsilon 1', 'Gene', (152, 177))	('esophageal squamous cell carcinoma', 'Disease', (80, 114))	('esophageal squamous cell carcinoma', 'Disease', (198, 232))
893194	28849204	In particular, inflammation or immune-associated molecules, including Toll-like receptor (TLR)-4 interleukin-6, -8 and chemokine C-X-C motif ligand 2 were significantly increased following PLCE1 knockdown.	('inflammation', 'Disease', 'MESH:D007249', (15, 27))	('increased', 'PosReg', (169, 178))	('TLR)-4', 'Gene', '7099', (90, 96))	('Toll-like receptor', 'MPA', (70, 88))	('inflammation', 'Disease', (15, 27))	('interleukin-6, -8 and chemokine C-X-C motif ligand 2', 'Gene', '2920;3569;3576', (97, 149))	('PLCE1', 'Gene', (189, 194))	('knockdown', 'Var', (195, 204))
893201	28849204	Afterwards, we have stably knockdown PLCE1 by siRNA in ESCC cell lines Eca109 and EC9706, knockdown of PLCE1 resulted in an increase of the apoptosis, a decrease in cell proliferation as well as migration and invasion, and an inhibition of the formation of lamellipodia and filopodia of F-actin in vitro, the effect of PLCE1 on cell migration, invasiveness, and motility is correlated with epithelial-mesenchymal transition (EMT) and cytoskeleton dynamics.	('increase', 'PosReg', (124, 132))	('lamellipodia', 'Disease', 'None', (257, 269))	('EC9706', 'CellLine', 'CVCL:E307', (82, 88))	('knockdown', 'Var', (90, 99))	('inhibition', 'NegReg', (226, 236))	('lamellipodia', 'Disease', (257, 269))	('PLCE1', 'Gene', (37, 42))	('apoptosis', 'CPA', (140, 149))	('cell proliferation', 'CPA', (165, 183))	('migration', 'CPA', (195, 204))	('invasiveness', 'Disease', 'MESH:D009362', (344, 356))	('invasiveness', 'Disease', (344, 356))	('PLCE1', 'Gene', (319, 324))	('cell migration', 'CPA', (328, 342))	('epithelial-mesenchymal transition', 'CPA', (390, 423))	('PLCE1', 'Gene', (103, 108))	('decrease', 'NegReg', (153, 161))
893202	28849204	To better understand the molecular mechanism of PLCE1, the mRNA expression profile of PLCE1 knockdown was analyzed by the Affymetrix Gene Chip Human genome arrays.	('Human', 'Species', '9606', (143, 148))	('PLCE1', 'Gene', (86, 91))	('knockdown', 'Var', (92, 101))
893204	28849204	Based on Gene Ontology enrichment and KEGG pathway analysis, we found that PLCE1 knockdown could impact a number of genes involved in proliferation, apoptosis, invasion and metastasis of tumor cells, et al and pathways including MAPK, Toll-like receptor, p53, Focal adhesion, et al.	('apoptosis', 'CPA', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('Focal adhesion', 'Disease', (260, 274))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('PLCE1', 'Gene', (75, 80))	('knockdown', 'Var', (81, 90))	('tumor', 'Disease', (187, 192))	('p53', 'Gene', '7157', (255, 258))	('MAPK', 'Gene', (229, 233))	('proliferation', 'CPA', (134, 147))	('p53', 'Gene', (255, 258))	('impact', 'Reg', (97, 103))
893216	28849204	To explore the influence of PLCE1 on downstream genes, the mRNA expression profile was analyzed using the Affymetrix GeneChip Human genome 3, IVT arrays which contain 49294 genes in Eca109 and EC9706 transfected with PLCE1 siRNA compared to control groups.	('Human', 'Species', '9606', (126, 131))	('transfected', 'Var', (200, 211))	('Eca109', 'Gene', (182, 188))	('EC9706 transfected', 'Var', (193, 211))	('EC9706', 'CellLine', 'CVCL:E307', (193, 199))	('PLCE1', 'Gene', (217, 222))
893218	28849204	Interestingly, the expression of inflammatory factors was significantly increased after PLCE1 gene silencing, such as IL-8, IL-6, CXCR4 and so on.	('IL-6', 'Gene', '3569', (124, 128))	('expression', 'MPA', (19, 29))	('IL-8', 'Gene', (118, 122))	('increased', 'PosReg', (72, 81))	('CXCR4', 'Gene', '7852', (130, 135))	('PLCE1', 'Gene', (88, 93))	('CXCR4', 'Gene', (130, 135))	('gene silencing', 'Var', (94, 108))	('IL-6', 'Gene', (124, 128))	('IL-8', 'Gene', '3576', (118, 122))
893220	28849204	3, these DEGs were sorted and categorized into 26 different functional categories by PLCE1 knockdown in ECa109 and EC9706 cells.	('EC9706', 'CellLine', 'CVCL:E307', (115, 121))	('PLCE1', 'Gene', (85, 90))	('knockdown', 'Var', (91, 100))
893221	28849204	Secondly, upregulated DEGs were enriched in anti-apoptosis (GO:0006916), negative regulation of apoptosis (GO:0043066), indicating theses terms might have direct or immediate adverse effect on apoptosis induction in PLCE1-siRNA-treated Eca109 and EC9706 cells.	('EC9706', 'CellLine', 'CVCL:E307', (247, 253))	('apoptosis', 'CPA', (193, 202))	('theses', 'Var', (131, 137))	('negative', 'NegReg', (73, 81))	('upregulated', 'PosReg', (10, 21))	('anti-apoptosis', 'CPA', (44, 58))
893222	28849204	Fourthly, we also found that many DEGs were significant enrichment in regulation of transcription, DNA-dependent (GO:0006355), signal transduction (GO:0007165), G-protein coupled receptor protein signaling pathway (GO:0007186), cell surface receptor linked signal transduction (GO:0007166), which suggested these changes were likely to participate in the oncogenesis and tumor development of ESCC.	('regulation', 'MPA', (70, 80))	('cell surface receptor', 'Gene', (228, 249))	('tumor', 'Disease', (371, 376))	('G-protein coupled receptor', 'Gene', '10663', (161, 187))	('cell surface receptor', 'Gene', '57126', (228, 249))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('GO:0007166', 'Var', (278, 288))	('participate', 'Reg', (336, 347))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('transcription', 'MPA', (84, 97))	('G-protein coupled receptor', 'Gene', (161, 187))	('ESCC', 'Disease', (392, 396))	('signal transduction', 'MPA', (127, 146))
893231	28849204	Compared with control group, by Q-RT-PCR analysis, all 6 genes were upregulated by PLCE1-siRNA treatment of EC9706 and ECa109 cells (Fig.	('EC9706', 'CellLine', 'CVCL:E307', (108, 114))	('upregulated', 'PosReg', (68, 79))	('EC9706', 'Var', (108, 114))
893239	28849204	Among them, DEGs are closely linked to a variety of different signaling networks, including the MAPK, p53, JAK-STAT, Toll-like receptor signaling pathways.	('DEGs', 'Var', (12, 16))	('p53', 'Gene', '7157', (102, 105))	('Toll-like receptor signaling pathways', 'Pathway', (117, 154))	('MAPK', 'Gene', (96, 100))	('linked', 'Reg', (29, 35))	('p53', 'Gene', (102, 105))	('JAK-STAT', 'Pathway', (107, 115))
893319	28831760	The primary cause of this gastro-aortic fistula was discontinuation of PPI medication of her own volition.	('discontinuation', 'Var', (52, 67))	('gastro-aortic fistula', 'Disease', (26, 47))	('gastro-aortic fistula', 'Disease', 'MESH:D005402', (26, 47))
893337	28652988	Besides environmental factors, genetic alterations have a marked role in the pathophysiology of this tumor, independently of the primary site.	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('genetic alterations', 'Var', (31, 50))
893528	19130303	Moreover, Beclin-1-/- mutant mice die early in embryogenesis and Beclin-1+/- mutant mice suffer from a high incidence of spontaneous tumors, establishing that Beclin-1 is a critical component of mammalian autophagy and a role for autophagy in tumor suppression.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('Beclin-1+/-', 'Gene', (65, 76))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', (133, 138))	('mammalian', 'Species', '9606', (195, 204))	('mice', 'Species', '10090', (29, 33))	('mutant', 'Var', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('mice', 'Species', '10090', (84, 88))	('tumor', 'Disease', (243, 248))
893577	19130303	Koneri and his colleagues investigated the function of Beclin-1 gene in colorectal cancer cell lines, transfection of the low Beclin-1 gene-expressing colon cancer cell line with the Beclin-1 gene resulted in cell growth inhibition, they concluded that Beclin-1 can inhibit the growth of colorectal cancer cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal cancer', 'Disease', (288, 305))	('growth', 'CPA', (278, 284))	('inhibition', 'NegReg', (221, 231))	('inhibit', 'NegReg', (266, 273))	('transfection', 'Var', (102, 114))	('Beclin-1', 'Gene', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colon cancer', 'Phenotype', 'HP:0003003', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (288, 305))	('colorectal cancer', 'Phenotype', 'HP:0003003', (288, 305))	('cell growth', 'CPA', (209, 220))	('colon cancer', 'Disease', 'MESH:D015179', (151, 163))	('colorectal cancer', 'Disease', (72, 89))	('colon cancer', 'Disease', (151, 163))
893579	19130303	These examples favor a cancer-killing role for autophagy, overexpression of Beclin-1 induces cell death and defection of autophagy may be an important mechanism in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('autophagy', 'CPA', (121, 130))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('overexpression', 'PosReg', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Beclin-1', 'Gene', (76, 84))	('defection', 'Var', (108, 117))	('cell death', 'CPA', (93, 103))
893581	19130303	Daniel discovered that blockade of Beclin-1 expression aggravates cell death in HepG2 cells.	('HepG2', 'CellLine', 'CVCL:0027', (80, 85))	('Beclin-1', 'Protein', (35, 43))	('blockade', 'Var', (23, 31))	('aggravates', 'PosReg', (55, 65))	('cell death', 'CPA', (66, 76))
893588	19130303	There was a tendency for shorter survival in patients with high HIF-1alpha expression, but this correlation did not reach statistical significance, probably owing to short periods of follow-up and the small number of patients enrolled in our study.	('patients', 'Species', '9606', (217, 225))	('shorter', 'NegReg', (25, 32))	('HIF-1alpha', 'Gene', '3091', (64, 74))	('survival', 'MPA', (33, 41))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (45, 53))	('HIF-1alpha', 'Gene', (64, 74))
893595	19130303	By knocking down the autophagy protein Beclin-1, hypoxia-induced cell death was reduced, hypoxia-induced cell death was also reduced upon treatment with the autophagy inhibitor 3-methyladenine.	('Beclin-1', 'Gene', (39, 47))	('autophagy', 'CPA', (21, 30))	('3-methyladenine', 'Chemical', 'MESH:C025946', (177, 192))	('hypoxia-induced cell death', 'Disease', 'MESH:D000860', (49, 75))	('hypoxia-induced cell death', 'Disease', (49, 75))	('reduced', 'NegReg', (80, 87))	('reduced', 'NegReg', (125, 132))	('hypoxia-induced cell death', 'Disease', 'MESH:D000860', (89, 115))	('knocking down', 'Var', (3, 16))	('hypoxia-induced cell death', 'Disease', (89, 115))
893604	19130303	There was a tendency of Beclin-1-induced autophagy inhibition by high expression of HIF-1alpha, which promotes tumor progression.	('inhibition', 'NegReg', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('promotes', 'PosReg', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Beclin-1-induced', 'Protein', (24, 40))	('HIF-1alpha', 'Gene', (84, 94))	('tumor', 'Disease', (111, 116))	('high expression', 'Var', (65, 80))	('HIF-1alpha', 'Gene', '3091', (84, 94))
893616	31351006	Low ghrelin was associated with a two-fold increase of GCA (HR Q1:Q4 = 2.00, 95% CI: 1.45-2.77; p-trend<0.001).	('ghrelin', 'Chemical', 'MESH:D054439', (4, 11))	('GCA', 'Disease', (55, 58))	('ghrelin', 'Protein', (4, 11))	('Low', 'Var', (0, 3))
893630	31351006	We have previously found that low serum ghrelin is associated with an increased risk of gastric and esophageal cancers many years later.	('ghrelin', 'Protein', (40, 47))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('gastric and esophageal cancer', 'Disease', 'MESH:D013274', (88, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('low', 'Var', (30, 33))	('ghrelin', 'Chemical', 'MESH:D054439', (40, 47))	('esophageal cancers', 'Disease', (100, 118))	('esophageal cancers', 'Disease', 'MESH:D004938', (100, 118))
893679	31351006	BMI and pepsinogen I/II ratio was lower in all three cancer subtypes, and H. pylori seropositivity was more prevalent among GCA and GNCA cases than controls.	('H. pylori', 'Disease', (74, 83))	('seropositivity', 'Var', (84, 98))	('GCA', 'Disease', (124, 127))	('pepsinogen I/II', 'Gene', 'None', (8, 23))	('prevalent', 'Reg', (108, 117))	('cancer', 'Disease', (53, 59))	('pepsinogen I/II', 'Gene', (8, 23))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (77, 98))	('lower', 'NegReg', (34, 39))	('H. pylori', 'Species', '210', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('GNCA', 'Gene', (132, 136))	('GNCA', 'Gene', 'None', (132, 136))
893683	31351006	H. pylori seropositivity was more common among cases (96%) than controls (92%), and mean pepsinogen I/II ratio was significantly lower (p<0.05) among cases.	('H. pylori', 'Species', '210', (0, 9))	('H. pylori', 'Disease', (0, 9))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (3, 24))	('pepsinogen I/II', 'Gene', 'None', (89, 104))	('pepsinogen I/II', 'Gene', (89, 104))	('seropositivity', 'Var', (10, 24))	('lower', 'NegReg', (129, 134))
893702	31351006	Surprisingly, we also found the inverse association between low ghrelin levels and (decreased) ESCC risk in the NIT study, which is contrary to our previous findings in Finland.	('low', 'Var', (60, 63))	('ESCC', 'Disease', (95, 99))	('ghrelin', 'Protein', (64, 71))	('ghrelin', 'Chemical', 'MESH:D054439', (64, 71))	('decreased', 'NegReg', (84, 93))	('inverse', 'NegReg', (32, 39))
893720	31351006	Alternatively, circulating ghrelin levels increase in cases with H. pylori seropositivity.	('ghrelin', 'Chemical', 'MESH:D054439', (27, 34))	('circulating ghrelin levels', 'MPA', (15, 41))	('seropositivity', 'Var', (75, 89))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (68, 89))	('H. pylori', 'Species', '210', (65, 74))	('H. pylori', 'Disease', (65, 74))	('increase', 'PosReg', (42, 50))
893721	31351006	Circulating ghrelin levels also increase in the presence of low BMI and malnutrition, and ghrelin levels decrease with increasing BMI and obesity.	('malnutrition', 'Phenotype', 'HP:0004395', (72, 84))	('ghrelin', 'MPA', (90, 97))	('increase', 'PosReg', (32, 40))	('ghrelin', 'Chemical', 'MESH:D054439', (90, 97))	('low BMI', 'Phenotype', 'HP:0045082', (60, 67))	('ghrelin', 'Chemical', 'MESH:D054439', (12, 19))	('obesity', 'Phenotype', 'HP:0001513', (138, 145))	('low BMI', 'Var', (60, 67))	('obesity', 'Disease', 'MESH:D009765', (138, 145))	('increasing BMI', 'Phenotype', 'HP:0031418', (119, 133))	('obesity', 'Disease', (138, 145))	('Circulating ghrelin levels', 'MPA', (0, 26))
893731	31351006	In both this and previous studies, alterations in serum ghrelin levels occurred before, and sometimes over 10 years before, the development of clinically evident gastric and esophageal cancers, raising the possibility that it might be useful as a risk stratification or early detection marker for these cancers, and indicating that low ghrelin may have an etiologic role in cancer initiation and progression.	('cancer', 'Disease', (374, 380))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Phenotype', 'HP:0002664', (303, 310))	('cancers', 'Disease', (185, 192))	('cancer', 'Disease', (185, 191))	('cancers', 'Disease', (303, 310))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('alterations', 'Var', (35, 46))	('cancer', 'Disease', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('ghrelin', 'Chemical', 'MESH:D054439', (336, 343))	('esophageal cancers', 'Disease', (174, 192))	('men', 'Species', '9606', (135, 138))	('cancer', 'Disease', 'MESH:D009369', (374, 380))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('gastric and esophageal cancer', 'Disease', 'MESH:D013274', (162, 191))	('cancers', 'Disease', 'MESH:D009369', (303, 310))	('esophageal cancers', 'Disease', 'MESH:D004938', (174, 192))	('ghrelin', 'Chemical', 'MESH:D054439', (56, 63))	('low', 'Var', (332, 335))
893752	32560537	EAC exhibits frequent genomic amplifications of VEGFA, ERBB2, GATA4, GATA6, and CCNE1 as well as deletions of SMAD4, while ESCC generally presents amplifications of CCND1, SOX2, TERT, FGFR1, MDM2, NKX2-1, and/or TP63 as well as deletions of RB1.	('SOX2', 'Gene', (172, 176))	('SOX2', 'Gene', '6657', (172, 176))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('CCNE1', 'Gene', '898', (80, 85))	('GATA6', 'Gene', '2627', (69, 74))	('SMAD4', 'Gene', (110, 115))	('VEGFA', 'Gene', (48, 53))	('GATA4', 'Gene', '2626', (62, 67))	('TP63', 'Gene', (212, 216))	('ERBB2', 'Gene', (55, 60))	('deletions', 'Var', (97, 106))	('RB1', 'Gene', (241, 244))	('MDM2', 'Gene', (191, 195))	('CCND1', 'Gene', '595', (165, 170))	('FGFR1', 'Gene', '2260', (184, 189))	('TERT', 'Gene', (178, 182))	('TP63', 'Gene', '8626', (212, 216))	('SMAD4', 'Gene', '4089', (110, 115))	('VEGFA', 'Gene', '7422', (48, 53))	('CCND1', 'Gene', (165, 170))	('GATA6', 'Gene', (69, 74))	('TERT', 'Gene', '7015', (178, 182))	('ERBB2', 'Gene', '2064', (55, 60))	('MDM2', 'Gene', '4193', (191, 195))	('GATA4', 'Gene', (62, 67))	('NKX2-1', 'Gene', '7080', (197, 203))	('RB1', 'Gene', '5925', (241, 244))	('NKX2-1', 'Gene', (197, 203))	('FGFR1', 'Gene', (184, 189))	('deletions', 'Var', (228, 237))	('CCNE1', 'Gene', (80, 85))
893753	32560537	At the level of point mutations shows EAC frequent mutations in TP53, CDKN2A, ARID1A, and SMAD4 while ESCC is frequently mutated in TP53, CSMD3, NOTCH1, and PIK3CA.	('CSMD3', 'Gene', '114788', (138, 143))	('ARID1A', 'Gene', '8289', (78, 84))	('mutations', 'Var', (51, 60))	('ARID1A', 'Gene', (78, 84))	('PIK3CA', 'Gene', (157, 163))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('EAC', 'Phenotype', 'HP:0011459', (38, 41))	('SMAD4', 'Gene', '4089', (90, 95))	('TP53', 'Gene', '7157', (64, 68))	('PIK3CA', 'Gene', '5290', (157, 163))	('TP53', 'Gene', (64, 68))	('CDKN2A', 'Gene', (70, 76))	('CDKN2A', 'Gene', '1029', (70, 76))	('SMAD4', 'Gene', (90, 95))	('NOTCH1', 'Gene', '4851', (145, 151))	('NOTCH1', 'Gene', (145, 151))	('CSMD3', 'Gene', (138, 143))
893776	32560537	isolated and identified SP cells in human esophageal cancer cell lines, the cells with the strongest dye efflux activity (SP cells) in EC9706 had higher clone formation efficiency than non-SP cells.	('higher', 'PosReg', (146, 152))	('esophageal cancer', 'Disease', (42, 59))	('clone formation efficiency', 'CPA', (153, 179))	('EC9706', 'Var', (135, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('strongest', 'PosReg', (91, 100))	('EC9706', 'CellLine', 'CVCL:E307', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('dye efflux activity', 'MPA', (101, 120))	('human', 'Species', '9606', (36, 41))
893793	32560537	Tumors consist of genetically and epigenetically various cell subpopulations, which is referred to as intratumor heterogeneity.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('epigenetically', 'Var', (34, 48))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
893804	32560537	Dysregulation of these pathways may also contribute to the undesirable progression of esophageal cancer.	('Dysregulation', 'Var', (0, 13))	('esophageal cancer', 'Disease', (86, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('contribute', 'Reg', (41, 51))
893808	32560537	MicroRNA-455-3p was reported to play key roles in promoting chemoresistance in vitro and tumorigenesis of ESCC cells in vivo.	('MicroRNA-455-3p', 'Var', (0, 15))	('chemoresistance', 'CPA', (60, 75))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('promoting', 'PosReg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
893809	32560537	Treatment with a miR-455-3p antagomir could sensitize ESCC cells to cisplatin and reduce the subpopulations of CD90+ and CD271+ (tumor-initiating cells) T-ICs via inactivation of Wnt/beta-catenin and TGF-beta signaling pathways.	('CD90', 'Gene', '7070', (111, 115))	('beta-catenin', 'Gene', (183, 195))	('beta-catenin', 'Gene', '1499', (183, 195))	('sensitize', 'Reg', (44, 53))	('tumor', 'Disease', (129, 134))	('Wnt', 'Gene', '80326', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Wnt', 'Gene', (179, 182))	('inactivation', 'PosReg', (163, 175))	('TGF-beta', 'Gene', '7039', (200, 208))	('CD271', 'Gene', '4804', (121, 126))	('TGF-beta', 'Gene', (200, 208))	('miR-455-3p', 'Chemical', '-', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('CD90', 'Gene', (111, 115))	('reduce', 'NegReg', (82, 88))	('miR-455-3p', 'Var', (17, 27))	('CD271', 'Gene', (121, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
893810	32560537	Interestingly, SB525334, a TGF-beta1 inhibitor, can significantly inhibit the migration and invasion of sphere-forming stem-like cells of KYSE70 and TE1, which display an increased self-renewal capacity, chemoresistance in vitro, and tumorigenesis in vivo.	('tumor', 'Disease', (234, 239))	('chemoresistance', 'CPA', (204, 219))	('TGF-beta1', 'Gene', '7040', (27, 36))	('TGF-beta1', 'Gene', (27, 36))	('inhibit', 'NegReg', (66, 73))	('SB525334', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('SB525334', 'Chemical', 'MESH:C521813', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('increased', 'PosReg', (171, 180))	('self-renewal capacity', 'CPA', (181, 202))
893823	32560537	Recent studies have demonstrated that genetic or pharmacological inhibition of YAP could repress CSC-like properties in vitro and attenuate tumor growth and CSC marker expression in ESCC xenograft models by directly activating its downstream target SOX9.	('repress', 'NegReg', (89, 96))	('attenuate', 'NegReg', (130, 139))	('CSC marker expression', 'MPA', (157, 178))	('activating', 'Reg', (216, 226))	('CSC-like properties', 'CPA', (97, 116))	('YAP', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('ESCC', 'Disease', (182, 186))	('SOX9', 'Gene', (249, 253))	('inhibition', 'Var', (65, 75))	('YAP', 'Gene', '10413', (79, 82))	('SOX9', 'Gene', '6662', (249, 253))	('tumor', 'Disease', (140, 145))
893830	32560537	The study found that the cell subset responsive to a Sox2 regulatory region (SRR2) reporter (RR cells) isolated from these ESCC cell lines contained significantly higher proportions of CD44-high and ALDH1A1-high cells.	('Sox2', 'Gene', '6657', (53, 57))	('ALDH1A1', 'Gene', '216', (199, 206))	('CD44-high', 'Var', (185, 194))	('Sox2', 'Gene', (53, 57))	('higher', 'PosReg', (163, 169))	('ALDH1A1', 'Gene', (199, 206))
893837	32560537	In EC, CSCs isolated from the ESCC cell line EC9706 were resistant to DNA damage through impaired induction of p53 and declined G1 checkpoint arrest, and presented a slow-cycling status with a lower level of phosphorylated Stat3, c-Myc, and a higher level of p27 when compared with the non-CSCs.	('p27', 'Gene', (259, 262))	('c-Myc', 'Gene', (230, 235))	('induction', 'MPA', (98, 107))	('checkpoint arrest', 'Disease', 'MESH:D006323', (131, 148))	('slow-cycling', 'MPA', (166, 178))	('p53', 'Gene', (111, 114))	('declined', 'NegReg', (119, 127))	('higher', 'PosReg', (243, 249))	('EC9706', 'CellLine', 'CVCL:E307', (45, 51))	('p53', 'Gene', '7157', (111, 114))	('c-Myc', 'Gene', '4609', (230, 235))	('Stat3', 'Gene', '6774', (223, 228))	('checkpoint arrest', 'Disease', (131, 148))	('impaired', 'NegReg', (89, 97))	('p27', 'Gene', '3429', (259, 262))	('EC9706', 'Var', (45, 51))	('Stat3', 'Gene', (223, 228))	('lower', 'NegReg', (193, 198))
893847	32560537	ESCC cells with ABCG2 overexpression showed cross-resistance to both irinotecan and 5-FU through the activation of the AhR pathways, which could be reversed by targeting AhR to further inhibit ABCG2 expression.	('expression', 'MPA', (199, 209))	('cross-resistance', 'MPA', (44, 60))	('ABCG2', 'Gene', '9429', (16, 21))	('AhR', 'Gene', (170, 173))	('ABCG2', 'Gene', (16, 21))	('AhR', 'Gene', '196', (170, 173))	('ABCG2', 'Gene', (193, 198))	('AhR', 'Gene', (119, 122))	('AhR', 'Gene', '196', (119, 122))	('irinotecan', 'Chemical', 'MESH:D000077146', (69, 79))	('ABCG2', 'Gene', '9429', (193, 198))	('inhibit', 'NegReg', (185, 192))	('overexpression', 'Var', (22, 36))	('5-FU', 'Chemical', 'MESH:D005472', (84, 88))
893848	32560537	To reverse MDR in cancer cells, modulating ROS may be a viable strategy.	('MDR', 'Disease', (11, 14))	('modulating', 'Var', (32, 42))	('ROS', 'Chemical', 'MESH:D017382', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('ROS', 'Protein', (43, 46))
893855	32560537	Clinical data suggested that EC patients with high expression of ALDH1 were more resistant to clinical interventions and had a poor long-term prognosis.	('patients', 'Species', '9606', (32, 40))	('high expression', 'Var', (46, 61))	('ALDH1', 'Gene', (65, 70))
893860	32560537	CAFs in ESCC were also reported to cause radio-resistance by regulating DNA damage response though promoting long noncoding RNA (lncRNA) DNM3OS expression via PDGFbeta/PDGFRbeta/FOXO1 signaling pathway.	('PDGFRbeta', 'Gene', (168, 177))	('ESCC', 'Gene', (8, 12))	('CAFs', 'Var', (0, 4))	('expression', 'MPA', (144, 154))	('PDGFRbeta', 'Gene', '5156', (168, 177))	('DNM3OS', 'Gene', (137, 143))	('FOXO1', 'Gene', (178, 183))	('DNM3OS', 'Gene', '100628315', (137, 143))	('FOXO1', 'Gene', '2308', (178, 183))	('regulating DNA damage response', 'MPA', (61, 91))	('PDGFbeta', 'Gene', (159, 167))	('long', 'MPA', (109, 113))	('promoting', 'PosReg', (99, 108))	('PDGFbeta', 'Gene', '5154', (159, 167))
893862	32560537	Some studies have reported that CSCs could usually be located in a hypoxic region in the TME, hypoxic condition of the CSC niche can also induce EMT as well as decrease inner ROS levels, which can further maintain cancer stemness and contribute to therapeutic resistance.	('therapeutic resistance', 'CPA', (248, 270))	('decrease', 'NegReg', (160, 168))	('cancer stemness', 'Disease', (214, 229))	('ROS', 'Chemical', 'MESH:D017382', (175, 178))	('EMT', 'CPA', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('induce', 'PosReg', (138, 144))	('hypoxic', 'Var', (94, 101))	('cancer stemness', 'Disease', 'MESH:D009369', (214, 229))	('maintain', 'PosReg', (205, 213))	('inner ROS levels', 'MPA', (169, 185))
893868	32560537	BMS-833923 is a potent and specific inhibitor of SMO in the Hh pathway, which is currently tested in a phase I trial (NCT00909402: completed, but results are not published yet) evaluating inhibition of SMO as a first-line therapy for unresectable metastatic EC patients in combination with Cisplatin and Capecitabine.	('Hh pathway', 'Pathway', (60, 70))	('SMO', 'Gene', '6608', (49, 52))	('SMO', 'Gene', (202, 205))	('SMO', 'Gene', (49, 52))	('SMO', 'Gene', '6608', (202, 205))	('inhibition', 'Var', (188, 198))	('Cisplatin', 'Chemical', 'MESH:D002945', (290, 299))	('unresectable metastatic EC', 'Disease', (234, 260))	('Capecitabine', 'Chemical', 'MESH:D000069287', (304, 316))	('patients', 'Species', '9606', (261, 269))	('BMS-833923', 'Gene', (0, 10))
893869	32560537	Additionally, Taladegib (LY-2940680) an alternative small molecule interfering with the Hh cascade through binding to the SMO receptor is currently evaluated (NCT02530437: active, not recruiting).	('Taladegib', 'Chemical', 'MESH:C581399', (14, 23))	('LY-2940680', 'Chemical', 'MESH:C581399', (25, 35))	('LY-2940680', 'Var', (25, 35))	('binding', 'Interaction', (107, 114))	('SMO', 'Gene', '6608', (122, 125))	('SMO', 'Gene', (122, 125))
893870	32560537	The amplification or drug induced overexpression of EGFR has long been considered as a marker for resistance and tumor progression.	('tumor', 'Disease', (113, 118))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('overexpression', 'PosReg', (34, 48))	('amplification', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
893872	32560537	It is now widely accepted that the oncogenesis and tumor heterogeneity are not exclusively dependent on aberrations or mutations of tumor cells, but also accompanied by the dynamic changes of microenvironmental compositions as well as the state and properties of surrounding stromal cells.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (51, 56))	('changes', 'Reg', (181, 188))	('tumor', 'Disease', (132, 137))	('accompanied', 'Reg', (154, 165))	('mutations', 'Var', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
893878	32560537	A reduced cell proliferation rate was observed in the EAC cell line OE19 treated with AMD3100, smaller primary tumor size, and fewer metastatic spread to lung, liver, and lymph node were further confirmed in OE19 injected mice under AMD3100 treatment.	('smaller', 'NegReg', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('mice', 'Species', '10090', (222, 226))	('AMD3100', 'Chemical', 'MESH:C088327', (233, 240))	('AMD3100', 'Chemical', 'MESH:C088327', (86, 93))	('EAC', 'Phenotype', 'HP:0011459', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cell proliferation rate', 'CPA', (10, 33))	('AMD3100', 'Var', (86, 93))	('reduced', 'NegReg', (2, 9))	('metastatic spread to', 'CPA', (133, 153))	('tumor', 'Disease', (111, 116))	('fewer', 'NegReg', (127, 132))
893888	32560537	Genetic knockdown of PD-1 alone, or in combination with chimeric antigen receptor (CAR) T cells, which carries a predefined affinity to a given tumor antigen, could significantly enhance immune reaction against a desired tumor type.	('tumor', 'Disease', (144, 149))	('chimeric antigen receptor', 'Gene', (56, 81))	('knockdown', 'Var', (8, 17))	('enhance', 'PosReg', (179, 186))	('PD-1', 'Gene', (21, 25))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PD-1', 'Gene', '5133', (21, 25))	('desired tumor', 'Disease', 'MESH:D020018', (213, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('immune reaction against', 'CPA', (187, 210))	('chimeric antigen receptor', 'Gene', '9970', (56, 81))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CAR', 'Gene', (83, 86))	('CAR', 'Gene', '9970', (83, 86))	('desired tumor', 'Disease', (213, 226))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
893897	32560537	In glioblastoma, tumor regrowth was significantly halted after the ablation of a subset of stem cell like endogenous tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('halted', 'NegReg', (50, 56))	('tumor', 'Disease', (17, 22))	('ablation', 'Var', (67, 75))	('tumor', 'Disease', (117, 122))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
893908	32583748	Long Noncoding RNA LINC00634 Functions as an Oncogene in Esophageal Squamous Cell Carcinoma Through the miR-342-3p/Bcl2L1 Axis Many long noncoding RNAs reportedly have tumor suppressive roles or are oncogenic in esophageal cancer.	('LINC00634', 'Gene', '339674', (19, 28))	('Carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('tumor', 'Disease', (168, 173))	('Bcl2L1', 'Gene', '598', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('LINC00634', 'Gene', (19, 28))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (68, 91))	('Squamous Cell Carcinoma', 'Disease', (68, 91))	('Bcl2L1', 'Gene', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('cancer', 'Disease', (223, 229))	('long noncoding RNAs', 'Var', (132, 151))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
893913	32583748	LINC00634 could target Bcl2L1 through miR-342-3p.	('Bcl2L1', 'Gene', (23, 29))	('target', 'Reg', (16, 22))	('LINC00634', 'Gene', '339674', (0, 9))	('LINC00634', 'Gene', (0, 9))	('Bcl2L1', 'Gene', '598', (23, 29))	('miR-342-3p', 'Var', (38, 48))	('miR-342-3p', 'Chemical', '-', (38, 48))
893915	32583748	We also show that the knockdown of LINC00634 decreased cell viability and increased cell apoptosis levels in EC9706 and EC1 cells through the miR-342-3p/Bcl2L1 axis.	('cell', 'MPA', (84, 88))	('EC1', 'Gene', (120, 123))	('LINC00634', 'Gene', (35, 44))	('EC9706', 'CellLine', 'CVCL:E307', (109, 115))	('increased cell apoptosis levels', 'Phenotype', 'HP:0030887', (74, 105))	('EC1', 'Gene', '4819', (120, 123))	('Bcl2L1', 'Gene', '598', (153, 159))	('decreased', 'NegReg', (45, 54))	('miR-342-3p', 'Chemical', '-', (142, 152))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('increased', 'PosReg', (74, 83))	('knockdown', 'Var', (22, 31))	('cell viability', 'CPA', (55, 69))	('Bcl2L1', 'Gene', (153, 159))	('LINC00634', 'Gene', '339674', (35, 44))
893937	32583748	SYBR Green real-time PCR assay was used to detect the expression of LINC00634, miR-342-3p, and Bcl2L1 mRNA, with the reaction conditions set according to the manufacturer's instructions.	('LINC00634', 'Gene', '339674', (68, 77))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('LINC00634', 'Gene', (68, 77))	('Bcl2L1', 'Gene', '598', (95, 101))	('miR-342-3p', 'Var', (79, 89))	('miR-342-3p', 'Chemical', '-', (79, 89))	('Bcl2L1', 'Gene', (95, 101))
893960	32583748	LINC00634 expression of EC cells (EC9706, Eca109, EC1, and KYSE30) was found to be significantly higher than that of esophageal epithelial cell Het-1a cells (P < .05; Figure 1C).	('EC9706', 'CellLine', 'CVCL:E307', (34, 40))	('higher', 'PosReg', (97, 103))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('expression', 'MPA', (10, 20))	('LINC00634', 'Gene', '339674', (0, 9))	('LINC00634', 'Gene', (0, 9))	('EC9706', 'Var', (34, 40))	('EC1', 'Gene', '4819', (50, 53))	('EC1', 'Gene', (50, 53))	('si', 'Chemical', 'MESH:D012825', (83, 85))
893970	32583748	To verify whether LINC00634 could bind to miR-342-3p, dual-luciferase reporter assay was conducted.	('miR-342-3p', 'Var', (42, 52))	('LINC00634', 'Gene', '339674', (18, 27))	('LINC00634', 'Gene', (18, 27))	('miR-342-3p', 'Chemical', '-', (42, 52))
893972	32583748	The results showed that the luciferase activity of cells cotransfected with WT-LINC00634 pmirGLO and miR-342-3p mimics was lower than in the other 3 groups of cells (P < .05; Figure 3B).	('lower', 'NegReg', (123, 128))	('miR-342-3p', 'Chemical', '-', (101, 111))	('activity', 'MPA', (39, 47))	('luciferase', 'Enzyme', (28, 38))	('LINC00634', 'Gene', '339674', (79, 88))	('LINC00634', 'Gene', (79, 88))	('miR-342-3p mimics', 'Var', (101, 118))
893974	32583748	The results showed that the miR-342-3p expression in cells transfected with si-LINC00634 was higher than in those with si-NC in EC9706 and EC1 cells (P < .05; Figure 3C).	('higher', 'PosReg', (93, 99))	('miR-342-3p', 'Chemical', '-', (28, 38))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('EC9706', 'CellLine', 'CVCL:E307', (128, 134))	('LINC00634', 'Gene', '339674', (79, 88))	('EC1', 'Gene', '4819', (139, 142))	('LINC00634', 'Gene', (79, 88))	('EC1', 'Gene', (139, 142))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('miR-342-3p', 'Var', (28, 38))
893975	32583748	We further detected miR-342-3p expression in EC tissues.	('si', 'Chemical', 'MESH:D012825', (37, 39))	('miR-342-3p', 'Var', (20, 30))	('miR-342-3p', 'Chemical', '-', (20, 30))	('detected', 'Reg', (11, 19))
893978	32583748	TargetScan was used to predict the targets of miR-342-3p, and results showed that the 3'-UTR of Bcl2L1 harbors miR-342-3p binding sites (Figure 4A).	('miR-342-3p', 'Var', (111, 121))	('binding', 'Interaction', (122, 129))	('Bcl2L1', 'Gene', '598', (96, 102))	('miR-342-3p', 'Chemical', '-', (111, 121))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('Bcl2L1', 'Gene', (96, 102))	('miR-342-3p', 'Chemical', '-', (46, 56))
893979	32583748	To verify whether miR-342-3p targets Bcl2L1, dual-luciferase reporter assay was utilized.	('miR-342-3p', 'Var', (18, 28))	('targets', 'Reg', (29, 36))	('miR-342-3p', 'Chemical', '-', (18, 28))	('Bcl2L1', 'Gene', '598', (37, 43))	('Bcl2L1', 'Gene', (37, 43))
893982	32583748	Western blotting results showed that in EC9706 and EC1 cells, Bcl2L1 protein expression in cells transfected with miR-342-3p mimics was lower than in those with miR-NC (P < .05; Figure 4C).	('lower', 'NegReg', (136, 141))	('miR-342-3p mimics', 'Var', (114, 131))	('Bcl2L1', 'Gene', (62, 68))	('EC1', 'Gene', (51, 54))	('miR-342-3p', 'Chemical', '-', (114, 124))	('EC1', 'Gene', '4819', (51, 54))	('EC9706', 'CellLine', 'CVCL:E307', (40, 46))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('Bcl2L1', 'Gene', '598', (62, 68))
893984	32583748	Results showed that in EC9706 and EC1 cells, the Bcl2L1 mRNA expression of cells transfected with si-LINC00634 or miR-342-3p mimics was lower than in those with miR-NC or si-NC (P < .05; Figure 4D).	('lower', 'NegReg', (136, 141))	('miR-342-3p mimics', 'Var', (114, 131))	('EC9706', 'CellLine', 'CVCL:E307', (23, 29))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('LINC00634', 'Gene', (101, 110))	('Bcl2L1', 'Gene', '598', (49, 55))	('EC1', 'Gene', (34, 37))	('EC1', 'Gene', '4819', (34, 37))	('miR-342-3p', 'Chemical', '-', (114, 124))	('Bcl2L1', 'Gene', (49, 55))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('LINC00634', 'Gene', '339674', (101, 110))
893987	32583748	Taken together, these results indicated that LINC00634 targeted Bcl2L1 through miR-342-3p.	('targeted', 'Reg', (55, 63))	('LINC00634', 'Gene', '339674', (45, 54))	('Bcl2L1', 'Gene', '598', (64, 70))	('miR-342-3p', 'Var', (79, 89))	('miR-342-3p', 'Chemical', '-', (79, 89))	('Bcl2L1', 'Gene', (64, 70))	('LINC00634', 'Gene', (45, 54))
893990	32583748	These results indicated that downregulation of miR-342-3p restores function of si-LINC00634.	('downregulation', 'NegReg', (29, 43))	('si', 'Chemical', 'MESH:D012825', (79, 81))	('LINC00634', 'Gene', '339674', (82, 91))	('LINC00634', 'Gene', (82, 91))	('miR-342-3p', 'Var', (47, 57))	('miR-342-3p', 'Chemical', '-', (47, 57))	('restores', 'PosReg', (58, 66))	('function', 'MPA', (67, 75))
893997	32583748	Then, we examined the effect of LINC00634 on proliferation in EC cells using CCK-8 assay and found that knockdown LINC00634 could decrease cell viability in EC9706 and EC1 cells.	('LINC00634', 'Gene', '339674', (114, 123))	('EC1', 'Gene', '4819', (168, 171))	('EC1', 'Gene', (168, 171))	('LINC00634', 'Gene', '339674', (32, 41))	('decrease', 'NegReg', (130, 138))	('LINC00634', 'Gene', (114, 123))	('EC9706', 'CellLine', 'CVCL:E307', (157, 163))	('LINC00634', 'Gene', (32, 41))	('cell viability', 'CPA', (139, 153))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('knockdown', 'Var', (104, 113))
894000	32583748	miR-342-3p was predicted to harbor LINC00634 binding sites using DIANA LncBASE Predicted.	('miR-342-3p', 'Chemical', '-', (0, 10))	('LINC00634', 'Gene', (35, 44))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('binding', 'Interaction', (45, 52))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('LINC00634', 'Gene', '339674', (35, 44))	('miR-342-3p', 'Var', (0, 10))
894002	32583748	miR-342-3p functions as a tumor suppressor in many kinds of tumors.	('miR-342-3p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', (60, 65))	('miR-342-3p', 'Var', (0, 10))	('tumors', 'Disease', (60, 66))
894004	32583748	TargetScan was used to predict the targets of miR-342-3p and 3'-UTR of Bcl2L1 was predicted to harbor miR-342-3p binding sites.	('Bcl2L1', 'Gene', '598', (71, 77))	('miR-342-3p', 'Var', (46, 56))	('miR-342-3p', 'Chemical', '-', (46, 56))	('miR-342-3p', 'Var', (102, 112))	('Bcl2L1', 'Gene', (71, 77))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('binding', 'Interaction', (113, 120))	('miR-342-3p', 'Chemical', '-', (102, 112))
894006	32583748	BCL2L1(Bcl-xL) belongs to the antiapoptotic Bcl-2 family member, and high Bcl-xL expression has indeed been associated with paclitaxel resistance in solid tumors.	('paclitaxel resistance', 'MPA', (124, 145))	('si', 'Chemical', 'MESH:D012825', (87, 89))	('Bcl-xL', 'Gene', (74, 80))	('Bcl-xL', 'Gene', '598', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Bcl-xL', 'Gene', '598', (7, 13))	('paclitaxel', 'Chemical', 'MESH:D017239', (124, 134))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('Bcl-xL', 'Gene', (7, 13))	('associated with', 'Reg', (108, 123))	('tumors', 'Disease', (155, 161))	('BCL2L1', 'Gene', (0, 6))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('high', 'Var', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('Bcl-2', 'Gene', (44, 49))	('Bcl-2', 'Gene', '596', (44, 49))	('BCL2L1', 'Gene', '598', (0, 6))
894011	32583748	CCK-8 cell counting kit-8 EC esophageal cancer FBS fetal bovine serum lncRNA long ncRNA miRNA microRNA MT mutant type ncRNA noncoding RNA qRT-PCR quantitative real-time-polymerase chain reaction 3'-UTR 3'-untranslated region WT wild type	('mutant', 'Var', (106, 112))	('FBS', 'Disease', 'MESH:D005198', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('FBS', 'Disease', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
894018	32475354	As the results shown, the pooled OR values of the risk of colorectal cancer and adenomas in patients with NAFLD were 1.72 (95%CI: 1.40-2.11) and 1.37 (95%CI: 1.29-1.46), respectively.	('adenomas', 'Disease', 'MESH:D000236', (80, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('adenomas', 'Disease', (80, 88))	('patients', 'Species', '9606', (92, 100))	('colorectal cancer', 'Disease', (58, 75))	('NAFLD', 'Var', (106, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (58, 75))
894020	32475354	The pooled OR value of the risk of breast cancer in patients with NAFLD was 1.69 (95%CI: 1.44-1.99).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('NAFLD', 'Var', (66, 71))	('patients', 'Species', '9606', (52, 60))
894021	32475354	In addition, NAFLD was also tightly associatied with the risk of gastric cancer, pancreatic cancer, prostate cancer, and esophageal cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('NAFLD', 'Var', (13, 18))	('prostate cancer', 'Disease', (100, 115))	('gastric cancer', 'Disease', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))	('pancreatic cancer', 'Disease', (81, 98))
894022	32475354	NAFLD could significantly increase the development risk of colorectal adenomas and cancer, intrahepatic and extrahepatic cholangiocarcinoma, breast, gastric, pancreatic, prostate, and esophageal cancer.	('breast', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (121, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('intrahepatic and extrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 139))	('colorectal adenomas', 'Disease', 'MESH:D015179', (59, 78))	('cancer', 'Disease', (195, 201))	('esophageal cancer', 'Disease', (184, 201))	('men', 'Species', '9606', (46, 49))	('NAFLD', 'Var', (0, 5))	('gastric', 'Disease', (149, 156))	('pancreatic', 'Disease', 'MESH:D010195', (158, 168))	('prostate', 'Disease', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('colorectal adenomas', 'Disease', (59, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('increase', 'PosReg', (26, 34))	('pancreatic', 'Disease', (158, 168))	('cancer', 'Disease', (83, 89))
894029	32475354	Accumulated evidence have shown that cardiovascular disease is the leading cause of death in patients with NAFLD, and malignancies at both gastrointestinal (liver, colon, esophagus, stomach, and pancreas) and extra-intestinal site (kidney in men, and breast in women) were also significant contributors to the mainly death of patients with NAFLD.	('colon', 'Disease', 'MESH:D003110', (164, 169))	('cardiovascular disease', 'Disease', 'MESH:D002318', (37, 59))	('patients', 'Species', '9606', (93, 101))	('death', 'Disease', (84, 89))	('colon', 'Disease', (164, 169))	('patients', 'Species', '9606', (326, 334))	('malignancies', 'Disease', 'MESH:D009369', (118, 130))	('men', 'Species', '9606', (242, 245))	('death', 'Disease', 'MESH:D003643', (317, 322))	('cardiovascular disease', 'Disease', (37, 59))	('death', 'Disease', (317, 322))	('men', 'Species', '9606', (263, 266))	('women', 'Species', '9606', (261, 266))	('NAFLD', 'Var', (107, 112))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (37, 59))	('esophagus', 'Disease', (171, 180))	('death', 'Disease', 'MESH:D003643', (84, 89))	('malignancies', 'Disease', (118, 130))
894031	32475354	In their study, they found that NAFLD potentially contributes to the risk of developing cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('NAFLD', 'Var', (32, 37))	('cholangiocarcinoma', 'Disease', (88, 106))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))
894050	32475354	The results indicated that patients with NAFLD have a significant risk of developing colorectal cancer (OR = 1.72, 95% CI: 1.40-2.11) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('patients', 'Species', '9606', (27, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('NAFLD', 'Var', (41, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
894053	32475354	The results indicated a significant developmental risk of colorectal adenoma in patients with NAFLD (OR = 1.37, 95% CI: 1.29-1.46) (Fig.	('colorectal adenoma', 'Disease', (58, 76))	('NAFLD', 'Var', (94, 99))	('patients', 'Species', '9606', (80, 88))	('developmental risk', 'Phenotype', 'HP:0001263', (36, 54))	('colorectal adenoma', 'Disease', 'MESH:D015179', (58, 76))	('men', 'Species', '9606', (43, 46))
894055	32475354	These results suggest that patients with NAFLD have a higher risk of developing colorectal cancer and colorectal adenoma than patients without NAFLD.	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('colorectal adenoma', 'Disease', 'MESH:D015179', (102, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('patients', 'Species', '9606', (27, 35))	('colorectal adenoma', 'Disease', (102, 120))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('NAFLD', 'Var', (41, 46))
894058	32475354	The results showed a significant risk of developing ICC in patients with NAFLD (OR = 2.46, 95% CI: 1.77-3.44) (Fig.	('ICC', 'Disease', (52, 55))	('patients', 'Species', '9606', (59, 67))	('NAFLD', 'Var', (73, 78))
894059	32475354	The results showed that the risk of developing ECC was significantly higher in patients with NAFLD (OR = 2.24, 95% CI: 1.58-3.17) than in patients without NAFLD (Table 1, Fig.	('ECC', 'Disease', (47, 50))	('patients', 'Species', '9606', (79, 87))	('NAFLD', 'Var', (93, 98))	('higher', 'PosReg', (69, 75))	('patients', 'Species', '9606', (138, 146))
894063	32475354	Three of the included studies evaluated the association between NAFLD and the risk of developing gastric cancer (Supplementary Table 1).	('gastric cancer', 'Disease', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('NAFLD', 'Var', (64, 69))	('men', 'Species', '9606', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('association', 'Interaction', (44, 55))
894064	32475354	The pooled OR of gastric cancer was 1.74 (95% CI: 1.03-2.95) (Table 1), which suggests that patients with NAFLD have a high risk of developing gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('patients', 'Species', '9606', (92, 100))	('gastric cancer', 'Disease', (143, 157))	('NAFLD', 'Var', (106, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('gastric cancer', 'Disease', (17, 31))	('gastric cancer', 'Disease', 'MESH:D013274', (17, 31))
894066	32475354	The pooled OR of pancreatic cancer was 2.12 (95% CI: 1.58-2.83) (Table 1), which suggests that patients with NAFLD have a high risk of developing pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('patients', 'Species', '9606', (95, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('pancreatic cancer', 'Disease', (146, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('NAFLD', 'Var', (109, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))
894067	32475354	In addition, it was observed that patients with NAFLD have a high risk of developing prostate cancer (OR = 1.36, 95% CI: 1.03-1.79) (Tables 1 and Supplementary Table 1).	('men', 'Species', '9606', (152, 155))	('prostate cancer', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (34, 42))	('NAFLD', 'Var', (48, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))
894068	32475354	Furthermore, two of the studies reported an association between NAFLD and a risk of developing esophageal cancer, with the OR value of esophageal cancer being 1.77 (95% CI: 1.19-2.62) (Tables 1 and Supplementary Table 1).	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('NAFLD', 'Var', (64, 69))	('esophageal cancer', 'Disease', (135, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('men', 'Species', '9606', (204, 207))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('esophageal cancer', 'Disease', (95, 112))	('association', 'Interaction', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
894079	32475354	In a previous meta-analysis which investigated the association of incident and recurrent colorectal cancer and adenoma with NAFLD, it was observed that the presence and severity of NAFLD were associated with an increased risk of incident colorectal cancer or adenomas.	('adenomas', 'Disease', 'MESH:D000236', (259, 267))	('colorectal cancer', 'Disease', (238, 255))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('adenoma', 'Disease', (259, 266))	('presence', 'Var', (156, 164))	('colorectal cancer', 'Disease', 'MESH:D015179', (238, 255))	('colorectal cancer', 'Disease', (89, 106))	('adenomas', 'Disease', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('NAFLD', 'Gene', (181, 186))	('adenoma', 'Disease', 'MESH:D000236', (111, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (238, 255))	('adenoma', 'Disease', 'MESH:D000236', (259, 266))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('adenoma', 'Disease', (111, 118))
894080	32475354	examined the association between NAFLD and colorectal tumors in asymptomatic adults who underwent a screening colonoscopy, they found that NAFLD was associated with a moderate increase in the risk of colorectal cancer and adenoma.	('NAFLD', 'Var', (139, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (200, 217))	('adenoma', 'Disease', 'MESH:D000236', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('adenoma', 'Disease', (222, 229))	('colon', 'Disease', 'MESH:D003110', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('colorectal tumors', 'Disease', 'MESH:D015179', (43, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (200, 217))	('colorectal cancer', 'Disease', (200, 217))	('colon', 'Disease', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('colorectal tumors', 'Disease', (43, 60))
894082	32475354	The results show that NAFLD significantly increases the risk of colorectal cancer (OR = 1.72, 95% CI: 1.40-2.11) and the risk of colorectal adenoma (OR = 1.37, 95% CI: 1.29-1.46) compared to healthy controls.	('increases', 'PosReg', (42, 51))	('colorectal cancer', 'Disease', (64, 81))	('NAFLD', 'Var', (22, 27))	('colorectal adenoma', 'Disease', 'MESH:D015179', (129, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('colorectal adenoma', 'Disease', (129, 147))
894085	32475354	conducted a meta-analysis to investigate a possible relationship between NAFLD and cholangiocarcinoma, they found that NAFLD was associated with both ICC (OR = 2.22, 95% CI: 1.52-3.24) and ECC (OR = 1.55, 95% CI: 1.03-2.33).	('associated', 'Reg', (129, 139))	('cholangiocarcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('ICC', 'Disease', (150, 153))	('NAFLD', 'Var', (119, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (83, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (83, 101))	('ECC', 'Disease', (189, 192))
894089	32475354	have verified that NAFLD may be associated with more severe renal cell carcinoma and shorter overall survival in Japanese populations.	('shorter', 'NegReg', (85, 92))	('overall survival', 'MPA', (93, 109))	('NAFLD', 'Var', (19, 24))	('renal cell carcinoma', 'Disease', (60, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (60, 80))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (60, 80))
894092	32475354	reported that patients with NAFLD possess the higher susceptibility to colorectal cancer in males, and breast cancer in females, whether there is the gender-related difference in the association of NAFLD and extrahepatic cancers remains unclear.	('susceptibility', 'Reg', (53, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('colorectal cancer', 'Disease', (71, 88))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('extrahepatic cancers', 'Disease', (208, 228))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('extrahepatic cancers', 'Disease', 'MESH:D009369', (208, 228))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('NAFLD', 'Var', (28, 33))	('patients', 'Species', '9606', (14, 22))
894093	32475354	A recent study demonstrated that patients with NAFLD are more likely to exhibit chronic inflammation with insulin resistance, which may generate a microenvironment conducive for cancer development.	('exhibit', 'Reg', (72, 79))	('men', 'Species', '9606', (159, 162))	('patients', 'Species', '9606', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('inflammation', 'Disease', 'MESH:D007249', (88, 100))	('NAFLD', 'Var', (47, 52))	('insulin resistance', 'Phenotype', 'HP:0000855', (106, 124))	('insulin', 'Gene', (106, 113))	('inflammation', 'Disease', (88, 100))	('cancer', 'Disease', (178, 184))	('insulin', 'Gene', '3630', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('men', 'Species', '9606', (192, 195))	('chronic', 'Disease', (80, 87))
894094	32475354	Emerging translational and epidemiologic data support that local ectopic fat may also affect functional factors, and in turn the paracrine pathway, to induce cancer development in the liver, pancreas, and breast.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('affect', 'Reg', (86, 92))	('ectopic fat', 'Var', (65, 76))	('induce', 'PosReg', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('paracrine pathway', 'Pathway', (129, 146))	('functional factors', 'MPA', (93, 111))	('men', 'Species', '9606', (172, 175))
894095	32475354	Therefore, the results of the present study are consistent with those of previous studies and they indicate that NAFLD is a risk factor for various extrahepatic cancers.	('extrahepatic cancers', 'Disease', 'MESH:D009369', (148, 168))	('extrahepatic cancers', 'Disease', (148, 168))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('NAFLD', 'Var', (113, 118))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('risk', 'Reg', (124, 128))
894102	32475354	The results indicate that NAFLD can significantly increase the risk of developing colorectal cancer and colorectal adenoma, ICC and ECC, and breast, gastric, pancreatic, prostate, and esophageal cancers.	('colorectal cancer', 'Disease', (82, 99))	('colorectal adenoma', 'Disease', (104, 122))	('breast', 'Disease', (141, 147))	('colorectal adenoma', 'Disease', 'MESH:D015179', (104, 122))	('NAFLD', 'Var', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('esophageal cancers', 'Disease', (184, 202))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('gastric', 'Disease', (149, 156))	('pancreatic', 'Disease', 'MESH:D010195', (158, 168))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('ICC', 'Disease', (124, 127))	('esophageal cancers', 'Disease', 'MESH:D004938', (184, 202))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('pancreatic', 'Disease', (158, 168))	('prostate', 'Disease', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('ECC', 'Disease', (132, 135))
894115	31908417	Further studies showed that AR-42 exerts its anti-ESCC effects mainly by upregulating the expression of p21 and blocking the transduction of multiple signaling cascades related to tumor growth, especially Stat3-mediated signaling.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('Stat3', 'Gene', '6774', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Stat3', 'Gene', (205, 210))	('p21', 'Gene', (104, 107))	('tumor', 'Disease', (180, 185))	('transduction of multiple signaling cascades', 'MPA', (125, 168))	('p21', 'Gene', '644914', (104, 107))	('ESCC', 'Disease', 'MESH:C562729', (50, 54))	('expression', 'MPA', (90, 100))	('upregulating', 'PosReg', (73, 85))	('AR-42', 'Var', (28, 33))	('blocking', 'NegReg', (112, 120))	('ESCC', 'Disease', (50, 54))
894116	31908417	Overall, AR-42 has significant potency for inhibiting ESCC cell growth and shows moderate effect in suppressing angiogenesis, displaying strong anti-ESCC effects in vitro and in vivo.	('inhibiting', 'NegReg', (43, 53))	('ESCC', 'Disease', (149, 153))	('AR-42', 'Var', (9, 14))	('ESCC', 'Disease', (54, 58))	('angiogenesis', 'CPA', (112, 124))	('ESCC', 'Disease', 'MESH:C562729', (149, 153))	('suppressing', 'NegReg', (100, 111))	('ESCC', 'Disease', 'MESH:C562729', (54, 58))
894122	31908417	Accumulating evidence has suggested that epigenetic regulation is involved in tumor occurrence and progression through affecting DNA methylation and histone post-translational modification, thereby influencing the chromatin structure and oncogene or tumor suppressor gene expression.	('oncogene', 'Gene', (238, 246))	('expression', 'MPA', (272, 282))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('influencing', 'Reg', (198, 209))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('affecting', 'Reg', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('involved', 'Reg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('DNA', 'Protein', (129, 132))	('tumor', 'Disease', (78, 83))	('chromatin structure', 'MPA', (214, 233))	('epigenetic regulation', 'Var', (41, 62))	('tumor', 'Disease', (250, 255))	('histone', 'Protein', (149, 156))
894124	31908417	Inhibition of HDACs has become a potential treatment strategy for these cancers.	('HDAC', 'Gene', (14, 18))	('HDAC', 'Gene', '9734', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('Inhibition', 'Var', (0, 10))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
894135	31908417	HDAC1 expression was then scored by Yuan Zhang and Rongsheng Tong according to the staining depth: no dyeing, "1"; pale yellow dyeing, "2"; yellow dyeing, "3"; and deep yellow or brown dyeing, "4".	('deep yellow or brown dyeing', 'Var', (164, 191))	('HDAC1', 'Gene', (0, 5))	('pale yellow dyeing', 'Var', (115, 133))	('HDAC1', 'Gene', '3065', (0, 5))
894147	31908417	ESCC cells cultured in 6-well plates were treated with AR-42 for 24 h, and then harvested for apoptosis test in flow cytometer following KeyGEN's Annexin V/PI double staining kit manual (Nanjing, Jiangsu, China).	('AR-42', 'Var', (55, 60))	('ESCC', 'Disease', 'MESH:C562729', (0, 4))	('Annexin V', 'Gene', '308', (146, 155))	('Annexin V', 'Gene', (146, 155))	('ESCC', 'Disease', (0, 4))
894168	31908417	As depicted in Figure 2B, AR-42 effectively restrained the viability of ESCC cells Eca109 and TE-1 in MTT assay with IC50 values of 0.44 muM and 0.28 muM, respectively, which is slightly more potent than that of another approved pan-HDAC inhibitor vorinostat (Corresponding IC50 values for vorinostat are 0.91 muM and 0.78 muM, respectively).	('HDAC', 'Gene', '9734', (233, 237))	('muM', 'Gene', '56925', (137, 140))	('muM', 'Gene', (150, 153))	('muM', 'Gene', (137, 140))	('viability', 'CPA', (59, 68))	('AR-42', 'Var', (26, 31))	('ESCC', 'Disease', 'MESH:C562729', (72, 76))	('muM', 'Gene', '56925', (323, 326))	('muM', 'Gene', '56925', (150, 153))	('vorinostat', 'Chemical', 'MESH:C111237', (290, 300))	('muM', 'Gene', '56925', (310, 313))	('restrained', 'NegReg', (44, 54))	('muM', 'Gene', (323, 326))	('MTT', 'Chemical', 'MESH:C022616', (102, 105))	('muM', 'Gene', (310, 313))	('HDAC', 'Gene', (233, 237))	('ESCC', 'Disease', (72, 76))	('vorinostat', 'Chemical', 'MESH:C111237', (248, 258))
894169	31908417	As a commonly used clinical chemotherapy drug for ESCC, cisplatin inhibited ESCC cell viability at micromolar concentrations.	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('ESCC', 'Disease', 'MESH:C562729', (76, 80))	('ESCC', 'Disease', 'MESH:C562729', (50, 54))	('inhibited', 'NegReg', (66, 75))	('ESCC', 'Disease', (76, 80))	('cisplatin', 'Var', (56, 65))	('ESCC', 'Disease', (50, 54))	('cell viability', 'CPA', (81, 95))
894173	31908417	As shown in Figure 3A, AR-42 significantly reduced the number of red-stained nuclei (proliferating cells) at 1 muM concentration in both Eca109 and TE-1 cells, exhibiting strong anti-proliferative ability against ESCC cells.	('ESCC', 'Disease', 'MESH:C562729', (213, 217))	('AR-42', 'Var', (23, 28))	('muM', 'Gene', '56925', (111, 114))	('ESCC', 'Disease', (213, 217))	('reduced', 'NegReg', (43, 50))	('muM', 'Gene', (111, 114))
894174	31908417	Meanwhile, AR-42 dose-dependently increased the total percentage of Eca109 in apoptotic cells (defined as the sum of both late and early apoptotic cells), with apoptotic rates of 16% +-1.2%, 37% +-1.7%, and 41% +-1.7% for 0.3 muM, 1 muM, and 3 muM concentration treatment groups, respectively (Figure 3B).	('muM', 'Gene', '56925', (226, 229))	('muM', 'Gene', (233, 236))	('muM', 'Gene', '56925', (244, 247))	('muM', 'Gene', (226, 229))	('Eca109', 'Gene', (68, 74))	('muM', 'Gene', (244, 247))	('AR-42', 'Var', (11, 16))	('muM', 'Gene', '56925', (233, 236))
894175	31908417	The pro-apoptotic activity of AR-42 was also detected in TE-1 cells, in which the Annexin V-positive populations markedly increased after exposure to AR-42 for 24 h even at a relative low concentration (Figure 3B).	('increased', 'PosReg', (122, 131))	('Annexin V', 'Gene', '308', (82, 91))	('Annexin V', 'Gene', (82, 91))	('AR-42', 'Var', (150, 155))
894177	31908417	As shown in Figure 4A, AR-42 reduced the number of migrating cells dose-dependently in the scratch assay, with an IC50 of about 2 muM.	('muM', 'Gene', (130, 133))	('AR-42', 'Var', (23, 28))	('reduced', 'NegReg', (29, 36))	('number of migrating cells', 'CPA', (41, 66))	('muM', 'Gene', '56925', (130, 133))
894180	31908417	AR-42 at 1.25 muM had little antiangiogenic potency in zebrafish, but dose-dependent inhibition could be observed at concentrations >2.5 muM.	('muM', 'Gene', '56925', (137, 140))	('muM', 'Gene', (137, 140))	('muM', 'Gene', '56925', (14, 17))	('AR-42', 'Var', (0, 5))	('muM', 'Gene', (14, 17))	('zebrafish', 'Species', '7955', (55, 64))	('antiangiogenic potency', 'MPA', (29, 51))
894183	31908417	The results showed that AR-42 strikingly elevated the acetylation level of histone H3 (Lys 9) (HDAC1 substrate) with little effect on HDAC1 expression (Figure 5), suggesting that it acts primarily by inhibiting HDAC1 activity rather than HDAC1 expression.	('HDAC1', 'Gene', (238, 243))	('HDAC1', 'Gene', (211, 216))	('H3', 'Chemical', 'MESH:C006633', (83, 85))	('histone H3', 'Protein', (75, 85))	('activity', 'MPA', (217, 225))	('acetyl', 'Chemical', 'MESH:C011632', (54, 60))	('acetylation level', 'MPA', (54, 71))	('HDAC1', 'Gene', (95, 100))	('HDAC1', 'Gene', (134, 139))	('HDAC1', 'Gene', '3065', (238, 243))	('HDAC1', 'Gene', '3065', (211, 216))	('Lys', 'Chemical', 'MESH:C026591', (87, 90))	('elevated', 'PosReg', (41, 49))	('inhibiting', 'NegReg', (200, 210))	('HDAC1', 'Gene', '3065', (95, 100))	('HDAC1', 'Gene', '3065', (134, 139))	('AR-42', 'Var', (24, 29))
894184	31908417	The cell cycle inhibitor p21 is frequently epigenetically silenced by HDACs in tumors, whereas the low expression of p21 was reversed after treatment with pan-HDAC inhibitor AR-42 in both Eca109 and TE-1 cells (Figure 5); this is one of the contributors for the anti-ESCC effects of AR-42.	('epigenetically', 'Var', (43, 57))	('p21', 'Gene', (25, 28))	('ESCC', 'Disease', (267, 271))	('HDAC', 'Gene', (70, 74))	('p21', 'Gene', '644914', (25, 28))	('p21', 'Gene', (117, 120))	('HDAC', 'Gene', '9734', (70, 74))	('HDAC', 'Gene', (159, 163))	('p21', 'Gene', '644914', (117, 120))	('tumors', 'Disease', (79, 85))	('HDAC', 'Gene', '9734', (159, 163))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('ESCC', 'Disease', 'MESH:C562729', (267, 271))	('silenced', 'NegReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
894186	31908417	As shown in Figure 5, Stat3 phosphorylation (Tyr705) was effectively suppressed by AR-42 at concentrations >=0.3 muM in both ESCC cell lines, whereas p-Akt (Ser473) and p-ERK (Thr202/Tyr204) could just be inhibited at concentrations >3 muM.	('muM', 'Gene', (113, 116))	('Ser', 'Chemical', 'MESH:C530429', (157, 160))	('Tyr705', 'Var', (45, 51))	('Thr', 'Chemical', 'MESH:C055175', (176, 179))	('Stat3', 'Gene', '6774', (22, 27))	('ESCC', 'Disease', 'MESH:C562729', (125, 129))	('Akt', 'Gene', (152, 155))	('Stat3', 'Gene', (22, 27))	('muM', 'Gene', '56925', (236, 239))	('ERK', 'Gene', '5594', (171, 174))	('suppressed', 'NegReg', (69, 79))	('ERK', 'Gene', (171, 174))	('muM', 'Gene', '56925', (113, 116))	('AR-42', 'Gene', (83, 88))	('Akt', 'Gene', '207', (152, 155))	('muM', 'Gene', (236, 239))	('ESCC', 'Disease', (125, 129))
894188	31908417	Overall, these data suggest that AR-42 inhibits the growth of ESCC cells by up-regulating the expression of p21 and blocking the transduction of multiple signaling cascades related to pro-proliferation and anti-apoptosis, especially the Stat3-mediated signaling.	('transduction of multiple signaling cascades', 'MPA', (129, 172))	('up-regulating', 'PosReg', (76, 89))	('growth', 'CPA', (52, 58))	('AR-42', 'Var', (33, 38))	('ESCC', 'Disease', 'MESH:C562729', (62, 66))	('p21', 'Gene', (108, 111))	('p21', 'Gene', '644914', (108, 111))	('blocking', 'NegReg', (116, 124))	('expression', 'MPA', (94, 104))	('Stat3', 'Gene', '6774', (237, 242))	('inhibits', 'NegReg', (39, 47))	('ESCC', 'Disease', (62, 66))	('Stat3', 'Gene', (237, 242))
894193	31908417	As displayed in Figure 6C, treatment with AR-42 (50 mg/kg) led to a remarkable increase in the acetylation level of histone H3 (Lys 9) and a substantial reduction in Ki67-positive cells (proliferating tumor cells) compared with treatment with vehicle control.	('increase', 'PosReg', (79, 87))	('reduction', 'NegReg', (153, 162))	('H3', 'Chemical', 'MESH:C006633', (124, 126))	('Lys', 'Chemical', 'MESH:C026591', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('acetylation level', 'MPA', (95, 112))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('AR-42', 'Var', (42, 47))	('acetyl', 'Chemical', 'MESH:C011632', (95, 101))	('tumor', 'Disease', (201, 206))
894194	31908417	In addition, CD31 immunohistochemical staining was adopted to label tumor vessels, and AR-42 could efficaciously diminish the vascular density in tumors at a dose of 50 mg/kg (Figure 6C).	('tumor', 'Disease', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('CD31', 'Gene', (13, 17))	('diminish', 'NegReg', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('CD31', 'Gene', '5175', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (146, 152))	('AR-42', 'Var', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
894195	31908417	Taken together, AR-42 could also significantly inhibit HDAC activity in vivo and exhibited anti-ESCC activity via anti-proliferation and pro-apoptosis effects, as well as blockade of angiogenesis.	('angiogenesis', 'CPA', (183, 195))	('ESCC', 'Disease', 'MESH:C562729', (96, 100))	('HDAC', 'Gene', (55, 59))	('AR-42', 'Var', (16, 21))	('anti-proliferation', 'CPA', (114, 132))	('HDAC', 'Gene', '9734', (55, 59))	('pro-apoptosis effects', 'CPA', (137, 158))	('inhibit', 'NegReg', (47, 54))	('ESCC', 'Disease', (96, 100))	('blockade', 'NegReg', (171, 179))
894205	31908417	The results of Western blot analysis showed that AR-42 exerts its anti-ESCC effects mainly through elevating the expression of cell cycle inhibitor p21 and inhibiting the activity of Stat3-mediated signaling.	('expression', 'MPA', (113, 123))	('Stat3', 'Gene', (183, 188))	('Stat3', 'Gene', '6774', (183, 188))	('ESCC', 'Disease', (71, 75))	('p21', 'Gene', (148, 151))	('cell', 'Protein', (127, 131))	('elevating', 'PosReg', (99, 108))	('p21', 'Gene', '644914', (148, 151))	('activity', 'MPA', (171, 179))	('ESCC', 'Disease', 'MESH:C562729', (71, 75))	('inhibiting', 'NegReg', (156, 166))	('AR-42', 'Var', (49, 54))
894288	31200666	1), MMP11 expression differences yielded particularly high fold changes and high AUCs.	('MMP11', 'Gene', '4320', (4, 9))	('differences', 'Var', (21, 32))	('high AUCs', 'MPA', (76, 85))	('fold changes', 'MPA', (59, 71))	('MMP11', 'Gene', (4, 9))
894303	31200666	MMP-7 activation is directly associated with APC, and it is well established that APC mutations are frequently implicated as among the first mutations that occurs in the disease history of colon polyps as they progress to cancer.	('mutations', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('MMP-7', 'Gene', (0, 5))	('APC', 'Disease', (82, 85))	('colon polyps', 'Disease', (189, 201))	('cancer', 'Disease', (222, 228))	('MMP-7', 'Gene', '4316', (0, 5))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('colon polyps', 'Disease', 'MESH:D003111', (189, 201))
894304	31200666	APC mutations often lead to increased beta-catenin and thus overexpression of MMP-7.	('increased', 'PosReg', (28, 37))	('beta-catenin', 'Gene', (38, 50))	('MMP-7', 'Gene', (78, 83))	('MMP-7', 'Gene', '4316', (78, 83))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('overexpression', 'PosReg', (60, 74))	('beta-catenin', 'Gene', '1499', (38, 50))	('APC', 'Disease', (0, 3))	('mutations', 'Var', (4, 13))
894322	31200666	It is likely that the dysregulation of one MMP alters the MMP ecosystem and means that MMPs are better predictors when analyzed in combination as opposed to individually.	('dysregulation', 'Var', (22, 35))	('MMP ecosystem', 'MPA', (58, 71))	('alters', 'Reg', (47, 53))	('MMPs', 'Gene', (87, 91))	('MMPs', 'Gene', '4312;4313;4314;4316;4317;4318;4319;4320;4321;4322;4323;4324;4325;4326;4327;64386;9313;118856;8510;10893;79148;64386;10893;79148;64386;10893;64066;79148', (87, 91))
894337	31200666	VHL mutation, whether inherited or sporadic is frequently implicated in the tumorigenesis of renal clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (93, 119))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('renal clear cell carcinoma', 'Disease', (93, 119))	('mutation', 'Var', (4, 12))	('VHL', 'Gene', (0, 3))	('implicated', 'Reg', (58, 68))	('VHL', 'Gene', '7428', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
894338	31200666	With the loss of VHL, HIF is no longer properly degraded and free to induce the expression of proteins needed in hypoxic conditions.	('hypoxic conditions', 'Disease', (113, 131))	('hypoxic conditions', 'Disease', 'MESH:D009135', (113, 131))	('loss', 'Var', (9, 13))	('VHL', 'Gene', (17, 20))	('VHL', 'Gene', '7428', (17, 20))
894339	31200666	This leads to the upregulation of MMP14 in kidney clear cell carcinoma in patients with deletion of VHL.	('upregulation', 'PosReg', (18, 30))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (43, 70))	('deletion', 'Var', (88, 96))	('MMP14', 'Gene', '4323', (34, 39))	('patients', 'Species', '9606', (74, 82))	('kidney clear cell carcinoma', 'Disease', (43, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('MMP14', 'Gene', (34, 39))	('VHL', 'Gene', (100, 103))	('VHL', 'Gene', '7428', (100, 103))
894444	27275735	For example, genetic polymorphisms found to be associated with cancer risk in some studies are often observed to have no association in other studies.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('genetic polymorphisms', 'Var', (13, 34))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('associated', 'Reg', (47, 57))	('cancer', 'Disease', (63, 69))
894520	28386209	According to the Japanese guidelines for diagnosis and treatment of esophageal cancer, T1a-EP or T1a-LPM SCC is considered an absolute indication for ER; T1a-MM or T1b-SM1, a relative indication; and T1b-SM2, an investigative stage (functionally speaking, a contraindication).	('esophageal cancer', 'Disease', 'MESH:D004938', (68, 85))	('T1a-MM', 'Var', (154, 160))	('SM2', 'Gene', '53366', (204, 207))	('SM1', 'Gene', '7911', (168, 171))	('SM1', 'Gene', (168, 171))	('SM2', 'Gene', (204, 207))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SCC', 'Gene', (105, 108))	('T1a-EP', 'Var', (87, 93))	('esophageal cancer', 'Disease', (68, 85))	('T1a-LPM', 'Var', (97, 104))	('SCC', 'Gene', '6317', (105, 108))
894530	28386209	The cancerous types of microvessels corresponding to histology of HGIN or invasive SCC are subclassified into three groups based upon an indication for ER as follows: an absolute indication type (HGIN, T1a-EP or T1a-LPM), a relative indication type (T1a-MM or T1b-SM1), and a contraindication type (T1b-SM2).	('HGIN', 'Var', (196, 200))	('SM2', 'Gene', '53366', (303, 306))	('cancerous', 'Disease', 'MESH:D009369', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('SCC', 'Gene', (83, 86))	('T1a-EP', 'Var', (202, 208))	('T1a-LPM', 'Var', (212, 219))	('SM2', 'Gene', (303, 306))	('SM1', 'Gene', '7911', (264, 267))	('SM1', 'Gene', (264, 267))	('cancerous', 'Disease', (4, 13))	('SCC', 'Gene', '6317', (83, 86))	('T1a-MM', 'Var', (250, 256))
894533	28386209	When B2 and B3 vessels are seen in target lesions, the histological invasion depth is predicted as T1a-MM or T1b-SM1 and T1b-SM2 or deeper, respectively.	('SM1', 'Gene', '7911', (113, 116))	('SM1', 'Gene', (113, 116))	('SM2', 'Gene', '53366', (125, 128))	('SM2', 'Gene', (125, 128))	('T1a-MM', 'Var', (99, 105))
894536	28386209	AVA-middle and AVA-large surrounded by B2 or B3 vessels are suggestive of T1a-MM or T1b-SM1 and T1b-SM2 invasive SCC, respectively.	('SCC', 'Gene', '6317', (113, 116))	('SM2', 'Gene', (100, 103))	('T1a-MM', 'Var', (74, 80))	('SCC', 'Gene', (113, 116))	('SM1', 'Gene', '7911', (88, 91))	('SM1', 'Gene', (88, 91))	('SM2', 'Gene', '53366', (100, 103))
894541	28386209	The depth of tumor invasion of the all lesions was estimated prior to treatment using a magnifying endoscope (GIF-H260Z or GIF-Q240Z; Olympus Corporation, Tokyo, Japan) combined with NBI.	('tumor', 'Disease', (13, 18))	('Q240Z', 'Var', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('H260Z', 'SUBSTITUTION', 'None', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('H260Z', 'Var', (114, 119))	('Q240Z', 'SUBSTITUTION', 'None', (127, 132))
894558	28386209	Table 5 shows the diagnostic values of B1, B2, and B3 vessels for estimating the depth of invasion of T1a-EP or T1a-LPM, T1a-MM or T1b-SM1, and T1b-SM2 tumors, respectively.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('T1a-MM', 'Var', (121, 127))	('SM2 tumors', 'Disease', 'MESH:D009369', (148, 158))	('SM2 tumors', 'Disease', (148, 158))	('SM1', 'Gene', (135, 138))	('B1, B2, and B3', 'Gene', '28905;2925;680', (39, 53))	('SM1', 'Gene', '7911', (135, 138))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
894566	28386209	In contrast, the sensitivity and PPV of B2 vessels for T1a-MM or T1b-SM1 tumors were both a suboptimal 75.0 %, while the diagnostic accuracy of white light endoscopy showed a lower value at 66-74 %.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('T1a-MM', 'Var', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('SM1', 'Gene', '7911', (69, 72))	('SM1', 'Gene', (69, 72))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
894567	28386209	Previous studies have indicated that T1a-MM or T1b-SM1 tumors without lymphovascular invasion had a significantly lower risk of lymph node metastasis and a good prognosis.	('lymph node metastasis', 'CPA', (128, 149))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('SM1', 'Gene', '7911', (51, 54))	('SM1', 'Gene', (51, 54))	('tumors', 'Disease', (55, 61))	('lower', 'NegReg', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('T1a-MM', 'Var', (37, 43))
894568	28386209	Therefore, T1a-MM or T1b-SM1 tumors are potential candidates for curative treatment by ER.	('tumors', 'Disease', (29, 35))	('SM1', 'Gene', (25, 28))	('T1a-MM', 'Var', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('SM1', 'Gene', '7911', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))
894569	28386209	Further study on the definition of B2 vessels is warranted to reduce the risk of unnecessary surgery for patients with T1a-MM or T1b-SM1 tumors.	('T1a-MM', 'Var', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('SM1', 'Gene', '7911', (133, 136))	('patients', 'Species', '9606', (105, 113))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('SM1', 'Gene', (133, 136))
894670	27729298	NRG Oncology RTOG 0246 was a multi-institutional, single arm, open-label, non-randomized phase II study, which enrolled forty-three patients from Sept 2003 to March 2008 with clinical stage T1-4N0-1M0 squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction (GEJ) from 19 sites.	('squamous cell', 'Disease', (201, 214))	('T1-4N0-1M0', 'Var', (190, 200))	('adenocarcinoma of the esophagus or gastroesophageal junction', 'Disease', 'MESH:C562730', (218, 278))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (223, 249))	('Oncology', 'Phenotype', 'HP:0002664', (4, 12))	('patients', 'Species', '9606', (132, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))
894768	26510453	Adenocarcinoma evolves from Barrett's esophagus, as evidenced by the fact that most driver mutations found in adenocarcinoma are already present in the preceding Barrett's esophagus lesions.	('Adenocarcinoma', 'Disease', (0, 14))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('mutations', 'Var', (91, 100))	('adenocarcinoma', 'Disease', (110, 124))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (28, 47))	('adenocarcinoma', 'Disease', 'MESH:D000230', (110, 124))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (162, 181))
894771	26510453	Notably, there are more insertions/deletions (indels) and C:G>G:C transversions in SCC, while A:T>C:G transversions are more common in adenocarcinoma.	('C:G>G:C transversions', 'Var', (58, 79))	('adenocarcinoma', 'Disease', 'MESH:D000230', (135, 149))	('A:T>C:G', 'Var', (94, 101))	('insertions/deletions', 'Var', (24, 44))	('SCC', 'Gene', (83, 86))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('transversions', 'Var', (66, 79))	('adenocarcinoma', 'Disease', (135, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
894772	26510453	These mutations appear to impact distinct molecular pathways in SCC compared with adenocarcinoma.	('SCC', 'Gene', '6317', (64, 67))	('adenocarcinoma', 'Disease', (82, 96))	('impact', 'Reg', (26, 32))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))	('adenocarcinoma', 'Disease', 'MESH:D000230', (82, 96))	('molecular pathways', 'Pathway', (42, 60))	('mutations', 'Var', (6, 15))	('SCC', 'Gene', (64, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
894773	26510453	For example, inactivating mutations of NOTCH1 were identified in 21% of SCCs but were not observed in adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('inactivating mutations', 'Var', (13, 35))	('NOTCH1', 'Gene', '4851', (39, 45))	('adenocarcinoma', 'Disease', (102, 116))	('NOTCH1', 'Gene', (39, 45))	('identified', 'Reg', (51, 61))	('adenocarcinoma', 'Disease', 'MESH:D000230', (102, 116))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('SCC', 'Gene', '6317', (72, 75))
894783	26510453	The diffuse or infiltrative type, which is associated with Epstein- Barr virus (EBV) infection and hereditary mutations in CDH1, is more common in younger age groups and has a worse prognosis than the intestinal type.	('Epstein- Barr virus (EBV) infection', 'Disease', 'MESH:D020031', (59, 94))	('mutations', 'Var', (110, 119))	('diffuse or infiltrative type', 'Disease', (4, 32))	('associated', 'Reg', (43, 53))	('CDH1', 'Gene', (123, 127))
894785	26510453	Given the limited utility of subtyping by histology or location, recent efforts have used comprehensive genetic analyses to define four molecular subtypes of gastric cancer: microsatellite unstable (21.6%), chromosomally unstable (49.8%), genomically stable (19.6%) and EBV related (8.8%).	('EBV', 'Species', '10376', (270, 273))	('gastric cancer', 'Disease', 'MESH:D013274', (158, 172))	('gastric cancer', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('gastric cancer', 'Phenotype', 'HP:0012126', (158, 172))	('microsatellite unstable', 'Var', (174, 197))
894793	26510453	Dimerization triggers auto-phosphorylation of the EGFR intracellular domain leading to the subsequent activation of downstream signaling pathways.	('Dimerization', 'Var', (0, 12))	('triggers', 'Reg', (13, 21))	('auto-phosphorylation', 'MPA', (22, 42))	('EGFR', 'Gene', '1956', (50, 54))	('downstream signaling pathways', 'Pathway', (116, 145))	('activation', 'PosReg', (102, 112))	('EGFR', 'Gene', (50, 54))
894794	26510453	Aberrant EGFR signaling leads to several hallmarks of cancer including increased proliferation, angiogenesis, metastasis and resistance to apoptosis.	('resistance to apoptosis', 'CPA', (125, 148))	('Aberrant', 'Var', (0, 8))	('metastasis', 'CPA', (110, 120))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('EGFR', 'Gene', '1956', (9, 13))	('angiogenesis', 'CPA', (96, 108))	('EGFR', 'Gene', (9, 13))	('increased', 'PosReg', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
894829	26510453	A non-significant improvement in PFS (1.6 months gefitinib vs 1.2 months placebo) was observed.	('gefitinib', 'Chemical', 'MESH:D000077156', (49, 58))	('gefitinib', 'Var', (49, 58))	('PFS', 'Disease', (33, 36))
894831	26510453	Odynophagia was improved in the gefitinib group, but other symptoms were similar between groups.	('gefitinib', 'Var', (32, 41))	('Odynophagia', 'Disease', (0, 11))	('Odynophagia', 'Phenotype', 'HP:0032043', (0, 11))	('gefitinib', 'Chemical', 'MESH:D000077156', (32, 41))	('improved', 'PosReg', (16, 24))
894833	26510453	The TRANS COG analysis evaluated the predictive value of EGFR copy number gain (CNG) in 295 patients treated on the COG trial using prospectively collected tumor samples.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('EGFR', 'Gene', '1956', (57, 61))	('copy number', 'Var', (62, 73))	('tumor', 'Disease', (156, 161))	('EGFR', 'Gene', (57, 61))
894876	26510453	Cross-trial comparison shows that peripheral neuropathy was the only side effect which was increased by the substitution of oxalipatin for cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('peripheral neuropathy', 'Disease', (34, 55))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (34, 55))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (34, 55))	('oxalipatin', 'Chemical', '-', (124, 134))	('substitution', 'Var', (108, 120))
894884	26510453	Additional studies of different chemotherapy regimens in combination with trastuzumab are ongoing including those with docetaxel and other chemotherapy combinations (NCT01295086, NCT01364493, NCT02004769 and NCT01928290).	('docetaxel', 'Chemical', 'MESH:D000077143', (119, 128))	('NCT01928290', 'Var', (208, 219))	('NCT01295086', 'Var', (166, 177))	('NCT01364493', 'Var', (179, 190))	('NCT02004769', 'Var', (192, 203))	('trastuzumab', 'Chemical', 'MESH:D000068878', (74, 85))
894918	26510453	While those receiving lapatinib had a statistically significant increase in RR (27% vs 8%), there was only a non-significant trend towards benefit in survival measures (OS 11.0 vs 8.9 months; PFS 5.4 vs 4.4 months).	('lapatinib', 'Chemical', 'MESH:D000077341', (22, 31))	('increase', 'PosReg', (64, 72))	('lapatinib', 'Var', (22, 31))	('OS', 'Chemical', '-', (169, 171))
894927	26510453	Other trials are studying afatinib in combination with trastuzumab or chemotherapy, including NCT01649271 (phase I, first-line afatinib/trastuzumab), NCT01743365 (phase II, first-line afatinib/cisplatin/5-FU), NCT01522768 (phase II, second-line afatinib/trastuzumab after progression on trastuzumab alone) and NCT02274012 and NCT02501603 (both phase II, second-line afatinib/paclitaxel after progression on trastuzumab alone).	('afatinib', 'Chemical', 'MESH:D000077716', (26, 34))	('afatinib', 'Chemical', 'MESH:D000077716', (366, 374))	('paclitaxel', 'Chemical', 'MESH:D017239', (375, 385))	('5-FU', 'Chemical', 'MESH:D005472', (203, 207))	('NCT02501603', 'Var', (326, 337))	('trastuzumab', 'Chemical', 'MESH:D000068878', (254, 265))	('trastuzumab', 'Chemical', 'MESH:D000068878', (55, 66))	('NCT01743365', 'Var', (150, 161))	('afatinib', 'Chemical', 'MESH:D000077716', (245, 253))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('afatinib', 'Chemical', 'MESH:D000077716', (184, 192))	('afatinib', 'Chemical', 'MESH:D000077716', (127, 135))	('trastuzumab', 'Chemical', 'MESH:D000068878', (287, 298))	('trastuzumab', 'Chemical', 'MESH:D000068878', (407, 418))	('NCT01649271', 'Var', (94, 105))	('NCT01522768', 'Var', (210, 221))	('trastuzumab', 'Chemical', 'MESH:D000068878', (136, 147))	('NCT02274012', 'Var', (310, 321))
894935	26510453	These normal functions are disrupted during cellular transformation in which aberrant VEGF pathway activity drives carcinogenesis, invasion and metastasis.	('invasion', 'CPA', (131, 139))	('VEGF', 'Gene', (86, 90))	('VEGF', 'Gene', '7422', (86, 90))	('metastasis', 'CPA', (144, 154))	('carcinogenesis', 'Disease', (115, 129))	('activity', 'MPA', (99, 107))	('aberrant', 'Var', (77, 85))
894937	26510453	Multiple preclinical studies have shown that VEGF enhances tumor growth and metastasis and that inhibition of the VEGF signaling cascade results in remarkable antitumor responses.	('enhances', 'PosReg', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('VEGF', 'Gene', (114, 118))	('VEGF', 'Gene', '7422', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('inhibition', 'Var', (96, 106))	('VEGF', 'Gene', '7422', (114, 118))	('VEGF', 'Gene', (45, 49))
894966	26510453	Although the objective RR was very low, the overall DCR was also improved at 49% for patients receiving ramucirumab vs 23% for placebo.	('improved', 'PosReg', (65, 73))	('DCR', 'MPA', (52, 55))	('ramucirumab', 'Chemical', 'MESH:C543333', (104, 115))	('patients', 'Species', '9606', (85, 93))	('ramucirumab', 'Var', (104, 115))	('objective', 'MPA', (13, 22))
894972	26510453	The DCR was higher in those receiving ramucirumab as well (80% vs 64%).	('ramucirumab', 'Var', (38, 49))	('DCR', 'MPA', (4, 7))	('ramucirumab', 'Chemical', 'MESH:C543333', (38, 49))	('higher', 'PosReg', (12, 18))
894973	26510453	Subgroup analysis showed that patients with GE-Ca appeared to have more benefit than those with stomach cancer.	('stomach cancer', 'Disease', 'MESH:D013274', (96, 110))	('stomach cancer', 'Phenotype', 'HP:0012126', (96, 110))	('benefit', 'PosReg', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('stomach cancer', 'Disease', (96, 110))	('patients', 'Species', '9606', (30, 38))	('GE-Ca', 'Var', (44, 49))
894988	26510453	One safety concern with ziv-aflibercept is gastrointestinal perforation, which may be more common than that seen with bevacizumab.	('gastrointestinal', 'Disease', (43, 59))	('ziv-aflibercept', 'Var', (24, 39))	('bevacizumab', 'Chemical', 'MESH:D000068258', (118, 129))	('gastrointestinal', 'Disease', 'MESH:D005767', (43, 59))
894999	26510453	The OS showed a trend towards improvement with regorafenib but did not reach significance (25 weeks for the regorafenib vs 19.4 weeks for placebo).	('regorafenib', 'Chemical', 'MESH:C559147', (47, 58))	('OS', 'Chemical', '-', (4, 6))	('improvement', 'PosReg', (30, 41))	('regorafenib', 'Chemical', 'MESH:C559147', (108, 119))	('regorafenib', 'Var', (108, 119))
895001	26510453	Other planned and ongoing trials are studying regorafenib in metastatic GE-Ca including NCT02241720 (single-agent regorafenib in the second line), NCT01913639 (regorafenib/FOLFOX in the first line), the REPEAT (NCT02406170) trial (regorafenib/paclitaxel in the second line) and NCT02234180 (adjuvant single-agent regorafenib after neoadjuvant chemotherapy and surgery for node-positive disease).	('NCT01913639', 'Var', (147, 158))	('regorafenib', 'Chemical', 'MESH:C559147', (46, 57))	('regorafenib', 'Chemical', 'MESH:C559147', (313, 324))	('REPEAT', 'Disease', (203, 209))	('REPEAT', 'Disease', 'MESH:D000647', (203, 209))	('regorafenib', 'Chemical', 'MESH:C559147', (114, 125))	('paclitaxel', 'Chemical', 'MESH:D017239', (243, 253))	('regorafenib', 'Chemical', 'MESH:C559147', (160, 171))	('NCT02234180', 'Var', (278, 289))	('FOLFOX', 'Chemical', '-', (172, 178))	('regorafenib', 'Chemical', 'MESH:C559147', (231, 242))
895009	26510453	These results have led to a number of additional trials of this agent including a randomized comparison of apatinib to docetaxel in the third-line setting and two studies of apatinib maintenance (either after adjuvant chemotherapy for localized disease or after first-line therapy for metastatic disease) (NCT02510469, NCT02509806, and NCT02409199).	('localized disease', 'Disease', 'MESH:D012594', (235, 252))	('apatinib', 'Chemical', 'MESH:C553458', (107, 115))	('docetaxel', 'Chemical', 'MESH:D000077143', (119, 128))	('NCT02509806', 'Var', (319, 330))	('NCT02409199', 'Var', (336, 347))	('apatinib', 'Chemical', 'MESH:C553458', (174, 182))	('NCT02510469', 'Var', (306, 317))	('localized disease', 'Disease', (235, 252))
895018	26510453	While missense mutations in the MET tyrosine kinase domain or juxtamembrane domain occur at a low frequency, MET overexpression or amplification is common in gastric cancers.	('gastric cancers', 'Disease', 'MESH:D013274', (158, 173))	('common', 'Reg', (148, 154))	('MET', 'MPA', (109, 112))	('overexpression', 'PosReg', (113, 127))	('missense mutations', 'Var', (6, 24))	('gastric cancers', 'Disease', (158, 173))	('tyrosine', 'Chemical', 'MESH:D014443', (36, 44))	('gastric cancers', 'Phenotype', 'HP:0012126', (158, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('gastric cancer', 'Phenotype', 'HP:0012126', (158, 172))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
895020	26510453	MET amplification is associated with poor prognosis as these tumors are typically high-grade adenocarcinoma that present at advanced stages.	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('MET amplification', 'Var', (0, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('adenocarcinoma', 'Disease', (93, 107))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
895021	26510453	Interestingly, HER2, MET and EGFR amplifications were mutually exclusive events among 489 patients with GE-Ca, and MET amplification was the strongest predictor of poor prognosis in this study.	('amplifications', 'Var', (34, 48))	('MET', 'Gene', (21, 24))	('HER2', 'Gene', (15, 19))	('HER2', 'Gene', '2064', (15, 19))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('patients', 'Species', '9606', (90, 98))
895035	26510453	These encouraging results led to the randomized phase III Rilomet-1 (NCT01697072) trial for patients who were treatment naive, HER2-negative and MET-positive by IHC.	('HER2', 'Gene', (127, 131))	('MET-positive', 'Var', (145, 157))	('patients', 'Species', '9606', (92, 100))	('HER2', 'Gene', '2064', (127, 131))
895038	26510453	Final analysis showed that OS, PFS and ORR were worse in patients receiving rilotumumab.	('OS', 'Chemical', '-', (27, 29))	('ORR', 'Disease', (39, 42))	('patients', 'Species', '9606', (57, 65))	('rilotumumab', 'Chemical', 'MESH:C524459', (76, 87))	('rilotumumab', 'Var', (76, 87))	('PFS', 'Disease', (31, 34))
895051	26510453	There is also a planned randomized placebo-controlled phase I/II trial (NCT02344810) studying the efficacy of FOLFOX alone or in combination with AMG 337 as first-line therapy of HER2-negative, high MET-expressing gastric and esophageal adenocarcinoma.	('high MET-expressing', 'Var', (194, 213))	('FOLFOX', 'Chemical', '-', (110, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('AMG', 'Gene', (146, 149))	('esophageal adenocarcinoma', 'Disease', (226, 251))	('AMG', 'Gene', '265', (146, 149))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (226, 251))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (226, 251))	('HER2', 'Gene', (179, 183))	('HER2', 'Gene', '2064', (179, 183))
895056	26510453	Preclinical experiments have shown that crizotinib can inhibit the growth of MET-overexpressing gastric cancer cell lines and in vivo tumor models.	('growth', 'MPA', (67, 73))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('crizotinib', 'Chemical', 'MESH:D000077547', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('gastric cancer', 'Disease', (96, 110))	('crizotinib', 'Var', (40, 50))	('inhibit', 'NegReg', (55, 62))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('tumor', 'Disease', (134, 139))
895057	26510453	An exploratory analysis of a phase I trial of crizotinib in solid tumor patients found that two of four patients with MET-amplified GE-Ca had transient tumor shrinkage.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('crizotinib', 'Chemical', 'MESH:D000077547', (46, 56))	('MET-amplified', 'Var', (118, 131))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('solid tumor', 'Disease', (60, 71))	('tumor', 'Disease', (66, 71))	('solid tumor', 'Disease', 'MESH:D009369', (60, 71))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('patients', 'Species', '9606', (104, 112))	('patients', 'Species', '9606', (72, 80))
895074	26510453	NCT02318901 (pembrolizumab plus trastuzumab) and NCT02443324 (pembrolizumab plus ramucirumab)).	('NCT02443324', 'Var', (49, 60))	('pembrolizumab plus trastuzumab', 'Disease', (13, 43))	('pembrolizumab plus ramucirumab', 'Disease', 'MESH:D007625', (62, 92))	('pembrolizumab plus trastuzumab', 'Disease', 'MESH:D007625', (13, 43))	('NCT02318901', 'Var', (0, 11))	('pembrolizumab plus ramucirumab', 'Disease', (62, 92))
895270	23084493	Only patients with the following tumor sites were considered and grouped for the analyses; mid esophagus [C15.1 (thoracic esophagus) and C15.4 (middle third of esophagus)]; and lower esophagus [C15.2 (abdominal esophagus) and C15.5 (lower third of esophagus)].	('patients', 'Species', '9606', (5, 13))	('C15.5', 'Var', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('C15.4', 'Var', (137, 142))	('tumor', 'Disease', (33, 38))
895292	23084493	Overall, patients treated with surgery+-radiotherapy had significantly improved median CSS (27 versus 13 months, p<0.001) and median OS (20 versus 12 months, p<0.001) compared to definitive radiation (Table 2).	('patients', 'Species', '9606', (9, 17))	('CSS', 'Chemical', '-', (87, 90))	('surgery+-radiotherapy', 'Var', (31, 52))	('CSS', 'CPA', (87, 90))	('OS', 'Chemical', '-', (133, 135))	('improved', 'PosReg', (71, 79))
895344	21599940	In a pseudometastatic model of ESCC in mice we demonstrated the existance of an additive effect of Slug silencing in reducing metastatic burden.	('Slug', 'Protein', (99, 103))	('silencing', 'Var', (104, 113))	('reducing', 'NegReg', (117, 125))	('metastatic burden', 'CPA', (126, 143))	('mice', 'Species', '10090', (39, 43))
895365	21599940	Primers used were for Slug: F: 5-AGA TGC ATA TTC GGA CCC ACA-3 and R: 5-CCTCAT GTT TGT GCA GGA GAG-3.	('ACA-3', 'Gene', '619562', (57, 62))	('R: 5-CCTCAT', 'Var', (67, 78))	('ACA-3', 'Gene', (57, 62))
895401	21599940	Furthermore, colony formation assay in monolayer culture showed that the number of surviving colonies of Slug siRNA-transfected cells was markedly decreased compared to those of control cells, and the number of surviving colonies of Slug cDNA-transfected cells was increased compared to those of control cells, although the difference was not significant (P = 0.072, Figure 2C), suggesting that knockdown of Slug expression inhibits colony formation, and slug overexpression seems to enhance colony formation.	('slug', 'Gene', (455, 459))	('decreased', 'NegReg', (147, 156))	('slug', 'Gene', '6591', (455, 459))	('enhance', 'PosReg', (484, 491))	('Slug', 'Gene', (408, 412))	('inhibits', 'NegReg', (424, 432))	('knockdown', 'Var', (395, 404))	('colony formation', 'CPA', (433, 449))	('colony formation', 'CPA', (492, 508))
895424	21599940	In our study we found that the knockdown of Slug expression inhibited invasion capability in EA109 cell lines in vitro, and overexpression of Slug increased the invasion capability in TE-13 cell lines in vitro.	('increased', 'PosReg', (147, 156))	('TE-13', 'CellLine', 'CVCL:4463', (184, 189))	('inhibited', 'NegReg', (60, 69))	('invasion capability in EA109 cell lines', 'CPA', (70, 109))	('knockdown', 'Var', (31, 40))	('EA109', 'CellLine', 'CVCL:E575', (93, 98))	('invasion capability in TE-13', 'CPA', (161, 189))	('Slug', 'Gene', (44, 48))
895427	21599940	has previously found knockdown of Slug expression promotes apoptosis and inhibits cell proliferation in esophageal adenocarcinoma cell in vitro.	('cell proliferation', 'CPA', (82, 100))	('inhibits', 'NegReg', (73, 81))	('Slug', 'Gene', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('apoptosis', 'CPA', (59, 68))	('esophageal adenocarcinoma', 'Disease', (104, 129))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (104, 129))	('knockdown', 'Var', (21, 30))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (104, 129))	('promotes', 'PosReg', (50, 58))
895433	21599940	To investigate whether the Slug knockdown can synergistically reduce the metastatic burden in ESCC, we used a EC109 pseudometastatic model in immunodeficient mice, Slug silencing did inhibit metastatic growth and the effects reached statistical significance.	('inhibit', 'NegReg', (183, 190))	('silencing', 'NegReg', (169, 178))	('mice', 'Species', '10090', (158, 162))	('EC109', 'CellLine', 'CVCL:6898', (110, 115))	('Slug', 'Gene', (164, 168))	('knockdown', 'Var', (32, 41))	('reduce', 'NegReg', (62, 68))	('immunodeficient', 'Disease', 'MESH:D007153', (142, 157))	('metastatic growth', 'CPA', (191, 208))	('immunodeficient', 'Disease', (142, 157))	('metastatic burden', 'CPA', (73, 90))	('ESCC', 'Disease', (94, 98))
895505	32878621	It is considered that the marked gain of histidine may enhance the total antioxidant and metal-binding capacity of the proteome of the cancer cell and thus potentially serve as a nonspecific compensatory mechanism to relieve consequences of the cancer-related aggravation of oxidative stress.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (245, 251))	('enhance', 'PosReg', (55, 62))	('oxidative stress', 'Phenotype', 'HP:0025464', (275, 291))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('gain', 'PosReg', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('histidine', 'Chemical', 'MESH:D006639', (41, 50))	('histidine', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('metal', 'Chemical', 'MESH:D008670', (89, 94))
895526	32878621	This study was supported by National Natural Science Foundation of China (U1504814), Major projects of science and Technology Department in Henan Province (16110311200, 161100311300) and Anyang Science Foundation of Henan province (2016).	('men', 'Species', '9606', (132, 135))	('16110311200', 'Var', (156, 167))	('U1504814', 'Var', (74, 82))	('161100311300', 'Var', (169, 181))
895532	32089740	The impact and mechanism of ectopic ZNF471 expression in esophageal squamous cell carcinoma (ESCC) cells was evaluated in vitro and in vivo.	('esophageal squamous cell carcinoma', 'Disease', (57, 91))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (57, 91))	('ZNF471', 'Gene', (36, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('ectopic', 'Var', (28, 35))	('ZNF471', 'Gene', '57573', (36, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))
895537	32089740	Conclusion: Our results demonstrate that ZNF471 is an important tumor suppressor and loss of ZNF471 functions hampers MAPK10/JNK3 signaling during esophageal carcinogenesis.	('loss', 'Var', (85, 89))	('hampers', 'NegReg', (110, 117))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (147, 172))	('ZNF471', 'Gene', '57573', (41, 47))	('tumor', 'Disease', (64, 69))	('JNK3', 'Gene', (125, 129))	('esophageal carcinogenesis', 'Disease', (147, 172))	('ZNF471', 'Gene', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('JNK3', 'Gene', '5602', (125, 129))	('ZNF471', 'Gene', '57573', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('ZNF471', 'Gene', (41, 47))
895540	32089740	Although the molecular mechanisms underlying esophageal carcinogenesis are largely unknown, epigenetic silencing of key tumor suppressor genes (TSGs) by promoter CpG methylation has been demonstrated to be critical for esophageal tumorigenesis.	('tumor', 'Disease', (230, 235))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (45, 70))	('esophageal carcinogenesis', 'Disease', (45, 70))	('methylation', 'Var', (166, 177))	('TSG', 'Gene', '57045', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('esophageal tumor', 'Disease', 'MESH:D004941', (219, 235))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('esophageal tumor', 'Disease', (219, 235))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('esophageal tumor', 'Phenotype', 'HP:0100751', (219, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('epigenetic silencing', 'Var', (92, 112))	('TSG', 'Gene', (144, 147))	('tumor', 'Disease', (120, 125))
895545	32089740	Deletion of 19q is frequent in multiple cancers including ESCC, cervical cancer, and nasopharyngeal carcinoma.	('nasopharyngeal carcinoma', 'Disease', (85, 109))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (85, 109))	('multiple cancers', 'Disease', 'MESH:D009369', (31, 47))	('nasopharyngeal carcinoma', 'Disease', 'MESH:C538339', (85, 109))	('frequent', 'Reg', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', (40, 46))	('ESCC', 'Disease', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('multiple cancers', 'Disease', (31, 47))	('Deletion of 19q', 'Var', (0, 15))
895546	32089740	Previously, our group has identified and defined several KRAB-ZFP proteins, including ZNF382, ZNF545, and ZNF331, as important novel TSGs frequently downregulated and methylated in carcinomas.	('methylated', 'Var', (167, 177))	('carcinomas', 'Disease', (181, 191))	('ZFP', 'Gene', '55888', (62, 65))	('TSG', 'Gene', '57045', (133, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('ZFP', 'Gene', (62, 65))	('ZNF545', 'Gene', '284406', (94, 100))	('TSG', 'Gene', (133, 136))	('downregulated', 'NegReg', (149, 162))	('ZNF382', 'Gene', (86, 92))	('ZNF382', 'Gene', '84911', (86, 92))	('ZNF331', 'Gene', '55422', (106, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('ZNF331', 'Gene', (106, 112))	('carcinomas', 'Disease', 'MESH:D002277', (181, 191))	('ZNF545', 'Gene', (94, 100))
895548	32089740	Frequent methylation of ZNF471 in cancer has been reported in colorectal and squamous cell carcinoma, and its biological functions have been reported to be involved in the regulation of cell proliferation, apoptosis, migration and invasion, as a tumor suppressor in gastric cancer.	('methylation', 'Var', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('apoptosis', 'CPA', (206, 215))	('reported', 'Reg', (50, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (266, 280))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('ZNF471', 'Gene', (24, 30))	('colorectal', 'Disease', (62, 72))	('invasion', 'CPA', (231, 239))	('gastric cancer', 'Disease', (266, 280))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('involved', 'Reg', (156, 164))	('tumor', 'Disease', (246, 251))	('ZNF471', 'Gene', '57573', (24, 30))	('migration', 'CPA', (217, 226))	('gastric cancer', 'Disease', 'MESH:D013274', (266, 280))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('cancer', 'Disease', (274, 280))	('cell proliferation', 'CPA', (186, 204))	('colorectal', 'Disease', 'MESH:D015179', (62, 72))	('cancer', 'Disease', (34, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
895564	32089740	ZNF471 methylation was detected in 92/147 (62.6%) tumors but only 22/89 (24.7%) paired adjacent non-tumor tissue samples, and 0/3 (0%) normal esophageal tissues (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ZNF471', 'Gene', '57573', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('methylation', 'Var', (7, 18))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('detected', 'Reg', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (50, 55))	('ZNF471', 'Gene', (0, 6))
895565	32089740	1F) (Table 1), thus suggesting that ZNF471 methylation is a common event in ESCC.	('methylation', 'Var', (43, 54))	('ESCC', 'Disease', (76, 80))	('ZNF471', 'Gene', (36, 42))	('ZNF471', 'Gene', '57573', (36, 42))
895571	32089740	ZNF471 expression was found to suppress the growth of both KYSE150 and KYSE410 cells (p<0.001) in colony formation assays (Fig.	('ZNF471', 'Gene', '57573', (0, 6))	('KYSE410', 'Var', (71, 78))	('growth', 'MPA', (44, 50))	('expression', 'Var', (7, 17))	('suppress', 'NegReg', (31, 39))	('ZNF471', 'Gene', (0, 6))	('colony formation assays', 'CPA', (98, 121))
895575	32089740	Flow cytometry analysis also showed that ZNF471 ectopic expression significantly increased the numbers of apoptotic cells in the KYSE150 (p<0.001) and KYSE 410 cell lines (p<0.01), compared with vector control cells (Fig.	('ZNF471', 'Gene', '57573', (41, 47))	('increased', 'PosReg', (81, 90))	('ZNF471', 'Gene', (41, 47))	('ectopic expression', 'Var', (48, 66))
895581	32089740	The results showed that ectopic expression of ZNF471 significantly decreased the numbers of migrating (p<0.001) (Fig.	('ectopic expression', 'Var', (24, 42))	('decreased', 'NegReg', (67, 76))	('ZNF471', 'Gene', '57573', (46, 52))	('ZNF471', 'Gene', (46, 52))
895588	32089740	The percentage of apoptosis in KYSE270 cells was significantly decreased after ZNF471 knockdown (p<0.001) (Fig.	('ZNF471', 'Gene', (79, 85))	('knockdown', 'Var', (86, 95))	('ZNF471', 'Gene', '57573', (79, 85))	('decreased', 'NegReg', (63, 72))	('KYSE270', 'CellLine', 'CVCL:1350', (31, 38))	('apoptosis', 'CPA', (18, 27))
895589	32089740	Moreover, we observed enhanced cell migration and invasion after ZNF471 knockdown.	('ZNF471', 'Gene', (65, 71))	('invasion', 'CPA', (50, 58))	('ZNF471', 'Gene', '57573', (65, 71))	('cell migration', 'CPA', (31, 45))	('knockdown', 'Var', (72, 81))	('enhanced', 'PosReg', (22, 30))
895590	32089740	The number of migrated and invading KYSE270 cells was dramatically higher after ZNF471 knockdown, compared with that in the control group (p<0.001) (Fig.	('ZNF471', 'Gene', (80, 86))	('higher', 'PosReg', (67, 73))	('ZNF471', 'Gene', '57573', (80, 86))	('knockdown', 'Var', (87, 96))	('KYSE270', 'CellLine', 'CVCL:1350', (36, 43))
895597	32089740	Tumor cells with frequent nuclear fragmentation were primarily observed in xenografts with ZNF471 expression, along with increases in MAPK10 staining, decreases in Ki-67 staining and increases in cell apoptosis (Fig.	('staining', 'MPA', (141, 149))	('Ki-67', 'Gene', (164, 169))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('increases', 'PosReg', (121, 130))	('expression', 'Var', (98, 108))	('decreases', 'NegReg', (151, 160))	('nuclear fragmentation', 'CPA', (26, 47))	('increases', 'PosReg', (183, 192))	('ZNF471', 'Gene', (91, 97))	('MAPK10', 'Protein', (134, 140))	('ZNF471', 'Gene', '57573', (91, 97))	('cell apoptosis', 'CPA', (196, 210))	('Ki-67', 'Gene', '17345', (164, 169))	('staining', 'MPA', (170, 178))
895600	32089740	The significantly regulated genes identified in both KYSE150 and KYSE410 cells were found to be involved in cell adhesion (PCDH family genes, CLDN1, CNTN1), cell apoptosis (MAPK10/JNK3, PYCARD), tumor suppression (TUSC3, SAMD9L) and immunity regulation (IFNL3).	('PYCARD', 'Gene', '29108', (186, 192))	('tumor', 'Disease', (195, 200))	('involved', 'Reg', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('KYSE410', 'Var', (65, 72))	('CNTN1', 'Gene', (149, 154))	('IFNL3', 'Gene', '282617', (254, 259))	('PCDH family genes', 'Gene', (123, 140))	('CLDN1', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('TUSC3', 'Gene', '7991', (214, 219))	('KYSE150', 'Var', (53, 60))	('PYCARD', 'Gene', (186, 192))	('cell adhesion', 'CPA', (108, 121))	('SAMD9L', 'Gene', (221, 227))	('IFNL3', 'Gene', (254, 259))	('JNK3', 'Gene', (180, 184))	('CLDN1', 'Gene', '9076', (142, 147))	('cell apoptosis', 'CPA', (157, 171))	('JNK3', 'Gene', '5602', (180, 184))	('CNTN1', 'Gene', '1272', (149, 154))	('TUSC3', 'Gene', (214, 219))	('SAMD9L', 'Gene', '219285', (221, 227))
895609	32089740	After knocking down of MAPK10 in ZNF471-stably transfected ESCC cells, the cell proliferation ability was restored, and the numbers of apoptotic cells decreased (Fig.	('restored', 'PosReg', (106, 114))	('cell proliferation ability', 'CPA', (75, 101))	('ZNF471', 'Gene', (33, 39))	('decreased', 'NegReg', (151, 160))	('ZNF471', 'Gene', '57573', (33, 39))	('MAPK10', 'Gene', (23, 29))	('numbers', 'CPA', (124, 131))	('knocking down', 'Var', (6, 19))
895616	32089740	We found that the core region of the binding site was segment 4(+419-+700) at the MAPK10 promoter in both KYSE150 and 293T cells (Fig.	('MAPK10', 'Gene', (82, 88))	('293T', 'CellLine', 'CVCL:0063', (118, 122))	('+419-+700', 'Var', (64, 73))
895627	32089740	In previous reports, our group has identified several KRAB-ZFP proteins, including ZNF382, ZNF545 and ZNF331, as important novel TSGs frequently downregulated and methylated in multiple carcinomas.	('TSG', 'Gene', '57045', (129, 132))	('ZFP', 'Gene', '55888', (59, 62))	('ZNF545', 'Gene', (91, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('ZFP', 'Gene', (59, 62))	('multiple carcinomas', 'Disease', 'MESH:C537656', (177, 196))	('TSG', 'Gene', (129, 132))	('ZNF382', 'Gene', (83, 89))	('multiple carcinomas', 'Disease', (177, 196))	('methylated', 'Var', (163, 173))	('ZNF331', 'Gene', (102, 108))	('downregulated', 'NegReg', (145, 158))	('ZNF331', 'Gene', '55422', (102, 108))	('ZNF382', 'Gene', '84911', (83, 89))	('ZNF545', 'Gene', '284406', (91, 97))
895629	32089740	Frequent ZNF471 methylation has been found in colorectal cancer and tongue squamous cell carcinoma.	('colorectal cancer', 'Disease', 'MESH:D015179', (46, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('ZNF471', 'Gene', (9, 15))	('found', 'Reg', (37, 42))	('ZNF471', 'Gene', '57573', (9, 15))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('colorectal cancer', 'Disease', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 98))	('tongue squamous cell carcinoma', 'Disease', (68, 98))	('methylation', 'Var', (16, 27))
895633	32089740	We found that restoration of ZNF471 significantly inhibited ESCC cell growth, through inducing G0/G1 arrest and apoptosis and reversing EMT, and further inhibited ESCC cell invasion and migration.	('restoration', 'Var', (14, 25))	('apoptosis', 'CPA', (112, 121))	('ZNF471', 'Gene', (29, 35))	('ESCC', 'Disease', (60, 64))	('inducing', 'NegReg', (86, 94))	('reversing', 'NegReg', (126, 135))	('ZNF471', 'Gene', '57573', (29, 35))	('G0/G1 arrest', 'CPA', (95, 107))	('inhibited', 'NegReg', (153, 162))	('inhibited', 'NegReg', (50, 59))	('EMT', 'CPA', (136, 139))
895661	32089740	ESCC cell lines used included: EC1, EC18, HKESC1, HKESC2, HKESC3, KYSE30, KYSE70, KYSE140, KYSE150, KYSE180, KYSE220, KYSE270, KYSE410, KYSE450, KYSE510, KYSE520, and SLMT1.	('KYSE220', 'Var', (109, 116))	('KYSE520', 'Var', (154, 161))	('EC1', 'Gene', (31, 34))	('KYSE150', 'Var', (91, 98))	('KYSE510', 'Var', (145, 152))	('EC1', 'Gene', '4819', (31, 34))	('KYSE30', 'Var', (66, 72))	('EC1', 'Gene', (36, 39))	('KYSE270', 'CellLine', 'CVCL:1350', (118, 125))	('KYSE270', 'Var', (118, 125))	('EC1', 'Gene', '4819', (36, 39))	('KYSE180', 'Var', (100, 107))
895685	32089740	The stably transfected ZNF471 cells were obtained using G418 with maintain concentration (200mug/ml for KYSE150, 175mug/ml for KYSE410).	('KYSE150', 'Var', (104, 111))	('KYSE410', 'Var', (127, 134))	('ZNF471', 'Gene', (23, 29))	('G418', 'Chemical', 'MESH:C010680', (56, 60))	('ZNF471', 'Gene', '57573', (23, 29))
895696	32089740	Briefly, cells were incubated with primary antibodies against E-cadherin (#sc-8426; Santa Cruz Biotechnology, Santa Cruz, CA) or vimentin (#sc-6260; Santa Cruz), or anti-FLAG M2 antibody (#14793; Cell Signaling Technology, Danvers, MA), and then incubated with Alexa Fluor  594- (Invitrogen Life Sciences, Carlsbad, CA) or FITC-conjugated (Dako, Carpinteria, CA) secondary antibodies against mouse or rabbit IgG.	('IgG', 'Protein', (408, 411))	('mouse', 'Species', '10090', (392, 397))	('#sc-6260', 'Var', (139, 147))
895698	32089740	Anti-Flag was obtained from Abm (#G188; Abm, Richmond, BC), anti-MAPK10 was obtained from Bioss (bs-2997R, Bioss, Beijing, China), and anti-Ki-67 was obtained from Abcam (ab15580; Abcam, Cambridge, UK).	('#G188;', 'Var', (33, 39))	('Ki-67', 'Gene', '17345', (140, 145))	('Ki-67', 'Gene', (140, 145))
895704	32089740	Anti-Flag was obtained from Abm (#G188; Abm), anti-MAPK10 was obtained from Bioss (bs-2997R, Bioss), and anti-Ki-67 was obtained from Abcam (ab15580; Abcam).	('Ki-67', 'Gene', '17345', (110, 115))	('Ki-67', 'Gene', (110, 115))	('#G188', 'Var', (33, 38))
895708	32089740	After being blocked with 5% nonfat milk, the membranes were incubated at 4 C overnight with the primary antibodies to the following: ZNF471 (HPA066695; Sigma-Aldrich), ZNF471 (Y158334; Abm), p21 (sc-126; Santa Cruz), p27 (sc-393380; Santa Cruz), cleaved caspase 3 (#9661; Cell Signaling Technology), cleaved caspase 8 (#8592; Cell Signaling Technology), cleaved PARP (#5625; Cell Signaling Technology), Cyclin D1 (#1677; Epitomics, Burlingame, CA,), E-cadherin (#1702-1; Epitomics), vimentin (#2707-1, Epitomics), N-cadherin (ab98952; Abcam), SNAIL (#3897; Cell Signaling Technology), anti-Flag (#G188; Abm), anti-Flag M2 (#14793; Cell Signaling Technology), MAPK10 (ab126591; Abcam), p-JNK (WL01295, Wanleibio, China), and beta-actin (sc-47778; Santa Cruz; loading control).	('N-cadherin', 'Gene', (514, 524))	('N-cadherin', 'Gene', '1000', (514, 524))	('beta-actin', 'Gene', '728378', (724, 734))	('p21', 'Gene', (191, 194))	('PARP', 'Gene', (362, 366))	('p21', 'Gene', '644914', (191, 194))	('ZNF471', 'Gene', '57573', (133, 139))	('caspase 3', 'Gene', (254, 263))	('SNAIL', 'Gene', '6615', (543, 548))	('SNAIL', 'Gene', (543, 548))	('caspase 3', 'Gene', '836', (254, 263))	('caspase 8', 'Gene', '841', (308, 317))	('ZNF471', 'Gene', (168, 174))	('Cyclin D1', 'Gene', '595', (403, 412))	('Cyclin D1', 'Gene', (403, 412))	('beta-actin', 'Gene', (724, 734))	('ab126591', 'Var', (667, 675))	('ZNF471', 'Gene', '57573', (168, 174))	('PARP', 'Gene', '1302', (362, 366))	('p27', 'Gene', '3429', (217, 220))	('p27', 'Gene', (217, 220))	('ZNF471', 'Gene', (133, 139))	('caspase 8', 'Gene', (308, 317))
895710	32089740	Promoter regions of genes were amplified by PCR and cloned into the pGL3/Basic plasmid with a seamless cloning kit (D7010S, Beyotime, Beijing, China), and further confirmed by sequencing.	('D7010S', 'Var', (116, 122))	('pGL3', 'Gene', '6391', (68, 72))	('pGL3', 'Gene', (68, 72))	('D7010S', 'SUBSTITUTION', 'None', (116, 122))
895717	32089740	diluted samples were incubated with rabbit anti-Flag M2 (5 mul) (#14793, Cell Signaling Technology), anti-histone H4 acetylation (5 mul) (NM_175054, Merck Millipore, Billerica, MA, USA) or anti-histone H2A phosphorylation (5 mul) (05-636, Upstate Biotechnology, Lake Placid, NY, USA) overnight at 4 C, and this was followed by capture with protein A/G magnetic beads (#9006, Cell Signaling Technology) for 2 h. Rabbit anti-histone H3 antibody (#4620, Cell Signaling Technology) and normal rabbit IgG (#2729, Cell Signaling Technology) were used as positive and negative controls, respectively.	('histone H4', 'Gene', '8294', (106, 116))	('histone H4', 'Gene', (106, 116))	('#4620', 'Var', (444, 449))
895791	30813145	Aberrant expression of HLA-II may result in insufficient immune response or autoimmunity reaction, which may result in lots of diseases including cancers.	('insufficient immune response', 'Phenotype', 'HP:0002721', (44, 72))	('HLA', 'Gene', '3117', (23, 26))	('cancers', 'Disease', (146, 153))	('Aberrant expression', 'Var', (0, 19))	('autoimmunity reaction', 'Disease', (76, 97))	('immune response', 'CPA', (57, 72))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('autoimmunity reaction', 'Disease', 'MESH:D004342', (76, 97))	('HLA', 'Gene', (23, 26))	('result in', 'Reg', (109, 118))	('diseases', 'Disease', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('autoimmunity', 'Phenotype', 'HP:0002960', (76, 88))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('insufficient', 'Disease', (44, 56))	('insufficient', 'Disease', 'MESH:D000309', (44, 56))
895816	30813145	In brief, after dewaxing, inactivating, endogenous peroxidase activity, and blocking cross-reactivity with preimmune serum, the sections were incubated over night at 4 C with the primary antibodies (antibody for HLA-DQA1 was diluted at 1:100).	('inactivating', 'Var', (26, 38))	('HLA-DQA1', 'Gene', '3117', (212, 220))	('HLA-DQA1', 'Gene', (212, 220))	('activity', 'MPA', (62, 70))
895841	30813145	Remarkably, high HLA-DQA1 expression was demonstrated to be associated with a shorter overall survival time (P = .029).	('expression', 'MPA', (26, 36))	('overall survival time', 'CPA', (86, 107))	('HLA-DQA1', 'Gene', (17, 25))	('high', 'Var', (12, 16))	('HLA-DQA1', 'Gene', '3117', (17, 25))	('shorter', 'NegReg', (78, 85))
895865	30813145	The percentage of patients expressing HLA-DQA1 is higher for negative family history than that of positive family history.	('HLA-DQA1', 'Gene', (38, 46))	('HLA-DQA1', 'Gene', '3117', (38, 46))	('patients', 'Species', '9606', (18, 26))	('negative family history', 'Var', (61, 84))
895883	30189359	Overexpression of AXL has been associated with chemotherapy drug resistance and poor prognosis in EAC.	('AXL', 'Gene', (18, 21))	('EAC', 'Phenotype', 'HP:0011459', (98, 101))	('chemotherapy drug resistance', 'MPA', (47, 75))	('EAC', 'Disease', (98, 101))	('Overexpression', 'Var', (0, 14))	('AXL', 'Gene', '558', (18, 21))	('drug resistance', 'Phenotype', 'HP:0020174', (60, 75))
895894	30189359	Acidic pHe increases not only the activation of some lysosomal proteases with acidic optimal pH but also the expression of some genes facilitating cell invasion.	('pHe', 'Chemical', 'MESH:D010649', (7, 10))	('activation', 'MPA', (34, 44))	('genes', 'Gene', (128, 133))	('cell invasion', 'CPA', (147, 160))	('expression', 'MPA', (109, 119))	('acidic', 'Var', (78, 84))	('lysosomal proteases', 'Enzyme', (53, 72))
895912	30189359	Knockdown of CTSB, MCT-1, or ARL8B was performed using the following shRNA lentivirus particles: TRCN0000003658, TRCN0000038340, and TRCN0000296944, respectively (Sigma-Aldrich).	('CTSB', 'Gene', (13, 17))	('ARL8B', 'Gene', '55207', (29, 34))	('TRCN0000296944', 'Var', (133, 147))	('ARL8B', 'Gene', (29, 34))	('MCT-1', 'Gene', (19, 24))	('TRCN0000003658', 'Var', (97, 111))	('CTSB', 'Gene', '1508', (13, 17))	('TRCN0000038340', 'Var', (113, 127))	('MCT-1', 'Gene', '6566', (19, 24))
895947	30189359	We also found that AXL expression was markedly higher in SK-GT-4 and FLO-1 cells than in the other cell lines (Figure S2A).	('AXL', 'Gene', '558', (19, 22))	('higher', 'PosReg', (47, 53))	('AXL', 'Gene', (19, 22))	('SK-GT-4', 'Var', (57, 64))	('SK-GT-4', 'Chemical', '-', (57, 64))	('FLO-1', 'Chemical', '-', (69, 74))
895953	30189359	The Transwell invasion assay data indicated that AXL knockdown significantly impaired the invasiveness of SK-GT-4 cells (P < .001, Figure 1, B and C) or FLO-1 cells (P < .001, Figure 1, D and E) relative to their respective control cells.	('SK-GT-4', 'Chemical', '-', (106, 113))	('FLO-1', 'Chemical', '-', (153, 158))	('invasiveness', 'CPA', (90, 102))	('knockdown', 'Var', (53, 62))	('impaired', 'NegReg', (77, 85))	('AXL', 'Gene', '558', (49, 52))	('AXL', 'Gene', (49, 52))
895954	30189359	Moreover, in line with the AXL genetic knockdown data, we found that the pharmacologic inhibition of AXL activity by R428, as indicated by Western blot analysis of p-AXL (Y779) (Figure S3A), significantly impaired the invasiveness of SK-GT-4 cells (P < .05, Figure S3, D and E) or FLO-1 cells (P < .001, Figure S3, F and G) in comparison with their respective vehicle-treated cells, without affecting their viability (Figure S3, B and C).	('SK-GT-4', 'Chemical', '-', (234, 241))	('AXL', 'Gene', (101, 104))	('impaired', 'NegReg', (205, 213))	('AXL', 'Gene', (166, 169))	('R428', 'Chemical', '-', (117, 121))	('AXL', 'Gene', '558', (27, 30))	('invasiveness', 'CPA', (218, 230))	('R428', 'Var', (117, 121))	('FLO-1', 'Chemical', '-', (281, 286))	('S3, B and C', 'Gene', '6188', (425, 436))	('AXL', 'Gene', '558', (166, 169))	('AXL', 'Gene', '558', (101, 104))	('AXL', 'Gene', (27, 30))
895955	30189359	We found that knockdown of AXL expression in SK-GT-4 cells (Figure 1, F and G) and FLO-1 cells (Figure 1, H and I) significantly decreased invasion (P < .001) into the CAM relative to their respective control cells.	('invasion', 'CPA', (139, 147))	('SK-GT-4', 'Chemical', '-', (45, 52))	('AXL', 'Gene', '558', (27, 30))	('knockdown', 'Var', (14, 23))	('AXL', 'Gene', (27, 30))	('decreased', 'NegReg', (129, 138))	('FLO-1', 'Chemical', '-', (83, 88))
895958	30189359	We found that lysosomes were significantly more peripheral in SK-GT-4-shControl cells than SK-GT-4-shAXL cells (P < .001, Figure 2, A and B) or in FLO-1-shControl cells relative to FLO-1-shAXL cells (P < .01, Figure 2, C and D).	('peripheral', 'MPA', (48, 58))	('FLO-1-shAXL', 'Chemical', '-', (181, 192))	('more', 'PosReg', (43, 47))	('lysosomes', 'MPA', (14, 23))	('FLO-1-shControl', 'Chemical', '-', (147, 162))	('SK-GT-4-shControl', 'Chemical', '-', (62, 79))	('SK-GT-4-shAXL', 'Chemical', '-', (91, 104))	('SK-GT-4-shControl', 'Var', (62, 79))
895959	30189359	Conversely, knockdown of AXL expression significantly increased perinuclear localization of lysosomes in SK-GT-4 cells (P < .001, Figure 2, A and B) and FLO-1 cells (P < .01, Figure 2, C and D) relative to their respective control cells.	('FLO-1', 'Chemical', '-', (153, 158))	('knockdown', 'Var', (12, 21))	('perinuclear localization of lysosomes', 'MPA', (64, 101))	('increased', 'PosReg', (54, 63))	('AXL', 'Gene', '558', (25, 28))	('SK-GT-4', 'Chemical', '-', (105, 112))	('AXL', 'Gene', (25, 28))
895960	30189359	In agreement with these data, the pharmacologic inhibition of AXL by R428 (0.2 muM) significantly decreased peripheral and increased perinuclear localization of lysosomes in SK-GT-4 cells (P < .001, Figure S3, H and I) and FLO-1 cells (P < .01, Figure S3, J and K) relative to their respective vehicle-treated control cells.	('increased', 'PosReg', (123, 132))	('peripheral', 'MPA', (108, 118))	('muM', 'Gene', '56925', (79, 82))	('S3, H and I', 'Gene', '6188', (206, 217))	('R428', 'Chemical', '-', (69, 73))	('AXL', 'Gene', '558', (62, 65))	('R428', 'Var', (69, 73))	('muM', 'Gene', (79, 82))	('perinuclear localization of lysosomes', 'MPA', (133, 170))	('FLO-1', 'Chemical', '-', (223, 228))	('decreased', 'NegReg', (98, 107))	('AXL', 'Gene', (62, 65))	('SK-GT-4', 'Chemical', '-', (174, 181))
895963	30189359	We found a significantly higher number of peripheral lysosomes in SK-GT-4-shControl cells relative to SK-GT-4-shAXL cells (P < .01, Figure 2, E and F, Video S1) or in FLO-1-shControl cells in comparison with FLO-1-shAXL cells (P < .001, Figure 2, G and H, Video S2), as indicated by automated tracking of the number of lysosome tracks per cell.	('SK-GT-4-shControl', 'Var', (66, 83))	('FLO-1-shControl', 'Chemical', '-', (167, 182))	('FLO-1-shAXL', 'Chemical', '-', (208, 219))	('higher', 'PosReg', (25, 31))	('SK-GT-4-shAXL', 'Chemical', '-', (102, 115))	('SK-GT-4-shControl', 'Chemical', '-', (66, 83))
895965	30189359	To investigate whether peripheral localization of lysosomes is required for AXL-dependent cell invasion, anterograde trafficking of lysosomes was inhibited by knocking down of ARL8B expression using RNA interference.	('ARL8B', 'Gene', (176, 181))	('AXL', 'Gene', (76, 79))	('knocking down', 'Var', (159, 172))	('anterograde trafficking of', 'CPA', (105, 131))	('inhibited', 'NegReg', (146, 155))	('ARL8B', 'Gene', '55207', (176, 181))	('AXL', 'Gene', '558', (76, 79))
895967	30189359	Indeed, assessment of LAMP-1-positive lysosomes localization revealed that knockdown of ARL8B expression significantly increased the percentage of cells with perinuclear lysosomes and decreased the fraction of those with peripheral lysosomes in SK-GT-4 cells (P < .001, Figure 3, B and C) and FLO-1 cells (P < .001, Figure 3, D and E) compared to their respective control cells.	('cells with perinuclear lysosomes', 'MPA', (147, 179))	('ARL8B', 'Gene', '55207', (88, 93))	('FLO-1', 'Chemical', '-', (293, 298))	('LAMP-1', 'Gene', '3916', (22, 28))	('knockdown', 'Var', (75, 84))	('decreased', 'NegReg', (184, 193))	('SK-GT-4', 'Chemical', '-', (245, 252))	('ARL8B', 'Gene', (88, 93))	('increased', 'PosReg', (119, 128))	('LAMP-1', 'Gene', (22, 28))
895971	30189359	Conversely, niclosamide significantly increased the perinuclear fraction of lysosomes in SK-GT-4 cells (P < .001, Figure S4, A and B) and in FLO-1 cells (P < .001, Figure S4, C and D) compared to their respective vehicle-treated cells.	('perinuclear fraction of lysosomes', 'MPA', (52, 85))	('FLO-1', 'Chemical', '-', (141, 146))	('niclosamide', 'Chemical', 'MESH:D009534', (12, 23))	('niclosamide', 'Var', (12, 23))	('S4, A and B', 'Gene', '6192', (121, 132))	('SK-GT-4', 'Chemical', '-', (89, 96))	('increased', 'PosReg', (38, 47))
895982	30189359	Moreover, the data revealed that knockdown of AXL expression reduced active cathepsin B secretion by approximately 50% in SK-GT-4 cells (Figure 4C) as well as FLO-1 cells (Figure 4D) in comparison with their respective control cells.	('SK-GT-4', 'Chemical', '-', (122, 129))	('FLO-1', 'Chemical', '-', (159, 164))	('cathepsin B', 'Gene', (76, 87))	('knockdown', 'Var', (33, 42))	('AXL', 'Gene', (46, 49))	('cathepsin B', 'Gene', '1508', (76, 87))	('reduced', 'NegReg', (61, 68))	('AXL', 'Gene', '558', (46, 49))
895984	30189359	As expected, knockdown of AXL expression significantly decreased cathepsin B activity by 50% in SK-GT-4 cells (P < .05, Figure 4E) and by 30% in FLO-1 cells (P < .05, Figure 4F) relative to their respective control cells.	('SK-GT-4', 'Chemical', '-', (96, 103))	('AXL', 'Gene', '558', (26, 29))	('FLO-1', 'Chemical', '-', (145, 150))	('cathepsin B', 'Gene', (65, 76))	('AXL', 'Gene', (26, 29))	('decreased', 'NegReg', (55, 64))	('cathepsin B', 'Gene', '1508', (65, 76))	('activity', 'MPA', (77, 85))	('knockdown', 'Var', (13, 22))
895985	30189359	Notably, our Western blot data showed that knockdown of AXL expression in SK-GT-4 and FLO-1 cells had no significant effect on the expression levels of intracellular cathepsin B proteins (Figure 4, C and D).	('AXL', 'Gene', (56, 59))	('knockdown', 'Var', (43, 52))	('cathepsin B', 'Gene', (166, 177))	('expression levels', 'MPA', (131, 148))	('SK-GT-4', 'Chemical', '-', (74, 81))	('cathepsin B', 'Gene', '1508', (166, 177))	('AXL', 'Gene', '558', (56, 59))	('FLO-1', 'Chemical', '-', (86, 91))
895987	30189359	Therefore, we tested whether cathepsin B is required for AXL-dependent cell invasion by knocking down cathepsin B expression using RNA interference.	('cathepsin B', 'Gene', '1508', (29, 40))	('AXL', 'Gene', '558', (57, 60))	('cathepsin B', 'Gene', '1508', (102, 113))	('cathepsin B', 'Gene', (29, 40))	('knocking', 'Var', (88, 96))	('AXL', 'Gene', (57, 60))	('tested', 'Reg', (14, 20))	('expression', 'MPA', (114, 124))	('cathepsin B', 'Gene', (102, 113))
895989	30189359	The Transwell invasion assay data revealed that knockdown of cathepsin B expression significantly impaired AXL-dependent invasion in SK-GT-4 cells (P < .001, Figure 4, H and I) or FLO-1 cells (P < .001, Figure 4, K and L) relative to their respective control cells.	('SK-GT-4', 'Chemical', '-', (133, 140))	('AXL', 'Gene', (107, 110))	('FLO-1', 'Chemical', '-', (180, 185))	('cathepsin B', 'Gene', '1508', (61, 72))	('impaired', 'NegReg', (98, 106))	('AXL', 'Gene', '558', (107, 110))	('cathepsin B', 'Gene', (61, 72))	('knockdown', 'Var', (48, 57))
895991	30189359	We found that inhibition of cathepsin B activity significantly impaired AXL-dependent invasion in SK-GT-4 cells (P < .001, Figure S5, A, B, G and H) or FLO-1 cells (P < .001, Figure S5, D, E, J and K) relative to their respective vehicle-treated cells.	('AXL', 'Gene', '558', (72, 75))	('FLO-1', 'Chemical', '-', (152, 157))	('AXL', 'Gene', (72, 75))	('SK-GT-4', 'Chemical', '-', (98, 105))	('cathepsin B', 'Gene', (28, 39))	('activity', 'MPA', (40, 48))	('cathepsin B', 'Gene', '1508', (28, 39))	('inhibition', 'Var', (14, 24))	('impaired', 'NegReg', (63, 71))
895996	30189359	We found that pH values of the CM from SK-GT-4-shAXL (pH 6.9) or FLO-1-shAXL (pH 6.8) cells were slightly less acidic than those from SK-GT-4-shControl (pH 6.6) or FLO-1-shControl (pH 6.6) cells (Figure S6).	('SK-GT-4-shAXL', 'Var', (39, 52))	('SK-GT-4-shControl', 'Chemical', '-', (134, 151))	('FLO-1-shAXL', 'Chemical', '-', (65, 76))	('FLO-1-shControl', 'Chemical', '-', (164, 179))	('less', 'NegReg', (106, 110))	('SK-GT-4-shAXL', 'Chemical', '-', (39, 52))	('FLO-1-shAXL', 'Var', (65, 76))	('acidic', 'MPA', (111, 117))
895998	30189359	Consistent with the pHe measurement data (Figure S6), lactate secretion was 25% higher in SK-GT-4-shControl cells (7.06 nmol/mul) relative to SK-GT-4-shAXL cells (5.32 nmol/mul, P < .01, Figure 5A) and 30% higher in FLO-1-shControl cells (6.04 nmol/mul) in comparison with FLO-1-shAXL cells (4.12 nmol/mul, P < .01, Figure 5A).	('SK-GT-4-shControl', 'Chemical', '-', (90, 107))	('SK-GT-4-shControl', 'Var', (90, 107))	('lactate', 'Chemical', 'MESH:D019344', (54, 61))	('SK-GT-4-shAXL', 'Chemical', '-', (142, 155))	('FLO-1-shControl', 'Chemical', '-', (216, 231))	('pHe', 'Chemical', 'MESH:D010649', (20, 23))	('higher', 'PosReg', (80, 86))	('FLO-1-shAXL', 'Chemical', '-', (273, 284))	('lactate secretion', 'MPA', (54, 71))
896006	30189359	Additionally, assessment of cell invasion in vitro revealed that MCT-1 knockdown significantly impaired the invasiveness of SK-GT-4 cells (P < .001, Figure 6, C and D) or FLO-1cells (P < .001, Figure 6, E and F) compared to their respective control cells.	('MCT-1', 'Gene', (65, 70))	('invasiveness of SK-GT-4 cells', 'CPA', (108, 137))	('MCT-1', 'Gene', '6566', (65, 70))	('SK-GT-4', 'Chemical', '-', (124, 131))	('impaired', 'NegReg', (95, 103))	('knockdown', 'Var', (71, 80))	('FLO-1', 'Chemical', '-', (171, 176))
896009	30189359	Furthermore, we found that inhibition of MCT-1 activity significantly impaired the invasiveness of SK-GT-4 cells (P < .001, Figure S7, B and C) as well as FLO-1 cells (P < .001, Figure S7, D and E) compared to their respective control cells without affecting their viability (Figure S7F).	('invasiveness', 'CPA', (83, 95))	('MCT-1', 'Gene', (41, 46))	('S7, B and C', 'Gene', '6264', (131, 142))	('FLO-1', 'Chemical', '-', (155, 160))	('MCT-1', 'Gene', '6566', (41, 46))	('inhibition', 'Var', (27, 37))	('activity', 'MPA', (47, 55))	('SK-GT-4', 'Chemical', '-', (99, 106))	('impaired', 'NegReg', (70, 78))
896011	30189359	We found that the mRNA levels of MCT-1 were significantly lower in SK-GT-4-shAXL (P < .05, Figure 6, G and H) or FLO-1-shAXL (P < .05, Figure 6, I and J) compared to their respective control cells.	('lower', 'NegReg', (58, 63))	('SK-GT-4-shAXL', 'Var', (67, 80))	('MCT-1', 'Gene', (33, 38))	('SK-GT-4-shAXL', 'Chemical', '-', (67, 80))	('FLO-1-shAXL', 'Chemical', '-', (113, 124))	('MCT-1', 'Gene', '6566', (33, 38))
896012	30189359	Moreover, MCT-1 protein expression was also decreased in SK-GT-4-shAXL (Figure 6K) or FLO-1-shAXL (Figure 6L) relative to their respective control cells.	('MCT-1', 'Gene', (10, 15))	('MCT-1', 'Gene', '6566', (10, 15))	('FLO-1-shAXL', 'Chemical', '-', (86, 97))	('SK-GT-4-shAXL', 'Var', (57, 70))	('protein', 'Protein', (16, 23))	('SK-GT-4-shAXL', 'Chemical', '-', (57, 70))	('decreased', 'NegReg', (44, 53))
896015	30189359	In fact, we found that both AKT and NF-kappaB pathways are downregulated in SK-GT-4-shAXL (Figure 7A) and FLO-1-shAXL (Figure 7B) compared to their respective control cells as assessed by Western blotting of p-AKT (S473) and p-NF-kappaB-p65 (S536).	('AKT', 'Gene', (210, 213))	('AKT', 'Gene', (28, 31))	('NF-kappaB', 'Gene', (36, 45))	('SK-GT-4-shAXL', 'Chemical', '-', (76, 89))	('downregulated', 'NegReg', (59, 72))	('NF-kappaB', 'Gene', '4790', (36, 45))	('p65', 'Gene', (237, 240))	('NF-kappaB', 'Gene', '4790', (227, 236))	('AKT', 'Gene', '207', (210, 213))	('AKT', 'Gene', '207', (28, 31))	('p65', 'Gene', '5970', (237, 240))	('NF-kappaB', 'Gene', (227, 236))	('SK-GT-4-shAXL', 'Var', (76, 89))	('FLO-1-shAXL', 'Chemical', '-', (106, 117))
896017	30189359	Indeed, inhibition of either NF-kappaB using BAY 11-7082 (5 muM) or AKT using MK2206 (20 muM) markedly downregulated MCT-1 protein expression in SK-GT-4 cells (Figure 7C) or FLO-1 cells (Figure 7D) relative to their respective control cells.	('NF-kappaB', 'Gene', (29, 38))	('muM', 'Gene', (60, 63))	('MCT-1', 'Gene', (117, 122))	('muM', 'Gene', (89, 92))	('inhibition', 'NegReg', (8, 18))	('SK-GT-4', 'Chemical', '-', (145, 152))	('MK2206', 'Var', (78, 84))	('MCT-1', 'Gene', '6566', (117, 122))	('AKT', 'Gene', '207', (68, 71))	('downregulated', 'NegReg', (103, 116))	('BAY 11-7082', 'Chemical', 'MESH:C434003', (45, 56))	('FLO-1', 'Chemical', '-', (174, 179))	('muM', 'Gene', '56925', (60, 63))	('muM', 'Gene', '56925', (89, 92))	('NF-kappaB', 'Gene', '4790', (29, 38))	('AKT', 'Gene', (68, 71))	('MK2206', 'Chemical', 'MESH:C548887', (78, 84))
896025	30189359	We found that AXL expression is concomitant with a peripheral distribution of lysosomes and knockdown of AXL expression redistributes lysosomes to a more perinuclear location.	('AXL', 'Gene', '558', (105, 108))	('AXL', 'Gene', (14, 17))	('knockdown', 'Var', (92, 101))	('AXL', 'Gene', (105, 108))	('AXL', 'Gene', '558', (14, 17))
896030	30189359	Consistent with Dykes and colleagues, we found that mesenchymal EAC cell lines expressing high levels of AXL display enhanced anterograde lysosome trafficking and that inhibition of lysosome trafficking by knocking down AXL does not seem to reverse EMT (data not shown) but does inhibit EMT-mediated cell invasion.	('anterograde lysosome trafficking', 'MPA', (126, 158))	('AXL', 'Gene', (220, 223))	('AXL', 'Gene', '558', (105, 108))	('EMT-mediated cell invasion', 'CPA', (287, 313))	('EAC', 'Phenotype', 'HP:0011459', (64, 67))	('knocking down', 'Var', (206, 219))	('AXL', 'Gene', '558', (220, 223))	('enhanced', 'PosReg', (117, 125))	('AXL', 'Gene', (105, 108))	('EMT', 'CPA', (249, 252))	('inhibit', 'NegReg', (279, 286))	('high', 'Var', (90, 94))
896031	30189359	Moreover, we showed that inhibition of AXL-dependent peripheral distribution of lysosomes by knocking down of ARL8B expression or using niclosamide strongly impairs cell invasion, demonstrating that AXL-mediated cell invasion requires an effective trafficking of lysosomes to the cell periphery.	('cell invasion', 'CPA', (165, 178))	('expression', 'MPA', (116, 126))	('AXL', 'Gene', '558', (39, 42))	('knocking down', 'Var', (93, 106))	('impairs', 'NegReg', (157, 164))	('ARL8B', 'Gene', (110, 115))	('AXL', 'Gene', '558', (199, 202))	('AXL', 'Gene', (39, 42))	('niclosamide', 'Chemical', 'MESH:D009534', (136, 147))	('inhibition', 'NegReg', (25, 35))	('AXL', 'Gene', (199, 202))	('ARL8B', 'Gene', '55207', (110, 115))
896041	30189359	In fact, our data indicate that MCT-1 is required for the secretion of lactate and cell invasion in AXL-expressing EAC cells, as knockdown or pharmacological inhibition of MCT-1 impairs these effects.	('AXL', 'Gene', (100, 103))	('MCT-1', 'Gene', (172, 177))	('lactate', 'Chemical', 'MESH:D019344', (71, 78))	('secretion of lactate', 'MPA', (58, 78))	('cell invasion', 'CPA', (83, 96))	('knockdown', 'Var', (129, 138))	('impairs', 'NegReg', (178, 185))	('MCT-1', 'Gene', '6566', (172, 177))	('MCT-1', 'Gene', (32, 37))	('AXL', 'Gene', '558', (100, 103))	('EAC', 'Phenotype', 'HP:0011459', (115, 118))	('MCT-1', 'Gene', '6566', (32, 37))
896049	30189359	We and others have observed that acidic pHe appears to transduce an intracellular signaling that activates the anterograde trafficking machinery, thereby enhancing lysosome peripheral distribution and exocytosis.	('anterograde trafficking machinery', 'MPA', (111, 144))	('activates', 'PosReg', (97, 106))	('enhancing', 'PosReg', (154, 163))	('pHe', 'Chemical', 'MESH:D010649', (40, 43))	('lysosome peripheral distribution', 'MPA', (164, 196))	('exocytosis', 'MPA', (201, 211))	('acidic', 'Var', (33, 39))
896064	30189359	Given our current knowledge of the mechanistic role of AXL in regulating cancer cell invasion, our data support future clinical trials to evaluate the therapeutic potential of R428 in highly invasive EAC.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('EAC', 'Disease', (200, 203))	('R428', 'Chemical', '-', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('AXL', 'Gene', '558', (55, 58))	('R428', 'Var', (176, 180))	('EAC', 'Phenotype', 'HP:0011459', (200, 203))	('AXL', 'Gene', (55, 58))
896146	29988148	In clinical samples, ESCC patients with high expression of PAI-1 in CAFs presented a significantly worse progression-free survival.	('high expression', 'Var', (40, 55))	('CAF', 'Gene', (68, 71))	('PAI-1', 'Gene', (59, 64))	('patients', 'Species', '9606', (26, 34))	('CAF', 'Gene', '8850', (68, 71))	('progression-free survival', 'CPA', (105, 130))	('clinical samples', 'Species', '191496', (3, 19))	('worse', 'NegReg', (99, 104))
896206	29988148	Antibodies used in the experiment were as follows: cleaved caspase-3, gammaH2AX, p-ERK1/2, ERK1/2, p-AKT, AKT, PAI-1, and GAPDH.	('AKT', 'Gene', (106, 109))	('caspase-3', 'Gene', '836', (59, 68))	('AKT', 'Gene', '207', (101, 104))	('cleaved', 'Var', (51, 58))	('gammaH2AX', 'Var', (70, 79))	('AKT', 'Gene', (101, 104))	('GAPDH', 'Gene', '2597', (122, 127))	('p-ERK', 'Gene', '9451', (81, 86))	('AKT', 'Gene', '207', (106, 109))	('caspase-3', 'Gene', (59, 68))	('p-ERK', 'Gene', (81, 86))	('gammaH2AX', 'Chemical', '-', (70, 79))	('GAPDH', 'Gene', (122, 127))
896224	29988148	Next, we determined the differences in cytokines secreted from CAFs treated with cisplatin or without cisplatin.	('CAF', 'Gene', (63, 66))	('cisplatin', 'Var', (81, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('cytokines secreted', 'MPA', (39, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('CAF', 'Gene', '8850', (63, 66))
896228	29988148	ELISA (Abcam, ab184863) confirmed that the PAI-1 concentration was much higher in the medium of CM CAFCIS compared with CM CAFCTR (Fig.	('PAI-1', 'Gene', (43, 48))	('concentration', 'MPA', (49, 62))	('CM CAFCIS', 'Var', (96, 105))	('CAFCIS', 'Chemical', '-', (99, 105))	('higher', 'PosReg', (72, 78))	('CAFCTR', 'Chemical', '-', (123, 129))
896250	29988148	Pretreatment with PAI-1 blocked cisplatin-induced phosphorylation of DNA damage and apoptosis markers, such as gammaH2AX and Cleaved Caspase-3 (Fig.	('gammaH2AX', 'Chemical', '-', (111, 120))	('phosphorylation', 'MPA', (50, 65))	('gammaH2AX', 'Var', (111, 120))	('DNA', 'Protein', (69, 72))	('PAI-1', 'Gene', (18, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('Caspase-3', 'Gene', (133, 142))	('Caspase-3', 'Gene', '836', (133, 142))
896270	29988148	After 3 weeks, KYSE-30+ NIH3T3PAI-1 tumors were larger than KYSE-30+ NIH3T3C and KYSE-30 alone tumors (Fig.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('NIH3T3C', 'CellLine', 'CVCL:0594', (69, 76))	('KYSE-30+ NIH3T3PAI-1', 'Var', (15, 35))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('NIH3T3PAI-1', 'CellLine', 'CVCL:0594', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Disease', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
896271	29988148	The preceding experiments suggested that in addition to its tumor-promoting effects, paracrine PAI-1 may influence the tumor response to cisplatin in vivo.	('paracrine', 'Var', (85, 94))	('tumor', 'Disease', (119, 124))	('PAI-1', 'Gene', (95, 100))	('influence', 'Reg', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('tumor', 'Disease', (60, 65))
896272	29988148	To test this hypothesis, we treated mice with tumors derived from KYSE-30 cells plus NIH3T3C or NIH3T3PAI-1 cells with 2 mg/kg cisplatin every 3 days for 3 weeks.	('NIH3T3PAI-1', 'CellLine', 'CVCL:0594', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('NIH3T3C', 'CellLine', 'CVCL:0594', (85, 92))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mice', 'Species', '10090', (36, 40))	('tumors', 'Disease', (46, 52))	('NIH3T3PAI-1', 'Var', (96, 107))	('NIH3T3C', 'Var', (85, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
896273	29988148	The results showed that KYSE-30 + NIH3T3PAI-1 attenuated the tumor inhibitory effects of cisplatin compared with KYSE-30 and KYSE-30 + NIH3T3C (Fig.	('KYSE-30 + NIH3T3PAI-1', 'Var', (24, 45))	('NIH3T3C', 'CellLine', 'CVCL:0594', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('NIH3T3PAI-1', 'CellLine', 'CVCL:0594', (34, 45))	('attenuated', 'NegReg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('tumor', 'Disease', (61, 66))
896279	29988148	To investigate the clinical significance of PAI-1 in patients' tumor tissues, we evaluated the correlation between PAI-1 expression in CAFs and clinicopathological characteristics of patients (Supplementary Table 1) and found that patients with high expression of PAI-1 in CAFs presented a significantly worse progression-free survival (PFS) after cisplatin chemotherapy (Fig.	('tumor', 'Disease', (63, 68))	('high expression', 'Var', (245, 260))	('CAF', 'Gene', (273, 276))	('patients', 'Species', '9606', (231, 239))	('patients', 'Species', '9606', (53, 61))	('CAF', 'Gene', '8850', (135, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (348, 357))	('clinical', 'Species', '191496', (19, 27))	('CAF', 'Gene', '8850', (273, 276))	('PAI-1', 'Gene', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('progression-free survival', 'CPA', (310, 335))	('worse', 'NegReg', (304, 309))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CAF', 'Gene', (135, 138))	('patients', 'Species', '9606', (183, 191))
896297	29988148	demonstrated that treatment-induced damage to the TME promotes prostate cancer therapy resistance through WNT16B.	('prostate cancer', 'Disease', 'MESH:D011471', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('prostate cancer', 'Phenotype', 'HP:0012125', (63, 78))	('prostate cancer', 'Disease', (63, 78))	('WNT16B', 'Gene', (106, 112))	('damage', 'Var', (36, 42))	('promotes', 'PosReg', (54, 62))
896318	29988148	PAI-1 decreased ROS levels, indicating that PAI-1 inhibits oxidative stress to protect tumor cells against cisplatin (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('PAI-1', 'Gene', (0, 5))	('PAI-1', 'Var', (44, 49))	('decreased', 'NegReg', (6, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('tumor', 'Disease', (87, 92))	('oxidative stress', 'Phenotype', 'HP:0025464', (59, 75))	('ROS levels', 'MPA', (16, 26))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ROS', 'Chemical', 'MESH:D017382', (16, 19))	('inhibits', 'NegReg', (50, 58))	('oxidative stress', 'MPA', (59, 75))
896334	28749616	It was determined that underweight and obesity-compared with normal weight-were significantly associated with 73% increased risk and 30% decreased risk of EC, respectively.	('obesity', 'Disease', 'MESH:D009765', (39, 46))	('obesity', 'Disease', (39, 46))	('underweight', 'Var', (23, 34))	('obesity', 'Phenotype', 'HP:0001513', (39, 46))	('decreased', 'NegReg', (137, 146))
896352	28749616	The presence of diabetes was defined when any of the follows was detected; the following criteria; (1) any claim per year for the prescription of antidiabetic medication under ICD-10 codes E10-14, or (2) fasting glucose level >=7 mmol/L(Yang et al., 2016).	('fasting glucose level', 'MPA', (204, 225))	('E10-14', 'Var', (189, 195))	('glucose', 'Chemical', 'MESH:D005947', (212, 219))	('diabetes', 'Disease', (16, 24))	('diabetes', 'Disease', 'MESH:D003920', (16, 24))
896353	28749616	Hypertension was defined when (1) at least one claim per year for the prescription of antihypertensive agent under ICD-10 codes I10-I15, or (2) systolic/diastolic blood pressure >=140/90 mmHg was proven(Yang et al., 2016).	('I10-I15', 'Var', (128, 135))	('Hypertension', 'Disease', 'MESH:D006973', (0, 12))	('Hypertension', 'Disease', (0, 12))	('Hypertension', 'Phenotype', 'HP:0000822', (0, 12))
896381	28749616	Obesity has been associated with the development EAC (Nilsson et al., 2003); because individuals with high BMI are more likely to experience gastro-esophageal reflux, they are more likely to develop Barrett's esophagus, which is a premalignant condition of EAC (Solaymani-Dodaran et al., 2004).	('gastro-esophageal reflux', 'Disease', 'MESH:D005764', (141, 165))	('high', 'Var', (102, 106))	("Barrett's esophagus", 'Disease', (199, 218))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (199, 218))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('experience', 'PosReg', (130, 140))	('esophageal reflux', 'Phenotype', 'HP:0002020', (148, 165))	('develop', 'PosReg', (191, 198))	('gastro-esophageal reflux', 'Disease', (141, 165))
896384	28749616	Smith et al., (2008) has reported the evidence for low BMI or leanness as a factor associated with an increased risk of ESCC in Western and Asian populations.	('leanness', 'Disease', (62, 70))	('leanness', 'Disease', 'MESH:D013851', (62, 70))	('ESCC', 'Disease', (120, 124))	('low BMI', 'Phenotype', 'HP:0045082', (51, 58))	('low', 'Var', (51, 54))
896389	28749616	The effects of this may further be amplified by undernutrition, which is usually associated with insufficiency of micronutrients from improper maintenance of anti-oxidants and immune functions (Venesky et al, 2012; Szuroczki et al., 2012; Lelijveld et al., 2016).	('insufficiency', 'Disease', (97, 110))	('undernutrition', 'Var', (48, 62))	('insufficiency', 'Disease', 'MESH:D000309', (97, 110))
896467	27478386	Overexpression of MAGEA4 mRNA in ESCC tumor was significantly associated with poor overall survival of patients with ESCC.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('overall survival', 'MPA', (83, 99))	('ESCC tumor', 'Disease', 'MESH:D004938', (33, 43))	('poor', 'NegReg', (78, 82))	('MAGEA4', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (103, 111))	('MAGEA4', 'Gene', '4103', (18, 24))	('ESCC tumor', 'Disease', (33, 43))
896651	22504051	For ESCC, EOR/drink-year estimates tended to increase with DPD then decrease (Table 3 and Figure 4).	('EOR/drink-year estimates', 'MPA', (10, 34))	('decrease', 'NegReg', (68, 76))	('DPD', 'Chemical', '-', (59, 62))	('DPD', 'Var', (59, 62))	('increase', 'PosReg', (45, 53))
896658	22504051	Finally, BMI significantly modified drinking patterns (P=0.04), but results were not consistent, with reduced EOR/drink-year estimates for 30+ BMI subjects but only in <5 DPD categories.	('DPD', 'Chemical', '-', (171, 174))	('drinking patterns', 'MPA', (36, 53))	('BMI', 'Var', (9, 12))	('30+ BMI', 'Var', (139, 146))	('reduced', 'NegReg', (102, 109))	('modified', 'Reg', (27, 35))	('EOR/drink-year estimates', 'MPA', (110, 134))
896675	22504051	For <7 DPD, inverse associations with drink-years were greater in those without reflux (P=0.01 for the test of no association) than with reflux (P=0.29), suggesting acid reflux may dissipate any health benefits from lower DPD.	('acid reflux', 'Phenotype', 'HP:0002020', (165, 176))	('DPD', 'Chemical', '-', (222, 225))	('dissipate', 'NegReg', (181, 190))	('DPD', 'Chemical', '-', (7, 10))	('acid reflux', 'Var', (165, 176))
896747	30584357	Sienel et al found that segmentectomy had more lymph node numbers (12 vs 6) and demonstrated significantly better cancer-specific survival (71 vs 48%) and lower local/regional recurrence (16% vs 55%) compared to wedge resection.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('lymph node numbers', 'CPA', (47, 65))	('better', 'PosReg', (107, 113))	('segmentectomy', 'Var', (24, 37))	('more', 'PosReg', (42, 46))	('lower', 'NegReg', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('local/regional recurrence', 'CPA', (161, 186))	('cancer', 'Disease', (114, 120))
896776	30584357	Another reason is that in females, AC is more frequent, EGFR mutation rates are higher, and the comprehensive treatment efficacy is better compared to males.	('EGFR', 'Gene', (56, 60))	('mutation', 'Var', (61, 69))	('higher', 'PosReg', (80, 86))	('EGFR', 'Gene', '1956', (56, 60))
896844	27863415	The DS2-induced apoptosis was significantly attenuated by knockdown of Bax proteins.	('apoptosis', 'CPA', (16, 25))	('Bax proteins', 'Protein', (71, 83))	('knockdown', 'Var', (58, 67))	('attenuated', 'NegReg', (44, 54))	('DS2', 'Chemical', '-', (4, 7))
896845	27863415	Meanwhile, the DS2 treatment caused generation of reactive oxygen species (ROS) in human esophageal cancer cells, but not in HEECs, which was attenuated by pretreatment with ROS scavenger N-acetylcysteine (NAC).	('esophageal cancer', 'Disease', (89, 106))	('ROS', 'Chemical', 'MESH:D017382', (174, 177))	('DS2', 'Chemical', '-', (15, 18))	('DS2', 'Var', (15, 18))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (50, 73))	('human', 'Species', '9606', (83, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('NAC', 'Chemical', 'MESH:D000111', (206, 209))	('ROS', 'Chemical', 'MESH:D017382', (75, 78))	('reactive oxygen species', 'MPA', (50, 73))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (188, 204))
896865	27863415	Figure 1B shows that DS2 inhibits the growth of four human tumor cell lines, including gastric carcinoma cell MGC-803, prostate cancer cell PC-3, as well as ESCC cell lines EC9706 and EC109 in a time- and dose-dependent manner.	('tumor', 'Disease', (59, 64))	('EC109', 'CellLine', 'CVCL:6898', (184, 189))	('gastric carcinoma', 'Disease', 'MESH:D013274', (87, 104))	('DS2', 'Var', (21, 24))	('gastric carcinoma', 'Disease', (87, 104))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (87, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('EC9706', 'CellLine', 'CVCL:E307', (173, 179))	('DS2', 'Chemical', '-', (21, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('prostate cancer', 'Disease', (119, 134))	('human', 'Species', '9606', (53, 58))	('inhibits', 'NegReg', (25, 33))	('growth', 'MPA', (38, 44))	('PC-3', 'CellLine', 'CVCL:0035', (140, 144))
896867	27863415	However, these inhibitions were not observed on proliferation of all four cell lines, with 4 muM oridonin treatment even for 48 h. It appears that DS2 is more potent in inhibiting the growth of human cancer cells than oridonin.	('growth', 'CPA', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('oridonin', 'Chemical', 'MESH:C011959', (97, 105))	('muM', 'Gene', '56925', (93, 96))	('human', 'Species', '9606', (194, 199))	('muM', 'Gene', (93, 96))	('DS2', 'Var', (147, 150))	('oridonin', 'Chemical', 'MESH:C011959', (218, 226))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('DS2', 'Chemical', '-', (147, 150))	('inhibiting', 'NegReg', (169, 179))	('cancer', 'Disease', (200, 206))
896870	27863415	As shown in Figure 2, a dramatic increase of G2/M phase was observed in EC9706 and EC109 cells treated by DS2 at 2, 4 and 8 muM for 12 h, and a decrease in G0/G1 and S phase cells was simultaneously observed.	('EC109', 'CellLine', 'CVCL:6898', (83, 88))	('G2/M phase', 'CPA', (45, 55))	('G0/G1', 'CPA', (156, 161))	('muM', 'Gene', '56925', (124, 127))	('EC9706', 'CellLine', 'CVCL:E307', (72, 78))	('increase', 'PosReg', (33, 41))	('muM', 'Gene', (124, 127))	('DS2', 'Var', (106, 109))	('DS2', 'Chemical', '-', (106, 109))	('S phase cells', 'CPA', (166, 179))
896871	27863415	Moreover, as a cyclin-dependent kinase inhibitor (CDKI), p21 protein levels were observably increased by DS2 in a dose-dependent manner (Figure 2E, 2F).	('CDKI', 'Gene', '1033', (50, 54))	('CDKI', 'Gene', (50, 54))	('p21', 'Gene', '644914', (57, 60))	('DS2', 'Var', (105, 108))	('cyclin-dependent kinase inhibitor', 'Gene', (15, 48))	('DS2', 'Chemical', '-', (105, 108))	('increased', 'PosReg', (92, 101))	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (15, 48))	('p21', 'Gene', (57, 60))
896875	27863415	As shown in the Figure 3A, cells treated by DS2 present typical apoptotic morphologies, such as cell crimp and rounding, as well as nuclear condensation and generation of apoptotic bodies, compared to controls.	('apoptotic bodies', 'CPA', (171, 187))	('DS2', 'Var', (44, 47))	('cell crimp', 'CPA', (96, 106))	('nuclear condensation', 'CPA', (132, 152))	('DS2', 'Chemical', '-', (44, 47))	('apoptotic morphologies', 'CPA', (64, 86))
896878	27863415	2, 4 and 8 muM DS2 treatments of EC9706 cells for 24 hours resulted in a significant increment of FITC-Annexin V+/PI- (early apoptosis) and FITC-Annexin V+/PI+ (late apoptosis) population, compared to untreated cells (Figure 3B, 3C and 3D).	('Annexin V', 'Gene', '308', (103, 112))	('Annexin V', 'Gene', (103, 112))	('increment', 'PosReg', (85, 94))	('muM', 'Gene', (11, 14))	('EC9706', 'Var', (33, 39))	('DS2', 'Chemical', '-', (15, 18))	('Annexin V', 'Gene', '308', (145, 154))	('FITC', 'Chemical', 'MESH:D016650', (98, 102))	('FITC', 'Chemical', 'MESH:D016650', (140, 144))	('Annexin V', 'Gene', (145, 154))	('EC9706', 'CellLine', 'CVCL:E307', (33, 39))	('muM', 'Gene', '56925', (11, 14))
896882	27863415	These results indicated that DS2 selectively caused apoptosis and proliferation inhibition in cancer cell lines without affecting normal cells significantly.	('DS2', 'Var', (29, 32))	('proliferation inhibition', 'CPA', (66, 90))	('DS2', 'Chemical', '-', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('apoptosis', 'CPA', (52, 61))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
896914	27863415	Especially, HAO472, an oridonin analog, was recently advanced into a phase I clinical trial (CTR20150246) in China by Hengrui Medicine Co. Ltd, for the treatment of acute myelogenous leukemia, which further confirms that ent-kaurane diterpenoids and their derivatives are the potential therapeutic agents in human cancers.	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (165, 191))	('ent-kaurane diterpenoids', 'Chemical', '-', (221, 245))	('cancers', 'Disease', 'MESH:D009369', (314, 321))	('acute myelogenous leukemia', 'Disease', (165, 191))	('HAO472', 'Var', (12, 18))	('cancers', 'Disease', (314, 321))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (165, 191))	('leukemia', 'Phenotype', 'HP:0001909', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('oridonin', 'Chemical', 'MESH:C011959', (23, 31))	('human', 'Species', '9606', (308, 313))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (171, 191))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))
896915	27863415	In this study, we investigated DS2, a novel diterpenoid analog, the potential anti-proliferation activity using a few of human cancer cell lines, and found that DS2 displayed more potent anti-proliferation properties in a tumor-selective manner than oridonin.	('diterpenoid', 'Chemical', 'MESH:D004224', (44, 55))	('DS2', 'Chemical', '-', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('anti-proliferation', 'CPA', (187, 205))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('cancer', 'Disease', (127, 133))	('human', 'Species', '9606', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('DS2', 'Var', (161, 164))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('oridonin', 'Chemical', 'MESH:C011959', (250, 258))	('DS2', 'Chemical', '-', (161, 164))
896928	27863415	More interestingly, Bax knockdown in EC9706 cells could afford statistically significant protection against DS2-induced drop of MMP and apoptosis.	('MMP', 'MPA', (128, 131))	('DS2', 'Chemical', '-', (108, 111))	('apoptosis', 'CPA', (136, 145))	('drop', 'MPA', (120, 124))	('Bax', 'Gene', (20, 23))	('knockdown', 'Var', (24, 33))	('EC9706', 'CellLine', 'CVCL:E307', (37, 43))
896930	27863415	It is important to point out, however, that Bax cannot fully explain the cytotoxicity caused by DS2 because the knockdown of Bax confers only partial protection against DS2-caused MMP collapse and apoptosis.	('cytotoxicity', 'Disease', 'MESH:D064420', (73, 85))	('apoptosis', 'CPA', (197, 206))	('Bax', 'Gene', (125, 128))	('MMP collapse', 'CPA', (180, 192))	('DS2', 'Chemical', '-', (169, 172))	('knockdown', 'Var', (112, 121))	('cytotoxicity', 'Disease', (73, 85))	('DS2', 'Chemical', '-', (96, 99))
896935	27863415	In the present study, we also proved that DS2 worked on cell-cycle progression, and was more potential than oridonin.	('DS2', 'Chemical', '-', (42, 45))	('DS2', 'Var', (42, 45))	('oridonin', 'Chemical', 'MESH:C011959', (108, 116))	('cell-cycle progression', 'CPA', (56, 78))
896937	27863415	Consistent with the previous reports, DS2 increased the levels of p21 protein in both the EC9706 and EC109 cells in dose-dependent manners.	('increased', 'PosReg', (42, 51))	('p21', 'Gene', (66, 69))	('EC109', 'CellLine', 'CVCL:6898', (101, 106))	('p21', 'Gene', '644914', (66, 69))	('EC9706', 'CellLine', 'CVCL:E307', (90, 96))	('DS2', 'Var', (38, 41))	('DS2', 'Chemical', '-', (38, 41))
896943	27863415	The present study indicates DS2 results in ROS generation in ESCC cells, and the DS2-induced drop of MMP, apoptosis, and increase of Bax are attenuated by NAC.	('DS2', 'Chemical', '-', (28, 31))	('ROS generation', 'MPA', (43, 57))	('increase', 'PosReg', (121, 129))	('apoptosis', 'CPA', (106, 115))	('ROS', 'Chemical', 'MESH:D017382', (43, 46))	('MMP', 'MPA', (101, 104))	('drop', 'NegReg', (93, 97))	('DS2', 'Chemical', '-', (81, 84))	('Bax', 'MPA', (133, 136))	('DS2-induced', 'Var', (81, 92))	('NAC', 'Chemical', 'MESH:D000111', (155, 158))	('DS2', 'Var', (28, 31))
896944	27863415	Moreover, the growth inhibition caused by DS2 is also completely reversed on cotreatment with ROS scavenger, NAC and GSH in EC9706 and EC109 cells.	('DS2', 'Chemical', '-', (42, 45))	('EC109', 'CellLine', 'CVCL:6898', (135, 140))	('GSH', 'Chemical', '-', (117, 120))	('ROS', 'Chemical', 'MESH:D017382', (94, 97))	('NAC', 'Chemical', 'MESH:D000111', (109, 112))	('EC9706', 'CellLine', 'CVCL:E307', (124, 130))	('growth', 'MPA', (14, 20))	('DS2', 'Var', (42, 45))
896947	27863415	The mechanisms of DS2-inducing apoptosis are, at least partly, through both ROS generation and the Bax-dependent mitochondria mediated pathway.	('DS2', 'Chemical', '-', (18, 21))	('Bax-dependent mitochondria mediated pathway', 'Pathway', (99, 142))	('ROS generation', 'MPA', (76, 90))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('apoptosis', 'CPA', (31, 40))	('DS2-inducing', 'Var', (18, 30))
896958	27863415	EC9706 cell line has been proven to be esophageal carcinoma of the fungating type, which is poorly-differentiated squamous cell carcinoma, and EC109 cell line is well-differentiated.	('EC9706', 'Var', (0, 6))	('EC109', 'CellLine', 'CVCL:6898', (143, 148))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (39, 59))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (39, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 137))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('squamous cell carcinoma', 'Disease', (114, 137))	('esophageal carcinoma', 'Disease', (39, 59))
896978	26905591	Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma This study describes the esophageal cancer methylation landscape and its impact on gene expression.	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('aberrant methylation', 'Var', (44, 64))	('CIMP', 'Chemical', '-', (22, 26))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (140, 165))	('esophageal adenocarcinoma', 'Disease', (140, 165))	('esophageal cancer', 'Disease', (191, 208))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (140, 165))	('methylation', 'Var', (53, 64))
896982	26905591	Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('aberrantly methylated', 'Var', (110, 131))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', (21, 26))
896984	26905591	The most hypermethylated tumors showed worse patient survival.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('hypermethylated', 'Var', (9, 24))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('patient', 'Species', '9606', (45, 52))
896989	26905591	It is well established that tumors arise through the accumulation of genetic and epigenetic aberrations and that these patterns of somatic changes differ from cancer to cancer.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (169, 175))	('tumors', 'Disease', (28, 34))	('epigenetic aberrations', 'Var', (81, 103))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('genetic', 'Var', (69, 76))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
896991	26905591	Aberrant methylation has been implicated in tumor initiation and progression in several cancer types, with hypermethylation of CpG islands and promoter regions associated with transcriptional silencing of tumor suppressor genes.	('cancer', 'Disease', (88, 94))	('silencing', 'NegReg', (192, 201))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('hypermethylation', 'Var', (107, 123))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('implicated', 'Reg', (30, 40))	('Aberrant methylation', 'Var', (0, 20))	('tumor', 'Disease', (205, 210))	('tumor initiation', 'Disease', 'MESH:D009369', (44, 60))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('tumor initiation', 'Disease', (44, 60))
896992	26905591	Considering that epigenetic regulation adds an extra layer of complexity in cancer development, further studies to gain more insight about the landscape of DNA methylation in EAC are required to better understand this complex disease.	('EAC', 'Phenotype', 'HP:0011459', (175, 178))	('epigenetic regulation', 'Var', (17, 38))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('EAC', 'Disease', (175, 178))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
897016	26905591	Methylation differences between 125 tumor and 19 BE were identified for each probe using linear regression (beta value = sample type BE or EAC).	('beta', 'Chemical', '-', (108, 112))	('Methylation', 'Var', (0, 11))	('BE', 'Phenotype', 'HP:0100580', (49, 51))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('BE', 'Phenotype', 'HP:0100580', (133, 135))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('EAC', 'Phenotype', 'HP:0011459', (139, 142))
897034	26905591	Tumors with CpG islands hypermethylation were first described in colon cancer and are referred to as 'CpG island methylator phenotype' (CIMP).	('hypermethylation', 'Var', (24, 40))	('colon cancer', 'Disease', (65, 77))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CIMP', 'Chemical', '-', (136, 140))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
897038	26905591	The highest ranked pathway affected by aberrant methylation, which has not previously been described in EAC, was neurophysiological process dynein-dynactin motor complex in axonal transport in neurons (Supplementary Table 9, available at Carcinogenesis Online), members of this pathway are involved in the neurotrophin-Trk signaling.	('Trk', 'Gene', (319, 322))	('Trk', 'Gene', '4914', (319, 322))	('neurotrophin', 'Gene', (306, 318))	('aberrant methylation', 'Var', (39, 59))	('neurotrophin', 'Gene', '627', (306, 318))	('EAC', 'Phenotype', 'HP:0011459', (104, 107))	('methylation', 'Var', (48, 59))
897039	26905591	The CIMP-like group is characterized by extensive hypermethylation of CpG islands with hypermethylation of CIMP marker genes identified in other studies (Figure 3A).	('CIMP-like', 'Disease', (4, 13))	('CpG islands', 'Protein', (70, 81))	('hypermethylation', 'Var', (50, 66))	('CIMP', 'Chemical', '-', (4, 8))	('CIMP', 'Chemical', '-', (107, 111))
897041	26905591	Extensively hypermethylated EACs tend to have poorer patient survival (Figure 3C and D).	('Extensively hypermethylated', 'Var', (0, 27))	('EAC', 'Phenotype', 'HP:0011459', (28, 31))	('poorer', 'NegReg', (46, 52))	('patient survival', 'CPA', (53, 69))	('patient', 'Species', '9606', (53, 60))
897042	26905591	The most hypermethylated tumors (n = 29, subgroup of the CIMP-like tumors) showed a trend of worse patient survival (P = 0.09) compared with the least hypermethylated (n = 29, subgroup of the non-CIMP tumors) (Figure 3C).	('CIMP-like', 'Disease', (57, 66))	('patient', 'Species', '9606', (99, 106))	('hypermethylated', 'Var', (9, 24))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('worse', 'NegReg', (93, 98))	('CIMP', 'Chemical', '-', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('CIMP', 'Chemical', '-', (196, 200))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Disease', (67, 73))
897043	26905591	The most hypermethylated tumors did show a significantly worse patient survival when compared with all other tumors (n = 94) (P = 0.039) (Figure 3D), an observation that requires further validation in other cohorts.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('hypermethylated', 'Var', (9, 24))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('patient survival', 'CPA', (63, 79))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('patient', 'Species', '9606', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('worse', 'NegReg', (57, 62))
897048	26905591	EAC, stomach and colon cancer formed two broad molecular subgroups, the first group contained CIMP-like tumors with extensive hypermethylation of CpG islands and hypermethylation of CIMP marker genes (Figure 4).	('CIMP', 'Chemical', '-', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('hypermethylation', 'Var', (162, 178))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('EAC', 'Phenotype', 'HP:0011459', (0, 3))	('colon cancer', 'Phenotype', 'HP:0003003', (17, 29))	('colon cancer', 'Disease', 'MESH:D015179', (17, 29))	('stomach', 'Disease', (5, 12))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('CpG islands', 'Protein', (146, 157))	('CIMP', 'Chemical', '-', (182, 186))	('colon cancer', 'Disease', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('EAC', 'Disease', (0, 3))	('hypermethylation', 'Var', (126, 142))
897060	26905591	Although the majority of hypomethylated CpG sites were located outside of CpG islands and in the body of genes, patterns reported previously in other cancers.	('hypomethylated', 'Var', (25, 39))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
897061	26905591	Unsupervised clustering showed good separation between squamous esophagus and BE and EAC, but not between EAC and BE, confirming previous reports that aberrant methylation is an early event in metaplasia-dysplasia-neoplasia progression.	('EAC', 'Phenotype', 'HP:0011459', (85, 88))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('metaplasia-dysplasia-neoplasia', 'Disease', 'MESH:D008679', (193, 223))	('EAC', 'Phenotype', 'HP:0011459', (106, 109))	('neoplasia', 'Phenotype', 'HP:0002664', (214, 223))	('aberrant methylation', 'Var', (151, 171))	('metaplasia-dysplasia-neoplasia', 'Disease', (193, 223))	('BE', 'Phenotype', 'HP:0100580', (78, 80))
897062	26905591	Pathway analysis identified enrichment of known cancer signaling pathways previously described as aberrantly methylated in EAC: cell adhesion, regulation of epithelial-to-mesenchymal transition and TGF and WNT signaling.	('TGF', 'CPA', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('EAC', 'Phenotype', 'HP:0011459', (123, 126))	('aberrantly methylated', 'Var', (98, 119))	('EAC', 'Disease', (123, 126))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cell adhesion', 'CPA', (128, 141))
897065	26905591	Other members of the highest ranked pathway which were aberrantly methylated in EAC are involved in chromosomal segregation and spindle assembly, these include the BUB3, AURKA, DYNC1I1 and DCTN2 and CHFR genes.	('BUB3', 'Gene', (164, 168))	('aberrantly methylated', 'Var', (55, 76))	('DYNC1I1', 'Gene', (177, 184))	('CHFR', 'Gene', (199, 203))	('CHFR', 'Gene', '55743', (199, 203))	('BUB3', 'Gene', '9184', (164, 168))	('EAC', 'Gene', (80, 83))	('AURKA', 'Gene', '6790', (170, 175))	('AURKA', 'Gene', (170, 175))	('DCTN2', 'Gene', '10540', (189, 194))	('DYNC1I1', 'Gene', '1780', (177, 184))	('DCTN2', 'Gene', (189, 194))	('EAC', 'Phenotype', 'HP:0011459', (80, 83))
897066	26905591	CHFR is involved in the mitotic G2-M checkpoint and has been reported hypermethylated in lung cancer, EAC and gastric cancer.	('gastric cancer', 'Disease', (110, 124))	('CHFR', 'Gene', (0, 4))	('CHFR', 'Gene', '55743', (0, 4))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('EAC', 'Phenotype', 'HP:0011459', (102, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('EAC', 'Disease', (102, 105))	('hypermethylated', 'Var', (70, 85))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))
897067	26905591	Here, members of the WNT signaling pathway were also aberrantly methylated, inhibition of WNT signaling has recently been reported to increase microtubule assembly rates, abnormal mitotic spindle formation and induction of aneuploidy and generation of lagging chromosomes.	('aneuploidy', 'Disease', (223, 233))	('methylated', 'Var', (64, 74))	('generation', 'CPA', (238, 248))	('induction', 'Reg', (210, 219))	('WNT', 'Gene', (90, 93))	('aberrantly methylated', 'Var', (53, 74))	('abnormal mitotic spindle formation', 'CPA', (171, 205))	('aneuploidy', 'Disease', 'MESH:D000782', (223, 233))	('inhibition', 'Var', (76, 86))	('increase', 'PosReg', (134, 142))	('microtubule assembly rates', 'MPA', (143, 169))
897069	26905591	Mutations of several mitotic checkpoint proteins have been found in different cancers but are not common.	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', (78, 85))	('found', 'Reg', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
897076	26905591	In gastric cancer, two CIMP subtypes have been identified, one of which was associated with Epstein-Barr virus-positive tumors and the other CIMP group associated with microsatellite instability.	('CIMP', 'Chemical', '-', (141, 145))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('microsatellite instability', 'Var', (168, 194))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CIMP', 'Chemical', '-', (23, 27))	('Epstein-Barr virus-positive tumors', 'Disease', (92, 126))	('associated', 'Reg', (76, 86))	('Epstein-Barr virus-positive tumors', 'Disease', 'MESH:D020031', (92, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('gastric cancer', 'Disease', (3, 17))	('associated', 'Reg', (152, 162))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
897079	26905591	In summary, this study described the methylation landscape of EAC and its impact on gene expression, these data suggest an orchestrated epigenetic deregulation with potentially a much stronger role in EAC carcinogenesis than anticipated.	('EAC', 'Disease', (201, 204))	('carcinogenesis', 'Disease', (205, 219))	('EAC', 'Phenotype', 'HP:0011459', (62, 65))	('epigenetic', 'Var', (136, 146))	('EAC', 'Phenotype', 'HP:0011459', (201, 204))	('carcinogenesis', 'Disease', 'MESH:D063646', (205, 219))
897080	26905591	Methylation patterns revealed two subtypes, one similar to the CIMP phenotype which was potentially associated with worse clinical outcome.	('Methylation', 'Var', (0, 11))	('CIMP', 'Chemical', '-', (63, 67))	('associated', 'Reg', (100, 110))
897146	32332662	Adachi et al have found that the risk of reflux esophagitis in individuals following eradication of H. pylori is lower as compared with those who are never infected.	('infected', 'Disease', (156, 164))	('eradication', 'Var', (85, 96))	('lower', 'NegReg', (113, 118))	('esophagitis', 'Phenotype', 'HP:0100633', (48, 59))	('H. pylori', 'Gene', (100, 109))	('infected', 'Disease', 'MESH:D007239', (156, 164))	('H. pylori', 'Species', '210', (100, 109))	('reflux esophagitis', 'Disease', 'MESH:D005764', (41, 59))	('reflux esophagitis', 'Disease', (41, 59))
897147	32332662	Oikawa et al have suggested that ND1+32656 GG and IL-8-251 T/T alleles may increase the risk of erosive esophagitis, even in an H. pylori-infected Japanese population.	('esophagitis', 'Phenotype', 'HP:0100633', (104, 115))	('ND1+32656 GG', 'Var', (33, 45))	('esophagitis', 'Disease', (104, 115))	('infected', 'Disease', 'MESH:D007239', (138, 146))	('IL-8-251', 'Gene', (50, 58))	('infected', 'Disease', (138, 146))	('increase', 'PosReg', (75, 83))	('esophagitis', 'Disease', 'MESH:D004938', (104, 115))	('H. pylori', 'Species', '210', (128, 137))
897148	32332662	Yucel has reported that the symptoms of gastroesophageal reflux disease improve after eradication of H. pylori in patients with antral gastritis and duodenal ulcers that have hyperacidity.	('gastritis', 'Disease', (135, 144))	('gastroesophageal reflux disease', 'Disease', (40, 71))	('H. pylori', 'Gene', (101, 110))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (40, 63))	('improve', 'PosReg', (72, 79))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (40, 71))	('eradication', 'Var', (86, 97))	('gastritis', 'Disease', 'MESH:D005756', (135, 144))	('H. pylori', 'Species', '210', (101, 110))	('ulcers', 'Disease', 'MESH:D014456', (158, 164))	('gastritis', 'Phenotype', 'HP:0005263', (135, 144))	('patients', 'Species', '9606', (114, 122))	('ulcers', 'Disease', (158, 164))	('duodenal ulcers', 'Phenotype', 'HP:0002588', (149, 164))
897157	31929811	The results revealed that the trials were of sufficient standard to draw reliable conclusions that ginsenoside Rg3 combined with chemotherapy could improve the objective response rate (ORR; OR 2.17, 95% CI 1.72-2.73), disease control rate (DCR; OR 2.83, 95% CI 2.02-3.96), 1-year survival rate (SR; OR = 2.33, 95% CI = 1.24-4.37), Karnofsky Performance Scale (KPS; OR 2.67, 95% CI 1.76-4.03), gastrointestinal dysfunction (OR 0.44, 95% CI 0.31-0.61), and the decline of leucocyte count (OR 0.28, 95% CI 0.21-0.38).	('ginsenoside', 'Var', (99, 110))	('leucocyte count', 'MPA', (470, 485))	('gastrointestinal dysfunction', 'Disease', (393, 421))	('gastrointestinal dysfunction', 'Phenotype', 'HP:0012719', (393, 421))	('disease control rate', 'CPA', (218, 238))	('decline', 'NegReg', (459, 466))	('gastrointestinal dysfunction', 'Disease', 'MESH:D005767', (393, 421))	('improve', 'PosReg', (148, 155))	('objective response rate', 'CPA', (160, 183))	('Karnofsky', 'Disease', (331, 340))
897235	30719422	Ultimately, the following factors were determined to be the negative predictors: Type GE, THTG, D1/D1+, tumor size > 30 mm, Bormann type 3-4, pTNM category greater than Stage IIA.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('TNM', 'Gene', (143, 146))	('D1/D1+', 'Var', (96, 102))	('THTG', 'Chemical', '-', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('TNM', 'Gene', '10178', (143, 146))
897236	30719422	The strongest surgical predictors that were associated with OS were THPG and D2/D2+ lymphadenectomy.	('THPG', 'Disease', (68, 72))	('THPG', 'Chemical', '-', (68, 72))	('OS', 'Chemical', 'MESH:D009992', (60, 62))	('D2/D2+ lymphadenectomy', 'Var', (77, 99))
897329	29342885	Acetaldehyde reacts with DNA inducing modifications, which, if not repaired, can result in mutations and lead to cancer development.	('modifications', 'Var', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lead to', 'Reg', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('result in', 'Reg', (81, 90))	('mutations', 'CPA', (91, 100))	('men', 'Species', '9606', (127, 130))	('Acetaldehyde', 'Chemical', 'MESH:D000079', (0, 12))
897336	29342885	Detrimental exposures in the oral cavity may lead to DNA damage that could result in mutations ultimately leading to the development of cancers of the upper aerodigestive tract (UADT).	('DNA', 'MPA', (53, 56))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('men', 'Species', '9606', (128, 131))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('result in', 'Reg', (75, 84))	('lead to', 'Reg', (45, 52))	('mutations', 'Var', (85, 94))	('UADT', 'Chemical', '-', (178, 182))	('men', 'Species', '9606', (5, 8))	('leading to', 'Reg', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
897353	29342885	Alcohol-derived acetaldehyde exposure in the oral cavity can be influenced by several factors such as, metabolism of oral mucosa cells and salivary glands, including deficiencies of enzymes taking part in ethanol metabolism, metabolism resulting from the oral microbiome, poor oral hygiene, as well as nutritional, psychosocial, and environmental factors (e.g., type of alcoholic beverage consumed, tobacco smoking).	('ethanol', 'Chemical', 'MESH:D000431', (205, 212))	('psychosocial', 'Disease', (315, 327))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('metabolism', 'MPA', (225, 235))	('acetaldehyde', 'Chemical', 'MESH:D000079', (16, 28))	('psychosocial', 'Disease', 'MESH:C535569', (315, 327))	('influenced', 'Reg', (64, 74))	('alcohol', 'Chemical', 'MESH:D000438', (370, 377))	('deficiencies', 'Var', (166, 178))	('tobacco', 'Species', '4097', (399, 406))	('poor oral', 'Phenotype', 'HP:0000160', (272, 281))	('men', 'Species', '9606', (340, 343))
897385	29342885	On the other hand, even if polymorphisms for CYP2E1 are reported, the relationship between the variants and acetaldehyde production has still to be clarified.	('CYP2E1', 'Gene', (45, 51))	('acetaldehyde production', 'MPA', (108, 131))	('acetaldehyde', 'Chemical', 'MESH:D000079', (108, 120))	('variants', 'Var', (95, 103))	('CYP2E1', 'Gene', '1571', (45, 51))
897386	29342885	Since CYP2E1 is involved in ethanol oxidation into acetaldehyde, it may be hypothesized that a more active variant of the enzyme would lead to an increased acetaldehyde production from ethanol.	('involved', 'Reg', (16, 24))	('CYP2E1', 'Gene', '1571', (6, 12))	('ethanol', 'Chemical', 'MESH:D000431', (185, 192))	('variant', 'Var', (107, 114))	('increased acetaldehyde production', 'Phenotype', 'HP:0003533', (146, 179))	('more active', 'PosReg', (95, 106))	('increased', 'PosReg', (146, 155))	('CYP2E1', 'Gene', (6, 12))	('acetaldehyde', 'Chemical', 'MESH:D000079', (51, 63))	('acetaldehyde production from ethanol', 'MPA', (156, 192))	('acetaldehyde', 'Chemical', 'MESH:D000079', (156, 168))	('ethanol', 'Chemical', 'MESH:D000431', (28, 35))
897392	29342885	Studies on the effect of ADH1C polymorphisms on the risk of developing UADT cancers have shown contradictory results.	('ADH1C', 'Gene', '126', (25, 30))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('ADH1C', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('UADT cancers', 'Disease', 'MESH:D006258', (71, 83))	('polymorphisms', 'Var', (31, 44))	('UADT cancers', 'Disease', (71, 83))
897399	29342885	It was found that the presence of the ADH1B*2 allele significantly increases the risk of oropharyngolaryngeal cancers, with an overall 6.68 odds ratio for subjects with the ADH1B*2 polymorphism in comparison with a 1 odds ratio for subjects with the ADH1B*1 polymorphism.	('polymorphism', 'Var', (181, 193))	('ADH1B', 'Gene', (173, 178))	('ADH1B', 'Gene', (250, 255))	('ADH1B', 'Gene', '125', (173, 178))	('oropharyngolaryngeal cancers', 'Disease', 'MESH:D009369', (89, 117))	('ADH1B', 'Gene', '125', (250, 255))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ADH1B', 'Gene', (38, 43))	('presence', 'Var', (22, 30))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('increases', 'PosReg', (67, 76))	('ADH1B', 'Gene', '125', (38, 43))	('oropharyngolaryngeal cancers', 'Disease', (89, 117))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (100, 117))
897401	29342885	Meanwhile, the coexistence of ADH2 and ALDH2 polymorphisms showed to have a synergistic effect on the risk of oropharyngolaryngeal cancers, with an overall odds ratio of 121.77.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('ALDH2', 'Gene', (39, 44))	('oropharyngolaryngeal cancers', 'Disease', (110, 138))	('oropharyngolaryngeal cancers', 'Disease', 'MESH:D009369', (110, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('coexistence', 'Var', (15, 26))	('ADH2', 'Gene', (30, 34))	('polymorphisms', 'Var', (45, 58))	('ADH2', 'Gene', '125', (30, 34))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (121, 138))
897417	29342885	This polymorphism has been shown to result in higher transcription and increased activity of CYP2E1, which may possibly lead to inter-individual differences in ethanol metabolism.	('CYP2E1', 'Gene', '1571', (93, 99))	('higher', 'PosReg', (46, 52))	('lead', 'Reg', (120, 124))	('ethanol', 'Chemical', 'MESH:D000431', (160, 167))	('CYP2E1', 'Gene', (93, 99))	('ethanol metabolism', 'MPA', (160, 178))	('polymorphism', 'Var', (5, 17))	('increased', 'PosReg', (71, 80))	('activity', 'MPA', (81, 89))	('transcription', 'MPA', (53, 66))
897419	29342885	This variant has been shown to enhance transcription of the CYP2E1 gene, but it seems not to be associated with an increased expression or activity of the enzyme.	('enhance', 'PosReg', (31, 38))	('variant', 'Var', (5, 12))	('CYP2E1', 'Gene', '1571', (60, 66))	('CYP2E1', 'Gene', (60, 66))	('transcription', 'MPA', (39, 52))
897429	29342885	On the other hand, an increased risk of cancers of the gastric, nasopharyngeal, hepatocellular, lung, and oral cavity was observed for the carriers of the variant alleles.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('lung', 'Disease', (96, 100))	('cancers of the gastric', 'Disease', (40, 62))	('hepatocellular', 'Disease', (80, 94))	('cancers of the gastric', 'Disease', 'MESH:D013274', (40, 62))	('nasopharyngeal', 'Disease', (64, 78))	('variant', 'Var', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('oral cavity', 'Disease', (106, 117))
897433	29342885	However, this interaction analysis was difficult to perform due to the low frequency of carriers of the CYP2E1 variants.	('CYP2E1', 'Gene', (104, 110))	('CYP2E1', 'Gene', '1571', (104, 110))	('variants', 'Var', (111, 119))
897438	29342885	Results did not show any significant alteration in the risk of developing esophageal cancer in respect to the CYP2E1 polymorphism.	('CYP2E1', 'Gene', '1571', (110, 116))	('polymorphism', 'Var', (117, 129))	('CYP2E1', 'Gene', (110, 116))	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
897442	29342885	This belief would imply individuals with ALDH/ADH polymorphisms exposed to alcohol and heavy drinkers with CYP2E1 polymorphism to have an increased risk of developing cancer of the liver.	('ADH', 'Gene', (46, 49))	('ADH', 'Gene', '10327', (46, 49))	('cancer of the liver', 'Phenotype', 'HP:0002896', (167, 186))	('CYP2E1', 'Gene', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('polymorphism', 'Var', (114, 126))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('CYP2E1', 'Gene', '1571', (107, 113))	('polymorphisms', 'Var', (50, 63))	('alcohol', 'Chemical', 'MESH:D000438', (75, 82))
897443	29342885	However, a study by Yokoyama and colleagues showed no increase in the risk of developing liver cancer in ALDH2 deficient subjects.	('liver cancer', 'Phenotype', 'HP:0002896', (89, 101))	('liver cancer', 'Disease', 'MESH:D006528', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ALDH2', 'Gene', (105, 110))	('liver cancer', 'Disease', (89, 101))	('deficient', 'Var', (111, 120))
897453	29342885	4-MP decreases the rate of ethanol elimination by a competitive inhibition of the oxidation of ethanol to acetaldehyde by ADH.	('ethanol elimination', 'MPA', (27, 46))	('4-MP', 'Var', (0, 4))	('acetaldehyde', 'Chemical', 'MESH:D000079', (106, 118))	('4-MP', 'Chemical', 'MESH:D000077604', (0, 4))	('ADH', 'Gene', (122, 125))	('ADH', 'Gene', '10327', (122, 125))	('oxidation of ethanol to acetaldehyde', 'MPA', (82, 118))	('inhibition', 'NegReg', (64, 74))	('ethanol', 'Chemical', 'MESH:D000431', (95, 102))	('decreases', 'NegReg', (5, 14))	('ethanol', 'Chemical', 'MESH:D000431', (27, 34))
897457	29342885	Another study measuring salivary acetaldehyde levels twice with a 1 h interval in intoxicated Japanese alcohol-dependent men found that acetaldehyde was higher in the saliva of ALDH2*1/*2 than in that of the ALDH2*1/*1 group, providing a possible mechanistic explanation for the increased risk for UADT cancers in this sub-population.	('acetaldehyde', 'Chemical', 'MESH:D000079', (33, 45))	('higher', 'PosReg', (153, 159))	('men', 'Species', '9606', (121, 124))	('UADT cancers', 'Disease', 'MESH:D006258', (298, 310))	('acetaldehyde', 'Chemical', 'MESH:D000079', (136, 148))	('cancers', 'Phenotype', 'HP:0002664', (303, 310))	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (24, 45))	('acetaldehyde', 'MPA', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('alcohol', 'Chemical', 'MESH:D000438', (103, 110))	('UADT cancers', 'Disease', (298, 310))	('ALDH2*1/*2', 'Var', (177, 187))
897460	29342885	Interestingly, the study found that after a brief mouth rinsing with ethanol, the salivary acetaldehyde concentration (measured at different time intervals up to 20 minutes after ethanol discharge) in ALDH2 deficient subjects did not differ from that of subjects with normal ALDH2.	('ethanol', 'Chemical', 'MESH:D000431', (179, 186))	('deficient', 'Var', (207, 216))	('ethanol', 'Chemical', 'MESH:D000431', (69, 76))	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (82, 103))	('ALDH2', 'Gene', (201, 206))	('salivary acetaldehyde concentration', 'MPA', (82, 117))	('acetaldehyde', 'Chemical', 'MESH:D000079', (91, 103))
897467	29342885	There is clear evidence that genetic polymorphisms of ALDH and ADH enzymes are associated to a modulation of acetaldehyde exposure in the oral cavity.	('genetic polymorphisms', 'Var', (29, 50))	('associated', 'Reg', (79, 89))	('acetaldehyde', 'Chemical', 'MESH:D000079', (109, 121))	('ALDH', 'Gene', (54, 58))	('acetaldehyde exposure', 'MPA', (109, 130))	('modulation', 'Reg', (95, 105))	('ADH', 'Gene', (63, 66))	('ADH', 'Gene', '10327', (63, 66))
897469	29342885	Even if a link between salivary acetaldehyde and oral cancer has only been hypothesized, it is important to identify subjects with ALDH/ADH polymorphisms through genetic testing and to make them aware of the potential risks related to alcohol consumption and high acetaldehyde exposure in the oral cavity.	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (23, 44))	('alcohol', 'Chemical', 'MESH:D000438', (235, 242))	('oral cancer', 'Disease', 'MESH:D009062', (49, 60))	('polymorphisms', 'Var', (140, 153))	('ADH', 'Gene', (136, 139))	('ADH', 'Gene', '10327', (136, 139))	('acetaldehyde', 'Chemical', 'MESH:D000079', (264, 276))	('oral cancer', 'Disease', (49, 60))	('high acetaldehyde', 'Phenotype', 'HP:0003533', (259, 276))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('acetaldehyde', 'Chemical', 'MESH:D000079', (32, 44))
897470	29342885	On the other hand, there is currently no knowledge of the role of CYP2E1 polymorphisms on acetaldehyde levels in the oral cavity, and further investigation is needed to cover this gap.	('CYP2E1', 'Gene', (66, 72))	('acetaldehyde levels', 'MPA', (90, 109))	('polymorphisms', 'Var', (73, 86))	('acetaldehyde', 'Chemical', 'MESH:D000079', (90, 102))	('CYP2E1', 'Gene', '1571', (66, 72))
897516	29342885	Results of this study were that salivary acetaldehyde concentration in the presence of L-cysteine was reduced by 59% compared to the placebo tablet, and that after alcohol intake up to two-thirds of acetaldehyde could be removed from saliva by slow and continuous release of L-cysteine.	('L-cysteine', 'Chemical', 'MESH:D003545', (87, 97))	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (32, 53))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('acetaldehyde', 'Chemical', 'MESH:D000079', (199, 211))	('acetaldehyde', 'Chemical', 'MESH:D000079', (41, 53))	('reduced', 'NegReg', (102, 109))	('L-cysteine', 'Chemical', 'MESH:D003545', (275, 285))	('L-cysteine', 'Var', (87, 97))	('salivary acetaldehyde concentration', 'MPA', (32, 67))
897518	29342885	Therefore, results from this study demonstrate how L-cysteine could be used to decrease acetaldehyde exposure in the oral cavity.	('L-cysteine', 'Chemical', 'MESH:D003545', (51, 61))	('decrease acetaldehyde exposure', 'Phenotype', 'HP:0003533', (79, 109))	('acetaldehyde', 'Chemical', 'MESH:D000079', (88, 100))	('acetaldehyde exposure', 'MPA', (88, 109))	('decrease', 'NegReg', (79, 87))	('L-cysteine', 'Var', (51, 61))
897525	29342885	In individuals carrying the normal ALDH and ADH alleles, the production of salivary acetaldehyde has been shown to come mainly from microbial origin than from metabolism of oral mucosa and glandular cells.	('ALDH', 'Gene', (35, 39))	('ADH', 'Gene', (44, 47))	('acetaldehyde', 'Chemical', 'MESH:D000079', (84, 96))	('salivary acetaldehyde', 'Phenotype', 'HP:0003533', (75, 96))	('ADH', 'Gene', '10327', (44, 47))	('alleles', 'Var', (48, 55))	('production of', 'MPA', (61, 74))
897546	29342885	The mechanisms by which streptococci produce a high amount of acetaldehyde from ethanol have been studied by constructing gene deletion mutants of Streptococcus gordonii V2016, which was identified to be able to produce high level of acetaldehyde from ethanol, and analysis of ADHs and ALDHs by zymograms.	('Streptococcus gordonii V2016', 'Disease', (147, 175))	('high level of acetaldehyde', 'Phenotype', 'HP:0003533', (220, 246))	('ethanol', 'Chemical', 'MESH:D000431', (80, 87))	('gene deletion mutants', 'Var', (122, 143))	('Streptococcus gordonii V2016', 'Disease', 'MESH:D011008', (147, 175))	('ADH', 'Gene', (277, 280))	('ethanol', 'Chemical', 'MESH:D000431', (252, 259))	('acetaldehyde', 'Chemical', 'MESH:D000079', (234, 246))	('ADH', 'Gene', '10327', (277, 280))	('mutants', 'Var', (136, 143))	('acetaldehyde', 'Chemical', 'MESH:D000079', (62, 74))	('high amount of acetaldehyde', 'Phenotype', 'HP:0003533', (47, 74))
897577	29342885	N2-ethyl-dG is also found in vivo, potentially due to the reducing action on N2-ethilydene-dG of GSH or vitamin C. Vaca and colleagues first developed a 32P-postlabelling method that was able to detect an increase of N2-ethyl-dG in liver DNA of rats given 10% ethanol in water (1 adduct per 108 nucleosides).	('increase', 'PosReg', (205, 213))	('nucleosides', 'Chemical', 'MESH:D009705', (295, 306))	('ethanol', 'Chemical', 'MESH:D000431', (260, 267))	('GSH', 'Chemical', 'MESH:D005978', (97, 100))	('N2-ethyl-dG', 'Var', (217, 228))	('vitamin C', 'Chemical', 'MESH:D001205', (104, 113))	('32P', 'Chemical', 'MESH:C000615311', (153, 156))	('N2-ethilydene-dG', 'Chemical', '-', (77, 93))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (217, 228))	('water', 'Chemical', 'MESH:D014867', (271, 276))	('rats', 'Species', '10116', (245, 249))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (0, 11))
897585	29342885	The mechanistic role of N2-ethyl-dG in carcinogenesis still remains unclear, but is possibly related to the DNA damage accumulating in the body due to inefficient DNA repair.	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (24, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (39, 53))	('N2-ethyl-dG', 'Var', (24, 35))	('carcinogenesis', 'Disease', (39, 53))
897590	29342885	N2-ethyl-dG strongly blocks replication by DNA polymerase alpha, but is bypassed by DNA polymerase eta by incorporation of dC opposite the lesion.	('DNA polymerase alpha', 'Gene', '5422', (43, 63))	('DNA polymerase alpha', 'Gene', (43, 63))	('blocks', 'NegReg', (21, 27))	('DNA polymerase eta', 'Gene', '5429', (84, 102))	('replication', 'MPA', (28, 39))	('N2-ethyl-dG', 'Var', (0, 11))	('dC', 'Chemical', '-', (123, 125))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (0, 11))	('DNA polymerase eta', 'Gene', (84, 102))
897592	29342885	Finally, another study demonstrated that N2-ethyl-dG in DNA exerts its principal biological activity by blocking translesion DNA synthesis in human cells, resulting in either failure of replication or frameshift deletion mutations.	('blocking', 'NegReg', (104, 112))	('human', 'Species', '9606', (142, 147))	('N2-ethyl-dG', 'Var', (41, 52))	('failure', 'NegReg', (175, 182))	('translesion DNA synthesis', 'MPA', (113, 138))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (41, 52))	('frameshift deletion mutations', 'Var', (201, 230))	('replication', 'MPA', (186, 197))
897593	29342885	On the other hand, N2-ethyl-dGTP incorporation by DNA polymerases was only studied in the presence of the replicative DNA polymerase delta, which only incorporated N2-ethyl-dGTP opposite the dC template, the correct base.	('DNA polymerase delta', 'Gene', (118, 138))	('N2-ethyl-dGTP', 'Chemical', 'MESH:C117229', (19, 32))	('N2-ethyl-dGTP', 'Var', (164, 177))	('dC', 'Chemical', '-', (191, 193))	('N2-ethyl-dGTP', 'Chemical', 'MESH:C117229', (164, 177))	('DNA polymerase delta', 'Gene', '5424', (118, 138))
897595	29342885	For what concerns the oral cavity, the hypothesis that ethanol-derived acetaldehyde exposure may result in DNA damage was supported by recent results showing the presence of N2-ethyl-dG in oral tissues and cells of non-human primates and humans exposed to alcohol.	('humans', 'Species', '9606', (238, 244))	('ethanol', 'Chemical', 'MESH:D000431', (55, 62))	('acetaldehyde', 'Chemical', 'MESH:D000079', (71, 83))	('human', 'Species', '9606', (219, 224))	('alcohol', 'Chemical', 'MESH:D000438', (256, 263))	('N2-ethyl-dG', 'Var', (174, 185))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (174, 185))	('human', 'Species', '9606', (238, 243))	('DNA', 'MPA', (107, 110))	('result', 'Reg', (97, 103))
897602	29342885	In summary, the mutagenic role of N2-ethyl-dG and its carcinogenicity still need to be assessed.	('N2-ethyl-dG', 'Var', (34, 45))	('carcinogenic', 'Disease', 'MESH:D063646', (54, 66))	('carcinogenic', 'Disease', (54, 66))	('N2-ethyl-dG', 'Chemical', 'MESH:C492934', (34, 45))
897610	29342885	However, despite being repaired, CrPdGs adducts have multiple biological effects.	('CrPdGs', 'Chemical', '-', (33, 39))	('CrPdGs', 'Gene', (33, 39))	('adducts', 'Var', (40, 47))
897720	27038040	rs1229984 GG located on ADH1B and rs671 GA located on ALDH2 were significantly associated with ESCC progression (P = 7.93 x 10-4 and P = 1.04 x 10-5).	('rs1229984', 'Mutation', 'rs1229984', (0, 9))	('rs1229984 GG', 'Var', (0, 12))	('SCC', 'Gene', (96, 99))	('ALDH2', 'Gene', (54, 59))	('rs671', 'Mutation', 'rs671', (34, 39))	('rs671 GA', 'Var', (34, 42))	('associated with', 'Reg', (79, 94))	('SCC', 'Gene', '6317', (96, 99))	('ADH1B', 'Gene', (24, 29))	('ADH1B', 'Gene', '125', (24, 29))	('ALDH2', 'Gene', '217', (54, 59))
897721	27038040	Patients with rs1229984 GG, those with rs671 GA, smokers, heavy alcohol drinkers (44 g/day ethanol), and presence of multiple Lugol-voiding lesions (LVLs) developed metachronous SCC more frequently (P = 3.20 x 10-3, 7.00 x 10-4, 4.00 x 10-4, 2.15 x 10-2, and 4.41 x 10-3, respectively), with hazard ratios were 2.84 (95% confidence interval [CI] = 1.43-5.63), 4.57 (95% CI = 1.80-15.42), 4.84 (95% CI = 1.89-16.41), and 2.34 (95% CI = 1.12-5.31), respectively.	('rs671 GA', 'Var', (39, 47))	('metachronous', 'CPA', (165, 177))	('alcohol', 'Chemical', 'MESH:D000438', (64, 71))	('rs1229984', 'Mutation', 'rs1229984', (14, 23))	('SCC', 'Gene', '6317', (178, 181))	('rs1229984 GG', 'Var', (14, 26))	('developed', 'PosReg', (155, 164))	('ethanol', 'Chemical', 'MESH:D000431', (91, 98))	('Patients', 'Species', '9606', (0, 8))	('alcohol drinker', 'Phenotype', 'HP:0030955', (64, 79))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (64, 80))	('rs671', 'Mutation', 'rs671', (39, 44))	('SCC', 'Gene', (178, 181))
897722	27038040	Multiple logistic regression analysis revealed that rs1229984 GG, rs671 GA, and smoking status were independently associated with the risk of developing metachronous SCCs after ESD.	('rs1229984', 'Mutation', 'rs1229984', (52, 61))	('rs1229984 GG', 'Var', (52, 64))	('SCC', 'Gene', (166, 169))	('rs671', 'Mutation', 'rs671', (66, 71))	('associated', 'Reg', (114, 124))	('rs671 GA', 'Var', (66, 74))	('SCC', 'Gene', '6317', (166, 169))
897723	27038040	Moreover, we found cumulative effects of these two genetic factors (rs1229984 GG and rs671 GA) and one environmental factor (tobacco smoking) which appear to increase metachrous SCCs after ESD of ESCC risk approximately nearly 12-fold.	('SCC', 'Gene', '6317', (197, 200))	('metachrous SCCs', 'Disease', (167, 182))	('rs671', 'Mutation', 'rs671', (85, 90))	('SCC', 'Gene', '6317', (178, 181))	('rs1229984', 'Mutation', 'rs1229984', (68, 77))	('rs671 GA', 'Var', (85, 93))	('SCC', 'Gene', (197, 200))	('tobacco', 'Species', '4097', (125, 132))	('metachrous SCCs', 'Disease', 'None', (167, 182))	('increase', 'PosReg', (158, 166))	('SCC', 'Gene', (178, 181))	('rs1229984 GG', 'Var', (68, 80))
897739	27038040	conducted a GWAS of the Japanese population and identified a strong association between ESCC and variants of the rs1229984 and rs671 alleles on the ADH1B and ALDH2 genes 17.	('ALDH2', 'Gene', '217', (158, 163))	('rs671', 'Var', (127, 132))	('ADH1B', 'Gene', '125', (148, 153))	('SCC', 'Gene', '6317', (89, 92))	('rs1229984', 'Mutation', 'rs1229984', (113, 122))	('rs671', 'Mutation', 'rs671', (127, 132))	('variants', 'Var', (97, 105))	('ALDH2', 'Gene', (158, 163))	('rs1229984', 'Var', (113, 122))	('ADH1B', 'Gene', (148, 153))	('SCC', 'Gene', (89, 92))
897750	27038040	We investigated the incidence of metachronous tumors in 117 patients using the Kaplan-Meier method and retrospectively investigated the clinicopathologic features associated with metachronous tumors, including alcohol consumption, smoking, multiple LVLs, history of CRT, rs1229984, and rs671.	('CRT', 'Disease', (266, 269))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('rs1229984', 'Mutation', 'rs1229984', (271, 280))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('patients', 'Species', '9606', (60, 68))	('metachronous tumors', 'Disease', 'MESH:D016609', (33, 52))	('rs671', 'Var', (286, 291))	('rs1229984', 'Var', (271, 280))	('metachronous tumors', 'Disease', 'MESH:D016609', (179, 198))	('rs671', 'Mutation', 'rs671', (286, 291))	('metachronous tumors', 'Disease', (33, 52))	('alcohol', 'Chemical', 'MESH:D000438', (210, 217))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('metachronous tumors', 'Disease', (179, 198))
897757	27038040	To analyze the potential risk factors, such as age (0 = 60 years/<60 years; 1 = >60 years), sex (0 = female, 1 = male), rs671 at ALDH2 (0 = AA+GG, 1 = GA), rs1229984 at ADH1B (0 = AA+AG, 1 = GG), alcohol consumption (0 = never or light drinker, 1 = heavy drinker), smoking (0 = never smoker, 1 = smoker), multiple LVLs (0 = none or <10 small LVLs, 1 = many more than 10 small LVLs or numerous irregularly shaped multiform LVLs 21, and CRT after ESD (0 = none, 1 = treatment); for metachronous tumors, we performed univariate analysis using the Kaplan-Meier method, log-rank test, and Cox's proportional hazards modeling.	('ADH1B', 'Gene', (169, 174))	('rs671', 'Mutation', 'rs671', (120, 125))	('Cox', 'Gene', '1351', (584, 587))	('Cox', 'Gene', (584, 587))	('ALDH2', 'Gene', (129, 134))	('ADH1B', 'Gene', '125', (169, 174))	('metachronous tumors', 'Disease', 'MESH:D016609', (480, 499))	('rs1229984', 'Mutation', 'rs1229984', (156, 165))	('alcohol', 'Chemical', 'MESH:D000438', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (493, 498))	('metachronous tumors', 'Disease', (480, 499))	('rs1229984', 'Var', (156, 165))	('tumors', 'Phenotype', 'HP:0002664', (493, 499))	('ALDH2', 'Gene', '217', (129, 134))
897759	27038040	Multiple logistic regression analysis was used to assess the contributions of confounding factors with the JMP statistical software package (SAS Institute Inc), and the following explanatory variables were included in the analysis: rs671 at ALDH2, rs1229984 at ADH1B, alcohol consumption, and smoking.	('ADH1B', 'Gene', '125', (261, 266))	('rs1229984', 'Mutation', 'rs1229984', (248, 257))	('ALDH2', 'Gene', '217', (241, 246))	('rs1229984', 'Var', (248, 257))	('ALDH2', 'Gene', (241, 246))	('rs671', 'Var', (232, 237))	('ADH1B', 'Gene', (261, 266))	('alcohol', 'Chemical', 'MESH:D000438', (268, 275))	('rs671', 'Mutation', 'rs671', (232, 237))
897762	27038040	The relationship between superficial ESCC and the ADH1B rs1229984 and ALDH2 rs671 alleles are shown in Table 1.	('rs1229984', 'Mutation', 'rs1229984', (56, 65))	('SCC', 'Gene', (38, 41))	('ADH1B', 'Gene', (50, 55))	('ALDH2', 'Gene', '217', (70, 75))	('rs1229984', 'Var', (56, 65))	('ADH1B', 'Gene', '125', (50, 55))	('rs671', 'Var', (76, 81))	('SCC', 'Gene', '6317', (38, 41))	('rs671', 'Mutation', 'rs671', (76, 81))	('ALDH2', 'Gene', (70, 75))
897763	27038040	Among the superficial ESCC patients, 36 (30.8%) had the ALDH2 rs671 allele characterized by the GG genotype, 80 (68.4%) had the GA genotype, and 1 (0.9%) had the AA genotype.	('SCC', 'Gene', '6317', (23, 26))	('rs671', 'Var', (62, 67))	('ALDH2', 'Gene', '217', (56, 61))	('patients', 'Species', '9606', (27, 35))	('rs671', 'Mutation', 'rs671', (62, 67))	('SCC', 'Gene', (23, 26))	('ALDH2', 'Gene', (56, 61))
897764	27038040	Furthermore, of the patients with the ADH1B rs1229984 allele, 31 (26.5%) had the GG genotype, 36 (30.8%) had the GG genotype, and 50 (42.7%) had the AA genotype.	('rs1229984', 'Var', (44, 53))	('ADH1B', 'Gene', (38, 43))	('patients', 'Species', '9606', (20, 28))	('ADH1B', 'Gene', '125', (38, 43))	('rs1229984', 'Mutation', 'rs1229984', (44, 53))
897765	27038040	The following was observed in the healthy controls: ALDH2 rs671: GG, 642 cases (57.1%); GA, 432 cases (38.4%); AA, 51 cases (4.5%) and ADH1B rs1229984: GG, 60 cases (5.3%); GA, 389 cases (34.6%); AA, 676 cases (60.1%).	('rs671', 'Var', (58, 63))	('ADH1B', 'Gene', '125', (135, 140))	('rs1229984', 'Mutation', 'rs1229984', (141, 150))	('ALDH2', 'Gene', '217', (52, 57))	('rs671', 'Mutation', 'rs671', (58, 63))	('rs1229984', 'Var', (141, 150))	('ALDH2', 'Gene', (52, 57))	('ADH1B', 'Gene', (135, 140))
897766	27038040	Replication analysis with an Armitage-trend model revealed that rs671 and rs1229984 were significantly associated with superficial ESCC (P = 5.62 x 10-5 and 1.65 x 10-9, OR = 1.75 and 2.43, respectively; data not shown).	('rs1229984', 'Var', (74, 83))	('rs671', 'Var', (64, 69))	('associated', 'Reg', (103, 113))	('rs671', 'Mutation', 'rs671', (64, 69))	('SCC', 'Gene', (132, 135))	('rs1229984', 'Mutation', 'rs1229984', (74, 83))	('SCC', 'Gene', '6317', (132, 135))
897767	27038040	Futhermore, we analyzed two SNPs, rs671 on ALDH2 and rs1229984 on ADH1B, using allelic, dominant, recessive, and overdominant models adjusted for age and sex.	('ADH1B', 'Gene', '125', (66, 71))	('rs671', 'Var', (34, 39))	('ALDH2', 'Gene', (43, 48))	('rs671', 'Mutation', 'rs671', (34, 39))	('rs1229984', 'Mutation', 'rs1229984', (53, 62))	('rs1229984', 'Var', (53, 62))	('ALDH2', 'Gene', '217', (43, 48))	('ADH1B', 'Gene', (66, 71))
897768	27038040	We found that rs1229984 on ADH1B showed the strongest association with superficial ESCC in the recessive model (allelic model: P = 1.35 x 10-3, OR = 2.05, 95% CI = 1.32-3.2; dominant model: P = 2.35 x 10-2, OR = 1.55; 95% CI = 0.8-3.03; recessive model: P = 7.93 x 10-4, OR = 3.94, 95% CI = 1.76-8.86).	('SCC', 'Gene', '6317', (84, 87))	('rs1229984', 'Mutation', 'rs1229984', (14, 23))	('rs1229984', 'Var', (14, 23))	('ADH1B', 'Gene', (27, 32))	('SCC', 'Gene', (84, 87))	('ADH1B', 'Gene', '125', (27, 32))	('association', 'Interaction', (54, 65))
897769	27038040	Consistent with previous reports 17, we found that rs671 exhibited the strongest association with development of superficial ESCC in the overdominant model (allelic model: P = 8.61 x 10-4, OR = 2.02, 95% CI = 1.32-3.14; dominant model: P = 5.18 x 10-5, OR = 3.99, 95% CI = 2.0-7.97; recessive model: P = 7.17 x 10-1, OR = 1.14, 95% CI = 0.14-9.04; overdominant model: P = 1.04 x 10-5, OR = 4.28, 95% CI = 2.18-8.39).	('rs671', 'Mutation', 'rs671', (51, 56))	('rs671', 'Var', (51, 56))	('SCC', 'Gene', '6317', (126, 129))	('SCC', 'Gene', (126, 129))
897775	27038040	To further validate the incidence of metachronous SCC development after ESD in association with genetic/environmental factors (age, sex, presence of multiple LVLs, alcohol consumption, smoking status, history of CRT for ESCCs treated with ESD, ALDH2 rs671, ADH1B rs1229984; Table S2).	('rs671', 'Mutation', 'rs671', (250, 255))	('SCC', 'Gene', '6317', (50, 53))	('ADH1B', 'Gene', (257, 262))	('SCC', 'Gene', (50, 53))	('ALDH2', 'Gene', '217', (244, 249))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('rs1229984', 'Mutation', 'rs1229984', (263, 272))	('SCC', 'Gene', (221, 224))	('rs1229984', 'Var', (263, 272))	('ALDH2', 'Gene', (244, 249))	('rs671', 'Var', (250, 255))	('SCC', 'Gene', '6317', (221, 224))	('ADH1B', 'Gene', '125', (257, 262))
897776	27038040	Presence of multiple LVLs, heavy alcohol consumption, smoking, rs671 GA, and rs1229984 GG significantly affected the incidence of metachronous tumors on the basis of the univariate analysis performed using the Kaplan-Meier method and log-rank test (P = 3.58 x 10-1, 2.46 x 10-2, 1.20 x 10-3, 1.70 x 10-3, and 1.72 x 10-3, respectively; Fig.	('rs1229984 GG', 'Var', (77, 89))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('alcohol', 'Chemical', 'MESH:D000438', (33, 40))	('metachronous tumors', 'Disease', 'MESH:D016609', (130, 149))	('heavy alcohol consumption', 'Phenotype', 'HP:0030955', (27, 52))	('rs671', 'Mutation', 'rs671', (63, 68))	('rs671 GA', 'Var', (63, 71))	('affected', 'Reg', (104, 112))	('metachronous tumors', 'Disease', (130, 149))	('rs1229984', 'Mutation', 'rs1229984', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
897778	27038040	The hazard ratios were as follows: heavy alcohol consumption, 2.34 (95% CI = 1.12-5.31); smoking, 4.84 (95% CI = 1.89-16.41); ALDH2 rs671 GA, 4.57 (95% CI = 1.80-15.42); and ADH1B rs1229984 GG, 2.84 (95% CI = 1.43-5.63; Table S2).	('ALDH2', 'Gene', '217', (126, 131))	('ALDH2', 'Gene', (126, 131))	('heavy alcohol consumption', 'Phenotype', 'HP:0030955', (35, 60))	('rs1229984', 'Mutation', 'rs1229984', (180, 189))	('ADH1B', 'Gene', (174, 179))	('rs1229984 GG', 'Var', (180, 192))	('alcohol', 'Chemical', 'MESH:D000438', (41, 48))	('ADH1B', 'Gene', '125', (174, 179))	('rs671 GA', 'Var', (132, 140))	('rs671', 'Mutation', 'rs671', (132, 137))
897779	27038040	Multivariate analysis revealed that ADH1B rs1229984 GG, ALDH2 rs671 GA, and smoking status were independently associated with the risk of developing metachronous SCCs after ESD (Table 3).	('rs1229984', 'Mutation', 'rs1229984', (42, 51))	('ADH1B', 'Gene', (36, 41))	('rs1229984 GG', 'Var', (42, 54))	('ALDH2', 'Gene', '217', (56, 61))	('ADH1B', 'Gene', '125', (36, 41))	('associated', 'Reg', (110, 120))	('rs671 GA', 'Var', (62, 70))	('SCC', 'Gene', (162, 165))	('rs671', 'Mutation', 'rs671', (62, 67))	('ALDH2', 'Gene', (56, 61))	('SCC', 'Gene', '6317', (162, 165))
897781	27038040	We found that the risk of metachronous SCC after ESD increased 4.56-fold (95% CI = 1.66-15.9) in patients with two risk factors and 11.95-fold (95% CI = 4.21-42.69) in patients with three risk factors, which was higher than that in patients with none or one risk factors; these findings therefore indicate the cumulative effects of these variants on metachronous SCC susceptibility.	('SCC', 'Gene', '6317', (39, 42))	('SCC', 'Gene', '6317', (363, 366))	('patients', 'Species', '9606', (232, 240))	('variants', 'Var', (338, 346))	('effects', 'Reg', (321, 328))	('patients', 'Species', '9606', (168, 176))	('SCC', 'Gene', (39, 42))	('SCC', 'Gene', (363, 366))	('patients', 'Species', '9606', (97, 105))
897783	27038040	Acetaldehyde, a primary metabolite of ethanol, is considered to be a plausible candidate with carcinogenic effects; in fact, acetaldehyde inhalation was shown to induce various types of tumors, particularly adenocarcinoma and SCC of the nasal mucosa, in animal models 24, 25.	('acetaldehyde', 'Var', (125, 137))	('ethanol', 'Chemical', 'MESH:D000431', (38, 45))	('SCC', 'Gene', (226, 229))	('adenocarcinoma', 'Disease', 'MESH:D000230', (207, 221))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('SCC', 'Gene', '6317', (226, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('acetaldehyde inhalation', 'Phenotype', 'HP:0003533', (125, 148))	('induce', 'PosReg', (162, 168))	('carcinogenic', 'Disease', 'MESH:D063646', (94, 106))	('acetaldehyde', 'Chemical', 'MESH:D000079', (125, 137))	('adenocarcinoma', 'Disease', (207, 221))	('carcinogenic', 'Disease', (94, 106))	('Acetaldehyde', 'Chemical', 'MESH:D000079', (0, 12))
897790	27038040	A previous GWAS identified two novel ESCC susceptibility genes: ADH1B (rs1229984) and ALDH2 (rs671) 17, 26.	('SCC', 'Gene', (38, 41))	('rs671', 'Var', (93, 98))	('ALDH2', 'Gene', '217', (86, 91))	('ADH1B', 'Gene', (64, 69))	('SCC', 'Gene', '6317', (38, 41))	('rs671', 'Mutation', 'rs671', (93, 98))	('rs1229984', 'Mutation', 'rs1229984', (71, 80))	('ADH1B', 'Gene', '125', (64, 69))	('ALDH2', 'Gene', (86, 91))	('rs1229984', 'Var', (71, 80))
897791	27038040	A nonsynonymous SNP (rs1229984) generates two allelic variants: ADH1B*1 (Arg48, G213) and ADH1B*2 (His48, A213).	('rs1229984', 'Mutation', 'rs1229984', (21, 30))	('ADH1B', 'Gene', '125', (90, 95))	('A213', 'Var', (106, 110))	('His48', 'Var', (99, 104))	('rs1229984', 'Var', (21, 30))	('His48', 'Chemical', '-', (99, 104))	('ADH1B', 'Gene', (64, 69))	('Arg48', 'Var', (73, 78))	('G213', 'Var', (80, 84))	('ADH1B', 'Gene', '125', (64, 69))	('Arg48', 'Chemical', '-', (73, 78))	('ADH1B', 'Gene', (90, 95))
897793	27038040	A nonsynonymous SNP (rs671) also generates two allelic variants: ALDH2*1 (Glu504, G1951) and ALDH2*2 (Lys504 A1951).	('Glu504', 'Var', (74, 80))	('rs671', 'Var', (21, 26))	('ALDH2', 'Gene', '217', (65, 70))	('rs671', 'Mutation', 'rs671', (21, 26))	('ALDH2', 'Gene', '217', (93, 98))	('ALDH2', 'Gene', (93, 98))	('Lys504 A1951', 'Var', (102, 114))	('ALDH2', 'Gene', (65, 70))	('G1951', 'Var', (82, 87))
897797	27038040	ADH1B rs1229984 GG allele and ALDH2 rs671 GA allele were found to be risk factors of ESCC.	('rs1229984', 'Mutation', 'rs1229984', (6, 15))	('rs671', 'Mutation', 'rs671', (36, 41))	('SCC', 'Gene', (86, 89))	('rs1229984 GG', 'Var', (6, 18))	('ALDH2', 'Gene', (30, 35))	('SCC', 'Gene', '6317', (86, 89))	('ADH1B', 'Gene', (0, 5))	('ADH1B', 'Gene', '125', (0, 5))	('risk', 'Reg', (69, 73))	('rs671 GA', 'Var', (36, 44))	('ALDH2', 'Gene', '217', (30, 35))
897804	27038040	ADH1B rs1229984 GG, ALDH2 rs671 GA, and smoking status, but not heavy alcohol consumption, were independently associated with the risk of developing metachronous SCCs after ESD in this study.	('ALDH2', 'Gene', '217', (20, 25))	('rs1229984', 'Mutation', 'rs1229984', (6, 15))	('rs1229984 GG', 'Var', (6, 18))	('rs671', 'Mutation', 'rs671', (26, 31))	('rs671 GA', 'Var', (26, 34))	('ALDH2', 'Gene', (20, 25))	('ADH1B', 'Gene', (0, 5))	('associated', 'Reg', (110, 120))	('SCC', 'Gene', (162, 165))	('alcohol', 'Chemical', 'MESH:D000438', (70, 77))	('ADH1B', 'Gene', '125', (0, 5))	('heavy alcohol consumption', 'Phenotype', 'HP:0030955', (64, 89))	('SCC', 'Gene', '6317', (162, 165))
897805	27038040	We believe that this is due to the genetic risk factors: rs1229984 GG allele and rs671 GA allele had a stronger influence and closer association, which would have diminished the effects of alcohol consumption.	('rs671', 'Mutation', 'rs671', (81, 86))	('association', 'Interaction', (133, 144))	('rs671 GA', 'Var', (81, 89))	('rs1229984', 'Mutation', 'rs1229984', (57, 66))	('alcohol', 'Chemical', 'MESH:D000438', (189, 196))	('rs1229984', 'Var', (57, 66))
897889	27366032	Smoking has been associated with risk of specific molecular phenotypes of colorectal cancer, including tumors characterized as microsatellite instability high or CIMP high or with BRAF mutations.	('BRAF', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('CIMP high', 'Var', (162, 171))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('BRAF', 'Gene', '673', (180, 184))	('colorectal cancer', 'Disease', (74, 91))	('CIMP', 'Chemical', '-', (162, 166))	('microsatellite instability', 'MPA', (127, 153))
897897	26039063	Perturbation of this process can give rise to numerous human diseases, such as atopic dermatitis, in which antigenic stimuli can penetrate the weakened epithelial barrier to initiate the allergic inflammatory cascade.	('give rise', 'Reg', (33, 42))	('atopic dermatitis', 'Disease', 'MESH:D003876', (79, 96))	('human', 'Species', '9606', (55, 60))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (79, 96))	('dermatitis', 'Phenotype', 'HP:0011123', (86, 96))	('atopic dermatitis', 'Disease', (79, 96))	('initiate', 'Reg', (174, 182))	('Perturbation', 'Var', (0, 12))
897907	26039063	Altered keratin distribution and/or function have been associated with multiple atopic epithelial barrier disorders such as atopic dermatitis (AD).	('keratin', 'Protein', (8, 15))	('associated', 'Reg', (55, 65))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (124, 141))	('Altered', 'Var', (0, 7))	('dermatitis', 'Phenotype', 'HP:0011123', (131, 141))	('AD', 'Disease', 'MESH:D000544', (143, 145))	('AD', 'Phenotype', 'HP:0001047', (143, 145))	('AD', 'Disease', (143, 145))	('atopic dermatitis', 'Disease', 'MESH:D003876', (124, 141))	('function', 'MPA', (36, 44))	('atopic dermatitis', 'Disease', (124, 141))
897909	26039063	Moreover, mutations in KRT5 and/or KRT14 are known to cause epidermolysis bullosa simplex (EBS), which is marked by skin blisters and cell fragility of basal keratinocytes.	('skin blisters', 'Phenotype', 'HP:0008066', (116, 129))	('cause', 'Reg', (54, 59))	('KRT5', 'Gene', (23, 27))	('KRT14', 'Gene', (35, 40))	('epidermolysis bullosa simplex', 'Disease', (60, 89))	('KRT5', 'Gene', '3852', (23, 27))	('KRT14', 'Gene', '3861', (35, 40))	('blisters', 'Phenotype', 'HP:0008066;HP:0200037', (121, 129))	('mutations', 'Var', (10, 19))
897915	26039063	Moreover, we show that the presence of IL-13 in the ALI culture system induces an overlapping gene signature and the disease-associated pathways observed in the inflamed esophageal mucosa of patients with EoE.	('ALI', 'Chemical', '-', (52, 55))	('EoE', 'Disease', (205, 208))	('patients', 'Species', '9606', (191, 199))	('EoE', 'Phenotype', 'HP:0410151', (205, 208))	('IL-13', 'Gene', (39, 44))	('presence', 'Var', (27, 35))	('induces', 'Reg', (71, 78))	('IL-13', 'Gene', '3596', (39, 44))
897953	26039063	Overexpression of GFP-tagged keratin 78 in EPC2-hTERT cells showed a filamentous network of KRT78 distribution throughout the cytoplasm (Fig 3C) reflecting that of other type II keratins.	('KRT78', 'Gene', (92, 97))	('KRT78', 'Gene', '196374', (92, 97))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (43, 53))	('type II keratin', 'Gene', '144501', (170, 185))	('keratin 78', 'Gene', (29, 39))	('filamentous', 'MPA', (69, 80))	('GFP-tagged', 'Var', (18, 28))	('keratin 78', 'Gene', '196374', (29, 39))	('type II keratin', 'Gene', (170, 185))
897954	26039063	Indeed, using the Human Intermediate Filament Mutation Database (http://www.interfil.org), domain structure analysis showed that KRT78 has a canonical keratin structure consisting of a head region (amino acids 1-111), coiled-coil region (amino acids 112-424), and tail region (amino acids 425-520) (Fig 4A).	('KRT78', 'Gene', '196374', (129, 134))	('KRT78', 'Gene', (129, 134))	('amino acids 425-520', 'Var', (277, 296))	('Human', 'Species', '9606', (18, 23))	('coiled-coil', 'MPA', (218, 229))	('amino acids 112-424', 'Var', (238, 257))
898000	26039063	Interestingly, mice deficient in keratin 4 (Krt4 -/-) exhibit basal cell hyperplasia in the esophagus, a key histopathological change associated with EoE, as well as a disrupted esophageal barrier that was susceptible to bacterial invasion.	('hyperplasia', 'Disease', (73, 84))	('EoE', 'Disease', (150, 153))	('EoE', 'Phenotype', 'HP:0410151', (150, 153))	('keratin', 'Protein', (33, 40))	('Krt4', 'Gene', '16682', (44, 48))	('deficient', 'Var', (20, 29))	('hyperplasia', 'Disease', 'MESH:D006965', (73, 84))	('Krt4', 'Gene', (44, 48))	('mice', 'Species', '10090', (15, 19))
898027	30825353	In conclusion, poor prognosis in EAC overexpressing SCCA1 is due to reduced tumor chemosensitivity as well as intratumoral immunity impairment, likely induced by this molecule.	('immunity impairment', 'Phenotype', 'HP:0002721', (123, 142))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('SCCA1', 'Gene', (52, 57))	('overexpressing', 'Var', (37, 51))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('SCCA1', 'Gene', '6317', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('reduced', 'NegReg', (68, 75))	('tumoral', 'Disease', (115, 122))	('tumoral', 'Disease', 'MESH:D009369', (115, 122))
898053	30825353	The primary Abs, murine IgG1, specific for the CD80, CD4, CD8, programmed death ligand-1 (PD-L1), PD-L2, and CD107 (Table S1) were added and incubated for 30 minutes at room temperature.	('CD80', 'Gene', (47, 51))	('CD8', 'Gene', (58, 61))	('CD8', 'Gene', (47, 50))	('PD-L1', 'Gene', '29126', (90, 95))	('PD-L2', 'Gene', (98, 103))	('PD-L2', 'Gene', '80380', (98, 103))	('CD80', 'Gene', '941', (47, 51))	('CD8', 'Gene', '925', (47, 50))	('CD8', 'Gene', '925', (58, 61))	('murine', 'Species', '10090', (17, 23))	('CD4', 'Gene', (53, 56))	('CD4', 'Gene', '920', (53, 56))	('CD107', 'Var', (109, 114))	('PD-L1', 'Gene', (90, 95))
898091	30825353	Tumor SCCA1 was higher in patients receiving docetaxel (P = .003) (Figure 3A), whereas SCCA1-IgM and free SCCA1 levels in serum were not significantly different in patients receiving docetaxel (Table S3).	('docetaxel', 'Var', (45, 54))	('higher', 'PosReg', (16, 22))	('SCCA1', 'Gene', (87, 92))	('docetaxel', 'Chemical', 'MESH:D000077143', (45, 54))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SCCA1', 'Gene', '6317', (106, 111))	('SCCA1', 'Gene', '6317', (6, 11))	('docetaxel', 'Chemical', 'MESH:D000077143', (183, 192))	('patients', 'Species', '9606', (26, 34))	('SCCA1', 'Gene', '6317', (87, 92))	('SCCA1', 'Gene', (106, 111))	('patients', 'Species', '9606', (164, 172))	('SCCA1', 'Gene', (6, 11))
898119	30825353	We observed that OE33 cells, overexpressing SCCA1, were more resistant to cell death than the control OE19 cells after treatment with epirubicin, docetaxel, and cisplatin, whereas cell viability was not affected by treatment with and 5-FU.	('cell death', 'CPA', (74, 84))	('overexpressing', 'Var', (29, 43))	('docetaxel', 'Chemical', 'MESH:D000077143', (146, 155))	('SCCA1', 'Gene', '6317', (44, 49))	('5-FU', 'Chemical', 'MESH:D005472', (234, 238))	('resistant', 'CPA', (61, 70))	('SCCA1', 'Gene', (44, 49))	('epirubicin', 'Chemical', 'MESH:D015251', (134, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (161, 170))
898120	30825353	Moreover, OE19 cells transfected to overexpress SCCA1 were more resistant to docetaxel treatment than OE33 expressing SCCA1 levels approximately 200 times less.	('SCCA1', 'Gene', (118, 123))	('SCCA1', 'Gene', '6317', (48, 53))	('resistant to docetaxel treatment', 'MPA', (64, 96))	('docetaxel', 'Chemical', 'MESH:D000077143', (77, 86))	('overexpress', 'Var', (36, 47))	('SCCA1', 'Gene', (48, 53))	('SCCA1', 'Gene', '6317', (118, 123))
898123	30825353	Thus, a reduced chemosensitivity in patients with high levels of SCCA1 could explain, at least in part, the poor prognosis of these patients.	('patients', 'Species', '9606', (36, 44))	('reduced', 'NegReg', (8, 15))	('SCCA1', 'Gene', '6317', (65, 70))	('high levels', 'Var', (50, 61))	('patients', 'Species', '9606', (132, 140))	('SCCA1', 'Gene', (65, 70))	('chemosensitivity', 'MPA', (16, 32))
898128	30825353	All these data indicate the presence of a direct or an indirect effect of high levels of SCCA1 expression on the immune surveillance mechanisms, resulting in intratumoral immunity impairment that might concur with the worse prognosis of patients with high SCCA1 expression.	('immunity impairment', 'Phenotype', 'HP:0002721', (171, 190))	('tumoral', 'Disease', 'MESH:D009369', (163, 170))	('SCCA1', 'Gene', '6317', (256, 261))	('SCCA1', 'Gene', '6317', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('SCCA1', 'Gene', (256, 261))	('tumoral', 'Disease', (163, 170))	('high levels', 'Var', (74, 85))	('SCCA1', 'Gene', (89, 94))	('patients', 'Species', '9606', (237, 245))
898148	28388691	Patients with high MYL9 expression in the tumor cells had poorer overall survival (OS) and recurrence-free survival.	('recurrence-free survival', 'CPA', (91, 115))	('overall', 'MPA', (65, 72))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('expression', 'MPA', (24, 34))	('poorer', 'NegReg', (58, 64))	('OS', 'Chemical', '-', (83, 85))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('MYL9', 'Gene', (19, 23))	('MYL9', 'Gene', '10398', (19, 23))
898149	28388691	Multivariate analysis revealed that high MYL9 expression in tumor cells was an independent and significant risk factor affecting OS after curative treatment (hazard ratio = 2.254, 95% confidence interval = 1.347-3.771, p = 0.002).	('tumor', 'Disease', (60, 65))	('MYL9', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('MYL9', 'Gene', '10398', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('OS', 'Chemical', '-', (129, 131))	('expression', 'MPA', (46, 56))	('high', 'Var', (36, 40))
898165	28388691	On the other hand, high MYL9 expression was significantly associated with late tumor-node-metastasis (TNM) stage and lymphatic metastasis in non-small cell lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('high', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (145, 167))	('associated', 'Reg', (58, 68))	('MYL9', 'Gene', (24, 28))	('lymphatic metastasis', 'CPA', (117, 137))	('MYL9', 'Gene', '10398', (24, 28))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (141, 167))	('tumor-node-metastasis', 'Disease', (79, 100))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (79, 100))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('expression', 'MPA', (29, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('non-small cell lung cancer', 'Disease', (141, 167))
898176	28388691	The ESCC cell lines KYSE30, KYSE140, KYSE180, KYSE410, KYSE510, and KYSE520 were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen, the German Resource Center for Biological Material.	('von', 'Disease', (113, 116))	('KYSE520', 'Var', (68, 75))	('KYSE410', 'Var', (46, 53))	('KYSE140', 'Var', (28, 35))	('von', 'Disease', 'MESH:D014842', (113, 116))	('KYSE510', 'Var', (55, 62))	('KYSE180', 'Var', (37, 44))
898194	28388691	MYL9 expression levels in the nine ESCC cell lines (KYSE30, KYSE180, KYSE140, KYSE410, KYSE510, KYSE520, HKESC1, EC18, EC109) were assessed and compared with NE1 cells by western blotting and qPCR.	('KYSE410', 'Var', (78, 85))	('MYL9', 'Gene', (0, 4))	('KYSE520', 'Var', (96, 103))	('MYL9', 'Gene', '10398', (0, 4))	('KYSE140', 'Var', (69, 76))	('HKESC1', 'CellLine', 'CVCL:D568', (105, 111))	('KYSE510', 'Var', (87, 94))	('EC109', 'CellLine', 'CVCL:6898', (119, 124))
898204	28388691	Therefore, we focused on aberrant MYL9 expression in tumor cells to investigate its clinical value.	('aberrant', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('MYL9', 'Gene', (34, 38))	('MYL9', 'Gene', '10398', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('clinical', 'Species', '191496', (84, 92))	('tumor', 'Disease', (53, 58))
898218	28388691	Kaplan-Meier analysis and the log-rank test showed that patients with high MYL9 expression had shorter RFS (p = 0.004, Fig 4A) and worse OS (p = 0.001, Fig 4B) than patients with low MYL9 expression.	('patients', 'Species', '9606', (56, 64))	('MYL9', 'Gene', (75, 79))	('RFS', 'MPA', (103, 106))	('MYL9', 'Gene', '10398', (75, 79))	('MYL9', 'Gene', (183, 187))	('patients', 'Species', '9606', (165, 173))	('MYL9', 'Gene', '10398', (183, 187))	('high', 'Var', (70, 74))	('shorter', 'NegReg', (95, 102))	('OS', 'Chemical', '-', (137, 139))
898219	28388691	The 5-year RFS and OS rates for the patients with high MYL9 expression were 50% and 64%, respectively, whereas the rates were 43% and 50%, respectively, for the patients with low MYL9 expression.	('MYL9', 'Gene', (179, 183))	('patients', 'Species', '9606', (36, 44))	('expression', 'Var', (60, 70))	('MYL9', 'Gene', '10398', (179, 183))	('MYL9', 'Gene', (55, 59))	('patients', 'Species', '9606', (161, 169))	('OS', 'Chemical', '-', (19, 21))	('MYL9', 'Gene', '10398', (55, 59))	('RFS', 'CPA', (11, 14))	('high', 'Var', (50, 54))
898223	28388691	In this study, we reveal via IHC the frequent aberrant expression of MYL9 in ESCC tissues.	('aberrant', 'Var', (46, 54))	('MYL9', 'Gene', '10398', (69, 73))	('MYL9', 'Gene', (69, 73))
898235	28388691	In MDA-MB-231 cells, MYL9 depletion did not affect cell cycle progression or induce cell death, but significantly reduced invasiveness.	('depletion', 'Var', (26, 35))	('MYL9', 'Gene', (21, 25))	('death', 'Disease', 'MESH:D003643', (89, 94))	('reduced', 'NegReg', (114, 121))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (3, 13))	('death', 'Disease', (89, 94))	('MYL9', 'Gene', '10398', (21, 25))	('invasiveness', 'CPA', (122, 134))
898238	28388691	Ser19 and/or Ter18 phosphorylation of MYL9 is crucial for its activation.	('Ter18 phosphorylation', 'Var', (13, 34))	('Ser19', 'Var', (0, 5))	('MYL9', 'Gene', (38, 42))	('MYL9', 'Gene', '10398', (38, 42))	('Ser19', 'Chemical', '-', (0, 5))
898240	28388691	Although treatment protocols that reduce MYL9 phosphorylation are beneficial for reducing the progression of invasion in hepatoma and ovarian cancer, dephosphorylation of myosin regulatory light chain (MYL9) by Y27632 induced an invasive phenotype in low invasive lung adenocarcinoma cell lines.	('ovarian cancer', 'Phenotype', 'HP:0100615', (134, 148))	('MYL9', 'Gene', (202, 206))	('MYL9', 'Gene', (41, 45))	('dephosphorylation of myosin', 'Disease', (150, 177))	('Y27632', 'Var', (211, 217))	('induced', 'Reg', (218, 225))	('MYL9', 'Gene', '10398', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('MYL9', 'Gene', '10398', (41, 45))	('invasive phenotype', 'CPA', (229, 247))	('hepatoma and ovarian cancer', 'Disease', 'MESH:D006528', (121, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('dephosphorylation of myosin', 'Disease', 'MESH:C564253', (150, 177))	('low invasive lung adenocarcinoma', 'Disease', (251, 283))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (264, 283))	('low invasive lung adenocarcinoma', 'Disease', 'MESH:D000077192', (251, 283))
898248	28388691	Inhibiting RhoA and ROCK activity partially restoreds osteogenic differentiation by inhibiting Hh-RhoA-Cofilin/MYL9 signaling.	('RhoA', 'Gene', (11, 15))	('osteogenic differentiation', 'CPA', (54, 80))	('Inhibiting', 'Var', (0, 10))	('RhoA', 'Gene', '387', (98, 102))	('MYL9', 'Gene', '10398', (111, 115))	('Cofilin', 'Gene', (103, 110))	('RhoA', 'Gene', '387', (11, 15))	('ROCK', 'Gene', (20, 24))	('RhoA', 'Gene', (98, 102))	('restoreds', 'PosReg', (44, 53))	('ROCK', 'Gene', '6093', (20, 24))	('MYL9', 'Gene', (111, 115))	('inhibiting', 'NegReg', (84, 94))	('Cofilin', 'Gene', '1072', (103, 110))
898252	28388691	Patients with high MYL9 expression in tumor cells have poor OS and recurrence-free survival.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('MYL9', 'Gene', '10398', (19, 23))	('OS', 'Chemical', '-', (60, 62))	('MYL9', 'Gene', (19, 23))	('recurrence-free survival', 'CPA', (67, 91))
898283	27575869	It is a complex genetic disease, and its progression requires the successive accumulation of several gene mutations including activated KRAS and inactivated CDKN2A, TP53, and SMAD4, which are already detectable in the premalignant lesions.	('SMAD4', 'Gene', '4089', (175, 180))	('KRAS', 'Gene', '3845', (136, 140))	('TP53', 'Gene', (165, 169))	('SMAD4', 'Gene', (175, 180))	('CDKN2A', 'Gene', (157, 163))	('KRAS', 'Gene', (136, 140))	('mutations', 'Var', (106, 115))	('CDKN2A', 'Gene', '1029', (157, 163))	('genetic disease', 'Disease', (16, 31))	('TP53', 'Gene', '7157', (165, 169))	('genetic disease', 'Disease', 'MESH:D030342', (16, 31))
898290	27575869	In contrast, the tumor suppressor miRNAs, miR-34 and miR-200a, are decreased in PDAC, and their restoration leads to inhibition of cancer properties.42, 43  Cancer stem cells are related to difficulties of targeting mutant KRAS in PDAC.44 Although KRAS ablation leads to tumor regression, a small population of PDAC cells acquired resistance to it and showed a high tumorigenic capacity with high CD44 and CD133 expressions.44 The CSC-like cells that survived KRAS ablation had high mitochondrial activity and showed high sensitivity to oxidative phosphorylation inhibitors, leading to inhibition of tumorigenesis.	('tumor', 'Disease', (600, 605))	('miR', 'Gene', '220972', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('ablation', 'Var', (465, 473))	('inhibition', 'NegReg', (586, 596))	('tumor', 'Disease', 'MESH:D009369', (600, 605))	('high', 'PosReg', (478, 482))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('miR-200a', 'Gene', (53, 61))	('miR', 'Gene', (53, 56))	('mitochondrial activity', 'MPA', (483, 505))	('KRAS', 'Gene', '3845', (248, 252))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', '220972', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (600, 605))	('tumor', 'Disease', (366, 371))	('KRAS', 'Gene', '3845', (460, 464))	('KRAS', 'Gene', (248, 252))	('miR-34', 'Gene', '407040', (42, 48))	('tumor', 'Disease', (17, 22))	('KRAS', 'Gene', '3845', (223, 227))	('sensitivity', 'MPA', (522, 533))	('tumor', 'Disease', (271, 276))	('miR', 'Gene', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('miR', 'Gene', (42, 45))	('KRAS', 'Gene', (460, 464))	('miR-200a', 'Gene', '406983', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('cancer', 'Disease', (131, 137))	('KRAS', 'Gene', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (157, 163))	('miR-34', 'Gene', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
898300	27575869	For example, EpCAM activates the Wnt signals, and CD24 is a STAT3-mediated Nanog regulator, which leads to cell cycle signaling.47, 54 The class IV intermediate filament protein nestin regulates cellular plasticity and the tumorigenesis of liver CSCs in a p53-dependent manner.	('EpCAM', 'Gene', '4072', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('signaling.47', 'Var', (118, 130))	('regulates', 'Reg', (185, 194))	('EpCAM', 'Gene', (13, 18))	('Nanog', 'Gene', '79923', (75, 80))	('STAT3', 'Gene', '6774', (60, 65))	('Nanog', 'Gene', (75, 80))	('p53', 'Gene', (256, 259))	('p53', 'Gene', '7157', (256, 259))	('STAT3', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cellular plasticity', 'CPA', (195, 214))
898305	27575869	Many genetic alterations are involved in esophageal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('esophageal', 'Disease', (41, 51))	('genetic alterations', 'Var', (5, 24))	('esophageal', 'Disease', 'MESH:D004941', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('involved', 'Reg', (29, 37))
898306	27575869	Inhibition of PIK3CA reduces the proliferation of CSCs in ESCC.	('proliferation of CSCs', 'CPA', (33, 54))	('Inhibition', 'Var', (0, 10))	('PIK3CA', 'Gene', (14, 20))	('ESCC', 'Disease', (58, 62))	('PIK3CA', 'Gene', '5290', (14, 20))	('reduces', 'NegReg', (21, 28))
898307	27575869	Phosphatidylinositol-3 kinase inhibition was more effective in cells harboring a PIK3CA mutation than in control cells.	('mutation', 'Var', (88, 96))	('Phosphatidylinositol-3 kinase inhibition', 'MPA', (0, 40))	('PIK3CA', 'Gene', (81, 87))	('PIK3CA', 'Gene', '5290', (81, 87))
898309	27575869	Cancer cells with high CD44 expression show characteristics of EMT.	('CD44', 'Protein', (23, 27))	('EMT', 'Gene', (63, 66))	('expression', 'MPA', (28, 38))	('EMT', 'Gene', '3702', (63, 66))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('high', 'Var', (18, 22))
898312	27575869	Moreover, gastric CSCs can even be isolated from the peripheral blood of GC patients using CD44 and CD54.	('CD54', 'Gene', (100, 104))	('CD54', 'Gene', '3383', (100, 104))	('patients', 'Species', '9606', (76, 84))	('CD44', 'Var', (91, 95))
898385	26081225	Both PD-L2+ and PD-L1+ tumors had a higher average number of PD-1+ TILs compared to tumors without PD-L2 or PD-L1 expression (7.2 vs 3.7, P=0.052 and 12.6 vs 2.5, P<0.001 respectively).	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('PD-1+', 'Gene', (61, 66))	('PD-L1+ tumors', 'Disease', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Disease', (84, 90))	('PD-L2+', 'Var', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('PD-L1+ tumors', 'Disease', 'MESH:D010300', (16, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
898389	26081225	Tumors with PD-L2 expression in all evaluated cores had a larger percentage of PD-L2+ cells (70-100% of tumor cells positive) compared to tumors with 1 or 2 positive cores (30-60% of tumor cells positive).	('PD-L2 expression', 'Var', (12, 28))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('expression', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
898391	26081225	Similarly, evaluation of whole-tumor slices showed PD-L1+ immune cells in 16/45 (35.6%) tumors, of which 7/16 were not identified on the TMAs.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (31, 36))	('TMAs', 'Chemical', 'MESH:C071868', (137, 141))	('PD-L1+', 'Var', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
898403	26081225	In order to test if constitutive PD-L2 expression is dependent upon IL4/IL13/STAT6 signaling, we knocked down STAT6 in the PD-L2-expressing cell lines OE33 and MKN7, which did not lead to a change in PD-L2 mRNA or protein expression (data not shown).	('IL4', 'Gene', (68, 71))	('knocked', 'Var', (97, 104))	('STAT6', 'Gene', (110, 115))	('IL13', 'Gene', (72, 76))	('STAT6', 'Gene', '6778', (110, 115))	('STAT6', 'Gene', (77, 82))	('IL13', 'Gene', '3596', (72, 76))	('protein expression', 'MPA', (214, 232))	('STAT6', 'Gene', '6778', (77, 82))	('IL4', 'Gene', '3565', (68, 71))
898408	26081225	Tumors with PD-1+ TILs had higher tumor stage (P<0.001), were more frequently poorly differentiated (P<0.001), and a trend towards absence of histologically confirmed BE (P=0.056).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (34, 39))	('poorly differentiated', 'CPA', (78, 99))	('BE', 'Phenotype', 'HP:0100580', (167, 169))	('PD-1+ TILs', 'Var', (12, 22))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
898409	26081225	PD-1 positivity correlated with an increased mortality (univariate Cox regression HR=1.89 (95% CI 1.38-2.6), P<0.000; Supplemental Figure S2).	('positivity', 'Var', (5, 15))	('PD-1', 'Gene', (0, 4))	('P<0.000; Supplemental Figure S2', 'Disease', 'MESH:C566917', (109, 140))	('Cox', 'Gene', '1351', (67, 70))	('Cox', 'Gene', (67, 70))	('P<0.000; Supplemental Figure S2', 'Disease', (109, 140))
898427	26081225	Recent studies have shown that Th2 polarization in esophageal cancer is associated with the infiltration of myeloid-derived suppressor cells (MDSC) and M2-polarized macrophages, suggesting the presence of other immune evasion mechanisms beyond the PD-1 pathway.	('Th2', 'Var', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancer', 'Disease', (51, 68))	('infiltration', 'CPA', (92, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))
898812	29552112	The effects of Nectin-2 in migration and invasion were then determined by wound healing and Transwell assays performed using ESCC cell lines (ECA109 and KYSE510) transfected with small interfering (si) RNA against Nectin-2.	('KYSE510', 'CellLine', 'CVCL:1354', (153, 160))	('Nectin-2', 'Gene', (214, 222))	('small interfering', 'Var', (179, 196))	('Nectin-2', 'Gene', '5819', (15, 23))	('Nectin-2', 'Gene', '5819', (214, 222))	('Nectin-2', 'Gene', (15, 23))
898815	29552112	In addition, the expression levels of Nectin-2 protein in ESCC tissues with advanced tumor stage (P=0.006) and poor differentiation (P=0.02) were increased compared with patients with early tumor stage and well to moderate differentiation.	('patients', 'Species', '9606', (170, 178))	('tumor', 'Disease', (85, 90))	('expression levels', 'MPA', (17, 34))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('Nectin-2', 'Gene', '5819', (38, 46))	('advanced tumor', 'Disease', 'MESH:D020178', (76, 90))	('increased', 'PosReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('poor differentiation', 'Var', (111, 131))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Nectin-2', 'Gene', (38, 46))	('ESCC', 'Disease', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('advanced tumor', 'Disease', (76, 90))
898816	29552112	Additionally, knockdown of Nectin-2 in the 2 ESCC cell lines could effectively suppress the cell migration and invasion abilities (P<0.05).	('Nectin-2', 'Gene', '5819', (27, 35))	('suppress', 'NegReg', (79, 87))	('Nectin-2', 'Gene', (27, 35))	('knockdown', 'Var', (14, 23))
898826	29552112	Studies have reported the aberrant expression of Nectins and revealed their important roles in numerous cancer types.	('numerous cancer', 'Disease', 'MESH:D009369', (95, 110))	('aberrant', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('expression', 'MPA', (35, 45))	('Nectins', 'Protein', (49, 56))	('numerous cancer', 'Disease', (95, 110))
898857	29552112	Transwell assay was performed to assess the migration and invasion abilities of ESCC cells transfected with si-Nectin-2 or si-con using a modified two-chamber migration assay with a pore size of 8 microm (Merck KGaA).	('Nectin-2', 'Gene', '5819', (111, 119))	('invasion abilities', 'CPA', (58, 76))	('si-con', 'Chemical', '-', (123, 129))	('si-con', 'Var', (123, 129))	('migration', 'CPA', (44, 53))	('Nectin-2', 'Gene', (111, 119))
898875	29552112	The average IRS of Nectin-2 protein in ESCC tissues obtained from patients with advanced tumor stage (P=0.006; Table I) and poor differentiation (P=0.02; Table I) was increased compared with tissues obtained from patients with early tumor stage and well-moderate differentiation.	('advanced tumor', 'Disease', (80, 94))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('Nectin-2', 'Gene', (19, 27))	('tumor', 'Disease', (233, 238))	('advanced tumor', 'Disease', 'MESH:D020178', (80, 94))	('poor differentiation', 'Var', (124, 144))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('increased', 'PosReg', (167, 176))	('Nectin-2', 'Gene', '5819', (19, 27))	('patients', 'Species', '9606', (213, 221))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('patients', 'Species', '9606', (66, 74))	('IRS of', 'MPA', (12, 18))
898876	29552112	To elucidate the involvement of Nectin-2 in ESCC cell migration and invasion abilities, Nectin-2 siRNA was used to knockdown the expression of Nectin-2 in the human ESCC ECA109 and KYSE510 cell lines.	('Nectin-2', 'Gene', (32, 40))	('Nectin-2', 'Gene', (88, 96))	('men', 'Species', '9606', (24, 27))	('Nectin-2', 'Gene', (143, 151))	('human', 'Species', '9606', (159, 164))	('Nectin-2', 'Gene', '5819', (88, 96))	('Nectin-2', 'Gene', '5819', (32, 40))	('KYSE510', 'CellLine', 'CVCL:1354', (181, 188))	('Nectin-2', 'Gene', '5819', (143, 151))	('knockdown', 'Var', (115, 124))
898877	29552112	2, the relative protein expression of Nectin-2 in ECA109 and KYSE510 cells was markedly decreased by transfection with Nectin-2 siRNA (P<0.001).	('Nectin-2', 'Gene', '5819', (38, 46))	('Nectin-2', 'Gene', (119, 127))	('KYSE510', 'CellLine', 'CVCL:1354', (61, 68))	('Nectin-2', 'Gene', (38, 46))	('decreased', 'NegReg', (88, 97))	('protein expression', 'MPA', (16, 34))	('transfection', 'Var', (101, 113))	('Nectin-2', 'Gene', '5819', (119, 127))
898893	29552112	Liang et al reported that positive Nectin-2 expression was associated with progression and poor prognosis in pancreatic ductal adenocarcinoma patients.	('expression', 'MPA', (44, 54))	('Nectin-2', 'Gene', '5819', (35, 43))	('pancreatic ductal adenocarcinoma', 'Disease', (109, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('positive', 'Var', (26, 34))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (109, 141))	('associated', 'Reg', (59, 69))	('Nectin-2', 'Gene', (35, 43))	('patients', 'Species', '9606', (142, 150))
898993	29357883	Accordingly, double-agent regimens tend to prolong the survival of patients with esophageal cancer, but cannot affect prognosis.	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('patients', 'Species', '9606', (67, 75))	('men', 'Species', '9606', (30, 33))	('survival', 'CPA', (55, 63))	('prolong', 'PosReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', (81, 98))	('double-agent', 'Var', (13, 25))
899002	29357883	Our study shows that the 5-year PFS rate and OS rate of double-agent therapy was higher than that of single-agent concurrent chemoradiotherapy for patients with unresectable esophageal SCC; however, there were no significant differences in univariate analysis and multivariate analysis.	('PFS', 'CPA', (32, 35))	('OS', 'Chemical', '-', (45, 47))	('SCC', 'Gene', (185, 188))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('higher', 'PosReg', (81, 87))	('double-agent', 'Var', (56, 68))	('SCC', 'Gene', '6317', (185, 188))	('PF', 'Chemical', 'MESH:C002997', (32, 34))	('patients', 'Species', '9606', (147, 155))
899018	26495015	Concrete mechanism related to arresting EC9706 cell cycle at the S phase inhibits proliferating cell nuclear antigen (PCNA) of transplanted tumors in nude mice and regulates PI3K/Akt-NF-kappaB transduction cascade.	('proliferating cell nuclear antigen', 'Gene', '5111', (82, 116))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('regulates', 'Reg', (164, 173))	('inhibits', 'NegReg', (73, 81))	('EC9706', 'Var', (40, 46))	('PI3K/Akt-NF-kappaB transduction cascade', 'Pathway', (174, 213))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('proliferating cell nuclear antigen', 'Gene', (82, 116))
899020	26495015	EC9706 cells are squamous carcinoma cells in esophagus, which are the chief type of EC in China, accounting for more than 95% in whole EC.	('EC9706', 'Var', (0, 6))	('squamous carcinoma', 'Disease', 'MESH:D002294', (17, 35))	('squamous carcinoma', 'Disease', (17, 35))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (17, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))
899047	26495015	As is shown in Figures 2 and 3, cells in S phase were less than those in Group BC after TDH and 5-FU were applied, which showed that TDH inhibited Ec9706 cells proliferation through blocking up cells from entering S phase from G1.	('blocking', 'NegReg', (182, 190))	('TDH', 'Var', (133, 136))	('inhibited', 'NegReg', (137, 146))	('Ec9706', 'CellLine', 'CVCL:E307', (147, 153))	('Ec9706 cells proliferation', 'CPA', (147, 173))	('cells', 'CPA', (194, 199))
899056	26037024	Quality of life at 1 year was better in the MIE group than in the OE group for the physical component summary SF36 [50 (6; 48-53) versus 45 (9; 42-48) p .003]; global health C30 [79 (10; 76-83) versus 67 (21; 60-75) p .004]; and pain OES18 module [6 (9; 2-8) versus 16 (16; 10-22) p .001], respectively.	('better', 'PosReg', (30, 36))	('pain', 'Phenotype', 'HP:0012531', (229, 233))	('global health', 'MPA', (160, 173))	('MIE', 'Var', (44, 47))	('OE', 'Chemical', '-', (66, 68))	('OE', 'Chemical', '-', (234, 236))	('pain', 'Disease', 'MESH:D010146', (229, 233))	('MIE', 'Chemical', '-', (44, 47))	('pain', 'Disease', (229, 233))
899104	26037024	Importantly, there are significantly better scores after 1-year follow-up for the MIE group as compared to the OE group.	('scores', 'MPA', (44, 50))	('OE', 'Chemical', '-', (111, 113))	('MIE', 'Chemical', '-', (82, 85))	('better', 'PosReg', (37, 43))	('MIE', 'Var', (82, 85))
899117	26037024	In this trial, MIE resulted in a better mid-term 1-year quality of life for the physical component summary of the SF-36 questionnaire, EORTC C30 global health domain and OES 18 pain domain compared to open esophagectomy.	('MIE', 'Var', (15, 18))	('pain', 'Phenotype', 'HP:0012531', (177, 181))	('MIE', 'Chemical', '-', (15, 18))	('pain', 'Disease', 'MESH:D010146', (177, 181))	('pain', 'Disease', (177, 181))	('SF-36', 'Gene', (114, 119))	('better', 'PosReg', (33, 39))	('OE', 'Chemical', '-', (170, 172))
899148	26037024	In conclusion, this first randomized trial shows that MIE for esophageal cancer is associated with a better mid-term 1-year quality of life compared to open esophagectomy.	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MIE', 'Chemical', '-', (54, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('MIE', 'Var', (54, 57))	('better', 'PosReg', (101, 107))
899213	24868270	An undiagnosed ZD may make endoscopy difficult and, due to manipulations in the diverticulum lumen, lead to gastrointestinal tract perforation.	('men', 'Species', '9606', (95, 98))	('manipulations', 'Var', (59, 72))	('lead to', 'Reg', (100, 107))	('gastrointestinal', 'Disease', (108, 124))
899314	32158193	NVP-BSK805, an Inhibitor of JAK2 Kinase, Significantly Enhances the Radiosensitivity of Esophageal Squamous Cell Carcinoma in vitro and in vivo Radiotherapy is one major curative treatment modality for esophageal squamous cell carcinoma (ESCC) patients.	('Esophageal Squamous Cell Carcinoma', 'Disease', (88, 122))	('ESCC', 'Disease', (238, 242))	('Enhances', 'PosReg', (55, 63))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:C562729', (88, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('JAK2', 'Gene', (28, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('Carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('NVP-BSK805', 'Var', (0, 10))	('JAK2', 'Gene', '3717', (28, 32))	('esophageal squamous cell carcinoma', 'Disease', (202, 236))	('ESCC', 'Disease', 'MESH:C562729', (238, 242))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (202, 236))	('patients', 'Species', '9606', (244, 252))	('Radiosensitivity', 'CPA', (68, 84))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (99, 122))
899315	32158193	This study aimed to find out small-molecular kinase inhibitors, which can significantly enhance the radiosensitivity of ESCC in vitro and in vivo.	('ESCC', 'Disease', 'MESH:C562729', (120, 124))	('radiosensitivity', 'CPA', (100, 116))	('ESCC', 'Disease', (120, 124))	('small-molecular', 'Var', (29, 44))	('enhance', 'PosReg', (88, 95))
899319	32158193	Among the 93 kinase inhibitors tested, we found NVP-BSK805, an inhibitor of JAK2 kinase, significantly radiosensitized ESCC cells through enhancing DSBs, inhibiting DNA damage repair and arresting cell cycle in G2/M or G0/G1 phase.	('DSBs', 'Chemical', '-', (148, 152))	('NVP-BSK805', 'Var', (48, 58))	('inhibiting', 'NegReg', (154, 164))	('DSBs', 'MPA', (148, 152))	('DNA damage repair', 'MPA', (165, 182))	('ESCC', 'Disease', (119, 123))	('arresting', 'Reg', (187, 196))	('enhancing', 'PosReg', (138, 147))	('cell cycle', 'CPA', (197, 207))	('ESCC', 'Disease', 'MESH:C562729', (119, 123))
899320	32158193	After treatment with NVP-BSK805, ESCC cells showed decreased clonogenic survival and delayed tumor growth in vivo.	('ESCC', 'Disease', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('NVP-BSK805', 'Var', (21, 31))	('tumor', 'Disease', (93, 98))	('decreased', 'NegReg', (51, 60))	('ESCC', 'Disease', 'MESH:C562729', (33, 37))	('clonogenic survival', 'CPA', (61, 80))	('delayed', 'NegReg', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
899325	32158193	Small-molecular kinase inhibitors had the ability to restrain tumor growth and enhance tumor response to chemoradiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (87, 92))	('enhance', 'PosReg', (79, 86))	('Small-molecular', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
899329	32158193	TG10129, a small molecular inhibitor of JAK2, was demonstrated to increase the radiosensitivity of lung cancer by inhibiting JAK2 downstream signaling.	('increase', 'PosReg', (66, 74))	('lung cancer', 'Disease', (99, 110))	('JAK2 downstream signaling', 'MPA', (125, 150))	('radiosensitivity', 'CPA', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('TG10129', 'Var', (0, 7))	('TG10129', 'Chemical', '-', (0, 7))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('increase the radiosensitivity of lung cancer', 'Phenotype', 'HP:0010997', (66, 110))	('inhibiting', 'NegReg', (114, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
899334	32158193	We found NVP-BSK805, an inhibitor of JAK2 kinase, significantly enhanced the radiosensitivity of ESCC cells both in vitro and in vivo.	('ESCC', 'Disease', 'MESH:C562729', (97, 101))	('NVP-BSK805', 'Var', (9, 19))	('radiosensitivity of', 'CPA', (77, 96))	('ESCC', 'Disease', (97, 101))	('enhanced', 'PosReg', (64, 72))
899337	32158193	The primary antibodies against JAK2, pJAK2 (Tyr 1007/Tyr 1008), GAPDH and goat anti-mouse secondary antibody were purchased from Santa Cruz Company (Dallas, TX, USA).	('goat', 'Species', '9925', (74, 78))	('pJAK2', 'Gene', (37, 42))	('GAPDH', 'Gene', '100860872', (64, 69))	('Tyr 1007/Tyr', 'Mutation', 'p.Y1007Y', (44, 56))	('mouse', 'Species', '10090', (84, 89))	('Tyr 1007/Tyr 1008', 'Var', (44, 61))	('JAK2', 'Gene', (31, 35))	('GAPDH', 'Gene', (64, 69))
899382	32158193	These results suggested that inhibition of JAK2 kinase increased irradiation-induced DSBs while suppressed DNA damage repair.	('JAK2 kinase', 'Enzyme', (43, 54))	('irradiation-induced', 'Disease', (65, 84))	('increased', 'PosReg', (55, 64))	('increased irradiation', 'Phenotype', 'HP:0011133', (55, 76))	('DSBs', 'Disease', (85, 89))	('suppressed', 'NegReg', (96, 106))	('DSBs', 'Chemical', '-', (85, 89))	('DNA damage repair', 'MPA', (107, 124))	('inhibition', 'Var', (29, 39))
899383	32158193	When KYSE-150 cells and KYSE-150R cells were pretreated with 10 muM NVP-BSK805 4 h before irradiation, their cell cycle was arrested at the most radiosensitive G2/M phase or G0/G1, respectively (Figure 2).	('cell cycle', 'CPA', (109, 119))	('muM', 'Gene', '56925', (64, 67))	('KYSE-150R', 'Var', (24, 33))	('muM', 'Gene', (64, 67))
899384	32158193	When pretreated with 5 or 10 muM NVP-BSK805 4 h before irradiation, the expression of JAK2 was inhibited while the expression of gamma-H2AX was increased in KYSE-150 cells and in KYSE-150R cells, suggesting inhibition of JAK2 kinase by NVP-BSK805 enhanced irradiation-induced DNA damage (Figure 1D and Supplementary Figure 3C-F).	('muM', 'Gene', (29, 32))	('gamma-H2AX', 'Chemical', '-', (129, 139))	('enhanced', 'PosReg', (247, 255))	('inhibition', 'Var', (207, 217))	('inhibited', 'NegReg', (95, 104))	('NVP-BSK805', 'Gene', (236, 246))	('muM', 'Gene', '56925', (29, 32))	('irradiation-induced DNA damage', 'CPA', (256, 286))	('increased', 'PosReg', (144, 153))
899391	32158193	When treated with the combination therapy of NVP-BSK805 and 12 Gy of fractionated radiation (IR) (12 Gy of fractionated radiation was performed according to 2 Gy per fraction on day 1,3,5,7,9,11, respectively, and the day when NVP-BSK805 was administered for the first time was defined as day 1), the time of xenograft tumors grown to 1500 m3 was significantly delayed compared with IR alone (59 d vs 37 d, p=0.0328), suggesting NVP-BSK805 had potent ability to improve the radiosensitivity of KYSE-150 xenograft tumors (Figure 4).	('NVP-BSK805', 'Var', (429, 439))	('radiosensitivity', 'CPA', (474, 490))	('xenograft tumors', 'Disease', (503, 519))	('xenograft tumors', 'Disease', 'MESH:D009369', (309, 325))	('tumor', 'Phenotype', 'HP:0002664', (513, 518))	('tumors', 'Phenotype', 'HP:0002664', (513, 519))	('xenograft tumors', 'Disease', (309, 325))	('xenograft tumors', 'Disease', 'MESH:D009369', (503, 519))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('improve', 'PosReg', (462, 469))	('tumors', 'Phenotype', 'HP:0002664', (319, 325))
899395	32158193	Survival analysis showed those p-JAK2-positive ESCC patients had a significantly poorer prognosis than those p-JAK2-negative patients after chemoradiotherapy (Figure 5C).	('ESCC', 'Disease', (47, 51))	('p-JAK2-positive', 'Var', (31, 46))	('poorer', 'NegReg', (81, 87))	('ESCC', 'Disease', 'MESH:C562729', (47, 51))	('patients', 'Species', '9606', (52, 60))	('patients', 'Species', '9606', (125, 133))
899396	32158193	These results suggested JAK2 kinase may be used as a prognostic factor of ESCC patients treated with chemoradiotherapy.	('JAK2', 'Var', (24, 28))	('ESCC', 'Disease', (74, 78))	('patients', 'Species', '9606', (79, 87))	('ESCC', 'Disease', 'MESH:C562729', (74, 78))
899398	32158193	Several kinase inhibitors such as wee1 kinase inhibitor AZD1775, inhibitor of DNA-PKcs kinase and ATR inhibitor were proven to enhance the radiosensitivity of human cancers.	('wee1', 'Gene', (34, 38))	('enhance', 'PosReg', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ATR', 'Gene', '545', (98, 101))	('ATR', 'Gene', (98, 101))	('DNA-PKcs', 'Gene', '5591', (78, 86))	('AZD1775', 'Var', (56, 63))	('human', 'Species', '9606', (159, 164))	('wee1', 'Gene', '7465', (34, 38))	('AZD1775', 'Chemical', 'MESH:C549567', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('DNA-PKcs', 'Gene', (78, 86))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))
899399	32158193	In our study, by screening of 93 kinase inhibitors, we found NVP-BSK805, a specific inhibitor of JAK2 kinase, significantly improved the radiosensitivity of esophageal cancer cells in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('improved', 'PosReg', (124, 132))	('esophageal cancer', 'Disease', (157, 174))	('radiosensitivity', 'CPA', (137, 153))	('NVP-BSK805', 'Var', (61, 71))
899402	32158193	Upon radiation, gamma-H2AX, a marker of DSBs (DNA double-strand breaks), was highly expressed and initiated the activation of DNA damage response in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('gamma-H2AX', 'Var', (16, 26))	('activation', 'PosReg', (112, 122))	('DSBs', 'Chemical', '-', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('DNA damage response', 'MPA', (126, 145))	('tumor', 'Disease', (149, 154))	('gamma-H2AX', 'Chemical', '-', (16, 26))
899406	32158193	Inhibition of DNA damage repair radiosensitized several types of human cancers.	('human', 'Species', '9606', (65, 70))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Disease', (71, 78))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
899407	32158193	Our study found inhibition of JAK2 kinase increased irradiation-induced DSBs while suppressed DNA damage repair in KYSE-150 cells and in KYSE-150R cells.	('increased', 'PosReg', (42, 51))	('DSBs', 'Disease', (72, 76))	('DSBs', 'Chemical', '-', (72, 76))	('JAK2 kinase', 'Enzyme', (30, 41))	('increased irradiation', 'Phenotype', 'HP:0011133', (42, 63))	('DNA damage repair', 'MPA', (94, 111))	('suppressed', 'NegReg', (83, 93))	('inhibition', 'Var', (16, 26))
899438	30719634	For the analysis, patients with a cM1a tumor according to TNM-6 were categorized as having cN+ according to TNM-7.	('cM1a', 'Var', (34, 38))	('cN+', 'Disease', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Disease', (39, 44))
899531	30003192	Furthermore, severe toxicities were observed as a result of high-dose IL-2, which induces a vascular permeability leak that leads to fluid retention and interstitial edema, and results in circulatory failure, lung edema, and renal dysfunction.	('renal dysfunction', 'Disease', (225, 242))	('lung edema', 'Disease', (209, 219))	('fluid retention', 'Phenotype', 'HP:0000969', (133, 148))	('results in', 'Reg', (177, 187))	('renal dysfunction', 'Phenotype', 'HP:0000083', (225, 242))	('IL-2', 'Gene', '3558', (70, 74))	('high-dose', 'Var', (60, 69))	('circulatory failure', 'Disease', (188, 207))	('leads to', 'Reg', (124, 132))	('lung edema', 'Phenotype', 'HP:0100598', (209, 219))	('renal dysfunction', 'Disease', 'MESH:D007674', (225, 242))	('vascular permeability leak', 'MPA', (92, 118))	('induces', 'Reg', (82, 89))	('edema', 'Phenotype', 'HP:0000969', (166, 171))	('toxicities', 'Disease', 'MESH:D064420', (20, 30))	('vascular permeability leak', 'Phenotype', 'HP:0030005', (92, 118))	('interstitial edema', 'Disease', (153, 171))	('lung edema', 'Disease', 'MESH:D004487', (209, 219))	('edema', 'Phenotype', 'HP:0000969', (214, 219))	('IL-2', 'Gene', (70, 74))	('circulatory failure', 'Disease', 'MESH:D012769', (188, 207))	('interstitial edema', 'Disease', 'MESH:D004487', (153, 171))	('toxicities', 'Disease', (20, 30))	('fluid retention', 'MPA', (133, 148))
899578	30003192	Neoantigens, a class of HLA-bound peptides that arise from tumor-specific mutations, are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance.	('tumor', 'Disease', (59, 64))	('bypass', 'NegReg', (165, 171))	('HLA', 'Gene', (24, 27))	('mutations', 'Var', (74, 83))	('HLA', 'Gene', '3123', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('central thymic tolerance', 'CPA', (172, 196))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
899601	30003192	Surprisingly, updated reports have indicated that patients with metastatic CRC who harbored the microsatellite instability-high (MSI-H) genotype achieved objective responses after disease progression on an intermittent dosing regimen of PD-1 inhibitors and finally achieved complete responses.50 The majority of colorectal cancers are proficient mismatch repair (pMMR) tumors, and approximately 15% show defective mismatch repair (dMMR), which can be measured by either the five-marker panel with fluorescent multiplex assay64 or by the lack of DNA mismatch repair proteins.65 Tumors with dMMR can have MSI-H and a somatic mutation frequency of more than 10- to 100-fold that of pMMR tumors.66 Hence, dMMR (MSI-H) tumor is thought to have the potential to encode "non-self" immunogenic antigens and predict responsiveness to the immune checkpoint blockade (Tables 2, 3, 4).	('tumor', 'Phenotype', 'HP:0002664', (684, 689))	('tumors', 'Disease', (684, 690))	('MSI-H) tumor', 'Disease', 'MESH:D009369', (707, 719))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('colorectal cancers', 'Disease', 'MESH:D015179', (312, 330))	('MSI-H', 'Disease', 'MESH:D000848', (707, 712))	('MSI-H', 'Disease', 'MESH:D000848', (603, 608))	('tumors', 'Disease', 'MESH:D009369', (684, 690))	('Tumors', 'Phenotype', 'HP:0002664', (577, 583))	('tumors', 'Phenotype', 'HP:0002664', (369, 375))	('colorectal cancer', 'Phenotype', 'HP:0003003', (312, 329))	('encode', 'Reg', (756, 762))	('tumor', 'Phenotype', 'HP:0002664', (714, 719))	('MSI-H', 'Disease', (129, 134))	('Tumor', 'Phenotype', 'HP:0002664', (577, 582))	('patients', 'Species', '9606', (50, 58))	('Tumors', 'Disease', (577, 583))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('tumors', 'Disease', (369, 375))	('dMMR', 'Chemical', '-', (701, 705))	('dMMR', 'Chemical', '-', (589, 593))	('cancers', 'Phenotype', 'HP:0002664', (323, 330))	('dMMR', 'Chemical', '-', (431, 435))	('tumors', 'Phenotype', 'HP:0002664', (684, 690))	('dMMR', 'Var', (701, 705))	('MSI-H', 'Disease', 'MESH:D000848', (129, 134))	('colorectal cancers', 'Disease', (312, 330))	('CR', 'Chemical', '-', (75, 77))	('Tumors', 'Disease', 'MESH:D009369', (577, 583))	('tumors', 'Disease', 'MESH:D009369', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('MSI-H', 'Disease', (707, 712))	('predict', 'Reg', (799, 806))	('MSI-H', 'Disease', (603, 608))
899608	30003192	These data support the hypothesis that the large proportion of mutant neoantigens in dMMR cancers make them sensitive to immune checkpoint blockade, regardless of the tissue of origin for the cancer,56 and the FDA approved the use of pembrolizumab in the treatment of patients with MSI-H or dMMR (Tables 2, 3).	('patients', 'Species', '9606', (268, 276))	('MSI-H', 'Disease', 'MESH:D000848', (282, 287))	('cancers', 'Disease', (90, 97))	('mutant', 'Var', (63, 69))	('dMMR', 'Chemical', '-', (291, 295))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('dMMR', 'Gene', (85, 89))	('dMMR', 'Chemical', '-', (85, 89))	('cancer', 'Disease', (192, 198))	('dMMR', 'Disease', (291, 295))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('MSI-H', 'Disease', (282, 287))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('pembrolizumab', 'Chemical', 'MESH:C582435', (234, 247))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
899610	30003192	Patients were given nivolumab at 3 mg/kg every 2 weeks until disease progression or unacceptable toxic effects (Table 2).57 The FDA approved nivolumab use in the treatment for MSI-H or dMMR metastatic colorectal cancer that has progressed following treatment (Table 3).	('MSI-H', 'Disease', 'MESH:D000848', (176, 181))	('colorectal cancer', 'Disease', 'MESH:D015179', (201, 218))	('dMMR', 'Var', (185, 189))	('nivolumab', 'Chemical', 'MESH:D000077594', (20, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (201, 218))	('Patients', 'Species', '9606', (0, 8))	('dMMR', 'Chemical', '-', (185, 189))	('MSI-H', 'Disease', (176, 181))	('nivolumab', 'Chemical', 'MESH:D000077594', (141, 150))	('colorectal cancer', 'Disease', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
899638	30003192	PDAC patients displayed an increased number of Treg and MDSC.71 Cyclophosphamide72 and metformin73 could downregulate the number and function of Treg, and cyclooxygenase (COX)-2 inhibitors75 and cimetidine76 could regulate MDSC.	('downregulate', 'NegReg', (105, 117))	('function', 'CPA', (133, 141))	('regulate', 'Reg', (214, 222))	('PDAC', 'Chemical', '-', (0, 4))	('patients', 'Species', '9606', (5, 13))	('cyclooxygenase (COX)-2', 'Gene', (155, 177))	('cyclooxygenase (COX)-2', 'Gene', '4513', (155, 177))	('cimetidine76', 'Chemical', '-', (195, 207))	('Cyclophosphamide72', 'Var', (64, 82))	('metformin73', 'Var', (87, 98))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('MDSC', 'Disease', (223, 227))	('metformin73', 'Chemical', '-', (87, 98))
899647	30003192	Combination studies using conventional agents and immune checkpoint therapies should thus clarify the conditions needed to create an "immunogenic" tumor microenvironment with subsequent clinical benefit for patients.86 We have reported that cetuximab strongly enhances immune cell infiltration into liver metastatic sites in CRC.46 Cetuximab induces antibody-dependent cell-mediated cytotoxicity and immunogenic cell death.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('cytotoxicity', 'Disease', (383, 395))	('patients', 'Species', '9606', (207, 215))	('cetuximab', 'Chemical', 'MESH:D000068818', (241, 250))	('immunogenic cell death', 'CPA', (400, 422))	('Cetuximab', 'Gene', (332, 341))	('cytotoxicity', 'Disease', 'MESH:D064420', (383, 395))	('Cetuximab', 'Chemical', 'MESH:D000068818', (332, 341))	('enhances', 'PosReg', (260, 268))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('CR', 'Chemical', '-', (325, 327))	('CRC', 'Phenotype', 'HP:0003003', (325, 328))	('cetuximab', 'Var', (241, 250))
899675	29580288	One study showed variable expression of PD-L1 in clonal plasma cells from MM and MGUS patients; however, patients with persistent minimal residual disease showed high expression of PD-L1 and PD-1.	('patients', 'Species', '9606', (105, 113))	('PD-L1', 'Var', (181, 186))	('PD-1', 'Gene', (191, 195))	('expression', 'MPA', (167, 177))	('patients', 'Species', '9606', (86, 94))
899679	29580288	Mechanisms of epigenetic and post-transcriptional modification include deacetylation and regulation by microRNAs (miRNAs), such as miRNA-34a, miRNA-200, miRNA-513, and miRNA-570.	('miRNA-570', 'Var', (168, 177))	('deacetylation', 'MPA', (71, 84))	('miRNA-200', 'Var', (142, 151))	('regulation', 'MPA', (89, 99))	('miRNA-513', 'Var', (153, 162))	('miRNA-34a', 'Gene', '407040', (131, 140))	('miRNA-34a', 'Gene', (131, 140))
899696	29580288	PD-L1 can also induce and maintain regulatory T cells, which will promote suppression of anti-tumor immune response.	('regulatory T cells', 'CPA', (35, 53))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('PD-L1', 'Var', (0, 5))	('suppression', 'CPA', (74, 85))
899699	29580288	showed that RPMI8226 and KMS-34 MM cells expressing surface PD-L1 had a proliferative advantage over cells from the same line that did not express PD-L1, as demonstrated by higher fraction of cells in the G2/M phase, higher levels of BrdU incorporation, percentage of Ki67 positivity, and more rapid proliferation in cell cultures.	('BrdU incorporation', 'MPA', (234, 252))	('cells', 'CPA', (192, 197))	('surface PD-L1', 'Var', (52, 65))	('BrdU', 'Chemical', 'MESH:D001973', (234, 238))	('PD-L1', 'Var', (60, 65))	('higher', 'PosReg', (217, 223))	('G2/M phase', 'CPA', (205, 215))	('proliferative advantage', 'CPA', (72, 95))	('higher', 'PosReg', (173, 179))
899700	29580288	Conversely, knockdown of PD-L1 in MOST-1 MM cells was associated with slower proliferation and decreased BrdU incorporation.	('decreased', 'NegReg', (95, 104))	('BrdU', 'Chemical', 'MESH:D001973', (105, 109))	('knockdown', 'Var', (12, 21))	('BrdU incorporation', 'CPA', (105, 123))	('slower', 'NegReg', (70, 76))	('MOST-1', 'CellLine', 'CVCL:B526', (34, 40))	('PD-L1', 'Gene', (25, 30))
899702	29580288	Overexpression of PD-L1 was associated with increased viability in an esophageal cancer cell line.	('viability', 'MPA', (54, 63))	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('Overexpression', 'Var', (0, 14))	('increased', 'PosReg', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PD-L1', 'Gene', (18, 23))
899705	29580288	Notably, an in vivo study has shown that tumor growth was decreased in a mouse model of gastric cancer with knockdown of PD-L1.	('PD-L1', 'Gene', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('knockdown', 'Var', (108, 117))	('gastric cancer', 'Disease', (88, 102))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('decreased', 'NegReg', (58, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('mouse', 'Species', '10090', (73, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
899706	29580288	In RPMI8226 cells, PD-L1+ cells had markedly higher expression levels of Bcl-2 and FasL expression compared to PD-L1- cells.	('PD-L1+', 'Var', (19, 25))	('Bcl-2', 'Gene', (73, 78))	('expression levels', 'MPA', (52, 69))	('FasL', 'Gene', (83, 87))	('Bcl-2', 'Gene', '596', (73, 78))	('FasL', 'Gene', '356', (83, 87))	('higher', 'PosReg', (45, 51))
899707	29580288	The levels of intracellular Bcl-2 and cell-surface FasL proteins were also higher in PD-L1+ cells.	('Bcl-2', 'Gene', (28, 33))	('Bcl-2', 'Gene', '596', (28, 33))	('FasL', 'Gene', (51, 55))	('PD-L1+ cells', 'Var', (85, 97))	('higher', 'PosReg', (75, 81))	('FasL', 'Gene', '356', (51, 55))
899708	29580288	Conversely, knockdown of PD-L1 in MOST-1 cells downregulated expression of anti-apoptotic genes (BCL2 and MCL1) and silencing of PD-L1 in colorectal cancer cell line and gastric cancer cell lines was associated with an increased apoptotic index.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('apoptotic index', 'CPA', (229, 244))	('PD-L1', 'Gene', (25, 30))	('increased', 'PosReg', (219, 228))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('MCL1', 'Gene', (106, 110))	('BCL2', 'Gene', '596', (97, 101))	('knockdown', 'Var', (12, 21))	('silencing', 'Var', (116, 125))	('increased apoptotic index', 'Phenotype', 'HP:0030887', (219, 244))	('gastric cancer', 'Disease', (170, 184))	('MCL1', 'Gene', '4170', (106, 110))	('downregulated', 'NegReg', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('BCL2', 'Gene', (97, 101))	('expression', 'MPA', (61, 71))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('PD-L1', 'Gene', (129, 134))	('colorectal cancer', 'Disease', (138, 155))	('MOST-1', 'CellLine', 'CVCL:B526', (34, 40))
899711	29580288	showed that knockdown of PD-L1 in colorectal cancer cell line, HCT116, was associated with reduced migration and invasion ability, with a reduced invasive index.	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('reduced', 'NegReg', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('knockdown', 'Var', (12, 21))	('colorectal cancer', 'Disease', (34, 51))	('HCT116', 'CellLine', 'CVCL:0291', (63, 69))	('reduced', 'NegReg', (91, 98))	('invasive index', 'CPA', (146, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (34, 51))	('invasion ability', 'CPA', (113, 129))	('PD-L1', 'Gene', (25, 30))
899713	29580288	Moreover, increased motility and invasiveness was shown in melanoma cell lines expressing PD-L1.	('PD-L1', 'Var', (90, 95))	('motility', 'CPA', (20, 28))	('invasiveness', 'CPA', (33, 45))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('increased', 'PosReg', (10, 19))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
899714	29580288	PD-L1 was also shown to induce tumor formation in malignant melanoma initiating cells.	('malignant melanoma', 'Disease', (50, 68))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('induce', 'PosReg', (24, 30))	('tumor', 'Disease', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('PD-L1', 'Var', (0, 5))	('malignant melanoma', 'Phenotype', 'HP:0002861', (50, 68))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('malignant melanoma', 'Disease', 'MESH:D008545', (50, 68))
899716	29580288	Conversely, knockdown of PD-L1 on MOST-1 cells was associated with increased apoptosis when treated with melphalan.	('apoptosis', 'CPA', (77, 86))	('knockdown', 'Var', (12, 21))	('melphalan', 'Chemical', 'MESH:D008558', (105, 114))	('MOST-1', 'CellLine', 'CVCL:B526', (34, 40))	('PD-L1', 'Gene', (25, 30))
899719	29580288	The cytotoxic activity of cytokine-induced killer cells was increased with knockdown of PD-L1 in gastric cancer cell lines.	('gastric cancer', 'Disease', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('PD-L1', 'Gene', (88, 93))	('knockdown', 'Var', (75, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('increased', 'PosReg', (60, 69))
899722	29580288	In a prospective study, expression of PD-L1 on tumor and infiltrating T-cells was associated with a higher risk of progression of MGUS to clinical malignancy.	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('associated', 'Reg', (82, 92))	('malignancy', 'Disease', (147, 157))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('PD-L1', 'Gene', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('expression', 'Var', (24, 34))	('MGUS', 'Disease', (130, 134))	('tumor', 'Disease', (47, 52))
899733	29580288	The negative predictive value for anti-PD-1 and anti-PD-L1 therapies has been reported to be as low as 58% for nivolumab and 45% for nivolumab plus ipilimumab in melanoma patients.	('nivolumab', 'Chemical', 'MESH:D000077594', (133, 142))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('anti-PD-1', 'Var', (34, 43))	('patients', 'Species', '9606', (171, 179))	('ipilimumab', 'Chemical', 'MESH:D000074324', (148, 158))	('nivolumab', 'Chemical', 'MESH:D000077594', (111, 120))
899745	29580288	highlighted the various clinical trials that are ongoing for PD-1/PD-L1 inhibitors in hematological malignancies including MM.	('hematological malignancies', 'Phenotype', 'HP:0004377', (86, 112))	('hematological malignancies', 'Disease', (86, 112))	('hematological malignancies', 'Disease', 'MESH:D019337', (86, 112))	('PD-1/PD-L1', 'Gene', (61, 71))	('inhibitors', 'Var', (72, 82))
899755	29580288	The patient with stringent complete response had deletion of 17p and amplification of CKS1B, was high-risk by GEP70, and had 50% plasma cell infiltration in the bone marrow at study entry.	('amplification', 'MPA', (69, 82))	('patient', 'Species', '9606', (4, 11))	('CKS1B', 'Gene', '1163', (86, 91))	('CKS1B', 'Gene', (86, 91))	('deletion of 17p', 'Var', (49, 64))
899769	29580288	Trials combining immunomodulators with anti-PD-L1 inhibitors durvalumab (NCT02685826) and atezolizumab (NCT02431208), as well as PD-1 inhibitor nivolumab (NCT02903381), were then suspended based on the safety concerns raised from pembrolizumab trials.	('atezolizumab', 'Chemical', 'MESH:C000594389', (90, 102))	('durvalumab', 'Chemical', 'MESH:C000613593', (61, 71))	('nivolumab', 'Chemical', 'MESH:D000077594', (144, 153))	('NCT02903381', 'Var', (155, 166))	('anti-PD-L1', 'Gene', (39, 49))	('NCT02685826', 'Var', (73, 84))	('NCT02431208', 'Var', (104, 115))	('pembrolizumab', 'Chemical', 'MESH:C582435', (230, 243))
899783	29580288	More recently, the combination of HDAC6 inhibitor and anti-PD-L1 antibody was shown to trigger cytotoxic T lymphocytes and NK cells mediated MM cell killing.	('combination', 'Interaction', (19, 30))	('trigger', 'PosReg', (87, 94))	('HDAC6', 'Gene', '10013', (34, 39))	('HDAC6', 'Gene', (34, 39))	('anti-PD-L1', 'Var', (54, 64))	('cytotoxic T lymphocytes', 'CPA', (95, 118))	('NK cells mediated MM cell killing', 'CPA', (123, 156))
899787	29580288	Preliminary data showed a 1.37-fold increase in soluble PD-L1 in the supernatant when HDAC3 was silenced in HS-5 stromal cells.	('HDAC3', 'Gene', '8841', (86, 91))	('silenced', 'Var', (96, 104))	('HDAC3', 'Gene', (86, 91))	('increase', 'PosReg', (36, 44))	('soluble', 'MPA', (48, 55))	('PD-L1', 'Gene', (56, 61))
899802	29580288	Preliminary results from phase 1 trial of trametinib with AKT inhibitor GSK2110183 (NCT01476137) revealed issues with tolerability, but there seems to be only one patient with MM in this cohort.	('tolerability', 'MPA', (118, 130))	('trametinib', 'Chemical', 'MESH:C560077', (42, 52))	('AKT', 'Gene', '207', (58, 61))	('patient', 'Species', '9606', (163, 170))	('GSK2110183', 'Chemical', 'MESH:C000595148', (72, 82))	('GSK2110183', 'Var', (72, 82))	('AKT', 'Gene', (58, 61))
899810	29580288	A trial of LCAR-B38M CAR T cells targeting BCMA in MM showed 100% objective response rate in 19 RRMM patients, with 18 having complete or near complete remission at a median follow-up of 6 months.	('patients', 'Species', '9606', (101, 109))	('BCMA', 'Gene', '608', (43, 47))	('BCMA', 'Gene', (43, 47))	('CAR', 'Gene', (21, 24))	('CAR', 'Gene', '9970', (21, 24))	('B38M', 'SUBSTITUTION', 'None', (16, 20))	('CAR', 'Gene', (12, 15))	('CAR', 'Gene', '9970', (12, 15))	('B38M', 'Var', (16, 20))
899822	29580288	There is an ongoing clinical trial of STAT3 inhibitor BBI608 alone or with bortezomib or dexamethasone in RRMM (NCT02352558).	('bortezomib', 'Chemical', 'MESH:D000069286', (75, 85))	('BBI608', 'Chemical', 'MESH:C000621033', (54, 60))	('dexamethasone', 'Chemical', 'MESH:D003907', (89, 102))	('STAT3', 'Gene', '6774', (38, 43))	('BBI608', 'Var', (54, 60))	('STAT3', 'Gene', (38, 43))
899828	29580288	There are five ongoing phase 1/2 and phase 2 clinical trials of Ibrutinib alone or in combination in RRMM, MM ineligible for transplant and high-risk smoldering MM (NCT01962792, NCT03015792, NCT01478581, NCT02548962, NCT02902965, NCT02943473).	('NCT01962792', 'Var', (165, 176))	('NCT01478581', 'Var', (191, 202))	('NCT02902965', 'Var', (217, 228))	('NCT02548962', 'Var', (204, 215))	('NCT03015792', 'Var', (178, 189))	('Ibrutinib', 'Chemical', 'MESH:C551803', (64, 73))	('NCT02943473', 'Var', (230, 241))
899830	29580288	Some of the most significant miRNAs regulating PD-L1 expression are the miR-34a, miR-200, and miR-197.	('miR-197', 'Gene', (94, 101))	('miR-34a', 'Gene', (72, 79))	('miR-200', 'Var', (81, 88))	('PD-L1', 'Gene', (47, 52))	('miR-197', 'Gene', '406974', (94, 101))	('expression', 'MPA', (53, 63))	('miR-34a', 'Gene', '407040', (72, 79))
899831	29580288	Some other miRNAs such as the miR15 family, miR-20b, miR-21, miR-93, miR-106b, miR-130b, miR-138-5p, miR-142-5p, miR-152, miR-193a-3p, miR-324-5p, miR-338-5p, miR-513, and miR-570 can also regulate PD-L1 expression in different cancer types.	('miR-152', 'Gene', '406943', (113, 120))	('regulate', 'Reg', (189, 197))	('miR-106b', 'Gene', '406900', (69, 77))	('miR-21', 'Gene', (53, 59))	('miR-570', 'Gene', '693155', (172, 179))	('PD-L1', 'Gene', (198, 203))	('miR-106b', 'Gene', (69, 77))	('miR-193a-3p', 'Var', (122, 133))	('miR-20b', 'Gene', (44, 51))	('miR-130b', 'Gene', '406920', (79, 87))	('miR-93', 'Gene', (61, 67))	('miR-130b', 'Gene', (79, 87))	('cancer', 'Disease', (228, 234))	('miR-324-5p', 'Var', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('miR-513', 'Var', (159, 166))	('expression', 'MPA', (204, 214))	('miR-93', 'Gene', '407051', (61, 67))	('miR-338-5p', 'Var', (147, 157))	('miR-152', 'Gene', (113, 120))	('miR-20b', 'Gene', '574032', (44, 51))	('miR-21', 'Gene', '406991', (53, 59))	('miR-570', 'Gene', (172, 179))	('miR-138-5p', 'Var', (89, 99))	('miR-142-5p', 'Var', (101, 111))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
899838	29580288	A mimic of miR-197 could sensitize PD-L1high drug-resistant cells to chemotherapy, thereby suggesting a role for miRNA replacement therapy.	('mimic', 'Var', (2, 7))	('sensitize', 'Reg', (25, 34))	('miR-197', 'Gene', (11, 18))	('miR-197', 'Gene', '406974', (11, 18))
899842	29580288	The expression of PD-L1 was not assessed in these studies; however, considering that miR-34a is a known regulator of PD-L1 expression and that PD-L1 expression can impact apoptosis, it would be interesting to investigate if the anti-MM effects of miR-34a can be partly attributed to the modulation of PD-L1 expression.	('anti-MM', 'CPA', (228, 235))	('PD-L1', 'Gene', (301, 306))	('miR-34a', 'Gene', (247, 254))	('apoptosis', 'CPA', (171, 180))	('miR-34a', 'Gene', '407040', (85, 92))	('PD-L1', 'Gene', (143, 148))	('impact', 'Reg', (164, 170))	('miR-34a', 'Gene', '407040', (247, 254))	('miR-34a', 'Gene', (85, 92))	('expression', 'Var', (149, 159))
899844	29580288	G0-203 was also found to downregulate PD-L1 expression in non-small cell lung carcinoma cells.	('expression', 'MPA', (44, 54))	('cell lung carcinoma', 'Disease', (68, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('G0-203', 'Var', (0, 6))	('downregulate', 'NegReg', (25, 37))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (62, 87))	('PD-L1', 'Gene', (38, 43))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (68, 87))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (58, 87))
899849	29580288	Another MUC1 peptide vaccine, ImMucin, is being studied in combination with recombinant human granulocyte-monocyte colony stimulating factor (hGM-CSF) in MM patients with MUC1 expression (NCT01232712).	('CSF', 'Gene', '1437', (146, 149))	('MUC1', 'Gene', (8, 12))	('MUC1', 'Gene', '4582', (8, 12))	('patients', 'Species', '9606', (157, 165))	('CSF', 'Gene', (146, 149))	('MUC1', 'Gene', (171, 175))	('MUC1', 'Gene', '4582', (171, 175))	('human', 'Species', '9606', (88, 93))	('NCT01232712', 'Var', (188, 199))
899855	28892299	Zinc (Zn) deficiency is a key risk factor for the occurrence and development of EC and affects progression by regulating microRNA (miRNA, miR) expression.	('Zn', 'Chemical', 'MESH:D015032', (6, 8))	('regulating', 'Reg', (110, 120))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', (138, 141))	('deficiency', 'Var', (10, 20))	('affects', 'Reg', (87, 94))	('miR', 'Gene', '220972', (131, 134))	('miR', 'Gene', (131, 134))
899873	28892299	collected 240 fasting serum samples from eastern and western regions of Golestan province that were considered high and low-risk regions for EC and found that the mean serum level of Zn in the high-risk region was significantly lower than that in the low-risk region.15  Micro-RNAs (miRNAs, miRs) are non-coding RNAs approximately 18-22 nucleotides in length that post-transcriptionally regulate gene expression by base-pairing to partially complementary sequences in the 3'-untranslated region (UTR) of their target messenger RNA (mRNA).	('base-pairing', 'Var', (415, 427))	('miR', 'Gene', '220972', (283, 286))	('miR', 'Gene', (291, 294))	('miR', 'Gene', (283, 286))	('Zn', 'Chemical', 'MESH:D015032', (183, 185))	('regulate', 'Reg', (387, 395))	('miR', 'Gene', '220972', (291, 294))	('gene', 'Gene', (396, 400))
899878	28892299	The relative levels of miR-21, miR-31, and miR-93 were significantly decreased, while the expression of miR-375 was significantly increased in EC cells cultured with Zn, with no difference in cell status.	('miR-31', 'Var', (31, 37))	('miR-21', 'Var', (23, 29))	('decreased', 'NegReg', (69, 78))	('Zn', 'Chemical', 'MESH:D015032', (166, 168))	('miR-93', 'Gene', '407051', (43, 49))	('expression', 'MPA', (90, 100))	('increased', 'PosReg', (130, 139))	('miR-93', 'Gene', (43, 49))	('miR-375', 'Var', (104, 111))
899881	28892299	MiR-21 overexpression was accompanied by downregulation of its tumor suppressors programmed cell death 4 (PDCD4) and tropomyosin alpha 1 chain (TPM1), whereas miR-31 overexpression was accompanied by downregulation of its tumor suppressor protein, phosphatase 2 regulatory subunit Balpha (PPP2R2A) in rats with Zn-deficient EC.19 Fong et al.	('rats', 'Species', '10116', (301, 305))	('tumor', 'Disease', (63, 68))	('MiR-21', 'Gene', (0, 6))	('PPP2R2A', 'Gene', '117104', (289, 296))	('miR-31', 'Var', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tropomyosin alpha 1 chain', 'Gene', (117, 142))	('TPM1', 'Gene', (144, 148))	('Zn-deficient EC.19 Fong', 'Disease', (311, 334))	('PPP2R2A', 'Gene', (289, 296))	('tumor', 'Disease', (222, 227))	('downregulation', 'NegReg', (41, 55))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Zn-deficient EC.19 Fong', 'Disease', 'MESH:D009261', (311, 334))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('downregulation', 'NegReg', (200, 214))	('tropomyosin alpha 1 chain', 'Gene', '24851', (117, 142))
899897	28892299	Follow-up data showed that patients with high miR-31 expression had a poorer prognosis for relapse-free and tumor-specific survival.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('miR-31', 'Gene', (46, 52))
899912	28892299	Patients with high miR-21 expression had lower radiotherapy sensitivity than those with low miR-21 expression, accompanied with a higher probability of recurrence.	('lower', 'NegReg', (41, 46))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('radiotherapy sensitivity', 'MPA', (47, 71))	('miR-21', 'Gene', (19, 25))
899917	28892299	Survival analysis indicated that high serum miR-223 expression and low miR-375 expression were associated with poor survival and could act as independent prognostic biomarkers for EC patients.30 In addition, a meta-analysis of 22 studies, including a total of 1946 EC patients from Canada, China, Germany, Japan, and the United States indicated that high miR-21 expression had a negative impact on overall survival (OS; HR 1.52, 95% CI 1.17-1.98; P = 0.001), whereas low miR-375 expression had a negative impact on OS (HR 0.53, 95% CI 0.39-0.73; P < 0.001).	('overall survival', 'MPA', (398, 414))	('high miR-21 expression', 'Var', (350, 372))	('low', 'NegReg', (467, 470))	('negative', 'NegReg', (379, 387))	('patients', 'Species', '9606', (268, 276))	('patients', 'Species', '9606', (183, 191))
899923	28892299	High miR-223 expression was associated with gender, tumor size, and tumor invasion depth in EC patients and predicted a significantly poorer prognosis.	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (95, 103))	('tumor', 'Disease', (52, 57))	('expression', 'MPA', (13, 23))	('associated', 'Reg', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('miR-223', 'Gene', (5, 12))
899927	28892299	FBXW7 mRNA expression was also significantly decreased, while c-Myc and c-Jun protein levels were enhanced in TE6 and TE15 cells following transfection with pre-miR-223 compared to those transfected with the negative control.	('enhanced', 'PosReg', (98, 106))	('c-Myc', 'Gene', '4609', (62, 67))	('c-Myc', 'Gene', (62, 67))	('decreased', 'NegReg', (45, 54))	('FBXW7', 'Gene', (0, 5))	('mRNA expression', 'MPA', (6, 21))	('transfection', 'Var', (139, 151))	('pre-miR-223', 'Var', (157, 168))
899931	28892299	Their results suggested that miR-223 expression is upregulated in EC cell lines OE33 and JHesoAD1 relative to HEEpiC cells and that miR-223-transfected cells exhibited a statistically significant increase in migratory and invasive potential.	('HEEpiC', 'CellLine', 'CVCL:S361', (110, 116))	('miR-223', 'Gene', (29, 36))	('rat', 'Species', '10116', (211, 214))	('miR-223-transfected', 'Var', (132, 151))	('upregulated', 'PosReg', (51, 62))	('expression', 'MPA', (37, 47))	('increase', 'PosReg', (196, 204))
899933	28892299	STK40 is a negative regulator of nuclear factor kappa B (NF-kappaB)-mediated transcription and acts as a tumor suppressor directly targeted by miR-31.36, 37, 38  Taccioli et al.	('nuclear factor kappa B', 'Gene', '4790', (33, 55))	('nuclear factor kappa B', 'Gene', (33, 55))	('NF-kappaB', 'Gene', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('negative', 'NegReg', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('STK40', 'Gene', (0, 5))	('tumor', 'Disease', (105, 110))	('NF-kappaB', 'Gene', '4790', (57, 66))	('miR-31.36', 'Var', (143, 152))
899939	28892299	Furthermore, the same relationship between miR-31 overexpression and STK40/NF-kappaB expression was also documented in human EC cell lines KYSE450, KYSE410, KYSE520, and KYSE510 in vitro.	('expression', 'MPA', (85, 95))	('KYSE520', 'Var', (157, 164))	('overexpression', 'PosReg', (50, 64))	('NF-kappaB', 'Gene', (75, 84))	('NF-kappaB', 'Gene', '4790', (75, 84))	('miR-31', 'Gene', (43, 49))	('KYSE410', 'Var', (148, 155))	('human', 'Species', '9606', (119, 124))
899953	28892299	Kaplan-Meier analysis showed that high miR-21 expression predicted a significantly lower disease-free survival in EC tissues than low miR-21 expression, suggesting that miR-21 expression is an unfavorable predictor of the survival in EC patients.	('disease-free survival', 'CPA', (89, 110))	('lower', 'NegReg', (83, 88))	('high', 'Var', (34, 38))	('miR-21', 'Gene', (39, 45))	('patients', 'Species', '9606', (237, 245))
899957	28892299	The results also suggested that miR-21 knockdown significantly increased PTEN protein expression, which was validated in EC cell line EC9706 transfected with a miR-21 inhibitor.	('EC9706', 'CellLine', 'CVCL:E307', (134, 140))	('PTEN', 'Gene', (73, 77))	('increased', 'PosReg', (63, 72))	('PTEN', 'Gene', '5728', (73, 77))	('knockdown', 'Var', (39, 48))	('miR-21', 'Gene', (32, 38))
899959	28892299	PTEN is a direct target of miR-21 and miR-21 suppressed PTEN expression by directly binding to the 3'-UTR of its mRNA.42  Wu et al.	('PTEN', 'Gene', (56, 60))	('miR-21', 'Var', (38, 44))	('PTEN', 'Gene', '5728', (56, 60))	('PTEN', 'Gene', '5728', (0, 4))	('binding', 'Interaction', (84, 91))	('suppressed', 'NegReg', (45, 55))	('PTEN', 'Gene', (0, 4))	('expression', 'MPA', (61, 71))
899966	28892299	examined miR-21 expression in 16 pairs of primary EC tissues and adjacent para-cancerous tissues and discovered that miR-21 was significantly upregulated in EC tissues and high miR-21 expression was associated with lymph node metastasis in EC patients.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lymph node metastasis', 'CPA', (215, 236))	('associated with', 'Reg', (199, 214))	('para-cancerous tissues', 'Disease', (74, 96))	('patients', 'Species', '9606', (243, 251))	('miR-21', 'Gene', (117, 123))	('miR-21', 'Gene', (177, 183))	('high', 'Var', (172, 176))	('expression', 'MPA', (184, 194))	('upregulated', 'PosReg', (142, 153))	('para-cancerous tissues', 'Disease', 'MESH:D009369', (74, 96))
899967	28892299	Silencing of miR-21 expression in EC cell lines EC9706 and EC-1 significantly inhibited cell proliferation and invasion and promoted apoptosis in vitro.	('miR-21', 'Gene', (13, 19))	('inhibited', 'NegReg', (78, 87))	('apoptosis', 'CPA', (133, 142))	('EC9706', 'CellLine', 'CVCL:E307', (48, 54))	('EC-1', 'Gene', (59, 63))	('promoted', 'PosReg', (124, 132))	('EC-1', 'CellLine', 'CVCL:5V05', (59, 63))	('Silencing', 'Var', (0, 9))	('rat', 'Species', '10116', (100, 103))
899976	28892299	These results suggest that MTDH is a direct target gene of miR-375.26  Kong et al.	('MTDH', 'Gene', (27, 31))	('MTDH', 'Gene', '92140', (27, 31))	('miR-375.26', 'Var', (59, 69))
899977	28892299	investigated miR-375 expression in 105 pairs of primary EC tissues and corresponding para-cancerous tissues, as well as in eight EC cell lines (KYSE30, KYSE140, KYSE180, KYSE410, KYSE510, KYSE520, EC109, and HKESC1).	('KYSE410', 'Var', (170, 177))	('KYSE30', 'Var', (144, 150))	('KYSE520', 'Var', (188, 195))	('para-cancerous tissues', 'Disease', 'MESH:D009369', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('KYSE510', 'Var', (179, 186))	('KYSE140', 'Var', (152, 159))	('para-cancerous tissues', 'Disease', (85, 107))	('KYSE180', 'Var', (161, 168))	('EC109', 'CellLine', 'CVCL:6898', (197, 202))	('miR-375', 'Gene', (13, 20))
899979	28892299	MiR-375 suppressed tumor cell proliferation, invasion, and metastasis and downregulation of miR-31 was mostly caused by promoter hypermethylation.	('metastasis', 'CPA', (59, 69))	('MiR-375', 'Gene', (0, 7))	('downregulation', 'NegReg', (74, 88))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('MiR-375', 'Gene', '494324', (0, 7))	('rat', 'Species', '10116', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('promoter hypermethylation', 'Var', (120, 145))	('tumor', 'Disease', (19, 24))	('invasion', 'CPA', (45, 53))	('miR-31', 'Gene', (92, 98))	('suppressed', 'NegReg', (8, 18))
899980	28892299	Moreover, there was a negative correlation between miR-375 and IGF1R in EC cell lines; miR-375 downregulated insulin-like growth factor 1 receptor (IGF1R) expression at both the mRNA and protein levels by binding to the 3'-UTR of IGF1R in vitro.	('IGF1R', 'Gene', (148, 153))	('IGF1R', 'Gene', '3480', (148, 153))	('downregulated', 'NegReg', (95, 108))	('IGF1R', 'Gene', (230, 235))	('expression', 'MPA', (155, 165))	('IGF1R', 'Gene', '3480', (230, 235))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (109, 146))	('IGF1R', 'Gene', (63, 68))	('binding', 'Interaction', (205, 212))	('insulin-like growth factor 1 receptor', 'Gene', (109, 146))	('miR-375', 'Var', (87, 94))	('IGF1R', 'Gene', '3480', (63, 68))
899982	28892299	At the same time, a significant negative correlation was observed between miR-375 and IGF1R in EC and validated the result in vitro.	('negative', 'NegReg', (32, 40))	('IGF1R', 'Gene', (86, 91))	('miR-375', 'Var', (74, 81))	('IGF1R', 'Gene', '3480', (86, 91))
900060	21804542	More than 50% of human cancers harbor mutations in TP53.	('TP53', 'Gene', (51, 55))	('human', 'Species', '9606', (17, 22))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('mutations', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
900065	21804542	Nucleolar stress is often caused by disruption of ribosomal biogenesis, which in turn can be caused by serum depletion and contact inhibition, agents like low-dose actinomycin D or mycophenolic acid or malfunction of nucleolar proteins.	('ribosomal', 'MPA', (50, 59))	('mycophenolic acid', 'Chemical', 'MESH:D009173', (181, 198))	('Nucleolar', 'Disease', (0, 9))	('disruption', 'Reg', (36, 46))	('caused', 'Reg', (93, 99))	('caused', 'Reg', (26, 32))	('malfunction', 'Var', (202, 213))	('actinomycin D', 'Chemical', 'MESH:D003609', (164, 177))
900071	21804542	Other evidence, however, suggests that PICT1 may not always dampen cancer progression.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('PICT1', 'Var', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('dampen', 'NegReg', (60, 66))
900072	21804542	In oligodendroglial tumors, deletion of the entire chromosome 19q arm, as well as loss of heterozygosity (LOH) at chromosome 19q13 is associated with longer disease-free survival after chemotherapy.	('longer', 'PosReg', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('disease-free survival', 'CPA', (157, 178))	('deletion', 'Var', (28, 36))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (3, 26))	('oligodendroglial tumors', 'Disease', (3, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('loss', 'Var', (82, 86))
900077	21804542	We show here that PICT1 is a key regulator of ribosomal protein-driven P53-mediated responses to nucleolar stress and that loss of PICT1 inhibits tumor growth owing to stabilization of P53.	('PICT1', 'Gene', (131, 136))	('P53', 'Protein', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('stabilization', 'MPA', (168, 181))	('loss', 'Var', (123, 127))	('inhibits', 'NegReg', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
900078	21804542	We generated mice bearing a null mutation of Pict1 (Supplementary Fig.	('mice', 'Species', '10090', (13, 17))	('Pict1', 'Gene', (45, 50))	('null mutation', 'Var', (28, 41))
900083	21804542	Because Dox- Pict1 ES cells behaved like wild-type (WT) ES cells in cell growth, cell cycle and apoptosis assays (Supplementary Fig.	('Dox', 'Chemical', 'MESH:D004318', (8, 11))	('apoptosis assays', 'CPA', (96, 112))	('cell growth', 'CPA', (68, 79))	('cell cycle', 'CPA', (81, 91))	('Dox- Pict1 ES', 'Var', (8, 21))
900086	21804542	Compared with Dox- cells, Dox+ cells showed greater expression of p53, p21Waf1 and p19Arf (Fig.	('Dox', 'Chemical', 'MESH:D004318', (14, 17))	('Dox', 'Chemical', 'MESH:D004318', (26, 29))	('expression', 'MPA', (52, 62))	('p21', 'Gene', (71, 74))	('p53', 'Var', (66, 69))	('p21', 'Gene', '644914', (71, 74))	('greater', 'PosReg', (44, 51))	('p19Arf', 'Var', (83, 89))
900088	21804542	The greater p53 expression in Dox+ cells was probably not due to DNA damage, because phospho-gamma-histone family member X (pgammaH2ax), which is a marker of DNA damage, was much lower in Dox+ cells than in ultraviolet (UV)-treated cells with comparable p53 activation (Fig.	('pgammaH2ax', 'Chemical', '-', (124, 134))	('lower', 'NegReg', (179, 184))	('phospho-gamma-histone', 'MPA', (85, 106))	('Dox+', 'Var', (188, 192))	('Dox', 'Chemical', 'MESH:D004318', (30, 33))	('Dox', 'Chemical', 'MESH:D004318', (188, 191))	('expression', 'MPA', (16, 26))
900091	21804542	Although p19Arf expression was greater in Dox+ than in Dox- cells (Fig.	('p19Arf', 'Var', (9, 15))	('Dox', 'Chemical', 'MESH:D004318', (42, 45))	('Dox', 'Chemical', 'MESH:D004318', (55, 58))	('greater', 'PosReg', (31, 38))	('expression', 'MPA', (16, 26))
900092	21804542	2a), siRNA-mediated p19Arf knockdown did not affect p53 protein expression, cell cycle arrest or apoptosis in Dox+ cells (Supplementary Fig.	('knockdown', 'Var', (27, 36))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('Dox', 'Chemical', 'MESH:D004318', (110, 113))	('p53', 'Gene', (52, 55))	('cell cycle', 'CPA', (76, 86))
900094	21804542	We therefore generated mice deficient in Pict1 specifically in T cells by crossing LckCre transgenic mice with Pict1flox mice (Supplementary Methods).	('transgenic mice', 'Species', '10090', (90, 105))	('Pict1', 'Gene', (41, 46))	('deficient', 'Var', (28, 37))	('mice', 'Species', '10090', (101, 105))	('mice', 'Species', '10090', (121, 125))	('mice', 'Species', '10090', (23, 27))
900104	21804542	Through cycloheximide studies, we found that p53 protein half-life was longer in Dox+ cells compared to Dox- cells (Fig.	('longer', 'PosReg', (71, 77))	('Dox+ cells', 'Var', (81, 91))	('Dox', 'Chemical', 'MESH:D004318', (104, 107))	('p53 protein', 'Protein', (45, 56))	('cycloheximide', 'Chemical', 'MESH:D003513', (8, 21))	('Dox', 'Chemical', 'MESH:D004318', (81, 84))
900105	21804542	3b), but Pict1 deficiency had no effect on p21 protein half-life (data not shown).	('p21', 'Gene', (43, 46))	('Pict1', 'Gene', (9, 14))	('deficiency', 'Var', (15, 25))	('p21', 'Gene', '644914', (43, 46))
900120	21804542	Although deficiency in nucleophosmin, nucleostemin or nucleolin causes P53 accumulation, the endogenous expression and localization of none of these proteins was impaired in Dox+ cells (Fig.	('P53', 'Gene', (71, 74))	('nucleolin', 'Gene', '4691', (54, 63))	('nucleostemin', 'Gene', (38, 50))	('nucleophosmin', 'Gene', '4869', (23, 36))	('deficiency', 'Var', (9, 19))	('nucleophosmin', 'Gene', (23, 36))	('Dox', 'Chemical', 'MESH:D004318', (174, 177))	('nucleostemin', 'Gene', '26354', (38, 50))	('nucleolin', 'Gene', (54, 63))	('accumulation', 'PosReg', (75, 87))
900140	21804542	As a result, p53 accumulates in Dox+ cells.	('p53', 'Var', (13, 16))	('Dox', 'Chemical', 'MESH:D004318', (32, 35))	('accumulates', 'PosReg', (17, 28))
900146	21804542	We observed neither growth inhibition nor P53 accumulation in TP53-mutated or P53-inactivated tumor cell lines that were treated with PICT1 shRNA (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PICT1', 'Var', (134, 139))	('tumor', 'Disease', (94, 99))
900149	21804542	We detected TP53 mutations in ~40% of our colorectal and esophageal cancer specimens, consistent with earlier reports.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal', 'Disease', 'MESH:D015179', (42, 52))	('esophageal cancer', 'Disease', (57, 74))	('colorectal', 'Disease', (42, 52))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('detected', 'Reg', (3, 11))
900156	21804542	Inhibition of Pict1 in ES cells and in various TP53-intact cancer cell lines led to P53 accumulation that inhibited cell growth in vitro.	('cell growth in vitro', 'CPA', (116, 136))	('Pict1', 'Gene', (14, 19))	('inhibited', 'NegReg', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('accumulation', 'PosReg', (88, 100))	('P53', 'Gene', (84, 87))
900159	21804542	Consistent with our finding that PICT1 knockdown inhibited the growth of TP53-intact glioma cells (Fig.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('knockdown', 'Var', (39, 48))	('growth', 'CPA', (63, 69))	('PICT1', 'Gene', (33, 38))	('glioma', 'Disease', (85, 91))	('inhibited', 'NegReg', (49, 58))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
900160	21804542	5b), oligodendroglial tumors with loss of chromosome 19q13 have a better disease outcome.	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (5, 28))	('oligodendroglial tumors', 'Disease', (5, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('loss of chromosome', 'Var', (34, 52))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))
900166	21804542	However, we found that amounts of ribosomal proteins other than Rpl11, including Rps7, were not decreased in the nucleolus by Pict1 deficiency.	('decreased', 'NegReg', (96, 105))	('Rpl11', 'Gene', '6135', (64, 69))	('Rps7', 'Gene', (81, 85))	('Pict1', 'Gene', (126, 131))	('Rpl11', 'Gene', (64, 69))	('deficiency', 'Var', (132, 142))	('Rps7', 'Gene', '6201', (81, 85))
900178	21804542	We transiently transfected Tet-regulatable Pict1-deficient ES cells (Pict1tetTg+; Pict13loxP/-; Supplementary Fig.	('Pict1-deficient', 'Gene', (43, 58))	('Pict13loxP/-', 'Var', (82, 94))	('Tet', 'Chemical', 'MESH:C010349', (27, 30))
900180	21804542	We added Dox (5 ng ml-1) to Pict1 ES cells to delete Pict1 and generate Dox+ cells (Supplementary Fig.	('Pict1', 'Gene', (53, 58))	('Dox', 'Chemical', 'MESH:D004318', (72, 75))	('Dox', 'Chemical', 'MESH:D004318', (9, 12))	('delete', 'Var', (46, 52))
900186	21804542	For shRNA studies, we produced lentiviruses containing PICT1 shRNA or scrambled shRNA (lenti-shRNA) and used them to infect tumor cells as previously described.	('infect tumor', 'Disease', (117, 129))	('infect tumor', 'Disease', 'MESH:D009369', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('PICT1', 'Var', (55, 60))
900191	21804542	4), we lysed Pict1 ES cells at various times after addition of 5 ng ml-1 doxycycline and incubated them with antibodies to Pict1, Mdm2 (Santa Cruz), Rpl11 or p53 (Novocastra) or control IgG (Santa Cruz).	('Rpl11', 'Gene', '6135', (149, 154))	('Mdm2', 'Var', (130, 134))	('doxycycline', 'Chemical', 'MESH:D004318', (73, 84))	('antibodies', 'Var', (109, 119))	('Rpl11', 'Gene', (149, 154))	('p53', 'Var', (158, 161))	('Pict1', 'Gene', (123, 128))
900214	25320732	The prognostic factors for mortality were age over 50 (OR 5.496, P=0.002), Child-Pugh class B (OR 3.979, P=0.001), and Child-Pugh class C (OR 10.861, P=0.000).	('Child', 'Species', '9606', (75, 80))	('Child-Pugh class C', 'Var', (119, 137))	('Child-Pugh class B', 'Var', (75, 93))	('Child', 'Species', '9606', (119, 124))
900260	25320732	Deaths from variceal bleeding occurred in 2 (0.6%) in Gr1 as compared to none in Gr2.	('bleeding', 'Disease', (21, 29))	('Gr1', 'Var', (54, 57))	('bleeding', 'Disease', 'MESH:D006470', (21, 29))
900292	25320732	Although infection-related deaths were more frequent in Gr2, complications with EVL resolved within 2 weeks of EVL and none were fatal.	('EVL', 'Chemical', '-', (80, 83))	('EVL', 'Chemical', '-', (111, 114))	('death', 'Disease', 'MESH:D003643', (27, 32))	('death', 'Disease', (27, 32))	('Gr2', 'Var', (56, 59))	('infection', 'Disease', (9, 18))	('infection', 'Disease', 'MESH:D007239', (9, 18))
900308	22646166	Conversely, silencing CUG-BP1 in esophageal cancer cells destabilizes survivin mRNA, lowering survivin protein levels.	('survivin', 'Gene', '11799', (70, 78))	('survivin', 'Gene', '11799', (94, 102))	('survivin', 'Gene', (70, 78))	('silencing', 'Var', (12, 21))	('CUG-BP1', 'Gene', (22, 29))	('lowering', 'NegReg', (85, 93))	('survivin', 'Gene', (94, 102))	('esophageal cancer', 'Disease', (33, 50))	('destabilizes', 'NegReg', (57, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
900309	22646166	Overexpression of CUG-BP1 in esophageal epithelial cells increases resistance to apoptosis, while silencing CUG-BP1 makes esophageal cancer cells more susceptible to chemotherapy-induced apoptosis.	('esophageal cancer', 'Disease', (122, 139))	('CUG-BP1', 'Gene', (108, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('resistance to apoptosis', 'MPA', (67, 90))	('silencing', 'Var', (98, 107))	('increases', 'PosReg', (57, 66))	('more', 'PosReg', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
900329	22646166	The experiments presented in this manuscript demonstrate for the first time that 1) overexpression of CUG-BP1 is strongly correlated with the overexpression of survivin observed in esophageal cancer cell lines and human specimens; 2) CUG-BP1 binds to the 3'untranslated region (UTR) of survivin mRNA; 3) this interaction increases the half-life of survivin mRNA in esophageal epithelial cells; and 4) silencing CUG-BP1 in esophageal cancer cells increases their susceptibility to chemotherapy-induced apoptosis.	('CUG-BP1', 'Gene', (411, 418))	('esophageal cancer', 'Disease', (181, 198))	('interaction', 'Interaction', (309, 320))	('survivin', 'Gene', (160, 168))	('increases', 'PosReg', (321, 330))	('half-life', 'MPA', (335, 344))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('increases', 'PosReg', (446, 455))	('esophageal cancer', 'Disease', 'MESH:D004938', (422, 439))	('survivin', 'Gene', '11799', (160, 168))	('survivin', 'Gene', (286, 294))	('survivin', 'Gene', (348, 356))	('esophageal cancer', 'Disease', (422, 439))	('human', 'Species', '9606', (214, 219))	('silencing', 'Var', (401, 410))	('survivin', 'Gene', '11799', (286, 294))	('survivin', 'Gene', '11799', (348, 356))	('rat', 'Species', '10116', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('esophageal cancer', 'Disease', 'MESH:D004938', (181, 198))	('susceptibility to chemotherapy-induced apoptosis', 'CPA', (462, 510))
900359	22646166	Whole cell lysates were used for IP in the presence of anti-CUG-BP1, anti-Ago2, or non-specific IgG.	('anti-CUG-BP1', 'Var', (55, 67))	('Ago2', 'Gene', '239528', (74, 78))	('Ago2', 'Gene', (74, 78))
900402	22646166	To demonstrate that the down-regulation of survivin expression following CUG-BP1 silencing was not merely a reflection of global changes in cell growth, we examined the effect of silencing CUG-BP1 on Cyclin-Dependent Kinase 4 (CDK4).	('CUG-BP1', 'Gene', (189, 196))	('CUG-BP1', 'Gene', (73, 80))	('survivin', 'Gene', '11799', (43, 51))	('Cyclin-Dependent Kinase 4', 'Gene', '12567', (200, 225))	('expression', 'MPA', (52, 62))	('silencing', 'Var', (81, 90))	('Cyclin-Dependent Kinase 4', 'Gene', (200, 225))	('rat', 'Species', '10116', (10, 13))	('survivin', 'Gene', (43, 51))	('silencing', 'Var', (179, 188))	('down-regulation', 'NegReg', (24, 39))
900403	22646166	Survivin mRNA was also decreased after silencing CUG-BP1 (Figure 3F).	('CUG-BP1', 'Gene', (49, 56))	('Survivin', 'Gene', '11799', (0, 8))	('Survivin', 'Gene', (0, 8))	('silencing', 'Var', (39, 48))	('decreased', 'NegReg', (23, 32))
900405	22646166	These studies show that silencing CUG-BP1 destabilizes survivin mRNA leading to decreased survivin protein expression in esophageal cancer cells.	('survivin', 'Gene', '11799', (90, 98))	('survivin', 'Gene', (55, 63))	('esophageal cancer', 'Disease', (121, 138))	('survivin', 'Gene', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('decreased', 'NegReg', (80, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('survivin', 'Gene', '11799', (55, 63))	('destabilizes', 'NegReg', (42, 54))	('CUG-BP1', 'Gene', (34, 41))	('silencing', 'Var', (24, 33))
900407	22646166	We postulate that in the presence of CUG-BP1, survivin mRNA is prevented from being transported to P-bodies, leading to its increased expression.	('survivin', 'Gene', '11799', (46, 54))	('expression', 'MPA', (134, 144))	('increased', 'PosReg', (124, 133))	('survivin', 'Gene', (46, 54))	('CUG-BP1', 'Var', (37, 44))
900408	22646166	To test this hypothesis, we measured the amount of survivin mRNA associated with Ago2, an important component of the P-body, following CUG-BP1 silencing.	('Ago2', 'Gene', (81, 85))	('survivin', 'Gene', (51, 59))	('Ago2', 'Gene', '239528', (81, 85))	('CUG-BP1', 'Gene', (135, 142))	('survivin', 'Gene', '11799', (51, 59))	('silencing', 'Var', (143, 152))
900409	22646166	After silencing CUG-BP1 in TE7 cells, the detected levels of survivin mRNA were increased in the Ago2-immunoprecipitated materials compared with cells treated with C-siRNA.	('increased', 'PosReg', (80, 89))	('survivin', 'Gene', '11799', (61, 69))	('CUG-BP1', 'Gene', (16, 23))	('Ago2', 'Gene', (97, 101))	('TE7', 'CellLine', 'CVCL:9972', (27, 30))	('Ago2', 'Gene', '239528', (97, 101))	('silencing', 'Var', (6, 15))	('survivin', 'Gene', (61, 69))
900412	22646166	As seen in Figure 4B, silencing both CUG-BP1 and Lsm4 abrogates the reduction in survivin protein levels observed when CUG-BP1 alone is silenced.	('abrogates', 'NegReg', (54, 63))	('survivin', 'Gene', '11799', (81, 89))	('silencing', 'Var', (22, 31))	('Lsm4', 'Gene', (49, 53))	('Lsm4', 'Gene', '50783', (49, 53))	('reduction', 'NegReg', (68, 77))	('CUG-BP1', 'Gene', (37, 44))	('survivin', 'Gene', (81, 89))
900413	22646166	Together, these studies suggest that CUG-BP1 prevents transport of survivin mRNA to the P-body, thus maintaining high survivin expression levels in esophageal cancer cells.	('high', 'PosReg', (113, 117))	('expression levels', 'MPA', (127, 144))	('survivin', 'Gene', '11799', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('survivin', 'Gene', (118, 126))	('esophageal cancer', 'Disease', (148, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (148, 165))	('prevents', 'NegReg', (45, 53))	('survivin', 'Gene', (67, 75))	('CUG-BP1', 'Var', (37, 44))	('survivin', 'Gene', '11799', (118, 126))	('transport of', 'MPA', (54, 66))
900415	22646166	Based on our findings that CUG-BP1 overexpression leads to increased survivin expression in nhESO cells, we hypothesized that overexpression of CUG-BP1 in nhESO cells would result in increased resistance to apoptosis.	('CUG-BP1', 'Gene', (27, 34))	('CUG-BP1', 'Gene', (144, 151))	('expression', 'MPA', (78, 88))	('nhESO', 'Chemical', '-', (92, 97))	('increased', 'PosReg', (183, 192))	('survivin', 'Gene', (69, 77))	('resistance to apoptosis', 'CPA', (193, 216))	('overexpression', 'Var', (35, 49))	('survivin', 'Gene', '11799', (69, 77))	('nhESO', 'Chemical', '-', (155, 160))	('increased', 'PosReg', (59, 68))
900420	22646166	Based on these findings, we further hypothesized that silencing CUG-BP1 would increase the susceptibility of TE7 cells to apoptosis.	('silencing', 'Var', (54, 63))	('apoptosis', 'CPA', (122, 131))	('TE7', 'CellLine', 'CVCL:9972', (109, 112))	('increase', 'PosReg', (78, 86))	('susceptibility', 'MPA', (91, 105))	('CUG-BP1', 'Gene', (64, 71))
900421	22646166	Following successful CUG-BP1 silencing, TE7 cells were induced with 10muM camptothecin for 6 hours and apoptosis was measured.	('TE7', 'CellLine', 'CVCL:9972', (40, 43))	('CUG-BP1', 'Gene', (21, 28))	('silencing', 'Var', (29, 38))	('camptothecin', 'Chemical', 'MESH:D002166', (74, 86))
900424	22646166	These findings indicate that silencing CUG-BP1 leads to increased susceptibility of esophageal cancer cells to apoptosis, possibly through decreased survivin protein levels.	('survivin', 'Gene', '11799', (149, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('susceptibility', 'MPA', (66, 80))	('silencing', 'Var', (29, 38))	('decreased', 'NegReg', (139, 148))	('esophageal cancer', 'Disease', (84, 101))	('CUG-BP1', 'Gene', (39, 46))	('survivin', 'Gene', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('apoptosis', 'CPA', (111, 120))
900442	22646166	Instead, IGF-1 was found to modulate improved stability and enhanced translation of a pre-existing pool of survivin mRNA, although the mechanism by which this occurred was not elucidated.	('modulate', 'Var', (28, 36))	('IGF-1', 'Gene', (9, 14))	('IGF-1', 'Gene', '16000', (9, 14))	('survivin', 'Gene', (107, 115))	('improved', 'PosReg', (37, 45))	('stability', 'MPA', (46, 55))	('survivin', 'Gene', '11799', (107, 115))	('enhanced', 'PosReg', (60, 68))	('translation', 'MPA', (69, 80))
900458	22646166	Similarly, in TE7 cells, silencing CUG-BP1 in TE7 cells was associated with an increase in CDK4 levels.	('increase', 'PosReg', (79, 87))	('silencing', 'Var', (25, 34))	('TE7', 'CellLine', 'CVCL:9972', (14, 17))	('CUG-BP1', 'Gene', (35, 42))	('TE7', 'CellLine', 'CVCL:9972', (46, 49))	('CDK4 levels', 'MPA', (91, 102))
900462	22646166	In addition, we found that silencing Lsm4, an important activator of decapping in P-bodies, abrogates the reduction of survivin levels in TE7 cells following silencing of CUG-BP1.	('TE7', 'CellLine', 'CVCL:9972', (138, 141))	('Lsm4', 'Gene', (37, 41))	('silencing', 'Var', (27, 36))	('Lsm4', 'Gene', '50783', (37, 41))	('silencing', 'Var', (158, 167))	('survivin', 'Gene', '11799', (119, 127))	('abrogates', 'NegReg', (92, 101))	('reduction', 'NegReg', (106, 115))	('CUG-BP1', 'Gene', (171, 178))	('survivin', 'Gene', (119, 127))
900465	22646166	Conversely, silencing CUG-BP1 in esophageal cancer cells increased the susceptibility of these cells to apoptosis.	('silencing', 'Var', (12, 21))	('CUG-BP1', 'Gene', (22, 29))	('susceptibility', 'MPA', (71, 85))	('esophageal cancer', 'Disease', (33, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
900467	22646166	The finding that altering CUG-BP1 expression directly correlated with survivin expression and cellular sensitivity to apoptosis suggested that CUG-BP1 mediates sensitivity to apoptosis by affecting survivin levels.	('survivin', 'Gene', '11799', (70, 78))	('survivin', 'Gene', '11799', (198, 206))	('survivin', 'Gene', (70, 78))	('affecting', 'Reg', (188, 197))	('CUG-BP1', 'Gene', (26, 33))	('survivin', 'Gene', (198, 206))	('CUG-BP1', 'Var', (143, 150))
900468	22646166	However, by simultaneously overexpressing CUG-BP1 and silencing surviving in TE7 cells, we were able to completely abrogate the increased sensitivity to camptothecin-induced apoptosis seen only with survivin silencing.	('CUG-BP1', 'Gene', (42, 49))	('abrogate', 'NegReg', (115, 123))	('survivin', 'Gene', (199, 207))	('silencing', 'Var', (54, 63))	('TE7', 'CellLine', 'CVCL:9972', (77, 80))	('survivin', 'Gene', '11799', (64, 72))	('sensitivity to camptothecin-induced apoptosis', 'MPA', (138, 183))	('survivin', 'Gene', '11799', (199, 207))	('survivin', 'Gene', (64, 72))	('camptothecin', 'Chemical', 'MESH:D002166', (153, 165))	('overexpressing', 'PosReg', (27, 41))
900469	22646166	This finding raises the possibility that CUG-BP1 can enhance the expression of other anti-apoptotic proteins in addition to survivin.	('CUG-BP1', 'Var', (41, 48))	('survivin', 'Gene', (124, 132))	('expression', 'MPA', (65, 75))	('enhance', 'PosReg', (53, 60))	('survivin', 'Gene', '11799', (124, 132))
900479	23508980	The presence of Barrett's esophagus or intestinal metaplasia in the esophagus is associated with a 30-fold increased risk over the general population of developing esophageal adenocarcinoma (EAC), a cancer with a rising incidence in Western countries and an overall 5-year survival rate of 19%.	('intestinal metaplasia', 'Disease', 'MESH:D008679', (39, 60))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (16, 35))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (164, 189))	('presence', 'Var', (4, 12))	('intestinal metaplasia', 'Disease', (39, 60))	('esophageal adenocarcinoma', 'Disease', (164, 189))	('EAC', 'Phenotype', 'HP:0011459', (191, 194))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (164, 189))
900519	33731185	After binding to its ligand, TYK2 is phosphorylated and activated at Tyr1054 or/and Tyr1055.	('Tyr1055', 'Var', (84, 91))	('binding', 'Interaction', (6, 13))	('Tyr1055', 'Chemical', '-', (84, 91))	('Tyr1054', 'Var', (69, 76))	('activated', 'PosReg', (56, 65))	('Tyr1054', 'Chemical', '-', (69, 76))	('TYK2', 'Protein', (29, 33))
900525	33731185	In this study, we found that TYK2 served as an oncogene in ESCC and its protein level was negatively associated with ESCC patients' overall survival rates.	('negatively', 'NegReg', (90, 100))	('protein level', 'MPA', (72, 85))	('patients', 'Species', '9606', (122, 130))	('ESCC', 'Disease', (59, 63))	('TYK2', 'Var', (29, 33))	('associated', 'Reg', (101, 111))	('ESCC', 'Disease', (117, 121))
900528	33731185	Antibodies to detect p-STAT3 (Cat#9145), STAT3 (Cat#9139), Bcl-2 (Cat#15071), GAPDH (Cat#2118), myeloid cell leukemia-1 (Mcl-1, Cat#94296), PARP (Cat#9542) and beta-actin (Cat#3700) were all purchased from CST antibody company (Beverly, MA, USA).	('PARP', 'Gene', '1302', (140, 144))	('Cat#15071', 'Var', (66, 75))	('Cat#3700', 'Var', (172, 180))	('PARP', 'Gene', (140, 144))	('myeloid cell leukemia-1', 'Gene', '4170', (96, 119))	('Cat#9139', 'Var', (48, 56))	('GAPDH', 'Gene', (78, 83))	('Cat#9145', 'Var', (30, 38))	('Cat#', 'Var', (146, 150))	('GAPDH', 'Gene', '2597', (78, 83))	('myeloid cell leukemia-1', 'Gene', (96, 119))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (96, 117))
900531	33731185	Human ESCC cell lines KYSE30, KYSE70, KYSE140, KYSE410, KYSE450 and KYSE510 were bought from the Type Culture Collection of Chinese Academy of Sciences (Shanghai, China) and the cell lines were mycoplasma-free and authenticated by STR analysis.	('Human', 'Species', '9606', (0, 5))	('KYSE510', 'Var', (68, 75))	('KYSE70', 'Var', (30, 36))	('KYSE140', 'Var', (38, 45))	('KYSE410', 'Var', (47, 54))	('KYSE140', 'Chemical', '-', (38, 45))	('KYSE450', 'Var', (56, 63))
900587	33731185	After knocking down of TYK2, the growth of KYSE140 and KYSE450 were suppressed (Fig.	('growth', 'MPA', (33, 39))	('KYSE450', 'Enzyme', (55, 62))	('suppressed', 'NegReg', (68, 78))	('KYSE140', 'Chemical', '-', (43, 50))	('TYK2', 'Gene', (23, 27))	('knocking down', 'Var', (6, 19))
900588	33731185	Furthermore, the tumor growth of Cell-derived xenograft (CDX) mice model was reduced after TYK2 knockdown (Fig.	('knockdown', 'Var', (96, 105))	('tumor', 'Disease', (17, 22))	('CDX', 'Chemical', '-', (57, 60))	('mice', 'Species', '10090', (62, 66))	('reduced', 'NegReg', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('TYK2', 'Gene', (91, 95))
900589	33731185	2d & e and Supplementary 1a) and the average of tumor weight in the TYK2 knockdown group was lower than the control group in the CDX mice model (Fig.	('CDX', 'Chemical', '-', (129, 132))	('mice', 'Species', '10090', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('the', 'Gene', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('was', 'NegReg', (89, 92))	('TYK2', 'Var', (68, 72))
900590	33731185	In addition, after TYK2 knockdown, the cell cycle was arrested at the G2/M phase in both KYSE140 and KYSE450 cell lines (Supplementary 1b).	('KYSE140', 'Chemical', '-', (89, 96))	('cell cycle', 'CPA', (39, 49))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('TYK2', 'Gene', (19, 23))	('knockdown', 'Var', (24, 33))	('arrest', 'Disease', (54, 60))
900591	33731185	Similarly, cell migration was also decreased following TYK2 knockdown in KYSE140 and KYSE450 (Supplementary 1c).	('cell migration', 'CPA', (11, 25))	('TYK2', 'Gene', (55, 59))	('decreased', 'NegReg', (35, 44))	('knockdown', 'Var', (60, 69))	('KYSE140', 'Chemical', '-', (73, 80))
900592	33731185	For the related mechanism study, we found that the STAT3 phosphorylation was inhibited after TYK2 knockdown in KYSE140 and KYSE450 cell lines (Fig.	('KYSE140', 'Chemical', '-', (111, 118))	('STAT3 phosphorylation', 'MPA', (51, 72))	('inhibited', 'NegReg', (77, 86))	('knockdown', 'Var', (98, 107))	('TYK2', 'Gene', (93, 97))
900595	33731185	The results predicted that cirsiliol achieves binding at PRO982 and VAL981 in the ATP binding pocket (Fig.	('PRO982', 'Var', (57, 63))	('ATP', 'Chemical', 'MESH:D000255', (82, 85))	('binding', 'Interaction', (46, 53))	('VAL981', 'Chemical', '-', (68, 74))	('VAL981', 'Var', (68, 74))	('cirsiliol', 'Chemical', 'MESH:C039824', (27, 36))	('PRO982', 'Chemical', '-', (57, 63))
900600	33731185	After single and double mutation, the amino sites, the cell lysate were harvested for pull down assay, which showed that the binding ability of cirsiliol was decreased after mutating the docking site to Alanine (Fig.	('decreased', 'NegReg', (158, 167))	('cirsiliol', 'Chemical', 'MESH:C039824', (144, 153))	('Alanine', 'Chemical', 'MESH:D000409', (203, 210))	('binding', 'Interaction', (125, 132))	('mutating', 'Var', (174, 182))
900605	33731185	Similarly, the colony counts of KYSE140 and KYSE450 were both decreased in a dose-dependent pattern after cirsiliol treatment (Fig.	('KYSE140', 'Chemical', '-', (32, 39))	('decreased', 'NegReg', (62, 71))	('cirsiliol', 'Chemical', 'MESH:C039824', (106, 115))	('colony counts', 'CPA', (15, 28))	('KYSE450', 'Var', (44, 51))
900607	33731185	Compared to the untreated group, results showed that the cell cycle of KYSE140 and KYSE450 was arrested at the G2/M phase (56.3 and 43.4% at 20 muM, respectively; Fig.	('KYSE140', 'Chemical', '-', (71, 78))	('KYSE450', 'Var', (83, 90))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('arrest', 'Disease', (95, 101))	('cell cycle', 'CPA', (57, 67))
900611	33731185	Thus, we treated TYK2 knockdown ESCC cells with cirsiliol.	('knockdown', 'Var', (22, 31))	('TYK2', 'Gene', (17, 21))	('cirsiliol', 'Chemical', 'MESH:C039824', (48, 57))
900615	33731185	Moreover, the inhibitory effect of cirsiliol on clone formation was also weakened after TYK2 knockdown (Fig.	('knockdown', 'Var', (93, 102))	('clone formation', 'CPA', (48, 63))	('TYK2', 'Gene', (88, 92))	('weakened', 'NegReg', (73, 81))	('cirsiliol', 'Chemical', 'MESH:C039824', (35, 44))	('inhibitory effect', 'MPA', (14, 31))
900616	33731185	Results showed that after transfected with wild type TYK2, cells sensitivity to cirsiliol was increased when compared with vehicle (Fig.	('increased', 'PosReg', (94, 103))	('cells sensitivity to cirsiliol', 'MPA', (59, 89))	('cirsiliol', 'Chemical', 'MESH:C039824', (80, 89))	('transfected', 'Var', (26, 37))	('TYK2', 'Gene', (53, 57))	('wild type', 'Var', (43, 52))
900628	33731185	Similarly, the tumor volumes of both cirsiliol treatment groups in LEG104 case were also reduced (Fig.	('cirsiliol', 'Chemical', 'MESH:C039824', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('LEG104', 'Var', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('reduced', 'NegReg', (89, 96))
900630	33731185	The average tumor weights of high cirsiliol concentration group in both cases were obviously lower than vehicle group (Fig.	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('high cirsiliol', 'Var', (29, 43))	('cirsiliol', 'Chemical', 'MESH:C039824', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('lower', 'NegReg', (93, 98))	('tumor', 'Disease', (12, 17))
900633	33731185	IHC analysis revealed that cirsiliol inhibited the phosphorylation of STAT3 and reduced Ki-67 protein level significantly after cirsiliol treatment (50 mg/kg) in LEG73 and LEG104 cases (Fig.	('STAT3', 'Protein', (70, 75))	('cirsiliol', 'Chemical', 'MESH:C039824', (27, 36))	('cirsiliol', 'Chemical', 'MESH:C039824', (128, 137))	('LEG73', 'Var', (162, 167))	('inhibited', 'NegReg', (37, 46))	('reduced', 'NegReg', (80, 87))	('phosphorylation', 'MPA', (51, 66))	('LEG104', 'Var', (172, 178))	('Ki-67 protein level', 'MPA', (88, 107))
900640	33731185	Furthermore, TYK2 inhibition could also block the invasiveness of breast cancer cells.	('invasiveness of breast cancer', 'Disease', 'MESH:D001943', (50, 79))	('TYK2', 'Protein', (13, 17))	('inhibition', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('block', 'NegReg', (40, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('invasiveness of breast cancer', 'Disease', (50, 79))
900644	33731185	Previous reports showed that cirsiliol induced radio sensitization in non-small cell lung cancer cell lines and inhibited interleukin (IL)-6-incuded STAT3 activation, and that cirsiliol could restrain the colony formation and migration of melanoma cells.	('radio sensitization', 'MPA', (47, 66))	('interleukin (IL)-6', 'Gene', (122, 140))	('lung cancer', 'Disease', (85, 96))	('interleukin (IL)-6', 'Gene', '3569', (122, 140))	('inhibited', 'NegReg', (112, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (70, 96))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('cirsiliol', 'Chemical', 'MESH:C039824', (176, 185))	('cirsiliol', 'Var', (176, 185))	('restrain', 'NegReg', (192, 200))	('cirsiliol', 'Chemical', 'MESH:C039824', (29, 38))
900686	33194679	The CNTN1 positivity rate increased as the corresponding tissues progressed from nontumor prostate tissues to high-grade prostatic intraepithelial neoplasia and to carcinomas.	('carcinomas', 'Disease', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (147, 156))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (131, 156))	('prostatic intraepithelial neoplasia', 'Disease', (121, 156))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('positivity', 'Var', (10, 20))	('CNTN1', 'Gene', (4, 9))	('tumor', 'Disease', (84, 89))	('increased', 'PosReg', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (121, 156))	('carcinomas', 'Disease', 'MESH:D009369', (164, 174))
900693	33194679	In transgenic mice injected with prostate cancer cells overexpressing CNTN1, xenograft tumorigenesis, lung metastases, and metastatic nodules were increased.	('overexpressing', 'Var', (55, 69))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('increased', 'PosReg', (147, 156))	('metastatic nodules', 'CPA', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('prostate cancer', 'Disease', (33, 48))	('tumor', 'Disease', (87, 92))	('CNTN1', 'Gene', (70, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (33, 48))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('transgenic mice', 'Species', '10090', (3, 18))	('lung metastases', 'Disease', (102, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('lung metastases', 'Disease', 'MESH:D009362', (102, 117))
900694	33194679	In transgenic mice injected with gastric cancer or lung adenocarcinoma cells where CNTN1 was knocked down, the number of lung metastases and metastatic nodules was significantly smaller than that of the control.	('lung metastases', 'Disease', 'MESH:D009362', (121, 136))	('gastric cancer', 'Disease', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('smaller', 'NegReg', (178, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (33, 47))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (51, 70))	('CNTN1', 'Gene', (83, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('knocked down', 'Var', (93, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (51, 70))	('transgenic mice', 'Species', '10090', (3, 18))	('lung metastases', 'Disease', (121, 136))	('lung adenocarcinoma', 'Disease', (51, 70))
900697	33194679	In lung adenocarcinoma, gastric cancer, and OSCC, knockdown of CNTN1 strongly impaired cell migratory and invasive capacities in vitro without influencing proliferation.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('knockdown', 'Var', (50, 59))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('CNTN1', 'Gene', (63, 68))	('impaired', 'NegReg', (78, 86))	('gastric cancer', 'Disease', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinoma', 'Disease', (3, 22))
900698	33194679	In in vivo studies, the weight and volume of the tumors, obtained from transgenic mice injected with gastric cancer cells with a knocked down CNTN1 expression were almost identical to those from the control group.	('knocked down', 'Var', (129, 141))	('gastric cancer', 'Disease', (101, 115))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('transgenic mice', 'Species', '10090', (71, 86))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('CNTN1', 'Gene', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
900700	33194679	However, in vitro knockdown of CNTN1 inhibited cancer cell proliferation, colony formation, migration, and invasion, whereas overexpression of CNTN1 increased tumor xenograft formation and metastasis in prostate cancer.	('inhibited', 'NegReg', (37, 46))	('prostate cancer', 'Phenotype', 'HP:0012125', (203, 218))	('increased', 'PosReg', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('invasion', 'CPA', (107, 115))	('CNTN1', 'Gene', (31, 36))	('cancer', 'Disease', (47, 53))	('migration', 'CPA', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('knockdown', 'Var', (18, 27))	('colony formation', 'CPA', (74, 90))	('tumor', 'Disease', (159, 164))	('cancer', 'Disease', (212, 218))	('metastasis in prostate cancer', 'Disease', (189, 218))	('metastasis in prostate cancer', 'Disease', 'MESH:D011471', (189, 218))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
900701	33194679	In contrast, ectopic expression of CNTN1 in DU145 prostate cancer cells displayed no effect on cell proliferation but enhanced cell invasion.	('cell invasion', 'CPA', (127, 140))	('prostate cancer', 'Disease', (50, 65))	('DU145', 'CellLine', 'CVCL:0105', (44, 49))	('enhanced', 'PosReg', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('CNTN1', 'Gene', (35, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('ectopic expression', 'Var', (13, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))
900702	33194679	Additionally, expression of CNTN1 was associated with cell proliferation in esophageal, thyroid, and breast cancers.	('expression', 'Var', (14, 24))	('cell proliferation', 'CPA', (54, 72))	('associated', 'Reg', (38, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('esophageal', 'Disease', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CNTN1', 'Gene', (28, 33))	('breast cancers', 'Phenotype', 'HP:0003002', (101, 115))	('breast cancers', 'Disease', 'MESH:D001943', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('breast cancers', 'Disease', (101, 115))	('thyroid', 'Disease', (88, 95))
900703	33194679	The volume and weight of xenograft tumors from nude mice, transfected with breast cancer cells overexpressing CNTN1, were significantly higher than those from the control.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('higher', 'PosReg', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('nude mice', 'Species', '10090', (47, 56))	('overexpressing', 'Var', (95, 109))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('CNTN1', 'Gene', (110, 115))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
900715	33194679	The inhibition of the AKT pathway in drug-resistant lung cancer cells using LY294002 conferred the same result without influencing CNTN1 expression.	('drug-resistant lung cancer', 'Disease', (37, 63))	('AKT', 'Gene', '207', (22, 25))	('drug-resistant lung cancer', 'Disease', 'MESH:D008175', (37, 63))	('LY294002', 'Var', (76, 84))	('AKT', 'Gene', (22, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('inhibition', 'NegReg', (4, 14))	('LY294002', 'Chemical', 'MESH:C085911', (76, 84))
900716	33194679	Moreover, after inhibiting AKT activation, the knockdown of CNTN1 failed to further reduce the invasive ability of cancer cells.	('reduce', 'NegReg', (84, 90))	('cancer', 'Disease', (115, 121))	('AKT', 'Gene', (27, 30))	('CNTN1', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('knockdown', 'Var', (47, 56))	('AKT', 'Gene', '207', (27, 30))	('inhibiting', 'NegReg', (16, 26))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
900718	33194679	Furthermore, knockdown of CNTN1 in prostate cancer cell lines also inhibited the PI3K/AKT pathway and suppressed the EMT process via concomitant upregulation of E-cadherin and downregulation of N-cadherin and vimentin.	('upregulation', 'PosReg', (145, 157))	('AKT', 'Gene', (86, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('N-cadherin', 'Gene', (194, 204))	('vimentin', 'Gene', '7431', (209, 217))	('knockdown', 'Var', (13, 22))	('prostate cancer', 'Disease', (35, 50))	('N-cadherin', 'Gene', '1000', (194, 204))	('vimentin', 'Gene', (209, 217))	('inhibited', 'NegReg', (67, 76))	('AKT', 'Gene', '207', (86, 89))	('suppressed', 'NegReg', (102, 112))	('E-cadherin', 'Gene', (161, 171))	('E-cadherin', 'Gene', '999', (161, 171))	('downregulation', 'NegReg', (176, 190))	('CNTN1', 'Gene', (26, 31))	('EMT process', 'CPA', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
900719	33194679	Additionally, knockdown of CNTN1 resulted in an increased expression of the PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) but not phosphatase and tensin homolog (PTEN).	('increased', 'PosReg', (48, 57))	('PHLPP2', 'Gene', (133, 139))	('expression', 'MPA', (58, 68))	('leucine', 'Chemical', 'MESH:D007930', (90, 97))	('CNTN1', 'Gene', (27, 32))	('PHLPP2', 'Gene', '23035', (133, 139))	('phosphatase and tensin homolog', 'Gene', '5728', (149, 179))	('knockdown', 'Var', (14, 23))	('PTEN', 'Gene', (181, 185))	('PH domain', 'Protein', (76, 85))	('PTEN', 'Gene', '5728', (181, 185))
900721	33194679	Furthermore, knockdown of CNTN1 in lung cancer cells decreased the expression of SIP1 and Slug but not Snail, which is the most studied E-cadherin transcription inhibitor.	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CNTN1', 'Gene', (26, 31))	('decreased', 'NegReg', (53, 62))	('E-cadherin', 'Gene', (136, 146))	('SIP1', 'Gene', '9839', (81, 85))	('E-cadherin', 'Gene', '999', (136, 146))	('lung cancer', 'Disease', (35, 46))	('Snail', 'Gene', '6615', (103, 108))	('Snail', 'Gene', (103, 108))	('Slug', 'Gene', '6591', (90, 94))	('Slug', 'Gene', (90, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('expression', 'MPA', (67, 77))	('SIP1', 'Gene', (81, 85))	('knockdown', 'Var', (13, 22))
900727	33194679	However, knockdown of CNTN1 in cancer cells led to a significant reduction in CNTN1, Slug, and N-cadherin expression as well as E-cadherin upregulation.	('Slug', 'Gene', '6591', (85, 89))	('E-cadherin', 'Gene', (128, 138))	('E-cadherin', 'Gene', '999', (128, 138))	('CNTN1', 'Gene', (22, 27))	('CNTN1', 'Gene', (78, 83))	('knockdown', 'Var', (9, 18))	('N-cadherin', 'Gene', '1000', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('upregulation', 'PosReg', (139, 151))	('expression', 'MPA', (106, 116))	('Slug', 'Gene', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('reduction', 'NegReg', (65, 74))	('N-cadherin', 'Gene', (95, 105))
900731	33194679	Furthermore, knockdown of CNTN1 attenuated cancer progression and significantly increased drug sensitivity and cisplatin-induced apoptosis in both cisplatin-resistant cancer cells and the control.	('cisplatin-induced apoptosis', 'CPA', (111, 138))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('CNTN1', 'Gene', (26, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('cancer', 'Disease', (43, 49))	('increased', 'PosReg', (80, 89))	('cancer', 'Disease', (167, 173))	('drug sensitivity', 'CPA', (90, 106))	('attenuated', 'NegReg', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('drug sensitivity', 'Phenotype', 'HP:0020174', (90, 106))	('knockdown', 'Var', (13, 22))
900732	33194679	In in vivo studies, CNTN1 knockdown in a xenograft mouse model of cisplatin-resistant lung adenocarcinoma also reversed cisplatin resistance and reduced the metastasis potency.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung adenocarcinoma', 'Disease', (86, 105))	('reduced', 'NegReg', (145, 152))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('metastasis potency', 'MPA', (157, 175))	('cisplatin resistance', 'MPA', (120, 140))	('CNTN1', 'Gene', (20, 25))	('mouse', 'Species', '10090', (51, 56))	('knockdown', 'Var', (26, 35))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('reversed', 'Reg', (111, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
900746	33194679	Moreover, a point mutation in the C/EBP response element reduced 80% of the CNTN1 promoter activity induced by VEGF-C, which could be abolished by SB203580 or PP1.	('PP1', 'Gene', (159, 162))	('SB203580', 'Chemical', 'MESH:C093642', (147, 155))	('VEGF-C', 'Gene', (111, 117))	('C/EBP', 'Gene', (34, 39))	('PP1', 'Gene', '5540', (159, 162))	('C/EBP', 'Gene', '1050', (34, 39))	('VEGF-C', 'Gene', '7424', (111, 117))	('point mutation', 'Var', (12, 26))	('reduced', 'NegReg', (57, 64))	('CNTN1', 'Gene', (76, 81))
900756	33194679	Further, inhibition of both nAChR by alpha-bungarotoxin and the ERK signaling pathway by PD98059 could reverse the increased expression of CNTN1 induced by NNK.	('inhibition', 'NegReg', (9, 19))	('PD98059', 'Chemical', 'MESH:C093973', (89, 96))	('increased', 'PosReg', (115, 124))	('ERK', 'Gene', '5594', (64, 67))	('nAChR', 'Gene', '1137', (28, 33))	('nAChR', 'Gene', (28, 33))	('expression', 'MPA', (125, 135))	('ERK', 'Gene', (64, 67))	('PD98059', 'Var', (89, 96))	('CNTN1', 'Gene', (139, 144))	('NNK', 'Chemical', 'MESH:C016583', (156, 159))
900757	33194679	Inhibition of the AKT pathway with LY294002 had no effect on CNTN1 expression.	('CNTN1', 'Gene', (61, 66))	('LY294002', 'Var', (35, 43))	('AKT', 'Gene', (18, 21))	('expression', 'MPA', (67, 77))	('LY294002', 'Chemical', 'MESH:C085911', (35, 43))	('AKT', 'Gene', '207', (18, 21))
900758	33194679	This indicated that NNK promoted lung cancer progression by upregulating CNTN1 expression via the alpha7 nAChR/ERK pathway but not the alpha7 nAChR/AKT pathway.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('AKT', 'Gene', '207', (148, 151))	('ERK', 'Gene', '5594', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('expression', 'MPA', (79, 89))	('nAChR', 'Gene', (105, 110))	('ERK', 'Gene', (111, 114))	('AKT', 'Gene', (148, 151))	('nAChR', 'Gene', '1137', (105, 110))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('nAChR', 'Gene', '1137', (142, 147))	('NNK', 'Chemical', 'MESH:C016583', (20, 23))	('promoted', 'PosReg', (24, 32))	('nAChR', 'Gene', (142, 147))	('CNTN1', 'Gene', (73, 78))	('upregulating', 'PosReg', (60, 72))	('NNK', 'Var', (20, 23))	('lung cancer', 'Disease', (33, 44))
900761	33194679	However, treatment with anti-CNTN1 antibodies inhibited cell invasion by 70%-80%, suggesting a critical role of CNTN1 in mediating cancer invasion induced by NNK.	('cancer', 'Disease', (131, 137))	('anti-CNTN1', 'Gene', (24, 34))	('CNTN1', 'Gene', (112, 117))	('NNK', 'Chemical', 'MESH:C016583', (158, 161))	('cell invasion', 'CPA', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('antibodies', 'Var', (35, 45))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('inhibited', 'NegReg', (46, 55))
900763	33194679	The knockdown of CNTN1 reduced cell migration and suppressed activation of RhoA and phosphorylation of p115 Rho guanine nucleotide exchange factor (RhoGEF, a RhoA activator) in gastric cancer.	('activation', 'MPA', (61, 71))	('suppressed', 'NegReg', (50, 60))	('gastric cancer', 'Disease', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cell migration', 'CPA', (31, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (177, 191))	('CNTN1', 'Gene', (17, 22))	('Rho guanine nucleotide exchange factor', 'Gene', '64283', (108, 146))	('Rho guanine nucleotide exchange factor', 'Gene', (108, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (177, 191))	('reduced', 'NegReg', (23, 30))	('knockdown', 'Var', (4, 13))	('phosphorylation', 'MPA', (84, 99))	('RhoA', 'Protein', (75, 79))
900764	33194679	Moreover, knockdown of CNTN1 significantly repressed the expression of cyclin D1 (CCND1), a target gene of the Notch1 pathway, indicating CNTN1 to potentially regulate the expression of CCND1 by activating Notch1 in thyroid cancer.	('CNTN1', 'Gene', (23, 28))	('thyroid cancer', 'Phenotype', 'HP:0002890', (216, 230))	('CCND1', 'Gene', (186, 191))	('CCND1', 'Gene', (82, 87))	('Notch1', 'Gene', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cyclin D1', 'Gene', (71, 80))	('Notch1', 'Gene', '4851', (111, 117))	('CNTN1', 'Gene', (138, 143))	('thyroid cancer', 'Disease', (216, 230))	('knockdown', 'Var', (10, 19))	('activating', 'PosReg', (195, 205))	('Notch1', 'Gene', (206, 212))	('cyclin D1', 'Gene', '595', (71, 80))	('Notch1', 'Gene', '4851', (206, 212))	('regulate', 'Reg', (159, 167))	('thyroid cancer', 'Disease', 'MESH:D013964', (216, 230))	('CCND1', 'Gene', '595', (186, 191))	('CCND1', 'Gene', '595', (82, 87))
900765	33194679	Additionally, CNTN1 expression was significantly increased in RET/PTC3 transgenic mice and suppressed by the RET inhibitor regorafenib.	('suppressed', 'NegReg', (91, 101))	('regorafenib', 'Chemical', 'MESH:C559147', (123, 134))	('expression', 'MPA', (20, 30))	('PTC3', 'Gene', '8031', (66, 70))	('increased', 'PosReg', (49, 58))	('transgenic', 'Var', (71, 81))	('transgenic mice', 'Species', '10090', (71, 86))	('PTC3', 'Gene', (66, 70))	('CNTN1', 'Gene', (14, 19))
900785	33194679	It is also reported that CNTN1 knockdown influences genes involved in tumorigenesis although its overexpression affects genes associated with cancer, immunologic disorders, and inflammation.	('overexpression', 'PosReg', (97, 111))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('immunologic disorders', 'Phenotype', 'HP:0002715', (150, 171))	('immunologic disorders', 'Disease', 'MESH:D007154', (150, 171))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('influences', 'Reg', (41, 51))	('inflammation', 'Disease', 'MESH:D007249', (177, 189))	('affects', 'Reg', (112, 119))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('inflammation', 'Disease', (177, 189))	('immunologic disorders', 'Disease', (150, 171))	('CNTN1', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('knockdown', 'Var', (31, 40))	('cancer', 'Disease', (142, 148))
900791	33194679	The expression of CNTN1 is correlated with drug resistance, and depletion of CNTN1 reverses the drug sensitivity in lung cancer cell lines.	('lung cancer', 'Disease', (116, 127))	('drug resistance', 'Phenotype', 'HP:0020174', (43, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('reverses', 'NegReg', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CNTN1', 'Gene', (77, 82))	('depletion', 'Var', (64, 73))	('expression', 'MPA', (4, 14))	('CNTN1', 'Gene', (18, 23))	('drug sensitivity', 'Phenotype', 'HP:0020174', (96, 112))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('correlated', 'Reg', (27, 37))	('drug sensitivity', 'MPA', (96, 112))	('drug resistance', 'Disease', (43, 58))
900818	31974709	In patients with histology proven, locally advanced resectable malignancy without metastases (cT1N + or cT3N0-3) or tumors of questionable resectability (cT4), neoadjuvant chemo(radio)therapy followed by surgery is the main treatment option.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('cT3N0-3', 'Var', (104, 111))	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('malignancy', 'Disease', (63, 73))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('metastases', 'Disease', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('metastases', 'Disease', 'MESH:D009362', (82, 92))
900857	32541523	Modified EIS with the use of a transparent cap resulted in lower rates of esophageal variceal recurrence, rebleeding, and complications, compared with direct EIS.	('bleeding', 'Disease', (108, 116))	('esophageal variceal recurrence', 'Phenotype', 'HP:0002040', (74, 104))	('lower', 'NegReg', (59, 64))	('Modified', 'Var', (0, 8))	('esophageal variceal recurrence', 'Disease', (74, 104))	('bleeding', 'Disease', 'MESH:D006470', (108, 116))
900909	32541523	Hou et al and Shiv et al found that early recurrence and multiple recurrence of esophageal varices were more likely in patients who underwent endoscopic ligation than among those who underwent sclerotherapy.	('Shiv', 'Species', '57667', (14, 18))	('endoscopic', 'Var', (142, 152))	('patients', 'Species', '9606', (119, 127))	('esophageal varices', 'Disease', (80, 98))	('esophageal varices', 'Phenotype', 'HP:0002040', (80, 98))
900924	27486097	Our analysis included 7,863 single nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signaling, oxidative stress, human leukocyte antigen, and NFkappaB.	('single nucleotide polymorphisms', 'Var', (28, 59))	('NFkappaB', 'Gene', (196, 204))	('NFkappaB', 'Gene', '4790', (196, 204))	('cyclooxygenase', 'MPA', (107, 121))	('human', 'Species', '9606', (167, 172))	('cytokine', 'MPA', (129, 137))	('oxidative stress', 'Phenotype', 'HP:0025464', (149, 165))
900926	27486097	Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05).	('MGST1', 'Gene', (17, 22))	('variants', 'Var', (42, 50))	('MGST1', 'Gene', '4257', (17, 22))	('men', 'Species', '9606', (6, 9))
900927	27486097	Three of these SNPs (rs3852575, rs73112090, rs4149204) were associated with similar elevations in EA risk.	('rs73112090', 'Mutation', 'rs73112090', (32, 42))	('rs3852575', 'Var', (21, 30))	('rs3852575', 'Mutation', 'rs3852575', (21, 30))	('rs4149204', 'Mutation', 'rs4149204', (44, 53))	('rs4149204', 'Var', (44, 53))	('elevations', 'Reg', (84, 94))	('rs73112090', 'Var', (32, 42))
900928	27486097	This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/EA, and suggests that variants in MGST1 influence disease susceptibility.	('influence', 'Reg', (163, 172))	('MGST1', 'Gene', (157, 162))	('variants', 'Var', (145, 153))	('inflammation', 'Disease', 'MESH:D007249', (57, 69))	('disease susceptibility', 'MPA', (173, 195))	('MGST1', 'Gene', '4257', (157, 162))	('inflammation', 'Disease', (57, 69))	('BE/EA', 'Disease', (120, 125))
900935	27486097	Inflammatory physiological changes such as oxidative stress are known to exert downstream genotoxic effects, and when sustained over extended periods, can promote the emergence of cancer-initiating mutations.	('oxidative stress', 'Phenotype', 'HP:0025464', (43, 59))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('mutations', 'Var', (198, 207))	('promote', 'PosReg', (155, 162))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
900942	27486097	Novel associations have been identified with variants in or near several transcription factors implicated in embryonic esophageal development, a transcriptional co-activator, and the human leukocyte antigen (HLA) region.	('associations', 'Interaction', (6, 18))	('embryonic esophageal', 'Disease', (109, 129))	('variants', 'Var', (45, 53))	('human', 'Species', '9606', (183, 188))	('transcription factors', 'Gene', (73, 94))	('men', 'Species', '9606', (137, 140))	('embryonic esophageal', 'Disease', 'MESH:D004941', (109, 129))
900943	27486097	Given the central role of inflammation in BE and EA pathogenesis, we examined genetic variation in five inflammation-related pathways:COX, cytokine signaling, oxidative stress, HLA, and NFkappaB:based on a novel principal components-based pathway analysis framework.	('inflammation', 'Disease', (104, 116))	('COX', 'MPA', (134, 137))	('inflammation', 'Disease', 'MESH:D007249', (26, 38))	('examined', 'Reg', (69, 77))	('cytokine signaling', 'MPA', (139, 157))	('genetic variation', 'Var', (78, 95))	('inflammation', 'Disease', (26, 38))	('oxidative stress', 'Phenotype', 'HP:0025464', (159, 175))	('inflammation', 'Disease', 'MESH:D007249', (104, 116))	('NFkappaB', 'Gene', '4790', (186, 194))	('NFkappaB', 'Gene', (186, 194))
900944	27486097	Using genotyping data from the International Barrett's Esophagus and Adenocarcinoma Consortium (BEACON) GWAS of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we selected 7,863 SNPs in 449 genes and assessed associations with risks of BE and EA in a pre-specified tiered fashion, first at the pathway level, next at the gene level, and ultimately at the SNP level.	("Barrett's Esophagus", 'Phenotype', 'HP:0100580', (45, 64))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))	('Adenocarcinoma', 'Disease', (69, 83))	('SNPs', 'Var', (182, 186))	('associations', 'Interaction', (213, 225))
900960	27486097	Unconditional logistic regression was used to compute odds ratios (ORs) for risk of BE or EA associated with a given SNP variant, under an additive model (per-allele) with adjustment for age, sex, and PC1,AIM-PC4,AIM, and correcting for multiple comparisons via the FDR method.	('variant', 'Var', (121, 128))	('PC1', 'Gene', (201, 204))	('PC4', 'Gene', '3854', (209, 212))	('SNP', 'Gene', (117, 120))	('PC4', 'Gene', (209, 212))	('PC1', 'Gene', '5167', (201, 204))	('BE or EA', 'Disease', (84, 92))	('men', 'Species', '9606', (178, 181))
900963	27486097	Summary statistics for the associations of 13 genotyped SNPs at the MGST1 locus and risk of BE were extracted and used in a subsequent meta-analysis based on the inverse-variance weighting method.	('associations', 'Interaction', (27, 39))	('SNPs', 'Var', (56, 60))	('MGST1', 'Gene', '4257', (68, 73))	('MGST1', 'Gene', (68, 73))
900966	27486097	To obtain a top-level, global assessment of the association between germline variation within five selected inflammation-related pathways (COX, cytokine signaling, oxidative stress, HLA, and NFkappaB) and risk of BE or EA, we employed a PCA-based approach.	('germline', 'Var', (68, 76))	('NFkappaB', 'Gene', '4790', (191, 199))	('inflammation', 'Disease', (108, 120))	('cytokine', 'MPA', (144, 152))	('BE or EA', 'Disease', (213, 221))	('association', 'Interaction', (48, 59))	('oxidative stress', 'Phenotype', 'HP:0025464', (164, 180))	('men', 'Species', '9606', (36, 39))	('NFkappaB', 'Gene', (191, 199))	('inflammation', 'Disease', 'MESH:D007249', (108, 120))
900968	27486097	A non-significant (P=0.07) association was observed for gene-level variation in MGST1 and risk of EA (Table S2).	('MGST1', 'Gene', (80, 85))	('variation', 'Var', (67, 76))	('MGST1', 'Gene', '4257', (80, 85))
900972	27486097	A second cluster of six SNPs satisfying FDR q<0.05 was situated at the 5' end of the MGST1 locus (Figure S2); modest to moderate LD was observed between rs2239676, the top-ranked SNP in this region, and the other five variants in close proximity.	('MGST1', 'Gene', (85, 90))	('MGST1', 'Gene', '4257', (85, 90))	('rs2239676', 'Mutation', 'rs2239676', (153, 162))	('rs2239676', 'Var', (153, 162))
900973	27486097	Based on data from the NIH Roadmap Epigenome Project, three of these 5' polymorphisms - rs2239676, rs2239677, and rs2975138 - lie within a 1.2-kilobase segment that spans the MGST1 transcriptional start site and is characterized by active chromatin marks in esophageal tissue (Figure S3).	('men', 'Species', '9606', (155, 158))	('MGST1', 'Gene', '4257', (175, 180))	('rs2239677', 'Mutation', 'rs2239677', (99, 108))	('rs2239676', 'Mutation', 'rs2239676', (88, 97))	('rs2239677', 'Var', (99, 108))	('rs2975138', 'Mutation', 'rs2975138', (114, 123))	('rs2975138 -', 'Var', (114, 125))	('MGST1', 'Gene', (175, 180))
900975	27486097	We next evaluated whether any of the 14 MGST1 variants associated with risk of BE in our primary analysis were similarly associated with altered BE risk in a large, independent sample set from the UK comprised of 1,851 BE patients and 3,496 control participants.	('participants', 'Species', '9606', (249, 261))	('associated', 'Reg', (121, 131))	('patients', 'Species', '9606', (222, 230))	('MGST1', 'Gene', (40, 45))	('variants', 'Var', (46, 54))	('MGST1', 'Gene', '4257', (40, 45))
900976	27486097	13 of the 14 SNPs were available for analysis, and of these, four variants exhibited borderline-significant (P<0.10) associations with BE: rs3852575, rs4149204, rs7312090, rs4149203 (Table 5).	('rs3852575', 'Mutation', 'rs3852575', (139, 148))	('rs7312090', 'Mutation', 'rs7312090', (161, 170))	('rs4149203', 'Mutation', 'rs4149203', (172, 181))	('associations', 'Reg', (117, 129))	('rs4149203', 'Var', (172, 181))	('rs4149204', 'Mutation', 'rs4149204', (150, 159))	('rs4149204', 'Var', (150, 159))	('rs3852575', 'Var', (139, 148))	('rs7312090', 'Var', (161, 170))
900978	27486097	Of the 13 SNPs with available genotyping and expression data in esophageal mucosa, two variants were associated (P<0.05) with differential MGST1 expression: rs4149186 A>C (P=7.9 x 10-5) and rs2975138 G>A (P=1.20 x 10-7) (Table S4).	('rs2975138 G>A', 'Var', (190, 203))	('MGST1', 'Gene', (139, 144))	('rs2975138', 'Mutation', 'rs2975138', (190, 199))	('MGST1', 'Gene', '4257', (139, 144))	('rs4149186 A>C', 'Var', (157, 170))	('rs4149186', 'Mutation', 'rs4149186', (157, 166))
900983	27486097	Drawing on genetic data from a large consortium-based GWAS, we found a significant association between variation in the COX pathway and risk of BE, and identified a gene-level signal for MGST1.	('variation', 'Var', (103, 112))	('COX pathway', 'Pathway', (120, 131))	('MGST1', 'Gene', '4257', (187, 192))	('MGST1', 'Gene', (187, 192))
900984	27486097	SNP-level analyses identified 14 individual MGST1 variants associated with elevated disease risk, including several intronic variants that were subsequently confirmed (P<5.5 x 10-5) in a meta-analysis encompassing a large independent sample set of additional BE cases and controls.	('associated with', 'Reg', (59, 74))	('MGST1', 'Gene', (44, 49))	('disease', 'Disease', (84, 91))	('variants', 'Var', (50, 58))	('MGST1', 'Gene', '4257', (44, 49))
900990	27486097	Some evidence exists for an association between genetic variation in the MGST1 gene and altered risk of colorectal cancer in Han Chinese.	('MGST1', 'Gene', (73, 78))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('genetic variation', 'Var', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('MGST1', 'Gene', '4257', (73, 78))	('colorectal cancer', 'Disease', (104, 121))
900996	27486097	Published eQTL data from a study of gene expression in various brain regions indicated that rs4149203 (and correlated SNPs) may be associated with altered MGST1 expression in cerebellum.	('rs4149203', 'Var', (92, 101))	('expression', 'MPA', (161, 171))	('associated', 'Reg', (131, 141))	('MGST1', 'Gene', '4257', (155, 160))	('rs4149203', 'Mutation', 'rs4149203', (92, 101))	('MGST1', 'Gene', (155, 160))	('altered', 'Reg', (147, 154))
900997	27486097	Proximity of several of these variants to an MGST1 splice junction also suggests a potential influence on (alternative) splicing regulation.	('influence', 'Reg', (93, 102))	('variants', 'Var', (30, 38))	('MGST1', 'Gene', '4257', (45, 50))	('MGST1', 'Gene', (45, 50))
900998	27486097	At the 5' end of MGST1, rs2239676 C>G was the top signal identified among a cluster of six variants associated with BE risk.	('MGST1', 'Gene', (17, 22))	('rs2239676', 'Mutation', 'rs2239676', (24, 33))	('rs2239676 C>G', 'Var', (24, 37))	('MGST1', 'Gene', '4257', (17, 22))
900999	27486097	Three of these variants lie in close proximity to the MGST1 transcriptional start site, within a region characterized as active chromatin in esophageal tissue; recruitment of Pol II and several transcription factors (eg, Hey1, MYC/MAX) has been reported.	('MGST1', 'Gene', '4257', (54, 59))	('MYC', 'Gene', (227, 230))	('MGST1', 'Gene', (54, 59))	('Pol II', 'Protein', (175, 181))	('MYC', 'Gene', '4609', (227, 230))	('Hey1', 'Gene', (221, 225))	('Hey1', 'Gene', '23462', (221, 225))	('recruitment', 'PosReg', (160, 171))	('variants', 'Var', (15, 23))	('men', 'Species', '9606', (167, 170))
901000	27486097	Our in silico eQTL analyses based on data from the GTEx project indicated that rs2975138 G>A and rs4149186 A>C, in particular, correlate with reduced MGST1 expression in esophageal mucosa.	('rs4149186 A>C', 'Var', (97, 110))	('reduced', 'NegReg', (142, 149))	('rs4149186', 'Mutation', 'rs4149186', (97, 106))	('MGST1', 'Gene', (150, 155))	('rs2975138 G>A', 'Var', (79, 92))	('expression', 'MPA', (156, 166))	('MGST1', 'Gene', '4257', (150, 155))	('rs2975138', 'Mutation', 'rs2975138', (79, 88))
901001	27486097	The rs2975138 variant modifies predicted motifs for estrogen receptor-alpha, Pax5, and Zfx, while rs4149186 alters recognition sequences for FoxA, FoxJ2, and Nkx2, among other regulators.	('Zfx', 'Gene', (87, 90))	('FoxJ2', 'Gene', (147, 152))	('rs4149186', 'Var', (98, 107))	('rs2975138', 'Var', (4, 13))	('motifs', 'MPA', (41, 47))	('Zfx', 'Gene', '7543', (87, 90))	('estrogen receptor-alpha', 'Gene', (52, 75))	('modifies', 'Reg', (22, 30))	('Pax5', 'Gene', '5079', (77, 81))	('FoxJ2', 'Gene', '55810', (147, 152))	('rs4149186', 'Mutation', 'rs4149186', (98, 107))	('alters', 'Reg', (108, 114))	('Pax5', 'Gene', (77, 81))	('estrogen receptor-alpha', 'Gene', '2099', (52, 75))	('recognition sequences', 'MPA', (115, 136))	('rs2975138', 'Mutation', 'rs2975138', (4, 13))
901002	27486097	The findings described above suggest that several of the identified variants may play a role in influencing MGST1 RNA expression levels.	('variants', 'Var', (68, 76))	('influencing', 'Reg', (96, 107))	('MGST1', 'Gene', (108, 113))	('MGST1', 'Gene', '4257', (108, 113))
901003	27486097	Additional studies, however, are warranted to investigate potential associations between selected variants and altered tissue-specific MGST1 expression, and to explore a possible causal basis for the observed findings.	('MGST1', 'Gene', (135, 140))	('MGST1', 'Gene', '4257', (135, 140))	('expression', 'MPA', (141, 151))	('associations', 'Interaction', (68, 80))	('variants', 'Var', (98, 106))
901007	27486097	Previous candidate gene-based studies have reported associations between germline variation in PTGS2 (COX-2) and altered risk of EA, while independent epidemiologic evidence has supported an inverse association between use of NSAIDs (inhibitors of COX-1 and COX-2 activity) and risk of EA.	('PTGS2', 'Gene', '5743', (95, 100))	('COX-1', 'Gene', '4512', (248, 253))	('COX-1', 'Gene', (248, 253))	('associations', 'Interaction', (52, 64))	('COX-2', 'Gene', '4513', (102, 107))	('germline variation', 'Var', (73, 91))	('COX-2', 'Gene', '4513', (258, 263))	('COX-2', 'Gene', (102, 107))	('COX-2', 'Gene', (258, 263))	('inverse', 'NegReg', (191, 198))	('PTGS2', 'Gene', (95, 100))
901011	27486097	Second, by reducing the dimensionality of the genotype matrix, PCA appreciably reduced the number of multiple comparisons and effectively increased our statistical power.	('increased', 'PosReg', (138, 147))	('reduced', 'NegReg', (79, 86))	('reducing', 'NegReg', (11, 19))	('men', 'Species', '9606', (26, 29))	('PCA', 'Var', (63, 66))	('dimensionality', 'MPA', (24, 38))
901014	27486097	Our assessment of 7,863 SNPs in 449 genes assigned to five pathways significantly expands past candidate gene-based efforts to examine genetic variation in inflammation-related loci in relation to risk of BE and EA.	('men', 'Species', '9606', (10, 13))	('SNPs', 'Var', (24, 28))	('inflammation', 'Disease', (156, 168))	('inflammation', 'Disease', 'MESH:D007249', (156, 168))
901018	27486097	Using a PCA framework for pathway-level and gene-level analyses, we describe evidence for novel associations between variation at the MGST1 locus and increased risk of BE.	('variation', 'Var', (117, 126))	('MGST1', 'Gene', (134, 139))	('MGST1', 'Gene', '4257', (134, 139))
901019	27486097	It appears possible that certain associated variants may act to influence expression levels of MGST1, a gene with known roles in the cellular response to oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (154, 170))	('influence', 'Reg', (64, 73))	('MGST1', 'Gene', (95, 100))	('expression levels', 'MPA', (74, 91))	('variants', 'Var', (44, 52))	('MGST1', 'Gene', '4257', (95, 100))
901020	27486097	Pending further validation in additional study populations, future studies are warranted to fine-map the identified association signals, assess experimentally the functional effects of these variants, and explore the biological role of MGST1 in BE/EA pathogenesis.	('MGST1', 'Gene', (236, 241))	('variants', 'Var', (191, 199))	('men', 'Species', '9606', (150, 153))	('BE/EA', 'Disease', (245, 250))	('MGST1', 'Gene', '4257', (236, 241))
901124	26855585	Association between the Cyclin D1 G870A polymorphism and the susceptibility to and prognosis of upper aerodigestive tract squamous cell carcinomas: an updated meta-analysis Several publications have investigated the association between the Cyclin D1 G to A substitution at nucleotide 870 (CCND1 G870A) polymorphism and squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT), but their conclusions still remain controversial.	('G870A', 'Mutation', 'rs9344', (295, 300))	('squamous cell carcinomas', 'Disease', (122, 146))	('CCND1', 'Gene', '595', (289, 294))	('Cyclin D1', 'Gene', '595', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('SCC', 'Gene', '6317', (344, 347))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('Cyclin D1', 'Gene', (24, 33))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (319, 342))	('CCND1', 'Gene', (289, 294))	('SCC', 'Gene', (344, 347))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))	('squamous cell carcinoma', 'Disease', (319, 342))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (122, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (122, 146))	('G870A', 'Mutation', 'rs9344', (34, 39))	('G to A substitution at nucleotide 870', 'Mutation', 'rs9344', (250, 287))	('polymorphism', 'Var', (302, 314))	('Cyclin D1', 'Gene', '595', (240, 249))	('Cyclin D1', 'Gene', (240, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (319, 342))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 145))
901125	26855585	We electronically searched the Chinese National Knowledge Infrastructure, PubMed, and Embase (up to January 2015) databases for case-control studies on the association between the CCND1 G870A polymorphism and SCC of the UADT, and 23 studies were included in total.	('CCND1', 'Gene', '595', (180, 185))	('SCC', 'Gene', '6317', (209, 212))	('SCC', 'Gene', (209, 212))	('G870A', 'Mutation', 'rs9344', (186, 191))	('association', 'Interaction', (156, 167))	('G870A', 'Var', (186, 191))	('CCND1', 'Gene', (180, 185))
901126	26855585	The meta-analysis results showed that there was a significant association between the CCND1 G870A polymorphism and the risk of SCC of the UADT (AA vs GG: odds ratio [OR] =1.33, 95% confidence interval [CI] =1.01-1.74, P<0.001 for heterogeneity; GA/AA vs GG: OR =1.24, 95% CI =1.01-1.51, P<0.001 for heterogeneity; AA vs GA/GG: OR =1.16, 95% CI =0.97-1.39, P<0.001 for heterogeneity; allele A vs allele G: OR =1.14, 95% CI =1.00-1.30, P<0.001 for heterogeneity; GA vs GG: OR =1.18, 95% CI =0.98-1.42, P<0.001 for heterogeneity).	('CCND1', 'Gene', (86, 91))	('SCC', 'Gene', (127, 130))	('G870A polymorphism', 'Var', (92, 110))	('CCND1', 'Gene', '595', (86, 91))	('SCC', 'Gene', '6317', (127, 130))	('polymorphism', 'Var', (98, 110))	('G870A', 'Mutation', 'rs9344', (92, 97))
901127	26855585	However, when analyzing prognosis, allele G was a potential risk factor for poor tumor differentiation (AA vs GA/GG: OR =2.60, 95% CI =1.15-5.86, P=0.836 for heterogeneity) and reduced disease-free intervals (OR =2.08, 95% CI =1.17-3.69, P=0.134 for heterogeneity).	('poor', 'NegReg', (76, 80))	('reduced', 'NegReg', (177, 184))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('allele G', 'Var', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('disease-free intervals', 'CPA', (185, 207))	('tumor', 'Disease', (81, 86))
901128	26855585	In the subgroup analysis, the cancer susceptibility of Asian groups, population-based control groups, nasopharyngeal cancer groups, and esophageal SCC groups were more likely to be affected by the CCND1 G870A polymorphism.	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('SCC', 'Gene', '6317', (147, 150))	('esophageal', 'Disease', 'MESH:D004941', (136, 146))	('SCC', 'Gene', (147, 150))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (102, 123))	('affected', 'Reg', (181, 189))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('pharyngeal cancer', 'Disease', (106, 123))	('G870A', 'Mutation', 'rs9344', (203, 208))	('pharyngeal cancer', 'Disease', 'MESH:D010610', (106, 123))	('cancer', 'Disease', (30, 36))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (106, 123))	('CCND1', 'Gene', '595', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('esophageal', 'Disease', (136, 146))	('CCND1', 'Gene', (197, 202))	('G870A', 'Var', (203, 208))	('cancer', 'Disease', 'MESH:D009369', (117, 123))
901130	26855585	The results of the present meta-analysis suggest that the variant CCND1 870A allele might confer an elevated risk of SCC of the UADT, particularly among Asians and individuals who have esophageal or nasopharyngeal cancers.	('nasopharyngeal cancers', 'Disease', 'MESH:D009303', (199, 221))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('nasopharyngeal cancers', 'Disease', (199, 221))	('CCND1', 'Gene', '595', (66, 71))	('SCC', 'Gene', (117, 120))	('esophageal', 'Disease', (185, 195))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (199, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('variant', 'Var', (58, 65))	('SCC', 'Gene', '6317', (117, 120))	('esophageal', 'Disease', 'MESH:D004941', (185, 195))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (203, 220))	('CCND1', 'Gene', (66, 71))
901136	26855585	Several publications have reported that CCND1 gene amplification is involved in the pathogenesis of a variety of cancers, including breast, prostate, esophagus, and lung cancer.	('involved', 'Reg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lung cancer', 'Disease', (165, 176))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('CCND1', 'Gene', (40, 45))	('cancers', 'Disease', (113, 120))	('breast', 'Disease', (132, 138))	('prostate', 'Disease', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('esophagus', 'Disease', (150, 159))	('gene amplification', 'Var', (46, 64))	('CCND1', 'Gene', '595', (40, 45))
901137	26855585	The CCND1 gene has an important polymorphism (rs603965) at codon 242 in exon 4 that results in a silent G to A substitution at nucleotide 870 (G870A).	('CCND1', 'Gene', '595', (4, 9))	('silent', 'NegReg', (97, 103))	('rs603965', 'Mutation', 'rs603965', (46, 54))	('G870A', 'Mutation', 'rs9344', (143, 148))	('G870A', 'Var', (143, 148))	('CCND1', 'Gene', (4, 9))	('G to A substitution at nucleotide 870', 'Mutation', 'rs9344', (104, 141))	('rs603965', 'Var', (46, 54))
901139	26855585	The association between the CCND1 G870A polymorphism and SCC of the UADT has been investigated by different authors, but their conclusions still remain controversial.	('SCC', 'Gene', '6317', (57, 60))	('CCND1', 'Gene', '595', (28, 33))	('G870A', 'Mutation', 'rs9344', (34, 39))	('G870A', 'Var', (34, 39))	('SCC', 'Gene', (57, 60))	('CCND1', 'Gene', (28, 33))
901140	26855585	A recent meta-analysis by Wen et al showed a possible relationship between the CCND1 G870A polymorphism and esophageal cancer risk, which was contrary to the results found from an earlier meta-analysis conducted by Cai et al.	('CCND1', 'Gene', '595', (79, 84))	('G870A', 'Mutation', 'rs9344', (85, 90))	('G870A', 'Var', (85, 90))	('esophageal cancer', 'Disease', (108, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('CCND1', 'Gene', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
901142	26855585	These studies did not assess the influence of the CCND1 G870A polymorphism on the prognosis of UADT cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('UADT cancers', 'Disease', 'MESH:D006258', (95, 107))	('CCND1', 'Gene', (50, 55))	('G870A', 'Mutation', 'rs9344', (56, 61))	('G870A', 'Var', (56, 61))	('CCND1', 'Gene', '595', (50, 55))	('UADT cancers', 'Disease', (95, 107))
901143	26855585	In addition, four additional studies reporting the association of the CCND1 G870A polymorphism with UADT SSC have been published.	('CCND1', 'Gene', '595', (70, 75))	('association', 'Interaction', (51, 62))	('UADT SSC', 'Disease', (100, 108))	('G870A', 'Mutation', 'rs9344', (76, 81))	('G870A', 'Var', (76, 81))	('CCND1', 'Gene', (70, 75))
901144	26855585	Therefore, we performed this meta-analysis including all relevant published studies to provide complementary and updated information on the relationship between the CCND1 G870A polymorphism and the susceptibility and prognosis of UADT SCC.	('CCND1', 'Gene', '595', (165, 170))	('G870A', 'Var', (171, 176))	('SCC', 'Gene', '6317', (235, 238))	('CCND1', 'Gene', (165, 170))	('SCC', 'Gene', (235, 238))	('G870A', 'Mutation', 'rs9344', (171, 176))
901145	26855585	We performed an electronic search of the Chinese National Knowledge Infrastructure, PubMed, and Embase (up to January 2015) databases for case-control studies on the association between the CCND1 G870A polymorphism and SCC of the UADT.	('CCND1', 'Gene', (190, 195))	('SCC', 'Gene', (219, 222))	('G870A', 'Mutation', 'rs9344', (196, 201))	('G870A', 'Var', (196, 201))	('SCC', 'Gene', '6317', (219, 222))	('CCND1', 'Gene', '595', (190, 195))
901146	26855585	The following terms were used in combination: Cyclin D1, CCND1, polymorphism, squamous cell carcinoma, oral cancer, laryngeal cancer, pharyngeal cancer, esophageal cancer, and case-control study.	('pharyngeal cancer', 'Disease', (134, 151))	('pharyngeal cancer', 'Disease', 'MESH:D010610', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('laryngeal cancer', 'Disease', 'MESH:D007822', (116, 132))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (134, 151))	('laryngeal cancer', 'Disease', (116, 132))	('CCND1', 'Gene', '595', (57, 62))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (116, 132))	('Cyclin D1', 'Gene', '595', (46, 55))	('Cyclin D1', 'Gene', (46, 55))	('CCND1', 'Gene', (57, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal cancer', 'Disease', (153, 170))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('polymorphism', 'Var', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('oral cancer', 'Disease', 'MESH:D009062', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('oral cancer', 'Disease', (103, 114))	('squamous cell carcinoma', 'Disease', (78, 101))
901147	26855585	Studies were included if they met the following criteria: 1) a case-control study design concerning the relationship between the CCND1 G870A polymorphism and SCC of the UADT; 2) SCC confirmed via histopathological evidence; 3) tumor sites located in the UADT (including oral cavity, larynx, pharynx, and esophagus); 4) reported odds ratios (ORs) with a 95% confidence interval (CI) (or crude data that allowed the 95% CI to be calculated); and 5) published in English or Chinese.	('SCC', 'Gene', '6317', (158, 161))	('tumor', 'Disease', (227, 232))	('SCC', 'Gene', '6317', (178, 181))	('CCND1', 'Gene', (129, 134))	('G870A', 'Mutation', 'rs9344', (135, 140))	('CCND1', 'Gene', '595', (129, 134))	('G870A', 'Var', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('SCC', 'Gene', (158, 161))	('SCC', 'Gene', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
901149	26855585	We pooled the ORs with 95% CIs to analyze the association between the CCND1 G870A polymorphism and susceptibility to SCC of the UADT.	('SCC', 'Gene', (117, 120))	('CCND1', 'Gene', '595', (70, 75))	('SCC', 'Gene', '6317', (117, 120))	('association', 'Interaction', (46, 57))	('G870A', 'Mutation', 'rs9344', (76, 81))	('G870A', 'Var', (76, 81))	('CCND1', 'Gene', (70, 75))
901152	26855585	Among the 23 included studies, the classic polymerase chain reaction-restriction fragment length polymorphism assay was the most frequently used method to genotype the CCND1 G870A polymorphism.	('CCND1', 'Gene', '595', (168, 173))	('G870A', 'Mutation', 'rs9344', (174, 179))	('G870A', 'Var', (174, 179))	('CCND1', 'Gene', (168, 173))
901153	26855585	Overall, the meta-analysis results suggested that there was a significant association between the CCND1 G870A polymorphism and risk of SCC of the UADT under the codominant model (AA vs GG: OR =1.33, 95% CI =1.01-1.74, P<0.001 for heterogeneity), the dominant model (GA/AA vs GG: OR =1.24, 95% CI =1.01-1.51, P<0.001 for heterogeneity), and the recessive model (AA vs GA/GG: OR =1.16, 95% CI =0.97-1.39, P<0.001 for heterogeneity).	('G870A', 'Mutation', 'rs9344', (104, 109))	('CCND1', 'Gene', (98, 103))	('SCC', 'Gene', (135, 138))	('G870A', 'Var', (104, 109))	('CCND1', 'Gene', '595', (98, 103))	('SCC', 'Gene', '6317', (135, 138))
901154	26855585	We also examined associations between the CCND1 G870A polymorphism and the patient prognosis of SCC, including tumor differentiation, tumor size, lymph node involvement, recurrence, and disease-free interval.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('CCND1', 'Gene', '595', (42, 47))	('SCC', 'Gene', (96, 99))	('G870A', 'Mutation', 'rs9344', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('G870A', 'Var', (48, 53))	('SCC', 'Gene', '6317', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('CCND1', 'Gene', (42, 47))	('associations', 'Interaction', (17, 29))	('patient', 'Species', '9606', (75, 82))	('tumor', 'Disease', (134, 139))
901160	26855585	The subgroup analysis of the tumor site revealed that the risks of nasopharyngeal cancer and esophageal SCC were more likely to be affected by the CCND1 G870A polymorphism.	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (67, 88))	('pharyngeal cancer', 'Disease', (71, 88))	('CCND1', 'Gene', '595', (147, 152))	('esophageal', 'Disease', 'MESH:D004941', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('pharyngeal cancer', 'Disease', 'MESH:D010610', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('SCC', 'Gene', '6317', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('SCC', 'Gene', (104, 107))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (71, 88))	('tumor', 'Disease', (29, 34))	('G870A', 'Mutation', 'rs9344', (153, 158))	('esophageal', 'Disease', (93, 103))	('CCND1', 'Gene', (147, 152))	('G870A', 'Var', (153, 158))	('affected', 'Reg', (131, 139))
901162	26855585	We were the first to conduct a meta-analysis involving 5,338 cases and 6,204 controls to evaluate the relationship between the CCND1 G870A polymorphism and susceptibility to SCC of the UADT.	('G870A', 'Var', (133, 138))	('SCC', 'Gene', (174, 177))	('CCND1', 'Gene', '595', (127, 132))	('susceptibility', 'Reg', (156, 170))	('SCC', 'Gene', '6317', (174, 177))	('G870A', 'Mutation', 'rs9344', (133, 138))	('CCND1', 'Gene', (127, 132))
901164	26855585	Finally, based on a total of 23 studies, our meta-analysis suggested that allele A of the CCND1 G870A polymorphism is associated with SCC development of the UADT, especially among Asian groups, groups with population-based controls, and groups of nasopharyngeal carcinoma and esophageal carcinoma.	('nasopharyngeal carcinoma', 'Disease', (247, 271))	('CCND1', 'Gene', (90, 95))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (247, 271))	('SCC', 'Gene', '6317', (134, 137))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (276, 296))	('CCND1', 'Gene', '595', (90, 95))	('G870A', 'Mutation', 'rs9344', (96, 101))	('G870A', 'Var', (96, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('esophageal carcinoma', 'Disease', (276, 296))	('associated with', 'Reg', (118, 133))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (276, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (247, 271))	('SCC', 'Gene', (134, 137))
901166	26855585	The CCND1 gene, which is located on chromosome 11q13, is polymorphic with a common G870A in the conserved splice donor region of exon 4 of the gene.	('CCND1', 'Gene', '595', (4, 9))	('G870A', 'Mutation', 'rs9344', (83, 88))	('donor', 'Species', '9606', (113, 118))	('G870A', 'Var', (83, 88))	('CCND1', 'Gene', (4, 9))
901167	26855585	The CCND1 G870A polymorphism has been reported to have a promising role in predicting carcinogenesis of SCC, but this conclusion is still debated.	('CCND1', 'Gene', '595', (4, 9))	('G870A', 'Mutation', 'rs9344', (10, 15))	('G870A', 'Var', (10, 15))	('SCC', 'Gene', (104, 107))	('CCND1', 'Gene', (4, 9))	('SCC', 'Gene', '6317', (104, 107))
901168	26855585	Matthias et al first investigated the influence of the CCND1 G870A polymorphism on the susceptibility to SCC of the head and neck (SCCHN), and no significant correlation was found.	('G870A', 'Mutation', 'rs9344', (61, 66))	('G870A', 'Var', (61, 66))	('SCC', 'Gene', '6317', (105, 108))	('CCND1', 'Gene', '595', (55, 60))	('SCC', 'Gene', (131, 134))	('SCC', 'Gene', (105, 108))	('SCC', 'Gene', '6317', (131, 134))	('CCND1', 'Gene', (55, 60))
901170	26855585	Similarly, Monteiro et al did not find any evident relationship between the CCND1 G870A polymorphism and laryngeal SCC susceptibility.	('CCND1', 'Gene', (76, 81))	('G870A', 'Var', (82, 87))	('G870A', 'Mutation', 'rs9344', (82, 87))	('CCND1', 'Gene', '595', (76, 81))	('SCC', 'Gene', (115, 118))	('SCC', 'Gene', '6317', (115, 118))
901174	26855585	A recent meta-analysis indicated that there was an overall lack of association between the CCND1 G870A polymorphism and head and neck cancer risk under all five genetic models, and no significant association was found in the subgroup analysis.	('lack', 'NegReg', (59, 63))	('head and neck cancer', 'Phenotype', 'HP:0012288', (120, 140))	('CCND1', 'Gene', (91, 96))	('G870A', 'Mutation', 'rs9344', (97, 102))	('neck cancer', 'Disease', 'MESH:D006258', (129, 140))	('neck cancer', 'Disease', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('G870A', 'Var', (97, 102))	('CCND1', 'Gene', '595', (91, 96))
901177	26855585	In the subgroup analysis of ethnicity, a remarkable association between CCND1 allele A and elevated cancer risk was observed among Asians but not other ethnicities.	('CCND1', 'Gene', (72, 77))	('CCND1', 'Gene', '595', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('allele A', 'Var', (78, 86))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
901179	26855585	In the subgroup analysis of the source of controls, allele A was found to be associated with increased cancer risk in the population-based subgroup.	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('allele A', 'Var', (52, 60))
901182	26855585	In our meta-analysis, a total of seven studies reported the interaction between smoking and the CCND1 G870A polymorphism in SCC susceptibility, but only two of them provided detailed genotype distributions of subgroups concerning smoking status.	('SCC', 'Gene', '6317', (124, 127))	('G870A', 'Var', (102, 107))	('CCND1', 'Gene', '595', (96, 101))	('SCC', 'Gene', (124, 127))	('interaction', 'Interaction', (60, 71))	('CCND1', 'Gene', (96, 101))	('G870A', 'Mutation', 'rs9344', (102, 107))
901183	26855585	Pooled data of these two studies failed to find any significant correlation between the CCND1 polymorphism and smoking.	('CCND1', 'Gene', '595', (88, 93))	('CCND1', 'Gene', (88, 93))	('polymorphism', 'Var', (94, 106))
901185	26855585	Wen et al's meta-analysis suggested that the CCND1 G870A polymorphism presents the potential for elevated risk in the development of esophageal malignancies, including both adenocarcinomas and SCCs.	('CCND1', 'Gene', (45, 50))	('esophageal malignancies', 'Phenotype', 'HP:0100751', (133, 156))	('CCND1', 'Gene', '595', (45, 50))	('G870A', 'Mutation', 'rs9344', (51, 56))	('adenocarcinomas', 'Disease', 'MESH:D000230', (173, 188))	('esophageal malignancies', 'Disease', 'MESH:D004938', (133, 156))	('SCC', 'Gene', (193, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('G870A', 'Var', (51, 56))	('esophageal malignancies', 'Disease', (133, 156))	('adenocarcinomas', 'Disease', (173, 188))	('SCC', 'Gene', '6317', (193, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))
901186	26855585	In the current study, the subgroup analysis of the tumor site showed that allele A was related to an elevated risk of nasopharyngeal and esophageal SCCs.	('esophageal SCCs', 'Disease', 'MESH:D004941', (137, 152))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('allele A', 'Var', (74, 82))	('esophageal SCCs', 'Disease', (137, 152))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
901188	26855585	Further analysis of the association between the CCND1 G870A polymorphism and the prognosis of SCC of the UADT was carried out.	('G870A', 'Var', (54, 59))	('CCND1', 'Gene', '595', (48, 53))	('SCC', 'Gene', (94, 97))	('SCC', 'Gene', '6317', (94, 97))	('CCND1', 'Gene', (48, 53))	('G870A', 'Mutation', 'rs9344', (54, 59))
901189	26855585	Patients with the AA genotype were more likely to have well-differentiated tumors, and allele G was a potential risk factor for reduced disease-free interval.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('disease-free interval', 'CPA', (136, 157))	('reduced', 'NegReg', (128, 135))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('allele G', 'Var', (87, 95))	('tumors', 'Disease', (75, 81))
901192	26855585	Thus, more data were required to validate the association between the CCND1 G870A polymorphism and the prognosis of SCC of the UADT.	('SCC', 'Gene', (116, 119))	('SCC', 'Gene', '6317', (116, 119))	('CCND1', 'Gene', '595', (70, 75))	('G870A', 'Mutation', 'rs9344', (76, 81))	('G870A', 'Var', (76, 81))	('CCND1', 'Gene', (70, 75))
901195	26855585	Despite these limitations, the results of the present meta-analysis suggest that the variant CCND1 870A allele might confer an elevated risk of SCC of the UADT, particularly among Asians and individuals who have esophageal or nasopharyngeal cancers.	('nasopharyngeal cancers', 'Disease', (226, 248))	('CCND1', 'Gene', '595', (93, 98))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (226, 247))	('SCC', 'Gene', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('variant', 'Var', (85, 92))	('esophageal', 'Disease', (212, 222))	('SCC', 'Gene', '6317', (144, 147))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (230, 247))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('esophageal', 'Disease', 'MESH:D004941', (212, 222))	('CCND1', 'Gene', (93, 98))	('nasopharyngeal cancers', 'Disease', 'MESH:D009303', (226, 248))
901197	26855585	These findings may help to understand the role of the CCND1 G870A polymorphism in the etiology of SCC of the UADT.	('G870A', 'Var', (60, 65))	('SCC', 'Gene', '6317', (98, 101))	('CCND1', 'Gene', (54, 59))	('CCND1', 'Gene', '595', (54, 59))	('G870A', 'Mutation', 'rs9344', (60, 65))	('SCC', 'Gene', (98, 101))
901207	26529313	The standard introduction of a post-neoadjuvant therapy PET-CT led to a reduction of overall health care costs per patient compared to a scenario without restaging with PET-CT ($34,088 vs. $36,490).	('reduction', 'NegReg', (72, 81))	('patient', 'Species', '9606', (115, 122))	('health care costs', 'MPA', (93, 110))	('PET-CT', 'Var', (56, 62))
901225	26529313	Neoadjuvant chemoradiotherapy followed by esophagectomy was indicated in patients deemed fit for surgery with histologically proven, locally advanced, resectable malignancy without distant metastases (cT1N+M0 or cT2-3N0-3M0).	('metastases', 'Disease', (189, 199))	('malignancy', 'Disease', 'MESH:D009369', (162, 172))	('metastases', 'Disease', 'MESH:D009362', (189, 199))	('cT2-3N0-3M0', 'Var', (212, 223))	('cT1N+M0', 'Var', (201, 208))	('malignancy', 'Disease', (162, 172))	('patients', 'Species', '9606', (73, 81))
901294	33159406	Many risk factors and crucial signals associated with SCC development in various tissues accelerate YAP1/TAZ accumulation, and mice possessing constitutively activated YAP1/TAZ show immediate carcinoma in situ (CIS) formation in these tissues.	('mice', 'Species', '10090', (127, 131))	('CIS', 'Phenotype', 'HP:0030075', (211, 214))	('carcinoma', 'Disease', (192, 201))	('accelerate', 'PosReg', (89, 99))	('YAP1/TAZ', 'Var', (168, 176))	('YAP1/TAZ accumulation', 'MPA', (100, 121))	('carcinoma', 'Disease', 'MESH:D009369', (192, 201))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (192, 209))	('immediate carcinoma in situ', 'Phenotype', 'HP:0030075', (182, 209))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
901300	33159406	In general, HPV+ SCCs display fewer mutations compared with HPV- SCCs, occur in younger people, and have a better prognosis.	('HPV+ SCCs', 'Disease', (12, 21))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('mutations', 'Var', (36, 45))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('people', 'Species', '9606', (88, 94))	('HPV', 'Species', '10566', (12, 15))	('HPV', 'Species', '10566', (60, 63))	('fewer', 'NegReg', (30, 35))
901302	33159406	In addition, HPV- SCCs often bear mutations of CDKN2A and CCND1 (Table 1).	('CCND1', 'Gene', '595', (58, 63))	('CDKN2A', 'Gene', (47, 53))	('SCC', 'Phenotype', 'HP:0002860', (18, 21))	('CDKN2A', 'Gene', '1029', (47, 53))	('bear', 'Reg', (29, 33))	('CCND1', 'Gene', (58, 63))	('HPV', 'Species', '10566', (13, 16))	('mutations', 'Var', (34, 43))
901303	33159406	HPV- CuSCCs exhibit mutations of KMT2C/D, RAS/RAF/AJUBA or NOTCH more frequently than other HPV- SCCs.	('AJUBA', 'Gene', '84962', (50, 55))	('HPV', 'Species', '10566', (92, 95))	('HPV', 'Species', '10566', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (7, 10))	('RAS', 'Gene', (42, 45))	('RAF', 'Gene', (46, 49))	('KMT2C/D', 'Gene', '58508', (33, 40))	('CuSCCs', 'Phenotype', 'HP:0006739', (5, 11))	('RAF', 'Gene', '22882', (46, 49))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('KMT2C/D', 'Gene', (33, 40))	('NOTCH', 'Gene', (59, 64))	('AJUBA', 'Gene', (50, 55))	('RAS', 'Gene', 'None', (42, 45))	('mutations', 'Var', (20, 29))
901304	33159406	All SCCs commonly show some mutation/amplification of PIK3CA/PTEN or TP63 (Table 1).	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('PIK3CA', 'Gene', '5290', (54, 60))	('mutation/amplification', 'Var', (28, 50))	('PTEN', 'Gene', (61, 65))	('PTEN', 'Gene', '5728', (61, 65))	('TP63', 'Gene', '8626', (69, 73))	('PIK3CA', 'Gene', (54, 60))	('TP63', 'Gene', (69, 73))
901305	33159406	Although TP53 shows the highest alteration rate in human SCCs, mice with loss of TP53 alone never develop spontaneous SCCs.	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('loss', 'Var', (73, 77))	('mice', 'Species', '10090', (63, 67))	('human', 'Species', '9606', (51, 56))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('TP53', 'Gene', (81, 85))
901306	33159406	13  Even when TP53 inactivation is coupled with K-RAS activation in the skin 14  or with Akt activation in the oral cavity, 15  SCCs take 6-7 mo to appear.	('activation', 'PosReg', (93, 103))	('TP53', 'Gene', (14, 18))	('K-RAS', 'Gene', (48, 53))	('K-RAS', 'Gene', '16653', (48, 53))	('activation', 'PosReg', (54, 64))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('inactivation', 'Var', (19, 31))	('Akt', 'CPA', (89, 92))
901307	33159406	Similarly, mice lacking TP53 or RB/p107/p130 develop carcinoma in situ (CIS) or invasive CvSCC only after estrogen exposure for 5-6 mo.	('carcinoma', 'Disease', 'MESH:D009369', (53, 62))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('develop', 'Reg', (45, 52))	('mice', 'Species', '10090', (11, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('CIS', 'Phenotype', 'HP:0030075', (72, 75))	('lacking', 'NegReg', (16, 23))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (53, 70))	('carcinoma', 'Disease', (53, 62))	('TP53', 'Var', (24, 28))	('invasive CvSCC', 'CPA', (80, 94))	('RB/p107/p130', 'Var', (32, 44))
901308	33159406	The fact that clones with multiple mutations of the above-mentioned genes are present not only in human tumors but also in normal SSE bolsters this hypothesis.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('human', 'Species', '9606', (98, 103))	('mutations', 'Var', (35, 44))
901314	33159406	Dysregulation of the Hippo-YAP pathway has been implicated in numerous cancer types.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('implicated', 'Reg', (48, 58))	('Hippo-YAP pathway', 'Pathway', (21, 38))
901339	33159406	36  As noted above, TP53 is mutated in 84% of HPV- HNSCC cases, with mutations of EGFR, CDKN2A/B, FADD, FAT Atypical Cadherin1 (FAT1), NFE2L2, and CCND1 also frequently observed.	('NFE2L2', 'Gene', (135, 141))	('mutations', 'Var', (69, 78))	('EGFR', 'Gene', (82, 86))	('FAT1', 'Gene', (128, 132))	('FADD', 'Gene', (98, 102))	('FAT Atypical Cadherin1', 'Gene', '2195', (104, 126))	('CCND1', 'Gene', '595', (147, 152))	('CDKN2A/B', 'Gene', '1029;1030', (88, 96))	('FAT Atypical Cadherin1', 'Gene', (104, 126))	('HPV', 'Species', '10566', (46, 49))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))	('EGFR', 'Gene', '1956', (82, 86))	('NFE2L2', 'Gene', '4780', (135, 141))	('HPV- HNSCC', 'Disease', (46, 56))	('CCND1', 'Gene', (147, 152))	('CDKN2A/B', 'Gene', (88, 96))	('FAT1', 'Gene', '2195', (128, 132))	('FADD', 'Gene', '8772', (98, 102))
901341	33159406	In contrast, mutations of NOTCH, TP63, and PI3K/PTEN are common in both HPV- and HPV+ HNSCC.	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('TP63', 'Gene', '8626', (33, 37))	('TP63', 'Gene', (33, 37))	('HPV+ HNSCC', 'Disease', (81, 91))	('HPV-', 'Disease', (72, 76))	('NOTCH', 'Gene', (26, 31))	('common', 'Reg', (57, 63))	('HPV', 'Species', '10566', (72, 75))	('HPV', 'Species', '10566', (81, 84))	('mutations', 'Var', (13, 22))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))
901344	33159406	13 ,  37   Several lines of evidence tie YAP1 activation to HNSCC genesis: (1) We generated mice with tongue-specific loss of Mob1a/b that led to constitutive activation of endogenous YAP1 in this tissue.	('activation', 'PosReg', (159, 169))	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('Mob1a/b', 'Gene', (126, 133))	('loss', 'Var', (118, 122))	('endogenous YAP1', 'MPA', (173, 188))	('mice', 'Species', '10090', (92, 96))	('Mob1a/b', 'Gene', '232157', (126, 133))
901345	33159406	33  These mutants developed tongue CIS with surprising rapidity and exhibited invasive HNSCC within 4 wk of Mob1a/b deletion.	('Mob1a/b', 'Gene', '232157', (108, 115))	('developed', 'Reg', (18, 27))	('invasive HNSCC', 'CPA', (78, 92))	('deletion', 'Var', (116, 124))	('tongue CIS', 'CPA', (28, 38))	('Mob1a/b', 'Gene', (108, 115))	('exhibited', 'Reg', (68, 77))	('CIS', 'Phenotype', 'HP:0030075', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
901355	33159406	4   In mice, uterus-specific loss of MOB1A/B leads to cervical CIS within 1 wk in a manner dependent on YAP1.	('leads to', 'Reg', (45, 53))	('mice', 'Species', '10090', (7, 11))	('loss', 'Var', (29, 33))	('MOB1A/B', 'Gene', (37, 44))	('CIS', 'Phenotype', 'HP:0030075', (63, 66))	('cervical CIS', 'CPA', (54, 66))
901356	33159406	42  Additional p53 deficiency in these mutants produces invasive tumors within 3 wk.	('invasive tumors', 'Disease', (56, 71))	('deficiency', 'Var', (19, 29))	('invasive tumors', 'Disease', 'MESH:D009361', (56, 71))	('p53', 'Gene', (15, 18))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
901357	33159406	In contrast, transgenic (Tg) mice showing modest activation of YAP (S127A), a constitutively active mutant form of YAP1, exhibit invasive CvSCC only after 6-8 mo.	('YAP (S127A', 'Var', (63, 73))	('SCC', 'Phenotype', 'HP:0002860', (140, 143))	('S127A', 'Mutation', 'rs762471803', (68, 73))	('invasive CvSCC', 'CPA', (129, 143))	('mice', 'Species', '10090', (29, 33))
901361	33159406	43 ,  44  This combination of HPV E6/E7-induced accumulation of YAP protein plus its release to the nucleus leads to vigorous YAP activation that may promote human cervical epithelial cell proliferation and eventually CIS onset.	('promote', 'PosReg', (150, 157))	('human', 'Species', '9606', (158, 163))	('activation', 'PosReg', (130, 140))	('CIS', 'Phenotype', 'HP:0030075', (218, 221))	('accumulation', 'PosReg', (48, 60))	('CIS onset', 'CPA', (218, 227))	('E6/E7-induced', 'Var', (34, 47))	('HPV', 'Species', '10566', (30, 33))	('YAP', 'MPA', (126, 129))	('HPV', 'Gene', (30, 33))	('human cervical epithelial cell proliferation', 'CPA', (158, 202))	('release to', 'MPA', (85, 95))
901364	33159406	CuSCCs exhibit the highest mutation rate among SCCs, 6 ,  7  with frequent alterations to TP53, NOTCH1, NOTCH2, KMT2D, FAT1-4 and HRAS/BRAF/AJUBA (Table 1).	('CuSCCs', 'Phenotype', 'HP:0006739', (0, 6))	('KMT2D', 'Gene', (112, 117))	('mutation', 'Var', (27, 35))	('NOTCH1', 'Gene', '4851', (96, 102))	('BRAF', 'Gene', '673', (135, 139))	('BRAF', 'Gene', (135, 139))	('alterations', 'Reg', (75, 86))	('FAT1-4', 'Gene', '2195;2196;120114;79633', (119, 125))	('HRAS', 'Gene', '3265', (130, 134))	('NOTCH2', 'Gene', '4853', (104, 110))	('HRAS', 'Gene', (130, 134))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('KMT2D', 'Gene', '8085', (112, 117))	('TP53', 'Gene', (90, 94))	('FAT1-4', 'Gene', (119, 125))	('AJUBA', 'Gene', '84962', (140, 145))	('NOTCH2', 'Gene', (104, 110))	('SCC', 'Phenotype', 'HP:0002860', (2, 5))	('AJUBA', 'Gene', (140, 145))	('NOTCH1', 'Gene', (96, 102))
901365	33159406	Mutations of CDKN2A (INK4A/ARF) and PI3KCA/PTEN are also common, as is amplification of tyrosine kinase receptor genes (Table 1).	('INK4A/ARF', 'Gene', '1029', (21, 30))	('CDKN2A', 'Gene', (13, 19))	('PTEN', 'Gene', (43, 47))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', '5728', (43, 47))	('CDKN2A', 'Gene', '1029', (13, 19))	('INK4A/ARF', 'Gene', (21, 30))	('amplification', 'MPA', (71, 84))
901367	33159406	45   Little information is known about Hippo/YAP signaling in CuSCCs, but accumulating evidence suggests that YAP1 activation is involved in CuSCC genesis: (1) LATS1 and LATS2 are mutated in 18% and 26% of CuSCCs, respectively12.	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('CuSCCs', 'Phenotype', 'HP:0006739', (206, 212))	('LATS1', 'Gene', (160, 165))	('CuSCCs', 'Phenotype', 'HP:0006739', (62, 68))	('LATS1', 'Gene', '9113', (160, 165))	('mutated', 'Var', (180, 187))	('CuSCC', 'Disease', (141, 146))	('SCC', 'Phenotype', 'HP:0002860', (208, 211))	('LATS2', 'Gene', (170, 175))	('LATS2', 'Gene', '26524', (170, 175))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))
901378	33159406	50  Like other HPV- SCCs, ESCCs usually exhibit mutations of genes involved in the cell cycle, apoptosis regulation, and histone modification, including TP53 (93%), FGFR3, CCND1, NOTCH1-3, CDKN2A, and KMT2D (Table 1).	('NOTCH1-3', 'Gene', (179, 187))	('CDKN2A', 'Gene', (189, 195))	('exhibit', 'Reg', (40, 47))	('FGFR3', 'Gene', '2261', (165, 170))	('NOTCH1-3', 'Gene', '4851;4853;4854', (179, 187))	('SCC', 'Phenotype', 'HP:0002860', (20, 23))	('KMT2D', 'Gene', (201, 206))	('KMT2D', 'Gene', '8085', (201, 206))	('CCND1', 'Gene', '595', (172, 177))	('SCC', 'Phenotype', 'HP:0002860', (27, 30))	('FGFR3', 'Gene', (165, 170))	('CDKN2A', 'Gene', '1029', (189, 195))	('HPV', 'Species', '10566', (15, 18))	('TP53', 'Gene', (153, 157))	('CCND1', 'Gene', (172, 177))	('mutations', 'Var', (48, 57))
901379	33159406	The risk of ESCC in Eastern China has been associated with certain polymorphisms of the FAT4 gene, which acts upstream of the Hippo core.	('SCC', 'Phenotype', 'HP:0002860', (13, 16))	('ESCC', 'Disease', (12, 16))	('FAT4', 'Gene', (88, 92))	('FAT4', 'Gene', '79633', (88, 92))	('associated', 'Reg', (43, 53))	('polymorphisms', 'Var', (67, 80))
901385	33159406	In mice, loss of YAP1 specifically in the esophagus decreases esophageal progenitor cell proliferation and stratification.	('YAP1', 'Gene', (17, 21))	('decreases', 'NegReg', (52, 61))	('mice', 'Species', '10090', (3, 7))	('loss', 'Var', (9, 13))	('esophageal progenitor cell proliferation', 'CPA', (62, 102))
901386	33159406	Conversely, Tg mice with constitutive Yap1 expression show enhanced cell proliferation that induces abnormal stratification of esophageal layers at E18.5.	('induces', 'Reg', (92, 99))	('cell proliferation', 'CPA', (68, 86))	('expression', 'Var', (43, 53))	('enhanced', 'PosReg', (59, 67))	('stratification', 'CPA', (109, 123))	('Yap1', 'Gene', (38, 42))	('mice', 'Species', '10090', (15, 19))	('Yap1', 'Gene', '22601', (38, 42))
901392	33159406	Although lung adenocarcinomas (LADCs) often exhibit EGFR mutations or ALK fusions, LSCCs are not driven by these oncogenic changes and so rarely respond to agents targeting them.	('ALK', 'Gene', '238', (70, 73))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('lung adenocarcinomas', 'Disease', (9, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (9, 29))	('fusions', 'Var', (74, 81))	('mutations', 'Var', (57, 66))	('exhibit', 'Reg', (44, 51))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (9, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('ALK', 'Gene', (70, 73))	('LADCs', 'Phenotype', 'HP:0030078', (31, 36))
901393	33159406	56  Almost all LSCCs feature TP53 alterations as well as mutations of oxidative stress response genes (KEAP1, NFE2L2), PI3K/PTEN pathway genes, squamous differentiation genes (TP63, SOX2), and cell cycle-related genes (CDKN2A/B) (Table 1).	('NFE2L2', 'Gene', (110, 116))	('TP63', 'Gene', (176, 180))	('TP63', 'Gene', '8626', (176, 180))	('KEAP1', 'Gene', '9817', (103, 108))	('PTEN', 'Gene', (124, 128))	('SOX2', 'Gene', '6657', (182, 186))	('CDKN2A/B', 'Gene', (219, 227))	('PTEN', 'Gene', '5728', (124, 128))	('KEAP1', 'Gene', (103, 108))	('mutations', 'Var', (57, 66))	('TP53', 'Gene', (29, 33))	('NFE2L2', 'Gene', '4780', (110, 116))	('oxidative stress', 'Phenotype', 'HP:0025464', (70, 86))	('CDKN2A/B', 'Gene', '1029;1030', (219, 227))	('alterations', 'Var', (34, 45))	('SCC', 'Phenotype', 'HP:0002860', (16, 19))	('SOX2', 'Gene', (182, 186))
901394	33159406	In a mouse model, the trans-differentiation of LADCs into LSCCs was associated with LKB1 inactivation and led to malignant progression as well as drug resistance.	('malignant progression', 'CPA', (113, 134))	('associated', 'Reg', (68, 78))	('inactivation', 'Var', (89, 101))	('LADCs', 'Phenotype', 'HP:0030078', (47, 52))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('drug resistance', 'CPA', (146, 161))	('drug resistance', 'Phenotype', 'HP:0020174', (146, 161))	('LKB1', 'Gene', (84, 88))	('mouse', 'Species', '10090', (5, 10))	('trans-differentiation', 'CPA', (22, 43))	('LKB1', 'Gene', '20869', (84, 88))	('led to', 'Reg', (106, 112))
901397	33159406	Work in mouse models and human LADC cell lines has confirmed that YAP hyperactivation promotes malignant progression of LADC.	('YAP', 'Gene', (66, 69))	('LADC', 'Disease', (120, 124))	('malignant progression', 'CPA', (95, 116))	('human', 'Species', '9606', (25, 30))	('promotes', 'PosReg', (86, 94))	('mouse', 'Species', '10090', (8, 13))	('hyperactivation', 'Var', (70, 85))
901402	33159406	The above body of work establishes that MOB1 deletion or YAP1 activation induces CIS formation within 5-9 d in the context of HNSCCs, CvSCCs, and CuSCCs.	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('MOB1', 'Gene', '55233', (40, 44))	('HNSCCs', 'Disease', 'MESH:D000077195', (126, 132))	('CIS', 'Phenotype', 'HP:0030075', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('induces', 'Reg', (73, 80))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('MOB1', 'Gene', (40, 44))	('HNSCCs', 'Disease', (126, 132))	('CuSCCs', 'Phenotype', 'HP:0006739', (146, 152))	('deletion', 'Var', (45, 53))	('CIS formation', 'MPA', (81, 94))	('YAP1', 'Gene', (57, 61))	('activation', 'PosReg', (62, 72))
901409	33159406	In the case of HNSCC, the HPV E6/E7 proteins are strong activators of YAP1, meaning that the threshold is exceeded by few other deleterious mutations to trigger the transition to SCC.	('E6/E7', 'Var', (30, 35))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('proteins', 'Protein', (36, 44))	('HPV', 'Species', '10566', (26, 29))	('activators', 'MPA', (56, 66))
901410	33159406	35  Considering that, in mice, YAP1 inhibition not only prevents SCC onset but also delays its progression, YAP1 may be an appealing target for molecular therapy of these devastating malignancies.	('progression', 'MPA', (95, 106))	('mice', 'Species', '10090', (25, 29))	('inhibition', 'Var', (36, 46))	('YAP1', 'Gene', (31, 35))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('SCC', 'Disease', (65, 68))	('delays', 'NegReg', (84, 90))	('malignancies', 'Disease', (183, 195))	('prevents', 'NegReg', (56, 64))
901411	33159406	One possible reason for the frequent and early onset of SCCs in mice bearing mutated elements of the Hippo pathway is the activation of DeltaNp63, the master regulator of proliferation, differentiation, and adhesion of SSE cells.	('SCCs', 'Disease', (56, 60))	('mutated', 'Var', (77, 84))	('activation', 'PosReg', (122, 132))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('DeltaNp63', 'Chemical', '-', (136, 145))	('DeltaNp63', 'Gene', (136, 145))	('mice', 'Species', '10090', (64, 68))
901421	33159406	We propose that, because YAP hyperactivation induces immediate CIS onset in mouse models, YAP must be the key molecule driving CIS with no need for any other gene alteration.	('YAP', 'Gene', (25, 28))	('immediate CIS onset', 'MPA', (53, 72))	('hyperactivation', 'Var', (29, 44))	('mouse', 'Species', '10090', (76, 81))	('CIS', 'Phenotype', 'HP:0030075', (127, 130))	('CIS', 'Phenotype', 'HP:0030075', (63, 66))
901423	33159406	In addition, our mouse models featuring mutations in the Hippo-YAP pathway currently constitute the world's fastest spontaneous cancer onset models.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('Hippo-YAP pathway', 'Gene', (57, 74))	('mouse', 'Species', '10090', (17, 22))	('mutations', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
901424	33159406	Cancer progression is synchronized in these mutant animals, and the tumors are easily visualized on the mouse exterior (especially in the HNSCC and CuSCC models).	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('SCC', 'Phenotype', 'HP:0002860', (140, 143))	('mouse', 'Species', '10090', (104, 109))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutant', 'Var', (44, 50))	('SCC', 'Phenotype', 'HP:0002860', (150, 153))
901430	33020452	IL32 was independently and positively associated with Ki67, HIF1A, and ACTA2 and negatively with TJP1 in tumors and with IL10Ra and BCLxL in non-transformed tumor-adjacent tissue.	('tumors', 'Disease', (105, 111))	('BCLxL', 'Gene', (132, 137))	('BCLxL', 'Gene', '598', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('HIF1A', 'Gene', '3091', (60, 65))	('IL32', 'Gene', '9235', (0, 4))	('ACTA2', 'Gene', (71, 76))	('TJP1', 'Gene', '7082', (97, 101))	('ACTA2', 'Gene', '59', (71, 76))	('negatively', 'NegReg', (81, 91))	('tumor', 'Disease', (105, 110))	('Ki67', 'Var', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('IL10Ra', 'Gene', '3587', (121, 127))	('tumor', 'Disease', (157, 162))	('HIF1A', 'Gene', (60, 65))	('TJP1', 'Gene', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('associated', 'Interaction', (38, 48))	('IL32', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('IL10Ra', 'Gene', (121, 127))
901495	33020452	There was no significant association between fold-change in IL32 expression and cancer overall TNM stage or its individual components.	('IL32', 'Gene', '9235', (60, 64))	('IL32', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('fold-change', 'Var', (45, 56))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
901509	33020452	In turn, fold-change in IL32 expression was independently associated with fold-change in expression of IL7Ra (rp = 0.40, p = 0.008) and SLC2A1 (rp = 0.56, p < 0.001) or fold-change in expression of CDKN1A (rp = 0.49, p = 0.001) and IL7 (rp = 0.43, p = 0.004), depending on regression model applied.	('fold-change', 'Var', (74, 85))	('expression', 'MPA', (89, 99))	('CDKN1A', 'Gene', (198, 204))	('CDKN1A', 'Gene', '1026', (198, 204))	('IL7', 'Gene', '3574', (232, 235))	('IL7Ra', 'Gene', (103, 108))	('IL7', 'Gene', (103, 106))	('IL32', 'Gene', '9235', (24, 28))	('IL7', 'Gene', (232, 235))	('IL7Ra', 'Gene', '3575', (103, 108))	('SLC2A1', 'Gene', '6513', (136, 142))	('IL32', 'Gene', (24, 28))	('fold-change', 'Var', (169, 180))	('IL7', 'Gene', '3574', (103, 106))	('expression', 'MPA', (184, 194))	('expression', 'MPA', (29, 39))	('SLC2A1', 'Gene', (136, 142))	('fold-change', 'Var', (9, 20))
901602	33020452	When analyzed with reference to cancer type, IL32 showed strong positive correlation with Ki67 in gastric tumors (r = 0.72, p = 0.009) and only a weaker tendency in colonic tumors (r = 0.41. p = 0.072).	('gastric tumors', 'Disease', (98, 112))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('positive', 'PosReg', (64, 72))	('cancer', 'Disease', (32, 38))	('IL32', 'Gene', '9235', (45, 49))	('gastric tumors', 'Phenotype', 'HP:0006753', (98, 112))	('correlation', 'Interaction', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('IL32', 'Gene', (45, 49))	('Ki67', 'Var', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('gastric tumors', 'Disease', 'MESH:D013274', (98, 112))	('colonic tumors', 'Disease', 'MESH:D003110', (165, 179))	('colonic tumors', 'Disease', (165, 179))
901694	29850009	indicated that higher number of CD20+ B cells in early stage of hypopharynx squamous cell carcinoma was associated with improved locoregional control.	('improved', 'PosReg', (120, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('hypopharynx squamous cell carcinoma', 'Disease', (64, 99))	('hypopharynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 99))	('locoregional control', 'CPA', (129, 149))	('CD20+ B cells', 'Var', (32, 45))	('hypopharynx squamous cell carcinoma', 'Phenotype', 'HP:0012182', (64, 99))	('early stage of hypopharynx', 'Phenotype', 'HP:3000053', (49, 75))
901712	28927132	Further investigations revealed that ectopic expression of ECRG4 inhibited cell proliferation, migration and invasion and promoted cell apoptosis in SMMC-7721 cells, which was mediated by the regulation of BAX and B cell lymphoma-2, in addition to the upregulation of epithelial-mesenchymal transition markers.	('lymphoma', 'Phenotype', 'HP:0002665', (221, 229))	('invasion', 'CPA', (109, 117))	('ECRG4', 'Gene', (59, 64))	('BAX', 'Gene', (206, 209))	('ectopic expression', 'Var', (37, 55))	('BAX', 'Gene', '581', (206, 209))	('promoted', 'PosReg', (122, 130))	('ECRG4', 'Gene', '84417', (59, 64))	('inhibited', 'NegReg', (65, 74))	('cell apoptosis', 'CPA', (131, 145))	('SMMC-7721', 'CellLine', 'CVCL:0534', (149, 158))	('migration', 'CPA', (95, 104))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (214, 229))	('cell proliferation', 'CPA', (75, 93))
901773	28927132	Kaplan-Meier survival curves also revealed the overall survival time of the low ECRG4 expression group was much shorter compared with the high ECRG4 expression group (Fig.	('low', 'Var', (76, 79))	('ECRG4', 'Gene', (143, 148))	('ECRG4', 'Gene', (80, 85))	('ECRG4', 'Gene', '84417', (143, 148))	('survival time', 'CPA', (55, 68))	('ECRG4', 'Gene', '84417', (80, 85))	('shorter', 'NegReg', (112, 119))
901795	28927132	In particular, low ECRG4 expression level was reported to significantly promote tumor cell migration and inhibit apoptosis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('ECRG4', 'Gene', '84417', (19, 24))	('low', 'Var', (15, 18))	('apoptosis', 'CPA', (113, 122))	('inhibit', 'NegReg', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('promote', 'PosReg', (72, 79))	('ECRG4', 'Gene', (19, 24))
901808	28927132	The survival analysis of the present study also demonstrated that the 5-year survival rate in patients underexpressing ECRG4 was lower compared with patients with high levels of ECRG4 expression (36.7 vs. 71.4%).	('patients', 'Species', '9606', (149, 157))	('ECRG4', 'Gene', (119, 124))	('ECRG4', 'Gene', (178, 183))	('patients', 'Species', '9606', (94, 102))	('survival', 'CPA', (77, 85))	('ECRG4', 'Gene', '84417', (119, 124))	('ECRG4', 'Gene', '84417', (178, 183))	('underexpressing', 'Var', (103, 118))	('lower', 'NegReg', (129, 134))
901818	28927132	This finding partially explained the observation in patient samples that those with low ECRG4 expression were more vulnerable to metastasis.	('ECRG4', 'Gene', '84417', (88, 93))	('low', 'Var', (84, 87))	('metastasis', 'CPA', (129, 139))	('patient', 'Species', '9606', (52, 59))	('expression', 'MPA', (94, 104))	('ECRG4', 'Gene', (88, 93))
901824	28927132	Although marked differences of 5-year survival rates between patients with high and low ECRG4 expression levels were observed, the sample size was too small to obtain statistical significance.	('low', 'NegReg', (84, 87))	('ECRG4', 'Gene', '84417', (88, 93))	('high', 'Var', (75, 79))	('patients', 'Species', '9606', (61, 69))	('expression levels', 'MPA', (94, 111))	('ECRG4', 'Gene', (88, 93))
901853	28118615	Endoscopically measured luminal stenosis was determined after reviewing each patient's preoperative upper GI endoscopy report and classified as two degrees: I, None stenosis or minimal stricture without resistance while passing endoscope; II, significant stenosis allowing endoscopic passage with remarkable resistance or severe stenosis preventing passage of the endoscope through the tumor site.	('tumor', 'Disease', (386, 391))	('luminal stenosis', 'Disease', (24, 40))	('tumor', 'Disease', 'MESH:D009369', (386, 391))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('patient', 'Species', '9606', (77, 84))	('stenosis', 'Var', (255, 263))	('luminal stenosis', 'Disease', 'MESH:D003251', (24, 40))
901871	28118615	Accordingly, patients with degree-Istenosis (n = 369) had a significantly better 5 year OS rate (45.0% vs. 27.7%; P = 0.000) than those patients with degree-II stenosis (n = 139) (Figure 1).	('better', 'PosReg', (74, 80))	('degree-Istenosis', 'Var', (27, 43))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (136, 144))	('OS', 'Chemical', '-', (88, 90))
901905	28118615	Our results validated the prognostic value of endoscopic tumor stenosis and suggested tumor with stenotic degree of II may imply a poor OS in patients with ESCC as compared to degree-I tumor.	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor stenosis', 'Disease', 'MESH:D003251', (57, 71))	('tumor', 'Disease', (86, 91))	('tumor stenosis', 'Disease', (57, 71))	('stenotic degree of II', 'Var', (97, 118))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('OS', 'Chemical', '-', (136, 138))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('patients', 'Species', '9606', (142, 150))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('ESCC', 'Disease', (156, 160))
901952	28723804	As to other malignances such as lung adenocarcinoma, LMVD was reported to cause worse prognosis, so was the same with colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('lung adenocarcinoma', 'Disease', (32, 51))	('LMVD', 'Var', (53, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (32, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('LMVD', 'Chemical', '-', (53, 57))	('colorectal cancer', 'Disease', (118, 135))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (32, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
901968	28723804	To conclude, high MVD is a prognostic factor among ESCC, and would lead to worse outcomes in these patients.	('patients', 'Species', '9606', (99, 107))	('ESCC', 'Disease', (51, 55))	('high MVD', 'Var', (13, 21))
902055	25386186	They concluded that the proportion of patients who developed a stricture was significantly lower in the stent group than in the control group.	('lower', 'NegReg', (91, 96))	('stent', 'Var', (104, 109))	('stricture', 'MPA', (63, 72))	('patients', 'Species', '9606', (38, 46))
902071	25120954	X-Linked Inhibitor of Apoptosis Protein - A Critical Death Resistance Regulator and Therapeutic Target for Personalized Cancer Therapy Defects in apoptosis regulation are one main cause of cancer development and may result from overexpression of anti-apoptotic proteins such as inhibitor of apoptosis proteins (IAPs).	('Defects', 'Var', (135, 142))	('Cancer', 'Disease', (120, 126))	('overexpression', 'PosReg', (228, 242))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('result', 'Reg', (216, 222))	('X-Linked Inhibitor of Apoptosis Protein', 'Gene', (0, 39))	('cause', 'Reg', (180, 185))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('X-Linked Inhibitor of Apoptosis Protein', 'Gene', '331', (0, 39))	('apoptosis', 'MPA', (146, 155))	('cancer', 'Disease', (189, 195))
902080	25120954	Aggressive cancer cells develop due to an accumulation of genetic and epigenetic abnormalities, defects in the intracellular signal transduction pathways, in proliferation and migration regulation, and the apoptotic cell death machinery.	('epigenetic abnormalities', 'Var', (70, 94))	('Aggressive cancer', 'Disease', 'MESH:D009369', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('genetic', 'Var', (58, 65))	('Aggressive cancer', 'Disease', (0, 17))	('apoptotic cell death machinery', 'CPA', (206, 236))	('defects', 'NegReg', (96, 103))	('intracellular signal transduction pathways', 'Pathway', (111, 153))	('proliferation', 'CPA', (158, 171))
902112	25120954	demonstrated that removal of the RING domain in vivo stabilizes the remaining XIAP protein but surprisingly also increases caspase-3 activity and TNF-sensitivity.	('caspase-3', 'Gene', '836', (123, 132))	('removal', 'Var', (18, 25))	('TNF', 'Gene', (146, 149))	('XIAP protein', 'Protein', (78, 90))	('stabilizes', 'MPA', (53, 63))	('activity', 'MPA', (133, 141))	('caspase-3', 'Gene', (123, 132))	('TNF', 'Gene', '7124', (146, 149))	('increases', 'PosReg', (113, 122))
902118	25120954	Lys48-branched ubiquitin chains label proteins for proteasomal degradation, whereas Lys63 and Lys11 linear linkages serve as docking sites in signal transduction, endocytosis and other cellular responses such as DNA-repair [reviewed in Ref.	('proteins', 'Protein', (38, 46))	('Lys63', 'Chemical', '-', (84, 89))	('proteasomal degradation', 'MPA', (51, 74))	('Lys48', 'Chemical', '-', (0, 5))	('Lys11', 'Chemical', '-', (94, 99))	('DNA-repair', 'Disease', (212, 222))	('Lys48-branched', 'Var', (0, 14))
902135	25120954	clearly demonstrated by crystallizing the TAB1/XIAP-BIR1 complex that the XIAP-BIR1 domain, for which no other function has been described until now, directly binds one molecule of TAB1 and thereby causes the formation of a complex where a dimer of XIAP-molecules binds two TAB1 proteins, which in turn recruit TAK1 proteins.	('binds', 'Interaction', (264, 269))	('TAK1', 'Gene', '6885', (311, 315))	('TAK1', 'Gene', (311, 315))	('BIR1', 'Gene', (52, 56))	('recruit', 'PosReg', (303, 310))	('domain', 'Var', (84, 90))	('binds', 'Interaction', (159, 164))	('BIR1', 'Gene', '3763', (79, 83))	('BIR1', 'Gene', '3763', (52, 56))	('complex', 'Interaction', (224, 231))	('causes', 'Reg', (198, 204))	('BIR1', 'Gene', (79, 83))	('TAB1 proteins', 'Protein', (274, 287))
902136	25120954	This dimerization is important for TAK1 activation, as mutation of the BIR1 dimerization interface reduces the ability to activate NFkappaB.	('BIR1', 'Gene', '3763', (71, 75))	('TAK1', 'Gene', '6885', (35, 39))	('TAK1', 'Gene', (35, 39))	('BIR1', 'Gene', (71, 75))	('reduces', 'NegReg', (99, 106))	('mutation', 'Var', (55, 63))	('NFkappaB', 'Gene', (131, 139))	('ability', 'MPA', (111, 118))	('NFkappaB', 'Gene', '4790', (131, 139))
902151	25120954	Patients with renal cell carcinoma with low XIAP expression had a longer postoperative disease-specific survival as compared to those with high expression in the 5 year follow-up.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('low', 'Var', (40, 43))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (14, 34))	('Patients', 'Species', '9606', (0, 8))	('XIAP', 'Gene', (44, 48))	('disease-specific survival', 'CPA', (87, 112))	('longer', 'PosReg', (66, 72))	('renal cell carcinoma', 'Disease', (14, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
902152	25120954	Treatment of XIAP siRNA in combination with paclitaxel, cisplatin, fluorouracil, and etoposide enhanced chemosensitivity in esophageal carcinoma cell lines demonstrating that knockdown of XIAP may be a strategy for cancer therapy in patients with esophageal carcinoma.	('fluorouracil', 'Chemical', 'MESH:D005472', (67, 79))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (247, 267))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (124, 144))	('paclitaxel', 'Chemical', 'MESH:D017239', (44, 54))	('enhanced', 'PosReg', (95, 103))	('cancer', 'Disease', (215, 221))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('esophageal carcinoma', 'Disease', (124, 144))	('etoposide', 'Chemical', 'MESH:D005047', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (247, 267))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (124, 144))	('knockdown', 'Var', (175, 184))	('patients', 'Species', '9606', (233, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('chemosensitivity', 'CPA', (104, 120))	('esophageal carcinoma', 'Disease', (247, 267))	('cancer', 'Disease', 'MESH:D009369', (215, 221))
902154	25120954	In human prostate and hepatocellular carcinoma cells, the XIAP expression correlates with apoptosis resistance and increased metastatic foci in vivo.	('XIAP', 'Gene', (58, 62))	('increased', 'PosReg', (115, 124))	('human', 'Species', '9606', (3, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('metastatic foci', 'CPA', (125, 140))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (22, 46))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (22, 46))	('hepatocellular carcinoma', 'Disease', (22, 46))	('apoptosis resistance', 'CPA', (90, 110))	('expression', 'Var', (63, 73))
902159	25120954	In prostate cancer, XIAP is significantly higher expressed in the cancer tissue than in prostatic intraepithelial neoplasia, or in normal or benign hyperplasia, but, surprisingly, high expression of XIAP predicts lower risk of tumor recurrence than low or intermediate XIAP expression in the tumor tissue.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('tumor', 'Disease', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', (3, 18))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (66, 72))	('benign hyperplasia', 'Disease', (141, 159))	('benign hyperplasia', 'Disease', 'MESH:D011470', (141, 159))	('neoplasia', 'Phenotype', 'HP:0002664', (114, 123))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('higher', 'PosReg', (42, 48))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (88, 123))	('XIAP', 'Gene', (199, 203))	('cancer', 'Disease', (12, 18))	('tumor', 'Disease', (292, 297))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (98, 123))	('prostatic intraepithelial neoplasia', 'Disease', (88, 123))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('high expression', 'Var', (180, 195))
902170	25120954	In a Phase I/II trial AEG35156 was effective in repressing XIAP mRNA levels and inducing apoptosis in CD34+CD38- AML stem cells.	('repressing XIAP mRNA levels', 'MPA', (48, 75))	('CD38', 'Gene', (107, 111))	('apoptosis', 'CPA', (89, 98))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('CD34', 'Gene', (102, 106))	('CD34', 'Gene', '947', (102, 106))	('AEG35156', 'Var', (22, 30))	('AML', 'Phenotype', 'HP:0004808', (113, 116))	('AML', 'Disease', (113, 116))	('inducing', 'Reg', (80, 88))	('CD38', 'Gene', '952', (107, 111))	('AEG35156', 'Chemical', 'MESH:C498209', (22, 30))
902178	25120954	Whereas the genetic deletion of XIAP causes only a very mild phenotype in knock-out mice, targeting of multiple IAPs, as it is achieved by high affinity SMAC-mimetics, may be detrimental to an organism as demonstrated by the deletion of cIAP1 together with cIAP2 or XIAP.	('deletion', 'Var', (225, 233))	('cIAP1', 'Gene', (237, 242))	('XIAP', 'Gene', (32, 36))	('deletion', 'Var', (20, 28))	('mice', 'Species', '10090', (84, 88))
902181	25120954	In these cells, mitochondrial outer membrane permeabilization is triggered by truncation of the BH3-only protein BID, which counteracts pro-survival proteins such as Bcl2 or BclxL, leads to Bax and Bak oligomerization, cytochrome c release, and caspase-9 activation at the apoptosome complex.	('BclxL', 'Gene', '598', (174, 179))	('BID', 'Gene', '637', (113, 116))	('caspase-9', 'Gene', (245, 254))	('cytochrome c', 'Gene', (219, 231))	('Bak', 'Gene', (198, 201))	('truncation', 'Var', (78, 88))	('activation', 'PosReg', (255, 265))	('Bax', 'Gene', (190, 193))	('mitochondrial outer membrane permeabilization', 'MPA', (16, 61))	('Bax', 'Gene', '581', (190, 193))	('caspase-9', 'Gene', '842', (245, 254))	('BH3-only', 'Gene', (96, 104))	('BclxL', 'Gene', (174, 179))	('cytochrome c', 'Gene', '54205', (219, 231))	('Bak', 'Gene', '578', (198, 201))	('oligomerization', 'MPA', (202, 217))	('Bcl2', 'Gene', (166, 170))	('BID', 'Gene', (113, 116))	('Bcl2', 'Gene', '596', (166, 170))
902184	25120954	This suggests that the activation of caspases in hepatocytes is normally blocked by XIAP and neutralization of XIAP may lead to significant damage of liver cells.	('neutralization', 'Var', (93, 107))	('caspases', 'Gene', (37, 45))	('lead to', 'Reg', (120, 127))	('damage', 'MPA', (140, 146))	('caspases', 'Gene', '839;841;842', (37, 45))
902185	25120954	In line with this study, Varfolomeev and colleagues found that BV6 in combination with FasL or DR5 agonistic antibodies rescues the effect of BID knockdown for apoptosis induction in different cancer cells.	('knockdown', 'Var', (146, 155))	('apoptosis', 'CPA', (160, 169))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('BV6', 'CellLine', 'CVCL:0182', (63, 66))	('cancer', 'Disease', (193, 199))	('BID', 'Gene', (142, 145))	('rescues', 'PosReg', (120, 127))	('FasL', 'Gene', (87, 91))	('DR5', 'Gene', (95, 98))	('FasL', 'Gene', '356', (87, 91))	('DR5', 'Gene', '8795', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('BID', 'Gene', '637', (142, 145))	('effect', 'MPA', (132, 138))
902200	25120954	Other compounds, e.g., small molecular XIAP-inhibitors from IDUN Pharmaceuticals/Pfizer were shown to cooperate with TRAIL to induce apoptosis and to inhibit clonogenic survival of childhood acute leukemia cells.	('small molecular', 'Var', (23, 38))	('TRAIL', 'Gene', '8743', (117, 122))	('induce', 'PosReg', (126, 132))	('inhibit', 'NegReg', (150, 157))	('apoptosis', 'CPA', (133, 142))	('TRAIL', 'Gene', (117, 122))	('acute leukemia', 'Phenotype', 'HP:0002488', (191, 205))	('leukemia', 'Disease', (197, 205))	('leukemia', 'Disease', 'MESH:D007938', (197, 205))	('leukemia', 'Phenotype', 'HP:0001909', (197, 205))
902204	25120954	Additional early small-molecule XIAP-inhibitors such as the polyphenylurea-based antagonists 1396-12 and 1396-34 efficiently inhibited the growth of prostate cancer xenografts in mice and showed little toxicity on normal tissues.	('1396-34', 'Var', (105, 112))	('toxicity', 'Disease', 'MESH:D064420', (202, 210))	('prostate cancer', 'Disease', 'MESH:D011471', (149, 164))	('toxicity', 'Disease', (202, 210))	('mice', 'Species', '10090', (179, 183))	('prostate cancer', 'Phenotype', 'HP:0012125', (149, 164))	('growth', 'CPA', (139, 145))	('inhibited', 'NegReg', (125, 134))	('polyphenylurea', 'Chemical', '-', (60, 74))	('XIAP-inhibitors', 'Gene', (32, 47))	('prostate cancer', 'Disease', (149, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
902210	25120954	Two of these compounds TL32711/Birinipant (Tetralogic Pharamceuticals) and HGS1029 (Human Genome Sciences) also successfully completed Phase I trials on advanced ovarian, peritoneal cancer, other refractory solid tumors and lymphoma (TL32711), and advanced solid tumors (HGS1029) allowing the determination of the maximum tolerable dose (MTD).	('solid tumors', 'Disease', 'MESH:D009369', (207, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('HGS1029', 'CellLine', 'CVCL:9D49', (271, 278))	('HGS1029', 'Var', (75, 82))	('TL32711', 'Var', (234, 241))	('lymphoma', 'Phenotype', 'HP:0002665', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('TL32711', 'Chemical', 'MESH:C582429', (234, 241))	('solid tumors', 'Disease', (257, 269))	('TL32711/Birinipant', 'Var', (23, 41))	('ovarian', 'Disease', (162, 169))	('cancer', 'Disease', (182, 188))	('Human', 'Species', '9606', (84, 89))	('ovarian', 'Disease', 'MESH:D010051', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Birinipant', 'Chemical', '-', (31, 41))	('tumors and lymphoma', 'Disease', 'MESH:D008223', (213, 232))	('solid tumors', 'Disease', (207, 219))	('solid tumors', 'Disease', 'MESH:D009369', (257, 269))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('HGS1029', 'CellLine', 'CVCL:9D49', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('TL32711', 'Chemical', 'MESH:C582429', (23, 30))	('cancer', 'Disease', 'MESH:D009369', (182, 188))
902211	25120954	However, SMAC-mimetics are expected to act mainly also as chemosensitizing drugs and to this end all combination Phase I trials, e.g., AT-406 in combination with daunorubicine/cytarabine or TL32711 in combination with gemcitabine were terminated.	('AT-406', 'Chemical', 'MESH:C559144', (135, 141))	('AT-406', 'Var', (135, 141))	('TL32711', 'Chemical', 'MESH:C582429', (190, 197))	('TL32711', 'Gene', (190, 197))	('cytarabine', 'Chemical', 'MESH:D003561', (176, 186))	('daunorubicine', 'Chemical', 'MESH:D003630', (162, 175))	('gemcitabine', 'Chemical', 'MESH:C056507', (218, 229))
902215	25120954	XIAP on one hand inhibits cell death execution by physical interaction with caspases and by causing their proteasomal degradation, on the other hand it also triggers survival signaling via the NFkappaB pathway thereby directly shifting the survival/death balance in cancer cells toward death resistance and NFkappaB-driven survival.	('proteasomal degradation', 'MPA', (106, 129))	('caspases', 'Gene', '839;841;842', (76, 84))	('NFkappaB', 'Gene', (307, 315))	('death balance', 'Disease', (249, 262))	('NFkappaB', 'Gene', '4790', (193, 201))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cell death execution', 'CPA', (26, 46))	('NFkappaB', 'Gene', (193, 201))	('caspases', 'Gene', (76, 84))	('interaction', 'Interaction', (59, 70))	('survival signaling', 'MPA', (166, 184))	('shifting', 'Reg', (227, 235))	('inhibits', 'NegReg', (17, 25))	('cancer', 'Disease', (266, 272))	('triggers', 'Reg', (157, 165))	('XIAP', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('NFkappaB', 'Gene', '4790', (307, 315))	('death balance', 'Disease', 'MESH:D003643', (249, 262))
902231	32796247	A prospective randomized trial has revealed that esophagectomy with 3-field extended lymphadenectomy could prevent recurrence and prolong survival after surgery; however, patients who underwent extended lymphadenectomy had significantly more postoperative complications, such as phrenic nerve palsy, tracheostomies, and recurrent nerve palsy in almost 60% of the patients, and the hospital death rate was as high as 7.9%.	('death', 'Disease', 'MESH:D003643', (390, 395))	('palsy', 'Disease', 'MESH:D010243', (336, 341))	('death', 'Disease', (390, 395))	('tracheostomies', 'Disease', (300, 314))	('phrenic nerve palsy', 'Disease', (279, 298))	('phrenic nerve palsy', 'Disease', 'MESH:D010243', (279, 298))	('patients', 'Species', '9606', (363, 371))	('palsy', 'Disease', (293, 298))	('patients', 'Species', '9606', (171, 179))	('extended lymphadenectomy', 'Phenotype', 'HP:0002716', (76, 100))	('palsy', 'Disease', (336, 341))	('tracheostomies', 'Disease', 'None', (300, 314))	('extended lymphadenectomy', 'Var', (194, 218))	('palsy', 'Disease', 'MESH:D010243', (293, 298))	('recurrent', 'Disease', (320, 329))	('extended lymphadenectomy', 'Phenotype', 'HP:0002716', (194, 218))
902306	32487238	Out of 12 SNPs, two SNPs rs12190287 of TCF21 and rs10046 of CYP19A1 were significantly associated with esophageal cancer with Odds Ratio (OR) 1.412 (1.09-1.8 at 95% CI, p = 0.008) and 1.54 (1.21-2.072 at 95% CI, p = 0.0007) within the population of Jammu and Kashmir.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('rs10046', 'Var', (49, 56))	('CYP19A1', 'Gene', '1588', (60, 67))	('TCF21', 'Gene', '6943', (39, 44))	('CYP19A1', 'Gene', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rs12190287', 'Var', (25, 35))	('associated with', 'Reg', (87, 102))	('rs10046', 'Mutation', 'rs10046', (49, 56))	('TCF21', 'Gene', (39, 44))	('rs12190287', 'Mutation', 'rs12190287', (25, 35))	('cancer', 'Disease', (114, 120))
902315	32487238	We attempted to investigate the role of cancer-related genetic variants in ESCC within the population of J&K.	('variants', 'Var', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('ESCC', 'Gene', (75, 79))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
902327	32487238	GTEx portal was used to determine NES (normalized effect size) value {Low, 2017 #12} and the gene expression of associated SNPs and variant effect prediction (Supplementary Figures 1 and 2).	('men', 'Species', '9606', (165, 168))	('variant', 'Var', (132, 139))	('SNPs', 'Disease', (123, 127))
902328	32487238	NES value for variants rs10046 is negative and rs12190287 was positive.	('rs12190287', 'Var', (47, 57))	('rs12190287', 'Mutation', 'rs12190287', (47, 57))	('rs10046', 'Mutation', 'rs10046', (23, 30))	('rs10046', 'Var', (23, 30))
902331	32487238	These SNPs are rs12190287 of TCF21 and rs10046 of CYP19A1.	('rs12190287', 'Mutation', 'rs12190287', (15, 25))	('rs10046', 'Mutation', 'rs10046', (39, 46))	('CYP19A1', 'Gene', '1588', (50, 57))	('TCF21', 'Gene', '6943', (29, 34))	('CYP19A1', 'Gene', (50, 57))	('TCF21', 'Gene', (29, 34))	('rs10046', 'Var', (39, 46))	('rs12190287', 'Var', (15, 25))
902332	32487238	In our study, the genetic variant rs12190287 has been evaluated concerning ESCC and it was observed that the variant under study was associated with the higher risk of ESCC within the population of Jammu and Kashmir with OR 1.412 (1.09-1.8, at 95% CI, p = 0.008).	('rs12190287', 'Var', (34, 44))	('ESCC', 'Disease', (168, 172))	('rs12190287', 'Mutation', 'rs12190287', (34, 44))
902333	32487238	The genetic variant in CYP19A1 (Cytochrome P450 family 19 sub-familyA1) rs10046 (C > T) has been associated with a higher risk of ESCC with OR 1.584 (1.21-2.072, at 95% CI, p = 0.007) as shown in Table 1.	('ESCC', 'Disease', (130, 134))	('CYP19A1', 'Gene', '1588', (23, 30))	('CYP19A1', 'Gene', (23, 30))	('rs10046', 'Mutation', 'rs10046', (72, 79))	('Cytochrome P450 family 19 sub-familyA1', 'Gene', (32, 70))	('rs10046 (C > T', 'Var', (72, 86))	('Cytochrome P450 family 19 sub-familyA1', 'Gene', '1588', (32, 70))
902345	32487238	In the SNP analysis we have replicated the newly identified variants (rs12190287 of TCF21, rs10046 of CYP19A1, rs2735940 of TERT, rs751402 of ERCC5, rs2699887 of SLC14A2, rs3792152 of REV1, rs10069690 of TERT, rs2981582 of FGFR2, rs1695 of GSTP1, rs251796 of TERF2, rs2229080 of DCC, rs1801010 of BCL2.	('rs2735940', 'Mutation', 'rs2735940', (111, 120))	('rs2981582', 'Var', (210, 219))	('REV1', 'Gene', '51455', (184, 188))	('ERCC5', 'Gene', '2073', (142, 147))	('TERT', 'Gene', (124, 128))	('rs1801010', 'Mutation', 'rs1801010', (284, 293))	('TCF21', 'Gene', (84, 89))	('rs12190287', 'Var', (70, 80))	('BCL2', 'Gene', '596', (297, 301))	('rs3792152', 'Mutation', 'rs3792152', (171, 180))	('rs2229080', 'Mutation', 'rs2229080', (266, 275))	('CYP19A1', 'Gene', (102, 109))	('rs1695', 'Mutation', 'rs1695', (230, 236))	('GSTP1', 'Gene', '2950', (240, 245))	('TERT', 'Gene', (204, 208))	('ERCC5', 'Gene', (142, 147))	('rs10069690', 'Mutation', 'rs10069690', (190, 200))	('TERT', 'Gene', '7015', (124, 128))	('REV1', 'Gene', (184, 188))	('TERT', 'Gene', '7015', (204, 208))	('GSTP1', 'Gene', (240, 245))	('rs10046', 'Var', (91, 98))	('rs3792152', 'Var', (171, 180))	('rs2229080', 'Var', (266, 275))	('BCL2', 'Gene', (297, 301))	('rs2735940', 'Var', (111, 120))	('rs251796', 'Mutation', 'rs251796', (247, 255))	('FGFR2', 'Gene', (223, 228))	('SLC14A2', 'Gene', '8170', (162, 169))	('rs10046', 'Mutation', 'rs10046', (91, 98))	('DCC', 'Gene', '1630', (279, 282))	('TCF21', 'Gene', '6943', (84, 89))	('rs2981582', 'Mutation', 'rs2981582', (210, 219))	('DCC', 'Gene', (279, 282))	('rs12190287', 'Mutation', 'rs12190287', (70, 80))	('rs10069690', 'Var', (190, 200))	('FGFR2', 'Gene', '2263', (223, 228))	('rs251796', 'Var', (247, 255))	('rs751402', 'Mutation', 'rs751402', (130, 138))	('TERF2', 'Gene', '7014', (259, 264))	('TERF2', 'Gene', (259, 264))	('rs1695', 'Var', (230, 236))	('SLC14A2', 'Gene', (162, 169))	('rs2699887', 'Var', (149, 158))	('CYP19A1', 'Gene', '1588', (102, 109))	('rs751402', 'Var', (130, 138))	('rs2699887', 'Mutation', 'rs2699887', (149, 158))	('rs1801010', 'Var', (284, 293))
902346	32487238	Two SNPs that were showing an increased risk of ESCC within the population of our study are rs12190287 of TCF21 and rs10046 of CYP19A1.	('rs10046', 'Var', (116, 123))	('rs12190287', 'Var', (92, 102))	('TCF21', 'Gene', (106, 111))	('rs12190287', 'Mutation', 'rs12190287', (92, 102))	('rs10046', 'Mutation', 'rs10046', (116, 123))	('CYP19A1', 'Gene', (127, 134))	('CYP19A1', 'Gene', '1588', (127, 134))	('TCF21', 'Gene', '6943', (106, 111))	('ESCC', 'Disease', (48, 52))
902350	32487238	rs12190287 (C > G) of TCF21 has been studied with Osteosarcoma risk in the Chinese population and was showing a higher risk of Osteosarcoma in the studied population.	('rs12190287 (C > G', 'Var', (0, 17))	('Osteosarcoma', 'Disease', (50, 62))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('Osteosarcoma', 'Disease', 'MESH:D012516', (50, 62))	('higher', 'Reg', (112, 118))	('Osteosarcoma', 'Disease', (127, 139))	('TCF21', 'Gene', '6943', (22, 27))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (127, 139))	('Osteosarcoma', 'Disease', 'MESH:D012516', (127, 139))	('TCF21', 'Gene', (22, 27))	('rs12190287', 'Mutation', 'rs12190287', (0, 10))
902353	32487238	The genetic variant rs10046 (C > T) has been significantly associated with Iranian women, Inuit women, and Xinjiang Uygur women.	('women', 'Species', '9606', (122, 127))	('associated', 'Reg', (59, 69))	('rs10046 (C > T', 'Var', (20, 34))	('rs10046', 'Mutation', 'rs10046', (20, 27))	('women', 'Species', '9606', (96, 101))	('women', 'Species', '9606', (83, 88))
902354	32487238	Both the genetic variants rs12190287 of TCF21 and rs10046 of CYP19A1 have been studied in multiple cancers which include breast, lung, neck, and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (145, 159))	('CYP19A1', 'Gene', '1588', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('multiple cancers', 'Disease', (90, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (145, 159))	('rs12190287', 'Mutation', 'rs12190287', (26, 36))	('TCF21', 'Gene', '6943', (40, 45))	('CYP19A1', 'Gene', (61, 68))	('neck', 'Disease', (135, 139))	('breast', 'Disease', (121, 127))	('rs10046', 'Var', (50, 57))	('gastric cancer', 'Disease', (145, 159))	('rs10046', 'Mutation', 'rs10046', (50, 57))	('multiple cancers', 'Disease', 'MESH:D009369', (90, 106))	('rs12190287', 'Var', (26, 36))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('lung', 'Disease', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TCF21', 'Gene', (40, 45))
902355	32487238	A recent study has observed that genetic variants that have been previously associated with one cancer are associated with other cancers too.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('associated', 'Reg', (107, 117))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('cancer', 'Disease', (129, 135))	('associated', 'Reg', (76, 86))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('genetic variants', 'Var', (33, 49))
902356	32487238	Cross cancer analysis has been done for the identification of variants to estimate the genetic correlation between them by using the data from GWAS.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Cross cancer', 'Disease', (0, 12))	('variants', 'Var', (62, 70))	('Cross cancer', 'Disease', 'MESH:D009369', (0, 12))
902358	32487238	rs2735940 was significantly associated with a higher risk of ESCC in the Chinese population.	('rs2735940', 'Var', (0, 9))	('ESCC', 'Disease', (61, 65))	('rs2735940', 'Mutation', 'rs2735940', (0, 9))
902360	32487238	rs751402 of ERCC5 (Excision Repair Cross Complementing Group 5) plays an important role in DNA damage and repair and its deficiency can lead to genomic instability and carcinogenesis.	('DNA', 'MPA', (91, 94))	('rs751402', 'Mutation', 'rs751402', (0, 8))	('lead to', 'Reg', (136, 143))	('ERCC5', 'Gene', (12, 17))	('deficiency', 'Var', (121, 131))	('Excision Repair Cross Complementing Group 5', 'Gene', (19, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (168, 182))	('ERCC5', 'Gene', '2073', (12, 17))	('carcinogenesis', 'Disease', (168, 182))	('rs751402', 'Var', (0, 8))	('Excision Repair Cross Complementing Group 5', 'Gene', '2073', (19, 62))	('genomic instability', 'CPA', (144, 163))
902361	32487238	There are two genetic variants rs751402 (C > T) and rs2298881 (A/C/T) rs751402 that have been associated with ESCC in the Chinese population and rs2298881 has been associated with other cancers like lung, gastric and laryngeal cancers across the population.	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('rs751402', 'Mutation', 'rs751402', (31, 39))	('cancers', 'Disease', (186, 193))	('rs2298881', 'Mutation', 'rs2298881', (145, 154))	('lung', 'Disease', (199, 203))	('associated', 'Reg', (94, 104))	('rs751402', 'Mutation', 'rs751402', (70, 78))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('associated', 'Reg', (164, 174))	('gastric', 'Disease', (205, 212))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (217, 234))	('ESCC', 'Disease', (110, 114))	('rs2298881', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('rs2298881', 'Mutation', 'rs2298881', (52, 61))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancers', 'Disease', (227, 234))
902362	32487238	rs2699887 of PIK3CA(Phosphatidylinositol-4-5-Biphosphate 3-Kinase Catalytic Sub- Unit Alpha) has been associated with ESCC in the USA (Texan population).	('ESCC', 'Disease', (118, 122))	('associated with', 'Reg', (102, 117))	('rs2699887', 'Var', (0, 9))	('PIK3CA', 'Gene', (13, 19))	('Phosphatidylinositol-4-5-Biphosphate', 'Chemical', 'MESH:D019269', (20, 56))	('rs2699887', 'Mutation', 'rs2699887', (0, 9))	('PIK3CA', 'Gene', '5290', (13, 19))
902363	32487238	rs3792152 of REV1(REV1, DNA Directed Polymerase) recruits DNA polymerases involved in translesion synthesis (TLS) of damaged DNA.	('REV1', 'Gene', (18, 22))	('REV1', 'Gene', '51455', (13, 17))	('rs3792152', 'Mutation', 'rs3792152', (0, 9))	('REV1', 'Gene', (13, 17))	('rs3792152', 'Var', (0, 9))	('REV1', 'Gene', '51455', (18, 22))
902364	32487238	Genetic variant rs3792152 of REV1 is associated with breast cancer risk in Thai women and rs2981582 ofFGFR2(Fibroblast Growth Factor Receptor 2) plays a vital role in the cell proliferation, migration, and apoptosis.	('FGFR2', 'Gene', '2263', (102, 107))	('women', 'Species', '9606', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('REV1', 'Gene', (29, 33))	('REV1', 'Gene', '51455', (29, 33))	('rs2981582', 'Var', (90, 99))	('rs3792152', 'Var', (16, 25))	('Fibroblast Growth Factor Receptor 2', 'Gene', '2263', (108, 143))	('migration', 'CPA', (191, 200))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('rs3792152', 'Mutation', 'rs3792152', (16, 25))	('associated', 'Reg', (37, 47))	('FGFR2', 'Gene', (102, 107))	('rs2981582', 'Mutation', 'rs2981582', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))	('Fibroblast Growth Factor Receptor 2', 'Gene', (108, 143))
902365	32487238	Genetic variant rs2981582 of FGFR2 has been associated with breast cancer in different women population (Dutch, Arabic, and West Siberia).	('associated', 'Reg', (44, 54))	('breast cancer', 'Disease', (60, 73))	('FGFR2', 'Gene', (29, 34))	('FGFR2', 'Gene', '2263', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs2981582', 'Var', (16, 25))	('women', 'Species', '9606', (87, 92))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('rs2981582', 'Mutation', 'rs2981582', (16, 25))
902366	32487238	rs1695 of GSTP1(Glutathione S-transferase Pi 1) belongs to a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds.	('GSTP1', 'Gene', (10, 15))	('rs1695', 'Var', (0, 6))	('conjugation', 'MPA', (143, 154))	('rs1695', 'Mutation', 'rs1695', (0, 6))	('Glutathione S-transferase Pi 1', 'Gene', (16, 46))	('GSTP1', 'Gene', '2950', (10, 15))	('Glutathione S-transferase Pi 1', 'Gene', '2950', (16, 46))	('catalyzing', 'MPA', (128, 138))
902367	32487238	The genetic variant rs1695 of GSTP1 has shown an increased risk of ESCC and EAC in the population of Kashmir Valley.	('EAC', 'Disease', (76, 79))	('GSTP1', 'Gene', (30, 35))	('ESCC', 'Disease', (67, 71))	('rs1695', 'Var', (20, 26))	('risk', 'Reg', (59, 63))	('rs1695', 'Mutation', 'rs1695', (20, 26))	('GSTP1', 'Gene', '2950', (30, 35))
902370	32487238	rs2229080 of DCC(Deleted in Colorectal Carcinoma Netrin1 Receptor) has been studied in the Chinese population concerning breast cancer and it was found that this variant has been associated with reduced breast cancer risk.	('reduced', 'NegReg', (195, 202))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('Deleted in Colorectal Carcinoma', 'Gene', (17, 48))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Disease', (203, 216))	('Deleted in Colorectal Carcinoma', 'Gene', '1630', (17, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('DCC', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('DCC', 'Gene', '1630', (13, 16))	('Carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('rs2229080', 'Mutation', 'rs2229080', (0, 9))	('rs2229080', 'Var', (0, 9))
902371	32487238	The genetic variant rs2229080 (C > G) has been studied in ESCC and gastric cancer patients in Kashmir Valley also and it has been observed that rs2229080 of DCC has shown no association with the risk of ESCC.	('rs2229080', 'Var', (144, 153))	('patients', 'Species', '9606', (82, 90))	('gastric cancer', 'Disease', (67, 81))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('DCC', 'Gene', (157, 160))	('ESCC', 'Disease', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('DCC', 'Gene', '1630', (157, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('rs2229080', 'Mutation', 'rs2229080', (20, 29))	('rs2229080', 'Mutation', 'rs2229080', (144, 153))
902373	32487238	rs1801018 of BCL2(B-cell lymphoma 2) contributes to programmed cell death and apoptosis and has been studied in ESCC in the Chinese population but there was no significant association observed between the variant and the risk of the disease.	('programmed cell death', 'CPA', (52, 73))	('rs1801018', 'Mutation', 'rs1801018', (0, 9))	('BCL2', 'Gene', (13, 17))	('apoptosis', 'CPA', (78, 87))	('rs1801018', 'Var', (0, 9))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (18, 33))	('ESCC', 'Disease', (112, 116))	('lymphoma', 'Phenotype', 'HP:0002665', (25, 33))	('BCL2', 'Gene', '596', (13, 17))
902378	32487238	The present study identified important regions of genetic variation associated with risk for the development of the disease.	('associated', 'Reg', (68, 78))	('men', 'Species', '9606', (104, 107))	('genetic variation', 'Var', (50, 67))
902446	31645619	Moreover, high PDW independently predicted depth of tumor (OR = 1.575, P = 0.040), lymph node metastasis (OR = 1.704, P = 0.009), pathological stage (OR = 0.464, P = 0.007), and nerve infiltration (OR = 1.527, P = 0.042) using logistic regression analysis (Table 3 and Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('depth of tumor', 'Disease', 'MESH:D007222', (43, 57))	('PDW', 'Gene', (15, 18))	('depth of tumor', 'Disease', (43, 57))	('nerve infiltration', 'CPA', (178, 196))	('high', 'Var', (10, 14))	('lymph node metastasis', 'CPA', (83, 104))
902448	31645619	In subgroup analysis according to lymph node metastasis and pathological stage, high PDW was related to worse OS for patients with or without lymph node metastasis (both P < 0.001) and less or more advanced stage (both P < 0.001) (Figs 4 and 5).	('patients', 'Species', '9606', (117, 125))	('high', 'Var', (80, 84))	('PDW', 'Gene', (85, 88))
902450	31645619	In a word, PDW was an independent prognostic factor for patients with ESCC undergoing surgery.	('PDW', 'Var', (11, 14))	('ESCC', 'Disease', (70, 74))	('patients', 'Species', '9606', (56, 64))	('ESCC', 'Disease', 'MESH:C562729', (70, 74))
902453	31645619	Recently, several studies revealed that a high PDW is an unfavorable prognosis factor in melanoma patients, laryngeal cancer, and gastric cancer.	('laryngeal cancer', 'Disease', (108, 124))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (108, 124))	('gastric cancer', 'Disease', (130, 144))	('patients', 'Species', '9606', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('high', 'Var', (42, 46))	('melanoma', 'Disease', (89, 97))	('laryngeal cancer', 'Disease', 'MESH:D007822', (108, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
902457	31645619	Moreover, high PDW was an independent predictor for ESCC patients with lymph node metastasis according to further subgroup analyses.	('patients', 'Species', '9606', (57, 65))	('ESCC', 'Disease', 'MESH:C562729', (52, 56))	('ESCC', 'Disease', (52, 56))	('high PDW', 'Var', (10, 18))
902481	30872408	Association of ADH1B Arg47His polymorphism with the risk of cancer: a meta-analysis Alcohol consumption has been established to be a major factor in the development and progress of cancer.	('Arg47His', 'SUBSTITUTION', 'None', (21, 29))	('ADH1B', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Association', 'Interaction', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('ADH1B', 'Gene', '125', (15, 20))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('Arg47His', 'Var', (21, 29))	('cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Alcohol', 'Chemical', 'MESH:D000438', (84, 91))
902482	30872408	Genetic polymorphisms of alcohol-metabolism genes result in differences between individuals in exposure to acetaldehyde, leading to possible carcinogenic effects.	('exposure to acetaldehyde', 'MPA', (95, 119))	('alcohol-metabolism genes', 'Gene', (25, 49))	('alcohol', 'Chemical', 'MESH:D000438', (25, 32))	('result in differences', 'Reg', (50, 71))	('Genetic polymorphisms', 'Var', (0, 21))	('acetaldehyde', 'Chemical', 'MESH:D000079', (107, 119))	('carcinogenic', 'Disease', 'MESH:D063646', (141, 153))	('carcinogenic', 'Disease', (141, 153))
902483	30872408	Arg47His (rs1229984 G > A) in ADH1B have been frequently studied for its potential effect on carcinogenesis.	('carcinogenesis', 'Disease', (93, 107))	('rs1229984', 'Mutation', 'rs1229984', (10, 19))	('Arg47His', 'SUBSTITUTION', 'None', (0, 8))	('ADH1B', 'Gene', (30, 35))	('rs1229984 G > A', 'Var', (10, 25))	('ADH1B', 'Gene', '125', (30, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (93, 107))	('Arg47His', 'Var', (0, 8))
902484	30872408	The pooled results indicated that ADH1B Arg47His polymorphism is significantly associated with the decreased risk of overall cancer (homozygous model, odds ratio (OR) = 0.62, 95% confidence interval (CI) = 0.49-0.77; heterozygous model, OR = 0.71, 95% CI = 0.60-0.84; recessive model, OR = 0.83, 95% CI = 0.76-0.91; dominant model, OR = 0.62, 95% CI = 0.53-0.72; and allele comparison, OR = 0.82, 95% CI = 0.75-0.89).	('decreased', 'NegReg', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Arg47His', 'Var', (40, 48))	('ADH1B', 'Gene', (34, 39))	('Arg47His', 'SUBSTITUTION', 'None', (40, 48))	('ADH1B', 'Gene', '125', (34, 39))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
902486	30872408	In conclusion, our meta-analysis suggested that ADH1B Arg47His polymorphism was significantly associated with decreased overall cancer risk.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('Arg47His', 'Var', (54, 62))	('decreased', 'NegReg', (110, 119))	('ADH1B', 'Gene', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Arg47His', 'SUBSTITUTION', 'None', (54, 62))	('ADH1B', 'Gene', '125', (48, 53))	('cancer', 'Disease', (128, 134))
902497	30872408	Amongst them, Arg47His (rs1229984 G > A) in ADH1B have been frequently studied for its potential effect on the carcinogenesis.	('carcinogenesis', 'Disease', (111, 125))	('rs1229984', 'Mutation', 'rs1229984', (24, 33))	('Arg47His', 'SUBSTITUTION', 'None', (14, 22))	('ADH1B', 'Gene', (44, 49))	('ADH1B', 'Gene', '125', (44, 49))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('rs1229984 G > A', 'Var', (24, 39))	('Arg47His', 'Var', (14, 22))
902499	30872408	Epidemiologic studies have extensively explored the association between ADH1B Arg47His polymorphism and cancer risk.	('ADH1B', 'Gene', '125', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ADH1B', 'Gene', (72, 77))	('Arg47His', 'Var', (78, 86))	('Arg47His', 'SUBSTITUTION', 'None', (78, 86))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
902500	30872408	Several meta-analyses published before 2016 associated this polymorphism only with esophageal, head and neck, gastric, colorectal, and upper aerodigestive tract cancer.	('upper aerodigestive tract cancer', 'Disease', (135, 167))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (135, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('colorectal', 'Disease', 'MESH:D015179', (119, 129))	('gastric', 'Disease', 'MESH:D013274', (110, 117))	('gastric', 'Disease', (110, 117))	('polymorphism', 'Var', (60, 72))	('esophageal', 'Disease', (83, 93))	('colorectal', 'Disease', (119, 129))
902501	30872408	However, no meta-analyses have ever investigated the association between ADH1B Arg47His polymorphism and overall cancer risk, including other types of cancer.	('ADH1B', 'Gene', '125', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Arg47His', 'SUBSTITUTION', 'None', (79, 87))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('Arg47His', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ADH1B', 'Gene', (73, 78))
902502	30872408	Therefore, we performed an updated meta-analysis including the most recent and relevant studies to clarify the association between ADH1B Arg47His polymorphism and the overall cancer risk, involving 66 studies with 31999 cases and 50964 controls.	('ADH1B', 'Gene', '125', (131, 136))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Arg47His', 'Var', (137, 145))	('Arg47His', 'SUBSTITUTION', 'None', (137, 145))	('ADH1B', 'Gene', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
902504	30872408	The inclusion criteria were as follows: (i) studies evaluating the association between ADH1B Arg47His polymorphism and overall cancer risk; (ii) case-control studies; (iii) studies with sufficient information to calculate the odds ratio (OR) and its 95% confidence interval (CI).	('Arg47His', 'Var', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Arg47His', 'SUBSTITUTION', 'None', (93, 101))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('ADH1B', 'Gene', (87, 92))	('ADH1B', 'Gene', '125', (87, 92))
902506	30872408	The strength of the association between ADH1B Arg47His polymorphism and overall cancer risk was evaluated by calculating ORs and 95% CIs.	('Arg47His', 'Var', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ADH1B', 'Gene', (40, 45))	('Arg47His', 'SUBSTITUTION', 'None', (46, 54))	('ADH1B', 'Gene', '125', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
902509	30872408	Ultimately, 64 articles investigating the association between ADH1B Arg47His polymorphism and cancer risk were included in the final meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Arg47His', 'Var', (68, 76))	('ADH1B', 'Gene', '125', (62, 67))	('ADH1B', 'Gene', (62, 67))	('Arg47His', 'SUBSTITUTION', 'None', (68, 76))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
902511	30872408	The main results for the association between ADH1B Arg47His polymorphism and cancer risk are shown in Table 2 and Figure 2.	('Arg47His', 'SUBSTITUTION', 'None', (51, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('ADH1B', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Arg47His', 'Var', (51, 59))	('ADH1B', 'Gene', '125', (45, 50))
902512	30872408	We found that ADH1B Arg47His polymorphism significantly associated with the decreased risk of overall cancer under all the five genetic models: homozygous model, OR = 0.62, 95% CI = 0.49-0.77; heterozygous model, OR = 0.71, 95% CI = 0.60-0.84; recessive model, OR = 0.83, 95% CI = 0.76-0.91; dominant model, OR = 0.62, 95% CI = 0.53-0.72; and allele comparison, OR = 0.82, 95% CI = 0.75-0.89.	('Arg47His', 'SUBSTITUTION', 'None', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('decreased', 'NegReg', (76, 85))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('ADH1B', 'Gene', (14, 19))	('Arg47His', 'Var', (20, 28))	('ADH1B', 'Gene', '125', (14, 19))
902515	30872408	Regarding the stratified analysis by cancer type, the ADH1B Arg47His polymorphism significantly decreased the risk of esophageal cancer: homozygous model, OR = 0.39, 95% CI = 0.28-0.55; heterozygous model, OR = 0.47, 95% CI = 0.34-0.66; recessive model, OR = 0.72, 95% CI = 0.62-0.83; dominant model, OR = 0.41, 95% CI = 0.31-0.54; and allele comparison, OR = 0.67, 95% CI = 0.57-0.78; upper aerodigestive tract cancer: homozygous model, OR = 0.31, 95% CI = 0.23-0.42; heterozygous model, OR = 0.33, 95% CI = 0.21-0.53; recessive model, OR = 0.70, 95% CI = 0.57-0.86; dominant model, OR = 0.39, 95% CI = 0.26-0.58; and allele comparison, OR = 0.62, 95% CI = 0.54-0.71; and head and neck cancer: homozygous model, OR = 0.55, 95% CI = 0.31-0.97; recessive model, OR = 0.78, 95% CI = 0.66-0.93; dominant model, OR = 0.64, 95% CI = 0.47-0.87; and allele comparison, OR = 0.80, 95% CI = 0.66-0.96.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (386, 418))	('cancer', 'Phenotype', 'HP:0002664', (687, 693))	('cancer', 'Phenotype', 'HP:0002664', (412, 418))	('decreased', 'NegReg', (96, 105))	('ADH1B', 'Gene', (54, 59))	('cancer type', 'Disease', 'MESH:D009369', (37, 48))	('Arg47His', 'Var', (60, 68))	('head and neck cancer', 'Phenotype', 'HP:0012288', (673, 693))	('ADH1B', 'Gene', '125', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Arg47His', 'SUBSTITUTION', 'None', (60, 68))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('upper aerodigestive tract cancer', 'Disease', (386, 418))	('head and neck cancer', 'Disease', 'MESH:D006258', (673, 693))	('cancer type', 'Disease', (37, 48))
902522	30872408	Arg47His (rs1229984 G > A) in ADH1B led to a single amino acid substitution of arginine (Arg) for histidine (His) at codon 47.	('His', 'Chemical', 'MESH:D006639', (5, 8))	('Arg', 'Chemical', 'MESH:D001120', (0, 3))	('His', 'Chemical', 'MESH:D006639', (109, 112))	('rs1229984', 'Mutation', 'rs1229984', (10, 19))	('Arg47His', 'SUBSTITUTION', 'None', (0, 8))	('ADH1B', 'Gene', (30, 35))	('histidine', 'Chemical', 'MESH:D006639', (98, 107))	('rs1229984 G > A', 'Var', (10, 25))	('ADH1B', 'Gene', '125', (30, 35))	('arginine', 'Chemical', 'MESH:D001120', (79, 87))	('Arg', 'Chemical', 'MESH:D001120', (89, 92))	('Arg47His', 'Var', (0, 8))
902524	30872408	To the best of our knowledge, this is the first meta-analysis investigating the association between ADH1B Arg47His polymorphism and the overall cancer risk.	('Arg47His', 'SUBSTITUTION', 'None', (106, 114))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('ADH1B', 'Gene', (100, 105))	('Arg47His', 'Var', (106, 114))	('ADH1B', 'Gene', '125', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
902525	30872408	Overall, ADH1B Arg47His polymorphism was associated with a decreased risk of overall cancer under all the five genetic models.	('ADH1B', 'Gene', '125', (9, 14))	('Arg47His', 'Var', (15, 23))	('decreased', 'NegReg', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('Arg47His', 'SUBSTITUTION', 'None', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('ADH1B', 'Gene', (9, 14))
902526	30872408	Stratified analysis by ethnicity revealed that ADH1B Arg47His polymorphism reduced cancer risk amongst Asians and mixed ethnicity group but increased risk amongst Caucasians.	('ADH1B', 'Gene', (47, 52))	('Arg47His', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('reduced', 'NegReg', (75, 82))	('ADH1B', 'Gene', '125', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Arg47His', 'SUBSTITUTION', 'None', (53, 61))	('increased', 'PosReg', (140, 149))	('cancer', 'Disease', (83, 89))
902527	30872408	Stratified analysis by cancer type revealed that ADH1B Arg47His polymorphism reduced risk in esophageal cancer, upper aerodigestive tract cancer, and head and neck cancer, while no effect was found on colorectal, hepatocellular, gastric and pancreatic cancer.	('colorectal', 'Disease', (201, 211))	('upper aerodigestive tract cancer', 'Disease', (112, 144))	('head and neck cancer', 'Disease', 'MESH:D006258', (150, 170))	('esophageal cancer', 'Disease', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (241, 258))	('Arg47His', 'Var', (55, 63))	('ADH1B', 'Gene', '125', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (112, 144))	('ADH1B', 'Gene', (49, 54))	('colorectal', 'Disease', 'MESH:D015179', (201, 211))	('pancreatic cancer', 'Disease', 'MESH:D010190', (241, 258))	('reduced', 'NegReg', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('head and neck cancer', 'Phenotype', 'HP:0012288', (150, 170))	('gastric', 'Disease', (229, 236))	('cancer type', 'Disease', (23, 34))	('hepatocellular', 'Disease', (213, 227))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pancreatic cancer', 'Disease', (241, 258))	('cancer type', 'Disease', 'MESH:D009369', (23, 34))	('Arg47His', 'SUBSTITUTION', 'None', (55, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('gastric', 'Disease', 'MESH:D013274', (229, 236))
902529	30872408	There were several meta-analyses focussed on ADH1B Arg47His polymorphism and only one particular type of cancer risk, such as esophageal, head and neck, gastric and colorectal cancer.	('esophageal', 'Disease', (126, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (165, 182))	('Arg47His', 'SUBSTITUTION', 'None', (51, 59))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('gastric', 'Disease', 'MESH:D013274', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gastric', 'Disease', (153, 160))	('colorectal cancer', 'Disease', (165, 182))	('ADH1B', 'Gene', (45, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Arg47His', 'Var', (51, 59))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('ADH1B', 'Gene', '125', (45, 50))
902531	30872408	found that the 47His allele was significantly associated with the reduced risk of this cancer when compared with the 47Arg allele.	('cancer', 'Disease', (87, 93))	('reduced', 'NegReg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('47His', 'Var', (15, 20))	('47His', 'Chemical', '-', (15, 20))	('Arg', 'Chemical', 'MESH:D001120', (119, 122))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
902532	30872408	For head and neck cancer, the 47His allele was also found to be associated with decreased risk of head and neck cancer amongst Asians only under the dominant model.	('47His', 'Chemical', '-', (30, 35))	('head and neck cancer', 'Phenotype', 'HP:0012288', (4, 24))	('decreased risk of head', 'Phenotype', 'HP:0000252', (80, 102))	('head and neck cancer', 'Disease', 'MESH:D006258', (98, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('decreased', 'NegReg', (80, 89))	('head and neck cancer', 'Disease', 'MESH:D006258', (4, 24))	('47His', 'Var', (30, 35))	('head and neck cancer', 'Phenotype', 'HP:0012288', (98, 118))
902533	30872408	found that ADH1B Arg47His polymorphism was associated with decreased risk of colorectal cancer supported by four studies.	('Arg47His', 'SUBSTITUTION', 'None', (17, 25))	('colorectal cancer', 'Disease', (77, 94))	('decreased', 'NegReg', (59, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('ADH1B', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Arg47His', 'Var', (17, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('ADH1B', 'Gene', '125', (11, 16))
902534	30872408	It was noteworthy that we found that ADH1B Arg47His polymorphism was associated with decreased cancer risk amongst Asians while increased cancer risk amongst Caucasians.	('cancer', 'Disease', (138, 144))	('ADH1B', 'Gene', (37, 42))	('decreased', 'NegReg', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('ADH1B', 'Gene', '125', (37, 42))	('increased', 'PosReg', (128, 137))	('Arg47His', 'Var', (43, 51))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Arg47His', 'SUBSTITUTION', 'None', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
902541	30872408	In conclusion, our meta-analysis suggested that ADH1B Arg47His polymorphism was significantly associated with the decreased overall cancer risk, especially for esophageal cancer and head and neck cancer amongst Asians.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('Arg47His', 'Var', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (171, 177))	('ADH1B', 'Gene', (48, 53))	('esophageal cancer', 'Disease', (160, 177))	('decreased', 'NegReg', (114, 123))	('head and neck cancer', 'Disease', 'MESH:D006258', (182, 202))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('Arg47His', 'SUBSTITUTION', 'None', (54, 62))	('ADH1B', 'Gene', '125', (48, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('head and neck cancer', 'Phenotype', 'HP:0012288', (182, 202))
902620	30241395	Many drugs are used in ESCC chemotherapies, including cisplatin, 5-flurouracil and epirubicin.	('cisplatin', 'Var', (54, 63))	('epirubicin', 'Chemical', 'MESH:D015251', (83, 93))	('epirubicin', 'Disease', (83, 93))	('SCC', 'Gene', (24, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('SCC', 'Gene', '6317', (24, 27))	('5-flurouracil', 'Chemical', '-', (65, 78))
902643	30241395	Culture of WHCO1 cells on decellularised ECMs in the presence of drugs resulted in more colonies being formed than those cultured on plastic in the presence of drugs (Figure 6A,B).	('ECM', 'Gene', '22915', (41, 44))	('WHCO1', 'Chemical', '-', (11, 16))	('ECM', 'Gene', (41, 44))	('colonies being formed', 'CPA', (88, 109))	('drugs', 'Var', (65, 70))	('more', 'PosReg', (83, 87))
902664	30241395	Both type I collagen and fibronectin knockdown through the use of siRNA showed decreased levels of both collagen and fibronectin in the media and cell lysates compared to control in transformed CT1 fibroblasts and WHCO1 cells (Supplemental Figure S5A,B).	('CT1', 'Gene', (194, 197))	('fibronectin', 'Gene', (117, 128))	('decreased levels of both collagen', 'Phenotype', 'HP:0030095', (79, 112))	('decreased', 'NegReg', (79, 88))	('levels of', 'MPA', (89, 98))	('knockdown', 'Var', (37, 46))	('fibronectin', 'Gene', '2335', (25, 36))	('fibronectin', 'Gene', '2335', (117, 128))	('WHCO1', 'Chemical', '-', (214, 219))	('decreased levels of both collagen and fibronectin', 'Phenotype', 'HP:0032463', (79, 128))	('CT1', 'Gene', '6535', (194, 197))	('men', 'Species', '9606', (233, 236))	('fibronectin', 'Gene', (25, 36))
902666	30241395	Beside the use of siRNA, the absence of ascorbic acid achieved the same knockdown of Type I collagen (data not shown).	('ascorbic acid', 'Chemical', 'MESH:D001205', (40, 53))	('knockdown', 'MPA', (72, 81))	('absence', 'Var', (29, 36))	('Type', 'Protein', (85, 89))
902675	30241395	Collectively our data suggest that knocking down certain ECM proteins may be effective in suppressing cancer development and enhancing chemotherapeutic effects.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ECM', 'Gene', (57, 60))	('chemotherapeutic effects', 'CPA', (135, 159))	('knocking down', 'Var', (35, 48))	('cancer', 'Disease', (102, 108))	('suppressing', 'NegReg', (90, 101))	('enhancing', 'PosReg', (125, 134))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('ECM', 'Gene', '22915', (57, 60))	('men', 'Species', '9606', (116, 119))
902725	30241395	Our data is in agreement with literature in showing that cisplatin induces G2/M cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('cisplatin', 'Var', (57, 66))	('G2/M cell cycle arrest', 'CPA', (75, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('men', 'Species', '9606', (20, 23))
902728	30241395	Epirubicin acts by intercalating DNA strands and has been reported to cause both G1 and G2/M cell cycle arrest.	('Epirubicin', 'Var', (0, 10))	('intercalating', 'Reg', (19, 32))	('G2/M cell cycle arrest', 'CPA', (88, 110))	('cause', 'Reg', (70, 75))	('Epirubicin', 'Chemical', 'MESH:D015251', (0, 10))	('DNA strands', 'Protein', (33, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))
902729	30241395	Several reports including those using the same concentration of epirubicin as we did in this study, have shown that epirubicin induces G1 and G2/M cell cycle arrest.	('epirubicin', 'Var', (116, 126))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (147, 164))	('epirubicin', 'Chemical', 'MESH:D015251', (116, 126))	('epirubicin', 'Chemical', 'MESH:D015251', (64, 74))	('induces', 'PosReg', (127, 134))	('G2/M cell cycle arrest', 'CPA', (142, 164))
902730	30241395	Our data show that epirubicin induces G2/M cell cycle arrest in WHCO1 cells.	('epirubicin', 'Var', (19, 29))	('epirubicin', 'Chemical', 'MESH:D015251', (19, 29))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('WHCO1', 'Chemical', '-', (64, 69))	('G2/M cell cycle arrest', 'CPA', (38, 60))
902735	30241395	The dynamics of the relationship between cancer cells and their microenvironment will determine whether oncogenic genes and mutations will exert their function.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (124, 133))	('men', 'Species', '9606', (76, 79))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
902757	30241395	Thus, cyclin D1 might be protected from degradation by the same pathways, resulting in its presence through the G1/S/G2 cell cycle phases.	('S/G2', 'Var', (115, 119))	('presence', 'MPA', (91, 99))	('S/G2', 'SUBSTITUTION', 'None', (115, 119))	('cyclin D1', 'Gene', '595', (6, 15))	('cyclin D1', 'Gene', (6, 15))
902764	30241395	In conclusion, we have advanced our understanding of cancer cell-ECM interaction through identifying that both type I collagen and fibronectin are involved in the proliferation and migration of esophageal cancer cells and that knocking down these two proteins can act in synergy with chemotherapeutic drugs in reducing the growth and migration of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('ECM', 'Gene', '22915', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('migration', 'CPA', (181, 190))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))	('fibronectin', 'Gene', '2335', (131, 142))	('esophageal cancer', 'Disease', (194, 211))	('cancer', 'Disease', (347, 353))	('reducing', 'NegReg', (310, 318))	('cancer', 'Disease', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('cancer', 'Disease', (205, 211))	('ECM', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('involved', 'Reg', (147, 155))	('knocking down', 'Var', (227, 240))	('fibronectin', 'Gene', (131, 142))	('cancer', 'Disease', 'MESH:D009369', (347, 353))
902811	30241395	The membranes were incubated overnight at 4  C with the following primary antibodies: anti-Ki67 antibody, anti-PCNA antibody, anti-Cyclin D1 antibody, anti-p-ERK1/2 (Thr202/Tyr204), anti-ERK2, anti-Akt, anti-p-Akt, anti-p21, anti-p53, anti-Bcl-2, anti-Bcl-xL antibody, anti-MMP-2 antibody, anti-MMP-9 antibody, anti-ITGalpha2 antibody, anti-type I collagen antibody, anti-fibronectin antibody, anti- ITGalpha3 antibody, anti- ITGalpha11 antibody, anti-ITGbeta1 and anti-GAPDH antibody.	('GAPDH', 'Gene', '2597', (470, 475))	('Akt', 'Gene', (198, 201))	('p53', 'Gene', '7157', (230, 233))	('GAPDH', 'Gene', (470, 475))	('Akt', 'Gene', '207', (198, 201))	('anti- ITGalpha11', 'Var', (420, 436))	('fibronectin', 'Gene', (372, 383))	('MMP-2', 'Gene', '4313', (274, 279))	('PCNA', 'Gene', (111, 115))	('ERK1/2', 'Gene', (158, 164))	('p53', 'Gene', (230, 233))	('Akt', 'Gene', (210, 213))	('ERK1/2', 'Gene', '5595;5594', (158, 164))	('Bcl-2', 'Gene', (240, 245))	('p21', 'Gene', (220, 223))	('beta1', 'Gene', (455, 460))	('p21', 'Gene', '644914', (220, 223))	('beta1', 'Gene', '3779', (455, 460))	('Akt', 'Gene', '207', (210, 213))	('MMP-9', 'Gene', '4318', (295, 300))	('fibronectin', 'Gene', '2335', (372, 383))	('MMP-9', 'Gene', (295, 300))	('MMP-2', 'Gene', (274, 279))	('PCNA', 'Gene', '5111', (111, 115))	('Cyclin D1', 'Gene', '595', (131, 140))	('Bcl-2', 'Gene', '596', (240, 245))	('Bcl-xL', 'Gene', (252, 258))	('Cyclin D1', 'Gene', (131, 140))	('ERK2', 'Gene', '5594', (187, 191))	('anti-', 'Var', (394, 399))	('Bcl-xL', 'Gene', '598', (252, 258))	('ERK2', 'Gene', (187, 191))
902873	30322005	Single-nucleotide polymorphisms (SNPs) in miRNA, miRNA-binding sites, and in its biogenesis pathway genes can alter miRNA expression patterns, thereby influencing cancer risk and prognosis.	('influencing', 'Reg', (151, 162))	('miR', 'Gene', '220972', (116, 119))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('miR', 'Gene', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('miR', 'Gene', '220972', (49, 52))	('prognosis', 'CPA', (179, 188))	('miR', 'Gene', (49, 52))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('alter', 'Reg', (110, 115))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
902899	30322005	Since the major consequence of miRNA:mRNA pairing is the loss of protein expression, resulting from either decreased transcript levels or by translational repression, alterations in miRNA expression patterns impact on the expression of oncoproteins and tumor suppressor proteins, thereby influencing cancer risk and prognosis.	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('impact', 'Reg', (208, 214))	('influencing', 'Reg', (288, 299))	('expression', 'MPA', (222, 232))	('cancer', 'Disease', (300, 306))	('miR', 'Gene', '220972', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('protein expression', 'MPA', (65, 83))	('miR', 'Gene', '220972', (31, 34))	('loss', 'NegReg', (57, 61))	('tumor', 'Disease', (253, 258))	('alterations', 'Var', (167, 178))	('translational', 'MPA', (141, 154))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('miR', 'Gene', (182, 185))	('decreased', 'NegReg', (107, 116))	('miR', 'Gene', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('oncoproteins', 'Protein', (236, 248))	('transcript levels', 'MPA', (117, 134))
902900	30322005	Given the diversity of pathways that are regulated by miRNAs, genetic polymorphisms in miRNAs, miRNA-processing machinery, and miRNA target sites are implicated in carcinogenesis.	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (95, 98))	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (54, 57))	('miR', 'Gene', '220972', (127, 130))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('miR', 'Gene', (127, 130))	('implicated', 'Reg', (150, 160))	('carcinogenesis', 'Disease', (164, 178))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('genetic polymorphisms', 'Var', (62, 83))
902901	30322005	MiRNA-related single-nucleotide polymorphisms (miR-SNPs) are defined as SNPs that occur in miRNA genes, at miRNA-binding sites, and in the miRNA processing machinery.	('single-nucleotide polymorphisms', 'Var', (14, 45))	('MiR', 'Gene', (0, 3))	('miR', 'Gene', (91, 94))	('miR', 'Gene', (139, 142))	('miR', 'Gene', '220972', (139, 142))	('MiR', 'Gene', '220972', (0, 3))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('miR', 'Gene', '220972', (107, 110))	('miR', 'Gene', (107, 110))	('miR', 'Gene', '220972', (91, 94))
902903	30322005	In 2016, Nariman-Saleh-Fam and colleagues used a bioinformatics approach to provide a catalog of the most potentially disruptive EC-implicated miRNA targetome polymorphisms, along with in silico insight into the pathways affected by such variations.	('polymorphisms', 'Var', (159, 172))	('miR', 'Gene', '220972', (143, 146))	('disruptive', 'NegReg', (118, 128))	('miR', 'Gene', (143, 146))
902912	30322005	The pooled information is synthesized in Figure 1, where we divided the EC-relevant miR-SNPs into three categories: (1) SNPs in miRNA-coding genes, (2) SNPs in miRNA-binding sites, and (3) SNPs in biogenesis machinery.	('miR', 'Gene', (160, 163))	('SNPs', 'Var', (152, 156))	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (84, 87))	('miR', 'Gene', '220972', (128, 131))	('miR', 'Gene', (128, 131))	('miR', 'Gene', '220972', (160, 163))
902915	30322005	Calin and colleagues mapped the chromosomal location of all known miRNA genes and discovered that many are located in regions that are frequently involved in chromosomal alterations, such as deletions or amplifications, usually found in many types of cancers.	('deletions', 'Var', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('miR', 'Gene', (66, 69))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('cancers', 'Disease', (251, 258))	('miR', 'Gene', '220972', (66, 69))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('amplifications', 'Var', (204, 218))
902917	30322005	The majority of SNPs in miRNA-coding genes usually occur in pre-miRNAs and can be responsible for changes in stem-loop structures, consequently affecting the production of mature miRNAs.	('stem-loop structures', 'MPA', (109, 129))	('SNPs', 'Var', (16, 20))	('affecting', 'Reg', (144, 153))	('miR', 'Gene', (64, 67))	('changes', 'Reg', (98, 105))	('miR', 'Gene', '220972', (64, 67))	('responsible', 'Reg', (82, 93))	('miR', 'Gene', '220972', (179, 182))	('miR', 'Gene', (179, 182))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))
902920	30322005	In this review, we found 22 studies that related a total of 13 SNPs in miRNA genes associated with an EC outcome (Table 1).	('miR', 'Gene', (71, 74))	('EC outcome', 'Disease', (102, 112))	('associated', 'Reg', (83, 93))	('SNPs', 'Var', (63, 67))	('miR', 'Gene', '220972', (71, 74))
902921	30322005	The most studied SNPs were miR-423 rs6505162, miR-196a-2 rs1161491,3 and miR-146a rs2910164, and they were all located in pre-miRNA regions with impact in the respective mature miRNA production.	('miR', 'Gene', (46, 49))	('miR-146a', 'Gene', '406938', (73, 81))	('miR-423', 'Gene', '494335', (27, 34))	('miR', 'Gene', (126, 129))	('miR', 'Gene', '220972', (27, 30))	('rs1161491', 'Mutation', 'rs1161491', (57, 66))	('rs2910164', 'Mutation', 'rs2910164', (82, 91))	('miR', 'Gene', '220972', (177, 180))	('miR', 'Gene', (27, 30))	('miR', 'Gene', '220972', (73, 76))	('miR-423', 'Gene', (27, 34))	('miR', 'Gene', (177, 180))	('miR-196a-2', 'Gene', (46, 56))	('miR-196a-2', 'Gene', '406973', (46, 56))	('rs6505162', 'Mutation', 'rs6505162', (35, 44))	('miR', 'Gene', (73, 76))	('miR', 'Gene', '220972', (46, 49))	('miR', 'Gene', '220972', (126, 129))	('rs6505162', 'Var', (35, 44))	('rs2910164', 'Var', (82, 91))	('miR-146a', 'Gene', (73, 81))
902922	30322005	The miR-423 rs6505162 SNP is located in pre-miR-423 and maps to 17q11.2, with a nucleotide alteration from C to A.	('miR-423', 'Gene', '494335', (4, 11))	('miR-423', 'Gene', (44, 51))	('rs6505162 SNP', 'Var', (12, 25))	('rs6505162', 'Mutation', 'rs6505162', (12, 21))	('miR-423', 'Gene', '494335', (44, 51))	('miR-423', 'Gene', (4, 11))
902923	30322005	Since both miR-423-3p and miR-423-5p are produced by the pre-miRNA of miR-423, it is possible for the polymorphism of pre-miR-423 to play different roles in cancer progression, and in different types of cancer.	('polymorphism', 'Var', (102, 114))	('miR-423', 'Gene', '494335', (11, 18))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', '220972', (11, 14))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('miR-423', 'Gene', '494335', (26, 33))	('miR', 'Gene', (70, 73))	('miR-423', 'Gene', '494335', (122, 129))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (61, 64))	('play', 'Reg', (133, 137))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', (11, 14))	('miR-423', 'Gene', (11, 18))	('miR-423', 'Gene', '494335', (70, 77))	('miR', 'Gene', (26, 29))	('miR-423', 'Gene', (26, 33))	('miR', 'Gene', (122, 125))	('miR-423', 'Gene', (122, 129))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', (157, 163))	('roles', 'Reg', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('miR-423', 'Gene', (70, 77))	('miR', 'Gene', '220972', (70, 73))
902925	30322005	The miR-146a rs2910164 G > C SNP is located in the precursor stem-loop region, opposite to the mature miRNA-146a sequence and involves a change from a G:U pair to a C:U mismatch, with an impact on mature miRNA-146a levels.	('impact', 'Reg', (187, 193))	('change', 'Reg', (137, 143))	('miR-146a', 'Gene', '406938', (4, 12))	('miRNA-146a', 'Gene', '406938', (102, 112))	('miR-146a', 'Gene', (4, 12))	('miRNA-146a', 'Gene', (204, 214))	('rs2910164 G > C', 'Var', (13, 28))	('miRNA-146a', 'Gene', '406938', (204, 214))	('rs2910164', 'Mutation', 'rs2910164', (13, 22))	('miRNA-146a', 'Gene', (102, 112))
902927	30322005	The miR-196a-2 rs11614913 C > T SNP is located in the stem-loop region opposite to the mature miR-196a-2, and the nucleotide change from C to T was suggested to alter the levels of the mature 3' passenger (3p) strand of miR-196a2 and the activity of its target mRNAs.	('activity', 'MPA', (238, 246))	('alter', 'Reg', (161, 166))	('rs11614913', 'Var', (15, 25))	('miR-196a-2', 'Gene', (4, 14))	('miR-196a-2', 'Gene', '406973', (4, 14))	('miR-196a2', 'Gene', (220, 229))	('levels', 'MPA', (171, 177))	('miR-196a-2', 'Gene', (94, 104))	('miR-196a-2', 'Gene', '406973', (94, 104))	('rs11614913', 'DBSNP_MENTION', 'None', (15, 25))	('miR-196a2', 'Gene', '406973', (220, 229))
902929	30322005	SNPs occurring in noncoding regions can affect transcriptional regulation or post-transcriptional gene expression, thereby affecting mRNA half life and resulting in altered protein levels trough the deregulation of miRNA-mRNA binding.	('altered', 'Reg', (165, 172))	('transcriptional regulation', 'MPA', (47, 73))	('affecting', 'Reg', (123, 132))	('SNPs', 'Var', (0, 4))	('mRNA half life', 'MPA', (133, 147))	('post-transcriptional gene', 'Gene', (77, 102))	('affect', 'Reg', (40, 46))	('protein levels trough', 'MPA', (173, 194))	('miR', 'Gene', '220972', (215, 218))	('miR', 'Gene', (215, 218))
902931	30322005	Roughly 180,000 SNPs in the human genome that are located in the 3'-UTR region were identified, along with about 2600 mature miRNA sequences that are deposited in the mirBase (v.21), which suggests that these SNPs may introduce miRNA-binding changes.	('introduce', 'Reg', (218, 227))	('human', 'Species', '9606', (28, 33))	('SNPs', 'Var', (209, 213))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (125, 128))	('miR', 'Gene', '220972', (228, 231))	('miR', 'Gene', (228, 231))	('changes', 'Reg', (242, 249))
902932	30322005	Despite the fact that the majority of the studies about polymorphisms in miRNA targets focus on the SNPs in 3'UTRs, it is important to note that some studies revealed that miRNAs could also bind to 5' UTRs or coding sequences of target mRNAs, suggesting that these variants could also affect miRNA regulation.	('affect', 'Reg', (285, 291))	('bind', 'Interaction', (190, 194))	('variants', 'Var', (265, 273))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', '220972', (292, 295))	('miR', 'Gene', (292, 295))	('miR', 'Gene', (172, 175))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))
902933	30322005	Functional SNPs in the miRNA target regions are likely to alter gene expression via affecting miRNA targeting, namely, through the creation or disruption of miRNA-binding sites.	('gene expression', 'MPA', (64, 79))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('miR', 'Gene', '220972', (157, 160))	('miR', 'Gene', (157, 160))	('affecting', 'Reg', (84, 93))	('miR', 'Gene', '220972', (94, 97))	('alter', 'Reg', (58, 63))	('miR', 'Gene', (94, 97))	('disruption', 'NegReg', (143, 153))	('Functional SNPs', 'Var', (0, 15))
902934	30322005	In this review, we found eight studies relating nine different SNPs in miRNA targets (8 in 3'-UTR regions and 1 in a coding sequence) with association with EC risk and outcome (Table 2).	('association', 'Interaction', (139, 150))	('miR', 'Gene', (71, 74))	('SNPs', 'Var', (63, 67))	('miR', 'Gene', '220972', (71, 74))
902935	30322005	In a study that evaluates the impact of SNP regulation of miRNA expression in colon-cancer risk, KIAA023 rs1053667 was found to be associated with differential expression of one of its target miRNAs, miR-19b-3p, in normal colon tissue when compared to tumor tissue.	('miR', 'Gene', '220972', (200, 203))	('expression', 'MPA', (160, 170))	('miR', 'Gene', (200, 203))	('rs1053667', 'Var', (105, 114))	('rs1053667', 'Mutation', 'rs1053667', (105, 114))	('miR', 'Gene', '220972', (192, 195))	('miR', 'Gene', (192, 195))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colon-cancer', 'Disease', (78, 90))	('KIAA023', 'Gene', (97, 104))	('tumor', 'Disease', (252, 257))	('colon-cancer', 'Disease', 'MESH:D015179', (78, 90))
902936	30322005	Histone lysine methyltransferase (SET8) rs16917496 results in a C to T transition that might destroy the G:C bond in the miR-502 and SET8 binding site, therefore modulating SET8 expression.	('SET8', 'Gene', (34, 38))	('G:C bond', 'MPA', (105, 113))	('destroy', 'NegReg', (93, 100))	('expression', 'MPA', (178, 188))	('modulating', 'Reg', (162, 172))	('binding', 'Interaction', (138, 145))	('miR-502', 'Gene', '574504', (121, 128))	('rs16917496', 'Mutation', 'rs16917496', (40, 50))	('SET8', 'Gene', (173, 177))	('SET8', 'Gene', '387893', (173, 177))	('SET8', 'Gene', (133, 137))	('SET8', 'Gene', '387893', (133, 137))	('SET8', 'Gene', '387893', (34, 38))	('rs16917496', 'Var', (40, 50))	('miR-502', 'Gene', (121, 128))	('C to T transition', 'MPA', (64, 81))
902939	30322005	The Basigin (BSG) rs11473 consists of a C to T transition that destroys the binding site of miR-483-5p at the 3'-UTR of BSG, resulting in higher mRNA levels of this gene.	('destroys', 'NegReg', (63, 71))	('Basigin', 'Gene', '682', (4, 11))	('mRNA levels', 'MPA', (145, 156))	('Basigin', 'Gene', (4, 11))	('miR', 'Gene', '220972', (92, 95))	('rs11473', 'Mutation', 'rs11473', (18, 25))	('miR', 'Gene', (92, 95))	('binding site', 'MPA', (76, 88))	('BSG', 'Gene', (13, 16))	('BSG', 'Gene', '682', (13, 16))	('BSG', 'Gene', (120, 123))	('higher', 'PosReg', (138, 144))	('BSG', 'Gene', '682', (120, 123))	('rs11473', 'Var', (18, 25))
902942	30322005	The rs1644730 is located in the 3'-UTR of RDH8 and its predicted miR-630 binding site.	('miR-630', 'Gene', '693215', (65, 72))	('RDH8', 'Gene', '50700', (42, 46))	('RDH8', 'Gene', (42, 46))	('rs1644730', 'Var', (4, 13))	('miR-630', 'Gene', (65, 72))	('rs1644730', 'Mutation', 'rs1644730', (4, 13))
902943	30322005	Given the significantly higher incidence of EAC among males versus females, a potential protective effect of estrogen has been proposed, which is in agreement with the fact that patients carrying the rs1644730 A allele presented decreased EAC risk.	('rs1644730 A', 'Var', (200, 211))	('patients', 'Species', '9606', (178, 186))	('rs1644730', 'Mutation', 'rs1644730', (200, 209))	('EAC', 'Disease', (44, 47))	('EAC', 'Disease', (239, 242))	('men', 'Species', '9606', (154, 157))	('decreased', 'NegReg', (229, 238))
902945	30322005	Two 3'-UTR SNPs, rs2866943 C>T and rs6029959 C>A, located in the binding sites of miR-218 and miR-142-5p, respectively, were studied in EC patients, but only rs2866943 was able to disrupt the inhibitory role of miR-218 on PRPT expression and act as a protective factor in ESCC risk.	('miR', 'Gene', '220972', (211, 214))	('miR', 'Gene', (211, 214))	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))	('rs2866943 C>T', 'Var', (17, 30))	('PRPT expression', 'MPA', (222, 237))	('patients', 'Species', '9606', (139, 147))	('rs2866943', 'Mutation', 'rs2866943', (158, 167))	('rs6029959', 'Mutation', 'rs6029959', (35, 44))	('rs2866943', 'Mutation', 'rs2866943', (17, 26))	('disrupt', 'NegReg', (180, 187))	('rs6029959 C>A', 'Var', (35, 48))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))	('ESCC', 'Disease', (272, 276))	('inhibitory role', 'MPA', (192, 207))	('rs2866943', 'Var', (158, 167))
902946	30322005	Patients carrying rs2866943 CT and TT genotypes presented a small tumor size as well as the low probability of metastasis.	('rs2866943 CT', 'Var', (18, 30))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('rs2866943', 'Mutation', 'rs2866943', (18, 27))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
902948	30322005	ErbB4 rs1595066 creates a binding site for miR-200*, a member of miR-200 tumor-suppressor miRNAs, and is associated with a lower EC risk, probably through the downregulation of ErbB4.	('ErbB4', 'Gene', '2066', (177, 182))	('ErbB4', 'Gene', '2066', (0, 5))	('miR', 'Gene', '220972', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('miR', 'Gene', (43, 46))	('lower', 'NegReg', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('miR', 'Gene', '220972', (65, 68))	('tumor', 'Disease', (73, 78))	('miR', 'Gene', (65, 68))	('rs1595066', 'Mutation', 'rs1595066', (6, 15))	('ErbB4', 'Gene', (177, 182))	('miR', 'Gene', '220972', (90, 93))	('downregulation', 'NegReg', (159, 173))	('miR', 'Gene', (90, 93))	('rs1595066', 'Var', (6, 15))	('binding', 'Interaction', (26, 33))	('ErbB4', 'Gene', (0, 5))
902950	30322005	The rs799917 T>C polymorphism located in the BRCA1 coding sequence influences miR-638-mediated regulation of BRCA1 expression.	('BRCA1', 'Gene', (109, 114))	('BRCA1', 'Gene', '672', (45, 50))	('BRCA1', 'Gene', '672', (109, 114))	('miR-638', 'Gene', '693223', (78, 85))	('BRCA1', 'Gene', (45, 50))	('influences', 'Reg', (67, 77))	('expression', 'MPA', (115, 125))	('miR-638', 'Gene', (78, 85))	('rs799917 T>C polymorphism', 'Var', (4, 29))	('rs799917', 'Mutation', 'rs799917', (4, 12))
902951	30322005	BRCA1 mRNA expression analyses showed that the rs799917 C allele carriers significantly decreased BRCA1 expression in both normal and cancer esophagus tissue compared with T allele carriers, suggesting that lower BRCA1 expression may lead to a higher risk of malignant transformation of esophagus cells.	('BRCA1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('BRCA1', 'Gene', (213, 218))	('expression', 'MPA', (219, 229))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('rs799917', 'Var', (47, 55))	('rs799917', 'Mutation', 'rs799917', (47, 55))	('expression', 'MPA', (104, 114))	('malignant transformation', 'CPA', (259, 283))	('esophagus', 'Disease', (287, 296))	('decreased', 'NegReg', (88, 97))	('BRCA1', 'Gene', '672', (98, 103))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA1', 'Gene', '672', (213, 218))	('lower', 'NegReg', (207, 212))	('BRCA1', 'Gene', (98, 103))
902953	30322005	The rs4245739 A>C SNP, located in the MDM4 3'-UTR, creates a binding site for miR-191, resulting in decreased MDM4 expression.	('MDM4', 'Gene', '4194', (110, 114))	('MDM4', 'Gene', (38, 42))	('MDM4', 'Gene', (110, 114))	('miR-191', 'Gene', (78, 85))	('rs4245739 A>C', 'Var', (4, 17))	('decreased', 'NegReg', (100, 109))	('rs4245739', 'Mutation', 'rs4245739', (4, 13))	('miR-191', 'Gene', '406966', (78, 85))	('MDM4', 'Gene', '4194', (38, 42))	('binding', 'Interaction', (61, 68))
902954	30322005	Rs4245739 AC and CC genotype carriers significantly decreased MDM4 expression in normal esophagus tissue compared with AA genotype carriers, indicating consistent genotype-phenotype correlation.	('MDM4', 'Gene', '4194', (62, 66))	('Rs4245739', 'Var', (0, 9))	('decreased', 'NegReg', (52, 61))	('Rs4245739', 'Mutation', 'Rs4245739', (0, 9))	('MDM4', 'Gene', (62, 66))	('expression', 'MPA', (67, 77))
902955	30322005	The rs6573 SNP is a substitution from A to C, and disrupts the binding of miR-196a to RAP1A 3'-UTR, resulting in a higher constitutive expression of RAP1A, which is a member of the RAS oncogene family.	('miR', 'Gene', (74, 77))	('miR', 'Gene', '220972', (74, 77))	('higher', 'PosReg', (115, 121))	('binding', 'Interaction', (63, 70))	('RAP1A', 'Gene', '5906', (86, 91))	('constitutive expression', 'MPA', (122, 145))	('rs6573', 'Mutation', 'rs6573', (4, 10))	('rs6573 SNP', 'Var', (4, 14))	('RAP1A', 'Gene', '5906', (149, 154))	('RAP1A', 'Gene', (86, 91))	('RAP1A', 'Gene', (149, 154))	('disrupts', 'NegReg', (50, 58))
902956	30322005	Wang and colleagues observed that RAP1A was overexpressed in ESCC tissue, and correlated with RAP1A rs6573 CC genotype and lymph-node metastasis.	('RAP1A', 'Gene', '5906', (34, 39))	('rs6573 CC', 'Var', (100, 109))	('lymph-node metastasis', 'CPA', (123, 144))	('RAP1A', 'Gene', (34, 39))	('RAP1A', 'Gene', '5906', (94, 99))	('rs6573', 'Mutation', 'rs6573', (100, 106))	('correlated', 'Reg', (78, 88))	('RAP1A', 'Gene', (94, 99))	('overexpressed', 'PosReg', (44, 57))
902959	30322005	The occurrence of SNPs in the components of the miRNA biogenesis pathway can affect transcription, processing, transport and target gene identification, consequently affecting the overall expression of miRNAs.	('expression', 'MPA', (188, 198))	('miR', 'Gene', '220972', (202, 205))	('miR', 'Gene', (48, 51))	('processing', 'MPA', (99, 109))	('miR', 'Gene', (202, 205))	('affect', 'Reg', (77, 83))	('transport', 'MPA', (111, 120))	('occurrence', 'Var', (4, 14))	('miR', 'Gene', '220972', (48, 51))	('transcription', 'MPA', (84, 97))	('SNPs', 'Var', (18, 22))	('affecting', 'Reg', (166, 175))
902960	30322005	In this review, we found three studies relating SNPs in XPO5, Gem-associated protein 3 (GEMIN3), and Gem-associated protein 4 (GEMIN4) genes with EC risk outcome, and all of the SNPs reported were associated with a better prognosis (Table 3).	('XPO5', 'Gene', (56, 60))	('XPO5', 'Gene', '57510', (56, 60))	('Gem-associated protein 3', 'Gene', (62, 86))	('GEMIN4', 'Gene', '50628', (127, 133))	('GEMIN3', 'Gene', '11218', (88, 94))	('Gem-associated protein 3', 'Gene', '11218', (62, 86))	('Gem-associated protein 4', 'Gene', (101, 125))	('GEMIN4', 'Gene', (127, 133))	('SNPs', 'Var', (48, 52))	('Gem-associated protein 4', 'Gene', '50628', (101, 125))	('GEMIN3', 'Gene', (88, 94))
902962	30322005	It has been postulated that XPO5 miRNA regulation can be a limiting step for miRNA development since its impairment can lead to pre-miRNA trapping in the nucleolus and therefore influence cancer risk.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (77, 80))	('miR', 'Gene', (33, 36))	('XPO5', 'Gene', '57510', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('men', 'Species', '9606', (90, 93))	('lead to', 'Reg', (120, 127))	('XPO5', 'Gene', (28, 32))	('men', 'Species', '9606', (111, 114))	('influence', 'Reg', (178, 187))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('miR', 'Gene', '220972', (132, 135))	('cancer', 'Disease', (188, 194))	('impairment', 'Var', (105, 115))	('miR', 'Gene', (132, 135))	('miR', 'Gene', '220972', (77, 80))
902963	30322005	The XPO5 rs11077 consists of an A to C transition that leads to the disruption of the miR-617 binding site and the creation of a new binding site for miR-4763-5p in XPO5 3'-UTR, with an impact on XPO5 mRNA levels.	('miR', 'Gene', '220972', (150, 153))	('binding', 'Interaction', (133, 140))	('miR', 'Gene', (150, 153))	('rs11077', 'Mutation', 'rs11077', (9, 16))	('binding', 'Interaction', (94, 101))	('miR', 'Gene', '220972', (86, 89))	('XPO5', 'Gene', (196, 200))	('miR', 'Gene', (86, 89))	('XPO5', 'Gene', (165, 169))	('disruption', 'NegReg', (68, 78))	('XPO5', 'Gene', (4, 8))	('XPO5', 'Gene', '57510', (165, 169))	('impact', 'Reg', (186, 192))	('XPO5', 'Gene', '57510', (196, 200))	('XPO5', 'Gene', '57510', (4, 8))	('rs11077', 'Var', (9, 16))
902964	30322005	In fact, patients' carriers of rs11077 AA genotype displayed a trend for high XPO5 expression in ESCC tissues, and these high XPO5 expression levels were also associated with high survival rates.	('patients', 'Species', '9606', (9, 17))	('rs11077 AA', 'Var', (31, 41))	('survival rates', 'CPA', (180, 194))	('XPO5', 'Gene', (78, 82))	('XPO5', 'Gene', '57510', (78, 82))	('associated', 'Reg', (159, 169))	('expression', 'MPA', (131, 141))	('XPO5', 'Gene', (126, 130))	('XPO5', 'Gene', '57510', (126, 130))	('expression', 'MPA', (83, 93))	('high', 'PosReg', (73, 77))	('rs11077', 'Mutation', 'rs11077', (31, 38))
902966	30322005	With the exception of GEMIN4 rs910924 that is located in a 5'-UTR, all the other studied GEMIN SNPs were missense variants, meaning that they resulted in different amino acid sequences that could impact GEMIN3 and GEMIN4 protein structure and consequent miRNA regulatory function.	('GEMIN4', 'Gene', '50628', (22, 28))	('GEMIN4', 'Gene', (214, 220))	('GEMIN4', 'Gene', (22, 28))	('GEMIN3', 'Gene', (203, 209))	('impact', 'Reg', (196, 202))	('miR', 'Gene', '220972', (254, 257))	('miR', 'Gene', (254, 257))	('GEMIN4', 'Gene', '50628', (214, 220))	('rs910924', 'Mutation', 'rs910924', (29, 37))	('rs910924', 'Var', (29, 37))	('resulted in', 'Reg', (142, 153))	('GEMIN3', 'Gene', '11218', (203, 209))
902970	30322005	SNPs in miRNA and miRNA-binding sites can potentially modulate miRNA-mRNA interaction and potentially create or destroy miRNA-binding sites, while those in biogenesis pathway genes can influence miRNA transcription either through altering transcription, processing, or maturation.	('altering', 'Reg', (230, 238))	('miR', 'Gene', '220972', (120, 123))	('modulate', 'Reg', (54, 62))	('miR', 'Gene', (120, 123))	('influence', 'Reg', (185, 194))	('miR', 'Gene', '220972', (195, 198))	('miR', 'Gene', (195, 198))	('SNPs', 'Var', (0, 4))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (18, 21))	('miR', 'Gene', (63, 66))	('miR', 'Gene', '220972', (18, 21))	('destroy', 'NegReg', (112, 119))	('miR', 'Gene', '220972', (8, 11))	('miR', 'Gene', (8, 11))
902974	30322005	Additionally, since EC is a type of cancer that involves multiple miR-SNPs with impact on the miRNA targetome, the candidate gene approach that considers one or few genes/SNPs at a time can give us the functional impact of that genetic variant in cancer risk or survival, but fails to relate that information with the molecular pathways involved.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('type of cancer', 'Disease', (28, 42))	('genetic variant', 'Var', (228, 243))	('variant', 'Var', (236, 243))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('miR', 'Gene', (66, 69))	('survival', 'CPA', (262, 270))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('miR', 'Gene', '220972', (66, 69))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('type of cancer', 'Disease', 'MESH:D009369', (28, 42))
902975	30322005	As such, more pathway-based approaches that evaluate the cumulative effect of multiple unfavorable genotypes on the miRNA targetome are needed to identify signatures of genetic variations capable of predicting EC therapy response and prognosis.	('variations', 'Var', (177, 187))	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', (116, 119))
902977	30322005	This type of approaches would shed some light on the fine regulatory mechanisms by which these variations contribute to EC pathogenesis instead of only focusing in cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('contribute', 'Reg', (106, 116))	('variations', 'Var', (95, 105))
903023	19276258	Peptides for influenza nucleoprotein NP206-229 (FWRGENGRKTRIAYERMCNILKGK), tetanus toxoid TT 830-844 (QYIKANSKFIGITEL), influenza hemagglutinin HA 307-319 (PKYVKQNTLKLAT), Melan A (ELAGIGILTV), and flu matrix (GILGFVFTL) were obtained from Bio-Synthesis (Lewisville, TX) with a purity of greater than 95% as determined by mass spectrometry.	('NP206-229', 'Var', (37, 46))	('tetanus', 'Disease', (75, 82))	('Melan A', 'Gene', '2315', (172, 179))	('tetanus', 'Disease', 'MESH:D013746', (75, 82))	('Melan A', 'Gene', (172, 179))
903073	19276258	Patients #N01, N03, N07, P005, and P011 had measurable CD8 T cell responses against NY-ESO-1 as detected by ELISPOT assays (Table 1).	('P011', 'Var', (35, 39))	('N07', 'Var', (20, 23))	('P005', 'Var', (25, 29))	('N03', 'Var', (15, 18))	('NY-ESO-1', 'Gene', (84, 92))	('Patients', 'Species', '9606', (0, 8))	('NY-ESO-1', 'Gene', '246100', (84, 92))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))
903085	19276258	Similarly, patients #P008 and P011 were found to have detectable CD4 T cell responses against NY-ESO-1 after depletion of regulatory T cells from their pre-vaccine blood samples (data not shown).	('NY-ESO-1', 'Gene', '246100', (94, 102))	('NY-ESO-1', 'Gene', (94, 102))	('CD4 T cell responses', 'CPA', (65, 85))	('P011', 'Var', (30, 34))	('detectable CD4 T cell response', 'Phenotype', 'HP:0005407', (54, 84))	('patients', 'Species', '9606', (11, 19))
903089	19276258	Similarly, patients #P003 and P007 developed CD4 T cell responses against NY-ESO-1 in the week 13 blood samples after depletion of regulatory T cells (data not shown).	('P007', 'Var', (30, 34))	('NY-ESO-1', 'Gene', '246100', (74, 82))	('NY-ESO-1', 'Gene', (74, 82))	('patients', 'Species', '9606', (11, 19))	('CD4 T cell responses against', 'MPA', (45, 73))
903111	19276258	Depletion of regulatory T cells prior to vaccination may allow for enhanced effector T cell responses with subsequent anti-tumor responses.	('tumor', 'Disease', (123, 128))	('enhanced effector T cell responses', 'Phenotype', 'HP:0031402', (67, 101))	('Depletion', 'Var', (0, 9))	('effector T cell responses', 'CPA', (76, 101))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('enhanced', 'PosReg', (67, 75))
903146	28288180	All antibodies used in this study were commercially purchased: choromogranin A (IS50230, dilution 1:1000, Dako, Glostrup, Denmark), synaptophysin (PA0299 Bond Ready-To-Use Primary antibody, Leica Biosysytems, Nussloch, Germany) and CD56 (CD56-1B6-R-7 Bond Ready-To-Use Primary antibody, Leica Biosysytems, Nussloch, Germany), Ki67 (M7240, dilution 1:100, Dako, Glostrup, Denmark), c-kit (A4502, dilution 1:100, Dako, Glostrup, Denmark), p53 (N1581, dilution 1:10, Dako, Glostrup, Denmark), p63 (413751, dilution 1:5, Nichirei, Tokyo, Japan), CK5/6 (M7237, dilution 1:250, Dako, Glostrup, Denmark) and CK20 (413491, dilution 1:1000, Nichirei, Tokyo, Japan).	('synaptophysin', 'Gene', '6855', (132, 145))	('p53', 'Gene', '7157', (437, 440))	('CD56', 'Gene', '4684', (238, 242))	('CK5/6', 'Gene', (542, 547))	('c-kit', 'Gene', '3815', (381, 386))	('p53', 'Gene', (437, 440))	('p63', 'Gene', (490, 493))	('CK20', 'Gene', (601, 605))	('p63', 'Gene', '8626', (490, 493))	('413751', 'Var', (495, 501))	('N1581', 'Var', (442, 447))	('CK20', 'Gene', '54474', (601, 605))	('synaptophysin', 'Gene', (132, 145))	('M7237', 'Var', (549, 554))	('CD56', 'Gene', (232, 236))	('CK5/6', 'Gene', '3852', (542, 547))	('c-kit', 'Gene', (381, 386))	('CD56', 'Gene', '4684', (232, 236))	('CD56', 'Gene', (238, 242))
903184	28288180	Heterozygosity is also frequently observed in neuroendocrine NEC of the esophagus as a pathologic feature and co-existence of squamous cell carcinoma and/or adenocarcinoma are also often observed.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 149))	('squamous cell carcinoma', 'Disease', (126, 149))	('adenocarcinoma', 'Disease', (157, 171))	('Heterozygosity', 'Var', (0, 14))	('NEC', 'Phenotype', 'HP:0100634', (61, 64))	('neuroendocrine NEC of the esophagus', 'Disease', (46, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (157, 171))	('observed', 'Reg', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
903190	28288180	Similar to squamous cell carcinoma of the esophagus in which the abnormality of p53 plays an important role in carcinogenesis, the abnormality of p53 might play some role in the carcinogenesis or progression for NEC of the esophagus.	('role', 'Reg', (166, 170))	('p53', 'Gene', (146, 149))	('NEC', 'Phenotype', 'HP:0100634', (212, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (11, 51))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (25, 51))	('p53', 'Gene', '7157', (80, 83))	('carcinogenesis', 'Disease', (178, 192))	('NEC of the esophagus', 'Disease', (212, 232))	('play', 'Reg', (156, 160))	('p53', 'Gene', (80, 83))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('abnormality', 'Var', (131, 142))	('carcinogenesis', 'Disease', (111, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('squamous cell carcinoma of the esophagus', 'Disease', (11, 51))	('p53', 'Gene', '7157', (146, 149))	('abnormality', 'Var', (65, 76))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))
903191	28288180	In pulmonary neuroendocrine tumors, protein abnormality, loss of heterozygosity and gene mutation were observed and the incidence of these abnormalities progressively increased with increasing severity of tumor type.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (13, 34))	('tumor', 'Disease', (28, 33))	('gene mutation', 'Var', (84, 97))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('pulmonary neuroendocrine tumors', 'Disease', 'MESH:D018358', (3, 34))	('pulmonary neuroendocrine tumors', 'Disease', (3, 34))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('protein', 'Protein', (36, 43))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('loss of', 'NegReg', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
903193	28288180	Huang reported a low frequency of CK20 positivity in NEC of the esophagus.	('CK20', 'Gene', (34, 38))	('CK20', 'Gene', '54474', (34, 38))	('NEC', 'Phenotype', 'HP:0100634', (53, 56))	('NEC of the esophagus', 'Disease', (53, 73))	('positivity', 'Var', (39, 49))
903195	28288180	There has been reported that p53 abnormality was also rare events in Merkel cell carcinoma of the skin.	('p53', 'Gene', (29, 32))	('Merkel cell carcinoma of the skin', 'Phenotype', 'HP:0030447', (69, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('Merkel cell carcinoma of the skin', 'Disease', 'MESH:D015266', (69, 102))	('p53', 'Gene', '7157', (29, 32))	('Merkel cell carcinoma of the skin', 'Disease', (69, 102))	('abnormality', 'Var', (33, 44))
903197	28288180	There were no significant differences of prognosis according to the immunohistochemical status of p53 and/or c-kit, or others (CK20 and Ki67).	('c-kit', 'Gene', (109, 114))	('Ki67', 'Var', (136, 140))	('c-kit', 'Gene', '3815', (109, 114))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))	('CK20', 'Gene', (127, 131))	('CK20', 'Gene', '54474', (127, 131))
903227	28191340	MetS is diagnosed if three or more of the following five medical conditions are met: elevated waist circumference (WC) (>= 90 cm for men and >= 80 cm for women), high serum triglycerides (TG) (>= 150 mg/dL), low levels of high density lipoprotein cholesterol (HDL-C) (< 40 mg/dL in males and < 50 mg/dL in females), elevated blood pressure (BP)) systolic >= 130 mmHg and/or diastolic >= 85 mmHg, (and increased fasting blood glucose (FBG) (>= 100 mg/dL).	('TG', 'Chemical', 'MESH:D014280', (188, 190))	('low', 'NegReg', (208, 211))	('high serum triglycerides', 'Phenotype', 'HP:0002155', (162, 186))	('elevated waist circumference', 'Phenotype', 'HP:0031819', (85, 113))	('blood pressure', 'MPA', (325, 339))	('men', 'Species', '9606', (156, 159))	('diastolic >= 85 mmHg', 'MPA', (374, 394))	('elevated', 'PosReg', (85, 93))	('women', 'Species', '9606', (154, 159))	('low levels of high density lipoprotein', 'Phenotype', 'HP:0003233', (208, 246))	('elevated blood pressure', 'Phenotype', 'HP:0032263', (316, 339))	('blood glucose', 'Disease', 'MESH:D006402', (419, 432))	('men', 'Species', '9606', (133, 136))	('high', 'Var', (162, 166))	('increased', 'PosReg', (401, 410))	('blood glucose', 'Disease', (419, 432))	('waist', 'MPA', (94, 99))	('elevated', 'PosReg', (316, 324))
903257	28191340	also revealed that MetS was significantly associated with a higher risk of reflux esophagitis (Odds ratio [OR]: 1.76, 95% confidence interval [CI]: 1.27 - 2.44, P = 0.001).	('MetS', 'Var', (19, 23))	('esophagitis', 'Phenotype', 'HP:0100633', (82, 93))	('reflux esophagitis', 'Disease', (75, 93))	('reflux esophagitis', 'Disease', 'MESH:D005764', (75, 93))
903268	28191340	Moreover, they reported that the prevalence of MetS in patients with reflux esophagitis was significantly higher than in those without reflux esophagitis (26.9% vs. 18.5%, P < 0.001), concluding that MetS could increase the risk of reflux esophagitis after a multivariate analysis (OR: 1.42, 95% CI: 1.26 - 1.60, P < 0.001).	('reflux esophagitis', 'Disease', 'MESH:D005764', (232, 250))	('reflux esophagitis', 'Disease', 'MESH:D005764', (135, 153))	('reflux esophagitis', 'Disease', (232, 250))	('esophagitis', 'Phenotype', 'HP:0100633', (76, 87))	('esophagitis', 'Phenotype', 'HP:0100633', (142, 153))	('patients', 'Species', '9606', (55, 63))	('esophagitis', 'Phenotype', 'HP:0100633', (239, 250))	('reflux esophagitis', 'Disease', 'MESH:D005764', (69, 87))	('MetS', 'Var', (200, 204))	('reflux esophagitis', 'Disease', (135, 153))	('reflux esophagitis', 'Disease', (69, 87))
903272	28191340	Moreover, the prevalence of MetS was higher in patients with GERD than in individuals without GERD (50% vs. 19.56%; P = 0.002), and after adjusting the age, sex, and BMI values, MetS was considered to be an independent factor associated with a 2.82-fold increase in risk of GERD (95%CI: 1.08 - 7.35, P = 0.03).	('MetS', 'Disease', (28, 32))	('GERD', 'Disease', 'MESH:D005764', (61, 65))	('GERD', 'Disease', (61, 65))	('patients', 'Species', '9606', (47, 55))	('MetS', 'Var', (178, 182))	('GERD', 'Disease', 'MESH:D005764', (94, 98))	('GERD', 'Disease', (94, 98))	('GERD', 'Disease', (274, 278))	('GERD', 'Disease', 'MESH:D005764', (274, 278))
903276	28191340	Univariate and multivariate logistic regression analysis in this study showed that central obesity, hypertension, hyperglycemia, hypertriglyceridemia, TC/HDL-C > 5, AST > 37 U/L, and ALT > 40 U/L could be significantly associated with a higher probability of developing erosive esophagitis (P < 0.05 for all).	('TC/HDL-C > 5', 'Var', (151, 163))	('obesity', 'Disease', (91, 98))	('hyperglycemia', 'Phenotype', 'HP:0003074', (114, 127))	('hypertension', 'Phenotype', 'HP:0000822', (100, 112))	('hypertriglyceridemia', 'Disease', 'MESH:D015228', (129, 149))	('hypertriglyceridemia', 'Disease', (129, 149))	('obesity', 'Disease', 'MESH:D009765', (91, 98))	('ALT > 40 U/L', 'Var', (183, 195))	('esophagitis', 'Disease', (278, 289))	('AST', 'Gene', '26503', (165, 168))	('esophagitis', 'Disease', 'MESH:D004941', (278, 289))	('hyperglycemia', 'Disease', (114, 127))	('associated', 'Reg', (219, 229))	('esophagitis', 'Phenotype', 'HP:0100633', (278, 289))	('TC', 'Chemical', '-', (151, 153))	('obesity', 'Phenotype', 'HP:0001513', (91, 98))	('hypertriglyceridemia', 'Phenotype', 'HP:0002155', (129, 149))	('hyperglycemia', 'Disease', 'MESH:D006943', (114, 127))	('AST', 'Gene', (165, 168))	('hypertension', 'Disease', 'MESH:D006973', (100, 112))	('central obesity', 'Phenotype', 'HP:0012743', (83, 98))	('hypertension', 'Disease', (100, 112))
903291	28191340	In addition, it was observed that the presence of MetS was considered to be a significant risk factor for the prevalence of both reflux esophagitis (OR: 2.21, 95% CI: 1.63 - 3.00, P < 0.0001) and GERD (OR: 1.871, 95% CI: 1.463 - 2.393, P < 0.0001), and it could also aggravate the reflux symptoms in patients with or without reflux esophagitis.	('presence', 'Var', (38, 46))	('esophagitis', 'Phenotype', 'HP:0100633', (332, 343))	('GERD', 'Disease', (196, 200))	('GERD', 'Disease', 'MESH:D005764', (196, 200))	('reflux symptoms', 'Phenotype', 'HP:0002020', (281, 296))	('reflux esophagitis', 'Disease', (325, 343))	('reflux esophagitis', 'Disease', 'MESH:D005764', (325, 343))	('reflux esophagitis', 'Disease', (129, 147))	('reflux esophagitis', 'Disease', 'MESH:D005764', (129, 147))	('esophagitis', 'Phenotype', 'HP:0100633', (136, 147))	('aggravate', 'PosReg', (267, 276))	('MetS', 'Var', (50, 54))	('patients', 'Species', '9606', (300, 308))	('reflux symptoms', 'Disease', (281, 296))
903295	28191340	The results obtained from the multivariate analysis revealed that particular factors such as male sex, BMI >= 27, smoking, and heavy drinking could independently increase the likelihood of progression from non-erosive to erosive esophagitis, along with reducing the likelihood of disease regression (P < 0.05 for all).	('increase', 'PosReg', (162, 170))	('BMI >= 27', 'Var', (103, 112))	('esophagitis', 'Phenotype', 'HP:0100633', (229, 240))	('esophagitis', 'Disease', (229, 240))	('non-erosive', 'Disease', (206, 217))	('esophagitis', 'Disease', 'MESH:D004941', (229, 240))	('heavy drinking', 'Var', (127, 141))
903297	28191340	Moreover, MetS was shown to be significantly associated with the progression of the disease to erosive esophagitis, which could indicate that patients with MetS have a significant risk of erosive esophagitis (relative risk [RR]: 1.75, 95% CI: 1.29 - 2.38, P < 0.05).	('esophagitis', 'Phenotype', 'HP:0100633', (196, 207))	('esophagitis', 'Disease', (196, 207))	('esophagitis', 'Disease', 'MESH:D004941', (196, 207))	('MetS', 'Var', (10, 14))	('esophagitis', 'Phenotype', 'HP:0100633', (103, 114))	('esophagitis', 'Disease', (103, 114))	('associated', 'Reg', (45, 55))	('esophagitis', 'Disease', 'MESH:D004941', (103, 114))	('patients', 'Species', '9606', (142, 150))
903309	28191340	However, the study that was conducted among men showed that the frequency of erosive esophagitis was significantly higher in patients with V-type MetS than in patients with S-type MetS.	('V-type MetS', 'Var', (139, 150))	('men', 'Species', '9606', (44, 47))	('esophagitis', 'Disease', (85, 96))	('higher', 'PosReg', (115, 121))	('patients', 'Species', '9606', (159, 167))	('esophagitis', 'Disease', 'MESH:D004941', (85, 96))	('esophagitis', 'Phenotype', 'HP:0100633', (85, 96))	('patients', 'Species', '9606', (125, 133))
903310	28191340	Further, according to the logistic regression analysis, the V-type MetS (OR: 3.80, 95% CI: 1.71 - 8.47, P < 0.005) was found to be a remarkable predictor of the increased prevalence of erosive esophagitis, as was the presence of hiatal hernia (P < 0.001).	('MetS', 'Var', (67, 71))	('hiatal hernia', 'Disease', 'MESH:D006551', (229, 242))	('hiatal hernia', 'Disease', (229, 242))	('esophagitis', 'Disease', (193, 204))	('esophagitis', 'Phenotype', 'HP:0100633', (193, 204))	('esophagitis', 'Disease', 'MESH:D004941', (193, 204))	('hiatal hernia', 'Phenotype', 'HP:0002036', (229, 242))	('hernia', 'Phenotype', 'HP:0100790', (236, 242))
903315	28191340	Moreover, the results demonstrated that the prevalence of erosive esophagitis in men with MetS was higher in patients with V-type MetS than in patients with S-type MetS, while no relationships were reported between erosive esophagitis and the types of MetS in women with MetS, which could be due to the greater accumulation of visceral fat in men compared to the accumulation of subcutaneous fat in women.	('esophagitis', 'Phenotype', 'HP:0100633', (223, 234))	('esophagitis', 'Disease', (223, 234))	('accumulation', 'PosReg', (311, 323))	('women', 'Species', '9606', (399, 404))	('men', 'Species', '9606', (262, 265))	('esophagitis', 'Disease', (66, 77))	('higher', 'PosReg', (99, 105))	('V-type MetS', 'Var', (123, 134))	('patients', 'Species', '9606', (109, 117))	('esophagitis', 'Disease', 'MESH:D004941', (66, 77))	('women', 'Species', '9606', (260, 265))	('esophagitis', 'Disease', 'MESH:D004941', (223, 234))	('esophagitis', 'Phenotype', 'HP:0100633', (66, 77))	('patients', 'Species', '9606', (143, 151))	('men', 'Species', '9606', (81, 84))	('men', 'Species', '9606', (343, 346))	('men', 'Species', '9606', (401, 404))
903322	28191340	Moreover, several studies observed that high BMI ranges, representing obesity, could increase the risk of GERD.	('high BMI ranges', 'Phenotype', 'HP:0031418', (40, 55))	('GERD', 'Disease', 'MESH:D005764', (106, 110))	('obesity', 'Phenotype', 'HP:0001513', (70, 77))	('GERD', 'Disease', (106, 110))	('high BMI ranges', 'Var', (40, 55))	('obesity', 'Disease', 'MESH:D009765', (70, 77))	('obesity', 'Disease', (70, 77))
903338	28191340	Above all, each component of MetS can somehow affect the incidence of GERD, indicating that the co-occurrence of three or more of the five above-mentioned components might be associated with the incidence of GERD.	('associated', 'Reg', (175, 185))	('co-occurrence', 'Var', (96, 109))	('men', 'Species', '9606', (145, 148))	('affect', 'Reg', (46, 52))	('GERD', 'Disease', (70, 74))	('GERD', 'Disease', 'MESH:D005764', (70, 74))	('GERD', 'Disease', 'MESH:D005764', (208, 212))	('GERD', 'Disease', (208, 212))
903345	28191340	Therefore, since MetS is a reliable predictive factor for the prevalence of GERD, alleviating the metabolic abnormalities in patients with GERD might cause significant potential benefits in the treatment of GERD.	('men', 'Species', '9606', (199, 202))	('metabolic abnormalities', 'Phenotype', 'HP:0001939', (98, 121))	('alleviating', 'Var', (82, 93))	('metabolic abnormalities', 'Disease', 'MESH:D008659', (98, 121))	('metabolic abnormalities', 'Disease', (98, 121))	('benefits', 'PosReg', (178, 186))	('GERD', 'Disease', 'MESH:D005764', (76, 80))	('GERD', 'Disease', (207, 211))	('GERD', 'Disease', (76, 80))	('GERD', 'Disease', 'MESH:D005764', (207, 211))	('GERD', 'Disease', (139, 143))	('GERD', 'Disease', 'MESH:D005764', (139, 143))	('patients', 'Species', '9606', (125, 133))
903359	27223088	Besides, several molecular and genetic biomarkers, such as the microRNA-3651, the overexpression and amplification of epithelial growth factor receptor (EGFR), SATB2 expression, has also showed promising prognostic value in ESCC by recent studies.	('microRNA-3651', 'Gene', (63, 76))	('SATB2', 'Gene', (160, 165))	('amplification', 'Var', (101, 114))	('epithelial growth factor receptor', 'Gene', (118, 151))	('epithelial growth factor receptor', 'Gene', '1956', (118, 151))	('SATB2', 'Gene', '23314', (160, 165))	('EGFR', 'Gene', '1956', (153, 157))	('overexpression', 'PosReg', (82, 96))	('ESCC', 'Disease', (224, 228))	('EGFR', 'Gene', (153, 157))
903366	27223088	Individual RDW values have been shown to be closely associated with poor outcome in cardiovascular diseases, pulmonary diseases and hepatic diseases.	('cardiovascular diseases', 'Disease', (84, 107))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (84, 107))	('hepatic diseases', 'Disease', 'MESH:D056486', (132, 148))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (84, 107))	('hepatic diseases', 'Disease', (132, 148))	('associated', 'Reg', (52, 62))	('pulmonary diseases', 'Disease', (109, 127))	('Individual RDW values', 'Var', (0, 21))	('pulmonary diseases', 'Disease', 'MESH:D008171', (109, 127))
903368	27223088	High RDW values were found to correlate with advanced tumor stage and invasiveness in non-small-cell lung cancer, breast cancer, and renal cancer patients.	('renal cancer', 'Phenotype', 'HP:0009726', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (86, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('renal cancer', 'Disease', 'MESH:D007680', (133, 145))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('patients', 'Species', '9606', (146, 154))	('lung cancer', 'Disease', (101, 112))	('High RDW values', 'Var', (0, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('invasiveness', 'CPA', (70, 82))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (90, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('tumor', 'Disease', (54, 59))	('renal cancer', 'Disease', (133, 145))	('breast cancer', 'Disease', (114, 127))
903370	27223088	Several researchers have focused on the relationship between inflammatory status in the host and RDW and revealed a close correlation between the two, and therefore, a high RDW value is associated with poor prognosis and aggressive behavior of cancer.	('aggressive behavior of cancer', 'Disease', (221, 250))	('aggressive behavior of cancer', 'Disease', 'MESH:D001523', (221, 250))	('aggressive behavior', 'Phenotype', 'HP:0000718', (221, 240))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('high', 'Var', (168, 172))	('RDW', 'MPA', (173, 176))	('poor prognosis', 'CPA', (202, 216))
903396	27223088	After adjusting for lymph node status, tumor depth, treatment, tumor size and GPS, we found that patients with a low HB/RDW ratio had a 1.416 times greater risk of dying during follow-up compared with those with a high HB/RDW (95% CI = 1.024-1.958, P = 0.035, Table 2).	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('low', 'Var', (113, 116))	('high HB', 'Phenotype', 'HP:0001900', (214, 221))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('men', 'Species', '9606', (57, 60))	('patients', 'Species', '9606', (97, 105))
903401	27223088	A significantly higher percentage of patients in the low HB/RDW group had T3/T4 ESCC (P=0.026), UICC/AJCC stage III disease (P=0.013), and underwent adjuvant therapy (P=0.022) (Table 1).	('T3/T4 ESCC', 'Disease', (74, 84))	('low HB/RDW', 'Var', (53, 63))	('patients', 'Species', '9606', (37, 45))	('II disease', 'Disease', (113, 123))	('underwent', 'Reg', (139, 148))	('II disease', 'Disease', 'MESH:D005776', (113, 123))
903404	27223088	Patients in the low HB/RDW group were found to present with higher NLR (P=0.004), PLR (P=0.001), RDW (P<0.001) and lower HB level (P<0.001) (Table 1).	('NLR', 'MPA', (67, 70))	('higher', 'PosReg', (60, 66))	('low HB/RDW', 'Var', (16, 26))	('HB level', 'MPA', (121, 129))	('PLR', 'MPA', (82, 85))	('lower', 'NegReg', (115, 120))	('Patients', 'Species', '9606', (0, 8))	('RDW', 'MPA', (97, 100))	('lower HB level', 'Phenotype', 'HP:0020062', (115, 129))
903406	27223088	The role of RDW has been increasingly appreciated, as RDW has been shown to closely correlate with risk of cardiovascular diseases and systematic inflammatory status.	('systematic inflammatory status', 'MPA', (135, 165))	('correlate', 'Reg', (84, 93))	('RDW', 'Var', (54, 57))	('cardiovascular diseases', 'Disease', (107, 130))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (107, 130))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (107, 130))
903409	27223088	Warwick et al analyzed a cohort of patients with non small cell lung cancer and identified a robust association of RDW with long term survival.	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('non small cell lung cancer', 'Disease', (49, 75))	('RDW', 'Var', (115, 118))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('association', 'Interaction', (100, 111))	('non small cell lung cancer', 'Disease', 'MESH:D002289', (49, 75))	('patients', 'Species', '9606', (35, 43))
903410	27223088	A retrospective study of symptomatic multiple myeloma by Lee et al revealed elevated RDW as a predictor of enhanced systematic inflammation and poor survival.	('myeloma', 'Disease', (46, 53))	('RDW', 'MPA', (85, 88))	('elevated', 'Var', (76, 84))	('enhanced', 'PosReg', (107, 115))	('myeloma', 'Disease', 'MESH:D009101', (46, 53))	('multiple myeloma', 'Phenotype', 'HP:0006775', (37, 53))	('systematic inflammation', 'MPA', (116, 139))
903416	27223088	Our results demonstrated that a low HB/RDW ratio (<0.989) is significantly associated with poor clinical outcome and a 1.416-fold greater risk of death in ESCC patients, which was further validated by bootstrap resembling model.	('low', 'NegReg', (32, 35))	('<0.989', 'Var', (50, 56))	('patients', 'Species', '9606', (160, 168))	('death', 'Disease', 'MESH:D003643', (146, 151))	('death', 'Disease', (146, 151))	('HB/RDW', 'Protein', (36, 42))	('ESCC', 'Disease', (155, 159))
903447	26986168	Epigastric Distress Caused by Esophageal Candidiasis in 2 Patients Who Received Sorafenib Plus Radiotherapy for Hepatocellular Carcinoma: Case Report Sorafenib followed by fractionated radiotherapy (RT) has been shown to decrease the phagocytic and candidacidal activities of antifungal agents due to radiosensitization.	('Sorafenib', 'Var', (150, 159))	('Epigastric Distress', 'Disease', (0, 19))	('Sorafenib', 'Chemical', 'MESH:D000077157', (80, 89))	('Epigastric Distress', 'Phenotype', 'HP:0410019', (0, 19))	('candida', 'Species', '5476', (249, 256))	('Hepatocellular Carcinoma', 'Disease', 'MESH:D006528', (112, 136))	('Esophageal Candidiasis', 'Disease', 'MESH:D002177', (30, 52))	('Hepatocellular Carcinoma', 'Disease', (112, 136))	('Carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('Sorafenib', 'Chemical', 'MESH:D000077157', (150, 159))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('Esophageal Candidiasis', 'Disease', (30, 52))	('decrease', 'NegReg', (221, 229))	('Patients', 'Species', '9606', (58, 66))
903638	18787394	1H and I), resulting in a previously described non-synonymous Gly 266 Glu alteration in TP53 (which also confirmed in the primary tumor).	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('TP53', 'Gene', '7157', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Gly 266 Glu', 'Mutation', 'rs193920774', (62, 73))	('TP53', 'Gene', (88, 92))	('non-synonymous Gly 266 Glu alteration', 'Var', (47, 84))
903640	18787394	In addition, there is no genomic evidence for wnt pathway activation, as discerned by absence of mutations in APC and in the exon 3 "hot spot" of CTNNB1 (data not shown).	('mutations', 'Var', (97, 106))	('CTNNB1', 'Gene', '1499', (146, 152))	('absence', 'NegReg', (86, 93))	('APC', 'Disease', 'MESH:D011125', (110, 113))	('wnt pathway', 'Pathway', (46, 57))	('APC', 'Disease', (110, 113))	('CTNNB1', 'Gene', (146, 152))
903646	34010294	The acetaldehyde breath test (ABT) may demonstrate ALDH2 gene polymorphisms.	('acetaldehyde', 'Chemical', 'MESH:D000079', (4, 16))	('ALDH2', 'Gene', '217', (51, 56))	('aldehyde breath', 'Disease', (8, 23))	('aldehyde breath', 'Disease', 'MESH:D016111', (8, 23))	('ABT', 'Chemical', '-', (30, 33))	('polymorphisms', 'Var', (62, 75))	('ALDH2', 'Gene', (51, 56))	('acetaldehyde breath', 'Phenotype', 'HP:0003533', (4, 23))
903666	34010294	According to a previous report, people with ALDH2*2 variants have higher risks of head and neck and esophageal cancers, because the ALDH2 activity in their tissues is much lower compared to that in the gastrointestinal tissues of healthy people.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('activity', 'MPA', (138, 146))	('ALDH2', 'Gene', (132, 137))	('gas', 'Gene', '79447', (202, 205))	('cancers', 'Disease', (111, 118))	('esophageal cancer', 'Disease', (100, 117))	('people', 'Species', '9606', (238, 244))	('ALDH2', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lower', 'NegReg', (172, 177))	('variants', 'Var', (52, 60))	('people', 'Species', '9606', (32, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('ALDH2', 'Gene', '217', (132, 137))	('gas', 'Gene', (202, 205))	('ALDH2', 'Gene', '217', (44, 49))
903719	34010294	In this study, we hypothesized that the ABT, which accurately identifies ALDH2 inactivity noninvasively as a disease marker for superficial ESCC and superficial HPSCC treated with ESD, would exhibit clinical significance and usefulness.	('ALDH2', 'Gene', (73, 78))	('SCC', 'Gene', (141, 144))	('SCC', 'Gene', (163, 166))	('SCC', 'Gene', '6317', (141, 144))	('ALDH2', 'Gene', '217', (73, 78))	('inactivity', 'Var', (79, 89))	('ABT', 'Chemical', '-', (40, 43))	('SCC', 'Gene', '6317', (163, 166))
903774	34010294	5) Since Plos One is a general interest journal, it would be helpful to readers to add a paragraph about the why people with an ALDH2*2 variant are more at risk for head and neck cancer.	('head and neck cancer', 'Phenotype', 'HP:0012288', (165, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('variant', 'Var', (136, 143))	('head and neck cancer', 'Disease', 'MESH:D006258', (165, 185))	('people', 'Species', '9606', (113, 119))	('ALDH2', 'Gene', '217', (128, 133))	('ALDH2', 'Gene', (128, 133))
903776	34010294	Adding inactivating ALDH2 genetics leads the environment of the head and neck more at risk for DNA damage, dysplasia and cancer.	('dysplasia', 'Disease', (107, 116))	('ALDH2', 'Gene', '217', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('men', 'Species', '9606', (52, 55))	('ALDH2', 'Gene', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('dysplasia', 'Disease', 'MESH:C536170', (107, 116))	('cancer', 'Disease', (121, 127))	('inactivating', 'Var', (7, 19))	('DNA damage', 'Disease', (95, 105))
903804	34010294	If possible, ALDH2 genotyping would markedly improve the significance of the findings.	('ALDH2', 'Gene', (13, 18))	('genotyping', 'Var', (19, 29))	('improve', 'PosReg', (45, 52))	('ALDH2', 'Gene', '217', (13, 18))
903814	34010294	As it is well known that the ADH1B polymorphism (rs1229984) among the Japanese strongly influence the rate of conversation of alcohol to acetaldehyde, the alcohol flushing reaction and risks of ESCC and HPSCC.	('conversation of alcohol to acetaldehyde', 'MPA', (110, 149))	('rate', 'MPA', (102, 106))	('SCC', 'Gene', (195, 198))	('ADH1B', 'Gene', '125', (29, 34))	('flushing', 'Phenotype', 'HP:0031284', (163, 171))	('influence', 'Reg', (88, 97))	('alcohol flushing reaction', 'Disease', 'MESH:D005483', (155, 180))	('rs1229984', 'Mutation', 'rs1229984', (49, 58))	('acetaldehyde', 'Chemical', 'MESH:D000079', (137, 149))	('SCC', 'Gene', '6317', (195, 198))	('alcohol', 'Chemical', 'MESH:D000438', (126, 133))	('rs1229984', 'Var', (49, 58))	('SCC', 'Gene', (205, 208))	('alcohol', 'Chemical', 'MESH:D000438', (155, 162))	('alcohol flushing reaction', 'Disease', (155, 180))	('ADH1B', 'Gene', (29, 34))	('SCC', 'Gene', '6317', (205, 208))
903822	34010294	Individuals with ALDH2*2 genotype were expected (as shown) to be statistically higher in the SCC group than the HC group.	('ALDH2', 'Gene', '217', (17, 22))	('SCC', 'Gene', (93, 96))	('ALDH2', 'Gene', (17, 22))	('genotype', 'Var', (25, 33))	('SCC', 'Gene', '6317', (93, 96))	('higher', 'PosReg', (79, 85))
903824	34010294	Higher A/E ratio in the multiple lesion group could be due to more subject with ALDH2*2 genotype and rather than due to multiple cancer per se.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('genotype', 'Var', (88, 96))	('cancer', 'Disease', (129, 135))	('A/E ratio', 'MPA', (7, 16))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('ALDH2', 'Gene', '217', (80, 85))	('Higher', 'PosReg', (0, 6))	('ALDH2', 'Gene', (80, 85))
903829	34010294	In other words, from these data, it only be drawn to conclude that A/E ratio is a good predictor of ALDH2*2 genotypes.	('ALDH2', 'Gene', (100, 105))	('genotypes', 'Var', (108, 117))	('ALDH2', 'Gene', '217', (100, 105))
903848	34010294	"It has been reported that the reason why people with ALDH2*2 variants have a higher risk of head and neck cancer and esophageal cancer is because the activity of ALDH2 in their tissues is much lower relative to other gastrointestinal tissues.	('head and neck cancer', 'Disease', 'MESH:D006258', (93, 113))	('people', 'Species', '9606', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('ALDH2', 'Gene', (163, 168))	('gas', 'Gene', '79447', (218, 221))	('ALDH2', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('variants', 'Var', (62, 70))	('head and neck cancer', 'Phenotype', 'HP:0012288', (93, 113))	('gas', 'Gene', (218, 221))	('activity', 'MPA', (151, 159))	('ALDH2', 'Gene', '217', (163, 168))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))	('lower', 'NegReg', (194, 199))	('ALDH2', 'Gene', '217', (54, 59))
903921	32845581	In contrast, among patients with ESCC, high BMI was associated with a worse prognosis (HR, 2.26; 95% CI = 1.29-3.24).	('high BMI', 'Var', (39, 47))	('ESCC', 'Disease', (33, 37))	('patients', 'Species', '9606', (19, 27))
903935	32845581	According to the Asian standard, BMI was categorized into three groups, underweight (< 18.5 kg/m2), normal weight (18.5-23 kg/m2), and overweight or obese >=23 kg/m2).	('obese', 'Disease', (149, 154))	('18.5-23', 'Var', (115, 122))	('< 18.5', 'Var', (85, 91))	('overweight', 'Phenotype', 'HP:0025502', (135, 145))	('obese', 'Disease', 'MESH:D009765', (149, 154))
903977	32845581	The 5-year OS rates of patients with low, normal, and high BMI in the never-drinker group were 35.02%, 28.60%, and 36.08% (P = 0.011), while the 5-year OS rates were 33.78%, 34.67%, and 37.67% (P = 0.009) in the drinkers' group, respectively.	('patients', 'Species', '9606', (23, 31))	('BMI', 'MPA', (59, 62))	('low', 'NegReg', (37, 40))	('high', 'Var', (54, 58))
904007	32845581	Our study suggested that the 5-year OS rates of patients with high and normal BMI were higher than those of patients with low BMI (P = 0.014).	('OS rates', 'CPA', (36, 44))	('low BMI', 'Phenotype', 'HP:0045082', (122, 129))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (108, 116))	('high', 'Var', (62, 66))	('normal', 'Var', (71, 77))	('BMI', 'Gene', (78, 81))	('higher', 'PosReg', (87, 93))
904010	32845581	For example, Sun et al [39] indicated that patients with low BMI (< 18.5) had a 2.22 times higher risk of EC-related death than patients with a high BMI (>=18.5) among never smokers.	('patients', 'Species', '9606', (43, 51))	('low BMI', 'Phenotype', 'HP:0045082', (57, 64))	('low', 'Var', (57, 60))	('death', 'Disease', 'MESH:D003643', (117, 122))	('death', 'Disease', (117, 122))	('patients', 'Species', '9606', (128, 136))
904013	32845581	In different smoking status, the prognostic impacts of obesity and low BMI on ESCC survival varied, but could not be eliminated.	('ESCC', 'Disease', (78, 82))	('low BMI', 'Phenotype', 'HP:0045082', (67, 74))	('obesity', 'Phenotype', 'HP:0001513', (55, 62))	('low BMI', 'Var', (67, 74))	('obesity', 'Disease', 'MESH:D009765', (55, 62))	('obesity', 'Disease', (55, 62))
904119	32489452	When stratified by pathological TNM staging, the OS of EJA patients with F-NLR 2 was poor compared with that of F-NLR 0 or 1 both in stages I - II and in stages III (all p < 0.001 in the combined set).	('TNM', 'Gene', (32, 35))	('F-NLR 2', 'Var', (73, 80))	('poor', 'NegReg', (85, 89))	('TNM', 'Gene', '10178', (32, 35))	('patients', 'Species', '9606', (59, 67))
904125	32489452	tried to combine the albumin-to-globulin ratio (AGR) and PNI to establish an innovative system to estimate its prognostic value in Siewert type III EJA, and found that AGR-PNI is associated with age, tumor size, NLR and PLR (all p < 0.05), serving as an independent predictor for OS of EJA patients.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('AGR-PNI', 'Var', (168, 175))	('associated', 'Reg', (179, 189))	('albumin', 'Gene', (21, 28))	('patients', 'Species', '9606', (290, 298))	('albumin', 'Gene', '213', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('AGR', 'Chemical', '-', (168, 171))	('NLR', 'Disease', (212, 215))	('AGR', 'Chemical', '-', (48, 51))
904126	32489452	Although there was no statistically significant relationship between AGR-PNI and pathological TNM stage (p = 0.607), patients with AGR-PNI 1 or 2 had better OS rates in stages I+II and III than that with AGR-PNI 3.	('AGR', 'Chemical', '-', (131, 134))	('AGR', 'Chemical', '-', (204, 207))	('better', 'PosReg', (150, 156))	('TNM', 'Gene', '10178', (94, 97))	('AGR-PNI 1 or 2', 'Var', (131, 145))	('AGR', 'Chemical', '-', (69, 72))	('patients', 'Species', '9606', (117, 125))	('TNM', 'Gene', (94, 97))
904146	32489452	Patients with region 1 (located in exon 1: from +245 to +413 bp) hypermethylation of LOC100130476 revealed significant poorer 5-year survival rates compared with those with region 1 unmethylation of the marker (P < 0.05).	('poorer', 'NegReg', (119, 125))	('hypermethylation', 'Var', (65, 81))	('LOC100130476', 'Gene', (85, 97))	('5-year survival rates', 'CPA', (126, 147))	('Patients', 'Species', '9606', (0, 8))
904147	32489452	The Cox multivariate analysis showed that the methylation of region 1 might be an independent prognostic marker of gastric cardia adenocarcinoma.	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (115, 144))	('methylation', 'Var', (46, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('gastric cardia adenocarcinoma', 'Disease', (115, 144))
904151	32489452	Results showed that the presence of CTCs was a predictor for OS and progression-free survival, and the mRNA transcripts were associated with tumor survival.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('presence', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('associated with', 'Reg', (125, 140))	('CTCs', 'Protein', (36, 40))	('progression-free survival', 'CPA', (68, 93))	('mRNA transcripts', 'MPA', (103, 119))
904257	31125790	Based on postoperative histopathological examination of a surgical specimen, the pathological stage of the gastric tube tumor was pT3N1M0 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('pT3N1M0', 'Var', (130, 137))	('gastric tube tumor', 'Disease', 'MESH:D013274', (107, 125))	('gastric tube tumor', 'Disease', (107, 125))
904271	31125790	Experimental studies show that ligation of the left gastric artery after ischemic conditioning promotes neovascularization of the intramural vascular network in a time-dependent manner.	('ligation', 'Var', (31, 39))	('ischemic', 'Disease', 'MESH:D007511', (73, 81))	('promotes', 'PosReg', (95, 103))	('ischemic', 'Disease', (73, 81))
904420	25733817	However, a higher rate of cardiovascular events including heart failure, hospitalizations, and deaths with CDDO-Me than with placebo prompted termination of a Phase III trial in October 2012.	('CDDO-Me', 'Chemical', '-', (107, 114))	('heart failure', 'Disease', (58, 71))	('cardiovascular', 'Disease', (26, 40))	('CDDO-Me', 'Var', (107, 114))	('cardiovascular events', 'Phenotype', 'HP:0001626', (26, 47))	('hospitalizations', 'Disease', (73, 89))	('heart failure', 'Phenotype', 'HP:0001635', (58, 71))	('heart failure', 'Disease', 'MESH:D006333', (58, 71))
904437	25733817	CDDO-Me acts as an activator of the Nrf2 pathway and an inhibitor of the NF-kappaB pathway.	('NF-kappaB pathway', 'Pathway', (73, 90))	('CDDO-Me', 'Var', (0, 7))	('Nrf2', 'Gene', '4780', (36, 40))	('CDDO-Me', 'Chemical', '-', (0, 7))	('Nrf2', 'Gene', (36, 40))	('activator', 'PosReg', (19, 28))
904496	25733817	In brief, the p38 MAP kinase inhibitor SB202190 (20 muM), the PI3K inhibitor wortmannin (10 muM), the Akt inhibitor MK-2206 (2.5 muM), the mTOR inhibitor rapamycin (0.5 muM), or the AMP-kinase inhibitor Compound C (10 muM) were used alone or in combination with 0.5 muM CDDO-Me to treat the cells for 24 hours.	('MK-2206', 'Chemical', 'MESH:C548887', (116, 123))	('p38', 'Gene', (14, 17))	('muM', 'Gene', (266, 269))	('muM', 'Gene', (92, 95))	('CDDO-Me', 'Chemical', '-', (270, 277))	('mTOR', 'Gene', (139, 143))	('muM', 'Gene', '56925', (52, 55))	('muM', 'Gene', '56925', (169, 172))	('muM', 'Gene', (52, 55))	('muM', 'Gene', (169, 172))	('rapamycin', 'Chemical', 'MESH:D020123', (154, 163))	('Akt', 'Gene', (102, 105))	('muM', 'Gene', '56925', (218, 221))	('muM', 'Gene', '56925', (129, 132))	('muM', 'Gene', (129, 132))	('muM', 'Gene', (218, 221))	('Akt', 'Gene', '207', (102, 105))	('mTOR', 'Gene', '2475', (139, 143))	('p38', 'Gene', '1432', (14, 17))	('SB202190', 'Chemical', 'MESH:C090942', (39, 47))	('muM', 'Gene', '56925', (92, 95))	('wortmannin', 'Chemical', 'MESH:D000077191', (77, 87))	('SB202190', 'Var', (39, 47))	('muM', 'Gene', '56925', (266, 269))	('AMP', 'Chemical', 'MESH:D000249', (182, 185))
904502	25733817	CM-H2DCFDA is cleaved by intracellular esterases to produce an impermeable, nonfluorescent active form, which further reacts with ROS to form a fluorescent product.	('ROS', 'Chemical', 'MESH:D017382', (130, 133))	('CM-H2DCFDA', 'Var', (0, 10))	('ROS', 'Protein', (130, 133))	('H2DCFDA', 'Chemical', 'MESH:C110400', (3, 10))	('nonfluorescent active', 'MPA', (76, 97))	('impermeable', 'MPA', (63, 74))
904515	25733817	When cells were treated with CDDO-Me at concentrations from 0.01 to 5 muM for 24 and 48 hours, the percentage of cellular viability of Ec109 was 102.8%-13.5% and 102.9%-3.2%, respectively; the percentage of cellular viability of KYSE70 was 106.7%-11.6% and 101.2%-8.9%, respectively; and the percentage of cellular viability of Het-1A was 103.5%-68.6% and 98.8%-48.4%, respectively.	('Ec109', 'Var', (135, 140))	('cellular', 'CPA', (207, 215))	('CDDO-Me', 'Chemical', '-', (29, 36))	('muM', 'Gene', '56925', (70, 73))	('muM', 'Gene', (70, 73))
904523	25733817	As shown in Figure 2A, both Ec109 and KYSE70 cells were arrested in G2/M phase after incubation with CDDO-Me for 24 hours, especially at the high concentration.	('KYSE70', 'Var', (38, 44))	('CDDO-Me', 'Chemical', '-', (101, 108))	('G2/M phase', 'CPA', (68, 78))
904536	25733817	A significant decrease in the Cdc2 and cyclin B1 expression level was observed in human ESCC cells treated with CDDO-Me.	('expression level', 'MPA', (49, 65))	('Cdc2', 'Gene', (30, 34))	('CDDO-Me', 'Chemical', '-', (112, 119))	('decrease', 'NegReg', (14, 22))	('Cdc2', 'Gene', '983', (30, 34))	('cyclin B1', 'Gene', '891', (39, 48))	('cyclin B1', 'Gene', (39, 48))	('CDDO-Me', 'Var', (112, 119))	('human', 'Species', '9606', (82, 87))
904537	25733817	In Ec109 cells, treatment with CDDO-Me at 0.25, 0.5, and 1.0 muM for 24 hours significantly decreased the level of Cdc2 by 24.2%, 30.3%, and 44.9% (P<0.05 by one-way ANOVA; Figure 2C and D), and suppressed the expression of cyclin B1 by 14.4%, 46.1%, and 41.6%, respectively, compared to the control cells (P<0.05 or 0.01 by one-way ANOVA; Figure 2C and D).	('cyclin B1', 'Gene', '891', (224, 233))	('cyclin B1', 'Gene', (224, 233))	('Cdc2', 'Gene', '983', (115, 119))	('level', 'MPA', (106, 111))	('CDDO-Me', 'Var', (31, 38))	('muM', 'Gene', (61, 64))	('suppressed', 'NegReg', (195, 205))	('expression', 'MPA', (210, 220))	('CDDO-Me', 'Chemical', '-', (31, 38))	('Cdc2', 'Gene', (115, 119))	('decreased', 'NegReg', (92, 101))	('men', 'Species', '9606', (21, 24))	('muM', 'Gene', '56925', (61, 64))
904548	25733817	Similarly, there was also a significant increase in the expression of p21Waf1/Cip1 in KYSE70 cells treated with CDDM-Me.	('Cip1', 'Gene', '1026', (78, 82))	('increase', 'PosReg', (40, 48))	('Cip1', 'Gene', (78, 82))	('expression', 'MPA', (56, 66))	('CDDM-Me', 'Chemical', '-', (112, 119))	('CDDM-Me', 'Var', (112, 119))
904553	25733817	To elucidate whether CDDO-Me decreases cell survival through the induction of apoptosis in human ESCC cells, we examined the effects of CDDO-Me on apoptosis in Ec109 and KYSE70 cells using flow cytometry.	('CDDO-Me', 'Var', (21, 28))	('CDDO-Me', 'Chemical', '-', (136, 143))	('decreases', 'NegReg', (29, 38))	('CDDO-Me', 'Chemical', '-', (21, 28))	('cell survival', 'CPA', (39, 52))	('human', 'Species', '9606', (91, 96))
904564	25733817	Incubation of Ec109 cells with CDDO-Me at 1.0 muM significantly decreased Bcl-xl and Bcl-2 expression level by 34.7% and 98.3%, respectively, compared to the control cells (P<0.05, 0.01, or 0.001 by one-way ANOVA; Figure 3C and D), but significantly increased the level of Bax and PUMA by 90.9% and 33.5% (P<0.05 or 0.01 by one-way ANOVA; Figure 3C and D), respectively.	('CDDO-Me', 'Var', (31, 38))	('Bax', 'Gene', '581', (273, 276))	('Bax', 'Gene', (273, 276))	('Bcl-xl', 'Gene', (74, 80))	('Bcl-2', 'Gene', '596', (85, 90))	('muM', 'Gene', '56925', (46, 49))	('Bcl-2', 'Gene', (85, 90))	('CDDO-Me', 'Chemical', '-', (31, 38))	('increased', 'PosReg', (250, 259))	('muM', 'Gene', (46, 49))	('Bcl-xl', 'Gene', '598', (74, 80))	('PUMA', 'MPA', (281, 285))	('decreased', 'NegReg', (64, 73))
904574	25733817	Treatment of Ec109 and KYSE70 cells with CDDO-Me for 24 hours significantly increased the release of cytochrome c. Taken together, CDDO-Me decreases cell survival through the induction of apoptosis via activation of mitochondrial pathway in human ESCC cells.	('CDDO-Me', 'Chemical', '-', (131, 138))	('men', 'Species', '9606', (5, 8))	('CDDO-Me', 'Chemical', '-', (41, 48))	('cytochrome c', 'Gene', (101, 113))	('human', 'Species', '9606', (241, 246))	('apoptosis', 'CPA', (188, 197))	('decreases', 'NegReg', (139, 148))	('cytochrome c', 'Gene', '54205', (101, 113))	('cell survival', 'CPA', (149, 162))	('CDDO-Me', 'Var', (131, 138))	('activation', 'PosReg', (202, 212))	('mitochondrial pathway', 'Pathway', (216, 237))
904588	25733817	CDDO-Me treatment led to a marked decrease in p-mTOR at Ser2448 in both Ec109 and KYSE70 cells.	('mTOR', 'Gene', '2475', (48, 52))	('Ser2448', 'Chemical', '-', (56, 63))	('mTOR', 'Gene', (48, 52))	('decrease', 'NegReg', (34, 42))	('CDDO-Me', 'Chemical', '-', (0, 7))	('Ser2448', 'Var', (56, 63))	('men', 'Species', '9606', (13, 16))
904594	25733817	CDDO-Me treatment significantly decreased the levels of p-PI3K at Tyr458 and p-Akt at Ser473 but increased the levels of p-AMPK at Thr172, p-p38 MAPK at Thr180, and PTEN in a dose-dependent manner in both Ec109 and KYSE70 cells.	('Ser473', 'Chemical', '-', (86, 92))	('increased', 'PosReg', (97, 106))	('p38 MAPK', 'Gene', (141, 149))	('men', 'Species', '9606', (13, 16))	('Thr172', 'Chemical', '-', (131, 137))	('Tyr458', 'Var', (66, 72))	('p38 MAPK', 'Gene', '1432', (141, 149))	('AMPK', 'Gene', (123, 127))	('AMPK', 'Gene', '5562', (123, 127))	('Thr180', 'Chemical', '-', (153, 159))	('decreased', 'NegReg', (32, 41))	('p-PI3K', 'MPA', (56, 62))	('Akt', 'Gene', '207', (79, 82))	('Tyr458', 'Chemical', '-', (66, 72))	('CDDO-Me', 'Chemical', '-', (0, 7))	('PTEN', 'Gene', (165, 169))	('Akt', 'Gene', (79, 82))	('PTEN', 'Gene', '5728', (165, 169))
904599	25733817	In KYSE70 cells, the level of beclin 1 was increased by 38.0%, 71.4%, and 90.4% at 0.25, 0.5, and 1.0 muM CDDO-Me, respectively, compared to the control cells (P<0.05 by one-way ANOVA; Figure 4D and E).	('CDDO-Me', 'Var', (106, 113))	('muM', 'Gene', (102, 105))	('KYSE70', 'Var', (3, 9))	('beclin 1', 'Gene', '8678', (30, 38))	('increased', 'PosReg', (43, 52))	('CDDO-Me', 'Chemical', '-', (106, 113))	('beclin 1', 'Gene', (30, 38))	('muM', 'Gene', '56925', (102, 105))	('0.25', 'Var', (83, 87))	('0.5', 'Var', (89, 92))
904604	25733817	CDDO-Me significantly increased the ratio of LC3-II over LC3-I from 0.57 (basal) to 0.76-1.28 (P<0.05 or 0.001 by one-way ANOVA; Figure 4D and E).	('LC3', 'Gene', (57, 60))	('CDDO-Me', 'Var', (0, 7))	('LC3', 'Gene', '84557', (45, 48))	('LC3', 'Gene', (45, 48))	('increased', 'PosReg', (22, 31))	('CDDO-Me', 'Chemical', '-', (0, 7))	('LC3', 'Gene', '84557', (57, 60))
904608	25733817	The results demonstrated that CDDO-Me predominantly induced apoptosis, with autophagy being the minor pathway in programmed cell death of Ec109 and KYSE70 cells.	('CDDO-Me', 'Chemical', '-', (30, 37))	('autophagy', 'CPA', (76, 85))	('CDDO-Me', 'Var', (30, 37))	('apoptosis', 'CPA', (60, 69))	('induced', 'Reg', (52, 59))
904613	25733817	In Ec109 cells, the percentage of autophagic cells was increased 6.6- and 13.8-fold after the incubation with 20 muM SB202190 and 10 muM Compound C, respectively.	('muM', 'Gene', (113, 116))	('muM', 'Gene', (133, 136))	('SB202190', 'Chemical', 'MESH:C090942', (117, 125))	('increased', 'PosReg', (55, 64))	('SB202190', 'Var', (117, 125))	('muM', 'Gene', '56925', (113, 116))	('muM', 'Gene', '56925', (133, 136))
904614	25733817	The percentage of apoptotic cells was increased 4.0-fold after 24-hour incubation with 20 muM SB202190.	('muM', 'Gene', '56925', (90, 93))	('SB202190', 'Chemical', 'MESH:C090942', (94, 102))	('apoptotic cells', 'CPA', (18, 33))	('muM', 'Gene', (90, 93))	('SB202190', 'Var', (94, 102))
904615	25733817	In KYSE70 cells, the number of autophagic cells were increased by 1,664.8% when treated with 20 muM SB202190 for 24 hours and apoptotic cells were increased by 292.9% when treated with 10 muM Compound C for 24 hours.	('SB202190', 'Chemical', 'MESH:C090942', (100, 108))	('muM', 'Gene', '56925', (96, 99))	('increased', 'PosReg', (147, 156))	('apoptotic cells', 'CPA', (126, 141))	('muM', 'Gene', (188, 191))	('muM', 'Gene', (96, 99))	('SB202190', 'Var', (100, 108))	('increased', 'PosReg', (53, 62))	('muM', 'Gene', '56925', (188, 191))
904616	25733817	In addition, 2.5 muM MK-2206 also enhanced the autophagy of KYSE70 cells.	('muM', 'Gene', '56925', (17, 20))	('autophagy of KYSE70 cells', 'CPA', (47, 72))	('enhanced', 'PosReg', (34, 42))	('muM', 'Gene', (17, 20))	('MK-2206', 'Var', (21, 28))	('MK-2206', 'Chemical', 'MESH:C548887', (21, 28))
904619	25733817	0.5 muM rapamycin or 2.5 muM MK-2206 significantly enhanced the CDDO-Me-induced autophagy, while incubation with 20 muM SB202190 significantly enhanced CDDO-Me-induced apoptosis.	('muM', 'Gene', '56925', (4, 7))	('rapamycin', 'Chemical', 'MESH:D020123', (8, 17))	('muM', 'Gene', (116, 119))	('enhanced', 'PosReg', (143, 151))	('muM', 'Gene', (25, 28))	('muM', 'Gene', (4, 7))	('enhanced', 'PosReg', (51, 59))	('CDDO-Me', 'Chemical', '-', (64, 71))	('MK-2206', 'Chemical', 'MESH:C548887', (29, 36))	('muM', 'Gene', '56925', (25, 28))	('MK-2206', 'Var', (29, 36))	('CDDO-Me-induced autophagy', 'CPA', (64, 89))	('SB202190', 'Chemical', 'MESH:C090942', (120, 128))	('muM', 'Gene', '56925', (116, 119))	('CDDO-Me', 'Chemical', '-', (152, 159))
904622	25733817	In KYSE70 cells, the number of CDDO-Me-induced autophagic cells was increased by 254.2%, 260.4%, and 1,397.6% when treated with 0.5 muM rapamycin, 10 muM wortmannin, or 2.5 muM MK-2206 for 24 hours, respectively, and CDDO-Me-induced apoptotic cells were increased by 58.1%, 69.5%, and 146.7% when treated with 10 muM wortmannin, 10 muM Compound C, or 20 muM SB202190 for 24 hours, respectively (Figure 5A-C).	('SB202190', 'Chemical', 'MESH:C090942', (358, 366))	('muM', 'Gene', '56925', (313, 316))	('muM', 'Gene', (313, 316))	('MK-2206', 'Chemical', 'MESH:C548887', (177, 184))	('CDDO-Me', 'Chemical', '-', (31, 38))	('SB202190', 'Var', (358, 366))	('rapamycin', 'Chemical', 'MESH:D020123', (136, 145))	('muM', 'Gene', '56925', (150, 153))	('wortmannin', 'Chemical', 'MESH:D000077191', (317, 327))	('increased', 'PosReg', (68, 77))	('muM', 'Gene', (150, 153))	('CDDO-Me-induced apoptotic cells', 'CPA', (217, 248))	('muM', 'Gene', '56925', (173, 176))	('CDDO-Me', 'Chemical', '-', (217, 224))	('muM', 'Gene', (173, 176))	('muM', 'Gene', '56925', (332, 335))	('increased', 'PosReg', (254, 263))	('muM', 'Gene', (332, 335))	('muM', 'Gene', '56925', (354, 357))	('wortmannin', 'Chemical', 'MESH:D000077191', (154, 164))	('muM', 'Gene', '56925', (132, 135))	('muM', 'Gene', (354, 357))	('muM', 'Gene', (132, 135))	('CDDO-Me-induced autophagic cells', 'CPA', (31, 63))
904624	25733817	PI3K and AMPK play an important role in the interplay for their dual modulating functions in both CDDO-Me-induced autophagy and apoptosis.	('CDDO-Me-induced', 'Gene', (98, 113))	('PI3K', 'Var', (0, 4))	('AMPK', 'Gene', '5562', (9, 13))	('AMPK', 'Gene', (9, 13))	('autophagy', 'CPA', (114, 123))	('CDDO-Me', 'Chemical', '-', (98, 105))	('apoptosis', 'CPA', (128, 137))
904626	25733817	The intracellular level of ROS was significantly decreased by CDDO-Me in both cell lines.	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('intracellular level of ROS', 'MPA', (4, 30))	('CDDO-Me', 'Var', (62, 69))	('decreased', 'NegReg', (49, 58))	('CDDO-Me', 'Chemical', '-', (62, 69))
904627	25733817	In Ec109 cells, treatment with CDDO-Me at 0.1 and 1.0 muM for 24 hours reduced the intracellular level of ROS by 21.1% and 36.8%, respectively, compared to the control cells (P<0.01 or 0.001 by one-way ANOVA; Figure 6A).	('muM', 'Gene', (54, 57))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))	('CDDO-Me', 'Var', (31, 38))	('intracellular level of ROS', 'MPA', (83, 109))	('reduced', 'NegReg', (71, 78))	('muM', 'Gene', '56925', (54, 57))	('CDDO-Me', 'Chemical', '-', (31, 38))	('men', 'Species', '9606', (21, 24))
904652	25733817	These results suggest that CDDO-Me attenuates the invasive capacity of human ESCC cells in vitro.	('attenuates', 'NegReg', (35, 45))	('invasive capacity of human ESCC cells', 'CPA', (50, 87))	('CDDO-Me', 'Var', (27, 34))	('CDDO-Me', 'Chemical', '-', (27, 34))	('human', 'Species', '9606', (71, 76))
904658	25733817	The E-cadherin expression level was increased 2.6-fold when treated with 1.0 muM CDDO-Me for 24 hours, compared to the control cells (P<0.05 by one-way ANOVA; Figure 7B and C).	('muM', 'Gene', (77, 80))	('CDDO-Me', 'Chemical', '-', (81, 88))	('increased', 'PosReg', (36, 45))	('muM', 'Gene', '56925', (77, 80))	('E-cadherin', 'Gene', '999', (4, 14))	('E-cadherin', 'Gene', (4, 14))	('CDDO-Me', 'Var', (81, 88))
904679	25733817	These results suggested that CDDO-Me inhibits EMT in human ESCC cells.	('CDDO-Me', 'Chemical', '-', (29, 36))	('EMT in human ESCC cells', 'CPA', (46, 69))	('human', 'Species', '9606', (53, 58))	('inhibits', 'NegReg', (37, 45))	('CDDO-Me', 'Var', (29, 36))
904690	25733817	Incubation of Ec109 cells with CDDO-Me at 1.0 muM significantly decreased Oct-4, Sox-2, Nanog, and Bmi-1 expression levels by 44.3%, 53.4%, 26.8%, and 44.2%, respectively, compared to the control cells (Figure 8A and B).	('Sox-2', 'Gene', (81, 86))	('Sox-2', 'Gene', '6657', (81, 86))	('Oct-4', 'Gene', (74, 79))	('CDDO-Me', 'Var', (31, 38))	('Nanog', 'Gene', '79923', (88, 93))	('Bmi-1', 'Gene', '648', (99, 104))	('muM', 'Gene', '56925', (46, 49))	('Nanog', 'Gene', (88, 93))	('Bmi-1', 'Gene', (99, 104))	('Oct-4', 'Gene', '5460', (74, 79))	('expression levels', 'MPA', (105, 122))	('CDDO-Me', 'Chemical', '-', (31, 38))	('8A and B', 'Gene', '23345', (210, 218))	('muM', 'Gene', (46, 49))	('decreased', 'NegReg', (64, 73))
904698	25733817	These results indicate that CDDO-Me suppresses the stemness of human ESCC cells.	('human', 'Species', '9606', (63, 68))	('stemness of human ESCC cells', 'CPA', (51, 79))	('suppresses', 'NegReg', (36, 46))	('CDDO-Me', 'Var', (28, 35))	('CDDO-Me', 'Chemical', '-', (28, 35))
904707	25733817	The present study showed that CDDO-Me significantly inhibited the growth of Ec109 and KYSE70 cells.	('KYSE70 cells', 'CPA', (86, 98))	('growth', 'CPA', (66, 72))	('CDDO-Me', 'Chemical', '-', (30, 37))	('inhibited', 'NegReg', (52, 61))	('CDDO-Me', 'Var', (30, 37))
904710	25733817	Cell cycle control is one of the major regulatory mechanisms of cell growth, and uncontrolled cell division or propagation of damaged DNA can contribute to genomic instability and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('propagation', 'CPA', (111, 122))	('tumor', 'Disease', (180, 185))	('genomic instability', 'CPA', (156, 175))	('uncontrolled', 'Var', (81, 93))	('contribute', 'Reg', (142, 152))
904730	25733817	Our study clearly showed that after 24-hour treatment with CDDO-Me, the expression of cleaved caspase-3 and -9 and PARP was significantly increased.	('caspase-3', 'Gene', (94, 103))	('increased', 'PosReg', (138, 147))	('men', 'Species', '9606', (49, 52))	('CDDO-Me', 'Var', (59, 66))	('PARP', 'Gene', '142', (115, 119))	('expression', 'MPA', (72, 82))	('caspase-3', 'Gene', '836', (94, 103))	('cleaved', 'MPA', (86, 93))	('CDDO-Me', 'Chemical', '-', (59, 66))	('PARP', 'Gene', (115, 119))
904731	25733817	These data indicate that CDDO-Me induces the apoptosis of human ESCC cells through mitochondrial membrane dysfunction.	('mitochondrial membrane dysfunction', 'MPA', (83, 117))	('human', 'Species', '9606', (58, 63))	('CDDO-Me', 'Var', (25, 32))	('CDDO-Me', 'Chemical', '-', (25, 32))	('apoptosis', 'CPA', (45, 54))
904734	25733817	These findings have shed light from different directions on the potential of modulating autophagy as a novel therapeutic strategy for malignant diseases.	('autophagy', 'CPA', (88, 97))	('malignant diseases', 'Disease', 'MESH:D009369', (134, 152))	('malignant diseases', 'Disease', (134, 152))	('modulating', 'Var', (77, 87))
904752	25733817	The results showed that CDDO-Me suppressed the phosphorylation of PI3K and Akt but elevated AMPK, p-p38 MAPK, and PTEN expression levels in both Ec109 and KYSE70 cells.	('expression levels', 'MPA', (119, 136))	('p38 MAPK', 'Gene', '1432', (100, 108))	('Akt', 'Gene', '207', (75, 78))	('AMPK', 'Gene', '5562', (92, 96))	('phosphorylation', 'MPA', (47, 62))	('AMPK', 'Gene', (92, 96))	('CDDO-Me', 'Var', (24, 31))	('PTEN', 'Gene', (114, 118))	('Akt', 'Gene', (75, 78))	('PTEN', 'Gene', '5728', (114, 118))	('CDDO-Me', 'Chemical', '-', (24, 31))	('elevated', 'PosReg', (83, 91))	('p38 MAPK', 'Gene', (100, 108))	('PI3K', 'Pathway', (66, 70))	('suppressed', 'NegReg', (32, 42))
904754	25733817	Autophagy can be activated in response to anticancer therapy by apoptosis-inducing agents that limit drug efficacy, and blockage of autophagy can facilitate apoptosis.	('limit drug efficacy', 'Phenotype', 'HP:0020173', (95, 114))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('apoptosis', 'CPA', (157, 166))	('cancer', 'Disease', (46, 52))	('autophagy', 'CPA', (132, 141))	('facilitate', 'PosReg', (146, 156))	('activated', 'PosReg', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('Autophagy', 'CPA', (0, 9))	('blockage', 'Var', (120, 128))
904764	25733817	Binding of AMP to the gamma subunit allosterically activates the complex, making it a more attractive substrate for phosphorylation at Thr172 in the activation loop of the alpha subunit by its major upstream AMPK kinase.	('activates', 'PosReg', (51, 60))	('AMPK', 'Gene', '5562', (208, 212))	('AMPK', 'Gene', (208, 212))	('Thr172', 'Chemical', '-', (135, 141))	('AMP', 'Chemical', 'MESH:D000249', (208, 211))	('AMP', 'Chemical', 'MESH:D000249', (11, 14))	('Thr172', 'Var', (135, 141))
904767	25733817	Previous studies have found that CDDO-Me inhibited the proliferation of cancer cells via the ROS generation.	('CDDO-Me', 'Chemical', '-', (33, 40))	('ROS generation', 'CPA', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ROS', 'Chemical', 'MESH:D017382', (93, 96))	('inhibited', 'NegReg', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('CDDO-Me', 'Var', (33, 40))	('cancer', 'Disease', (72, 78))
904768	25733817	In contrast, the results of the current study showed that CDDO-Me attenuated the ROS level in human ESCC cells.	('ROS level', 'MPA', (81, 90))	('CDDO-Me', 'Var', (58, 65))	('attenuated', 'NegReg', (66, 76))	('human', 'Species', '9606', (94, 99))	('CDDO-Me', 'Chemical', '-', (58, 65))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))
904772	25733817	Subsequently, we found that CDDO-Me induced the nuclear translocation of Nrf2 and activated the downstream target genes, such as HO-1, NQO1, and GST, especially at the lower concentration.	('NQO1', 'Gene', (135, 139))	('NQO1', 'Gene', '1728', (135, 139))	('nuclear translocation', 'MPA', (48, 69))	('GST', 'Gene', (145, 148))	('activated', 'PosReg', (82, 91))	('GST', 'Gene', '373156', (145, 148))	('Nrf2', 'Gene', '4780', (73, 77))	('CDDO-Me', 'Var', (28, 35))	('HO-1', 'Gene', (129, 133))	('HO-1', 'Gene', '3162', (129, 133))	('Nrf2', 'Gene', (73, 77))	('CDDO-Me', 'Chemical', '-', (28, 35))
904778	25733817	Our findings indicated that following treatment with 0.5 muM CDDO-Me for 24 hours, the invasive ability of both Ec109 and KYSE70 cells was remarkably reduced.	('CDDO-Me', 'Var', (61, 68))	('muM', 'Gene', (57, 60))	('CDDO-Me', 'Chemical', '-', (61, 68))	('men', 'Species', '9606', (43, 46))	('reduced', 'NegReg', (150, 157))	('muM', 'Gene', '56925', (57, 60))	('invasive ability of', 'CPA', (87, 106))
904786	25733817	Interestingly, here we showed that incubation of CDDO-Me led to a reversion of EMT progress, characterized by decreased expression of transcription factors Snail, Slug, and ZEB1, and mesenchymal markers vimentin and N-cadherin, and increased expression of epithelial markers E-cadherin, and tight junction proteins ZO-1 and claudin 1, which was in agreement with the cell invasion assay of human ESCC cell lines in vitro.	('expression', 'MPA', (242, 252))	('CDDO-Me', 'Var', (49, 56))	('Slug', 'Gene', '6591', (163, 167))	('E-cadherin', 'Gene', (275, 285))	('E-cadherin', 'Gene', '999', (275, 285))	('CDDO-Me', 'Chemical', '-', (49, 56))	('Snail', 'Gene', (156, 161))	('expression', 'MPA', (120, 130))	('ZEB1', 'Gene', (173, 177))	('human', 'Species', '9606', (390, 395))	('decreased', 'NegReg', (110, 119))	('N-cadherin', 'Gene', (216, 226))	('men', 'Species', '9606', (205, 208))	('increased', 'PosReg', (232, 241))	('N-cadherin', 'Gene', '1000', (216, 226))	('Slug', 'Gene', (163, 167))	('Snail', 'Gene', '6615', (156, 161))	('ZO-1 and claudin 1', 'Gene', '7082;9076', (315, 333))	('ZEB1', 'Gene', '6935', (173, 177))	('vimentin', 'Gene', '7431', (203, 211))	('EMT progress', 'CPA', (79, 91))	('men', 'Species', '9606', (353, 356))	('vimentin', 'Gene', (203, 211))
904796	25733817	We demonstrated that CDDO-Me induced cell cycle arrest, apoptosis, and autophagy, and inhibited ROS level, cell invasion, EMT, and stemness in ESCC cells.	('CDDO-Me', 'Var', (21, 28))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (37, 54))	('cell invasion', 'CPA', (107, 120))	('ESCC', 'Disease', (143, 147))	('ROS level', 'MPA', (96, 105))	('CDDO-Me', 'Chemical', '-', (21, 28))	('autophagy', 'CPA', (71, 80))	('inhibited', 'NegReg', (86, 95))	('apoptosis', 'CPA', (56, 65))	('cell cycle arrest', 'CPA', (37, 54))	('stemness', 'CPA', (131, 139))	('EMT', 'CPA', (122, 125))
904797	25733817	Induction of apoptosis by CDDO-Me is via activation of the mitochondrial pathway, while the induction of autophagy is via the inhibition of the PI3K/Akt/mTOR pathway.	('Akt', 'Gene', (149, 152))	('mTOR', 'Gene', (153, 157))	('CDDO-Me', 'Chemical', '-', (26, 33))	('mTOR', 'Gene', '2475', (153, 157))	('apoptosis', 'CPA', (13, 22))	('inhibition', 'NegReg', (126, 136))	('Akt', 'Gene', '207', (149, 152))	('CDDO-Me', 'Var', (26, 33))	('autophagy', 'CPA', (105, 114))	('activation', 'PosReg', (41, 51))	('mitochondrial pathway', 'Pathway', (59, 80))
904805	25407528	A growing body of evidence suggests that dysregulation of any of the PLG/PLA system components may result in tumor growth and metastasis formation.	('result', 'Reg', (99, 105))	('PLA', 'Gene', (73, 76))	('dysregulation', 'Var', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('PLA', 'Gene', '5340', (73, 76))
904828	25407528	Activation of PAR-1 by PLA induces Cyr61 gene expression in fibroblasts and cleavage of PAR-4 activates platelets.	('Cyr61', 'Gene', (35, 40))	('Cyr61', 'Gene', '3491', (35, 40))	('PLA', 'Gene', '5340', (23, 26))	('cleavage', 'Var', (76, 84))	('PAR-4', 'Gene', '9002', (88, 93))	('PAR-4', 'Gene', (88, 93))	('PAR-1', 'Gene', '2149', (14, 19))	('PAR-1', 'Gene', (14, 19))	('PLA', 'Gene', (23, 26))
904838	25407528	In the MMTV-PymT model of mammary gland carcinogenesis, PLG deficiency markedly reduced the number of spontaneous pulmonary metastases pointing towards the in vivo role of PLG in tumor spread.	('carcinogenesis', 'Disease', 'MESH:D063646', (40, 54))	('deficiency', 'Var', (60, 70))	('carcinogenesis', 'Disease', (40, 54))	('PLG', 'Gene', (56, 59))	('reduced', 'NegReg', (80, 87))	('pulmonary metastases', 'Disease', (114, 134))	('pulmonary metastases', 'Disease', 'MESH:D009362', (114, 134))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('MMTV', 'Species', '11757', (7, 11))	('tumor', 'Disease', (179, 184))
904873	25407528	Here, (i) ENO-1 on monocytes, neurons, carcinoma cells, lymphoid cells, myoblasts and pathogenic bacteria; (ii) CK8 on carcinoma cells; (iii) p11 on endothelial cells; and (iv) glyceraldehyde-3-phosphate dehydrogenase (GAPDH) on bacteria are the best characterized ones.	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (177, 217))	('GAPDH', 'Gene', '2597', (219, 224))	('carcinoma', 'Disease', (119, 128))	('ENO-1', 'Gene', (10, 15))	('GAPDH', 'Gene', (219, 224))	('carcinoma', 'Disease', 'MESH:D002277', (39, 48))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (177, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('p11', 'Gene', (142, 145))	('carcinoma', 'Disease', 'MESH:D002277', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinoma', 'Disease', (39, 48))	('ENO-1', 'Gene', '2023', (10, 15))	('CK8', 'Var', (112, 115))	('p11', 'Gene', '6281', (142, 145))
904898	25407528	Moreover, antibodies directed against ENO-1 were found in sera from NSCLC patients and were more prevalent in advanced stages of the disease.	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('prevalent', 'Reg', (97, 106))	('SCLC', 'Phenotype', 'HP:0030357', (69, 73))	('ENO-1', 'Gene', (38, 43))	('patients', 'Species', '9606', (74, 82))	('ENO-1', 'Gene', '2023', (38, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('antibodies', 'Var', (10, 20))	('NSCLC', 'Disease', (68, 73))	('found', 'Reg', (49, 54))
904904	25407528	In agreement with these results, Tu and colleagues reported that knockdown of ENO-1 in human breast cancer cells results in suppression of cell proliferation and increased sensitivity to 4-OHT.	('increased', 'PosReg', (162, 171))	('human', 'Species', '9606', (87, 92))	('suppression', 'NegReg', (124, 135))	('ENO-1', 'Gene', '2023', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('sensitivity to 4-OHT', 'MPA', (172, 192))	('cell proliferation', 'CPA', (139, 157))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('knockdown', 'Var', (65, 74))	('4-OHT', 'Chemical', 'MESH:C032278', (187, 192))	('ENO-1', 'Gene', (78, 83))
904915	25407528	The vast majority of the studies dedicated to the role of ENO-1 in cancer biology describe changes in total ENO-1 expression and the impact of these alterations on cell proliferation, viability, and activation of gene transcription.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('changes', 'Reg', (91, 98))	('ENO-1', 'Gene', '2023', (108, 113))	('alterations', 'Var', (149, 160))	('cancer', 'Disease', (67, 73))	('gene transcription', 'MPA', (213, 231))	('ENO-1', 'Gene', (58, 63))	('cell proliferation', 'CPA', (164, 182))	('activation', 'PosReg', (199, 209))	('viability', 'CPA', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('ENO-1', 'Gene', (108, 113))	('ENO-1', 'Gene', '2023', (58, 63))	('expression', 'MPA', (114, 124))
904919	25407528	The same group further demonstrates that blockage of cell surface-bound ENO-1 reduces PLA-dependent ECM breakdown and thus cell invasion resulting in diminished metastatic potential of lung cancer cells in vivo.	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('ENO-1', 'Gene', '2023', (72, 77))	('cell invasion', 'CPA', (123, 136))	('diminished', 'NegReg', (150, 160))	('lung cancer', 'Disease', (185, 196))	('ENO-1', 'Gene', (72, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('reduces', 'NegReg', (78, 85))	('blockage', 'Var', (41, 49))	('metastatic potential of', 'CPA', (161, 184))	('PLA', 'Gene', '5340', (86, 89))	('PLA', 'Gene', (86, 89))
904937	25407528	Besides breast and lung cancer, abnormal CK8 expression has been linked to the pathogenesis of other human carcinomas including oral squamous cell carcinoma, erythroleukemia, pancreatic and colon cancer.	('erythroleukemia', 'Disease', (158, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('linked', 'Reg', (65, 71))	('leukemia', 'Phenotype', 'HP:0001909', (165, 173))	('carcinomas', 'Disease', (107, 117))	('CK8', 'Gene', (41, 44))	('breast and lung cancer', 'Disease', 'MESH:D001943', (8, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('colon cancer', 'Phenotype', 'HP:0003003', (190, 202))	('human', 'Species', '9606', (101, 106))	('pancreatic and colon cancer', 'Disease', 'MESH:D010190', (175, 202))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (133, 156))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('carcinomas', 'Disease', 'MESH:D002277', (107, 117))	('erythroleukemia', 'Disease', 'MESH:D004915', (158, 173))	('expression', 'MPA', (45, 55))	('abnormal', 'Var', (32, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('squamous cell carcinoma', 'Disease', (133, 156))
904943	25407528	These observations strongly suggest that the presence of CK8 in sera of patients is a cause rather than a consequence of esophageal cancer.	('esophageal cancer', 'Disease', (121, 138))	('CK8', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('presence', 'Var', (45, 53))	('patients', 'Species', '9606', (72, 80))
904945	25407528	Mice overexpressing CK8 in epidermis developed severe epidermal and hair follicle dysplasia leading to the development of areas of neoplastic transformation.	('CK8', 'Var', (20, 23))	('overexpressing', 'Var', (5, 19))	('hair follicle dysplasia', 'Disease', 'MESH:D000072717', (68, 91))	('hair follicle dysplasia', 'Disease', (68, 91))	('Mice', 'Species', '10090', (0, 4))
904972	25407528	Accordingly, re-expression of ANX2 inhibited migration of cancer cells without affecting their proliferation and apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ANX2', 'Gene', '302', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('inhibited', 'NegReg', (35, 44))	('re-expression', 'Var', (13, 26))	('cancer', 'Disease', (58, 64))	('ANX2', 'Gene', (30, 34))
904978	25407528	Recent studies revealed the importance of ANX2 posttranslational modifications for its transport to the cell surface and thus invasive and metastatic potential of cancer cells, supporting previously published observations.	('ANX2', 'Gene', (42, 46))	('transport to the cell surface', 'MPA', (87, 116))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ANX2', 'Gene', '302', (42, 46))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('posttranslational', 'Var', (47, 64))
904979	25407528	An association between abnormal ANX2 expression and progression of cancer was also observed in patients with renal and ovarian carcinoma.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('renal and ovarian carcinoma', 'Disease', 'MESH:D007680', (109, 136))	('cancer', 'Disease', (67, 73))	('patients', 'Species', '9606', (95, 103))	('ANX2', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (119, 136))	('abnormal', 'Var', (23, 31))	('expression', 'MPA', (37, 47))	('observed', 'Reg', (83, 91))	('ANX2', 'Gene', '302', (32, 36))
904984	25407528	This study strongly suggests that interference with ANX-2-mediated pericellular proteolytic activity may provide a novel strategy for specific inhibition of neoangiogenesis in human breast cancer.	('ANX-2', 'Gene', '302', (52, 57))	('ANX-2', 'Gene', (52, 57))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('breast cancer', 'Disease', (182, 195))	('neoangiogenesis', 'CPA', (157, 172))	('human', 'Species', '9606', (176, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('interference', 'Var', (34, 46))	('inhibition', 'NegReg', (143, 153))
905003	25407528	Abnormal organization of ACT into microfilaments seems to be one of the main features of colon carcinoma as well.	('colon carcinoma', 'Disease', 'MESH:D015179', (89, 104))	('colon carcinoma', 'Disease', (89, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('Abnormal', 'Var', (0, 8))	('ACT', 'Protein', (25, 28))
905007	25407528	Collectively, all these findings imply that dysregulated expression of ACT and its abnormal compartmentalization determine invasiveness of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('expression', 'MPA', (57, 67))	('determine', 'Reg', (113, 122))	('ACT', 'Gene', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('dysregulated', 'Var', (44, 56))	('cancer', 'Disease', (139, 145))
905008	25407528	Altogether, dysregulated expression of PLG-Rs seems to be a reliable indicator of the disease stage and patients survival in several types of tumor (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('expression', 'MPA', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('dysregulated', 'Var', (12, 24))	('patients', 'Species', '9606', (104, 112))	('PLG-Rs', 'Gene', (39, 45))
905020	25407528	Inhibition of tyrosine protein kinases or mutation of tyrosine 23 to alanine blocked ANX2 externalization, consequently decreasing PLA generation and pancreatic ductal adenocarcinoma invasion.	('tyrosine', 'Enzyme', (14, 22))	('PLA', 'Gene', '5340', (131, 134))	('blocked', 'NegReg', (77, 84))	('pancreatic ductal adenocarcinoma invasion', 'Disease', (150, 191))	('decreasing', 'NegReg', (120, 130))	('ANX2', 'Gene', '302', (85, 89))	('PLA', 'Gene', (131, 134))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (150, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('mutation', 'Var', (42, 50))	('pancreatic ductal adenocarcinoma invasion', 'Disease', 'MESH:D021441', (150, 191))	('ANX2', 'Gene', (85, 89))	('tyrosine 23 to alanine', 'Mutation', 'p.Y23A', (54, 76))
905033	25407528	However, a growing body of evidence suggests that dysregulated expression and cellular localization of PLG-R may be associated with the development and progression of different types of human cancer as well (Figure 2).	('expression', 'MPA', (63, 73))	('PLG-R', 'Gene', (103, 108))	('dysregulated', 'Var', (50, 62))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('human', 'Species', '9606', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('associated', 'Reg', (116, 126))
905064	24949383	All EUS examinations were performed with Pentax Hitachi EG38UT or EG38UTK linear electronic probes (Pentax Precision Instruments, Orangeburg, New York) connected to a Hitachi scanner (8500 or Prerius system).	('EG38UTK', 'Var', (66, 73))	('men', 'Species', '9606', (123, 126))	('EG38UT', 'Var', (56, 62))
905076	24949383	Surgical treatment without neoadjuvant therapy was given to patients with T1bN0 or T2N0.	('T2N0', 'Var', (83, 87))	('patients', 'Species', '9606', (60, 68))	('T1bN0', 'Var', (74, 79))	('men', 'Species', '9606', (14, 17))
905077	24949383	Neoadjuvant therapy follow by surgery was indicated to patients with T2N+, T3N0 or T3N+.	('patients', 'Species', '9606', (55, 63))	('T3N+', 'Var', (83, 87))	('T2N+', 'Var', (69, 73))	('T3N0', 'Var', (75, 79))
905110	24949383	showed that EUS increased patient's selection for pre-operative neoadjuvant chemotherapy, increased survival and reduced the recurrence rate.	('patient', 'Species', '9606', (26, 33))	('EUS', 'Var', (12, 15))	('recurrence', 'MPA', (125, 135))	('increased', 'PosReg', (90, 99))	('survival', 'CPA', (100, 108))	('increased', 'PosReg', (16, 25))	('reduced', 'NegReg', (113, 120))
905119	20388212	p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in Esophageal Squamous Cell Carcinoma Tumor suppressor genes p53 and p16INK4a and the proto-oncogene MDM2 are considered to be essential G1 cell cycle regulatory genes whose loss of function is associated with ESCC carcinogenesis.	('p53', 'Gene', '7157', (128, 131))	('Carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('p16', 'Gene', (35, 38))	('hypermethylation', 'Var', (9, 25))	('Esophageal Squamous Cell Carcinoma', 'Disease', (70, 104))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('p16INK4a', 'Gene', '1029', (136, 144))	('p16INK4a', 'Gene', '1029', (0, 8))	('p16', 'Gene', '1029', (35, 38))	('p53', 'Gene', (128, 131))	('MDM2', 'Gene', (43, 47))	('loss of function', 'NegReg', (241, 257))	('p53', 'Gene', '7157', (30, 33))	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (277, 296))	('MDM2', 'Gene', '4193', (43, 47))	('p16', 'Gene', (136, 139))	('p16', 'Gene', (0, 3))	('p53', 'Gene', (30, 33))	('MDM2', 'Gene', (168, 172))	('p16', 'Gene', '1029', (136, 139))	('p16', 'Gene', '1029', (0, 3))	('ESCC carcinogenesis', 'Disease', (277, 296))	('p16INK4a', 'Gene', (136, 144))	('p16INK4a', 'Gene', (0, 8))	('MDM2', 'Gene', '4193', (168, 172))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('Tumor', 'Phenotype', 'HP:0002664', (105, 110))
905120	20388212	We assessed the aberrant methylation of the p16 gene and its impact on p16INK4a protein expression and correlations with p53 and MDM2 protein expressions in patients with ESCC in the Golestan province of northeastern Iran in which ESCC has the highest incidence of cancer, well above the world average.	('aberrant', 'Var', (16, 24))	('p16', 'Gene', (71, 74))	('p16', 'Gene', (44, 47))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('ESCC', 'Disease', (171, 175))	('patients', 'Species', '9606', (157, 165))	('p16', 'Gene', '1029', (71, 74))	('p16', 'Gene', '1029', (44, 47))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))
905125	20388212	Aberrant methylation of the p16INK4a gene was detected in 31/50 (62%) of esophageal tumor samples, while two of the adjacent normal mucosa were methylated (P < 0.001).	('methylation', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('esophageal tumor', 'Disease', 'MESH:D004938', (73, 89))	('p16INK4a', 'Gene', (28, 36))	('detected', 'Reg', (46, 54))	('Aberrant methylation', 'Var', (0, 20))	('esophageal tumor', 'Disease', (73, 89))	('esophageal tumor', 'Phenotype', 'HP:0100751', (73, 89))
905126	20388212	p16INK4a aberrant methylation was significantly associated with decreased p16 protein expression (P = 0.033), as well as the overexpression of p53 (P = 0.020).	('aberrant methylation', 'Var', (9, 29))	('p16', 'Gene', (74, 77))	('p53', 'Gene', '7157', (143, 146))	('p16', 'Gene', (0, 3))	('p16', 'Gene', '1029', (74, 77))	('p16', 'Gene', '1029', (0, 3))	('overexpression', 'PosReg', (125, 139))	('p53', 'Gene', (143, 146))	('decreased', 'NegReg', (64, 73))
905127	20388212	p16 hypermethylation is the principal mechanism of p16 protein underexpression and plays an important role in ESCC development.	('p16', 'Gene', '1029', (51, 54))	('p16', 'Gene', (0, 3))	('underexpression', 'NegReg', (63, 78))	('p16', 'Gene', (51, 54))	('role', 'Reg', (102, 106))	('ESCC', 'Disease', (110, 114))	('p16', 'Gene', '1029', (0, 3))	('men', 'Species', '9606', (122, 125))	('hypermethylation', 'Var', (4, 20))
905133	20388212	Several genetic and epigenetic alterations are involved in esophageal carcinogenesis.	('involved', 'Reg', (47, 55))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (59, 84))	('epigenetic alterations', 'Var', (20, 42))	('esophageal carcinogenesis', 'Disease', (59, 84))
905135	20388212	Tumor suppressor genes P53 and p16INK4a and the proto-oncogene MDM2 (Murine Double Minute 2), are considered to be essential G1 cell cycle regulatory genes and whose loss of function is associated with cancer development.	('men', 'Species', '9606', (216, 219))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('p16INK4a', 'Var', (31, 39))	('P53', 'Gene', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('P53', 'Gene', '22060', (23, 26))	('Murine Double Minute 2', 'Gene', (69, 91))	('associated', 'Reg', (186, 196))	('Murine Double Minute 2', 'Gene', '17246', (69, 91))	('loss of function', 'NegReg', (166, 182))	('cancer', 'Disease', (202, 208))	('MDM2', 'Gene', (63, 67))
905137	20388212	Abnormalities of this gene, such as gene mutation, can lead to the loss of regulation of cell growth, DNA repair, or apoptosis, all of which are responsible for carcinogenesis.	('regulation of', 'MPA', (75, 88))	('Abnormalities', 'Var', (0, 13))	('DNA', 'CPA', (102, 105))	('mutation', 'Var', (41, 49))	('loss of', 'NegReg', (67, 74))	('carcinogenesis', 'Disease', 'MESH:D063646', (161, 175))	('apoptosis', 'CPA', (117, 126))	('carcinogenesis', 'Disease', (161, 175))
905140	20388212	Acting as a cyclin-dependent kinase inhibitor (CDKI), p16INK4a binds to and inhibits the activity of CDK4 and CDK6 and arrests the cell cycle in the G1/S phase in a p53-dependent pathway [.	('p53', 'Gene', (165, 168))	('p53', 'Gene', '7157', (165, 168))	('CDK4', 'Gene', (101, 105))	('arrest', 'Disease', (119, 125))	('activity', 'MPA', (89, 97))	('CDKI', 'Gene', '1033', (47, 51))	('cyclin-dependent kinase inhibitor', 'Gene', (12, 45))	('CDKI', 'Gene', (47, 51))	('CDK4', 'Gene', '1019', (101, 105))	('cell cycle', 'CPA', (131, 141))	('inhibits', 'NegReg', (76, 84))	('CDK6', 'Gene', (110, 114))	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (12, 45))	('CDK6', 'Gene', '1021', (110, 114))	('arrest', 'Disease', 'MESH:D006323', (119, 125))	('p16INK4a', 'Var', (54, 62))	('binds', 'Interaction', (63, 68))
905141	20388212	DNA methylation in the normally unmethylated promoter region of tumor suppressor genes, such as p16INK4a, is a critical mechanism for their inactivation and is commonly associated with the repression of gene transcription which promotes the development of cancers, including ESCC carcinogenesis.	('ESCC carcinogenesis', 'Disease', 'MESH:D063646', (275, 294))	('promotes', 'PosReg', (228, 236))	('tumor', 'Disease', (64, 69))	('men', 'Species', '9606', (248, 251))	('cancers', 'Disease', 'MESH:D009369', (256, 263))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('cancers', 'Disease', (256, 263))	('methylation', 'Var', (4, 15))	('p16INK4a', 'Gene', (96, 104))	('ESCC carcinogenesis', 'Disease', (275, 294))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('inactivation', 'NegReg', (140, 152))
905142	20388212	Previous reports from Iran showed that p16 hypermethylation in the promoter region is a common mechanism for the inactivation of this gene in ESCC and gastric cancer development in Khorasan province of northeastern Iran.	('p16', 'Gene', (39, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('gastric cancer', 'Disease', (151, 165))	('men', 'Species', '9606', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('p16', 'Gene', '1029', (39, 42))	('ESCC', 'Disease', (142, 146))	('hypermethylation', 'Var', (43, 59))	('inactivation', 'NegReg', (113, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))
905143	20388212	Aberrant p16 hypermethylation is also suggested as a possible epigenetic risk factor in familial ESCC.	('Aberrant', 'Var', (0, 8))	('familial ESCC', 'Disease', (88, 101))	('p16', 'Gene', '1029', (9, 12))	('hypermethylation', 'Var', (13, 29))	('p16', 'Gene', (9, 12))
905144	20388212	In addition, p53 alterations, including the mutation of p53, have been identified as a frequent event in ESCC development in northeastern Iran.	('ESCC', 'Disease', (105, 109))	('mutation', 'Var', (44, 52))	('p53', 'Gene', (56, 59))	('men', 'Species', '9606', (117, 120))	('p53', 'Gene', '7157', (56, 59))	('p53', 'Gene', (13, 16))	('alterations', 'Var', (17, 28))	('p53', 'Gene', '7157', (13, 16))
905146	20388212	p16, p53 and MDM2 protein expression was assessed to identify the association of p16INK4a gene methylation with the expression of these cell cycle proteins in a population with a high incidence of ESCC in northeastern Iran.	('expression', 'MPA', (116, 126))	('methylation', 'Var', (95, 106))	('association', 'Interaction', (66, 77))	('ESCC', 'Disease', (197, 201))	('p16', 'Gene', (0, 3))	('p16', 'Gene', '1029', (81, 84))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '7157', (5, 8))	('p16', 'Gene', '1029', (0, 3))	('p16', 'Gene', (81, 84))
905158	20388212	Bisulfite modification of DNA results in conversion of unmethylated cytosine residues into uracil, whereas, the methylated cytosine residues, remains unchanged.	('unmethylated cytosine residues', 'MPA', (55, 85))	('uracil', 'MPA', (91, 97))	('cytosine', 'Chemical', 'MESH:D003596', (123, 131))	('cytosine', 'Chemical', 'MESH:D003596', (68, 76))	('modification', 'Var', (10, 22))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('conversion', 'MPA', (41, 51))	('uracil', 'Chemical', 'MESH:D014498', (91, 97))
905173	20388212	The cutoff values for abnormal expression were determined as follows: MDM2 > 30%; p53 > 5%; p16 < 5%.	('p16', 'Gene', (92, 95))	('MDM2', 'Var', (70, 74))	('p16', 'Gene', '1029', (92, 95))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('> 5%', 'Var', (86, 90))
905195	20388212	(Table 2) Twenty one out of thirty one (67.7%) methylation-positive esophageal tumors showed a complete lack of immunoreactivity of p16.	('lack', 'NegReg', (104, 108))	('methylation-positive', 'Var', (47, 67))	('esophageal tumors', 'Disease', 'MESH:D004938', (68, 85))	('esophageal tumors', 'Phenotype', 'HP:0100751', (68, 85))	('p16', 'Gene', '1029', (132, 135))	('esophageal tumors', 'Disease', (68, 85))	('esophageal tumor', 'Phenotype', 'HP:0100751', (68, 84))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('immunoreactivity', 'MPA', (112, 128))	('p16', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
905199	20388212	Moreover, p16 methylation was more frequent in cases with concomitant accumulation of p53 and loss of p16 proteins i.e.	('p53', 'Gene', '7157', (86, 89))	('p16', 'Gene', (102, 105))	('loss', 'NegReg', (94, 98))	('p16', 'Gene', (10, 13))	('methylation', 'Var', (14, 25))	('accumulation', 'PosReg', (70, 82))	('p16', 'Gene', '1029', (102, 105))	('frequent', 'Reg', (35, 43))	('p16', 'Gene', '1029', (10, 13))	('p53', 'Gene', (86, 89))
905203	20388212	The median survival duration of patients with p16 hypermethylation was 8 months, whereas it was 5 months for patients without hypermethylation.	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (109, 117))	('p16', 'Gene', '1029', (46, 49))	('hypermethylation', 'Var', (50, 66))	('p16', 'Gene', (46, 49))
905208	20388212	Thus, we assessed p16 hypermethylation as an important mechanism of gene silencing, its impact on the p16 protein expression, along with its correlation with the p53 and MDM2 protein expression.	('p16', 'Gene', '1029', (18, 21))	('impact', 'Reg', (88, 94))	('p53', 'Gene', (162, 165))	('gene silencing', 'NegReg', (68, 82))	('p16', 'Gene', (102, 105))	('p16', 'Gene', '1029', (102, 105))	('p53', 'Gene', '7157', (162, 165))	('hypermethylation', 'Var', (22, 38))	('p16', 'Gene', (18, 21))	('expression', 'MPA', (114, 124))
905209	20388212	We showed that p16 protein expression was significantly associated with methylation of the p16 gene, indicating that p16 methylation may play a critical role in the silencing of this important tumor suppressor gene.	('p16', 'Gene', (15, 18))	('p16', 'Gene', (91, 94))	('p16', 'Gene', '1029', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('expression', 'MPA', (27, 37))	('associated', 'Reg', (56, 66))	('methylation', 'Var', (72, 83))	('p16', 'Gene', '1029', (15, 18))	('p16', 'Gene', '1029', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('p16', 'Gene', (117, 120))	('tumor', 'Disease', (193, 198))	('protein', 'Protein', (19, 26))
905210	20388212	On the other hand, significant differences in both methylation and loss of protein expression of p16 in tumoral tissue compared to the normal tissue confirms the critical role of these genetic and epigenetic alterations in the development of ESCC in this high-incidence region.	('ESCC', 'Disease', (242, 246))	('p16', 'Gene', '1029', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('epigenetic alterations', 'Var', (197, 219))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('loss of', 'NegReg', (67, 74))	('methylation', 'Var', (51, 62))	('p16', 'Gene', (97, 100))	('men', 'Species', '9606', (234, 237))	('protein expression', 'MPA', (75, 93))
905212	20388212	Previous reports of p16 methylation varied between 40-90% among ESCC patients in the Far East.	('ESCC', 'Disease', (64, 68))	('p16', 'Gene', (20, 23))	('methylation', 'Var', (24, 35))	('patients', 'Species', '9606', (69, 77))	('p16', 'Gene', '1029', (20, 23))
905213	20388212	Xing et al studied 40 ESCC patients and detected the p16 gene hypermethylation in 40% of tumor samples.	('hypermethylation', 'Var', (62, 78))	('p16', 'Gene', (53, 56))	('ESCC', 'Disease', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('patients', 'Species', '9606', (27, 35))	('p16', 'Gene', '1029', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
905215	20388212	Wang et al showed the aberrant hypermethylation of p16, as a frequent event, in 88% of ESCC patients in China.	('p16', 'Gene', '1029', (51, 54))	('patients', 'Species', '9606', (92, 100))	('aberrant hypermethylation', 'Var', (22, 47))	('p16', 'Gene', (51, 54))	('ESCC', 'Disease', (87, 91))
905217	20388212	In support of their data, this study indicates the critical role of p16 methylation in ESCC development in this high risk region.	('p16', 'Gene', (68, 71))	('ESCC development', 'Disease', (87, 103))	('methylation', 'Var', (72, 83))	('men', 'Species', '9606', (99, 102))	('p16', 'Gene', '1029', (68, 71))
905219	20388212	We showed that in two ESCC patients, p16 methylation occurred not only in the tumoral cells but also in the corresponding normal tissue.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('ESCC', 'Disease', (22, 26))	('occurred', 'Reg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('methylation', 'Var', (41, 52))	('patients', 'Species', '9606', (27, 35))	('p16', 'Gene', '1029', (37, 40))	('tumor', 'Disease', (78, 83))	('p16', 'Gene', (37, 40))
905221	20388212	In line with our data on p16 methylation in normal tissue, Hibi et al presented one case of p16 methylation in the normal tissue in addition to WBCs of peripheral blood.	('p16', 'Gene', (92, 95))	('p16', 'Gene', (25, 28))	('p16', 'Gene', '1029', (92, 95))	('methylation', 'Var', (96, 107))	('p16', 'Gene', '1029', (25, 28))
905226	20388212	We can speculate that the presence of p16 methylation in normal tissue of these two studied ESCC patients may prone them to trigger tumor formation in these tissues.	('ESCC', 'Disease', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('p16', 'Gene', (38, 41))	('methylation', 'Var', (42, 53))	('tumor', 'Disease', (132, 137))	('prone', 'PosReg', (110, 115))	('presence', 'Var', (26, 34))	('p16', 'Gene', '1029', (38, 41))	('patients', 'Species', '9606', (97, 105))
905227	20388212	Although p16 hypermethylation most often occurs in the late preneoplastic stages (i.e.	('occurs', 'Reg', (41, 47))	('hypermethylation', 'Var', (13, 29))	('p16', 'Gene', '1029', (9, 12))	('p16', 'Gene', (9, 12))
905229	20388212	Environmental factors, previously reported as influencing aberrant hypermethylation, such as exposure to carcinogens or dietary factors,, along with a possible genetic predisposition, such as DNA methyltransferase activation, may be responsible for the epigenetic alterations and methylation induction in the normal tissue of this small proportion.	('epigenetic', 'MPA', (253, 263))	('methylation', 'MPA', (280, 291))	('men', 'Species', '9606', (7, 10))	('hypermethylation', 'Var', (67, 83))
905232	20388212	This suggested that other molecular mechanisms, such as point mutation, homozygous deletion or loss of heterozygosity, may contribute to p16 gene inactivation.	('loss of heterozygosity', 'Var', (95, 117))	('p16', 'Gene', (137, 140))	('point mutation', 'Var', (56, 70))	('inactivation', 'NegReg', (146, 158))	('homozygous deletion', 'Var', (72, 91))	('p16', 'Gene', '1029', (137, 140))
905234	20388212	This can possibly be explained by hemi-methylation of the p16 gene.	('p16', 'Gene', '1029', (58, 61))	('hemi-methylation', 'Var', (34, 50))	('p16', 'Gene', (58, 61))
905236	20388212	It has been hypothesized that p53 alterations may concomitantly occur with alterations in p16INK4a in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('carcinogenesis', 'Disease', (102, 116))	('p53', 'Gene', (30, 33))	('alterations', 'Var', (75, 86))	('p53', 'Gene', '7157', (30, 33))	('alterations', 'Var', (34, 45))
905237	20388212	As for the p53-MDM2 pathway, when the p16 methylation status was compared with the p53 and MDM2 protein expression in ESCC patients, we observed that ESCC tumors with p16 epigenetic inactivation more often harbored increased levels of p53 protein expression.	('p53', 'Gene', (11, 14))	('p53', 'Gene', (83, 86))	('ESCC tumor', 'Disease', (150, 160))	('epigenetic inactivation', 'Var', (171, 194))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('p16', 'Gene', (167, 170))	('ESCC tumor', 'Disease', 'MESH:D004938', (150, 160))	('tumors', 'Disease', (155, 161))	('p53', 'Gene', '7157', (235, 238))	('p16', 'Gene', '1029', (167, 170))	('p53', 'Gene', '7157', (11, 14))	('p53', 'Gene', '7157', (83, 86))	('p16', 'Gene', (38, 41))	('levels', 'MPA', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('increased', 'PosReg', (215, 224))	('p53', 'Gene', (235, 238))	('p16', 'Gene', '1029', (38, 41))
905238	20388212	To our knowledge, this is the first report indicating the association between p16 hypermethylation and p53 protein accumulation in ESCC.	('association', 'Interaction', (58, 69))	('p16', 'Gene', (78, 81))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('protein', 'Protein', (107, 114))	('p16', 'Gene', '1029', (78, 81))	('accumulation', 'PosReg', (115, 127))	('hypermethylation', 'Var', (82, 98))	('ESCC', 'Disease', (131, 135))
905241	20388212	Ishii et al reported more extensive DNA methylation in neoplastic lesions of ESCC with a p53 mutation than in those with wild-type p53, when assessing the promoter hypermethylation of 14 tumor suppressor genes; however p16 hypermethylation was not independently associated with p53 mutation.	('DNA methylation', 'MPA', (36, 51))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('p53', 'Gene', (278, 281))	('p53', 'Gene', '7157', (278, 281))	('ESCC', 'Disease', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (55, 73))	('p53', 'Gene', (131, 134))	('p16', 'Gene', (219, 222))	('p53', 'Gene', '7157', (131, 134))	('tumor', 'Disease', (187, 192))	('p53', 'Gene', (89, 92))	('p53', 'Gene', '7157', (89, 92))	('mutation', 'Var', (93, 101))	('p16', 'Gene', '1029', (219, 222))
905245	20388212	On the other hand, p16 hypermethylation is associated with a larger accumulation of abnormal protein expression in both p16-Rb and p53-MDM2 pathways.	('p16', 'Gene', (19, 22))	('p16', 'Gene', '1029', (120, 123))	('p16', 'Gene', (120, 123))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('p16', 'Gene', '1029', (19, 22))	('hypermethylation', 'Var', (23, 39))	('abnormal protein expression', 'MPA', (84, 111))
905246	20388212	All these findings in addition to correlation between p16 hypermethylation and p53 abnormal accumulation, indicate a possible overlap and cross-talk between the involved pathways.	('p16', 'Gene', (54, 57))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('hypermethylation', 'Var', (58, 74))	('p16', 'Gene', '1029', (54, 57))	('cross-talk', 'Reg', (138, 148))
905247	20388212	Although it has been reported that p16 hypermethylation is a predisposing epigenetic trait in the familial ESCC in Iran, the role of other factors such as environmental factors has not yet been ruled out.	('p16', 'Gene', '1029', (35, 38))	('men', 'Species', '9606', (162, 165))	('hypermethylation', 'Var', (39, 55))	('p16', 'Gene', (35, 38))
905249	20388212	Concomitant p16 hypermethylation and p53 overexpression may be a consequence of various environmental, dietary or lifestyle factors peculiar to this region, associated with an increased susceptibility to ESCC.	('ESCC', 'Disease', (204, 208))	('p16', 'Gene', (12, 15))	('p16', 'Gene', '1029', (12, 15))	('hypermethylation', 'Var', (16, 32))	('men', 'Species', '9606', (95, 98))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('overexpression', 'PosReg', (41, 55))
905251	20388212	In summary, we conclude that p16 gene silencing caused by hypermethylation of CpG islands may be a major mechanism in the ESCC development.	('p16', 'Gene', (29, 32))	('hypermethylation', 'Var', (58, 74))	('ESCC', 'Disease', (122, 126))	('p16', 'Gene', '1029', (29, 32))	('silencing', 'NegReg', (38, 47))	('men', 'Species', '9606', (134, 137))
905253	20388212	This is the first study indicating the association between p16 hypermethylation and p53 protein overexpression.	('p16', 'Gene', '1029', (59, 62))	('hypermethylation', 'Var', (63, 79))	('p16', 'Gene', (59, 62))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('overexpression', 'PosReg', (96, 110))	('protein', 'Protein', (88, 95))
905254	20388212	The impact of p16 hypermethylation on accumulation of abnormally expressed proteins in the p53-MDM2 pathway, along with the observed concomitant accumulation of p53 with either MDM2 overexpression or decreased p16 expression, suggests a possible cross-talk of the involved pathways in ESCC development in northeastern Iran.	('p16', 'Gene', '1029', (14, 17))	('cross-talk', 'Reg', (246, 256))	('hypermethylation', 'Var', (18, 34))	('accumulation', 'PosReg', (38, 50))	('p16', 'Gene', (210, 213))	('men', 'Species', '9606', (297, 300))	('p16', 'Gene', (14, 17))	('p53', 'Gene', (91, 94))	('accumulation', 'PosReg', (145, 157))	('decreased', 'NegReg', (200, 209))	('ESCC', 'Disease', (285, 289))	('p53', 'Gene', '7157', (91, 94))	('proteins', 'Protein', (75, 83))	('p53', 'Gene', (161, 164))	('p16', 'Gene', '1029', (210, 213))	('expression', 'MPA', (214, 224))	('p53', 'Gene', '7157', (161, 164))
905362	31703631	In the present cohort, cervical anastomosis was preferred to intrathoracic anastomosis (66.9% vs. 32.1%), which was probably because leakage in the neck results in less morbidity, and is easier to manage.	('cervical anastomosis', 'Phenotype', 'HP:0002949', (23, 43))	('leakage', 'Var', (133, 140))	('intrathoracic anastomosis', 'Disease', 'MESH:D006045', (61, 86))	('intrathoracic anastomosis', 'Disease', (61, 86))
905367	31703631	Although the ligation of the thoracic duct has been shown to reduce the incidence of postoperative chyle leakage, this procedure was not performed in approximately half of patients in the present study, leading to a 1.2% incidence of chylothorax.	('postoperative', 'MPA', (85, 98))	('reduce', 'NegReg', (61, 67))	('chylothorax', 'Disease', (234, 245))	('ligation', 'Var', (13, 21))	('chylothorax', 'Phenotype', 'HP:0010310', (234, 245))	('patients', 'Species', '9606', (172, 180))
905437	31662822	Indeed, in a systematic review and meta-analysis comprising of 15 non-randomized trials comparing ESD to EMR, they found that although ESD had higher curative resection rates and lesser local recurrence rates, it was balanced by more time-consuming procedures and higher rates of bleeding and perforation].	('ESD', 'Var', (135, 138))	('bleeding', 'Disease', 'MESH:D006470', (280, 288))	('bleeding', 'Disease', (280, 288))	('curative resection', 'CPA', (150, 168))	('higher', 'PosReg', (143, 149))
905493	30975989	The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role.	('ERBB4', 'Gene', (27, 32))	('patient', 'Species', '9606', (46, 53))	('ERBB4', 'Gene', '2066', (27, 32))	('mutations', 'Var', (33, 42))
905494	30975989	18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508).	('BRCA1/2', 'Gene', (27, 34))	('patients', 'Species', '9606', (7, 15))	('high-level contribution of signature 3', 'MPA', (65, 103))	('variants', 'Var', (35, 43))
905495	30975989	Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells.	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('BRCA1/2', 'Gene', (26, 33))	('increased', 'PosReg', (47, 56))	('knockdown', 'Var', (13, 22))	('sensitivity to cisplatin', 'MPA', (57, 81))
905499	30975989	Here, the authors carry out multi-region sampling of Chinese ESCC samples, and find recurrent ERBB4 mutations, BRCA1/2 variants, and amplification of CD274; together with high levels of genomic and T-cell receptor heterogeneity.	('mutations', 'Var', (100, 109))	('CD274', 'Gene', '29126', (150, 155))	('BRCA1/2', 'Gene', (111, 118))	('amplification', 'Var', (133, 146))	('CD274', 'Gene', (150, 155))	('ERBB4', 'Gene', '2066', (94, 99))	('variants', 'Var', (119, 127))	('ERBB4', 'Gene', (94, 99))
905505	30975989	Using multi-region sequencing, they confirmed early mutational events of mutations in TP53, CDKN2A and copy number alterations (CNAs) in 11q (CCND1), 3q (SOX2), 9p (CDKN2A), and identified sharply genomic changes between simple hyperplasia and dysplasia, of which simple hyperplasia harbored no or very low number of mutations.	('CCND1', 'Gene', (142, 147))	('CDKN2A', 'Gene', (92, 98))	('hyperplasia and dysplasia', 'Disease', 'MESH:D006965', (228, 253))	('hyperplasia', 'Disease', (228, 239))	('TP53', 'Gene', '7157', (86, 90))	('CCND1', 'Gene', '595', (142, 147))	('hyperplasia', 'Disease', 'MESH:D006965', (271, 282))	('CDKN2A', 'Gene', '1029', (92, 98))	('TP53', 'Gene', (86, 90))	('CDKN2A', 'Gene', (165, 171))	('hyperplasia', 'Disease', 'MESH:D006965', (228, 239))	('CDKN2A', 'Gene', '1029', (165, 171))	('SOX2', 'Gene', '6657', (154, 158))	('hyperplasia', 'Disease', (271, 282))	('mutations', 'Var', (73, 82))	('SOX2', 'Gene', (154, 158))
905514	30975989	Moreover, mutation burden was higher in ESCC patients harboring larger tumor volume than those with smaller tumor (Wilcoxon rank sum test, P = 0.068, Supplementary Fig.	('ESCC', 'Disease', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (108, 113))	('mutation', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('higher', 'Reg', (30, 36))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Disease', (71, 76))
905515	30975989	At patient level, mutations per patient identified by multi-region sequencing were significantly greater than those with single-regional analysis or the mutation data from The Cancer Genome Atlas (TCGA) (Wilcoxon rank sum test, P = 0.021 and P = 0.037, respectively, Supplementary Fig.	('patient', 'Species', '9606', (3, 10))	('Cancer Genome Atlas', 'Disease', (176, 195))	('greater', 'PosReg', (97, 104))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (176, 195))	('patient', 'Species', '9606', (32, 39))	('mutations', 'Var', (18, 27))
905516	30975989	To assess ITH in ESCC, we characterized tumor evolution as a phylogenetic tree structure (Methods) with the trunk representing ubiquitous mutations that present in all tumor regions, the shared branches representing heterogeneous mutations that present in some but not all tumor regions, and the private branches representing mutations that present in only one tumor region.	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (361, 366))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('mutations', 'Var', (138, 147))
905517	30975989	These results suggested that the majority of mutations occurred after carcinoma transformation.	('mutations', 'Var', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinoma transformation', 'Disease', (70, 94))	('carcinoma transformation', 'Disease', 'MESH:D020518', (70, 94))	('occurred', 'Reg', (55, 63))
905522	30975989	Most of driver mutations in TP53, PIK3CA, ZNF750, and BRCA2 were mapped to the trunks of the phylogenetic trees, whereas mutations in NOTCH1, CREBBP, PTCH1, MET, mTOR, and AXIN2 almost always occurred in late evolution (Fig.	('mTOR', 'Gene', (162, 166))	('NOTCH1', 'Gene', (134, 140))	('AXIN2', 'Gene', '8313', (172, 177))	('CREBBP', 'Gene', '1387', (142, 148))	('PIK3CA', 'Gene', (34, 40))	('PTCH1', 'Gene', (150, 155))	('mTOR', 'Gene', '2475', (162, 166))	('NOTCH1', 'Gene', '4851', (134, 140))	('TP53', 'Gene', (28, 32))	('mutations', 'Var', (15, 24))	('ZNF750', 'Gene', '79755', (42, 48))	('ZNF750', 'Gene', (42, 48))	('MET', 'Gene', (157, 160))	('AXIN2', 'Gene', (172, 177))	('BRCA2', 'Gene', (54, 59))	('CREBBP', 'Gene', (142, 148))	('TP53', 'Gene', '7157', (28, 32))	('PIK3CA', 'Gene', '5290', (34, 40))	('PTCH1', 'Gene', '5727', (150, 155))	('BRCA2', 'Gene', '675', (54, 59))
905523	30975989	Particularly, mutations in ERBB4, which were previously less reported in ESCC, were observed in five patients (12.8%).	('patients', 'Species', '9606', (101, 109))	('ERBB4', 'Gene', '2066', (27, 32))	('observed', 'Reg', (84, 92))	('ERBB4', 'Gene', (27, 32))	('mutations', 'Var', (14, 23))
905525	30975989	In 39-Mseq cohort, we found five novel point mutations of ERBB4 (Fig.	('point mutations', 'Var', (39, 54))	('ERBB4', 'Gene', (58, 63))	('ERBB4', 'Gene', '2066', (58, 63))
905526	30975989	We integrated previous ESCC studies and found additional 22 of ERBB4 mutations in the TCGA (1, n = 90), early Chinese (11, n = 289), and Japanese (10, n = 144) cohorts.	('mutations', 'Var', (69, 78))	('ERBB4', 'Gene', '2066', (63, 68))	('ERBB4', 'Gene', (63, 68))
905527	30975989	Additionally, we found 13 ERBB4 mutations in our independent whole-genome sequencing ESCC cohort (n = 508, referred as 508-WGS ESCC cohort, Supplementary Fig.	('ERBB4', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('ERBB4', 'Gene', '2066', (26, 31))	('ESCC', 'Disease', (85, 89))
905528	30975989	In all, 72.5% of the total 40 mutations occurred in extracellular or kinase domain of ErbB4 (Fig.	('occurred', 'Reg', (40, 48))	('ErbB4', 'Gene', (86, 91))	('mutations', 'Var', (30, 39))	('ErbB4', 'Gene', '2066', (86, 91))
905532	30975989	These results suggest that ERBB4 mutations may play an oncogenic role in ESCC and is probably a potential therapeutic target for ESCC treatment.	('ERBB4', 'Gene', (27, 32))	('ESCC', 'Disease', (73, 77))	('ERBB4', 'Gene', '2066', (27, 32))	('mutations', 'Var', (33, 42))
905534	30975989	These copy number events distinguish the clones within tumor and often result in amplifications of oncogenes and deletions of tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('deletions', 'Var', (113, 122))	('result in', 'Reg', (71, 80))	('tumor', 'Disease', (55, 60))	('oncogenes', 'Gene', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('amplifications', 'MPA', (81, 95))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
905548	30975989	Particularly, one of these nine patients, ESCC001, showed a relatively higher contribution of signature 29 (~15%).	('patients', 'Species', '9606', (32, 40))	('signature', 'Var', (94, 103))	('higher contribution', 'PosReg', (71, 90))
905552	30975989	Moreover, the number of trunk mutations significantly correlated with the burden of APOBEC mutations across 39 patients (Fig.	('APOBEC', 'Gene', (84, 90))	('mutations', 'Var', (91, 100))	('patients', 'Species', '9606', (111, 119))	('correlated', 'Reg', (54, 64))
905553	30975989	Several studies have confirmed that signature 3 was strongly associated with BRCA1/2 mutations in breast, pancreatic, and ovarian cancers.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('BRCA1/2', 'Gene', (77, 84))	('ovarian cancers', 'Phenotype', 'HP:0100615', (122, 137))	('mutations', 'Var', (85, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))	('pancreatic', 'Disease', 'MESH:D010195', (106, 116))	('ovarian cancers', 'Disease', (122, 137))	('ovarian cancers', 'Disease', 'MESH:D010051', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('breast', 'Disease', (98, 104))	('associated', 'Reg', (61, 71))	('pancreatic', 'Disease', (106, 116))
905554	30975989	In 39-Mseq cohort, four patients with pathogenic germline alterations in BRCA1/2 genes showed high levels of signature 3, three patients with ubiquitous somatic mutations in BRCA1/2 also exhibited elevated level of signature 3.	('BRCA1/2', 'Gene', (73, 80))	('signature 3', 'MPA', (109, 120))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (128, 136))	('alterations', 'Var', (58, 69))
905556	30975989	Loss of heterozygosity (LOH) at the BRCA1/2 loci was detected in six out of the seven patients with BRCA1/2 alterations that exhibited high signature 3 level, highlighting the clinical link between the biallelic inactivation of BRCA1/2 and signature 3 in ESCC (Fig.	('BRCA1/2', 'Gene', (100, 107))	('alterations', 'Var', (108, 119))	('clinical', 'Species', '191496', (176, 184))	('BRCA1/2', 'Gene', (36, 43))	('Loss', 'NegReg', (0, 4))	('patients', 'Species', '9606', (86, 94))
905558	30975989	Of these seven patients, only case ESCC025 had deleterious germline BRCA1/2 mutations (Fig.	('BRCA1/2', 'Gene', (68, 75))	('patients', 'Species', '9606', (15, 23))	('mutations', 'Var', (76, 85))
905559	30975989	The association between signature 3 and tumors with other homologous recombination (HR) pathway gene mutations, such as BRIP1, MSH2, RAD54B, and PALB2, was less solid (Fig.	('PALB2', 'Gene', '79728', (145, 150))	('PALB2', 'Gene', (145, 150))	('mutations', 'Var', (101, 110))	('MSH2', 'Gene', (127, 131))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('MSH2', 'Gene', '4436', (127, 131))	('RAD54B', 'Gene', '25788', (133, 139))	('BRIP1', 'Gene', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('BRIP1', 'Gene', '83990', (120, 125))	('tumors', 'Disease', (40, 46))	('RAD54B', 'Gene', (133, 139))
905561	30975989	Notably, these results were further verified in the 508-WGS ESCC cohort, in which elevated signature 3 contribution was observed in 20 out of 21 ESCCs with germline BRCA1/2 variant but not in tumors harboring somatic mutations in other HR pathway genes (Fig.	('variant', 'Var', (173, 180))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('elevated', 'PosReg', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('BRCA1/2', 'Gene', (165, 172))
905562	30975989	Since the specific sensitivity of tumors with BRCA1/2 mutations to platinum therapy was described in breast cancer and ovarian cancer, we expected the effects to be identical in ESCC.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('ovarian cancer', 'Disease', 'MESH:D010051', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (54, 63))	('BRCA1/2', 'Gene', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('platinum', 'Chemical', 'MESH:D010984', (67, 75))	('ovarian cancer', 'Disease', (119, 133))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
905563	30975989	As a result, BRCA1/2 knockdown dramatically increased sensitivity to cisplatin in KYSE410 and ZEC-014-1 cells (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('ZEC-014-1', 'CellLine', 'CVCL:E298', (94, 103))	('sensitivity to cisplatin', 'MPA', (54, 78))	('increased', 'PosReg', (44, 53))	('BRCA1/2', 'Gene', (13, 20))	('knockdown', 'Var', (21, 30))
905564	30975989	9b, c), indicating a potential novel therapeutic strategy to ESCC patients with BRCA1/2 mutations.	('ESCC', 'Disease', (61, 65))	('mutations', 'Var', (88, 97))	('BRCA1/2', 'Gene', (80, 87))	('patients', 'Species', '9606', (66, 74))
905568	30975989	To investigate the universal evolutionary patterns within ESCC, we constructed the multi-region tree of tumors based on somatic single-nucleotide variants (SNVs) and further used CNA data to support the final phylogenetic trees (Methods, Supplementary Figs.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('single-nucleotide', 'Var', (128, 145))
905572	30975989	Intermixed samples were also observed in patients ESCC035, ESCC026, and ESCC043 (Supplementary Fig.	('patients', 'Species', '9606', (41, 49))	('ESCC043', 'Var', (72, 79))	('ESCC035', 'Var', (50, 57))
905584	30975989	Intriguingly, amplification of PD-L1 (CD274), an important biomarker for immunotherapy, was heterogeneous in patients ESCC015 and ESCC012.	('CD274', 'Gene', '29126', (38, 43))	('patients', 'Species', '9606', (109, 117))	('amplification', 'Var', (14, 27))	('PD-L1', 'Gene', '29126', (31, 36))	('CD274', 'Gene', (38, 43))	('ESCC015', 'Var', (118, 125))	('PD-L1', 'Gene', (31, 36))
905585	30975989	Of eight sequenced regional samples in ESCC012, three lymph nodes with metastatic TCs harbored PD-L1 amplifications (>=4 copies).	('amplifications', 'Var', (101, 115))	('PD-L1', 'Gene', (95, 100))	('PD-L1', 'Gene', '29126', (95, 100))	('TCs', 'Chemical', '-', (82, 85))
905588	30975989	Parallel evolution also involved mutations of driver genes, such as NOTCH1, TP53, and PIK3CA mutations, of which parallel NOTCH1 mutations were found in patients ESCC015 and ESCC043 (Supplementary Data 2).	('patients', 'Species', '9606', (153, 161))	('NOTCH1', 'Gene', '4851', (122, 128))	('NOTCH1', 'Gene', (122, 128))	('mutations', 'Var', (129, 138))	('TP53', 'Gene', '7157', (76, 80))	('NOTCH1', 'Gene', '4851', (68, 74))	('PIK3CA', 'Gene', (86, 92))	('mutations', 'Var', (33, 42))	('found', 'Reg', (144, 149))	('TP53', 'Gene', (76, 80))	('NOTCH1', 'Gene', (68, 74))	('PIK3CA', 'Gene', '5290', (86, 92))
905589	30975989	To examine whether CD274 amplifications are associated with PD-L1 protein level, we performed immunohistochemical (IHC) analysis to evaluate PD-L1 expression.	('associated', 'Reg', (44, 54))	('PD-L1', 'Gene', (141, 146))	('PD-L1', 'Gene', '29126', (141, 146))	('CD274', 'Gene', (19, 24))	('PD-L1', 'Gene', (60, 65))	('amplifications', 'Var', (25, 39))	('PD-L1', 'Gene', '29126', (60, 65))	('CD274', 'Gene', '29126', (19, 24))
905593	30975989	These data implicate that focal CD274 amplification may be associated with PD-L1 expression in ESCC.	('CD274', 'Gene', (32, 37))	('PD-L1', 'Gene', (75, 80))	('ESCC', 'Disease', (95, 99))	('associated', 'Reg', (59, 69))	('PD-L1', 'Gene', '29126', (75, 80))	('CD274', 'Gene', '29126', (32, 37))	('amplification', 'Var', (38, 51))	('expression', 'MPA', (81, 91))
905594	30975989	Moreover, the genomic heterogeneity of CD274 led to differential expression of PD-L1 in regions for ESCC012 but caused no significant changes for ESCC015, whose T3 region showing the absence of CD274 amplification (Fig.	('ESCC012', 'Var', (100, 107))	('CD274', 'Gene', (194, 199))	('CD274', 'Gene', (39, 44))	('PD-L1', 'Gene', (79, 84))	('expression', 'MPA', (65, 75))	('CD274', 'Gene', '29126', (194, 199))	('CD274', 'Gene', '29126', (39, 44))	('PD-L1', 'Gene', '29126', (79, 84))
905604	30975989	However, within intra-patients, we observed variations of overall TCR repertoire, including the T cell clonality, high-frequent clones, and V-J gene pairing diversity (Fig.	('V-J gene pairing', 'Var', (140, 156))	('TCR', 'Gene', '6962', (66, 69))	('patients', 'Species', '9606', (22, 30))	('T cell clonality', 'CPA', (96, 112))	('TCR', 'Gene', (66, 69))
905621	30975989	Moreover, BRCA1/2 knockdown ESCC cells were more sensitive to platinum treatment.	('platinum', 'Chemical', 'MESH:D010984', (62, 70))	('knockdown', 'Var', (18, 27))	('more', 'PosReg', (44, 48))	('sensitive', 'MPA', (49, 58))	('BRCA1/2', 'Gene', (10, 17))
905622	30975989	These results are probably helpful for treatment of ESCC patients with BRCA mutation, especially for inoperable ones.	('patients', 'Species', '9606', (57, 65))	('BRCA', 'Gene', '672', (71, 75))	('ESCC', 'Disease', (52, 56))	('mutation', 'Var', (76, 84))	('BRCA', 'Gene', (71, 75))
905624	30975989	In our data, we found that some patients (sporadic or familial) with high-level signature 3 had no BRCA1/2 mutations that were probably owing to epigenetic changes or other events.	('BRCA1/2', 'Gene', (99, 106))	('patients', 'Species', '9606', (32, 40))	('mutations', 'Var', (107, 116))
905658	30975989	For mutation validation, we randomly chose three samples (ESCC012 T5, ESCC014 T1, ESCC035 L2) with high mutation rate (2 standard deviations larger than the mean value of the regions in the same patient), re-constructed WES library, and performed the same sequencing and mutation-calling strategy.	('patient', 'Species', '9606', (195, 202))	('ESCC014 T1', 'Var', (70, 80))	('ESCC035 L2', 'Var', (82, 92))	('ESCC012 T5', 'Var', (58, 68))
905659	30975989	Due to the limited blood samples available, we only performed TCR repertoire sequencing on 10 patients (ESCC001, ESCC002, ESCC015, ESCC025, ESCC026, ESCC029, ESCC030, ESCC031, ESCC035, and ESCC036).	('ESCC031', 'Var', (167, 174))	('patients', 'Species', '9606', (94, 102))	('ESCC030', 'Var', (158, 165))	('TCR', 'Gene', '6962', (62, 65))	('ESCC015', 'Var', (122, 129))	('ESCC025', 'Var', (131, 138))	('ESCC035', 'Var', (176, 183))	('ESCC036', 'Var', (189, 196))	('ESCC002', 'Var', (113, 120))	('TCR', 'Gene', (62, 65))	('ESCC029', 'Var', (149, 156))	('ESCC026', 'Var', (140, 147))
905661	30975989	Samples with low tumor content often have ambiguous copy number changes and mutations of very low variant allele frequency.	('copy number changes', 'Var', (52, 71))	('mutations', 'Var', (76, 85))	('low tumor', 'Disease', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('low tumor', 'Disease', 'MESH:D009800', (13, 22))
905663	30975989	Somatic SNVs were called by MutTect with default parameters based on paired alignment files (tumor and normal), and filtered these SNVs with supported reads >=4 (<=2) and coverage >=14 (>=10) in tumors (normal).	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('coverage >=14', 'Var', (171, 184))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
905666	30975989	Variants among 25 DNA repair genes (BRCA1, BRCA2, MRE11A, NBN, RAD50, RAD51C, RAD51B, RAD52, XRCC2, BLM, EME1, RPA1, POLD1, TOP3A, RAD54B, TOP3B, BARD1, BRIP1, MLH1, MSH2, PALB2, CHEK2, FAM175A, MSH6, RAD51D) were extracted from the call set and filtered with at least 30x coverage and variant allele frequency (VAF) >8%.	('EME1', 'Gene', '146956', (105, 109))	('CHEK2', 'Gene', (179, 184))	('Variants', 'Var', (0, 8))	('TOP3A', 'Gene', '7156', (124, 129))	('EME1', 'Gene', (105, 109))	('RAD54B', 'Gene', (131, 137))	('RAD51D', 'Gene', '5892', (201, 207))	('RPA1', 'Gene', '6117', (111, 115))	('BRCA2', 'Gene', '675', (43, 48))	('RAD51B', 'Gene', '5890', (78, 84))	('MSH2', 'Gene', (166, 170))	('BRCA1', 'Gene', '672', (36, 41))	('CHEK2', 'Gene', '11200', (179, 184))	('POLD1', 'Gene', '5424', (117, 122))	('RAD51C', 'Gene', '5889', (70, 76))	('BRCA1', 'Gene', (36, 41))	('RAD50', 'Gene', (63, 68))	('BRIP1', 'Gene', (153, 158))	('RPA1', 'Gene', (111, 115))	('FAM175A', 'Gene', '84142', (186, 193))	('PALB2', 'Gene', (172, 177))	('MRE11A', 'Gene', '4361', (50, 56))	('XRCC2', 'Gene', (93, 98))	('NBN', 'Gene', '4683', (58, 61))	('MSH6', 'Gene', (195, 199))	('FAM175A', 'Gene', (186, 193))	('MSH2', 'Gene', '4436', (166, 170))	('RAD52', 'Gene', (86, 91))	('RAD51C', 'Gene', (70, 76))	('RAD50', 'Gene', '10111', (63, 68))	('MSH6', 'Gene', '2956', (195, 199))	('TOP3B', 'Gene', (139, 144))	('RAD51B', 'Gene', (78, 84))	('RAD51D', 'Gene', (201, 207))	('PALB2', 'Gene', '79728', (172, 177))	('BARD1', 'Gene', '580', (146, 151))	('TOP3A', 'Gene', (124, 129))	('POLD1', 'Gene', (117, 122))	('BLM', 'Gene', (100, 103))	('NBN', 'Gene', (58, 61))	('MLH1', 'Gene', (160, 164))	('BARD1', 'Gene', (146, 151))	('RAD54B', 'Gene', '25788', (131, 137))	('TOP3B', 'Gene', '8940', (139, 144))	('MRE11A', 'Gene', (50, 56))	('RAD52', 'Gene', '5893', (86, 91))	('BLM', 'Gene', '641', (100, 103))	('BRIP1', 'Gene', '83990', (153, 158))	('BRCA2', 'Gene', (43, 48))	('XRCC2', 'Gene', '7516', (93, 98))	('MLH1', 'Gene', '4292', (160, 164))
905669	30975989	The LogR of segments and VAF values of heterozygous mutations were then processed with AllelicCapseg (http://archive.broadinstitute.org/cancer/cga/acsbeta) to generate allelic segmentation copy number data for all samples.	('mutations', 'Var', (52, 61))	('cga', 'Gene', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cga', 'Gene', '1113', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
905671	30975989	Next, non-silent variants that were located within these genes were evaluated if they met one of the following criteria: (i) either an exact match or at least three mutations located within 15 bp of the variant were found in COSMIC, and (ii) if the gene was annotated as recessive by COSMIC and the variant was deemed to be deleterious, including stop-gain, frameshift, and splicing mutation, and had a SIFT score <0.05 or a PolyPhen score >0.995 (refs.	('stop-gain', 'Disease', (347, 356))	('frameshift', 'Var', (358, 368))	('SIFT', 'Disease', (403, 407))	('splicing mutation', 'Var', (374, 391))	('SIFT', 'Disease', 'None', (403, 407))	('variant', 'Var', (299, 306))
905673	30975989	Then for each consensus segment with allelic imbalance, two log-truncated normal distributions were created with their mu set as the theoretical B-allele fraction (BAF) corresponding to major copy number and minor copy number.	('minor copy number', 'Var', (208, 225))	('BAF', 'Gene', (164, 167))	('imbalance', 'Phenotype', 'HP:0002172', (45, 54))	('BAF', 'Gene', '8815', (164, 167))	('major copy number', 'Var', (186, 203))
905681	30975989	For instance, CDKN2A deletion was absent in T1 and T5 samples from ESCC015 patient (Supplementary Data 2); however, it is not consistent with phylogenetic tree shown in Supplementary Figs.	('CDKN2A', 'Gene', '1029', (14, 20))	('ESCC015', 'Gene', (67, 74))	('deletion', 'Var', (21, 29))	('patient', 'Species', '9606', (75, 82))	('CDKN2A', 'Gene', (14, 20))
905695	30975989	All cells were tested for mycoplasma contamination and maintained under the humidified 5% CO2 atmosphere at 37  C. Lentivirus HBLV-U6 carrying four shRNA separately (BRCA1-shRNA1: GAGTATGCAAACAGCTATAAT; BRCA1-shRNA2: TTGCAACCTGAGGTCTATAAA; BRCA2-shRNA1: GCAGCCATTAAATTGTCCATA; BRCA2-shRNA3: CCTCTGAAAGTGGACTGGAAA) targeting BRCA1/2 and the corresponding negative control (NC) siRNA were used to knock down BRCA1/2 in ESCC cell lines (KYSE410 and ZEC-014-1).	('BRCA2', 'Gene', '675', (240, 245))	('ZEC-014-1', 'CellLine', 'CVCL:E298', (446, 455))	('BRCA1', 'Gene', '672', (324, 329))	('BRCA1', 'Gene', '672', (166, 171))	('BRCA1', 'Gene', '672', (406, 411))	('BRCA1', 'Gene', (203, 208))	('BRCA2', 'Gene', '675', (277, 282))	('BRCA2', 'Gene', (277, 282))	('BRCA1', 'Gene', (166, 171))	('BRCA1', 'Gene', (406, 411))	('BRCA2', 'Gene', (240, 245))	('BRCA1', 'Gene', (324, 329))	('BRCA1', 'Gene', '672', (203, 208))	('CO2', 'Chemical', '-', (90, 93))	('knock down', 'Var', (395, 405))
905699	30975989	Twenty-seven mutations including five novel point mutations from 39-Mseq cohort and 22 mutations from the TCGA, early Chinese, and Japanese cohorts distribute at extracellular and kinase domain regions of ErbB4.	('ErbB4', 'Gene', '2066', (205, 210))	('mutations', 'Var', (13, 22))	('ErbB4', 'Gene', (205, 210))
905714	30975989	Then HEK293T, KYSE150, and KYSE180 cells were infected with lentiviruses.	('HEK293T', 'Var', (5, 12))	('infected', 'Reg', (46, 54))	('KYSE180', 'Var', (27, 34))	('HEK293T', 'CellLine', 'CVCL:0063', (5, 12))
905721	30975989	Yikun Cheng, Shixing Guo, E.X., C.C., L.Z., P.K., L.C., X.Z., Jing Liu, Jiayi Li, R. S, Shiping Guo and Yaoping Li provided clinical samples, coordinated, and performed pathology review.	('P.K.', 'Var', (44, 48))	('clinical samples', 'Species', '191496', (124, 140))	('L.C.', 'Var', (50, 54))
905726	30406028	Adjusted risk estimates for ESCC-specific mortality for prediabetic patients relative to normal patients were statistically significant in the blood type B- group (hazard ratio [HR]: 1.71; 95% confidence interval [CI]: 1.33-2.20; P < 0.001), but not in the blood type B+ group (HR: 1.12; 95% CI: 0.77-1.64; P = 0.5544).	('prediabetic', 'Disease', 'MESH:D011236', (56, 67))	('prediabetic', 'Disease', (56, 67))	('ESCC-specific', 'Disease', (28, 41))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (96, 104))	('significant', 'Reg', (124, 135))	('blood type B-', 'Var', (143, 156))
905748	30406028	Prediabetes was defined according to the diagnostic criteria proposed by the Chinese Medical Association Diabetes Society in 2017, that is, any participant with fasting blood glucose >=6.1 mmol/L and <7.0 mmol/L, or 2-hour plasma glucose >=7.8 and <11.1 mmol/L.	('Diabetes Society', 'Disease', (105, 121))	('blood glucose', 'Chemical', 'MESH:D001786', (169, 182))	('Diabetes Society', 'Disease', 'MESH:D003920', (105, 121))	('Prediabetes', 'Disease', 'MESH:D011236', (0, 11))	('>=6.1', 'Var', (183, 188))	('participant', 'Species', '9606', (144, 155))	('Prediabetes', 'Disease', (0, 11))	('glucose', 'Chemical', 'MESH:D005947', (230, 237))	('glucose', 'Chemical', 'MESH:D005947', (175, 182))
905752	30406028	Clinicopathologic characteristics were obtained from medical charts and pathological reports, including tumor nodes metastasis (TNM) stage (I, II, III and IV), tumor size (in centimeters), depth of invasion (T1, T2, T3, and T4), regional lymph node metastasis (LNM) (N0, N1, N2, and N3), distant metastasis (M0 andM1), histological differentiation (poor, moderate, well) and embolus (positivity and negativity).	('regional lymph node metastasis', 'CPA', (229, 259))	('embolus', 'Disease', (375, 382))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('embolus', 'Disease', 'MESH:D004617', (375, 382))	('tumor', 'Disease', (104, 109))	('tumor nodes metastasis', 'Disease', 'MESH:D009362', (104, 126))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('distant metastasis', 'CPA', (288, 306))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor nodes metastasis', 'Disease', (104, 126))	('tumor', 'Disease', (160, 165))	('M0', 'Var', (308, 310))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
905760	30406028	The prevalence rates of hypertension and dyslipidemia were significantly higher in the blood type A group than the others (P < 0.05).	('blood type A', 'Var', (87, 99))	('hypertension', 'Disease', 'MESH:D006973', (24, 36))	('dyslipidemia', 'Disease', 'MESH:D050171', (41, 53))	('dyslipidemia', 'Phenotype', 'HP:0003119', (41, 53))	('hypertension', 'Disease', (24, 36))	('hypertension', 'Phenotype', 'HP:0000822', (24, 36))	('dyslipidemia', 'Disease', (41, 53))	('higher', 'PosReg', (73, 79))
905772	30406028	Besides, aging (HR: 1.01; 95% CI: 1.00-1.02; P = 0.0387) and dyslipidemia (HR: 1.14; 95% CI: 1.14-1.68; P = 0.0010) were also associated with the significant risk of ESCC-specific mortality in the blood type B- group, but not in the blood type B+ group (Table 2).	('associated', 'Reg', (126, 136))	('ESCC-specific mortality', 'Disease', (166, 189))	('dyslipidemia', 'Disease', 'MESH:D050171', (61, 73))	('dyslipidemia', 'Phenotype', 'HP:0003119', (61, 73))	('dyslipidemia', 'Disease', (61, 73))	('blood type B-', 'Var', (197, 210))
905785	30406028	For instance, a study by Qin and colleagues showed that ESCC patients with the blood type AB had a significantly worse overall survival than patients with the other blood types, especially in patients with negative lymph nodes metastasis.	('patients', 'Species', '9606', (141, 149))	('patients', 'Species', '9606', (192, 200))	('patients', 'Species', '9606', (61, 69))	('Qin', 'Gene', '2290', (25, 28))	('overall survival', 'MPA', (119, 135))	('blood type AB', 'Var', (79, 92))	('Qin', 'Gene', (25, 28))	('worse', 'NegReg', (113, 118))
905793	30406028	Taken together, our findings indicate that prediabetes can predict the significant risk of ESCC-specific mortality in Chinese Han patients with the blood types O and A, while the prediction was nonsignificant for the blood types B and AB.	('ESCC-specific mortality', 'Disease', (91, 114))	('blood', 'Var', (148, 153))	('diabetes', 'Disease', (46, 54))	('patients', 'Species', '9606', (130, 138))	('diabetes', 'Disease', 'MESH:D003920', (46, 54))
905816	27681764	Previous studies have shown normal tissue FDG-PET uptake is associated with radiation pneumonitis and esophagitis.	('FDG', 'Chemical', 'MESH:D019788', (42, 45))	('esophagitis', 'Disease', 'MESH:D004941', (102, 113))	('normal', 'Var', (28, 34))	('pneumonitis', 'Disease', 'MESH:D011014', (86, 97))	('esophagitis', 'Disease', (102, 113))	('esophagitis', 'Phenotype', 'HP:0100633', (102, 113))	('associated', 'Reg', (60, 70))	('pneumonitis', 'Disease', (86, 97))
905837	27681764	The normalized SUV equation is:   Where SUVMean<5Gy is the average FDG uptake in the low-dose region of the esophagus and SUV(x,y,z)>5Gy is the voxel FDG uptake value.	('FDG', 'Chemical', 'MESH:D019788', (150, 153))	('FDG uptake', 'MPA', (67, 77))	('FDG', 'Chemical', 'MESH:D019788', (67, 70))	('SUVMean<5Gy', 'Var', (40, 51))
905851	27681764	Model features in the form of nSUV were used to predict >=grade 2 esophagitis at time of PET study, and >=grade 2 maximum treatment grade.	('esophagitis', 'Phenotype', 'HP:0100633', (66, 77))	('esophagitis', 'Disease', (66, 77))	('esophagitis', 'Disease', 'MESH:D004941', (66, 77))	('nSUV', 'Chemical', '-', (30, 34))	('>=grade', 'Var', (104, 111))
905871	27681764	The ability of nSUV to stratify patients on the basis of esophagitis grade at the time of the PET study, as well as the maximum esophagitis grade, is shown for nSUVAxMax1 in Figure 2 A,B.	('patients', 'Species', '9606', (32, 40))	('nSUV', 'Chemical', '-', (160, 164))	('esophagitis', 'Phenotype', 'HP:0100633', (128, 139))	('esophagitis', 'Disease', (128, 139))	('nSUV', 'Chemical', '-', (15, 19))	('esophagitis', 'Disease', 'MESH:D004941', (128, 139))	('esophagitis', 'Phenotype', 'HP:0100633', (57, 68))	('esophagitis', 'Disease', (57, 68))	('esophagitis', 'Disease', 'MESH:D004941', (57, 68))	('nSUVAxMax1', 'Var', (160, 170))
905963	26989389	Besides hand-sewn anastomosis the use of stapler devices - circular-stapled (CS) and linear-stapled (LS) - are common alternatives.	('LS', 'Chemical', '-', (101, 103))	('CS', 'Chemical', '-', (77, 79))	('circular-stapled', 'Disease', (59, 75))	('linear-stapled', 'Var', (85, 99))
905986	26718452	At 72 and 96 h after transfection, the proliferation of Eca109 cells in the siRNA-Gal-3 group was decreased compared with that in the siRNA-Control and untransfected groups (P<0.001 and P=0.004, respectively).	('Gal-3', 'Gene', '3958', (82, 87))	('rat', 'Species', '10116', (46, 49))	('transfection', 'Var', (21, 33))	('proliferation', 'CPA', (39, 52))	('decreased', 'NegReg', (98, 107))	('Gal-3', 'Gene', (82, 87))
905987	26718452	Furthermore, Transwell assays demonstrated that inhibition of galecin-3 significantly reduced the migration and invasion of Eca109 cells compared with that in the other groups (P<0.05).	('galecin-3', 'Protein', (62, 71))	('reduced', 'NegReg', (86, 93))	('rat', 'Species', '10116', (101, 104))	('invasion of Eca109 cells', 'CPA', (112, 136))	('rat', 'Species', '10116', (37, 40))	('inhibition', 'Var', (48, 58))
905989	26718452	Galectin-3 knockdown significantly enhanced the apoptotic rate of Eca109 cells compared with that in the siRNA-control and untreated groups (P=0.031 and P=0.047, respectively).	('apoptotic rate', 'CPA', (48, 62))	('Galectin-3', 'Gene', (0, 10))	('enhanced', 'PosReg', (35, 43))	('Galectin-3', 'Gene', '3958', (0, 10))	('rat', 'Species', '10116', (58, 61))	('knockdown', 'Var', (11, 20))
905990	26718452	In conclusion, following successful knockdown of galecin-3 expression in Eca109 cells, the cell proliferation, migration and invasion were reduced, while the apoptosis was enhanced, which indicates that galectin silencing may represent a therapeutic strategy for EC.	('rat', 'Species', '10116', (103, 106))	('rat', 'Species', '10116', (114, 117))	('rat', 'Species', '10116', (252, 255))	('enhanced', 'PosReg', (172, 180))	('apoptosis', 'CPA', (158, 167))	('knockdown', 'Var', (36, 45))	('silencing', 'NegReg', (212, 221))	('galecin-3', 'Gene', (49, 58))	('reduced', 'NegReg', (139, 146))	('invasion', 'CPA', (125, 133))	('cell proliferation', 'CPA', (91, 109))
906039	26718452	The effects of galectin-3 silencing on the proliferation of Eca109 cells were assessed using a CCK-8 assay (Fig.	('rat', 'Species', '10116', (50, 53))	('silencing', 'Var', (26, 35))	('galectin-3', 'Protein', (15, 25))
906041	26718452	2A, B and E), the proliferative rate was significantly decreased following 72 h of transfection (P<0.001), and it was further decreased at 96 h after transfection (P=0.004 and P=0.001 vs. siRNA-control and untreated groups, respectively) (Fig.	('decreased', 'NegReg', (126, 135))	('rat', 'Species', '10116', (32, 35))	('decreased', 'NegReg', (55, 64))	('transfection', 'Var', (83, 95))	('rat', 'Species', '10116', (25, 28))	('proliferative rate', 'CPA', (18, 36))
906056	26718452	The present study performed knockdown of galectin-3 using siRNA-Gal-3, which was shown to significantly reduce the migration and invasion abilities of Eca109 cells compared with those of untreated cells or those transfected with siRNA-control.	('rat', 'Species', '10116', (118, 121))	('Gal-3', 'Gene', (64, 69))	('Gal-3', 'Gene', '3958', (64, 69))	('galectin-3', 'Gene', (41, 51))	('reduce', 'NegReg', (104, 110))	('knockdown', 'Var', (28, 37))	('invasion abilities', 'CPA', (129, 147))
906058	26718452	Kobayashi et al showed that transient silencing of galectin-3 reduced the migration and invasion of three human pancreatic cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (106, 111))	('rat', 'Species', '10116', (77, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('silencing', 'Var', (38, 47))	('pancreatic cancer', 'Disease', (112, 129))	('galectin-3', 'Gene', (51, 61))	('reduced', 'NegReg', (62, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))
906061	26718452	It has been reported that inhibition of galectin-3 expression reduced the motility of human colon cancer and glioblastoma cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('motility of human', 'CPA', (74, 91))	('galectin-3', 'Protein', (40, 50))	('glioblastoma', 'Disease', (109, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('inhibition', 'Var', (26, 36))	('human', 'Species', '9606', (86, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('colon cancer', 'Disease', (92, 104))	('reduced', 'NegReg', (62, 69))
906064	26718452	However, a study by Junking et al indicated that galectin-3 silencing enhanced cell motility; downregulation of galectin-3 expression was associated with lymphatic invasion, metastasis potential and poor differentiation of cholangiocarcinoma (CCA).	('CCA', 'Phenotype', 'HP:0030153', (243, 246))	('cholangiocarcinoma', 'Disease', (223, 241))	('expression', 'MPA', (123, 133))	('galectin-3', 'Gene', (112, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (223, 241))	('cell motility', 'CPA', (79, 92))	('enhanced', 'PosReg', (70, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (223, 241))	('silencing', 'Var', (60, 69))	('galectin-3', 'Gene', (49, 59))	('metastasis potential', 'CPA', (174, 194))	('lymphatic invasion', 'CPA', (154, 172))	('downregulation', 'NegReg', (94, 108))	('poor differentiation', 'CPA', (199, 219))
906070	26718452	The present study also analyzed the effects of galectin-3 silencing on Eca109-cell proliferation.	('galectin-3', 'Protein', (47, 57))	('rat', 'Species', '10116', (90, 93))	('silencing', 'Var', (58, 67))
906071	26718452	At 72 and 96 h after transfection, decreased cell proliferation in the siRNA-Gal-3 treated group was observed compared with that in the siRNA-control and untreated groups, whereas at 24 and 48 h after transfection, no significant difference in the proliferative rate was found among the three groups.	('Gal-3', 'Gene', '3958', (77, 82))	('Gal-3', 'Gene', (77, 82))	('cell proliferation', 'CPA', (45, 63))	('transfection', 'Var', (21, 33))	('decreased', 'NegReg', (35, 44))	('rat', 'Species', '10116', (255, 258))	('rat', 'Species', '10116', (57, 60))	('rat', 'Species', '10116', (262, 265))
906077	26718452	Silencing of galectin-3 was shown to promote apoptosis of Eca109 cells, which was concordant with the results of previous studies and confirmed the anti-apoptotic activity of galectin-3 in tumor cells.	('tumor', 'Disease', (189, 194))	('promote', 'PosReg', (37, 44))	('galectin-3', 'Gene', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('apoptosis', 'CPA', (45, 54))	('Silencing', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
906078	26718452	Shi et al revealed that silencing of galectin-3 with siRNA contributed to the stimulation of apoptosis in human colorectal cancer cells.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (106, 111))	('stimulation', 'PosReg', (78, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('apoptosis', 'CPA', (93, 102))	('galectin-3', 'Protein', (37, 47))	('silencing', 'Var', (24, 33))
906079	26718452	Lin et al demonstrated that siRNA-mediated galectin-3 knockdown induced apoptosis, while increased expression of galectin-3 enhanced chemoresistance to doxorubicin with reduced doxo-rubicin-induced apoptosis and expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).	('doxorubicin', 'Chemical', 'MESH:D004317', (152, 163))	('expression', 'MPA', (99, 109))	('galectin-3', 'Gene', (43, 53))	('knockdown', 'Var', (54, 63))	('doxo-rubicin', 'Chemical', 'MESH:D004317', (177, 189))	('galectin-3', 'Gene', (113, 123))	('expression', 'MPA', (212, 222))	('reduced', 'NegReg', (169, 176))	('enhanced', 'PosReg', (124, 132))	('chemoresistance', 'CPA', (133, 148))	('apoptosis', 'CPA', (72, 81))	('rat', 'Species', '10116', (17, 20))	('tumor necrosis factor-related apoptosis-inducing ligand', 'Gene', '8743', (226, 281))	('increased', 'PosReg', (89, 98))	('doxo-rubicin-induced', 'MPA', (177, 197))	('TRAIL', 'Gene', '8743', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('TRAIL', 'Gene', (283, 288))
906139	25663931	Additional analysis of the subgroups identified that in the CCRT patients, the five-year OS rate in the low PLT group was significantly lower compared with the moderate PLT group (56.9 vs. 76.7%; P=0.007; Table II; Fig.	('patients', 'Species', '9606', (65, 73))	('lower', 'NegReg', (136, 141))	('low', 'Var', (104, 107))
906140	25663931	Furthermore, the five-year OS and DMFS rates in the high PLT group were significantly lower compared with the moderate PLT group (OS: 60.7 vs. 76.7%; P=0.022; DMFS: 77.4 vs. 89.5%; P=0.012; Table II; Fig.	('DMFS', 'Chemical', '-', (34, 38))	('lower', 'NegReg', (86, 91))	('DMFS', 'Chemical', '-', (159, 163))	('high', 'Var', (52, 56))	('DMFS', 'CPA', (34, 38))
906142	25663931	However, the five-year OS and DMFS rates in the high PLT group were significantly lower than those in the moderate PLT group (OS: 76.4 vs. 83.2%; P=0.001; DMFS: 86.0 vs. 94.9%; P<0.001; Table II; Fig.	('DMFS', 'Chemical', '-', (30, 34))	('DMFS', 'Chemical', '-', (155, 159))	('DMFS', 'CPA', (30, 34))	('high', 'Var', (48, 52))	('lower', 'NegReg', (82, 87))
906143	25663931	2C and D) and the five-year DMFS rate in the high PLT group was significantly lower than that in the low PLT group (86.0 vs. 93.5%; P=0.025; Table II; Fig.	('DMFS', 'Chemical', '-', (28, 32))	('high PLT', 'Var', (45, 53))	('lower', 'NegReg', (78, 83))	('DMFS', 'CPA', (28, 32))
906146	25663931	Additionally, a high PLT count was significantly associated with a poor DMFS rate in the RT patients in comparison with a low PLT count (P=0.025).	('PLT', 'Gene', (21, 24))	('high', 'Var', (16, 20))	('poor', 'NegReg', (67, 71))	('patients', 'Species', '9606', (92, 100))	('DMFS rate', 'MPA', (72, 81))	('DMFS', 'Chemical', '-', (72, 76))
906149	25663931	In addition, a high PLT count was independently associated with a poor DMFS rate compared with a low PLT count (HR, 2.454; 95% CI, 1.121-5.372; Table III; Fig.	('high', 'Var', (15, 19))	('PLT', 'Gene', (20, 23))	('DMFS rate', 'MPA', (71, 80))	('DMFS', 'Chemical', '-', (71, 75))	('poor', 'NegReg', (66, 70))
906151	25663931	The study demonstrated that in comparison to a moderate PLT count, a low PLT count was significantly and independently associated with a poor OS rate in CCRT patients, and a high PLT count was significantly and independently associated with poor OS and DMFS rates in CCRT and RT patients.	('low', 'Var', (69, 72))	('PLT', 'MPA', (73, 76))	('PLT', 'Gene', (179, 182))	('poor OS', 'MPA', (137, 144))	('poor OS', 'MPA', (241, 248))	('patients', 'Species', '9606', (279, 287))	('CCRT', 'Disease', (153, 157))	('patients', 'Species', '9606', (158, 166))	('associated', 'Reg', (225, 235))	('CCRT', 'Disease', (267, 271))	('DMFS', 'Chemical', '-', (253, 257))	('associated', 'Reg', (119, 129))
906160	25663931	However, in CCRT patients in the present study, the association between low or high PLT count and DMFS was not significant, and a low PLT count was significantly associated with a poor OS rate compared with a moderate PLT count, despite exhibiting a greater negative effect on OS than a high PLT count.	('DMFS', 'Chemical', '-', (98, 102))	('low', 'Var', (130, 133))	('patients', 'Species', '9606', (17, 25))	('poor OS rate', 'CPA', (180, 192))
906266	12845306	LaBerge reported an 18% incidence of hepatic encephalopathy after TIPS, and in our study, its incidence among Group 1 patients (gastric varix without gastrorenal shunt and TIPS) was similar.	('gastric varix', 'Phenotype', 'HP:0030169', (128, 141))	('encephalopathy', 'Phenotype', 'HP:0001298', (45, 59))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (37, 59))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (37, 59))	('hepatic encephalopathy', 'Disease', (37, 59))	('TIPS', 'Var', (66, 70))	('patients', 'Species', '9606', (118, 126))
906271	12845306	In our study, the Child-Pugh score showed a statistically significant improvement in patients who underwent BRTO, though in three TIPS patients in Group 1 and three in Group 2, the Child-Pugh score worsened.	('patients', 'Species', '9606', (135, 143))	('improvement', 'PosReg', (70, 81))	('Child', 'Species', '9606', (181, 186))	('Child', 'Species', '9606', (18, 23))	('patients', 'Species', '9606', (85, 93))	('BRTO', 'Chemical', '-', (108, 112))	('BRTO', 'Var', (108, 112))
906299	33725995	Postoperative changes in the anatomical pathway of the upper digestive tract, perioperative fasting (usually 5-7 days), surgical trauma stress, absorption of endotoxin and destruction of mucosal barrier lead to the disorder of digestive tract flora, resulting in a series of gastrointestinal complications and aggravating the poor nutritional status of postoperative patients with esophageal cancer.	('esophageal cancer', 'Disease', (381, 398))	('disorder', 'MPA', (215, 223))	('disorder of digestive tract', 'Phenotype', 'HP:0011024', (215, 242))	('digestive tract flora', 'MPA', (227, 248))	('esophageal cancer', 'Disease', 'MESH:D004938', (381, 398))	('gastrointestinal complications', 'Phenotype', 'HP:0004798', (275, 305))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('patients', 'Species', '9606', (367, 375))	('lead to', 'Reg', (203, 210))	('changes', 'Var', (14, 21))	('gastrointestinal complications', 'MPA', (275, 305))	('resulting in', 'Reg', (250, 262))	('trauma stress', 'Disease', (129, 142))	('aggravating', 'PosReg', (310, 321))	('trauma stress', 'Disease', 'MESH:D000079225', (129, 142))
906303	33725995	Existing studies have confirmed that changes in the composition of digestive tract flora are closely related to esophageal cancer and digestive tract carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('carcinogenesis', 'Disease', 'MESH:D063646', (150, 164))	('changes', 'Var', (37, 44))	('carcinogenesis', 'Disease', (150, 164))	('esophageal cancer', 'Disease', (112, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))	('related', 'Reg', (101, 108))
906334	33725995	After operation, the gastrointestinal tract of patients with esophageal cancer is mostly in a state of hypodynamic, and up to 50% of patients will have disturbance of gastric emptying, gastric dumping syndrome, dysphagia and other phenomena, which can lead to enteral nutritional intolerance, adverse reactions such as reflux, vomiting, abdominal distension, constipation, diarrhea, and even serious complications such as aspiration pneumonia and severe malnutrition.	('lead to', 'Reg', (252, 259))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('dysphagia', 'Disease', 'MESH:D003680', (211, 220))	('diarrhea', 'Disease', 'MESH:D003967', (373, 381))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (47, 55))	('dysphagia', 'Disease', (211, 220))	('constipation', 'Disease', (359, 371))	('aspiration pneumonia', 'Disease', (422, 442))	('esophageal cancer', 'Disease', (61, 78))	('disturbance', 'Var', (152, 163))	('gastric dumping syndrome', 'Disease', 'MESH:D004377', (185, 209))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('enteral nutritional', 'Disease', (260, 279))	('gastric emptying', 'Disease', (167, 183))	('gastric dumping syndrome', 'Disease', (185, 209))	('gastric emptying', 'Phenotype', 'HP:0002578', (167, 183))	('abdominal distension', 'Disease', (337, 357))	('abdominal distension', 'Phenotype', 'HP:0003270', (337, 357))	('dysphagia', 'Phenotype', 'HP:0002015', (211, 220))	('malnutrition', 'Phenotype', 'HP:0004395', (454, 466))	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (422, 442))	('diarrhea', 'Phenotype', 'HP:0002014', (373, 381))	('constipation', 'Phenotype', 'HP:0002019', (359, 371))	('severe malnutrition', 'Disease', (447, 466))	('aspiration', 'Phenotype', 'HP:0002835', (422, 432))	('vomiting', 'Disease', 'MESH:D014839', (327, 335))	('diarrhea', 'Disease', (373, 381))	('constipation', 'Disease', 'MESH:D003248', (359, 371))	('vomiting', 'Phenotype', 'HP:0002013', (327, 335))	('pneumonia', 'Phenotype', 'HP:0002090', (433, 442))	('reflux', 'Disease', (319, 325))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (422, 442))	('vomiting', 'Disease', (327, 335))
906357	33578739	Genomic profiling of primary non-cardia GC has led to the identification of four tumor subgroups: 9% positive for Epstein-Barr virus, 22% microsatellite unstable, 20% genomically stable and 50% chromosomally unstable tumors.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('Epstein-Barr', 'MPA', (114, 126))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('microsatellite unstable', 'Var', (138, 161))	('positive', 'Reg', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
906360	33578739	True hereditary GC accounts for about 1-3% of all GC mainly due to mutations in Cadherin-1 (CDH1) and catenin alpha-1 (CTNNA1) mutations.	('CTNNA1', 'Gene', '1495', (119, 125))	('catenin alpha-1', 'Gene', '1495', (102, 117))	('Cadherin-1', 'Gene', (80, 90))	('catenin alpha-1', 'Gene', (102, 117))	('due', 'Reg', (60, 63))	('mutations', 'Var', (67, 76))	('CDH1', 'Gene', (92, 96))	('Cadherin-1', 'Gene', '999', (80, 90))	('mutations', 'Var', (127, 136))	('CDH1', 'Gene', '999', (92, 96))	('CTNNA1', 'Gene', (119, 125))
906368	33578739	In the United States, diets including fiber, vitamin B6, beta-carotene and vitamin C were inversely correlated with esophageal cancer, while consumption of animal protein, cholesterol and vitamin B12 were directly associated with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('correlated', 'Interaction', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('vitamin B6', 'Chemical', 'MESH:D025101', (45, 55))	('vitamin C', 'Chemical', 'MESH:D001205', (75, 84))	('vitamin B6', 'Var', (45, 55))	('beta-carotene', 'Chemical', 'MESH:D019207', (57, 70))	('cholesterol', 'Chemical', 'MESH:D002784', (172, 183))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('beta-carotene', 'Var', (57, 70))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', (127, 133))	('inversely', 'NegReg', (90, 99))	('vitamin B12', 'Chemical', 'MESH:D014805', (188, 199))
906388	33578739	From our discussion thus far, it can be seen that at the molecular level, gene mutations are distinct and impact the phenotypes of these tumors.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('impact', 'Reg', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('mutations', 'Var', (79, 88))
906399	33578739	Correa's Cascade was pioneered by Pelayo Correa and is a detailed histological classification of all of the histological changes that occur in the gastric epithelium that start with infection with Helicobacter pylori, proceeds to the formation of precancerous lesions and eventually culminates in GC.	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('Helicobacter pylori', 'Var', (197, 216))	('infection', 'Disease', (182, 191))	('precancerous lesions', 'Disease', 'MESH:D011230', (247, 267))	('infection', 'Disease', 'MESH:D007239', (182, 191))	('precancerous lesions', 'Disease', (247, 267))	('Helicobacter pylori', 'Species', '210', (197, 216))	('culminates', 'Reg', (283, 293))
906404	33578739	It can be seen that Phe, Tyr and Trp biosynthesis has been rated as important (indicated by dark red color), has several differential metabolites in the pathway (indicated by the size of the circle) and has the greatest impact (indicated by the x-axis).	('Tyr', 'Chemical', 'MESH:D014443', (25, 28))	('Trp', 'Gene', (33, 36))	('Phe', 'Chemical', 'MESH:D010649', (20, 23))	('Trp', 'Chemical', 'MESH:D014364', (33, 36))	('differential metabolites', 'MPA', (121, 145))	('Phe', 'Var', (20, 23))	('Tyr', 'Disease', (25, 28))
906407	33578739	Kynurenine, a major metabolite of Trp via the enzyme indoleamine-2,3-dioxygenase (IDO1), induces immunosuppression by binding to and activating the transcription factor aryl hydrocarbon receptor (AhR).	('AhR', 'Gene', '196', (196, 199))	('IDO1', 'Gene', (82, 86))	('activating', 'PosReg', (133, 143))	('induces', 'Reg', (89, 96))	('Kynurenine', 'Var', (0, 10))	('Trp', 'Chemical', 'MESH:D014364', (34, 37))	('IDO1', 'Gene', '3620', (82, 86))	('binding', 'Interaction', (118, 125))	('aryl hydrocarbon receptor', 'Gene', '196', (169, 194))	('Kynurenine', 'Chemical', 'MESH:D007737', (0, 10))	('aryl hydrocarbon receptor', 'Gene', (169, 194))	('immunosuppression', 'CPA', (97, 114))	('AhR', 'Gene', (196, 199))
906418	33578739	Gln is the amino acid that is consumed the most by cancer cells and inhibition of glutaminase which converts Gln to Glu, by CB-839 is in pre-clinical and clinical trials.	('Glu', 'Chemical', 'MESH:D018698', (116, 119))	('CB-839', 'Gene', (124, 130))	('inhibition', 'Var', (68, 78))	('glutaminase', 'Gene', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Gln', 'Chemical', 'MESH:D005973', (109, 112))	('CB-839', 'Chemical', 'MESH:C000593334', (124, 130))	('glutaminase', 'Gene', '2744', (82, 93))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('Gln', 'Chemical', 'MESH:D005973', (0, 3))
906419	33578739	The enzyme glutamate dehydrogenase is responsible for the bioconversion of Glu to alpha-ketoglutamate for use in the TCA cycle and inhibition of this enzyme has been used to inhibit tumor growth.	('tumor', 'Disease', (182, 187))	('TCA', 'Chemical', 'MESH:D013656', (117, 120))	('glutamate', 'Chemical', 'MESH:D018698', (11, 20))	('inhibit', 'NegReg', (174, 181))	('responsible', 'Reg', (38, 49))	('Glu', 'Chemical', 'MESH:D018698', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('glutamate', 'Chemical', 'MESH:D018698', (92, 101))	('inhibition', 'Var', (131, 141))	('alpha-ketoglutamate', 'Chemical', 'MESH:C088956', (82, 101))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
906448	33578739	Inhibiting cysteine uptake has been shown to reduce cancer cell viability which was caused by uncontrolled oxidative stresses.	('cysteine', 'Chemical', 'MESH:D003545', (11, 19))	('Inhibiting', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (107, 123))	('oxidative stresses', 'Phenotype', 'HP:0025464', (107, 125))	('cysteine uptake', 'MPA', (11, 26))	('reduce', 'NegReg', (45, 51))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
906470	33578739	It has been previously reported that high enzyme activity of the kynurenine pathway is associated with immune escape, tumor progression and migration.	('immune escape', 'CPA', (103, 116))	('kynurenine pathway', 'Pathway', (65, 83))	('high', 'Var', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('associated', 'Reg', (87, 97))	('tumor', 'Disease', (118, 123))	('kynurenine', 'Chemical', 'MESH:D007737', (65, 75))	('enzyme activity', 'MPA', (42, 57))	('migration', 'CPA', (140, 149))
906471	33578739	It has also been demonstrated that kynurenine inhibits T-cell proliferation and induces T-cell apoptosis, leading to immune tolerance and a tumor progression/metastatic microenvironment.	('kynurenine', 'Var', (35, 45))	('immune tolerance', 'CPA', (117, 133))	('T-cell apoptosis', 'CPA', (88, 104))	('T-cell proliferation', 'CPA', (55, 75))	('inhibits', 'NegReg', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('leading', 'PosReg', (106, 113))	('kynurenine', 'Chemical', 'MESH:D007737', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('induces', 'Reg', (80, 87))	('tumor', 'Disease', (140, 145))
906474	33578739	Their results showed that the ratios of KYN/TRP, 5HTP/TRP, 5HIAA/TRP and 5HT/TRP exhibited a similar up-regulated tendency among healthy controls, ESCC and mESCC patients and that the ratios of KYN/TRP and 5HTP/TRP were significantly different between metastatic ESCC and ESCC patients.	('KYN', 'Chemical', 'MESH:D007737', (40, 43))	('TRP', 'Chemical', 'MESH:D014364', (54, 57))	('5HT/TRP', 'Var', (73, 80))	('TRP', 'Chemical', 'MESH:D014364', (77, 80))	('5HTP/TRP', 'Var', (49, 57))	('5HIAA', 'Chemical', '-', (59, 64))	('TRP', 'Chemical', 'MESH:D014364', (198, 201))	('patients', 'Species', '9606', (277, 285))	('5HTP', 'Chemical', 'MESH:D006916', (206, 210))	('up-regulated', 'PosReg', (101, 113))	('TRP', 'Chemical', 'MESH:D014364', (211, 214))	('TRP', 'Chemical', 'MESH:D014364', (44, 47))	('ESCC', 'Disease', (272, 276))	('patients', 'Species', '9606', (162, 170))	('5HIAA/TRP', 'Var', (59, 68))	('metastatic ESCC', 'Disease', (252, 267))	('TRP', 'Chemical', 'MESH:D014364', (65, 68))	('5HT', 'Chemical', 'MESH:D012701', (49, 52))	('5HT', 'Chemical', 'MESH:D012701', (73, 76))	('KYN', 'Chemical', 'MESH:D007737', (194, 197))	('KYN/TRP', 'Var', (40, 47))	('5HTP', 'Chemical', 'MESH:D006916', (49, 53))	('5HT', 'Chemical', 'MESH:D012701', (206, 209))
906479	33578739	While butyrate has been shown to have beneficial effects, in the context of APC mutations as is found in nearly all of CRC, butyrate was shown to promote proliferation of aberrant epithelial cells contributing to increased cancer polyp formation.	('APC', 'Gene', '324', (76, 79))	('butyrate', 'Chemical', 'MESH:D002087', (6, 14))	('butyrate', 'Chemical', 'MESH:D002087', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('APC', 'Gene', (76, 79))	('cancer', 'Disease', (223, 229))	('proliferation', 'CPA', (154, 167))	('increased', 'PosReg', (213, 222))	('promote', 'PosReg', (146, 153))
906499	32341351	Using genomic sequencing of 612 ESCC patients, we analyzed the associations of ZNF750 mutations with clinicopathologic features and its prognostic value.	('mutations', 'Var', (86, 95))	('ESCC', 'Disease', (32, 36))	('associations', 'Interaction', (63, 75))	('patients', 'Species', '9606', (37, 45))	('ZNF750', 'Gene', (79, 85))
906500	32341351	The results showed ZNF750 mutations/deletions are significantly associated with malignant progression and poor prognosis of ESCC patients.	('associated', 'Reg', (64, 74))	('mutations/deletions', 'Var', (26, 45))	('patients', 'Species', '9606', (129, 137))	('ESCC', 'Disease', (124, 128))	('ZNF750', 'Gene', (19, 25))	('malignant progression', 'CPA', (80, 101))
906501	32341351	Decreased ZNF750 in ESCC cells induces enhanced angiogenesis of human umbilical vein endothelial cells (HUVECs) and human arterial endothelial cells (HAECs), and the effect may be indirectly mediated by FOXC2.	('Decreased', 'Var', (0, 9))	('human', 'Species', '9606', (64, 69))	('ZNF750', 'Gene', (10, 16))	('HUVEC', 'CellLine', 'CVCL:2959', (104, 109))	('enhanced', 'PosReg', (39, 47))	('angiogenesis', 'CPA', (48, 60))	('human', 'Species', '9606', (116, 121))
906503	32341351	Our study reveals a novel mechanism of ZNF750, highlights a significance of ZNF750 as a metastatic and prognostic biomarker, and offers potential therapeutic targets for ESCC patients harboring ZNF750 mutations.	('mutations', 'Var', (201, 210))	('ZNF750', 'Gene', (76, 82))	('patients', 'Species', '9606', (175, 183))	('ZNF750', 'Gene', (194, 200))	('ESCC', 'Disease', (170, 174))
906505	32341351	Recent studies have profiled ESCC genomic alterations and have identified significantly mutated genes (SMGs) including TP53, ZNF750, NOTCH1, FAT1, NFE2L2, copy number amplifications occurring in SOX2, TERT, FGFR1, MDM1, and common deletions of RB1 etc.	('FAT1', 'Gene', (141, 145))	('ZNF750', 'Gene', (125, 131))	('TP53', 'Gene', '7157', (119, 123))	('FGFR1', 'Gene', (207, 212))	('RB1', 'Gene', (244, 247))	('NFE2L2', 'Gene', '4780', (147, 153))	('NOTCH1', 'Gene', (133, 139))	('TERT', 'Gene', (201, 205))	('MDM1', 'Gene', (214, 218))	('FAT1', 'Gene', '2195', (141, 145))	('copy number amplifications', 'Var', (155, 181))	('deletions', 'Var', (231, 240))	('TERT', 'Gene', '7015', (201, 205))	('RB1', 'Gene', '5925', (244, 247))	('NOTCH1', 'Gene', '4851', (133, 139))	('NFE2L2', 'Gene', (147, 153))	('MDM1', 'Gene', '56890', (214, 218))	('TP53', 'Gene', (119, 123))	('FGFR1', 'Gene', '2260', (207, 212))	('SOX2', 'Gene', '6657', (195, 199))	('SOX2', 'Gene', (195, 199))
906509	32341351	ZNF750 also suppressed migration of SCC cells by directly inhibiting transactivation of LAMC2.	('migration of SCC cells', 'CPA', (23, 45))	('transactivation', 'MPA', (69, 84))	('LAMC2', 'Gene', (88, 93))	('inhibiting', 'NegReg', (58, 68))	('LAMC2', 'Gene', '3918', (88, 93))	('suppressed', 'NegReg', (12, 22))	('ZNF750', 'Var', (0, 6))
906510	32341351	Recent attempts to decipher the significance of ZNF750 for tumorigenesis in ESCC have revealed that ZNF750 might act as a tumor suppressor gene.	('ZNF750', 'Var', (100, 106))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('ESCC', 'Disease', (76, 80))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
906512	32341351	In this study, we reveal the associations ZNF750 mutations and/or deletions with clinical variables using genomic sequencing data of 612 pairs of ESCC tumor and normal samples from China and explore the molecular mechanism through which ZNF750 plays a critical role in driving the formation of metastatic ESCC.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('ZNF750', 'Gene', (42, 48))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', (151, 156))	('associations', 'Interaction', (29, 41))	('deletions', 'Var', (66, 75))	('metastatic ESCC', 'Disease', (294, 309))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
906514	32341351	Our findings reveal an underlying mechanism by which loss-function of ZNF750 contributes to ESCC progression, provide a potential metastatic and prognostic biomarker and several therapeutic targets for ESCC patients harboring ZNF750 mutations and/or deletions.	('patients', 'Species', '9606', (207, 215))	('deletions', 'Var', (250, 259))	('ESCC', 'Disease', (92, 96))	('ZNF750', 'Gene', (226, 232))	('loss-function', 'NegReg', (53, 66))	('ZNF750', 'Gene', (70, 76))	('ESCC', 'Disease', (202, 206))	('mutations', 'Var', (233, 242))
906519	32341351	Together with our previous 104 ESCC patients recruited from the Taihang Mountain of North-Central China, we analyzed the associations of ZNF750 mutations with patients' clinical features in a cohort of 612 ESCC patients in this study.	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (36, 44))	('ZNF750', 'Gene', (137, 143))	('mutations', 'Var', (144, 153))	('patients', 'Species', '9606', (159, 167))
906522	32341351	We also imputed deviation in the allele frequency of heterozygous single-nucleotide variation to predict the tumor purity and ploidy for each sample with a median of 51.18%.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('single-nucleotide variation', 'Var', (66, 93))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
906523	32341351	For each paired sample, somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) were detected by MuTect2 (http://archive.broadinstitute.org/cancer/cga/mutect).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('single-nucleotide variants', 'Var', (32, 58))	('cga', 'Gene', '1113', (177, 180))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cga', 'Gene', (177, 180))
906528	32341351	Immortalized esophageal epithelial cell SHEE and ESCC cell lines KYSE140, KYSE150, KYSE180, KYSE410, KYSE510, KYSE450, Colo680N, ECA109 were stored at Shanxi key laboratory of carcinogenesis and translational research on esophageal cancer, Shanxi Medical University.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('KYSE180', 'Var', (83, 90))	('cancer', 'Disease', (232, 238))	('KYSE410', 'Var', (92, 99))	('KYSE150', 'CellLine', 'CVCL:1348', (74, 81))	('KYSE150', 'Var', (74, 81))	('carcinogenesis', 'Disease', 'MESH:D063646', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('KYSE180', 'CellLine', 'CVCL:1349', (83, 90))	('carcinogenesis', 'Disease', (176, 190))	('KYSE510', 'Var', (101, 108))	('HE', 'Chemical', '-', (41, 43))	('KYSE450', 'CellLine', 'CVCL:1353', (110, 117))
906555	32341351	Approximately 1 x 107 cells transfected with pcDNA3.1-HA ZNF750-wt were cross-linked in 1% formaldehyde at 37  C for 10 min, and then 1.25 M glycine was added to quench the excess formaldehyde at room temperature for 5 min.	('pcDNA3.1-HA', 'Var', (45, 56))	('formaldehyde', 'Chemical', 'MESH:D005557', (91, 103))	('glycine', 'Chemical', 'MESH:D005998', (141, 148))	('formaldehyde', 'Chemical', 'MESH:D005557', (180, 192))	('ZNF750-wt', 'Gene', (57, 66))
906561	32341351	RIP was performed to assess the interaction between DANCR and miR-4707-3p using a Magna RIP kit (Millipore, USA) according to the manufacturer's instruction.	('RIP', 'Gene', '3267', (0, 3))	('RIP', 'Gene', (88, 91))	('RIP', 'Gene', (0, 3))	('RIP', 'Gene', '3267', (88, 91))	('miR-4707-3p', 'Var', (62, 73))	('interaction', 'Interaction', (32, 43))
906572	32341351	Moreover, we observed recurrent mutations in noncoding regions of ZNF750, being mutated in 48 out of 508 (9.5%) tumors that have WGS data available.	('tumors', 'Disease', (112, 118))	('ZNF750', 'Gene', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
906576	32341351	Although most features were not statistically significant, this analysis identified the following statistically significant patterns: (i) ZNF750 mutations (n = 48 tumors) were significantly associated with late pathological stage (P = 0.000078), (ii) patients harboring ZNF750 mutations exhibited more lymph node metastasis (P = 0.00011) and more distant metastasis (P = 0.001) compared with patients harboring no mutations in ZNF750 (Table 1), and (iii) patients in subgroup of "ZNF750-wt" showed significantly better survival as compared to patients in subgroup of "mutated" (Kaplan-Meier analysis, P = 0.026; Cox regression, P = 0.029, hazard ratio (HR): 1.541, 95% confidence interval (CI): 1.044-2.261) (Fig.	('patients', 'Species', '9606', (455, 463))	('lymph node metastasis', 'CPA', (302, 323))	('mutations', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('better', 'PosReg', (512, 518))	('tumors', 'Disease', (163, 169))	('mutations', 'Var', (277, 286))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('ZNF750', 'Gene', (138, 144))	('associated', 'Reg', (190, 200))	('patients', 'Species', '9606', (251, 259))	('patients', 'Species', '9606', (392, 400))	('patients', 'Species', '9606', (543, 551))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('distant metastasis', 'CPA', (347, 365))	('ZNF750', 'Gene', (270, 276))
906577	32341351	Strikingly, analysis of copy number alterations in 508 pairs of WGS revealed that ZNF750 copy number loss (n = 71) was statistically associated with more lymph node metastasis (P = 0.046) compared with patients harboring no deletions in ZNF750.	('ZNF750', 'Gene', (82, 88))	('loss', 'NegReg', (101, 105))	('copy number', 'Var', (89, 100))	('patients', 'Species', '9606', (202, 210))	('lymph node metastasis', 'CPA', (154, 175))	('more', 'PosReg', (149, 153))
906578	32341351	Subsequently, Kaplan-Meier's analysis revealed that patients with ZNF750 copy number loss developed more-frequent recurrence and had poorer survival (P = 0.048, Fig.	('poorer', 'NegReg', (133, 139))	('recurrence', 'MPA', (114, 124))	('ZNF750', 'Gene', (66, 72))	('survival', 'MPA', (140, 148))	('patients', 'Species', '9606', (52, 60))	('copy number loss', 'Var', (73, 89))
906580	32341351	Together, these findings suggest that there are clear associations between ZNF750 mutations/deletions and clinical characteristics of Chinese ESCC patients, supporting the clinical potential of ZNF750 mutations/deletions with its ability to estimate the metastasis and survival of patients with ESCC.	('patients', 'Species', '9606', (281, 289))	('mutations/deletions', 'Var', (82, 101))	('associations', 'Interaction', (54, 66))	('patients', 'Species', '9606', (147, 155))	('ZNF750', 'Gene', (194, 200))	('ZNF750', 'Gene', (75, 81))	('mutations/deletions', 'Var', (201, 220))
906585	32341351	We found that the proliferation rates of HUVEC were not significantly increased when treated with conditioned medium from KYSE140 cells with ZNF750 knockdown.	('HUVEC', 'CellLine', 'CVCL:2959', (41, 46))	('knockdown', 'Var', (148, 157))	('ZNF750', 'Gene', (141, 147))
906598	32341351	Importantly, knockdown FOXC2 in ZNF750 knockdown KYSE140 cells decreased the ability of migration, invasion and tube formation in HUVEC cells treated with conditioned medium (CM) from ZNF750 knockdown KYSE140 cells and KYSE450 cells, respectively (Fig.	('decreased', 'NegReg', (63, 72))	('KYSE450', 'CellLine', 'CVCL:1353', (219, 226))	('tube formation', 'CPA', (112, 126))	('FOXC2', 'Gene', (23, 28))	('knockdown', 'Var', (13, 22))	('HUVEC', 'CellLine', 'CVCL:2959', (130, 135))
906600	32341351	We then detected the effect of ZNF750 and FOXC2 on Ang-2 and VEGFs, and found ZNF750 knockdown induced up-regulation of Ang-2 and VEGFs in ESCC cells whereas downregulated FOXC2 reversed the phenomenon (Fig.	('Ang-2', 'Gene', (120, 125))	('up-regulation', 'PosReg', (103, 116))	('FOXC2', 'Gene', (172, 177))	('Ang-2', 'Gene', (51, 56))	('Ang-2', 'Gene', '285', (51, 56))	('knockdown', 'Var', (85, 94))	('VEGFs', 'MPA', (130, 135))	('Ang-2', 'Gene', '285', (120, 125))	('ZNF750', 'Gene', (78, 84))
906601	32341351	Thus, FOXC2 may act as a mediator of tumor angiogenesis induced by ZNF750 knockdown in ESCC.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('FOXC2', 'Gene', (6, 11))	('knockdown', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('ESCC', 'Disease', (87, 91))	('ZNF750', 'Gene', (67, 73))
906608	32341351	4h), indicating that miR-4707-3p probably binds to the predicted MRE region of DANCR, thus downregulates DANCR expression (Fig.	('miR-4707-3p', 'Var', (21, 32))	('downregulates', 'NegReg', (91, 104))	('DANCR', 'Protein', (105, 110))	('4h', 'Chemical', '-', (0, 2))
906609	32341351	Moreover, RNA-Binding Protein Immunoprecipitation Assay (RIP) experiment using antibody against Ago2 in KYSE150 cell extracts showed that DANCR and miR-4707-3p were preferentially enriched in Ago2-containing miRNPs relative to the control IgG immunoprecipitates (Fig.	('preferentially', 'PosReg', (165, 179))	('Ago2', 'Gene', (96, 100))	('RNA-Binding Protein Immunoprecipitation Assay', 'Gene', (10, 55))	('RIP', 'Gene', (57, 60))	('KYSE150', 'CellLine', 'CVCL:1348', (104, 111))	('RNA-Binding Protein Immunoprecipitation Assay', 'Gene', '3267', (10, 55))	('Ago2', 'Gene', '27161', (192, 196))	('RIP', 'Gene', '3267', (57, 60))	('miR-4707-3p', 'Var', (148, 159))	('Ago2', 'Gene', '27161', (96, 100))	('Ago2', 'Gene', (192, 196))
906610	32341351	4j), indicating that DANCR, likely through interacting with miR-4707-3p, was present in Ago2-containing miRNPs.	('Ago2', 'Gene', (88, 92))	('Ago2', 'Gene', '27161', (88, 92))	('miR-4707-3p', 'Var', (60, 71))	('interacting', 'Interaction', (43, 54))
906611	32341351	Silence of miR-4707-3p led to an increase of FOXC2 mRNA and protein level in KYSE-150 cells whereas augmentation of miR-4707-3p caused a decrease of FOXC2 in Eca109 cells (Fig.	('decrease', 'NegReg', (137, 145))	('FOXC2', 'Gene', (45, 50))	('increase', 'PosReg', (33, 41))	('KYSE-150', 'CellLine', 'CVCL:1348', (77, 85))	('miR-4707-3p', 'Var', (116, 127))	('miR-4707-3p', 'Var', (11, 22))	('Silence', 'Var', (0, 7))
906613	32341351	Given that the DANCR/miR-4707-3p/FOXC2 axis in ESCC, we hypothesize ZNF750 may directly downregulate DANCR expression, strengthened the interaction of miR-4707-3p with FOXC2-3'UTR in a ceRNA manner, leading to degradation of FOXC2 mRNA, thus playing tumor suppressive role in ESCC.	('degradation', 'MPA', (210, 221))	('downregulate', 'NegReg', (88, 100))	('ESCC', 'Disease', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('FOXC2', 'Gene', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('DANCR', 'Protein', (101, 106))	('miR-4707-3p', 'Var', (151, 162))	('strengthened', 'PosReg', (119, 131))	('interaction', 'Interaction', (136, 147))	('ZNF750', 'Var', (68, 74))	('tumor', 'Disease', (250, 255))	('ESCC', 'Disease', (276, 280))
906614	32341351	To further validate this hypothesis, western blot and qPCR were used to detect the expression of DANCR, miR-4707-3p, FOXC2 in ZNF750 knockdown or overexpression cells and xenograft mouse samples.	('DANCR', 'Gene', (97, 102))	('FOXC2', 'Gene', (117, 122))	('mouse', 'Species', '10090', (181, 186))	('miR-4707-3p', 'Var', (104, 115))
906622	32341351	Consistent with our paired ESCC samples, we found the negatively correlation of ZNF750 mRNA with FOXC2 mRNA in 92 ESCC cases (r = -0.2151, P = 0.0395), 513 cases of head and neck squamous cell carcinoma (r = -0.2211, P < 0.0001), 493 cases of squamous cell carcinoma of lung (r = -0.1327, P = 0.0031), and 300 cases of cervical squamous cell carcinoma (r = -0.1518, P = 0.0085), suggesting a possibility of ZNF750 deregulates FOXC2 expression in human squamous cell carcinoma (Fig.	('human', 'Species', '9606', (446, 451))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 202))	('expression', 'MPA', (432, 442))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (452, 475))	('cervical squamous cell carcinoma', 'Disease', (319, 351))	('neck squamous cell carcinoma', 'Disease', (174, 202))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (328, 351))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (174, 202))	('squamous cell carcinoma of lung', 'Disease', (243, 274))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (319, 351))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (452, 475))	('carcinoma of lung', 'Phenotype', 'HP:0100526', (257, 274))	('deregulates', 'NegReg', (414, 425))	('FOXC2', 'Gene', (426, 431))	('carcinoma', 'Phenotype', 'HP:0030731', (466, 475))	('squamous cell carcinoma', 'Disease', (452, 475))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('squamous cell carcinoma of lung', 'Disease', 'MESH:D002294', (243, 274))	('ZNF750', 'Var', (407, 413))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (328, 351))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (243, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
906623	32341351	6c-e).These datas indicate a possibility of ZNF750 deregulates FOXC2 expression in human squamous cell carcinoma.	('deregulates', 'NegReg', (51, 62))	('FOXC2', 'Gene', (63, 68))	('human', 'Species', '9606', (83, 88))	('expression', 'MPA', (69, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('ZNF750', 'Var', (44, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('squamous cell carcinoma', 'Disease', (89, 112))
906625	32341351	In this study, we profiled mutation and copy number alterations of ZNF750 and uncovered its potential prognostic value for ESCC patients in an enlarged ESCC cohort.	('ESCC', 'Disease', (123, 127))	('mutation', 'Var', (27, 35))	('enlarged ESCC', 'Phenotype', 'HP:0003565', (143, 156))	('ZNF750', 'Gene', (67, 73))	('patients', 'Species', '9606', (128, 136))	('copy number alterations', 'Var', (40, 63))
906629	32341351	Together with several lines of functional evidences, ZNF750 may work in a loss-of-function manner and its dysregulation may be crucial for tumor formation and progression in ESCC.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('dysregulation', 'Var', (106, 119))	('ESCC', 'Disease', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('ZNF750', 'Gene', (53, 59))	('loss-of-function', 'NegReg', (74, 90))
906633	32341351	In this study, we found that loss-function of ZNF750 significant promoted tumor angiogenesis, which indicates anti-angiogenesis might be an efficient method in the inhibition of the growth and metastasis of ESCC with ZNF750 mutation or deletion.	('ESCC', 'Disease', (207, 211))	('growth', 'CPA', (182, 188))	('ZNF750', 'Gene', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('loss-function', 'NegReg', (29, 42))	('deletion', 'Var', (236, 244))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutation', 'Var', (224, 232))	('promoted', 'PosReg', (65, 73))	('tumor', 'Disease', (74, 79))	('ZNF750', 'Gene', (46, 52))
906635	32341351	In agreement with previous reports on various types of human cancers, DANCR may also act as an oncogene in ESCC progression, supporting that DANCR may offer a potential therapeutic target for those ESCC patients harboring mutations of ZNF750.	('ESCC', 'Disease', (198, 202))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('patients', 'Species', '9606', (203, 211))	('mutations', 'Var', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF750', 'Gene', (235, 241))	('ESCC', 'Disease', (107, 111))
906637	32341351	MiR-4707-3p was previously rarely reported in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('MiR-4707-3p', 'Var', (0, 11))	('human', 'Species', '9606', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('MiR-4707-3p', 'Chemical', '-', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
906638	32341351	Functionally, knockdown of miR-4707-3p promoted tumor angiogenesis probably by releasing the oncogenic role of FOXC2.	('promoted', 'PosReg', (39, 47))	('releasing', 'PosReg', (79, 88))	('tumor', 'Disease', (48, 53))	('FOXC2', 'Gene', (111, 116))	('miR-4707-3p', 'Var', (27, 38))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
906641	32341351	Hence, besides the DANCR, our study provides evidence to support additional potential therapeutic target, FOXC2, for those ESCC patients with ZNF750 mutations.	('ZNF750', 'Gene', (142, 148))	('patients', 'Species', '9606', (128, 136))	('mutations', 'Var', (149, 158))	('ESCC', 'Disease', (123, 127))
906648	32276343	MiR-144s are located in the chromosomal region 17q11.2, which is subject to significant damage in many types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('MiR-144s', 'Var', (0, 8))
906649	32276343	In this review, we assess the involvement of miR-144s in several cancer types by illustrating the possible target genes that are related to each cancer, and we also briefly describe the clinical applications of miR-144s as a diagnostic and prognostic tool in cancers.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('cancers', 'Disease', (259, 266))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('men', 'Species', '9606', (37, 40))	('miR-144s', 'Var', (211, 219))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', (259, 265))
906656	32276343	Among several miRNAs assessed, miR-144s seem to have a role in several cancers.	('role', 'Reg', (55, 59))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('miR-144s', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
906658	32276343	The miR-144 hairpin gives rise to the "guide strand" miR-144-5p and the sister "passenger" strand miR-144-3p (Figure 1B).	('miR-144-3p', 'Chemical', '-', (98, 108))	('miR-144', 'Gene', (4, 11))	('miR-144-5p', 'Var', (53, 63))
906674	32276343	In particular, animal studies showed that the deletion of the miR-144 locus in aged mice induces the development of B-cell lymphoma and acute myeloid leukemia.	('deletion', 'Var', (46, 54))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (116, 131))	('induces', 'Reg', (89, 96))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (136, 158))	('men', 'Species', '9606', (108, 111))	('miR-144', 'Gene', (62, 69))	('acute myeloid leukemia', 'Disease', (136, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (142, 158))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (136, 158))	('B-cell lymphoma', 'Disease', (116, 131))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (116, 131))	('mice', 'Species', '10090', (84, 88))
906682	32276343	Since rLN showed a higher level of miR-144 and a lower number of Foxp3+ cells, the authors hypothesized that both events might cooperate in supporting the proliferation of FL cells.	('Foxp3', 'Gene', (65, 70))	('proliferation', 'CPA', (155, 168))	('miR-144', 'Var', (35, 42))	('lower', 'NegReg', (49, 54))	('Foxp3', 'Gene', '50943', (65, 70))
906696	32276343	Evidence showed that several miRNAs, including miR-144, miR-181a, miR-18a, miR-34c, miR-34a, miR-140, miR-137, miR-148b, and miR-429, which were significantly upregulated in CNS, enhanced the permeability of blood tumor barrier (BTB) and downregulated the expression of junction-related proteins.	('BTB', 'Chemical', '-', (229, 232))	('miR-144', 'Var', (47, 54))	('blood tumor', 'Disease', (208, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('miR-34a', 'Gene', (84, 91))	('expression', 'MPA', (256, 266))	('miR-137', 'Gene', (102, 109))	('miR-34c', 'Gene', '407042', (75, 82))	('miR-18a', 'Gene', (66, 73))	('miR-148b', 'Gene', '442892', (111, 119))	('miR-34c', 'Gene', (75, 82))	('junction-related proteins', 'Protein', (270, 295))	('miR-137', 'Gene', '406928', (102, 109))	('miR-148b', 'Gene', (111, 119))	('miR-34a', 'Gene', '407040', (84, 91))	('miR-429', 'Gene', '554210', (125, 132))	('downregulated', 'NegReg', (238, 251))	('blood tumor', 'Phenotype', 'HP:0004377', (208, 219))	('permeability', 'MPA', (192, 204))	('miR-18a', 'Gene', '406953', (66, 73))	('upregulated', 'PosReg', (159, 170))	('miR-181a', 'Var', (56, 64))	('enhanced', 'PosReg', (179, 187))	('miR-140', 'Gene', (93, 100))	('blood tumor', 'Disease', 'MESH:D007022', (208, 219))	('miR-429', 'Gene', (125, 132))	('miR-140', 'Gene', '406932', (93, 100))
906700	32276343	By using Real-time PCR, luciferase reporter assay, and bioinformatics tools, they also that reported that the deletion of TUG1 via upregulation of miR-144 increased BTB permeability, and down-regulated the expression of the tight junction proteins ZO-1, occludin, and claudin-5.	('down-regulated', 'NegReg', (187, 201))	('ZO-1', 'Gene', '7082', (248, 252))	('upregulation', 'PosReg', (131, 143))	('occludin', 'Gene', (254, 262))	('miR-144', 'Gene', (147, 154))	('increased', 'PosReg', (155, 164))	('BTB permeability', 'MPA', (165, 181))	('expression', 'MPA', (206, 216))	('PC', 'Phenotype', 'HP:0002894', (19, 21))	('TUG1', 'Gene', '55000', (122, 126))	('claudin-5', 'Gene', (268, 277))	('BTB', 'Chemical', '-', (165, 168))	('occludin', 'Gene', '100506658', (254, 262))	('claudin-5', 'Gene', '7122', (268, 277))	('ZO-1', 'Gene', (248, 252))	('deletion', 'Var', (110, 118))	('TUG1', 'Gene', (122, 126))
906706	32276343	In 2008, WHO classified seven AML subtypes: 1:AML with recurrent genetic abnormalities and with gene mutations; 2:AML with myelodysplasia-related changes; 3:therapy-related myeloid neoplasms; 4:AML not otherwise specified (NOS); 5:myeloid sarcoma; 6:myeloid proliferations related to the Down syndrome; and, 7:blastic plasmacytoid dendritic cell neoplasms.	('AML', 'Disease', (114, 117))	('AML', 'Disease', 'MESH:D015470', (194, 197))	('neoplasm', 'Phenotype', 'HP:0002664', (181, 189))	('AML', 'Phenotype', 'HP:0004808', (114, 117))	('neoplasms', 'Phenotype', 'HP:0002664', (346, 355))	('AML', 'Disease', (194, 197))	('myeloid', 'Disease', (250, 257))	('myeloid neoplasms', 'Disease', (173, 190))	('AML', 'Phenotype', 'HP:0004808', (194, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('neoplasm', 'Phenotype', 'HP:0002664', (346, 354))	('blastic', 'CPA', (310, 317))	('myelodysplasia', 'Disease', (123, 137))	('myeloid sarcoma', 'Disease', 'MESH:D023981', (231, 246))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('myeloid sarcoma', 'Disease', (231, 246))	('mutations', 'Var', (101, 110))	('AML', 'Disease', 'MESH:D015470', (30, 33))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (173, 190))	('dendritic cell neoplasms', 'Disease', 'MESH:D054740', (331, 355))	('AML', 'Phenotype', 'HP:0004808', (46, 49))	('Down syndrome', 'Disease', (288, 301))	('AML', 'Disease', (46, 49))	('AML', 'Disease', (30, 33))	('AML', 'Phenotype', 'HP:0004808', (30, 33))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (173, 190))	('OS', 'Phenotype', 'HP:0002669', (224, 226))	('myelodysplasia', 'Phenotype', 'HP:0002863', (123, 137))	('genetic abnormalities', 'Disease', 'MESH:D030342', (65, 86))	('myelodysplasia', 'Disease', 'MESH:D009190', (123, 137))	('genetic abnormalities', 'Disease', (65, 86))	('dendritic cell neoplasms', 'Disease', (331, 355))	('neoplasms', 'Phenotype', 'HP:0002664', (181, 190))	('AML', 'Disease', 'MESH:D015470', (114, 117))
906710	32276343	They assessed the expression of miR-144-3p in the BM and peripheral blood of AML patients and healthy controls.	('AML', 'Disease', 'MESH:D015470', (77, 80))	('patients', 'Species', '9606', (81, 89))	('AML', 'Disease', (77, 80))	('miR-144-3p', 'Var', (32, 42))	('miR-144-3p', 'Chemical', '-', (32, 42))	('expression', 'MPA', (18, 28))	('AML', 'Phenotype', 'HP:0004808', (77, 80))
906712	32276343	The result showed that miR-144-3p was significantly higher in both the peripheral blood and BM of AML patients when compared with the controls and in HL-60 cells.	('AML', 'Disease', 'MESH:D015470', (98, 101))	('patients', 'Species', '9606', (102, 110))	('HL-60', 'CellLine', 'CVCL:0002', (150, 155))	('higher', 'PosReg', (52, 58))	('AML', 'Phenotype', 'HP:0004808', (98, 101))	('miR-144-3p', 'Chemical', '-', (23, 33))	('AML', 'Disease', (98, 101))	('miR-144-3p', 'Var', (23, 33))
906713	32276343	In this study, the downregulation of miR-144-3p, as an oncogene, via the upregulation of NRF2, reduced cell viability and promoted apoptosis.	('NRF2', 'Gene', (89, 93))	('cell viability', 'CPA', (103, 117))	('reduced', 'NegReg', (95, 102))	('miR-144-3p', 'Var', (37, 47))	('promoted', 'PosReg', (122, 130))	('miR-144-3p', 'Chemical', '-', (37, 47))	('apoptosis', 'CPA', (131, 140))	('NRF2', 'Gene', '4780', (89, 93))	('downregulation', 'NegReg', (19, 33))	('upregulation', 'PosReg', (73, 85))
906716	32276343	Mutations of the FLT3 gene occur in almost 30% of all AML cases, with the internal tandem duplication (ITD) expressing the most common type of FLT3 mutation.	('AML', 'Disease', 'MESH:D015470', (54, 57))	('FLT3', 'Gene', '2322', (143, 147))	('FLT3', 'Gene', '2322', (17, 21))	('Mutations', 'Var', (0, 9))	('AML', 'Phenotype', 'HP:0004808', (54, 57))	('AML', 'Disease', (54, 57))	('FLT3', 'Gene', (143, 147))	('internal tandem duplication', 'Var', (74, 101))	('FLT3', 'Gene', (17, 21))
906717	32276343	FLT3 gene alterations are associated with a form of AML that is known as cytogenetically normal AML (CN-AML).	('AML', 'Disease', (96, 99))	('alterations', 'Var', (10, 21))	('AML', 'Phenotype', 'HP:0004808', (104, 107))	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('AML', 'Disease', (104, 107))	('FLT3', 'Gene', '2322', (0, 4))	('AML', 'Disease', (52, 55))	('AML', 'Disease', 'MESH:D015470', (104, 107))	('AML', 'Disease', 'MESH:D015470', (96, 99))	('FLT3', 'Gene', (0, 4))	('associated', 'Reg', (26, 36))	('AML', 'Phenotype', 'HP:0004808', (96, 99))	('AML', 'Disease', 'MESH:D015470', (52, 55))
906720	32276343	They reported the downregulation of miR-144 and upregulation of FLT3, homeobox genes (MEIS1, PBX3, HOXB3) as a possible target of miR-144 in CN-AML.	('AML', 'Phenotype', 'HP:0004808', (144, 147))	('HOXB3', 'Gene', '3213', (99, 104))	('AML', 'Disease', (144, 147))	('miR-144', 'Var', (130, 137))	('HOXB3', 'Gene', (99, 104))	('FLT3', 'Gene', '2322', (64, 68))	('PBX3', 'Gene', (93, 97))	('PBX3', 'Gene', '5090', (93, 97))	('AML', 'Disease', 'MESH:D015470', (144, 147))	('MEIS1', 'Gene', '4211', (86, 91))	('MEIS1', 'Gene', (86, 91))	('FLT3', 'Gene', (64, 68))	('downregulation', 'NegReg', (18, 32))	('miR-144', 'Gene', (36, 43))	('upregulation', 'PosReg', (48, 60))
906724	32276343	The acute myeloid leukemia 1 protein/protein ETO (AML1/ETO; A/E) fusion gene is responsible for 15% of AML cases and 15-26.7% of young patients with EMI.	('patients', 'Species', '9606', (135, 143))	('AML', 'Disease', 'MESH:D015470', (50, 53))	('AML', 'Phenotype', 'HP:0004808', (50, 53))	('AML1', 'Gene', '861', (50, 54))	('AML', 'Disease', (50, 53))	('ETO', 'Gene', '862', (55, 58))	('acute myeloid leukemia', 'Disease', (4, 26))	('AML', 'Disease', 'MESH:D015470', (103, 106))	('AML1', 'Gene', (50, 54))	('AML', 'Disease', (103, 106))	('AML', 'Phenotype', 'HP:0004808', (103, 106))	('ETO', 'Gene', '862', (45, 48))	('fusion', 'Var', (65, 71))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (4, 26))	('responsible', 'Reg', (80, 91))	('ETO', 'Gene', (55, 58))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (4, 26))	('leukemia', 'Phenotype', 'HP:0001909', (18, 26))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (10, 26))	('ETO', 'Gene', (45, 48))
906727	32276343	The patients with high expression of APP were more prone to developing EMI  Acute lymphoblastic leukemia (ALL) is a multi-factorial malignancy with an incidence of over 6000 new cases per year in the United States.	('EMI  Acute lymphoblastic leukemia', 'Phenotype', 'HP:0004812', (71, 104))	('Acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (76, 104))	('multi-factorial malignancy', 'Disease', 'MESH:D009369', (116, 142))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('Acute lymphoblastic leukemia', 'Disease', (76, 104))	('ALL', 'Phenotype', 'HP:0006721', (106, 109))	('multi-factorial malignancy', 'Disease', (116, 142))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (82, 104))	('patients', 'Species', '9606', (4, 12))	('APP', 'Gene', (37, 40))	('high expression', 'Var', (18, 33))	('Acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (76, 104))
906737	32276343	evaluated the regulatory feedback between the myc and the miR-144/451 clusters in CML.	('CML', 'Phenotype', 'HP:0005506', (82, 85))	('CML', 'Disease', (82, 85))	('myc', 'Gene', (46, 49))	('miR-144/451', 'Var', (58, 69))	('myc', 'Gene', '4609', (46, 49))	('CML', 'Disease', 'MESH:D015464', (82, 85))
906747	32276343	They reported the upregulation of several miRNAs in CLL, including miR-144-5p, miR-144-3p, miR-28-5p, miR-486-5p, and miR-486-3p.	('miR-28', 'Gene', (91, 97))	('upregulation', 'PosReg', (18, 30))	('miR-144-3p', 'Var', (79, 89))	('miR-144-5p', 'Var', (67, 77))	('miR-28', 'Gene', '407020', (91, 97))	('CLL', 'Phenotype', 'HP:0005550', (52, 55))	('miR-486-3p', 'Var', (118, 128))	('miR-486-5p', 'Var', (102, 112))	('miR-144-3p', 'Chemical', '-', (79, 89))
906753	32276343	Furthermore, miR-144 by downregulation of MET signaling reduced GC progression that eventually blocks the activation of the Akt pathway.	('Akt', 'Gene', (124, 127))	('miR-144', 'Var', (13, 20))	('reduced', 'NegReg', (56, 63))	('MET', 'Gene', (42, 45))	('MET', 'Gene', '4233', (42, 45))	('downregulation', 'NegReg', (24, 38))	('Akt', 'Gene', '207', (124, 127))	('GC', 'Phenotype', 'HP:0012126', (64, 66))
906760	32276343	The results showed that miR-144-3p, miR-134-5p, and miR-451a were deregulated in GC, but using these miRNAs had a moderate diagnostic value.	('miR-144-3p', 'Chemical', '-', (24, 34))	('miR-134', 'Gene', (36, 43))	('miR-134', 'Gene', '406924', (36, 43))	('miR-451a', 'Gene', '574411', (52, 60))	('miR-451a', 'Gene', (52, 60))	('deregulated', 'MPA', (66, 77))	('GC', 'Phenotype', 'HP:0012126', (81, 83))	('miR-144-3p', 'Var', (24, 34))
906767	32276343	C-X C motif chemokine ligand 11 (CXCL11) is another target of miR-144 in CRC.	('C-X C motif chemokine ligand 11', 'Gene', '6373', (0, 31))	('CXCL11', 'Gene', (33, 39))	('CXCL11', 'Gene', '6373', (33, 39))	('C-X C motif chemokine ligand 11', 'Gene', (0, 31))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))	('miR-144', 'Var', (62, 69))
906771	32276343	The mTOR is a downstream effector of the PI3K/AKT pathway and it is a target of miR-144 in CRC.	('PI3K/AKT pathway', 'Pathway', (41, 57))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('miR-144', 'Var', (80, 87))
906778	32276343	demonstrated that miR-144-3p was reduced in PC tissues and PANC-1 cells.	('miR-144-3p', 'Var', (18, 28))	('PC', 'Phenotype', 'HP:0002894', (44, 46))	('miR-144-3p', 'Chemical', '-', (18, 28))	('reduced', 'NegReg', (33, 40))	('PANC-1', 'CellLine', 'CVCL:0480', (59, 65))
906779	32276343	MiR-144-3p expression inhibited cell growth in the S-phase cell-cycle, leading to cell apoptosis in vitro.	('MiR-144-3p expression', 'Var', (0, 21))	('inhibited', 'NegReg', (22, 31))	('cell apoptosis', 'CPA', (82, 96))	('leading', 'Reg', (71, 78))	('MiR-144-3p', 'Chemical', '-', (0, 10))	('cell growth in the S-phase cell-cycle', 'CPA', (32, 69))
906780	32276343	MiR-144-3p regulated proline-rich protein 11 (PRR11 3'-UTR).	('proline-rich protein 11', 'Gene', '55771', (21, 44))	('proline-rich protein 11', 'Gene', (21, 44))	('PRR11', 'Gene', '55771', (46, 51))	('MiR-144-3p', 'Var', (0, 10))	('MiR-144-3p', 'Chemical', '-', (0, 10))	('PRR11', 'Gene', (46, 51))
906781	32276343	When the PC cells were transfected with miR-144-3p, PRR11 decreased, with the upregulation of p-JNK and p-p38, with a key role in cancer progression impairment.	('men', 'Species', '9606', (155, 158))	('PRR11', 'Gene', '55771', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('JNK', 'Gene', '5599', (96, 99))	('PC', 'Phenotype', 'HP:0002894', (9, 11))	('cancer', 'Disease', (130, 136))	('decreased', 'NegReg', (58, 67))	('PRR11', 'Gene', (52, 57))	('p38', 'Gene', '1432', (106, 109))	('upregulation', 'PosReg', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miR-144-3p', 'Var', (40, 50))	('miR-144-3p', 'Chemical', '-', (40, 50))	('p38', 'Gene', (106, 109))	('JNK', 'Gene', (96, 99))
906783	32276343	So far, miR-144-3p induced cell cycle inhibition and apoptosis in PC cell impairing PRR11.	('apoptosis', 'CPA', (53, 62))	('PRR11', 'Gene', '55771', (84, 89))	('miR-144-3p', 'Var', (8, 18))	('miR-144-3p', 'Chemical', '-', (8, 18))	('PRR11', 'Gene', (84, 89))	('cell cycle inhibition', 'CPA', (27, 48))	('PC', 'Phenotype', 'HP:0002894', (66, 68))
906784	32276343	Additionally, in another in vitro study, the MiR-144-3p results downregulated in vitro evaluations.	('MiR-144-3p', 'Chemical', '-', (45, 55))	('MiR-144-3p', 'Var', (45, 55))	('downregulated', 'NegReg', (64, 77))
906785	32276343	MiR-144-3p overexpression reduces PC cell growth, chemotaxis, and metastasis.	('MiR-144-3p', 'Var', (0, 10))	('PC', 'Phenotype', 'HP:0002894', (34, 36))	('MiR-144-3p', 'Chemical', '-', (0, 10))	('chemotaxis', 'CPA', (50, 60))	('reduces', 'NegReg', (26, 33))	('overexpression', 'PosReg', (11, 25))	('metastasis', 'CPA', (66, 76))
906786	32276343	demonstrated that MiR-144-3p enhancing could downregulated PC cell migration, proliferation, and invasion by inhibiting the expression of FOSB So far, enhancing miR-144 could provide a new target against PC, even if more studies are warranted.	('OS', 'Phenotype', 'HP:0002669', (139, 141))	('PC', 'Phenotype', 'HP:0002894', (204, 206))	('inhibiting', 'NegReg', (109, 119))	('FOSB', 'Gene', '2354', (138, 142))	('miR-144', 'Gene', (161, 168))	('enhancing', 'PosReg', (151, 160))	('downregulated', 'NegReg', (45, 58))	('MiR-144-3p', 'Var', (18, 28))	('expression', 'MPA', (124, 134))	('MiR-144-3p', 'Chemical', '-', (18, 28))	('invasion', 'CPA', (97, 105))	('PC', 'Phenotype', 'HP:0002894', (59, 61))	('FOSB', 'Gene', (138, 142))
906791	32276343	MiR-144 triggers Nrf2 mRNA degeneration by targeting the 3'UTR region and it leads to reverse chemoresistance in HCC cell lines.	('reverse chemoresistance', 'CPA', (86, 109))	('Nrf2', 'Gene', '4780', (17, 21))	('Nrf2', 'Gene', (17, 21))	('MiR-144', 'Var', (0, 7))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('mRNA', 'MPA', (22, 26))	('CC', 'Phenotype', 'HP:0002664', (114, 116))	('triggers', 'Reg', (8, 16))
906794	32276343	Another study detected that the levels of miR-141-3p were significantly increased in serum extracellular vehicles (EVs) and liver cancer tissues as compared with serum and the distal liver tissues in HCC patients.	('patients', 'Species', '9606', (204, 212))	('miR-141-3p', 'Chemical', '-', (42, 52))	('increased', 'PosReg', (72, 81))	('HCC', 'Phenotype', 'HP:0001402', (200, 203))	('liver cancer', 'Phenotype', 'HP:0002896', (124, 136))	('liver cancer', 'Disease', 'MESH:D006528', (124, 136))	('levels', 'MPA', (32, 38))	('liver cancer', 'Disease', (124, 136))	('EVs', 'Chemical', '-', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('serum extracellular vehicles', 'MPA', (85, 113))	('miR-141-3p', 'Var', (42, 52))	('CC', 'Phenotype', 'HP:0002664', (201, 203))
906796	32276343	MiR-141-3p also leads to invasion and metastasis of HCC by the direct targeting of SMAD4 and SGK3.	('leads to', 'Reg', (16, 24))	('HCC', 'Phenotype', 'HP:0001402', (52, 55))	('MiR-141-3p', 'Var', (0, 10))	('MiR-141-3p', 'Chemical', '-', (0, 10))	('SMAD4', 'Gene', '4089', (83, 88))	('SGK3', 'Gene', (93, 97))	('invasion', 'CPA', (25, 33))	('SGK3', 'Gene', '23678', (93, 97))	('targeting', 'Reg', (70, 79))	('SMAD4', 'Gene', (83, 88))	('CC', 'Phenotype', 'HP:0002664', (53, 55))	('metastasis', 'CPA', (38, 48))	('HCC', 'Disease', (52, 55))
906807	32276343	Additionally, they found the platelet activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1) as one of the targets of miR-144 in CCA.	('CCA', 'Phenotype', 'HP:0030153', (143, 146))	('targets', 'Reg', (121, 128))	('PAFAH1B1', 'Gene', (97, 105))	('PAFAH1B1', 'Gene', '5048', (97, 105))	('platelet activating factor acetylhydrolase 1b regulatory subunit 1', 'Gene', '5048', (29, 95))	('CC', 'Phenotype', 'HP:0002664', (143, 145))	('CCA', 'Disease', (143, 146))	('miR-144', 'Var', (132, 139))
906809	32276343	The high expression of miR-144-3p, miR-144-5p, and miR-451 through targeting Myc and P-ERK led to the apoptosis and inhibition of migration, invasion, and proliferation of EC cells.	('invasion', 'CPA', (141, 149))	('ERK', 'Gene', (87, 90))	('Myc', 'Gene', (77, 80))	('miR-451', 'Gene', (51, 58))	('miR-144-3p', 'Chemical', '-', (23, 33))	('apoptosis', 'CPA', (102, 111))	('proliferation', 'CPA', (155, 168))	('inhibition', 'NegReg', (116, 126))	('miR-451', 'Gene', '574411', (51, 58))	('migration', 'CPA', (130, 139))	('Myc', 'Gene', '4609', (77, 80))	('miR-144-5p', 'Var', (35, 45))	('miR-144-3p', 'Var', (23, 33))	('ERK', 'Gene', '5594', (87, 90))
906819	32276343	displayed that miR-144-3p inhibited the growth and metastasis of tumor cells by targeting mitogen-activated protein kinase 6 (MAPK6).	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('inhibited', 'NegReg', (26, 35))	('miR-144-3p', 'Chemical', '-', (15, 25))	('miR-144-3p', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mitogen-activated protein kinase 6', 'Gene', '5597', (90, 124))	('MAPK6', 'Gene', (126, 131))	('targeting', 'Reg', (80, 89))	('MAPK6', 'Gene', '5597', (126, 131))	('mitogen-activated protein kinase 6', 'Gene', (90, 124))
906822	32276343	The expression of miR-144, miR-93, and miR-382 was reduced in primary ovarian tumors.	('miR-382', 'Gene', (39, 46))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('reduced', 'NegReg', (51, 58))	('primary ovarian tumors', 'Disease', (62, 84))	('miR-93', 'Gene', '407051', (27, 33))	('ovarian tumors', 'Phenotype', 'HP:0100615', (70, 84))	('miR-93', 'Gene', (27, 33))	('expression', 'MPA', (4, 14))	('primary ovarian tumors', 'Disease', 'MESH:D010051', (62, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('miR-144', 'Var', (18, 25))	('miR-382', 'Gene', '494331', (39, 46))
906832	32276343	found that miR-124 and miR-144 directly targeted the 3'UTR of PIM1 and, via its downregulation, led to hypoxia-induced autophagy and increased radiosensitivity of PrC.	('miR-144', 'Var', (23, 30))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (133, 159))	('PIM1', 'Gene', '5292', (62, 66))	('led to', 'Reg', (96, 102))	('PrC', 'Phenotype', 'HP:0012125', (163, 166))	('hypoxia', 'Disease', 'MESH:D000860', (103, 110))	('miR-124', 'Var', (11, 18))	('PIM1', 'Gene', (62, 66))	('radiosensitivity', 'CPA', (143, 159))	('increased', 'PosReg', (133, 142))	('hypoxia', 'Disease', (103, 110))	('downregulation', 'NegReg', (80, 94))
906833	32276343	determined that miR-144-3 prevents proliferation and leads to cell death in PrC by targeting CEP55.	('death', 'Disease', 'MESH:D003643', (67, 72))	('death', 'Disease', (67, 72))	('miR-144-3', 'Var', (16, 25))	('proliferation', 'CPA', (35, 48))	('prevents', 'NegReg', (26, 34))	('PrC', 'Phenotype', 'HP:0012125', (76, 79))	('targeting', 'Reg', (83, 92))	('CEP55', 'Gene', '55165', (93, 98))	('CEP55', 'Gene', (93, 98))
906837	32276343	Studies showed that both miR-144-5p and miR-144-3p were significantly downregulated in RCC.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('CC', 'Phenotype', 'HP:0002664', (88, 90))	('downregulated', 'NegReg', (70, 83))	('miR-144-3p', 'Var', (40, 50))	('miR-144-5p', 'Var', (25, 35))	('miR-144-3p', 'Chemical', '-', (40, 50))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
906839	32276343	Furthermore, miR-144-3p leads to the suppression of invasion and migration, by targeting MAP3K8; so far, it can act as a tumor suppressor.	('miR-144-3p', 'Chemical', '-', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('MAP3K8', 'Gene', '1326', (89, 95))	('targeting', 'Reg', (79, 88))	('suppression', 'NegReg', (37, 48))	('MAP3K8', 'Gene', (89, 95))	('miR-144-3p', 'Var', (13, 23))
906840	32276343	showed that the overexpression of miR-144-3p promoted proliferation, metastasis, and sunitinib resistance by targeting AT-rich interactive domain-containing protein 1A (ARID1A) in clear cell renal cell carcinoma (ccRCC).	('targeting', 'Reg', (109, 118))	('AT-rich interactive domain-containing protein 1A', 'Gene', (119, 167))	('proliferation', 'CPA', (54, 67))	('ARID1A', 'Gene', (169, 175))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (180, 211))	('miR-144-3p', 'Chemical', '-', (34, 44))	('promoted', 'PosReg', (45, 53))	('ARID1A', 'Gene', '8289', (169, 175))	('sunitinib', 'Chemical', 'MESH:D000077210', (85, 94))	('metastasis', 'CPA', (69, 79))	('clear cell renal cell carcinoma', 'Disease', (180, 211))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (191, 211))	('ccRCC', 'Phenotype', 'HP:0006770', (213, 218))	('RCC', 'Disease', (215, 218))	('CC', 'Phenotype', 'HP:0002664', (216, 218))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('AT-rich interactive domain-containing protein 1A', 'Gene', '8289', (119, 167))	('miR-144-3p', 'Var', (34, 44))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (180, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
906842	32276343	Additionally, in a recent survey, the antitumor roles of miR-451a, miR-144-5p, and miR-144-3p were confirmed in RCC.	('tumor', 'Disease', (42, 47))	('miR-144-5p', 'Var', (67, 77))	('CC', 'Phenotype', 'HP:0002664', (113, 115))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('miR-144-3p', 'Var', (83, 93))	('miR-144-3p', 'Chemical', '-', (83, 93))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('miR-451a', 'Gene', '574411', (57, 65))	('miR-451a', 'Gene', (57, 65))
906843	32276343	The assays determined that miR-144-5p and miR-144-3p significantly reduced the migration and invasion in RCC cells, proposing these miRNAs behaved as tumor suppressor miRNAs in RCC.	('miR-144-3p', 'Var', (42, 52))	('miR-144-3p', 'Chemical', '-', (42, 52))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('CC', 'Phenotype', 'HP:0002664', (106, 108))	('CC', 'Phenotype', 'HP:0002664', (178, 180))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('reduced', 'NegReg', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('miR-144-5p', 'Var', (27, 37))	('tumor', 'Disease', (150, 155))
906844	32276343	Computational analyses recognized a total of 65 possible targets of miR-144-5p in RCC cells.	('miR-144-5p', 'Var', (68, 78))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('CC', 'Phenotype', 'HP:0002664', (83, 85))
906846	32276343	Among them, the expression of SDC3 was directly regulated by miR-144-5p, and its upregulation enhanced RCC cell invasiveness.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('miR-144-5p', 'Var', (61, 71))	('SDC3', 'Gene', (30, 34))	('SDC3', 'Gene', '9672', (30, 34))	('CC', 'Phenotype', 'HP:0002664', (104, 106))	('upregulation enhanced', 'PosReg', (81, 102))	('regulated', 'Reg', (48, 57))	('expression', 'MPA', (16, 26))
906847	32276343	reported a significantly higher level of miR-144-3p in 106 ccRCC plasmas as compared with healthy individuals, suggesting the role of miR-144-3p as a novel and unique plasma biomarker for the diagnosis of ccRCC.	('miR-144-3p', 'Chemical', '-', (41, 51))	('higher', 'PosReg', (25, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('miR-144-3p', 'Chemical', '-', (134, 144))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('RCC', 'Disease', (207, 210))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('CC', 'Phenotype', 'HP:0002664', (62, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('miR-144-3p', 'MPA', (41, 51))	('RCC', 'Disease', (61, 64))	('CC', 'Phenotype', 'HP:0002664', (208, 210))	('miR-144-3p', 'Var', (134, 144))
906854	32276343	found miR-144-5p acts as a tumor suppressor by directly targeting CCNE1/2 in BlC.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('CC', 'Phenotype', 'HP:0002664', (66, 68))	('CCNE1', 'Gene', '898', (66, 71))	('BlC', 'Phenotype', 'HP:0009725', (77, 80))	('targeting', 'Reg', (56, 65))	('miR-144-5p', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CCNE1', 'Gene', (66, 71))
906855	32276343	This study was conducted to evaluate the functional roles of miR-144-3p and miR-144-5p and their modulation of targets in BlC cells.	('miR-144-5p', 'Var', (76, 86))	('miR-144-3p', 'Var', (61, 71))	('BlC', 'Phenotype', 'HP:0009725', (122, 125))	('miR-144-3p', 'Chemical', '-', (61, 71))
906856	32276343	Their results showed that miR-144-5p, via the direct targeting of CCNE1, CCNE2, CDC25A, and PKMYT1, dramatically repressed the cell proliferation of BlC cells.	('PKMYT1', 'Gene', (92, 98))	('CCNE2', 'Gene', (73, 78))	('cell proliferation of BlC', 'CPA', (127, 152))	('BlC', 'Phenotype', 'HP:0009725', (149, 152))	('CDC25A', 'Gene', (80, 86))	('CCNE2', 'Gene', '9134', (73, 78))	('CC', 'Phenotype', 'HP:0002664', (66, 68))	('miR-144-5p', 'Var', (26, 36))	('repressed', 'PosReg', (113, 122))	('CCNE1', 'Gene', '898', (66, 71))	('PKMYT1', 'Gene', '9088', (92, 98))	('CC', 'Phenotype', 'HP:0002664', (73, 75))	('CCNE1', 'Gene', (66, 71))	('CDC25A', 'Gene', '993', (80, 86))
906859	32276343	They reported three significant upregulated blood miRNAs (miR-26b-5p, miR-144-5p, and miR-374-5p) in invasive BlC patients when compared with the control group.	('patients', 'Species', '9606', (114, 122))	('BlC', 'Phenotype', 'HP:0009725', (110, 113))	('invasive BlC', 'Disease', (101, 113))	('miR-26b', 'Gene', '407017', (58, 65))	('miR-374-5p', 'Var', (86, 96))	('miR-26b', 'Gene', (58, 65))	('miR-144-5p', 'Var', (70, 80))	('upregulated', 'PosReg', (32, 43))
906863	32276343	The concentrations of miR-144 duplex (miR-144-5p and miR-144-3p) were significantly reduced in squamous NSCLC tissues as compared to healthy adjacent tissues.	('concentrations', 'MPA', (4, 18))	('squamous NSCLC', 'Disease', (95, 109))	('reduced', 'NegReg', (84, 91))	('squamous NSCLC', 'Disease', 'MESH:D002294', (95, 109))	('miR-144-3p', 'Chemical', '-', (53, 63))	('SCLC', 'Phenotype', 'HP:0030357', (105, 109))	('miR-144-3p', 'Var', (53, 63))	('miR-144', 'Protein', (22, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
906864	32276343	It was observed that both miR-144-5p and miR-144-3p had tumor inhibitory effects by targeting several oncogenes in squamous NSCLC including neuronal calcium sensor 1 (NCS1), solute carrier family 44 member 5 (SLC44A5), and myristoylated alanine rich protein kinase C substrate (MARCKS) genes.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR-144-3p', 'Var', (41, 51))	('squamous NSCLC', 'Disease', 'MESH:D002294', (115, 129))	('MARCKS', 'Gene', '4082', (278, 284))	('neuronal calcium sensor 1', 'Gene', '23413', (140, 165))	('SCLC', 'Phenotype', 'HP:0030357', (125, 129))	('SLC44A5', 'Gene', '204962', (209, 216))	('myristoylated alanine rich protein kinase C substrate', 'Gene', '4082', (223, 276))	('NCS1', 'Gene', '23413', (167, 171))	('squamous NSCLC', 'Disease', (115, 129))	('miR-144-3p', 'Chemical', '-', (41, 51))	('tumor', 'Disease', (56, 61))	('oncogenes', 'Gene', (102, 111))	('solute carrier family 44 member 5', 'Gene', (174, 207))	('SLC44A5', 'Gene', (209, 216))	('MARCKS', 'Gene', (278, 284))	('NCS1', 'Gene', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))	('neuronal calcium sensor 1', 'Gene', (140, 165))	('miR-144-5p', 'Var', (26, 36))	('solute carrier family 44 member 5', 'Gene', '204962', (174, 207))	('targeting', 'Reg', (84, 93))
906870	32276343	They reported lower expression of miR-144-3p in NSCLC tissue when compared with the normal tissue.	('NSCLC', 'Disease', (48, 53))	('expression', 'MPA', (20, 30))	('SCLC', 'Phenotype', 'HP:0030357', (49, 53))	('lower', 'NegReg', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('miR-144-3p', 'Var', (34, 44))	('miR-144-3p', 'Chemical', '-', (34, 44))
906871	32276343	Additionally, miR-144-3p expression was significantly associated with stage, metastasis, and invasion of tumor cells, suggesting that miR-144-3p could function as a potential tumor biomarker in the prognosis prediction for NSCLC and as a potential clinical target in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('NSCLC', 'Disease', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('miR-144-3p', 'Chemical', '-', (14, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (223, 228))	('miR-144-3p', 'Var', (134, 144))	('metastasis', 'CPA', (77, 87))	('miR-144-3p', 'Gene', (14, 24))	('tumor', 'Disease', (105, 110))	('associated', 'Reg', (54, 64))	('tumor', 'Disease', (175, 180))	('SCLC', 'Phenotype', 'HP:0030357', (224, 228))	('lung cancer', 'Disease', (267, 278))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('miR-144-3p', 'Chemical', '-', (134, 144))	('NSCLC', 'Disease', 'MESH:D002289', (223, 228))	('stage', 'CPA', (70, 75))	('lung cancer', 'Disease', 'MESH:D008175', (267, 278))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
906879	32276343	The results showed miR-144 with eight other miRNAs, including let-7e, miR-203, miR-340, miR-34a, miR-423, miR-582, miR-7-1, and miR-9 were significantly down-regulated in the tissue samples of mesothelioma patients when compared to normal tissues.	('mesothelioma', 'Disease', (193, 205))	('miR-9', 'Var', (128, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (193, 205))	('miR-423', 'Gene', '494335', (97, 104))	('miR-144', 'Gene', (19, 26))	('miR-582', 'Gene', '693167', (106, 113))	('let-7e', 'Gene', (62, 68))	('miR-340', 'Gene', '442908', (79, 86))	('miR-340', 'Gene', (79, 86))	('miR-7-1', 'Gene', '407043', (115, 122))	('miR-34a', 'Gene', (88, 95))	('miR-203', 'Gene', (70, 77))	('let-7e', 'Gene', '406887', (62, 68))	('miR-582', 'Gene', (106, 113))	('miR-423', 'Gene', (97, 104))	('miR-7-1', 'Gene', (115, 122))	('miR-34a', 'Gene', '407040', (88, 95))	('patients', 'Species', '9606', (206, 214))	('down-regulated', 'NegReg', (153, 167))	('miR-203', 'Gene', '406986', (70, 77))
906884	32276343	Additionally, this study showed that the expression of miR-144 can repress the process of EMT in MCF-7 and MDA-MB-231 cell lines.	('process of EMT', 'CPA', (79, 93))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (107, 117))	('miR-144', 'Gene', (55, 62))	('MCF-7', 'CellLine', 'CVCL:0031', (97, 102))	('repress', 'NegReg', (67, 74))	('expression', 'Var', (41, 51))
906886	32276343	found that miR-144 might function as an oncomiR by an increase in the survival rate of breast cancer cells.	('miR-144', 'Var', (11, 18))	('increase', 'PosReg', (54, 62))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('survival rate', 'CPA', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
906891	32276343	demonstrated that miR-144-3p, by targeting of ETS-1 and insulin receptor substrate 1 (IRS1) in laryngeal squamous cell carcinoma, led to the inhibition of metastasis and invasion of tumor cells.	('ETS-1', 'Gene', (46, 51))	('insulin receptor substrate 1', 'Gene', '3667', (56, 84))	('inhibition', 'NegReg', (141, 151))	('metastasis', 'CPA', (155, 165))	('tumor', 'Disease', (182, 187))	('ETS-1', 'Gene', '2113', (46, 51))	('insulin receptor substrate 1', 'Gene', (56, 84))	('IRS1', 'Gene', '3667', (86, 90))	('miR-144-3p', 'Var', (18, 28))	('miR-144-3p', 'Chemical', '-', (18, 28))	('IRS1', 'Gene', (86, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('targeting', 'NegReg', (33, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('squamous cell carcinoma', 'Disease', (105, 128))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 128))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
906892	32276343	Moreover, miR-144-3p, by inhibition of E-cadherin, reduces cellular EMT in laryngeal squamous cell carcinoma.	('miR-144-3p', 'Chemical', '-', (10, 20))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('reduces', 'NegReg', (51, 58))	('miR-144-3p', 'Var', (10, 20))	('cellular EMT', 'CPA', (59, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('inhibition', 'NegReg', (25, 35))	('squamous cell carcinoma', 'Disease', (85, 108))
906900	32276343	Moreover, miR-144 targets ZEB 1 and ZEB2 and inhibits the invasion of tumor cells, which suggests the role of miR-144 as a tumor suppressor in TC.	('ZEB2', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (123, 128))	('TC', 'Phenotype', 'HP:0002890', (143, 145))	('inhibits', 'NegReg', (45, 53))	('tumor', 'Disease', (70, 75))	('miR-144', 'Gene', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('miR-144', 'Var', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('ZEB 1', 'Gene', '6935', (26, 31))	('ZEB2', 'Gene', '9839', (36, 40))	('ZEB 1', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
906903	32276343	Another in vitro study displayed that miR-144-3p is involved in cell cycle progression and EMT.	('miR-144-3p', 'Chemical', '-', (38, 48))	('EMT', 'CPA', (91, 94))	('involved', 'Reg', (52, 60))	('cell cycle progression', 'CPA', (64, 86))	('miR-144-3p', 'Var', (38, 48))
906907	32276343	Several studies verified the downregulation of MiR-144-3p in GBM over non-neoplastic brain tissues.	('downregulation', 'NegReg', (29, 43))	('MiR-144-3p', 'Chemical', '-', (47, 57))	('neoplastic brain', 'Phenotype', 'HP:0030692', (74, 90))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('GBM', 'Disease', (61, 64))	('MiR-144-3p', 'Var', (47, 57))
906908	32276343	MiR-144-3p negatively exerts tumor growth and apoptosis in glioma cells by targeting topoisomerase II alpha (TOP2A).	('apoptosis', 'CPA', (46, 55))	('glioma', 'Disease', (59, 65))	('negatively', 'NegReg', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('targeting', 'Reg', (75, 84))	('MiR-144-3p', 'Var', (0, 10))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('MiR-144-3p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (29, 34))	('TOP2A', 'Gene', '7153', (109, 114))	('TOP2A', 'Gene', (109, 114))
906910	32276343	indicated that miR-144-3p inhibits metastasis by targeting FZD7.	('FZD7', 'Gene', '8324', (59, 63))	('inhibits', 'NegReg', (26, 34))	('metastasis', 'CPA', (35, 45))	('miR-144-3p', 'Chemical', '-', (15, 25))	('FZD7', 'Gene', (59, 63))	('miR-144-3p', 'Var', (15, 25))	('targeting', 'Reg', (49, 58))
906922	32276343	Additionally, the upregulation of TAGLN, as a target of miR-144, is inversely associated with miR-144 expression Rho-associated kinases 1 and 2 (ROCK1 and ROCK2) are other targets of miR-144 that downregulate them by the upregulation of miR-144, and it has an important role in suppressing the proliferation and invasion.	('ROCK2', 'Gene', '9475', (155, 160))	('upregulation', 'PosReg', (18, 30))	('OC', 'Phenotype', 'HP:0100615', (156, 158))	('TAGLN', 'Gene', '6876', (34, 39))	('ROCK1', 'Gene', '6093', (145, 150))	('upregulation', 'PosReg', (221, 233))	('miR-144', 'Var', (237, 244))	('downregulate', 'NegReg', (196, 208))	('miR-144', 'Gene', (94, 101))	('suppressing', 'NegReg', (278, 289))	('ROCK2', 'Gene', (155, 160))	('TAGLN', 'Gene', (34, 39))	('ROCK1', 'Gene', (145, 150))	('OC', 'Phenotype', 'HP:0100615', (146, 148))
906924	32276343	Mice deficient of miR-144 have shown to undergo impairment in late erythrocyte maturation, which further leads to splenomegaly, mild anemia, and erythroid hyperplasia.	('erythroid hyperplasia', 'Disease', 'MESH:D006965', (145, 166))	('erythroid hyperplasia', 'Phenotype', 'HP:0012132', (145, 166))	('impairment', 'NegReg', (48, 58))	('erythroid hyperplasia', 'Disease', (145, 166))	('late erythrocyte maturation', 'CPA', (62, 89))	('splenomegaly', 'Disease', 'MESH:D013163', (114, 126))	('anemia', 'Disease', (133, 139))	('splenomegaly', 'Phenotype', 'HP:0001744', (114, 126))	('miR-144', 'Gene', (18, 25))	('men', 'Species', '9606', (54, 57))	('anemia', 'Disease', 'MESH:D000740', (133, 139))	('Mice', 'Species', '10090', (0, 4))	('leads to', 'Reg', (105, 113))	('anemia', 'Phenotype', 'HP:0001903', (133, 139))	('splenomegaly', 'Disease', (114, 126))	('deficient', 'Var', (5, 14))
906950	30946321	However, different cut-off values of tumor volume were postulated by different studies, for instance, Crehange et al first reported that 100 cm3 was the optimal cut-off value to distinguish OS.	('100 cm3', 'Var', (137, 144))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (37, 42))
906956	30946321	The inclusion criteria were: patients with the initial diagnosis of ESCC, EC staging under UICC stage I to IV (according to the 7th Union for International Cancer Control), body weight >=50 kg and <=100 kg, Karnofsky performance status (KPS) score >80 values patients who underwent IMRT, hematological and biochemical profiling before undergoing any treatment, regular follow-up.	('patients', 'Species', '9606', (29, 37))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('patients', 'Species', '9606', (259, 267))	('ESCC', 'Disease', (68, 72))	('<=100 kg', 'Var', (197, 205))	('>=50 kg', 'Var', (185, 192))
906984	30946321	The optimal cut-off values for the correlation between GTVnd, RGTVnd and N classification in OS were 0.365 cm3 and 0.007, respectively (P < .001; Table 2).	('0.007', 'Var', (115, 120))	('0.365 cm3', 'Var', (101, 110))	('GTV', 'Gene', (63, 66))	('GTV', 'Gene', (55, 58))	('GTV', 'Gene', '9334', (63, 66))	('GTV', 'Gene', '9334', (55, 58))
906988	30946321	The optimal cut-off values for GTVp and GTVnd were 54.150 cm3 and 0.365cm3, respectively.	('GTV', 'Gene', '9334', (31, 34))	('0.365cm3', 'Var', (66, 74))	('GTV', 'Gene', (40, 43))	('GTV', 'Gene', '9334', (40, 43))	('GTV', 'Gene', (31, 34))	('GTVp', 'Gene', '9334', (31, 35))	('GTVp', 'Gene', (31, 35))
907064	30931254	According to a report encompassing 465 Caucasian gastric cancer cases, patients with high expression of PD-L1 on both TC and TIC had the best OS.	('high expression', 'Var', (85, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('OS', 'Chemical', '-', (142, 144))	('patients', 'Species', '9606', (71, 79))	('TIC', 'Phenotype', 'HP:0100033', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('TC', 'Chemical', '-', (118, 120))	('gastric cancer', 'Disease', (49, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))	('PD-L1', 'Gene', (104, 109))
907129	30931254	High PD-L1 and PD-1 expression on TIC was significantly associated with a prolonged OS (p = 0.023 and p = 0.004, respectively).	('High', 'Var', (0, 4))	('TIC', 'Phenotype', 'HP:0100033', (34, 37))	('PD-L1', 'Gene', (5, 10))	('prolonged', 'Disease', (74, 83))	('OS', 'Chemical', '-', (84, 86))	('associated with', 'Reg', (56, 71))	('PD-1', 'Gene', (15, 19))
907134	30931254	High PD-1 expression was significantly associated with a prolonged OS in gastric cancer (p = 0.041), whereas a borderline significant association was observed between high PD-1 expression and a shorter OS (p = 0.053) in esophageal cancer.	('OS', 'Chemical', '-', (202, 204))	('esophageal cancer', 'Disease', (220, 237))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('High', 'Var', (0, 4))	('esophageal cancer', 'Disease', 'MESH:D004938', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('OS', 'Chemical', '-', (67, 69))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('PD-1', 'Gene', (5, 9))	('gastric cancer', 'Disease', (73, 87))
907139	30931254	dMMR was significantly associated with higher age (p = 0.001) and lower N stage (p = 0.012).	('dMMR', 'Chemical', '-', (0, 4))	('dMMR', 'Var', (0, 4))	('N stage', 'CPA', (72, 79))	('lower', 'NegReg', (66, 71))
907145	30931254	on gastric cancer wherein patients with high expression of PD-L1 on TIC had a significantly better OS in both univariable and multivariable analysis and patients with high expression of PD-L1 on TC had a significantly improved survival in univariable analyses.	('survival', 'MPA', (227, 235))	('TC', 'Chemical', '-', (195, 197))	('patients', 'Species', '9606', (153, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TIC', 'Phenotype', 'HP:0100033', (68, 71))	('patients', 'Species', '9606', (26, 34))	('PD-L1', 'Var', (59, 64))	('gastric cancer', 'Disease', (3, 17))	('OS', 'Chemical', '-', (99, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('improved', 'PosReg', (218, 226))	('better', 'PosReg', (92, 98))
907152	30931254	In another study on chemoradiotherapy-naive esophageal cancer (n = 354), PD-1 positivity correlated with increased mortality, but not after adjusting for other prognostic factors.	('mortality', 'Disease', (115, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('positivity', 'Var', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PD-1', 'Gene', (73, 77))	('increased', 'PosReg', (105, 114))	('esophageal cancer', 'Disease', (44, 61))
907168	30931254	Regarding PD-1, high mRNA expression was found to be significantly associated with a prolonged OS in gastric cancer, thus validating the immunohistochemical data, whereas a borderline significant trend towards an association with a shorter OS was seen in esophageal cancer.	('OS', 'Chemical', '-', (240, 242))	('gastric cancer', 'Disease', (101, 115))	('high', 'Var', (16, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('PD-1', 'Gene', (10, 14))	('esophageal cancer', 'Disease', (255, 272))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('mRNA expression', 'MPA', (21, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (255, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('OS', 'Chemical', '-', (95, 97))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('associated with', 'Reg', (67, 82))
907173	30931254	(n = 487), wherein PD-L1 positivity (>= 1%) on both TC and TIC was more frequently observed in dMMR tumours.	('PD-L1', 'Gene', (19, 24))	('tumours', 'Disease', (100, 107))	('TIC', 'Phenotype', 'HP:0100033', (59, 62))	('positivity', 'Var', (25, 35))	('dMMR', 'Chemical', '-', (95, 99))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('TC', 'Chemical', '-', (52, 54))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('dMMR', 'Disease', (95, 99))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('observed', 'Reg', (83, 91))
907178	30931254	(n = 509) demonstrated that patients with positive (>5%) PD-L1 TC expression and high CD8+ T cell infiltration was associated with an improved OS, and positive PD-L1 status correlated with high CD8+ T cell infiltration.	('CD8', 'Gene', (194, 197))	('improved', 'PosReg', (134, 142))	('CD8', 'Gene', '925', (194, 197))	('positive', 'Var', (42, 50))	('PD-L1', 'Gene', (57, 62))	('CD8', 'Gene', (86, 89))	('CD8', 'Gene', '925', (86, 89))	('TC', 'Chemical', '-', (63, 65))	('patients', 'Species', '9606', (28, 36))	('OS', 'Chemical', '-', (143, 145))
907191	30931254	Accordingly, this could potentially strengthen the hypothesis that the beneficial prognostic value of high PD-L1 TIC expression in EG adenocarcinoma is due to its positive association with CD8+ T cell density, as demonstrated in the present study.	('adenocarcinoma', 'Disease', (134, 148))	('association', 'Interaction', (172, 183))	('high', 'Var', (102, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('adenocarcinoma', 'Disease', 'MESH:D000230', (134, 148))	('CD8', 'Gene', (189, 192))	('EG', 'Chemical', '-', (131, 133))	('CD8', 'Gene', '925', (189, 192))	('PD-L1', 'Gene', (107, 112))	('TIC', 'Phenotype', 'HP:0100033', (113, 116))
907218	28243329	In the univariate analyses, patients with a pN0 stage (log rank, p=0.028) and adjuvant chemotherapy (log rank, p=0.032) exhibited more favorable overall survival.	('patients', 'Species', '9606', (28, 36))	('overall survival', 'CPA', (145, 161))	('pN0 stage', 'Var', (44, 53))
907253	28243329	Patients with pN0 disease exhibited a more favorable OS than patients with pN1-3 disease (median OS: 29.5 vs. 23.0 months, respectively, log rank, p=0.028) (Figure 1).	('pN1', 'Gene', (75, 78))	('pN0 disease', 'Var', (14, 25))	('patients', 'Species', '9606', (61, 69))	('OS', 'Chemical', '-', (97, 99))	('OS', 'Chemical', '-', (53, 55))	('Patients', 'Species', '9606', (0, 8))	('pN1', 'Gene', '5270', (75, 78))
907268	28243329	R1 resection has been associated with a poor prognosis in many cancer types, including pancreatic, rectal, and lung cancers.	('pancreatic', 'Disease', 'MESH:D010195', (87, 97))	('pancreatic', 'Disease', (87, 97))	('lung cancers', 'Phenotype', 'HP:0100526', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('lung cancers', 'Disease', (111, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('R1 resection', 'Var', (0, 12))	('rectal', 'Disease', (99, 105))	('lung cancers', 'Disease', 'MESH:D008175', (111, 123))	('cancer', 'Disease', (63, 69))
907343	26297050	In IBD, dysregulated activation of the gut mucosal immune system driven by genetic susceptibility loci and environmental factors leads to chronic inflammation.	('inflammation', 'Disease', 'MESH:D007249', (146, 158))	('inflammation', 'Disease', (146, 158))	('dysregulated', 'Var', (8, 20))	('activation', 'PosReg', (21, 31))	('leads to', 'Reg', (129, 137))
907349	26297050	Ultimately, mutations in the Wnt/APC and/or inflammatory signaling pathways such as PI3K/AKT support dysregulated beta-catenin activity which in turn leads to the transcription of genes such as Cyclins, Axin2 and c-Myc that promote proliferation and tumor growth.	('APC', 'Disease', 'MESH:D011125', (33, 36))	('APC', 'Disease', (33, 36))	('AKT', 'Gene', '207', (89, 92))	('rat', 'Species', '10116', (239, 242))	('promote', 'PosReg', (224, 231))	('tumor', 'Disease', (250, 255))	('Cyclins', 'Gene', (194, 201))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('leads to', 'Reg', (150, 158))	('c-Myc', 'Gene', (213, 218))	('dysregulated beta-catenin activity', 'MPA', (101, 135))	('transcription', 'MPA', (163, 176))	('c-Myc', 'Gene', '4609', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('AKT', 'Gene', (89, 92))	('Axin2', 'Gene', (203, 208))	('mutations', 'Var', (12, 21))	('proliferation', 'CPA', (232, 245))	('Axin2', 'Gene', '8313', (203, 208))
907360	26297050	NF-kappaB modulation, may contribute to mesalamine's chemo-preventative properties.	('contribute', 'Reg', (26, 36))	('NF-kappaB', 'Protein', (0, 9))	('mesalamine', 'Chemical', 'MESH:D019804', (40, 50))	('modulation', 'Var', (10, 20))
907361	26297050	TNFalpha inhibitors, another potent mainstay of IBD therapy, reduces tumorigenesis in experimental CAC models, but it is not yet clear if they do so in humans.	('TNFalpha', 'Gene', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('humans', 'Species', '9606', (152, 158))	('reduces', 'NegReg', (61, 68))	('inhibitors', 'Var', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
907373	26297050	This group described the now classical mechanism whereby IDO1 expression in professional antigen presenting cells (APCs, monocytes/macrophages, dendritic cells) reduces local tryptophan concentrations, which reduces T cell proliferation and thus inhibits T cell-mediated immune response (Figure 2).	('APC', 'Disease', (115, 118))	('rat', 'Species', '10116', (193, 196))	('reduces T cell', 'Phenotype', 'HP:0005403', (208, 222))	('reduces', 'NegReg', (161, 168))	('T cell proliferation', 'CPA', (216, 236))	('T cell-mediated immune response', 'CPA', (255, 286))	('reduces', 'NegReg', (208, 215))	('rat', 'Species', '10116', (230, 233))	('tryptophan', 'Chemical', 'MESH:D014364', (175, 185))	('APC', 'Disease', 'MESH:D011125', (115, 118))	('IDO1', 'Gene', (57, 61))	('inhibits', 'NegReg', (246, 254))	('expression', 'Var', (62, 72))	('local tryptophan concentrations', 'MPA', (169, 200))
907380	26297050	Functionally relevant IDO1 gene polymorphisms correlate with a more severe disease phenotype in Crohn's disease.	('polymorphisms', 'Var', (32, 45))	("Crohn's disease", 'Disease', 'MESH:D003424', (96, 111))	("Crohn's disease", 'Disease', (96, 111))	('IDO1', 'Gene', (22, 26))	("Crohn's disease", 'Phenotype', 'HP:0100280', (96, 111))
907386	26297050	In IBD, chronic inflammation can cause DNA damage by oxidative and nitrosative stress, resulting in genetic and epigenetic alterations placing these patients at a higher risk for developing CAC.	('cause', 'Reg', (33, 38))	('patients', 'Species', '9606', (149, 157))	('inflammation', 'Disease', 'MESH:D007249', (16, 28))	('CAC', 'Disease', (190, 193))	('inflammation', 'Disease', (16, 28))	('epigenetic alterations', 'Var', (112, 134))	('genetic', 'Var', (100, 107))	('rat', 'Species', '10116', (127, 130))
907396	26297050	Inhibition of IDO1 increases anti-tumor immunity in a number of tumor models.	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (34, 39))	('IDO1', 'Gene', (14, 18))	('increases', 'PosReg', (19, 28))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
907398	26297050	These effects have also been reported for TDO and for the IDO2 inhibitor or D-1mT (indoximod).	('IDO2', 'Gene', (58, 62))	('TDO', 'Gene', '6999', (42, 45))	('indoximod', 'Chemical', 'MESH:C525396', (83, 92))	('IDO2', 'Gene', '169355', (58, 62))	('D-1mT', 'Var', (76, 81))	('TDO', 'Gene', (42, 45))
907405	26297050	High IDO1 expression at the tumor invasion front is an independent adverse prognostic factor for overall survival and metachronous CRC metastases, and high density of IDO1 expressing cells in the tumor draining lymph nodes was associated with a reduced 5 year survival rates in colon cancer patients.	('tumor', 'Disease', (28, 33))	('colon cancer', 'Disease', (278, 290))	('tumor', 'Disease', (196, 201))	('IDO1', 'Gene', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('rat', 'Species', '10116', (269, 272))	('High', 'Var', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (135, 145))	('expression', 'MPA', (10, 20))	('patients', 'Species', '9606', (291, 299))	('high density', 'Var', (151, 163))	('colon cancer', 'Phenotype', 'HP:0003003', (278, 290))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('metastases', 'Disease', (135, 145))	('reduced', 'NegReg', (245, 252))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('colon cancer', 'Disease', 'MESH:D015179', (278, 290))	('IDO1', 'Gene', (167, 171))	('5 year survival rates', 'CPA', (253, 274))	('overall survival', 'CPA', (97, 113))
907409	26297050	KRAS and beta-Catenin mutations are common in AOM-induced pre-neoplastic lesions in rats.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (62, 80))	('beta-Catenin', 'Gene', (9, 21))	('beta-Catenin', 'Gene', '84353', (9, 21))	('mutations', 'Var', (22, 31))	('rats', 'Species', '10116', (84, 88))	('KRAS', 'Gene', (0, 4))
907410	26297050	Though it is not known if these mutations drive the expression of IDO1 in CRC, this has been in a model of KRAS driven lung carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('IDO1', 'Gene', (66, 70))	('lung carcinoma', 'Disease', 'MESH:D008175', (119, 133))	('lung carcinoma', 'Disease', (119, 133))	('mutations', 'Var', (32, 41))
907416	26297050	In a mouse model of esophageal carcinoma, overexpression of the extracellular matrix protein periostin and a mutant p53 induced STAT1, which in turn induced IDO1.	('induced', 'PosReg', (120, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('esophageal carcinoma', 'Disease', (20, 40))	('STAT1', 'MPA', (128, 133))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (20, 40))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (20, 40))	('mutant', 'Var', (109, 115))	('mouse', 'Species', '10090', (5, 10))	('induced', 'Reg', (149, 156))	('IDO1', 'Disease', (157, 161))	('p53', 'Gene', (116, 119))
907425	26297050	Moreover, we found a specific role for epithelial IDO1 by demonstrating that gene silencing reduced proliferation in CRC cell lines which constitutively expressed IDO1.	('gene silencing', 'Var', (77, 91))	('rat', 'Species', '10116', (65, 68))	('proliferation', 'CPA', (100, 113))	('IDO1', 'Gene', (163, 167))	('reduced', 'NegReg', (92, 99))	('rat', 'Species', '10116', (107, 110))
907431	26297050	CpG oligonucleotides (CpG-ODNs), a Toll-like receptor (TLR) 9 agonist induces IDO1 throughout the GI tract and protect from murine colitis.	('induces', 'PosReg', (70, 77))	('colitis', 'Disease', 'MESH:D003092', (131, 138))	('protect', 'Reg', (111, 118))	('CpG', 'Var', (0, 3))	('colitis', 'Disease', (131, 138))	('oligonucleotides', 'Chemical', 'MESH:D009841', (4, 20))	('IDO1', 'Gene', (78, 82))	('colitis', 'Phenotype', 'HP:0002583', (131, 138))	('murine', 'Species', '10090', (124, 130))
907433	26297050	For example, contrary to these findings, in a mouse model of sepsis, IDO1 activity exacerbates inflammation and disease activity by increasing the sensitivity of TLR4.	('increasing', 'PosReg', (132, 142))	('exacerbates', 'PosReg', (83, 94))	('sepsis', 'Disease', (61, 67))	('sepsis', 'Phenotype', 'HP:0100806', (61, 67))	('sensitivity', 'MPA', (147, 158))	('IDO1', 'Gene', (69, 73))	('sepsis', 'Disease', 'MESH:D018805', (61, 67))	('inflammation', 'Disease', 'MESH:D007249', (95, 107))	('mouse', 'Species', '10090', (46, 51))	('inflammation', 'Disease', (95, 107))	('disease activity', 'CPA', (112, 128))	('activity', 'Var', (74, 82))
907436	26297050	Treatment with CpG-ODNs has also been shown to enhance the efficacy of chemotherapeutic agents in several mouse tumor models.	('CpG-ODNs', 'Var', (15, 23))	('enhance', 'PosReg', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('efficacy', 'CPA', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('mouse', 'Species', '10090', (106, 111))
907437	26297050	Additionally, treatment with an IDO1 inhibitor augments the anti-tumor effects of the TLR7 agonist imiquimod in mice inoculated with colon carcinoma cells.	('colon carcinoma', 'Disease', (133, 148))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('augments', 'NegReg', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('IDO1', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('inhibitor', 'Var', (37, 46))	('mice', 'Species', '10090', (112, 116))	('colon carcinoma', 'Disease', 'MESH:D015179', (133, 148))
907454	26297050	One study suggested that AHR may actually be a tumor suppressor in CRC as its genetic ablation led to beta-catenin accumulation and increased cecal tumor formation in both wildtype and ApcMin/+ mice.	('genetic ablation', 'Var', (78, 94))	('ablation', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CRC', 'Disease', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (148, 153))	('increased', 'PosReg', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('AHR', 'Gene', (25, 28))	('mice', 'Species', '10090', (194, 198))	('tumor', 'Disease', (47, 52))	('beta-catenin accumulation', 'MPA', (102, 127))
907464	26297050	If colon carcinoma cells produce NAD+ from QA, antitumor efficacy of IDO1 inhibitors could potentially be enhanced by concurrent blockade of other enzymes involved in NAD+ synthesis such as nicotinamide phosphoribosyltransferase using the specific inhibitor FK866.	('FK866', 'Chemical', 'MESH:C480543', (258, 263))	('colon carcinoma', 'Disease', 'MESH:D015179', (3, 18))	('NAD+', 'Chemical', 'MESH:D009243', (167, 171))	('colon carcinoma', 'Disease', (3, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('enhanced', 'PosReg', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('IDO1', 'Gene', (69, 73))	('inhibitors', 'Var', (74, 84))	('tumor', 'Disease', (51, 56))	('blockade', 'NegReg', (129, 137))	('nicotinamide', 'Chemical', 'MESH:D009536', (190, 202))	('NAD+', 'Chemical', 'MESH:D009243', (33, 37))	('QA', 'Chemical', 'MESH:D017378', (43, 45))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
907476	26297050	Overexpression of IDO1 in metastatic pancreatic ductal adenocarcinoma (PDA) was shown to be associated with increased T cell numbers.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (37, 69))	('T cell numbers', 'CPA', (118, 132))	('increased', 'PosReg', (108, 117))	('PDA', 'Chemical', '-', (71, 74))	('increased T cell', 'Phenotype', 'HP:0100828', (108, 124))	('IDO1', 'Gene', (18, 22))	('pancreatic ductal adenocarcinoma', 'Disease', (37, 69))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (37, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('Overexpression', 'Var', (0, 14))
907479	26297050	IDO1 inhibitor INCB023483 was shown to inhibit the growth of murine PAN02 pancreatic cell-derived tumors in WT and IDO1-/- mice, highlighting that tumor-derived IDO1 contributes to pancreatic tumor growth and immune evasion.	('tumors', 'Disease', (98, 104))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (181, 197))	('tumor', 'Disease', (98, 103))	('mice', 'Species', '10090', (123, 127))	('tumor', 'Disease', (147, 152))	('INCB023483', 'Chemical', '-', (15, 25))	('inhibit', 'NegReg', (39, 46))	('pancreatic', 'Disease', 'MESH:D010195', (74, 84))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('murine', 'Species', '10090', (61, 67))	('immune', 'MPA', (209, 215))	('pancreatic tumor', 'Disease', (181, 197))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('growth', 'MPA', (51, 57))	('INCB023483', 'Var', (15, 25))	('tumor', 'Disease', (192, 197))	('pancreatic tumor', 'Disease', 'MESH:D010190', (181, 197))	('pancreatic', 'Disease', 'MESH:D010195', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('pancreatic', 'Disease', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('pancreatic', 'Disease', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
907482	26297050	In a mouse model of p53 mutant esophageal cancer, the expression of IDO1 was shown to be associated with expression of periostin, an extracellular matrix protein involved in esophageal carcinoma metastasis.	('mutant', 'Var', (24, 30))	('associated', 'Reg', (89, 99))	('p53', 'Gene', (20, 23))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (174, 194))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('esophageal cancer', 'Disease', (31, 48))	('esophageal carcinoma metastasis', 'Disease', (174, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('mouse', 'Species', '10090', (5, 10))	('esophageal carcinoma metastasis', 'Disease', 'MESH:D009362', (174, 205))	('IDO1', 'Gene', (68, 72))
907485	26297050	Imatinib is a drug which targets mutated KIT oncoproteins and produces clinical response in 80% of patients.	('KIT oncoproteins', 'Protein', (41, 57))	('patients', 'Species', '9606', (99, 107))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('mutated', 'Var', (33, 40))
907504	26297050	Based on these results INCB24360 is currently being evaluated as a combination with Ipilimumab for melanoma in a phase Ib/2 study and advanced ovarian cancer as a monotherapy.	('INCB24360', 'Chemical', '-', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	('ovarian cancer', 'Disease', 'MESH:D010051', (143, 157))	('ovarian cancer', 'Disease', (143, 157))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('INCB24360', 'Var', (23, 32))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (84, 94))
907506	26297050	The TDO pathway is important because IDO1 inhibitors typically do not target its activity and it is possible that IDO1 inhibition could enhance TDO expression or function.	('inhibition', 'Var', (119, 129))	('function', 'MPA', (162, 170))	('TDO', 'Gene', (4, 7))	('TDO', 'Gene', (144, 147))	('IDO1', 'Gene', (114, 118))	('expression', 'MPA', (148, 158))	('enhance', 'PosReg', (136, 143))	('TDO', 'Gene', '6999', (4, 7))	('TDO', 'Gene', '6999', (144, 147))
907511	26297050	Specific gene silencing of both IDO1 and TDO in specific cell types may be one way to get around this problem.	('TDO', 'Gene', '6999', (41, 44))	('IDO1', 'Gene', (32, 36))	('TDO', 'Gene', (41, 44))	('gene silencing', 'Var', (9, 23))
907518	26297050	Genetic manipulation is another promising option for targeting tryptophan metabolism in cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tryptophan', 'Chemical', 'MESH:D014364', (63, 73))	('Genetic manipulation', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
907519	26297050	Using RNA interference, Zheng and colleagues illustrated that silencing IDO1 reduced melanoma tumor growth both in vitro and in vivo.	('silencing', 'Var', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('melanoma tumor', 'Disease', (85, 99))	('IDO1', 'Gene', (72, 76))	('melanoma tumor', 'Disease', 'MESH:D008545', (85, 99))	('reduced', 'NegReg', (77, 84))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('rat', 'Species', '10116', (51, 54))
907520	26297050	This same group subsequently demonstrated that silencing IDO1 in dendritic cells which have been loaded with murine breast cancer antigens significantly enhanced the efficacy of this DC-based vaccine approach.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('rat', 'Species', '10116', (36, 39))	('murine', 'Species', '10090', (109, 115))	('silencing', 'Var', (47, 56))	('enhanced', 'PosReg', (153, 161))	('IDO1', 'Gene', (57, 61))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('efficacy', 'MPA', (166, 174))
907522	26297050	In most preclinical models, just as with the Phase I clinical trials, IDO1 inhibition alone slowed neoplastic growth but did not eliminate or prevent the tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('inhibition', 'Var', (75, 85))	('neoplastic growth', 'CPA', (99, 116))	('IDO1', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('slowed', 'NegReg', (92, 98))
907524	26297050	However, in breast cancer cell lines IDO1 gene silencing enhanced the effect of radiation therapy, suggesting this may be an effective option.	('breast cancer', 'Disease', (12, 25))	('radiation therapy', 'CPA', (80, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('gene silencing', 'Var', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('IDO1', 'Gene', (37, 41))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('enhanced', 'PosReg', (57, 65))
907534	26297050	Orally administered small molecule inhibitors of IDO1, the most prevalent enzyme in this pathway, have demonstrated safety and tolerability in Phase I human trials.	('rat', 'Species', '10116', (110, 113))	('IDO1', 'Gene', (49, 53))	('human', 'Species', '9606', (151, 156))	('inhibitors', 'Var', (35, 45))	('small molecule inhibitors', 'Var', (20, 45))
907567	25650663	Our results revealed that severe chronic inflammation was more frequently observed in dysplastic tissues (80.9%), such as low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia (HGIN) in comparison with that in non-dysplastic (normal/hyperplasia) tissues (40.7%) (P<0.001) (Figure 1b-d), indicating a potential link between chronic inflammation and gastric cardia carcinogenesis.	('neoplasia', 'Phenotype', 'HP:0002664', (196, 205))	('intraepithelial neoplasia', 'Disease', (132, 157))	('chronic inflammation', 'Disease', 'MESH:D007249', (33, 53))	('chronic inflammation', 'Disease', (33, 53))	('intraepithelial neoplasia', 'Disease', (180, 205))	('hyperplasia', 'Disease', (263, 274))	('low-grade', 'Var', (122, 131))	('hyperplasia', 'Disease', 'MESH:D006965', (263, 274))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (132, 157))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (180, 205))	('non-dysplastic', 'Disease', 'MESH:D004416', (240, 254))	('dysplastic tissues', 'Disease', (86, 104))	('dysplastic tissues', 'Disease', 'MESH:D004416', (86, 104))	('chronic inflammation', 'Disease', 'MESH:D007249', (353, 373))	('gastric cardia carcinogenesis', 'Disease', 'MESH:D004938', (378, 407))	('chronic inflammation', 'Disease', (353, 373))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (132, 157))	('gastric cardia carcinogenesis', 'Disease', (378, 407))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (180, 205))	('non-dysplastic', 'Disease', (240, 254))	('high-grade', 'Var', (169, 179))	('neoplasia', 'Phenotype', 'HP:0002664', (148, 157))
907579	25650663	The activation of ataxia telangiectasia mutated kinase (ATM) by phosphorylation at Ser1981 is an early event at DNA damage loci as well.	('ataxia telangiectasia mutated kinase', 'Gene', (18, 54))	('telangiectasia', 'Phenotype', 'HP:0001009', (25, 39))	('ataxia telangiectasia mutated kinase', 'Gene', '472', (18, 54))	('DNA', 'Disease', (112, 115))	('Ser1981', 'Chemical', '-', (83, 90))	('phosphorylation', 'Var', (64, 79))	('ATM', 'Gene', '472', (56, 59))	('ataxia', 'Phenotype', 'HP:0001251', (18, 24))	('Ser1981', 'Var', (83, 90))	('activation', 'PosReg', (4, 14))	('ATM', 'Gene', (56, 59))
907607	25650663	DNA double-strand breaks (DSBs) are the most serious form of DNA damage and are difficult to repair accurately.	('double-strand breaks', 'Var', (4, 24))	('DSBs', 'Chemical', '-', (26, 30))	('DNA', 'Disease', (0, 3))
907609	25650663	Phosphorylated H2AX is considered to be a reliable biomarker of DSBs.	('Phosphorylated', 'Var', (0, 14))	('DSBs', 'Disease', (64, 68))	('H2AX', 'Gene', '3014', (15, 19))	('DSBs', 'Chemical', '-', (64, 68))	('H2AX', 'Gene', (15, 19))
907610	25650663	Our previous study showed that CagA+ H. pylori could induce strong DNA damage in human immortalized esophageal epithelial cells.	('DNA damage', 'MPA', (67, 77))	('H. pylori', 'Species', '210', (37, 46))	('human', 'Species', '9606', (81, 86))	('CagA+ H. pylori', 'Var', (31, 46))
907617	25650663	Our results suggest a hypothesis (Figure 4) that increased gastric cardia epithelial cells harboring DDR in the milieu of chronic inflammation may precipitate carcinogenesis.	('carcinogenesis', 'Disease', (159, 173))	('precipitate', 'Reg', (147, 158))	('increased gastric', 'Phenotype', 'HP:0005207', (49, 66))	('gastric cardia epithelia', 'Disease', (59, 83))	('increased', 'PosReg', (49, 58))	('DDR', 'Var', (101, 104))	('chronic inflammation', 'Disease', (122, 142))	('gastric cardia epithelia', 'Disease', 'MESH:D004938', (59, 83))	('chronic inflammation', 'Disease', 'MESH:D007249', (122, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))
907634	25650663	Positive controls were used for each of the antibodies (breast cancer tissues for gammaH2AX and phospho-ATM Ser1981), while in the negative controls the PBS was substituted for the primary antibody.	('ATM', 'Gene', '472', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Ser1981', 'Chemical', '-', (108, 115))	('gammaH2AX', 'Chemical', '-', (82, 91))	('gammaH2AX', 'Var', (82, 91))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('ATM', 'Gene', (104, 107))	('PBS', 'Chemical', 'MESH:D007854', (153, 156))
907711	23957669	Among the controls, the consumption of CML-AGE had statistically significant positive correlation with that of total meat (r = 0.61), total fat (r = 0.54), saturated fat (r = 0.53), protein (r = 0.51), egg (r = 0.27), and cholesterol (r = 0.56), and inverse correlation with dark green vegetables consumption (r = - 0.05, P = 0.13).	('protein', 'Protein', (182, 189))	('positive', 'PosReg', (77, 85))	('cholesterol', 'Chemical', 'MESH:D002784', (222, 233))	('saturated fat', 'Chemical', '-', (156, 169))	('CML-AGE', 'Var', (39, 46))	('CML', 'Chemical', 'MESH:C048496', (39, 42))
907724	23957669	The investigators found similar to our study that saturated fat was associated with an increased risk of long-segment BE (OR=1.05; 95% CI 1.01-1.09, per gram/day).	('saturated fat', 'Chemical', '-', (50, 63))	('long-segment', 'Disease', (105, 117))	('saturated fat', 'Var', (50, 63))	('men', 'Species', '9606', (113, 116))
907799	22557942	Several reports have also suggested that tissue blood flow is worse during the intra-operative and postoperative periods among patients with leakage than those without leakage.	('patients', 'Species', '9606', (127, 135))	('worse', 'NegReg', (62, 67))	('leakage', 'Var', (141, 148))	('tissue blood flow', 'CPA', (41, 58))
907817	18493439	0-IIb and 0-IIa type lesions are indications for endoscopic esophageal mucosal resection (EEMR), while 0-I, 0-IIc+0-IIa, and 0-III lesions should be candidates for radical surgical resection.	('0-IIa type', 'Var', (10, 20))	('esophageal mucosal', 'Disease', 'MESH:D052016', (60, 78))	('esophageal mucosal', 'Disease', (60, 78))
907902	30365065	Of note, a ceRNA subnetwork was isolated, consisting of two circRNAs (hsa_circ_0008287 and hsa_circ_0005027) and one miRNA (hsa-miR-548c-3p), which significantly affect both ErbB and Hippo signaling pathways.	('Hippo signaling pathways', 'Pathway', (183, 207))	('affect', 'Reg', (162, 168))	('miR-548c', 'Gene', (128, 136))	('hsa_circ_0008287', 'Var', (70, 86))	('miR', 'Gene', '220972', (128, 131))	('ErbB', 'Gene', (174, 178))	('miR', 'Gene', (117, 120))	('miR', 'Gene', (128, 131))	('ErbB', 'Gene', '1956', (174, 178))	('miR', 'Gene', '220972', (117, 120))	('miR-548c', 'Gene', '693129', (128, 136))	('hsa_circ_0005027', 'Var', (91, 107))
907910	30365065	In addition, circRNAs are widely involved in cancer; ciRS-7 in HeLa cells, Hsa_ circ_001569 in colorectal cancer, circHIPK3 in several types of cancer, f-circM9, f-circPR in hematological malignancy, and circTCF25 in urinary bladder carcinoma.	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('circHIPK3', 'Var', (114, 123))	('urinary bladder carcinoma', 'Disease', (217, 242))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('HeLa', 'CellLine', 'CVCL:0030', (63, 67))	('colorectal cancer', 'Disease', (95, 112))	('hematological malignancy', 'Disease', (174, 198))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('hematological malignancy', 'Disease', 'MESH:D019337', (174, 198))	('cancer', 'Disease', (45, 51))	('urinary bladder carcinoma', 'Disease', 'MESH:D001749', (217, 242))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (225, 242))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('hematological malignancy', 'Phenotype', 'HP:0004377', (174, 198))	('ciRS-7', 'Gene', '103611090', (53, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('ciRS-7', 'Gene', (53, 59))
907952	30365065	In the Hippo miRNA-ceRNA network, we also isolated a subnetwork consisting of circRNAs (hsa_circ_0008287 and hsa_circ_0005027), miRNAs (hsa-miR-548c-3p) and 61 Hippo pathway genes, which had the most interaction between miRNAs and targeted genes (Fig.	('Hippo', 'Gene', (160, 165))	('miR', 'Gene', '220972', (13, 16))	('miR-548c', 'Gene', (140, 148))	('miR', 'Gene', (13, 16))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('interaction', 'Interaction', (200, 211))	('miR', 'Gene', '220972', (220, 223))	('miR', 'Gene', (220, 223))	('miR-548c', 'Gene', '693129', (140, 148))	('miR', 'Gene', '220972', (128, 131))	('miR', 'Gene', (128, 131))	('hsa_circ_0008287', 'Var', (88, 104))
907965	30365065	The present study demonstrated that aberrantly expressed circRNAs have extensive interactions with miRNAs, and those miRNAs exerted their effect on multiple cancer-related pathways.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('aberrantly expressed', 'Var', (36, 56))	('effect', 'Reg', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('miR', 'Gene', '220972', (117, 120))	('cancer', 'Disease', (157, 163))	('miR', 'Gene', (117, 120))	('interactions', 'Interaction', (81, 93))
907968	30365065	In addition, ErbB1 amplification is correlated with a hypopharyngeal primary site.	('amplification', 'Var', (19, 32))	('correlated', 'Reg', (36, 46))	('ErbB1', 'Gene', '1956', (13, 18))	('hypopharyngeal', 'Disease', 'MESH:D007012', (54, 68))	('ErbB1', 'Gene', (13, 18))	('hypopharyngeal', 'Disease', (54, 68))
907984	30365065	Taken together, the present study indicated that hsa_ circ_0008287 and hsa_circ_0005027 were downregulated in HCa and competitively bound miR-548c-3p with ErbB and Hippo signaling pathway genes.	('hsa_circ_0005027', 'Var', (71, 87))	('miR-548c', 'Gene', (138, 146))	('HCa', 'Disease', (110, 113))	('miR-548c', 'Gene', '693129', (138, 146))	('bound', 'Interaction', (132, 137))	('downregulated', 'NegReg', (93, 106))	('hsa_ circ_0008287', 'Var', (49, 66))	('ErbB', 'Gene', (155, 159))	('ErbB', 'Gene', '1956', (155, 159))
907985	30365065	Further studies are warranted on the roles of hsa_circ_0008287, hsa_circ_0005027, and miR-548c-3p as potential diagnostic biomarkers and therapeutic targets for HCa.	('miR-548c', 'Gene', '693129', (86, 94))	('hsa_circ_0005027', 'Var', (64, 80))	('HCa', 'Disease', (161, 164))	('miR-548c', 'Gene', (86, 94))
907990	30257714	In FDG avid ESCCs, metabolic tumor length (ML) using SegPHL (MLPHL), fixed SUV 2.5 threshold (ML2.5), and fixed 40% of maximum SUV (SUVmax) (ML40%) were measured.	('PHL', 'Chemical', '-', (56, 59))	('metabolic tumor', 'Disease', (19, 34))	('ML', 'Disease', 'MESH:C537366', (43, 45))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('ML', 'Disease', 'MESH:C537366', (61, 63))	('fixed', 'Var', (69, 74))	('metabolic tumor', 'Disease', 'MESH:D008659', (19, 34))	('PHL', 'Chemical', '-', (63, 66))	('FDG', 'Chemical', 'MESH:D019788', (3, 6))	('ML', 'Disease', 'MESH:C537366', (141, 143))	('ML', 'Disease', 'MESH:C537366', (94, 96))
908087	30257714	The frequency of metastatic LNs on pathologic specimens tended to be higher in FDG avid ESCCs than in FDG non-avid ESCCs but without statistical significance (p = 0.0941).	('FDG', 'Chemical', 'MESH:D019788', (79, 82))	('men', 'Species', '9606', (51, 54))	('FDG', 'Var', (79, 82))	('FDG', 'Chemical', 'MESH:D019788', (102, 105))	('higher', 'PosReg', (69, 75))	('metastatic LNs', 'CPA', (17, 31))
908200	29100288	Lentivirus mediated knockdown of XIST inhibited proliferation, migration and invasion of esophageal squamous cancer cells in vitro and suppressed tumor growth in vivo.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('XIST', 'Gene', (33, 37))	('proliferation', 'CPA', (48, 61))	('squamous cancer', 'Phenotype', 'HP:0002860', (100, 115))	('invasion', 'CPA', (77, 85))	('tumor', 'Disease', (146, 151))	('inhibited', 'NegReg', (38, 47))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (89, 115))	('esophageal squamous cancer', 'Disease', (89, 115))	('knockdown', 'Var', (20, 29))	('suppressed', 'NegReg', (135, 145))	('migration', 'CPA', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
908209	29100288	LncRNA-based mechanisms have been involved in cell fates control, and their dysregulation have been shown to be associated with several human diseases including cancer.	('human', 'Species', '9606', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('LncRNA-based', 'Protein', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('dysregulation', 'Var', (76, 89))	('cancer', 'Disease', (161, 167))	('associated', 'Reg', (112, 122))
908214	29100288	On the other hand, deletion of XIST in the mice resulted in a highly aggressive myeloproliferative neoplasm with 100% penetrance, indicating tumor-suppressive effects of XIST.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('mice', 'Species', '10090', (43, 47))	('neoplasm', 'Phenotype', 'HP:0002664', (99, 107))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (80, 107))	('myeloproliferative neoplasm', 'Disease', (80, 107))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('deletion', 'Var', (19, 27))	('tumor', 'Disease', (141, 146))	('myeloproliferative neoplasm', 'Disease', 'MESH:D009196', (80, 107))	('XIST', 'Gene', (31, 35))
908217	29100288	We then detected expression of XIST in a panel of ESCC cancer cells including KYSE30, KYSE510, KYSE410, KYSE520, KYSE140 and KYSE150 and one immortalized normal epithelial cells (NE1).	('KYSE30', 'Var', (78, 84))	('KYSE150', 'Var', (125, 132))	('KYSE410', 'Var', (95, 102))	('detected', 'Reg', (8, 16))	('KYSE510', 'Var', (86, 93))	('expression', 'MPA', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('NE1', 'CellLine', 'CVCL:E306', (179, 182))	('KYSE520', 'Var', (104, 111))	('KYSE150', 'CellLine', 'CVCL:1348', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('KYSE140', 'Var', (113, 120))	('cancer', 'Disease', (55, 61))	('ESCC', 'Disease', (50, 54))
908220	29100288	Our results showed that patients with high XIST level had a significantly shortened overall survival as well as disease-free survival than those with low XIST level (Figure 1C and 1D).	('disease-free survival', 'CPA', (112, 133))	('overall survival', 'CPA', (84, 100))	('high XIST level', 'Var', (38, 53))	('patients', 'Species', '9606', (24, 32))	('shortened', 'NegReg', (74, 83))
908227	29100288	CCK-8 assays revealed that knockdown of XIST significantly suppressed cell growth in KYSE30 and KYSE150 cells (Figure 2B).	('knockdown', 'Var', (27, 36))	('XIST', 'Gene', (40, 44))	('KYSE150', 'CellLine', 'CVCL:1348', (96, 103))	('suppressed', 'NegReg', (59, 69))	('cell growth', 'CPA', (70, 81))
908228	29100288	Decreased migration and invasion capacity of KYSE30 and KYSE150 cells was observed after knockdown of XIST (Figure 3A and 3B).	('invasion capacity', 'CPA', (24, 41))	('Decreased', 'NegReg', (0, 9))	('XIST', 'Gene', (102, 106))	('KYSE150', 'CellLine', 'CVCL:1348', (56, 63))	('knockdown', 'Var', (89, 98))	('migration', 'CPA', (10, 19))
908230	29100288	XIST knockdown resulted in elevated expression of E-cadherin and beta-catenin and decreased expression of N-cadherin, indicating EMT underlies the pro-metastasis roles of XIST (Figure 3C and 3D).	('E-cadherin', 'Gene', (50, 60))	('knockdown', 'Var', (5, 14))	('beta-catenin', 'Gene', '1499', (65, 77))	('N-cadherin', 'Gene', (106, 116))	('E-cadherin', 'Gene', '999', (50, 60))	('elevated', 'PosReg', (27, 35))	('beta-catenin', 'Gene', (65, 77))	('N-cadherin', 'Gene', '1000', (106, 116))	('XIST', 'Gene', (0, 4))	('decreased', 'NegReg', (82, 91))	('expression', 'MPA', (36, 46))	('expression', 'MPA', (92, 102))
908236	29100288	Next, we cloned the wild type (pmirGLO-XIST-WT) and mutated binding site (pmirGLO-XIST-Mut) of miR-101 in the XIST sequence into the reporter vector and employed luciferase assays to confirm the direct relationship between miR-101 and XIST.	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (95, 98))	('mutated', 'Var', (52, 59))	('miR', 'Gene', '220972', (223, 226))	('miR', 'Gene', (223, 226))
908240	29100288	Regulative correlations of EZH2 and miR-101 (Figure 5A) have been well documented in several human cancers and overexpressed EZH2 predicts poor prognosis of ESCC patients.	('patients', 'Species', '9606', (162, 170))	('overexpressed', 'Var', (111, 124))	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('ESCC', 'Disease', (157, 161))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('EZH2', 'Gene', (125, 129))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (36, 39))
908251	29100288	We found that tumors in the knockdown groups grew slower than that in the NC group (Figure 7A-7C).	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('knockdown', 'Var', (28, 37))	('grew', 'CPA', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('slower', 'NegReg', (50, 56))
908252	29100288	Further analysis indicated that XIST was significantly reduced in the xenografts from the knockdown groups, while expression of miR-101 was elevated compared with that in the control group (Figure 7D and 7E).	('XIST', 'Gene', (32, 36))	('knockdown', 'Var', (90, 99))	('reduced', 'NegReg', (55, 62))	('miR', 'Gene', '220972', (128, 131))	('elevated', 'PosReg', (140, 148))	('miR', 'Gene', (128, 131))	('expression', 'MPA', (114, 124))
908253	29100288	Altogether, knockdown of XIST suppresses tumor growth via regulation of miR-101/EZH2 axis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('miR', 'Gene', '220972', (72, 75))	('regulation', 'Reg', (58, 68))	('tumor', 'Disease', (41, 46))	('suppresses', 'NegReg', (30, 40))	('knockdown', 'Var', (12, 21))	('XIST', 'Gene', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('miR', 'Gene', (72, 75))
908255	29100288	Silence of XIST expression significantly inhibited the proliferation, migration and invasion capacity of ESCC cells in vitro and suppressed tumor growth in vivo.	('suppressed', 'NegReg', (129, 139))	('migration', 'CPA', (70, 79))	('proliferation', 'CPA', (55, 68))	('XIST expression', 'Gene', (11, 26))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('inhibited', 'NegReg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('invasion capacity', 'CPA', (84, 101))	('Silence', 'Var', (0, 7))	('tumor', 'Disease', (140, 145))
908256	29100288	Furthermore, our data provided the first evidence that XIST functions as a molecular sponge for miR-101 and EZH2 and knockdown of XIST exerted tumor-suppressive functions in human ESCC by epigenetic regulation of EZH2 via reciprocal repression of miR-101.	('human', 'Species', '9606', (174, 179))	('tumor', 'Disease', (143, 148))	('XIST', 'Gene', (130, 134))	('EZH2', 'Gene', (213, 217))	('miR', 'Gene', (247, 250))	('miR', 'Gene', '220972', (247, 250))	('miR', 'Gene', '220972', (96, 99))	('epigenetic regulation', 'Var', (188, 209))	('miR', 'Gene', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('ESCC', 'Disease', (180, 184))	('knockdown', 'Var', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
908258	29100288	Dysregulated expression of XIST was associated with initiation, progression and metastasis of several cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('metastasis', 'CPA', (80, 90))	('progression', 'CPA', (64, 75))	('expression', 'MPA', (13, 23))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('XIST', 'Gene', (27, 31))	('Dysregulated', 'Var', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('associated', 'Reg', (36, 46))
908262	29100288	found that mice with deleted XIST expression developed highly aggressive hematopoietic disorders, indicating tumor suppressive roles of XIST.	('deleted', 'Var', (21, 28))	('hematopoietic disorders', 'Disease', (73, 96))	('XIST', 'Gene', (29, 33))	('hematopoietic disorders', 'Phenotype', 'HP:0001871', (73, 96))	('developed', 'PosReg', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mice', 'Species', '10090', (11, 15))	('hematopoietic disorders', 'Disease', 'MESH:D019337', (73, 96))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
908264	29100288	EZH2 constitutes the main component of PRC2 as a transcriptional repressor and dysregulation of EZH2 is implicated in progression of many types of human cancers including ESCC.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('implicated', 'Reg', (104, 114))	('cancers', 'Disease', (153, 160))	('human', 'Species', '9606', (147, 152))	('EZH2', 'Gene', (96, 100))	('dysregulation', 'Var', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
908266	29100288	Our studies revealed that knockdown of XIST resulted in downregulation of EZH2 and reintroduction of EZH2 without the binding site for miR-101 significantly attenuated the anti-proliferation effects after knockdown of XIST, which is in concordance with a recent report demonstrating oncogenic roles of XIST in gastric cancer.	('miR', 'Gene', (135, 138))	('attenuated', 'NegReg', (157, 167))	('EZH2', 'Gene', (74, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (310, 324))	('anti-proliferation effects', 'CPA', (172, 198))	('XIST', 'Gene', (39, 43))	('gastric cancer', 'Phenotype', 'HP:0012126', (310, 324))	('downregulation', 'NegReg', (56, 70))	('knockdown', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('miR', 'Gene', '220972', (135, 138))	('gastric cancer', 'Disease', (310, 324))
908272	29100288	Six esophageal squamous cell carcinoma cell lines (KYSE30, KYSE510, KYSE410, KYSE520, KYSE140 and KYSE150) were purchased from the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ, Braunschweig, Germany).	('KYSE520', 'Var', (77, 84))	('KYSE150', 'CellLine', 'CVCL:1348', (98, 105))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (4, 38))	('von', 'Disease', 'MESH:D014842', (149, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('KYSE140', 'Var', (86, 93))	('KYSE410', 'Var', (68, 75))	('esophageal squamous cell carcinoma', 'Disease', (4, 38))	('von', 'Disease', (149, 152))	('KYSE510', 'Var', (59, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('KYSE30', 'Var', (51, 57))	('KYSE150', 'Var', (98, 105))
908358	26167022	The sternocleidomastoid is tested by asking the patient to turn the head to the left or right or to anteflect the head against resistance.	('patient', 'Species', '9606', (48, 55))	('anteflect', 'Var', (100, 109))	('sternocleidomastoid', 'Disease', 'MESH:C535977', (4, 23))	('sternocleidomastoid', 'Disease', (4, 23))
908361	26167022	If there is a lesion of the nerve, the tongue will deviate toward the affected side or there may be wasting and fasciculations if the lesion is not acute.	('tongue will deviate', 'Phenotype', 'HP:0000162', (39, 58))	('fasciculations', 'Phenotype', 'HP:0002380', (112, 126))	('wasting', 'CPA', (100, 107))	('fasciculations', 'Disease', (112, 126))	('lesion', 'Var', (14, 20))	('deviate', 'NegReg', (51, 58))	('fasciculations', 'Disease', 'MESH:D005207', (112, 126))
908389	26167022	Brown-Vialetto-Van Lare-syndrome is due to mutations in the SLC52A1 gene encoding the human riboflavin transporter-1.	('SLC52A1', 'Gene', '55065', (60, 67))	('SLC52A1', 'Gene', (60, 67))	('human', 'Species', '9606', (86, 91))	('due to', 'Reg', (36, 42))	('mutations', 'Var', (43, 52))	('Brown-Vialetto-Van Lare-syndrome', 'Disease', (0, 32))	('riboflavin', 'Chemical', 'MESH:D012256', (92, 102))
908390	26167022	Substitution of riboflavin has a beneficial effect and prolongs life expectancy.	('Substitution', 'Var', (0, 12))	('riboflavin', 'Protein', (16, 26))	('beneficial', 'PosReg', (33, 43))	('riboflavin', 'Chemical', 'MESH:D012256', (16, 26))	('prolongs', 'PosReg', (55, 63))	('life expectancy', 'CPA', (64, 79))
908392	26167022	It follows an autosomal recessive trait of inheritance and is due to mutations in the ALADIN gene, which encodes a nuclear pore complex component.	('mutations', 'Var', (69, 78))	('due to', 'Reg', (62, 68))	('ALADIN', 'Gene', '8086', (86, 92))	('autosomal recessive trait', 'Disease', (14, 39))	('ALADIN', 'Gene', (86, 92))
908398	26167022	In X-linked Charcot-Marie-Tooth disease due to mutations in the GJB1 gene, neuropathy may be associated with vocal cord paralysis.	('GJB1', 'Gene', '2705', (64, 68))	('X-linked Charcot-Marie-Tooth disease', 'Disease', 'MESH:C535919', (3, 39))	('neuropathy', 'Phenotype', 'HP:0009830', (75, 85))	('vocal cord paralysis', 'Disease', 'MESH:D014826', (109, 129))	('vocal cord paralysis', 'Phenotype', 'HP:0001605', (109, 129))	('due', 'Reg', (40, 43))	('neuropathy', 'Disease', (75, 85))	('mutations', 'Var', (47, 56))	('paralysis', 'Phenotype', 'HP:0003470', (120, 129))	('associated', 'Reg', (93, 103))	('X-linked Charcot-Marie-Tooth disease', 'Disease', (3, 39))	('GJB1', 'Gene', (64, 68))	('vocal cord paralysis', 'Disease', (109, 129))	('neuropathy', 'Disease', 'MESH:D009422', (75, 85))
908411	26167022	Also, dissection of the vertebral artery may go along with hypoglossal palsy.	('hypoglossal palsy', 'Disease', (59, 76))	('dissection', 'Var', (6, 16))	('hypoglossal palsy', 'Disease', 'MESH:D020437', (59, 76))
908412	26167022	Dissection of the internal carotid artery may even lead to Villaret's-syndrome or Collet-Sicard-syndrome.	('Collet-Sicard-syndrome', 'Disease', (82, 104))	('Dissection', 'Var', (0, 10))	("Villaret's-syndrome", 'Disease', (59, 78))	('lead to', 'Reg', (51, 58))	("Villaret's-syndrome", 'Disease', 'MESH:D010300', (59, 78))	('Collet-Sicard-syndrome', 'Disease', 'MESH:D013577', (82, 104))
908414	26167022	Dissection of the internal carotid artery may result in dysphonia and homolateral shoulder paralysis due to palsy of the vagal and accessory nerves.	('palsy of the vagal', 'Disease', (108, 126))	('palsy of the vagal', 'Disease', 'MESH:D010243', (108, 126))	('dysphonia', 'Disease', 'MESH:D055154', (56, 65))	('result in', 'Reg', (46, 55))	('dysphonia', 'Phenotype', 'HP:0001618', (56, 65))	('paralysis', 'Disease', (91, 100))	('Dissection', 'Var', (0, 10))	('paralysis', 'Phenotype', 'HP:0003470', (91, 100))	('paralysis due to palsy', 'Phenotype', 'HP:0010628', (91, 113))	('paralysis', 'Disease', 'MESH:D010243', (91, 100))	('dysphonia', 'Disease', (56, 65))
908440	26167022	Injury of the vagal nerve may increase vagal tone, which consecutively may diminish the anti-inflammatory capacity of patients with TBI.	('TBI', 'Disease', 'MESH:D000070642', (132, 135))	('vagal tone', 'MPA', (39, 49))	('Injury of the vagal nerve', 'Phenotype', 'HP:0002886', (0, 25))	('anti-inflammatory capacity', 'MPA', (88, 114))	('diminish', 'NegReg', (75, 83))	('increase', 'PosReg', (30, 38))	('Injury', 'Var', (0, 6))	('TBI', 'Disease', (132, 135))	('patients', 'Species', '9606', (118, 126))
908500	26167022	This GBS variant manifests with dysphagia, weakness of facial muscles, neck flexors, and proximal upper limb muscles, ophthalmoplegia, ataxia, and autonomic dysfunction (heart rate, bladder).	('autonomic dysfunction', 'Phenotype', 'HP:0012332', (147, 168))	('ophthalmoplegia', 'Phenotype', 'HP:0000602', (118, 133))	('variant', 'Var', (9, 16))	('dysphagia', 'Disease', 'MESH:D003680', (32, 41))	('weakness of facial muscles', 'Disease', 'MESH:D018908', (43, 69))	('ophthalmoplegia', 'Disease', (118, 133))	('weakness of facial muscles', 'Disease', (43, 69))	('weakness of facial muscles', 'Phenotype', 'HP:0030319', (43, 69))	('dysphagia', 'Disease', (32, 41))	('ataxia', 'Phenotype', 'HP:0001251', (135, 141))	('ataxia', 'Disease', 'MESH:D001259', (135, 141))	('dysphagia', 'Phenotype', 'HP:0002015', (32, 41))	('ataxia', 'Disease', (135, 141))	('ophthalmoplegia', 'Disease', 'MESH:D009886', (118, 133))	('autonomic dysfunction', 'Disease', 'MESH:D001342', (147, 168))	('autonomic dysfunction', 'Disease', (147, 168))
908529	26167022	Chiari-I malformation may lead to compression of the LCN between the PICA and the herniated cerebellar tonsil.	('Chiari-I', 'Gene', (0, 8))	('lead to', 'Reg', (26, 33))	('LCN', 'Chemical', '-', (53, 56))	('hernia', 'Phenotype', 'HP:0100790', (82, 88))	('PICA', 'Phenotype', 'HP:0011856', (69, 73))	('Chiari-I malformation', 'Phenotype', 'HP:0007099', (0, 21))	('malformation', 'Var', (9, 21))
908581	23837098	Additionally, such negative consequences of chronic PPI administration as hypergastrinemia, and disturbances of the bacterial gastric microflora, potentially promoting the development of some malignancies, should not be underestimated.	('malignancies', 'Disease', 'MESH:D009369', (192, 204))	('men', 'Species', '9606', (179, 182))	('hypergastrinemia', 'Disease', (74, 90))	('malignancies', 'Disease', (192, 204))	('hypergastrinemia', 'Disease', 'None', (74, 90))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (74, 90))	('PPI', 'Var', (52, 55))	('promoting', 'PosReg', (158, 167))
908701	23157945	Current data from Western populations are indicating an emerging consensus that D2 resection with sparing of pancreas and spleen (also called D1+) is not associated with increased perioperative mortality .	('pancreas', 'Disease', 'MESH:D010190', (109, 117))	('D2 resection', 'Var', (80, 92))	('pancreas', 'Disease', (109, 117))
908702	23157945	Although a recent update of the Dutch D1D2 trial  indicated a significantly decreased gastric cancer-related death rate in the D2 group as compared to D1, it remains to be proven whether D2/D1+ vs. D1 resection in Western populations significantly increases overall survival (OS) .	('D2/D1+', 'Var', (187, 193))	('overall survival', 'MPA', (258, 274))	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('decreased gastric cancer', 'Phenotype', 'HP:0006753', (76, 100))	('increases', 'PosReg', (248, 257))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('decreased', 'NegReg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (86, 100))
908741	23157945	As mentioned above, meta-analyses showed neoadjuvant therapy to improve OS compared with surgery alone for esophageal cancer, including GEJ.	('improve', 'PosReg', (64, 71))	('esophageal cancer', 'Disease', (107, 124))	('GEJ', 'Disease', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('neoadjuvant', 'Var', (41, 52))
908746	23157945	Patients with T1N+ or T2-T3N0-1 tumors were included, the majority presenting with adenocarcinoma of the distal or junctional esophagus.	('adenocarcinoma', 'Disease', (83, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('Patients', 'Species', '9606', (0, 8))	('T2-T3N0-1', 'Var', (22, 31))	('T1N+', 'Var', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('tumors', 'Disease', (32, 38))	('presenting with', 'Reg', (67, 82))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
908801	23157945	In this study, OS, local control, and non-cancer-related death were significantly better with IMRT when compared to 3DCRT .	('better', 'PosReg', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('local control', 'CPA', (19, 32))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (42, 48))	('IMRT', 'Var', (94, 98))
908874	33553671	Although we had not used controls, patients with caustic-induced sequelae had poor QoL in all domains of the score (physical, psychological, social, and environmental) compared to previously described values for normal individuals.	('sequelae', 'Var', (65, 73))	('poor', 'NegReg', (78, 82))	('caustic-induced', 'Disease', (49, 64))	('QoL', 'MPA', (83, 86))	('patients', 'Species', '9606', (35, 43))
908951	32478299	In patients with metastatic disease, the presence of ECOG PS 3-4, grade-III histology, and liver metastasis adversely affected survival, whereas CT administration significantly improved survival.	('survival', 'CPA', (127, 135))	('metastatic disease', 'Disease', (17, 35))	('ECOG', 'Gene', (53, 57))	('patients', 'Species', '9606', (3, 11))	('affected', 'Reg', (118, 126))	('improved', 'PosReg', (177, 185))	('liver metastasis', 'Disease', 'MESH:D009362', (91, 107))	('liver metastasis', 'Disease', (91, 107))	('presence', 'Var', (41, 49))
908973	32478299	Similarly, in meta-analysis conducted by Urschel et al., which included nine randomized trials comparing NACRT to surgery alone, both 3-year survival and local control rate were found to be better in the NACRT arm.	('NACRT', 'Var', (204, 209))	('NACRT', 'Chemical', '-', (204, 209))	('better', 'PosReg', (190, 196))	('NACRT', 'Chemical', '-', (105, 110))	('local control', 'CPA', (154, 167))
909002	32163489	High alcohol consumption was associated with increased risk of first variceal bleeding, both at univariate analysis (SHR 7.73 [1.71-34.9]) and multivariate analysis (SHR 13.9 [2.51-77.0]).	('alcohol', 'Chemical', 'MESH:D000438', (5, 12))	('bleeding', 'Disease', 'MESH:D006470', (78, 86))	('bleeding', 'Disease', (78, 86))	('High alcohol consumption', 'Phenotype', 'HP:0030955', (0, 24))	('High alcohol consumption', 'Var', (0, 24))
909040	32163489	In accordance with definitions suggested by EASL CLIF Consortium in the context of acute-on-chronic liver failure, biochemical criteria for liver failure were defined as either INR > 2.5 or serum bilirubin > 200 mumol/L.	('liver failure', 'Disease', (100, 113))	('bilirubin', 'Chemical', 'MESH:D001663', (196, 205))	('CLIF', 'Gene', (49, 53))	('chronic liver failure', 'Phenotype', 'HP:0100626', (92, 113))	('CLIF', 'Gene', '56938', (49, 53))	('serum bilirubin', 'MPA', (190, 205))	('acute-on-chronic liver failure', 'Phenotype', 'HP:0006554', (83, 113))	('liver failure', 'Phenotype', 'HP:0001399', (140, 153))	('liver failure', 'Disease', 'MESH:D017093', (140, 153))	('liver failure', 'Disease', (140, 153))	('liver failure', 'Phenotype', 'HP:0001399', (100, 113))	('liver failure', 'Disease', 'MESH:D017093', (100, 113))	('INR', 'Var', (177, 180))
909065	32163489	Patients with high alcohol consumption had higher Child Pugh score and presented more often with variceal bleeding.	('Child', 'Species', '9606', (50, 55))	('high alcohol consumption', 'Var', (14, 38))	('alcohol', 'Chemical', 'MESH:D000438', (19, 26))	('higher', 'PosReg', (43, 49))	('Patients', 'Species', '9606', (0, 8))	('bleeding', 'Disease', 'MESH:D006470', (106, 114))	('high alcohol consumption', 'Phenotype', 'HP:0030955', (14, 38))	('bleeding', 'Disease', (106, 114))	('Child Pugh score', 'CPA', (50, 66))
909074	32163489	In a multivariate model including these factors, risk of death without LT was still associated with female sex (SHR 0.59 [0.40-0.86]), age (SHR 1.05 [1.04-1.07] per year), Child Pugh class B (SHR 1.54 [1.03-2.32]) and Child Pugh class C (SHR 4.29 [2.57-7.17]).	('death', 'Disease', 'MESH:D003643', (57, 62))	('death', 'Disease', (57, 62))	('Child', 'Species', '9606', (172, 177))	('Child Pugh class C', 'Var', (218, 236))	('Child', 'Species', '9606', (218, 223))
909102	32163489	Female sex was associated with significant reduction in risk of death without LT after adjustment for age, Child Pugh class, etiology and mode of presentation (variceal bleeding or not).	('bleeding', 'Disease', 'MESH:D006470', (169, 177))	('death', 'Disease', 'MESH:D003643', (64, 69))	('men', 'Species', '9606', (93, 96))	('reduction', 'NegReg', (43, 52))	('Female sex', 'Var', (0, 10))	('bleeding', 'Disease', (169, 177))	('death', 'Disease', (64, 69))	('Child', 'Species', '9606', (107, 112))
909116	32163489	Interestingly, in two large studies exploring factors associated with in-hospital mortality among patients with lower gastrointestinal bleeding, female sex was independently associated with reduced mortality.	('mortality', 'MPA', (198, 207))	('lower gastrointestinal bleeding', 'Disease', (112, 143))	('patients', 'Species', '9606', (98, 106))	('lower gastrointestinal bleeding', 'Disease', 'MESH:D006471', (112, 143))	('reduced', 'NegReg', (190, 197))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (118, 143))	('female sex', 'Var', (145, 155))
909184	32190739	Univariate analysis variables comprised of age (<=60 years and >60 years), gender (male or female), tumor length (<4 cm and >=4 cm), location of the tumor (upper, middle and lower), tumor differentiation (poorly, moderately and well differentiated), T stage (T1, T2, T3 and T4), N stage (N0, N1, N2, and N3) as well as the number of NLNs (0-9, 10-14, 15-19 and >=20 NLNs).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (149, 154))	('N0', 'Var', (288, 290))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
909192	32190739	When the numbers of NLNs were 9 or less, 10 to 14, 15 to 19 and 20 or more, the median survival time was 13 months, 27 months, 39 months and 47 months (P<0.001) respectively, and the 3-year patient survival rates were 21.7% (26/120), 40.0% (66/165), 61.2% (92/152) and 77.5% (110/142) respectively(P<0.001), as shown in Table 1 and Fig 1.	('10 to', 'Var', (41, 46))	('patient survival', 'CPA', (190, 206))	('patient', 'Species', '9606', (190, 197))
909216	32190739	We found that thoracic ESCC patients with higher numbers of NLNs were more likely to have better survival rates in contrast to those with less NLNs, irrespective of their node-positive or -negative status.	('ESCC', 'Disease', 'MESH:D000077277', (23, 27))	('ESCC', 'Disease', (23, 27))	('survival rates', 'CPA', (97, 111))	('SCC', 'Phenotype', 'HP:0002860', (24, 27))	('NLNs', 'Var', (60, 64))	('better', 'PosReg', (90, 96))	('patients', 'Species', '9606', (28, 36))
909229	32190739	found a high number of NLNs was an indicator of greater lymphocyte infiltration, not only in the invasive central but also in the margin region of tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('lymphocyte infiltration', 'CPA', (56, 79))	('greater', 'PosReg', (48, 55))	('NLNs', 'Var', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
909317	31561459	Obesity-related alterations in the amounts and/or spectrum of adipokine release have been linked to metabolic disorders such as hyperlipidemia and type 2 diabetes and are increasingly recognized as a key factor linking obesity with cancer.	('metabolic disorders', 'Disease', (100, 119))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('obesity', 'Phenotype', 'HP:0001513', (219, 226))	('Obesity', 'Disease', 'MESH:D009765', (0, 7))	('linked', 'Reg', (90, 96))	('hyperlipidemia and type 2 diabetes', 'Disease', 'MESH:D003924', (128, 162))	('cancer', 'Disease', (232, 238))	('hyperlipidemia', 'Phenotype', 'HP:0003077', (128, 142))	('alterations', 'Var', (16, 27))	('Obesity', 'Disease', (0, 7))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('amounts', 'MPA', (35, 42))	('obesity', 'Disease', 'MESH:D009765', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('metabolic disorders', 'Disease', 'MESH:D008659', (100, 119))	('obesity', 'Disease', (219, 226))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (147, 162))	('rat', 'Species', '10116', (20, 23))
909350	31561459	These results were validated in an in vivo xenograft model, where BALB/c nu/nu mice injected S.C. with OE21 human esophageal carcinoma cells along with CAMs had more infiltrated MSCs than those mice injected with OE21 cells alone.	('infiltrated MSCs', 'CPA', (166, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('OE21', 'Var', (103, 107))	('more', 'PosReg', (161, 165))	('mice', 'Species', '10090', (79, 83))	('esophageal carcinoma', 'Disease', (114, 134))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (114, 134))	('human', 'Species', '9606', (108, 113))	('rat', 'Species', '10116', (172, 175))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (114, 134))	('mice', 'Species', '10090', (194, 198))
909358	31561459	Conditioned media from CAMs, more so than conditioned media from ATMs and NTMs, stimulated migration and Matrigel invasion of OE21 cells, which could be partially blocked by chemerin neutralization, siRNA knockdown of chemerin or chemerin1, or pharmacological antagonism of chemerin1 with CCX832.	('stimulated', 'PosReg', (80, 90))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('rat', 'Species', '10116', (94, 97))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('NTM', 'Gene', (74, 77))	('knockdown', 'Var', (205, 214))	('migration', 'CPA', (91, 100))	('NTM', 'Gene', '50863', (74, 77))
909362	31561459	In the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus (BE) to high-grade dysplasia BE and esophageal carcinoma, a significant increase in myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) density was observed that coincided with increased expression of their respective chemotactic factors, macrophage inflammatory protein-3 alpha (MIP3alpha), and chemerin in the same regions.	('macrophage inflammatory protein-3 alpha', 'Gene', '6364', (324, 363))	('increase', 'PosReg', (142, 150))	('expression', 'MPA', (272, 282))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (106, 126))	('mDC', 'Gene', (178, 181))	('mDC', 'Gene', '20299', (178, 181))	('BE', 'Phenotype', 'HP:0100580', (99, 101))	('BE', 'Disease', 'MESH:D001471', (99, 101))	('dysplasia', 'Disease', (18, 27))	("Barrett's esophagus", 'Disease', (50, 69))	('MIP3alpha', 'Gene', '6364', (365, 374))	('dysplasia', 'Disease', (89, 98))	('high-grade', 'Var', (78, 88))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (50, 69))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (50, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('myeloid dendritic', 'Disease', 'MESH:D007635', (154, 171))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (106, 126))	('BE', 'Phenotype', 'HP:0100580', (71, 73))	('myeloid dendritic', 'Disease', (154, 171))	('metaplasia-dysplasia-carcinoma', 'Disease', (7, 37))	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (7, 37))	('dysplasia', 'Disease', 'MESH:D015792', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('BE', 'Disease', 'MESH:D001471', (71, 73))	('increased', 'PosReg', (262, 271))	('esophageal carcinoma', 'Disease', (106, 126))	('dysplasia', 'Disease', 'MESH:D015792', (89, 98))	('MIP3alpha', 'Gene', (365, 374))	('macrophage inflammatory protein-3 alpha', 'Gene', (324, 363))
909396	31561459	While CCRL2 expression was detectable in several colorectal cell lines (SW480, SW620, LS174T, Caco2), siRNA-mediated knockdown of CCRL2 mRNA reduced proliferation, colony formation and migration only in LS174T cells.	('rat', 'Species', '10116', (156, 159))	('reduced', 'NegReg', (141, 148))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('migration', 'CPA', (185, 194))	('proliferation', 'CPA', (149, 162))	('N', 'Chemical', 'MESH:D009584', (138, 139))	('rat', 'Species', '10116', (188, 191))	('colony formation', 'CPA', (164, 180))	('CCRL2', 'Gene', (130, 135))	('knockdown', 'Var', (117, 126))	('CCRL2', 'Gene', (6, 11))
909411	31561459	Localized chemerin expression in melanoma has been demonstrated to decrease the presence of pDCs in the tumor microenvironment, ultimately inhibiting immune escape mechanisms.	('presence', 'MPA', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('decrease', 'NegReg', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('expression', 'Var', (19, 29))	('tumor', 'Disease', (104, 109))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('rat', 'Species', '10116', (58, 61))	('immune escape mechanisms', 'CPA', (150, 174))	('pDCs', 'Protein', (92, 96))	('inhibiting', 'NegReg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
909419	31561459	Similarly, mice injected hepatically with PVTT-1-Che cells exhibited reduced liver tumor foci development, a 1.3-fold increase in survival (54 days versus 41 days) compared to mice injected with control PVTT-1 cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('survival', 'CPA', (130, 138))	('reduced', 'NegReg', (69, 76))	('increase', 'PosReg', (118, 126))	('liver tumor', 'Disease', 'MESH:D008113', (77, 88))	('PVTT-1-Che', 'Var', (42, 52))	('men', 'Species', '9606', (101, 104))	('liver tumor', 'Disease', (77, 88))	('mice', 'Species', '10090', (11, 15))	('mice', 'Species', '10090', (176, 180))	('liver tumor', 'Phenotype', 'HP:0002896', (77, 88))
909447	31561459	detected no significant difference in recurrence-free survival or disease-free survival between patients classified with having low (<= 130.5 ng/mL) and high (> 130.5 ng/mL) serum chemerin concentration.	('rat', 'Species', '10116', (196, 199))	('> 130.5 ng/mL', 'Var', (159, 172))	('patients', 'Species', '9606', (96, 104))	('serum chemerin concentration', 'MPA', (174, 202))
909463	31561459	Interestingly, mice transplanted with human chemerin-expressing H295R tumors had higher serum concentrations of human chemerin but proportionally lower mouse serum chemerin suggesting a type of negative regulatory feedback mechanism.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('rat', 'Species', '10116', (101, 104))	('human', 'Species', '9606', (38, 43))	('higher', 'PosReg', (81, 87))	('H295R', 'Var', (64, 69))	('mouse', 'Species', '10090', (152, 157))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('lower', 'NegReg', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mouse serum chemerin', 'MPA', (152, 172))	('mice', 'Species', '10090', (15, 19))	('human', 'Species', '9606', (112, 117))	('serum concentrations of human chemerin', 'MPA', (88, 126))
909473	31561459	In further support of a direct tumor suppressive (rather than immune-mediated) effect of chemerin, H295R cells with stable expression of human chemerin had decreased colony formation and invasion in in vitro assays and formed smaller tumors when xenografted into the flanks immunodeficient T-cell deficient athymic nude and T, B, and NK-cell deficient and macrophage and dendritic cell-impaired NOD Scid gamma mice.	('colony formation', 'CPA', (166, 182))	('tumor', 'Disease', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('chemerin', 'Gene', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('mice', 'Species', '10090', (410, 414))	('human', 'Species', '9606', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('H295R', 'Var', (99, 104))	('flanks immunodeficient T-cell deficient athymic nude', 'Disease', 'MESH:D021501', (267, 319))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('smaller', 'NegReg', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('decreased', 'NegReg', (156, 165))	('N', 'Chemical', 'MESH:D009584', (334, 335))	('rat', 'Species', '10116', (50, 53))	('tumor', 'Disease', (31, 36))	('N', 'Chemical', 'MESH:D009584', (395, 396))	('tumors', 'Disease', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
909485	31561459	In the study by Krawczyk et al., foamy macrophages were histologically identified in 82% of pRCC tumors and the macrophages expressed cell surface markers CD689 and CD163 that are characteristic of the M2 anti-inflammatory phenotype.	('CD163', 'Var', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('foamy macrophages', 'Phenotype', 'HP:0003651', (33, 50))	('pRCC', 'Disease', 'MESH:D002292', (92, 96))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('pRCC', 'Disease', (92, 96))	('CD689', 'Var', (155, 160))	('pRCC', 'Phenotype', 'HP:0006766', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
909518	31561459	Depletion experiments indicated a critical role of NK cells and CD8+ T cells in the tumor suppression response to chemerin, while the depletion of CD4+ T regulatory cells enhanced tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('enhanced', 'PosReg', (171, 179))	('CD8', 'Gene', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('CD4', 'Gene', '920', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('depletion', 'Var', (134, 143))	('CD8', 'Gene', '925', (64, 67))	('tumor', 'Disease', (180, 185))	('men', 'Species', '9606', (16, 19))	('tumor', 'Disease', (84, 89))	('N', 'Chemical', 'MESH:D009584', (51, 52))	('CD4', 'Gene', (147, 150))
909559	31561459	However, while serum chemerin concentrations increased with Gleason score, the opposite effect was observed for chemerin expression in prostate tumor tissue.	('prostate tumor', 'Phenotype', 'HP:0100787', (135, 149))	('increased', 'PosReg', (45, 54))	('rat', 'Species', '10116', (37, 40))	('prostate tumor', 'Disease', 'MESH:D011471', (135, 149))	('serum chemerin concentrations', 'MPA', (15, 44))	('Gleason', 'Var', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('prostate tumor', 'Disease', (135, 149))
909583	29552129	Eca109 and EC9706 EC cells were transfected with a lentiviral vector to inhibit galectin-3 expression, or a control vector.	('EC9706', 'Var', (11, 17))	('expression', 'MPA', (91, 101))	('EC9706 EC', 'CellLine', 'CVCL:E307', (11, 20))	('galectin-3', 'Gene', '3958', (80, 90))	('inhibit', 'NegReg', (72, 79))	('galectin-3', 'Gene', (80, 90))
909586	29552129	Eca109 and EC9706 cells formed typical tubular networks; the number of tubular networks markedly decreased subsequent to galectin-3 knockdown.	('knockdown', 'Var', (132, 141))	('galectin-3', 'Gene', '3958', (121, 131))	('EC9706', 'CellLine', 'CVCL:E307', (11, 17))	('decreased', 'NegReg', (97, 106))	('galectin-3', 'Gene', (121, 131))
909610	29552129	The sequences of the three viral vector frames were as follows: LGALS3-RNAi (33755-), 5'-CACGCTTCAATGAGAACAA; LGALS3-RNAi (33756-), 5'-CGGTGAAGCCCAATGCAAA; LGALS3-RNAi (33757-), 5'-CTGGAAACCCAAACCCTCA.	('LGALS3', 'Gene', '3958', (110, 116))	('LGALS3', 'Gene', '3958', (156, 162))	('LGALS3', 'Gene', (110, 116))	('LGALS3', 'Gene', '3958', (64, 70))	('33757-', 'Var', (169, 175))	('LGALS3', 'Gene', (156, 162))	('33755-', 'Var', (77, 83))	('33756-', 'Var', (123, 129))	('LGALS3', 'Gene', (64, 70))
909613	29552129	At 80% confluence, the Eca-109 and EC9706 cells were released into a single cell suspension by digestion with trypsin-EDTA (Beyotime Institute of Biotechnology, Haimen, China) and seeded at 30,000-50,000 cells/ml in 6-well tissue culture plates (Corning Incorporated).	('Eca-109', 'Gene', (23, 30))	('EC9706', 'Var', (35, 41))	('EDTA', 'Chemical', 'MESH:D004492', (118, 122))	('EC9706', 'CellLine', 'CVCL:E307', (35, 41))	('rat', 'Species', '10116', (261, 264))
909621	29552129	A total of six groups of cells (Eca109, EC9706, Eca109/NEO, EC9706/NEO, Eca109/galectin-3 and EC9706/galectin-3) were harvested at 72 h after transfection.	('galectin-3', 'Gene', '3958', (79, 89))	('galectin-3', 'Gene', (101, 111))	('EC9706/NEO', 'Var', (60, 70))	('galectin-3', 'Gene', (79, 89))	('EC9706', 'Var', (40, 46))	('EC9706', 'CellLine', 'CVCL:E307', (94, 100))	('galectin-3', 'Gene', '3958', (101, 111))	('EC9706', 'CellLine', 'CVCL:E307', (40, 46))	('EC9706', 'CellLine', 'CVCL:E307', (60, 66))
909631	29552129	1B and 2B); however, there was no significant difference in the galectin-3 protein expression levels between the Eca109 and Eca109/NEO or EC9706 and EC9706/NEO cells (Figs.	('EC9706', 'Var', (138, 144))	('galectin-3', 'Gene', (64, 74))	('Eca109/NEO', 'Var', (124, 134))	('EC9706', 'CellLine', 'CVCL:E307', (138, 144))	('EC9706', 'CellLine', 'CVCL:E307', (149, 155))	('EC9706/NEO', 'Var', (149, 159))	('galectin-3', 'Gene', '3958', (64, 74))
909647	29552129	It was previously revealed that the silencing of VE-cadherin resulted in a marked redistribution of EphA2 on the cell surface; however, VE-cadherin expression level was unaltered following the silencing of EphA2, indicating that VE-cadherin regulates EphA2.	('EphA2', 'Gene', (100, 105))	('expression level', 'MPA', (148, 164))	('EphA2', 'Gene', (251, 256))	('EphA2', 'Gene', '1969', (251, 256))	('VE-cadherin', 'Gene', '1003', (49, 60))	('VE-cadherin', 'Gene', (136, 147))	('EphA2', 'Gene', '1969', (100, 105))	('EphA2', 'Gene', '1969', (206, 211))	('VE-cadherin', 'Gene', (229, 240))	('silencing', 'Var', (193, 202))	('VE-cadherin', 'Gene', '1003', (229, 240))	('silencing', 'Var', (36, 45))	('VE-cadherin', 'Gene', '1003', (136, 147))	('EphA2', 'Gene', (206, 211))	('VE-cadherin', 'Gene', (49, 60))	('redistribution', 'MPA', (82, 96))
909648	29552129	Accordingly, a significant decrease in the expression level of VE-cadherin was not identified in the present study, although there was a decrease in the EphA2 and MMP-2 expression level in Eca109 and EC9706 cells following galectin-3 silencing.	('MMP-2', 'Gene', '4313', (163, 168))	('galectin-3', 'Gene', '3958', (223, 233))	('decrease', 'NegReg', (137, 145))	('expression level', 'MPA', (169, 185))	('EphA2', 'Gene', (153, 158))	('VE-cadherin', 'Gene', '1003', (63, 74))	('EC9706', 'CellLine', 'CVCL:E307', (200, 206))	('MMP-2', 'Gene', (163, 168))	('galectin-3', 'Gene', (223, 233))	('EphA2', 'Gene', '1969', (153, 158))	('silencing', 'Var', (234, 243))	('VE-cadherin', 'Gene', (63, 74))
909653	29245271	Metastatic esophageal cancer presenting as shock by injury of vagus nerve mimicking baroreceptor reflex Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata.	('spinal injury', 'Disease', (146, 159))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('bone metastases', 'Disease', 'MESH:D009362', (167, 182))	('spinal injury', 'Disease', 'MESH:D013124', (146, 159))	('Neurogenic shock', 'Disease', 'MESH:D012769', (104, 120))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('bone metastases', 'Disease', (167, 182))	('cause', 'Reg', (294, 299))	('disturbance of the vagus nerve', 'Phenotype', 'HP:0002886', (218, 248))	('patients', 'Species', '9606', (193, 201))	('shock', 'Phenotype', 'HP:0031273', (300, 305))	('cancer', 'Disease', (22, 28))	('injury of vagus nerve', 'Phenotype', 'HP:0002886', (52, 73))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (186, 192))	('shock', 'Disease', (300, 305))	('shock', 'Phenotype', 'HP:0031273', (115, 120))	('Metastatic esophageal cancer', 'Disease', 'MESH:D004938', (0, 28))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('shock by injury of vagus nerve', 'Disease', 'MESH:D061223', (43, 73))	('shock', 'Phenotype', 'HP:0031273', (43, 48))	('Metastatic esophageal cancer', 'Disease', (0, 28))	('Neurogenic shock', 'Disease', (104, 120))	('shock by injury of vagus nerve', 'Disease', (43, 73))	('disturbance', 'Var', (218, 229))
909669	29245271	In this report, we present a case of neurogenic shock caused by a pathological baroreceptor reflex through disturbance of the vagus nerve supplying the aortic arch baroreceptors due to a large left cervical lymph node metastasis of esophageal cancer.	('disturbance of the vagus nerve', 'Phenotype', 'HP:0002886', (107, 137))	('neurogenic shock', 'Disease', 'MESH:D012769', (37, 53))	('caused by', 'Reg', (54, 63))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (198, 228))	('neurogenic shock', 'Disease', (37, 53))	('baroreceptor reflex', 'MPA', (79, 98))	('metastasis of esophageal cancer', 'Disease', (218, 249))	('disturbance', 'Var', (107, 118))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (218, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('pathological', 'Var', (66, 78))	('shock', 'Phenotype', 'HP:0031273', (48, 53))
909708	29245271	As TRPV1, a receptor for protons, and P2X, a receptor for ATP, are expressed on axons, excitatory impulses evoked by stimulation of these receptors might be a cause of pathological reflexes.	('pathological reflex', 'Phenotype', 'HP:0031826', (168, 187))	('ATP', 'Chemical', 'MESH:D000255', (58, 61))	('excitatory impulses evoked', 'MPA', (87, 113))	('cause', 'Reg', (159, 164))	('TRPV1', 'Gene', (3, 8))	('P2X', 'Var', (38, 41))	('TRPV1', 'Gene', '7442', (3, 8))
909724	28633632	The roles of miR-455-3p in activation of the Wnt/beta-catenin and transforming growth factor-beta (TGF-beta)/Smad pathways were determined by luciferase and RNA immunoprecipitation assays.	('beta-catenin', 'Gene', (49, 61))	('transforming growth factor-beta', 'Gene', (66, 97))	('beta-catenin', 'Gene', '1499', (49, 61))	('miR-455-3p', 'Chemical', '-', (13, 23))	('transforming growth factor-beta', 'Gene', '7040', (66, 97))	('TGF-beta', 'Gene', '7040', (99, 107))	('miR-455-3p', 'Var', (13, 23))	('activation', 'PosReg', (27, 37))	('TGF-beta', 'Gene', (99, 107))
909725	28633632	We found that miR-455-3p played essential roles in ESCC chemoresistance and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('ESCC', 'Disease', (51, 55))	('miR-455-3p', 'Chemical', '-', (14, 24))	('miR-455-3p', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
909726	28633632	Treatment with a miR-455-3p antagomir dramatically chemosensitized ESCC cells and reduced the subpopulations of CD90+ and CD271+ T-ICs via deactivation of multiple stemness-associated pathways, including Wnt/beta-catenin and TGF-beta signaling.	('ESCC', 'Disease', (67, 71))	('TGF-beta', 'Gene', '7040', (225, 233))	('chemosensitized', 'Reg', (51, 66))	('deactivation', 'NegReg', (139, 151))	('TGF-beta', 'Gene', (225, 233))	('stemness-associated pathways', 'Pathway', (164, 192))	('CD271+', 'Var', (122, 128))	('beta-catenin', 'Gene', (208, 220))	('miR-455-3p', 'Chemical', '-', (17, 27))	('miR-455-3p', 'Var', (17, 27))	('CD90', 'Gene', '7070', (112, 116))	('beta-catenin', 'Gene', '1499', (208, 220))	('reduced', 'NegReg', (82, 89))	('CD90', 'Gene', (112, 116))
909727	28633632	Importantly, miR-455-3p exhibited aberrant upregulation in various human cancer types, and was significantly associated with decreased overall survival of cancer patients.	('cancer', 'Disease', (73, 79))	('patients', 'Species', '9606', (162, 170))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('decreased', 'NegReg', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('overall survival', 'CPA', (135, 151))	('miR-455-3p', 'Chemical', '-', (13, 23))	('miR-455-3p', 'Var', (13, 23))	('upregulation', 'PosReg', (43, 55))	('human', 'Species', '9606', (67, 72))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
909728	28633632	Our results demonstrate that miR-455-3p functions as an oncomiR in ESCC progression and may provide a potential therapeutic target to achieve better clinical outcomes in cancer patients.	('miR-455-3p', 'Chemical', '-', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('ESCC', 'Disease', (67, 71))	('miR-455-3p', 'Var', (29, 39))	('cancer', 'Disease', (170, 176))	('patients', 'Species', '9606', (177, 185))	('clinical', 'Species', '191496', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
909735	28633632	found that CD133+ HCC cells display a preferential capacity for self-renewal and in vivo tumor initiation.	('self-renewal', 'CPA', (64, 76))	('HCC', 'Phenotype', 'HP:0001402', (18, 21))	('tumor initiation', 'Disease', (89, 105))	('preferential', 'PosReg', (38, 50))	('CD133+', 'Var', (11, 17))	('HCC', 'Gene', (18, 21))	('tumor initiation', 'Disease', 'MESH:D009369', (89, 105))	('HCC', 'Gene', '619501', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
909737	28633632	The identification and characterization of T-ICs has revealed that multiple intracellular signaling pathways, activated by heritable genetic and epigenetic alterations and the tumor microenvironment, are involved in the induction and maintenance of T-IC-like traits and are constitutively overactivated in T-ICs.	('epigenetic alterations', 'Var', (145, 167))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('intracellular', 'Pathway', (76, 89))	('T-IC-like', 'Disease', (249, 258))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
909744	28633632	Herein, we report that treatment with antagomir-455-3p chemosensitized esophageal squamous cell carcinoma (ESCC) cells and reduced the CD90+ and CD271+ T-IC subpopulations via the inhibition of multiple stemness-associated pathways, including Wnt/beta-catenin and TGF-beta signaling.	('TGF-beta', 'Gene', '7040', (264, 272))	('stemness-associated pathways', 'Pathway', (203, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('TGF-beta', 'Gene', (264, 272))	('beta-catenin', 'Gene', '1499', (247, 259))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('antagomir-455-3p', 'Var', (38, 54))	('CD90', 'Gene', '7070', (135, 139))	('CD90', 'Gene', (135, 139))	('CD271+', 'Var', (145, 151))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('beta-catenin', 'Gene', (247, 259))	('inhibition', 'NegReg', (180, 190))	('reduced', 'NegReg', (123, 130))
909770	28633632	Furthermore, in vivo limiting dilution assay showed EC-CR cells exhibited an increased capacity to form tumors compared with EC-UT cells.	('EC-UT', 'CellLine', 'CVCL:X006', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('EC-CR', 'Var', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('EC-CR', 'Chemical', '-', (52, 57))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('increased', 'PosReg', (77, 86))
909772	28633632	Consistently, in an in vitro tumorsphere formation assay, EC-CR cells formed significantly larger and more numerous tumorspheres than EC-UT cells (Fig.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('numerous tumorspheres', 'Disease', 'None', (107, 128))	('EC-CR', 'Var', (58, 63))	('EC-CR', 'Chemical', '-', (58, 63))	('more', 'PosReg', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('EC-UT', 'CellLine', 'CVCL:X006', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('numerous tumorspheres', 'Disease', (107, 128))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Disease', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
909773	28633632	The proportions of CD90+ and CD271+ cells, previously identified as T-IC subpopulations in ESCC, and side-population (SP) cells increased among EC-CR cells compared with EC-UT cells (Fig.	('EC-UT', 'CellLine', 'CVCL:X006', (170, 175))	('EC-CR', 'Chemical', '-', (144, 149))	('CD271+ cells', 'Var', (29, 41))	('ESCC', 'Disease', (91, 95))	('SP', 'Chemical', '-', (118, 120))	('increased', 'PosReg', (128, 137))	('CD90', 'Gene', '7070', (19, 23))	('CD90', 'Gene', (19, 23))	('EC-CR', 'Var', (144, 149))
909778	28633632	Strikingly, gene set enrichment analysis (GSEA) of The Cancer Genome Atlas (TCGA) datasets revealed that ESCC exhibiting high miR-455-3p expression was enriched in resistance gene sets for chemotherapeutic drugs such as CDDP, DOC, doxorubicin, gefitinib, dasatinib, cyclophosphamide, and vincristine, whereas ESCC exhibiting low miR-455-3p expression was enriched in chemotherapy sensitive gene sets (Fig.	('miR-455-3p expression', 'Var', (126, 147))	('CDDP', 'Chemical', 'MESH:D002945', (220, 224))	('GSEA', 'Chemical', '-', (42, 46))	('miR-455-3p', 'Chemical', '-', (329, 339))	('miR-455-3p', 'Chemical', '-', (126, 136))	('DOC', 'Chemical', 'MESH:D000077143', (226, 229))	('Cancer Genome Atlas', 'Disease', (55, 74))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (55, 74))
909779	28633632	2b and Additional file 2: Figure S1A), suggesting that miR-455-3p contributes to ESCC chemoresistance.	('miR-455-3p', 'Var', (55, 65))	('contributes', 'Reg', (66, 77))	('ESCC', 'Disease', (81, 85))	('miR-455-3p', 'Chemical', '-', (55, 65))
909780	28633632	As predicted, overexpressing miR-455-3p conferred resistance to CDDP and DOC in EC-UT and Kyse30 cells, but silencing miR-455-3p enhanced the sensitivity of EC-CR and Eca109 cells to chemotherapeutic agents (Additional file 2: Figure S1B).	('miR-455-3p', 'Chemical', '-', (118, 128))	('enhanced', 'PosReg', (129, 137))	('EC-UT', 'CellLine', 'CVCL:X006', (80, 85))	('miR-455-3p', 'Chemical', '-', (29, 39))	('silencing', 'Var', (108, 117))	('CDDP', 'MPA', (64, 68))	('miR-455-3p', 'Gene', (118, 128))	('resistance', 'MPA', (50, 60))	('sensitivity', 'MPA', (142, 153))	('DOC', 'Chemical', 'MESH:D000077143', (73, 76))	('CDDP', 'Chemical', 'MESH:D002945', (64, 68))	('EC-CR', 'Chemical', '-', (157, 162))
909782	28633632	Collectively, these results suggest that miR-455-3p plays an important role in ESCC chemoresistance.	('miR-455-3p', 'Var', (41, 51))	('ESCC', 'Disease', (79, 83))	('miR-455-3p', 'Chemical', '-', (41, 51))
909783	28633632	Consistent with the GSEA of TCGA datasets, through which miR-455-3p expression was found to be significantly associated with stemness signatures, miR-455-3p-transduced cells formed larger and more numerous tumorspheres containing higher proportions of CD90+/CD271+ and SP cells than control cells (Fig.	('miR-455-3p', 'Chemical', '-', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('miR-455-3p-transduced', 'Var', (146, 167))	('miR-455-3p', 'Chemical', '-', (57, 67))	('SP', 'Chemical', '-', (269, 271))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('more', 'PosReg', (192, 196))	('numerous tumorspheres', 'Disease', 'None', (197, 218))	('CD90', 'Gene', '7070', (252, 256))	('CD90', 'Gene', (252, 256))	('numerous tumorspheres', 'Disease', (197, 218))	('larger', 'PosReg', (181, 187))	('GSEA', 'Chemical', '-', (20, 24))
909784	28633632	Importantly, limiting dilution and serial transplantation assays revealed a significantly higher tumor incidence and greater tumor-forming capacity in miR-455-3p-transduced ESCC cells than in control cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('ESCC', 'Disease', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('greater', 'PosReg', (117, 124))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (125, 130))	('miR-455-3p', 'Chemical', '-', (151, 161))	('miR-455-3p-transduced', 'Var', (151, 172))	('higher', 'PosReg', (90, 96))
909785	28633632	2f), indicating that miR-455-3p contributes to the tumor-forming and self-renewal capabilities of ESCC cells.	('self-renewal capabilities', 'CPA', (69, 94))	('contributes', 'PosReg', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('ESCC', 'Disease', (98, 102))	('miR-455-3p', 'Chemical', '-', (21, 31))	('miR-455-3p', 'Var', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
909788	28633632	Similarly, silencing of miR-455-3p drastically enhanced the inhibitory effect of CDDP on tumor growth in Eca109 cells and increased the apoptotic rate in Eca109 tumors (Additional file 3: Figure S2A and B).	('silencing', 'Var', (11, 20))	('enhanced', 'PosReg', (47, 55))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('inhibitory effect', 'MPA', (60, 77))	('miR-455-3p', 'Chemical', '-', (24, 34))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('miR-455-3p', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('CDDP', 'Gene', (81, 85))	('CDDP', 'Chemical', 'MESH:D002945', (81, 85))	('increased', 'PosReg', (122, 131))	('apoptotic rate', 'CPA', (136, 150))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (89, 94))
909789	28633632	These results demonstrate that silencing miR-455-3p causes the chemosensitization of ESCC cells.	('miR-455-3p', 'Gene', (41, 51))	('silencing', 'Var', (31, 40))	('miR-455-3p', 'Chemical', '-', (41, 51))	('ESCC', 'Disease', (85, 89))	('causes', 'Reg', (52, 58))	('chemosensitization', 'CPA', (63, 81))
909790	28633632	Consistent with the enhancement of T-IC-like traits in ESCC cells by miR-455-3p, the antagomir-455-3p significantly repressed the tumor-initiating and self-renewal abilities of ESCC cells in vivo, and exerted an inhibitory effect on the tumorsphere-forming abilities of EC-CR and Eca109 cells in vitro (Fig.	('EC-CR', 'Chemical', '-', (270, 275))	('antagomir-455-3p', 'Var', (85, 101))	('tumor', 'Disease', (237, 242))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('repressed', 'NegReg', (116, 125))	('miR-455-3p', 'Chemical', '-', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('miR-455-3p', 'Var', (69, 79))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
909791	28633632	3b and c and Additional file 3: Figure S2C), providing further evidence that miR-455-3p contributes to the T-IC-like traits of ESCC cells.	('T-IC-like traits', 'CPA', (107, 123))	('miR-455-3p', 'Chemical', '-', (77, 87))	('miR-455-3p', 'Var', (77, 87))
909792	28633632	Concordantly, silencing miR-455-3p in EC-CR and Eca109 cells significantly decreased the proportion of CD90+/CD271+ and SP cells and reduced the expression of stemness-associated factors (Fig.	('CD90', 'Gene', '7070', (103, 107))	('EC-CR', 'Chemical', '-', (38, 43))	('stemness-associated factors', 'CPA', (159, 186))	('CD90', 'Gene', (103, 107))	('SP cells', 'CPA', (120, 128))	('miR-455-3p', 'Chemical', '-', (24, 34))	('silencing miR-455-3p', 'Var', (14, 34))	('expression', 'MPA', (145, 155))	('miR-455-3p', 'Var', (24, 34))	('SP', 'Chemical', '-', (120, 122))	('reduced', 'NegReg', (133, 140))	('decreased', 'NegReg', (75, 84))
909793	28633632	Consistent with TCGA analysis, the results of which showed that miR-455-3p was markedly upregulated in ESCC and correlated with shorter overall and disease-free survival in patients with ESCC (Fig.	('ESCC', 'Disease', (187, 191))	('upregulated', 'PosReg', (88, 99))	('patients', 'Species', '9606', (173, 181))	('overall', 'CPA', (136, 143))	('miR-455-3p', 'Chemical', '-', (64, 74))	('shorter', 'NegReg', (128, 135))	('miR-455-3p', 'Var', (64, 74))	('disease-free survival', 'CPA', (148, 169))	('ESCC', 'Disease', (103, 107))
909795	28633632	Importantly, patients with higher miR-455-3p expression experienced shorter overall and disease-free survival, whereas patients with lower miR-455-3p expression experienced longer overall and disease-free survival (P < 0.05; Fig.	('disease-free survival', 'CPA', (88, 109))	('longer', 'PosReg', (173, 179))	('miR-455-3p expression', 'Var', (34, 55))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (119, 127))	('miR-455-3p', 'Chemical', '-', (34, 44))	('miR-455-3p', 'Chemical', '-', (139, 149))	('shorter', 'NegReg', (68, 75))
909797	28633632	Thus, both TCGA analysis and these results suggest a potential link between miR-455-3p overexpression and ESCC progression.	('miR-455-3p', 'Chemical', '-', (76, 86))	('ESCC', 'Disease', (106, 110))	('miR-455-3p', 'Var', (76, 86))
909799	28633632	4c and d and Additional file 4: Figure S3C, both in vitro and in vivo chemoresistance experiments indicated that PDEC2 cells with higher miR-455-3p expression exhibited greater resistance to chemotherapeutic drugs than PDEC1 cells with lower miR-455-3p expression.	('miR-455-3p', 'Chemical', '-', (242, 252))	('higher', 'PosReg', (130, 136))	('PDEC1', 'CellLine', 'CVCL:B526', (219, 224))	('miR-455-3p', 'Chemical', '-', (137, 147))	('greater', 'PosReg', (169, 176))	('resistance to chemotherapeutic drugs', 'MPA', (177, 213))	('PDEC2', 'CellLine', 'CVCL:1901', (113, 118))	('miR-455-3p', 'Var', (137, 147))	('PDEC2', 'Gene', (113, 118))
909800	28633632	Importantly, silencing miR-455-3p dramatically enhanced the sensitivity of PDEC2 cells to chemotherapeutic drugs, and reduced the percentages of CD90+/CD271+ and SP cells and tumorsphere-forming capability of PDEC2 cells (Fig.	('tumors', 'Disease', (175, 181))	('SP cells', 'CPA', (162, 170))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('enhanced', 'PosReg', (47, 55))	('miR-455-3p', 'Chemical', '-', (23, 33))	('PDEC2', 'CellLine', 'CVCL:1901', (75, 80))	('CD90', 'Gene', '7070', (145, 149))	('reduced', 'NegReg', (118, 125))	('silencing', 'Var', (13, 22))	('CD90', 'Gene', (145, 149))	('SP', 'Chemical', '-', (162, 164))	('PDEC2', 'CellLine', 'CVCL:1901', (209, 214))	('miR-455-3p', 'Gene', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('sensitivity', 'MPA', (60, 71))
909801	28633632	Together, these results support the contribution of miR-455-3p to the chemoresistance and tumorigenesis of ESCC.	('chemoresistance', 'CPA', (70, 85))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('miR-455-3p', 'Chemical', '-', (52, 62))	('miR-455-3p', 'Var', (52, 62))	('ESCC', 'Disease', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
909802	28633632	Consistent with the GSEA findings that miR-455-3p levels were significantly correlated with gene signatures regulated by the Wnt/beta-catenin and TGF-beta/Smad pathways (Fig.	('miR-455-3p', 'Var', (39, 49))	('TGF-beta', 'Gene', '7040', (146, 154))	('beta-catenin', 'Gene', '1499', (129, 141))	('TGF-beta', 'Gene', (146, 154))	('miR-455-3p', 'Chemical', '-', (39, 49))	('beta-catenin', 'Gene', (129, 141))	('GSEA', 'Chemical', '-', (20, 24))	('gene signatures', 'MPA', (92, 107))	('correlated', 'Reg', (76, 86))
909803	28633632	5a and Additional file 5: Figure S4A), overexpression of miR-455-3p significantly enhanced, but silencing of miR-455-3p reduced, luciferase reporter activities and levels of expression of nuclear beta-catenin, phosphorylated (p)-Smad2, and downstream genes in their respective pathways (Fig.	('enhanced', 'PosReg', (82, 90))	('beta-catenin', 'Gene', '1499', (196, 208))	('Smad2', 'Gene', (229, 234))	('expression', 'MPA', (174, 184))	('miR-455-3p', 'Chemical', '-', (57, 67))	('beta-catenin', 'Gene', (196, 208))	('activities', 'MPA', (149, 159))	('miR-455-3p', 'Chemical', '-', (109, 119))	('miR-455-3p', 'Var', (57, 67))	('luciferase', 'Enzyme', (129, 139))	('miR-455-3p', 'Gene', (109, 119))	('silencing', 'NegReg', (96, 105))	('reduced', 'NegReg', (120, 127))	('Smad2', 'Gene', '4087', (229, 234))	('levels', 'MPA', (164, 170))
909804	28633632	5b and c and Additional file 5: Figure S4B), suggesting that miR-455-3p contributes to activation of the Wnt/beta-catenin and TGF-beta/Smad pathways in ESCC.	('TGF-beta', 'Gene', (126, 134))	('activation', 'PosReg', (87, 97))	('miR-455-3p', 'Chemical', '-', (61, 71))	('miR-455-3p', 'Var', (61, 71))	('beta-catenin', 'Gene', (109, 121))	('beta-catenin', 'Gene', '1499', (109, 121))	('TGF-beta', 'Gene', '7040', (126, 134))	('ESCC', 'Disease', (152, 156))
909807	28633632	Analysis using publicly available algorithms (Target Scan, miRWalk, and miRanda) showed that a number of negative regulators, including DKK3, GSK3beta, TCF7L1, IGFBP4, AMER1, CSNK1A1, TLE3, TLE4, TCF3, NKD2, SOX1, and SOST (Wnt/beta-catenin pathway) and Smurf2, NEDD4L, FKBP1A, BAMBI, PAK2, SKI, and PPM1A (TGF-beta/Smad pathway), were potential targets of miR-455-3p (Fig.	('BAMBI', 'Gene', (278, 283))	('DKK3', 'Gene', '27122', (136, 140))	('AMER1', 'Gene', (168, 173))	('NEDD4L', 'Gene', (262, 268))	('TGF-beta', 'Gene', (307, 315))	('Smurf2', 'Gene', (254, 260))	('NEDD4L', 'Gene', '23327', (262, 268))	('GSK3beta', 'Gene', '2932', (142, 150))	('miR-455-3p', 'Var', (357, 367))	('BAMBI', 'Gene', '25805', (278, 283))	('SKI', 'Gene', '6497', (291, 294))	('PAK2', 'Gene', (285, 289))	('SOST', 'Gene', (218, 222))	('CSNK1A1', 'Gene', (175, 182))	('CSNK1A1', 'Gene', '1452', (175, 182))	('IGFBP4', 'Gene', (160, 166))	('PAK2', 'Gene', '5062', (285, 289))	('AMER1', 'Gene', '139285', (168, 173))	('SOX1', 'Gene', '6656', (208, 212))	('TCF7L1', 'Gene', (152, 158))	('TLE3', 'Gene', (184, 188))	('NKD2', 'Gene', (202, 206))	('SOST', 'Gene', '50964', (218, 222))	('GSK3beta', 'Gene', (142, 150))	('PPM1A', 'Gene', '5494', (300, 305))	('TLE4', 'Gene', (190, 194))	('NKD2', 'Gene', '85409', (202, 206))	('FKBP1A', 'Gene', (270, 276))	('Smurf2', 'Gene', '64750', (254, 260))	('TLE4', 'Gene', '7091', (190, 194))	('FKBP1A', 'Gene', '2280', (270, 276))	('SKI', 'Gene', (291, 294))	('beta-catenin', 'Gene', (228, 240))	('IGFBP4', 'Gene', '3487', (160, 166))	('beta-catenin', 'Gene', '1499', (228, 240))	('PPM1A', 'Gene', (300, 305))	('TGF-beta', 'Gene', '7040', (307, 315))	('TCF3', 'Gene', (196, 200))	('DKK3', 'Gene', (136, 140))	('TLE3', 'Gene', '7090', (184, 188))	('miR-455-3p', 'Chemical', '-', (357, 367))	('TCF3', 'Gene', '6929', (196, 200))	('SOX1', 'Gene', (208, 212))	('TCF7L1', 'Gene', '83439', (152, 158))
909808	28633632	RIP assays revealed a higher degree of association of miR-455-3p with DKK3, GSK3beta, Smurf2, and PPM1A in both EC-CR and Eca109 cells (Fig.	('GSK3beta', 'Gene', (76, 84))	('miR-455-3p', 'Chemical', '-', (54, 64))	('miR-455-3p', 'Var', (54, 64))	('PPM1A', 'Gene', (98, 103))	('GSK3beta', 'Gene', '2932', (76, 84))	('DKK3', 'Gene', '27122', (70, 74))	('Smurf2', 'Gene', (86, 92))	('DKK3', 'Gene', (70, 74))	('PPM1A', 'Gene', '5494', (98, 103))	('Smurf2', 'Gene', '64750', (86, 92))	('EC-CR', 'Chemical', '-', (112, 117))	('association', 'Interaction', (39, 50))
909810	28633632	These results suggest that miR-455-3p activates the Wnt/beta-catenin and TGF-beta/Smad pathways by directly binding to the 3' UTRs of a number of negative regulators.	('TGF-beta', 'Gene', '7040', (73, 81))	('TGF-beta', 'Gene', (73, 81))	('beta-catenin', 'Gene', (56, 68))	('binding', 'Interaction', (108, 115))	('beta-catenin', 'Gene', '1499', (56, 68))	('miR-455-3p', 'Var', (27, 37))	('miR-455-3p', 'Chemical', '-', (27, 37))	('activates', 'PosReg', (38, 47))
909811	28633632	Analysis of TCGA datasets indicated that miR-455-3p was also markedly upregulated in other human cancers, including gastric, lung, bladder, breast, cervical, kidney, and uterine cancers (Fig.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('gastric', 'Disease', (116, 123))	('uterine cancers', 'Phenotype', 'HP:0010784', (170, 185))	('breast', 'Disease', (140, 146))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('kidney', 'Disease', (158, 164))	('cancers', 'Disease', (97, 104))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('bladder', 'Disease', (131, 138))	('miR-455-3p', 'Chemical', '-', (41, 51))	('lung', 'Disease', (125, 129))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('miR-455-3p', 'Var', (41, 51))	('cervical', 'Disease', (148, 156))	('upregulated', 'PosReg', (70, 81))	('human', 'Species', '9606', (91, 96))
909812	28633632	6a), suggesting that miR-455-3p may also function as an oncomiR in other human cancers.	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miR-455-3p', 'Chemical', '-', (21, 31))	('human', 'Species', '9606', (73, 78))	('miR-455-3p', 'Var', (21, 31))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
909813	28633632	Importantly, higher miR-455-3p expression was associated with shorter overall survival and significantly correlated with gene signatures regulated by the Wnt/beta-catenin and TGF-beta/Smad pathways in gastric, kidney, and lung cancers (Fig.	('miR-455-3p', 'Chemical', '-', (20, 30))	('gastric', 'Disease', (201, 208))	('gene signatures', 'MPA', (121, 136))	('higher', 'PosReg', (13, 19))	('correlated', 'Reg', (105, 115))	('miR-455-3p', 'Var', (20, 30))	('TGF-beta', 'Gene', '7040', (175, 183))	('beta-catenin', 'Gene', (158, 170))	('overall survival', 'MPA', (70, 86))	('beta-catenin', 'Gene', '1499', (158, 170))	('lung cancers', 'Disease', 'MESH:D008175', (222, 234))	('expression', 'MPA', (31, 41))	('lung cancers', 'Disease', (222, 234))	('TGF-beta', 'Gene', (175, 183))	('shorter', 'NegReg', (62, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('lung cancers', 'Phenotype', 'HP:0100526', (222, 234))	('kidney', 'Disease', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))
909814	28633632	Furthermore, RIP assays indicated that miR-455-3p was associated with different negative regulators of the Wnt/beta-catenin and TGF-beta/Smad pathways in gastric and kidney cancer cells (Fig.	('TGF-beta', 'Gene', '7040', (128, 136))	('miR-455-3p', 'Var', (39, 49))	('TGF-beta', 'Gene', (128, 136))	('beta-catenin', 'Gene', (111, 123))	('gastric and kidney cancer', 'Disease', 'MESH:D013274', (154, 179))	('kidney cancer', 'Phenotype', 'HP:0009726', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('beta-catenin', 'Gene', '1499', (111, 123))	('miR-455-3p', 'Chemical', '-', (39, 49))	('negative regulators', 'MPA', (80, 99))
909815	28633632	Moreover, silencing miR-455-3p in gastric and bladder cancer cells dramatically decreased the transcriptional activities of the Wnt/beta-catenin and TGF-beta/Smad pathways and CDDP resistance (Fig.	('CDDP resistance', 'CPA', (176, 191))	('TGF-beta', 'Gene', '7040', (149, 157))	('miR-455-3p', 'Chemical', '-', (20, 30))	('beta-catenin', 'Gene', (132, 144))	('silencing miR-455-3p', 'Var', (10, 30))	('bladder cancer', 'Disease', (46, 60))	('TGF-beta', 'Gene', (149, 157))	('miR-455-3p', 'Var', (20, 30))	('decreased', 'NegReg', (80, 89))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('CDDP', 'Chemical', 'MESH:D002945', (176, 180))	('beta-catenin', 'Gene', '1499', (132, 144))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('transcriptional activities', 'MPA', (94, 120))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
909816	28633632	Altogether, these results imply that aberrant miR-455-3p expression activates T-IC-associated signaling pathways, leading to cancer progression, chemotherapy failure, and poor clinical outcomes (Fig.	('leading to', 'Reg', (114, 124))	('miR-455-3p', 'Chemical', '-', (46, 56))	('T-IC-associated signaling pathways', 'Pathway', (78, 112))	('miR-455-3p', 'Var', (46, 56))	('clinical', 'Species', '191496', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('activates', 'PosReg', (68, 77))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('chemotherapy failure', 'CPA', (145, 165))	('aberrant miR-455-3p', 'Var', (37, 56))
909817	28633632	It is generally acknowledged that an association exists between T-ICs and poor prognosis, tumor recurrence, and chemoradiotherapy failure in multiple human cancers.	('human', 'Species', '9606', (150, 155))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('T-ICs', 'Var', (64, 69))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
909820	28633632	Furthermore, we demonstrated that miR-455-3p plays essential roles in ESCC chemoresistance and tumorigenesis, and that treatment with a miR-455-3p antagomir chemosensitizes ESCC cells and reduces ESCC T-ICs subpopulations.	('ESCC', 'Disease', (173, 177))	('miR-455-3p', 'Chemical', '-', (136, 146))	('miR-455-3p', 'Chemical', '-', (34, 44))	('miR-455-3p', 'Var', (136, 146))	('ESCC', 'Disease', (196, 200))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('chemosensitizes', 'CPA', (157, 172))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ESCC chemoresistance', 'CPA', (70, 90))	('tumor', 'Disease', (95, 100))	('reduces', 'NegReg', (188, 195))
909821	28633632	Our results suggest that the chemoresistant ESCC cells examined in our study possess T-IC-like traits, and that miR-455-3p represents a potential therapeutic target to achieve better clinical outcomes in cancer patients.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('patients', 'Species', '9606', (211, 219))	('miR-455-3p', 'Chemical', '-', (112, 122))	('clinical', 'Species', '191496', (183, 191))	('miR-455-3p', 'Var', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('T-IC-like', 'CPA', (85, 94))
909822	28633632	We found that the proportions of both CD90+ and CD271+ cells, previously identified as ESCC T-ICs, were increased among chemoresistant ESCC cells, suggesting the existence of multiple T-IC subpopulations within ESCC tumors.	('CD271+', 'Var', (48, 54))	('increased', 'PosReg', (104, 113))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Disease', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('CD90', 'Gene', '7070', (38, 42))	('CD90', 'Gene', (38, 42))
909824	28633632	The same phenomenon was also observed in liver (CD24+ and CD133+) and colon (CD44+ and CD26+) cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('CD44', 'Gene', '960', (77, 81))	('CD24', 'Gene', '100133941', (48, 52))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('CD44', 'Gene', (77, 81))	('CD133+', 'Var', (58, 64))	('colon', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('CD26', 'Gene', '1803', (87, 91))	('liver', 'Disease', (41, 46))	('CD26', 'Gene', (87, 91))	('CD24', 'Gene', (48, 52))	('cancers', 'Disease', (94, 101))
909826	28633632	We found that miR-455-3p overexpression significantly increased, but miR-455-3p inhibition reduced, the subpopulations of CD90+ and CD271+ T-ICs, suggesting that miR-455-3p functions in the interconversion between ESCC cells and ESCC T-IC subpopulations.	('increased', 'PosReg', (54, 63))	('reduced', 'NegReg', (91, 98))	('CD90', 'Gene', '7070', (122, 126))	('CD271+', 'Var', (132, 138))	('miR-455-3p', 'Chemical', '-', (14, 24))	('miR-455-3p', 'Chemical', '-', (162, 172))	('miR-455-3p', 'Chemical', '-', (69, 79))	('CD90', 'Gene', (122, 126))
909830	28633632	We found that silencing of miR-455-3p simultaneously deactivated multiple T-IC-associated pathways, resulting in functional inhibition of ESCC chemoresistance and tumor recurrence, suggesting that miR-455-3p may be a suitable therapeutic target for the treatment of ESCC.	('miR-455-3p', 'Gene', (27, 37))	('silencing', 'Var', (14, 23))	('inhibition', 'NegReg', (124, 134))	('miR-455-3p', 'Chemical', '-', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('deactivated', 'NegReg', (53, 64))	('tumor', 'Disease', (163, 168))	('miR-455-3p', 'Chemical', '-', (27, 37))	('T-IC-associated pathways', 'Pathway', (74, 98))	('ESCC', 'Disease', (138, 142))
909832	28633632	Consistent with our finding that miR-455-3p is upregulated in ESCC and multiple distinct cancer types, miR-455-3p is also overexpressed in glioma, oral squamous cell cancer, and triple-negative breast cancer, where it contributes to cancer chemoresistance, proliferation, and invasion/migration.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (201, 207))	('glioma', 'Disease', (139, 145))	('upregulated', 'PosReg', (47, 58))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (152, 172))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('overexpressed', 'PosReg', (122, 135))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('contributes', 'Reg', (218, 229))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('miR-455-3p', 'Chemical', '-', (33, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (166, 172))	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (147, 172))	('oral squamous cell cancer', 'Disease', (147, 172))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('miR-455-3p', 'Gene', (33, 43))	('miR-455-3p', 'Chemical', '-', (103, 113))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (194, 207))	('proliferation', 'CPA', (257, 270))	('cancer', 'Disease', (233, 239))	('miR-455-3p', 'Var', (103, 113))	('ESCC', 'Disease', (62, 66))	('invasion/migration', 'CPA', (276, 294))
909833	28633632	However, miR-455-3p is reportedly downregulated in prostate and colon cancer, and upregulation of miR-455-3p can inhibit the cancer proliferation.	('miR-455-3p', 'Chemical', '-', (98, 108))	('downregulated', 'NegReg', (34, 47))	('colon cancer', 'Disease', 'MESH:D015179', (64, 76))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('miR-455-3p', 'Var', (98, 108))	('miR-455-3p', 'Gene', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('inhibit', 'NegReg', (113, 120))	('colon cancer', 'Disease', (64, 76))	('upregulation', 'PosReg', (82, 94))	('cancer', 'Disease', (125, 131))	('prostate', 'Disease', (51, 59))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('miR-455-3p', 'Chemical', '-', (9, 19))
909834	28633632	These studies imply that miR-455-3p can act as either an oncomiR or a tumor-suppressive miRNA depending on the tumor type.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (111, 116))	('miR-455-3p', 'Chemical', '-', (25, 35))	('miR-455-3p', 'Var', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
909836	28633632	Furthermore, we demonstrated that aberrantly expressed miR-455-3p in ESCC cells simultaneously activates Wnt/beta-catenin and TGF-beta/Smad signaling through concurrent suppression of multiple negative regulators of these pathways.	('TGF-beta', 'Gene', (126, 134))	('negative regulators', 'Pathway', (193, 212))	('suppression', 'NegReg', (169, 180))	('beta-catenin', 'Gene', (109, 121))	('activates', 'PosReg', (95, 104))	('TGF-beta', 'Gene', '7040', (126, 134))	('miR-455-3p', 'Chemical', '-', (55, 65))	('miR-455-3p', 'Var', (55, 65))	('beta-catenin', 'Gene', '1499', (109, 121))
909838	28633632	In this study, we identified miR-455-3p as essential for ESCC chemoresistance both in vivo and in vitro.	('chemoresistance', 'CPA', (62, 77))	('miR-455-3p', 'Chemical', '-', (29, 39))	('ESCC', 'Disease', (57, 61))	('miR-455-3p', 'Var', (29, 39))
909839	28633632	We found that miR-455-3p levels are significantly correlated with poorer disease-free survival and overall survival in patients with primary ESCC.	('patients', 'Species', '9606', (119, 127))	('poorer', 'NegReg', (66, 72))	('disease-free survival', 'CPA', (73, 94))	('miR-455-3p levels', 'Var', (14, 31))	('overall survival', 'CPA', (99, 115))	('miR-455-3p', 'Chemical', '-', (14, 24))
909840	28633632	Inhibition of miR-455-3p chemosensitizes ESCC cells and reduces the subpopulations of CD90+ and CD271+ T-ICs via the suppression of multiple T-IC-associated pathways, including the Wnt/beta-catenin and TGF-beta pathways.	('suppression', 'NegReg', (117, 128))	('TGF-beta', 'Gene', (202, 210))	('miR-455-3p', 'Gene', (14, 24))	('CD90', 'Gene', '7070', (86, 90))	('beta-catenin', 'Gene', '1499', (185, 197))	('CD271+', 'Var', (96, 102))	('CD90', 'Gene', (86, 90))	('T-IC-associated pathways', 'Pathway', (141, 165))	('reduces', 'NegReg', (56, 63))	('ESCC', 'Disease', (41, 45))	('subpopulations', 'MPA', (68, 82))	('miR-455-3p', 'Chemical', '-', (14, 24))	('TGF-beta', 'Gene', '7040', (202, 210))	('beta-catenin', 'Gene', (185, 197))
909841	28633632	Importantly, miR-455-3p is aberrantly upregulated in numerous cancers and significantly associated with the decreased overall survival of cancer patients.	('patients', 'Species', '9606', (145, 153))	('cancer', 'Disease', (138, 144))	('numerous cancers', 'Disease', 'MESH:D009369', (53, 69))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('upregulated', 'PosReg', (38, 49))	('miR-455-3p', 'Chemical', '-', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('overall', 'MPA', (118, 125))	('decreased', 'NegReg', (108, 117))	('miR-455-3p', 'Var', (13, 23))	('numerous cancers', 'Disease', (53, 69))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
909848	23597192	Furthermore, Jaridonin resulted in a significant loss of mitochondrial membrane potential, release of cytochrome c into the cytosol, and then activation of Caspase-9 and -3, leading to activation of the mitochondria mediated apoptosis.	('loss', 'NegReg', (49, 53))	('mitochondria mediated apoptosis', 'CPA', (203, 234))	('Caspase-9 and -3', 'Gene', '842;836', (156, 172))	('activation', 'PosReg', (142, 152))	('Jaridonin', 'Var', (13, 22))	('Jaridonin', 'Chemical', 'MESH:C587044', (13, 22))	('activation', 'PosReg', (185, 195))	('cytochrome c', 'Gene', (102, 114))	('mitochondrial membrane potential', 'MPA', (57, 89))	('cytochrome c', 'Gene', '54205', (102, 114))
909921	23597192	The IC50 values for oridonin treatment of EC109, EC9706, and EC1 cells for 48 hours were 19.7, 31.3 and 25.8muM, respectively.	('oridonin', 'Chemical', 'MESH:C011959', (20, 28))	('EC1', 'CellLine', 'CVCL:5V05', (61, 64))	('EC9706', 'Var', (49, 55))	('EC1', 'CellLine', 'CVCL:5V05', (42, 45))	('muM', 'Gene', '56925', (108, 111))	('EC109', 'Var', (42, 47))	('EC9706', 'CellLine', 'CVCL:E307', (49, 55))	('muM', 'Gene', (108, 111))	('EC109', 'CellLine', 'CVCL:6898', (42, 47))	('men', 'Species', '9606', (34, 37))
909929	23597192	10, 20 and 40muM Jaridonin treatments of EC9706 cells for 24 hours resulted in a significant increase of FITC-Annexin V positive /PI negative (early apoptosis) population up to 7.4%, 26.5% and 45.9%, respectively, compared to control treated cells (3.6%) (Figs.	('to 7', 'Species', '1214577', (174, 178))	('increase', 'PosReg', (93, 101))	('muM', 'Gene', (13, 16))	('Jaridonin', 'Chemical', 'MESH:C587044', (17, 26))	('EC9706', 'CellLine', 'CVCL:E307', (41, 47))	('FITC', 'Chemical', 'MESH:D016650', (105, 109))	('men', 'Species', '9606', (32, 35))	('Annexin V', 'Gene', '308', (110, 119))	('Annexin V', 'Gene', (110, 119))	('muM', 'Gene', '56925', (13, 16))	('EC9706', 'Var', (41, 47))
909951	23597192	(7C) shows that L-NAC reduced the cellular levels of the Jaridonin induced hydrogen peroxide by about 21.2 to 33.2% (Ps<0.05).	('cellular levels', 'MPA', (34, 49))	('L-NAC', 'Var', (16, 21))	('L-NAC', 'Chemical', 'MESH:C086501', (16, 21))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (75, 92))	('reduced', 'NegReg', (22, 29))	('Jaridonin', 'Chemical', 'MESH:C587044', (57, 66))
909987	23597192	Nevertheless, since about 50% of cancers have mutant p53, it is important to know whether Jaridonin can also induce apoptosis in p53 mutant ESCC cells.	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('apoptosis', 'CPA', (116, 125))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('Jaridonin', 'Chemical', 'MESH:C587044', (90, 99))	('mutant', 'Var', (46, 52))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutant', 'Var', (133, 139))	('induce', 'PosReg', (109, 115))
909988	23597192	Studies are therefore in progress to compare the apoptotic effects of Jaridonin between p53 wild-type, mutant and knockout cell lines for determining the requirements of p53.	('mutant', 'Var', (103, 109))	('p53', 'Gene', (170, 173))	('p53', 'Gene', (88, 91))	('Jaridonin', 'Chemical', 'MESH:C587044', (70, 79))	('p53', 'Gene', '7157', (88, 91))	('p53', 'Gene', '7157', (170, 173))	('men', 'Species', '9606', (161, 164))
910033	20155622	In addition, cyanidin reduced the growth of human colon cancer cell lines HT29 and HCT116 and, cyanidin 3-O-beta-D glucoside induced apoptosis and inhibited growth of human lymphoid leukemia Molt 4B cells.	('human', 'Species', '9606', (44, 49))	('glucoside', 'Chemical', 'MESH:D005960', (115, 124))	('O-beta', 'Species', '95145', (106, 112))	('apoptosis', 'CPA', (133, 142))	('cyanidin', 'Chemical', 'MESH:C017154', (13, 21))	('cyanidin', 'Var', (95, 103))	('HCT116', 'CellLine', 'CVCL:0291', (83, 89))	('human', 'Species', '9606', (167, 172))	('colon cancer', 'Disease', 'MESH:D015179', (50, 62))	('leukemia', 'Phenotype', 'HP:0001909', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('HT29', 'CellLine', 'CVCL:0320', (74, 78))	('lymphoid leukemia', 'Disease', (173, 190))	('lymphoid leukemia', 'Disease', 'MESH:D007945', (173, 190))	('inhibited', 'NegReg', (147, 156))	('colon cancer', 'Disease', (50, 62))	('reduced', 'NegReg', (22, 29))	('cyanidin', 'Chemical', 'MESH:C017154', (95, 103))	('growth', 'CPA', (157, 163))	('Molt 4B', 'Phenotype', 'HP:0500055', (191, 198))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (173, 190))	('growth', 'CPA', (34, 40))	('colon cancer', 'Phenotype', 'HP:0003003', (50, 62))
910046	20155622	RE-149 is a spontaneously immortalized cell line with low tumorigenic potential in syngeneic hosts, and RE-149 DHD, derived from treatment of RE-149 cells with benzo(a)pyrene dihydrodiol, is highly tumorigenic and has a point mutation in the p53 tumor suppressor gene.	('benzo(a)pyrene dihydrodiol', 'Chemical', '-', (160, 186))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('point mutation', 'Var', (220, 234))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('p53', 'Gene', (242, 245))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (246, 251))	('p53', 'Gene', '301300', (242, 245))
910095	20155622	The base sequences of the two genes were as follows: COX-2, sense 5'-ATGCTCTTCCGAGCTGTGCT-3' and antisense 5'CATGGGAGTTGGGCAGTCA3' and i-NOS, sense 5'CCACAATACAATACTACTTGC3' and antisense 5'GGGCTATAAGTTGCTGA3'.	('i-NOS', 'Gene', '24599', (135, 140))	('i-NOS', 'Gene', (135, 140))	('antisense', 'Var', (178, 187))
910120	20155622	RE-149 cells showed the same pattern of anthocyanin uptake as RE-149 DHD cells, but the levels of anthocyanins in RE-149 cells were 100 times lower than in RE-149 DHD cells (compare Figs.	('anthocyanin', 'Chemical', 'MESH:D000872', (98, 109))	('anthocyanins', 'Chemical', 'MESH:D000872', (98, 110))	('lower', 'NegReg', (142, 147))	('levels of anthocyanins', 'MPA', (88, 110))	('RE-149', 'Var', (114, 120))	('anthocyanin', 'Chemical', 'MESH:D000872', (40, 51))
910126	20155622	Interestingly, treatment of RE-149 DHD cells with 50 microg/ml of either cyanidin-3-O-glucoside or cyanidin-3-O-rutinoside led to significant (p<0.05) reductions in both COX-2 and i-NOS expression.	('cyanidin-3-O-rutinoside', 'Chemical', '-', (99, 122))	('i-NOS', 'Gene', '24599', (180, 185))	('i-NOS', 'Gene', (180, 185))	('cyanidin-3-O-rutinoside', 'Var', (99, 122))	('cyanidin-3-O-glucoside', 'Chemical', 'MESH:C114438', (73, 95))	('COX-2', 'Enzyme', (170, 175))	('reductions', 'NegReg', (151, 161))
910168	20155622	In conclusion, the EtOH extract of BRB, and the component anthocyanins in BRB, cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside, selectively inhibited the growth and stimulated the apoptosis of RE-149 DHD cells, an effect that was increased by adding fresh extract or anthocyanins daily.	('anthocyanins', 'Chemical', 'MESH:D000872', (270, 282))	('growth', 'CPA', (157, 163))	('EtOH', 'Chemical', 'MESH:D000431', (19, 23))	('cyanidin-3-O-rutinoside', 'Chemical', '-', (106, 129))	('inhibited', 'NegReg', (143, 152))	('cyanidin-3-O-rutinoside', 'Var', (106, 129))	('anthocyanins', 'Chemical', 'MESH:D000872', (58, 70))	('stimulated', 'PosReg', (168, 178))	('apoptosis', 'CPA', (183, 192))	('cyanidin-3-O-glucoside', 'Chemical', 'MESH:C114438', (79, 101))
910173	27107065	As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in EC that may serve as biomarkers might help predict patient outcome and guide treatment.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (92, 101))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('patient', 'Species', '9606', (156, 163))
910176	27107065	The Ion PGM and AmpliSeq Cancer Panel was used to identify mutations at 737 hotspot loci of 45 cancer-related genes in 64 EC samples from Chinese patients.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('AmpliSeq Cancer', 'Disease', (16, 31))	('AmpliSeq Cancer', 'Disease', 'MESH:D009369', (16, 31))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('patients', 'Species', '9606', (146, 154))
910177	27107065	Frequent mutations were found in TP53 and less frequent mutations in PIK3CA, FBXW7 and KRAS.	('FBXW7', 'Gene', '55294', (77, 82))	('KRAS', 'Gene', (87, 91))	('FBXW7', 'Gene', (77, 82))	('KRAS', 'Gene', '3845', (87, 91))	('mutations', 'Var', (9, 18))	('TP53', 'Gene', '7157', (33, 37))	('PIK3CA', 'Gene', (69, 75))	('TP53', 'Gene', (33, 37))	('PIK3CA', 'Gene', '5290', (69, 75))
910178	27107065	These results demonstrate that targeted sequencing can reliably identify mutations in individual tumors that make this technology a possibility for clinical use.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('mutations', 'Var', (73, 82))
910188	27107065	These targets include specific gene mutations in disrupted signaling pathways, such as those associated with vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), receptor tyrosine-protein kinase erbB-2 (ERBB2) and others.	('epidermal growth factor receptor', 'Gene', '1956', (152, 184))	('vascular endothelial growth factor', 'Gene', '7422', (109, 143))	('VEGF', 'Gene', (145, 149))	('receptor tyrosine-protein kinase erbB-2', 'Gene', (193, 232))	('mutations', 'Var', (36, 45))	('ERBB2', 'Gene', '2064', (234, 239))	('EGFR', 'Gene', (186, 190))	('EGFR', 'Gene', '1956', (186, 190))	('ERBB2', 'Gene', (234, 239))	('signaling pathways', 'Pathway', (59, 77))	('epidermal growth factor receptor', 'Gene', (152, 184))	('VEGF', 'Gene', '7422', (145, 149))	('receptor tyrosine-protein kinase erbB-2', 'Gene', '2064', (193, 232))	('vascular endothelial growth factor', 'Gene', (109, 143))
910189	27107065	Many of the drugs targeting those mutations have shown promising results with minimal side effects in patients of other cancer types and are currently in clinical trials in EC patients.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mutations', 'Var', (34, 43))
910190	27107065	Individual cancer DNA sequencing is also useful to identify gene mutations that may interfere with drug effectiveness.	('interfere', 'NegReg', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('interfere with drug effectiveness', 'Phenotype', 'HP:0020173', (84, 117))	('mutations', 'Var', (65, 74))
910191	27107065	For example, KRAS mutations, which are found in a small percentage of ECs, have been found to confer resistance to EGFR inhibitors, including tyrosine kinase inhibitors and monoclonal antibodies that slow or halt uncontrolled cell growth.	('uncontrolled', 'MPA', (213, 225))	('resistance', 'MPA', (101, 111))	('EGFR', 'Gene', '1956', (115, 119))	('slow', 'NegReg', (200, 204))	('tyrosine kinase inhibitors', 'MPA', (142, 168))	('EGFR', 'Gene', (115, 119))	('halt', 'NegReg', (208, 212))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
910192	27107065	Hence, the identification of KRAS mutations may spare patients from unnecessary drug toxicity from an EGFR inhibitor rendered ineffective by the mutation.	('toxicity', 'Disease', 'MESH:D064420', (85, 93))	('toxicity', 'Disease', (85, 93))	('patients', 'Species', '9606', (54, 62))	('KRAS', 'Gene', (29, 33))	('spare', 'NegReg', (48, 53))	('KRAS', 'Gene', '3845', (29, 33))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('mutations', 'Var', (34, 43))
910194	27107065	For example, TP53 mutations, which are found in more than 40% of ECs, have been shown to correspond to poorer patient responses to the neoadjuvant chemotherapeutic agents fluorouracil and cisplatin, and patients with these mutations have reduced overall survival compared to those with wild-type TP53.	('TP53', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (296, 300))	('poorer', 'NegReg', (103, 109))	('reduced', 'NegReg', (238, 245))	('TP53', 'Gene', (296, 300))	('overall survival', 'MPA', (246, 262))	('patient', 'Species', '9606', (203, 210))	('fluorouracil', 'Chemical', 'MESH:D005472', (171, 183))	('patients', 'Species', '9606', (203, 211))	('patient', 'Species', '9606', (110, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (188, 197))	('patient responses', 'MPA', (110, 127))	('TP53', 'Gene', '7157', (13, 17))	('mutations', 'Var', (223, 232))	('mutations', 'Var', (18, 27))
910196	27107065	In the current study, we used the Ion PGM and Ion AmpliSeq Cancer Panel to analyze 737 mutational hotspots from 45 known tumor-suppressor genes and oncogenes to identify genetic mutations in 64 esophageal cancer samples from Chinese patients.	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor-suppressor', 'Gene', (121, 137))	('cancer', 'Disease', (205, 211))	('AmpliSeq Cancer', 'Disease', 'MESH:D009369', (50, 65))	('AmpliSeq Cancer', 'Disease', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('patients', 'Species', '9606', (233, 241))	('tumor-suppressor', 'Gene', '7248', (121, 137))	('mutations', 'Var', (178, 187))
910207	27107065	In order to eliminate base calling errors, several filtering steps were employed to generate final variant calling: the first filter was fixed at an average total coverage depth >100, each variant coverage >20, a variant frequency of each sample >5% and p-value <0.01; the second filter was visually inspecting the mutations using Integrative Genomics Viewer (IGV) software (http//www.broadinstitute.org/igv) or SAMtools software (http://samtools.sourceforge.net), along with eliminating possible DNA strand-specific errors; the third filter was set as variants within 737 hotspots, as per manufacturer's instructions; and the final filtering step eliminated variants in amplicon AMPL339432 (PIK3CA, exon13, chr3:178938822-178938906), which is not uniquely matched in the human genome.	('PIK3CA', 'Gene', '5290', (692, 698))	('variants', 'Var', (659, 667))	('eliminated', 'NegReg', (648, 658))	('chr3:178938822-178938906', 'STRUCTURAL_ABNORMALITY', 'None', (708, 732))	('MPL', 'Gene', (681, 684))	('MPL', 'Gene', '4352', (681, 684))	('human', 'Species', '9606', (772, 777))	('PIK3CA', 'Gene', (692, 698))
910208	27107065	We used the COSMIC database and MyCancerGenome database (http://www.mycancergenome.org/) to assess reappearing esophageal cancer mutations.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (129, 138))	('Cancer', 'Disease', (34, 40))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
910209	27107065	Sequencing with the Ion PGM revealed that 18 of the 64 (28.1%) esophageal cancers in our sample set had one mutation in various genes and one of these samples contained a combination of three missense mutations.	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('esophageal cancers', 'Disease', (63, 81))	('esophageal cancers', 'Disease', 'MESH:D004938', (63, 81))	('mutation', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
910212	27107065	We identified TP53 mutations in 20.3% (13/64) of samples at known hotspot locations in exon 5 (p.A159V, p.R175H, p.C176F, p.C275Y and p.H179R), exon 7 (p.S241F), exon 8 (p.C275Y, p.P278S and p. E298*) and exon 10 (p.R342*).	('TP53', 'Gene', (14, 18))	('p.P278S', 'Var', (179, 186))	('p.C176F', 'Mutation', 'rs786202962', (113, 120))	('p.R342*', 'Var', (214, 221))	('p.S241F', 'Mutation', 'rs28934573', (152, 159))	('p.H179R', 'Var', (134, 141))	('p.C275Y', 'Mutation', 'rs863224451', (170, 177))	('p.C275Y', 'Var', (170, 177))	('p.C275Y', 'Var', (122, 129))	('p.C275Y', 'Mutation', 'rs863224451', (122, 129))	('p.A159V', 'Var', (95, 102))	('p.R175H', 'Var', (104, 111))	('TP53', 'Gene', '7157', (14, 18))	('p.A159V', 'Mutation', 'p.A159V', (95, 102))	('p.R175H', 'Mutation', 'rs28934578', (104, 111))	('p.S241F', 'Var', (152, 159))	('E298*', 'SUBSTITUTION', 'None', (194, 199))	('p.C176F', 'Var', (113, 120))	('p.R342*', 'Mutation', 'p.R342*', (214, 221))	('E298*', 'Var', (194, 199))	('p.P278S', 'Mutation', 'rs17849781', (179, 186))	('mutations', 'Var', (19, 28))	('p.H179R', 'Mutation', 'rs1057519991', (134, 141))
910213	27107065	While more TP53 mutations were found in ESCCs vs. EACs (22.9% vs. 14.3%, respectively), this difference was not significant (p=0.523).	('ESCCs', 'Disease', (40, 45))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('found', 'Reg', (31, 36))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))
910214	27107065	Additionally, TP53 mutations occurred at roughly equal proportions between males and females (18.5% vs. 21.6%, respectively).	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))
910215	27107065	PIK3CA mutations were identified in 3/64 samples (4.7%): one EAC and two ESCC, all from male patients.	('EAC', 'Phenotype', 'HP:0011459', (61, 64))	('PIK3CA', 'Gene', (0, 6))	('identified', 'Reg', (22, 32))	('PIK3CA', 'Gene', '5290', (0, 6))	('patients', 'Species', '9606', (93, 101))	('mutations', 'Var', (7, 16))
910216	27107065	These were all missense mutations located in exon 9 at the known hotspot residues p.E542K and p.E545K.	('p.E542K', 'Mutation', 'rs121913273', (82, 89))	('p.E542K', 'Var', (82, 89))	('p.E545K', 'Mutation', 'rs104886003', (94, 101))	('p.E545K', 'Var', (94, 101))
910217	27107065	Two samples (3.1%) contained a mutation in the FBXW7 gene: one in exon 8 (p.R465C) and one in exon 9 (p.R505L).	('p.R465C', 'Var', (74, 81))	('FBXW7', 'Gene', (47, 52))	('p.R465C', 'Mutation', 'rs867384286', (74, 81))	('p.R505L', 'Mutation', 'rs1057519896', (102, 109))	('FBXW7', 'Gene', '55294', (47, 52))
910218	27107065	Interestingly, the EAC sample with the FBXW7 p.A465C mutation also contained two KRAS mutations, one in exon 2 (p.G13D) and the other in exon 3 (p.A59T).	('KRAS', 'Gene', '3845', (81, 85))	('FBXW7', 'Gene', (39, 44))	('p.G13D', 'Mutation', 'rs112445441', (112, 118))	('EAC', 'Phenotype', 'HP:0011459', (19, 22))	('p.A59T', 'Mutation', 'rs121913528', (145, 151))	('KRAS', 'Gene', (81, 85))	('FBXW7', 'Gene', '55294', (39, 44))	('p.A465C', 'Var', (45, 52))	('p.A465C', 'Mutation', 'p.A465C', (45, 52))
910219	27107065	Our detected mutations were compared to those in esophageal cancer from the COSMIC database and MyCancerGenome database; we found that two of our mutations (FBXW7 p.R505L and KRAS p.A59T) have not been previously reported in esophageal cancers.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('esophageal cancers', 'Disease', (225, 243))	('FBXW7', 'Gene', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('p.R505L', 'Mutation', 'rs1057519896', (163, 170))	('KRAS', 'Gene', '3845', (175, 179))	('esophageal cancers', 'Disease', 'MESH:D004938', (225, 243))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('cancer', 'Disease', (236, 242))	('Cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('KRAS', 'Gene', (175, 179))	('FBXW7', 'Gene', '55294', (157, 162))	('p.R505L', 'Var', (163, 170))	('p.A59T', 'Mutation', 'rs121913528', (180, 186))	('cancer', 'Disease', (60, 66))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
910220	27107065	In the current study we used the high-throughput Ion PGM and AmpliSeq Cancer Panel to sequence 64 esophageal cancers from Chinese patients by which we identified mutations in TP53, PIK3CA, FBXW7 and KRAS in the sample population.	('KRAS', 'Gene', '3845', (199, 203))	('TP53', 'Gene', (175, 179))	('mutations', 'Var', (162, 171))	('esophageal cancers', 'Disease', 'MESH:D004938', (98, 116))	('FBXW7', 'Gene', '55294', (189, 194))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('FBXW7', 'Gene', (189, 194))	('PIK3CA', 'Gene', (181, 187))	('patients', 'Species', '9606', (130, 138))	('PIK3CA', 'Gene', '5290', (181, 187))	('AmpliSeq Cancer', 'Disease', (61, 76))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('TP53', 'Gene', '7157', (175, 179))	('AmpliSeq Cancer', 'Disease', 'MESH:D009369', (61, 76))	('esophageal cancers', 'Disease', (98, 116))	('KRAS', 'Gene', (199, 203))
910224	27107065	Of the mutations identified in our study, TP53 was most commonly mutated with 20.3% of samples containing a mutation in this gene.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('mutation', 'Var', (108, 116))
910226	27107065	Additionally, TP53 mutations significantly impair the regulatory tumor suppressor activity of p53.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('p53', 'Gene', (94, 97))	('tumor', 'Disease', (65, 70))	('p53', 'Gene', '7157', (94, 97))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('impair', 'NegReg', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
910227	27107065	Although an estimated 80% of TP53 mutations are missense resulting in a stable full-length protein, most mutant p53 proteins lose their DNA-binding activity, leading to faulty growth inhibition and apoptotic properties.	('growth inhibition', 'CPA', (176, 193))	('lose', 'NegReg', (125, 129))	('missense', 'Var', (48, 56))	('apoptotic properties', 'CPA', (198, 218))	('DNA-binding', 'Interaction', (136, 147))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('p53', 'Gene', (112, 115))	('mutations', 'Var', (34, 43))	('mutant', 'Var', (105, 111))	('p53', 'Gene', '7157', (112, 115))	('proteins', 'Protein', (116, 124))	('resulting in', 'Reg', (57, 69))
910228	27107065	TP53 mutations have been widely studied, as these are some of the most common gene mutations present in greater than 50% of all patients with various types of cancer, and TP53 mutations are specifically present in 36-80% of esophageal cancers.	('TP53', 'Gene', (171, 175))	('cancer', 'Disease', (159, 165))	('TP53', 'Gene', '7157', (0, 4))	('mutations', 'Var', (176, 185))	('TP53', 'Gene', (0, 4))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('esophageal cancers', 'Disease', (224, 242))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('present', 'Reg', (203, 210))	('esophageal cancers', 'Disease', 'MESH:D004938', (224, 242))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('TP53', 'Gene', '7157', (171, 175))
910229	27107065	The TP53 mutation rate found in our sample set was lower than previous reports, which may reflect our relatively small sample size and the tendency for mutation rates to vary greatly depending on the population and geographic location.	('mutation', 'Var', (9, 17))	('lower', 'NegReg', (51, 56))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
910230	27107065	TP53 mutations have previously been used as prognostic markers for patient survival in various cancers.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('mutations', 'Var', (5, 14))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('patient', 'Species', '9606', (67, 74))
910231	27107065	In one clinical study, EC patients without TP53 mutations who underwent curative resection survived nearly twice as long as those who had TP53 mutations.	('TP53', 'Gene', '7157', (138, 142))	('TP53', 'Gene', (138, 142))	('patients', 'Species', '9606', (26, 34))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
910232	27107065	While this study did not find any correlation between treatment response or patient survival and specific TP53 mutations, other research suggests that different TP53 point mutations may indeed influence the patient outcome or response to treatment.	('mutations', 'Var', (111, 120))	('TP53', 'Gene', (161, 165))	('influence', 'Reg', (193, 202))	('response to treatment', 'CPA', (226, 247))	('patient', 'Species', '9606', (76, 83))	('patient', 'Species', '9606', (207, 214))	('patient outcome', 'CPA', (207, 222))	('point mutations', 'Var', (166, 181))	('TP53', 'Gene', '7157', (161, 165))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
910233	27107065	One such clinical study found that patients with TP53 mutations in the zinc-binding domains (L2 and L3, amino acids 163195 and 236-251, respectively) were more resistant to chemotherapy or radiation and had significantly poorer prognoses compared to patients without TP53 mutations or with TP53 mutations outside L2 or L3.	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('resistant', 'CPA', (160, 169))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (250, 258))	('TP53', 'Gene', '7157', (267, 271))	('TP53', 'Gene', '7157', (290, 294))	('patients', 'Species', '9606', (35, 43))	('TP53', 'Gene', (290, 294))	('poorer', 'NegReg', (221, 227))	('TP53', 'Gene', (267, 271))
910234	27107065	Additional studies indicate that L2-L3 mutations are correlated with decreased survival time in patients with breast and colorectal cancer.	('survival time', 'CPA', (79, 92))	('decreased', 'NegReg', (69, 78))	('breast', 'Disease', (110, 116))	('L2-L3', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (39, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('colorectal cancer', 'Disease', (121, 138))	('patients', 'Species', '9606', (96, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
910235	27107065	Five of the TP53 mutations identified in our study (p.R175H, p.C176F, p.C176Y, H179R, p.S241F) were found within the L2-L3 zinc binding domain.	('p.C176F', 'Var', (61, 68))	('p.C176Y', 'Var', (70, 77))	('p.R175H', 'Mutation', 'rs28934578', (52, 59))	('p.S241F', 'Mutation', 'rs28934573', (86, 93))	('TP53', 'Gene', '7157', (12, 16))	('p.C176F', 'Mutation', 'rs786202962', (61, 68))	('p.C176Y', 'Mutation', 'rs786202962', (70, 77))	('TP53', 'Gene', (12, 16))	('H179R', 'Mutation', 'rs1057519991', (79, 84))	('H179R', 'Var', (79, 84))	('p.R175H', 'Var', (52, 59))	('p.S241F', 'Var', (86, 93))
910237	27107065	The PIK3CA gene encodes for the catalytic subunit p110a of class IA phosphatidylinositol 3-kinases (PI3Ks) and mutations in this gene, while common in many cancers, including breast and colon, are only found in roughly 5% of ECs.	('mutations', 'Var', (111, 120))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('common', 'Reg', (141, 147))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('PIK3CA', 'Gene', (4, 10))	('colon', 'Disease', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('PIK3CA', 'Gene', '5290', (4, 10))	('breast', 'Disease', (175, 181))
910238	27107065	The two PIK3CA mutations we identified at p.E542K and p.E545K are known hotspot mutations in the PIK3CA helical domain that have previously been identified in various cancers.	('p.E542K', 'Var', (42, 49))	('PIK3CA', 'Gene', (97, 103))	('PIK3CA', 'Gene', '5290', (8, 14))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('p.E542K', 'Mutation', 'rs121913273', (42, 49))	('p.E545K', 'Var', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('PIK3CA', 'Gene', (8, 14))	('p.E545K', 'Mutation', 'rs104886003', (54, 61))	('PIK3CA', 'Gene', '5290', (97, 103))
910239	27107065	These mutations alter interactions with other regulatory proteins like p85 and RAS and elevate lipid kinase activity that leads to an activation of downstream Akt signaling, which in turn regulates several signaling pathways controlling, among others, cell survival, proliferation and apoptosis.	('alter', 'Reg', (16, 21))	('Akt', 'Gene', (159, 162))	('interactions', 'Interaction', (22, 34))	('elevate lipid', 'Phenotype', 'HP:0003077', (87, 100))	('regulates', 'Reg', (188, 197))	('lipid kinase', 'Enzyme', (95, 107))	('activation', 'PosReg', (134, 144))	('RAS', 'Protein', (79, 82))	('elevate', 'PosReg', (87, 94))	('proliferation', 'CPA', (267, 280))	('p85', 'Gene', '5295', (71, 74))	('signaling pathways', 'Pathway', (206, 224))	('cell survival', 'CPA', (252, 265))	('Akt', 'Gene', '207', (159, 162))	('apoptosis', 'CPA', (285, 294))	('p85', 'Gene', (71, 74))	('mutations', 'Var', (6, 15))
910240	27107065	Mutations in PIK3CA may offer valuable prognostic information as recent clinical studies indicate that these mutations are associated with a better prognosis in certain ESCC patients.	('ESCC', 'Disease', (169, 173))	('PIK3CA', 'Gene', (13, 19))	('patients', 'Species', '9606', (174, 182))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))
910241	27107065	PIK3CA mutations have been found to interfere with anti-EGFR therapy and, as some of these drugs are currently being tested in some EC patients, identifying these mutations prior to drug administration may save a number of patients from unnecessary toxicities from treatments rendered ineffective by the mutations.	('toxicities', 'Disease', 'MESH:D064420', (249, 259))	('patients', 'Species', '9606', (135, 143))	('mutations', 'Var', (163, 172))	('interfere', 'NegReg', (36, 45))	('save', 'NegReg', (206, 210))	('EGFR', 'Gene', '1956', (56, 60))	('PIK3CA', 'Gene', (0, 6))	('EGFR', 'Gene', (56, 60))	('toxicities', 'Disease', (249, 259))	('PIK3CA', 'Gene', '5290', (0, 6))	('patients', 'Species', '9606', (223, 231))	('mutations', 'Var', (7, 16))
910244	27107065	Mutations in FBXW7 impair Cyclin E degradation and are associated with decreased genetic stability and impaired growth regulation.	('FBXW7', 'Gene', '55294', (13, 18))	('FBXW7', 'Gene', (13, 18))	('Cyclin E degradation', 'MPA', (26, 46))	('Mutations', 'Var', (0, 9))	('growth regulation', 'CPA', (112, 129))	('genetic stability', 'CPA', (81, 98))	('decreased', 'NegReg', (71, 80))	('impair', 'NegReg', (19, 25))	('impaired', 'NegReg', (103, 111))
910245	27107065	A recent clinical study found EC patients with low FBXW7 expression to have a significantly poorer overall survival than those with higher expression levels.	('expression', 'MPA', (57, 67))	('patients', 'Species', '9606', (33, 41))	('overall survival', 'MPA', (99, 115))	('low', 'Var', (47, 50))	('FBXW7', 'Gene', '55294', (51, 56))	('FBXW7', 'Gene', (51, 56))	('poorer', 'NegReg', (92, 98))
910246	27107065	RAS proteins are critical components of signaling pathways that help regulate cell proliferation, differentiation, cell cycle regulation and angiogenesis, while mutations in KRAS lead to constitutive activation and impaired regulatory functions.	('angiogenesis', 'CPA', (141, 153))	('KRAS', 'Gene', '3845', (174, 178))	('regulatory functions', 'MPA', (224, 244))	('constitutive', 'MPA', (187, 199))	('activation', 'PosReg', (200, 210))	('mutations', 'Var', (161, 170))	('regulate', 'Reg', (69, 77))	('cell cycle regulation', 'CPA', (115, 136))	('differentiation', 'CPA', (98, 113))	('KRAS', 'Gene', (174, 178))	('cell proliferation', 'CPA', (78, 96))
910247	27107065	While KRAS mutations are uncommon events in ECs that are found in only 2-3% of samples, they are nonetheless clinically relevant as KRAS mutations cause resistance to currently used anti-EGFR therapies in various cancers, such as colorectal and lung.	('KRAS', 'Gene', '3845', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('KRAS', 'Gene', (132, 136))	('resistance', 'MPA', (153, 163))	('KRAS', 'Gene', '3845', (132, 136))	('EGFR', 'Gene', '1956', (187, 191))	('cause', 'Reg', (147, 152))	('mutations', 'Var', (137, 146))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('EGFR', 'Gene', (187, 191))	('colorectal', 'Disease', 'MESH:D015179', (230, 240))	('cancers', 'Disease', (213, 220))	('lung', 'Disease', (245, 249))	('colorectal', 'Disease', (230, 240))	('KRAS', 'Gene', (6, 10))
910263	30196157	In prior studies of patients with chronic GERD symptoms, 3-8% will have long-segment (>=3cm) Barrett's esophagus, and 10-15% of these patients will have short-segment Barrett's esophagus, in comparison with an estimated overall prevalence of 1.6-5.6% of BE of any length in the general population without reported GERD symptoms.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (93, 112))	('men', 'Species', '9606', (162, 165))	('patients', 'Species', '9606', (134, 142))	("Barrett's esophagus", 'Disease', (167, 186))	('men', 'Species', '9606', (80, 83))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (167, 186))	('patients', 'Species', '9606', (20, 28))	('short-segment', 'Var', (153, 166))
910334	30196157	We suspect that many patients with uncomplicated GERD received some anti-secretory therapy prior to having EGD, and that patients with sSSBE may have milder forms of esophagitis or disease that is better controlled with medical treatment, compared to individuals with sLSBE.	('esophagitis or disease', 'Disease', (166, 188))	('sSSBE', 'Var', (135, 140))	('patients', 'Species', '9606', (21, 29))	('esophagitis', 'Phenotype', 'HP:0100633', (166, 177))	('esophagitis or disease', 'Disease', 'MESH:D004935', (166, 188))	('men', 'Species', '9606', (233, 236))	('patients', 'Species', '9606', (121, 129))
910335	30196157	Chronic GERD can cause Barrett's esophagus, which can lead to esophageal adenocarcinoma (EAC).	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (62, 87))	('lead to', 'Reg', (54, 61))	("Barrett's esophagus", 'Disease', (23, 42))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (23, 42))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (62, 87))	('cause', 'Reg', (17, 22))	('Chronic GERD', 'Var', (0, 12))	('esophageal adenocarcinoma', 'Disease', (62, 87))
910398	30697611	Multivariate analysis showed that detection of Pseudomonas aeruginosa in a perioperative bacteriological culture was an independent factor associated with the occurrence of postoperative pneumonia (Table S1).	('pneumonia', 'Phenotype', 'HP:0002090', (187, 196))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (173, 196))	('Pseudomonas aeruginosa', 'Var', (47, 69))	('associated', 'Reg', (139, 149))	('Pseudomonas aeruginosa', 'Species', '287', (47, 69))	('postoperative pneumonia', 'Disease', (173, 196))
910416	30697611	However, in the present study, the detection of Pseudomonas aeruginosa in a perioperative routine bacteriological culture was significantly associated with the occurrence of postoperative pneumonia.	('Pseudomonas aeruginosa', 'Var', (48, 70))	('associated with', 'Reg', (140, 155))	('Pseudomonas aeruginosa', 'Species', '287', (48, 70))	('postoperative pneumonia', 'Disease', (174, 197))	('pneumonia', 'Phenotype', 'HP:0002090', (188, 197))	('postoperative pneumonia', 'Disease', 'MESH:D010149', (174, 197))
910423	30697611	One potential explanation is that using cephazolin until the second postoperative day may have decreased the detection rate of bacteria such as Haemophilus parainfluenzae, Klebsiella pneumoniae and Streptococcus pneumoniae.	('decreased', 'NegReg', (95, 104))	('Haemophilus parainfluenzae', 'Disease', (144, 170))	('Streptococcus pneumoniae', 'Species', '1313', (198, 222))	('Streptococcus pneumoniae', 'Disease', (198, 222))	('Klebsiella pneumoniae', 'Disease', (172, 193))	('pneumonia', 'Phenotype', 'HP:0002090', (212, 221))	('Klebsiella pneumoniae', 'Species', '573', (172, 193))	('cephazolin', 'Var', (40, 50))	('detection rate', 'MPA', (109, 123))	('pneumonia', 'Phenotype', 'HP:0002090', (183, 192))	('cephazolin', 'Chemical', 'MESH:D002437', (40, 50))
910437	29997523	Pooled results showed that high level of HMGA2 was significantly correlated with poor OS (HR = 1.88, 95% confidence interval (CI) = 1.68-2.11, P < 0.001) and poor DFS (HR = 2.49, 95% CI = 1.44-4.28, P = 0.001) in cancer patients.	('poor', 'Disease', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('HMGA2', 'Gene', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (220, 228))	('HMGA2', 'Gene', '8091', (41, 46))	('cancer', 'Disease', (213, 219))	('high level', 'Var', (27, 37))	('poor OS', 'Disease', (81, 88))
910438	29997523	However, subgroup analyses revealed that the high expressed HMGA2 was associated with poor OS in head and neck cancer, gastric cancer and colorectal cancer, but not esophageal cancer and ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('esophageal cancer', 'Disease', (165, 182))	('HMGA2', 'Gene', '8091', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gastric cancer', 'Disease', (119, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('ovarian cancer', 'Disease', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('high expressed', 'Var', (45, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('HMGA2', 'Gene', (60, 65))	('head and neck cancer', 'Phenotype', 'HP:0012288', (97, 117))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('poor OS', 'Disease', (86, 93))	('colorectal cancer', 'Disease', (138, 155))	('head and neck cancer', 'Disease', 'MESH:D006258', (97, 117))
910473	29997523	Pooled results also demonstrated that high HMGA2 expression was associated with shorter DFS in cancer patients (HR = 2.49, 95% CI = 1.44-4.28) (Figure 3).	('DFS', 'MPA', (88, 91))	('HMGA2', 'Gene', '8091', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', (95, 101))	('high', 'Var', (38, 42))	('expression', 'MPA', (49, 59))	('HMGA2', 'Gene', (43, 48))	('shorter', 'NegReg', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
910477	29997523	Results show that high expression level of HMGA2 was associated with poor OS in gastric cancer (HR = 1.94, 95% CI = 1.42-2.65, P < 0.001), head and neck cancer (HR = 1.77, 95% CI = 1.37-2.29, P < 0.001), colorectal cancer (HR = 2.13, 95% CI = 1.48-3.05, P < 0.001) and other cancers (HR = 2, 95% CI = 1.68-2.40, P < 0.001), but not esophageal cancer (HR = 1.15, 95% CI = 0.55-2.37, P = 0.712) and ovarian cancer (HR = 1.07, 95% CI = 0.55-2.37, P = 0.712).	('gastric cancer', 'Disease', (80, 94))	('HMGA2', 'Gene', '8091', (43, 48))	('poor OS', 'Disease', (69, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('high expression level', 'Var', (18, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('head and neck cancer', 'Phenotype', 'HP:0012288', (139, 159))	('ovarian cancer', 'Disease', 'MESH:D010051', (397, 411))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('colorectal cancer', 'Disease', 'MESH:D015179', (204, 221))	('HMGA2', 'Gene', (43, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('colorectal cancer', 'Disease', (204, 221))	('cancers', 'Disease', (275, 282))	('head and neck cancer', 'Disease', 'MESH:D006258', (139, 159))	('ovarian cancer', 'Disease', (397, 411))	('esophageal cancer', 'Disease', 'MESH:D004938', (332, 349))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('ovarian cancer', 'Phenotype', 'HP:0100615', (397, 411))	('esophageal cancer', 'Disease', (332, 349))
910478	29997523	As a result, we found that high level of HMGA2 was related with poor OS in 13 types of cancers.	('cancers', 'Disease', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('HMGA2', 'Gene', (41, 46))	('HMGA2', 'Gene', '8091', (41, 46))	('related', 'Reg', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('high level', 'Var', (27, 37))	('poor OS', 'Disease', (64, 71))
910484	29997523	Results showed that there was no publication bias existed in studies on HMGA2 overexpression in association with OS (P = 0.597.	('overexpression', 'Var', (78, 92))	('HMGA2', 'Gene', '8091', (72, 77))	('HMGA2', 'Gene', (72, 77))
910490	29997523	Significant association between high expressed HMGA2 and poor overall survival in patients was found in 14 types of cancers.	('HMGA2', 'Gene', '8091', (47, 52))	('high expressed', 'Var', (32, 46))	('poor', 'NegReg', (57, 61))	('patients', 'Species', '9606', (82, 90))	('HMGA2', 'Gene', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('overall survival', 'MPA', (62, 78))
910492	29997523	Considering the TCGA datasets and our meta-analysis, we identified correlation between high HMGA2 expression and head and neck cancer, pancreatic ductal adenocarcinoma, ccRCC, hepatocellular carcinoma, esophageal adenocarcinoma and ovarian carcinoma, except breast cancer and gastric cancer.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (135, 167))	('esophageal adenocarcinoma and ovarian carcinoma', 'Disease', 'MESH:D010051', (202, 249))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('hepatocellular carcinoma', 'Disease', (176, 200))	('high', 'Var', (87, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('gastric cancer', 'Disease', (276, 290))	('HMGA2', 'Gene', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (202, 227))	('head and neck cancer', 'Phenotype', 'HP:0012288', (113, 133))	('correlation', 'Interaction', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (135, 167))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (276, 290))	('breast cancer', 'Disease', (258, 271))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('HMGA2', 'Gene', '8091', (92, 97))	('pancreatic ductal adenocarcinoma', 'Disease', (135, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('head and neck cancer', 'Disease', 'MESH:D006258', (113, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (176, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))	('ccRCC', 'Disease', (169, 174))	('expression', 'MPA', (98, 108))
910500	29997523	The meta-analysis results suggested that high expression of HMGA2 was associated with shorter OS and DFS in patients with cancers.	('patients', 'Species', '9606', (108, 116))	('HMGA2', 'Gene', '8091', (60, 65))	('shorter', 'NegReg', (86, 93))	('high expression', 'Var', (41, 56))	('HMGA2', 'Gene', (60, 65))	('DFS', 'CPA', (101, 104))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))
910504	29997523	Patients with high expressed HMGA2 in ccRCC, head and neck cancer, hepatocellular carcinoma and pancreatic ductal adenocarcinoma showed a significant shorter OS than patients with a low level of HMGA2 expression.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('head and neck cancer', 'Phenotype', 'HP:0012288', (45, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (96, 128))	('HMGA2', 'Gene', (29, 34))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('Patients', 'Species', '9606', (0, 8))	('HMGA2', 'Gene', (195, 200))	('ccRCC', 'Disease', (38, 43))	('pancreatic ductal adenocarcinoma', 'Disease', (96, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('head and neck cancer', 'Disease', 'MESH:D006258', (45, 65))	('high expressed', 'Var', (14, 28))	('hepatocellular carcinoma', 'Disease', (67, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (96, 128))	('shorter', 'NegReg', (150, 157))	('HMGA2', 'Gene', '8091', (29, 34))	('HMGA2', 'Gene', '8091', (195, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('patients', 'Species', '9606', (166, 174))
910513	29997523	A study conducted by suggested silencing HMGA2 expression in ovarian cancer cells could have a therapeutic effect on ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (61, 75))	('silencing', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (117, 131))	('ovarian cancer', 'Disease', (61, 75))	('HMGA2', 'Gene', '8091', (41, 46))	('ovarian cancer', 'Disease', (117, 131))	('HMGA2', 'Gene', (41, 46))	('ovarian cancer', 'Phenotype', 'HP:0100615', (61, 75))
910522	28734226	Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells Esophageal cancer is the sixth most common cause of cancer-related death worldwide.	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Apoptosis', 'CPA', (51, 60))	('Esophageal Cancer', 'Disease', (64, 81))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (64, 81))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('Esophageal cancer', 'Disease', (88, 105))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', (99, 105))	('Inhibition', 'Var', (0, 10))	('Modulates', 'Reg', (41, 50))	('Esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('pRB Pathway', 'Pathway', (14, 25))
910524	28734226	Alterations in the signaling pathway of the tumor suppressor gene Rb-1, which encodes a phosphoprotein (pRB) that negatively regulates the G1/S transition of the cell cycle, are present in 70% of all tumors, but its role in esophageal cancer is still unclear.	('Rb-1', 'Gene', '5925', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('esophageal cancer', 'Disease', (224, 241))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Alterations', 'Var', (0, 11))	('negatively', 'NegReg', (114, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (224, 241))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('G1/S', 'CPA', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('tumor', 'Disease', (44, 49))	('Rb-1', 'Gene', (66, 70))
910527	28734226	We investigated the status of phosphorylation of pRB along esophageal tumorigenesis stages, as well as whether hyperphosphorylation of pRB could suppress apoptosis induced by cisplatin, 5-FU, or TNF-alpha in esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('suppress', 'NegReg', (145, 153))	('esophageal tumor', 'Disease', 'MESH:D004938', (59, 75))	('apoptosis', 'CPA', (154, 163))	('esophageal tumor', 'Disease', (59, 75))	('esophageal cancer', 'Disease', (208, 225))	('5-FU', 'Chemical', 'MESH:D005472', (186, 190))	('hyperphosphorylation', 'Var', (111, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('esophageal tumor', 'Phenotype', 'HP:0100751', (59, 75))	('pRB', 'Gene', (135, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))
910529	28734226	When RB-1 was knocked down or CDK inhibitors reduced the levels of phosphorylated pRB, opposite apoptotic effects were observed, depending on the combination of drugs tested: whereas TNF-alpha- and cisplatin-induced apoptosis increased, 5-FU-induced apoptosis decreased.	('levels of phosphorylated', 'MPA', (57, 81))	('decreased', 'NegReg', (260, 269))	('reduced', 'NegReg', (45, 52))	('RB-1', 'Gene', '5925', (5, 9))	('apoptosis', 'CPA', (216, 225))	('knocked down', 'Var', (14, 26))	('5-FU', 'Chemical', 'MESH:D005472', (237, 241))	('cisplatin', 'Chemical', 'MESH:D002945', (198, 207))	('RB-1', 'Gene', (5, 9))
910542	28734226	Mutations in Rb-1 occur in childhood retina tumor, in 90% of small cell lung cancers (SCLC), and in 70% of bladder cancers.	('small cell lung cancers', 'Phenotype', 'HP:0030357', (61, 84))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Disease', (115, 122))	('occur', 'Reg', (18, 23))	('bladder cancers', 'Phenotype', 'HP:0009725', (107, 122))	('Rb-1', 'Gene', '5925', (13, 17))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('retina tumor', 'Phenotype', 'HP:0009919', (37, 49))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancers', 'Phenotype', 'HP:0100526', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('Rb-1', 'Gene', (13, 17))
910546	28734226	This finding suggests that, in esophageal adenocarcinoma, as in colon cancers and glioblastomas, the pRB pathway may be altered by pRB hyperphosphorylation, rather than by the loss of Rb-1.	('colon cancers', 'Phenotype', 'HP:0003003', (64, 77))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (31, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (31, 56))	('altered', 'Reg', (120, 127))	('glioblastomas', 'Phenotype', 'HP:0012174', (82, 95))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('pRB', 'Protein', (131, 134))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('esophageal adenocarcinoma', 'Disease', (31, 56))	('Rb-1', 'Gene', (184, 188))	('glioblastoma', 'Disease', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('Rb-1', 'Gene', '5925', (184, 188))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('pRB pathway', 'Pathway', (101, 112))	('hyperphosphorylation', 'Var', (135, 155))
910548	28734226	Additionally, Sarbia and colleagues showed that loss of pRb expression is not a common event in esophageal adenocarcinoma.	('pRb', 'Gene', (56, 59))	('loss', 'Var', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (96, 121))	('esophageal adenocarcinoma', 'Disease', (96, 121))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (96, 121))
910553	28734226	Our results suggest that combining CDK inhibitors and currently used chemotherapeutic agents can block proliferation and increase cancer cell death and is a promising strategy to treat esophagus cancer.	('inhibitors', 'Var', (39, 49))	('esophagus cancer', 'Disease', 'MESH:D004938', (185, 201))	('proliferation', 'CPA', (103, 116))	('increase cancer cell death', 'Disease', (121, 147))	('block', 'NegReg', (97, 102))	('CDK', 'Protein', (35, 38))	('increase cancer cell death', 'Disease', 'MESH:D003643', (121, 147))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophagus cancer', 'Disease', (185, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
910565	28734226	Cells were kept under 5% CO2 at 37  C. The cell lines were genetically tested by STR-PCR (the investigated loci were D2S1338, D19S433, CSF1PO, TPOX, TH01, vWA, d16S539, d7s820, d13s317, D5S818, FGA, D3S1358, D18S51, D8S1179, D21S11, and amelogenia) to confirm origin and rule out cross-contamination.	('D19S433', 'Var', (126, 133))	('D8S1179', 'Var', (216, 223))	('D2S1338', 'Var', (117, 124))	('FGA', 'Gene', (194, 197))	('D18S51', 'Var', (208, 214))	('d13s317', 'Var', (177, 184))	('d7s820', 'Var', (169, 175))	('CO2', 'Chemical', '-', (25, 28))	('D5S818', 'Var', (186, 192))	('D21S11', 'Var', (225, 231))	('D3S1358', 'Var', (199, 206))	('d16S539', 'Var', (160, 167))	('FGA', 'Gene', '2243', (194, 197))
910587	28734226	In the TE-13 squamous cell carcinoma cell line, pRB inhibition, either through silencing, Ros, or Flavo treatment, also increased TNF/CHX-induced cell death (P < .001 for pRB silencing or Ros pretreatment and P < .001 for Flavo pretreatment; Figure 2D).	('Flavo', 'Chemical', 'MESH:C077990', (222, 227))	('squamous cell carcinoma', 'Disease', (13, 36))	('Ros', 'Chemical', 'MESH:D000077546', (90, 93))	('TNF', 'Gene', '7124', (130, 133))	('Flavo', 'Chemical', 'MESH:C077990', (98, 103))	('pRB', 'Gene', (171, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('Ros', 'Chemical', 'MESH:D000077546', (188, 191))	('pRB', 'Gene', (48, 51))	('CHX', 'Chemical', 'MESH:D003513', (134, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (13, 36))	('silencing', 'Var', (175, 184))	('increased', 'PosReg', (120, 129))	('TNF', 'Gene', (130, 133))	('silencing', 'Var', (79, 88))	('inhibition', 'NegReg', (52, 62))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 36))
910589	28734226	Because protein synthesis inhibitors are too toxic for use in cancer therapy, we also tested whether CDK inhibitors or pRB silencing could enhance TNF-alpha-induced cell death without cycloheximide.	('pRB', 'Gene', (119, 122))	('inhibitors', 'Var', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cycloheximide', 'Chemical', 'MESH:D003513', (184, 197))	('silencing', 'Var', (123, 132))	('cell death', 'CPA', (165, 175))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tested', 'Reg', (86, 92))	('enhance', 'PosReg', (139, 146))	('CDK', 'Protein', (101, 104))
910590	28734226	CDK inhibitors did increase the TNF-alpha-induced activated caspase 3/7 levels, but the effectiveness of each inhibitor depended on the cell line.	('caspase 3', 'Gene', '836', (60, 69))	('increase', 'PosReg', (19, 27))	('CDK', 'Gene', (0, 3))	('inhibitors', 'Var', (4, 14))	('caspase 3', 'Gene', (60, 69))
910593	28734226	In TE-13 cells, Flavo, Ros, or pRB knockdown induced a small but significant increase in the percentage of caspase-positive cells after TNF-alpha treatment.	('knockdown', 'Var', (35, 44))	('Flavo', 'Chemical', 'MESH:C077990', (16, 21))	('pRB', 'Gene', (31, 34))	('Ros', 'Chemical', 'MESH:D000077546', (23, 26))	('increase', 'PosReg', (77, 85))
910594	28734226	The highest increase to 15% of caspase-positive cells (a two-fold increase of the TNF-alpha -induced cell death) was obtained with Flavo + TNF-alpha.	('Flavo + TNF-alpha', 'Var', (131, 148))	('increase', 'PosReg', (12, 20))	('caspase-positive cells', 'CPA', (31, 53))	('Flavo', 'Chemical', 'MESH:C077990', (131, 136))
910597	28734226	In OE-21 cells (Figure 3B), the percentage of 5-FU-induced caspase-positive cells dropped from 19% to 10% after Ros pretreatment (P < .001), to 8% after pRB silencing (P < .001), whereas Flavo treatment had no effect on 5-FU-induced cell death.	('dropped', 'NegReg', (82, 89))	('5-FU', 'Chemical', 'MESH:D005472', (220, 224))	('pRB', 'Gene', (153, 156))	('Ros', 'Protein', (112, 115))	('Ros', 'Chemical', 'MESH:D000077546', (112, 115))	('OE', 'Chemical', 'MESH:C108709', (3, 5))	('silencing', 'Var', (157, 166))	('5-FU', 'Chemical', 'MESH:D005472', (46, 50))	('Flavo', 'Chemical', 'MESH:C077990', (187, 192))
910598	28734226	In TE-13 cells, 5-FU-induced cell death declined from 22% to 13% after pRB silencing (P < .001), and to 14% after Ros pretreatment (P < .001), with Flavo having no significant effect.	('5-FU', 'Chemical', 'MESH:D005472', (16, 20))	('Ros', 'Chemical', 'MESH:D000077546', (114, 117))	('declined', 'NegReg', (40, 48))	('silencing', 'Var', (75, 84))	('Flavo', 'Chemical', 'MESH:C077990', (148, 153))	('cell death', 'CPA', (29, 39))	('pRB', 'Gene', (71, 74))
910602	28734226	Table 1 summarizes the effect of different combinations of pRB inactivation methods and chemotherapeutic agents on human esophageal cancer cell death.	('esophageal cancer', 'Disease', (121, 138))	('inactivation', 'Var', (63, 75))	('pRB', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('human', 'Species', '9606', (115, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))
910611	28734226	We also showed that, in general, down-regulation of pRB phosphorylation by CDK inhibitors, or silencing of pRB with siRNA, sensitizes both adenocarcinoma and squamous cell carcinoma esophageal cell lines to the chemotherapeutic agent cisplatin and to the cytokine TNF-alpha.	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('adenocarcinoma and squamous cell carcinoma esophageal', 'Disease', 'MESH:D000077277', (139, 192))	('silencing', 'Var', (94, 103))	('down-regulation', 'NegReg', (33, 48))	('pRB', 'Protein', (52, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('pRB', 'Gene', (107, 110))	('sensitizes', 'Reg', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('phosphorylation', 'MPA', (56, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))
910612	28734226	However, inhibition of pRB phosphorylation increased the resistance of esophageal cancer cell lines to 5-FU, an anticancer drug used worldwide, regardless of whether the cell death was detected by caspase 3/7 activity (Figure 2, Figure 3, Figure 4) or pyknotic nuclei (data not shown).	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (116, 122))	('resistance', 'MPA', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('5-FU', 'Chemical', 'MESH:D005472', (103, 107))	('caspase 3', 'Gene', (197, 206))	('caspase 3', 'Gene', '836', (197, 206))	('increased', 'PosReg', (43, 52))	('esophageal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pRB', 'Protein', (23, 26))	('inhibition', 'Var', (9, 19))
910617	28734226	Thus, it may be the case that, in the esophageal cell lines analyzed in our study, autophagy works as a death mechanism induced by 5-FU, which would explain the increased cell resistance observed when pRB function was modulated.	('5-FU', 'Chemical', 'MESH:D005472', (131, 135))	('autophagy', 'CPA', (83, 92))	('5-FU', 'Var', (131, 135))
910619	28734226	Accordingly, the phosphorylation resistant form of RB1 causes contrasting effects in response to different apoptotic stimuli.	('response to different apoptotic stimuli', 'MPA', (85, 124))	('RB1', 'Gene', (51, 54))	('phosphorylation', 'Var', (17, 32))	('RB1', 'Gene', '5925', (51, 54))
910624	28734226	These results suggest that pRB phosphorylation protects some esophageal cancer cells against TNF-alpha-induced cell death and, more importantly, that this combination may have the potential to increase the survival of esophageal cancer patients.	('pRB', 'Protein', (27, 30))	('esophageal cancer', 'Disease', (61, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('increase', 'PosReg', (193, 201))	('survival', 'CPA', (206, 214))	('patients', 'Species', '9606', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('esophageal cancer', 'Disease', (218, 235))	('phosphorylation', 'Var', (31, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))
910634	28734226	Our findings indicate that modulation of the pRB pathway and/or the use of CDK inhibitors should be considered for optimal and, possibly, tailored treatment of esophageal cancer.	('modulation', 'Var', (27, 37))	('pRB pathway', 'Pathway', (45, 56))	('esophageal cancer', 'Disease', (160, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
910638	27956498	Further experiments revealed that CCAT1 knockdown significantly repressed the proliferation and migration both in vitro and in vivo.	('migration', 'CPA', (96, 105))	('CCAT1', 'Gene', (34, 39))	('knockdown', 'Var', (40, 49))	('proliferation', 'CPA', (78, 91))	('repressed', 'NegReg', (64, 73))	('CCAT1', 'Gene', '100507056', (34, 39))
910639	27956498	RNA-seq analysis revealed that CCAT1 knockdown preferentially affected genes that are linked to cell proliferation, cell migration and cell adhesion.	('CCAT1', 'Gene', '100507056', (31, 36))	('CCAT1', 'Gene', (31, 36))	('knockdown', 'Var', (37, 46))	('cell proliferation', 'CPA', (96, 114))	('affected', 'Reg', (62, 70))
910654	27956498	In our present study, we found that H3K27 acetylation could activate CCAT1 and CCAT1 was significantly upregulated in ESCC tissues compared with the corresponding non-tumor tissues and may serve as an independent predictor for the overall survival in ESCC.	('CCAT1', 'Gene', '100507056', (79, 84))	('ESCC', 'Disease', (118, 122))	('acetylation', 'Var', (42, 53))	('CCAT1', 'Gene', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (167, 172))	('H3K27', 'Protein', (36, 41))	('ESCC', 'Disease', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('activate', 'PosReg', (60, 68))	('upregulated', 'PosReg', (103, 114))	('CCAT1', 'Gene', (79, 84))	('CCAT1', 'Gene', '100507056', (69, 74))
910656	27956498	RNA-seq analysis revealed that CCAT1 knockdown preferentially affected genes that are linked to proliferation and migration-related genes.	('CCAT1', 'Gene', '100507056', (31, 36))	('CCAT1', 'Gene', (31, 36))	('knockdown', 'Var', (37, 46))	('affected', 'Reg', (62, 70))	('genes', 'MPA', (71, 76))
910665	27956498	The CCAT1 fragments for RNA pull down assays were then used as a template for generating constructs carrying deletions using respective primers.	('CCAT1', 'Gene', '100507056', (4, 9))	('deletions', 'Var', (109, 118))	('CCAT1', 'Gene', (4, 9))
910688	27956498	Total RNA from the Eca-109 cells with CCAT1 knockdown and control Eca-109 cells were isolated and quantified.	('CCAT1', 'Gene', '100507056', (38, 43))	('knockdown', 'Var', (44, 53))	('CCAT1', 'Gene', (38, 43))
910707	27956498	The median survival time for low CCAT1 expression groups was 44.162 +- 2.442 months, while that for high CCAT1 expression groups was only 30.646 +- 2.507 months.	('low', 'Var', (29, 32))	('CCAT1', 'Gene', '100507056', (33, 38))	('CCAT1', 'Gene', '100507056', (105, 110))	('CCAT1', 'Gene', (33, 38))	('CCAT1', 'Gene', (105, 110))
910712	27956498	To explore the mechanism of high expression of CCAT1 in ESCC, firstly, by using UCSC Genome Bioinformatics Site (http://genome.ucsc.edu/), we found high enrichment of H3K27Ac at the promoter of CCAT1.	('CCAT1', 'Gene', '100507056', (194, 199))	('CCAT1', 'Gene', (194, 199))	('H3K27Ac', 'Var', (167, 174))	('CCAT1', 'Gene', '100507056', (47, 52))	('CCAT1', 'Gene', (47, 52))
910717	27956498	Then MTT assays showed that knockdown of CCAT1 expression significantly inhibited cell proliferation compared with the control cells.	('MTT', 'Chemical', 'MESH:C070243', (5, 8))	('CCAT1', 'Gene', (41, 46))	('cell proliferation', 'CPA', (82, 100))	('knockdown', 'Var', (28, 37))	('inhibited', 'NegReg', (72, 81))	('CCAT1', 'Gene', '100507056', (41, 46))
910719	27956498	Similarly, the result of colony-formation assay revealed that clonogenic survival was significantly decreased following knockdown of CCAT1.	('clonogenic survival', 'CPA', (62, 81))	('CCAT1', 'Gene', '100507056', (133, 138))	('knockdown', 'Var', (120, 129))	('decreased', 'NegReg', (100, 109))	('CCAT1', 'Gene', (133, 138))
910722	27956498	Next, transwell assays revealed that knockdown of CCAT1 significantly repressed cell migration compared with the control cells.	('repressed', 'NegReg', (70, 79))	('knockdown', 'Var', (37, 46))	('cell migration', 'CPA', (80, 94))	('CCAT1', 'Gene', '100507056', (50, 55))	('CCAT1', 'Gene', (50, 55))
910724	27956498	To further confirm the function of CCAT1, rescue experiment found that overexpression of CCAT1 could significantly reverse CCAT1 knockdown-mediated growth and migration suppression (Figure 2E).	('CCAT1', 'Gene', (123, 128))	('CCAT1', 'Gene', '100507056', (35, 40))	('CCAT1', 'Gene', (35, 40))	('CCAT1', 'Gene', '100507056', (89, 94))	('CCAT1', 'Gene', '100507056', (123, 128))	('CCAT1', 'Gene', (89, 94))	('knockdown-mediated', 'Var', (129, 147))	('growth', 'MPA', (148, 154))
910729	27956498	These findings indicate that knockdown of CCAT1 inhibits tumor growth in vivo.	('CCAT1', 'Gene', (42, 47))	('knockdown', 'Var', (29, 38))	('inhibits', 'NegReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('CCAT1', 'Gene', '100507056', (42, 47))	('tumor', 'Disease', (57, 62))
910736	27956498	A common set of 828 mRNAs showed >=1.5-fold increased abundance and silencing CCAT1 also reduced the abundance (<=1.5-fold) of 553 genes (Figure 4A, Supplementary Table S2).	('abundance', 'MPA', (101, 110))	('abundance', 'MPA', (54, 63))	('CCAT1', 'Gene', '100507056', (78, 83))	('CCAT1', 'Gene', (78, 83))	('silencing', 'Var', (68, 77))	('reduced', 'NegReg', (89, 96))	('increased', 'PosReg', (44, 53))
910750	27956498	Using a series of CCAT1 deletion mapping, the EZH2 binding activity mapped to nucleotides 1-600 of CCAT1, while the SUV39H1 binding activity mapped to nucleotides 2400-2795 (Figure 5C).	('SUV39H1', 'Gene', '6839', (116, 123))	('CCAT1', 'Gene', (18, 23))	('binding', 'Interaction', (51, 58))	('EZH2', 'Gene', '2146', (46, 50))	('deletion', 'Var', (24, 32))	('CCAT1', 'Gene', '100507056', (99, 104))	('CCAT1', 'Gene', (99, 104))	('EZH2', 'Gene', (46, 50))	('SUV39H1', 'Gene', (116, 123))	('CCAT1', 'Gene', '100507056', (18, 23))
910753	27956498	Knockdown CCAT1 (ASO) of the IP abrogated the interaction between EZH2 and SUV39H1, suggesting that CCAT1 is required to bridge this interaction (Figure 5C).	('Knockdown', 'Var', (0, 9))	('CCAT1', 'Gene', (100, 105))	('EZH2', 'Gene', (66, 70))	('EZH2', 'Gene', '2146', (66, 70))	('SUV39H1', 'Gene', (75, 82))	('abrogated', 'NegReg', (32, 41))	('SUV39H1', 'Gene', '6839', (75, 82))	('CCAT1', 'Gene', '100507056', (10, 15))	('interaction', 'Interaction', (46, 57))	('CCAT1', 'Gene', '100507056', (100, 105))	('CCAT1', 'Gene', (10, 15))
910754	27956498	Then the role of EZH2/SUV39H1 in coregulating suppression of these CCAT1-suppressed genes was investigated by EZH2 and SUV39H1 knockdown (EZH2, the key catalytic subunit of PRC2 histone methyltransferase), and most were induced by knockdown of EZH2/SUV39H1 (Figure 5D).	('EZH2', 'Gene', (17, 21))	('EZH2', 'Gene', '2146', (244, 248))	('knockdown', 'Var', (231, 240))	('CCAT1', 'Gene', '100507056', (67, 72))	('EZH2', 'Gene', (110, 114))	('EZH2', 'Gene', (244, 248))	('EZH2', 'Gene', '2146', (138, 142))	('SUV39H1', 'Gene', (22, 29))	('EZH2', 'Gene', '2146', (110, 114))	('SUV39H1', 'Gene', (249, 256))	('EZH2', 'Gene', (138, 142))	('CCAT1', 'Gene', (67, 72))	('SUV39H1', 'Gene', (119, 126))	('SUV39H1', 'Gene', '6839', (22, 29))	('SUV39H1', 'Gene', '6839', (249, 256))	('SUV39H1', 'Gene', '6839', (119, 126))	('knockdown', 'Var', (127, 136))	('EZH2', 'Gene', '2146', (17, 21))
910755	27956498	In addition, many studies have shown that these genes were affected by promoter hypermethylation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('promoter hypermethylation', 'Var', (71, 96))	('affected', 'Reg', (59, 67))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
910756	27956498	Then ChIP assays demonstrated that knockdown of CCAT1 decreased the binding of EZH2/SUV39H1 and H3K27me3/H3K9me3 levels across the promoters of the most coregulating genes (Figure 5E).	('knockdown', 'Var', (35, 44))	('binding', 'Interaction', (68, 75))	('CCAT1', 'Gene', (48, 53))	('H3K27me3/H3K9me3 levels', 'MPA', (96, 119))	('EZH2', 'Gene', (79, 83))	('EZH2', 'Gene', '2146', (79, 83))	('SUV39H1', 'Gene', (84, 91))	('decreased', 'NegReg', (54, 63))	('SUV39H1', 'Gene', '6839', (84, 91))	('CCAT1', 'Gene', '100507056', (48, 53))
910758	27956498	In addition, Hypermethylation of the SPRY4 promoter region has been reported to contribute to SPRY4 transcriptional inactivation.	('SPRY4', 'Gene', '81848', (94, 99))	('transcriptional', 'MPA', (100, 115))	('SPRY4', 'Gene', '81848', (37, 42))	('Hypermethylation', 'Var', (13, 29))	('SPRY4', 'Gene', (94, 99))	('SPRY4', 'Gene', (37, 42))
910759	27956498	Our results found that knockdown of CCAT1 by using ASO decreased the binding of EZH2/SUV39H1 and H3K27 trimethylation/H3K9 trimethylation levels across the promoters of SPRY4, and overexpression of CCAT1 could increase the binding of EZH2/SUV39H1 and H3K27 trimethylation/H3K9 trimethylation levels, confirming that SPRY4 was a bona target of CCAT1-regulated genes.	('H3K27 trimethylation/H3K9 trimethylation levels', 'MPA', (251, 298))	('SPRY4', 'Gene', (316, 321))	('binding', 'Interaction', (69, 76))	('CCAT1', 'Gene', '100507056', (343, 348))	('SUV39H1', 'Gene', '6839', (85, 92))	('CCAT1', 'Gene', (343, 348))	('CCAT1', 'Gene', '100507056', (198, 203))	('H3K27 trimethylation/H3K9 trimethylation levels', 'MPA', (97, 144))	('EZH2', 'Gene', (80, 84))	('CCAT1', 'Gene', (198, 203))	('SPRY4', 'Gene', '81848', (316, 321))	('EZH2', 'Gene', '2146', (80, 84))	('increase', 'PosReg', (210, 218))	('SUV39H1', 'Gene', (239, 246))	('decreased', 'NegReg', (55, 64))	('SPRY4', 'Gene', (169, 174))	('EZH2', 'Gene', '2146', (234, 238))	('EZH2', 'Gene', (234, 238))	('knockdown', 'Var', (23, 32))	('binding', 'Interaction', (223, 230))	('SPRY4', 'Gene', '81848', (169, 174))	('CCAT1', 'Gene', '100507056', (36, 41))	('SUV39H1', 'Gene', (85, 92))	('CCAT1', 'Gene', (36, 41))	('SUV39H1', 'Gene', '6839', (239, 246))	('overexpression', 'PosReg', (180, 194))
910764	27956498	These results suggest that CCAT1 affects ESCC cell growth and migration at least partly through the epigenetic repression of SPRY4 by serving as modular scaffold for EZH2 and SUV39H1 in nucleus.	('migration', 'CPA', (62, 71))	('SUV39H1', 'Gene', '6839', (175, 182))	('CCAT1', 'Gene', '100507056', (27, 32))	('CCAT1', 'Gene', (27, 32))	('affects', 'Reg', (33, 40))	('SPRY4', 'Gene', (125, 130))	('EZH2', 'Gene', (166, 170))	('EZH2', 'Gene', '2146', (166, 170))	('epigenetic repression', 'Var', (100, 121))	('SPRY4', 'Gene', '81848', (125, 130))	('SUV39H1', 'Gene', (175, 182))	('ESCC cell growth', 'CPA', (41, 57))
910765	27956498	RNA-Seq found that knockdown of CCAT1 could obviously decrease a series of genes that promote proliferation and migration in ESCC.	('decrease', 'NegReg', (54, 62))	('CCAT1', 'Gene', '100507056', (32, 37))	('knockdown', 'Var', (19, 28))	('promote', 'PosReg', (86, 93))	('proliferation', 'CPA', (94, 107))	('CCAT1', 'Gene', (32, 37))	('migration', 'CPA', (112, 121))	('ESCC', 'Disease', (125, 129))
910774	27956498	Further experiments found that knockdown CCAT1 increased miR-7 expression, and opposite results were found in CCAT1 overexpression.	('CCAT1', 'Gene', '100507056', (110, 115))	('CCAT1', 'Gene', (41, 46))	('CCAT1', 'Gene', (110, 115))	('miR-7', 'Gene', (57, 62))	('increased', 'PosReg', (47, 56))	('CCAT1', 'Gene', '100507056', (41, 46))	('miR-7', 'Gene', '10859', (57, 62))	('knockdown', 'Var', (31, 40))
910776	27956498	To validate the effects of miR-7, we cloned the CCAT1, mutant CCAT1, 3'UTR of HOXB13 and mutant 3'UTR of HOXB13 downstream of diverse luciferase genes, and co-transfected these reporters with miR-7 mimics in Eca-109 and TE-1 cells.	('miR-7', 'Gene', (27, 32))	('CCAT1', 'Gene', '100507056', (62, 67))	('HOXB13', 'Gene', '10481', (105, 111))	('CCAT1', 'Gene', (48, 53))	('CCAT1', 'Gene', (62, 67))	('HOXB13', 'Gene', '10481', (78, 84))	('miR-7', 'Gene', '10859', (192, 197))	('TE-1', 'CellLine', 'CVCL:1759', (220, 224))	('miR-7', 'Gene', '10859', (27, 32))	('mutant', 'Var', (55, 61))	('HOXB13', 'Gene', (105, 111))	('HOXB13', 'Gene', (78, 84))	('CCAT1', 'Gene', '100507056', (48, 53))	('miR-7', 'Gene', (192, 197))	('mutant', 'Var', (89, 95))
910778	27956498	However, miR-7 had no effect on mutant reporters of CCAT1 and 3'UTR of HOXB13 (Figure 7C).	('HOXB13', 'Gene', '10481', (71, 77))	('CCAT1', 'Gene', (52, 57))	('miR-7', 'Gene', (9, 14))	('HOXB13', 'Gene', (71, 77))	('mutant', 'Var', (32, 38))	('miR-7', 'Gene', '10859', (9, 14))	('CCAT1', 'Gene', '100507056', (52, 57))
910780	27956498	Importantly, as a result, knockdown CCAT1 significantly reduced the luciferase intensity of 3'UTR of HOXB13, indicating that CCAT1 is required for the abundant expression of HOXB13 (Figure 7C).	('HOXB13', 'Gene', '10481', (101, 107))	('CCAT1', 'Gene', (125, 130))	('HOXB13', 'Gene', '10481', (174, 180))	('HOXB13', 'Gene', (101, 107))	('reduced', 'NegReg', (56, 63))	('luciferase', 'Enzyme', (68, 78))	('CCAT1', 'Gene', '100507056', (36, 41))	('knockdown', 'Var', (26, 35))	('CCAT1', 'Gene', (36, 41))	('HOXB13', 'Gene', (174, 180))	('CCAT1', 'Gene', '100507056', (125, 130))
910785	27956498	Moreover, knockdown HOXB13 induced obviously proliferation and migration suppression in Eca-109 cells.	('proliferation', 'CPA', (45, 58))	('suppression', 'NegReg', (73, 84))	('HOXB13', 'Gene', '10481', (20, 26))	('HOXB13', 'Gene', (20, 26))	('knockdown', 'Var', (10, 19))	('migration', 'CPA', (63, 72))
910786	27956498	In addition, knockdown HOXB13 could reverse CCAT1-mediated growth and migration promotion (Figure 7E and Supplementary Figure S1C).	('HOXB13', 'Gene', '10481', (23, 29))	('growth', 'CPA', (59, 65))	('CCAT1', 'Gene', '100507056', (44, 49))	('reverse', 'NegReg', (36, 43))	('HOXB13', 'Gene', (23, 29))	('CCAT1', 'Gene', (44, 49))	('knockdown', 'Var', (13, 22))
910787	27956498	To further confirm the sequence site of function of CCAT1, we constructed a plasmid with a mutation of the mir7 target sequence in CCAT1.	('mir7', 'Gene', '10859', (107, 111))	('mutation', 'Var', (91, 99))	('CCAT1', 'Gene', (52, 57))	('mir7', 'Gene', (107, 111))	('CCAT1', 'Gene', (131, 136))	('CCAT1', 'Gene', '100507056', (131, 136))	('CCAT1', 'Gene', '100507056', (52, 57))
910788	27956498	Then MTT, BrdU and transwell assays showed that mutant plasmid of CCAT1 could not promote cell growth and migration of ECSS cell (Figure 7F).	('mutant', 'Var', (48, 54))	('MTT', 'Chemical', 'MESH:C070243', (5, 8))	('CCAT1', 'Gene', (66, 71))	('cell growth', 'CPA', (90, 101))	('CCAT1', 'Gene', '100507056', (66, 71))
910792	27956498	Moreover, high CCAT1 expression in ESCC tissues was associated with a poor prognosis and could be an independent prognostic indicator.	('CCAT1', 'Gene', '100507056', (15, 20))	('CCAT1', 'Gene', (15, 20))	('high', 'Var', (10, 14))	('expression', 'MPA', (21, 31))
910800	27956498	Our previous studies also found that EZH2 could epigenetically repress lncRNA SPRY4-IT1 in lung cancer and SP1 induce upregulation of lncRNA TINCR and E2F1 induce lncRNA ANRIL in gastric cancer and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('TINCR', 'Gene', (141, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (179, 193))	('epigenetically', 'Var', (48, 62))	('TINCR', 'Gene', '257000', (141, 146))	('E2F1', 'Gene', (151, 155))	('SP1', 'Gene', (107, 110))	('lung cancer', 'Disease', (198, 209))	('upregulation', 'PosReg', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ANRIL', 'Gene', '100048912', (170, 175))	('gastric cancer', 'Disease', (179, 193))	('lncRNA', 'Gene', (71, 77))	('E2F1', 'Gene', '1869', (151, 155))	('lung cancer', 'Disease', (91, 102))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (78, 87))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('gastric cancer', 'Disease', 'MESH:D013274', (179, 193))	('EZH2', 'Gene', '2146', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('EZH2', 'Gene', (37, 41))	('ANRIL', 'Gene', (170, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('SPRY4-IT1', 'Gene', (78, 87))	('repress', 'NegReg', (63, 70))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
910801	27956498	In our study, we found that inhibition of CCAT1 could repress ESCC cell proliferation and migration both in vitro and in vivo.	('CCAT1', 'Gene', (42, 47))	('migration', 'CPA', (90, 99))	('inhibition', 'Var', (28, 38))	('repress', 'NegReg', (54, 61))	('CCAT1', 'Gene', '100507056', (42, 47))	('ESCC', 'Disease', (62, 66))
910803	27956498	We found that knockdown CCAT1 induced inhibition of proliferation and migration ESCC cell line by RNA-Seq, and noting that results of gene ontology analysis was mainly proliferation and migration related.	('proliferation', 'CPA', (52, 65))	('knockdown', 'Var', (14, 23))	('CCAT1', 'Gene', '100507056', (24, 29))	('inhibition', 'NegReg', (38, 48))	('CCAT1', 'Gene', (24, 29))
910807	27956498	Moreover, previous studies have found that DNA methylation of the SPRY4 promoter region has been reported to contribute to SPRY4 transcriptional inactivation.	('SPRY4', 'Gene', (123, 128))	('SPRY4', 'Gene', (66, 71))	('DNA methylation', 'Var', (43, 58))	('transcriptional', 'MPA', (129, 144))	('SPRY4', 'Gene', '81848', (123, 128))	('SPRY4', 'Gene', '81848', (66, 71))
910808	27956498	Our results found that histone methylation (H3K9me3 and H3K9me3) mediated by CCAT1 could also contribute to the lower expression of SPRY4 in cancer.	('SPRY4', 'Gene', '81848', (132, 137))	('lower', 'NegReg', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CCAT1', 'Gene', '100507056', (77, 82))	('SPRY4', 'Gene', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('H3K9me3', 'Var', (56, 63))	('CCAT1', 'Gene', (77, 82))	('expression', 'MPA', (118, 128))	('cancer', 'Disease', (141, 147))
910809	27956498	Our results demonstrated that CCAT1 serves as modular scaffold for EZH2 and SUV39H1, thus epigenetically silencing of SPRY4 in nucleus.	('SPRY4', 'Gene', '81848', (118, 123))	('SUV39H1', 'Gene', (76, 83))	('epigenetically silencing', 'Var', (90, 114))	('CCAT1', 'Gene', '100507056', (30, 35))	('SUV39H1', 'Gene', '6839', (76, 83))	('SPRY4', 'Gene', (118, 123))	('CCAT1', 'Gene', (30, 35))	('EZH2', 'Gene', (67, 71))	('EZH2', 'Gene', '2146', (67, 71))
910810	27956498	The dysregulation of HOX gene expression has been shown in many diverse cancers.	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('HOX gene', 'Gene', (21, 29))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
910811	27956498	As a member of the HOX gene family, high levels of HOXB13 promote tumorigenesis in different types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('HOXB13', 'Gene', (51, 57))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Disease', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('promote', 'PosReg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('HOXB13', 'Gene', '10481', (51, 57))	('high levels', 'Var', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
910818	27956498	In summary, CCAT1 promotes cell growth and migration through epigenetically regulating transcription of SPRY4 in nucleus.	('CCAT1', 'Gene', '100507056', (12, 17))	('transcription', 'MPA', (87, 100))	('CCAT1', 'Gene', (12, 17))	('promotes', 'PosReg', (18, 26))	('SPRY4', 'Gene', (104, 109))	('cell growth', 'CPA', (27, 38))	('SPRY4', 'Gene', '81848', (104, 109))	('epigenetically regulating', 'Var', (61, 86))
910916	21966219	Unless the history and examination specifically suggests upper gastrointestinal mucosal disease or an abnormality of motor function, tests such as esophagogas-troduodenoscopy, small bowel series, gastric emptying studies, electrogastrography, or antroduodenal manometry would not normally be ordered in palliative care patients (see Table 2).	('abnormality', 'Var', (102, 113))	('patients', 'Species', '9606', (319, 327))	('upper gastrointestinal mucosal disease', 'Disease', 'MESH:D005767', (57, 95))	('gastric emptying', 'Phenotype', 'HP:0002578', (196, 212))	('gastrointestinal mucosal disease', 'Phenotype', 'HP:0011024', (63, 95))	('upper gastrointestinal mucosal disease', 'Disease', (57, 95))	('esophagogas-troduodenoscopy', 'Disease', (147, 174))
910932	21966219	Prokinetic agents stimulate the motility of the upper gastrointestinal tract by four potential mechanisms: activation of 5HT4 receptors, releasing acetylcholine from enteric neurons to stimulate the cholinergic system in the gut wall; blockade of 5HT3 receptors; activation of motilin receptors; or releasing the dopaminergic "brake" on gastric emptying.	('acetylcholine', 'Chemical', 'MESH:D000109', (147, 160))	('5HT4', 'Gene', (121, 125))	('cholinergic system', 'MPA', (199, 217))	('5HT3 receptors', 'Protein', (247, 261))	('releasing acetylcholine from', 'MPA', (137, 165))	('releasing', 'PosReg', (299, 308))	('blockade', 'Var', (235, 243))	('gastric emptying', 'Phenotype', 'HP:0002578', (337, 353))	('5HT4', 'Chemical', '-', (121, 125))	('dopamine', 'Chemical', 'MESH:D004298', (313, 321))	('dopaminergic "brake" on gastric emptying', 'MPA', (313, 353))	('motility of the upper gastrointestinal tract', 'Disease', (32, 76))	('motilin', 'Gene', (277, 284))	('stimulate', 'PosReg', (185, 194))	('motility of the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (32, 76))	('motilin', 'Gene', '4295', (277, 284))	('stimulate', 'PosReg', (18, 27))	('activation', 'PosReg', (107, 117))
910978	21966219	The side effects of haloperidol are similar to those of the phenothiazines, except that haloperidol causes less sedation and hypotension.	('haloperidol', 'Chemical', 'MESH:D006220', (88, 99))	('hypotension', 'Disease', (125, 136))	('haloperidol', 'Var', (88, 99))	('phenothiazines', 'Chemical', 'MESH:D010640', (60, 74))	('haloperidol', 'Chemical', 'MESH:D006220', (20, 31))	('hypotension', 'Phenotype', 'HP:0002615', (125, 136))	('sedation', 'MPA', (112, 120))	('hypotension', 'Disease', 'MESH:D007022', (125, 136))
911064	21966219	In this situation, octreotide reduces secretion of fluids by the intestine and pancreas, reduces gastrointestinal motility, and causes vasoconstriction.	('gastrointestinal motility', 'Disease', (97, 122))	('octreotide', 'Var', (19, 29))	('secretion of fluids', 'MPA', (38, 57))	('octreotide', 'Chemical', 'MESH:D015282', (19, 29))	('pancreas', 'Disease', (79, 87))	('pancreas', 'Disease', 'MESH:D010190', (79, 87))	('gastrointestinal motility', 'Disease', 'MESH:D015835', (97, 122))	('causes', 'Reg', (128, 134))	('reduces', 'NegReg', (30, 37))	('reduces', 'NegReg', (89, 96))	('vasoconstriction', 'MPA', (135, 151))
911130	21128236	Alain et al reported that rapamycin could significantly increase the replicative capability of an interferon (IFN)-sensitive VSV mutant (DeltaM51) in malignant glioma cells.	('increase', 'PosReg', (56, 64))	('VSV', 'Species', '11276', (125, 128))	('DeltaM51', 'Var', (137, 145))	('malignant glioma', 'Disease', (150, 166))	('malignant glioma', 'Disease', 'MESH:D005910', (150, 166))	('rapamycin', 'Chemical', 'MESH:D020123', (26, 35))	('DeltaM51', 'DELETION', 'None', (137, 145))	('replicative capability', 'CPA', (69, 91))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
911131	21128236	This enhancing effect apparently derived from the reduced inhibitory effect of type I IFNs on VSV (DeltaM51) replication once mTORC1 signaling was interrupted by rapamycin.	('mTORC1', 'Gene', '382056', (126, 132))	('mTORC1', 'Gene', (126, 132))	('DeltaM51', 'Var', (99, 107))	('DeltaM51', 'DELETION', 'None', (99, 107))	('reduced', 'NegReg', (50, 57))	('inhibitory effect', 'MPA', (58, 75))	('rapamycin', 'Chemical', 'MESH:D020123', (162, 171))	('VSV', 'Species', '11276', (94, 97))
911140	21128236	EC9706, a human esophageal carcinoma cell line, was a gift of Dr. Mingrong Wang.	('EC9706', 'Var', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('human', 'Species', '9606', (10, 15))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('esophageal carcinoma', 'Disease', (16, 36))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (16, 36))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (16, 36))
911142	21128236	Baco-1 is an HSV-1-based oncolytic virus, constructed by deleting both copies of the ICP34.5 gene.	('deleting', 'Var', (57, 65))	('ICP34.5', 'Gene', (85, 92))	('Baco-1', 'Chemical', '-', (0, 6))	('HSV-1', 'Species', '10298', (13, 18))
911170	21128236	To test the hypothesis that inhibition of mTOR signaling might improve the replication potential of Baco-1 in otherwise resistant cells, we examined virus growth in EC9706 cells, a human esophageal carcinoma line shown in our previous studies to be highly resistant to oncolytic HSV replication.	('replication', 'MPA', (75, 86))	('mTOR', 'Gene', '2475', (42, 46))	('human', 'Species', '9606', (181, 186))	('mTOR', 'Gene', (42, 46))	('EC9706', 'CellLine', 'CVCL:E307', (165, 171))	('Baco-1', 'Chemical', '-', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('inhibition', 'Var', (28, 38))	('esophageal carcinoma', 'Disease', (187, 207))	('improve', 'PosReg', (63, 70))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (187, 207))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (187, 207))
911184	21128236	3C, LY294002 significantly enhanced the replication and spread of the virus in all three cell lines.	('replication', 'MPA', (40, 51))	('LY294002', 'Var', (4, 12))	('enhanced', 'PosReg', (27, 35))	('spread', 'CPA', (56, 62))	('LY294002', 'Chemical', 'MESH:C085911', (4, 12))
911186	21128236	Nevertheless, these results indicate that more than one component of the PI3K/Akt/mTOR axis is involved in regulating oncolytic HSV replication in these highly resistant tumor cells, and that drugs as such rapamycin and LY294002 may be combined with HSV-based virotherapy to enhance the therapeutic effect.	('LY294002', 'Var', (220, 228))	('rapamycin', 'Chemical', 'MESH:D020123', (206, 215))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('enhance', 'PosReg', (275, 282))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Akt', 'Gene', '207', (78, 81))	('rapamycin', 'Var', (206, 215))	('tumor', 'Disease', (170, 175))	('mTOR', 'Gene', (82, 86))	('Akt', 'Gene', (78, 81))	('LY294002', 'Chemical', 'MESH:C085911', (220, 228))	('mTOR', 'Gene', '2475', (82, 86))	('involved', 'Reg', (95, 103))	('oncolytic HSV replication', 'MPA', (118, 143))
911188	21128236	To address this issue, we examined the effect of the drug on strain 17 (17+), a wild-type HSV-1; FusOn-H2, which was constructed from an HSV-2 by mutating the N-terminal region of the ICP 10 gene and, ApE-Mir-3, an HSV-1-based oncolytic virus in which the glycoprotein H (gH) gene is controlled by tissue-specific microRNAs (miRNAs), including let-7 and mir-122 (Fu et al, unpublished data).	('HSV-1', 'Species', '10298', (90, 95))	('mir-122', 'Gene', (354, 361))	('mutating', 'Var', (146, 154))	('HSV-1', 'Species', '10298', (215, 220))	('HSV-2', 'Species', '10310', (137, 142))
911212	21128236	In the case of VSV, rapamycin inhibition of the mTOR pathway is believed to enhance virus replication by reducing type I IFN production via an inhibitory effect on phosphorylation of its effector proteins, 4E-BPs and S6Ks.	('virus replication', 'CPA', (84, 101))	('mTOR', 'Gene', '2475', (48, 52))	('inhibition', 'Var', (30, 40))	('mTOR', 'Gene', (48, 52))	('VSV', 'Species', '11276', (15, 18))	('phosphorylation', 'MPA', (164, 179))	('rapamycin', 'Chemical', 'MESH:D020123', (20, 29))	('enhance', 'PosReg', (76, 83))	('reducing', 'NegReg', (105, 113))	('type I IFN production', 'MPA', (114, 135))
911241	21552467	In addition, patients with nodularity in their BE (defined as subtle mucosal elevation of diameter <= 1 cm) had 2.6 times the risk of EAC as those without nodularity (95% CI, 1.24-5.43).	('patients', 'Species', '9606', (13, 21))	('EAC', 'Phenotype', 'HP:0011459', (134, 137))	('BE', 'Phenotype', 'HP:0100580', (47, 49))	('EAC', 'Disease', (134, 137))	('nodularity', 'Var', (27, 37))
911246	21552467	Initial prospective studies showed that 69% (9/13) of patients who had aneuploidy or tetraploidy in their initial biopsies later went on to develop HGD or EAC whereas 0% (0/49) of patients who did not have these DNA content abnormalities progressed.	('EAC', 'Disease', (155, 158))	('develop', 'PosReg', (140, 147))	('patients', 'Species', '9606', (54, 62))	('aneuploidy', 'Disease', (71, 81))	('aneuploidy', 'Disease', 'MESH:D000782', (71, 81))	('EAC', 'Phenotype', 'HP:0011459', (155, 158))	('tetraploidy', 'Var', (85, 96))	('patients', 'Species', '9606', (180, 188))	('HGD', 'Disease', (148, 151))
911250	21552467	Abnormal DNA content has been found to be a result of inactivation of p53.	('DNA content', 'MPA', (9, 20))	('p53', 'Gene', '7157', (70, 73))	('inactivation', 'Var', (54, 66))	('p53', 'Gene', (70, 73))
911252	21552467	DNA copy number changes involving > 70 Mbp were associated with a higher risk of progression to esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('Mbp', 'Gene', '4155', (39, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('Mbp', 'Gene', (39, 42))	('copy number changes', 'Var', (4, 23))
911281	21552467	In BE, inactivation of p16 commonly occurs through LOH of 9p21 or p16 methylation, and less commonly via mutations.	('inactivation', 'NegReg', (7, 19))	('p16', 'Gene', (23, 26))	('9p21', 'Protein', (58, 62))	('p16', 'Gene', (66, 69))	('LOH', 'Var', (51, 54))	('mutations', 'Var', (105, 114))	('p16', 'Gene', '1029', (23, 26))	('BE', 'Phenotype', 'HP:0100580', (3, 5))	('methylation', 'Protein', (70, 81))	('p16', 'Gene', '1029', (66, 69))
911283	21552467	Among BE patients, it appears that p16 LOH, promoter methylation, and mutations have strong independent effects on BE cells in clonal expansions and precedes other lesions such as p53 abnormalities, aneuploidy, and tetraploidy.	('patients', 'Species', '9606', (9, 17))	('mutations', 'Var', (70, 79))	('p16', 'Gene', '1029', (35, 38))	('aneuploidy', 'Disease', 'MESH:D000782', (199, 209))	('abnormalities', 'Var', (184, 197))	('BE', 'Phenotype', 'HP:0100580', (6, 8))	('p53', 'Gene', (180, 183))	('p53', 'Gene', '7157', (180, 183))	('BE', 'Phenotype', 'HP:0100580', (115, 117))	('p16', 'Gene', (35, 38))	('tetraploidy', 'Disease', (215, 226))	('aneuploidy', 'Disease', (199, 209))
911287	21552467	Although p53 mutations can be inherited in Li-Fraumeni syndrome, in BE the abnormal p53 usually occurs when one allele has been deleted (usually via mutation) and the other allele is functionally inactivated often due to loss of heterozygosity (LOH) in a two-hit mechanism.	('loss of', 'NegReg', (221, 228))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('BE', 'Phenotype', 'HP:0100580', (68, 70))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (43, 63))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('mutations', 'Var', (13, 22))	('Li-Fraumeni syndrome', 'Disease', (43, 63))
911289	21552467	Missense mutations of the p53 gene result in amino acid substitutions in the protein which causes it to have a much longer half-life than normal, resulting in accumulation in the nucleus where its overexpression can be detected by immunohistochemical staining.	('result in', 'Reg', (35, 44))	('accumulation', 'PosReg', (159, 171))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('Missense mutations', 'Var', (0, 18))
911293	21552467	In a study of BE patients with LGD, 56% (5/9) of patients with positive p53 overexpression progressed on to high-grade dysplasia or cancer compared to 0% (0/16) of patients with negative p53 overexpression.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('overexpression progressed', 'PosReg', (76, 101))	('dysplasia', 'Disease', 'MESH:D004476', (119, 128))	('BE', 'Phenotype', 'HP:0100580', (14, 16))	('p53', 'Gene', (187, 190))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', '7157', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('positive', 'Var', (63, 71))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (164, 172))	('dysplasia', 'Disease', (119, 128))
911301	21552467	Other issues have arisen with p53 overexpression, including its nonspecificity for p53 gene mutations, with greater than 25% false negative and false positive results compared to DNA sequencing, making it problematic to use as a clinical marker for predicting the development of cancer in patients with BE.	('BE', 'Phenotype', 'HP:0100580', (303, 305))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('overexpression', 'PosReg', (34, 48))	('mutations', 'Var', (92, 101))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('patients', 'Species', '9606', (289, 297))
911302	21552467	These are likely due to the fact that some p53 gene mutations will cause truncations which result in a protein that can not be detected by immunohistochemistry.	('mutations', 'Var', (52, 61))	('cause', 'Reg', (67, 72))	('protein', 'Protein', (103, 110))	('truncations', 'MPA', (73, 84))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))
911308	21552467	Antibodies to p53 were detected in the plasma of esophageal cancer patients in a very small study, and in two patients they were detected before progression to cancer.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('Antibodies', 'Var', (0, 10))	('esophageal cancer', 'Disease', (49, 66))	('patients', 'Species', '9606', (67, 75))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('patients', 'Species', '9606', (110, 118))
911317	21552467	In cancers, however, hypermethylation often occurs in CpG islands and inhibits DNA transcription, resulting in the silencing of gene expression.	('hypermethylation', 'Var', (21, 37))	('silencing', 'MPA', (115, 124))	('inhibits', 'NegReg', (70, 78))	('DNA transcription', 'MPA', (79, 96))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('gene expression', 'MPA', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
911318	21552467	For example, hypermethylation has been found to play a role in the inactivation of several tumor suppressor genes, leading to neoplastic progression.	('leading to', 'Reg', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('neoplastic progression', 'CPA', (126, 148))	('inactivation', 'MPA', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('hypermethylation', 'Var', (13, 29))	('tumor', 'Disease', (91, 96))
911319	21552467	Hypermethylation of various genes have been found in BE and EAC, with p16 methylation being the most well-studied.	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('p16', 'Gene', '1029', (70, 73))	('BE', 'Phenotype', 'HP:0100580', (53, 55))	('Hypermethylation', 'Var', (0, 16))	('EAC', 'Disease', (60, 63))	('found', 'Reg', (44, 49))	('p16', 'Gene', (70, 73))
911321	21552467	In a retrospective longitudinal case control study of BE patients with negative or low-grade dysplasia, methylation of p16 (OR=1.74, 95% CI 1.33-2.20), RUNX3 (OR=1.80, 95% CI 1.08-2.81), and HPP1 (OR=1.77, 95% CI 1.06-2.81) were associated with an increased risk of progression to high-grade dysplasia or EAC.	('dysplasia', 'Disease', (93, 102))	('p16', 'Gene', (119, 122))	('low-grade dysplasia', 'Disease', 'MESH:D008228', (83, 102))	('EAC', 'Phenotype', 'HP:0011459', (305, 308))	('dysplasia', 'Disease', 'MESH:D004476', (292, 301))	('HPP1', 'Gene', (191, 195))	('patients', 'Species', '9606', (57, 65))	('BE', 'Phenotype', 'HP:0100580', (54, 56))	('EAC', 'Disease', (305, 308))	('RUNX3', 'Gene', (152, 157))	('dysplasia', 'Disease', 'MESH:D004476', (93, 102))	('low-grade dysplasia', 'Disease', (83, 102))	('RUNX3', 'Gene', '864', (152, 157))	('p16', 'Gene', '1029', (119, 122))	('methylation', 'Var', (104, 115))	('HPP1', 'Gene', '780897', (191, 195))	('dysplasia', 'Disease', (292, 301))
911322	21552467	Another study found that BE mucosa adjacent to EAC was frequently methylated in APC (100%), TIMP3 (91%), and TERT (92%) compared to BE mucosa from patients negative for dysplasia (36%, 23%, and 17%, respectively).	('APC', 'Disease', 'MESH:D011125', (80, 83))	('BE', 'Phenotype', 'HP:0100580', (132, 134))	('APC', 'Disease', (80, 83))	('TERT', 'Gene', '7015', (109, 113))	('dysplasia', 'Disease', (169, 178))	('TIMP3', 'Gene', (92, 97))	('methylated', 'Var', (66, 76))	('dysplasia', 'Disease', 'MESH:D004476', (169, 178))	('TIMP3', 'Gene', '7078', (92, 97))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('patients', 'Species', '9606', (147, 155))	('BE', 'Phenotype', 'HP:0100580', (25, 27))	('TERT', 'Gene', (109, 113))
911323	21552467	A subsequent longitudinal case-control study of BE patients showed that methylation of both p16 and APC was a strong predictor of subsequent progression to cancer (OR 14.97; 95% CI 1.73-infinity).	('p16', 'Gene', (92, 95))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('APC', 'Disease', 'MESH:D011125', (100, 103))	('methylation', 'Var', (72, 83))	('APC', 'Disease', (100, 103))	('p16', 'Gene', '1029', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('patients', 'Species', '9606', (51, 59))	('BE', 'Phenotype', 'HP:0100580', (48, 50))
911325	21552467	In summary, methylation of various genes has shown promise as a biomarker for progression in BE patients in phase 3 studies.	('methylation', 'Var', (12, 23))	('BE', 'Phenotype', 'HP:0100580', (93, 95))	('genes', 'Gene', (35, 40))	('patients', 'Species', '9606', (96, 104))
911327	21552467	Recently, a prospective study of BE patients found that a combination of DNA content abnormalities (tetraploidy and aneuploidy), 17p LOH, and 9pLOH provided the best prediction of risk for EAC (RR = 38.7; 95% CI 10.8-138.5).	('tetraploidy and aneuploidy', 'Disease', 'MESH:D057891', (100, 126))	('patients', 'Species', '9606', (36, 44))	('BE', 'Phenotype', 'HP:0100580', (33, 35))	('17p LOH', 'Var', (129, 136))	('EAC', 'Phenotype', 'HP:0011459', (189, 192))	('9pLOH', 'Var', (142, 147))	('DNA', 'MPA', (73, 76))	('EAC', 'Disease', (189, 192))
911329	21552467	In another prospective study of BE patients, the combination of genetic instability and clonal expansion predicted progression to EAC.	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('BE', 'Phenotype', 'HP:0100580', (32, 34))	('genetic instability', 'Var', (64, 83))	('EAC', 'Disease', (130, 133))	('patients', 'Species', '9606', (35, 43))	('predicted', 'Reg', (105, 114))	('clonal expansion', 'Var', (88, 104))
911333	21552467	In this study, the combination of factors that best predicted progression included the number of clones, genetic divergence, p53 LOH, and ploidy abnormalities.	('ploidy abnormalities', 'Disease', 'MESH:D000014', (138, 158))	('LOH', 'NegReg', (129, 132))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('genetic divergence', 'Var', (105, 123))	('ploidy abnormalities', 'Disease', (138, 158))
911334	21552467	A recent study using SNP arrays found that changes in DNA copy number were common in esophageal cancers, with an average of 97 copy number changes per cancer.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('esophageal cancers', 'Disease', 'MESH:D004938', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('changes', 'Var', (43, 50))	('common', 'Reg', (75, 81))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('DNA', 'Gene', (54, 57))	('esophageal cancers', 'Disease', (85, 103))
911341	21552467	Based on findings from the studies discussed above, it appears that p16 inactivation via LOH or methylation is one of the earliest events in the carcinogenesis sequence.	('LOH', 'Var', (89, 92))	('p16', 'Gene', (68, 71))	('inactivation', 'NegReg', (72, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (145, 159))	('methylation', 'Var', (96, 107))	('p16', 'Gene', '1029', (68, 71))	('carcinogenesis', 'Disease', (145, 159))
911342	21552467	This is followed by p53 inactivation via mutations and LOH, which then leads to DNA content abnormalities such as aneuploidy and tetraploidy.	('mutations', 'Var', (41, 50))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('inactivation', 'NegReg', (24, 36))	('DNA content abnormalities', 'MPA', (80, 105))	('aneuploidy', 'Disease', (114, 124))	('LOH', 'Var', (55, 58))	('aneuploidy', 'Disease', 'MESH:D000782', (114, 124))	('tetraploidy', 'Disease', (129, 140))	('leads to', 'Reg', (71, 79))
911350	21552467	Biomarkers currently in phase 3 studies include Mcm2, cyclin A, cyclin D1 (although with mixed results), and methylation of various genes.	('Mcm2', 'Gene', '4171', (48, 52))	('cyclin A', 'Gene', '890', (54, 62))	('methylation', 'Var', (109, 120))	('Mcm2', 'Gene', (48, 52))	('cyclin D1', 'Gene', '595', (64, 73))	('cyclin D1', 'Gene', (64, 73))	('cyclin A', 'Gene', (54, 62))
911357	18537156	Poultry was most strongly associated with gastric cardia adenocarcinoma (OR = 1.89, 95% CI = 1.15, 3.11) and non-cardia gastric adenocarcinoma (OR = 1.90, 95% CI = 1.19, 3.03).	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('associated', 'Interaction', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('Poultry', 'Var', (0, 7))	('non-cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (109, 142))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (42, 71))	('non-cardia gastric adenocarcinoma', 'Disease', (109, 142))	('gastric cardia adenocarcinoma', 'Disease', (42, 71))
911358	18537156	High-fat dairy was associated with increased risk of both esophageal and gastric cardia adenocarcinoma.	('gastric cardia adenocarcinoma', 'Disease', (73, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('esophageal', 'Disease', 'MESH:D004941', (58, 68))	('esophageal', 'Disease', (58, 68))	('High-fat', 'Var', (0, 8))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (73, 102))
911370	18537156	However, two other case-control studies of esophageal cancer reported an inverse association with milk consumption, although these studies did not distinguish between adenocarcinoma and squamous cell carcinoma.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('squamous cell carcinoma', 'Disease', (186, 209))	('milk consumption', 'Var', (98, 114))	('adenocarcinoma', 'Disease', 'MESH:D000230', (167, 181))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (186, 209))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('esophageal cancer', 'Disease', (43, 60))	('inverse', 'NegReg', (73, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('adenocarcinoma', 'Disease', (167, 181))
911418	18537156	Analyses of food subgroups showed significantly increased risks with poultry (OR = 1.90, 95% CI: 1.19, 3.03), high-nitrite meats (OR = 1.88, 95% CI: 1.24, 2.84), and refined grains (OR = 1.51, 95% CI: 1.25, 1.82), and a significantly decreased risk with low-fat dairy products (OR = 0.60, 95% CI: 0.41, 0.88), as shown in Table 3.	('poultry', 'Disease', (69, 76))	('nitrite', 'Chemical', 'MESH:D009573', (115, 122))	('high-nitrite', 'Var', (110, 122))
911423	18537156	Furthermore, consumption of high-fat dairy products was associated with an increased risk of both subtypes of esophageal cancer and with gastric cardia adenocarcinoma, and low-fat dairy intake with a decreased risk of non-cardia gastric adenocarcinoma.	('low-fat', 'Var', (172, 179))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (137, 166))	('esophageal cancer', 'Disease', (110, 127))	('gastric cardia adenocarcinoma', 'Disease', (137, 166))	('non-cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (218, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('non-cardia gastric adenocarcinoma', 'Disease', (218, 251))
911434	18537156	Our finding that high-fat dairy products are associated with an increased risk of both subtypes of esophageal cancer stands in contrast to case-control studies of esophageal cancer that each found no association with dairy products, or a reduced risk with higher milk consumption.	('high-fat', 'Var', (17, 25))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('esophageal cancer', 'Disease', (163, 180))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('esophageal cancer', 'Disease', (99, 116))
911454	18537156	also reported an inverse association between legume intake and risk of cancers of the upper aerodigestive tract, particularly of the esophagus, although they did not distinguish between subtypes of this cancer.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Disease', (71, 77))	('inverse', 'NegReg', (17, 24))	('legume', 'Var', (45, 51))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
911486	20816503	The animal models used are either carcinogen-induced with carcinogens specific for particular organ sites or they are transgenic/mutant animals with insertions, deletions, or mutations at targeted gene sites known to enhance cancers in a specific organ.	('enhance', 'PosReg', (217, 224))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('transgenic', 'Species', '10090', (118, 128))	('deletions', 'Var', (161, 170))	('cancers', 'Disease', (225, 232))	('mutations', 'Var', (175, 184))	('insertions', 'Var', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
911515	20816503	Interestingly, EGFR inhibitors have been highly effective in treatment of human ER+ mammary tumors.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('inhibitors', 'Var', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('EGFR', 'Gene', (15, 19))	('human', 'Species', '9606', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
911526	20816503	One is a relatively complex p53 knockout mouse model which also has BRCA1 knocked out in the breast tissue.	('BRCA1', 'Gene', (68, 73))	('mouse', 'Species', '10090', (41, 46))	('knocked out', 'Var', (74, 85))
911529	20816503	A second model for the basal-like ER- subtype involves the induction of tumors by SV40 T-antigen in C3(1) mice.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mice', 'Species', '10090', (106, 110))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))	('SV40', 'Var', (82, 86))
911547	20816503	Various carcinogens can cause lung adenomas (most with KRAS mutations) in this model, including benzo[a]pyrene (B[a]P), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), vinyl carbamate, diethylnitrosamine, uracil mustard and urethane.	('KRAS', 'Gene', (55, 59))	('lung adenomas', 'Disease', (30, 43))	('vinyl carbamate', 'Chemical', 'MESH:C017963', (174, 189))	('cause', 'Reg', (24, 29))	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (96, 110))	('uracil mustard', 'Chemical', 'MESH:D014499', (211, 225))	('NNK', 'Chemical', 'MESH:C016583', (168, 171))	('lung adenomas', 'Disease', 'MESH:D000236', (30, 43))	('4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone', 'Chemical', 'MESH:C016583', (120, 166))	('B[a]P', 'Chemical', 'MESH:D001564', (112, 117))	('mutations', 'Var', (60, 69))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (191, 209))	('urethane', 'Chemical', 'MESH:D014520', (230, 238))
911560	20816503	To increase the relevance of this model to human lung cancer, alterations of the major tumor suppressor genes p53 and/or p16 have been incorporated.	('p16', 'Gene', '1029', (121, 124))	('p53', 'Gene', (110, 113))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('rat', 'Species', '10116', (66, 69))	('tumor', 'Disease', (87, 92))	('lung cancer', 'Disease', (49, 60))	('p16', 'Gene', (121, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('alterations', 'Var', (62, 73))	('rat', 'Species', '10116', (142, 145))	('human', 'Species', '9606', (43, 48))
911561	20816503	The resulting models develop adenocarcinomas with much greater frequency, exhibit more chromosome amplifications and deletions, and more closely resemble human adenocarcinomas by gene array analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('human', 'Species', '9606', (154, 159))	('chromosome amplifications', 'CPA', (87, 112))	('adenocarcinomas', 'Disease', 'MESH:D000230', (29, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('deletions', 'Var', (117, 126))	('adenocarcinomas', 'Disease', 'MESH:D000230', (160, 175))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))	('adenocarcinomas', 'Disease', (29, 44))	('adenocarcinomas', 'Disease', (160, 175))
911582	20816503	In addition to lung tumors, NNK also induces nasal cavity tumors.	('induces', 'Reg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (20, 26))	('lung tumors', 'Disease', (15, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('lung tumors', 'Phenotype', 'HP:0100526', (15, 26))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('NNK', 'Chemical', 'MESH:C016583', (28, 31))	('lung tumors', 'Disease', 'MESH:D008175', (15, 26))	('NNK', 'Var', (28, 31))
911592	20816503	Over the past 5-8 years major efforts have been undertaken to induce lung tumors with cigarette smoke in wild type A/J mice, A/J mice with a dominant-negative p53 mutation, and Swiss albino mice.	('mice', 'Species', '10090', (119, 123))	('p53', 'Gene', (159, 162))	('lung tumors', 'Disease', 'MESH:D008175', (69, 80))	('induce', 'PosReg', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mice', 'Species', '10090', (129, 133))	('mice', 'Species', '10090', (190, 194))	('lung tumors', 'Phenotype', 'HP:0100526', (69, 80))	('lung tumors', 'Disease', (69, 80))	('mutation', 'Var', (163, 171))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
911617	20816503	Three genetically engineered models of intestinal cancer that mimic germline mutations predisposing subjects to colorectal cancer have been developed for prevention screening.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('intestinal cancer', 'Disease', 'MESH:D007414', (39, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('intestinal cancer', 'Disease', (39, 56))	('germline mutations', 'Var', (68, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
911618	20816503	The first two mouse models (Min/+ and APC 1638 mice), both containing germline mutations in the APC gene, similar to patients with FAP, develop multiple intestinal lesions.	('mouse', 'Species', '10090', (14, 19))	('APC', 'Gene', (96, 99))	('FAP', 'Disease', (131, 134))	('FAP', 'Disease', 'MESH:C567782', (131, 134))	('patients', 'Species', '9606', (117, 125))	('mice', 'Species', '10090', (47, 51))	('mutations', 'Var', (79, 88))	('develop', 'Reg', (136, 143))
911621	20816503	The third model is the MSH2 mismatch repair-deficient mouse that carries a conditional homozygous deletion of the MSH2 gene; the deletion is confined to the colon.	('MSH2', 'Gene', (23, 27))	('deletion', 'Var', (98, 106))	('MSH2', 'Gene', '17685', (114, 118))	('MSH2', 'Gene', '17685', (23, 27))	('mouse', 'Species', '10090', (54, 59))	('MSH2', 'Gene', (114, 118))
911631	20816503	In fact, naproxen, NO-naproxen, and gefitinib (Iressa ) have recently been shown to inhibit the development of large palpable tumors more effectively than the development of microscopic adenocarcinomas, implying that these agents preferentially inhibit tumor progression compared to their effect on the growth of early lesions.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('Iressa', 'Chemical', 'MESH:D000077156', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (126, 132))	('inhibit', 'NegReg', (245, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('gefitinib', 'Gene', (36, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('adenocarcinomas', 'Disease', 'MESH:D000230', (186, 201))	('NO-naproxen', 'Chemical', 'MESH:C111751', (19, 30))	('adenocarcinomas', 'Disease', (186, 201))	('naproxen', 'Chemical', 'MESH:D009288', (22, 30))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('inhibit', 'NegReg', (84, 91))	('tumor', 'Disease', (253, 258))	('gefitinib', 'Chemical', 'MESH:D000077156', (36, 45))	('tumor', 'Disease', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('naproxen', 'Chemical', 'MESH:D009288', (9, 17))	('NO-naproxen', 'Var', (19, 30))
911644	20816503	Loss of the phosphatase and tensin homologue (PTEN) tumor suppressor gene is seen early in human prostate cancer, so mouse models with PTEN alterations are also being evaluated to determine their applicability to screening.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('mouse', 'Species', '10090', (117, 122))	('phosphatase and tensin homologue', 'Gene', '5728', (12, 44))	('Loss', 'NegReg', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('alterations', 'Var', (140, 151))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('rat', 'Species', '10116', (144, 147))	('prostate cancer', 'Disease', (97, 112))	('human', 'Species', '9606', (91, 96))
911645	20816503	Most recently it appears that a model employing a knockout of PTEN, combined with a translocation of the transcriptional activator ETS-related gene, ERG, onto an androgen responsive promoter, may be a particularly appealing prostate model to pursue.	('PTEN', 'Gene', (62, 66))	('knockout', 'Var', (50, 58))	('ERG', 'Gene', (149, 152))	('ERG', 'Gene', '13876', (149, 152))	('translocation', 'MPA', (84, 97))
911651	20816503	Thus, the resulting tumors are induced by UV light, as are human squamous cell skin cancers, and the driving mutations are p53 mutations that arise at the site of thymidine dimers.	('human', 'Species', '9606', (59, 64))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('squamous cell skin cancer', 'Phenotype', 'HP:0006739', (65, 90))	('thymidine', 'Chemical', 'MESH:D013936', (163, 172))	('squamous cell skin cancer', 'Disease', 'MESH:D002294', (65, 90))	('cell skin cancers', 'Disease', (74, 91))	('skin cancers', 'Phenotype', 'HP:0008069', (79, 91))	('skin cancer', 'Phenotype', 'HP:0008069', (79, 90))	('squamous cell skin cancer', 'Disease', (65, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('p53', 'Gene', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (127, 136))	('cell skin cancers', 'Disease', 'MESH:D012878', (74, 91))
911657	20816503	In another skin cancer model, mice with a PTCH gene knocked out are highly susceptible to UV-induced basal cell carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('knocked out', 'Var', (52, 63))	('mice', 'Species', '10090', (30, 34))	('basal cell carcinomas', 'Disease', (101, 122))	('susceptible', 'Reg', (75, 86))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (101, 122))	('skin cancer', 'Disease', (11, 22))	('skin cancer', 'Phenotype', 'HP:0008069', (11, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('skin cancer', 'Disease', 'MESH:D012878', (11, 22))	('PTCH', 'Gene', (42, 46))	('PTCH', 'Gene', '19206', (42, 46))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (101, 122))
911658	20816503	These mice have been shown to respond to a number of agents, including NSAIDs, RAR receptor agonists, CP31398 (a p53 stabilizer) and cyclopamine.	('CP31398', 'Var', (102, 109))	('CP31398', 'Chemical', 'MESH:C402665', (102, 109))	('cyclopamine', 'Chemical', 'MESH:C000541', (133, 144))	('mice', 'Species', '10090', (6, 10))	('respond', 'MPA', (30, 37))	('RAR receptor', 'Protein', (79, 91))	('cyclopamine', 'MPA', (133, 144))	('NSAIDs', 'MPA', (71, 77))
911668	20816503	A recently reported BRCA1 model will also be explored since BRCA1 mutation carriers provide one of the few clearly defined populations with a high ovarian cancer risk.	('BRCA1', 'Gene', (60, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('high ovarian cancer', 'Disease', 'MESH:D010051', (142, 161))	('high ovarian cancer', 'Disease', (142, 161))	('mutation', 'Var', (66, 74))
911682	20816503	The induction of cancer in rat tongue by 4-NQO has become a model for chemoprevention studies of head and neck cancer.	('4-NQO', 'Var', (41, 46))	('4-NQO', 'Chemical', 'MESH:D015112', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('head and neck cancer', 'Phenotype', 'HP:0012288', (97, 117))	('neck cancer', 'Disease', 'MESH:D006258', (106, 117))	('cancer', 'Disease', (17, 23))	('rat', 'Species', '10116', (27, 30))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('neck cancer', 'Disease', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
911683	20816503	Oral lesions produced in rats by 4-NQO resemble human lesions in that many are ulcerated and appear as endophytic abnormalities of the tongue.	('abnormalities of the tongue', 'Phenotype', 'HP:0000157', (114, 141))	('rat', 'Species', '10116', (83, 86))	('endophytic abnormalities of the tongue', 'Disease', 'MESH:D014060', (103, 141))	('Oral lesions', 'Phenotype', 'HP:0100649', (0, 12))	('rats', 'Species', '10116', (25, 29))	('human', 'Species', '9606', (48, 53))	('4-NQO', 'Var', (33, 38))	('endophytic abnormalities of the tongue', 'Disease', (103, 141))	('4-NQO', 'Chemical', 'MESH:D015112', (33, 38))	('rat', 'Species', '10116', (25, 28))
911688	20816503	Additional data suggest strong inhibition by EGFR inhibitors and moderate efficacy with the PPARgamma agonist, rosiglitazone, and the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA).	('inhibition', 'NegReg', (31, 41))	('inhibitors', 'Var', (50, 60))	('EGFR', 'Gene', (45, 49))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (111, 124))	('suberoylanilide hydroxamic acid', 'Chemical', 'MESH:D000077337', (172, 203))	('rat', 'Species', '10116', (69, 72))	('SAHA', 'Chemical', 'MESH:D000077337', (205, 209))
911692	20816503	In fact, the resulting tumors routinely have mutations in the KRAS gene.	('mutations', 'Var', (45, 54))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('KRAS', 'Gene', (62, 66))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
911706	20816503	There are at least four other general points that can be deduced from our animal cancer prevention studies: 1) For many of the agents one can initiate treatment long after the initiation of cancer either by a carcinogen or by a transgene and still observe a preventive effect; this is important because the intervention in most phase 2 and phase 3 prevention trials is relatively late in the cancer process.	('transgene', 'Var', (228, 237))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', (392, 398))	('cancer', 'Disease', 'MESH:D009369', (392, 398))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
911707	20816503	2) Virtually no agent is strongly effective in all organ sites; thus, NSAIDs/celecoxib are highly effective in colon, skin, bladder, esophagus and head and neck cancers but routinely less effective in cancers of the breast, lung and prostate.	('celecoxib', 'Chemical', 'MESH:D000068579', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('lung', 'Disease', (224, 228))	('cancers', 'Disease', (201, 208))	('NSAIDs/celecoxib', 'Var', (70, 86))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('neck cancers', 'Disease', (156, 168))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancers', 'Disease', (161, 168))	('neck cancers', 'Disease', 'MESH:D006258', (156, 168))	('bladder', 'Disease', (124, 131))	('head and neck cancer', 'Phenotype', 'HP:0012288', (147, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('esophagus', 'Disease', (133, 142))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('skin', 'Disease', (118, 122))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('colon', 'Disease', (111, 116))	('breast', 'Disease', (216, 222))	('head and neck cancers', 'Phenotype', 'HP:0012288', (147, 168))
911718	18159596	At 40 weeks, the incidence of Barrett's esophagus was similar between control and sulindac-treated groups, but the incidence of adenocarcinoma was significantly lower in the 1000 ppm sulindac-treated group than either the control or 500 ppm sulindac-treated groups.	('sulindac', 'Chemical', 'MESH:D013467', (183, 191))	('lower', 'NegReg', (161, 166))	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (30, 49))	('1000 ppm', 'Var', (174, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('sulindac', 'Chemical', 'MESH:D013467', (82, 90))	('adenocarcinoma', 'Disease', (128, 142))	('sulindac', 'Chemical', 'MESH:D013467', (241, 249))
911733	18159596	One of the most widely accepted mechanisms for the NSAID anticancer effect concerns reduced prostaglandin synthesis due to reduced COX activity.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('prostaglandin', 'Chemical', 'MESH:D011453', (92, 105))	('COX activity', 'MPA', (131, 143))	('cancer', 'Disease', (61, 67))	('reduced prostaglandin synthesis', 'Phenotype', 'HP:0003566', (84, 115))	('reduced', 'NegReg', (84, 91))	('prostaglandin synthesis', 'MPA', (92, 115))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('NSAID', 'Var', (51, 56))	('reduced', 'NegReg', (123, 130))
911734	18159596	Recent studies have reported that COX-2 inhibitors prevent esophageal adenocarcinoma in rats.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (59, 84))	('inhibitors', 'Var', (40, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('esophageal adenocarcinoma', 'Disease', (59, 84))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (59, 84))	('COX-2', 'Gene', '29527', (34, 39))	('COX-2', 'Gene', (34, 39))	('rats', 'Species', '10116', (88, 92))
911787	18159596	At 40 weeks, the Barrett's esophagus incidence was similar between the control and sulindac-treated groups, but the incidence of adenocarcinoma was significantly lower in the 1000 ppm sulindac-treated group than the control or 500 ppm sulindac-treated groups (Fig.	('adenocarcinoma', 'Disease', (129, 143))	('sulindac', 'Chemical', 'MESH:D013467', (184, 192))	('sulindac', 'Chemical', 'MESH:D013467', (235, 243))	('1000 ppm', 'Var', (175, 183))	('adenocarcinoma', 'Disease', 'MESH:D000230', (129, 143))	('lower', 'NegReg', (162, 167))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (17, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('sulindac', 'Chemical', 'MESH:D013467', (83, 91))
911792	18159596	Cyclin D1 expression was increased in rats undergoing EGDA compared with those undergoing the sham surgery and with the sulindac-treatment groups (Fig.	('increased', 'PosReg', (25, 34))	('Cyclin D1', 'Gene', '58919', (0, 9))	('rats', 'Species', '10116', (38, 42))	('EGDA', 'Phenotype', 'HP:0100628', (54, 58))	('expression', 'MPA', (10, 20))	('EGDA', 'Var', (54, 58))	('EGDA', 'Chemical', '-', (54, 58))	('sulindac', 'Chemical', 'MESH:D013467', (120, 128))	('Cyclin D1', 'Gene', (0, 9))
911798	18159596	Moreover, a selective COX-2 inhibitor suppressed rat esophageal adenocarcinoma induced by duodenal reflux.	('esophageal adenocarcinoma', 'Disease', (53, 78))	('inhibitor', 'Var', (28, 37))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (53, 78))	('suppressed', 'NegReg', (38, 48))	('duodenal reflux', 'Phenotype', 'HP:0002020', (90, 105))	('COX-2', 'Gene', '29527', (22, 27))	('COX-2', 'Gene', (22, 27))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (53, 78))	('rat', 'Species', '10116', (49, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
911804	18159596	In contrast, a recent study reported that a COX-2 inhibitor prevented the esophageal inflammation-Barrett's esophagus-adenocarcinoma sequence in rats.	('prevented', 'NegReg', (60, 69))	("esophageal inflammation-Barrett's esophagus-adenocarcinoma", 'Disease', 'MESH:D001471', (74, 132))	('esophageal inflammation', 'Phenotype', 'HP:0100633', (74, 97))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (98, 117))	('COX-2', 'Gene', '29527', (44, 49))	('COX-2', 'Gene', (44, 49))	('inhibitor', 'Var', (50, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('rats', 'Species', '10116', (145, 149))
911860	33613762	What's more, in a recent study investigating chemoradiotherapy with simultaneous integrated boost of radiotherapy dose (SIB-RT) in EC, all patients had nonregional nodal disease, and survival benefit was observed in all the patients receiving SIB-RT, indicating the value of local control in EC patients with nonregional disease.	('nodal disease', 'Disease', (164, 177))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (295, 303))	('patients', 'Species', '9606', (224, 232))	('nodal disease', 'Disease', 'MESH:D013611', (164, 177))	('SIB-RT', 'Var', (243, 249))
911888	32322892	In cases of perforation, if the patient shows relevant comorbidity (cardiovascular disease, previous respiratory condition, end-stage renal disease, moderate-severe liver disease, diabetes, obesity), low performance status (PS) (American Society of Anesthesiologists score > 3, Eastern Cooperative Oncology Group (ECOG) PS >= 2, or Karnofsky <= 60%) and/or organ dysfunction is present, and critical beds are limited due to a high volume of COVID-19 positive patients, always try conservative measures first.	('end-stage renal disease', 'Phenotype', 'HP:0003774', (124, 147))	('obesity', 'Disease', 'MESH:D009765', (190, 197))	('COVID-19', 'Disease', 'MESH:C000657245', (441, 449))	('liver disease', 'Disease', 'MESH:D008107', (165, 178))	('patients', 'Species', '9606', (459, 467))	('renal disease', 'Disease', 'MESH:D007674', (134, 147))	('COVID-19', 'Disease', (441, 449))	('moderate-severe', 'Disease', (149, 164))	('organ dysfunction', 'Disease', 'MESH:D009102', (357, 374))	('diabetes', 'Disease', 'MESH:D003920', (180, 188))	('respiratory condition', 'Phenotype', 'HP:0002795', (101, 122))	('patient', 'Species', '9606', (32, 39))	('liver disease', 'Disease', (165, 178))	('previous', 'Disease', (92, 100))	('obesity', 'Phenotype', 'HP:0001513', (190, 197))	('patient', 'Species', '9606', (459, 466))	('low', 'Var', (200, 203))	('Oncology', 'Phenotype', 'HP:0002664', (298, 306))	('diabetes', 'Disease', (180, 188))	('organ dysfunction', 'Disease', (357, 374))	('renal disease', 'Phenotype', 'HP:0000112', (134, 147))	('obesity', 'Disease', (190, 197))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (68, 90))	('cardiovascular disease', 'Disease', 'MESH:D002318', (68, 90))	('renal disease', 'Disease', (134, 147))	('liver disease', 'Phenotype', 'HP:0001392', (165, 178))	('cardiovascular disease', 'Disease', (68, 90))
912006	31988752	The details of uNGAL level in septic patients were > 21.7 to < 50 ng/mg creatinine (n = 2), 50 to < 150 ng/mg creatinine (n = 11), 15 to < 1000 ng/mg creatinine (n = 17), and > 1000 ng/mg creatinine (n = 15).	('> 21.7 to < 50', 'Var', (51, 65))	('creatinine', 'Chemical', 'MESH:D003404', (188, 198))	('> 1000 ng/mg', 'Var', (175, 187))	('15 to < 1000 ng/mg', 'Var', (131, 149))	('patients', 'Species', '9606', (37, 45))	('creatinine', 'Chemical', 'MESH:D003404', (72, 82))	('creatinine', 'Chemical', 'MESH:D003404', (110, 120))	('NGAL', 'Gene', (16, 20))	('NGAL', 'Gene', '3934', (16, 20))	('creatinine', 'Chemical', 'MESH:D003404', (150, 160))
912010	31988752	Among these patients, uNGAL levels were remarkably elevated in 1 patient with loops enteritis (18,473.5 ng/mg creatinine) on ICU day 2 and 1 patient with obstructive jaundice due to cholangiocarcinoma (10,069.1 ng/mg creatinine) (AKI stage 2) on ICU day 1.	('AKI', 'Disease', (230, 233))	('loops enteritis', 'Disease', 'MESH:D004751', (78, 93))	('obstructive jaundice', 'Disease', 'MESH:D041781', (154, 174))	('creatinine', 'Chemical', 'MESH:D003404', (110, 120))	('patient', 'Species', '9606', (65, 72))	('elevated', 'PosReg', (51, 59))	('NGAL', 'Gene', (23, 27))	('patients', 'Species', '9606', (12, 20))	('AKI', 'Disease', 'MESH:D058186', (230, 233))	('patient', 'Species', '9606', (141, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('obstructive jaundice', 'Disease', (154, 174))	('loops enteritis', 'Disease', (78, 93))	('NGAL', 'Gene', '3934', (23, 27))	('creatinine', 'Chemical', 'MESH:D003404', (217, 227))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (182, 200))	('patient', 'Species', '9606', (12, 19))	('jaundice', 'Phenotype', 'HP:0000952', (166, 174))	('cholangiocarcinoma', 'Disease', (182, 200))	('18,473.5', 'Var', (95, 103))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (182, 200))
912011	31988752	On the other hand, the peak uNGAL levels of 8 patients with urinary tract infection were 5203.7, 354.7, 3979.9, 10011, 6799.4, 4457.8, 4268.9, and 8660 ng/mg creatinine.	('8660 ng/mg', 'Var', (147, 157))	('354.7', 'Var', (97, 102))	('urinary tract infection', 'Disease', (60, 83))	('3979.9', 'Var', (104, 110))	('patients', 'Species', '9606', (46, 54))	('creatinine', 'Chemical', 'MESH:D003404', (158, 168))	('urinary tract infection', 'Disease', 'MESH:D014552', (60, 83))	('10011', 'Var', (112, 117))	('6799.4', 'Var', (119, 125))	('4457.8', 'Var', (127, 133))	('NGAL', 'Gene', (29, 33))	('urinary tract infection', 'Phenotype', 'HP:0000010', (60, 83))	('NGAL', 'Gene', '3934', (29, 33))	('4268.9', 'Var', (135, 141))
912012	31988752	Only 1 of these patients developed AKI stage 3 whose uNGAL level was 4457.8 ng/mg creatinine and underwent continuous renal replacement therapy.	('creatinine', 'Chemical', 'MESH:D003404', (82, 92))	('AKI', 'Disease', (35, 38))	('AKI', 'Disease', 'MESH:D058186', (35, 38))	('patients', 'Species', '9606', (16, 24))	('NGAL', 'Gene', (54, 58))	('4457.8', 'Var', (69, 75))	('NGAL', 'Gene', '3934', (54, 58))
912013	31988752	In the esophagectomy group, uNGAL levels were < 21.7 ng/mg creatinine (within normal range) (n = 5), 21.7 - < 50 ng/mg creatinine (n = 11), 50 - < 150 ng/mg creatinine (n = 19), and 150 - < 1000 ng/mg creatinine (n = 5).	('creatinine', 'Chemical', 'MESH:D003404', (119, 129))	('creatinine', 'Chemical', 'MESH:D003404', (157, 167))	('NGAL', 'Gene', '3934', (29, 33))	('creatinine', 'Chemical', 'MESH:D003404', (59, 69))	('creatinine', 'Chemical', 'MESH:D003404', (201, 211))	('21.7 - < 50', 'Var', (101, 112))	('NGAL', 'Gene', (29, 33))	('esophagectomy', 'Disease', (7, 20))
912036	31988752	In the present study, uNGAL levels were 50 to < 150 ng/mg creatinine (n = 30), 150 to < 1000 ng/mg creatinine (n = 28), and > 1000 ng/mg creatinine (n = 15).	('NGAL', 'Gene', '3934', (23, 27))	('creatinine', 'Chemical', 'MESH:D003404', (99, 109))	('creatinine', 'Chemical', 'MESH:D003404', (58, 68))	('150 to < 1000 ng/mg', 'Var', (79, 98))	('creatinine', 'Chemical', 'MESH:D003404', (137, 147))	('NGAL', 'Gene', (23, 27))
912111	29675663	When grown in "progenitor" media, clusters of uniform cells expressing CK14, integrin alpha6 (CD49f), and p63 appeared.	('p63', 'Gene', (106, 109))	('CD49f', 'Gene', (94, 99))	('CK14', 'Var', (71, 75))	('integrin alpha6', 'Gene', '3655', (77, 92))	('CD49f', 'Gene', '3655', (94, 99))	('p63', 'Gene', '8626', (106, 109))	('integrin alpha6', 'Gene', (77, 92))
912113	29675663	While the outer cells expressed CK14, CD49f, and p63, inner cells appeared differentiated with expression of suprabasal CK4.	('CD49f', 'Gene', '3655', (38, 43))	('CK4', 'Gene', (120, 123))	('p63', 'Gene', (49, 52))	('CK4', 'Gene', '3851', (120, 123))	('p63', 'Gene', '8626', (49, 52))	('CD49f', 'Gene', (38, 43))	('CK14', 'Var', (32, 36))
912117	29675663	Using elegant genetic lineage tracing techniques, they showed that this MLE originated from basal epithelial progenitor cells found at the mouse SCJ proximal to the gastric cardia that express the transcription factor P63, squamous CK5, and columnar CK7 (triple positive cells).	('gastric cardia', 'Disease', 'MESH:D004938', (165, 179))	('mouse', 'Species', '10090', (139, 144))	('gastric cardia', 'Disease', (165, 179))	('P63', 'Var', (218, 221))
912122	29675663	The glands secrete mucus, bicarbonate, and growth factors, and when injured can undergo proliferative acinar ductal metaplasia characterized by the expression of CK7.	('bicarbonate', 'Chemical', 'MESH:D001639', (26, 37))	('rat', 'Species', '10116', (95, 98))	('proliferative acinar ductal metaplasia', 'Disease', (88, 126))	('CK7', 'Var', (162, 165))
912129	29675663	For example, a specific P16 point mutation identified in the epithelium of the esophageal gland duct was also present in a contiguous metaplastic crypt of Barrett's dysplasia, whereas neo-squamous islands arising from squamous ducts were P16 wild-type.	('point mutation', 'Var', (28, 42))	('present', 'Reg', (110, 117))	("Barrett's dysplasia", 'Disease', 'MESH:D001471', (155, 174))	('P16', 'Gene', (24, 27))	("Barrett's dysplasia", 'Disease', (155, 174))	('P16', 'Gene', (238, 241))	('esophageal gland duct', 'Phenotype', 'HP:0100628', (79, 100))	('P16', 'Gene', '1029', (24, 27))	('P16', 'Gene', '1029', (238, 241))
912218	30740166	According to the prevalence of the tumour process (Table 1), patients were distributed according to the international classification of staging (TNM, 2011) as follows, stage IIa, T3N0M0, 59.56% (218), then stage IIIa, T4aN0M0, 16.93% (62) and Ib stage T2N0M0 was only 10.65% (39) p < 0.05.	('TNM', 'Gene', '10178', (145, 148))	('T3N0M0', 'Var', (179, 185))	('patients', 'Species', '9606', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('TNM', 'Gene', (145, 148))	('tumour', 'Disease', (35, 41))
912225	30740166	The right-sided thoracotomy in the V intercostal space and after revision of the pleural cavity, clarification of the extent of the tumour process, mobilises the oesophagus above the aortic arch with the intersection and ligation of the unpaired vein.	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('mobilises', 'Var', (148, 157))	('tumour', 'Disease', (132, 138))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))
912278	29072678	MT1-MMP cleaves the N-terminal ligand-binding domain of EphA2 and inactivates its ligand-dependent tumor-suppressing activity.	('tumor', 'Disease', (99, 104))	('EphA2', 'Gene', (56, 61))	('MT1-MMP', 'Gene', '4323', (0, 7))	('ligand-dependent', 'MPA', (82, 98))	('MT1-MMP', 'Gene', (0, 7))	('N-terminal ligand-binding domain', 'MPA', (20, 52))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cleaves', 'Var', (8, 15))	('inactivates', 'NegReg', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
912279	29072678	Therefore, specific detection of the cleaved N-terminal EphA2 fragment in blood might be an effective biomarker to diagnose malignant tumors.	('men', 'Species', '9606', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('EphA2', 'Protein', (56, 61))	('malignant tumors', 'Disease', (124, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cleaved', 'Var', (37, 44))	('malignant tumors', 'Disease', 'MESH:D018198', (124, 140))
912293	29072678	In the presence of ephrins, EphA2 suppresses ErbB receptor signals, whereas ligand-independent EphA2 signals cooperate with ErbB receptor-mediated signals to promote tumor growth and invasion.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('promote', 'PosReg', (158, 165))	('suppresses', 'NegReg', (34, 44))	('tumor', 'Disease', (166, 171))	('ErbB', 'Gene', (45, 49))	('ErbB', 'Gene', '1956', (45, 49))	('invasion', 'CPA', (183, 191))	('ErbB', 'Gene', (124, 128))	('EphA2', 'Var', (28, 33))	('ErbB', 'Gene', '1956', (124, 128))
912304	29072678	Forced expression of an uncleavable EphA2 mutant in carcinoma cells altered cell morphology to epithelial-like forms, and suppressed tumor growth and lung metastasis in mice.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('mutant', 'Var', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('suppressed', 'NegReg', (122, 132))	('expression', 'Species', '29278', (7, 17))	('carcinoma', 'Disease', (52, 61))	('lung metastasis', 'Disease', 'MESH:D009362', (150, 165))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EphA2', 'Gene', (36, 41))	('lung metastasis', 'Disease', (150, 165))	('cell morphology', 'CPA', (76, 91))	('mice', 'Species', '10090', (169, 173))	('tumor', 'Disease', (133, 138))	('carcinoma', 'Disease', 'MESH:D002277', (52, 61))	('altered', 'Reg', (68, 75))
912348	29072678	This suggests that, in addition to the expression of MT1-MMP and EphA2, other factors could be involved in releasing the EphA2 fragment into blood vessels from cancer cells.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('EphA2', 'Var', (121, 126))	('cancer', 'Disease', (160, 166))	('men', 'Species', '9606', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('expression', 'Species', '29278', (39, 49))	('MT1-MMP', 'Gene', (53, 60))	('MT1-MMP', 'Gene', '4323', (53, 60))	('releasing', 'MPA', (107, 116))
912363	29072678	Epitopes of the pAbs 371805 and C20 consisted of EphA2 ligand-binding and cytoplasmic domains, respectively.	('pAbs', 'Chemical', 'MESH:D010129', (16, 20))	('EphA2', 'Protein', (49, 54))	('pAbs', 'Var', (16, 20))	('C20', 'Var', (32, 35))
912386	27882726	The high expression instead of mutation of p53 is predictive of overall survival in patients with esophageal squamous-cell carcinoma: a meta-analysis Esophageal squamous-cell carcinoma (ESCC) is one of the deadliest cancers where biomarkers are needed for assist guiding management.	('esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (98, 132))	('deadliest cancers', 'Disease', 'MESH:D009369', (206, 223))	('patients', 'Species', '9606', (84, 92))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Esophageal squamous-cell carcinoma', 'Disease', (150, 184))	('mutation', 'Var', (31, 39))	('esophageal squamous-cell carcinoma', 'Disease', (98, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('deadliest cancers', 'Disease', (206, 223))	('expression', 'MPA', (9, 19))	('Esophageal squamous-cell carcinoma', 'Disease', 'MESH:D000077277', (150, 184))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))
912387	27882726	We performed a meta-analysis to clarify the prognostic value of p53 high expression and TP53 mutations, which remain controversial for decades in patients with ESCC.	('ESCC', 'Disease', (160, 164))	('mutations', 'Var', (93, 102))	('high expression', 'PosReg', (68, 83))	('TP53', 'Gene', '7157', (88, 92))	('p53', 'Gene', (64, 67))	('TP53', 'Gene', (88, 92))	('patients', 'Species', '9606', (146, 154))	('p53', 'Gene', '7157', (64, 67))
912388	27882726	We searched PubMed, Ovid MEDLINE, Embase, and Current Contents Connect to identify studies published between January 1990 and February 2016 of esophageal cancer populations that measured p53 expression and/or mutation status and reported hazard ratios (HRs), or adequate data for estimation of HRs for survival for p53-defined subgroups.	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('p53', 'Gene', (187, 190))	('p53', 'Gene', '7157', (187, 190))	('mutation', 'Var', (209, 217))	('p53', 'Gene', (315, 318))	('p53', 'Gene', '7157', (315, 318))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('expression', 'MPA', (191, 201))	('esophageal cancer', 'Disease', (143, 160))
912390	27882726	The p53 high expression was associated with reduced survival (HR: 1.35, 95% CI: 1.21-1.50, I 2 = 42%).	('p53', 'Gene', '7157', (4, 7))	('survival', 'MPA', (52, 60))	('reduced', 'NegReg', (44, 51))	('high expression', 'Var', (8, 23))	('p53', 'Gene', (4, 7))
912391	27882726	Patients with ESCC and p53 high expression have reduced overall survival, and this effect is independent of tumor stage and greater than that of TP53 mutations.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('overall survival', 'MPA', (56, 72))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('reduced', 'NegReg', (48, 55))	('tumor', 'Disease', (108, 113))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (27, 42))	('ESCC', 'Gene', (14, 18))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))
912398	27882726	Recently, we and colleagues reported large-scale genomic sequencing studies showing that ESCC harbors a very high TP53 mutation rate of up to 90% 9, 10, 11, 12, 13, 14, 15.	('mutation', 'Var', (119, 127))	('to 9', 'Species', '1214577', (139, 143))	('TP53', 'Gene', '7157', (114, 118))	('TP53', 'Gene', (114, 118))
912399	27882726	These mutations, mostly causing p53 single amino acid substitutions, result in expression of full-length p53 protein, but loss of wild-type tumor-suppressive function, indicating a central role of p53 in ESCC.	('ESCC', 'Disease', (204, 208))	('expression', 'MPA', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('p53', 'Gene', (32, 35))	('p53', 'Gene', (105, 108))	('p53', 'Gene', (197, 200))	('p53', 'Gene', '7157', (105, 108))	('p53', 'Gene', '7157', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('p53', 'Gene', '7157', (32, 35))	('loss', 'NegReg', (122, 126))	('single amino acid substitutions', 'Var', (36, 67))	('result in', 'Reg', (69, 78))	('protein', 'Protein', (109, 116))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', (140, 145))
912400	27882726	Meanwhile, in esophageal adenocarcinoma (EAC), the second major subtype of esophageal cancer, the prognostic value of TP53 mutations was clarified better than that of p53 high expression.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (14, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TP53', 'Gene', '7157', (118, 122))	('p53', 'Gene', '7157', (167, 170))	('TP53', 'Gene', (118, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (14, 39))	('p53', 'Gene', (167, 170))	('esophageal cancer', 'Disease', (75, 92))	('esophageal adenocarcinoma', 'Disease', (14, 39))	('mutations', 'Var', (123, 132))
912404	27882726	The search strategy included MeSH terms and text words for o/esophagus* or o/esophageal*, p53* or TP53* or 17p* or 17p13*, carcinoma*.	('p53', 'Gene', (90, 93))	('17p* or 17p13*', 'Var', (107, 121))	('carcinoma', 'Disease', (123, 132))	('esophageal', 'Disease', (77, 87))	('p53', 'Gene', '7157', (90, 93))	('esophageal', 'Disease', 'MESH:D004941', (77, 87))	('TP53', 'Gene', '7157', (98, 102))	('carcinoma', 'Disease', 'MESH:D002277', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('o/esophagus*', 'Disease', (59, 71))	('TP53', 'Gene', (98, 102))
912405	27882726	Eligibility criteria for inclusion were the studies evaluated the correlation between p53 expression and/or TP53 mutation status and overall survival among ESCC patients with calculation of hazard ratios (HR) and 95% confidence interval (CI), or reported sufficient information for their estimation.	('mutation', 'Var', (113, 121))	('evaluated', 'Reg', (52, 61))	('TP53', 'Gene', '7157', (108, 112))	('p53', 'Gene', '7157', (86, 89))	('TP53', 'Gene', (108, 112))	('patients', 'Species', '9606', (161, 169))	('ESCC', 'Disease', (156, 160))	('p53', 'Gene', (86, 89))
912411	27882726	Therefore, TP53 gene mutations were interpreted to represent nuclear p53 protein overexpression by all authors of the included studies, although loss of p53 protein expression has also been associated with TP53 gene mutations 16.	('TP53', 'Gene', '7157', (206, 210))	('TP53', 'Gene', (206, 210))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('loss', 'NegReg', (145, 149))	('expression', 'MPA', (165, 175))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '7157', (153, 156))	('protein', 'Protein', (157, 164))	('mutations', 'Var', (21, 30))
912430	27882726	The effect of p53 status on overall survival appeared to be smaller among studies performing TP53 gene mutation assessments (sequencing and SSCP) (HR: 1.24, 95% CI: 0.94-1.64, P = 0.13, n = 11, I 2 = 37%) compared with studies performing p53 expression assessments with IHC (pooled HR: 1.39, 95% CI: 1.23-1.56, P < 0.00001, n = 45, I 2 = 46%; Fig.	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (238, 241))	('p53', 'Gene', '7157', (238, 241))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutation', 'Var', (103, 111))	('smaller', 'NegReg', (60, 67))
912432	27882726	The prognostic effect of p53 high expression was more pronounced in the subset of 16 studies assessed as low risk of bias (HR: 1.47, 95% CI: 1.29-1.67, P < 0.00001, I 2 = 15%; Fig.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('high', 'Var', (29, 33))
912433	27882726	Subgroup analysis of studies that determined p53 high expression status using IHC by different cut-off value showed that the prognostic effect of p53 high expression was smaller in the subset of 13 studies with higher cut-off value (HR: 1.21, 95% CI: 0.99-1.47, P = 0.06, I 2=46%) compared with the estimates from 32 studies with lower cut-off value.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('high expression', 'Var', (150, 165))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('prognostic effect', 'MPA', (125, 142))	('smaller', 'NegReg', (170, 177))
912435	27882726	The present meta-analysis provides coherent evidence that the high expression instead of mutation of p53 is a significant negative independent prognostic marker in ESCC patients.	('patients', 'Species', '9606', (169, 177))	('negative', 'NegReg', (122, 130))	('mutation', 'Var', (89, 97))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('ESCC', 'Disease', (164, 168))	('high', 'PosReg', (62, 66))
912441	27882726	TP53 mutation rate increased with usage of this advanced sequencing assay (Fig.	('TP53', 'Gene', '7157', (0, 4))	('increased', 'PosReg', (19, 28))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
912442	27882726	The prognostic value of TP53 mutation has been proved in various types of cancer 27.	('mutation', 'Var', (29, 37))	('TP53', 'Gene', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('TP53', 'Gene', '7157', (24, 28))
912443	27882726	There might be poorer prognosis in patients with TP53 mutation.	('TP53', 'Gene', (49, 53))	('mutation', 'Var', (54, 62))	('TP53', 'Gene', '7157', (49, 53))	('patients', 'Species', '9606', (35, 43))
912444	27882726	Thus, the high TP53 mutation rate could be one potential explanation for the poor prognosis of ESCC patients.	('ESCC', 'Disease', (95, 99))	('mutation', 'Var', (20, 28))	('TP53', 'Gene', '7157', (15, 19))	('patients', 'Species', '9606', (100, 108))	('TP53', 'Gene', (15, 19))
912446	27882726	Differential survival outcomes were observed in patients with different types of TP53 mutation 28, such as mutation location in ovarian and breast cancers 29.	('breast cancers', 'Phenotype', 'HP:0003002', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('mutation', 'Var', (86, 94))	('patients', 'Species', '9606', (48, 56))	('TP53', 'Gene', '7157', (81, 85))	('ovarian and breast cancers', 'Disease', 'MESH:D010051', (128, 154))	('TP53', 'Gene', (81, 85))
912455	27882726	As the high frequency of TP53 mutation in ESCC, and evidence from recent studies showed that p53 missense mutations abrogate its tumor-suppressive function and lead to a "gain-of-function" that promotes cancer, it might be worthwhile to try those approaches in the treatment of this deadly cancer 6, 32, 33.	('promotes', 'PosReg', (194, 202))	('TP53', 'Gene', (25, 29))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('p53', 'Gene', (93, 96))	('mutation', 'Var', (30, 38))	('p53', 'Gene', '7157', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cancer', 'Disease', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Disease', (203, 209))	('abrogate', 'NegReg', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Disease', (129, 134))	('TP53', 'Gene', '7157', (25, 29))	('missense mutations', 'Var', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
912460	27882726	The present meta-analysis shows that p53 high expression instead of mutation is predictive of overall survival in ESCC patients.	('ESCC', 'Disease', (114, 118))	('mutation', 'Var', (68, 76))	('patients', 'Species', '9606', (119, 127))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))
912462	26754874	The chromosome 3q26 OncCassette: a multigenic driver of human cancer Recurrent copy number variations (CNVs) are genetic alterations commonly observed in human tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('human', 'Species', '9606', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('human', 'Species', '9606', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Disease', (160, 166))	('copy number', 'Var', (79, 90))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
912463	26754874	One of the most frequent CNVs in human tumors involves copy number gains (CNGs) at chromosome 3q26, which is estimated to occur in >20% of human tumors.	('tumors', 'Disease', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('CNG', 'Chemical', '-', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('copy number gains', 'Var', (55, 72))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('human', 'Species', '9606', (33, 38))	('human', 'Species', '9606', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (39, 45))
912464	26754874	The high prevalence and frequent occurrence of 3q26 CNG suggest that it drives the biology of tumors harboring this genetic alteration.	('3q26 CNG', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('CNG', 'Chemical', '-', (52, 55))
912469	26754874	Integration of available genetic, genomic, biochemical and functional data demonstrates that SOX2, ECT2, PRKCI and PIK3CA are cooperating oncogenes that function within an integrated cell signaling network that drives a highly aggressive, stem-like phenotype in LSCC tumors harboring 3q26 amplification.	('drives', 'PosReg', (211, 217))	('SCC', 'Gene', '6317', (263, 266))	('SOX2', 'Gene', (93, 97))	('SOX2', 'Gene', '6657', (93, 97))	('PRKCI', 'Gene', '5584', (105, 110))	('PRKCI', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('3q26 amplification', 'Var', (284, 302))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('PIK3CA', 'Gene', (115, 121))	('SCC', 'Gene', (263, 266))	('tumors', 'Disease', (267, 273))	('PIK3CA', 'Gene', '5290', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (267, 273))
912471	26754874	Genomic analysis indicates that the 3q26 OncCassette also operates in other major tumor types that exhibit frequent 3q26 CNGs, including head and neck squamous cell carcinoma (HNSCC), ovarian serous cancer and cervical cancer.	('neck squamous cell carcinoma (HNSCC), ovarian serous cancer', 'Disease', 'MESH:D000077195', (146, 205))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (184, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('3q26 CNGs', 'Var', (116, 125))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (137, 174))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cervical cancer', 'Disease', 'MESH:D002583', (210, 225))	('CNG', 'Chemical', '-', (121, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cervical cancer', 'Disease', (210, 225))	('tumor', 'Disease', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
912473	26754874	Cancer is a disease of progressive genetic alterations that conspire to drive a cellular phenotype characterized by uncontrolled growth, aggressive invasive behavior, enhanced survival, evasion of immune surveillance, and resistance to therapeutic interventions.	('enhanced', 'PosReg', (167, 175))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('alterations', 'Var', (43, 54))	('aggressive invasive behavior', 'Phenotype', 'HP:0000718', (137, 165))	('survival', 'CPA', (176, 184))
912475	26754874	In M-type tumors, somatic mutations that either activate oncogenes or inactivate tumor suppressor genes are the predominant genetic alterations.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('M-type tumors', 'Disease', 'MESH:C566367', (3, 16))	('tumor', 'Disease', (10, 15))	('activate', 'PosReg', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutations', 'Var', (26, 35))	('oncogenes', 'Protein', (57, 66))	('M-type tumors', 'Disease', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('inactivate', 'NegReg', (70, 80))	('tumor', 'Disease', (81, 86))
912476	26754874	In contrast, in C-type tumors recurrent gene copy number variations (CNVs) are the predominant genetic alterations.	('C-type tumors', 'Disease', 'MESH:D019698', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('C-type tumors', 'Disease', (16, 29))	('gene copy number variations', 'Var', (40, 67))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
912477	26754874	Many of the key oncogenic driver mutations occurring in M-type tumors have been identified, molecularly characterized, functionally validated, and in some cases therapeutically targeted; prominent examples include EGFR, BRAF and PI3KCA mutations that are key drivers of oncogenic phenotypes.	('M-type tumors', 'Disease', (56, 69))	('M-type tumors', 'Disease', 'MESH:C566367', (56, 69))	('PI3', 'Gene', (229, 232))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('EGFR', 'Gene', '1956', (214, 218))	('BRAF', 'Gene', '673', (220, 224))	('mutations', 'Var', (236, 245))	('EGFR', 'Gene', (214, 218))	('BRAF', 'Gene', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PI3', 'Gene', '5266', (229, 232))
912478	26754874	Likewise, prevalent recurring inactivating mutations in tumor suppressor genes, including those in TP53, CDKN2A (p16), PTEN and APC, have been well-documented and molecularly characterized.	('TP53', 'Gene', (99, 103))	('p16', 'Gene', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CDKN2A', 'Gene', (105, 111))	('tumor', 'Disease', (56, 61))	('CDKN2A', 'Gene', '1029', (105, 111))	('p16', 'Gene', '1029', (113, 116))	('APC', 'Disease', 'MESH:D011125', (128, 131))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('TP53', 'Gene', '7157', (99, 103))	('APC', 'Disease', (128, 131))	('inactivating mutations', 'Var', (30, 52))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
912480	26754874	Comparative Genomic Hybridization (CGH) studies and more recent global genomic initiatives, such as The Cancer Genome Atlas (TCGA) project, have revealed that C-type tumors exhibit frequent and recurrent CNVs, both CNGs, or deletions, often encompassing large chromosomal regions (including, in some cases, entire chromosomal arms).	('C-type tumors', 'Disease', 'MESH:D019698', (159, 172))	('CNG', 'Chemical', '-', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('C-type tumors', 'Disease', (159, 172))	('CNGs', 'Disease', (215, 219))	('CNVs', 'Var', (204, 208))	('deletions', 'Var', (224, 233))	('Cancer', 'Disease', (104, 110))	('Cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))
912482	26754874	Recurrent CNVs involving loss of specific chromosomal regions are in some cases associated with loss of specific tumor suppressor genes; the most prevalent CNV in human tumors involves loss of chromosome 9p21 containing the prominent tumor suppressor target CDKN2A (reviewed in).	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (234, 239))	('loss', 'Var', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('human', 'Species', '9606', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (169, 174))	('CDKN2A', 'Gene', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (169, 175))	('CDKN2A', 'Gene', '1029', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
912483	26754874	However, for many recurrent CNVs involving chromosome loss, the relevant tumor suppressor(s) remain to be conclusively identified and functionally validated.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('chromosome loss', 'Var', (43, 58))
912486	26754874	Examples of CNGs driving oncogene activation through increased expression include amplification of CMYC at chromosome 8q24, cyclin D1 (CCND1) at chromosome 11q23, and EGFR at chromosome 7p11.	('cyclin D1', 'Gene', '595', (124, 133))	('CNG', 'Chemical', '-', (12, 15))	('CCND1', 'Gene', (135, 140))	('cyclin D1', 'Gene', (124, 133))	('CMYC', 'Gene', '4609', (99, 103))	('amplification', 'Var', (82, 95))	('CMYC', 'Gene', (99, 103))	('expression', 'MPA', (63, 73))	('CCND1', 'Gene', '595', (135, 140))	('increased', 'PosReg', (53, 62))	('activation', 'PosReg', (34, 44))	('EGFR', 'Gene', '1956', (167, 171))	('oncogene', 'Gene', (25, 33))	('EGFR', 'Gene', (167, 171))
912487	26754874	However, unlike the situation involving specific oncogenic somatic mutations, in which a distinct mutation specifically defines the molecular target of the genetic alteration, the relevant target(s) of many recurrent cancer-associated CNGs are not readily apparent in the context of tumor biology.	('CNG', 'Chemical', '-', (235, 238))	('mutation', 'Var', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('tumor', 'Disease', (283, 288))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
912488	26754874	Herein, we describe the genomic, genetic and functional characterization of the most common CNG event in human tumors, 3q26 amplification.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('CNG', 'Chemical', '-', (92, 95))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('3q26 amplification', 'Var', (119, 137))	('human', 'Species', '9606', (105, 110))
912492	26754874	A GISTIC score of +1 or +2 was considered to indicate the presence of significant CNG in that gene.	('TIC', 'Disease', (5, 8))	('TIC', 'Disease', 'None', (5, 8))	('CNG', 'Chemical', '-', (82, 85))	('CNG', 'Var', (82, 85))	('TIC', 'Phenotype', 'HP:0100033', (5, 8))
912499	26754874	Tumors were segregated into two groups; those exhibiting CNG at the locus for the gene being interrogated and those exhibiting no CNG at that locus.	('CNG', 'Chemical', '-', (57, 60))	('CNG', 'Var', (57, 60))	('CNG', 'Chemical', '-', (130, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
912501	26754874	35 of the 50 genes were found to exhibit expression that was significantly higher in tumors harboring CNG at that gene than in those not exhibiting CNG.	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('expression', 'MPA', (41, 51))	('higher', 'PosReg', (75, 81))	('CNG', 'Chemical', '-', (102, 105))	('CNG', 'Var', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('CNG', 'Chemical', '-', (148, 151))	('tumors', 'Disease', (85, 91))
912505	26754874	Independent CGH analyses revealed prevalent 3q26 CNVs in cervical (77-90%), esophageal (50-69%), HNSCC (50-91%), LSCC (77-85%), ovarian serous (36-51%) and endometrial serous cancers (50%).	('cervical', 'Disease', (57, 65))	('3q26', 'Gene', (44, 48))	('SCC', 'Gene', '6317', (99, 102))	('endometrial serous cancers', 'Disease', (156, 182))	('SCC', 'Gene', (114, 117))	('esophageal', 'Disease', (76, 86))	('endometrial serous cancers', 'Disease', 'MESH:D016889', (156, 182))	('SCC', 'Gene', '6317', (114, 117))	('ovarian serous', 'Disease', 'MESH:D010051', (128, 142))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('ovarian serous', 'Disease', (128, 142))	('SCC', 'Gene', (99, 102))	('CNVs', 'Var', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
912506	26754874	3q26 CNGs were also observed in 76% of small cell lung cancers (SCLC), though the estimate of prevalence in SCLC must be considered tentative given the extremely small sample size of these studies.	('small cell lung cancers', 'Phenotype', 'HP:0030357', (39, 62))	('3q26', 'Var', (0, 4))	('small cell lung cancers', 'Disease', (39, 62))	('lung cancers', 'Phenotype', 'HP:0100526', (50, 62))	('CNG', 'Chemical', '-', (5, 8))	('SCLC', 'Disease', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('SCLC', 'Disease', 'MESH:D018288', (64, 68))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (39, 61))	('small cell lung cancers', 'Disease', 'MESH:D055752', (39, 62))	('observed', 'Reg', (20, 28))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('SCLC', 'Disease', (108, 112))	('SCLC', 'Disease', 'MESH:D018288', (108, 112))
912510	26754874	Analysis revealed extremely prevalent chromosome 3q26 CNGs in LSCC (85%), esophageal (85%), ovarian serous (85%), cervical (78%), HNSCC (75%) and bladder (60%) cancers.	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('CNG', 'Chemical', '-', (54, 57))	('bladder', 'Disease', (146, 153))	('chromosome', 'Var', (38, 48))	('SCC', 'Gene', (63, 66))	('cancers', 'Disease', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('SCC', 'Gene', (132, 135))	('cervical', 'Disease', (114, 122))	('CNGs', 'Var', (54, 58))	('SCC', 'Gene', '6317', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ovarian serous', 'Disease', (92, 106))	('prevalent', 'Reg', (28, 37))	('ovarian serous', 'Disease', 'MESH:D010051', (92, 106))	('SCC', 'Gene', '6317', (132, 135))	('esophageal', 'Disease', (74, 84))
912511	26754874	3q26 CNGs were of intermediate prevalence (20-35%) in stomach, lung adenocarcinoma, breast, uterine and liver cancers, and of lower, but significant, prevalence (10-18%) in prostate, pancreatic, sarcoma, glioblastoma, kidney and colorectal cancers (Figure 1).	('glioblastoma', 'Disease', 'MESH:D005909', (204, 216))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (63, 82))	('CNG', 'Chemical', '-', (5, 8))	('breast', 'Disease', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (63, 82))	('glioblastoma', 'Disease', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('kidney and colorectal cancers', 'Disease', 'MESH:D015179', (218, 247))	('uterine', 'Disease', (92, 99))	('liver cancers', 'Disease', 'MESH:D006528', (104, 117))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('pancreatic', 'Disease', 'MESH:D010195', (183, 193))	('sarcoma', 'Disease', (195, 202))	('3q26', 'Var', (0, 4))	('prostate', 'Disease', (173, 181))	('liver cancers', 'Phenotype', 'HP:0002896', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung adenocarcinoma', 'Disease', (63, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('pancreatic', 'Disease', (183, 193))	('stomach', 'Disease', (54, 61))	('liver cancers', 'Disease', (104, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
912512	26754874	Our analysis confirms earlier CGH studies demonstrating very high frequency 3q26 CNGs in many tumors types (i.e.	('CNG', 'Chemical', '-', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('3q26 CNGs', 'Var', (76, 85))
912516	26754874	Several lines of experimental evidence indicate that 3q26 CNG is an oncogenic driver in affected tumors.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CNG', 'Chemical', '-', (58, 61))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('3q26 CNG', 'Var', (53, 61))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
912517	26754874	First, 3q26 CNGs are observed in precancerous lesions, demonstrating that this is an early event in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('precancerous lesions', 'Disease', 'MESH:D011230', (33, 53))	('precancerous lesions', 'Disease', (33, 53))	('3q26 CNGs', 'Var', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('CNG', 'Chemical', '-', (12, 15))
912519	26754874	Both the CIS and the subsequent LSCC lesion harbored specific 3q26 CNG, indicating occurrence of this event prior to progression to malignant LSCC.	('SCC', 'Gene', (143, 146))	('SCC', 'Gene', '6317', (33, 36))	('3q26 CNG', 'Var', (62, 70))	('SCC', 'Gene', '6317', (143, 146))	('SCC', 'Gene', (33, 36))	('CNG', 'Chemical', '-', (67, 70))
912520	26754874	Similarly, 3q26 CNGs were found to be present in both early stage pre-invasive lung squamous cell lesions and in invasive LSCCs, albeit at a higher frequency in the more advanced lesions.	('CNG', 'Chemical', '-', (16, 19))	('lung squamous cell lesions', 'Disease', (79, 105))	('3q26', 'Var', (11, 15))	('SCC', 'Gene', '6317', (123, 126))	('squamous cell lesions', 'Phenotype', 'HP:0002860', (84, 105))	('lung squamous cell lesions', 'Disease', 'MESH:D002294', (79, 105))	('SCC', 'Gene', (123, 126))
912522	26754874	Since 3q26 CNGs are detected in pre-invasive lesions that progress to LSCC, 3q26 CNG, and/or increased expression of 3q26 target genes, has been proposed as a biomarker of early pre-cancerous lesions with a high potential for progression to invasive LSCC.	('cancerous lesions', 'Disease', 'MESH:D009062', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CNG', 'Chemical', '-', (81, 84))	('cancerous lesions', 'Disease', (182, 199))	('SCC', 'Gene', '6317', (251, 254))	('increased', 'PosReg', (93, 102))	('expression', 'MPA', (103, 113))	('3q26 CNG', 'Var', (76, 84))	('CNG', 'Chemical', '-', (11, 14))	('SCC', 'Gene', '6317', (71, 74))	('SCC', 'Gene', (71, 74))	('SCC', 'Gene', (251, 254))
912523	26754874	Similar findings of 3q26 CNGs in early malignant or preneoplastic lesions have been observed in cervical cancer and HNSCC.	('preneoplastic lesions', 'CPA', (52, 73))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (55, 73))	('SCC', 'Gene', (118, 121))	('CNG', 'Chemical', '-', (25, 28))	('3q26 CNGs', 'Var', (20, 29))	('cervical cancer', 'Disease', 'MESH:D002583', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('SCC', 'Gene', '6317', (118, 121))	('cervical cancer', 'Disease', (96, 111))
912524	26754874	CGH analysis of normal cervical epithelium, dysplasias (subcategorized as mild, moderate and severe), and stage I invasive carcinomas, revealed that 3q26 CNGs are the most consistent chromosomal aberration occurring in dysplastic cells that progress to invasive cervical carcinoma.	('3q26 CNGs', 'Var', (149, 158))	('dysplastic', 'Disease', 'MESH:D004416', (219, 229))	('carcinomas', 'Disease', (123, 133))	('CNG', 'Chemical', '-', (154, 157))	('dysplastic', 'Disease', (219, 229))	('invasive cervical carcinoma', 'Disease', 'MESH:D002575', (253, 280))	('invasive cervical carcinoma', 'Disease', (253, 280))	('dysplasias', 'Disease', (44, 54))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (183, 205))	('progress', 'PosReg', (241, 249))	('dysplasias', 'Disease', 'MESH:D004476', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('carcinomas', 'Disease', 'MESH:D002277', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
912525	26754874	Likewise, a study of HNSCC found 3q26 CNGs in 3% of normal mucosa, 25% of premalignant tissue, and 56% of invasive HNSCCs, while a second report found frequent 3q CNGs in low grade HNSCCs.	('3q26 CNGs', 'Var', (33, 42))	('SCC', 'Gene', '6317', (23, 26))	('SCC', 'Gene', (117, 120))	('SCC', 'Gene', (183, 186))	('invasive HNSCCs', 'Disease', 'MESH:D000077195', (106, 121))	('SCC', 'Gene', '6317', (183, 186))	('CNG', 'Chemical', '-', (38, 41))	('SCC', 'Gene', '6317', (117, 120))	('SCC', 'Gene', (23, 26))	('CNG', 'Chemical', '-', (163, 166))	('invasive HNSCCs', 'Disease', (106, 121))
912528	26754874	In primary HNSCC tumors, 3q26 CNG is associated with significantly higher rates of tumor recurrence and cancer-related death, and with shorter disease-specific survival when compared to tumors not harboring 3q26 CNG.	('tumor', 'Disease', (83, 88))	('tumors', 'Disease', (17, 23))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Disease', (104, 110))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (11, 23))	('3q26 CNG', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('HNSCC tumors', 'Disease', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (17, 22))	('higher', 'PosReg', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', (186, 192))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('disease-specific survival', 'CPA', (143, 168))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('CNG', 'Chemical', '-', (30, 33))	('CNG', 'Chemical', '-', (212, 215))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('shorter', 'NegReg', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
912529	26754874	Consistent with this observation, 3q26 CNG is more frequently observed in high grade ovarian serous tumors when compared to low grade tumors, suggesting an association with disease progression and acquisition of an aggressive phenotype in ovarian cancer.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('ovarian serous tumors', 'Disease', 'MESH:D010051', (85, 106))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('3q26 CNG', 'Var', (34, 42))	('tumors', 'Disease', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('association', 'Interaction', (156, 167))	('observed', 'Reg', (62, 70))	('ovarian serous tumors', 'Disease', (85, 106))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('ovarian cancer', 'Disease', 'MESH:D010051', (239, 253))	('ovarian serous tumors', 'Phenotype', 'HP:0012887', (85, 106))	('tumors', 'Disease', (100, 106))	('CNG', 'Chemical', '-', (39, 42))	('ovarian cancer', 'Disease', (239, 253))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('ovarian cancer', 'Phenotype', 'HP:0100615', (239, 253))
912530	26754874	Similarly, 3q26 CNGs were found at significantly higher frequencies in metastatic esophageal squamous cell carcinomas when compared to those tumors that did not metastasize.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal squamous cell carcinomas', 'Disease', (82, 117))	('CNG', 'Chemical', '-', (16, 19))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (82, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('higher frequencies', 'PosReg', (49, 67))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (93, 117))	('3q26 CNGs', 'Var', (11, 20))
912531	26754874	These findings support a role for 3q26 CNG in tumor aggressiveness, progression and/or clinical outcome in essentially all of the major tumor types that frequently harbor this alteration.	('3q26 CNG', 'Var', (34, 42))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (46, 66))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CNG', 'Chemical', '-', (39, 42))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor aggressiveness', 'Disease', (46, 66))	('aggressiveness', 'Phenotype', 'HP:0000718', (52, 66))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
912532	26754874	The third line of evidence that 3q26 CNG is an oncogenic driver comes from a genetic analysis of strain-specific differences in susceptibility to tobacco smoke carcinogen-induced LSCC in the mouse.	('CNG', 'Chemical', '-', (37, 40))	('SCC', 'Gene', (180, 183))	('3q26', 'Var', (32, 36))	('mouse', 'Species', '10090', (191, 196))	('SCC', 'Gene', '6317', (180, 183))	('tobacco', 'Species', '4097', (146, 153))
912544	26754874	We further reasoned that the most critical target genes within this group would exhibit expression that is driven by 3q26 CNG in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('3q26 CNG', 'Var', (117, 125))	('CNG', 'Chemical', '-', (122, 125))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('human', 'Species', '9606', (129, 134))	('expression', 'MPA', (88, 98))
912550	26754874	The genomic analysis above indicates that 3q26 CNG drives tumorigenesis by coordinately overexpressing a set of core genes that functionally interact within a signaling network.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('3q26 CNG', 'Var', (42, 50))	('CNG', 'Chemical', '-', (47, 50))	('overexpressing', 'PosReg', (88, 102))	('drives', 'PosReg', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
912558	26754874	Likewise, ectopic expression of SOX2 in HNSCC cells promotes "stemness" while SOX2 knockdown (KD) in HNSCC TICs reduces self-renewal, chemoresistance and tumorigenicity, demonstrating a functional role for SOX2 in 3q26 amplified cancers.	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('knockdown', 'Var', (83, 92))	('tumor', 'Disease', (154, 159))	('TIC', 'Disease', (107, 110))	('SOX2', 'Gene', '6657', (32, 36))	('SOX2', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('promotes', 'PosReg', (52, 60))	('SCC', 'Gene', '6317', (42, 45))	('KD', 'Disease', 'MESH:C537017', (94, 96))	('TICs', 'Phenotype', 'HP:0100033', (107, 111))	('ectopic expression', 'Var', (10, 28))	('reduces', 'NegReg', (112, 119))	('SOX2', 'Gene', (206, 210))	('SOX2', 'Gene', '6657', (206, 210))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('SCC', 'Gene', (42, 45))	('cancers', 'Disease', (229, 236))	('TIC', 'Phenotype', 'HP:0100033', (107, 110))	('SOX2', 'Gene', '6657', (78, 82))	('SCC', 'Gene', '6317', (103, 106))	('SOX2', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('self-renewal', 'CPA', (120, 132))	('SCC', 'Gene', (103, 106))	('chemoresistance', 'CPA', (134, 149))	('TIC', 'Disease', 'None', (107, 110))
912561	26754874	Gene amplification drives SOX2 expression in lung, esophageal and other squamous cell cancers.	('lung', 'Disease', (45, 49))	('squamous cell cancers', 'Disease', (72, 93))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('drives', 'Reg', (19, 25))	('esophageal', 'Disease', (51, 61))	('Gene amplification', 'Var', (0, 18))	('expression', 'MPA', (31, 41))	('squamous cell cancers', 'Disease', 'MESH:D002294', (72, 93))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('SOX2', 'Gene', '6657', (26, 30))	('SOX2', 'Gene', (26, 30))
912562	26754874	ShRNA-mediated knockdown of SOX2 expression and candidate neighboring genes in 3q26 amplified and non-amplified cancer cell lines revealed that inhibition of SOX2 expression had the largest differential anti-proliferative effect on 3q26 amplified SCC cell lines.	('SOX2', 'Gene', '6657', (28, 32))	('SCC', 'Gene', (247, 250))	('SOX2', 'Gene', (28, 32))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('inhibition', 'Var', (144, 154))	('SCC', 'Gene', '6317', (247, 250))	('anti-proliferative effect', 'CPA', (203, 228))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SOX2', 'Gene', (158, 162))	('SOX2', 'Gene', '6657', (158, 162))
912577	26754874	These findings are consistent with the prevalence of chromosome 3q26 CNGs in LSCCs and the relatively rare occurrence of 3q26 CNGs in LADCs.	('SCC', 'Gene', '6317', (78, 81))	('chromosome 3q26 CNGs', 'Var', (53, 73))	('CNG', 'Chemical', '-', (126, 129))	('CNG', 'Chemical', '-', (69, 72))	('SCC', 'Gene', (78, 81))
912579	26754874	In addition to LSCC, ovarian tumors also show tumor-specific amplification at 3q26.	('ovarian tumors', 'Disease', 'MESH:D010051', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (46, 51))	('SCC', 'Gene', (16, 19))	('amplification', 'Var', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('SCC', 'Gene', '6317', (16, 19))	('ovarian tumors', 'Disease', (21, 35))	('ovarian tumors', 'Phenotype', 'HP:0100615', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
912580	26754874	Ect2 is overexpressed in ovarian tumors harboring ECT2 amplification compared to whole normal ovary indicating that tumor-specific ECT2 amplification also drives Ect2 expression in ovarian tumors.	('amplification', 'Var', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('ECT2', 'Gene', (131, 135))	('ovarian tumors', 'Phenotype', 'HP:0100615', (181, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('expression', 'MPA', (167, 177))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (33, 38))	('ovarian tumors', 'Disease', (25, 39))	('ovarian tumors', 'Disease', 'MESH:D010051', (25, 39))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Ect2', 'Gene', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('ovarian tumors', 'Disease', (181, 195))	('ovarian tumors', 'Disease', 'MESH:D010051', (181, 195))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (116, 121))	('ovarian tumors', 'Phenotype', 'HP:0100615', (25, 39))
912581	26754874	Thus, a major mechanism driving Ect2 expression is tumor-specific amplification of ECT2 as part of the 3q26 amplicon.	('amplification', 'Var', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('Ect2', 'Gene', (32, 36))	('ECT2', 'Gene', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
912584	26754874	PIK3CA is frequently targeted for oncogenic activation either by somatic mutation or CNG as part of the 3q26 amplicon.	('CNG', 'Chemical', '-', (85, 88))	('PIK3CA', 'Gene', '5290', (0, 6))	('CNG', 'Var', (85, 88))	('PIK3CA', 'Gene', (0, 6))
912585	26754874	PIK3CA is frequently mutated in breast, endometrial, colorectal, urinary tract and ovarian cancers (reviewed in).	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('urinary tract and ovarian cancers', 'Disease', 'MESH:D014571', (65, 98))	('colorectal', 'Disease', (53, 63))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('endometrial', 'Disease', (40, 51))	('PIK3CA', 'Gene', (0, 6))	('ovarian cancers', 'Phenotype', 'HP:0100615', (83, 98))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast', 'Disease', (32, 38))	('mutated', 'Var', (21, 28))	('colorectal', 'Disease', 'MESH:D015179', (53, 63))
912586	26754874	These "hot spot" mutations, H1047R, E545K and E542K, are non-synonymous missense mutations that confer constitutive kinase activity.	('E545K', 'Var', (36, 41))	('E542K', 'Var', (46, 51))	('H1047R', 'Mutation', 'rs121913279', (28, 34))	('constitutive kinase activity', 'MPA', (103, 131))	('E542K', 'Mutation', 'rs121913273', (46, 51))	('H1047R', 'Var', (28, 34))	('E545K', 'Mutation', 'rs104886003', (36, 41))
912587	26754874	Amplification of PIK3CA has been found in primary ovarian tumors and ovarian cancer cell lines, primary cervical tumors and cervical cancer cell lines, HNSCC primary tumors and LSCC.	('SCC', 'Gene', '6317', (154, 157))	('primary ovarian tumors', 'Disease', (42, 64))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('SCC', 'Gene', '6317', (178, 181))	('PIK3CA', 'Gene', '5290', (17, 23))	('primary ovarian tumors', 'Disease', 'MESH:D010051', (42, 64))	('SCC', 'Gene', (154, 157))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('primary cervical tumors', 'Disease', 'MESH:D002583', (96, 119))	('HNSCC primary tumors', 'Disease', (152, 172))	('SCC', 'Gene', (178, 181))	('ovarian cancer', 'Disease', (69, 83))	('found', 'Reg', (33, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('cervical cancer', 'Disease', (124, 139))	('cervical cancer', 'Disease', 'MESH:D002583', (124, 139))	('HNSCC primary tumors', 'Disease', 'MESH:D000077195', (152, 172))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('PIK3CA', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cervical tumors', 'Phenotype', 'HP:0030159', (104, 119))	('Amplification', 'Var', (0, 13))	('primary cervical tumors', 'Disease', (96, 119))	('ovarian tumors', 'Phenotype', 'HP:0100615', (50, 64))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))
912590	26754874	CNGs in PIK3CA have been shown to correlate with its mRNA expression in HNSCC cell primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('CNGs', 'Var', (0, 4))	('primary tumors', 'Disease', (83, 97))	('primary tumors', 'Disease', 'MESH:D009369', (83, 97))	('CNG', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('SCC', 'Gene', (74, 77))	('PIK3CA', 'Gene', (8, 14))	('mRNA expression', 'MPA', (53, 68))	('SCC', 'Gene', '6317', (74, 77))	('PIK3CA', 'Gene', '5290', (8, 14))
912591	26754874	CNGs in PIK3CA are prevalent in thyroid cancer, particularly follicular thyroid carcinoma (FTC) and anaplastic thyroid carcinoma (ATC) sub-types which exhibit 24% and 42% CNG, respectively.	('CNGs', 'Var', (0, 4))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (72, 89))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (111, 128))	('CNG', 'Chemical', '-', (171, 174))	('thyroid cancer', 'Phenotype', 'HP:0002890', (32, 46))	('follicular thyroid carcinoma', 'Disease', (61, 89))	('PIK3CA', 'Gene', '5290', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (100, 128))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (100, 128))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('thyroid cancer', 'Disease', (32, 46))	('CNG', 'Chemical', '-', (0, 3))	('PIK3CA', 'Gene', (8, 14))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (61, 89))	('prevalent', 'Reg', (19, 28))	('follicular thyroid carcinoma', 'Disease', 'MESH:D018263', (61, 89))	('thyroid cancer', 'Disease', 'MESH:D013964', (32, 46))	('anaplastic thyroid carcinoma', 'Disease', (100, 128))
912592	26754874	Several studies have shown that PIK3CA amplification is associated with overexpression of p110alpha in thyroid tumors.	('PIK3CA', 'Gene', '5290', (32, 38))	('p110alpha', 'Gene', (90, 99))	('p110alpha', 'Gene', '5290', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('amplification', 'Var', (39, 52))	('thyroid tumors', 'Disease', (103, 117))	('thyroid tumors', 'Disease', 'MESH:D013959', (103, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (56, 66))	('overexpression', 'MPA', (72, 86))	('PIK3CA', 'Gene', (32, 38))
912593	26754874	Endometrial tumors with 3q amplification overexpress PIK3CA when compared with unamplified tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Endometrial tumors', 'Disease', 'MESH:D016889', (0, 18))	('PIK3CA', 'Gene', '5290', (53, 59))	('3q amplification', 'Var', (24, 40))	('overexpress', 'PosReg', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('PIK3CA', 'Gene', (53, 59))	('Endometrial tumors', 'Disease', (0, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
912594	26754874	In a separate study, 9 of 15 (60.0%) gastric cancer cell lines and 17 of 55 (30.9%) primary gastric carcinomas harbored PIK3CA amplification, whereas no normal and benign tumor tissues showed abnormal amplification.	('PIK3CA', 'Gene', (120, 126))	('gastric carcinomas', 'Disease', 'MESH:D013274', (92, 110))	('gastric carcinomas', 'Disease', (92, 110))	('gastric cancer', 'Disease', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('PIK3CA', 'Gene', '5290', (120, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('amplification', 'Var', (127, 140))
912595	26754874	In addition, amplification of PIK3CA in gastric tumor cell lines was strongly associated with increased transcript level.	('PIK3CA', 'Gene', (30, 36))	('transcript level', 'MPA', (104, 120))	('increased', 'PosReg', (94, 103))	('PIK3CA', 'Gene', '5290', (30, 36))	('gastric tumor', 'Disease', (40, 53))	('amplification', 'Var', (13, 26))	('gastric tumor', 'Disease', 'MESH:D013274', (40, 53))	('gastric tumor', 'Phenotype', 'HP:0006753', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
912601	26754874	PKCiota expression is predictive of poor outcome in patients with bile duct, lung, ovarian, pancreatic and prostate cancers.	('PKCiota expression', 'Var', (0, 18))	('pancreatic', 'Disease', 'MESH:D010195', (92, 102))	('ovarian', 'Disease', (83, 90))	('ovarian', 'Disease', 'MESH:D010051', (83, 90))	('pancreatic', 'Disease', (92, 102))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('bile duct', 'Disease', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('lung', 'Disease', (77, 81))	('prostate cancers', 'Phenotype', 'HP:0012125', (107, 123))	('patients', 'Species', '9606', (52, 60))
912606	26754874	PRKCI is frequently amplified in NSCLC, and amplification drives PKCiota expression in NSCLC primary tumors and established cell lines.	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('amplification', 'Var', (44, 57))	('PRKCI', 'Gene', (0, 5))	('expression', 'MPA', (73, 83))	('PRKCI', 'Gene', '5584', (0, 5))	('NSCLC', 'Disease', (33, 38))	('NSCLC primary tumors', 'Disease', (87, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('NSCLC primary tumors', 'Disease', 'MESH:D009369', (87, 107))	('PKCiota', 'Gene', (65, 72))
912607	26754874	Disruption of PKCiota signaling blocks transformed growth of NSCLC cell lines with PRKCI amplification, demonstrating that PKCiota is a critical target of 3q26 amplification in NSCLC.	('NSCLC', 'Disease', (177, 182))	('NSCLC', 'Disease', (61, 66))	('amplification', 'Var', (89, 102))	('PRKCI', 'Gene', '5584', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('PRKCI', 'Gene', (83, 88))	('Disruption', 'Var', (0, 10))
912608	26754874	PRKCI amplification is associated with lymph node metastases in ESCC, and PKCiota promotes metastasis of ESCC cell lines.	('promotes', 'PosReg', (82, 90))	('SCC', 'Gene', (65, 68))	('SCC', 'Gene', '6317', (106, 109))	('metastases', 'Disease', (50, 60))	('PRKCI', 'Gene', (0, 5))	('metastasis', 'CPA', (91, 101))	('SCC', 'Gene', '6317', (65, 68))	('PRKCI', 'Gene', '5584', (0, 5))	('amplification', 'Var', (6, 19))	('metastases', 'Disease', 'MESH:D009362', (50, 60))	('associated', 'Reg', (23, 33))	('SCC', 'Gene', (106, 109))
912610	26754874	PRKCI is frequently amplified and overexpressed in ovarian serous cancer and PRKCI amplification predicts poor patient survival.	('ovarian serous cancer', 'Disease', 'MESH:D010051', (51, 72))	('PRKCI', 'Gene', '5584', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('poor', 'NegReg', (106, 110))	('ovarian serous cancer', 'Disease', (51, 72))	('PRKCI', 'Gene', (77, 82))	('PRKCI', 'Gene', (0, 5))	('PRKCI', 'Gene', '5584', (0, 5))	('patient', 'Species', '9606', (111, 118))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (51, 72))	('amplification', 'Var', (83, 96))	('overexpressed', 'PosReg', (34, 47))
912613	26754874	As described above, each of the four 3q26 nodal genes, SOX2, ECT2, PIK3CA and PRKCI, have individually been shown to function in the establishment and maintenance of the transformed phenotype of 3q26 driven tumors.	('PIK3CA', 'Gene', '5290', (67, 73))	('SOX2', 'Gene', (55, 59))	('ECT2', 'Gene', (61, 65))	('SOX2', 'Gene', '6657', (55, 59))	('PRKCI', 'Gene', '5584', (78, 83))	('function', 'Reg', (117, 125))	('PIK3CA', 'Gene', (67, 73))	('PRKCI', 'Gene', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('3q26', 'Var', (195, 199))
912614	26754874	It is also quite evident that these genes operate in a tumor environment in which they are coordinately amplified and overexpressed in tumors harboring 3q26 CNGs, demonstrating that these genes are genetically integrated with the oncogenic behavior of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CNG', 'Chemical', '-', (157, 160))	('tumor', 'Disease', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Disease', (55, 60))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('3q26 CNGs', 'Var', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
912618	26754874	SKIL/SNO, which resides at 3q26, was found to be consistently over-expressed in ESCC cell lines and primary tumors that exhibit 3q26 amplification, suggesting that this gene is a potential target of 3q26 amplification.	('SCC', 'Gene', '6317', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('SNO', 'Gene', (5, 8))	('over-expressed', 'PosReg', (62, 76))	('primary tumors', 'Disease', (100, 114))	('amplification', 'Var', (133, 146))	('SKIL', 'Gene', (0, 4))	('primary tumors', 'Disease', 'MESH:D009369', (100, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('3q26', 'Gene', (128, 132))	('SCC', 'Gene', (81, 84))	('SKIL', 'Gene', '6498', (0, 4))	('SNO', 'Gene', '22904', (5, 8))
912624	26754874	Like PKCiota and Par6, RNAi-mediated knockdown of Ect2 in NSCLC cells inhibits Rac1 activation and transformation.	('NSCLC', 'Disease', (58, 63))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('knockdown', 'Var', (37, 46))	('inhibits', 'NegReg', (70, 78))	('Par6', 'Gene', (17, 21))	('Rac1', 'Gene', '5879', (79, 83))	('Ect2', 'Gene', (50, 54))	('Par6', 'Gene', '50855', (17, 21))	('Rac1', 'Gene', (79, 83))
912636	26754874	This study led us to hypothesize that the oncogenic function of PKCiota is to establish and maintain a TIC phenotype in LSCC tumors harboring 3q26 CNG as well.	('TIC', 'Disease', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('3q26 CNG', 'Var', (142, 150))	('SCC', 'Gene', (121, 124))	('tumors', 'Disease', (125, 131))	('CNG', 'Chemical', '-', (147, 150))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('TIC', 'Phenotype', 'HP:0100033', (103, 106))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('SCC', 'Gene', '6317', (121, 124))	('TIC', 'Disease', 'None', (103, 106))
912645	26754874	The realization that 3q26 CNG drives oncogenesis through coordinated overexpression of biochemically and functionally linked genes presents both challenges and opportunities for therapeutic intervention.	('drives', 'PosReg', (30, 36))	('overexpression', 'PosReg', (69, 83))	('oncogenesis', 'CPA', (37, 48))	('3q26 CNG', 'Var', (21, 29))	('CNG', 'Chemical', '-', (26, 29))
912655	26754874	Our initial clinical experience with these agents has demonstrated proof of principle for PKCiota inhibition using ATM or ANF as a viable therapeutic approach in both LSCC and ovarian serous cancer, tumor types exhibiting frequent 3q26 CNGs.	('tumor', 'Disease', (199, 204))	('SCC', 'Gene', (168, 171))	('CNG', 'Chemical', '-', (236, 239))	('3q26 CNGs', 'Var', (231, 240))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (176, 197))	('ovarian serous cancer', 'Disease', 'MESH:D010051', (176, 197))	('SCC', 'Gene', '6317', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('ovarian serous cancer', 'Disease', (176, 197))	('ANF', 'Chemical', 'MESH:D001310', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('PKCiota', 'Enzyme', (90, 97))
912663	26754874	Further functional characterization of the 3q26 OncCassette holds considerable promise of revealing further opportunities for development of novel combined therapeutic intervention strategies that target unique vulnerabilities of 3q26 CNG driven tumors.	('3q26', 'Var', (230, 234))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('CNG', 'Chemical', '-', (235, 238))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumors', 'Disease', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (246, 252))
912664	21110870	Single nucleotide polymorphisms in the mitochondrial displacement loop and outcome of esophageal squamous cell carcinoma Accumulation of single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) has been described for different types of cancers and might be associated with cancer risk and disease outcome.	('single nucleotide polymorphisms', 'Var', (137, 168))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Disease', (318, 324))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (86, 120))	('associated', 'Reg', (302, 312))	('cancer', 'Disease', (281, 287))	('men', 'Species', '9606', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('esophageal squamous cell carcinoma', 'Disease', (86, 120))	('men', 'Species', '9606', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancers', 'Disease', (281, 288))
912665	21110870	We used a population-based series of esophageal squamous cell carcinoma (ESCC) patients for investigating the prediction power of SNPs in mitochondrial D-loop.	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('SNPs', 'Var', (130, 134))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (37, 71))	('patients', 'Species', '9606', (79, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('esophageal squamous cell carcinoma', 'Disease', (37, 71))
912667	21110870	The SNP sites of nucleotides 16274G/A, 16278C/T and 16399A/G were identified for prediction of post-operational survival by the log-rank test.	('16399A/G', 'Mutation', 'g.16399A>G', (52, 60))	('16278C/T', 'Var', (39, 47))	('nucleotides', 'Var', (17, 28))	('16274G/A', 'Mutation', 'g.16274G>A', (29, 37))	('16278C/T', 'Mutation', 'g.16278C>T', (39, 47))	('16399A/G', 'Var', (52, 60))
912670	21110870	Genetic polymorphisms in the D-loop are independent prognostic markers for patients with ESCC.	('ESCC', 'Disease', (89, 93))	('patients', 'Species', '9606', (75, 83))	('D-loop', 'Gene', (29, 35))	('Genetic polymorphisms', 'Var', (0, 21))
912674	21110870	The performance status, the TNM stage, and lymph node metastases seem to be the predictive factors of esophageal cancer; some molecular factors, such as p53 mutaion and NF-kappaB expression level, also show predictive power for esophageal cancer outcome.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('NF-kappaB', 'Gene', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('TNM', 'Gene', '10178', (28, 31))	('NF-kappaB', 'Gene', '4790', (169, 178))	('metastases', 'Disease', (54, 64))	('p53', 'Gene', (153, 156))	('esophageal cancer', 'Disease', (228, 245))	('predictive power', 'Reg', (207, 223))	('metastases', 'Disease', 'MESH:D009362', (54, 64))	('TNM', 'Gene', (28, 31))	('esophageal cancer', 'Disease', (102, 119))	('p53', 'Gene', '7157', (153, 156))	('mutaion', 'Var', (157, 164))	('expression level', 'MPA', (179, 195))	('esophageal cancer', 'Disease', 'MESH:D004938', (228, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
912676	21110870	mtDNA is believed to be more susceptible to DNA damage and acquires mutations at a higher rate than nuclear DNA, because of the high levels of reactive oxygen species (ROS), the lack of protective histones, and limited capacity for DNA repair in the mitochondria.	('ROS', 'Chemical', 'MESH:D017382', (168, 171))	('levels of reactive oxygen species', 'MPA', (133, 166))	('lack', 'NegReg', (178, 182))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (143, 166))	('mutations', 'Var', (68, 77))	('protective histones', 'Protein', (186, 205))
912702	21110870	A dramatic difference in survival rate appeared at 16274, 16278 (refers to rs41458645 in NCBI SNP database, http://www.ncbi.nlm.nih.gov/snp/) and 16399 alleles by the log-rank test (Figure 1).	('16274', 'Var', (51, 56))	('survival', 'CPA', (25, 33))	('16278', 'Var', (58, 63))	('16399', 'Var', (146, 151))	('rs41458645', 'Mutation', 'rs41458645', (75, 85))	('rs41458645', 'Var', (75, 85))
912706	21110870	The same was seen for the rare allele 16399G genotype when compared with matched alleles 16399A at the 16399 site in ESCC patients (relative risk, 3.483; 95% CI, 1.068 - 11.359; p = 0.039) (Table 2).	('ESCC', 'Disease', (117, 121))	('patients', 'Species', '9606', (122, 130))	('16399G', 'Var', (38, 44))
912707	21110870	These data demonstrated the strong prediction power of 16278C/T and 16399A/G on outcome for ESCC patients.	('16278C/T', 'Mutation', 'g.16278C>T', (55, 63))	('ESCC', 'Disease', (92, 96))	('16399A/G', 'Var', (68, 76))	('16399A/G', 'Mutation', 'g.16399A>G', (68, 76))	('16278C/T', 'Var', (55, 63))	('patients', 'Species', '9606', (97, 105))
912709	21110870	The present study has extended those analyses to determine the cancer risk and the post-operational survival-associated germline SNPs in a continuous sequence of mtDNA between nucleotides 16190 and 583 in ESCC patients.	('germline SNPs', 'Disease', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('nucleotides 16190', 'Var', (176, 193))	('patients', 'Species', '9606', (210, 218))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('ESCC', 'Disease', (205, 209))	('cancer', 'Disease', (63, 69))
912710	21110870	Three SNPs, 16274G/A, 16278C/T and 16399A/G, were identified for their association with post-operational survival at statistically significant levels by the log-rank test.	('16274G/A', 'Mutation', 'g.16274G>A', (12, 20))	('post-operational survival', 'CPA', (88, 113))	('16278C/T', 'Var', (22, 30))	('16274G/A', 'Var', (12, 20))	('16278C/T', 'Mutation', 'g.16278C>T', (22, 30))	('16399A/G', 'Var', (35, 43))	('16399A/G', 'Mutation', 'g.16399A>G', (35, 43))
912711	21110870	Multivariate survival analysis identified 16278C/T and 16399A/G to be independent prediction markers for ESCC outcome.	('16278C/T', 'Mutation', 'g.16278C>T', (42, 50))	('ESCC', 'Disease', (105, 109))	('16399A/G', 'Var', (55, 63))	('16278C/T', 'Var', (42, 50))	('16399A/G', 'Mutation', 'g.16399A>G', (55, 63))
912712	21110870	We suggest for the first time that SNPs in the D-loop is a prognostic factor in ESCC patients.	('patients', 'Species', '9606', (85, 93))	('SNPs in', 'Var', (35, 42))	('ESCC', 'Disease', (80, 84))
912713	21110870	The relative risk (RR) of death in patients was significantly higher (16278C versus 16278T, RR, 3.001; 95% CI, 1.029 - 8.756; p = 0.044.	('death', 'Disease', 'MESH:D003643', (26, 31))	('16278T', 'Var', (84, 90))	('death', 'Disease', (26, 31))	('higher', 'PosReg', (62, 68))	('patients', 'Species', '9606', (35, 43))
912714	21110870	Nucleotides 16278 and 16399 are located in hypervariable segment 1 (HV1), which is associated with high rates of mutation, but the functional significance of these SNPs in HV1 is not known.	('men', 'Species', '9606', (60, 63))	('HV1', 'Gene', (68, 71))	('16399', 'Var', (22, 27))
912715	21110870	Minor alleles of 16278T and 16399G are associated with dramatically shorter period of postoperative survival; the survival curve decreased rapidly in patients carrying these alleles (Figure 1).	('16399G', 'Var', (28, 34))	('patients', 'Species', '9606', (150, 158))	('period', 'MPA', (76, 82))	('decreased', 'NegReg', (129, 138))	('shorter', 'NegReg', (68, 75))
912718	21110870	It is very interesting if a nucleotide substitution can render an individual susceptible to a tumour but subsequently modulates prognosis of that tumour.	('tumour', 'Disease', (94, 100))	('tumour', 'Disease', (146, 152))	('nucleotide substitution', 'Var', (28, 51))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('modulates', 'Reg', (118, 127))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('render', 'Reg', (56, 62))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('susceptible', 'MPA', (77, 88))
912719	21110870	SNPs in this region might affect mtDNA replication and lead to alteration of the electron transport chain, which is responsible for the release of highly reactive oxygen species (ROS) and could contribute to nuclear genome damage as well as cancer initiation and promotion.	('cancer initiation', 'Disease', (241, 258))	('nuclear genome damage', 'CPA', (208, 229))	('ROS', 'Chemical', 'MESH:D017382', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('release of highly reactive oxygen species', 'MPA', (136, 177))	('promotion', 'PosReg', (263, 272))	('electron transport chain', 'Pathway', (81, 105))	('affect', 'Reg', (26, 32))	('mtDNA replication', 'CPA', (33, 50))	('SNPs', 'Var', (0, 4))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (154, 177))	('cancer initiation', 'Disease', 'MESH:D009369', (241, 258))	('lead to alteration', 'Reg', (55, 73))	('contribute', 'Reg', (194, 204))
912789	18990747	Furthermore, the associations between tooth loss, DMFT, or oral hygiene and ESCC were stronger than the association between ever using tobacco and ESCC, OR (95% CI) = 1.47 (0.98 - 2.21).	('tobacco', 'Species', '4097', (135, 142))	('DMFT', 'Var', (50, 54))	('tooth loss', 'Disease', (38, 48))	('tooth loss', 'Disease', 'MESH:D016388', (38, 48))	('oral', 'Disease', (59, 63))	('ESCC', 'Disease', (76, 80))	('associations', 'Interaction', (17, 29))	('tooth loss', 'Phenotype', 'HP:0006480', (38, 48))	('DMFT', 'Chemical', '-', (50, 54))
912822	33969734	Retrospective and meta-analysis studies have revealed distinct benefits of MIE, namely improved clinical outcomes, such as shorter hospital stays, lower incidence of respiratory complications, and lower overall morbidity.	('respiratory complications', 'Disease', (166, 191))	('improved', 'PosReg', (87, 95))	('MIE', 'Var', (75, 78))	('respiratory complications', 'Phenotype', 'HP:0011947', (166, 191))	('respiratory complications', 'Disease', 'MESH:D012131', (166, 191))
912862	33969734	Although there were no statistically significant differences regarding pneumothorax, atelectasis, or respiratory failure between the two groups, FMIE was associated with fewer pulmonary infections (6.8% vs. 25%; P = 0.039).	('pulmonary infections', 'Disease', (176, 196))	('pneumothorax', 'Disease', 'MESH:D011030', (71, 83))	('pneumothorax', 'Disease', (71, 83))	('pulmonary infections', 'Phenotype', 'HP:0006532', (176, 196))	('fewer', 'NegReg', (170, 175))	('respiratory failure', 'Disease', (101, 120))	('respiratory failure', 'Disease', 'MESH:D012131', (101, 120))	('pneumothorax', 'Phenotype', 'HP:0002107', (71, 83))	('FMIE', 'Var', (145, 149))	('pulmonary infection', 'Phenotype', 'HP:0006532', (176, 195))	('respiratory failure', 'Phenotype', 'HP:0002878', (101, 120))	('atelectasis', 'Phenotype', 'HP:0100750', (85, 96))	('pulmonary infections', 'Disease', 'MESH:D012141', (176, 196))
912864	33969734	The operation time (230 vs. 268 minutes; P < 0.001) was significantly lower in the FMIE group vs the SMIE group.	('lower', 'NegReg', (70, 75))	('SMIE', 'Chemical', '-', (101, 105))	('FMIE', 'Var', (83, 87))
912868	33969734	A repeated-measures analysis of the Student's t-test also indicated that WBC and NEUT were statistically significantly higher in the SMIE group than in the FMIE group, according to different time-point comparisons.	('NEUT', 'CPA', (81, 85))	('WBC', 'CPA', (73, 76))	('SMIE', 'Chemical', '-', (133, 137))	('SMIE', 'Var', (133, 137))	('higher', 'PosReg', (119, 125))
912870	33969734	In addition, NEUT on POD 2 and POD 4 (P = 0.006 and P = 0.005, respectively) was significantly higher in the SMIE group.	('SMIE', 'Chemical', '-', (109, 113))	('NEUT on', 'CPA', (13, 20))	('higher', 'PosReg', (95, 101))	('SMIE', 'Var', (109, 113))
912886	33969734	In this study, we demonstrated that patients who underwent FMIE had less postoperative drainage volumes and lower inflammatory biomarker concentrations regarding WBC and NEUT levels, which is indicative of a reduced inflammatory response.	('patients', 'Species', '9606', (36, 44))	('inflammatory biomarker concentrations', 'MPA', (114, 151))	('FMIE', 'Var', (59, 63))	('drainage volumes', 'MPA', (87, 103))	('less', 'NegReg', (68, 72))	('lower inflammatory biomarker', 'Phenotype', 'HP:0012648', (108, 136))	('lower', 'NegReg', (108, 113))	('postoperative', 'MPA', (73, 86))	('reduced inflammatory response', 'Phenotype', 'HP:0012648', (208, 237))
913008	31251350	The results also showed that patients who were heavy drinkers (>7750) had a significantly poorer prognosis than their counterparts (HR 2.116, 95% CI = 1.078-4.156, P = 0.029).	('>7750', 'Var', (63, 68))	('patients', 'Species', '9606', (29, 37))	('poorer', 'NegReg', (90, 96))
913086	29142922	Furthermore, the incidence of malignancies in the first years after a diagnosis of vasculitis was not significantly increased among patients with GPA.	('vasculitis', 'Phenotype', 'HP:0002633', (83, 93))	('vasculitis', 'Disease', 'MESH:D014657', (83, 93))	('malignancies', 'Disease', (30, 42))	('vasculitis', 'Disease', (83, 93))	('GPA', 'Var', (146, 149))	('patients', 'Species', '9606', (132, 140))	('malignancies', 'Disease', 'MESH:D009369', (30, 42))
913118	28461757	Upon initiation of EMT, loss of E-cadherin could promote tumor progression by enhancing the capacity of cells to invade.	('enhancing', 'PosReg', (78, 87))	('loss', 'Var', (24, 28))	('E-cadherin', 'Gene', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('E-cadherin', 'Gene', '999', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('promote', 'PosReg', (49, 56))	('tumor', 'Disease', (57, 62))
913137	28461757	Cells cultured for 24 h with (Eca109/GM and 9706/GM) or without (Eca109 and 9706) rhGM-CSF were washed twice with PBS and then re-suspended in 1x working solution at 1x106 cells/mL.	('GM-CSF', 'Gene', '1437', (84, 90))	('GM', 'Chemical', '-', (49, 51))	('Eca109/GM', 'Var', (30, 39))	('Eca109', 'Var', (65, 71))	('GM-CSF', 'Gene', (84, 90))	('GM', 'Chemical', '-', (84, 86))	('GM', 'Chemical', '-', (37, 39))
913187	28461757	Urdinguio et al discovered that the 5-year survival rates were high in colon cancer patients overexpressing GM-CSF and their receptors.	('rat', 'Species', '10116', (52, 55))	('overexpressing', 'Var', (93, 107))	('patients', 'Species', '9606', (84, 92))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('colon cancer', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('GM-CSF', 'Gene', (108, 114))	('high', 'PosReg', (63, 67))	('GM-CSF', 'Gene', '1437', (108, 114))
913197	28461757	Significantly decreased cell migration was also observed in the Eca109/GM and 9706/GM groups compared to the untreated groups.	('cell migration', 'CPA', (24, 38))	('decreased', 'NegReg', (14, 23))	('rat', 'Species', '10116', (32, 35))	('GM', 'Chemical', '-', (83, 85))	('9706/GM', 'Var', (78, 85))	('Eca109/GM', 'Var', (64, 73))	('GM', 'Chemical', '-', (71, 73))
913202	28461757	Jiang et al demonstrated that the expression of GM-CSF was negatively correlated with COX-2 and iNOS levels in cervical cancer cells, and thus, tumor tissues expressing high levels of GM-CSF were likely to have lower levels of iNOS and COX-2.	('high', 'Var', (169, 173))	('iNOS', 'Gene', '4843', (96, 100))	('expression', 'MPA', (34, 44))	('GM-CSF', 'Gene', '1437', (48, 54))	('lower', 'NegReg', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cervical cancer', 'Disease', (111, 126))	('COX-2', 'Gene', (86, 91))	('cervical cancer', 'Disease', 'MESH:D002583', (111, 126))	('negatively', 'NegReg', (59, 69))	('COX-2', 'Gene', (236, 241))	('tumor', 'Disease', (144, 149))	('COX-2', 'Gene', '5743', (86, 91))	('iNOS', 'Gene', (227, 231))	('GM-CSF', 'Gene', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('COX-2', 'Gene', '5743', (236, 241))	('iNOS', 'Gene', (96, 100))	('iNOS', 'Gene', '4843', (227, 231))	('GM-CSF', 'Gene', (48, 54))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('GM-CSF', 'Gene', '1437', (184, 190))
913221	28461757	Liu et al showed that the arginine methyltransferase, PRMT5, originally identified as JAK-binding protein 1, could be phosphorylated and attenuated by oncogenic JAK2 mutant kinase.	('JAK2', 'Gene', '3717', (161, 165))	('PRMT5', 'Gene', (54, 59))	('JAK2', 'Gene', (161, 165))	('mutant', 'Var', (166, 172))	('JAK-binding protein 1', 'Gene', (86, 107))	('JAK-binding protein 1', 'Gene', '10419', (86, 107))	('PRMT5', 'Gene', '10419', (54, 59))	('attenuated', 'NegReg', (137, 147))
913262	27528228	Patients with elevated CRP (> 10.0 mg/L) and decreased albumin (< 45.6 g/L) levels were allocated a score of 2, those with only one of these two abnormalities were assigned a score of 1, and those with neither of the two abnormalities were classified as having a score of 0.	('> 10.0', 'Var', (28, 34))	('CRP', 'Gene', (23, 26))	('decreased', 'NegReg', (45, 54))	('albumin', 'Gene', (55, 62))	('albumin', 'Gene', '213', (55, 62))	('decreased albumin', 'Phenotype', 'HP:0003073', (45, 62))	('Patients', 'Species', '9606', (0, 8))	('CRP', 'Gene', '1401', (23, 26))	('elevated', 'PosReg', (14, 22))	('elevated CRP', 'Phenotype', 'HP:0011227', (14, 26))
913269	27528228	The results demonstrated that the mGPS was significantly correlated with tumor length, pT stage, pTNM stage and adjuvant treatment (Table 1).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('correlated', 'Reg', (57, 67))	('mGPS', 'Var', (34, 38))	('tumor', 'Disease', (73, 78))	('pT stage', 'Disease', (87, 95))	('pTNM stage', 'Disease', (97, 107))
913272	27528228	The S-mGPS was confirmed to be significantly associated with age, tumor length, pT stage, pTNM stage, alcohol consumption and adjuvant treatment (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('S-mGPS', 'Var', (4, 10))	('pTNM stage', 'Disease', (90, 100))	('associated', 'Reg', (45, 55))	('alcohol', 'Chemical', 'MESH:D000438', (102, 109))	('pT stage', 'Disease', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
913276	27528228	As for OS, patients with high preoperative mGPS (HR, 1.583; 95% CI, 1.165-2.151; P = 0.003; Figure 1B) and S-mGPS (HR, 1.875; 95% CI, 1.351-2.603; P < 0.001; Figure 1D) tended to have impaired OS by univariate analysis.	('mGPS', 'MPA', (43, 47))	('S-mGPS', 'Var', (107, 113))	('impaired OS', 'Disease', (184, 195))	('impaired OS', 'Disease', 'MESH:C567932', (184, 195))	('patients', 'Species', '9606', (11, 19))
913278	27528228	In addition, the 246 patients who migrated to the S-mGPS-1 group demonstrated significantly more poorer DFS and OS than those who remained in the S-mGPS-0 group (Figure 2).	('patients', 'Species', '9606', (21, 29))	('S-mGPS-1', 'Var', (50, 58))	('poorer', 'NegReg', (97, 103))
913317	27566562	Since their discovery in 1993, altered miRNA expression has been demonstrated to be associated with several diseases.	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('altered', 'Var', (31, 38))	('associated', 'Reg', (84, 94))	('diseases', 'Disease', (108, 116))
913347	27566562	The viability of KYSE170 cells transfected with the control mimics was markedly inhibited by 5-FU or cisplatin.	('viability', 'CPA', (4, 13))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('5-FU', 'Var', (93, 97))	('KYSE170', 'CellLine', 'CVCL:1358', (17, 24))	('5-FU', 'Chemical', 'MESH:D005472', (93, 97))	('cisplatin', 'Var', (101, 110))	('inhibited', 'NegReg', (80, 89))
913348	27566562	Concerning 5-FU, the inhibitory effect was significantly reduced in miR-23a-transfected ESCC cells; whereas for cisplatin, the inhibitory effect was significantly reduced in miR-223- and miR-23a-transfected ESCC cells.	('miR-223', 'Gene', (174, 181))	('miR-23a', 'Gene', (187, 194))	('miR-23a', 'Gene', '407010', (68, 75))	('5-FU', 'Var', (11, 15))	('reduced', 'NegReg', (163, 170))	('miR-223', 'Gene', '407008', (174, 181))	('miR-23a', 'Gene', (68, 75))	('5-FU', 'Chemical', 'MESH:D005472', (11, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('reduced', 'NegReg', (57, 64))	('miR-23a', 'Gene', '407010', (187, 194))	('inhibitory effect', 'MPA', (21, 38))
913384	27566562	Eight ESCC-associated miRNAs have been reported in ESCC tissues in response to chemotherapy: miR-27a, miR-200c, let-7, miR-483, miR-214, miR-113a/b, miR-24 and miR-634.	('miR', 'Gene', (102, 105))	('miR-200c', 'Gene', (102, 110))	('miR', 'Gene', (93, 96))	('ESCC-associated', 'Disease', (6, 21))	('miR-27a', 'Gene', (93, 100))	('miR', 'Gene', '220972', (137, 140))	('let-7', 'Var', (112, 117))	('miR-214', 'Gene', '406996', (128, 135))	('miR-634', 'Gene', (160, 167))	('miR', 'Gene', '220972', (128, 131))	('miR-483', 'Gene', (119, 126))	('miR', 'Gene', '220972', (160, 163))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (137, 140))	('miR-483', 'Gene', '619552', (119, 126))	('miR', 'Gene', '220972', (149, 152))	('miR', 'Gene', (128, 131))	('miR-634', 'Gene', '693219', (160, 167))	('miR', 'Gene', (160, 163))	('miR-214', 'Gene', (128, 135))	('miR', 'Gene', '220972', (22, 25))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (119, 122))	('miR-27a', 'Gene', '407018', (93, 100))	('miR', 'Gene', (149, 152))	('miR-200c', 'Gene', '406985', (102, 110))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (22, 25))
913454	27566562	To overexpress each miR, the mimic (Assay ID: MC12301 (miR-223), MC10711 (miR-23b), MC10632 (miR-103a) and MC10644 (miR-23a)) or control mimic miRNA (mirVana miRNA mimic Negative Control #1) selected from the mirVana miRNA mimic panel (Ambion, Austin, TX, USA) was transfected into cells (50 muM) using Lipofectamine RNAiMAX (Invitrogen) according to the manufacturer's instructions.	('miR-23b', 'Gene', (74, 81))	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (93, 96))	('miR', 'Gene', '220972', (74, 77))	('miR', 'Gene', (116, 119))	('miR-223', 'Gene', (55, 62))	('miR', 'Gene', (20, 23))	('miR', 'Gene', '220972', (217, 220))	('Lipofectamine', 'Chemical', 'MESH:C086724', (303, 316))	('miR', 'Gene', (74, 77))	('muM', 'Gene', '56925', (292, 295))	('miR', 'Gene', '220972', (158, 161))	('miR', 'Gene', '220972', (143, 146))	('muM', 'Gene', (292, 295))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (217, 220))	('MC10632', 'Var', (84, 91))	('miR-23b', 'Gene', '407011', (74, 81))	('miR-223', 'Gene', '407008', (55, 62))	('miR', 'Gene', (158, 161))	('MC10644', 'Var', (107, 114))	('miR', 'Gene', (143, 146))	('miR-23a', 'Gene', '407010', (116, 123))	('MC12301', 'Var', (46, 53))	('miR-23a', 'Gene', (116, 123))	('miR', 'Gene', (55, 58))	('miR', 'Gene', '220972', (93, 96))	('MC10711', 'Var', (65, 72))
913470	26756568	Kaplan-Meier survival analysis revealed that high expression of AFAP1-AS1 was significantly associated with shorter progression free survival (PFS) (median, 15 months vs. 27 months, P < 0.001) and overall survival (OS) (median, 29 months vs. 42 months, P < 0.001).	('progression free survival', 'CPA', (116, 141))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (64, 73))	('shorter', 'NegReg', (108, 115))	('overall survival', 'CPA', (197, 213))	('AFAP1-AS1', 'Gene', (64, 73))	('high expression', 'Var', (45, 60))	('OS', 'Chemical', '-', (215, 217))
913471	26756568	In the multivariate analysis, high expression of AFAP1-AS1 was found to be an independent risk factor to predict poor PFS (HR, 1.626; P = 0.027) and OS (HR, 1.888; P = 0.004).	('high expression', 'Var', (30, 45))	('OS', 'Chemical', '-', (149, 151))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (49, 58))	('AFAP1-AS1', 'Gene', (49, 58))
913484	26756568	Examples include lncRNA MALAT1 in prostate cancer, MVIH in hepatocellular carcinoma and FENDRR in gastric cancer, suggesting that lncRNAs could serve as a diagnostic and prognostic biomarkers for human malignancies 11, 12, 13.	('MALAT1', 'Gene', (24, 30))	('prostate cancer', 'Disease', (34, 49))	('MVIH in hepatocellular carcinoma', 'Disease', (51, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('MALAT1', 'Gene', '378938', (24, 30))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (59, 83))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lncRNA', 'Var', (17, 23))	('gastric cancer', 'Disease', (98, 112))	('FENDRR', 'Gene', '400550', (88, 94))	('FENDRR', 'Gene', (88, 94))	('malignancies', 'Disease', 'MESH:D009369', (202, 214))	('human', 'Species', '9606', (196, 201))	('MVIH in hepatocellular carcinoma', 'Disease', 'MESH:D006528', (51, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('malignancies', 'Disease', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (34, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (34, 49))
913505	26756568	The normal esophageal epithelial cell (Het-1A) and human ESCC cells (KYSE30, KYSE70, KYSE150, KYSE450, KYSE510, and TE10) were maintained in RPMI-1640 medium (Invitrogen, Carlsbad CA) supplemented with 10% fetal bovine serum (Gibco, Grand Island, NY) at 37 C with 5% CO2.	('RPMI-1640 medium', 'Chemical', '-', (141, 157))	('KYSE70', 'Var', (77, 83))	('bovine', 'Species', '9913', (212, 218))	('KYSE450', 'Var', (94, 101))	('CO2', 'Chemical', '-', (267, 270))	('human', 'Species', '9606', (51, 56))	('KYSE150', 'Var', (85, 92))	('KYSE510', 'Var', (103, 110))	('KYSE30', 'Var', (69, 75))
913510	26756568	We established cisplatin-resistant ESCC cell line in KYSE30, because the expressions of the majority of the lncRNAs were lower in KYSE30 when compared with other ESCC cell lines.	('expressions', 'MPA', (73, 84))	('KYSE30', 'Var', (130, 136))	('lower', 'NegReg', (121, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))
913536	26756568	Simultaneously, KYSE30-R also exhibited cross-resistance to 5-FU (~threefold) and paclitaxel (~fivefold) (Table 3 and Figure 1), two anticancer drugs that are widely used in combination with cisplatin for the treatment of ESCC.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('KYSE30-R', 'Var', (16, 24))	('cross-resistance', 'MPA', (40, 56))	('ESCC', 'Disease', (222, 226))	('5-FU', 'Chemical', '-', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (191, 200))	('cancer', 'Disease', (137, 143))	('paclitaxel', 'Chemical', 'MESH:D017239', (82, 92))
913543	26756568	Moreover, we also examined the levels of AFAP1-AS1 in ESCC cell lines, including KYSE30, KYSE70, KYSE150, KYSE450, KYSE510, TE10 cells and normal esophageal mucosa cell Het-1A.	('KYSE30', 'Var', (81, 87))	('AFAP1-AS1', 'Gene', (41, 50))	('KYSE150', 'Var', (97, 104))	('KYSE450', 'Var', (106, 113))	('KYSE70', 'Var', (89, 95))	('KYSE510', 'Var', (115, 122))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (41, 50))
913569	26756568	The multivariate cox proportional hazard regression analysis indicated that high expression of AFAP1-AS1 was the most significantly unfavorable prognostic factor of OS (HR, 1.888; 95%CI, 1.223-2.915; P = 0.004) followed by lack of dCRT response (HR, 1.672; 95%CI, 1.103-2.538; P = 0.015, Table 5).	('OS', 'Chemical', '-', (165, 167))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (95, 104))	('cox', 'Gene', (17, 20))	('cox', 'Gene', '1351', (17, 20))	('AFAP1-AS1', 'Gene', (95, 104))	('dCRT', 'Gene', (231, 235))	('dCRT', 'Gene', '45841', (231, 235))	('high expression', 'Var', (76, 91))
913579	26756568	In this study, we observed that high expression of AFAP1-AS1 was significantly correlated with poor response to dCRT in patients with ESCC.	('high', 'Var', (32, 36))	('dCRT', 'Gene', (112, 116))	('AFAP1-AS1', 'Gene', (51, 60))	('dCRT', 'Gene', '45841', (112, 116))	('ESCC', 'Disease', (134, 138))	('patients', 'Species', '9606', (120, 128))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (51, 60))	('correlated', 'Reg', (79, 89))
913582	26756568	Fan Y and his colleagues demonstrated that lncRNA UCA1 was up-regulated in patients with metastatic bladder cancer after cisplatin-based chemotherapy, and over-expression of UCA1 significantly increased cell viability in cisplatin treatment by regulating wnt signaling 28.	('up-regulated', 'PosReg', (59, 71))	('bladder cancer', 'Disease', (100, 114))	('wnt signaling 28', 'Pathway', (255, 271))	('cell viability', 'CPA', (203, 217))	('cisplatin', 'Chemical', 'MESH:D002945', (221, 230))	('UCA1', 'Gene', '652995', (174, 178))	('UCA1', 'Gene', '652995', (50, 54))	('UCA1', 'Gene', (50, 54))	('patients', 'Species', '9606', (75, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('lncRNA', 'MPA', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('increased', 'PosReg', (193, 202))	('regulating', 'Reg', (244, 254))	('over-expression', 'Var', (155, 170))	('UCA1', 'Gene', (174, 178))	('bladder cancer', 'Disease', 'MESH:D001749', (100, 114))
913591	26756568	For example, the lncRNA AC096655.1-002 was significantly down-regulated in gastric cancer tissues compared with paired adjacent normal tissues, and use of this lncRNA alone provided a remarkable improvement in the diagnosis of gastric cancer compared with classic tumor marker serum carcinoembryonic antigen 39.	('down-regulated', 'NegReg', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('gastric cancer', 'Phenotype', 'HP:0012126', (227, 241))	('tumor', 'Disease', (264, 269))	('gastric cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('gastric cancer', 'Disease', (227, 241))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('improvement', 'PosReg', (195, 206))	('gastric cancer', 'Disease', 'MESH:D013274', (227, 241))	('AC096655.1-002', 'Var', (24, 38))
913596	26756568	However, our multivariate analysis demonstrated that high expression of AFAP1-AS1 was the most significantly unfavorable prognostic factor of OS surpassing the advanced TNM stage and the lack of primary CR.	('AFAP1-AS1', 'Gene', (72, 81))	('OS', 'Chemical', '-', (142, 144))	('CR', 'Chemical', '-', (203, 205))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (72, 81))	('high expression', 'Var', (53, 68))
913637	26526791	In multivariate analysis, we adjusted for age (continuous), sex, family size (continuous), education (illiteracy/primary school/primary high school/secondary high school and above), tobacco smoking (never/ever smoker of any tobacco), alcohol drinking (never/ever), missing & filled teeth (MFT, none/1 ~ 4/ >= 4), times of tooth brushing per day (<2 times/ >= 2 times), daily consumption of pickled vegetables (<10 g/ >= 10 g) and daily consumption of fresh fruits (<27.5 g/ >= 27.5 g).	('tooth brushing', 'Disease', 'MESH:D014076', (322, 336))	('missing', 'Var', (265, 272))	('tobacco', 'Species', '4097', (182, 189))	('alcohol drinking', 'Phenotype', 'HP:0030955', (234, 250))	('tooth brushing', 'Phenotype', 'HP:0000670', (322, 336))	('tooth brushing', 'Disease', (322, 336))	('alcohol', 'Chemical', 'MESH:D000438', (234, 241))	('tobacco', 'Species', '4097', (224, 231))	('vegetables', 'Var', (398, 408))
913682	24911057	Assessment of the Potential Diagnostic Value of Serum p53 Antibody for Cancer: A Meta-Analysis Mutant p53 protein over-expression has been reported to induce serum antibodies against p53.	('Cancer', 'Disease', (71, 77))	('protein', 'Protein', (106, 113))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (183, 186))	('Mutant', 'Var', (95, 101))	('induce', 'PosReg', (151, 157))	('over-expression', 'PosReg', (114, 129))	('p53', 'Gene', (54, 57))	('p53', 'Gene', '7157', (183, 186))	('p53', 'Gene', '7157', (54, 57))	('p53', 'Gene', (102, 105))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
913697	24911057	Cancer has long been recognized as a multi-step process that involves not only genetic changes conferring growth advantage, but also factors that disrupt regulation of growth and differentiation.	('genetic changes', 'Var', (79, 94))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('regulation', 'MPA', (154, 164))	('growth advantage', 'CPA', (106, 122))
357364	24911057	Mutations in the tumor suppressor gene p53 are the most commonly observed genetic abnormalities in human cancers.	('tumor', 'Disease', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('genetic abnormalities', 'Disease', (74, 95))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('genetic abnormalities', 'Disease', 'MESH:D030342', (74, 95))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('human', 'Species', '9606', (99, 104))
913700	24911057	Mutations in this gene cause an accumulation of non-functional proteins, due to increased stability and a longer half-life of several hours compared with the 20 min half-life for wild-type p53.	('p53', 'Gene', '7157', (189, 192))	('increased', 'PosReg', (80, 89))	('stability', 'MPA', (90, 99))	('Mutations', 'Var', (0, 9))	('accumulation', 'PosReg', (32, 44))	('non-functional proteins', 'MPA', (48, 71))	('p53', 'Gene', (189, 192))
913764	24911057	Shigeo Yoshizawa thought p53 Abs are usually IgG, indicating a secondary response after prolonged immunization by p53 protein accumulation; thus it is reasonable to presume that such p53 Abs could be used as an early indicator of p53 mutations in tumors in which such alterations occur early during tumoral progression(see Reference 89 in File S1).	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Disease', (247, 253))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('p53', 'Gene', '7157', (230, 233))	('tumoral', 'Disease', (299, 306))	('tumoral', 'Disease', 'MESH:D009369', (299, 306))	('mutations', 'Var', (234, 243))	('p53', 'Gene', (230, 233))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))
913804	21242966	GSK3beta-mediated phosphorylation of Fbx4 Ser12 during the G1/S transition regulates Fbx4 dimerization, which in turn governs Fbx4-driven E3 ligase activity.	('dimerization', 'MPA', (90, 102))	('regulates', 'Reg', (75, 84))	('Fbx4', 'Gene', (37, 41))	('activity', 'MPA', (148, 156))	('Ser12', 'Var', (42, 47))	('Ser12', 'Chemical', '-', (42, 47))	('governs', 'Reg', (118, 125))	('Fbx4', 'MPA', (85, 89))
913805	21242966	In esophageal carcinomas that overexpress cyclin D1, Fbx4 is subject to inactivating mutations that specifically disrupt dimerization, highlighting the biological significance of this regulatory mechanism.	('dimerization', 'MPA', (121, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('Fbx4', 'Gene', (53, 57))	('esophageal carcinomas', 'Disease', (3, 24))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (3, 23))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (3, 24))	('mutations', 'Var', (85, 94))	('disrupt', 'NegReg', (113, 120))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (3, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('overexpress', 'PosReg', (30, 41))
913807	21242966	We provide evidence that phosphorylation of Ser-12 generates a docking site for 14-3-3epsilon.	('docking site', 'MPA', (63, 75))	('phosphorylation', 'Var', (25, 40))	('Ser-12', 'Chemical', '-', (44, 50))
913808	21242966	14-3-3epsilon binds to endogenous Fbx4 and this association is impaired by mutations that target either Ser-8 or Ser-12 in Fbx4, suggesting that this N-terminal motif in Fbx4 directs its interaction with 14-3-3epsilon.	('Fbx4', 'Gene', (170, 174))	('binds', 'Interaction', (14, 19))	('Fbx4', 'Gene', (123, 127))	('Ser', 'Chemical', 'MESH:D012694', (104, 107))	('interaction', 'Interaction', (187, 198))	('mutations', 'Var', (75, 84))	('Ser', 'Chemical', 'MESH:D012694', (113, 116))	('impaired', 'NegReg', (63, 71))	('Ser-12', 'Chemical', '-', (113, 119))
913812	21242966	Extensive research has established that dysregulation of cyclin D1 in human cancer is often post-translationally mediated and is a driving oncogenic process.	('dysregulation', 'Var', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('cyclin D1', 'Protein', (57, 66))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
913819	21242966	Significantly, Fbx4 dimerization stimulates its E3 activity; the N-terminal DD is required both in vitro and in vivo for Fbx4-mediated cyclin D1 degradation.	('cyclin D1', 'MPA', (135, 144))	('stimulates', 'PosReg', (33, 43))	('E3 activity', 'MPA', (48, 59))	('Fbx4', 'Gene', (15, 19))	('DD', 'Chemical', '-', (76, 78))	('dimerization', 'Var', (20, 32))
913822	21242966	The importance of this regulatory mechanism is underscored by the observation that mutations in critical dimerization and phosphorylation motifs of Fbx4 are found in human cancer and are accompanied by cyclin D1 accumulation.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('accumulation', 'PosReg', (212, 224))	('dimerization', 'MPA', (105, 117))	('human', 'Species', '9606', (166, 171))	('phosphorylation', 'MPA', (122, 137))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cyclin D1', 'MPA', (202, 211))	('cancer', 'Disease', (172, 178))	('Fbx4', 'Gene', (148, 152))
913823	21242966	Of note, while many cancer-derived mutations target residues that directly mediate dimerization or phosphorylation, some mutations fall outside these regions, yet still inhibit dimerization highlighting the need for further mechanistic insights.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('inhibit', 'NegReg', (169, 176))	('mutations', 'Var', (121, 130))	('phosphorylation', 'MPA', (99, 114))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('dimerization', 'MPA', (177, 189))	('cancer', 'Disease', (20, 26))	('dimerization', 'MPA', (83, 95))	('fall', 'Phenotype', 'HP:0002527', (131, 135))	('mutations', 'Var', (35, 44))
913825	21242966	14-3-3 consensus-binding sequences have been identified through comprehensive analysis of their client proteins, which revealed two modes of consensus phospho-serine/threonine sites, RSXpSXP or RXF/YXpSXP.	('RXF/YXpSXP', 'Var', (194, 204))	('threonine', 'Chemical', 'MESH:D013912', (166, 175))	('RSXpSXP', 'Var', (183, 190))	('phospho-serine', 'Chemical', 'MESH:D010768', (151, 165))
913826	21242966	Our data demonstrate that 14-3-3epsilon facilitates Fbx4 dimerization and that this interaction requires Ser8, which is frequently mutated in human cancer, and p-Ser12.	('cancer', 'Disease', (148, 154))	('p-Ser12', 'Var', (160, 167))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('Ser8', 'Chemical', '-', (105, 109))	('Fbx4', 'Gene', (52, 56))	('p-Ser12', 'Chemical', '-', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('dimerization', 'MPA', (57, 69))	('human', 'Species', '9606', (142, 147))	('Ser8', 'Var', (105, 109))	('facilitates', 'PosReg', (40, 51))
913827	21242966	Consistent with a cell cycle regulated function, Fbx4 binding to 14-3-3epsilon is dependent on p-Ser12 and restricted to the G1/S and S phase, where phosphorylation of Fbx4 and Fbx4 activity is maximal.	('activity', 'MPA', (182, 190))	('dependent', 'Reg', (82, 91))	('p-Ser12', 'Var', (95, 102))	('p-Ser12', 'Chemical', '-', (95, 102))	('phosphorylation', 'MPA', (149, 164))	('Fbx4', 'Gene', (49, 53))	('binding', 'Interaction', (54, 61))
913828	21242966	We found that expression of 14-3-3epsilon positively regulates Fbx4 dimerization in vivo and that 14-3-3epsilon contributes to cyclin D1 ubiquitylation and clearance.	('regulates', 'Reg', (53, 62))	('expression', 'Species', '29278', (14, 24))	('cyclin D1 ubiquitylation', 'MPA', (127, 151))	('dimerization', 'MPA', (68, 80))	('14-3-3epsilon', 'Var', (98, 111))	('clearance', 'MPA', (156, 165))	('Fbx4', 'Gene', (63, 67))
913830	21242966	Because previous work revealed that Fbx4-depletion in NIH3T3 cells promotes anchorage independent growth and this phenotype can be reversed by reconstitution with shRNA-resistant Fbx4, we determined whether anchorage-independent growth of select human esophageal cancer cell lines with altered Fbx4 activity could be attenuated by reconstitution with wild type Fbx4.	('anchorage-independent growth', 'CPA', (207, 235))	('activity', 'MPA', (299, 307))	('esophageal cancer', 'Disease', 'MESH:D004938', (252, 269))	('promotes', 'PosReg', (67, 75))	('altered', 'Var', (286, 293))	('Fbx4', 'Enzyme', (294, 298))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('human', 'Species', '9606', (246, 251))	('esophageal cancer', 'Disease', (252, 269))	('NIH3T3', 'CellLine', 'CVCL:0594', (54, 60))	('anchorage independent growth', 'CPA', (76, 104))
913831	21242966	TE8 cells (Fbx4 activity is diminished due to GSK3beta inhibition by high Akt expression) and TE15 cells (wild type Fbx4) show a marked decrease in anchorage-independent growth upon Fbx4 expression, suggesting that increased Fbx4 function can overcome low endogenous activity and even, enhance normal activity (Figure 1a,b).	('Akt', 'Gene', '11651', (74, 77))	('decrease', 'NegReg', (136, 144))	('expression', 'Var', (78, 88))	('diminished', 'NegReg', (28, 38))	('GSK3beta', 'Enzyme', (46, 54))	('Akt', 'Gene', (74, 77))	('enhance', 'PosReg', (286, 293))	('normal activity', 'MPA', (294, 309))	('expression', 'Species', '29278', (187, 197))	('high', 'Var', (69, 73))	('anchorage-independent growth', 'CPA', (148, 176))	('inhibition', 'NegReg', (55, 65))	('expression', 'Species', '29278', (78, 88))
913832	21242966	However, the growth of TE10 cells (which express the heterozygous dimerization-defective S8R mutation) in soft agar (Figure 1b) and on plastic (Figure 1c) was largely refractory to expression of exogenous wild type Fbx4.	('S8R', 'Mutation', 'rs762437813', (89, 92))	('growth', 'MPA', (13, 19))	('agar', 'Chemical', 'MESH:D000362', (111, 115))	('S8R', 'Gene', (89, 92))	('mutation', 'Var', (93, 101))	('expression', 'Species', '29278', (181, 191))
913833	21242966	This result is consistent with our previous finding that the S8R mutation exerts dominant negative characteristics when co-expressed with wild type Fbx4.	('S8R', 'Mutation', 'rs762437813', (61, 64))	('negative', 'NegReg', (90, 98))	('S8R', 'Var', (61, 64))
913835	21242966	Indeed, the half-life of cyclin D1 from S8R-expressing TE10 cells was prolonged when compared to wild type Fbx4 expressing TE15 cells (Figure 1d).	('S8R-expressing', 'Var', (40, 54))	('cyclin D1', 'Protein', (25, 34))	('prolonged', 'PosReg', (70, 79))	('half-life', 'MPA', (12, 21))	('S8R', 'Mutation', 'rs762437813', (40, 43))
913836	21242966	Furthermore, expression of exogenous wild type as well as phospho-mimetic S12E Fbx4 decreased steady-state cyclin D1 levels in TE8 cells with low endogenous Fbx4 activity (Figure 1e).	('S12E', 'Var', (74, 78))	('expression', 'Species', '29278', (13, 23))	('Fbx4', 'Gene', (79, 83))	('S12E', 'Mutation', 'p.S12E', (74, 78))	('decreased', 'NegReg', (84, 93))
913839	21242966	To explore the defect in Fbx4 function associated with the S8R mutation, we utilized mass spectrometry to identify proteins that bound differentially to wild type versus Fbx4S8R.	('Fbx4S8R', 'Gene', (170, 177))	('S8R', 'Mutation', 'rs762437813', (174, 177))	('S8R', 'Mutation', 'rs762437813', (59, 62))	('Fbx4', 'Gene', (25, 29))	('bound', 'Interaction', (129, 134))	('S8R', 'Var', (59, 62))
913840	21242966	14-3-3epsilon was enriched in wild type Fbx4 purified complexes versus S8R Fbx4 (Figure 2a).	('Fbx4', 'Gene', (40, 44))	('S8R', 'Var', (71, 74))	('S8R', 'Mutation', 'rs762437813', (71, 74))
913842	21242966	The decreased binding of 14-3-3epsilon to Fbx4S8R and S12A mutants compared to wild type supported the requirement of both Ser-8 and phosphorylated Ser-12 for Fbx4/14-3-3epsilon association in vivo (Figure 2c,d).	('decreased', 'NegReg', (4, 13))	('S12A', 'SUBSTITUTION', 'None', (54, 58))	('association', 'Interaction', (178, 189))	('S12A', 'Var', (54, 58))	('binding', 'Interaction', (14, 21))	('Ser-12', 'Chemical', '-', (148, 154))	('Ser', 'Chemical', 'MESH:D012694', (148, 151))	('Fbx4S8R', 'Gene', (42, 49))	('Ser', 'Chemical', 'MESH:D012694', (123, 126))
913843	21242966	Furthermore, substitution of S12 with a phospho-mimetic glutamate residue significantly increased 14-3-3epsilon association (Figure 2e).	('S12', 'Gene', (29, 32))	('14-3-3epsilon association', 'MPA', (98, 123))	('glutamate', 'Chemical', 'MESH:D018698', (56, 65))	('substitution', 'Var', (13, 25))	('increased', 'PosReg', (88, 97))
913844	21242966	Consistent with a direct interaction, recombinant GST-tagged 14-3-3epsilon pulled down Fbx4 produced in Sf9 cells; in contrast, binding of Fbx4S8R and Fbx4S12A to recombinant 14-3-3 was attenuated (Figure 2f).	('Fbx4S12A', 'Var', (151, 159))	('attenuated', 'NegReg', (186, 196))	('binding', 'Interaction', (128, 135))	('pulled down', 'NegReg', (75, 86))	('Fbx4', 'Gene', (87, 91))	('Sf9', 'CellLine', 'CVCL:0549', (104, 107))
913845	21242966	Mutant Fbx4S8R exhibited reduced GST-14-3-3epsilon binding and the 14-3-3epsilon K49E mutant decreased Fbx4 association, indicating that Fbx4 is a typical 14-3-3 client protein (Figure 2g).	('reduced', 'NegReg', (25, 32))	('GST-14-3-3epsilon binding', 'Interaction', (33, 58))	('S8R', 'Mutation', 'rs762437813', (11, 14))	('K49E', 'Mutation', 'p.K49E', (81, 85))	('decreased', 'NegReg', (93, 102))	('association', 'Interaction', (108, 119))	('Fbx4S8R', 'Gene', (7, 14))	('Fbx4', 'Protein', (103, 107))	('Mutant', 'Var', (0, 6))
913849	21242966	We also verified the role of GSK3beta-dependent phosphorylation of Ser-12 by introducing a dominant-negative kinase dead (kd) GSK3beta mutant in 3T3 cells.	('3T3', 'CellLine', 'CVCL:0594', (145, 148))	('mutant', 'Var', (135, 141))	('GSK3beta', 'Gene', (126, 134))	('Ser-12', 'Chemical', '-', (67, 73))
913850	21242966	NIH3T3 cells transfected with Fbx4, Fbx4S8R or Fbx4S12A were visualized processed for immunofluorescence microscopy (Figure 4a) or subjected to nuclear fractionation (Figure 4b).	('NIH3T3', 'CellLine', 'CVCL:0594', (0, 6))	('Fbx4S8R', 'Var', (36, 43))	('Fbx4', 'Gene', (30, 34))	('Fbx4S12A', 'Var', (47, 55))	('S8R', 'Mutation', 'rs762437813', (40, 43))
913851	21242966	These results were confirmed with the endogenous Fbx4 mutant S8R in TE10 cells, which exhibited no detectable nuclear accumulation by immunofluorescence (Figure 4c).	('mutant', 'Var', (54, 60))	('Fbx4', 'Gene', (49, 53))	('S8R', 'Mutation', 'rs762437813', (61, 64))
913854	21242966	Conversly, overexpression of 14-3-3epsilon increased the dimerization of Fbx4 (Figure 5c).	('14-3-3epsilon', 'Var', (29, 42))	('expression', 'Species', '29278', (15, 25))	('dimerization', 'MPA', (57, 69))	('Fbx4', 'Gene', (73, 77))	('increased', 'PosReg', (43, 52))	('overexpression', 'PosReg', (11, 25))
913856	21242966	Indeed, in vitro ubiquitylation of cyclin D1 by Fbx4-directed SCF complexes was enhanced upon addition of 14-3-3epsilon; the presence of increasing amounts of 14-3-3epsilon likely resulted in protein aggregation, thereby compromising functional ligase (Figure 5d).	('compromising', 'NegReg', (221, 233))	('Fbx4-directed', 'Gene', (48, 61))	('protein aggregation', 'Disease', (192, 211))	('14-3-3epsilon', 'Var', (159, 172))	('cyclin D1', 'Protein', (35, 44))	('functional ligase', 'MPA', (234, 251))	('ubiquitylation', 'MPA', (17, 31))	('protein aggregation', 'Disease', 'MESH:D066263', (192, 211))	('SCF', 'Gene', (62, 65))	('enhanced', 'PosReg', (80, 88))	('SCF', 'Gene', '4254', (62, 65))	('resulted in', 'Reg', (180, 191))
913857	21242966	Conversely, Fbx4S8R exhibited decreased ubiquitylating capacity and the presence of 14-3-3epsilon actually decreased activity raising the possibility that 14-3-3 proteins may provide more than a single function.	('activity', 'MPA', (117, 125))	('Fbx4S8R', 'Var', (12, 19))	('decreased', 'NegReg', (107, 116))	('ubiquitylating capacity', 'MPA', (40, 63))	('S8R', 'Mutation', 'rs762437813', (16, 19))	('decreased', 'NegReg', (30, 39))
913861	21242966	In summary, we have shown that human cancer-derived Fbx4 mutations of S8 and S12 exhibit impaired 14-3-3epsilon recognition and that the presence of 14-3-3epsilon is essential for maximal Fbx4 activity.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('human', 'Species', '9606', (31, 36))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('impaired', 'NegReg', (89, 97))	('Fbx4', 'Gene', (52, 56))	('14-3-3epsilon recognition', 'MPA', (98, 123))
913863	21242966	By analysis of binding partners for wild type Fbx4 versus a cancer derived, dimerization-deficient Fbx4 mutant, we identified 14-3-3epsilon.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('mutant', 'Var', (104, 110))	('Fbx4', 'Gene', (99, 103))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('binding', 'Interaction', (15, 22))
913864	21242966	These multiple levels of regulation, combined with the observation that Fbx4 is frequently mutated in cyclin D1 overexpressing human cancers, suggest that precise temporal control of Fbx4 is a crucial tumor suppressive mechanism.	('crucial tumor', 'Disease', (193, 206))	('Fbx4', 'Gene', (72, 76))	('crucial tumor', 'Disease', 'MESH:D009369', (193, 206))	('human', 'Species', '9606', (127, 132))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('mutated', 'Var', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
913868	21242966	The specificity of our interaction is underscored by the marked reduction in 14-3-3epsilon binding upon either Fbx4S8R or S12A mutation, indicating the association requires precise interactions that utilize several residues within the 14-3-3epsilon binding motif.	('Fbx4S8R', 'Gene', (111, 118))	('interactions', 'Interaction', (181, 193))	('14-3-3epsilon', 'Protein', (77, 90))	('S12A', 'SUBSTITUTION', 'None', (122, 126))	('S12A', 'Var', (122, 126))	('reduction', 'NegReg', (64, 73))	('binding', 'Interaction', (91, 98))
913869	21242966	Moreover, charge reversing mutation of 14-3-3epsilon lysine 49, which sits in the substrate binding pocket and directly complements phosphoserine/threonines on targets, to arginine abolished association with Fbx4, providing evidence that Fbx4 interacts with the established amphipathic groove on 14-3-3epsilon.	('threonines', 'Chemical', 'MESH:D013912', (146, 156))	('abolished', 'NegReg', (181, 190))	('Fbx4', 'Gene', (208, 212))	('lysine', 'Chemical', 'MESH:D008239', (53, 59))	('arginine', 'Chemical', 'MESH:D001120', (172, 180))	('mutation', 'Var', (27, 35))	('association', 'Interaction', (191, 202))	('phosphoserine', 'Chemical', 'MESH:D010768', (132, 145))
913872	21242966	However, we do not expect this to be the case, since mutation of S12A, which implies a relative lack of associated 14-3-3epsilon, does not impair skp1 binding.	('skp1', 'Gene', '6500', (146, 150))	('binding', 'Interaction', (151, 158))	('impair', 'NegReg', (139, 145))	('S12A', 'SUBSTITUTION', 'None', (65, 69))	('S12A', 'Var', (65, 69))	('skp1', 'Gene', (146, 150))
913875	21242966	We have previously shown that mutations in the dimerization domain affecting the 14-3-3epsilon binding motif of Fbx4 occur in esophageal cancer and these included the phosphorylation site S12 and P13.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('occur', 'Reg', (117, 122))	('Fbx4', 'Gene', (112, 116))	('P13', 'Gene', (196, 199))	('mutations', 'Var', (30, 39))	('P13', 'Gene', '440926', (196, 199))	('esophageal cancer', 'Disease', (126, 143))
913877	21242966	Recently, S8R mutations were also detected at a similar rate in a subset of breast cancers and these mutations correlate with cyclin D1 overexpression, suggesting that this defect spans multiple cyclin D1-driven malignancies.	('expression', 'Species', '29278', (140, 150))	('S8R', 'Gene', (10, 13))	('malignancies', 'Disease', 'MESH:D009369', (212, 224))	('mutations', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('S8R', 'Mutation', 'rs762437813', (10, 13))	('malignancies', 'Disease', (212, 224))	('overexpression', 'PosReg', (136, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (76, 90))	('breast cancers', 'Disease', 'MESH:D001943', (76, 90))	('cyclin D1', 'MPA', (126, 135))	('breast cancers', 'Disease', (76, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('mutations', 'Var', (14, 23))
913879	21242966	Loss of 14-3-3epsilon itself has been reported to track with regions of chromosomal deletion in small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))	('small cell lung cancer', 'Disease', (96, 118))	('chromosomal deletion', 'Var', (72, 92))	('Loss', 'NegReg', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('small cell lung cancer', 'Disease', 'MESH:D055752', (96, 118))
913881	21242966	Future unbiased, genome-wide association studies will be useful to determine whether perturbations along 14-3-3epsilon/Fbx4/cyclin D1 pathway contribute to cyclin D1 driven cancers.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancers', 'Disease', (173, 180))	('perturbations', 'Var', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cyclin', 'MPA', (156, 162))
913886	21242966	WT, S8R and S12A Fbx4 expression vectors were previously described.	('S8R', 'Var', (4, 7))	('S12A', 'SUBSTITUTION', 'None', (12, 16))	('S12A', 'Var', (12, 16))	('S8R', 'Mutation', 'rs762437813', (4, 7))	('expression vectors', 'Species', '29278', (22, 40))
913915	32500029	Epigenetically, EAC resembles the CIN subtype of GC.	('Epigenetically', 'Var', (0, 14))	('CIN', 'Disease', (34, 37))	('CIN', 'Disease', 'MESH:D007674', (34, 37))
914029	32500029	In GEC, CPS >= 1 and CPS >= 10 scores have been explored as important cut-offs to subclassify patients and these levels have been studied in greatest depth in clinical trials using pembrolizumab.	('patients', 'Species', '9606', (94, 102))	('CPS', 'Chemical', '-', (8, 11))	('CPS >= 10', 'Var', (21, 30))	('CPS >', 'Var', (8, 13))	('pembrolizumab', 'Chemical', 'MESH:C582435', (181, 194))	('CPS', 'Chemical', '-', (21, 24))
914032	32500029	However, in both CPS 0 and CPS >= 1 subgroups, 3 complete responses (CR) were detected, and median OS was similar between both groups (5.8 vs. 4.9 months) (Table 3).	('CPS', 'Chemical', '-', (27, 30))	('complete', 'Disease', (49, 57))	('CPS', 'Chemical', '-', (17, 20))	('CPS >= 1', 'Var', (27, 35))
914038	32500029	In post-hoc unplanned analysis, patients with CPS >= 10 had an improved OS with pembrolizumab compared to paclitaxel (10.4 vs. 8 months) (Table 3).	('patients', 'Species', '9606', (32, 40))	('improved', 'PosReg', (63, 71))	('pembrolizumab', 'Chemical', 'MESH:C582435', (80, 93))	('CPS', 'Chemical', '-', (46, 49))	('CPS >= 10', 'Var', (46, 55))	('paclitaxel', 'Chemical', 'MESH:D017239', (106, 116))
914041	32500029	In unplanned, post-hoc analysis, pembrolizumab had significantly improved survival compared to chemotherapy in the CPS >= 10 subgroup (17.4 vs. 10.8 months).	('improved', 'PosReg', (65, 73))	('CPS', 'Chemical', '-', (115, 118))	('survival', 'MPA', (74, 82))	('pembrolizumab', 'Chemical', 'MESH:C582435', (33, 46))	('pembrolizumab', 'Var', (33, 46))
914065	32500029	However, using the 22C3 assay, the CPS >=1 population had a survival benefit for avelumab vs chemotherapy (15 vs. 12 months, HR 0.72).	('avelumab', 'Chemical', 'MESH:C000609138', (81, 89))	('CPS', 'Chemical', '-', (35, 38))	('benefit', 'PosReg', (69, 76))	('avelumab', 'Var', (81, 89))	('CPS >=1', 'Var', (35, 42))	('survival', 'MPA', (60, 68))
914069	32500029	This cut-off is suggested at CPS >=1 for third-line and CPS >=10 in first-line.	('CPS', 'Chemical', '-', (56, 59))	('CPS >=10', 'Var', (56, 64))	('CPS', 'Chemical', '-', (29, 32))	('CPS >=1', 'Var', (29, 36))
914070	32500029	Of note however, are the occurrences of responses (including CR) and prolonged survival of patients with CPS 0 (albiet at lower rates compared to higher CPS scores).	('albiet', 'Chemical', '-', (112, 118))	('patients', 'Species', '9606', (91, 99))	('CPS 0', 'Var', (105, 110))	('survival', 'CPA', (79, 87))	('CPS', 'Chemical', '-', (105, 108))	('CPS', 'Chemical', '-', (153, 156))	('responses', 'MPA', (40, 49))
914072	32500029	The adaptive immune system has the ability to recognize somatic mutations that occur in tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('mutations', 'Var', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
914074	32500029	Mismatch repair protein (MMR) deficiency occurs in several tumor types including gastrointestinal colorectal, gastric, pancreaticobiliary, small intestine, endometrial, prostate, and ovarian cancer.	('pancreaticobiliary', 'Disease', (119, 137))	('colorectal', 'Disease', 'MESH:D015179', (98, 108))	('tumor', 'Disease', (59, 64))	('deficiency', 'Var', (30, 40))	('ovarian cancer', 'Disease', (183, 197))	('prostate', 'Disease', (169, 177))	('gastric', 'Disease', (110, 117))	('endometrial', 'Disease', (156, 167))	('colorectal', 'Disease', (98, 108))	('occurs', 'Reg', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('ovarian cancer', 'Disease', 'MESH:D010051', (183, 197))	('MMR', 'Gene', (25, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (183, 197))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('small intestine', 'Disease', (139, 154))
914075	32500029	MMR deficiency occurs through mutations in genes that recognize and correct errors in mismatched nucleotides (MLH1, MSH2, MSH6, and PMS2) or through methylation-induced gene silencing of the promoter of MLH1.	('MSH6', 'Gene', '2956', (122, 126))	('MSH2', 'Gene', (116, 120))	('errors', 'Var', (76, 82))	('MSH2', 'Gene', '4436', (116, 120))	('MMR deficiency', 'Disease', 'MESH:C536928', (0, 14))	('PMS2', 'Gene', (132, 136))	('MMR deficiency', 'Disease', (0, 14))	('MLH1', 'Gene', '4292', (110, 114))	('MLH1', 'Gene', (110, 114))	('mutations', 'Var', (30, 39))	('methylation-induced', 'Var', (149, 168))	('gene', 'Var', (169, 173))	('MLH1', 'Gene', (203, 207))	('PMS2', 'Gene', '5395', (132, 136))	('MLH1', 'Gene', '4292', (203, 207))	('MSH6', 'Gene', (122, 126))
914076	32500029	Germline mutations in MMR proteins are associated with Lynch syndrome, although a majority of MMR deficient tumors are sporadic and occur through MLH1 promoter methylation.	('Germline mutations', 'Var', (0, 18))	('MMR deficient tumors', 'Disease', (94, 114))	('Lynch syndrome', 'Disease', (55, 69))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('MMR', 'Gene', (22, 25))	('Lynch syndrome', 'Disease', 'MESH:D003123', (55, 69))	('MMR deficient tumors', 'Disease', 'MESH:C536928', (94, 114))	('associated', 'Reg', (39, 49))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('MLH1', 'Gene', '4292', (146, 150))	('occur', 'Reg', (132, 137))	('MLH1', 'Gene', (146, 150))
914095	32500029	Mutations in several other genes such a POLE and POLD1 have also been associated with high TMB.	('high TMB', 'Disease', (86, 94))	('POLD1', 'Gene', (49, 54))	('POLD1', 'Gene', '5424', (49, 54))	('associated', 'Reg', (70, 80))	('POLE', 'Gene', (40, 44))	('Mutations', 'Var', (0, 9))	('TMB', 'Chemical', '-', (91, 94))
914096	32500029	High TMB has also been associated with smoking-related cancers such as lung cancer and head and neck cancers, and UV-associated cancers such as melanoma.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('TMB', 'Chemical', '-', (5, 8))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Disease', (128, 135))	('High', 'Var', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('head and neck cancers', 'Phenotype', 'HP:0012288', (87, 108))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('associated', 'Reg', (23, 33))	('cancers', 'Disease', (55, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('head and neck cancers', 'Disease', 'MESH:D006258', (87, 108))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lung cancer', 'Disease', (71, 82))
914118	32500029	Recent studies in MSI-H tumors have shown that the extent of response to ICI is associated with the specific accumulation of insertion-deletion mutations.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('MSI-H tumors', 'Disease', 'MESH:D009369', (18, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('insertion-deletion mutations', 'Var', (125, 153))	('MSI-H tumors', 'Disease', (18, 30))
914135	32500029	"Altered-excluded tumors" have no T-cell infiltration at the tumor bed, but presence of T-cells at the tumor invasive margins, epigenetic modifications within the tumor microenvironment and aberrant tumor stroma and vasculature.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('epigenetic modifications', 'Var', (127, 151))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumors', 'Disease', (18, 24))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', (18, 23))	('aberrant tumor stroma', 'Disease', 'MESH:D002869', (190, 211))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('aberrant tumor stroma', 'Disease', (190, 211))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('presence', 'Reg', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', (61, 66))
914152	32500029	Methylation of FOXP1 was found to be predictive of ICI response.	('Methylation', 'Var', (0, 11))	('FOXP1', 'Gene', '27086', (15, 20))	('ICI response', 'CPA', (51, 63))	('FOXP1', 'Gene', (15, 20))
914153	32500029	In GC, somatic epigenetic promoter alterations have been described to be involved in tumor immune editing.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('epigenetic promoter alterations', 'Var', (15, 46))	('involved', 'Reg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
914163	32500029	One of the best examples of a negative predictive biomarker is the use of RAS mutations to predict for lack of benefit of anti-EGFR therapy in colorectal cancer.	('colorectal cancer', 'Disease', (143, 160))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('EGFR', 'Gene', '1956', (127, 131))	('RAS', 'Gene', (74, 77))	('EGFR', 'Gene', (127, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))
914178	29034995	Malfunctioning of oncogenes stands as the inherent characteristic of tumorigenesis, which can be brought about by genetic alterations mainly including gain of function mutation, amplifications, and epigenetic activation 3.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('amplifications', 'Var', (178, 192))	('tumor', 'Disease', (69, 74))	('gain of function', 'PosReg', (151, 167))	('mutation', 'Var', (168, 176))	('epigenetic activation 3', 'Var', (198, 221))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
914179	29034995	Abnormal phosphorylation of nonreceptor tyrosine kinase c-Src, hereafter referred to as Src, has long been considered as notoriously morbific for inducing carcinogenesis in the ways of proliferation, adhesion, angiogenesis, invasion, and apoptosis.	('apoptosis', 'CPA', (238, 247))	('c-Src', 'Gene', '6714', (56, 61))	('Abnormal phosphorylation', 'Var', (0, 24))	('carcinogenesis', 'Disease', (155, 169))	('phosphorylation', 'Var', (9, 24))	('Src', 'Gene', '6714', (88, 91))	('adhesion', 'CPA', (200, 208))	('Src', 'Gene', (58, 61))	('Src', 'Gene', '6714', (58, 61))	('carcinogenesis', 'Disease', 'MESH:D063646', (155, 169))	('invasion', 'CPA', (224, 232))	('inducing', 'Reg', (146, 154))	('angiogenesis', 'CPA', (210, 222))	('Src', 'Gene', (88, 91))	('c-Src', 'Gene', (56, 61))
914180	29034995	More recently, disorganized amplification is proven to be another manner to cause dysregulation of Src in cancer.	('dysregulation of Src in cancer', 'Disease', (82, 112))	('dysregulation of Src in cancer', 'Disease', 'MESH:D009369', (82, 112))	('disorganized amplification', 'Var', (15, 41))	('cause', 'Reg', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
914181	29034995	Amplification was found in up to 20% of the advanced human colorectal cancers.	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal cancers', 'Disease', 'MESH:D015179', (59, 77))	('human', 'Species', '9606', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('colorectal cancers', 'Disease', (59, 77))
914187	29034995	Theoretically, aberrant expression of miRNAs whose target genes are cancer-related might initiate the changes in cell functions toward heterogeneity.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('changes', 'MPA', (102, 109))	('expression', 'MPA', (24, 34))	('cell functions toward heterogeneity', 'MPA', (113, 148))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('cancer', 'Disease', (68, 74))	('aberrant', 'Var', (15, 23))	('initiate', 'Reg', (89, 97))
914201	29034995	The antibodies used were as follows: anti-c-Src (B-12) (sc-8056, Santa Cruz Biotechnology, CA) and anti-GAPDH (sc-365062).	('sc-365062', 'Var', (111, 120))	('GAPDH', 'Gene', '2597', (104, 109))	('GAPDH', 'Gene', (104, 109))	('c-Src', 'Gene', (42, 47))	('c-Src', 'Gene', '6714', (42, 47))
914202	29034995	The full-length human Src 3'-UTR and the mutant Src 3'-UTR were cloned into the p-MIR-reporter vector (Ambion, Austin, TX), respectively.	('Src 3', 'Gene', '8202', (22, 27))	('MIR', 'Gene', '220972', (82, 85))	('MIR', 'Gene', (82, 85))	('mutant', 'Var', (41, 47))	('Src 3', 'Gene', (48, 53))	('human', 'Species', '9606', (16, 21))	('Src 3', 'Gene', '8202', (48, 53))	('Src 3', 'Gene', (22, 27))
914205	29034995	RNA interference through the siRNA targeting human Src was designed and synthesized by GenePharma (Shanghai, China) to knockdown Src.	('Src', 'Gene', (129, 132))	('Src', 'Gene', '6714', (129, 132))	('human', 'Species', '9606', (45, 50))	('Src', 'Gene', (51, 54))	('Src', 'Gene', '6714', (51, 54))	('knockdown', 'Var', (119, 128))
914241	29034995	On the contrary, the luciferase activity of mutated p-MIR-reporter vector with introduced point mutations within the miR-1 binding site remained steady under the overexpression manipulation (Fig.	('activity', 'MPA', (32, 40))	('point mutations', 'Var', (90, 105))	('miR', 'Gene', '220972', (117, 120))	('luciferase', 'Enzyme', (21, 31))	('miR', 'Gene', (117, 120))	('MIR', 'Gene', '220972', (54, 57))	('MIR', 'Gene', (54, 57))
914245	29034995	As a result, knockdown of Src by siRNA lowered proliferation rate and raised apoptosis of TE-1 cells (Fig.	('raised', 'PosReg', (70, 76))	('lowered', 'NegReg', (39, 46))	('Src', 'Gene', (26, 29))	('Src', 'Gene', '6714', (26, 29))	('apoptosis', 'CPA', (77, 86))	('proliferation rate', 'CPA', (47, 65))	('TE-1', 'CellLine', 'CVCL:1759', (90, 94))	('knockdown', 'Var', (13, 22))
914248	29034995	Moreover, to highlight the core roles of Src in modulating these biological processes, we simultaneously transfected the cells with miR-1 mimic and vectors carrying the ORF of Src without the miR-1-responsive 3'-UTR, expecting the effects of miR-1 could be attenuated by Src overexpression.	('miR', 'Gene', '220972', (192, 195))	('miR', 'Gene', (192, 195))	('Src', 'Gene', (271, 274))	('Src', 'Gene', '6714', (271, 274))	('Src', 'Gene', (41, 44))	('Src', 'Gene', '6714', (41, 44))	('Src', 'Gene', (176, 179))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', (132, 135))	('miR', 'Gene', '220972', (242, 245))	('miR', 'Gene', (242, 245))	('Src', 'Gene', '6714', (176, 179))	('ORF', 'Var', (169, 172))
914263	29034995	Pro-proliferative and antiapoptotic functions of Src in TE-1 cells were further unraveled with silencing and overexpression manipulations.	('antiapoptotic functions', 'CPA', (22, 45))	('Src', 'Gene', (49, 52))	('Src', 'Gene', '6714', (49, 52))	('silencing', 'Var', (95, 104))	('Pro-proliferative', 'CPA', (0, 17))	('TE-1', 'CellLine', 'CVCL:1759', (56, 60))
914265	29034995	Surprisingly, not only the presence or absence but also single nucleotide polymorphisms(SNPs) of these posttranscriptional regulators can contribute to tumorigenesis 26, 27, suggesting their mighty and irreplaceable roles played in this biological process.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('absence', 'NegReg', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('single nucleotide polymorphisms', 'Var', (56, 87))	('tumor', 'Disease', (152, 157))	('contribute', 'Reg', (138, 148))
914273	29034995	For instance, miR-1 expresses in a chamber-specific manner during cardiogenesis and misregulation of miR-1 causes heart defects.	('miR', 'Gene', '220972', (101, 104))	('heart defects', 'Disease', 'MESH:D006331', (114, 127))	('heart defects', 'Phenotype', 'HP:0030680', (114, 127))	('causes', 'Reg', (107, 113))	('misregulation', 'Var', (84, 97))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('heart defects', 'Disease', (114, 127))	('miR', 'Gene', (101, 104))
914275	29034995	Loss of miR-1 also leads to the expression of GJA1 (connexin 43) and CACNA1C (Cav1.2) to generate calcium- and gap-junction channels in myotonic dystrophy 36.	('CACNA1C', 'Gene', '775', (69, 76))	('miR', 'Gene', '220972', (8, 11))	('Cav1.2', 'Gene', '775', (78, 84))	('connexin 43', 'Gene', (52, 63))	('myotonic dystrophy', 'Disease', (136, 154))	('CACNA1C', 'Gene', (69, 76))	('myotonic dystrophy', 'Disease', 'MESH:D009223', (136, 154))	('generate', 'PosReg', (89, 97))	('connexin 43', 'Gene', '2697', (52, 63))	('GJA1', 'Gene', (46, 50))	('Cav1.2', 'Gene', (78, 84))	('leads to', 'Reg', (19, 27))	('Loss', 'Var', (0, 4))	('miR', 'Gene', (8, 11))	('GJA1', 'Gene', '2697', (46, 50))
914282	28912415	The role of cell proliferation, clonogenic survival, migration, and invasion in vitro, as well as the sensitization to paclitaxel, were determined after knockdown of ATF1 by siRNA.	('knockdown', 'Var', (153, 162))	('invasion', 'CPA', (68, 76))	('ATF1', 'Gene', (166, 170))	('migration', 'CPA', (53, 62))	('clonogenic survival', 'CPA', (32, 51))	('paclitaxel', 'Chemical', 'MESH:D017239', (119, 129))
914284	28912415	Moreover, silencing of ATF1 significantly enhanced the sensitivity of esophageal cancer cells to paclitaxel.	('esophageal cancer', 'Disease', (70, 87))	('sensitivity', 'MPA', (55, 66))	('enhanced', 'PosReg', (42, 50))	('paclitaxel', 'Chemical', 'MESH:D017239', (97, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('ATF1', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('silencing', 'Var', (10, 19))
914295	28912415	Moreover, silencing of ATF1 significantly sensitized ESCC cells to paclitaxel.	('sensitized', 'Reg', (42, 52))	('ESCC', 'Disease', (53, 57))	('paclitaxel', 'Chemical', 'MESH:D017239', (67, 77))	('ATF1', 'Gene', (23, 27))	('silencing', 'Var', (10, 19))
914306	28912415	EC1 cells were transfected with ATF1 siRNA or negative control siRNA.	('EC1', 'Gene', (0, 3))	('ATF1', 'Var', (32, 36))	('EC1', 'Gene', '4819', (0, 3))
914315	28912415	Results showed that knockdown of ATF1 by specific siRNA, siATF1-1, significantly inhibited cell proliferation (Figure 2A-2C) and colony formation (Figure 2D, 2E) in both EC1 and Kyse450 cells.	('inhibited', 'NegReg', (81, 90))	('colony formation', 'CPA', (129, 145))	('ATF1', 'Gene', (33, 37))	('EC1', 'Gene', (170, 173))	('knockdown', 'Var', (20, 29))	('EC1', 'Gene', '4819', (170, 173))	('cell proliferation', 'CPA', (91, 109))
914317	28912415	As shown in Figure 3, knockdown of ATF1 triggered S cell cycle arrest in both EC1 and Kyse450 cells.	('EC1', 'Gene', '4819', (78, 81))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('EC1', 'Gene', (78, 81))	('cell cycle arrest', 'CPA', (52, 69))	('knockdown', 'Var', (22, 31))	('ATF1', 'Gene', (35, 39))
914320	28912415	Results showed that knockdown of ATF1 inhibited soft agar colony capacity of EC1 cell (Figure 4A), and downregulating the expression of ATF1 inhibited EC1 cell invasion by transwell assay (Figure 4B) and cell migration by wound-healing assay (Figure 4C).	('ATF1', 'Gene', (136, 140))	('downregulating', 'NegReg', (103, 117))	('agar', 'Chemical', 'MESH:D000362', (53, 57))	('expression', 'MPA', (122, 132))	('EC1', 'Gene', (151, 154))	('EC1', 'Gene', '4819', (151, 154))	('inhibited', 'NegReg', (38, 47))	('cell migration', 'CPA', (204, 218))	('ATF1', 'Gene', (33, 37))	('knockdown', 'Var', (20, 29))	('EC1', 'Gene', (77, 80))	('inhibited', 'NegReg', (141, 150))	('EC1', 'Gene', '4819', (77, 80))
914322	28912415	Results showed that knockdown of ATF1 significantly enhanced the cytotoxicity of paclitaxel and inhibited cell growth in a dose-dependent manner (Figure 5).	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('enhanced', 'PosReg', (52, 60))	('paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('ATF1', 'Gene', (33, 37))	('cell growth', 'CPA', (106, 117))	('cytotoxicity', 'Disease', (65, 77))	('inhibited', 'NegReg', (96, 105))	('knockdown', 'Var', (20, 29))
914332	28912415	Overexpression of ATF1 has been shown to upregulate the expression of matrix metalloproteinase 2 (MMP-2) and contributes to the acquisition of the metastatic phenotype in melanoma cells.	('contributes', 'Reg', (109, 120))	('ATF1', 'Gene', (18, 22))	('MMP-2', 'Gene', '4313', (98, 103))	('matrix metalloproteinase 2', 'Gene', '4313', (70, 96))	('matrix metalloproteinase 2', 'Gene', (70, 96))	('upregulate', 'PosReg', (41, 51))	('expression', 'MPA', (56, 66))	('melanoma', 'Disease', (171, 179))	('Overexpression', 'Var', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('MMP-2', 'Gene', (98, 103))
914342	28912415	Here, we demonstrate that silencing of ATF1 enhanced the cytotoxicity of paclitaxel in ESCC cells and suggests that targeting ATF1 may be an effective means of increasing paclitaxel efficacy.	('increasing', 'PosReg', (160, 170))	('ATF1', 'Gene', (126, 130))	('cytotoxicity', 'Disease', (57, 69))	('paclitaxel', 'Chemical', 'MESH:D017239', (73, 83))	('paclitaxel', 'Chemical', 'MESH:D017239', (171, 181))	('silencing', 'Var', (26, 35))	('cytotoxicity', 'Disease', 'MESH:D064420', (57, 69))	('ATF1', 'Gene', (39, 43))	('enhanced', 'PosReg', (44, 52))
914344	28912415	Furthermore, silencing of ATF1 significantly enhanced the efficiency of paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (72, 82))	('paclitaxel', 'Enzyme', (72, 82))	('enhanced', 'PosReg', (45, 53))	('efficiency', 'MPA', (58, 68))	('ATF1', 'Gene', (26, 30))	('silencing', 'Var', (13, 22))
914396	26765443	Among the patients with a follow-up duration <=5 years, those with SCI exhibited a significantly higher risk of hematologic malignancy and liver cancer and had a significantly lower risk of colorectal cancer compared with the patients without SCI (Table 5).	('hematologic malignancy', 'Disease', (112, 134))	('liver cancer', 'Disease', (139, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SCI', 'Var', (67, 70))	('hematologic malignancy', 'Disease', 'MESH:D019337', (112, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (190, 207))	('hematologic malignancy', 'Phenotype', 'HP:0004377', (112, 134))	('patients', 'Species', '9606', (226, 234))	('liver cancer', 'Disease', 'MESH:D006528', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('patients', 'Species', '9606', (10, 18))	('liver cancer', 'Phenotype', 'HP:0002896', (139, 151))	('SCI', 'Phenotype', 'HP:0100561', (67, 70))	('colorectal cancer', 'Disease', (190, 207))	('SCI', 'Phenotype', 'HP:0100561', (243, 246))
914404	26765443	In this study, a significantly lower risk of colorectal cancer was found in the SCI group compared with the control group.	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('colorectal cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lower', 'NegReg', (31, 36))	('SCI', 'Var', (80, 83))	('colorectal cancer', 'Disease', 'MESH:D015179', (45, 62))	('SCI', 'Phenotype', 'HP:0100561', (80, 83))
914407	26765443	In a study of colonoscopic lesions in patients with SCI, Han et al found no difference in cancer detection between an SCI and control group; inflammatory bowel disease, which is a risk factor for cancer, was more common in the SCI group, but not significantly so (P = 0.06).	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('SCI', 'Var', (227, 230))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (141, 167))	('inflammatory bowel disease', 'Disease', (141, 167))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (141, 167))	('cancer', 'Disease', (196, 202))	('SCI', 'Phenotype', 'HP:0100561', (227, 230))	('patients', 'Species', '9606', (38, 46))	('SCI', 'Phenotype', 'HP:0100561', (52, 55))	('SCI', 'Phenotype', 'HP:0100561', (118, 121))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
914444	22675487	Hospital stay was long with thransthoracic resection (WMD =  -5.80, 95% CI -10.38- -1.23) but did not seem to differ in number of harvested lymph nodes, operation time, blood loss, numbers of patients needing transfusion, and reoperation rate.	('thransthoracic', 'Var', (28, 42))	('needing transfusion', 'Phenotype', 'HP:0011888', (201, 220))	('blood loss', 'Disease', 'MESH:D006473', (169, 179))	('patients', 'Species', '9606', (192, 200))	('blood loss', 'Disease', (169, 179))
914476	22675487	Our result showed no obvious differences were observed between the group with transthoracic resection and group without transthoracic resection for type 2 and 3 GEJ cancers (Table 3, Figure 2).	('transthoracic', 'Var', (78, 91))	('GEJ cancers', 'Disease', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('GEJ cancers', 'Disease', 'MESH:D009369', (161, 172))
914477	22675487	These analyses showed that the incidences of complications, such as anastomotic leakage, wound infection, cardiovascular complications, and hoarseness were not significantly different between patients treated with transthrocotomy and those without transthrocotomy (P>0.05).	('cardiovascular complications', 'Disease', (106, 134))	('cardiovascular complications', 'Disease', 'MESH:D002318', (106, 134))	('anastomotic leak', 'Disease', 'MESH:D057868', (68, 84))	('hoarseness', 'Phenotype', 'HP:0001609', (140, 150))	('patients', 'Species', '9606', (192, 200))	('anastomotic leak', 'Disease', (68, 84))	('transthrocotomy', 'Var', (214, 229))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (106, 134))	('hoarseness', 'Disease', (140, 150))
914480	22675487	Patients undergoing transthrocotomy seemed to experience more chylous leakage and longer ICU stay than patients without transthrocotomy (P<0.05) (Table 4).	('transthrocotomy', 'Var', (20, 35))	('longer', 'PosReg', (82, 88))	('chylous leakage', 'MPA', (62, 77))	('Patients', 'Species', '9606', (0, 8))	('ICU stay', 'MPA', (89, 97))	('patients', 'Species', '9606', (103, 111))	('longer ICU stay', 'Phenotype', 'HP:0007906', (82, 97))
914481	22675487	Hospital stay was long with thransthoracic resection (WMD = -5.80, 95% CI -10.38- -1.23) but did not seem to differ in number of harvested lymph nodes, operation time, blood loss, numbers of patients needing transfusion, and reoperation rate (Table 5).	('needing transfusion', 'Phenotype', 'HP:0011888', (200, 219))	('thransthoracic', 'Var', (28, 42))	('patients', 'Species', '9606', (191, 199))	('blood loss', 'Disease', (168, 178))	('blood loss', 'Disease', 'MESH:D006473', (168, 178))
914485	22675487	Furthermore, non-transthoracic resection theoretically minimizes respiratory complications, decreases risk of anastomotic leakage, reduces the incidence of postoperative symptoms associated to gastroesophageal reflux, and avoids a painful incision of transthoracic resection.	('respiratory complications', 'MPA', (65, 90))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (193, 216))	('respiratory complications', 'Phenotype', 'HP:0011947', (65, 90))	('non-transthoracic', 'Var', (13, 30))	('reduces', 'NegReg', (131, 138))	('minimizes', 'NegReg', (55, 64))	('anastomotic leak', 'Disease', 'MESH:D057868', (110, 126))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (193, 216))	('gastroesophageal reflux', 'Disease', (193, 216))	('anastomotic leak', 'Disease', (110, 126))
914489	22675487	And for type 2 and 3 cancers, our results also showed no obvious differences were observed between the groups with transthoracic resection and without transthoracic resection for survival.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('transthoracic', 'Var', (115, 128))
914491	22675487	Although some authors reported there were no significant differences of pulmonary complications between transthoracic resection and non-transthoracic resection, more pulmonary complications were observed following transthoracic resection.	('pulmonary complications', 'Disease', 'MESH:D008171', (72, 95))	('transthoracic', 'Var', (214, 227))	('pulmonary complications', 'Phenotype', 'HP:0006532', (166, 189))	('pulmonary complications', 'Disease', (166, 189))	('pulmonary complications', 'Disease', 'MESH:D008171', (166, 189))	('pulmonary complications', 'Phenotype', 'HP:0006532', (72, 95))	('pulmonary complications', 'Disease', (72, 95))
914493	22675487	There seemed to be a higher incidence of chylous leakage and longer ICU stay in patients undergoing transthrocotomy than patients without transthrocotomy.	('patients', 'Species', '9606', (80, 88))	('transthrocotomy', 'Var', (100, 115))	('ICU stay', 'MPA', (68, 76))	('chylous leakage', 'Disease', (41, 56))	('longer ICU stay', 'Phenotype', 'HP:0007906', (61, 76))	('patients', 'Species', '9606', (121, 129))
914496	22675487	Other analyses failed to show any significant differences on the incidences of complications, such as wound infection, cardiovascular complications, and hoarseness, between patients treated with transthrocotomy and those without transthrocotomy.	('hoarseness', 'Phenotype', 'HP:0001609', (153, 163))	('patients', 'Species', '9606', (173, 181))	('transthrocotomy', 'Var', (195, 210))	('hoarseness', 'Disease', (153, 163))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (119, 147))	('wound infection', 'Disease', (102, 117))	('cardiovascular complications', 'Disease', 'MESH:D002318', (119, 147))	('cardiovascular complications', 'Disease', (119, 147))
914498	22675487	At the same time, with respect to the operation related events, transthoracic resection had significant differences from non-transthoracic resection in length of hospital stay, and was apt to more blood loss and longer operation time despite of no statistical differences.	('transthoracic', 'Var', (64, 77))	('more', 'PosReg', (192, 196))	('blood loss', 'Disease', 'MESH:D006473', (197, 207))	('differences', 'Reg', (104, 115))	('blood loss', 'Disease', (197, 207))
914505	22675487	Compared with patients with type III tumors, pN0 and pM0 categories were more common in patients with type I and II tumors.	('type III tumors', 'Disease', 'MESH:D009369', (28, 43))	('pN0', 'Var', (45, 48))	('patients', 'Species', '9606', (88, 96))	('type III tumors', 'Disease', (28, 43))	('II tumors', 'Disease', (113, 122))	('II tumors', 'Disease', 'MESH:D009369', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('type I', 'Disease', (102, 108))	('common', 'Reg', (78, 84))	('II tumors', 'Disease', 'MESH:D009369', (34, 43))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('patients', 'Species', '9606', (14, 22))
914513	33146702	miR-19b-3p transferred by exosomes could significantly reduce EC9706 cells apoptosis rate, promote cell migration and invasion, and could target the inhibition of PTEN expression.	('EC9706 cells apoptosis rate', 'CPA', (62, 89))	('promote', 'PosReg', (91, 98))	('expression', 'MPA', (168, 178))	('miR-19b-3p', 'Var', (0, 10))	('PTEN', 'Gene', (163, 167))	('EC9706', 'CellLine', 'CVCL:E307', (62, 68))	('PTEN', 'Gene', '5728', (163, 167))	('reduce', 'NegReg', (55, 61))	('invasion', 'CPA', (118, 126))	('miR-19b-3p', 'Chemical', '-', (0, 10))
914515	33146702	In summary, our results reveal that miR-19b-3p transferred by exosomes can target PTEN to regulate ESCA biological functions in the receptor EC9706 cells.	('ESCA biological functions', 'MPA', (99, 124))	('EC9706', 'CellLine', 'CVCL:E307', (141, 147))	('miR-19b-3p', 'Chemical', '-', (36, 46))	('PTEN', 'Gene', (82, 86))	('regulate', 'Reg', (90, 98))	('PTEN', 'Gene', '5728', (82, 86))	('miR-19b-3p', 'Var', (36, 46))
914528	33146702	Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('reduces', 'NegReg', (72, 79))	('tumor', 'Disease', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('miRNA-142-3p inhibitor', 'Var', (49, 71))
914530	33146702	MiR-19b-3p promotes human pancreatic cancer Capan-2 cells proliferation by targeting phosphatase and tension homolog (PTEN).	('human', 'CPA', (20, 25))	('human', 'Species', '9606', (20, 25))	('Capan-2', 'CellLine', 'CVCL:0026', (44, 51))	('MiR-19b-3p', 'Chemical', '-', (0, 10))	('targeting', 'Reg', (75, 84))	('phosphatase', 'Protein', (85, 96))	('PTEN', 'Gene', '5728', (118, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('PTEN', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('promotes', 'PosReg', (11, 19))	('pancreatic cancer', 'Disease', (26, 43))	('MiR-19b-3p', 'Var', (0, 10))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))
914531	33146702	MiR-19b-3p is associated with the risk and severity of knee osteoarthritis and induced extracellular matrix degradation and inflammatory injury in chondrocytes, and can be used as a potential biomarker for diseases such as Alzheimer's disease and gastric cancer.	('extracellular matrix degradation', 'MPA', (87, 119))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (223, 242))	('gastric cancer', 'Phenotype', 'HP:0012126', (247, 261))	('knee osteoarthritis', 'Phenotype', 'HP:0005086', (55, 74))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('MiR-19b-3p', 'Chemical', '-', (0, 10))	("Alzheimer's disease", 'Disease', (223, 242))	('gastric cancer', 'Disease', 'MESH:D013274', (247, 261))	('inflammatory injury', 'Disease', 'MESH:D007249', (124, 143))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (223, 242))	('associated', 'Reg', (14, 24))	('inflammatory injury', 'Disease', (124, 143))	('osteoarthritis', 'Phenotype', 'HP:0002758', (60, 74))	('osteoarthritis', 'Disease', (60, 74))	('gastric cancer', 'Disease', (247, 261))	('induced', 'Reg', (79, 86))	('MiR-19b-3p', 'Var', (0, 10))	('osteoarthritis', 'Disease', 'MESH:D010003', (60, 74))
914533	33146702	In addition, some scholars found that miR-19b-3p inhibits breast cancer cell proliferation by regulating PI3K/Akt pathway.	('Akt', 'Gene', (110, 113))	('miR-19b-3p', 'Var', (38, 48))	('inhibits', 'NegReg', (49, 57))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('PI3', 'Gene', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('miR-19b-3p', 'Chemical', '-', (38, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('Akt', 'Gene', '207', (110, 113))	('PI3', 'Gene', '5266', (105, 108))
914535	33146702	Study have reported that cancer stem cells exosomes transported miR-19b-3p into clear cell renal cell carcinoma cells and initiated EMT promoting metastasis.	('miR-19b-3p', 'Var', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('initiated', 'PosReg', (122, 131))	('renal cell carcinoma', 'Disease', (91, 111))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('EMT', 'Gene', (132, 135))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (80, 111))	('EMT', 'Gene', '3702', (132, 135))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('miR-19b-3p', 'Chemical', '-', (64, 74))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (91, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Disease', (25, 31))
914536	33146702	However, the molecular regulatory mechanism of exosome-transferred miR-19b-3p in ESCA is unknown.	('ESCA', 'Disease', (81, 85))	('miR-19b-3p', 'Var', (67, 77))	('miR-19b-3p', 'Chemical', '-', (67, 77))
914540	33146702	About 10% exosomes-free FBS and 1% penicillin/streptomycin (15140163, ThermoFisher, U.S.A.) were added to RPMI-1640 medium (61870044, ThermoFisher, U.S.A.) to get a cell complete medium.	('streptomycin', 'Chemical', 'MESH:D013307', (46, 58))	('15140163', 'Var', (60, 68))	('RPMI-1640 medium', 'Chemical', '-', (106, 122))	('penicillin', 'Chemical', 'MESH:D010406', (35, 45))	('61870044', 'Var', (124, 132))
914542	33146702	The pcDNA3.1 (V79520) and PTEN (A15629, A15630) were purchased from ThermoFisher Company, and mimic control (miR1N0000001-1-5), miR-19b-3p mimic (MQPS0000777-1-100) were obtained from RIBOBIO Company (https://www.ribobio.com/).	('miR-19b-3p', 'Chemical', '-', (128, 138))	('A15629', 'Var', (32, 38))	('PTEN', 'Gene', (26, 30))	('PTEN', 'Gene', '5728', (26, 30))
914543	33146702	EC9706 cells were transfected with miR-19b-3p mimic or PTEN.	('miR-19b-3p mimic', 'Var', (35, 51))	('PTEN', 'Gene', '5728', (55, 59))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('miR-19b-3p', 'Chemical', '-', (35, 45))	('PTEN', 'Gene', (55, 59))
914563	33146702	At the interface between the gel and the concentrated gel, the voltage was changed to 120 V, and then the protein was transferred to the PVDF membrane (HVLP04700, Millipore, U.S.A.) under a constant current of 200 mA for 2 h. After blocking for 2 h, primary antibodies as PTEN (1/1000, #9552, 54 KD, Cell Signaling Technology, U.S.A.), MMP-2 (1 mug/ml, ab37150, 72 KD, Abcam), E-Cadherin (1/1000, #14472, 80KD, CST), Vimentin (1/1000, ab92547, 54 KD, Abcam), and GAPDH (1/5000, ab8245, 36KD, Abcam) were incubated at 4 C overnight.	('PTEN', 'Gene', '5728', (272, 276))	('MMP-2', 'Gene', (336, 341))	('GAPDH', 'Gene', '2597', (463, 468))	('GAPDH', 'Gene', (463, 468))	('1/1000', 'Var', (427, 433))	('Vimentin', 'Gene', (417, 425))	('CST', 'Gene', (411, 414))	('KD', 'Disease', 'MESH:C537017', (447, 449))	('Vimentin', 'Gene', '7431', (417, 425))	('E-Cadherin', 'Gene', (377, 387))	('KD', 'Disease', 'MESH:C537017', (296, 298))	('MMP-2', 'Gene', '4313', (336, 341))	('KD', 'Disease', 'MESH:C537017', (365, 367))	('KD', 'Disease', 'MESH:C537017', (488, 490))	('E-Cadherin', 'Gene', '999', (377, 387))	('CST', 'Gene', '106478911', (411, 414))	('KD', 'Disease', 'MESH:C537017', (407, 409))	('PTEN', 'Gene', (272, 276))
914564	33146702	Corresponding secondary antibodies such as Goat Anti-Rabbit IgG H&L (HRP) (1:5000, ab205718) and Goat Anti-Mouse IgG H&L (HRP) (1:5000, ab205719) were incubated at room temperature for 2 h, and TBST was used to wash the membrane for three times, 10 min/time.	(') (', 'Var', (72, 75))	('HRP', 'Var', (122, 125))	('TBST', 'Chemical', '-', (194, 198))
914579	33146702	To verify the database prediction results, RT-qPCR was used to compare the miR-19b-3p expression in the plasma of healthy controls and ESCA patients, showing that the expression of miR-19b-3p in the plasma of ESCA patients was apparently higher than that of healthy samples (P<0.001, Figure 1B).	('higher', 'PosReg', (238, 244))	('ESCA', 'Disease', (209, 213))	('miR-19b-3p', 'Var', (181, 191))	('patients', 'Species', '9606', (214, 222))	('miR-19b-3p', 'Chemical', '-', (75, 85))	('miR-19b-3p', 'Chemical', '-', (181, 191))	('patients', 'Species', '9606', (140, 148))	('expression', 'MPA', (167, 177))
914583	33146702	After miR-19b-3p transfection, miR-19b-3p expression was apparently up-regulated in donor cells and exosomes, while miR-19b-3p expression was also remarkable up-regulated in recipient cells (P<0.001, Figure 2C).	('miR-19b-3p', 'Chemical', '-', (31, 41))	('miR-19b-3p transfection', 'Var', (6, 29))	('transfection', 'Var', (17, 29))	('expression', 'MPA', (42, 52))	('miR-19b-3p', 'Chemical', '-', (116, 126))	('miR-19b-3p', 'Gene', (31, 41))	('up-regulated', 'PosReg', (68, 80))	('miR-19b-3p', 'Chemical', '-', (6, 16))
914584	33146702	After co-culture of EC9706 cells (donor cells) transfected with cy3- miR-19b-3p mimic and GFP-EC9706 cells (recipient cells) for 24 h, the cy3-miR-19b-3p content in the recipient cells was increased significantly (magnification x 100, scale bar = 100 mum, Figure 2D).	('EC9706', 'CellLine', 'CVCL:E307', (20, 26))	('cy3-miR-19b-3p', 'Chemical', '-', (139, 153))	('miR-19b-3p', 'Chemical', '-', (69, 79))	('cy3- miR-19b-3p', 'Var', (64, 79))	('cy3', 'Chemical', '-', (139, 142))	('EC9706', 'CellLine', 'CVCL:E307', (94, 100))	('cy3-miR-19b-3p content', 'MPA', (139, 161))	('GFP-EC9706', 'Var', (90, 100))	('miR-19b-3p', 'Chemical', '-', (143, 153))	('cy3', 'Chemical', '-', (64, 67))	('increased', 'PosReg', (189, 198))
914586	33146702	Flow cytometry results showed that miR-19b-3p transferred by exosomes could significantly reduce the apoptosis rates of recipient cells (P<0.001, Figure 3A,B).	('apoptosis rates of recipient cells', 'CPA', (101, 135))	('miR-19b-3p', 'Var', (35, 45))	('reduce', 'NegReg', (90, 96))	('miR-19b-3p', 'Chemical', '-', (35, 45))
914590	33146702	Luciferase analysis showed that miR-19b-3p up-regulation could significantly inhibit the fluorescence of PTEN-WT, but had no effect on the fluorescence of PTEN-MUT (P<0.001, Figure 4B).	('fluorescence', 'MPA', (89, 101))	('PTEN', 'Gene', (155, 159))	('PTEN', 'Gene', '5728', (155, 159))	('inhibit', 'NegReg', (77, 84))	('miR-19b-3p', 'Chemical', '-', (32, 42))	('PTEN', 'Gene', (105, 109))	('PTEN', 'Gene', '5728', (105, 109))	('up-regulation', 'PosReg', (43, 56))	('miR-19b-3p', 'Var', (32, 42))
914591	33146702	RT-qPCR and Western blot were used to detect the effect of donor-derived exosomes miR-19b-3p on the expression of PTEN in EC9706 cells after co-culture for 24 h, and found that miR-19b-3p transferred by exosomes could effectively target the inhibition of PTEN expression in recipient cells (P<0.001, Figure 4C-E).	('expression', 'MPA', (260, 270))	('EC9706', 'CellLine', 'CVCL:E307', (122, 128))	('miR-19b-3p', 'Chemical', '-', (177, 187))	('PTEN', 'Gene', (114, 118))	('PTEN', 'Gene', '5728', (114, 118))	('miR-19b-3p', 'Chemical', '-', (82, 92))	('PTEN', 'Gene', '5728', (255, 259))	('PTEN', 'Gene', (255, 259))	('miR-19b-3p', 'Var', (177, 187))
914592	33146702	In order to further understand the effects of exosomes-transferred miR-19b-3p and PTEN on regulating the motor capacity of the receptor EC9706 cells, overexpressing PTEN and miR-19b-3p transferred by exosomes were successfully transfected into cells for research.	('EC9706', 'CellLine', 'CVCL:E307', (136, 142))	('miR-19b-3p', 'Var', (174, 184))	('miR-19b-3p', 'Chemical', '-', (67, 77))	('miR-19b-3p', 'Chemical', '-', (174, 184))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))	('PTEN', 'Gene', (165, 169))	('PTEN', 'Gene', '5728', (165, 169))
914593	33146702	Our results showed that overexpression of PTEN could effectively promote the expression of PTEN in recipient cells, and miR-19b-3p transferred by exosomes could effectively reverse the up-regulation of PTEN expression (P<0.001, Figure 5A-C).	('up-regulation', 'PosReg', (185, 198))	('PTEN', 'Gene', (42, 46))	('expression', 'MPA', (77, 87))	('PTEN', 'Gene', '5728', (42, 46))	('miR-19b-3p', 'Chemical', '-', (120, 130))	('promote', 'PosReg', (65, 72))	('PTEN', 'Gene', (202, 206))	('PTEN', 'Gene', (91, 95))	('expression', 'MPA', (207, 217))	('PTEN', 'Gene', '5728', (202, 206))	('PTEN', 'Gene', '5728', (91, 95))	('miR-19b-3p', 'Var', (120, 130))
914594	33146702	PTEN overexpression could promote apoptosis, while miR-19b-3p transferred by exosomes significantly reversed the effect of PTEN overexpression on the apoptosis of recipient cells (P<0.001, Figure 5D,E).	('miR-19b-3p', 'Var', (51, 61))	('apoptosis', 'CPA', (34, 43))	('PTEN', 'Gene', (123, 127))	('PTEN', 'Gene', '5728', (123, 127))	('PTEN', 'Gene', (0, 4))	('miR-19b-3p', 'Chemical', '-', (51, 61))	('PTEN', 'Gene', '5728', (0, 4))
914596	33146702	PTEN overexpression can significantly inhibit cell invasion, while miR-19b-3p transferred by exosomes significantly reversed the inhibitory effect of PTEN overexpression on cell invasion (P<0.001, Figure 6C,D).	('miR-19b-3p', 'Chemical', '-', (67, 77))	('cell invasion', 'CPA', (46, 59))	('miR-19b-3p', 'Var', (67, 77))	('PTEN', 'Gene', (150, 154))	('PTEN', 'Gene', (0, 4))	('inhibit', 'NegReg', (38, 45))	('PTEN', 'Gene', '5728', (150, 154))	('PTEN', 'Gene', '5728', (0, 4))
914597	33146702	In addition, overexpression of PTEN could significantly down-regulate MMP-2 and vimentin, and up-regulate E-cadherin; and miR-19b-3p transferred by exosomes significantly inhibited the regulation of PTEN overexpression on EMT-related proteins (P<0.001, Figure 6E-G).	('PTEN', 'Gene', '5728', (199, 203))	('PTEN', 'Gene', (31, 35))	('miR-19b-3p', 'Var', (122, 132))	('EMT', 'Gene', '3702', (222, 225))	('PTEN', 'Gene', '5728', (31, 35))	('up-regulate', 'PosReg', (94, 105))	('miR-19b-3p', 'Chemical', '-', (122, 132))	('vimentin', 'Gene', '7431', (80, 88))	('inhibited', 'NegReg', (171, 180))	('MMP-2', 'Gene', (70, 75))	('vimentin', 'Gene', (80, 88))	('E-cadherin', 'Gene', (106, 116))	('down-regulate', 'NegReg', (56, 69))	('regulation', 'MPA', (185, 195))	('E-cadherin', 'Gene', '999', (106, 116))	('MMP-2', 'Gene', '4313', (70, 75))	('PTEN', 'Gene', (199, 203))	('EMT', 'Gene', (222, 225))
914603	33146702	miR-19b-3p is abnormally expressed in many cancers such as breast cancer and pancreatic cancer.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('miR-19b-3p', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('cancers', 'Disease', (43, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('miR-19b-3p', 'Chemical', '-', (0, 10))	('pancreatic cancer', 'Disease', (77, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
914604	33146702	found that miR-19b-3p is up-regulated in nasopharyngeal carcinoma, and miR-19b-3p increases the radiation resistance of nasopharyngeal carcinoma cells by activating the TNFAIP3/NF-kappaB signaling pathway.	('TNFAIP3', 'Gene', '7128', (169, 176))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (120, 144))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (41, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('NF-kappaB', 'Gene', (177, 186))	('miR-19b-3p', 'Chemical', '-', (71, 81))	('TNFAIP3', 'Gene', (169, 176))	('carcinoma', 'Disease', (56, 65))	('radiation resistance', 'CPA', (96, 116))	('increases', 'PosReg', (82, 91))	('carcinoma', 'Disease', 'MESH:D009369', (56, 65))	('carcinoma', 'Disease', (135, 144))	('miR-19b-3p', 'Var', (71, 81))	('miR-19b-3p', 'Chemical', '-', (11, 21))	('carcinoma', 'Disease', 'MESH:D009369', (135, 144))	('NF-kappaB', 'Gene', '4790', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('activating', 'PosReg', (154, 164))
914606	33146702	We found miR-19b-3p was higher in ESCA samples, plasma, and cells than in the healthy group, suggesting that miR-19b-3p may play a tumorigenic role in the progression of ESCA.	('miR-19b-3p', 'Chemical', '-', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('miR-19b-3p', 'Chemical', '-', (109, 119))	('tumor', 'Disease', (131, 136))	('ESCA', 'Disease', (170, 174))	('miR-19b-3p', 'Var', (109, 119))	('play', 'Reg', (124, 128))
914611	33146702	For example, miR-21 was highly expression in exosomes in ESCA, and anti-miR-21 inhibited the chemotherapy resistance of ESCA in vitro; exosome-derived miR-339-5p mediates radiosensitivity by targeting Cdc25A in locally advanced esophageal squamous cell carcinoma.	('miR-21', 'Gene', '406991', (72, 78))	('Cdc25A', 'Gene', (201, 207))	('targeting', 'Reg', (191, 200))	('esophageal squamous cell carcinoma', 'Disease', (228, 262))	('miR-21', 'Gene', (13, 19))	('Cdc25A', 'Gene', '993', (201, 207))	('miR-21', 'Gene', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('miR-339-5p', 'Chemical', '-', (151, 161))	('miR-21', 'Gene', '406991', (13, 19))	('chemotherapy resistance', 'CPA', (93, 116))	('inhibited', 'NegReg', (79, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (239, 262))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (228, 262))	('miR-339-5p', 'Var', (151, 161))
914612	33146702	miR-19b-3p In the present study, an in vitro cell co-culture model that simulated ESCA microenvironment was established and the effects of ESCA-derived exosomes transferred miR-19b-3p on EC9706 cells was further explored.	('miR-19b-3p', 'Chemical', '-', (173, 183))	('miR-19b-3p', 'Var', (0, 10))	('EC9706', 'CellLine', 'CVCL:E307', (187, 193))	('miR-19b-3p', 'Var', (173, 183))	('miR-19b-3p', 'Chemical', '-', (0, 10))
914613	33146702	We found that miR-19b-3p transferred by exosomes from donor cells could enter the recipient cells and regulate their apoptosis, migration and invasion.	('miR-19b-3p', 'Chemical', '-', (14, 24))	('regulate', 'Reg', (102, 110))	('migration', 'CPA', (128, 137))	('miR-19b-3p', 'Var', (14, 24))	('apoptosis', 'CPA', (117, 126))	('invasion', 'CPA', (142, 150))
914614	33146702	It is suggested that miR-19b-3p transferred by exosomes may play a role as an oncogene in ESCA.	('ESCA', 'Disease', (90, 94))	('miR-19b-3p', 'Var', (21, 31))	('miR-19b-3p', 'Chemical', '-', (21, 31))
914615	33146702	miR-19b-3p, which is a complex molecular regulatory network with target genes and related signaling pathways, plays a key role in the development of cancer.	('cancer', 'Disease', (149, 155))	('miR-19b-3p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('miR-19b-3p', 'Chemical', '-', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
914618	33146702	Mutation or inactivation of PTEN gene is closely related to tumorigenesis, metastasis, deterioration and prognosis.	('PTEN', 'Gene', (28, 32))	('PTEN', 'Gene', '5728', (28, 32))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('metastasis', 'CPA', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('related', 'Reg', (49, 56))	('inactivation', 'Var', (12, 24))	('tumor', 'Disease', (60, 65))
914620	33146702	Our research showed that miR-19b-3p transferred by exosomes can effectively target the inhibition of PTEN expression in recipient cells, suggesting that PTEN may be one of the pathways for miR-19b-3p transferred by exosomes to promote ESCA progression.	('miR-19b-3p', 'Var', (189, 199))	('PTEN', 'Gene', (101, 105))	('PTEN', 'Gene', '5728', (101, 105))	('PTEN', 'Gene', (153, 157))	('PTEN', 'Gene', '5728', (153, 157))	('promote', 'PosReg', (227, 234))	('ESCA', 'Disease', (235, 239))	('miR-19b-3p', 'Chemical', '-', (189, 199))	('miR-19b-3p', 'Chemical', '-', (25, 35))
914627	33146702	More importantly, our research suggested that miR-19b-3p may affect the expression of downstream EMT-related proteins through the PTEN pathway to promote the migration of receptor EC9706 cells.	('miR-19b-3p', 'Chemical', '-', (46, 56))	('EMT', 'Gene', (97, 100))	('EMT', 'Gene', '3702', (97, 100))	('expression', 'MPA', (72, 82))	('affect', 'Reg', (61, 67))	('EC9706', 'CellLine', 'CVCL:E307', (180, 186))	('PTEN', 'Gene', '5728', (130, 134))	('PTEN', 'Gene', (130, 134))	('miR-19b-3p', 'Var', (46, 56))	('promote', 'PosReg', (146, 153))	('migration', 'CPA', (158, 167))
914628	33146702	In summary, our study found that miR-19b-3p expression is abnormally high in ESCA.	('ESCA', 'Disease', (77, 81))	('high', 'PosReg', (69, 73))	('miR-19b-3p', 'Var', (33, 43))	('miR-19b-3p', 'Chemical', '-', (33, 43))
914629	33146702	In addition, miR-19b-3p transferred by exosomes can affect the apoptosis and migration of recipient ESCA cells through the PTEN pathway.	('miR-19b-3p', 'Var', (13, 23))	('miR-19b-3p', 'Chemical', '-', (13, 23))	('apoptosis', 'CPA', (63, 72))	('PTEN', 'Gene', (123, 127))	('PTEN', 'Gene', '5728', (123, 127))	('affect', 'Reg', (52, 58))
914740	31632469	Moreover, in a phase II trial by Schuler et al., the addition of IMAB362 significantly elongated survival lifespan among patients with CLDN18.2 positivity compared with capecitabine plus oxaliplatin plus epirubicin alone.	('capecitabine', 'Chemical', 'MESH:C110904', (169, 181))	('oxaliplatin', 'Chemical', 'MESH:C030110', (187, 198))	('epirubicin', 'Chemical', 'MESH:D015251', (204, 214))	('positivity', 'Var', (144, 154))	('IMAB362', 'Gene', (65, 72))	('CLDN18', 'Gene', (135, 141))	('elongated', 'PosReg', (87, 96))	('survival lifespan', 'CPA', (97, 114))	('CLDN18', 'Gene', '51208', (135, 141))	('patients', 'Species', '9606', (121, 129))
914839	31571986	Zhu et al compared the effects of different radiotherapy doses on the treatment of esophageal cancer; the results showed that after IMRT, patients in the high-dose group (2.13 Gy/30f) were significantly more likely to achieve complete remission (CR) than patients in the conventional dose group (2 Gy/30f).	('esophageal cancer', 'Disease', (83, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('patients', 'Species', '9606', (255, 263))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('complete', 'Disease', (226, 234))	('2.13 Gy/30f', 'Var', (171, 182))	('patients', 'Species', '9606', (138, 146))
914857	31261541	Logistic regression analysis revealed that the patients with sharp objects developed more complications than those with non-sharp ones (odds ratio, 2.85; 95% confidence interval, 1.08-7.50; P = .034).	('patients', 'Species', '9606', (47, 55))	('rat', 'Species', '10116', (141, 144))	('complications', 'CPA', (90, 103))	('sharp objects', 'Var', (61, 74))
914858	31261541	The prevalence of complications was increased in the patients with long foreign body retention time (>24 hours) and sharp objects.	('patients', 'Species', '9606', (53, 61))	('complications', 'Disease', (18, 31))	('sharp', 'Var', (116, 121))
914894	31261541	The univariate and multivariate analyses indicated that general anesthesia (OR, 5.92; 95% CI, 2.27-15.42; P < .001) and sharp objects (OR, 11.00; 95% CI, 1.23-98.86, P = .032) significantly increased the risk of perforation.	('perforation', 'Disease', (212, 223))	('rat', 'Species', '10116', (217, 220))	('sharp objects', 'Var', (120, 133))
914924	31261541	Moreover, sharp objects and long retention time strongly increased the incidence of complications, especially perforation.	('sharp objects', 'Var', (10, 23))	('perforation', 'Disease', (110, 121))	('rat', 'Species', '10116', (115, 118))	('increased', 'PosReg', (57, 66))
914930	30891877	Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors Blockade of programmed cell death ligand-1 with durvalumab has shown efficacy and safety in large, international studies of patients with advanced solid tumors.	('as', 'Chemical', 'MESH:D001151', (148, 150))	('Blockade', 'Var', (88, 96))	('durvalumab', 'Chemical', 'MESH:C000613593', (29, 39))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('durvalumab', 'Chemical', 'MESH:C000613593', (136, 146))	('tumors', 'Disease', (241, 247))	('solid tumors', 'Disease', 'MESH:D009369', (235, 247))	('patients', 'Species', '9606', (212, 220))	('solid tumors', 'Disease', 'MESH:D009369', (75, 87))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('solid tumors', 'Disease', (235, 247))	('patients', 'Species', '9606', (52, 60))	('solid tumors', 'Disease', (75, 87))
914993	30891877	The DLT evaluable set included all patients enrolled in the dose-escalation phase who received >=2 doses of durvalumab for q2w and q3w dose groups and >=1 dose of durvalumab for the q4w group and completed the safety follow up through the DLT evaluable period or experienced any DLT.	('durvalumab', 'Chemical', 'MESH:C000613593', (163, 173))	('q2w', 'Var', (123, 126))	('as', 'Chemical', 'MESH:D001151', (78, 80))	('patients', 'Species', '9606', (35, 43))	('q3w', 'Var', (131, 134))	('durvalumab', 'Chemical', 'MESH:C000613593', (108, 118))
915033	30891877	Reduction in tumor size >=30% was observed in two patients in the 10 mg/kg q2w dose group (including the patient with a PR).	('tumor', 'Disease', (13, 18))	('patient', 'Species', '9606', (105, 112))	('patients', 'Species', '9606', (50, 58))	('as', 'Chemical', 'MESH:D001151', (31, 33))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('Reduction', 'NegReg', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('q2w', 'Var', (75, 78))	('patient', 'Species', '9606', (50, 57))
915038	30891877	At 3 months after the end of treatment, one of one evaluable patient in the 1.0 mg/kg q2w dose group and one of two evaluable patients in the 20 mg/kg q4w dose group had a detectable sPD-L1 titer, with titers of 82.3 and 142, respectively.	('patient', 'Species', '9606', (61, 68))	('PD-L1', 'Gene', (184, 189))	('sPD', 'Gene', (183, 186))	('PD-L1', 'Gene', '29126', (184, 189))	('sPD', 'Gene', '3239', (183, 186))	('patient', 'Species', '9606', (126, 133))	('q2w', 'Var', (86, 89))	('patients', 'Species', '9606', (126, 134))
915070	29568234	MiRNAs act by base-pairing with their target mRNAs through complementarity at the 3' untranslated regions (UTRs) of the target mRNAs.	('base-pairing', 'MPA', (14, 26))	('complementarity', 'Var', (59, 74))	('men', 'Species', '9606', (65, 68))
915110	29568234	Remarkably, as showed in Table 1, a significant association existed between miR-21 and TNM stage, indicating patients with high miR-21 level was significantly correlated with advanced TNM stage in ESCC.	('correlated', 'Reg', (159, 169))	('TNM', 'Gene', (184, 187))	('patients', 'Species', '9606', (109, 117))	('ESCC', 'Disease', (197, 201))	('TNM', 'Gene', '10178', (87, 90))	('miR-21', 'Var', (128, 134))	('TNM', 'Gene', '10178', (184, 187))	('TNM', 'Gene', (87, 90))
915118	29568234	To determine the role of miR-21 in ESCC under irradiation, TE-1 cells were transfected with miR-21 mimics, inhibitor or NC vector.	('TE-1', 'CellLine', 'CVCL:1759', (59, 63))	('miR-21', 'Gene', (92, 98))	('mimics', 'Var', (99, 105))
915124	29568234	We then examined the effects of miR-21 knockdown or expression on caspase 3 and PARP activities (apoptosis marker) after 6 Gy irradiation for 48 h. MiR-21 knockdown markedly increased the PARP activity and caspase 3 activity, compared with control or NC, while overexpression of miR-21 significantly decreased the PARP activity and caspase 3 activity (Fig.	('caspase 3', 'Gene', (66, 75))	('PARP', 'Gene', (188, 192))	('caspase 3', 'Gene', '836', (66, 75))	('PARP', 'Gene', (80, 84))	('PARP', 'Gene', '1302', (314, 318))	('activity', 'MPA', (342, 350))	('activity', 'MPA', (216, 224))	('knockdown', 'Var', (155, 164))	('caspase 3', 'Gene', (332, 341))	('caspase 3', 'Gene', '836', (332, 341))	('PARP', 'Gene', (314, 318))	('caspase 3', 'Gene', (206, 215))	('caspase 3', 'Gene', '836', (206, 215))	('PARP', 'Gene', '1302', (80, 84))	('PARP', 'Gene', '1302', (188, 192))	('activity', 'MPA', (193, 201))	('MiR-21', 'Gene', (148, 154))	('MiR-21', 'Gene', '406991', (148, 154))	('increased', 'PosReg', (174, 183))
915143	29568234	Results showed that miR-21 was significantly increased in ESCC cell lines after irradiation, suggesting miR-21 might contribute in evading cancer therapy.	('miR-21', 'Gene', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('increased', 'PosReg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('miR-21', 'Var', (104, 110))	('contribute', 'Reg', (117, 127))	('cancer', 'Disease', (139, 145))
915146	29568234	At the molecular level, cleaved-caspase-3 and cleaved-PARP were increased in miR-21 knockdown cells under irradiation.	('knockdown', 'Var', (84, 93))	('PARP', 'Gene', '1302', (54, 58))	('increased', 'PosReg', (64, 73))	('miR-21', 'Gene', (77, 83))	('PARP', 'Gene', (54, 58))	('cleaved-caspase-3', 'MPA', (24, 41))
915148	29568234	The findings suggested that dysregulation of miR-21 might associate with development and radiation-resistance of cancer via regulating the cell apoptosis.	('miR-21', 'Gene', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('dysregulation', 'Var', (28, 41))	('cancer', 'Disease', (113, 119))	('men', 'Species', '9606', (80, 83))	('regulating', 'Reg', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cell apoptosis', 'CPA', (139, 153))	('associate', 'Reg', (58, 67))
915159	27524910	A small minority of cases are associated with hereditary genetic abnormalities including constitutional mutations in CDH1 (causing hereditary diffuse gastric cancer) and in the mismatch repair genes which characterize Lynch syndrome.	('associated', 'Reg', (30, 40))	('hereditary genetic abnormalities', 'Disease', 'MESH:D030342', (46, 78))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('CDH1', 'Gene', (117, 121))	('constitutional mutations', 'Var', (89, 113))	('gastric cancer', 'Disease', (150, 164))	('Lynch syndrome', 'Disease', (218, 232))	('CDH1', 'Gene', '999', (117, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('Lynch syndrome', 'Disease', 'MESH:D003123', (218, 232))	('hereditary genetic abnormalities', 'Disease', (46, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('causing', 'Reg', (123, 130))	('mismatch repair genes', 'Gene', (177, 198))
915166	27524910	Of relevance to angiogenic targeting, both the genomically stable and the chromosomal-instability subtypes have demonstrated amplifications of potentially therapeutically-targetable receptor tyrosine kinases, in particular the gene coding for ligand vascular endothelial growth factor (VEGF)-A.	('vascular endothelial growth factor', 'Gene', '7422', (250, 284))	('VEGF', 'Gene', (286, 290))	('amplifications', 'Var', (125, 139))	('VEGF', 'Gene', '7422', (286, 290))	('vascular endothelial growth factor', 'Gene', (250, 284))
915232	27524910	The use of subsequent lines of therapy was comparable between treatment arms at 45.7% for ramucirumab and 46% for placebo, but was substantially higher in Asian patients (almost 70% vs almost 40%) and may go some way to explaining the differential in OS seen.	('OS', 'Chemical', '-', (251, 253))	('ramucirumab', 'Chemical', 'MESH:C543333', (90, 101))	('patients', 'Species', '9606', (161, 169))	('ramucirumab', 'Var', (90, 101))	('higher', 'PosReg', (145, 151))
915303	25388215	Many genes involved in esophageal adenocarcinoma display hypermethylation, leading to their downregulation.	('downregulation', 'NegReg', (92, 106))	('esophageal adenocarcinoma', 'Disease', (23, 48))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (23, 48))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (23, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('hypermethylation', 'Var', (57, 73))
915306	25388215	Many microRNAs have been associated with the development of Barrett's esophagus and esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (84, 109))	("Barrett's esophagus", 'Disease', (60, 79))	('associated', 'Reg', (25, 35))	('esophageal adenocarcinoma', 'Disease', (84, 109))	('men', 'Species', '9606', (52, 55))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (60, 79))	('microRNAs', 'Var', (5, 14))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (84, 109))
915317	25388215	While the molecular mechanism of the transition into adenocarcinoma is not clear, it has been speculated that GERD may cause genetic and epigenetic changes in the epithelium leading to the characteristics seen in Barrett's esophagus and EAC.	('adenocarcinoma', 'Disease', (53, 67))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('GERD', 'Phenotype', 'HP:0002020', (110, 114))	("Barrett's esophagus", 'Disease', (213, 232))	('cause', 'Reg', (119, 124))	('epigenetic changes', 'Var', (137, 155))	('EAC', 'Phenotype', 'HP:0011459', (237, 240))	('GERD', 'Var', (110, 114))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (213, 232))	('EAC', 'Disease', (237, 240))	('leading to', 'Reg', (174, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
915327	25388215	Mutations in these genes have been implicated in the progression of many cancers including EAC.	('cancers', 'Disease', (73, 80))	('EAC', 'Disease', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('Mutations', 'Var', (0, 9))	('EAC', 'Phenotype', 'HP:0011459', (91, 94))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('implicated', 'Reg', (35, 45))
915328	25388215	While some genetic linkages have been found, epigenetics may be more helpful in predicting the progression of esophageal adenocarcinoma in patients with Barrett's esophagus.	('esophageal adenocarcinoma', 'Disease', (110, 135))	('patients', 'Species', '9606', (139, 147))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (110, 135))	('epigenetics', 'Var', (45, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (110, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	("Barrett's esophagus", 'Disease', (153, 172))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (153, 172))
915335	25388215	MGMT mutations have been implicated in a number of cancers, including esophageal squamous cell carcinoma.	('MGMT', 'Gene', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('esophageal squamous cell carcinoma', 'Disease', (70, 104))	('implicated', 'Reg', (25, 35))	('cancers', 'Disease', (51, 58))	('MGMT', 'Gene', '4255', (0, 4))
915336	25388215	Hypermethylation of this gene has been found to be associated with esophageal adenocarcinoma, but not necessarily with a patient's outcome.	('esophageal adenocarcinoma', 'Disease', (67, 92))	('Hypermethylation', 'Var', (0, 16))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (67, 92))	('associated', 'Reg', (51, 61))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (67, 92))	('patient', 'Species', '9606', (121, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
915338	25388215	Overexpression of the DNMT1 gene was found to be associated with ESCC and correlated with lymph node metastasis.	('associated', 'Reg', (49, 59))	('DNMT1', 'Gene', (22, 27))	('DNMT1', 'Gene', '1786', (22, 27))	('correlated', 'Reg', (74, 84))	('lymph node metastasis', 'Disease', (90, 111))	('Overexpression', 'Var', (0, 14))	('ESCC', 'Disease', (65, 69))	('lymph node metastasis', 'Disease', 'MESH:D009362', (90, 111))
915340	25388215	There are three main mechanisms in which DNA methylation can result in carcinogenesis: base substitution gene mutation, where a 5-methylcytosine is deaminated to thymine; aberrant DNA methylation, which can be associated with allelic loss; and hypermethylation, which may correlate to inactivation of tumor suppressor genes.	('hypermethylation', 'Var', (244, 260))	('aberrant', 'Var', (171, 179))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (128, 144))	('tumor suppressor', 'Gene', (301, 317))	('carcinogenesis', 'Disease', (71, 85))	('result in', 'Reg', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('DNA', 'Gene', (180, 183))	('base substitution gene', 'Gene', (87, 109))	('mutation', 'Var', (110, 118))	('tumor suppressor', 'Gene', '7248', (301, 317))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))	('thymine', 'Chemical', 'MESH:D013941', (162, 169))
915341	25388215	Hypermethylation-associated silencing of tumor suppressor genes is the most recognized epigenetic disruption, first discovered in the retinoblastoma gene (Rb1).	('tumor suppressor', 'Gene', '7248', (41, 57))	('retinoblastoma', 'Gene', (134, 148))	('Rb1', 'Gene', (155, 158))	('Hypermethylation-associated', 'Var', (0, 27))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('retinoblastoma', 'Phenotype', 'HP:0009919', (134, 148))	('Rb1', 'Gene', '5925', (155, 158))	('tumor suppressor', 'Gene', (41, 57))	('silencing', 'NegReg', (28, 37))	('retinoblastoma', 'Gene', '5925', (134, 148))
915342	25388215	Table 1 summarizes the results of studies examining hypermethylation in various genes in Barrett's esophagus and esophageal adenocarcinoma.	('hypermethylation', 'Var', (52, 68))	("Barrett's esophagus", 'Disease', (89, 108))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (89, 108))	('esophageal adenocarcinoma', 'Disease', (113, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (113, 138))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (113, 138))
915344	25388215	In fact, since these studies do not establish a temporal relationship between aberrant methylation patterns and dysplasia, hypermethylation could be a result rather than a cause of the dysplasia.	('aberrant', 'Var', (78, 86))	('dysplasia', 'Disease', (112, 121))	('hypermethylation', 'Var', (123, 139))	('dysplasia', 'Disease', 'MESH:D004476', (112, 121))	('dysplasia', 'Disease', (185, 194))	('dysplasia', 'Disease', 'MESH:D004476', (185, 194))
915345	25388215	None-the-less, careful and well-designed studies are warranted to establish causal or consequential effect of hypermethylation of genes at various stages of the initiation, progression and chronicity of metaplasia-dysplasia-adenocarcinoma in the esophagus.	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', 'MESH:D008679', (203, 238))	('hypermethylation', 'Var', (110, 126))	('metaplasia-dysplasia-adenocarcinoma', 'Disease', (203, 238))
915348	25388215	This could be supported by the study of Kwong and colleagues who found that high levels of methylation in the DLEC1 gene were associated with carcinogenesis in the lung, kidney and esophagus.	('carcinogenesis', 'Disease', (142, 156))	('esophagus', 'Disease', (181, 190))	('methylation', 'Var', (91, 102))	('associated with', 'Reg', (126, 141))	('high levels', 'Var', (76, 87))	('DLEC1', 'Gene', (110, 115))	('DLEC1', 'Gene', '9940', (110, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (142, 156))
915352	25388215	One study found that Wnt-related genes, such as APC, SFRP1, and WIF1, are more highly methylated in the development of neoplasia from metaplasia, than in the development of metaplasia.	('men', 'Species', '9606', (165, 168))	('metaplasia', 'Disease', 'MESH:D008679', (173, 183))	('neoplasia', 'Disease', 'MESH:D009369', (119, 128))	('neoplasia', 'Phenotype', 'HP:0002664', (119, 128))	('WIF1', 'Gene', '11197', (64, 68))	('metaplasia', 'Disease', 'MESH:D008679', (134, 144))	('metaplasia', 'Disease', (173, 183))	('men', 'Species', '9606', (111, 114))	('Wnt-related genes', 'Gene', (21, 38))	('methylated', 'Var', (86, 96))	('APC', 'Gene', (48, 51))	('metaplasia', 'Disease', (134, 144))	('SFRP1', 'Gene', '6422', (53, 58))	('WIF1', 'Gene', (64, 68))	('neoplasia', 'Disease', (119, 128))	('APC', 'Gene', '324', (48, 51))	('highly', 'PosReg', (79, 85))	('SFRP1', 'Gene', (53, 58))
915354	25388215	Similarly, P16 hypermethylation is seen in higher frequency in Barrett's dysplasia than in the Barrett's metaplasia.	("Barrett's dysplasia", 'Disease', (63, 82))	('P16', 'Gene', (11, 14))	("Barrett's dysplasia", 'Disease', 'MESH:D001471', (63, 82))	('hypermethylation', 'Var', (15, 31))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (95, 115))	('P16', 'Gene', '1029', (11, 14))	("Barrett's metaplasia", 'Disease', (95, 115))
915355	25388215	Another study found that the hypermethylation of CDKN2A, TIMP3, ESR1 genes is associated with the onset of Barrett's metaplasia.	('associated with', 'Reg', (78, 93))	('CDKN2A', 'Gene', '1029', (49, 55))	('TIMP3', 'Gene', '7078', (57, 62))	('TIMP3', 'Gene', (57, 62))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (107, 127))	('ESR1', 'Gene', '2099', (64, 68))	('hypermethylation', 'Var', (29, 45))	("Barrett's metaplasia", 'Disease', (107, 127))	('CDKN2A', 'Gene', (49, 55))	('ESR1', 'Gene', (64, 68))
915356	25388215	Furthermore, the study by Wild and colleagues found that E-cadherin hypermethylation is an important marker in the transition from dysplasia into adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (146, 160))	('dysplasia', 'Disease', (131, 140))	('dysplasia', 'Disease', 'MESH:D004476', (131, 140))	('E-cadherin', 'Gene', (57, 67))	('E-cadherin', 'Gene', '999', (57, 67))	('hypermethylation', 'Var', (68, 84))	('adenocarcinoma', 'Disease', (146, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
915358	25388215	Also, few of these genes, for example SFRP1, have been characterized in esophageal squamous cell carcinoma, and may also be hypermethylated in EAC.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('SFRP1', 'Gene', (38, 43))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (72, 106))	('EAC', 'Phenotype', 'HP:0011459', (143, 146))	('esophageal squamous cell carcinoma', 'Disease', (72, 106))	('EAC', 'Disease', (143, 146))	('SFRP1', 'Gene', '6422', (38, 43))	('hypermethylated', 'Var', (124, 139))
915414	25388215	A study by Shah and colleagues found that the APC gene in the plasma was hypermethylated in late-stage EAC, but not in BE; tissue APC gene showed hypermethylation even in early stages.	('EAC', 'Disease', (103, 106))	('APC', 'Gene', '324', (46, 49))	('APC', 'Gene', (130, 133))	('APC', 'Gene', '324', (130, 133))	('BE', 'Phenotype', 'HP:0100580', (119, 121))	('APC', 'Gene', (46, 49))	('EAC', 'Phenotype', 'HP:0011459', (103, 106))	('hypermethylated', 'Var', (73, 88))
915466	25784931	All EBV-positive tumors displayed CDKN2A promoter hypermethylation and 80% had PIK3CA mutations.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (86, 95))	('promoter', 'MPA', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('PIK3CA', 'Gene', (79, 85))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('EBV-positive', 'Gene', (4, 16))	('PIK3CA', 'Gene', '5290', (79, 85))	('EBV', 'Species', '10376', (4, 7))
915468	25784931	Microsatellite unstable (MSI) tumors generally lacked targetable amplifications although mutations in PIK3CA, HER2, HER3, and EGFR were noted.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('PIK3CA', 'Gene', (102, 108))	('EGFR', 'Gene', (126, 130))	('Microsatellite unstable (MSI) tumors', 'Disease', 'MESH:D053842', (0, 36))	('PIK3CA', 'Gene', '5290', (102, 108))	('HER3', 'Gene', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutations', 'Var', (89, 98))	('HER2', 'Gene', '2064', (110, 114))	('HER2', 'Gene', (110, 114))	('HER3', 'Gene', '2065', (116, 120))	('EGFR', 'Gene', '1956', (126, 130))
915470	25784931	Genomically stable gastric tumors are enriched for the diffuse histological variant and have newly described mutations in RHOA which acts through several effectors to control actin-myosin-dependent cell contractility and motility.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('gastric tumors', 'Phenotype', 'HP:0006753', (19, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('myosin', 'Gene', (181, 187))	('motility', 'CPA', (221, 229))	('RHOA', 'Gene', '387', (122, 126))	('gastric tumor', 'Phenotype', 'HP:0006753', (19, 32))	('mutations', 'Var', (109, 118))	('gastric tumors', 'Disease', (19, 33))	('myosin', 'Gene', '79784', (181, 187))	('RHOA', 'Gene', (122, 126))	('gastric tumors', 'Disease', 'MESH:D013274', (19, 33))
915474	25784931	Chromosomal aberrations leading to gene dysregulation have been reported in esophageal cancer including amplifications on 8q and 17q mapped to the C-MYC and ERBB2 oncogenes.	('amplifications on', 'Var', (104, 121))	('gene dysregulation', 'MPA', (35, 53))	('ERBB2', 'Gene', (157, 162))	('esophageal cancer', 'Disease', (76, 93))	('ERBB2', 'Gene', '2064', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('C-MYC', 'Gene', (147, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('C-MYC', 'Gene', '4609', (147, 152))
915477	25784931	In addition, two genes reported to have homozygous deletions in esophageal cancer are p16/CDKN2A and FHIT.	('CDKN2A', 'Gene', '1029', (90, 96))	('FHIT', 'Gene', '2272', (101, 105))	('homozygous deletions', 'Var', (40, 60))	('esophageal cancer', 'Disease', (64, 81))	('p16', 'Gene', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CDKN2A', 'Gene', (90, 96))	('FHIT', 'Gene', (101, 105))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('p16', 'Gene', '1029', (86, 89))
915481	25784931	A host of additional genes have been studied for mutations in esophageal cancer, but in most of these single gene studies, very few mutations have been identified.	('esophageal cancer', 'Disease', (62, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (49, 58))
915483	25784931	Inactivating mutations of NOTCH1 were identified in 21% of esophageal squamous cell carcinomas but not in adenocarcinomas.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('adenocarcinomas', 'Disease', 'MESH:D000230', (106, 121))	('identified', 'Reg', (38, 48))	('esophageal squamous cell carcinomas', 'Disease', (59, 94))	('NOTCH1', 'Gene', (26, 32))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (59, 94))	('NOTCH1', 'Gene', '4851', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinomas', 'Disease', (106, 121))	('Inactivating mutations', 'Var', (0, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (70, 94))
915485	25784931	Amplified genes were noted in 37% of gastric/esophageal tumors, including ERBB2, FGFR1, FGFR2, EGFR, and MET, suggesting that some of these may be viable targets in esophageal cancer although amplification of some of these may be more prevalent in gastric tumors.	('esophageal cancer', 'Disease', (165, 182))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('FGFR1', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('esophageal tumors', 'Phenotype', 'HP:0100751', (45, 62))	('gastric tumors', 'Disease', 'MESH:D013274', (248, 262))	('EGFR', 'Gene', '1956', (95, 99))	('gastric tumors', 'Phenotype', 'HP:0006753', (248, 262))	('FGFR2', 'Gene', (88, 93))	('FGFR1', 'Gene', '2260', (81, 86))	('amplification', 'Var', (192, 205))	('FGFR2', 'Gene', '2263', (88, 93))	('esophageal tumors', 'Disease', (45, 62))	('gastric tumors', 'Disease', (248, 262))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('EGFR', 'Gene', (95, 99))	('ERBB2', 'Gene', (74, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('esophageal tumors', 'Disease', 'MESH:D004938', (45, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('gastric tumor', 'Phenotype', 'HP:0006753', (248, 261))	('ERBB2', 'Gene', '2064', (74, 79))
915488	25784931	The TOGA trial was a phase III prospective trial which demonstrated the benefits of adding trastuzumab, a humanized monoclonal antibody targeting HER2, to a platinum-based doublet in the presence of HER2 IHC 2+ or FISH amplified metastatic gastroesophageal or gastric cancer.	('human', 'Species', '9606', (106, 111))	('IHC 2+', 'Var', (204, 210))	('HER2', 'Gene', '2064', (146, 150))	('amplified', 'PosReg', (219, 228))	('gastric cancer', 'Disease', (260, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('gastroesophageal', 'Disease', (240, 256))	('gastric cancer', 'Disease', 'MESH:D013274', (260, 274))	('platinum', 'Chemical', 'MESH:D010984', (157, 165))	('HER2', 'Gene', (199, 203))	('gastric cancer', 'Phenotype', 'HP:0012126', (260, 274))	('trastuzumab', 'Chemical', 'MESH:D000068878', (91, 102))	('HER2', 'Gene', '2064', (199, 203))	('HER2', 'Gene', (146, 150))	('gastroesophageal', 'Disease', 'MESH:D005764', (240, 256))
915504	25784931	A meta-analysis of 7 studies concluded that EGFR expression correlates with decreased survival in gastric cancer.	('survival', 'MPA', (86, 94))	('gastric cancer', 'Disease', (98, 112))	('decreased', 'NegReg', (76, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('expression', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
915505	25784931	In addition, preclinical data suggest that a subset of gastric cancers (20%) with EGFR amplification and overexpression can respond to cetuximab therapy.	('EGFR', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('overexpression', 'PosReg', (105, 119))	('cetuximab', 'Chemical', 'MESH:D000068818', (135, 144))	('respond', 'Reg', (124, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('gastric cancers', 'Disease', (55, 70))	('gastric cancers', 'Disease', 'MESH:D013274', (55, 70))	('gastric cancers', 'Phenotype', 'HP:0012126', (55, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('EGFR', 'Gene', '1956', (82, 86))	('amplification', 'Var', (87, 100))
915518	25784931	Tumors which harbor high C-MET expression are more likely to have poor survival rates.	('C-MET', 'Gene', (25, 30))	('Tumors', 'Disease', (0, 6))	('expression', 'MPA', (31, 41))	('high', 'Var', (20, 24))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('C-MET', 'Gene', '4233', (25, 30))
915547	25784931	The sonic hedgehog (SHH) pathway is crucial for normal cell differentiation and aberrant function affects gastric cell proliferation, migration, and invasion.	('SHH', 'Gene', (20, 23))	('affects', 'Reg', (98, 105))	('aberrant function', 'Var', (80, 97))	('sonic hedgehog', 'Gene', (4, 18))	('SHH', 'Gene', '6469', (20, 23))	('gastric cell proliferation', 'CPA', (106, 132))	('migration', 'CPA', (134, 143))	('sonic hedgehog', 'Gene', '6469', (4, 18))	('invasion', 'CPA', (149, 157))
915550	25784931	However, the expression of CD44, a gastric cancer stem cell marker, was associated with improved survival in the group who received the SHH inhibitor suggesting that SHH inhibition may only be effective in those with high CD44 expression.	('SHH', 'Gene', '6469', (166, 169))	('SHH', 'Gene', (136, 139))	('CD44', 'Gene', '960', (222, 226))	('survival', 'MPA', (97, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('CD44', 'Gene', '960', (27, 31))	('CD44', 'Gene', (222, 226))	('SHH', 'Gene', (166, 169))	('SHH', 'Gene', '6469', (136, 139))	('expression', 'Var', (13, 23))	('CD44', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('improved', 'PosReg', (88, 96))	('gastric cancer', 'Disease', (35, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))
915559	25784931	Amplification of the FGFR2 (fibroblast growth factor receptor 2) has been associated with tumorigenesis and results in downstream activation of the MAPK/PI3K pathways.	('Amplification', 'Var', (0, 13))	('FGFR2', 'Gene', (21, 26))	('FGFR2', 'Gene', '2263', (21, 26))	('fibroblast growth factor receptor 2', 'Gene', (28, 63))	('activation', 'PosReg', (130, 140))	('tumor', 'Disease', (90, 95))	('fibroblast growth factor receptor 2', 'Gene', '2263', (28, 63))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MAPK', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('MAPK', 'Gene', '5595;5594;5595', (148, 152))	('associated', 'Reg', (74, 84))
915565	25784931	Phosphorylated mTOR, indicating constitutive activation, has been associated with tumor progression and worse prognosis in gastric cancer patients.	('Phosphorylated', 'Var', (0, 14))	('associated with', 'Reg', (66, 81))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mTOR', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mTOR', 'Gene', '2475', (15, 19))	('gastric cancer', 'Disease', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('tumor', 'Disease', (82, 87))	('patients', 'Species', '9606', (138, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))
915566	25784931	Genetic alterations affecting the PI3K/Akt/mTOR pathway are frequently found in gastric cancer.	('Genetic alterations', 'Var', (0, 19))	('gastric cancer', 'Disease', (80, 94))	('Akt', 'Gene', '207', (39, 42))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('found', 'Reg', (71, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('mTOR', 'Gene', (43, 47))	('Akt', 'Gene', (39, 42))	('mTOR', 'Gene', '2475', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
915568	25784931	A phase Ib trial has been completed combining a PI3K inhibitor BYL719 with a HSP inhibitor AUY922 in metastatic gastric cancer patients whose tumors are HER2 amplified or who harbor a PI3K mutation.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('HER2', 'Gene', (153, 157))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('gastric cancer', 'Disease', (112, 126))	('HER2', 'Gene', '2064', (153, 157))	('PI3K', 'Var', (184, 188))	('patients', 'Species', '9606', (127, 135))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))
915573	25784931	Many of the clinical trials involving molecularly targeted agents in gastroesophageal cancer have had initially promising results which do not persist later in larger phase II/III studies.	('molecularly', 'Var', (38, 49))	('gastroesophageal cancer', 'Disease', (69, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (69, 92))
915596	22668811	The MIE Ivor Lewis approach was associated with reduced recurrent laryngeal nerve injury and mortality of 0.9% and is now our preferred approach.	('laryngeal nerve injury', 'Disease', (66, 88))	('MIE', 'Var', (4, 7))	('laryngeal nerve injury', 'Disease', 'MESH:D061224', (66, 88))	('reduced', 'NegReg', (48, 55))	('MIE', 'Chemical', '-', (4, 7))	('mortality', 'CPA', (93, 102))
915638	22668811	There were 11 additional deaths that occurred in-hospital beyond 30 days; the combined total 30-day and in-hospital mortality for the entire cohort was 2.8% (28/1011) (1.7% in the MIE-Ivor Lewis group and 3.95% in the MIE-neck group).	('MIE', 'Chemical', '-', (180, 183))	('death', 'Disease', 'MESH:D003643', (25, 30))	('death', 'Disease', (25, 30))	('MIE', 'Chemical', '-', (218, 221))	('MIE-Ivor', 'Var', (180, 188))
915804	33790649	Finally, different types of colors were used to indicate the burden of EC cancer per district based on the following category: Red color for the districts which had 31 and above patients, Pink color for the districts which had 21 to 30 patients yellow color for the districts which had 11 to 20 patients and Green color for the districts which have 1 to 10 patients.	('yellow', 'Var', (245, 251))	('EC cancer', 'Disease', (71, 80))	('patients', 'Species', '9606', (236, 244))	('patients', 'Species', '9606', (295, 303))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (357, 365))	('EC cancer', 'Disease', 'MESH:D009369', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
915865	32814726	published the first study reporting that low levels of plasma protein C were associated with venous thrombosis.	('protein C', 'Gene', '5624', (62, 71))	('venous thrombosis', 'Disease', (93, 110))	('low', 'Var', (41, 44))	('protein C', 'Gene', (62, 71))	('low levels of plasma protein C', 'Phenotype', 'HP:0005543', (41, 71))	('venous thrombosis', 'Disease', 'MESH:D020246', (93, 110))	('venous thrombosis', 'Phenotype', 'HP:0004936', (93, 110))	('associated', 'Reg', (77, 87))
915874	32814726	The patient was clinically diagnosed with T1bN0M0, stage I squamous cell carcinoma of the esophagus, according to the TNM Classification of Malignant Tumours, 8th edition.	('TNM', 'Gene', (118, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('squamous cell carcinoma', 'Disease', (59, 82))	('patient', 'Species', '9606', (4, 11))	('Tumours', 'Phenotype', 'HP:0002664', (150, 157))	('T1bN0M0', 'Var', (42, 49))	('Malignant Tumours', 'Disease', (140, 157))	('TNM', 'Gene', '10178', (118, 121))	('Malignant Tumours', 'Disease', 'MESH:D009369', (140, 157))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (73, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
915893	32814726	A histological examination revealed squamous cell carcinoma of the esophagus, and the definitive diagnosis was pT1N0M0, pStage I (TNM Classification, 8th edition).	('pT1N0M0', 'Var', (111, 118))	('TNM', 'Gene', '10178', (130, 133))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (50, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('TNM', 'Gene', (130, 133))	('revealed', 'Reg', (27, 35))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (36, 59))	('squamous cell carcinoma', 'Disease', (36, 59))
915954	32666847	Given the nodularity and high-grade dysplasia in Barrett's esophagus, radiofrequency ablation was not considered the optimal first treatment.	('dysplasia', 'Disease', (36, 45))	('dysplasia', 'Disease', 'MESH:C536170', (36, 45))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (49, 68))	('nodularity', 'Var', (10, 20))
916023	32695165	Pembrolizumab monotherapy was approved for first-line treatment of metastatic NSCLC, and the survival rate of metastatic NSCLC patients with negative gene mutations with high PD-L1 expression (tumor proportion score >=50%) was significantly improved compared with double platinum chemotherapy.	('mutations', 'Var', (155, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('improved', 'PosReg', (241, 249))	('PD-L1', 'Gene', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('survival', 'CPA', (93, 101))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('PD-L1', 'Gene', '29126', (175, 180))	('metastatic NSCLC', 'Disease', (67, 83))	('high', 'Var', (170, 174))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
916055	30881802	The anatomical barrier was saved by means of a radialis free flap deflected laterally to the prevertebral fascia.	('deflected', 'Var', (66, 75))	('fascia', 'Disease', 'None', (106, 112))	('fascia', 'Disease', (106, 112))
916076	29160958	For example, a simple IHC panel with Ki67 and p53 has been reported for predicting patient outcome in luminal-type breast cancer (Kobayashi et al., 2013).	('Ki67', 'Var', (37, 41))	('luminal-type breast cancer', 'Disease', 'MESH:D001943', (102, 128))	('p53', 'Gene', (46, 49))	('p53', 'Gene', '7157', (46, 49))	('patient', 'Species', '9606', (83, 90))	('luminal-type breast cancer', 'Disease', (102, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
916152	29160958	The clinical importance of amplification of Her-2/Neu (c-erbB-2) has been proved in breast cancer.	('Her-2/Neu', 'Gene', '2064', (44, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('c-erbB-2', 'Gene', (55, 63))	('c-erbB-2', 'Gene', '2064', (55, 63))	('Her-2/Neu', 'Gene', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('amplification', 'Var', (27, 40))	('breast cancer', 'Disease', (84, 97))
916346	27594190	For tumors higher than T1b, multimodality therapy should be considered after complete staging and discussion with the multidisciplinary team.	('T1b', 'Var', (23, 26))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
916385	27594190	2) microsatellite instability (MSIH) in 20% with loss of function of MLH1 and alterations in PIK3CA, 3) genomically stable (GS) in 20% (enriched with diffuse-type of GAC) with recurrent RhoA mutations and gene fusions, and 4) 9% associated with Ebstein Barr Virus (EBV) that tend to have many PIK3CA alterations, and amplifications of PD-L1/2 and JAK1/2.	('microsatellite instability', 'MPA', (3, 29))	('MSIH', 'Disease', 'None', (31, 35))	('JAK1/2', 'Gene', '3716;3717', (347, 353))	('PD-L1/2', 'Gene', '29126;80380', (335, 342))	('JAK1/2', 'Gene', (347, 353))	('amplifications', 'Var', (317, 331))	('PD-L1/2', 'Gene', (335, 342))	('MLH1', 'Gene', (69, 73))	('PIK3CA', 'Gene', (93, 99))	('MSIH', 'Disease', (31, 35))	('mutations', 'Var', (191, 200))	('loss of function', 'NegReg', (49, 65))	('MLH1', 'Gene', '4292', (69, 73))	('Ebstein Barr Virus', 'Disease', 'MESH:D004437', (245, 263))	('associated', 'Reg', (229, 239))	('PIK3CA', 'Gene', '5290', (293, 299))	('RhoA', 'Gene', (186, 190))	('GAC', 'Gene', '2744', (166, 169))	('GS', 'Disease', 'MESH:D011125', (124, 126))	('PIK3CA', 'Gene', '5290', (93, 99))	('alterations', 'Var', (300, 311))	('RhoA', 'Gene', '387', (186, 190))	('alterations', 'Var', (78, 89))	('PIK3CA', 'Gene', (293, 299))	('Ebstein Barr Virus', 'Disease', (245, 263))	('GAC', 'Gene', (166, 169))
916388	27594190	RhoA mutations have been identified in diffuse-type of GACs prior to TCGA analyses and whether these can be targeted or not remains to be seen.	('RhoA', 'Gene', '387', (0, 4))	('GAC', 'Gene', '2744', (55, 58))	('mutations', 'Var', (5, 14))	('GAC', 'Gene', (55, 58))	('RhoA', 'Gene', (0, 4))
916389	27594190	reported mutations in ELMO1 associated with increased cellular invasion.	('associated', 'Reg', (28, 38))	('ELMO1', 'Gene', '9844', (22, 27))	('mutations', 'Var', (9, 18))	('ELMO1', 'Gene', (22, 27))	('increased', 'PosReg', (44, 53))	('cellular invasion', 'CPA', (54, 71))
916392	27594190	Other DNA alterations implicated in squamous cell EC are KRAS, BRAF, and PIK3CA, p53 expression, and methylation of long interspersed nucleotide element-1 (LINE-1).	('expression', 'MPA', (85, 95))	('PIK3CA', 'Gene', '5290', (73, 79))	('squamous cell EC', 'Disease', (36, 52))	('men', 'Species', '9606', (148, 151))	('KRAS', 'Gene', (57, 61))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('KRAS', 'Gene', '3845', (57, 61))	('PIK3CA', 'Gene', (73, 79))	('BRAF', 'Gene', '673', (63, 67))	('methylation', 'Var', (101, 112))	('BRAF', 'Gene', (63, 67))
916393	27594190	LINE-1 hypomethylation is associated with poor prognosis in esophageal SCC.	('esophageal SCC', 'Disease', 'MESH:D004941', (60, 74))	('esophageal SCC', 'Disease', (60, 74))	('hypomethylation', 'Var', (7, 22))	('LINE-1', 'Gene', (0, 6))
916405	27513557	It has been reported that 5-azacytidine suppresses the biological behavior of esophageal cancer cells.	('5-azacytidine', 'Var', (26, 39))	('suppresses', 'NegReg', (40, 50))	('biological behavior of', 'CPA', (55, 77))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('5-azacytidine', 'Chemical', 'MESH:D001374', (26, 39))
916406	27513557	In this study, using Transwell invasion and cell proliferation assays, we demonstrated that 5-azacytidine significantly inhibited the metastasis and proliferation of EC9706 cells, and upregulated the expression of cadherin 1 (CDH1) and SRY-box containing gene 17 (SOX17).	('SOX17', 'Gene', (264, 269))	('CDH1', 'Gene', '999', (226, 230))	('rat', 'Species', '10116', (56, 59))	('rat', 'Species', '10116', (156, 159))	('5-azacytidine', 'Var', (92, 105))	('rat', 'Species', '10116', (81, 84))	('inhibited', 'NegReg', (120, 129))	('5-azacytidine', 'Chemical', 'MESH:D001374', (92, 105))	('EC9706', 'CellLine', 'CVCL:E307', (166, 172))	('expression', 'MPA', (200, 210))	('CDH1', 'Gene', (226, 230))	('upregulated', 'PosReg', (184, 195))	('cadherin 1', 'Gene', (214, 224))	('cadherin 1', 'Gene', '999', (214, 224))
916408	27513557	Furthermore, 5-azacytidine remarkably reduced the CDH1 and SOX17 promoter methylation levels, suggesting that 5-azacytidine upregulates the expression of SOX17 and CDH1 by inhibiting the methylation of the SOX17 and CDH1 promoter.	('SOX17', 'Gene', (154, 159))	('upregulates', 'PosReg', (124, 135))	('expression', 'MPA', (140, 150))	('CDH1', 'Gene', (164, 168))	('CDH1', 'Gene', '999', (216, 220))	('CDH1', 'Gene', '999', (164, 168))	('5-azacytidine', 'Chemical', 'MESH:D001374', (13, 26))	('inhibiting', 'NegReg', (172, 182))	('methylation', 'MPA', (187, 198))	('CDH1', 'Gene', (50, 54))	('5-azacytidine', 'Chemical', 'MESH:D001374', (110, 123))	('CDH1', 'Gene', '999', (50, 54))	('CDH1', 'Gene', (216, 220))	('5-azacytidine', 'Var', (110, 123))
916409	27513557	The findings of our study confirm that 5-azacytidine suppresses the proliferation and metastasis of EC9706 esophageal cancer cells by upregulating the expression of CDH1 and SOX17.	('CDH1', 'Gene', (165, 169))	('5-azacytidine', 'Var', (39, 52))	('SOX17', 'Gene', (174, 179))	('proliferation', 'CPA', (68, 81))	('suppresses', 'NegReg', (53, 63))	('CDH1', 'Gene', '999', (165, 169))	('upregulating', 'PosReg', (134, 146))	('rat', 'Species', '10116', (75, 78))	('esophageal cancer', 'Disease', (107, 124))	('expression', 'MPA', (151, 161))	('EC9706', 'CellLine', 'CVCL:E307', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('5-azacytidine', 'Chemical', 'MESH:D001374', (39, 52))	('metastasis', 'CPA', (86, 96))
916419	27513557	Aberrant DNA methylation leads to the inactivation of tumor suppressor genes in the development and progression of cancers, including esophageal cancer.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('esophageal cancer', 'Disease', 'MESH:D004938', (134, 151))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('Aberrant', 'Var', (0, 8))	('inactivation', 'NegReg', (38, 50))	('cancers', 'Disease', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('DNA', 'Gene', (9, 12))	('tumor', 'Disease', (54, 59))	('esophageal cancer', 'Disease', (134, 151))
916424	27513557	Frequent methylation of SOX17 promoter was detected in colon, liver, breast and lung cancers.	('methylation', 'Var', (9, 20))	('SOX17 promoter', 'Gene', (24, 38))	('lung cancers', 'Phenotype', 'HP:0100526', (80, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('breast and lung cancers', 'Disease', 'MESH:D001943', (69, 92))	('colon', 'Disease', (55, 60))	('detected', 'Reg', (43, 51))	('liver', 'Disease', (62, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
916425	27513557	The hypermethylation of the SOX17 promoter and the lower expression of SOX17 has previously been shown in breast cancer, resulting in cancer cell proliferation.	('expression', 'MPA', (57, 67))	('breast cancer', 'Disease', (106, 119))	('SOX17', 'Gene', (28, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('rat', 'Species', '10116', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (113, 119))	('lower', 'NegReg', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('SOX17', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('hypermethylation', 'Var', (4, 20))
916428	27513557	The hypermethylation of the CDH1 and SOX17 promoters and the reduced expression of CDH1 and SOX17 have been reported to occur in esophageal cancer.	('CDH1', 'Gene', (83, 87))	('CDH1', 'Gene', (28, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))	('CDH1', 'Gene', '999', (83, 87))	('expression', 'MPA', (69, 79))	('CDH1', 'Gene', '999', (28, 32))	('esophageal cancer', 'Disease', (129, 146))	('SOX17', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('reduced', 'NegReg', (61, 68))	('hypermethylation', 'Var', (4, 20))
916430	27513557	Based on the facts that 5-azacytidine can affect DNA methylation and that the promoters of tumor suppressor genes are usually downregulated by high hypermethylation in esophageal cancer, in this study, we aimed to examine the effects of treatment with 5-azacytidine on esophageal cancer cells and to elucidate the mechanisms responsible for its antitumor activity in esophageal cancer.	('5-azacytidine', 'Chemical', 'MESH:D001374', (252, 265))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('esophageal cancer', 'Disease', (269, 286))	('DNA methylation', 'MPA', (49, 64))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('tumor', 'Disease', (91, 96))	('high hypermethylation', 'Var', (143, 164))	('esophageal cancer', 'Disease', 'MESH:D004938', (367, 384))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('esophageal cancer', 'Disease', (367, 384))	('affect', 'Reg', (42, 48))	('downregulated', 'NegReg', (126, 139))	('5-azacytidine', 'Chemical', 'MESH:D001374', (24, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (168, 185))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (349, 354))	('esophageal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('esophageal cancer', 'Disease', 'MESH:D004938', (269, 286))
916462	27513557	The results of CCK-8 assay revealed that the viability of the EC9706 cells was markedly suppressed following treatment with 5-azacytidine (Fig.	('EC9706', 'CellLine', 'CVCL:E307', (62, 68))	('viability', 'CPA', (45, 54))	('5-azacytidine', 'Chemical', 'MESH:D001374', (124, 137))	('5-azacytidine', 'Var', (124, 137))	('suppressed', 'NegReg', (88, 98))
916463	27513557	In addition, the results of Transwell invasion assay indicated that the invasive ability of the EC9706 cells was significantly decreased following treatment with 5-azacytidine (Fig.	('decreased', 'NegReg', (127, 136))	('invasive ability of the EC9706 cells', 'CPA', (72, 108))	('EC9706', 'CellLine', 'CVCL:E307', (96, 102))	('5-azacytidine', 'Chemical', 'MESH:D001374', (162, 175))	('5-azacytidine', 'Var', (162, 175))
916466	27513557	Therefore, in this study, RT-qPCR and western blot analysis were performed to analyze the expression of CDH1 and SOX17 in the EC9706 cells treated with 5-azacytidine (50 microM) for 72 h. The results revealed that the CDH1 and SOX17 expression levels were significantly increased in the 5-azacytidine treatment group, in comparison to the DMSO vehicle control (Fig.	('CDH1', 'Gene', (104, 108))	('5-azacytidine', 'Var', (287, 300))	('EC9706', 'CellLine', 'CVCL:E307', (126, 132))	('expression levels', 'MPA', (233, 250))	('CDH1', 'Gene', '999', (104, 108))	('increased', 'PosReg', (270, 279))	('CDH1', 'Gene', (218, 222))	('5-azacytidine', 'Chemical', 'MESH:D001374', (152, 165))	('DMSO', 'Chemical', 'MESH:D004121', (339, 343))	('5-azacytidine', 'Chemical', 'MESH:D001374', (287, 300))	('CDH1', 'Gene', '999', (218, 222))
916467	27513557	The results of western blot analysis also revealed that the CDH1 and SOX17 protein expression levels were significantly upregulated by 5-azacytidine treatment (Fig.	('upregulated', 'PosReg', (120, 131))	('SOX17', 'Gene', (69, 74))	('5-azacytidine', 'Chemical', 'MESH:D001374', (135, 148))	('CDH1', 'Gene', (60, 64))	('CDH1', 'Gene', '999', (60, 64))	('5-azacytidine', 'Var', (135, 148))
916468	27513557	To further confirm the involvement of CDH1 in the inhibition of EC9706 cell invasion induced by 5-azacytidine, the cells were transfected with CDH1 siRNA to knockdown CDH1 expression.	('EC9706', 'CellLine', 'CVCL:E307', (64, 70))	('CDH1', 'Gene', (38, 42))	('CDH1', 'Gene', '999', (167, 171))	('CDH1', 'Gene', '999', (38, 42))	('expression', 'MPA', (172, 182))	('knockdown', 'Var', (157, 166))	('5-azacytidine', 'Chemical', 'MESH:D001374', (96, 109))	('CDH1', 'Gene', (167, 171))	('CDH1', 'Gene', (143, 147))	('CDH1', 'Gene', '999', (143, 147))
916471	27513557	Western blot analysis also revealed that 5-azacytidine significantly downregulated the expression of matrix metalloproteinase (MMP)2 and MMP9.	('matrix metalloproteinase (MMP)2', 'Gene', '4313', (101, 132))	('5-azacytidine', 'Chemical', 'MESH:D001374', (41, 54))	('5-azacytidine', 'Var', (41, 54))	('downregulated', 'NegReg', (69, 82))	('expression', 'MPA', (87, 97))	('MMP9', 'Gene', (137, 141))
916474	27513557	To verify the involvement of SOX17 in the inhibition of EC9706 cell proliferation by 5-azacytidine, SOX17 siRNA was used to knockdown SOX17 expression.	('knockdown', 'Var', (124, 133))	('5-azacytidine', 'Chemical', 'MESH:D001374', (85, 98))	('rat', 'Species', '10116', (75, 78))	('EC9706', 'CellLine', 'CVCL:E307', (56, 62))	('SOX17', 'Gene', (134, 139))
916477	27513557	Flow cytometry displayed the effects of 5-azacytidine and SOX17 on cell apoptosis.	('5-azacytidine', 'Var', (40, 53))	('5-azacytidine', 'Chemical', 'MESH:D001374', (40, 53))	('effects', 'Reg', (29, 36))
916480	27513557	These results indicate the involvement of SOX17 in the inhibition of EC9706 cell proliferation by 5-azacytidine.	('5-azacytidine', 'Var', (98, 111))	('EC9706 cell proliferation', 'CPA', (69, 94))	('rat', 'Species', '10116', (88, 91))	('EC9706', 'CellLine', 'CVCL:E307', (69, 75))	('involvement', 'Reg', (27, 38))	('inhibition', 'NegReg', (55, 65))	('5-azacytidine', 'Chemical', 'MESH:D001374', (98, 111))
916482	27513557	We hypothesized that 5-azacytidine upregulates the expression of CDH1 and SOX17 via their promoter methylation.	('promoter methylation', 'MPA', (90, 110))	('CDH1', 'Gene', (65, 69))	('CDH1', 'Gene', '999', (65, 69))	('5-azacytidine', 'Chemical', 'MESH:D001374', (21, 34))	('5-azacytidine', 'Var', (21, 34))	('expression', 'MPA', (51, 61))	('SOX17', 'Gene', (74, 79))	('upregulates', 'PosReg', (35, 46))
916490	27513557	It has been reported that epigenetic behaviors, such as DNA methylation, play important roles in the development and metastasis of esophageal cancer.	('metastasis of esophageal cancer', 'Disease', (117, 148))	('roles', 'Reg', (88, 93))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (117, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('epigenetic', 'Var', (26, 36))
916496	27513557	We found that the expression levels of SOX17 and CDH1 were significantly upregulated in the EC9706 cells by 5-azacytidine.	('CDH1', 'Gene', (49, 53))	('expression levels', 'MPA', (18, 35))	('CDH1', 'Gene', '999', (49, 53))	('5-azacytidine', 'Chemical', 'MESH:D001374', (108, 121))	('upregulated', 'PosReg', (73, 84))	('SOX17', 'Gene', (39, 44))	('EC9706', 'CellLine', 'CVCL:E307', (92, 98))	('5-azacytidine', 'Var', (108, 121))
916498	27513557	To further confirm our hypothesis, siRNAs were used to knockdown the expression of SOX17 and CDH1 in the EC9706 cells.	('knockdown', 'Var', (55, 64))	('CDH1', 'Gene', (93, 97))	('SOX17', 'Gene', (83, 88))	('CDH1', 'Gene', '999', (93, 97))	('EC9706', 'CellLine', 'CVCL:E307', (105, 111))
916499	27513557	We found that the siRNA-mediated downregulation of CDH1 was greatly impaired by 5-azacytidine, while the 5-azacytidine-induced inhibition of EC9706 cell growth and the induction of apoptosis were significantly attenuated by the siRNA-mediated downregulation of SOX17.	('CDH1', 'Gene', (51, 55))	('attenuated', 'NegReg', (210, 220))	('CDH1', 'Gene', '999', (51, 55))	('EC9706', 'CellLine', 'CVCL:E307', (141, 147))	('downregulation', 'NegReg', (243, 257))	('impaired', 'NegReg', (68, 76))	('5-azacytidine', 'Chemical', 'MESH:D001374', (80, 93))	('5-azacytidine', 'Var', (80, 93))	('5-azacytidine', 'Chemical', 'MESH:D001374', (105, 118))	('downregulation', 'NegReg', (33, 47))
916502	27513557	Our results revealed that the methylation of the SOX17 and CDH1 promoters was significantly decreased by 5-azacytidine treatment in the EC9706 cells.	('EC9706', 'CellLine', 'CVCL:E307', (136, 142))	('CDH1', 'Gene', '999', (59, 63))	('SOX17', 'Gene', (49, 54))	('5-azacytidine', 'Chemical', 'MESH:D001374', (105, 118))	('decreased', 'NegReg', (92, 101))	('methylation', 'MPA', (30, 41))	('5-azacytidine', 'Var', (105, 118))	('CDH1', 'Gene', (59, 63))
916504	27513557	In conclusion, the findings of our study confirm that 5-azacytidine inhibits esophageal cancer cell proliferation and metastasis by exerting inhibitory effects on the methylation of SOX17 and CDH1 promoters.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('CDH1', 'Gene', '999', (192, 196))	('5-azacytidine', 'Var', (54, 67))	('inhibitory effects', 'NegReg', (141, 159))	('SOX17', 'Protein', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('5-azacytidine', 'Chemical', 'MESH:D001374', (54, 67))	('methylation', 'MPA', (167, 178))	('inhibits', 'NegReg', (68, 76))	('CDH1', 'Gene', (192, 196))	('rat', 'Species', '10116', (107, 110))
916524	24519853	Two BRM promoter insertion polymorphisms increase the risk of early-stage upper aerodigestive tract cancers Brahma (BRM) has a key function in chromatin remodeling.	('BRM', 'Gene', (116, 119))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('increase', 'Reg', (41, 49))	('BRM', 'Gene', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('insertion polymorphisms', 'Var', (17, 40))	('BRM', 'Gene', '6595', (116, 119))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('Brahma', 'Gene', '6595', (108, 114))	('Brahma', 'Gene', (108, 114))	('BRM', 'Gene', '6595', (4, 7))	('cancers', 'Disease', (100, 107))
916525	24519853	Two germline BRM promoter insertion-deletion polymorphisms, BRM-741 and BRM-1321, have been previously associated with an increased risk of lung cancer in smokers and head and neck cancer.	('lung cancer', 'Disease', (140, 151))	('insertion-deletion polymorphisms', 'Var', (26, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('BRM', 'Gene', (13, 16))	('BRM', 'Gene', '6595', (72, 75))	('head and neck cancer', 'Phenotype', 'HP:0012288', (167, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('head and neck cancer', 'Disease', 'MESH:D006258', (167, 187))	('BRM', 'Gene', '6595', (60, 63))	('BRM', 'Gene', '6595', (13, 16))	('BRM', 'Gene', (72, 75))	('associated with', 'Reg', (103, 118))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('BRM', 'Gene', (60, 63))
916526	24519853	To further evaluate their role in cancer susceptibility particularly in early disease, we conducted a preplanned case-control study to investigate the association between the BRM promoter variants and stage I/II upper aerodigestive tract (UADT) cancers (i.e., lung, esophageal, head and neck), a group of early-stage malignancies in which molecular and genetic etiologic factors are poorly understood.	('variants', 'Var', (188, 196))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('BRM', 'Gene', (175, 178))	('association', 'Interaction', (151, 162))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('cancer', 'Disease', (245, 251))	('cancers', 'Disease', (245, 252))	('malignancies', 'Disease', 'MESH:D009369', (317, 329))	('BRM', 'Gene', '6595', (175, 178))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('malignancies', 'Disease', (317, 329))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('stage I/II upper aerodigestive tract', 'Disease', (201, 237))	('esophageal', 'Disease', (266, 276))	('lung', 'Disease', (260, 264))
916528	24519853	The double homozygous BRM promoter variants were associated with a significantly increased risk of early stage UADT cancers (adjusted odds ratio [aOR], 2.46; 95% confidence interval [CI], 1.7-3.8).	('variants', 'Var', (35, 43))	('BRM', 'Gene', '6595', (22, 25))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('stage UADT cancers', 'Disease', 'MESH:D006258', (105, 123))	('stage UADT cancers', 'Disease', (105, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BRM', 'Gene', (22, 25))
916530	24519853	The relationship between the BRM polymorphisms and early-stage UADT cancers was independent of age, sex, smoking status, histology, and clinical stage.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('polymorphisms', 'Var', (33, 46))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('stage UADT cancers', 'Disease', (57, 75))	('BRM', 'Gene', '6595', (29, 32))	('stage UADT cancers', 'Disease', 'MESH:D006258', (57, 75))	('BRM', 'Gene', (29, 32))
916531	24519853	These findings suggest that the BRM promoter double insertion homozygotes may be associated with an increased risk of early-stage UADT cancers independent of smoking status and histology, which must be further validated in other populations.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('stage UADT cancers', 'Disease', 'MESH:D006258', (124, 142))	('stage UADT cancers', 'Disease', (124, 142))	('BRM', 'Gene', '6595', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('BRM', 'Gene', (32, 35))	('double insertion', 'Var', (45, 61))
916533	24519853	Altered epigenetic regulation affects normal gene transcription and is potentially tumorigenic.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('epigenetic', 'Var', (8, 18))	('normal gene transcription', 'MPA', (38, 63))	('Altered epigenetic', 'Var', (0, 18))	('tumor', 'Disease', (83, 88))	('affects', 'Reg', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
916541	24519853	The loss of BRM is also associated with poorer prognosis in nonsmall cell lung cancer, supporting its role in lung cancer pathogenesis and progression.	('poorer', 'NegReg', (40, 46))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRM', 'Gene', '6595', (12, 15))	('nonsmall cell lung cancer', 'Disease', (60, 85))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (60, 85))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('BRM', 'Gene', (12, 15))	('loss', 'Var', (4, 8))
916543	24519853	The sequencing of the BRM promoter in BRM-deficient lung cancer cell lines and primary lung tumors identified two novel germline insertion variants, BRM-741 (rs34480940; 7 bp indel [insertion-deletion] polymorphism) and BRM-1321 (rs3832613 or rs59259177; 6 bp indel polymorphism), that are postulated to recruit MEF2 and histone deacetylases.	('BRM', 'Gene', '6595', (149, 152))	('rs3832613', 'Mutation', 'rs3832613', (230, 239))	('BRM', 'Gene', '6595', (22, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BRM', 'Gene', '6595', (220, 223))	('7 bp indel', 'Mutation', 'c.delins7', (170, 180))	('rs59259177', 'Mutation', 'rs59259177', (243, 253))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('BRM', 'Gene', '6595', (38, 41))	('primary lung tumors', 'Disease', 'MESH:D008175', (79, 98))	('MEF2', 'Gene', '4205', (312, 316))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('rs34480940', 'Mutation', 'rs34480940', (158, 168))	('deficient lung', 'Phenotype', 'HP:0002089', (42, 56))	('MEF2', 'Gene', (312, 316))	('lung tumors', 'Phenotype', 'HP:0100526', (87, 98))	('rs34480940;', 'Var', (158, 169))	('BRM', 'Gene', (149, 152))	('recruit', 'PosReg', (304, 311))	('primary lung tumors', 'Disease', (79, 98))	('BRM', 'Gene', (22, 25))	('rs3832613', 'Var', (230, 239))	('BRM', 'Gene', (220, 223))	('6 bp indel', 'Mutation', 'c.delins6', (255, 265))	('BRM', 'Gene', (38, 41))	('BRM-deficient lung cancer', 'Disease', 'MESH:D008175', (38, 63))	('rs59259177', 'Var', (243, 253))	('BRM-deficient lung cancer', 'Disease', (38, 63))
916545	24519853	Furthermore, in a case-control analysis of 1119 smokers, double homozygosity for the BRM promoter variants was most strongly associated with the risk of lung cancer independent of histology (adjusted odds ratio [aOR], 2.19; 95% confidence interval [CI], 1.40-3.43; P = 0.0006).	('double homozygosity', 'Var', (57, 76))	('BRM', 'Gene', (85, 88))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('BRM', 'Gene', '6595', (85, 88))	('lung cancer', 'Disease', (153, 164))	('associated with', 'Reg', (125, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('variants', 'Var', (98, 106))
916547	24519853	In addition, another case-control study from our group demonstrated that homozygosity for the BRM promoter polymorphisms increased the risk of head and neck squamous cell carcinoma, particularly for the double homozygotes (aOR, 2.23; 95% CI, 1.5-3.4; P < 0.001).	('increased', 'PosReg', (121, 130))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (143, 180))	('BRM', 'Gene', (94, 97))	('polymorphisms', 'Var', (107, 120))	('neck squamous cell carcinoma', 'Disease', (152, 180))	('homozygosity', 'Var', (73, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (152, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('BRM', 'Gene', '6595', (94, 97))
916551	24519853	Given the earlier associations between the BRM promoter variants and lung cancer among smokers and head and neck cancer across all stages, we sought to determine whether BRM-741 and BRM-1321 are similarly correlated with esophageal cancer, to characterize the BRM-risk association specifically in early-stage UADT malignancies, as well as to assess whether the increased risk of malignancy is restricted to ever-smokers.	('malignancy', 'Disease', 'MESH:D009369', (379, 389))	('BRM', 'Gene', '6595', (260, 263))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('head and neck cancer', 'Phenotype', 'HP:0012288', (99, 119))	('BRM', 'Gene', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('BRM', 'Gene', (43, 46))	('associations', 'Interaction', (18, 30))	('lung cancer', 'Disease', (69, 80))	('malignancy', 'Disease', (379, 389))	('BRM', 'Gene', (182, 185))	('BRM', 'Gene', '6595', (170, 173))	('head and neck cancer', 'Disease', 'MESH:D006258', (99, 119))	('BRM', 'Gene', '6595', (43, 46))	('variants', 'Var', (56, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (221, 238))	('BRM', 'Gene', (260, 263))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('correlated', 'Reg', (205, 215))	('esophageal cancer', 'Disease', (221, 238))	('malignancies', 'Disease', 'MESH:D009369', (314, 326))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('BRM', 'Gene', '6595', (182, 185))	('malignancies', 'Disease', (314, 326))
916553	24519853	To this end, we conducted a preplanned case-control study to investigate the correlation between the BRM promoter variants and early-stage UADT cancers, as well as the factors that influence this association, including smoking status and histology.	('BRM', 'Gene', '6595', (101, 104))	('variants', 'Var', (114, 122))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('stage UADT cancers', 'Disease', (133, 151))	('BRM', 'Gene', (101, 104))	('stage UADT cancers', 'Disease', 'MESH:D006258', (133, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
916556	24519853	Eligibility criteria included age 18 years or older, ability to communicate in English, self-reported Caucasian ancestry, and lack of cognitive deficits to ensure that participants had an understanding of the study.	('cognitive deficits', 'Phenotype', 'HP:0100543', (134, 152))	('cognitive deficits', 'Disease', (134, 152))	('participants', 'Species', '9606', (168, 180))	('Caucasian', 'Var', (102, 111))	('cognitive deficits', 'Disease', 'MESH:D003072', (134, 152))
916574	24519853	The risk of early-stage UADT cancers was significantly increased by more than twofold in patients with the double homozygous variants (aOR, 2.46; 95% CI, 1.7-3.8; P < 0.0001).	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('stage UADT cancers', 'Disease', 'MESH:D006258', (18, 36))	('stage UADT cancers', 'Disease', (18, 36))	('increased', 'PosReg', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (89, 97))	('double homozygous', 'Var', (107, 124))
916576	24519853	Separate analyses of the three UADT cancers showed that double homozygosity for the BRM variants was significantly correlated with lung (aOR, 2.61; 95% CI, 1.5-4.9; P = 0.006) and head and neck cancers (aOR, 2.75; 95% CI, 1.4-5.6; P = 0.004).	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('correlated', 'Reg', (115, 125))	('UADT cancers', 'Disease', (31, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('BRM', 'Gene', '6595', (84, 87))	('lung', 'Disease', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('UADT cancers', 'Disease', 'MESH:D006258', (31, 43))	('head and neck cancer', 'Phenotype', 'HP:0012288', (180, 200))	('head and neck cancers', 'Disease', 'MESH:D006258', (180, 201))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('variants', 'Var', (88, 96))	('double homozygosity', 'Var', (56, 75))	('head and neck cancers', 'Phenotype', 'HP:0012288', (180, 201))	('BRM', 'Gene', (84, 87))
916578	24519853	The effects of several clinical factors on the association between the BRM promoter polymorphisms and stage I/II UADT cancers were determined (Fig.	('association', 'Interaction', (47, 58))	('BRM', 'Gene', '6595', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('II UADT cancers', 'Disease', 'MESH:D006258', (110, 125))	('II UADT cancers', 'Disease', (110, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('BRM', 'Gene', (71, 74))	('polymorphisms', 'Var', (84, 97))
916579	24519853	The magnitude of risk with the double homozygous BRM variants was not influenced by age, sex or smoking status.	('BRM', 'Gene', '6595', (49, 52))	('BRM', 'Gene', (49, 52))	('variants', 'Var', (53, 61))
916585	24519853	This case-control study found that double homozygosity for the BRM germline promoter insertion polymorphisms, BRM-741 and BRM-1321, was significantly associated with an increased risk of early-stage UADT cancers by more than twofold.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('BRM', 'Gene', '6595', (110, 113))	('BRM', 'Gene', (122, 125))	('stage UADT cancers', 'Disease', 'MESH:D006258', (193, 211))	('BRM', 'Gene', (63, 66))	('stage UADT cancers', 'Disease', (193, 211))	('BRM', 'Gene', '6595', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BRM', 'Gene', (110, 113))	('double homozygosity', 'Var', (35, 54))	('BRM', 'Gene', '6595', (63, 66))	('associated with', 'Reg', (150, 165))
916588	24519853	previously showed that the double homozygous BRM variants increased the risk of stages I-IV lung cancer among active and ex-smokers (aOR, 2.19; 95% CI, 1.4-3.4; P = 0.0006).	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('variants', 'Var', (49, 57))	('BRM', 'Gene', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('I-IV lung cancer', 'Disease', 'MESH:D008175', (87, 103))	('I-IV lung cancer', 'Disease', (87, 103))	('BRM', 'Gene', '6595', (45, 48))
916590	24519853	In addition, this study expands our understanding of the etiologic relevance of the BRM promoter polymorphisms.	('BRM', 'Gene', (84, 87))	('BRM', 'Gene', '6595', (84, 87))	('polymorphisms', 'Var', (97, 110))
916591	24519853	First, the higher lung cancer risk of the BRM variants was observed in lifetime never-smokers, which suggests that these genetic polymorphisms confer risk independent of smoking status.	('BRM', 'Gene', '6595', (42, 45))	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('BRM', 'Gene', (42, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('variants', 'Var', (46, 54))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
916595	24519853	While there are somatic genetic changes that are more prevalent in never-smoking lung cancer patients (e.g., EGFR mutations, ALK translocations), the BRM polymorphisms are potential germline biomarkers that may identify a subset of never-smokers with a twofold greater risk of lung cancer.	('BRM', 'Gene', (150, 153))	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Disease', (277, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('mutations', 'Var', (114, 123))	('ALK', 'Gene', '238', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('polymorphisms', 'Var', (154, 167))	('EGFR', 'Gene', '1956', (109, 113))	('BRM', 'Gene', '6595', (150, 153))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('lung cancer', 'Disease', 'MESH:D008175', (277, 288))	('EGFR', 'Gene', (109, 113))	('patients', 'Species', '9606', (93, 101))	('ALK', 'Gene', (125, 128))
916597	24519853	In addition, the association between the BRM promoter variants and UADT cancers observed in this study has potential therapeutic implications.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('UADT cancers', 'Disease', 'MESH:D006258', (67, 79))	('BRM', 'Gene', (41, 44))	('UADT cancers', 'Disease', (67, 79))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('BRM', 'Gene', '6595', (41, 44))	('variants', 'Var', (54, 62))
916598	24519853	While the double homozygous variants lead to the epigenetic loss of BRM expression in cancer cell lines and primary lung tumors, Gramling et al.	('epigenetic', 'Var', (49, 59))	('primary lung tumors', 'Disease', 'MESH:D008175', (108, 127))	('BRM', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('expression', 'MPA', (72, 82))	('lung tumors', 'Phenotype', 'HP:0100526', (116, 127))	('BRM', 'Gene', '6595', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('primary lung tumors', 'Disease', (108, 127))	('cancer', 'Disease', (86, 92))
916600	24519853	Although further study will be required to clarify the role of epigenetic BRM silencing as an oncogenic driver in the pathogenesis of UADT cancers, the current data raise the possibility of reversing this epigenetic dysregulation as a novel therapeutic and/or preventive approach in these malignancies.	('UADT cancers', 'Disease', (134, 146))	('epigenetic', 'Var', (63, 73))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('silencing', 'NegReg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('malignancies', 'Disease', 'MESH:D009369', (289, 301))	('BRM', 'Gene', '6595', (74, 77))	('UADT cancers', 'Disease', 'MESH:D006258', (134, 146))	('malignancies', 'Disease', (289, 301))	('BRM', 'Gene', (74, 77))
916604	24519853	Future molecular studies will be needed to evaluate the consequences of these promoter variant genotypes on BRM expression and their mechanisms in promoting cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('promoting', 'PosReg', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('BRM', 'Gene', (108, 111))	('cancer', 'Disease', (157, 163))	('variant', 'Var', (87, 94))	('BRM', 'Gene', '6595', (108, 111))
916605	24519853	First, the small number of esophageal cancer patients was underpowered to detect a smaller association of less than twofold with the double homozygous BRM variants.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('esophageal cancer', 'Disease', (27, 44))	('variants', 'Var', (155, 163))	('BRM', 'Gene', (151, 154))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))	('patients', 'Species', '9606', (45, 53))	('BRM', 'Gene', '6595', (151, 154))
916609	24519853	In summary, we have shown that the double homozygous BRM germline variants are associated with an increased risk of early-stage UADT cancers.	('BRM', 'Gene', (53, 56))	('associated', 'Reg', (79, 89))	('BRM', 'Gene', '6595', (53, 56))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('variants', 'Var', (66, 74))	('stage UADT cancers', 'Disease', 'MESH:D006258', (122, 140))	('stage UADT cancers', 'Disease', (122, 140))	('double homozygous', 'Var', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
916611	24519853	Further studies are needed to understand the biology of the BRM promoter variants in carcinogenesis and to validate their clinical utility as potential biomarkers that predict the risk of UADT cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('variants', 'Var', (73, 81))	('UADT cancers', 'Disease', 'MESH:D006258', (188, 200))	('BRM', 'Gene', '6595', (60, 63))	('carcinogenesis', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('UADT cancers', 'Disease', (188, 200))	('BRM', 'Gene', (60, 63))
916612	24528540	Inactivation of miR-34a by aberrant CpG methylation in Kazakh patients with esophageal carcinoma Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with dismal prognosis and high incidence and mortality in Kazakh population.	('CpG', 'Protein', (36, 39))	('miR-34a', 'Gene', '407040', (16, 23))	('aberrant', 'Var', (27, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (97, 131))	('miR-34a', 'Gene', (16, 23))	('Esophageal squamous cell carcinoma', 'Disease', (97, 131))	('esophageal carcinoma', 'Disease', (76, 96))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('aggressive tumor', 'Disease', 'MESH:D001523', (145, 161))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (76, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (76, 96))	('patients', 'Species', '9606', (62, 70))	('aggressive tumor', 'Disease', (145, 161))	('Inactivation', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
916614	24528540	The reduced expression of miR-34a by methylation in various cancers has been reported.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('reduced', 'NegReg', (4, 11))	('methylation', 'Var', (37, 48))	('miR-34a', 'Gene', '407040', (26, 33))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('miR-34a', 'Gene', (26, 33))	('expression', 'MPA', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
916617	24528540	We found that miR-34a is more frequently methylated in ESCC (0.133 +- 0.040) than in controls (0.066 +- 0.045, P < 0.01).	('miR-34a', 'Gene', '407040', (14, 21))	('miR-34a', 'Gene', (14, 21))	('methylated', 'Var', (41, 51))	('ESCC', 'Disease', (55, 59))
916619	24528540	The hypermethylation of miR-34a CpG_8.9 was associated with the advanced UICC stage III/IV of the esophageal cancers, and the hypermethylation of CpG_8.9 and CpG_5 of miR-34a was significantly correlated with lymph node metastasis.	('miR-34a', 'Gene', '407040', (24, 31))	('esophageal cancers', 'Disease', 'MESH:D004938', (98, 116))	('miR-34a', 'Gene', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('esophageal cancers', 'Disease', (98, 116))	('miR-34a', 'Gene', '407040', (167, 174))	('lymph', 'Disease', (209, 214))	('associated with', 'Reg', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('correlated with', 'Reg', (193, 208))	('miR-34a', 'Gene', (167, 174))	('advanced UICC stage III/IV', 'Disease', (64, 90))	('hypermethylation', 'Var', (126, 142))	('hypermethylation', 'Var', (4, 20))
916620	24528540	Our findings suggest that miR-34a is involved in the etiology of ESCC and that hypermethylated miR-34a is a potential biomarker for ESCC diagnosis and prognosis.	('miR-34a', 'Gene', '407040', (26, 33))	('miR-34a', 'Gene', '407040', (95, 102))	('miR-34a', 'Gene', (26, 33))	('ESCC', 'Disease', (65, 69))	('hypermethylated', 'Var', (79, 94))	('miR-34a', 'Gene', (95, 102))	('ESCC', 'Disease', (132, 136))	('involved', 'Reg', (37, 45))
916623	24528540	Genetic defects, including the mutation or amplification of oncogenes and the inhibition of tumor-suppressor genes, such as EGFR, KRAS, pRb, and cyclin D1 mutations, are involved in the carcinogenesis of ESCC.	('ESCC', 'Disease', (204, 208))	('cyclin D1', 'Gene', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('oncogenes', 'Gene', (60, 69))	('KRAS', 'Gene', '3845', (130, 134))	('cyclin D1', 'Gene', '595', (145, 154))	('EGFR', 'Gene', '1956', (124, 128))	('amplification', 'Var', (43, 56))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('inhibition', 'NegReg', (78, 88))	('KRAS', 'Gene', (130, 134))	('pRb', 'Gene', (136, 139))	('Genetic defects', 'Disease', (0, 15))	('mutations', 'Var', (155, 164))	('Genetic defects', 'Disease', 'MESH:D030342', (0, 15))	('EGFR', 'Gene', (124, 128))	('involved', 'Reg', (170, 178))	('tumor', 'Disease', (92, 97))	('pRb', 'Gene', '5925', (136, 139))
916624	24528540	In addition, it is well established that p53 mutation is the most common genetic alteration in 60.6% of ESCC.	('common', 'Reg', (66, 72))	('p53', 'Gene', (41, 44))	('mutation', 'Var', (45, 53))	('ESCC', 'Disease', (104, 108))	('p53', 'Gene', '7157', (41, 44))
916625	24528540	By contrast, gene methylation is an alternative mechanism of gene inactivation that occurs early tumor progression and thus alters gene expression without changing the DNA sequence.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('alters', 'Reg', (124, 130))	('gene methylation', 'Var', (13, 29))	('gene expression', 'MPA', (131, 146))
916626	24528540	Similar to genetic mutations, transcriptional silencing by CpG methylation is stably inherited to the next cell generation and may therefore allow the clonal expansion of a cell population with a selective advantage during tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('allow', 'Reg', (141, 146))	('methylation', 'Var', (63, 74))	('transcriptional', 'MPA', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('CpG', 'Gene', (59, 62))
916629	24528540	Widespread miRNA is dysregulated in various human malignancies by changes in DNA copy number and epigenetic inactivation, although their exact functions during carcinogenesis are still being examined.	('human', 'Species', '9606', (44, 49))	('malignancies', 'Disease', (50, 62))	('DNA', 'Gene', (77, 80))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('changes', 'Reg', (66, 73))	('epigenetic inactivation', 'Var', (97, 120))	('malignancies', 'Disease', 'MESH:D009369', (50, 62))
916633	24528540	The reduced or absent expression of miR-34a was reported in 110 cancer cells lines, such as breast, lung, colon, kidney, melanoma, bladder, pancreatic carcinoma, lymphoma, and myeloma and cell lines, and two different types of primary cancers (melanoma and primary neuroblastoma samples) because of the aberrant CpG methylation of its promoter.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('melanoma', 'Disease', (121, 129))	('lymphoma', 'Phenotype', 'HP:0002665', (162, 170))	('neuroblastoma', 'Disease', (265, 278))	('reduced', 'NegReg', (4, 11))	('aberrant', 'Var', (303, 311))	('neuroblastoma', 'Phenotype', 'HP:0003006', (265, 278))	('absent', 'NegReg', (15, 21))	('miR-34a', 'Gene', (36, 43))	('breast', 'Disease', (92, 98))	('neuroblastoma', 'Disease', 'MESH:D009447', (265, 278))	('colon', 'Disease', (106, 111))	('primary cancers', 'Disease', 'MESH:D009369', (227, 242))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Disease', (64, 70))	('miR-34a', 'Gene', '407040', (36, 43))	('myeloma', 'Disease', 'MESH:D009101', (176, 183))	('lymphoma', 'Disease', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanoma', 'Disease', (244, 252))	('lymphoma', 'Disease', 'MESH:D008223', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('bladder', 'Disease', (131, 138))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('lung', 'Disease', (100, 104))	('CpG methylation', 'Var', (312, 327))	('expression', 'MPA', (22, 32))	('myeloma', 'Disease', (176, 183))	('primary cancers', 'Disease', (227, 242))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (140, 160))	('cancer', 'Disease', (235, 241))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('pancreatic carcinoma', 'Disease', (140, 160))
916634	24528540	However, only one study have reported that the miR-34a was silenced in ESCC cell lines and re-expression miR-34a can inhibit the ESCC proliferation by reducing the C-met and Cyclin D1 expression, yet the correlation between downregulation/loss of miR-34a expression and promoter methylation in ESCC was not clean, especially in the Kazakh population.	('C-met', 'Gene', (164, 169))	('ESCC proliferation', 'CPA', (129, 147))	('reducing', 'NegReg', (151, 159))	('miR-34a', 'Gene', '407040', (105, 112))	('miR-34a', 'Gene', (47, 54))	('Cyclin D1', 'Gene', '595', (174, 183))	('C-met', 'Gene', '4233', (164, 169))	('re-expression', 'Var', (91, 104))	('miR-34a', 'Gene', '407040', (47, 54))	('miR-34a', 'Gene', (105, 112))	('miR-34a', 'Gene', '407040', (247, 254))	('expression', 'MPA', (184, 194))	('miR-34a', 'Gene', (247, 254))	('downregulation/loss', 'NegReg', (224, 243))	('Cyclin D1', 'Gene', (174, 183))	('inhibit', 'NegReg', (117, 124))
916635	24528540	Given that aberrant DNA methylation is an important mechanism for gene transcription and protein expression silencing, in the present study, we accordingly therefore hypothesized whether epigenetic modifications indirectly modulate miR-34a expression by silencing or activating miR-34a genes in Kazakh ESCC patients.	('miR-34a', 'Gene', (278, 285))	('miR-34a', 'Gene', '407040', (232, 239))	('miR-34a', 'Gene', (232, 239))	('aberrant', 'Var', (11, 19))	('expression', 'MPA', (240, 250))	('patients', 'Species', '9606', (307, 315))	('activating', 'PosReg', (267, 277))	('silencing', 'NegReg', (254, 263))	('epigenetic modifications', 'Var', (187, 211))	('miR-34a', 'Gene', '407040', (278, 285))	('modulate', 'Reg', (223, 231))	('ESCC', 'Disease', (302, 306))
916680	24528540	To determine whether CpG methylation is accompanied by decreased miR-34a expression, we examined expression of miR-34a mRNA by real-time PCR in the same cohort (tumor n = 59; normal n = 34) used for the methylation analysis.	('miR-34a', 'Gene', (65, 72))	('miR-34a', 'Gene', '407040', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('miR-34a', 'Gene', (111, 118))	('decreased', 'NegReg', (55, 64))	('methylation', 'Var', (25, 36))	('expression', 'MPA', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('miR-34a', 'Gene', '407040', (65, 72))	('tumor', 'Disease', (161, 166))
916681	24528540	The results, consistent with our expectation, indicated that the miR-34a gene showed a nearly two-fold decrease in expression in Kazakh ESCC patients with a high level of methylation compared with that in normal tissues (0.079 +- 0.094 vs. 0.277 +- 0.045, P < 0.0001; Figure 4).	('miR-34a', 'Gene', (65, 72))	('methylation', 'Var', (171, 182))	('expression', 'MPA', (115, 125))	('decrease', 'NegReg', (103, 111))	('miR-34a', 'Gene', '407040', (65, 72))	('patients', 'Species', '9606', (141, 149))
916684	24528540	These results demonstrated that the hypermethylation of the miR-34a promoter region might be the reason for the suppression of mRNA in Kazakh ESCC tissues.	('miR-34a', 'Gene', '407040', (60, 67))	('mRNA', 'MPA', (127, 131))	('hypermethylation', 'Var', (36, 52))	('miR-34a', 'Gene', (60, 67))	('suppression', 'NegReg', (112, 123))
916691	24528540	These results suggest that aberrant promoter methylation plays an important role in the down-regulation of miR-34a gene expression in Kazakh patients with esophageal cancer.	('miR-34a', 'Gene', '407040', (107, 114))	('expression', 'MPA', (120, 130))	('aberrant', 'Var', (27, 35))	('esophageal cancer', 'Disease', (155, 172))	('miR-34a', 'Gene', (107, 114))	('promoter', 'MPA', (36, 44))	('down-regulation', 'NegReg', (88, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patients', 'Species', '9606', (141, 149))
916695	24528540	Patterns of aberrant miRNA expression are involved in ESCC, and miRNA acts as oncogenes or tumor suppressors.	('ESCC', 'Disease', (54, 58))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('involved', 'Reg', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('aberrant', 'Var', (12, 20))	('tumor', 'Disease', (91, 96))
916698	24528540	Consequence, with non-quantitative MSP method in Chinese Han population and the quantitative MassARRAY approach in Kazakh population, the uniformity of the methylation of the miR-34a promoter in both studies strengthens the association between such methylation and ESCC.	('ESCC', 'Disease', (265, 269))	('methylation', 'Var', (249, 260))	('miR-34a', 'Gene', (175, 182))	('association', 'Interaction', (224, 235))	('strengthens', 'PosReg', (208, 219))	('miR-34a', 'Gene', '407040', (175, 182))	('methylation', 'Var', (156, 167))
916699	24528540	Although miR-34a is epigenetically silenced in numerous cancers, including colorectal, pancreatic, mammary, ovarian, urothelial, renal cell carcinomas, and soft tissue sarcomas, the finding presented here is the first to demonstrate the suppression of miR-34a via promoter methylation in Kazakh patients with esophageal cancer.	('pancreatic', 'Disease', (87, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('miR-34a', 'Gene', '407040', (252, 259))	('numerous cancers', 'Disease', 'MESH:D009369', (47, 63))	('ovarian', 'Disease', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('ovarian', 'Disease', 'MESH:D010051', (108, 115))	('mammary', 'Disease', (99, 106))	('suppression', 'NegReg', (237, 248))	('colorectal', 'Disease', 'MESH:D015179', (75, 85))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (129, 150))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('numerous cancers', 'Disease', (47, 63))	('renal cell carcinomas', 'Disease', (129, 150))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (129, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (309, 326))	('soft tissue sarcomas', 'Disease', (156, 176))	('miR-34a', 'Gene', (9, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (156, 176))	('esophageal cancer', 'Disease', (309, 326))	('promoter methylation', 'Var', (264, 284))	('pancreatic', 'Disease', 'MESH:D010195', (87, 97))	('miR-34a', 'Gene', '407040', (9, 16))	('patients', 'Species', '9606', (295, 303))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (156, 176))	('colorectal', 'Disease', (75, 85))	('urothelial', 'Disease', (117, 127))	('miR-34a', 'Gene', (252, 259))
916700	24528540	Recent data suggest that dysregulation of miR-34a exists in various types of human cancers and is associated with clinic treatment.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('miR-34a', 'Gene', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('dysregulation', 'Var', (25, 38))	('miR-34a', 'Gene', '407040', (42, 49))	('associated', 'Reg', (98, 108))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
916705	24528540	Recently, there is growing evidence that p53 abnormality is not always associated with the down-regulation of miR-34a in human cancer tissues, although several groups have shown that the well-known tumour suppressive activity of p53 is at least in part moderated by miR-34a.	('tumour', 'Disease', (198, 204))	('p53', 'Gene', '7157', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('miR-34a', 'Gene', (110, 117))	('abnormality', 'Var', (45, 56))	('down-regulation', 'NegReg', (91, 106))	('miR-34a', 'Gene', '407040', (266, 273))	('p53', 'Gene', (229, 232))	('p53', 'Gene', '7157', (229, 232))	('human', 'Species', '9606', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('miR-34a', 'Gene', (266, 273))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', (127, 133))	('miR-34a', 'Gene', '407040', (110, 117))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('p53', 'Gene', (41, 44))
916707	24528540	Deletion or mutation of p53 is associated with miR-34a down-regulation in chronic lymphocytic leukemia and ovarian cancers.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('lymphocytic leukemia and ovarian cancers', 'Disease', 'MESH:D010051', (82, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('miR-34a', 'Gene', '407040', (47, 54))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (74, 102))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('mutation', 'Var', (12, 20))	('miR-34a', 'Gene', (47, 54))	('ovarian cancers', 'Phenotype', 'HP:0100615', (107, 122))	('down-regulation', 'NegReg', (55, 70))	('Deletion', 'Var', (0, 8))
916708	24528540	While in neuroblastoma and small-cell lung cancer, no significant correlation between p53 mutation and miR-34a dysregulation is observed.	('neuroblastoma', 'Disease', (9, 22))	('p53', 'Gene', '7157', (86, 89))	('miR-34a', 'Gene', '407040', (103, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('miR-34a', 'Gene', (103, 110))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (27, 49))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('small-cell lung cancer', 'Disease', (27, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (90, 98))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))	('p53', 'Gene', (86, 89))
916709	24528540	However, there was no direct correlation between the deletion or mutation of p53 and miR-34a expression levels in ESCC samples.	('ESCC', 'Disease', (114, 118))	('deletion', 'Var', (53, 61))	('expression levels', 'MPA', (93, 110))	('miR-34a', 'Gene', '407040', (85, 92))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('mutation', 'Var', (65, 73))	('miR-34a', 'Gene', (85, 92))
916710	24528540	Like other malignancies, mutations of p53 are common molecular genetic events in 60.6% of ESCC.	('mutations', 'Var', (25, 34))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('malignancies', 'Disease', 'MESH:D009369', (11, 23))	('malignancies', 'Disease', (11, 23))	('ESCC', 'Disease', (90, 94))
916711	24528540	The observation of aberrant methylation of miR-34a-induced inactivation raises an important regulation mechanism for miR-34a in the etiology of Kazakh ESCC.	('miR-34a', 'Gene', '407040', (117, 124))	('miR-34a', 'Gene', (117, 124))	('methylation', 'MPA', (28, 39))	('miR-34a', 'Gene', '407040', (43, 50))	('miR-34a', 'Gene', (43, 50))	('aberrant', 'Var', (19, 27))	('inactivation', 'MPA', (59, 71))
916712	24528540	It has been hypothesized that miR-34a promoter methylation preferentially occurs in tumors expressing mutant-type p53 in esophageal carcinoma.	('occurs', 'Reg', (74, 80))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('miR-34a', 'Gene', '407040', (30, 37))	('esophageal carcinoma', 'Disease', (121, 141))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (121, 141))	('miR-34a', 'Gene', (30, 37))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (121, 141))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mutant-type', 'Var', (102, 113))
916713	24528540	Clearly, future studies are required to obtain a more complete understanding of the consequence of miR-34a delivery to ESCC cells with mutant-type p53.	('p53', 'Gene', (147, 150))	('mutant-type', 'Var', (135, 146))	('miR-34a', 'Gene', '407040', (99, 106))	('miR-34a', 'Gene', (99, 106))	('p53', 'Gene', '7157', (147, 150))
916715	24528540	This observation is in good agreement with the report that the methylation of miR-34 promoter is correlated with the metastatic potential of tumor cells, such as SIHN-011B, osteosarcoma and breast cancer cells lines, but not accordance with the results from Chen et al..	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('correlated', 'Reg', (97, 107))	('miR-34', 'Gene', '407040', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('osteosarcoma', 'Phenotype', 'HP:0002669', (173, 185))	('tumor', 'Disease', (141, 146))	('miR-34', 'Gene', (78, 84))	('methylation', 'Var', (63, 74))	('SIHN-011B, osteosarcoma', 'Disease', 'MESH:D012516', (162, 185))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('metastatic potential of', 'CPA', (117, 140))
916717	24528540	However, the exact mechanism for the function of miR-34a epigenetic silencing in metastasis formation remains unambiguous.	('epigenetic silencing', 'Var', (57, 77))	('metastasis formation', 'CPA', (81, 101))	('miR-34a', 'Gene', (49, 56))	('miR-34a', 'Gene', '407040', (49, 56))
916805	23346537	In the palliative group, severe esophageal toxicities were more common in the patients with advanced T stage (T3 or T4) at the time of re-RT.	('esophageal toxicities', 'Disease', 'MESH:D004935', (32, 53))	('T4', 'Var', (116, 118))	('patients', 'Species', '9606', (78, 86))	('esophageal toxicities', 'Disease', (32, 53))
916827	20186319	Epigenetic plasticity provides the mechanism for tissue differentiation and physiological response to the changing environment; abnormal regulation of epigenetic information is involved in many human diseases including cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('abnormal', 'Var', (128, 136))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('human', 'Species', '9606', (194, 199))	('cancer', 'Disease', (219, 225))	('involved', 'Reg', (177, 185))
916828	20186319	Epigenetic alterations are hallmarks of human cancer (for reviews see).	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('human', 'Species', '9606', (40, 45))
916868	17134496	Genome-wide loss of heterozygosity and copy number alteration in esophageal squamous cell carcinoma using the Affymetrix GeneChip Mapping 10 K array Esophageal squamous cell carcinoma (ESCC) is a common malignancy worldwide.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('malignancy', 'Disease', 'MESH:D009369', (203, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('malignancy', 'Disease', (203, 213))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('esophageal squamous cell carcinoma', 'Disease', (65, 99))	('loss', 'NegReg', (12, 16))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (149, 183))	('copy number alteration', 'Var', (39, 61))	('Esophageal squamous cell carcinoma', 'Disease', (149, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (65, 99))
916869	17134496	Genome-wide detection of chromosomal changes was performed using the Affymetrix GeneChip 10 K single nucleotide polymorphism (SNP) array, including loss of heterozygosity (LOH) and copy number alterations (CNA), for 26 pairs of matched germ-line and micro-dissected tumor DNA samples.	('loss', 'Var', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('copy', 'Var', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))
916871	17134496	Genetic instabilities are characteristic of most human cancers.	('instabilities', 'Disease', (8, 21))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (49, 54))	('Genetic', 'Var', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('instabilities', 'Disease', 'MESH:D043171', (8, 21))	('cancers', 'Disease', (55, 62))
916872	17134496	Genome-wide detection of chromosomal changes, including loss of heterozygosity (LOH) and copy number alterations (CNA), either gain or loss, are the focus of substantial attention in cancer research.	('cancer', 'Disease', (183, 189))	('copy number alterations', 'Var', (89, 112))	('loss', 'NegReg', (56, 60))	('loss', 'NegReg', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
916876	17134496	Recently, the discovery of large-scale genome-wide copy number variation has stimulated interest in elucidating the role of CNA in the development of malignancy.	('malignancy', 'Disease', (150, 160))	('copy number variation', 'Var', (51, 72))	('malignancy', 'Disease', 'MESH:D009369', (150, 160))
916877	17134496	Several studies on allelic imbalance or loss in cancers and cancer cell lines using the 10 K SNP array have been published.	('allelic', 'Var', (19, 26))	('loss in cancers', 'Disease', (40, 55))	('imbalance', 'Phenotype', 'HP:0002172', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('loss in cancers', 'Disease', 'MESH:D009369', (40, 55))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
916889	17134496	LOH in four cases (SHE0832, SHE0864, SHE1264, and SHE1490) was performed using DNA from micro-dissected adjacent normal tissue in addition to blood-derived germ-line DNA to see if this affected results, but findings were very similar with both of these two sources of DNA (Table 1).	('SHE1264', 'CellLine', 'CVCL:3970', (37, 44))	('SHE1490', 'Var', (50, 57))	('affected', 'Reg', (185, 193))	('SHE1264', 'Var', (37, 44))	('SHE0832', 'Var', (19, 26))	('SHE0864', 'Var', (28, 35))
916895	17134496	The 46 SNPs that are located within genes map to 32 genes and include four SNPs in the introns of ZNF618, and two SNPs each in the introns of ITPR1, FLJ14834, LHFP, ITGAE, MYH3 and MYOCD.	('LHFP', 'Gene', '10186', (159, 163))	('MYOCD', 'Gene', '93649', (181, 186))	('LHFP', 'Gene', (159, 163))	('ZNF618', 'Gene', '114991', (98, 104))	('ITGAE', 'Gene', '3682', (165, 170))	('MYH3', 'Gene', (172, 176))	('MYH3', 'Gene', '4621', (172, 176))	('ITPR1', 'Gene', (142, 147))	('ITGAE', 'Gene', (165, 170))	('ZNF618', 'Gene', (98, 104))	('ITPR1', 'Gene', '3708', (142, 147))	('FLJ14834', 'Var', (149, 157))	('MYOCD', 'Gene', (181, 186))
916946	29386089	The results showed that GAS5 expression was increased in EC cells (ECA109, TE-1, TE-3, and EC9706) compared to SHEE cells.	('GAS5', 'Protein', (24, 28))	('ECA109', 'Var', (67, 73))	('increased', 'PosReg', (44, 53))	('expression', 'MPA', (29, 39))	('EC9706', 'CellLine', 'CVCL:E307', (91, 97))
916956	29386089	Accumulating evidence showed that abnormal expressions of lncRNAs could regulate many key biological processes in various cancers.	('lncRNAs', 'Protein', (58, 65))	('abnormal expressions', 'Phenotype', 'HP:0100022', (34, 54))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('regulate', 'Reg', (72, 80))	('abnormal expressions', 'Var', (34, 54))
916962	29386089	We found that GAS5 was highly expressed in EC cells, and knockdown of GAS5 inhibited cell viability, migration, and invasion and induced apoptosis in EC9706 cells.	('EC9706', 'CellLine', 'CVCL:E307', (150, 156))	('apoptosis', 'CPA', (137, 146))	('migration', 'CPA', (101, 110))	('inhibited', 'NegReg', (75, 84))	('induced', 'Reg', (129, 136))	('invasion', 'CPA', (116, 124))	('knockdown', 'Var', (57, 66))	('GAS5', 'Gene', (70, 74))	('cell viability', 'CPA', (85, 99))
916963	29386089	Moreover, GAS5 acted as a molecular sponge to regulate miR-301a, and inhibition of miR-301a alleviated the protumor effects of GAS5 in EC9706 cells.	('miR-301a', 'Gene', (83, 91))	('miR-301a', 'Gene', (55, 63))	('miR-301a', 'Gene', '407027', (55, 63))	('miR-301a', 'Gene', '407027', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('alleviated', 'NegReg', (92, 102))	('EC9706', 'CellLine', 'CVCL:E307', (135, 141))	('inhibition', 'Var', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
916981	29386089	To mutate the putative binding site of miR-301a in the GAS5, the sequence of putative binding site was replaced and was named as GAS5-mutated type (GAS5-mt).	('miR-301a', 'Gene', '407027', (39, 47))	('mutate', 'Var', (3, 9))	('binding', 'Interaction', (23, 30))	('miR-301a', 'Gene', (39, 47))
916995	29386089	As indicated in Figure 1, the expression level of GAS5 was prominently increased in ECA109 and EC9706 cells compared with that in SHEE cells (p < 0.05 or p < 0.01).	('EC9706', 'CellLine', 'CVCL:E307', (95, 101))	('ECA109', 'Var', (84, 90))	('EC9706', 'Var', (95, 101))	('GAS5', 'Protein', (50, 54))	('increased', 'PosReg', (71, 80))	('expression level', 'MPA', (30, 46))
916996	29386089	Furthermore, the expression level of GAS5 was highest in EC9706 cells than that in other cell lines; therefore, the EC9706 cell line was selected to use for subsequent study.	('highest', 'Reg', (46, 53))	('EC9706', 'Var', (57, 63))	('EC9706', 'CellLine', 'CVCL:E307', (116, 122))	('expression level', 'MPA', (17, 33))	('EC9706', 'CellLine', 'CVCL:E307', (57, 63))	('GAS5', 'Protein', (37, 41))
916999	29386089	Figure 2B-E shows that knockdown of GAS5 significantly decreased cell viability, migration, and invasion but increased apoptosis in EC9706 cells (p < 0.05, p < 0.01, or p < 0.001).	('knockdown', 'Var', (23, 32))	('cell viability', 'CPA', (65, 79))	('apoptosis', 'CPA', (119, 128))	('decreased', 'NegReg', (55, 64))	('invasion', 'CPA', (96, 104))	('migration', 'CPA', (81, 90))	('EC9706', 'CellLine', 'CVCL:E307', (132, 138))	('increased', 'PosReg', (109, 118))	('GAS5', 'Gene', (36, 40))
917000	29386089	Furthermore, Western blot analysis revealed that the expression level of Bcl-2 was downregulated by knockdown of GAS5 (p < 0.01).	('GAS5', 'Gene', (113, 117))	('knockdown', 'Var', (100, 109))	('Bcl-2', 'Gene', (73, 78))	('Bcl-2', 'Gene', '596', (73, 78))	('expression level', 'MPA', (53, 69))	('downregulated', 'NegReg', (83, 96))
917001	29386089	However, Bax, cleaved caspase 3, and cleaved caspase 9 expression levels were upregulated by knockdown of GAS5 (p < 0.01 or p < 0.001).	('knockdown', 'Var', (93, 102))	('Bax', 'Gene', (9, 12))	('upregulated', 'PosReg', (78, 89))	('GAS5', 'Gene', (106, 110))	('cleaved caspase', 'MPA', (14, 29))	('expression levels', 'MPA', (55, 72))	('caspase 9', 'Gene', (45, 54))	('Bax', 'Gene', '581', (9, 12))	('caspase 9', 'Gene', '842', (45, 54))
917006	29386089	Additionally, the qRT-PCR results showed that the miR-301a expression level was significantly elevated by knockdown of GAS5 compared with the sh-NC group (p < 0.01) (Fig.	('elevated', 'PosReg', (94, 102))	('GAS5', 'Gene', (119, 123))	('knockdown', 'Var', (106, 115))	('miR-301a', 'Gene', (50, 58))	('miR-301a', 'Gene', '407027', (50, 58))	('expression level', 'MPA', (59, 75))
917012	29386089	Coincidently, the Transwell assay revealed that miR-301a suppression rescued the cell migration and invasion abilities reduced by GAS5 knockdown (p < 0.05) (Fig.	('miR-301a', 'Gene', (48, 56))	('knockdown', 'Var', (135, 144))	('GAS5', 'Gene', (130, 134))	('invasion abilities', 'CPA', (100, 118))	('miR-301a', 'Gene', '407027', (48, 56))	('suppression', 'NegReg', (57, 68))	('reduced', 'NegReg', (119, 126))	('cell migration', 'CPA', (81, 95))
917014	29386089	Western blot analysis revealed that miR-301a suppression reversed the effect of GAS5 knockdown on apoptosis-associated factor expression (p < 0.01 or p < 0.001) (Fig.	('suppression', 'NegReg', (45, 56))	('apoptosis-associated factor expression', 'MPA', (98, 136))	('miR-301a', 'Gene', (36, 44))	('miR-301a', 'Gene', '407027', (36, 44))	('knockdown', 'Var', (85, 94))	('GAS5', 'Gene', (80, 84))
917018	29386089	As displayed in Figure 5A-C, CXCR4 expression was significantly increased by miR-301a overexpression but decreased by miR-301 suppression (p < 0.01), indicating that CXCR4 expression was positively regulated by miR-301a.	('miR-301', 'Gene', (118, 125))	('CXCR4', 'Gene', (166, 171))	('miR-301', 'Gene', (211, 218))	('CXCR4', 'Gene', '7852', (29, 34))	('miR-301', 'Gene', '407027', (77, 84))	('miR-301', 'Gene', '407027', (211, 218))	('miR-301', 'Gene', (77, 84))	('miR-301a', 'Gene', (211, 219))	('overexpression', 'Var', (86, 100))	('CXCR4', 'Gene', (29, 34))	('miR-301', 'Gene', '407027', (118, 125))	('CXCR4', 'Gene', '7852', (166, 171))	('miR-301a', 'Gene', (77, 85))	('miR-301a', 'Gene', '407027', (211, 219))	('increased', 'PosReg', (64, 73))	('miR-301a', 'Gene', '407027', (77, 85))	('decreased', 'NegReg', (105, 114))
917021	29386089	Western blot results showed that the protein level of CXCR4 was obviously reduced by silencing of CXCR4 in EC9706 cells (Fig.	('CXCR4', 'Gene', '7852', (98, 103))	('CXCR4', 'Gene', '7852', (54, 59))	('EC9706', 'CellLine', 'CVCL:E307', (107, 113))	('CXCR4', 'Gene', (98, 103))	('CXCR4', 'Gene', (54, 59))	('silencing', 'Var', (85, 94))	('reduced', 'NegReg', (74, 81))
917039	29386089	Overexpression of GSA5 could suppress tumor growth, migration, and invasion, as well as induce apoptosis and enhance radiosensitivity in these cancers.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('suppress', 'NegReg', (29, 37))	('invasion', 'CPA', (67, 75))	('radiosensitivity', 'CPA', (117, 133))	('apoptosis', 'CPA', (95, 104))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('induce', 'PosReg', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancers', 'Disease', (143, 150))	('Overexpression', 'Var', (0, 14))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (109, 133))	('GSA5', 'Gene', (18, 22))	('enhance', 'PosReg', (109, 116))
917046	29386089	Moreover, GAS5 inhibited tumor malignancy by downregulation of miR-222 in glioma.	('inhibited', 'NegReg', (15, 24))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('tumor malignancy', 'Disease', 'MESH:D009369', (25, 41))	('miR-222', 'Gene', '407007', (63, 70))	('glioma', 'Disease', (74, 80))	('downregulation', 'NegReg', (45, 59))	('GAS5', 'Var', (10, 14))	('tumor malignancy', 'Disease', (25, 41))	('miR-222', 'Gene', (63, 70))
917052	29386089	Silencing of CXCR2 and CXCR7 has been reported to protect against EC by suppressing cell growth and inducing apoptosis.	('CXCR2', 'Gene', '3579', (13, 18))	('CXCR7', 'Gene', (23, 28))	('inducing', 'Reg', (100, 108))	('CXCR2', 'Gene', (13, 18))	('apoptosis', 'CPA', (109, 118))	('cell growth', 'CPA', (84, 95))	('CXCR7', 'Gene', '57007', (23, 28))	('suppressing', 'NegReg', (72, 83))	('Silencing', 'Var', (0, 9))
917061	29386089	Furthermore, a previous study confirmed that inhibition of NF-kappaB could reduce cell proliferation, suppress migration and invasion, induce apoptosis, and enhance sensitivity to chemotherapeutic drugs in EC.	('enhance', 'PosReg', (157, 164))	('reduce', 'NegReg', (75, 81))	('apoptosis', 'CPA', (142, 151))	('NF-kappaB', 'Gene', '4790', (59, 68))	('cell proliferation', 'CPA', (82, 100))	('sensitivity to chemotherapeutic', 'MPA', (165, 196))	('NF-kappaB', 'Gene', (59, 68))	('induce', 'PosReg', (135, 141))	('inhibition', 'Var', (45, 55))	('suppress', 'NegReg', (102, 110))
917073	30911684	Since the sequencing of the first genomic DNA from a leukemia patient, various studies have identified somatic and germline variants in key cancer genes.	('leukemia', 'Disease', (53, 61))	('patient', 'Species', '9606', (62, 69))	('variants', 'Var', (124, 132))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('leukemia', 'Phenotype', 'HP:0001909', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('leukemia', 'Disease', 'MESH:D007938', (53, 61))
917074	30911684	Although large-scale sequencing projects such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) continue to catalog variants across cancer types, only a minority of patients harbor tumors with genomic aberrations associated with sensitivity to targeted therapy.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('Cancer Genome Atlas', 'Disease', (53, 72))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('Cancer', 'Disease', 'MESH:D009369', (53, 59))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('variants', 'Var', (154, 162))	('tumors', 'Disease', (219, 225))	('Cancer', 'Disease', (102, 108))	('cancer', 'Disease', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (53, 72))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('Cancer', 'Disease', 'MESH:D009369', (102, 108))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Cancer', 'Disease', (53, 59))
917076	30911684	PD-L1 and PD-L2 on tumor cells or antigen-presenting cells suppress T-cell immune response by binding to PD-1 on T-cells.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('binding', 'Interaction', (94, 101))	('PD-L2', 'Var', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PD-L1', 'Var', (0, 5))	('T-cell immune response', 'CPA', (68, 90))	('tumor', 'Disease', (19, 24))	('suppress', 'NegReg', (59, 67))	('PD-1', 'Gene', (105, 109))
917077	30911684	To escape attack by immune cells, tumor cells overexpress PD-L1 by gene amplification, utilization of an ectopic promoter, and disruption of 3' untranslated regions (3' UTRs), in addition to PTEN loss-of function and EGFR mutations.	('EGFR', 'Gene', '1956', (217, 221))	('EGFR', 'Gene', (217, 221))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PTEN', 'Gene', (191, 195))	('PTEN', 'Gene', '5728', (191, 195))	('disruption', 'Var', (127, 137))	('mutations', 'Var', (222, 231))	('PD-L1', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('loss-of function', 'NegReg', (196, 212))	('overexpress', 'PosReg', (46, 57))
917078	30911684	Other studies indicate that EGFR mutations are not associated with an increased PD-L1 expression and a better clinical response of PD-L1 immune checkpoint inhibitors.	('PD-L1', 'Gene', (80, 85))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('expression', 'MPA', (86, 96))	('increased PD', 'Phenotype', 'HP:0008151', (70, 82))
917080	30911684	Anti-PD-1 and anti-PD-L1 immune checkpoint blockades show favorable clinical outcome for treating patients with high PD-1 and PD-L1 expression.	('PD-1', 'Gene', (117, 121))	('PD-L1', 'Gene', (126, 131))	('high', 'Var', (112, 116))	('patients', 'Species', '9606', (98, 106))
917087	30911684	Here, using TCGA RNA-Seq data for six virus-associated tumors, we systematically study the associations between virus-positivity and the tumor microenvironment, as measured by expression of PD-L1, PD-L2, PD-1, CD80, CD86, CTLA-4, Tim-3, LAG3, and 4-1BB and the prevalence of infiltrating immune cells across multiple types of human cancers.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CD86', 'Gene', '942', (216, 220))	('CD86', 'Gene', (216, 220))	('CD80', 'Gene', (210, 214))	('4-1BB', 'Gene', (247, 252))	('PD-L2', 'Gene', (197, 202))	('cancers', 'Disease', 'MESH:D009369', (332, 339))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('LAG3', 'Gene', (237, 241))	('4-1BB', 'Gene', '3604', (247, 252))	('human', 'Species', '9606', (326, 331))	('Tim-3', 'Gene', '84868', (230, 235))	('PD-L1', 'Var', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', (55, 61))	('CTLA-4', 'Gene', '1493', (222, 228))	('tumor', 'Disease', (137, 142))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('CTLA-4', 'Gene', (222, 228))	('cancers', 'Disease', (332, 339))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Disease', (55, 60))	('associations', 'Interaction', (91, 103))	('CD80', 'Gene', '941', (210, 214))	('LAG3', 'Gene', '3902', (237, 241))	('Tim-3', 'Gene', (230, 235))	('PD-1', 'Gene', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
917090	30911684	In addition, we found HPV integrations at PD-L1 and PD-L2 are associated with high expression of these genes.	('associated', 'Reg', (62, 72))	('integrations', 'Var', (26, 38))	('HPV', 'Species', '10566', (22, 25))	('expression', 'MPA', (83, 93))	('PD-L1', 'Gene', (42, 47))	('PD-L2', 'Gene', (52, 57))
917099	30911684	Of these, we identified three tumors with HPV integrations at PD-L1 or PD-L2 by using discordant read pair analysis (Methods, Fig.	('integrations', 'Var', (46, 58))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('HPV', 'Species', '10566', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
917104	30911684	Although different integration patterns and anatomic sites were observed in the three tumors, HPV integrations at PD-L1 or PD-L2 were all accompanied by higher expression levels of these genes compared with those in virus-negative tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('PD-L1', 'Gene', (114, 119))	('higher', 'PosReg', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('HPV', 'Species', '10566', (94, 97))	('integrations', 'Var', (98, 110))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('expression levels', 'MPA', (160, 177))	('PD-L2', 'Gene', (123, 128))	('tumors', 'Disease', (231, 237))
917108	30911684	This result indicates that high PD-L1 or PD-L2 expression induced by HPV integration is a phenomenon that is selectively associated with HPV in HNSC tumors, with PD-L1 or PD-L2 integrations occurring in 4.2% of HNSC HPV-positive tumors.	('HNSC', 'Phenotype', 'HP:0012288', (211, 215))	('integration', 'Var', (73, 84))	('HPV', 'Species', '10566', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('HNSC HPV-positive tumors', 'Disease', 'MESH:D030361', (211, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('PD-L1', 'Gene', (32, 37))	('HPV', 'Gene', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('expression', 'MPA', (47, 57))	('HNSC HPV-positive tumors', 'Disease', (211, 235))	('HPV', 'Species', '10566', (137, 140))	('HPV', 'Species', '10566', (216, 219))	('HNSC', 'Phenotype', 'HP:0012288', (144, 148))	('PD-L2', 'Gene', (41, 46))	('associated', 'Reg', (121, 131))	('HNSC tumors', 'Disease', 'MESH:D009369', (144, 155))	('HNSC tumors', 'Disease', (144, 155))
917116	30911684	In HNSC, we found that three tumors with HPV integrations had high expression of PD-L1 or PD-L2, i.e., TCGA-CV-5443 and TCGA-T2-A6X0 with 11.8 and 9.2 for PD-L1 and TCGA-HL-7533 with 10 for PD-L2 (RSEM in log2 scale).	('HPV', 'Species', '10566', (41, 44))	('PD-L1', 'Gene', (81, 86))	('TCGA-HL-7533', 'CellLine', 'CVCL:2492', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('integrations', 'Var', (45, 57))	('TCGA-CV-5443', 'Var', (103, 115))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('expression', 'MPA', (67, 77))	('tumors', 'Disease', (29, 35))	('HNSC', 'Phenotype', 'HP:0012288', (3, 7))	('PD-L2', 'Gene', (90, 95))
917119	30911684	However, we found a higher level of PD-L1, PD-L2, CD80, CD86, Tim-3, LAG3, and 4-1BB in EBV-positive STAD and cytomegalovirus-positive colon and rectum adenocarcinoma than in virus-negative tumor samples (Fig.	('PD-L2', 'Var', (43, 48))	('PD-L1', 'MPA', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('Tim-3', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('4-1BB', 'Gene', (79, 84))	('colon and rectum adenocarcinoma', 'Disease', 'MESH:D012004', (135, 166))	('EBV', 'Species', '10376', (88, 91))	('Tim-3', 'Gene', '84868', (62, 67))	('tumor', 'Disease', (190, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('LAG3', 'Gene', (69, 73))	('CD80', 'Gene', (50, 54))	('LAG3', 'Gene', '3902', (69, 73))	('CD86', 'Gene', '942', (56, 60))	('CD86', 'Gene', (56, 60))	('4-1BB', 'Gene', '3604', (79, 84))	('CD80', 'Gene', '941', (50, 54))
917133	30911684	3, we separated samples into four different groups based on supervised clustering results, i.e., Virus-/T-celllow, HPV+/T-celllow, Virus-/T-cellhigh, and HPV+/T-cellhigh.	('HPV+/T-celllow', 'Disease', (115, 129))	('HPV', 'Species', '10566', (115, 118))	('HPV+/T-cellhigh', 'Var', (154, 169))	('Virus-/T-celllow', 'Disease', (97, 113))	('HPV', 'Species', '10566', (154, 157))	('Virus-/T-cellhigh', 'Disease', (131, 148))
917148	30911684	For instance, an ICOS signature was identified in EBV-positive STAD (Supplementary Table 2) as well as HPV-positive HNSC; The expression of ICOS increases about two-fold in EBV-positive STAD and HPV-positive HNSC compared to virus-negative samples.	('HPV', 'Species', '10566', (195, 198))	('EBV-positive', 'Var', (173, 185))	('expression', 'MPA', (126, 136))	('HNSC', 'Phenotype', 'HP:0012288', (208, 212))	('HPV', 'Species', '10566', (103, 106))	('EBV', 'Species', '10376', (173, 176))	('ICOS', 'Gene', (17, 21))	('ICOS', 'Gene', (140, 144))	('EBV', 'Species', '10376', (50, 53))	('HNSC', 'Phenotype', 'HP:0012288', (116, 120))	('increases', 'PosReg', (145, 154))	('ICOS', 'Gene', '29851', (17, 21))	('ICOS', 'Gene', '29851', (140, 144))
917171	30911684	We found that immune response is associated with a positive prognosis in patients with HPV-positive HNSC, but not in those with virus-negative HNSC (Fig.	('HNSC', 'Disease', (100, 104))	('HPV-positive', 'Var', (87, 99))	('HPV', 'Species', '10566', (87, 90))	('HNSC', 'Phenotype', 'HP:0012288', (143, 147))	('HNSC', 'Phenotype', 'HP:0012288', (100, 104))	('immune response', 'CPA', (14, 29))	('patients', 'Species', '9606', (73, 81))
917175	30911684	The HPV-positive cohort contained no variants in either TP53 or CDKN2A and only one in FAT1; in the HPV-negative cohort, these genes were frequently mutated.	('HPV', 'Species', '10566', (4, 7))	('HPV', 'Species', '10566', (100, 103))	('TP53', 'Gene', '7157', (56, 60))	('CDKN2A', 'Gene', (64, 70))	('CDKN2A', 'Gene', '1029', (64, 70))	('TP53', 'Gene', (56, 60))	('variants', 'Var', (37, 45))	('FAT1', 'Gene', '2195', (87, 91))	('FAT1', 'Gene', (87, 91))
917184	30911684	We also found samples with HPV integrations in other immune-related genes (NR4A2, TBC1D1, BTNL9, DTX1, FOXP1, INPP4B, PDE4D, and STAT4) have an increased expression of these genes.	('PDE4D', 'Gene', (118, 123))	('HPV', 'Species', '10566', (27, 30))	('BTNL9', 'Gene', (90, 95))	('FOXP1', 'Gene', '27086', (103, 108))	('DTX1', 'Gene', (97, 101))	('NR4A2', 'Gene', '4929', (75, 80))	('STAT4', 'Gene', (129, 134))	('integrations', 'Var', (31, 43))	('PDE4D', 'Gene', '5144', (118, 123))	('INPP4B', 'Gene', (110, 116))	('BTNL9', 'Gene', '153579', (90, 95))	('TBC1D1', 'Gene', (82, 88))	('NR4A2', 'Gene', (75, 80))	('FOXP1', 'Gene', (103, 108))	('increased', 'PosReg', (144, 153))	('expression', 'MPA', (154, 164))
917185	30911684	Previous studies show that high expression of NR4A2, BTNL9, FOXP1, or PDE4D can antagonize immune response or is associated with tumor progression.	('FOXP1', 'Gene', '27086', (60, 65))	('immune response', 'CPA', (91, 106))	('associated with', 'Reg', (113, 128))	('antagonize', 'NegReg', (80, 90))	('BTNL9', 'Gene', (53, 58))	('FOXP1', 'Gene', (60, 65))	('PDE4D', 'Gene', '5144', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('NR4A2', 'Gene', (46, 51))	('PDE4D', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('high expression', 'Var', (27, 42))	('tumor', 'Disease', (129, 134))	('BTNL9', 'Gene', '153579', (53, 58))	('NR4A2', 'Gene', '4929', (46, 51))
917200	30911684	One explanation is that HBV promotes cancer in a different way than EBV/HPV, which are directly oncogenic, HBV promotes cancer by making the liver cirrhotic/inflamed chronically.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('liver cirrhotic', 'Disease', 'MESH:D008103', (141, 156))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('liver cirrhotic', 'Disease', (141, 156))	('HBV', 'Var', (107, 110))	('EBV', 'Species', '10376', (68, 71))	('HBV', 'Species', '10407', (24, 27))	('HPV', 'Species', '10566', (72, 75))	('promotes', 'PosReg', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('HBV', 'Species', '10407', (107, 110))
917214	30911684	In addition, though the current work does not identify clear mechanisms by which virus infection affects PD-L1 and PD-L2 expression, it nonetheless suggests that viruses may aid tumors in evading the PD-1 immune checkpoint pathway across multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('PD-1 immune checkpoint pathway', 'Pathway', (200, 230))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('virus infection', 'Disease', (81, 96))	('aid', 'PosReg', (174, 177))	('cancer', 'Disease', (247, 253))	('viruses', 'Var', (162, 169))	('evading', 'CPA', (188, 195))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('virus infection', 'Disease', 'MESH:D015658', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
917443	24367208	As can be seen from Table 8, an LS of >20 kPa drastically increases the risk for HCC.	('LS', 'Chemical', '-', (32, 34))	('HCC', 'Gene', '619501', (81, 84))	('LS of >20 kPa', 'Var', (32, 45))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('HCC', 'Gene', (81, 84))
917459	24367208	We propose this more open and critical procedure since misinterpretations or biases can rapidly harm the patient and delay other important diagnostic or therapeutic measures.	('patient', 'Species', '9606', (105, 112))	('harm', 'NegReg', (96, 100))	('misinterpretations', 'Var', (55, 73))	('delay', 'NegReg', (117, 122))	('biases', 'Var', (77, 83))
917488	24367208	Thus, mechanical stop of bile flow or hepatic vein blood flow dramatically increase LS, and both conditions are known to cause cirrhosis.	('LS', 'Chemical', '-', (84, 86))	('cirrhosis', 'Phenotype', 'HP:0001394', (127, 136))	('stop of bile', 'Phenotype', 'HP:0001396', (17, 29))	('cause', 'Reg', (121, 126))	('cirrhosis', 'Disease', 'MESH:D005355', (127, 136))	('increase', 'PosReg', (75, 83))	('mechanical stop', 'Var', (6, 21))	('cirrhosis', 'Disease', (127, 136))
917595	22914345	The infection can cause non-cardia gastric cancer, yet is associated with a decreased risk of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (94, 119))	('esophageal adenocarcinoma', 'Disease', (94, 119))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (24, 49))	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (94, 119))	('cause', 'Reg', (18, 23))	('non-cardia gastric cancer', 'Disease', (24, 49))	('infection', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
917598	22914345	In a nested case control study from Norway, H. pylori seropositivity was inversely associated with cardia cancer (OR 0.27).	('H. pylori', 'Species', '210', (44, 53))	('seropositivity', 'Var', (54, 68))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (47, 68))	('cardia cancer', 'Disease', 'MESH:D004938', (99, 112))	('inversely', 'NegReg', (73, 82))	('H. pylori', 'Gene', (44, 53))	('cardia cancer', 'Disease', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
917601	22914345	In stratified analyses the positive association with reflux was only observed in patients without atrophic gastritis, which suggests that H. pylori may mediate or even inhibit the effects of reflux in the cardia.	('H. pylori', 'Var', (138, 147))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (98, 116))	('patients', 'Species', '9606', (81, 89))	('cardia', 'Disease', 'MESH:D004938', (205, 211))	('cardia', 'Disease', (205, 211))	('H. pylori', 'Species', '210', (138, 147))	('inhibit', 'NegReg', (168, 175))	('effects of reflux', 'MPA', (180, 197))	('gastritis', 'Phenotype', 'HP:0005263', (107, 116))	('atrophic gastritis', 'Disease', 'MESH:D005757', (98, 116))	('atrophic gastritis', 'Disease', (98, 116))
917602	22914345	In a recent meta-analysis, H. pylori was associated with an increased risk of cardia cancer in studies from countries at "high risk" for gastric cancer, but an inverse association existed in countries at "low risk" for gastric cancer (i.e., Western countries).	('H. pylori', 'Var', (27, 36))	('cardia cancer', 'Disease', 'MESH:D004938', (78, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (219, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastric cancer', 'Disease', (137, 151))	('H. pylori', 'Species', '210', (27, 36))	('cardia cancer', 'Disease', (78, 91))	('gastric cancer', 'Disease', (219, 233))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (219, 233))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
917634	22869451	Although not yet well defined, the risk associated with non-alcoholic steatohepatitis (NASH)-related cirrhosis was 2.6% per year in one study, suggesting that persons with NASH-related cirrhosis may have HCC risks as high as those for persons with viral hepatitis-related cirrhosis.	('viral hepatitis', 'Disease', (248, 263))	('cirrhosis', 'Disease', (272, 281))	('persons', 'Species', '9606', (159, 166))	('viral hepatitis', 'Phenotype', 'HP:0006562', (248, 263))	('cirrhosis', 'Disease', 'MESH:D005355', (101, 110))	('hepatitis', 'Phenotype', 'HP:0012115', (254, 263))	('NASH-related', 'Var', (172, 184))	('cirrhosis', 'Phenotype', 'HP:0001394', (101, 110))	('non-alcoholic steatohepatitis', 'Disease', (56, 85))	('HCC', 'Gene', '619501', (204, 207))	('cirrhosis', 'Disease', (101, 110))	('viral hepatitis', 'Disease', 'MESH:D006525', (248, 263))	('cirrhosis', 'Disease', 'MESH:D005355', (272, 281))	('cirrhosis', 'Disease', 'MESH:D005355', (185, 194))	('HCC', 'Gene', (204, 207))	('persons', 'Species', '9606', (235, 242))	('cirrhosis', 'Phenotype', 'HP:0001394', (185, 194))	('hepatitis', 'Phenotype', 'HP:0012115', (76, 85))	('cirrhosis', 'Phenotype', 'HP:0001394', (272, 281))	('non-alcoholic steatohepatitis', 'Disease', 'MESH:D005234', (56, 85))	('cirrhosis', 'Disease', (185, 194))
917655	22869451	study, 38 of the 50 propranolol-treated patients and 34 of the 43 non-propranolol-treated patients had ligation of esophageal veins (banding).	('patients', 'Species', '9606', (40, 48))	('esophageal veins', 'Disease', 'MESH:D004941', (115, 131))	('propranolol', 'Chemical', 'MESH:D011433', (70, 81))	('patients', 'Species', '9606', (90, 98))	('esophageal veins', 'Disease', (115, 131))	('ligation', 'Var', (103, 111))	('propranolol', 'Chemical', 'MESH:D011433', (20, 31))
917671	32869542	Genetic variants in GHR and PLCE1 genes are associated with susceptibility to esophageal cancer Esophageal cancer (EC) is the leading cause of cancer-related mortality worldwide.	('associated', 'Reg', (44, 54))	('GHR', 'Gene', (20, 23))	('GHR', 'Gene', '2690', (20, 23))	('susceptibility', 'Reg', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mortality', 'Disease', 'MESH:D003643', (158, 167))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('mortality', 'Disease', (158, 167))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('PLCE1', 'Gene', (28, 33))	('Genetic variants', 'Var', (0, 16))	('PLCE1', 'Gene', '51196', (28, 33))
917672	32869542	The association between gene growth hormone receptor (GHR) and phospholipase C epsilon 1 (PLCE1) polymorphisms and the EC risk were identified in this study.	('PLCE1', 'Gene', (90, 95))	('PLCE1', 'Gene', '51196', (90, 95))	('growth hormone receptor', 'Gene', (29, 52))	('GHR', 'Gene', '2690', (54, 57))	('growth hormone receptor', 'Gene', '2690', (29, 52))	('GHR', 'Gene', (54, 57))	('polymorphisms', 'Var', (97, 110))	('phospholipase C epsilon 1', 'Gene', '51196', (63, 88))	('phospholipase C epsilon 1', 'Gene', (63, 88))
917673	32869542	Two SNPs (rs6898743 of GHR and rs2274223 of PLCE1) were selected and genotyped.	('rs2274223', 'Var', (31, 40))	('rs6898743', 'Var', (10, 19))	('PLCE1', 'Gene', (44, 49))	('PLCE1', 'Gene', '51196', (44, 49))	('rs2274223', 'DBSNP_MENTION', 'None', (31, 40))	('rs6898743', 'DBSNP_MENTION', 'None', (10, 19))	('GHR', 'Gene', '2690', (23, 26))	('GHR', 'Gene', (23, 26))
917674	32869542	In the allelic frequencies analysis, the rs6898743 of GHR was associated with decreased susceptibility of EC (OR = 0.83, 95% CI: 0.70-1.00, p = 0.049), while rs2274223 of PLCE1 was associated with increased 0.25-fold EC risk (OR = 1.25, 95% CI: 1.02-1.53, p = 0.037).	('rs2274223', 'DBSNP_MENTION', 'None', (158, 167))	('rs6898743', 'Var', (41, 50))	('GHR', 'Gene', '2690', (54, 57))	('PLCE1', 'Gene', (171, 176))	('PLCE1', 'Gene', '51196', (171, 176))	('GHR', 'Gene', (54, 57))	('rs6898743', 'DBSNP_MENTION', 'None', (41, 50))	('rs2274223', 'Var', (158, 167))	('decreased', 'NegReg', (78, 87))
917675	32869542	The "GC" genotype of rs6898743 was associated with a 0.24-fold decreased risk of EC under co-dominant model (OR = 0.76, 95% CI: 0.58-0.99, p = 0.046), and the "GA" genotype of rs2274223 was associated with increased EC risk under co-dominant model (OR = 1.36, 95% CI: 1.04-1.77, p = 0.023).	('rs2274223', 'Var', (176, 185))	('rs6898743', 'Var', (21, 30))	('decreased', 'NegReg', (63, 72))	('rs6898743', 'DBSNP_MENTION', 'None', (21, 30))	('rs2274223', 'DBSNP_MENTION', 'None', (176, 185))
917676	32869542	Using GTEx database, rs2274223 was found to be significant associated with increased PLCE1 expression (p = 4.1 x 10-7) in esophagus muscularis.	('esophagus muscularis', 'Disease', (122, 142))	('expression', 'MPA', (91, 101))	('rs2274223', 'DBSNP_MENTION', 'None', (21, 30))	('PLCE1', 'Gene', (85, 90))	('PLCE1', 'Gene', '51196', (85, 90))	('increased', 'PosReg', (75, 84))	('rs2274223', 'Var', (21, 30))
917678	32869542	The gene GHR and PLCE1 polymorphisms are associated with EC in the general population and the results need to be verified in future.	('polymorphisms', 'Var', (23, 36))	('associated', 'Reg', (41, 51))	('GHR', 'Gene', '2690', (9, 12))	('GHR', 'Gene', (9, 12))	('PLCE1', 'Gene', (17, 22))	('PLCE1', 'Gene', '51196', (17, 22))
917679	32869542	The variant rs6898743 from GHR and rs2274223 of PLCE1 are associated with esophageal cancer risk and rs2274223 may influence PLCE1 gene expression in Chinese population.	('PLCE1', 'Gene', '51196', (48, 53))	('PLCE1', 'Gene', (125, 130))	('expression', 'MPA', (136, 146))	('rs2274223', 'Var', (35, 44))	('GHR', 'Gene', (27, 30))	('associated', 'Reg', (58, 68))	('rs6898743', 'DBSNP_MENTION', 'None', (12, 21))	('rs2274223', 'Var', (101, 110))	('PLCE1', 'Gene', '51196', (125, 130))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('rs2274223', 'DBSNP_MENTION', 'None', (101, 110))	('PLCE1', 'Gene', (48, 53))	('rs6898743', 'Var', (12, 21))	('influence', 'Reg', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('rs2274223', 'DBSNP_MENTION', 'None', (35, 44))	('GHR', 'Gene', '2690', (27, 30))
917685	32869542	Previous studies identified the GC genotype of GHR rs6898743 in 475 ESCC patients and 475 matched controls in Netherlands, and found a negative association between GHR polymorphisms and ESCC risk (Ong et al., 2014).	('GHR', 'Gene', '2690', (164, 167))	('GHR', 'Gene', (47, 50))	('ESCC', 'Disease', (68, 72))	('rs6898743', 'Var', (51, 60))	('rs6898743', 'DBSNP_MENTION', 'None', (51, 60))	('negative', 'NegReg', (135, 143))	('GHR', 'Gene', '2690', (47, 50))	('patients', 'Species', '9606', (73, 81))	('ESCC', 'Disease', (186, 190))	('GHR', 'Gene', (164, 167))
917686	32869542	Because of disproportionately effects of EC in different ethnicities and races (Deng et al., 2017), it is meaningful to identify whether the rs6898743 of GHR gene was associated with EC in Chinese Han.	('rs6898743', 'Var', (141, 150))	('GHR', 'Gene', (154, 157))	('GHR', 'Gene', '2690', (154, 157))	('associated', 'Reg', (167, 177))	('rs6898743', 'DBSNP_MENTION', 'None', (141, 150))
917689	32869542	Related studies on PLCE1 variants were performed in the Asian population, and the results indicated that PLCE1 rs2274223 polymorphism was associated with an increased risk of ESCC (G. Li et al., 2020; Xue, Zhu, Wang, He, & Zheng, 2015).	('rs2274223', 'Var', (111, 120))	('PLCE1', 'Gene', (19, 24))	('PLCE1', 'Gene', '51196', (19, 24))	('PLCE1', 'Gene', (105, 110))	('PLCE1', 'Gene', '51196', (105, 110))	('ESCC', 'Disease', (175, 179))	('rs2274223', 'DBSNP_MENTION', 'None', (111, 120))
917691	32869542	Based on the above findings, we conducted this association analysis between the GHR and PLCE1 gene polymorphisms with the EC risk to further explore the role of these SNPs in northwest China.	('polymorphisms', 'Var', (99, 112))	('PLCE1', 'Gene', (88, 93))	('PLCE1', 'Gene', '51196', (88, 93))	('GHR', 'Gene', (80, 83))	('GHR', 'Gene', '2690', (80, 83))	('association', 'Interaction', (47, 58))
917697	32869542	We selected rs6898743 in GHR (NG_011688.2) and rs2274223 in PLCE1 (NG_015799.1) from the 1000 Genomes Project data (http://www.internationalgenome.org/) to analysis with minor allele frequency (MAF) >5%.	('GHR', 'Gene', '2690', (25, 28))	('rs2274223', 'DBSNP_MENTION', 'None', (47, 56))	('rs6898743', 'DBSNP_MENTION', 'None', (12, 21))	('rs2274223', 'Var', (47, 56))	('PLCE1', 'Gene', (60, 65))	('PLCE1', 'Gene', '51196', (60, 65))	('rs6898743', 'Var', (12, 21))	('GHR', 'Gene', (25, 28))
917700	32869542	The online database (http://www.gtexportal.org/) was used to investigate the association between selected SNPs (rs2274223, rs6898743) and gene expression (GHR and PLCE1).	('rs6898743', 'Var', (123, 132))	('PLCE1', 'Gene', (163, 168))	('GHR', 'Gene', '2690', (155, 158))	('PLCE1', 'Gene', '51196', (163, 168))	('rs2274223', 'DBSNP_MENTION', 'None', (112, 121))	('GHR', 'Gene', (155, 158))	('rs6898743', 'DBSNP_MENTION', 'None', (123, 132))	('rs2274223', 'Var', (112, 121))
917703	32869542	The rs6898743 of GHR was correlated with EC risk reduction through the Pearson chi-squared test (OR = 0.83, 95% CI: 0.70-1.00, p = 0.049), while the rs2274223 of PLCE1 was associated with EC risk increased 0.25-fold (OR = 1.25, 95% CI: 1.02-1.53, p = 0.037).	('GHR', 'Gene', (17, 20))	('GHR', 'Gene', '2690', (17, 20))	('rs6898743', 'Var', (4, 13))	('reduction', 'NegReg', (49, 58))	('PLCE1', 'Gene', '51196', (162, 167))	('rs2274223', 'Var', (149, 158))	('rs6898743', 'DBSNP_MENTION', 'None', (4, 13))	('PLCE1', 'Gene', (162, 167))	('rs2274223', 'DBSNP_MENTION', 'None', (149, 158))
917704	32869542	Predicted by RegulomeDB database, there was no data about SNP rs6898743 function annotation, but rs2274223 is evaluated as 3a and is classified as "transcription factor binding + any motif + DNase peak."	('rs6898743', 'Var', (62, 71))	('rs2274223', 'DBSNP_MENTION', 'None', (97, 106))	('rs2274223', 'Var', (97, 106))	('rs6898743', 'DBSNP_MENTION', 'None', (62, 71))
917705	32869542	As shown in Table 3, we found that the "GC" genotype of rs6898743 was associated with a reduced EC risk under co-dominant (OR = 0.76, 95% CI: 0.58-0.99, p = 0.046), dominant (OR = 0.75, 95% CI: 0.59-0.97, p = 0.029), and log-additive models (OR = 0.83, 95% CI: 0.70-1.00, p = 0.045).	('rs6898743', 'Var', (56, 65))	('reduced', 'NegReg', (88, 95))	('rs6898743', 'DBSNP_MENTION', 'None', (56, 65))
917708	32869542	Under the gender stratified analysis, there was the associations between rs2274223 and the increased risk of EC among males under dominant (OR = 1.39, 95% CI: 1.04-1.86, p = 0.028) model and log-additive model (OR = 1.33, 95% CI: 1.05-1.69, p = 0.017).	('rs2274223', 'Var', (73, 82))	('associations', 'Interaction', (52, 64))	('rs2274223', 'DBSNP_MENTION', 'None', (73, 82))
917709	32869542	In the age stratified analysis, there was the associations between rs6898743 and the decreased risk of EC among patients greater than or equal to 64 years old under co-dominant (OR = 0.65, 95% CI: 0.44-0.96, p = 0.028) and dominant models (OR = 0.66, 95% CI: 0.46-0.95, p = 0.025).	('rs6898743', 'DBSNP_MENTION', 'None', (67, 76))	('decreased', 'NegReg', (85, 94))	('rs6898743', 'Var', (67, 76))	('patients', 'Species', '9606', (112, 120))
917710	32869542	For rs6898743, GC+GG genotype carriers were less likely to have regional lymph node metastasis (OR = 0.65, 95% CI: 0.42-1.00, p = 0.048) than CC genotype carriers under dominant model.	('rs6898743', 'DBSNP_MENTION', 'None', (4, 13))	('less', 'NegReg', (44, 48))	('rs6898743', 'Var', (4, 13))	('regional lymph node metastasis', 'CPA', (64, 94))
917712	32869542	The results also showed no association between rs6898743 and rs2274223 and the risk of EC in the tumor stage stratified analysis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('rs2274223', 'DBSNP_MENTION', 'None', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('rs6898743', 'DBSNP_MENTION', 'None', (47, 56))	('tumor', 'Disease', (97, 102))	('rs2274223', 'Var', (61, 70))	('rs6898743', 'Var', (47, 56))
917713	32869542	Using the GTEx database, the SNP rs2274223 was found to be associated with the cis-gene expression.	('cis-gene expression', 'MPA', (79, 98))	('rs2274223', 'Var', (33, 42))	('rs2274223', 'DBSNP_MENTION', 'None', (33, 42))	('associated', 'Reg', (59, 69))
917715	32869542	We compared the expression of PLCE1 among individuals with different genotypes and found that the risk allele of rs2274223 (Figure 1) was associated with increased PLCE1 expression (p = 4.1 x 10-7) in esophagus muscularis tissues.	('rs2274223', 'DBSNP_MENTION', 'None', (113, 122))	('PLCE1', 'Gene', (30, 35))	('PLCE1', 'Gene', '51196', (164, 169))	('PLCE1', 'Gene', (164, 169))	('rs2274223', 'Var', (113, 122))	('PLCE1', 'Gene', '51196', (30, 35))	('increased', 'PosReg', (154, 163))	('expression', 'MPA', (170, 180))
917718	32869542	We found that genetic variant rs6898743 in GHR was significantly associated with a decreased risk of EC, while rs2274223 in PLCE1 was associated with an increasing EC risk.	('rs6898743', 'Var', (30, 39))	('rs2274223', 'Var', (111, 120))	('PLCE1', 'Gene', (124, 129))	('PLCE1', 'Gene', '51196', (124, 129))	('decreased', 'NegReg', (83, 92))	('rs6898743', 'DBSNP_MENTION', 'None', (30, 39))	('GHR', 'Gene', '2690', (43, 46))	('rs2274223', 'DBSNP_MENTION', 'None', (111, 120))	('GHR', 'Gene', (43, 46))
917719	32869542	Based on the GTEx portal, we found that the risk allele of rs2274223 was associated with increased expression of PLCE1 in esophagus muscularis samples.	('expression', 'MPA', (99, 109))	('rs2274223', 'DBSNP_MENTION', 'None', (59, 68))	('PLCE1', 'Gene', (113, 118))	('PLCE1', 'Gene', '51196', (113, 118))	('increased', 'PosReg', (89, 98))	('rs2274223', 'Var', (59, 68))
917721	32869542	As a transmembrane receptor for growth hormone, the GHR gene has been studied on obesity in Korean (Yang, 2016), and rs6898743 showed a significant association with obesity.	('growth hormone', 'Gene', (32, 46))	('obesity', 'Phenotype', 'HP:0001513', (165, 172))	('rs6898743', 'Var', (117, 126))	('growth hormone', 'Gene', '2688', (32, 46))	('obesity', 'Disease', 'MESH:D009765', (81, 88))	('GHR', 'Gene', (52, 55))	('GHR', 'Gene', '2690', (52, 55))	('obesity', 'Disease', (81, 88))	('association', 'Interaction', (148, 159))	('obesity', 'Disease', 'MESH:D009765', (165, 172))	('rs6898743', 'DBSNP_MENTION', 'None', (117, 126))	('obesity', 'Disease', (165, 172))	('obesity', 'Phenotype', 'HP:0001513', (81, 88))
917723	32869542	(2010) analyzed 102 SNPs in the Insulin-like growth factor (IGF) axis and characterized the genetic variant rs6898743 of GHR gene, which appeared to be associated with EAC, in an Irish population-based case control study.	('EAC', 'Phenotype', 'HP:0011459', (168, 171))	('GHR', 'Gene', '2690', (121, 124))	('rs6898743', 'Var', (108, 117))	('GHR', 'Gene', (121, 124))	('EAC', 'Disease', (168, 171))	('associated', 'Reg', (152, 162))	('rs6898743', 'DBSNP_MENTION', 'None', (108, 117))
917724	32869542	(2014) found the GC genotype of rs6898743 of GHR gene was negatively associated with ESCC in a Dutch case-control study.	('GHR', 'Gene', '2690', (45, 48))	('GHR', 'Gene', (45, 48))	('rs6898743', 'DBSNP_MENTION', 'None', (32, 41))	('associated', 'Reg', (69, 79))	('ESCC', 'Disease', (85, 89))	('rs6898743', 'Var', (32, 41))	('negatively', 'NegReg', (58, 68))
917725	32869542	In this research, we investigated the association between the genetic variant rs6898743 of GHR gene and the EC risk in a Chinese case control population, and we concluded a positive result in accordance with McElholm et al.	('association', 'Interaction', (38, 49))	('rs6898743', 'DBSNP_MENTION', 'None', (78, 87))	('GHR', 'Gene', '2690', (91, 94))	('rs6898743', 'Var', (78, 87))	('GHR', 'Gene', (91, 94))
917727	32869542	found rs2274223 of PLCE1 was related with gastric cancer (p = 8.40 x 10-9) and ESCC (p = 3.85 x 10-9) (Abnet et al., 2010).	('gastric cancer', 'Phenotype', 'HP:0012126', (42, 56))	('related', 'Reg', (29, 36))	('PLCE1', 'Gene', (19, 24))	('PLCE1', 'Gene', '51196', (19, 24))	('rs2274223', 'DBSNP_MENTION', 'None', (6, 15))	('ESCC', 'Disease', (79, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (42, 56))	('gastric cancer', 'Disease', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('rs2274223', 'Var', (6, 15))
917729	32869542	Besides, in the stratification analysis on age and gender, we also found that rs2274223 acted as a risk factor of EC in males under dominant and additive models with p-values of 0.028 and 0.017, respectively.	('risk', 'Reg', (99, 103))	('rs2274223', 'DBSNP_MENTION', 'None', (78, 87))	('rs2274223', 'Var', (78, 87))
917730	32869542	However, the limited number of the selected SNPs in genes GHE and PLCE1 is one of the restrictions in this study.	('PLCE1', 'Gene', (66, 71))	('SNPs', 'Var', (44, 48))	('GHE', 'Gene', (58, 61))	('PLCE1', 'Gene', '51196', (66, 71))
917732	32869542	The variants rs6898743 of GHR and rs2274223 of PLCE1 are associated with the EC risk and rs2274223 may influence the PLCE1 gene expression in Chinese population.	('rs6898743', 'Var', (13, 22))	('rs2274223', 'DBSNP_MENTION', 'None', (89, 98))	('PLCE1', 'Gene', (47, 52))	('rs2274223', 'DBSNP_MENTION', 'None', (34, 43))	('PLCE1', 'Gene', '51196', (117, 122))	('PLCE1', 'Gene', '51196', (47, 52))	('GHR', 'Gene', '2690', (26, 29))	('GHR', 'Gene', (26, 29))	('influence', 'Reg', (103, 112))	('expression', 'MPA', (128, 138))	('rs6898743', 'DBSNP_MENTION', 'None', (13, 22))	('rs2274223', 'Var', (89, 98))	('rs2274223', 'Var', (34, 43))	('PLCE1', 'Gene', (117, 122))	('associated', 'Reg', (57, 67))
917741	32589328	However, we found no association between the expression of miR-766-3p in tissue and ESCC prognosis.	('miR-766-3p', 'Chemical', '-', (59, 69))	('miR-766-3p', 'Var', (59, 69))	('ESCC', 'Disease', (84, 88))
917742	32589328	In vitro results showed that miR-766-3p promotes cell migration and invasion, but not cell proliferation.	('miR-766-3p', 'Chemical', '-', (29, 39))	('cell migration', 'CPA', (49, 63))	('invasion', 'CPA', (68, 76))	('miR-766-3p', 'Var', (29, 39))	('promotes', 'PosReg', (40, 48))
917743	32589328	By using dual-luciferase reporter assay, HOXA13 was confirmed as a direct target gene of miR-766-3p.	('HOXA13', 'Gene', '3209', (41, 47))	('miR-766-3p', 'Chemical', '-', (89, 99))	('HOXA13', 'Gene', (41, 47))	('miR-766-3p', 'Var', (89, 99))
917747	32589328	Therefore, miR-766 levels in serum exosomes could serve as a prognostic marker to be used in assessing esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (103, 137))	('miR-766', 'Var', (11, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal squamous cell carcinoma', 'Disease', (103, 137))
917755	32589328	A recent study showed that tissue miR-766 was associated with prognosis in hepatocellular carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('patients', 'Species', '9606', (100, 108))	('tissue miR-766', 'Var', (27, 41))	('hepatocellular carcinoma', 'Disease', (75, 99))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (75, 99))	('associated', 'Reg', (46, 56))
917756	32589328	Functional studies have indicated that miR-766 can promote cell proliferation by directly targeting SOX6 expression in colorectal cancer 17 or by directly targeting NR3C2 expression in hepatocellular carcinoma.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('hepatocellular carcinoma', 'Disease', (185, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('cell proliferation', 'CPA', (59, 77))	('targeting', 'Reg', (155, 164))	('expression', 'MPA', (105, 115))	('SOX6', 'Gene', '55553', (100, 104))	('NR3C2', 'Gene', '4306', (165, 170))	('targeting', 'Reg', (90, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (185, 209))	('colorectal cancer', 'Disease', (119, 136))	('miR-766', 'Var', (39, 46))	('expression', 'MPA', (171, 181))	('SOX6', 'Gene', (100, 104))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (185, 209))	('NR3C2', 'Gene', (165, 170))	('promote', 'PosReg', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
917759	32589328	We further evaluated the expression of the miR-766-3p in serum exosome and tissue from ESCC patients by using qRT-PCR, and cell experiments were carried out to explore the function of miR-766-3p in ESCC.	('ESCC', 'Disease', (198, 202))	('miR-766-3p', 'Chemical', '-', (43, 53))	('miR-766-3p', 'Var', (43, 53))	('patients', 'Species', '9606', (92, 100))	('ESCC', 'Disease', (87, 91))	('miR-766-3p', 'Chemical', '-', (184, 194))
917760	32589328	Moreover, we used bioinformatic analysis and dual-luciferase reporter assay to predict and identify the potential target gene of miR-766-3p in ESCC.	('miR-766-3p', 'Var', (129, 139))	('miR-766-3p', 'Chemical', '-', (129, 139))	('ESCC', 'Disease', (143, 147))
917795	32589328	Four luciferase plasmids (including psicheck2 vector, miRNA mimics NC + HOXA13(WT), miR-766-3p mimics + HOXA13(WT), miR-766-3p mimics + HOXA13(MUT)) were constructed.	('HOXA13', 'Gene', '3209', (136, 142))	('miR-766-3p', 'Chemical', '-', (84, 94))	('HOXA13', 'Gene', (72, 78))	('HOXA13', 'Gene', (104, 110))	('miR-766-3p', 'Chemical', '-', (116, 126))	('HOXA13', 'Gene', '3209', (104, 110))	('HOXA13', 'Gene', '3209', (72, 78))	('miR-766-3p', 'Var', (116, 126))	('HOXA13', 'Gene', (136, 142))
917797	32589328	Then, to analyze the association between miR-766-3p and HOXA13 gene expression, the vectors with miR-766-3p or miRNA mimics NC were transfected into TE-1, total RNA was extracted using the TRIzol Reagent and Protein Isolation Kit (Life Technologies).	('age', 'Gene', (198, 201))	('miR-766-3p', 'Chemical', '-', (97, 107))	('Kit', 'Gene', '3815', (226, 229))	('TRIzol', 'Chemical', 'MESH:C411644', (189, 195))	('HOXA13', 'Gene', (56, 62))	('HOXA13', 'Gene', '3209', (56, 62))	('miR-766-3p', 'Var', (97, 107))	('age', 'Gene', '5973', (198, 201))	('miR-766-3p', 'Chemical', '-', (41, 51))	('TE-1', 'CellLine', 'CVCL:1759', (149, 153))	('Kit', 'Gene', (226, 229))
917834	32589328	A log-rank test showed that there was no significant difference (for OS, P = .700, Figure S5) in survival between patients with higher and lower expression levels of miR-766-3p.	('miR-766-3p', 'Chemical', '-', (166, 176))	('miR-766-3p', 'Var', (166, 176))	('expression levels', 'MPA', (145, 162))	('lower', 'NegReg', (139, 144))	('patients', 'Species', '9606', (114, 122))
917835	32589328	The results showed that the migration and invasion of TE-1 cells were significantly increased in cells treated with miR-766-3p mimic (Figure 3A).	('miR-766-3p mimic', 'Var', (116, 132))	('miR-766-3p', 'Chemical', '-', (116, 126))	('increased', 'PosReg', (84, 93))	('invasion of TE-1 cells', 'CPA', (42, 64))	('TE-1', 'CellLine', 'CVCL:1759', (54, 58))
917837	32589328	However, Transwell invasion assays indicated that the miR-766-3p mimic-treated group had higher numbers of KYSE150 cells penetrating the matrix than the NC group (P < .05).	('KYSE150 cells penetrating the matrix', 'CPA', (107, 143))	('KYSE150', 'CellLine', 'CVCL:1348', (107, 114))	('miR-766-3p', 'Chemical', '-', (54, 64))	('higher', 'PosReg', (89, 95))	('miR-766-3p', 'Var', (54, 64))
917838	32589328	These results suggested that miR-766-3p promoted ESCC cell progression.	('miR-766-3p', 'Chemical', '-', (29, 39))	('miR-766-3p', 'Var', (29, 39))	('ESCC', 'Disease', (49, 53))	('promoted', 'PosReg', (40, 48))
917839	32589328	There was no significant difference in OD value among the groups treated with NC, miR-766-3p inhibitor, or miR-766-3p mimic (P > .05) in either TE-1 cells or KYSE150 cells (Figure 4).	('miR-766-3p', 'Var', (107, 117))	('TE-1', 'CellLine', 'CVCL:1759', (144, 148))	('miR-766-3p', 'Chemical', '-', (82, 92))	('OD value', 'MPA', (39, 47))	('miR-766-3p', 'Chemical', '-', (107, 117))	('KYSE150', 'CellLine', 'CVCL:1348', (158, 165))
917840	32589328	These data suggest that the overexpression of miR-766-3p could not promote ESCC cell proliferation.	('miR-766-3p', 'Chemical', '-', (46, 56))	('ESCC', 'Disease', (75, 79))	('miR-766-3p', 'Var', (46, 56))
917843	32589328	18  To clarify the HOXA13 target genes of miR-766-3p, we determined a binding relationship between miR-766-3p and HOXA13 using biological prediction tool TargetScan (Figure 6A).	('binding', 'Interaction', (70, 77))	('miR-766-3p', 'Chemical', '-', (99, 109))	('miR-766-3p', 'Chemical', '-', (42, 52))	('HOXA13', 'Gene', (114, 120))	('HOXA13', 'Gene', '3209', (114, 120))	('HOXA13', 'Gene', (19, 25))	('miR-766-3p', 'Var', (99, 109))	('HOXA13', 'Gene', '3209', (19, 25))
917844	32589328	To validate the binding ability between miR-766-3p and HOXA13, we carried out the dual-luciferase reporter assay.	('HOXA13', 'Gene', (55, 61))	('miR-766-3p', 'Chemical', '-', (40, 50))	('HOXA13', 'Gene', '3209', (55, 61))	('miR-766-3p', 'Var', (40, 50))	('binding', 'Interaction', (16, 23))
917846	32589328	Findings concluded by qRT-PCR suggested that HOXA13 was downregulated in miR-766-3p mimic-transfected TE-1 cells (Figure 6C).	('miR-766-3p', 'Chemical', '-', (73, 83))	('TE-1', 'CellLine', 'CVCL:1759', (102, 106))	('HOXA13', 'Gene', (45, 51))	('miR-766-3p', 'Var', (73, 83))	('HOXA13', 'Gene', '3209', (45, 51))	('downregulated', 'NegReg', (56, 69))
917847	32589328	Together, it could be elucidated that miR-766-3p could specifically bind with HOXA13.	('HOXA13', 'Gene', (78, 84))	('HOXA13', 'Gene', '3209', (78, 84))	('bind', 'Interaction', (68, 72))	('miR-766-3p', 'Chemical', '-', (38, 48))	('miR-766-3p', 'Var', (38, 48))
917850	32589328	In addition, our data show that miR-766-3p promotes cell migration and invasion but not cell proliferation.	('promotes', 'PosReg', (43, 51))	('cell migration', 'CPA', (52, 66))	('miR-766-3p', 'Chemical', '-', (32, 42))	('invasion', 'CPA', (71, 79))	('miR-766-3p', 'Var', (32, 42))
917855	32589328	16  We assumed that serum exosomal miR-766-3p promoted lymph node metastasis of ESCC through the communication between cells of exosomes, leading to a poor prognosis for ESCC.	('lymph node metastasis', 'CPA', (55, 76))	('promoted', 'PosReg', (46, 54))	('miR-766-3p', 'Var', (35, 45))	('communication', 'MPA', (97, 110))	('miR-766-3p', 'Chemical', '-', (35, 45))	('ESCC', 'Disease', (80, 84))	('ESCC', 'Disease', (170, 174))
917856	32589328	In addition, we found that miR-766-3p levels in exosomes from serum was upregulated in ESCC through a significant association with OS and DFS.	('miR-766-3p', 'Var', (27, 37))	('ESCC', 'Disease', (87, 91))	('upregulated', 'PosReg', (72, 83))	('miR-766-3p', 'Chemical', '-', (27, 37))	('DFS', 'Disease', (138, 141))
917857	32589328	Similarly, Chao et al 16  confirmed that high expression of miR-766 in tissue was positively correlated with poor OS and DFS in hepatocellular cancer (P < .05), based on TCGA.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('DFS in hepatocellular cancer', 'Disease', 'MESH:D006528', (121, 149))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (128, 149))	('DFS in hepatocellular cancer', 'Disease', (121, 149))	('poor OS', 'Disease', (109, 116))	('miR-766', 'Var', (60, 67))
917863	32589328	However, our finding revealed that the expression of miR-776-3p in tissue was no associated with prognosis in ESCC patients, and TCGA data analysis also indicated that there was no significant difference in survival between patients with higher and lower expression of miR-766-3p in tissue.	('3p', 'Chemical', '-', (277, 279))	('miR-776-3p', 'Var', (53, 63))	('patients', 'Species', '9606', (115, 123))	('miR-766-3p', 'Var', (269, 279))	('ESCC', 'Disease', (110, 114))	('patients', 'Species', '9606', (224, 232))	('3p', 'Chemical', '-', (61, 63))	('lower', 'NegReg', (249, 254))	('miR-766-3p', 'Chemical', '-', (269, 279))
917865	32589328	We undertook a series of in vitro analyses to understand the functional role of miR-766-3p in tumor progression in ESCC.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('ESCC', 'Disease', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('miR-766-3p', 'Var', (80, 90))	('tumor', 'Disease', (94, 99))	('miR-766-3p', 'Chemical', '-', (80, 90))
917868	32589328	32  In the present study, using dual-luciferase reporter assay, we confirmed that miR-766-3p regulates HOXA13 expression in TE-1 cells.	('HOXA13', 'Gene', (103, 109))	('miR-766-3p', 'Chemical', '-', (82, 92))	('HOXA13', 'Gene', '3209', (103, 109))	('TE-1', 'CellLine', 'CVCL:1759', (124, 128))	('expression', 'MPA', (110, 120))	('regulates', 'Reg', (93, 102))	('miR-766-3p', 'Var', (82, 92))
917946	31037328	Results of one study are particularly interesting: that swallowing function appeared to be preserved to a similar extent between patients in whom cervical lymph node dissection was not performed and patients in whom the infrahyoid muscles were transected bilaterally to facilitate laryngeal elevation after cervical lymph node dissection.	('swallowing function', 'CPA', (56, 75))	('cervical lymph node dissection', 'Phenotype', 'HP:0025289', (307, 337))	('laryngeal elevation', 'CPA', (281, 300))	('patients', 'Species', '9606', (129, 137))	('cervical lymph node dissection', 'Phenotype', 'HP:0025289', (146, 176))	('patients', 'Species', '9606', (199, 207))	('facilitate', 'PosReg', (270, 280))	('transected', 'Var', (244, 254))
917957	31037328	In conclusion, postoperative swallowing difficulty after surgery for thoracic esophageal cancer is affected very little by the presence of RLNP but greatly by inclusion of cervical lymph node dissection in the operative procedure.	('RLNP', 'Gene', (139, 143))	('thoracic esophageal cancer', 'Disease', (69, 95))	('swallowing difficulty', 'Phenotype', 'HP:0002015', (29, 50))	('cervical lymph node dissection', 'Phenotype', 'HP:0025289', (172, 202))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (69, 95))	('presence', 'Var', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
917981	31423256	Preoperative radiation (50.4 Gy/28 Fr) with the DCF regimen consisting of docetaxel 30 mg/m2 (days 1 and 8), cisplatin 10 mg/m2 (days 1-5), and 5-FU 400 mg/m2/day (days 1-5) was performed for patients with cT4aN1 esophageal cancer pathologically diagnosed as SCC by endoscopic biopsy, based on the indications at our institution as previously reported.	('SCC', 'Gene', '6317', (259, 262))	('esophageal cancer', 'Disease', 'MESH:D004938', (213, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('5-FU', 'Chemical', 'MESH:D005472', (144, 148))	('DCF', 'Chemical', 'MESH:D015649', (48, 51))	('patients', 'Species', '9606', (192, 200))	('cT4aN1', 'Var', (206, 212))	('docetaxel', 'Chemical', 'MESH:D000077143', (74, 83))	('SCC', 'Gene', (259, 262))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('esophageal cancer', 'Disease', (213, 230))
917982	31423256	Surgery for PMME was carried out according to our standard surgical treatment for thoracic esophageal cancer and consisted of a subtotal esophagectomy with two or three field lymphadenectomies, reconstruction of the gastric tube via the retrosternal or posterior mediastinal route, and anastomosis in the cervical area from the cervical incision, as previously described.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('PMME', 'Chemical', '-', (12, 16))	('thoracic esophageal cancer', 'Disease', (82, 108))	('anastomosis', 'Var', (286, 297))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (82, 108))
917985	31423256	Antibodies used for immunohistochemical staining included anti-HMB45, anti-Melan A, anti-S100, and anti-cytokeratin (CK) AE1/AE3.	('AE3', 'Gene', '6508', (125, 128))	('anti-Melan', 'Var', (70, 80))	('anti-S100', 'Var', (84, 93))	('AE1', 'Gene', '6521', (121, 124))	('anti-HMB45', 'Var', (58, 68))	('AE3', 'Gene', (125, 128))	('AE1', 'Gene', (121, 124))	('anti-cytokeratin', 'Var', (99, 115))
918002	31423256	The patient diagnosed with cT1bN2 PMME by endoscopic examination without biopsy (patient 1) received preoperative chemotherapy with three cycles of the DAV regimen as previously described, and the clinical response to preoperative treatment was stable disease (SD) according to the RECIST (ver.1.1) criteria.	('stable disease', 'Disease', (245, 259))	('SD', 'Disease', 'MESH:D029461', (261, 263))	('patient', 'Species', '9606', (81, 88))	('cT1bN2 PMME', 'Var', (27, 38))	('DAV', 'Chemical', '-', (152, 155))	('patient', 'Species', '9606', (4, 11))	('PMME', 'Chemical', '-', (34, 38))
918003	31423256	The patient misdiagnosed with cT4aN1 squamous cell carcinoma by pretherapeutic endoscopic biopsy (patient 4) received preoperative chemoradiotherapy with two cycles of the DCF regimen with concurrent irradiation (50.4 Gy/28 Fr), and the clinical response to chemoradiation was stable disease (SD).	('cT4aN1', 'Var', (30, 36))	('stable disease', 'Disease', (277, 291))	('patient', 'Species', '9606', (98, 105))	('SD', 'Disease', 'MESH:D029461', (293, 295))	('DCF', 'Chemical', 'MESH:D015649', (172, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('patient', 'Species', '9606', (4, 11))	('squamous cell carcinoma', 'Disease', (37, 60))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
918034	31423256	In addition, the tumor characteristics of the soft and polypoid mass may mask clinical symptoms in patients with PMME, suggesting that physicians must consider the fact that polypoid masses in the middle and lower third of the esophagus may be special types of cancer, specifically PMME.	('PMME', 'Chemical', '-', (282, 286))	('tumor', 'Disease', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('PMME', 'Chemical', '-', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('patients', 'Species', '9606', (99, 107))	('PMME', 'Disease', (282, 286))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Disease', (261, 267))	('polypoid', 'Var', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
918036	31423256	The majority of the resected specimens are reported to show positivity for immunomarkers including HMB-45, Melan-A, and S-100, while epithelium markers such as CK AE1/AE3 are negative, as seen in the present study.	('positivity', 'Var', (60, 70))	('AE3', 'Gene', (167, 170))	('S-100', 'Gene', (120, 125))	('Melan-A', 'Gene', (107, 114))	('HMB-45', 'Gene', (99, 105))	('S-100', 'Chemical', '-', (120, 125))	('AE1', 'Gene', '6521', (163, 166))	('AE1', 'Gene', (163, 166))	('AE3', 'Gene', '6508', (167, 170))
918043	31423256	Immune-checkpoint inhibitors including anti-PD-1 antibody (nivolumab) and anti-CTLA-4 antibody (ipilimumab) represent a novel treatment strategy for malignant melanoma, were approved by the Food and Drug Administration (FDA) in 2014, and are available for use in PMME treatment in Japan.	('ipilimumab', 'Chemical', 'MESH:D000074324', (96, 106))	('CTLA-4', 'Gene', (79, 85))	('malignant melanoma', 'Phenotype', 'HP:0002861', (149, 167))	('nivolumab', 'Chemical', 'MESH:D000077594', (59, 68))	('PMME', 'Chemical', '-', (263, 267))	('malignant melanoma', 'Disease', 'MESH:D008545', (149, 167))	('malignant melanoma', 'Disease', (149, 167))	('anti-PD-1', 'Var', (39, 48))	('CTLA-4', 'Gene', '1493', (79, 85))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
918063	31213896	Compared with the FLR-low (<=3.03) group, the FLR-high (>3.03) group included older patients (chi2=7.267, P=0.007), showed higher postoperative overall morbidity (24.7% vs 14.8%, chi2=5.414, P=0.020) and tended to die within one year (23.5% vs 10.9%, chi2=10.871, P=0.001).	('FLR-high', 'Var', (46, 54))	('higher', 'PosReg', (123, 129))	('patients', 'Species', '9606', (84, 92))
918093	31213896	The FLR-high group included older patients (chi2=7.267, P=0.007), showed higher postoperative overall morbidity (24.7% vs 14.8%, chi2=5.414, P=0.020) and tended to die within one year (23.5% vs 10.9%, chi2=10.871, P=0.001) when compared with the FLR-low group.	('patients', 'Species', '9606', (34, 42))	('FLR-high', 'Var', (4, 12))	('higher', 'PosReg', (73, 79))
918098	31213896	Notably, compared with the FLR-low group, the FLR-high group independently predicted a worse OS (HR: 1.448, 95%CI: 1.073-1.952, P=0.015) and a worse DFS (HR: 1.445, 95%CI: 1.084-1.925, P=0.012) in patients with ESCC.	('FLR-high', 'Var', (46, 54))	('ESCC', 'Disease', (211, 215))	('patients', 'Species', '9606', (197, 205))	('DFS', 'MPA', (149, 152))
918113	31213896	Steinbrecher et al in their animal experiment revealed that alphaMbeta2-mediated engagement of fibrinogen was mechanistically coupled to local inflammatory processes and epithelial alterations that contributed to adenoma formation, which showed a unique link between fibrinogen and the development of inflammation-driven malignancy.	('inflammation-driven malignancy', 'Disease', 'MESH:D007249', (301, 331))	('adenoma', 'Disease', 'MESH:D000236', (213, 220))	('fibrinogen', 'Gene', '2244', (267, 277))	('fibrinogen', 'Gene', (267, 277))	('fibrinogen', 'Gene', '2244', (95, 105))	('adenoma', 'Disease', (213, 220))	('inflammation-driven malignancy', 'Disease', (301, 331))	('fibrinogen', 'Gene', (95, 105))	('contributed', 'Reg', (198, 209))	('alphaMbeta2-mediated', 'Var', (60, 80))	('coupled', 'Reg', (126, 133))
918120	31213896	Our study demonstrated that preoperative FLR level could act as an independent prognostic marker for ESCC patients, where higher FLR was significantly associated with poor OS, poor DFS and higher incidence of first-year mortality after surgery.	('higher', 'Var', (122, 128))	('associated', 'Reg', (151, 161))	('FLR', 'MPA', (129, 132))	('DFS', 'MPA', (181, 184))	('patients', 'Species', '9606', (106, 114))	('ESCC', 'Disease', (101, 105))	('poor', 'Disease', (167, 171))
918224	29370817	Each PDX was assessed for molecular characteristics including copy number variations, somatic mutations, and signaling pathway abnormalities and these were similar to patient results.	('signaling pathway', 'Pathway', (109, 126))	('patient', 'Species', '9606', (167, 174))	('copy number variations', 'Var', (62, 84))	('abnormalities', 'Var', (127, 140))
918276	29370817	Apart from the 139 genes with nonsynonymous single nucleotide variants (SNVs), 79 genes including insertions and deletions (InDels) in protein-coding regions were identified in the 23 PDXs.	('insertions', 'Var', (98, 108))	('InDel', 'Chemical', '-', (124, 129))	('deletions', 'Var', (113, 122))
918277	29370817	KMT2D was the most frequently mutated gene, involving the 7 frameshift inDel, one nonframeshift inDel and 7 missense mutation followed by EP300, PIK3CA, ALK and ERBB2.	('ALK', 'Gene', (153, 156))	('ERBB2', 'Gene', '2064', (161, 166))	('frameshift inDel', 'Var', (60, 76))	('EP300', 'Gene', (138, 143))	('ERBB2', 'Gene', (161, 166))	('EP300', 'Gene', '2033', (138, 143))	('ALK', 'Gene', '238', (153, 156))	('KMT2D', 'Gene', (0, 5))	('KMT2D', 'Gene', '8085', (0, 5))	('PIK3CA', 'Gene', (145, 151))	('PIK3CA', 'Gene', '5290', (145, 151))
918282	29370817	As was shown in Additional file 2: Figure S1, in agreement with the CNA analysis, the relative mRNA expression of FGF3 (Additional file 2: Figure S1a, p < 0.001), FGF4 (Additional file 2: Figure S1b, p < 0.001) and FGF19 (Additional file 2: Figure S1c, p < 0.05) was enhanced in amplification group (CNA >= 5).	('FGF3', 'Gene', (114, 118))	('mRNA expression', 'MPA', (95, 110))	('amplification', 'Var', (279, 292))	('FGF4', 'Gene', '2249', (163, 167))	('FGF19', 'Gene', '9965', (215, 220))	('FGF3', 'Gene', '2248', (114, 118))	('FGF4', 'Gene', (163, 167))	('FGF19', 'Gene', (215, 220))	('enhanced', 'PosReg', (267, 275))
918283	29370817	Abnormal genes with SNV, InDel or amplifications were analyzed with DAVID Bioinformatics Resources 6.7, and significantly altered pathways (p < 0.05) were enriched and presented (Fig.	('InDel', 'Var', (25, 30))	('amplifications', 'Var', (34, 48))	('pathways', 'Pathway', (130, 138))	('InDel', 'Chemical', '-', (25, 30))	('altered', 'Reg', (122, 129))
918306	29370817	For example, in our previous study, the anti-tumor effect of CDK4/6 inhibitor SHR6390 was demonstrated in ESCC.	('CDK4/6', 'Gene', '1019;1021', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('ESCC', 'Disease', (106, 110))	('CDK4/6', 'Gene', (61, 67))	('SHR6390', 'Var', (78, 85))	('SHR6390', 'Chemical', '-', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
918308	29370817	Apart from it, somatic mutations in the tyrosine-kinase domain of EGFR were identified in 30-50% non-small-cell lung cancers (NSCLCs) patients, among which the TKIs response rate increased to approximately 75%.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancers', 'Disease', 'MESH:D008175', (112, 124))	('NSCLCs', 'Disease', 'MESH:D002289', (126, 132))	('identified', 'Reg', (76, 86))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', '1956', (66, 70))	('patients', 'Species', '9606', (134, 142))	('lung cancers', 'Phenotype', 'HP:0100526', (112, 124))	('NSCLCs', 'Disease', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('increased', 'PosReg', (179, 188))	('lung cancers', 'Disease', (112, 124))	('mutations in the', 'Var', (23, 39))
918309	29370817	But the EGFR mutations appear to be a rare studied field in ESCC.	('mutations', 'Var', (13, 22))	('EGFR', 'Gene', '1956', (8, 12))	('EGFR', 'Gene', (8, 12))
918310	29370817	In our study, the disrupted ERBB pathway including mutation in ERBB2 (35%), which can be used to explore the TKIs therapy in esophageal cancer.	('ERBB', 'Gene', '1956', (63, 67))	('ERBB', 'Gene', '1956', (28, 32))	('disrupted', 'Reg', (18, 27))	('ERBB2', 'Gene', '2064', (63, 68))	('esophageal cancer', 'Disease', (125, 142))	('ERBB2', 'Gene', (63, 68))	('mutation', 'Var', (51, 59))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('ERBB', 'Gene', (63, 67))	('ERBB', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
918311	29370817	Besides, in a cohort of metastatic renal cell carcinoma patients, mutations in TSC2 were more common in patients who experienced clinical benefit from mTOR inhibitors than in those who progressed, indicating that the mutation of TSC2 would be a good prognosis indicator for mTOR inhibitors.	('mutations', 'Var', (66, 75))	('patients', 'Species', '9606', (56, 64))	('TSC2', 'Gene', '7249', (79, 83))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (35, 55))	('common', 'Reg', (94, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (35, 55))	('TSC2', 'Gene', (79, 83))	('TSC2', 'Gene', '7249', (229, 233))	('mTOR', 'Gene', '2475', (274, 278))	('mTOR', 'Gene', (274, 278))	('TSC2', 'Gene', (229, 233))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('patients', 'Species', '9606', (104, 112))	('renal cell carcinoma', 'Disease', (35, 55))
918312	29370817	But there is no related studies in esophageal cancer, so the PDX models with TSC2 mutation will provided a useful tool.	('mutation', 'Var', (82, 90))	('esophageal cancer', 'Disease', (35, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('TSC2', 'Gene', '7249', (77, 81))	('TSC2', 'Gene', (77, 81))
918317	29370817	PDX patient-derived xenografts ESCC esophageal squamous cell carcinoma SNV single nucleotide variant InDel insertion and deletion CNA copy number alteration NGS next generation sequencing	('esophageal squamous cell carcinoma', 'Disease', (36, 70))	('patient', 'Species', '9606', (4, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('single nucleotide variant InDel insertion', 'Var', (75, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (36, 70))	('InDel', 'Chemical', '-', (101, 106))	('deletion', 'Var', (121, 129))
918318	27259248	Study of single nucleotide polymorphisms of FBW7 and its substrate genes revealed a predictive factor for paclitaxel plus cisplatin chemotherapy in Chinese patients with advanced esophageal squamous cell carcinoma Paclitaxel plays a major role in the treatment of advanced esophageal squamous cell carcinoma.	('patients', 'Species', '9606', (156, 164))	('esophageal squamous cell carcinoma', 'Disease', (273, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('FBW7', 'Gene', '55294', (44, 48))	('esophageal squamous cell carcinoma', 'Disease', (179, 213))	('FBW7', 'Gene', (44, 48))	('single nucleotide polymorphisms', 'Var', (9, 40))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (273, 307))	('men', 'Species', '9606', (256, 259))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (284, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('Paclitaxel', 'Chemical', 'MESH:D017239', (214, 224))	('paclitaxel', 'Chemical', 'MESH:D017239', (106, 116))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (179, 213))
918323	27259248	Statistical analysis revealed that patients with mTOR rs1057079 AG (ORadjusted: 4.59; 95% CI: 1.78-11.86) genotype had significant correlation with the clinical response of paclitaxel when compared with AA genotype after adjustment for sex, age, and chemotherapy cycle.	('mTOR', 'Gene', (49, 53))	('rs1057079 AG', 'Var', (54, 66))	('mTOR', 'Gene', '2475', (49, 53))	('men', 'Species', '9606', (227, 230))	('paclitaxel', 'Chemical', 'MESH:D017239', (173, 183))	('correlation', 'Reg', (131, 142))	('clinical response of paclitaxel', 'MPA', (152, 183))	('rs1057079', 'Mutation', 'rs1057079', (54, 63))	('patients', 'Species', '9606', (35, 43))
918334	27259248	It has been reported that single nucleotide polymorphisms (SNPs) have association with radiation and chemotherapy dependent pathways.	('radiation', 'Disease', 'MESH:D004194', (87, 96))	('association', 'Interaction', (70, 81))	('single nucleotide polymorphisms', 'Var', (26, 57))	('radiation', 'Disease', (87, 96))
918336	27259248	Similar results were also observed in ovarian cancer cell lines with naturally occurring F-box and WD repeat domain-containing 7 (FBW7) mutations.	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('FBW7', 'Gene', '55294', (130, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (38, 52))	('FBW7', 'Gene', (130, 134))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('ovarian cancer', 'Disease', (38, 52))	('F-box and WD repeat domain-containing 7', 'Gene', '55294', (89, 128))
918346	27259248	The genotype distributions of the 11 selected SNPs of FBW7 and its substrate genes and the efficacy of paclitaxel are shown in Table 2.	('SNPs', 'Var', (46, 50))	('FBW7', 'Gene', (54, 58))	('FBW7', 'Gene', '55294', (54, 58))	('paclitaxel', 'Chemical', 'MESH:D017239', (103, 113))
918347	27259248	The results of unconditional logistic regression analysis of the genotypes revealed that the patients with mTOR rs1057079 AG (ORadjusted: 4.59; 95% CI: 1.78-11.86) genotype had significant correlation with the clinical response of paclitaxel when compared with AA genotype after adjustment for sex, age, and chemotherapy cycle.	('mTOR', 'Gene', (107, 111))	('men', 'Species', '9606', (285, 288))	('rs1057079 AG', 'Var', (112, 124))	('clinical response of paclitaxel', 'MPA', (210, 241))	('mTOR', 'Gene', '2475', (107, 111))	('paclitaxel', 'Chemical', 'MESH:D017239', (231, 241))	('correlation with', 'Reg', (189, 205))	('patients', 'Species', '9606', (93, 101))	('rs1057079', 'Mutation', 'rs1057079', (112, 121))
918350	27259248	The results of unconditional logistic regression analysis of the genotypes in myb rs7435589 revealed that, compared with AA genotype, the individuals with AG genotype (OR adjusted: 2.86; 95% CI: 1.28-6.39) had significant correlation with the adverse events after adjustment for sex, age, and chemotherapy cycle.	('myb', 'Gene', (78, 81))	('correlation', 'Interaction', (222, 233))	('rs7435589', 'Var', (82, 91))	('myb', 'Gene', '4602', (78, 81))	('adverse events', 'Disease', (243, 257))	('men', 'Species', '9606', (270, 273))	('rs7435589', 'Mutation', 'rs7435589', (82, 91))
918351	27259248	Similarly, the genotype distributions of the SNPs results also showed that SNPs rs10521 in NOTCH1 had significant difference.	('NOTCH1', 'Gene', (91, 97))	('NOTCH1', 'Gene', '4851', (91, 97))	('rs10521', 'Var', (80, 87))	('rs10521', 'Mutation', 'rs10521', (80, 87))
918353	27259248	Haplotype analysis was performed with two SNPs (rs210940 and 7435589) across the myb gene, four SNPs (rs1057079, rs17036508, rs2536 and rs2295080) across the mTOR gene and two SNPs (rs3124591 and rs10521) across the NOTCH1 gene.	('rs1057079', 'Mutation', 'rs1057079', (102, 111))	('myb', 'Gene', '4602', (81, 84))	('NOTCH1', 'Gene', '4851', (216, 222))	('rs2536', 'Mutation', 'rs2536', (125, 131))	('NOTCH1', 'Gene', (216, 222))	('myb', 'Gene', (81, 84))	('rs210940', 'Mutation', 'rs210940', (48, 56))	('rs10521', 'Mutation', 'rs10521', (196, 203))	('rs2295080', 'Var', (136, 145))	('rs17036508', 'Var', (113, 123))	('7435589', 'Var', (61, 68))	('rs3124591', 'DBSNP_MENTION', 'None', (182, 191))	('rs3124591', 'Var', (182, 191))	('mTOR', 'Gene', (158, 162))	('rs1057079', 'Var', (102, 111))	('rs2536', 'Var', (125, 131))	('rs10521', 'Var', (196, 203))	('rs210940', 'Var', (48, 56))	('rs17036508', 'Mutation', 'rs17036508', (113, 123))	('rs2295080', 'Mutation', 'rs2295080', (136, 145))	('mTOR', 'Gene', '2475', (158, 162))
918356	27259248	On the contrary, haplotypes of Grs1057079Crs17036508Trs2536Grs2295080and Ars1057079Crs17036508Trs2536Trs2295080 can decrease the risk of an infaust efficacy of paclitaxel [OR (95%CI): 0.25 (0.07-0.96) and OR (95%CI): 0.12 (0.02-0.96)].	('rs2295080', 'Mutation', 'rs2295080', (60, 69))	('rs1057079', 'Mutation', 'rs1057079', (32, 41))	('decrease', 'NegReg', (116, 124))	('Ars1057079Crs17036508Trs2536Trs2295080', 'Var', (73, 111))	('rs2536', 'Mutation', 'rs2536', (53, 59))	('rs17036508', 'Mutation', 'rs17036508', (84, 94))	('rs2536', 'Mutation', 'rs2536', (95, 101))	('paclitaxel', 'Chemical', 'MESH:D017239', (160, 170))	('rs2295080', 'Mutation', 'rs2295080', (102, 111))	('rs17036508', 'Mutation', 'rs17036508', (42, 52))	('Grs1057079Crs17036508Trs2536Grs2295080and', 'Var', (31, 72))	('rs1057079', 'Mutation', 'rs1057079', (74, 83))
918357	27259248	At the same time, neither of the haplotypes across the myb gene nor the NOTCH gene was associated with an increased or decreased infaust efficacy of paclitaxel risk (p>0.05).	('NOTCH', 'Gene', (72, 77))	('decreased', 'NegReg', (119, 128))	('haplotypes', 'Var', (33, 43))	('paclitaxel', 'Chemical', 'MESH:D017239', (149, 159))	('myb', 'Gene', (55, 58))	('myb', 'Gene', '4602', (55, 58))	('infaust efficacy', 'MPA', (129, 145))
918360	27259248	The data showed that patients with mTOR rs1057079 AG genotype had longer PFS when compared with AA genotype after adjustment for sex, age, and chemotherapy cycle.	('rs1057079', 'Mutation', 'rs1057079', (40, 49))	('rs1057079 AG', 'Var', (40, 52))	('mTOR', 'Gene', (35, 39))	('mTOR', 'Gene', '2475', (35, 39))	('patients', 'Species', '9606', (21, 29))	('longer', 'PosReg', (66, 72))	('PFS', 'CPA', (73, 76))	('men', 'Species', '9606', (120, 123))
918362	27259248	The median PFS of AG genotypes and AA genotypes in mTOR rs1057079 was 17.31 months (95% CI: 15.9-18.67 months) and 9.8 months (95% CI: 8.58-11.02 months) (p = 0.019), respectively (Figure 1).	('mTOR', 'Gene', (51, 55))	('mTOR', 'Gene', '2475', (51, 55))	('rs1057079', 'Mutation', 'rs1057079', (56, 65))	('rs1057079', 'Var', (56, 65))
918367	27259248	Study has shown that loss of FBW7 leads to an elevated expression of the c-Jun, c-Myc, and Notch-1 oncoproteins, all of which are capable of promoting cell growth.	('loss', 'Var', (21, 25))	('Notch-1', 'Gene', '4851', (91, 98))	('c-Myc', 'Gene', '4609', (80, 85))	('elevated', 'PosReg', (46, 54))	('c-Jun', 'Gene', (73, 78))	('promoting', 'PosReg', (141, 150))	('FBW7', 'Gene', (29, 33))	('expression', 'MPA', (55, 65))	('c-Myc', 'Gene', (80, 85))	('FBW7', 'Gene', '55294', (29, 33))	('c-Jun', 'Gene', '3725', (73, 78))	('cell growth', 'CPA', (151, 162))	('Notch-1', 'Gene', (91, 98))
918368	27259248	Tumors with mutant FBW7 were more resistant to paclitaxel compared to FBW7 wild-type parental tumors.	('FBW7', 'Gene', (70, 74))	('resistant to paclitaxel', 'MPA', (34, 57))	('parental tumors', 'Disease', 'MESH:D063129', (85, 100))	('FBW7', 'Gene', (19, 23))	('parental tumors', 'Disease', (85, 100))	('mutant', 'Var', (12, 18))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('paclitaxel', 'Chemical', 'MESH:D017239', (47, 57))	('FBW7', 'Gene', '55294', (70, 74))	('FBW7', 'Gene', '55294', (19, 23))
918370	27259248	We detected Myb rs210940, rs7435589, mTOR rs1057079, rs17036508, rs2536, rs2295080, NOTCH rs3124591, rs10521, c-Myc, SREBF2 and FBW7 genotypes.	('rs2536', 'Mutation', 'rs2536', (65, 71))	('rs10521', 'Var', (101, 108))	('rs210940', 'Var', (16, 24))	('rs3124591', 'DBSNP_MENTION', 'None', (90, 99))	('rs7435589', 'Mutation', 'rs7435589', (26, 35))	('mTOR', 'Gene', '2475', (37, 41))	('rs2295080', 'Var', (73, 82))	('rs3124591', 'Var', (90, 99))	('FBW7', 'Gene', (128, 132))	('Myb', 'Gene', (12, 15))	('SREBF2', 'Gene', (117, 123))	('rs17036508', 'Mutation', 'rs17036508', (53, 63))	('rs1057079', 'Var', (42, 51))	('SREBF2', 'Gene', '6721', (117, 123))	('rs210940', 'Mutation', 'rs210940', (16, 24))	('FBW7', 'Gene', '55294', (128, 132))	('rs10521', 'Mutation', 'rs10521', (101, 108))	('Myb', 'Gene', '4602', (12, 15))	('rs2536', 'Var', (65, 71))	('rs1057079', 'Mutation', 'rs1057079', (42, 51))	('c-Myc', 'Gene', (110, 115))	('rs2295080', 'Mutation', 'rs2295080', (73, 82))	('c-Myc', 'Gene', '4609', (110, 115))	('rs7435589', 'Var', (26, 35))	('mTOR', 'Gene', (37, 41))	('rs17036508', 'Var', (53, 63))
918371	27259248	Our results demonstrate that patients with mTOR rs1057079 AG (ORadjusted: 4.59; 95% CI: 1.78-11.86) genotype have significant correlation with the efficacy of paclitaxel when compared with AA genotype after adjustment for sex, age, and chemotherapy cycle.	('patients', 'Species', '9606', (29, 37))	('paclitaxel', 'Chemical', 'MESH:D017239', (159, 169))	('correlation', 'Interaction', (126, 137))	('rs1057079', 'Mutation', 'rs1057079', (48, 57))	('efficacy', 'MPA', (147, 155))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))	('men', 'Species', '9606', (213, 216))	('rs1057079 AG', 'Var', (48, 60))
918372	27259248	Patients with mTOR rs1057079 AG genotype experienced an ORR of 47.2% with the mPFS of 17.3 months (95% CI: 15.9-18.67 months).	('mTOR', 'Gene', '2475', (14, 18))	('rs1057079 AG', 'Var', (19, 31))	('Patients', 'Species', '9606', (0, 8))	('rs1057079', 'Mutation', 'rs1057079', (19, 28))	('mTOR', 'Gene', (14, 18))
918373	27259248	However the mPFS of patients with mTOR rs1057079 AA genotype was 9.8 months (8.58-11.02 months).	('patients', 'Species', '9606', (20, 28))	('mTOR', 'Gene', '2475', (34, 38))	('rs1057079', 'Var', (39, 48))	('rs1057079', 'Mutation', 'rs1057079', (39, 48))	('mTOR', 'Gene', (34, 38))
918378	27259248	The data demonstrated that patients with myb rs7435589 AG genotype and rs10521 AG type in NOTCH1 had high risk of grade 3-4 adverse events after receiving paclitaxel plus cisplatin chemotherapy.	('rs7435589', 'Mutation', 'rs7435589', (45, 54))	('paclitaxel', 'Chemical', 'MESH:D017239', (155, 165))	('myb', 'Gene', (41, 44))	('myb', 'Gene', '4602', (41, 44))	('rs7435589 AG', 'Var', (45, 57))	('patients', 'Species', '9606', (27, 35))	('rs10521 AG type', 'Var', (71, 86))	('NOTCH1', 'Gene', '4851', (90, 96))	('NOTCH1', 'Gene', (90, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('rs10521', 'Mutation', 'rs10521', (71, 78))
918381	27259248	Two studies have assessed associations between functional SNPs in mTOR gene and risk of ESCC in Chinese populations.	('mTOR', 'Gene', (66, 70))	('ESCC', 'Disease', (88, 92))	('mTOR', 'Gene', '2475', (66, 70))	('SNPs', 'Var', (58, 62))	('functional SNPs', 'Var', (47, 62))
918382	27259248	They genotyped several mTOR SNPs in ESCC patients and found a significantly altered risk of ESCC associated withmTOR rs1883965 and mTOR rs2295080.	('ESCC', 'Disease', (92, 96))	('rs1883965', 'Var', (117, 126))	('mTOR', 'Gene', (131, 135))	('rs2295080', 'Var', (136, 145))	('mTOR', 'Gene', '2475', (131, 135))	('rs1883965', 'Mutation', 'rs1883965', (117, 126))	('patients', 'Species', '9606', (41, 49))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (112, 116))	('mTOR', 'Gene', '2475', (23, 27))	('mTOR', 'Gene', (112, 116))	('rs2295080', 'Mutation', 'rs2295080', (136, 145))
918384	27259248	Only mTOR FRAP1:rs11121704 homozygosity was associated with a poor response to paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (79, 89))	('FRAP1', 'Gene', '2475', (10, 15))	('rs11121704', 'Mutation', 'rs11121704', (16, 26))	('response', 'MPA', (67, 75))	('mTOR', 'Gene', (5, 9))	('mTOR', 'Gene', '2475', (5, 9))	('rs11121704', 'Var', (16, 26))	('FRAP1', 'Gene', (10, 15))
918385	27259248	Gratifyingly, our work unveiled significant association between genetic variants in mTOR and the clinical response of paclitaxel in patients with ESC, although it is too eary for us to conclude that mTOR rs1057079 AG is the biomarker of paclitaxel response since the sample sizes of this study is relatively small.	('mTOR', 'Gene', (199, 203))	('genetic variants', 'Var', (64, 80))	('mTOR', 'Gene', '2475', (84, 88))	('paclitaxel', 'Chemical', 'MESH:D017239', (118, 128))	('mTOR', 'Gene', (84, 88))	('rs1057079', 'Mutation', 'rs1057079', (204, 213))	('rs1057079', 'Var', (204, 213))	('mTOR', 'Gene', '2475', (199, 203))	('patients', 'Species', '9606', (132, 140))	('paclitaxel', 'Chemical', 'MESH:D017239', (237, 247))
918386	27259248	Currently, we are enrolling patients in a large sample size clinical trial to further verify the association between SNPs of mTOR and the response of paclitaxel.	('mTOR', 'Gene', '2475', (125, 129))	('mTOR', 'Gene', (125, 129))	('paclitaxel', 'Chemical', 'MESH:D017239', (150, 160))	('patients', 'Species', '9606', (28, 36))	('SNPs', 'Var', (117, 121))
918388	27259248	To conclude, in SNPs of FBW7 and its substrate genes, the mTOR rs1057079 AG genotype could be used to predict the clinical response and to achieve better mPFS of patients with advanced ESCC treated with TP regimen as first-line chemotherapy.	('men', 'Species', '9606', (210, 213))	('patients', 'Species', '9606', (162, 170))	('mTOR', 'Gene', (58, 62))	('rs1057079', 'Mutation', 'rs1057079', (63, 72))	('rs1057079 AG', 'Var', (63, 75))	('FBW7', 'Gene', '55294', (24, 28))	('ESCC', 'Disease', (185, 189))	('TP', 'Chemical', 'MESH:C011314', (203, 205))	('FBW7', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (58, 62))
918400	27259248	Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to analyze the polymorphisms of mTOR rs1057079, rs17036508, rs2536, rs2295080, NOTCH rs3124591, rs10521, c-Myc, SREBF2 and FBW7 rs7685296.	('rs17036508', 'Mutation', 'rs17036508', (135, 145))	('FBW7', 'Gene', '55294', (210, 214))	('SREBF2', 'Gene', '6721', (199, 205))	('rs1057079', 'Var', (124, 133))	('rs7685296', 'Mutation', 'rs7685296', (215, 224))	('rs7685296', 'Var', (215, 224))	('rs2536', 'Var', (147, 153))	('c-Myc', 'Gene', (192, 197))	('men', 'Species', '9606', (42, 45))	('rs1057079', 'Mutation', 'rs1057079', (124, 133))	('mTOR', 'Gene', (119, 123))	('c-Myc', 'Gene', '4609', (192, 197))	('rs10521', 'Var', (183, 190))	('rs2295080', 'Mutation', 'rs2295080', (155, 164))	('rs17036508', 'Var', (135, 145))	('mTOR', 'Gene', '2475', (119, 123))	('rs2536', 'Mutation', 'rs2536', (147, 153))	('CR', 'Chemical', '-', (69, 71))	('rs3124591', 'DBSNP_MENTION', 'None', (172, 181))	('rs2295080', 'Var', (155, 164))	('rs3124591', 'Var', (172, 181))	('rs10521', 'Mutation', 'rs10521', (183, 190))	('SREBF2', 'Gene', (199, 205))	('FBW7', 'Gene', (210, 214))
918433	26317795	We found the expression levels of CCL5 were significantly elevated in T3-T4 stage patients, compared with their T1-T2 stage counterparts (2.196 +- 2.009 vs. 1.555 +- 1.193, p < 0.05) (Table 1).	('expression levels', 'MPA', (13, 30))	('CCL5', 'Gene', (34, 38))	('T3-T4', 'Var', (70, 75))	('patients', 'Species', '9606', (82, 90))	('CCL5', 'Gene', '6352', (34, 38))	('elevated', 'PosReg', (58, 66))
918595	17054793	In vitro treatment with guggulsterone was associated with a significant increase in the percentage of apoptotic cells and of the caspase 3 activity.	('increase', 'PosReg', (72, 80))	('caspase 3', 'Gene', (129, 138))	('activity', 'MPA', (139, 147))	('caspase 3', 'Gene', '836', (129, 138))	('guggulsterone', 'Chemical', 'MESH:C023617', (24, 37))	('guggulsterone', 'Var', (24, 37))
918637	17054793	FXR is a nuclear receptor activated by bile acids, in particular chenodeoxycholic acid, which are abundantly present in bile, a component of refluxate in BE.	('FXR', 'Gene', '9971', (0, 3))	('BE', 'Phenotype', 'HP:0100580', (154, 156))	('chenodeoxycholic acid', 'Chemical', 'MESH:D002635', (65, 86))	('bile acids', 'Chemical', 'MESH:D001647', (39, 49))	('FXR', 'Gene', (0, 3))	('chenodeoxycholic acid', 'Var', (65, 86))
918641	17054793	A similar induction of apoptosis by guggulsterone has been reported in human cells derived from lung carcinoma and leukaemia.	('lung carcinoma and leukaemia', 'Disease', 'MESH:D007938', (96, 124))	('apoptosis', 'CPA', (23, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('guggulsterone', 'Var', (36, 49))	('guggulsterone', 'Chemical', 'MESH:C023617', (36, 49))	('human', 'Species', '9606', (71, 76))
918644	17054793	When treated with the FXR agonist GW4064 (which is a more potent agonist than chenodeoxycholic acid), BE-derived cells disclosed a slight, not significant increase of apoptosis.	('GW4064', 'Chemical', 'MESH:C412815', (34, 40))	('FXR', 'Gene', (22, 25))	('apoptosis', 'CPA', (167, 176))	('FXR', 'Gene', '9971', (22, 25))	('chenodeoxycholic acid', 'Chemical', 'MESH:D002635', (78, 99))	('GW4064', 'Var', (34, 40))	('BE', 'Phenotype', 'HP:0100580', (102, 104))
918655	17054793	In summary, the results of this study indicate that the bile acid receptor FXR is focally overexpressed in BE and that treatment with guggulsterone, an FXR antagonist, significantly enhances apoptosis in a human BE-derived cell line.	('apoptosis', 'CPA', (191, 200))	('FXR', 'Gene', (152, 155))	('human', 'Species', '9606', (206, 211))	('bile acid', 'Chemical', 'MESH:D001647', (56, 65))	('FXR', 'Gene', '9971', (152, 155))	('FXR', 'Gene', (75, 78))	('FXR', 'Gene', '9971', (75, 78))	('guggulsterone', 'Var', (134, 147))	('guggulsterone', 'Chemical', 'MESH:C023617', (134, 147))	('enhances', 'PosReg', (182, 190))	('BE', 'Phenotype', 'HP:0100580', (212, 214))	('BE', 'Phenotype', 'HP:0100580', (107, 109))
918672	17054793	The following ligands were used: FXR agonist GW4064 (GlaxoSmithKline, Research Triangle Park, USA) at a final concentration of 5 muM, FXR antagonist guggulsterone (Steraloids, Newport, USA) at 20 muM, VDR agonist lithocholic acid (Sigma) at 30 muM and VDR antagonist ZK168281 (Schering, Berlin, Germany) at 1 muM.	('VDR', 'Gene', (201, 204))	('ZK168281', 'Chemical', 'MESH:C417690', (267, 275))	('FXR', 'Gene', '9971', (33, 36))	('muM', 'Gene', '56925', (129, 132))	('GW4064', 'Var', (45, 51))	('muM', 'Gene', (129, 132))	('guggulsterone', 'Chemical', 'MESH:C023617', (149, 162))	('VDR', 'Gene', '7421', (201, 204))	('FXR', 'Gene', '9971', (134, 137))	('rat', 'Species', '10116', (117, 120))	('muM', 'Gene', '56925', (309, 312))	('VDR', 'Gene', (252, 255))	('FXR', 'Gene', (33, 36))	('muM', 'Gene', (309, 312))	('Steraloids', 'Chemical', '-', (164, 174))	('muM', 'Gene', '56925', (196, 199))	('GW4064', 'Chemical', 'MESH:C412815', (45, 51))	('muM', 'Gene', '56925', (244, 247))	('muM', 'Gene', (196, 199))	('FXR', 'Gene', (134, 137))	('VDR', 'Gene', '7421', (252, 255))	('muM', 'Gene', (244, 247))	('lithocholic acid', 'Chemical', 'MESH:D008095', (213, 229))
918726	33510126	The prognostic risk score was calculated according to the corresponding regression coefficient, where the risk score=(0.460965xTP73exp)+(-0.4529xDAPK1exp)+ (-1.1353xBECN1exp)+(1.75806xATG12exp)+ (0.680104xSIRT1exp)+(-0.92933xCAPN1exp)+ (1.647224xVAMP7exp)+(1.638798xATG5exp).	('BECN1', 'Gene', '8678', (165, 170))	('VAMP7', 'Gene', (246, 251))	('DAPK1', 'Gene', (145, 150))	('ATG5', 'Gene', '9474', (266, 270))	('BECN1', 'Gene', (165, 170))	('DAPK1', 'Gene', '1612', (145, 150))	('VAMP7', 'Gene', '6845', (246, 251))	('ATG5', 'Gene', (266, 270))	('0.460965xTP73exp', 'Var', (118, 134))
918757	33510126	Some studies have found that Beclin-1 gene mutation or gene knockout cells could not form an effective autophagosome to clear damaged organelles, and mitochondria could not repair DNA and protein damage, leading to aggregation of harmful substances, inflammatory factors, and cytokines, thus inducing tumor formation.	('leading to', 'Reg', (204, 214))	('Beclin-1', 'Gene', '8678', (29, 37))	('aggregation', 'MPA', (215, 226))	('mutation', 'Var', (43, 51))	('inducing', 'Reg', (292, 300))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('protein damage', 'Disease', 'MESH:D009422', (188, 202))	('protein damage', 'Disease', (188, 202))	('tumor', 'Disease', (301, 306))	('Beclin-1', 'Gene', (29, 37))
918765	33510126	Another study found that ATG5 protein expression in several gastric cancer cell lines was higher than that in regular gastric mucosa epithelial cell lines; the high expression of ATG5 in gastric cancer promoted the occurrence and development of tumors.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ATG5', 'Gene', (179, 183))	('occurrence', 'CPA', (215, 225))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('gastric cancer', 'Phenotype', 'HP:0012126', (187, 201))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('ATG5', 'Gene', (25, 29))	('tumors', 'Disease', (245, 251))	('gastric cancer', 'Disease', (187, 201))	('high expression', 'Var', (160, 175))	('gastric cancer', 'Disease', (60, 74))	('promoted', 'PosReg', (202, 210))	('ATG5', 'Gene', '9474', (179, 183))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('gastric cancer', 'Disease', 'MESH:D013274', (187, 201))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('ATG5', 'Gene', '9474', (25, 29))
918770	33510126	VAMP7 inactivation could significantly reduce the ability of breast cancer cells to degrade the extracellular matrix, which may be the molecular mechanism of potential tumor cell metastasis.	('reduce', 'NegReg', (39, 45))	('degrade the extracellular matrix', 'MPA', (84, 116))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('tumor', 'Disease', (168, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('inactivation', 'Var', (6, 18))	('VAMP7', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('VAMP7', 'Gene', '6845', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
918796	32356485	Downregulation of MMP11 enhanced bladder cancer cell migration and invasion in BC cells, indicating it might be a good prognostic marker for the survival of patients with bladder cancer.	('MMP11', 'Gene', (18, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('invasion', 'CPA', (67, 75))	('bladder cancer', 'Disease', (33, 47))	('MMP11', 'Gene', '4320', (18, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (171, 185))	('bladder cancer', 'Disease', (171, 185))	('Downregulation', 'Var', (0, 14))	('patients', 'Species', '9606', (157, 165))	('enhanced', 'PosReg', (24, 32))	('bladder cancer', 'Phenotype', 'HP:0009725', (33, 47))
918826	32356485	The expression of miR-139-3p in ESCA/ESCC was significantly upregulated in GSE114110, GSE112264, and GSE113486, whereas no statistical significance was observed in the GSE112840 data set (Figure 3D).	('GSE112264', 'Var', (86, 95))	('GSE', 'Chemical', '-', (86, 89))	('upregulated', 'PosReg', (60, 71))	('miR-139-3p', 'Gene', (18, 28))	('GSE', 'Chemical', '-', (101, 104))	('expression', 'MPA', (4, 14))	('GSE113486', 'Var', (101, 110))	('GSE114110', 'Var', (75, 84))	('GSE', 'Chemical', '-', (75, 78))	('ESCA', 'Phenotype', 'HP:0011459', (32, 36))	('GSE', 'Chemical', '-', (168, 171))	('miR-139-3p', 'Gene', '406931', (18, 28))
918873	31905960	PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis Phosphoinositide kinases (PIKs) are a group of lipid kinases that are important upstream activators of various significant signaling pathways.	('PIK3CA', 'Gene', '5290', (0, 6))	('Mutations', 'Var', (12, 21))	('Solid Malignancies', 'Disease', (25, 43))	('PIK3CA', 'Gene', (0, 6))
918874	31905960	Hyperactivation of the PI3K/AKT/mTOR pathways:either via mutations or genomic amplification:confers key oncogenic activity, essential for the development and progression of several solid tumors.	('oncogenic', 'CPA', (104, 113))	('mTOR', 'Gene', '2475', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('solid tumors', 'Disease', (181, 193))	('mTOR', 'Gene', (32, 36))	('mutations', 'Var', (57, 66))	('solid tumors', 'Disease', 'MESH:D009369', (181, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
918875	31905960	Alterations in the PIK3CA gene are associated with poor prognosis of solid malignancies.	('PIK3CA', 'Gene', (19, 25))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (35, 45))	('solid malignancies', 'Disease', (69, 87))	('solid malignancies', 'Disease', 'MESH:D018250', (69, 87))
918876	31905960	Although the literature reports contradictory prognostic values of PIK3CA in aggressive cancers, most of the available data highlight the important role of PIK3CA mutation in mediating tumorigenesis via increased signaling of the PI3K/AKT/mTOR survival pathway.	('tumor', 'Disease', (185, 190))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('signaling', 'MPA', (213, 222))	('mTOR', 'Gene', (239, 243))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('mTOR', 'Gene', '2475', (239, 243))	('aggressive cancers', 'Disease', 'MESH:D009369', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('aggressive cancers', 'Disease', (77, 95))	('mutation', 'Var', (163, 171))	('PIK3CA', 'Gene', (156, 162))	('increased', 'PosReg', (203, 212))
918878	31905960	This article reviews the role of PIK3CA mutations and inhibitors of PI3K/AKT/mTOR pathways in major cancer types and examines its association with clinicopathological parameters and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mTOR', 'Gene', '2475', (77, 81))	('mutations', 'Var', (40, 49))	('mTOR', 'Gene', (77, 81))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('PIK3CA', 'Gene', (33, 39))	('association', 'Interaction', (130, 141))
918881	31905960	PI3K is activated by a growth factor bound receptor tyrosine kinase (RTK), and once activated, it phosphorylates other signaling molecules, in a substrate specific manner, resulting in downstream conduction of chemical signals.	('PI3K', 'Var', (0, 4))	('receptor tyrosine kinase', 'Gene', '5979', (43, 67))	('resulting in', 'Reg', (172, 184))	('conduction of chemical signals', 'MPA', (196, 226))	('RTK', 'Gene', '5979', (69, 72))	('receptor tyrosine kinase', 'Gene', (43, 67))	('RTK', 'Gene', (69, 72))
918885	31905960	The present review discusses the association of mutations in the PIK3CA p110a catalytic subunit of PI3K due to the increasing reports of the altered protein product of this gene being involved in several human cancer types.	('cancer', 'Disease', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PI3K', 'Gene', (99, 103))	('p110a', 'Gene', '5290', (72, 77))	('PIK3CA', 'Gene', (65, 71))	('p110a', 'Gene', (72, 77))	('human', 'Species', '9606', (204, 209))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('involved', 'Reg', (184, 192))	('mutations', 'Var', (48, 57))
918886	31905960	Gene insertions, deletions, and somatic missense mutations in this gene have been reported in many human cancer types, like colon, breast, brain, liver, stomach, and lung cancers.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colon', 'Disease', (124, 129))	('reported', 'Reg', (82, 90))	('missense mutations', 'Var', (40, 58))	('stomach', 'Disease', (153, 160))	('breast', 'Disease', (131, 137))	('liver', 'Disease', (146, 151))	('lung cancers', 'Disease', 'MESH:D008175', (166, 178))	('deletions', 'Var', (17, 26))	('lung cancers', 'Disease', (166, 178))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (171, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('lung cancers', 'Phenotype', 'HP:0100526', (166, 178))	('brain', 'Disease', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('human', 'Species', '9606', (99, 104))
918887	31905960	were the first to show the association of PI3Ks, especially its subunit p110alpha, with cancer.	('p110alpha', 'Gene', (72, 81))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('p110alpha', 'Gene', '5290', (72, 81))	('association', 'Interaction', (27, 38))	('PI3Ks', 'Var', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
918891	31905960	In these tumors, the PTEN mutation results in the constitutive activation of the PI3K pathway.	('mutation', 'Var', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PTEN', 'Gene', (21, 25))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('PI3K pathway', 'Pathway', (81, 93))	('tumors', 'Disease', (9, 15))	('PTEN', 'Gene', '5728', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('activation', 'PosReg', (63, 73))
918893	31905960	Mutations in the regulatory subunit of PI3K (p85) have been reported in ovarian and colon cancers.	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('ovarian', 'Disease', 'MESH:D010049', (72, 79))	('p85', 'Gene', '5295', (45, 48))	('ovarian', 'Disease', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon cancers', 'Disease', (84, 97))	('p85', 'Gene', (45, 48))	('colon cancers', 'Phenotype', 'HP:0003003', (84, 97))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('colon cancers', 'Disease', 'MESH:D015179', (84, 97))	('reported', 'Reg', (60, 68))
918894	31905960	A recent study demonstrated 13% mutational frequency of PIK3CA in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mutational', 'Var', (32, 42))	('solid tumors', 'Disease', (66, 78))	('PIK3CA', 'Gene', (56, 62))
918896	31905960	The present review article discussed the role of PIK3CA mutations in various types of solid malignancies in terms of prevalence, potential correlation with clinicopathological parameters, and role in PI3K-targeted inhibition.	('PIK3CA', 'Gene', (49, 55))	('mutations', 'Var', (56, 65))	('solid malignancies', 'Disease', (86, 104))	('solid malignancies', 'Disease', 'MESH:D018250', (86, 104))
918897	31905960	Missense mutations in PIK3CA are commonly found in several types of breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (68, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('breast cancers', 'Disease', (68, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('found', 'Reg', (42, 47))	('breast cancers', 'Phenotype', 'HP:0003002', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('PIK3CA', 'Gene', (22, 28))	('Missense mutations', 'Var', (0, 18))
918898	31905960	The PIK3CA mutations in breast cancer were initially reported by Samuels et al..	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('PIK3CA', 'Gene', (4, 10))	('breast cancer', 'Disease', (24, 37))
918899	31905960	In their study, only one out of 12 patients had mutation in PIK3CA.	('mutation', 'Var', (48, 56))	('PIK3CA', 'Gene', (60, 66))	('patients', 'Species', '9606', (35, 43))
918902	31905960	It is now believed that mutations of PIK3CA are found in 20-30% of all human breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (77, 91))	('breast cancers', 'Disease', (77, 91))	('human', 'Species', '9606', (71, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('found', 'Reg', (48, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (77, 91))	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', (37, 43))
918903	31905960	Several studies have evaluated the correlation of PIK3CA mutations with clinicopathological parameters such as estrogen receptor (ER)/progesterone receptor (PR) positivity, the presence of lymph node metastases, and response to therapy in breast cancers (Table 1).	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('breast cancers', 'Disease', 'MESH:D001943', (239, 253))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('breast cancers', 'Disease', (239, 253))	('ER', 'Gene', '2099', (130, 132))	('metastases', 'Disease', (200, 210))	('metastases', 'Disease', 'MESH:D009362', (200, 210))	('estrogen receptor', 'Gene', (111, 128))	('mutations', 'Var', (57, 66))	('progesterone receptor', 'Gene', '5241', (134, 155))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('estrogen receptor', 'Gene', '2099', (111, 128))	('breast cancers', 'Phenotype', 'HP:0003002', (239, 253))	('progesterone receptor', 'Gene', (134, 155))	('PIK3CA', 'Gene', (50, 56))
918904	31905960	were the first to report a definite clinicopathological correlate of PIK3CA mutations in breast cancer.	('mutations', 'Var', (76, 85))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('PIK3CA', 'Gene', (69, 75))
918905	31905960	They reported that PIK3CA mutations were frequently seen in tumors with normally expressed PTEN, ER, PR, and ERBB2 genes, as well as in tumors with nodal involvement.	('tumors', 'Disease', (136, 142))	('PIK3CA', 'Gene', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('ERBB2', 'Gene', '2064', (109, 114))	('seen', 'Reg', (52, 56))	('ERBB2', 'Gene', (109, 114))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ER', 'Gene', '2099', (97, 99))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('PTEN', 'Gene', (91, 95))	('PTEN', 'Gene', '5728', (91, 95))	('ER', 'Gene', '2099', (109, 111))	('tumors', 'Disease', (60, 66))
918906	31905960	Studies demonstrated that mutations in PIK3CA were more common in hormone receptor-positive and HER2-positive breast cancers.	('common', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('hormone receptor', 'Gene', (66, 82))	('breast cancers', 'Phenotype', 'HP:0003002', (110, 124))	('hormone receptor', 'Gene', '3164', (66, 82))	('mutations', 'Var', (26, 35))	('breast cancers', 'Disease', 'MESH:D001943', (110, 124))	('breast cancers', 'Disease', (110, 124))	('HER2', 'Gene', (96, 100))	('HER2', 'Gene', '2064', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('PIK3CA', 'Gene', (39, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
918907	31905960	In a recent study by Wu et al., it was shown that PIK3CA mutations were positively associated with ER-positive, PR-positive, and low Ki67 labeling index, and negatively correlated with the triple-negative breast cancer subtype.	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('mutations', 'Var', (57, 66))	('associated', 'Reg', (83, 93))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('ER', 'Gene', '2099', (99, 101))	('PIK3CA', 'Gene', (50, 56))	('breast cancer', 'Disease', (205, 218))	('negatively', 'NegReg', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
918908	31905960	PIK3CA mutations were not associated with age at diagnosis, tumor stage, lymph node status, tumor size, or HER2 status.	('HER2', 'Gene', '2064', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (60, 65))	('HER2', 'Gene', (107, 111))	('mutations', 'Var', (7, 16))
918909	31905960	demonstrated that PIK3CA mutation significantly reduced disease-free survival (DFS) compared to wild-type (WT) PIK3CA in patients with ER-positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('mutation', 'Var', (25, 33))	('reduced', 'NegReg', (48, 55))	('ER', 'Gene', '2099', (135, 137))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('PIK3CA', 'Gene', (18, 24))	('disease-free survival', 'CPA', (56, 77))	('patients', 'Species', '9606', (121, 129))
918910	31905960	Subsequent studies reported that PIK3CA mutations were highly associated with the morphology, race, ER status, PR status, and HER2 status in breast cancer.	('ER', 'Gene', '2099', (100, 102))	('associated', 'Reg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('mutations', 'Var', (40, 49))	('breast cancer', 'Disease', (141, 154))	('HER2', 'Gene', (126, 130))	('HER2', 'Gene', '2064', (126, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('PIK3CA', 'Gene', (33, 39))	('ER', 'Gene', '2099', (127, 129))
918911	31905960	Recently, co-mutation of TP53 and PIK3CA was found to be associated with poor survival in residual disease after neoadjuvant chemotherapy in breast cancer.	('PIK3CA', 'Gene', (34, 40))	('TP53', 'Gene', (25, 29))	('co-mutation', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('TP53', 'Gene', '7157', (25, 29))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('poor', 'NegReg', (73, 77))	('residual disease', 'Disease', (90, 106))	('associated', 'Reg', (57, 67))
918912	31905960	In addition, studies have reported exon 9 mutations are independently associated with early recurrence and death, whereas exon 20 PIK3CA mutations are associated with optimal prognosis.	('PIK3CA', 'Gene', (130, 136))	('exon 9 mutations', 'Var', (35, 51))	('associated', 'Reg', (70, 80))	('death', 'Disease', 'MESH:D003643', (107, 112))	('early recurrence', 'CPA', (86, 102))	('death', 'Disease', (107, 112))	('mutations', 'Var', (42, 51))
918914	31905960	Another important clinicopathological correlate of PIK3CA mutation is that they are more frequently found in lobular breast cancers as compared to ductal breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancers', 'Disease', 'MESH:D001943', (154, 168))	('breast cancers', 'Phenotype', 'HP:0003002', (117, 131))	('breast cancers', 'Disease', (154, 168))	('breast cancers', 'Disease', 'MESH:D001943', (117, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('breast cancers', 'Disease', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutation', 'Var', (58, 66))	('PIK3CA', 'Gene', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('found', 'Reg', (100, 105))
918915	31905960	reported that this observation was specific for patients with exon 9 mutations.	('exon 9 mutations', 'Var', (62, 78))	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (48, 56))
918916	31905960	PIK3CA mutations have also been correlated with response to therapy in breast cancer.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('correlated', 'Reg', (32, 42))	('PIK3CA', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('mutations', 'Var', (7, 16))
918917	31905960	reported that mutations in PIK3CA make breast cancers resistant to antibody-based therapeutic trastuzumab.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('PIK3CA', 'Gene', (27, 33))	('resistant', 'MPA', (54, 63))	('trastuzumab', 'Chemical', 'MESH:D000068878', (94, 105))	('breast cancers', 'Phenotype', 'HP:0003002', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancers', 'Disease', 'MESH:D001943', (39, 53))	('breast cancers', 'Disease', (39, 53))	('mutations', 'Var', (14, 23))
918918	31905960	have suggested that over activation of PIK3CA due to oncogenic mutations rendered breast cancer cells refractive to the anti-HER2 agent Lapatinib.	('mutations', 'Var', (63, 72))	('HER2', 'Gene', (125, 129))	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('HER2', 'Gene', '2064', (125, 129))	('Lapatinib', 'Chemical', 'MESH:D000077341', (136, 145))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('PIK3CA', 'Gene', (39, 45))	('over activation', 'PosReg', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
918919	31905960	found no association between PIK3CA mutations and a response to anthracyline and paclitaxel-based chemotherapy.	('PIK3CA', 'Gene', (29, 35))	('paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('anthracyline', 'Chemical', '-', (64, 76))	('mutations', 'Var', (36, 45))
918921	31905960	Mutations in the PIK3CA have been reported to be associated with resistance to several antitumor agents such as paclitaxel, tamoxifen, and trastuzumab.	('PIK3CA', 'Gene', (17, 23))	('associated', 'Reg', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Mutations', 'Var', (0, 9))	('paclitaxel', 'Chemical', 'MESH:D017239', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('trastuzumab', 'Chemical', 'MESH:D000068878', (139, 150))	('tumor', 'Disease', (91, 96))	('tamoxifen', 'Chemical', 'MESH:D013629', (124, 133))	('resistance', 'MPA', (65, 75))
918922	31905960	It has been shown that PI3K and ER pathways have a synergistic effect on tumor progression.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('ER', 'Gene', '2099', (32, 34))	('PI3K', 'Var', (23, 27))
918923	31905960	Recently, it was shown that Everolimus treatment along with chemotherapy suppressed PIK3CA, ESR1, and GATA3 gene mutation.	('mutation', 'Var', (113, 121))	('Everolimus', 'Chemical', 'MESH:D000068338', (28, 38))	('ESR1', 'Gene', '2099', (92, 96))	('GATA3', 'Gene', (102, 107))	('PIK3CA', 'Gene', (84, 90))	('suppressed', 'NegReg', (73, 83))	('ESR1', 'Gene', (92, 96))	('GATA3', 'Gene', '2625', (102, 107))
918925	31905960	A recent study reported PIK3CA mutation frequency of 14% in Belgian colorectal cancer patients.	('PIK3CA', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Belgian colorectal cancer', 'Disease', (60, 85))	('Belgian colorectal cancer', 'Disease', 'MESH:D015179', (60, 85))	('mutation', 'Var', (31, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('patients', 'Species', '9606', (86, 94))
918926	31905960	Another recent study on Chinese colon cancer patients reported a mutation frequency of 18.94%, and these mutations were more prevalent in the right-side colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('prevalent', 'Reg', (125, 134))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('colon cancer', 'Disease', (32, 44))	('patients', 'Species', '9606', (45, 53))	('mutation', 'Var', (65, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('colon cancer', 'Phenotype', 'HP:0003003', (32, 44))	('colon cancer', 'Disease', 'MESH:D015179', (32, 44))	('colorectal cancer', 'Disease', (153, 170))
918927	31905960	Another study also supported this finding but showed no correlation of PIK3CA gene mutations with clinical parameters such as gender, age, cancer stage, or differentiation.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PIK3CA', 'Gene', (71, 77))	('cancer', 'Disease', (139, 145))
918928	31905960	PIK3CA mutations were reported to be more prevalent in the "protruded-type" of colon cancer as compared to the "flat-type" colon cancers.	('flat-type" colon cancers', 'Disease', (112, 136))	('prevalent', 'Reg', (42, 51))	('colon cancer', 'Disease', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('flat-type" colon cancers', 'Disease', 'MESH:D015179', (112, 136))	('colon cancer', 'Phenotype', 'HP:0003003', (123, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('PIK3CA', 'Gene', (0, 6))	('colon cancer', 'Disease', 'MESH:D015179', (123, 135))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colon cancers', 'Phenotype', 'HP:0003003', (123, 136))	('mutations', 'Var', (7, 16))
918929	31905960	Family history or inherited predisposition did not have any effect on the frequency of PIK3CA gene mutations in colorectal cancer.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('mutations', 'Var', (99, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('PIK3CA', 'Gene', (87, 93))
918931	31905960	The mutational frequency of PIK3CA in colon cancers shows gender bias with more frequency in the females as compared to the males.	('colon cancers', 'Phenotype', 'HP:0003003', (38, 51))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('colon cancers', 'Disease', 'MESH:D015179', (38, 51))	('PIK3CA', 'Gene', (28, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (38, 50))	('colon cancers', 'Disease', (38, 51))	('mutational', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
918932	31905960	However, a recent study did not find any significant difference between male and female colon cancer patients with respect to frequency of PIK3CA mutations.	('patients', 'Species', '9606', (101, 109))	('colon cancer', 'Phenotype', 'HP:0003003', (88, 100))	('mutations', 'Var', (146, 155))	('colon cancer', 'Disease', 'MESH:D015179', (88, 100))	('colon cancer', 'Disease', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PIK3CA', 'Gene', (139, 145))
918933	31905960	All the cases with PIK3CA mutations in poorly differentiated clusters had nodal metastases, high pathological TNM stage, and lymphatic invasion.	('PIK3CA', 'Gene', (19, 25))	('lymphatic invasion', 'CPA', (125, 143))	('metastases', 'Disease', (80, 90))	('metastases', 'Disease', 'MESH:D009362', (80, 90))	('TNM', 'Gene', '10178', (110, 113))	('mutations', 'Var', (26, 35))	('TNM', 'Gene', (110, 113))
918934	31905960	A recent study highlighted that PIK3CA mutation is associated with decreased risk of peritoneal metastases in metastatic colorectal cancer.	('mutation', 'Var', (39, 47))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colorectal cancer', 'Disease', (121, 138))	('decreased', 'NegReg', (67, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))	('metastases', 'Disease', (96, 106))	('PIK3CA', 'Gene', (32, 38))
918936	31905960	Similarly, PIK3CA amplifications were associated with the occurrence of diffuse-type and poorly differentiated gastric cancers and peritoneal recurrence as compared to those without PIK3CA amplifications.	('gastric cancers', 'Disease', (111, 126))	('gastric cancers', 'Phenotype', 'HP:0012126', (111, 126))	('associated with', 'Reg', (38, 53))	('peritoneal recurrence', 'Disease', (131, 152))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('PIK3CA', 'Gene', (11, 17))	('amplifications', 'Var', (18, 32))	('diffuse-type', 'Disease', (72, 84))	('poorly', 'Disease', (89, 95))	('gastric cancers', 'Disease', 'MESH:D013274', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
918937	31905960	It was also demonstrated that PIK3CA mutations conferred resistance to colon cancer cells against anti-EGFR antibodies.	('PIK3CA', 'Gene', (30, 36))	('EGFR', 'Gene', '1956', (103, 107))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('EGFR', 'Gene', (103, 107))	('resistance', 'MPA', (57, 67))	('mutations', 'Var', (37, 46))	('colon cancer', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
918939	31905960	Furthermore, another study even reported PIK3CA mutation to be associated with good prognosis in patients with microsatellite stability (MSS) stage I-III colon cancer with a significantly increased five-year relapse-free interval in patients with PIK3CA-mutated MSS tumors vs. those with PIK3CA WT MSS tumors.	('PIK3CA-mutated', 'Var', (247, 261))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('PIK3CA', 'Gene', (41, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('tumors', 'Disease', (302, 308))	('mutation', 'Var', (48, 56))	('patients', 'Species', '9606', (97, 105))	('tumors', 'Disease', 'MESH:D009369', (302, 308))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('patients', 'Species', '9606', (233, 241))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colon cancer', 'Disease', (154, 166))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('increased', 'PosReg', (188, 197))	('tumors', 'Disease', (266, 272))
918940	31905960	Interestingly, recent clinical trials have strongly highlighted that low-dose aspirin (100 mg/day) can act as therapy in colorectal cancer patients positive for PIK3CA mutations and who have undergone surgical resection in terms of reducing the risk of recurrence.	('patients', 'Species', '9606', (139, 147))	('aspirin', 'Chemical', 'MESH:D001241', (78, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('PIK3CA', 'Gene', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('positive', 'Reg', (148, 156))	('colorectal cancer', 'Disease', (121, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))	('mutations', 'Var', (168, 177))
918941	31905960	PIK3CA gene amplifications have been reported in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('PIK3CA', 'Gene', (0, 6))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('amplifications', 'Var', (12, 26))	('reported', 'Reg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
918942	31905960	The frequency of PIK3CA gene mutation in lung cancer varies significantly.	('mutation', 'Var', (29, 37))	('PIK3CA', 'Gene', (17, 23))	('lung cancer', 'Disease', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
918943	31905960	reported a low frequency of PIK3CA mutations (4%) in lung cancer, with higher frequency seen in squamous cell carcinoma (7%) as compared to adenocarcinoma (2%).	('squamous cell carcinoma', 'Disease', (96, 119))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 119))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('adenocarcinoma', 'Disease', (140, 154))	('PIK3CA', 'Gene', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('mutations', 'Var', (35, 44))
918945	31905960	Kawano et al., for the first time, reported the amplification of mutant PIK3CA alleles in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutant', 'Var', (65, 71))	('PIK3CA', 'Gene', (72, 78))	('amplification', 'MPA', (48, 61))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
918946	31905960	PI3K pathway alterations have been identified in over 50% of lung squamous cell carcinoma cases.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('lung squamous cell carcinoma', 'Disease', (61, 89))	('identified', 'Reg', (35, 45))	('PI3K pathway', 'Pathway', (0, 12))	('alterations', 'Var', (13, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))
918947	31905960	However, a recent study in young lung adenocarcinoma patients demonstrated the absence of PIK3CA gene mutations.	('patients', 'Species', '9606', (53, 61))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (33, 52))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (33, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('PIK3CA', 'Gene', (90, 96))	('absence', 'NegReg', (79, 86))	('mutations', 'Var', (102, 111))	('lung adenocarcinoma', 'Disease', (33, 52))
918949	31905960	The frequency of PIK3CA gene mutations was higher in metastatic lung adenocarcinoma than in primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('primary tumors', 'Disease', 'MESH:D001932', (92, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('PIK3CA gene', 'Gene', (17, 28))	('higher', 'Reg', (43, 49))	('mutations', 'Var', (29, 38))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (64, 83))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('lung adenocarcinoma', 'Disease', (64, 83))	('primary tumors', 'Disease', (92, 106))
918950	31905960	PIK3CA mutation was significantly associated with higher risk of lung failure in patients undergoing lung stereotactic body radiation therapy.	('associated', 'Reg', (34, 44))	('lung failure', 'Disease', 'MESH:D008171', (65, 77))	('patients', 'Species', '9606', (81, 89))	('PIK3CA', 'Gene', (0, 6))	('lung failure', 'Disease', (65, 77))	('mutation', 'Var', (7, 15))	('stereotactic body', 'Phenotype', 'HP:0000733', (106, 123))
918951	31905960	PIK3CA mutations were reported to be associated with invasive growth, vacuolar signs, and margin lobulation on chest CT. PIK3CA gene mutations were shown to be associated with metastases, poor prognosis, and shorter PFS times.	('PFS times', 'CPA', (216, 225))	('metastases', 'Disease', 'MESH:D009362', (176, 186))	('PIK3CA', 'Gene', (121, 127))	('vacuolar signs', 'Phenotype', 'HP:0001922', (70, 84))	('mutations', 'Var', (133, 142))	('poor prognosis', 'CPA', (188, 202))	('metastases', 'Disease', (176, 186))	('associated', 'Reg', (160, 170))
918952	31905960	Contradictory findings are reported in the literature regarding the role of PIK3CA gene mutations in thyroid cancers.	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (101, 115))	('mutations', 'Var', (88, 97))	('PIK3CA', 'Gene', (76, 82))	('thyroid cancers', 'Disease', (101, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('thyroid cancers', 'Disease', 'MESH:D013964', (101, 116))
918954	31905960	However, these studies indicate that PIK3CA mutations are prevalent in aplastic thyroid cancer and follicular thyroid cancer as compared to papillary carcinoma of the thyroid.	('thyroid cancer', 'Phenotype', 'HP:0002890', (110, 124))	('papillary carcinoma of the thyroid', 'Disease', 'MESH:C536915', (140, 174))	('thyroid cancer', 'Phenotype', 'HP:0002890', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('mutations', 'Var', (44, 53))	('follicular thyroid cancer', 'Disease', (99, 124))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (99, 124))	('aplastic thyroid cancer', 'Disease', 'MESH:D013964', (71, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (99, 124))	('aplastic thyroid cancer', 'Disease', (71, 94))	('papillary carcinoma of the thyroid', 'Disease', (140, 174))	('PIK3CA', 'Gene', (37, 43))	('prevalent', 'Reg', (58, 67))
918955	31905960	In an initial study, PIK3CA mutations were identified in the highest proportion in the anaplastic thyroid carcinomas (16%), followed by follicular thyroid carcinomas (8%), and papillary thyroid carcinomas (2%).	('anaplastic thyroid carcinomas', 'Phenotype', 'HP:0011779', (87, 116))	('PIK3CA', 'Gene', (21, 27))	('follicular thyroid carcinomas', 'Disease', 'MESH:C572845', (136, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (186, 204))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (147, 164))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (98, 116))	('papillary thyroid carcinomas', 'Disease', 'MESH:C536915', (176, 204))	('follicular thyroid carcinomas', 'Phenotype', 'HP:0006731', (136, 165))	('papillary thyroid carcinomas', 'Disease', (176, 204))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (176, 204))	('follicular thyroid carcinomas', 'Disease', (136, 165))	('thyroid carcinomas', 'Disease', (98, 116))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (186, 203))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (147, 165))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (98, 115))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (186, 204))	('mutations', 'Var', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (98, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (176, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (147, 165))
918956	31905960	Subsequent studies have shown varying prevalence of mutation in different subtypes of thyroid cancer, but PIK3CA mutations were the most commonly found in anaplastic cancers and the least observed in papillary.	('thyroid cancer', 'Phenotype', 'HP:0002890', (86, 100))	('cancers', 'Disease', (166, 173))	('thyroid cancer', 'Disease', (86, 100))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('PIK3CA', 'Gene', (106, 112))	('thyroid cancer', 'Disease', 'MESH:D013964', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (113, 122))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('found', 'Reg', (146, 151))
918957	31905960	reported the frequency of PIK3CA mutations to be 13% in follicular thyroid carcinomas and 1% in papillary thyroid carcinomas.	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (67, 85))	('follicular thyroid carcinomas', 'Disease', 'MESH:C572845', (56, 85))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (106, 124))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (96, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (67, 84))	('mutations', 'Var', (33, 42))	('follicular thyroid carcinomas', 'Phenotype', 'HP:0006731', (56, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('papillary thyroid carcinomas', 'Disease', 'MESH:C536915', (96, 124))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (106, 123))	('follicular thyroid carcinomas', 'Disease', (56, 85))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (96, 124))	('papillary thyroid carcinomas', 'Disease', (96, 124))	('PIK3CA', 'Gene', (26, 32))
918958	31905960	reported a 2% frequency of PIK3CA mutations in papillary thyroid carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('papillary thyroid carcinoma', 'Disease', 'MESH:C536915', (47, 74))	('papillary thyroid carcinoma', 'Disease', (47, 74))	('PIK3CA', 'Gene', (27, 33))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (57, 74))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (47, 74))	('mutations', 'Var', (34, 43))
918959	31905960	reported a 14% frequency of PIK3CA mutations in anaplastic thyroid cancer.	('PIK3CA', 'Gene', (28, 34))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (48, 73))	('thyroid cancer', 'Phenotype', 'HP:0002890', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('aplastic thyroid cancer', 'Disease', 'MESH:D013964', (50, 73))	('aplastic thyroid cancer', 'Disease', (50, 73))	('mutations', 'Var', (35, 44))
918960	31905960	This distribution of PIK3CA mutations among thyroid cancer subtypes may raise the valid possibility of it playing a role towards more aggressive cancer development, mirroring the different natural history of anaplastic (most aggressive) vs. papillary thyroid cancer (least aggressive).	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('PIK3CA', 'Gene', (21, 27))	('playing', 'Reg', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('anaplastic', 'Disease', (208, 218))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (241, 265))	('thyroid cancer', 'Disease', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('thyroid cancer', 'Disease', 'MESH:D013964', (251, 265))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('thyroid cancer', 'Phenotype', 'HP:0002890', (251, 265))	('cancer', 'Disease', (259, 265))	('thyroid cancer', 'Disease', 'MESH:D013964', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('thyroid cancer', 'Phenotype', 'HP:0002890', (44, 58))	('cancer', 'Disease', (52, 58))	('mutations', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('papillary thyroid cancer', 'Disease', (241, 265))	('papillary thyroid cancer', 'Disease', 'MESH:C536915', (241, 265))
918964	31905960	reported a protective effect of SNP rs17849071 of PIK3CA gene in follicular thyroid cancer.	('thyroid cancer', 'Phenotype', 'HP:0002890', (76, 90))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (65, 90))	('rs17849071', 'DBSNP_MENTION', 'None', (36, 46))	('rs17849071', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('follicular thyroid cancer', 'Disease', (65, 90))	('PIK3CA', 'Gene', (50, 56))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (65, 90))
918965	31905960	BRAF and PIK3CA mutations cooperatively promoted anaplastic thyroid cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('aplastic thyroid cancer', 'Disease', 'MESH:D013964', (51, 74))	('promoted', 'PosReg', (40, 48))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (49, 74))	('aplastic thyroid cancer', 'Disease', (51, 74))	('mutations', 'Var', (16, 25))	('BRAF', 'Gene', '673', (0, 4))	('thyroid cancer', 'Phenotype', 'HP:0002890', (60, 74))	('PIK3CA', 'Gene', (9, 15))	('BRAF', 'Gene', (0, 4))
918966	31905960	Additionally, in cooperation with KRAS mutations, PIK3CA mutations were reported to be associated with metastasis in thyroid cancer.	('KRAS', 'Gene', '3845', (34, 38))	('thyroid cancer', 'Phenotype', 'HP:0002890', (117, 131))	('thyroid cancer', 'Disease', 'MESH:D013964', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (57, 66))	('associated with', 'Reg', (87, 102))	('PIK3CA', 'Gene', (50, 56))	('KRAS', 'Gene', (34, 38))	('thyroid cancer', 'Disease', (117, 131))	('metastasis', 'CPA', (103, 113))
918967	31905960	Studies conducted to elucidate the role of PIK3CA mutations in the clinicopathological parameters and prognosis point that these mutations have minimal association with the prognosis of thyroid cancers.	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('mutations', 'Var', (50, 59))	('thyroid cancer', 'Phenotype', 'HP:0002890', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('thyroid cancers', 'Disease', (186, 201))	('minimal', 'NegReg', (144, 151))	('thyroid cancers', 'Disease', 'MESH:D013964', (186, 201))	('PIK3CA', 'Gene', (43, 49))
918968	31905960	However, the presence of PIK3CA mutation, along with other activating mutations, resulted in increased rates of mortality and aggressive metastasis.	('aggressive metastasis', 'Disease', (126, 147))	('increased', 'PosReg', (93, 102))	('PIK3CA', 'Gene', (25, 31))	('mortality', 'CPA', (112, 121))	('presence', 'Var', (13, 21))	('mutation', 'Var', (32, 40))	('aggressive metastasis', 'Disease', 'MESH:D009362', (126, 147))
918969	31905960	PIK3CA gene mutations are frequently observed in head and neck carcinoma.	('mutations', 'Var', (12, 21))	('observed', 'Reg', (37, 45))	('PIK3CA', 'Gene', (0, 6))	('neck carcinoma', 'Disease', (58, 72))	('neck carcinoma', 'Disease', 'MESH:D006258', (58, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
918970	31905960	An initial study reported PIK3CA mutational frequency of 11% in squamous cell carcinoma in pharyngeal cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('mutational', 'Var', (33, 43))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (91, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 87))	('PIK3CA', 'Gene', (26, 32))	('squamous cell carcinoma', 'Disease', (64, 87))
918971	31905960	The same group further reported a higher frequency (21%) of PIK3CA mutation in tumors of mixed origin.	('mutation', 'Var', (67, 75))	('PIK3CA', 'Gene', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
918974	31905960	HNSCC patients were reported to harbor PIK3CA mutations at even higher frequency, with a mutational frequency of 31%.	('patients', 'Species', '9606', (6, 14))	('PIK3CA', 'Gene', (39, 45))	('mutations', 'Var', (46, 55))
918975	31905960	In salivary duct carcinoma (SDC), the mutation frequency of PIK3CA was shown to be 28%.	('SDC', 'Disease', 'MESH:D012465', (28, 31))	('PIK3CA', 'Gene', (60, 66))	('salivary duct carcinoma', 'Disease', 'MESH:D012465', (3, 26))	('mutation', 'Var', (38, 46))	('SDC', 'Disease', (28, 31))	('salivary duct carcinoma', 'Disease', (3, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
918976	31905960	Novel mutations in PIK3CA were recently reported as candidate driver events in human papillomavirus (HPV)-positive OSCCs.	('PIK3CA', 'Gene', (19, 25))	('human papillomavirus', 'Disease', (79, 99))	('papilloma', 'Phenotype', 'HP:0012740', (85, 94))	('human papillomavirus', 'Species', '10566', (79, 99))	('HPV', 'Species', '10566', (101, 104))	('mutations', 'Var', (6, 15))
918979	31905960	While one study revealed no association between PIK3CA and responsiveness to PI3K-targeted drugs, another group reported PIK3CA mutations to be associated with potential benefit from matched targeted therapy in parathyroid carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('mutations', 'Var', (128, 137))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (215, 232))	('parathyroid carcinoma', 'Disease', 'MESH:D010282', (211, 232))	('PIK3CA', 'Gene', (121, 127))	('benefit', 'PosReg', (170, 177))	('parathyroid carcinoma', 'Disease', (211, 232))	('parathyroid carcinoma', 'Phenotype', 'HP:0006780', (211, 232))
918980	31905960	In a recent study evaluating the effect of nonsteroidal anti-inflammatory drugs (NSAID) on survival in head and neck cancer, patients with PIK3CA mutations or amplification showed prolonged disease-specific survival and overall survival with NSAID use as compared with non-NSAID users.	('amplification', 'Var', (159, 172))	('mutations', 'Var', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('head and neck cancer', 'Phenotype', 'HP:0012288', (103, 123))	('PIK3CA', 'Gene', (139, 145))	('prolonged', 'PosReg', (180, 189))	('disease-specific survival', 'CPA', (190, 215))	('head and neck cancer', 'Disease', 'MESH:D006258', (103, 123))	('overall survival', 'CPA', (220, 236))	('patients', 'Species', '9606', (125, 133))
918981	31905960	Mutations in PIK3CA gene were associated with improved outcomes among metastatic HPV-positive oropharyngeal cancer, with similar results reported in HPV-negative oropharyngeal cancer.	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (97, 114))	('PIK3CA', 'Gene', (13, 19))	('HPV', 'Species', '10566', (149, 152))	('HPV-positive', 'Disease', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('improved', 'PosReg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Mutations', 'Var', (0, 9))	('outcomes', 'MPA', (55, 63))	('HPV', 'Species', '10566', (81, 84))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (165, 182))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
918983	31905960	Initial reports of PIK3CA gene mutations in esophageal cancers demonstrated that these mutations were present in 12% of squamous cell carcinomas and 6% of adenocarcinomas of the esophagus.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (120, 144))	('PIK3CA', 'Gene', (19, 25))	('esophageal cancers', 'Disease', (44, 62))	('mutations', 'Var', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('squamous cell carcinomas', 'Disease', (120, 144))	('esophageal cancers', 'Disease', 'MESH:D004938', (44, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (120, 144))	('adenocarcinomas of the esophagus', 'Disease', (155, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('adenocarcinomas of the esophagus', 'Disease', 'MESH:C562730', (155, 187))	('present', 'Reg', (102, 109))
918984	31905960	showed no involvement of PIK3CA mutations in esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('PIK3CA', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (45, 79))	('esophageal squamous cell carcinoma', 'Disease', (45, 79))
918985	31905960	Recently, PIK3CA mutations were identified in 21.7% of chagasic megaesophagus associated with esophageal squamous cell carcinoma cases.	('associated', 'Reg', (78, 88))	('PIK3CA', 'Gene', (10, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('mutations', 'Var', (17, 26))	('identified', 'Reg', (32, 42))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (94, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))	('chagasic megaesophagus', 'Disease', (55, 77))
918988	31905960	A meta-analysis showed that PIK3CA mutation has no significant effects on overall survival and disease-free survival in esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('PIK3CA', 'Gene', (28, 34))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (120, 154))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('mutation', 'Var', (35, 43))
918989	31905960	However, patients with PIK3CA gene mutations in exon 9 have better disease-free survival and overall survival rates.	('better', 'PosReg', (60, 66))	('patients', 'Species', '9606', (9, 17))	('PIK3CA gene', 'Gene', (23, 34))	('overall survival rates', 'CPA', (93, 115))	('mutations in', 'Var', (35, 47))	('disease-free survival', 'CPA', (67, 88))
918990	31905960	showed that PIK3CA gene mutations are independent favorable prognostic marker in esophageal cancer patients in terms of survival.	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (24, 33))	('esophageal cancer', 'Disease', (81, 98))	('PIK3CA', 'Gene', (12, 18))
918991	31905960	The PI3K/AKT/mTOR pathway is altered in approximately 20% cases, by mutations in PIK3CA gene.	('PIK3CA', 'Gene', (81, 87))	('mTOR', 'Gene', (13, 17))	('altered', 'Reg', (29, 36))	('mTOR', 'Gene', '2475', (13, 17))	('mutations', 'Var', (68, 77))
918992	31905960	Next generation sequencing revealed the presence of PIK3CA gene mutations in RCC but not in the clear cell subtype (cc-RCC), which is the major and most deadly RCC.	('RCC', 'Disease', 'MESH:D002292', (160, 163))	('RCC', 'Disease', (160, 163))	('PIK3CA', 'Gene', (52, 58))	('RCC', 'Disease', (77, 80))	('RCC', 'Disease', 'MESH:D002292', (77, 80))	('RCC', 'Disease', 'MESH:D002292', (119, 122))	('RCC', 'Disease', (119, 122))	('mutations', 'Var', (64, 73))
918994	31905960	PIK3CA mutations have also been reported in nephroblastomatosis or Wilms tumor.	('Wilms tumor', 'Disease', (67, 78))	('Wilms tumor', 'Disease', 'MESH:D009396', (67, 78))	('nephroblastomatosis', 'Disease', (44, 63))	('Wilms tumor', 'Phenotype', 'HP:0002667', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PIK3CA', 'Gene', (0, 6))	('nephroblastomatosis', 'Disease', 'MESH:C536399', (44, 63))	('reported', 'Reg', (32, 40))	('nephroblastomatosis', 'Phenotype', 'HP:0008643', (44, 63))	('mutations', 'Var', (7, 16))
918995	31905960	PIK3CA mutations have been reported in urothelial papilloma cases.	('reported', 'Reg', (27, 35))	('papilloma', 'Phenotype', 'HP:0012740', (50, 59))	('urothelial papilloma', 'Disease', (39, 59))	('PIK3CA', 'Gene', (0, 6))	('urothelial papilloma', 'Disease', 'MESH:D010212', (39, 59))	('mutations', 'Var', (7, 16))
918996	31905960	PIK3CA gene amplification has been observed in recurrent ovarian cancer and yolk sac tumors.	('ovarian cancer', 'Disease', 'MESH:D010051', (57, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('ovarian cancer', 'Disease', (57, 71))	('amplification', 'Var', (12, 25))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PIK3CA', 'Gene', (0, 6))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (47, 71))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('observed', 'Reg', (35, 43))	('yolk sac tumors', 'Disease', (76, 91))	('yolk sac tumors', 'Disease', 'MESH:D018240', (76, 91))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
918997	31905960	In addition, PIK3CA mutation was identified in 38% endometrial cancer samples.	('PIK3CA', 'Gene', (13, 19))	('endometrial cancer', 'Disease', (51, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutation', 'Var', (20, 28))	('endometrial cancer', 'Phenotype', 'HP:0012114', (51, 69))	('identified', 'Reg', (33, 43))	('endometrial cancer', 'Disease', 'MESH:D016889', (51, 69))
918998	31905960	Amplification of PIK3CA has been associated with pathogenesis of cervical cancer.	('Amplification', 'Var', (0, 13))	('PIK3CA', 'Gene', (17, 23))	('associated', 'Reg', (33, 43))	('cervical cancer', 'Disease', (65, 80))	('cervical cancer', 'Disease', 'MESH:D002583', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
918999	31905960	reported PIK3CA mutations in 14% invasive cervical carcinomas, while Cui et al.	('invasive cervical carcinomas', 'Disease', (33, 61))	('invasive cervical carcinomas', 'Disease', 'MESH:D002583', (33, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (9, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
919000	31905960	reported these mutations in 8.15% of invasive cervical carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('invasive cervical carcinomas', 'Disease', (37, 65))	('invasive cervical carcinomas', 'Disease', 'MESH:D002583', (37, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mutations', 'Var', (15, 24))
919001	31905960	PIK3CA gene mutation has also been identified in small cell carcinoma of cervix.	('small cell carcinoma', 'Disease', (49, 69))	('small cell carcinoma', 'Disease', 'MESH:D018288', (49, 69))	('identified', 'Reg', (35, 45))	('carcinoma of cervix', 'Phenotype', 'HP:0030079', (60, 79))	('PIK3CA', 'Gene', (0, 6))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (49, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('mutation', 'Var', (12, 20))
919002	31905960	A recent study in cervical cancer showed that PIK3CA mutation status did not have any significant association with clinicopathological characteristics but highlighted an association with poor overall survival.	('poor', 'NegReg', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutation status', 'Var', (53, 68))	('overall survival', 'MPA', (192, 208))	('cervical cancer', 'Disease', (18, 33))	('cervical cancer', 'Disease', 'MESH:D002583', (18, 33))	('PIK3CA', 'Gene', (46, 52))
919004	31905960	PIK3CA mutations were observed in 10% of bladder cancer patients and are associated with cisplatin resistance and a migratory phenotype in cervical cancer cells.	('patients', 'Species', '9606', (56, 64))	('cervical cancer', 'Disease', 'MESH:D002583', (139, 154))	('cisplatin resistance', 'MPA', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cervical cancer', 'Disease', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('migratory', 'CPA', (116, 125))	('PIK3CA', 'Gene', (0, 6))	('associated', 'Reg', (73, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (41, 55))	('bladder cancer', 'Disease', (41, 55))	('mutations', 'Var', (7, 16))
919007	31905960	Hyperactivation of PI3K signaling is a hallmark of cancer, and activating mutations in this pathway are common in solid malignancies.	('solid malignancies', 'Disease', (114, 132))	('activating', 'PosReg', (63, 73))	('Hyperactivation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('hallmark of cancer', 'Disease', (39, 57))	('PI3K signaling', 'Pathway', (19, 33))	('hallmark of cancer', 'Disease', 'MESH:D009369', (39, 57))	('solid malignancies', 'Disease', 'MESH:D018250', (114, 132))
919008	31905960	Preclinical tests have demonstrated that cancer cell lines derived from solid cancers became sensitive to hormone therapy, chemotherapy, or other targeted therapies when they are treated with PI3K or mTOR inhibitors.	('PI3K', 'Var', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mTOR', 'Gene', (200, 204))	('mTOR', 'Gene', '2475', (200, 204))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('sensitive', 'Reg', (93, 102))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
919009	31905960	The PI3K/AKT/mTOR pathway inhibitors were found to be effective in improving progression-free survival in patients with PI3K pathway mutations.	('PI3K', 'Gene', (120, 124))	('improving', 'PosReg', (67, 76))	('mutations', 'Var', (133, 142))	('mTOR', 'Gene', (13, 17))	('patients', 'Species', '9606', (106, 114))	('mTOR', 'Gene', '2475', (13, 17))	('progression-free survival', 'CPA', (77, 102))
919014	31905960	Although PI3K mutations were thought to be associated with oncogenesis, it was only in the year 2004, its contributory role in cancer has been established unequivocally.	('PI3K mutations', 'Var', (9, 23))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (127, 133))
919017	31905960	Literature search reveals that a number of studies have established the role of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations in oncogenesis.	('oncogenesis', 'CPA', (174, 185))	('PIK3CA', 'Gene', (153, 159))	('mutations', 'Var', (161, 170))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (80, 117))
919018	31905960	The Cancer Genome Atlas has concluded mutations of PIK3CA as one of the most common genetic events associated with at least 12 different types of solid cancers.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('PIK3CA', 'Gene', (51, 57))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('mutations', 'Var', (38, 47))	('associated', 'Reg', (99, 109))
919019	31905960	Commonly-identified cancers of solid tumors associated with PI3K3CA are breast cancer (>30% of total cases), bladder cancer (>20% of total cases), colorectal cancer (>17% of total cancer), and squamous cell cancer of head neck region (>15% of total cases).	('PI3K3CA', 'Var', (60, 67))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('solid tumors', 'Disease', 'MESH:D009369', (31, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('cancer', 'Disease', (207, 213))	('squamous cell cancer of head neck', 'Disease', (193, 226))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('squamous cell cancer of head neck', 'Disease', 'MESH:C535575', (193, 226))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('bladder cancer', 'Disease', (109, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('cancer', 'Disease', (20, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('colorectal cancer', 'Disease', (147, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('solid tumors', 'Disease', (31, 43))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (193, 213))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancers', 'Disease', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
919021	31905960	From January 2013 to December 2014, 19,784 tumor samples (of more than 40 different types of cancer) sent by thousands of doctors across 60 countries were tested at a single commercial laboratory for molecular profiling to identify genetic and proteomic aberrations in the PI3K pathway.	('aberrations', 'Var', (254, 265))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PI3K pathway', 'Pathway', (273, 285))	('tumor', 'Disease', (43, 48))
919022	31905960	They found around 38% of the patients had one or more mutations in the PI3K pathway proteins; the most common aberration (30%) was loss of PTEN (phosphatase and tensin homologue) followed by mutations in PIK3CA (13%).	('patients', 'Species', '9606', (29, 37))	('phosphatase and tensin homologue', 'Gene', '5728', (145, 177))	('mutations', 'Var', (54, 63))	('loss', 'NegReg', (131, 135))	('PI3K pathway proteins', 'Pathway', (71, 92))	('PTEN', 'Gene', (139, 143))	('mutations', 'Var', (191, 200))	('PTEN', 'Gene', '5728', (139, 143))	('PIK3CA', 'Gene', (204, 210))
919023	31905960	PIK3CA mutation was associated most commonly with endometrial (37%), breast (31%), cervical (29%), and anal cancers (27%).	('associated', 'Reg', (20, 30))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cervical', 'Disease', (83, 91))	('endometrial', 'Disease', (50, 61))	('breast', 'Disease', (69, 75))	('PIK3CA', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutation', 'Var', (7, 15))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))
919027	31905960	Most commonly associated cancer varieties with PIK3CA mutation were endometrial cancer (uterine corpus) (52%) and breast carcinoma (33.6%).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('mutation', 'Var', (54, 62))	('PIK3CA', 'Gene', (47, 53))	('breast carcinoma', 'Phenotype', 'HP:0003002', (114, 130))	('endometrial cancer', 'Phenotype', 'HP:0012114', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('endometrial cancer', 'Disease', 'MESH:D016889', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('breast carcinoma', 'Disease', 'MESH:D001943', (114, 130))	('breast carcinoma', 'Disease', (114, 130))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (25, 31))	('endometrial cancer', 'Disease', (68, 86))	('cancer', 'Disease', (80, 86))
919028	31905960	Discovery of PIK3CA mutations in majority of cancers has led to new targets for treatment of those cancers.	('PIK3CA', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (20, 29))
919030	31905960	All these studies indicate that PI3K pathway inhibitors in solid malignancies improved progression-free survival in cancer types with PI3K mutations.	('solid malignancies', 'Disease', (59, 77))	('mutations', 'Var', (139, 148))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('progression-free survival', 'CPA', (87, 112))	('PI3K', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('solid malignancies', 'Disease', 'MESH:D018250', (59, 77))	('improved', 'PosReg', (78, 86))
919032	31905960	PIK3CA gene mutations are clinically important in most solid malignancies.	('mutations', 'Var', (12, 21))	('solid malignancies', 'Disease', (55, 73))	('PIK3CA', 'Gene', (0, 6))	('important', 'Reg', (37, 46))	('solid malignancies', 'Disease', 'MESH:D018250', (55, 73))
919033	31905960	In addition, these mutations have implications in the effectiveness of the treatment and prognosis of cancers.	('implications', 'Reg', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (19, 28))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
919034	31905960	However, contradictory reports exist in the literature regarding the effect of PIK3CA gene mutations on the prognosis of different cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('PIK3CA', 'Gene', (79, 85))	('mutations', 'Var', (91, 100))
919036	31905960	However, larger prospective studies should be conducted to further elucidate the role of PIK3CA mutations in solid malignancies.	('PIK3CA', 'Gene', (89, 95))	('solid malignancies', 'Disease', 'MESH:D018250', (109, 127))	('solid malignancies', 'Disease', (109, 127))	('mutations', 'Var', (96, 105))
919171	28726780	In addition, FOXQ1 overexpressed in human esophageal cancer cells and ablation of FOXQ1 restrained the tumourigenic ability of the esophageal cancer cells (EC109 and EC9706) in a mouse xenograft model in vivo.	('mouse', 'Species', '10090', (179, 184))	('esophageal cancer', 'Disease', (42, 59))	('tumourigenic ability', 'CPA', (103, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('restrained', 'NegReg', (88, 98))	('FOXQ1', 'Gene', (82, 87))	('esophageal cancer', 'Disease', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('EC1', 'Gene', '4819', (156, 159))	('EC1', 'Gene', (156, 159))	('FOXQ1', 'Gene', (13, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (131, 148))	('EC9706', 'CellLine', 'CVCL:E307', (166, 172))	('human', 'Species', '9606', (36, 41))	('ablation', 'Var', (70, 78))
919174	28726780	Two pathways, p53/p21 and p16INK4a/Rb (retinoblastoma), can orchestrate the development of senescence in response to DNA damage, oxidative stress and oncogene activation.	('oxidative stress', 'Phenotype', 'HP:0025464', (129, 145))	('p21', 'Gene', (18, 21))	('p53', 'Gene', (14, 17))	('p16INK4a/Rb', 'Var', (26, 37))	('p53', 'Gene', '7157', (14, 17))	('retinoblastoma', 'Disease', 'MESH:D012175', (39, 53))	('retinoblastoma', 'Disease', (39, 53))	('p21', 'Gene', '644914', (18, 21))	('retinoblastoma', 'Phenotype', 'HP:0009919', (39, 53))
919189	28726780	It has been reported that miR-320 can suppress colorectal cancer by targeting FOXQ1.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('miR-320', 'Var', (26, 33))	('FOXQ1', 'Gene', (78, 83))	('targeting', 'Reg', (68, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('miR-320', 'Chemical', '-', (26, 33))	('suppress', 'NegReg', (38, 46))
919199	28726780	In order to clarify whether the expression profiles of FOXQ1 and p16INK4a with aging could be recapitulated in vivo, we examined their protein level in several tissues from young (3 months) and old (18 months) adult BALB/c mice.	('mice', 'Species', '10090', (223, 227))	('examined', 'Reg', (120, 128))	('FOXQ1', 'Gene', (55, 60))	('p16INK4a', 'Var', (65, 73))
919200	28726780	Growth curve and crystal violet staining assays indicated that the 2BS cells with ectopic FOXQ1 expression displayed higher proliferation rate (Figure 2a) and more colony formation (Figure 2b) than those in the cells with empty vector.	('FOXQ1', 'Gene', (90, 95))	('ectopic', 'Var', (82, 89))	('proliferation rate', 'CPA', (124, 142))	('higher', 'PosReg', (117, 123))	('crystal violet', 'Chemical', 'MESH:D005840', (17, 31))	('colony formation', 'CPA', (164, 180))	('more', 'PosReg', (159, 163))
919201	28726780	Meanwhile, miR30-FOXQ1 also resulted in emerging the morphological features of senescence, characterized by enlarged and flattened cell size, increased senescence-associated heterochromatin foci (Figure 2c), elevated activity of senescence-associated beta-galactosidase (SA-beta-gal), a biomarker for senescent cells (Figures 2d and e), and reduced S and increased G1 compartments (Figure 2f) compared with scramble control vector.	('G1 compartments', 'MPA', (365, 380))	('elevated', 'PosReg', (208, 216))	('increased', 'PosReg', (142, 151))	('activity', 'MPA', (217, 225))	('senescence', 'Disease', (79, 89))	('increased', 'PosReg', (355, 364))	('miR30-FOXQ1', 'Var', (11, 22))	('SA', 'Chemical', 'MESH:C012546', (271, 273))	('reduced', 'NegReg', (341, 348))	('beta-gal', 'Chemical', '-', (251, 259))	('enlarged', 'PosReg', (108, 116))	('senescence-associated', 'CPA', (152, 173))	('beta-gal', 'Chemical', '-', (274, 282))
919202	28726780	Conversely, LPC-FOXQ1 induced much lower SA-beta-gal activity (Figures 2d and e) and less cell cycle progression (Figure 2f) than the infection with its corresponding empty control vector.	('infection', 'Disease', 'MESH:D007239', (134, 143))	('cell cycle progression', 'CPA', (90, 112))	('SA', 'Chemical', 'MESH:C012546', (41, 43))	('less', 'NegReg', (85, 89))	('lower', 'NegReg', (35, 40))	('SA-beta-gal activity', 'MPA', (41, 61))	('LPC-FOXQ1', 'Var', (12, 21))	('beta-gal', 'Chemical', '-', (44, 52))	('infection', 'Disease', (134, 143))
919209	28726780	We found that the protein level of IkappaBalpha, an inhibitor of NF-kappaB, positively correlated with FOXQ1 and SIRT1, while the level of p65RelA displayed an opposite tendency with FOXQ1 and SIRT1 (Figure 3a).	('FOXQ1', 'Var', (103, 108))	('p65', 'Gene', (139, 142))	('IkappaBalpha', 'Gene', (35, 47))	('correlated', 'Reg', (87, 97))	('SIRT1', 'Gene', '23411', (113, 118))	('protein level', 'MPA', (18, 31))	('SIRT1', 'Gene', (193, 198))	('p65', 'Gene', '5970', (139, 142))	('NF-kappaB', 'Gene', '4790', (65, 74))	('SIRT1', 'Gene', (113, 118))	('NF-kappaB', 'Gene', (65, 74))	('IkappaBalpha', 'Gene', '4792', (35, 47))	('SIRT1', 'Gene', '23411', (193, 198))
919216	28726780	LPC-FOXQ1 markedly decreased the mRNA abundance of IL-6 and IL-8 compared with control transfection (Figure 4a).	('mRNA abundance', 'MPA', (33, 47))	('IL-8', 'Gene', (60, 64))	('IL-6', 'Gene', (51, 55))	('IL-6', 'Gene', '3569', (51, 55))	('decreased', 'NegReg', (19, 28))	('LPC-FOXQ1', 'Var', (0, 9))	('IL-8', 'Gene', '3576', (60, 64))
919217	28726780	In contrast, FOXQ1 deletion significantly elevated IL-6 and IL-8 mRNA levels (Figure 4b).	('deletion', 'Var', (19, 27))	('IL-8', 'Gene', (60, 64))	('elevated IL-6', 'Phenotype', 'HP:0030783', (42, 55))	('IL-6', 'Gene', (51, 55))	('IL-6', 'Gene', '3569', (51, 55))	('FOXQ1', 'Gene', (13, 18))	('elevated', 'PosReg', (42, 50))	('IL-8', 'Gene', '3576', (60, 64))
919226	28726780	In addition, real-time PCR results demonstrated that FOXQ1 overexpression led to the decrease of IL-6 and IL-8 expression levels, which was eliminated by inhibition of SIRT1 activity with EX-527 (Figure 4f).	('FOXQ1', 'Gene', (53, 58))	('overexpression', 'Var', (59, 73))	('IL-6', 'Gene', '3569', (97, 101))	('EX-527', 'Chemical', 'MESH:C550547', (188, 194))	('SIRT1', 'Gene', '23411', (168, 173))	('IL-8', 'Gene', '3576', (106, 110))	('IL-8', 'Gene', (106, 110))	('decrease', 'NegReg', (85, 93))	('SIRT1', 'Gene', (168, 173))	('IL-6', 'Gene', (97, 101))
919234	28726780	Next, we silenced FOXQ1 by using lentivirus in EC109 and EC9706 cells.	('EC1', 'Gene', (47, 50))	('EC1', 'Gene', '4819', (47, 50))	('silenced', 'Var', (9, 17))	('FOXQ1', 'Gene', (18, 23))	('EC9706', 'CellLine', 'CVCL:E307', (57, 63))
919235	28726780	The MTT assay demonstrated that silence of FOXQ1 caused cell growth retardation compared with its corresponding empty vector control (Figure 5b).	('growth retardation', 'Disease', 'MESH:D006130', (61, 79))	('growth retardation', 'Disease', (61, 79))	('FOXQ1', 'Gene', (43, 48))	('silence', 'Var', (32, 39))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('growth retardation', 'Phenotype', 'HP:0001510', (61, 79))
919238	28726780	To this end, stable EC109 and EC9706 cells transduced with either FOXQ1 silencing or control lentiviral vector were subcutaneously injected into the flank of NOD/SCID mice, and tumor growth was monitored over a period of 30 days.	('EC9706', 'CellLine', 'CVCL:E307', (30, 36))	('silencing', 'Var', (72, 81))	('EC1', 'Gene', '4819', (20, 23))	('EC1', 'Gene', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('NOD', 'Gene', '1822', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('SCID', 'Disease', 'MESH:D053632', (162, 166))	('FOXQ1', 'Gene', (66, 71))	('SCID', 'Disease', (162, 166))	('tumor', 'Disease', (177, 182))	('mice', 'Species', '10090', (167, 171))	('NOD', 'Gene', (158, 161))
919239	28726780	The mean tumor volume and weight of the FOXQ1 silencing vector-expressing EC109 and EC9706 xenografts grew at a slower rate than those derived from the xenografts expressing control vector (Figures 6a-c).	('slower', 'NegReg', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('EC9706', 'Var', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('FOXQ1', 'Gene', (40, 45))	('tumor', 'Disease', (9, 14))	('EC9706', 'CellLine', 'CVCL:E307', (84, 90))	('EC1', 'Gene', (74, 77))	('EC1', 'Gene', '4819', (74, 77))
919251	28726780	Conversely, FOXQ1 silencing could stimulate the production of these SASP factors and might thus contribute to the premature senescence.	('silencing', 'Var', (18, 27))	('FOXQ1', 'Gene', (12, 17))	('production', 'MPA', (48, 58))	('stimulate', 'PosReg', (34, 43))	('SASP', 'Gene', (68, 72))	('premature senescence', 'CPA', (114, 134))	('contribute', 'Reg', (96, 106))	('SASP', 'Gene', '7295', (68, 72))
919254	28726780	Compared with the corresponding tumor cells transduced with empty control vector, the growth of human esophageal cancer cells was retarded in the FOXQ1 silencing vector-expressing EC109 and EC9706 cells both in vitro and in vivo.	('silencing', 'NegReg', (152, 161))	('growth of human', 'CPA', (86, 101))	('FOXQ1', 'Gene', (146, 151))	('retarded', 'Disease', (130, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('EC9706', 'Var', (190, 196))	('human', 'Species', '9606', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('retarded', 'Disease', 'MESH:D008607', (130, 138))	('EC1', 'Gene', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('EC9706', 'CellLine', 'CVCL:E307', (190, 196))	('EC1', 'Gene', '4819', (180, 183))	('esophageal cancer', 'Disease', (102, 119))	('tumor', 'Disease', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
919258	28726780	Given that Foxq1 mutant mice are available, it can be helpful to use this animal model to investigate tissue and organ senescence in our future work.	('Foxq1', 'Gene', (11, 16))	('mutant', 'Var', (17, 23))	('mice', 'Species', '10090', (24, 28))
919268	28726780	The primary antibodies used for western blot analysis were as follows: anti-FOXQ1, anti-SIRT1, anti-p16 and anti-beta-actin were from Santa Cruz Biotechnology (Santa Cruz, CA, USA).	('SIRT1', 'Gene', '23411', (88, 93))	('SIRT1', 'Gene', (88, 93))	('anti-FOXQ1', 'Var', (71, 81))	('beta-actin', 'Gene', '728378', (113, 123))	('beta-actin', 'Gene', (113, 123))	('p16', 'Gene', (100, 103))	('SA', 'Chemical', 'MESH:C012546', (177, 179))	('p16', 'Gene', '1029', (100, 103))
919277	28726780	Besides, HET-1A, EC1, EC109, EC9706, TE1 and TE13 cells were maintained in RPMI-1640 medium supplemented with 10% FBS.	('EC1', 'Gene', (17, 20))	('EC1', 'Gene', '4819', (17, 20))	('FBS', 'Disease', (114, 117))	('EC9706', 'Var', (29, 35))	('RPMI-1640 medium', 'Chemical', '-', (75, 91))	('FBS', 'Disease', 'MESH:D005198', (114, 117))	('EC1', 'Gene', (22, 25))	('EC9706', 'CellLine', 'CVCL:E307', (29, 35))	('EC1', 'Gene', '4819', (22, 25))
919292	28726780	Thereafter, the cells were treated with 1 mg/ml RNase A (R6513, Sigma) at 37  C for 30 min, resuspended in 0.5 ml of PBS and stained with propidium iodide in the dark for 30 min.	('propidium iodide', 'Chemical', 'MESH:D011419', (138, 154))	('RNase A', 'Gene', (48, 55))	('R6513', 'Var', (57, 62))	('RNase A', 'Gene', '6035', (48, 55))
919368	25406082	The overall analysis of all gastrointestinal cancers showed that circulating miRNAs have a relatively good diagnostic performance in gastrointestinal cancers, with a sensitivity of 0.75, a specificity of 0.81 and an AUC of 0.85.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (28, 51))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (133, 157))	('gastrointestinal cancers', 'Disease', (133, 157))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (133, 156))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('gastrointestinal cancers', 'Disease', (28, 52))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (28, 52))	('circulating miRNAs', 'Var', (65, 83))
919432	25406082	The molecular basis for the limitation of single miRNA as a tumor biomarker is that aberrant levels of single miRNA might be associated with several different types of cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('associated', 'Reg', (125, 135))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('tumor', 'Disease', (60, 65))	('aberrant', 'Var', (84, 92))
919440	25363593	Silencing of insulin-like growth factor-1 receptor enhances the radiation sensitivity of human esophageal squamous cell carcinoma in vitro and in vivo Esophageal squamous cell carcinoma (ESCC) is a prevalent fatal cancer worldwide, and the number of deaths due to this disease is increasing.	('human', 'Species', '9606', (89, 94))	('esophageal squamous cell carcinoma', 'Disease', (95, 129))	('cancer', 'Disease', (214, 220))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (151, 185))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (13, 50))	('radiation sensitivity', 'CPA', (64, 85))	('Esophageal squamous cell carcinoma', 'Disease', (151, 185))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (95, 129))	('enhances', 'PosReg', (51, 59))	('Silencing', 'Var', (0, 9))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('insulin-like growth factor-1 receptor', 'Gene', (13, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
919445	25363593	In addition, the Eca-109 and TE-1 cells that were irradiated following IGF-1r knockdown contained 16.2% and 20.3% apoptotic cells, respectively.	('Eca', 'Chemical', '-', (17, 20))	('IGF-1r', 'Gene', '3480', (71, 77))	('knockdown', 'Var', (78, 87))	('apoptotic cells', 'CPA', (114, 129))	('IGF-1r', 'Gene', (71, 77))	('TE-1', 'CellLine', 'CVCL:1759', (29, 33))
919446	25363593	The results of the current study suggest that IGF-1r knockdown may enhance the radiation sensitivity of ESCC and increase the therapeutic effects of radiation both in vitro and in vivo.	('IGF-1r', 'Gene', '3480', (46, 52))	('knockdown', 'Var', (53, 62))	('ESCC', 'Disease', (104, 108))	('increase', 'PosReg', (113, 121))	('enhance', 'PosReg', (67, 74))	('radiation sensitivity', 'CPA', (79, 100))	('therapeutic effects of radiation', 'CPA', (126, 158))	('IGF-1r', 'Gene', (46, 52))
919453	25363593	Abnormal gene expression or modifications including certain genetic or epigenetic alterations, such as those found in tumor-suppressor genes or oncogenes, may cause tumor initiation.	('modifications', 'Var', (28, 41))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('epigenetic alterations', 'Var', (71, 93))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', (118, 123))	('cause', 'Reg', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('genetic', 'Var', (60, 67))	('tumor', 'Disease', (165, 170))
919461	25363593	In the current study, it was hypothesized that radiation sensitivity will be enhanced after effective inhibition of IGF-1r through siRNA gene-silencing technology, which will result in a higher therapeutic efficacy in treating ESCC patients.	('siRNA', 'MPA', (131, 136))	('enhanced', 'PosReg', (77, 85))	('gene-silencing', 'Var', (137, 151))	('patients', 'Species', '9606', (232, 240))	('radiation sensitivity', 'CPA', (47, 68))	('IGF-1r', 'Gene', '3480', (116, 122))	('inhibition', 'NegReg', (102, 112))	('IGF-1r', 'Gene', (116, 122))	('ESCC', 'Disease', (227, 231))	('higher', 'PosReg', (187, 193))
919482	25363593	In addition, a difference in IGF-1r expression between Eca-109 and TE-1 cells was also observed, with IGF-1r expression being much higher in TE-1 cells than in Eca-109 cells (Figure 1A).	('IGF-1r', 'Gene', '3480', (29, 35))	('IGF-1r', 'Gene', (102, 108))	('expression', 'MPA', (109, 119))	('Eca', 'Chemical', '-', (55, 58))	('IGF-1r', 'Gene', '3480', (102, 108))	('TE-1', 'Var', (141, 145))	('TE-1', 'CellLine', 'CVCL:1759', (141, 145))	('Eca', 'Chemical', '-', (160, 163))	('IGF-1r', 'Gene', (29, 35))	('TE-1', 'CellLine', 'CVCL:1759', (67, 71))	('higher', 'PosReg', (131, 137))
919490	25363593	After radiotherapy, the number of Eca-109 cells decreased by approximately 67.3% in the presence of IGF-1r siRNA transfection, and there was a 78.9% reduction in the TE-1 cells after radiation (Figure 2).	('transfection', 'Var', (113, 125))	('reduction', 'NegReg', (149, 158))	('Eca', 'Chemical', '-', (34, 37))	('TE-1 cells', 'CPA', (166, 176))	('IGF-1r', 'Gene', (100, 106))	('decreased', 'NegReg', (48, 57))	('IGF-1r', 'Gene', '3480', (100, 106))	('TE-1', 'CellLine', 'CVCL:1759', (166, 170))	('Eca-109 cells', 'CPA', (34, 47))
919491	25363593	In the TE-1 cells, the inhibition of cell proliferation after IGF-1r siRNA transfection was much higher than in the Eca-109 cells (P <0.01, n =6); this difference may result from the different expression levels of IGF-1r in these two cell lines.	('Eca', 'Chemical', '-', (116, 119))	('higher', 'PosReg', (97, 103))	('IGF-1r', 'Gene', '3480', (214, 220))	('IGF-1r', 'Gene', (62, 68))	('transfection', 'Var', (75, 87))	('TE-1', 'CellLine', 'CVCL:1759', (7, 11))	('inhibition', 'NegReg', (23, 33))	('IGF-1r', 'Gene', '3480', (62, 68))	('IGF-1r', 'Gene', (214, 220))	('cell proliferation', 'CPA', (37, 55))
919493	25363593	To test the effect of IGF-1r knockdown on Eca-109 and TE-1 cell apoptosis, flow cytometry was used to investigate the percentage of apoptotic cells.	('knockdown', 'Var', (29, 38))	('IGF-1r', 'Gene', '3480', (22, 28))	('Eca', 'Chemical', '-', (42, 45))	('IGF-1r', 'Gene', (22, 28))	('TE-1', 'CellLine', 'CVCL:1759', (54, 58))
919505	25363593	These in vivo results confirmed that IGF-1r silencing can increase the radiation sensitivity of ESCC tumors in this established tumor model.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('increase', 'PosReg', (58, 66))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('IGF-1r', 'Gene', '3480', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('radiation sensitivity', 'CPA', (71, 92))	('ESCC tumors', 'Disease', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ESCC tumors', 'Disease', 'MESH:D004938', (96, 107))	('tumor', 'Disease', (128, 133))	('silencing', 'Var', (44, 53))	('IGF-1r', 'Gene', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
919509	25363593	Thus, we demonstrated that greater therapeutic efficacy may be obtained by enhancing the sensitivity of tumors to radiotherapy in the presence of IGF-1r siRNA knockdown.	('IGF-1r', 'Gene', '3480', (146, 152))	('sensitivity', 'MPA', (89, 100))	('knockdown', 'Var', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('enhancing', 'PosReg', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('IGF-1r', 'Gene', (146, 152))
919513	25363593	The therapeutic efficacy of irradiation on cell proliferation was dramatically enhanced in the presence of IGF-1r siRNA application in vitro, and this effect on the inhibition of cell proliferation was higher than the effect after radiation therapy alone.	('cell proliferation', 'CPA', (179, 197))	('enhanced', 'PosReg', (79, 87))	('IGF-1r', 'Gene', (107, 113))	('presence', 'Var', (95, 103))	('therapeutic efficacy', 'CPA', (4, 24))	('IGF-1r', 'Gene', '3480', (107, 113))	('cell proliferation', 'CPA', (43, 61))
919515	25363593	The effect of radiation therapy on cell apoptosis was also modulated after transfection with IGF-1r siRNA in TE-1 and Eca-109 cells, and a significant enhancement in the percentage of apoptotic cells was observed after combination therapy.	('IGF-1r', 'Gene', '3480', (93, 99))	('transfection', 'Var', (75, 87))	('Eca', 'Chemical', '-', (118, 121))	('modulated', 'Reg', (59, 68))	('IGF-1r', 'Gene', (93, 99))	('cell apoptosis', 'CPA', (35, 49))	('enhancement', 'PosReg', (151, 162))	('TE-1', 'CellLine', 'CVCL:1759', (109, 113))
919582	24303395	However, an outstanding feature of this series was the high rate of opium abuse (9%) in the patients included in the study, which has been proposed as a possible cause of several cancers such as esophageal and laryngeal cancer.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('opium abuse', 'Var', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('esophageal', 'Disease', (195, 205))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (210, 226))	('patients', 'Species', '9606', (92, 100))	('cause', 'Reg', (162, 167))	('esophageal', 'Disease', 'MESH:D004941', (195, 205))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('laryngeal cancer', 'Disease', 'MESH:D007822', (210, 226))	('cancers', 'Disease', (179, 186))	('laryngeal cancer', 'Disease', (210, 226))
919630	21930957	For each run, a parameter set (transition probabilities between health states) was randomly selected from within the bounds covering all reasonably likely rates for each transition, producing a wide and thorough sampling of potential progression rate combinations and resulting pre-cancer health state prevalences and age-adjusted esophageal adenocarcinoma incidences.	('esophageal adenocarcinoma', 'Disease', (331, 356))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (331, 356))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('combinations', 'Var', (251, 263))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (331, 356))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Disease', (282, 288))
919684	21930957	Ideally our model would have included such markers of central obesity; however, our analysis only simulated males, where there is a strong correlation between high BMI values and the presence of central obesity.	('central obesity', 'Phenotype', 'HP:0012743', (54, 69))	('obesity', 'Phenotype', 'HP:0001513', (62, 69))	('obesity', 'Phenotype', 'HP:0001513', (203, 210))	('central obesity', 'Phenotype', 'HP:0012743', (195, 210))	('obesity', 'Disease', 'MESH:D009765', (62, 69))	('obesity', 'Disease', 'MESH:D009765', (203, 210))	('obesity', 'Disease', (62, 69))	('high', 'Var', (159, 163))	('obesity', 'Disease', (203, 210))
919809	17640341	Unadjusted model results indicate that esophageal dysplasia was significantly associated with a family history of cancer, missing 12-31 teeth and having poor oral health.	('esophageal dysplasia', 'Disease', (39, 59))	('associated', 'Reg', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('poor oral', 'Phenotype', 'HP:0000160', (153, 162))	('missing', 'Var', (122, 129))	('having poor oral health', 'Phenotype', 'HP:0000670', (146, 169))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (39, 59))	('cancer', 'Disease', (114, 120))
919845	17640341	Using data from NHANES III (1988-94) to investigate acute-phase inflammatory markers and periodontitis, Slade has suggested that pocket depth is most likely associated with active periodontal disease.	('periodontal disease', 'Phenotype', 'HP:0000704', (180, 199))	('associated', 'Reg', (157, 167))	('periodontitis', 'Disease', 'MESH:D010518', (89, 102))	('periodontitis', 'Disease', (89, 102))	('periodontitis', 'Phenotype', 'HP:0000704', (89, 102))	('pocket depth', 'Var', (129, 141))	('active periodontal disease', 'Disease', (173, 199))
920005	30686898	Subsequent research confirmed that the muscarinic receptor agonists carbachol and 5-hydroxytryptamine (5-HT) can increase the intracellular calcium concentration and promote duodenal bicarbonate secretion after stimulating mouse duodenal mucosal or epithelial cells and confirmed that disturbing or inhibiting the function of NCX1 can obviously block the intracellular calcium change and promote bicarbonate secretion.	('mouse', 'Species', '10090', (223, 228))	('intracellular calcium change', 'Phenotype', 'HP:0003575', (355, 383))	('carbachol', 'Chemical', 'MESH:D002217', (68, 77))	('NCX1', 'Gene', (326, 330))	('calcium', 'Chemical', 'MESH:D002118', (140, 147))	('bicarbonate', 'Chemical', 'MESH:D001639', (183, 194))	('inhibiting', 'NegReg', (299, 309))	('increase the intracellular calcium concentration', 'Phenotype', 'HP:0003575', (113, 161))	('5-hydroxytryptamine', 'Chemical', 'MESH:D012701', (82, 101))	('promote', 'PosReg', (388, 395))	('calcium', 'Chemical', 'MESH:D002118', (369, 376))	('block', 'NegReg', (345, 350))	('rat', 'Species', '10116', (155, 158))	('bicarbonate', 'Chemical', 'MESH:D001639', (396, 407))	('promote', 'PosReg', (166, 173))	('duodenal bicarbonate secretion', 'MPA', (174, 204))	('intracellular calcium concentration', 'MPA', (126, 161))	('increase', 'PosReg', (113, 121))	('disturbing', 'Var', (285, 295))	('intracellular calcium change', 'MPA', (355, 383))	('bicarbonate secretion', 'MPA', (396, 417))
920009	30686898	Compared with that in the wild-type model, the contraction amplitude induced by AchE and SP after NCX2 knockout was significantly reduced; although NCX1 also plays a role in the regulation of ileal contraction, this decline was not evident in the NCX1 knockout model.	('ileal contraction', 'MPA', (192, 209))	('contraction amplitude', 'MPA', (47, 68))	('NCX2', 'Gene', (98, 102))	('AchE', 'Disease', 'MESH:D010146', (80, 84))	('AchE', 'Disease', (80, 84))	('reduced', 'NegReg', (130, 137))	('knockout', 'Var', (103, 111))
920012	30686898	Furthermore, it was found that the secretion of the mucin MUC5AC induced by ATP depends on the influx of Ca2+ into colonic goblet cells and that ATP requires the activation of TRPM5 channels to increase intracellular Na+, which activates the NCX reverse transport mode and increases intracellular Ca2+ uptake; thus, inhibiting NCX can significantly reduce the MUC5AC secretion in goblet cells.	('MUC5AC', 'Gene', '17833', (360, 366))	('MUC5AC', 'Gene', '17833', (58, 64))	('NCX', 'Gene', '29715', (327, 330))	('reduce', 'NegReg', (349, 355))	('mucin', 'Gene', '100508689', (52, 57))	('increases', 'PosReg', (273, 282))	('MUC5AC', 'Gene', (360, 366))	('MUC5AC', 'Gene', (58, 64))	('intracellular Ca2+ uptake', 'MPA', (283, 308))	('inhibiting', 'Var', (316, 326))	('ATP', 'Chemical', 'MESH:D000255', (145, 148))	('NCX', 'Gene', (242, 245))	('ATP', 'Chemical', 'MESH:D000255', (76, 79))	('TRPM5', 'Gene', '56843', (176, 181))	('NCX', 'Gene', '29715', (242, 245))	('increase', 'PosReg', (194, 202))	('TRPM5', 'Gene', (176, 181))	('increase intracellular Na+', 'Phenotype', 'HP:0003575', (194, 220))	('intracellular Na+', 'MPA', (203, 220))	('NCX', 'Gene', (327, 330))	('mucin', 'Gene', (52, 57))
920015	30686898	Kazuhiro et al have found that in a diarrhea model induced with magnesium sulfate or 5-HT, the diarrhea in NCX2 heterozygous knockout mice (NCX2 HET) was more serious than that in wild-type mice (WT), but the diarrhea in NCX1 heterozygous knockout mice (NCX1 HET) showed no significant changes from that of WT.	('knockout', 'Var', (125, 133))	('mice', 'Species', '10090', (134, 138))	('diarrhea', 'Phenotype', 'HP:0002014', (209, 217))	('HET', 'Gene', (145, 148))	('diarrhea', 'Disease', 'MESH:D003967', (209, 217))	('diarrhea', 'Disease', (209, 217))	('HET', 'Gene', '18400', (259, 262))	('mice', 'Species', '10090', (248, 252))	('magnesium sulfate', 'Chemical', 'MESH:D008278', (64, 81))	('HET', 'Gene', '18400', (145, 148))	('diarrhea', 'Phenotype', 'HP:0002014', (36, 44))	('diarrhea', 'Phenotype', 'HP:0002014', (95, 103))	('HET', 'Gene', (259, 262))	('mice', 'Species', '10090', (190, 194))	('diarrhea', 'Disease', (36, 44))	('diarrhea', 'Disease', (95, 103))	('diarrhea', 'Disease', 'MESH:D003967', (36, 44))	('diarrhea', 'Disease', 'MESH:D003967', (95, 103))
920032	30686898	The mutation also increases the beta-cell resistance to hypoxia, and Ncx1+/- islets show a 2-4 times higher rate of curing diabetes than Ncx1+/+ islets when transplanted into diabetic animals.	('diabetes', 'Disease', 'MESH:D003920', (123, 131))	('diabetic', 'Disease', 'MESH:D003920', (175, 183))	('diabetes', 'Disease', (123, 131))	('rat', 'Species', '10116', (108, 111))	('higher', 'PosReg', (101, 107))	('increases', 'PosReg', (18, 27))	('Ncx1', 'Gene', (69, 73))	('Ncx1', 'Gene', '21909', (69, 73))	('diabetic', 'Disease', (175, 183))	('mutation', 'Var', (4, 12))	('beta-cell resistance', 'CPA', (32, 52))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('beta-cell resistance', 'Phenotype', 'HP:0006279', (32, 52))	('Ncx1', 'Gene', '21909', (137, 141))	('hypoxia', 'Disease', (56, 63))	('Ncx1', 'Gene', (137, 141))
920034	30686898	In summary, the different NCX1 expression and transport modes can regulate insulin secretion, so selective inhibition of NCX1 may improve insulin secretion, which provides more theoretical evidence for novel glucose-sensitive insulinotropic drugs for type 2 diabetes that target NCX1.	('improve', 'PosReg', (130, 137))	('NCX1', 'Gene', (121, 125))	('diabetes', 'Disease', (258, 266))	('insulin', 'Gene', (75, 82))	('insulin', 'Gene', '3630', (75, 82))	('insulin', 'Gene', (226, 233))	('glucose', 'Chemical', 'MESH:D005947', (208, 215))	('diabetes', 'Disease', 'MESH:D003920', (258, 266))	('insulin', 'Gene', '3630', (226, 233))	('insulin', 'Gene', (138, 145))	('inhibition', 'Var', (107, 117))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (251, 266))	('regulate', 'Reg', (66, 74))	('insulin', 'Gene', '3630', (138, 145))
920042	30686898	However, it is generally accepted that alterations in TGF-beta signaling and its downstream SMAD pathway play an important role in pancreatic cancer development.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('SMAD', 'Gene', (92, 96))	('SMAD', 'Gene', '17128', (92, 96))	('TGF-beta', 'Gene', '21803', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rat', 'Species', '10116', (43, 46))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('pancreatic cancer', 'Disease', (131, 148))	('alterations', 'Var', (39, 50))	('TGF-beta', 'Gene', (54, 62))
920065	29416654	In this study, we investigated the effect of ESCCAL_1 knockdown on ESCC tumorigenicity using a xenograft mouse model and explored the underlying molecular mechanism.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('knockdown', 'Var', (54, 63))	('ESCC tumor', 'Disease', 'MESH:D004938', (67, 77))	('mouse', 'Species', '10090', (105, 110))	('ESCC tumor', 'Disease', (67, 77))	('ESCCAL_1', 'Gene', (45, 53))	('ESCCAL_1', 'Gene', '101805492', (45, 53))
920066	29416654	Here we showed that ESCCAL_1 knockdown significantly inhibited EC9706 cell growth in nude mice.	('inhibited', 'NegReg', (53, 62))	('knockdown', 'Var', (29, 38))	('ESCCAL_1', 'Gene', '101805492', (20, 28))	('EC9706', 'CellLine', 'CVCL:E307', (63, 69))	('nude mice', 'Species', '10090', (85, 94))	('ESCCAL_1', 'Gene', (20, 28))	('EC9706 cell growth', 'CPA', (63, 81))
920076	29416654	We have previously demonstrated that expression of lncRNA ESCCAL_1 was significantly increased in ESCC and inhibition of ESCCAL_1 expression promotes apoptosis and decreasing invasion in ESCC cell lines.	('ESCCAL_1', 'Gene', (58, 66))	('ESCCAL_1', 'Gene', '101805492', (58, 66))	('expression', 'MPA', (130, 140))	('ESCCAL_1', 'Gene', (121, 129))	('ESCCAL_1', 'Gene', '101805492', (121, 129))	('apoptosis', 'CPA', (150, 159))	('ESCC', 'Disease', (98, 102))	('invasion', 'CPA', (175, 183))	('decreasing', 'NegReg', (164, 174))	('increased', 'PosReg', (85, 94))	('inhibition', 'Var', (107, 117))	('expression', 'MPA', (37, 47))	('promotes', 'PosReg', (141, 149))
920078	29416654	In present study, we evaluated the effect of ESCCAL_1 knockdown on ESCC tumorigenicity in a xenograft mouse model, and further investigated signaling pathways alterations in xenografted tumor samples using protein arrays.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('knockdown', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('ESCC tumor', 'Disease', 'MESH:D004938', (67, 77))	('tumor', 'Disease', (72, 77))	('mouse', 'Species', '10090', (102, 107))	('tumor', 'Disease', (186, 191))	('ESCC tumor', 'Disease', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('ESCCAL_1', 'Gene', (45, 53))	('ESCCAL_1', 'Gene', '101805492', (45, 53))
920089	29416654	We also observed that the proteins levels of phosphorylated c-Jun N-terminal kinase (p-JNK), phosphorylated focal adhesion kinase (p-FAK), phosphorylated glycogen synthase kinase 3beta (p-GSK3beta) and phosphorylated sarcoma (p-Src) were decreased in slowly growing tumor tissues following ESCCAL_1 knockdown (Figure 2A-2B).	('FAK', 'Gene', '14083', (133, 136))	('Src', 'Gene', (228, 231))	('tumor', 'Disease', (266, 271))	('JNK', 'Gene', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('sarcoma', 'Disease', 'MESH:D012509', (217, 224))	('ESCCAL_1', 'Gene', '101805492', (290, 298))	('decreased', 'NegReg', (238, 247))	('JNK', 'Gene', '26419', (87, 90))	('sarcoma', 'Disease', (217, 224))	('glycogen synthase kinase 3beta', 'Gene', '56637', (154, 184))	('GSK3beta', 'Gene', '56637', (188, 196))	('GSK3beta', 'Gene', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('Src', 'Gene', '20779', (228, 231))	('proteins levels', 'MPA', (26, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('phosphorylated', 'MPA', (45, 59))	('FAK', 'Gene', (133, 136))	('ESCCAL_1', 'Gene', (290, 298))	('glycogen synthase kinase 3beta', 'Gene', (154, 184))	('knockdown', 'Var', (299, 308))
920090	29416654	These data suggest that ESCCAL_1 knockdown predominantly decreased activities of protein kinases.	('ESCCAL_1', 'Gene', '101805492', (24, 32))	('knockdown', 'Var', (33, 42))	('activities', 'MPA', (67, 77))	('protein', 'Enzyme', (81, 88))	('decreased', 'NegReg', (57, 66))	('ESCCAL_1', 'Gene', (24, 32))
920093	29416654	However, the expression levels of p-JNK1, p-FAK and p-Src were reduced significantly in the tumors after ESCCAL_1 knockdown when compared to the NC group (p < 0.001) (Figure 3A-3B).	('expression levels', 'MPA', (13, 30))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('reduced', 'NegReg', (63, 70))	('FAK', 'Gene', '14083', (44, 47))	('knockdown', 'Var', (114, 123))	('FAK', 'Gene', (44, 47))	('ESCCAL_1', 'Gene', (105, 113))	('ESCCAL_1', 'Gene', '101805492', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('JNK1', 'Gene', '26419', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('Src', 'Gene', '20779', (54, 57))	('tumors', 'Disease', (92, 98))	('Src', 'Gene', (54, 57))	('JNK1', 'Gene', (36, 40))
920096	29416654	In order to examine the effects of ESCCAL_1 knockdown on apoptotic signaling pathways, Western blot analysis was used to detect gene expressions invovling apoptosis and cell survival including p-p38alpha, p53, p21, Bcl-2, BAX and Caspase-3.	('BAX', 'Gene', (222, 225))	('ESCCAL_1', 'Gene', '101805492', (35, 43))	('BAX', 'Gene', '12028', (222, 225))	('p21', 'Gene', (210, 213))	('Caspase-3', 'Gene', '12367', (230, 239))	('p21', 'Gene', '12575', (210, 213))	('p53', 'Gene', (205, 208))	('p53', 'Gene', '22060', (205, 208))	('Bcl-2', 'Gene', '12043', (215, 220))	('cell survival', 'CPA', (169, 182))	('Bcl-2', 'Gene', (215, 220))	('p-p38alpha', 'Var', (193, 203))	('apoptosis', 'CPA', (155, 164))	('Caspase-3', 'Gene', (230, 239))	('ESCCAL_1', 'Gene', (35, 43))
920097	29416654	Our data revealed that ESCCAL_1 knockdown significantly increased the phosphorylation of p38alpha, which was consistent with the result of phosphor-kinase array (p < 0.05) (Figure 4A-4B).	('increased', 'PosReg', (56, 65))	('knockdown', 'Var', (32, 41))	('ESCCAL_1', 'Gene', (23, 31))	('phosphorylation', 'MPA', (70, 85))	('ESCCAL_1', 'Gene', '101805492', (23, 31))	('p38alpha', 'Protein', (89, 97))
920099	29416654	These data indicated that inhibition of ESCCAL_1 expression increased apoptosis and decreased survival in tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('ESCCAL_1', 'Gene', (40, 48))	('inhibition', 'Var', (26, 36))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('expression', 'MPA', (49, 59))	('ESCCAL_1', 'Gene', '101805492', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('apoptosis', 'CPA', (70, 79))	('decreased', 'NegReg', (84, 93))	('increased', 'PosReg', (60, 69))
920101	29416654	Previous studies have shown that knockdown of ESCCAL_1 by small interfering RNAs could inhibit invasion and promote apoptosis in ESCC cell line EC9706, high expression of ESCCAL_1 transcript was found to be correlated with poor prognosis of ESCC.	('invasion', 'CPA', (95, 103))	('ESCCAL_1', 'Gene', (46, 54))	('EC9706', 'CellLine', 'CVCL:E307', (144, 150))	('apoptosis', 'CPA', (116, 125))	('knockdown', 'Var', (33, 42))	('RNAs', 'Gene', (76, 80))	('ESCCAL_1', 'Gene', (171, 179))	('correlated', 'Reg', (207, 217))	('small interfering', 'Var', (58, 75))	('ESCCAL_1', 'Gene', '101805492', (46, 54))	('promote', 'PosReg', (108, 115))	('ESCCAL_1', 'Gene', '101805492', (171, 179))	('ESCC', 'Disease', (241, 245))	('inhibit', 'NegReg', (87, 94))
920103	29416654	In this study, we observed that knockdown of ESCCAL_1 could remarkably inhibit tumor growth of ESCC in a xenograft mouse model.	('tumor', 'Disease', (79, 84))	('inhibit', 'NegReg', (71, 78))	('ESCC', 'Disease', (95, 99))	('knockdown', 'Var', (32, 41))	('mouse', 'Species', '10090', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('ESCCAL_1', 'Gene', (45, 53))	('ESCCAL_1', 'Gene', '101805492', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
920104	29416654	Consistent with our previous study that knockdown of ESCCAL_1 suppresses ESCC cell proliferation in vitro (data not shown), our result of tumor growth assay in vivo also revealed that down-regulation of ESCCAL_1 inhibits ESCC cell growth in xenografts nude mice.	('inhibits', 'NegReg', (212, 220))	('ESCCAL_1', 'Gene', (203, 211))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('knockdown', 'Var', (40, 49))	('down-regulation', 'NegReg', (184, 199))	('ESCCAL_1', 'Gene', (53, 61))	('ESCCAL_1', 'Gene', '101805492', (53, 61))	('nude mice', 'Species', '10090', (252, 261))	('ESCC cell proliferation', 'CPA', (73, 96))	('suppresses', 'NegReg', (62, 72))	('ESCC', 'Disease', (221, 225))	('ESCCAL_1', 'Gene', '101805492', (203, 211))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
920105	29416654	So we screened multiple signaling pathways which might be affected by ESCCAL_1 knockdown in xenografts tumor tissues using phospho-kinase array.	('ESCCAL_1', 'Gene', (70, 78))	('ESCCAL_1', 'Gene', '101805492', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('signaling pathways', 'Pathway', (24, 42))	('knockdown', 'Var', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
920106	29416654	We found a series of phosphorylation of kinases proteins whose expression levels were either increased or decreased following ESCCAL_1 knockdown, these kinase proteins include p-p38alpha, p-JNK, p-GSK3beta, p-Src, p-STAT5a and p-FAK.	('decreased', 'NegReg', (106, 115))	('expression levels', 'MPA', (63, 80))	('JNK', 'Gene', '26419', (190, 193))	('FAK', 'Gene', '14083', (229, 232))	('Src', 'Gene', '20779', (209, 212))	('FAK', 'Gene', (229, 232))	('JNK', 'Gene', (190, 193))	('Src', 'Gene', (209, 212))	('increased', 'PosReg', (93, 102))	('p-p38alpha', 'Var', (176, 186))	('p-STAT5a', 'Var', (214, 222))	('GSK3beta', 'Gene', (197, 205))	('phosphorylation', 'MPA', (21, 36))	('ESCCAL_1', 'Gene', (126, 134))	('ESCCAL_1', 'Gene', '101805492', (126, 134))	('GSK3beta', 'Gene', '56637', (197, 205))
920113	29416654	Our results displayed that the phosphorylation levels of Src, FAK and JNK were significantly decreased following ESCCAL_1 knockdown (Figure 5), suggesting that down-regulation of ESCCAL_1 inhibits tumor growth probably by inactivation of Src/FAK/JNK pathway.	('FAK', 'Gene', (242, 245))	('Src', 'Gene', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('JNK', 'Gene', (246, 249))	('down-regulation', 'NegReg', (160, 175))	('ESCCAL_1', 'Gene', (113, 121))	('inhibits', 'NegReg', (188, 196))	('JNK', 'Gene', '26419', (246, 249))	('FAK', 'Gene', '14083', (242, 245))	('knockdown', 'Var', (122, 131))	('Src', 'Gene', '20779', (238, 241))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('ESCCAL_1', 'Gene', '101805492', (179, 187))	('JNK', 'Gene', (70, 73))	('Src', 'Gene', '20779', (57, 60))	('decreased', 'NegReg', (93, 102))	('FAK', 'Gene', (62, 65))	('ESCCAL_1', 'Gene', '101805492', (113, 121))	('JNK', 'Gene', '26419', (70, 73))	('inactivation', 'NegReg', (222, 234))	('FAK', 'Gene', '14083', (62, 65))	('ESCCAL_1', 'Gene', (179, 187))	('Src', 'Gene', (238, 241))	('tumor', 'Disease', (197, 202))	('phosphorylation levels', 'MPA', (31, 53))
920117	29416654	If DNA repair fails, accumulation of p53 can stimulate the process of apoptosis to clear away the damaged cells.	('p53', 'Gene', '22060', (37, 40))	('accumulation', 'Var', (21, 33))	('stimulate', 'PosReg', (45, 54))	('p53', 'Gene', (37, 40))	('apoptosis', 'CPA', (70, 79))
920120	29416654	Our data also showed that apoptosis associated proteins Caspase-3 and BAX were dramatically increased and Bcl-2 significantly decreased after ESCCAL_1 knockdown.	('decreased', 'NegReg', (126, 135))	('ESCCAL_1', 'Gene', (142, 150))	('ESCCAL_1', 'Gene', '101805492', (142, 150))	('apoptosis', 'CPA', (26, 35))	('Caspase-3', 'Gene', (56, 65))	('Caspase-3', 'Gene', '12367', (56, 65))	('increased', 'PosReg', (92, 101))	('BAX', 'Gene', '12028', (70, 73))	('BAX', 'Gene', (70, 73))	('Bcl-2', 'Gene', '12043', (106, 111))	('Bcl-2', 'Gene', (106, 111))	('knockdown', 'Var', (151, 160))
920124	29416654	In summary, our data indicate that knockdown of ESCCAL_1 inhibits tumor growth in an ESCC xenografts mouse model, inactivation of Src and activation of p38alpha may be two cross-talk pathways responsible to the resulting phynotype.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('knockdown', 'Var', (35, 44))	('ESCCAL_1', 'Gene', (48, 56))	('ESCCAL_1', 'Gene', '101805492', (48, 56))	('tumor', 'Disease', (66, 71))	('inactivation', 'NegReg', (114, 126))	('Src', 'Gene', '20779', (130, 133))	('Src', 'Gene', (130, 133))	('mouse', 'Species', '10090', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('p38alpha', 'Enzyme', (152, 160))	('inhibits', 'NegReg', (57, 65))	('activation', 'PosReg', (138, 148))
920128	29416654	In this experiment, the vector hU6-MCS-CMV-EGFP (GV155) (Genechem, China) was used to generate ESCCAL_1-shRNA or nonsense-shRNA (under human U6 promoter) according to the manufacture's instruction, the shuttle vector and viral packaging system were cotransfected into HEK293T cells to replicate competent lentivirus.	('shuttle vector', 'Species', '45197', (202, 216))	('ESCCAL_1', 'Gene', (95, 103))	('ESCCAL_1', 'Gene', '101805492', (95, 103))	('human', 'Species', '9606', (135, 140))	('nonsense-shRNA', 'Var', (113, 127))	('HEK293T', 'CellLine', 'CVCL:0063', (268, 275))
920129	29416654	The EC9706 cells infected with ESCCAL_1-shRNA or nonsense-shRNA Lentivirus were used for xenografts as our previously described.	('ESCCAL_1', 'Gene', '101805492', (31, 39))	('EC9706', 'CellLine', 'CVCL:E307', (4, 10))	('nonsense-shRNA', 'Var', (49, 63))	('ESCCAL_1', 'Gene', (31, 39))
920130	29416654	Then, the nude mice were divided into two groups: Negative control (NC) (n = 6), injection of nonsense-shRNA Lentivirus infected EC9706 cells subcutaneously into the back flank; Knockdown (KD) (n = 6), injection of ESCCAL_1-shRNA Lentivirus infected EC9706 cells subcutaneously into the back flank.	('EC9706', 'CellLine', 'CVCL:E307', (129, 135))	('Knockdown', 'Var', (178, 187))	('ESCCAL_1', 'Gene', (215, 223))	('ESCCAL_1', 'Gene', '101805492', (215, 223))	('back flank', 'Disease', 'MESH:D021501', (166, 176))	('Lentivirus infected', 'Disease', 'MESH:D016180', (109, 128))	('Lentivirus infected', 'Disease', (109, 128))	('back flank', 'Disease', 'MESH:D021501', (287, 297))	('nude mice', 'Species', '10090', (10, 19))	('Lentivirus infected', 'Disease', 'MESH:D016180', (230, 249))	('EC9706', 'CellLine', 'CVCL:E307', (250, 256))	('Lentivirus infected', 'Disease', (230, 249))	('back flank', 'Disease', (166, 176))	('back flank', 'Disease', (287, 297))
920138	28223736	Percutaneous electrochemotherapy in the treatment of portal vein tumor thrombosis at hepatic hilum in patients with hepatocellular carcinoma in cirrhosis: A feasibility study To treated with electrochemotherapy (ECT) a prospective case series of patients with liver cirrhosis and Vp3-Vp4- portal vein tumor thrombus (PVTT) from hepatocellular carcinoma (HCC), in order to evaluate the feasibility, safety and efficacy of this new non thermal ablative technique in those patients.	('patients', 'Species', '9606', (246, 254))	('liver cirrhosis', 'Disease', (260, 275))	('vein tumor thrombus', 'Disease', (296, 315))	('patients', 'Species', '9606', (102, 110))	('cirrhosis', 'Phenotype', 'HP:0001394', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (116, 140))	('tumor thrombosis at hepatic hilum', 'Phenotype', 'HP:0030243', (65, 98))	('vein tumor thrombosis', 'Phenotype', 'HP:0004936', (60, 81))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (260, 275))	('PVTT', 'Phenotype', 'HP:0030242', (317, 321))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (328, 352))	('portal vein tumor thrombus', 'Phenotype', 'HP:0030242', (289, 315))	('hepatocellular carcinoma in cirrhosis', 'Disease', (116, 153))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (116, 140))	('HCC', 'Phenotype', 'HP:0001402', (354, 357))	('vein tumor thrombus', 'Phenotype', 'HP:0004936', (296, 315))	('vein tumor thrombosis', 'Disease', 'MESH:D020246', (60, 81))	('portal vein tumor thrombosis', 'Phenotype', 'HP:0030242', (53, 81))	('patients', 'Species', '9606', (470, 478))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (328, 352))	('liver cirrhosis', 'Disease', 'MESH:D008103', (260, 275))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('vein tumor thrombus', 'Disease', 'MESH:D013927', (296, 315))	('Vp3-Vp4-', 'Var', (280, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cirrhosis', 'Phenotype', 'HP:0001394', (266, 275))	('hepatocellular carcinoma in cirrhosis', 'Disease', 'MESH:D008103', (116, 153))	('hepatocellular carcinoma', 'Disease', (328, 352))	('vein tumor thrombosis', 'Disease', (60, 81))
920141	28223736	All patients underwent ECT treatment (Cliniporator Vitae , IGEA SpA, Carpi, Modena, Italy) of Vp3-Vp4 PVTT in a single session.	('PVTT', 'Phenotype', 'HP:0030242', (102, 106))	('SpA', 'Gene', (64, 67))	('Vp3-Vp4 PVTT', 'Var', (94, 106))	('patients', 'Species', '9606', (4, 12))	('SpA', 'Gene', '729238', (64, 67))
920148	28223736	In patients with cirrhosis, ECT seems effective and safe for curative treatment of Vp3-Vp4 PVTT from HCC.	('cirrhosis', 'Disease', (17, 26))	('PVTT', 'Phenotype', 'HP:0030242', (91, 95))	('HCC', 'Phenotype', 'HP:0001402', (101, 104))	('Vp3-Vp4 PVTT', 'Var', (83, 95))	('cirrhosis', 'Phenotype', 'HP:0001394', (17, 26))	('patients', 'Species', '9606', (3, 11))	('cirrhosis', 'Disease', 'MESH:D005355', (17, 26))
920165	28223736	A potential ideal ablation technique for Vp3-Vp4 PVTT should be able to kill tumor cells in the portal vessels without heat generation and without affecting patency of main bile ducts, arterial vessels and even without any damage to PV walls.	('Vp3-Vp4 PVTT', 'Var', (41, 53))	('PVTT', 'Phenotype', 'HP:0030242', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
920168	28223736	From December 2014 to December 2015, 42 patients (29 male, 13 female, age range 48-91 year) with Vp3-Vp4 PVTT were observed at our Unit of Hepatology and Interventional Ultrasound in a tertiary care Institution - A. Tortora Cancer Hospital.	('Tortora Cancer', 'Disease', 'MESH:D009369', (216, 230))	('patients', 'Species', '9606', (40, 48))	('Cancer', 'Phenotype', 'HP:0002664', (224, 230))	('Vp3-Vp4 PVTT', 'Var', (97, 109))	('Tortora Cancer', 'Disease', (216, 230))	('PVTT', 'Phenotype', 'HP:0030242', (105, 109))
920201	28223736	Four patients showed 1 (3 cases) or 2 (1 case) HCC nodules synchronous with Vp3-PVTT (all patients) and Vp4-PVTT (one case).	('Vp3-PVTT', 'Disease', (76, 84))	('patients', 'Species', '9606', (5, 13))	('Vp4-PVTT', 'Var', (104, 112))	('PVTT', 'Phenotype', 'HP:0030242', (108, 112))	('HCC', 'Phenotype', 'HP:0001402', (47, 50))	('PVTT', 'Phenotype', 'HP:0030242', (80, 84))	('patients', 'Species', '9606', (90, 98))
920254	28223736	One month CEUS confirmed absence of enhancement in the treated Vp3-Vp4 PVTT, and also showed bland complete thrombosis of main portal trunk and upper mesenteric vein.	('thrombosis', 'Disease', (108, 118))	('portal trunk', 'Phenotype', 'HP:0025154', (127, 139))	('Vp3-Vp4 PVTT', 'Var', (63, 75))	('thrombosis of main portal trunk', 'Phenotype', 'HP:0030242', (108, 139))	('absence', 'NegReg', (25, 32))	('thrombosis', 'Disease', 'MESH:D013927', (108, 118))	('PVTT', 'Phenotype', 'HP:0030242', (71, 75))	('enhancement', 'MPA', (36, 47))
920277	28223736	Mild-moderate improvement in survival of patients with Vp1-Vp2 PVTT have been reported with TACE and TARE.	('Vp1-Vp2 PVTT', 'Var', (55, 67))	('improvement', 'PosReg', (14, 25))	('PVTT', 'Phenotype', 'HP:0030242', (63, 67))	('survival', 'MPA', (29, 37))	('patients', 'Species', '9606', (41, 49))	('TARE', 'Species', '3908', (101, 105))
920283	28223736	The high risk of damage to main bile ducts (stricture, rupture, obstruction) and to the hepatic artery (bleeding, pseudoaneurysm, arterio-portal fistula) after ablation of tumors in the center of the liver has been well described and demonstrated both in vivo experimental studies and in patients series.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('ablation', 'Var', (160, 168))	('fistula', 'Disease', (145, 152))	('pseudoaneurysm', 'Disease', (114, 128))	('fistula', 'Disease', 'MESH:D005402', (145, 152))	('pseudoaneurysm', 'Disease', 'MESH:D017541', (114, 128))	('patients', 'Species', '9606', (288, 296))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('pseudoaneurysm', 'Phenotype', 'HP:0031625', (114, 128))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('rupture, obstruction', 'Disease', 'MESH:D012421', (55, 75))	('hepatic artery', 'Disease', (88, 102))	('bleeding', 'Disease', 'MESH:D006470', (104, 112))	('hepatic artery', 'Disease', 'MESH:D056486', (88, 102))	('bleeding', 'Disease', (104, 112))
920288	28223736	A potential ideal ablation technique for Vp3-Vp4 PVTT should be able to kill tumor cells in the portal vessels without heat generation and without affecting patency of main bile ducts, arterial vessels and even without any damage to PV wall.	('Vp3-Vp4 PVTT', 'Var', (41, 53))	('PVTT', 'Phenotype', 'HP:0030242', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
920290	28223736	ECT is a local tumor ablation modality that, through reversible electroporation, enhances cell membrane permeability, and enables non-permeant or poorly permeant chemotherapeutic agents to enter cells, greatly enhancing their efficacy in killing tumor cells.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('enhances', 'PosReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (15, 20))	('electroporation', 'Var', (64, 79))	('enhancing', 'PosReg', (210, 219))	('tumor', 'Disease', (246, 251))	('cell membrane permeability', 'MPA', (90, 116))
920306	28223736	On this assumption, we started this prospective study on a series of consecutive cirrhotic patients affected from HCC and Vp3-Vp4 PVTT.	('PVTT', 'Phenotype', 'HP:0030242', (130, 134))	('patients', 'Species', '9606', (91, 99))	('HCC', 'Phenotype', 'HP:0001402', (114, 117))	('Vp3-Vp4', 'Var', (122, 129))	('affected', 'Reg', (100, 108))
920334	28223736	This article entitled by Tarantino et al showed that "In patients with cirrhosis, ECT seems effective and safe for curative treatment of Vp3-Vp4 PVTT from HCC".	('Vp3-Vp4 PVTT', 'Var', (137, 149))	('cirrhosis', 'Phenotype', 'HP:0001394', (71, 80))	('cirrhosis', 'Disease', 'MESH:D005355', (71, 80))	('patients', 'Species', '9606', (57, 65))	('cirrhosis', 'Disease', (71, 80))	('HCC', 'Phenotype', 'HP:0001402', (155, 158))	('PVTT', 'Phenotype', 'HP:0030242', (145, 149))
920337	27525226	Therefore, inhibition of tumor growth and also induction of radiosensitivity may be provided by hdm2 inhibitors.	('inhibitors', 'Var', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('hdm2', 'Gene', (96, 100))	('radiosensitivity', 'MPA', (60, 76))	('inhibition', 'NegReg', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
920341	27525226	Radioresistance causes failure in the esophageal cancer treatment, also in neoadjuvant therapy.	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('Radioresistance', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
920344	27525226	It was shown that hdm2-siRNA have induced MCF-7 cell apoptosis and reduced reproduction of the cell.	('MCF-7', 'CellLine', 'CVCL:0031', (42, 47))	('MCF-7', 'Gene', (42, 47))	('hdm2-siRNA', 'Var', (18, 28))	('reduced', 'NegReg', (67, 74))	('reproduction of the cell', 'CPA', (75, 99))
920348	27525226	NM_002392) was corresponded to the coding regions 59-80 after the start codon, and the mock siRNA sequence was 5'-AAUAGUGUAUACGGCAUGCdTdT-3'.	('TdT', 'Gene', (134, 137))	('NM_002392', 'Var', (0, 9))	('TdT', 'Gene', '1791', (134, 137))
920366	27525226	Improved cancer treatment and increased radiosensitivity of esophageal tumor cells may be provided by silencing the related oncogenes.	('silencing', 'Var', (102, 111))	('cancer treatment', 'CPA', (9, 25))	('oncogenes', 'Protein', (124, 133))	('esophageal tumor', 'Disease', (60, 76))	('esophageal tumor', 'Phenotype', 'HP:0100751', (60, 76))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('radiosensitivity', 'CPA', (40, 56))	('increased', 'PosReg', (30, 39))	('Improved', 'PosReg', (0, 8))	('esophageal tumor', 'Disease', 'MESH:D004938', (60, 76))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (30, 56))
920381	26400625	Additionally, increasing DII has been shown to be associated with the increased glucose intolerant and dyslipidemic components of metabolic syndrome, shift work status in a large population-based survey in the USA, increased risk of asthma in Australia, colorectal cancer in case-control studies in Spain and in cohort studies in USA and pancreatic and prostate cancers in Italy.	('cancers', 'Phenotype', 'HP:0002664', (362, 369))	('asthma in Australia', 'Disease', 'MESH:D001249', (233, 252))	('glucose intolerant', 'Phenotype', 'HP:0001952', (80, 98))	('increased glucose', 'Phenotype', 'HP:0003074', (70, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (254, 271))	('pain', 'Phenotype', 'HP:0012531', (300, 304))	('prostate cancers', 'Phenotype', 'HP:0012125', (353, 369))	('DII', 'Var', (25, 28))	('DII', 'Chemical', '-', (25, 28))	('colorectal cancer', 'Disease', (254, 271))	('asthma', 'Phenotype', 'HP:0002099', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('asthma in Australia', 'Disease', (233, 252))	('increased glucose intolerant and dyslipidemic components of metabolic syndrome', 'Disease', 'MESH:D018149', (70, 148))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('pancreatic and prostate cancers', 'Disease', 'MESH:D010190', (338, 369))	('colorectal cancer', 'Disease', 'MESH:D015179', (254, 271))
920415	26400625	In particular, participants in DII> 1.20 category had lower BMI, physical activity, tobacco exposure and were slightly older, more likely to be men and educated.	('participants', 'Species', '9606', (15, 27))	('men', 'Species', '9606', (144, 147))	('tobacco exposure', 'CPA', (84, 100))	('DII', 'Chemical', '-', (31, 34))	('tobacco', 'Species', '4097', (84, 91))	('lower BMI', 'Phenotype', 'HP:0045082', (54, 63))	('BMI', 'MPA', (60, 63))	('physical activity', 'CPA', (65, 82))	('DII', 'Var', (31, 34))	('lower', 'NegReg', (54, 59))
920418	26400625	When analysis was carried out with DII expressed as a dichotomous variable, and adjusting for age, subjects with DII score >1.20 were at 655% times higher risk of having ESCC compared to subjects with DII <=1.20 (ORDII (> 1.20/<=1.20) =7.55 CI=2.63-21.70).	('DII', 'Chemical', '-', (113, 116))	('DII', 'Chemical', '-', (35, 38))	('DII', 'Chemical', '-', (201, 204))	('DII', 'Chemical', '-', (215, 218))	('DII score >1.20', 'Var', (113, 128))	('ESCC', 'Disease', (170, 174))
920419	26400625	After multivariate adjustment, subjects with DII >1.20 were at 724% higher risk of having ESCC compared to subjects with DII <=1.20 (ORDII (>1.20/<=1.20) =8.24; CI=2.03-33.47).	('DII', 'Chemical', '-', (45, 48))	('DII', 'Chemical', '-', (121, 124))	('ESCC', 'Disease', (90, 94))	('DII', 'Chemical', '-', (135, 138))	('men', 'Species', '9606', (25, 28))	('DII >1.20', 'Var', (45, 54))
920420	26400625	In this case-control study, we observed that subjects with the higher DII (i.e., those who had the most pro-inflammatory diets) were at increased risk of developing ESCC, a result supporting our hypothesis that consuming a more pro-inflammatory diet, is associated with an increased risk of ESCC.	('DII', 'Var', (70, 73))	('DII', 'Chemical', '-', (70, 73))	('ESCC', 'Disease', (165, 169))	('ESCC', 'Disease', (291, 295))
920451	26557784	morphology codes 8140-8144, 8210, 8211, 8255-8323, 8480-8490, 8570-8574, and 8576 were used to identify ACE, and 8052-8076 and 8083 were used to identify SCC, respectively, by use of SEER*Stat software version 8.0.4.	('8052-8076', 'Var', (113, 122))	('8210', 'Var', (28, 32))	('SCC', 'Gene', '6317', (154, 157))	('8140-8144', 'Var', (17, 26))	('8570-8574', 'Var', (62, 71))	('8211', 'Var', (34, 38))	('8576', 'Var', (77, 81))	('8480-8490', 'Var', (51, 60))	('ACE', 'Gene', '1636', (104, 107))	('8255-8323', 'Var', (40, 49))	('SCC', 'Gene', (154, 157))	('ACE', 'Gene', (104, 107))
920574	24774780	Sharma compared the treatment-related complications in groups 1 (20 Gy BT boost) and 2 (15 Gy BT boost) and reported strictures in 24% vs. 8% (p = 0.029), respectively, ulceration in 30% vs. 28% (p = 0.8), respectively, and tracheoesophageal fistulae in 12% of patients in both groups.	('15 Gy BT boost', 'Var', (88, 102))	('BT boost', 'Chemical', '-', (94, 102))	('tracheoesophageal fistulae', 'Phenotype', 'HP:0002575', (224, 250))	('BT boost', 'Chemical', '-', (71, 79))	('tracheoesophageal fistulae', 'Disease', (224, 250))	('patients', 'Species', '9606', (261, 269))	('ulceration', 'Disease', (169, 179))	('tracheoesophageal fistulae', 'Disease', 'MESH:D014138', (224, 250))	('strictures', 'Disease', (117, 127))
920583	24774780	Table 3 shows that NBT + EBRT with or without CT resulted in treatment complication similar to that which has been reported.	('NBT + EBRT', 'Chemical', '-', (19, 29))	('NBT + EBRT', 'Var', (19, 29))	('treatment', 'Disease', (61, 70))
920584	24774780	Because 252Cf NBT is a form of high-LET radiotherapy, we believe that it is superior to conventional X-ray radiotherapy in treating radio-resistant esophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('252Cf', 'Var', (8, 13))	('esophageal cancers', 'Disease', (148, 166))	('NBT', 'Chemical', '-', (14, 17))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('esophageal cancers', 'Disease', 'MESH:D004938', (148, 166))
920598	23918832	Prognostic Role of Lemur Tyrosine Kinase-3 germline polymorphisms in Adjuvant Gastric Cancer in Japan and the United States Lemur tyrosine kinase-3 (LMTK3) was recently identified as estrogen receptor (ER) -alpha modulator related to endocrine therapy resistance, and its polymorphisms rs9989661 (T>C) T/T genotype and rs8108419 (G>A) G/G or A/G genotype predicted improved outcomes in breast cancer.	('Lemur Tyrosine Kinase-3', 'Gene', (19, 42))	('Adjuvant Gastric Cancer', 'Disease', 'MESH:D013274', (69, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (386, 399))	('Lemur tyrosine kinase-3', 'Gene', '114783', (124, 147))	('rs9989661', 'Mutation', 'rs9989661', (286, 295))	('breast cancer', 'Disease', 'MESH:D001943', (386, 399))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (78, 92))	('Adjuvant Gastric Cancer', 'Disease', (69, 92))	('LMTK3', 'Gene', (149, 154))	('improved', 'PosReg', (365, 373))	('breast cancer', 'Disease', (386, 399))	('rs8108419 (G>A) G/G', 'Var', (319, 338))	('rs8108419', 'Mutation', 'rs8108419', (319, 328))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Lemur tyrosine kinase-3', 'Gene', (124, 147))	('estrogen receptor (ER) -alpha', 'Gene', (183, 212))	('Lemur Tyrosine Kinase-3', 'Gene', '114783', (19, 42))	('LMTK3', 'Gene', '114783', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('rs9989661 (T>C) T/T', 'Var', (286, 305))	('estrogen receptor (ER) -alpha', 'Gene', '2099', (183, 212))
920601	23918832	When gender was considered, in multivariate analysis, harboring rs9989661 T/T genotype was associated with disease-free survival (HR 4.37; 95% CI, 2.08-9.18; p<0.0001) and overall survival (OS) (HR 3.69; 95% CI, 1.65-8.24; p=0.0014) in the Japanese males and time to recurrence (HR 7.29; 95% CI, 1.07-49.80; p=0.043) in the US females.	('overall survival', 'CPA', (172, 188))	('rs9989661 T/T', 'Var', (64, 77))	('OS', 'Chemical', '-', (190, 192))	('disease-free survival', 'CPA', (107, 128))	('rs9989661', 'Mutation', 'rs9989661', (64, 73))	('associated', 'Reg', (91, 101))
920602	23918832	Meanwhile, harboring rs8108419 G/G genotype was associated with OS in the Japanese females (HR 3.04; 95% CI, 1.08-8.56; p=0.035) and the US males (HR 3.39; 95% CI, 1.31-8.80; p=0.012).	('associated', 'Reg', (48, 58))	('OS', 'Chemical', '-', (64, 66))	('rs8108419', 'Mutation', 'rs8108419', (21, 30))	('rs8108419 G/G', 'Var', (21, 34))
920612	23918832	In addition, specific genetic alternations are associated with clinicopathologic features and prognosis in gastric cancer.	('genetic alternations', 'Var', (22, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gastric cancer', 'Disease', (107, 121))	('associated', 'Reg', (47, 57))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))
920614	23918832	These molecular diversities of genetic alternations, which reflect clinicopathologic features based on regional differences, have led to different prognosis with a lack of standard chemotherapeutic strategies across the world for gastric cancer patients.	('patients', 'Species', '9606', (245, 253))	('gastric cancer', 'Disease', (230, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('alternations', 'Var', (39, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (230, 244))	('gastric cancer', 'Phenotype', 'HP:0012126', (230, 244))
920629	23918832	Lower LMTK3 protein expression and its germline polymorphisms rs9989661 (T>C) T/T genotype and rs8108419 (G>A) G/G or A/G genotypes were associated with favorable clinicopathological profiles and better prognosis in ERalpha+ breast cancer.	('LMTK3', 'Gene', (6, 11))	('expression', 'MPA', (20, 30))	('ERalpha', 'Gene', '2099', (216, 223))	('ERalpha', 'Gene', (216, 223))	('rs9989661 (T>C) T/T', 'Var', (62, 81))	('rs8108419', 'Mutation', 'rs8108419', (95, 104))	('Lower', 'NegReg', (0, 5))	('rs8108419 (G>A) G/G', 'Var', (95, 114))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('LMTK3', 'Gene', '114783', (6, 11))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', (225, 238))	('rs9989661', 'Mutation', 'rs9989661', (62, 71))
920630	23918832	Meanwhile, we recently reported inverse results that rs9989661 T/T genotype was associated with worse prognosis in CRC.	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('rs9989661', 'Mutation', 'rs9989661', (53, 62))	('rs9989661', 'Var', (53, 62))	('CRC', 'Disease', (115, 118))
920631	23918832	Given these opposing results which reflect the different biology based on predominant ERs distributions among breast and CRC and growing data suggesting an important role of estrogen in gastric cancer, we hypothesized that LMTK3 polymorphisms may have different prognostic roles in breast and GI cancers.	('gastric cancer', 'Disease', (186, 200))	('breast and GI cancers', 'Disease', 'MESH:D001943', (282, 303))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('ER', 'Gene', '2099', (86, 88))	('GI cancer', 'Phenotype', 'HP:0007378', (293, 302))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('LMTK3', 'Gene', (223, 228))	('CRC', 'Phenotype', 'HP:0003003', (121, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Phenotype', 'HP:0002664', (296, 303))	('polymorphisms', 'Var', (229, 242))	('LMTK3', 'Gene', '114783', (223, 228))
920632	23918832	Since the prognostic role of LMTK3 polymorphisms in gastric cancer is unknown and the regional differences in epidemiology and clinicopathologic features are recognized, we tested whether LMTK3 polymorphisms in gastric cancer will be associated with outcome in two ethnically and epidemiologically different cohorts from Japan and the US.	('tested', 'Reg', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('LMTK3', 'Gene', (188, 193))	('associated', 'Reg', (234, 244))	('gastric cancer', 'Disease', (211, 225))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('LMTK3', 'Gene', '114783', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('LMTK3', 'Gene', (29, 34))	('LMTK3', 'Gene', '114783', (188, 193))	('gastric cancer', 'Disease', (52, 66))	('polymorphisms', 'Var', (194, 207))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))
920651	23918832	The Cox proportional hazards regression model with stratification factors were fitted to re-evaluate the association between LMTK3 polymorphisms and outcomes considering the imbalanced in the distributions of baseline characters in both cohorts.	('LMTK3', 'Gene', '114783', (125, 130))	('Cox', 'Gene', '1351', (4, 7))	('Cox', 'Gene', (4, 7))	('LMTK3', 'Gene', (125, 130))	('polymorphisms', 'Var', (131, 144))	('imbalance', 'Phenotype', 'HP:0002172', (174, 183))
920652	23918832	With 169 patients in the Japanese cohort and 137 patients in the US cohort, we would have 80% power to detect a minimum hazard ratio 1.8-2.0 in DFS and TTR across a range of the variant allele frequencies (0.2-0.5) in a dominant model using a 0.05 level two-sided log-rank test.	('patients', 'Species', '9606', (9, 17))	('TTR', 'Disease', (152, 155))	('variant', 'Var', (178, 185))	('DFS', 'Disease', (144, 147))	('patients', 'Species', '9606', (49, 57))
920660	23918832	Final success rates of LMTK3 genotyping in the Japanese and the US cohorts were 167 (99%) and 125 (91%) for rs9989661 and 165 (98%) and 127 (93%) for rs8108419, respectively.	('rs9989661', 'Mutation', 'rs9989661', (108, 117))	('rs8108419', 'Mutation', 'rs8108419', (150, 159))	('LMTK3', 'Gene', '114783', (23, 28))	('rs9989661', 'Var', (108, 117))	('rs8108419', 'Var', (150, 159))	('LMTK3', 'Gene', (23, 28))
920661	23918832	The allelic frequencies of rs9989661 were not within the probability limits of Hardy-Weinberg equilibrium in both cohorts (Chi-Square p value <0.05).	('Hardy-Weinberg equilibrium', 'Disease', (79, 105))	('rs9989661', 'Mutation', 'rs9989661', (27, 36))	('rs9989661', 'Var', (27, 36))
920662	23918832	In addition, significantly different allelic distributions in LMTK3 rs9989661 were found between both cohorts (Suppl.	('rs9989661', 'Var', (68, 77))	('LMTK3', 'Gene', (62, 67))	('rs9989661', 'Mutation', 'rs9989661', (68, 77))	('LMTK3', 'Gene', '114783', (62, 67))
920663	23918832	Moreover, strong linkage disequilibrium between rs9989661 C allele and rs8108419 G allele was found in the Japanese cohort (D' = 0.967, r2 = 0.338), while weak linkage disequilibrium between rs9989661 T allele and rs8108419 G allele was found in the US cohort (D' = 0.512, r2 = 0.042).	('rs8108419', 'Mutation', 'rs8108419', (214, 223))	('rs8108419', 'Mutation', 'rs8108419', (71, 80))	('rs9989661', 'Mutation', 'rs9989661', (191, 200))	('rs9989661 C', 'Var', (48, 59))	('rs8108419 G', 'Var', (71, 82))	('linkage', 'Interaction', (17, 24))	('rs9989661', 'Mutation', 'rs9989661', (48, 57))
920666	23918832	After analyzing according to gender, in rs9989661, the Japanese males harboring T/T genotype had shorter median DFS of 0.9 years (95% CI, 0.3-6.1+ years) and median OS of 1.7 years (95% CI, 0.6-6.1+ years) compared with median DFS of 20.1+ years (95% CI, 2.4-20.1+ years) (HR 2.05; 95% CI, 1.05-4.00; p=0.030.)	('OS', 'Chemical', '-', (165, 167))	('DFS', 'MPA', (112, 115))	('rs9989661', 'Mutation', 'rs9989661', (40, 49))	('T/T', 'Var', (80, 83))	('shorter', 'NegReg', (97, 104))
920668	23918832	The US females harboring T/T genotype had a shorter median TTR of 1.7 years (95% CI, 0.7-7.0+ years) compared with 7.0 years (95% CI, 3.7 -8.3+ years) for CT or CC genotype (HR 2.70; 95% CI, 1.01-7.19; p=0.025), however, no significant difference was found in OS (Table 4).	('OS', 'Chemical', '-', (260, 262))	('T/T', 'Var', (25, 28))	('shorter', 'NegReg', (44, 51))	('TTR', 'MPA', (59, 62))
920671	23918832	Multivariate analysis for LMTK3 rs9989661 and rs8108419 was stratified by age, stage and adjuvant chemotherapy in the Japanese cohort and by N stage, race, and adjuvant chemotherapy in the US cohort, LMTK3 rs9989661 remained significantly associated with DFS (HR 4.37; 95% CI, 2.08-9.18; p<0.0001) and OS (HR 3.69; 95% CI, 1.65-8.24; p=0.0014) in the Japanese males and TTR (HR 7.29; 95% CI, 1.07-49.80; p=0.043) in the US females (Table 3, 4).	('associated', 'Reg', (239, 249))	('OS', 'Chemical', '-', (302, 304))	('LMTK3', 'Gene', '114783', (200, 205))	('DFS', 'Disease', (255, 258))	('rs9989661', 'Mutation', 'rs9989661', (32, 41))	('TTR', 'Disease', (370, 373))	('LMTK3', 'Gene', '114783', (26, 31))	('LMTK3', 'Gene', (200, 205))	('rs9989661', 'Var', (32, 41))	('rs8108419', 'Mutation', 'rs8108419', (46, 55))	('rs9989661', 'Mutation', 'rs9989661', (206, 215))	('LMTK3', 'Gene', (26, 31))
920672	23918832	LMTK3 rs8108419 was also associated with only OS in the Japanese females (HR 3.04; 95% CI, 1.08-8.56; p=0.035) and in the US males (HR 3.39; 95% CI, 1.31-8.80; p=0.012) (Table 3, 4).	('rs8108419', 'Var', (6, 15))	('LMTK3', 'Gene', (0, 5))	('OS', 'Chemical', '-', (46, 48))	('rs8108419', 'Mutation', 'rs8108419', (6, 15))	('LMTK3', 'Gene', '114783', (0, 5))
920676	23918832	Moreover, postmenopausal HRT reduced the incidence of CRC and gastric cancer.	('men', 'Species', '9606', (14, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CRC', 'Disease', (54, 57))	('postmenopausal HRT', 'Phenotype', 'HP:0008209', (10, 28))	('postmenopausal', 'Var', (10, 24))	('reduced', 'NegReg', (29, 36))	('gastric cancer', 'Disease', (62, 76))	('CRC', 'Phenotype', 'HP:0003003', (54, 57))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))
920689	23918832	LMTK3 polymorphisms were associated with the better outcome in ERalpha+ breast cancer but worse outcome in CRC.	('LMTK3', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('polymorphisms', 'Var', (6, 19))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('ERalpha', 'Gene', '2099', (63, 70))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('ERalpha', 'Gene', (63, 70))	('LMTK3', 'Gene', '114783', (0, 5))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
920691	23918832	These opposite results between breast and GI cancers in LMTK3 polymorphisms are consistent with the different ERs distributions in the breast and in the GI tract, suggesting that the prognostic role of LMTK3 polymorphisms reflects different predominant ERs distributions in different organs.	('LMTK3', 'Gene', '114783', (202, 207))	('GI cancer', 'Phenotype', 'HP:0007378', (42, 51))	('breast and GI cancers', 'Disease', 'MESH:D001943', (31, 52))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('ER', 'Gene', '2099', (110, 112))	('LMTK3', 'Gene', (202, 207))	('LMTK3', 'Gene', (56, 61))	('polymorphisms', 'Var', (62, 75))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('ER', 'Gene', '2099', (253, 255))	('LMTK3', 'Gene', '114783', (56, 61))
920694	23918832	Moreover, it was reported that phosphorylation of ERbeta was associated with better survival in ERalpha+ breast cancer via posttranslational modifications.	('better', 'PosReg', (77, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('ERalpha', 'Gene', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('ERbeta', 'Gene', (50, 56))	('survival', 'MPA', (84, 92))	('ERalpha', 'Gene', '2099', (96, 103))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('phosphorylation', 'Var', (31, 46))	('breast cancer', 'Disease', (105, 118))	('ERbeta', 'Gene', '2100', (50, 56))
920696	23918832	The functions of these polymorphisms remain unclear; hence, the F-SNP database was used for the LMTK3 rs9989661 and rs8108419.	('LMTK3', 'Gene', '114783', (96, 101))	('rs8108419', 'Mutation', 'rs8108419', (116, 125))	('LMTK3', 'Gene', (96, 101))	('rs9989661', 'Mutation', 'rs9989661', (102, 111))	('rs8108419', 'Var', (116, 125))	('rs9989661', 'Var', (102, 111))
920697	23918832	These findings suggest that these polymorphisms may affect LMTK3 gene expression levels.	('LMTK3', 'Gene', (59, 64))	('expression levels', 'MPA', (70, 87))	('polymorphisms', 'Var', (34, 47))	('LMTK3', 'Gene', '114783', (59, 64))	('affect', 'Reg', (52, 58))
920701	23918832	In this study, rs9989661 T/T genotype and rs8108419 G/G genotype were associated with worse outcome, especially rs9989661 T/T genotype predicted recurrence of gastric cancer; hence, rs9989661 may reflect more cancer-specific prognosis in gastric cancer.	('gastric cancer', 'Disease', (238, 252))	('cancer', 'Disease', (167, 173))	('rs9989661', 'Mutation', 'rs9989661', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('gastric cancer', 'Disease', 'MESH:D013274', (159, 173))	('rs9989661', 'Mutation', 'rs9989661', (15, 24))	('cancer', 'Disease', (246, 252))	('gastric cancer', 'Disease', 'MESH:D013274', (238, 252))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('rs8108419', 'Mutation', 'rs8108419', (42, 51))	('rs8108419 G/G', 'Var', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('rs9989661', 'Var', (112, 121))	('rs9989661', 'Mutation', 'rs9989661', (182, 191))	('T/T', 'Var', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('rs9989661 T/T', 'Var', (15, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (159, 173))	('predicted', 'Reg', (135, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (238, 252))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('rs9989661', 'Var', (182, 191))	('cancer', 'Disease', (209, 215))	('gastric cancer', 'Disease', (159, 173))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
920706	23918832	The multivariate analysis of rs8108419 revealed the true association with OS when adjusting the imbalance in the distribution of the baseline prognostic factors; hence, rs8108419 G/G genotype might serve as negative prognostic factors in OS.	('rs8108419', 'Mutation', 'rs8108419', (29, 38))	('imbalance', 'Phenotype', 'HP:0002172', (96, 105))	('OS', 'Chemical', '-', (238, 240))	('rs8108419', 'Var', (29, 38))	('OS', 'Chemical', '-', (74, 76))	('rs8108419', 'Mutation', 'rs8108419', (169, 178))	('rs8108419 G/G', 'Var', (169, 182))
920718	23918832	Moreover, increasing data from preclinical studies have shown that cross-talk between HER2 and ER leads to a hormone-independent state in HER2 co-overexpression in breast cancer cells.	('HER2', 'Gene', (86, 90))	('hormone-independent state', 'MPA', (109, 134))	('co-overexpression', 'Var', (143, 160))	('HER2', 'Gene', '2064', (138, 142))	('HER2', 'Gene', '2064', (86, 90))	('cross-talk', 'Var', (67, 77))	('ER', 'Gene', '2099', (87, 89))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('ER', 'Gene', '2099', (139, 141))	('co-overexpression', 'PosReg', (143, 160))	('breast cancer', 'Disease', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('ER', 'Gene', '2099', (95, 97))	('HER2', 'Gene', (138, 142))
920722	23918832	On the other hand, rs8108419 G/G genotype was associated with OS without tumor recurrence in the US males and the Japanese females.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('OS', 'Chemical', '-', (62, 64))	('rs8108419 G/G', 'Var', (19, 32))	('rs8108419', 'Mutation', 'rs8108419', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('associated', 'Reg', (46, 56))
920725	23918832	Significant different allele frequencies in rs9989661 in the two cohorts and different linkage disequilibrium, rs9989661 C allele and rs8108419 G allele in the Japanese cohort and rs9989661 T allele and rs8108419 G allele in the US cohort, may explain these data.	('rs9989661', 'Mutation', 'rs9989661', (180, 189))	('rs9989661', 'Mutation', 'rs9989661', (111, 120))	('rs8108419 G', 'Var', (203, 214))	('rs8108419', 'Mutation', 'rs8108419', (134, 143))	('rs9989661', 'Var', (180, 189))	('rs9989661', 'Var', (111, 120))	('rs8108419', 'Mutation', 'rs8108419', (203, 212))	('rs9989661', 'Mutation', 'rs9989661', (44, 53))	('rs8108419 G', 'Var', (134, 145))	('rs9989661', 'Var', (44, 53))
920728	23918832	The prognostic role of LMTK3 polymorphisms reflects predominant ER distribution in each organ, and its prognostic impact should be taken into account given the complexities consisting of regional differences both in physiology and genetic alternations of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (255, 269))	('LMTK3', 'Gene', '114783', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('LMTK3', 'Gene', (23, 28))	('gastric cancer', 'Disease', (255, 269))	('ER', 'Gene', '2099', (64, 66))	('polymorphisms', 'Var', (29, 42))	('gastric cancer', 'Disease', 'MESH:D013274', (255, 269))
920731	23918832	Our results in the LMTK3 polymorphisms analysis in gastric cancer are the first in GI cancer and shed new light on the differences between the responses on ERalpha versus ERbeta expressing cancers; however, several biological issues remain to be elucidated with the goal of shedding light on the new possibility of prevention and possible treatment in GI cancer.	('ERalpha', 'Gene', '2099', (156, 163))	('men', 'Species', '9606', (344, 347))	('LMTK3', 'Gene', '114783', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('GI cancer', 'Disease', (352, 361))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('GI cancer', 'Disease', 'MESH:D009369', (83, 92))	('GI cancer', 'Phenotype', 'HP:0007378', (83, 92))	('ERbeta', 'Gene', '2100', (171, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (51, 65))	('ERbeta', 'Gene', (171, 177))	('polymorphisms', 'Var', (25, 38))	('GI cancer', 'Disease', 'MESH:D009369', (352, 361))	('GI cancer', 'Phenotype', 'HP:0007378', (352, 361))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('LMTK3', 'Gene', (19, 24))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('ERalpha', 'Gene', (156, 163))	('cancers', 'Disease', (189, 196))	('gastric cancer', 'Disease', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('GI cancer', 'Disease', (83, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (51, 65))
920732	23918832	In conclusion, LMTK3 polymorphisms may serve as a prognostic factor candidate in gastric cancer and may help to select patients who benefit from more careful observation or aggressive treatment.	('men', 'Species', '9606', (189, 192))	('help', 'Reg', (104, 108))	('patients', 'Species', '9606', (119, 127))	('LMTK3', 'Gene', '114783', (15, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('polymorphisms', 'Var', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('LMTK3', 'Gene', (15, 20))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
920735	22449186	Methylation of TFPI-2 is an early event of esophageal carcinogenesis To explore the epigenetic changes and the function of TFPI-2 in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Methylation', 'Var', (0, 11))	('TFPI-2', 'Gene', '7980', (15, 21))	('TFPI-2', 'Gene', '7980', (123, 129))	('TFPI-2', 'Gene', (15, 21))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (43, 68))	('esophageal cancer', 'Disease', (133, 150))	('TFPI-2', 'Gene', (123, 129))	('esophageal carcinogenesis', 'Disease', (43, 68))
920737	22449186	TFPI-2 expression was regulated by promoter region hypermethylation in human esophageal cancer cell lines, and TFPI-2 expression is inversely correlated with methylation in primary cancer.	('TFPI-2', 'Gene', (0, 6))	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('hypermethylation', 'Var', (51, 67))	('TFPI-2', 'Gene', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('regulated', 'Reg', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('cancer', 'Disease', (181, 187))	('human', 'Species', '9606', (71, 76))
920738	22449186	Methylation was found in 28.2, 33.3 and 33.3% of grade 1, 2 and 3 esophageal dysplasia, and 67% of primary esophageal cancer, but no methylation was found in normal mucosa.	('esophageal dysplasia', 'Disease', 'MESH:D004941', (66, 86))	('Methylation', 'Var', (0, 11))	('esophageal cancer', 'Disease', (107, 124))	('found', 'Reg', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('grade 1', 'Disease', (49, 56))	('esophageal dysplasia', 'Disease', (66, 86))
920739	22449186	Methylation is significantly related to tumor differentiation.	('related', 'Reg', (29, 36))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
920740	22449186	TFPI-2 is frequently methylated in esophageal cancer with a progression tendency.	('TFPI-2', 'Gene', (0, 6))	('methylated', 'Var', (21, 31))	('esophageal cancer', 'Disease', (35, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
920761	22449186	Nine esophageal cancer cell lines (TE3, TE10, YSE2, KYSE30, KYSE70, KYSE140, KYSE150, KYSE450 and KYSE510) were used in this study.	('KYSE140', 'Var', (68, 75))	('KYSE510', 'Var', (98, 105))	('esophageal cancer', 'Disease', (5, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (5, 22))
920763	22449186	Esophageal cancer cell lines (TE3, TE10, YSE2, KYSE30, KYSE70, KYSE140, KYSE150, KYSE450 and KYSE510) were split to a low density (30% confluence) at 12 h before treatment.	('KYSE150', 'Var', (72, 79))	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('KYSE30', 'Var', (47, 53))	('KYSE140', 'Var', (63, 70))	('Esophageal cancer', 'Disease', (0, 17))	('KYSE510', 'Var', (93, 100))	('KYSE70', 'Var', (55, 61))	('KYSE450', 'Var', (81, 88))
920805	22449186	These results demonstrate that TFPI-2 is silenced by promoter region methylation in certain esophageal cancer cell lines.	('TFPI-2', 'Gene', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('esophageal cancer', 'Disease', (92, 109))	('methylation', 'Var', (69, 80))	('silenced', 'NegReg', (41, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
920807	22449186	As shown in Figure 2A1, 2A2 & 2A3, 67% (71 of 106) of primary esophageal cancer were methylated, 33.3% (three out of nine) of ED3, 33.3% (four out of 12) of ED2 and 28.2% (11 out of 39) of ED1 were methylated.	('were', 'Var', (80, 84))	('ED2', 'Gene', '10804', (157, 160))	('ED1', 'Gene', (189, 192))	('esophageal cancer', 'Disease', (62, 79))	('ED3', 'Gene', (126, 129))	('ED3', 'Gene', '10913', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))	('ED1', 'Gene', '1896', (189, 192))	('ED2', 'Gene', (157, 160))
920808	22449186	These results indicated TFPI-2 was methylated in the early stage of esophageal carcinogenesis.	('methylated', 'Var', (35, 45))	('esophageal carcinogenesis', 'Disease', (68, 93))	('TFPI-2', 'Gene', (24, 30))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (68, 93))
920812	22449186	As shown in Table 1, TFPI-2 methylation is significantly related to tumor differentiation (chi2 test, p = 0.0323).	('tumor', 'Disease', (68, 73))	('TFPI-2', 'Gene', (21, 27))	('related', 'Reg', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('methylation', 'Var', (28, 39))
920813	22449186	No association was found significantly between TFPI-2 methylation and age, gender, smoking, alcohol, tumor size, stage or metastasis.	('alcohol', 'Chemical', 'MESH:D000438', (92, 99))	('methylation', 'Var', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('TFPI-2', 'Gene', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
920818	22449186	Twenty seven cases were methylated and ten cases were unmethylated in cancer tissue.	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('methylated', 'Var', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))
920829	22449186	As shown in Figure 5C, c-Myc, cyclin D1 and MMP-2 expression were reduced by restoration of TFPI-2 expression.	('expression', 'MPA', (99, 109))	('reduced', 'NegReg', (66, 73))	('MMP-2', 'Gene', (44, 49))	('c-Myc', 'Gene', '4609', (23, 28))	('MMP-2', 'Gene', '4313', (44, 49))	('cyclin D1', 'Gene', '595', (30, 39))	('restoration', 'Var', (77, 88))	('TFPI-2', 'Gene', (92, 98))	('c-Myc', 'Gene', (23, 28))	('cyclin D1', 'Gene', (30, 39))	('expression', 'MPA', (50, 60))
920841	22449186	Regulation of TFPI-2 expression by methylation was further validated by reactivation of TFPI-2 methylated esophageal cancer cell lines with DAC treatment.	('methylated', 'Var', (95, 105))	('reactivation', 'Var', (72, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('TFPI-2', 'Gene', (14, 20))	('TFPI-2', 'Gene', (88, 94))	('esophageal cancer', 'Disease', (106, 123))
920843	22449186	The results show that methylation occurred early and frequently in esophageal cancer, but not in normal mucosa.	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('frequently', 'Reg', (53, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('methylation', 'Var', (22, 33))
920845	22449186	These data indicate TFPI-2 methylation may be a suitable candidate as an early detection marker and that TFPI-2 may play an important role in esophageal cancer.	('esophageal cancer', 'Disease', (142, 159))	('methylation', 'Var', (27, 38))	('TFPI-2', 'Gene', (105, 111))	('play', 'Reg', (116, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TFPI-2', 'Gene', (20, 26))
920846	22449186	Further, the promoter region methylation of TFPI-2 is inversely related to its expression in paired esophageal cancer and adjacent tissue (chi2 test, p = 0.0039).	('methylation', 'Var', (29, 40))	('expression', 'MPA', (79, 89))	('esophageal cancer', 'Disease', (100, 117))	('related', 'Reg', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (100, 117))	('TFPI-2', 'Gene', (44, 50))	('promoter', 'MPA', (13, 21))
920847	22449186	These results demonstrate that TFPI-2 is regulated by DNA methylation in esophageal primary cancer and that TFPI-2 induces esophageal cancer differentiation.	('TFPI-2', 'Gene', (31, 37))	('esophageal cancer', 'Disease', (123, 140))	('esophageal primary cancer', 'Disease', (73, 98))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('esophageal primary cancer', 'Disease', 'MESH:D004938', (73, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('induces', 'Reg', (115, 122))	('TFPI-2', 'Var', (108, 114))
920851	22449186	As shown in Figure 5, TFPI-2 induced apoptosis in esophageal cancer cell lines, and re-expression of TFPI-2 reduced the ratio of G0/1 and S phase cells and increased G2/M phase cells.	('G2/M phase cells', 'CPA', (166, 182))	('re-expression', 'Var', (84, 97))	('reduced', 'NegReg', (108, 115))	('increased', 'PosReg', (156, 165))	('TFPI-2', 'Gene', (101, 107))	('esophageal cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
920852	22449186	c-Myc, cyclin D1 and MMP-2 expression were reduced after restoration of TFPI-2 expression.	('expression', 'MPA', (79, 89))	('TFPI-2', 'Gene', (72, 78))	('MMP-2', 'Gene', (21, 26))	('expression', 'MPA', (27, 37))	('c-Myc', 'Gene', '4609', (0, 5))	('restoration', 'Var', (57, 68))	('cyclin D1', 'Gene', '595', (7, 16))	('MMP-2', 'Gene', '4313', (21, 26))	('reduced', 'NegReg', (43, 50))	('cyclin D1', 'Gene', (7, 16))	('c-Myc', 'Gene', (0, 5))
920859	22449186	Epigenetic therapy is becoming an effective approach for different tumor.	('different tumor', 'Disease', (57, 72))	('Epigenetic', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('different tumor', 'Disease', 'MESH:D009369', (57, 72))
920864	22449186	Methylation of TFPI-2 was in progression during esophageal carcinogenesis.	('Methylation', 'Var', (0, 11))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (48, 73))	('TFPI-2', 'Gene', (15, 21))	('esophageal carcinogenesis', 'Disease', (48, 73))
920865	22449186	TFPI-2 methylation was significantly related to tumor differentiation (p = 0.0323), and TFPI-2 staining was inversely correlated with DNA methylation in esophageal cancer and adjacent tissues (p = 0.0039).	('TFPI-2', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('DNA methylation', 'MPA', (134, 149))	('tumor', 'Disease', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('related', 'Reg', (37, 44))	('correlated', 'Reg', (118, 128))	('methylation', 'Var', (7, 18))	('TFPI-2', 'Gene', (88, 94))	('esophageal cancer', 'Disease', (153, 170))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('inversely', 'NegReg', (108, 117))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
920866	22449186	TFPI-2 methylation was reversible by 5-aza-2'-deoxycytidine in esophageal cancer.	('TFPI-2', 'Gene', (0, 6))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('methylation', 'Var', (7, 18))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (37, 59))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
920867	22449186	Expression of c-Myc, cyclin D1 and MMP-2 was reduced when restoration of TFPI-2 expression in esophageal cancer cell line.	('restoration', 'Var', (58, 69))	('reduced', 'NegReg', (45, 52))	('c-Myc', 'Gene', (14, 19))	('TFPI-2', 'Gene', (73, 79))	('Expression', 'MPA', (0, 10))	('esophageal cancer', 'Disease', (94, 111))	('MMP-2', 'Gene', (35, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('expression', 'MPA', (80, 90))	('cyclin D1', 'Gene', '595', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('MMP-2', 'Gene', '4313', (35, 40))	('cyclin D1', 'Gene', (21, 30))	('c-Myc', 'Gene', '4609', (14, 19))
920868	22449186	TFPI-2 was frequently methylated in esophageal cancer.	('TFPI-2', 'Gene', (0, 6))	('esophageal cancer', 'Disease', 'MESH:D004938', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('methylated', 'Var', (22, 32))	('esophageal cancer', 'Disease', (36, 53))
920869	22449186	TFPI-2 methylation was related to esophageal cancer differentiation.	('TFPI-2', 'Gene', (0, 6))	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('related', 'Reg', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('methylation', 'Var', (7, 18))
920871	22449186	Silencing of TFPI-2 may cause colony formation, invasion, migration and proliferation in esophageal cancer.	('esophageal cancer', 'Disease', (89, 106))	('colony formation', 'CPA', (30, 46))	('migration', 'CPA', (58, 67))	('cause', 'Reg', (24, 29))	('proliferation', 'CPA', (72, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('invasion', 'CPA', (48, 56))	('Silencing', 'Var', (0, 9))	('TFPI-2', 'Gene', (13, 19))
921023	11319942	Briefly, lymphatic vessel invasion was graded according to the following: ly0: none; ly1: mild; ly2: moderate; and ly3: severe.	('ly2', 'Var', (96, 99))	('ly3', 'Gene', (115, 118))	('ly0', 'Chemical', '-', (74, 77))	('ly3', 'Gene', '926', (115, 118))	('lymphatic vessel invasion', 'CPA', (9, 34))
921038	11319942	Lymphatic vessel invasion gradings included: 1 ly0, 18 ly1, 24 ly2, and 2 ly3.	('ly2', 'Var', (63, 66))	('ly3', 'Gene', (74, 77))	('ly0', 'Chemical', '-', (47, 50))	('ly3', 'Gene', '926', (74, 77))	('Lymphatic vessel invasion', 'CPA', (0, 25))
921039	11319942	Since the ly0 and ly3 numbers were low, lymphatic vessel invasion was classified into two groups: ly0+ly1 and ly2+ly3.	('ly3', 'Gene', '926', (18, 21))	('ly3', 'Gene', (18, 21))	('ly3', 'Gene', '926', (114, 117))	('ly3', 'Gene', (114, 117))	('ly0+ly1', 'Var', (98, 105))	('ly0', 'Chemical', '-', (98, 101))	('ly0', 'Chemical', '-', (10, 13))	('lymphatic vessel invasion', 'CPA', (40, 65))
921040	11319942	Lymph node metastasis in the ly0+ly1 and ly2+ly3 groups was 6/19 (31.6%) and 17/26 (65.4%), respectively.	('ly3', 'Gene', '926', (45, 48))	('ly3', 'Gene', (45, 48))	('ly0+ly1', 'Var', (29, 36))	('ly0', 'Chemical', '-', (29, 32))	('Lymph node metastasis', 'CPA', (0, 21))
921042	11319942	Expression of nm23-H1 gene product in the ly0+ly1 and ly2+ly3 groups was 12/19 (63.2%) and 5/26 (19.2%), respectively, while numbers for the nm23-H1 negative cases were 7/19 (36.8%) and 21/26 (80.8%), respectively, indicating an inverse relationship between nm23-H1 gene product expression and lymphatic vessel invasion (p < 0.01).	('nm23-H1', 'Gene', (141, 148))	('inverse', 'NegReg', (229, 236))	('nm23-H1', 'Gene', (258, 265))	('lymphatic vessel invasion', 'CPA', (294, 319))	('nm23-H1', 'Gene', (14, 21))	('nm23-H1', 'Gene', '4830', (258, 265))	('ly3', 'Gene', '926', (58, 61))	('ly0+ly1', 'Var', (42, 49))	('ly3', 'Gene', (58, 61))	('nm23-H1', 'Gene', '4830', (141, 148))	('ly0', 'Chemical', '-', (42, 45))	('nm23-H1', 'Gene', '4830', (14, 21))
921053	11319942	demonstrated positive nm23 staining in 13 (29%) of 45 patients with T3-4N1M0 esophageal carcinoma, and Iizuka et al.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (77, 97))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (77, 97))	('patients', 'Species', '9606', (54, 62))	('nm23', 'Gene', '4830', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('T3-4N1M0', 'Var', (68, 76))	('nm23', 'Gene', (22, 26))	('esophageal carcinoma', 'Disease', (77, 97))
921074	11319942	suggested that, in colorectal cancer, allelic deletion of the nm23-H1 gene has been shown to have possible antimetastatic functions.	('nm23-H1', 'Gene', (62, 69))	('allelic deletion', 'Var', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('antimetastatic functions', 'CPA', (107, 131))	('colorectal cancer', 'Disease', 'MESH:D015179', (19, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (19, 36))	('nm23-H1', 'Gene', '4830', (62, 69))	('colorectal cancer', 'Disease', (19, 36))
921075	11319942	Although we did not determine allelic deletion in the presence of nm23-H1 gene product expression in our study, the possibility remains that changes in the nm23-H1 locus have an antimetastatic function in esophageal squamous cell carcinoma as well.	('antimetastatic function', 'CPA', (178, 201))	('nm23-H1', 'Gene', (156, 163))	('changes', 'Var', (141, 148))	('nm23-H1', 'Gene', '4830', (156, 163))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (205, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('nm23-H1', 'Gene', (66, 73))	('esophageal squamous cell carcinoma', 'Disease', (205, 239))	('nm23-H1', 'Gene', '4830', (66, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (216, 239))
921178	30510650	Among the neoplastic esophageal lesions, 25.9% (7.27) harbored high risk types (HPV35, HPV39 and HPV45 were the most common high-risk types in neoplastic group, which were detected in 3 cases each), 18.5% (5.27) harbored low risk types and 62.9% (17.27) were untypable.	('HPV', 'Species', '10566', (97, 100))	('HPV39', 'Var', (87, 92))	('neoplastic esophageal lesions', 'Disease', 'MESH:D004938', (10, 39))	('HPV', 'Species', '10566', (87, 90))	('HPV', 'Species', '10566', (80, 83))	('HPV35', 'Species', '10587', (80, 85))	('neoplastic esophageal lesions', 'Disease', (10, 39))	('neoplastic esophageal lesions', 'Phenotype', 'HP:0100751', (10, 39))	('HPV45', 'Var', (97, 102))
921187	30510650	In non- neoplastic group, only 5.8% (3.52) of esophagitis specimens contained EBV DNA sequence and EBV infection was not found in samples with esophageal dysplasia and normal histology.	('EBV infection', 'Disease', (99, 112))	('EBV infection', 'Disease', 'MESH:D020031', (99, 112))	('EBV DNA', 'Var', (78, 85))	('esophageal dysplasia', 'Disease', (143, 163))	('EBV', 'Species', '10376', (99, 102))	('EBV', 'Species', '10376', (78, 81))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (143, 163))	('esophagitis', 'Disease', (46, 57))	('esophagitis', 'Phenotype', 'HP:0100633', (46, 57))	('esophagitis', 'Disease', 'MESH:D004941', (46, 57))
921194	30510650	In non-neoplastic group, 55.6% (5.9) of esophageal dysplasia, and 36.5% (19.52) of esophagitis specimens contained MCPyV DNA sequence.	('esophageal dysplasia', 'Disease', (40, 60))	('contained', 'Reg', (105, 114))	('esophagitis', 'Phenotype', 'HP:0100633', (83, 94))	('esophagitis', 'Disease', (83, 94))	('esophagitis', 'Disease', 'MESH:D004941', (83, 94))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (40, 60))	('MCPyV', 'Species', '493803', (115, 120))	('MCPyV DNA sequence', 'Var', (115, 133))
921200	30510650	Additionally, the mean MCPyV copy number was higher in poorly differentiated (27.3x10-6+-47.3x10-6) and well differentiated (15.5x10-6+-35.8x10-6) tumors compared to other histopathologic groups however, this difference was not statistically significant (p=0.245) (fig.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('copy number', 'Var', (29, 40))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('higher', 'PosReg', (45, 51))	('MCPyV', 'Gene', (23, 28))	('MCPyV', 'Species', '493803', (23, 28))
921216	30510650	HPV35, HPV39 and HPV45 were the most common high-risk types in neoplastic group, while HPV56 was most prevalent high-risk type in non-neoplastic samples.	('HPV', 'Species', '10566', (7, 10))	('HPV35', 'Var', (0, 5))	('HPV35', 'Species', '10587', (0, 5))	('HPV', 'Species', '10566', (0, 3))	('HPV39', 'Var', (7, 12))	('HPV', 'Species', '10566', (87, 90))	('HPV45', 'Var', (17, 22))	('HPV', 'Species', '10566', (17, 20))	('neoplastic group', 'Disease', (63, 79))
921232	25169894	Global population-specific variation in miRNA associated with cancer risk and clinical biomarkers MiRNA expression profiling is being actively investigated as a clinical biomarker and diagnostic tool to detect multiple cancer types and stages as well as other complex diseases.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('associated', 'Reg', (46, 56))	('variation', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('miRNA', 'Gene', (40, 45))	('cancer', 'Disease', (219, 225))
921236	25169894	Notably, hsa-mir-202, a potential breast cancer biomarker, was found to show significantly high allele frequency differentiation at SNP rs12355840, which is known to affect miRNA expression levels in vivo and subsequently breast cancer mortality.	('miRNA expression levels', 'MPA', (173, 196))	('breast cancer', 'Disease', (222, 235))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('hsa-mir-202', 'Gene', (9, 20))	('breast cancer', 'Disease', (34, 47))	('rs12355840', 'Mutation', 'rs12355840', (136, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('SNP rs12355840', 'Var', (132, 146))	('affect', 'Reg', (166, 172))	('hsa-mir-202', 'Gene', '574448', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))
921243	25169894	We identified 7 PD variants within miRNA that have been experimentally linked to onset, progression, and/or metastasis of cancers with known health disparities between patients of European and African descent.	('miRNA', 'Gene', (35, 40))	('linked to', 'Reg', (71, 80))	('metastasis of cancers', 'Disease', (108, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('metastasis of cancers', 'Disease', 'MESH:D009362', (108, 129))	('variants', 'Var', (19, 27))
921244	25169894	Specifically, we find a T-allele at SNP rs12355840 in hsa-mir-202, that has been shown to increase miRNA expression in vivo and to be protective against breast cancer mortality, and to be highly PD between African and non-African populations.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('increase', 'PosReg', (90, 98))	('rs12355840', 'Mutation', 'rs12355840', (40, 50))	('hsa-mir-202', 'Gene', (54, 65))	('miRNA expression', 'MPA', (99, 115))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('SNP rs12355840', 'Var', (36, 50))	('hsa-mir-202', 'Gene', '574448', (54, 65))	('breast cancer', 'Disease', (153, 166))
921246	25169894	The second, a "C/T" SNP at chr1 62544469, was located in the 3' strand of hsa-mir-942 and was present in one Hadza and two Sandawe individuals.	('hsa-mir-942', 'Gene', '100126331', (74, 85))	('chr1 62544469', 'Var', (27, 40))	('hsa-mir-942', 'Gene', (74, 85))
921248	25169894	Lastly, a "CT" deletion located on chromosome 6 in the 3' strand of hsa-mir-4640 was found in 9 individuals from 7 global populations (namely, 1 Pygmy, 2 Sandawe, 1 Yoruba, 1 Maasai, 2 African-Americans, 1 Mexican-American and 1 Gujarati Indian individual).	('deletion', 'Var', (15, 23))	('hsa-mir-4640', 'Gene', (68, 80))	('hsa-mir-4640', 'Gene', '100616237', (68, 80))
921249	25169894	Using miRNA target prediction software, we determined that in the absence of the "CT" mutation in miRNA hsa-mir-4640, the 3' strand was predicted to individually target 316 binding sites in 79 genes (Additional file 1: Table S3).	('hsa-mir-4640', 'Gene', '100616237', (104, 116))	('binding', 'Interaction', (173, 180))	('hsa-mir-4640', 'Gene', (104, 116))	('mutation', 'Var', (86, 94))
921251	25169894	Among the Hadza hunter-gatherers, we found two high frequency PSMAs with allele frequency >= 50% in the Hadza only, a novel "A/C" SNP in the stem-loop of hsa-mir-1291 and an "A/G" SNP (rs111566161) in the 3' mature sequence of miRNA hsa-mir-4711.	('hsa-mir-1291', 'Gene', (154, 166))	('rs111566161', 'Var', (185, 196))	('hsa-mir-4711', 'Gene', '100616409', (233, 245))	('PSMAs', 'Disease', (62, 67))	('rs111566161', 'Mutation', 'rs111566161', (185, 196))	('hsa-mir-1291', 'Gene', '100302221', (154, 166))	('hsa-mir-4711', 'Gene', (233, 245))
921260	25169894	The hsa-mir-196a-2 T-allele at SNP rs11614913 has been significantly associated with increased risk for esophageal cancer in non-smoking European males but decreased risk for breast, lung and gastric cancers in Chinese populations.	('gastric cancer', 'Phenotype', 'HP:0012126', (192, 206))	('rs11614913', 'Var', (35, 45))	('SNP', 'Var', (31, 34))	('gastric cancers', 'Disease', 'MESH:D013274', (192, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('gastric cancers', 'Disease', (192, 207))	('lung', 'Disease', (183, 187))	('gastric cancers', 'Phenotype', 'HP:0012126', (192, 207))	('esophageal cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('hsa-mir-196a-2', 'Gene', (4, 18))	('decreased', 'NegReg', (156, 165))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('rs11614913', 'Mutation', 'rs11614913', (35, 45))	('hsa-mir-196a-2', 'Gene', '406973', (4, 18))	('breast', 'Disease', (175, 181))
921264	25169894	Specifically, a novel "CT" deletion found in 7 of the 14 globally diverse populations altered the predicted mRNA targets of hsa-mir-4640 to include 3 additional targets and removed all of its 79 original predicted targets from regulation, indicative of the disruptive potential of seed sequencing indels on miRNA function.	('hsa-mir-4640', 'Gene', (124, 136))	('removed', 'NegReg', (173, 180))	('altered', 'Reg', (86, 93))	('deletion', 'Var', (27, 35))	('mRNA targets', 'MPA', (108, 120))	('hsa-mir-4640', 'Gene', '100616237', (124, 136))
921266	25169894	Aberrant cell division during mitosis or aberrant gene expression levels during chromosome segregation often result in chromosomal instability, which is a key diagnostic feature of most cancers.	('Aberrant cell division during mitosis', 'Phenotype', 'HP:0011018', (0, 37))	('aberrant', 'Var', (41, 49))	('Aberrant', 'Var', (0, 8))	('chromosomal', 'Disease', (119, 130))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancers', 'Disease', (186, 193))	('mitosis', 'Disease', (30, 37))	('chromosomal instability', 'Phenotype', 'HP:0040012', (119, 142))	('mitosis', 'Disease', 'None', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('result in', 'Reg', (109, 118))
921267	25169894	The disruption of cell division by altering gene expression levels in response to mitotic instability has been strongly correlated with tumor development and progression; both in vitro and in vivo evidence have demonstrated that in the absence of other cell cycle and DNA repair defects, mitotic disruption can transform cells and predispose them toward cancer.	('cancer', 'Disease', (354, 360))	('mitotic disruption', 'Var', (288, 306))	('transform', 'Reg', (311, 320))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('predispose', 'Reg', (331, 341))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cells', 'CPA', (321, 326))	('cancer', 'Disease', 'MESH:D009369', (354, 360))	('tumor', 'Disease', (136, 141))
921278	25169894	First, the hsa-mir-423 SNP rs6505162 has been shown to confer reduced risk for breast cancer in women of European decent in GWAS.	('rs6505162', 'Mutation', 'rs6505162', (27, 36))	('hsa-mir-423', 'Gene', (11, 22))	('rs6505162', 'Var', (27, 36))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('hsa-mir-423', 'Gene', '494335', (11, 22))	('women', 'Species', '9606', (96, 101))	('reduced', 'NegReg', (62, 69))
921279	25169894	Second, the hsa-mir-196a-2 SNP rs11614913 CC genotype has been significantly associated with increased risk for breast, lung and gastric cancers in Chinese populations; conversely, the homozygous TT genotype has been significantly associated with esophageal cancer in non-smoking European males.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gastric cancers', 'Disease', 'MESH:D013274', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('esophageal cancer', 'Disease', (247, 264))	('hsa-mir-196a-2', 'Gene', '406973', (12, 26))	('gastric cancers', 'Disease', (129, 144))	('gastric cancers', 'Phenotype', 'HP:0012126', (129, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (247, 264))	('breast', 'Disease', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('rs11614913', 'Mutation', 'rs11614913', (31, 41))	('rs11614913 CC', 'Var', (31, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))	('associated', 'Reg', (231, 241))	('lung', 'Disease', (120, 124))	('hsa-mir-196a-2', 'Gene', (12, 26))
921280	25169894	We observed a significantly higher frequency of the hsa-mir-196a-2 C-allele at SNP rs11614913 in African compared to non-African populations (FST = 0.41; p < 0.001) (Figure 5D).	('rs11614913', 'Mutation', 'rs11614913', (83, 93))	('hsa-mir-196a-2', 'Gene', '406973', (52, 66))	('hsa-mir-196a-2', 'Gene', (52, 66))	('SNP rs11614913', 'Var', (79, 93))
921281	25169894	Third, hsa-mir-520h expression was determined to be significantly associated with E1A-mediated tumor suppression and cell migration during cancer metastasis and inhibition of hsa-mir-520h significantly decreased the downstream ability of cancer cells to migrate and invade other areas of the body.	('decreased', 'NegReg', (202, 211))	('hsa-mir-520h', 'Gene', (175, 187))	('cancer metastasis', 'Disease', (139, 156))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (238, 244))	('inhibition', 'Var', (161, 171))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('hsa-mir-520h', 'Gene', (7, 19))	('cancer metastasis', 'Disease', 'MESH:D009362', (139, 156))	('hsa-mir-520h', 'Gene', '574493', (175, 187))	('tumor', 'Disease', (95, 100))	('cancer', 'Disease', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cell migration', 'CPA', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('associated', 'Reg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('hsa-mir-520h', 'Gene', '574493', (7, 19))
921284	25169894	Finally, multiple studies have linked miRNAs hsa-mir-1908, hsa-mir-647 and hsa-mir-943 expression to various cancers known to have ethnic specific disparities.	('linked', 'Reg', (31, 37))	('hsa-mir-943', 'Gene', (75, 86))	('hsa-mir-647', 'Gene', '693232', (59, 70))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('hsa-mir-943', 'Gene', '100126332', (75, 86))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('hsa-mir-1908', 'Gene', '100302263', (45, 57))	('hsa-mir-647', 'Gene', (59, 70))	('hsa-mir-1908', 'Gene', (45, 57))	('miRNAs', 'Var', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
921285	25169894	Overall, these studies demonstrate that genetic variability within miRNA has the potential to vary miRNA expression and/or mRNA target binding which can be strongly correlated with the onset of multiple cancers, the progression of cancer metastasis and the response to drug therapies.	('genetic variability', 'Var', (40, 59))	('multiple cancers', 'Disease', (194, 210))	('miRNA expression', 'MPA', (99, 115))	('correlated with', 'Reg', (165, 180))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('vary', 'Reg', (94, 98))	('cancer metastasis', 'Disease', (231, 248))	('miRNA', 'Gene', (67, 72))	('binding', 'Interaction', (135, 142))	('multiple cancers', 'Disease', 'MESH:D009369', (194, 210))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('mRNA target', 'MPA', (123, 134))	('cancer metastasis', 'Disease', 'MESH:D009362', (231, 248))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
921286	25169894	Thus, we suggest that population-differentiated variation in miRNA may contribute to ethnic disparities seen in certain forms of cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('contribute', 'Reg', (71, 81))	('variation', 'Var', (48, 57))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('miRNA', 'Gene', (61, 66))
921287	25169894	Here, we identified several miRNA genetic variants that are highly differentiated among human populations and uncovered a set of HPD-miRNAs that play a role in the suppression, susceptibility, and metastasis of cancer cells.	('susceptibility', 'CPA', (177, 191))	('metastasis of cancer', 'Disease', 'MESH:D009362', (197, 217))	('variants', 'Var', (42, 50))	('metastasis of cancer', 'Disease', (197, 217))	('suppression', 'CPA', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('human', 'Species', '9606', (88, 93))
921290	25169894	Variants were defined as autosomal alleles that differ from the human reference genome build (GRCh37/hg19), and novel variants are defined as variants that are absent from dbSNP (db135).	('human', 'Species', '9606', (64, 69))	('Variants', 'Var', (0, 8))	('variants', 'Var', (118, 126))
921293	25169894	Experimental datasets consisted of: 6 ENCODE (Encyclopedia of DNA elements) cell line RNA sequencing datasets (GM1287- a lymphoblastoid cell line produced from the blood of a female donor with northern and western European ancestry, H1_hESC- a human embryonic stem cell line, Hela_S3- an immortalized cell line from an African-American female patient with cervical cancer, K562- an immortalized cell line from a female patient with chronic myelogenous leukemia (CML), HepG2- a cell line produced from a male patient with liver carcinoma, and NHEK- a epidermal keratinocyte cell line), 13 cancer deep sequencing datasets from the Cancer Genome Atlas (TCGA) (BLCA - Bladder Urothelial Carcinoma, BRCA - Breast invasive carcinoma, COAD - Colon adenocarcinoma, HNSC - Head and Neck squamous cell carcinoma, KIRC - Kidney renal clear cell carcinoma, KIRP - Kidney renal papillary cell carcinoma, LAML - Acute Myeloid Leukemia, LIHC - Liver hepatocellular carcinoma, LUAD - Lung adenocarcinoma, LUSC - Lung squamous cell carcinoma, READ - Rectum adenocarcinoma, STAD - Stomach adenocarcinoma, and UCEC - Uterine Corpus Endometrioid Carcinoma), 2 deep sequencing Gene Expression Omnibus (GEO) datasets (GSE31999 and GSE37765), and 24 microarray datasets from GEO (GSE2564, GSE9234, GSE11255, GSE12250, GSE14224, GSE14473, GSE14794, GSE14834, GSE15387, GSE15745, GSE16558, GSE16654, GSE16759, GSE17306, GSE17491, GSE17498, GSE18155, GSE18693, GSE18899, GSE19350, GSE20692, GSE21032_1, GSE21032_2, GSE21321).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (1001, 1024))	('AML', 'Disease', (892, 895))	('Cancer Genome Atlas', 'Disease', (629, 648))	('HepG2', 'CellLine', 'CVCL:0027', (468, 473))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (778, 801))	('leukemia', 'Phenotype', 'HP:0001909', (452, 460))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (432, 460))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (1001, 1024))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (1063, 1085))	('Kidney renal papillary cell carcinoma', 'Disease', (852, 889))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (778, 801))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (852, 889))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (440, 460))	('human', 'Species', '9606', (244, 249))	('patient', 'Species', '9606', (419, 426))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('cancer', 'Disease', 'MESH:D009369', (588, 594))	('GSE16654', 'Var', (1365, 1373))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (859, 889))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (432, 460))	('Stomach adenocarcinoma', 'Disease', (1063, 1085))	('carcinoma', 'Phenotype', 'HP:0030731', (527, 536))	('K562', 'CellLine', 'CVCL:0004', (373, 377))	('Myeloid Leukemia', 'Disease', 'MESH:D007951', (904, 920))	('carcinoma', 'Phenotype', 'HP:0030731', (746, 755))	('READ - Rectum adenocarcinoma', 'Disease', 'MESH:D012004', (1026, 1054))	('Neck squamous cell carcinoma', 'Disease', (773, 801))	('Neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (773, 801))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (810, 843))	('donor', 'Species', '9606', (182, 187))	('GSE2564', 'Var', (1257, 1264))	('Carcinoma', 'Phenotype', 'HP:0030731', (683, 692))	('carcinoma', 'Phenotype', 'HP:0030731', (717, 726))	('LUAD - Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (961, 987))	('CML', 'Disease', 'MESH:D015464', (462, 465))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (701, 726))	('Corpus Endometrioid Carcinoma', 'Disease', 'MESH:D016889', (1106, 1135))	('LIHC - Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (922, 959))	('CML', 'Disease', (462, 465))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (996, 1024))	('patient', 'Species', '9606', (343, 350))	('AML', 'Disease', 'MESH:D015470', (892, 895))	('liver carcinoma', 'Disease', 'MESH:D006528', (521, 536))	('carcinoma', 'Phenotype', 'HP:0030731', (834, 843))	('GSE12250', 'Var', (1285, 1293))	('GSE14794', 'Var', (1315, 1323))	('cancer', 'Disease', (365, 371))	('cancer', 'Disease', (588, 594))	('Myeloid Leukemia', 'Disease', (904, 920))	('READ - Rectum adenocarcinoma', 'Disease', (1026, 1054))	('Corpus Endometrioid Carcinoma', 'Disease', (1106, 1135))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (904, 920))	('carcinoma', 'Phenotype', 'HP:0030731', (792, 801))	('squamous cell carcinoma', 'Disease', (1001, 1024))	('Urothelial Carcinoma, BRCA - Breast invasive carcinoma, COAD - Colon adenocarcinoma', 'Disease', 'MESH:D029424', (672, 755))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (629, 648))	('liver carcinoma', 'Phenotype', 'HP:0001402', (521, 536))	('Kidney renal clear cell carcinoma', 'Disease', (810, 843))	('Hela', 'CellLine', 'CVCL:0030', (276, 280))	('Head and Neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (764, 801))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (968, 987))	('liver carcinoma', 'Disease', (521, 536))	('GSE14473', 'Var', (1305, 1313))	('Carcinoma', 'Phenotype', 'HP:0030731', (1126, 1135))	('chronic myelogenous leukemia', 'Disease', (432, 460))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (898, 920))	('cancer', 'Phenotype', 'HP:0002664', (588, 594))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('cervical cancer', 'Disease', 'MESH:D002583', (356, 371))	('patient', 'Species', '9606', (508, 515))	('LUAD - Lung adenocarcinoma', 'Disease', (961, 987))	('cervical cancer', 'Disease', (356, 371))	('Cancer', 'Phenotype', 'HP:0002664', (629, 635))	('Leukemia', 'Phenotype', 'HP:0001909', (912, 920))	('- Kidney renal clear cell carcinoma', 'Phenotype', 'HP:0006770', (808, 843))	('Endometrioid Carcinoma', 'Phenotype', 'HP:0012114', (1113, 1135))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (935, 959))	('LIHC - Liver hepatocellular carcinoma', 'Disease', (922, 959))
921351	24479799	Restoration of miR-133a in cancer cells inhibited proliferation, migration, invasion and resulted in G2/S arrest hence validating the tumor suppressive function of miR-133a in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Restoration', 'Var', (0, 11))	('miR-1', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('resulted', 'Reg', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('invasion', 'CPA', (76, 84))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('miR-1', 'Gene', (164, 169))	('miR-1', 'Gene', '79187', (15, 20))	('G2/S arrest', 'CPA', (101, 112))	('proliferation', 'CPA', (50, 63))	('tumor', 'Disease', (134, 139))	('migration', 'CPA', (65, 74))	('inhibited', 'NegReg', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('miR-1', 'Gene', '79187', (164, 169))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', (176, 182))
921361	24479799	Overexpression of miRNA-21 in esophageal tumors was associated with positive lymph nodes and decreased survival of esophageal cancer patients.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('miRNA-21', 'Gene', (18, 26))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('esophageal tumors', 'Disease', 'MESH:D004938', (30, 47))	('esophageal tumors', 'Phenotype', 'HP:0100751', (30, 47))	('patients', 'Species', '9606', (133, 141))	('decreased', 'NegReg', (93, 102))	('esophageal cancer', 'Disease', (115, 132))	('esophageal tumors', 'Disease', (30, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('Overexpression', 'Var', (0, 14))	('survival', 'CPA', (103, 111))	('miRNA-21', 'Gene', '406991', (18, 26))
921362	24479799	Significant decrease in cell proliferation and invasion were observed when anti-miR- 21 was overexpressed in human esophageal squamous cell carcinoma cell lines (TE6, TE8, TE10, TE11, TE12, TE14, KYSE30).	('decrease', 'NegReg', (12, 20))	('human', 'Species', '9606', (109, 114))	('TE8', 'Var', (167, 170))	('miR- 21', 'Gene', (80, 87))	('TE11', 'Var', (178, 182))	('KYSE30', 'Var', (196, 202))	('cell proliferation', 'CPA', (24, 42))	('miR- 21', 'Gene', '406991', (80, 87))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (115, 149))	('TE14', 'Var', (190, 194))	('invasion', 'CPA', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('TE10', 'Var', (172, 176))	('overexpressed', 'PosReg', (92, 105))	('esophageal squamous cell carcinoma', 'Disease', (115, 149))	('TE12', 'Var', (184, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('TE6', 'Var', (162, 165))
921366	24479799	Liu et al documented the tumor suppressor role of cluster of two miRNAs, miR-143 and miR-145 in esophageal cancer and observed a significant association between risk of esophageal cancer development with silencing of these miRNAs.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('miR', 'Gene', (85, 88))	('miR-145', 'Gene', '406937', (85, 92))	('tumor suppressor', 'Gene', '7248', (25, 41))	('silencing', 'Var', (204, 213))	('miR-145', 'Gene', (85, 92))	('miR', 'Gene', '220972', (65, 68))	('miR-143', 'Gene', '406935', (73, 80))	('miR', 'Gene', '220972', (73, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (169, 186))	('miR-143', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('esophageal cancer', 'Disease', (169, 186))	('miR', 'Gene', (65, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('miR', 'Gene', '220972', (223, 226))	('miR', 'Gene', (73, 76))	('miR', 'Gene', '220972', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('tumor suppressor', 'Gene', (25, 41))	('miR', 'Gene', (223, 226))
921367	24479799	Several lines of evidence have established that 5q region of the genomic DNA is more frequently lost or deleted in esophageal cancer and human miR-145 and miR-143 were predicted to be associated with 5q33 genomic region.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (137, 142))	('deleted', 'Var', (104, 111))	('esophageal cancer', 'Disease', (115, 132))	('miR-143', 'Gene', '406935', (155, 162))	('miR-145', 'Gene', (143, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('associated', 'Reg', (184, 194))	('miR-145', 'Gene', '406937', (143, 150))	('miR-143', 'Gene', (155, 162))
921399	24479799	Abnormal expression of miRNAs has also been associated with drug resistance resulting in poor prognosis and reduced patient survival.	('associated', 'Reg', (44, 54))	('miR', 'Gene', '220972', (23, 26))	('Abnormal expression', 'Var', (0, 19))	('miR', 'Gene', (23, 26))	('reduced', 'NegReg', (108, 115))	('patient', 'Species', '9606', (116, 123))	('drug resistance', 'MPA', (60, 75))	('drug resistance', 'Phenotype', 'HP:0020174', (60, 75))	('patient survival', 'CPA', (116, 132))
921414	24479799	Molecular studies and clinicopathological analysis of GBCs revealed strong association of aberrantly over-expressed miR-20a with growth, distant metastasis and poor prognosis.	('aberrantly over-expressed', 'Var', (90, 115))	('miR-20a', 'Gene', (116, 123))	('miR-20a', 'Gene', '406982', (116, 123))	('distant metastasis', 'CPA', (137, 155))	('growth', 'CPA', (129, 135))
921420	24479799	Various single nucleotide polymorphisms (SNPs) in miRNA genes lead to variations in miRNA expression resulting in diverse functions and, therefore, may represent ideal candidate biomarkers for cancer prognosis.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (50, 53))	('miR', 'Gene', (84, 87))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('variations', 'Var', (70, 80))	('single nucleotide polymorphisms', 'Var', (8, 39))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('functions', 'MPA', (122, 131))
921421	24479799	Patients carrying more than two variant alleles due to hsa-miR-146a G>C polymorphism (rs2910164), hsa-mir-196a2 C>T (rs11614913) polymorphism and hsa-mir-499 T>C (rs3746444) polymorphism were associated with increased overall risk of developing GBC with borderline significance.	('rs2910164', 'Mutation', 'rs2910164', (86, 95))	('mir', 'Gene', '220972', (102, 105))	('rs2910164', 'Var', (86, 95))	('GBC', 'Disease', (245, 248))	('mir', 'Gene', (150, 153))	('miR-146a', 'Gene', (59, 67))	('Patients', 'Species', '9606', (0, 8))	('rs3746444', 'Mutation', 'rs3746444', (163, 172))	('mir', 'Gene', (102, 105))	('rs11614913', 'Mutation', 'rs11614913', (117, 127))	('miR-146a', 'Gene', '406938', (59, 67))	('mir', 'Gene', '220972', (150, 153))
921448	24479799	Higher expression of miR-451 and miR-486-5p, and lower expression of let-7c, let-7d, let-7f, and miR-200c in the FNA samples of PC patients was also reported recently.	('miR-451', 'Gene', '574411', (21, 28))	('miR', 'Gene', (21, 24))	('PC', 'Phenotype', 'HP:0002894', (128, 130))	('let-7c', 'Gene', (69, 75))	('let-7d', 'Gene', '406886', (77, 83))	('miR', 'Gene', '220972', (97, 100))	('miR-451', 'Gene', (21, 28))	('patients', 'Species', '9606', (131, 139))	('miR', 'Gene', '220972', (33, 36))	('miR-200c', 'Gene', '406985', (97, 105))	('let-7c', 'Gene', '406885', (69, 75))	('let-7d', 'Gene', (77, 83))	('expression', 'MPA', (7, 17))	('expression', 'MPA', (55, 65))	('lower', 'NegReg', (49, 54))	('miR', 'Gene', (97, 100))	('let-7f', 'Var', (85, 91))	('miR-200c', 'Gene', (97, 105))	('miR', 'Gene', (33, 36))	('miR', 'Gene', '220972', (21, 24))	('Higher', 'PosReg', (0, 6))
921451	24479799	The study reported the association of disease outcome with deregulation of miR-30a-3p, miR-105, miR-127, miR-187, miR-452, and miR-518a-2.	('miR', 'Gene', '220972', (75, 78))	('disease', 'Disease', (38, 45))	('miR-1', 'Gene', (87, 92))	('miR-1', 'Gene', (96, 101))	('miR-187', 'Gene', (105, 112))	('miR-452', 'Gene', (114, 121))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', '220972', (105, 108))	('miR', 'Gene', (75, 78))	('miR-1', 'Gene', '79187', (105, 110))	('miR-127', 'Gene', (96, 103))	('miR', 'Gene', '220972', (96, 99))	('miR-1', 'Gene', '79187', (87, 92))	('miR-1', 'Gene', '79187', (96, 101))	('miR', 'Gene', (114, 117))	('miR', 'Gene', (105, 108))	('deregulation', 'Var', (59, 71))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (96, 99))	('miR-518a-2', 'Gene', '574491', (127, 137))	('miR-127', 'Gene', '406914', (96, 103))	('miR', 'Gene', '220972', (87, 90))	('miR-452', 'Gene', '574412', (114, 121))	('miR', 'Gene', (127, 130))	('miR-1', 'Gene', (105, 110))	('miR-518a-2', 'Gene', (127, 137))	('miR', 'Gene', (87, 90))	('miR-187', 'Gene', '406963', (105, 112))
921456	24479799	After calculating prognostic index (PI) for these five miRNAs, the median survival was observed to be 1.09 years [95% Confidence Interval (CI), 0.98-1.43] for PI > median PI compared to 2.23 years (CI 1.84-4.36) for PI < median.	('miR', 'Gene', '220972', (55, 58))	('PI > median', 'Var', (159, 170))	('miR', 'Gene', (55, 58))
921487	24479799	The same study identified alterations in a set of interconnected miRNA regulatory networks that governed various cellular processes, including epithelial to mesenchymal transition (EMT).	('governed', 'Reg', (96, 104))	('alterations', 'Var', (26, 37))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('epithelial to mesenchymal transition', 'CPA', (143, 179))
921498	24479799	The KRAS and TP53 mutations are present in a significant proportion of CRC patients (5-20%), and a recent study has indicated that the miRNA let-7a regulates KRAS through TP53 in the KRAS mutant HCT116 cells.	('miR', 'Gene', (135, 138))	('TP53', 'Gene', (171, 175))	('TP53', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (4, 8))	('KRAS', 'Gene', '3845', (158, 162))	('HCT116', 'CellLine', 'CVCL:0291', (195, 201))	('KRAS', 'Gene', (183, 187))	('KRAS', 'Gene', '3845', (183, 187))	('TP53', 'Gene', '7157', (13, 17))	('patients', 'Species', '9606', (75, 83))	('TP53', 'Gene', '7157', (171, 175))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('regulates', 'Reg', (148, 157))	('KRAS', 'Gene', (158, 162))	('miR', 'Gene', '220972', (135, 138))	('KRAS', 'Gene', (4, 8))	('mutant', 'Var', (188, 194))
921514	24479799	However, miRNA deregulation contributes to tumorigenesis by augmenting several cellular processes like cell proliferation, migration and invasion.	('augmenting', 'NegReg', (60, 70))	('invasion', 'CPA', (137, 145))	('cellular processes', 'CPA', (79, 97))	('cell proliferation', 'CPA', (103, 121))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('deregulation', 'Var', (15, 27))	('tumor', 'Disease', (43, 48))	('miR', 'Gene', '220972', (9, 12))	('migration', 'CPA', (123, 132))	('miR', 'Gene', (9, 12))
921533	32957082	RAI14 silencing suppresses progression of esophageal cancer via the STAT3 pathway Esophageal cancer (EC) is an aggressive malignancy that has an unclear molecular pathogenesis.	('cancer', 'Disease', (93, 99))	('suppresses', 'NegReg', (16, 26))	('RAI14', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('EC', 'Phenotype', 'HP:0011459', (101, 103))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('progression', 'CPA', (27, 38))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('aggressive malignancy', 'Disease', 'MESH:D009369', (111, 132))	('STAT3', 'Gene', '6774', (68, 73))	('aggressive malignancy', 'Disease', (111, 132))	('RAI14', 'Gene', '26064', (0, 5))	('silencing', 'Var', (6, 15))	('STAT3', 'Gene', (68, 73))
921536	32957082	Conversely, RAI14 knockdown induced apoptosis and cell cycle arrest.	('arrest', 'Disease', (61, 67))	('knockdown', 'Var', (18, 27))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('apoptosis', 'CPA', (36, 45))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('RAI14', 'Gene', (12, 17))
921537	32957082	RAI14 activated STAT3, upregulated Mcl-1 and cyclin D1, and inhibited cleaved caspase-3.	('caspase-3', 'Gene', '836', (78, 87))	('Mcl-1', 'MPA', (35, 40))	('upregulated', 'PosReg', (23, 34))	('caspase-3', 'Gene', (78, 87))	('inhibited', 'NegReg', (60, 69))	('activated', 'PosReg', (6, 15))	('cyclin D1', 'Gene', '595', (45, 54))	('STAT3', 'MPA', (16, 21))	('RAI14', 'Var', (0, 5))	('cyclin D1', 'Gene', (45, 54))
921551	32957082	To explore the role of RAI14 in EC, we ectopically expressed RAI14 in TE-14 cells and knocked down RAI14 in TE-1 cells.	('RAI14', 'Gene', (99, 104))	('EC', 'Phenotype', 'HP:0011459', (32, 34))	('TE-1', 'CellLine', 'CVCL:1759', (108, 112))	('TE-1', 'CellLine', 'CVCL:1759', (70, 74))	('knocked', 'Var', (86, 93))	('RAI14', 'Gene', (61, 66))
921553	32957082	However, the expression of RAI14 was blocked in TE-1 cells that were transfected with siRNA-1, siRNA-2, or siRNA-3 as compared with that in TE-1 cells that were transfected with siNC (P < 0.05) (Figure 2A).	('siRNA-1', 'Var', (86, 93))	('siRNA-2', 'Var', (95, 102))	('expression', 'MPA', (13, 23))	('siNC', 'Disease', (178, 182))	('siRNA-3', 'Var', (107, 114))	('TE-1', 'CellLine', 'CVCL:1759', (140, 144))	('blocked', 'NegReg', (37, 44))	('RAI14', 'Gene', (27, 32))	('TE-1', 'CellLine', 'CVCL:1759', (48, 52))	('siNC', 'Disease', 'None', (178, 182))
921554	32957082	Further, the expression of RAI14 was markedly elevated in the RAI14-transfected TE-14 cells as compared with that in the TE-14 vector control cells (Figure 2B).	('elevated', 'PosReg', (46, 54))	('RAI14-transfected', 'Var', (62, 79))	('expression', 'MPA', (13, 23))	('RAI14', 'Gene', (27, 32))	('TE-1', 'CellLine', 'CVCL:1759', (121, 125))	('TE-1', 'CellLine', 'CVCL:1759', (80, 84))
921557	32957082	The proliferation curve of the EC cells shows that there was no notable difference in cell viability between RAI14-knockdown cells and siNC-transfected cells before 12 h. However, at 24, 48, and 72 h after RAI14 knockdown, cell viability was clearly attenuated as compared with that in the siNC-transfected cells (P < 0.05).	('cell viability', 'CPA', (223, 237))	('siNC', 'Disease', 'None', (290, 294))	('RAI14', 'Gene', (206, 211))	('knockdown', 'Var', (212, 221))	('siNC', 'Disease', (135, 139))	('attenuated', 'NegReg', (250, 260))	('siNC', 'Disease', (290, 294))	('EC', 'Phenotype', 'HP:0011459', (31, 33))	('siNC', 'Disease', 'None', (135, 139))
921558	32957082	Additionally, there was no significant difference in cell viability between cells that were transfected with siRAI14-1 or siRAI14-2 (Figure 3A).	('siRAI14', 'Chemical', '-', (109, 116))	('siRAI14-1', 'Var', (109, 118))	('siRAI14', 'Chemical', '-', (122, 129))	('siRAI14-2', 'Var', (122, 131))
921560	32957082	However, the apoptosis rate in cells that overexpressed RAI14 was markedly reduced as compared with that in the vector-transfected cells (P < 0.05), whereas the apoptosis rate in RAI14-knockdown cells was significantly elevated as compared with that in the siNC-transfected cells.	('RAI14', 'Var', (56, 61))	('siNC', 'Disease', (257, 261))	('overexpressed', 'PosReg', (42, 55))	('reduced', 'NegReg', (75, 82))	('apoptosis', 'CPA', (161, 170))	('siNC', 'Disease', 'None', (257, 261))	('apoptosis rate', 'CPA', (13, 27))	('elevated', 'PosReg', (219, 227))
921561	32957082	Cells that were transfected with siRNA-RAI14 showed cell cycle arrest at the G1 phase, and the proportion of cells in the S phase that were transfected with siRNA-RAI14 was decreased as compared with in the siNC-transfected cells (P < 0.05) (Figure 3D).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('siRNA-RAI14', 'Var', (157, 168))	('arrest', 'Disease', (63, 69))	('siNC', 'Disease', (207, 211))	('siRNA-RAI14', 'Var', (33, 44))	('decreased', 'NegReg', (173, 182))	('siNC', 'Disease', 'None', (207, 211))
921565	32957082	Results from the GSEA revealed that the level of RAI14 was positively correlated with the STAT3-activated signatures (Figure 5A).	('STAT3-activated signatures', 'MPA', (90, 116))	('GSEA', 'Chemical', '-', (17, 21))	('RAI14', 'Var', (49, 54))
921569	32957082	However, the expression of Mcl-1 was increased and cleaved caspase-3 was reduced in TE-14 cells that overexpressed RAI14 as compared with the expression of Mcl-1 and cleaved caspase-3 in the vector control group (P < 0.05).	('caspase-3', 'Gene', '836', (59, 68))	('caspase-3', 'Gene', '836', (174, 183))	('RAI14', 'Var', (115, 120))	('expression', 'MPA', (13, 23))	('reduced', 'NegReg', (73, 80))	('overexpressed', 'PosReg', (101, 114))	('Mcl-1', 'Gene', (27, 32))	('caspase-3', 'Gene', (174, 183))	('increased', 'PosReg', (37, 46))	('cleaved', 'MPA', (51, 58))	('caspase-3', 'Gene', (59, 68))	('TE-1', 'CellLine', 'CVCL:1759', (84, 88))
921570	32957082	Cyclin D1 promotes the transition from G1-to-S and regulates tumorigenesis, and the expression of cyclin D1 was significantly suppressed in RAI14 knockdown-cells as compared with that in the siNC group.	('siNC', 'Disease', 'None', (191, 195))	('knockdown-cells', 'Var', (146, 161))	('suppressed', 'NegReg', (126, 136))	('RAI14', 'Gene', (140, 145))	('Cyclin D1', 'Gene', '595', (0, 9))	('siNC', 'Disease', (191, 195))	('promotes', 'PosReg', (10, 18))	('cyclin D1', 'Gene', '595', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cyclin D1', 'Gene', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('regulates', 'Reg', (51, 60))	('expression', 'MPA', (84, 94))	('Cyclin D1', 'Gene', (0, 9))	('tumor', 'Disease', (61, 66))	('transition', 'MPA', (23, 33))
921573	32957082	The phosphorylation of STAT3 in both the vector-transfected or RAI14-transfected cells that were treated with AG490 was significantly decreased as compared with that in cells that were treated with DMSO.	('decreased', 'NegReg', (134, 143))	('DMSO', 'Chemical', 'MESH:D004121', (198, 202))	('STAT3', 'Protein', (23, 28))	('phosphorylation', 'MPA', (4, 19))	('AG490', 'Var', (110, 115))	('AG490', 'Chemical', 'MESH:C095512', (110, 115))
921574	32957082	In parallel, the expression levels of Mcl-1 and cyclin D1 were decreased and the level of cleaved caspase-3 was increased in cells that were treated with AG490 as compared with those in cells that were treated with DMSO (Figure 6A).	('cyclin D1', 'Gene', (48, 57))	('expression levels', 'MPA', (17, 34))	('DMSO', 'Chemical', 'MESH:D004121', (215, 219))	('AG490', 'Var', (154, 159))	('decreased', 'NegReg', (63, 72))	('caspase-3', 'Gene', (98, 107))	('AG490', 'Chemical', 'MESH:C095512', (154, 159))	('increased', 'PosReg', (112, 121))	('caspase-3', 'Gene', '836', (98, 107))	('cyclin D1', 'Gene', '595', (48, 57))	('Mcl-1', 'MPA', (38, 43))
921576	32957082	However, the proliferation rate of cells that were transfected with RAI14 was higher than that of vector control cells even in the presence of AG490 (Figure 6B).	('AG490', 'Chemical', 'MESH:C095512', (143, 148))	('RAI14', 'Var', (68, 73))	('higher', 'PosReg', (78, 84))	('proliferation rate', 'CPA', (13, 31))
921577	32957082	The antiapoptotic effect of RAI14 was rescued in AG490-treated cells (apoptosis rate, 28.4 +- 0.7%) as compared with that in DMSO-treated cells (apoptosis rate, 2.1 +- 0.5%), and AG490 markedly increased the apoptosis rate in the vector control group (at least 13.4-fold) (Figure 6C, 6E).	('AG490', 'Chemical', 'MESH:C095512', (49, 54))	('apoptosis rate', 'CPA', (208, 222))	('antiapoptotic effect', 'MPA', (4, 24))	('AG490-treated', 'Var', (49, 62))	('AG490', 'Var', (179, 184))	('AG490', 'Chemical', 'MESH:C095512', (179, 184))	('DMSO', 'Chemical', 'MESH:D004121', (125, 129))
921578	32957082	Similarly, results from the cell cycle analysis revealed that AG490 exerted an inhibitory effect on the G1-to-S transition.	('G1-to-S transition', 'CPA', (104, 122))	('inhibitory', 'NegReg', (79, 89))	('AG490', 'Chemical', 'MESH:C095512', (62, 67))	('AG490', 'Var', (62, 67))
921579	32957082	After incubation with AG490, the proportion of cells in the S phase decreased from 40.7 +- 5.0% to 7.8 +- 5.2% in the vector control group and from 45.2 +- 1.6% to 22.3 +- 1% in the RAI14-transfected group (Figure 6D, 6F).	('cells in', 'CPA', (47, 55))	('decreased', 'NegReg', (68, 77))	('AG490', 'Chemical', 'MESH:C095512', (22, 27))	('AG490', 'Var', (22, 27))
921585	32957082	Ki67 functions as a proliferation marker in cancer, and the levels of RAI14 and Ki67 were significantly decreased in the xenograft tumors in the RAI14-knockdown mice as compared with those in the xenograft tumors in the control mice (Figure 7F) (P < 0.05 vs. siNC).	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('Ki67', 'Gene', (0, 4))	('mice', 'Species', '10090', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('Ki67', 'Gene', (80, 84))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('decreased', 'NegReg', (104, 113))	('tumors', 'Disease', (206, 212))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('siNC', 'Disease', (259, 263))	('mice', 'Species', '10090', (161, 165))	('Ki67', 'Gene', '17345', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('Ki67', 'Gene', '17345', (80, 84))	('levels', 'MPA', (60, 66))	('tumors', 'Disease', (131, 137))	('siNC', 'Disease', 'None', (259, 263))	('cancer', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('RAI14-knockdown', 'Var', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
921586	32957082	These findings suggest that RAI14 silencing suppresses tumor progression in vivo.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('suppresses', 'NegReg', (44, 54))	('RAI14', 'Gene', (28, 33))	('tumor', 'Disease', (55, 60))	('silencing', 'Var', (34, 43))
921592	32957082	These findings suggest that RAI14 may serve as a clinical prognostic indicator for different cancers.	('cancers', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('RAI14', 'Var', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
921593	32957082	Here, we found that RAI14 was also upregulated in EC cell lines, and results from gain- and loss-of-function experiments revealed that RAI14 silencing inhibited the proliferation, migration, and invasion of EC cells in vitro and suppressed tumorigenesis in vivo.	('silencing', 'Var', (141, 150))	('tumor', 'Disease', (240, 245))	('suppressed', 'NegReg', (229, 239))	('EC', 'Phenotype', 'HP:0011459', (207, 209))	('EC', 'Phenotype', 'HP:0011459', (50, 52))	('migration', 'CPA', (180, 189))	('invasion', 'CPA', (195, 203))	('inhibited', 'NegReg', (151, 160))	('RAI14', 'Gene', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('proliferation', 'CPA', (165, 178))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
921594	32957082	Further experiments showed that RAI14 silencing induced apoptosis and cell cycle arrest, indicating the oncogenic function and the multifold mechanical involvement of RAI14 in EC.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('EC', 'Phenotype', 'HP:0011459', (176, 178))	('apoptosis', 'CPA', (56, 65))	('RAI14', 'Gene', (32, 37))	('arrest', 'Disease', (81, 87))	('silencing', 'Var', (38, 47))
921595	32957082	The TMOD3/RAI14/VWF axis interacts with the cytoskeleton in prostate cancer, and Liu and colleagues revealed that cell migration and the invasion of melanoma was impaired by RAI14 depletion via regulating the AFAP1-AS1/miR-653-5p/RAI14 axis.	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('prostate cancer', 'Disease', (60, 75))	('VWF', 'Gene', '7450', (16, 19))	('impaired', 'NegReg', (162, 170))	('AS1', 'Gene', '5729', (215, 218))	('cell migration', 'CPA', (114, 128))	('miR-653', 'Gene', (219, 226))	('AFAP1', 'Gene', '60312', (209, 214))	('VWF', 'Gene', (16, 19))	('TMOD3', 'Gene', (4, 9))	('TMOD3', 'Gene', '29766', (4, 9))	('miR-653', 'Gene', '724023', (219, 226))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('AFAP1', 'Gene', (209, 214))	('RAI14', 'Protein', (174, 179))	('AS1', 'Gene', (215, 218))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('depletion', 'Var', (180, 189))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))
921608	32957082	These studies also imply that RAI14 regulates STAT3 by interacting with its upstream factors, including c-Src, heme oxygenase-1, and IL-6.	('c-Src', 'Gene', (104, 109))	('heme oxygenase-1', 'Gene', (111, 127))	('c-Src', 'Gene', '6714', (104, 109))	('IL-6', 'Gene', (133, 137))	('STAT3', 'MPA', (46, 51))	('RAI14', 'Var', (30, 35))	('heme oxygenase-1', 'Gene', '3162', (111, 127))	('IL-6', 'Gene', '3569', (133, 137))	('interacting', 'Interaction', (55, 66))
921611	32957082	Abnormalities in cyclin D1 are common in squamous cell carcinoma and adenocarcinoma.	('common', 'Reg', (31, 37))	('squamous cell carcinoma', 'Disease', (41, 64))	('Abnormalities', 'Var', (0, 13))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))	('adenocarcinoma', 'Disease', (69, 83))	('cyclin D1', 'Gene', '595', (17, 26))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))	('cyclin D1', 'Gene', (17, 26))
921612	32957082	In the current study, the knockdown of RAI14 or inhibition of STAT3 activation reduced the expression of cyclin D1 and ultimately induced cell cycle arrest.	('STAT3', 'Gene', (62, 67))	('expression', 'MPA', (91, 101))	('reduced', 'NegReg', (79, 86))	('induced', 'Reg', (130, 137))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('arrest', 'Disease', (149, 155))	('cyclin D1', 'Gene', '595', (105, 114))	('knockdown', 'Var', (26, 35))	('cyclin D1', 'Gene', (105, 114))	('RAI14', 'Gene', (39, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (138, 155))
921615	32957082	p-STAT3 is reported to bind to a serum inducible element (SIE)-like binding site in the mouse Mcl-1 promoter and potentiate Mcl-1 expression in v-src-transformed NIH3T3 cells.	('potentiate', 'PosReg', (113, 123))	('expression', 'MPA', (130, 140))	('src', 'Gene', (146, 149))	('p-STAT3', 'Var', (0, 7))	('bind', 'Interaction', (23, 27))	('NIH3T3', 'CellLine', 'CVCL:0594', (162, 168))	('mouse', 'Species', '10090', (88, 93))	('Mcl-1', 'Gene', (124, 129))	('src', 'Gene', '20779', (146, 149))
921639	32957082	Next, 20 mug of protein from each sample was separated by 10% sodium dodecyl sulfate-polyacrylamide gels (SDS-PAGE), transferred to polyvinylidene fluoride membranes, and incubated with the following primary antibodies overnight: anti-RAI14, anti-Mcl-1, anti-cleaved caspase-3, anti-cyclin D1, anti-STAT3, anti-p-STAT3 and anti-GAPDH.	('polyvinylidene fluoride', 'Chemical', 'MESH:C024865', (132, 155))	('anti-p-STAT3', 'Var', (306, 318))	('sodium dodecyl sulfate', 'Chemical', 'MESH:D012967', (62, 84))	('cyclin D1', 'Gene', '595', (283, 292))	('anti-STAT3', 'Var', (294, 304))	('caspase-3', 'Gene', (267, 276))	('cyclin D1', 'Gene', (283, 292))	('SDS', 'Chemical', 'MESH:D012967', (106, 109))	('anti-cleaved', 'Var', (254, 266))	('GAPDH', 'Gene', '2597', (328, 333))	('anti-RAI14', 'Var', (230, 240))	('GAPDH', 'Gene', (328, 333))	('polyacrylamide', 'Chemical', 'MESH:C016679', (85, 99))	('caspase-3', 'Gene', '836', (267, 276))
921661	31183640	Among all patients, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio > 70% was associated with reduced risk of overall postoperative complications, cardiovascular complications, atrial fibrillation, pulmonary complications, and pneumonia.	('FEV1', 'Phenotype', 'HP:0032342', (53, 57))	('cardiovascular complications', 'Disease', 'MESH:D002318', (172, 200))	('> 70', 'Var', (93, 97))	('pneumonia', 'Phenotype', 'HP:0002090', (252, 261))	('postoperative complications', 'CPA', (143, 170))	('pulmonary complications', 'Phenotype', 'HP:0006532', (223, 246))	('pneumonia', 'Disease', (252, 261))	('pneumonia', 'Disease', 'MESH:D011014', (252, 261))	('atrial fibrillation', 'Disease', 'MESH:D001281', (202, 221))	('pulmonary complications', 'Disease', (223, 246))	('atrial fibrillation', 'Disease', (202, 221))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (202, 221))	('forced expiratory volume in 1 s', 'Phenotype', 'HP:0032342', (20, 51))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (172, 200))	('reduced', 'NegReg', (119, 126))	('pulmonary complications', 'Disease', 'MESH:D008171', (223, 246))	('patients', 'Species', '9606', (10, 18))	('cardiovascular complications', 'Disease', (172, 200))
921677	31183640	The outcomes evaluated included 30-day and in-hospital complications, which were defined as: postoperative respiratory failure requiring critical care admission, postoperative atrial fibrillation requiring treatment, according to postoperative Clavien-Dindo severity classification, anastomotic leakage or conduit necrosis (endoscopically or radiographically verified), reoperation for any cause, pneumonia defined by the individual investigator when at least one of the following criteria were fulfilled: new and persistent or progressive and persistent radiographic infiltrate, and at least one of: fever (> 38.0  C or > 100.4  F), leukopenia (<= 4000 WBC/mm3), or leukocytosis (> 12,000 WBC/mm3), for adults > 70 years old, altered mental status with no other recognized cause, and at least two of the following: new onset of purulent sputum or change in character of sputum, or increased respiratory secretions, or increased suctioning requirements, new-onset or worsening cough, or dyspnea, or tachypnea, rales or bronchial breath sounds, worsening gas exchange [e.g., O2 desaturations (e.g., PaO2/FiO2 < 240)], increased oxygen requirements, or increased ventilator demand.	('change', 'Reg', (848, 854))	('bronchial breath sounds', 'Phenotype', 'HP:0031994', (1019, 1042))	('increased', 'PosReg', (1117, 1126))	('cough', 'Phenotype', 'HP:0012735', (977, 982))	('tachypnea', 'Disease', 'MESH:D059246', (999, 1008))	('rales', 'Disease', (1010, 1015))	('postoperative respiratory failure', 'Disease', (93, 126))	('leukocytosis', 'Disease', 'MESH:D007964', (667, 679))	('leukocytosis', 'Phenotype', 'HP:0001974', (667, 679))	('worsening', 'Reg', (1044, 1053))	('bronchial breath', 'Phenotype', 'HP:0002098', (1019, 1035))	('leukocytosis', 'Disease', (667, 679))	('atrial fibrillation', 'Disease', 'MESH:D001281', (176, 195))	('postoperative respiratory failure', 'Disease', 'MESH:D012131', (93, 126))	('tachypnea', 'Disease', (999, 1008))	('bronchial breath', 'Disease', 'MESH:D001982', (1019, 1035))	('tachypnea', 'Phenotype', 'HP:0002789', (999, 1008))	('gas exchange', 'MPA', (1054, 1066))	('dyspnea', 'Disease', (987, 994))	('PaO2/FiO2', 'Var', (1098, 1107))	('cough', 'Disease', 'MESH:D003371', (977, 982))	('ventilator demand', 'MPA', (1161, 1178))	('pneumonia', 'Phenotype', 'HP:0002090', (397, 406))	('dyspnea', 'Disease', 'MESH:D004417', (987, 994))	('respiratory failure requiring critical care admission', 'Phenotype', 'HP:0004887', (107, 160))	('anastomotic leak', 'Disease', (283, 299))	('pneumonia', 'Disease', 'MESH:D011014', (397, 406))	('cough', 'Disease', (977, 982))	('oxygen requirements', 'MPA', (1127, 1146))	('respiratory secretions', 'MPA', (892, 914))	('leukopenia', 'Disease', 'MESH:D007970', (634, 644))	('fever', 'Phenotype', 'HP:0001945', (601, 606))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (176, 195))	('necrosis', 'Disease', 'MESH:D009336', (314, 322))	('anastomotic leak', 'Disease', 'MESH:D057868', (283, 299))	('increased', 'PosReg', (882, 891))	('leukopenia', 'Phenotype', 'HP:0001882', (634, 644))	('increased', 'PosReg', (1151, 1160))	('increased', 'PosReg', (919, 928))	('pneumonia', 'Disease', (397, 406))	('rales', 'Phenotype', 'HP:0030830', (1010, 1015))	('suctioning requirements', 'MPA', (929, 952))	('leukopenia', 'Disease', (634, 644))	('necrosis', 'Disease', (314, 322))	('respiratory failure', 'Phenotype', 'HP:0002878', (107, 126))	('O2 desaturations', 'MPA', (1074, 1090))	('bronchial breath', 'Disease', (1019, 1035))	('dyspnea', 'Phenotype', 'HP:0002094', (987, 994))	('atrial fibrillation', 'Disease', (176, 195))	('conduit necrosis', 'Phenotype', 'HP:0010885', (306, 322))
921691	31183640	Cardiac comorbidity was associated with increased risk of cardiovascular complications, pulmonary complications, and Clavien-Dindo score >= IIIa regardless of neoadjuvant treatment.	('cardiovascular complications', 'Disease', 'MESH:D002318', (58, 86))	('Clavien-Dindo score', 'Disease', (117, 136))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (58, 86))	('Cardiac comorbidity', 'Disease', (0, 19))	('pulmonary complications', 'Phenotype', 'HP:0006532', (88, 111))	('pulmonary complications', 'Disease', (88, 111))	('pulmonary complications', 'Disease', 'MESH:D008171', (88, 111))	('>= IIIa', 'Var', (137, 144))	('cardiovascular complications', 'Disease', (58, 86))
921694	31183640	Unadjusted analyses showed that FEV1/FVC ratio > 70% was associated with reduced overall postoperative complications, cardiovascular complications, atrial fibrillation, pulmonary complications, and pneumonia.	('pulmonary complications', 'Disease', (169, 192))	('atrial fibrillation', 'Disease', (148, 167))	('pulmonary complications', 'Disease', 'MESH:D008171', (169, 192))	('pneumonia', 'Phenotype', 'HP:0002090', (198, 207))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (118, 146))	('reduced', 'NegReg', (73, 80))	('cardiovascular complications', 'Disease', 'MESH:D002318', (118, 146))	('postoperative complications', 'CPA', (89, 116))	('cardiovascular complications', 'Disease', (118, 146))	('pneumonia', 'Disease', (198, 207))	('> 70', 'Var', (47, 51))	('pneumonia', 'Disease', 'MESH:D011014', (198, 207))	('pulmonary complications', 'Phenotype', 'HP:0006532', (169, 192))	('FEV1', 'Phenotype', 'HP:0032342', (32, 36))	('atrial fibrillation', 'Disease', 'MESH:D001281', (148, 167))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (148, 167))
921695	31183640	Adjusted analyses showed that FEV1/FVC ratio > 70% was associated with reduced risk of overall postoperative complications (OR 0.57, 95% CI 0.37-0.89) and atrial fibrillation (OR 0.46, 95% CI 0.28-0.75, Table 5).	('postoperative complications', 'CPA', (95, 122))	('FEV1', 'Phenotype', 'HP:0032342', (30, 34))	('reduced', 'NegReg', (71, 78))	('> 70', 'Var', (45, 49))	('atrial fibrillation', 'Disease', 'MESH:D001281', (155, 174))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (155, 174))	('atrial fibrillation', 'Disease', (155, 174))
921696	31183640	LVEF > 55% was associated with decreased risk of anastomotic leak (adjusted OR 0.34, 95% CI 0.12-0.95), but was otherwise unrelated to postoperative outcomes.	('anastomotic leak', 'Disease', 'MESH:D057868', (49, 65))	('> 55%', 'Var', (5, 10))	('anastomotic leak', 'Disease', (49, 65))	('decreased', 'NegReg', (31, 40))
921704	31183640	For those measures, FEV1/FVC ratio > 70% was independently associated with a decreased risk of overall postoperative complications, cardiovascular complications, atrial fibrillation, pulmonary complications, and pneumonia.	('pulmonary complications', 'Disease', (183, 206))	('atrial fibrillation', 'Disease', (162, 181))	('pulmonary complications', 'Disease', 'MESH:D008171', (183, 206))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (132, 160))	('> 70', 'Var', (35, 39))	('cardiovascular complications', 'Disease', 'MESH:D002318', (132, 160))	('FEV1', 'Phenotype', 'HP:0032342', (20, 24))	('pneumonia', 'Phenotype', 'HP:0002090', (212, 221))	('cardiovascular complications', 'Disease', (132, 160))	('postoperative complications', 'CPA', (103, 130))	('pneumonia', 'Disease', (212, 221))	('pneumonia', 'Disease', 'MESH:D011014', (212, 221))	('pulmonary complications', 'Phenotype', 'HP:0006532', (183, 206))	('decreased', 'NegReg', (77, 86))	('atrial fibrillation', 'Disease', 'MESH:D001281', (162, 181))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (162, 181))
921712	31183640	Furthermore, cytotoxic agents may impair myocellular proliferation by disrupting the mammalian target of rapamycin kinase pathway, while cisplatin also negatively impacts muscle function through a number of mechanisms including impaired Akt phosphorylation, leading to sustained activation of the degradative proteasome and autophagy systems, and altered nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling.	('impair', 'NegReg', (34, 40))	('cisplatin', 'Var', (137, 146))	('impaired', 'NegReg', (228, 236))	('mammalian target of rapamycin kinase pathway', 'Pathway', (85, 129))	('altered', 'Reg', (347, 354))	('muscle function', 'CPA', (171, 186))	('negatively', 'NegReg', (152, 162))	('degradative', 'CPA', (297, 308))	('disrupting', 'NegReg', (70, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('autophagy systems', 'CPA', (324, 341))	('mammalian', 'Species', '9606', (85, 94))	('Akt', 'Gene', '207', (237, 240))	('impacts', 'Reg', (163, 170))	('Akt', 'Gene', (237, 240))	('activation', 'PosReg', (279, 289))	('myocellular proliferation', 'CPA', (41, 66))
921744	30464513	Defects in this gene correlate with multiple human diseases, including cardiovascular disease, central obesity, nonketotic hypoglycemia, diabetes, and World Health Organization-defined metabolic syndrome.	('diabetes', 'Disease', 'MESH:D003920', (137, 145))	('central obesity', 'Phenotype', 'HP:0012743', (95, 110))	('cardiovascular disease', 'Disease', 'MESH:D002318', (71, 93))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (71, 93))	('central obesity', 'Disease', (95, 110))	('obesity', 'Phenotype', 'HP:0001513', (103, 110))	('Defects', 'Var', (0, 7))	('hypoglycemia', 'Phenotype', 'HP:0001943', (123, 135))	('human', 'Species', '9606', (45, 50))	('nonketotic hypoglycemia', 'Disease', 'MESH:D007003', (112, 135))	('nonketotic hypoglycemia', 'Phenotype', 'HP:0001958', (112, 135))	('correlate', 'Reg', (21, 30))	('cardiovascular disease', 'Disease', (71, 93))	('central obesity', 'Disease', 'MESH:D056128', (95, 110))	('metabolic syndrome', 'Disease', 'MESH:D008659', (185, 203))	('diabetes', 'Disease', (137, 145))	('metabolic syndrome', 'Disease', (185, 203))	('nonketotic hypoglycemia', 'Disease', (112, 135))
921771	30464513	The positive staining tumor cell proportions could be divided into four grades as follows: 1 (<20%), 2 (20%-40%), 3 (40%-70%), and 4 (>70%).	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('20', 'Var', (104, 106))
921777	30464513	We detected ACADL expression via qPCR and Western blotting analysis in NEECs and ESCC cell lines, which include KYSE-510, KYSE-410, KYSE-520, EC18, KYSE-30, KYSE-109 and KYSE-140.	('KYSE-30', 'Var', (148, 155))	('ACADL', 'Gene', (12, 17))	('ACADL', 'Gene', '33', (12, 17))	('EC18', 'CellLine', 'CVCL:5V07', (142, 146))	('KYSE-520', 'Var', (132, 140))	('KYSE-410', 'Var', (122, 130))	('KYSE-510', 'Var', (112, 120))	('KYSE-140', 'Var', (170, 178))	('KYSE-109', 'Var', (157, 165))
921796	30464513	In the low ACADL expression group, >60% of patients had better 5-year survival time, but the percent who had a better a 5-year survival time in the high ACADL expression group was <20% (Figure 4A).	('5-year', 'MPA', (63, 69))	('ACADL', 'Gene', (153, 158))	('ACADL', 'Gene', '33', (153, 158))	('ACADL', 'Gene', '33', (11, 16))	('patients', 'Species', '9606', (43, 51))	('better', 'PosReg', (56, 62))	('low', 'Var', (7, 10))	('ACADL', 'Gene', (11, 16))
921806	30464513	Defects in this gene would cause long-chain acyl-CoA dehydrogenase deficiency, resulting in dysregulation of the gene in development and disease, and bringing about a false metabolic pattern in human body.	('false', 'Reg', (167, 172))	('resulting in', 'Reg', (79, 91))	('dysregulation', 'MPA', (92, 105))	('-chain acyl-CoA dehydrogenase deficiency', 'Phenotype', 'HP:0100950', (37, 77))	('Defects', 'Var', (0, 7))	('long-chain acyl-CoA dehydrogenase deficiency', 'Disease', (33, 77))	('cause', 'Reg', (27, 32))	('bringing about', 'Reg', (150, 164))	('human', 'Species', '9606', (194, 199))	('long-chain acyl-CoA dehydrogenase deficiency', 'Disease', 'MESH:C535690', (33, 77))
921829	29673198	Evaluation of survival signaling cascades showed that although the MEK-ERK and Akt pathways were activated in the presence of drugs, BaP was a stronger activator of the MEK-ERK and Akt pathways than the drugs.	('ERK', 'Gene', (173, 176))	('ERK', 'Gene', '5594', (71, 74))	('BaP', 'Var', (133, 136))	('ERK', 'Gene', (71, 74))	('MEK', 'Gene', (169, 172))	('MEK', 'Gene', (67, 70))	('activator', 'PosReg', (152, 161))	('MEK', 'Gene', '5609', (169, 172))	('MEK', 'Gene', '5609', (67, 70))	('BaP', 'Chemical', '-', (133, 136))	('ERK', 'Gene', '5594', (173, 176))	('activated', 'PosReg', (97, 106))
921863	29673198	At 24 h after the start of the experiment, cisplatin, 5-fluorouracil, and paclitaxel caused downregulation of both Ki67 and PCNA.	('Ki67', 'Gene', (115, 119))	('downregulation', 'NegReg', (92, 106))	('5-fluorouracil', 'Var', (54, 68))	('cisplatin', 'Var', (43, 52))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (54, 68))	('Ki67', 'Gene', '17345', (115, 119))	('paclitaxel', 'Chemical', 'MESH:D017239', (74, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('PCNA', 'CPA', (124, 128))
921864	29673198	This downregulation was reversed in the presence of BaP, showing that BaP can increase WHCO1 cancer cell proliferation (Supplementary Figure S2A,C,E).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('BaP', 'Chemical', '-', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('BaP', 'Chemical', '-', (52, 55))	('increase', 'PosReg', (78, 86))	('BaP', 'Var', (70, 73))
921876	29673198	At 12 h and 24 h, however, the presence of BaP caused significant increases in CYP1A1 protein levels (Figure 3A).	('CYP1A1 protein levels', 'MPA', (79, 100))	('increases', 'PosReg', (66, 75))	('BaP', 'Gene', (43, 46))	('BaP', 'Chemical', '-', (43, 46))	('presence', 'Var', (31, 39))
921877	29673198	The treatment of WHCO1 cells with 5-fluorouracil and BaP resulted in a significant increase in CYP1A2 protein levels especially after 24 h (Figure 3A).	('increase', 'PosReg', (83, 91))	('5-fluorouracil', 'Var', (34, 48))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (34, 48))	('BaP', 'Chemical', '-', (53, 56))	('CYP1A2 protein levels', 'MPA', (95, 116))
921881	29673198	The use of both cisplatin and BaP resulted in a significant increase in CYP1A1 and CYP1B1, higher than when each is used separately, thus having a synergistic effect on CYP1A1 and CYP1B1 gene expression (Figure 3B).	('CYP1A1', 'Gene', (72, 78))	('CYP1A1', 'Gene', (169, 175))	('CYP1B1', 'Var', (83, 89))	('BaP', 'Var', (30, 33))	('cisplatin', 'Var', (16, 25))	('increase', 'PosReg', (60, 68))	('CYP1B1', 'Gene', (180, 186))	('BaP', 'Chemical', '-', (30, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))
921891	29673198	Treatment of WHCO1 cells with a combination of 5-fluorouracil and cisplatin induced increased apoptosis compared to the individual drugs (Figure 4A,B, top panel).	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('apoptosis', 'CPA', (94, 103))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (47, 61))	('5-fluorouracil', 'Var', (47, 61))
921910	29673198	The treatment of WHCO1 cells with cisplatin and 5-fluorouracil caused significant increases in CYP1B1 mRNA levels, while there were no major changes to the levels of CYP1A2 and GSTP1 mRNA levels (Figure 7A).	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('CYP1B1 mRNA levels', 'MPA', (95, 113))	('increases', 'PosReg', (82, 91))	('5-fluorouracil', 'Var', (48, 62))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (48, 62))
921953	29673198	Similar to our results, paclitaxel has been shown to cause G2 cell cycle arrest.	('paclitaxel', 'Var', (24, 34))	('paclitaxel', 'Chemical', 'MESH:D017239', (24, 34))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))	('G2 cell cycle arrest', 'CPA', (59, 79))
921954	29673198	Our initial investigations, using individual drugs, showed that BaP reverses the effects of cisplatin, 5-fluorouracil, and paclitaxel on WHCO1 esophageal cancer cell proliferation by 20-30% compared to that of controls.	('WHCO1 esophageal cancer', 'Disease', 'MESH:D004938', (137, 160))	('WHCO1 esophageal cancer', 'Disease', (137, 160))	('BaP', 'Var', (64, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('reverses', 'NegReg', (68, 76))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (103, 117))	('paclitaxel', 'Chemical', 'MESH:D017239', (123, 133))	('BaP', 'Chemical', '-', (64, 67))
921960	29673198	Interestingly, inhibition of the AhR has been shown to down-regulate cyclin and Cdk-2 expression.	('expression', 'MPA', (86, 96))	('Cdk-2', 'Gene', (80, 85))	('AhR', 'Gene', (33, 36))	('cyclin', 'Gene', '5111', (69, 75))	('AhR', 'Gene', '196', (33, 36))	('down-regulate', 'NegReg', (55, 68))	('Cdk-2', 'Gene', '1017', (80, 85))	('inhibition', 'Var', (15, 25))	('cyclin', 'Gene', (69, 75))
921961	29673198	Thus, it is possible that an up-regulation in Cdk2 activity, in this case caused by cisplatin and 5-fluorouracil, could be linked to a corresponding up-regulation in AhR activity ultimately resulting in increased CYP1 expression.	('activity', 'MPA', (51, 59))	('CYP1', 'Gene', (213, 217))	('up-regulation', 'PosReg', (149, 162))	('5-fluorouracil', 'Var', (98, 112))	('cisplatin', 'Var', (84, 93))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (98, 112))	('CYP1', 'Gene', '1543', (213, 217))	('Cdk2', 'Gene', '1017', (46, 50))	('activity', 'MPA', (170, 178))	('up-regulation', 'PosReg', (29, 42))	('AhR', 'Gene', (166, 169))	('Cdk2', 'Gene', (46, 50))	('AhR', 'Gene', '196', (166, 169))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('increased', 'PosReg', (203, 212))
921971	29673198	The present study suggest that BaP can reverse the effects of drugs on cancer cells, including apoptosis, and this may be mediated by the activation of survival pathways such as MEK-ERK and Akt pathways in addition to upregulation of proteins such as Bcl-2 and Bcl-xL.	('Bcl-2', 'Gene', (251, 256))	('MEK', 'Gene', (178, 181))	('Bcl-2', 'Gene', '596', (251, 256))	('MEK', 'Gene', '5609', (178, 181))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('BaP', 'Chemical', '-', (31, 34))	('Akt pathways', 'Pathway', (190, 202))	('Bcl-xL', 'Gene', '598', (261, 267))	('cancer', 'Disease', (71, 77))	('apoptosis', 'CPA', (95, 104))	('upregulation', 'PosReg', (218, 230))	('Bcl-xL', 'Gene', (261, 267))	('ERK', 'Gene', '5594', (182, 185))	('ERK', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('BaP', 'Var', (31, 34))	('activation', 'PosReg', (138, 148))	('survival pathways', 'CPA', (152, 169))
921973	29673198	WHCO1 and WHCO5 cells, derived from primary oesophageal squamous cell carcinoma in South Africa, were maintained in Dulbecco's Modified Eagle Medium (DMEM) (Sigma-Aldrich, St. Louis, MO, USA) supplemented with 10% foetal bovine serum (FBS) (GIBCO, Invitrogen, Carlsbad, CA, USA), penicillin (100 U/mL), and streptomycin (100 microg/mL) (Sigma-Aldrich, St. Louis, MO, USA) at 37  C in a humidified atmosphere of 5% CO2.	('DMEM', 'Chemical', '-', (150, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('FBS', 'Disease', 'MESH:D005198', (235, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 79))	('100 microg/mL', 'Var', (321, 334))	('WHCO5', 'Chemical', '-', (10, 15))	('FBS', 'Disease', (235, 238))	('bovine', 'Species', '9913', (221, 227))	('oesophageal squamous cell carcinoma', 'Disease', (44, 79))
921976	29673198	Cell were treated by the addition of cisplatin (Mw 300.05; CAS 15663-27-1; Sigma, Marlborough, MA, USA), 5-fluorouracil (Mw 130.08 g/mol; CAS 51-21-8; Sigma), paclitaxel (Mw 853.91 g/mol; CAS 33069-62-4; Sigma), or BaP (Mw 252.31; CAS 50-32-8; Sigma) at the indicated concentrations for different time periods.	('CAS', 'Gene', (231, 234))	('CAS', 'Gene', '9564', (231, 234))	('paclitaxel', 'Chemical', 'MESH:D017239', (159, 169))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (105, 119))	('Mw 853.91', 'Var', (171, 180))	('CAS', 'Gene', (188, 191))	('CAS', 'Gene', '9564', (188, 191))	('CAS', 'Gene', (59, 62))	('BaP', 'Chemical', '-', (215, 218))	('CAS', 'Gene', '9564', (59, 62))	('Mw', 'Var', (121, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('CAS', 'Gene', (138, 141))	('CAS', 'Gene', '9564', (138, 141))
921998	29673198	Immunoblot analysis was performed using the following primary antibodies: rabbit anti-Ki67, goat anti-CYP1A1, rabbit anti-GAPDH, rabbit anti-PCNA, mouse CYP1A2, rabbit anti-CYP1B1, rabbit anti-GSTP1, rabbit anti-p-38 MAP kinase, anti-p-ERK 1, 2, anti-ERK 2, anti-p-Akt, and anti-Akt.	('anti-p-Akt', 'Var', (258, 268))	('mouse', 'Species', '10090', (147, 152))	('rabbit', 'Species', '9986', (110, 116))	('rabbit', 'Species', '9986', (200, 206))	('goat', 'Species', '9925', (92, 96))	('ERK 2', 'Gene', '26413', (251, 256))	('rabbit', 'Species', '9986', (74, 80))	('Ki67', 'Gene', '17345', (86, 90))	('ERK 1, 2', 'Gene', '5595', (236, 244))	('rabbit', 'Species', '9986', (129, 135))	('rabbit', 'Species', '9986', (161, 167))	('rabbit', 'Species', '9986', (181, 187))	('ERK 2', 'Gene', (251, 256))	('Ki67', 'Gene', (86, 90))
922002	28489582	Association between the ERCC2 Asp312Asn polymorphism and risk of cancer Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries.	('ERCC2', 'Gene', (24, 29))	('Asp312Asn', 'SUBSTITUTION', 'None', (30, 39))	('death', 'Disease', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('polymorphism', 'Var', (40, 52))	('death', 'Disease', 'MESH:D003643', (103, 108))	('death', 'Disease', (103, 108))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ERCC2', 'Gene', '2068', (24, 29))	('Association', 'Interaction', (0, 11))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('death', 'Disease', 'MESH:D003643', (177, 182))	('Asp312Asn', 'Var', (30, 39))
922005	28489582	There is contrasting evidence on the association between the ERCC2 Asp312Asn polymorphism and the risk of cancer.	('association', 'Interaction', (37, 48))	('Asp312Asn', 'SUBSTITUTION', 'None', (67, 76))	('ERCC2', 'Gene', '2068', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('ERCC2', 'Gene', (61, 66))	('Asp312Asn', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
922006	28489582	The overall analysis suggested a significant association between the ERCC2 Asp312Asn polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ERCC2', 'Gene', (69, 74))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Asp312Asn', 'SUBSTITUTION', 'None', (75, 84))	('Asp312Asn', 'Var', (75, 84))	('ERCC2', 'Gene', '2068', (69, 74))
922008	28489582	In summary, our results suggested that ERCC2 Asp312Asn polymorphism is associated with increased cancer risk.	('cancer', 'Disease', (97, 103))	('ERCC2', 'Gene', '2068', (39, 44))	('Asp312Asn', 'Var', (45, 54))	('Asp312Asn', 'SUBSTITUTION', 'None', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ERCC2', 'Gene', (39, 44))	('associated', 'Reg', (71, 81))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
922010	28489582	Furthermore, the ERCC2 Asp312Asn polymorphism is associated with bladder, esophageal, and gastric cancers, but not with breast, head and neck, lung, prostate, and skin cancers, and non-Hodgkin lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (193, 201))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('associated', 'Reg', (49, 59))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (185, 201))	('gastric cancers', 'Disease', 'MESH:D013274', (90, 105))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('skin cancer', 'Phenotype', 'HP:0008069', (163, 174))	('gastric cancers', 'Disease', (90, 105))	('gastric cancers', 'Phenotype', 'HP:0012126', (90, 105))	('non-Hodgkin lymphoma', 'Disease', (181, 201))	('lung', 'Disease', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (181, 201))	('ERCC2', 'Gene', (17, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('skin cancers', 'Phenotype', 'HP:0008069', (163, 175))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (181, 201))	('ERCC2', 'Gene', '2068', (17, 22))	('prostate', 'Disease', (149, 157))	('skin cancers', 'Disease', (163, 175))	('bladder', 'Disease', (65, 72))	('Asp312Asn', 'SUBSTITUTION', 'None', (23, 32))	('breast', 'Disease', (120, 126))	('esophageal', 'Disease', (74, 84))	('skin cancers', 'Disease', 'MESH:D012878', (163, 175))	('Asp312Asn', 'Var', (23, 32))
922014	28489582	Among genetic factors, genetic and epigenetic mutations, such as aberrant DNA methylation, can lead to carcinogenesis.	('lead to', 'Reg', (95, 102))	('aberrant', 'Var', (65, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('DNA', 'Protein', (74, 77))	('carcinogenesis', 'Disease', (103, 117))
922019	28489582	The helicase participates in DNA unwinding as part of the NER pathway, and plays an important role in the recognition and repair of structurally unrelated DNA lesions containing bulky adducts and thymidine dimers.	('bulky', 'Var', (178, 183))	('thymidine', 'Chemical', 'MESH:D013936', (196, 205))	('helicase', 'Protein', (4, 12))	('participates', 'Reg', (13, 25))	('NER pathway', 'Pathway', (58, 69))
922020	28489582	Some studies have shown that ERCC2 polymorphisms may be related to reduced DNA repair due to a possible reduction in its helicase activity.	('reduction', 'NegReg', (104, 113))	('DNA repair', 'MPA', (75, 85))	('ERCC2', 'Gene', '2068', (29, 34))	('helicase', 'Protein', (121, 129))	('reduced', 'NegReg', (67, 74))	('ERCC2', 'Gene', (29, 34))	('polymorphisms', 'Var', (35, 48))	('activity', 'MPA', (130, 138))
922021	28489582	There are two important single nucleotide polymorphisms (SNPs) in the ERCC2 gene.	('ERCC2', 'Gene', '2068', (70, 75))	('single nucleotide polymorphisms', 'Var', (24, 55))	('ERCC2', 'Gene', (70, 75))
922022	28489582	One is the Lys751Gln polymorphism, which has been shown to be involved in genetic susceptibility to some cancer types.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('Lys751Gln', 'SUBSTITUTION', 'None', (11, 20))	('involved', 'Reg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Lys751Gln', 'Var', (11, 20))
922023	28489582	Another common ERCC2 polymorphism in the coding region is Asp312Asn (rs1799793), which is characterized by a G to A transition at position 312 in exon 10 causing an aspartic acid (Asp) to asparagine amino acid (Asn) exchange.	('aspartic acid', 'Chemical', 'MESH:D001224', (165, 178))	('aspartic acid', 'MPA', (165, 178))	('ERCC2', 'Gene', '2068', (15, 20))	('Asp', 'Chemical', 'MESH:D001224', (58, 61))	('Asp312Asn', 'Var', (58, 67))	('Asp312Asn', 'SUBSTITUTION', 'None', (58, 67))	('Asn', 'Chemical', '-', (211, 214))	('asparagine amino acid', 'Chemical', '-', (188, 209))	('rs1799793', 'Mutation', 'rs1799793', (69, 78))	('G to A transition at position 312', 'Mutation', 'c.312G>A', (109, 142))	('ERCC2', 'Gene', (15, 20))	('Asp', 'Chemical', 'MESH:D001224', (180, 183))	('Asn', 'Chemical', '-', (64, 67))	('causing', 'Reg', (154, 161))
922025	28489582	To provide a comprehensive assessment of and to clarify associations between the ERCC2 Asp312Asn polymorphisms and the risk of cancer, we performed a meta-analysis of all the eligible case-control studies.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Asp312Asn', 'Var', (87, 96))	('Asp312Asn', 'SUBSTITUTION', 'None', (87, 96))	('cancer', 'Disease', (127, 133))	('ERCC2', 'Gene', '2068', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('polymorphisms', 'Var', (97, 110))	('ERCC2', 'Gene', (81, 86))
922028	28489582	Overall, the results of our meta-analysis showed a significant association between the ERCC2 polymorphism and cancer risk (Table 2).	('cancer', 'Disease', (110, 116))	('ERCC2', 'Gene', (87, 92))	('polymorphism', 'Var', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ERCC2', 'Gene', '2068', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
922029	28489582	In order to evaluate the effects of specific study characteristics on the association between the ERCC2 polymorphism and cancer risk, we performed subgroup analysis if there were 6 or more studies.	('polymorphism', 'Var', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ERCC2', 'Gene', '2068', (98, 103))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('ERCC2', 'Gene', (98, 103))	('association', 'Interaction', (74, 85))
922031	28489582	For control source subgroup, we found a significant association between the ERCC2 polymorphism and cancer risk when the source of the controls was hospital-based (HB).	('ERCC2', 'Gene', '2068', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('ERCC2', 'Gene', (76, 81))	('cancer', 'Disease', (99, 105))	('polymorphism', 'Var', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
922033	28489582	According to the type of cancer, the ERCC2 polymorphism was associated with a significantly higher risk of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('bladder cancer', 'Disease', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('type of cancer', 'Disease', (17, 31))	('ERCC2', 'Gene', '2068', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('ERCC2', 'Gene', (37, 42))	('polymorphism', 'Var', (43, 55))	('type of cancer', 'Disease', 'MESH:D009369', (17, 31))	('associated', 'Reg', (60, 70))
922035	28489582	Similarly, the results of subgroups of other cancers indicated no association with the ERCC2 polymorphism, including head and neck, lung, prostate, and skin cancers and non-Hodgkin lymphoma.	('polymorphism', 'Var', (93, 105))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('skin cancers', 'Disease', (152, 164))	('skin cancers', 'Disease', 'MESH:D012878', (152, 164))	('ERCC2', 'Gene', (87, 92))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (173, 189))	('ERCC2', 'Gene', '2068', (87, 92))	('lung', 'Disease', (132, 136))	('non-Hodgkin lymphoma', 'Disease', (169, 189))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (169, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (181, 189))	('cancers', 'Disease', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('skin cancer', 'Phenotype', 'HP:0008069', (152, 163))	('cancers', 'Disease', (45, 52))	('prostate', 'Disease', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('skin cancers', 'Phenotype', 'HP:0008069', (152, 164))
922037	28489582	In the group with gastric cancer, the ERCC2 polymorphism was confirmed to increase the risk of cancer in the homozygote comparison and the recessive model, but not in the heterozygote comparison and the dominant model.	('gastric cancer', 'Disease', (18, 32))	('ERCC2', 'Gene', (38, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', (95, 101))	('increase', 'PosReg', (74, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('polymorphism', 'Var', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('ERCC2', 'Gene', '2068', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
922044	28489582	In the relationship between gene polymorphisms and cancer risk, the ERCC2 Asp312Asn polymorphism is an important risk factor.	('ERCC2', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Asp312Asn', 'Var', (74, 83))	('ERCC2', 'Gene', '2068', (68, 73))	('Asp312Asn', 'SUBSTITUTION', 'None', (74, 83))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
922045	28489582	Impaired DNA repair capacity is a risk factor for the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('DNA repair', 'MPA', (9, 19))	('Impaired', 'Var', (0, 8))	('cancer', 'Disease', (69, 75))
922046	28489582	The ERCC2 Asp312Asn polymorphism influences DNA repair through the NER pathway.	('ERCC2', 'Gene', (4, 9))	('Asp312Asn', 'Var', (10, 19))	('DNA repair', 'MPA', (44, 54))	('NER pathway', 'Pathway', (67, 78))	('Asp312Asn', 'SUBSTITUTION', 'None', (10, 19))	('influences', 'Reg', (33, 43))	('ERCC2', 'Gene', '2068', (4, 9))
922047	28489582	To date, many publications have shown an association between the ERCC2 Asp312Asn polymorphism and risk of cancer.	('ERCC2', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('ERCC2', 'Gene', '2068', (65, 70))	('Asp312Asn', 'SUBSTITUTION', 'None', (71, 80))	('cancer', 'Disease', (106, 112))	('Asp312Asn', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
922048	28489582	In order to resolve this conflict, we performed a meta-analysis that evaluates the relationship between the ERCC2 Asp312Asn polymorphism and risk of cancer.	('cancer', 'Disease', (149, 155))	('ERCC2', 'Gene', '2068', (108, 113))	('polymorphism', 'Var', (124, 136))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ERCC2', 'Gene', (108, 113))	('Asp312Asn', 'Var', (114, 123))	('Asp312Asn', 'SUBSTITUTION', 'None', (114, 123))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
922049	28489582	In our meta-analysis, the association of the ERCC2 Asp312Asn polymorphism with the risk of cancer was evaluated in 38,848 cases and 48,928 controls.	('ERCC2', 'Gene', '2068', (45, 50))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('ERCC2', 'Gene', (45, 50))	('Asp312Asn', 'Var', (51, 60))	('Asp312Asn', 'SUBSTITUTION', 'None', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('association', 'Interaction', (26, 37))
922050	28489582	A significant association was observed between the ERCC2 Asp312Asn polymorphism and overall cancer risk in all genetic models.	('ERCC2', 'Gene', '2068', (51, 56))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('ERCC2', 'Gene', (51, 56))	('Asp312Asn', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Asp312Asn', 'SUBSTITUTION', 'None', (57, 66))
922058	28489582	In the subgroup analysis according to the cancer site, a significant association with the ERCC2 Asp312Asn polymorphism was observed for bladder, esophageal, and gastric cancers; however, no significant association was observed for breast, head and neck, lung, prostate, and skin cancers, and non- Hodgkin lymphoma.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ERCC2', 'Gene', (90, 95))	('non- Hodgkin lymphoma', 'Disease', 'MESH:D008228', (292, 313))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lymphoma', 'Phenotype', 'HP:0002665', (305, 313))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('cancer', 'Disease', (279, 285))	('skin cancer', 'Phenotype', 'HP:0008069', (274, 285))	('ERCC2', 'Gene', '2068', (90, 95))	('lung', 'Disease', (254, 258))	('gastric cancers', 'Disease', (161, 176))	('gastric cancers', 'Disease', 'MESH:D013274', (161, 176))	('gastric cancers', 'Phenotype', 'HP:0012126', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('skin cancers', 'Phenotype', 'HP:0008069', (274, 286))	('gastric cancer', 'Phenotype', 'HP:0012126', (161, 175))	('Asp312Asn', 'SUBSTITUTION', 'None', (96, 105))	('prostate', 'Disease', (260, 268))	('bladder', 'Disease', (136, 143))	('esophageal', 'Disease', (145, 155))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (297, 313))	('skin cancers', 'Disease', (274, 286))	('non- Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (292, 313))	('Asp312Asn', 'Var', (96, 105))	('skin cancers', 'Disease', 'MESH:D012878', (274, 286))	('non- Hodgkin lymphoma', 'Disease', (292, 313))	('cancer', 'Disease', (42, 48))	('breast', 'Disease', (231, 237))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
922059	28489582	Some previous meta-analyses assessed the effect of the ERCC2 Asp312Asn polymorphism on the risk of these cancers and reached conclusions consistent with those of our study.	('ERCC2', 'Gene', '2068', (55, 60))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('ERCC2', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Asp312Asn', 'Var', (61, 70))	('Asp312Asn', 'SUBSTITUTION', 'None', (61, 70))
922060	28489582	suggested that the ERCC2 Asp312Asn polymorphism might be associated with an increased risk of bladder cancer and esophageal cancer, respectively.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Asp312Asn', 'Var', (25, 34))	('Asp312Asn', 'SUBSTITUTION', 'None', (25, 34))	('ERCC2', 'Gene', '2068', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('ERCC2', 'Gene', (19, 24))	('esophageal cancer', 'Disease', (113, 130))	('associated', 'Reg', (57, 67))
922062	28489582	suggested that the ERCC2 Asp312Asn polymorphism was not associated with breast cancer, head and neck cancer, and skin cancer, respectively.	('skin cancer', 'Phenotype', 'HP:0008069', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('skin cancer', 'Disease', (113, 124))	('head and neck cancer', 'Phenotype', 'HP:0012288', (87, 107))	('Asp312Asn', 'Var', (25, 34))	('skin cancer', 'Disease', 'MESH:D012878', (113, 124))	('ERCC2', 'Gene', '2068', (19, 24))	('associated', 'Reg', (56, 66))	('Asp312Asn', 'SUBSTITUTION', 'None', (25, 34))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', (72, 85))	('ERCC2', 'Gene', (19, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('head and neck cancer', 'Disease', 'MESH:D006258', (87, 107))
922063	28489582	suggested that the ERCC2 Asp312Asn polymorphism contributed to the risk of non-Hodgkin lymphoma, lung cancer, and prostate cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (75, 95))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (75, 95))	('Asp312Asn', 'Var', (25, 34))	('ERCC2', 'Gene', '2068', (19, 24))	('Asp312Asn', 'SUBSTITUTION', 'None', (25, 34))	('non-Hodgkin lymphoma', 'Disease', (75, 95))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (79, 95))	('ERCC2', 'Gene', (19, 24))	('lung cancer', 'Disease', (97, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('prostate cancer', 'Disease', (114, 129))
922065	28489582	Moreover, the exact mechanism for the associations between different cancer sites and the ERCC2 Asp312Asn polymorphism is not clear; the mechanism of carcinogenesis may differ between different cancer sites and the ERCC2 genetic variants may exert varying effects in different cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (150, 164))	('ERCC2', 'Gene', (90, 95))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('ERCC2', 'Gene', '2068', (90, 95))	('cancer', 'Disease', (277, 283))	('ERCC2', 'Gene', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('Asp312Asn', 'SUBSTITUTION', 'None', (96, 105))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('ERCC2', 'Gene', '2068', (215, 220))	('cancers', 'Disease', (277, 284))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', (194, 200))	('Asp312Asn', 'Var', (96, 105))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('carcinogenesis', 'Disease', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('effects', 'Reg', (256, 263))
922067	28489582	indicated that the ERCC2 Asp312Asn polymorphism was not associated with the development of HCC.	('HCC', 'Disease', (91, 94))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('Asp312Asn', 'SUBSTITUTION', 'None', (25, 34))	('Asp312Asn', 'Var', (25, 34))	('ERCC2', 'Gene', '2068', (19, 24))	('associated', 'Reg', (56, 66))	('ERCC2', 'Gene', (19, 24))
922068	28489582	demonstrated no relationship between ERCC2 Asp312Asn polymorphism and osteosarcoma.	('ERCC2', 'Gene', '2068', (37, 42))	('osteosarcoma', 'Phenotype', 'HP:0002669', (70, 82))	('osteosarcoma', 'Disease', (70, 82))	('osteosarcoma', 'Disease', 'MESH:D012516', (70, 82))	('ERCC2', 'Gene', (37, 42))	('Asp312Asn', 'SUBSTITUTION', 'None', (43, 52))	('Asp312Asn', 'Var', (43, 52))
922069	28489582	this polymorphism was associated with an overall increase in chromosomal damage in oral cancer.	('chromosomal damage in oral cancer', 'Disease', (61, 94))	('increase', 'PosReg', (49, 57))	('polymorphism', 'Var', (5, 17))	('chromosomal damage in oral cancer', 'Disease', 'MESH:D009062', (61, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
922070	28489582	observed a slightly lower statistical significance between the ERCC2 Asp312Asn polymorphism and colorectal cancer.	('ERCC2', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Asp312Asn', 'SUBSTITUTION', 'None', (69, 78))	('Asp312Asn', 'Var', (69, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('colorectal cancer', 'Disease', (96, 113))	('ERCC2', 'Gene', '2068', (63, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
922073	28489582	Therefore, the equivocal association between the ERCC2 Asp312Asn polymorphism and some diseases remains to be confirmed.	('ERCC2', 'Gene', (49, 54))	('Asp312Asn', 'Var', (55, 64))	('ERCC2', 'Gene', '2068', (49, 54))	('Asp312Asn', 'SUBSTITUTION', 'None', (55, 64))
922079	28489582	In summary, our meta-analysis suggested that the ERCC2 Asp312Asn polymorphism is associated with increased cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ERCC2', 'Gene', (49, 54))	('Asp312Asn', 'Var', (55, 64))	('Asp312Asn', 'SUBSTITUTION', 'None', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('ERCC2', 'Gene', '2068', (49, 54))
922083	28489582	A systematic search of articles relating to the ERCC2 Asp312Asn polymorphism and cancer was conducted by 2 researchers, using the PubMed, EMBASE, Science Direct, Web of Science and the China National Knowledge Infrastructure (CNKI) databases.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('ERCC2', 'Gene', (48, 53))	('cancer', 'Disease', (81, 87))	('Asp312Asn', 'Var', (54, 63))	('Asp312Asn', 'SUBSTITUTION', 'None', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ERCC2', 'Gene', '2068', (48, 53))
922084	28489582	The search strategy was based on various combinations of the following terms: "xeroderma pigmentosum group d protein "[MeSH Terms] OR "xeroderma pigmentosum group d protein" [All Fields] OR "ercc2" [All Fields]) AND Asp312Asn [All Fields] AND ("neoplasms" [MeSH Terms] OR "neoplasms" [All Fields] OR "cancer" [All Fields].	('Asp312Asn', 'SUBSTITUTION', 'None', (216, 225))	('xeroderma pigmentosum group d', 'Gene', (79, 108))	('neoplasms', 'Phenotype', 'HP:0002664', (245, 254))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('"neoplasms', 'Disease', 'MESH:D009369', (272, 282))	('neoplasms', 'Phenotype', 'HP:0002664', (273, 282))	('ercc2', 'Gene', (191, 196))	('cancer', 'Disease', (301, 307))	('"neoplasms', 'Disease', (272, 282))	('xeroderma pigmentosum group d', 'Gene', '2068', (79, 108))	('ercc2', 'Gene', '2068', (191, 196))	('"neoplasms', 'Disease', 'MESH:D009369', (244, 254))	('xeroderma pigmentosum group d', 'Gene', (135, 164))	('xeroderma pigmentosum group d', 'Gene', '2068', (135, 164))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('"neoplasms', 'Disease', (244, 254))	('Asp312Asn', 'Var', (216, 225))
922085	28489582	The following inclusion criteria were set and reviewed by two independent investigators: (I) case-control study; (II) evaluation of the ERCC2 Asp312Asn polymorphism and cancer; and (III) detailed data available for calculating ORs and the corresponding 95% CIs.	('cancer', 'Disease', (169, 175))	('ERCC2', 'Gene', (136, 141))	('Asp312Asn', 'Var', (142, 151))	('Asp312Asn', 'SUBSTITUTION', 'None', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ERCC2', 'Gene', '2068', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
922092	28489582	The primary objective of our meta-analysis was to calculate ORs and their 95% CIs to evaluate the association between ERCC2 Asp312Asn and cancer risks.	('association', 'Interaction', (98, 109))	('cancer', 'Disease', (138, 144))	('ERCC2', 'Gene', '2068', (118, 123))	('Asp312Asn', 'Var', (124, 133))	('Asp312Asn', 'SUBSTITUTION', 'None', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('ERCC2', 'Gene', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
922095	28489582	NER nucleotide excision repair ERCC2 excision repair cross-complementing group 2 XPD Xeroderma pigmentosum group D TFIIH transcription factor IIH SNPs single nucleotide polymorphisms Asn asparagine amino acid HB hospital-based PB population-based HCC hepatocellular cancer CNKI China National Knowledge Infrastructure TSA trial sequential analysis	('transcription factor IIH', 'Gene', (121, 145))	('Xeroderma pigmentosum', 'Disease', (85, 106))	('excision repair cross-complementing group 2', 'Gene', '2068', (37, 80))	('TFIIH', 'Gene', (115, 120))	('XPD', 'Gene', '2068', (81, 84))	('Asn', 'Chemical', '-', (183, 186))	('asparagine amino acid', 'Chemical', '-', (187, 208))	('transcription factor IIH', 'Gene', '2068', (121, 145))	('TSA', 'Chemical', '-', (318, 321))	('ERCC2', 'Gene', (31, 36))	('TFIIH', 'Gene', '2068', (115, 120))	('hepatocellular cancer', 'Disease', (251, 272))	('XPD', 'Gene', (81, 84))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (251, 272))	('ERCC2', 'Gene', '2068', (31, 36))	('excision repair cross-complementing group 2', 'Gene', (37, 80))	('PB', 'Chemical', '-', (227, 229))	('single nucleotide polymorphisms', 'Var', (151, 182))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (251, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('HCC', 'Phenotype', 'HP:0001402', (247, 250))	('Xeroderma pigmentosum', 'Disease', 'MESH:D014983', (85, 106))
922127	27165741	Development of these tumors is linked closely to genomic perturbations, genetic mutations and/or altered expression of key molecules involved in various stages of squamous cell lineage commitment and/or terminal differentiation.	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('altered', 'Var', (97, 104))	('expression', 'MPA', (105, 115))	('genetic mutations', 'Var', (72, 89))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
922139	27165741	However, it is becoming increasingly clear that SCCs share important properties, as revealed by a commonality of genomic, genetic and epigenetic alterations and a similar impact of the underlying mesenchyme.	('SCC', 'Gene', (48, 51))	('SCC', 'Gene', '6317', (48, 51))	('epigenetic alterations', 'Var', (134, 156))
922144	27165741	UVB (280-315 nm) causes direct DNA damage, with a typical, but not exclusive, signature of C T substitutions, resulting from covalent cyclobutane dimer formation between adjacent pyrimidine rings.	('substitutions', 'Var', (95, 108))	('cyclobutane', 'Chemical', 'MESH:D003503', (134, 145))	('pyrimidine', 'Chemical', 'MESH:C030986', (179, 189))	('DNA damage', 'MPA', (31, 41))
922146	27165741	UVA causes additional multiple effects, including chromosomal aberrations and widespread alterations in cellular proteins and lipids.	('UVA', 'Disease', (0, 3))	('alterations', 'Reg', (89, 100))	('lipids', 'Chemical', 'MESH:D008055', (126, 132))	('chromosomal aberrations', 'Var', (50, 73))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (50, 73))
922168	27165741	Pathogens create pro-oncogenic environments in two major ways: 1) expression of pathogen-derived oncogenes and/or inactivation of host tumor suppressor genes; 2) chronic inflammation and reduced immunosurveillance.	('host tumor', 'Disease', (130, 140))	('host tumor', 'Disease', 'MESH:D006086', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('inflammation', 'Disease', 'MESH:D007249', (170, 182))	('inactivation', 'Var', (114, 126))	('immunosurveillance', 'CPA', (195, 213))	('inflammation', 'Disease', (170, 182))	('reduced', 'NegReg', (187, 194))
922173	27165741	Generally, HPV-positive HNSCC has a better clinical prognosis than its HPV-negative counterpart.	('SCC', 'Gene', (26, 29))	('SCC', 'Gene', '6317', (26, 29))	('HPV-positive', 'Var', (11, 23))
922174	27165741	The reasons for this remain to be understood but may be due to their different genetic causes, whereas HPV-related cancers tend to retain wild type TP53, while HPV-negative tumors are very frequently associated with pro-oncogenic gain-of-function mutations in TP53 and other genes.	('TP53', 'Gene', (260, 264))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('TP53', 'MPA', (148, 152))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('gain-of-function', 'PosReg', (230, 246))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (247, 256))	('HPV-related', 'Disease', (103, 114))
922181	27165741	EBV-induced oncogenesis results from a multistep process involving a number of genetic and epigenetic (methylation) changes in the host genome (including CDKN2A inactivation and CCNDD1 amplification) coupled with persistent EBV infection.	('inactivation', 'Var', (161, 173))	('EBV infection', 'Disease', (224, 237))	('oncogenesis', 'Disease', (12, 23))	('EBV infection', 'Disease', 'MESH:D020031', (224, 237))	('CDKN2A', 'Gene', (154, 160))	('CCNDD1', 'Gene', (178, 184))	('changes', 'Reg', (116, 123))	('CDKN2A', 'Gene', '1029', (154, 160))	('EBV', 'Species', '10376', (0, 3))	('EBV', 'Species', '10376', (224, 227))
922189	27165741	Chronic inflammation is thought to cause metaplasia of the transitional urothelium into squamous tissue before an accumulation of oncogenic mutations that culminate in uncontrolled cell growth.	('Chronic inflammation', 'Disease', (0, 20))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))	('mutations', 'Var', (140, 149))	('cause', 'Reg', (35, 40))	('metaplasia', 'Disease', (41, 51))
922196	27165741	An important finding is that a large fraction of gene mutations found in tumors are already present in normal tissues, so that accumulation and combination of these mutations may be more important than their individual occurrence.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
922197	27165741	As an alternative to clonal selection, a "Big Bang" mode of cancer development is also possible, whereby clinically detectable tumors result from expansion of a single cell population with genetically dominant alterations intermingled with "private" (i.e.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('alterations', 'Var', (210, 221))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
922200	27165741	However, the presence of clones with multiple mutations of these genes also in normal epithelium suggests that they may have a more passenger than driver function and/or act in concert with other determinants of carcinogenesis.	('carcinogenesis', 'Disease', (212, 226))	('mutations', 'Var', (46, 55))	('carcinogenesis', 'Disease', 'MESH:D063646', (212, 226))
922204	27165741	For example, in studies of LSCCs and CvSCCs researchers found a total of 8.1 and 4.2 mutations per megabase, respectively.	('SCC', 'Gene', '6317', (39, 42))	('SCC', 'Gene', (28, 31))	('mutations', 'Var', (85, 94))	('SCC', 'Gene', '6317', (28, 31))	('SCC', 'Gene', (39, 42))
922206	27165741	In fact, one study in HNSCC estimated that copy number alterations (CNAs) affecting discrete chromosomal regions and polyploidy account for up to 70% of tumors.	('copy number alterations', 'Var', (43, 66))	('SCC', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('SCC', 'Gene', '6317', (24, 27))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
922207	27165741	In another study, focused on CSCC and associated precursor lesions, UV hotspot mutations in the kinetochore KNSTRN gene were reported to cause disruption of chromatid cohesion and aneuploidy.	('SCC', 'Gene', '6317', (30, 33))	('aneuploidy', 'Disease', (180, 190))	('cause', 'Reg', (137, 142))	('aneuploidy', 'Disease', 'MESH:D000782', (180, 190))	('SCC', 'Gene', (30, 33))	('disruption', 'CPA', (143, 153))	('KNSTRN', 'Gene', '90417', (108, 114))	('mutations', 'Var', (79, 88))	('KNSTRN', 'Gene', (108, 114))
922209	27165741	However, mutations of certain genes appear to be more frequent or potentially specific to a given SCC.	('SCC', 'Gene', '6317', (98, 101))	('mutations', 'Var', (9, 18))	('SCC', 'Gene', (98, 101))
922211	27165741	A complex interplay between environmental risk factors, host genetic predisposition and tumor cell genomics/genetics/epigenetics may nurture certain mutations preferentially.	('tumor', 'Disease', (88, 93))	('mutations', 'Var', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
922213	27165741	The broad spectrum of gene alterations identified in SCCs may be grouped into two categories: one, with a likely cancer driver function in a variety of cancer types, and the other, affecting genes with a preferential or selective role in SCCs in a mutation gene network centered around squamous cell fate decisions and/or the squamous terminal differentiation program.	('SCC', 'Gene', '6317', (53, 56))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('affecting', 'Reg', (181, 190))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('SCC', 'Gene', (238, 241))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('SCC', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('SCC', 'Gene', '6317', (238, 241))	('alterations', 'Var', (27, 38))
922214	27165741	By analysis of large data sets of tumors, specific gene mutations that are mutually exclusive with others can be identified, even if statistical significance of negative associations is limited to very few cases (Figures 2 and 3).	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('mutations', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
922215	27165741	TP53 mutations are the most frequently identified somatic mutations in SCCs from all body sites (Table 2).	('SCC', 'Gene', '6317', (71, 74))	('SCC', 'Gene', (71, 74))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
922217	27165741	The second involves modulation of gene expression by mutant p53 mediated by its association with other transcriptional factors.	('gene expression', 'MPA', (34, 49))	('p53', 'Gene', (60, 63))	('modulation', 'Reg', (20, 30))	('association', 'Interaction', (80, 91))	('mutant', 'Var', (53, 59))	('p53', 'Gene', '7157', (60, 63))
922218	27165741	The third results from altered DNA binding specificity of mutant p53.	('mutant', 'Var', (58, 64))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('DNA binding', 'Interaction', (31, 42))	('altered', 'Reg', (23, 30))
922219	27165741	As a result, a whole range of deregulated genes has been identified with pro-survival, pro-invasive and pro-tumorigenic functions.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('pro-survival', 'CPA', (73, 85))	('deregulated', 'Var', (30, 41))	('tumor', 'Disease', (108, 113))
922220	27165741	The different impact on tumorigenesis of missense versus loss of function TP53 mutations is best appreciated in mouse models, with "knock-in" missense mutations resulting in a shift towards epithelial-derived cancers (see, for instance,).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('loss of function', 'NegReg', (57, 73))	('missense', 'Var', (41, 49))	('tumor', 'Disease', (24, 29))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancers', 'Disease', (209, 216))	('mouse', 'Species', '10090', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('TP53', 'Gene', (74, 78))	('epithelial-derived', 'Disease', (190, 208))	('mutations', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
922221	27165741	Suppression of p105-Rb activity by loss-of-function mutations of the CDK inhibitor CDKN2A is also very common in SCCs, while mutations of the RB1 gene itself have been found less frequently except in ESCC.	('mutations', 'Var', (52, 61))	('CDKN2A', 'Gene', '1029', (83, 89))	('SCC', 'Gene', '6317', (113, 116))	('p105-Rb', 'Gene', '5925', (15, 22))	('RB1', 'Gene', (142, 145))	('loss-of-function', 'NegReg', (35, 51))	('SCC', 'Gene', (201, 204))	('RB1', 'Gene', '5925', (142, 145))	('SCC', 'Gene', '6317', (201, 204))	('p105-Rb', 'Gene', (15, 22))	('Suppression', 'NegReg', (0, 11))	('SCC', 'Gene', (113, 116))	('CDKN2A', 'Gene', (83, 89))
922222	27165741	Interestingly, putative cancer driver mutations in many genes including TP53 are already frequent in normal photo-exposed skin, with the notable exception of CDKN2A mutations, suggesting that these may be a critical trigger of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('CDKN2A', 'Gene', (158, 164))	('TP53', 'Gene', (72, 76))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('CDKN2A', 'Gene', '1029', (158, 164))	('mutations', 'Var', (38, 47))
922223	27165741	As mentioned, the incidence of TP53 and CDKN2A/RB1 mutations is much reduced in HNSCCs and CvSCCs linked with HPV infection.	('SCC', 'Gene', (82, 85))	('mutations', 'Var', (51, 60))	('SCC', 'Gene', '6317', (82, 85))	('RB1', 'Gene', '5925', (47, 50))	('reduced', 'NegReg', (69, 76))	('TP53', 'Gene', (31, 35))	('HPV infection', 'Disease', 'MESH:D030361', (110, 123))	('SCC', 'Gene', (93, 96))	('CDKN2A', 'Gene', (40, 46))	('CDKN2A', 'Gene', '1029', (40, 46))	('SCC', 'Gene', '6317', (93, 96))	('RB1', 'Gene', (47, 50))	('HPV infection', 'Disease', (110, 123))
922225	27165741	The genes coding for Cyclin D1 and c-Myc are also commonly amplified in SCCs (Figures 2 and 3) and amplification of these genes, like TP53 and CDKN2A mutations, are frequent in HPV (-) HNSCCs but rare or absent in their HPV (+) counterparts.	('c-Myc', 'Gene', '4609', (35, 40))	('TP53', 'Gene', (134, 138))	('SCC', 'Gene', '6317', (72, 75))	('SCC', 'Gene', (187, 190))	('c-Myc', 'Gene', (35, 40))	('SCC', 'Gene', (72, 75))	('CDKN2A', 'Gene', (143, 149))	('mutations', 'Var', (150, 159))	('amplification', 'Var', (99, 112))	('SCC', 'Gene', '6317', (187, 190))	('Cyclin D1', 'Gene', '595', (21, 30))	('CDKN2A', 'Gene', '1029', (143, 149))	('Cyclin D1', 'Gene', (21, 30))	('HPV', 'Disease', (177, 180))
922227	27165741	Loss-of-function mutations in FBXW7 are especially frequent in CvSCC, but occur also in SCCs from other body sites (Table 2).	('Loss-of-function', 'NegReg', (0, 16))	('FBXW7', 'Gene', '55294', (30, 35))	('FBXW7', 'Gene', (30, 35))	('SCC', 'Gene', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('SCC', 'Gene', (88, 91))	('mutations', 'Var', (17, 26))	('SCC', 'Gene', '6317', (88, 91))
922229	27165741	SCCs are also linked to frequent amplification and, in some cases, mutations of tyrosine kinase receptor genes (Figures 2 and 3; Table 2).	('SCC', 'Gene', (0, 3))	('tyrosine kinase', 'Gene', '7294', (80, 95))	('SCC', 'Gene', '6317', (0, 3))	('mutations', 'Var', (67, 76))	('tyrosine kinase', 'Gene', (80, 95))
922230	27165741	The frequent amplification of EGFR and closely related ERBB2 can contribute to elevated receptor activity in HNSCCs and ESCCs.	('EGFR', 'Gene', (30, 34))	('receptor activity', 'MPA', (88, 105))	('SCC', 'Gene', (121, 124))	('SCC', 'Gene', (111, 114))	('amplification', 'Var', (13, 26))	('elevated', 'PosReg', (79, 87))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))	('SCC', 'Gene', '6317', (111, 114))	('EGFR', 'Gene', '1956', (30, 34))	('SCC', 'Gene', '6317', (121, 124))
922231	27165741	Interestingly, in a recent comprehensive study of HNSCCs, EGFR amplification was found in 15% of the (HPV-) tumors but in none of their (HPV+) counterparts.	('EGFR', 'Gene', '1956', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('EGFR', 'Gene', (58, 62))	('SCC', 'Gene', (52, 55))	('found', 'Reg', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('SCC', 'Gene', '6317', (52, 55))	('amplification', 'Var', (63, 76))	('HPV-) tumors', 'Disease', 'MESH:D030361', (102, 114))
922233	27165741	A favorable response to small molecule inhibitors is observed in the case of activating EGFR mutations, such as frequently occurring in lung adenocarcinomas but not squamous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (136, 156))	('squamous carcinomas', 'Disease', 'MESH:D002294', (165, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('mutations', 'Var', (93, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('EGFR', 'Gene', '1956', (88, 92))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (165, 183))	('lung adenocarcinomas', 'Disease', (136, 156))	('activating', 'PosReg', (77, 87))	('EGFR', 'Gene', (88, 92))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (136, 156))	('squamous carcinomas', 'Disease', (165, 184))
922234	27165741	By contrast, some beneficial effects are elicited by treatment with anti-EGFR antibodies even in the absence of EGFR mutations, through mechanisms that are still poorly understood.	('EGFR', 'Gene', (112, 116))	('EGFR', 'Gene', '1956', (73, 77))	('beneficial effects', 'PosReg', (18, 36))	('antibodies', 'Var', (78, 88))	('EGFR', 'Gene', (73, 77))	('EGFR', 'Gene', '1956', (112, 116))
922242	27165741	Unlike EGFR, at least in LSCCs, amplification of FGFR genes can be accompanied by activating mutations mapping to the extracellular or intracellular regions of the receptors, making these molecules possible therapeutic targets.	('SCC', 'Gene', '6317', (26, 29))	('mutations', 'Var', (93, 102))	('activating', 'PosReg', (82, 92))	('EGFR', 'Gene', (7, 11))	('FGFR', 'Gene', (49, 53))	('amplification', 'Var', (32, 45))	('SCC', 'Gene', (26, 29))	('EGFR', 'Gene', '1956', (7, 11))
922243	27165741	Importantly, FGFR1, FGFR2 and FGFR3 gene fusions have been identified also in various cancer types, including HNSCCs and LSCCs.	('SCC', 'Gene', (122, 125))	('identified', 'Reg', (59, 69))	('SCC', 'Gene', '6317', (112, 115))	('FGFR1', 'Gene', (13, 18))	('FGFR3', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('SCC', 'Gene', '6317', (122, 125))	('FGFR1', 'Gene', '2260', (13, 18))	('FGFR2', 'Gene', '2263', (20, 25))	('fusions', 'Var', (41, 48))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('FGFR2', 'Gene', (20, 25))	('cancer', 'Disease', (86, 92))	('FGFR3', 'Gene', '2261', (30, 35))	('SCC', 'Gene', (112, 115))
922245	27165741	While FGFR gene activation is mostly viewed as pro-oncogenic, activating FGFR3 mutations were the most frequent genetic alteration found in expanding clones of keratinocytes in photo-aged but otherwise normal human skin.	('human', 'Species', '9606', (209, 214))	('activating', 'PosReg', (62, 72))	('FGFR3', 'Gene', '2261', (73, 78))	('FGFR3', 'Gene', (73, 78))	('mutations', 'Var', (79, 88))
922247	27165741	Consistent with this view, activating FGFR3 mutations are also found in >40% of seborrheic keratosis, very common keratinocyte-derived tumors of the skin that do not, or very rarely, progress into malignancy.	('FGFR3', 'Gene', '2261', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('activating', 'PosReg', (27, 37))	('tumors of the skin', 'Phenotype', 'HP:0008069', (135, 153))	('FGFR3', 'Gene', (38, 43))	('seborrheic keratosis', 'Disease', (80, 100))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('mutations', 'Var', (44, 53))	('seborrheic keratosis', 'Phenotype', 'HP:0031287', (80, 100))	('malignancy', 'Disease', 'MESH:D009369', (197, 207))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('seborrheic keratosis', 'Disease', 'MESH:D017492', (80, 100))	('malignancy', 'Disease', (197, 207))
922250	27165741	Mutations of HRAS are found with variable frequency in SCCs from various body sites, a likely reflection of the fact that activation of the pathway at other levels, such as tyrosine kinase receptors, can also occur.	('HRAS', 'Gene', (13, 17))	('tyrosine kinase', 'Gene', (173, 188))	('SCC', 'Gene', (55, 58))	('tyrosine kinase', 'Gene', '7294', (173, 188))	('Mutations', 'Var', (0, 9))	('SCC', 'Gene', '6317', (55, 58))	('HRAS', 'Gene', '3265', (13, 17))
922251	27165741	In this context, it is interesting to note that, in a comprehensive study of HNSCC, HRAS mutations were selectively found in HPV-negative tumors and that no HRAS mutations were detected in a previous study of cervical cancer, the other major SCC type associated with HPV infection.	('HRAS', 'Gene', (157, 161))	('HRAS', 'Gene', '3265', (84, 88))	('SCC', 'Gene', (242, 245))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('mutations', 'Var', (89, 98))	('HRAS', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('cervical cancer', 'Disease', 'MESH:D002583', (209, 224))	('SCC', 'Gene', '6317', (79, 82))	('cervical cancer', 'Disease', (209, 224))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('HPV infection', 'Disease', 'MESH:D030361', (267, 280))	('HPV infection', 'Disease', (267, 280))	('SCC', 'Gene', (79, 82))	('tumors', 'Disease', (138, 144))	('found', 'Reg', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('HRAS', 'Gene', '3265', (157, 161))	('SCC', 'Gene', '6317', (242, 245))
922252	27165741	An elevated frequency of HRAS mutations (>20%), with a lower frequency of KRAS and NRAS mutations, was reported in two genomic studies of cutaneous SCCs, which may reflect the fact that overall gene mutation frequency in these tumors is substantially higher than in SCCs of internal organs.	('NRAS', 'Gene', '4893', (83, 87))	('HRAS', 'Gene', (25, 29))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('KRAS', 'Gene', (74, 78))	('SCC', 'Gene', (148, 151))	('mutations', 'Var', (30, 39))	('SCC', 'Gene', (266, 269))	('KRAS', 'Gene', '3845', (74, 78))	('SCCs of internal organs', 'Phenotype', 'HP:0005217', (266, 289))	('NRAS', 'Gene', (83, 87))	('HRAS', 'Gene', '3265', (25, 29))	('SCC', 'Gene', '6317', (148, 151))	('SCC', 'Gene', '6317', (266, 269))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
922253	27165741	Importantly, an even greater frequency of HRAS mutations (>40%) was found in cutaneous SCCs and keratoacanthomas that develop in melanoma patients treated with the B-RAF inhibitor vemurafenib.	('HRAS', 'Gene', '3265', (42, 46))	('B-RAF', 'Gene', '673', (164, 169))	('HRAS', 'Gene', (42, 46))	('SCC', 'Gene', (87, 90))	('keratoacanthomas', 'Disease', 'MESH:D007636', (96, 112))	('mutations', 'Var', (47, 56))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('B-RAF', 'Gene', (164, 169))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('keratoacanthomas', 'Disease', (96, 112))	('vemurafenib', 'Chemical', 'MESH:D000077484', (180, 191))	('SCC', 'Gene', '6317', (87, 90))	('patients', 'Species', '9606', (138, 146))
922255	27165741	As in many other tumor types, the PI3K/AKT signaling pathway is frequently affected by gene amplification and/or mutations, consistent with its key role in cell survival.	('tumor', 'Disease', (17, 22))	('affected', 'Reg', (75, 83))	('gene amplification', 'Var', (87, 105))	('AKT', 'Gene', '207', (39, 42))	('mutations', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('AKT', 'Gene', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
922267	27165741	In fact, amplification of the TP63 locus is a strikingly common occurrence in this type of tumors, cervical carcinoma included, while TP63 amplification is found rarely in other tumor types with the exception of uterine carcinosarcoma (Figures 2 and 3).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('carcinosarcoma', 'Disease', (220, 234))	('tumor', 'Disease', (91, 96))	('carcinoma', 'Disease', 'MESH:D002277', (108, 117))	('tumor', 'Disease', (178, 183))	('carcinosarcoma', 'Disease', 'MESH:D002296', (220, 234))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('TP63', 'Gene', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('amplification', 'Var', (9, 22))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (212, 234))	('TP63', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TP63', 'Gene', '8626', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Disease', (91, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinoma', 'Disease', (108, 117))	('TP63', 'Gene', '8626', (30, 34))
922269	27165741	TP63 missense mutations of uncertain significance have been found only in a small minority of SCCs (specifically HNSCCs), while they are a frequent occurrence in melanomas, consistent with a proposed role of TP63 in malignant progression of this tumor type.	('missense mutations', 'Var', (5, 23))	('TP63', 'Gene', '8626', (208, 212))	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('SCC', 'Gene', (94, 97))	('TP63', 'Gene', (208, 212))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('SCC', 'Gene', (115, 118))	('melanomas', 'Disease', (162, 171))	('SCC', 'Gene', '6317', (94, 97))	('TP63', 'Gene', '8626', (0, 4))	('tumor', 'Disease', (246, 251))	('TP63', 'Gene', (0, 4))	('SCC', 'Gene', '6317', (115, 118))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))
922277	27165741	TP63, SOX2 and PIK3CA reside in the 3q chromosomal region and co-amplification of these genes together with FGFR1 has been recently reported in LSCCs, pointing to a possibly important level of cross-activation.	('FGFR1', 'Gene', '2260', (108, 113))	('SOX2', 'Gene', '6657', (6, 10))	('PIK3CA', 'Gene', '5290', (15, 21))	('SCC', 'Gene', (145, 148))	('reported', 'Reg', (132, 140))	('PIK3CA', 'Gene', (15, 21))	('co-amplification', 'Var', (62, 78))	('TP63', 'Gene', '8626', (0, 4))	('SCC', 'Gene', '6317', (145, 148))	('FGFR1', 'Gene', (108, 113))	('TP63', 'Gene', (0, 4))	('SOX2', 'Gene', (6, 10))
922278	27165741	In LSCCs, SOX2 and PRKCI are frequently also co-amplified, with phosphorylation of SOX2 by protein kinase C iota, the PRKCI gene product, enhancing Hedgehog ligand production and consequently increased cancer stem cell potential.	('SCC', 'Gene', (4, 7))	('SOX2', 'Gene', (10, 14))	('SOX2', 'Gene', (83, 87))	('PRKCI', 'Gene', '5584', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('PRKCI', 'Gene', '5584', (19, 24))	('PRKCI', 'Gene', (118, 123))	('SOX2', 'Gene', '6657', (83, 87))	('PRKCI', 'Gene', (19, 24))	('SCC', 'Gene', '6317', (4, 7))	('phosphorylation', 'Var', (64, 79))	('Hedgehog ligand production', 'MPA', (148, 174))	('enhancing', 'PosReg', (138, 147))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('SOX2', 'Gene', '6657', (10, 14))	('increased', 'PosReg', (192, 201))
922286	27165741	More directly, in the skin, NRF2 function has been linked to heterogeneity of SCC stem cell populations, with association and stabilization of NRF2 by p21CDKN1A resulting in enhanced ROS protection and resistance to chemotherapeutic agents.	('enhanced', 'PosReg', (174, 182))	('SCC', 'Gene', '6317', (78, 81))	('NRF2', 'Gene', (28, 32))	('CDKN1A', 'Gene', '1026', (154, 160))	('stabilization', 'Var', (126, 139))	('resistance', 'CPA', (202, 212))	('CDKN1A', 'Gene', (154, 160))	('association', 'Interaction', (110, 121))	('ROS', 'Chemical', 'MESH:D017382', (183, 186))	('ROS protection', 'CPA', (183, 197))	('NRF2', 'Gene', '4780', (143, 147))	('NRF2', 'Gene', '4780', (28, 32))	('SCC', 'Gene', (78, 81))	('NRF2', 'Gene', (143, 147))
922291	27165741	This gene is a direct target of p53 in keratinocytes and its down-modulation in keratinocyte-derived tumors and SCCs - with resulting defects in differentiation - can be explained by mutation of TP53, down-modulation of TP53 expression by increased EGFR activation or pharmacological inhibition of calcineurin activity via increased ATF3 expression.	('TP53', 'Gene', (220, 224))	('increased', 'PosReg', (323, 332))	('defects', 'NegReg', (134, 141))	('p53', 'Gene', '7157', (32, 35))	('down-modulation', 'NegReg', (61, 76))	('EGFR', 'Gene', (249, 253))	('TP53', 'Gene', (195, 199))	('differentiation', 'CPA', (145, 160))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('p53', 'Gene', (32, 35))	('mutation', 'Var', (183, 191))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('down-modulation', 'NegReg', (201, 216))	('SCC', 'Gene', '6317', (112, 115))	('ATF3', 'Gene', '467', (333, 337))	('EGFR', 'Gene', '1956', (249, 253))	('tumors', 'Disease', (101, 107))	('SCC', 'Gene', (112, 115))	('ATF3', 'Gene', (333, 337))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
922294	27165741	In ESCC cells, compromised NOTCH1 expression, resulting from concomitant loss of TP53 and KLF5 transcription, was linked to malignant progression, and in primary esophageal keratinocytes Notch activation induces senescence through a p16INK4a-dependent mechanism.	('SCC', 'Gene', (4, 7))	('loss', 'NegReg', (73, 77))	('expression', 'MPA', (34, 44))	('activation', 'PosReg', (193, 203))	('linked', 'Reg', (114, 120))	('senescence', 'MPA', (212, 222))	('KLF5', 'Gene', (90, 94))	('Notch', 'Var', (187, 192))	('SCC', 'Gene', '6317', (4, 7))	('p16INK4a', 'Gene', (233, 241))	('TP53', 'Gene', (81, 85))	('KLF5', 'Gene', '688', (90, 94))	('NOTCH1', 'Gene', (27, 33))	('malignant progression', 'CPA', (124, 145))	('induces', 'Reg', (204, 211))	('compromised', 'NegReg', (15, 26))	('p16INK4a', 'Gene', '1029', (233, 241))
922295	27165741	Together with reduced expression, inactivating mutations of NOTCH1 have been found with elevated frequency in HNSCC, LSCC, ESCC and CSCC (Figures 2-4; Table 2), consistent with a role in tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('SCC', 'Gene', '6317', (133, 136))	('SCC', 'Gene', '6317', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('SCC', 'Gene', (118, 121))	('SCC', 'Gene', (124, 127))	('NOTCH1', 'Gene', (60, 66))	('tumor', 'Disease', (187, 192))	('SCC', 'Gene', '6317', (118, 121))	('SCC', 'Gene', '6317', (124, 127))	('SCC', 'Gene', (133, 136))	('inactivating mutations', 'Var', (34, 56))	('SCC', 'Gene', (112, 115))
922296	27165741	However, as discussed in the context of CvSCCs, this may be an over-simplification, consistent with the identification of activating NOTCH1 mutations in a subset of HNSCCs.	('activating', 'PosReg', (122, 132))	('SCC', 'Gene', '6317', (167, 170))	('SCC', 'Gene', (42, 45))	('NOTCH1', 'Gene', (133, 139))	('SCC', 'Gene', '6317', (42, 45))	('mutations', 'Var', (140, 149))	('SCC', 'Gene', (167, 170))
922299	27165741	Like NOTCH1, NOTCH2 and NOTCH3 are also mutated frequently in SCCs, with both missense substitutions and nonsense and frameshift alterations (Table 2, Figure 4).	('missense substitutions', 'Var', (78, 100))	('frameshift alterations', 'Var', (118, 140))	('NOTCH3', 'Gene', (24, 30))	('nonsense', 'Var', (105, 113))	('NOTCH1', 'Gene', (5, 11))	('SCC', 'Gene', '6317', (62, 65))	('NOTCH2', 'Gene', (13, 19))	('SCC', 'Gene', (62, 65))
922300	27165741	While NOTCH2 does not play an essential role in keratinocyte differentiation and tumor suppression, combined loss of NOTCH1 and NOTCH2 has more significant consequences than loss of NOTCH1 alone, pointing to a complementary function of the two receptors.	('NOTCH2', 'Gene', (128, 134))	('loss', 'Var', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('NOTCH1', 'Gene', (117, 123))	('tumor', 'Disease', (81, 86))
922302	27165741	The specific role that this receptor may play in human stratified epithelia and cancer has only started to be addressed, with the finding that loss of NOTCH3 in the esophageal epithelium disrupts normal stratification and differentiation.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('human', 'Species', '9606', (49, 54))	('NOTCH3', 'Gene', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('disrupts', 'NegReg', (187, 195))	('loss', 'Var', (143, 147))	('cancer', 'Disease', (80, 86))
922304	27165741	Mutations in genes encoding classical adherens junctions and desmosomal proteins, like DSG1-4, occur in SCCs of various types but with relatively low frequencies.	('DSG1-4', 'Gene', (87, 93))	('occur', 'Reg', (95, 100))	('DSG1-4', 'Gene', '1828;1829;1830;147409', (87, 93))	('SCC', 'Gene', (104, 107))	('Mutations', 'Var', (0, 9))	('SCC', 'Gene', '6317', (104, 107))
922305	27165741	By contrast, frequently mutated is FAT1 (Figures 2 and 3; Table 2), belonging to the cadherin superfamily, whose ortholog in Drosophila plays a well demonstrated tumor suppressing function as well as a key role in planar cell polarity.	('mutated', 'Var', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('FAT1', 'Gene', '2195', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('FAT1', 'Gene', (35, 39))	('tumor', 'Disease', (162, 167))	('cadherin', 'Gene', (85, 93))	('cadherin', 'Gene', '999', (85, 93))	('Drosophila', 'Species', '7227', (125, 135))
922309	27165741	Epigenetic regulators, specifically enzymes involved in DNA methylation and histone modification, are attractive drug targets, as epigenetic alterations are potentially reversible and can critically regulate the balance between cancer stem cell renewal and commitment to differentiation.	('cancer', 'Disease', (228, 234))	('commitment to differentiation', 'CPA', (257, 286))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('epigenetic alterations', 'Var', (130, 152))	('regulate', 'Reg', (199, 207))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
922318	27165741	MLL translocations result in MLL fusion proteins that play a causative role in acute myelogenous leukemia.	('MLL', 'Gene', '4297', (29, 32))	('translocations', 'Var', (4, 18))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (79, 105))	('result in', 'Reg', (19, 28))	('acute myelogenous leukemia', 'Disease', (79, 105))	('MLL', 'Gene', '4297', (0, 3))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (79, 105))	('MLL', 'Gene', (0, 3))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('MLL', 'Gene', (29, 32))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (85, 105))
922319	27165741	Truncating or missense mutations in these genes have also been described in a variety of tumors, including most SCCs, especially CvSCC (Figures 2 and 3; Table 2).	('described', 'Reg', (63, 72))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('SCC', 'Gene', '6317', (112, 115))	('SCC', 'Gene', (131, 134))	('missense mutations', 'Var', (14, 32))	('Truncating', 'Var', (0, 10))	('SCC', 'Gene', '6317', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('SCC', 'Gene', (112, 115))
922320	27165741	The specific consequences of these mutations in SCC development remain to be established.	('SCC', 'Gene', (48, 51))	('SCC', 'Gene', '6317', (48, 51))	('mutations', 'Var', (35, 44))
922321	27165741	MED1, coding for a component of the transcriptional coactivator complex Mediator (MED) with an essential role in keratinocyte differentiation, is also frequently mutated in SCCs.	('MED', 'Disease', (0, 3))	('MED', 'Disease', 'MESH:D010009', (82, 85))	('mutated', 'Var', (162, 169))	('SCC', 'Gene', (173, 176))	('MED', 'Disease', 'MESH:D010009', (0, 3))	('MED1', 'Gene', '5469', (0, 4))	('MED1', 'Gene', (0, 4))	('MED', 'Disease', (82, 85))	('SCC', 'Gene', '6317', (173, 176))
922322	27165741	The impact of mutations in this and other chromatin modifying genes in SCC development remains an interesting topic for future studies.	('mutations', 'Var', (14, 23))	('SCC', 'Gene', (71, 74))	('SCC', 'Gene', '6317', (71, 74))
922323	27165741	Besides mutations of these genes, additional evidence points to a key role of epigenetic modifications in SCC development.	('SCC', 'Gene', '6317', (106, 109))	('mutations', 'Var', (8, 17))	('epigenetic modifications', 'Var', (78, 102))	('SCC', 'Gene', (106, 109))
922327	27165741	As depicted in Figure 5, an essential commonality that distinguishes SCCs from all other cancer types are genetic alterations of specific determinants of squamous differentiation, most notably NOTCH, TP63 and SOX2 genes, and their interplay with general regulators of the cancer process such as p53 as well as cyclin D1, the latter downstream of EGFR and RAS activation.	('EGFR', 'Gene', (346, 350))	('interplay', 'Interaction', (231, 240))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('TP63', 'Gene', (200, 204))	('SCC', 'Gene', (69, 72))	('cancer', 'Disease', (89, 95))	('p53', 'Gene', '7157', (295, 298))	('SOX2', 'Gene', '6657', (209, 213))	('SOX2', 'Gene', (209, 213))	('TP63', 'Gene', '8626', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('alterations', 'Var', (114, 125))	('cyclin D1', 'Gene', (310, 319))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('EGFR', 'Gene', '1956', (346, 350))	('p53', 'Gene', (295, 298))	('cyclin D1', 'Gene', '595', (310, 319))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('NOTCH', 'Gene', (193, 198))	('SCC', 'Gene', '6317', (69, 72))	('cancer', 'Disease', (272, 278))
922328	27165741	Furthermore, growth/differentiation of epithelial cells is tightly linked to cell adhesion, and altered expression and/or mutations in cell adhesion genes like CDH1, CTNND1 and DSG1-3 (coding for E-cadherin, p120-catenin and desmogleins, respectively) and integrin receptor genes play a critical role in various aspects of SCC behavior.	('DSG1-3', 'Gene', (177, 183))	('DSG1-3', 'Gene', '1828;1829;1830', (177, 183))	('p120-catenin', 'Gene', (208, 220))	('CTNND1', 'Gene', (166, 172))	('CTNND1', 'Gene', '1500', (166, 172))	('SCC', 'Gene', (323, 326))	('CDH1', 'Gene', (160, 164))	('p120-catenin', 'Gene', '1500', (208, 220))	('mutations', 'Var', (122, 131))	('SCC', 'Gene', '6317', (323, 326))	('E-cadherin', 'Gene', (196, 206))	('E-cadherin', 'Gene', '999', (196, 206))	('CDH1', 'Gene', '999', (160, 164))
922342	27165741	SCCs in various body sites are among the cancer types with the highest percentage of somatic genetic mutations, and mutations of HLA genes in these tumors suggest a possible stratification of patients for their predicted response to immunomodulatory agents.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('SCC', 'Gene', (0, 3))	('mutations', 'Var', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('patients', 'Species', '9606', (192, 200))	('SCC', 'Gene', '6317', (0, 3))	('HLA', 'Gene', (129, 132))	('mutations', 'Var', (116, 125))	('tumors', 'Disease', (148, 154))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
922343	27165741	An important concept is that genetic alterations of tumors can impact the immune microenvironment, opening some novel windows of opportunity for treatment around STK11 (LKB1)/AMPK signaling.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('genetic alterations', 'Var', (29, 48))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('STK11', 'Gene', (162, 167))	('LKB1', 'Gene', (169, 173))	('impact', 'Reg', (63, 69))	('LKB1', 'Gene', '6794', (169, 173))	('STK11', 'Gene', '6794', (162, 167))
922350	27042222	The non-4L group experienced less blood loss than the 4L group (P = 0.009).	('less', 'NegReg', (29, 33))	('non-4L', 'Var', (4, 10))	('blood loss', 'Disease', (34, 44))	('blood loss', 'Disease', 'MESH:D006473', (34, 44))
922378	27042222	The non-4L group experienced significantly lower thoracic blood loss than the 4L group.	('thoracic blood loss', 'Disease', 'MESH:D006473', (49, 68))	('thoracic blood loss', 'Disease', (49, 68))	('non-4L', 'Var', (4, 10))	('lower', 'NegReg', (43, 48))
922416	27042222	4L node dissection increased thoracic blood loss, there were no significant differences in blood transfusion and postoperative major complications between the two groups.	('dissection', 'Var', (8, 18))	('increased', 'PosReg', (19, 28))	('thoracic blood loss', 'Disease', 'MESH:D006473', (29, 48))	('thoracic blood loss', 'Disease', (29, 48))
922420	25203442	The Functional TP53 rs1042522 and MDM4 rs4245739 Genetic Variants Contribute to Non-Hodgkin Lymphoma Risk As a heterogeneous kind of malignances, Non-Hodgkin lymphoma (NHL) is the most common hematologic cancer worldwide with the significantly increased morbidity in China.	('rs1042522', 'Var', (20, 29))	('MDM4', 'Gene', '4194', (34, 38))	('hematologic cancer', 'Phenotype', 'HP:0004377', (192, 210))	('MDM4', 'Gene', (34, 38))	('rs4245739', 'Mutation', 'rs4245739', (39, 48))	('Non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (146, 166))	('Non-Hodgkin Lymphoma', 'Phenotype', 'HP:0012539', (80, 100))	('Non-Hodgkin Lymphoma', 'Disease', (80, 100))	('rs1042522', 'Mutation', 'rs1042522', (20, 29))	('Hodgkin Lymphoma', 'Phenotype', 'HP:0012189', (84, 100))	('Non-Hodgkin lymphoma', 'Disease', (146, 166))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (150, 166))	('hematologic cancer', 'Disease', 'MESH:D009369', (192, 210))	('TP53', 'Gene', '7157', (15, 19))	('NHL', 'Phenotype', 'HP:0012539', (168, 171))	('Non-Hodgkin Lymphoma', 'Disease', 'MESH:D008228', (80, 100))	('hematologic cancer', 'Disease', (192, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('lymphoma', 'Phenotype', 'HP:0002665', (158, 166))	('Non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (146, 166))	('rs4245739', 'Var', (39, 48))	('TP53', 'Gene', (15, 19))	('Lymphoma', 'Phenotype', 'HP:0002665', (92, 100))
922422	25203442	An rs4245739 A>C polymorphism locating in the MDM4 3'-untranslated region creates a miR-191 target site and results in allele-specific MDM4 expression.	('results in', 'Reg', (108, 118))	('expression', 'MPA', (140, 150))	('miR-191', 'Gene', '406966', (84, 91))	('rs4245739', 'Mutation', 'rs4245739', (3, 12))	('rs4245739 A>C', 'Var', (3, 16))	('MDM4', 'Gene', (135, 139))	('miR-191', 'Gene', (84, 91))
922423	25203442	In this study, we examined the association between this polymorphism as well as the TP53 Arg72Pro (rs1042522 G>C) genetic variant and Non-Hodgkin Lymphoma (NHL) risk in a Chinese Han population.	('Non-Hodgkin Lymphoma', 'Disease', (134, 154))	('Arg72Pro', 'SUBSTITUTION', 'None', (89, 97))	('NHL', 'Phenotype', 'HP:0012539', (156, 159))	('Non-Hodgkin Lymphoma', 'Disease', 'MESH:D008228', (134, 154))	('Lymphoma', 'Phenotype', 'HP:0002665', (146, 154))	('association', 'Interaction', (31, 42))	('rs1042522', 'Mutation', 'rs1042522', (99, 108))	('TP53', 'Gene', '7157', (84, 88))	('Arg72Pro', 'Var', (89, 97))	('Hodgkin Lymphoma', 'Phenotype', 'HP:0012189', (138, 154))	('TP53', 'Gene', (84, 88))	('Non-Hodgkin Lymphoma', 'Phenotype', 'HP:0012539', (134, 154))
922425	25203442	We also observed a significantly decreased NHL risks among carriers of the MDM4 rs4245739 C allele compared with those with the A allele in Chinese (P = 0.014 for the AC genotype).	('NHL', 'Disease', (43, 46))	('MDM4', 'Gene', (75, 79))	('rs4245739 C', 'Var', (80, 91))	('rs4245739', 'Mutation', 'rs4245739', (80, 89))	('NHL', 'Phenotype', 'HP:0012539', (43, 46))	('decreased', 'NegReg', (33, 42))
922427	25203442	Our results indicate that the TP53 Arg72Pro and the MDM4 rs4245739 polymorphisms contribute to NHL susceptibility and support the hypothesis that genetic variants in the TP53 pathway genes can act as important modifiers of NHL risk.	('TP53', 'Gene', (30, 34))	('contribute', 'Reg', (81, 91))	('rs4245739', 'Var', (57, 66))	('Arg72Pro', 'SUBSTITUTION', 'None', (35, 43))	('NHL', 'Phenotype', 'HP:0012539', (95, 98))	('MDM4', 'Gene', (52, 56))	('rs4245739', 'Mutation', 'rs4245739', (57, 66))	('TP53', 'Gene', '7157', (170, 174))	('TP53', 'Gene', (170, 174))	('NHL', 'Disease', (223, 226))	('NHL', 'Phenotype', 'HP:0012539', (223, 226))	('Arg72Pro', 'Var', (35, 43))	('TP53', 'Gene', '7157', (30, 34))	('NHL', 'Disease', (95, 98))
922434	25203442	After interacting with MDM2 protein through the RING finger domain, MDM4 could repress degradation of MDM2 protein.	('MDM2', 'Gene', '4193', (23, 27))	('degradation', 'MPA', (87, 98))	('MDM2', 'Gene', '4193', (102, 106))	('MDM2', 'Gene', (23, 27))	('MDM2', 'Gene', (102, 106))	('repress', 'NegReg', (79, 86))	('MDM4', 'Var', (68, 72))	('interacting', 'Interaction', (6, 17))
922436	25203442	A functional single nucleotide polymorphism (SNP) (rs4245739 A>C) in the 3'-untranslated region (3'-UTR) of MDM4 has been identified, which creates a target binding site of miR-191.	('rs4245739', 'Mutation', 'rs4245739', (51, 60))	('binding', 'Interaction', (157, 164))	('miR-191', 'Gene', '406966', (173, 180))	('MDM4', 'Gene', (108, 112))	('miR-191', 'Gene', (173, 180))	('rs4245739 A>C', 'Var', (51, 64))
922437	25203442	In ovarian cancer, retinoblastoma and esophageal cancer cells, miR-191 could selectively bind to the MDM4-C allele mRNA but not the MDM4-A allele mRNA, which resulting in a statistically significant increased expression of MDM4 mRNA and protein among the MDM4 rs4245739 A allele carriers.	('expression', 'MPA', (209, 219))	('esophageal cancer', 'Disease', (38, 55))	('MDM4', 'Gene', (255, 259))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('retinoblastoma', 'Disease', 'MESH:D012175', (19, 33))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('rs4245739', 'Mutation', 'rs4245739', (260, 269))	('ovarian cancer', 'Disease', (3, 17))	('bind', 'Interaction', (89, 93))	('retinoblastoma', 'Phenotype', 'HP:0009919', (19, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('retinoblastoma', 'Disease', (19, 33))	('increased', 'PosReg', (199, 208))	('rs4245739 A', 'Var', (260, 271))	('miR-191', 'Gene', '406966', (63, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('miR-191', 'Gene', (63, 70))	('MDM4', 'Protein', (223, 227))
922438	25203442	In addition, ovarian cancer patients with rs4245739 AA genotype who do not express the estrogen receptor had a 4.2-fold [95% confidence interval (CI)  = 1.2-13.5; P = 0.02] increased risk of recurrence and 5.5-fold (95% CI = 1.5-20.5; P = 0.01) increased risk of tumor-related death compared with cases with AC or CC genotype.	('recurrence', 'CPA', (191, 201))	('death', 'Disease', 'MESH:D003643', (277, 282))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('death', 'Disease', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('estrogen receptor', 'Gene', (87, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (13, 27))	('estrogen receptor', 'Gene', '2099', (87, 104))	('ovarian cancer', 'Disease', 'MESH:D010051', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', (263, 268))	('rs4245739', 'Var', (42, 51))	('rs4245739', 'Mutation', 'rs4245739', (42, 51))	('ovarian cancer', 'Disease', (13, 27))	('patients', 'Species', '9606', (28, 36))
922439	25203442	Our previous studies also indicated that significantly decreased breast cancer and esophageal cancer risks among carriers of the MDM4 rs4245739 C allele compared with those with the A allele in Chinese.	('esophageal cancer', 'Disease', (83, 100))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('rs4245739', 'Mutation', 'rs4245739', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('rs4245739 C', 'Var', (134, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('decreased', 'NegReg', (55, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('MDM4', 'Gene', (129, 133))
922440	25203442	There is also a functional TP53 SNP at codon 72 (rs1042522 G>C) resulting in Arg>Pro amino acid substitution.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('rs1042522', 'Mutation', 'rs1042522', (49, 58))	('Arg', 'MPA', (77, 80))	('Arg', 'Chemical', 'MESH:D001120', (77, 80))	('rs1042522 G>C', 'Var', (49, 62))	('Pro amino acid', 'Chemical', '-', (81, 95))
922441	25203442	The 72Arg allele seems to induce apoptosis with much faster kinetics compared to the 72Pro allele, and the 72Pro variant might be more competent during controlling of cell cycle arrest and DNA repair.	('Arg', 'Chemical', 'MESH:D001120', (6, 9))	('apoptosis', 'CPA', (33, 42))	('arrest', 'Disease', (178, 184))	('Pro', 'Chemical', 'MESH:D011392', (109, 112))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (167, 184))	('arrest', 'Disease', 'MESH:D006323', (178, 184))	('72Arg', 'Var', (4, 9))	('induce', 'Reg', (26, 32))	('Pro', 'Chemical', 'MESH:D011392', (87, 90))
922442	25203442	Considering the essential role of TP53 and MDM4 during carcinogenesis, we hypothesized that the TP53 Arg72Pro and MDM4 rs4245739 genetic polymorphism may be involved in NHL development.	('NHL', 'Phenotype', 'HP:0012539', (169, 172))	('Arg72Pro', 'Var', (101, 109))	('involved', 'Reg', (157, 165))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', (96, 100))	('rs4245739', 'Var', (119, 128))	('Arg72Pro', 'SUBSTITUTION', 'None', (101, 109))	('NHL', 'Disease', (169, 172))	('rs4245739', 'Mutation', 'rs4245739', (119, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('MDM4', 'Gene', (114, 118))	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', '7157', (96, 100))	('carcinogenesis', 'Disease', (55, 69))
922448	25203442	PCR-based restriction fragment length polymorphism (RFLP) was used to determine TP53 Arg72Pro and MDM4 rs4245739 A>C genotypes as previously reported.	('Arg72Pro', 'SUBSTITUTION', 'None', (85, 93))	('MDM4', 'Gene', (98, 102))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('rs4245739', 'Mutation', 'rs4245739', (103, 112))	('Arg72Pro', 'Var', (85, 93))	('rs4245739 A>C', 'Var', (103, 116))
922450	25203442	The differences in demographic variables and genotype distributions of TP53 Arg72Pro and MDM4 rs4245739 SNPs between NHL patients and controls were examined via Pearson's chi2 test.	('Arg72Pro', 'Var', (76, 84))	('rs4245739', 'Mutation', 'rs4245739', (94, 103))	('Arg72Pro', 'SUBSTITUTION', 'None', (76, 84))	('NHL', 'Disease', (117, 120))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('patients', 'Species', '9606', (121, 129))	('NHL', 'Phenotype', 'HP:0012539', (117, 120))
922451	25203442	Associations between TP53 Arg72Pro genotypes or MDM4 rs4245739 genotypes and NHL susceptibility were calculated by OR and their 95% CIs using the unconditional logistic regression model.	('TP53', 'Gene', (21, 25))	('rs4245739', 'Var', (53, 62))	('NHL', 'Phenotype', 'HP:0012539', (77, 80))	('rs4245739', 'Mutation', 'rs4245739', (53, 62))	('Arg72Pro', 'Var', (26, 34))	('MDM4', 'Gene', (48, 52))	('Arg72Pro', 'SUBSTITUTION', 'None', (26, 34))	('NHL', 'Disease', (77, 80))	('TP53', 'Gene', '7157', (21, 25))
922455	25203442	The allelic and genotype frequencies of TP53 Arg72Pro and MDM4 rs4245739 A>C SNPs were showed in Table 2.	('Arg72Pro', 'SUBSTITUTION', 'None', (45, 53))	('MDM4', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (40, 44))	('rs4245739 A>C', 'Var', (63, 76))	('TP53', 'Gene', (40, 44))	('rs4245739', 'Mutation', 'rs4245739', (63, 72))	('Arg72Pro', 'Var', (45, 53))
922456	25203442	For the TP53 Arg72Pro polymorphism, the TP53 72Pro allele frequency was 0.383 among healthy controls and 0.483 among NHL patients.	('Pro', 'Chemical', 'MESH:D011392', (47, 50))	('TP53', 'Gene', '7157', (40, 44))	('Arg72Pro', 'Var', (13, 21))	('TP53', 'Gene', (40, 44))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('Pro', 'Chemical', 'MESH:D011392', (18, 21))	('Arg72Pro', 'SUBSTITUTION', 'None', (13, 21))	('patients', 'Species', '9606', (121, 129))	('NHL', 'Phenotype', 'HP:0012539', (117, 120))
922457	25203442	The frequency for the MDM4 rs4245739 C allele was 0.069 among healthy controls and 0.033 among NHL patients.	('MDM4', 'Gene', (22, 26))	('NHL', 'Phenotype', 'HP:0012539', (95, 98))	('patients', 'Species', '9606', (99, 107))	('rs4245739 C', 'Var', (27, 38))	('rs4245739', 'Mutation', 'rs4245739', (27, 36))
922459	25203442	The frequencies of TP53 Arg/Arg, Arg/Pro and Pro/Pro genotypes among NHL patients were significantly different from those among controls (chi2 = 11.29, P = 0.004, df = 2).	('Arg', 'Chemical', 'MESH:D001120', (28, 31))	('Arg', 'Chemical', 'MESH:D001120', (24, 27))	('Pro', 'Chemical', 'MESH:D011392', (37, 40))	('different', 'Reg', (101, 110))	('NHL', 'Disease', (69, 72))	('Arg', 'Chemical', 'MESH:D001120', (33, 36))	('TP53', 'Gene', '7157', (19, 23))	('Arg/Pro', 'Var', (33, 40))	('TP53', 'Gene', (19, 23))	('Pro', 'Chemical', 'MESH:D011392', (49, 52))	('patients', 'Species', '9606', (73, 81))	('Pro', 'Chemical', 'MESH:D011392', (45, 48))	('NHL', 'Phenotype', 'HP:0012539', (69, 72))
922460	25203442	The frequencies of MDM4 rs4245739 AA, AC and CC genotypes among NHL patients were also significantly different from those among controls (chi2 = 6.76, P = 0.034, df = 2).	('NHL', 'Disease', (64, 67))	('different', 'Reg', (101, 110))	('patients', 'Species', '9606', (68, 76))	('NHL', 'Phenotype', 'HP:0012539', (64, 67))	('rs4245739', 'Mutation', 'rs4245739', (24, 33))	('rs4245739 AA', 'Var', (24, 36))	('MDM4', 'Gene', (19, 23))
922461	25203442	Associations between genotypes of TP53 Arg72Pro and MDM4 rs4245739 A>C SNPs and NHL risk were then calculated (Table 2).	('rs4245739 A>C', 'Var', (57, 70))	('TP53', 'Gene', (34, 38))	('NHL', 'Phenotype', 'HP:0012539', (80, 83))	('MDM4', 'Gene', (52, 56))	('Arg72Pro', 'Var', (39, 47))	('rs4245739', 'Mutation', 'rs4245739', (57, 66))	('Arg72Pro', 'SUBSTITUTION', 'None', (39, 47))	('NHL', 'Disease', (80, 83))	('TP53', 'Gene', '7157', (34, 38))
922463	25203442	The MDM4 rs4245739 C allele was showed to be a protective allele.	('rs4245739 C', 'Var', (9, 20))	('MDM4', 'Gene', (4, 8))	('rs4245739', 'Mutation', 'rs4245739', (9, 18))
922464	25203442	Individuals having the rs4245739 AC genotype had an OR of 0.45 (95% CI = 0.24-0.85, P = 0.014) for developing NHL compared with individual having the rs4245739 AA genotype (Table 2).	('NHL', 'Phenotype', 'HP:0012539', (110, 113))	('rs4245739 AC', 'Var', (23, 35))	('rs4245739', 'Mutation', 'rs4245739', (23, 32))	('rs4245739', 'Mutation', 'rs4245739', (150, 159))	('NHL', 'Disease', (110, 113))	('developing', 'PosReg', (99, 109))
922465	25203442	We also examined whether there are gene-gene interaction between MDM4 and TP53 polymorphisms, but the results were negative (P interaction = 0.681).	('TP53', 'Gene', '7157', (74, 78))	('MDM4', 'Gene', (65, 69))	('TP53', 'Gene', (74, 78))	('polymorphisms', 'Var', (79, 92))
922466	25203442	The risk of NHL associated with the TP53 Arg72Pro or MDM4 rs4245739 genotypes was further examined by stratifying for age, sex, pathology and Ann Arbor stage (Table 3 and 4).	('Arg72Pro', 'SUBSTITUTION', 'None', (41, 49))	('NHL', 'Phenotype', 'HP:0012539', (12, 15))	('TP53', 'Gene', '7157', (36, 40))	('Arg72Pro', 'Var', (41, 49))	('rs4245739', 'Var', (58, 67))	('TP53', 'Gene', (36, 40))	('NHL', 'Disease', (12, 15))	('MDM4', 'Gene', (53, 57))	('rs4245739', 'Mutation', 'rs4245739', (58, 67))
922473	25203442	Also, we observed a significantly decreased NHL risk among carriers of the MDM4 rs4245739 C allele compared with those with the A allele in Chinese.	('rs4245739 C', 'Var', (80, 91))	('MDM4', 'Gene', (75, 79))	('rs4245739', 'Mutation', 'rs4245739', (80, 89))	('decreased', 'NegReg', (34, 43))	('NHL', 'Phenotype', 'HP:0012539', (44, 47))	('NHL', 'Disease', (44, 47))
922474	25203442	These results are in line with functional relevance of TP53 Arg72Pro as well as MDM4 rs4245739 polymorphism.	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('Arg72Pro', 'Var', (60, 68))	('rs4245739', 'Var', (85, 94))	('rs4245739', 'Mutation', 'rs4245739', (85, 94))	('MDM4', 'Gene', (80, 84))	('Arg72Pro', 'SUBSTITUTION', 'None', (60, 68))
922475	25203442	There are several studies which have investigated association between the TP53 Arg72Pro SNP and NHL susceptibility.	('Arg72Pro', 'SUBSTITUTION', 'None', (79, 87))	('NHL', 'Disease', (96, 99))	('TP53', 'Gene', '7157', (74, 78))	('Arg72Pro', 'Var', (79, 87))	('NHL', 'Phenotype', 'HP:0012539', (96, 99))	('TP53', 'Gene', (74, 78))
922476	25203442	In Korean, Kim et al examined the association between this TP53 Arg72Pro polymorphism and NHL risk through a Korean large-scale case-control study (945 cases and 1700 controls).	('association', 'Interaction', (34, 45))	('NHL', 'Phenotype', 'HP:0012539', (90, 93))	('TP53', 'Gene', (59, 63))	('Arg72Pro', 'Var', (64, 72))	('NHL', 'Disease', (90, 93))	('Arg72Pro', 'SUBSTITUTION', 'None', (64, 72))	('TP53', 'Gene', '7157', (59, 63))
922478	25203442	Additionally, Weng Y et al evaluate the role of TP53 Arg72Pro polymorphism in development of hematological cancer through a meta-analysis.	('hematological cancer', 'Disease', 'MESH:D009369', (93, 113))	('hematological cancer', 'Disease', (93, 113))	('TP53', 'Gene', '7157', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TP53', 'Gene', (48, 52))	('Arg72Pro', 'Var', (53, 61))	('hematological cancer', 'Phenotype', 'HP:0004377', (93, 113))	('Arg72Pro', 'SUBSTITUTION', 'None', (53, 61))
922479	25203442	They found that significantly increased non-Hodgkin lymphomas risk was found in TP53 Arg72Pro polymorphism heterozygote model (Arg/Pro vs. Arg/Arg: OR = 1.18, 95% CI = 1.02-1.35) and dominant model (Arg/Pro+Pro/Pro vs. Arg/Arg: OR = 1.18, 95% CI = 1.03-1.34).	('non-Hodgkin lymphomas', 'Phenotype', 'HP:0012539', (40, 61))	('Arg', 'Chemical', 'MESH:D001120', (139, 142))	('increased', 'PosReg', (30, 39))	('Arg72Pro', 'Var', (85, 93))	('Pro', 'Chemical', 'MESH:D011392', (211, 214))	('non-Hodgkin lymphomas', 'Disease', 'MESH:D008228', (40, 61))	('TP53', 'Gene', '7157', (80, 84))	('lymphomas', 'Phenotype', 'HP:0002665', (52, 61))	('Pro', 'Chemical', 'MESH:D011392', (203, 206))	('Pro', 'Chemical', 'MESH:D011392', (90, 93))	('Arg', 'Chemical', 'MESH:D001120', (127, 130))	('Arg', 'Chemical', 'MESH:D001120', (199, 202))	('Arg', 'Chemical', 'MESH:D001120', (143, 146))	('Arg72Pro', 'SUBSTITUTION', 'None', (85, 93))	('Arg/Pro+Pro/Pro', 'Var', (199, 214))	('Pro', 'Chemical', 'MESH:D011392', (131, 134))	('Arg', 'Chemical', 'MESH:D001120', (223, 226))	('Hodgkin lymphomas', 'Phenotype', 'HP:0012189', (44, 61))	('non-Hodgkin lymphomas', 'Disease', (40, 61))	('Arg', 'Chemical', 'MESH:D001120', (85, 88))	('Arg/Pro', 'Var', (127, 134))	('Pro', 'Chemical', 'MESH:D011392', (207, 210))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (44, 60))	('TP53', 'Gene', (80, 84))	('lymphoma', 'Phenotype', 'HP:0002665', (52, 60))	('Arg', 'Chemical', 'MESH:D001120', (219, 222))
922480	25203442	These results are in line with our findings, indicating that TP53 Arg72Pro polymorphism may contribute to NHL susceptibility.	('NHL', 'Disease', (106, 109))	('contribute', 'Reg', (92, 102))	('Arg72Pro', 'SUBSTITUTION', 'None', (66, 74))	('NHL', 'Phenotype', 'HP:0012539', (106, 109))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('Arg72Pro', 'Var', (66, 74))
922481	25203442	Wynendaele et al found that the rs4245739 genetic variant in the MDM4 3'UTR creates a miR-191 target site, which was associated with survival of Caucasian ovarian cancer patients.	('patients', 'Species', '9606', (170, 178))	('miR-191', 'Gene', '406966', (86, 93))	('rs4245739', 'Var', (32, 41))	('MDM4', 'Gene', (65, 69))	('miR-191', 'Gene', (86, 93))	('associated with', 'Reg', (117, 132))	('rs4245739', 'Mutation', 'rs4245739', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('ovarian cancer', 'Disease', 'MESH:D010051', (155, 169))	('ovarian cancer', 'Disease', (155, 169))
922483	25203442	These data are consistent with results of the current study and provide evidences supporting that genetic variants located in miRNA target sites may function as a new class of regulators modifying cancer risk.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('genetic variants', 'Var', (98, 114))	('cancer', 'Disease', (197, 203))	('modifying', 'Reg', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
922484	25203442	We expected that there should be a gene-gene interaction between MDM4 rs4245739 and TP53 Arg72Pro genetic variants since the functional TP53 codon 72 Arg>Pro change could depress the activities of TP53 in inducing apoptosis and suppressing transformation and MDM4 can negatively regulate TP53 tumor suppression function.	('apoptosis', 'CPA', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('Arg72Pro', 'SUBSTITUTION', 'None', (89, 97))	('TP53', 'Gene', (84, 88))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (197, 201))	('rs4245739', 'Mutation', 'rs4245739', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('depress', 'NegReg', (171, 178))	('TP53', 'Gene', (288, 292))	('inducing', 'PosReg', (205, 213))	('TP53', 'Gene', '7157', (84, 88))	('activities', 'MPA', (183, 193))	('TP53', 'Gene', '7157', (197, 201))	('Arg72Pro', 'Var', (89, 97))	('TP53', 'Gene', (136, 140))	('Arg>Pro', 'Var', (150, 157))	('codon', 'Var', (141, 146))	('negatively', 'NegReg', (268, 278))	('72 Arg>Pro', 'Mutation', 'rs1042522', (147, 157))	('TP53', 'Gene', '7157', (288, 292))	('tumor', 'Disease', (293, 298))	('suppressing', 'NegReg', (228, 239))	('rs4245739', 'Var', (70, 79))
922486	25203442	However, in the current study, we only observed significant association between MDM4 rs4245739 SNP and NHL in males.	('rs4245739', 'Mutation', 'rs4245739', (85, 94))	('NHL', 'Disease', (103, 106))	('rs4245739 SNP', 'Var', (85, 98))	('MDM4', 'Gene', (80, 84))	('NHL', 'Phenotype', 'HP:0012539', (103, 106))
922490	25203442	In summary, our data demonstrated that functional TP53 Arg72Pro and MDM4 rs4245739 polymorphisms were significantly associated with NHL risk in a Chinese population.	('NHL', 'Phenotype', 'HP:0012539', (132, 135))	('Arg72Pro', 'SUBSTITUTION', 'None', (55, 63))	('rs4245739', 'Mutation', 'rs4245739', (73, 82))	('TP53', 'Gene', '7157', (50, 54))	('NHL', 'Disease', (132, 135))	('TP53', 'Gene', (50, 54))	('rs4245739', 'Var', (73, 82))	('Arg72Pro', 'Var', (55, 63))	('MDM4', 'Gene', (68, 72))	('associated', 'Reg', (116, 126))
922493	24103528	The aim of this study was to investigate the existence of EGFR mutations in Chinese esophageal squamous cell carcinomas.	('mutations', 'Var', (63, 72))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (95, 119))	('EGFR', 'Gene', (58, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('esophageal squamous cell carcinomas', 'Disease', (84, 119))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (84, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))
922495	24103528	The most common EGFR mutations, including in-frame deletions in exon 19 and base substitutions in exon 21, were detected by denaturing high performance liquid chromatography (DHPLC) and direct sequencing simultaneously.	('in-frame deletions', 'Var', (42, 60))	('DHPLC', 'Chemical', '-', (175, 180))	('EGFR', 'Gene', (16, 20))	('base substitutions', 'Var', (76, 94))	('mutations', 'Var', (21, 30))
922496	24103528	In this study, L858R missense mutations of the EGFR gene were found in 8 out of 127 patients (6.3%) by DHPLC but no mutation was observed by direct sequencing.	('patients', 'Species', '9606', (84, 92))	('L858R missense mutations', 'Var', (15, 39))	('DHPLC', 'Chemical', '-', (103, 108))	('found', 'Reg', (62, 67))	('EGFR', 'Gene', (47, 51))	('L858R', 'Mutation', 'rs121434568', (15, 20))
922498	24103528	The incidence of EGFR mutations was relatively high using DHPLC method but no mutation with direct sequencing in Chinese ESCC patients.	('DHPLC', 'Chemical', '-', (58, 63))	('mutations', 'Var', (22, 31))	('patients', 'Species', '9606', (126, 134))	('EGFR', 'Gene', (17, 21))
922503	24103528	Studies have showed that the kinase domain mutations of the EGFR gene in the non-small-cell lung cancer (NSCLC) tissues correlate with clinical responses to gefitinib.	('lung cancer', 'Disease', (92, 103))	('kinase domain mutations', 'Var', (29, 52))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (81, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('NSCLC', 'Disease', (105, 110))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (77, 103))	('EGFR', 'Gene', (60, 64))	('gefitinib', 'Chemical', 'MESH:D000077156', (157, 166))
922505	24103528	K-RAS mutations are associated with intrinsic tyrosine kinase inhibitor (TKI) resistance in patients with lung cancer.	('K-RAS', 'Protein', (0, 5))	('associated', 'Reg', (20, 30))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (92, 100))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('mutations', 'Var', (6, 15))
922507	24103528	However, it remains unclear whether EGFR mutations in esophageal cancer predict benefits from treatment with EGFR inhibitors.	('mutations', 'Var', (41, 50))	('benefits', 'PosReg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('EGFR', 'Gene', (36, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))
922508	24103528	Several studies have investigated the status of EGFR mutations in esophageal carcinoma and appear to suggest that EGFR mutations in esophageal carcinoma are rare but do exist.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (66, 86))	('EGFR', 'Gene', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('mutations', 'Var', (53, 62))	('esophageal carcinoma', 'Disease', (132, 152))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (132, 152))	('esophageal carcinoma', 'Disease', (66, 86))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (66, 86))	('EGFR', 'Gene', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('mutations', 'Var', (119, 128))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (132, 152))
922509	24103528	Among these, one report carried out in Chinese patients found EGFR mutations in 14% of tumors, which is relatively higher than other regional research results.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('patients', 'Species', '9606', (47, 55))	('EGFR', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
922510	24103528	In this study, we investigated the existence of hot spot mutations in exon 19 and 21 of EGFR in Chinese ESCC patients with another sensitive method based on denaturing high performance liquid chromatography (DHPLC) as well as direct sequencing, simultaneously, and screened the status of K-RAS gene (codon 12/13) mutation by direct sequencing as well.	('mutations', 'Var', (57, 66))	('EGFR', 'Gene', (88, 92))	('DHPLC', 'Chemical', '-', (208, 213))	('patients', 'Species', '9606', (109, 117))
922516	24103528	EGFR exon 19 deletion mutations were analyzed using DHPLC as described previously.	('DHPLC', 'Chemical', '-', (52, 57))	('deletion mutations', 'Var', (13, 31))	('EGFR exon', 'Gene', (0, 9))
922517	24103528	The most common mutation, L858R in exon 21 of EGFR, was detected using the restriction enzyme enriched mutation method as described except replacing polyacrylamide gel electrophoresis with DHPLC in the analyzing process.	('L858R', 'Var', (26, 31))	('DHPLC', 'Chemical', '-', (189, 194))	('L858R', 'Mutation', 'rs121434568', (26, 31))	('polyacrylamide', 'Chemical', 'MESH:C016679', (149, 163))	('EGFR', 'Gene', (46, 50))
922521	24103528	A heterozygous mutation of the K-RAS gene (c.35 G > T; p.Gly12Cys) was detected in 2 out of the 127 patients (1.6%) by sequencing analysis (Figure 2), despite low level mutations.	('c.35 G > T', 'Var', (43, 53))	('K-RAS', 'Gene', (31, 36))	('p.Gly12Cys', 'Mutation', 'rs121913530', (55, 65))	('patients', 'Species', '9606', (100, 108))	('c.35 G > T', 'Mutation', 'rs121913529', (43, 53))
922522	24103528	In NSCLC, a growing number of studies demonstrated that patients with EGFR mutations, mainly deletions in exon 19 and L858R mutation in exon 21, would benefit from EGFR-TKI treatment, particularly among those of Asian ethnicity.	('patients', 'Species', '9606', (56, 64))	('benefit', 'PosReg', (151, 158))	('NSCLC', 'Disease', (3, 8))	('deletions in', 'Var', (93, 105))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('L858R', 'Var', (118, 123))	('rat', 'Species', '10116', (45, 48))	('L858R', 'Mutation', 'rs121434568', (118, 123))
922524	24103528	However, several studies have investigated the status of EGFR mutations in esophageal carcinoma and they mostly showed a very low frequency of EGFR-activating mutations.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (75, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('mutations', 'Var', (62, 71))	('esophageal carcinoma', 'Disease', (75, 95))	('EGFR', 'Gene', (57, 61))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (75, 95))
922525	24103528	It should be noted that EGFR mutations were detected by a high sensitive method instead of direct sequencing only in a few studies, and one of them reported relatively higher frequency of EGFR mutations in 14% of tumors including G719X missense mutation (n = 1), in-frame deletion (n = 2), and L858R missense mutation (n = 5).	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('G719X', 'Mutation', 'p.G719X', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('L858R', 'Mutation', 'rs121434568', (294, 299))	('mutations', 'Var', (193, 202))	('higher', 'PosReg', (168, 174))	('in-frame deletion', 'Var', (263, 280))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('G719X missense mutation', 'Var', (230, 253))	('EGFR', 'Gene', (188, 192))	('L858R missense mutation', 'Var', (294, 317))
922526	24103528	In this study, a high sensitivity DHPLC-based method, as well as conventional direct sequencing, were performed to screen deletions in exon 19 and L858R mutation in exon 21 of the EGFR gene in 127 Chinese ESCC patients, respectively.	('DHPLC', 'Chemical', '-', (34, 39))	('L858R', 'Var', (147, 152))	('L858R', 'Mutation', 'rs121434568', (147, 152))	('EGFR', 'Gene', (180, 184))	('patients', 'Species', '9606', (210, 218))	('deletions in', 'Var', (122, 134))
922527	24103528	The results showed that 7% of the ESCC samples harbored EGFR mutations detected by DHPLC compared with no observed EGFR mutation by direct sequencing, which may be partly attributed to the high sensitivity of DHPLC in mutation detection.	('harbored', 'Reg', (47, 55))	('DHPLC', 'Chemical', '-', (209, 214))	('DHPLC', 'Chemical', '-', (83, 88))	('DHPLC', 'Gene', (83, 88))	('mutations', 'Var', (61, 70))	('ESCC', 'Disease', (34, 38))	('EGFR', 'Gene', (56, 60))
922528	24103528	Our findings were consistent with a previous study in which Scorpion-ARMS, another high sensitivity method to detect EGFR mutation, was performed to screen EGFR mutation in Chinese ESCC patients.	('mutation', 'Var', (161, 169))	('EGFR', 'Gene', (156, 160))	('patients', 'Species', '9606', (186, 194))
922530	24103528	Together with other findings, our data indicated that EGFR mutations exist in esophageal carcinoma at low levels, which is difficult to detect by conventional DNA sequencing.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (78, 98))	('mutations', 'Var', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal carcinoma', 'Disease', (78, 98))	('EGFR', 'Gene', (54, 58))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (78, 98))
922531	24103528	This partly explains the variant frequency of EGFR mutations in several studies with different sensitivity methods and complicates the efficacy of targeted therapies in some patients except for etiological factors.	('patients', 'Species', '9606', (174, 182))	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', (46, 50))
922532	24103528	The existence of low levels of EGFR mutation in ESCC indicates the presence of intra-tumor EGFR mutational heterogeneity, suggesting high sensitivity method should be preferred for studies exploring the correlation between EGFR mutations and TKI treatment in ESCC patients.	('ESCC', 'Disease', (259, 263))	('intra-tumor', 'Disease', (79, 90))	('EGFR', 'Gene', (31, 35))	('patients', 'Species', '9606', (264, 272))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('intra-tumor', 'Disease', 'MESH:D009369', (79, 90))	('mutation', 'Var', (36, 44))
922533	24103528	Our findings demonstrated that the incidence of EGFR mutations in Chinese patients with ESCC was relatively higher than that of previous reports, partly as a result of mutation detection with a high sensitivity method.	('ESCC', 'Disease', (88, 92))	('patients', 'Species', '9606', (74, 82))	('EGFR', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('rat', 'Species', '10116', (20, 23))
922618	23234600	Copy numbers among the OtHV3 positive sea lions, however, were much lower than those of the case sea lion (ranges = 0.01 to 0.22 versus 5 205 to 72 164 viral copies/ng DNA).	('lions', 'Species', '9689', (42, 47))	('OtHV3', 'Gene', (23, 28))	('lower', 'NegReg', (68, 73))	('lion', 'Species', '9689', (42, 46))	('sea', 'Gene', (38, 41))	('sea', 'Gene', '6395', (38, 41))	('sea', 'Gene', '6395', (97, 100))	('lion', 'Species', '9689', (101, 105))	('sea', 'Gene', (97, 100))	('Copy numbers', 'MPA', (0, 12))	('positive', 'Var', (29, 37))
922620	23234600	TMMC stranded sea lions were more likely to be OtHV3-positive compared to the Navy's healthy sea lions (22/63, 34.9% versus 3/24, 12.5%; P = 0.04).	('TMMC', 'Var', (0, 4))	('lions', 'Species', '9689', (18, 23))	('lions', 'Species', '9689', (97, 102))	('sea', 'Gene', (14, 17))	('sea', 'Gene', (93, 96))	('sea', 'Gene', '6395', (14, 17))	('sea', 'Gene', '6395', (93, 96))	('OtHV3-positive', 'Gene', (47, 61))
922637	23234600	In humans, the esophagus is the most common nongenital viscera affected by herpesvirus infections, with one study demonstrating that 41 of 50 people with herpes lesions in the esophagus postmortem had no other body part affected.	('viscera affected by herpesvirus infections', 'Phenotype', 'HP:0005353', (55, 97))	('herpes lesions', 'Phenotype', 'HP:0005353', (154, 168))	('herpesvirus infections', 'Phenotype', 'HP:0005353', (75, 97))	('people', 'Species', '9606', (142, 148))	('lesions', 'Var', (161, 168))	('affected', 'Reg', (63, 71))	('herpesvirus infections', 'Disease', 'MESH:D006566', (75, 97))	('herpesvirus infection', 'Phenotype', 'HP:0005353', (75, 96))	('humans', 'Species', '9606', (3, 9))	('herpesvirus infections', 'Disease', (75, 97))
922676	29688867	Aberrant activation of oncogenes and tumor-related signaling pathways can induce the metabolic reprogramming of prostate or breast cancer cells, producing specific metabolic fingerprints.	('activation', 'PosReg', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Aberrant', 'Var', (0, 8))	('metabolic reprogramming', 'CPA', (85, 108))	('prostate', 'Disease', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('oncogenes', 'Protein', (23, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('breast cancer', 'Disease', (124, 137))	('induce', 'Reg', (74, 80))
922677	29688867	Furthermore, the inactivation of tumor suppressor genes is an important factor underlying tumor metabolic changes.	('inactivation', 'Var', (17, 29))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
922681	29688867	Metabolic changes can induce radioresistance as well, and the alterations in the glycolytic metabolism were shown to contribute to radioresistance development.	('contribute', 'Reg', (117, 127))	('glycolytic metabolism', 'MPA', (81, 102))	('rat', 'Species', '10116', (66, 69))	('radioresistance development', 'CPA', (131, 158))	('induce', 'Reg', (22, 28))	('Metabolic changes', 'Var', (0, 17))	('alterations', 'Var', (62, 73))	('radioresistance', 'CPA', (29, 44))
922689	29688867	The IR induces oxidative stress in cancers cells, and free OH radicals are considered the IR-induced common mediators of DNA damage, including single-strand breaks (SSB) and double-strand breaks (DSB), which disturb the DNA structure, triggering cell death.	('cell', 'CPA', (246, 250))	('double-strand breaks', 'Var', (174, 194))	('SSB', 'Chemical', '-', (165, 168))	('free OH radicals', 'Chemical', '-', (54, 70))	('triggering', 'Reg', (235, 245))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('oxidative stress', 'MPA', (15, 31))	('single-strand breaks', 'Var', (143, 163))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('oxidative stress', 'Phenotype', 'HP:0025464', (15, 31))
922690	29688867	Combined, these effects lead to the DNA damage, chromosomal instability, mutation and apoptosis in cancer cells, ultimately killing them (Fig.	('chromosomal instability', 'Phenotype', 'HP:0040012', (48, 71))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('killing', 'NegReg', (124, 131))	('cancer', 'Disease', (99, 105))	('lead to', 'Reg', (24, 31))	('chromosomal instability', 'CPA', (48, 71))	('apoptosis', 'CPA', (86, 95))	('mutation', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('DNA', 'MPA', (36, 39))
922695	29688867	PI3K signaling pathway regulates the steady-state homologous recombination levels, promoting DNA damage repair, and the PI3K inhibitor PI-103 can significantly enhance radiation-induced death.	('promoting', 'PosReg', (83, 92))	('PI3', 'Gene', '5266', (0, 3))	('PI3', 'Gene', '5266', (120, 123))	('PI-103', 'Var', (135, 141))	('PI-103', 'Chemical', 'MESH:C522973', (135, 141))	('DNA damage repair', 'MPA', (93, 110))	('PI3', 'Gene', (120, 123))	('enhance', 'PosReg', (160, 167))	('radiation-induced death', 'CPA', (168, 191))	('homologous recombination levels', 'MPA', (50, 81))	('PI3', 'Gene', (0, 3))
922701	29688867	For example, the cell adhesion molecule vitronectin (VTN) is an important oncogene, and the dysregulation of its expression promotes the migration and invasion of nasopharyngeal carcinoma (NPC) as well as resistance of the NPC cells to radiotherapy.	('NPC', 'Phenotype', 'HP:0100630', (189, 192))	('dysregulation', 'Var', (92, 105))	('NPC', 'Gene', (223, 226))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (163, 187))	('promotes', 'PosReg', (124, 132))	('NPC', 'Gene', (189, 192))	('expression', 'MPA', (113, 123))	('VTN', 'Gene', (53, 56))	('NPC', 'Gene', '4864', (223, 226))	('VTN', 'Gene', '7448', (53, 56))	('vitronectin', 'Gene', (40, 51))	('NPC', 'Gene', '4864', (189, 192))	('nasopharyngeal carcinoma', 'Disease', (163, 187))	('invasion', 'CPA', (151, 159))	('migration', 'CPA', (137, 146))	('rat', 'Species', '10116', (140, 143))	('resistance', 'CPA', (205, 215))	('vitronectin', 'Gene', '7448', (40, 51))	('NPC', 'Phenotype', 'HP:0100630', (223, 226))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (163, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))
922702	29688867	Additionally, many miRNAs, e.g., miR-29c and miR-22, have tumor-suppressor roles, and the alteration in their expression in lung and breast cancer cells represents an important cause of radioresistance.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('breast cancer', 'Disease', (133, 146))	('miR-22', 'Gene', '407004', (45, 51))	('rat', 'Species', '10116', (94, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('miR-29c', 'Gene', (33, 40))	('miR-22', 'Gene', (45, 51))	('miR-29c', 'Gene', '407026', (33, 40))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('expression', 'MPA', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('alteration', 'Var', (90, 100))
922706	29688867	Its dysfunctions may promote the development of systemic autoimmune diseases, such as lupus, while in cancer, it may promote or inhibit the survival and proliferation of cancer cells in the TME.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibit', 'NegReg', (128, 135))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (57, 76))	('cancer', 'Disease', (170, 176))	('lupus', 'Disease', (86, 91))	('rat', 'Species', '10116', (160, 163))	('survival', 'CPA', (140, 148))	('systemic autoimmune diseases', 'Disease', 'MESH:D020274', (48, 76))	('dysfunctions', 'Var', (4, 16))	('promote', 'PosReg', (21, 28))	('systemic autoimmune diseases', 'Disease', (48, 76))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('promote', 'PosReg', (117, 124))	('lupus', 'Disease', 'MESH:D008180', (86, 91))
922736	29688867	The inhibition of mitochondrial respiration by mitochondrial respiratory modulators (e.g., di-nitro phenol) leads to a considerable increase in the glycolytic index.	('increase', 'PosReg', (132, 140))	('di-nitro phenol', 'Chemical', 'MESH:D004140', (91, 106))	('rat', 'Species', '10116', (66, 69))	('mitochondrial respiration', 'MPA', (18, 43))	('rat', 'Species', '10116', (37, 40))	('di-nitro phenol', 'Var', (91, 106))	('glycolytic index', 'MPA', (148, 164))	('inhibition', 'NegReg', (4, 14))
922745	29688867	Additionally, WZB117, a small molecule, acts as a specific inhibitor of GLUT1, overcoming the resistance of cancer cells to radiation.	('overcoming', 'PosReg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('WZB117', 'Chemical', 'MESH:C576807', (14, 20))	('WZB117', 'Var', (14, 20))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
922747	29688867	Furthermore, the antisense oligonucleotide chain (AS-ODNs) of GLUT1 can also induce the radiosensitivity of laryngeal carcinoma cells (Fig.	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (108, 127))	('antisense oligonucleotide chain', 'Var', (17, 48))	('induce', 'PosReg', (77, 83))	('oligonucleotide', 'Chemical', 'MESH:D009841', (27, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('GLUT1', 'Gene', (62, 67))	('radiosensitivity', 'CPA', (88, 104))	('laryngeal carcinoma', 'Disease', (108, 127))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (108, 127))
922750	29688867	Alterations in glucose metabolism after radiotherapy can lead to the accumulation of large amounts of lactic acid, which is one of the unique malignant tumor phenotypes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('glucose metabolism', 'Disease', (15, 33))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Alterations', 'Var', (0, 11))	('lead to', 'Reg', (57, 64))	('tumor', 'Disease', (152, 157))	('lactic acid', 'Chemical', 'MESH:D019344', (102, 113))	('glucose metabolism', 'Disease', 'MESH:D044882', (15, 33))	('lactic acid', 'MPA', (102, 113))	('accumulation of', 'MPA', (69, 84))	('rat', 'Species', '10116', (4, 7))
922767	29688867	Acting as a tumor suppressor, the expression of miR-34 was shown to negatively correlate with radioresistance development and to induce the sensitivity of the hepatocellular carcinoma cells to radiotherapy by inhibiting the expression of LDHA (Fig.	('miR-34', 'Gene', '407040', (48, 54))	('sensitivity', 'MPA', (140, 151))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (159, 183))	('induce', 'PosReg', (129, 135))	('hepatocellular carcinoma', 'Disease', (159, 183))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (159, 183))	('inhibiting', 'NegReg', (209, 219))	('radioresistance development', 'CPA', (94, 121))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('expression', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('LDHA', 'Gene', (238, 242))	('expression', 'MPA', (224, 234))	('miR-34', 'Gene', (48, 54))	('tumor', 'Disease', (12, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('negatively', 'NegReg', (68, 78))	('LDHA', 'Gene', '3939', (238, 242))
922807	29688867	The mechanisms underlying the development of radioresistance may include the following: An increasing number of studies have shown that, by targeting HIF1 activity, tumor antioxidant capacity can be reduced, as it affects the TME and promotes the sensitivity of solid tumors to radiotherapy.	('HIF1', 'Gene', '3091', (150, 154))	('tumor', 'Disease', (165, 170))	('activity', 'MPA', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('affects', 'Reg', (214, 221))	('promotes', 'PosReg', (234, 242))	('targeting', 'Var', (140, 149))	('tumor', 'Disease', (268, 273))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('solid tumors', 'Disease', (262, 274))	('HIF1', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('TME', 'MPA', (226, 229))	('solid tumors', 'Disease', 'MESH:D009369', (262, 274))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('reduced', 'NegReg', (199, 206))
922808	29688867	By combining HIF1 targeting and radiotherapy, improved therapeutic effects can be achieved.	('targeting', 'Var', (18, 27))	('HIF1', 'Gene', '3091', (13, 17))	('HIF1', 'Gene', (13, 17))	('therapeutic effects', 'CPA', (55, 74))
922810	29688867	Additionally, HIF1alpha inhibition leads to the downregulation of stem cell markers and a decrease in radioresistance of cervical cancer cells.	('stem cell markers', 'CPA', (66, 83))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('HIF1alpha', 'Gene', (14, 23))	('inhibition', 'Var', (24, 34))	('downregulation', 'NegReg', (48, 62))	('HIF1alpha', 'Gene', '3091', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('decrease', 'NegReg', (90, 98))
922811	29688867	Various HIF1 inhibitors function through different signaling pathways, thereby enhancing the efficacy of radiotherapy.	('function', 'Reg', (24, 32))	('efficacy of radiotherapy', 'CPA', (93, 117))	('HIF1', 'Gene', (8, 12))	('inhibitors', 'Var', (13, 23))	('enhancing', 'PosReg', (79, 88))	('signaling pathways', 'Pathway', (51, 69))	('HIF1', 'Gene', '3091', (8, 12))
922813	29688867	KNK437 can abrogate hypoxia-induced anti-radiation effects by targeting both AKT and HIF1alpha.	('KNK437', 'Var', (0, 6))	('HIF1alpha', 'Gene', (85, 94))	('AKT', 'Pathway', (77, 80))	('HIF1alpha', 'Gene', '3091', (85, 94))	('targeting', 'Reg', (62, 71))	('hypoxia', 'Disease', (20, 27))	('hypoxia', 'Disease', 'MESH:D000860', (20, 27))	('abrogate', 'NegReg', (11, 19))
922818	29688867	NVP-BEZ235, an inhibitor of PI3K/mTOR signaling pathway, can inhibit the activation of HIF1alpha/VEGF signaling pathway in endometrial cancer and suppress radioresistance development.	('activation', 'PosReg', (73, 83))	('NVP-BEZ235', 'Var', (0, 10))	('endometrial cancer', 'Disease', 'MESH:D016889', (123, 141))	('VEGF', 'Gene', (97, 101))	('radioresistance development', 'CPA', (155, 182))	('suppress', 'NegReg', (146, 154))	('BEZ235', 'Chemical', 'MESH:C531198', (4, 10))	('mTOR', 'Gene', '2475', (33, 37))	('endometrial cancer', 'Phenotype', 'HP:0012114', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('HIF1alpha', 'Gene', (87, 96))	('mTOR', 'Gene', (33, 37))	('inhibit', 'NegReg', (61, 68))	('PI3', 'Gene', '5266', (28, 31))	('HIF1alpha', 'Gene', '3091', (87, 96))	('VEGF', 'Gene', '7422', (97, 101))	('endometrial cancer', 'Disease', (123, 141))	('PI3', 'Gene', (28, 31))
922819	29688867	As STAT3 inhibitors, NSC74859 and Stattic can improve the radiosensitivity of esophageal cancer through the inhibition of hypoxia and radiation-induced STAT3 activation, as well as the expression of HIF1alpha and VEGF.	('STAT3', 'Gene', (3, 8))	('NSC74859', 'Var', (21, 29))	('STAT3', 'Gene', '6774', (152, 157))	('inhibition', 'NegReg', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('VEGF', 'Gene', (213, 217))	('radiosensitivity', 'CPA', (58, 74))	('HIF1alpha', 'Gene', (199, 208))	('hypoxia', 'Disease', (122, 129))	('STAT3', 'Gene', (152, 157))	('VEGF', 'Gene', '7422', (213, 217))	('hypoxia', 'Disease', 'MESH:D000860', (122, 129))	('HIF1alpha', 'Gene', '3091', (199, 208))	('STAT3', 'Gene', '6774', (3, 8))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('improve', 'PosReg', (46, 53))
922831	29688867	The M2 isoform (PKM2) is a key regulator of glycolysis, expressed only in cancer cells, and targeting this molecule can inhibit cell viability, induce G2/M arrest, and promote apoptosis.	('induce', 'PosReg', (144, 150))	('G2/M arrest', 'CPA', (151, 162))	('targeting', 'Var', (92, 101))	('PKM2', 'Gene', (16, 20))	('PKM2', 'Gene', '5315', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('promote', 'PosReg', (168, 175))	('cancer', 'Disease', (74, 80))	('cell viability', 'CPA', (128, 142))	('inhibit', 'NegReg', (120, 127))	('apoptosis', 'CPA', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
922842	29688867	The combination of 2-DG and histone deacetylase transferase inhibitors can induce apoptosis in glioblastoma cells, while 2-DG can also significantly inhibit the expression of HK2 and induce apoptosis (Fig.	('inhibit', 'NegReg', (149, 156))	('2-DG', 'Chemical', 'MESH:D003847', (19, 23))	('glioblastoma', 'Disease', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('apoptosis', 'CPA', (82, 91))	('expression', 'MPA', (161, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('2-DG', 'Chemical', 'MESH:D003847', (121, 125))	('HK2', 'Gene', (175, 178))	('HK2', 'Gene', '3099', (175, 178))	('2-DG', 'Var', (121, 125))	('induce', 'PosReg', (183, 189))	('apoptosis', 'CPA', (190, 199))
922867	29688867	This suggests that radiotherapy can lead to the considerable alterations in the mitochondrial protein expression, and therefore induce radioresistance.	('mitochondrial protein expression', 'MPA', (80, 112))	('rat', 'Species', '10116', (65, 68))	('radiotherapy', 'Var', (19, 31))	('alterations', 'Reg', (61, 72))	('induce', 'Reg', (128, 134))	('radioresistance', 'CPA', (135, 150))
922870	29688867	After silencing ATAD3A, the expression of ATM, histone H2AX, and H3 was shown to decrease, inhibiting the DNA damage repair and ultimately promoting tumor cell radiosensitivity.	('inhibiting', 'NegReg', (91, 101))	('ATM', 'Gene', '472', (42, 45))	('decrease', 'NegReg', (81, 89))	('DNA damage repair', 'MPA', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cell radiosensitivity', 'Phenotype', 'HP:0010997', (155, 176))	('expression', 'MPA', (28, 38))	('ATAD3A', 'Gene', '55210', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('promoting', 'PosReg', (139, 148))	('tumor', 'Disease', (149, 154))	('ATM', 'Gene', (42, 45))	('ATAD3A', 'Gene', (16, 22))	('silencing', 'Var', (6, 15))	('histone H2AX', 'Protein', (47, 59))
922873	29688867	Mutations in the SIRT3 Thr150Ala/Ser159Ala lead to a decrease in MnSOD activity and the production of mitochondrial ATP, increasing sensitivity to radiotherapy.	('Thr150Ala', 'SUBSTITUTION', 'None', (23, 32))	('production of mitochondrial ATP', 'MPA', (88, 119))	('MnSOD', 'Gene', (65, 70))	('SIRT3', 'Gene', '23410', (17, 22))	('SIRT3', 'Gene', (17, 22))	('decrease', 'NegReg', (53, 61))	('ATP', 'Chemical', 'MESH:D000255', (116, 119))	('Ser159Ala', 'Chemical', '-', (33, 42))	('sensitivity', 'MPA', (132, 143))	('Thr150Ala', 'Var', (23, 32))	('Mutations', 'Var', (0, 9))	('increasing', 'PosReg', (121, 131))	('MnSOD', 'Gene', '6648', (65, 70))
922878	29688867	Mitochondrial MKP1 confers radioresistance to HER2 overexpressing breast cancer cells, and by co-suppressing the expression of MKP1 and HER2, breast cancer cell apoptosis can be induced, while inhibiting radioresistance (Fig.	('MKP1', 'Gene', (14, 18))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('breast cancer', 'Disease', (142, 155))	('HER2', 'Gene', '2064', (136, 140))	('expression', 'MPA', (113, 123))	('HER2', 'Gene', '2064', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MKP1', 'Gene', '1843', (127, 131))	('radioresistance', 'CPA', (204, 219))	('inhibiting', 'NegReg', (193, 203))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HER2', 'Gene', (136, 140))	('MKP1', 'Gene', (127, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('MKP1', 'Gene', '1843', (14, 18))	('induced', 'PosReg', (178, 185))	('HER2', 'Gene', (46, 50))	('co-suppressing', 'Var', (94, 108))	('radioresistance', 'CPA', (27, 42))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('breast cancer', 'Disease', (66, 79))
922884	29688867	MEK-specific inhibitor PD98059 was shown to prevent the observed effects of MEK/ERK on MMP and the development of radioresistance.	('prevent', 'NegReg', (44, 51))	('ERK', 'Gene', '5594', (80, 83))	('MEK', 'Gene', (0, 3))	('MMP', 'Disease', (87, 90))	('PD98059', 'Chemical', 'MESH:C093973', (23, 30))	('ERK', 'Gene', (80, 83))	('MEK', 'Gene', '5609', (0, 3))	('MEK', 'Gene', (76, 79))	('MEK', 'Gene', '5609', (76, 79))	('PD98059', 'Var', (23, 30))
922891	29688867	3), suggesting that the mtKATP pathway is a key regulator of radiosensitivity in gliomas, and the blockers and inhibitors of mtKATP channel and MAPK/ERK kinase, respectively, may represent novel therapeutics of the treatment of gliomas.	('mtKATP', 'Gene', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('ERK', 'Gene', (149, 152))	('gliomas', 'Disease', 'MESH:D005910', (228, 235))	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('gliomas', 'Disease', (228, 235))	('gliomas', 'Phenotype', 'HP:0009733', (228, 235))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('ATP', 'Chemical', 'MESH:D000255', (128, 131))	('gliomas', 'Disease', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('inhibitors', 'Var', (111, 121))	('ERK', 'Gene', '5594', (149, 152))	('blockers', 'Var', (98, 106))
922893	29688867	An increasing number of studies demonstrated that radioresistance development can be associated with tumor metabolism, as the radiotherapy may induce alterations in many molecules and signaling pathways involved in the tumor cell metabolism, and metabolic changes may affect the efficacy of radiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('affect', 'Reg', (268, 274))	('tumor', 'Disease', (219, 224))	('rat', 'Species', '10116', (154, 157))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('rat', 'Species', '10116', (39, 42))	('radioresistance development', 'CPA', (50, 77))	('alterations', 'Reg', (150, 161))	('radiotherapy', 'Var', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('efficacy of radiotherapy', 'CPA', (279, 303))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('metabolic changes', 'CPA', (246, 263))
922915	28607662	Short-term complications include bleeding, shock, airway edema, esophagus perforation, and death, and long-term complications include tightness in various parts of the gastrointestinal tract, tracheoesophageal fistula, shortening of esophagus, incompetent lower esophageal sphincter and increased esophageal carcinoma in children.	('edema', 'Disease', (57, 62))	('tightness', 'Disease', 'MESH:C536920', (134, 143))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (192, 217))	('shock', 'Disease', (43, 48))	('esophageal sphincter', 'Disease', 'MESH:D009122', (262, 282))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (297, 317))	('tracheoesophageal fistula', 'Disease', (192, 217))	('death', 'Disease', 'MESH:D003643', (91, 96))	('esophageal sphincter', 'Disease', (262, 282))	('bleeding', 'Disease', 'MESH:D006470', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('gastrointestinal tract', 'Disease', (168, 190))	('esophageal carcinoma', 'Disease', (297, 317))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (168, 190))	('incompetent', 'Disease', (244, 255))	('esophagus', 'Disease', (64, 73))	('shock', 'Disease', 'MESH:D012769', (43, 48))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (192, 217))	('bleeding', 'Disease', (33, 41))	('increased', 'PosReg', (287, 296))	('edema', 'Phenotype', 'HP:0000969', (57, 62))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (297, 317))	('death', 'Disease', (91, 96))	('edema', 'Disease', 'MESH:D004487', (57, 62))	('shock', 'Phenotype', 'HP:0031273', (43, 48))	('children', 'Species', '9606', (321, 329))	('tightness', 'Disease', (134, 143))	('shortening', 'Var', (219, 229))
923056	25041052	As a result, the incidence of febrile neutropenia was lower with the modified DCF regimen (6%) than with the 3-weekly DCF regimen (17%), and the RR was higher with the modified DCF regimen (52%) than with the 3-weekly DCF regimen (34%).	('men', 'Species', '9606', (126, 129))	('higher', 'PosReg', (152, 158))	('men', 'Species', '9606', (185, 188))	('febrile neutropenia', 'Disease', 'MESH:D009503', (30, 49))	('men', 'Species', '9606', (86, 89))	('neutropenia', 'Phenotype', 'HP:0001875', (38, 49))	('modified DCF', 'Var', (69, 81))	('men', 'Species', '9606', (226, 229))	('DCF', 'Chemical', '-', (118, 121))	('DCF', 'Chemical', '-', (177, 180))	('modified', 'Var', (168, 176))	('DCF', 'Chemical', '-', (78, 81))	('DCF', 'Chemical', '-', (218, 221))	('lower', 'NegReg', (54, 59))	('febrile neutropenia', 'Disease', (30, 49))
923091	25826212	miRNome analysis identified four down-regulated miRNAs in metastasis positive primary tumors compared to metastasis negative tumors: miR-92a-3p (p=0.0001), miR-141-3p (p=0.0022), miR-451-1a (p=0.0181) and miR133a-3p (p=0.0304).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR-451-1a', 'Var', (179, 189))	('primary tumors', 'Disease', 'MESH:D009369', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('miR-141-3p', 'Var', (156, 166))	('down-regulated', 'NegReg', (33, 47))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('miR133a-3p', 'Var', (205, 215))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('miR-92a-3p', 'Var', (133, 143))	('metastasis', 'Disease', (58, 68))	('primary tumors', 'Disease', (78, 92))
923100	25826212	There has been an increased interest in non-coding RNAs (ncRNA) and microRNAs (miRNAs) and their potential use as indicators of cancer behavior.	('non-coding', 'Var', (40, 50))	('cancer behavior', 'Disease', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer behavior', 'Disease', 'MESH:D009369', (128, 143))
923156	25826212	IPA identified 4 focus miRNAs related to metastasis and upper gastrointestinal tract cancer (>=4 fold change) that were downregulated in metastasis positive samples versus metastasis negative samples: 1) miR-92a-3p (p = 0.0001, fold change >14), miR-141-3p (p = 0.0022, fold change >9), miR-451-1a (p = 0.0181, fold change >12) and miR133a-3p (p = 0.0304, fold change >9) (S2 Fig.).	('miR133a-3p', 'Var', (332, 342))	('downregulated', 'NegReg', (120, 133))	('miR-92a-3p', 'Var', (204, 214))	('metastasis and upper gastrointestinal tract cancer', 'Disease', 'MESH:D009362', (41, 91))	('miR-141-3p', 'Var', (246, 256))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('miR-451-1a', 'Var', (287, 297))
923157	25826212	The 4 focus miRNAs symbols miR-92a-3p, miR-141-3p, miR-451-1a, and miR133a-3p were mapped from the dataset ID rno-miR-32-5p, rno-miR-141-3p, rno-miR-451-5p, and rno-miR-133b-3p respectively.	('miR-451-5p', 'Gene', '100616404', (145, 155))	('miR-133b', 'Gene', (165, 173))	('miR-32-5p', 'Gene', (114, 123))	('rno-miR-141-3p', 'Var', (125, 139))	('miR-133b', 'Gene', '100314078', (165, 173))	('miR-32-5p', 'Gene', '442899', (114, 123))	('miR-451-5p', 'Gene', (145, 155))
923158	25826212	To determine if the selected miRNA signature would predict significant changes in expression of genes within the canonical neoplastic and metastasis pathways, IPA was used to identify 1 upstream negative regulator (KRAS) of miR-141-3p and 6 downstream, positively regulated targets (AGO2, BCL2L11, AKT1, ZEB2, CDKN1B, BCL2) of the 4 miRNAs.	('AKT1', 'Gene', (298, 302))	('miR-141-3p', 'Var', (224, 234))	('expression', 'MPA', (82, 92))	('BCL2L11', 'Gene', '10018', (289, 296))	('BCL2L11', 'Gene', (289, 296))	('CDKN1B', 'Gene', (310, 316))	('KRAS', 'Gene', (215, 219))	('KRAS', 'Gene', '3845', (215, 219))	('AKT1', 'Gene', '207', (298, 302))
923174	25826212	Recently, miRNAs have been found to have a direct, non-coding role in tumor suppression by targeting several oncogenes involved in specific cancer-related pathways.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('targeting', 'Reg', (91, 100))	('tumor', 'Disease', (70, 75))	('oncogenes', 'Gene', (109, 118))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('miRNAs', 'Var', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
923187	25826212	The 4 miRNAs (miR-92a-3p, miR-451a, miR-141-3p, and miR-133-3p) were significantly down regulated in metastasis positive tumors.	('miR-451a', 'Gene', '574411', (26, 34))	('miR-451a', 'Gene', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('miR-92a-3p', 'Var', (14, 24))	('down regulated', 'NegReg', (83, 97))	('metastasis positive tumors', 'Disease', (101, 127))	('metastasis positive tumors', 'Disease', 'MESH:D009362', (101, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('miR-141-3p', 'Var', (36, 46))	('miR-133-3p', 'Var', (52, 62))
923193	25826212	miR-100 targets AGO2, miR-199a-3p and miR-145 target ZEB2, miR-143 targets BCL2, and miR-199a-5p targets CDKN1B, which are 4 of 7 genes targeted by the rat miRNA signature in the present study.	('BCL2', 'Gene', (75, 79))	('rat', 'Species', '10116', (152, 155))	('miR-145', 'Gene', (38, 45))	('miR-199a-3p', 'Var', (22, 33))	('CDKN1B', 'Gene', (105, 111))	('miR-143', 'Var', (59, 66))	('miR-199a-5p', 'Var', (85, 96))	('miR-100', 'Gene', (0, 7))
923332	24551190	The expression patterns of 6 randomly selected genes in tumor tissues detected by RT-PCR, except SORBS2, were fully consistent with those from the cDNA microarray results (Figure 1A).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('SORBS2', 'Gene', (97, 103))	('tumor', 'Disease', (56, 61))	('expression', 'MPA', (4, 14))	('RT-PCR', 'Var', (82, 88))	('SORBS2', 'Gene', '8470', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
923342	24551190	Patients with CTTN overexpression had significantly shorter disease-specific survival rate than those without CTTN overexpression in both I+IIA subgroup (n = 113, p = 0.001, Figure 3A) and IIB+III subgroup (n = 85, p = 0.027, Figure 3B), indicating that CTTN could be a valuable prognostic marker for ESCC.	('CTTN', 'Gene', '2017', (254, 258))	('CTTN', 'Gene', '2017', (110, 114))	('ESCC', 'Disease', (301, 305))	('shorter', 'NegReg', (52, 59))	('disease-specific survival rate', 'CPA', (60, 90))	('Patients', 'Species', '9606', (0, 8))	('overexpression', 'Var', (19, 33))	('CTTN', 'Gene', (254, 258))	('CTTN', 'Gene', (14, 18))	('CTTN', 'Gene', (110, 114))	('CTTN', 'Gene', '2017', (14, 18))
923359	24551190	Remodeling of the actin cytoskeleton has effects on cell migration, motility, and adhesion, as well as on tumor invasion and metastasis.	('metastasis', 'CPA', (125, 135))	('effects', 'Reg', (41, 48))	('cell migration', 'CPA', (52, 66))	('Remodeling', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('adhesion', 'CPA', (82, 90))	('motility', 'CPA', (68, 76))	('tumor', 'Disease', (106, 111))
923360	24551190	Overexpression of cortactin is associated with increased invasiveness of hepatocellular carcinoma cells.	('cortactin', 'Gene', '2017', (18, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (73, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('invasiveness of hepatocellular carcinoma', 'Disease', (57, 97))	('increased', 'PosReg', (47, 56))	('invasiveness of hepatocellular carcinoma', 'Disease', 'MESH:D006528', (57, 97))	('Overexpression', 'Var', (0, 14))	('cortactin', 'Gene', (18, 27))
923399	23095512	Interestingly, curcumin with or without 5-fluorouracil and oxaliplatin significantly reduced the number of cells showing CSC-markers CD44 and CD166 in a colon cancer cell line that had survived previous treatment with 5-fluorouracil.	('CD44', 'Var', (133, 137))	('curcumin', 'Chemical', 'MESH:D003474', (15, 23))	('CD166', 'Gene', '214', (142, 147))	('colon cancer', 'Disease', 'MESH:D015179', (153, 165))	('colon cancer', 'Phenotype', 'HP:0003003', (153, 165))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (218, 232))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (40, 54))	('colon cancer', 'Disease', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('CD166', 'Gene', (142, 147))	('reduced', 'NegReg', (85, 92))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (59, 70))
923455	23095512	When the cell lines were ranked from low to high according to their sensitivity to 60 muM curcumin the order was: KY-5, YES-1, TE-8, TE-1, KY-10, and YES-2.	('KY-5', 'Chemical', '-', (114, 118))	('TE', 'Chemical', 'MESH:D013691', (127, 129))	('YES-1', 'Gene', (120, 125))	('TE', 'Chemical', 'MESH:D013691', (133, 135))	('muM', 'Gene', '56925', (86, 89))	('TE-8', 'Var', (127, 131))	('YES-2', 'Gene', (150, 155))	('KY-5', 'Var', (114, 118))	('muM', 'Gene', (86, 89))	('KY-10', 'Var', (139, 144))	('YES-1', 'Gene', '7525', (120, 125))	('YES-2', 'Gene', '7526', (150, 155))	('curcumin', 'Chemical', 'MESH:D003474', (90, 98))	('TE-1', 'Var', (133, 137))
923462	23095512	The number of surviving colonies formed after 60 muM curcumin was 0, 8, 17, 19, 25, and too many colonies to count for YES-2, TE-1, TE-8, KY-10, YES-1, and KY-5, respectively.	('YES-1', 'Gene', '7525', (145, 150))	('TE-1', 'Var', (126, 130))	('KY-10', 'Var', (138, 143))	('muM', 'Gene', '56925', (49, 52))	('KY-5', 'Chemical', '-', (156, 160))	('KY-5', 'Var', (156, 160))	('YES-2', 'Gene', (119, 124))	('curcumin', 'Chemical', 'MESH:D003474', (53, 61))	('muM', 'Gene', (49, 52))	('TE', 'Chemical', 'MESH:D013691', (132, 134))	('TE-8', 'Var', (132, 136))	('YES-2', 'Gene', '7526', (119, 124))	('YES-1', 'Gene', (145, 150))	('TE', 'Chemical', 'MESH:D013691', (126, 128))
923468	23095512	ALDH1A1 expression level was significantly higher in KY-5 than in all other lines.	('higher', 'PosReg', (43, 49))	('KY-5', 'Chemical', '-', (53, 57))	('expression level', 'MPA', (8, 24))	('ALDH1A1', 'Gene', '216', (0, 7))	('KY-5', 'Var', (53, 57))	('ALDH1A1', 'Gene', (0, 7))
923478	23095512	In addition, the results also showed that KY-5S, YES-1S and YES-2S had lower NF-kappaB levels when compared with the original cell lines (Figure 3B).	('YES-2', 'Gene', (60, 65))	('NF-kappaB', 'Gene', '4790', (77, 86))	('NF-kappaB', 'Gene', (77, 86))	('KY-5S', 'Var', (42, 47))	('YES-1', 'Gene', (49, 54))	('YES-2', 'Gene', '7526', (60, 65))	('KY-5S', 'Chemical', '-', (42, 47))	('YES-1', 'Gene', '7525', (49, 54))	('lower', 'NegReg', (71, 76))
923479	23095512	However, TE-1S and TE-8S showed increased NF-kappaB levels relative to the original lines, but KY-10S showed no difference from KY-10.	('NF-kappaB', 'Gene', '4790', (42, 51))	('TE-1S', 'Var', (9, 14))	('increased', 'PosReg', (32, 41))	('TE', 'Chemical', 'MESH:D013691', (19, 21))	('NF-kappaB', 'Gene', (42, 51))	('TE', 'Chemical', 'MESH:D013691', (9, 11))
923483	23095512	Staining for ALDH1 was significantly higher in KY5 than in all other lines.	('Staining', 'MPA', (0, 8))	('higher', 'PosReg', (37, 43))	('ALDH1', 'Gene', (13, 18))	('KY5', 'Var', (47, 50))	('ALDH1', 'Gene', '216', (13, 18))
923485	23095512	Also, TE-8 staining was significantly higher than YES-1, TE-1 and KY-10.	('YES-1', 'Gene', (50, 55))	('TE-8', 'Var', (6, 10))	('YES-1', 'Gene', '7525', (50, 55))	('TE', 'Chemical', 'MESH:D013691', (6, 8))	('TE', 'Chemical', 'MESH:D013691', (57, 59))	('higher', 'PosReg', (38, 44))
923497	23095512	The percentage of cells in the high-staining subpopulations of the curcumin-surviving lines ranged from 0 for TE-8S and TE-1S to 12.2% for KY-5S.	('TE-1S', 'Var', (120, 125))	('KY-5S', 'Chemical', '-', (139, 144))	('curcumin', 'Chemical', 'MESH:D003474', (67, 75))	('TE', 'Chemical', 'MESH:D013691', (110, 112))	('TE-8S', 'Var', (110, 115))	('TE', 'Chemical', 'MESH:D013691', (120, 122))
923499	23095512	For example, the mean intensities of the low- and high-staining YES-1 subpopulations were 175.47 +- 89.99 and 446.47 +- 31.21.	('446.47 +-', 'Var', (110, 119))	('YES-1', 'Gene', (64, 69))	('YES-1', 'Gene', '7525', (64, 69))	('high-staining', 'PosReg', (50, 63))
923500	23095512	The mean intensity of the high-staining cells of the other three lines was 438.96 +- 55.38, 463.79 +- 50.66, and 470.20 +- 53.77 for YES-2, YES-1S, and YES-2S, respectively.	('YES-2', 'Gene', (133, 138))	('YES-2', 'Gene', '7526', (152, 157))	('YES-1', 'Gene', (140, 145))	('463.79', 'Var', (92, 98))	('YES-2', 'Gene', '7526', (133, 138))	('YES-1', 'Gene', '7525', (140, 145))	('YES-2', 'Gene', (152, 157))
923538	23095512	Additionally, the other three lines showed the same (KY-10) or more NF-kappaB expression (TE-1 & TE-8) in the surviving lines, and this result was confirmed using immunocytochemistry with the same three lines (TE-1, TE-8, KY-10, data not shown).	('TE', 'Chemical', 'MESH:D013691', (216, 218))	('expression', 'MPA', (78, 88))	('TE', 'Chemical', 'MESH:D013691', (210, 212))	('NF-kappaB', 'Gene', '4790', (68, 77))	('NF-kappaB', 'Gene', (68, 77))	('TE', 'Chemical', 'MESH:D013691', (90, 92))	('TE', 'Chemical', 'MESH:D013691', (97, 99))	('KY-10', 'Var', (53, 58))	('more', 'PosReg', (63, 67))
923585	23095512	reported that difluorinated-curcumin, a novel curcumin analog, together with other chemotherapeutic agents reduced the CSC cell markers CD44 and CD166 in chemo-resistant colon cancer cells.	('colon cancer', 'Phenotype', 'HP:0003003', (170, 182))	('colon cancer', 'Disease', 'MESH:D015179', (170, 182))	('curcumin', 'Chemical', 'MESH:D003474', (46, 54))	('CD166', 'Gene', '214', (145, 150))	('reduced', 'NegReg', (107, 114))	('colon cancer', 'Disease', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('CSC', 'Disease', (119, 122))	('curcumin', 'Chemical', 'MESH:D003474', (28, 36))	('difluorinated-curcumin', 'Var', (14, 36))	('difluorinated-curcumin', 'Chemical', '-', (14, 36))	('CD44', 'MPA', (136, 140))	('CD166', 'Gene', (145, 150))
923663	33530324	In addition, S. lupi produces hypertrophic osteopathy and aortic lesions, leading to thromboembolism, aortic rupture and sudden death.	('S. lupi', 'Var', (13, 20))	('thromboembolism', 'Disease', (85, 100))	('aortic rupture', 'Disease', (102, 116))	('sudden death', 'Disease', 'MESH:D003645', (121, 133))	('S. lupi', 'Species', '304461', (13, 20))	('hypertrophic osteopathy and aortic lesions', 'Disease', 'MESH:D001018', (30, 72))	('aortic rupture', 'Phenotype', 'HP:0031649', (102, 116))	('leading to', 'Reg', (74, 84))	('thromboembolism', 'Disease', 'MESH:D013923', (85, 100))	('sudden death', 'Disease', (121, 133))	('thromboembolism', 'Phenotype', 'HP:0001907', (85, 100))	('aortic rupture', 'Disease', 'MESH:D001014', (102, 116))
923682	33530324	Furthermore, circulating VEGF in plasma and serum was significantly higher in dogs with neoplastic nodules compared to dogs with non-neoplastic nodules.	('neoplastic nodules', 'Phenotype', 'HP:0002664', (88, 106))	('neoplastic nodule', 'Phenotype', 'HP:0002664', (88, 105))	('neoplastic nodules', 'Phenotype', 'HP:0002664', (133, 151))	('higher', 'PosReg', (68, 74))	('VEGF', 'Gene', '403802', (25, 29))	('neoplastic nodules', 'Var', (88, 106))	('neoplastic nodule', 'Phenotype', 'HP:0002664', (133, 150))	('dogs', 'Species', '9615', (78, 82))	('VEGF', 'Gene', (25, 29))	('dogs', 'Species', '9615', (119, 123))
923751	33530324	The S. haematobium orthologs H03-H-IPSE and H06-H-IPSE induce the proliferation of mouse urothelial cells and are internalized by urothelial and neuronal cells, promoting procarcinogenic programs.	('H06', 'CellLine', 'CVCL:M564', (44, 47))	('H03', 'CellLine', 'CVCL:J167', (29, 32))	('carcinogenic', 'Disease', 'MESH:D063646', (174, 186))	('carcinogenic', 'Disease', (174, 186))	('mouse', 'Species', '10090', (83, 88))	('proliferation', 'CPA', (66, 79))	('rat', 'Species', '10116', (73, 76))	('induce', 'PosReg', (55, 61))	('H06-H-IPSE', 'Var', (44, 54))	('S. haematobium', 'Species', '6185', (4, 18))	('promoting', 'PosReg', (161, 170))	('H03-H-IPSE', 'Var', (29, 39))
923781	33530324	An increased mutation rate precedes alterations in oncogenes and tumor suppressor genes, which in combination with prosurvival signals, the inhibition of apoptosis and the stimulation of proliferation pathways induced by Sl-ESP such as galectin, 14-3-3 protein, HSP70 and HSP90, may promote neoplastic nodule formation.	('HSP90', 'Gene', '3320', (272, 277))	('rat', 'Species', '10116', (40, 43))	('14-3-3', 'Gene', (246, 252))	('tumor', 'Disease', (65, 70))	('rat', 'Species', '10116', (22, 25))	('Sl-ESP', 'Chemical', '-', (221, 227))	('inhibition', 'NegReg', (140, 150))	('neoplastic nodule formation', 'CPA', (291, 318))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('HSP70', 'Gene', (262, 267))	('promote', 'PosReg', (283, 290))	('stimulation', 'PosReg', (172, 183))	('apoptosis', 'CPA', (154, 163))	('proliferation', 'CPA', (187, 200))	('14-3-3', 'Gene', '10971', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('rat', 'Species', '10116', (194, 197))	('mutation', 'Var', (13, 21))	('HSP90', 'Gene', (272, 277))	('HSP70', 'Gene', '3308', (262, 267))	('neoplastic nodule', 'Phenotype', 'HP:0002664', (291, 308))
923844	33536206	In a mouse model, the therapeutic combination of anti-PD-L1 and anti-TGF-beta1 drugs reduced TGF-beta signaling in stromal cells, facilitated T cell penetration into the tumor parenchyma, and promoted tumor regression.	('anti-PD-L1', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TGF-beta signaling', 'MPA', (93, 111))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('promoted', 'PosReg', (192, 200))	('facilitated', 'PosReg', (130, 141))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (170, 175))	('anti-TGF-beta1', 'Gene', (64, 78))	('mouse', 'Species', '10090', (5, 10))	('tumor', 'Disease', (201, 206))	('reduced', 'NegReg', (85, 92))
923851	33536206	Hence, aberrantly high expression of Ln-gamma2 was significantly related to the attenuated response to anti-PD-1 blockade therapy, which was useful for predicting the unfavorable outcomes of patients with NSCLC or ESCC.	('aberrantly high', 'Var', (7, 22))	('Ln-gamma2', 'Gene', '3918', (37, 46))	('ESCC', 'Disease', (214, 218))	('response', 'MPA', (91, 99))	('patients', 'Species', '9606', (191, 199))	('NSCLC', 'Phenotype', 'HP:0030358', (205, 210))	('attenuated', 'NegReg', (80, 90))	('NSCLC', 'Disease', (205, 210))	('Ln-gamma2', 'Gene', (37, 46))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('expression', 'MPA', (23, 33))
923860	33536206	First, analyses of the Gene Expression Omnibus (GEO) public sequencing data indicated a lower level of the Ln-gamma2 mRNA in anti-PD-1 responders than in progressors with melanoma (GSE79691 and GSE78220) or urothelial cancer (GSE111636) (fig.	('Ln-gamma2', 'Gene', '3918', (107, 116))	('urothelial cancer', 'Disease', 'MESH:D014523', (207, 224))	('Ln-gamma2', 'Gene', (107, 116))	('GSE79691', 'Var', (181, 189))	('GSE78220', 'Var', (194, 202))	('GSE111636', 'Var', (226, 235))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('melanoma', 'Disease', (171, 179))	('level', 'MPA', (94, 99))	('urothelial cancer', 'Disease', (207, 224))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('lower', 'NegReg', (88, 93))
923863	33536206	In addition, high expression of Ln-gamma2 predicts a longer treatment duration in NSCLC or ESCC patients treated with anti-PD-1 drugs than those with low level of Ln-gamma2 (fig.	('Ln-gamma2', 'Gene', '3918', (32, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('high', 'Var', (13, 17))	('ESCC', 'Disease', (91, 95))	('Ln-gamma2', 'Gene', (163, 172))	('patients', 'Species', '9606', (96, 104))	('Ln-gamma2', 'Gene', (32, 41))	('NSCLC', 'Disease', (82, 87))	('Ln-gamma2', 'Gene', '3918', (163, 172))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
923868	33536206	A correlation analysis of the clinicopathological characteristics showed that high Ln-gamma2 expression was significantly associated with tumor differentiation (P = 0.003), adjacent organ invasion (P = 0.047), and the tumor size (P < 0.001) (Fig.	('associated', 'Reg', (122, 132))	('high', 'Var', (78, 82))	('tumor', 'Disease', (138, 143))	('Ln-gamma2', 'Gene', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('adjacent organ invasion', 'CPA', (173, 196))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('expression', 'MPA', (93, 103))	('Ln-gamma2', 'Gene', '3918', (83, 92))	('tumor', 'Disease', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
923872	33536206	Survival analyses based on the results of IHC staining suggested that ESCC patients with high Ln-gamma2 expression had a shorter overall survival than patients with low Ln-gamma2 expression (P = 0.017) (fig.	('Ln-gamma2', 'Gene', '3918', (94, 103))	('patients', 'Species', '9606', (75, 83))	('Ln-gamma2', 'Gene', (94, 103))	('patients', 'Species', '9606', (151, 159))	('high', 'Var', (89, 93))	('shorter', 'NegReg', (121, 128))	('Ln-gamma2', 'Gene', (169, 178))	('overall survival', 'MPA', (129, 145))	('ESCC', 'Disease', (70, 74))	('Ln-gamma2', 'Gene', '3918', (169, 178))
923874	33536206	Together, high Ln-gamma2 promotes NSCLC and ESCC progression.	('NSCLC', 'Disease', (34, 39))	('ESCC', 'Disease', (44, 48))	('promotes', 'PosReg', (25, 33))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('Ln-gamma2', 'Gene', (15, 24))	('high', 'Var', (10, 14))	('Ln-gamma2', 'Gene', '3918', (15, 24))
923879	33536206	IHC staining of A549- or KYSE510-derived xenografted tumors also indicated near coexpression of alpha-SMA and Ln-gamma2 (fig.	('coexpression', 'MPA', (80, 92))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('Ln-gamma2', 'Gene', '3918', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Ln-gamma2', 'Gene', (110, 119))	('alpha-SMA', 'Gene', '58', (96, 105))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('KYSE510-derived', 'Var', (25, 40))	('KYSE510', 'CellLine', 'CVCL:1354', (25, 32))	('tumors', 'Disease', (53, 59))	('A549', 'CellLine', 'CVCL:0023', (16, 20))	('alpha-SMA', 'Gene', (96, 105))
923895	33536206	Silencing TGFBR1 with two small interfering RNAs (siRNAs) blocked the up-regulation of Ln-gamma2 and AP1 activation in tumor cells induced by CAF-derived conditioned media (fig.	('TGFBR1', 'Gene', (10, 16))	('tumor', 'Disease', (119, 124))	('CAF', 'Gene', '8850', (142, 145))	('up-regulation', 'PosReg', (70, 83))	('Ln-gamma2', 'Gene', (87, 96))	('activation', 'PosReg', (105, 115))	('blocked', 'NegReg', (58, 65))	('AP1', 'Gene', '3725', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Ln-gamma2', 'Gene', '3918', (87, 96))	('AP1', 'Gene', (101, 104))	('CAF', 'Gene', (142, 145))	('Silencing', 'Var', (0, 9))	('TGFBR1', 'Gene', '7046', (10, 16))
923918	33536206	C57BL/6 mice were subcutaneously inoculated with the mouse Lewis lung cancer cell line LLC or primary ESCC cell line MEC2 after Ln-gamma2 silencing to explore the therapeutic potential of targeting Ln-gamma2.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('Ln-gamma2', 'Gene', '3918', (128, 137))	('Ln-gamma2', 'Gene', '3918', (198, 207))	('MEC2', 'CellLine', 'CVCL:1871', (117, 121))	('silencing', 'Var', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('Ln-gamma2', 'Gene', (128, 137))	('Ln-gamma2', 'Gene', (198, 207))	('mouse', 'Species', '10090', (53, 58))	('mice', 'Species', '10090', (8, 12))
923941	33536206	As part of the specialized hepatocellular carcinoma (HCC) cancer stem cell niche, Ln-332 leads to chemoresistance and quiescence in HCC by maintaining cell stemness.	('Ln-332', 'Var', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('hepatocellular carcinoma (HCC) cancer', 'Disease', 'MESH:D006528', (27, 64))	('leads to', 'Reg', (89, 97))	('HCC', 'Phenotype', 'HP:0001402', (132, 135))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (27, 51))	('maintaining', 'PosReg', (139, 150))	('quiescence', 'MPA', (118, 128))	('chemoresistance', 'CPA', (98, 113))	('HCC', 'Phenotype', 'HP:0001402', (53, 56))	('cell stemness', 'CPA', (151, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
923947	33536206	In vitro chemotaxis assays revealed the reduced migration of T cells after supplementation of the monomeric Ln-gamma2 chain, which suggested the key role of the Ln-gamma2 in regulating T cell exclusion from the tumor nests.	('Ln-gamma2', 'Gene', (161, 170))	('supplementation', 'Var', (75, 90))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('migration of T cells', 'CPA', (48, 68))	('Ln-gamma2', 'Gene', (108, 117))	('Ln-gamma2', 'Gene', '3918', (161, 170))	('reduced', 'NegReg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('Ln-gamma2', 'Gene', '3918', (108, 117))
923952	33536206	High TCR reads are associated with increased T cell infiltration into the tumor nests, which indicated a shorter survival for patients with lower-grade glioma.	('TCR', 'Gene', '6962', (5, 8))	('increased', 'PosReg', (35, 44))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('increased T cell', 'Phenotype', 'HP:0100828', (35, 51))	('glioma', 'Disease', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TCR', 'Gene', (5, 8))	('tumor', 'Disease', (74, 79))	('patients', 'Species', '9606', (126, 134))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('shorter', 'NegReg', (105, 112))
923964	33536206	However, TGFBR1 blockade has been shown to affect multiple immune-related pathways and the EMT of tumor cells.	('TGFBR1', 'Gene', '7046', (9, 15))	('blockade', 'Var', (16, 24))	('TGFBR1', 'Gene', (9, 15))	('immune-related pathways', 'Pathway', (59, 82))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('affect', 'Reg', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
923966	33536206	Our in vitro and in vivo studies revealed similar effects of galunisertib and anti-TGF-beta1 on T cell infiltration.	('galunisertib', 'Gene', (61, 73))	('T cell infiltration', 'CPA', (96, 115))	('galunisertib', 'Chemical', 'MESH:C557799', (61, 73))	('anti-TGF-beta1', 'Var', (78, 92))
923968	33536206	In addition, aberrantly high expression of the Ln-gamma2 protein determined using IHC staining was significantly related to the attenuated efficacy of anti-PD-1 blockade therapy and predicted the unfavorable outcomes of patients with NSCLC and ESCC in the present study.	('NSCLC', 'Disease', (234, 239))	('predicted', 'Reg', (182, 191))	('efficacy', 'MPA', (139, 147))	('Ln-gamma2', 'Gene', '3918', (47, 56))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('attenuated', 'NegReg', (128, 138))	('high', 'PosReg', (24, 28))	('patients', 'Species', '9606', (220, 228))	('ESCC', 'Disease', (244, 248))	('aberrantly', 'Var', (13, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (234, 239))	('expression', 'MPA', (29, 39))	('Ln-gamma2', 'Gene', (47, 56))
923972	33536206	Moreover, high Ln-gamma2 expression was associated with poor differentiation and adjacent tissue invasion in patients with NSCLC and ESCC.	('poor differentiation', 'CPA', (56, 76))	('NSCLC', 'Disease', (123, 128))	('patients', 'Species', '9606', (109, 117))	('ESCC', 'Disease', (133, 137))	('expression', 'MPA', (25, 35))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('adjacent tissue invasion', 'CPA', (81, 105))	('Ln-gamma2', 'Gene', (15, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('high', 'Var', (10, 14))	('Ln-gamma2', 'Gene', '3918', (15, 24))
924012	33536206	After blocking, the slides were incubated with the primary antibodies to Ln-gamma2 (#ab210959, Abcam; dilution ratio, 1:500), pan-cytokeratin (#ab7753, Abcam; dilution ratio, 1:400), alpha-SMA (#19245, Cell Signaling Technology; dilution ratio, 1:200), CD3 (#ab1669, Abcam; dilution ratio, 1:150 dilution), CD4 (#ab183685, Abcam; dilution ratio, 1:200 dilution), CD8 (#ab217344, Abcam; dilution ratio, 1:200 dilution), EpCAM (#36746, Cell Signaling Technology; dilution ratio, 1:100), p-c-Jun (Ser73) (#3270, Cell Signaling Technology; dilution ratio, 1:800), and p-c-Fos (Ser32) (#5348, Cell Signaling Technology; dilution ratio, 1:200) at 4 C overnight in a moist chamber.	('Ser73', 'Chemical', '-', (494, 499))	('alpha-SMA', 'Gene', '58', (183, 192))	('CD8', 'Gene', (363, 366))	('c-Jun', 'Gene', '3725', (487, 492))	('alpha-SMA', 'Gene', (183, 192))	('CD8', 'Gene', '925', (363, 366))	('EpCAM', 'Gene', '4072', (419, 424))	('Ln-gamma2', 'Gene', (73, 82))	('c-Fos', 'Gene', (566, 571))	('CD4', 'Gene', (307, 310))	('CD4', 'Gene', '920', (307, 310))	('#36746', 'Var', (426, 432))	('c-Jun', 'Gene', (487, 492))	('Ser32', 'Chemical', '-', (573, 578))	('c-Fos', 'Gene', '2353', (566, 571))	('Ln-gamma2', 'Gene', '3918', (73, 82))	('EpCAM', 'Gene', (419, 424))
924018	33536206	Nonspecific binding was blocked with 5% bovine serum albumin for 30 min at 37 C. The slides were incubated with Ln-gamma2 (#ab210959, Abcam; 1:500 dilution) or CD3 (#ab1669, Abcam; 1:150 dilution) antibodies at 4 C overnight in a humidified chamber.	('Ln-gamma2', 'Gene', '3918', (112, 121))	('serum albumin', 'Gene', '213', (47, 60))	('CD3', 'Protein', (160, 163))	('serum albumin', 'Gene', (47, 60))	('#ab210959', 'Var', (123, 132))	('Ln-gamma2', 'Gene', (112, 121))
924033	33536206	The ChIP-qPCR assay was performed according to a standard procedure using the Simple ChIP Enzymatic ChIP Kit (#9003, Cell Signaling Technology) with normal rabbit IgG (#2729, Cell Signaling Technology) and primary antibodies against p-c-Fos (Ser32) (#5348, Cell Signaling Technology) or p-c-Jun (Ser73) (#3270, Cell Signaling Technology).	('c-Fos', 'Gene', (235, 240))	('#5348', 'Var', (250, 255))	('Ser32', 'Chemical', '-', (242, 247))	('Kit', 'Gene', (105, 108))	('c-Jun', 'Gene', (289, 294))	('Ser73', 'Chemical', '-', (296, 301))	('c-Fos', 'Gene', '2353', (235, 240))	('Kit', 'Gene', '3815', (105, 108))	('c-Jun', 'Gene', '3725', (289, 294))
924071	33376396	In one study, the S+RT group had poor survival compared to the SA group (P<0.05).	('SA', 'Gene', '6296', (63, 65))	('survival', 'CPA', (38, 46))	('S+RT', 'Var', (18, 22))	('poor', 'NegReg', (33, 37))
924072	33376396	Wang and colleagues found that S+RT improved not only disease-free survival (DFS) (34.9% vs.11.3%, P <0.001) but also 5-year overall survival (OS) (48.1% vs 30.2%, P=0.007) compared to SA in pT2N0M0 ESCC patients with high Ku80 expression.	('S+RT', 'Var', (31, 35))	('patients', 'Species', '9606', (204, 212))	('Ku80', 'Gene', (223, 227))	('disease-free', 'MPA', (54, 66))	('overall', 'MPA', (125, 132))	('SA', 'Gene', '6296', (185, 187))	('improved', 'PosReg', (36, 44))	('Ku80', 'Gene', '7520', (223, 227))	('OS', 'Gene', '17451', (143, 145))
924073	33376396	Although there was no OS difference in the study of Xiao and colleagues, subgroup analysis showed that S+RT can improve the 5-year OS from 13.1% to 35.1% for patients with stage III ESCC (P=0.027) and from 14.7% to 29.2% for patients with positive lymph nodes (P=0.0698).	('OS', 'Gene', '17451', (131, 133))	('improve', 'PosReg', (112, 119))	('patients', 'Species', '9606', (225, 233))	('ESCC', 'Disease', (182, 186))	('OS', 'Gene', '17451', (22, 24))	('patients', 'Species', '9606', (158, 166))	('S+RT', 'Var', (103, 107))
924074	33376396	In the latest RCT, S+RT improved the 3-year DFS from 58.7% to 75.1% (P=0.03) and decreased the locoregional recurrence rate from 32.5% to 10.0% (P=0.001) in patients with pT2-3N0M0 ESCC.	('decreased', 'NegReg', (81, 90))	('improved', 'PosReg', (24, 32))	('DFS', 'MPA', (44, 47))	('locoregional recurrence rate', 'CPA', (95, 123))	('S+RT', 'Var', (19, 23))	('patients', 'Species', '9606', (157, 165))	('pT2-3N0M0', 'Var', (171, 180))
924079	33376396	A large number of retrospective studies have suggested that S+RT or S+CRT can improve survival for patients with poor prognostic factors, such as node-positive disease, stage III/IV disease, large tumors, and advanced T stage.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('improve', 'PosReg', (78, 85))	('survival', 'MPA', (86, 94))	('node-positive disease', 'Disease', (146, 167))	('CRT', 'Gene', '799', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('S+RT', 'Var', (60, 64))	('patients', 'Species', '9606', (99, 107))	('CRT', 'Gene', (70, 73))	('stage III/IV disease', 'Disease', (169, 189))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('large', 'Disease', (191, 196))	('tumors', 'Disease', (197, 203))
924090	33376396	In the NCCN guidelines, surveillance is recommended for clinical T1-2N0M0 EC patients with negative margins (R0 resection) after radical surgery regardless of the pathological stage (p Any T, Any N) and CRT+S is recommended for patients with resectable clinical T3-4N0M0 or T1-4N+M0 diseases.	('CRT', 'Gene', '799', (203, 206))	('CRT', 'Gene', (203, 206))	('patients', 'Species', '9606', (228, 236))	('EC', 'Phenotype', 'HP:0011459', (74, 76))	('patients', 'Species', '9606', (77, 85))	('T1-2N0M0', 'Var', (65, 73))
924091	33376396	However, there is no recommendation for patients with pathological T3-4N0M0 or T1-4N+M0 diseases who do not receive any preoperative therapies.	('patients', 'Species', '9606', (40, 48))	('T1-4N+M0', 'Var', (79, 87))	('T3-4N0M0', 'Var', (67, 75))
924094	33376396	Therefore, in the latest Guideline of the Chinese Society of Clinical Oncology (CSCO), it is suggested that S+RT or S+CRT may be chosen for patients with node-positive disease in the annotations.	('CRT', 'Gene', '799', (118, 121))	('CRT', 'Gene', (118, 121))	('patients', 'Species', '9606', (140, 148))	('Oncology', 'Phenotype', 'HP:0002664', (70, 78))	('S+RT', 'Var', (108, 112))
924100	33376396	The RTOG 85-01 trial confirmed that combined chemotherapy and radiotherapy increased the survival of patients with T1-3N0-1M0 ESCC compared with radiotherapy alone and chemotherapy or chemoradiotherapy is recommended as the standard neoadjuvant treatment for locally advanced EC.	('patients', 'Species', '9606', (101, 109))	('EC', 'Phenotype', 'HP:0011459', (276, 278))	('T1-3N0-1M0 ESCC', 'Var', (115, 130))	('survival', 'CPA', (89, 97))	('increased', 'PosReg', (75, 84))
924123	33376396	In Fok's study, lesions in the intrathoracic stomach (gastritis, gastric ulcer, bleeding gastric ulcer, penetrating gastric ulcer and fistula to trachea) were found in 34 patients (37%) in the S+RT group and four patients in the SA group (6%) (P<0.001).	('SA', 'Gene', '6296', (229, 231))	('patients', 'Species', '9606', (213, 221))	('gastric ulcer', 'Disease', (65, 78))	('S+RT', 'Var', (193, 197))	('gastric ulcer', 'Disease', 'MESH:D013276', (65, 78))	('gastric ulcer', 'Phenotype', 'HP:0002592', (116, 129))	('patients', 'Species', '9606', (171, 179))	('fistula to trachea', 'Disease', 'MESH:C557675', (134, 152))	('gastritis', 'Phenotype', 'HP:0005263', (54, 63))	('gastric ulcer', 'Disease', 'MESH:D013276', (89, 102))	('bleeding gastric ulcer', 'Disease', 'MESH:D013276', (80, 102))	('gastric ulcer', 'Phenotype', 'HP:0002592', (65, 78))	('fistula to trachea', 'Disease', (134, 152))	('gastritis', 'Disease', 'MESH:D005756', (54, 63))	('gastritis', 'Disease', (54, 63))	('gastric ulcer', 'Phenotype', 'HP:0002592', (89, 102))	('gastric ulcer', 'Disease', (116, 129))	('bleeding gastric ulcer', 'Disease', (80, 102))	('gastric ulcer', 'Disease', 'MESH:D013276', (116, 129))
924127	33376396	In another study, respiratory symptoms in 25 patients, postoperative death in 3 patients and leaks in 11 patients were observed in the S+RT group (42 patients) while respiratory symptoms in 15 patients, postoperative death in 3 patients and leaks in 7 patients were observed in the SA group (39 patients).	('patients', 'Species', '9606', (80, 88))	('postoperative death', 'Disease', (203, 222))	('respiratory symptoms', 'Phenotype', 'HP:0011947', (166, 186))	('postoperative death', 'Disease', 'MESH:D003643', (203, 222))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (45, 53))	('respiratory symptoms', 'Disease', (166, 186))	('SA', 'Gene', '6296', (282, 284))	('respiratory symptoms', 'Disease', 'MESH:D012818', (166, 186))	('patients', 'Species', '9606', (252, 260))	('patients', 'Species', '9606', (228, 236))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (105, 113))	('postoperative death', 'Disease', (55, 74))	('postoperative death', 'Disease', 'MESH:D003643', (55, 74))	('respiratory symptoms', 'Phenotype', 'HP:0011947', (18, 38))	('S+RT', 'Var', (135, 139))	('patients', 'Species', '9606', (295, 303))	('respiratory symptoms', 'Disease', (18, 38))	('respiratory symptoms', 'Disease', 'MESH:D012818', (18, 38))
924154	33125935	These omics-driven approaches have proven quite effective in identifying small molecule inhibitors that are toxic to parasitic nematodes and have multiple applications to anthelmintic research.	('parasitic nematodes', 'Disease', (117, 136))	('parasitic nematodes', 'Disease', 'MESH:D009349', (117, 136))	('small', 'Var', (73, 78))
924159	33125935	The A. suum system provided compelling evidence that NITs can cause tissue damage inclusive of cell death, which is a specific end point with important implications for anthelmintic research.	('NITs', 'Var', (53, 57))	('A. suum', 'Species', '6253', (4, 11))	('NITs', 'Chemical', '-', (53, 57))	('cell death', 'CPA', (95, 105))	('tissue damage', 'CPA', (68, 81))
924191	33125935	Combretastatin A4 (C7744), Sigma-Aldrich, St. Louis MO, binds to tubulin at the colchicine binding site, similar to albendazole, was identified as toxic for A. suum L3 and L4 and was used to compare effects with albendazole in this investigation.	('C7744', 'Var', (19, 24))	('albendazole', 'Chemical', 'MESH:D015766', (212, 223))	('colchicine', 'Chemical', 'MESH:D003078', (80, 90))	('binds', 'Interaction', (56, 61))	('A. suum', 'Species', '6253', (157, 164))	('albendazole', 'Chemical', 'MESH:D015766', (116, 127))	('Combretastatin', 'Chemical', 'MESH:C040105', (0, 14))
924195	33125935	L4 larvae were used for these assays because toxic effects on L3 can induce the larvae ensheathed with deformation (LED) phenotype, which involves molting (days 2-3 in culture) and is associated with other pathologic changes that would confound interpretation of results reflected by PI labeling.	('deformation', 'Disease', 'MESH:D009140', (103, 114))	('toxic effects', 'Var', (45, 58))	('deformation', 'Disease', (103, 114))	('induce', 'PosReg', (69, 75))	('molting', 'CPA', (147, 154))
924254	33125935	As an example, leflunomide consistently caused PI labeling to occur in multiple organs, cells and regions, although with some variation, as did staurosporine.	('staurosporine', 'Chemical', 'MESH:D019311', (144, 157))	('PI labeling', 'MPA', (47, 58))	('leflunomide', 'Var', (15, 26))	('leflunomide', 'Chemical', 'MESH:D000077339', (15, 26))
924255	33125935	In contrast, both alvocidib and CID1067700 effects were more, but not exclusively, restricted to intestinal cells, with CID1067700 producing the most intestinocentric profile.	('CID1067700', 'Var', (120, 130))	('alvocidib', 'Chemical', 'MESH:C077990', (18, 27))	('intestinocentric profile', 'MPA', (150, 174))	('CID1067700', 'Chemical', 'MESH:C000607523', (32, 42))	('CID1067700', 'Chemical', 'MESH:C000607523', (120, 130))
924262	33125935	Leflunomide, staurosporine and CID1067700 were selected because leflunomide and staurosporine cause PI staining in nuclei of cells in all organ systems evaluated, whereas the IC50 for leflunomide is substantially higher than staurosporine, and PI staining conferred by CID1067700 treatment was restricted primarily to the intestine under conditions used here.	('leflunomide', 'Var', (64, 75))	('CID1067700', 'Chemical', 'MESH:C000607523', (31, 41))	('CID1067700', 'Chemical', 'MESH:C000607523', (269, 279))	('leflunomide', 'Chemical', 'MESH:D000077339', (184, 195))	('staurosporine', 'Chemical', 'MESH:D019311', (13, 26))	('Leflunomide', 'Chemical', 'MESH:D000077339', (0, 11))	('staurosporine', 'Chemical', 'MESH:D019311', (80, 93))	('cause', 'Reg', (94, 99))	('leflunomide', 'Chemical', 'MESH:D000077339', (64, 75))	('staurosporine', 'Chemical', 'MESH:D019311', (225, 238))
924315	33125935	Cell targets and pathways disrupted by NITs represent points at which cell death processes can be initiated, and thus can provide information of importance to general anthelmintic strategies.	('NITs', 'Var', (39, 43))	('pathways', 'Pathway', (17, 25))	('NITs', 'Chemical', '-', (39, 43))
924329	33125935	Additionally, at 4 h, UDP glucuronosyltransferase is also upregulated by leflunomide treatment, also resulting in increased UMP production (Fig.	('UMP production', 'MPA', (124, 138))	('leflunomide', 'Chemical', 'MESH:D000077339', (73, 84))	('increased', 'PosReg', (114, 123))	('upregulated', 'PosReg', (58, 69))	('leflunomide', 'Var', (73, 84))	('UDP glucuronosyltransferase', 'Enzyme', (22, 49))	('UMP', 'Chemical', 'MESH:D014542', (124, 127))
924338	33125935	After 2 h, the only significant KEGG pathway enriched among the 74 genes only upregulated by CID1067700 was "cytoskeleton proteins" (P = 0.017), and included three myosin genes, troponin T, a tubulin gene and a plectin gene.	('CID1067700', 'Chemical', 'MESH:C000607523', (93, 103))	('upregulated', 'PosReg', (78, 89))	('CID1067700', 'Var', (93, 103))
924347	33125935	Taken together, these results provide specific information on cell components that are induced by staurosporine and might mediate the terminal cell death process.	('staurosporine', 'Chemical', 'MESH:D019311', (98, 111))	('staurosporine', 'Var', (98, 111))	('induced', 'Reg', (87, 94))
924361	33125935	In contrast, CID1067700 and alvocidib produced more intestinocentric labeling, which may indicate inhibition of target/pathways preferentially expressed in intestinal cells, or a greater sensitivity of intestinal cells once inhibition is achieved.	('alvocidib', 'Chemical', 'MESH:C077990', (28, 37))	('intestinocentric labeling', 'MPA', (52, 77))	('CID1067700', 'Var', (13, 23))	('CID1067700', 'Chemical', 'MESH:C000607523', (13, 23))
924379	33125935	CID1067700 is a RAB GTPase inhibitor, and gene responses to this treatment differed from that of leflunomide, demonstrating specificity, and included cytoskeletal components that may reflect disruption of vesicular transport pathways.	('included', 'Reg', (141, 149))	('leflunomide', 'Chemical', 'MESH:D000077339', (97, 108))	('CID1067700', 'Var', (0, 10))	('CID1067700', 'Chemical', 'MESH:C000607523', (0, 10))
924389	33125935	Because inhibitors of stress response proteins can enhance effects of anthelmintics, including parasitic nematodes, it will be of interest to determine if this gene response is common to other toxic perturbations in A. suum and other parasitic nematodes.	('parasitic nematodes', 'Disease', 'MESH:D009349', (234, 253))	('A. suum', 'Species', '6253', (216, 223))	('parasitic nematodes', 'Disease', (95, 114))	('enhance', 'PosReg', (51, 58))	('effects', 'MPA', (59, 66))	('parasitic nematodes', 'Disease', (234, 253))	('parasitic nematodes', 'Disease', 'MESH:D009349', (95, 114))	('inhibitors', 'Var', (8, 18))
924428	32103990	Exclusion criteria were conducted if any one of the following conditions was met: (1) history of other malignancies; (2) ESCC with T4b, M1 or recurrence; (3) preoperative radiotherapy or chemotherapy; Overall survival (OS) was defined as the interval between surgery and death or last observation.	('ESCC', 'Disease', 'MESH:C562729', (121, 125))	('death', 'Disease', 'MESH:D003643', (271, 276))	('death', 'Disease', (271, 276))	('ESCC', 'Disease', (121, 125))	('T4b', 'Var', (131, 134))
924458	32103990	By Kaplan-Meier analysis, overall survival (OS) was obviously more favorable in high expression of Id-4 than those with low expression (mean, 62.2 versus 46.2 months; median, 75.6 versus 44.3 months; p=0.007; Figure 4A).	('Id-4', 'Gene', '3400', (99, 103))	('Id-4', 'Gene', (99, 103))	('favorable', 'PosReg', (67, 76))	('overall', 'MPA', (26, 33))	('high expression', 'Var', (80, 95))
924463	32103990	The results of qRT-PCR and Western blotting showed that Id-4 protein level was increased significantly after transfection (Figure 5A and B).	('Id-4', 'Gene', '3400', (56, 60))	('Id-4', 'Gene', (56, 60))	('increased', 'PosReg', (79, 88))	('transfection', 'Var', (109, 121))
924473	32103990	However, Id-4 has been deemed as a tumor suppressor because it is epigenetically silenced in various cancers, such as cancer of prostate, breast, stomach, colorectum, and the hematopoietic and lymphoid tissues, as reported.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('stomach', 'Disease', (146, 153))	('cancers', 'Disease', (101, 108))	('cancer of prostate', 'Disease', (118, 136))	('breast', 'Disease', (138, 144))	('colorectum', 'Disease', (155, 165))	('tumor', 'Disease', (35, 40))	('cancer of prostate', 'Disease', 'MESH:D011471', (118, 136))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('epigenetically', 'Var', (66, 80))	('cancer of prostate', 'Phenotype', 'HP:0012125', (118, 136))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Id-4', 'Gene', '3400', (9, 13))	('Id-4', 'Gene', (9, 13))
924474	32103990	Vitro studies have also demonstrated that ectopic Id-4 expression could inhibit proliferation, promote senescence, apoptosis and sensitivity to chemotherapeutic drugs.	('Id-4', 'Gene', (50, 54))	('sensitivity', 'CPA', (129, 140))	('promote', 'PosReg', (95, 102))	('proliferation', 'CPA', (80, 93))	('ectopic', 'Var', (42, 49))	('senescence', 'CPA', (103, 113))	('inhibit', 'NegReg', (72, 79))	('Id-4', 'Gene', '3400', (50, 54))	('apoptosis', 'CPA', (115, 124))
924477	32103990	Aberrant promoter methylation of Id-4 followed by the decreased expression of Id-4 is one of the potential molecular mechanisms, which has been confirmed in prostate cancer, breast cancer, lung cancer, colorectal cancer, and lymphocytic leukemia.	('Id-4', 'Gene', (33, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('colorectal cancer', 'Disease', (202, 219))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (225, 245))	('Id-4', 'Gene', '3400', (33, 37))	('Id-4', 'Gene', (78, 82))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('Aberrant', 'Var', (0, 8))	('breast cancer', 'Disease', (174, 187))	('leukemia', 'Phenotype', 'HP:0001909', (237, 245))	('promoter methylation', 'MPA', (9, 29))	('lung cancer', 'Disease', (189, 200))	('decreased', 'NegReg', (54, 63))	('Id-4', 'Gene', '3400', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('expression', 'MPA', (64, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('lymphocytic leukemia', 'Disease', (225, 245))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('prostate cancer', 'Disease', (157, 172))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))
924503	30705941	Stricture formation causes patients to suffer from severe symptoms, such as dysphagia, vomiting, and weight loss.	('Stricture', 'Var', (0, 9))	('dysphagia', 'Disease', (76, 85))	('dysphagia', 'Disease', 'MESH:D003680', (76, 85))	('patient', 'Species', '9606', (27, 34))	('weight loss', 'Disease', 'MESH:D015431', (101, 112))	('patients', 'Species', '9606', (27, 35))	('dysphagia', 'Phenotype', 'HP:0002015', (76, 85))	('vomiting', 'Phenotype', 'HP:0002013', (87, 95))	('weight loss', 'Disease', (101, 112))	('vomiting', 'Disease', (87, 95))	('vomiting', 'Disease', 'MESH:D014839', (87, 95))	('weight loss', 'Phenotype', 'HP:0001824', (101, 112))
924504	30705941	The occurrence of post-ESD stricture has been associated with mucosal defects to more than three-quarters of the total circumferential area    , and its incidence has been reported to be greater than 70 %     .	('mucosal defects', 'Disease', 'MESH:D052016', (62, 77))	('mucosal defects', 'Disease', (62, 77))	('associated', 'Reg', (46, 56))	('post-ESD', 'Var', (18, 26))	('stricture', 'Disease', (27, 36))
924604	28454086	Association between genetic variants and esophageal cancer risk We investigated whether single nucleotide polymorphisms (SNPs) in the nuclear assembly factor 1 (NAF1) and TNFAIP3-interacting protein 1 (TNIP1) gene were associated with susceptibility to esophageal cancer in a Chinese Han population.	('NAF1', 'Gene', (161, 165))	('susceptibility', 'Reg', (235, 249))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('associated', 'Reg', (219, 229))	('TNIP1', 'Gene', '10318', (202, 207))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('TNFAIP3-interacting protein 1', 'Gene', '10318', (171, 200))	('NAF1', 'Gene', '92345', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('esophageal cancer', 'Disease', 'MESH:D004938', (253, 270))	('TNFAIP3-interacting protein 1', 'Gene', (171, 200))	('esophageal cancer', 'Disease', (253, 270))	('single nucleotide polymorphisms', 'Var', (88, 119))	('Association', 'Interaction', (0, 11))	('TNIP1', 'Gene', (202, 207))	('esophageal cancer', 'Disease', (41, 58))
924606	28454086	Patients with the AG genotype of rs2320615 were at lower risk of developing esophageal cancer than those with the GG genotype (adjusted odds ratio [OR] = 0.64, 95% confidence interval [CI] = 0.46-0.90, P = 0.009).	('rs2320615', 'Var', (33, 42))	('esophageal cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lower', 'NegReg', (51, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('Patients', 'Species', '9606', (0, 8))	('rs2320615', 'Mutation', 'rs2320615', (33, 42))
924607	28454086	The rs2320615 SNP was found to be associated with a decreased the risk of esophageal cancer in the dominant model (adjusted OR = 0.70, 95% CI = 0.51-0.96, P = 0.026).	('decreased', 'NegReg', (52, 61))	('rs2320615', 'Mutation', 'rs2320615', (4, 13))	('rs2320615', 'Var', (4, 13))	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
924608	28454086	These results provide the first evidence that the rs2320615 in NAF1 was associated with reduced risk of esophageal cancer.	('NAF1', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('NAF1', 'Gene', '92345', (63, 67))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('rs2320615', 'Mutation', 'rs2320615', (50, 59))	('reduced', 'NegReg', (88, 95))	('rs2320615', 'Var', (50, 59))
924615	28454086	In addition, a genome-wide meta-analysis found that one SNP (rs7675998) in NAF1 was associated with telomere length (P = 4.35x10-16).	('associated with', 'Reg', (84, 99))	('NAF1', 'Gene', (75, 79))	('rs7675998', 'Mutation', 'rs7675998', (61, 70))	('NAF1', 'Gene', '92345', (75, 79))	('telomere length', 'CPA', (100, 115))	('rs7675998', 'Var', (61, 70))
924616	28454086	Rs2320615 was reported to be the best surrogates for rs7675998 (pairwise r2 = 0.89) and which was found to be associated with longer TL (P-trend = 3.3x10-4).	('rs7675998', 'Mutation', 'rs7675998', (53, 62))	('Rs2320615', 'Mutation', 'Rs2320615', (0, 9))	('longer', 'PosReg', (126, 132))	('Rs2320615', 'Var', (0, 9))	('rs7675998', 'Var', (53, 62))
924617	28454086	Interestingly, short telomere lengths have been associated with esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (64, 89))	('short telomere lengths', 'Var', (15, 37))	('associated', 'Reg', (48, 58))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (64, 89))	('short telomere lengths', 'Phenotype', 'HP:0031413', (15, 37))
924622	28454086	Given the importance of telomere length and the NF-kappaB signaling pathway in the development and maintenance of esophageal cancer, we hypothesized genetic polymorphisms in NAF1 and TNIP1 may influence esophageal cancer susceptibility.	('TNIP1', 'Gene', (183, 188))	('NAF1', 'Gene', (174, 178))	('influence', 'Reg', (193, 202))	('polymorphisms', 'Var', (157, 170))	('esophageal cancer', 'Disease', (203, 220))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('NAF1', 'Gene', '92345', (174, 178))	('NF-kappaB', 'Gene', '4790', (48, 57))	('esophageal cancer', 'Disease', 'MESH:D004938', (203, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('TNIP1', 'Gene', '10318', (183, 188))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('NF-kappaB', 'Gene', (48, 57))
924625	28454086	The five SNPs (rs2320615, rs3792792, rs4958881, rs7708392, and rs10036748) were successfully genotyped in the esophageal cancer cases and healthy controls.	('rs2320615', 'Var', (15, 24))	('rs7708392', 'Var', (48, 57))	('rs10036748', 'Var', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('rs4958881', 'Var', (37, 46))	('rs10036748', 'Mutation', 'rs10036748', (63, 73))	('esophageal cancer', 'Disease', (110, 127))	('rs4958881', 'Mutation', 'rs4958881', (37, 46))	('rs7708392', 'Mutation', 'rs7708392', (48, 57))	('rs3792792', 'Var', (26, 35))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('rs3792792', 'Mutation', 'rs3792792', (26, 35))	('rs2320615', 'Mutation', 'rs2320615', (15, 24))
924628	28454086	The AG genotype of rs2320615 was associated with significantly lower risk of esophageal cancer than the GG genotype, both before and after adjustment for age and gender (OR = 0.67, 95% CI: 0.50-0.90, P = 0.008; adjusted OR = 0.64, 95% CI: 0.46-0.90, P = 0.009, respectively).	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('rs2320615', 'Var', (19, 28))	('lower', 'NegReg', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('rs2320615', 'Mutation', 'rs2320615', (19, 28))
924629	28454086	Furthermore, the SNP (rs2320615) was significantly associated with esophageal cancer risk under the dominant model after adjustment for age and gender (adjusted OR = 0.70, 95% CI: 0.51-0.96, P = 0.026).	('rs2320615', 'Mutation', 'rs2320615', (22, 31))	('rs2320615', 'Var', (22, 31))	('associated with', 'Reg', (51, 66))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))
924630	28454086	However, no significant association was found between TNIP1 polymorphisms and esophageal cancer risk.	('polymorphisms', 'Var', (60, 73))	('TNIP1', 'Gene', (54, 59))	('TNIP1', 'Gene', '10318', (54, 59))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
924631	28454086	As shown in Figure 1, we conducted linkage disequilibrium analysis for the four SNPs, and one linkage disequilibrium block consisted of two SNPs (rs7708392 and rs10036748) which exhibited statistically significant linkage (r2 = 0.98).	('rs7708392', 'Var', (146, 155))	('rs10036748', 'Mutation', 'rs10036748', (160, 170))	('rs10036748', 'Var', (160, 170))	('rs7708392', 'Mutation', 'rs7708392', (146, 155))
924632	28454086	This case-control study was designed to investigate whether genetic variants of NAF1 and TNIP1 were associated with the risk of esophageal cancer in the Han Chinese population.	('genetic variants', 'Var', (60, 76))	('esophageal cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('associated', 'Reg', (100, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('TNIP1', 'Gene', (89, 94))	('NAF1', 'Gene', (80, 84))	('NAF1', 'Gene', '92345', (80, 84))	('TNIP1', 'Gene', '10318', (89, 94))
924633	28454086	Our data demonstrated that the rs2320615 in NAF1 was associated with significantly reduced risk of esophageal cancer.	('NAF1', 'Gene', '92345', (44, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('reduced', 'NegReg', (83, 90))	('rs2320615', 'Mutation', 'rs2320615', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rs2320615', 'Var', (31, 40))	('NAF1', 'Gene', (44, 48))	('esophageal cancer', 'Disease', (99, 116))
924635	28454086	This chaperone protein is involved in the formation and activity of telomerase, and a previous study indicated that NAF1 polymorphism (rs7675998) is associated with mean telomere length.	('NAF1', 'Gene', (116, 120))	('rs7675998', 'Var', (135, 144))	('rs7675998', 'Mutation', 'rs7675998', (135, 144))	('mean telomere', 'MPA', (165, 178))	('NAF1', 'Gene', '92345', (116, 120))	('associated', 'Reg', (149, 159))	('polymorphism (rs7675998', 'Var', (121, 144))
924636	28454086	Interestingly, short leukocyte telomere lengths are associated with significantly increased risk of developing esophageal cancer.	('short', 'Var', (15, 20))	('esophageal cancer', 'Disease', (111, 128))	('short leukocyte telomere lengths', 'Phenotype', 'HP:0031413', (15, 47))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
924637	28454086	Our results suggested that NAF1 polymorphisms are associated with the risk of esophageal cancer.	('polymorphisms', 'Var', (32, 45))	('NAF1', 'Gene', (27, 31))	('NAF1', 'Gene', '92345', (27, 31))	('associated', 'Reg', (50, 60))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
924638	28454086	However, it remains unclear whether these NAF1 polymorphisms affect telomere length by affecting specific protein synthesis and function, and ultimately the susceptibility to esophageal cancer.	('esophageal cancer', 'Disease', (175, 192))	('specific protein synthesis', 'MPA', (97, 123))	('polymorphisms', 'Var', (47, 60))	('NAF1', 'Gene', (42, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('telomere', 'MPA', (68, 76))	('function', 'MPA', (128, 136))	('affect', 'Reg', (61, 67))	('affecting', 'Reg', (87, 96))	('NAF1', 'Gene', '92345', (42, 46))
924639	28454086	Our results demonstrated that the genotype AG of rs2320615 in NAF1 was associated with a significantly reduced risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('reduced', 'NegReg', (103, 110))	('NAF1', 'Gene', (62, 66))	('rs2320615', 'Mutation', 'rs2320615', (49, 58))	('NAF1', 'Gene', '92345', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('rs2320615', 'Var', (49, 58))	('esophageal cancer', 'Disease', (119, 136))
924640	28454086	A study found that the rs2320615 is associated with longer telomere length.	('longer telomere length', 'CPA', (52, 74))	('rs2320615', 'Mutation', 'rs2320615', (23, 32))	('rs2320615', 'Var', (23, 32))
924642	28454086	It is possible that polymorphisms can affect the expression of genes and thus render individuals susceptible to esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('render', 'Reg', (78, 84))	('polymorphisms', 'Var', (20, 33))	('expression of', 'MPA', (49, 62))	('esophageal cancer', 'Disease', (112, 129))	('affect', 'Reg', (38, 44))	('genes', 'Protein', (63, 68))	('susceptible', 'Reg', (97, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
924643	28454086	Two recent GWASs revealed that rs7708392 and rs10036748 were associated with the risk of systemic lupus erythematosus.	('rs7708392', 'Mutation', 'rs7708392', (31, 40))	('rs7708392', 'Var', (31, 40))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (89, 117))	('rs10036748', 'Var', (45, 55))	('rs10036748', 'Mutation', 'rs10036748', (45, 55))	('systemic lupus erythematosus', 'Disease', (89, 117))	('associated', 'Reg', (61, 71))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (89, 117))
924644	28454086	A previous report also indicated that the G allele of rs7708392 and the C allele of rs10036748 were associated with increased risk of gastric carcinoma, and that the haplotype CT (rs7708392-rs10036748) was associated with a reduced risk of gastric carcinoma.	('rs7708392', 'Mutation', 'rs7708392', (180, 189))	('rs7708392', 'Mutation', 'rs7708392', (54, 63))	('gastric carcinoma', 'Disease', 'MESH:D013274', (240, 257))	('rs7708392', 'Var', (54, 63))	('gastric carcinoma', 'Disease', (134, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('rs10036748', 'Mutation', 'rs10036748', (190, 200))	('rs10036748', 'Var', (84, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('gastric carcinoma', 'Disease', (240, 257))	('rs10036748', 'Mutation', 'rs10036748', (84, 94))	('rs7708392-rs10036748', 'Var', (180, 200))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (134, 151))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (240, 257))	('gastric carcinoma', 'Disease', 'MESH:D013274', (134, 151))
924645	28454086	In addition, a significantly decreased association was found between the allele T of rs10036748 and asthma risk.	('rs10036748', 'Mutation', 'rs10036748', (85, 95))	('rs10036748', 'Var', (85, 95))	('asthma', 'Disease', 'MESH:D001249', (100, 106))	('asthma', 'Disease', (100, 106))	('asthma', 'Phenotype', 'HP:0002099', (100, 106))	('decreased', 'NegReg', (29, 38))	('association', 'Interaction', (39, 50))
924652	28454086	In conclusion, the current study has identified that rs2320615 in the NAF1 was associated with the risk of esophageal cancer in the Han Chinese population.	('associated', 'Reg', (79, 89))	('rs2320615', 'Var', (53, 62))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('NAF1', 'Gene', (70, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('NAF1', 'Gene', '92345', (70, 74))	('rs2320615', 'Mutation', 'rs2320615', (53, 62))
924659	28454086	Five SNPs (rs2320615, rs3792792, rs4958881, rs7708392 and rs10036748) with had minor allele frequency > 5% in the HapMap of the Chinese Han Beijing population that have been reported to be associated with the risk of several diseases and cancers, including systemic lupus erythematosus, systemic sclerosis, asthma, and gastric carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (327, 336))	('gastric carcinoma', 'Disease', 'MESH:D013274', (319, 336))	('rs10036748', 'Var', (58, 68))	('systemic sclerosis', 'Disease', (287, 305))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (257, 285))	('asthma', 'Disease', 'MESH:D001249', (307, 313))	('gastric carcinoma', 'Disease', (319, 336))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (257, 285))	('asthma', 'Phenotype', 'HP:0002099', (307, 313))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (319, 336))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('cancers', 'Disease', (238, 245))	('asthma', 'Disease', (307, 313))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('rs2320615', 'Var', (11, 20))	('associated', 'Reg', (189, 199))	('rs2320615', 'Mutation', 'rs2320615', (11, 20))	('rs7708392', 'Mutation', 'rs7708392', (44, 53))	('rs3792792', 'Mutation', 'rs3792792', (22, 31))	('systemic sclerosis', 'Disease', 'MESH:D012595', (287, 305))	('systemic lupus erythematosus', 'Disease', (257, 285))	('cancers', 'Disease', 'MESH:D009369', (238, 245))	('rs4958881', 'Var', (33, 42))	('rs10036748', 'Mutation', 'rs10036748', (58, 68))	('rs4958881', 'Mutation', 'rs4958881', (33, 42))	('rs7708392', 'Var', (44, 53))	('rs3792792', 'Var', (22, 31))
924679	28415738	This report evaluates the therapeutic effect of cetuximab (anti-EGFR) and trastuzumab (anti-HER2) targeted NIR-tPDT in Esophageal adenocarcinoma in vitro and, as a first, describes modulation of the EGFR and HER2 receptors with use of TKIs, as a tool to enhance the therapeutic effect and applicability of NIR-tPDT.	('HER2', 'Gene', (208, 212))	('cetuximab', 'Chemical', 'MESH:D000068818', (48, 57))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (119, 144))	('EGFR', 'Gene', (199, 203))	('enhance', 'PosReg', (254, 261))	('HER2', 'Gene', '2064', (208, 212))	('tPDT', 'Chemical', '-', (111, 115))	('HER2', 'Gene', '2064', (92, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('HER2', 'Gene', (92, 96))	('tPDT', 'Chemical', '-', (310, 314))	('trastuzumab', 'Chemical', 'MESH:D000068878', (74, 85))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('Esophageal adenocarcinoma', 'Disease', (119, 144))	('modulation', 'Var', (181, 191))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (119, 144))	('EGFR', 'Gene', '1956', (199, 203))
924691	28415738	In addition, adding 133nM unbound IRDye700DX, which is equivalent to the dye present in a conjugate dose of 10 mug/ml, showed only a minor nonsignificant increase in cytotoxicity upon irradiation compared to the untreated cells (+2%, P = 0.350; Supplementary Figure 2B).	('cytotoxicity', 'Disease', 'MESH:D064420', (166, 178))	('IRDye700DX', 'Var', (34, 44))	('cytotoxicity', 'Disease', (166, 178))
924698	28415738	The microscopic images presented in Supplementary Figure 3B demonstrate the effect of NIR-tPDT in the EAC cell lines; already after one hour following NIR-tPDT, both cell lines appeared to have a uniform orange/red colored nucleus, indicating rapid necrotic cell death.	('necrotic cell death', 'Disease', (249, 268))	('tPDT', 'Chemical', '-', (90, 94))	('tPDT', 'Chemical', '-', (155, 159))	('NIR-tPDT', 'Var', (151, 159))	('necrotic cell death', 'Disease', 'MESH:D003643', (249, 268))
924703	28415738	After doing so, receptor modulation still resulted in significant additional cell death when treated subsequently with NIR-tPDT (trastuzumab: 5 J/cm2 +24% P = 0.032, 10 J/cm2+24% P = 0.013; cetuximab: 10 J/cm2 36% P = 0.012, 20 J/cm2 39% P = 0.026; Figure 4B).	('trastuzumab', 'Chemical', 'MESH:D000068878', (129, 140))	('cell death', 'CPA', (77, 87))	('modulation', 'Var', (25, 35))	('cetuximab', 'Chemical', 'MESH:D000068818', (190, 199))	('tPDT', 'Chemical', '-', (123, 127))
924707	28415738	As such, we can conclude that NIR-tPDT seems a promising treatment option for esophageal adenocarcinoma and that TKI pretreatment is able to optimize the therapeutic effect of this novel cancer-selective treatment, making it interesting for future clinical translation.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tPDT', 'Chemical', '-', (34, 38))	('esophageal adenocarcinoma', 'Disease', (78, 103))	('cancer', 'Disease', (187, 193))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (78, 103))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (78, 103))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('NIR-tPDT', 'Var', (30, 38))
924715	28415738	For instance, NIR-tPDT following an irradical (incomplete) endoscopic mucosal resection might help to prevent highly invasive esophagectomy.	('tPDT', 'Chemical', '-', (18, 22))	('NIR-tPDT', 'Var', (14, 22))	('highly invasive esophagectomy', 'Disease', (110, 139))
924718	28415738	The receptor expression results show that OE33 is a high expressing EGFR and HER2 cell line, which is in concordance with previous literature.	('HER2', 'Gene', (77, 81))	('HER2', 'Gene', '2064', (77, 81))	('EGFR', 'Gene', '1956', (68, 72))	('OE33', 'Var', (42, 46))	('EGFR', 'Gene', (68, 72))
924722	28415738	NIR-tPDT is thought to be a cancer-selective therapy with minimal damage to surrounding healthy tissue.	('tPDT', 'Chemical', '-', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('NIR-tPDT', 'Var', (0, 8))	('cancer', 'Disease', (28, 34))
924725	28415738	Previously, it was already demonstrated that EGFR targeted NIR-tPDT was only successful in EGFR positive cells by using a mixed tumor model that contained both receptor positive and negative cells.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', (45, 49))	('tPDT', 'Chemical', '-', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('NIR-tPDT', 'Var', (59, 67))	('EGFR', 'Gene', '1956', (91, 95))	('EGFR', 'Gene', '1956', (45, 49))
924726	28415738	Our results meet this assumption, since NIR-tPDT showed a higher cell kill in the OE33 cells compared to FLO-1; the baseline EGFR and HER2 receptor expression of the OE33 cells is considerably higher than that of the FLO-1 cells, implying its receptor selectivity.	('OE33', 'Var', (166, 170))	('tPDT', 'Chemical', '-', (44, 48))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (125, 129))	('HER2', 'Gene', (134, 138))	('cell kill', 'CPA', (65, 74))	('expression', 'MPA', (148, 158))	('HER2', 'Gene', '2064', (134, 138))	('higher', 'PosReg', (193, 199))
924730	28415738	They employed virus mediated HER2 transduction in negative HER2 expressing breast cancer cells, with which they concluded that NIR-tPDT resulted in effectively and selectively killing of the HER2-transducted cells in vitro.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('HER2', 'Gene', (191, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('HER2', 'Gene', (29, 33))	('HER2', 'Gene', '2064', (191, 195))	('HER2', 'Gene', '2064', (29, 33))	('tPDT', 'Chemical', '-', (131, 135))	('NIR-tPDT', 'Var', (127, 135))	('HER2', 'Gene', (59, 63))	('HER2', 'Gene', '2064', (59, 63))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
924732	28415738	For the EAC cell lines used in our study, OE33 and FLO-1, no previous literature on TKI responsiveness was yet available; as such, we are the first to demonstrate that TKI administration is indeed able to significantly upregulate EGFR and HER2 receptor expression in EAC cells.	('EGFR', 'Gene', '1956', (230, 234))	('EGFR', 'Gene', (230, 234))	('expression', 'MPA', (253, 263))	('TKI', 'Var', (168, 171))	('HER2', 'Gene', (239, 243))	('HER2', 'Gene', '2064', (239, 243))	('upregulate', 'PosReg', (219, 229))
924733	28415738	More importantly, our results demonstrate that EAC cells, which already express the receptor to some extent, will gain additive effect from NIR-tPDT treatment after receptor modulation.	('NIR-tPDT', 'Var', (140, 148))	('gain', 'PosReg', (114, 118))	('tPDT', 'Chemical', '-', (144, 148))	('additive', 'MPA', (119, 127))
924736	28415738	In addition, we demonstrated that pretreatment with the TKIs erlotinib and lapatinib induces significant growth receptor upregulation.	('growth receptor', 'CPA', (105, 120))	('upregulation', 'PosReg', (121, 133))	('erlotinib', 'Chemical', 'MESH:D000069347', (61, 70))	('TKIs', 'Var', (56, 60))	('lapatinib', 'Chemical', 'MESH:D000077341', (75, 84))
924858	27885434	Conversely, a trend towards a longer OS was observed in EC patients with high miR-375 expression, and patients with low miR-375 expression had worse outcomes (Fig.	('EC', 'Chemical', '-', (56, 58))	('patients', 'Species', '9606', (102, 110))	('miR-375', 'Gene', '494324', (78, 85))	('miR-375', 'Gene', '494324', (120, 127))	('OS', 'Chemical', '-', (37, 39))	('patients', 'Species', '9606', (59, 67))	('miR-375', 'Gene', (78, 85))	('high', 'Var', (73, 77))	('miR-375', 'Gene', (120, 127))
924860	27885434	We then compared survival between (a) patients with high miR-375 expression and low miR-21 expression and patients with either (b) high miR-21 expression or (c) low miR-375 expression.	('expression', 'MPA', (91, 101))	('low', 'NegReg', (80, 83))	('miR-375', 'Gene', (165, 172))	('miR-375', 'Gene', '494324', (57, 64))	('miR-21', 'Gene', '406991', (84, 90))	('patients', 'Species', '9606', (38, 46))	('miR-21', 'Gene', (84, 90))	('expression', 'MPA', (65, 75))	('high', 'Var', (52, 56))	('miR-375', 'Gene', '494324', (165, 172))	('miR-21', 'Gene', '406991', (136, 142))	('miR-375', 'Gene', (57, 64))	('patients', 'Species', '9606', (106, 114))	('miR-21', 'Gene', (136, 142))
924926	27885434	Both the univariate analysis and the multivariate analysis demonstrated that there was a trend towards increased survival in patients with high levels of miR-375 (HR 0.47, 95% CI 0.26-0.87).	('survival', 'CPA', (113, 121))	('increased', 'PosReg', (103, 112))	('miR-375', 'Gene', '494324', (154, 161))	('high levels', 'Var', (139, 150))	('miR-375', 'Gene', (154, 161))	('rat', 'Species', '10116', (66, 69))	('patients', 'Species', '9606', (125, 133))
924927	27885434	A meta-analysis based on data from studies of Asian populations was performed, and we found that a low level of miR-375 was significantly associated with a worse prognosis (HR 0.56; 95% CI 0.43-0.73).	('miR-375', 'Gene', '494324', (112, 119))	('low level', 'Var', (99, 108))	('miR-375', 'Gene', (112, 119))
924932	27885434	In addition, we found it interesting that the patients with high levels of miR-21 were more likely to have low expression levels of miR-375.	('patients', 'Species', '9606', (46, 54))	('miR-375', 'Gene', '494324', (132, 139))	('miR-375', 'Gene', (132, 139))	('miR-21', 'Gene', '406991', (75, 81))	('low expression levels', 'MPA', (107, 128))	('high levels', 'Var', (60, 71))	('miR-21', 'Gene', (75, 81))
924933	27885434	To further verify the prognostic value of miR-21 and miR-375, survival was analyzed in patients with both high miR-375 expression and low miR-21 expression, and the results were compared to survival in patients with either high miR-21 expression or low miR-375 expression.	('expression', 'MPA', (119, 129))	('miR-375', 'Gene', '494324', (253, 260))	('miR-21', 'Gene', '406991', (138, 144))	('miR-21', 'Gene', (42, 48))	('miR-21', 'Gene', '406991', (228, 234))	('high', 'Var', (106, 110))	('miR-375', 'Gene', (111, 118))	('miR-375', 'Gene', (53, 60))	('miR-21', 'Gene', (138, 144))	('miR-21', 'Gene', (228, 234))	('expression', 'MPA', (145, 155))	('low', 'NegReg', (134, 137))	('miR-375', 'Gene', (253, 260))	('miR-21', 'Gene', '406991', (42, 48))	('patients', 'Species', '9606', (202, 210))	('patients', 'Species', '9606', (87, 95))	('miR-375', 'Gene', '494324', (111, 118))	('miR-375', 'Gene', '494324', (53, 60))
924934	27885434	We found that the patients with both high miR-375 expression and low miR-21 expression had significantly better outcomes.	('better', 'PosReg', (105, 111))	('miR-375', 'Gene', (42, 49))	('high', 'Var', (37, 41))	('miR-21', 'Gene', (69, 75))	('low', 'NegReg', (65, 68))	('patients', 'Species', '9606', (18, 26))	('miR-375', 'Gene', '494324', (42, 49))	('miR-21', 'Gene', '406991', (69, 75))
925057	24829610	The risk of nodal disease in pT1a (intra-mucosal) lesions has been shown in most studies to be less than 5%, compared to 12 to 37% in pT1b (submucosal) lesions .	('intra-mucosal', 'Disease', (35, 48))	('pT1a', 'Var', (29, 33))	('nodal disease', 'Disease', 'MESH:D013611', (12, 25))	('intra-mucosal', 'Disease', 'MESH:D052016', (35, 48))	('nodal disease', 'Disease', (12, 25))
925065	24829610	It appears that, at present, pT1a esophageal cancer can be treated quite safely with EMR alone, however pT1b cancers warrant a more invasive esophagectomy and lymphadenectomy until we can improve on current preoperative investigations .	('esophageal cancer', 'Disease', (34, 51))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('pT1b', 'Var', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
925070	24829610	At the current time however, isolated tumor cells (ITCs), are still considered pN0 disease even though a New England Journal of Medicine paper, published in 2009, found that patients with favorable early-stage breast cancer and either micrometastases or ITCs in regional lymph nodes had a reduced 5-year rate of disease-free survival .	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('metastases', 'Disease', (240, 250))	('disease-free survival', 'CPA', (312, 333))	('reduced', 'NegReg', (289, 296))	('ITCs', 'Var', (254, 258))	('metastases', 'Disease', 'MESH:D009362', (240, 250))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('breast cancer', 'Disease', (210, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
925071	24829610	In esophageal cancer, even in patients with pT1N0M0 disease, micrometastases are associated with a significant negative impact on survival .	('metastases', 'Disease', (66, 76))	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('pT1N0M0', 'Var', (44, 51))	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('patients', 'Species', '9606', (30, 38))	('negative', 'NegReg', (111, 119))	('survival', 'MPA', (130, 138))
925118	23646150	The proliferation inhibition rate increased from 6.21% to 49.86%, whereas the apoptosis rate increased from 9.3% to 48.1% when HCCC-9810 cells were cultured with 50% hUC-MSC conditioned media for 24 h. Immunoblot analysis showed that the expression of phosphor-PDK1 (Ser241), phosphor-Akt (Ser 437 and Thr308), phosphorylated glycogen synthase kinase 3beta (phospho-GSK-3betaSer9), beta-catenin, cyclin-D1, and c-myc were down-regulated.	('Akt', 'Gene', (285, 288))	('beta-catenin', 'Gene', (382, 394))	('down-regulated', 'NegReg', (422, 436))	('beta-catenin', 'Gene', '1499', (382, 394))	('Akt', 'Gene', '207', (285, 288))	('Ser', 'Chemical', 'MESH:D012694', (290, 293))	('PDK1', 'Gene', (261, 265))	('Ser', 'Chemical', 'MESH:D012694', (267, 270))	('Thr308', 'Var', (302, 308))	('c-myc', 'Gene', (411, 416))	('Ser', 'Chemical', 'MESH:D012694', (375, 378))	('expression', 'MPA', (238, 248))	('cyclin-D1', 'Gene', '595', (396, 405))	('cyclin-D1', 'Gene', (396, 405))	('Ser 437', 'Var', (290, 297))	('HCCC-9810', 'CellLine', 'CVCL:6908', (127, 136))	('Thr308', 'Chemical', '-', (302, 308))	('PDK1', 'Gene', '5163', (261, 265))	('c-myc', 'Gene', '4609', (411, 416))
925119	23646150	We further demonstrated that CHIR99021, a GSK-3beta inhibitor reversed the suppressive effects of hUC-MSCs on HCCC-9810 cells and increased the expression of beta-catenin.	('GSK-3beta', 'Gene', '2932', (42, 51))	('GSK-3beta', 'Gene', (42, 51))	('beta-catenin', 'Gene', (158, 170))	('beta-catenin', 'Gene', '1499', (158, 170))	('expression', 'MPA', (144, 154))	('CHIR99021', 'Var', (29, 38))	('HCCC-9810', 'CellLine', 'CVCL:6908', (110, 119))	('increased', 'PosReg', (130, 139))
925178	23646150	Flow-cytometric analysis of cell surface antigens showed that the cells were positive for CD44, CD29, and CD105, but were negative for CD34 and CD45 (Fig.	('CD44', 'Gene', (90, 94))	('positive', 'Reg', (77, 85))	('CD34', 'Gene', (135, 139))	('CD45', 'Gene', '5788', (144, 148))	('CD29', 'Gene', '3688', (96, 100))	('CD29', 'Gene', (96, 100))	('CD105', 'Var', (106, 111))	('CD44', 'Gene', '960', (90, 94))	('CD45', 'Gene', (144, 148))	('CD34', 'Gene', '947', (135, 139))
925189	23646150	Results showed that on the 50th day after injection, the mice injected with HCCC-9810 cells and hUC-MSCs had a lower tumor incidence than the control groups, and the mean volume of tumors of the mice injected with tumor cells and MSCs was dramatically lower than that of control groups: 7 mice developed detectable tumors on day 35-40 (average tumor volume = 1.3 cm3 on day 50), and 3 mice had not developed any tumors when they were killed on day 50.	('tumors', 'Phenotype', 'HP:0002664', (412, 418))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('HCCC-9810 cells', 'Var', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mice', 'Species', '10090', (195, 199))	('tumors', 'Disease', (412, 418))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('mice', 'Species', '10090', (385, 389))	('tumor', 'Disease', (344, 349))	('mice', 'Species', '10090', (289, 293))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('tumors', 'Disease', (315, 321))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (412, 418))	('tumor', 'Disease', 'MESH:D009369', (412, 417))	('lower', 'NegReg', (111, 116))	('tumor', 'Disease', (214, 219))	('mice', 'Species', '10090', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Disease', (412, 417))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('HCCC-9810', 'CellLine', 'CVCL:6908', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (315, 320))	('lower', 'NegReg', (252, 257))
925190	23646150	In contrast, mice injected with HCCC-9810 only, or a mixture of HCCC-9810 and HUVEV, formed detectable tumors (average tumor volumes were 2.6 cm3 and 2.5 cm3, respectively on day 50) (P<0.01, Table 1).	('HCCC-9810', 'Var', (64, 73))	('mice', 'Species', '10090', (13, 17))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('HCCC-9810', 'CellLine', 'CVCL:6908', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('HCCC-9810', 'CellLine', 'CVCL:6908', (32, 41))
925192	23646150	The mean tumor volume in the hUC-MSCs group was significantly smaller compared with that of the control.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('smaller', 'NegReg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('hUC-MSCs', 'Var', (29, 37))
925193	23646150	The average tumor volume decreased to 1.4 cm3 in the MSCs group, whereas it continued to increase to 3.5 cm3 in the HUVEC control group by day 70 (P<0.01, Fig.	('MSCs', 'Var', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('decreased', 'NegReg', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
925198	23646150	Immunoblot analysis showed that, compared with control groups, treatment of HCCC-9810 cells with hUC-MSC conditioned media resulted in reduced phosphorylation of PI3KY458, PDK1Ser241, AktThr308, and AktSer473, while the total Akt level did not change.	('Akt', 'Gene', '207', (184, 187))	('phosphorylation', 'MPA', (143, 158))	('Akt', 'Gene', (184, 187))	('PDK1Ser241', 'Var', (172, 182))	('Akt', 'Gene', '207', (226, 229))	('reduced', 'NegReg', (135, 142))	('Akt', 'Gene', '207', (199, 202))	('HCCC-9810', 'CellLine', 'CVCL:6908', (76, 85))	('PI3KY458', 'Enzyme', (162, 170))	('Akt', 'Gene', (226, 229))	('Akt', 'Gene', (199, 202))
925219	23646150	6A, the GSK-3beta inhibitors CHIR99021 significantly rescued HCCC-9810 cells from the inhibitory effects of hUC-MSCs conditioned media (P<0.001), whereas the GSK-3beta activator SNP significantly increased the inhibitory effects of hUC-MSCs conditioned media (P<0.001).	('HCCC-9810', 'CellLine', 'CVCL:6908', (61, 70))	('CHIR99021', 'Var', (29, 38))	('GSK-3beta', 'Gene', '2932', (8, 17))	('GSK-3beta', 'Gene', (8, 17))	('inhibitory effects', 'MPA', (86, 104))	('GSK-3beta', 'Gene', '2932', (158, 167))	('GSK-3beta', 'Gene', (158, 167))
925220	23646150	Treatment with CHIR99021 increased beta-catenin protein levels in the conditioned media-treated group, while SNP treatment resulted in decreased beta-catenin protein levels (Fig.	('beta-catenin', 'Gene', (35, 47))	('increased', 'PosReg', (25, 34))	('beta-catenin', 'Gene', (145, 157))	('beta-catenin', 'Gene', '1499', (35, 47))	('CHIR99021', 'Var', (15, 24))	('beta-catenin', 'Gene', '1499', (145, 157))	('decreased', 'NegReg', (135, 144))
925236	23646150	Dysregulation of beta-catenin and other Wnt components lead to nuclear localization of beta-catenin, activation of Wnt target genes, including c-Myc, cyclin D1, cyclooxygenase-2, matrix metalloproteinase-7, gastrin, and ITF-2 and enhance tumor formation.	('nuclear localization', 'MPA', (63, 83))	('beta-catenin', 'Gene', '1499', (17, 29))	('enhance', 'PosReg', (230, 237))	('Dysregulation', 'Var', (0, 13))	('activation', 'PosReg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('cyclooxygenase-2, matrix metalloproteinase-7', 'Gene', '5743;4316', (161, 205))	('ITF-2', 'Gene', '6925', (220, 225))	('beta-catenin', 'Gene', (87, 99))	('ITF-2', 'Gene', (220, 225))	('beta-catenin', 'Gene', '1499', (87, 99))	('gastrin', 'Gene', '2520', (207, 214))	('cyclin D1', 'Gene', (150, 159))	('c-Myc', 'Gene', (143, 148))	('cyclin D1', 'Gene', '595', (150, 159))	('tumor', 'Disease', (238, 243))	('c-Myc', 'Gene', '4609', (143, 148))	('gastrin', 'Gene', (207, 214))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('beta-catenin', 'Gene', (17, 29))
925242	23646150	It has been shown that in response to certain growth stimuli, PI3K-activated AKT can phosphorylate GSK-3beta at Ser9, leading to inactivation of GSK-3beta and augmentation of beta-catenin-TCF4 transcriptional activity.	('AKT', 'Gene', (77, 80))	('GSK-3beta', 'Gene', '2932', (99, 108))	('AKT', 'Gene', '207', (77, 80))	('beta-catenin', 'Gene', '1499', (175, 187))	('augmentation', 'PosReg', (159, 171))	('GSK-3beta', 'Gene', '2932', (145, 154))	('GSK-3beta', 'Gene', (145, 154))	('Ser9', 'Chemical', '-', (112, 116))	('PI3K-activated', 'Var', (62, 76))	('GSK-3beta', 'Gene', (99, 108))	('inactivation', 'NegReg', (129, 141))	('beta-catenin', 'Gene', (175, 187))	('TCF4', 'Gene', (188, 192))	('TCF4', 'Gene', '6925', (188, 192))
925248	23646150	We treated HCCC-9810 cells with IGF-1 in combination with hUC-MSC conditioned media, and found an increase in the expression of phosphor-Akt (Ser 437 and Thr308).	('Thr308', 'Chemical', '-', (154, 160))	('IGF-1', 'Gene', '3479', (32, 37))	('IGF-1', 'Gene', (32, 37))	('Akt', 'Gene', '207', (137, 140))	('HCCC-9810', 'CellLine', 'CVCL:6908', (11, 20))	('Ser', 'Chemical', 'MESH:D012694', (142, 145))	('increase', 'PosReg', (98, 106))	('Akt', 'Gene', (137, 140))	('expression', 'MPA', (114, 124))	('Ser 437', 'Var', (142, 149))
925311	32000397	All patients had deteriorated liver function: 81.1% Child-Pugh class B and 18.9% Child-Pugh class C. All-cause mortality was significantly higher in the EVL + NSBB group than in the EVL only group not only in non-matched cohort, but also in matched cohort (48.9% vs 31.2%; P = .039).	('Child', 'Species', '9606', (81, 86))	('deteriorated liver function', 'Phenotype', 'HP:0001410', (17, 44))	('EVL + NSBB', 'Var', (153, 163))	('All-cause mortality', 'MPA', (101, 120))	('Child', 'Species', '9606', (52, 57))	('patients', 'Species', '9606', (4, 12))	('higher', 'PosReg', (139, 145))
925312	32000397	More people died from hepatic failure in the EVL + NSBB group than that in the EVL only group (40.5% vs 20.0%; P = .020).	('EVL + NSBB', 'Var', (45, 55))	('people', 'Species', '9606', (5, 11))	('hepatic failure', 'Disease', 'MESH:D017093', (22, 37))	('hepatic failure', 'Disease', (22, 37))	('hepatic failure', 'Phenotype', 'HP:0001399', (22, 37))
925323	32000397	For example, it has been shown that NSBB is helpful in the prognosis of spontaneous bacterial peritonitis (SBP) by reducing inflammation and that it can improve prognosis of patients awaiting liver transplantation.	('prognosis', 'MPA', (161, 170))	('inflammation', 'Disease', (124, 136))	('peritonitis', 'Phenotype', 'HP:0002586', (94, 105))	('NSBB', 'Var', (36, 40))	('bacterial peritonitis', 'Disease', (84, 105))	('patients', 'Species', '9606', (174, 182))	('improve', 'PosReg', (153, 160))	('reducing', 'NegReg', (115, 123))	('bacterial peritonitis', 'Disease', 'MESH:D010534', (84, 105))	('inflammation', 'Disease', 'MESH:D007249', (124, 136))
925393	32000397	From the standpoint of advocating the use of NSBB, the use of NSBB has been associated with decreased liver transplantation and increased survival in patients with advanced liver cirrhosis.	('NSBB', 'Var', (62, 66))	('decreased liver', 'Phenotype', 'HP:0001410', (92, 107))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (173, 188))	('cirrhosis', 'Phenotype', 'HP:0001394', (179, 188))	('advanced liver cirrhosis', 'Phenotype', 'HP:0100626', (164, 188))	('advanced liver cirrhosis', 'Disease', (164, 188))	('increased', 'PosReg', (128, 137))	('liver', 'Disease', (102, 107))	('advanced liver cirrhosis', 'Disease', 'MESH:D008103', (164, 188))	('survival', 'CPA', (138, 146))	('patients', 'Species', '9606', (150, 158))	('decreased', 'NegReg', (92, 101))
925402	32000397	Actual drug use, changes in drug doses, other accompanying diseases, and differences in drug metabolism and drug susceptibility between each person will have some effects on benefits and harms that can be gained from the use of NSBB through various known or unknown routes.	('changes', 'Var', (17, 24))	('differences', 'Reg', (73, 84))	('effects', 'Reg', (163, 170))	('person', 'Species', '9606', (141, 147))
925465	31996171	On ROC analysis (Table 2), the respective sensitivities and specificities for ESCC detection were 50 and 97.81% for PET/CT scan and 100 and 81.75% for NBI endoscopy; the area under the curve (AUC) values were 0.739 [95% confidence interval (CI), 0.660-0.808; p = 0.004] for PET/CT scan and 0.909 (95% CI, 0.850-0.950; p < 0.001) for NBI endoscopy (Fig.	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('PET/CT scan', 'Var', (274, 285))	('ESCC', 'Disease', (78, 82))
925470	31996171	Among the variables, including age, sex, high-risk HNC location, and advanced stage of HNC, only high-risk HNC location was predictive of the risk for development of SPC of the esophagus, with an odds ratio (OR) of 4.7 (95% CI, 1.26-17.55; p = 0.025).	('HNC', 'Phenotype', 'HP:0012288', (87, 90))	('HNC', 'Phenotype', 'HP:0012288', (107, 110))	('high-risk', 'Var', (97, 106))	('SPC of the esophagus', 'Disease', (166, 186))	('HNC', 'Phenotype', 'HP:0012288', (51, 54))	('men', 'Species', '9606', (158, 161))
925665	30384402	Most early gastric cancers are seen as orange-red, orange or orange-white in LCI.	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('gastric cancer', 'Phenotype', 'HP:0012126', (11, 25))	('LCI', 'Chemical', '-', (77, 80))	('gastric cancers', 'Disease', (11, 26))	('gastric cancers', 'Disease', 'MESH:D013274', (11, 26))	('gastric cancers', 'Phenotype', 'HP:0012126', (11, 26))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('orange-white', 'Var', (61, 73))
925704	30384402	Successful H. pylori eradication brings dramatic changes in inflammation and acid-related molecules in the gastric mucosa.	('eradication', 'Var', (21, 32))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('acid-related molecules', 'MPA', (77, 99))	('inflammation', 'Disease', (60, 72))	('changes', 'Reg', (49, 56))	('H. pylori', 'Species', '210', (11, 20))	('H. pylori', 'Disease', (11, 20))
925770	29497828	Fatigue, nausea and vomiting, pain, appetite loss, reflux, and taste scores were significant lower (superior) in the transmediastinal esophagectomy group (P = 0.003, 0.032, 0.025, 0.018, 0.001, 0.041, respectively).	('Fatigue', 'Phenotype', 'HP:0012378', (0, 7))	('reflux', 'MPA', (51, 57))	('transmediastinal', 'Var', (117, 133))	('appetite loss', 'Phenotype', 'HP:0004396', (36, 49))	('pain', 'Disease', 'MESH:D010146', (30, 34))	('nausea and vomiting', 'Disease', 'MESH:D020250', (9, 28))	('vomiting', 'Phenotype', 'HP:0002013', (20, 28))	('taste scores', 'MPA', (63, 75))	('lower', 'NegReg', (93, 98))	('nausea', 'Phenotype', 'HP:0002018', (9, 15))	('pain', 'Phenotype', 'HP:0012531', (30, 34))	('Fatigue', 'Disease', (0, 7))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (9, 28))	('appetite loss', 'Disease', 'MESH:D001068', (36, 49))	('appetite loss', 'Disease', (36, 49))	('pain', 'Disease', (30, 34))
925808	29497828	As for the recurrent laryngeal nerve, radical lymph dissections along the nerve may impair the patients' QOL.	('radical lymph dissections', 'Var', (38, 63))	('impair', 'NegReg', (84, 90))	('patients', 'Species', '9606', (95, 103))
925926	26420728	Up to now, several risk factors related to EC have been previously evaluated, including cigarette smoking, alcohol consumption, low vegetable intake and family history of cancer, BMI and ABO blood group.	('low', 'Var', (128, 131))	('ABO blood group', 'Gene', (187, 202))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('ABO blood group', 'Gene', '28', (187, 202))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('alcohol', 'Chemical', 'MESH:D000438', (107, 114))
925988	26420728	In a sample of 496 patients who underwent esophagectomy, Yang and his colleagues found that patients with blood group O had a significantly worse overall survival than non-O blood groups.	('patients', 'Species', '9606', (19, 27))	('overall survival', 'MPA', (146, 162))	('patients', 'Species', '9606', (92, 100))	('blood group O', 'Var', (106, 119))	('worse', 'NegReg', (140, 145))
925995	26420728	It has been shown that the modified expression of blood group antigens on the surface of tumor cells may alter cell motility, resistance to apoptosis and immune escape.	('alter', 'Reg', (105, 110))	('modified', 'Var', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cell motility', 'CPA', (111, 124))	('immune escape', 'CPA', (154, 167))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('resistance to apoptosis', 'CPA', (126, 149))
926036	25874561	As the major exposure of interest, smoking status was analyzed in univariate analysis with other confounders, including age (as a continuous variable), gender, body mass index (BMI) (as a continuous variable), alcohol drinking (non-drinker, drinker), tumor diameter (less than or equal to 3, between 3 and 5, or greater than 5 cm), and AJCC stage (0-I, II, or III).	('tumor', 'Disease', (251, 256))	('alcohol drinking', 'Phenotype', 'HP:0030955', (210, 226))	('less than', 'Var', (267, 276))	('alcohol', 'Chemical', 'MESH:D000438', (210, 217))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
926062	25874561	Recently, several studies in vitro have demonstrated that nicotine decreased the chemosensitivity of esophageal cancer cell lines.	('nicotine', 'Var', (58, 66))	('nicotine', 'Chemical', 'MESH:D009538', (58, 66))	('esophageal cancer', 'Disease', (101, 118))	('chemosensitivity of', 'CPA', (81, 100))	('decreased', 'NegReg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))
926148	24974835	Of these, the authors demonstrated in vitro inhibition of breast cancer cell growth using an inhibitor to FGFR2, one of the oncogenes identified as being upregulated in TNBC.	('upregulated', 'PosReg', (154, 165))	('TNBC', 'Disease', 'None', (169, 173))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('FGFR2', 'Gene', '2263', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('TNBC', 'Disease', (169, 173))	('inhibition', 'NegReg', (44, 54))	('inhibitor', 'Var', (93, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('FGFR2', 'Gene', (106, 111))
926188	20920372	Singleplex qPCR was performed after first strand cDNA synthesis using 2x Taqman Universal PCR Master Mix (Applied Biosystems, Inc., Cat#4364338) and Amplitaq Gold DNA polymerase, LD (Applied Biosystems, Inc., Cat#4338857) and specific primer/probe sets (Applied Biosystems, Inc.).	('Cat#4338857', 'Var', (209, 220))	('Mix', 'Gene', '83881', (101, 104))	('Mix', 'Gene', (101, 104))
926189	20920372	Five cases were tested with commercially available optimized primer/probe sets for MMP-3 [TaqMan Gene Expression Assays, Inventoried Assay ID: Hs00233962 for MMP-3 (stromelysin-1, progelatinase), Applied BioSystems, Inc., Cat.# 4331182] and MMP-10 [TaqMan Gene Expression Assays, Inventoried Assay ID: Hs00233987 for MMP-10 (stromelysin-2), Applied BioSystems, Inc., Cat.# 4331182] gene expression levels.	('Cat.# 4331182]', 'Var', (367, 381))	('stromelysin-1', 'Gene', '4314', (165, 178))	('MMP-3', 'Gene', '4314', (158, 163))	('MMP-10', 'Gene', (241, 247))	('stromelysin-2', 'Gene', '4319', (325, 338))	('MMP-3', 'Gene', (158, 163))	('MMP-10', 'Gene', '4319', (241, 247))	('MMP-3', 'Gene', '4314', (83, 88))	('MMP-10', 'Gene', (317, 323))	('stromelysin-2', 'Gene', (325, 338))	('stromelysin-1', 'Gene', (165, 178))	('MMP-10', 'Gene', '4319', (317, 323))	('MMP-3', 'Gene', (83, 88))
926208	20920372	Activated MMP-9 (82 kDa) was not seen in any of the esophageal samples, but the expression of pro-MMP-9 (92 kDa) was elevated in 18 out of 24 tumors (75%) in the study.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MMP-9', 'Gene', (10, 15))	('MMP-9', 'Gene', '4318', (10, 15))	('MMP-9', 'Gene', '4318', (98, 103))	('tumors', 'Disease', (142, 148))	('expression', 'MPA', (80, 90))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('92 kDa', 'Var', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('MMP-9', 'Gene', (98, 103))	('elevated', 'PosReg', (117, 125))
926229	19236713	Microsatellite Instability has again been confirmed to be an important predictor in patients with stage II colon cancer receiving adjuvant treatment.	('patients', 'Species', '9606', (84, 92))	('Microsatellite Instability', 'Var', (0, 26))	('stage II colon cancer', 'Disease', (98, 119))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('stage II colon cancer', 'Disease', 'MESH:D015179', (98, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
926245	19236713	KRAS can harbor oncogenic mutation, mostly in codon 12 and 13, that yields a constitutively active protein, and such mutation is found in approximately 30% to 50% of CRC.	('mutation', 'Var', (26, 34))	('constitutively active protein', 'MPA', (77, 106))	('yields', 'Reg', (68, 74))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
926246	19236713	Several retrospective analyses of tumor samples in CRC patients receiving anti-EGFR antibody treatment have shown that patients with mutated KRAS did not benefit from anti-EGFR therapy.	('KRAS', 'Gene', (141, 145))	('tumor', 'Disease', (34, 39))	('KRAS', 'Gene', '3845', (141, 145))	('patients', 'Species', '9606', (119, 127))	('mutated', 'Var', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
926251	19236713	Mutated KRAS was detected in 192 patients (36%), and in these patients adding cetuximab to FOLFIRI did not improve RR or PFS.	('patients', 'Species', '9606', (33, 41))	('Mutated', 'Var', (0, 7))	('FOLFIRI', 'Chemical', '-', (91, 98))	('KRAS', 'Gene', (8, 12))	('cetuximab', 'Chemical', 'MESH:D000068818', (78, 87))	('KRAS', 'Gene', '3845', (8, 12))	('detected', 'Reg', (17, 25))	('patients', 'Species', '9606', (62, 70))
926253	19236713	In contrast, there was no benefit at all in RR or PFS among patients with mutant K-RAS receiving FOLFIRI plus cetuximab vs. FOLFIRI alone.	('K-RAS', 'Gene', (81, 86))	('FOLFIRI', 'Chemical', '-', (97, 104))	('cetuximab', 'Chemical', 'MESH:D000068818', (110, 119))	('patients', 'Species', '9606', (60, 68))	('PFS', 'Disease', (50, 53))	('K-RAS', 'Gene', '3845', (81, 86))	('mutant', 'Var', (74, 80))	('FOLFIRI', 'Chemical', '-', (124, 131))
926258	19236713	In patients with mutant KRAS, RR was worse in FOLFOX plus cetuximab (33% vs. 49% in FOLFOX, p = 0.11), and this turned into significantly worse median PFS (5.5 months vs. 8.6 months in FOLFOX, p = 0.019).	('cetuximab', 'Chemical', 'MESH:D000068818', (58, 67))	('KRAS', 'Gene', '3845', (24, 28))	('FOLFOX', 'Chemical', '-', (185, 191))	('PFS', 'MPA', (151, 154))	('worse', 'NegReg', (138, 143))	('FOLFOX', 'Chemical', '-', (84, 90))	('patients', 'Species', '9606', (3, 11))	('FOLFOX', 'Chemical', '-', (46, 52))	('mutant', 'Var', (17, 23))	('KRAS', 'Gene', (24, 28))
926259	19236713	Skin toxicity has previously been shown to correlate with clinical benefits such as RR, PFS and overall survival in patients with advanced CRC receiving anti-EGFR antibody.	('overall survival', 'CPA', (96, 112))	('Skin toxicity', 'Disease', 'MESH:D012871', (0, 13))	('anti-EGFR antibody', 'Var', (153, 171))	('patients', 'Species', '9606', (116, 124))	('Skin toxicity', 'Disease', (0, 13))	('benefits', 'PosReg', (67, 75))	('PFS', 'Disease', (88, 91))
926265	19236713	However, none of the patients with mutated KRAS in either arm achieved a response.	('patients', 'Species', '9606', (21, 29))	('KRAS', 'Gene', (43, 47))	('mutated', 'Var', (35, 42))	('KRAS', 'Gene', '3845', (43, 47))
926268	19236713	The retrospective analyses of KRAS data from CRYSTAL, OPUS and EVEREST have further demonstrated patients with K-RAS mutant CRC do not benefit from anti-EGFR antibody treatment.	('rat', 'Species', '10116', (91, 94))	('mutant', 'Var', (117, 123))	('K-RAS', 'Gene', '3845', (111, 116))	('K-RAS', 'Gene', (111, 116))	('KRAS', 'Gene', (30, 34))	('KRAS', 'Gene', '3845', (30, 34))	('patients', 'Species', '9606', (97, 105))
926271	19236713	National Comprehensive Cancer Network has recently revised its CRC practice guideline, and recommends CRC patients with know KRAS mutations should not be treated with anti-EGFR antibody alone or in combination with other anticancer agents.	('Cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('KRAS', 'Gene', (125, 129))	('cancer', 'Disease', (225, 231))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('KRAS', 'Gene', '3845', (125, 129))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('mutations', 'Var', (130, 139))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))
926283	19236713	Median PFS was significantly reduced in patients on double antibody with chemotherapy (9.6 months) compared with bevacizumab plus chemotherapy (10.7 months, p = 0.018), but there was no differences in RR and overall survival (OS) between these 2 groups.	('PFS', 'MPA', (7, 10))	('overall', 'CPA', (208, 215))	('patients', 'Species', '9606', (40, 48))	('bevacizumab', 'Chemical', 'MESH:D000068258', (113, 124))	('reduced', 'NegReg', (29, 36))	('double antibody', 'Var', (52, 67))
926284	19236713	In patients with mutated KRAS, the addition of cetuximab to chemotherapy and bevacizumab resulted in significantly decreased PFS (8.6 months vs. 12.5 months, p = 0.043).	('decreased', 'NegReg', (115, 124))	('bevacizumab', 'Chemical', 'MESH:D000068258', (77, 88))	('patients', 'Species', '9606', (3, 11))	('PFS', 'MPA', (125, 128))	('cetuximab', 'Chemical', 'MESH:D000068818', (47, 56))	('KRAS', 'Gene', (25, 29))	('mutated', 'Var', (17, 24))	('KRAS', 'Gene', '3845', (25, 29))
926286	19236713	Data from both PACCE and CAIRO-2 studies have indicated no benefit of adding anti-EGFR antibody to bevacizumab and chemotherapy in the first-line treatment of advanced CRC, and patients with mutant KRAS tumors had worse outcome on double antibodies and chemotherapy compared to bevacizumab and chemotherapy.	('KRAS tumors', 'Disease', (198, 209))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('patients', 'Species', '9606', (177, 185))	('bevacizumab', 'Chemical', 'MESH:D000068258', (99, 110))	('KRAS tumors', 'Disease', 'MESH:D009369', (198, 209))	('mutant', 'Var', (191, 197))	('bevacizumab', 'Chemical', 'MESH:D000068258', (278, 289))
926318	19236713	In MOSAIC study, the OS in stage III patients was not statistically different till median of 6-year follow-up, with 4.4% better in FOLFOX (73.0%) vs. 5-FU/LV (68.6%; hazard ratio [HR] 0.80; p = 0.029).	('5-FU', 'Chemical', 'MESH:D005472', (150, 154))	('rat', 'Species', '10116', (173, 176))	('FOLFOX', 'Var', (131, 137))	('patients', 'Species', '9606', (37, 45))	('better', 'PosReg', (121, 127))	('FOLFOX', 'Chemical', '-', (131, 137))	('LV', 'Chemical', 'MESH:D002955', (155, 157))
926324	19236713	It has been shown that 5-FU-based adjuvant chemotherapy may not benefit patients with stage II or III colon cancer exhibiting microsatellite instability (MSI).	('5-FU', 'Chemical', 'MESH:D005472', (23, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('III colon cancer', 'Disease', 'MESH:D015179', (98, 114))	('microsatellite instability', 'Var', (126, 152))	('III colon cancer', 'Disease', (98, 114))	('patients', 'Species', '9606', (72, 80))
926326	19236713	Those with high MSI were stratified as having deficient mismatch repair (dMMR) and those with microsatellite stability or low MSI were stratified as having proficient mismatch repair (pMMR).	('mismatch repair', 'MPA', (56, 71))	('dMMR', 'Chemical', '-', (73, 77))	('rat', 'Species', '10116', (137, 140))	('rat', 'Species', '10116', (27, 30))	('high MSI', 'Var', (11, 19))	('deficient', 'NegReg', (46, 55))
926352	19236713	Despite the early closure, a significantly decreased incidence of grade 2 or higher neurotoxicity was observed in patients receiving CaMg (22% vs. 41% in the placebo group, p = 0.038).	('CaMg', 'Var', (133, 137))	('neurotoxicity', 'Disease', (84, 97))	('CaMg', 'Chemical', '-', (133, 137))	('patients', 'Species', '9606', (114, 122))	('decreased', 'NegReg', (43, 52))	('neurotoxicity', 'Disease', 'MESH:D020258', (84, 97))
926353	19236713	The time to development of grade 2 or higher neurotoxicity was also prolonged in the CaMg group.	('CaMg', 'Var', (85, 89))	('prolonged', 'PosReg', (68, 77))	('neurotoxicity', 'Disease', (45, 58))	('CaMg', 'Chemical', '-', (85, 89))	('neurotoxicity', 'Disease', 'MESH:D020258', (45, 58))
926435	19236713	The MD Anderson group presented data on single nucleotide polymorphisms (SNPs) of genes involved in gemcitabine metabolism and showed that cytidine deaminase and deoxycytidine kinase alleles were associated with an improved survival, albeit at the cost of increased toxicity.	('deoxycytidine kinase', 'Gene', (162, 182))	('cytidine deaminase', 'Gene', '978', (139, 157))	('gemcitabine', 'Chemical', 'MESH:C056507', (100, 111))	('alleles', 'Var', (183, 190))	('toxicity', 'Disease', 'MESH:D064420', (266, 274))	('improved', 'PosReg', (215, 223))	('deoxycytidine kinase', 'Gene', '1633', (162, 182))	('cytidine deaminase', 'Gene', (139, 157))	('toxicity', 'Disease', (266, 274))	('single nucleotide polymorphisms', 'Var', (40, 71))	('survival', 'MPA', (224, 232))
926459	19236713	Neutropenia occurred more frequently with docetaxel and cisplatin, while diarrhea was more likely with 5-FU and cisplatin.	('docetaxel', 'Var', (42, 51))	('docetaxel', 'Chemical', 'MESH:D000077143', (42, 51))	('Neutropenia', 'Disease', 'MESH:D009503', (0, 11))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('diarrhea', 'Phenotype', 'HP:0002014', (73, 81))	('5-FU', 'Chemical', 'MESH:D005472', (103, 107))	('diarrhea', 'Disease', 'MESH:D003967', (73, 81))	('Neutropenia', 'Phenotype', 'HP:0001875', (0, 11))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('diarrhea', 'Disease', (73, 81))	('cisplatin', 'Var', (56, 65))	('Neutropenia', 'Disease', (0, 11))
926502	31119872	The perioperative complication rates were also similar between the groups, but the treatment time and costs were significantly reduced in the HFRT group (P < 0.05).	('HFRT', 'Var', (142, 146))	('HFRT', 'Chemical', '-', (142, 146))	('costs', 'CPA', (102, 107))	('treatment time', 'CPA', (83, 97))	('reduced', 'NegReg', (127, 134))
926506	31119872	Several studies have reported that its use has improved local control, progression free survival (PFS), and overall survival (OS) in comparison with surgery alone.1, 2, 3 Conventional fractionated radiotherapy (CFRT) is the most commonly used neoadjuvant option for esophageal cancer, but the efficacy and safety of preoperative hypofractionated radiotherapy (HFRT), which delivers a dose larger than 2 Gray (Gy) per fraction in a lower overall dose, has also been studied in some patients with esophageal cancer.4, 5 These studies have indicated that preoperative HFRT could improve the local control rate of esophageal cancer and potentially increase patient survival compared with surgery alone.	('patient', 'Species', '9606', (653, 660))	('PF', 'Chemical', 'MESH:C002997', (98, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (266, 283))	('cancer', 'Phenotype', 'HP:0002664', (621, 627))	('HFRT', 'Chemical', '-', (360, 364))	('patient survival', 'CPA', (653, 669))	('esophageal cancer', 'Disease', 'MESH:D004938', (495, 512))	('HFRT', 'Var', (565, 569))	('esophageal cancer', 'Disease', (266, 283))	('HFRT', 'Chemical', '-', (565, 569))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('patients', 'Species', '9606', (481, 489))	('improve', 'PosReg', (576, 583))	('esophageal cancer', 'Disease', (495, 512))	('patient', 'Species', '9606', (481, 488))	('esophageal cancer', 'Disease', 'MESH:D004938', (610, 627))	('local control', 'CPA', (588, 601))	('increase', 'PosReg', (644, 652))	('esophageal cancer', 'Disease', (610, 627))	('cancer', 'Phenotype', 'HP:0002664', (506, 512))
926537	31119872	Overall, 13 of the 42 patients who received HFRT (31.0%) developed grade 3 or 4 leukopenia compared to 25 of the 68 patients who received CFRT (36.8%) (P = 0.546).	('HFRT', 'Chemical', '-', (44, 48))	('leukopenia', 'Phenotype', 'HP:0001882', (80, 90))	('patients', 'Species', '9606', (116, 124))	('leukopenia', 'Disease', 'MESH:D007970', (80, 90))	('leukopenia', 'Disease', (80, 90))	('patients', 'Species', '9606', (22, 30))	('HFRT', 'Var', (44, 48))
926541	31119872	The average total costs for patients treated with HFRT were significantly less (23205.86 +- 5862.65 yuan) compared with that for those treated with CFRT (39170.38 +- 8752.78 yuan; P = 0.000).	('costs', 'MPA', (18, 23))	('less', 'NegReg', (74, 78))	('HFRT', 'Var', (50, 54))	('HFRT', 'Chemical', '-', (50, 54))	('patients', 'Species', '9606', (28, 36))
926542	31119872	The average costs related to radiotherapy were also significantly lower in the HFRT group (14218.67 +- 5424.12 yuan) than in the CFRT group (28750.94 +- 7093.25 yuan; P = 0.000).	('HFRT', 'Chemical', '-', (79, 83))	('lower', 'NegReg', (66, 71))	('HFRT', 'Var', (79, 83))	('costs', 'MPA', (12, 17))
926568	31119872	A total of six treatment-related deaths due to esophageal fistulas, pneumonia, cardiotoxicity, or hematological toxicity occurred in the MHFRT arm.	('MHFRT', 'Chemical', '-', (137, 142))	('death', 'Disease', (33, 38))	('cardiotoxicity', 'Disease', 'MESH:D066126', (79, 93))	('esophageal fistulas', 'Disease', (47, 66))	('cardiotoxicity', 'Disease', (79, 93))	('hematological toxicity', 'Disease', 'MESH:D006402', (98, 120))	('hematological toxicity', 'Disease', (98, 120))	('pneumonia', 'Phenotype', 'HP:0002090', (68, 77))	('esophageal fistulas', 'Disease', 'MESH:D004937', (47, 66))	('MHFRT', 'Var', (137, 142))	('pneumonia', 'Disease', (68, 77))	('pneumonia', 'Disease', 'MESH:D011014', (68, 77))	('death', 'Disease', 'MESH:D003643', (33, 38))
926573	31119872	On comparing the time commitments and costs related to therapy, we found that preoperative HFRT can significantly shorten the durations of both radiotherapy and hospitalization (16.7 and 69.0 days, respectively) compared with CFRT (32.8 and 80.4 days, respectively) by requiring fewer fractions.	('shorten', 'NegReg', (114, 121))	('HFRT', 'Var', (91, 95))	('HFRT', 'Chemical', '-', (91, 95))
926582	29478325	There is a consensus that aberrant levels of reactive oxygen species (ROS), commonly observed in cancer, stimulate primary cell immortalization and progression of carcinogenesis.	('primary cell immortalization', 'CPA', (115, 143))	('aberrant', 'Var', (26, 34))	('cancer', 'Disease', (97, 103))	('carcinogenesis', 'Disease', (163, 177))	('stimulate', 'PosReg', (105, 114))	('aberrant levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (26, 68))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (163, 177))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (45, 68))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
926594	29478325	O2 - is a short-lived, highly reactive radical that, in aberrant levels, causes a high number of modifications in cellular functions.	('modifications', 'Reg', (97, 110))	('cellular functions', 'MPA', (114, 132))	('O2 -', 'Var', (0, 4))	('O2', 'Chemical', '-', (0, 2))	('causes', 'Reg', (73, 79))
926600	29478325	The half-life of H2O2 is markedly longer than that of O2 -.	('half-life', 'MPA', (4, 13))	('O2', 'Chemical', '-', (54, 56))	('O2', 'Chemical', '-', (19, 21))	('longer', 'PosReg', (34, 40))	('H2O2', 'Chemical', 'MESH:D006861', (17, 21))	('H2O2', 'Var', (17, 21))
926604	29478325	Although H2O2 may passively diffuse through membrane structures, a recent article demonstrated that H2O2 passes the cell membrane, mainly through the aquaporin 3 (AQP3) integral membrane protein channel.	('H2O2', 'Chemical', 'MESH:D006861', (100, 104))	('H2O2', 'Var', (100, 104))	('AQP3', 'Gene', '360', (163, 167))	('H2O2', 'Chemical', 'MESH:D006861', (9, 13))	('aquaporin 3', 'Gene', '360', (150, 161))	('rat', 'Species', '10116', (89, 92))	('aquaporin 3', 'Gene', (150, 161))	('AQP3', 'Gene', (163, 167))
926606	29478325	In mammalian cells, such as thyrocytes and hepatocytes, and even in some microbes, H2O2 has been shown to have growth and survival supportive characteristics at low physiological intracellular levels (0.001-0.7 muM), whereas higher levels (20-200 muM) induce growth arrest, and levels above that eventually cause cell death, thus suggesting a dose-dependent response in signal transduction, cell growth, and survival.	('growth arrest', 'Disease', (259, 272))	('H2O2', 'Var', (83, 87))	('H2O2', 'Chemical', 'MESH:D006861', (83, 87))	('survival supportive', 'CPA', (122, 141))	('growth', 'CPA', (111, 117))	('muM', 'Gene', (247, 250))	('0.001-0.7', 'Var', (201, 210))	('growth arrest', 'Phenotype', 'HP:0001510', (259, 272))	('muM', 'Gene', '56925', (211, 214))	('muM', 'Gene', (211, 214))	('muM', 'Gene', '56925', (247, 250))	('growth arrest', 'Disease', 'MESH:D006323', (259, 272))	('mammalian', 'Species', '9606', (3, 12))
926607	29478325	At high concentrations, H2O2, similar to other ROS, reacts with various cellular macromolecules, causing oxidative stress, DNA damage, mutagenesis, and apoptosis; however, at lower physiological concentrations, H2O2 modifies cellular signal transduction by stimulating or inhibiting signaling molecule activation.	('H2O2', 'Var', (24, 28))	('H2O2', 'Chemical', 'MESH:D006861', (211, 215))	('DNA damage', 'MPA', (123, 133))	('rat', 'Species', '10116', (15, 18))	('oxidative stress', 'MPA', (105, 121))	('H2O2', 'Var', (211, 215))	('inhibiting', 'NegReg', (272, 282))	('mutagenesis', 'CPA', (135, 146))	('ROS', 'Chemical', 'MESH:D017382', (47, 50))	('cellular signal transduction', 'MPA', (225, 253))	('stimulating', 'PosReg', (257, 268))	('rat', 'Species', '10116', (202, 205))	('apoptosis', 'CPA', (152, 161))	('H2O2', 'Chemical', 'MESH:D006861', (24, 28))	('oxidative stress', 'Phenotype', 'HP:0025464', (105, 121))	('causing', 'Reg', (97, 104))	('activation', 'MPA', (302, 312))	('signaling molecule', 'Pathway', (283, 301))	('modifies', 'Reg', (216, 224))
926610	29478325	H2O2-derived activation of RTKs is based on its ability to induce the oxidative inactivation of PTPs by modifying the catalytic site cysteine amino acids.	('catalytic site cysteine amino acids', 'MPA', (118, 153))	('oxidative inactivation', 'MPA', (70, 92))	('modifying', 'Reg', (104, 113))	('induce', 'Reg', (59, 65))	('H2O2-derived', 'Var', (0, 12))	('PTPs', 'Gene', (96, 100))	('PTPs', 'Gene', '5805', (96, 100))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('cysteine amino acids', 'Chemical', '-', (133, 153))
926616	29478325	In general, the imbalanced production of ROS, especially H2O2, may affect signal transduction by promoting cancer cell survival, proliferation, migration, and drug resistance.	('ROS', 'Chemical', 'MESH:D017382', (41, 44))	('ROS', 'Protein', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('promoting', 'PosReg', (97, 106))	('affect', 'Reg', (67, 73))	('drug resistance', 'CPA', (159, 174))	('migration', 'CPA', (144, 153))	('imbalanced production', 'Phenotype', 'HP:0002172', (16, 37))	('drug resistance', 'Phenotype', 'HP:0020174', (159, 174))	('H2O2', 'Chemical', 'MESH:D006861', (57, 61))	('H2O2', 'Var', (57, 61))	('proliferation', 'CPA', (129, 142))	('signal transduction', 'MPA', (74, 93))	('rat', 'Species', '10116', (136, 139))	('rat', 'Species', '10116', (147, 150))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('imbalanced production', 'MPA', (16, 37))
926617	29478325	Although cancer cells become adapted to increased ROS levels, the aberrant supraphysiological levels of either O2 - or H2O2 markedly influence cell survival by reducing cell cycling and cell proliferation.	('cancer', 'Disease', (9, 15))	('O2', 'Chemical', '-', (111, 113))	('influence', 'Reg', (133, 142))	('cell cycling', 'CPA', (169, 181))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('O2', 'Chemical', '-', (121, 123))	('cell proliferation', 'CPA', (186, 204))	('rat', 'Species', '10116', (198, 201))	('H2O2', 'Chemical', 'MESH:D006861', (119, 123))	('H2O2', 'Var', (119, 123))	('increased ROS levels', 'Phenotype', 'HP:0025464', (40, 60))	('reducing', 'NegReg', (160, 168))	('ROS', 'Chemical', 'MESH:D017382', (50, 53))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cell survival', 'CPA', (143, 156))
926634	29478325	The extracellular stimulus-induced mitogenic RAS-MEK-ERK and PKC-PKA pathways control the hyperactivation of radical production through increased NOX1 gene expression and phosphorylation of NOXA1 at Ser282 and Ser172, thereby decreasing the affinity of RAC1 for NOX1 (Fig.	('PKC', 'Gene', '112476', (61, 64))	('NOX1', 'Gene', '27035', (262, 266))	('ERK', 'Gene', (53, 56))	('PKC', 'Gene', (61, 64))	('NOXA1', 'Gene', '10811', (190, 195))	('affinity', 'Interaction', (241, 249))	('NOX1', 'Gene', (262, 266))	('decreasing', 'NegReg', (226, 236))	('radical production', 'MPA', (109, 127))	('hyperactivation', 'Disease', 'None', (90, 105))	('NOX1', 'Gene', '27035', (146, 150))	('Ser172', 'Var', (210, 216))	('MEK', 'Gene', '5609', (49, 52))	('RAC1', 'Gene', (253, 257))	('NOXA1', 'Gene', (190, 195))	('increased', 'PosReg', (136, 145))	('hyperactivation', 'Disease', (90, 105))	('Ser282', 'Chemical', '-', (199, 205))	('Ser172', 'Chemical', '-', (210, 216))	('NOX1', 'Gene', (146, 150))	('RAC1', 'Gene', '5879', (253, 257))	('ERK', 'Gene', '5594', (53, 56))	('MEK', 'Gene', (49, 52))	('phosphorylation', 'MPA', (171, 186))	('expression', 'MPA', (156, 166))
926636	29478325	Overexpression of this enzyme has been shown to promote the carcinogenic conversion of NIH-3T3 fibroblasts, causing morphological changes, increased anchorage-independent growth, and increased tumor formation in vivo.	('carcinogenic', 'Disease', (60, 72))	('morphological changes', 'CPA', (116, 137))	('increased', 'PosReg', (183, 192))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('increased', 'PosReg', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Overexpression', 'Var', (0, 14))	('NIH-3T3', 'CellLine', 'CVCL:0594', (87, 94))	('tumor', 'Disease', (193, 198))	('promote', 'PosReg', (48, 55))	('anchorage-independent growth', 'CPA', (149, 177))	('carcinogenic', 'Disease', 'MESH:D063646', (60, 72))
926638	29478325	NADPH oxidase NOX1-induced tumorigenesis is mediated primarily by a signal transduction pathway composed of mutated K-RASV12-stimulated p38MAPK, 3-phosphoinositide-dependent protein kinase-1 (PDPK1), and PKC delta (PKCdelta) (Fig.	('PKC delta', 'Gene', (204, 213))	('3-phosphoinositide-dependent protein kinase-1', 'Gene', '5170', (145, 190))	('PDPK1', 'Gene', '5170', (192, 197))	('NOX1', 'Gene', '27035', (14, 18))	('K-RASV12-stimulated', 'Gene', (116, 135))	('mutated', 'Var', (108, 115))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('NOX1', 'Gene', (14, 18))	('NADPH', 'Gene', (0, 5))	('NADPH', 'Gene', '1666', (0, 5))	('PKCdelta', 'Gene', '5580', (215, 223))	('p38', 'Gene', '26073', (136, 139))	('PKCdelta', 'Gene', (215, 223))	('p38', 'Gene', (136, 139))	('PDPK1', 'Gene', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('3-phosphoinositide-dependent protein kinase-1', 'Gene', (145, 190))	('PKC delta', 'Gene', '5580', (204, 213))
926640	29478325	Activated PDPK1 phosphorylates PKCdelta at Thr505 allowing the direct interaction of PKCdelta with the SH region of the p47phox homologue NOXO1, which is consequently phosphorylated at Ser348 and Ser379.	('NOXO1', 'Gene', (138, 143))	('p47phox', 'Gene', '653361', (120, 127))	('Ser379', 'Chemical', '-', (196, 202))	('PKCdelta', 'Gene', '5580', (85, 93))	('interaction', 'Interaction', (70, 81))	('p47phox', 'Gene', (120, 127))	('Ser379', 'Var', (196, 202))	('Thr505', 'Chemical', '-', (43, 49))	('Ser348', 'Chemical', '-', (185, 191))	('PDPK1', 'Gene', '5170', (10, 15))	('NOXO1', 'Gene', '124056', (138, 143))	('PKCdelta', 'Gene', '5580', (31, 39))	('PKCdelta', 'Gene', (31, 39))	('PDPK1', 'Gene', (10, 15))	('PKCdelta', 'Gene', (85, 93))
926648	29478325	Phosphorylation of LIMK1 at Thr508 causes inactivation of cofilin by Ser3 phosphorylation, inhibition of actin depolymerization, and accumulation of actin fibers.	('inactivation', 'NegReg', (42, 54))	('cofilin', 'Gene', (58, 65))	('Phosphorylation', 'Var', (0, 15))	('Ser3 phosphorylation', 'MPA', (69, 89))	('actin fibers', 'MPA', (149, 161))	('Thr508', 'Var', (28, 34))	('actin depolymerization', 'MPA', (105, 127))	('Thr508', 'Chemical', '-', (28, 34))	('inhibition', 'NegReg', (91, 101))	('LIMK1', 'Gene', '3984', (19, 24))	('LIMK1', 'Gene', (19, 24))	('Ser3', 'Chemical', '-', (69, 73))	('cofilin', 'Gene', '1072', (58, 65))	('accumulation', 'PosReg', (133, 145))
926650	29478325	Interestingly, H2O2 can inactivate low-molecular-weight phosphotyrosine phosphatase (LMW-PTP), which results in increased p190RHO-small GTPase activator protein (GAP) production and subsequent inactivation of RHO-ROCK-LIMK pathway (Fig.	('low-molecular-weight phosphotyrosine phosphatase', 'Gene', (35, 83))	('p19', 'Gene', '1029', (122, 125))	('H2O2', 'Chemical', 'MESH:D006861', (15, 19))	('H2O2', 'Var', (15, 19))	('GTP', 'Chemical', 'MESH:D006160', (136, 139))	('LIMK', 'Gene', '3984', (218, 222))	('inactivate', 'NegReg', (24, 34))	('inactivation', 'NegReg', (193, 205))	('increased', 'PosReg', (112, 121))	('LMW-PTP', 'Gene', (85, 92))	('LIMK', 'Gene', (218, 222))	('low-molecular-weight phosphotyrosine phosphatase', 'Gene', '52', (35, 83))	('p19', 'Gene', (122, 125))	('LMW-PTP', 'Gene', '52', (85, 92))
926653	29478325	Phosphorylation induces the degradation of IkappaBalpha, increasing NFkappaB activity, which in turn augments matrix metalloproteinase 9 (MMP9) expression and initiates extracellular matrix (ECM) degradation with consequent cancer cell invasion.	('augments', 'NegReg', (101, 109))	('increasing', 'PosReg', (57, 67))	('MMP9', 'Gene', (138, 142))	('matrix metalloproteinase 9', 'Gene', (110, 136))	('degradation', 'MPA', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('expression', 'MPA', (144, 154))	('Phosphorylation', 'Var', (0, 15))	('NFkappaB', 'Gene', (68, 76))	('initiates', 'Reg', (159, 168))	('MMP9', 'Gene', '4318', (138, 142))	('NFkappaB', 'Gene', '4790', (68, 76))	('IkappaBalpha', 'Gene', '4792', (43, 55))	('matrix metalloproteinase 9', 'Gene', '4318', (110, 136))	('activity', 'MPA', (77, 85))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (224, 230))	('IkappaBalpha', 'Gene', (43, 55))
926666	29478325	More specifically, the association of small GTPase RAC activates the two-step electron transfer reaction: (i) electron transfer from NADPH to FAD, which results in the formation of NADP+ and FADH2 and (ii) electron transfer to cyt b588-associated heme and molecular oxygen, resulting in the formation of H+ and O2 -.	('association', 'Var', (23, 34))	('electron transfer', 'MPA', (78, 95))	('FAD', 'Chemical', 'MESH:D005182', (191, 194))	('activates', 'PosReg', (55, 64))	('electron transfer', 'MPA', (206, 223))	('electron transfer', 'MPA', (110, 127))	('O2', 'Chemical', '-', (311, 313))	('oxygen', 'Chemical', 'MESH:D010100', (266, 272))	('FAD', 'Chemical', 'MESH:D005182', (142, 145))	('NADP+', 'Chemical', 'MESH:D009249', (181, 186))	('NADPH', 'Gene', (133, 138))	('RAC', 'Gene', (51, 54))	('NADPH', 'Gene', '1666', (133, 138))	('formation', 'MPA', (291, 300))	('RAC', 'Gene', '207', (51, 54))	('cyt b', 'Gene', '4519', (227, 232))	('heme', 'Chemical', 'MESH:D006418', (247, 251))	('cyt b', 'Gene', (227, 232))	('GTP', 'Chemical', 'MESH:D006160', (44, 47))
926674	29478325	DAG recruits PKC to the cell membrane, and IP3 promotes calcium (Ca2+) channel opening with a consequent temporal intracellular increase of Ca2+, which further enhances the activation of PKC, a crucially important kinase in the initiation of NADPH oxidase complex assembly (Fig.	('PKC', 'Gene', '112476', (13, 16))	('calcium', 'Chemical', 'MESH:D002118', (56, 63))	('Ca2+', 'Chemical', 'MESH:D000069285', (140, 144))	('NADPH', 'Gene', '1666', (242, 247))	('increase', 'PosReg', (128, 136))	('enhances', 'PosReg', (160, 168))	('Ca2+', 'Chemical', 'MESH:D000069285', (65, 69))	('DAG', 'Chemical', 'MESH:D004075', (0, 3))	('PKC', 'Gene', (187, 190))	('Ca2+', 'MPA', (140, 144))	('PKC', 'Gene', '112476', (187, 190))	('IP3', 'Var', (43, 46))	('IP3', 'Chemical', 'MESH:D015544', (43, 46))	('PKC', 'Gene', (13, 16))	('NADPH', 'Gene', (242, 247))	('intracellular increase', 'Phenotype', 'HP:0003575', (114, 136))
926696	29478325	Recent studies suggested that in acute myeloid leukemia (AML) cells, mutated FMS-like tyrosine kinase 3 with internal tandem duplications (FLT3-ITDs) increases the synthesis of transcription factor signal transducer and activator of transcription 5 (STAT5), which binds to the NOX4 promoter region at IFN-gamma activated sequence elements, activating NOX4 gene transcription.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (33, 55))	('IFN-gamma', 'Gene', '3458', (301, 310))	('IFN-gamma', 'Gene', (301, 310))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (33, 55))	('FMS-like tyrosine kinase 3', 'Gene', (77, 103))	('NOX4', 'Gene', '50507', (351, 355))	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (39, 55))	('mutated', 'Var', (69, 76))	('AML', 'Disease', 'MESH:D015470', (57, 60))	('NOX4', 'Gene', (351, 355))	('FLT3', 'Gene', (139, 143))	('AML', 'Disease', (57, 60))	('AML', 'Phenotype', 'HP:0004808', (57, 60))	('synthesis', 'MPA', (164, 173))	('FLT3', 'Gene', '2322', (139, 143))	('activating', 'PosReg', (340, 350))	('NOX4', 'Gene', '50507', (277, 281))	('MS', 'Phenotype', 'HP:0002863', (78, 80))	('transcription', 'MPA', (361, 374))	('increases', 'PosReg', (150, 159))	('NOX4', 'Gene', (277, 281))	('acute myeloid leukemia', 'Disease', (33, 55))	('signal transducer and activator of transcription 5', 'Gene', '6776', (198, 248))	('FMS-like tyrosine kinase 3', 'Gene', '2322', (77, 103))	('STAT5', 'Gene', '6776', (250, 255))	('STAT5', 'Gene', (250, 255))
926698	29478325	NADPH oxidase NOX4-derived O2 - and H2O2 then contribute to the inactivation of protein tyrosine phosphatase, receptor type J (PTPRJ, also known as DEP-1), a transmembrane PTP that negatively regulates FLT3 signaling activity, and the transformation of primary cells.	('PTPRJ', 'Gene', (127, 132))	('H2O2', 'Chemical', 'MESH:D006861', (36, 40))	('PTPRJ', 'Gene', '5795', (127, 132))	('PTP', 'Gene', (172, 175))	('FLT3', 'Gene', (202, 206))	('protein tyrosine phosphatase, receptor type J', 'Gene', '5795', (80, 125))	('O2', 'Chemical', '-', (27, 29))	('H2O2', 'Var', (36, 40))	('FLT3', 'Gene', '2322', (202, 206))	('PTP', 'Gene', '10076', (127, 130))	('inactivation', 'NegReg', (64, 76))	('NADPH', 'Gene', (0, 5))	('NADPH', 'Gene', '1666', (0, 5))	('O2', 'Chemical', '-', (38, 40))	('negatively regulates', 'NegReg', (181, 201))	('NOX4', 'Gene', '50507', (14, 18))	('PTP', 'Gene', '10076', (172, 175))	('transformation of primary cells', 'CPA', (235, 266))	('NOX4', 'Gene', (14, 18))	('PTP', 'Gene', (127, 130))
926699	29478325	Hence, NADPH oxidase NOX4-derived inactivation of PTPRJ could explain increased FLT3 activation and the consequent transformation of hematopoietic cells.	('FLT3', 'Gene', '2322', (80, 84))	('NOX4', 'Gene', (21, 25))	('increased', 'PosReg', (70, 79))	('inactivation', 'Var', (34, 46))	('PTPRJ', 'Gene', '5795', (50, 55))	('NADPH', 'Gene', (7, 12))	('FLT3', 'Gene', (80, 84))	('activation', 'PosReg', (85, 95))	('NADPH', 'Gene', '1666', (7, 12))	('NOX4', 'Gene', '50507', (21, 25))	('PTPRJ', 'Gene', (50, 55))
926702	29478325	Additional evidence for the tumor-promoting role of NADPH oxidase NOX4 was offered by a study demonstrating NADPH oxidase NOX4 increased expression of cyclin-dependent kinase 1 (CDK1) and cell division cycle 25C/M-phase inducer phosphatase 3 (CDC25c), both of which promote cell cycling, anchorage-independent growth, and melanoma tumorigenesis in vivo.	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('tumor', 'Disease', (28, 33))	('NADPH', 'Gene', (52, 57))	('NOX4', 'Gene', '50507', (122, 126))	('CDC25c', 'Gene', '995', (243, 249))	('NADPH', 'Gene', (108, 113))	('NADPH', 'Gene', '1666', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('NADPH', 'Gene', '1666', (108, 113))	('NOX4', 'Gene', '50507', (66, 70))	('NOX4', 'Gene', (122, 126))	('CDC25c', 'Gene', (243, 249))	('expression', 'MPA', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('NOX4', 'Gene', (66, 70))	('CDK1', 'Gene', '983', (178, 182))	('CDK1', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('melanoma tumorigenesis', 'Disease', 'MESH:D063646', (322, 344))	('rat', 'Species', '10116', (101, 104))	('anchorage-independent growth', 'CPA', (288, 316))	('cell cycling', 'CPA', (274, 286))	('melanoma', 'Phenotype', 'HP:0002861', (322, 330))	('25C/M', 'SUBSTITUTION', 'None', (208, 213))	('melanoma tumorigenesis', 'Disease', (322, 344))	('cyclin-dependent kinase 1', 'Gene', '983', (151, 176))	('25C/M', 'Var', (208, 213))	('promote', 'PosReg', (266, 273))	('tumor', 'Disease', (331, 336))	('increased', 'PosReg', (127, 136))	('cyclin-dependent kinase 1', 'Gene', (151, 176))
926713	29478325	This "TGFbeta paradox" is caused by the modification of p53.	('TGFbeta', 'Gene', '7039', (6, 13))	('modification', 'Var', (40, 52))	('p53', 'Gene', (56, 59))	('caused by', 'Reg', (26, 35))	('p53', 'Gene', '7157', (56, 59))	('TGFbeta', 'Gene', (6, 13))
926714	29478325	Wild-type p53, which binds to the nuclear SMAD complex, inhibits growth together with tumor suppressor p63, whereas mutated p53, by binding to the SMAD complex, does not suppress growth and, additionally, inhibits p63 binding to SMAD complex.	('p53', 'Gene', '7157', (10, 13))	('inhibits', 'NegReg', (56, 64))	('inhibits', 'NegReg', (205, 213))	('SMAD', 'Gene', (147, 151))	('SMAD', 'Gene', '4089;4089', (42, 46))	('p53', 'Gene', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('p63', 'Gene', (103, 106))	('SMAD', 'Gene', (42, 46))	('binding', 'Interaction', (218, 225))	('mutated', 'Var', (116, 123))	('p63', 'Gene', '8626', (103, 106))	('p63', 'Gene', (214, 217))	('p63', 'Gene', '8626', (214, 217))	('p53', 'Gene', '7157', (124, 127))	('SMAD', 'Gene', '4089;4089', (229, 233))	('growth', 'MPA', (65, 71))	('SMAD', 'Gene', (229, 233))	('p53', 'Gene', (124, 127))	('tumor', 'Disease', (86, 91))	('SMAD', 'Gene', '4089;4089', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
926723	29478325	Although all five splice variants are expressed in vascular endothelial and smooth muscle cells, the expression of the splice variants shows also tissue-specific expression pattern: NOX5alpha is mainly expressed in the spleen, NOX5beta is mainly expressed in the testis, and truncated NOX5e is mainly expressed in esophageal cancer.	('truncated', 'Var', (275, 284))	('esophageal cancer', 'Disease', (314, 331))	('expressed', 'Reg', (301, 310))	('esophageal cancer', 'Disease', 'MESH:D004938', (314, 331))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))
926731	29478325	Ca2+-dependent activation of PKCalpha and PKCe causes the phosphorylation of NOX5 at Ser490, Thr494, and Ser498.	('activation', 'PosReg', (15, 25))	('Ser490', 'Chemical', '-', (85, 91))	('Ser490', 'Var', (85, 91))	('Ca2+', 'Chemical', 'MESH:D000069285', (0, 4))	('PKCalpha', 'Gene', (29, 37))	('NOX5', 'Protein', (77, 81))	('phosphorylation', 'MPA', (58, 73))	('PKCalpha', 'Gene', '5578', (29, 37))	('Ser498', 'Var', (105, 111))	('PKCe', 'Gene', '5581', (42, 46))	('Thr494', 'Var', (93, 99))	('Thr494', 'Chemical', '-', (93, 99))	('Ser498', 'Chemical', '-', (105, 111))	('PKCe', 'Gene', (42, 46))
926735	29478325	Indeed, direct interaction between calcium/calmodulin-dependent kinase II (CAMKII) and NOX5 results in NOX5 phosphorylation at Ser475, Ser498, Ser502, Ser675, and Thr494 (Fig.	('CAMKII', 'Gene', '818', (75, 81))	('NOX5 phosphorylation', 'MPA', (103, 123))	('Ser502', 'Chemical', '-', (143, 149))	('Ser675', 'Chemical', '-', (151, 157))	('Ser498', 'Var', (135, 141))	('Ser475', 'Chemical', '-', (127, 133))	('Ser498', 'Chemical', '-', (135, 141))	('Ser675', 'Var', (151, 157))	('Thr494', 'Var', (163, 169))	('Thr494', 'Chemical', '-', (163, 169))	('calcium/calmodulin-dependent kinase II', 'Gene', '818', (35, 73))	('Ser502', 'Var', (143, 149))	('interaction', 'Interaction', (15, 26))	('Ser475', 'Var', (127, 133))	('calcium/calmodulin-dependent kinase II', 'Gene', (35, 73))	('CAMKII', 'Gene', (75, 81))
926752	29478325	In the dismutation reaction, the negatively charged substrate O2 - is guided into the positively charged channel of the enzyme by the electrostatic field created by the His-61, Glu-119, Lys-120, Glu130, Glu-131, and Lys-134 network.	('Glu130', 'Var', (195, 201))	('His-61', 'Var', (169, 175))	('Glu', 'Chemical', 'MESH:D018698', (203, 206))	('Glu', 'Chemical', 'MESH:D018698', (195, 198))	('Lys-134', 'Var', (216, 223))	('Glu130', 'Chemical', '-', (195, 201))	('Glu', 'Chemical', 'MESH:D018698', (177, 180))	('Lys-120', 'Var', (186, 193))	('Lys', 'Chemical', 'MESH:D008239', (186, 189))	('His', 'Chemical', 'MESH:D006639', (169, 172))	('rat', 'Species', '10116', (57, 60))	('Glu-131', 'Var', (203, 210))	('Glu-119', 'Var', (177, 184))	('O2', 'Chemical', '-', (62, 64))	('Lys', 'Chemical', 'MESH:D008239', (216, 219))
926753	29478325	Once positively charged lysine amino acids of the network have attracted the substrate into the channel, Arg-141 further directs O2 - into the copper-containing active center where the redox reaction of copper occurs.	('copper', 'Chemical', 'MESH:D003300', (143, 149))	('Arg-141', 'Var', (105, 112))	('substrate into the', 'MPA', (77, 95))	('attracted', 'PosReg', (63, 72))	('lysine amino acids', 'Chemical', '-', (24, 42))	('O2', 'Chemical', '-', (129, 131))	('O2 - into', 'MPA', (129, 138))	('Arg', 'Chemical', 'MESH:D001120', (105, 108))	('rat', 'Species', '10116', (82, 85))	('copper', 'Chemical', 'MESH:D003300', (203, 209))
926757	29478325	SOD1 has been shown to increase PLC-PKC signal transduction that opens voltage-gated Ca2+ channels, allowing Ca2+ influx and causing an increased intracellular Ca2+ concentration in human neuroblastoma cells (Fig.	('allowing', 'PosReg', (100, 108))	('Ca2+', 'Chemical', 'MESH:D000069285', (85, 89))	('intracellular Ca2+ concentration', 'MPA', (146, 178))	('human', 'Species', '9606', (182, 187))	('Ca2+ influx', 'MPA', (109, 120))	('neuroblastoma', 'Disease', 'MESH:D009447', (188, 201))	('Ca2+', 'Chemical', 'MESH:D000069285', (160, 164))	('increase', 'PosReg', (23, 31))	('PKC', 'Gene', (36, 39))	('neuroblastoma', 'Disease', (188, 201))	('PLC', 'Gene', (32, 35))	('SOD1', 'Var', (0, 4))	('increased', 'PosReg', (136, 145))	('rat', 'Species', '10116', (172, 175))	('PLC', 'Gene', '3339', (32, 35))	('Ca2+', 'Chemical', 'MESH:D000069285', (109, 113))	('PKC', 'Gene', '112476', (36, 39))	('neuroblastoma', 'Phenotype', 'HP:0003006', (188, 201))
926760	29478325	The evidence connecting SOD1 and ALS is based on observations suggesting a high number of mutations that affect the ability of the enzyme to increase the risk of ALS development.	('mutations', 'Var', (90, 99))	('ALS', 'Gene', '6647', (162, 165))	('ALS', 'Phenotype', 'HP:0007354', (162, 165))	('ALS', 'Gene', (162, 165))	('ALS', 'Gene', '6647', (33, 36))	('ALS', 'Gene', (33, 36))	('ALS', 'Phenotype', 'HP:0007354', (33, 36))
926761	29478325	Hitherto, there are at least 170 known mutations that are linked to ALS.	('linked', 'Reg', (58, 64))	('ALS', 'Gene', '6647', (68, 71))	('mutations', 'Var', (39, 48))	('ALS', 'Gene', (68, 71))	('ALS', 'Phenotype', 'HP:0007354', (68, 71))
926762	29478325	Mice carrying mutant SOD1 show up to 50-fold reduced affinity for zinc located at the active center of the enzyme.	('reduced', 'NegReg', (45, 52))	('affinity', 'MPA', (53, 61))	('mutant', 'Var', (14, 20))	('Mice', 'Species', '10090', (0, 4))	('SOD1', 'Gene', (21, 25))
926763	29478325	Under reducing conditions, mutant SOD1 can regulate NOX2 activation by stabilizing RAC1 through direct binding to the small GTPase in a redox-insensitive manner, enhancing the NOX2 complex assembly and ROS production.	('mutant', 'Var', (27, 33))	('ROS', 'Chemical', 'MESH:D017382', (202, 205))	('binding', 'Interaction', (103, 110))	('ROS production', 'MPA', (202, 216))	('GTP', 'Chemical', 'MESH:D006160', (124, 127))	('NOX2', 'Gene', '1536', (52, 56))	('NOX2', 'Gene', (52, 56))	('NOX2', 'Gene', '1536', (176, 180))	('enhancing', 'PosReg', (162, 171))	('NOX2', 'Gene', (176, 180))	('RAC1', 'Gene', '5879', (83, 87))	('SOD1', 'Gene', (34, 38))	('RAC1', 'Gene', (83, 87))
926764	29478325	Both wild-type and mutant SOD1 interact with RAC1, maintaining the small GTPase in the active GTP-bound form.	('GTPase', 'Protein', (73, 79))	('GTP', 'Chemical', 'MESH:D006160', (94, 97))	('RAC1', 'Gene', '5879', (45, 49))	('GTP', 'Chemical', 'MESH:D006160', (73, 76))	('mutant', 'Var', (19, 25))	('SOD1', 'Gene', (26, 30))	('RAC1', 'Gene', (45, 49))	('maintaining', 'Reg', (51, 62))
926765	29478325	Importantly, the interaction between wild-type SOD1 and RAC1 is disrupted at increased H2O2 concentrations, thus allowing the hydrolysis of GTP from RAC1, whereas mutant SOD1 lacks redox sensitivity, maintaining the active RAC1-GTP complex, NADPH oxidase NOX2 oxidative burst, and increased production of ROS.	('GTP', 'Chemical', 'MESH:D006160', (140, 143))	('GTP', 'MPA', (140, 143))	('NADPH', 'Gene', (241, 246))	('NADPH', 'Gene', '1666', (241, 246))	('increased', 'PosReg', (281, 290))	('hydrolysis', 'MPA', (126, 136))	('RAC1', 'Gene', (223, 227))	('production', 'MPA', (291, 301))	('NOX2', 'Gene', (255, 259))	('maintaining', 'PosReg', (200, 211))	('RAC1', 'Gene', (56, 60))	('ROS', 'MPA', (305, 308))	('rat', 'Species', '10116', (99, 102))	('SOD1', 'Gene', (170, 174))	('GTP', 'Chemical', 'MESH:D006160', (228, 231))	('ROS', 'Chemical', 'MESH:D017382', (305, 308))	('RAC1', 'Gene', '5879', (223, 227))	('oxidative burst', 'Phenotype', 'HP:0003203', (260, 275))	('RAC1', 'Gene', '5879', (56, 60))	('interaction', 'Interaction', (17, 28))	('H2O2', 'Chemical', 'MESH:D006861', (87, 91))	('NOX2', 'Gene', '1536', (255, 259))	('active', 'MPA', (216, 222))	('RAC1', 'Gene', (149, 153))	('mutant', 'Var', (163, 169))	('RAC1', 'Gene', '5879', (149, 153))
926768	29478325	Inhibition of SOD1 with the ATN-224 small-molecule inhibitor has been suggested to inhibit epidermal growth factor (EGF)- and insulin growth factor (IGF)-stimulated mitogen signal transduction through ERK1/2 kinases.	('SOD1', 'Gene', (14, 18))	('ATN-224', 'Gene', (28, 35))	('ATN-224', 'Chemical', 'MESH:C020809', (28, 35))	('EGF', 'Gene', (116, 119))	('Inhibition', 'Var', (0, 10))	('EGF', 'Gene', '1950', (116, 119))	('ERK1', 'Gene', '5595', (201, 205))	('inhibit', 'NegReg', (83, 90))	('ERK1', 'Gene', (201, 205))
926769	29478325	Mechanistically, the inhibition of SOD1 maintains the concentration of H2O2 at levels that are not adequate to inhibit PTPs, thereby allowing the PTP-mediated inactivation of RTK phosphorylation and attenuation of corresponding downstream signal transduction.	('PTP', 'Gene', (146, 149))	('RTK', 'Protein', (175, 178))	('PTP', 'Gene', '10076', (146, 149))	('inactivation', 'NegReg', (159, 171))	('downstream signal transduction', 'MPA', (228, 258))	('PTPs', 'Gene', (119, 123))	('SOD1', 'Gene', (35, 39))	('PTPs', 'Gene', '5805', (119, 123))	('PTP', 'Gene', (119, 122))	('rat', 'Species', '10116', (61, 64))	('H2O2', 'Chemical', 'MESH:D006861', (71, 75))	('H2O2', 'Var', (71, 75))	('PTP', 'Gene', '10076', (119, 122))	('attenuation', 'NegReg', (199, 210))
926770	29478325	Inhibition of SOD1 by ATN-224 conceivably increases the intracellular O2 - concentration, which, surprisingly, leads to the inhibition of glutathione peroxidase activity with a consequently increased lethal level of intracellular H2O2 concentration.	('intracellular O2 - concentration', 'MPA', (56, 88))	('glutathione peroxidase', 'Enzyme', (138, 160))	('SOD1', 'Gene', (14, 18))	('inhibition', 'NegReg', (124, 134))	('rat', 'Species', '10116', (242, 245))	('increases', 'PosReg', (42, 51))	('O2', 'Chemical', '-', (70, 72))	('O2', 'Chemical', '-', (232, 234))	('ATN-224', 'Chemical', 'MESH:C020809', (22, 29))	('increased', 'PosReg', (190, 199))	('rat', 'Species', '10116', (82, 85))	('lethal level of intracellular H2O2 concentration', 'MPA', (200, 248))	('Inhibition', 'Var', (0, 10))	('ATN-224', 'Gene', (22, 29))	('activity', 'MPA', (161, 169))	('H2O2', 'Chemical', 'MESH:D006861', (230, 234))
926771	29478325	H2O2 induces the expression of proapoptotic Bcl-2 interacting mediator of cell death (BIM) and BCL2 binding component 3 (PUMA), and phosphorylation of p38MAPK, which then causes decreased antiapoptotic factor myeloid cell leukemia 1 (MCL1) expression.	('decreased', 'NegReg', (178, 187))	('BCL2', 'Gene', (95, 99))	('MCL1', 'Gene', (234, 238))	('leukemia', 'Phenotype', 'HP:0001909', (222, 230))	('MCL1', 'Gene', '4170', (234, 238))	('expression', 'MPA', (17, 27))	('expression', 'MPA', (240, 250))	('Bcl-2', 'Gene', (44, 49))	('BIM', 'Gene', (86, 89))	('p38', 'Gene', '26073', (151, 154))	('Bcl-2', 'Gene', '12043', (44, 49))	('phosphorylation', 'MPA', (132, 147))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('p38', 'Gene', (151, 154))	('BIM', 'Gene', '10018', (86, 89))	('myeloid cell leukemia', 'Disease', 'MESH:D007951', (209, 230))	('BCL2', 'Gene', '12043', (95, 99))	('myeloid cell leukemia', 'Disease', (209, 230))	('antiapoptotic factor', 'MPA', (188, 208))	('H2O2', 'Var', (0, 4))
926778	29478325	The study of the contribution of SOD1 to glycolysis suggested that Saccharomyces cerevisiae yeast casein kinase 1 gamma (CK1gamma) homologues Yck1p and Yck2p are stabilized by SOD1 dismutase function.	('yeast', 'Species', '4932', (92, 97))	('CK1gamma', 'Gene', (121, 129))	('Saccharomyces cerevisiae', 'Species', '4932', (67, 91))	('CK1', 'Species', '2498238', (121, 124))	('Yck2p', 'Var', (152, 157))	('Yck1p', 'Var', (142, 147))
926787	29478325	Similar data were obtained for Bcl-2-overexpressing metastatic B16 melanoma cells treated with SOD2 and Bcl2 antisense oligonucleotides.	('B16', 'CellLine', 'CVCL:N540', (63, 66))	('Bcl-2', 'Gene', (31, 36))	('Bcl2', 'Gene', '12043', (104, 108))	('Bcl2', 'Gene', (104, 108))	('Bcl-2', 'Gene', '12043', (31, 36))	('melanoma', 'Disease', (67, 75))	('oligonucleotides', 'Chemical', 'MESH:D009841', (119, 135))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('antisense oligonucleotides', 'Var', (109, 135))
926797	29478325	In addition, increased SOD2 expression is correlated with an increased epithelial-mesenchymal transition (EMT) score in different breast cancer subtypes, whereas the RNAi silencing of SOD2 decreases EMT-related protein (VIMENTIN, beta-CATENIN, SLUG, N-CADHERIN, TWIST, zinc finger E-box binding homeobox 2 [ZEB2], and SNAIL) expression, strongly suggesting a stimulatory role for SOD2 in cancer cell migration and metastasis.	('decreases', 'NegReg', (189, 198))	('TWIST', 'Gene', (262, 267))	('decreases EMT', 'Phenotype', 'HP:0032198', (189, 202))	('zinc finger E-box binding homeobox 2', 'Gene', (269, 305))	('SOD2', 'Gene', (184, 188))	('increased', 'PosReg', (61, 70))	('EMT-related', 'Protein', (199, 210))	('cancer', 'Disease', (137, 143))	('TWIST', 'Gene', '7291', (262, 267))	('VIMENTIN', 'Gene', '7431', (220, 228))	('increased', 'PosReg', (13, 22))	('ZEB2', 'Gene', (307, 311))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('rat', 'Species', '10116', (403, 406))	('zinc finger E-box binding homeobox 2', 'Gene', '9839', (269, 305))	('beta-CATENIN', 'Gene', (230, 242))	('SLUG', 'Gene', '6591', (244, 248))	('N-CADHERIN', 'Gene', '1000', (250, 260))	('SLUG', 'Gene', (244, 248))	('SOD2', 'Gene', (23, 27))	('silencing', 'Var', (171, 180))	('cancer', 'Disease', (388, 394))	('ZEB2', 'Gene', '9839', (307, 311))	('beta-CATENIN', 'Gene', '1499', (230, 242))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('expression', 'MPA', (325, 335))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('SNAIL', 'Gene', '6615', (318, 323))	('SNAIL', 'Gene', (318, 323))	('VIMENTIN', 'Gene', (220, 228))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('N-CADHERIN', 'Gene', (250, 260))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('breast cancer', 'Disease', (130, 143))	('epithelial-mesenchymal transition', 'CPA', (71, 104))	('expression', 'MPA', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (388, 394))
926819	29478325	Interestingly, increased SOD3 expression has a stimulatory effect on RAS activation by GTP loading, suggesting a positive feedback loop: SOD3 increases RAS activation, which induces downstream signaling, causing increased SOD3 production (Fig.	('SOD3 production', 'MPA', (222, 237))	('increases', 'PosReg', (142, 151))	('activation', 'MPA', (156, 166))	('GTP', 'Chemical', 'MESH:D006160', (87, 90))	('SOD3', 'Var', (137, 141))	('RAS', 'Protein', (152, 155))	('increased', 'PosReg', (212, 221))
926829	29478325	In advanced cancers, RAS-induced epigenetic methylation and acetylation have been shown to contribute to more pronounce silencing of SOD3.	('epigenetic methylation', 'Var', (33, 55))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('acetylation', 'MPA', (60, 71))	('SOD3', 'Gene', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('silencing', 'MPA', (120, 129))
926830	29478325	Therefore, the regulation of SOD3 expression can be divided into reversible regulation by small GTPase regulatory genes, mir21, or p38MAPK and irreversible epigenetic silencing by methylation and acetylation.	('SOD3', 'Gene', (29, 33))	('GTPase regulatory genes', 'Gene', (96, 119))	('GTP', 'Chemical', 'MESH:D006160', (96, 99))	('p38', 'Gene', (131, 134))	('epigenetic silencing', 'Var', (156, 176))	('mir21', 'Gene', '406991', (121, 126))	('mir21', 'Gene', (121, 126))	('methylation', 'Var', (180, 191))	('p38', 'Gene', '26073', (131, 134))
926834	29478325	More recent works have demonstrated a dose-dependent growth response for the enzyme, clarifying the controversy between recently and previously published data and demonstrating that, at the physiological level or at moderately increased level, SOD3 supports cell proliferation and cell survival, and reduces apoptosis by regulating RAS activation.	('apoptosis', 'CPA', (308, 317))	('supports', 'PosReg', (249, 257))	('reduces', 'NegReg', (300, 307))	('RAS', 'Protein', (332, 335))	('rat', 'Species', '10116', (270, 273))	('cell proliferation', 'CPA', (258, 276))	('activation', 'MPA', (336, 346))	('rat', 'Species', '10116', (170, 173))	('rat', 'Species', '10116', (30, 33))	('rat', 'Species', '10116', (220, 223))	('cell survival', 'CPA', (281, 294))	('SOD3', 'Var', (244, 248))
926836	29478325	It is not quite clear how enzyme overexpression increases RTK phosphorylation, but it could be mediated by the ability of H2O2 to oxidatively inactivate PTPs by modifying the catalytic site cysteine amino acids, thereby causing persistent RTK activation as a response of ligand binding to the receptor.	('inactivate', 'NegReg', (142, 152))	('PTPs', 'Gene', '5805', (153, 157))	('causing', 'Reg', (220, 227))	('PTPs', 'Gene', (153, 157))	('ligand binding', 'Interaction', (271, 285))	('RTK', 'MPA', (239, 242))	('activation', 'PosReg', (243, 253))	('RTK phosphorylation', 'MPA', (58, 77))	('cysteine amino acids', 'Chemical', '-', (190, 210))	('modifying', 'Reg', (161, 170))	('H2O2', 'Chemical', 'MESH:D006861', (122, 126))	('H2O2', 'Var', (122, 126))	('catalytic', 'MPA', (175, 184))
926840	29478325	Thus, SOD3-driven modification of small GTPase regulatory gene expression inhibits the progression of signal transduction downstream of RAS.	('progression of signal transduction downstream', 'MPA', (87, 132))	('modification', 'Var', (18, 30))	('inhibits', 'NegReg', (74, 82))	('small GTPase', 'Protein', (34, 46))	('GTP', 'Chemical', 'MESH:D006160', (40, 43))
926841	29478325	Moderately increased (~2- to 4-fold increased enzyme activation level and 10- to 15-fold increased mRNA level) SOD3 expression stimulates GTP loading to small GTPases, thus allowing cell membrane signal transduction to pass RAS to the downstream signaling network (Fig.	('mRNA level', 'MPA', (99, 109))	('SOD3', 'Gene', (111, 115))	('cell membrane signal transduction', 'MPA', (182, 215))	('increased', 'PosReg', (11, 20))	('GTP loading', 'MPA', (138, 149))	('allowing', 'Reg', (173, 181))	('stimulates', 'PosReg', (127, 137))	('expression', 'Var', (116, 126))	('GTP', 'Chemical', 'MESH:D006160', (138, 141))	('GTP', 'Chemical', 'MESH:D006160', (159, 162))	('increased', 'PosReg', (36, 45))	('rat', 'Species', '10116', (4, 7))	('increased', 'PosReg', (89, 98))	('enzyme activation level', 'MPA', (46, 69))
926892	29478325	Modifications in the intracellular Ca2+ concentrations consecutively activate downstream signaling, stimulating the PKC pathway that causes increased NADPH NOX and SOD activation (Fig.	('PKC', 'Gene', '112476', (116, 119))	('NADPH', 'Gene', (150, 155))	('NADPH', 'Gene', '1666', (150, 155))	('activate', 'PosReg', (69, 77))	('SOD', 'Gene', '6647', (164, 167))	('rat', 'Species', '10116', (47, 50))	('Ca2+', 'Chemical', 'MESH:D000069285', (35, 39))	('activation', 'PosReg', (168, 178))	('Modifications', 'Var', (0, 13))	('increased', 'PosReg', (140, 149))	('SOD', 'Gene', (164, 167))	('stimulating', 'Reg', (100, 111))	('PKC', 'Gene', (116, 119))
926897	29478325	In ALS models, Ca2+ has been demonstrated to cause conformational changes, increasing SOD1 beta-sheet structures and consequently increasing neurotoxic SOD1 aggregation into the cells, therefore promoting disease progression.	('SOD1 beta-sheet', 'Protein', (86, 101))	('ALS', 'Phenotype', 'HP:0007354', (3, 6))	('increasing', 'PosReg', (75, 85))	('rat', 'Species', '10116', (36, 39))	('increasing', 'PosReg', (130, 140))	('ALS', 'Gene', (3, 6))	('neurotoxic', 'Disease', 'MESH:D020258', (141, 151))	('ALS', 'Gene', '6647', (3, 6))	('Ca2+', 'Var', (15, 19))	('Ca2+', 'Chemical', 'MESH:D000069285', (15, 19))	('neurotoxic', 'Disease', (141, 151))	('promoting', 'PosReg', (195, 204))
926899	29478325	H2O2 produced by SOD2 induces oxidative inactivation of PTEN by conversion of the sulfhydrul groups to a disulfide causing more compact protein structure.	('more', 'PosReg', (123, 127))	('PTEN', 'Gene', (56, 60))	('PTEN', 'Gene', '5728', (56, 60))	('disulfide', 'Chemical', 'MESH:D004220', (105, 114))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))	('oxidative inactivation', 'MPA', (30, 52))
926901	29478325	SOD2 function then increases the cellular content of PIP2, which also functions as a mediator of GPCR signaling, stimulating the PLC-IP3/DAG signaling pathway and leading to increased Ca2+ synthesis.	('stimulating', 'PosReg', (113, 124))	('DAG', 'Chemical', 'MESH:D004075', (137, 140))	('PLC-IP3/DAG signaling pathway', 'Pathway', (129, 158))	('GPCR', 'Gene', '10663', (97, 101))	('cellular content', 'MPA', (33, 49))	('Ca2+ synthesis', 'MPA', (184, 198))	('increases', 'PosReg', (19, 28))	('PLC-IP3', 'Chemical', '-', (129, 136))	('function', 'Var', (5, 13))	('Ca2+', 'Chemical', 'MESH:D000069285', (184, 188))	('PIP2', 'Chemical', 'MESH:D019269', (53, 57))	('increased', 'PosReg', (174, 183))	('GPCR', 'Gene', (97, 101))	('SOD2', 'Gene', (0, 4))
926914	29478325	Interestingly, small GTPase activity is affected also by SOD1, especially by mutant SOD1, by direct interaction, as demonstrated in ALS models.	('affected', 'Reg', (40, 48))	('activity', 'MPA', (28, 36))	('interaction', 'Interaction', (100, 111))	('GTP', 'Chemical', 'MESH:D006160', (21, 24))	('ALS', 'Gene', (132, 135))	('ALS', 'Gene', '6647', (132, 135))	('SOD1', 'Gene', (84, 88))	('rat', 'Species', '10116', (123, 126))	('ALS', 'Phenotype', 'HP:0007354', (132, 135))	('GTPase', 'Protein', (21, 27))	('mutant', 'Var', (77, 83))
926915	29478325	As described above, the interaction between small GTPase RAC1 and SOD1 is enhanced by mutations in the SOD1 gene that maintains downstream RAC1 signaling, leading to increased inflammatory cytokine production and the risk of ALS development (Fig.	('SOD1', 'Gene', (103, 107))	('mutations', 'Var', (86, 95))	('inflammatory cytokine production', 'MPA', (176, 208))	('RAC1', 'Gene', '5879', (139, 143))	('interaction', 'Interaction', (24, 35))	('SOD1', 'Gene', (66, 70))	('increased', 'PosReg', (166, 175))	('RAC1', 'Gene', '5879', (57, 61))	('RAC1', 'Gene', (139, 143))	('ALS', 'Gene', '6647', (225, 228))	('RAC1', 'Gene', (57, 61))	('ALS', 'Phenotype', 'HP:0007354', (225, 228))	('ALS', 'Gene', (225, 228))	('enhanced', 'PosReg', (74, 82))	('GTP', 'Chemical', 'MESH:D006160', (50, 53))
926917	29478325	The SRC proto-oncogene has been demonstrated to activate NADPH oxidases NOX1-, NOX3-, NOX4-, and NOX5-induced O2 - production in cancer models and to increase mutant SOD1 aggregate formation in ALS.	('NOX3', 'Gene', '50508', (79, 83))	('NOX1', 'Gene', '27035', (72, 76))	('SOD1', 'Gene', (166, 170))	('cancer', 'Disease', (129, 135))	('ALS', 'Phenotype', 'HP:0007354', (194, 197))	('increase', 'PosReg', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('NOX1', 'Gene', (72, 76))	('NOX5-induced O2 - production', 'MPA', (97, 125))	('mutant', 'Var', (159, 165))	('NOX3', 'Gene', (79, 83))	('rat', 'Species', '10116', (39, 42))	('NADPH', 'Gene', (57, 62))	('NADPH', 'Gene', '1666', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('ALS', 'Gene', (194, 197))	('SRC', 'Gene', '6714', (4, 7))	('O2', 'Chemical', '-', (110, 112))	('NOX4', 'Gene', '50507', (86, 90))	('activate', 'PosReg', (48, 56))	('aggregate formation', 'MPA', (171, 190))	('ALS', 'Gene', '6647', (194, 197))	('NOX4', 'Gene', (86, 90))	('SRC', 'Gene', (4, 7))
926925	29478325	A recent study utilizing induced pluripotent stem cells (iPSCs) derived from ALS patient with SOD1 mutations suggested that increased phosphorylation of SRC-ABL (Abelson murine leukemia viral oncogene homologue 1) causes the degeneration of motor neurons differentiated from iPSCs.	('SRC', 'Gene', '6714', (153, 156))	('patient', 'Species', '9606', (81, 88))	('rat', 'Species', '10116', (231, 234))	('ALS', 'Gene', (77, 80))	('ABL', 'Gene', '25', (157, 160))	('leukemia', 'Disease', (177, 185))	('leukemia', 'Disease', 'MESH:D007938', (177, 185))	('phosphorylation', 'MPA', (134, 149))	('SRC', 'Gene', (153, 156))	('increased', 'PosReg', (124, 133))	('degeneration', 'NegReg', (225, 237))	('SOD1', 'Gene', (94, 98))	('ALS', 'Gene', '6647', (77, 80))	('ABL', 'Gene', (157, 160))	('ALS', 'Phenotype', 'HP:0007354', (77, 80))	('murine', 'Species', '10090', (170, 176))	('mutations', 'Var', (99, 108))	('motor neurons differentiated', 'CPA', (241, 269))	('leukemia', 'Phenotype', 'HP:0001909', (177, 185))
926926	29478325	Interestingly, the inhibition of SRC-ABL inhibited motor neuron degeneration by reducing SOD1 misfolding and restoring energy homeostasis.	('rat', 'Species', '10116', (70, 73))	('inhibition', 'Var', (19, 29))	('SRC', 'Gene', '6714', (33, 36))	('SRC', 'Gene', (33, 36))	('SOD1 misfolding', 'MPA', (89, 104))	('energy homeostasis', 'MPA', (119, 137))	('ABL', 'Gene', (37, 40))	('motor neuron degeneration', 'CPA', (51, 76))	('restoring', 'PosReg', (109, 118))	('inhibited', 'NegReg', (41, 50))	('ABL', 'Gene', '25', (37, 40))	('reducing', 'NegReg', (80, 88))	('motor neuron degeneration', 'Phenotype', 'HP:0007373', (51, 76))
926929	29478325	In numerous cancers, aberrant ROS production regulates proliferation, survival, angiogenesis, and stroma remodeling.	('angiogenesis', 'CPA', (80, 92))	('ROS', 'Protein', (30, 33))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('aberrant', 'Var', (21, 29))	('cancers', 'Disease', (12, 19))	('proliferation', 'CPA', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('regulates', 'Reg', (45, 54))	('survival', 'CPA', (70, 78))	('rat', 'Species', '10116', (62, 65))	('stroma remodeling', 'CPA', (98, 115))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
926942	29478325	ROS then promote SRC-mediated phosphorylation of protein kinase D1 at Tyr95, Tyr432, Tyr436, and Tyr502 with consequent activation of NFkappaB, increased expression of RTK EGFR, and its ligands EGF and TGFalpha.	('EGFR', 'Gene', (172, 176))	('Tyr95', 'Chemical', '-', (70, 75))	('NFkappaB', 'Gene', (134, 142))	('SRC', 'Gene', (17, 20))	('Tyr436', 'Chemical', '-', (85, 91))	('Tyr432', 'Var', (77, 83))	('promote', 'PosReg', (9, 16))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('Tyr502', 'Chemical', '-', (97, 103))	('Tyr502', 'Var', (97, 103))	('activation', 'PosReg', (120, 130))	('ROS', 'Gene', (0, 3))	('TGFalpha', 'Gene', (202, 210))	('EGF', 'Gene', (172, 175))	('EGF', 'Gene', '1950', (194, 197))	('EGFR', 'Gene', '1956', (172, 176))	('Tyr95', 'Var', (70, 75))	('Tyr436', 'Var', (85, 91))	('TGFalpha', 'Gene', '7039', (202, 210))	('increased', 'PosReg', (144, 153))	('EGF', 'Gene', (194, 197))	('Tyr432', 'Chemical', '-', (77, 83))	('NFkappaB', 'Gene', '4790', (134, 142))	('protein kinase D1', 'Enzyme', (49, 66))	('SRC', 'Gene', '6714', (17, 20))	('EGF', 'Gene', '1950', (172, 175))	('expression', 'MPA', (154, 164))
926949	29478325	Aberrations in the availability of the thyroid-stimulating hormone (TSH) ligand or mutations in downstream cascades disrupt the delicate signaling network, resulting in various thyroid pathologies; thus, the constant stable level secretion of TSH is important for normal thyroid function.	('mutations', 'Var', (83, 92))	('thyroid pathologies', 'Disease', (177, 196))	('delicate signaling network', 'Pathway', (128, 154))	('TSH', 'Chemical', 'MESH:D013972', (243, 246))	('TSH', 'Chemical', 'MESH:D013972', (68, 71))	('rat', 'Species', '10116', (4, 7))	('Aberrations', 'Var', (0, 11))	('resulting in', 'Reg', (156, 168))	('disrupt', 'NegReg', (116, 123))
926951	29478325	Increased TSH levels activate downstream growth signal transduction, causing thyroid enlargement known as goiter, the most common thyroid disorder characterized by hyperplasia and hypertrophy.	('thyroid disorder', 'Disease', (130, 146))	('activate', 'PosReg', (21, 29))	('goiter', 'Disease', (106, 112))	('TSH', 'MPA', (10, 13))	('thyroid enlargement', 'Disease', 'MESH:D013959', (77, 96))	('causing', 'Reg', (69, 76))	('thyroid enlargement', 'Disease', (77, 96))	('hyperplasia', 'Disease', (164, 175))	('hypertrophy', 'Disease', 'MESH:D006984', (180, 191))	('thyroid enlargement', 'Phenotype', 'HP:0008249', (77, 96))	('thyroid disorder', 'Phenotype', 'HP:0000820', (130, 146))	('TSH', 'Chemical', 'MESH:D013972', (10, 13))	('Increased', 'Var', (0, 9))	('hyperplasia', 'Disease', 'MESH:D006965', (164, 175))	('goiter', 'Disease', 'MESH:D006042', (106, 112))	('thyroid disorder', 'Disease', 'MESH:D013959', (130, 146))	('hypertrophy', 'Disease', (180, 191))	('growth signal transduction', 'Pathway', (41, 67))	('goiter', 'Phenotype', 'HP:0000853', (106, 112))	('Increased TSH', 'Phenotype', 'HP:0002925', (0, 13))
926953	29478325	Thyroid tumors originate from follicular and parafollicular C cells by genetic and epigenetic alterations, with consequent uncontrolled activation of signaling pathways maintaining thyroid cancer progression.	('thyroid cancer', 'Disease', 'MESH:D013964', (181, 195))	('signaling pathways', 'Pathway', (150, 168))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('rat', 'Species', '10116', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('Thyroid tumors', 'Disease', 'MESH:D013966', (0, 14))	('thyroid cancer', 'Phenotype', 'HP:0002890', (181, 195))	('thyroid cancer', 'Disease', (181, 195))	('epigenetic alterations', 'Var', (83, 105))	('Thyroid tumors', 'Disease', (0, 14))
926954	29478325	Until now, the observed mutated genes include BRAF, RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kalpha), PTEN, TP53, beta-CATENIN, anaplastic lymphoma kinase (ALK), isocitrate dehydrogenase 1 (IDH1), rearrangement of rearranged during transfection (RET)-PTC, and paired box 8 (PAX8)-peroxisome proliferator-activated receptor gamma (PPARgamma) resulting in aberrantly activated signal transduction pathways downstream of mutated genes.	('PPARgamma', 'Gene', (369, 378))	('PTEN', 'Gene', (141, 145))	('PAX8', 'Gene', (313, 317))	('PI3Kalpha', 'Gene', '5290', (129, 138))	('ALK', 'Gene', '238', (195, 198))	('beta-CATENIN', 'Gene', (153, 165))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('TP53', 'Gene', (147, 151))	('RET', 'Gene', '5979', (285, 288))	('IDH1', 'Gene', (229, 233))	('PTEN', 'Gene', '5728', (141, 145))	('PAX8', 'Gene', '7849', (313, 317))	('beta-CATENIN', 'Gene', '1499', (153, 165))	('ALK', 'Gene', (195, 198))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (57, 127))	('anaplastic lymphoma kinase', 'Gene', '238', (167, 193))	('signal transduction pathways', 'Pathway', (414, 442))	('aberrantly', 'Reg', (393, 403))	('isocitrate dehydrogenase 1', 'Gene', (201, 227))	('isocitrate dehydrogenase 1', 'Gene', '3417', (201, 227))	('anaplastic lymphoma kinase', 'Gene', (167, 193))	('PPARgamma', 'Gene', '5468', (369, 378))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (167, 186))	('IDH1', 'Gene', '3417', (229, 233))	('RET', 'Gene', (285, 288))	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (319, 367))	('PI3Kalpha', 'Gene', (129, 138))	('TP53', 'Gene', '7157', (147, 151))	('activated', 'PosReg', (404, 413))	('PTC', 'Gene', (290, 293))	('PTC', 'Gene', '5979', (290, 293))	('lymphoma', 'Phenotype', 'HP:0002665', (178, 186))	('peroxisome proliferator-activated receptor gamma', 'Gene', (319, 367))	('rearrangement', 'Var', (236, 249))
926955	29478325	RAS and BRAFV600E mutations constitutively activate the Ras Association Domain Family Member 1 (RASSF1):mammalian STE20-like protein kinase 1 (MST1) :FOXO3 signaling pathway, and MEK1/2-ERK1/2 pathway.	('RASSF1', 'Gene', (96, 102))	('RAS', 'Gene', (0, 3))	('BRAFV600E', 'Mutation', 'rs113488022', (8, 17))	('FOXO3', 'Gene', (150, 155))	('Ras Association Domain Family Member 1', 'Gene', '11186', (56, 94))	('mammalian STE20-like protein kinase 1', 'Gene', '6789', (104, 141))	('MEK', 'Gene', '5609', (179, 182))	('MST1', 'Gene', (143, 147))	('MS', 'Phenotype', 'HP:0002863', (143, 145))	('BRAFV600E', 'Gene', (8, 17))	('activate', 'PosReg', (43, 51))	('ERK1', 'Gene', (186, 190))	('MEK', 'Gene', (179, 182))	('FOXO3', 'Gene', '2309', (150, 155))	('mammalian STE20-like protein kinase 1', 'Gene', (104, 141))	('ERK1', 'Gene', '5595', (186, 190))	('Ras Association Domain Family Member 1', 'Gene', (56, 94))	('MST1', 'Gene', '4485', (143, 147))	('RASSF1', 'Gene', '11186', (96, 102))	('mutations', 'Var', (18, 27))
926959	29478325	The PI3K-AKT pathway is activated by a mutation in PI3Kalpha encoding the catalytic p110alpha subunit or in the PTEN phosphatase gene that functions as a tumor suppressor regulating PI3K activity.	('PI3', 'Gene', (4, 7))	('PI3', 'Gene', (51, 54))	('tumor', 'Disease', (154, 159))	('AKT', 'Gene', '207', (9, 12))	('PI3', 'Gene', '5266', (182, 185))	('p110alpha', 'Gene', '5290', (84, 93))	('PI3Kalpha', 'Gene', '5290', (51, 60))	('p110alpha', 'Gene', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('PTEN', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PI3', 'Gene', (182, 185))	('activated', 'PosReg', (24, 33))	('mutation', 'Var', (39, 47))	('PI3Kalpha', 'Gene', (51, 60))	('PI3', 'Gene', '5266', (51, 54))	('PI3', 'Gene', '5266', (4, 7))	('AKT', 'Gene', (9, 12))	('PTEN', 'Gene', '5728', (112, 116))
926962	29478325	Mutations affecting the pathway are less common in follicular thyroid adenoma than in follicular thyroid carcinoma, and therefore, mutations affecting PI3K activity may promote the conversion of adenoma cells to carcinoma cells.	('adenoma', 'Disease', 'MESH:D000236', (195, 202))	('follicular thyroid carcinoma', 'Disease', 'MESH:C572845', (86, 114))	('conversion', 'CPA', (181, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('thyroid adenoma', 'Disease', 'MESH:D013964', (62, 77))	('carcinoma', 'Disease', (105, 114))	('thyroid adenoma', 'Disease', (62, 77))	('PI3', 'Gene', '5266', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('Mutations', 'Var', (0, 9))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (86, 114))	('adenoma', 'Disease', (70, 77))	('thyroid adenoma', 'Phenotype', 'HP:0000854', (62, 77))	('carcinoma', 'Disease', (212, 221))	('adenoma', 'Disease', 'MESH:D000236', (70, 77))	('activity', 'MPA', (156, 164))	('carcinoma', 'Disease', 'MESH:D002277', (105, 114))	('PI3', 'Gene', (151, 154))	('follicular thyroid carcinoma', 'Disease', (86, 114))	('mutations', 'Var', (131, 140))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (97, 114))	('carcinoma', 'Disease', 'MESH:D002277', (212, 221))	('adenoma', 'Disease', (195, 202))	('promote', 'PosReg', (169, 176))
927009	29478325	NOX5 expression demonstrated a moderate 17.6% (SD 27.4) increase in PTC tissue (Fig.	('increase', 'PosReg', (56, 64))	('rat', 'Species', '10116', (23, 26))	('NOX5', 'Var', (0, 4))	('PTC', 'Gene', (68, 71))	('PTC', 'Gene', '5979', (68, 71))	('rat', 'Species', '10116', (35, 38))
927021	29478325	Colon cancer, similar to thyroid cancer, is a well-characterized disease, which often progresses from benign adenoma to malignant adenocarcinoma and gains oncogene mutations influencing signal transduction, thereby altering redox gene expression.	('adenoma to malignant adenocarcinoma', 'Disease', 'MESH:D000230', (109, 144))	('thyroid cancer', 'Phenotype', 'HP:0002890', (25, 39))	('Colon cancer', 'Phenotype', 'HP:0003003', (0, 12))	('redox gene expression', 'MPA', (224, 245))	('oncogene', 'Gene', (155, 163))	('gains', 'PosReg', (149, 154))	('thyroid cancer', 'Disease', 'MESH:D013964', (25, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('Colon cancer', 'Disease', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('adenoma to malignant adenocarcinoma', 'Disease', (109, 144))	('signal transduction', 'MPA', (186, 205))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Colon cancer', 'Disease', 'MESH:D015179', (0, 12))	('altering', 'Reg', (215, 223))	('mutations', 'Var', (164, 173))	('thyroid cancer', 'Disease', (25, 39))
927022	29478325	Colon tumorigenesis is caused by genotoxic stress-derived protumorigenic DNA mutations, activation of oncogenes, and inactivation of tumor suppressor genes in which ROS have a contributory function.	('tumor', 'Disease', (61, 66))	('activation', 'PosReg', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('ROS', 'Chemical', 'MESH:D017382', (165, 168))	('inactivation', 'Var', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('oncogenes', 'Gene', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('caused', 'Reg', (23, 29))	('tumor', 'Disease', (6, 11))
927026	29478325	Characteristically, these early events include inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene that controls growth-promoting WNT signaling by forming the beta-catenin destruction complex together with axis inhibition protein (AXIN), CK1, glycogen synthase kinase 3beta (GSK3beta), causing cytoplasmic degradation of beta-catenin.	('axis inhibition protein', 'Gene', '8312', (239, 262))	('beta-catenin', 'Gene', '1499', (192, 204))	('beta-catenin', 'Gene', (354, 366))	('adenomatous polyposis coli (APC) tumor', 'Disease', 'MESH:D011125', (77, 115))	('CK1', 'Species', '2498238', (271, 274))	('AXIN', 'Gene', (264, 268))	('AXIN', 'Gene', '8312', (264, 268))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('beta-catenin', 'Gene', '1499', (354, 366))	('GSK3beta', 'Gene', (308, 316))	('GSK3beta', 'Gene', '2931', (308, 316))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (77, 98))	('axis inhibition protein', 'Gene', (239, 262))	('inactivating mutations', 'Var', (47, 69))	('beta-catenin', 'Gene', (192, 204))	('cytoplasmic degradation', 'MPA', (327, 350))	('causing', 'Reg', (319, 326))
927027	29478325	Mutations in APC result in the disrupted function of the beta-catenin destruction complex, increased accumulation of beta-catenin in the cytoplasm, and eventually increased beta-catenin translocation into the nucleus.	('beta-catenin', 'Gene', (117, 129))	('APC', 'Disease', 'MESH:D011125', (13, 16))	('function', 'MPA', (41, 49))	('increased', 'PosReg', (163, 172))	('APC', 'Disease', (13, 16))	('beta-catenin', 'Gene', '1499', (117, 129))	('beta-catenin', 'Gene', (173, 185))	('Mutations', 'Var', (0, 9))	('increased accumulation', 'PosReg', (91, 113))	('disrupted', 'NegReg', (31, 40))	('beta-catenin', 'Gene', (57, 69))	('beta-catenin', 'Gene', '1499', (173, 185))	('beta-catenin', 'Gene', '1499', (57, 69))
927029	29478325	Recently, the importance of changes in colon microbiota has been suggested to increase cancer risk by producing bacterial toxins, such as colibactin.	('increase cancer', 'Disease', (78, 93))	('colibactin', 'Chemical', 'MESH:C569566', (138, 148))	('increase cancer', 'Disease', 'MESH:D009369', (78, 93))	('bacterial toxins', 'MPA', (112, 128))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('changes', 'Var', (28, 35))
927043	29478325	Metastatic cancer progression has been shown to commit mutations affecting proto-oncogenes, especially those of KRAS, NRAS, and BRAF that promote cellular migration and invasion, causing characteristic metastasis to the liver, lung, bone, and brain.	('Metastatic cancer', 'Disease', (0, 17))	('Metastatic cancer', 'Disease', 'MESH:D009369', (0, 17))	('BRAF', 'Gene', '673', (128, 132))	('causing', 'Reg', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('invasion', 'CPA', (169, 177))	('mutations', 'Var', (55, 64))	('NRAS', 'Gene', (118, 122))	('NRAS', 'Gene', '4893', (118, 122))	('cellular migration', 'CPA', (146, 164))	('promote', 'PosReg', (138, 145))	('KRAS', 'Gene', (112, 116))	('rat', 'Species', '10116', (158, 161))	('KRAS', 'Gene', '3845', (112, 116))	('metastasis', 'CPA', (202, 212))	('BRAF', 'Gene', (128, 132))
927045	29478325	The accumulation of genetic lesions in tumor suppressor gene TP53 and the switch of the tumor suppressor TGFbetaR-SMAD pathway into a tumor promoter by mutation in SMAD4 are further drivers of tumor progression, indicating the complex nature of the disease.	('genetic lesions', 'Disease', 'MESH:D020022', (20, 35))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('SMAD', 'Gene', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('TP53', 'Gene', (61, 65))	('SMAD', 'Gene', '4089;4089', (114, 118))	('SMAD4', 'Gene', (164, 169))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (88, 93))	('mutation', 'Var', (152, 160))	('SMAD', 'Gene', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('genetic lesions', 'Disease', (20, 35))	('tumor', 'Disease', (39, 44))	('TP53', 'Gene', '7157', (61, 65))	('tumor', 'Disease', (134, 139))	('SMAD4', 'Gene', '4089', (164, 169))	('TGFbeta', 'Gene', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('TGFbeta', 'Gene', '7039', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('SMAD', 'Gene', '4089;4089', (164, 168))
927051	29478325	According to previous publications, phosphorylated FOXO3a is translocated from the nucleus into the cytoplasm, inactivating the mRNA synthesis of the target genes SOD1, SOD2, and catalase but also increasing mir21 expression, which targets SOD3 mRNA 3'UTR, resulting in degradation of mRNA.	('catalase', 'Gene', (179, 187))	('phosphorylated', 'Var', (36, 50))	('inactivating', 'NegReg', (111, 123))	('increasing', 'PosReg', (197, 207))	('mir21', 'Gene', '406991', (208, 213))	('catalase', 'Gene', '847', (179, 187))	('mir21', 'Gene', (208, 213))	('mRNA synthesis', 'MPA', (128, 142))	('FOXO3a', 'Gene', '2309', (51, 57))	('degradation', 'MPA', (270, 281))	('FOXO3a', 'Gene', (51, 57))	('mRNA', 'MPA', (285, 289))	('expression', 'MPA', (214, 224))
927069	29478325	The database suggests increased overall mRNA synthesis for SOD1 and SOD2 in adenocarcinoma (142% and 77.1%, respectively), although the variations between patients are high as observed in adenoma development: SD 347.4 for SOD1 and SD 108.1 for SOD2.	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('adenoma', 'Disease', 'MESH:D000236', (188, 195))	('SD 347.4', 'Var', (209, 217))	('adenoma', 'Disease', (188, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('increased', 'PosReg', (22, 31))	('mRNA synthesis', 'MPA', (40, 54))	('adenocarcinoma', 'Disease', (76, 90))	('SOD2', 'Gene', (68, 72))	('patients', 'Species', '9606', (155, 163))	('SOD1', 'Gene', (59, 63))
927080	29478325	Breast cancer risk factors are frequently associated with oxidative stress-linked phenomena, such as aging, obesity, smoking, or alcohol consumption, and the pedigree of patients, which is the basis for the hereditary breast/ovarian syndrome that can be caused by mutations in BREAST CANCER 1 (BRCA1), BRCA2, and TP53 tumor suppressor genes.	('mutations', 'Var', (264, 273))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('BREAST CANCER 1', 'Gene', '672', (277, 292))	('obesity', 'Disease', 'MESH:D009765', (108, 115))	('BRCA2', 'Gene', (302, 307))	('TP53', 'Gene', (313, 317))	('hereditary breast/ovarian syndrome', 'Disease', 'MESH:D061325', (207, 241))	('tumor', 'Disease', (318, 323))	('caused by', 'Reg', (254, 263))	('BREAST CANCER 1', 'Gene', (277, 292))	('patients', 'Species', '9606', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('hereditary breast/ovarian syndrome', 'Disease', (207, 241))	('BRCA2', 'Gene', '675', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('obesity', 'Phenotype', 'HP:0001513', (108, 115))	('CANCER', 'Phenotype', 'HP:0002664', (284, 290))	('BREAST CANCER', 'Phenotype', 'HP:0003002', (277, 290))	('BRCA1', 'Gene', '672', (294, 299))	('TP53', 'Gene', '7157', (313, 317))	('BRCA1', 'Gene', (294, 299))	('associated', 'Reg', (42, 52))	('alcohol', 'Chemical', 'MESH:D000438', (129, 136))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('oxidative stress', 'Phenotype', 'HP:0025464', (58, 74))	('Breast cancer', 'Disease', (0, 13))	('obesity', 'Disease', (108, 115))
927086	29478325	In breast cancer, germ line mutations in BRCA1 and BRCA2 are examples of genomic instability that increases tumor susceptibility.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('BRCA2', 'Gene', (51, 56))	('BRCA1', 'Gene', '672', (41, 46))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('BRCA1', 'Gene', (41, 46))	('tumor', 'Disease', (108, 113))	('BRCA2', 'Gene', '675', (51, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('increases', 'PosReg', (98, 107))	('mutations', 'Var', (28, 37))
927090	29478325	Alternatively, AKT1 phosphorylation may increase SP1 transcription factor synthesis and subsequent NADPH oxidase NOX4 production, which is paralleled with increased F-actin polymerization, invapodia formation, and increased invasion.	('NADPH', 'Gene', (99, 104))	('NADPH', 'Gene', '1666', (99, 104))	('NOX4', 'Gene', '50507', (113, 117))	('increased', 'PosReg', (155, 164))	('increase', 'PosReg', (40, 48))	('AKT1', 'Gene', '207', (15, 19))	('increased', 'PosReg', (214, 223))	('invasion', 'CPA', (224, 232))	('phosphorylation', 'Var', (20, 35))	('NOX4', 'Gene', (113, 117))	('F-actin polymerization', 'MPA', (165, 187))	('AKT1', 'Gene', (15, 19))	('SP1 transcription factor synthesis', 'MPA', (49, 83))
927102	29478325	Characteristically, NSCLC may develop resistance to therapy by driver mutations in EGFR, BIM, KRAS, MET, and HER2 that alter downstream signaling, allowing the tumors to bypass the upstream tyrosine kinase-targeted therapy.	('KRAS', 'Gene', (94, 98))	('EGFR', 'Gene', (83, 87))	('tyrosine', 'Chemical', 'MESH:D014443', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('BIM', 'Gene', (89, 92))	('tumors', 'Disease', (160, 166))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('HER2', 'Gene', '2064', (109, 113))	('BIM', 'Gene', '10018', (89, 92))	('NSCLC', 'Disease', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('EGFR', 'Gene', '1956', (83, 87))	('mutations', 'Var', (70, 79))	('MET', 'Gene', (100, 103))	('alter', 'Reg', (119, 124))	('HER2', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (94, 98))	('downstream signaling', 'MPA', (125, 145))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
927103	29478325	SCLC, which accounts for ~15% of lung cancers, is a highly aggressive and highly vascularized metastatic form of cancer characterized by mutations in TP53 and the transcriptional corepressor RB1, disruption of several signaling networks, and overexpression of MYC, MYCL, and MYCN transcription factors.	('SCLC', 'Gene', '7864', (0, 4))	('TP53', 'Gene', (150, 154))	('MYC', 'Gene', '4609', (260, 263))	('MYCN', 'Gene', (275, 279))	('MYC', 'Gene', (265, 268))	('MYCL', 'Gene', (265, 269))	('cancer', 'Disease', (113, 119))	('MYC', 'Gene', '4609', (275, 278))	('RB1', 'Gene', '5925', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('overexpression', 'PosReg', (242, 256))	('MYCL', 'Gene', '4610', (265, 269))	('lung cancers', 'Disease', 'MESH:D008175', (33, 45))	('lung cancers', 'Disease', (33, 45))	('MYC', 'Gene', '4609', (265, 268))	('cancer', 'Disease', (38, 44))	('TP53', 'Gene', '7157', (150, 154))	('disruption', 'Reg', (196, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancers', 'Phenotype', 'HP:0100526', (33, 45))	('MYCN', 'Gene', '4613', (275, 279))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('MYC', 'Gene', (260, 263))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('MYC', 'Gene', (275, 278))	('RB1', 'Gene', (191, 194))	('mutations', 'Var', (137, 146))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('SCLC', 'Gene', (0, 4))
927105	29478325	Although the oncogene mutations identified in lung cancers affect several signaling pathways that regulate redox enzyme expression, the role of ROS in lung carcinogenesis is not completely characterized.	('affect', 'Reg', (59, 65))	('lung cancers', 'Phenotype', 'HP:0100526', (46, 58))	('signaling pathways', 'Pathway', (74, 92))	('lung carcinogenesis', 'Disease', (151, 170))	('ROS', 'Chemical', 'MESH:D017382', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (151, 170))	('lung cancers', 'Disease', (46, 58))	('mutations', 'Var', (22, 31))	('redox enzyme expression', 'MPA', (107, 130))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('lung cancers', 'Disease', 'MESH:D008175', (46, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
927106	29478325	Studies performed in lung cancer models have resulted in interesting novel observations, such as NADPH oxidase NOX1-coordinated inhibition of p53 acetylation at Lys382 that affects p53 proapoptotic function; increased NOX2 expression in NSCLC patients, which correlates with decreased survival; and a novel role for the NADPH oxidase NOX3 in the regulation of redox balance in NSCLC causing a selective degradation of mutant EGFR.	('EGFR', 'Gene', (425, 429))	('NOX3', 'Gene', (334, 338))	('NOX1', 'Gene', '27035', (111, 115))	('NSCLC', 'Disease', 'MESH:D002289', (237, 242))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('NSCLC', 'Disease', (237, 242))	('NOX1', 'Gene', (111, 115))	('p53', 'Gene', '7157', (142, 145))	('patients', 'Species', '9606', (243, 251))	('lung cancer', 'Disease', (21, 32))	('Lys382', 'Chemical', '-', (161, 167))	('NADPH', 'Gene', (320, 325))	('NADPH', 'Gene', (97, 102))	('NADPH', 'Gene', '1666', (97, 102))	('EGFR', 'Gene', '1956', (425, 429))	('NOX2', 'Gene', (218, 222))	('NADPH', 'Gene', '1666', (320, 325))	('p53', 'Gene', '7157', (181, 184))	('survival', 'MPA', (285, 293))	('p53', 'Gene', (142, 145))	('NSCLC', 'Disease', 'MESH:D002289', (377, 382))	('increased', 'PosReg', (208, 217))	('affects', 'Reg', (173, 180))	('NOX2', 'Gene', '1536', (218, 222))	('mutant', 'Var', (418, 424))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('p53', 'Gene', (181, 184))	('NOX3', 'Gene', '50508', (334, 338))	('NSCLC', 'Disease', (377, 382))	('decreased', 'NegReg', (275, 284))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('proapoptotic function', 'MPA', (185, 206))	('degradation', 'NegReg', (403, 414))
927116	29478325	13B), thereby suggesting that mutations and alterations in signal transduction pathways in lung adenocarcinoma markedly affect NOX5 regulation.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (91, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('lung adenocarcinoma', 'Disease', (91, 110))	('signal transduction pathways', 'Pathway', (59, 87))	('alterations', 'Reg', (44, 55))	('mutations', 'Var', (30, 39))	('affect', 'Reg', (120, 126))	('NOX5 regulation', 'MPA', (127, 142))	('rat', 'Species', '10116', (48, 51))
927140	29478325	The contribution of O2 - and H2O2 has been linked to the malignant transformation of hematopoietic cells, although H2O2-producing SOD3 stimulates hematopoiesis by increasing primitive progenitor cell differentiation.	('primitive progenitor cell differentiation', 'CPA', (174, 215))	('H2O2', 'Chemical', 'MESH:D006861', (29, 33))	('H2O2', 'Chemical', 'MESH:D006861', (115, 119))	('hematopoiesis', 'Disease', (146, 159))	('O2', 'Chemical', '-', (117, 119))	('O2', 'Chemical', '-', (20, 22))	('malignant transformation', 'CPA', (57, 81))	('stimulates', 'PosReg', (135, 145))	('O2', 'Chemical', '-', (31, 33))	('H2O2-producing', 'Var', (115, 129))	('increasing', 'PosReg', (163, 173))	('hematopoiesis', 'Disease', 'MESH:C536227', (146, 159))
927144	29478325	Mutations in plasma membrane-bound FLT3-ITD, a major genetic lesion leading to AML development, have been demonstrated to cause altered signal transduction, phosphorylation of STAT5, and consequent activation of RAC1, increasing ROS production.	('altered', 'Reg', (128, 135))	('STAT5', 'Gene', (176, 181))	('ROS production', 'MPA', (229, 243))	('increasing ROS production', 'Phenotype', 'HP:0025464', (218, 243))	('Mutations', 'Var', (0, 9))	('ROS', 'Chemical', 'MESH:D017382', (229, 232))	('AML', 'Disease', 'MESH:D015470', (79, 82))	('genetic lesion', 'Disease', (53, 67))	('AML', 'Disease', (79, 82))	('increasing', 'PosReg', (218, 228))	('AML', 'Phenotype', 'HP:0004808', (79, 82))	('activation', 'PosReg', (198, 208))	('phosphorylation', 'MPA', (157, 172))	('FLT3', 'Gene', (35, 39))	('RAC1', 'Gene', (212, 216))	('FLT3', 'Gene', '2322', (35, 39))	('rat', 'Species', '10116', (113, 116))	('RAC1', 'Gene', '5879', (212, 216))	('signal transduction', 'MPA', (136, 155))	('STAT5', 'Gene', '6776', (176, 181))	('genetic lesion', 'Disease', 'MESH:D020022', (53, 67))
927145	29478325	ROS-derived inactivation or decreased expression of phosphotyrosine phosphatases, such as SHP-1 and DEP-1/PTRRJ, may then contribute to transformation of 32D mouse hematopoietic progenitor cells and TF-1 human erythroblast.	('tyrosine', 'Chemical', 'MESH:D014443', (59, 67))	('SHP-1', 'Gene', '23957', (90, 95))	('mouse', 'Species', '10090', (158, 163))	('decreased', 'NegReg', (28, 37))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('expression', 'MPA', (38, 48))	('TF-1 human erythroblast', 'CPA', (199, 222))	('contribute to', 'Reg', (122, 135))	('DEP-1/PTRRJ', 'Gene', (100, 111))	('inactivation', 'Var', (12, 24))	('human', 'Species', '9606', (204, 209))	('transformation', 'CPA', (136, 150))	('SHP-1', 'Gene', (90, 95))
927148	29478325	CML is frequently caused by translocation mutation between chromosomes 9 and 22 resulting in the formation of chimeric BCR-ABL kinase, which then stimulates synthesis of NADPH oxidase NOX4.	('chimeric', 'Var', (110, 118))	('NOX4', 'Gene', '50507', (184, 188))	('BCR-ABL', 'Gene', (119, 126))	('CML', 'Disease', 'MESH:D015464', (0, 3))	('CML', 'Phenotype', 'HP:0005506', (0, 3))	('BCR-ABL', 'Gene', '25', (119, 126))	('stimulates', 'PosReg', (146, 156))	('NOX4', 'Gene', (184, 188))	('NADPH', 'Gene', (170, 175))	('CML', 'Disease', (0, 3))	('caused by', 'Reg', (18, 27))	('NADPH', 'Gene', '1666', (170, 175))	('translocation mutation', 'Var', (28, 50))	('synthesis', 'MPA', (157, 166))
927150	29478325	Oxygen radicals, DNA base modifications, and aberrant SOD and CATALASE expression contribute to the progression of chronic lymphocytic leukemia (CLL), acute lymphoplastic leukemia, monoclonal B lymphocytosis (MBL), a disease marked by B-cell expansion, and the CLL phenotype, which characteristically show increased levels of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in lymphocytes and in urine.	('CATALASE', 'Gene', (62, 70))	('B lymphocytosis', 'Phenotype', 'HP:0010976', (192, 207))	('MBL', 'Gene', (209, 212))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (115, 143))	('acute lymphoplastic leukemia', 'Disease', 'MESH:D054198', (151, 179))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))	('acute lymphoplastic leukemia', 'Disease', (151, 179))	('Oxygen radicals', 'Chemical', 'MESH:D017382', (0, 15))	('CLL', 'Phenotype', 'HP:0005550', (145, 148))	('lymphocytosis', 'Phenotype', 'HP:0100827', (194, 207))	('increased', 'PosReg', (306, 315))	('CATALASE', 'Gene', '847', (62, 70))	('8-oxo-dG', 'Chemical', 'MESH:C067134', (351, 359))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('aberrant', 'Var', (45, 53))	('MBL', 'Gene', '4153', (209, 212))	('SOD', 'Gene', (54, 57))	("levels of 8-oxo-2'-deoxyguanosine", 'MPA', (316, 349))	('lymphoplastic leukemia', 'Phenotype', 'HP:0005526', (157, 179))	('monoclonal B lymphocytosis', 'Gene', (181, 207))	("8-oxo-2'-deoxyguanosine", 'Chemical', 'MESH:C067134', (326, 349))	('SOD', 'Gene', '6647', (54, 57))	('CLL', 'Phenotype', 'HP:0005550', (261, 264))	('monoclonal B lymphocytosis', 'Gene', '4153', (181, 207))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (115, 143))	('chronic lymphocytic leukemia', 'Disease', (115, 143))
927153	29478325	The authors suggested that ROS-derived genomic instability contributes to the clonal expansion of bone marrow CD34+ cells in RAS-BCL2 mutation-harboring mice modeling MS/AML development.	('BCL2', 'Gene', (129, 133))	('AML', 'Disease', 'MESH:D015470', (170, 173))	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('BCL2', 'Gene', '12043', (129, 133))	('MS', 'Disease', 'MESH:D009103', (167, 169))	('MS', 'Phenotype', 'HP:0002863', (167, 169))	('AML', 'Phenotype', 'HP:0004808', (170, 173))	('AML', 'Disease', (170, 173))	('mice', 'Species', '10090', (153, 157))	('mutation-harboring', 'Var', (134, 152))
927166	29478325	ROS production is most noticeably affected by GPCR activation, Ca2+ signaling, and H2O2-directed modification of the activation level of small GTPase RAC, which is an important subunit in NADPH oxidase NOX1, NOX2, and possibly also in NOX3.	('GPCR', 'Gene', (46, 50))	('NADPH', 'Gene', (188, 193))	('NADPH', 'Gene', '1666', (188, 193))	('RAC', 'Gene', (150, 153))	('RAC', 'Gene', '207', (150, 153))	('H2O2', 'Chemical', 'MESH:D006861', (83, 87))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('NOX3', 'Gene', '50508', (235, 239))	('GPCR', 'Gene', '10663', (46, 50))	('NOX1', 'Gene', '27035', (202, 206))	('modification', 'Var', (97, 109))	('GTP', 'Chemical', 'MESH:D006160', (143, 146))	('Ca2+', 'Chemical', 'MESH:D000069285', (63, 67))	('NOX1', 'Gene', (202, 206))	('H2O2-directed', 'Gene', (83, 96))	('NOX3', 'Gene', (235, 239))	('NOX2', 'Gene', (208, 212))	('ROS production', 'MPA', (0, 14))	('affected', 'Reg', (34, 42))	('NOX2', 'Gene', '1536', (208, 212))
927170	29478325	Importantly, in vitro cell models may have limitations in modeling cancer depending on the mutations in oncogenes, activation status of the signaling pathways, and the differences in mechanisms of individual redox gene induction, which then influence redox gene expression.	('redox gene', 'Gene', (208, 218))	('oncogenes', 'Gene', (104, 113))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('redox gene expression', 'MPA', (251, 272))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (91, 100))	('influence', 'Reg', (241, 250))
927171	29478325	Although the data observed in the cell culture model systems have unquestionably demonstrated the role of O2 - and H2O2 in tumorigenesis, the differences in the in vitro and in vivo model systems used could explain some contradictory conclusions in the function of redox enzymes in cancer.	('tumor', 'Disease', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('H2O2', 'Chemical', 'MESH:D006861', (115, 119))	('H2O2', 'Var', (115, 119))	('rat', 'Species', '10116', (88, 91))	('O2', 'Chemical', '-', (106, 108))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('O2', 'Chemical', '-', (117, 119))	('cancer', 'Disease', (282, 288))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
927198	30595890	Macroscopic pathologic examination surprisingly showed extra-mucosal colonic tumor with stenosis (Fig.3) but without macroscopic communication with the lumen (Fig.4).	('extra-mucosal colonic tumor', 'Disease', 'MESH:D015179', (55, 82))	('colonic tumor with stenosis', 'Phenotype', 'HP:0012851', (69, 96))	('colonic tumor', 'Phenotype', 'HP:0100273', (69, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('stenosis', 'Var', (88, 96))	('extra-mucosal colonic tumor', 'Disease', (55, 82))
927217	30595890	In this respect 18fdg-PET-CT is superior to any other imaging method to detect synchronous lesions.	('synchronous lesions', 'Disease', (79, 98))	('18fdg-PET-CT', 'Var', (16, 28))	('18fdg', 'Chemical', 'MESH:D019788', (16, 21))	('synchronous lesions', 'Disease', 'MESH:D009378', (79, 98))
927336	27517157	The 5-year RFS rates of patients with pN0, pN1, pN2 and pN3 were 40.7%, 26.8%, 17.9% and 5.5%, respectively (P < 0.001, 2A).	('RFS', 'MPA', (11, 14))	('pN0', 'Var', (38, 41))	('pN1', 'Gene', '5270', (43, 46))	('pN2', 'Gene', (48, 51))	('pN3', 'Gene', '6336', (56, 59))	('pN1', 'Gene', (43, 46))	('pN3', 'Gene', (56, 59))	('pN2', 'Gene', '351', (48, 51))	('patients', 'Species', '9606', (24, 32))
927337	27517157	The 5-year OS rates of patients with pN0, pN1, pN2 and pN3 were 47.7%, 31.4%, 19.7% and 7.0%, respectively (P < 0.001, 2B).	('pN3', 'Gene', '6336', (55, 58))	('pN2', 'Gene', (47, 50))	('OS', 'Chemical', '-', (11, 13))	('pN3', 'Gene', (55, 58))	('patients', 'Species', '9606', (23, 31))	('pN2', 'Gene', '351', (47, 50))	('pN1', 'Gene', '5270', (42, 45))	('pN0', 'Var', (37, 40))	('pN1', 'Gene', (42, 45))
927338	27517157	The 5-year RFS rates of patients with rN0, rN1, rN2 and rN3 were 40.7%, 25.9%, 13.7% and 1.9%, respectively (P < 0.001, 2C).	('RFS', 'MPA', (11, 14))	('rN3', 'Gene', (56, 59))	('patients', 'Species', '9606', (24, 32))	('rN3', 'Gene', '310159', (56, 59))	('rN1', 'Var', (43, 46))	('rN0', 'Var', (38, 41))
927339	27517157	The 5-year OS rates of patients with rN0, rN1, rN2 and rN3 were 47.7%, 30.2%, 17.3% and 2.5%, respectively (P < 0.001, 2D).	('OS', 'Chemical', '-', (11, 13))	('patients', 'Species', '9606', (23, 31))	('rN3', 'Gene', (55, 58))	('rN0', 'Var', (37, 40))	('rN2', 'Var', (47, 50))	('rN3', 'Gene', '310159', (55, 58))
927405	27517157	The TrNM staging system is as follows: I (IA, T1rN0; IB, T1rN1, T2rN0); II (IIA, T1rN2, T2rN1, T3rN0; IIB, T1rN3, T2rN2, T3rN1, T4arN0); IIIA(T2rN3, T3rN2, T4arN1); IIIB(T3rN3, T4arN2, T4brN0, T4brN1); IIIC(T4arN3, T4brN2, T4brN3).	('rN3', 'Gene', (210, 213))	('rN3', 'Gene', (144, 147))	('T4brN0', 'Var', (185, 191))	('rN3', 'Gene', (172, 175))	('rN3', 'Gene', '310159', (109, 112))	('T4arN2', 'Var', (177, 183))	('T4brN1', 'Var', (193, 199))	('T4brN2', 'Var', (215, 221))	('rN3', 'Gene', '310159', (172, 175))	('rN3', 'Gene', '310159', (226, 229))	('rN3', 'Gene', '310159', (210, 213))	('rN3', 'Gene', (109, 112))	('rN3', 'Gene', '310159', (144, 147))	('T4arN1', 'Var', (156, 162))	('rN3', 'Gene', (226, 229))
927424	26383162	Individual antigen testing showed that CagA positivity was associated with increased risk of both noncardia and cardia adenocarcinoma, which is similar to some other Asian populations, while two antigens were associated with lower risk of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('CagA', 'Gene', (39, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('noncardia and cardia adenocarcinoma', 'Disease', 'MESH:D004938', (98, 133))	('gastric cancer', 'Disease', (239, 253))	('gastric cancer', 'Disease', 'MESH:D013274', (239, 253))	('positivity', 'Var', (44, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (239, 253))
927427	26383162	With regards to anatomic subsite and geography, most Western studies have shown that H. pylori is a strong risk factor for noncardia gastric adenocarcinoma, whereas it is either not associated with, or is associated with a lower risk of cardia gastric adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (126, 155))	('noncardia gastric adenocarcinoma', 'Disease', 'MESH:D013274', (123, 155))	('H. pylori', 'Species', '210', (85, 94))	('cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (237, 266))	('noncardia gastric adenocarcinoma', 'Disease', (123, 155))	('H. pylori', 'Var', (85, 94))	('cardia gastric adenocarcinoma', 'Disease', (237, 266))	('risk', 'Reg', (107, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
927428	26383162	By contrast, in some high-risk areas of the world for esophageal cancer, such as the Taihang Mountain region of China, H. pylori seropositivity is associated with modest increases in the risk of both cardia and noncardia gastric adenocarcinoma.	('increases', 'Reg', (170, 179))	('seropositivity', 'Var', (129, 143))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (122, 143))	('H. pylori', 'Species', '210', (119, 128))	('cardia and noncardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (200, 243))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))
927432	26383162	In addition to cagA and vacA, H. pylori has many other genetic variations that may confer higher or lower carcinogenic potential.	('H. pylori', 'Gene', (30, 39))	('H. pylori', 'Species', '210', (30, 39))	('carcinogenic', 'Disease', 'MESH:D063646', (106, 118))	('carcinogenic', 'Disease', (106, 118))	('variations', 'Var', (63, 73))	('lower', 'NegReg', (100, 105))
927463	26383162	H. pylori positivity was not significantly associated with cancer (i.e., all gastric, cardia, and noncardia adenocarcinomas) by either multiplex serology or whole-cell ELISA (Table 2).	('cardia', 'Disease', 'MESH:D004938', (86, 92))	('cardia', 'Disease', (86, 92))	('H. pylori', 'Species', '210', (0, 9))	('noncardia adenocarcinomas', 'Disease', 'MESH:D000230', (98, 123))	('positivity', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cardia', 'Disease', (101, 107))	('pylori positivity', 'Phenotype', 'HP:0005202', (3, 20))	('cardia', 'Disease', 'MESH:D004938', (101, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('associated', 'Reg', (43, 53))	('gastric', 'Disease', (77, 84))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('H. pylori', 'Gene', (0, 9))	('noncardia adenocarcinomas', 'Disease', (98, 123))
927465	26383162	The proportions of cases and controls seropositive for each of the 15 H. pylori antigens, and related risk estimates for gastric adenocarcinoma and its subtypes are shown in Table 2.	('gastric adenocarcinoma', 'Disease', (121, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (121, 143))	('H. pylori', 'Species', '210', (70, 79))	('seropositive', 'Var', (38, 50))
927472	26383162	We investigated the combination of CagA and VacA seropositivity as the two more established virulence factors for gastric cancer and found that positivity to either antigen alone did not associate with increased risk of gastric cancer whereas double seropositivity did, although the estimate for cardia cancer was not statistically significant.	('gastric cancer', 'Disease', 'MESH:D013274', (220, 234))	('gastric cancer', 'Disease', (114, 128))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (202, 234))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('positivity', 'Var', (144, 154))	('cardia cancer', 'Disease', (296, 309))	('gastric cancer', 'Phenotype', 'HP:0012126', (220, 234))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cardia cancer', 'Disease', 'MESH:D004938', (296, 309))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('gastric cancer', 'Disease', (220, 234))
927475	26383162	In this case-control study, we found no association between H. pylori seropositivity (either by whole-cell ELISA test or multiplex serology) and gastric (cardia or non-cardia) adenocarcinoma risk, but this is likely due to limited power to detect an association in a population where 95% of controls were seropositive.	('H. pylori', 'Gene', (60, 69))	('H. pylori', 'Species', '210', (60, 69))	('seropositivity', 'Var', (70, 84))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (63, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('gastric (cardia or non-cardia) adenocarcinoma', 'Disease', 'MESH:D004938', (145, 190))
927476	26383162	However, we found that seropositivity to CagA was associated with a significantly increased risk of gastric cardia and non-cardia adenocarcinoma and a significant association between seropositivity to VacA antigen and risk of gastric non-cardia adenocarcinoma.	('gastric cardia', 'Disease', (100, 114))	('seropositivity', 'Var', (23, 37))	('gastric cardia', 'Disease', 'MESH:D004938', (100, 114))	('non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (119, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('gastric non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (226, 259))	('non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (234, 259))	('CagA', 'Gene', (41, 45))	('gastric non-cardia adenocarcinoma', 'Disease', (226, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('non-cardia adenocarcinoma', 'Disease', (119, 144))	('seropositivity', 'Var', (183, 197))
927478	26383162	We also had an unexpected finding that seropositivity to two antigens, NapA and GroEL, were associated with reduced risk of gastric cancer.	('gastric cancer', 'Disease', (124, 138))	('seropositivity', 'Var', (39, 53))	('NapA', 'Chemical', '-', (71, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('reduced risk of gastric cancer', 'Phenotype', 'HP:0006753', (108, 138))	('reduced', 'NegReg', (108, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
927480	26383162	Previous studies of H. pylori seropositivity in the Taihang Mountains have shown modest, but statistically significant, increased risks for both gastric cardia and non-cardia adenocarcinoma.	('gastric cardia', 'Disease', (145, 159))	('seropositivity', 'Var', (30, 44))	('gastric cardia', 'Disease', 'MESH:D004938', (145, 159))	('pylori seropositivity', 'Phenotype', 'HP:0005202', (23, 44))	('H. pylori', 'Species', '210', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (164, 189))	('non-cardia adenocarcinoma', 'Disease', (164, 189))
927481	26383162	This is in contrast to other parts of the world, particularly Western countries, where H. pylori is strongly associated with non-cardia adenocarcinoma but is either not associated or inversely associated with cardia adenocarcinoma risk.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('associated', 'Reg', (109, 119))	('non-cardia adenocarcinoma', 'Disease', (125, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('cardia adenocarcinoma', 'Disease', 'MESH:D004938', (129, 150))	('H. pylori', 'Species', '210', (87, 96))	('non-cardia adenocarcinoma', 'Disease', 'MESH:D004938', (125, 150))	('cardia adenocarcinoma', 'Disease', 'MESH:D004938', (209, 230))	('cardia adenocarcinoma', 'Disease', (209, 230))	('H. pylori', 'Var', (87, 96))
927506	26383162	In conclusion, in our population-based case-control study of gastric adenocarcinoma risk in Northeastern Iran we found that seropositivity to CagA H. pylori antigen was associated with increased risk of both non-cardia and cardia gastric adenocarcinoma, while seropositivity to VacA was also associated with an increased risk of gastric non-cardia cancer.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (61, 83))	('gastric adenocarcinoma', 'Disease', (61, 83))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (230, 252))	('gastric adenocarcinoma', 'Disease', (230, 252))	('H. pylori', 'Species', '210', (147, 156))	('non-cardia and cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (208, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('gastric non-cardia cancer', 'Disease', (329, 354))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('gastric non-cardia cancer', 'Disease', 'MESH:D013274', (329, 354))	('seropositivity', 'Var', (124, 138))
927507	26383162	We also found that seropositivity to GroEL and NapA may be associated with a lower risk of non-cardia gastric adenocarcinoma.	('NapA', 'Chemical', '-', (47, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('NapA', 'Gene', (47, 51))	('non-cardia gastric adenocarcinoma', 'Disease', 'MESH:D004938', (91, 124))	('GroEL', 'Protein', (37, 42))	('non-cardia gastric adenocarcinoma', 'Disease', (91, 124))	('seropositivity', 'Var', (19, 33))
927510	26901778	We found that acid-induced increase in NOX5-S expression was significantly decreased by the Rho kinase (ROCK) inhibitor Y27632 in BE mucosal biopsies and FLO-1 EA cells.	('NOX5-S expression', 'MPA', (39, 56))	('Y27632', 'Var', (120, 126))	('Y27632', 'Chemical', 'MESH:C108830', (120, 126))	('increase', 'PosReg', (27, 35))	('decreased', 'NegReg', (75, 84))
927511	26901778	The acid-induced increase in NOX5-S expression and H2O2 production was significantly decreased by knockdown of Rho kinase ROCK2, but not by knockdown of ROCK1.	('ROCK1', 'Gene', (153, 158))	('NOX5-S expression', 'MPA', (29, 46))	('decreased', 'NegReg', (85, 94))	('knockdown', 'Var', (98, 107))	('ROCK2', 'Gene', (122, 127))	('ROCK2', 'Gene', '9475', (122, 127))	('increase', 'PosReg', (17, 25))	('H2O2 production', 'MPA', (51, 66))	('H2O2', 'Chemical', 'MESH:D006861', (51, 55))	('ROCK1', 'Gene', '6093', (153, 158))
927514	26901778	The calcium ionophore A23187 significantly increased the Rho kinase activity and NOX5-S mRNA expression.	('A23187', 'Chemical', 'MESH:D000001', (22, 28))	('Rho kinase', 'Enzyme', (57, 67))	('NOX5-S mRNA expression', 'CPA', (81, 103))	('A23187', 'Var', (22, 28))	('increased', 'PosReg', (43, 52))	('calcium', 'Chemical', 'MESH:D002118', (4, 11))
927538	26901778	For the acid treatment, FLO-1 cells were exposed to acidic DMEM (pH 4.0), acidic medium plus Y27632 (10-6M) or normal DMEM (control) for 1 h, washed, and cultured in fresh medium (pH 7.2, without phenol red) for an additional 24 h. For the Y27632 group, Y27632 (10-6 M) was added to the culture medium in this additional 24-h culture.	('DMEM', 'Chemical', '-', (59, 63))	('Y27632', 'Chemical', 'MESH:C108830', (254, 260))	('Y27632', 'Chemical', 'MESH:C108830', (240, 246))	('Y27632', 'Chemical', 'MESH:C108830', (93, 99))	('pH 4', 'Gene', '54681', (65, 69))	('DMEM', 'Chemical', '-', (118, 122))	('Y27632', 'Var', (240, 246))	('pH 4', 'Gene', (65, 69))	('phenol red', 'Chemical', 'MESH:D010637', (196, 206))
927547	26901778	BE mucosal biopsy tissues were first equilibrated in culture for 2 h and then exposed to acidic medium (pH 4.0), acidic medium with Y27632 (10-6 M), or control medium (pH 7.2), for 1 h. After washing twice, BE mucosa biopsies were cultured in the fresh medium without phenol red, pH 7.2, for an additional 24 h. For the Y27632 group, Y27632 (10-6 M) was added to the culture medium in this additional 24-h culture.	('Y27632', 'Var', (334, 340))	('phenol red', 'Chemical', 'MESH:D010637', (268, 278))	('Y27632', 'Chemical', 'MESH:C108830', (334, 340))	('Y27632', 'Chemical', 'MESH:C108830', (320, 326))	('Y27632', 'Chemical', 'MESH:C108830', (132, 138))	('pH 4', 'Gene', '54681', (104, 108))	('pH 4', 'Gene', (104, 108))	('Y27632', 'Var', (320, 326))
927558	26901778	The primers used were: NOX5-S sense (5'- AAGACTCCATCACGGGGCTGCA-3'), NOX5-S antisense (5'-CCTTCAGCACCTTGGCCAGA -3'), beta-Actin sense (5'- ACGATGCCCCCCGGGCCGTCTT-3'), beta-Actin antisense (5'- TCTCTTGCTCTGGGCCTCGTCGCCC-3'), GAPDH: sense 5'-CATGACCACAGTCCATGCCATCAC-3', antisense 5'-AGGTCCACCACCCTGTTGC TGTA-3'.	('beta-Actin', 'Gene', (117, 127))	('antisense', 'Var', (269, 278))	('beta-Actin', 'Gene', '728378', (117, 127))	('GAPDH', 'Gene', '2597', (224, 229))	('GAPDH', 'Gene', (224, 229))	('beta-Actin', 'Gene', (167, 177))	('beta-Actin', 'Gene', '728378', (167, 177))
927570	26901778	For the A23187 treatment, cells were treated with 1 muM A23817 for 24 hours.	('A23187', 'Var', (8, 14))	('muM', 'Gene', '56925', (52, 55))	('muM', 'Gene', (52, 55))	('A23817', 'Chemical', '-', (56, 62))	('A23187', 'Chemical', 'MESH:D000001', (8, 14))
927575	26901778	Y27632, A23187, DMEM culture medium, EGTA, thapsigargin and other reagents were purchased from Sigma (St. Louis, MO).	('thapsigargin', 'Chemical', 'MESH:D019284', (43, 55))	('Y27632', 'Chemical', 'MESH:C108830', (0, 6))	('A23187', 'Var', (8, 14))	('EGTA', 'Chemical', 'MESH:D004533', (37, 41))	('S', 'Chemical', 'MESH:D013455', (102, 103))	('Y27632', 'Var', (0, 6))	('S', 'Chemical', 'MESH:D013455', (95, 96))	('DMEM', 'Chemical', '-', (16, 20))	('A23187', 'Chemical', 'MESH:D000001', (8, 14))
927584	26901778	To test whether ROCK participates in acid-induced NOX5-S expression and H2O2 production, we first used ROCK1 and ROCK2 siRNAs to knock down ROCK1 and ROCK2 expression, respectively.	('knock', 'Var', (129, 134))	('ROCK1', 'Gene', '6093', (140, 145))	('H2O2', 'Chemical', 'MESH:D006861', (72, 76))	('ROCK2', 'Gene', (113, 118))	('ROCK2', 'Gene', (150, 155))	('ROCK2', 'Gene', '9475', (150, 155))	('ROCK1', 'Gene', (140, 145))	('ROCK1', 'Gene', '6093', (103, 108))	('ROCK1', 'Gene', (103, 108))	('ROCK2', 'Gene', '9475', (113, 118))
927587	26901778	Knockdown of ROCK1, however, did not affect NOX5-S expression (Fig 3C and 3D, S4 Fig) and H2O2 production (Fig 3E) induced by acid treatment.	('Knockdown', 'Var', (0, 9))	('S', 'Chemical', 'MESH:D013455', (49, 50))	('ROCK1', 'Gene', '6093', (13, 18))	('H2O2', 'Chemical', 'MESH:D006861', (90, 94))	('NOX5-S expression', 'MPA', (44, 61))	('ROCK1', 'Gene', (13, 18))	('S', 'Chemical', 'MESH:D013455', (78, 79))	('H2O2 production', 'MPA', (90, 105))
927598	26901778	Fig 6B shows that A23187 significantly increased Rho kinase activity, suggesting that intracellular calcium increase may activate Rho kinase in FLO-1 EA cells.	('calcium', 'Chemical', 'MESH:D002118', (100, 107))	('intracellular calcium increase', 'MPA', (86, 116))	('A23187', 'Var', (18, 24))	('intracellular calcium increase', 'Phenotype', 'HP:0003575', (86, 116))	('Rho kinase', 'Enzyme', (130, 140))	('activate', 'PosReg', (121, 129))	('increased', 'PosReg', (39, 48))	('Rho kinase', 'Enzyme', (49, 59))	('A23187', 'Chemical', 'MESH:D000001', (18, 24))
927599	26901778	Similarly, A23187 significantly increased NOX5-S mRNA expression in FLO-1 cells (Fig 7B) as well as in OE33 cells (Fig 7D).	('A23187', 'Chemical', 'MESH:D000001', (11, 17))	('NOX5-S mRNA expression', 'MPA', (42, 64))	('increased', 'PosReg', (32, 41))	('S', 'Chemical', 'MESH:D013455', (47, 48))	('A23187', 'Var', (11, 17))	('S', 'Chemical', 'MESH:D013455', (0, 1))
927602	26901778	ROS may damage DNA, RNA, lipids, and proteins, leading to increasing mutation and altered functions of enzymes and proteins (e.g.	('lipids', 'Chemical', 'MESH:D008055', (25, 31))	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('functions', 'MPA', (90, 99))	('enzymes', 'Enzyme', (103, 110))	('increasing', 'PosReg', (58, 68))	('mutation', 'MPA', (69, 77))	('altered', 'Reg', (82, 89))
927607	26901778	Acid-induced ROS production was abolished by knockdown of NOX5-S expression.	('NOX5-S', 'Protein', (58, 64))	('abolished', 'NegReg', (32, 41))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))	('knockdown', 'Var', (45, 54))
927614	26901778	We found that knockdown of ROCK2 with ROCK2 siRNA significantly decreased acid-induced increase in NOX5-S expression and H2O2 production in FLO-1 and/or OE33 cells.	('ROCK2', 'Gene', '9475', (27, 32))	('H2O2', 'Chemical', 'MESH:D006861', (121, 125))	('increase', 'PosReg', (87, 95))	('NOX5-S expression', 'MPA', (99, 116))	('ROCK2', 'Gene', (27, 32))	('ROCK2', 'Gene', (38, 43))	('ROCK2', 'Gene', '9475', (38, 43))	('knockdown', 'Var', (14, 23))	('H2O2 production', 'MPA', (121, 136))	('decreased', 'NegReg', (64, 73))
927618	26901778	We found that acid-induced activation of Rho kinase and increase in NOX5-S expression may depend on intracellular calcium increase because 1) acid significantly increased Rho kinase activity and NOX5-S expression, an increase which was blocked by the removal of calcium, 2) A23187 significantly increased Rho kinase activity and NOX5-S expression.	('activity', 'MPA', (182, 190))	('calcium', 'Chemical', 'MESH:D002118', (262, 269))	('intracellular calcium increase', 'Phenotype', 'HP:0003575', (100, 130))	('A23187', 'Chemical', 'MESH:D000001', (274, 280))	('calcium', 'Chemical', 'MESH:D002118', (114, 121))	('activity', 'MPA', (316, 324))	('Rho kinase', 'Enzyme', (171, 181))	('A23187', 'Var', (274, 280))	('NOX5-S expression', 'MPA', (195, 212))	('Rho', 'MPA', (305, 308))	('NOX5-S', 'MPA', (329, 335))	('increased', 'PosReg', (161, 170))	('increased', 'PosReg', (295, 304))	('1) acid', 'Chemical', '-', (139, 146))
927718	25974088	High EZH2 expression was significantly associated with shorter overall (hazard ratio [HR] 1.74, 95% CI: 1.46-2.07), disease-free (HR 1.59, 95% CI: 1.27-1.99), metastasis-free (HR 2.19, 95% CI: 1.38-3.47), progression-free (HR 2.53, 95% CI: 1.52-4.21), cancer-specific (HR 3.13, 95% CI: 1.70-5.74), and disease-specific (HR 2.29, 95% CI: 1.56-3.35) survival, but not recurrence-free survival (HR 1.38, 95% CI: 0.93-2.06).	('disease-free', 'CPA', (116, 128))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('High', 'Var', (0, 4))	('cancer', 'Disease', (252, 258))	('metastasis-free', 'CPA', (159, 174))	('shorter', 'NegReg', (55, 62))	('expression', 'MPA', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('EZH2', 'Gene', '2146', (5, 9))	('progression-free', 'CPA', (205, 221))	('EZH2', 'Gene', (5, 9))
927727	25974088	In vitro overexpression of EZH2 in cancer cell lines has been shown to activate their proliferation, migration, and invasion abilities.2 In contrast, knockdown of EZH2 using siRNA or shRNA results in cell growth inhibition and suppression of oncogenic capacity.	('cell growth inhibition', 'CPA', (200, 222))	('suppression', 'NegReg', (227, 238))	('EZH2', 'Gene', (27, 31))	('EZH2', 'Gene', '2146', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('knockdown', 'Var', (150, 159))	('EZH2', 'Gene', '2146', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('EZH2', 'Gene', (163, 167))	('cancer', 'Disease', (35, 41))	('oncogenic capacity', 'CPA', (242, 260))
927754	25974088	A combined analysis showed that high EZH2 expression predicted poor OS in cancer (HR 1.74, 95% CI: 1.46-2.07; p<0.00001) with significant heterogeneity (I2 = 83.9%) (Table 1 and Fig 2).	('high', 'Var', (32, 36))	('poor', 'Disease', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('expression', 'MPA', (42, 52))	('cancer', 'Disease', (74, 80))	('EZH2', 'Gene', '2146', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('EZH2', 'Gene', (37, 41))
927756	25974088	Subgroup analysis revealed high EZH2 expression was significantly associated with poor OS in NSCLC (HR 1.65, 95% CI: 1.16-2.35; p = 0.006), female reproductive system carcinoma (HR 1.77, 95% CI: 1.29-2.41; p = 0.060), and oral tongue cancer (HR 3.59, 95% CI: 1.29-9.97; p = 0.014) (Table 1).	('system carcinoma', 'Disease', (160, 176))	('NSCLC', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('system carcinoma', 'Disease', 'MESH:D034721', (160, 176))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('high', 'Var', (27, 31))	('oral tongue cancer', 'Disease', 'MESH:D014062', (222, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('EZH2', 'Gene', '2146', (32, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('expression', 'MPA', (37, 47))	('EZH2', 'Gene', (32, 36))	('oral tongue cancer', 'Disease', (222, 240))
927764	25974088	Associations between high EZH2 expression and DFS, RFS, MFS, PFS, CSS, and DSS are presented in Tables 2 and 3.	('EZH2', 'Gene', '2146', (26, 30))	('MFS', 'Disease', (56, 59))	('EZH2', 'Gene', (26, 30))	('DSS', 'Gene', (75, 78))	('DSS', 'Gene', '5376', (75, 78))	('RFS', 'Disease', (51, 54))	('high', 'Var', (21, 25))	('RFS', 'Chemical', '-', (51, 54))	('expression', 'MPA', (31, 41))	('CSS', 'Disease', (66, 69))	('CSS', 'Chemical', '-', (66, 69))	('PFS', 'Disease', (61, 64))	('DFS', 'Disease', (46, 49))	('MFS', 'Disease', 'MESH:D008382', (56, 59))
927766	25974088	Significant heterogeneity was observed for DFS and RFS (Table 2), but not MFS, CSS, or DSS (Table 3).	('CSS', 'Chemical', '-', (79, 82))	('MFS', 'Disease', 'MESH:D008382', (74, 77))	('MFS', 'Disease', (74, 77))	('RFS', 'Disease', (51, 54))	('DFS', 'Var', (43, 46))	('RFS', 'Chemical', '-', (51, 54))	('DSS', 'Gene', (87, 90))	('DSS', 'Gene', '5376', (87, 90))
927770	25974088	Furthermore, since the above-mentioned results for MFS, CSS, and DSS were also obtained from multivariate analysis, high EZH2 expression might be an independent prognostic factor for DFS, MFS, CSS, and DSS in various cancer types.	('DSS', 'Gene', '5376', (65, 68))	('high', 'Var', (116, 120))	('CSS', 'Chemical', '-', (193, 196))	('CSS', 'Chemical', '-', (56, 59))	('EZH2', 'Gene', '2146', (121, 125))	('MFS', 'Disease', 'MESH:D008382', (188, 191))	('DSS', 'Gene', (202, 205))	('MFS', 'Disease', (188, 191))	('cancer', 'Disease', (217, 223))	('EZH2', 'Gene', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('DSS', 'Gene', (65, 68))	('CSS', 'Disease', (193, 196))	('DFS', 'Disease', (183, 186))	('MFS', 'Disease', 'MESH:D008382', (51, 54))	('DSS', 'Gene', '5376', (202, 205))	('MFS', 'Disease', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
927771	25974088	The subgroup analysis according to sample size did not change the significant association between high EZH2 expression and DFS of cancer patients.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('EZH2', 'Gene', '2146', (103, 107))	('high', 'Var', (98, 102))	('patients', 'Species', '9606', (137, 145))	('EZH2', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
927776	25974088	No evidence of publication bias was detected in for either DFS or RFS (DFS, p = 0.44 via Egger's test; RFS, p = 0.48 via Egger's test) (S2 Table).	('RFS', 'Chemical', '-', (66, 69))	('DFS', 'Var', (59, 62))	('RFS', 'Chemical', '-', (103, 106))	('RFS', 'Var', (66, 69))
927779	25974088	For each disease, high EZH2 expression was significantly associated with some clinicopathological characteristics that are indicative of poor prognosis and disease aggressiveness.	('expression', 'MPA', (28, 38))	('aggressiveness', 'Disease', (164, 178))	('aggressiveness', 'Phenotype', 'HP:0000718', (164, 178))	('high', 'Var', (18, 22))	('aggressiveness', 'Disease', 'MESH:D001523', (164, 178))	('EZH2', 'Gene', '2146', (23, 27))	('associated', 'Reg', (57, 67))	('EZH2', 'Gene', (23, 27))
927780	25974088	Regarding predictive factors for breast cancer, high EZH2 expression was significantly associated with the absence of estrogen receptor (positive vs. negative: OR 0.15, 95% CI: 0.11-0.20) and progesterone receptor (positive vs. negative: OR 0.30, 95% CI: 0.23-0.39) expression.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('expression', 'MPA', (266, 276))	('estrogen receptor', 'Gene', '2099', (118, 135))	('breast cancer', 'Disease', (33, 46))	('expression', 'MPA', (58, 68))	('estrogen receptor', 'Gene', (118, 135))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('progesterone receptor', 'Gene', (192, 213))	('high', 'Var', (48, 52))	('absence', 'NegReg', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('progesterone receptor', 'Gene', '5241', (192, 213))	('EZH2', 'Gene', (53, 57))	('EZH2', 'Gene', '2146', (53, 57))
927788	25974088	Subgroup analysis revealed that high EZH2 expression might predict poor OS in NSCLC, endometrial carcinoma, and oral tongue carcinoma, as well as poor DFS in renal cell carcinoma.	('endometrial carcinoma', 'Disease', (85, 106))	('high', 'Var', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('expression', 'MPA', (42, 52))	('oral tongue carcinoma', 'Disease', (112, 133))	('NSCLC', 'Disease', (78, 83))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (158, 178))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (85, 106))	('poor', 'Disease', (67, 71))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (85, 106))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (117, 133))	('renal cell carcinoma', 'Disease', (158, 178))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (158, 178))	('EZH2', 'Gene', '2146', (37, 41))	('EZH2', 'Gene', (37, 41))	('oral tongue carcinoma', 'Disease', 'MESH:D014062', (112, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
927796	25974088	Moreover, in a study of colorectal carcinoma, it was reported that the C/C allelic variant of EZH2 was more significantly correlated with poor PFS and OS than were two other variants (C/T or T/T).	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('C/C allelic', 'Var', (71, 82))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (24, 44))	('EZH2', 'Gene', '2146', (94, 98))	('EZH2', 'Gene', (94, 98))	('colorectal carcinoma', 'Disease', (24, 44))	('poor', 'NegReg', (138, 142))
927797	25974088	In future studies, we can additionally investigate the prognostic significance of EZH2 single-nucleotide polymorphisms for cancer survival.	('EZH2', 'Gene', (82, 86))	('single-nucleotide polymorphisms', 'Var', (87, 118))	('EZH2', 'Gene', '2146', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
927801	25974088	Furthermore, we found that high EZH2 expression was more closely associated with poor OS in Asian patients than in Western populations, in which EZH2 had no significant predictive value for DFS.	('patients', 'Species', '9606', (98, 106))	('high', 'Var', (27, 31))	('associated', 'Reg', (65, 75))	('EZH2', 'Gene', '2146', (145, 149))	('EZH2', 'Gene', '2146', (32, 36))	('EZH2', 'Gene', (145, 149))	('expression', 'MPA', (37, 47))	('EZH2', 'Gene', (32, 36))	('poor OS', 'Disease', (81, 88))
927803	25974088	The results based on higher-quality reports revealed that high EZH2 expression was significantly associated with OS, but not with DFS or RFS.	('expression', 'MPA', (68, 78))	('EZH2', 'Gene', '2146', (63, 67))	('RFS', 'Chemical', '-', (137, 140))	('EZH2', 'Gene', (63, 67))	('high', 'Var', (58, 62))	('associated', 'Reg', (97, 107))
927825	25974088	Fourth, some analyses were based on a limited number of studies, leading to inevitable bias in our analysis of the association between high EZH2 expression and OS.	('high', 'Var', (135, 139))	('EZH2', 'Gene', '2146', (140, 144))	('EZH2', 'Gene', (140, 144))	('expression', 'MPA', (145, 155))
927891	20922573	Six single nucleotide polymorphisms (SNPs) in the AURKA (rs2273535), ERBB2 (rs1136201), MDM2 (rs2279744), CDH1 (rs5030625), CDKN2A (rs11515), and TP73 (rs2273953) genes were genotyped in a consecutive cohort of 346 esophageal cancer patients, who had underwent surgical resection with curative intent.	('CDKN2A', 'Gene', (124, 130))	('rs1136201', 'Var', (76, 85))	('rs2273953', 'Var', (152, 161))	('rs11515', 'Var', (132, 139))	('rs2273535', 'Var', (57, 66))	('rs2279744', 'Mutation', 'rs2279744', (94, 103))	('CDKN2A', 'Gene', '1029', (124, 130))	('AURKA', 'Gene', '6790', (50, 55))	('rs2273953', 'Mutation', 'rs2273953', (152, 161))	('ERBB2', 'Gene', (69, 74))	('AURKA', 'Gene', (50, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (215, 232))	('rs5030625', 'Var', (112, 121))	('CDH1', 'Gene', '999', (106, 110))	('MDM2', 'Gene', (88, 92))	('rs2273535', 'Mutation', 'rs2273535', (57, 66))	('TP73', 'Gene', '7161', (146, 150))	('rs1136201', 'Mutation', 'rs1136201', (76, 85))	('esophageal cancer', 'Disease', (215, 232))	('ERBB2', 'Gene', '2064', (69, 74))	('patients', 'Species', '9606', (233, 241))	('CDH1', 'Gene', (106, 110))	('MDM2', 'Gene', '4193', (88, 92))	('TP73', 'Gene', (146, 150))	('rs2279744', 'Var', (94, 103))	('rs11515', 'Mutation', 'rs11515', (132, 139))	('rs5030625', 'Mutation', 'rs5030625', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
927894	20922573	However, in a multivariate analysis, patients with EAC carrying the heterozygous MDM2 (rs2279744) T/G genotype had significantly improved DFS compared with patients carrying the wild-type genotype (adjusted hazard ratio (AHR), 0.63; 95% confidence interval (CI) [0.45-0.88]).	('patients', 'Species', '9606', (156, 164))	('T/G', 'Var', (98, 101))	('patients', 'Species', '9606', (37, 45))	('rs2279744) T/G', 'Var', (87, 101))	('MDM2', 'Gene', '4193', (81, 85))	('MDM2', 'Gene', (81, 85))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('DFS', 'MPA', (138, 141))	('improved', 'PosReg', (129, 137))	('rs2279744', 'Mutation', 'rs2279744', (87, 96))
927895	20922573	Patients with EAC harboring the homozygous CDH1 (rs5030625) GA/GA genotype had a significantly reduced survival as compared with patients carrying the wild-type genotype AHR 4.0, 95% CI [1.4-11].	('survival', 'MPA', (103, 111))	('patients', 'Species', '9606', (129, 137))	('Patients', 'Species', '9606', (0, 8))	('rs5030625', 'Var', (49, 58))	('rs5030625', 'Mutation', 'rs5030625', (49, 58))	('CDH1', 'Gene', (43, 47))	('EAC', 'Phenotype', 'HP:0011459', (14, 17))	('reduced', 'NegReg', (95, 102))	('CDH1', 'Gene', '999', (43, 47))
927896	20922573	In a large cohort of esophageal cancer patients, the MDM2 T/G and CDH1 GA/GA genotype confer risk of death in patients with EAC.	('esophageal cancer', 'Disease', (21, 38))	('T/G', 'Var', (58, 61))	('MDM2', 'Gene', '4193', (53, 57))	('patients', 'Species', '9606', (39, 47))	('MDM2', 'Gene', (53, 57))	('CDH1', 'Gene', (66, 70))	('CDH1', 'Gene', '999', (66, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (21, 38))	('GA/GA', 'Var', (71, 76))	('death', 'Disease', 'MESH:D003643', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('death', 'Disease', (101, 106))	('EAC', 'Phenotype', 'HP:0011459', (124, 127))	('patients', 'Species', '9606', (110, 118))	('EAC', 'Disease', (124, 127))
927905	20922573	In this way, SNPs in proto-oncogenes and tumor suppressor genes can potentially alter the risk for metastatic or aggressive tumor, resulting in differences in clinical outcome.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('aggressive tumor', 'Disease', (113, 129))	('tumor', 'Disease', (41, 46))	('differences', 'Reg', (144, 155))	('tumor', 'Disease', (124, 129))	('SNPs', 'Var', (13, 17))	('proto-oncogenes', 'Gene', (21, 36))	('metastatic', 'CPA', (99, 109))	('aggressive tumor', 'Disease', 'MESH:D001523', (113, 129))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('alter', 'Reg', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
927907	20922573	In addition, polymorphisms with effects on protein function have been identified in these proto-oncogenes and tumor suppressor genes.	('protein function', 'MPA', (43, 59))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('polymorphisms', 'Var', (13, 26))	('effects', 'Reg', (32, 39))	('proto-oncogenes', 'Gene', (90, 105))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
927908	20922573	Based on these results, we postulated that functional SNPs in the AURKA (AURKA_NM_003600.2; rs2273535 c.449 T>A), ERBB2 (ERBB2_NM004448.2; rs1136201 c.655 A>G), MDM2 (MDM2_NM002392.2; rs2279744 309 T>G), CDH1 (CDH1_NM004360.3; rs5030625 -347 G>GA), CDKN2A (CDKN2A_NM000077.3; rs11515 c.712 C>G), and TP73 (TP73_NM005427.1; rs2273953 81 G > A) genes may serve as molecular markers for clinical outcome in patients with esophageal adenocarcinoma (EAC) or esophageal squamous cell carcinoma (ESCC) who underwent surgical resection.	('-347 G>GA', 'Mutation', 'c.-347G>GA', (237, 246))	('rs2273535', 'Mutation', 'rs2273535', (92, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (478, 487))	('patients', 'Species', '9606', (404, 412))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (418, 443))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (418, 443))	('ERBB2', 'Gene', '2064', (121, 126))	('CDH1', 'Gene', '999', (204, 208))	('CDKN2A', 'Gene', (257, 263))	('ERBB2', 'Gene', '2064', (114, 119))	('AURKA', 'Gene', '6790', (66, 71))	('AURKA', 'Gene', (66, 71))	('CDH1', 'Gene', '999', (210, 214))	('MDM2', 'Gene', (161, 165))	('CDKN2A', 'Gene', (249, 255))	('esophageal squamous cell carcinoma', 'Disease', (453, 487))	('esophageal adenocarcinoma', 'Disease', (418, 443))	('TP73', 'Gene', '7161', (300, 304))	('CDH1', 'Gene', (204, 208))	('81 G > A', 'Mutation', 'rs1060504184', (333, 341))	('CDKN2A', 'Gene', '1029', (257, 263))	('CDH1', 'Gene', (210, 214))	('c.712 C>G', 'Mutation', 'c.712C>G', (284, 293))	('AURKA', 'Gene', '6790', (73, 78))	('MDM2', 'Gene', (167, 171))	('c.655 A>G', 'Mutation', 'rs1136201', (149, 158))	('MDM2', 'Gene', '4193', (161, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (434, 443))	('TP73', 'Gene', '7161', (306, 310))	('TP73', 'Gene', (300, 304))	('AURKA', 'Gene', (73, 78))	('rs5030625', 'Mutation', 'rs5030625', (227, 236))	('c.449 T>A', 'Mutation', 'rs564190636', (102, 111))	('rs1136201', 'Mutation', 'rs1136201', (139, 148))	('CDKN2A', 'Gene', '1029', (249, 255))	('rs11515', 'Mutation', 'rs11515', (276, 283))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (464, 487))	('309 T>G', 'Var', (194, 201))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (453, 487))	('rs2279744', 'Mutation', 'rs2279744', (184, 193))	('MDM2', 'Gene', '4193', (167, 171))	('309 T>G', 'SUBSTITUTION', 'None', (194, 201))	('TP73', 'Gene', (306, 310))	('rs2273953', 'Mutation', 'rs2273953', (323, 332))	('ERBB2', 'Gene', (121, 126))	('EAC', 'Phenotype', 'HP:0011459', (445, 448))	('ERBB2', 'Gene', (114, 119))
927922	20922573	For the polymorphism in CDH1 (rs5030625), amplified PCR products were visualized on a denaturing polyacrylamide gel.	('rs5030625', 'Var', (30, 39))	('rs5030625', 'Mutation', 'rs5030625', (30, 39))	('CDH1', 'Gene', (24, 28))	('CDH1', 'Gene', '999', (24, 28))	('polyacrylamide', 'Chemical', 'MESH:C016679', (97, 111))
927923	20922573	For detection of the restriction length polymorphisms in ERBB2 (rs1136201) and AURKA (rs2273535), PCR products were digested for 16 h at the appropriate temperature with10 U of restriction endonuclease BsmAI, MspI, or APOI (Promega, Madison, WI, USA), respectively.	('AURKA', 'Gene', (79, 84))	('ERBB2', 'Gene', '2064', (57, 62))	('ERBB2', 'Gene', (57, 62))	('rs1136201', 'Var', (64, 73))	('rs2273535', 'Var', (86, 95))	('AURKA', 'Gene', '6790', (79, 84))	('rs2273535', 'Mutation', 'rs2273535', (86, 95))	('rs1136201', 'Mutation', 'rs1136201', (64, 73))
927925	20922573	The polymorphisms in CDKN2A (rs11515), MDM2 (rs2279744), and TP73 (rs2273953) were genotyped by bi-directional sequencing.	('rs11515', 'Var', (29, 36))	('rs2273953', 'Mutation', 'rs2273953', (67, 76))	('MDM2', 'Gene', '4193', (39, 43))	('rs2279744', 'Mutation', 'rs2279744', (45, 54))	('MDM2', 'Gene', (39, 43))	('rs2279744', 'Var', (45, 54))	('rs2273953', 'Var', (67, 76))	('CDKN2A', 'Gene', (21, 27))	('rs11515', 'Mutation', 'rs11515', (29, 36))	('TP73', 'Gene', '7161', (61, 65))	('TP73', 'Gene', (61, 65))	('CDKN2A', 'Gene', '1029', (21, 27))
927946	20922573	However, in a multivariate analysis, patients with EAC carrying the heterozygous MDM2 (rs2279744) T/G genotype had significantly improved DFS compared with patients carrying the wild-type T/T genotype (adjusted hazard ratio (AHR) 0.63, 95% confidence interval (CI) [0.45-0.88], P = 0.007).	('patients', 'Species', '9606', (156, 164))	('T/G', 'Var', (98, 101))	('patients', 'Species', '9606', (37, 45))	('rs2279744) T/G', 'Var', (87, 101))	('MDM2', 'Gene', '4193', (81, 85))	('MDM2', 'Gene', (81, 85))	('EAC', 'Phenotype', 'HP:0011459', (51, 54))	('DFS', 'MPA', (138, 141))	('improved', 'PosReg', (129, 137))	('rs2279744', 'Mutation', 'rs2279744', (87, 96))
927948	20922573	Also, patients with EAC harboring the homozygous CDH1 (rs5030625) GA/GA genotype had a significantly reduced survival as compared with patients carrying the wild-type G/G genotype AHR 4.0, 95% CI [1.4-11], P = 0.008.	('CDH1', 'Gene', (49, 53))	('patients', 'Species', '9606', (135, 143))	('CDH1', 'Gene', '999', (49, 53))	('survival', 'MPA', (109, 117))	('EAC', 'Phenotype', 'HP:0011459', (20, 23))	('reduced', 'NegReg', (101, 108))	('patients', 'Species', '9606', (6, 14))	('rs5030625', 'Mutation', 'rs5030625', (55, 64))	('rs5030625) GA/GA', 'Var', (55, 71))	('GA/GA', 'Var', (66, 71))
927950	20922573	In the present study, we determined the relationship between inter-individual DNA variations in six bona fide proto-oncogenes and tumor suppressor genes and DFS in a large cohort of Caucasian patients with esophageal cancer.	('variations', 'Var', (82, 92))	('esophageal cancer', 'Disease', (206, 223))	('patients', 'Species', '9606', (192, 200))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (206, 223))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
927951	20922573	After adjustment for potential confounders, the variant genotypes of SNPs located in the promoter region of the MDM2 and CDH1 gene were significantly associated with DFS in patients with EAC.	('MDM2', 'Gene', '4193', (112, 116))	('CDH1', 'Gene', (121, 125))	('patients', 'Species', '9606', (173, 181))	('MDM2', 'Gene', (112, 116))	('CDH1', 'Gene', '999', (121, 125))	('DFS', 'Disease', (166, 169))	('EAC', 'Phenotype', 'HP:0011459', (187, 190))	('variant', 'Var', (48, 55))	('associated with', 'Reg', (150, 165))
927952	20922573	The results of the present study showed a significant survival benefit for patients harboring the MDM2 T/G as compared with patients carrying the wild-type T/T genotype.	('MDM2', 'Gene', '4193', (98, 102))	('MDM2', 'Gene', (98, 102))	('benefit', 'PosReg', (63, 70))	('patients', 'Species', '9606', (75, 83))	('T/G', 'Var', (103, 106))	('patients', 'Species', '9606', (124, 132))	('survival', 'CPA', (54, 62))
927954	20922573	The most intensively characterized MDM2 polymorphism is the T309G promoter SNP located in the first intron.	('T309G', 'Mutation', 'rs2279744', (60, 65))	('MDM2', 'Gene', '4193', (35, 39))	('T309G promoter', 'Var', (60, 74))	('MDM2', 'Gene', (35, 39))
927956	20922573	Therefore, it could be expected that the variant MDM2 genotypes (T/G and G/G) are associated with adverse outcome in esophageal cancer patients (as shown in other cancer types).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('patients', 'Species', '9606', (135, 143))	('associated', 'Reg', (82, 92))	('esophageal cancer', 'Disease', (117, 134))	('T/G', 'Var', (65, 68))	('G/G', 'Var', (73, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('MDM2', 'Gene', '4193', (49, 53))	('MDM2', 'Gene', (49, 53))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (128, 134))
927957	20922573	However, the present study showed improved survival in patients with the MDM2 T/G genotype compared with the wild-type T/T genotype.	('T/G', 'Var', (78, 81))	('improved', 'PosReg', (34, 42))	('survival', 'MPA', (43, 51))	('MDM2', 'Gene', '4193', (73, 77))	('MDM2', 'Gene', (73, 77))	('patients', 'Species', '9606', (55, 63))
927959	20922573	Among breast cancer patients with the wild-type MDM2 genotype (T/T), a mutant TP53 status and aberrant TP53 expression in breast tumors were associated with poor survival.	('breast tumors', 'Phenotype', 'HP:0100013', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('TP53', 'Gene', '7157', (103, 107))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('breast cancer', 'Disease', (6, 19))	('mutant', 'Var', (71, 77))	('patients', 'Species', '9606', (20, 28))	('TP53', 'Gene', '7157', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MDM2', 'Gene', (48, 52))	('aberrant', 'Var', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('TP53', 'Gene', (103, 107))	('breast tumors', 'Disease', 'MESH:D001943', (122, 135))	('poor', 'NegReg', (157, 161))	('breast tumors', 'Disease', (122, 135))	('MDM2', 'Gene', '4193', (48, 52))	('expression', 'MPA', (108, 118))	('TP53', 'Gene', (78, 82))
927960	20922573	The tumor TP53 status was not associated with breast cancer survival among carriers of the variant MDM2 allele (T/G or G/G).	('tumor', 'Disease', (4, 9))	('T/G', 'Var', (112, 115))	('TP53', 'Gene', (10, 14))	('MDM2', 'Gene', '4193', (99, 103))	('MDM2', 'Gene', (99, 103))	('TP53', 'Gene', '7157', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('breast cancer', 'Disease', (46, 59))	('G/G', 'Var', (119, 122))
927961	20922573	Since TP53 is the most frequently mutated gene in EAC, it could be hypothesized that the tumors of most patients with the T/T genotype harbor a TP53 mutation, which could lead to a reduced survival as observed in the present study.	('survival', 'MPA', (189, 197))	('T/T', 'Var', (122, 125))	('TP53', 'Gene', (144, 148))	('reduced', 'NegReg', (181, 188))	('tumors', 'Disease', (89, 95))	('TP53', 'Gene', (6, 10))	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', '7157', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutation', 'Var', (149, 157))	('patients', 'Species', '9606', (104, 112))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))
927962	20922573	In a previously well-conducted study, the known TP53 codon 72 Arg/Pro and MDM2 polymorphisms were genotyped in 300 patients with EAC and 63 patients with ESCC.	('MDM2', 'Gene', '4193', (74, 78))	('patients', 'Species', '9606', (115, 123))	('TP53', 'Gene', '7157', (48, 52))	('MDM2', 'Gene', (74, 78))	('EAC', 'Phenotype', 'HP:0011459', (129, 132))	('TP53', 'Gene', (48, 52))	('72 Arg/Pro', 'Var', (59, 69))	('EAC', 'Disease', (129, 132))	('patients', 'Species', '9606', (140, 148))	('72 Arg/Pro', 'SUBSTITUTION', 'None', (59, 69))
927963	20922573	As in concordance with the results of the present study, patients with EAC harboring the MDM2 T/G genotype had a borderline improved overall survival as compared with patients carrying the wild-type genotype (AHR for death 0.70, 95% CI [0.50-0.99], P = 0.04).	('EAC', 'Phenotype', 'HP:0011459', (71, 74))	('patients', 'Species', '9606', (57, 65))	('improved', 'PosReg', (124, 132))	('EAC', 'Disease', (71, 74))	('patients', 'Species', '9606', (167, 175))	('death', 'Disease', (217, 222))	('death', 'Disease', 'MESH:D003643', (217, 222))	('T/G', 'Var', (94, 97))	('MDM2', 'Gene', '4193', (89, 93))	('overall survival', 'MPA', (133, 149))	('MDM2', 'Gene', (89, 93))
927964	20922573	But unlike the present study, the MDM2 variant genotype did correlate with marked reduced survival in patients with ESCC.	('survival', 'MPA', (90, 98))	('ESCC', 'Disease', (116, 120))	('patients', 'Species', '9606', (102, 110))	('MDM2', 'Gene', '4193', (34, 38))	('variant', 'Var', (39, 46))	('MDM2', 'Gene', (34, 38))	('reduced', 'NegReg', (82, 89))
927965	20922573	In this study, patients carrying the CDH1 GA/GA genotype had a significantly reduced survival as compared with patients with the wild-type G/G genotype.	('patients', 'Species', '9606', (15, 23))	('CDH1', 'Gene', (37, 41))	('reduced', 'NegReg', (77, 84))	('survival', 'MPA', (85, 93))	('GA/GA', 'Var', (42, 47))	('CDH1', 'Gene', '999', (37, 41))	('patients', 'Species', '9606', (111, 119))
927968	20922573	The GA-allele has been associated with significant suppression of CDH1 promoter activity in colorectal and gastric cancer cell lines.	('colorectal', 'Disease', 'MESH:D015179', (92, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('suppression', 'NegReg', (51, 62))	('colorectal', 'Disease', (92, 102))	('CDH1', 'Gene', (66, 70))	('CDH1', 'Gene', '999', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('GA-allele', 'Var', (4, 13))	('gastric cancer', 'Disease', (107, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))
927969	20922573	It can be hypothesized that the GA-allele might enhance the progression of esophageal cancer by reducing CDH1 transcription resulting in a decrease in CDH1 protein expression and impairment of cell-cell adhesion.	('CDH1', 'Gene', (151, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('CDH1', 'Gene', '999', (151, 155))	('CDH1', 'Gene', '999', (105, 109))	('reducing', 'NegReg', (96, 104))	('GA-allele', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CDH1', 'Gene', (105, 109))	('enhance', 'PosReg', (48, 55))	('transcription', 'MPA', (110, 123))	('cell-cell adhesion', 'CPA', (193, 211))	('protein expression', 'MPA', (156, 174))	('esophageal cancer', 'Disease', (75, 92))	('impairment', 'NegReg', (179, 189))	('decrease', 'NegReg', (139, 147))
927980	20922573	Patients with EAC carrying the heterozygous MDM2 T/G genotype had twofold reduced risk of disease recurrence, and patients with the homozygous CDH1 GA/GA had a fourfold increased risk of disease recurrence.	('MDM2', 'Gene', '4193', (44, 48))	('MDM2', 'Gene', (44, 48))	('T/G', 'Var', (49, 52))	('reduced', 'NegReg', (74, 81))	('Patients', 'Species', '9606', (0, 8))	('EAC', 'Phenotype', 'HP:0011459', (14, 17))	('patients', 'Species', '9606', (114, 122))	('CDH1', 'Gene', (143, 147))	('EAC', 'Disease', (14, 17))	('CDH1', 'Gene', '999', (143, 147))
928010	15978128	Consequently, UICC stages I and II were seen to be more prevalent in those patients who had undergone transhiatal procedures (p < 0.0005) (Table 1).	('prevalent', 'Reg', (56, 65))	('transhiatal', 'Var', (102, 113))	('patients', 'Species', '9606', (75, 83))	('UICC stages I', 'Disease', (14, 27))
928014	15978128	The rate of general complications, with 42.6% (20/47) versus 21.6% (22/102) (p = 0.011), was higher following the transthoracic approach, which was associated with a higher rate of pneumonia.	('pneumonia', 'Phenotype', 'HP:0002090', (181, 190))	('transthoracic', 'Var', (114, 127))	('pneumonia', 'Disease', (181, 190))	('pneumonia', 'Disease', 'MESH:D011014', (181, 190))
928018	15978128	The median lymph node-ratio (quotient between the number of tumor-infiltrated lymph nodes and the total number of lymph nodes dissected) during transthoracic resection was seen to be 0.10 versus 0 for the transhiatal as compared with 0.154 versus 0.111 for the transthoracic procedure, respectively (p > 0.05) (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('transhiatal', 'Var', (205, 216))	('tumor', 'Disease', 'MESH:D009369', (60, 65))
928019	15978128	The median and the five-year survival rates for the total patient population were markedly better following transhiatal resection than subsequent to the transthoracic procedure (16 months and 32.1% as compared with 16 months and 13.6%, respectively; p = 0.018) (Table 4).	('patient', 'Species', '9606', (58, 65))	('better', 'PosReg', (91, 97))	('transhiatal resection', 'Var', (108, 129))
928024	15978128	A relevant advantage to the transhiatal in comparison with the transthoracic operative procedure (n = 32; median survival time: 17 months; p = 0.044) was also to be seen for tumor localizations in the distal third of the esophagus (n = 86; median survival time: 30 months).	('tumor', 'Disease', (174, 179))	('transhiatal', 'Var', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('advantage', 'PosReg', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
928034	15978128	Our data show that through transhiatal esophagectomy, a five-year survival rate of 54.1% was seen in patients without (pN0) and of 22.4% in those with lymph node involvement (pN1).	('transhiatal', 'Var', (27, 38))	('pN1', 'Gene', '5270', (175, 178))	('patients', 'Species', '9606', (101, 109))	('pN1', 'Gene', (175, 178))
928053	33469301	Kaplan-Meier analysis revealed that high ACTL6A expression was significantly associated with poor overall survival (OS) (P = 0.008, HR= 2.562, 95% CI: 1.241-5.289), and decision curve analysis (DCA) demonstrated that ACTL6A could increase the clinical prognostic efficiency of the original clinical prediction model.	('overall', 'MPA', (98, 105))	('DCA', 'Chemical', '-', (194, 197))	('expression', 'MPA', (48, 58))	('ACTL6A', 'Gene', (41, 47))	('increase', 'PosReg', (230, 238))	('poor', 'NegReg', (93, 97))	('high', 'Var', (36, 40))
928054	33469301	ACTL6A knockdown resulted in G1 phase arrest, with downregulation of cyclin D1, CDK2 and S6K1/pS6 pathway proteins and upregulation of p21 and p27, while overexpression of ACTL6A facilitated the entry of more cells into S phase with upregulated cyclin D1, CDK2 and S6K1/pS6 pathway proteins and downregulated p21 and p27.	('p27', 'Gene', '3429', (143, 146))	('arrest', 'Disease', (38, 44))	('pS6', 'Gene', (94, 97))	('p27', 'Gene', (143, 146))	('S phase', 'CPA', (220, 227))	('upregulation', 'PosReg', (119, 131))	('p27', 'Gene', '3429', (317, 320))	('p27', 'Gene', (317, 320))	('facilitated', 'PosReg', (179, 190))	('pS6', 'Gene', '338413', (270, 273))	('downregulated', 'NegReg', (295, 308))	('p21', 'Gene', (309, 312))	('cyclin D1', 'Gene', (245, 254))	('CDK2', 'Gene', '1017', (256, 260))	('upregulated', 'PosReg', (233, 244))	('pS6', 'Gene', '338413', (94, 97))	('p21', 'Gene', (135, 138))	('ACTL6A', 'Gene', (0, 6))	('CDK2', 'Gene', (256, 260))	('arrest', 'Disease', 'MESH:D006323', (38, 44))	('cyclin D1', 'Gene', (69, 78))	('CDK2', 'Gene', '1017', (80, 84))	('cyclin D1', 'Gene', '595', (245, 254))	('CDK2', 'Gene', (80, 84))	('cyclin D1', 'Gene', '595', (69, 78))	('downregulation', 'NegReg', (51, 65))	('p21', 'Gene', '1026', (309, 312))	('p21', 'Gene', '1026', (135, 138))	('pS6', 'Gene', (270, 273))	('knockdown', 'Var', (7, 16))
928063	33469301	In general, the SWI/SNF complex acts as a tumor suppressor; however, protein subunits of this complex are frequently mutated or lost in tumors, creating circumstances that are permissive for cancer development.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (191, 197))	('mutated', 'Var', (117, 124))	('tumor', 'Disease', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('lost', 'NegReg', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', (136, 141))
928065	33469301	Deficiency of Brg1 was previously shown to induce cell cycle arrest through an RB-dependent mechanism, and Brg1 is preferentially recruited by p53 to a subset of p53-dependent promoters, including the p21 promoter, in melanoma.	('arrest', 'Disease', (61, 67))	('Brg1', 'Gene', '6597', (107, 111))	('p53', 'Gene', '7157', (143, 146))	('p53', 'Gene', (162, 165))	('p21', 'Gene', '1026', (201, 204))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('p21', 'Gene', (201, 204))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('p53', 'Gene', '7157', (162, 165))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('Brg1', 'Gene', (14, 18))	('Brg1', 'Gene', '6597', (14, 18))	('p53', 'Gene', (143, 146))	('Brg1', 'Gene', (107, 111))	('preferentially recruited', 'PosReg', (115, 139))	('Deficiency', 'Var', (0, 10))
928068	33469301	ACTL6A expression leads to cell cycle arrest in head and neck squamous cell carcinoma (HNSCC) and epidermal squamous cell carcinoma (SCC) by interacting with the p21 promoter directly.	('arrest', 'Disease', (38, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('neck squamous cell carcinoma', 'Disease', (57, 85))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (27, 44))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (57, 85))	('p21', 'Gene', '1026', (162, 165))	('epidermal squamous cell carcinoma', 'Disease', (98, 131))	('ACTL6A', 'Gene', (0, 6))	('interacting', 'Interaction', (141, 152))	('arrest', 'Disease', 'MESH:D006323', (38, 44))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('epidermal squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 131))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (48, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('p21', 'Gene', (162, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('expression', 'Var', (7, 17))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
928073	33469301	S6K1 always phosphorylates S6 protein at Ser235, Ser236, Ser240, Ser244, and Ser247.	('Ser244', 'Var', (65, 71))	('Ser247', 'Var', (77, 83))	('Ser236', 'Var', (49, 55))	('Ser236', 'Chemical', '-', (49, 55))	('Ser235', 'Chemical', '-', (41, 47))	('Ser240', 'Chemical', '-', (57, 63))	('S6 protein', 'Protein', (27, 37))	('Ser235', 'Var', (41, 47))	('Ser240', 'Var', (57, 63))	('Ser244', 'Chemical', '-', (65, 71))	('Ser247', 'Chemical', '-', (77, 83))
928090	33469301	EC1 cells were transfected with virus cloned with stable ACTL6A knockdown sequence and TE7 cells were transfected with virus cloned with full-length ACTL6A sequence.	('TE7', 'CellLine', 'CVCL:9972', (87, 90))	('EC1', 'Gene', '4819', (0, 3))	('EC1', 'Gene', (0, 3))	('ACTL6A', 'Gene', (57, 63))	('knockdown', 'Var', (64, 73))
928097	33469301	Primary antibodies used in the whole experiment are listed below: ACTL6A (NB100-61628) from Novus Biologicals (USA); p21 (#2946), CDK2 (#18048), S6 (#2217) and pS6 (#5364) from Cell Signaling Technology (USA); S6K1 (sc-8418) from Santa Cruz; GAPDH (10494-1-AP), cyclinD1 (26939-1-AP) and p27 (25614-1-AP) from Proteintech (Wuhan, China).	('CDK2', 'Gene', (130, 134))	('pS6', 'Gene', '338413', (160, 163))	('cyclinD1', 'Gene', (262, 270))	('p21', 'Gene', '1026', (117, 120))	('cyclinD1', 'Gene', '595', (262, 270))	('CDK2', 'Gene', '1017', (130, 134))	('p21', 'Gene', (117, 120))	('26939-1-AP', 'Var', (272, 282))	('GAPDH', 'Gene', '2597', (242, 247))	('#18048', 'Var', (136, 142))	('pS6', 'Gene', (160, 163))	('GAPDH', 'Gene', (242, 247))	('p27', 'Gene', '3429', (288, 291))	('p27', 'Gene', (288, 291))
928120	33469301	The OS prognosis of the group with positive ACTL6A expression in both ESCC tissues and corresponding noncancerous tissues was the worst among all four groups (P=0.009, Figure 1H).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('positive', 'Var', (35, 43))	('ACTL6A', 'Gene', (44, 50))	('expression', 'MPA', (51, 61))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
928121	33469301	In addition, univariate and multivariate Cox regression analysis showed that positive ACTL6A expression was a significant and independent prognostic marker of the OS of ESCC patients (Table 2).	('positive', 'Var', (77, 85))	('ESCC patients', 'Disease', (169, 182))	('patients', 'Species', '9606', (174, 182))	('expression', 'MPA', (93, 103))	('SCC', 'Phenotype', 'HP:0002860', (170, 173))	('ACTL6A', 'Gene', (86, 92))
928125	33469301	To analyze the proliferation stimulation effect of ACTL6A on ESCC, we used seven ESCC cell lines: TE7, KYSE510, KYSE150, KYSE450, EC1, EC9706 and EC109.	('KYSE150', 'CellLine', 'CVCL:1348', (112, 119))	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('EC9706', 'Var', (135, 141))	('EC1', 'Gene', '4819', (130, 133))	('EC1', 'Gene', (130, 133))	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('EC1', 'Gene', (146, 149))	('KYSE450', 'Var', (121, 128))	('KYSE510', 'Var', (103, 110))	('EC9706', 'CellLine', 'CVCL:E307', (135, 141))	('TE7', 'CellLine', 'CVCL:9972', (98, 101))	('KYSE150', 'Var', (112, 119))	('EC1', 'Gene', '4819', (146, 149))
928134	33469301	These results demonstrated that the proportion of cells in G1 phase significantly increased in EC1 cells transduced with Lv-shACTL6A compared with mock-transduced EC1 cells, while the proportion of cells in S phase significantly increased in TE7 cells transduced with Lv-ACTL6A compared with TE7 cells transduced with empty vector (Figure 3A).	('TE7', 'CellLine', 'CVCL:9972', (242, 245))	('G1 phase', 'CPA', (59, 67))	('increased', 'PosReg', (229, 238))	('EC1', 'Gene', '4819', (163, 166))	('EC1', 'Gene', (163, 166))	('Lv-shACTL6A', 'Var', (121, 132))	('increased', 'PosReg', (82, 91))	('TE7', 'CellLine', 'CVCL:9972', (292, 295))	('EC1', 'Gene', '4819', (95, 98))	('EC1', 'Gene', (95, 98))
928139	33469301	ACTL6A expression resulted in upregulated S6K1 and pS6, while ACTL6A knockdown downregulated these proteins; the expression level of S6 remained the same, indicating that ACTL6A regulates the S6K1/pS6 pathway by affecting pS6 phosphorylation in TE7 and EC1 cells (Figure 3C).	('ACTL6A', 'Var', (171, 177))	('pS6', 'Gene', (51, 54))	('affecting', 'Reg', (212, 221))	('pS6', 'Gene', '338413', (222, 225))	('upregulated', 'PosReg', (30, 41))	('phosphorylation', 'MPA', (226, 241))	('regulates', 'Reg', (178, 187))	('downregulated', 'NegReg', (79, 92))	('EC1', 'Gene', (253, 256))	('pS6', 'Gene', '338413', (51, 54))	('TE7', 'CellLine', 'CVCL:9972', (245, 248))	('EC1', 'Gene', '4819', (253, 256))	('pS6', 'Gene', (197, 200))	('S6K1', 'MPA', (42, 46))	('ACTL6A', 'Gene', (0, 6))	('pS6', 'Gene', (222, 225))	('pS6', 'Gene', '338413', (197, 200))
928140	33469301	To validate the effect of ACTL6A on ESCC cells in vivo, we subcutaneously injected TE7 cells transduced with Lv-ACTL6A or Lv-CON and EC1 cells transduced with Lv-shACTL6A-1 or Lv-shCON into the flank region of 5-week-old nude mice to establish a mouse xenograft model.	('EC1', 'Gene', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('mouse', 'Species', '10090', (246, 251))	('nude mice', 'Species', '10090', (221, 230))	('Lv-ACTL6A', 'Var', (109, 118))	('EC1', 'Gene', '4819', (133, 136))	('TE7', 'CellLine', 'CVCL:9972', (83, 86))
928143	33469301	Immunohistochemical analysis also showed that Ki67, S6K1 and pS6 expression was significantly higher in xenograft mouse model tissues with ACTL6A overexpression than in control tissues and was markedly lower in xenograft mouse model tissues with suppressed ACTL6A than in mock-transduced vector tissues, which indicated that the expression of ACTL6A played a vital role in the proliferation of ESCC cells in vivo (Figure 4E).	('Ki67', 'Gene', (46, 50))	('pS6', 'Gene', '338413', (61, 64))	('ACTL6A overexpression', 'Var', (139, 160))	('SCC', 'Phenotype', 'HP:0002860', (395, 398))	('lower', 'NegReg', (202, 207))	('mouse', 'Species', '10090', (221, 226))	('overexpression', 'Var', (146, 160))	('S6K1', 'Gene', (52, 56))	('expression', 'MPA', (65, 75))	('mouse', 'Species', '10090', (114, 119))	('Ki67', 'Gene', '17345', (46, 50))	('pS6', 'Gene', (61, 64))	('higher', 'PosReg', (94, 100))
928145	33469301	In this research, we demonstrated that patients with positive ACTL6A expression had obviously shortened OS compared with those with negative ACTL6A expression.	('patients', 'Species', '9606', (39, 47))	('expression', 'Var', (69, 79))	('shortened', 'NegReg', (94, 103))	('ACTL6A', 'Gene', (62, 68))	('positive', 'Var', (53, 61))
928150	33469301	Our subsequent mechanistic research demonstrated the tumor promoting effects of ACTL6A upregulation and the antitumor effects of ACTL6A knockdown in ESCC cells in vitro and in vivo.	('ESCC', 'Disease', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('knockdown', 'Var', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ACTL6A', 'Gene', (129, 135))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (112, 117))	('SCC', 'Phenotype', 'HP:0002860', (150, 153))	('ACTL6A', 'Gene', (80, 86))	('upregulation', 'PosReg', (87, 99))
928151	33469301	Our flow cytometry results showed that ACTL6A knockdown led to G1 phase arrest, whereas ACTL6A upregulation caused cells to accumulate in S phase in ESCC cells upon PI labeling.	('arrest', 'Disease', 'MESH:D006323', (72, 78))	('knockdown', 'Var', (46, 55))	('ACTL6A', 'Gene', (88, 94))	('arrest', 'Disease', (72, 78))	('ACTL6A', 'Gene', (39, 45))	('accumulate', 'PosReg', (124, 134))	('S phase', 'CPA', (138, 145))	('upregulation', 'PosReg', (95, 107))	('SCC', 'Phenotype', 'HP:0002860', (150, 153))
928153	33469301	These results are in line with the discovery for laryngeal squamous cell carcinoma cells that ACTL6A cooperates with p63 to inhibit p21, a cell-cycle-regulatory gene, and epidermal growth factor (EGF) family ligand NRG1, and the loss of endogenous ACTL6A results in the accumulation of cells in G1/G07.	('ACTL6A', 'Gene', (248, 254))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('ACTL6A', 'Gene', (94, 100))	('NRG1', 'Gene', (215, 219))	('squamous cell carcinoma', 'Disease', (59, 82))	('p21', 'Gene', '1026', (132, 135))	('NRG1', 'Gene', '3084', (215, 219))	('p21', 'Gene', (132, 135))	('cells in G1/G07', 'CPA', (286, 301))	('p63', 'Gene', (117, 120))	('loss', 'Var', (229, 233))	('accumulation', 'PosReg', (270, 282))	('inhibit', 'NegReg', (124, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('p63', 'Gene', '8626', (117, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
928158	33469301	Ji et al revealed that ACTL6A overexpression promotes cellular proliferation in vitro and in vivo possibly through the direct interaction and stabilization of the transcriptional regulator YAP/TAZ.	('interaction', 'Interaction', (126, 137))	('YAP', 'Gene', (189, 192))	('ACTL6A', 'Gene', (23, 29))	('promotes', 'PosReg', (45, 53))	('cellular proliferation', 'CPA', (54, 76))	('YAP', 'Gene', '55249', (189, 192))	('TAZ', 'Gene', '6901', (193, 196))	('overexpression', 'Var', (30, 44))	('TAZ', 'Gene', (193, 196))
928161	33469301	Our results showed that knockdown of ACTL6A led to suppression of cell cycle progression by inhibiting the expression of cyclin D1 and CDK2, while changes in the expression of S6K1 and pS6 had the same tendency.	('cyclin D1', 'Gene', (121, 130))	('CDK2', 'Gene', '1017', (135, 139))	('cyclin D1', 'Gene', '595', (121, 130))	('pS6', 'Gene', (185, 188))	('ACTL6A', 'Gene', (37, 43))	('suppression', 'NegReg', (51, 62))	('cell cycle progression', 'CPA', (66, 88))	('expression', 'MPA', (107, 117))	('pS6', 'Gene', '338413', (185, 188))	('CDK2', 'Gene', (135, 139))	('knockdown', 'Var', (24, 33))	('inhibiting', 'NegReg', (92, 102))
928163	33469301	Thus, it is reasonable to speculate that deletion of ACTL6A leads to suppression of the S6K1/pS6 pathway, resulting in a delay in entry into S phase in ESCC.	('entry into S phase in ESCC', 'MPA', (130, 156))	('suppression', 'NegReg', (69, 80))	('ACTL6A', 'Gene', (53, 59))	('pS6', 'Gene', (93, 96))	('deletion', 'Var', (41, 49))	('delay', 'NegReg', (121, 126))	('pS6', 'Gene', '338413', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))
928165	33469301	In addition, liver-specific S6 knockout in mice led to severe cell cycle arrest, indicating the critical role of S6 in cell cycle progression.	('mice', 'Species', '10090', (43, 47))	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('arrest', 'Disease', (73, 79))	('knockout', 'Var', (31, 39))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))
928166	33469301	In conclusion, the present study indicates that a clinical model including the ACTL6A expression level may predict patient outcome more efficiently than a model that does not include ACTL6A expression, and mechanistic studies demonstrated that ACTL6A may function to promote oncogenesis and growth in vitro and in vivo via phosphorylation of S6.	('promote', 'PosReg', (267, 274))	('oncogenesis', 'CPA', (275, 286))	('growth', 'CPA', (291, 297))	('ACTL6A', 'Var', (244, 250))	('patient', 'Species', '9606', (115, 122))	('phosphorylation', 'Var', (323, 338))
928168	33208781	Through a series of screening, miR-34a-5p, miR-148a-3p and miR-181a-5p were selected as EC-associated miRNAs.	('miR-148a', 'Gene', (43, 51))	('miR-181a-5p', 'Chemical', '-', (59, 70))	('miR-181a-5p', 'Var', (59, 70))	('miR-34a-5p', 'Var', (31, 41))	('EC-associated', 'Disease', (88, 101))	('miR-34a-5p', 'Chemical', '-', (31, 41))	('miR-148a', 'Gene', '406940', (43, 51))
928170	33208781	Compared with normal controls, the level of miR-34a-5p increased while miR-148a-3p and miR-181a-5p decreased in EC and benign patients (P < 0.001), and the level of miR-181a-5p in early EC patients was significantly lower (P < 0.001).	('decreased', 'NegReg', (99, 108))	('lower', 'NegReg', (216, 221))	('miR-148a', 'Gene', (71, 79))	('miR-181a-5p', 'Chemical', '-', (87, 98))	('increased', 'PosReg', (55, 64))	('miR-34a-5p', 'Chemical', '-', (44, 54))	('miR-181a-5p', 'Var', (87, 98))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (189, 197))	('miR-181a-5p', 'Chemical', '-', (165, 176))	('miR-148a', 'Gene', '406940', (71, 79))
928171	33208781	According to logistic regression analysis, combined detection of miR-34a-5p, miR-148a-3p and Cyfra21-1 provided the highest diagnosis efficiency of 85.07% with sensitivity and specificity reaching 85.45% and 84.71%.	('miR-148a', 'Gene', '406940', (77, 85))	('miR-148a', 'Gene', (77, 85))	('miR-34a-5p', 'Var', (65, 75))	('Cyfra21-1', 'Var', (93, 102))	('miR-34a-5p', 'Chemical', '-', (65, 75))
928172	33208781	Compared with preoperative samples, the level of miR-34a-5p decreased while miR-148a-3p and miR-181a-5p increased in postoperative samples (P < 0.001).	('miR-34a-5p', 'Chemical', '-', (49, 59))	('decreased', 'NegReg', (60, 69))	('miR-34a-5p', 'MPA', (49, 59))	('miR-148a', 'Gene', (76, 84))	('increased', 'PosReg', (104, 113))	('miR-148a', 'Gene', '406940', (76, 84))	('miR-181a-5p', 'Chemical', '-', (92, 103))	('miR-181a-5p', 'Var', (92, 103))
928173	33208781	Collectively, this first developed, novel absolute quantitative RT-qPCR method exhibits high application value in detecting miRNAs, miR-34a-5p, miR-148a-3p and miR-181a-5p may serve as potential biomarkers in the diagnosis and prognosis of EC, and miR-181a-5p probably could serve as a new biomarker for early EC.	('miRNAs', 'Var', (124, 130))	('miR-34a-5p', 'Chemical', '-', (132, 142))	('miR-148a', 'Gene', '406940', (144, 152))	('miR-181a-5p', 'Chemical', '-', (248, 259))	('miR-148a', 'Gene', (144, 152))	('miR-181a-5p', 'Var', (248, 259))	('miR-181a-5p', 'Chemical', '-', (160, 171))	('miR-181a-5p', 'Var', (160, 171))	('miR-34a-5p', 'Var', (132, 142))
928176	33208781	There was evidence that patients with advanced EC or metastasis had a five-year survival rate of less than 20%, which was much lower than the concurrent survival rate of patients diagnosed with early cancer.	('patients', 'Species', '9606', (170, 178))	('metastasis', 'Var', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('less', 'NegReg', (97, 101))	('patients', 'Species', '9606', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
928182	33208781	Studies have shown that the expressions of miRNAs are involved in the developments, invasion and metastasis of several kinds of cancers, including colorectal cancer, breast cancer, lung cancer, which are hopefully to become potential biomarkers in plasma in the diagnosis and therapy.	('invasion', 'CPA', (84, 92))	('miRNAs', 'Var', (43, 49))	('metastasis', 'CPA', (97, 107))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('breast cancer', 'Disease', (166, 179))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('cancers', 'Disease', (128, 135))	('developments', 'CPA', (70, 82))	('lung cancer', 'Disease', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('involved', 'Reg', (54, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('colorectal cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('expressions', 'Var', (28, 39))
928185	33208781	In this study, firstly, we obtained three miRNAs (miR-34a-5p, miR-148a-3p, miR-181a-5p) from 13 candidate miRNAs in the plasma samples of discovery cohort.	('miR-34a-5p', 'Var', (50, 60))	('miR-148a', 'Gene', '406940', (62, 70))	('miR-34a-5p', 'Chemical', '-', (50, 60))	('miR-148a', 'Gene', (62, 70))	('miR-181a-5p', 'Chemical', '-', (75, 86))	('miR-181a-5p', 'Var', (75, 86))
928186	33208781	Through a series of screening procedures, three kinds of EC-associated candidate miRNAs (miR-34a-5p, miR-148a-3p, miR-181a-5p) were selected from 13 candidate miRNAs in plasma samples of discovery cohort (30 patients with EC and 30 normal controls) by SYBR GREEN (Table 1).	('patients', 'Species', '9606', (208, 216))	('miR-181a-5p', 'Chemical', '-', (114, 125))	('miR-181a-5p', 'Var', (114, 125))	('miR-34a-5p', 'Var', (89, 99))	('miR-34a-5p', 'Chemical', '-', (89, 99))	('EC-associated', 'Disease', (57, 70))	('miR-148a', 'Gene', '406940', (101, 109))	('SYBR GREEN', 'Chemical', '-', (252, 262))	('miR-148a', 'Gene', (101, 109))
928187	33208781	The stand curves (R2 > 0.99) were established for quantitative detection of the three kinds of miRNAs (miR-34a-5p, miR-148a-3p and miR-181a-5p).	('miR-181a-5p', 'Chemical', '-', (131, 142))	('miR-181a-5p', 'Var', (131, 142))	('miR-34a-5p', 'Var', (103, 113))	('miR-148a', 'Gene', '406940', (115, 123))	('miR-148a', 'Gene', (115, 123))	('miR-34a-5p', 'Chemical', '-', (103, 113))
928191	33208781	According to the examination results, The expression levels of miR-34a-5p, miR-148a-3p and miR-181a-5p in EC patients, benign esophageal diseases patients and normal controls were statistically significant (P < 0.001).	('miR-34a-5p', 'Chemical', '-', (63, 73))	('miR-148a', 'Gene', '406940', (75, 83))	('miR-148a', 'Gene', (75, 83))	('patients', 'Species', '9606', (109, 117))	('expression', 'MPA', (42, 52))	('significant', 'Reg', (194, 205))	('benign esophageal diseases', 'Disease', (119, 145))	('miR-181a-5p', 'Chemical', '-', (91, 102))	('miR-181a-5p', 'Var', (91, 102))	('miR-34a-5p', 'Var', (63, 73))	('patients', 'Species', '9606', (146, 154))	('benign esophageal diseases', 'Disease', 'MESH:D004935', (119, 145))
928192	33208781	Compared with normal controls, the level of miR-34a-5p increased, while the levels of miR-148a-3p and miR-181a-5p decreased in EC patients (Fig.	('levels', 'MPA', (76, 82))	('increased', 'PosReg', (55, 64))	('miR-34a-5p', 'Chemical', '-', (44, 54))	('miR-34a-5p', 'MPA', (44, 54))	('decreased', 'NegReg', (114, 123))	('patients', 'Species', '9606', (130, 138))	('miR-148a', 'Gene', '406940', (86, 94))	('miR-148a', 'Gene', (86, 94))	('miR-181a-5p', 'Chemical', '-', (102, 113))	('miR-181a-5p', 'Var', (102, 113))
928194	33208781	ROC curve analysis showed that in distinguishing EC patients from normal controls, the areas under the curves(AUC) of miR-34a-5p, miR-148a-3p, miR-181a-5p were 0.8213, 0.8079, and 0.7814, respectively (Fig.	('miR-181a-5p', 'Var', (143, 154))	('miR-34a-5p', 'Chemical', '-', (118, 128))	('miR-148a', 'Gene', '406940', (130, 138))	('miR-148a', 'Gene', (130, 138))	('miR-181a-5p', 'Chemical', '-', (143, 154))	('0.7814', 'Var', (180, 186))	('patients', 'Species', '9606', (52, 60))	('miR-34a-5p', 'Var', (118, 128))
928196	33208781	The optimal cut-off values of miR-34a-5p, miR-148a-3p, miR-181a-5p, CEA and Cyfra21-1 were 6.461, 9.394, 6.330, 4.60 ng/mL and 3.39 ng/mL.	('miR-181a-5p', 'Chemical', '-', (55, 66))	('miR-34a-5p', 'Var', (30, 40))	('miR-148a', 'Gene', '406940', (42, 50))	('CEA', 'Chemical', '-', (68, 71))	('miR-181a-5p', 'Var', (55, 66))	('miR-34a-5p', 'Chemical', '-', (30, 40))	('miR-148a', 'Gene', (42, 50))
928198	33208781	Thus, miR-34a-5p, miR-148a-3p and miR-181a-5p in plasma could be complemented by the levels of CEA and Cyfra21-1 in plasma for the auxiliary diagnosis of EC.	('CEA', 'Chemical', '-', (95, 98))	('miR-181a-5p', 'Var', (34, 45))	('miR-148a', 'Gene', '406940', (18, 26))	('miR-148a', 'Gene', (18, 26))	('miR-34a-5p', 'Var', (6, 16))	('miR-181a-5p', 'Chemical', '-', (34, 45))	('miR-34a-5p', 'Chemical', '-', (6, 16))
928199	33208781	These findings validated the performance of miR-34a-5p, miR-148a-3p and miR-181a-5p as plasma markers for EC diagnosis.	('miR-181a-5p', 'Chemical', '-', (72, 83))	('miR-34a-5p', 'Var', (44, 54))	('miR-181a-5p', 'Var', (72, 83))	('miR-34a-5p', 'Chemical', '-', (44, 54))	('miR-148a', 'Gene', '406940', (56, 64))	('miR-148a', 'Gene', (56, 64))
928202	33208781	Based on economic benefit, the model of the panel of miR-34a-5p, miR-148a-3p and Cyfra21-1 which was of the highest diagnostic efficiency (85.07%) was chosen, and a mathematical diagnostic model through Logistics regression was obtained: Y = 2.774*miR-34a-5p - 5.536*miR-148a-3p + 0.881*Cyfra21-1.	('miR-34a-5p', 'Var', (53, 63))	('miR-34a-5p', 'Chemical', '-', (248, 258))	('miR-148a', 'Gene', (267, 275))	('miR-34a-5p', 'Chemical', '-', (53, 63))	('miR-148a', 'Gene', '406940', (65, 73))	('miR-148a', 'Gene', (65, 73))	('miR-148a', 'Gene', '406940', (267, 275))
928203	33208781	The ROC curve analysis showed that the AUC of the panel of miR-34a-5p, miR-148a-3p and Cyfra21-1 was 0.9196, with sensitivity and specificity reaching 85.45% and 84.71% (Fig.	('miR-148a', 'Gene', (71, 79))	('miR-34a-5p', 'Var', (59, 69))	('Cyfra21-1', 'Var', (87, 96))	('miR-34a-5p', 'Chemical', '-', (59, 69))	('miR-148a', 'Gene', '406940', (71, 79))
928204	33208781	In the 67 patients with early EC, logistic regression analysis of the combination of miR-34a-5p, miR-148a-3p and Cyfra21-1 also showed that the combined model had a higher diagnostic efficiency (Table 4) than those of other panels.	('miR-34a-5p', 'Var', (85, 95))	('Cyfra21-1', 'Var', (113, 122))	('higher', 'PosReg', (165, 171))	('diagnostic efficiency', 'MPA', (172, 193))	('miR-34a-5p', 'Chemical', '-', (85, 95))	('miR-148a', 'Gene', '406940', (97, 105))	('patients', 'Species', '9606', (10, 18))	('miR-148a', 'Gene', (97, 105))
928205	33208781	All of the above results indicated that the combined detection of the panel of miR-34a-5p, miR-148a-3p and Cyfra21-1 in plasma provided a higher diagnosis efficiency thereby further improving the accuracy of diagnosis.	('diagnosis efficiency', 'MPA', (145, 165))	('miR-34a-5p', 'Var', (79, 89))	('miR-148a', 'Gene', '406940', (91, 99))	('miR-34a-5p', 'Chemical', '-', (79, 89))	('higher', 'PosReg', (138, 144))	('Cyfra21-1', 'Var', (107, 116))	('miR-148a', 'Gene', (91, 99))	('improving', 'PosReg', (182, 191))
928209	33208781	The expression level of miR-181a-5p in early EC patients was significantly lower than that of normal controls (P < 0.001, Fig.	('expression level', 'MPA', (4, 20))	('lower', 'NegReg', (75, 80))	('early EC', 'Disease', (39, 47))	('miR-181a-5p', 'Var', (24, 35))	('patients', 'Species', '9606', (48, 56))	('miR-181a-5p', 'Chemical', '-', (24, 35))
928210	33208781	According to the ROC curve analysis of diagnostic efficiency of miR-181a-5p in early EC patients, the value of AUC was 0.7457, the diagnostic sensitivity and specificity were 85.07% and 62.94% with the optimal cutoff value of 6.330 (Fig.	('miR-181a-5p', 'Var', (64, 75))	('early EC', 'Disease', (79, 87))	('miR-181a-5p', 'Chemical', '-', (64, 75))	('patients', 'Species', '9606', (88, 96))
928214	33208781	In the process of exploring the ability of miR-181a-5p to distinguish early ECs from normal controls, we found that in the serial testing of miR-181a-5p and CEA, the specificity increased dramatically to 100%, while the sensitivity dropped to 11.1%.	('miR-181a-5p', 'Chemical', '-', (43, 54))	('CEA', 'Chemical', '-', (157, 160))	('miR-181a-5p', 'Var', (141, 152))	('specificity', 'MPA', (166, 177))	('increased', 'PosReg', (178, 187))	('miR-181a-5p', 'Chemical', '-', (141, 152))
928216	33208781	Consistently, serial testing of miR-181a-5p and Cyfra21-1 increased specificity while reduced sensitivity, and parallel testing of miR-181a-5p and Cyfra21-1 failed to improve diagnostic efficiency.	('reduced', 'NegReg', (86, 93))	('increased', 'PosReg', (58, 67))	('sensitivity', 'MPA', (94, 105))	('miR-181a-5p', 'Chemical', '-', (131, 142))	('miR-181a-5p', 'Chemical', '-', (32, 43))	('miR-181a-5p', 'Var', (32, 43))	('Cyfra21-1', 'Var', (48, 57))	('specificity', 'MPA', (68, 79))
928217	33208781	Indeed, the sensitivity of miR-181a-5p in the diagnosis of early EC was much higher than those of conventional tumor markers (CEA and Cyfra21-1).	('miR-181a-5p', 'Chemical', '-', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('miR-181a-5p', 'Var', (27, 38))	('higher', 'PosReg', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('early EC', 'Disease', (59, 67))	('tumor', 'Disease', (111, 116))	('CEA', 'Chemical', '-', (126, 129))
928218	33208781	Our results provided evidence that the expression level of miR-181a-5p in plasma could be used to distinguish early EC patients from normal controls with clinically satisfactory sensitivity, which might be a new biomarker for early EC.	('miR-181a-5p', 'Var', (59, 70))	('patients', 'Species', '9606', (119, 127))	('early EC', 'Disease', (110, 118))	('expression', 'MPA', (39, 49))	('miR-181a-5p', 'Chemical', '-', (59, 70))
928220	33208781	The examination results showed that, compared with the preoperative samples, the level of miR-34a-5p significantly decreased, while the levels of miR-148a-3p and miR-181a-5p significantly increased in the postoperative samples (P < 0.001, Fig.	('miR-34a-5p', 'Chemical', '-', (90, 100))	('miR-34a-5p', 'MPA', (90, 100))	('increased', 'PosReg', (188, 197))	('miR-181a-5p', 'Chemical', '-', (162, 173))	('decreased', 'NegReg', (115, 124))	('miR-181a-5p', 'Var', (162, 173))	('miR-148a', 'Gene', '406940', (146, 154))	('miR-148a', 'Gene', (146, 154))
928221	33208781	These results suggested that the levels of miR-34a-5p, miR-148a-3p and miR-181a-5p in plasma might be valuable predictors of postoperative prognosis for EC patients.	('patients', 'Species', '9606', (156, 164))	('miR-34a-5p', 'Var', (43, 53))	('miR-181a-5p', 'Chemical', '-', (71, 82))	('miR-34a-5p', 'Chemical', '-', (43, 53))	('miR-148a', 'Gene', '406940', (55, 63))	('miR-148a', 'Gene', (55, 63))	('miR-181a-5p', 'Var', (71, 82))
928228	33208781	Compared with the SYBR Green qPCR, the AllGlo qPCR method had a higher sensitivity and a wider linear range (103-1010 copies/muL), meaning that we could easily detect the miRNAs which were expressed in low abundance in the circulation.	('detect', 'Reg', (160, 166))	('muL', 'Gene', (125, 128))	('muL', 'Gene', '4591', (125, 128))	('miRNAs', 'Var', (171, 177))
928230	33208781	We found that the expression level of miR-34a-5p increased, whereas the expression levels of miR-148a-3p and miR-181a-5p decreased in the plasma of EC.	('expression level', 'MPA', (18, 34))	('expression levels', 'MPA', (72, 89))	('increased', 'PosReg', (49, 58))	('decreased', 'NegReg', (121, 130))	('miR-148a', 'Gene', '406940', (93, 101))	('miR-34a-5p', 'Var', (38, 48))	('miR-148a', 'Gene', (93, 101))	('miR-181a-5p', 'Chemical', '-', (109, 120))	('miR-34a-5p', 'Chemical', '-', (38, 48))	('miR-181a-5p', 'Var', (109, 120))
928231	33208781	The results indicated that the plasma levels of miR-34a-5p, miR-148a-3p and miR-181a-5p could serve as biomarkers for EC diagnosis.	('miR-148a', 'Gene', (60, 68))	('miR-181a-5p', 'Chemical', '-', (76, 87))	('miR-181a-5p', 'Var', (76, 87))	('miR-34a-5p', 'Var', (48, 58))	('miR-34a-5p', 'Chemical', '-', (48, 58))	('miR-148a', 'Gene', '406940', (60, 68))
928233	33208781	and Han et al, miR-34a-5p could inhibit proliferation, migration, invasion and epithelial-mesenchymal transition in Esophageal Squamous Cell Carcinoma by targeting lymphoid enhancer-binding factor 1 and suppressing the Hippo-YAP1/TAZ signaling pathway, and The lncRNA CRNDE could promote colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/beta-catenin signaling.	('colorectal cancer', 'Disease', (288, 305))	('promote', 'PosReg', (280, 287))	('miR-34a-5p', 'Chemical', '-', (15, 25))	('inhibit', 'NegReg', (32, 39))	('lymphoid enhancer-binding factor 1', 'Gene', (164, 198))	('Carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('proliferation', 'CPA', (40, 53))	('lymphoid enhancer-binding factor 1', 'Gene', '51176', (164, 198))	('migration', 'CPA', (55, 64))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (127, 150))	('chemoresistance', 'CPA', (329, 344))	('suppressing', 'NegReg', (203, 214))	('colorectal cancer', 'Phenotype', 'HP:0003003', (288, 305))	('invasion', 'CPA', (66, 74))	('beta-catenin', 'Gene', (388, 400))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('beta-catenin', 'Gene', '1499', (388, 400))	('epithelial-mesenchymal transition', 'CPA', (79, 112))	('YAP1', 'Gene', '10413', (225, 229))	('Squamous Cell Carcinoma', 'Disease', (127, 150))	('CRNDE', 'Gene', '643911', (268, 273))	('CRNDE', 'Gene', (268, 273))	('miR-181a-5p-mediated', 'Var', (349, 369))	('TAZ', 'Gene', '6901', (230, 233))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('colorectal cancer', 'Disease', 'MESH:D015179', (288, 305))	('TAZ', 'Gene', (230, 233))	('miR-181a-5p', 'Chemical', '-', (349, 360))	('YAP1', 'Gene', (225, 229))
928237	33208781	The expression level of miR-181a-5p was lower in early EC patients than that in normal controls with the sensitivity 85.07%, indicating that miR-181a-5p could be used as a biomarker for early diagnosis of EC.	('expression level', 'MPA', (4, 20))	('miR-181a-5p', 'Chemical', '-', (24, 35))	('miR-181a-5p', 'Var', (141, 152))	('patients', 'Species', '9606', (58, 66))	('lower', 'NegReg', (40, 45))	('miR-181a-5p', 'Chemical', '-', (141, 152))
928239	33208781	Similar to the Roman index, this mathematical formula has a strong practicality, with which we can evaluate the risk of EC based on the examination results of miR-34a-5p, miR-148a-3p and Cyfra21-1, reducing the false negative rate, thus improving the diagnosis efficiency of EC.	('miR-34a-5p', 'Chemical', '-', (159, 169))	('false negative', 'MPA', (211, 225))	('Cyfra21-1', 'Var', (187, 196))	('miR-148a', 'Gene', '406940', (171, 179))	('miR-148a', 'Gene', (171, 179))	('improving', 'PosReg', (237, 246))	('reducing', 'NegReg', (198, 206))	('miR-34a-5p', 'Var', (159, 169))
928240	33208781	In this study, when compared with the preoperative samples, the level of miR-34a-5p significantly decreased, while the levels of miR-148a-3p and miR-181a-5p significantly increased in the postoperative samples (P < 0.001, Fig.	('miR-148a', 'Gene', (129, 137))	('miR-34a-5p', 'Chemical', '-', (73, 83))	('miR-148a', 'Gene', '406940', (129, 137))	('miR-181a-5p', 'Chemical', '-', (145, 156))	('miR-181a-5p', 'Var', (145, 156))	('decreased', 'NegReg', (98, 107))	('increased', 'PosReg', (171, 180))	('miR-34a-5p', 'Var', (73, 83))
928242	33208781	Through this study, we found that the expression level of miR-34a-5p was positively correlated with the development of tumor tissue to a certain extent.	('expression level', 'MPA', (38, 54))	('tumor', 'Disease', (119, 124))	('correlated', 'Reg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('miR-34a-5p', 'Var', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('miR-34a-5p', 'Chemical', '-', (58, 68))
928243	33208781	In addition, recent studies also showed that miR-34a-5p played an important role in the immune system, especially in the chemotherapy process of patients with malignant tumors.	('patients', 'Species', '9606', (145, 153))	('miR-34a-5p', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('malignant tumors', 'Disease', (159, 175))	('malignant tumors', 'Disease', 'MESH:D009369', (159, 175))	('miR-34a-5p', 'Chemical', '-', (45, 55))
928244	33208781	's study showed that altered expression of survivin, regulated by miRNAs, such as miR-34a-5p, may result in apoptosis resistance and auto-reactivity in lymphocytes from patients and have important roles in systemic sclerosis pathogenicity.	('patients', 'Species', '9606', (169, 177))	('roles', 'Reg', (197, 202))	('result in', 'Reg', (98, 107))	('miR-34a-5p', 'Var', (82, 92))	('systemic sclerosis', 'Disease', 'MESH:D012595', (206, 224))	('auto-reactivity', 'CPA', (133, 148))	('miR-34a-5p', 'Chemical', '-', (82, 92))	('systemic sclerosis', 'Disease', (206, 224))	('survivin', 'Protein', (43, 51))	('apoptosis resistance', 'CPA', (108, 128))
928247	33208781	These studies have directly or indirectly shown that miR-34a-5p has an important regulatory role in the function of the body's immune system.	('miR-34a-5p', 'Chemical', '-', (53, 63))	('miR-34a-5p', 'Var', (53, 63))	('regulatory', 'MPA', (81, 91))
928252	33208781	Meanwhile, by using this developed method, we identified that miR-34a-5p, miR-148a-3p and miR-181a-5p may serve as novel noninvasive biomarkers for EC diagnosis and prognosis, especially, miR-181a-5p probably could be used as a new biomarker for early EC.	('miR-148a', 'Gene', (74, 82))	('miR-181a-5p', 'Chemical', '-', (90, 101))	('miR-181a-5p', 'Chemical', '-', (188, 199))	('miR-181a-5p', 'Var', (90, 101))	('miR-34a-5p', 'Var', (62, 72))	('miR-148a', 'Gene', '406940', (74, 82))	('miR-181a-5p', 'Var', (188, 199))	('miR-34a-5p', 'Chemical', '-', (62, 72))
928302	32793448	In another study of patients with T1a-M2/M3 or T1b SEC who underwent ESD or esophagectomy in China, no significant difference was observed in overall survival recurrence, or metastasis in patients with T1a or T1b SEC treated with ESD or esophagectomy.	('T1b', 'Var', (47, 50))	('T1a-M2/M3', 'Var', (34, 43))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (20, 28))	('metastasis', 'CPA', (174, 184))
928315	32793448	For clinical T1a (M3) or T1b (SM1-SM2) disease, diagnostic ESD may be safely applied for organ preservation.	('SM1-SM2', 'Gene', '7911;53366', (30, 37))	('T1b', 'Var', (25, 28))	('SM1-SM2', 'Gene', (30, 37))
928400	32184470	This is consistent with the finding that caffeine induces gastric acid secretion, relaxes the LES, and worsens GERD.	('LES', 'MPA', (94, 97))	('caffeine', 'Var', (41, 49))	('relaxes', 'MPA', (82, 89))	('gastric acid secretion', 'MPA', (58, 80))	('GERD', 'Disease', (111, 115))	('worsens', 'NegReg', (103, 110))	('GERD', 'Disease', 'MESH:D005764', (111, 115))	('caffeine', 'Chemical', 'MESH:D002110', (41, 49))	('induces', 'Reg', (50, 57))
928433	32184470	Specifically, SSRIs decrease cultured human colon cancer cell viability; suppress cell division in rat colonic tumors, and slow human colorectal tumor xenograft growth.	('colorectal tumor', 'Disease', 'MESH:D015179', (134, 150))	('colon cancer', 'Disease', 'MESH:D015179', (44, 56))	('slow', 'NegReg', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cell division', 'CPA', (82, 95))	('colorectal tumor', 'Disease', (134, 150))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('suppress', 'NegReg', (73, 81))	('decrease', 'NegReg', (20, 28))	('colon cancer', 'Disease', (44, 56))	('human', 'Species', '9606', (128, 133))	('human', 'Species', '9606', (38, 43))	('colonic tumors', 'Disease', 'MESH:D015179', (103, 117))	('rat', 'Species', '10116', (99, 102))	('colonic tumors', 'Disease', (103, 117))	('SSRIs', 'Var', (14, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))
928462	31499608	A 50-mm superficial esophageal cancer (0-IIb) was revealed in the distal esophagus using a laser endoscopic system (EG-L590ZW, LL-7000 and VP-7000; Fujifilm Co., Tokyo, Japan).	('esophageal cancer', 'Disease', (20, 37))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('EG-L590ZW', 'Var', (116, 125))	('LL-7000', 'Var', (127, 134))	('VP-7000', 'Var', (139, 146))	('VP-7000', 'Chemical', 'MESH:C030911', (139, 146))
928543	31297133	To confirm whether miR-216a-5p directly targets the 3'-UTR of TCTN1, the wild-type or mutant 3'-UTR of TCTN1 was amplified and cloned into the vector psiCHECK-2 to construct luciferase reporter plasmids (WT TCTN1 or MUT TCTN1, respectively).	('miR', 'Gene', '220972', (19, 22))	('216a', 'Chemical', '-', (23, 27))	('miR', 'Gene', (19, 22))	('mutant', 'Var', (86, 92))	('TCTN1', 'Gene', (103, 108))	('TCTN1', 'Gene', (220, 225))	('TCTN1', 'Gene', (62, 67))	('TCTN1', 'Gene', '79600', (220, 225))	('TCTN1', 'Gene', '79600', (103, 108))	('TCTN1', 'Gene', '79600', (62, 67))	('TCTN1', 'Gene', (207, 212))	('TCTN1', 'Gene', '79600', (207, 212))	('5p', 'Chemical', '-', (28, 30))
928551	31297133	The miR-216a-5p expression levels were also measured in four human ESCC cell lines: KYSE150, EC9706, KYSE30 and TE-9.	('TE-9', 'CellLine', 'CVCL:1767', (112, 116))	('EC9706', 'Var', (93, 99))	('miR', 'Gene', (4, 7))	('miR', 'Gene', '220972', (4, 7))	('5p', 'Chemical', '-', (13, 15))	('EC9706', 'CellLine', 'CVCL:E307', (93, 99))	('human', 'Species', '9606', (61, 66))	('216a', 'Chemical', '-', (8, 12))
928553	31297133	Among the four ESCC cell lines, EC9706 and TE-9 expressed the lowest miR-216a-5p levels and were thus selected for further analyses.	('TE-9', 'CellLine', 'CVCL:1767', (43, 47))	('lowest', 'NegReg', (62, 68))	('216a', 'Chemical', '-', (73, 77))	('EC9706', 'Var', (32, 38))	('5p', 'Chemical', '-', (78, 80))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('EC9706', 'CellLine', 'CVCL:E307', (32, 38))
928572	31297133	The CCK-8 assay revealed that the cell proliferation rate was remarkably impaired in siTCTN1 transfected EC9706 and TE-9 cells compared with siNC groups (Fig.	('cell proliferation rate', 'CPA', (34, 57))	('impaired', 'NegReg', (73, 81))	('TCTN1', 'Gene', (87, 92))	('TE-9', 'CellLine', 'CVCL:1767', (116, 120))	('transfected', 'Var', (93, 104))	('TCTN1', 'Gene', '79600', (87, 92))	('EC9706', 'CellLine', 'CVCL:E307', (105, 111))
928573	31297133	Consistently, TCTN1 knockdown significantly increased the overall apoptotic percentage from 9.58% +- 0.44 to 24.84% +- 0.74% in EC9706 and from 9.79% +- 0.21 to 20.98% +- 0.58% in TE-9 cells (Fig.	('TCTN1', 'Gene', (14, 19))	('TCTN1', 'Gene', '79600', (14, 19))	('increased', 'PosReg', (44, 53))	('EC9706', 'CellLine', 'CVCL:E307', (128, 134))	('knockdown', 'Var', (20, 29))	('TE-9', 'CellLine', 'CVCL:1767', (180, 184))	('apoptotic percentage', 'CPA', (66, 86))
928592	31297133	Generally, the biological behaviors of ESCC cells with knockdown of TCTN1 tended to imitate these cells with overexpression of miR-216a-5p.	('TCTN1', 'Gene', (68, 73))	('knockdown', 'Var', (55, 64))	('TCTN1', 'Gene', '79600', (68, 73))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (127, 130))	('5p', 'Chemical', '-', (136, 138))	('216a', 'Chemical', '-', (131, 135))	('biological behaviors', 'CPA', (15, 35))
928603	31297133	Accumulating evidence indicates that the processes of neoplastic transformation, development and tumorigenesis involve abnormalities in apoptosis signaling pathways.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('development', 'CPA', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('apoptosis signaling pathways', 'Pathway', (136, 164))	('neoplastic transformation', 'CPA', (54, 79))	('tumor', 'Disease', (97, 102))	('men', 'Species', '9606', (88, 91))	('abnormalities', 'Var', (119, 132))
928610	31297133	Silencing of TCTN1 was suggested to induce human thyroid cancer cell apoptosis through over-expression of cleaved caspase-3 and PARP and repression of Bcl-2.	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('Bcl-2', 'Gene', (151, 156))	('TCTN1', 'Gene', (13, 18))	('thyroid cancer', 'Disease', (49, 63))	('Bcl-2', 'Gene', '596', (151, 156))	('TCTN1', 'Gene', '79600', (13, 18))	('PARP', 'Gene', '1302', (128, 132))	('thyroid cancer', 'Disease', 'MESH:D013964', (49, 63))	('cleaved', 'MPA', (106, 113))	('over-expression', 'PosReg', (87, 102))	('repression', 'NegReg', (137, 147))	('PARP', 'Gene', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Silencing', 'Var', (0, 9))	('induce', 'PosReg', (36, 42))	('human', 'Species', '9606', (43, 48))
928611	31297133	Silencing of TCTN1 by lentivirus-mediated RNA interference in gastric cancer and pancreatic cancer cells and reduction of proliferation were observed, suggesting that the knockdown of TCTN1 is sufficient to inhibit cell viability.	('inhibit', 'NegReg', (207, 214))	('TCTN1', 'Gene', '79600', (13, 18))	('reduction', 'NegReg', (109, 118))	('TCTN1', 'Gene', (184, 189))	('knockdown', 'Var', (171, 180))	('gastric cancer', 'Disease', (62, 76))	('RNA interference', 'MPA', (42, 58))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('TCTN1', 'Gene', '79600', (184, 189))	('cell viability', 'CPA', (215, 229))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Silencing', 'NegReg', (0, 9))	('proliferation', 'CPA', (122, 135))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('TCTN1', 'Gene', (13, 18))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('pancreatic cancer', 'Disease', (81, 98))
928714	29373910	However, Miyazaki et al., (2005) They showed that Cox-2 positivity was related to the prognosis of the patients.	('related', 'Reg', (71, 78))	('Cox-2', 'Gene', '4513', (50, 55))	('positivity', 'Var', (56, 66))	('Cox-2', 'Gene', (50, 55))	('patients', 'Species', '9606', (103, 111))
928716	29373910	The survival of patients with positive VEGF expression was significantly worse, in relation to the non-expressed VEGF.	('positive', 'Var', (30, 38))	('patients', 'Species', '9606', (16, 24))	('expression', 'Var', (44, 54))	('VEGF', 'Gene', (113, 117))	('survival', 'CPA', (4, 12))	('VEGF', 'Gene', (39, 43))	('worse', 'NegReg', (73, 78))	('VEGF', 'Gene', '7422', (113, 117))	('VEGF', 'Gene', '7422', (39, 43))
928724	29373910	In this meta-analysis, high expression of VEGF in esophageal CPB was associated with an approximate 80% risk for an increased risk of death from the disease.	('esophageal', 'Disease', (50, 60))	('high expression', 'Var', (23, 38))	('death', 'Disease', 'MESH:D003643', (134, 139))	('death', 'Disease', (134, 139))	('VEGF', 'Gene', '7422', (42, 46))	('VEGF', 'Gene', (42, 46))
928805	28885561	With regard to NSCLC, although cardiac toxicity has largely been understudied, population-based analyses have demonstrated independently increased risks of cardiac pathologies in patients that received RT, chemotherapy or CRT.	('cardiac toxicity', 'Disease', (31, 47))	('chemotherapy', 'Var', (206, 218))	('cardiac toxicity', 'Disease', 'MESH:D066126', (31, 47))	('cardiac pathologies', 'Disease', (156, 175))	('NSCLC', 'Disease', (15, 20))	('patients', 'Species', '9606', (179, 187))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))
928840	28885561	In the second, despite IMRT being more commonly delivered to patients with more advanced disease and larger target volumes in the trial, IMRT was associated with less grade >=3 pneumonitis (p = 0.039) and lower heart doses (p < 0.05).	('less', 'NegReg', (162, 166))	('IMRT', 'Var', (137, 141))	('pneumonitis', 'Disease', (177, 188))	('heart doses', 'MPA', (211, 222))	('patients', 'Species', '9606', (61, 69))	('pneumonitis', 'Disease', 'MESH:D011014', (177, 188))	('lower', 'NegReg', (205, 210))
928850	28885561	Over the past decade, molecular oncology has rapidly elucidated so-called "driver mutations" for NSCLC that have led to the emergence of targeted therapies.	('NSCLC', 'Disease', (97, 102))	('mutations', 'Var', (82, 91))	('oncology', 'Phenotype', 'HP:0002664', (32, 40))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))
928851	28885561	Standard treatment for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutant NSCLC now involves biologic therapies.	('epidermal growth factor receptor', 'Gene', (23, 55))	('NSCLC', 'Disease', (107, 112))	('ALK', 'Gene', (95, 98))	('men', 'Species', '9606', (14, 17))	('mutant', 'Var', (100, 106))	('anaplastic lymphoma kinase', 'Gene', (67, 93))	('epidermal growth factor receptor', 'Gene', '1956', (23, 55))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('EGFR', 'Gene', '1956', (57, 61))	('ALK', 'Gene', '238', (95, 98))	('anaplastic lymphoma kinase', 'Gene', '238', (67, 93))	('EGFR', 'Gene', (57, 61))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (67, 86))
928864	28900487	As cancer is a disease of genome instability and a resulting of accumulation of genetic alteration, mounting chromosomal and genomic technologies were developed and progressed rapidly which could be used for characterizing patients in genomics level.	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('genetic alteration', 'Var', (80, 98))	('cancer', 'Disease', (3, 9))	('patients', 'Species', '9606', (223, 231))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
928878	28900487	FISH, used fluorescent probes that bind to those parts with a high degree of sequence complementarity, was widely used to detect the amplification, deletion, and gene rearrangement of the targeted sequences on chromosome in situ, with the signal capturing by fluorescence microscopy.	('deletion', 'Var', (148, 156))	('men', 'Species', '9606', (176, 179))	('men', 'Species', '9606', (92, 95))	('gene rearrangement', 'Var', (162, 180))
928888	28900487	CGH is a powerful method that can survey the entire genome of tumor cells to detect DNA CNAs in one hybridization experiment, and has an improved resolution compared to the more traditional cytogenetic analysis techniques of FISH which are limited by the resolution of the microscope utilized.	('resolution', 'MPA', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('DNA', 'Var', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('men', 'Species', '9606', (120, 123))
928895	28900487	Studies on ESCC samples revealed that recurrent, high-level amplifications in 3q26.32-33, 3q27.1, 7p11, 7p22.3, 8p11.23, 8q21.11, 8q24.21, 11q13.2-11q13.3, 11q22, 12p12.1, 12q15-q21.1, 13q22.1, 14q11.2, 14q13.3, 18q11.2, and 19q13.11-q13.12, and homozygous deletions in 1p15.4, 2q22.1-22.2, 3p14.2, 4p16.1-p15.1, 4q34.3-q35.1, 5q12.1, 6p22.1, 9p21.3, 9p24.1, 13q14.2, 14q12, and 22q13.1.	('p15', 'Gene', (271, 274))	('p15', 'Gene', '1030', (271, 274))	('deletions', 'Var', (257, 266))	('p15', 'Gene', (306, 309))	('p15', 'Gene', '1030', (306, 309))
928897	28900487	The most frequently mutated genes in ESCC, including TP53 , PIK3CA , BRCA2 , EGFR , NRF2 , CDKN2A  were detected by several groups using traditional methods, such as PCR-sequencing or PCR-SSCP.	('TP53', 'Gene', (53, 57))	('BRCA2', 'Gene', '675', (69, 74))	('PIK3CA', 'Gene', (60, 66))	('CDKN2A', 'Gene', (91, 97))	('ESCC', 'Gene', (37, 41))	('PIK3CA', 'Gene', '5290', (60, 66))	('NRF2', 'Gene', '4780', (84, 88))	('CDKN2A', 'Gene', '1029', (91, 97))	('EGFR', 'Gene', '1956', (77, 81))	('TP53', 'Gene', '7157', (53, 57))	('NRF2', 'Gene', (84, 88))	('BRCA2', 'Gene', (69, 74))	('EGFR', 'Gene', (77, 81))	('mutated', 'Var', (20, 27))
928902	28900487	Signature A was characterized by C>G, C>T, and C>A mutations at TpCpX trinucleotides and was associated with mutations in the APOBEC family of cytidine deaminases.	('mutations', 'Var', (51, 60))	('C>G', 'Var', (33, 36))	('APOBEC', 'Gene', (126, 132))	('trinucleotides', 'Chemical', '-', (70, 84))	('C>T', 'Var', (38, 41))	('C>A mutations', 'Var', (47, 60))	('TpCpX', 'Gene', (64, 69))	('associated', 'Reg', (93, 103))	('mutations', 'Var', (109, 118))
928903	28900487	Signature B was characterized by an enrichment of C>T mutations at XpCpG trinucleotides because of an elevated rate of spontaneous 5-methyl-cytosine deamination.	('spontaneous 5-methyl-cytosine deamination', 'MPA', (119, 160))	('XpCpG', 'Gene', (67, 72))	('men', 'Species', '9606', (42, 45))	('elevated', 'PosReg', (102, 110))	('trinucleotides', 'Chemical', '-', (73, 87))	('C>T mutations', 'Var', (50, 63))
928906	28900487	However, NOTCH1 mutations had a better outcome than those individuals without deleterious mutations.	('mutations', 'Var', (16, 25))	('NOTCH1', 'Gene', '4851', (9, 15))	('NOTCH1', 'Gene', (9, 15))
928909	28900487	detected the CCND1 amplification on 100 ESCCs and 11 normal tissues using real-time qPCR and found that 41% of the patients had CCND1 amplification, which has a short survival time compared with the patients without CCND1 amplification.	('patients', 'Species', '9606', (115, 123))	('CCND1', 'Gene', '595', (216, 221))	('CCND1', 'Gene', '595', (13, 18))	('CCND1', 'Gene', (128, 133))	('CCND1', 'Gene', (216, 221))	('amplification', 'Var', (134, 147))	('CCND1', 'Gene', '595', (128, 133))	('patients', 'Species', '9606', (199, 207))	('CCND1', 'Gene', (13, 18))
928912	28900487	A copy number gain of SOX2 was observed in 6 of the 40 primary ESCCs (15%).	('copy number gain', 'Var', (2, 18))	('SOX2', 'Gene', '6657', (22, 26))	('primary ESCCs', 'Disease', (55, 68))	('SOX2', 'Gene', (22, 26))
928914	28900487	The amplification of FGFR1 was validated by FISH and high FGFR1 amplification is an independent poor prognostic factor in resected ESCC.	('amplification', 'MPA', (64, 77))	('high', 'Var', (53, 57))	('FGFR1', 'Gene', (21, 26))	('FGFR1', 'Gene', (58, 63))	('FGFR1', 'Gene', '2260', (58, 63))	('FGFR1', 'Gene', '2260', (21, 26))	('ESCC', 'Disease', (131, 135))
928915	28900487	And our group's result showed that high FGFR1 amplification is a delayed poor prognostic factor in stage I and II patients (unpublished data).	('amplification', 'Var', (46, 59))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('patients', 'Species', '9606', (114, 122))	('high', 'Var', (35, 39))
928916	28900487	Relative high-level deletion in 2q22.1-22.2 (LRP1B), 9p21.3 (CDKN2A/B), 5q12.1 (PDE4D), 9p24.1 (PTPRD), and 3p14.2 (FHIT) were detected.	('LRP1B', 'Gene', '53353', (45, 50))	('FHIT', 'Gene', (116, 120))	('PTPRD', 'Gene', '5789', (96, 101))	('PDE4D', 'Gene', '5144', (80, 85))	('PTPRD', 'Gene', (96, 101))	('FHIT', 'Gene', '2272', (116, 120))	('deletion', 'Var', (20, 28))	('CDKN2A/B', 'Gene', '1029;1030', (61, 69))	('PDE4D', 'Gene', (80, 85))	('LRP1B', 'Gene', (45, 50))	('CDKN2A/B', 'Gene', (61, 69))
928921	28900487	These evaluations found FBXW7 copy number loss rates of 44.7% (17/38) in the clinical samples.	('copy number', 'Var', (30, 41))	('FBXW7', 'Gene', (24, 29))	('FBXW7', 'Gene', '55294', (24, 29))	('clinical samples', 'Species', '191496', (77, 93))
929041	27391348	Finally, Kaplan-Meier plot of TCGA samples confirmed that high IMP2 expression is linked to a shorter survival time in esophageal cancer patients (Figure 3E; p = 0.008).	('survival time', 'CPA', (102, 115))	('expression', 'MPA', (68, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('IMP2', 'Gene', '10644', (63, 67))	('shorter', 'NegReg', (94, 101))	('patients', 'Species', '9606', (137, 145))	('IMP2', 'Gene', (63, 67))	('high', 'Var', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal cancer', 'Disease', (119, 136))
929043	27391348	Autoantibodies against IMP2 have recently also been described to be elevated in ESCC.	('ESCC', 'Disease', (80, 84))	('IMP2', 'Gene', (23, 27))	('elevated', 'PosReg', (68, 76))	('Autoantibodies', 'Var', (0, 14))	('IMP2', 'Gene', '10644', (23, 27))
929053	27391348	Based on both published marker genes that are predictive for survival and on a Kaplan-Meier survival analysis we showed that high IMP2 expression was linked to short survival.	('IMP2', 'Gene', (130, 134))	('expression', 'MPA', (135, 145))	('linked to', 'Reg', (150, 159))	('short survival', 'Disease', (160, 174))	('high', 'Var', (125, 129))	('IMP2', 'Gene', '10644', (130, 134))
929058	27391348	The observed correlation of IMP2 and signaling pathways such as MAPK and Jak-STAT seems reasonable since IMP2 expression results in increased levels of IGF2, which can activate both of these pathways.	('IMP2', 'Gene', (105, 109))	('levels', 'MPA', (142, 148))	('IGF2', 'Gene', (152, 156))	('activate', 'PosReg', (168, 176))	('increased', 'PosReg', (132, 141))	('IMP2', 'Gene', '10644', (28, 32))	('increased levels of IGF2', 'Phenotype', 'HP:0030269', (132, 156))	('IGF2', 'Gene', '3481', (152, 156))	('IMP2', 'Gene', (28, 32))	('IMP2', 'Gene', '10644', (105, 109))	('expression', 'Var', (110, 120))
929072	27835996	In terms of precision medicine, ~540 million people in the world have a genetic variant of the aldehyde dehydrogenase 2 (ALDH2) enzyme causing a flushing response and tachycardia after alcohol consumption.	('tachycardia', 'Phenotype', 'HP:0001649', (167, 178))	('people', 'Species', '9606', (45, 51))	('aldehyde dehydrogenase 2', 'Gene', '217', (95, 119))	('flushing', 'Disease', (145, 153))	('tachycardia', 'Disease', 'MESH:D013610', (167, 178))	('tachycardia', 'Disease', (167, 178))	('aldehyde dehydrogenase 2', 'Gene', (95, 119))	('flushing', 'Disease', 'MESH:D005483', (145, 153))	('alcohol', 'Chemical', 'MESH:D000438', (185, 192))	('ALDH2', 'Gene', '217', (121, 126))	('causing', 'Reg', (135, 142))	('genetic variant', 'Var', (72, 87))	('ALDH2', 'Gene', (121, 126))	('flushing', 'Phenotype', 'HP:0031284', (145, 153))
929075	27835996	Here we provide examples why patients with an ALDH2*2 variant need more individualized medical management which is becoming a more standard practice in the precision medicine era.	('patients', 'Species', '9606', (29, 37))	('variant', 'Var', (54, 61))	('ALDH2', 'Gene', (46, 51))	('ALDH2', 'Gene', '217', (46, 51))
929078	27835996	Another example is recommendations for disease surveillance based upon single gene variants which increase the risk for colon cancer as seen in individuals with Lynch syndrome or familial adenomatous polyposis.	('Lynch syndrome', 'Disease', (161, 175))	('familial adenomatous polyposis', 'Disease', (179, 209))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Lynch syndrome', 'Disease', 'MESH:D003123', (161, 175))	('variants', 'Var', (83, 91))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (179, 209))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (188, 209))	('colon cancer', 'Disease', (120, 132))
929080	27835996	For example, a variant in P450 CYP2C19 reduces the amount of the active form of clopidogrel (a drug given when treating atrial fibrillation).	('CYP2C19', 'Gene', '1557', (31, 38))	('variant', 'Var', (15, 22))	('atrial fibrillation', 'Disease', 'MESH:D001281', (120, 139))	('CYP2C19', 'Gene', (31, 38))	('amount of the active form of clopidogrel', 'MPA', (51, 91))	('atrial fibrillation', 'Disease', (120, 139))	('atrial fibrillation', 'Phenotype', 'HP:0005110', (120, 139))	('reduces', 'NegReg', (39, 46))	('clopidogrel', 'Chemical', 'MESH:D000077144', (80, 91))
929085	27835996	Approximately 540 million people have a genetic variant of the aldehyde dehydrogenase 2 (ALDH2) enzyme which causes a flushing response and tachycardia after alcohol consumption (Fig.	('causes', 'Reg', (109, 115))	('flushing', 'Disease', (118, 126))	('flushing', 'Disease', 'MESH:D005483', (118, 126))	('tachycardia', 'Disease', (140, 151))	('tachycardia', 'Phenotype', 'HP:0001649', (140, 151))	('tachycardia', 'Disease', 'MESH:D013610', (140, 151))	('genetic variant', 'Var', (40, 55))	('alcohol', 'Chemical', 'MESH:D000438', (158, 165))	('ALDH2', 'Gene', (89, 94))	('aldehyde dehydrogenase 2', 'Gene', '217', (63, 87))	('people', 'Species', '9606', (26, 32))	('flushing', 'Phenotype', 'HP:0031284', (118, 126))	('aldehyde dehydrogenase 2', 'Gene', (63, 87))	('ALDH2', 'Gene', '217', (89, 94))
929087	27835996	Recently, extensive reviews have covered the molecular biology and importance of the ALDH2*2 variant in human health.	('ALDH2', 'Gene', (85, 90))	('human', 'Species', '9606', (104, 109))	('ALDH2', 'Gene', '217', (85, 90))	('variant', 'Var', (93, 100))
929088	27835996	Here, we concisely discuss 2 examples of how the ALDH2*2 variant factors into decisions regarding medical management and drug selection.	('ALDH2', 'Gene', '217', (49, 54))	('variant', 'Var', (57, 64))	('ALDH2', 'Gene', (49, 54))	('factors', 'Reg', (65, 72))
929089	27835996	We believe these two examples should be used as a foundation for developing a more defined precision medicine platform for those with an ALDH2*2 variant.	('variant', 'Var', (145, 152))	('ALDH2', 'Gene', (137, 142))	('ALDH2', 'Gene', '217', (137, 142))
929093	27835996	The acetaldehyde produced from breaking down alcohol also is metabolized to acetaldehyde by the ALDH2 enzyme.	('acetaldehyde', 'Chemical', 'MESH:D000079', (4, 16))	('breaking down', 'Phenotype', 'HP:0001061', (31, 44))	('ALDH2', 'Gene', '217', (96, 101))	('metabolized', 'MPA', (61, 72))	('ALDH2', 'Gene', (96, 101))	('alcohol', 'Chemical', 'MESH:D000438', (45, 52))	('breaking', 'Var', (31, 39))	('acetaldehyde', 'Chemical', 'MESH:D000079', (76, 88))
929095	27835996	Reactive aldehyde carcinogens are less efficiently metabolized by those with an ALDH2*2 variant.	('Reactive aldehyde', 'MPA', (0, 17))	('aldehyde', 'Chemical', 'MESH:D000447', (9, 17))	('variant', 'Var', (88, 95))	('ALDH2', 'Gene', '217', (80, 85))	('less', 'NegReg', (34, 38))	('ALDH2', 'Gene', (80, 85))
929096	27835996	With this in mind, people with an ALDH2*2 variant are at a much greater risk for esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('ALDH2', 'Gene', '217', (34, 39))	('people', 'Species', '9606', (19, 25))	('ALDH2', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', (81, 98))	('variant', 'Var', (42, 49))
929098	27835996	Alarmingly, people with an ALDH2*2 variant and also an alcohol dehydrogenase variant (ADH1B, that causes a rapid conversion of alcohol to acetaldehyde) with a history of drinking alcohol and smoking cigarettes, have an odds ratio of 189 for developing esophageal cancer (Fig.	('ALDH2', 'Gene', (27, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (252, 269))	('ADH1B', 'Gene', '125', (86, 91))	('causes', 'Reg', (98, 104))	('alcohol', 'Chemical', 'MESH:D000438', (127, 134))	('ALDH2', 'Gene', '217', (27, 32))	('alcohol', 'Chemical', 'MESH:D000438', (179, 186))	('people', 'Species', '9606', (12, 18))	('acetaldehyde', 'Chemical', 'MESH:D000079', (138, 150))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('esophageal cancer', 'Disease', (252, 269))	('alcohol', 'Chemical', 'MESH:D000438', (55, 62))	('variant', 'Var', (35, 42))	('ADH1B', 'Gene', (86, 91))
929101	27835996	Further, screening for the ALDH2*2 gene could be used as topic of conversation with patients as a preventative measure to reduce esophageal cancer risk.	('ALDH2', 'Gene', (27, 32))	('patients', 'Species', '9606', (84, 92))	('ALDH2', 'Gene', '217', (27, 32))	('esophageal cancer', 'Disease', (129, 146))	('screening', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('esophageal cancer', 'Disease', 'MESH:D004938', (129, 146))
929102	27835996	These discussions could include how the ALDH2*2 variant in combination with lifestyle choices such as drinking alcohol or smoking cigarettes increases the relative risk of developing esophageal cancer.	('ALDH2', 'Gene', (40, 45))	('increases', 'PosReg', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('esophageal cancer', 'Disease', (183, 200))	('esophageal cancer', 'Disease', 'MESH:D004938', (183, 200))	('ALDH2', 'Gene', '217', (40, 45))	('variant', 'Var', (48, 55))	('alcohol', 'Chemical', 'MESH:D000438', (111, 118))
929105	27835996	The efficacy of several drugs are impacted by the ALDH2*2 variant.	('impacted', 'Reg', (34, 42))	('ALDH2', 'Gene', (50, 55))	('variant', 'Var', (58, 65))	('efficacy', 'MPA', (4, 12))	('ALDH2', 'Gene', '217', (50, 55))
929107	27835996	Importantly, those with an ALDH2*2 variant are less efficient at breaking down nitroglycerin to nitric oxide, effectively limiting the vasodilatory effect of nitroglycerin.	('nitroglycerin', 'Chemical', 'MESH:D005996', (79, 92))	('vasodilatory effect of nitroglycerin', 'MPA', (135, 171))	('ALDH2', 'Gene', '217', (27, 32))	('less', 'NegReg', (47, 51))	('breaking down', 'Phenotype', 'HP:0001061', (65, 78))	('breaking down nitroglycerin to nitric oxide', 'MPA', (65, 108))	('nitroglycerin', 'Chemical', 'MESH:D005996', (158, 171))	('ALDH2', 'Gene', (27, 32))	('variant', 'Var', (35, 42))	('nitric oxide', 'Chemical', 'MESH:D009569', (96, 108))	('limiting', 'NegReg', (122, 130))
929109	27835996	Studies in East Asians, measuring forearm blood flow response to nitroglycerin show that ALDH2*2 variants have a 40 % reduced response compared to those without a *2 variant as measured by vasodilation (Fig.	('nitroglycerin', 'Chemical', 'MESH:D005996', (65, 78))	('ALDH2', 'Gene', (89, 94))	('reduced', 'NegReg', (118, 125))	('variants', 'Var', (97, 105))	('vasodilation', 'MPA', (189, 201))	('response', 'MPA', (126, 134))	('ALDH2', 'Gene', '217', (89, 94))
929114	27835996	Many of these nitroglycerin applications in medical practice may need to consider potential ALDH2*2 variant effects on nitroglycerin efficacy.	('variant', 'Var', (100, 107))	('ALDH2', 'Gene', (92, 97))	('effects', 'Reg', (108, 115))	('nitroglycerin efficacy', 'MPA', (119, 141))	('ALDH2', 'Gene', '217', (92, 97))	('nitroglycerin', 'Chemical', 'MESH:D005996', (119, 132))	('nitroglycerin', 'Chemical', 'MESH:D005996', (14, 27))
929116	27835996	With a focus on precision medicine and the high prevalence of the ALDH2*2 variant within the East Asian population, clinicians should consider whether a patient has this variant which increases the risk for specific diseases such as esophageal cancer and limits the metabolism of specific drugs such as nitroglycerin.	('nitroglycerin', 'Chemical', 'MESH:D005996', (303, 316))	('esophageal cancer', 'Disease', (233, 250))	('increases', 'Reg', (184, 193))	('variant', 'Var', (170, 177))	('ALDH2', 'Gene', '217', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('variant', 'Var', (74, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (233, 250))	('patient', 'Species', '9606', (153, 160))	('ALDH2', 'Gene', (66, 71))	('metabolism of specific drugs', 'MPA', (266, 294))	('limits', 'NegReg', (255, 261))
929117	27835996	One option to consider is more frequent screening for esophageal cancer for those with both the ALDH2*2 variant and a history of smoking cigarettes and/or consuming alcohol.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('ALDH2', 'Gene', '217', (96, 101))	('esophageal cancer', 'Disease', (54, 71))	('ALDH2', 'Gene', (96, 101))	('alcohol', 'Chemical', 'MESH:D000438', (165, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('variant', 'Var', (104, 111))
929118	27835996	When the potential influence of the ALDH2*2 variant is taken into consideration, relative to disease risk and drug metabolism, patients with the ALDH2*2 variant can begin receiving personalized medical management which will become standard practice in the precision medicine era.	('variant', 'Var', (153, 160))	('ALDH2', 'Gene', (36, 41))	('patients', 'Species', '9606', (127, 135))	('ALDH2', 'Gene', '217', (145, 150))	('ALDH2', 'Gene', (145, 150))	('ALDH2', 'Gene', '217', (36, 41))
929210	26989387	A study from Shanghai with 189 patients who had radical surgery for an eSCC showed no LNM in m1 and m2 tumors but 11% LNM in the m3, 24% in the sm1, 20.5% in the sm2, and 43.8% in the sm3 subgroup.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('patients', 'Species', '9606', (31, 39))	('LNM', 'Var', (118, 121))	('sm3', 'Chemical', '-', (184, 187))	('sm2', 'Gene', (162, 165))	('sm2', 'Gene', '53366', (162, 165))
929214	26989387	The risk of distant metastases was 0% in m1-m3 and sm1 tumors as well as 9% in sm2 and 13% in sm3 stages.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('m1-m3', 'Var', (41, 46))	('sm3', 'Chemical', '-', (94, 97))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('sm2', 'Gene', (79, 82))	('sm2', 'Gene', '53366', (79, 82))	('tumors', 'Disease', (55, 61))	('sm1', 'Disease', (51, 54))	('metastases', 'Disease', (20, 30))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('metastases', 'Disease', 'MESH:D009362', (20, 30))
929230	26989387	Combining the results of all endoscopically and surgically treated patients in our center, the percentage of SR was 8.25% (32/388 patients) in m3/m4 tumors and 29.8% (37/124) in sm1 tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('patients', 'Species', '9606', (67, 75))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('m3/m4', 'Var', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
929283	26426606	Zhu et al found that meat consumption is associated with the risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('esophageal cancer', 'Disease', (69, 86))	('meat', 'Var', (21, 25))
929322	26426606	Antioxidants may also play a role in the pathogenesis of reflux esophagitis and EAC and may be more important in terms of progression rather than initiation of the disease process; however, low intake of vitamin C and E correlates significantly with the development of SCC as well as EAC in males.	('reflux esophagitis', 'Disease', 'MESH:D005764', (57, 75))	('EAC', 'Disease', (80, 83))	('SCC', 'Gene', (269, 272))	('SCC', 'Phenotype', 'HP:0002860', (269, 272))	('reflux esophagitis', 'Disease', (57, 75))	('esophagitis', 'Phenotype', 'HP:0100633', (64, 75))	('low intake of vitamin C', 'Phenotype', 'HP:0100510', (190, 213))	('vitamin C', 'Chemical', 'MESH:D001205', (204, 213))	('EAC', 'Disease', (284, 287))	('low intake', 'Var', (190, 200))	('SCC', 'Gene', '6317', (269, 272))	('EAC', 'Phenotype', 'HP:0011459', (80, 83))	('initiation of the disease', 'Disease', 'MESH:D007319', (146, 171))	('initiation of the disease', 'Disease', (146, 171))	('EAC', 'Phenotype', 'HP:0011459', (284, 287))
929376	33937047	Subgroup analysis showed that compared with cancer patients aged <50, 50-59, and 60-69, patients with GEJ cancer without distant metastasis aged 70-79 and > = 80 had the worse prognosis, and the difference was statistically significant ( Figure S3 ); Compared with Grade I and II cancer patients, Grade III patients with GEJ cancer without distant metastasis had the worse prognosis, and the difference was statistically significant ( Figures 4A, B ); compared with patients with stage T1a cancer, the prognosis of patients with GEJ cancer without distant metastasis in stage T1b, T1NOS, T2, T3, and T4 were worse ( Figures 4C-G ).	('cancer', 'Disease', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (490, 496))	('age', 'Gene', '5973', (572, 575))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('patients', 'Species', '9606', (307, 315))	('age', 'Gene', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('T1NOS', 'Var', (581, 586))	('cancer', 'Disease', (533, 539))	('patients', 'Species', '9606', (466, 474))	('age', 'Gene', (140, 143))	('cancer', 'Disease', (325, 331))	('age', 'Gene', '5973', (482, 485))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Disease', (490, 496))	('age', 'Gene', '5973', (60, 63))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('age', 'Gene', '5973', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (490, 496))	('cancer', 'Disease', 'MESH:D009369', (533, 539))	('age', 'Gene', (572, 575))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('patients', 'Species', '9606', (287, 295))	('patients', 'Species', '9606', (515, 523))	('age', 'Gene', (482, 485))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
929422	32466419	(3) Results: In 45/57 ESCC patients with evaluable CTC counts at CT pre-cycle III, positive CTC2 (>=3 CTCs) is independently associated with response at interim reassessment and progression-free survival (PFS) in multivariate analysis.	('progression-free survival', 'CPA', (178, 203))	('ESCC', 'Disease', (22, 26))	('CTC2', 'Gene', (92, 96))	('positive', 'Var', (83, 91))	('patients', 'Species', '9606', (27, 35))	('associated with', 'Reg', (125, 140))
929423	32466419	In 42/57 ESCC patients with changes of CTC1/CTC2 and cfDNA1/cfDNA2, patients categorized into four risk groups based on the number of favorable and unfavorable changes of CTC1/CTC2 and cfDNA1/cfDNA2, were independently associated with overall survival (OS) by multivariate analysis.	('ESCC', 'Disease', (9, 13))	('CTC1', 'Gene', (39, 43))	('associated', 'Reg', (219, 229))	('CTC1', 'Gene', (171, 175))	('overall survival', 'MPA', (235, 251))	('patients', 'Species', '9606', (68, 76))	('changes', 'Var', (28, 35))	('patients', 'Species', '9606', (14, 22))	('CTC1', 'Gene', '80169', (39, 43))	('CTC1', 'Gene', '80169', (171, 175))	('cfDNA1/cfDNA2', 'Gene', (53, 66))
929474	32466419	Furthermore, patients categorized as high CTC group (at least 3 CTCs, median TTP 68 days) at CTC2 experienced statistically significant shorter time of progression evaluated by imaging reassessment compared to those of the low CTC group (0-2 CTCs, median TTP 94 days) (Figure 2Ai).	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (136, 143))	('CTC2', 'Var', (93, 97))	('time', 'MPA', (144, 148))
929475	32466419	The median PFS of patients of the high CTC group at CTC2 (median PFS 75 days) was statistically significantly shorter compared to those of the low CTC group (median PFS 125 days) (Figure 2Aii).	('Aii', 'Gene', '114548', (188, 191))	('PFS', 'MPA', (11, 14))	('shorter', 'NegReg', (110, 117))	('CTC2', 'Var', (52, 56))	('patients', 'Species', '9606', (18, 26))	('Aii', 'Gene', (188, 191))
929476	32466419	The median OS of patients from the high CTC group at CTC2 (median OS 162 days) was statistically significantly shorter compared to those from the low CTC group (median OS 298 days) (Figure 2Aiii).	('Aii', 'Gene', (190, 193))	('patients', 'Species', '9606', (17, 25))	('shorter', 'NegReg', (111, 118))	('Aii', 'Gene', '114548', (190, 193))	('CTC2', 'Var', (53, 57))
929481	32466419	Patients with high baseline cfDNA1 (median OS 172 days) had a statistically significant shorter OS time compared to those with low baseline cfDNA1 (median OS 302 days) (p = 0.007) (Figure 2Biv).	('shorter', 'NegReg', (88, 95))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('cfDNA1', 'Var', (28, 34))
929482	32466419	Patients with high cfDNA2 at pre-cycle III (median OS 172 days) had a statistically significant shorter OS time compared to those with low cfDNA2 (median OS 479 days) (p = 0.009) (Figure 2Bv).	('shorter', 'NegReg', (96, 103))	('OS time', 'MPA', (104, 111))	('cfDNA2', 'Var', (19, 25))	('high cfDNA2', 'Var', (14, 25))	('Patients', 'Species', '9606', (0, 8))
929484	32466419	Patients with unfavorable changes of both high cfDNA1 (>=3.360) and cfDNA2 (>=3.2817) are categorized into the high-risk group, while others including those with both low cfDNA1 and cfDNA2, or from high cfDNA1 to low cfDNA2, or with low cfDNA1 and high cfDNA2 are categorized into the low-risk group.	('high', 'Var', (42, 46))	('Patients', 'Species', '9606', (0, 8))	('>=3.2817', 'Var', (76, 84))
929494	32466419	Patients with two favorable changes of 0-1 mark, combining CTC1/CTC2 and cfDNA1/cfDNA2, were designated as the low-risk group (0).	('Patients', 'Species', '9606', (0, 8))	('CTC1', 'Gene', '80169', (59, 63))	('CTC1', 'Gene', (59, 63))	('cfDNA1/cfDNA2', 'Var', (73, 86))
929514	32466419	However, stratification of the 26 patients without previous treatment with high baseline CTC counts (median TTP 61 days) revealed a statistically significant shorter progression time for clinical interim reassessment for patients with low baseline CTC counts (median TTP 94 days) (p = 0.037) (Figure S2B); no such significant difference was observed for the group of 24 patients with previous treatment (Figure S2C).	('progression', 'MPA', (166, 177))	('shorter', 'NegReg', (158, 165))	('patients', 'Species', '9606', (221, 229))	('low', 'Var', (235, 238))	('patients', 'Species', '9606', (370, 378))	('patients', 'Species', '9606', (34, 42))
929516	32466419	The clinical utility of higher cfDNA level or detection of copy number variants (CNVs) or single nucleotide variants (CNVs) are predictive and useful for stratification of esophageal cancer outcomes of patients into both early-stage and advanced cohorts.	('single nucleotide variants', 'Var', (90, 116))	('cancer', 'Disease', (183, 189))	('copy number variants', 'Var', (59, 79))	('higher', 'PosReg', (24, 30))	('patients', 'Species', '9606', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cfDNA level', 'MPA', (31, 42))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
929560	32466419	; investigation, J.M.Y.K., H.Y.N., J.C.W., R.C.W.L., and H.C.H.F.	('R.C.W.L.', 'Var', (43, 51))	('H.C.H.F', 'Var', (57, 64))	('H.C.H.F', 'CellLine', 'CVCL:Y658', (57, 64))
929578	32508911	In the second phase, the swine died or were euthanized in 2 to 4 weeks after ablation, and the rate and severity of esophageal stricture were reported to be positively correlated with energy density; with low energy density (9.7 and 10.6 J/cm2), no stricture was seen and with high energy density (>22 J/cm2), stricture was seen in all animals.	('died', 'Disease', (31, 35))	('esophageal stricture', 'Phenotype', 'HP:0002043', (116, 136))	('died', 'Disease', 'MESH:D003643', (31, 35))	('9.7', 'Var', (225, 228))	('esophageal stricture', 'Disease', (116, 136))	('swine', 'Species', '9823', (25, 30))
929598	32508911	The new, simplified Japan Esophageal Society (JES) classification of IPCLs has proved to be high in accuracy for the diagnosis of the invasion depth of superficial ESCC, with 90.5% overall accuracy rate of the type B microvessels (representing cancerous lesions) and satisfactory intra- and interobserver agreement.	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('type', 'Var', (210, 214))	('cancerous lesions', 'Disease', 'MESH:D009369', (244, 261))	('cancerous lesions', 'Disease', (244, 261))
929629	32508911	As RFA may destroy the mucosa but reserve the submucosal layer, it is possible that these "submucosal DI" being the nest for tumor to come back.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('DI', 'Chemical', '-', (102, 104))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('RFA', 'Var', (3, 6))
929632	32508911	Current researches demonstrated that RFA caused approximately 0-28.6% postprocedure esophageal stenosis and all of which could relieve through a median of 2.5-5.5 sessions of dilation (Table 2).	('esophageal stenosis', 'Disease', 'MESH:D004940', (84, 103))	('esophageal stenosis', 'Phenotype', 'HP:0010450', (84, 103))	('esophageal stenosis', 'Disease', (84, 103))	('RFA', 'Var', (37, 40))
929636	32508911	An animal study had revealed that Lugol's staining right before RFA caused more postprocedure stenosis, which may be due to the severe inflammation and fibrosis caused by Lugol's solution.	('Lugol', 'Chemical', 'MESH:C010389', (171, 176))	('inflammation', 'Disease', 'MESH:D007249', (135, 147))	('Lugol', 'Chemical', 'MESH:C010389', (34, 39))	('inflammation', 'Disease', (135, 147))	("Lugol's staining", 'Var', (34, 50))	('fibrosis', 'Disease', 'MESH:D005355', (152, 160))	('fibrosis', 'Disease', (152, 160))	('postprocedure stenosis', 'CPA', (80, 102))
929664	31527546	Multivariable Cox proportional hazard regression models revealed that high expression of FGF8 was an independent prognostic factor for diminished overall survival for all patients and for neoadjuvantly treated patients.	('FGF8', 'Gene', (89, 93))	('FGF8', 'Gene', '2253', (89, 93))	('overall survival', 'MPA', (146, 162))	('patients', 'Species', '9606', (171, 179))	('Cox', 'Gene', (14, 17))	('Cox', 'Gene', '1351', (14, 17))	('high expression', 'Var', (70, 85))	('patients', 'Species', '9606', (210, 218))	('diminished', 'NegReg', (135, 145))
929682	31527546	The growth factor induces autocrine survival signaling via the FGF receptor FGFR3-IIIc and blocking of this receptor inhibits tumor growth by inducing apoptosis.	('FGF', 'Gene', (76, 79))	('autocrine survival signaling', 'MPA', (26, 54))	('induces', 'PosReg', (18, 25))	('inducing', 'NegReg', (142, 150))	('inhibits', 'NegReg', (117, 125))	('FGFR3', 'Gene', '2261', (76, 81))	('FGF', 'Gene', '2246;2247;2253;8817', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('FGF', 'Gene', '2246;2247;2253;8817', (76, 79))	('FGF', 'Gene', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('apoptosis', 'CPA', (151, 160))	('FGFR3', 'Gene', (76, 81))	('blocking', 'Var', (91, 99))	('tumor', 'Disease', (126, 131))
929683	31527546	Alternatively, FGF18 effects may be mediated by FGFR4, a receptor for which a polymorphic variant exists that causes substitution of an arginine for a glycine at position 388 in the transmembrane domain.	('FGFR4', 'Gene', (48, 53))	('arginine for a glycine at position 388', 'Mutation', 'rs351855', (136, 174))	('causes', 'Reg', (110, 116))	('arginine', 'MPA', (136, 144))	('FGF18', 'Gene', '8817', (15, 20))	('FGF18', 'Gene', (15, 20))	('substitution', 'Var', (117, 129))	('variant', 'Var', (90, 97))	('FGFR4', 'Gene', '2264', (48, 53))
929686	31527546	Recently, we could show that the expression of FGF8 was strongly associated with the regression grade in neoadjuvantly treated colorectal cancer patients.	('patients', 'Species', '9606', (145, 153))	('expression', 'Var', (33, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('regression', 'Disease', (85, 95))	('associated', 'Reg', (65, 75))	('colorectal cancer', 'Disease', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('FGF8', 'Gene', (47, 51))	('rectal cancer', 'Phenotype', 'HP:0100743', (131, 144))	('FGF8', 'Gene', '2253', (47, 51))
929722	31527546	However, Kaplan-Meier analysis shows a significant correlation between high FGF8 expression (p = 0.006) and reduced patients' OS, high FGF18 expression (p = 0.026) was significantly associated with longer patients' OS.	('patients', 'Species', '9606', (205, 213))	('high', 'Var', (130, 134))	('patients', 'Species', '9606', (116, 124))	('FGF8', 'Gene', (76, 80))	('FGF8', 'Gene', '2253', (76, 80))	('FGF18', 'Gene', '8817', (135, 140))	('FGF18', 'Gene', (135, 140))	('expression', 'MPA', (81, 91))
929724	31527546	Univariable Cox proportional hazard regression revealed that high expression of FGF8 (HR 0.61, 95% CI 0.43-0.87, p = 0.006), advanced tumor stage (HR 2.74, 95% CI 1.37-5.50, p = 0.005), poor tumor differentiation (HR 0.57, 95% CI 0.39-0.83, p = 0.003), high lymph node ratio (HR 1.93, 95% CI 1.35-2.77, p < 0.001), positive resection margin (HR 2.06, 95% CI 1.36-3.10, p < 0.001), and receiving adjuvant treatment (HR 1.55, 95% CI 1.10-2.18, p = 0.013) were significantly associated with impaired patients OS, whereas high expression of FGF18 (HR 0.6, 95% CI 0.45-0.95, p = 0.027), negative lymph node status (HR 0.23, 95% CI 0.14-0.39, p < 0.001), and low UICC staging (HR 0.34, 95% CI 0.19-0.63, p < 0.001), were significantly associated with improved OS (Table 2).	('patients OS', 'CPA', (497, 508))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('FGF18', 'Gene', '8817', (537, 542))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Cox', 'Gene', '1351', (12, 15))	('high expression', 'Var', (518, 533))	('impaired', 'Disease', (488, 496))	('patients', 'Species', '9606', (497, 505))	('improved', 'PosReg', (745, 753))	('Cox', 'Gene', (12, 15))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', (134, 139))	('high lymph node', 'Phenotype', 'HP:0002716', (253, 268))	('impaired', 'Disease', 'MESH:D008569', (488, 496))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('FGF8', 'Gene', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('FGF8', 'Gene', '2253', (80, 84))	('FGF18', 'Gene', (537, 542))
929730	31527546	In multivariable analysis, high FGF8 (HR 0.68, 95% CI 0.46-0.99, p = 0.04) was identified as the only independent predictor for shorter OS.	('FGF8', 'Gene', (32, 36))	('shorter OS', 'Disease', (128, 138))	('FGF8', 'Gene', '2253', (32, 36))	('high', 'Var', (27, 31))
929743	31527546	With regard to FGF18, our observations in AEG contradict older reports: our previously published findings on FGF18 expression demonstrated increased tumor cell survival and migration caused by FGF18 expression in colorectal cancer.	('FGF18', 'Gene', '8817', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('FGF18', 'Gene', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('increased', 'PosReg', (139, 148))	('migration', 'CPA', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('AEG', 'Disease', 'MESH:D013274', (42, 45))	('colorectal cancer', 'Disease', 'MESH:D015179', (213, 230))	('FGF18', 'Gene', (15, 20))	('FGF18', 'Gene', '8817', (193, 198))	('colorectal cancer', 'Disease', (213, 230))	('expression', 'Var', (199, 209))	('AEG', 'Disease', (42, 45))	('FGF18', 'Gene', '8817', (15, 20))	('FGF18', 'Gene', (109, 114))	('rectal cancer', 'Phenotype', 'HP:0100743', (217, 230))	('tumor', 'Disease', (149, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (213, 230))
929746	31527546	In contrast to these results, our data show a significantly improved OS in neoadjuvantly treated patients with adenocarcinomas of the esophago-gastric junction when the tumors are high in FGF18.	('FGF18', 'Gene', '8817', (188, 193))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('adenocarcinomas of the esophago-gastric junction', 'Disease', (111, 159))	('FGF18', 'Gene', (188, 193))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('adenocarcinomas of the esophago-gastric junction', 'Disease', 'MESH:D013274', (111, 159))	('improved', 'PosReg', (60, 68))	('tumors', 'Disease', (169, 175))	('high', 'Var', (180, 184))	('patients', 'Species', '9606', (97, 105))
929785	30311151	In clinical studies, aggressive metastatic disease and poor prognosis have been correlated with high telomerase expression and activity in ovarian, breast, colorectal, prostate, and gastric cancer and melanoma, and some previous studies have shown the aberrant amplification of the hTERC gene in Barrett's esophagus and ESCC.	('aggressive metastatic disease', 'Disease', 'MESH:C538445', (21, 50))	("Barrett's esophagus", 'Disease', (296, 315))	('high', 'PosReg', (96, 100))	('gastric cancer', 'Disease', (182, 196))	('activity', 'MPA', (127, 135))	('expression', 'MPA', (112, 122))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('breast', 'Disease', (148, 154))	('ovarian', 'Disease', (139, 146))	('TERC', 'Gene', '7012', (283, 287))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (296, 315))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))	('ESCC', 'Disease', (320, 324))	('TERC', 'Gene', (283, 287))	('aberrant', 'Var', (252, 260))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanoma', 'Disease', (201, 209))	('aggressive metastatic disease', 'Disease', (21, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('colorectal', 'Disease', (156, 166))	('telomerase', 'Protein', (101, 111))
929843	30311151	Previous studies have shown a potential correlation between high telomerase expression and poor prognosis and aggressive metastasis of some malignancies, including ovarian, breast, prostate, liver and colorectal cancer, and melanoma.	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('liver', 'Disease', (191, 196))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('high', 'Var', (60, 64))	('malignancies', 'Disease', (140, 152))	('telomerase', 'Protein', (65, 75))	('breast', 'Disease', (173, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (201, 218))	('expression', 'MPA', (76, 86))	('aggressive metastasis', 'CPA', (110, 131))	('prostate', 'Disease', (181, 189))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('colorectal cancer', 'Disease', (201, 218))	('melanoma', 'Disease', (224, 232))	('ovarian', 'Disease', (164, 171))
929868	30050313	Blockade of this pathway markedly attenuated CEP55-mediated proliferation, migration, invasion and epithelial-mesenchymal transition of ESCC cells.	('epithelial-mesenchymal transition of', 'CPA', (99, 135))	('Blockade', 'Var', (0, 8))	('CEP55', 'Gene', '55165', (45, 50))	('migration', 'CPA', (75, 84))	('CEP55', 'Gene', (45, 50))	('invasion', 'CPA', (86, 94))	('attenuated', 'NegReg', (34, 44))
929881	30050313	However, the prognostic value of CEP55 in patients with pN0 ESCC and its biological function in ESCC cells remain unclear.	('patients', 'Species', '9606', (42, 50))	('CEP55', 'Gene', '55165', (33, 38))	('pN0', 'Var', (56, 59))	('CEP55', 'Gene', (33, 38))
929893	30050313	Five established human ESCC cell lines (Eca109, KYSE150, KYSE450, EC9706 and TE-1) and one normal human esophageal epithelial cell line (HET-1A) were purchased from the Cell Bank of the Shanghai Institute in China.	('KYSE150', 'Var', (48, 55))	('KYSE450', 'Var', (57, 64))	('human', 'Species', '9606', (17, 22))	('EC9706', 'CellLine', 'CVCL:E307', (66, 72))	('EC', 'Phenotype', 'HP:0011459', (66, 68))	('human', 'Species', '9606', (98, 103))
929932	30050313	Thus, Eca109 and KYSE450 cells were used to knock down CEP55 with shRNA.	('knock down', 'Var', (44, 54))	('CEP55', 'Gene', '55165', (55, 60))	('CEP55', 'Gene', (55, 60))
929937	30050313	Clonogenic assays showed that CEP55 knockdown abrogated the colony-formation ability of Eca109 and KYSE450 cells (P<0.001; Figure 3Ba and Bb).	('CEP55', 'Gene', '55165', (30, 35))	('colony-formation ability', 'CPA', (60, 84))	('CEP55', 'Gene', (30, 35))	('abrogated', 'NegReg', (46, 55))	('knockdown', 'Var', (36, 45))
929944	30050313	In addition, the invasive ability was altered with the changed expression of CEP55 in ESCC cells (P<0.01; Figure 4Ba-d).	('altered', 'Reg', (38, 45))	('CEP55', 'Gene', '55165', (77, 82))	('changed', 'Reg', (55, 62))	('CEP55', 'Gene', (77, 82))	('invasive ability', 'CPA', (17, 33))	('expression', 'Var', (63, 73))
929952	30050313	Administration of LY294002 (20 microM), wortmannin (5 microM) and MK2206 (1 microM) markedly decreased the proliferation of ESCC cells.	('wortmannin', 'Chemical', 'MESH:D000077191', (40, 50))	('proliferation', 'CPA', (107, 120))	('LY294002', 'Var', (18, 26))	('MK2206', 'Chemical', 'MESH:C548887', (66, 72))	('decreased', 'NegReg', (93, 102))	('MK2206', 'Var', (66, 72))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))	('ESCC', 'Disease', (124, 128))
929980	30050313	Thus, CEP55 knockdown decreased the expression of pAktS473 and pAktT308 and CEP55 overexpression increased the activation of AktS473 and AktT308.	('Akt', 'Gene', (51, 54))	('increased', 'PosReg', (97, 106))	('Akt', 'Gene', (125, 128))	('Akt', 'Gene', '207', (64, 67))	('knockdown', 'Var', (12, 21))	('CEP55', 'Gene', (6, 11))	('Akt', 'Gene', '207', (137, 140))	('CEP55', 'Gene', '55165', (6, 11))	('Akt', 'Gene', '207', (51, 54))	('Akt', 'Gene', (64, 67))	('Akt', 'Gene', (137, 140))	('Akt', 'Gene', '207', (125, 128))	('CEP55', 'Gene', '55165', (76, 81))	('CEP55', 'Gene', (76, 81))	('expression', 'MPA', (36, 46))	('decreased', 'NegReg', (22, 31))
929982	30050313	Next, LY294002, wortmannin and MK2206 were used to block the PI3K/Akt pathway.	('Akt', 'Gene', (66, 69))	('LY294002', 'Var', (6, 14))	('wortmannin', 'Chemical', 'MESH:D000077191', (16, 26))	('MK2206', 'Chemical', 'MESH:C548887', (31, 37))	('LY294002', 'Chemical', 'MESH:C085911', (6, 14))	('Akt', 'Gene', '207', (66, 69))	('MK2206', 'Var', (31, 37))
930001	29730081	EoEe2 demonstrated an inflammatory and steroid-refractory phenotype (RR 2 77, 95% CI 1 11-6 95, p=0 0376), and showed the highest expression of cytokines and steroid-responding genes.	('steroid', 'Chemical', 'MESH:D013256', (39, 46))	('expression', 'MPA', (130, 140))	('steroid', 'Chemical', 'MESH:D013256', (158, 165))	('EoEe2', 'Var', (0, 5))	('highest', 'PosReg', (122, 129))	('EoE', 'Phenotype', 'HP:0410151', (0, 3))
930050	29730081	Endoscopic edema was significantly higher in EoEe2 and EoEe3 compared to EoEe1 (p=0 0096 and p=0 0017, respectively).	('edema', 'Disease', 'MESH:D004487', (11, 16))	('edema', 'Disease', (11, 16))	('EoE', 'Phenotype', 'HP:0410151', (45, 48))	('EoEe2', 'Var', (45, 50))	('EoE', 'Phenotype', 'HP:0410151', (55, 58))	('EoE', 'Phenotype', 'HP:0410151', (73, 76))	('EoEe3', 'Var', (55, 60))	('edema', 'Phenotype', 'HP:0000969', (11, 16))	('higher', 'PosReg', (35, 41))
930052	29730081	EoEe1 was associated with a normal-appearing esophagus (RR=3 27, 95%CI 1 04-10 27, p=0 0443) and inversely associated with a history of esophageal dilation (RR=0 27, 95% CI 0 09-0 82, p=0 0105).	('esophageal dilation', 'Disease', 'MESH:D002311', (136, 155))	('associated', 'Reg', (107, 117))	('EoE', 'Phenotype', 'HP:0410151', (0, 3))	('EoEe1', 'Var', (0, 5))	('esophageal dilation', 'Disease', (136, 155))
930053	29730081	EoEe2 was associated with steroid refractoriness (RR=2 77, 95% CI 1 11-6 95, p=0 0376).	('steroid refractoriness', 'MPA', (26, 48))	('EoE', 'Phenotype', 'HP:0410151', (0, 3))	('steroid', 'Chemical', 'MESH:D013256', (26, 33))	('EoEe2', 'Var', (0, 5))
930065	29730081	Fourth, focusing on the unique features of the disease endotypes, we report that EoEe1 has the mildest phenotype, most closely resembling findings seen in normal biopsies; EoEe2 is characterized by substantial inflammatory changes, type 2 immune responses, and evidence of refractoriness to steroids; and EoEe3 is associated with the presence of a narrow-caliber esophagus, the highest degree of endoscopic and histologic severity, and the lowest expression of epithelial differentiation genes.	('EoE', 'Phenotype', 'HP:0410151', (305, 308))	('EoE', 'Phenotype', 'HP:0410151', (81, 84))	('expression', 'MPA', (447, 457))	('EoEe3', 'Var', (305, 310))	('EoE', 'Phenotype', 'HP:0410151', (172, 175))	('lowest', 'NegReg', (440, 446))	('EoEe2', 'Var', (172, 177))	('epithelial differentiation genes', 'Gene', (461, 493))	('steroids', 'Chemical', 'MESH:D013256', (291, 299))	('narrow-caliber esophagus', 'Disease', (348, 372))
930067	29730081	For example, given that fibrostenotic EoE is often steroid resistant, EoEe2 and EoEe3 likely represent more complex or severe phenotypes and may well require novel therapies in addition to:or instead of:inflammatory control.	('EoEe3', 'Var', (80, 85))	('EoE', 'Phenotype', 'HP:0410151', (70, 73))	('steroid', 'Chemical', 'MESH:D013256', (51, 58))	('EoEe2', 'Var', (70, 75))	('EoE', 'Phenotype', 'HP:0410151', (38, 41))	('fibrostenotic EoE', 'Disease', (24, 41))	('EoE', 'Phenotype', 'HP:0410151', (80, 83))
930072	29730081	EoEe2, representing 29% of subjects, had particularly high type 2 immune response mechanisms and a steroid-refractory phenotype.	('high', 'PosReg', (54, 58))	('EoEe2', 'Var', (0, 5))	('EoE', 'Phenotype', 'HP:0410151', (0, 3))	('type', 'CPA', (59, 63))	('steroid', 'Chemical', 'MESH:D013256', (99, 106))
930081	29730081	Additionally, our findings suggest distinct therapeutic strategies, with EoEe2 being more amenable to specific anti-type 2 immune therapy such as anti-IL-4Ralpha rather than anti-IL-13 (which shows less differentiation between the three endotypes).	('IL-13', 'Gene', '3596', (179, 184))	('IL-4Ralpha', 'Gene', (151, 161))	('IL-4Ralpha', 'Gene', '3566', (151, 161))	('EoE', 'Phenotype', 'HP:0410151', (73, 76))	('EoEe2', 'Var', (73, 78))	('IL-13', 'Gene', (179, 184))
930083	29730081	Thus, subjects in EoEe2 could represent those subjects whose EoE would better respond to anti-TSLP biologics currently being tested.	('EoE', 'Phenotype', 'HP:0410151', (61, 64))	('EoEe2', 'Var', (18, 23))	('TSLP', 'Gene', '85480', (94, 98))	('EoE', 'Phenotype', 'HP:0410151', (18, 21))	('TSLP', 'Gene', (94, 98))
930133	26310928	Cox proportional hazards model revealed that CA19-9 positivity, but not CEA positivity, was an independent prognostic factor in patients with EGJ adenocarcinoma for cancer-specific survival (multivariate hazard ratio [HR] = 3.89, 95% confidence interval [CI] 1.41-10.33; P = 0.010) and overall survival (multivariate HR = 2.43, 95% CI 1.03-5.35; P = 0.043).	('CEA', 'Gene', '1048', (72, 75))	('CA19-9', 'Chemical', 'MESH:C086528', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('CEA', 'Gene', (72, 75))	('overall survival', 'CPA', (286, 302))	('positivity', 'Var', (52, 62))	('CA19-9', 'Gene', (45, 51))	('EGJ adenocarcinoma', 'Disease', (142, 160))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (142, 160))	('patients', 'Species', '9606', (128, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
930137	26310928	CA19-9, a member of the Lewis family also known as sialyl Lewis A, is another general serum tumor marker used in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDA).	('CA19-9', 'Var', (0, 6))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (113, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('gastrointestinal cancers', 'Disease', (113, 137))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PDA', 'Phenotype', 'HP:0006725', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (92, 97))	('pancreatic ductal adenocarcinoma', 'Disease', (149, 181))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (149, 181))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (149, 181))
930145	26310928	We also hypothesized that CEA or CA19-9 can be a prognostic marker in EGJ adenocarcinoma.	('CA19-9', 'Var', (33, 39))	('CEA', 'Gene', '1048', (26, 29))	('EGJ adenocarcinoma', 'Disease', (70, 88))	('CA19-9', 'Chemical', 'MESH:C086528', (33, 39))	('CEA', 'Gene', (26, 29))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (70, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
930161	26310928	The Kaplan-Meier method and log-rank test were used for survival analysis according to the tumor marker status (CEA <=5.0 vs. >5.0 ng/mL and CA19-9 <= 37 vs. >37 U/mL).	('CA19-9', 'Chemical', 'MESH:C086528', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CEA', 'Gene', (112, 115))	('CEA', 'Gene', '1048', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CA19-9 <= 37', 'Var', (141, 153))	('tumor', 'Disease', (91, 96))
930172	26310928	Besides, the lymph node metastasis showed borderline significant associations with CEA positivity and CA19-9 positivity (P = 0.010 and 0.022, respectively) (Table2).	('CEA', 'Gene', (83, 86))	('CEA', 'Gene', '1048', (83, 86))	('CA19-9', 'Gene', (102, 108))	('positivity', 'Var', (87, 97))	('lymph node metastasis', 'CPA', (13, 34))	('CA19-9', 'Chemical', 'MESH:C086528', (102, 108))	('positivity', 'Var', (109, 119))
930177	26310928	In log-rank test, CEA (>5.0 ng/mL) and CA19-9 (>37 U/mL) positivity were significantly associated with poorer cancer-specific survivals (P = 0.016 and 0.010, respectively) and overall survivals (P = 0.044 and 0.004, respectively) (Fig.2).	('CA19-9', 'Gene', (39, 45))	('overall survivals', 'CPA', (176, 193))	('cancer', 'Disease', (110, 116))	('poorer', 'NegReg', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('>5.0 ng/mL', 'Var', (23, 33))	('CA19-9', 'Chemical', 'MESH:C086528', (39, 45))	('CEA', 'Gene', '1048', (18, 21))	('positivity', 'Var', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('CEA', 'Gene', (18, 21))
930178	26310928	However, Cox multivariate analysis importantly showed that CA19-9 positivity (>37 U/mL), but not CEA (>5.0 ng/mL) positivity, was an exclusive independent prognostic factor for cancer-specific survival (multivariate HR = 3.89, 95% CI 1.41-10.33; P = 0.010) and overall survival (multivariate HR = 2.43, 95% CI 1.03-5.35; P = 0.043) (Table3).	('CEA', 'Gene', '1048', (97, 100))	('overall survival', 'CPA', (261, 277))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('CA19-9', 'Chemical', 'MESH:C086528', (59, 65))	('CEA', 'Gene', (97, 100))	('positivity', 'Var', (66, 76))	('CA19-9', 'Gene', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
930180	26310928	Intriguingly, CA19-9 had a greater prognostic impact in the patients with T4 tumor, compared to those with T1, or T2-3 tumor.	('tumor', 'Disease', (119, 124))	('patients', 'Species', '9606', (60, 68))	('CA19-9', 'Chemical', 'MESH:C086528', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (77, 82))	('CA19-9', 'Var', (14, 20))
930190	26310928	In their study, the incidence of CA19-9 positivity was 12.3%, which was similar to that found in our study.	('CA19-9', 'Chemical', 'MESH:C086528', (33, 39))	('CA19-9', 'Gene', (33, 39))	('positivity', 'Var', (40, 50))
930191	26310928	Although they did not examine the prognostic role of CA19-9, they showed that preoperative positivity for CA19-9 had higher sensitivity and specificity for advanced stage compared with CEA, which also supports our conclusion that CA19-9 is a more useful prognostic marker than CEA.	('CA19-9', 'Chemical', 'MESH:C086528', (230, 236))	('CA19-9', 'Gene', (106, 112))	('CA19-9', 'Chemical', 'MESH:C086528', (53, 59))	('CEA', 'Gene', (277, 280))	('advanced stage', 'CPA', (156, 170))	('CEA', 'Gene', '1048', (277, 280))	('higher', 'PosReg', (117, 123))	('CEA', 'Gene', '1048', (185, 188))	('positivity', 'Var', (91, 101))	('CA19-9', 'Chemical', 'MESH:C086528', (106, 112))	('CEA', 'Gene', (185, 188))
930192	26310928	Our study also showed that CA19-9 positivity was significantly correlated with depth of tumor invasion.	('correlated', 'Reg', (63, 73))	('CA19-9', 'Chemical', 'MESH:C086528', (27, 33))	('positivity', 'Var', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CA19-9', 'Protein', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
930194	26310928	Of note, our study showed that CA19-9 is a prognostic marker, beyond tumor depth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CA19-9', 'Chemical', 'MESH:C086528', (31, 37))	('tumor', 'Disease', (69, 74))	('CA19-9', 'Var', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
930196	26310928	CA19-9 is also known as a marker of inflammation.	('inflammation', 'Disease', 'MESH:D007249', (36, 48))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('inflammation', 'Disease', (36, 48))	('CA19-9', 'Var', (0, 6))
930197	26310928	Our data suggested that CA19-9 positivity may represent an inflammation, which may display more aggressive phenotype rather than tumor depth of invasion, in the patient with EGJ adenocarcinoma.	('EGJ adenocarcinoma', 'Disease', (174, 192))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (174, 192))	('patient', 'Species', '9606', (161, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('CA19-9', 'Gene', (24, 30))	('CA19-9', 'Chemical', 'MESH:C086528', (24, 30))	('positivity', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('inflammation', 'Disease', 'MESH:D007249', (59, 71))	('inflammation', 'Disease', (59, 71))
930199	26310928	However, for instance, in colorectal cancer, BRAF mutations status is an important and useful prognostic marker, despite its low prevalence rate of around 5%.	('mutations', 'Var', (50, 59))	('colorectal cancer', 'Disease', (26, 43))	('colorectal cancer', 'Disease', 'MESH:D015179', (26, 43))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (26, 43))
930200	26310928	Considering that CA19-9 positivity possessed a significant prognostic impact on EGJ adenocarcinoma in this study, the proportion of 12.9% was not ignorable, but may be useful in the management of this cancer, such as in decision of neoadjuvant treatment application.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cancer', 'Disease', (201, 207))	('positivity', 'Var', (24, 34))	('CA19-9', 'Gene', (17, 23))	('EGJ adenocarcinoma', 'Disease', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('men', 'Species', '9606', (249, 252))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (80, 98))	('men', 'Species', '9606', (188, 191))	('CA19-9', 'Chemical', 'MESH:C086528', (17, 23))
930204	26310928	Although some studies found a prognostic relevance of HER2 amplification in EGJ adenocarcinoma, Okines et al.	('HER2', 'Gene', (54, 58))	('EGJ adenocarcinoma', 'Disease', (76, 94))	('HER2', 'Gene', '2064', (54, 58))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (76, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('amplification', 'Var', (59, 72))
930207	26310928	High COX2 expression in EGJ adenocarcinoma identified by immunohistochemistry (IHC) has been reportedly associated with lymph node metastases and poor outcome.	('metastases', 'Disease', (131, 141))	('COX2', 'Gene', '5743', (5, 9))	('COX2', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (24, 42))	('EGJ adenocarcinoma', 'Disease', (24, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('metastases', 'Disease', 'MESH:D009362', (131, 141))	('associated', 'Reg', (104, 114))
930216	26310928	In conclusion, this study demonstrated that CA19-9 may be a useful prognostic serum tumor marker in patients with EGJ adenocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('CA19-9', 'Var', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('tumor', 'Disease', (84, 89))	('patients', 'Species', '9606', (100, 108))	('CA19-9', 'Chemical', 'MESH:C086528', (44, 50))	('EGJ adenocarcinoma', 'Disease', 'MESH:D000230', (114, 132))	('EGJ adenocarcinoma', 'Disease', (114, 132))
930241	19174784	At the increased concentrations accompanying a high-fat diet, bile acids affect epithelial function and integrity by triggering various signaling pathways and processes including induction of apoptosis, mitochondrial alterations, oxidative/nitrosative stress, DNA damage, and mutations.	('integrity', 'CPA', (104, 113))	('mitochondrial alterations', 'CPA', (203, 228))	('oxidative/nitrosative stress', 'MPA', (230, 258))	('affect', 'Reg', (73, 79))	('epithelial function', 'CPA', (80, 99))	('mutations', 'Var', (276, 285))	('bile acids', 'Chemical', 'MESH:D001647', (62, 72))	('DNA damage', 'MPA', (260, 270))	('apoptosis', 'CPA', (192, 201))	('triggering', 'Reg', (117, 127))	('oxidative/nitrosative stress', 'Phenotype', 'HP:0025464', (230, 258))	('mitochondrial alterations', 'Phenotype', 'HP:0012103', (203, 228))	('signaling pathways', 'Pathway', (136, 154))
930334	19174784	DCA has been shown to induce chromosomal instability in esophageal cells using a micronucleus cytokinesis assay.	('chromosomal instability', 'CPA', (29, 52))	('DCA', 'Chemical', 'MESH:D003840', (0, 3))	('DCA', 'Var', (0, 3))	('chromosomal instability', 'Phenotype', 'HP:0040012', (29, 52))	('induce', 'Reg', (22, 28))
930377	24222110	Squamous cell carcinoma (SCC) of the oral mucosa is an excellent candidate cancer for assessment of chemoprevention: lesions are amenable to oral delivery of chemopreventive agents, effects can be visually monitored during treatment, and modulation or inhibition of genes or gene products involved in oral SCC constitute molecular targets against which chemopreventive approaches can be tested and validated.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('SCC', 'Gene', (25, 28))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('cancer', 'Disease', (75, 81))	('SCC', 'Gene', '6317', (25, 28))	('Squamous cell carcinoma', 'Disease', (0, 23))	('SCC', 'Gene', (306, 309))	('SCC', 'Phenotype', 'HP:0002860', (306, 309))	('modulation', 'Var', (238, 248))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('SCC', 'Gene', '6317', (306, 309))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 23))
930420	24222110	Hamster genes for analysis included: beta-actin control (Actb), p16 (Cdkn2a), p13Arf (Cdkn2a-Arf), p53 (Trp53), cyclin B2 (Ccnb2), B-cell CLL/lymphoma 2 (Bcl2), Bcl2-associated X protein (Bax), cyclin-dependent kinase 2 (Cdk2), cellular homologue of the avian myelocytomatosis virus oncogene (c-Myc), and vascular endothelial growth factor (Vegf) (target genes).	('Cdkn2a', 'Gene', (69, 75))	('Cdkn2a', 'Gene', (86, 92))	('Bcl2', 'Gene', (161, 165))	('Bcl2', 'Gene', (154, 158))	('Bcl2', 'Gene', '12043', (154, 158))	('Cdkn2a', 'Gene', '1029', (86, 92))	('Cdkn2a', 'Gene', '1029', (69, 75))	('p13Arf', 'Var', (78, 84))	('avian myelocytomatosis virus', 'Species', '11867', (254, 282))	('lymphoma', 'Disease', (142, 150))	('Cdk2', 'Gene', (221, 225))	('Trp53', 'Gene', (104, 109))	('Hamster', 'Species', '10034', (0, 7))	('B-cell CLL/lymphoma', 'Phenotype', 'HP:0012191', (131, 150))	('lymphoma', 'Disease', 'MESH:D008223', (142, 150))	('lymphoma', 'Phenotype', 'HP:0002665', (142, 150))	('Trp53', 'Gene', '22059', (104, 109))	('Bcl2', 'Gene', '12043', (161, 165))
930451	24222110	After DMBA treatment of cheek pouches for six weeks, followed by six weeks with 5% LS pellets, there was a significant reduction (p-value <0.05) in expression of p16 and p13Arf and a significant increase in expression of Trp53 and Bcl2 when compared to DMBA treatment only.	('reduction', 'NegReg', (119, 128))	('DMBA', 'Chemical', 'MESH:D015127', (253, 257))	('Trp53', 'Gene', '22059', (221, 226))	('Trp53', 'Gene', (221, 226))	('DMBA', 'Chemical', 'MESH:D015127', (6, 10))	('p16', 'Protein', (162, 165))	('Bcl2', 'Gene', (231, 235))	('Bcl2', 'Gene', '12043', (231, 235))	('LS', 'Chemical', '-', (83, 85))	('expression', 'MPA', (148, 158))	('expression', 'MPA', (207, 217))	('p13Arf', 'Var', (170, 176))	('increase', 'PosReg', (195, 203))
930500	24222110	After six weeks of feeding with 5% LS pellets, there was a significant reduction (p-value <0.05) in expression of p16 and p13Arf and a significant increase in expression of Trp53 and Bcl2 when compared to DMBA treatment only.	('p13Arf', 'Var', (122, 128))	('Trp53', 'Gene', '22059', (173, 178))	('reduction', 'NegReg', (71, 80))	('Bcl2', 'Gene', '12043', (183, 187))	('Bcl2', 'Gene', (183, 187))	('expression', 'MPA', (100, 110))	('expression', 'MPA', (159, 169))	('Trp53', 'Gene', (173, 178))	('increase', 'PosReg', (147, 155))	('p16', 'Gene', (114, 117))	('LS', 'Chemical', '-', (35, 37))	('DMBA', 'Chemical', 'MESH:D015127', (205, 209))
930502	24222110	showed that 55% of tumors from the head and neck had CDKN2A over-expressed, primarily resulting from point mutations and intragenic deletions.	('over-expressed', 'PosReg', (60, 74))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('CDKN2A', 'Gene', (53, 59))	('CDKN2A', 'Gene', '1029', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('resulting from', 'Reg', (86, 100))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('deletions', 'Var', (132, 141))	('point mutations', 'Var', (101, 116))
930503	24222110	In our current studies, the frequency of Cdkn2a alterations was 70.6% in DMBA-induced tumors, the majority (67.6%) of which were deletions or methylation, that is consistent with the incidence found in human oral SCC.	('deletions', 'Var', (129, 138))	('Cdkn2a', 'Gene', '1029', (41, 47))	('rat', 'Species', '10116', (52, 55))	('SCC', 'Phenotype', 'HP:0002860', (213, 216))	('SCC', 'Gene', '6317', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('alterations', 'Var', (48, 59))	('human', 'Species', '9606', (202, 207))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('DMBA', 'Chemical', 'MESH:D015127', (73, 77))	('methylation', 'Var', (142, 153))	('Cdkn2a', 'Gene', (41, 47))	('SCC', 'Gene', (213, 216))
930514	24222110	Furthermore, administration of LS after induction of moderate to severe dysplasia was just as effective in inhibiting tumor formation as administration of LS before, during, and after carcinogen treatment.	('dysplasia', 'Disease', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('moderate', 'Var', (53, 61))	('dysplasia', 'Disease', 'MESH:D004476', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('inhibiting', 'NegReg', (107, 117))	('tumor', 'Disease', (118, 123))	('rat', 'Species', '10116', (21, 24))	('LS', 'Chemical', '-', (31, 33))	('LS', 'Chemical', '-', (155, 157))	('rat', 'Species', '10116', (57, 60))	('rat', 'Species', '10116', (145, 148))
930535	22958781	The levels of Grade >=3 radiation pneumonitis at 12 months according to RTOG toxicity scoring were significantly (p = 0.002) lower for IMRT than for 3D-CRT, being 8% (95% CI 4%-19%) and 32% (95% CI 26%-40%), respectively.	('toxicity', 'Disease', 'MESH:D064420', (77, 85))	('pneumonitis', 'Disease', 'MESH:D011014', (34, 45))	('toxicity', 'Disease', (77, 85))	('IMRT', 'Var', (135, 139))	('pneumonitis', 'Disease', (34, 45))	('lower', 'NegReg', (125, 130))
930538	22958781	The hazard ratio for 4DCT/IMRT was 0.33 (95% CI 0.13-0.82; p = 0.017) for Grade >=3 radiation pneumonitis, indicating lower toxicity rates were associated with 4DCT/IMRT.	('pneumonitis', 'Disease', 'MESH:D011014', (94, 105))	('toxicity', 'Disease', 'MESH:D064420', (124, 132))	('toxicity', 'Disease', (124, 132))	('4DCT/IMRT', 'Var', (160, 169))	('pneumonitis', 'Disease', (94, 105))
930660	22893866	This phenomenon can be explained by the fact that the amount of liver fibrosis is lower because hepatitis B virus tends to generate macronodular cirrhosis.	('liver fibrosis', 'Phenotype', 'HP:0001395', (64, 78))	('hepatitis B virus', 'Species', '10407', (96, 113))	('men', 'Species', '9606', (10, 13))	('hepatitis', 'Phenotype', 'HP:0012115', (96, 105))	('liver fibrosis', 'Disease', (64, 78))	('cirrhosis', 'Disease', (145, 154))	('macronodular cirrhosis', 'Phenotype', 'HP:0006577', (132, 154))	('hepatitis', 'Var', (96, 105))	('liver fibrosis', 'Disease', 'MESH:D008103', (64, 78))	('cirrhosis', 'Phenotype', 'HP:0001394', (145, 154))	('cirrhosis', 'Disease', 'MESH:D005355', (145, 154))
930703	22893866	In this prospective, longitudinal study of 577 patients with CHB, those with LSPS >=5.5 had higher cumulative incidence rates of esophageal variceal bleeding during the follow-up period and LSPS score >=6.5 was an independent risk factor of variceal bleeding from HEV, indicating that prophylactic treatment should be considered in these high risk patients (Fig.	('patients', 'Species', '9606', (348, 356))	('esophageal variceal bleeding', 'Disease', (129, 157))	('higher', 'PosReg', (92, 98))	('esophageal variceal bleeding', 'Phenotype', 'HP:0002040', (129, 157))	('LSPS score >=6.5', 'Var', (190, 206))	('CHB', 'Disease', 'None', (61, 64))	('men', 'Species', '9606', (303, 306))	('patients', 'Species', '9606', (47, 55))	('variceal bleeding', 'Disease', (241, 258))	('esophageal variceal bleeding', 'Disease', 'MESH:D004932', (129, 157))	('CHB', 'Disease', (61, 64))
930706	22893866	In this study, TE value was selected as one of independent risk factors for HCC development, and patients with higher TE values had a significantly higher risk of HCC development, with a hazard ratio of 16.7 with 10.1-15 kPa, 20.9 with 15.1-20 kPa, 25.6 with 20.1-25 kPa, 45.5 with over 25 kPa, as compared to under 10 kPa (Fig.	('HCC', 'Gene', '619501', (76, 79))	('HCC', 'Gene', '619501', (163, 166))	('HCC', 'Phenotype', 'HP:0001402', (163, 166))	('men', 'Species', '9606', (87, 90))	('HCC', 'Phenotype', 'HP:0001402', (76, 79))	('TE values', 'Var', (118, 127))	('TE', 'Chemical', '-', (118, 120))	('HCC', 'Gene', (163, 166))	('TE', 'Chemical', '-', (15, 17))	('HCC', 'Gene', (76, 79))	('men', 'Species', '9606', (174, 177))	('patients', 'Species', '9606', (97, 105))
930708	22893866	In this study, stratified TE value was also identified as an independent risk factor for HCC development, with relative risks of 3.07, 4.68, 5.55, and 6.60 for respective TE values of 8-13 kPa, 13-18 kPa, 18-23 kPa, and >23 kPa compared TE value to under 8 kPa (Fig.	('HCC', 'Gene', (89, 92))	('men', 'Species', '9606', (100, 103))	('>23 kPa', 'Var', (220, 227))	('HCC', 'Gene', '619501', (89, 92))	('TE', 'Chemical', '-', (26, 28))	('HCC', 'Phenotype', 'HP:0001402', (89, 92))	('TE', 'Chemical', '-', (237, 239))	('TE', 'Chemical', '-', (171, 173))
930709	22893866	Interestingly, when patients with available follow-up TE values were analyzed, the risk of HCC development can be changed according to the pattern of the changes in TE values, which proposed the potential role for TE as a dynamic monitoring tool for risk estimation of HCC development.	('HCC', 'Gene', '619501', (91, 94))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('HCC', 'Gene', (269, 272))	('changes', 'Var', (154, 161))	('TE', 'Chemical', '-', (214, 216))	('TE', 'Chemical', '-', (54, 56))	('HCC', 'Phenotype', 'HP:0001402', (269, 272))	('patients', 'Species', '9606', (20, 28))	('HCC', 'Gene', '619501', (269, 272))	('men', 'Species', '9606', (280, 283))	('men', 'Species', '9606', (102, 105))	('TE', 'Chemical', '-', (165, 167))	('HCC', 'Gene', (91, 94))
930713	22893866	TE values was selected as independent predictor of LRE development and patients with a TE value>19 kPa were at significantly greater risk than those with a TE value <=19 kPa.	('men', 'Species', '9606', (62, 65))	('patients', 'Species', '9606', (71, 79))	('TE', 'Chemical', '-', (87, 89))	('LRE development', 'CPA', (51, 66))	('TE', 'Chemical', '-', (156, 158))	('TE value>19 kPa', 'Var', (87, 102))	('TE', 'Chemical', '-', (0, 2))
930717	22893866	In this study, multivariate analysis revealed that TE values >25.6 kPa was identified as the only predictor of postoperative insufficiency.	('postoperative insufficiency', 'Disease', 'MESH:D000309', (111, 138))	('TE', 'Chemical', '-', (51, 53))	('TE values >25.6 kPa', 'Var', (51, 70))	('postoperative insufficiency', 'Disease', (111, 138))
930721	22893866	In the study, patient with preoperative TE values >13.4 kPa were at greater risk for recurrence with a hazard ratio of 1.925 (P=0.010, Fig.	('TE', 'Chemical', '-', (40, 42))	('recurrence', 'Disease', (85, 95))	('patient', 'Species', '9606', (14, 21))	('TE values >13.4 kPa', 'Var', (40, 59))
930733	22893866	In a previous study, BMI>28 kg/m2 and waist circumference were significantly associated with TE failure.	('TE failure', 'Disease', (93, 103))	('TE failure', 'Disease', 'MESH:D017093', (93, 103))	('BMI', 'Var', (21, 24))	('associated', 'Reg', (77, 87))
930799	34022798	Currently, RFA has the highest amount of supporting evidence for clinical application, and has been recommended as the standard ablation technique, especially for Barrett's neoplasia, by several national and international associations for endoscopy.	('RFA', 'Var', (11, 14))	("Barrett's neoplasia", 'Disease', (163, 182))	('neoplasia', 'Phenotype', 'HP:0002664', (173, 182))	("Barrett's neoplasia", 'Disease', 'MESH:D001471', (163, 182))
930815	33390934	However, it remains unclear whether proliferation of esophageal cancer stem-like cells (ECSLCs) is suppressed by SNX-2112 with knockdown of STAT3 (shSTAT3).	('SNX-2112', 'Chemical', 'MESH:C534922', (113, 121))	('suppressed', 'NegReg', (99, 109))	('knockdown', 'Var', (127, 136))	('STAT3', 'Gene', (140, 145))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('shSTAT3', 'Chemical', '-', (147, 154))	('proliferation', 'CPA', (36, 49))	('esophageal', 'Disease', (53, 63))	('SNX-2112', 'Gene', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
930817	33390934	We found that the expression level of both STAT3 and p-STAT3 was higher in clinical esophageal cancer tissue than in the adjacent normal tissue, using western blot and qPCR analysis.	('p-STAT3', 'Var', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('expression level', 'MPA', (18, 34))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('higher', 'PosReg', (65, 71))
930818	33390934	We demonstrated that SNX-2112 inhibited cancer cell proliferation, decreased ABCB1 and ABCG2 gene expression levels and reduced the colony formation capacity of ECSLCs, which was enhanced by STAT3 silencing.	('ABCG2', 'Gene', (87, 92))	('reduced', 'NegReg', (120, 127))	('ABCB1', 'Gene', (77, 82))	('ABCB1', 'Gene', '5243', (77, 82))	('inhibited', 'NegReg', (30, 39))	('ABCG2', 'Gene', '9429', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('SNX-2112', 'Chemical', 'MESH:C534922', (21, 29))	('cancer', 'Disease', (40, 46))	('colony formation capacity of ECSLCs', 'CPA', (132, 167))	('decreased', 'NegReg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('SNX-2112', 'Var', (21, 29))
930821	33390934	In addition, SNX-2112 with shSTAT3 inhibited the proliferation of ECSLCs in vivo.	('SNX-2112', 'Chemical', 'MESH:C534922', (13, 21))	('shSTAT3', 'Gene', (27, 34))	('inhibited', 'NegReg', (35, 44))	('proliferation of ECSLCs', 'CPA', (49, 72))	('shSTAT3', 'Chemical', '-', (27, 34))	('SNX-2112', 'Var', (13, 21))
930838	33390934	Extracellular Hsp90 upregulates stemness markers, promotes self-renewal, and enhances tumor sphere growth in prostate cancer patients, which suggest that extracellular Hsp90 is a modulator of CSCs in prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('patients', 'Species', '9606', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('self-renewal', 'CPA', (59, 71))	('Extracellular', 'Var', (0, 13))	('promotes', 'PosReg', (50, 58))	('CSCs in prostate cancer', 'Disease', (192, 215))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('stemness markers', 'CPA', (32, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (109, 124))	('CSCs in prostate cancer', 'Disease', 'MESH:D011471', (192, 215))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))	('prostate cancer', 'Disease', (109, 124))	('tumor', 'Disease', (86, 91))	('enhances', 'PosReg', (77, 85))	('upregulates', 'PosReg', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
930839	33390934	Inhibition of extracellular Hsp90 using the monoclonal antibody mAb4C5 reduced the activity of breast CSC in vitro and significantly inhibited the growth of breast cancer cells in vivo.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('activity', 'MPA', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('growth', 'CPA', (147, 153))	('breast cancer', 'Disease', (157, 170))	('inhibited', 'NegReg', (133, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('reduced', 'NegReg', (71, 78))	('Inhibition', 'Var', (0, 10))	('extracellular Hsp90', 'Protein', (14, 33))	('breast', 'Disease', (95, 101))
930840	33390934	Additionally, inhibition of Hsp90 using novel C-terminal inhibitors KU711 and KU757 completely prevented the self-renewal of head and neck squamous cell carcinoma CSCs.	('prevented', 'NegReg', (95, 104))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (125, 162))	('neck squamous cell carcinoma CSCs', 'Disease', 'MESH:D000077195', (134, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('inhibition', 'NegReg', (14, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('KU711', 'Chemical', '-', (68, 73))	('neck squamous cell carcinoma CSCs', 'Disease', (134, 167))	('KU757', 'Var', (78, 83))	('self-renewal of', 'CPA', (109, 124))	('KU711', 'Var', (68, 73))	('KU757', 'Chemical', '-', (78, 83))	('Hsp90', 'Protein', (28, 33))
930845	33390934	For example, SNX-2112 inhibited melanoma cell proliferation in a dose-dependent manner to a more significant level than 17-AAG and the IC50 values of 17-AAG and SNX-2112 at 48 h were 1.25 and 0.16 muM, respectively.	('SNX-2112', 'Chemical', 'MESH:C534922', (13, 21))	('inhibited', 'NegReg', (22, 31))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('SNX-2112', 'Chemical', 'MESH:C534922', (161, 169))	('melanoma', 'Disease', (32, 40))	('SNX-2112', 'Var', (13, 21))	('17-AAG', 'Chemical', 'MESH:C112765', (120, 126))	('17-AAG', 'Chemical', 'MESH:C112765', (150, 156))
930850	33390934	STAT3 is constitutively activated by tyrosine phosphorylation in numerous cancers, including esophageal cancer.	('numerous cancers', 'Disease', (65, 81))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (104, 110))	('numerous cancers', 'Disease', 'MESH:D009369', (65, 81))	('tyrosine', 'Chemical', 'MESH:D014443', (37, 45))	('activated', 'PosReg', (24, 33))	('tyrosine phosphorylation', 'Var', (37, 61))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
930851	33390934	Aberrant expression of STAT3 has been implicated in malignant transformation and tumor progression.	('Aberrant expression', 'Var', (0, 19))	('malignant transformation', 'CPA', (52, 76))	('STAT3', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('implicated', 'Reg', (38, 48))	('tumor', 'Disease', (81, 86))
930858	33390934	In the present study, we investigated the molecular mechanisms underlying the ECSLCs-targeting effects of STAT3 knockdown combined with SNX-2112.	('SNX-2112', 'Chemical', 'MESH:C534922', (136, 144))	('knockdown', 'Var', (112, 121))	('STAT3', 'Gene', (106, 111))
930860	33390934	Finally, knockdown of STAT3, along with SNX-2112 administration, inhibited the growth of ECSLCs in vivo.	('knockdown', 'Var', (9, 18))	('STAT3', 'Gene', (22, 27))	('inhibited', 'NegReg', (65, 74))	('growth of ECSLCs in vivo', 'CPA', (79, 103))	('SNX-2112', 'Chemical', 'MESH:C534922', (40, 48))
930892	33390934	Membranes were blocked with 5% skimmed milk in TBS containing 0.05% Tween-20 (TBST) for 1.5 h and were incubated with primary antibodies [Bcl2, Cell Signaling Technology (CST), c15071; Bax, CST, #5023; p38, abcam, ab32142; p-p38, abcam, ab126425; ERK, CST, #4695; p-ERK, CST, #4370; JNK, CST, #9252; p-JNK, CST, #9255; STAT3, CST, #9139; p-STAT3 (Tyr705), CST, #9145; GAPDH, CST, #5174] at 4 C overnight.	('GAPDH', 'Gene', (368, 373))	('Tyr705', 'Chemical', '-', (347, 353))	('ERK', 'Gene', (266, 269))	('TBS', 'Chemical', '-', (78, 81))	('Bax', 'Gene', (185, 188))	('TBS', 'Chemical', '-', (47, 50))	('ERK', 'Gene', '5594', (247, 250))	('p38', 'Gene', (202, 205))	('JNK', 'Gene', (302, 305))	('Bax', 'Gene', '581', (185, 188))	('Bcl2', 'Gene', (138, 142))	('p38', 'Gene', (225, 228))	('JNK', 'Gene', '5599', (302, 305))	('ERK', 'Gene', (247, 250))	('Bcl2', 'Gene', '596', (138, 142))	('Tween-20', 'Chemical', 'MESH:D011136', (68, 76))	('p38', 'Gene', '5594', (202, 205))	('JNK', 'Gene', (283, 286))	('JNK', 'Gene', '5599', (283, 286))	('p-STAT3 (Tyr705', 'Var', (338, 353))	('p38', 'Gene', '5594', (225, 228))	('GAPDH', 'Gene', '2597', (368, 373))	('ERK', 'Gene', '5594', (266, 269))	('TBST', 'Chemical', '-', (78, 82))
930919	33390934	Tissue sections were incubated with primary antibodies [p-ERK, CST, #4695, 1:100; p-AKT (Ser473), CST, #4060, 1:100; STAT3, CST, #9139; p-STAT3 (Tyr705), CST, #9145].	('AKT', 'Gene', '207', (84, 87))	('p-STAT3 (Tyr705', 'Var', (136, 151))	('Tyr705', 'Chemical', '-', (145, 151))	('ERK', 'Gene', '5594', (58, 61))	('AKT', 'Gene', (84, 87))	('Ser473', 'Chemical', '-', (89, 95))	('ERK', 'Gene', (58, 61))
930937	33390934	SNX-2112, along with shSTAT3, remarkably suppressed cell proliferation compared with shSTAT3 and SNX-2112 alone (Figure 3B).	('SNX-2112', 'Chemical', 'MESH:C534922', (0, 8))	('cell proliferation', 'CPA', (52, 70))	('suppressed', 'NegReg', (41, 51))	('shSTAT3', 'Chemical', '-', (85, 92))	('SNX-2112', 'Chemical', 'MESH:C534922', (97, 105))	('shSTAT3', 'Chemical', '-', (21, 28))	('SNX-2112', 'Var', (0, 8))
930946	33390934	These results suggest that SNX-2112 and shSTAT3 combination remarkably increased G2/M phase arrest compared with SNX-2112 or shSTAT3 alone.	('SNX-2112', 'Chemical', 'MESH:C534922', (113, 121))	('SNX-2112', 'Gene', (27, 35))	('shSTAT3', 'Chemical', '-', (125, 132))	('SNX-2112', 'Chemical', 'MESH:C534922', (27, 35))	('shSTAT3', 'Chemical', '-', (40, 47))	('increased G2/M phase arrest', 'Phenotype', 'HP:0003214', (71, 98))	('combination', 'Var', (48, 59))	('arrest', 'Disease', 'MESH:D006323', (92, 98))	('increased', 'PosReg', (71, 80))	('shSTAT3', 'Gene', (40, 47))	('arrest', 'Disease', (92, 98))
930970	33390934	SNX-2112 reduced the expression level of ABCB1 and ABCG2, which was reversed by STAT3 overexpression (Figures 7A,B).	('ABCG2', 'Gene', (51, 56))	('SNX-2112', 'Chemical', 'MESH:C534922', (0, 8))	('reduced', 'NegReg', (9, 16))	('ABCG2', 'Gene', '9429', (51, 56))	('ABCB1', 'Gene', (41, 46))	('ABCB1', 'Gene', '5243', (41, 46))	('SNX-2112', 'Var', (0, 8))	('expression level', 'MPA', (21, 37))
930974	33390934	Taken together, these results suggest that SNX-2112 with shSTAT3 inhibited the proliferation of ECSLCs.	('shSTAT3', 'Chemical', '-', (57, 64))	('inhibited', 'NegReg', (65, 74))	('SNX-2112', 'Var', (43, 51))	('shSTAT3', 'Gene', (57, 64))	('SNX-2112', 'Chemical', 'MESH:C534922', (43, 51))
930984	33390934	In their study, they found that 17-DMAG simultaneously inactivated both AKT and ERK signaling, which were its client proteins, and synergistically potentiated the cytotoxicity of cisplatin.	('AKT', 'Gene', '207', (72, 75))	('ERK', 'Gene', '5594', (80, 83))	('17-DMAG', 'Chemical', 'MESH:C448659', (32, 39))	('cytotoxicity', 'Disease', 'MESH:D064420', (163, 175))	('ERK', 'Gene', (80, 83))	('AKT', 'Gene', (72, 75))	('inactivated', 'NegReg', (55, 66))	('potentiated', 'PosReg', (147, 158))	('cytotoxicity', 'Disease', (163, 175))	('17-DMAG', 'Var', (32, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))
930985	33390934	The glioma tumor-initiating cells were inhibited in a dose-dependent manner by NVP-HSP990, another Hsp90 inhibitor.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('inhibited', 'NegReg', (39, 48))	('glioma', 'Phenotype', 'HP:0009733', (4, 10))	('glioma tumor', 'Disease', (4, 16))	('NVP-HSP990', 'Var', (79, 89))	('glioma tumor', 'Disease', 'MESH:D005910', (4, 16))
930986	33390934	NVP-HSP990 disrupted cell-cycle control mechanisms by decreased CDK2 and CDK4 levels and increased glioma tumor-initiating cell apoptosis levels.	('cell-cycle control mechanisms', 'MPA', (21, 50))	('CDK4', 'Gene', '1019', (73, 77))	('CDK2', 'Gene', '1017', (64, 68))	('glioma tumor', 'Disease', (99, 111))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('disrupted', 'Reg', (11, 20))	('glioma tumor', 'Disease', 'MESH:D005910', (99, 111))	('decreased', 'NegReg', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('increased', 'PosReg', (89, 98))	('CDK2', 'Gene', (64, 68))	('CDK4', 'Gene', (73, 77))	('NVP-HSP990', 'Var', (0, 10))
930988	33390934	For example, 17-AAG, an Hsp90 inhibitor, induced apoptosis and disrupted transcriptional functionality of HIF1alpha, which is a client protein of Hsp90, and 17-AAG decreased the colony formation ability of mouse lymphoma CSCs and human myeloid leukemia CSCs.	('17-AAG', 'Chemical', 'MESH:C112765', (157, 163))	('lymphoma CSCs', 'Disease', 'MESH:D008223', (212, 225))	('HIF1alpha', 'Gene', '15251', (106, 115))	('human', 'Species', '9606', (230, 235))	('HIF1alpha', 'Gene', (106, 115))	('transcriptional functionality', 'MPA', (73, 102))	('myeloid leukemia CSCs', 'Disease', (236, 257))	('leukemia', 'Phenotype', 'HP:0001909', (244, 252))	('mouse', 'Species', '10090', (206, 211))	('disrupted', 'NegReg', (63, 72))	('myeloid leukemia CSCs', 'Disease', 'MESH:D007951', (236, 257))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (236, 252))	('colony formation ability', 'CPA', (178, 202))	('lymphoma CSCs', 'Disease', (212, 225))	('lymphoma', 'Phenotype', 'HP:0002665', (212, 220))	('17-AAG', 'Var', (157, 163))	('decreased', 'NegReg', (164, 173))	('apoptosis', 'CPA', (49, 58))	('17-AAG', 'Chemical', 'MESH:C112765', (13, 19))
930995	33390934	High ABCB1 protein expression has been identified as an independent predictor of early recurrence and death for EAC and ESCC patients treated with chemoradiotherapy based on 5-fluorouracil and cisplatin.	('ABCB1', 'Gene', (5, 10))	('death', 'Disease', 'MESH:D003643', (102, 107))	('ABCB1', 'Gene', '5243', (5, 10))	('High', 'Var', (0, 4))	('death', 'Disease', (102, 107))	('protein', 'Protein', (11, 18))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('ESCC', 'Disease', (120, 124))	('EAC', 'Disease', (112, 115))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (174, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('patients', 'Species', '9606', (125, 133))
930997	33390934	Other studies confirmed ABCG2 protein overexpression in the majority (75%) of esophageal cancer tissues and high ABCG2 protein correlates with poor prognosis of ESCC patients.	('ABCG2', 'Gene', (24, 29))	('ABCG2', 'Gene', '9429', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('ESCC', 'Disease', (161, 165))	('overexpression', 'PosReg', (38, 52))	('cancer', 'Disease', (89, 95))	('high', 'Var', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('protein', 'Protein', (30, 37))	('ABCG2', 'Gene', (113, 118))	('patients', 'Species', '9606', (166, 174))	('ABCG2', 'Gene', '9429', (113, 118))
931003	33390934	In our studies, we found that ABCB1 and ABCG2 levels were reduced by SNX-2112 with shSTAT3.	('ABCG2', 'Gene', '9429', (40, 45))	('ABCB1', 'Gene', (30, 35))	('ABCB1', 'Gene', '5243', (30, 35))	('SNX-2112', 'Chemical', 'MESH:C534922', (69, 77))	('ABCG2', 'Gene', (40, 45))	('reduced', 'NegReg', (58, 65))	('shSTAT3', 'Chemical', '-', (83, 90))	('SNX-2112', 'Var', (69, 77))
931007	33390934	CD34+ cell and STAT3 inhibition by antisense oligonucleotides led to reduced viability and increased apoptosis in leukemic cell lines.	('reduced', 'NegReg', (69, 76))	('antisense oligonucleotides', 'Var', (35, 61))	('CD34', 'Gene', '947', (0, 4))	('oligonucleotides', 'Chemical', 'MESH:D009841', (45, 61))	('CD34', 'Gene', (0, 4))	('increased', 'PosReg', (91, 100))	('apoptosis', 'CPA', (101, 110))
931009	33390934	In this study, we found that p-STAT3 (Tyr705) was upregulated in clinical esophageal cancer samples.	('p-STAT3 (Tyr705', 'Var', (29, 44))	('upregulated', 'PosReg', (50, 61))	('Tyr705', 'Chemical', '-', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
931011	33390934	SNX-2112 with shSTAT3 inhibited ECSLCs tumor growth in vivo.	('inhibited', 'NegReg', (22, 31))	('SNX-2112', 'Chemical', 'MESH:C534922', (0, 8))	('shSTAT3', 'Gene', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ECSLCs tumor', 'Disease', 'MESH:D009369', (32, 44))	('ECSLCs tumor', 'Disease', (32, 44))	('shSTAT3', 'Chemical', '-', (14, 21))	('SNX-2112', 'Var', (0, 8))
931017	33390934	STAT3 overexpression reversed the anticancer effects of SNX-2112 in ECSLCs suggesting that the combination treatment of SNX-2112 with shSTAT3 suppresses ECSLCs proliferation through the STAT3 pathway.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('suppresses', 'NegReg', (142, 152))	('STAT3 pathway', 'Pathway', (186, 199))	('SNX-2112', 'Chemical', 'MESH:C534922', (56, 64))	('SNX-2112', 'Chemical', 'MESH:C534922', (120, 128))	('shSTAT3', 'Chemical', '-', (134, 141))	('ECSLCs proliferation', 'CPA', (153, 173))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('SNX-2112', 'Var', (120, 128))	('shSTAT3', 'Gene', (134, 141))
931091	33321911	The upstream signal PI3K/Akt activates TOR, thereby suppressing autophagy.	('activates', 'PosReg', (29, 38))	('TOR', 'Chemical', '-', (39, 42))	('autophagy', 'CPA', (64, 73))	('suppressing', 'NegReg', (52, 63))	('TOR', 'Protein', (39, 42))	('PI3K/Akt', 'Var', (20, 28))
931160	33321911	We blocked the membrane in 5% milk and incubated it overnight in primary antibodies against PARP, caspase-3, cleaved-PARP, cleaved-caspase-3, LC3, p62, Akt, p-Akt, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), followed by incubation with horseradish peroxidase-conjugated secondary antibodies.	('PARP', 'Gene', (92, 96))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (168, 208))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (168, 208))	('p62', 'Var', (147, 150))	('cleaved-caspase-3', 'Var', (123, 140))	('caspase-3', 'Gene', (98, 107))	('GAPDH', 'Gene', '2597', (210, 215))	('GAPDH', 'Gene', (210, 215))	('LC3', 'Gene', (142, 145))	('Akt', 'Pathway', (152, 155))	('horseradish', 'Species', '3704', (246, 257))	('cleaved-PARP', 'Var', (109, 121))	('p-Akt', 'Pathway', (157, 162))
931188	32796715	New chemotherapeutic regimens were introduced into clinical practice in the last few years, the most promising being the FLOT regimen (Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel), which demonstrated higher histopathological regression rates and which was shown to be an independent prognostic factor for overall and disease-free survival.	('Leucovorin', 'Chemical', 'MESH:D002955', (149, 159))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (161, 172))	('Docetaxel', 'Chemical', 'MESH:D000077143', (178, 187))	('Leucovorin', 'Var', (149, 159))	('higher', 'PosReg', (209, 215))	('Fluorouracil', 'Chemical', 'MESH:D005472', (135, 147))
931195	32796715	A total of 72% of all patients demonstrated ypT3/ypT4 tumors and 56% of patients had lymph node metastases.	('ypT3/ypT4', 'Var', (44, 53))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('patients', 'Species', '9606', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('metastases', 'Disease', (96, 106))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))	('patients', 'Species', '9606', (72, 80))
931253	32777763	The histopathological findings revealed only squamous cell carcinoma, and the pathological diagnosis was esophageal squamous cell carcinoma, pT1bN0M0, pathological stage I.	('esophageal squamous cell carcinoma', 'Disease', (105, 139))	('squamous cell carcinoma', 'Disease', (45, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 68))	('pT1bN0M0', 'Var', (141, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (105, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))
931318	19444905	Low raw fruit and vegetable consumption has been associated with increased risk of the 2 primary histological subtypes of esophageal cancer, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), in both case-control and prospective cohort studies.	('esophageal cancer', 'Disease', (122, 139))	('esophageal squamous cell carcinoma', 'Disease', (177, 211))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('adenocarcinoma', 'Disease', 'MESH:D000230', (152, 166))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (141, 166))	('EAC', 'Phenotype', 'HP:0011459', (168, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (177, 211))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('adenocarcinoma', 'Disease', (152, 166))	('Low', 'Var', (0, 3))
931384	19444905	The only significant association was for high vs. low isoflavonoid consumption and ESCC risk (OR, 0.43, 95% CI, 0.20-0.93; ptrend = 0.01; Table IV; continuous OR per mg/1,000 kcal increase, 0.98, 95% CI, 0.96-1.00).	('low', 'NegReg', (50, 53))	('isoflavonoid', 'Protein', (54, 66))	('high', 'Var', (41, 45))	('isoflavonoid', 'Chemical', '-', (54, 66))	('ESCC', 'Disease', (83, 87))
931387	19444905	The only exception was that high flavone consumption was associated with decreased ESCC risk in men who smoked less than 20 cigarettes daily (ptrend = 0.02) but with increased ESCC risk in men who smoked at least 20 cigarettes daily (ptrend = 0.16; pinteraction = 0.02).	('ESCC', 'Disease', (176, 180))	('men', 'Species', '9606', (96, 99))	('men', 'Species', '9606', (189, 192))	('decreased', 'NegReg', (73, 82))	('decreased ESCC', 'Phenotype', 'HP:0025022', (73, 87))	('high flavone', 'Var', (28, 40))	('increased ESCC', 'Phenotype', 'HP:0003565', (166, 180))	('ESCC', 'Disease', (83, 87))	('flavone', 'Chemical', 'MESH:C043562', (33, 40))
931397	19444905	The strongest inverse relationship was observed between ESCC risk and high vs. low flavanone intake (OR, 0.57, 95% CI, 0.30-1.08; ptrend = 0.08; Table IV; continuous OR per mg/1,000 kcal increase, 0.98, 95% CI, 0.97-0.999).	('ESCC', 'Disease', (56, 60))	('flavanone', 'Chemical', 'MESH:C028610', (83, 92))	('low', 'NegReg', (79, 82))	('inverse', 'NegReg', (14, 21))	('high', 'Var', (70, 74))
931426	19444905	Furthermore, limitations in the flavonoid and proanthocyanidin composition database, variations in the food quantities of recipes or grouped foods, and variability in flavonoid and proanthocyanidin content due to climatic, growing, soil and harvesting conditions of plants and storage and preparation conditions of foods will cause measurement error and might have led to attenuated risk estimates.	('cause', 'Reg', (326, 331))	('measurement', 'MPA', (332, 343))	('proanthocyanidin', 'Chemical', 'MESH:C013221', (46, 62))	('flavonoid', 'Chemical', 'MESH:D005419', (167, 176))	('flavonoid', 'Chemical', 'MESH:D005419', (32, 41))	('proanthocyanidin', 'Chemical', 'MESH:C013221', (181, 197))	('error', 'Disease', (344, 349))	('men', 'Species', '9606', (339, 342))	('variability', 'Var', (152, 163))	('error', 'Disease', 'MESH:D012030', (344, 349))
931445	30874451	Disruption of circadian rhythms can have adverse consequences including the promotion of and/or exacerbation of a wide variety of gastrointestinal disorders and diseases.	('gastrointestinal disorders', 'Disease', 'MESH:D005767', (130, 156))	('gastrointestinal disorders', 'Disease', (130, 156))	('promotion', 'PosReg', (76, 85))	('gastrointestinal disorders', 'Phenotype', 'HP:0011024', (130, 156))	('intestinal disorders', 'Phenotype', 'HP:0011024', (136, 156))	('exacerbation', 'PosReg', (96, 108))	('Disruption', 'Var', (0, 10))
931449	30874451	Two clock-controlled genes are Period (Per1, Per2, Per3) and Cryptochrome (Cry1, Cry2).	('Per3', 'Gene', (51, 55))	('Per3', 'Gene', '8863', (51, 55))	('Per1', 'Var', (39, 43))	('Cryptochrome', 'Gene', (61, 73))
931455	30874451	Disruption of circadian rhythms suppresses melatonin production; therefore, sleep disturbances may be one manifestation of circadian rhythm disruption.	('suppresses', 'NegReg', (32, 42))	('melatonin', 'Chemical', 'MESH:D008550', (43, 52))	('sleep disturbance', 'Phenotype', 'HP:0002360', (76, 93))	('melatonin production', 'MPA', (43, 63))	('sleep disturbances', 'Disease', 'MESH:D012893', (76, 94))	('sleep disturbances', 'Phenotype', 'HP:0002360', (76, 94))	('sleep disturbances', 'Disease', (76, 94))	('circadian rhythm disruption', 'Phenotype', 'HP:0006979', (123, 150))	('Disruption', 'Var', (0, 10))
931456	30874451	Disruption of circadian rhythms and poor sleep quality can both impact gastrointestinal (GI) tract function and both are linked to GI symptoms and disease.	('GI symptoms', 'Disease', (131, 142))	('linked', 'Reg', (121, 127))	('impact', 'Reg', (64, 70))	('poor sleep', 'Phenotype', 'HP:0002360', (36, 46))	('circadian rhythms', 'MPA', (14, 31))	('GI symptoms', 'Disease', 'MESH:D051271', (131, 142))	('Disruption', 'Var', (0, 10))
931461	30874451	The normal circadian rhythms observed in wild type mice are disrupted by genetic manipulation of the circadian clock.	('circadian rhythms', 'MPA', (11, 28))	('disrupted', 'NegReg', (60, 69))	('mice', 'Species', '10090', (51, 55))	('genetic manipulation', 'Var', (73, 93))
931462	30874451	For example, both BMAL1 mutant mice and Clock mutant mice demonstrate disrupted rhythmic cellular proliferation in the GI tract.	('mutant', 'Var', (24, 30))	('rhythmic cellular proliferation in the GI tract', 'CPA', (80, 127))	('BMAL1', 'Gene', (18, 23))	('mice', 'Species', '10090', (31, 35))	('mice', 'Species', '10090', (53, 57))	('disrupted', 'NegReg', (70, 79))
931468	30874451	Wild type mice show rhythmic changes in stool output, intracolonic pressure, and colonic muscle contractility which are altered in mice with a mutation in the molecular circadian clock (i.e., Per1/2 double knockout).	('altered', 'Reg', (120, 127))	('mice', 'Species', '10090', (10, 14))	('intracolonic pressure', 'MPA', (54, 75))	('colonic muscle', 'Disease', (81, 95))	('mutation', 'Var', (143, 151))	('colonic muscle', 'Disease', 'MESH:D003108', (81, 95))	('mice', 'Species', '10090', (131, 135))	('stool output', 'MPA', (40, 52))
931469	30874451	Indeed, polymorphisms in components of the molecular circadian clock (i.e., Clock and Per3) are associated with poor gastric motility in humans.	('gastric motility', 'Disease', 'MESH:D013274', (117, 133))	('gastric motility', 'Disease', (117, 133))	('associated', 'Reg', (96, 106))	('poor gastric motility', 'Phenotype', 'HP:0002578', (112, 133))	('humans', 'Species', '9606', (137, 143))	('Clock', 'Gene', (76, 81))	('Per3', 'Gene', (86, 90))	('Per3', 'Gene', '8863', (86, 90))	('polymorphisms', 'Var', (8, 21))
931470	30874451	Thus, it is likely that disruption of circadian rhythms negatively impacts GI motility and thereby intestinal disorders in which dysmobility is a feature such as irritable bowel syndrome (IBS), functional dyspepsia, gastroparesis, GI symptoms in diabetes, and Parkinson's disease, just to name a few.	('diabetes', 'Disease', 'MESH:D003920', (246, 254))	('IBS', 'Disease', 'MESH:D043183', (188, 191))	('IBS', 'Disease', (188, 191))	("Parkinson's disease", 'Disease', (260, 279))	('irritable', 'Phenotype', 'HP:0000737', (162, 171))	('gastroparesis', 'Disease', 'MESH:D018589', (216, 229))	('gastroparesis', 'Phenotype', 'HP:0002578', (216, 229))	('impacts GI motility', 'Disease', (67, 86))	('intestinal disorders', 'Disease', 'MESH:D007410', (99, 119))	('gastroparesis', 'Disease', (216, 229))	('diabetes', 'Disease', (246, 254))	("Parkinson's disease", 'Disease', 'MESH:D010300', (260, 279))	('negatively', 'NegReg', (56, 66))	('dyspepsia', 'Disease', 'MESH:D004415', (205, 214))	('dyspepsia', 'Phenotype', 'HP:0410281', (205, 214))	('GI symptoms', 'Disease', 'MESH:D051271', (231, 242))	('irritable bowel syndrome', 'Disease', 'MESH:D043183', (162, 186))	('impacts GI motility', 'Disease', 'MESH:D015835', (67, 86))	('dyspepsia', 'Disease', (205, 214))	('GI symptoms', 'Disease', (231, 242))	('irritable bowel syndrome', 'Disease', (162, 186))	('intestinal disorders', 'Disease', (99, 119))	('intestinal disorders', 'Phenotype', 'HP:0011024', (99, 119))	('disruption', 'Var', (24, 34))
931474	30874451	Studies of mice with a genetic modification that disrupts the molecular circadian clock have been useful in demonstrating that that the circadian clock plays a role in protein absorption.	('modification', 'Var', (31, 43))	('mice', 'Species', '10090', (11, 15))	('protein absorption', 'MPA', (168, 186))	('genetic modification', 'Var', (23, 43))
931475	30874451	Specifically, mice that have both Cry1 and Cry2 (critical components of the molecular circadian clock) knocked out have blunted expression of NHE3.	('Cry1', 'Gene', (34, 38))	('mice', 'Species', '10090', (14, 18))	('NHE3', 'Gene', (142, 146))	('blunted', 'NegReg', (120, 127))	('Cry2', 'Gene', (43, 47))	('expression', 'MPA', (128, 138))	('knocked', 'Var', (103, 110))
931480	30874451	In fact, mice that have a mutation in the molecular circadian clock (i.e., specifically the Clock gene) do not show circadian fluctuations in Sglt1, Glut2, or Glut5.	('Sglt1', 'Gene', (142, 147))	('Sglt1', 'Gene', '20537', (142, 147))	('mutation', 'Var', (26, 34))	('Glut5', 'Gene', (159, 164))	('Glut5', 'Gene', '56485', (159, 164))	('Glut2', 'Gene', '20526', (149, 154))	('mice', 'Species', '10090', (9, 13))	('Glut2', 'Gene', (149, 154))
931485	30874451	For example, absorption of triglycerides and cholesterol demonstrates a diurnal fluctuation that is associated with variation in the production of apolipoprotein B-lipoproteins (ApoB) and the intestinal microsomal triglyceride transfer protein (MTP) (Figure 1).	('variation', 'Var', (116, 125))	('MTP', 'Gene', '4547', (245, 248))	('triglycerides', 'Chemical', 'MESH:D014280', (27, 40))	('apolipoprotein B-lipoproteins', 'Protein', (147, 176))	('cholesterol', 'Chemical', 'MESH:D002784', (45, 56))	('MTP', 'Gene', (245, 248))
931491	30874451	Genetic manipulation of the molecular circadian clock in mice (i.e., Cry1/Cry2 double knock out and Clock mutant mice) blunts the expression of the Na+/H+ exchanger NHE3 mRNA.	('mice', 'Species', '10090', (57, 61))	('expression', 'MPA', (130, 140))	('mutant', 'Var', (106, 112))	('blunts', 'NegReg', (119, 125))	('Na+/H+ exchanger NHE3 mRNA', 'MPA', (148, 174))	('mice', 'Species', '10090', (113, 117))
931494	30874451	Accordingly, dysfunction of the intestinal barrier (i.e., gut leakiness) can promote or exacerbate inflammation-mediated diseases including those in the GI tract.	('dysfunction', 'Var', (13, 24))	('promote', 'PosReg', (77, 84))	('inflammation', 'Disease', 'MESH:D007249', (99, 111))	('exacerbate', 'PosReg', (88, 98))	('inflammation', 'Disease', (99, 111))	('leakiness', 'Disease', 'MESH:C535298', (62, 71))	('leakiness', 'Disease', (62, 71))	('gut', 'Disease', (58, 61))
931495	30874451	In mice, disruption of rhythms (i.e., light:dark shifting or Clock gene mutation) impairs intestinal barrier integrity.	('impairs', 'NegReg', (82, 89))	('mice', 'Species', '10090', (3, 7))	('Clock gene', 'Gene', (61, 71))	('intestinal barrier integrity', 'CPA', (90, 118))	('mutation', 'Var', (72, 80))
931498	30874451	The importance of the molecular circadian clock in this phenomenon is highlighted in a study demonstrating that alcohol-induced barrier dysfunction are inhibited when Per2 or Clock are knocked out in Caco-2 cells (immortalized intestinal epithelial cells that model the intestinal barrier).	('knocked out', 'Var', (185, 196))	('Per2', 'Gene', (167, 171))	('Caco-2', 'CellLine', 'CVCL:0025', (200, 206))	('Clock', 'Gene', (175, 180))	('alcohol', 'Chemical', 'MESH:D000438', (112, 119))	('alcohol-induced barrier dysfunction', 'Disease', (112, 147))	('inhibited', 'NegReg', (152, 161))
931501	30874451	Similarly, circadian misalignment exacerbates alcohol-induced effects on the barrier in humans.	('alcohol', 'Chemical', 'MESH:D000438', (46, 53))	('humans', 'Species', '9606', (88, 94))	('exacerbates', 'PosReg', (34, 45))	('misalignment', 'Var', (21, 33))	('circadian misalignment', 'Var', (11, 33))
931503	30874451	For example, the intestinal microbiota from mice with genetic circadian disruption (e.g., knockout of Per1 and Per2) do not exhibit an intrinsic oscillation.	('intrinsic', 'MPA', (135, 144))	('Per2', 'Gene', (111, 115))	('mice', 'Species', '10090', (44, 48))	('knockout', 'Var', (90, 98))	('Per1', 'Gene', (102, 106))
931504	30874451	In addition, studies have demonstrated that circadian disruption in the host (i.e., light:dark shifting, Clock gene mutation) result in dysbiosis which is an abnormal intestinal microbiota community structure.	('dysbiosis', 'Disease', (136, 145))	('dysbiosis', 'Disease', 'MESH:D064806', (136, 145))	('mutation', 'Var', (116, 124))	('circadian disruption', 'MPA', (44, 64))	('result in', 'Reg', (126, 135))	('Clock gene', 'Gene', (105, 115))
931512	30874451	It is not surprising then that disruption of circadian rhythms can lead to immune dysfunction which can manifest as increased susceptibility to infection and cancer and/or unchecked tissue and systemic inflammation.	('infection', 'Disease', (144, 153))	('lead to', 'Reg', (67, 74))	('infection', 'Disease', 'MESH:D007239', (144, 153))	('susceptibility to infection', 'Phenotype', 'HP:0002719', (126, 153))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('disruption', 'Var', (31, 41))	('inflammation', 'Disease', 'MESH:D007249', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('inflammation', 'Disease', (202, 214))	('immune dysfunction', 'Disease', (75, 93))
931513	30874451	For example, mice that undergo a chronic jet lag model (i.e., mimics one transatlantic flight per week for four weeks) have increased IL-6 production upon administration of LPS compared to non-circadian disrupted mice.	('mice', 'Species', '10090', (13, 17))	('mice', 'Species', '10090', (213, 217))	('increased', 'PosReg', (124, 133))	('LPS', 'Var', (173, 176))	('IL-6', 'Gene', (134, 138))	('IL-6', 'Gene', '16193', (134, 138))	('increased IL-6', 'Phenotype', 'HP:0030783', (124, 138))
931524	30874451	It is often difficult to differentiate between the effects of circadian misalignment and sleep deprivation and these studies are no exception; however, there is sufficient evidence that the effects of circadian misalignment cannot be fully explained by effects on sleep suggesting that, at least in part, disruption of normal circadian rhythms can promote metabolic syndrome.	('sleep deprivation', 'Disease', (89, 106))	('disruption', 'Var', (305, 315))	('metabolic syndrome', 'Disease', 'MESH:D024821', (356, 374))	('sleep deprivation', 'Disease', 'MESH:D012892', (89, 106))	('metabolic syndrome', 'Disease', (356, 374))	('promote', 'PosReg', (348, 355))
931528	30874451	Circadian rhythm disruption induced by genetically manipulating the molecular clock results in drastic differences in immune function compared to wild type mice.	('Circadian rhythm disruption', 'MPA', (0, 27))	('genetically manipulating', 'Var', (39, 63))	('immune function', 'CPA', (118, 133))	('Circadian rhythm disruption', 'Phenotype', 'HP:0006979', (0, 27))	('mice', 'Species', '10090', (156, 160))	('differences', 'Reg', (103, 114))
931530	30874451	Bmal1 knockout mice and Per2 knockout mice have increased mortality following exposure to E. Coli-derived lipopolysaccharide (LPS) compared to wild type mice with similar results obtained for L. monocytogenes infection.	('L. monocytogenes', 'Species', '1639', (192, 208))	('knockout', 'Var', (29, 37))	('infection', 'Disease', (209, 218))	('mice', 'Species', '10090', (38, 42))	('E. Coli', 'Species', '562', (90, 97))	('infection', 'Disease', 'MESH:D007239', (209, 218))	('Per2', 'Gene', (24, 28))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (106, 124))	('mortality', 'Disease', 'MESH:D003643', (58, 67))	('Bmal1', 'Gene', (0, 5))	('mice', 'Species', '10090', (153, 157))	('mice', 'Species', '10090', (15, 19))	('mortality', 'Disease', (58, 67))
931552	30874451	Disruption of circadian rhythms causes intestinal barrier dysfunction, intestinal microbiota dysbiosis, and intestinal inflammation, all of which are factors that promote IBD pathogenesis.	('IBD', 'Disease', 'MESH:D015212', (171, 174))	('intestinal barrier dysfunction', 'Disease', (39, 69))	('dysbiosis', 'Disease', (93, 102))	('dysbiosis', 'Disease', 'MESH:D064806', (93, 102))	('intestinal inflammation', 'Disease', 'MESH:D007249', (108, 131))	('IBD', 'Phenotype', 'HP:0002037', (171, 174))	('IBD', 'Disease', (171, 174))	('causes', 'Reg', (32, 38))	('intestinal inflammation', 'Disease', (108, 131))	('Disruption', 'Var', (0, 10))
931557	30874451	However, a polymorphism in the molecular circadian clock gene Per3 is associated with increased use of immunosuppressive drugs and stricturing/fistulizing phenotype in CD.	('polymorphism', 'Var', (11, 23))	('associated', 'Reg', (70, 80))	('CD', 'Phenotype', 'HP:0100280', (168, 170))	('Per3', 'Gene', (62, 66))	('Per3', 'Gene', '8863', (62, 66))
931561	30874451	We speculate that the effects of circadian rhythm disruption on IBD may be the result of impaired ability of intestinal cells to regenerate (i.e., cell proliferation) following inflammation-mediated damage and/or mucosal immune dysregulation.	('disruption', 'Var', (50, 60))	('circadian', 'MPA', (33, 42))	('inflammation', 'Disease', 'MESH:D007249', (177, 189))	('cell proliferation', 'CPA', (147, 165))	('inflammation', 'Disease', (177, 189))	('circadian rhythm disruption', 'Phenotype', 'HP:0006979', (33, 60))	('IBD', 'Phenotype', 'HP:0002037', (64, 67))	('immune dysregulation', 'Phenotype', 'HP:0002958', (221, 241))	('impaired', 'NegReg', (89, 97))	('IBD', 'Disease', (64, 67))	('regenerate', 'CPA', (129, 139))	('IBD', 'Disease', 'MESH:D015212', (64, 67))
931566	30874451	In addition, environmental disruption of circadian rhythms achieved by repeatedly altering the light:dark cycle worsens intestinal inflammation and the development of polyps in mice predisposed to do so (i.e., APClox468 mice).	('polyps', 'Disease', (167, 173))	('intestinal inflammation', 'Disease', 'MESH:D007249', (120, 143))	('intestinal inflammation', 'Disease', (120, 143))	('polyps', 'Disease', 'MESH:D011127', (167, 173))	('worsens', 'NegReg', (112, 119))	('mice', 'Species', '10090', (220, 224))	('mice', 'Species', '10090', (177, 181))	('altering', 'Var', (82, 90))
931607	30874451	Furthermore, even if circadian rhythm disruption is a consequence of disease, correcting circadian rhythm could (and should) improve disease course since circadian disruption promotes inflammation.	('disease', 'MPA', (133, 140))	('circadian rhythm disruption', 'Phenotype', 'HP:0006979', (21, 48))	('inflammation', 'Disease', 'MESH:D007249', (184, 196))	('promotes', 'PosReg', (175, 183))	('inflammation', 'Disease', (184, 196))	('circadian', 'MPA', (89, 98))	('circadian', 'MPA', (154, 163))	('improve', 'PosReg', (125, 132))	('correcting', 'Var', (78, 88))
931643	30775562	In patients with a transthoracic anastomosis, transection of the esophagus occurred approximately at the level of the azygous vein and the anastomosis was constructed with a gastric conduit either using a handsewn or stapling technique.	('transthoracic', 'Var', (19, 32))	('patients', 'Species', '9606', (3, 11))	('transection', 'CPA', (46, 57))
931689	30671195	The present review focuses on the growing recognition of a relationship between P. gingivalis and orodigestive cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('P. gingivalis', 'Species', '837', (80, 93))	('P. gingivalis', 'Var', (80, 93))
931693	30671195	In addition, P. gingivalis accelerates cell cycling and suppresses apoptosis in cultures of primary oral epithelial cells.	('apoptosis', 'CPA', (67, 76))	('P. gingivalis', 'Var', (13, 26))	('P. gingivalis', 'Species', '837', (13, 26))	('cell cycling', 'CPA', (39, 51))	('accelerates', 'PosReg', (27, 38))	('suppresses', 'NegReg', (56, 66))
931697	30671195	In addition, P. gingivalis can be implicated in precancerous gastric and colon lesions, esophageal squamous cell carcinoma, head and neck (larynx, throat, lip, mouth and salivary glands) carcinoma, and pancreatic cancer.	('precancerous gastric', 'Disease', (48, 68))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('implicated', 'Reg', (34, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (202, 219))	('carcinoma', 'Disease', (113, 122))	('esophageal squamous cell carcinoma', 'Disease', (88, 122))	('P. gingivalis', 'Var', (13, 26))	('carcinoma', 'Disease', 'MESH:D002277', (187, 196))	('colon lesions', 'Disease', (73, 86))	('saliva', 'Disease', 'None', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('P. gingivalis', 'Species', '837', (13, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (202, 219))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (88, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('carcinoma', 'Disease', 'MESH:D002277', (113, 122))	('lip, mouth', 'Disease', 'MESH:D002971', (155, 165))	('saliva', 'Disease', (170, 176))	('pancreatic cancer', 'Disease', (202, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('precancerous gastric', 'Disease', 'MESH:D011230', (48, 68))	('colon lesions', 'Disease', 'MESH:D003108', (73, 86))	('carcinoma', 'Disease', (187, 196))
931698	30671195	The fact that distant organs can be involved clearly emphasizes that P. gingivalis has systemic tumorigenic effects in addition to the local effects in its native territory, the oral cavity.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('P. gingivalis', 'Species', '837', (69, 82))	('tumor', 'Disease', (96, 101))	('P. gingivalis', 'Var', (69, 82))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
931700	30671195	Thus, there may be a direct relationship between P. gingivalis and orodigestive cancers.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('P. gingivalis', 'Species', '837', (49, 62))	('P. gingivalis', 'Var', (49, 62))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
931705	30671195	It is also noteworthy that P. gingivalis can invade oral epithelial and endothelial cells and induce potent production of pro-inflammatory cytokines.	('production of pro-inflammatory cytokines', 'MPA', (108, 148))	('induce', 'Reg', (94, 100))	('P. gingivalis', 'Var', (27, 40))	('P. gingivalis', 'Species', '837', (27, 40))
931706	30671195	Increasing evidence implicates P. gingivalis in the etiology of oral, gastrointestinal, and pancreatic cancers.	('gastrointestinal', 'Disease', (70, 86))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancers', 'Disease', 'MESH:D010190', (92, 110))	('pancreatic cancers', 'Disease', (92, 110))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('P. gingivalis', 'Species', '837', (31, 44))	('oral', 'Disease', (64, 68))	('P. gingivalis', 'Var', (31, 44))	('gastrointestinal', 'Disease', 'MESH:D005767', (70, 86))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (92, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
931720	30671195	The production of IL-6 in epithelial cells was increased by P. gingivalis activating the Janus kinase 2 (JAK2) and Glycogen synthase kinase 3 beta (GSK3beta) pathways.	('P. gingivalis', 'Var', (60, 73))	('increased', 'PosReg', (47, 56))	('P. gingivalis', 'Species', '837', (60, 73))	('production', 'MPA', (4, 14))
931735	30671195	In culture experiments, the membrane fraction of P. gingivalis caused upregulation of the immune-regulatory receptor PD-L1 (B7-H1) in oral squamous carcinoma cells and gingival epithelial cells.	('upregulation', 'PosReg', (70, 82))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('B7-H1', 'Gene', (124, 129))	('oral squamous carcinoma', 'Disease', (134, 157))	('P. gingivalis', 'Species', '837', (49, 62))	('P. gingivalis', 'Var', (49, 62))	('B7-H1', 'Gene', '29126', (124, 129))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (139, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('men', 'Species', '9606', (17, 20))
931752	30671195	Increased expression of ZEB1 was also caused by P. gingivalis in a dual species community with F. nucleatum or S. gordonii.	('F. nucleatum', 'Species', '851', (95, 107))	('P. gingivalis', 'Var', (48, 61))	('expression', 'MPA', (10, 20))	('P. gingivalis', 'Species', '837', (48, 61))	('S. gordonii', 'Species', '1302', (111, 122))	('Increased', 'PosReg', (0, 9))	('ZEB1', 'Gene', (24, 28))	('caused', 'Reg', (38, 44))
931755	30671195	In addition, knockdown of ZEB1 with siRNA inhibited the P. gingivalis-induced increase in mesenchymal markers and epithelial cell migration.	('increase', 'PosReg', (78, 86))	('inhibited', 'NegReg', (42, 51))	('P. gingivalis', 'Species', '837', (56, 69))	('P. gingivalis-induced', 'Gene', (56, 77))	('knockdown', 'Var', (13, 22))
931756	30671195	Interestingly, in mice, oral infection with P. gingivalis enhanced ZEB1 levels in gingival tissues.	('P. gingivalis', 'Var', (44, 57))	('oral infection', 'Disease', 'MESH:D020820', (24, 38))	('P. gingivalis', 'Species', '837', (44, 57))	('enhanced', 'PosReg', (58, 66))	('oral infection', 'Disease', (24, 38))	('mice', 'Species', '10090', (18, 22))	('ZEB1 levels', 'MPA', (67, 78))
931759	30671195	The in vitro and in vivo studies listed above showed that P. gingivalis may contribute to a mesenchymal phenotype driving the progression of cancer in co-operation with other oral bacteria.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('P. gingivalis', 'Species', '837', (58, 71))	('P. gingivalis', 'Var', (58, 71))	('contribute', 'Reg', (76, 86))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('mesenchymal phenotype', 'CPA', (92, 113))	('cancer', 'Disease', (141, 147))
931761	30671195	Porphyromonas gingivalis activated the signaling cascade extracellular signal-regulated kinase 1/2 (ERK1/2)-Ets1, p38/Heath-shock-protein 27 (HSP27) and Protease activated receptor 2 (PAR2)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathways to produce proMMP-9 expression.	('proMMP-9', 'Gene', (281, 289))	('shock', 'Phenotype', 'HP:0031273', (124, 129))	('Porphyromonas', 'Var', (0, 13))	('Porphyromonas gingivalis', 'Species', '837', (0, 24))	('proMMP', 'Chemical', '-', (281, 287))
931765	30671195	In addition, P. gingivalis mutants that lacked gingipain proteases, failed to activate MMP-9.	('gingipain proteases', 'Disease', (47, 66))	('mutants', 'Var', (27, 34))	('gingipain proteases', 'Disease', 'MESH:C566273', (47, 66))	('lacked', 'NegReg', (40, 46))	('P. gingivalis', 'Species', '837', (13, 26))
931767	30671195	Further, this investigation highlighted the increase of HSP27 in oral cancer cells infected with P. gingivalis and HSP27's role in the activation of MMP9 in infected cells.	('activation', 'PosReg', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('oral cancer', 'Disease', 'MESH:D009062', (65, 76))	('P. gingivalis', 'Var', (97, 110))	('increase', 'PosReg', (44, 52))	('HSP27', 'Protein', (56, 61))	('HSP27', 'Protein', (115, 120))	('MMP9', 'Gene', (149, 153))	('oral cancer', 'Disease', (65, 76))	('P. gingivalis', 'Species', '837', (97, 110))
931769	30671195	Hence, HSP27 was actively investigated as a viable therapeutic target in cancer therapies using anti-sense oligonucleotides and/or pharmacological inhibitors.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('HSP27', 'Protein', (7, 12))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('anti-sense oligonucleotides', 'Var', (96, 123))	('oligonucleotides', 'Chemical', 'MESH:D009841', (107, 123))
931773	30671195	Exposure to P. gingivalis increased the invasive ability of cells derived from OSCC such as OSC-20 and SAS by upregulating interleukin 8 (IL-8) and matrix metalloproteinases, particularly MMP-1 and MMP-2.	('matrix', 'Enzyme', (148, 154))	('SAS', 'CellLine', 'CVCL:1675', (103, 106))	('invasive ability', 'CPA', (40, 56))	('upregulating', 'PosReg', (110, 122))	('gingivalis increased', 'Phenotype', 'HP:0000212', (15, 35))	('IL-8', 'Gene', '3576', (138, 142))	('increased', 'PosReg', (26, 35))	('IL-8', 'Gene', (138, 142))	('P. gingivalis', 'Species', '837', (12, 25))	('P. gingivalis', 'Var', (12, 25))
931778	30671195	Thus, P. gingivalis increased the invasiveness of OSCC cells by IL-8-dependent upregulation of matrix metalloproteinases.	('increased', 'PosReg', (20, 29))	('IL-8', 'Gene', '3576', (64, 68))	('IL-8', 'Gene', (64, 68))	('P. gingivalis', 'Var', (6, 19))	('P. gingivalis', 'Species', '837', (6, 19))	('matrix', 'Enzyme', (95, 101))	('gingivalis increased', 'Phenotype', 'HP:0000212', (9, 29))	('upregulation', 'PosReg', (79, 91))	('invasiveness of OSCC cells', 'CPA', (34, 60))
931781	30671195	Porphyromonas gingivalis induced changes in the level and phosphorylation status of proteins that display multilevel control on the eukaryotic cell cycle involving cyclins, p53 and Phosphatidylinositol-4,5-bisphosphate 3-kinase (P13K).	('phosphorylation status of proteins', 'MPA', (58, 92))	('changes', 'Reg', (33, 40))	('P13K', 'Mutation', 'p.P13K', (229, 233))	('Porphyromonas', 'Var', (0, 13))	('level', 'MPA', (48, 53))	('Porphyromonas gingivalis', 'Species', '837', (0, 24))
931784	30671195	In primary cultures of short-term gingival epithelial cells, P. gingivalis inhibited apoptosis by upregulating the anti-apoptotic molecule Bcl-2 and downregulating the pro-apoptotic Bad protein.	('upregulating', 'PosReg', (98, 110))	('P. gingivalis', 'Var', (61, 74))	('P. gingivalis', 'Species', '837', (61, 74))	('anti-apoptotic molecule Bcl-2', 'MPA', (115, 144))	('downregulating', 'NegReg', (149, 163))	('inhibited', 'NegReg', (75, 84))	('apoptosis', 'CPA', (85, 94))
931785	30671195	reported that P. gingivalis blocks apoptosis and increases survival of primary gingival epithelial cells through activation of the pPI3K/Akt survival pathway.	('pPI3K/Akt survival pathway', 'Pathway', (131, 157))	('P. gingivalis', 'Var', (14, 27))	('P. gingivalis', 'Species', '837', (14, 27))	('increases', 'PosReg', (49, 58))	('activation', 'PosReg', (113, 123))	('survival', 'CPA', (59, 67))	('apoptosis', 'CPA', (35, 44))
931786	30671195	suggested that one mechanism by which P. gingivalis can block apoptosis in gingival epithelial cells is through manipulation of the P13K/Akt and JAK/Stat pathway that controls intrinsic mitochondrial cell death pathways.	('P13K', 'Mutation', 'p.P13K', (132, 136))	('manipulation', 'Reg', (112, 124))	('P. gingivalis', 'Species', '837', (38, 51))	('P. gingivalis', 'Var', (38, 51))	('apoptosis', 'CPA', (62, 71))	('P13K/Akt and', 'Pathway', (132, 144))
931787	30671195	Akt is a major component of anti-apoptotic pathways that are stimulated by P. gingivalis.	('P. gingivalis', 'Species', '837', (75, 88))	('P. gingivalis', 'Var', (75, 88))	('anti-apoptotic pathways', 'Pathway', (28, 51))	('stimulated', 'PosReg', (61, 71))	('Akt', 'Pathway', (0, 3))
931788	30671195	ATP by ligation of P2X7 receptors.	('P2X7 receptors', 'Protein', (19, 33))	('ligation', 'Var', (7, 15))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))
931790	30671195	In addition, miRNA-203 from P. gingivalis suppresses SOC6 that has an important role in modulating mitochondrial dynamics and subsequent apoptotic events.	('P. gingivalis', 'Species', '837', (28, 41))	('SOC6', 'Gene', (53, 57))	('suppresses', 'NegReg', (42, 52))	('miRNA-203', 'Var', (13, 22))	('modulating', 'Reg', (88, 98))	('mitochondrial dynamics', 'MPA', (99, 121))
931794	30671195	Although several published studies have dealt with the effect of P. gingivalis on oral epithelial cells, little is known about its effect on cancer cells.	('P. gingivalis', 'Species', '837', (65, 78))	('P. gingivalis', 'Var', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
931795	30671195	When oral cancer cells were invaded by P. gingivalis FDC 381, proliferation of the cells were inhibited through arrest of the G1 cell cycle.	('oral cancer', 'Disease', (5, 16))	('P. gingivalis FDC', 'Var', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('oral cancer', 'Disease', 'MESH:D009062', (5, 16))	('proliferation of the cells', 'CPA', (62, 88))	('arrest', 'Disease', 'MESH:D006323', (112, 118))	('P. gingivalis', 'Species', '837', (39, 52))	('arrest', 'Disease', (112, 118))	('inhibited', 'NegReg', (94, 103))	('G1 cell cycle', 'CPA', (126, 139))
931799	30671195	Researchers have also found that P. gingivalis increases cell proliferation by accelerating cell cycling or by pro-survival signaling via modulation of apoptosis.	('gingivalis increases', 'Phenotype', 'HP:0000212', (36, 56))	('accelerating', 'PosReg', (79, 91))	('cell cycling', 'CPA', (92, 104))	('P. gingivalis', 'Species', '837', (33, 46))	('pro-survival signaling', 'MPA', (111, 133))	('increases', 'PosReg', (47, 56))	('modulation', 'Reg', (138, 148))	('P. gingivalis', 'Var', (33, 46))	('apoptosis', 'CPA', (152, 161))	('cell proliferation', 'CPA', (57, 75))
931820	30671195	Such changes can contribute to cancer and autoimmune and inflammatory diseases including periodontitis.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('changes', 'Var', (5, 12))	('periodontitis', 'Disease', 'MESH:D010518', (89, 102))	('periodontitis', 'Disease', (89, 102))	('periodontitis', 'Phenotype', 'HP:0000704', (89, 102))	('contribute', 'Reg', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
931821	30671195	Both DNA and histone modifications, two major epigenetic regulations, have been detected in periodontitis, and gene expression here can be affected by DNA methylation.	('periodontitis', 'Disease', 'MESH:D010518', (92, 105))	('periodontitis', 'Phenotype', 'HP:0000704', (92, 105))	('periodontitis', 'Disease', (92, 105))	('methylation', 'Var', (155, 166))	('detected', 'Reg', (80, 88))	('gene expression', 'MPA', (111, 126))	('affected', 'Reg', (139, 147))
931825	30671195	Protein citrullination deregulates the host's inflammatory signaling network by changing the spatial arrangement of the original 3D-structure and function of the protein.	('citrullination', 'Var', (8, 22))	('Protein', 'Protein', (0, 7))	('changing', 'Reg', (80, 88))	('men', 'Species', '9606', (108, 111))	('inflammatory signaling network', 'Pathway', (46, 76))	('spatial arrangement of', 'MPA', (93, 115))	('deregulates', 'Reg', (23, 34))	('function', 'MPA', (146, 154))
931831	30671195	Inhibitors of PAD can suppress both tumor progression and inflammatory symptoms.	('Inhibitors', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('inflammatory symptoms', 'CPA', (58, 79))	('PAD', 'Gene', (14, 17))	('suppress', 'NegReg', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
931834	30671195	detected with immune histochemistry a high frequency of P. gingivalis in ESCC, i.e.	('ESCC', 'Phenotype', 'HP:0011459', (73, 77))	('ESCC', 'Disease', (73, 77))	('P. gingivalis', 'Species', '837', (56, 69))	('P. gingivalis', 'Var', (56, 69))
931846	30671195	In a study by Yuan et al., P. gingivalis was detected preferentially and frequently in esophageal cancer and dysplasia of the esophagus, but rarely in matching non-cancerous portions.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('dysplasia of the esophagus', 'Disease', 'MESH:D004938', (109, 135))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancerous', 'Disease', 'MESH:D009369', (164, 173))	('esophageal cancer', 'Disease', (87, 104))	('dysplasia of the esophagus', 'Disease', (109, 135))	('P. gingivalis', 'Var', (27, 40))	('P. gingivalis', 'Species', '837', (27, 40))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('cancerous', 'Disease', (164, 173))
931859	30671195	Periodontopathogens may contribute by acting alone or together with other pancreatic cancer risk factors such as smoking, obesity and the ABO genetic variant.	('genetic variant', 'Var', (142, 157))	('obesity', 'Phenotype', 'HP:0001513', (122, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('obesity', 'Disease', 'MESH:D009765', (122, 129))	('pancreatic cancer', 'Disease', (74, 91))	('obesity', 'Disease', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
931864	30671195	Thus, participants with P. gingivalis had a 59% higher risk of developing cancer than those without, and patients with A. actinomycetemcomitans had a 50% risk.	('patients', 'Species', '9606', (105, 113))	('P. gingivalis', 'Var', (24, 37))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('A. actinomycetemcomitans', 'Species', '714', (119, 143))	('P. gingivalis', 'Species', '837', (24, 37))	('participants', 'Species', '9606', (6, 18))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
931866	30671195	In a European nested case-control study involving 404 pancreatic cancer cases and 410 controls, high IgG antibody levels (>200 ng/mL) to P. gingivalis ATCC 53978, which is strongly associated with destruction of the periodontium, were associated with a > 2-fold increased risk to pancreatic cancer after adjusting for known risk factors, compared to those with lower antibody levels (<=200 ng/mL).	('P. gingivalis', 'Species', '837', (137, 150))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (280, 297))	('>200 ng/mL', 'Var', (122, 132))	('associated with', 'Reg', (181, 196))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('pancreatic cancer', 'Disease', (54, 71))	('pancreatic cancer', 'Disease', (280, 297))	('high IgG', 'Phenotype', 'HP:0003237', (96, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (54, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (280, 297))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('lower antibody levels', 'Phenotype', 'HP:0004313', (361, 382))
931867	30671195	In addition, subjects with high levels of antibodies to common oral bacteria had a 45% lower risk of pancreatic cancer compared to those with lower antibody levels.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (101, 118))	('lower', 'NegReg', (87, 92))	('pancreatic cancer', 'Disease', (101, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (101, 118))	('antibodies', 'Var', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lower antibody levels', 'Phenotype', 'HP:0004313', (142, 163))
931870	30671195	It seems plausible that P. gingivalis can reach the pancreas and contribute in pancreatic carcinogenesis.	('pancreas', 'Disease', 'MESH:D010190', (52, 60))	('P. gingivalis', 'Var', (24, 37))	('pancreatic carcinogenesis', 'Disease', (79, 104))	('P. gingivalis', 'Species', '837', (24, 37))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (79, 104))	('pancreas', 'Disease', (52, 60))	('contribute', 'Reg', (65, 75))
931879	30671195	Several other possible mechanisms exerted by P. gingivalis, a keystone pathogen in periodontitis, are discussed in the current review.	('P. gingivalis', 'Species', '837', (45, 58))	('P. gingivalis', 'Var', (45, 58))	('periodontitis', 'Disease', 'MESH:D010518', (83, 96))	('periodontitis', 'Phenotype', 'HP:0000704', (83, 96))	('periodontitis', 'Disease', (83, 96))
931882	30671195	Not every person either carries P. gingivalis that may induce cancer, irrespective of periodontitis and may be associated with worse prognosis.	('person', 'Species', '9606', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('induce', 'Reg', (55, 61))	('associated', 'Reg', (111, 121))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('periodontitis', 'Disease', 'MESH:D010518', (86, 99))	('periodontitis', 'Disease', (86, 99))	('periodontitis', 'Phenotype', 'HP:0000704', (86, 99))	('P. gingivalis', 'Species', '837', (32, 45))	('P. gingivalis', 'Var', (32, 45))
931884	30671195	The fact that pancreatic and gastric cancers can be associated with P. gingivalis suggests that oral microorganisms, bacterially-secreted effectors, inflammatory cells and mediators travel with saliva and blood to distant sites and induce systemic carcinogenic effects.	('saliva', 'Disease', (194, 200))	('pancreatic', 'Disease', (14, 24))	('P. gingivalis', 'Var', (68, 81))	('gastric cancers', 'Disease', (29, 44))	('gastric cancers', 'Phenotype', 'HP:0012126', (29, 44))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('P. gingivalis', 'Species', '837', (68, 81))	('associated', 'Reg', (52, 62))	('carcinogenic', 'Disease', 'MESH:D063646', (248, 260))	('carcinogenic', 'Disease', (248, 260))	('gastric cancer', 'Phenotype', 'HP:0012126', (29, 43))	('induce', 'Reg', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('pancreatic', 'Disease', 'MESH:D010195', (14, 24))	('saliva', 'Disease', 'None', (194, 200))	('gastric cancers', 'Disease', 'MESH:D013274', (29, 44))
931885	30671195	This is also supported by the finding that a greater serum level of P. gingivalis IgG can be associated with orodigestive cancer.	('P. gingivalis', 'Var', (68, 81))	('greater', 'PosReg', (45, 52))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('P. gingivalis', 'Species', '837', (68, 81))	('associated', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('serum level', 'MPA', (53, 64))
931886	30671195	It is compelling to propose that there may be a direct relationship between P. gingivalis and orodigestive cancers, where the contribution to carcinogenesis may be due to secondary intrusion of the oral microorganism outside of its primary location (oral cavity), yet still within anatomically continuous regions.	('carcinogenesis', 'Disease', (142, 156))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('P. gingivalis', 'Var', (76, 89))	('P. gingivalis', 'Species', '837', (76, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (142, 156))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
931901	29581734	The aberrant expression of miRs has also been identified in ESCC.	('ESCC', 'Disease', (60, 64))	('aberrant', 'Var', (4, 12))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('identified', 'Reg', (46, 56))
931941	29581734	The 3'-UTR of CUL4B with wild-type or mutant binding sites for miR-133b was amplified and subcloned into the pGL3 vector (Promega Corp., Madison, WI, USA), respectively.	('mutant', 'Var', (38, 44))	('CUL4B', 'Gene', '8450', (14, 19))	('miR-133b', 'Gene', '442890', (63, 71))	('binding', 'Interaction', (45, 52))	('miR-133b', 'Gene', (63, 71))	('pGL3', 'Gene', (109, 113))	('CUL4B', 'Gene', (14, 19))	('pGL3', 'Gene', '6391', (109, 113))
931942	29581734	Eca-109 and KYSE150 cells were co-transfected with 150 ng miR-133b or miR-negative control plasmids and 50 ng pGL3-CUL4B wild-type or mutant reporter plasmids using Lipofectamine 2000.	('CUL4B', 'Gene', (115, 120))	('pGL3', 'Gene', (110, 114))	('miR-133b', 'Gene', '442890', (58, 66))	('CUL4B', 'Gene', '8450', (115, 120))	('miR-133b', 'Gene', (58, 66))	('pGL3', 'Gene', '6391', (110, 114))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (165, 183))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('mutant', 'Var', (134, 140))
931947	29581734	Similarly, miR-133b expression in the six ESCC cell lines TE-1 (P<0.01), TE-8 (P<0.05), KYSE150 (P<0.05), KYSE450 (P<0.05), Eca-109 (P<0.01), and EC9706 (P<0.05), was significantly lower than that in the normal esophageal epithelial cell lines Het-1A and HEEC (Fig.	('expression', 'MPA', (20, 30))	('miR-133b', 'Gene', '442890', (11, 19))	('lower', 'NegReg', (181, 186))	('KYSE450', 'Var', (106, 113))	('TE-1', 'Gene', (58, 62))	('miR-133b', 'Gene', (11, 19))	('KYSE150', 'Var', (88, 95))	('EC9706', 'CellLine', 'CVCL:E307', (146, 152))	('TE-1', 'Gene', '57816', (58, 62))
931952	29581734	Endogenous expression of CUL4B was significantly inhibited following transfection of miR-133b in KYSE150 and Eca-109 cells compared with the control (P<0.05; Fig.	('CUL4B', 'Gene', (25, 30))	('Endogenous expression', 'MPA', (0, 21))	('CUL4B', 'Gene', '8450', (25, 30))	('miR-133b', 'Gene', (85, 93))	('transfection', 'Var', (69, 81))	('inhibited', 'NegReg', (49, 58))	('miR-133b', 'Gene', '442890', (85, 93))
931983	29581734	The mechanism underlying CUL4B function in cancer progression remains unclear; however, CUL4B may serve a role in epigenetic changes, including heterochromatin formation, histone modification, parental imprinting or X-chromosome inactivation.	('CUL4B', 'Gene', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('X-chromosome inactivation', 'Var', (216, 241))	('CUL4B', 'Gene', '8450', (25, 30))	('histone modification', 'MPA', (171, 191))	('cancer', 'Disease', (43, 49))	('CUL4B', 'Gene', (88, 93))	('heterochromatin', 'MPA', (144, 159))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('role', 'Reg', (106, 110))	('CUL4B', 'Gene', '8450', (88, 93))	('epigenetic changes', 'MPA', (114, 132))
932067	26695440	Active Yap1 with ectopic expression in breast TICs promoted their colony formation in vitro (p< 0.01) and self-renewal in vivo (p< 0.01), and led to a 4-fold increase in TIC frequency (p< 0.05).	('increase', 'PosReg', (158, 166))	('TIC', 'Gene', '23550', (46, 49))	('self-renewal', 'CPA', (106, 118))	('TIC', 'Gene', '23550', (170, 173))	('TIC', 'Gene', (46, 49))	('TICs', 'Phenotype', 'HP:0100033', (46, 50))	('TIC', 'Gene', (170, 173))	('promoted', 'PosReg', (51, 59))	('Yap1', 'Gene', (7, 11))	('ectopic expression', 'Var', (17, 35))	('TIC', 'Phenotype', 'HP:0100033', (170, 173))	('TIC', 'Phenotype', 'HP:0100033', (46, 49))	('colony formation', 'CPA', (66, 82))
932069	26695440	The loss of Yap1 led to a dramatic growth disadvantage of breast TICs in vitro (p< 0.01) and in vivo (p< 0.01), and it also led to an over 200-fold decrease in TIC frequency (p< 0.01).	('TIC', 'Gene', '23550', (65, 68))	('TIC', 'Gene', (65, 68))	('Yap1', 'Gene', (12, 16))	('TIC', 'Phenotype', 'HP:0100033', (65, 68))	('TIC', 'Gene', '23550', (160, 163))	('TICs', 'Phenotype', 'HP:0100033', (65, 69))	('TIC', 'Gene', (160, 163))	('TIC', 'Phenotype', 'HP:0100033', (160, 163))	('decrease', 'NegReg', (148, 156))	('loss', 'Var', (4, 8))
932094	26695440	Two cell surface markers (EpCAM-Pecy7 and CD49f-APC) were used to identify 2 cell subsets using FACS, namely, basal/stem cells (TICs, CD49fhighEpCAMlow, approximately 57.6 %) and luminal cells (NTCs, CD49flowEpCAMhigh, approximately 34.1 %) in primary breast tumor (Figure 1A), as reported in a previous study.	('TIC', 'Gene', '23550', (128, 131))	('CD49flowEpCAMhigh', 'Var', (200, 217))	('TIC', 'Gene', (128, 131))	('breast tumor', 'Phenotype', 'HP:0100013', (252, 264))	('TIC', 'Phenotype', 'HP:0100033', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('FACS', 'Gene', '14081', (96, 100))	('TICs', 'Phenotype', 'HP:0100033', (128, 132))	('breast tumor', 'Disease', 'MESH:D001943', (252, 264))	('breast tumor', 'Disease', (252, 264))	('FACS', 'Gene', (96, 100))
932112	26695440	To test the function of Yap1 in breast TICs, we introduced active Yap1 with a S127A mutation into TICs using lentivirus infection (lentivirus-Yap1).	('S127A', 'Mutation', 'rs762471803', (78, 83))	('TIC', 'Phenotype', 'HP:0100033', (98, 101))	('S127A', 'Var', (78, 83))	('TICs', 'Phenotype', 'HP:0100033', (98, 102))	('lentivirus infection', 'Disease', (109, 129))	('TIC', 'Gene', '23550', (39, 42))	('TIC', 'Gene', '23550', (98, 101))	('Yap1', 'Gene', (66, 70))	('TIC', 'Gene', (39, 42))	('TIC', 'Gene', (98, 101))	('lentivirus infection', 'Disease', 'MESH:D016180', (109, 129))	('TIC', 'Phenotype', 'HP:0100033', (39, 42))	('TICs', 'Phenotype', 'HP:0100033', (39, 43))
932113	26695440	Next, qRT-PCR (Supplementary Figure S1C) and western blotting (Figure 2A) showed more active Yap1 in the nucleus of TICs transfected with lentivirus-Yap1 than inthe nucleus of those transfected with an empty vector (EV).	('TICs', 'Phenotype', 'HP:0100033', (116, 120))	('TIC', 'Phenotype', 'HP:0100033', (116, 119))	('Yap1', 'Gene', (93, 97))	('active', 'MPA', (86, 92))	('lentivirus-Yap1', 'Var', (138, 153))	('TIC', 'Gene', '23550', (116, 119))	('TIC', 'Gene', (116, 119))	('EV', 'Chemical', '-', (216, 218))
932114	26695440	As shown in Figure 2B and 2C, the TICs harboringactive Yap1 generated more colonies, indicating the expansion of these TICs in vitro (p< 0.001, n = 8).	('colonies', 'CPA', (75, 83))	('TICs', 'Phenotype', 'HP:0100033', (119, 123))	('harboringactive', 'Var', (39, 54))	('TIC', 'Phenotype', 'HP:0100033', (34, 37))	('TICs', 'Phenotype', 'HP:0100033', (34, 38))	('TIC', 'Gene', (119, 122))	('Yap1', 'Gene', (55, 59))	('TIC', 'Gene', '23550', (119, 122))	('TIC', 'Gene', '23550', (34, 37))	('more', 'PosReg', (70, 74))	('TIC', 'Gene', (34, 37))	('TIC', 'Phenotype', 'HP:0100033', (119, 122))
932118	26695440	For the same number of seeding cells, TICs with active Yap1 consistently had more colonies than TICs with EV transfection (p< 0.001, n= 6, Figure 2B and 2D), suggesting that active Yap1 could promote TIC self-renewal.	('TIC', 'Gene', (38, 41))	('colonies', 'CPA', (82, 90))	('TIC', 'Gene', '23550', (38, 41))	('TIC', 'Phenotype', 'HP:0100033', (200, 203))	('active Yap1', 'Var', (48, 59))	('more', 'PosReg', (77, 81))	('TIC', 'Gene', '23550', (200, 203))	('promote', 'PosReg', (192, 199))	('active', 'Var', (174, 180))	('TIC', 'Phenotype', 'HP:0100033', (38, 41))	('TIC', 'Gene', (200, 203))	('TIC', 'Phenotype', 'HP:0100033', (96, 99))	('TICs', 'Phenotype', 'HP:0100033', (38, 42))	('TICs', 'Phenotype', 'HP:0100033', (96, 100))	('EV', 'Chemical', '-', (106, 108))	('TIC', 'Gene', '23550', (96, 99))	('TIC', 'Gene', (96, 99))
932123	26695440	After introduction of active Yap1, TIC colonies contained significantly more p63- and Krt14-positive cells, but fewer Krt18-positive cells (Figure 2E and 2F), indicating that active Yap1 promotes self-renewal and inhibits differentiation of TICs.	('TIC', 'Gene', (241, 244))	('Krt14', 'Gene', '3861', (86, 91))	('inhibits', 'NegReg', (213, 221))	('TIC', 'Gene', '23550', (35, 38))	('TIC', 'Phenotype', 'HP:0100033', (241, 244))	('TIC', 'Gene', (35, 38))	('p63', 'Gene', '8626', (77, 80))	('self-renewal', 'CPA', (196, 208))	('Krt18', 'Gene', (118, 123))	('TIC', 'Phenotype', 'HP:0100033', (35, 38))	('Krt18', 'Gene', '3875', (118, 123))	('TICs', 'Phenotype', 'HP:0100033', (241, 245))	('promotes', 'PosReg', (187, 195))	('p63', 'Gene', (77, 80))	('differentiation', 'CPA', (222, 237))	('TIC', 'Gene', '23550', (241, 244))	('active Yap1', 'Var', (175, 186))	('Krt14', 'Gene', (86, 91))
932126	26695440	We also transfected TICs with lentivirus-Yap1 or -EV, sorted infected TICs (GFP+), and then transplanted them to syngeneic mice.	('TIC', 'Gene', '23550', (70, 73))	('TIC', 'Phenotype', 'HP:0100033', (20, 23))	('TIC', 'Gene', (70, 73))	('infected TICs', 'Disease', 'MESH:D020323', (61, 74))	('EV', 'Chemical', '-', (50, 52))	('TICs', 'Phenotype', 'HP:0100033', (20, 24))	('TIC', 'Phenotype', 'HP:0100033', (70, 73))	('infected TICs', 'Disease', (61, 74))	('TICs', 'Phenotype', 'HP:0100033', (70, 74))	('lentivirus-Yap1', 'Var', (30, 45))	('TIC', 'Gene', (20, 23))	('mice', 'Species', '10090', (123, 127))	('TIC', 'Gene', '23550', (20, 23))
932133	26695440	Nevertheless, with the inoculation of the same number of TICs with or without active Yap1 in FVB/NJ female mice, active Yap1 formed dramatically bigger tumors than mice with the EV control (Supplementary Figure S1D).	('TICs', 'Phenotype', 'HP:0100033', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('mice', 'Species', '10090', (164, 168))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('bigger', 'PosReg', (145, 151))	('mice', 'Species', '10090', (107, 111))	('TIC', 'Gene', '23550', (57, 60))	('EV', 'Chemical', '-', (178, 180))	('TIC', 'Gene', (57, 60))	('tumors', 'Disease', (152, 158))	('active Yap1', 'Var', (113, 124))	('TIC', 'Phenotype', 'HP:0100033', (57, 60))
932135	26695440	Consistent with in vivo data, Yap1 active TICs gave rise to much more colonies than TICs infected with empty vectors (p< 0.001, n = 6, Figure 3E).	('TICs', 'Phenotype', 'HP:0100033', (84, 88))	('TICs infected', 'Disease', (84, 97))	('TIC', 'Gene', (42, 45))	('Yap1 active', 'Var', (30, 41))	('TIC', 'Gene', '23550', (84, 87))	('TIC', 'Phenotype', 'HP:0100033', (42, 45))	('TIC', 'Gene', (84, 87))	('TICs infected', 'Disease', 'MESH:D020323', (84, 97))	('colonies', 'CPA', (70, 78))	('TICs', 'Phenotype', 'HP:0100033', (42, 46))	('more', 'PosReg', (65, 69))	('TIC', 'Phenotype', 'HP:0100033', (84, 87))	('TIC', 'Gene', '23550', (42, 45))
932140	26695440	Taken together, active Yap1 could promote TIC self-renewal and increase TIC frequency in breast tumors.	('active', 'Var', (16, 22))	('increase', 'PosReg', (63, 71))	('TIC', 'Gene', (42, 45))	('TIC', 'Gene', '23550', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Yap1', 'Gene', (23, 27))	('TIC', 'Gene', (72, 75))	('breast tumors', 'Phenotype', 'HP:0100013', (89, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('breast tumor', 'Phenotype', 'HP:0100013', (89, 101))	('TIC', 'Phenotype', 'HP:0100033', (42, 45))	('promote', 'PosReg', (34, 41))	('breast tumors', 'Disease', 'MESH:D001943', (89, 102))	('TIC', 'Phenotype', 'HP:0100033', (72, 75))	('breast tumors', 'Disease', (89, 102))	('TIC', 'Gene', '23550', (42, 45))
932141	26695440	Next, we asked whether knock-out of Yap1 (Yap1-ko) could specifically block TIC growth both in vivo and in vitro.	('Yap1', 'Gene', (36, 40))	('TIC', 'Gene', '23550', (76, 79))	('block', 'NegReg', (70, 75))	('TIC', 'Gene', (76, 79))	('knock-out', 'Var', (23, 32))	('TIC', 'Phenotype', 'HP:0100033', (76, 79))
932151	26695440	FACS analysis of these tumors revealed that approximately 60 % of GFP+ cells switched from original tdTomato+GFP- cells, indicating active Cre recombinase and knock-out of Yap1 within these cells (Figure 4E).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('FACS', 'Gene', '14081', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Yap1', 'Gene', (172, 176))	('FACS', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('knock-out', 'Var', (159, 168))
932155	26695440	Finally, to directly test whether a Yap1-ko could inhibit tumor initiating ability within breast tumors, we performed LDA in vivo.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('breast tumors', 'Disease', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Yap1-ko', 'Var', (36, 43))	('inhibit', 'NegReg', (50, 57))	('LDA', 'Chemical', '-', (118, 121))	('tumor', 'Disease', (97, 102))	('breast tumors', 'Phenotype', 'HP:0100013', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('breast tumor', 'Phenotype', 'HP:0100013', (90, 102))	('breast tumors', 'Disease', 'MESH:D001943', (90, 103))
932157	26695440	However, Yap1-ko led to a more than 200 times lower TIC frequency (1/174,779) (p< 0.001, Table 1).	('Yap1-ko', 'Var', (9, 16))	('TIC', 'Gene', (52, 55))	('TIC', 'Gene', '23550', (52, 55))	('lower', 'NegReg', (46, 51))	('TIC', 'Phenotype', 'HP:0100033', (52, 55))
932158	26695440	With the inoculation of the same number of TICs with Yap1-flp or Yap1-ko in FVB/NJ female mice, Yap1-ko formed dramatically smaller tumors compared to mice with Yap1-flp TICs (Supplementary Figure S1D).	('Yap1-flp', 'Gene', '10413', (161, 169))	('Yap1-flp', 'Gene', (53, 61))	('smaller', 'NegReg', (124, 131))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('TICs', 'Phenotype', 'HP:0100033', (170, 174))	('TICs', 'Phenotype', 'HP:0100033', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Yap1-flp', 'Gene', (161, 169))	('Yap1-flp TICs', 'Disease', 'MESH:D020323', (161, 174))	('TIC', 'Gene', (170, 173))	('mice', 'Species', '10090', (90, 94))	('TIC', 'Phenotype', 'HP:0100033', (170, 173))	('tumors', 'Disease', (132, 138))	('TIC', 'Gene', (43, 46))	('TIC', 'Phenotype', 'HP:0100033', (43, 46))	('Yap1-flp TICs', 'Disease', (161, 174))	('mice', 'Species', '10090', (151, 155))	('Yap1-flp', 'Gene', '10413', (53, 61))	('TIC', 'Gene', '23550', (170, 173))	('TIC', 'Gene', '23550', (43, 46))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('Yap1-ko', 'Var', (96, 103))
932176	26695440	Interestingly, within ER-positive cancers (ERpos), the Yap1high status did not correlate with patient survival outcome compared with the Yap1low status (104/220 vs. 204/418, p> 0.05) (Figure 6C, Table 2).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Yap1high status', 'Var', (55, 70))	('ER', 'Gene', '2099', (22, 24))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('patient', 'Species', '9606', (94, 101))	('ER', 'Gene', '2099', (43, 45))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))
932177	26695440	However, in ER-negative cancers (ERneg), the Yap1high status consistently had a lower survival rate in human patients compared with the Yap1low status (80/199 vs. 159/255, p< 0.05) (Figure 6D, Table 2), suggesting that Yap1 may be a potential driver gene for treating this breast cancer subtype.	('Yap1high', 'Var', (45, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('human', 'Species', '9606', (103, 108))	('patients', 'Species', '9606', (109, 117))	('ER', 'Gene', '2099', (33, 35))	('survival rate', 'CPA', (86, 99))	('ER', 'Gene', '2099', (12, 14))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('lower', 'NegReg', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))	('breast cancer', 'Disease', (273, 286))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))
932187	26695440	Thus, we can conclude that active Yap1 promotes the self-renewal and tumor initiation of TICs but not NTCs.	('TIC', 'Phenotype', 'HP:0100033', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('promotes', 'PosReg', (39, 47))	('tumor', 'Disease', (69, 74))	('TICs', 'Phenotype', 'HP:0100033', (89, 93))	('TIC', 'Gene', '23550', (89, 92))	('Yap1', 'Gene', (34, 38))	('self-renewal', 'CPA', (52, 64))	('active', 'Var', (27, 33))	('TIC', 'Gene', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
932189	26695440	Consequently, the loss of Yap1 led to a dramatic growth disadvantage of TICs both in vivo and in vitro, and it significantly decreased TIC frequency within these breast tumors.	('breast tumors', 'Disease', (162, 175))	('breast tumors', 'Disease', 'MESH:D001943', (162, 175))	('TIC', 'Gene', '23550', (72, 75))	('loss', 'Var', (18, 22))	('TIC', 'Gene', '23550', (135, 138))	('TIC', 'Gene', (72, 75))	('decreased', 'NegReg', (125, 134))	('TIC', 'Gene', (135, 138))	('Yap1', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('TIC', 'Phenotype', 'HP:0100033', (72, 75))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('TIC', 'Phenotype', 'HP:0100033', (135, 138))	('breast tumors', 'Phenotype', 'HP:0100013', (162, 175))	('breast tumor', 'Phenotype', 'HP:0100013', (162, 174))	('TICs', 'Phenotype', 'HP:0100033', (72, 76))
932208	26695440	However, we did not find that significant changes in the expression of these genes correlated with Yap1 activation or deletion (data not shown), with the exception of Smad3.	('activation', 'PosReg', (104, 114))	('Smad3', 'Gene', (167, 172))	('Yap1', 'Gene', (99, 103))	('deletion', 'Var', (118, 126))	('Smad3', 'Gene', '4088', (167, 172))
932216	26695440	Moreover, Yap1 activates the TGF-beta-induced epithelial-to-mesenchymal transition (EMT) in non-transformed mammary epithelial cells and initiates the development of the heart valve.	('activates', 'PosReg', (15, 24))	('TGF-beta', 'Gene', '7040', (29, 37))	('epithelial-to-mesenchymal transition', 'CPA', (46, 82))	('TGF-beta', 'Gene', (29, 37))	('initiates', 'Reg', (137, 146))	('Yap1', 'Var', (10, 14))	('development of the heart valve', 'CPA', (151, 181))
932227	26695440	Intriguingly, our preliminary data confirmed that ectopic expression of active Yap1 dramatically decreased the cytoplasmic ROS level in breast TICs (Supplementary Figure S2B and S2C), while Yap1-ko increased ROS stresses in breast TICs (Supplementary Figure S2B and S2D).	('ROS', 'Chemical', 'MESH:D017382', (123, 126))	('TIC', 'Phenotype', 'HP:0100033', (231, 234))	('TIC', 'Phenotype', 'HP:0100033', (143, 146))	('TICs', 'Phenotype', 'HP:0100033', (231, 235))	('TICs', 'Phenotype', 'HP:0100033', (143, 147))	('cytoplasmic ROS level', 'MPA', (111, 132))	('TIC', 'Gene', '23550', (231, 234))	('Yap1-ko', 'Var', (190, 197))	('increased', 'PosReg', (198, 207))	('TIC', 'Gene', (231, 234))	('decreased', 'NegReg', (97, 106))	('Yap1', 'Gene', (79, 83))	('ROS', 'Chemical', 'MESH:D017382', (208, 211))	('TIC', 'Gene', '23550', (143, 146))	('ROS stresses', 'MPA', (208, 220))	('TIC', 'Gene', (143, 146))
932240	26695440	Using a primary mouse breast tumor model, we show that ectopic expression of active Yap1 increases TIC self-renewal and TIC frequency within these tumors, while the loss of endogenous Yap1 disrupts TIC self-renewal and decreases TIC frequency.	('TIC', 'Phenotype', 'HP:0100033', (120, 123))	('Yap1', 'Gene', (84, 88))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('TIC', 'Gene', (229, 232))	('TIC', 'Phenotype', 'HP:0100033', (229, 232))	('mouse', 'Species', '10090', (16, 21))	('TIC', 'Gene', (198, 201))	('TIC', 'Gene', '23550', (120, 123))	('TIC', 'Phenotype', 'HP:0100033', (198, 201))	('loss', 'Var', (165, 169))	('decreases', 'NegReg', (219, 228))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('TIC', 'Gene', '23550', (229, 232))	('disrupts', 'NegReg', (189, 197))	('TIC', 'Gene', '23550', (198, 201))	('TIC', 'Gene', (99, 102))	('increases', 'PosReg', (89, 98))	('Yap1', 'Gene', (184, 188))	('TIC', 'Phenotype', 'HP:0100033', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('breast tumor', 'Disease', 'MESH:D001943', (22, 34))	('TIC', 'Gene', '23550', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('breast tumor', 'Phenotype', 'HP:0100013', (22, 34))	('tumors', 'Disease', (147, 153))	('breast tumor', 'Disease', (22, 34))	('TIC', 'Gene', (120, 123))
932241	26695440	Moreover, active Yap1 promotes the self-renewal of breast TICs by inhibiting Smad3 signaling.	('promotes', 'PosReg', (22, 30))	('TIC', 'Phenotype', 'HP:0100033', (58, 61))	('Smad3', 'Gene', (77, 82))	('Yap1', 'Gene', (17, 21))	('inhibiting', 'NegReg', (66, 76))	('TICs', 'Phenotype', 'HP:0100033', (58, 62))	('active', 'Var', (10, 16))	('self-renewal', 'CPA', (35, 47))	('TIC', 'Gene', '23550', (58, 61))	('TIC', 'Gene', (58, 61))	('Smad3', 'Gene', '4088', (77, 82))
932256	26695440	Similarly, 1 mug/mL of 4-Hydroxytamoxifen (Sigma, #68047-06-3) was supplemented in culture medium to knock out the Yap1 gene in vitro.	('Yap1', 'Gene', (115, 119))	('4-Hydroxytamoxifen', 'Chemical', '-', (23, 41))	('knock', 'Var', (101, 106))
932257	26695440	Alternatively, active adenovirus-Cre (Vector Biolabs, #1045) was used to knock out the Yap1flox/flox allele (Yap1-flp) in vitro.	('knock out', 'Var', (73, 82))	('Yap1-flp', 'Gene', (109, 117))	('Yap1-flp', 'Gene', '10413', (109, 117))	('Yap1flox/flox', 'Gene', (87, 100))
932259	26695440	Primary antibodies used in current study included anti-mouse Yap1 (Abcam, #ab56701), TAZ (Cell signaling, #4883), Histone H4 (Santa Cruz, #sc-25260), Hsp90 (Santa Cruz, #sc-8262), p-Smad2 (Santa Cruz, #sc-101801), Smad3 (Cell signaling, #9513), p-Smad3 (Santa Cruz, #sc-11769), Krt14 (Santa Cruz, #sc-43310), Krt18 (Santa Cruz, #sc-45406) and p63 (Abcam, #ab124762).	('Santa', 'Var', (285, 290))	('Hsp90', 'Gene', '3320', (150, 155))	('Smad3', 'Gene', '4088', (214, 219))	('TAZ', 'Gene', (85, 88))	('Smad3', 'Gene', (214, 219))	('TAZ', 'Gene', '6901', (85, 88))	('p63', 'Gene', '8626', (343, 346))	('Smad3', 'Gene', '4088', (247, 252))	('mouse', 'Species', '10090', (55, 60))	('Smad2', 'Gene', '4087', (182, 187))	('Krt14', 'Gene', '3861', (278, 283))	('Smad3', 'Gene', (247, 252))	('Smad2', 'Gene', (182, 187))	('Hsp90', 'Gene', (150, 155))	('p63', 'Gene', (343, 346))	('Krt18', 'Gene', (309, 314))	('Krt14', 'Gene', (278, 283))	('Krt18', 'Gene', '3875', (309, 314))
932262	26695440	DyLight 594 AffiniPure Goat Anti-Mouse IgG (1:1,000 dilution; Abbkine, #A23410) and DyLight 488 AffiniPure Goat Anti-Mouse IgG (1:1,000 dilution; Abbkine, #A23210) were used as secondary antibodies for red and green fluorescence, respectively.	('#A23410', 'Var', (71, 78))	('#A23210', 'Var', (155, 162))	('Goat', 'Species', '9925', (23, 27))	('Mouse', 'Species', '10090', (33, 38))	('Goat', 'Species', '9925', (107, 111))	('Mouse', 'Species', '10090', (117, 122))
932305	26864297	Briefly, patients with locally advanced and resectable EC (stage II and III; T2-3N0M0 and T1-3N1M0) were treated with preoperative chemoradiotherapy (CRT) followed by esophagectomy.	('patients', 'Species', '9606', (9, 17))	('T1-3N1M0', 'Var', (90, 98))	('T2-3N0M0', 'Var', (77, 85))
932359	33061962	conducted a randomized trial comparing gastric cancer detection rates in the LCI+WLI and WLI groups and reported that the detection rate of gastric cancers was higher in the LCI+WLI group than in the WLI group.	('LCI+WLI', 'Var', (174, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('detection', 'MPA', (122, 131))	('gastric cancer', 'Disease', (39, 53))	('gastric cancers', 'Disease', 'MESH:D013274', (140, 155))	('higher', 'PosReg', (160, 166))	('gastric cancers', 'Disease', (140, 155))	('gastric cancers', 'Phenotype', 'HP:0012126', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gastric cancer', 'Phenotype', 'HP:0012126', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
932372	27539828	Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene lead to malfunctioning or absent CFTR protein, which impairs mucosal clearance mechanisms causing recurring lung infections, inflammation, and airflow obstruction.	('CFTR', 'Gene', (102, 106))	('lung infections', 'Phenotype', 'HP:0006532', (177, 192))	('malfunctioning', 'MPA', (77, 91))	('inflammation', 'Disease', 'MESH:D007249', (194, 206))	('Mutations', 'Var', (0, 9))	('obstruction', 'Disease', 'MESH:D000402', (220, 231))	('cystic fibrosis transmembrane regulator', 'Gene', '1080', (17, 56))	('CFTR', 'Gene', '1080', (58, 62))	('inflammation', 'Disease', (194, 206))	('impairs', 'NegReg', (122, 129))	('CFTR', 'Gene', (58, 62))	('lung infections', 'Disease', (177, 192))	('obstruction', 'Disease', (220, 231))	('protein', 'Protein', (107, 114))	('CFTR', 'Gene', '1080', (102, 106))	('mucosal clearance mechanisms', 'CPA', (130, 158))	('absent', 'NegReg', (95, 101))	('lung infections', 'Disease', 'MESH:D012141', (177, 192))	('cystic fibrosis transmembrane regulator', 'Gene', (17, 56))
932446	27539828	CFTR mutations may directly contribute to colorectal cancer since CFTR may act as a tumor suppressor gene.	('CFTR', 'Gene', '1080', (66, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CFTR', 'Gene', (0, 4))	('colorectal cancer', 'Disease', (42, 59))	('mutations', 'Var', (5, 14))	('CFTR', 'Gene', (66, 70))	('tumor', 'Disease', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('contribute', 'Reg', (28, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))	('CFTR', 'Gene', '1080', (0, 4))
932511	31207910	The patients in the POI group showed a tendency toward higher albumin levels than those in the control group preoperatively; however, both group averages were within the normal range (Albumin*: POI group: 4.14 +- 0.06 g/dL vs. control group: 4.01 +- 0.03 g/dL, p = 0.086).	('POI', 'Var', (194, 197))	('patients', 'Species', '9606', (4, 12))	('higher albumin', 'Phenotype', 'HP:0012117', (55, 69))	('albumin levels', 'MPA', (62, 76))	('higher', 'PosReg', (55, 61))
932512	31207910	On the other hand, the patients in the POI group had significantly higher inflammatory indicators and worse nutritional statuses at the fourth week postoperatively.	('higher', 'PosReg', (67, 73))	('POI', 'Var', (39, 42))	('patients', 'Species', '9606', (23, 31))	('nutritional statuses', 'MPA', (108, 128))	('inflammatory indicators', 'MPA', (74, 97))	('worse', 'Reg', (102, 107))
932514	31207910	As the result of sub-analysis, the POI group had a significantly lower postoperative survival in the patients with stage 0-II esophageal cancer (mean survival time: POI group: 4.8 +- 0.6 years, control group: 6.9 +- 0.3 years, p = 0.003).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('patients', 'Species', '9606', (101, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('lower', 'NegReg', (65, 70))	('POI', 'Var', (35, 38))	('postoperative survival', 'MPA', (71, 93))	('esophageal cancer', 'Disease', (126, 143))
932529	31207910	Although patients in the POI group fulfilled NR as calculated at the fourth week postoperatively using EN by jejunostomy, they had a significantly worse nutritional status at the sixth month postoperatively and their prognosis was worse than that for control group patients.	('patients', 'Species', '9606', (9, 17))	('worse', 'NegReg', (147, 152))	('POI', 'Var', (25, 28))	('nutritional status', 'MPA', (153, 171))	('patients', 'Species', '9606', (265, 273))
932532	31207910	Hospital stay of the patients in the POI group was longer than that of the control group because the POI group exhibited a markedly higher rate of postoperative complications, morbidity, and meal interruption.	('higher', 'PosReg', (132, 138))	('patients', 'Species', '9606', (21, 29))	('POI', 'Var', (101, 104))
932539	31207910	Furthermore, CPRs lead to increase in stomach motility, changes in cardiac function, rise in blood pressure, increase in the respiratory quotient (as described in a study using rats), and increase in the metabolic rate by postprandial thermogenesis as a non-secretory reaction.	('cardiac function', 'MPA', (67, 83))	('stomach motility', 'Disease', (38, 54))	('blood pressure', 'MPA', (93, 107))	('stomach motility', 'Disease', 'MESH:D013272', (38, 54))	('respiratory quotient', 'MPA', (125, 145))	('increase', 'PosReg', (109, 117))	('CPRs', 'Var', (13, 17))	('increase in stomach', 'Phenotype', 'HP:0005207', (26, 45))	('rise in blood pressure', 'Phenotype', 'HP:0032263', (85, 107))	('increase', 'PosReg', (188, 196))	('rise', 'PosReg', (85, 89))	('CPRs', 'Chemical', '-', (13, 17))	('increase', 'PosReg', (26, 34))	('metabolic rate', 'MPA', (204, 218))	('rats', 'Species', '10116', (177, 181))	('changes', 'Reg', (56, 63))
932662	29733523	These codes correspond to the following clinical/histologic diagnoses: neuroendocrine neoplasms (8240), NET (8249), gastrinoma (8153), somatostatinoma (8156), endocrine tumor (8158), gangliocytic paraganglioma (8683), and neuroendocrine carcinoma (8246).	('8156', 'Var', (152, 156))	('endocrine tumor', 'Disease', (159, 174))	('somatostatinoma', 'Disease', (135, 150))	('somatostatinoma', 'Disease', 'MESH:D013005', (135, 150))	('NET', 'Disease', (104, 107))	('neoplasm', 'Phenotype', 'HP:0002664', (86, 94))	('gangliocytic paraganglioma', 'Disease', (183, 209))	('8153', 'Var', (128, 132))	('8240', 'Var', (97, 101))	('8158', 'Var', (176, 180))	('endocrine tumor', 'Disease', 'MESH:D004701', (159, 174))	('gastrinoma', 'Disease', 'MESH:D015408', (116, 126))	('neuroendocrine neoplasms', 'Disease', (71, 95))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (71, 95))	('neuroendocrine carcinoma', 'Disease', (222, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('paraganglioma', 'Phenotype', 'HP:0002668', (196, 209))	('endocrine tumor', 'Phenotype', 'HP:0100568', (159, 174))	('NET', 'Phenotype', 'HP:0100634', (104, 107))	('gastrinoma', 'Disease', (116, 126))	('neuroendocrine neoplasm', 'Phenotype', 'HP:0100634', (71, 94))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('gangliocytic paraganglioma', 'Disease', 'MESH:D010235', (183, 209))	('8683', 'Var', (211, 215))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (222, 246))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (222, 246))	('neoplasms', 'Phenotype', 'HP:0002664', (86, 95))	('neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (71, 95))
932678	29733523	We took all risk factors selected from the multivariate analysis into consideration, which suggested that surgical resection of the primary sites could lower the risk of tumor-specific death (HR = 0.37, CI: 0.30-0.46, P < 0.01), whereas surgical resection of the metastatic sites did not confer an extra survival benefit (HR = 0.82, CI: 0.63-1.06, P = 0.14).	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('surgical resection', 'Var', (106, 124))	('tumor', 'Disease', (170, 175))	('lower', 'NegReg', (152, 157))
932763	28423526	Similar, high density of M2 macrophages in tumor islet also were correlated with lymph node metastasis of ESCCs (P < 0.05).	('high density', 'Var', (9, 21))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ESCCs', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('correlated with', 'Reg', (65, 80))	('lymph node metastasis', 'CPA', (81, 102))	('tumor', 'Disease', (43, 48))
932771	28423526	We compared three categories of MMP9 positive staining combinations (1+, 2+/3+, and 1+/2+/3+) to MMP9 negative (0) staining (Table 4).	('1+/2+/3+', 'Var', (84, 92))	('MMP9', 'Gene', '4318', (97, 101))	('MMP9', 'Gene', (97, 101))	('MMP9', 'Gene', '4318', (32, 36))	('MMP9', 'Gene', (32, 36))
932776	28423526	Cases with high MMP9 expression showed strong invasion (T3-T4 vs T1-T2 = 63.1% vs 40.0%; P < 0.05) and metastasis (pN+ vs pN- =73.5% vs 37.7%; P = 0.001), and were clearly present in advanced ESCC stages (III-IV vs I-II = 78.9% vs 40.3%; P < 0.001) (Table 5).	('ESCC', 'Disease', (192, 196))	('high', 'Var', (11, 15))	('MMP9', 'Gene', '4318', (16, 20))	('MMP9', 'Gene', (16, 20))	('metastasis', 'CPA', (103, 113))	('invasion', 'CPA', (46, 54))
932785	28423526	Moreover, after Multivariate Cox proportional hazard analysis, we found high-density of M2 macrophages in tumor stroma could serve as an independent prognostic factor for the patients of Kazakh ESCCs (HR = 5.464, P < 0.05, Table 6).	('tumor stroma', 'Disease', 'MESH:D009369', (106, 118))	('tumor stroma', 'Disease', (106, 118))	('patients', 'Species', '9606', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('high-density', 'Var', (72, 84))
932794	28423526	He and Clear's studies also showed that a high-density of macrophages was associated with worse prognosis in oral cancer and Follicular lymphoma.	('Follicular lymphoma', 'Disease', 'MESH:D008224', (125, 144))	('oral cancer', 'Disease', (109, 120))	('Follicular lymphoma', 'Disease', (125, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('high-density', 'Var', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('oral cancer', 'Disease', 'MESH:D009062', (109, 120))
932799	28423526	We found the mean value of MVD in tumor was significantly higher compared to corresponding CAN tissues, similar to classify of M2 macrophages density, high MVD in tumor was significantly associated with more malignant phenotypes including lymph node metastasis and clinical stage progression.	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('lymph node metastasis', 'CPA', (239, 260))	('high', 'Var', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('clinical stage progression', 'CPA', (265, 291))	('malignant phenotypes', 'CPA', (208, 228))	('more', 'PosReg', (203, 207))	('MVD', 'MPA', (156, 159))	('tumor', 'Disease', (163, 168))	('associated with', 'Reg', (187, 202))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
932805	28423526	Furthermore, high expression of MMP9 was significantly associated with invasion depth, lymph node metastasis and later clinical stage of Kazakh ESCCs.	('high', 'Var', (13, 17))	('associated', 'Reg', (55, 65))	('invasion depth', 'CPA', (71, 85))	('MMP9', 'Gene', '4318', (32, 36))	('MMP9', 'Gene', (32, 36))	('lymph node metastasis', 'CPA', (87, 108))
932811	28423526	Moreover, the results were also similar to some tumor vitro studies, genetic ablation of MMP9 in tumor recipients, resulting in decreased MVD in developing tumors and even preventing the angiogenic switch during cancer progression, provided original evidence for the functional involvement of host MMP9 in tumor angiogenesis.	('MMP9', 'Gene', '4318', (89, 93))	('MMP9', 'Gene', (89, 93))	('angiogenic switch', 'MPA', (187, 204))	('ablation', 'Var', (77, 85))	('tumor', 'Disease', (306, 311))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Disease', (156, 161))	('preventing', 'NegReg', (172, 182))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (97, 102))	('decreased', 'NegReg', (128, 137))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('MMP9', 'Gene', '4318', (298, 302))	('MMP9', 'Gene', (298, 302))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (48, 53))	('men', 'Species', '9606', (285, 288))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Disease', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumors', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
932812	28423526	Specific ablation of MMP9 positive TAMs with zoledronic acid resulted in reduced tumor angiogenesis, leading to a conclusion that TAMs deliver angiogenesis-inducing MMP9 are implicated in invasion-promoting processes such as flicking of the angiogenic switch.	('TAMs', 'Chemical', '-', (130, 134))	('MMP9', 'Gene', '4318', (165, 169))	('MMP9', 'Gene', '4318', (21, 25))	('ablation', 'Var', (9, 17))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (45, 60))	('reduced', 'NegReg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('TAMs', 'Chemical', '-', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('MMP9', 'Gene', (165, 169))	('tumor', 'Disease', (81, 86))	('MMP9', 'Gene', (21, 25))
932846	26559488	Patients with esophageal adenocarcinoma histology and clinical stage T1bN1-N3 or T2-T4aN-/+M0 were divided into 2 treatment groups: (1) neoadjuvant chemoradiation followed by surgery and (2) surgery alone.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (14, 39))	('T2-T4aN-/+M0', 'Var', (81, 93))	('T1bN1-N3', 'Var', (69, 77))	('Patients', 'Species', '9606', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (14, 39))	('esophageal adenocarcinoma', 'Disease', (14, 39))
932855	26559488	Patients with cN+ esophageal adenocarcinoma benefit significantly from neoadjuvant chemoradiation.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (18, 43))	('Patients', 'Species', '9606', (0, 8))	('cN+', 'Var', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (18, 43))	('esophageal adenocarcinoma', 'Disease', (18, 43))
932867	26559488	The American College of Surgeons National Cancer Database (NCDB) from 1998-2006 was queried for patients with adenocarcinoma of the middle and lower esophagus who had clinical stage T1bN1-N3M0 or T2-T4aN-/+M0 disease.	('adenocarcinoma of the middle', 'Disease', (110, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('T2-T4aN-/+M0', 'Var', (196, 208))	('Cancer', 'Disease', 'MESH:D009369', (42, 48))	('Cancer', 'Disease', (42, 48))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('patients', 'Species', '9606', (96, 104))	('adenocarcinoma of the middle', 'Disease', 'MESH:D020244', (110, 138))
932872	26559488	The following International Classification of Diseases for Oncology, Third Revision codes were used to identify patients with adenocarcinoma: 8140-8148, 8200-8239, 8260-8263, 8480-8496, 8500-8503, and 8560-8573.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('adenocarcinoma', 'Disease', (126, 140))	('8560-8573', 'Var', (201, 210))	('adenocarcinoma', 'Disease', 'MESH:D000230', (126, 140))	('patients', 'Species', '9606', (112, 120))	('Oncology', 'Phenotype', 'HP:0002664', (59, 67))	('8140-8148', 'Var', (142, 151))	('8480-8496', 'Var', (175, 184))	('8200-8239', 'Var', (153, 162))	('8500-8503', 'Var', (186, 195))	('8260-8263', 'Var', (164, 173))
932887	26559488	Short-term outcomes showed that patients treated with NA+S had higher rates of negative margins and pathologic complete response, fewer nodes examined and fewer positive nodes, and decreased inpatient postoperative stay and 30-day mortality.	('pathologic complete response', 'CPA', (100, 128))	('fewer', 'NegReg', (155, 160))	('negative margins', 'CPA', (79, 95))	('patients', 'Species', '9606', (32, 40))	('inpatient postoperative stay', 'CPA', (191, 219))	('NA+S', 'Var', (54, 58))	('fewer', 'NegReg', (130, 135))	('patient', 'Species', '9606', (193, 200))	('patient', 'Species', '9606', (32, 39))	('higher', 'PosReg', (63, 69))	('decreased', 'NegReg', (181, 190))
932890	26559488	Patients with NA+S had better OS compared with surgery-alone patients (3-year OS, 49% vs 38%, respectively; P < .001) as shown in Figure 2A.	('better', 'PosReg', (23, 29))	('patients', 'Species', '9606', (61, 69))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (30, 32))	('OS', 'Chemical', '-', (78, 80))	('NA+S', 'Var', (14, 18))
932895	26559488	For cN+ patients, patients in the NA+S group were also younger, more privately insured with higher incomes, and had lower in-patient stay and 30-day mortality (Table 2 and Table 3).	('lower', 'NegReg', (116, 121))	('in-patient stay', 'MPA', (122, 137))	('patients', 'Species', '9606', (8, 16))	('30-day', 'CPA', (142, 148))	('cN+', 'Var', (4, 7))	('patient', 'Species', '9606', (18, 25))	('patients', 'Species', '9606', (18, 26))	('patient', 'Species', '9606', (8, 15))	('patient', 'Species', '9606', (125, 132))	('NA+S', 'Var', (34, 38))
932899	26559488	For cN+ patients, OS was significantly better for the NA+S group on both the unadjusted (3-year OS, 47% vs 25%, respectively; P < .001) and propensity score-adjusted (HR, 0.52; 95% CI, 0.42-0.66; P < .001) analyses (Figure 3B).	('patients', 'Species', '9606', (8, 16))	('OS', 'Chemical', '-', (18, 20))	('NA+S', 'Var', (54, 58))	('better', 'PosReg', (39, 45))	('OS', 'Chemical', '-', (96, 98))
932903	26559488	For truly node-positive patients, 3-year OS was significantly better for the NA+S group (34% vs 18%; P < .001) (Figure 3D).	('OS', 'Chemical', '-', (41, 43))	('better', 'PosReg', (62, 68))	('NA+S', 'Var', (77, 81))	('patients', 'Species', '9606', (24, 32))
932905	26559488	Neoadjuvant chemoradiation for esophageal cancer has been tested in several large clinical trials and has shown benefit for oncologic outcomes, thus establishing this approach as the standard of care for T1bN1-N3 or T2-T4aN-/+M0 patients prior to surgery.	('patients', 'Species', '9606', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('esophageal cancer', 'Disease', (31, 48))	('T2-T4aN-/+M0', 'Var', (216, 228))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('T1bN1-N3', 'Var', (204, 212))
932921	26559488	A study using the NCDB has shown survival benefits of neoadjuvant chemoradiation for patients with clinical T2-3N0 and cT1-3N+ patients, although this study also included patients with squamous cell carcinoma, corroborating the findings of other randomized trials.	('T2-3N0', 'Var', (108, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('squamous cell carcinoma', 'Disease', (185, 208))	('cT1', 'Gene', '1489', (119, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (185, 208))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (127, 135))	('cT1', 'Gene', (119, 122))	('benefits', 'PosReg', (42, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
932942	23354359	However, laparoscopic total gastrectomy (LTG) for gastric cancer has not become as popular as LDG, because reconstruction is more complex after LTG than after LDG, especially for esophagojejunostomy.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('esophagojejunostomy', 'Disease', (179, 198))	('gastric cancer', 'Disease', (50, 64))	('LTG', 'Var', (144, 147))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))
932952	23354359	When we find a narrow esophageal hiatus that diminishes the working space during laparoscopic functional end-to-end esophagojejunostomy, we extend the hiatus to incise the diaphragm in the ventral direction because incising the esophageal crus to extend the hiatus can generate pneumothorax.	('esophageal hiatus', 'Disease', 'MESH:D006551', (22, 39))	('pneumothorax', 'Phenotype', 'HP:0002107', (278, 290))	('diminishes', 'NegReg', (45, 55))	('end esophagojejunostomy', 'Phenotype', 'HP:0100628', (112, 135))	('working space', 'MPA', (60, 73))	('esophageal hiatus', 'Disease', (22, 39))	('pneumothorax', 'Disease', (278, 290))	('generate', 'Reg', (269, 277))	('incising', 'Var', (215, 223))
932960	23354359	The type of lymph node dissection was D1+ in 62 (95.4 %) patients and D2+ splenectomy in 3 (4.6 %) patients, and 30.2 +- 12.4 lymph nodes were dissected.	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (57, 65))	('D1+', 'Var', (38, 41))	('D2+', 'Var', (70, 73))
932988	19360286	We have earlier reported that gene expression profile of non-familial ESCC in Assam, a high-risk zone for esophageal cancer in India, are highly consistent with ESCC in China.	('esophageal cancer', 'Disease', (106, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('non-familial', 'Var', (57, 69))
933003	19360286	Hybridized arrays were scanned at 5 mum resolution on an Agilent DNA microarray scanner; model G2565AA at 100% laser power and 30% PMT at 635 nm for Cy5-labelled samples and at 532 nm for Cy3-labeled samples.	('Cy5', 'Chemical', 'MESH:C085321', (149, 152))	('Cy5-labelled', 'Var', (149, 161))	('Cy3', 'Chemical', '-', (188, 191))	('G2565AA', 'Var', (95, 102))	('G2565AA', 'Mutation', 'c.2565G>AA', (95, 102))
933030	19360286	Loss of expression of type IV collagen alpha5 and alpha6 chains, associated with the hypermethylation of their promoter region, has also been reported in colorectal cancer.	('hypermethylation', 'Var', (85, 101))	('Loss of', 'NegReg', (0, 7))	('colorectal cancer', 'Disease', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('type IV collagen alpha5', 'Protein', (22, 45))	('expression', 'MPA', (8, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))	('alpha6 chains', 'Protein', (50, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))
933036	19360286	MAPK7 deficiency leads to an increased expression of VEGF, deregulation of which has been shown to impede angiogenic remodeling and vascular stabilization.	('MAPK7', 'Gene', (0, 5))	('deficiency', 'Var', (6, 16))	('impede', 'NegReg', (99, 105))	('VEGF', 'Gene', (53, 57))	('increased', 'PosReg', (29, 38))	('angiogenic remodeling', 'CPA', (106, 127))	('expression', 'MPA', (39, 49))	('vascular stabilization', 'CPA', (132, 154))	('VEGF', 'Gene', '7422', (53, 57))	('MAPK7', 'Gene', '5598', (0, 5))
933053	19360286	Overexpression of arginase in colorectal carcinoma is associated with metastasis.	('metastasis', 'CPA', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('colorectal carcinoma', 'Disease', (30, 50))	('Overexpression', 'Var', (0, 14))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (30, 50))	('arginase', 'Gene', (18, 26))	('associated', 'Reg', (54, 64))	('arginase', 'Gene', '46717', (18, 26))
933073	32434481	We found that the presence of TATE was significantly associated with improved OS, but not with DFS in all types of cancers.	('presence', 'Var', (18, 26))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('improved', 'PosReg', (69, 77))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
933094	32434481	In this meta-analysis, we discovered that the presence of TATE was notably associated with improved OS (HR = 0.82, 95% CI 0.68 to 0.99, P = 0.041) in patients with solid tumor.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('presence', 'Var', (46, 54))	('tumor', 'Disease', (170, 175))	('patients', 'Species', '9606', (150, 158))	('improved', 'PosReg', (91, 99))
933177	31114132	In a randomized trial comparing standard protocol biopsies with i-SCAN or acetic acid chromoendoscopy, use of i-SCAN was comparable to acetic acid and superior to random biopsies in diagnosing intestinal metaplasia.	('acetic acid', 'Chemical', 'MESH:D019342', (135, 146))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (193, 214))	('acetic acid', 'Chemical', 'MESH:D019342', (74, 85))	('i-SCAN', 'Var', (110, 116))	('intestinal metaplasia', 'Disease', (193, 214))
933237	31114132	While several biomarkers for BE in the areas of dysplasia, genome markers, and gene expression alterations have been discovered, a single, ideal biomarker for BE has yet be identified.	('BE', 'Phenotype', 'HP:0100580', (159, 161))	('BE', 'Phenotype', 'HP:0100580', (29, 31))	('dysplasia', 'Disease', 'MESH:D004476', (48, 57))	('alterations', 'Var', (95, 106))	('dysplasia', 'Disease', (48, 57))
933241	31114132	One of the sentinel events that occurs in the progression of BE to neoplasia is the inactivation of p53.	('neoplasia', 'Disease', (67, 76))	('BE', 'Phenotype', 'HP:0100580', (61, 63))	('neoplasia', 'Disease', 'MESH:D009369', (67, 76))	('neoplasia', 'Phenotype', 'HP:0002664', (67, 76))	('inactivation', 'Var', (84, 96))	('p53', 'Gene', (100, 103))	('p53', 'Gene', '7157', (100, 103))
933243	31114132	Recently, a prospective study evaluated aberrant p53 expression to predict progression to HGD or EAC.	('EAC', 'Disease', (97, 100))	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (49, 52))	('EAC', 'Phenotype', 'HP:0011459', (97, 100))	('HGD', 'Disease', (90, 93))	('aberrant', 'Var', (40, 48))
933245	31114132	Aberrant p53 expression was evaluated in all of the subjects and was found significantly more often in those who developed HGD or EAC (63.6%) compared to subjects did not progress (7.5%).	('Aberrant', 'Var', (0, 8))	('EAC', 'Phenotype', 'HP:0011459', (130, 133))	('HGD', 'Disease', (123, 126))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('EAC', 'Disease', (130, 133))
933247	31114132	Using abnormal DNA, P53, Cyclin A, and Aspergillus oryzae lectin (AOL) in routine paraffin embedded biopsies sections, conditional logistic regression analysis was used on this patient population to estimate an odds ratio of progression.	('abnormal', 'Var', (6, 14))	('P53', 'Gene', (20, 23))	('Aspergillus oryzae', 'Species', '5062', (39, 57))	('P53', 'Gene', '7157', (20, 23))	('paraffin', 'Chemical', 'MESH:D010232', (82, 90))	('patient', 'Species', '9606', (177, 184))	('Cyclin A', 'Protein', (25, 33))
933255	31118785	Nutritional and clinical outcomes of chemoradiotherapy for clinical T1N0M0 esophageal carcinoma Purpose: Whether nutritional assessment and management improves clinical outcomes in patients with clinical T1N0M0 esophageal squamous cell carcinoma (ESCC) who undergo chemoradiotherapy remains to be demonstrated.	('esophageal squamous cell carcinoma', 'Disease', (211, 245))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (75, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('clinical T1N0M0', 'Var', (195, 210))	('patients', 'Species', '9606', (181, 189))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (211, 245))	('esophageal carcinoma', 'Disease', (75, 95))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (75, 95))
933281	31118785	The current study retrospectively reviewed the nutritional status and clinical outcomes in patients with clinical T1N0M0 esophageal squamous cell carcinoma (ESCC) who underwent chemoradiotherapy from our institutional database.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('patients', 'Species', '9606', (91, 99))	('T1N0M0', 'Var', (114, 120))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (121, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('esophageal squamous cell carcinoma', 'Disease', (121, 155))
933287	31118785	Our institution has not provided any regular nutritional care (counseling or supports) for patients with cT1N0M0 ESCC during chemoradiotherapy except for the patients with severe dysphagia or odynophagia.	('dysphagia or odynophagia', 'Disease', 'MESH:D003680', (179, 203))	('cT1N0M0 ESCC', 'Var', (105, 117))	('patients', 'Species', '9606', (91, 99))	('dysphagia', 'Phenotype', 'HP:0002015', (179, 188))	('odynophagia', 'Phenotype', 'HP:0032043', (192, 203))	('dysphagia or odynophagia', 'Disease', (179, 203))	('patients', 'Species', '9606', (158, 166))
933342	31118785	To our knowledge, this is the first study that investigates the changes of nutritional status in patients with clinical T1N0M0 ESCC who underwent chemoradiotherapy and explores the association between their changes in nutritional status and clinical outcomes.	('nutritional status', 'MPA', (75, 93))	('T1N0M0 ESCC', 'Var', (120, 131))	('patients', 'Species', '9606', (97, 105))
933343	31118785	This study demonstrated that half of the patients with clinical T1N0M0 ESCC were at risk of undernutrition at pre-chemoradiotherapy, which worsens the nutritional status and increases the serum CRP concentration.	('increases', 'PosReg', (174, 183))	('CRP', 'Gene', (194, 197))	('nutritional status', 'MPA', (151, 169))	('CRP', 'Gene', '1401', (194, 197))	('patients', 'Species', '9606', (41, 49))	('undernutrition', 'Disease', (92, 106))	('T1N0M0 ESCC', 'Var', (64, 75))	('worsens', 'PosReg', (139, 146))
933344	31118785	Unexpectedly, the severity of body weight loss was similar in patients with clinical T1N0M0 ESCC who underwent chemoradiotherapy and those with locally advanced ESCC: grades 1, 2, and 3 body weight loss were reported as 31%, 4%, 0%-2%, respectively.	('weight loss', 'Phenotype', 'HP:0001824', (191, 202))	('body weight loss', 'Disease', 'MESH:D015431', (30, 46))	('body weight loss', 'Disease', (30, 46))	('weight loss', 'Phenotype', 'HP:0001824', (35, 46))	('T1N0M0', 'Var', (85, 91))	('body weight loss', 'Disease', 'MESH:D015431', (186, 202))	('patients', 'Species', '9606', (62, 70))	('body weight loss', 'Disease', (186, 202))
933347	31118785	Forty-eight percentage of the patients with clinical T1N0M0 esophageal carcinoma without dysphagia showed that the NRI was under 100 before chemoradiotherapy.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (60, 80))	('dysphagia', 'Phenotype', 'HP:0002015', (89, 98))	('dysphagia', 'Disease', 'MESH:D003680', (89, 98))	('T1N0M0', 'Var', (53, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('patients', 'Species', '9606', (30, 38))	('esophageal carcinoma', 'Disease', (60, 80))	('dysphagia', 'Disease', (89, 98))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (60, 80))
933363	31118785	Although the clinical impact of nutritional status on the clinical outcome remains unclear, patients with clinical T1N0M0 ESCC were at risk of undernutrition at pre- and post-chemoradiotherapy.	('patients', 'Species', '9606', (92, 100))	('undernutrition', 'MPA', (143, 157))	('T1N0M0 ESCC', 'Var', (115, 126))
933366	31118785	Patients with clinical T1N0M0 ESCC were at risk of undernutrition at pre- and post-chemoradiotherapy.	('Patients', 'Species', '9606', (0, 8))	('undernutrition', 'MPA', (51, 65))	('T1N0M0 ESCC', 'Var', (23, 34))
933420	30899455	We found that hyperbilirubinemia (odds ratio [OR]: 38.6, 95% confidence of interval [CI]: 2.4-613.6) was independently associated with the occurrence of PICs, in addition to intraoperative blood transfusion (OR: 5.9, 95% CI: 1.1-33.2); elevated CRP level of 15 mg/dL or more, which was the median value of peak CRP levels within 7 days following esophagectomy in all cases (OR: 8.2, 95% CI: 2.0-33.8); and transthoracic esophagectomy (OR: 24.8, 95% CI: 3.4-180.3).	('transthoracic esophagectomy', 'Var', (406, 433))	('PICs', 'Disease', (153, 157))	('CRP', 'Gene', (311, 314))	('CRP', 'Gene', (245, 248))	('CRP', 'Gene', '1401', (245, 248))	('elevated', 'PosReg', (236, 244))	('PICs', 'Chemical', '-', (153, 157))	('hyperbilirubinemia', 'Disease', 'MESH:D006932', (14, 32))	('CRP', 'Gene', '1401', (311, 314))	('elevated CRP', 'Phenotype', 'HP:0011227', (236, 248))	('hyperbilirubinemia', 'Phenotype', 'HP:0002904', (14, 32))	('intraoperative blood transfusion', 'Disease', 'MESH:D006402', (174, 206))	('intraoperative blood transfusion', 'Disease', (174, 206))	('hyperbilirubinemia', 'Disease', (14, 32))
933435	30899455	PICs was the only independent risk factor of postoperative hyperbilirubinemia (data not shown, OR: 14.8, 95% CI: 1.86-118.05, P = 0.011).	('postoperative hyperbilirubinemia', 'Disease', 'MESH:D010149', (45, 77))	('postoperative hyperbilirubinemia', 'Disease', (45, 77))	('PICs', 'Var', (0, 4))	('hyperbilirubinemia', 'Phenotype', 'HP:0002904', (59, 77))	('PICs', 'Chemical', '-', (0, 4))
933486	30175081	According to studies conducted in Iran, more than 90% of esophageal cancers related to squamous cell carcinoma and this subtype of esophageal cancer were associated with tobacco and alcohol consumption, hot food and beverage, ingestion of N-nitroso compounds, smoking, and chewing nass (chewing tobacco mixture).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('N-nitroso compounds', 'Chemical', '-', (239, 258))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (87, 110))	('tobacco', 'Species', '4097', (295, 302))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('squamous cell carcinoma', 'Disease', (87, 110))	('ingestion', 'Var', (226, 235))	('alcohol', 'Chemical', 'MESH:D000438', (182, 189))	('chewing nass', 'Disease', (273, 285))	('esophageal cancers', 'Disease', (57, 75))	('associated', 'Reg', (154, 164))	('tobacco', 'Species', '4097', (170, 177))	('esophageal cancers', 'Disease', 'MESH:D004938', (57, 75))
933538	28744145	Regarding TCGA data, decreased miR-144-3p levels were detected in 354 HCC tissues (8.9139+-1.5986) compared to 50 adjacent normal liver tissues (10.7721+-0.9156, P<0.001; Figure 1A).	('decreased', 'NegReg', (21, 30))	('miR-144', 'Gene', (31, 38))	('miR-144', 'Gene', '406936', (31, 38))	('8.9139+-1.5986', 'Var', (83, 97))
933543	28744145	In contrast to the adjacent normal liver tissue (2.6200+-0.9263), miR-144-3p was significantly underexpressed in HCC tissue (1.3208+-0.7594, P<0.001) with a significant ROC curve (AUC=0.867, 95% CI: 0.817 to 0.916, P<0.001), as shown in Table 2, Figures 2B and 3A.	('miR-144', 'Gene', '406936', (66, 73))	('1.3208+-0.7594', 'Var', (125, 139))	('underexpressed', 'NegReg', (95, 109))	('miR-144', 'Gene', (66, 73))
933544	28744145	Regarding the associations between the expression of miR-144-3p and the clinical characteristics in HCC, we found that the downregulation of miR-144-3p was detected in HCC with metastasis (1.1120+-0.5994, P=0.006; Figure 3B), advanced tumor node metastasis (TNM) stage (1.1596+-0.5821, P=0.001; Figure 3C) and tumor capsular infiltration (1.1746+-0.6991, P=0.047; Figure 3D), compared to the HCC without metastasis (1.5433+-0.8504), early TNM stage (1.8559+-1.0146) and without tumor capsular infiltration (1.4833+-0.7977), respectively.	('tumor node metastasis', 'Disease', (235, 256))	('miR-144', 'Gene', '406936', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (478, 483))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Disease', (478, 483))	('1.1746+-0.6991', 'Var', (339, 353))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('downregulation', 'NegReg', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('miR-144', 'Gene', (141, 148))	('1.1120+-0.5994', 'Var', (189, 203))	('tumor node metastasis', 'Disease', 'MESH:D009362', (235, 256))	('tumor', 'Disease', (310, 315))	('tumor', 'Disease', (235, 240))	('miR-144', 'Gene', '406936', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (478, 483))	('miR-144', 'Gene', (53, 60))
933547	28744145	Regarding the differential expression of miR-144-3p between HCC and nontumor liver tissues, six studies of microarrays in the GEO database (GSE41874, GSE40744, GSE21362, GSE22058, GSE12717, GSE57555), which involved 226 HCC tissues with 212 nontumor liver tissues, were included for this meta-analysis.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('GSE40744', 'Var', (150, 158))	('GSE12717', 'Var', (180, 188))	('GSE41874', 'Var', (140, 148))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('miR-144', 'Gene', (41, 48))	('GSE22058', 'Var', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('GSE21362', 'Var', (160, 168))	('miR-144', 'Gene', '406936', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
933604	26553224	It remains unclear how variations in p-STAT3 expression influence clinical outcomes in esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('STAT3', 'Gene', '6774', (39, 44))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('STAT3', 'Gene', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('influence', 'Reg', (56, 65))	('variations', 'Var', (23, 33))
933655	26553224	The median overall survival time on this study of 8.9 months in patients with positive expression of pSTAT3 and 9.9 months in p-STAT3 negative group is comparable to the results in phase II and III studies testing platinoid-based combinations.	('STAT3', 'Gene', '6774', (128, 133))	('patients', 'Species', '9606', (64, 72))	('STAT3', 'Gene', (128, 133))	('STAT3', 'Gene', '6774', (102, 107))	('positive expression', 'Var', (78, 97))	('STAT3', 'Gene', (102, 107))
933666	26553224	More importantly, high expression of STAT3 was found to have a highly significant relationship with advanced tumor stage (P = 0.047) and poor prognosis (P = 0.023).	('advanced tumor', 'Disease', 'MESH:D020178', (100, 114))	('STAT3', 'Gene', '6774', (37, 42))	('STAT3', 'Gene', (37, 42))	('high', 'Var', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('advanced tumor', 'Disease', (100, 114))
933668	26553224	Similarly, in our study, we determined that high expression of STAT3 significantly correlated with poor prognosis.	('correlated', 'Reg', (83, 93))	('high', 'Var', (44, 48))	('STAT3', 'Gene', (63, 68))	('STAT3', 'Gene', '6774', (63, 68))
933687	26530740	In breast cancer and prostate cancer, dose escalation has been shown to improve LC or biochemical disease control but not OS.	('prostate cancer', 'Disease', 'MESH:D011471', (21, 36))	('dose escalation', 'Var', (38, 53))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('prostate cancer', 'Phenotype', 'HP:0012125', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('improve', 'PosReg', (72, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('prostate cancer', 'Disease', (21, 36))	('biochemical', 'CPA', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
933710	26530740	RTOG 0129 compared accelerated RT with a concomitant boost to standard RT in patients receiving cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('patients', 'Species', '9606', (77, 85))	('accelerated', 'PosReg', (19, 30))	('RTOG', 'Var', (0, 4))
933729	26530740	Viani and colleagues reported a meta-analysis in 2009 that demonstrated that dose escalated RT was associated with higher rates of freedom from biochemical failure than conventional-dose RT, at the expense of higher rates of grade 2 and higher late gastrointestinal toxicity.	('late gastrointestinal toxicity', 'Disease', (244, 274))	('higher', 'PosReg', (209, 215))	('Viani', 'Chemical', '-', (0, 5))	('late gastrointestinal toxicity', 'Disease', 'MESH:D005767', (244, 274))	('dose escalated', 'Var', (77, 91))	('freedom from biochemical failure', 'MPA', (131, 163))
933736	26530740	Updated data from the MRC RT-01 trial, which was the largest study in included in the Viani meta-analysis and in which all patients received ADT, demonstrated that dose escalation improved biochemical progression free survival and freedom from the use of salvage ADT.	('ADT', 'Chemical', '-', (141, 144))	('MRC RT-01', 'CellLine', 'CVCL:D923', (22, 31))	('patients', 'Species', '9606', (123, 131))	('improved', 'PosReg', (180, 188))	('ADT', 'Chemical', '-', (263, 266))	('biochemical progression free survival', 'CPA', (189, 226))	('Viani', 'Chemical', '-', (86, 91))	('dose escalation', 'Var', (164, 179))
933773	25438156	SHEE were cultured in DMEM supplemented with 10% fetal bovine serum at 37 C under 5% CO2, KYSE150 and KYSE510 were cultured in RPMI 1640 and NE3 was cultured in DK-SFM supplement.	('KYSE150', 'Var', (90, 97))	('KYSE510', 'Var', (102, 109))	('CO2', 'Chemical', '-', (85, 88))	('bovine', 'Species', '9913', (55, 61))	('KYSE510', 'CellLine', 'CVCL:1354', (102, 109))	('DMEM', 'Chemical', '-', (22, 26))
933780	25438156	The following antibodies were employed: anti-PARP(1:1000), anti-STAT1 (1:1000) and anti-p-STAT1(Tyr-701)(1:1000), anti-FLAG (1:1000), anti-caspase 3 (1:1000), anti-survivin (1:1000), anti- Bcl-2 (1:1000), anti-p21 (1:1000) and anti-cyclin D1(1:1000), all of which were purchased from Cell Signaling (Danvers, MA, USA).	('Bcl-2', 'Gene', '596', (189, 194))	('anti-', 'Var', (183, 188))	('PARP', 'Gene', '1302', (45, 49))	('p21', 'Gene', (210, 213))	('STAT1', 'Gene', '6772', (64, 69))	('PARP', 'Gene', (45, 49))	('STAT1', 'Gene', (90, 95))	('caspase 3', 'Gene', (139, 148))	('caspase 3', 'Gene', '836', (139, 148))	('cyclin D1', 'Gene', '595', (232, 241))	('cyclin D1', 'Gene', (232, 241))	('STAT1', 'Gene', '6772', (90, 95))	('STAT1', 'Gene', (64, 69))	('p21', 'Gene', '1026', (210, 213))	('Bcl-2', 'Gene', (189, 194))
933793	25438156	We also performed MTS assay, and we found a significant increase in the number of viable cells after Bcl-xL or survivin was transfected into KYSE150 and KYSE510 cells ( Figure 2B ).	('KYSE510', 'CellLine', 'CVCL:1354', (153, 160))	('Bcl-xL', 'Gene', (101, 107))	('increase', 'PosReg', (56, 64))	('survivin', 'Protein', (111, 119))	('transfected', 'Var', (124, 135))	('KYSE510', 'Var', (153, 160))	('Bcl-xL', 'Gene', '598', (101, 107))
933794	25438156	As shown in  Figure 2C , using trypan blue to count the number of viable cells, we found that transfection of Bcl-xL or survivin into KYSE150 and KYSE510 cells led to a significant increase in cell growth, as compared to cells transfected with the empty vector (p<0.05 in both cell lines).	('trypan blue', 'Chemical', 'MESH:D014343', (31, 42))	('KYSE510', 'CellLine', 'CVCL:1354', (146, 153))	('cell growth', 'CPA', (193, 204))	('Bcl-xL', 'Gene', '598', (110, 116))	('KYSE150', 'Var', (134, 141))	('KYSE510', 'Var', (146, 153))	('Bcl-xL', 'Gene', (110, 116))	('transfection', 'Var', (94, 106))	('increase', 'PosReg', (181, 189))	('survivin', 'Gene', (120, 128))
933954	29973579	The 18F-FDG PET/CT was interpreted as showing a "partially obstructive distal esophageal carcinoma with infiltrative wall thickening and mediastinal adenopathy".	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (78, 98))	('adenopathy', 'Disease', (149, 159))	('18F-FDG', 'Var', (4, 11))	('adenopathy', 'Disease', 'MESH:D000072281', (149, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal carcinoma', 'Disease', (78, 98))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (78, 98))
934027	29467557	The first biological analyses showed isolated thrombocytopenia of 107 G/L, and normal renal and hepatic functions.	('107 G/L', 'SUBSTITUTION', 'None', (66, 73))	('thrombocytopenia', 'Disease', 'MESH:D013921', (46, 62))	('107 G/L', 'Var', (66, 73))	('isolated thrombocytopenia', 'Phenotype', 'HP:0001973', (37, 62))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (46, 62))	('thrombocytopenia', 'Disease', (46, 62))	('renal', 'MPA', (86, 91))
934098	28771241	Endoscopic mucosal resection was performed using a gastroscope (GIF-Q260J or GIF-Q240Z; Olympus Optical Co., Tokyo, Japan) with a disposable transparent attachment (D-206-04; Olympus) mounted on the tip of the endoscope.	('Q240Z', 'Var', (81, 86))	('Q260J', 'Var', (68, 73))	('Q240Z', 'SUBSTITUTION', 'None', (81, 86))	('Q260J', 'SUBSTITUTION', 'None', (68, 73))
934099	28771241	Endoscopic submucosal dissection was performed using a gastroscope (GIF-Q260J or GIF-Q240Z; Olympus) with a disposable transparent attachment (D-201-11804; Olympus) mounted on the tip of the endoscope.	('Q240Z', 'SUBSTITUTION', 'None', (85, 90))	('Q240Z', 'Var', (85, 90))	('Q260J', 'SUBSTITUTION', 'None', (72, 77))	('Q260J', 'Var', (72, 77))
934175	28567017	Recently, an Food and Drug Administration (FDA) approved anthelmintic drug, pyrvinium was demonstrated to induce lymphoma T-cell apoptosis in mitochondrial respiration-dependent manner.	('rat', 'Species', '10116', (97, 100))	('pyrvinium', 'Var', (76, 85))	('lymphoma', 'Disease', 'MESH:D008223', (113, 121))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('induce', 'PosReg', (106, 112))	('rat', 'Species', '10116', (161, 164))	('pyrvinium', 'Chemical', 'MESH:C024631', (76, 85))	('rat', 'Species', '10116', (35, 38))	('lymphoma', 'Disease', (113, 121))
934176	28567017	Moreover, inhibition of mitochondrial respiration by As2O3 showed a great potential to enhance drug-induced apoptosis in human leukemia cells.	('inhibition', 'NegReg', (10, 20))	('leukemia', 'Disease', (127, 135))	('mitochondrial respiration', 'MPA', (24, 49))	('leukemia', 'Disease', 'MESH:D007938', (127, 135))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('rat', 'Species', '10116', (43, 46))	('enhance', 'PosReg', (87, 94))	('As2O3', 'Var', (53, 58))	('As2O3', 'Chemical', 'MESH:D000077237', (53, 58))	('human', 'Species', '9606', (121, 126))	('drug-induced apoptosis', 'CPA', (95, 117))
934187	28567017	Antibodies for beta-actin, cleaved caspase-3, cleaved caspase-9, cleaved caspase-8, beta-actin, Bcl-2, Bax, Bad, and cleaved-poly ADP ribose polymerase (PARP) were purchased from Cell Signal Technology (MA, United States).	('beta-actin', 'Gene', (15, 25))	('caspase-3', 'Gene', (35, 44))	('Bcl-2', 'Gene', (96, 101))	('beta-actin', 'Gene', '728378', (84, 94))	('Bcl-2', 'Gene', '596', (96, 101))	('beta-actin', 'Gene', (84, 94))	('cleaved', 'Var', (65, 72))	('cleaved-poly ADP ribose polymerase', 'Gene', '142', (117, 151))	('Bax', 'Gene', '581', (103, 106))	('caspase-3', 'Gene', '836', (35, 44))	('cleaved-poly ADP ribose polymerase', 'Gene', (117, 151))	('beta-actin', 'Gene', '728378', (15, 25))	('Bax', 'Gene', (103, 106))
934212	28567017	As shown in Figure 1B, in esophageal cancer cell lines, the inhibitory concentration 50% (IC50) values were calculated to be 2.42, 40.76, and 44.88 mug/ml for KYSE-150, KYSE-450, and KYSE-70, respectively.	('KYSE-450', 'Var', (169, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (26, 43))	('rat', 'Species', '10116', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('KYSE-150', 'CellLine', 'CVCL:1348', (159, 167))	('KYSE-150', 'Var', (159, 167))	('esophageal cancer', 'Disease', (26, 43))	('KYSE-70', 'Var', (183, 190))
934216	28567017	In parallel experiments on colon cancer cell lines, HCT116 cell were more sensitive to AZOX with IC50 at 8 mug/ml than SW480 cell (IC50, 45.44 mug/ml) (Figure 1D).	('SW480', 'CellLine', 'CVCL:0546', (119, 124))	('sensitive', 'MPA', (74, 83))	('colon cancer', 'Phenotype', 'HP:0003003', (27, 39))	('IC50', 'Var', (97, 101))	('HCT116', 'CellLine', 'CVCL:0291', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colon cancer', 'Disease', 'MESH:D015179', (27, 39))	('AZOX', 'Chemical', 'MESH:C087670', (87, 91))	('colon cancer', 'Disease', (27, 39))
934230	28567017	As shown in Figure 4A, the cleavage of caspase-3 and caspase-9, showed time-dependent and dose-dependent increases, indicating that AZOX induced KYSE-150 cell apoptosis via activating the caspase-3 and caspase-9.	('KYSE-150', 'CellLine', 'CVCL:1348', (145, 153))	('caspase-3', 'Gene', '836', (188, 197))	('caspase-9', 'Enzyme', (202, 211))	('caspase-3', 'Gene', (39, 48))	('caspase-9', 'Gene', (53, 62))	('cleavage', 'MPA', (27, 35))	('caspase-3', 'Gene', (188, 197))	('AZOX', 'Chemical', 'MESH:C087670', (132, 136))	('activating', 'PosReg', (173, 183))	('AZOX', 'Var', (132, 136))	('caspase-3', 'Gene', '836', (39, 48))	('increases', 'PosReg', (105, 114))
934231	28567017	Interestingly, the expression of cleaved caspase-8 was significantly increased by AZOX in KYSE-150 cells (Supplementary Figure 1A).	('caspase-8', 'Protein', (41, 50))	('expression', 'MPA', (19, 29))	('KYSE-150', 'CellLine', 'CVCL:1348', (90, 98))	('increased', 'PosReg', (69, 78))	('AZOX', 'Var', (82, 86))	('cleaved', 'MPA', (33, 40))	('AZOX', 'Chemical', 'MESH:C087670', (82, 86))
934233	28567017	The pro-survival protein Bcl-2 showed slightly decrease by AZOX with a corresponding increased level of Bax (Figure 4A).	('level', 'MPA', (95, 100))	('Bcl-2', 'Gene', (25, 30))	('Bcl-2', 'Gene', '596', (25, 30))	('decrease', 'NegReg', (47, 55))	('AZOX', 'Chemical', 'MESH:C087670', (59, 63))	('Bax', 'Gene', '581', (104, 107))	('AZOX', 'Var', (59, 63))	('increased', 'PosReg', (85, 94))	('Bax', 'Gene', (104, 107))
934262	28567017	Generally, initiator caspases (caspase-8 or caspase-9) activate the downstream effector caspase-3, subsequently cleaving PARP and causing the morphological and biochemical changes in apoptotic cells.	('caspases', 'Gene', (21, 29))	('cleaving', 'Var', (112, 120))	('caspases', 'Gene', '841;12370;842;12371', (21, 29))	('apoptotic cells', 'CPA', (183, 198))	('caspase-3', 'Gene', (88, 97))	('causing', 'Reg', (130, 137))	('caspase-9', 'Gene', (44, 53))	('caspase-3', 'Gene', '836', (88, 97))	('PARP', 'Protein', (121, 125))
934264	28567017	Here in our results, the active caspase-9, caspase-8, caspase-3, and PARP, were remarkably increased by AZOX in KYSE-150 cells, indicating that the apoptosis pathway is one of the anti-cancer mechanisms of AZOX.	('active', 'MPA', (25, 31))	('caspase-3', 'Gene', (54, 63))	('caspase-3', 'Gene', '836', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('AZOX', 'Chemical', 'MESH:C087670', (206, 210))	('caspase-8', 'Enzyme', (43, 52))	('AZOX', 'Chemical', 'MESH:C087670', (104, 108))	('KYSE-150', 'CellLine', 'CVCL:1348', (112, 120))	('AZOX', 'Var', (104, 108))	('PARP', 'Gene', (69, 73))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('increased', 'PosReg', (91, 100))	('cancer', 'Disease', (185, 191))
934268	28567017	The imbalance of Bcl-2/Bax can induce the release of cytochrome c from the mitochondria, which can bind with the Apaf-1 and pro-caspase-9 to form apoptosome.	('Bcl-2', 'Gene', (17, 22))	('Bcl-2', 'Gene', '596', (17, 22))	('Apaf-1', 'Gene', '317', (113, 119))	('induce', 'Reg', (31, 37))	('cytochrome c', 'Gene', (53, 65))	('form', 'Reg', (141, 145))	('Bax', 'Gene', (23, 26))	('cytochrome c', 'Gene', '54205', (53, 65))	('imbalance', 'Var', (4, 13))	('bind', 'Interaction', (99, 103))	('Bax', 'Gene', '581', (23, 26))	('Apaf-1', 'Gene', (113, 119))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
934272	28567017	Meanwhile, the cytosolic level of cytochrome c released from mitochondria was increased by AZOX accompanied with the cleavage of caspase-9 and caspase-3.	('caspase-3', 'Gene', '836', (143, 152))	('AZOX', 'Var', (91, 95))	('caspase-9', 'Protein', (129, 138))	('cytochrome c', 'Gene', '54205', (34, 46))	('AZOX', 'Chemical', 'MESH:C087670', (91, 95))	('increased', 'PosReg', (78, 87))	('cleavage', 'MPA', (117, 125))	('caspase-3', 'Gene', (143, 152))	('cytochrome c', 'Gene', (34, 46))
934629	29930885	Many recent studies have found various single nucleotide polymorphisms (SNPs) in micro RNA (miRNA) sequences in SCC patients compared with controls.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('SCC', 'Gene', '6317', (112, 115))	('patients', 'Species', '9606', (116, 124))	('single nucleotide polymorphisms', 'Var', (39, 70))	('SCC', 'Gene', (112, 115))
934630	29930885	These mutations, under the potential effects of factors like alcohol and tobacco, may lead to an alteration of miRNA expression and contribute to carcinogenesis.	('miRNA', 'Protein', (111, 116))	('contribute', 'Reg', (132, 142))	('carcinogenesis', 'Disease', (146, 160))	('alteration', 'Reg', (97, 107))	('alcohol', 'Chemical', 'MESH:D000438', (61, 68))	('lead to', 'Reg', (86, 93))	('tobacco', 'Species', '4097', (73, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))	('mutations', 'Var', (6, 15))
934631	29930885	Others have reported polymorphic mutations in genes coding for metabolic enzymes, Deoxyribonucleic acid (DNA) repair enzymes and cytokines, which may contribute toward SCC susceptibility.	('SCC', 'Gene', (168, 171))	('SCC', 'Phenotype', 'HP:0002860', (168, 171))	('polymorphic mutations', 'Var', (21, 42))	('SCC', 'Gene', '6317', (168, 171))	('contribute', 'Reg', (150, 160))
934799	29343986	They found that patients with the LCAFRT regime could achieve a better 5-year survival rate (34% vs 15% for patients with conventional fractionation) and LC rate (55% vs 21% for patients with conventional fractionation).	('LCAFRT', 'Var', (34, 40))	('LC rate', 'CPA', (154, 161))	('5-year survival rate', 'CPA', (71, 91))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (108, 116))	('LCAFRT', 'Chemical', '-', (34, 40))
934808	29343986	But the incidence rates of grade 3 and 4 toxicities seemed higher in the LCAHRT+ CT arm (46%) than those in the LCAHRT arm (25%), and the grade 5 toxicities for the two group were 6% and 0%, respectively.	('toxicities', 'Disease', (41, 51))	('toxicities', 'Disease', (146, 156))	('toxicities', 'Disease', 'MESH:D064420', (41, 51))	('LCAHRT+ CT', 'Var', (73, 83))	('higher', 'PosReg', (59, 65))	('toxicities', 'Disease', 'MESH:D064420', (146, 156))
934919	27380936	Additionally, substantially more signals were detected by HPTH59-b than by TRF1 (Supplementary Fig.	('HPTH59-b', 'Chemical', '-', (58, 66))	('HPTH59-b', 'Var', (58, 66))	('more', 'PosReg', (28, 32))	('signals', 'MPA', (33, 40))
934922	27380936	Testis sections containing gonadal tissues, where primordial germ cells (PGCs) are located, were treated with HPTH59-b (red) and anti-DDX4/MVH antibody (green).	('MVH', 'Gene', '13206', (139, 142))	('HPTH59-b', 'Var', (110, 118))	('PGC', 'Gene', '5225', (73, 76))	('PGC', 'Gene', (73, 76))	('MVH', 'Gene', (139, 142))	('DDX4', 'Gene', (134, 138))	('DDX4', 'Gene', '54514', (134, 138))	('HPTH59-b', 'Chemical', '-', (110, 118))
934929	27380936	Indeed, telomere shortening has been observed in carcinoma from bladder, esophageal, gastric, head and neck, ovarian, and renal cells.	('carcinoma', 'Disease', 'MESH:D002277', (49, 58))	('telomere shortening', 'Phenotype', 'HP:0031413', (8, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('observed', 'Reg', (37, 45))	('carcinoma', 'Disease', (49, 58))	('telomere shortening', 'Var', (8, 27))	('esophageal', 'Disease', (73, 83))	('gastric', 'Disease', (85, 92))
934939	27380936	S2, HPTH59-b generated more telomere signals with lower background noise than did immunostaining with a TRF1 antibody, whereas with cultured cells, HPTH59-b showed a staining efficiency comparable to that of a TRF1 antibody.	('HPTH59-b', 'Var', (4, 12))	('HPTH59-b', 'Chemical', '-', (148, 156))	('more', 'PosReg', (23, 27))	('telomere signals', 'MPA', (28, 44))	('HPTH59-b', 'Chemical', '-', (4, 12))
935055	22609385	Furthermore, considerable in-vitro and ex-vivo data suggest that bile salts are equally caustic to the esophageal epithelium and are by themselves sufficient to cause BE and BE related cancer.	('cause', 'Reg', (161, 166))	('bile salts', 'Chemical', 'MESH:D001647', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('bile', 'Var', (65, 69))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
935125	21490835	The extensive polymorphism on the endoscopic findings characterizing EE was classified in a recent work according to a manometric and histopathological relationship: Alterations in the esophageal calibre can be related with motor disturbances affecting the two distal thirds of the organ, while varying degrees of intensity in histological damage induced by activation and degranulation of eosinophilic leukocytes lead to different endoscopic patterns, which could be classified in 4 well-defined categories: granular, corrugated, undulated and exudative.	('exudative', 'Disease', (545, 554))	('lead to', 'Reg', (414, 421))	('related', 'Reg', (211, 218))	('motor disturbances', 'Disease', (224, 242))	('granular', 'Disease', (509, 517))	('EE', 'Phenotype', 'HP:0410151', (69, 71))	('undulated', 'Disease', (531, 540))	('motor disturbances', 'Disease', 'MESH:D019957', (224, 242))	('corrugated', 'Disease', (519, 529))	('endoscopic', 'Disease', (432, 442))	('Alterations', 'Var', (166, 177))
935190	32252506	The resulting model had an accuracy of 0.97, 0.97, and 0.98 for polyps <=5 mm, 6-9 mm, and >=10 mm, respectively, and processed 100 fps, capable of being run during live colonoscopy.	('polyps', 'Disease', (64, 70))	('polyps', 'Disease', 'MESH:D011127', (64, 70))	('<=5 mm', 'Var', (71, 77))
935203	32252506	AI models in IBD scoring lead to the possibility of CNNs increasing interobserver agreement in IBD disease scores without additional physicians or more complicated scoring systems.	('increasing', 'PosReg', (57, 67))	('IBD disease', 'Disease', 'MESH:D015212', (95, 106))	('IBD', 'Disease', 'MESH:D015212', (13, 16))	('CNNs', 'Chemical', '-', (52, 56))	('CNNs', 'Var', (52, 56))	('IBD', 'Phenotype', 'HP:0002037', (95, 98))	('IBD', 'Phenotype', 'HP:0002037', (13, 16))	('IBD', 'Disease', (95, 98))	('IBD disease', 'Disease', (95, 106))	('IBD', 'Disease', 'MESH:D015212', (95, 98))	('IBD', 'Disease', (13, 16))
935274	29736175	Its dysregulation is associated with insulin resistance, diabetes, and carcinogenesis and may potentially be a powerful biomarker and candidate target for relevant diseases.	('insulin resistance', 'Phenotype', 'HP:0000855', (37, 55))	('insulin', 'Gene', (37, 44))	('dysregulation', 'Var', (4, 17))	('associated', 'Reg', (21, 31))	('carcinogenesis', 'Disease', (71, 85))	('insulin', 'Gene', '3630', (37, 44))	('diabetes', 'Disease', (57, 65))	('diabetes', 'Disease', 'MESH:D003920', (57, 65))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
935283	29736175	Recent genome-wide studies suggest IGF2BP2 as a susceptibility gene for human type 2 diabetes mellitus (T2DM), and a single nucleotide polymorphism (SNP, rs4402960) in the second intron is associated with T2DM.	('diabetes mellitus', 'Disease', 'MESH:D003920', (85, 102))	('T2DM', 'Disease', (205, 209))	('rs4402960', 'Var', (154, 163))	('associated', 'Reg', (189, 199))	('human', 'Species', '9606', (72, 77))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (78, 93))	('diabetes mellitus', 'Disease', (85, 102))	('IGF2BP2', 'Gene', (35, 42))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (85, 102))	('rs4402960', 'Mutation', 'rs4402960', (154, 163))
935289	29736175	Furthermore, studies from independent laboratories suggest that IGF2BP2 participates in the maintenance of cancer stem cells (CSCs), implicating that IGF2BP2 may be important for the chemoresistance and recurrence of the diseases.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('IGF2BP2', 'Var', (150, 157))
935297	29736175	Homologs of human IGF2BP2 have been identified as IGF2BP2a and IGF2BP2b in Danio rerio.	('IGF2BP2a', 'Gene', (50, 58))	('IGF2BP2b', 'Var', (63, 71))	('human', 'Species', '9606', (12, 17))	('Danio rerio', 'Species', '7955', (75, 86))	('IGF2BP2', 'Gene', (18, 25))
935306	29736175	Tandem repeats of RRMs and KHs in IGF2BPs are pivotal for their affinity, specificity, and versatility in RNA binding.	('KHs', 'Gene', (27, 30))	('affinity', 'Interaction', (64, 72))	('IGF2', 'Gene', '3481', (34, 38))	('Tandem repeats', 'Var', (0, 14))	('IGF2', 'Gene', (34, 38))	('RNA binding', 'Interaction', (106, 117))
935310	29736175	For instance, the linker between RRM2 and KH1 domains of IGF2BP2 can be activated by mTOR and promotes its binding to IGF2 mRNA.	('IGF2', 'Gene', '3481', (118, 122))	('mTOR', 'Gene', (85, 89))	('IGF2', 'Gene', '3481', (57, 61))	('linker', 'Var', (18, 24))	('KH1', 'Gene', (42, 45))	('IGF2', 'Gene', (118, 122))	('IGF2', 'Gene', (57, 61))	('RRM2', 'Gene', (33, 37))	('binding', 'Interaction', (107, 114))	('mTOR', 'Gene', '2475', (85, 89))	('RRM2', 'Gene', '6241', (33, 37))	('promotes', 'PosReg', (94, 102))	('KH1', 'Gene', '3754', (42, 45))
935316	29736175	IGF2BP2 deletion in mice alters the translation of 15 IGF2BP2 target mRNAs, including 13 transcripts encoding mitochondrial components such as UCP1.	('translation', 'MPA', (36, 47))	('IGF2BP2', 'Gene', (54, 61))	('mice', 'Species', '10090', (20, 24))	('IGF2BP2', 'Gene', (0, 7))	('alters', 'Reg', (25, 31))	('deletion', 'Var', (8, 16))
935328	29736175	A similar function of IGF2BP2 in stemness maintenance may also exist under pathological conditions; deletion of IGF2BP2 gene in glioblastoma stem cells impairs their clonogenecity.	('IGF2BP2', 'Gene', (112, 119))	('clonogenecity', 'CPA', (166, 179))	('glioblastoma', 'Disease', (128, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('deletion', 'Var', (100, 108))	('impairs', 'NegReg', (152, 159))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))
935332	29736175	Later isolation of mRNAs comigrating with polysomes obtained from the brown fat of mice with IGF2BP2 deletion identified 13 transcripts encoding mitochondrial components.	('deletion', 'Var', (101, 109))	('IGF2BP2', 'Gene', (93, 100))	('mice', 'Species', '10090', (83, 87))
935334	29736175	Significance of IGF2BP2 in metabolism has been confirmed by the phenotypic features demonstrated by mice with IGF2BP2 deletion.	('mice', 'Species', '10090', (100, 104))	('deletion', 'Var', (118, 126))	('IGF2BP2', 'Gene', (110, 117))
935352	29736175	In a recent study, a photocatalytic activity-enhanced deoxyribose nucleotide cross-linking and immunoprecipitation (PAR-CLIP) assay demonstrated that IGF2BP2 bound to Let-7 miRNA recognition elements and suppressed the Let-7-mediated gene silencing independent of LIN28 proteins (Figure 4), which are encoded by Let-7 target mRNAs, but inhibit the maturation of Let-7.	('bound', 'Interaction', (158, 163))	('Let-7-mediated gene silencing', 'MPA', (219, 248))	('deoxyribose nucleotide', 'Chemical', '-', (54, 76))	('maturation', 'MPA', (348, 358))	('LIN28', 'Gene', (264, 269))	('IGF2BP2', 'Var', (150, 157))	('LIN28', 'Gene', '79727', (264, 269))	('Let-7', 'Gene', (167, 172))	('inhibit', 'NegReg', (336, 343))	('suppressed', 'NegReg', (204, 214))
935354	29736175	Aberrant alterations in the expression of these genes are associated with cancer and diabetic nephropathy.	('diabetic nephropathy', 'Disease', 'MESH:D003928', (85, 105))	('associated', 'Reg', (58, 68))	('diabetic nephropathy', 'Disease', (85, 105))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('expression', 'MPA', (28, 38))	('cancer', 'Disease', (74, 80))	('nephropathy', 'Phenotype', 'HP:0000112', (94, 105))	('Aberrant alterations in', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
935359	29736175	Disruption of IGF2BP2 function, unsurprisingly, results in a variety of diseases and disorders such as diabetes and cancer (Table 2).	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('diabetes', 'Disease', (103, 111))	('diabetes', 'Disease', 'MESH:D003920', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('results in', 'Reg', (48, 58))	('diseases and disorders', 'Disease', 'MESH:D004194', (72, 94))	('IGF2BP2', 'Gene', (14, 21))	('Disruption', 'Var', (0, 10))
935363	29736175	Livers of mice overexpressing the IGF2BP2 splice variant p62 highly expressed the stem cell marker DLK1 and secreted DLK1 into the blood; DLK1was previously shown to correspond with poor survival in HCC.	('p62', 'Var', (57, 60))	('DLK1', 'Gene', (99, 103))	('mice', 'Species', '10090', (10, 14))	('DLK1', 'Gene', '13386', (99, 103))	('secreted', 'MPA', (108, 116))	('DLK1', 'Gene', '13386', (138, 142))	('DLK1', 'Gene', '13386', (117, 121))	('DLK1', 'Gene', (138, 142))	('DLK1', 'Gene', (117, 121))	('HCC', 'Phenotype', 'HP:0001402', (199, 202))	('poor', 'NegReg', (182, 186))	('IGF2BP2', 'Gene', (34, 41))
935367	29736175	More convincingly, mice with liver-specific overexpression of IGF2BP2 show more fat deposition and an earlier and more intense fibrogenesis than their wild-type littermates when they are fed a methionine-choline-deficient (MCD) diet, suggesting a driving role of IGF2BP2 in the pathogenesis of NAFLD.	('fibrogenesis', 'CPA', (127, 139))	('methionine', 'Chemical', 'MESH:D008715', (193, 203))	('MCD', 'Disease', 'MESH:D012514', (223, 226))	('more', 'PosReg', (75, 79))	('overexpression', 'PosReg', (44, 58))	('MCD', 'Disease', (223, 226))	('IGF2BP2', 'Var', (62, 69))	('choline', 'Chemical', 'MESH:D002794', (204, 211))	('fat', 'CPA', (80, 83))	('mice', 'Species', '10090', (19, 23))
935370	29736175	The increase of CTGF could be induced by interleukin-13 (IL-13) which is upregulated in IGF2BP2 transgenic mice.	('transgenic', 'Var', (96, 106))	('interleukin-13', 'Gene', '16163', (41, 55))	('interleukin-13', 'Gene', (41, 55))	('IGF2BP2', 'Gene', (88, 95))	('transgenic mice', 'Species', '10090', (96, 111))	('CTGF', 'Gene', (16, 20))	('upregulated', 'PosReg', (73, 84))	('IL-13', 'Gene', (57, 62))	('increase', 'PosReg', (4, 12))	('CTGF', 'Gene', '14219', (16, 20))
935371	29736175	Highlighting the importance of this IGF2BP2-IL13-CTGF axis in pathology, blockade of the IL-13 receptor in a mouse nonalcoholic steatohepatitis (NASH) model reduced fibrosis.	('CTGF', 'Gene', (49, 53))	('fibrosis', 'Disease', 'MESH:D005355', (165, 173))	('fibrosis', 'Disease', (165, 173))	('mouse', 'Species', '10090', (109, 114))	('steatohepatitis', 'Disease', (128, 143))	('CTGF', 'Gene', '14219', (49, 53))	('steatohepatitis', 'Disease', 'MESH:D005234', (128, 143))	('IL13', 'Gene', '16163', (44, 48))	('blockade', 'Var', (73, 81))	('hepatitis', 'Phenotype', 'HP:0012115', (134, 143))	('IL13', 'Gene', (44, 48))	('reduced', 'NegReg', (157, 164))
935373	29736175	In addition, IGF2BP2 may also modulate levels of tumor suppressor phosphatase and tensin homolog, affect activities of extracellular-signal regulated kinases, and contribute to the progression from NAFLD to HCC.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('contribute to', 'Reg', (163, 176))	('HCC', 'Disease', (207, 210))	('levels of', 'MPA', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('HCC', 'Phenotype', 'HP:0001402', (207, 210))	('tumor', 'Disease', (49, 54))	('IGF2BP2', 'Var', (13, 20))	('modulate', 'Reg', (30, 38))	('activities', 'MPA', (105, 115))	('affect', 'Reg', (98, 104))	('extracellular-signal regulated kinases', 'Pathway', (119, 157))	('NAFLD', 'Disease', (198, 203))
935376	29736175	Silencing IGF2BP2 reduces the oxygen consumption rate of gliomaspheres and the activities of complexes I and IV and inhibits the clonogenicity in vitro and tumorigenicity in mice.	('activities', 'MPA', (79, 89))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('reduces', 'NegReg', (18, 25))	('oxygen consumption', 'MPA', (30, 48))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('IGF2BP2', 'Gene', (10, 17))	('Silencing', 'Var', (0, 9))	('inhibits', 'NegReg', (116, 124))	('oxygen', 'Chemical', 'MESH:D010100', (30, 36))
935378	29736175	Downregulating IGF2BP2 sensitizes cells to chemotherapy, likely through the inhibition of the PI3K/Akt signaling cascade, which is thought to be responsible for chemoresistance in many malignancies.	('inhibition', 'NegReg', (76, 86))	('Akt', 'Gene', '207', (99, 102))	('IGF2BP2', 'Gene', (15, 22))	('malignancies', 'Disease', 'MESH:D009369', (185, 197))	('sensitizes', 'Reg', (23, 33))	('malignancies', 'Disease', (185, 197))	('Downregulating', 'Var', (0, 14))	('Akt', 'Gene', (99, 102))
935385	29736175	The data indicate a gradual increase in the number of patients with an IGF2BP2 autoimmune response with cancer progression, indicating that IGF2BP2 may be associated with colon cancer transformation.	('cancer', 'Disease', (177, 183))	('IGF2BP2', 'Gene', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (171, 183))	('patients', 'Species', '9606', (54, 62))	('autoimmune response', 'Phenotype', 'HP:0002960', (79, 98))	('colon cancer', 'Disease', 'MESH:D015179', (171, 183))	('associated with', 'Reg', (155, 170))	('colon cancer', 'Disease', (171, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('IGF2BP2', 'Var', (140, 147))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
935391	29736175	At the molecular level, IGF2BP2 protects RAF1 mRNA from the miR-195-mediated degradation.	('RAF1', 'Gene', (41, 45))	('RAF1', 'Gene', '5894', (41, 45))	('IGF2BP2', 'Var', (24, 31))	('miR-195', 'Gene', (60, 67))	('miR-195', 'Gene', '406971', (60, 67))
935404	29736175	Alterations in the IGF2BP2 gene may have potential prognostic value in gastrointestinal cancer.	('gastrointestinal cancer', 'Disease', (71, 94))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (71, 94))	('Alterations', 'Var', (0, 11))	('IGF2BP2', 'Gene', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (71, 94))
935405	29736175	In gastric cancer patients treated by first-line combinational therapy with epirubicin, oxaliplatin, and 5-fluorouracil, IGF2BP2 polymorphisms rs4402960 and rs6769511 are less common in patients with disease progression than in those with controlled disease.	('epirubicin', 'Chemical', 'MESH:D015251', (76, 86))	('common', 'Reg', (176, 182))	('IGF2BP2', 'Gene', (121, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('patients', 'Species', '9606', (186, 194))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (105, 119))	('rs6769511', 'Mutation', 'rs6769511', (157, 166))	('gastric cancer', 'Disease', (3, 17))	('rs4402960', 'Var', (143, 152))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (88, 99))	('patients', 'Species', '9606', (18, 26))	('rs6769511', 'Var', (157, 166))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('rs4402960', 'Mutation', 'rs4402960', (143, 152))
935406	29736175	Whether these nucleotide changes improve the response of gastric cancer patients to chemotherapies remains to be confirmed in future studies.	('improve', 'PosReg', (33, 40))	('gastric cancer', 'Disease', (57, 71))	('nucleotide', 'Var', (14, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('response', 'MPA', (45, 53))	('patients', 'Species', '9606', (72, 80))
935408	29736175	Immunohistochemical analysis for the recommended markers, such as p53, Ki67, and p16, can be of limited help in some difficult cases, suggesting that more definitive markers are needed.	('Ki67', 'Var', (71, 75))	('p53', 'Gene', '7157', (66, 69))	('p16', 'Gene', '1029', (81, 84))	('p16', 'Gene', (81, 84))	('p53', 'Gene', (66, 69))
935421	29736175	In a small cohort of patients with testicular tumors originating from germ cells (30 cases) and somatic cells (3 cases), immunoreactivities of IGF2BP1, IGF2BP2, and IGF2BP3 were frequently observed but with different patterns.	('testicular tumors', 'Phenotype', 'HP:0010788', (35, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('IGF2BP2', 'Var', (152, 159))	('IGF2BP1', 'Gene', (143, 150))	('patients', 'Species', '9606', (21, 29))	('IGF2BP3', 'Var', (165, 172))	('testicular tumors', 'Disease', (35, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('testicular tumors', 'Disease', 'MESH:D013736', (35, 52))
935427	29736175	IGF2BP1 promotes the enrichment and survival of a population of CD24+CD44+ tumor-initiating cells in colorectal cancer.	('CD24+CD44+', 'Var', (64, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('enrichment', 'CPA', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('IGF2BP1', 'Gene', (0, 7))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('promotes', 'PosReg', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('survival', 'CPA', (36, 44))	('tumor', 'Disease', (75, 80))
935431	29736175	The short isoform of IGF2BP2, p62, is overexpressed in HCC with stem-like features and hypervascularization, and the livers of p62 transgenic mice highly express the stem cell marker DLK1 and generate tumors with more aggressive and stem-like phenotype.	('p62', 'Var', (127, 130))	('generate', 'PosReg', (192, 200))	('DLK1', 'Gene', '13386', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('IGF2BP2', 'Gene', (21, 28))	('DLK1', 'Gene', (183, 187))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('highly', 'PosReg', (147, 153))	('HCC', 'Phenotype', 'HP:0001402', (55, 58))	('transgenic mice', 'Species', '10090', (131, 146))
935438	29736175	Hyperglycemia, hyperinsulinemia, and dysregulation of IGFs and adipokines are among the major mechanisms that facilitate tumorigenesis and cancer progression.	('hyperinsulinemia', 'Disease', (15, 31))	('Hyperglycemia', 'Disease', 'MESH:D006943', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('dysregulation', 'Var', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Hyperglycemia', 'Disease', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('facilitate', 'PosReg', (110, 120))	('tumor', 'Disease', (121, 126))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (15, 31))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('Hyperglycemia', 'Phenotype', 'HP:0003074', (0, 13))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (15, 31))	('IGFs', 'Protein', (54, 58))	('cancer', 'Disease', (139, 145))
935442	29736175	Elevated IGF2 predisposes patients to diabetes and is believed to be involved in the association between diabetes and increased breast cancer incidence in African-American women.	('IGF2', 'Gene', '3481', (9, 13))	('diabetes', 'Disease', 'MESH:D003920', (105, 113))	('diabetes', 'Disease', (38, 46))	('diabetes', 'Disease', 'MESH:D003920', (38, 46))	('Elevated IGF2', 'Phenotype', 'HP:0030269', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('patients', 'Species', '9606', (26, 34))	('IGF2', 'Gene', (9, 13))	('diabetes', 'Disease', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('predisposes', 'Reg', (14, 25))	('women', 'Species', '9606', (172, 177))	('Elevated', 'Var', (0, 8))
935446	29736175	The IGF2BP2 rs4402960 polymorphism, which conveys an increased risk of type 2 diabetes, also increases the risks of colon and breast cancer according to the results from independent studies.	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (71, 86))	('colon and breast cancer', 'Disease', 'MESH:D001943', (116, 139))	('increases', 'PosReg', (93, 102))	('rs4402960', 'Mutation', 'rs4402960', (12, 21))	('IGF2BP2', 'Gene', (4, 11))	('diabetes', 'Disease', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('rs4402960', 'Var', (12, 21))	('diabetes', 'Disease', 'MESH:D003920', (78, 86))
935448	29736175	In gastric cancer, IGF2BP2 rs4402960 and rs6769511 are more often detected in patients responsive to a combinational chemotherapy of epirubicin, oxaliplatin, and 5-fluorouracil.	('epirubicin', 'Chemical', 'MESH:D015251', (133, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('rs6769511', 'Var', (41, 50))	('rs4402960', 'Mutation', 'rs4402960', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('detected', 'Reg', (66, 74))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (145, 156))	('IGF2BP2', 'Gene', (19, 26))	('patients', 'Species', '9606', (78, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('rs4402960', 'Var', (27, 36))	('gastric cancer', 'Disease', (3, 17))	('rs6769511', 'Mutation', 'rs6769511', (41, 50))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (162, 176))
935449	29736175	These findings highlight the importance of these polymorphisms of IGF2BP2 in diabetes and cancer development; however, how the genetic variations affect the expression of IGF2BP2 and IGF2 is uncertain, and their functional consequences in diabetes and cancer progression require further characterization.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IGF2', 'Gene', (171, 175))	('diabetes', 'Disease', (239, 247))	('diabetes', 'Disease', 'MESH:D003920', (77, 85))	('variations', 'Var', (135, 145))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('IGF2', 'Gene', (183, 187))	('IGF2', 'Gene', (66, 70))	('cancer', 'Disease', (252, 258))	('affect', 'Reg', (146, 152))	('IGF2', 'Gene', '3481', (171, 175))	('IGF2', 'Gene', '3481', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('diabetes', 'Disease', 'MESH:D003920', (239, 247))	('diabetes', 'Disease', (77, 85))	('expression', 'MPA', (157, 167))	('IGF2', 'Gene', '3481', (66, 70))	('cancer', 'Disease', (90, 96))
935462	29736175	Its amplification and overexpression in many cancers correlate with cancer progression and predict poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('overexpression', 'PosReg', (22, 36))	('cancers', 'Disease', (45, 52))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('amplification', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancer', 'Disease', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancer', 'Disease', (45, 51))
935464	29736175	In addition, IGF2BP2 exhibits counteracting roles against tumor suppressor Let-7 miRNA by preventing the Let-7-mediated RNA degradation.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('preventing', 'NegReg', (90, 100))	('IGF2BP2', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Let-7-mediated RNA degradation', 'MPA', (105, 135))
935469	29736175	In one aspect, IGF2BP2 functions in insulin-induced signaling and metabolism, and depletion of IGF2BP2 in mice leads to glucose tolerance, insulin sensitivity, increased energy expenditure, slower body growth, and resistance to diet-induced obesity and fatty liver.	('energy expenditure', 'CPA', (170, 188))	('IGF2BP2', 'Gene', (15, 22))	('insulin', 'Gene', '3630', (139, 146))	('fatty liver', 'Disease', 'MESH:D005234', (253, 264))	('obesity', 'Disease', (241, 248))	('glucose tolerance', 'Disease', 'MESH:D018149', (120, 137))	('insulin', 'Gene', (36, 43))	('depletion', 'Var', (82, 91))	('leads to', 'Reg', (111, 119))	('fatty liver', 'Disease', (253, 264))	('obesity', 'Disease', 'MESH:D009765', (241, 248))	('diet-induced obesity', 'Phenotype', 'HP:0012743', (228, 248))	('resistance', 'CPA', (214, 224))	('slower body growth', 'CPA', (190, 208))	('increased energy expenditure', 'Phenotype', 'HP:0012339', (160, 188))	('mice', 'Species', '10090', (106, 110))	('insulin', 'Gene', (139, 146))	('increased', 'PosReg', (160, 169))	('glucose tolerance', 'Disease', (120, 137))	('obesity', 'Phenotype', 'HP:0001513', (241, 248))	('insulin', 'Gene', '3630', (36, 43))	('fatty liver', 'Phenotype', 'HP:0001397', (253, 264))	('IGF2BP2', 'Gene', (95, 102))
935470	29736175	It will be important to characterize whether mice with IGF2BP2 deletion are more resistant to spontaneous tumorigenesis.	('IGF2BP2', 'Gene', (55, 62))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('deletion', 'Var', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('resistant', 'CPA', (81, 90))	('tumor', 'Disease', (106, 111))
935471	29156846	S100A14 rs11548103 G>A polymorphism is associated with a decreased risk of esophageal cancer in a Chinese population In China in 2009, esophageal cancer was the fifth most commonly diagnosed malignancy and the fourth leading cause of malignancy-related death.	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('malignancy', 'Disease', 'MESH:D009369', (234, 244))	('malignancy', 'Disease', (234, 244))	('malignancy', 'Disease', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('esophageal cancer', 'Disease', (135, 152))	('S100A14', 'Gene', (0, 7))	('rs11548103', 'Mutation', 'rs11548103', (8, 18))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('malignancy', 'Disease', 'MESH:D009369', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('esophageal cancer', 'Disease', (75, 92))	('decreased', 'NegReg', (57, 66))	('rs11548103 G>A', 'Var', (8, 22))	('S100A14', 'Gene', '57402', (0, 7))
935475	29156846	When the S100A14 rs11548103 GG genotype was considered as the reference group, the GA genotype associated with decreased risk of ESCC (GA vs. GG: adjusted OR = 0.73, 95% CI = 0.57-0.93, p = 0.009).	('S100A14', 'Gene', (9, 16))	('rs11548103', 'Var', (17, 27))	('ESCC', 'Disease', (129, 133))	('rs11548103', 'Mutation', 'rs11548103', (17, 27))	('decreased', 'NegReg', (111, 120))	('S100A14', 'Gene', '57402', (9, 16))
935476	29156846	Logistic regression analyses showed that the MLH1 rs1800734 C>T, SMAD7 rs12953717 C>T and CCL22/MDC rs4359426C>A polymorphisms were not associated with the risk of ESCC in any of the models tested.	('rs4359426C>A', 'DBSNP_MENTION', 'None', (100, 112))	('SMAD7', 'Gene', (65, 70))	('rs12953717 C>T', 'Var', (71, 85))	('MDC', 'Gene', '6367', (96, 99))	('MLH1', 'Gene', '4292', (45, 49))	('MLH1', 'Gene', (45, 49))	('ESCC', 'Disease', (164, 168))	('CCL22', 'Gene', '6367', (90, 95))	('rs1800734', 'Mutation', 'rs1800734', (50, 59))	('rs1800734 C>T', 'Var', (50, 63))	('MDC', 'Gene', (96, 99))	('SMAD7', 'Gene', '4092', (65, 70))	('rs4359426C>A', 'Var', (100, 112))	('rs12953717', 'Mutation', 'rs12953717', (71, 81))	('CCL22', 'Gene', (90, 95))
935477	29156846	Our findings indicated that, in a Chinese population, rs11548103 might contribute to a decreased risk of ESCC.	('rs11548103', 'Var', (54, 64))	('ESCC', 'Disease', (105, 109))	('rs11548103', 'Mutation', 'rs11548103', (54, 64))	('decreased', 'NegReg', (87, 96))
935480	29156846	Single nucleotide polymorphisms (SNPs), as individual genetic risk factors, might play a vital role in ESCC carcinogenesis in addition to certain environmental risk factors.	('ESCC', 'Disease', (103, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('carcinogenesis', 'Disease', (108, 122))
935488	29156846	One genetic variant of S100A14 (461G>A, rs11548103) is located in the 5'-untranslated region (UTR) and has been shown to disrupt a p53-binding site.	('461G>A', 'Mutation', 'rs11548103', (32, 38))	('S100A14', 'Gene', (23, 30))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('disrupt', 'NegReg', (121, 128))	('S100A14', 'Gene', '57402', (23, 30))	('461G>A', 'Var', (32, 38))	('rs11548103', 'Var', (40, 50))	('rs11548103', 'Mutation', 'rs11548103', (40, 50))
935490	29156846	Additionally, a previous study reported that rs11548103-A was associated with risk for ESCC.	('ESCC', 'Disease', (87, 91))	('rs11548103-A', 'Var', (45, 57))	('rs11548103', 'Mutation', 'rs11548103', (45, 55))
935493	29156846	The rs1800734 (-93G/A) polymorphism in MLH1 is located in the promoter region, which is responsible for the transcriptional activity of this gene.	('rs1800734', 'Mutation', 'rs1800734', (4, 13))	('MLH1', 'Gene', '4292', (39, 43))	('MLH1', 'Gene', (39, 43))	('-93G/A', 'Mutation', 'rs1800734', (15, 21))	('rs1800734 (-93G/A', 'Var', (4, 21))
935495	29156846	The rs12953717-T allele at SMAD7 has been associated with increased susceptibility to colorectal cancer (CRC) among both Caucasians and Asians.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('CRC', 'Disease', (105, 108))	('rs12953717', 'Mutation', 'rs12953717', (4, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('SMAD7', 'Gene', (27, 32))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('rs12953717-T', 'Var', (4, 16))	('SMAD7', 'Gene', '4092', (27, 32))	('CRC', 'Disease', 'MESH:D015179', (105, 108))
935497	29156846	Rs4359426, a variant of CCL22, has been shown to associate with over-expression of CCL22 mRNA and susceptibility to atopic dermatitis in a gain-of-function manner.	('gain-of-function', 'PosReg', (139, 155))	('susceptibility', 'Reg', (98, 112))	('Rs4359426', 'Var', (0, 9))	('dermatitis', 'Phenotype', 'HP:0011123', (123, 133))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (116, 133))	('atopic dermatitis', 'Disease', 'MESH:D003876', (116, 133))	('CCL22', 'Gene', '6367', (24, 29))	('CCL22', 'Gene', '6367', (83, 88))	('atopic dermatitis', 'Disease', (116, 133))	('over-expression', 'PosReg', (64, 79))	('CCL22', 'Gene', (24, 29))	('mRNA', 'MPA', (89, 93))	('Rs4359426', 'Mutation', 'Rs4359426', (0, 9))	('CCL22', 'Gene', (83, 88))
935498	29156846	Genetic variants in S100A14 (rs11548103G>A), MLH1 (rs1800734 C>T), SMAD7 (rs12953717C>T) and CCL22/MDC (rs4359426C>A) may contribute to the etiology of ESCC.	('rs12953717C>T', 'Var', (74, 87))	('MDC', 'Gene', '6367', (99, 102))	('MLH1', 'Gene', (45, 49))	('S100A14', 'Gene', (20, 27))	('SMAD7', 'Gene', (67, 72))	('MDC', 'Gene', (99, 102))	('contribute', 'Reg', (122, 132))	('MLH1', 'Gene', '4292', (45, 49))	('rs1800734', 'Mutation', 'rs1800734', (51, 60))	('CCL22', 'Gene', (93, 98))	('ESCC', 'Disease', (152, 156))	('rs4359426C>A', 'Var', (104, 116))	('rs11548103G>A', 'Var', (29, 42))	('SMAD7', 'Gene', '4092', (67, 72))	('CCL22', 'Gene', '6367', (93, 98))	('rs12953717C>T', 'DBSNP_MENTION', 'None', (74, 87))	('rs11548103G>A', 'DBSNP_MENTION', 'None', (29, 42))	('S100A14', 'Gene', '57402', (20, 27))	('rs4359426C>A', 'DBSNP_MENTION', 'None', (104, 116))	('rs1800734 C>T', 'Var', (51, 64))
935499	29156846	Table 2 presents information on S100A14 rs11548103G>A, MLH1 rs1800734 C>T, SMAD7 rs12953717 C>T and CCL22/MDC rs4359426 C>A.	('rs11548103G>A', 'DBSNP_MENTION', 'None', (40, 53))	('SMAD7', 'Gene', '4092', (75, 80))	('rs12953717 C>T', 'Var', (81, 95))	('S100A14', 'Gene', '57402', (32, 39))	('MDC', 'Gene', '6367', (106, 109))	('CCL22', 'Gene', '6367', (100, 105))	('rs4359426', 'Mutation', 'rs4359426', (110, 119))	('MLH1', 'Gene', '4292', (55, 59))	('rs1800734', 'Mutation', 'rs1800734', (60, 69))	('MDC', 'Gene', (106, 109))	('rs11548103G>A', 'Var', (40, 53))	('MLH1', 'Gene', (55, 59))	('CCL22', 'Gene', (100, 105))	('rs12953717', 'Mutation', 'rs12953717', (81, 91))	('rs1800734 C>T', 'Var', (60, 73))	('S100A14', 'Gene', (32, 39))	('SMAD7', 'Gene', (75, 80))	('rs4359426 C>A', 'Var', (110, 123))
935500	29156846	As shown in Table 3, the GG, GA and AA allele frequencies of rs11548103 were 51.2, 37.8 and 10.9%, respectively, in the ESCC group and 45.5, 44.3 and 10.2%, respectively, in the healthy control group.	('rs11548103', 'Mutation', 'rs11548103', (61, 71))	('ESCC', 'Disease', (120, 124))	('rs11548103', 'Var', (61, 71))
935501	29156846	Logistic regression analyses indicated that rs1800734, rs12953717 and rs4359426 were not associated with the risk of ESCC in any of the models (Table 3).	('rs12953717', 'Var', (55, 65))	('rs1800734', 'Mutation', 'rs1800734', (44, 53))	('rs4359426', 'Mutation', 'rs4359426', (70, 79))	('rs12953717', 'Mutation', 'rs12953717', (55, 65))	('ESCC', 'Disease', (117, 121))	('rs4359426', 'Var', (70, 79))	('rs1800734', 'Var', (44, 53))
935502	29156846	To evaluate the effects of rs11548103 on ESCC risk according to different age groups, sex, tobacco consumption and drinking status, we performed stratification analyses.	('ESCC', 'Disease', (41, 45))	('rs11548103', 'Var', (27, 37))	('tobacco', 'Species', '4097', (91, 98))	('rs11548103', 'Mutation', 'rs11548103', (27, 37))
935503	29156846	A significantly decreased risk of ESCC associated with rs11548103 was evident among younger patients (GA vs. GG: adjusted OR = 0.69, 95% CI = 0.49-0.98, p = 0.038), male patients (GA/AA vs. GG: adjusted OR = 0.70, 95% CI = 0.53-0.92, p = 0.012) and patients who never drink (GA/AA vs. GG: adjusted OR = 0.72, 95% CI = 0.55-0.94, p = 0.017) or smoke (GA/AA vs. GG: adjusted OR = 0.72, 95% CI = 0.54-0.96, p = 0.025) (Table 4).	('patients', 'Species', '9606', (170, 178))	('rs11548103', 'Var', (55, 65))	('patients', 'Species', '9606', (249, 257))	('rs11548103', 'Mutation', 'rs11548103', (55, 65))	('patients', 'Species', '9606', (92, 100))	('ESCC', 'Disease', (34, 38))	('decreased', 'NegReg', (16, 25))
935504	29156846	In the present hospital-based case-control study of ESCC, we identified that rs11548103 was associated with decreased risk of ESCC.	('decreased', 'NegReg', (108, 117))	('rs11548103', 'Var', (77, 87))	('ESCC', 'Disease', (126, 130))	('rs11548103', 'Mutation', 'rs11548103', (77, 87))
935512	29156846	In a previous study, rs11548103was demonstrated to diminish a p53-binding site and was correlated with decreased expression of S100A14 both in vitro and in vivo in target tissues.	('expression', 'MPA', (113, 123))	('S100A14', 'Gene', '57402', (127, 134))	('S100A14', 'Gene', (127, 134))	('rs11548103', 'Mutation', 'rs11548103', (21, 31))	('decreased', 'NegReg', (103, 112))	('rs11548103was', 'Var', (21, 34))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('diminish', 'NegReg', (51, 59))
935513	29156846	Furthermore, a case-control analysis showed that the S100A14 rs11548103-A allele was associated with susceptibility to ESCC among smokers.	('ESCC', 'Disease', (119, 123))	('S100A14', 'Gene', '57402', (53, 60))	('rs11548103-A', 'Var', (61, 73))	('rs11548103', 'Mutation', 'rs11548103', (61, 71))	('susceptibility', 'Reg', (101, 115))	('S100A14', 'Gene', (53, 60))
935519	29156846	Fourth, we did not obtain detailed cancer metastasis and survival information, which further restricted the analysis of S100A14 rs11548103 G>A polymorphism in ESCC progression and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer metastasis', 'Disease', (35, 52))	('S100A14', 'Gene', (120, 127))	('rs11548103', 'Mutation', 'rs11548103', (128, 138))	('cancer metastasis', 'Disease', 'MESH:D009362', (35, 52))	('S100A14', 'Gene', '57402', (120, 127))	('rs11548103 G>A', 'Var', (128, 142))	('ESCC', 'Disease', (159, 163))
935520	29156846	In conclusion, our study found that rs11548103 may decrease the risk of ESCC.	('rs11548103', 'Mutation', 'rs11548103', (36, 46))	('decrease', 'NegReg', (51, 59))	('ESCC', 'Disease', (72, 76))	('rs11548103', 'Var', (36, 46))
935528	29156846	Using chi2 statistical tests, we tested whether there were differences between cases and controls in the distributions of demographic characteristics (age and sex), selected variables (smoking and alcohol consumption), and the rs11548103, rs1800734, rs12953717 and rs4359426 genotypes.	('tested', 'Reg', (33, 39))	('rs11548103', 'Var', (227, 237))	('rs4359426', 'Mutation', 'rs4359426', (265, 274))	('rs11548103', 'Mutation', 'rs11548103', (227, 237))	('rs1800734', 'Var', (239, 248))	('rs12953717', 'Var', (250, 260))	('rs4359426', 'Var', (265, 274))	('rs1800734', 'Mutation', 'rs1800734', (239, 248))	('alcohol', 'Chemical', 'MESH:D000438', (197, 204))	('rs12953717', 'Mutation', 'rs12953717', (250, 260))
935530	29156846	LD linkage disequilibrium OR odds ratio CI confidential interval SNPs single nucleotide polymorphisms ESCC esophageal squamous cell carcinoma	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('single nucleotide polymorphisms', 'Var', (70, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))
935537	28640252	Moreover, loss-of-function assays in ESCC cells showed that knockdown of lnc-ATB inhibited cell proliferation and migration both in vitro and in vivo.	('lnc-ATB', 'Gene', (73, 80))	('loss-of-function', 'NegReg', (10, 26))	('inhibited', 'NegReg', (81, 90))	('knockdown', 'Var', (60, 69))	('lnc-ATB', 'Chemical', '-', (73, 80))
935553	28640252	Dysregulation of lnc-ATB have been reported in human tumors including gastric, colorectal, brain, pancreatic and renal cancer.	('reported', 'Reg', (35, 43))	('gastric', 'Disease', (70, 77))	('Dysregulation', 'Var', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('colorectal', 'Disease', 'MESH:D015179', (79, 89))	('brain', 'Disease', (91, 96))	('pancreatic and renal cancer', 'Disease', 'MESH:D007680', (98, 125))	('lnc-ATB', 'Chemical', '-', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('colorectal', 'Disease', (79, 89))	('human', 'Species', '9606', (47, 52))	('lnc-ATB', 'Gene', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (53, 59))	('renal cancer', 'Phenotype', 'HP:0009726', (113, 125))
935557	28640252	Furthermore, expression of Lnc-ATB was also determined in a panel ESCC cancer cell lines (KYSE30, Eca109, Eca9706, KYSE510, KYSE520, KYSE410, KYSE140 and KYSE150) and one immortalized normal epithelial cells (NE1).	('Eca9706', 'CellLine', 'CVCL:E307', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('KYSE410', 'Var', (133, 140))	('Lnc-ATB', 'Gene', (27, 34))	('KYSE520', 'Var', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
935567	28640252	To explore the functional relevance of dysregulated lnc-ATB in ESCC, KYSE30 and Eca109 cells were selected for further analysis.	('lnc-ATB', 'Chemical', '-', (52, 59))	('lnc-ATB', 'Gene', (52, 59))	('dysregulated', 'Var', (39, 51))	('ESCC', 'Disease', (63, 67))
935570	28640252	CCK-8 assays revealed that knockdown of lnc-ATB significantly decreased cell viability of ESCC cell lines (KYSE30 and Eca109) (Figure 2b).	('knockdown', 'Var', (27, 36))	('decreased', 'NegReg', (62, 71))	('cell viability', 'CPA', (72, 86))	('lnc-ATB', 'Gene', (40, 47))	('ESCC', 'Disease', (90, 94))	('lnc-ATB', 'Chemical', '-', (40, 47))
935571	28640252	On the other hand, KYSE30 and Eca109 cells with relative high lnc-ATB expression showed faster proliferation rate than that of KYSE140 and KYSE410 cells with low lnc-ATB expression (Supplementary Figure 2A).	('high', 'Var', (57, 61))	('lnc-ATB', 'Chemical', '-', (62, 69))	('faster', 'PosReg', (88, 94))	('lnc-ATB', 'Chemical', '-', (162, 169))	('expression', 'Var', (70, 80))	('lnc-ATB', 'Gene', (62, 69))
935572	28640252	Moreover, knockdown of lnc-ATB significantly suppressed formation of colonies compared with sh-control group in KYSE30 and Eca109 cells (Figure 2c).	('lnc-ATB', 'Chemical', '-', (23, 30))	('lnc-ATB', 'Gene', (23, 30))	('suppressed', 'NegReg', (45, 55))	('knockdown', 'Var', (10, 19))	('formation of colonies', 'CPA', (56, 77))
935573	28640252	We then investigated whether the anti-proliferation roles of lnc-ATB knockdown was associated with cell cycle arrest or increased apoptosis.	('lnc-ATB', 'Chemical', '-', (61, 68))	('apoptosis', 'CPA', (130, 139))	('arrest', 'Disease', 'MESH:D006323', (110, 116))	('anti-proliferation', 'CPA', (33, 51))	('arrest', 'Disease', (110, 116))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (99, 116))	('lnc-ATB', 'Gene', (61, 68))	('knockdown', 'Var', (69, 78))
935574	28640252	As shown in Figure 2d and Supplementary Figure 2B, knockdown of lnc-ATB significantly induced G2/M phase arrest and apoptosis in KYSE30 and Eca109 cells.	('apoptosis', 'CPA', (116, 125))	('lnc-ATB', 'Chemical', '-', (64, 71))	('arrest', 'Disease', 'MESH:D006323', (105, 111))	('lnc-ATB', 'Gene', (64, 71))	('induced', 'Reg', (86, 93))	('arrest', 'Disease', (105, 111))	('knockdown', 'Var', (51, 60))
935578	28640252	Western blot analysis revealed that knockdown of lnc-ATB led to elevated expression of the epithelial markers including E-cadherin and beta-catenin and decreased expression of the mesenchymal marker N-cadherin (Figures 3b and c), indicating that EMT may be associated with the pro-metastasis effects of lnc-ATB in ESCC.	('ESCC', 'Disease', (314, 318))	('elevated', 'PosReg', (64, 72))	('N-cadherin', 'Gene', (199, 209))	('beta-catenin', 'Gene', (135, 147))	('E-cadherin', 'Gene', (120, 130))	('knockdown', 'Var', (36, 45))	('decreased', 'NegReg', (152, 161))	('expression', 'MPA', (162, 172))	('expression', 'MPA', (73, 83))	('lnc-ATB', 'Chemical', '-', (49, 56))	('lnc-ATB', 'Chemical', '-', (303, 310))	('E-cadherin', 'Gene', '999', (120, 130))	('beta-catenin', 'Gene', '1499', (135, 147))	('N-cadherin', 'Gene', '1000', (199, 209))	('lnc-ATB', 'Gene', (49, 56))
935579	28640252	We then injected Eca109 cells with lnc-ATB suppression into the tail vein of nude mice and found that the metastatic nodules in the lung were significantly decreased in the knockdown group compared with that in the control group (Figures 3d and e).	('knockdown', 'Var', (173, 182))	('nude mice', 'Species', '10090', (77, 86))	('lnc-ATB', 'Chemical', '-', (35, 42))	('decreased', 'NegReg', (156, 165))	('suppression', 'NegReg', (43, 54))	('metastatic nodules in the lung', 'CPA', (106, 136))	('lnc-ATB', 'Gene', (35, 42))
935584	28640252	We found that expression of miR-200b was remarkably increased after knockdown of lnc-ATB (Figure 4b).	('lnc-ATB', 'Chemical', '-', (81, 88))	('increased', 'PosReg', (52, 61))	('miR-200b', 'Gene', '406984', (28, 36))	('expression', 'MPA', (14, 24))	('knockdown', 'Var', (68, 77))	('lnc-ATB', 'Gene', (81, 88))	('miR-200b', 'Gene', (28, 36))
935585	28640252	Next, we constructed luciferase reporters, which contain wild-type (WT) or mutated (Mut) miR-200b-binding sites, for direct binding validations (Figure 4c).	('mutated', 'Var', (75, 82))	('miR-200b', 'Gene', (89, 97))	('miR-200b', 'Gene', '406984', (89, 97))
935591	28640252	Moreover, expression of Kindlin-2 was suppressed in KYSE30 and Eca109 cells after knockdown of lnc-ATB (Figure 5d).	('lnc-ATB', 'Chemical', '-', (95, 102))	('suppressed', 'NegReg', (38, 48))	('knockdown', 'Var', (82, 91))	('lnc-ATB', 'Gene', (95, 102))	('expression', 'MPA', (10, 20))	('Kindlin-2', 'Gene', (24, 33))	('Kindlin-2', 'Gene', '10979', (24, 33))
935592	28640252	qRT-PCR analysis indicated that mRNA level of Kindlin-2 was decreased by lnc-ATB knockdown (Figure 5e).	('Kindlin-2', 'Gene', (46, 55))	('lnc-ATB', 'Gene', (73, 80))	('decreased', 'NegReg', (60, 69))	('Kindlin-2', 'Gene', '10979', (46, 55))	('knockdown', 'Var', (81, 90))	('mRNA level', 'MPA', (32, 42))	('lnc-ATB', 'Chemical', '-', (73, 80))
935594	28640252	Immunoblotting showed that active RhoA and phosphorylated FAK was suppressed after knockdown of lnc-ATB (Figure 5f).	('active', 'MPA', (27, 33))	('FAK', 'Gene', (58, 61))	('lnc-ATB', 'Chemical', '-', (96, 103))	('FAK', 'Gene', '5747', (58, 61))	('suppressed', 'NegReg', (66, 76))	('RhoA', 'Gene', '387', (34, 38))	('knockdown', 'Var', (83, 92))	('RhoA', 'Gene', (34, 38))	('lnc-ATB', 'Gene', (96, 103))
935597	28640252	Moreover, attenuation of Kindlin-2 significantly reversed the anti-migration roles of lnc-ATB knockdown (Figure 6c).	('lnc-ATB', 'Gene', (86, 93))	('knockdown', 'Var', (94, 103))	('Kindlin-2', 'Gene', '10979', (25, 34))	('lnc-ATB', 'Chemical', '-', (86, 93))	('attenuation', 'NegReg', (10, 21))	('Kindlin-2', 'Gene', (25, 34))	('anti-migration', 'CPA', (62, 76))
935600	28640252	Immunostaining of Ki-67 and Kindlin-2 in dissected tumors showed that silencing of lnc-ATB inhibited proliferation and Kindlin-2 of ESCC cells (Figures 7f-h), indicating that knockdown of lnc-ATB significantly suppressed tumor growth via miR-200b/Kindlin-2 in vivo.	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('Kindlin-2', 'Gene', '10979', (28, 37))	('lnc-ATB', 'Chemical', '-', (188, 195))	('silencing', 'Var', (70, 79))	('inhibited', 'NegReg', (91, 100))	('tumor', 'Disease', (51, 56))	('proliferation', 'CPA', (101, 114))	('miR-200b', 'Gene', '406984', (238, 246))	('Kindlin-2', 'Gene', (247, 256))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('lnc-ATB', 'Gene', (83, 90))	('tumor', 'Disease', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('lnc-ATB', 'Chemical', '-', (83, 90))	('Kindlin-2', 'Gene', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('Kindlin-2', 'Gene', '10979', (247, 256))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))	('suppressed', 'NegReg', (210, 220))	('Kindlin-2', 'Gene', (28, 37))	('Kindlin-2', 'Gene', '10979', (119, 128))	('miR-200b', 'Gene', (238, 246))
935603	28640252	Dysregulation of lncRNAs has been previously reported in a wide range of human cancers including ESCC.	('cancers', 'Disease', (79, 86))	('reported', 'Reg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Dysregulation', 'Var', (0, 13))	('human', 'Species', '9606', (73, 78))	('lncRNAs', 'Protein', (17, 24))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('ESCC', 'Disease', (97, 101))
935613	28640252	Previous studies have indicated that knockdown of lnc-ATB inhibited EMT and cell invasion in hepatocellular carcinoma and colorectal cancer in vitro as well as tumor growth in the nude mice.	('nude mice', 'Species', '10090', (180, 189))	('lnc-ATB', 'Chemical', '-', (50, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (93, 117))	('hepatocellular carcinoma', 'Disease', (93, 117))	('colorectal cancer', 'Disease', (122, 139))	('knockdown', 'Var', (37, 46))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (93, 117))	('lnc-ATB', 'Gene', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('inhibited', 'NegReg', (58, 67))	('tumor', 'Disease', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
935615	28640252	Silencing of lnc-ATB expression significantly suppressed proliferation and migration of ESCC cells compared with control.	('lnc-ATB', 'Chemical', '-', (13, 20))	('proliferation', 'CPA', (57, 70))	('lnc-ATB', 'Gene', (13, 20))	('Silencing', 'Var', (0, 9))	('suppressed', 'NegReg', (46, 56))
935619	28640252	Tumor-suppressive effects of miR-200 family has been repeatedly verified during the past few years, whereby miR-200c initiates malignant transformation by modulation of cancer stem cells, and decreased miR-200 promotes distant metastasis via regulation of the EMT activator ZEB1 and ZEB2.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-200c', 'Gene', '406985', (108, 116))	('cancer', 'Disease', (169, 175))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', '220972', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('miR', 'Gene', (108, 111))	('miR-200c', 'Gene', (108, 116))	('miR', 'Gene', (29, 32))	('ZEB1', 'Gene', (274, 278))	('promotes', 'PosReg', (210, 218))	('ZEB2', 'Gene', (283, 287))	('miR', 'Gene', (202, 205))	('modulation', 'Reg', (155, 165))	('ZEB2', 'Gene', '9839', (283, 287))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('decreased', 'Var', (192, 201))	('distant metastasis', 'CPA', (219, 237))	('malignant transformation', 'CPA', (127, 151))	('ZEB1', 'Gene', '6935', (274, 278))	('miR', 'Gene', '220972', (108, 111))
935622	28640252	Our results showed that expression of miR-200b was significantly upregulated after knockdown of lnc-ATB, and further dual luciferase assays confirmed direct binding of lnc-ATB and miR-200b.	('binding', 'Interaction', (157, 164))	('expression', 'MPA', (24, 34))	('lnc-ATB', 'Chemical', '-', (168, 175))	('miR-200b', 'Gene', '406984', (38, 46))	('knockdown', 'Var', (83, 92))	('lnc-ATB', 'Chemical', '-', (96, 103))	('miR-200b', 'Gene', '406984', (180, 188))	('miR-200b', 'Gene', (38, 46))	('upregulated', 'PosReg', (65, 76))	('miR-200b', 'Gene', (180, 188))	('lnc-ATB', 'Gene', (96, 103))
935624	28640252	Furthermore, overexpression of Kindlin-2 was observed in the invasive front of malignant mesothelioma and breast cancer, whereas knockdown of Kindlin-2 exerts tumor-suppressive roles.	('Kindlin-2', 'Gene', '10979', (142, 151))	('Kindlin-2', 'Gene', '10979', (31, 40))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (79, 101))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('knockdown', 'Var', (129, 138))	('invasive front', 'CPA', (61, 75))	('tumor', 'Disease', (159, 164))	('overexpression', 'PosReg', (13, 27))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (79, 101))	('Kindlin-2', 'Gene', (142, 151))	('Kindlin-2', 'Gene', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('malignant mesothelioma', 'Disease', (79, 101))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
935627	28640252	Attenuation of the anti-proliferative roles of lnc-ATB knockdown by re-induction of Kindlin-2 in ESCC cells further demonstrated the role of the lnc-ATB/miR-200b/Kindlin-2 axis in tumor metastasis.	('knockdown', 'Var', (55, 64))	('Kindlin-2', 'Gene', '10979', (162, 171))	('anti-proliferative', 'CPA', (19, 37))	('miR-200b', 'Gene', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Kindlin-2', 'Gene', (84, 93))	('lnc-ATB', 'Chemical', '-', (47, 54))	('Attenuation', 'NegReg', (0, 11))	('Kindlin-2', 'Gene', '10979', (84, 93))	('lnc-ATB', 'Gene', (47, 54))	('lnc-ATB', 'Chemical', '-', (145, 152))	('miR-200b', 'Gene', '406984', (153, 161))	('tumor metastasis', 'Disease', 'MESH:D009362', (180, 196))	('Kindlin-2', 'Gene', (162, 171))	('tumor metastasis', 'Disease', (180, 196))
935628	28640252	Notably, this mechanism may correlate with our clinical observations that the loss of miR-200b in ESCC tumors is associated with lymph node metastasis, advanced clinical stage and short survival.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('associated', 'Reg', (113, 123))	('ESCC tumors', 'Disease', (98, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('ESCC tumors', 'Disease', 'MESH:D004938', (98, 109))	('lymph node metastasis', 'CPA', (129, 150))	('miR-200b', 'Gene', '406984', (86, 94))	('loss', 'Var', (78, 82))	('miR-200b', 'Gene', (86, 94))
935634	28640252	The human ESCC cell lines (KYSE150, KYSE140, KYSE410, KYSE520, KYSE510, Ec109, Ec9706 and KYSE30) were obtained either from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China) or purchased from the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ, Braunschweig, Germany).	('KYSE150', 'Var', (27, 34))	('Ec109', 'Var', (72, 77))	('Ec9706', 'Var', (79, 85))	('human', 'Species', '9606', (4, 9))	('von', 'Disease', 'MESH:D014842', (231, 234))	('KYSE510', 'Var', (63, 70))	('KYSE30', 'Var', (90, 96))	('KYSE520', 'Var', (54, 61))	('KYSE410', 'Var', (45, 52))	('Ec9706', 'CellLine', 'CVCL:E307', (79, 85))	('von', 'Disease', (231, 234))
935655	28640252	The primary antibodies used in our study include E-cadherin (1:500), Vimentin (1:500), beta-catenin (1:500, Cell Signaling Technology), Kindlin-2 (1:2000, Millipore, Bedford, MA, USA) p-FAK(Tyr397) (1:1000, Cell Signaling Technology), FAK (1:500, Cell Signaling Technology), active RhoA (1:500, Cell Signaling Technology), total RhoA (1:500, Cell Signaling Technology) and GAPDH (1:5000, Sigma, Sigma-Aldrich, St. Louis, MO, USA).	('FAK', 'Gene', (235, 238))	('FAK', 'Gene', (186, 189))	('beta-catenin', 'Gene', (87, 99))	('FAK', 'Gene', '5747', (235, 238))	('Vimentin', 'Gene', '7431', (69, 77))	('beta-catenin', 'Gene', '1499', (87, 99))	('Kindlin-2', 'Gene', (136, 145))	('RhoA', 'Gene', (282, 286))	('GAPDH', 'Gene', '2597', (373, 378))	('FAK', 'Gene', '5747', (186, 189))	('Vimentin', 'Gene', (69, 77))	('Kindlin-2', 'Gene', '10979', (136, 145))	('RhoA', 'Gene', (329, 333))	('E-cadherin', 'Gene', (49, 59))	('E-cadherin', 'Gene', '999', (49, 59))	('RhoA', 'Gene', '387', (282, 286))	('GAPDH', 'Gene', (373, 378))	('1:5000', 'Var', (380, 386))	('RhoA', 'Gene', '387', (329, 333))
935658	28640252	The pcDNA3.1-ATB-Mut vector, which contains point mutations in the miR-200b response elements was generated with a Quick Change Site-Directed Mutagenesis kit (Stratagene, Agilent Technologies).	('point mutations', 'Var', (44, 59))	('miR-200b', 'Gene', '406984', (67, 75))	('miR-200b', 'Gene', (67, 75))
935677	28599425	Furthermore, it was found that CD63 knockdown increased the invasiveness of TE-1 cells through the upregulation of matrix metalloproteinase (MMP) expression via promoting epithelial-mesenchymal transition.	('epithelial-mesenchymal transition', 'CPA', (171, 204))	('increased', 'PosReg', (46, 55))	('upregulation', 'PosReg', (99, 111))	('CD63', 'Gene', (31, 35))	('MMP', 'Gene', (141, 144))	('knockdown', 'Var', (36, 45))	('invasiveness of TE-1 cells', 'CPA', (60, 86))	('TE-1', 'CellLine', 'CVCL:1759', (76, 80))	('expression', 'MPA', (146, 156))	('promoting', 'PosReg', (161, 170))
935691	28599425	Sordat et al has reported that substrate-immobilized anti-CD63 antibodies are able to enhance colon carcinoma cell migration and invasion.	('anti-CD63', 'Var', (53, 62))	('colon carcinoma cell migration', 'Disease', (94, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('antibodies', 'Protein', (63, 73))	('enhance', 'PosReg', (86, 93))	('invasion', 'CPA', (129, 137))	('colon carcinoma cell migration', 'Disease', 'MESH:D003110', (94, 124))
935693	28599425	Kwon et al suggested that CD63 negativity is able to predict poor prognosis for early-stage lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('negativity', 'Var', (31, 41))	('lung adenocarcinoma', 'Disease', (92, 111))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))	('CD63', 'Gene', (26, 30))
935699	28599425	Inactivation of its downstream targets, including Cyclin-D1, c-Jun, c-Myc, and matrix metalloproteinase 7 (MMP-7).	('c-Myc', 'Gene', (68, 73))	('c-Jun', 'Gene', '3725', (61, 66))	('matrix metalloproteinase 7', 'Gene', (79, 105))	('Cyclin-D1', 'Gene', '595', (50, 59))	('MMP-7', 'Gene', (107, 112))	('c-Jun', 'Gene', (61, 66))	('c-Myc', 'Gene', '4609', (68, 73))	('matrix metalloproteinase 7', 'Gene', '4316', (79, 105))	('Cyclin-D1', 'Gene', (50, 59))	('Inactivation', 'Var', (0, 12))	('MMP-7', 'Gene', '4316', (107, 112))
935717	28599425	The human esophageal cancer cell line TE-1 was cultured in Dulbecco's modified Eagle's medium (Thermo Fisher Scientific Inc., Waltham, MA, USA) supplemented with 10% fetal bovine serum (FBS; Gibco; Thermo Fisher Scientific, Inc.) and antibiotics (100 U/ml penicillin and 100 microg/streptomycin, Sigma-Aldrich; Merck KGaA).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (59, 93))	('human', 'Species', '9606', (4, 9))	('esophageal cancer', 'Disease', (10, 27))	('streptomycin', 'Chemical', 'MESH:D013307', (282, 294))	('bovine', 'Species', '9913', (172, 178))	('TE-1', 'CellLine', 'CVCL:1759', (38, 42))	('100 U/ml', 'Var', (247, 255))	('penicillin', 'Chemical', 'MESH:D010406', (256, 266))	('esophageal cancer', 'Disease', 'MESH:D004938', (10, 27))
935739	28599425	To investigate the role of reduced CD63 expression in the migration of EC, the esophageal cancer cells TE-1 were transfected with CD63-silencing RNA.	('esophageal cancer', 'Disease', (79, 96))	('EC', 'Phenotype', 'HP:0011459', (71, 73))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('TE-1', 'CellLine', 'CVCL:1759', (103, 107))	('CD63-silencing', 'Var', (130, 144))
935741	28599425	4B and C, the ability of TE-1 cells to invade through the Matrigel and membrane was increased by CD63 knockdown when compared with the control cells or the empty plasmid transfected cells.	('increased', 'PosReg', (84, 93))	('CD63', 'Gene', (97, 101))	('knockdown', 'Var', (102, 111))	('TE-1', 'CellLine', 'CVCL:1759', (25, 29))
935742	28599425	The CD63 siRNA transfected TE-1 cells exhibited a ~2-fold higher invasiveness than the control cells.	('TE-1', 'CellLine', 'CVCL:1759', (27, 31))	('CD63', 'Var', (4, 8))	('higher', 'PosReg', (58, 64))	('invasiveness', 'CPA', (65, 77))
935744	28599425	4D and E, CD63 knockdown noticeably reduced the wound area, suggesting that CD63 knockdown enhanced the migration capability of esophageal cancer.	('wound area', 'CPA', (48, 58))	('migration capability', 'CPA', (104, 124))	('esophageal cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('CD63', 'Gene', (76, 80))	('knockdown', 'Var', (81, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('reduced', 'NegReg', (36, 43))	('enhanced', 'PosReg', (91, 99))
935748	28599425	5, TE-1 cells transfected with CD63 siRNA exhibited downregulation of E-cadherin expression and upregulation of vimentin when compared with the control cells or the empty plasmid transfected cells.	('CD63 siRNA', 'Var', (31, 41))	('TE-1', 'CellLine', 'CVCL:1759', (3, 7))	('vimentin', 'Gene', '7431', (112, 120))	('downregulation', 'NegReg', (52, 66))	('upregulation', 'PosReg', (96, 108))	('vimentin', 'Gene', (112, 120))	('E-cadherin', 'Gene', (70, 80))	('E-cadherin', 'Gene', '999', (70, 80))	('expression', 'MPA', (81, 91))
935749	28599425	The matrix metalloproteinase MMP-2 and MMP-9 expression was increased by CD63 knockdown.	('MMP-2', 'Gene', '4313', (29, 34))	('CD63', 'Gene', (73, 77))	('knockdown', 'Var', (78, 87))	('matrix metalloproteinase', 'Protein', (4, 28))	('expression', 'MPA', (45, 55))	('MMP-9', 'Gene', '4318', (39, 44))	('MMP-9', 'Gene', (39, 44))	('MMP-2', 'Gene', (29, 34))	('increased', 'PosReg', (60, 69))
935750	28599425	These results suggest that CD63 knockdown regulates the invasiveness of esophageal cancer cells via promoting EMT.	('CD63', 'Gene', (27, 31))	('EMT', 'CPA', (110, 113))	('promoting', 'PosReg', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('knockdown', 'Var', (32, 41))	('invasiveness of esophageal cancer', 'Disease', (56, 89))	('regulates', 'Reg', (42, 51))	('invasiveness of esophageal cancer', 'Disease', 'MESH:D004938', (56, 89))
935756	28599425	In the present study, the protein levels of CD63 in EC tissues were revealed to be significantly increased compared with adjacent tumor tissues or the normal esophagus mucosa tissues.	('increased', 'PosReg', (97, 106))	('CD63', 'Var', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('protein levels', 'MPA', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('EC', 'Phenotype', 'HP:0011459', (52, 54))	('tumor', 'Disease', (130, 135))
935758	28599425	The hematogenous metastasis of CD63-negative human melanoma cells in nude mice may be reduced by CD63 transfection.	('reduced', 'NegReg', (86, 93))	('melanoma cells', 'Disease', (51, 65))	('transfection', 'Var', (102, 114))	('CD63', 'Gene', (97, 101))	('human', 'Species', '9606', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma cells', 'Disease', 'MESH:D008545', (51, 65))	('nude mice', 'Species', '10090', (69, 78))	('hematogenous metastasis', 'CPA', (4, 27))
935759	28599425	Kwon et al suggested that CD63 negativity has a potential as a biomarker for predicting poor prognosis in earlier stage lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (120, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('negativity', 'Var', (31, 41))	('CD63', 'Gene', (26, 30))	('lung adenocarcinoma', 'Disease', (120, 139))
935761	28599425	In the current study, CD63 negativity was significantly associated with advanced tumor stage and a greater number of metastatic lymph nodes in EC.	('associated', 'Reg', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('EC', 'Phenotype', 'HP:0011459', (143, 145))	('negativity', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CD63', 'Gene', (22, 26))	('tumor', 'Disease', (81, 86))
935765	28599425	Following siRNA-induced CD63 knockdown, the invasiveness of TE-1 cells was enhanced.	('CD63', 'Gene', (24, 28))	('knockdown', 'Var', (29, 38))	('enhanced', 'PosReg', (75, 83))	('invasiveness of TE-1 cells', 'CPA', (44, 70))	('TE-1', 'CellLine', 'CVCL:1759', (60, 64))
935778	28599425	In addition, the epithelial marker E-cadherin was downregulated and the mesenchymal maker vimentin was upregulated by CD63 knockdown, suggesting that CD63 may function as a potent inhibitor of metastasis in EC via regulating the EMT.	('regulating', 'Reg', (214, 224))	('E-cadherin', 'Gene', '999', (35, 45))	('vimentin', 'Gene', '7431', (90, 98))	('EC', 'Phenotype', 'HP:0011459', (207, 209))	('epithelial', 'MPA', (17, 27))	('vimentin', 'Gene', (90, 98))	('EMT', 'CPA', (229, 232))	('CD63', 'Gene', (118, 122))	('downregulated', 'NegReg', (50, 63))	('knockdown', 'Var', (123, 132))	('upregulated', 'PosReg', (103, 114))	('E-cadherin', 'Gene', (35, 45))
935781	28599425	The present study identified that MMP-2 and MMP-9 expression levels were increased by CD63 knockdown, suggesting that CD63 knockdown-induced EC invasion may be due to MMP-2 and MMP-9 overexpression through the activation of EMT signal pathway.	('knockdown-induced', 'Var', (123, 140))	('MMP-2', 'Gene', (167, 172))	('increased', 'PosReg', (73, 82))	('EC', 'Phenotype', 'HP:0011459', (141, 143))	('MMP-2', 'Gene', (34, 39))	('CD63', 'Gene', (86, 90))	('MMP-2', 'Gene', '4313', (167, 172))	('EC invasion', 'CPA', (141, 152))	('MMP-9', 'Gene', (177, 182))	('CD63', 'Gene', (118, 122))	('MMP-9', 'Gene', '4318', (177, 182))	('MMP-9', 'Gene', '4318', (44, 49))	('MMP-2', 'Gene', '4313', (34, 39))	('EMT signal pathway', 'Pathway', (224, 242))	('expression', 'MPA', (50, 60))	('MMP-9', 'Gene', (44, 49))	('overexpression', 'PosReg', (183, 197))
935783	28599425	CD63 knockdown enhanced EC cell invasion, and was mediated by MMP-2 and MMP-9 overexpression through the activation of EMT signaling pathway.	('EMT signaling pathway', 'Pathway', (119, 140))	('CD63', 'Gene', (0, 4))	('MMP-9', 'Gene', '4318', (72, 77))	('knockdown', 'Var', (5, 14))	('MMP-9', 'Gene', (72, 77))	('MMP-2', 'Gene', (62, 67))	('overexpression', 'PosReg', (78, 92))	('EC cell invasion', 'CPA', (24, 40))	('EC', 'Phenotype', 'HP:0011459', (24, 26))	('enhanced', 'PosReg', (15, 23))	('MMP-2', 'Gene', '4313', (62, 67))
935805	25884700	These considerations explain why genetically engineered mouse models (GEMMs) are inadequate to mimick broad, unselected patient populations; they are driven by a very well defined set of driver mutations which can never reflect the diverse spectrum of genetic aberrations found in human tumors.	('tumors', 'Disease', (287, 293))	('patient', 'Species', '9606', (120, 127))	('mouse', 'Species', '10090', (56, 61))	('mutations', 'Var', (194, 203))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('human', 'Species', '9606', (281, 286))	('tumors', 'Disease', 'MESH:D009369', (287, 293))
935813	25884700	This ligand is notably absent from both the developing as well as the healthy adult pancreas, but its aberrant expression in the pancreas has been shown to drive tumor progression, and inhibition of its downstream signaling pathway is effective in some preclinical models for PDAC.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('drive', 'PosReg', (156, 161))	('inhibition', 'Var', (185, 195))	('tumor', 'Disease', (162, 167))	('PDAC', 'Phenotype', 'HP:0006725', (276, 280))	('expression', 'MPA', (111, 121))	('PDAC', 'Chemical', '-', (276, 280))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('PDAC', 'Disease', (276, 280))	('aberrant', 'Var', (102, 110))
935885	25884700	Whereas most cultures (among which the PDAC cultures PC053M and PC067 shown in Figure 2A) were found to display the cobblestone morphology characteristic for epithelial cells, the esophageal line EAC027 grew semi-adherently with viable floating cell aggregates (Figure 2A), a feature previously described for established EAC lines.	('EAC', 'Phenotype', 'HP:0011459', (321, 324))	('PC053M', 'CellLine', 'CVCL:C035', (53, 59))	('PC067', 'Var', (64, 69))	('PDAC', 'Phenotype', 'HP:0006725', (39, 43))	('EAC', 'Phenotype', 'HP:0011459', (196, 199))	('cobblestone morphology', 'CPA', (116, 138))	('PC053M', 'Var', (53, 59))	('PDAC', 'Chemical', '-', (39, 43))
935887	25884700	The histology of tumors that grew from these cells injected in mice (subcutaneously for EAC007B and orthotopically for PC053M) strongly resembled that of regrafted PDX tumors (Figure 2B-C).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('EAC', 'Phenotype', 'HP:0011459', (88, 91))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('mice', 'Species', '10090', (63, 67))	('EAC007B', 'Var', (88, 95))	('PC053M', 'CellLine', 'CVCL:C035', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
936029	24290360	We also separately examined the association between high MUC2 expression (H score>100) and survival in T1b EAC, but there were only 8 cases with high level MUC2 expression.	('EAC', 'Gene', '1540', (107, 110))	('examined', 'Reg', (19, 27))	('EAC', 'Gene', (107, 110))	('MUC2', 'Gene', (156, 160))	('MUC2', 'Gene', '4583', (156, 160))	('high', 'Var', (52, 56))	('MUC2', 'Gene', (57, 61))	('MUC2', 'Gene', '4583', (57, 61))
936056	24290360	However, we saw no association between MUC2 expression and EGFR amplification.	('MUC2', 'Gene', '4583', (39, 43))	('EGFR', 'Gene', (59, 63))	('amplification', 'Var', (64, 77))	('EGFR', 'Gene', '1956', (59, 63))	('MUC2', 'Gene', (39, 43))
936057	24290360	High-level EGFR amplification described by Marx et al., was rare in our study, precluding a conclusive assessment of its influence on survival in superficial EAC.	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('amplification', 'Var', (16, 29))	('EAC', 'Gene', '1540', (158, 161))	('EAC', 'Gene', (158, 161))
936077	23621168	Adiposity is linked to an increased risk of many cancers, including cancers of the endometrium, kidney, gallbladder, breast, and colon .	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('breast', 'Disease', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('gallbladder', 'Disease', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancers', 'Disease', (68, 75))	('kidney', 'Disease', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('colon', 'Disease', 'MESH:D015179', (129, 134))	('Adiposity', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('linked to', 'Reg', (13, 22))	('cancers', 'Disease', (49, 56))	('colon', 'Disease', (129, 134))
936078	23621168	Moreover, excess weight is an established risk factor for death from cancer .	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('death', 'Disease', 'MESH:D003643', (58, 63))	('death', 'Disease', (58, 63))	('excess', 'Var', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
936081	23621168	Although some studies have reported increased postoperative morbidity and duration of hospital stay in esophageal cancer patients with high BMI , others have found no difference .	('high BMI', 'Var', (135, 143))	('esophageal cancer', 'Disease', (103, 120))	('postoperative morbidity', 'CPA', (46, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('increased', 'PosReg', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('patients', 'Species', '9606', (121, 129))
936082	23621168	Similarly, while several studies have reported no difference in survival between obese and non-obese patients , others  have reported better survival outcomes in patients with high BMI.	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (101, 109))	('high BMI', 'Var', (176, 184))	('better', 'PosReg', (134, 140))	('obese', 'Disease', 'MESH:D009765', (81, 86))	('obese', 'Disease', 'MESH:D009765', (95, 100))	('obese', 'Disease', (81, 86))	('obese', 'Disease', (95, 100))	('non-obese', 'Disease', (91, 100))	('non-obese', 'Disease', 'MESH:D009765', (91, 100))
936117	23621168	On univariate analysis, disease stage 3 (P < 0.001), T stage 3 or 4 (P = 0.039), tumor location (P = 0.023), nodal involvement (P < 0.001), definitive chemoradiotherapy (P < 0.001), readmission within 60 days of surgery (P = 0.019), >= grade 2 dysphagia (P = 0.014), any anorexia (P = 0.020), >= grade 2 hematologic toxicity (P = 0.030), and any treatment-related anemia (P = 0.010) were significantly associated with shorter survival.	('shorter', 'NegReg', (418, 425))	('dysphagia', 'Phenotype', 'HP:0002015', (244, 253))	('nodal', 'Gene', (109, 114))	('anorexia', 'Disease', 'MESH:D000855', (271, 279))	('nodal', 'Gene', '4838', (109, 114))	('men', 'Species', '9606', (122, 125))	('anemia', 'Phenotype', 'HP:0001903', (364, 370))	('men', 'Species', '9606', (351, 354))	('anemia', 'Disease', (364, 370))	('tumor', 'Disease', (81, 86))	('anorexia', 'Phenotype', 'HP:0002039', (271, 279))	('>= grade 2', 'Var', (293, 303))	('dysphagia', 'Disease', 'MESH:D003680', (244, 253))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('dysphagia', 'Disease', (244, 253))	('anorexia', 'Disease', (271, 279))	('hematologic toxicity', 'Disease', (304, 324))	('hematologic toxicity', 'Disease', 'MESH:D006402', (304, 324))	('anemia', 'Disease', 'MESH:D000740', (364, 370))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
936129	23621168	Despite comparable doses of radiation delivered and no differences in radiation modality used, high-BMI patients were significantly less likely to have high-grade esophagitis, stricture, and hematologic toxicities such as anemia, leukopenia, and neutropenia.	('neutropenia', 'Phenotype', 'HP:0001875', (246, 257))	('less', 'NegReg', (132, 136))	('leukopenia', 'Disease', 'MESH:D007970', (230, 240))	('leukopenia', 'Disease', (230, 240))	('hematologic toxicities', 'Disease', (191, 213))	('anemia', 'Disease', 'MESH:D000740', (222, 228))	('esophagitis', 'Phenotype', 'HP:0100633', (163, 174))	('esophagitis', 'Disease', (163, 174))	('anemia', 'Disease', (222, 228))	('hematologic toxicities', 'Disease', 'MESH:D006402', (191, 213))	('esophagitis', 'Disease', 'MESH:D004941', (163, 174))	('neutropenia', 'Disease', (246, 257))	('patients', 'Species', '9606', (104, 112))	('leukopenia', 'Phenotype', 'HP:0001882', (230, 240))	('anemia', 'Phenotype', 'HP:0001903', (222, 228))	('high-BMI', 'Var', (95, 103))	('neutropenia', 'Disease', 'MESH:D009503', (246, 257))	('stricture', 'Disease', (176, 185))
936140	23621168	While Melis et al  demonstrated longer OS/PFS for high-BMI patients, their study used pre-surgery BMI rather than pre-neoadjuvant treatment BMI, which may have been a confounding factor.	('longer', 'PosReg', (32, 38))	('OS/PFS', 'MPA', (39, 45))	('men', 'Species', '9606', (135, 138))	('patients', 'Species', '9606', (59, 67))	('high-BMI', 'Var', (50, 58))
936307	22307565	The earlier Nutritional Intervention Trial conducted in Linxian, China, well recognized as the highest incidence area for esophageal SCC in the world, had demonstrated that supplementation with vitamins and minerals (50 mug selenium, 30 mg vitamin E, and 15 mg beta-carotene) decreased mortality from all causes, cancer overall, and gastric cancer.	('men', 'Species', '9606', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('all causes', 'Disease', (301, 311))	('gastric cancer', 'Disease', (333, 347))	('beta-carotene', 'Chemical', 'MESH:D019207', (261, 274))	('cancer', 'Disease', (341, 347))	('50 mug', 'Var', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('decreased', 'NegReg', (276, 285))	('gastric cancer', 'Disease', 'MESH:D013274', (333, 347))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('mortality', 'MPA', (286, 295))	('gastric cancer', 'Phenotype', 'HP:0012126', (333, 347))	('rat', 'Species', '10116', (162, 165))	('SCC', 'Gene', '6317', (133, 136))	('vitamin E', 'Chemical', 'MESH:D014810', (240, 249))	('selenium', 'Chemical', 'MESH:D012643', (224, 232))	('cancer', 'Disease', (313, 319))	('SCC', 'Gene', (133, 136))
936312	22307565	Clinical trials of these berries and their extracts now include oral delivery for prevention of non-small-cell lung cancer (NCT00681512) and familial adenomatous polyposis (NCT00770991); lozenges for treatment of oral SCC (NCT01465776) and head and neck cancer (NCT01469429); and oral gels in a multi-center oral cancer chemoprevention trial (NCT01192204; also see refs.).	('NCT01469429', 'Var', (262, 273))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('lung cancer', 'Disease', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('SCC', 'Gene', '6317', (218, 221))	('NCT00770991', 'Var', (173, 184))	('multi-center oral cancer', 'Disease', (295, 319))	('SCC', 'Gene', (218, 221))	('head and neck cancer', 'Phenotype', 'HP:0012288', (240, 260))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('men', 'Species', '9606', (205, 208))	('familial adenomatous polyposis', 'Disease', (141, 171))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (150, 171))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (141, 171))	('NCT00681512', 'Var', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('NCT01465776', 'Var', (223, 234))	('multi-center oral cancer', 'Disease', 'MESH:D009062', (295, 319))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (96, 122))	('head and neck cancer', 'Disease', 'MESH:D006258', (240, 260))
936380	22307565	Plants naturally host a large external microbial community, but improper agricultural practices can bring unacceptably high levels of human pathogens (e.g., E. coli 0157:H7) into contact with fruits and vegetables destined for the market.	('bring', 'Reg', (100, 105))	('human', 'Species', '9606', (134, 139))	('E. coli', 'Species', '562', (157, 164))	('improper', 'Var', (64, 72))
936470	20514215	As one of the most widely used platinum-containing anticancer drugs of chemotherapy for EC, CDDP is believed to induce tumor cell death as a result of the formation of CDDP-DNA adducts, which inhibit DNA replication and transcription.	('CDDP', 'Var', (92, 96))	('tumor', 'Disease', (119, 124))	('CDDP', 'Chemical', '-', (168, 172))	('transcription', 'MPA', (220, 233))	('death', 'Disease', 'MESH:D003643', (130, 135))	('death', 'Disease', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('inhibit', 'NegReg', (192, 199))	('CDDP', 'Chemical', '-', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('platinum', 'Chemical', 'MESH:D010984', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Disease', (55, 61))	('DNA replication', 'MPA', (200, 215))
936513	18297350	Their series consists of 18 selected patients with Barrett's esophagus and high-grade dysplasia (n = 9), adenocarcinoma in situ (n = 2), superficial adenocarcinoma (n = 5) or T2-3 esophageal adenocarcinoma (n = 2) without clinical evidence of lymph node metastases.	('adenocarcinoma', 'Disease', 'MESH:D000230', (105, 119))	('T2-3', 'Var', (175, 179))	('adenocarcinoma', 'Disease', (149, 163))	("Barrett's esophagus", 'Disease', (51, 70))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (180, 205))	('metastases', 'Disease', 'MESH:D009362', (254, 264))	('patients', 'Species', '9606', (37, 45))	('adenocarcinoma', 'Disease', 'MESH:D000230', (191, 205))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (180, 205))	('metastases', 'Disease', (254, 264))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (51, 70))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (51, 70))	('esophageal adenocarcinoma', 'Disease', (180, 205))	('adenocarcinoma', 'Disease', 'MESH:D000230', (149, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('dysplasia', 'Disease', (86, 95))	('adenocarcinoma', 'Disease', (105, 119))	('dysplasia', 'Disease', 'MESH:D004476', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('adenocarcinoma', 'Disease', (191, 205))
936579	30482065	As shown in Table 3, the incidence rate of damage to renal and liver function, nausea, vomiting, and diarrhea in the Aidi group was significantly lower than that in the control group both in short and long chemotherapy cycles.	('Aidi', 'Var', (117, 121))	('Aidi', 'Chemical', '-', (117, 121))	('vomiting', 'Disease', 'MESH:D014839', (87, 95))	('damage to renal and liver function', 'Disease', 'MESH:D056486', (43, 77))	('nausea', 'Phenotype', 'HP:0002018', (79, 85))	('nausea', 'Disease', (79, 85))	('nausea', 'Disease', 'MESH:D009325', (79, 85))	('lower', 'NegReg', (146, 151))	('vomiting', 'Phenotype', 'HP:0002013', (87, 95))	('diarrhea', 'Phenotype', 'HP:0002014', (101, 109))	('diarrhea', 'Disease', 'MESH:D003967', (101, 109))	('vomiting', 'Disease', (87, 95))	('diarrhea', 'Disease', (101, 109))
936582	30482065	The patients with increasing ECOG score (ie, worse PS) in the Aidi group were significantly less than those in the control group.	('Aidi', 'Var', (62, 66))	('Aidi', 'Chemical', '-', (62, 66))	('PS', 'Chemical', '-', (51, 53))	('less', 'NegReg', (92, 96))	('patients', 'Species', '9606', (4, 12))	('ECOG', 'MPA', (29, 33))
936627	30482065	Damage to liver and renal and gastrointestinal reactions that occurred during chemotherapy in the Aidi group were significantly less than that in the control group, as shown in Table 3.	('liver and renal and gastrointestinal reactions', 'Disease', 'MESH:D056486', (10, 56))	('Aidi', 'Chemical', '-', (98, 102))	('Aidi', 'Var', (98, 102))	('less', 'NegReg', (128, 132))
936633	30482065	Besides, this study suggests that patients taking Aidi injection in conventional dosages might experience a higher improvement rate of PS and lower incidence rate of chemotherapy-related toxicity compared to the non-Aidi group and the group receiving lower dosages.	('PS', 'Chemical', '-', (135, 137))	('Aidi injection', 'Chemical', '-', (50, 64))	('improvement', 'PosReg', (115, 126))	('Aidi', 'Var', (50, 54))	('Aidi', 'Chemical', '-', (50, 54))	('toxicity', 'Disease', 'MESH:D064420', (187, 195))	('patients', 'Species', '9606', (34, 42))	('toxicity', 'Disease', (187, 195))	('Aidi', 'Chemical', '-', (216, 220))
936638	30482065	Yet from the subgroup of gastric cancer in the stratified analysis, the improvement rate of PS in the Aidi group was significantly higher than that in the control group (OR = 3.7, 95% CI 1.9-7.2).	('improvement', 'PosReg', (72, 83))	('Aidi', 'Chemical', '-', (102, 106))	('PS', 'Chemical', '-', (92, 94))	('gastric cancer', 'Phenotype', 'HP:0012126', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Aidi', 'Var', (102, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (25, 39))	('gastric cancer', 'Disease', (25, 39))	('higher', 'PosReg', (131, 137))
936641	30482065	These results revealed that patients with gastric cancer could benefit from using Aidi injection compared with non-Aidi-users.	('Aidi injection', 'Chemical', '-', (82, 96))	('gastric cancer', 'Phenotype', 'HP:0012126', (42, 56))	('Aidi', 'Chemical', '-', (115, 119))	('gastric cancer', 'Disease', (42, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (42, 56))	('Aidi', 'Chemical', '-', (82, 86))	('Aidi', 'Var', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('patients', 'Species', '9606', (28, 36))
936643	30482065	In our study, the result of presence of hepatic insufficiency substantially inhibited any gains (OR = 0.5, 95% CI 0.2-1.0) in PS compared with normal liver function.	('hepatic insufficiency', 'Disease', (40, 61))	('presence', 'Var', (28, 36))	('gains', 'PosReg', (90, 95))	('PS', 'Chemical', '-', (126, 128))	('normal liver function', 'Phenotype', 'HP:0001410', (143, 164))	('inhibited', 'NegReg', (76, 85))	('hepatic insufficiency', 'Phenotype', 'HP:0001399', (40, 61))	('hepatic insufficiency', 'Disease', 'MESH:D000309', (40, 61))
936702	29738752	Patients with  NLR > 2.87 had a significantly lower likelihood of pCR compared with patients with  NLR <= 2.87 (OR, 0.28 [95% CI, 0.07-0.85], p=0.036; See Tables 3-4).	('pCR', 'Disease', (66, 69))	('patients', 'Species', '9606', (84, 92))	('NLR > 2.87', 'Var', (15, 25))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (46, 51))
936718	29738752	Hence, high NLR is associated, not only with reduced treatment response, but also with worse outcomes in many solid tumors, including ESCC.	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('reduced', 'NegReg', (45, 52))	('treatment response', 'CPA', (53, 71))	('ESCC', 'Disease', (134, 138))	('solid tumors', 'Disease', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('high', 'Var', (7, 11))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('NLR', 'Gene', (12, 15))
936745	28454121	The invasiveness of the cells were suppressed by treating with sb203580 (p38/MAPK inhibitor) or HY-13805 (PP2, Src inhibitor).	('sb203580', 'Chemical', 'MESH:C093642', (63, 71))	('HY-13805', 'Var', (96, 104))	('PP2', 'Gene', (106, 109))	('Src', 'Gene', '6714', (111, 114))	('p38', 'Gene', (73, 76))	('PP2', 'Gene', '4888', (106, 109))	('HY-13805', 'Chemical', '-', (96, 104))	('suppressed', 'NegReg', (35, 45))	('p38', 'Gene', '5594', (73, 76))	('sb203580', 'Var', (63, 71))	('Src', 'Gene', (111, 114))	('invasiveness of the cells', 'CPA', (4, 29))
936746	28454121	furthermore, p38/MAPK inhibition could block the KLF17-induced reduction of p-p38/MAPK and uPA, and Src inhibition enhanced the KLF17-induced suppression of p-Src and uPA in A549 and H322 cells.	('uPA', 'Gene', (167, 170))	('uPA', 'Gene', '5328', (167, 170))	('Src', 'Gene', '6714', (159, 162))	('H322', 'CellLine', 'CVCL:1556', (183, 187))	('p38', 'Gene', '5594', (13, 16))	('suppression', 'NegReg', (142, 153))	('p38', 'Gene', '5594', (78, 81))	('Src', 'Gene', (100, 103))	('inhibition', 'Var', (104, 114))	('A549', 'CellLine', 'CVCL:0023', (174, 178))	('uPA', 'Gene', (91, 94))	('uPA', 'Gene', '5328', (91, 94))	('Src', 'Gene', '6714', (100, 103))	('KLF17', 'Gene', '128209', (49, 54))	('KLF17', 'Gene', '128209', (128, 133))	('reduction', 'NegReg', (63, 72))	('KLF17', 'Gene', (49, 54))	('KLF17', 'Gene', (128, 133))	('enhanced', 'PosReg', (115, 123))	('Src', 'Gene', (159, 162))	('p38', 'Gene', (78, 81))	('p38', 'Gene', (13, 16))
936763	28454121	Downregulation of uPA and its receptors can inhibit tumor cell growth, invasion and survival.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('inhibit', 'NegReg', (44, 51))	('invasion', 'CPA', (71, 79))	('Downregulation', 'Var', (0, 14))	('uPA', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('survival', 'CPA', (84, 92))	('uPA', 'Gene', '5328', (18, 21))
936788	28454121	As expected, the ectopic expression of KLF17 led to the downregulation of uPA protein in A549 and H322 cells (Figure 2B, 2C).	('KLF17', 'Gene', (39, 44))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('uPA', 'Gene', (74, 77))	('uPA', 'Gene', '5328', (74, 77))	('downregulation', 'NegReg', (56, 70))	('H322', 'CellLine', 'CVCL:1556', (98, 102))	('ectopic expression', 'Var', (17, 35))	('KLF17', 'Gene', '128209', (39, 44))
936789	28454121	For further validation of whether uPA expression was suppressed by KLF17 at a transcriptional level, luciferase vectors containing different sequences were co-transfected with pcDNA3.1(+)-KLF17 or mock vectors in 293FT cells for 48 h, and then, they were detected by a dual-luciferase reporter assay, and the results showed that the promoter sequence (-2950 to -2000) was bound by the KLF17 protein, but not in the -2000 to +200 region.	('293FT', 'CellLine', 'CVCL:6911', (213, 218))	('KLF17', 'Gene', '128209', (188, 193))	('KLF17', 'Gene', (67, 72))	('KLF17', 'Gene', '128209', (385, 390))	('uPA', 'Gene', (34, 37))	('KLF17', 'Gene', (188, 193))	('uPA', 'Gene', '5328', (34, 37))	('KLF17', 'Gene', (385, 390))	('KLF17', 'Gene', '128209', (67, 72))	('-2950 to -2000', 'Var', (352, 366))
936790	28454121	These data demonstrated that KLF17 protein could combine with the uPA promoter sequence at (-2950 to -2000) and inhibited the expression of uPA (Figure 2D and 2E).	('-2950 to -2000', 'Var', (92, 106))	('expression', 'MPA', (126, 136))	('inhibited', 'NegReg', (112, 121))	('uPA', 'Gene', (140, 143))	('KLF17', 'Gene', '128209', (29, 34))	('uPA', 'Gene', (66, 69))	('combine', 'Interaction', (49, 56))	('uPA', 'Gene', '5328', (140, 143))	('uPA', 'Gene', '5328', (66, 69))	('KLF17', 'Gene', (29, 34))
936809	28454121	There is increasing evidence indicating that uPA was activated by the p38/MAPK and Src signaling pathways, and inhibiton of the p38/MAPK and Src also supress the invasion of cancer cells.	('activated', 'PosReg', (53, 62))	('p38', 'Gene', (128, 131))	('p38', 'Gene', (70, 73))	('supress', 'NegReg', (150, 157))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('Src', 'Gene', (141, 144))	('Src', 'Gene', (83, 86))	('p38', 'Gene', '5594', (128, 131))	('p38', 'Gene', '5594', (70, 73))	('Src', 'Gene', '6714', (141, 144))	('uPA', 'Gene', (45, 48))	('Src', 'Gene', '6714', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('uPA', 'Gene', '5328', (45, 48))	('inhibiton', 'Var', (111, 120))
936814	28454121	The invasion asssy showed that inhibition of p38/MAPK and Src suppressed the invasion of A549 and H322 cells in a dose-dependent manner (Supplementary Figure 1).	('p38', 'Gene', (45, 48))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('Src', 'Gene', (58, 61))	('Src', 'Gene', '6714', (58, 61))	('p38', 'Gene', '5594', (45, 48))	('suppressed', 'NegReg', (62, 72))	('H322', 'CellLine', 'CVCL:1556', (98, 102))	('inhibition', 'Var', (31, 41))	('men', 'Species', '9606', (143, 146))
936815	28454121	The western blot analysis showed that p38/MAPK inhibition led to a decrease in the expression of p-p38/MAPK or uPA in a dose-dependent manner in the parental or control groups, but p38/MAPK inhibition could block the KLF17-induced reduction of p-p38/MAPK and uPA in the KLF17-overexpression groups.	('p38', 'Gene', (181, 184))	('p38', 'Gene', (99, 102))	('expression', 'MPA', (83, 93))	('uPA', 'Gene', (111, 114))	('KLF17', 'Gene', '128209', (217, 222))	('uPA', 'Gene', '5328', (111, 114))	('p38', 'Gene', '5594', (181, 184))	('p38', 'Gene', '5594', (38, 41))	('KLF17', 'Gene', (217, 222))	('p38', 'Gene', '5594', (99, 102))	('decrease', 'NegReg', (67, 75))	('inhibition', 'Var', (47, 57))	('uPA', 'Gene', (259, 262))	('p38', 'Gene', (246, 249))	('uPA', 'Gene', '5328', (259, 262))	('KLF17', 'Gene', '128209', (270, 275))	('KLF17', 'Gene', (270, 275))	('p38', 'Gene', '5594', (246, 249))	('p38', 'Gene', (38, 41))
936853	28454121	In addition, Src inhibition enhanced the KLF17-induced suppression of p-Src and uPA in the KLF17-overexpression groups of A549 and H322 cells.	('uPA', 'Gene', (80, 83))	('KLF17', 'Gene', (91, 96))	('suppression', 'NegReg', (55, 66))	('Src', 'Gene', (13, 16))	('Src', 'Gene', '6714', (13, 16))	('uPA', 'Gene', '5328', (80, 83))	('KLF17', 'Gene', '128209', (41, 46))	('enhanced', 'PosReg', (28, 36))	('H322', 'CellLine', 'CVCL:1556', (131, 135))	('inhibition', 'Var', (17, 27))	('Src', 'Gene', '6714', (72, 75))	('KLF17', 'Gene', (41, 46))	('Src', 'Gene', (72, 75))	('KLF17', 'Gene', '128209', (91, 96))	('A549', 'CellLine', 'CVCL:0023', (122, 126))
936861	28454121	Lentivirus vector pLV.0-KLF17 containing the human KLF17 coding sequence(NM_173484;1170 bp) or the control empty vector (pLV.0-NC) were purchased from GeneCopoeia (MD).	('KLF17', 'Gene', '128209', (24, 29))	('KLF17', 'Gene', '128209', (51, 56))	('human', 'Species', '9606', (45, 50))	('NM_173484', 'Var', (73, 82))	('KLF17', 'Gene', (24, 29))	('KLF17', 'Gene', (51, 56))
936882	28454121	Additionally, different mutations of the uPA promoter sequences were ligated into the pGL3-Basic vector in the same manner, which were named as pGL3-uPA (-2950/+200 bp) and pGL3-uPA (-2000 /+200 bp).	('pGL3', 'Gene', (86, 90))	('pGL3', 'Gene', '6391', (144, 148))	('uPA', 'Gene', '5328', (149, 152))	('-2950/+200 bp', 'Var', (154, 167))	('uPA', 'Gene', '5328', (41, 44))	('pGL3', 'Gene', (173, 177))	('uPA', 'Gene', (178, 181))	('-2000 /+200', 'Var', (183, 194))	('uPA', 'Gene', (41, 44))	('uPA', 'Gene', '5328', (178, 181))	('pGL3', 'Gene', '6391', (86, 90))	('uPA', 'Gene', (149, 152))	('pGL3', 'Gene', '6391', (173, 177))	('pGL3', 'Gene', (144, 148))
936884	28454121	For the reporter assays, The pGL3-Basic and different pGL3-uPA mutant vectors were co-transfected into HEK-293FT cells in 24-well plates with pcDNA3.1(+)-KLF17 or negative control vector (pcDNA3.1(+)) and Renilla plasmid (20 ng) using Lipofectamine 2000 (Invitrogen).	('mutant', 'Var', (63, 69))	('293FT', 'CellLine', 'CVCL:6911', (107, 112))	('HEK-293', 'CellLine', 'CVCL:0045', (103, 110))	('KLF17', 'Gene', (154, 159))	('Lipofectamine', 'Chemical', 'MESH:C086724', (235, 248))	('pGL3', 'Gene', (29, 33))	('pGL3', 'Gene', (54, 58))	('uPA', 'Gene', (59, 62))	('uPA', 'Gene', '5328', (59, 62))	('pGL3', 'Gene', '6391', (29, 33))	('pGL3', 'Gene', '6391', (54, 58))	('KLF17', 'Gene', '128209', (154, 159))
936932	28529615	The survival rate decreased in high FAR patients compared with low FAR patients (p <0.001; Fig.	('survival rate', 'CPA', (4, 17))	('high FAR', 'Var', (31, 39))	('decreased', 'NegReg', (18, 27))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (71, 79))
936947	28529615	In addition, several studies reported that anticoagulants, such as low-molecular-weight heparins and heparins, may prolong survival in cancer patients by preventing the progression of metastasis.	('cancer', 'Disease', (135, 141))	('survival', 'CPA', (123, 131))	('heparins', 'Chemical', 'MESH:D006493', (101, 109))	('heparins', 'Chemical', 'MESH:D006493', (88, 96))	('low-molecular-weight', 'Var', (67, 87))	('prolong', 'PosReg', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('preventing', 'NegReg', (154, 164))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
937009	28536608	Univariate analysis showed that, among the clinicopathological factors examined in this study, the extent of primary tumor (risk ratio, 4.184; p < 0.0001), lymph node metastasis (risk ratio, 4.149; p < 0.0001), lymphatic invasion (risk ratio, 6.622; p = 0.003), vein invasion (risk ratio, 2.816; p = 0.0003), and immunostaining for TCF4/TCF7L2 (risk ratio, 2.506; p = 0.0049) were statistically significant prognostic factors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('lymph node metastasis', 'CPA', (156, 177))	('immunostaining', 'Var', (313, 327))	('tumor', 'Disease', (117, 122))	('vein invasion', 'CPA', (262, 275))	('TCF7L2', 'Gene', (337, 343))	('lymphatic invasion', 'CPA', (211, 229))	('TCF7L2', 'Gene', '6934', (337, 343))	('TCF4', 'Gene', (332, 336))	('TCF4', 'Gene', '6925', (332, 336))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
937031	28536608	In addition, patients with high nuclear expression of TCF4/TCF7L2 had a poorer prognosis (Fig.	('high nuclear', 'Var', (27, 39))	('patients', 'Species', '9606', (13, 21))	('TCF7L2', 'Gene', (59, 65))	('TCF4', 'Gene', (54, 58))	('TCF4', 'Gene', '6925', (54, 58))	('TCF7L2', 'Gene', '6934', (59, 65))
937069	27240449	BMI was divided into five groups based upon the commonly accepted classification: underweight (BMI < 18.5 kg/m2), Normal weight (BMI >=18.5 and <25.0 kg/m2), overweight (BMI >=25.0 and <30.0 kg/m2), obesity class I (BMI >=30 and < 35 kg/m2), obesity class II or III (BMI >=35 kg/m2).	('obesity class I', 'Phenotype', 'HP:0025499', (199, 214))	('obesity', 'Disease', (242, 249))	('obesity', 'Phenotype', 'HP:0001513', (199, 206))	('obesity class I', 'Phenotype', 'HP:0025499', (242, 257))	('obesity class II', 'Disease', (242, 258))	('obesity class II or III', 'Phenotype', 'HP:0025501', (242, 265))	('underweight', 'Disease', (82, 93))	('overweight', 'Phenotype', 'HP:0025502', (158, 168))	('obesity', 'Disease', 'MESH:D009765', (199, 206))	('obesity', 'Phenotype', 'HP:0001513', (242, 249))	('overweight', 'Disease', (158, 168))	('obesity', 'Disease', (199, 206))	('BMI >=30', 'Var', (216, 224))	('obesity class II', 'Phenotype', 'HP:0025500', (242, 258))	('obesity class II', 'Disease', 'MESH:D009765', (242, 258))	('obesity', 'Disease', 'MESH:D009765', (242, 249))
937082	27240449	These include age >65, congestive heart failure, Zubrod Score>1, past or current smoking status, BMI >35, squamous histology and McKeown or "three hole" esophagectomy.	('squamous', 'Disease', (106, 114))	('congestive heart failure', 'Phenotype', 'HP:0001635', (23, 47))	('congestive heart failure', 'Disease', (23, 47))	('congestive heart failure', 'Disease', 'MESH:D006333', (23, 47))	('BMI >35', 'Var', (97, 104))	('McK', 'Gene', (129, 132))	('McK', 'Gene', '1158', (129, 132))
937107	27468417	We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC).	('EAC', 'Phenotype', 'HP:0011459', (184, 187))	('EAC', 'Gene', '1540', (184, 187))	('EAC', 'Gene', (184, 187))	('predispose', 'Reg', (131, 141))	('BE', 'Phenotype', 'HP:0100580', (177, 179))	('variants', 'Var', (117, 125))
937121	27468417	The results of the segregation analysis led us to conduct a linkage study in 42 pedigrees to identify genomic regions that might contain genetic variants that predispose individuals to develop BE and EAC.	('EAC', 'Gene', '1540', (200, 203))	('predispose', 'Reg', (159, 169))	('BE', 'Phenotype', 'HP:0100580', (193, 195))	('variants', 'Var', (145, 153))	('EAC', 'Gene', (200, 203))	('EAC', 'Phenotype', 'HP:0011459', (200, 203))
937146	27468417	(2010) studied IGF Axis Polymorphisms and reported SNPs in three genes (IGF1, IGF1R, and GHR) to be associated with BE, EAC, or reflux esophagitis.	('reflux esophagitis', 'Disease', (128, 146))	('reflux esophagitis', 'Disease', 'MESH:D005764', (128, 146))	('IGF1', 'Gene', (78, 82))	('IGF1R', 'Gene', (78, 83))	('IGF1', 'Gene', '3479', (72, 76))	('associated', 'Reg', (100, 110))	('IGF1R', 'Gene', '3480', (78, 83))	('EAC', 'Phenotype', 'HP:0011459', (120, 123))	('BE', 'Phenotype', 'HP:0100580', (116, 118))	('SNPs', 'Var', (51, 55))	('IGF1', 'Gene', '3479', (78, 82))	('EAC', 'Gene', '1540', (120, 123))	('IGF1', 'Gene', (72, 76))	('esophagitis', 'Phenotype', 'HP:0100633', (135, 146))	('EAC', 'Gene', (120, 123))	('GHR', 'Gene', (89, 92))	('GHR', 'Gene', '2690', (89, 92))
937148	27468417	The associated SNP rs6214 in IGF1 that was reported by McElholm et al.	('IGF1', 'Gene', (29, 33))	('rs6214', 'Mutation', 'rs6214', (19, 25))	('SNP rs6214', 'Var', (15, 25))	('IGF1', 'Gene', '3479', (29, 33))
937150	27468417	The associated SNPs (rs2715425 and rs4966044) in IGF1R are located in the linkage region on chromosome 15, 840 kb from the peak SNP rs2045112.	('rs2715425', 'Var', (21, 30))	('rs4966044', 'Mutation', 'rs4966044', (35, 44))	('rs2715425', 'Mutation', 'rs2715425', (21, 30))	('IGF1R', 'Gene', '3480', (49, 54))	('rs2045112', 'Var', (132, 141))	('rs4966044', 'Var', (35, 44))	('rs2045112', 'Mutation', 'rs2045112', (132, 141))	('IGF1R', 'Gene', (49, 54))
937151	27468417	(2011) reported linkage on 8q21 (rs3097418) and association on 8q22, which are both located in our linkage regions.	('rs3097418', 'Mutation', 'rs3097418', (33, 42))	('rs3097418', 'Var', (33, 42))	('association', 'Interaction', (48, 59))	('linkage', 'Var', (16, 23))
937157	27468417	Furthermore, although there is no reported association located in the linkage region on chromosome 2q31 that we identified by multiple linkage analyses, prior studies have reported somatic mutations in genes mapping to this region in Barrett's adenocarcinomas (Walch et al.	("Barrett's adenocarcinomas", 'Disease', (234, 259))	('mutations', 'Var', (189, 198))	("Barrett's adenocarcinomas", 'Disease', 'MESH:D001471', (234, 259))
937158	27468417	In addition, in the Genotype-Tissue Expression (GTEx) database (GTEx Consortium, 2015), we found that rs711814 in the chromosome 2 linkage region is a significant cis-eQTL (P = 0.0000031) that regulates the KIAA1715 expressed in esophagus mucosa, and the peak SNP rs3205421 in the chromosome 12 region is a significant cis-eQTL (P = 2 x 10-13) that regulates the GNPTAB gene expressed in esophagus muscularis (http://www.gtexportal.org/home/eqtls/).	('GNPTAB', 'Gene', (363, 369))	('regulates', 'Reg', (193, 202))	('KIAA1715', 'Gene', (207, 215))	('rs3205421', 'Mutation', 'rs3205421', (264, 273))	('rs711814', 'Mutation', 'rs711814', (102, 110))	('rs711814', 'Var', (102, 110))	('KIAA1715', 'Gene', '80856', (207, 215))	('GNPTAB', 'Gene', '79158', (363, 369))
937160	27468417	If, for example, evidence for linkage changes when BMI is included as a covariate, a genome-wide association study of this obesity-related disease would locate the risk variants by addressing the impact of BMI on the association(Schaid et al.	('variants', 'Var', (169, 177))	('obesity', 'Disease', (123, 130))	('obesity', 'Disease', 'MESH:D009765', (123, 130))	('obesity', 'Phenotype', 'HP:0001513', (123, 130))
937335	30350456	The mean utility scores of each patient subgroup were 0.158, 0.289, 0.303, 0.296, and 0.505 (95% CIs: 0.108-0.208, 0.243-0.336, 0.261-0.346, 0.244-0.347, and 0.437-0.573) lower than controls, respectively.	('0.243-0.336', 'Var', (115, 126))	('0.296', 'Var', (75, 80))	('utility scores', 'MPA', (9, 23))	('patient', 'Species', '9606', (32, 39))	('lower', 'NegReg', (171, 176))
937426	30087123	Serologic case-control studies also provide conflicting evidence, with a meta-analysis reporting an odds ratio (OR) of 1.89 (95% confidence interval [CI] = 1.09 to 3.29) for HPV16 E6 antibodies and ESCC, but no association for E7 antibodies.	('SCC', 'Gene', (199, 202))	('HPV16', 'Species', '333760', (174, 179))	('SCC', 'Gene', '6317', (199, 202))	('HPV16', 'Gene', (174, 179))	('E6 antibodies', 'Var', (180, 193))
937430	30087123	We recently reported that in addition to HPV16, detection of several beta and gamma HPV species and types in the oral cavity were positively associated with risk of head and neck cancer independent of HPV16.	('HPV', 'Species', '10566', (41, 44))	('HPV16', 'Species', '333760', (201, 206))	('head and neck cancer', 'Phenotype', 'HP:0012288', (165, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('HPV', 'Species', '10566', (201, 204))	('associated with', 'Reg', (141, 156))	('head and neck cancer', 'Disease', 'MESH:D006258', (165, 185))	('HPV16', 'Species', '333760', (41, 46))	('HPV', 'Species', '10566', (84, 87))	('detection', 'Var', (48, 57))
937458	30087123	For alpha HPVs, we examined associations for the following exposures: HPV16; other high-risk (HR) oncogenic HPV types i.e., HPV18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59; other non-HR alpha HPV types; and any alpha HPV type.	('HPV', 'Species', '10566', (10, 13))	('HPV', 'Species', '10566', (124, 127))	('HPV', 'Species', '10566', (108, 111))	('HPV', 'Species', '10566', (70, 73))	('HPV', 'Species', '10566', (215, 218))	('HPV', 'Species', '10566', (190, 193))	('HPV16', 'Species', '333760', (70, 75))	('HPV18', 'Var', (124, 129))	('HPV16', 'Var', (70, 75))
937494	30087123	There were also no statistically significant associations between oral HPV coinfection and risk of esophageal cancer.	('oral HPV', 'Gene', (66, 74))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('coinfection', 'Var', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('HPV', 'Species', '10566', (71, 74))	('esophageal cancer', 'Disease', (99, 116))
937505	30087123	A number of studies from China have reported a positive association between oncogenic HPVs and esophageal cancer.	('HPV', 'Species', '10566', (86, 89))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('esophageal cancer', 'Disease', (95, 112))	('oncogenic HPVs', 'Var', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
937510	30087123	A meta-analysis of serologic case-control studies reported an OR of 1.89 (95%CI, 1.09 - 3.29) between HPV16 E6 antibodies and risk of ESCC, but there was no association for E7 antibodies.	('E6 antibodies', 'Var', (108, 121))	('HPV16', 'Species', '333760', (102, 107))	('HPV16', 'Gene', (102, 107))	('SCC', 'Gene', (135, 138))	('antibodies', 'Var', (111, 121))	('SCC', 'Gene', '6317', (135, 138))
937558	30615715	In that case, the EEGS result is closer to Obs.1 than GTDP because the modified Canny map in EEGS enhances the edge details, thus compensating for the loss of precision of the vertical gradients used by GTDP.	('enhances', 'PosReg', (98, 106))	('edge', 'MPA', (111, 115))	('modified', 'Var', (71, 79))	('GTDP', 'Chemical', '-', (54, 58))	('GTDP', 'Chemical', '-', (203, 207))
937577	29426342	When the dosimetric parameters of the dose distributions for the treatment of patients with locally advanced stage III ESCC were compared between PBT and 3DCRT or IMRT, PBT enabled a significant reduction in the dose to the lung and heart, compared with 3DCRT or IMRT.	('dose', 'MPA', (212, 216))	('reduction', 'NegReg', (195, 204))	('patients', 'Species', '9606', (78, 86))	('PBT', 'Var', (169, 172))
937624	29426342	When the dosimetric parameters between the PBT and 3DCRT plans were compared, all the PBT domestic variables regarding the lung dose except for the lung V10 GyE and V15 GyE were significantly lower than those of the dummy 3DCRT plans (Table 3).	('GyE', 'Chemical', '-', (169, 172))	('V15', 'Gene', '28814', (165, 168))	('lower', 'NegReg', (192, 197))	('lung dose', 'MPA', (123, 132))	('V10 GyE', 'Var', (153, 160))	('GyE', 'Chemical', '-', (157, 160))	('V15', 'Gene', (165, 168))
937642	29426342	Actually, in a study comparing PBT with photon radiation therapy for esophageal cancer evaluated according to the tumor control probability (TCP) and the normal tissue complication probability (NTCP), the PBT plans were able to reduce the doses to structures of the lung and heart better like this study and appeared to have clear therapeutic advantages over photon radiation therapy.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('esophageal cancer', 'Disease', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PBT', 'Var', (205, 208))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('tumor', 'Disease', (114, 119))	('doses', 'MPA', (239, 244))	('reduce', 'NegReg', (228, 234))
937643	29426342	compared 4-dimensional computed tomography-based treatment plans with PBT or IMRT for distal esophageal cancer, and the application of PBT resulted in a more significant dose reduction to the lung than IMRT; however, no improvement in the dose to the heart was seen.	('dose', 'MPA', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('PBT', 'Var', (135, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('reduction', 'NegReg', (175, 184))
937707	29228748	Third, KRAS mutation status can also affect the efficacy of anti-EGFR therapy.	('KRAS', 'Gene', '3845', (7, 11))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('affect', 'Reg', (37, 43))	('mutation', 'Var', (12, 20))	('KRAS', 'Gene', (7, 11))
937712	29228748	Several studies in these cancers have suggested that EGFR expression, EGFR gene copy number, or expression of other EGFR ligands (epiregulin and amphiregulin) might be potential biomarkers for efficacy of anti-EGFR antibodies.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('amphiregulin', 'Gene', (145, 157))	('EGFR', 'Gene', (210, 214))	('EGFR', 'Gene', '1956', (70, 74))	('expression', 'MPA', (96, 106))	('EGFR', 'Gene', (70, 74))	('amphiregulin', 'Gene', '374', (145, 157))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('copy number', 'Var', (80, 91))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('cancers', 'Disease', (25, 32))	('EGFR', 'Gene', '1956', (116, 120))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('EGFR', 'Gene', (116, 120))	('EGFR', 'Gene', '1956', (210, 214))
937880	28086225	While some authors have also explored the potential correlation between its expression in squamous cell carcinoma and its lymphatic metastasis, we found that D2-40 was significantly expressed in the basal layer cells in the normal squamous epithelium but not in squamous cells above the basal layer.	('D2-40', 'Var', (158, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))
937899	28086225	In patients with missing expression, the poloidal disorder of cells in the basal layer, was replaced by atypical tumor cells.	('tumor', 'Disease', (113, 118))	('missing expression', 'Var', (17, 35))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('poloidal disorder of', 'MPA', (41, 61))
937900	28086225	In lesions with non-continuous PDPN expression, the squamous epithelial layer was almost completely tumorized except a small number of residual basal layer cells were occasionally visible.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('PDPN', 'Gene', '10630', (31, 35))	('PDPN', 'Gene', (31, 35))	('non-continuous', 'Var', (16, 30))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
937937	28086225	Our study confirmed that displaying the basal layer with D2-40 clone of PDPN is a potential biomarker to identify the presence of any infiltration.	('PDPN', 'Gene', '10630', (72, 76))	('PDPN', 'Gene', (72, 76))	('rat', 'Species', '10116', (140, 143))	('D2-40 clone', 'Var', (57, 68))
937999	24131756	However, in the 113 cases with positive lymph nodes, the 5-year OS rates were 5.2% for patients with high EGFR expression, and 12.5% for those with low expression (P = 0.067).	('expression', 'MPA', (111, 121))	('EGFR', 'Gene', '1956', (106, 110))	('high', 'Var', (101, 105))	('patients', 'Species', '9606', (87, 95))	('EGFR', 'Gene', (106, 110))
938001	24131756	Furthermore, in 87 cases of patients with stage T3N0M0 IIA (UICC seventh edition) disease, the 5-year OS rate for patients with high EGFR expression was significantly lower than those with low EGFR expression (29.3% compared with 48.3%; P = 0.026).	('lower', 'NegReg', (167, 172))	('UICC seventh edition', 'Disease', 'MESH:D005155', (60, 80))	('EGFR', 'Gene', '1956', (193, 197))	('stage T3N0M0 IIA', 'Var', (42, 58))	('UICC seventh edition', 'Disease', (60, 80))	('EGFR', 'Gene', (193, 197))	('expression', 'MPA', (138, 148))	('EGFR', 'Gene', '1956', (133, 137))	('high', 'Var', (128, 132))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (28, 36))	('EGFR', 'Gene', (133, 137))
938011	24131756	More importantly, OS and DFS rates were significantly lower in patients with high EGFR expression than in patients with little or no EGFR expression.	('EGFR', 'Gene', (82, 86))	('high', 'Var', (77, 81))	('EGFR', 'Gene', '1956', (133, 137))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (63, 71))	('EGFR', 'Gene', '1956', (82, 86))	('EGFR', 'Gene', (133, 137))	('lower', 'NegReg', (54, 59))
938017	24131756	showed that the 5-year OS rate was about 60% for T2N0M0 esophageal cancer and about 50% for T3N0M0, a difference that is statistically significant.	('esophageal cancer', 'Disease', (56, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('T2N0M0', 'Var', (49, 55))
938026	24131756	Clinically, EGFR mutation and aberrant overexpression may lead to human carcinogenesis and tumor progression, including esophageal cancer.	('overexpression', 'PosReg', (39, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('aberrant', 'Var', (30, 38))	('tumor', 'Disease', (91, 96))	('mutation', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('human', 'Species', '9606', (66, 71))	('lead to', 'Reg', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('EGFR', 'Gene', '1956', (12, 16))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('carcinogenesis', 'Disease', (72, 86))	('EGFR', 'Gene', (12, 16))	('esophageal cancer', 'Disease', (120, 137))
938028	24131756	Thus, such treatment may extend to esophageal cancer patients with high EGFR expression and provide a survival benefit.	('expression', 'MPA', (77, 87))	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (53, 61))	('EGFR', 'Gene', '1956', (72, 76))	('esophageal cancer', 'Disease', (35, 52))	('EGFR', 'Gene', (72, 76))	('esophageal cancer', 'Disease', 'MESH:D004938', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('survival benefit', 'CPA', (102, 118))
938030	24131756	This study also showed that the OS and DFS rates were significantly lower in ESCC patients with high EGFR expression than in those with low EGFR expression.	('lower', 'NegReg', (68, 73))	('EGFR', 'Gene', (140, 144))	('ESCC', 'Disease', (77, 81))	('patients', 'Species', '9606', (82, 90))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('high', 'Var', (96, 100))	('EGFR', 'Gene', '1956', (140, 144))
938033	24131756	Therefore, our current data suggest that EGFR expression should be included as a supplement to UICC staging, especially for T2/T3N0M0 and lymph node-negative patients.	('patients', 'Species', '9606', (158, 166))	('EGFR', 'Gene', '1956', (41, 45))	('EGFR', 'Gene', (41, 45))	('T2/T3N0M0', 'Var', (124, 133))
938042	32323889	Comprehensive genomic profiling obtained from liver metastases identified numerous genomic alterations including amplification of NTRK1.	('liver metastases', 'Disease', 'MESH:D009362', (46, 62))	('NTRK1', 'Gene', (130, 135))	('NTRK1', 'Gene', '4914', (130, 135))	('amplification', 'Var', (113, 126))	('liver metastases', 'Disease', (46, 62))
938044	32323889	Although larotrectinib is only approved for the treatment of cancers with NTRK gene fusions, treatment was started and led to a shrinkage of the primary tumor as well as the liver and lung metastases within 6 weeks according to RECIST criteria accompanied by tumor marker decrease.	('gene fusions', 'Var', (79, 91))	('liver and lung metastases', 'Disease', 'MESH:D009362', (174, 199))	('TRK', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('TRK', 'Gene', '4914', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('decrease', 'NegReg', (272, 280))	('tumor', 'Disease', (153, 158))	('cancers', 'Disease', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('shrinkage', 'NegReg', (128, 137))	('tumor', 'Disease', (259, 264))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('larotrectinib', 'Chemical', 'MESH:C000609083', (9, 22))
938046	32323889	The use of comprehensive genomic profiling, specifically F1CDx, enabled the selection of a targeted therapy that led to a rapid reduction of the tumor and its metastases according to RECIST criteria.	('metastases', 'Disease', (159, 169))	('reduction of the tumor', 'Disease', 'MESH:D007022', (128, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('metastases', 'Disease', 'MESH:D009362', (159, 169))	('F1CDx', 'Var', (57, 62))	('reduction of the tumor', 'Disease', (128, 150))	('F1CDx', 'Chemical', '-', (57, 62))
938057	32323889	Gene fusions lead to transcription of chimeric TRK oncoproteins that are constitutively active and serve as oncogenic drivers in a wide variety of cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Gene fusions', 'Var', (0, 12))	('fusions', 'Var', (5, 12))	('transcription', 'MPA', (21, 34))	('lead to', 'Reg', (13, 20))	('TRK', 'Gene', (47, 50))	('TRK', 'Gene', '4914', (47, 50))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('chimeric', 'Var', (38, 46))
938060	32323889	Larotrectinib is an orally available selective inhibitor of the TRK receptor family that has shown significant clinical benefit in pediatric and adult patients with NTRK gene fusion in recent years and is now approved in the European Union (EU) and the U.S. 3, 4.	('benefit', 'PosReg', (120, 127))	('TRK', 'Gene', (166, 169))	('TRK', 'Gene', '4914', (166, 169))	('TRK', 'Gene', (64, 67))	('TRK', 'Gene', '4914', (64, 67))	('patients', 'Species', '9606', (151, 159))	('gene fusion', 'Var', (170, 181))	('Larotrectinib', 'Chemical', 'MESH:C000609083', (0, 13))
938072	32323889	In a search of 879 cases with squamous cell carcinoma of the esophagus identified in the Foundation Medicine database, NTRK1 fusions were detected in none and gene amplification in two cases (0.2%).	('detected', 'Reg', (138, 146))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (44, 70))	('fusions', 'Var', (125, 132))	('gene amplification', 'Var', (159, 177))	('NTRK1', 'Gene', '4914', (119, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('NTRK1', 'Gene', (119, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 53))	('squamous cell carcinoma', 'Disease', (30, 53))
938073	32323889	Furthermore, to our knowledge, this is merely the second published case of a patient with NTRK gene amplification who received larotrectinib.	('TRK', 'Gene', (91, 94))	('TRK', 'Gene', '4914', (91, 94))	('larotrectinib', 'Chemical', 'MESH:C000609083', (127, 140))	('patient', 'Species', '9606', (77, 84))	('gene amplification', 'Var', (95, 113))
938085	32323889	FoundationOne CDx is a solid tumor genomic profiling test that detects clinically relevant mutations in cancer-associated genes and provides a comprehensive molecular tumor profile 13, 14, 15, 16.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('FoundationOne CDx', 'Chemical', '-', (0, 17))	('tumor', 'Disease', (29, 34))	('mutations', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', (167, 172))
938089	32323889	The microsatellite status was stable and the tumor mutational burden was classified as intermediate with 10 Muts/Mb.	('tumor', 'Disease', (45, 50))	('microsatellite', 'Var', (4, 18))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))
938109	32323889	In numerous malignancies, mutations in NTRK gene family have been confirmed, although only fusions, in-frame deletions, and splice variations have been identified as oncogenic 1.	('splice variations', 'Var', (124, 141))	('TRK', 'Gene', (40, 43))	('TRK', 'Gene', '4914', (40, 43))	('fusions', 'Var', (91, 98))	('mutations', 'Var', (26, 35))	('malignancies', 'Disease', 'MESH:D009369', (12, 24))	('malignancies', 'Disease', (12, 24))
938110	32323889	Very little has been reported about NTRK gene alterations in esophageal carcinoma.	('esophageal carcinoma', 'Disease', (61, 81))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('TRK', 'Gene', (37, 40))	('TRK', 'Gene', '4914', (37, 40))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (61, 81))	('alterations', 'Var', (46, 57))
938111	32323889	Considering our findings, NTRK1 alterations in squamous cell carcinoma occur at an extremely low frequency of 0.2%, as identified in the Foundation Medicine database.	('NTRK1', 'Gene', '4914', (26, 31))	('alterations', 'Var', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 70))	('NTRK1', 'Gene', (26, 31))	('squamous cell carcinoma', 'Disease', (47, 70))
938122	32323889	Similar to ERBB2 gene amplification, which is a well-established class of driver gene alteration in breast and gastric cancer, protein overexpression of NTRK amplified tumors is inconsistent.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('tumors', 'Disease', (168, 174))	('TRK', 'Gene', (154, 157))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('TRK', 'Gene', '4914', (154, 157))	('breast and gastric cancer', 'Disease', 'MESH:D001943', (100, 125))	('ERBB2', 'Gene', (11, 16))	('alteration', 'Var', (86, 96))	('ERBB2', 'Gene', '2064', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
938123	32323889	Recently, NTRK amplification (copy number >=4) was reported to result in a protein overexpression in 14.8% of patients 22.	('protein', 'MPA', (75, 82))	('amplification (copy number >=4', 'Var', (15, 45))	('TRK', 'Gene', (11, 14))	('TRK', 'Gene', '4914', (11, 14))	('overexpression', 'PosReg', (83, 97))	('result in', 'Reg', (63, 72))	('patients', 'Species', '9606', (110, 118))
938130	32323889	Additional investigation is needed to elucidate whether these genes mediate resistance to NTRK inhibition and if cotargeting them augments anti-NTRK antitumor activity.	('mediate', 'Reg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('augments', 'NegReg', (130, 138))	('TRK', 'Gene', (91, 94))	('TRK', 'Gene', '4914', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('genes', 'Var', (62, 67))	('TRK', 'Gene', (145, 148))	('TRK', 'Gene', '4914', (145, 148))
938132	32323889	NTRK1: neurotrophic receptor tyrosine kinase 1RK  CCND1: cyclin D1  CCND2: cyclin D2  CCND3: cyclin D3  EGFR: epidermal growth factor receptor  PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha  CDK6: cyclin dependent kinase 6  HGF: hepatocyte growth factor  SOX2: SRY-box transcription factor 2  CDKN2A/B: cyclin dependent kinase inhibitor 2A/B  EPHB4: ePH receptor B4  FGF19: fibroblast growth factor 19  FGF3: fibroblast growth factor 3  FGF4: fibroblast growth factor 4  MCL1: MCL1 apoptosis regulator  PIM1: Pim-1 proto-oncogene, serine/threonine Kinase  TP53: tumor protein P53  VEGFA: vascular endothelial growth factor A  Conception/design: Dirk Hempel, Thomas Wieland, Beate Solfrank, Vera Grossmann, Johanna Steinhard, Andrea Frick, Louisa Hempel, Thomas Eberl, Andreas Gaumann  Provision of study material or patients: Dirk Hempel, Thomas Wieland, Beate Solfrank, Vera Grossmann, Johanna Steinhard, Andrea Frick, Louisa Hempel, Thomas Eberl, Andreas Gaumann  Manuscript writing: Dirk Hempel, Thomas Wieland, Beate Solfrank, Vera Grossmann, Johanna Steinhard, Andrea Frick, Louisa Hempel, Thomas Eberl, Andreas Gaumann  Final approval of manuscript: Dirk Hempel, Thomas Wieland, Beate Solfrank, Vera Grossmann, Johanna Steinhard, Andrea Frick, Louisa Hempel, Thomas Eberl, Andreas Gaumann  Vera Grossmann: Foundation Medicine Germany GmbH (E).	('PIM1', 'Gene', (536, 540))	('MCL1', 'Gene', (504, 508))	('PIM1', 'Gene', '5292', (536, 540))	('patients', 'Species', '9606', (849, 857))	('HGF', 'Gene', (257, 260))	('PIK3CA', 'Gene', '5290', (144, 150))	('TP53', 'Gene', '7157', (589, 593))	('tumor', 'Phenotype', 'HP:0002664', (595, 600))	('SOX2', 'Gene', '6657', (288, 292))	('CDK6', 'Gene', (224, 228))	('SOX2', 'Gene', (288, 292))	('CCND2', 'Gene', (68, 73))	('CCND1', 'Gene', '595', (50, 55))	('CCND3', 'Gene', '896', (86, 91))	('CCND2', 'Gene', '894', (68, 73))	('MCL1', 'Gene', (510, 514))	('Pim-1', 'Gene', (542, 547))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (152, 189))	('MCL1', 'Gene', '4170', (504, 508))	('EGFR', 'Gene', (104, 108))	('CCND1', 'Gene', (50, 55))	('NTRK1', 'Gene', '4914', (0, 5))	('VEGFA', 'Gene', '7422', (614, 619))	('FGF3', 'Gene', (436, 440))	('FGF19', 'Gene', '9965', (400, 405))	('FGF19', 'Gene', (400, 405))	('FGF3', 'Gene', '2248', (436, 440))	('EPHB4', 'Gene', (376, 381))	('NTRK1', 'Gene', (0, 5))	('MCL1', 'Gene', '4170', (510, 514))	('PIK3CA', 'Gene', (144, 150))	('FGF4', 'Gene', (470, 474))	('vascular endothelial growth factor', 'Gene', '7422', (621, 655))	('serine', 'Chemical', 'MESH:D012694', (564, 570))	('2A/B', 'SUBSTITUTION', 'None', (330, 334))	('2A/B', 'Var', (330, 334))	('TP53', 'Gene', (589, 593))	('tumor', 'Disease', (595, 600))	('EGFR', 'Gene', '1956', (104, 108))	('CCND3', 'Gene', (86, 91))	('vascular endothelial growth factor', 'Gene', (621, 655))	('tumor', 'Disease', 'MESH:D009369', (595, 600))	('2A/B', 'SUBSTITUTION', 'None', (370, 374))	('2A/B', 'Var', (370, 374))	('HGF', 'Gene', '3082', (257, 260))	('CDK6', 'Gene', '1021', (224, 228))	('Pim-1', 'Gene', '5292', (542, 547))	('EPHB4', 'Gene', '2050', (376, 381))	('VEGFA', 'Gene', (614, 619))	('FGF4', 'Gene', '2249', (470, 474))
938154	30561411	H. pylori has been established as a major cause of chronic gastritis, duodenal ulcer, peptic ulcer, dyspepsia and gastric cancer.	('dyspepsia', 'Disease', (100, 109))	('chronic gastritis', 'Phenotype', 'HP:0005231', (51, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('H. pylori', 'Species', '210', (0, 9))	('ulcer', 'Disease', (93, 98))	('H. pylori', 'Var', (0, 9))	('chronic gastritis', 'Disease', 'MESH:D005756', (51, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('ulcer', 'Disease', 'MESH:D014456', (79, 84))	('duodenal ulcer', 'Phenotype', 'HP:0002588', (70, 84))	('chronic gastritis', 'Disease', (51, 68))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('gastric cancer', 'Disease', (114, 128))	('ulcer', 'Disease', 'MESH:D014456', (93, 98))	('ulcer', 'Disease', (79, 84))	('peptic ulcer', 'Phenotype', 'HP:0004398', (86, 98))	('gastritis', 'Phenotype', 'HP:0005263', (59, 68))	('cause', 'Reg', (42, 47))	('dyspepsia', 'Disease', 'MESH:D004415', (100, 109))	('dyspepsia', 'Phenotype', 'HP:0410281', (100, 109))
938217	30681987	We found that phillygenin inhibited the growth of SH-1-V1 cells and exhibited an IC50 of 6 muM.	('inhibited', 'NegReg', (26, 35))	('phillygenin', 'Var', (14, 25))	('phillygenin', 'Chemical', 'MESH:C542294', (14, 25))	('growth', 'CPA', (40, 46))	('muM', 'Gene', '56925', (91, 94))	('muM', 'Gene', (91, 94))
938218	30681987	Investigation of the underlying mechanism revealed that phillygenin triggered apoptotic cell death of the SH-1-V1 cells, which was also associated with enhancement of Bax expression and decreased expression of Bcl-2.	('expression', 'MPA', (171, 181))	('phillygenin', 'Chemical', 'MESH:C542294', (56, 67))	('apoptotic cell death', 'CPA', (78, 98))	('enhancement', 'PosReg', (152, 163))	('Bcl-2', 'Gene', (210, 215))	('Bcl-2', 'Gene', '596', (210, 215))	('expression', 'MPA', (196, 206))	('decreased', 'NegReg', (186, 195))	('Bax', 'Gene', (167, 170))	('phillygenin', 'Var', (56, 67))	('Bax', 'Gene', '581', (167, 170))
938220	30681987	Phillygenin also caused a significant increase in ROS production, concomitant with decreased MMP levels.	('Phillygenin', 'Var', (0, 11))	('increase', 'PosReg', (38, 46))	('MMP levels', 'MPA', (93, 103))	('decreased', 'NegReg', (83, 92))	('increase in ROS production', 'Phenotype', 'HP:0025464', (38, 64))	('ROS', 'Chemical', '-', (50, 53))	('ROS production', 'MPA', (50, 64))
938222	30681987	In brief, phillygenin inhibited in vitro and in vivo cancer cell growth in drug-resistant human esophageal cancer cells, and these effects were mediated via apoptosis, ROS generation, mitochondrial membrane potential loss, and activation of the NF-kappaB signalling pathway.	('inhibited', 'NegReg', (22, 31))	('apoptosis', 'CPA', (157, 166))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('human', 'Species', '9606', (90, 95))	('mitochondrial membrane potential', 'MPA', (184, 216))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('NF-kappaB', 'Gene', (245, 254))	('phillygenin', 'Chemical', 'MESH:C542294', (10, 21))	('NF-kappaB', 'Gene', '4790', (245, 254))	('loss', 'NegReg', (217, 221))	('cancer', 'Disease', (53, 59))	('ROS generation', 'MPA', (168, 182))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (107, 113))	('ROS', 'Chemical', '-', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal cancer', 'Disease', (96, 113))	('phillygenin', 'Var', (10, 21))	('activation', 'PosReg', (227, 237))
938234	30681987	Further, phillygenin can also induce G2/M cell cycle arrest of SH-1-V1 esophageal cancer cells.	('phillygenin', 'Chemical', 'MESH:C542294', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('SH-1-V1 esophageal cancer', 'Disease', 'MESH:D004938', (63, 88))	('SH-1-V1 esophageal cancer', 'Disease', (63, 88))	('G2/M cell cycle arrest', 'CPA', (37, 59))	('phillygenin', 'Var', (9, 20))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (42, 59))
938235	30681987	The in vivo evaluation of phillygenin revealed that it inhibited the tumor volume and weight, indicative of its anticancer potential.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('phillygenin', 'Chemical', 'MESH:C542294', (26, 37))	('tumor', 'Disease', (69, 74))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('phillygenin', 'Var', (26, 37))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('inhibited', 'NegReg', (55, 64))
938261	30681987	The microscopic analysis of the phillygenin-treated esophageal cancer cells revealed that treatment with phillygenin resulted ed some morphological changes, such as blebbing and shrinkage of the nuclear and plasma membrane in the esophageal cancer cells (Figure 2).	('phillygenin', 'Chemical', 'MESH:C542294', (32, 43))	('phillygenin', 'Chemical', 'MESH:C542294', (105, 116))	('esophageal cancer', 'Disease', 'MESH:D004938', (230, 247))	('shrinkage', 'NegReg', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('esophageal cancer', 'Disease', (52, 69))	('blebbing', 'CPA', (165, 173))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('phillygenin', 'Var', (105, 116))	('esophageal cancer', 'Disease', (230, 247))
938262	30681987	To determine if phillygenin triggers apoptotic cell death of esophageal carcinoma cells, the cells were treated with phillygenin and subjected to propidium iodide staining, showing that phillygenin induced apoptotic cell death in the esophageal cancer cells (Figure 3).	('esophageal carcinoma', 'Disease', (61, 81))	('esophageal cancer', 'Disease', (234, 251))	('propidium iodide', 'Chemical', 'MESH:D011419', (146, 162))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('phillygenin', 'Chemical', 'MESH:C542294', (16, 27))	('phillygenin', 'Chemical', 'MESH:C542294', (186, 197))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (61, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (234, 251))	('apoptotic cell death', 'CPA', (206, 226))	('phillygenin', 'Chemical', 'MESH:C542294', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('phillygenin', 'Var', (186, 197))
938263	30681987	Analysis of the protein expression of the apoptosis biomarker proteins revealed that phillygenin increase the expression of Bax and cleaved caspase 3 and 9, and the expression of Bcl-2 was decreased in a concentration-dependent manner (Figure 4).	('increase', 'PosReg', (97, 105))	('decreased', 'NegReg', (189, 198))	('Bax', 'Gene', '581', (124, 127))	('phillygenin', 'Chemical', 'MESH:C542294', (85, 96))	('expression', 'MPA', (165, 175))	('caspase', 'Gene', (140, 147))	('expression', 'MPA', (110, 120))	('Bcl-2', 'Gene', (179, 184))	('Bax', 'Gene', (124, 127))	('Bcl-2', 'Gene', '596', (179, 184))	('cleaved', 'MPA', (132, 139))	('phillygenin', 'Var', (85, 96))
938267	30681987	It was found that phillygenin caused remarkable increase in the percentage of the SH-1-V1 esophageal cancer cells in G2 phase of the cell cycle.	('G2 phase of the cell cycle', 'CPA', (117, 143))	('SH-1-V1 esophageal cancer', 'Disease', (82, 107))	('phillygenin', 'Var', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('SH-1-V1 esophageal cancer', 'Disease', 'MESH:D004938', (82, 107))	('phillygenin', 'Chemical', 'MESH:C542294', (18, 29))	('increase', 'PosReg', (48, 56))
938269	30681987	These results clearly indicate that phillygenin induces G2/M cell cycle arrest of SH-1-V1 esophageal cancer cells.	('phillygenin', 'Chemical', 'MESH:C542294', (36, 47))	('G2/M cell cycle arrest', 'CPA', (56, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('SH-1-V1 esophageal cancer', 'Disease', 'MESH:D004938', (82, 107))	('phillygenin', 'Var', (36, 47))	('SH-1-V1 esophageal cancer', 'Disease', (82, 107))
938272	30681987	We found that phillygenin causes considerable decrease in the expression of the NF-kappaB protein.	('phillygenin', 'Var', (14, 25))	('expression', 'MPA', (62, 72))	('NF-kappaB', 'Gene', '4790', (80, 89))	('phillygenin', 'Chemical', 'MESH:C542294', (14, 25))	('decrease', 'NegReg', (46, 54))	('NF-kappaB', 'Gene', (80, 89))
938275	30681987	Additionally, phillygenin also decreased the weight and volume of the xenografted tumors (Figure 9A, 9B).	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('phillygenin', 'Var', (14, 25))	('decreased', 'NegReg', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('phillygenin', 'Chemical', 'MESH:C542294', (14, 25))
938281	30681987	Phillygenin also increased the concentration of Bax and caspase 3 and 9, which was also associated with decreased Bcl-2 expression.	('Phillygenin', 'Var', (0, 11))	('increased', 'PosReg', (17, 26))	('concentration', 'MPA', (31, 44))	('Bcl-2', 'Gene', (114, 119))	('caspase 3', 'Protein', (56, 65))	('decreased', 'NegReg', (104, 113))	('Bcl-2', 'Gene', '596', (114, 119))	('Bax', 'Gene', '581', (48, 51))	('Bax', 'Gene', (48, 51))
938284	30681987	Herein, we observed that phillygenin increased ROS and decreased MMP levels of SH-1-V1 cells.	('phillygenin', 'Var', (25, 36))	('MMP levels', 'MPA', (65, 75))	('decreased', 'NegReg', (55, 64))	('ROS', 'MPA', (47, 50))	('phillygenin', 'Chemical', 'MESH:C542294', (25, 36))	('increased', 'PosReg', (37, 46))	('ROS', 'Chemical', '-', (47, 50))
938292	30681987	Phillygenin is a tetrahydrofurofuran lignan and many related molecules have shown anticancer effects; for example, tetrahydrofurofuran-type lignans inhibit breast cancer growth.	('tetrahydrofurofuran', 'Chemical', '-', (17, 36))	('tetrahydrofurofuran-type', 'Var', (115, 139))	('inhibit', 'NegReg', (148, 155))	('lignans', 'Chemical', 'MESH:D017705', (140, 147))	('tetrahydrofurofuran lignan', 'Chemical', '-', (17, 43))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('tetrahydrofurofuran', 'Chemical', '-', (115, 134))	('breast cancer', 'Disease', (156, 169))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (86, 92))
938294	30681987	Given these promising results, the anticancer effects of phillygenin were also evaluated against the xenografted tumors and it was found that phillygenin reduced the weight and volume of the xenografted tumors, indicative of the anticancer potential of phillygenin.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Disease', (113, 119))	('phillygenin', 'Var', (142, 153))	('phillygenin', 'Chemical', 'MESH:C542294', (57, 68))	('cancer', 'Disease', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('phillygenin', 'Chemical', 'MESH:C542294', (142, 153))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('phillygenin', 'Chemical', 'MESH:C542294', (253, 264))	('cancer', 'Disease', (233, 239))	('reduced', 'NegReg', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
938296	30681987	Phillygenin also inhibits the growth of xenografted tumors and thus deserves further investigations.	('inhibits', 'NegReg', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Phillygenin', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))
938297	26949387	Interaction of XRCC1 Arg399Gln Polymorphism and Alcohol Consumption Influences Susceptibility of Esophageal Cancer Background.	('Interaction', 'Interaction', (0, 11))	('Arg399Gln', 'Var', (21, 30))	('Arg399Gln', 'SUBSTITUTION', 'None', (21, 30))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('XRCC1', 'Gene', '7515', (15, 20))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (97, 114))	('Influences', 'Reg', (68, 78))	('Cancer', 'Disease', (108, 114))	('Esophageal Cancer', 'Disease', (97, 114))	('Alcohol', 'Chemical', 'MESH:D000438', (48, 55))	('Cancer', 'Disease', 'MESH:D009369', (108, 114))	('XRCC1', 'Gene', (15, 20))
938298	26949387	To explore the correlation between the Arg399Gln polymorphism and susceptibility to esophageal cancer in Korean and Han Chinese individuals in Harbin, China, and its potential interaction with alcohol consumption.	('alcohol', 'Chemical', 'MESH:D000438', (193, 200))	('Arg399Gln', 'Var', (39, 48))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('Arg399Gln', 'SUBSTITUTION', 'None', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
938301	26949387	Genotyping of the Arg399Gln locus of XRCC1 was performed by PCR-RFLP.	('Arg399Gln', 'SUBSTITUTION', 'None', (18, 27))	('Arg399Gln', 'Var', (18, 27))	('XRCC1', 'Gene', (37, 42))
938302	26949387	The XRCC1 Arg399Gln polymorphism does not appear to be associated with esophageal cancer in individuals of Korean or Han Chinese descent in Harbin, China.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Arg399Gln', 'Var', (10, 19))	('Arg399Gln', 'SUBSTITUTION', 'None', (10, 19))	('XRCC1', 'Gene', (4, 9))	('associated', 'Reg', (55, 65))	('esophageal cancer', 'Disease', (71, 88))
938304	26949387	Many cancers result from damage to DNA that eventually affects DNA stability and leads to the malignant transformation of cells.	('leads to', 'Reg', (81, 89))	('damage', 'Var', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('result from', 'Reg', (13, 24))	('DNA', 'Gene', (35, 38))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('DNA stability', 'CPA', (63, 76))	('malignant transformation of cells', 'CPA', (94, 127))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('affects', 'Reg', (55, 62))
938305	26949387	The DNA damage repair gene XRCC1 (X-ray repair cross complementing gene 1) functions in base excision repair and the repair of single-strand breaks that are caused by ionizing radiation and oxidative damage.	('functions', 'Reg', (75, 84))	('base excision repair', 'MPA', (88, 108))	('X-ray repair cross complementing gene 1', 'Gene', (34, 73))	('single-strand', 'Var', (127, 140))	('ionizing radiation', 'Disease', (167, 185))	('X-ray repair cross complementing gene 1', 'Gene', '7515', (34, 73))	('XRCC1', 'Gene', (27, 32))	('ionizing radiation', 'Disease', 'MESH:D004194', (167, 185))	('repair', 'MPA', (117, 123))
938306	26949387	Importantly, polymorphisms in XRCC1 are correlated with susceptibility to various tumors.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('XRCC1', 'Gene', (30, 35))	('susceptibility', 'Reg', (56, 70))	('polymorphisms', 'Var', (13, 26))	('correlated', 'Reg', (40, 50))
938308	26949387	At least one polymorphism in XRCC1, Arg194Trp, has been associated with the occurrence of EC; in contrast, the Arg280His variant appears not to be associated with the occurrence of EC, and conflicting reports have made the contribution of the Arg399Gln variant to the disease unclear.	('Arg280His', 'Var', (111, 120))	('EC', 'Disease', (90, 92))	('Arg280His', 'SUBSTITUTION', 'None', (111, 120))	('Arg194Trp', 'SUBSTITUTION', 'None', (36, 45))	('associated', 'Reg', (56, 66))	('Arg399Gln', 'Var', (243, 252))	('Arg399Gln', 'SUBSTITUTION', 'None', (243, 252))	('Arg194Trp', 'Var', (36, 45))	('XRCC1', 'Gene', (29, 34))
938310	26949387	The distribution of the Arg399Gln polymorphism of XRCC1 was identified, and genotypes were studied in relation to both esophageal cancer and alcohol consumption.	('XRCC1', 'Gene', (50, 55))	('Arg399Gln', 'Var', (24, 33))	('Arg399Gln', 'SUBSTITUTION', 'None', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal cancer', 'Disease', (119, 136))
938318	26949387	Hardy-Weinberg equilibrium was used to test the genotype distributions of the XRCC1 Arg399Gln locus in both Korean and Han Chinese populations.	('Arg399Gln', 'SUBSTITUTION', 'None', (84, 93))	('XRCC1', 'Gene', (78, 83))	('Arg399Gln', 'Var', (84, 93))
938320	26949387	Previous research has produced conflicting results regarding the contribution of the XRCC1 Arg399Gln polymorphism to the risk of esophageal cancer.	('XRCC1', 'Gene', (85, 90))	('esophageal cancer', 'Disease', (129, 146))	('Arg399Gln', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Arg399Gln', 'SUBSTITUTION', 'None', (91, 100))
938321	26949387	One study demonstrated an increased risk of EC in individuals with the Gln/Gln genotype, and the Arg399Gln polymorphism was correlated with susceptibility to EC.	('Arg399Gln', 'SUBSTITUTION', 'None', (97, 106))	('Gln/Gln', 'Var', (71, 78))	('Arg399Gln', 'Var', (97, 106))
938322	26949387	No increased likelihood of EC was identified for any genotype, which indicates that the XRCC1 Arg399Gln polymorphism may not be correlated with EC in Harbin city (Heilongjiang Province, China).	('XRCC1', 'Gene', (88, 93))	('Arg399Gln', 'SUBSTITUTION', 'None', (94, 103))	('correlated', 'Reg', (128, 138))	('Arg399Gln', 'Var', (94, 103))
938323	26949387	Thus, the findings of this study corroborate previous results indicating that the XRCC1 Arg399Gln polymorphism does not contribute to EC risk.	('Arg399Gln', 'Var', (88, 97))	('Arg399Gln', 'SUBSTITUTION', 'None', (88, 97))	('XRCC1', 'Gene', (82, 87))
938340	25488346	Multiple studies have demonstrated that MRE surpasses other non-invasive tests such as serum tests for liver function and TE for detection and staging of liver fibrosis.	('MRE', 'Var', (40, 43))	('liver fibrosis', 'Phenotype', 'HP:0001395', (154, 168))	('liver fibrosis', 'Disease', (154, 168))	('liver fibrosis', 'Disease', 'MESH:D008103', (154, 168))
938367	25488346	Chronic liver diseases like viral hepatitis, autoimmune hepatitis and steatohepatitis are characterized by liver fibrosis and inflammation, and studies have shown that the presence of hepatitis activity may influence liver stiffness measured with MRE whereas another study did not show any such influence.	('hepatitis', 'Phenotype', 'HP:0012115', (184, 193))	('hepatitis activity', 'Disease', (184, 202))	('inflammation', 'Disease', (126, 138))	('liver fibrosis', 'Disease', 'MESH:D008103', (107, 121))	('influence', 'Reg', (207, 216))	('hepatitis', 'Phenotype', 'HP:0012115', (56, 65))	('Chronic liver diseases', 'Disease', 'MESH:D058625', (0, 22))	('hepatitis activity', 'Disease', 'MESH:D006505', (184, 202))	('viral hepatitis', 'Disease', 'MESH:D006525', (28, 43))	('autoimmune hepatitis and steatohepatitis', 'Disease', 'MESH:D005234', (45, 85))	('liver diseases', 'Phenotype', 'HP:0001392', (8, 22))	('liver stiffness', 'Disease', 'MESH:D017093', (217, 232))	('liver fibrosis', 'Phenotype', 'HP:0001395', (107, 121))	('Chronic liver diseases', 'Disease', (0, 22))	('liver stiffness', 'Disease', (217, 232))	('presence', 'Var', (172, 180))	('viral hepatitis', 'Disease', (28, 43))	('liver disease', 'Phenotype', 'HP:0001392', (8, 21))	('hepatitis', 'Phenotype', 'HP:0012115', (76, 85))	('inflammation', 'Disease', 'MESH:D007249', (126, 138))	('viral hepatitis', 'Phenotype', 'HP:0006562', (28, 43))	('liver fibrosis', 'Disease', (107, 121))	('hepatitis', 'Phenotype', 'HP:0012115', (34, 43))
938371	25488346	NAFLD is the most common cause of chronic liver disease in adults in the United States and is increasing in prevalence among children and adolescents.	('chronic liver disease', 'Disease', 'MESH:D058625', (34, 55))	('children', 'Species', '9606', (125, 133))	('NAFLD', 'Var', (0, 5))	('liver disease', 'Phenotype', 'HP:0001392', (42, 55))	('cause', 'Reg', (25, 30))	('chronic liver disease', 'Disease', (34, 55))
938438	25078091	Reoperation can achieve adequate debridement and promote conventional drainage but is not a reliable way to achieve fistula closure and is associated with high morbidity and mortality.	('Reoperation', 'Var', (0, 11))	('fistula closure', 'Disease', (116, 131))	('promote', 'PosReg', (49, 56))	('fistula closure', 'Disease', 'MESH:D005402', (116, 131))	('conventional drainage', 'MPA', (57, 78))
938445	25078091	The objectives of this study were to investigate whether E-TNPD could work as a convenient and reliable method of promoting post-esophagectomy fistula closure by improving trans-fistula drainage and to establish an effective complement to existing therapy.	('improving', 'PosReg', (162, 171))	('fistula drainage', 'Disease', 'MESH:D005402', (178, 194))	('E-TNPD', 'Var', (57, 63))	('fistula drainage', 'Disease', (178, 194))	('promoting', 'PosReg', (114, 123))	('fistula closure', 'Disease', (143, 158))	('esophagectomy fistula closure', 'Phenotype', 'HP:0100628', (129, 158))	('fistula closure', 'Disease', 'MESH:D005402', (143, 158))
938501	25078091	In addition, the E-TNPD method resulted in a significantly higher closure rate and fewer strictures in patients with intrathoracic leaks compared with the SEMS/SEPS methods.	('closure', 'MPA', (66, 73))	('fewer', 'NegReg', (83, 88))	('strictures', 'CPA', (89, 99))	('higher', 'PosReg', (59, 65))	('patients', 'Species', '9606', (103, 111))	('E-TNPD', 'Var', (17, 23))
938511	22315367	Aberrant Vimentin Methylation Is Characteristic of Upper Gastrointestinal Pathologies We have previously established aberrant DNA methylation of Vimentin exon-1 (VIM methylation) as a common epigenetic event in colon cancer and as a biomarker for detecting colon neoplasia.	('colon neoplasia', 'Disease', 'MESH:D009369', (257, 272))	('colon neoplasia', 'Phenotype', 'HP:0100273', (257, 272))	('Aberrant', 'Var', (0, 8))	('VIM', 'Gene', (162, 165))	('colon cancer', 'Disease', (211, 223))	('colon neoplasia', 'Disease', (257, 272))	('Vimentin', 'Gene', (145, 153))	('Vimentin', 'Gene', (9, 17))	('aberrant', 'Var', (117, 125))	('Gastrointestinal Pathologies', 'Phenotype', 'HP:0011024', (57, 85))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('neoplasia', 'Phenotype', 'HP:0002664', (263, 272))	('VIM', 'Gene', '7431', (162, 165))	('Vimentin', 'Gene', '7431', (145, 153))	('Vimentin', 'Gene', '7431', (9, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (211, 223))	('colon cancer', 'Disease', 'MESH:D015179', (211, 223))
938514	22315367	We find that acquisition of aberrant VIM methylation is highly common in these neoplasms, but largely absent in controls.	('neoplasms', 'Disease', (79, 88))	('VIM', 'Gene', '7431', (37, 40))	('methylation', 'MPA', (41, 52))	('neoplasms', 'Disease', 'MESH:D009369', (79, 88))	('aberrant', 'Var', (28, 36))	('VIM', 'Gene', (37, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (79, 88))
938515	22315367	The highest frequency of VIM methylation was detected in lesions of the distal esophagus, including 91% of Barrett's esophagus (BE, n=11), 100% of high grade dysplasia (HGD, n=5), and 81% of esophageal adenocarcinoma (EAC, n=26), but absent in controls (n=9).	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (107, 126))	('methylation', 'Var', (29, 40))	('dysplasia', 'Disease', 'MESH:D004476', (158, 167))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (191, 216))	('BE', 'Phenotype', 'HP:0100580', (128, 130))	('esophageal adenocarcinoma', 'Disease', (191, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('VIM', 'Gene', '7431', (25, 28))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (191, 216))	('dysplasia', 'Disease', (158, 167))	("Barrett's esophagus", 'Disease', (107, 126))	('VIM', 'Gene', (25, 28))
938516	22315367	VIM methylation similarly was detected in 87% of signet ring (n=15) and 53% of intestinal type gastric cancers (n=17).	('gastric cancers', 'Phenotype', 'HP:0012126', (95, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('methylation', 'Var', (4, 15))	('VIM', 'Gene', '7431', (0, 3))	('signet ring', 'Disease', (49, 60))	('detected', 'Reg', (30, 38))	('intestinal type gastric cancers', 'Disease', (79, 110))	('VIM', 'Gene', (0, 3))	('intestinal type gastric cancers', 'Disease', 'MESH:D013274', (79, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))
938517	22315367	Moreover, in tests of cytology brushings VIM methylation proved detectable in 100% of BE cases (n=7), 100% of HGD cases (n=4), and 83% of EAC cases (n=18), but was absent in all controls (n=5).	('BE', 'Phenotype', 'HP:0100580', (86, 88))	('VIM', 'Gene', '7431', (41, 44))	('methylation', 'Var', (45, 56))	('VIM', 'Gene', (41, 44))	('HGD', 'Disease', (110, 113))	('detectable', 'Reg', (64, 74))
938518	22315367	These findings establish aberrant VIM methylation as a highly common epigenetic alteration in neoplasia of the upper gastrointestinal tract, and demonstrate that Barrett's esophagus, even without dysplasia, already contains epigenetic alterations characteristic of adenocarcinoma.	('dysplasia', 'Disease', (196, 205))	('epigenetic alterations', 'MPA', (224, 246))	('dysplasia', 'Disease', 'MESH:D004476', (196, 205))	('aberrant', 'Var', (25, 33))	('methylation', 'Var', (38, 49))	('neoplasia', 'Phenotype', 'HP:0002664', (94, 103))	('VIM', 'Gene', '7431', (34, 37))	('neoplasia of the upper gastrointestinal tract', 'Disease', (94, 139))	('neoplasia of the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (94, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('adenocarcinoma', 'Disease', (265, 279))	('adenocarcinoma', 'Disease', 'MESH:D000230', (265, 279))	('VIM', 'Gene', (34, 37))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (162, 181))
938519	22315367	These findings suggest VIM methylation as a biomarker of upper gastrointestinal neoplasia with potential for development as molecular cytology in esophageal screening.	('VIM', 'Gene', '7431', (23, 26))	('VIM', 'Gene', (23, 26))	('methylation', 'Var', (27, 38))	('neoplasia', 'Phenotype', 'HP:0002664', (80, 89))	('gastrointestinal neoplasia', 'Phenotype', 'HP:0007378', (63, 89))	('upper gastrointestinal neoplasia', 'Disease', 'MESH:D009369', (57, 89))	('upper gastrointestinal neoplasia', 'Disease', (57, 89))
938520	22315367	Acquisition of aberrant DNA methylation in CpG-rich DNA islands is a common event in a variety of human cancers, and in some instances is a mechanism of gene silencing.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('aberrant', 'Var', (15, 23))	('cancers', 'Disease', (104, 111))	('human', 'Species', '9606', (98, 103))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
938521	22315367	Aberrantly methylated DNA can also serve as a tumor biomarker that can be detected in tumor tissues, as well as in blood, stool and urine of patients with certain types of cancer.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('DNA', 'Gene', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('Aberrantly methylated', 'Var', (0, 21))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('patients', 'Species', '9606', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
938522	22315367	We have previously reported that methylation of a CpG island overlapping the first exon of the human Vimentin (VIM) gene is detected in 53-83% of colon tumors, but is virtually absent in normal colonic epithelium.	('detected', 'Reg', (124, 132))	('human', 'Species', '9606', (95, 100))	('methylation', 'Var', (33, 44))	('colon tumors', 'Phenotype', 'HP:0100273', (146, 158))	('VIM', 'Gene', (111, 114))	('colon tumors', 'Disease', 'MESH:D015179', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Vimentin', 'Gene', (101, 109))	('colon tumors', 'Disease', (146, 158))	('Vimentin', 'Gene', '7431', (101, 109))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('VIM', 'Gene', '7431', (111, 114))
938523	22315367	Based on these findings, detection of VIM methylation in either fecal DNA or in blood has been adapted as a method for early detection of colon cancers.	('colon cancers', 'Phenotype', 'HP:0003003', (138, 151))	('colon cancers', 'Disease', 'MESH:D015179', (138, 151))	('VIM', 'Gene', '7431', (38, 41))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('colon cancer', 'Phenotype', 'HP:0003003', (138, 150))	('methylation', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('VIM', 'Gene', (38, 41))	('colon cancers', 'Disease', (138, 151))
938524	22315367	In this study, we investigated whether VIM methylation has a role in upper gastrointestinal tract carcinogenesis, and if so, whether it also can be developed as biomarker for clinical detection of upper gastrointestinal neoplasms.	('upper gastrointestinal neoplasms', 'Disease', (197, 229))	('VIM', 'Gene', '7431', (39, 42))	('methylation', 'Var', (43, 54))	('upper gastrointestinal neoplasms', 'Disease', 'MESH:D004067', (197, 229))	('gastrointestinal neoplasms', 'Phenotype', 'HP:0007378', (203, 229))	('neoplasms', 'Phenotype', 'HP:0002664', (220, 229))	('upper gastrointestinal tract carcinogenesis', 'Disease', (69, 112))	('VIM', 'Gene', (39, 42))	('role', 'Reg', (61, 65))	('upper gastrointestinal tract carcinogenesis', 'Disease', 'MESH:D063646', (69, 112))	('clinical', 'Species', '191496', (175, 183))
938547	22315367	High level VIM methylation was detected in 2 of 9 squamous carcinomas of the esophagus, ranging from10%-100% of total tumor DNA.	('detected', 'Reg', (31, 39))	('methylation', 'Var', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (50, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('VIM', 'Gene', '7431', (11, 14))	('squamous carcinomas', 'Disease', (50, 69))	('tumor', 'Disease', (118, 123))	('squamous carcinomas', 'Disease', 'MESH:D002294', (50, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('VIM', 'Gene', (11, 14))
938552	22315367	As shown in Figure 1, high level VIM methylation ranging from 10%-100% was detected in FFPE tissue DNA from 10 of 11 (91%) cases of BE without dysplasia and 5 of 5 BE cases with high grade dysplasia (HGD).	('VIM', 'Gene', '7431', (33, 36))	('dysplasia', 'Disease', 'MESH:D004476', (189, 198))	('BE', 'Phenotype', 'HP:0100580', (132, 134))	('dysplasia', 'Disease', 'MESH:D004476', (143, 152))	('methylation', 'Var', (37, 48))	('VIM', 'Gene', (33, 36))	('BE', 'Phenotype', 'HP:0100580', (164, 166))	('detected', 'Reg', (75, 83))	('dysplasia', 'Disease', (143, 152))	('dysplasia', 'Disease', (189, 198))
938553	22315367	These findings suggested that VIM methylation is an early and frequent epigenetic alteration in the BE sequence from metaplasia to dysplasia to EAC in the distal esophagus.	('VIM', 'Gene', '7431', (30, 33))	('BE', 'Phenotype', 'HP:0100580', (100, 102))	('methylation', 'Var', (34, 45))	('metaplasia to dysplasia', 'Disease', (117, 140))	('metaplasia to dysplasia', 'Disease', 'MESH:D008679', (117, 140))	('VIM', 'Gene', (30, 33))	('EAC', 'Disease', (144, 147))
938554	22315367	In all 4 cases, the high level of VIM methylation detected in the EAC was also detected in the synchronous BE and/or BE with high grade dysplasia tissue (Supplementary Fig.	('detected', 'Reg', (79, 87))	('BE', 'Phenotype', 'HP:0100580', (107, 109))	('methylation', 'Var', (38, 49))	('VIM', 'Gene', '7431', (34, 37))	('dysplasia', 'Disease', (136, 145))	('VIM', 'Gene', (34, 37))	('dysplasia', 'Disease', 'MESH:D004476', (136, 145))	('BE', 'Phenotype', 'HP:0100580', (117, 119))
938557	22315367	In two individuals in which BE progressed over time, in one case to HGD and in the other to EAC, both the initial BE specimen and the progressed specimen showed VIM methylation.	('BE', 'Phenotype', 'HP:0100580', (28, 30))	('VIM', 'Gene', '7431', (161, 164))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('methylation', 'Var', (165, 176))	('VIM', 'Gene', (161, 164))
938558	22315367	In two additional individuals in which BE did not progress, both the early and later specimens showed VIM methylation.	('showed', 'Reg', (95, 101))	('VIM', 'Gene', '7431', (102, 105))	('BE', 'Phenotype', 'HP:0100580', (39, 41))	('methylation', 'Var', (106, 117))	('VIM', 'Gene', (102, 105))
938559	22315367	Only in one individual, VIM methylation was detected in 2 concurrent biopsies of BE, but was absent in a BE specimen obtained from the same individual 4 years earlier (patient 14: supplementary Fig.	('patient', 'Species', '9606', (168, 175))	('BE', 'Phenotype', 'HP:0100580', (81, 83))	('detected', 'Reg', (44, 52))	('VIM', 'Gene', '7431', (24, 27))	('BE', 'Phenotype', 'HP:0100580', (105, 107))	('methylation', 'Var', (28, 39))	('VIM', 'Gene', (24, 27))
938560	22315367	This is consistent with a model of VIM methylation as an early epigenetic event in carcinogenesis and of EAC arising from an initiated field of BE.	('methylation', 'Var', (39, 50))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('VIM', 'Gene', '7431', (35, 38))	('BE', 'Phenotype', 'HP:0100580', (144, 146))	('carcinogenesis', 'Disease', (83, 97))	('VIM', 'Gene', (35, 38))
938561	22315367	The findings of high level VIM methylation in archival specimens of BE, HGD, and EAC lesions of the esophagus suggested that VIM methylation might be useful as a biomarker to assist in detection of these diseases.	('HGD', 'Disease', (72, 75))	('VIM', 'Gene', (125, 128))	('VIM', 'Gene', '7431', (27, 30))	('BE', 'Phenotype', 'HP:0100580', (68, 70))	('methylation', 'Var', (31, 42))	('EAC lesions of', 'Disease', (81, 95))	('VIM', 'Gene', (27, 30))	('VIM', 'Gene', '7431', (125, 128))
938563	22315367	Using this approach, detectable VIM methylation was found in 7 of 7 BE patients, 4 of 4 HGD patients, and 15 of 18 EAC patients.	('patients', 'Species', '9606', (71, 79))	('VIM', 'Gene', (32, 35))	('patients', 'Species', '9606', (119, 127))	('methylation', 'Var', (36, 47))	('patients', 'Species', '9606', (92, 100))	('BE', 'Phenotype', 'HP:0100580', (68, 70))	('VIM', 'Gene', '7431', (32, 35))
938567	22315367	The finding of VIM methylation in cases but not in controls was statistically significant for each of the groups tested using generalized linear models with contrasts (p=0.00049 for all comparisons; p= 0.006 for BE versus controls, p=0.011 for HGD versus controls, p=0.0067 for EAC versus controls).	('BE', 'Phenotype', 'HP:0100580', (212, 214))	('VIM', 'Gene', (15, 18))	('methylation', 'Var', (19, 30))	('VIM', 'Gene', '7431', (15, 18))
938568	22315367	The finding of methylation in cases but not in controls remained statistically significant for each of the groups tested even if a stringent cut-off of 10% methylation is used to classify cases as "VIM-methylated" (which would be 100-fold above the detection limit that separates cases from controls in this study) using generalized linear models with contrasts (p=0.0125 for all comparisons, p= 0.001 for BE versus controls, p=0.0083 for HGD versus controls, p=0.0028 for EAC versus controls).	('methylation', 'Var', (15, 26))	('VIM', 'Gene', '7431', (198, 201))	('BE', 'Phenotype', 'HP:0100580', (406, 408))	('VIM', 'Gene', (198, 201))
938570	22315367	In all 4 of these cases, VIM methylation was easily and well detected in the undirected sample, as well as the targeted brushing (data not shown).	('methylation', 'Var', (29, 40))	('VIM', 'Gene', (25, 28))	('VIM', 'Gene', '7431', (25, 28))	('amp', 'Chemical', 'MESH:D000249', (89, 92))
938571	22315367	This preliminary observation suggests that testing VIM methylation in undirected brushings of the esophagus could potentially be used as a less invasive alternative to conventional endoscopic screening for BE.	('VIM', 'Gene', '7431', (51, 54))	('BE', 'Phenotype', 'HP:0100580', (206, 208))	('VIM', 'Gene', (51, 54))	('methylation', 'Var', (55, 66))
938572	22315367	The finding of highly frequent VIM methylation in esophageal lesions raised the possibility that VIM methylation might typify epithelial neoplasia throughout the upper gastrointestinal tract, as well as in the colon.	('esophageal lesions', 'Disease', (50, 68))	('VIM', 'Gene', (31, 34))	('VIM', 'Gene', (97, 100))	('epithelial neoplasia', 'Disease', 'MESH:D009369', (126, 146))	('upper gastrointestinal tract', 'Disease', (162, 190))	('epithelial neoplasia', 'Phenotype', 'HP:0031492', (126, 146))	('epithelial neoplasia', 'Disease', (126, 146))	('VIM', 'Gene', '7431', (31, 34))	('esophageal lesions', 'Disease', 'MESH:D004935', (50, 68))	('VIM', 'Gene', '7431', (97, 100))	('methylation', 'Var', (35, 46))	('upper gastrointestinal tract', 'Disease', 'MESH:D004067', (162, 190))	('neoplasia', 'Phenotype', 'HP:0002664', (137, 146))	('methylation', 'Var', (101, 112))
938575	22315367	High levels of VIM methylation (10%-100%) were identified in thirteen of fifteen (87%) signet ring gastric cancers and in nine of 17 (53%) intestinal type gastric cancers (Fig.	('intestinal type gastric cancers', 'Disease', 'MESH:D013274', (139, 170))	('intestinal type gastric cancers', 'Disease', (139, 170))	('gastric cancers', 'Disease', (99, 114))	('methylation', 'Var', (19, 30))	('gastric cancers', 'Disease', 'MESH:D013274', (99, 114))	('gastric cancers', 'Phenotype', 'HP:0012126', (99, 114))	('gastric cancer', 'Phenotype', 'HP:0012126', (155, 169))	('VIM', 'Gene', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('gastric cancers', 'Disease', 'MESH:D013274', (155, 170))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('gastric cancers', 'Phenotype', 'HP:0012126', (155, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('VIM', 'Gene', '7431', (15, 18))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
938577	22315367	Low level VIM methylation (1%-10%) was further detected in FFPE tissue specimens from an additional 3 intestinal type gastric cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('VIM', 'Gene', '7431', (10, 13))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('methylation', 'Var', (14, 25))	('intestinal type gastric cancers', 'Disease', (102, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('gastric cancers', 'Phenotype', 'HP:0012126', (118, 133))	('detected', 'Reg', (47, 55))	('intestinal type gastric cancers', 'Disease', 'MESH:D013274', (102, 133))	('VIM', 'Gene', (10, 13))
938578	22315367	VIM methylation was not detected in any of 5 FFPE normal gastric mucosa samples from cancer free individuals (Fig 5A, normal 1), and was also not detected in 5 of 7 FFPE accompanying normal gastric mucosa samples from individuals with gastric cancer (Fig 3A, normal 2).	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('gastric cancer', 'Phenotype', 'HP:0012126', (235, 249))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('gastric cancer', 'Disease', (235, 249))	('cancer', 'Disease', (243, 249))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (85, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (235, 249))	('VIM', 'Gene', '7431', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('amp', 'Chemical', 'MESH:D000249', (206, 209))	('VIM', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('amp', 'Chemical', 'MESH:D000249', (73, 76))
938581	22315367	Supporting this latter possibility is the finding that in one individual who harbored both a gastric cancer and a gastric dysplasia, both lesions were positive for VIM methylation (data not shown).	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('VIM', 'Gene', '7431', (164, 167))	('positive', 'Reg', (151, 159))	('gastric dysplasia', 'Disease', 'MESH:D013274', (114, 131))	('gastric dysplasia', 'Disease', (114, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('methylation', 'Var', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('VIM', 'Gene', (164, 167))	('gastric cancer', 'Disease', (93, 107))
938582	22315367	VIM methylation was not limited to stomach, but was also detected in FFPE tissue samples from cancer of the duodenum, pancreas and distal small intestine, (Fig 3B).	('amp', 'Chemical', 'MESH:D000249', (82, 85))	('methylation', 'Var', (4, 15))	('VIM', 'Gene', '7431', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('pancreas', 'Disease', (118, 126))	('detected', 'Reg', (57, 65))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('VIM', 'Gene', (0, 3))	('cancer', 'Disease', (94, 100))	('pancreas', 'Disease', 'MESH:D010190', (118, 126))
938584	22315367	These results demonstrate that aberrant VIM methylation is a common epigenetic event in neoplasias of the upper gastrointestinal tract.	('methylation', 'Var', (44, 55))	('aberrant', 'Var', (31, 39))	('neoplasias of the upper gastrointestinal tract', 'Disease', (88, 134))	('VIM', 'Gene', (40, 43))	('neoplasia', 'Phenotype', 'HP:0002664', (88, 97))	('neoplasias', 'Phenotype', 'HP:0002664', (88, 98))	('neoplasias of the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (88, 134))	('VIM', 'Gene', '7431', (40, 43))
938585	22315367	We particularly observed the highest frequency of VIM methylation in neoplasia of the lower esophagus, with high level VIM-methylation detected in 91% of BE, 100% of HGD, and 81% of EAC.	('VIM', 'Gene', '7431', (50, 53))	('neoplasia', 'Phenotype', 'HP:0002664', (69, 78))	('VIM', 'Gene', '7431', (119, 122))	('methylation', 'Var', (54, 65))	('neoplasia', 'Disease', 'MESH:D009369', (69, 78))	('VIM', 'Gene', (50, 53))	('VIM', 'Gene', (119, 122))	('BE', 'Phenotype', 'HP:0100580', (154, 156))	('neoplasia', 'Disease', (69, 78))
938586	22315367	These findings establish VIM methylation as a highly frequent DNA alteration in BE and BE derived neoplasias.	('BE', 'Phenotype', 'HP:0100580', (80, 82))	('methylation', 'Var', (29, 40))	('BE', 'Phenotype', 'HP:0100580', (87, 89))	('neoplasias', 'Disease', (98, 108))	('frequent', 'Reg', (53, 61))	('VIM', 'Gene', '7431', (25, 28))	('neoplasias', 'Phenotype', 'HP:0002664', (98, 108))	('neoplasia', 'Phenotype', 'HP:0002664', (98, 107))	('VIM', 'Gene', (25, 28))	('neoplasias', 'Disease', 'MESH:D009369', (98, 108))
938587	22315367	The high frequency of VIM methylation across BE, HGD, and EAC, the co-synchronous detection of VIM methylation in BE and adjacent EAC specimens, and the presence of high level VIM methylation in BE lesions several years prior to VIM methylated HGD and EAC, provide further molecular evidence of BE as the precursor lesion for EAC cancers.	('cancers', 'Disease', 'MESH:D009369', (330, 337))	('BE', 'Phenotype', 'HP:0100580', (114, 116))	('BE', 'Phenotype', 'HP:0100580', (295, 297))	('EAC', 'Disease', (326, 329))	('VIM', 'Gene', '7431', (176, 179))	('methylation', 'Var', (180, 191))	('VIM', 'Gene', '7431', (95, 98))	('VIM', 'Gene', (176, 179))	('VIM', 'Gene', (95, 98))	('cancers', 'Phenotype', 'HP:0002664', (330, 337))	('VIM', 'Gene', '7431', (22, 25))	('cancers', 'Disease', (330, 337))	('VIM', 'Gene', '7431', (229, 232))	('methylation', 'Var', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('VIM', 'Gene', (22, 25))	('VIM', 'Gene', (229, 232))	('BE', 'Phenotype', 'HP:0100580', (195, 197))	('BE', 'Phenotype', 'HP:0100580', (45, 47))
938593	22315367	Our finding of VIM methylation as a highly frequent, highly specific, early biomarker of BE that is readily detectable in esophageal brushings by a highly sensitive methylation specific PCR, provides the initial evidence to support a molecular cytology approach to minimally invasive clinical screening and early detection of asymptomatic premalignant stage disease based on this biomarker.	('methylation', 'Var', (19, 30))	('VIM', 'Gene', (15, 18))	('clinical', 'Species', '191496', (284, 292))	('BE', 'Phenotype', 'HP:0100580', (89, 91))	('VIM', 'Gene', '7431', (15, 18))
938594	22315367	Moreover, our detection of VIM methylation in 87% of signet ring and 53% of intestinal type gastric cancers makes VIM methylation among the most common DNA alterations associated with gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('VIM', 'Gene', (114, 117))	('gastric cancers', 'Phenotype', 'HP:0012126', (92, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('VIM', 'Gene', '7431', (27, 30))	('intestinal type gastric cancers', 'Disease', 'MESH:D013274', (76, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('VIM', 'Gene', '7431', (114, 117))	('VIM', 'Gene', (27, 30))	('signet ring', 'Disease', (53, 64))	('methylation', 'Var', (118, 129))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('gastric cancer', 'Disease', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('intestinal type gastric cancers', 'Disease', (76, 107))
938596	22315367	VIM methylation may accordingly add to the panel of other methylated markers that have been described for detection of this disease.	('VIM', 'Gene', (0, 3))	('VIM', 'Gene', '7431', (0, 3))	('methylation', 'Var', (4, 15))
938597	22315367	Combined with our previous findings of VIM methylation in up to 83% of colon cancers, VIM methylation emerges as a high frequency epigenetic finding associated with neoplasia in both the upper and the lower gastrointestinal tract.	('VIM', 'Gene', (86, 89))	('neoplasia', 'Disease', 'MESH:D009369', (165, 174))	('VIM', 'Gene', '7431', (39, 42))	('neoplasia', 'Phenotype', 'HP:0002664', (165, 174))	('gastrointestinal tract', 'Disease', (207, 229))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('colon cancers', 'Disease', (71, 84))	('VIM', 'Gene', '7431', (86, 89))	('associated with', 'Reg', (149, 164))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (207, 229))	('colon cancers', 'Phenotype', 'HP:0003003', (71, 84))	('VIM', 'Gene', (39, 42))	('methylation', 'Var', (90, 101))	('neoplasia', 'Disease', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colon cancers', 'Disease', 'MESH:D015179', (71, 84))
938598	22315367	VIM methylation can be detected in DNA isolated from feces in 77% of colon cancer patients, and the American Cancer Society has added fecal DNA screening to their guidelines of methods endorsed for colon cancer screening.	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('colon cancer', 'Disease', (69, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (198, 210))	('colon cancer', 'Disease', 'MESH:D015179', (198, 210))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('VIM', 'Gene', '7431', (0, 3))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colon cancer', 'Disease', (198, 210))	('colon cancer', 'Phenotype', 'HP:0003003', (69, 81))	('colon cancer', 'Disease', 'MESH:D015179', (69, 81))	('VIM', 'Gene', (0, 3))
938599	22315367	However, one important question regarding this approach has been the finding that some individuals with VIM methylation detected in stool DNA have normal colonoscopies.	('VIM', 'Gene', '7431', (104, 107))	('VIM', 'Gene', (104, 107))	('colonoscopies', 'Disease', (154, 167))	('methylation', 'Var', (108, 119))
938600	22315367	Our observations that VIM methylation is also common in neoplasias of the upper gastrointestinal tract raise the intriguing possibility that in some individuals the detection of VIM methylation in stool DNA may reflect the presence of neoplasia in the upper GI tract.	('neoplasias of the upper gastrointestinal tract', 'Disease', (56, 102))	('neoplasia', 'Phenotype', 'HP:0002664', (56, 65))	('VIM', 'Gene', (178, 181))	('VIM', 'Gene', '7431', (178, 181))	('neoplasia', 'Disease', (235, 244))	('neoplasia', 'Disease', 'MESH:D009369', (56, 65))	('VIM', 'Gene', (22, 25))	('methylation', 'Var', (182, 193))	('neoplasias of the upper gastrointestinal tract', 'Disease', 'MESH:D004067', (56, 102))	('VIM', 'Gene', '7431', (22, 25))	('common', 'Reg', (46, 52))	('neoplasias', 'Phenotype', 'HP:0002664', (56, 66))	('reflect', 'Reg', (211, 218))	('neoplasia', 'Disease', 'MESH:D009369', (235, 244))	('neoplasia', 'Phenotype', 'HP:0002664', (235, 244))	('neoplasia', 'Disease', (56, 65))
938796	21358837	To date, no other clinical factors have been found to influence the risk of pericardial effusion significantly following chemoradiotherapy for esophageal cancer, and high-dose radiation to the pericardium is the only significant risk associated with pericardial effusion.	('high-dose radiation', 'Var', (166, 185))	('pericardial effusion', 'Phenotype', 'HP:0001698', (76, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('pericardial effusion', 'Phenotype', 'HP:0001698', (250, 270))	('pericardial effusion', 'Disease', (76, 96))	('pericardial effusion', 'Disease', (250, 270))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('pericardial effusion', 'Disease', 'MESH:D010490', (76, 96))	('esophageal cancer', 'Disease', (143, 160))	('pericardial effusion', 'Disease', 'MESH:D010490', (250, 270))
939080	31683722	While alterations in autophagy have been associated with carcinogenesis across tissues, cell type- and context-dependent roles for autophagy have been reported.	('alterations', 'Var', (6, 17))	('autophagy', 'CPA', (21, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (57, 71))	('associated', 'Reg', (41, 51))	('carcinogenesis', 'Disease', (57, 71))	('rat', 'Species', '10116', (10, 13))
939086	31683722	ESCC arises via malignant transformation of esophageal epithelial cells with activation of epidermal growth factor receptor (EGFR) and cyclin D1 oncogenes and mutations in the tumor suppressor gene TP53 representing common genetic alterations.	('cyclin D1', 'Gene', '595', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('epidermal growth factor receptor', 'Gene', '1956', (91, 123))	('cyclin D1', 'Gene', (135, 144))	('mutations', 'Var', (159, 168))	('EGFR', 'Gene', '1956', (125, 129))	('tumor', 'Disease', (176, 181))	('activation', 'PosReg', (77, 87))	('rat', 'Species', '10116', (235, 238))	('TP53', 'Gene', '7157', (198, 202))	('EGFR', 'Gene', (125, 129))	('ESCC', 'Disease', (0, 4))	('TP53', 'Gene', (198, 202))	('epidermal growth factor receptor', 'Gene', (91, 123))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
939127	31683722	MicroRNA (miR)-503-mediated proliferation, migration, and invasion of Eca109 and Eca9706 ESCC cells has also been linked to autophagy activation occurring in response to diminished mTORC1 activation.	('Eca9706', 'Var', (81, 88))	('rat', 'Species', '10116', (46, 49))	('proliferation', 'CPA', (28, 41))	('autophagy', 'CPA', (124, 133))	('mTORC1', 'Gene', '382056', (181, 187))	('activation', 'PosReg', (134, 144))	('invasion', 'CPA', (58, 66))	('migration', 'CPA', (43, 52))	('Eca9706 ESCC', 'CellLine', 'CVCL:E307', (81, 93))	('mTORC1', 'Gene', (181, 187))	('rat', 'Species', '10116', (35, 38))
939140	31683722	While the aforementioned studies describe activation of autophagy as a mechanism to promote ESCC carcinogenesis, inactivation of autophagy by the DNA repair protein RAD51 has been reported to enhance proliferation in ESCC.	('enhance', 'PosReg', (192, 199))	('RAD51', 'Gene', '5888', (165, 170))	('rat', 'Species', '10116', (207, 210))	('carcinogenesis', 'Disease', (97, 111))	('promote', 'PosReg', (84, 91))	('proliferation', 'CPA', (200, 213))	('autophagy', 'CPA', (129, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (97, 111))	('inactivation', 'Var', (113, 125))	('RAD51', 'Gene', (165, 170))
939143	31683722	RAD51 loss increased autophagy flux and 3MA-mediated autophagy inhibition restored CHK1 expression and soft agar colony formation in RAD51-depleted Ec109 and Ec9706 ESCC cells, respectively.	('loss', 'NegReg', (6, 10))	('RAD51', 'Gene', '5888', (0, 5))	('increased', 'PosReg', (11, 20))	('CHK1', 'Gene', (83, 87))	('3MA', 'Chemical', 'MESH:C025946', (40, 43))	('RAD51', 'Gene', (133, 138))	('Ec9706', 'Var', (158, 164))	('autophagy flux', 'CPA', (21, 35))	('CHK1', 'Gene', '1111', (83, 87))	('restored', 'PosReg', (74, 82))	('soft agar colony formation', 'CPA', (103, 129))	('expression', 'MPA', (88, 98))	('RAD51', 'Gene', '5888', (133, 138))	('RAD51', 'Gene', (0, 5))	('Ec9706 ESCC', 'CellLine', 'CVCL:E307', (158, 169))
939157	31683722	Additionally, the consequences of these alterations in autophagy as they relate to esophageal carcinogenesis has yet to be fully elucidated.	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (83, 108))	('autophagy', 'CPA', (55, 64))	('esophageal carcinogenesis', 'Disease', (83, 108))	('rat', 'Species', '10116', (44, 47))	('alterations', 'Var', (40, 51))
939166	31683722	Specifically, low diffuse cytoplasmic LC3 staining or high staining for either of the other two LC3 staining patterns was associated with poor overall survival.	('LC3', 'Gene', '84557', (96, 99))	('LC3', 'Gene', '84557', (38, 41))	('LC3', 'Gene', (96, 99))	('LC3', 'Gene', (38, 41))	('poor', 'NegReg', (138, 142))	('low', 'Var', (14, 17))	('overall', 'MPA', (143, 150))
939168	31683722	In one study, neither expression of LC3B nor the tumor suppressor protein p53 alone correlated with ESCC patient outcome; however, patients with high co-expression of LC3 and p53 displayed decreased five-year survival as compared to those with low co-expression.	('LC3', 'Gene', '84557', (167, 170))	('patients', 'Species', '9606', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('LC3', 'Gene', (167, 170))	('patient', 'Species', '9606', (105, 112))	('decreased', 'NegReg', (189, 198))	('LC3B', 'Gene', '81631', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('high co-expression', 'Var', (145, 163))	('p53', 'Gene', (74, 77))	('LC3B', 'Gene', (36, 40))	('LC3', 'Gene', '84557', (36, 39))	('LC3', 'Gene', (36, 39))	('patient', 'Species', '9606', (131, 138))	('p53', 'Gene', (175, 178))	('p53', 'Gene', '7157', (74, 77))	('p53', 'Gene', '7157', (175, 178))
939169	31683722	Expression of LC3 alone failed to reach statistical significance in terms of association with EAC survival; however, patients with low levels of both LC3B and p62, an autophagy cargo-identifying protein, fared worse than those with high co-expression or 'mixed' type lesions (displaying high expression of LC3 and low expression of p62 or vice versa).	('low', 'Var', (131, 134))	('p62', 'Gene', '8878', (332, 335))	('LC3B', 'Gene', (150, 154))	('p62', 'Gene', (332, 335))	('LC3', 'Gene', '84557', (14, 17))	('LC3', 'Gene', '84557', (306, 309))	('p62', 'Gene', '8878', (159, 162))	('LC3', 'Gene', (14, 17))	('p62', 'Gene', (159, 162))	('worse', 'NegReg', (210, 215))	('patients', 'Species', '9606', (117, 125))	('LC3B', 'Gene', '81631', (150, 154))	('LC3', 'Gene', (306, 309))	('EAC', 'Phenotype', 'HP:0011459', (94, 97))	('LC3', 'Gene', '84557', (150, 153))	('LC3', 'Gene', (150, 153))
939179	31683722	One study demonstrated that patients with low ULK1 had decreased survival rates, while the other showed that patients with high expression of ULK1 had lower survival rates.	('ULK1', 'Gene', (142, 146))	('ULK1', 'Gene', (46, 50))	('patients', 'Species', '9606', (109, 117))	('rat', 'Species', '10116', (166, 169))	('ULK1', 'Gene', '8408', (142, 146))	('ULK1', 'Gene', '8408', (46, 50))	('rat', 'Species', '10116', (74, 77))	('decreased', 'NegReg', (55, 64))	('lower', 'NegReg', (151, 156))	('low', 'Var', (42, 45))	('rat', 'Species', '10116', (17, 20))	('patients', 'Species', '9606', (28, 36))	('survival rates', 'MPA', (157, 171))	('survival', 'MPA', (65, 73))
939180	31683722	In addition to immunostaining staining of autophagy markers in esophageal cancer patient tissues samples, genomic studies have identified alterations in genes associated with the autophagy pathway in both ESCC and EAC.	('patient', 'Species', '9606', (81, 88))	('EAC', 'Phenotype', 'HP:0011459', (214, 217))	('rat', 'Species', '10116', (142, 145))	('alterations', 'Var', (138, 149))	('autophagy pathway', 'CPA', (179, 196))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('EAC', 'Disease', (214, 217))	('cancer', 'Disease', (74, 80))	('ESCC', 'Disease', (205, 209))
939181	31683722	A large scale integrated genomic characterization of esophageal cancer revealed three subtypes, ESCC1-3, two of which displayed deep deletions in ATG7, the protein product of which mediates LC3 lipidation and AV formation.	('ATG7', 'Gene', (146, 150))	('deletions', 'Var', (133, 142))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('rat', 'Species', '10116', (19, 22))	('LC3', 'Gene', '84557', (190, 193))	('LC3', 'Gene', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('mediates', 'Reg', (181, 189))
939182	31683722	In ESCC1, which was most commonly identified in Asian patients and characterized by mutations in the NRF2 oxidative stress response pathway, ATG7 deletions were found in 12% of patients.	('NRF2', 'Gene', '4780', (101, 105))	('ATG7', 'Gene', (141, 145))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (177, 185))	('NRF2', 'Gene', (101, 105))	('oxidative stress', 'Phenotype', 'HP:0025464', (106, 122))	('found', 'Reg', (161, 166))	('ESCC1', 'Gene', (3, 8))	('mutations', 'Var', (84, 93))	('deletions', 'Var', (146, 155))
939183	31683722	Frequency of ATG7 deletions was 25% in ESCC3, which was comprised exclusively of North American patients and displayed genetic alterations that are predicted to activate PI3K signaling.	('activate', 'PosReg', (161, 169))	('rat', 'Species', '10116', (131, 134))	('ESCC3', 'Gene', (39, 44))	('PI3K signaling', 'Pathway', (170, 184))	('deletions', 'Var', (18, 27))	('ATG7', 'Gene', (13, 17))	('patients', 'Species', '9606', (96, 104))
939184	31683722	ATG7 deletions were absent in the ESCC2 subtype, which was identified most frequently in Eastern European and South American patients and in which NOTCH1 mutations were most prevalent.	('ESCC2', 'Gene', (34, 39))	('NOTCH1', 'Gene', '4851', (147, 153))	('NOTCH1', 'Gene', (147, 153))	('mutations', 'Var', (154, 163))	('ATG7', 'Gene', (0, 4))	('prevalent', 'Reg', (174, 183))	('deletions', 'Var', (5, 14))	('patients', 'Species', '9606', (125, 133))
939188	31683722	Two protein products resulting from this RPS6KB1-VMP1 fusion were identified in ~10% of EAC tumors, with each lacking the full kinase domain of RPS6KB1 and containing a truncated form of VMP1.	('fusion', 'Var', (54, 60))	('EAC', 'Phenotype', 'HP:0011459', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('EAC tumors', 'Disease', (88, 98))	('full kinase domain', 'MPA', (122, 140))	('lacking', 'NegReg', (110, 117))	('RPS6KB1-VMP1', 'Gene', (41, 53))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('EAC tumors', 'Disease', 'MESH:C536611', (88, 98))	('RPS6KB1', 'Gene', (144, 151))
939193	31683722	Given the presence of deep deletions in the ATG7 gene and the presence of RPS6KB1-VMP1 gene fusions in subsets of esophageal cancer patients, it may be critical to take into account the impact of patient genetics upon the use of autophagy factors as biomarkers in esophageal cancer.	('RPS6KB1-VMP1', 'Gene', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('deep deletions', 'Var', (22, 36))	('fusions', 'Var', (92, 99))	('patient', 'Species', '9606', (196, 203))	('ATG7', 'Gene', (44, 48))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))	('cancer', 'Disease', (275, 281))
939201	31683722	In KYSE450, genetic inhibition of Beclin-1 and ATG7 together decreased AV induction following 5FU treatment concurrent with diminished cell viability, indicating that autophagy contributes to chemoresistance.	('Beclin-1', 'Protein', (34, 42))	('decreased', 'NegReg', (61, 70))	('cell viability', 'CPA', (135, 149))	('KYSE450', 'CellLine', 'CVCL:1353', (3, 10))	('5FU', 'Chemical', '-', (94, 97))	('ATG7', 'Gene', (47, 51))	('AV induction', 'MPA', (71, 83))	('genetic inhibition', 'Var', (12, 30))	('diminished', 'NegReg', (124, 134))	('autophagy', 'CPA', (167, 176))
939209	31683722	In this study, we reported that the lysosomotropic drugs CQ and Lys05 decreased CD44high CSCs in TE11 ESCC xenograft tumors concurrent with increased oxidative stress.	('CD44', 'Gene', (80, 84))	('oxidative stress', 'Phenotype', 'HP:0025464', (150, 166))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (140, 166))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Lys05', 'Chemical', 'MESH:C573930', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('decreased', 'NegReg', (70, 79))	('tumors', 'Disease', (117, 123))	('Lys05', 'Var', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('CQ', 'Chemical', 'MESH:D002738', (57, 59))	('CD44', 'Gene', '960', (80, 84))
939211	31683722	In line with this notion, Feng and colleagues have devised a nanoliposome-based delivery platform that facilitates delivery of LY294002, a PI3K inhibitor that inhibits autophagy, prior to that of 5FU, and reported that nanoliposomes loaded with 5FU and LY294002 augmented cytotoxicity in an ESCC xenograft tumor model as compared to free cocktail combinations.	('autophagy', 'CPA', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('inhibits', 'NegReg', (159, 167))	('5FU', 'Chemical', '-', (196, 199))	('LY294002', 'Chemical', 'MESH:C085911', (253, 261))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('LY294002', 'Chemical', 'MESH:C085911', (127, 135))	('ESCC', 'Disease', (291, 295))	('tumor', 'Disease', (306, 311))	('augmented cytotoxicity', 'Disease', 'MESH:D064420', (262, 284))	('LY294002', 'Var', (253, 261))	('augmented cytotoxicity', 'Disease', (262, 284))	('5FU', 'Chemical', '-', (245, 248))	('LY294002', 'Var', (127, 135))
939220	31683722	A protective role of autophagy in response to radiation was demonstrated in vivo as pharmacological autophagy inhibition sensitized Ec9706 and Ec109 ESCC xenograft tumors to irradiation by inducing apoptosis and inhibiting angiogenesis.	('Ec9706', 'CellLine', 'CVCL:E307', (132, 138))	('rat', 'Species', '10116', (67, 70))	('apoptosis', 'CPA', (198, 207))	('sensitized', 'PosReg', (121, 131))	('Ec9706', 'Var', (132, 138))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('inhibiting', 'NegReg', (212, 222))	('angiogenesis', 'CPA', (223, 235))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('Ec109', 'Var', (143, 148))	('inducing', 'PosReg', (189, 197))
939242	31683722	In the ESCC cell line EC9706, GX15-070 alone induced cell death, and the agent also displayed synergism when combined with 5FU or carboplatin.	('cell death', 'CPA', (53, 63))	('GX15-070', 'Var', (30, 38))	('carboplatin', 'Chemical', 'MESH:D016190', (130, 141))	('EC9706', 'CellLine', 'CVCL:E307', (22, 28))	('5FU', 'Chemical', '-', (123, 126))
939243	31683722	GX15-070 was also noted to induce autophagy in EC9706 cells, and inhibition of autophagy with 3MA enhanced cell death induced by GX15-70.	('enhanced', 'PosReg', (98, 106))	('autophagy', 'CPA', (34, 43))	('autophagy', 'CPA', (79, 88))	('inhibition', 'NegReg', (65, 75))	('EC9706', 'CellLine', 'CVCL:E307', (47, 53))	('3MA', 'Chemical', 'MESH:C025946', (94, 97))	('GX15-070', 'Var', (0, 8))	('cell death', 'CPA', (107, 117))	('GX15-70', 'Var', (129, 136))
939244	31683722	Activation of autophagy by GX15-070 was associated with an increase in Beclin-1 mRNA, but no change in activation of the PI3K/Akt/mTORC1 signaling axis.	('autophagy', 'CPA', (14, 23))	('mTORC1', 'Gene', (130, 136))	('GX15-070', 'Var', (27, 35))	('Beclin-1', 'Protein', (71, 79))	('mTORC1', 'Gene', '382056', (130, 136))	('increase', 'PosReg', (59, 67))
939248	31683722	The PPI Esomeprazole has been demonstrated to induce apoptosis associated with oxidative stress in EAC cell lines, but not the BE cell line CPA.	('CPA', 'Gene', '1357', (140, 143))	('oxidative stress', 'MPA', (79, 95))	('EAC', 'Phenotype', 'HP:0011459', (99, 102))	('BE', 'Phenotype', 'HP:0100580', (127, 129))	('apoptosis', 'MPA', (53, 62))	('rat', 'Species', '10116', (37, 40))	('CPA', 'Gene', (140, 143))	('PPI', 'Var', (4, 7))	('oxidative stress', 'Phenotype', 'HP:0025464', (79, 95))	('induce', 'PosReg', (46, 52))	('Esomeprazole', 'Chemical', 'MESH:D064098', (8, 20))
939260	31683722	In the ESCC cell lines EC109, EC9706, and K562, resveratrol induced sub-G1 cell cycle arrest and apoptosis.	('EC9706', 'CellLine', 'CVCL:E307', (30, 36))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('arrest', 'Disease', (86, 92))	('K562', 'CellLine', 'CVCL:0004', (42, 46))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (75, 92))	('resveratrol', 'Chemical', 'MESH:D000077185', (48, 59))	('EC9706', 'Var', (30, 36))	('EC109', 'CellLine', 'CVCL:6898', (23, 28))	('apoptosis', 'CPA', (97, 106))
939264	31683722	The ginsenoside Rk3 was recently shown to limit cell proliferation and colony formation in the ESCC cell lines Eca109 and KYSE150 in vitro, as well as KYSE150 tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('limit', 'NegReg', (42, 47))	('ginsenoside', 'Chemical', 'MESH:D036145', (4, 15))	('rat', 'Species', '10116', (60, 63))	('cell proliferation', 'CPA', (48, 66))	('colony formation', 'CPA', (71, 87))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('KYSE150', 'Var', (151, 158))
939265	31683722	Rk3-mediated cytotoxicity in these cells was associated with G1 cell cycle arrest, apoptosis, and autophagy, the latter attributed to decreased PI3K/Akt/mTOR signaling.	('decreased', 'NegReg', (134, 143))	('cytotoxicity', 'Disease', (13, 25))	('mTOR', 'Gene', (153, 157))	('mTOR', 'Gene', '2475', (153, 157))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('arrest', 'Disease', 'MESH:D006323', (75, 81))	('autophagy', 'CPA', (98, 107))	('apoptosis', 'CPA', (83, 92))	('cytotoxicity', 'Disease', 'MESH:D064420', (13, 25))	('arrest', 'Disease', (75, 81))	('Rk3-mediated', 'Var', (0, 12))
939269	31683722	In contrast to these in vitro-based findings, OE19 xenograft tumors in mice subjected to oral C-PAC administration displayed decreased tumor growth, as well as evidence of autophagy and suppression of PI3K/Akt/mTORC1 signaling.	('mice', 'Species', '10090', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('mTORC1', 'Gene', (210, 216))	('PAC', 'Phenotype', 'HP:0006699', (96, 99))	('mTORC1', 'Gene', '382056', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('OE19', 'Var', (46, 50))	('tumors', 'Disease', (61, 67))	('rat', 'Species', '10116', (108, 111))	('autophagy', 'CPA', (172, 181))	('C-PAC', 'Chemical', '-', (94, 99))	('decreased', 'NegReg', (125, 134))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('suppression', 'NegReg', (186, 197))	('tumor', 'Disease', (61, 66))
939281	31683722	When thinking about how to best utilize autophagy inhibitors for cancer therapy, it will be critical to accurately define (1) whether autophagy is activated or stalled in human patients; and (2) how modulation of autophagy will impact cancer cells.	('modulation', 'Var', (199, 209))	('rat', 'Species', '10116', (108, 111))	('autophagy', 'CPA', (213, 222))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('patients', 'Species', '9606', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('human', 'Species', '9606', (171, 176))	('impact', 'Reg', (228, 234))
939304	31602267	Genome sequencing, exome sequencing, transcriptome sequencing, and array comparative genomic hybridization of ESCC tissues have identified many mutated genes, genomic amplified or deleted regions, and aberrantly expressed transcripts.	('ESCC', 'Disease', 'MESH:C562729', (110, 114))	('mutated', 'Var', (144, 151))	('ESCC', 'Disease', (110, 114))
939307	31602267	miRNAs induce their targets transcripts degradation and/or translation repression via base pairing with target transcripts.	('degradation', 'NegReg', (40, 51))	('targets transcripts', 'MPA', (20, 39))	('miR', 'Gene', (0, 3))	('translation', 'MPA', (59, 70))	('miR', 'Gene', '22877', (0, 3))	('base pairing', 'Var', (86, 98))
939344	31602267	After being blocked, the membranes were incubated with NF90 specific primary antibody (ab131004, Abcam, Hong Kong, China) and beta-actin specific primary antibody (66009-1-Ig, Proteintech, Rosemont, IL, USA).	('NF90', 'Gene', (55, 59))	('66009-1-Ig', 'Var', (164, 174))	('NF90', 'Gene', '3609', (55, 59))
939364	31602267	Furthermore, we inhibited NF90 in Eca-109 cells via transfecting NF90 specific shRNAs, and the results displayed that depletion of NF90 significantly downregulated miR-548k expression (Figure 1C and 1D).	('depletion', 'Var', (118, 127))	('NF90', 'Gene', (65, 69))	('inhibited', 'NegReg', (16, 25))	('downregulated', 'NegReg', (150, 163))	('NF90', 'Gene', '3609', (26, 30))	('miR-548k', 'Gene', '100313770', (164, 172))	('NF90', 'Gene', (131, 135))	('miR-548k', 'Gene', (164, 172))	('NF90', 'Gene', '3609', (65, 69))	('NF90', 'Gene', (26, 30))	('NF90', 'Gene', '3609', (131, 135))
939373	31602267	The results displayed that depletion of NF90 significantly shortened the half-life of pri-miR-548k transcript (Figure 1G).	('shortened', 'NegReg', (59, 68))	('half-life', 'MPA', (73, 82))	('NF90', 'Gene', (40, 44))	('miR-548k', 'Gene', (90, 98))	('depletion', 'Var', (27, 36))	('miR-548k', 'Gene', '100313770', (90, 98))	('NF90', 'Gene', '3609', (40, 44))
939381	31602267	In addition, we also constructed NF90 depleted Eca-109 cells via transfecting NF90 specific shRNAs.	('NF90', 'Gene', '3609', (78, 82))	('transfecting', 'Var', (65, 77))	('NF90', 'Gene', (33, 37))	('NF90', 'Gene', (78, 82))	('NF90', 'Gene', '3609', (33, 37))
939382	31602267	Glo cell viability assay displayed that depletion of NF90 decreased cell viability of Eca-109 cells (Figure 2D).	('cell viability', 'CPA', (68, 82))	('NF90', 'Gene', '3609', (53, 57))	('depletion', 'Var', (40, 49))	('decreased', 'NegReg', (58, 67))	('NF90', 'Gene', (53, 57))
939383	31602267	EdU incorporation assay further displayed that depletion of NF90 inhibited cell proliferation of Eca-109 cells (Figure 2E).	('NF90', 'Gene', '3609', (60, 64))	('depletion', 'Var', (47, 56))	('cell proliferation of Eca-109 cells', 'CPA', (75, 110))	('EdU', 'Chemical', 'MESH:C031086', (0, 3))	('inhibited', 'NegReg', (65, 74))	('NF90', 'Gene', (60, 64))
939384	31602267	Transwell migration assay displayed that depletion of NF90 inhibited cell migration of Eca-109 cells (Figure 2F).	('cell migration of Eca-109 cells', 'CPA', (69, 100))	('inhibited', 'NegReg', (59, 68))	('depletion', 'Var', (41, 50))	('NF90', 'Gene', (54, 58))	('NF90', 'Gene', '3609', (54, 58))
939397	31602267	As displayed in Figure 4B and 4C, enhanced expression of NF90 downregulated lncRNA-LET expression, and while depletion of NF90 upregulated lncRNA-LET expression.	('expression', 'MPA', (150, 160))	('enhanced', 'PosReg', (34, 42))	('NF90', 'Gene', '3609', (122, 126))	('lncRNA-LET', 'Gene', (76, 86))	('expression', 'Var', (43, 53))	('depletion', 'Var', (109, 118))	('lncRNA-LET', 'Gene', '101241892', (76, 86))	('downregulated', 'NegReg', (62, 75))	('upregulated', 'PosReg', (127, 138))	('lncRNA-LET', 'Gene', (139, 149))	('lncRNA-LET', 'Gene', '101241892', (139, 149))	('NF90', 'Gene', (57, 61))	('NF90', 'Gene', (122, 126))	('NF90', 'Gene', '3609', (57, 61))
939409	31602267	Then, the expression of miR-548k and pri-miR-548k were detected, and the results displayed that depletion of lncRNA-LET upregulated the expression of miR-548k and pri-miR-548k (Figure 4H).	('expression', 'MPA', (136, 146))	('miR-548k', 'Gene', '100313770', (150, 158))	('miR-548k', 'Gene', (167, 175))	('miR-548k', 'Gene', '100313770', (41, 49))	('upregulated', 'PosReg', (120, 131))	('miR-548k', 'Gene', (41, 49))	('miR-548k', 'Gene', (150, 158))	('miR-548k', 'Gene', '100313770', (24, 32))	('miR-548k', 'Gene', (24, 32))	('depletion', 'Var', (96, 105))	('miR-548k', 'Gene', '100313770', (167, 175))	('lncRNA-LET', 'Gene', (109, 119))	('lncRNA-LET', 'Gene', '101241892', (109, 119))
939421	31602267	Conversely, depletion of NF90 downregulated HIF-1alpha and VEGF, upregulated KLF10, downregulated EGFR, and upregulated p53, which were consistent with the effects of miR-548k depletion on KLF10 and EGFR, and also the effects of lncRNA-LET overexpression on p53.	('p53', 'Gene', (258, 261))	('miR-548k', 'Gene', (167, 175))	('HIF-1alpha', 'Gene', '3091', (44, 54))	('VEGF', 'Gene', '7422', (59, 63))	('KLF10', 'Gene', (77, 82))	('p53', 'Gene', '7157', (120, 123))	('upregulated', 'PosReg', (108, 119))	('VEGF', 'Gene', (59, 63))	('miR-548k', 'Gene', '100313770', (167, 175))	('depletion', 'Var', (12, 21))	('EGFR', 'Gene', (98, 102))	('KLF10', 'Gene', '7071', (189, 194))	('lncRNA-LET', 'Gene', (229, 239))	('KLF10', 'Gene', '7071', (77, 82))	('HIF-1alpha', 'Gene', (44, 54))	('p53', 'Gene', (120, 123))	('NF90', 'Gene', (25, 29))	('EGFR', 'Gene', (199, 203))	('EGFR', 'Gene', '1956', (98, 102))	('upregulated', 'PosReg', (65, 76))	('downregulated', 'NegReg', (84, 97))	('downregulated', 'NegReg', (30, 43))	('p53', 'Gene', '7157', (258, 261))	('NF90', 'Gene', '3609', (25, 29))	('KLF10', 'Gene', (189, 194))	('lncRNA-LET', 'Gene', '101241892', (229, 239))	('EGFR', 'Gene', '1956', (199, 203))
939425	31602267	Conversely, depletion of miR-548k downregulated HIF-1alpha and VEGF, upregulated KLF10, downregulated EGFR, and upregulated p53, which were consistent with the effects of NF90 depletion on HIF-1alpha and VEGF, and also the effects of lncRNA-LET overexpression on p53.	('miR-548k', 'Gene', '100313770', (25, 33))	('downregulated', 'NegReg', (34, 47))	('VEGF', 'Gene', (204, 208))	('upregulated', 'PosReg', (69, 80))	('p53', 'Gene', '7157', (263, 266))	('EGFR', 'Gene', '1956', (102, 106))	('NF90', 'Gene', (171, 175))	('downregulated', 'NegReg', (88, 101))	('depletion', 'Var', (12, 21))	('lncRNA-LET', 'Gene', '101241892', (234, 244))	('HIF-1alpha', 'Gene', (189, 199))	('p53', 'Gene', (263, 266))	('HIF-1alpha', 'Gene', '3091', (48, 58))	('NF90', 'Gene', '3609', (171, 175))	('p53', 'Gene', '7157', (124, 127))	('VEGF', 'Gene', '7422', (63, 67))	('KLF10', 'Gene', (81, 86))	('EGFR', 'Gene', (102, 106))	('lncRNA-LET', 'Gene', (234, 244))	('HIF-1alpha', 'Gene', (48, 58))	('VEGF', 'Gene', (63, 67))	('p53', 'Gene', (124, 127))	('upregulated', 'PosReg', (112, 123))	('miR-548k', 'Gene', (25, 33))	('HIF-1alpha', 'Gene', '3091', (189, 199))	('VEGF', 'Gene', '7422', (204, 208))	('KLF10', 'Gene', '7071', (81, 86))
939504	31453041	Multiple studies have employed various altered fractionation regimens in the management of NSCLC patients with radiotherapy alone and a benefit to survival outcomes has been suggested with the use of modified fractionation compared to conventional fractionation.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('modified fractionation', 'Var', (200, 222))	('NSCLC', 'Disease', (91, 96))	('patients', 'Species', '9606', (97, 105))
939546	31453041	No correlation was observed between the grade of pneumonitis and bilateral lung V5, V20, V30, V40 or mean lung dose (Table 3).	('V30', 'Var', (89, 92))	('V40', 'Var', (94, 97))	('pneumonitis', 'Disease', 'MESH:D011014', (49, 60))	('pneumonitis', 'Disease', (49, 60))
939550	31453041	Acute grade 2 esophagitis was associated with the maximum dose to the esophagus (OR 1.07, 95% CI 1.02-1.16, p=0.03) and occurred in 9% of patients with a maximum esophageal dose <=60 Gy and 44% of those with doses >60 Gy (p=0.02).	('<=60', 'Var', (178, 182))	('esophagitis', 'Phenotype', 'HP:0100633', (14, 25))	('esophagitis', 'Disease', (14, 25))	('esophagitis', 'Disease', 'MESH:D004941', (14, 25))	('patients', 'Species', '9606', (138, 146))
939558	31453041	While multiple studies have noted improved tumor control with a BED10 >100 Gy using hypofractionated regimens, variation in statistical methods, dose prescription and delivery, treatment schedule, and definitions of recurrence limit the generalizability of this conclusion.	('improved', 'PosReg', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('BED10 >100 Gy', 'Var', (64, 77))
939569	31453041	In this report, our data support the assertion that HRT to 70.2 Gy is a safe and effective alternative with a reasonably low risk of grade 1-2 esophagitis.	('HRT to 70.2 Gy', 'Var', (52, 66))	('esophagitis', 'Phenotype', 'HP:0100633', (143, 154))	('esophagitis', 'Disease', (143, 154))	('esophagitis', 'Disease', 'MESH:D004941', (143, 154))
939571	31453041	A Canadian, multi-institutional phase II trial included patients with T1-3N0 NSCLC that were ineligible for surgical resection due to underlying comorbidity or declined surgery.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('patients', 'Species', '9606', (56, 64))	('T1-3N0', 'Var', (70, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('NSCLC', 'Disease', (77, 82))
939682	28039180	The following confounders were included in the propensity matching: age >=70 years; male gender; American Society of Anesthesiologists (ASA) grade; clinical tumour (cT) stage; and clinical nodal (cN) positivity or negativity.	('negativity', 'Var', (214, 224))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('ASA', 'Chemical', '-', (136, 139))	('tumour', 'Disease', (157, 163))
939699	28039180	Although the incidence of anastomotic leak was higher in the NCRS group, in-hospital mortality and other major postoperative complications were similar.	('higher', 'PosReg', (47, 53))	('anastomotic leak', 'Disease', 'MESH:D057868', (26, 42))	('NCRS', 'Var', (61, 65))	('anastomotic leak', 'Disease', (26, 42))
939731	26377193	The odds ratio for BE associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal p-value=0.0005, false discovery rate=0.042).	('heartburn', 'Phenotype', 'HP:0002020', (54, 63))	('heartburn', 'Disease', (54, 63))	('BE', 'Phenotype', 'HP:0100580', (19, 21))	('rs2687201', 'Var', (145, 154))	('reflux', 'Disease', (67, 73))	('rs2687201', 'Mutation', 'rs2687201', (145, 154))
939732	26377193	Odds ratios (95% confidence intervals) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91,7.56), 3.56 (2.85,4.44), and 3.97 (2.47,6.37), respectively.	('rs2687201', 'Var', (122, 131))	('reflux', 'Disease', (63, 69))	('heartburn', 'Phenotype', 'HP:0002020', (50, 59))	('heartburn', 'Disease', (50, 59))	('rs2687201', 'Mutation', 'rs2687201', (122, 131))	('participants', 'Species', '9606', (76, 88))
939733	26377193	Reflux symptoms are more strongly associated with BE risk among persons homozygous for the major allele of rs2687201, which lies ~75 kb downstream of the transcription factor gene FOXP1.	('associated', 'Reg', (34, 44))	('persons', 'Species', '9606', (64, 71))	('Reflux symptoms', 'Disease', (0, 15))	('Reflux symptoms', 'Phenotype', 'HP:0002020', (0, 15))	('rs2687201', 'Var', (107, 116))	('rs2687201', 'Mutation', 'rs2687201', (107, 116))	('BE', 'Phenotype', 'HP:0100580', (50, 52))	('FOXP1', 'Gene', (180, 185))
939738	26377193	Recently, large genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) for BE, including variants in or near FOXF1, TBX5, GDF7, and the major histocompatibility complex (MHC) genes.	('variants', 'Var', (136, 144))	('TBX5', 'Gene', (163, 167))	('MHC', 'Gene', (217, 220))	('TBX5', 'Gene', '6910', (163, 167))	('FOXF1', 'Gene', (156, 161))	('GDF7', 'Gene', (169, 173))	('BE', 'Phenotype', 'HP:0100580', (122, 124))	('GDF7', 'Gene', '151449', (169, 173))	('FOXF1', 'Gene', '2294', (156, 161))
939740	26377193	Notably, the GWAS based on the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) reported that risk of BE and EA is influenced by many germline variants of small effect and, perhaps not surprisingly, genetic heritability is largely shared between the two diseases.	('BE', 'Phenotype', 'HP:0100580', (83, 85))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (45, 70))	('variants', 'Var', (154, 162))	('BE', 'Phenotype', 'HP:0100580', (113, 115))	('Esophageal Adenocarcinoma', 'Disease', (45, 70))	('EA', 'Phenotype', 'HP:0011459', (84, 86))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (45, 70))	('EA', 'Phenotype', 'HP:0011459', (120, 122))
939741	26377193	smoking and variants of GSTM1, GSTT1 and VEGF.	('VEGF', 'Gene', '7422', (41, 45))	('variants', 'Var', (12, 20))	('GSTM1', 'Gene', '2944', (24, 29))	('GSTT1', 'Gene', '2952', (31, 36))	('VEGF', 'Gene', (41, 45))	('GSTT1', 'Gene', (31, 36))	('GSTM1', 'Gene', (24, 29))
939747	26377193	Seven SNPs confirmed as associated with risk of EA or BE were included in our analysis: rs3072 in 2p24.1 (GDF7), rs2687201 in 3p14 (FOXP1), rs9257809 in 6p21 (MHC), rs11789015 in 9q22 (BARX1), rs2701108 in 12q24.21 (TBX5), rs9936833 in 16q24 (FOXF1), and rs10419226 in 19p13 (CRTC1).	('BARX1', 'Gene', (185, 190))	('EA', 'Phenotype', 'HP:0011459', (48, 50))	('rs2701108', 'Mutation', 'rs2701108', (193, 202))	('rs9936833', 'Mutation', 'rs9936833', (223, 232))	('TBX5', 'Gene', (216, 220))	('CRTC1', 'Gene', (276, 281))	('rs3072', 'Mutation', 'rs3072', (88, 94))	('FOXF1', 'Gene', (243, 248))	('rs9257809', 'Var', (140, 149))	('rs2701108', 'Var', (193, 202))	('rs10419226', 'Mutation', 'rs10419226', (255, 265))	('rs2687201', 'Mutation', 'rs2687201', (113, 122))	('GDF7', 'Gene', (106, 110))	('rs2687201', 'Var', (113, 122))	('rs9936833', 'Var', (223, 232))	('rs3072', 'Var', (88, 94))	('FOXF1', 'Gene', '2294', (243, 248))	('rs10419226', 'Var', (255, 265))	('rs9257809', 'Mutation', 'rs9257809', (140, 149))	('BARX1', 'Gene', '56033', (185, 190))	('p21', 'Gene', (154, 157))	('CRTC1', 'Gene', '23373', (276, 281))	('p21', 'Gene', '644914', (154, 157))	('GDF7', 'Gene', '151449', (106, 110))	('rs11789015', 'Var', (165, 175))	('rs11789015', 'Mutation', 'rs11789015', (165, 175))	('BE', 'Phenotype', 'HP:0100580', (54, 56))	('TBX5', 'Gene', '6910', (216, 220))
939756	26377193	The presence of at least one minor allele of rs2687201 appeared to decrease the magnitude of disease risk associated with GERD.	('rs2687201', 'Var', (45, 54))	('GERD', 'Disease', (122, 126))	('rs2687201', 'Mutation', 'rs2687201', (45, 54))	('decrease', 'NegReg', (67, 75))
939758	26377193	In sensitivity analyses, where the missing data in risk factors were accounted for by the inverse probability weighting method, the interaction between rs2687201 and GERD remained statistically significant (Supplementary Table 3).	('interaction', 'Interaction', (132, 143))	('rs2687201', 'Var', (152, 161))	('significant', 'Reg', (194, 205))	('rs2687201', 'Mutation', 'rs2687201', (152, 161))
939759	26377193	In a separate analysis, where BE and EA case participants were combined into a single case group, the significance level of the interaction between rs2687201 and GERD decreased (Supplementary Table A4).	('rs2687201', 'Var', (148, 157))	('rs2687201', 'Mutation', 'rs2687201', (148, 157))	('BE', 'Phenotype', 'HP:0100580', (30, 32))	('interaction', 'Interaction', (128, 139))	('participants', 'Species', '9606', (45, 57))	('GERD', 'MPA', (162, 166))	('EA', 'Phenotype', 'HP:0011459', (37, 39))	('decreased', 'NegReg', (167, 176))
939761	26377193	In Table 3, the three risk factors were investigated simultaneously in one logistic regression model for their interactions with the rs2687201 variant, the only SNP with an interaction P value satisfying the Bonferroni significance threshold.	('rs2687201', 'Var', (133, 142))	('rs2687201', 'Mutation', 'rs2687201', (133, 142))	('interactions', 'Interaction', (111, 123))
939770	26377193	The rs2687201 variant (chromosome 3p13) is located 75 kb distal to the FOXP1 3'UTR, in a ~1-Mb intergenic region containing several pseudogenes (RNPC3P1, UQCRHP4, COX6CP6, HMGB1P36) and a predicted ~130-bp "novel miRNA" locus (AC096971.1) (Figure S1).	('rs2687201', 'Var', (4, 13))	('RNPC3P1', 'Gene', '654340', (145, 152))	('HMGB1P36', 'Gene', (172, 180))	('COX6CP6', 'Gene', (163, 170))	('UQCRHP4', 'Gene', '100128448', (154, 161))	('HMGB1P36', 'Gene', '100419968', (172, 180))	('RNPC3P1', 'Gene', (145, 152))	('COX6CP6', 'Gene', '100289131', (163, 170))	('UQCRHP4', 'Gene', (154, 161))	('rs2687201', 'Mutation', 'rs2687201', (4, 13))
939771	26377193	Based on data from the 1000 Genomes Project, rs2687201 is in strong linkage disequilibrium (LD) (r2>0.8) with ~60 other SNPs, located within 30-60 kb (20 SNPs with r2>0.94).	('rs2687201', 'Var', (45, 54))	('linkage', 'Interaction', (68, 75))	('rs2687201', 'Mutation', 'rs2687201', (45, 54))
939773	26377193	DNA regulatory motifs for multiple transcriptional regulators (e.g., CPHX, IK-2, ZNF143, HOXA9/10, MEF2, CTCF, RAD21, YY1, and NF-kappaB) are predicted to be altered by rs2687201 or other nearby variants in high LD (r2>0.90).	('RAD21', 'Gene', (111, 116))	('HOXA9', 'Gene', '3205', (89, 94))	('ZNF143', 'Gene', (81, 87))	('YY1', 'Gene', (118, 121))	('MEF2', 'Gene', (99, 103))	('RAD21', 'Gene', '5885', (111, 116))	('MEF2', 'Gene', '4205', (99, 103))	('HOXA9', 'Gene', (89, 94))	('rs2687201', 'Mutation', 'rs2687201', (169, 178))	('rs2687201', 'Var', (169, 178))	('YY1', 'Gene', '7528', (118, 121))	('CTCF', 'Gene', (105, 109))	('NF-kappaB', 'Gene', (127, 136))	('altered', 'Reg', (158, 165))	('CPHX', 'Gene', (69, 73))	('ZNF143', 'Gene', '7702', (81, 87))	('CTCF', 'Gene', '10664', (105, 109))
939775	26377193	Further assessment of the 13 imputed SNPs with more significant interaction P values than rs2687201 revealed that several of these variants (eg, rs2597312, rs7611254, rs1522554) are situated in putative enhancer sequences according to data from the Roadmap Epigenome Project (Supplementary Table 6.1); most of the 13 SNPs also appear to alter predicted DNA regulatory motifs.	('DNA regulatory motifs', 'MPA', (353, 374))	('rs1522554', 'Mutation', 'rs1522554', (167, 176))	('rs1522554', 'Var', (167, 176))	('rs2687201', 'Mutation', 'rs2687201', (90, 99))	('rs2597312', 'Var', (145, 154))	('rs2597312', 'Mutation', 'rs2597312', (145, 154))	('alter', 'Reg', (337, 342))	('rs7611254', 'Var', (156, 165))	('rs7611254', 'Mutation', 'rs7611254', (156, 165))
939776	26377193	The precise functional effects of rs2687201 and/or linked variants on expression levels of FOXP1 or other neighboring loci remain to be determined.	('rs2687201', 'Var', (34, 43))	('expression levels', 'MPA', (70, 87))	('FOXP1', 'Gene', (91, 96))	('rs2687201', 'Mutation', 'rs2687201', (34, 43))
939779	26377193	In subsequent studies, expression of FOXP1 was associated with improved survival in breast cancer, but reduced survival in diffuse large B-cell lymphoma.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('FOXP1', 'Gene', (37, 42))	('improved', 'PosReg', (63, 71))	('reduced', 'NegReg', (103, 110))	('diffuse large B-cell lymphoma', 'Disease', (123, 152))	('expression', 'Var', (23, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (137, 152))	('breast cancer', 'Disease', (84, 97))
939781	26377193	It is interesting to note that genetic variation (rs9936833) in proximity to another FOX family member, FOXF1, has also been associated with altered risk of BE.	('associated', 'Reg', (125, 135))	('genetic variation (rs9936833', 'Var', (31, 59))	('rs9936833', 'Var', (50, 59))	('FOXF1', 'Gene', '2294', (104, 109))	('rs9936833', 'Mutation', 'rs9936833', (50, 59))	('BE', 'Phenotype', 'HP:0100580', (157, 159))	('FOXF1', 'Gene', (104, 109))
939863	25018682	Neuman et al reported the largest chain that involved 487,229 cases; they showed that dysphagia or odynphagia, regurgitation and globus were significantly more common in patients with cervical inlet patch.	('patients', 'Species', '9606', (170, 178))	('cervical', 'Var', (184, 192))	('regurgitation', 'Disease', 'MESH:D001022', (111, 124))	('dysphagia', 'Phenotype', 'HP:0002015', (86, 95))	('regurgitation', 'Disease', (111, 124))	('dysphagia or odynphagia', 'Disease', 'MESH:D003680', (86, 109))	('globus', 'Disease', (129, 135))	('dysphagia or odynphagia', 'Disease', (86, 109))
939944	33170461	Pre-specified exploratory subgroup analyses assessed the association between OS and stratification factors or baseline variables, including PD-L1 expression (< 1%, >= 1%, < 5%, >= 5%, < 10%, and >= 10%), age (< 65 years vs. >= 65 years), sex, race (Asian vs white), Eastern Cooperative Oncology Group (ECOG) performance status (PS; 0 vs. 1), prior surgery, prior radiotherapy, and history of smoking.	('< 5%', 'Var', (171, 175))	('< 1%', 'Var', (158, 162))	('< 10%', 'Var', (184, 189))	('PD-L1', 'Gene', (140, 145))	('PD-L1', 'Gene', '29126', (140, 145))	('Oncology', 'Phenotype', 'HP:0002664', (286, 294))
939960	33170461	In the subgroup analysis, OS was numerically longer in the nivolumab group consistently versus the chemotherapy group in the Japanese subpopulation (Fig.	('nivolumab', 'Var', (59, 68))	('longer', 'PosReg', (45, 51))	('nivolumab', 'Chemical', 'MESH:D000077594', (59, 68))
939982	33170461	In the subgroup analysis, OS was consistently numerically longer in the nivolumab group versus the chemotherapy group in the Japanese subpopulation, which was similar to the trend observed in the overall ITT population.	('longer', 'PosReg', (58, 64))	('nivolumab', 'Var', (72, 81))	('nivolumab', 'Chemical', 'MESH:D000077594', (72, 81))
939988	33170461	After study treatment discontinuation, the proportion of patients who received subsequent anticancer treatment in the Japanese subpopulation and the overall ITT population was numerically higher in the nivolumab group [58.8% (80/136) and 53% (112/210)] than in the chemotherapy group [47.1% (65/138) and 47% (99/209)].	('nivolumab', 'Var', (202, 211))	('patients', 'Species', '9606', (57, 65))	('higher', 'PosReg', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('nivolumab', 'Chemical', 'MESH:D000077594', (202, 211))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
940209	32030915	Besides, pioneering studies have implied that intervention of the Hedgehog pathway may prevent the progression of Barrett's esophagus to invasive esophageal adenocarcinoma,53 and more researches are needed to clarify its effectiveness.	('Hedgehog pathway', 'Pathway', (66, 82))	('intervention', 'Var', (46, 58))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (114, 133))	('prevent', 'NegReg', (87, 94))	('invasive esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (137, 171))	('invasive esophageal adenocarcinoma', 'Disease', (137, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
940281	31883400	The biological characteristics of IL-33 were determined in HET-1A and 7 other ESCC cell lines including Eca-109, KYSE-450, KYSE-70, EC9706, EC9706 clone EC1, TE-1, and TE-7 by RT-PCR and western blot analysis (Figure 2A,B).	('EC9706', 'CellLine', 'CVCL:E307', (140, 146))	('ESCC', 'Disease', (78, 82))	('KYSE-450', 'CellLine', 'CVCL:1353', (113, 121))	('EC9706', 'Var', (132, 138))	('EC9706', 'Var', (140, 146))	('EC9706', 'CellLine', 'CVCL:E307', (132, 138))	('EC1', 'Gene', '4819', (153, 156))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('EC1', 'Gene', (153, 156))
940293	31883400	Results revealed that the active form of NF-kappaB (phosphorylated NF-kappaB) and CCL2 were markedly decreased by knockdown of IL-33 together with addition of NF-kappaB inhibitor compared to the control group (Figure 3H).	('CCL2', 'Gene', (82, 86))	('NF-kappaB', 'Gene', '4790', (67, 76))	('NF-kappaB', 'Gene', (67, 76))	('knockdown', 'Var', (114, 123))	('IL-33', 'Gene', (127, 132))	('decreased', 'NegReg', (101, 110))	('NF-kappaB', 'Gene', '4790', (41, 50))	('NF-kappaB', 'Gene', '4790', (159, 168))	('active', 'MPA', (26, 32))	('NF-kappaB', 'Gene', (41, 50))	('NF-kappaB', 'Gene', (159, 168))
940294	31883400	However, after knockdown of receptor ST2, the expression of CCL2 and NF-kappaB was upregulated (Figure 3H).	('knockdown', 'Var', (15, 24))	('NF-kappaB', 'Gene', '4790', (69, 78))	('ST2', 'Gene', (37, 40))	('upregulated', 'PosReg', (83, 94))	('NF-kappaB', 'Gene', (69, 78))	('expression', 'MPA', (46, 56))	('CCL2', 'Gene', (60, 64))	('ST2', 'Gene', '6761', (37, 40))
940295	31883400	Additionally, both the expression of CCL2 and phosphorylated NF-kappaB were decreased by knockdown of receptor ST2 and addition of IL-33 (Figure 3H), indicating that IL-33 might regulate NF-kappaB signaling by binding to its receptor ST2 to affect the function of CCL2.	('function', 'MPA', (252, 260))	('NF-kappaB', 'Gene', (187, 196))	('ST2', 'Gene', '6761', (234, 237))	('ST2', 'Gene', (111, 114))	('regulate', 'Reg', (178, 186))	('NF-kappaB', 'Gene', (61, 70))	('binding', 'Interaction', (210, 217))	('expression', 'MPA', (23, 33))	('decreased', 'NegReg', (76, 85))	('CCL2', 'Gene', (264, 268))	('ST2', 'Gene', '6761', (111, 114))	('knockdown', 'Var', (89, 98))	('NF-kappaB', 'Gene', '4790', (187, 196))	('affect', 'Reg', (241, 247))	('ST2', 'Gene', (234, 237))	('NF-kappaB', 'Gene', '4790', (61, 70))	('CCL2', 'Gene', (37, 41))
940296	31883400	Furthermore, RT-PCR was carried out to analyze the CCL2 and IL-33 gene levels in 35 ESCC patients and 76 ESCC patients from The Cancer Genome Atlas, the results showed that IL-33 is significantly associated with CCL2 (Figure 3I).	('ESCC', 'Disease', (105, 109))	('ESCC', 'Disease', (84, 88))	('associated', 'Reg', (196, 206))	('patients', 'Species', '9606', (89, 97))	('ESCC', 'Disease', 'MESH:C562729', (84, 88))	('Cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ESCC', 'Disease', 'MESH:C562729', (105, 109))	('CCL2', 'Disease', (212, 216))	('IL-33', 'Var', (173, 178))	('patients', 'Species', '9606', (110, 118))
940298	31883400	Our results showed the proportion of CD4+ cells was higher in the OE-IL-33 group than in the control (Figure 4A).	('CD4', 'Gene', '920', (37, 40))	('OE-IL-33', 'Var', (66, 74))	('CD4', 'Gene', (37, 40))	('higher', 'PosReg', (52, 58))
940304	31883400	Then we investigated whether IL-33 knockdown or overexpression could affect the CCL2 level with or without TGF-beta.	('knockdown', 'Var', (35, 44))	('affect', 'Reg', (69, 75))	('TGF-beta', 'Gene', (107, 115))	('CCL2 level', 'MPA', (80, 90))	('TGF-beta', 'Gene', '7039', (107, 115))	('IL-33', 'Gene', (29, 34))
940305	31883400	Results showed that protein levels of CCL2 decreased significantly after knocking down IL-33 or with addition of TGF-beta (Figure 4G).	('TGF-beta', 'Gene', '7039', (113, 121))	('knocking down', 'Var', (73, 86))	('IL-33', 'Gene', (87, 92))	('TGF-beta', 'Gene', (113, 121))	('protein levels', 'MPA', (20, 34))	('decreased', 'NegReg', (43, 52))
940312	31883400	These findings suggested that knockdown of IL-33 could reduce tumor burden and inhibit formation of tumors in vivo.	('inhibit', 'NegReg', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('IL-33', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (62, 67))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('knockdown', 'Var', (30, 39))	('reduce', 'NegReg', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
940315	31883400	We analyzed EMT-related genes from tumor tissues of nude mice and found that expression of N-CAD, slug, VIM, and ZEB2 in shIL-33 group was lower in the control group (Figure 5G).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('expression', 'MPA', (77, 87))	('VIM', 'Gene', (104, 107))	('ZEB2', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('N-CAD', 'Gene', (91, 96))	('slug', 'Gene', (98, 102))	('shIL-33', 'Var', (121, 128))	('lower', 'NegReg', (139, 144))	('nude mice', 'Species', '10090', (52, 61))
940320	31883400	Our IHC results showed the expression of Foxp3 and CCL2 was downregulated by knockdown of IL-33 (Figure 6C).	('CCL2', 'Gene', (51, 55))	('Foxp3', 'Gene', '50943', (41, 46))	('Foxp3', 'Gene', (41, 46))	('knockdown', 'Var', (77, 86))	('expression', 'MPA', (27, 37))	('IL-33', 'Gene', (90, 95))	('downregulated', 'NegReg', (60, 73))
940321	31883400	We observed that, when IL-33 was knocked down, the mRNA expression levels of Foxp3 and CCL2 were also decreased (Figure 6D), which indicated a positive correlation between Foxp3 and CCL2 in ESCC.	('ESCC', 'Disease', (190, 194))	('Foxp3', 'Gene', '50943', (172, 177))	('decreased', 'NegReg', (102, 111))	('IL-33', 'Gene', (23, 28))	('Foxp3', 'Gene', (172, 177))	('Foxp3', 'Gene', '50943', (77, 82))	('ESCC', 'Disease', 'MESH:C562729', (190, 194))	('mRNA expression levels', 'MPA', (51, 73))	('Foxp3', 'Gene', (77, 82))	('knocked down', 'Var', (33, 45))
940337	31883400	Reportedly, CCL2 has the ability to promote invasion and migration in prostatic carcinoma and ovarian carcinoma.33, 34 Interleukin-33 knockdown strongly downregulated CCL2, which could partly explain why IL-33 knockdown impacted the reduced invasive capacity of ESCC cells.	('ovarian carcinoma', 'Disease', 'MESH:D010051', (94, 111))	('reduced', 'NegReg', (233, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('invasive capacity', 'CPA', (241, 258))	('ESCC', 'Disease', 'MESH:C562729', (262, 266))	('ovarian carcinoma', 'Disease', (94, 111))	('prostatic carcinoma', 'Disease', 'MESH:D011471', (70, 89))	('prostatic carcinoma', 'Phenotype', 'HP:0012125', (70, 89))	('Interleukin-33', 'Gene', (119, 133))	('knockdown', 'Var', (134, 143))	('prostatic carcinoma', 'Disease', (70, 89))	('Interleukin-33', 'Gene', '90865', (119, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('ESCC', 'Disease', (262, 266))	('CCL2', 'Gene', (167, 171))	('downregulated', 'NegReg', (153, 166))
940340	31883400	Furthermore, we knocked down ST2, an IL-33 receptor, and the ability of IL-33 to downregulate CCL2 was decreased.	('knocked', 'Var', (16, 23))	('downregulate', 'NegReg', (81, 93))	('decreased', 'NegReg', (103, 112))	('ST2', 'Gene', (29, 32))	('CCL2', 'Gene', (94, 98))	('ST2', 'Gene', '6761', (29, 32))
940342	31883400	Interleukin-33 could recruit IL-1R-associated kinase 1 and 4 to the receptor complex in cytoplasmic region of ST2 by binding to the IL-33 receptor, which triggers numerous signaling downstream, including NF-kappaB, that might lead to inflammation.26 Activated NF-kappaB enhances the expression of various proteins that could promote metastasis.24, 25, 28 In our results, after knockdown of IL-33, the level of CCL2 was decreased when the NF-kappaB pathway was inhibited.	('knockdown', 'Var', (377, 386))	('IL-33', 'Gene', (390, 395))	('inflammation', 'Disease', (234, 246))	('NF-kappaB', 'Gene', (204, 213))	('NF-kappaB', 'Gene', '4790', (260, 269))	('NF-kappaB', 'Gene', (438, 447))	('ST2', 'Gene', (110, 113))	('decreased', 'NegReg', (419, 428))	('NF-kappaB', 'Gene', (260, 269))	('ST2', 'Gene', '6761', (110, 113))	('Interleukin-33', 'Gene', (0, 14))	('Interleukin-33', 'Gene', '90865', (0, 14))	('NF-kappaB', 'Gene', '4790', (204, 213))	('inflammation', 'Disease', 'MESH:D007249', (234, 246))	('NF-kappaB', 'Gene', '4790', (438, 447))	('level', 'MPA', (401, 406))
940343	31883400	Furthermore, after knockdown of IL-33 receptor ST2 together with applying recombinant protein IL-33, we observed that IL-33 could trigger the NF-kappaB pathway and promote the expression of CCL2.	('promote', 'PosReg', (164, 171))	('CCL2', 'Gene', (190, 194))	('expression', 'MPA', (176, 186))	('NF-kappaB', 'Gene', '4790', (142, 151))	('ST2', 'Gene', (47, 50))	('NF-kappaB', 'Gene', (142, 151))	('trigger', 'PosReg', (130, 137))	('IL-33', 'Var', (118, 123))	('ST2', 'Gene', '6761', (47, 50))
940351	31883400	In summary, our study shows that IL-33 could promote tumor progress by upregulating CCL2 expression and recruiting Tregs through the NF-kappaB pathway, and IL-33 could promote ESCC metastasis in part by regulating EMT.	('ESCC', 'Disease', (176, 180))	('upregulating', 'PosReg', (71, 83))	('IL-33', 'Var', (156, 161))	('expression', 'MPA', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('NF-kappaB', 'Gene', (133, 142))	('regulating', 'Reg', (203, 213))	('promote', 'PosReg', (168, 175))	('ESCC', 'Disease', 'MESH:C562729', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Tregs', 'CPA', (115, 120))	('EMT', 'CPA', (214, 217))	('promote', 'PosReg', (45, 52))	('tumor', 'Disease', (53, 58))	('CCL2', 'Gene', (84, 88))	('IL-33', 'Gene', (33, 38))	('NF-kappaB', 'Gene', '4790', (133, 142))
940365	30876442	Currently, many research institutions adopt the dose of 50.4Gy based on RTOG94-05, which shows that patients in the high-dose group (64.8Gy) have no improvement in terms of overall survival (OS) or local control compared with patients in the low-dose group (50.4Gy).	('64.8Gy', 'Var', (133, 139))	('overall survival', 'CPA', (173, 189))	('OS', 'Chemical', '-', (191, 193))	('local control', 'CPA', (198, 211))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (226, 234))
940370	30876442	For cavity organ like esophagus, such high fraction size may cause serious consequences such as esophageal perforation, severe radiation-related esophagitis, etc.	('cause', 'Reg', (61, 66))	('esophageal perforation', 'Disease', (96, 118))	('esophagitis', 'Phenotype', 'HP:0100633', (145, 156))	('esophagitis', 'Disease', (145, 156))	('esophagitis', 'Disease', 'MESH:D004941', (145, 156))	('high fraction size', 'Var', (38, 56))
940371	30876442	adopted the dose mode of 66Gy/2.2Gy/30f to gross tumor and 54Gy/1.8Gy/30f to subclinical diseases.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('54Gy/1.8Gy/30f', 'Var', (59, 73))	('tumor', 'Disease', (49, 54))
940401	30876442	The prophylactic PTVs received a stable dose of 50.40Gy /1.8Gy /28f, while the therapeutic PGTVs were planned to be prescribed with three consecutive dose levels: 60.76Gy /2.17Gy /28f (dose level 1), 61.88Gy /2.21Gy /28f (dose level 2) and 64.12Gy /2.29Gy /28f (dose level 3).	('PTV', 'Chemical', '-', (17, 20))	('61.88Gy /2.21Gy /28f', 'Var', (200, 220))	('60.76Gy /2.17Gy /28f', 'Var', (163, 183))	('64.12Gy /2.29Gy /28f', 'Var', (240, 260))	('50.40Gy /1.8Gy /28f', 'Var', (48, 67))
940670	26266659	The percentage of change in body weight and diamine oxidase activity from before chemotherapy was higher in the Gln plus ED group than in the control group.	('higher', 'PosReg', (98, 104))	('body weight', 'CPA', (28, 39))	('activity', 'MPA', (60, 68))	('Gln', 'Chemical', 'MESH:D005973', (112, 115))	('Gln plus ED', 'Var', (112, 123))	('diamine oxidase', 'Gene', (44, 59))	('diamine oxidase', 'Gene', '26', (44, 59))
940684	26266659	We therefore conducted a randomized phase II study for investigation of efficacy and safety at Gln plus ED or Gln alone compared to no treatment on oral mucositis in patients with esophageal cancer undergoing chemotherapy.	('Gln', 'Chemical', 'MESH:D005973', (110, 113))	('Gln', 'Var', (95, 98))	('esophageal cancer', 'Disease', (180, 197))	('oral mucositis', 'Disease', (148, 162))	('Gln', 'Chemical', 'MESH:D005973', (95, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('oral mucositis', 'Disease', 'MESH:D013280', (148, 162))	('patients', 'Species', '9606', (166, 174))
940689	26266659	Patients also had to have an Eastern Cooperative Oncology Group performance status of 0-1, a life expectancy of >12 weeks, and adequate liver, bone marrow, renal, and cardiovascular function (serum bilirubin <=1.5 mg/dL, neutrophil count >=1500/mm3, serum aspartate aminotransferase and alanine aminotransferase levels <= twice the upper limit of normal range, platelet count >=10 x 104/mm3, hemoglobin >=8.0 g/dL, and creatinine <=1.2 mg/dL [or creatinine clearance >60 mL/min]).	('creatinine', 'MPA', (419, 429))	('hemoglobin', 'MPA', (392, 402))	('alanine aminotransferase', 'Gene', (287, 311))	('creatinine clearance', 'MPA', (446, 466))	('alanine aminotransferase', 'Gene', '2875', (287, 311))	('Patients', 'Species', '9606', (0, 8))	('Oncology', 'Phenotype', 'HP:0002664', (49, 57))	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (250, 282))	('platelet count', 'MPA', (361, 375))	('>=10', 'Var', (376, 380))	('serum bilirubin', 'MPA', (192, 207))
940700	26266659	The primary objective of this study was to determine the effect of Gln and Gln plus ED on the incidence grade of oral mucositis during 2 cycles of chemotherapy.	('Gln', 'Var', (67, 70))	('oral mucositis', 'Disease', 'MESH:D013280', (113, 127))	('Gln', 'Var', (75, 78))	('Gln', 'Chemical', 'MESH:D005973', (67, 70))	('Gln', 'Chemical', 'MESH:D005973', (75, 78))	('oral mucositis', 'Disease', (113, 127))
940703	26266659	Patients were assigned in a 1:1:1 ratio to receive Gln, Gln plus ED, or no additional treatment (control).	('Gln', 'Chemical', 'MESH:D005973', (56, 59))	('Patients', 'Species', '9606', (0, 8))	('Gln', 'Var', (51, 54))	('Gln', 'Var', (56, 59))	('Gln', 'Chemical', 'MESH:D005973', (51, 54))
940704	26266659	During the chemotherapy cycles, patients continued to receive Gln or Gln plus ED every day.	('Gln', 'Chemical', 'MESH:D005973', (69, 72))	('patients', 'Species', '9606', (32, 40))	('Gln', 'Var', (62, 65))	('Gln plus', 'Var', (69, 77))	('Gln', 'Chemical', 'MESH:D005973', (62, 65))
940718	26266659	A proportional odds model was used to the evaluation of treatment effect (Gln and Gln + ED) and adjusted effect of five covariates (age, sex, cancer stage, treatment, and body mass index).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('Gln + ED', 'Var', (82, 90))	('Gln', 'Var', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Gln', 'Chemical', 'MESH:D005973', (74, 77))	('Gln', 'Chemical', 'MESH:D005973', (82, 85))	('cancer', 'Disease', (142, 148))
940722	26266659	During this study, oral mucositis of grade >=2 developed in approximately 60 % of patients in the control group, and the incidence of oral mucositis was significantly lower in the Gln plus ED group (10 %) than in the control group (Fig.	('lower', 'NegReg', (167, 172))	('Gln', 'Chemical', 'MESH:D005973', (180, 183))	('oral mucositis', 'Disease', (19, 33))	('patients', 'Species', '9606', (82, 90))	('oral mucositis', 'Disease', (134, 148))	('Gln plus ED', 'Var', (180, 191))	('oral mucositis', 'Disease', 'MESH:D013280', (19, 33))	('oral mucositis', 'Disease', 'MESH:D013280', (134, 148))
940723	26266659	In addition, during the first cycle of chemotherapy, the incidence of oral mucositis was significantly lower in the Gln plus ED group than in the control group (P = 0.040) (Fig.	('oral mucositis', 'Disease', (70, 84))	('lower', 'NegReg', (103, 108))	('oral mucositis', 'Disease', 'MESH:D013280', (70, 84))	('Gln', 'Chemical', 'MESH:D005973', (116, 119))	('Gln plus ED', 'Var', (116, 127))
940726	26266659	The results of the multivariate analysis demonstrated that in addition to Gln plus ED (odds ratio = 0.1, P = 0.02), cancer stage (odds ratio = 13.3, P = 0.01) was an independent factor affecting mucositis grade during chemotherapy (Table 2).	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('affecting', 'Reg', (185, 194))	('Gln', 'Chemical', 'MESH:D005973', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Gln plus ED', 'Var', (74, 85))	('mucositis', 'Disease', (195, 204))	('mucositis', 'Disease', 'MESH:D052016', (195, 204))
940728	26266659	The Gln plus ED group showed a significant increase in DAO activity during chemotherapy (approximately 1.3 times the DAO activity measured before chemotherapy) (Table 3).	('DAO activity', 'MPA', (55, 67))	('Gln', 'Chemical', 'MESH:D005973', (4, 7))	('Gln plus ED', 'Var', (4, 15))	('increase', 'PosReg', (43, 51))
940730	26266659	On the other hand, body weight was maintained in the Gln plus ED group, and changes in body weight were significantly different between the Gln plus ED and control groups (1.70 vs. -5.40 %, respectively; P = 0.01) (Table 3).	('Gln', 'Var', (140, 143))	('Gln', 'Chemical', 'MESH:D005973', (53, 56))	('body', 'MPA', (87, 91))	('Gln', 'Chemical', 'MESH:D005973', (140, 143))
940732	26266659	For example, plasma Gln tended to be higher in the Gln and Gln plus ED groups than in the control group (-3.64, 9.91, and 9.59 %, respectively; Table 3).	('Gln plus ED', 'Var', (59, 70))	('higher', 'PosReg', (37, 43))	('plasma Gln', 'MPA', (13, 23))	('Gln', 'Var', (51, 54))	('Gln', 'Chemical', 'MESH:D005973', (20, 23))	('Gln', 'Chemical', 'MESH:D005973', (59, 62))	('Gln', 'Chemical', 'MESH:D005973', (51, 54))
940739	26266659	In one case in the Gln group and two cases in the control group, the second cycle of chemotherapy was delayed for 3-4 days because of grade 3 mucositis.	('mucositis', 'Disease', (142, 151))	('grade', 'Disease', (134, 139))	('Gln', 'Var', (19, 22))	('mucositis', 'Disease', 'MESH:D052016', (142, 151))	('Gln', 'Chemical', 'MESH:D005973', (19, 22))
940741	26266659	This is the first study to show that Gln plus ED can prevent oral mucositis in patients receiving chemotherapy.	('oral mucositis', 'Disease', (61, 75))	('Gln', 'Chemical', 'MESH:D005973', (37, 40))	('patients', 'Species', '9606', (79, 87))	('Gln plus ED', 'Var', (37, 48))	('oral mucositis', 'Disease', 'MESH:D013280', (61, 75))
940742	26266659	Moreover, the results of the multivariate analysis demonstrated that Gln plus ED and cancer stage were independent factors affecting mucositis grade during chemotherapy.	('Gln', 'Chemical', 'MESH:D005973', (69, 72))	('Gln plus ED', 'Var', (69, 80))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('affecting', 'Reg', (123, 132))	('cancer', 'Disease', (85, 91))	('mucositis', 'Disease', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mucositis', 'Disease', 'MESH:D052016', (133, 142))
940743	26266659	Additionally, in our study, Gln plus ED had beneficial effects on the integrity of the intestinal mucosa, as indicated by DAO measurements and body weight.	('Gln plus ED', 'Var', (28, 39))	('integrity of the intestinal mucosa', 'CPA', (70, 104))	('beneficial effects', 'PosReg', (44, 62))	('Gln', 'Chemical', 'MESH:D005973', (28, 31))
940747	26266659	Previous reports indicated that the Gln decreased the subjective symptoms of stomatitis in chemotherapy, radiotherapy, and hematopoietic stem cell transplantation.	('Gln', 'Var', (36, 39))	('subjective symptoms', 'MPA', (54, 73))	('stomatitis', 'Phenotype', 'HP:0010280', (77, 87))	('Gln', 'Chemical', 'MESH:D005973', (36, 39))	('stomatitis', 'Disease', 'MESH:D013280', (77, 87))	('stomatitis', 'Disease', (77, 87))	('decreased', 'NegReg', (40, 49))
940755	26266659	suggested that the mixture of hydroxyl-methylbutyrate, arginine, and Gln (HMB/Arg/Gln 16 g) was effective against cancer cachexia.	('hydroxyl-methylbutyrate', 'Chemical', '-', (30, 53))	('Gln', 'Chemical', 'MESH:D005973', (69, 72))	('arginine', 'Chemical', 'MESH:D001120', (55, 63))	('cachexia', 'Phenotype', 'HP:0004326', (121, 129))	('cancer cachexia', 'Disease', 'MESH:D002100', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Arg/Gln 16', 'SUBSTITUTION', 'None', (78, 88))	('HMB', 'Chemical', 'MESH:C004961', (74, 77))	('cancer cachexia', 'Disease', (114, 129))	('Gln', 'Chemical', 'MESH:D005973', (82, 85))	('Arg/Gln 16', 'Var', (78, 88))
940760	26266659	It cannot be ruled out that absorptive kinetics may be different between marzulene  and marzulene  plus ED, but various amino acids, including Gln, in ED might have resulted in the prevention of oral mucositis.	('oral mucositis', 'Disease', 'MESH:D013280', (195, 209))	('marzulene', 'Chemical', 'MESH:C111545', (88, 97))	('Gln', 'Var', (143, 146))	('resulted in', 'Reg', (165, 176))	('oral mucositis', 'Disease', (195, 209))	('Gln', 'Chemical', 'MESH:D005973', (143, 146))	('marzulene', 'Chemical', 'MESH:C111545', (73, 82))
940767	26266659	In fact, our trial showed significantly higher levels of DAO activity, an indicator of intestinal mucosal integrity, in the Gln plus ED group than in the control group.	('DAO activity', 'MPA', (57, 69))	('Gln plus ED', 'Var', (124, 135))	('higher', 'PosReg', (40, 46))	('Gln', 'Chemical', 'MESH:D005973', (124, 127))
940790	26266659	In conclusion, Gln plus ED may prevent chemotherapy-induced oral mucositis in esophageal cancer patients, and this effect may contribute to the maintenance of intestinal mucosal integrity and body weight during chemotherapy.	('Gln', 'Var', (15, 18))	('oral mucositis in esophageal cancer', 'Disease', 'MESH:D004938', (60, 95))	('oral mucositis in esophageal cancer', 'Disease', (60, 95))	('Gln', 'Chemical', 'MESH:D005973', (15, 18))	('contribute', 'Reg', (126, 136))	('prevent', 'NegReg', (31, 38))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
940841	17176471	In squamous cell carcinoma, patients with a weak CXCR4 expression had a mean survival of 25 (+/- 5 SD) months after surgery as compared to only 17 (+/- 4 SD) months in the group with strong chemokine expression (Figure 3).	('CXCR4', 'Gene', (49, 54))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('CXCR4', 'Gene', '7852', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('weak', 'Var', (44, 48))	('patients', 'Species', '9606', (28, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('squamous cell carcinoma', 'Disease', (3, 26))
940847	17176471	Our data provide evidence that expression of CXCR4 by primary tumor cells is associated with malignant transformation in esophageal cancer, consistent with recent findings by Kaifi et al, but contrasted to a preceding investigation of Mitra et al., who used reverse transcriptase-polymerase chain reaction.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('esophageal cancer', 'Disease', (121, 138))	('malignant transformation', 'CPA', (93, 117))	('tumor', 'Disease', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('CXCR4', 'Gene', (45, 50))	('CXCR4', 'Gene', '7852', (45, 50))	('expression', 'Var', (31, 41))	('associated with', 'Reg', (77, 92))
940851	17176471	Interestingly, CXCR4 is regulated by different external factors, such as hypoxia (hif-1- pathway) and the activation of adenosine-receptors, as well as by internal alterations as the inactivation of tumor suppressor genes pVHL, p53, over-expression of NFkB and DNA methylation.	('CXCR4', 'Gene', '7852', (15, 20))	('NFkB', 'Gene', (252, 256))	('CXCR4', 'Gene', (15, 20))	('pVHL', 'Gene', '7428', (222, 226))	('hypoxia', 'Disease', (73, 80))	('pVHL', 'Gene', (222, 226))	('over-expression', 'PosReg', (233, 248))	('p53', 'Gene', '7157', (228, 231))	('hypoxia', 'Disease', 'MESH:D000860', (73, 80))	('hif-1', 'Gene', (82, 87))	('activation', 'PosReg', (106, 116))	('tumor', 'Disease', (199, 204))	('p53', 'Gene', (228, 231))	('DNA', 'Gene', (261, 264))	('inactivation', 'Var', (183, 195))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('adenosine-receptors', 'Protein', (120, 139))	('hif-1', 'Gene', '3091', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
940854	17176471	This homing theory is underlined by the findings, that the presence of micrometastatic tumor cells in lymph nodes and bone marrow has been associated with poorer survival.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('micrometastatic', 'Var', (71, 86))	('tumor', 'Disease', (87, 92))	('poorer', 'NegReg', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
940877	33912448	A review of the literature on microsurgery versus extensive local excision for melanoma showed that after controlling for potential confounding variables, patients treated for melanoma with microsurgery were more likely to be alive at five years than those treated for melanoma with extensive local excision.	('melanoma', 'Phenotype', 'HP:0002861', (269, 277))	('microsurgery', 'Var', (190, 202))	('melanoma', 'Disease', (269, 277))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', 'MESH:D008545', (269, 277))	('melanoma', 'Disease', (176, 184))	('patients', 'Species', '9606', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
940942	33912448	In humans, dysregulation of genes such as cofactors and chromatin can lead to many diseases.	('lead to', 'Reg', (70, 77))	('humans', 'Species', '9606', (3, 9))	('diseases', 'Disease', (83, 91))	('dysregulation', 'Var', (11, 24))
940958	33912448	It has been reported that patients with bladder cancer with high expression of KIF20A have poorer tumor stages and that KIF20A promotes metastasis and proliferation of bladder cancer cells.	('KIF20A', 'Gene', (79, 85))	('high expression', 'Var', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Disease', (98, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (168, 182))	('bladder cancer', 'Disease', (168, 182))	('KIF20A', 'Gene', '10112', (79, 85))	('proliferation', 'CPA', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('bladder cancer', 'Phenotype', 'HP:0009725', (168, 182))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('KIF20A', 'Gene', (120, 126))	('promotes', 'PosReg', (127, 135))	('patients', 'Species', '9606', (26, 34))	('metastasis', 'CPA', (136, 146))	('KIF20A', 'Gene', '10112', (120, 126))
940964	33912448	A study of TPX2 in esophageal cancer showed that the 5-year survival rate of esophageal cancer patients with concomitant high TPX2 expression levels was significantly lower than that of esophageal cancer patients with low TPX2 expression levels.	('esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('esophageal cancer', 'Disease', (77, 94))	('survival rate', 'CPA', (60, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (19, 36))	('TPX2', 'Gene', (11, 15))	('patients', 'Species', '9606', (204, 212))	('TPX2', 'Gene', '22974', (11, 15))	('esophageal cancer', 'Disease', (19, 36))	('esophageal cancer', 'Disease', (186, 203))	('lower', 'NegReg', (167, 172))	('TPX2', 'Gene', (222, 226))	('expression levels', 'MPA', (131, 148))	('TPX2', 'Gene', (126, 130))	('TPX2', 'Gene', '22974', (222, 226))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('TPX2', 'Gene', '22974', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('patients', 'Species', '9606', (95, 103))	('high', 'Var', (121, 125))
940965	33912448	Interestingly, in our study, patients with high TPX2 expression of melanoma had a relatively shorter overall survival than patients with low expression.	('patients', 'Species', '9606', (29, 37))	('TPX2', 'Gene', '22974', (48, 52))	('overall survival', 'MPA', (101, 117))	('high', 'Var', (43, 47))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('patients', 'Species', '9606', (123, 131))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('shorter', 'NegReg', (93, 100))	('TPX2', 'Gene', (48, 52))
940967	33912448	The main diseases known to be associated with this gene are Ceroid Lipofuscinosis, Neuronal, 2.	('Ceroid Lipofuscinosis', 'Disease', 'MESH:D009472', (60, 81))	('Ceroid Lipofuscinosis', 'Disease', (60, 81))	('Neuronal', 'Disease', (83, 91))	('gene', 'Var', (51, 55))
941057	30250561	The outcome of the Voice Handicap Index (P=0.032), understandability of speech (P<0.001), normalcy of diet (P=0.041), senses (P=0.006), speech (P<0.001) and social contact (P=0.004) were significantly improved in the group receiving OPL compared with the group receiving TL.	('senses', 'MPA', (118, 124))	('social contact', 'CPA', (157, 171))	('improved', 'PosReg', (201, 209))	('OPL', 'Var', (233, 236))	('OPL', 'Chemical', '-', (233, 236))	('understandability of speech', 'MPA', (51, 78))	('TL', 'Chemical', '-', (271, 273))	('normalcy', 'MPA', (90, 98))	('speech', 'MPA', (136, 142))	('Voice Handicap', 'MPA', (19, 33))
941061	30250561	Strategies to preserve the larynx are not recommended for patients with T4a LC or T4a HPC, particularly those with cartilage invasion, and initial surgery is generally employed as the primary treatment method.	('cartilage invasion', 'Disease', (115, 133))	('HPC', 'Disease', 'MESH:C537262', (86, 89))	('HPC', 'Disease', (86, 89))	('patients', 'Species', '9606', (58, 66))	('T4a', 'Var', (82, 85))	('cartilage invasion', 'Disease', 'MESH:D002357', (115, 133))
941147	30250561	The survival outcomes do not indicate that patients treated with OPL have an improved prognosis compared with TL, or that patients treated with TL have a better prognosis compared with CRT, as patients with T4b stage disease and extensive cartilage invasion often receive either TL or CRT as primary treatment.	('T4b', 'Var', (207, 210))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (43, 51))	('TL', 'Chemical', '-', (144, 146))	('cartilage invasion', 'Disease', 'MESH:D002357', (239, 257))	('patients', 'Species', '9606', (122, 130))	('cartilage invasion', 'Disease', (239, 257))	('OPL', 'Chemical', '-', (65, 68))	('TL', 'Chemical', '-', (279, 281))	('TL', 'Chemical', '-', (110, 112))
941233	25822223	Heightened awareness is warranted for patients who received myeloablative TBI, those who had HCT at ages < 18 years, those with prior or concurrent GVHD of any form and those who had HCT for hereditary disorders, such as Fanconi anemia.	('Fanconi anemia', 'Phenotype', 'HP:0001994', (221, 235))	('GVHD', 'Disease', 'MESH:D006086', (148, 152))	('GVHD', 'Disease', (148, 152))	('Fanconi anemia', 'Disease', (221, 235))	('patients', 'Species', '9606', (38, 46))	('hereditary disorders', 'Disease', (191, 211))	('Fanconi anemia', 'Disease', 'MESH:D005199', (221, 235))	('TBI', 'Chemical', 'MESH:D013828', (74, 77))	('anemia', 'Phenotype', 'HP:0001903', (229, 235))	('hereditary disorders', 'Disease', 'MESH:D030342', (191, 211))	('myeloablative', 'Var', (60, 73))
941259	25822223	A pediatric study showed an increased incidence of pharyngeal cancer after autologous HCT, whereas an adult study did not report oropharyngeal cancer after autologous HCT.	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('oropharyngeal cancer', 'Disease', (129, 149))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('autologous HCT', 'Var', (75, 89))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (129, 149))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (51, 68))
941274	25822223	In particular, extensive-type cGVHD was a risk factor for esophageal cancer (RR = 5.3).	('esophageal cancer', 'Disease', (58, 75))	('cGVHD', 'Chemical', '-', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('extensive-type', 'Var', (15, 29))
941332	25822223	The incidence of breast cancer was increased among patients > 50 years of age who received BU-CY conditioning regimen, but the incidence was not increased among patients of similar age in another study.	('increased', 'PosReg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('breast cancer', 'Disease', (17, 30))	('men', 'Species', '9606', (114, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('BU-CY', 'Chemical', '-', (91, 96))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (51, 59))	('BU-CY', 'Var', (91, 96))
941344	25822223	As HPV of high-risk subtypes such as HPV16 and HPV18 causes > 90% of cases, routine HPV vaccination is recommended for females aged 9-26 years.	('causes', 'Reg', (53, 59))	('HPV18', 'Gene', (47, 52))	('HPV16', 'Species', '333760', (37, 42))	('HPV16', 'Var', (37, 42))	('men', 'Species', '9606', (108, 111))	('HPV', 'Species', '10566', (84, 87))	('HPV', 'Species', '10566', (37, 40))	('HPV', 'Species', '10566', (47, 50))	('HPV', 'Species', '10566', (3, 6))
941525	19572178	Although some of these plasma compositional changes are likely to have an impact on immune function, which may in turn indirectly influence tumor growth or recurrence, others are not immune system-related at all.	('recurrence', 'CPA', (156, 166))	('influence', 'Reg', (130, 139))	('changes', 'Var', (44, 51))	('impact', 'Reg', (74, 80))	('immune', 'CPA', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
941526	19572178	Instead, these "other" alterations may have an impact on angiogenesis, apoptosis, and tumor growth via other mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('impact', 'Reg', (47, 53))	('apoptosis', 'CPA', (71, 80))	('tumor', 'Disease', (86, 91))	('angiogenesis', 'CPA', (57, 69))	('rat', 'Species', '10116', (27, 30))	('alterations', 'Var', (23, 34))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
941556	19572178	According to some studies, CO2 pneumoperitoneum may inhibit or downregulate peritoneal macrophage function.	('inhibit', 'NegReg', (52, 59))	('CO2', 'Chemical', 'MESH:D002245', (27, 30))	('downregulate', 'NegReg', (63, 75))	('peritoneal macrophage function', 'CPA', (76, 106))	('CO2', 'Var', (27, 30))
941677	19572178	In addition, the laparoscopic patients had a higher pain score than those undergoing open surgery.	('laparoscopic', 'Var', (17, 29))	('pain', 'Phenotype', 'HP:0012531', (52, 56))	('pain', 'Disease', 'MESH:D010146', (52, 56))	('pain', 'Disease', (52, 56))	('patients', 'Species', '9606', (30, 38))	('higher', 'PosReg', (45, 51))
941693	19572178	A consequence of conversion is that morbidity and mortality are greater in the converted group than for patients who undergo open surgery initially.	('converted', 'Var', (79, 88))	('morbidity', 'CPA', (36, 45))	('patients', 'Species', '9606', (104, 112))
941850	19572178	Reflux of gastric juice occurs commonly after esophagectomy and gastric pull-up because the lower esophageal sphincter has been excised, and patients should be advised to eat several hours before lying down at night and to sleep with the head of the bed elevated.	('pull-up', 'Var', (72, 79))	('Reflux of gastric juice', 'MPA', (0, 23))	('Reflux of gastric', 'Phenotype', 'HP:0002020', (0, 17))	('esophageal sphincter', 'Disease', (98, 118))	('patients', 'Species', '9606', (141, 149))	('esophageal sphincter', 'Disease', 'MESH:D009122', (98, 118))
941944	19572178	The early and late complication rates were significantly decreased in the MIE group.	('MIE', 'Chemical', '-', (74, 77))	('MIE', 'Var', (74, 77))	('decreased', 'NegReg', (57, 66))	('rat', 'Species', '10116', (32, 35))
941998	19572178	Higher morbidity and mortality rates have been associated with the D2 lymphadenectomy than with the standard D1.	('mortality', 'CPA', (21, 30))	('D2 lymphadenectomy', 'Var', (67, 85))	('rat', 'Species', '10116', (31, 34))
942352	33937330	The high expression of PERK was associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC.	('HNSC', 'Phenotype', 'HP:0012288', (128, 132))	('BRCA', 'Gene', '672', (79, 83))	('BRCA', 'Gene', (79, 83))	('THCA', 'Phenotype', 'HP:0002890', (89, 93))	('KIRP', 'Disease', (68, 72))	('high', 'Var', (4, 8))	('THCA', 'Disease', (89, 93))	('PERK', 'Gene', (23, 27))	('LGG', 'Disease', (74, 77))	('PERK', 'Gene', '9451', (23, 27))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))
942355	33937330	Conclusion: The high expression of PERK could promote the infiltration of multiple immune cells in the tumor microenvironment and could deteriorate the outcomes of patients with breast and thyroid cancers, suggesting that PERK as well as tumor-infiltrating immune cells could be taken as potential biomarkers of prognosis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('infiltration', 'CPA', (58, 70))	('deteriorate', 'NegReg', (136, 147))	('thyroid cancer', 'Phenotype', 'HP:0002890', (189, 203))	('PERK', 'Gene', '9451', (222, 226))	('patients', 'Species', '9606', (164, 172))	('outcomes', 'CPA', (152, 160))	('high expression', 'Var', (16, 31))	('promote', 'PosReg', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('tumor', 'Disease', (103, 108))	('PERK', 'Gene', (35, 39))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('breast and thyroid cancers', 'Disease', 'MESH:D001943', (178, 204))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('PERK', 'Gene', '9451', (35, 39))	('PERK', 'Gene', (222, 226))
942384	33937330	Inhibitors augment T-cell activity by blocking programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) and show remarkable clinical effects (Topalian et al.,; Gordon et al.,).	('PD-L1', 'Gene', '29126', (103, 108))	('blocking', 'NegReg', (38, 46))	('augment', 'PosReg', (11, 18))	('programmed cell death protein 1', 'Gene', (47, 78))	('programmed cell death protein 1', 'Gene', '5133', (47, 78))	('Inhibitors', 'Var', (0, 10))	('PD-1', 'Gene', '5133', (90, 94))	('PD-L1', 'Gene', (103, 108))	('T-cell activity', 'CPA', (19, 34))	('PD-1', 'Gene', (90, 94))	('PD-1', 'Gene', (80, 84))	('PD-1', 'Gene', '5133', (80, 84))
942415	33937330	A previous study has shown that PERK inhibition by siRNA or GSK2656157 (a small molecule inhibitor against the PERK/elF2alpha/ATF4 pathway) might improve clinical prognosis and enhance the treatment of esophageal squamous cell carcinoma (ESCC) patients (Wang et al.,), but little research is reported in other types of cancers.	('ATF4', 'Gene', '468', (126, 130))	('cancers', 'Phenotype', 'HP:0002664', (319, 326))	('cancers', 'Disease', (319, 326))	('PERK', 'Gene', '9451', (111, 115))	('esophageal squamous cell carcinoma', 'Disease', (202, 236))	('patients', 'Species', '9606', (244, 252))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('GSK2656157', 'Var', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('inhibition', 'NegReg', (37, 47))	('clinical prognosis', 'CPA', (154, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (202, 236))	('PERK', 'Gene', (32, 36))	('cancers', 'Disease', 'MESH:D009369', (319, 326))	('treatment', 'CPA', (189, 198))	('GSK2656157', 'Chemical', 'MESH:C000597302', (60, 70))	('improve', 'PosReg', (146, 153))	('enhance', 'PosReg', (177, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('PERK', 'Gene', (111, 115))	('ATF4', 'Gene', (126, 130))	('PERK', 'Gene', '9451', (32, 36))
942417	33937330	According to the PrognoScan database, the high expression of PERK was associated with a poor prognosis in brain cancer (shorter OS, p = 0.003) and soft tissue cancer (shorter DRFS, p = 0.008) and related to a favorable prognosis in lung cancer (longer OS and RFS, p < 0.05, Figure 3).	('soft tissue cancer', 'Phenotype', 'HP:0031459', (147, 165))	('cancer', 'Disease', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('high expression', 'Var', (42, 57))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PERK', 'Gene', (61, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('brain cancer', 'Phenotype', 'HP:0030692', (106, 118))	('cancer', 'Disease', (237, 243))	('PERK', 'Gene', '9451', (61, 65))	('brain cancer', 'Disease', 'MESH:D001932', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('lung cancer', 'Disease', (232, 243))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('brain cancer', 'Disease', (106, 118))
942421	33937330	The high expression of PERK was associated with a favorable prognosis in bladder carcinoma (p = 0.006), esophageal squamous cell carcinoma (p = 0.0022), lung adenocarcinoma (p = 0.0054), rectum adenocarcinoma (p = 0.026), and thymoma (p = 0.039, Figure 4) and related to a poor prognosis in kidney renal papillary cell carcinoma (p = 0.014), liver hepatocellular carcinoma (p = 0.023), and thyroid carcinoma (p = 0.0036, Figure 4).	('bladder carcinoma', 'Phenotype', 'HP:0002862', (73, 90))	('thymoma', 'Disease', (226, 233))	('bladder carcinoma', 'Disease', 'MESH:D001749', (73, 90))	('high expression', 'Var', (4, 19))	('thymoma', 'Phenotype', 'HP:0100522', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('kidney renal papillary cell carcinoma', 'Disease', (291, 328))	('rectum adenocarcinoma', 'Disease', (187, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('PERK', 'Gene', '9451', (23, 27))	('lung adenocarcinoma', 'Disease', (153, 172))	('bladder carcinoma', 'Disease', (73, 90))	('esophageal squamous cell carcinoma', 'Disease', (104, 138))	('liver hepatocellular carcinoma', 'Disease', (342, 372))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (390, 407))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (153, 172))	('thyroid carcinoma', 'Disease', (390, 407))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (291, 328))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (153, 172))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (187, 208))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (390, 407))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (298, 328))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (348, 372))	('thymoma', 'Disease', 'MESH:D013945', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (104, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('PERK', 'Gene', (23, 27))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (342, 372))
942425	33937330	According to the UALCAN database, the high expression of PERK was associated with a poor prognosis in kidney renal papillary cell carcinoma (KIRP) (p = 0.01), brain lower grade glioma (LGG) (p = 0.00016), and THCA (p = 0.017, Figure 5).	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (109, 139))	('THCA', 'Phenotype', 'HP:0002890', (209, 213))	('high expression', 'Var', (38, 53))	('glioma', 'Disease', (177, 183))	('THCA', 'Disease', (209, 213))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('kidney renal papillary cell carcinoma', 'Disease', (102, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('PERK', 'Gene', (57, 61))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (102, 139))	('PERK', 'Gene', '9451', (57, 61))
942426	33937330	Consistent with the results of the Kaplan:Meier plotter database, PERK expression in BRCA had a poor prognosis (OS < 4,000 days, ~130 months, p = 0.025, Figure 5).	('BRCA', 'Gene', (85, 89))	('PERK', 'Gene', (66, 70))	('expression', 'Var', (71, 81))	('PERK', 'Gene', '9451', (66, 70))	('BRCA', 'Phenotype', 'HP:0003002', (85, 89))	('BRCA', 'Gene', '672', (85, 89))
942428	33937330	Together, the high expression of PERK is associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC.	('THCA', 'Phenotype', 'HP:0002890', (98, 102))	('THCA', 'Disease', (98, 102))	('PERK', 'Gene', '9451', (33, 37))	('PERK', 'Gene', (33, 37))	('HNSC', 'Phenotype', 'HP:0012288', (137, 141))	('LGG', 'Disease', (83, 86))	('KIRP', 'Disease', (77, 81))	('high', 'Var', (14, 18))	('BRCA', 'Phenotype', 'HP:0003002', (88, 92))	('BRCA', 'Gene', '672', (88, 92))	('BRCA', 'Gene', (88, 92))	('HNSC', 'Disease', (137, 141))
942461	33937330	Lung cancer was an exception where high levels of PERK expression showed a better prognosis.	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('PERK', 'Gene', (50, 54))	('high levels', 'Var', (35, 46))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('PERK', 'Gene', '9451', (50, 54))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
942463	33937330	The UALCAN database analysis demonstrated that the high expression of PERK was associated with a poor prognosis in KIRP, LGG, THCA, and BRCA (Figure 5).	('KIRP', 'Disease', (115, 119))	('PERK', 'Gene', (70, 74))	('LGG', 'Disease', (121, 124))	('THCA', 'Phenotype', 'HP:0002890', (126, 130))	('THCA', 'Disease', (126, 130))	('BRCA', 'Gene', '672', (136, 140))	('PERK', 'Gene', '9451', (70, 74))	('high expression', 'Var', (51, 66))	('BRCA', 'Phenotype', 'HP:0003002', (136, 140))	('BRCA', 'Gene', (136, 140))
942466	33937330	Inhibition of CREB3L1 by genetic or pharmacological methods suppresses cancer cell invasion and metastasis (Feng et al.,).	('CREB3L1', 'Gene', '90993', (14, 21))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('suppresses', 'NegReg', (60, 70))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CREB3L1', 'Gene', (14, 21))
942467	33937330	Another report showed that inhibition of the PERK-eIF2alpha-GRP94 signaling pathway silenced the epidermal growth factor receptor (EGFR) and then increased the radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells (Zhang et al.,).	('radiosensitivity', 'CPA', (160, 176))	('EGFR', 'Gene', (131, 135))	('inhibition', 'Var', (27, 37))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('squamous cell carcinoma', 'Disease', (233, 256))	('PERK', 'Gene', '9451', (45, 49))	('increased', 'PosReg', (146, 155))	('silenced', 'NegReg', (84, 92))	('OSCC', 'Phenotype', 'HP:0012182', (258, 262))	('GRP94', 'Gene', '7184', (60, 65))	('EGFR', 'Gene', '1956', (131, 135))	('eIF2alpha', 'Gene', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('GRP94', 'Gene', (60, 65))	('eIF2alpha', 'Gene', '83939', (50, 59))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (219, 256))	('epidermal growth factor receptor', 'Gene', (97, 129))	('PERK', 'Gene', (45, 49))	('epidermal growth factor receptor', 'Gene', '1956', (97, 129))
942486	33937330	Expansion of myeloid-derived suppressor cells (MDSCs) has emerged as a key mechanism of antitumor immune evasion and correlates with a poor clinical outcome and resistance to cancer immunotherapy (Lu et al.,).	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('Expansion', 'Var', (0, 9))
942488	33937330	PERK deletion transformed MDSCs into myeloid cells that activated CD8+ T-cell-mediated immunity against cancer (Mohamed et al.,).	('PERK', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('PERK', 'Gene', '9451', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CD8', 'Gene', (66, 69))	('CD8', 'Gene', '925', (66, 69))	('activated', 'PosReg', (56, 65))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
942489	33937330	Another study showed that inhibition of PERK in CD8+ T cells abrogates mitochondrial ROS generation in PD-1+ CD8+ tumor-infiltrating lymphocytes (TILs), which boosts CD8+ TIL viability and enhances antitumor immunity (Hurst et al.,).	('abrogates', 'NegReg', (61, 70))	('boosts', 'PosReg', (159, 165))	('CD8', 'Gene', '925', (48, 51))	('ROS', 'Chemical', '-', (85, 88))	('CD8', 'Gene', '925', (166, 169))	('CD8', 'Gene', '925', (109, 112))	('tumor', 'Disease', (202, 207))	('inhibition', 'Var', (26, 36))	('tumor', 'Disease', (114, 119))	('mitochondrial ROS generation', 'MPA', (71, 99))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('PD-1', 'Gene', (103, 107))	('CD8', 'Gene', (48, 51))	('PERK', 'Gene', (40, 44))	('PD-1', 'Gene', '5133', (103, 107))	('enhances', 'PosReg', (189, 197))	('CD8', 'Gene', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('CD8', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PERK', 'Gene', '9451', (40, 44))
942549	33535987	Significant differences in DFS and DSS were observed between patients with TRG 1a/1b and TRG2/3 (P< 0.05) but not between patients with TRG1a and TRG1b (P> 0.05) (Fig.	('TRG 1a/1b', 'Var', (75, 84))	('TRG2/3', 'Gene', (89, 95))	('TRG', 'Chemical', '-', (146, 149))	('TRG2/3', 'Gene', '7196;7197', (89, 95))	('patients', 'Species', '9606', (61, 69))	('TRG', 'Chemical', '-', (89, 92))	('DFS', 'MPA', (27, 30))	('patients', 'Species', '9606', (122, 130))	('TRG', 'Chemical', '-', (75, 78))	('DSS', 'Gene', (35, 38))	('differences', 'Reg', (12, 23))	('DSS', 'Gene', '5376', (35, 38))	('TRG', 'Chemical', '-', (136, 139))
942570	33535987	A step-by-step increase in tumour regression should be paralleled by a step-by-step increase in survival, however, some authors have argued whether the prognosis of cases showing 1-10% VRTC is inferior than those of patients with 0% VRTC.	('VRTC', 'Chemical', '-', (185, 189))	('VRTC', 'Chemical', '-', (233, 237))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('patients', 'Species', '9606', (216, 224))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('1-10%', 'Var', (179, 184))	('tumour', 'Disease', (27, 33))
942578	33535987	Given the same histological subtype in China, Japanese grading system was also evaluated in our study: G0-1a, more than 2/3 residual carcinoma, G1b, 1/3 to 2/3 residual carcinoma, G2, < 1/3 residual carcinoma and G3, 0% residual carcinoma.	('carcinoma', 'Disease', 'MESH:D009369', (229, 238))	('carcinoma', 'Disease', 'MESH:D009369', (133, 142))	('G0-1a', 'Var', (103, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinoma', 'Disease', (199, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('carcinoma', 'Disease', 'MESH:D009369', (199, 208))	('carcinoma', 'Disease', (169, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('residual', 'Disease', (124, 132))	('carcinoma', 'Disease', (229, 238))	('G1b', 'Var', (144, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinoma', 'Disease', 'MESH:D009369', (169, 178))	('carcinoma', 'Disease', (133, 142))
942579	33535987	Our date demonstrated that OS was best for patients with G3 and worst for patients with G0-1a, but there was no statistical difference in survival between patients with G1b and G2, who were in an intermediate prognostic category.	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (155, 163))	('G1b', 'Var', (169, 172))	('G0-1a', 'Var', (88, 93))
942670	29238207	It has been broadly accepted that inhibitory T-cell immune checkpoints contribute to tumor immune escape through negative immune regulatory signals (cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], programmed cell death 1 [PD-1], B7-H3, and B7-H4, etc).	('PD-1', 'Gene', (228, 232))	('tumor', 'Disease', (85, 90))	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', (149, 192))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('B7-H3', 'Var', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('PD-1', 'Gene', '5133', (228, 232))	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', '397286', (149, 192))
942685	29238207	T-cells have been the primary focus of cancer immunotherapy primarily due to their ability to initiate diverse immunoreactions via CD4+ helper T-cells that provoke innate and adaptive immunity.	('CD4+ helper', 'Var', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))
942707	29238207	The ligation of PD-L1/PD-L2 to PD-1 inhibits the PI3K/AKT pathway and downregulates expression of the antiapoptotic gene Bcl-xl to promote T-cell apoptosis.	('PD-1', 'Gene', '5133', (31, 35))	('T-cell apoptosis', 'CPA', (139, 155))	('PD-L2', 'Gene', (22, 27))	('Bcl-xl', 'Gene', '598', (121, 127))	('PD-L2', 'Gene', '80380', (22, 27))	('AKT', 'Gene', '207', (54, 57))	('inhibits', 'NegReg', (36, 44))	('downregulates', 'NegReg', (70, 83))	('AKT', 'Gene', (54, 57))	('PD-1', 'Gene', (31, 35))	('expression', 'MPA', (84, 94))	('Bcl-xl', 'Gene', (121, 127))	('ligation', 'Var', (4, 12))	('promote', 'PosReg', (131, 138))
942716	29238207	In vitro and in vivo studies have shown that deficiency of CTLA-4 in Tregs leads to systemic lymphoproliferation, fatal T-cell-mediated autoimmune disease, increased IgE production, and furthermore, potent tumor immunity.	('lymphoproliferation', 'Disease', 'MESH:C565232', (93, 112))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('CTLA-4', 'Gene', (59, 65))	('autoimmune disease', 'Disease', (136, 154))	('tumor', 'Disease', (206, 211))	('increased', 'PosReg', (156, 165))	('autoimmune disease', 'Disease', 'MESH:D001327', (136, 154))	('IgE production', 'MPA', (166, 180))	('autoimmune disease', 'Phenotype', 'HP:0002960', (136, 154))	('lymphoproliferation', 'Disease', (93, 112))	('deficiency', 'Var', (45, 55))	('potent', 'PosReg', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
942721	29238207	Malm et al showed that the PD-1 expression in healthy peripheral blood donors is generally under 15%, while the rate surged to over 50% of both the CD4+ and CD8+ T-cells among the PBLs, draining lymph nodes and TILs in the tumor microenvironment in HNSCC patients.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('CD8', 'Gene', (157, 160))	('PD-1', 'Gene', (27, 31))	('HNSCC', 'Disease', (249, 254))	('CD8', 'Gene', '925', (157, 160))	('PD-1', 'Gene', '5133', (27, 31))	('patients', 'Species', '9606', (255, 263))	('HNSCC', 'Phenotype', 'HP:0012288', (249, 254))	('CD4+', 'Var', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('expression', 'MPA', (32, 42))
942758	29238207	Several studies have explored the association between oncogenesis and CTLA-4 single nucleotide polymorphisms (SNPs), namely +49A/G (rs231775), -1661A/G (rs4553808), -318C/T (rs5742909), -1722T/C (rs733618), and CT60G/A (rs3087243) SNPs, etc.	('rs231775', 'Var', (132, 140))	('oncogenesis', 'CPA', (54, 65))	('rs3087243', 'Var', (220, 229))	('CTLA-4', 'Gene', (70, 76))	('+49A/G', 'Mutation', 'rs231775', (124, 130))	('rs733618', 'Var', (196, 204))	('-1661A/G', 'Mutation', 'rs4553808', (143, 151))	('rs5742909', 'Var', (174, 183))	('rs4553808', 'Var', (153, 162))	('rs231775', 'Mutation', 'rs231775', (132, 140))	('-1722T/C', 'Mutation', 'rs733618', (186, 194))	('CT60G', 'Mutation', 'c.60CT>G', (211, 216))	('-318C/T', 'Mutation', 'rs5742909', (165, 172))	('rs5742909', 'Mutation', 'rs5742909', (174, 183))	('rs3087243', 'Mutation', 'rs3087243', (220, 229))	('rs733618', 'Mutation', 'rs733618', (196, 204))	('rs4553808', 'Mutation', 'rs4553808', (153, 162))
942759	29238207	Kammerer et al found that the genotype CTLA-4 (-1661A/G) was detected more frequently in patients with OSCC than in healthy controls, and that several combinations of SNPs were found only in patient tissues.	('OSCC', 'Disease', (103, 107))	('patient', 'Species', '9606', (89, 96))	('-1661A/G', 'Mutation', 'rs4553808', (47, 55))	('CTLA-4', 'Gene', (39, 45))	('patients', 'Species', '9606', (89, 97))	('patient', 'Species', '9606', (191, 198))	('-1661A/G', 'Var', (47, 55))
942776	29238207	Ipilimumab is currently being assessed in clinical trials in combination with cetuximab and intensity-modulated radiotherapy in patients with advanced HNSCC (NCT01860430 and NCT01935921).	('HNSCC', 'Phenotype', 'HP:0012288', (151, 156))	('advanced HNSCC', 'Disease', (142, 156))	('cetuximab', 'Chemical', 'MESH:D000068818', (78, 87))	('NCT01860430', 'Var', (158, 169))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (0, 10))	('NCT01935921', 'Var', (174, 185))	('patients', 'Species', '9606', (128, 136))
942789	29238207	Some Phase II/III trials are underway to evaluate the clinical efficacy (ORR, response duration, and side effects) of pembrolizumab in R/M HNSCC (NCT02255097, NCT02252042).	('NCT02255097', 'Var', (146, 157))	('pembrolizumab', 'Chemical', 'MESH:C582435', (118, 131))	('HNSCC', 'Phenotype', 'HP:0012288', (139, 144))	('NCT02252042', 'Var', (159, 170))
942791	29238207	In patients with HNSCC refractory to platinum therapy, a randomized Phase III trial of nivolumab (NCT02105636) resulted in improved OS compared with treatment with the weekly methotrexate, docetaxel, or cetuximab (NCT02105636).	('HNSCC', 'Phenotype', 'HP:0012288', (17, 22))	('docetaxel', 'Chemical', 'MESH:D000077143', (189, 198))	('platinum', 'Chemical', 'MESH:D010984', (37, 45))	('NCT02105636', 'Var', (98, 109))	('nivolumab', 'Chemical', 'MESH:D000077594', (87, 96))	('patients', 'Species', '9606', (3, 11))	('improved', 'PosReg', (123, 131))	('cetuximab', 'Chemical', 'MESH:D000068818', (203, 212))	('methotrexate', 'Chemical', 'MESH:D008727', (175, 187))
942793	29238207	At present, representative antibodies targeting PD-L1 include BMS-936559 (also known as MDX1105), MPDL3280A, and durvalumab (MEDI-4736), which have been applied as monotherapy or adjuncts to conventional therapies in clinical trials for a variety of tumors.	('MPDL3280A', 'Var', (98, 107))	('tumors', 'Disease', (250, 256))	('durvalumab', 'Chemical', 'MESH:C000613593', (113, 123))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('BMS-936559', 'Var', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('PD-L1', 'Gene', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (250, 256))
942794	29238207	Two ongoing Phase I trials, with anti-PD-L1 mAb (IgG1 isotype) MEDI-4736 (NCT01693562) and anti-PD-1 mAb (IgG4 isotype) MK-3475 (NCT01848834), have recruited cohorts of R/M HNSCC patients.	('PD-1', 'Gene', (96, 100))	('PD-1', 'Gene', '5133', (96, 100))	('R/M HNSCC', 'Disease', (169, 178))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('patients', 'Species', '9606', (179, 187))	('NCT01693562', 'Var', (74, 85))	('NCT01693562', 'CellLine', 'None', (74, 85))	('MK-3475', 'Chemical', 'MESH:C582435', (120, 127))
942795	29238207	The disease control rate at 6 months was 15% (18% for PD-L1-positive vs 11% for PD-L1-negative), and the ORR in patients with HNSCC was 11%.	('patients', 'Species', '9606', (112, 120))	('HNSCC', 'Phenotype', 'HP:0012288', (126, 131))	('disease control', 'CPA', (4, 19))	('PD-L1-positive', 'Var', (54, 68))
942798	29238207	In another randomized Phase I/II trial to assess the combination of MEDI-4738 with either AZD9150 or AZD5069 in patients with metastatic squamous cell carcinoma of head and neck (NCT02499328), the clinical safety/efficacy and ORR are being evaluated.	('squamous cell carcinoma', 'Disease', (137, 160))	('combination', 'Interaction', (53, 64))	('AZD5069', 'Chemical', 'MESH:C000597960', (101, 108))	('patients', 'Species', '9606', (112, 120))	('AZD5069', 'Var', (101, 108))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (151, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('AZD9150', 'Chemical', 'MESH:C000610954', (90, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (137, 160))	('MEDI-4738', 'Gene', (68, 77))	('AZD9150', 'Var', (90, 97))
942799	29238207	Some trials evaluating the utility of MEDI-4736 monotherapy alone or in conjunction with tremelimumab (anti-CTLA-4) compared to the standard treatment for first-line R/M HNSCC are ongoing (NCT02551159, NCT02369874, NCT02319044).	('NCT02319044', 'Var', (215, 226))	('NCT02369874', 'Var', (202, 213))	('NCT02551159', 'Var', (189, 200))	('tremelimumab', 'Chemical', 'MESH:C520704', (89, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (170, 175))
942802	29238207	Blockades of immune checkpoints have proved to play a vital role in enhancing immune surveillance and tumor cell clearance, which provides oncologists with a significant set of antitumor therapies with promising potentials.	('tumor', 'Disease', (181, 186))	('Blockades', 'Var', (0, 9))	('enhancing', 'PosReg', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('immune surveillance', 'CPA', (78, 97))
942816	28243112	It was reported that mutant EGFR signaling pathway activation induced PD-L1 expression on bronchial epithelial cells, and EGFR inhibitors could decrease the upregulated PD-L1 expression in non-small-cell lung cancer (NSCLC) cell lines.	('PD-L1', 'Gene', (169, 174))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (189, 215))	('upregulated', 'PosReg', (157, 168))	('PD-L1', 'Gene', '29126', (169, 174))	('lung cancer', 'Disease', (204, 215))	('expression', 'MPA', (175, 185))	('PD-L1', 'Gene', (70, 75))	('PD-L1', 'Gene', '29126', (70, 75))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('NSCLC', 'Disease', 'MESH:D002289', (217, 222))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('NSCLC', 'Disease', (217, 222))	('activation induced', 'PosReg', (51, 69))	('mutant', 'Var', (21, 27))	('decrease', 'NegReg', (144, 152))	('expression', 'MPA', (76, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (217, 222))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (193, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
942830	28243112	The membrane was then hybridized with the indicated primary antibodies specific to human EGFR, phospho-EGFR (Tyr1068), STAT3, and phospho-STAT3 (Tyr705), then with the corresponding secondary antibodies conjugated with horseradish peroxidase, and detected using a chemiluminescence assay (EMD Millipore, Temecula, CA, USA).	('STAT3', 'Gene', (138, 143))	('Tyr705', 'Var', (145, 151))	('Tyr1068', 'Chemical', '-', (109, 116))	('Tyr705', 'Chemical', '-', (145, 151))	('human', 'Species', '9606', (83, 88))	('STAT3', 'Gene', '6774', (119, 124))	('horseradish', 'Species', '3704', (219, 230))	('STAT3', 'Gene', '6774', (138, 143))	('STAT3', 'Gene', (119, 124))	('Tyr1068', 'Var', (109, 116))
942846	28243112	Unexpectedly, the same changes of phosphorylation of STAT3 were found as phosphorylation of EGFR occurred only in kyse30 cells, not in TE1 and CaEs-17 cells.	('phosphorylation', 'MPA', (34, 49))	('STAT3', 'Gene', '6774', (53, 58))	('STAT3', 'Gene', (53, 58))	('phosphorylation', 'MPA', (73, 88))	('EGFR', 'Gene', (92, 96))	('kyse30', 'Var', (114, 120))
942847	28243112	To further assess the molecular pathways involved in PD-L1 expression in ESCC cells following EGFR activation, the EGFR downstream signaling pathways were examined in wild-type EGFR expression kyse30 and TE1 cells, and EGFR mutant TE7 cells using PathScan  EGFR signaling antibody array kit.	('PD-L1', 'Gene', (53, 58))	('mutant', 'Var', (224, 230))	('PD-L1', 'Gene', '29126', (53, 58))
942857	28243112	In NSCLC, it was reported that PD-L1-positive status was significantly associated with the presence of EGFR mutation, could be induced by activation of EGFR mutant that contributed to immune escape, and had better outcome by EGFR-tyrosine kinase inhibitors.	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('PD-L1', 'Gene', '29126', (31, 36))	('EGFR', 'Gene', (103, 107))	('EGFR', 'Gene', (152, 156))	('mutation', 'Var', (108, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('PD-L1', 'Gene', (31, 36))
942859	28243112	As EGFR gene mutation leading to the constitutive activation of EGFR signaling pathways is most common in lung cancer, there may be some difference in PD-L1 expression in ESCC because EGFR overexpression is the main reason for the dysregulation of EGFR signaling pathways in ESCC.	('EGFR signaling pathways', 'Pathway', (64, 87))	('common', 'Reg', (96, 102))	('EGFR', 'Gene', (3, 7))	('PD-L1', 'Gene', '29126', (151, 156))	('lung cancer', 'Disease', (106, 117))	('mutation', 'Var', (13, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('activation', 'PosReg', (50, 60))	('overexpression', 'PosReg', (189, 203))	('PD-L1', 'Gene', (151, 156))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))
942873	28243112	Similar results have been reported that STAT3 expression was not correlated with PD-L1 expression in high EGFR expression tumor specimens of head and neck cancer, and STAT3 inhibitor could not reduce PD-L1 expression in EGFR mutant lung cancer cells although it attenuated STAT3 phosphorylation.	('PD-L1', 'Gene', (200, 205))	('PD-L1', 'Gene', (81, 86))	('STAT3', 'Gene', '6774', (167, 172))	('PD-L1', 'Gene', '29126', (200, 205))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('mutant', 'Var', (225, 231))	('STAT3', 'Gene', (40, 45))	('PD-L1', 'Gene', '29126', (81, 86))	('head and neck cancer', 'Phenotype', 'HP:0012288', (141, 161))	('tumor', 'Disease', (122, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('attenuated', 'NegReg', (262, 272))	('STAT3', 'Gene', '6774', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('STAT3', 'Gene', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('lung cancer', 'Disease', (232, 243))	('reduce PD', 'Phenotype', 'HP:0032198', (193, 202))	('EGFR', 'Gene', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('STAT3', 'Gene', '6774', (273, 278))	('neck cancer', 'Disease', 'MESH:D006258', (150, 161))	('STAT3', 'Gene', (167, 172))	('neck cancer', 'Disease', (150, 161))
942874	28243112	Mutant EGFR upregulated PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC.	('NSCLC', 'Disease', (87, 92))	('AKT', 'Gene', (49, 52))	('MEK', 'Gene', (57, 60))	('MEK', 'Gene', '5609', (57, 60))	('EGFR', 'Gene', (7, 11))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('ERK', 'Gene', '5594', (61, 64))	('AKT', 'Gene', '207', (49, 52))	('PD-L1', 'Gene', (24, 29))	('activating', 'PosReg', (33, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('Mutant', 'Var', (0, 6))	('ERK', 'Gene', (61, 64))	('upregulated', 'PosReg', (12, 23))	('PD-L1', 'Gene', '29126', (24, 29))
942876	28243112	Contrastingly, another study reported that EGFR activation by EGF stimulation, exon-19 deletions, and L858R mutation could induce PD-L1 expression through p-ERK1/2-p-c-Jun but not through p-AKT-p-S6 pathway in EGFR-driven NSCLC.	('induce', 'PosReg', (123, 129))	('EGF', 'Gene', (62, 65))	('NSCLC', 'Disease', (222, 227))	('AKT', 'Gene', (190, 193))	('c-Jun', 'Gene', '3725', (166, 171))	('EGF', 'Gene', '1950', (210, 213))	('c-Jun', 'Gene', (166, 171))	('expression', 'MPA', (136, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (222, 227))	('EGF', 'Gene', '1950', (43, 46))	('AKT', 'Gene', '207', (190, 193))	('EGF', 'Gene', (210, 213))	('EGF', 'Gene', '1950', (62, 65))	('ERK1/2', 'Gene', (157, 163))	('ERK1/2', 'Gene', '5595;5594', (157, 163))	('L858R mutation', 'Var', (102, 116))	('exon-19', 'Var', (79, 86))	('EGF', 'Gene', (43, 46))	('L858R', 'Mutation', 'rs121434568', (102, 107))	('PD-L1', 'Gene', (130, 135))	('PD-L1', 'Gene', '29126', (130, 135))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))
942951	27822378	Among preoperative SF-36 components, role emotional and PCS scores of patients undergoing chemoradiotherapy were significantly lower than those without (P = 0.019).	('patients', 'Species', '9606', (70, 78))	('role', 'CPA', (37, 41))	('lower', 'NegReg', (127, 132))	('PCS scores', 'MPA', (56, 66))	('SF-36', 'Gene', (19, 24))	('chemoradiotherapy', 'Var', (90, 107))
943055	21420070	The alterations of specific miRNAs may further elucidate steps in the metastatic pathway and allow for development of targeted therapy.	('rat', 'Species', '10116', (8, 11))	('alterations', 'Var', (4, 15))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('elucidate', 'Reg', (47, 56))	('metastatic pathway', 'Pathway', (70, 88))
943069	21420070	Furthermore, aberrant expression of miRNAs has been linked to development and progression of cancer and has been shown to have prognostic significance in several tumor types, including lung, neuroblastoma, colon, pancreatic and lymphocytic leukemia.	('lung', 'Disease', (185, 189))	('tumor', 'Disease', (162, 167))	('miR', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('pancreatic and lymphocytic leukemia', 'Disease', 'MESH:D010190', (213, 248))	('neuroblastoma', 'Disease', (191, 204))	('neuroblastoma', 'Phenotype', 'HP:0003006', (191, 204))	('aberrant', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('neuroblastoma', 'Disease', 'MESH:D009447', (191, 204))	('significance', 'Reg', (138, 150))	('expression', 'MPA', (22, 32))	('cancer', 'Disease', (93, 99))	('linked', 'Reg', (52, 58))	('leukemia', 'Phenotype', 'HP:0001909', (240, 248))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colon', 'Disease', (206, 211))	('miR', 'Gene', '220972', (36, 39))
943070	21420070	These reports suggest that miRNAs play an influential role in tumorigenic processes, and the identification of miRNAs aberrantly expressed in esophageal adenocarcinomas may lead to a better understanding of disease development and progression.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))	('esophageal adenocarcinomas', 'Disease', (142, 168))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (142, 167))	('tumor', 'Disease', (62, 67))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (142, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))	('lead to', 'Reg', (173, 180))	('aberrantly expressed', 'Var', (118, 138))
943134	21420070	Kaplan-Meier survival analysis demonstrated a significant worse survival for patients with high expression of miR-143 (log Rank = 0.037), and miR-145 (Log Rank p=0.023).	('miR-145', 'Gene', (142, 149))	('worse', 'NegReg', (58, 63))	('high', 'Var', (91, 95))	('miR-145', 'Gene', '406937', (142, 149))	('patients', 'Species', '9606', (77, 85))	('miR-143', 'Gene', '406935', (110, 117))	('rat', 'Species', '10116', (38, 41))	('miR-143', 'Gene', (110, 117))
943137	21420070	However, it is apparent that miRNA expression plays a crucial role in regulating gene expression, and their aberrant expression can contribute to the development and progression of cancer.	('contribute', 'Reg', (132, 142))	('miR', 'Gene', '220972', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('miR', 'Gene', (29, 32))	('development', 'CPA', (150, 161))	('aberrant expression', 'Var', (108, 127))	('regulating gene expression', 'MPA', (70, 96))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))
943161	21420070	Finally, the alteration of specific miRNAs may further elucidate steps in the metastatic pathway and allow for development of targeted therapy.	('alteration', 'Var', (13, 23))	('elucidate', 'Reg', (55, 64))	('metastatic pathway', 'Pathway', (78, 96))	('rat', 'Species', '10116', (17, 20))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (36, 39))
943168	18715498	The radicality of resection was inversely related to T stage: an R0 resection was achieved in 98-100% of T0/1 tumors and only 14% of T4 tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('T0/1', 'Var', (105, 109))
943247	18715498	R0 resection rates varied from 97-100% with T0/1 tumours to 0-17% for T3-4 tumours.	('tumours', 'Disease', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Disease', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('T0/1', 'Var', (44, 48))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
943248	18715498	In keeping with previous studies, R0 resections were significantly associated with improved overall survival and hence the group benefiting most from this operative approach would appear to be those patients with early (T1-2) tumours.	('improved', 'PosReg', (83, 91))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('R0 resections', 'Var', (34, 47))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('overall survival', 'MPA', (92, 108))	('tumours', 'Disease', 'MESH:D009369', (226, 233))	('tumours', 'Disease', (226, 233))	('patients', 'Species', '9606', (199, 207))
943254	18715498	Furthermore, quality of life data suggests patients undergoing a transhiatal approach have fewer physical symptoms and better activity levels in the short term compared to the transthoracic approach although these differences become less evident by 1 year.	('transhiatal', 'Var', (65, 76))	('activity levels', 'MPA', (126, 141))	('better', 'PosReg', (119, 125))	('patients', 'Species', '9606', (43, 51))	('physical symptoms', 'MPA', (97, 114))	('fewer', 'NegReg', (91, 96))
943267	26958940	By exogenously introducing each of two major isoforms, TIA1a and TIA1b, only TIA1a, which was localized to both the nucleus and cytoplasm, promoted anchorage-dependent and anchorage-independent ESCC cell proliferation.	('promoted', 'PosReg', (139, 147))	('SCC', 'Gene', (195, 198))	('TIA1a', 'Var', (77, 82))	('SCC', 'Gene', '6317', (195, 198))
943272	26958940	Given the central role of RBPs in the regulation of gene expression, malfunction of RBP or mutations in the RNA elements they recognize can lead to cancer development and progression.	('cancer', 'Disease', (148, 154))	('malfunction', 'Var', (69, 80))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('RBP', 'Gene', '57794', (84, 87))	('lead to', 'Reg', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('progression', 'CPA', (171, 182))	('mutations', 'Var', (91, 100))	('RBP', 'Gene', (84, 87))	('RBP', 'Gene', (26, 29))	('RBP', 'Gene', '57794', (26, 29))
943294	26958940	Most ESCC cells constitutively express TIA1-v2 mRNA and a small amount of TIA1-v1 mRNA (Supplementary Figure S3A), resulting in the predominant expression of TIA1a protein compared with TIA1b protein (Supplementary Figure S2B).	('expression', 'MPA', (144, 154))	('TIA1a', 'Var', (158, 163))	('SCC', 'Gene', (6, 9))	('SCC', 'Gene', '6317', (6, 9))
943298	26958940	By silencing endogenous TIA1 using three different siRNAs, cell proliferation was significantly suppressed in KYSE140, KYSE180 and TE4 cells.	('silencing', 'Var', (3, 12))	('KYSE180', 'CellLine', 'CVCL:1349', (119, 126))	('KYSE140', 'Var', (110, 117))	('cell proliferation', 'CPA', (59, 77))	('KYSE180', 'Var', (119, 126))	('TIA1', 'Gene', (24, 28))	('endogenous', 'Protein', (13, 23))	('suppressed', 'NegReg', (96, 106))
943300	26958940	These results suggest that TIA1 silencing in ESCC cells contributes to cell cycle arrest at the G1-S checkpoint and the induction of apoptosis.	('arrest', 'Disease', (82, 88))	('apoptosis', 'CPA', (133, 142))	('silencing', 'Var', (32, 41))	('TIA1', 'Gene', (27, 31))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (71, 88))	('SCC', 'Gene', (46, 49))	('arrest', 'Disease', 'MESH:D006323', (82, 88))	('SCC', 'Gene', '6317', (46, 49))
943303	26958940	These results indicate the distinct functions of TIA1a and TIA1b in ESCC cells: TIA1a promotes anchorage-dependent and anchorage-independent cell proliferation, while TIA1b does not.	('SCC', 'Gene', (69, 72))	('SCC', 'Gene', '6317', (69, 72))	('promotes', 'PosReg', (86, 94))	('TIA1a', 'Var', (80, 85))
943304	26958940	In comparison with depletion of TIA1b, anchorage-dependent cell proliferation was more effectively suppressed by depletion of TIA1a with an increased p21WAF1/Cip1 protein level and extensive cleavage of PARP (Supplementary Figure S5A, S5B).	('anchorage-dependent cell proliferation', 'CPA', (39, 77))	('S5B', 'Gene', (235, 238))	('suppressed', 'NegReg', (99, 109))	('TIA1a', 'Gene', (126, 131))	('Cip1', 'Gene', '1026', (158, 162))	('depletion', 'Var', (113, 122))	('PARP', 'Gene', (203, 207))	('PARP', 'Gene', '142', (203, 207))	('increased p21WAF1/Cip1 protein level', 'Phenotype', 'HP:0003240', (140, 176))	('Cip1', 'Gene', (158, 162))	('increased', 'PosReg', (140, 149))	('S5B', 'Gene', '5711', (235, 238))	('cleavage', 'MPA', (191, 199))
943313	26958940	In those nine genes, the effects of TIA1 knockdown on the levels of the proteins encoded by the SKP2, CCNA2, CHK1 and CHK2 mRNAs were assessed.	('CHK1', 'Gene', '1111', (109, 113))	('CHK2', 'Gene', '11200', (118, 122))	('TIA1', 'Gene', (36, 40))	('CHK1', 'Gene', (109, 113))	('knockdown', 'Var', (41, 50))	('CCNA2', 'Gene', (102, 107))	('SKP2', 'Gene', (96, 100))	('CHK2', 'Gene', (118, 122))
943318	26958940	In an mRNA decay assay using KYSE180 cells, TIA1 knockdown decreased the stability of SKP2 mRNA but did not alter that of CCNA2 mRNA (Figure 6B).	('knockdown', 'Var', (49, 58))	('KYSE180', 'CellLine', 'CVCL:1349', (29, 36))	('TIA1', 'Gene', (44, 48))	('stability', 'MPA', (73, 82))	('decreased', 'NegReg', (59, 68))
943320	26958940	In an mRNA decay assay using KYSE140 and KYSE180 cells transfected with reporter constructs containing the coding sequence (CDS) of the firefly luciferase gene (Luc2) with the 3' UTR of SKP2 or Luc2 alone, TIA1 knockdown decreased the Luc2 mRNA expression level (Figure 6C and Supplementary Figure S8B).	('Luc2 mRNA expression level', 'MPA', (235, 261))	('decreased', 'NegReg', (221, 230))	('knockdown', 'Var', (211, 220))	('TIA1', 'Gene', (206, 210))	('KYSE180', 'CellLine', 'CVCL:1349', (41, 48))	('mRNA decay', 'MPA', (6, 16))
943322	26958940	In the polysome profiling assay using KYSE180 cells, TIA1 depletion caused a shift in CCNA2 mRNA from heavy to light polysomal fractions (Figure 6D and Supplementary Figure S9B).	('CCNA2', 'Gene', (86, 91))	('shift', 'Reg', (77, 82))	('TIA1', 'Gene', (53, 57))	('mRNA', 'MPA', (92, 96))	('KYSE180', 'CellLine', 'CVCL:1349', (38, 45))	('depletion', 'Var', (58, 67))
943324	26958940	In 52 tumors for which serial sections were available, IHC revealed that the expression levels of SKP2 and CCNA2 proteins in tumor cells correlated positively with the cytoplasmic TIA1 expression level (Figure 6E) and tended to be associated with worse overall survival (Supplementary Figure S10A and S10B), although CCNA2 immunoreactivity did not reach a statistically significant level.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('S10B', 'SUBSTITUTION', 'None', (301, 305))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('S10B', 'Var', (301, 305))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('overall survival', 'MPA', (253, 269))	('SKP2', 'Gene', (98, 102))	('proteins', 'Protein', (113, 121))	('associated with', 'Reg', (231, 246))	('S10A', 'SUBSTITUTION', 'None', (292, 296))	('expression levels', 'MPA', (77, 94))	('CCNA2', 'Gene', (107, 112))	('S10A', 'Var', (292, 296))	('tumors', 'Disease', (6, 12))	('tumor', 'Disease', (6, 11))	('worse', 'NegReg', (247, 252))	('tumor', 'Disease', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('cytoplasmic TIA1 expression level', 'MPA', (168, 201))
943334	26958940	Indeed, cytoplasmic HuR expression has been shown to be associated with malignant clinicopathological features and poor prognosis in ESCC, indicating that ectopically localized HuR is involved in cancer-promoting RNA metabolism and contributes to the progression of ESCC.	('SCC', 'Gene', '6317', (267, 270))	('HuR', 'Gene', '1994', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('HuR', 'Gene', (20, 23))	('SCC', 'Gene', '6317', (134, 137))	('ectopically', 'Var', (155, 166))	('associated', 'Reg', (56, 66))	('HuR', 'Gene', (177, 180))	('HuR', 'Gene', '1994', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('SCC', 'Gene', (267, 270))	('contributes', 'Reg', (232, 243))	('SCC', 'Gene', (134, 137))
943337	26958940	In this study, we found that TIA1a and TIA1b exert distinct effects on ESCC cell proliferation: TIA1a promotes anchorage-dependent and anchorage-independent cell proliferation, whereas TIA1b tends to inhibit cell proliferation and/or induces cell death.	('promotes', 'PosReg', (102, 110))	('cell proliferation', 'CPA', (208, 226))	('inhibit', 'NegReg', (200, 207))	('induces', 'Reg', (234, 241))	('SCC', 'Gene', (72, 75))	('TIA1b', 'Var', (185, 190))	('TIA1a', 'Var', (96, 101))	('SCC', 'Gene', '6317', (72, 75))	('cell death', 'CPA', (242, 252))
943339	26958940	Because a larger fraction of TIA1a localizes to the cytoplasm, compared with TIA1b, and because exogenously introduced each isoform shows different mRNA binding affinities, TIA1a may function as an oncogene in ESCC through localizing to the cytoplasm and contributing to specific aspects of RNA metabolism.	('SCC', 'Gene', '6317', (211, 214))	('localizing', 'MPA', (223, 233))	('TIA1a', 'Var', (173, 178))	('RNA metabolism', 'MPA', (291, 305))	('contributing', 'Reg', (255, 267))	('localizes', 'MPA', (35, 44))	('mRNA binding', 'Interaction', (148, 160))	('SCC', 'Gene', (211, 214))
943369	26958940	The full coding sequences of human TIA1 variant 1 (NM_022037), TIA1 variant 2 (NM_022173), SKP2 (NM_005983), and CCNA2 (NM_001237) were amplified by PCR (Supplementary Table S7) using cDNA prepared from KYSE140 cells.	('NM_022173', 'Var', (79, 88))	('NM_001237', 'Var', (120, 129))	('NM_022037', 'Var', (51, 60))	('variant', 'Var', (40, 47))	('TIA1', 'Gene', (63, 67))	('human', 'Species', '9606', (29, 34))	('NM_005983', 'Var', (97, 106))	('TIA1', 'Gene', (35, 39))
943371	26958940	To establish ESCC cell lines stably overexpressing each TIA1 isoform, cells were infected with each TIA1 variant-expressing retroviruses and selected by treatment with 0.5 mg/mL G418 for four weeks.	('SCC', 'Gene', (14, 17))	('G418', 'Chemical', 'MESH:C010680', (178, 182))	('TIA1', 'Gene', (100, 104))	('SCC', 'Gene', '6317', (14, 17))	('variant-expressing', 'Var', (105, 123))
943413	24949380	first described that GISTs are believed to originate from interstitial cells of Cajal or related stem cells and the mutation in KIT seems to play a gatekeeper role in the transformation of interstitial cells of Cajal into a GIST.	('KIT', 'Gene', (128, 131))	('mutation', 'Var', (116, 124))	('gatekeeper', 'Species', '111938', (148, 158))	('GISTs', 'Phenotype', 'HP:0100723', (21, 26))
943429	24949380	Aberrant pancreas are also called ectopic or heterotopic pancreas.	('heterotopic pancreas', 'Disease', (45, 65))	('heterotopic pancreas', 'Disease', 'MESH:D063192', (45, 65))	('heterotopic pancreas', 'Phenotype', 'HP:0006278', (45, 65))	('Aberrant', 'Var', (0, 8))
943545	24094137	The reasons for these cases might be: cutting off the lower esophageal before anastomosis;operating in situ avoided mucosal injury by excessive traction on the esophagus; and reduced risks of anastomotic leakage.	('anastomotic leak', 'Disease', 'MESH:D057868', (192, 208))	('cutting', 'Var', (38, 45))	('mucosal injury', 'Disease', 'MESH:D052016', (116, 130))	('anastomotic leak', 'Disease', (192, 208))	('mucosal injury', 'Disease', (116, 130))
943547	24094137	As far as possible, we used a 25-mm EEA stapler in most cases because the use of the 21-mm DST-EEA causes anastomotic stenosis at a higher rate.	('causes', 'Reg', (99, 105))	('DST-EEA', 'Var', (91, 98))	('anastomotic stenosis', 'Disease', (106, 126))	('anastomotic stenosis', 'Disease', 'MESH:D057868', (106, 126))	('EEA', 'Chemical', '-', (36, 39))	('EEA', 'Chemical', '-', (95, 98))
943669	21188213	Furthermore, overexpression and amplification of HER2 have also been shown to correlate with poor prognosis and with resistance to conventional adjuvant chemotherapy and tamoxifen in breast cancer.	('poor prognosis', 'CPA', (93, 107))	('resistance', 'CPA', (117, 127))	('amplification', 'Var', (32, 45))	('overexpression', 'PosReg', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('HER2', 'Gene', (49, 53))	('tamoxifen', 'Chemical', 'MESH:D013629', (170, 179))	('breast cancer', 'Disease', (183, 196))	('HER2', 'Gene', '2064', (49, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
943698	21188213	Nine studies (totalling 1,232 samples) examining the frequency of HER2 amplification in gastroesophageal cancer showed a mean HER2 positivity rate of 19.2% (range 7-43%), which is similar to the reported percentage of protein overexpression.	('HER2', 'Gene', '2064', (66, 70))	('amplification', 'Var', (71, 84))	('gastroesophageal cancer', 'Disease', (88, 111))	('HER2', 'Gene', (126, 130))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (88, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('HER2', 'Gene', '2064', (126, 130))	('HER2', 'Gene', (66, 70))
943699	21188213	In breast cancer, it is generally thought that HER2 overexpression is the direct result of gene amplification.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('HER2', 'Gene', (47, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('HER2', 'Gene', '2064', (47, 51))	('overexpression', 'PosReg', (52, 66))	('gene amplification', 'Var', (91, 109))
943701	21188213	Nevertheless, primary results from a very recent phase III trial (ToGA) containing >3,800 advanced esophageal and gastric cancer samples showed that the frequency of samples with amplification but without corresponding overexpression was high (23%) compared to that in breast cancer suggesting that FISH testing may be the more relevant procedure to conduct on these tumor specimens.	('tumor', 'Disease', (367, 372))	('gastric cancer', 'Disease', (114, 128))	('esophageal', 'Disease', (99, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('breast cancer', 'Disease', 'MESH:D001943', (269, 282))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('esophageal', 'Disease', 'MESH:D004941', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('breast cancer', 'Disease', (269, 282))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (269, 282))	('amplification', 'Var', (179, 192))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))
943703	21188213	The pattern seen in breast cancer, where amplification of HER2 leads to an overexpression of the protein, does not seem to have been fully confirmed in gastric cancer yet.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('gastric cancer', 'Disease', 'MESH:D013274', (152, 166))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('gastric cancer', 'Disease', (152, 166))	('breast cancer', 'Disease', (20, 33))	('leads to', 'Reg', (63, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('overexpression of the protein', 'MPA', (75, 104))	('amplification', 'Var', (41, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (58, 62))
943710	21188213	A recent review combining data from 24 studies (6,542 patients) calculated a weighted mean of 19% HER2 positivity.	('positivity', 'Var', (103, 113))	('patients', 'Species', '9606', (54, 62))	('HER2', 'Gene', '2064', (98, 102))	('HER2', 'Gene', (98, 102))
943716	21188213	Studies that specifically analyzed HER2 expression and/or amplification in Barrett's esophagus reported positivity rates of 38-50% and showed an association with progression from Barrett's esophagus to dysplasia and adenocarcinoma.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (75, 94))	('HER2', 'Gene', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	("Barrett's esophagus to dysplasia and adenocarcinoma", 'Disease', 'MESH:D001471', (179, 230))	('HER2', 'Gene', '2064', (35, 39))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (179, 198))	('association', 'Interaction', (145, 156))	('amplification', 'Var', (58, 71))
943726	21188213	Generally, higher rates of HER2 heterogeneity have been reported in gastric cancer (5%) compared to breast cancer (1.5%).	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('gastric cancer', 'Disease', (68, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('HER2', 'Gene', (27, 31))	('HER2', 'Gene', '2064', (27, 31))	('heterogeneity', 'Var', (32, 45))
943735	21188213	HER2 positivity was higher in esophageal junction cancers (33%) than gastric cancer (21%), and tumors classified as intestinal type (32%) were significantly more likely to be HER2-positive than diffuse (only 6%) or mixed (20%) types.	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('HER2', 'Gene', '2064', (175, 179))	('HER2', 'Gene', '2064', (0, 4))	('tumors', 'Disease', (95, 101))	('esophageal', 'Disease', (30, 40))	('higher', 'PosReg', (20, 26))	('positivity', 'Var', (5, 15))	('gastric cancer', 'Disease', (69, 83))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('HER2', 'Gene', (175, 179))	('HER2', 'Gene', (0, 4))	('esophageal', 'Disease', 'MESH:D004941', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
943825	18853262	Though there have been no cohort study to our knowledge examining the association between smoking and esophageal adenocarcinoma or Barrett's esophagus, several case-control studies have suggested that smoking increases the risk of esophageal adenocarcinoma, and that this increased risk may persist for many years after smoking cessation.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (231, 256))	('smoking', 'Var', (201, 208))	('esophageal adenocarcinoma', 'Disease', (231, 256))	('esophageal adenocarcinoma', 'Disease', (102, 127))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (231, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (102, 127))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (131, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))
943839	18853262	GERD comparison group members were randomly selected from persons with the following characteristics prior to their index date: a GERD-related diagnosis code (ICD-9 codes 530.11 [reflux esophagitis) or 530.81 [gastroesophageal reflux]); a prescription for at least 90 days supply of a histamine-2 receptor antagonist or a proton pump inhibitor (medications used for treating GERD symptoms) in the previous year (from electronic pharmacy records); no prior diagnosis of Barrett's esophagus; and an esophagogastroduodenoscopy close to the index date that did not demonstrate esophageal columnar metaplasia of any type.	('esophageal columnar metaplasia', 'Disease', 'MESH:D008679', (573, 603))	('ICD', 'Disease', (159, 162))	("Barrett's esophagus", 'Disease', (469, 488))	('persons', 'Species', '9606', (58, 65))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (469, 488))	('esophageal columnar metaplasia', 'Disease', (573, 603))	('esophagitis', 'Phenotype', 'HP:0100633', (186, 197))	('530.81', 'Var', (202, 208))	('esophagitis', 'Disease', (186, 197))	('esophagitis', 'Disease', 'MESH:D004941', (186, 197))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (210, 233))	('ICD', 'Disease', 'OMIM:252500', (159, 162))
943843	18853262	Third, we examined whether the effects of smoking were modified by other risk factors by stratifying the results by GERD symptoms (more than once a week vs. never/less than once a month), alcohol use (none vs. at least one serving per day), obesity (BMI>30 vs. BMI 18.5-25), and abdominal obesity (1st quartile vs. 3rd&4th quartiles of abdominal circumference).	('alcohol use', 'Phenotype', 'HP:0030955', (188, 199))	('abdominal obesity', 'Disease', 'MESH:D056128', (279, 296))	('alcohol', 'Chemical', 'MESH:D000438', (188, 195))	('obesity', 'Phenotype', 'HP:0001513', (241, 248))	('GERD symptoms', 'Disease', (116, 129))	('abdominal obesity', 'Phenotype', 'HP:0012743', (279, 296))	('abdominal obesity', 'Disease', (279, 296))	('obesity', 'Disease', 'MESH:D009765', (241, 248))	('obesity', 'Phenotype', 'HP:0001513', (289, 296))	('obesity', 'Disease', (241, 248))	('obesity', 'Disease', 'MESH:D009765', (289, 296))	('BMI', 'Var', (250, 253))	('obesity', 'Disease', (289, 296))
943897	33782465	At this timepoint, the neoepithelium was hyperplastic and contained proliferating Ki67 + pan-CK + cells.	('rat', 'Species', '10116', (75, 78))	('Ki67', 'Var', (82, 86))	('proliferating', 'CPA', (68, 81))
943927	33782465	Over the course of 7 days of graft implantation, inhibition of pan-caspase activity fully rescued epithelial deficiencies encountered in groups treated with c-MET and TrkA antagonists alone.	('epithelial deficiencies', 'Disease', 'MESH:D002277', (98, 121))	('caspase', 'Gene', (67, 74))	('epithelial deficiencies', 'Disease', (98, 121))	('caspase', 'Gene', '25166;83584;64044;58918', (67, 74))	('inhibition', 'Var', (49, 59))	('activity', 'MPA', (75, 83))
943930	33782465	We first analyzed the effects of the Akt inhibitor, GSK690693 on the phosphorylation of the downstream Akt target, m-TOR since GSK690693 is known to upregulate Akt phosphorylation via a feedback loop, but not its downstream effectors.	('GSK690693', 'Chemical', 'MESH:C528328', (52, 61))	('Akt', 'Pathway', (160, 163))	('GSK690693', 'Var', (127, 136))	('GSK690693', 'Chemical', 'MESH:C528328', (127, 136))	('upregulate', 'PosReg', (149, 159))
943932	33782465	We next observed that pharmacologic inhibition of PI3K or Akt activation via NVP-BEZ235 and GSK690693, respectively led to significant reductions in pan-CK + epithelia in neotissues compared to corresponding vehicle-treated controls (Fig.	('reductions', 'NegReg', (135, 145))	('PI3K', 'Pathway', (50, 54))	('GSK690693', 'Chemical', 'MESH:C528328', (92, 101))	('GSK690693', 'Var', (92, 101))	('NVP-BEZ235', 'Var', (77, 87))	('activation', 'PosReg', (62, 72))	('Akt', 'Pathway', (58, 61))	('pan-CK', 'MPA', (149, 155))
943938	33782465	We then performed immunoblotting of other anti-apoptotic regulators, Birc2 and Birc3, in rats treated with c-MET, TrkA, or Akt inhibitors or vehicle controls given their known role as negative regulators of caspase function.	('Birc3', 'Gene', (79, 84))	('rats', 'Species', '10116', (89, 93))	('caspase', 'Gene', '25166;83584;64044;58918', (207, 214))	('inhibitors', 'Var', (127, 137))	('caspase', 'Gene', (207, 214))
943948	33782465	For instance, EGFR signaling has been shown to promote epithelial proliferation in the porcine esophagus following mucosal damage induced by sclerotherapy, however our study demonstrated that inhibition of this pathway produced no significant effects on either mitogenic activity or de novo epithelial formation.	('promote', 'PosReg', (47, 54))	('mitogenic activity', 'CPA', (261, 279))	('inhibition', 'Var', (192, 202))	('mucosal damage', 'Disease', 'MESH:D052016', (115, 129))	('mucosal damage', 'Disease', (115, 129))	('rat', 'Species', '10116', (181, 184))	('epithelial proliferation', 'CPA', (55, 79))	('rat', 'Species', '10116', (73, 76))	('EGFR', 'Protein', (14, 18))
943967	33782465	In addition, pan-caspase inhibition has also been shown to enhance skeletal muscle repair after crush injury of the soleus muscle in rats.	('enhance', 'PosReg', (59, 66))	('crush injury', 'Disease', (96, 108))	('crush injury', 'Disease', 'MESH:D000071576', (96, 108))	('caspase', 'Gene', '25166;83584;64044;58918', (17, 24))	('caspase', 'Gene', (17, 24))	('inhibition', 'Var', (25, 35))	('skeletal muscle repair', 'CPA', (67, 89))	('rats', 'Species', '10116', (133, 137))
943991	33782465	The experimental design consisted of animals exposed to the following inhibitors alone or in combination: SU11274, c-MET inhibitor (6 mg/kg); erlotinib, epidermal growth factor receptor (EGFR) inhibitor (10 mg/kg); NVP-BEZ235, PI3K inhibitor (10 mg/kg); GSK690693, Akt inhibitor (10 mg/kg); GW441756, TrkA inhibitor (1.7 mg/kg); crenolanib, platelet-derived growth factor receptor (PDGFR) inhibitor (10 mg/kg); and carbobenzoxy-valyl-alanyl-aspartyl-[Omethyl]-fluoromethylketone (Z-VAD-fmk), pan-caspase inhibitor (5 mg/kg).	('PDGFR', 'Gene', (382, 387))	('caspase', 'Gene', (496, 503))	('PDGFR', 'Gene', '5159', (382, 387))	('caspase', 'Gene', '25166;83584;64044;58918', (496, 503))	('SU11274', 'Var', (106, 113))	('growth factor', 'Gene', '79215', (163, 176))	('growth factor', 'Gene', '79215', (358, 371))	('epidermal growth factor receptor', 'Gene', (153, 185))	('GW441756', 'Var', (291, 299))	('epidermal growth factor receptor', 'Gene', '24329', (153, 185))	('growth factor', 'Gene', (358, 371))	('GSK690693', 'Chemical', 'MESH:C528328', (254, 263))	('GSK690693', 'Var', (254, 263))	('Z-VAD-fmk', 'Chemical', 'MESH:C096713', (480, 489))
944003	33782465	Database searching parameters were set as follows: (a) trypsin, up to two missed cleavage, (b) precursor ion tolerance of 10 ppm and fragment ion tolerance of 0.02 Da, (c) fixed modifications include carbamidomethylation of cysteines and TMT6plex modification of lysines and peptide N-term, and (d) variable modifications include acetylation of protein N-term, oxidation of methionine and deamidation of asparagines and glutamines.	('acetylation of', 'MPA', (330, 344))	('deamidation of asparagines', 'MPA', (389, 415))	('glutamines', 'Chemical', 'MESH:D005973', (420, 430))	('asparagines', 'Chemical', 'MESH:D001216', (404, 415))	('methionine', 'Chemical', 'MESH:D008715', (374, 384))	('oxidation of methionine', 'MPA', (361, 384))	('cysteines', 'Chemical', 'MESH:D003545', (224, 233))	('protein', 'Protein', (345, 352))	('lysines', 'Chemical', 'MESH:D008239', (263, 270))	('TMT6plex', 'Var', (238, 246))	('carbamidomethylation', 'Var', (200, 220))
944034	32377720	Following XPD overexpression, the expression levels of PI3K, p-AKT, c-Myc, Cyclin D1, Bcl-2, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 were markedly downregulated, while the expression level of p21 was markedly upregulated.	('c-Myc', 'Gene', (68, 73))	('Bcl-2', 'Gene', (86, 91))	('c-Myc', 'Gene', '4609', (68, 73))	('vascular endothelial growth factor', 'Gene', '7422', (93, 127))	('p21', 'Gene', (231, 234))	('p21', 'Gene', '644914', (231, 234))	('VEGF', 'Gene', '7422', (129, 133))	('Bcl-2', 'Gene', '596', (86, 91))	('matrix metalloproteinase (MMP)-9', 'Gene', '4318', (139, 171))	('XPD', 'Gene', '2068', (10, 13))	('VEGF', 'Gene', (129, 133))	('vascular endothelial growth factor', 'Gene', (93, 127))	('AKT,', 'Gene', '207', (63, 67))	('PI3K', 'Var', (55, 59))	('upregulated', 'PosReg', (248, 259))	('expression levels', 'MPA', (34, 51))	('XPD', 'Gene', (10, 13))	('Cyclin D1', 'Gene', '595', (75, 84))	('Cyclin D1', 'Gene', (75, 84))	('downregulated', 'NegReg', (186, 199))	('expression', 'MPA', (211, 221))
944046	32377720	A previous study found that XPD gene polymorphism increases the risk of lung cancer in residents of coal mines.	('XPD', 'Gene', (28, 31))	('increases', 'PosReg', (50, 59))	('XPD', 'Gene', '2068', (28, 31))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('polymorphism', 'Var', (37, 49))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
944047	32377720	XPD polymorphisms are associated with the development of pre oral cancer as well as oral cancer and its clinical course.	('XPD', 'Gene', (0, 3))	('XPD', 'Gene', '2068', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('polymorphisms', 'Var', (4, 17))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('associated', 'Reg', (22, 32))	('cancer', 'Disease', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
944051	32377720	An XPD gene-encoding plasmid was trans-fected into ESCC cell lines (EC9706 and EC109 cells), and changes in the molecular biological behavior of EC9706 or EC109 cells were observed.	('XPD', 'Gene', (3, 6))	('EC109', 'CellLine', 'CVCL:6898', (79, 84))	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('EC9706', 'Var', (145, 151))	('EC109', 'CellLine', 'CVCL:6898', (155, 160))	('XPD', 'Gene', '2068', (3, 6))	('EC9706', 'CellLine', 'CVCL:E307', (145, 151))	('changes', 'Reg', (97, 104))
944058	32377720	Primary antibodies against phosphoinositide 3-kinase (PI3K; #4249), AKT (#4685), p-AKT (Ser473) (#4060), Bcl-2 (#15071), p21 (#2947), p-p65 (Ser536) (#3033), p65 (#8242), p-signal transducer and activator of transcription 3 (STAT3; Tyr705) (#9145), STAT3 (#12640), p-p38 mitogen-activated protein kinase (MAPK; Thr180/Tyr182) (#4511), p38 MAPK (#8690) and beta-actin (#4970) were purchased from Cell Signaling Technology, Inc. Horseradish peroxidase-conjugated secondary antibodies (ZB-2305 and ZB-2306) were purchased from Beijing Zhongshan Golden Bridge Biotechnology Co. Ltd. Cisplatin, fluorouracil and LY294002 were purchased from MedChemExpress (MCE).	('LY294002', 'Var', (607, 615))	('AKT', 'Gene', '207', (83, 86))	('p65', 'Gene', '5970', (158, 161))	('p21', 'Gene', (121, 124))	('p21', 'Gene', '644914', (121, 124))	('fluorouracil', 'Chemical', 'MESH:D005472', (590, 602))	('Horseradish', 'Species', '3704', (427, 438))	('beta-actin', 'Gene', '728378', (356, 366))	('LY294002', 'Chemical', 'MESH:C085911', (607, 615))	('phosphoinositide 3-kinase', 'Gene', '5293', (27, 52))	('AKT', 'Gene', (68, 71))	('p38 mitogen-activated protein kinase', 'Gene', (267, 303))	('signal transducer and activator of transcription 3', 'Gene', '6774', (173, 223))	('STAT3', 'Gene', (225, 230))	('AKT', 'Gene', (83, 86))	('p65', 'Gene', (158, 161))	('STAT3', 'Gene', (249, 254))	('p65', 'Gene', (136, 139))	('Bcl-2', 'Gene', (105, 110))	('p38 mitogen-activated protein kinase', 'Gene', '1432', (267, 303))	('phosphoinositide 3-kinase', 'Gene', (27, 52))	('STAT3', 'Gene', '6774', (225, 230))	('STAT3', 'Gene', '6774', (249, 254))	('beta-actin', 'Gene', (356, 366))	('AKT', 'Gene', '207', (68, 71))	('Bcl-2', 'Gene', '596', (105, 110))	('p65', 'Gene', '5970', (136, 139))
944064	32377720	The EC9706 or EC109 Cells were divided into 3 groups as follows: i) The untransfected control group (Ctrl); ii) pEGFP-N2 empty plasmid transfection group (pEGFP-N2); and iii) the pEGFP-N2/XPD plasmid transfection group (pEGFP-N2/XPD).	('pEGFP-N2', 'Chemical', '-', (220, 228))	('pEGFP-N2', 'Chemical', '-', (179, 187))	('XPD', 'Gene', '2068', (188, 191))	('EC9706', 'CellLine', 'CVCL:E307', (4, 10))	('pEGFP-N2', 'Chemical', '-', (155, 163))	('pEGFP-N2', 'Var', (112, 120))	('XPD', 'Gene', (229, 232))	('XPD', 'Gene', (188, 191))	('EC109', 'CellLine', 'CVCL:6898', (14, 19))	('pEGFP-N2', 'Chemical', '-', (112, 120))	('XPD', 'Gene', '2068', (229, 232))
944065	32377720	At 48 h following the transfection of the pEGFP-N2 or pEGFP-N2/XPD plasmids, green fluorescence was observed under a fluorescence microscope (Olympus Corp.).	('pEGFP-N2', 'Chemical', '-', (42, 50))	('XPD', 'Gene', (63, 66))	('XPD', 'Gene', '2068', (63, 66))	('pEGFP-N2', 'Chemical', '-', (54, 62))	('pEGFP-N2', 'Var', (42, 50))
944067	32377720	At 0, 24, 48, 72 or 96 h following transfection with XPD plasmid, the EC9706 or EC109 cells were seeded into 96-well culture plates at a density of 4x103 cells/well.	('EC9706', 'Var', (70, 76))	('XPD', 'Gene', '2068', (53, 56))	('EC109', 'CellLine', 'CVCL:6898', (80, 85))	('EC9706', 'CellLine', 'CVCL:E307', (70, 76))	('XPD', 'Gene', (53, 56))
944068	32377720	In addition, for the pEGFP-N2/XPD + LY294002 group, the EC9706 or EC109 cells were treated with 10 micromol/l of LY294002 for 0, 24, 48, 72 or 96 h following transfection with XPD plasmid.	('LY294002', 'Chemical', 'MESH:C085911', (36, 44))	('XPD', 'Gene', '2068', (30, 33))	('EC109', 'CellLine', 'CVCL:6898', (66, 71))	('LY294002', 'Chemical', 'MESH:C085911', (113, 121))	('pEGFP-N2', 'Chemical', '-', (21, 29))	('XPD', 'Gene', (176, 179))	('EC9706', 'CellLine', 'CVCL:E307', (56, 62))	('LY294002', 'Var', (113, 121))	('XPD', 'Gene', '2068', (176, 179))	('XPD', 'Gene', (30, 33))
944070	32377720	The EC9706 or EC109 cells in each group were trypsinized and collected by centrifugation at 37 C for 5 min at a speed of 1,000 x g. A total of 1x105 cells were then resuspended in 500 microl of buffer and incubated with Annexin V-FITC/PI kit for 15 min at room temperature.	('Annexin V', 'Gene', '308', (220, 229))	('EC9706', 'CellLine', 'CVCL:E307', (4, 10))	('Annexin V', 'Gene', (220, 229))	('EC9706', 'Var', (4, 10))	('EC109', 'CellLine', 'CVCL:6898', (14, 19))
944072	32377720	A total of 2x105 EC9706 or EC109 cells were seeded into the upper chamber of the insert in serum-free DMEM.	('EC109', 'CellLine', 'CVCL:6898', (27, 32))	('EC9706', 'CellLine', 'CVCL:E307', (17, 23))	('EC9706', 'Var', (17, 23))	('EC109 cells', 'Var', (27, 38))	('DMEM', 'Chemical', '-', (102, 106))
944074	32377720	Following incubation in a humidified incubator at 37 C 5% CO2 and 95% air for 48 h, EC9706 or EC109 cells remaining on the insert's top layer were wiped off with a cotton swab.	('EC109', 'Gene', (94, 99))	('EC9706', 'Var', (84, 90))	('EC109', 'CellLine', 'CVCL:6898', (94, 99))	('CO2', 'Chemical', 'MESH:D002245', (58, 61))	('EC9706', 'CellLine', 'CVCL:E307', (84, 90))
944093	32377720	2A, cells successfully transfected with pEGFP-N2/XPD or pEGFP-N2 plasmid exhibited green fluorescence.	('pEGFP-N2', 'Var', (56, 64))	('green fluorescence', 'MPA', (83, 101))	('XPD', 'Gene', (49, 52))	('XPD', 'Gene', '2068', (49, 52))	('pEGFP-N2', 'Chemical', '-', (56, 64))	('pEGFP-N2', 'Chemical', '-', (40, 48))
944099	32377720	3C-E, compared with the Ctrl group and the pEGFP-N2 group, the apoptotic rate of the EC9706 or EC109 cells in the pEGFP-N2/XPD group was significantly higher (P<0.001).	('XPD', 'Gene', '2068', (123, 126))	('apoptotic rate', 'CPA', (63, 77))	('pEGFP-N2', 'Chemical', '-', (114, 122))	('EC9706', 'Var', (85, 91))	('higher', 'PosReg', (151, 157))	('EC109', 'CellLine', 'CVCL:6898', (95, 100))	('XPD', 'Gene', (123, 126))	('EC9706', 'CellLine', 'CVCL:E307', (85, 91))	('pEGFP-N2', 'Chemical', '-', (43, 51))
944105	32377720	There was no significant difference in the migratory and invasive capacities between the pEGFP-N2 group and Ctrl group (P>0.05; Fig.	('pEGFP-N2', 'Chemical', '-', (89, 97))	('pEGFP-N2', 'Var', (89, 97))	('migratory', 'CPA', (43, 52))
944108	32377720	4, the results of CCK-8 assay revealed that compared with the Ctrl group and the pEGFP-N2 group, the chemosensitivity of the EC9706 and EC109 cells to cisplatin or fluorouracil in the pEGFP-N2/XPD group was markedly enhanced (P<0.05 or P<0.01).	('EC9706', 'Var', (125, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('pEGFP-N2', 'Chemical', '-', (81, 89))	('enhanced', 'PosReg', (216, 224))	('EC9706', 'CellLine', 'CVCL:E307', (125, 131))	('fluorouracil', 'MPA', (164, 176))	('XPD', 'Gene', (193, 196))	('fluorouracil', 'Chemical', 'MESH:D005472', (164, 176))	('pEGFP-N2', 'Chemical', '-', (184, 192))	('EC109', 'CellLine', 'CVCL:6898', (136, 141))	('XPD', 'Gene', '2068', (193, 196))	('CCK-8', 'Chemical', 'MESH:D012844', (18, 23))	('chemosensitivity', 'MPA', (101, 117))
944112	32377720	5A and B, compared with the pEGFP-N2 group and the Ctrl group, the mRNA expression levels of PI3K, Bcl-2, c-Myc, Cyclin D1, VEGF and MMP-9 in the EC9706 or EC109 cells of pEGFP-N2/XPD group were markedly decreased (P<0.05 or P<0.01), whereas the mRNA expression of p21 was markedly increased (P<0.01).	('c-Myc', 'Gene', (106, 111))	('Cyclin D1', 'Gene', '595', (113, 122))	('c-Myc', 'Gene', '4609', (106, 111))	('Cyclin D1', 'Gene', (113, 122))	('EC9706', 'CellLine', 'CVCL:E307', (146, 152))	('pEGFP-N2', 'Chemical', '-', (171, 179))	('increased', 'PosReg', (282, 291))	('pEGFP-N2', 'Chemical', '-', (28, 36))	('EC9706', 'Var', (146, 152))	('XPD', 'Gene', (180, 183))	('Bcl-2', 'Gene', (99, 104))	('mRNA expression', 'MPA', (246, 261))	('decreased', 'NegReg', (204, 213))	('Bcl-2', 'Gene', '596', (99, 104))	('mRNA expression levels', 'MPA', (67, 89))	('p21', 'Gene', (265, 268))	('p21', 'Gene', '644914', (265, 268))	('MMP-9', 'Gene', '4318', (133, 138))	('EC109', 'CellLine', 'CVCL:6898', (156, 161))	('VEGF', 'Gene', '7422', (124, 128))	('MMP-9', 'Gene', (133, 138))	('XPD', 'Gene', '2068', (180, 183))	('VEGF', 'Gene', (124, 128))
944113	32377720	There was no significant difference in mRNA expression level of AKT among the pEGFP-N2/XPD, pEGFP-N2 and Ctrl groups (P>0.05).	('pEGFP-N2', 'Chemical', '-', (78, 86))	('pEGFP-N2', 'Var', (92, 100))	('AKT', 'Gene', '207', (64, 67))	('XPD', 'Gene', (87, 90))	('XPD', 'Gene', '2068', (87, 90))	('AKT', 'Gene', (64, 67))	('mRNA expression level', 'MPA', (39, 60))	('pEGFP-N2', 'Chemical', '-', (92, 100))
944115	32377720	There was no significant difference in the protein expression level of AKT among the pEGFP-N2/XPD, pEGFP-N2 and Ctrl groups (P>0.05).	('AKT', 'Gene', '207', (71, 74))	('pEGFP-N2', 'Chemical', '-', (85, 93))	('pEGFP-N2', 'Chemical', '-', (99, 107))	('XPD', 'Gene', (94, 97))	('pEGFP-N2', 'Var', (99, 107))	('XPD', 'Gene', '2068', (94, 97))	('AKT', 'Gene', (71, 74))	('protein expression level', 'MPA', (43, 67))
944116	32377720	In addition, there was no significant difference in the expression levels of PI3K/AKT signaling pathway-associated factors between the pEGFP-N2 group and the Ctrl group (P>0.05).	('pEGFP-N2', 'Var', (135, 143))	('expression levels', 'MPA', (56, 73))	('AKT', 'Gene', '207', (82, 85))	('pEGFP-N2', 'Chemical', '-', (135, 143))	('AKT', 'Gene', (82, 85))
944119	32377720	The results revealed that XPD overexpression markedly inhibited the proliferative capabilities of the EC9706 or EC109 cells, and LY294002 significantly enhanced the suppressive effects (Fig.	('XPD', 'Gene', '2068', (26, 29))	('inhibited', 'NegReg', (54, 63))	('suppressive effects', 'CPA', (165, 184))	('EC9706', 'CellLine', 'CVCL:E307', (102, 108))	('LY294002', 'Chemical', 'MESH:C085911', (129, 137))	('EC109', 'CellLine', 'CVCL:6898', (112, 117))	('LY294002', 'Var', (129, 137))	('XPD', 'Gene', (26, 29))	('enhanced', 'PosReg', (152, 160))	('proliferative capabilities', 'CPA', (68, 94))
944120	32377720	To determine the association between XPD and other signaling pathways in ESCC, such as the NF-kappaB, JAK2/STAT3 and MAPK signaling pathways, the protein expression levels of p65, p-p65, STAT3, p-STAT3, p38 MAPK and p-p38 MAPK were detected in the EC9706 cells following the overexpression of XPD.	('NF-kappaB', 'Gene', '4790', (91, 100))	('XPD', 'Gene', (293, 296))	('EC9706', 'CellLine', 'CVCL:E307', (248, 254))	('JAK2', 'Gene', '3717', (102, 106))	('p-p38 MAPK', 'Var', (216, 226))	('XPD', 'Gene', (37, 40))	('STAT3', 'Gene', (196, 201))	('STAT3', 'Gene', (107, 112))	('p65', 'Gene', (182, 185))	('p65', 'Gene', (175, 178))	('STAT3', 'Gene', (187, 192))	('JAK2', 'Gene', (102, 106))	('p38 MAPK', 'Var', (203, 211))	('XPD', 'Gene', '2068', (293, 296))	('STAT3', 'Gene', '6774', (107, 112))	('STAT3', 'Gene', '6774', (196, 201))	('STAT3', 'Gene', '6774', (187, 192))	('NF-kappaB', 'Gene', (91, 100))	('p65', 'Gene', '5970', (182, 185))	('p65', 'Gene', '5970', (175, 178))	('XPD', 'Gene', '2068', (37, 40))
944128	32377720	XPD751 polymorphism has been shown to be associated with the occurrence and development of a wide range of malignancies, such as esophageal cancer, gastric cancer, and colorectal cancer.	('associated', 'Reg', (41, 51))	('polymorphism', 'Var', (7, 19))	('XPD', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('gastric cancer', 'Disease', (148, 162))	('XPD', 'Gene', '2068', (0, 3))	('cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (156, 162))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('malignancies', 'Disease', 'MESH:D009369', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (179, 185))	('malignancies', 'Disease', (107, 119))
944150	31754291	Our previous lncRNA microarray results have shown that lncRNA XLOC_001659 is upregulated in esophageal cancer (EC) tissues, with a fold change of 20.9 relative to normal esophageal tissues.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('upregulated', 'PosReg', (77, 88))	('EC', 'Disease', 'MESH:D004938', (111, 113))	('XLOC_001659', 'Var', (62, 73))	('lncRNA', 'Gene', (55, 61))	('esophageal cancer', 'Disease', (92, 109))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
944157	31754291	CCK-8 assay showed that knockdown of lncRNAXLOC_001659 significantly inhibited ESCC cell proliferation.	('ESCC', 'Disease', 'MESH:C562729', (79, 83))	('ESCC', 'Disease', (79, 83))	('lncRNAXLOC_001659', 'Var', (37, 54))	('inhibited', 'NegReg', (69, 78))
944158	31754291	Colony formation and Transwell invasion assays showed that knockdown of lncRNAXLOC_001659 or overexpression of miR-490-5p significantly inhibited ESCC cell growth and invasion.	('miR-490', 'Gene', (111, 118))	('ESCC', 'Disease', 'MESH:C562729', (146, 150))	('inhibited', 'NegReg', (136, 145))	('lncRNAXLOC_001659', 'Var', (72, 89))	('ESCC', 'Disease', (146, 150))	('miR-490', 'Gene', '574443', (111, 118))
944159	31754291	Furthermore, lncRNAXLOC_001659 acts as an endogenous sponge by competitively binding to miR-490-5p to downregulate miR-490-5p.	('miR-490', 'Gene', '574443', (115, 122))	('miR-490', 'Gene', (115, 122))	('miR-490', 'Gene', '574443', (88, 95))	('miR-490', 'Gene', (88, 95))	('lncRNAXLOC_001659', 'Var', (13, 30))	('downregulate', 'NegReg', (102, 114))	('binding', 'Interaction', (77, 84))
944160	31754291	Further results confirmed that miR-490-5p targeted PIK3CA, and the recovery of PIK3CA rescued lncRNAXLOC_001659 knockdown or miR-490-5p overexpression-mediated inhibition of cell proliferation and invasion, which suggested the presence of an lncRNAXLOC_001659/miR-490-5p/PIK3CA regulatory axis.	('miR-490', 'Gene', (125, 132))	('invasion', 'CPA', (197, 205))	('cell proliferation', 'CPA', (174, 192))	('miR-490', 'Gene', (260, 267))	('miR-490', 'Gene', '574443', (260, 267))	('PIK3CA', 'Gene', (271, 277))	('inhibition', 'NegReg', (160, 170))	('PIK3CA', 'Gene', (51, 57))	('PIK3CA', 'Gene', (79, 85))	('miR-490', 'Gene', '574443', (31, 38))	('miR-490', 'Gene', (31, 38))	('PIK3CA', 'Gene', '5290', (271, 277))	('PIK3CA', 'Gene', '5290', (51, 57))	('lncRNAXLOC_001659', 'Var', (94, 111))	('PIK3CA', 'Gene', '5290', (79, 85))	('miR-490', 'Gene', '574443', (125, 132))
944163	31754291	Our previous lncRNA microarray results have shown that lncRNA XLOC_001659 is upregulated in esophageal squamous cell carcinoma (ESCC) tissues, with a fold change of 20.9 relative to normal esophageal tissues.	('esophageal squamous cell carcinoma', 'Disease', (92, 126))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (92, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('upregulated', 'PosReg', (77, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('ESCC', 'Disease', 'MESH:C562729', (128, 132))	('XLOC_001659', 'Var', (62, 73))	('lncRNA', 'Gene', (55, 61))	('ESCC', 'Disease', (128, 132))
944174	31754291	Our previous lncRNA microarray analysis has shown that lncRNA XLOC_001659 is upregulated in EC tissues, with a fold change of 20.9 relative to normal esophageal tissues distant from the tumor.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('upregulated', 'PosReg', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('XLOC_001659', 'Var', (62, 73))	('lncRNA', 'Gene', (55, 61))	('EC', 'Disease', 'MESH:D004938', (92, 94))
944175	31754291	In this study, we investigated the expression of lncRNA XLOC_001659 in ESCC and its effect on proliferation and invasion of EC cells.	('ESCC', 'Disease', (71, 75))	('lncRNA XLOC_001659', 'Var', (49, 67))	('ESCC', 'Disease', 'MESH:C562729', (71, 75))	('EC', 'Disease', 'MESH:D004938', (124, 126))
944188	31754291	RT-qPCR was performed on an ABI 7500 Fast Real-Time PCR System (Applied Biosystems, Foster City, CA, United States) to detect the relative expression of XLOC_001659 and miR-490-5p.	('XLOC_001659', 'Var', (153, 164))	('miR-490', 'Gene', '574443', (169, 176))	('miR-490', 'Gene', (169, 176))
944205	31754291	To further investigate the biological function of lncRNA XLOC_001659, we knocked down lncRNA XLOC_001659 in ESCC cell lines and performed RT-qPCR.	('ESCC', 'Disease', 'MESH:C562729', (108, 112))	('lncRNA XLOC_001659', 'Gene', (86, 104))	('knocked', 'Var', (73, 80))	('ESCC', 'Disease', (108, 112))
944207	31754291	CCK-8 assay showed that ESCC cell lines transfected with siRNA-lncXLOC_001659 had a significantly lower proliferation rate than the ESCC cell lines in the NC group and the blank control group (Figure 1C).	('ESCC', 'Disease', 'MESH:C562729', (24, 28))	('proliferation rate', 'CPA', (104, 122))	('ESCC', 'Disease', 'MESH:C562729', (132, 136))	('ESCC', 'Disease', (24, 28))	('siRNA-lncXLOC_001659', 'Var', (57, 77))	('ESCC', 'Disease', (132, 136))	('lower', 'NegReg', (98, 103))
944208	31754291	In addition, the cell migration measured by Transwell invasion assay showed that knockdown of lncXLOC_001659 significantly reduced the invasion of ESCC cell lines (Figure 1E).	('knockdown', 'Var', (81, 90))	('invasion of ESCC', 'Disease', (135, 151))	('invasion of ESCC', 'Disease', 'MESH:C562729', (135, 151))	('lncXLOC_001659', 'Gene', (94, 108))	('reduced', 'NegReg', (123, 130))
944209	31754291	All of these results revealed that knockdown of lncRNA XLOC_001659 inhibited the growth and invasion of ESCC cells.	('inhibited', 'NegReg', (67, 76))	('lncRNA', 'Gene', (48, 54))	('XLOC_001659', 'Var', (55, 66))	('invasion of ESCC', 'Disease', 'MESH:C562729', (92, 108))	('invasion of ESCC', 'Disease', (92, 108))
944212	31754291	To further confirm the interaction between lncRNA XLOC_001659 and miR-490-5p, we constructed a recombinant reporter vector containing wild type (WT) or mutant (MUT) lncRNA XLOC_001659 to perform dual-luciferase reporter assay.	('miR-490', 'Gene', '574443', (66, 73))	('miR-490', 'Gene', (66, 73))	('mutant', 'Var', (152, 158))	('lncRNA', 'Gene', (165, 171))
944217	31754291	To determine whether miR-490-5p and lncRNA XLOC_001659 have similar effects on the proliferation and invasion of the ESCC cell lines, we overexpressed miR-490-5p and knocked down lncRNA XLOC_001659 in the EC9706 and EC-1 cells.	('EC9706', 'CellLine', 'CVCL:E307', (205, 211))	('ESCC', 'Disease', 'MESH:C562729', (117, 121))	('EC-1', 'CellLine', 'CVCL:E025', (216, 220))	('miR-490', 'Gene', '574443', (21, 28))	('lncRNA XLOC_001659', 'Gene', (179, 197))	('miR-490', 'Gene', (21, 28))	('miR-490', 'Gene', '574443', (151, 158))	('knocked down', 'Var', (166, 178))	('miR-490', 'Gene', (151, 158))	('ESCC', 'Disease', (117, 121))	('XLOC_001659', 'Gene', (186, 197))
944220	31754291	The results of Transwell invasion assay showed that knockdown of lncXLOC_001659 and overexpression of miR-490-5p rendered the degree of invasion in ESCC cell lines far lower than in the corresponding NC groups (Figure 3C).	('overexpression', 'PosReg', (84, 98))	('lower', 'NegReg', (168, 173))	('lncXLOC_001659', 'Var', (65, 79))	('ESCC', 'Disease', 'MESH:C562729', (148, 152))	('invasion', 'CPA', (136, 144))	('miR-490', 'Gene', '574443', (102, 109))	('miR-490', 'Gene', (102, 109))	('ESCC', 'Disease', (148, 152))
944232	31754291	Transwell invasion assay showed that knockdown of lncXLOC_001659 or overexpression of miR-490-5p significantly inhibited the cell invasion ability, whereas co-transfection with pcDNA-PIK3CA partially eliminated the inhibitory effect (Figure 5B).	('PIK3CA', 'Gene', (183, 189))	('overexpression', 'PosReg', (68, 82))	('miR-490', 'Gene', '574443', (86, 93))	('miR-490', 'Gene', (86, 93))	('inhibited', 'NegReg', (111, 120))	('cell invasion ability', 'CPA', (125, 146))	('lncXLOC_001659', 'Var', (50, 64))	('PIK3CA', 'Gene', '5290', (183, 189))
944241	31754291	The lncRNA XLOC_001659 was upregulated in ESCC cells, and silencing the expression of lncRNA XLOC_001659 attenuated the proliferation and invasion of ESCC cells.	('proliferation', 'CPA', (120, 133))	('ESCC', 'Disease', 'MESH:C562729', (42, 46))	('invasion of ESCC', 'Disease', 'MESH:C562729', (138, 154))	('invasion of ESCC', 'Disease', (138, 154))	('expression', 'MPA', (72, 82))	('ESCC', 'Disease', (150, 154))	('attenuated', 'NegReg', (105, 115))	('ESCC', 'Disease', (42, 46))	('lncRNA XLOC_001659', 'Gene', (86, 104))	('XLOC_001659', 'Gene', (93, 104))	('ESCC', 'Disease', 'MESH:C562729', (150, 154))	('silencing', 'Var', (58, 67))
944254	31754291	In conclusion, we here investigated the biological roles of lncRNA XLOC_001659 in ESCC cells and showed that lncRNA XLOC_001659 was overexpressed in ESCC cells.	('ESCC', 'Disease', (149, 153))	('lncRNA XLOC_001659', 'Var', (109, 127))	('ESCC', 'Disease', (82, 86))	('ESCC', 'Disease', 'MESH:C562729', (149, 153))	('ESCC', 'Disease', 'MESH:C562729', (82, 86))
944255	31754291	Silencing lncRNA XLOC_001659 expression inhibited the proliferation and invasion of ESCC cells.	('inhibited', 'NegReg', (40, 49))	('invasion of ESCC', 'Disease', (72, 88))	('lncRNA XLOC_001659', 'Gene', (10, 28))	('invasion of ESCC', 'Disease', 'MESH:C562729', (72, 88))	('Silencing', 'Var', (0, 9))
944258	31754291	For this reason, we speculate that lncRNA XLOC_001659 may be a cancer-promoting gene and a new target for the diagnosis and treatment of ESCC.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ESCC', 'Disease', (137, 141))	('lncRNA XLOC_001659', 'Var', (35, 53))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('ESCC', 'Disease', 'MESH:C562729', (137, 141))	('cancer', 'Disease', (63, 69))
944261	31754291	Our previous lncRNA microarray analysis has shown that lncRNA XLOC_001659 is upregulated in EC tissues.	('EC', 'Disease', 'MESH:D004938', (92, 94))	('upregulated', 'PosReg', (77, 88))	('XLOC_001659', 'Var', (62, 73))
944264	31754291	In this study, we investigated the expression of lncRNAXLOC_001659 in ESCC and its effect on proliferation and invasion of EC cells.	('EC', 'Disease', 'MESH:D004938', (123, 125))	('ESCC', 'Disease', (70, 74))	('ESCC', 'Disease', 'MESH:C562729', (70, 74))	('lncRNAXLOC_001659', 'Var', (49, 66))
944265	31754291	Our study is the first to report the expression and role of lncRNAXLOC_001659 in ESCC.	('lncRNAXLOC_001659', 'Var', (60, 77))	('ESCC', 'Disease', 'MESH:C562729', (81, 85))	('ESCC', 'Disease', (81, 85))
944266	31754291	In this study, we analyzed the expression of lncRNAXLOC_001659 in ESCC and its effect on the proliferation and invasion of EC cells.	('EC', 'Disease', 'MESH:D004938', (123, 125))	('lncRNAXLOC_001659', 'Var', (45, 62))	('ESCC', 'Disease', 'MESH:C562729', (66, 70))	('ESCC', 'Disease', (66, 70))
944267	31754291	The purpose of this study was to explore the role of lncRNA XLOC_001659 in ESCC tumorigenesis and progression.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('XLOC_001659', 'Var', (60, 71))	('ESCC', 'Disease', (75, 79))	('tumor', 'Disease', (80, 85))	('ESCC', 'Disease', 'MESH:C562729', (75, 79))
944270	31754291	Knockdown of lncRNAXLOC_001659 significantly inhibited ESCC cell proliferation and invasion.	('ESCC', 'Disease', 'MESH:C562729', (55, 59))	('lncRNAXLOC_001659', 'Var', (13, 30))	('invasion', 'CPA', (83, 91))	('ESCC', 'Disease', (55, 59))	('inhibited', 'NegReg', (45, 54))
944282	28454387	The survival period of patients with negative WIF1 and positive ROR2 protein expression was demonstrated to be significantly decreased compared with that of patients with positive WIF1 and negative ROR2 protein expression (P<0.0001).	('ROR2', 'Gene', (64, 68))	('ROR2', 'Gene', '4920', (64, 68))	('patients', 'Species', '9606', (23, 31))	('decreased', 'NegReg', (125, 134))	('WIF1', 'Gene', (46, 50))	('protein', 'Protein', (69, 76))	('WIF1', 'Gene', (180, 184))	('patients', 'Species', '9606', (157, 165))	('WIF1', 'Gene', '11197', (180, 184))	('positive', 'Var', (55, 63))	('WIF1', 'Gene', '11197', (46, 50))	('survival period', 'CPA', (4, 19))	('ROR2', 'Gene', (198, 202))	('negative', 'NegReg', (37, 45))	('ROR2', 'Gene', '4920', (198, 202))
944301	28454387	According to previous studies, ROR2 expression is associated with the tumorigenesis, progression, biological behavior and prognosis of various types of malignant tumor, including gastric cancer, rectal carcinoma, liver cancer, breast cancer, esophageal squamous cell carcinoma and medulloblastoma.	('gastric cancer', 'Phenotype', 'HP:0012126', (179, 193))	('esophageal squamous cell carcinoma', 'Disease', (242, 276))	('rectal carcinoma', 'Disease', 'MESH:D012004', (195, 211))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('liver cancer', 'Phenotype', 'HP:0002896', (213, 225))	('liver cancer', 'Disease', (213, 225))	('tumor', 'Disease', (162, 167))	('ROR2', 'Gene', (31, 35))	('ROR2', 'Gene', '4920', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('expression', 'Var', (36, 46))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (242, 276))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('gastric cancer', 'Disease', (179, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (253, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (195, 211))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('breast cancer', 'Disease', (227, 240))	('gastric cancer', 'Disease', 'MESH:D013274', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('liver cancer', 'Disease', 'MESH:D006528', (213, 225))	('medulloblastoma', 'Disease', 'MESH:D008527', (281, 296))	('rectal carcinoma', 'Disease', (195, 211))	('medulloblastoma', 'Phenotype', 'HP:0002885', (281, 296))	('tumor', 'Disease', (70, 75))	('malignant tumor', 'Disease', (152, 167))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('medulloblastoma', 'Disease', (281, 296))	('malignant tumor', 'Disease', 'MESH:D018198', (152, 167))	('associated', 'Reg', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
944363	28454387	Positive WIF1 protein expression had a positive correlation with the post-operative survival rate and a negative correlation with the post-operative death rate, making it a protective factor; however, positive ROR2 protein expression was identified to have a negative correlation with the post-operative survival rate and a positive correlation with the death rate, making it a risk factor (Table IV).	('ROR2', 'Gene', (210, 214))	('ROR2', 'Gene', '4920', (210, 214))	('WIF1', 'Gene', (9, 13))	('positive', 'Var', (201, 209))	('WIF1', 'Gene', '11197', (9, 13))	('protein', 'Protein', (215, 222))	('negative', 'NegReg', (259, 267))
944368	28454387	This is achieved by CK1-mediated phosphorylation at Ser45, followed by Ser33, Ser37, and Thr41 phosphorylation by glycogen synthase kinase (GSK) 3beta, which leads to decreased cytoplasmic accumulation of beta-catenin.	('Ser33', 'Chemical', '-', (71, 76))	('Ser45', 'Chemical', '-', (52, 57))	('Ser33', 'Var', (71, 76))	('Ser37', 'Var', (78, 83))	('CK1', 'Species', '2498238', (20, 23))	('Ser45', 'Var', (52, 57))	('beta-catenin', 'Gene', (205, 217))	('beta-catenin', 'Gene', '1499', (205, 217))	('Thr41', 'Chemical', '-', (89, 94))	('Ser37', 'Chemical', '-', (78, 83))	('CK1-mediated', 'Var', (20, 32))	('decreased', 'NegReg', (167, 176))
944376	28454387	The results of the methylation-specific polymerase chain reaction demonstrated that hypermethylation of CpG islands in the region surrounding the WIF1 promoter was associated with the decreased expression of WIF1.	('WIF1', 'Gene', (146, 150))	('WIF1', 'Gene', '11197', (146, 150))	('decreased', 'NegReg', (184, 193))	('WIF1', 'Gene', (208, 212))	('expression', 'MPA', (194, 204))	('WIF1', 'Gene', '11197', (208, 212))	('hypermethylation', 'Var', (84, 100))
944379	28454387	Decreased or silenced expression of WIF1 in rectal carcinoma, chronic leukemia and pleural mesothelioma was caused by hypermethylation of CpG islands within the WIF1 promoter.	('silenced', 'NegReg', (13, 21))	('chronic leukemia', 'Phenotype', 'HP:0005558', (62, 78))	('WIF1', 'Gene', '11197', (36, 40))	('pleural mesothelioma', 'Disease', (83, 103))	('Decreased', 'NegReg', (0, 9))	('hypermethylation', 'Var', (118, 134))	('WIF1', 'Gene', (36, 40))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('WIF1', 'Gene', '11197', (161, 165))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (44, 60))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (83, 103))	('leukemia', 'Disease', (70, 78))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (83, 103))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('WIF1', 'Gene', (161, 165))	('expression', 'MPA', (22, 32))	('rectal carcinoma', 'Disease', (44, 60))	('CpG', 'Protein', (138, 141))	('rectal carcinoma', 'Disease', 'MESH:D012004', (44, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
944397	28454387	It has been observed that the expression of ROR2 protein is associated with the incidence, development, biological behavior and prognosis of multiple types of malignant tumor, including gastric cancer, rectal carcinoma, liver cancer, breast cancer, esophageal squamous cell carcinoma and medulloblastoma.	('esophageal squamous cell carcinoma', 'Disease', (249, 283))	('rectal carcinoma', 'Disease', 'MESH:D012004', (202, 218))	('liver cancer', 'Phenotype', 'HP:0002896', (220, 232))	('protein', 'Protein', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('expression', 'Var', (30, 40))	('liver cancer', 'Disease', (220, 232))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('ROR2', 'Gene', '4920', (44, 48))	('ROR2', 'Gene', (44, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (260, 283))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (249, 283))	('gastric cancer', 'Disease', (186, 200))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('breast cancer', 'Disease', (234, 247))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (202, 218))	('associated', 'Reg', (60, 70))	('medulloblastoma', 'Phenotype', 'HP:0002885', (288, 303))	('malignant tumor', 'Disease', (159, 174))	('medulloblastoma', 'Disease', 'MESH:D008527', (288, 303))	('liver cancer', 'Disease', 'MESH:D006528', (220, 232))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('medulloblastoma', 'Disease', (288, 303))	('rectal carcinoma', 'Disease', (202, 218))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('malignant tumor', 'Disease', 'MESH:D018198', (159, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
944403	28454387	Furthermore, the paracancerous epithelium and the ductal epithelium of benign lesions with positive ROR2 and/or negative WIF1 expression displayed, and the ductal epithelium of benign lesions demonstrated mild to severe atypical hyperplasia or intraepithelial neoplasia grade II and III.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('negative', 'NegReg', (112, 120))	('ROR2', 'Gene', '4920', (100, 104))	('WIF1', 'Gene', (121, 125))	('ROR2', 'Gene', (100, 104))	('paracancerous epithelium', 'Disease', 'MESH:C536309', (17, 41))	('hyperplasia', 'Disease', (229, 240))	('WIF1', 'Gene', '11197', (121, 125))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (244, 269))	('hyperplasia', 'Disease', 'MESH:D006965', (229, 240))	('paracancerous epithelium', 'Disease', (17, 41))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (244, 269))	('neoplasia', 'Phenotype', 'HP:0002664', (260, 269))	('intraepithelial neoplasia', 'Disease', (244, 269))	('positive', 'Var', (91, 99))	('epithelial neoplasia', 'Phenotype', 'HP:0031492', (249, 269))
944515	28435284	The median OS period of patients with positive LNM (median OS, 27 months) was found to be significantly shorter than that of those with negative LNM (median OS, 38.1 months, P=0.01; Figure 4).	('positive', 'Var', (38, 46))	('shorter', 'NegReg', (104, 111))	('patients', 'Species', '9606', (24, 32))
944551	28435284	These findings suggest that the imbalance between CTSB and CysC may contribute to tumorigenesis.	('CTSB', 'Gene', '1508', (50, 54))	('CysC', 'Gene', '1471', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('imbalance', 'Var', (32, 41))	('contribute', 'Reg', (68, 78))	('imbalance', 'Phenotype', 'HP:0002172', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('CTSB', 'Gene', (50, 54))	('CysC', 'Gene', (59, 63))	('tumor', 'Disease', (82, 87))
944565	26604784	Multivariate analysis indicated that the positivity of PNI was an independent prognostic factor for both DMFS (hazard ratio [HR] =2.35, P=0.039) and OS (HR =3.56, P=0.002).	('positivity', 'Var', (41, 51))	('PNI', 'Gene', (55, 58))	('OS', 'Chemical', '-', (149, 151))	('DMFS', 'Disease', (105, 109))	('DMFS', 'Chemical', '-', (105, 109))
944598	26604784	The presence of PNI was significantly associated with DMFS in the univariate analysis (P=0.009, Figure 1).	('associated', 'Reg', (38, 48))	('PNI', 'Gene', (16, 19))	('presence', 'Var', (4, 12))	('DMFS', 'Disease', (54, 58))	('DMFS', 'Chemical', '-', (54, 58))
944634	26251921	Significant epigenetic silencing of GPCR expression occurs in HNSCC compared with normal tissue, and is significantly correlated with clinical behavior.	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('GPCR', 'Gene', '441931', (36, 40))	('GPCR', 'Gene', (36, 40))	('HNSCC', 'Disease', (62, 67))	('correlated', 'Reg', (118, 128))	('epigenetic silencing', 'Var', (12, 32))
944638	26251921	Hypermethylation of GALR1, GALR2, TACR1, and SST1 is associated with significantly reduced disease-free survival and a higher recurrence rate.	('disease-free survival', 'CPA', (91, 112))	('GALR1', 'Gene', (20, 25))	('GALR2', 'Gene', (27, 32))	('reduced', 'NegReg', (83, 90))	('Hypermethylation', 'Var', (0, 16))	('GALR2', 'Gene', '8811', (27, 32))	('TACR1', 'Gene', (34, 39))	('SST1', 'Gene', '6751', (45, 49))	('recurrence rate', 'CPA', (126, 141))	('TACR1', 'Gene', '6869', (34, 39))	('GALR1', 'Gene', '2587', (20, 25))	('SST1', 'Gene', (45, 49))
944645	26251921	Furthermore, surgery can lead to serious functional disorders such as dysphagia, or mastication and communication disorder following removal of the tongue, pharynx, and larynx.	('mastication and communication disorder', 'Disease', 'MESH:D003147', (84, 122))	('dysphagia', 'Disease', (70, 79))	('lead to', 'Reg', (25, 32))	('dysphagia', 'Phenotype', 'HP:0002015', (70, 79))	('dysphagia', 'Disease', 'MESH:D003680', (70, 79))	('surgery', 'Var', (13, 20))
944653	26251921	Furthermore, epigenetic repression of GPCR expression is closely related to prognosis and/or the response to chemotherapy.	('related', 'Reg', (65, 72))	('epigenetic repression', 'Var', (13, 34))	('GPCR', 'Gene', '441931', (38, 42))	('GPCR', 'Gene', (38, 42))
944657	26251921	Previous studies in pharmacology demonstrated that stimulation of GALR1 inhibits forskolin-stimulated cAMP production, and this inhibition was observed as a pertussis toxin (PTX)-sensitive manner in transfected cell lines.	('forskolin-stimulated cAMP production', 'MPA', (81, 117))	('forskolin', 'Chemical', 'MESH:D005576', (81, 90))	('stimulation', 'Var', (51, 62))	('GALR1', 'Gene', (66, 71))	('cAMP', 'Chemical', 'MESH:D000242', (102, 106))	('inhibits', 'NegReg', (72, 80))	('GALR1', 'Gene', '2587', (66, 71))
944677	26251921	LY294002, the PI3K inhibitor, did not cancel out either ERK1/2 activation or inhibition of cell proliferation induced by galanin and GALR1.	('LY294002', 'Var', (0, 8))	('galanin', 'Gene', '51083', (121, 128))	('ERK1/2', 'Gene', (56, 62))	('galanin', 'Gene', (121, 128))	('GALR1', 'Gene', '2587', (133, 138))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('inhibition', 'NegReg', (77, 87))	('GALR1', 'Gene', (133, 138))	('cell proliferation', 'CPA', (91, 109))
944688	26251921	They found that methylation of GALR1 promoter region is one of the most common molecular alterations in endometrial cancer, and it predicted the presence of endometrial malignancy with a specificity of 78.9% and a sensitivity of 92.7%.	('GALR1', 'Gene', '2587', (31, 36))	('endometrial cancer', 'Disease', (104, 122))	('endometrial malignancy', 'Disease', (157, 179))	('endometrial cancer', 'Phenotype', 'HP:0012114', (104, 122))	('GALR1', 'Gene', (31, 36))	('predicted', 'Reg', (131, 140))	('endometrial malignancy', 'Disease', 'MESH:D014591', (157, 179))	('endometrial cancer', 'Disease', 'MESH:D016889', (104, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('methylation', 'Var', (16, 27))
944690	26251921	In general, tumor suppressor genes may be inactivated by point mutations, homozygous deletions, or loss of heterozygosity and aberrant methylation in intractable cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('loss of heterozygosity', 'Var', (99, 121))	('cancers', 'Disease', (162, 169))	('homozygous deletions', 'Var', (74, 94))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('inactivated', 'NegReg', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('aberrant methylation', 'Var', (126, 146))	('tumor', 'Disease', (12, 17))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('point mutations', 'Var', (57, 72))
944691	26251921	Methylation of CpG sites within the promoter region is often associated with silenced gene expression; within tumor suppressor loci this can engender tumorigenesis.	('silenced gene expression', 'MPA', (77, 101))	('Methylation', 'Var', (0, 11))	('engender', 'Reg', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('associated', 'Reg', (61, 71))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
944694	26251921	Loss of GALR1 expression is related to hypermethylation of key CpG sites within transcription factor binding domains.	('GALR1', 'Gene', '2587', (8, 13))	('Loss', 'NegReg', (0, 4))	('expression', 'MPA', (14, 24))	('hypermethylation', 'Var', (39, 55))	('GALR1', 'Gene', (8, 13))
944697	26251921	The experiments using clinical HNSCC samples demonstrated that GALR1 methylation was significantly correlated with reduced survival rates, tumor stage, lymph node status, increased tumor size, cyclin D1 expression and p16 methylation.	('reduced', 'NegReg', (115, 122))	('cyclin D1', 'Gene', (193, 202))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('increased', 'PosReg', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('GALR1', 'Gene', (63, 68))	('p16', 'Gene', (218, 221))	('cyclin D1', 'Gene', '595', (193, 202))	('p16', 'Gene', '1029', (218, 221))	('methylation', 'Var', (69, 80))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('lymph node status', 'CPA', (152, 169))	('survival rates', 'CPA', (123, 137))	('tumor', 'Disease', (181, 186))	('HNSCC', 'Phenotype', 'HP:0012288', (31, 36))	('expression', 'MPA', (203, 213))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('GALR1', 'Gene', '2587', (63, 68))
944698	26251921	In multivariate analysis, taking into account age, tumor site, smoking, tumor stage, and cyclin D1 expression, only GALR1 methylation and stage were significant predictors of poor survival.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (72, 77))	('methylation', 'Var', (122, 133))	('tumor', 'Disease', (51, 56))	('GALR1', 'Gene', '2587', (116, 121))	('cyclin D1', 'Gene', '595', (89, 98))	('cyclin D1', 'Gene', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('GALR1', 'Gene', (116, 121))
944701	26251921	Indeed, Kaplan-Meier plots showed that galanin methylation in clinical tumor samples was significantly related to reduced disease-free survival (DFS; Figure 3A).	('disease-free survival', 'CPA', (122, 143))	('galanin', 'Gene', '51083', (39, 46))	('reduced', 'NegReg', (114, 121))	('methylation', 'Var', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('galanin', 'Gene', (39, 46))	('tumor', 'Disease', (71, 76))
944702	26251921	Patients with GALR1 methylation also had a significantly reduced DFS (Figure 3B).	('GALR1', 'Gene', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('methylation', 'Var', (20, 31))	('DFS', 'MPA', (65, 68))	('reduced', 'NegReg', (57, 64))	('GALR1', 'Gene', '2587', (14, 19))
944703	26251921	Furthermore, methylation of both galanin and GALR1 was associated with a DFS rate of 0%, in comparison to 58.5% in the absence of methylation of both (Figure 3C).	('GALR1', 'Gene', '2587', (45, 50))	('galanin', 'Gene', '51083', (33, 40))	('methylation', 'Var', (13, 24))	('GALR1', 'Gene', (45, 50))	('galanin', 'Gene', (33, 40))	('DFS', 'MPA', (73, 76))
944704	26251921	Methylation of either galanin or GALR1 was related to a DFS rate of 24.4%, in comparison to 58.5% in the absence of methylation of either (Figure 3D).	('GALR1', 'Gene', '2587', (33, 38))	('galanin', 'Gene', '51083', (22, 29))	('Methylation', 'Var', (0, 11))	('GALR1', 'Gene', (33, 38))	('galanin', 'Gene', (22, 29))	('DFS', 'MPA', (56, 59))
944705	26251921	The adjusted odds ratio for recurrence when galanin was methylated in the primary tumor was 8.95 (p = 0.002), and when both galanin and GALR1 were methylated was 23.84.	('GALR1', 'Gene', (136, 141))	('galanin', 'Gene', (124, 131))	('galanin', 'Gene', '51083', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('methylated', 'Var', (56, 66))	('GALR1', 'Gene', '2587', (136, 141))	('galanin', 'Gene', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('galanin', 'Gene', '51083', (124, 131))
944718	26251921	While some studies have shown GALR2 to be proproliferative, others indicate that reintroduction of GALR2 into tumor cell lines established from pheochromocytoma, neuroblastoma and HNSCC are susceptible to galanin-mediated apoptosis and/or growth inhibition.	('GALR2', 'Gene', '8811', (99, 104))	('galanin', 'Gene', '51083', (205, 212))	('neuroblastoma', 'Disease', (162, 175))	('susceptible', 'Reg', (190, 201))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('HNSCC', 'Phenotype', 'HP:0012288', (180, 185))	('galanin', 'Gene', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('neuroblastoma', 'Phenotype', 'HP:0003006', (162, 175))	('reintroduction', 'Var', (81, 95))	('pheochromocytoma', 'Disease', (144, 160))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (144, 160))	('GALR2', 'Gene', (30, 35))	('GALR2', 'Gene', '8811', (30, 35))	('GALR2', 'Gene', (99, 104))	('neuroblastoma', 'Disease', 'MESH:D009447', (162, 175))	('pheochromocytoma', 'Disease', 'MESH:D010673', (144, 160))
944719	26251921	Using cells stably overexpressing GALR2 we also showed that GALR2 has both antiproliferative (Figure 4A,B) and proapoptotic effects (Figure 4C) in p53 mutant HNSCC cells.	('GALR2', 'Gene', (34, 39))	('mutant', 'Var', (151, 157))	('GALR2', 'Gene', '8811', (34, 39))	('proapoptotic effects', 'CPA', (111, 131))	('p53', 'Gene', '7157', (147, 150))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))	('GALR2', 'Gene', (60, 65))	('antiproliferative', 'CPA', (75, 92))	('GALR2', 'Gene', '8811', (60, 65))	('p53', 'Gene', (147, 150))
944743	26251921	reported that GALR2 hypermethylation indicated a specificity of 95% and sensitivity of 85% in colon cancer from normal tissue, and is also a candidate biomarker for both colon and breast cancer.	('GALR2', 'Gene', (14, 19))	('hypermethylation', 'Var', (20, 36))	('GALR2', 'Gene', '8811', (14, 19))	('colon and breast cancer', 'Disease', 'MESH:D001943', (170, 193))	('colon cancer', 'Disease', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
944745	26251921	Furthermore, colorectal cancer patients with GALR2 hypermethylation were more responsive to bevacizumab and cetuximab treatment.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('hypermethylation', 'Var', (51, 67))	('GALR2', 'Gene', (45, 50))	('cetuximab', 'Chemical', 'MESH:D000068818', (108, 117))	('colorectal cancer', 'Disease', (13, 30))	('GALR2', 'Gene', '8811', (45, 50))	('bevacizumab', 'Chemical', 'MESH:D000068258', (92, 103))	('more', 'PosReg', (73, 77))	('responsive', 'MPA', (78, 88))	('patients', 'Species', '9606', (31, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
944752	26251921	In analysis using 100 DNA samples from untreated primary HNSCC tumors, the promoter of GALR2 was methylated in 31.1% of cases and unmethylated in 69%.	('GALR2', 'Gene', '8811', (87, 92))	('GALR2', 'Gene', (87, 92))	('HNSCC tumors', 'Disease', (57, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (57, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('methylated', 'Var', (97, 107))
944755	26251921	Eleven percent of the samples from HNSCC tumors were hypermethylated on all three genes of Galanin, GALR1 and GALR2, 19% of those tumors were hypermethylated two of three genes, 22% were hypermethylated only a single gene, and 48% were did not methylate any gene.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('hypermethylated', 'Var', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('GALR2', 'Gene', (110, 115))	('Galanin', 'Gene', (91, 98))	('Galanin', 'Gene', '51083', (91, 98))	('tumors', 'Disease', (41, 47))	('GALR1', 'Gene', (100, 105))	('GALR2', 'Gene', '8811', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('HNSCC tumors', 'Disease', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (35, 47))	('GALR1', 'Gene', '2587', (100, 105))
944756	26251921	We have also observed that GALR2 promoter methylation is related to significant decrease in DFS by a statistical analysis (Figure 6A).	('GALR2', 'Gene', (27, 32))	('DFS', 'MPA', (92, 95))	('GALR2', 'Gene', '8811', (27, 32))	('methylation', 'Var', (42, 53))	('decrease', 'NegReg', (80, 88))
944757	26251921	Methylation of both Galanin and GALR2 was related to a DFS rate of 12.5%, as compared with 61.6% in no methylation of these all genes (Figure 6B).	('Galanin', 'Gene', '51083', (20, 27))	('Methylation', 'Var', (0, 11))	('DFS', 'Disease', (55, 58))	('GALR2', 'Gene', '8811', (32, 37))	('GALR2', 'Gene', (32, 37))	('Galanin', 'Gene', (20, 27))
944758	26251921	If GALR2, GALR1, or Galanin were methylated, the DFS rate was 28.3%; this contrasts with a DFS of 61.6% in no methylation of these all genes (Figure 6C).	('GALR2', 'Gene', (3, 8))	('Galanin', 'Gene', '51083', (20, 27))	('GALR2', 'Gene', '8811', (3, 8))	('GALR1', 'Gene', (10, 15))	('GALR1', 'Gene', '2587', (10, 15))	('Galanin', 'Gene', (20, 27))	('methylated', 'Var', (33, 43))
944760	26251921	In a multivariate logistic regression analysis that accounted for sex, age, stage grouping, alcohol intake, smoking status, and methylated genes, the methylation of GALR2 in the primary tumor was related to an adjusted odds ratio for recurrence of 3.12.	('related to', 'Reg', (196, 206))	('GALR2', 'Gene', '8811', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('methylation', 'Var', (150, 161))	('alcohol', 'Chemical', 'MESH:D000438', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('recurrence', 'CPA', (234, 244))	('GALR2', 'Gene', (165, 170))
944761	26251921	Both Galanin and GALR2 methylated patients had a significantly higher odds ratio (9.05) for recurrence, compared with those patients in whom neither gene was methylated.	('GALR2', 'Gene', (17, 22))	('methylated', 'Var', (23, 33))	('recurrence', 'CPA', (92, 102))	('GALR2', 'Gene', '8811', (17, 22))	('Galanin', 'Gene', (5, 12))	('Galanin', 'Gene', '51083', (5, 12))	('patients', 'Species', '9606', (34, 42))	('higher', 'PosReg', (63, 69))	('patients', 'Species', '9606', (124, 132))
944762	26251921	Thus, GALR2 methylation is an independent biomarker in HNSCC, and GALR2 methylated patients exhibited a high odds ratio for recurrence.	('GALR2', 'Gene', '8811', (6, 11))	('GALR2', 'Gene', (6, 11))	('GALR2', 'Gene', (66, 71))	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('HNSCC', 'Disease', (55, 60))	('GALR2', 'Gene', '8811', (66, 71))	('methylated', 'Var', (72, 82))	('patients', 'Species', '9606', (83, 91))	('methylation', 'Var', (12, 23))
944777	26251921	Hypermethylation of TAC1 was reported in esophageal cancer, colon cancer, and breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('TAC1', 'Gene', '6863', (20, 24))	('colon cancer', 'Phenotype', 'HP:0003003', (60, 72))	('colon cancer', 'Disease', 'MESH:D015179', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (41, 58))	('TAC1', 'Gene', (20, 24))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colon cancer', 'Disease', (60, 72))	('reported', 'Reg', (29, 37))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))	('esophageal cancer', 'Disease', (41, 58))
944778	26251921	Overall patient survival is related to TAC1 methylation status in squamous cell carcinoma, but not in esophageal adenocarcinoma of the esophagus.	('TAC1', 'Gene', (39, 43))	('squamous cell carcinoma', 'Disease', (66, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 89))	('esophageal adenocarcinoma of the esophagus', 'Disease', (102, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('patient', 'Species', '9606', (8, 15))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))	('esophageal adenocarcinoma of the esophagus', 'Disease', 'MESH:C562730', (102, 144))	('methylation status', 'Var', (44, 62))	('TAC1', 'Gene', '6863', (39, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
944783	26251921	The cutoff NMVs for TAC1 (0.108) and TACR1 (0.008) were determined by the ROC curves for >95% specificity and high sensitivity.	('TACR1', 'Gene', (37, 42))	('TAC1', 'Gene', '6863', (20, 24))	('TACR1', 'Gene', '6869', (37, 42))	('TAC1', 'Gene', (20, 24))	('0.108', 'Var', (26, 31))
944785	26251921	TAC1 promoter methylation was significantly related to recurrence events, p16 methylation, E-cadherin methylation, and galanin methylation.	('p16', 'Gene', (74, 77))	('TAC1', 'Gene', '6863', (0, 4))	('methylation', 'Var', (78, 89))	('related', 'Reg', (44, 51))	('galanin', 'Gene', '51083', (119, 126))	('E-cadherin', 'Gene', (91, 101))	('E-cadherin', 'Gene', '999', (91, 101))	('TAC1', 'Gene', (0, 4))	('recurrence events', 'Disease', (55, 72))	('p16', 'Gene', '1029', (74, 77))	('galanin', 'Gene', (119, 126))	('promoter', 'MPA', (5, 13))
944788	26251921	Among patients with stage III and IV HNSCC, the 5-year DFS rate in the group of patients with TACR1 methylation was 31.4%, as compared with 56.7% in the group with nonmethylated TAC1.	('TACR1', 'Gene', '6869', (94, 99))	('patients', 'Species', '9606', (80, 88))	('TAC1', 'Gene', '6863', (178, 182))	('TAC1', 'Gene', (178, 182))	('HNSCC', 'Phenotype', 'HP:0012288', (37, 42))	('methylation', 'Var', (100, 111))	('DFS', 'Disease', (55, 58))	('patients', 'Species', '9606', (6, 14))	('TACR1', 'Gene', (94, 99))
944789	26251921	Both TAC1 and TACR1 methylation was associated with a DFS rate of 9.8% versus 54.9% in neither methylation of them.	('TAC1', 'Gene', (5, 9))	('DFS', 'Disease', (54, 57))	('TACR1', 'Gene', (14, 19))	('TAC1', 'Gene', '6863', (5, 9))	('methylation', 'Var', (20, 31))	('TACR1', 'Gene', '6869', (14, 19))
944792	26251921	Multivariate logistic-regression analysis revealed the estimated odds of recurrence related to methylation of TAC1 and TACR1.	('TAC1', 'Gene', '6863', (110, 114))	('methylation', 'Var', (95, 106))	('TACR1', 'Gene', (119, 124))	('TACR1', 'Gene', '6869', (119, 124))	('TAC1', 'Gene', (110, 114))
944793	26251921	When TAC1 methylation was observed in primary tumors, the adjusted odds ratio for recurrence was 3.35.	('TAC1', 'Gene', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('TAC1', 'Gene', '6863', (5, 9))	('methylation', 'Var', (10, 21))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
944794	26251921	Patients with both TAC1 and TACR1 methylation had a significantly higher an adjusted odds ratio for recurrence, which was 5.09.	('TAC1', 'Gene', (19, 23))	('methylation', 'Var', (34, 45))	('Patients', 'Species', '9606', (0, 8))	('TACR1', 'Gene', (28, 33))	('TAC1', 'Gene', '6863', (19, 23))	('higher', 'PosReg', (66, 72))	('TACR1', 'Gene', '6869', (28, 33))
944798	26251921	Hypermethylation of SST has been described in renal cancer, colon cancer, esophageal cancer, and gastric cancer, but it remains to be explored in HNSCC.	('gastric cancer', 'Disease', (97, 111))	('HNSCC', 'Phenotype', 'HP:0012288', (146, 151))	('colon cancer', 'Disease', 'MESH:D015179', (60, 72))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('renal cancer', 'Disease', 'MESH:D007680', (46, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('colon cancer', 'Disease', (60, 72))	('esophageal cancer', 'Disease', (74, 91))	('SST', 'Gene', (20, 23))	('described', 'Reg', (33, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colon cancer', 'Phenotype', 'HP:0003003', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('renal cancer', 'Disease', (46, 58))	('SST', 'Gene', '6750', (20, 23))	('renal cancer', 'Phenotype', 'HP:0009726', (46, 58))
944803	26251921	Methylation of SST was significantly related to several clinicopathologic factors, including tumor size, stage, DAPK methylation, TAC1 methylation, and GALR2 methylation.	('methylation', 'Var', (135, 146))	('DAPK', 'Gene', (112, 116))	('DAPK', 'Gene', '1612', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TAC1', 'Gene', (130, 134))	('TAC1', 'Gene', '6863', (130, 134))	('Methylation', 'Var', (0, 11))	('GALR2', 'Gene', (152, 157))	('related', 'Reg', (37, 44))	('tumor', 'Disease', (93, 98))	('SST', 'Gene', '6750', (15, 18))	('GALR2', 'Gene', '8811', (152, 157))	('SST', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
944804	26251921	SSTR1 methylation was significantly correlated with tumor size, stage, and methylation of galanin, GALR2, TAC1, TAC1R, H-cadherin, MGMT, DAPK, and DCC methylation.	('tumor', 'Disease', (52, 57))	('TAC1', 'Gene', (106, 110))	('correlated', 'Reg', (36, 46))	('methylation', 'MPA', (75, 86))	('SSTR1', 'Gene', (0, 5))	('SSTR1', 'Gene', '6751', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('galanin', 'Gene', '51083', (90, 97))	('DAPK', 'Gene', (137, 141))	('TAC1', 'Gene', (112, 116))	('galanin', 'Gene', (90, 97))	('MGMT', 'Gene', (131, 135))	('methylation', 'Var', (6, 17))	('TAC1', 'Gene', '6863', (106, 110))	('TAC1R', 'Gene', '6869', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('GALR2', 'Gene', '8811', (99, 104))	('DAPK', 'Gene', '1612', (137, 141))	('TAC1R', 'Gene', (112, 117))	('TAC1', 'Gene', '6863', (112, 116))	('MGMT', 'Gene', '4255', (131, 135))	('H-cadherin', 'Protein', (119, 129))	('GALR2', 'Gene', (99, 104))
944806	26251921	SST and SSTR1 methylation was not associated with an altered DFS rate when compared with lower methylation levels.	('SST', 'Gene', '6750', (8, 11))	('SST', 'Gene', (0, 3))	('DFS', 'MPA', (61, 64))	('SSTR1', 'Gene', (8, 13))	('SSTR1', 'Gene', '6751', (8, 13))	('methylation', 'Var', (14, 25))	('SST', 'Gene', (8, 11))	('SST', 'Gene', '6750', (0, 3))
944807	26251921	When only patients with oral cavity and oropharynx cancer were analyzed, the DFS rate of patients with both SST and SSTR1 methylation was 48.1%, and that of the other (unmethylated) group was 81.4%.	('SST', 'Gene', '6750', (108, 111))	('DFS', 'MPA', (77, 80))	('SST', 'Gene', (116, 119))	('methylation', 'Var', (122, 133))	('SST', 'Gene', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('patients', 'Species', '9606', (89, 97))	('SST', 'Gene', '6750', (116, 119))	('SSTR1', 'Gene', (116, 121))	('SSTR1', 'Gene', '6751', (116, 121))	('patients', 'Species', '9606', (10, 18))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
944808	26251921	Either SST methylation or SSTR1 methylation elevated the odds of recurrence, but not significantly in multivariate logistic-regression analysis.	('methylation', 'Var', (32, 43))	('recurrence', 'Disease', (65, 75))	('elevated', 'PosReg', (44, 52))	('SST', 'Gene', (7, 10))	('SST', 'Gene', '6750', (26, 29))	('methylation', 'Var', (11, 22))	('SSTR1', 'Gene', (26, 31))	('SST', 'Gene', '6750', (7, 10))	('SSTR1', 'Gene', '6751', (26, 31))	('SST', 'Gene', (26, 29))
944810	26251921	The DFS of patients with both SSTR1 and TAC1 methylation was significantly higher than that of patients without methylation.	('patients', 'Species', '9606', (95, 103))	('higher', 'PosReg', (75, 81))	('DFS', 'MPA', (4, 7))	('TAC1', 'Gene', '6863', (40, 44))	('methylation', 'Var', (45, 56))	('SSTR1', 'Gene', (30, 35))	('SSTR1', 'Gene', '6751', (30, 35))	('patients', 'Species', '9606', (11, 19))	('TAC1', 'Gene', (40, 44))
944811	26251921	Methylation of both galanin and SSTR1 was associated with lower DFS rate than the absence of methylation (0% versus 59.0%, respectively).	('DFS rate', 'MPA', (64, 72))	('galanin', 'Gene', (20, 27))	('lower', 'NegReg', (58, 63))	('Methylation', 'Var', (0, 11))	('SSTR1', 'Gene', (32, 37))	('galanin', 'Gene', '51083', (20, 27))	('SSTR1', 'Gene', '6751', (32, 37))
944812	26251921	Patients in whom GALR2 and SSTR1 were methylated survived significantly shorter than those in which both genes were not methylated.	('GALR2', 'Gene', (17, 22))	('SSTR1', 'Gene', (27, 32))	('SSTR1', 'Gene', '6751', (27, 32))	('GALR2', 'Gene', '8811', (17, 22))	('shorter', 'NegReg', (72, 79))	('methylated', 'Var', (38, 48))	('Patients', 'Species', '9606', (0, 8))
944813	26251921	The DFS of the patients with both SSTR1 and GALR1 methylation was significantly higher than that of patients without methylation of these genes.	('GALR1', 'Gene', (44, 49))	('SSTR1', 'Gene', '6751', (34, 39))	('patients', 'Species', '9606', (15, 23))	('DFS', 'MPA', (4, 7))	('GALR1', 'Gene', '2587', (44, 49))	('patients', 'Species', '9606', (100, 108))	('SSTR1', 'Gene', (34, 39))	('higher', 'PosReg', (80, 86))	('methylation', 'Var', (50, 61))
944814	26251921	Together, these data indicate that SST and SSTR1 gene inactivation via CpG hypermethylation plays a role during HNSCC tumorigenesis, and that this methylation level may serve as a significant biomarker.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('SST', 'Gene', '6750', (43, 46))	('SST', 'Gene', (35, 38))	('HNSCC', 'Disease', (112, 117))	('tumor', 'Disease', (118, 123))	('SSTR1', 'Gene', (43, 48))	('inactivation', 'NegReg', (54, 66))	('SSTR1', 'Gene', '6751', (43, 48))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('SST', 'Gene', '6750', (35, 38))	('hypermethylation', 'Var', (75, 91))	('SST', 'Gene', (43, 46))
944824	26251921	High HPV titer is significantly related to high p16 expression, and it was significantly associated with the desirable response to CRT, IC, and OS.	('associated with', 'Reg', (89, 104))	('p16', 'Gene', '1029', (48, 51))	('high', 'Var', (43, 47))	('p16', 'Gene', (48, 51))	('HPV', 'Species', '10566', (5, 8))
944827	26251921	In the multivariate analysis, GALR1 methylation and stage were significant predictors of poor survival.	('GALR1', 'Gene', (30, 35))	('GALR1', 'Gene', '2587', (30, 35))	('methylation', 'Var', (36, 47))
944828	26251921	Patients with hypermethylated GALR1 had a significantly reduced DFS.	('GALR1', 'Gene', (30, 35))	('DFS', 'MPA', (64, 67))	('reduced', 'NegReg', (56, 63))	('Patients', 'Species', '9606', (0, 8))	('GALR1', 'Gene', '2587', (30, 35))	('hypermethylated', 'Var', (14, 29))
944829	26251921	Both galanin and GALR1 methylation was associated with a DFS rate of 0%, in comparison to 58.5% in no methylation of these genes.	('methylation', 'Var', (23, 34))	('GALR1', 'Gene', (17, 22))	('galanin', 'Gene', '51083', (5, 12))	('galanin', 'Gene', (5, 12))	('GALR1', 'Gene', '2587', (17, 22))
944830	26251921	We found that methylation of GALR2 promoter was also related to significant decrease in DFS.	('DFS', 'MPA', (88, 91))	('GALR2', 'Gene', (29, 34))	('methylation', 'Var', (14, 25))	('GALR2', 'Gene', '8811', (29, 34))	('decrease', 'NegReg', (76, 84))
944831	26251921	Both galanin and GALR2 methylation was related to a DFS rate of 12.5%, as compared with 61.6% in no methylation of these genes.	('GALR2', 'Gene', (17, 22))	('GALR2', 'Gene', '8811', (17, 22))	('methylation', 'Var', (23, 34))	('galanin', 'Gene', '51083', (5, 12))	('galanin', 'Gene', (5, 12))	('DFS', 'Disease', (52, 55))
944833	26251921	TAC1 methylation in HNSCCs significantly correlated with methylation of p16, E-cadherin, galanin, and reduced DFS.	('TAC1', 'Gene', '6863', (0, 4))	('methylation', 'Var', (5, 16))	('p16', 'Gene', '1029', (72, 75))	('HNSCC', 'Phenotype', 'HP:0012288', (20, 25))	('E-cadherin', 'Gene', (77, 87))	('galanin', 'Gene', '51083', (89, 96))	('E-cadherin', 'Gene', '999', (77, 87))	('TAC1', 'Gene', (0, 4))	('methylation', 'MPA', (57, 68))	('galanin', 'Gene', (89, 96))	('p16', 'Gene', (72, 75))	('DFS', 'MPA', (110, 113))	('reduced', 'NegReg', (102, 109))	('correlated', 'Reg', (41, 51))
944834	26251921	TAC1 hypermethylated patients in Stage III and IV had significantly shorter survivals than patients without TAC1 methylation.	('TAC1', 'Gene', '6863', (0, 4))	('patients', 'Species', '9606', (91, 99))	('survivals', 'MPA', (76, 85))	('TAC1', 'Gene', '6863', (108, 112))	('hypermethylated', 'Var', (5, 20))	('TAC1', 'Gene', (0, 4))	('patients', 'Species', '9606', (21, 29))	('TAC1', 'Gene', (108, 112))	('shorter', 'NegReg', (68, 75))
944835	26251921	In multivariate logistic-regression analysis, methylation of either the TAC1/TACR1 gene pair or of TAC1 was related to an odds ratio for recurrence of 3.35 and 5.09, respectively.	('methylation', 'Var', (46, 57))	('TAC1', 'Gene', (99, 103))	('TACR1', 'Gene', (77, 82))	('TAC1', 'Gene', '6863', (72, 76))	('TACR1', 'Gene', '6869', (77, 82))	('TAC1', 'Gene', (72, 76))	('related', 'Reg', (108, 115))	('TAC1', 'Gene', '6863', (99, 103))
944836	26251921	Methylation of each specific GPCR is associated with its own discrete value as a prognostic factor.	('Methylation', 'Var', (0, 11))	('GPCR', 'Gene', '441931', (29, 33))	('GPCR', 'Gene', (29, 33))
944839	26251921	As the number of methylated genes in a given tumor sample increases, so does the predictive power related to both prognosis and/or the success of various treatment regimens.	('methylated genes', 'Var', (17, 33))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))
944853	26251921	Ligands inhibiting CXCR4 such as AMD070, AMD3100, AMD3465, BKT140, CTCE-9908, FC131, MSX-122, plerixafor, RCP168, TN14003, T22, and T140 are being evaluated for their efficacy in prevention of metastasis.	('BKT140', 'Gene', (59, 65))	('CXCR4', 'Gene', (19, 24))	('CTCE', 'Chemical', '-', (67, 71))	('AMD3100', 'Var', (41, 48))	('MSX-122', 'Chemical', 'MESH:C573792', (85, 92))	('AMD070', 'Var', (33, 39))	('inhibiting', 'NegReg', (8, 18))	('AMD3465', 'Var', (50, 57))	('CXCR4', 'Gene', '7852', (19, 24))
944858	26251921	It was already reported that humanized antibodies to CXCL8/IL-8 were shown to inhibit melanoma tumor growth, angiogenesis, and metastasis.	('melanoma tumor', 'Disease', 'MESH:D008545', (86, 100))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('IL-8', 'Gene', '3576', (59, 63))	('angiogenesis', 'CPA', (109, 121))	('inhibit', 'NegReg', (78, 85))	('CXCL8', 'Gene', '3576', (53, 58))	('IL-8', 'Gene', (59, 63))	('human', 'Species', '9606', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CXCL8', 'Gene', (53, 58))	('antibodies', 'Var', (39, 49))	('metastasis', 'CPA', (127, 137))	('melanoma tumor', 'Disease', (86, 100))
944916	20392477	In these diseases, mutations that represent intrinsic defects in eosinophils cause eosinophil proliferation and tissue infiltration including the skin.	('eosin', 'Chemical', 'MESH:D004801', (83, 88))	('eosinophil proliferation', 'CPA', (83, 107))	('tissue infiltration', 'CPA', (112, 131))	('cause', 'Reg', (77, 82))	('mutations', 'Var', (19, 28))	('eosin', 'Chemical', 'MESH:D004801', (65, 70))
944919	20392477	Clonal eosinophilia is often associated with rearrangements involving the genes of the platelet-derived growth factors A and B (PDGFRA, PDGFRB) resulting in increased tyrosine kinase activity.	('increased tyrosine kinase', 'Phenotype', 'HP:0003231', (157, 182))	('Clonal eosinophilia', 'Phenotype', 'HP:0032151', (0, 19))	('Clonal eosinophilia', 'Disease', 'MESH:C580365', (0, 19))	('Clonal eosinophilia', 'Disease', (0, 19))	('rearrangements', 'Var', (45, 59))	('PDGFRA', 'Gene', '5156', (128, 134))	('platelet-derived growth factors A and B', 'Gene', '5156', (87, 126))	('PDGFRA', 'Gene', (128, 134))	('increased', 'PosReg', (157, 166))	('PDGFRB', 'Gene', '5159', (136, 142))	('associated', 'Reg', (29, 39))	('tyrosine kinase activity', 'MPA', (167, 191))	('eosinophilia', 'Phenotype', 'HP:0001880', (7, 19))	('PDGFRB', 'Gene', (136, 142))
944920	20392477	Notably, patients with HES due to the fusion of the PFGFRA and FIP1L1 genes respond to imatinib therapy.	('patients', 'Species', '9606', (9, 17))	('HES', 'Disease', (23, 26))	('imatinib', 'Chemical', 'MESH:D000068877', (87, 95))	('fusion', 'Var', (38, 44))	('FIP1L1', 'Gene', '81608', (63, 69))	('PFGFRA', 'Gene', (52, 58))	('FIP1L1', 'Gene', (63, 69))	('respond', 'Reg', (76, 83))
944960	20392477	IL-5 as well as eotaxin are abundant in blister fluids and the production of IL-5 is associated with blood eosinophilia and significant eosinophil infiltration in the skin of BP patients.	('eotaxin', 'Gene', '6356', (16, 23))	('eosinophil infiltration', 'Phenotype', 'HP:0001880', (136, 159))	('eosin', 'Chemical', 'MESH:D004801', (107, 112))	('eotaxin', 'Gene', (16, 23))	('blood eosinophilia', 'Disease', 'MESH:D004802', (101, 119))	('patients', 'Species', '9606', (178, 186))	('eosin', 'Chemical', 'MESH:D004801', (136, 141))	('eosinophil infiltration in the skin', 'Phenotype', 'HP:0032022', (136, 171))	('eosinophilia', 'Phenotype', 'HP:0001880', (107, 119))	('blood eosinophilia', 'Disease', (101, 119))	('production', 'Var', (63, 73))	('eosinophil infiltration', 'CPA', (136, 159))	('IL-5', 'Gene', (77, 81))	('associated', 'Reg', (85, 95))	('blister', 'Phenotype', 'HP:0008066;HP:0200037', (40, 47))
944962	20392477	In dermatitis herpetiformis, a specific cutaneous manifestation of gluten-sensitive enteropathy due to anti-tissue transglutaminase antibodies, a neutrophilic infiltrate undermingled with eosinophils is found in the papillary dermis.	('dermatitis herpetiformis', 'Disease', 'MESH:D003874', (3, 27))	('dermatitis', 'Phenotype', 'HP:0011123', (3, 13))	('enteropathy', 'Phenotype', 'HP:0002242', (84, 95))	('eosin', 'Chemical', 'MESH:D004801', (188, 193))	('due', 'Reg', (96, 99))	('enteropathy', 'Disease', (84, 95))	('anti-tissue', 'Var', (103, 114))	('enteropathy', 'Disease', 'MESH:C538273', (84, 95))	('dermatitis herpetiformis', 'Disease', (3, 27))
944981	20392477	Monoclonal antibodies against IL-5 have provided insight into the potential role of eosinophils in asthma.	('Monoclonal', 'Var', (0, 10))	('IL-5', 'Gene', (30, 34))	('asthma', 'Phenotype', 'HP:0002099', (99, 105))	('eosin', 'Chemical', 'MESH:D004801', (84, 89))	('asthma', 'Disease', 'MESH:D001249', (99, 105))	('asthma', 'Disease', (99, 105))
944987	20392477	There was about a 50% reduction in severe exacerbations (SE) in the 750 mg group, but the study was not powered to look at exacerbations and this did not quite reach significance p<0.061).	('750 mg', 'Var', (68, 74))	('SE', 'Disease', 'None', (57, 59))	('severe exacerbations', 'MPA', (35, 55))	('reduction', 'NegReg', (22, 31))
944989	20392477	Another caveat to the conclusion that eosinophils are not causal in asthma pathophysiology is that while mepolizumab was very good at reducing blood and sputum eosinophils it only had a modest (50%) reduction in bronchial wall eosinophils.	('eosin', 'Chemical', 'MESH:D004801', (38, 43))	('bronchial wall eosinophils', 'MPA', (212, 238))	('asthma', 'Disease', (68, 74))	('reducing', 'NegReg', (134, 142))	('sputum eosinophils', 'Phenotype', 'HP:0032017', (153, 171))	('asthma', 'Phenotype', 'HP:0002099', (68, 74))	('asthma', 'Disease', 'MESH:D001249', (68, 74))	('mepolizumab', 'Chemical', 'MESH:C434107', (105, 116))	('eosin', 'Chemical', 'MESH:D004801', (160, 165))	('reduction', 'NegReg', (199, 208))	('mepolizumab', 'Var', (105, 116))	('eosin', 'Chemical', 'MESH:D004801', (227, 232))
945081	20392477	Notably, overexpression of IL-5 induces EE and neutralization of IL-5 completely blocks allergen or IL-13-induced EE in mice.	('overexpression', 'PosReg', (9, 23))	('mice', 'Species', '10090', (120, 124))	('blocks', 'NegReg', (81, 87))	('neutralization', 'Var', (47, 61))	('IL-5', 'Gene', (27, 31))	('IL-5', 'Gene', (65, 69))
945083	20392477	Notably, dysregulated expression of ~1% of the human genome led to the identification of an EE genetic signature.	('human', 'Species', '9606', (47, 52))	('expression', 'MPA', (22, 32))	('dysregulated', 'Var', (9, 21))
945085	20392477	Furthermore, a single nucleotide polymorphism (SNP) in the eotaxin-3 was overrepresented in EE patients compared with control individuals.	('eotaxin-3', 'Gene', '10344', (59, 68))	('patients', 'Species', '9606', (95, 103))	('eotaxin-3', 'Gene', (59, 68))	('overrepresented', 'PosReg', (73, 88))	('single nucleotide polymorphism', 'Var', (15, 45))
945086	20392477	Interestingly, mice with a genetic ablation of the eotaxin receptor (CCR3) were protected from the development of experimental EE.	('CCR3', 'Gene', '12771', (69, 73))	('eotaxin', 'Gene', '6356', (51, 58))	('genetic ablation', 'Var', (27, 43))	('CCR3', 'Gene', (69, 73))	('mice', 'Species', '10090', (15, 19))	('eotaxin', 'Gene', (51, 58))
945100	20392477	A recent study also showed the promising effect of anti-human-IL-13 antibody in an animal model of IL-13-induced airway and esophageal eosinophilia.	('anti-human-IL-13', 'Var', (51, 67))	('human', 'Species', '9606', (56, 61))	('esophageal eosinophilia', 'Disease', (124, 147))	('eosinophilia', 'Phenotype', 'HP:0001880', (135, 147))	('esophageal eosinophilia', 'Disease', 'MESH:D004802', (124, 147))
945176	33562270	We have also used patient's autoantibodies to demonstrate that changes in EC glycosylation could generate cancer glyconeoantigens, reinforcing the enormous potential of glycoproteomics for biomarker discovery.	('generate', 'Reg', (97, 105))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('EC glycosylation', 'MPA', (74, 90))	('patient', 'Species', '9606', (18, 25))	('changes', 'Var', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
945183	33562270	Namely, these tumors often overexpress sialyl-Tn (STn), which results from a premature stop in O-glycans elongation by sialylation of the Tn antigen.	('sialylation', 'Var', (119, 130))	('O-glycans', 'Chemical', '-', (95, 104))	('Tn', 'Chemical', 'MESH:C009497', (51, 53))	('overexpress', 'PosReg', (27, 38))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Tn', 'Chemical', 'MESH:C009497', (138, 140))	('O-glycans', 'Protein', (95, 104))	('sialyl-Tn', 'Var', (39, 48))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('Tn', 'Chemical', 'MESH:C009497', (46, 48))	('stop', 'NegReg', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
945205	33562270	Even though early stage ESCC, which constitutes the bulk of the prospective series, are known to shed modest numbers of cancer cells into hematogenous circulation, we were able to detect STn positive CTCs (DAPI+, STn+, pan-CK-, CD45-) in 20% of the patients (Figure 1B).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Tn', 'Chemical', 'MESH:C009497', (188, 190))	('patients', 'Species', '9606', (249, 257))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('Tn', 'Chemical', 'MESH:C009497', (214, 216))	('DAPI+', 'Var', (206, 211))	('DAPI', 'Chemical', '-', (206, 210))	('CD45-', 'Var', (228, 233))
945218	33562270	According to Figure 2A, Kyse-30 mainly expressed extended core 2 O-glycans (m/z 1021.53, 1195.62, 1382.71, 1470.76) as well as T (m/z 572.31) and sialyl-T antigens (m/z 933.48).	('2 O-glycans', 'Chemical', '-', (63, 74))	('m/z', 'Var', (76, 79))	('sialyl-T antigens', 'Protein', (146, 163))	('extended core 2 O-glycans', 'Protein', (49, 74))
945225	33562270	As shown in Figure 2A, Kyse-30 ST6GALNAC1 KI cells gained the capacity to express the STn, whereas the antigen was not observed in mock cells.	('Kyse-30', 'Var', (23, 30))	('ST6GALNAC1', 'Gene', (31, 41))	('gained', 'PosReg', (51, 57))	('Tn', 'Chemical', 'MESH:C009497', (87, 89))	('ST6GALNAC1', 'Gene', '55808', (31, 41))	('express', 'MPA', (74, 81))	('STn', 'MPA', (86, 89))
945227	33562270	Subsequent functional studies showed that STn overexpression was accompanied by a striking decrease in cell proliferation (55 and 70% in relation to mock and wild type cells; Figure 2C), suggesting that STn expression may contribute to a quasi-quiescent state, which is frequently observed in more aggressive cancer cell phenotypes.	('contribute', 'Reg', (222, 232))	('overexpression', 'PosReg', (46, 60))	('STn', 'Var', (203, 206))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('cell proliferation', 'CPA', (103, 121))	('quasi-quiescent', 'MPA', (238, 253))	('Tn', 'Chemical', 'MESH:C009497', (204, 206))	('aggressive cancer', 'Disease', 'MESH:D009369', (298, 315))	('Tn', 'Chemical', 'MESH:C009497', (43, 45))	('aggressive cancer', 'Disease', (298, 315))	('decrease', 'NegReg', (91, 99))
945228	33562270	Concomitantly, STn-expressing cells significantly increased their invasive capacity in vitro compared to both mock and wild type control cells (Figure 2D), as previously observed for other glycoengineered cancer cell models of different origins (breast, gastric, bladder).	('glycoengineered cancer', 'Disease', (189, 211))	('gastric', 'Disease', (254, 261))	('increased', 'PosReg', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('Tn', 'Chemical', 'MESH:C009497', (16, 18))	('STn-expressing cells', 'Var', (15, 35))	('glycoengineered cancer', 'Disease', 'MESH:D009369', (189, 211))	('invasive capacity in vitro', 'CPA', (66, 92))
945230	33562270	Namely, it is well described that the substitution of elongated glycans by shorter sialylated antigens, such as STn, promotes a profound remodeling of the plasma membrane glycoproteome, triggering important oncogenic signaling pathways involved in cell proliferation.	('oncogenic signaling pathways', 'Pathway', (207, 235))	('elongated glycans', 'Protein', (54, 71))	('substitution', 'Var', (38, 50))	('remodeling', 'MPA', (137, 147))	('promotes', 'PosReg', (117, 125))	('triggering', 'Reg', (186, 196))	('glycans', 'Chemical', 'MESH:D011134', (64, 71))	('Tn', 'Chemical', 'MESH:C009497', (113, 115))
945260	33562270	Although lacking tumor specificity, high GLUT1 levels, characterized by both high extension and high staining intensity, showed a trend association with the presence of metastases and associated with distant recurrence (p = 0.026, Table 4), reinforcing observations from other authors linking this protein to metastasis.	('tumor', 'Disease', (17, 22))	('metastases', 'Disease', (169, 179))	('distant recurrence', 'CPA', (200, 218))	('metastases', 'Disease', 'MESH:D009362', (169, 179))	('associated', 'Reg', (184, 194))	('GLUT1', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('GLUT1', 'Gene', '6513', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('high', 'Var', (36, 40))
945272	33562270	Replacement of extended by shorter glycoforms such as the STn antigen may explain the existence of a lower molecular weight GLUT1 band.	('GLUT1', 'Gene', '6513', (124, 129))	('Tn', 'Chemical', 'MESH:C009497', (59, 61))	('lower', 'NegReg', (101, 106))	('Replacement', 'Var', (0, 11))	('GLUT1', 'Gene', (124, 129))	('men', 'Species', '9606', (7, 10))
945280	33562270	We found that patients with STn negative tumors and expressing low levels of GLUT1 exhibited longer disease-free survival compared to patients with tumors presenting other glycophenotypes (p = 0.027, log-rank; Figure 4D).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('GLUT1', 'Gene', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('GLUT1', 'Gene', '6513', (77, 82))	('low levels', 'Var', (63, 73))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (134, 142))	('Tn', 'Chemical', 'MESH:C009497', (29, 31))	('tumors', 'Disease', (148, 154))	('disease-free survival', 'CPA', (100, 121))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('longer', 'PosReg', (93, 99))	('patients', 'Species', '9606', (14, 22))
945281	33562270	In addition, STn positive tumors with high GLUT1 favored worse patient survival, reinforcing the close link between the GLUT1-STn molecular signatures and cancer aggressiveness.	('GLUT1', 'Gene', (43, 48))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (155, 176))	('GLUT1', 'Gene', (120, 125))	('GLUT1', 'Gene', '6513', (43, 48))	('Tn', 'Chemical', 'MESH:C009497', (127, 129))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('GLUT1', 'Gene', '6513', (120, 125))	('patient survival', 'CPA', (63, 79))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('high', 'Var', (38, 42))	('Tn', 'Chemical', 'MESH:C009497', (14, 16))	('cancer aggressiveness', 'Disease', (155, 176))	('patient', 'Species', '9606', (63, 70))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('aggressiveness', 'Phenotype', 'HP:0000718', (162, 176))	('tumors', 'Disease', (26, 32))	('worse', 'NegReg', (57, 62))
945339	33562270	Endogenous peroxidases were inactivated by 3% hydrogen peroxide (Merck KGaA, Darmstadt, Germany) incubation for 5 min, followed by blockage of unspecific links for 5 min with Protein Block (Leica Biosystems, Wetzlar, Germany).	('blockage', 'Var', (131, 139))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (46, 63))	('inactivated', 'NegReg', (28, 39))	('unspecific links', 'Protein', (143, 159))	('Endogenous peroxidases', 'Enzyme', (0, 22))
945340	33562270	Finally, tissue sections were separately incubated with 0.5 microg/mL monoclonal antibody (moAb) anti-STn (B72.3+CC49; Abcam, Cambridge, UK) and moAb anti-GLUT1 (EPR3915; Abcam, Cambridge, UK) at the dilution of 1:750.	('B72.3+CC49;', 'Var', (107, 118))	('Tn', 'Chemical', 'MESH:C009497', (103, 105))	('EPR3915;', 'Var', (162, 170))	('GLUT1', 'Gene', (155, 160))	('GLUT1', 'Gene', '6513', (155, 160))
945368	33562270	Carbamidomethylcysteine was selected as a fixed modification, while oxidation of methionine (+15.9949 Da) and the presence of the STn antigen (+494.1748 Da) were considered as variable modifications.	('+15.9949 Da', 'Var', (93, 104))	('methionine', 'Chemical', 'MESH:D008715', (81, 91))	('Carbamidomethylcysteine', 'Chemical', 'MESH:C034636', (0, 23))	('Tn', 'Chemical', 'MESH:C009497', (131, 133))	('+494.1748 Da', 'Var', (143, 155))
945372	33562270	High STn expression was associated with increased probability of developing distant metastases, which was supported by the identification of STn in CTCs and reinforced by studies in vitro linking STn to increased cellular invasion.	('High', 'Var', (0, 4))	('Tn', 'Chemical', 'MESH:C009497', (6, 8))	('metastases', 'Disease', (84, 94))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('expression', 'MPA', (9, 19))	('Tn', 'Chemical', 'MESH:C009497', (142, 144))	('STn', 'Gene', (5, 8))	('Tn', 'Chemical', 'MESH:C009497', (197, 199))
945526	30834254	Poor prognosis was observed in patients with high platelet counts, PLR, NLR, and low lymphocyte percentage.	('PLR', 'Disease', (67, 70))	('low', 'Var', (81, 84))	('NLR', 'Disease', (72, 75))	('low lymphocyte percentage', 'Phenotype', 'HP:0001888', (81, 106))	('patients', 'Species', '9606', (31, 39))	('high platelet counts', 'Phenotype', 'HP:0001894', (45, 65))	('high platelet count', 'Phenotype', 'HP:0001894', (45, 64))
945575	30834254	At pretreatment and posttreatment, P values were, respectively, .018 for OS, .035 for TPD, and .012 for TM and .010 for OS, .042 for TPD, and .010 for TM.	('OS', 'Chemical', '-', (73, 75))	('TPD', 'Disease', (86, 89))	('TPD', 'Chemical', '-', (133, 136))	('men', 'Species', '9606', (29, 32))	('TM', 'Chemical', '-', (151, 153))	('.012', 'Var', (95, 99))	('TPD', 'Chemical', '-', (86, 89))	('OS', 'Chemical', '-', (120, 122))	('TM', 'Chemical', '-', (104, 106))	('men', 'Species', '9606', (11, 14))
945602	30834254	High platelet count is related to poor prognosis in various cancers.	('High platelet count', 'Phenotype', 'HP:0001894', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('High', 'Var', (0, 4))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
945619	30834254	A high ALC during CCRT was associated with a high rate of pathologically complete remission for patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('high', 'Var', (2, 6))	('esophageal cancer', 'Disease', (110, 127))	('ALC', 'MPA', (7, 10))	('patients', 'Species', '9606', (96, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))
945624	30834254	reported a meta-analysis on the prognostic role of PLR in esophageal cancer: in a total of 6699 patients from 16 studies (17 cohorts), elevated PLR predicted poorer OS (HR, 1.389) and shorter disease-free survival (HR, 1.404).	('poorer', 'NegReg', (158, 164))	('disease-free survival', 'CPA', (192, 213))	('OS', 'Chemical', '-', (165, 167))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('shorter', 'NegReg', (184, 191))	('patients', 'Species', '9606', (96, 104))	('PLR', 'Var', (144, 147))
945630	30834254	As per a previous study, inflammation may contribute to tumor initiation through genetic mutations, genomic instability, and epigenetic modifications.	('inflammation', 'Disease', (25, 37))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('genomic instability', 'CPA', (100, 119))	('genetic mutations', 'Var', (81, 98))	('tumor', 'Disease', (56, 61))	('contribute', 'Reg', (42, 52))	('epigenetic modifications', 'Var', (125, 149))	('inflammation', 'Disease', 'MESH:D007249', (25, 37))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
945637	27450204	This study is to investigate the role of alcohol dehydrogenase 1B (ADH1B) gene Arg47His polymorphism in esophageal cancer susceptibility.	('Arg47His', 'SUBSTITUTION', 'None', (79, 87))	('ADH1B', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('alcohol dehydrogenase 1B', 'Gene', (41, 65))	('esophageal cancer', 'Disease', (104, 121))	('ADH1B', 'Gene', '125', (67, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))	('Arg47His', 'Var', (79, 87))	('alcohol dehydrogenase 1B', 'Gene', '125', (41, 65))
945639	27450204	Overall, we found that the 47His allele was significant associated with the decreased risk of esophageal cancer when compared with the 47Arg allele in total populations (A vs. G: OR = 0.67, 95 % CI = 0.59-0.76, P < 0.00001).	('47His', 'Var', (27, 32))	('esophageal cancer', 'Disease', (94, 111))	('47His', 'Chemical', '-', (27, 32))	('decreased', 'NegReg', (76, 85))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Arg', 'Chemical', 'MESH:D001120', (137, 140))
945640	27450204	Subgroup analysis by ethnicity showed that ADH1B Arg47His variant was associated with the decreased esophageal cancer risk under all the genetic models (P < 0.00001) among Asians, especially in Chinese and Japanese; while in non-Asians, no significant correlation was detected in any genetic models (P > 0.05).	('ADH1B', 'Gene', (43, 48))	('decreased esophageal cancer', 'Disease', 'MESH:D004938', (90, 117))	('decreased esophageal cancer', 'Disease', (90, 117))	('Arg47His', 'SUBSTITUTION', 'None', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ADH1B', 'Gene', '125', (43, 48))	('Arg47His', 'Var', (49, 57))
945641	27450204	Furthermore, Arg/Arg genotype of ADH1B Arg47His variant combined with drinking, smoking and males appeared to show a high risk in patients with esophageal cancer.	('ADH1B', 'Gene', (33, 38))	('ADH1B', 'Gene', '125', (33, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('risk', 'Reg', (122, 126))	('Arg/Arg', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Arg47His', 'Var', (39, 47))	('patients', 'Species', '9606', (130, 138))	('Arg', 'Chemical', 'MESH:D001120', (39, 42))	('Arg', 'Chemical', 'MESH:D001120', (13, 16))	('Arg47His', 'SUBSTITUTION', 'None', (39, 47))	('Arg', 'Chemical', 'MESH:D001120', (17, 20))	('esophageal cancer', 'Disease', (144, 161))
945642	27450204	Our results suggested that ADH1B gene Arg47His variant was associated with the decreased esophageal cancer risk.	('decreased esophageal cancer', 'Disease', (79, 106))	('decreased esophageal cancer', 'Disease', 'MESH:D004938', (79, 106))	('Arg47His', 'SUBSTITUTION', 'None', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('ADH1B', 'Gene', (27, 32))	('ADH1B', 'Gene', '125', (27, 32))	('Arg47His', 'Var', (38, 46))
945647	27450204	The established risk factors for this disease are environmental factors (alcohol drinking, smoking, infecting bacteria or virus), genetic factors (mutations in enzymes that metabolize alcohol), cultural factors (high-temperature food items such as pork braised in brown sauce and old stocked rice), obesity and gastroesophageal reflux.	('alcohol', 'Chemical', 'MESH:D000438', (184, 191))	('infecting bacteria', 'Disease', (100, 118))	('obesity', 'Phenotype', 'HP:0001513', (299, 306))	('alcohol', 'Chemical', 'MESH:D000438', (73, 80))	('alcohol', 'Var', (73, 80))	('infecting bacteria', 'Disease', 'MESH:D007239', (100, 118))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (311, 334))	('mutations in', 'Var', (147, 159))	('obesity', 'Disease', 'MESH:D009765', (299, 306))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (311, 334))	('gastroesophageal reflux', 'Disease', (311, 334))	('men', 'Species', '9606', (57, 60))	('alcohol drinking', 'Phenotype', 'HP:0030955', (73, 89))	('obesity', 'Disease', (299, 306))	('rice', 'Species', '4530', (292, 296))
945657	27450204	Single nucleotide polymorphisms (SNPs) occurring in this gene may be capable of altering ethanol metabolism, and individuals expressing the ADH1B variants would have different alcohol elimination rates.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('ADH1B', 'Gene', (140, 145))	('alcohol elimination rates', 'MPA', (176, 201))	('different', 'Reg', (166, 175))	('ADH1B', 'Gene', '125', (140, 145))	('ethanol', 'Chemical', 'MESH:D000431', (89, 96))	('variants', 'Var', (146, 154))	('altering', 'Reg', (80, 88))	('alcohol', 'Chemical', 'MESH:D000438', (176, 183))	('ethanol metabolism', 'MPA', (89, 107))
945658	27450204	One of the most studied SNP was Arg47His (rs1229984), a G to A base transition in exon 3 leading to the substitution of arginine (ADH1B*1) to histidine (ADH1B*2) at codon 47th position.	('ADH1B', 'Gene', (153, 158))	('Arg47His', 'Var', (32, 40))	('rs1229984', 'Var', (42, 51))	('ADH1B', 'Gene', '125', (153, 158))	('rs1229984', 'Mutation', 'rs1229984', (42, 51))	('arginine', 'Chemical', 'MESH:D001120', (120, 128))	('ADH1B', 'Gene', (130, 135))	('Arg47His', 'SUBSTITUTION', 'None', (32, 40))	('ADH1B', 'Gene', '125', (130, 135))	('substitution', 'Var', (104, 116))	('histidine', 'Chemical', 'MESH:D006639', (142, 151))
945660	27450204	This variant was shown to be strongly associated with alcohol dependence, abuse, consumption, and alcohol-induced liver diseases.	('alcohol dependence', 'Disease', (54, 72))	('alcohol', 'Chemical', 'MESH:D000438', (54, 61))	('abuse', 'Disease', (74, 79))	('associated', 'Reg', (38, 48))	('alcohol', 'Chemical', 'MESH:D000438', (98, 105))	('alcohol dependence', 'Phenotype', 'HP:0030955', (54, 72))	('variant', 'Var', (5, 12))	('consumption', 'Disease', (81, 92))	('liver diseases', 'Phenotype', 'HP:0001392', (114, 128))	('liver diseases', 'Disease', (114, 128))	('liver diseases', 'Disease', 'MESH:D008107', (114, 128))	('alcohol dependence', 'Disease', 'MESH:D000437', (54, 72))
945661	27450204	Several studies have identified the relationship between ADH1B polymorphism and esophageal cancer susceptibility, but the consistent results were not obtained.	('ADH1B', 'Gene', (57, 62))	('polymorphism', 'Var', (63, 75))	('ADH1B', 'Gene', '125', (57, 62))	('esophageal cancer', 'Disease', (80, 97))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
945662	27450204	demonstrated that ADH1B Arg47His variant was associated with esophageal cancer in Japanese and might be used in personalized prevention programs, while Ma et al.	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('Arg47His', 'SUBSTITUTION', 'None', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('associated', 'Reg', (45, 55))	('ADH1B', 'Gene', (18, 23))	('ADH1B', 'Gene', '125', (18, 23))	('esophageal cancer', 'Disease', (61, 78))	('Arg47His', 'Var', (24, 32))
945663	27450204	did not show significant associations between variations in the ADH1B gene and esophageal squamous cell carcinoma (ESCC) risk in Chinese.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('ADH1B', 'Gene', (64, 69))	('ADH1B', 'Gene', '125', (64, 69))	('variations', 'Var', (46, 56))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))
945666	27450204	The MeSH terms were as follows: "esophageal cancer or oesophageal cancer or esophageal squamous cell carcinomas or esophageal adenocarcinomas," "alcohol dehydrogenase or ADH1B or ADH2," and "polymorphism or variant or mutation" as well as their combinations.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('esophageal squamous cell carcinomas', 'Disease', (76, 111))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (76, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('ADH2', 'Gene', '125', (179, 183))	('alcohol dehydrogenase', 'Gene', (145, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('alcohol dehydrogenase', 'Gene', '10327', (145, 166))	('oesophageal cancer', 'Disease', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('polymorphism', 'Var', (191, 203))	('esophageal cancer', 'Disease', (33, 50))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (115, 141))	('ADH1B', 'Gene', '125', (170, 175))	('oesophageal cancer', 'Disease', 'MESH:D009369', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('esophageal adenocarcinomas', 'Disease', (115, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('ADH2', 'Gene', (179, 183))	('esophageal cancer', 'Disease', 'MESH:D004938', (55, 72))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (87, 111))	('ADH1B', 'Gene', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
945667	27450204	The inclusion criteria were as follows: (1) case-control studies evaluating the correlation of ADH1B Arg47His polymorphism in esophageal cancer occurrence; (2) patents with esophageal cancer should be diagnosed clinically and confirmed histologically, the controls should be age-, ethnicity-matched participants without malignancy and digestive and chronic diseases; (3) the genotype information were available to extract; and (4) the genotypes of controls were consistent with Hardy-Weinberg equilibrium (HWE).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Hardy-Weinberg equilibrium', 'Disease', (478, 504))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('Arg47His', 'Var', (101, 109))	('ADH1B', 'Gene', (95, 100))	('malignancy', 'Disease', 'MESH:D009369', (320, 330))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('malignancy', 'Disease', (320, 330))	('chronic diseases', 'Disease', (349, 365))	('ADH1B', 'Gene', '125', (95, 100))	('chronic diseases', 'Disease', 'MESH:D002908', (349, 365))	('esophageal cancer', 'Disease', (173, 190))	('Arg47His', 'SUBSTITUTION', 'None', (101, 109))	('participants', 'Species', '9606', (299, 311))	('esophageal cancer', 'Disease', (126, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (173, 190))
945668	27450204	The pooled odds ratio (OR) with its 95 % confidence interval (CI) were employed to estimate the association between ADH1B Arg47His variant and esophageal carcinoma susceptibility.	('esophageal carcinoma', 'Disease', (143, 163))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (143, 163))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (143, 163))	('ADH1B', 'Gene', (116, 121))	('association', 'Interaction', (96, 107))	('ADH1B', 'Gene', '125', (116, 121))	('Arg47His', 'Var', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('Arg47His', 'SUBSTITUTION', 'None', (122, 130))
945673	27450204	The ADH1B Arg47His variant was measured in eight methods.	('ADH1B', 'Gene', '125', (4, 9))	('ADH1B', 'Gene', (4, 9))	('Arg47His', 'SUBSTITUTION', 'None', (10, 18))	('Arg47His', 'Var', (10, 18))
945674	27450204	Table 2 displayed the alleles and genotypes information of ADH1B Arg47His variant in each included studies.	('ADH1B', 'Gene', (59, 64))	('Arg47His', 'Var', (65, 73))	('ADH1B', 'Gene', '125', (59, 64))	('Arg47His', 'SUBSTITUTION', 'None', (65, 73))
945675	27450204	Table 3 listed the results of the association between the ADH1B Arg47His polymorphism and esophageal cancer susceptibility.	('association', 'Interaction', (34, 45))	('Arg47His', 'Var', (64, 72))	('esophageal cancer', 'Disease', (90, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('ADH1B', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Arg47His', 'SUBSTITUTION', 'None', (64, 72))	('ADH1B', 'Gene', '125', (58, 63))
945676	27450204	Overall, we found that the frequency of 47His allele was higher than the 47Arg allele in both cases and controls, and the statistical analysis demonstrated that the 47His allele was significant associated with the decreased risk of esophageal cancer in total populations (His vs. Arg: OR = 0.67, 95 % CI = 0.59-0.76, P < 0.00001) as shown in Fig.	('47His', 'Chemical', '-', (165, 170))	('His', 'Chemical', 'MESH:D006639', (167, 170))	('His', 'Chemical', 'MESH:D006639', (272, 275))	('His', 'Chemical', 'MESH:D006639', (42, 45))	('Arg', 'Chemical', 'MESH:D001120', (280, 283))	('Arg', 'Chemical', 'MESH:D001120', (75, 78))	('esophageal cancer', 'Disease', (232, 249))	('decreased', 'NegReg', (214, 223))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('47His', 'Var', (165, 170))	('47His', 'Chemical', '-', (40, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (232, 249))
945677	27450204	In Asians, ADH1B 47His variant was shown to be associated with the decreased esophageal cancer risk under all the genetic models (P < 0.00001); while in non-Asians, no significant correlation was detected in any genetic models (P > 0.05).	('47His', 'Var', (17, 22))	('47His', 'Chemical', '-', (17, 22))	('decreased esophageal cancer', 'Disease', 'MESH:D004938', (67, 94))	('decreased esophageal cancer', 'Disease', (67, 94))	('ADH1B', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ADH1B', 'Gene', '125', (11, 16))
945681	27450204	Our result demonstrated that ADH1B Arg47His variant was a protective factor for cancer risk in Chinese and Japanese populations as shown in Fig.	('ADH1B', 'Gene', '125', (29, 34))	('Arg47His', 'SUBSTITUTION', 'None', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('ADH1B', 'Gene', (29, 34))	('Arg47His', 'Var', (35, 43))	('cancer', 'Disease', (80, 86))
945682	27450204	Fifteen studies estimated the combined effect of ADH1B Arg47His polymorphism and alcohol drinking on esophageal cancer risk.	('ADH1B', 'Gene', '125', (49, 54))	('alcohol', 'Chemical', 'MESH:D000438', (81, 88))	('alcohol drinking', 'Phenotype', 'HP:0030955', (81, 97))	('Arg47His', 'SUBSTITUTION', 'None', (55, 63))	('esophageal cancer', 'Disease', (101, 118))	('ADH1B', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Arg47His', 'Var', (55, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))
945684	27450204	Based on these data, we could only assess the combined effect on esophageal cancer susceptibility under the Arg/Arg versus His/His+Arg/His model.	('His', 'Chemical', 'MESH:D006639', (123, 126))	('esophageal cancer', 'Disease', (65, 82))	('His', 'Chemical', 'MESH:D006639', (127, 130))	('Arg', 'Chemical', 'MESH:D001120', (108, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('Arg', 'Chemical', 'MESH:D001120', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Arg/Arg', 'Var', (108, 115))	('Arg', 'Chemical', 'MESH:D001120', (112, 115))	('His', 'Chemical', 'MESH:D006639', (135, 138))	('His/His+Arg/His', 'Var', (123, 138))
945685	27450204	Our results found that Arg/Arg genotype compared with the His carrier of His/His and Arg/His genotypes was significantly associated with the increased higher risk of esophageal cancer in the drinking group (OR = 3.15, 95 % CI = 2.66-3.74, P < 0.00001) and lower in the non-drinking group (OR = 1.71, 95 % CI = 1.23-2.38, P = 0.001) as shown in Fig.	('Arg/Arg', 'Var', (23, 30))	('His', 'Chemical', 'MESH:D006639', (89, 92))	('His', 'Chemical', 'MESH:D006639', (58, 61))	('esophageal cancer', 'Disease', (166, 183))	('His', 'Chemical', 'MESH:D006639', (73, 76))	('His', 'Chemical', 'MESH:D006639', (77, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('Arg', 'Chemical', 'MESH:D001120', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('Arg', 'Chemical', 'MESH:D001120', (85, 88))	('Arg/His', 'Var', (85, 92))	('Arg', 'Chemical', 'MESH:D001120', (27, 30))
945686	27450204	Four articles considered the combined effect of ADH1B Arg47His polymorphism and tobacco smoking on esophageal cancer susceptibility, containing 2382 patients and 4792 controls.	('patients', 'Species', '9606', (149, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('Arg47His', 'Var', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ADH1B', 'Gene', (48, 53))	('Arg47His', 'SUBSTITUTION', 'None', (54, 62))	('ADH1B', 'Gene', '125', (48, 53))	('tobacco', 'Species', '4097', (80, 87))	('esophageal cancer', 'Disease', (99, 116))
945687	27450204	Our result demonstrated that the Arg/Arg genotype was associated with esophageal cancer occurrence in both non-smokers (OR = 2.40, 95 % CI = 1.44-3.98, P = 0.0007) and smokers (OR = 3.35, 95 % CI = 2.22-5.05, P < 0.00001) in the random-effect model as shown in Fig.	('Arg/Arg', 'Var', (33, 40))	('esophageal cancer', 'Disease', (70, 87))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('Arg', 'Chemical', 'MESH:D001120', (33, 36))	('Arg', 'Chemical', 'MESH:D001120', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('associated', 'Reg', (54, 64))
945688	27450204	Our result showed that the Arg/Arg genotype of ADH1B Arg47His variant increased the esophageal cancer risk in male patients (OR = 3.44, 95 % CI = 2.42-4.89, P < 0.0001), while not in female patients (OR = 1.62, 95 % CI = 0.90-2.91, P = 0.11) as shown in Fig.	('patients', 'Species', '9606', (115, 123))	('Arg', 'Chemical', 'MESH:D001120', (31, 34))	('increased', 'PosReg', (70, 79))	('ADH1B', 'Gene', (47, 52))	('patients', 'Species', '9606', (190, 198))	('Arg47His', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ADH1B', 'Gene', '125', (47, 52))	('Arg/Arg', 'Var', (27, 34))	('Arg', 'Chemical', 'MESH:D001120', (53, 56))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('Arg47His', 'SUBSTITUTION', 'None', (53, 61))	('Arg', 'Chemical', 'MESH:D001120', (27, 30))
945689	27450204	Our results showed that the ADH1B Arg47His variant was correlated with the decreased occurrence of esophageal cancer under all the genetic models among total population.	('Arg47His', 'SUBSTITUTION', 'None', (34, 42))	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('ADH1B', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ADH1B', 'Gene', '125', (28, 33))	('Arg47His', 'Var', (34, 42))	('esophageal cancer', 'Disease', (99, 116))	('decreased', 'NegReg', (75, 84))
945690	27450204	Subgroup analysis by ethnicity demonstrated that this variant was associated with the decreased cancer risk in Asian populations as well, especially in Chinese and Japanese.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('variant', 'Var', (54, 61))	('decreased', 'NegReg', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
945691	27450204	Furthermore, we found that the combined effect of Arg/Arg genotype in ADH1B Arg47His variant and alcohol drinking, tobacco smoking, and male patients revealed a higher risk on esophageal cancer risk when compared with the His carrier of His/His and Arg/His genotypes, respectively.	('His', 'Chemical', 'MESH:D006639', (253, 256))	('Arg', 'Chemical', 'MESH:D001120', (76, 79))	('Arg', 'Chemical', 'MESH:D001120', (249, 252))	('Arg', 'Chemical', 'MESH:D001120', (50, 53))	('patients', 'Species', '9606', (141, 149))	('Arg/Arg', 'Var', (50, 57))	('alcohol', 'Chemical', 'MESH:D000438', (97, 104))	('His', 'Chemical', 'MESH:D006639', (241, 244))	('Arg47His', 'SUBSTITUTION', 'None', (76, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (176, 193))	('tobacco', 'Species', '4097', (115, 122))	('His', 'Chemical', 'MESH:D006639', (81, 84))	('ADH1B', 'Gene', '125', (70, 75))	('esophageal cancer', 'Disease', (176, 193))	('Arg', 'Chemical', 'MESH:D001120', (54, 57))	('ADH1B', 'Gene', (70, 75))	('Arg47His', 'Var', (76, 84))	('His', 'Chemical', 'MESH:D006639', (237, 240))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('alcohol drinking', 'Phenotype', 'HP:0030955', (97, 113))	('His', 'Chemical', 'MESH:D006639', (222, 225))
945695	27450204	Genetic variations might be involved in esophageal cancer development and predict the prognosis.	('esophageal cancer', 'Disease', 'MESH:D004938', (40, 57))	('men', 'Species', '9606', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('involved', 'Reg', (28, 36))	('predict', 'Reg', (74, 81))	('Genetic variations', 'Var', (0, 18))	('esophageal cancer', 'Disease', (40, 57))
945702	27450204	In addition, ADH1B expression could result in high blood acetaldehyde levels, which can easily give rise to DNA damage, and finally cause the cancer occurrence.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('DNA damage', 'MPA', (108, 118))	('acetaldehyde', 'Chemical', 'MESH:D000079', (57, 69))	('high blood acetaldehyde levels', 'MPA', (46, 76))	('ADH1B', 'Gene', (13, 18))	('expression', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('result in', 'Reg', (36, 45))	('give rise', 'Reg', (95, 104))	('ADH1B', 'Gene', '125', (13, 18))	('blood acetaldehyde', 'Phenotype', 'HP:0003533', (51, 69))	('cause', 'Reg', (132, 137))	('cancer', 'Disease', (142, 148))
945703	27450204	Genetic polymorphisms of ADH1B could modulate exposure levels to ethanol.	('ethanol', 'Chemical', 'MESH:D000431', (65, 72))	('modulate', 'Reg', (37, 45))	('ADH1B', 'Gene', (25, 30))	('Genetic polymorphisms', 'Var', (0, 21))	('ADH1B', 'Gene', '125', (25, 30))	('exposure levels to ethanol', 'MPA', (46, 72))
945705	27450204	Among which, the Arg47His variant (ADH2*2) was the most studied.	('Arg47His', 'Var', (17, 25))	('Arg47His', 'SUBSTITUTION', 'None', (17, 25))	('ADH2', 'Gene', (35, 39))	('ADH2', 'Gene', '125', (35, 39))
945707	27450204	SNPs of ADH1B gene (the major alcohol-metabolizing enzyme gene) may modify the effects of alcohol on metabolic and clinical phenotypes.	('ADH1B', 'Gene', (8, 13))	('alcohol', 'Chemical', 'MESH:D000438', (30, 37))	('ADH1B', 'Gene', '125', (8, 13))	('SNPs', 'Var', (0, 4))	('effects', 'MPA', (79, 86))	('modify', 'Reg', (68, 74))	('alcohol', 'Chemical', 'MESH:D000438', (90, 97))
945712	27450204	Previous studies have found that ADH1B Arg47His polymorphism was associated with the pathogenesis of cancers such as colorectal cancer and head and neck cancer, while no positive correlation was found in hepatocellular carcinoma and gastric cancer.	('ADH1B', 'Gene', '125', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('associated', 'Reg', (65, 75))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (204, 228))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('ADH1B', 'Gene', (33, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (233, 247))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (204, 228))	('Arg47His', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('head and neck cancer', 'Phenotype', 'HP:0012288', (139, 159))	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('colorectal cancer', 'Disease', (117, 134))	('gastric cancer', 'Disease', (233, 247))	('hepatocellular carcinoma', 'Disease', (204, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('head and neck cancer', 'Disease', 'MESH:D006258', (139, 159))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (233, 247))	('Arg47His', 'SUBSTITUTION', 'None', (39, 47))
945713	27450204	Several studies have identified the association between ADH1B polymorphism and esophagus cancer susceptibility.	('esophagus cancer', 'Disease', 'MESH:D004938', (79, 95))	('polymorphism', 'Var', (62, 74))	('ADH1B', 'Gene', (56, 61))	('ADH1B', 'Gene', '125', (56, 61))	('esophagus cancer', 'Disease', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
945716	27450204	found that the magnitude of effect of ADH1B polymorphisms was greater in subjects who were heavy drinkers, heavy smokers, and had esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('greater', 'PosReg', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('polymorphisms', 'Var', (44, 57))	('ADH1B', 'Gene', (38, 43))	('ADH1B', 'Gene', '125', (38, 43))	('esophageal cancer', 'Disease', (130, 147))
945719	27450204	Thirdly, the combined effect of ADH1B Arg47His variant and age group also should be focused on.	('Arg47His', 'SUBSTITUTION', 'None', (38, 46))	('Arg47His', 'Var', (38, 46))	('ADH1B', 'Gene', '125', (32, 37))	('ADH1B', 'Gene', (32, 37))
945720	27450204	Lastly, other polymorphisms in ADH1B gene or other ADH genes which might alter the metabolism of alcohol should be included.	('metabolism of alcohol', 'MPA', (83, 104))	('polymorphisms', 'Var', (14, 27))	('ADH', 'Gene', (51, 54))	('ADH1B', 'Gene', (31, 36))	('ADH', 'Gene', (31, 34))	('ADH', 'Gene', '10327', (31, 34))	('ADH', 'Gene', '10327', (51, 54))	('ADH1B', 'Gene', '125', (31, 36))	('alter', 'Reg', (73, 78))	('alcohol', 'Chemical', 'MESH:D000438', (97, 104))
945721	27450204	In conclusion, our results suggested that ADH1B Arg47His polymorphism might be a protective factor on esophageal cancer susceptibility in Asians.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('Arg47His', 'SUBSTITUTION', 'None', (48, 56))	('ADH1B', 'Gene', (42, 47))	('ADH1B', 'Gene', '125', (42, 47))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Arg47His', 'Var', (48, 56))
945722	27450204	The Arg/Arg genotypes combined with alcohol drinking, tobacco smoking, and males might be strongly increased the risk of esophageal cancer.	('tobacco', 'Species', '4097', (54, 61))	('alcohol drinking', 'Phenotype', 'HP:0030955', (36, 52))	('alcohol', 'Chemical', 'MESH:D000438', (36, 43))	('Arg', 'Chemical', 'MESH:D001120', (8, 11))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Arg/Arg', 'Var', (4, 11))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('increased', 'PosReg', (99, 108))	('Arg', 'Chemical', 'MESH:D001120', (4, 7))
945723	27450204	AC, adenocarcinomas; ADH, alcohol dehydrogenase gene; ADH1B, alcohol dehydrogenase 1B; ALD, aldehyde dehydrogenases; CI, confidence interval; OR, odds ratio; SCC, squamous cell carcinomas; SNPs, single nucleotide polymorphisms	('single nucleotide polymorphisms', 'Var', (195, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('ADH', 'Gene', '10327', (54, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (9, 19))	('alcohol dehydrogenase 1B', 'Gene', (61, 85))	('alcohol dehydrogenase', 'Gene', '10327', (61, 82))	('ADH', 'Gene', '10327', (21, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('ALD', 'Disease', 'MESH:D000326', (87, 90))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (163, 187))	('SCC', 'Phenotype', 'HP:0002860', (158, 161))	('adenocarcinomas', 'Disease', 'MESH:D000230', (4, 19))	('adenocarcinomas', 'Disease', (4, 19))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (163, 187))	('ALD', 'Disease', (87, 90))	('alcohol dehydrogenase', 'Gene', (26, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('ADH', 'Gene', (54, 57))	('ADH', 'Gene', (21, 24))	('alcohol dehydrogenase', 'Gene', '10327', (26, 47))	('squamous cell carcinomas', 'Disease', (163, 187))	('ADH1B', 'Gene', '125', (54, 59))	('alcohol dehydrogenase 1B', 'Gene', '125', (61, 85))	('ADH1B', 'Gene', (54, 59))	('aldehyde', 'Chemical', 'MESH:D000447', (92, 100))
945724	25237569	Single-Nucleotide Polymorphisms Within MicroRNAs Sequences and Their 3' UTR Target Sites May Regulate Gene Expression in Gastrointestinal Tract Cancers Esophageal, stomach, and colorectal cancers are commonly lethal gastrointestinal tract (GIT) neoplasms, causing almost two million deaths worldwide each year.	('Gastrointestinal Tract Cancers', 'Disease', (121, 151))	('Regulate', 'Reg', (93, 101))	('gastrointestinal tract (GIT) neoplasms', 'Disease', 'MESH:D004067', (216, 254))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('Cancers', 'Phenotype', 'HP:0002664', (144, 151))	('Esophageal', 'Disease', (152, 162))	('Gastrointestinal Tract Cancers', 'Disease', 'MESH:D004067', (121, 151))	('stomach', 'Disease', (164, 171))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('colorectal cancers', 'Disease', 'MESH:D015179', (177, 195))	('Single-Nucleotide Polymorphisms', 'Var', (0, 31))	('Gene Expression', 'MPA', (102, 117))	('colorectal cancers', 'Disease', (177, 195))
945726	25237569	Accordingly, recent works have shown that single-nucleotide polymorphisms (SNPs) within miRNAs coding sequence (miR-SNPs) and miRNA target sites (target-SNPs) may further contribute to increased risk of developing cancer.	('miR', 'Gene', (88, 91))	('cancer', 'Disease', (214, 220))	('contribute', 'Reg', (171, 181))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', '220972', (126, 129))	('miR', 'Gene', (112, 115))	('miR', 'Gene', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('single-nucleotide polymorphisms', 'Var', (42, 73))	('miR', 'Gene', '220972', (88, 91))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
945740	25237569	Researchers have obtained an overwhelming amount of data suggesting that single-nucleotide polymorphisms (SNPs) in miRNAs (miR-SNPs) and their target sites (target-SNPs) may be associated with an altered risk of developing cancer.	('single-nucleotide polymorphisms', 'Var', (73, 104))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('associated', 'Reg', (177, 187))	('cancer', 'Disease', (223, 229))	('miR', 'Gene', '220972', (115, 118))	('miR', 'Gene', (115, 118))
945743	25237569	Using an in silico approach, we extracted information on SNPs in GIT cancer-related miRNA-target mRNAs.	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (84, 87))	('SNPs', 'Var', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
945751	25237569	Next, we annotated miRNAs-target gene pairs in all of these groups and extracted information about the presence of SNPs in miRNA sequence (miR-SNPs) and in the 3' UTR mRNA sequence (target-SNPs) by using different bioinformatics resources (Table 1).	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', '220972', (139, 142))	('miR', 'Gene', (19, 22))	('miR', 'Gene', (139, 142))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('SNPs', 'Var', (115, 119))
945762	25237569	The differential expression of genes reported in four previous studies (experiment accession IDs: E-GEOD-13471, E-GEOD-1420, E-GEOD-19249, E-GEOD-19826, E-GEOD-23878, E-GEOD-2685, E-MTAB-57, E-MTAB-62, and E-MTAB-145) were downloaded and employed in this work.	('E-GEOD-19826', 'Var', (139, 151))	('men', 'Species', '9606', (78, 81))	('E-GEOD-2685', 'Var', (167, 178))	('E-GEOD-19249', 'Var', (125, 137))	('E-GEOD-1420', 'Var', (112, 123))	('E-GEOD-13471', 'Var', (98, 110))	('E-GEOD-23878', 'Var', (153, 165))
945781	25237569	Among these SNPs, rs8190315 and rs3212986 are located in BID and ERCC1, respectively.	('rs3212986', 'Mutation', 'rs3212986', (32, 41))	('ERCC1', 'Gene', (65, 70))	('ERCC1', 'Gene', '2067', (65, 70))	('rs8190315', 'Mutation', 'rs8190315', (18, 27))	('rs3212986', 'Var', (32, 41))	('BID', 'Gene', '637', (57, 60))	('rs8190315', 'Var', (18, 27))	('BID', 'Gene', (57, 60))
945786	25237569	Increasing evidences propose that SNPs within miRNAs and their 3' UTR binding sites may play active roles in a variety of human diseases, especially GIT cancers.	('miR', 'Gene', (46, 49))	('human', 'Species', '9606', (122, 127))	('play', 'Reg', (88, 92))	('especially GIT cancers', 'Disease', 'MESH:D009369', (138, 160))	('SNPs', 'Var', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('especially GIT cancers', 'Disease', (138, 160))	('roles', 'Reg', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('miR', 'Gene', '220972', (46, 49))
945790	25237569	MiR-SNP can alter the expression level of the wild-type miRNA, whereas the presence of a functional SNP in the 3' UTR target site may potentially affect the binding with a specific miRNAs and alter the posttranscriptional regulation by miRNAs.	('miR', 'Gene', '220972', (236, 239))	('MiR', 'Gene', (0, 3))	('miR', 'Gene', (236, 239))	('binding', 'Interaction', (157, 164))	('MiR', 'Gene', '220972', (0, 3))	('alter', 'Reg', (12, 17))	('posttranscriptional regulation', 'MPA', (202, 232))	('alter', 'Reg', (192, 197))	('affect', 'Reg', (146, 152))	('expression level', 'MPA', (22, 38))	('miR', 'Gene', (181, 184))	('miR', 'Gene', '220972', (181, 184))	('miR', 'Gene', '220972', (56, 59))	('presence', 'Var', (75, 83))	('miR', 'Gene', (56, 59))
945794	25237569	Incidentally, we further explored the functional roles of some of these variants by indicating that 11 SNPs with strong evidence of association with a variety of diseases ranging from breast cancer to orofacial cleft actually are located inside binding sites of clinically important miRNAs.	('orofacial cleft actually', 'Disease', (201, 225))	('miR', 'Gene', '220972', (283, 286))	('miR', 'Gene', (283, 286))	('variants', 'Var', (72, 80))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('association', 'Interaction', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', (184, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('orofacial cleft actually', 'Disease', 'MESH:D002972', (201, 225))
945795	25237569	The most noteworthy SNP may be rs3212986 in ERCC1 gene with reported association with multiple cancer types including, but not limited to, estrogen-related cancers (breast, cervical, and ovarian), smoking-related cancers (lung, esophageal, bladder, head and neck, and pancreatic cancer), and brain tumors.	('pancreatic cancer', 'Disease', 'MESH:D010190', (268, 285))	('esophageal', 'Disease', (228, 238))	('cancer', 'Disease', (279, 285))	('ERCC1', 'Gene', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('pancreatic cancer', 'Disease', (268, 285))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('association', 'Interaction', (69, 80))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('cancers', 'Disease', (213, 220))	('cancer', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('brain tumors', 'Phenotype', 'HP:0030692', (292, 304))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('brain tumors', 'Disease', 'MESH:D001932', (292, 304))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (268, 285))	('rs3212986', 'Var', (31, 40))	('bladder', 'Disease', (240, 247))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('rs3212986', 'Mutation', 'rs3212986', (31, 40))	('ERCC1', 'Gene', '2067', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('brain tumors', 'Disease', (292, 304))	('cervical', 'Disease', (173, 181))
945797	25237569	In summary, our data provided a comprehensive source of prioritized and annotated candidate polymorphisms within miRNAs sequences and their 3' UTR target sites in GIT cancers, which could facilitate the process of selecting the right candidate miRNA-target genes for functional studies and focusing on potentially relevant polymorphisms for further association studies.	('polymorphisms', 'Var', (92, 105))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (113, 116))	('GIT cancers', 'Disease', (163, 174))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('miR', 'Gene', '220972', (244, 247))	('miR', 'Gene', (244, 247))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('GIT cancers', 'Disease', 'MESH:D009369', (163, 174))
945801	24065124	However, in patients with genotype 1b, the sustained virological response (SVR) rate was significantly lower in the cirrhosis and the splenectomy/PSE groups compared to the chronic hepatitis group.	('patients', 'Species', '9606', (12, 20))	('sustained virological response', 'MPA', (43, 73))	('cirrhosis', 'Phenotype', 'HP:0001394', (116, 125))	('genotype 1b', 'Var', (26, 37))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (173, 190))	('cirrhosis', 'Disease', 'MESH:D005355', (116, 125))	('lower', 'NegReg', (103, 108))	('chronic hepatitis', 'Disease', 'MESH:D056487', (173, 190))	('cirrhosis', 'Disease', (116, 125))	('chronic hepatitis', 'Disease', (173, 190))	('hepatitis', 'Phenotype', 'HP:0012115', (181, 190))
945803	24065124	Patients with genotype 2a/2b were more likely to achieve an SVR than genotype 1b.	('genotype 2a/2b', 'Var', (14, 28))	('achieve', 'PosReg', (49, 56))	('SVR', 'MPA', (60, 63))	('Patients', 'Species', '9606', (0, 8))
945804	24065124	Prognostic factors for SVR in patients with genotype 1b included the absence of esophageal and gastric varices, high serum ALT, low AST/ALT ratio, and the major homo type of the IL28B gene.	('IL28B', 'Gene', (178, 183))	('high serum ALT', 'MPA', (112, 126))	('genotype 1b', 'Var', (44, 55))	('high serum ALT', 'Phenotype', 'HP:0031964', (112, 126))	('gastric varices', 'Phenotype', 'HP:0030169', (95, 110))	('AST', 'Gene', (132, 135))	('patients', 'Species', '9606', (30, 38))	('esophageal', 'Disease', (80, 90))	('IL28B', 'Gene', '282617', (178, 183))	('low AST', 'Phenotype', 'HP:0032198', (128, 135))	('AST', 'Gene', '26503', (132, 135))	('SVR', 'Disease', (23, 26))	('esophageal and gastric varices', 'Phenotype', 'HP:0002040', (80, 110))
945805	24065124	Splenectomy- or PSE-facilitated induction of IFN in patients with genotype 2a/2b was more likely to achieve an SVR by an IFN dose maintenance regimen.	('SVR', 'MPA', (111, 114))	('IFN', 'Gene', '3439', (45, 48))	('IFN', 'Gene', '3439', (121, 124))	('achieve', 'PosReg', (100, 107))	('IFN', 'Gene', (45, 48))	('IFN', 'Gene', (121, 124))	('patients', 'Species', '9606', (52, 60))	('genotype 2a/2b', 'Var', (66, 80))
945806	24065124	Patients with genotype 1b have a low SVR regardless of splenectomy/PSE.	('SVR', 'MPA', (37, 40))	('low', 'NegReg', (33, 36))	('genotype 1b', 'Var', (14, 25))	('Patients', 'Species', '9606', (0, 8))
945813	24065124	As an antiviral therapy for chronic hepatitis C, pegylated interferon (PEG-IFN) in combination with ribavirin (RBV) has resulted in remarkably favorable outcomes, with a sustained virological response (SVR) obtained in approximately 80 % of patients with genotypes 2 and 3 and, more impressively, 40-50 % of patients with genotype 1 and a refractory high viral load.	('interferon', 'Gene', (59, 69))	('PEG', 'Chemical', '-', (71, 74))	('chronic hepatitis C', 'Disease', 'MESH:D019698', (28, 47))	('IFN', 'Gene', (75, 78))	('IFN', 'Gene', '3439', (75, 78))	('hepatitis', 'Phenotype', 'HP:0012115', (36, 45))	('patients', 'Species', '9606', (308, 316))	('ribavirin', 'Chemical', 'MESH:D012254', (100, 109))	('genotype 1', 'Var', (322, 332))	('chronic hepatitis C', 'Disease', (28, 47))	('interferon', 'Gene', '3439', (59, 69))	('sustained', 'MPA', (170, 179))	('RBV', 'Chemical', 'MESH:D012254', (111, 114))	('pegylated', 'Var', (49, 58))	('patients', 'Species', '9606', (241, 249))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (28, 45))
945821	24065124	Recently, studies have reported that the interferon sensitivity-determining region (ISDR) and amino acid substitutions of core 70 and core 91 in the core region of HCV are important prognostic indicators of IFN's therapeutic effect.	('IFN', 'Gene', (207, 210))	('amino acid substitutions', 'Var', (94, 118))	('interferon', 'Gene', '3439', (41, 51))	('IFN', 'Gene', '3439', (207, 210))	('HCV', 'Species', '11103', (164, 167))	('interferon', 'Gene', (41, 51))
945852	24065124	The IL28B gene (rs 8099917) was measured using the TaqMan probe method, as previously reported.	('IL28B', 'Gene', (4, 9))	('IL28B', 'Gene', '282617', (4, 9))	('rs 8099917', 'Var', (16, 26))
945874	24065124	The SVR rates of patients with genotype 1b and a high viral load and patients with genotype 2a/2b were 36.0 % (82/228 patients) and 73.2 % (52/71 patients), respectively.	('patients', 'Species', '9606', (17, 25))	('SVR', 'MPA', (4, 7))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (146, 154))	('patients', 'Species', '9606', (118, 126))	('genotype 1b', 'Var', (31, 42))
945875	24065124	In chronic hepatitis groups A and B, the SVR rates of patients with genotype 1b and a high viral load and patients with genotype 2a/2b were 46.4 % (71/153 patients) and 80.4 % (45/56 patients), respectively.	('hepatitis', 'Phenotype', 'HP:0012115', (11, 20))	('patients', 'Species', '9606', (54, 62))	('chronic hepatitis', 'Disease', 'MESH:D056487', (3, 20))	('chronic hepatitis', 'Disease', (3, 20))	('genotype 1b', 'Var', (68, 79))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (183, 191))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (3, 20))
945876	24065124	In the cirrhosis groups C, D, and E, the SVR rates of patients with genotype 1b and a high viral load and patients with genotype 2a/2b were 14.7 % (11/75 patients) and 46.7 % (7/15 patients), respectively.	('cirrhosis', 'Disease', (7, 16))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (154, 162))	('cirrhosis', 'Phenotype', 'HP:0001394', (7, 16))	('genotype 1b', 'Var', (68, 79))	('cirrhosis', 'Disease', 'MESH:D005355', (7, 16))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (181, 189))
945877	24065124	In both patients with genotype 1b and a high viral load and patients with genotype 2a/2b, the SVR rates of the cirrhosis group were significantly lower than those of the chronic hepatitis group (P < 0.00001, P = 0.009, respectively).	('high', 'Var', (40, 44))	('SVR rates', 'MPA', (94, 103))	('cirrhosis', 'Disease', (111, 120))	('genotype 1b', 'Var', (22, 33))	('patients', 'Species', '9606', (60, 68))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (170, 187))	('lower', 'NegReg', (146, 151))	('cirrhosis', 'Phenotype', 'HP:0001394', (111, 120))	('chronic hepatitis', 'Disease', 'MESH:D056487', (170, 187))	('genotype 2a/2b', 'Var', (74, 88))	('chronic hepatitis', 'Disease', (170, 187))	('cirrhosis', 'Disease', 'MESH:D005355', (111, 120))	('hepatitis', 'Phenotype', 'HP:0012115', (178, 187))	('patients', 'Species', '9606', (8, 16))
945878	24065124	In patients with genotype 1b and a high viral load, the SVR rates in groups A, B, C, D, and E were 46.7 % (70/150 patients), 33.3 % (1/3 patients), 20.5 % (8/39 patients), 0 % (0/11 patients), and 12.0 % (3/25 patients), respectively.	('viral load', 'MPA', (40, 50))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (182, 190))	('genotype 1b', 'Var', (17, 28))	('patients', 'Species', '9606', (210, 218))	('patients', 'Species', '9606', (114, 122))
945879	24065124	In patients with genotype 2a/2b, the SVR rates in groups A, B, C, D, and E were 80.0 % (44/55 patients), 100 % (1/1 patient), 33.3 % (3/9 patients), 100 % (1/1 patient), and 60.0 % (3/5 patients), respectively.	('patients', 'Species', '9606', (94, 102))	('patient', 'Species', '9606', (116, 123))	('SVR', 'MPA', (37, 40))	('patient', 'Species', '9606', (3, 10))	('patients', 'Species', '9606', (3, 11))	('patient', 'Species', '9606', (138, 145))	('patient', 'Species', '9606', (94, 101))	('patient', 'Species', '9606', (160, 167))	('genotype 2a/2b', 'Var', (17, 31))	('patient', 'Species', '9606', (186, 193))	('patients', 'Species', '9606', (138, 146))	('patients', 'Species', '9606', (186, 194))
945880	24065124	In patients with genotype 1b and a high viral load in the cirrhosis group, patient characteristics were compared between those who did (SVR group) and those who did not achieve an SVR (non-SVR group) (Table 3).	('viral load', 'MPA', (40, 50))	('cirrhosis', 'Disease', (58, 67))	('patient', 'Species', '9606', (3, 10))	('patients', 'Species', '9606', (3, 11))	('cirrhosis', 'Disease', 'MESH:D005355', (58, 67))	('cirrhosis', 'Phenotype', 'HP:0001394', (58, 67))	('genotype 1b', 'Var', (17, 28))	('patient', 'Species', '9606', (75, 82))
945882	24065124	With regard to liver enzymes, serum alanine aminotransferase was significantly higher in the SVR group compared to that of the non-SVR group (112.6 +- 92.9 IU/l vs. 66.5 +- 38.0 IU/l, P = 0.027).	('higher', 'PosReg', (79, 85))	('alanine aminotransferase', 'Gene', (36, 60))	('alanine aminotransferase', 'Gene', '2875', (36, 60))	('SVR', 'Var', (93, 96))
945883	24065124	Furthermore, the AST/ALT ratio was significantly lower in the SVR group compared to the non-SVR group (0.85 +- 0.17 vs. 1.04 +- 0.27, P = 0.022).	('SVR', 'Var', (62, 65))	('AST', 'Gene', '26503', (17, 20))	('AST', 'Gene', (17, 20))	('lower', 'NegReg', (49, 54))
945897	24065124	In this study, in the chronic hepatitis group, the SVR rates of PEG-IFN/RBV therapy in patients with genotype 1b and a high viral load and patients with genotype 2a/2b were 46.4 and 80.4 %, respectively.	('genotype 1b', 'Var', (101, 112))	('PEG', 'Chemical', '-', (64, 67))	('IFN', 'Gene', '3439', (68, 71))	('patients', 'Species', '9606', (139, 147))	('IFN', 'Gene', (68, 71))	('RBV', 'Chemical', 'MESH:D012254', (72, 75))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (22, 39))	('viral load', 'MPA', (124, 134))	('patients', 'Species', '9606', (87, 95))	('chronic hepatitis', 'Disease', 'MESH:D056487', (22, 39))	('hepatitis', 'Phenotype', 'HP:0012115', (30, 39))	('chronic hepatitis', 'Disease', (22, 39))
945898	24065124	In comparison, in the cirrhosis group, the SVR rates in patients with genotype 1b and patients with genotype 2a/2b were 14.7 and 46.7 %, respectively, indicating a significantly poorer therapeutic effect.	('patients', 'Species', '9606', (56, 64))	('poorer', 'NegReg', (178, 184))	('cirrhosis', 'Phenotype', 'HP:0001394', (22, 31))	('cirrhosis', 'Disease', 'MESH:D005355', (22, 31))	('SVR', 'MPA', (43, 46))	('poorer therapeutic effect', 'Phenotype', 'HP:0020173', (178, 203))	('cirrhosis', 'Disease', (22, 31))	('genotype 1b', 'Var', (70, 81))	('patients', 'Species', '9606', (86, 94))
945905	24065124	The SVR rates were 20.5 and 33.3 % in patients with genotype 1b and high viral load and patients with genotype 2a/2b, demonstrating a low therapeutic effect rate.	('genotype 1b', 'Var', (52, 63))	('high', 'Var', (68, 72))	('patients', 'Species', '9606', (88, 96))	('viral', 'MPA', (73, 78))	('patients', 'Species', '9606', (38, 46))
945914	24065124	These procedures also improved the platelet count and allowed 18 of the total 30 (60.0 %) who underwent these procedures to maintain 80 % or more of the IFN dose for 24 weeks or more.	('procedures', 'Var', (6, 16))	('IFN', 'Gene', (153, 156))	('improved', 'PosReg', (22, 30))	('platelet', 'MPA', (35, 43))	('IFN', 'Gene', '3439', (153, 156))
945916	24065124	However, in patients with genotype 1b in the treated group, the SVR rate was low at 12.0 %, and the therapeutic effect rate failed to improve.	('SVR rate', 'MPA', (64, 72))	('low', 'NegReg', (77, 80))	('patients', 'Species', '9606', (12, 20))	('genotype 1b', 'Var', (26, 37))
945917	24065124	Although we cannot completely clarify why the improvement of drug adherence did not result in a favorable outcome, the presence of advanced liver fibrosis and its related portal hypertension could also influence the SVR rate, as well as the adherence to IFN therapy.	('portal', 'Disease', (171, 177))	('liver fibrosis', 'Phenotype', 'HP:0001395', (140, 154))	('hypertension', 'Disease', 'MESH:D006973', (178, 190))	('IFN', 'Gene', (254, 257))	('hypertension', 'Disease', (178, 190))	('liver fibrosis', 'Disease', (140, 154))	('hypertension', 'Phenotype', 'HP:0000822', (178, 190))	('IFN', 'Gene', '3439', (254, 257))	('influence', 'Reg', (202, 211))	('portal hypertension', 'Phenotype', 'HP:0001409', (171, 190))	('presence', 'Var', (119, 127))	('liver fibrosis', 'Disease', 'MESH:D008103', (140, 154))	('SVR rate', 'MPA', (216, 224))
945920	24065124	Recently, ISDR and amino acid substitutions of core 70 and core 91 in the core region of HCV have been reported as factors associated with the therapeutic effect of PEG-IFN/RBV combination therapy for patients with genotype 1b and a high viral load.	('associated with', 'Reg', (123, 138))	('patients', 'Species', '9606', (201, 209))	('amino acid substitutions', 'Var', (19, 43))	('RBV', 'Chemical', 'MESH:D012254', (173, 176))	('IFN', 'Gene', '3439', (169, 172))	('PEG', 'Chemical', '-', (165, 168))	('HCV', 'Species', '11103', (89, 92))	('IFN', 'Gene', (169, 172))
945921	24065124	In the human genome, a single nucleotide polymorphism (SNPs) of IL28B is an important factor.	('human', 'Species', '9606', (7, 12))	('IL28B', 'Gene', (64, 69))	('IL28B', 'Gene', '282617', (64, 69))	('single nucleotide polymorphism', 'Var', (23, 53))
945922	24065124	Therefore, these factors were included in our analysis of prognostic factors for a therapeutic effect leading to SVR in patients with genotype 1b and a high viral load.	('genotype 1b', 'Var', (134, 145))	('patients', 'Species', '9606', (120, 128))	('SVR', 'Disease', (113, 116))
945929	24065124	In patients with genotype 1b and a high viral load, the therapeutic effect rate was low even in those with the TT allele of the IL28B genetic polymorphism.	('IL28B', 'Gene', '282617', (128, 133))	('viral load', 'MPA', (40, 50))	('low', 'NegReg', (84, 87))	('therapeutic', 'MPA', (56, 67))	('patients', 'Species', '9606', (3, 11))	('genotype 1b', 'Var', (17, 28))	('IL28B', 'Gene', (128, 133))
945931	24065124	In patients with the TG/GG allele of the IL28B genetic polymorphism, treatment outcomes were even worse.	('TG/GG allele', 'Var', (21, 33))	('patients', 'Species', '9606', (3, 11))	('IL28B', 'Gene', (41, 46))	('IL28B', 'Gene', '282617', (41, 46))	('TG', 'Chemical', '-', (21, 23))
945934	24065124	Hence, splenectomy or PSE appears to be indicated for the purpose of IFN therapy in patients with genotype 2a/2b who are more likely to achieve an SVR by dose maintenance.	('achieve', 'PosReg', (136, 143))	('patients', 'Species', '9606', (84, 92))	('IFN', 'Gene', '3439', (69, 72))	('genotype 2a/2b', 'Var', (98, 112))	('SVR', 'MPA', (147, 150))	('IFN', 'Gene', (69, 72))
945936	24065124	There were five chronic hepatitis patients with genotype 1b and a low viral load, while there were no patients with genotype 1b and a low viral load in the cirrhosis groups (groups C, D, and E).	('hepatitis', 'Phenotype', 'HP:0012115', (24, 33))	('cirrhosis', 'Phenotype', 'HP:0001394', (156, 165))	('patients', 'Species', '9606', (102, 110))	('viral load', 'MPA', (70, 80))	('cirrhosis', 'Disease', (156, 165))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (16, 33))	('patients', 'Species', '9606', (34, 42))	('low', 'NegReg', (66, 69))	('chronic hepatitis', 'Disease', 'MESH:D056487', (16, 33))	('cirrhosis', 'Disease', 'MESH:D005355', (156, 165))	('genotype 1b', 'Var', (48, 59))	('chronic hepatitis', 'Disease', (16, 33))
945947	24065124	Currently, it is not indicated in patients with cirrhosis, and its therapeutic effect is suboptimal for those who did not respond to pretreatment and patients with the TG/GG allele of the IL28B genetic polymorphism.	('cirrhosis', 'Disease', (48, 57))	('TG/GG', 'Var', (168, 173))	('IL28B', 'Gene', (188, 193))	('cirrhosis', 'Phenotype', 'HP:0001394', (48, 57))	('IL28B', 'Gene', '282617', (188, 193))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (34, 42))	('cirrhosis', 'Disease', 'MESH:D005355', (48, 57))	('TG', 'Chemical', '-', (168, 170))
945952	24065124	These studies involve patients who did not respond to pretreatment, and all of them achieved an SVR, although many have the TG/GG allele of the IL28B genetic polymorphism.	('TG', 'Chemical', '-', (124, 126))	('IL28B', 'Gene', (144, 149))	('TG/GG', 'Var', (124, 129))	('patients', 'Species', '9606', (22, 30))	('IL28B', 'Gene', '282617', (144, 149))	('SVR', 'MPA', (96, 99))	('achieved', 'PosReg', (84, 92))
945962	21517111	Especially, the frequency of antibodies to HSP70 in ESCC sera was significantly higher than that in normal human sera.	('antibodies', 'Var', (29, 39))	('human', 'Species', '9606', (107, 112))	('HSP70', 'Protein', (43, 48))	('ESCC', 'Disease', (52, 56))	('higher', 'PosReg', (80, 86))
945996	21517111	More recently, several studies have been performed to detect autoantibody against HSP70 in different types of cancer such as esophageal, liver and nasopharyngeal cancer as well as head and neck cancer.	('neck cancer', 'Disease', (189, 200))	('autoantibody', 'Var', (61, 73))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (147, 168))	('liver', 'Disease', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('HSP70', 'Protein', (82, 87))	('esophageal', 'Disease', (125, 135))	('nasopharyngeal cancer', 'Disease', (147, 168))	('head and neck cancer', 'Phenotype', 'HP:0012288', (180, 200))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('detect', 'Reg', (54, 60))	('neck cancer', 'Disease', 'MESH:D006258', (189, 200))
945999	21517111	Overexpression of HMGB1 has been observed in many types of cancer, including breast, colon and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('observed', 'Reg', (33, 41))	('HMGB1', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Overexpression', 'Var', (0, 14))	('breast', 'Disease', (77, 83))	('colon and lung cancer', 'Disease', 'MESH:D008175', (85, 106))
946001	21517111	In one of our recent studies, we have identified and characterized autoantibody to HSP70 in hepatocellular carcinoma (HCC) as a potential biomarker.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('autoantibody', 'Var', (67, 79))	('HSP70', 'Protein', (83, 88))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('hepatocellular carcinoma', 'Disease', (92, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))
946011	21505180	Current use of E+P therapy was found to be associated with a decreased risk of esophageal SCC, but no association was observed with esophageal adenocarcinoma.	('esophageal SCC', 'Disease', (79, 93))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (132, 157))	('E+P', 'Chemical', '-', (15, 18))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (132, 157))	('esophageal SCC', 'Disease', 'MESH:D004941', (79, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('decreased', 'NegReg', (61, 70))	('E+P therapy', 'Var', (15, 26))	('esophageal adenocarcinoma', 'Disease', (132, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
946017	21505180	In another study, breastfeeding was associated with a significant 59% (95% CI: 18%-80%) lower risk of esophageal adenocarcinoma.	('breastfeeding', 'Var', (18, 31))	('esophageal adenocarcinoma', 'Disease', (102, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (102, 127))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))	('lower', 'NegReg', (88, 93))
946064	21505180	The reduced risk appears to be concentrated among baseline E+P users (HR=0.25, 95% CI: 0.07-0.86 in 3 cases) as no association was observed for E-alone (HR=0.96, 95% CI: 0.28-3.29, in 6 cases).	('E+P', 'Chemical', '-', (59, 62))	('reduced', 'NegReg', (4, 11))	('E+P', 'Var', (59, 62))
946065	21505180	A non-significant reduction of risk of esophageal SCC was also observed with the duration of use of E-alone and E+P (data not shown).	('E+P', 'Chemical', '-', (112, 115))	('E+P', 'Var', (112, 115))	('esophageal SCC', 'Disease', (39, 53))	('esophageal SCC', 'Disease', 'MESH:D004941', (39, 53))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))
946079	21505180	Esophageal SCC mortality was inversely related with use of E+P, although non-significantly, consistent with the relationship observed with incidence of esophageal SCC.	('inversely', 'NegReg', (29, 38))	('SCC', 'Gene', (11, 14))	('SCC', 'Phenotype', 'HP:0002860', (11, 14))	('esophageal SCC', 'Disease', (152, 166))	('SCC', 'Gene', (163, 166))	('SCC', 'Gene', '6317', (11, 14))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('E+P', 'Chemical', '-', (59, 62))	('esophageal SCC', 'Disease', 'MESH:D004941', (152, 166))	('E+P', 'Var', (59, 62))	('SCC', 'Gene', '6317', (163, 166))
946090	21505180	Interestingly, we found that breastfeeding was associated with a non-significant 54% reduction of risk of esophageal adenocarcinoma (HR=0.44, 95% CI: 0.18-1.07), similar to the 59% reduction (95% CI: 18-80%) found in a case-control study from the UK.	('breastfeeding', 'Var', (29, 42))	('esophageal adenocarcinoma', 'Disease', (106, 131))	('reduction', 'NegReg', (85, 94))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (106, 131))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (106, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
946094	21505180	This study found that use of E+P among women with intact uterus was associated with a decreased risk (HR=0.41, 95% CI: 0.15-1.14).	('women', 'Species', '9606', (39, 44))	('decreased', 'NegReg', (86, 95))	('E+P', 'Var', (29, 32))	('E+P', 'Chemical', '-', (29, 32))
946114	19291787	Most (94%) patients had genotype 1 infection.	('patients', 'Species', '9606', (11, 19))	('infection', 'Disease', 'MESH:D007239', (35, 44))	('genotype 1', 'Var', (24, 34))	('infection', 'Disease', (35, 44))
946204	19291787	One study included only patients with baseline Metavir F0-1 (absent or portal tract fibrosis), another study had 26 patients with Metavir F3 (bridging fibrosis) but none had F4 (cirrhosis), and the third study included 18 patients with Ishak fibrosis >=3.	('cirrhosis', 'Disease', (178, 187))	('Metavir F3', 'Var', (130, 140))	('absent or portal tract', 'Phenotype', 'HP:0031942', (61, 83))	('patients', 'Species', '9606', (116, 124))	('fibrosis', 'Disease', (151, 159))	('patients', 'Species', '9606', (222, 230))	('fibrosis', 'Disease', 'MESH:D005355', (151, 159))	('cirrhosis', 'Disease', 'MESH:D005355', (178, 187))	('cirrhosis', 'Phenotype', 'HP:0001394', (178, 187))	('fibrosis', 'Disease', (84, 92))	('portal tract fibrosis', 'Phenotype', 'HP:0006580', (71, 92))	('fibrosis', 'Disease', (242, 250))	('patients', 'Species', '9606', (24, 32))	('fibrosis', 'Disease', 'MESH:D005355', (242, 250))	('fibrosis', 'Disease', 'MESH:D005355', (84, 92))	('Metavir F0-1', 'Var', (47, 59))
946206	19291787	In this fourth study, 13 patients had Metavir F2-3 (septal/bridging fibrosis) but none had F4.	('patients', 'Species', '9606', (25, 33))	('fibrosis', 'Disease', 'MESH:D005355', (68, 76))	('fibrosis', 'Disease', (68, 76))	('Metavir F2-3', 'Var', (38, 50))
946253	30646096	In this case-control study involving 142 patients with Barrett high-grade dysplasia and esophageal adenocarcinoma, HPV positivity was associated with a significantly improved disease-free survival compared with viral negativity.	('positivity', 'Var', (119, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (88, 113))	('disease-free survival', 'CPA', (175, 196))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('dysplasia', 'Disease', (74, 83))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('improved', 'PosReg', (166, 174))	('patients', 'Species', '9606', (41, 49))	('dysplasia', 'Disease', 'MESH:D004476', (74, 83))	('HPV', 'Species', '10566', (115, 118))	('HPV', 'Gene', (115, 118))
946271	30646096	Positivity for E6 and E7 mRNA, high p16INK4A expression, and low p53 expression were not associated with improved DFS.	('p16INK4A', 'Gene', (36, 44))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('E7 mRNA', 'Var', (22, 29))	('low', 'Var', (61, 64))	('p16INK4A', 'Gene', '1029', (36, 44))	('expression', 'MPA', (69, 79))	('expression', 'MPA', (45, 55))	('DFS', 'Disease', (114, 117))
946272	30646096	On multivariate analysis, superior DFS was demonstrated for HPV (HR, 0.39; 95% CI, 0.18-0.85; P = .02), biologically active virus (HR, 0.36; 95% CI, 0.15-0.86; P = .02), E6 and E7 mRNA (HR, 0.36; 95% CI, 0.14-0.96; P = .04), and high p16 expression (HR, 0.49; 95% CI, 0.27-0.89; P = .02).	('E7 mRNA', 'Var', (177, 184))	('p16', 'Gene', (234, 237))	('HPV', 'Species', '10566', (60, 63))	('p16', 'Gene', '1029', (234, 237))	('expression', 'MPA', (238, 248))
946277	30646096	Increasing high-risk HPV viral load and integration status has been linked with more severe disease along the Barrett metaplasia-dysplasia-adenocarcinoma sequence.	('HPV', 'Species', '10566', (21, 24))	('HPV', 'Gene', (21, 24))	('high-risk', 'Var', (11, 20))	('linked with', 'Reg', (68, 79))	('integration status', 'Var', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('Barrett metaplasia-dysplasia-adenocarcinoma', 'Disease', (110, 153))	('Barrett metaplasia-dysplasia-adenocarcinoma', 'Disease', 'MESH:D001471', (110, 153))
946303	30646096	Patients with locally advanced disease (T3 or T4 N0 or any T stage with N1) were potential candidates for neoadjuvant or adjuvant treatment.	('T4 N0', 'Var', (46, 51))	('T3', 'Var', (40, 42))	('Patients', 'Species', '9606', (0, 8))
946311	30646096	In addition, cervical cancer tissue, HNSCC samples, BE and BD, EAC, and esophageal squamous cell carcinoma (ESCC), which all had detectable transcriptionally active HPV (DNA positive by PCR and the presence of >=1 of 2 markers of biological activity, ie, E6 and E7 mRNA and/or p16INK4A), served as positive controls.	('E7 mRNA', 'Var', (262, 269))	('BE', 'Phenotype', 'HP:0100580', (52, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('HPV', 'Species', '10566', (165, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (72, 106))	('p16INK4A', 'Gene', (277, 285))	('cervical cancer', 'Disease', (13, 28))	('cervical cancer', 'Disease', 'MESH:D002583', (13, 28))	('HNSCC', 'Phenotype', 'HP:0012288', (37, 42))	('EAC', 'Phenotype', 'HP:0011459', (63, 66))	('esophageal squamous cell carcinoma', 'Disease', (72, 106))	('p16INK4A', 'Gene', '1029', (277, 285))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
946316	30646096	Using this criterion, we have demonstrated that high p16 expression is associated with HPV-associated BD and EAC with reasonable sensitivity and specificity as others have in HNSCC.	('expression', 'MPA', (57, 67))	('HPV-associated BD', 'Disease', (87, 104))	('p16', 'Gene', (53, 56))	('EAC', 'Phenotype', 'HP:0011459', (109, 112))	('HPV', 'Species', '10566', (87, 90))	('EAC', 'Disease', (109, 112))	('p16', 'Gene', '1029', (53, 56))	('high', 'Var', (48, 52))	('associated', 'Reg', (71, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (175, 180))
946318	30646096	Mutations of TP53 were confirmed by sequencing of the gene using the semiconductor-based Ion Torrent sequencing platform (ThermoFisher) according to the manufacturer's instructions as previously published.	('TP53', 'Gene', '7157', (13, 17))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (13, 17))
946321	30646096	Survival analysis was conducted using the Kaplan-Meier method to estimate the DFS and OS of the 5 HPV variables, ie, viral DNA status, transcriptionally active HPV, E6 and E7 mRNA, p16, and p53.	('p16', 'Gene', '1029', (181, 184))	('OS', 'Chemical', '-', (86, 88))	('p53', 'Gene', (190, 193))	('p53', 'Gene', '7157', (190, 193))	('p16', 'Gene', (181, 184))	('HPV', 'Species', '10566', (160, 163))	('E7 mRNA', 'Var', (172, 179))	('HPV', 'Species', '10566', (98, 101))
946326	30646096	A total of 142 patients were tested for HPV status, p16INK4A IHC, and E6 and E7 mRNA ISH (eFigure 1 in the Supplement).	('patients', 'Species', '9606', (15, 23))	('p16INK4A', 'Gene', '1029', (52, 60))	('E7 mRNA ISH', 'Var', (77, 88))	('HPV', 'Species', '10566', (40, 43))	('p16INK4A', 'Gene', (52, 60))	('tested', 'Reg', (29, 35))
946345	30646096	Kaplan-Meier graphs for DFS and OS of patients categorized by HPV, transcriptionally active virus, E6 and E7 mRNA, and high expression of p16 and low expression of p53 are shown in the Figure and in eFigure 1, eFigure 2, and eFigure 3 in the Supplement.	('p53', 'Gene', '7157', (164, 167))	('expression', 'MPA', (150, 160))	('p16', 'Gene', '1029', (138, 141))	('E7 mRNA', 'Var', (106, 113))	('expression', 'MPA', (124, 134))	('p16', 'Gene', (138, 141))	('OS', 'Chemical', '-', (32, 34))	('patients', 'Species', '9606', (38, 46))	('p53', 'Gene', (164, 167))	('HPV', 'Species', '10566', (62, 65))
946347	30646096	Conversely, positive status for E6 and E7 mRNA, high expression of p16INK4A, and low expression of p53 were not associated with improved DFS.	('p16INK4A', 'Gene', (67, 75))	('DFS', 'Disease', (137, 140))	('E7 mRNA', 'Var', (39, 46))	('p16INK4A', 'Gene', '1029', (67, 75))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))
946352	30646096	This resulted in a significantly enhanced DFS for HPV DNA positivity (HR, 0.36; 95% CI, 0.17-0.77; P = .009), presence of transcriptionally active virus (HR, 0.31; 95% CI, 0.13-0.72; P = .006), and E6 and E7 mRNA detection (HR, 0.32; 95% CI, 0.12-0.83; P = .02) (model 3 in Table 3).	('presence', 'Var', (110, 118))	('HPV DNA positivity', 'MPA', (50, 68))	('DFS', 'MPA', (42, 45))	('HPV', 'Species', '10566', (50, 53))	('enhanced', 'PosReg', (33, 41))
946355	30646096	Seventy-three (55.3%) harbored mutated TP53 and 59 (44.7%) had wild type.	('mutated', 'Var', (31, 38))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
946356	30646096	In the 73 specimens with TP53 mutations, 50 (68.5%) were missense mutations present in the DNA binding domain (exons 5-8; aa102-292), 2 (2.7%) were missense mutations in the oligomerization domain (exons 9-10), and 2 contained frameshift mutations in exons 5 and 8 that induced a loss of both DNA binding and oligomerization domains.	('TP53', 'Gene', (25, 29))	('loss', 'NegReg', (280, 284))	('mutations', 'Var', (30, 39))	('oligomerization domains', 'MPA', (309, 332))	('DNA', 'MPA', (293, 296))	('TP53', 'Gene', '7157', (25, 29))
946357	30646096	In 35 of 37 HPV-positive patients with HGD and EAC with successful sequencing, TP53 mutations were detected in only 9 patients (25.7%) compared with 64 of 97 (66.0%) in the viral-negative group (difference, -40.3%; 95% CI, -57.5% to -23.0%; P < .001 [Fisher exact test]).	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('EAC', 'Phenotype', 'HP:0011459', (47, 50))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (25, 33))	('HPV', 'Species', '10566', (12, 15))	('patients', 'Species', '9606', (118, 126))
946359	30646096	Esophageal lesional HPV status and associated viral transcriptional markers, ie, E6 and E7 mRNA (gold standard) and p16INK4A (surrogate marker) are associated with improved DFS in patients with HGD and EAC.	('improved', 'PosReg', (164, 172))	('HGD', 'Disease', (194, 197))	('p16INK4A', 'Gene', (116, 124))	('E7 mRNA', 'Var', (88, 95))	('EAC', 'Phenotype', 'HP:0011459', (202, 205))	('p16INK4A', 'Gene', '1029', (116, 124))	('Esophageal lesional HPV status', 'Disease', (0, 30))	('Esophageal lesional HPV status', 'Disease', 'MESH:D030361', (0, 30))	('DFS', 'Disease', (173, 176))	('patients', 'Species', '9606', (180, 188))
946371	30646096	A previous study found that HPV-positive EAC harbored approximately 50% fewer nonsilent somatic mutations than HPV-negative EAC.	('nonsilent somatic mutations', 'MPA', (78, 105))	('HPV', 'Species', '10566', (28, 31))	('fewer', 'NegReg', (72, 77))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('HPV', 'Species', '10566', (111, 114))	('EAC', 'Phenotype', 'HP:0011459', (124, 127))	('HPV-positive', 'Var', (28, 40))
946374	30646096	In this study, we similarly found that only a quarter of HPV-positive HGD and EAC lesions harbored TP53 mutations vs two-thirds of HPV-negative HGD and EAC having the same molecular aberration.	('TP53', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('positive HGD', 'Phenotype', 'HP:0410246', (61, 73))	('EAC', 'Phenotype', 'HP:0011459', (78, 81))	('EAC', 'Disease', (78, 81))	('HPV', 'Species', '10566', (131, 134))	('harbored', 'Reg', (90, 98))	('TP53', 'Gene', '7157', (99, 103))	('HPV', 'Species', '10566', (57, 60))	('EAC', 'Phenotype', 'HP:0011459', (152, 155))	('HGD', 'Disease', (70, 73))
946375	30646096	Although patients with EAC who have p53 mutations have been shown to have reduced OS in a recent meta-analysis, we could not confirm the same in our study.	('patients', 'Species', '9606', (9, 17))	('EAC', 'Phenotype', 'HP:0011459', (23, 26))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('mutations', 'Var', (40, 49))	('EAC', 'Disease', (23, 26))	('OS', 'Chemical', '-', (82, 84))	('reduced', 'NegReg', (74, 81))
946378	30646096	Patients whose HGD and EAC harbored transcriptionally active HPV (n = 30) were significantly younger (mean [SD] age, 61.4 [11.9] years) compared with patients with esophageal lesions devoid of biologically active virus (n = 112) (mean [SD] age, 67.2 [11.9] years).	('HPV', 'Gene', (61, 64))	('transcriptionally', 'Var', (36, 53))	('esophageal lesions', 'Disease', 'MESH:D004935', (164, 182))	('EAC', 'Phenotype', 'HP:0011459', (23, 26))	('esophageal lesions', 'Disease', (164, 182))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (150, 158))	('HPV', 'Species', '10566', (61, 64))
946383	30646096	Patients with HPV-positive HNSCC are generally 10 years younger and have more early T-stage but advanced N-stage disease, although they respond better to treatment and have a better outcome than patients with HPV-negative HNSCC.	('HPV', 'Species', '10566', (14, 17))	('HNSCC', 'Phenotype', 'HP:0012288', (27, 32))	('N-stage disease', 'Disease', 'MESH:D058625', (105, 120))	('Patients', 'Species', '9606', (0, 8))	('HNSCC', 'Phenotype', 'HP:0012288', (222, 227))	('patients', 'Species', '9606', (195, 203))	('N-stage disease', 'Disease', (105, 120))	('HPV', 'Species', '10566', (209, 212))	('HPV-positive', 'Var', (14, 26))
946473	29149923	Metoclopramide is a dopamine receptor antagonist (D2) which also activates 5-hydroxytryptamine (5HT4) receptors for the combined effect of increased peristalsis of the duodenum and jejunum, increased tone and amplitude of gastric contractions, and relaxation of the pyloric sphincter and duodenal bulb, while simultaneously increasing lower esophageal sphincter tone.	('5-hydroxytryptamine', 'Chemical', 'MESH:D012701', (75, 94))	('tone', 'MPA', (200, 204))	('gastric contractions', 'Disease', 'MESH:D013274', (222, 242))	('esophageal sphincter', 'Disease', 'MESH:D009122', (341, 361))	('increasing', 'PosReg', (324, 334))	('amplitude', 'MPA', (209, 218))	('increased peristalsis', 'Phenotype', 'HP:0100770', (139, 160))	('gastric contractions', 'Disease', (222, 242))	('increased', 'PosReg', (139, 148))	('esophageal sphincter', 'Disease', (341, 361))	('Metoclopramide', 'Var', (0, 14))	('Metoclopramide', 'Chemical', 'MESH:D008787', (0, 14))	('5HT', 'Chemical', 'MESH:D012701', (96, 99))	('activates', 'PosReg', (65, 74))	('sphincter tone', 'Phenotype', 'HP:0002839', (352, 366))	('peristalsis', 'CPA', (149, 160))	('5HT4) receptors', 'Protein', (96, 111))	('increased', 'PosReg', (190, 199))	('relaxation', 'CPA', (248, 258))
946485	29149923	Interestingly, a study of SSc patients revealed that the lower esophageal sphincter pressure was increased significantly by both intravenous cimetidine and famotidine.	('increased', 'PosReg', (97, 106))	('esophageal sphincter', 'Disease', (63, 83))	('famotidine', 'Var', (156, 166))	('cimetidine', 'Chemical', 'MESH:D002927', (141, 151))	('esophageal sphincter', 'Disease', 'MESH:D009122', (63, 83))	('patients', 'Species', '9606', (30, 38))	('sphincter pressure', 'Phenotype', 'HP:0002839', (74, 92))	('famotidine', 'Chemical', 'MESH:D015738', (156, 166))
946491	29149923	Erythromycin in lower doses than those required for antibiotic effectiveness is believed to act as a motilin agonist as well as motilin mimic, thus stimulating gastric peristalsis.	('motilin', 'Gene', (101, 108))	('motilin', 'Gene', '4295', (128, 135))	('motilin', 'Gene', '4295', (101, 108))	('Erythromycin', 'Chemical', 'MESH:D004917', (0, 12))	('gastric peristalsis', 'MPA', (160, 179))	('Erythromycin', 'Var', (0, 12))	('stimulating', 'PosReg', (148, 159))	('motilin', 'Gene', (128, 135))	('gastric peristalsis', 'Phenotype', 'HP:0100770', (160, 179))
946520	29149923	Of note, while erythromycin can treat gastroparesis through its effects on motilin, it can also decrease small intestinal motility.	('erythromycin', 'Var', (15, 27))	('motilin', 'Gene', (75, 82))	('motilin', 'Gene', '4295', (75, 82))	('small intestinal motility', 'CPA', (105, 130))	('decrease', 'NegReg', (96, 104))	('gastroparesis', 'Disease', (38, 51))	('gastroparesis', 'Disease', 'MESH:D018589', (38, 51))	('gastroparesis', 'Phenotype', 'HP:0002578', (38, 51))	('erythromycin', 'Chemical', 'MESH:D004917', (15, 27))	('effects', 'Reg', (64, 71))
946527	28938579	PM10 (p=0.046) and NO2 (p=0.03) both had significant linear correlations with esophageal cancer mortality rates.	('NO2', 'Var', (19, 22))	('NO2', 'Chemical', 'MESH:D009585', (19, 22))	('PM10', 'Var', (0, 4))	('PM10', 'Chemical', '-', (0, 4))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
946528	28938579	After introducing smoking as a risk factor in models of multiple linear regression analyses, PM10 was still an independent risk factor that increased esophageal cancer mortality rates.	('esophageal cancer', 'Disease', (150, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('increased', 'PosReg', (140, 149))	('PM10', 'Var', (93, 97))	('PM10', 'Chemical', '-', (93, 97))
946551	28938579	PM10 levels and NO2 levels both had significant linear correlations with age-standardized esophageal cancer mortality rates.	('NO2', 'Chemical', 'MESH:D009585', (16, 19))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('PM10', 'Chemical', '-', (0, 4))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('PM10 levels', 'Var', (0, 11))
946552	28938579	After introducing smoking rates as an adjustment, PM10 was still an independent risk factor that increased esophageal cancer mortality rates in Shandong Province.	('PM10', 'Chemical', '-', (50, 54))	('increased', 'PosReg', (97, 106))	('esophageal cancer', 'Disease', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('PM10', 'Var', (50, 54))
946557	28938579	Though there were more male patients than female patients in both groups, the proportion of female patients elevated in high PM10 level group.	('high PM10', 'Var', (120, 129))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (49, 57))	('elevated', 'PosReg', (108, 116))	('PM10', 'Chemical', '-', (125, 129))	('patients', 'Species', '9606', (28, 36))
946560	28938579	There was statistically significant difference in gender distributions (p=0.02) between high PM10 level group and low PM10 level group after subgroup analysis.	('high PM10 level', 'Var', (88, 103))	('PM10', 'Chemical', '-', (118, 122))	('PM10', 'Chemical', '-', (93, 97))	('significant', 'Reg', (24, 35))
946566	28938579	After introducing city-level smoking rates as an adjustment, PM10 was still an independent risk factor that contributed to excess esophageal cancer mortality.	('excess esophageal cancer', 'Disease', 'MESH:D004938', (123, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('PM10', 'Var', (61, 65))	('PM10', 'Chemical', '-', (61, 65))	('excess esophageal cancer', 'Disease', (123, 147))
946570	28938579	In ecologic surveys in China, Deoxynivalenol was linked with a higher incidence of esophageal cancer.	('Deoxynivalenol', 'Chemical', 'MESH:C007262', (30, 44))	('esophageal cancer', 'Disease', (83, 100))	('Deoxynivalenol', 'Var', (30, 44))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))
946580	28938579	In contrary to our hypothesis, PM10 didn't increase the degree of malignancy of ESCC (Table 4).	('malignancy', 'Disease', 'MESH:D009369', (66, 76))	('malignancy', 'Disease', (66, 76))	('PM10', 'Var', (31, 35))	('PM10', 'Chemical', '-', (31, 35))	('ESCC', 'Disease', (80, 84))
946585	28938579	What's more, PM10 might have little influence on the clinicopathological features of ESCC, or the influence only contributed marginally that could be covered up by other factors.	('PM10', 'Var', (13, 17))	('PM10', 'Chemical', '-', (13, 17))	('ESCC', 'Disease', (85, 89))
946592	28938579	Even though PM10 was still an independent risk factor that increased esophageal cancer mortality rates after introducing smoking as an adjustment, the models were not robust enough for the amount of samples.	('PM10', 'Var', (12, 16))	('PM10', 'Chemical', '-', (12, 16))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('increased', 'PosReg', (59, 68))
946614	28938579	So we might come to the conclusion that air pollution, especially PM10, had an adverse effect on esophageal cancer.	('esophageal cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('PM10', 'Var', (66, 70))	('PM10', 'Chemical', '-', (66, 70))
946634	28938579	Gravimetric method, chemiluminescence method and ultraviolet fluorescence method were used to measure PM10, NO2 and SO2, respectively.	('SO2', 'Chemical', 'MESH:D013458', (116, 119))	('PM10', 'Var', (102, 106))	('PM10', 'Chemical', '-', (102, 106))	('NO2', 'Var', (108, 111))	('NO2', 'Chemical', 'MESH:D009585', (108, 111))
946638	28938579	The city-level mean concentrations of PM10, SO2, NO2 were plotted against the age-standardized mortality rates of esophageal cancer in 2015, respectively.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('PM10', 'Var', (38, 42))	('PM10', 'Chemical', '-', (38, 42))	('NO2', 'Chemical', 'MESH:D009585', (49, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('SO2', 'Chemical', 'MESH:D013458', (44, 47))
946641	28938579	Multiple linear regression analyses of esophageal cancer mortality rates were run with the combination of mean concentrations of PM10, SO2, NO2 and city-level smoking rates.	('PM10', 'Var', (129, 133))	('PM10', 'Chemical', '-', (129, 133))	('NO2', 'Chemical', 'MESH:D009585', (140, 143))	('esophageal cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('SO2', 'Chemical', 'MESH:D013458', (135, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))
946653	28938579	ESCC esophageal squamous cell carcinoma PM10 particulate matter less than 10 mum in aerodynamic diameter PM2.5 particulate matter less than 2.5 mum in aerodynamic diameter IARC International Agency for Research on Cancer SDCDC Shandong Center for Disease Control and Prevention SDEPB Shandong Environmental Protection Bureau PAHs polycyclic aromatic hydrocarbons.	('PM2', 'Chemical', '-', (105, 108))	('PM10', 'Var', (40, 44))	('PM10', 'Chemical', '-', (40, 44))	('SDEPB', 'Chemical', '-', (278, 283))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (5, 39))	('SDCDC', 'Chemical', '-', (221, 226))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (330, 362))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('Cancer', 'Phenotype', 'HP:0002664', (214, 220))	('esophageal squamous cell carcinoma', 'Disease', (5, 39))	('PAHs', 'Chemical', 'MESH:D011084', (325, 329))
946699	28638233	However, unlike the above two cases, the outer layer cells of the neoplastic tubules were immunoreactive for CK34bE12 and CK5/6, but immunonegative for SMA.	('CK34bE12', 'Var', (109, 117))	('SMA', 'Gene', (152, 155))	('CK5/6', 'Gene', '3852', (122, 127))	('SMA', 'Gene', '6606', (152, 155))	('CK5/6', 'Gene', (122, 127))
946731	27877224	To determine whether knockdown the expression of ATP7A could reverse the platinum-resistance of EC109/DDP cells or not, we used RNA interference system to explore the role of ATP7A in platinum resistance.	('platinum-resistance', 'CPA', (73, 92))	('ATP7A', 'Gene', (49, 54))	('platinum', 'Chemical', 'MESH:D010984', (73, 81))	('ATP7A', 'Gene', '538', (49, 54))	('DDP', 'Gene', (102, 105))	('platinum', 'Chemical', 'MESH:D010984', (184, 192))	('ATP7A', 'Gene', (175, 180))	('DDP', 'Gene', '1678', (102, 105))	('ATP7A', 'Gene', '538', (175, 180))	('knockdown', 'Var', (21, 30))
946734	27877224	ATP7A targeted small interfering RNA duplex at 100nM final concentration added into DDP-resistant cancer cells (EC109/DDP) markedly inhibited the expression of ATP7A as determined by Western blot (83.0%) and partially reversed DDP-resistance (37.09%), moreover, it also increased cell apoptosis at different DDP concentrations.	('DDP', 'Gene', '1678', (118, 121))	('DDP', 'Gene', '1678', (308, 311))	('cancer', 'Disease', (98, 104))	('DDP', 'Gene', (118, 121))	('expression', 'MPA', (146, 156))	('DDP', 'Gene', (308, 311))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inhibited', 'NegReg', (132, 141))	('cell apoptosis', 'CPA', (280, 294))	('DDP', 'Gene', '1678', (84, 87))	('DDP', 'Gene', (84, 87))	('DDP', 'Gene', '1678', (227, 230))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('DDP', 'Gene', (227, 230))	('ATP7A', 'Gene', (0, 5))	('ATP7A', 'Gene', '538', (0, 5))	('small', 'Var', (15, 20))	('increased', 'PosReg', (270, 279))	('ATP7A', 'Gene', (160, 165))	('ATP7A', 'Gene', '538', (160, 165))
946798	27877224	As shown in Figure 2, ATP7A expressions in EC109/DDP cells changed after treatment with different final concentration of ATP7A-targeted siRNA sequences (25nM, 50nM and 100nM) for 80h.	('ATP7A', 'Gene', (121, 126))	('ATP7A', 'Gene', '538', (121, 126))	('DDP', 'Gene', (49, 52))	('ATP7A', 'Gene', (22, 27))	('25nM', 'Var', (153, 157))	('ATP7A', 'Gene', '538', (22, 27))	('DDP', 'Gene', '1678', (49, 52))	('changed', 'Reg', (59, 66))
946806	27877224	Silencing ATPA was able to partially reverse DDP-resistance in EC109/DDP cells.	('DDP', 'Gene', '1678', (45, 48))	('ATPA', 'Gene', (10, 14))	('DDP', 'Gene', (69, 72))	('DDP', 'Gene', (45, 48))	('Silencing', 'Var', (0, 9))	('ATPA', 'Chemical', '-', (10, 14))	('DDP', 'Gene', '1678', (69, 72))
946821	27877224	Moreover, in EC109/DDP cells, ATP7A siRNA knockdown (83.0%) was able to partially reverse DDP-resistance (37.09%).	('DDP', 'Gene', (19, 22))	('DDP', 'Gene', '1678', (90, 93))	('siRNA', 'Gene', (36, 41))	('DDP', 'Gene', (90, 93))	('DDP', 'Gene', '1678', (19, 22))	('ATP7A', 'Gene', (30, 35))	('ATP7A', 'Gene', '538', (30, 35))	('knockdown', 'Var', (42, 51))
946823	27877224	In our study, silencing of ATP7A increased cells apoptosis rate in EC109/DDP, so reduced expression of ATP7A by siRNA knockdown resulted in enhancement of DDP-sensitivity and increased DDP-induced apoptosis.	('silencing', 'Var', (14, 23))	('ATP7A', 'Gene', (27, 32))	('DDP', 'Gene', '1678', (73, 76))	('expression', 'MPA', (89, 99))	('ATP7A', 'Gene', (103, 108))	('ATP7A', 'Gene', '538', (27, 32))	('ATP7A', 'Gene', '538', (103, 108))	('increased cells apoptosis rate', 'Phenotype', 'HP:0030887', (33, 63))	('DDP', 'Gene', (185, 188))	('DDP', 'Gene', (155, 158))	('DDP', 'Gene', (73, 76))	('increased', 'PosReg', (33, 42))	('enhancement', 'PosReg', (140, 151))	('reduced', 'NegReg', (81, 88))	('increased', 'PosReg', (175, 184))	('cells apoptosis rate', 'CPA', (43, 63))	('DDP', 'Gene', '1678', (185, 188))	('DDP', 'Gene', '1678', (155, 158))
946828	27877224	Thus, silencing the copper transporters resulting in copper level change which may have an additional benefit to reduce angiogenesis.	('reduce', 'NegReg', (113, 119))	('copper level', 'MPA', (53, 65))	('change', 'Reg', (66, 72))	('angiogenesis', 'CPA', (120, 132))	('copper', 'Chemical', 'MESH:D003300', (53, 59))	('copper', 'Chemical', 'MESH:D003300', (20, 26))	('copper', 'Enzyme', (20, 26))	('silencing', 'Var', (6, 15))
946830	27877224	reported that knock-out of Ctr1 in murine embryonic fibroblasts led to reduced uptake of DDP, CBDCA and to a lesser extent of L-OHP.	('uptake', 'MPA', (79, 85))	('DDP', 'Gene', (89, 92))	('Ctr1', 'Gene', (27, 31))	('reduced', 'NegReg', (71, 78))	('CBDCA', 'Chemical', 'MESH:D016190', (94, 99))	('DDP', 'Gene', '1678', (89, 92))	('L-OHP', 'Chemical', 'MESH:D000077150', (126, 131))	('knock-out', 'Var', (14, 23))	('murine', 'Species', '10090', (35, 41))
946836	27877224	But Mangala, LS reported that silencing of ATP7A gene had no significant effect on the sensitivity of resistant cells to DDP, while ATP7B silencing resulted in partial enhancement of DDP-sensitivity and increased DNA adduct formation in cisplatin-resistant ovarian cells.	('cisplatin', 'Chemical', 'MESH:D002945', (237, 246))	('DDP', 'Gene', '1678', (121, 124))	('silencing', 'Var', (138, 147))	('DDP', 'Gene', '1678', (183, 186))	('ATP7B', 'Gene', (132, 137))	('DDP', 'Gene', (121, 124))	('DDP', 'Gene', (183, 186))	('ATP7A', 'Gene', (43, 48))	('ATP7A', 'Gene', '538', (43, 48))	('enhancement', 'PosReg', (168, 179))	('ATP7B', 'Gene', '540', (132, 137))	('DNA adduct formation', 'MPA', (213, 233))	('increased', 'PosReg', (203, 212))
946884	27191723	Taqman assays (Applied Biosystems, Forster City, CA, USA) were used to measure the expression of BMPR1a (Hs01034913_g1), BMPR1b (Hs00176144_m1), BMPR2 (Hs00176148_m1) and SNAIL2 (Hs00950344_m1).	('Hs00176148_m1', 'Var', (152, 165))	('Hs00950344_m1', 'Var', (179, 192))	('SNAIL2', 'Gene', '6591', (171, 177))	('SNAIL2', 'Gene', (171, 177))	('BMPR1b', 'Gene', (121, 127))	('Hs00176144_m1', 'Var', (129, 142))	('BMPR2', 'Gene', (145, 150))	('BMPR1a', 'Gene', '657', (97, 103))	('BMPR2', 'Gene', '659', (145, 150))	('BMPR1b', 'Gene', '658', (121, 127))	('BMPR1a', 'Gene', (97, 103))	('Hs01034913_g1', 'Var', (105, 118))
946885	27191723	Expression of the reference genes GAPDH (Hs4333764F) and B2M (Hs4333766F) were used for normalization.	('Hs4333766F', 'Var', (62, 72))	('B2M', 'Gene', '567', (57, 60))	('GAPDH', 'Gene', (34, 39))	('B2M', 'Gene', (57, 60))	('Hs4333764F', 'Var', (41, 51))	('GAPDH', 'Gene', '2597', (34, 39))
946986	27191723	In the future, manipulation of the BMP4 pathway may help to prevent neoplastic progression in BE patients.	('BE', 'Phenotype', 'HP:0100580', (94, 96))	('BMP4', 'Gene', '652', (35, 39))	('manipulation', 'Var', (15, 27))	('neoplastic progression', 'CPA', (68, 90))	('BMP4', 'Gene', (35, 39))	('patients', 'Species', '9606', (97, 105))
946994	24065096	In addition, use of DNA assays for clinical medicine can be significantly sensitive and specific if cancer-specific DNA alterations are tested instead of elevation of circulating DNA concentration.	('clinical', 'Species', '191496', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('alterations', 'Var', (120, 131))
946999	24065096	However, there is still a challenge to authenticate the actual clinical validity of various CCFDNA alterations as potential cancer biomarkers in practice for individual tumor types.	('clinical', 'Species', '191496', (63, 71))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('alterations', 'Var', (99, 110))	('tumor', 'Disease', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
947006	24065096	Additional minor source include cell lysis by the necrotic pathway, spontaneous release of newly synthesized nucleic acids, break down of blood cells, break down of any pathogens such as bacteria or viruses, and leukocyte surface DNA.	('break', 'MPA', (124, 129))	('necrotic', 'Disease', 'MESH:D009336', (50, 58))	('necrotic', 'Disease', (50, 58))	('cell lysis', 'CPA', (32, 42))	('break', 'Var', (151, 156))	('release of newly synthesized nucleic acids', 'MPA', (80, 122))
947007	24065096	For example, apoptosis has been found to produce fragments of ~180 bp, whereas necrosis results in higher molecular weight fragments.	('necrosis', 'Disease', (79, 87))	('apoptosis', 'CPA', (13, 22))	('necrosis', 'Disease', 'MESH:D009336', (79, 87))	('fragments', 'Var', (49, 58))	('men', 'Species', '9606', (53, 56))	('men', 'Species', '9606', (127, 130))
947033	24065096	In comparison to traditional techniques including phenol chloroform and alcohol extraction, methylation on beads yields a 1.5- to 5-fold improvement in extraction efficiency.	('men', 'Species', '9606', (144, 147))	('methylation', 'Var', (92, 103))	('phenol chloroform', 'Chemical', '-', (50, 67))	('extraction', 'MPA', (152, 162))	('alcohol', 'Chemical', 'MESH:D000438', (72, 79))	('improvement', 'PosReg', (137, 148))
947035	24065096	Thus, point mutations, copy number variations, loss of heterozygosity or aneuploidy can be detected.	('loss of heterozygosity', 'Var', (47, 69))	('aneuploidy', 'Disease', (73, 83))	('copy number variations', 'Var', (23, 45))	('point mutations', 'Var', (6, 21))	('aneuploidy', 'Disease', 'MESH:D000782', (73, 83))
947040	24065096	In particular, CpG methylation in the promoter region of certain genes has been observed as the earliest and most frequent alteration in some cancers by causing silencing of tumor suppressors.	('tumor', 'Disease', (174, 179))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('CpG methylation', 'Var', (15, 30))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('silencing', 'NegReg', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
947042	24065096	Hence, the prognostic value of aberrant DNA methylation and therapeutic implications of demethylation of methylated genes could further improve the management of patients with different kinds of malignancies.	('patients', 'Species', '9606', (162, 170))	('improve', 'PosReg', (136, 143))	('malignancies', 'Disease', 'MESH:D009369', (195, 207))	('aberrant', 'Var', (31, 39))	('malignancies', 'Disease', (195, 207))	('men', 'Species', '9606', (154, 157))
947043	24065096	Examination of serum for circulating tumor DNA with abnormal methylation patterns offers a possible method for early detection of several cancers.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('methylation', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
947054	24065096	Expansions of microsatellite DNA repeats contribute to the inheritance of nearly 30 developmental and neurological disorders.	('neurological disorders', 'Disease', 'MESH:D009422', (102, 124))	('Expansions', 'Var', (0, 10))	('microsatellite DNA repeats', 'Protein', (14, 40))	('neurological disorders', 'Disease', (102, 124))	('men', 'Species', '9606', (91, 94))	('contribute', 'Reg', (41, 51))	('inheritance', 'Reg', (59, 70))
947062	24065096	Recent tumor genome sequencing confirmed that one tumor often consists of multiple cell subpopulations (clones) which bear different, but related, genetic profiles such as mutation and copy number variation (CNV) profiles.	('tumor', 'Disease', (7, 12))	('copy number variation', 'Var', (185, 206))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
947063	24065096	Identification of genetic variations (SNP, CNV) and epigenetic alterations from primary tumor cells has become a common method to discover genes critical to the development, progression, and therapeutic resistance of cancer.	('epigenetic alterations', 'Var', (52, 74))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('men', 'Species', '9606', (168, 171))	('tumor', 'Disease', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
947065	24065096	The genetic variation in genes associated with angiogenesis, major histocompatibility complexes (MHCs), the immune system, and inflammation may affect the final outcome and survival in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (192, 200))	('angiogenesis', 'CPA', (47, 59))	('inflammation', 'Disease', 'MESH:D007249', (127, 139))	('inflammation', 'Disease', (127, 139))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('affect', 'Reg', (144, 150))	('genetic variation', 'Var', (4, 21))	('final outcome', 'CPA', (155, 168))	('cancer', 'Disease', (185, 191))	('survival', 'CPA', (173, 181))
947067	24065096	Genetic variants in growth factor signaling (e.g., EGFR, ERBB2, and FGF1) appear to also influence cancer risk.	('ERBB2', 'Gene', '2064', (57, 62))	('EGFR', 'Gene', (51, 55))	('influence', 'Reg', (89, 98))	('ERBB2', 'Gene', (57, 62))	('FGF1', 'Gene', '2246', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('FGF1', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Genetic variants', 'Var', (0, 16))	('EGFR', 'Gene', '1956', (51, 55))
947068	24065096	For example genetic variations have been associated with survival after diagnosis with breast cancer.	('genetic variations', 'Var', (12, 30))	('associated with', 'Reg', (41, 56))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
947069	24065096	Even in triple negative breast cancer there are novel variants as a result of splicing.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('breast cancer', 'Disease', (24, 37))	('splicing', 'Var', (78, 86))
947071	24065096	In hepatocellular carcinoma, the presence of A1762T/G1764A alteration was independently associated with the risk of HCC.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('G1764A', 'SUBSTITUTION', 'None', (52, 58))	('A1762T', 'Var', (45, 51))	('HCC', 'Disease', (116, 119))	('G1764A', 'Var', (52, 58))	('associated', 'Reg', (88, 98))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('A1762T', 'SUBSTITUTION', 'None', (45, 51))
947072	24065096	Genetic variations have been detected in most of the solid and hematopoietic tumors.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (63, 83))	('detected', 'Reg', (29, 37))	('hematopoietic tumors', 'Disease', (63, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Genetic variations', 'Var', (0, 18))
947076	24065096	There is high detection concordance for critical "hot-spot" mutations in matched CCFDNA and archival tumor tissue.	('CCFDNA', 'Disease', (81, 87))	('archival tumor', 'Disease', (92, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutations', 'Var', (60, 69))	('archival tumor', 'Disease', 'MESH:D009369', (92, 106))
947077	24065096	In summary, genetics alterations include decreased strand stability, presence of specific oncogenes, methylation or mutation of tumor suppressor genes, gene amplification, and microsatellite alterations.	('methylation', 'Var', (101, 112))	('oncogenes', 'Gene', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('strand stability', 'CPA', (51, 67))	('mutation', 'Var', (116, 124))	('decreased', 'NegReg', (41, 50))	('microsatellite alterations', 'Var', (176, 202))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('gene', 'Gene', (152, 156))
947083	24065096	For these cases, aberrant hypermethylation of the DCR2 promoter of the serum DNA has been helpful in predicting prognosis, therapeutic efficacy, and detecting reoccurrence in (non MNA) neuroblastomas.	('neuroblastoma', 'Phenotype', 'HP:0003006', (185, 198))	('DCR2', 'Gene', (50, 54))	('neuroblastomas', 'Phenotype', 'HP:0003006', (185, 199))	('neuroblastomas', 'Disease', 'MESH:D009447', (185, 199))	('aberrant hypermethylation', 'Var', (17, 42))	('DCR2', 'Gene', '8793', (50, 54))	('neuroblastomas', 'Disease', (185, 199))
947085	24065096	CCFDNA in glial tumors is useful for both LOH and aberrant gene promoter methylation.	('aberrant gene', 'Var', (50, 63))	('glial tumors', 'Disease', 'MESH:D005910', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('glial tumors', 'Disease', (10, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
947097	24065096	Also, as in neuroblastoma, the patients with glial tumors are characterized by a higher frequency of RASSF1A hypermethylation that differentiates primary from metastatic brain cancers.	('RASSF1A', 'Gene', '11186', (101, 108))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('neuroblastoma', 'Disease', 'MESH:D009447', (12, 25))	('glial tumors', 'Disease', 'MESH:D005910', (45, 57))	('neuroblastoma', 'Disease', (12, 25))	('brain cancers', 'Disease', 'MESH:D001932', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('brain cancers', 'Disease', (170, 183))	('RASSF1A', 'Gene', (101, 108))	('glial tumors', 'Disease', (45, 57))	('differentiates', 'Reg', (131, 145))	('patients', 'Species', '9606', (31, 39))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('neuroblastoma', 'Phenotype', 'HP:0003006', (12, 25))	('hypermethylation', 'Var', (109, 125))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('primary', 'Disease', (146, 153))
947100	24065096	The LOH at all markers was found in the fraction containing short DNA fragments than in the fraction containing the long DNA molecules, The most notable among these markers is LOH of D12S1725 which has been mapped to cyclin D2 and is correlated with shorter overall survival.	('overall survival', 'CPA', (258, 274))	('LOH', 'Var', (176, 179))	('men', 'Species', '9606', (74, 77))	('cyclin D2', 'Gene', '894', (217, 226))	('cyclin D2', 'Gene', (217, 226))	('shorter', 'NegReg', (250, 257))	('D12S1725', 'Var', (183, 191))
947102	24065096	Amplified HER2 in CCFDNA is a useful marker in patients with HER2-positive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('HER2-positive breast cancer', 'Disease', (61, 88))	('patients', 'Species', '9606', (47, 55))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (61, 88))	('HER2', 'Gene', (61, 65))	('HER2', 'Gene', (10, 14))	('HER2', 'Gene', '2064', (61, 65))	('HER2', 'Gene', '2064', (10, 14))	('Amplified', 'Var', (0, 9))
947104	24065096	The detection of methylated genes in circulating DNA found in serum is also associated with the detection of circulating tumor cells in blood.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('associated', 'Reg', (76, 86))	('methylated genes', 'Var', (17, 33))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
947106	24065096	Methylation status of ERbeta (estrogen receptor beta) and RARbeta2 (retinoic acid receptor beta2) in serum could also potentially be used to predict invasive ductal breast carcinoma.	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (149, 181))	('RARbeta', 'Gene', '5915', (58, 65))	('predict', 'Reg', (141, 148))	('ERbeta', 'Gene', '2100', (22, 28))	('Methylation', 'Var', (0, 11))	('ERbeta', 'Gene', (22, 28))	('RARbeta', 'Gene', (58, 65))	('estrogen receptor beta', 'Gene', (30, 52))	('breast carcinoma', 'Phenotype', 'HP:0003002', (165, 181))	('estrogen receptor beta', 'Gene', '2100', (30, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('invasive ductal breast carcinoma', 'Disease', (149, 181))
947107	24065096	Hence, concurrent ERbeta and RARbeta2 methylation as well as loss of ERbeta expression may serve as good prognostic markers.	('ERbeta', 'Gene', (18, 24))	('ERbeta', 'Gene', (69, 75))	('RARbeta', 'Gene', (29, 36))	('methylation', 'Var', (38, 49))	('expression', 'MPA', (76, 86))	('ERbeta', 'Gene', '2100', (18, 24))	('loss', 'NegReg', (61, 65))	('RARbeta', 'Gene', '5915', (29, 36))	('ERbeta', 'Gene', '2100', (69, 75))
947109	24065096	The methylation statuses of CST6, APC, and RASSF1A have been shown to be independent prognostic markers in breast cancer patients.	('RASSF1A', 'Gene', '11186', (43, 50))	('APC', 'Gene', (34, 37))	('CST6', 'Gene', (28, 32))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('methylation statuses', 'Var', (4, 24))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('APC', 'Gene', '324', (34, 37))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('CST6', 'Gene', '1474', (28, 32))	('patients', 'Species', '9606', (121, 129))	('RASSF1A', 'Gene', (43, 50))
947110	24065096	Methylated RASSF1A, cyclin D2, and RARbeta2 genes in CCFDNA are detected in 95% of breast cancer patients.	('CCFDNA', 'Disease', (53, 59))	('RARbeta', 'Gene', '5915', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('RASSF1A', 'Gene', (11, 18))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('cyclin D2', 'Gene', '894', (20, 29))	('detected', 'Reg', (64, 72))	('RASSF1A', 'Gene', '11186', (11, 18))	('RARbeta', 'Gene', (35, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('Methylated', 'Var', (0, 10))	('cyclin D2', 'Gene', (20, 29))	('patients', 'Species', '9606', (97, 105))
947111	24065096	In addition, aberrant hypermethylation of p16 and CDH1 (E-cadherin or CD324 which is a tumor suppressor gene) are found in the plasma of 82% of breast cancer patients.	('CD324', 'Gene', '999', (70, 75))	('p16', 'Gene', '1029', (42, 45))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CD324', 'Gene', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('tumor', 'Disease', (87, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('aberrant hypermethylation', 'Var', (13, 38))	('p16', 'Gene', (42, 45))	('CDH1', 'Gene', (50, 54))	('CDH1', 'Gene', '999', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patients', 'Species', '9606', (158, 166))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))
947112	24065096	Specifically, aberrant p16 methylation in plasma and elevated serum CEA levels were associated with advanced tumor stage, tumor size, and extensive nodal metastasis as well.	('p16', 'Gene', (23, 26))	('methylation', 'MPA', (27, 38))	('elevated', 'PosReg', (53, 61))	('elevated serum CEA', 'Phenotype', 'HP:0031029', (53, 71))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('aberrant', 'Var', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CEA', 'Gene', (68, 71))	('CEA', 'Gene', '1048', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('associated', 'Reg', (84, 94))	('p16', 'Gene', '1029', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (109, 114))	('extensive nodal metastasis', 'CPA', (138, 164))
947116	24065096	BRCA1 methylation frequency has been found to be different among responsive and non-responsive groups.	('BRCA1', 'Gene', '672', (0, 5))	('methylation', 'Var', (6, 17))	('BRCA1', 'Gene', (0, 5))
947139	24065096	Furthermore, unmethylated CDH1/CDH13 in serum samples is most likely associated with better disease-free survival.	('better', 'PosReg', (85, 91))	('CDH1', 'Gene', (31, 35))	('CDH13', 'Gene', '1012', (31, 36))	('associated', 'Reg', (69, 79))	('CDH1', 'Gene', '999', (31, 35))	('CDH1', 'Gene', '999', (26, 30))	('CDH1', 'Gene', (26, 30))	('CDH13', 'Gene', (31, 36))	('disease-free survival', 'CPA', (92, 113))	('unmethylated', 'Var', (13, 25))
947142	24065096	Hypermethylation of RASSF1A (tumor suppressor gene) was found in circulating tumor-specific DNA in 43.1% of patients.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('Hypermethylation', 'Var', (0, 16))	('RASSF1A', 'Gene', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('RASSF1A', 'Gene', '11186', (20, 27))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', (77, 82))	('found', 'Reg', (56, 61))
947144	24065096	Hypermethylation of RASSF1A was more frequently encountered in stage III and IV than stage I and II tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('encountered', 'Reg', (48, 59))	('stage III', 'Disease', (63, 72))	('Hypermethylation', 'Var', (0, 16))	('RASSF1A', 'Gene', (20, 27))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('RASSF1A', 'Gene', '11186', (20, 27))	('II tumors', 'Disease', (97, 106))	('II tumors', 'Disease', 'MESH:D009369', (97, 106))
947146	24065096	Also, the presence of KRAS mutations in mucinous ovarian cancer along with CCFDNA and p53-antibody in serous tumors was correlated with the highest risk of cancer progression.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', (57, 63))	('serous tumors', 'Disease', 'MESH:D018284', (102, 115))	('KRAS', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('p53', 'Gene', '7157', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('correlated', 'Reg', (120, 130))	('serous tumors', 'Disease', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('p53', 'Gene', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mucinous ovarian cancer', 'Disease', 'MESH:D010051', (40, 63))	('mucinous ovarian cancer', 'Phenotype', 'HP:0031494', (40, 63))	('cancer', 'Disease', (156, 162))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mucinous ovarian cancer', 'Disease', (40, 63))	('KRAS', 'Gene', '3845', (22, 26))
947147	24065096	This methodology has allowed for the identification of LOH at D10S1765 and D6S1581 as novel blood-based biomarkers for ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('ovarian cancer', 'Disease', 'MESH:D010051', (119, 133))	('D6S1581', 'Var', (75, 82))	('ovarian cancer', 'Disease', (119, 133))
947156	24065096	Mutations of p53 have also been reported as common mutations in solid tumors, including non-Hodgkins lymphoma, and have been implicated in drug resistance and poor prognosis.	('solid tumors', 'Disease', (64, 76))	('lymphoma', 'Phenotype', 'HP:0002665', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('non-Hodgkins lymphoma', 'Disease', (88, 109))	('Hodgkins lymphoma', 'Phenotype', 'HP:0012189', (92, 109))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Mutations', 'Var', (0, 9))	('non-Hodgkins lymphoma', 'Phenotype', 'HP:0012539', (88, 109))	('p53', 'Gene', (13, 16))	('drug resistance', 'Phenotype', 'HP:0020174', (139, 154))	('non-Hodgkins lymphoma', 'Disease', 'MESH:D008228', (88, 109))	('p53', 'Gene', '7157', (13, 16))	('implicated', 'Reg', (125, 135))
947157	24065096	The mutation in TP53 at codon 249 (Ser-249, considered a hallmark of mutagenesis by aflatoxin) and in CTNNB1 (gene encoding beta-catenin) in CCFDNA may suggest a role of aflatoxin in hepatocarcinogenesis.	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (183, 203))	('beta-catenin', 'Gene', (124, 136))	('Ser', 'Chemical', 'MESH:D012694', (35, 38))	('CCFDNA', 'Disease', (141, 147))	('beta-catenin', 'Gene', '1499', (124, 136))	('CTNNB1', 'Gene', (102, 108))	('mutation', 'Var', (4, 12))	('aflatoxin', 'Chemical', 'MESH:D000348', (170, 179))	('CTNNB1', 'Gene', '1499', (102, 108))	('TP53', 'Gene', '7157', (16, 20))	('hepatocarcinogenesis', 'Disease', (183, 203))	('aflatoxin', 'Chemical', 'MESH:D000348', (84, 93))	('TP53', 'Gene', (16, 20))
947158	24065096	Hypermethylation of RASSF1A is considered an early event in the pathogenesis of HCC and can be found in premalignant liver tissues.	('RASSF1A', 'Gene', (20, 27))	('RASSF1A', 'Gene', '11186', (20, 27))	('HCC', 'Disease', (80, 83))	('Hypermethylation', 'Var', (0, 16))
947159	24065096	Hypermethylation of RASSF1A sequences were detected in the sera of 93% of HCC patients, 58% of HBV carriers, and 8% of the healthy volunteers.	('Hypermethylation', 'Var', (0, 16))	('HCC', 'Disease', (74, 77))	('RASSF1A', 'Gene', (20, 27))	('patients', 'Species', '9606', (78, 86))	('RASSF1A', 'Gene', '11186', (20, 27))	('detected', 'Reg', (43, 51))
947160	24065096	Aberrant methylation of p16 was detected in the plasma/serum samples of 81% of HCC.	('p16', 'Gene', '1029', (24, 27))	('Aberrant', 'Var', (0, 8))	('p16', 'Gene', (24, 27))	('detected', 'Reg', (32, 40))	('methylation', 'MPA', (9, 20))
947164	24065096	Specifically, microsatellite instability and loss of heterozygosity of D8S277, D8S298, and D8S1771 at chromosome 8p were detected on the plasma DNA of HCC patients.	('microsatellite instability', 'MPA', (14, 40))	('D8S298', 'Var', (79, 85))	('detected', 'Reg', (121, 129))	('HCC', 'Disease', (151, 154))	('heterozygosity', 'MPA', (53, 67))	('patients', 'Species', '9606', (155, 163))	('loss', 'NegReg', (45, 49))	('D8S1771', 'Var', (91, 98))	('S298', 'CellLine', 'CVCL:A556', (81, 85))	('D8S277', 'Var', (71, 77))
947175	24065096	Quantification of circulating plasma DNA revealed that up to 61% of patients with esophageal carcinoma have detectable levels of methylated DAPK (Death-associated protein kinase) or APC (adenomatous polyposis coli gene) promoter DNA.	('Death-associated protein kinase', 'Gene', '1612', (146, 177))	('Death-associated protein kinase', 'Gene', (146, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('APC', 'Gene', (182, 185))	('methylated', 'Var', (129, 139))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (82, 102))	('adenomatous polyposis coli gene', 'Gene', (187, 218))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (82, 102))	('DAPK', 'Gene', (140, 144))	('DAPK', 'Gene', '1612', (140, 144))	('APC', 'Gene', '324', (182, 185))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (187, 213))	('patients', 'Species', '9606', (68, 76))	('adenomatous polyposis coli gene', 'Gene', '324', (187, 218))	('esophageal carcinoma', 'Disease', (82, 102))
947178	24065096	Monitoring and early diagnosis of gastric cancer can be detected by epigenetic changes of cell-free serum DNA of RUNX3, MGMT, p15, and hMLH1 hypermethylation using RTQ-PCR, fluorescence-based assay, and methylation-specific PCR (MSP).	('RUNX3', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('epigenetic changes', 'Var', (68, 86))	('p15', 'Gene', (126, 129))	('hypermethylation', 'Var', (141, 157))	('p15', 'Gene', '1030', (126, 129))	('gastric cancer', 'Disease', (34, 48))	('hMLH1', 'Gene', (135, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('MGMT', 'Gene', '4255', (120, 124))	('MGMT', 'Gene', (120, 124))	('RUNX3', 'Gene', '864', (113, 118))	('hMLH1', 'Gene', '4292', (135, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))
947180	24065096	Early detection of colorectal tumors through the identification of mutant DNA in serum or plasma is a clinically useful biomarker for screening, detecting, and monitoring therapy response.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('colorectal tumors', 'Disease', 'MESH:D015179', (19, 36))	('clinical', 'Species', '191496', (102, 110))	('colorectal tumors', 'Disease', (19, 36))	('mutant', 'Var', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('DNA', 'Gene', (74, 77))
947183	24065096	Other studies have shown that mutated circulating DNA may depend on tumor clonality, i.e., whether the source is from tumor cells, tumor-associated stromal cells, or surrounding normal cells.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutated', 'Var', (30, 37))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
947185	24065096	The aberrant methylation status of specific genes in the serum of patients with colorectal cancer has the potential to become a pre-therapeutic predictor of outcome.	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('aberrant methylation status', 'Var', (4, 31))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('patients', 'Species', '9606', (66, 74))
947187	24065096	Methylated SEPT9 DNA has been identified as a sensitive marker for screening and it is considered a valuable biomarker for the detection of minimally invasive colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('SEPT9', 'Gene', (11, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('SEPT9', 'Gene', '10801', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Methylated', 'Var', (0, 10))	('colorectal cancer', 'Disease', (159, 176))
947188	24065096	Other studies utilizing multivariate analysis have shown that methylated HPP1 and/or HLTF serum DNA is independently associated with poor outcome and a relative risk of mortality.	('HPP1', 'Gene', (73, 77))	('HLTF', 'Gene', '6596', (85, 89))	('HLTF', 'Gene', (85, 89))	('associated', 'Reg', (117, 127))	('methylated', 'Var', (62, 72))	('HPP1', 'Gene', '780897', (73, 77))	('HL', 'Phenotype', 'HP:0012189', (85, 87))
947189	24065096	Interestingly, serum methylation of hMLH1 was not associated with a higher risk of mortality.	('hMLH1', 'Gene', (36, 41))	('hMLH1', 'Gene', '4292', (36, 41))	('serum methylation', 'Var', (15, 32))
947191	24065096	KRAS mutations are frequent drivers of acquired resistance to cetuximab in colorectal cancers.	('cetuximab', 'Chemical', 'MESH:D000068818', (62, 71))	('colorectal cancers', 'Disease', (75, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('mutations', 'Var', (5, 14))	('acquired resistance', 'MPA', (39, 58))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('KRAS', 'Gene', (0, 4))	('colorectal cancers', 'Disease', 'MESH:D015179', (75, 93))	('KRAS', 'Gene', '3845', (0, 4))
947192	24065096	Studies have suggested that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression.	('KRAS', 'Gene', '3845', (45, 49))	('KRAS', 'Gene', (45, 49))	('mutant', 'Var', (50, 56))
947194	24065096	Recently, point mutations of serum KRAS2 have been identified which may provide information to substantially impact the management of late stage colorectal carcinoma (distant metastasis).	('KRAS2', 'Gene', '3845', (35, 40))	('men', 'Species', '9606', (126, 129))	('colorectal carcinoma', 'Disease', (145, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('impact', 'Reg', (109, 115))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (145, 165))	('KRAS2', 'Gene', (35, 40))	('point mutations', 'Var', (10, 25))
947196	24065096	There are very high ALU-qPCR values with ALU115 primers, which lowered the serum DNA integrity, so the absolute serum DNA may be a better serum biomarker than DNA integrity.	('ALU115 primers', 'Var', (41, 55))	('ALU-qPCR', 'MPA', (20, 28))	('lowered', 'NegReg', (63, 70))	('serum DNA integrity', 'MPA', (75, 94))	('ALU115', 'Chemical', '-', (41, 47))
947198	24065096	On the other hand, ALU247 and ALU247/ALU115-qPCR biomarkers may be important in detecting and monitoring CRC patients in both early and late stages.	('patients', 'Species', '9606', (109, 117))	('CRC', 'Disease', (105, 108))	('ALU115', 'Chemical', '-', (37, 43))	('ALU247', 'Chemical', '-', (19, 25))	('ALU247/ALU115-qPCR', 'Var', (30, 48))	('ALU247', 'Chemical', '-', (30, 36))	('ALU247', 'Var', (19, 25))
947200	24065096	Other mutations that have been identified as clinically significant include microsatellite instability, BRAF, and SMAD4.	('SMAD4', 'Gene', (114, 119))	('microsatellite instability', 'Var', (76, 102))	('SMAD4', 'Gene', '4089', (114, 119))	('BRAF', 'Gene', '673', (104, 108))	('BRAF', 'Gene', (104, 108))	('clinical', 'Species', '191496', (45, 53))
947206	24065096	Patients with persistent aberrations of plasma DNA integrity had significantly poorer survival probability than those with reduced DNA integrity after treatment.	('aberrations', 'Var', (25, 36))	('survival', 'MPA', (86, 94))	('plasma DNA', 'MPA', (40, 50))	('poorer', 'NegReg', (79, 85))	('men', 'Species', '9606', (156, 159))	('Patients', 'Species', '9606', (0, 8))
947210	24065096	Aberrant hypermethylated promoter DNA of at least one of the five following genes; CDH1, p16, DAPK1, p15, and RASSF1A was detectable in 71% of plasma of NPC patients before treatment.	('DAPK1', 'Gene', (94, 99))	('CDH1', 'Gene', (83, 87))	('p16', 'Gene', (89, 92))	('Aberrant hypermethylated', 'Var', (0, 24))	('RASSF1A', 'Gene', (110, 117))	('NPC', 'Phenotype', 'HP:0100630', (153, 156))	('CDH1', 'Gene', '999', (83, 87))	('patients', 'Species', '9606', (157, 165))	('DAPK1', 'Gene', '1612', (94, 99))	('p16', 'Gene', '1029', (89, 92))	('RASSF1A', 'Gene', '11186', (110, 117))	('NPC', 'Disease', 'MESH:D052556', (153, 156))	('NPC', 'Disease', (153, 156))	('p15', 'Gene', (101, 104))	('p15', 'Gene', '1030', (101, 104))	('men', 'Species', '9606', (178, 181))
947213	24065096	Even though there is no significant difference in plasma DNA concentration of EBV-positive and -negative normal individuals, the EBV-DNA is a sensitive and specific marker in monitoring NPC by its ability to detect early recurrence.	('EBV-DNA', 'Var', (129, 136))	('NPC', 'Phenotype', 'HP:0100630', (186, 189))	('NPC', 'Disease', 'MESH:D052556', (186, 189))	('NPC', 'Disease', (186, 189))
947216	24065096	An activating point mutation of the BRAF oncogene results in a V600E amino acid missense mutation that is found in a majority of PTCs.	('BRAF', 'Gene', (36, 40))	('V600E amino', 'Var', (63, 74))	('activating', 'PosReg', (3, 13))	('PTC', 'Phenotype', 'HP:0002895', (129, 132))	('V600E', 'Mutation', 'rs113488022', (63, 68))	('BRAF', 'Gene', '673', (36, 40))
947219	24065096	In DLBCL the MGMT promoter hypermethylation along with p53 mutation are useful prognostic markers for favorable prognosis.	('p53', 'Gene', '7157', (55, 58))	('p53', 'Gene', (55, 58))	('mutation', 'Var', (59, 67))	('MGMT', 'Gene', (13, 17))	('MGMT', 'Gene', '4255', (13, 17))
947220	24065096	In addition, rearranged immunoglobulin heavy chain DNA has been found in the plasma of patients with non-Hodgkin's lymphoma and acute B cell leukemia.	('lymphoma', 'Phenotype', 'HP:0002665', (115, 123))	('B cell leukemia', 'Disease', 'MESH:D015448', (134, 149))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (101, 123))	('B cell leukemia', 'Disease', (134, 149))	('rearranged', 'Var', (13, 23))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (105, 123))	('found', 'Reg', (64, 69))	('leukemia', 'Phenotype', 'HP:0001909', (141, 149))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (101, 123))	("non-Hodgkin's lymphoma", 'Disease', (101, 123))	('patients', 'Species', '9606', (87, 95))
947222	24065096	Genetic variations due to methylation changes or LOH have been detected in the CCFDNA of NSCLCs.	('methylation changes', 'Var', (26, 45))	('LOH', 'Var', (49, 52))	('NSCLC', 'Disease', (89, 94))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))
947225	24065096	Hypermethylation of RASSF1A, p14 (ARF) and APC are useful prognostic markers in patients receiving gemcitabine, and testing plasma DNA for K-RAS mutation is helpful in monitoring NSCLC patients receiving paclitaxel and carboplatin.	('p14', 'Gene', '1029', (29, 32))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('patients', 'Species', '9606', (80, 88))	('carboplatin', 'Chemical', 'MESH:D016190', (219, 230))	('gemcitabine', 'Chemical', 'MESH:C056507', (99, 110))	('APC', 'Gene', '324', (43, 46))	('APC', 'Gene', (43, 46))	('RASSF1A', 'Gene', (20, 27))	('Hypermethylation', 'Var', (0, 16))	('paclitaxel', 'Chemical', 'MESH:D017239', (204, 214))	('ARF', 'Disease', 'MESH:D058186', (34, 37))	('K-RAS', 'Gene', '3845', (139, 144))	('RASSF1A', 'Gene', '11186', (20, 27))	('patients', 'Species', '9606', (185, 193))	('p14', 'Gene', (29, 32))	('K-RAS', 'Gene', (139, 144))	('ARF', 'Disease', (34, 37))	('NSCLC', 'Disease', (179, 184))
947226	24065096	Furthermore, detection of epidermal growth factor receptor (EGFR) mutations using plasma DNA is essential to determine appropriate lung cancer treatment and monitoring.	('mutations', 'Var', (66, 75))	('epidermal growth factor receptor', 'Gene', '1956', (26, 58))	('men', 'Species', '9606', (148, 151))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('EGFR', 'Gene', '1956', (60, 64))	('lung cancer', 'Disease', (131, 142))	('epidermal growth factor receptor', 'Gene', (26, 58))	('EGFR', 'Gene', (60, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
947228	24065096	Microsatellite markers or LOH are useful for the detection of alterations in the plasma DNA of SCLC patients.	('Microsatellite', 'Var', (0, 14))	('plasma DNA', 'MPA', (81, 91))	('SCLC', 'Disease', (95, 99))	('patients', 'Species', '9606', (100, 108))	('SCLC', 'Disease', 'MESH:D018288', (95, 99))	('alterations', 'Reg', (62, 73))
947239	24065096	The methylation of the GSTP1 gene was found in 25% of free plasma DNA and in 94% of tissue samples.	('found', 'Reg', (38, 43))	('GSTP1', 'Gene', (23, 28))	('GSTP1', 'Gene', '2950', (23, 28))	('methylation', 'Var', (4, 15))
947240	24065096	GSTP1 gene methylation is also associated with increased risk of PCA despite negative prostate biopsy.	('GSTP1', 'Gene', (0, 5))	('PCA', 'Disease', (65, 68))	('associated', 'Reg', (31, 41))	('methylation', 'Var', (11, 22))	('GSTP1', 'Gene', '2950', (0, 5))	('prostate', 'Disease', 'MESH:D011472', (86, 94))	('prostate', 'Disease', (86, 94))
947249	24065096	BRAFV600E is the most represented somatic point mutation in cutaneous melanoma.	('BRAFV600E', 'Var', (0, 9))	('cutaneous melanoma', 'Disease', (60, 78))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))
947252	24065096	LOH at microsatellite markers D1S243, D6S311, D9S161 and D19S246 in the plasma is also associated with malignant mucosal melanoma (MMM).	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('D19S246', 'Var', (57, 64))	('malignant mucosal melanoma', 'Disease', 'MESH:D008545', (103, 129))	('D9S161', 'Var', (46, 52))	('D6S311', 'Var', (38, 44))	('associated with', 'Reg', (87, 102))	('D1S243', 'Var', (30, 36))	('malignant mucosal melanoma', 'Disease', (103, 129))
947255	24065096	In 90% of squamous cell carcinomas of the oral cavity, there is a microsatellite alteration in serum DNA that is identical to those in the corresponding tumor DNA.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('microsatellite alteration', 'Var', (66, 91))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (10, 34))	('carcinomas of the oral cavity', 'Phenotype', 'HP:0100649', (24, 53))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('squamous cell carcinomas', 'Disease', (10, 34))	('squamous cell carcinomas of the oral cavity', 'Phenotype', 'HP:0030413', (10, 53))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (10, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))
947303	21694830	Treatment-elated morbidity was defined as hepatic (increase of liver function tests; alanine aminotransferase >50 iU/l, aspartate aminotransferase >40 iU/l and gamma-glutamyl transferase >60 iU/l), renal, radiation esophagitis, neutropenia requiring treatment and others such as thrombosis or nausea.	('alanine aminotransferase', 'MPA', (85, 109))	('>50 iU/l', 'Var', (110, 118))	('increase of liver function tests', 'Phenotype', 'HP:0002910', (51, 83))	('thrombosis', 'Disease', 'MESH:D013927', (279, 289))	('neutropenia', 'Disease', 'MESH:D009503', (228, 239))	('radiation esophagitis', 'Disease', 'MESH:D004194', (205, 226))	('neutropenia', 'Phenotype', 'HP:0001875', (228, 239))	('>60 iU/l', 'Var', (187, 195))	('thrombosis', 'Disease', (279, 289))	('nausea', 'Phenotype', 'HP:0002018', (293, 299))	('esophagitis', 'Phenotype', 'HP:0100633', (215, 226))	('renal', 'Disease', (198, 203))	('>40 iU/l', 'Var', (147, 155))	('liver function tests', 'MPA', (63, 83))	('nausea', 'Disease', (293, 299))	('gamma-glutamyl', 'Var', (160, 174))	('neutropenia', 'Disease', (228, 239))	('increase of liver', 'Phenotype', 'HP:0002240', (51, 68))	('aspartate aminotransferase', 'MPA', (120, 146))	('nausea', 'Disease', 'MESH:D009325', (293, 299))	('hepatic', 'Disease', (42, 49))	('radiation esophagitis', 'Disease', (205, 226))